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+{"text": "A majority of healthcare today occurs in private homes and is performed by older adults and their informal caregivers. However, only recently have we begun to understand more about the healthcare work of older adults and their caregivers and the home as a healthcare delivery system. Work science allows us to conceptualize the healthcare activities of older adults and their caregivers as a type of health-related work that has been conceptualized under the broad term, patient work. Applying a patient work lens can offer a unique perspective to addressing the persistent and pervasive challenges faced by older adults and their caregivers as they manage their healthcare at home and across healthcare settings. I will describe the historical development of the patient work approach and highlight recent efforts to use a patient work approach to understand and support the work of older adults and their caregivers providing care in the home."}
+{"text": "Innovative technology can improve the lives of older adults, including those diagnosed with dementia, and their caregivers. Yet a lack of careful attention to preferences and needs of end-users and continuous updates to resources could leave consumers without a valuable user experience. This symposium will cover exemplar cases of innovative technologies, available resources, and current research. The first presentation will discuss virtual reality used among older adults with dementia and the opportunities to further explore it\u2019s use as an intervention. The second presentation will share the process of seeking stakeholders\u2019 preferences in the design specifications for a socially assistive robot and how the perspectives shaped the development of the Quori robot. The third presentation will focus on detailing the Information Quality Framework for Online Dementia Care Resources. The fourth presentation will discuss the implications of a systematic review that revealed researchers are reporting on all older adults within a category of 65 and older, thus failing to present variance among different older age cohorts. These presentations will all conclude with a discussion on opportunities for improvement in the respective areas."}
+{"text": "We present an algorithm for recovering the PRS behind a sequence of such automata, and apply it to the sequences of automata extracted from trained RNNs using the We present an algorithm for extracting a subclass of the context free grammars (CFGs) from a trained recurrent neural network (RNN). We develop a new framework, Extracting the learned language of an RNN is important to facilitate understanding of the RNN and to verify its correctness. Furthermore, the extracted CFG can augment the RNN in classifying correct sentences, as the RNN\u2019s predictive accuracy decreases when the recursion depth and distance between matching delimiters of its input sequences increases."}
+{"text": "The brain anxiety network is composed of a number of interconnected cortical regions that detect threats and execute appropriate defensive responses via projections to the shell of the nucleus accumbens (NAcSh), dorsolateral region of the bed nucleus of the stria terminalis (BSTDL) and lateral region of the central nucleus of the amygdala (CeL). The paraventricular nucleus of the thalamus (PVT) is anatomically positioned to integrate threat- and arousal-related signals from cortex and hypothalamus and then relay these signals to neural circuits in the NAcSh, BSTDL, and CeL that mediate defensive responses. This review describes the anatomical connections of the PVT that support the view that the PVT may be a critical node in the brain anxiety network. Experimental findings are reviewed showing that the arousal peptides orexins (hypocretins) act at the PVT to promote avoidance of potential threats especially following exposure of rats to a single episode of footshocks. Recent anatomical and experimental findings are discussed which show that neurons in the PVT provide divergent projections to subcortical regions that mediate defensive behaviors and that the projection to the NAcSh is critical for the enhanced social avoidance displayed in rats exposed to footshocks. A theoretical model is proposed for how the PVT integrates cortical and hypothalamic signals to modulate the behavioral responses associated with anxiety and other challenging situations. Anxiety is an ethologically advantageous emotion that maximizes survival because it promotes avoidance of potential harm in situations where dangers can emerge quickly . It is cThe present review presents evidence that the paraventricular nucleus of the thalamus (PVT) may be a critical node in the brain anxiety network. Anatomical details of how the PVT is connected with many components of the brain\u2019s anxiety network are presented as well as recent evidence showing that neurotransmission to the PVT from orexin neurons in the hypothalamus contributes to stress-induced anxiety. The review also discusses recent anatomical evidence that shows that neurons in the PVT provide divergent projections to key striatal-like subcortical regions involved in the various defensive responses. Finally, a model is described that postulates that the PVT integrates and amplifies cortical signals related to threats and relays these signals to activate subcortical circuits that modulate defensive responses including avoidance of potential threats.impending threat and is often experimentally defined in rodents as freezing to conditioned cues or contexts. In contrast, anxiety is a response to potential threats and is operationally defined as avoidance of potential risks involving open spaces, bright lights, and novel conspecifics  peptides are exclusively found in neurons of the lateral and perifornical region of the posterior hypothalamus . The bio2-panic provocation model of panic anxiety (Experimental evidence indicates that orexins are involved in fear and anxiety. For instance, systemic administration of a non-specific orexin receptor antagonist reduces fear potentiated startle and the increases in heart rate and blood pressure that are produced when rats are placed in the context previously associated with footshocks . Researc anxiety . Another anxiety . There i anxiety .The areas of the brain where the orexin peptides or antagonists act to modulate anxiety and fear remained largely unexplored until recently. Orexin fibers and receptors are found in many of the regions of the anxiety network including the BSTDL and CeL  and admiIn summary, stress and anxiety are complementary states that engage many of the same neural circuits . Orexin There is experimental evidence that the PVT mediates freezing to conditioned tones as well as the immediate anxiogenic effects of footshocks  via a prNeurons in the NAcSh and cEA integrate signals from a number of sources including the thalamus, cortex and other areas of the brain resulting in the selection and expression of appropriate behavioral responses via activation of multisynaptic descending pathways . This caThe model emphasizes the hypothesis that the PVT integrates top-down signals related to potential threats with bottom-up signals related to emotional and behavioral states to energize defensive responses by activating descending pathways in the NAcSh and cEA. Cortical areas where the memory of aversive experience is processed and stored would provide the key signals that trigger striatal neurons to generate defensive response. The model advances the view that the PVT receives and integrates threat-related signals from the cortex along with behavioral or emotional state signals from the hypothalamus and brainstem. In this model, the PVT serves to integrate threat and situational information in a way that promotes appropriate defensive responses via its divergent projections to the NAcSh and cEA. The model also proposes that the PVT serves to promote or amplify the influence of the cortex on subcortical regions. The proposed model is focused on how the PVT regulates defensive behaviors. Nonetheless, the model is also pertinent for understanding how the PVT mediates appetitive behaviors. For example, recent evidence shows that signals from orexin and prelimbic cortical neurons converge and act at the PVT to modulate reward seeking responses to cues in a manner similar to what is predicted by the model .Going forward it will be important to design experiments in which the contribution of the PVT on complex behavior can be examined in experimental situations where both appetitive and aversive outcomes are possible as recently done by some research groups . It woulThe author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Engineering genetic material for treatment of disease is a promising method which has been used for the treatment of different human pathologies for several decades  contains atypical microRNA2911. This Chinese herb is used for treating influenza infection and the authors have provided evidence to show that this microRNA directly targets influenza virus and is the active ingredient of honeysuckle herb for the treatment of flu . The exact biological manifestation of many of these ncRNAs are yet to be discovered  is another possibility.D. discoideum needs to go through cycles of multicellular development is a speculation that during the multicellular phase in which cyclic AMP signals, some novel ncRNAs might develop. The behavior of prestalk and prespore cells are different and novel genetic material might be eliminated in the cycle through sloughing off of the stalk cells. In summary D. discoideum is a promising model to examine how the symbiont fends off a novel pathogen (mainly a virus) for which the amoeba does not have a well-established defense mechanism.This suggestion that The efforts of using CRISPR-Cas9 technology for human gene editing and treatment of viruses is opening a new horizon for novel treatment methods. However, still there are several steps to take before we can safely and effectively use this technology for a viral infection treatment. Here I suggested a theoretical framework of using symbiotic relation between prokaryotes and eukaryotes for generating RNA-based therapeutics which might be used in human as well. This approach entails exposing the symbiont to a bacteriophage and searching for new genetic materials which are produced to eliminate the infection in the whole symbiont.The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The authors recently reported on the potential of targeting SRC kinase signaling in pancreatic cancer stem cells . During This error does not affect any of the data or conclusions in the article, and all densitometric analyses remain the same. The authors apologize for any confusion this error may have caused to the readers."}
+{"text": "After this article  was publPLOS ONE\u2019s Editorial Board confirmed that the replacement blot images support the results and conclusions as reported in the article.The authors commented that these experiments were repeated about three times at the time of the original experiments, and this duplication in the published figure may have arisen due to errors in preparing the figure. The authors have provided replacement data from a different replicate of the Mitochondrial fraction CytC and VDAC blot experiments, along with an updated version of the graph in In addition, the authors clarified that in preparing Figs The raw blot images for the S1 File(TIF)Click here for additional data file.S2 File(DOCX)Click here for additional data file."}
+{"text": "In this first stage of an 8 state initiative designed to assist nursing homes in reducing unnecessary hospital readmissions, 16 nursing homes were identified and invited by CMS and state agency advisors to participate in the pilot study of the effects of intervention (use of the Guide). Selected facilities received an online orientation to the project and onsite visit from project team leadership prior to launch. Pre and post implementation data were uploaded to a secure section of the project website by the facilities. Three facilities withdrew due to change in top management and a fourth facility provided incomplete data resulting in data for analysis from 12 pilot facilities. Results show the average reduction in readmissions was 31.2% for the project period as compared with the 3-month pre-project period. This presentation will include facility reports of the effect of Guide use on resident and family decision making."}
+{"text": "The elucidation of better treatments for solid tumors and especially malignant glial tumors is a priority. Better understanding of the molecular underpinnings of treatment response and resistance are critical determinants in the success for this endeavor. Recently, a battery of novel tools have surfaced that allow to interrogate tumor cell metabolism to more precise extent than this was possible in the earlier days. At the forefront of these developments are the extracellular flux and carbon tracing analyses. Through utilization of these techniques our group made the recent observation that acute and chronic c-MET inhibition drives fatty acid oxidation that in turn can be therapeutically targeted for drug combination therapies. Herein, we summarize and comment on some of our key findings related to this study. In the 1920s of the last century biochemist Otto Warburg made the remarkable and astonishing discovery that malignant cells heavily utilize glucose and metabolize it to lactic acid despite the presence of sufficient oxygen , 4. In t"}
+{"text": "MyCovenant. The data deals with the Monitoring Emission Inventories submitted by local authorities by 2016. Data has been processed and elaborated to highlights specific features of signatories and the policies they have adopted in the development of their Sustainable Energy Action Plans (SEAP). Available data relates to the mitigation policies in the SEAPs and includes their carbon reduction potential, the status of implementation and the class of governance. The CoM gathers together thousands of local authorities who voluntary committed to decarbonisation and increase resilience in their territory. Therefore, this data can be of interest for local policy makers and urban planners to identify successful examples in cities with comparable contexts and to identify possible measures in several sectors for climate change mitigation.This data article relates to and complement the research paper: \"Assessment of climate change mitigation policies in 315 cities in the Covenant of Mayors initiative\"  Specifications TableValue of the DataThe data gives quantitative and qualitative information on the local mitigation policies implemented to achieve the 20% carbon reduction target by local authorities which are part of the Covenant of Mayors up to 2016Climate change research, local government, policy makers, urban science are the fields where this data provides valuable information.Data can be used for comparisons with other data on local policies, for investigation on climate change mitigation and adaptation, for further analysis. Urban planners and local policy makers can benefit from the dataThe data supports regular evaluation of the carbon reduction target within the CoM initiative and the sharing of successful approaches and methodologies.The data gives insight on mitigation policies in different sectors adopted in local authorities across Europe.11-\u201cSignatories\u201d: the information on local authorities 2-2), the responsible local organisation for the implementation and the status of implementation.\u201cPolicies\u201d the mitigation policies included in the MEIs submitted by local authorities, with specification on sectors , mode of governance, the corresponding carbon reduction potential (tCOCities play a key role in the climate challenge and are the place where local experimental governance aiming at meeting low carbon objectives can be tested In particular, the variables included in the dataset are:2The experimental design of the study is to relate the local authorities\u2019 characteristics with their planned mitigation policies and the governance approach. Detailed studies and investigation on multi-level governance and policies were previously developed and investigated to base the structure of the analysis ,6. The dThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."}
+{"text": "The recruitment of participants for chronic disease clinical trial research is often challenging. Further complicating participant recruitment occurs when the intervention is dyadic . Despite the strong support in favor of dyadic interventions for certain chronic diseases , researchers have not systematically shared challenges and opportunities for dyadic recruitment. During the recruitment for a yoga and self-management education intervention for people with chronic pain and their caregivers, several steps were taken to recruit and screen potential participants for the study. In this presentation, we will provide an overview of common recruitment challenges for physical activity and chronic disease self-management studies as well as the actual challenges encountered and our procedures for overcoming these obstacles. We will present our consort figure with attention toward inclusion and exclusion criteria of both care receivers and caregivers. Additional discussion will include specific challenges encountered when recruiting and screening caregivers . The need for innovative clinical trial research with caregivers and care recipient dyads is essential as new care practices continue to evolve and demands on health care utilization increase. Lessons learned from this study may prove useful for future researchers as they embark on developing and testing dyadic interventions among adults with chronic disease and their caregivers."}
+{"text": "Employers are facing significant demographic changes in their workforce as the US population continues to age and older workers seek to delay retirement until later ages. The challenges associated with workforce aging vary substantially across the economy and vary by industry, occupation, and size of the organization. This analysis highlights the findings from employer surveys and workshops of senior HR leaders. The article summarizes the findings from our three-year research project including whether employers perceive that workforce aging is a challenge to their organization and if so, what changes in compensation and working conditions are being made to accommodate the changes in age structure"}
+{"text": "With this notice, Frontiers states its awareness of concerns regarding the validity of the participant data in this study. An investigation is currently being conducted by Kashan University of Medical Sciences research ethics committee. This expression of concern has been posted while Frontiers awaits the outcome of that investigation and will then be updated accordingly."}
+{"text": "Has American society become more socially disconnected as Robert Putnam argues in Bowling Alone? Claude Fischer disputes this contention with evidence that Americans remain about as connected to friends and family as in the past. We address this debate with data for older adults from the National Social Life, Health and Aging Study, collected in 2005, 2010, and 2015. We compare social participation as reported at ages 57 to 68 for members of the Silent Generation cohort vs the Baby Boom cohort. We find that the gender gap in social participation evident for the Silent Generation does not exist at all for younger Baby Boomers, only appearing after age 62. These same cohort differences appear for participation in religious services and organized groups. This suggest that the gendered separation of social roles that characterized older generations is becoming less pronounced, with implications for social support and social isolation."}
+{"text": "Asking older adults What Matters to them and assuring that care plans are aligned with these preferences is the cornerstone of an Age-Friendly Health System (AFHS). Health systems have struggled to identify clear ways to ask this question and meaningfully utilize the responses. Both simple and complex options for addressing this challenge have been developed at Rush University Medical Center. At Rush, nurses began asking every inpatient What Matters and placing the response on the white board in the patient\u2019s room. Results of this practice include increased awareness of staff and significant increases in patient satisfaction. Qualitative analysis of responses yields increased awareness of patterns that the hospital can more systematically address. The Rush Center for Excellence in Aging hosts Schaalman Senior Voices, in which older adults from diverse backgrounds are given the unique opportunity to offer their perspectives on life, health and aging related to \u201cWhat Matters\u201d to them. The films have been used effectively to stimulate conversations among older adults and families in the community and in health professions courses, and with health systems executives. The Rush College of Medicine has integrated AFHS training into communication skills for medical students. Faculty introduce the 4Ms and demonstrate methods for having What Matters (WM) conversations. Students then practice WM conversations with simulated patients; some have had the opportunity to practice with real patients in preceptorships. Implications for the health system and community will be discussed as Rush builds an Age-Friendly Health Community."}
+{"text": "This data article presents supplementary material for our report \u201cRole of obstetricians in promoting pregnancy-related knowledge among women with epilepsy in Japan\u201d . To provide more effective preconception counseling and perinatal care, we surveyed the attitude of epileptologists and obstetricians about pregnancy-related issues in women with epilepsy (WWE). Obstetricians said they needed information from epileptologists about seizure for management of WWE. Half of epileptologists did not feel the need to communicate with obstetricians before their patients\u2019 pregnancy; they only contacted obstetricians after their patients became pregnant, and they only referred patients to an obstetrician if requested by the patient. Specifications TableValue of the Data\u2022This dataset provides the viewpoints of epileptologists and obstetricians toward pregnancy-related issues of WWE.\u2022These data help readers to understand present issues and the need to build a system of coordination between epileptologists and obstetricians.\u2022These data, obtained from epileptologists and obstetricians, provide additional insight to the accompanying article 1The data in this article consist of additional figures and tables provided in a report 2We mailed questionnaires and consent forms. In total, 115 epileptologists returned the questionnaires  and 187 obstetricians returned the survey . Data were collected from May to June 2019.3Informed consent was obtained from respondents, and all procedures performed in the study were in accordance with the principals of the Declaration of Helsinki. This study was approved by the Medical Research Ethics Committee of Tokyo Medical and Dental University (M2018\u2013290).The authors declare that they have no known competing financial interests or personal relationships which have, or could be perceived to have, influenced the work reported in this article."}
+{"text": "Many Chinese older adults suffer from oral health diseases and problems due to low oral health literacy, limited dental coverage and lack of dental care services for this segment of the population in China. However, so few studies have been conducted to examine social and behavior factors related to oral health among Chinese older adults. This symposium examines how socioeconomic status (SES) and health behaviors are associated with oral health among Chinese older adults. The first paper used the Nanjing Centenarians Study to examine the association between health behaviors and oral health among Chinese centenarians. The results showed that health behaviors were associated with self-rated oral health and edentulism. Using the Chinese Longitudinal Healthy Longevity Survey, the second one employed an \u2018after death\u2019 approach to examine risk factors for orofacial pain symptoms at the end of life among Chinese older adults. The third paper investigated the association between SES and tooth loss among middle-aged and older adults in ten cities of China. SES played a stronger role in tooth retention for non-migrants and migrants with high education vs those migrants with low education. The last paper examined the association between health behaviors and retention of teeth among Chinese older adults using data from the Chinese 4th National Oral health Survey. This symposium provides empirical evidence on the current status of oral health and health behaviors at the national level, and also suggests that is critical to improve oral health education and access to dental care."}
+{"text": "In the original article, we neglected to acknowledge the HRSM project NANOBILD for infrastructure support. The corrected acknowledgment statement appears below:The authors thank Dietmar Pum  for technical advice and acknowledge the HRSM project NANOBILD for infrastructure support.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "Home and Community Based Services has grown as an alternative to nursing homes over the past 30 years. While there are extensive data on nursing home staffing, there is a dearth of similar information about Medicaid financed home care. We use data from 2014-2016 Pennsylvania Medicaid to examine personal care for elderly with and without dementia across the range of physical disability. One challenge is that even though physical function can be measured in terms of discrete tasks , analysis of the amount of care people receive has to take into account the combination of dementia and combinations of ADL limitations. We found that older adults with dementia receive one hour more of personal care per day at the lowest level of disability and 1.5 hours at the highest level. The increased need for caregiving hours should be incorporated into policies that guide HCBS programs."}
+{"text": "Major causes of brachial plexopathy in patients with breast cancer are metastatic invasion or radiation damage to the plexus. Differentiation between the two pathologies is important for appropriate treatment planning. The complicated anatomy of the plexus makes this a difficult area to image accurately. Magnetic resonance imaging (MRI) is the imaging modality of choice for diagnostic evaluation of these cases. We presented a case to demonstrate the role of"}
+{"text": "With the passage of the new \u201cSupporting Older Americans Act of 2020,\u201d Congress acknowledged and address several under appreciated issues -the growing social isolation and loneliness of older adults, and the significant role that the aging network does and can play in providing supportive services to older adults with advanced illness . This presentation will provide information on these and other pieces of the OAA puzzle."}
+{"text": "Immunosenescence is described as a decline in the normal functioning of the immune system associated with physiologic ageing. Immunosenescence contributes to reduced efficacy to vaccination and increased susceptibility to infectious diseases in the elderly. Extensive studies of laboratory animal models of ageing or donor lymphocyte analysis have identified changes in immunity caused by the ageing process. Most of these studies have identified phenotypic and functional changes in innate and adaptive immunity. However, it is unclear which of these defects are critical for impaired immune defense against infection. This review describes the changes that occur in innate and adaptive immunity with ageing and some age-related viral diseases where defects in a key component of immunity contribute to the high mortality rate in mouse models of ageing."}
+{"text": "From the grassroots development of creative aging research to broad base community collaborations that address the issues of today and tomorrow, this presentation will illustrate how state departments of aging and state arts agencies can combine to partnership with research universities to demonstrate the efficacy of the arts to mediate problems of loneliness, isolation and caregiver stress. This case study will show how resources can be expanded and effective practices established through community based research to find ways to build healthy and engaging communities that serve to break down the barriers of isolation and promote social networks."}
+{"text": "It is important to predict the environment around the breathing human because inhalationof virus  is recently severe worldwide problem, and air pollutioncaused by diesel emission particle (DEP) and asbestos attract a great deal of attention.In the present study, three\u2010dimensional numerical simulation was carried out to predictunsteady flows around a breathing human and how suspended particulate matter  reaches the human nose in inhalation and exhalation. In the calculation, wefind out smaller breathing angle and the closer distance between the human nose andpollutant region are effective in the inhalation of SPM."}
+{"text": "Arts programming can address chronic conditions prevalent among older adults. An overview of an implementation of the revised nationwide Opening Minds through Arts (OMA) program anchors the symposium. The paper reports an implementation by an area university and an eldercare facility to recruit and train student volunteers to collaborate with persons living with dementia, and create paintings for a public exhibition. The Arts for a Lifetime Program used bi-weekly student led programming in a long-term care community; the paper includes an overview of materials used throughout the program and reports resident preferences for materials. A report of results of an ethnographic investigation of the impact of creative aging fine arts programs on older adults adds information about how participation might influence the older person\u2019s self-esteem or perceptions of aging. The presentation about creation of music modules investigates the potential of music therapy for the promotion of healing for older adults managing pain. The final paper describes the methodology lessons learned from ARTmail, a community engaged study of the benefits of a structured participatory arts program for older adults with memory symptoms or cognitive impairment. Presentations in this symposium inform identification and development of opportunities to create and engage in meaningful experiences with older adults."}
+{"text": "Communication models describe the flow of signals among nodes of a network. In neural systems, communication models are increasingly applied to investigate network dynamics across the whole brain, with the ultimate aim to understand how signal flow gives rise to brain function. Communication models range from diffusion-like processes to those related to infectious disease transmission and those inspired by engineered communication systems like the internet. This Focus Feature brings together novel investigations of a diverse range of mechanisms and strategies that could shape communication in mammal whole-brain networks. How does a massive network of neurons give rise to intercommunication across the entire brain? As advances are made in understanding mammalian brain network structure . However, this does not mean that a subset of nodes cannot exert strong influence on the entire network. The Focus Feature concludes with two papers that consider the role of controllability, a notion borrowed from the study of dynamical systems in physics. Controllability in networks captures the degree to which network dynamics can be driven by a small subset of nodes.Patankar et al.  examine Finally, Srivastava et al.  provide This collection of studies broadens the range of communication models in brain networks and highlights novel structural and functional demands that are likely at play. One can expect that this work will lead to further blossoming in this area of investigation and a deeper consideration of network communication in other areas of brain science."}
+{"text": "Background: Children and adolescents are especially vulnerable to mental, neurological and substance use disorders during various stages of their growth and development. They often require specialized personnel whose training is time consuming and costly. Consequently many children and adolescents remain untreated in developing countries. This paper describes steps Uganda is taking to develop local capacity for child and adolescent mental health services through training of multi-disciplinary teams.Methods: A 2 year training programme was introduced in accordance with the Ugandan Ministry of Health Child and Adolescent Mental Health Strategy. This had been jointly developed in 2008 by Mbarara University of Science and Technology, Makerere University, the Uganda Ministry of Health and East London Foundation NHS Trust, United Kingdom (UK). The initial funding for the programme focused on monitoring and evaluation of the training, quality of clinical practice and clinical activity data.Results: Fifty health workers have been trained and are now working at regional referral hospitals and non-governmental organizations. Monitoring and evaluation demonstrated major increases in the range of disorders and client numbers  over 6 years. There was increased confidence, knowledge and skills in assessment. Learning in a multidisciplinary environment was interesting and helpful. Assessments were more thorough and child centred and more psychological treatments were being used. Programme graduates are now contributing as trainers.Conclusion: The clinically focused multidisciplinary training has yielded rewarding outcomes across Uganda. Ongoing support and collaborative work can expand service capacity in child and adolescent mental health for Uganda and other developing countries. Children and adolescents are vulnerable to certain specific mental, neurological and substance use disorders (MNS) due to their incomplete physical, mental and social growth and development \u20133. The mChildhood MNS disorders have unique presentations and their treatment differs significantly from those disorders first presenting in older adolescents and adults \u201314. ThesIn Uganda many children suffer psychological trauma from war, abuse and bereavement but in common with other LMICs , few chiStigma is one of the challenges facing children and adolescents with mental disorders , especiaThis paper describes steps Uganda is taking to develop local capacity for child and adolescent mental health services through training of multi-disciplinary teams with the introduction of a university accredited Advanced Diploma in CAMH for public health workers and national CAMH policy guidelines. The process, achievements and results of UK project monitoring and evaluation are described with discussion of challenges faced and relevance to other LMICs.In 2008 a national strategy for child and adolescent mental health in Uganda was developed by a partnership of the Faculties of Medicine of Mbarara University of Science and Technology, Makerere University, Ugandan Ministry of Health and the Butabika East London Link . The aims of the strategy were to develop a specialist child and adolescent mental health service for Uganda by providing dedicated out-patient and in-patient care with trained specialists at regional level and developing a multi-disciplinary workforce that can train professionals in health and education at district level to recognize child mental health problems and educate the population in prevention. The core requirement of the strategy was specialist training. In order to introduce a national training programme four Ugandan professionals were trained in the UK on Commonwealth Scholarships when a draft curriculum was jointly drafted.The Butabika Link East London Link obtained funding for two projects (2012\u20132017) from the Health Partnership Scheme of the Department for International Development, UK government, to develop and implement a multi-disciplinary training programme in CAMH for mental health and child health professionals in Uganda. The majority of the training in the initial course was provided by UK CAMH professionals but the second project evaluated the delivery of the course by the new cohort of trained Ugandan professionals and secured university accreditation from Mbarara University of Science and Technology as the Advanced Diploma in CAMH. The initial training programme was preceded by a training the trainers course and further training of trainers took place in preparation for the Ugandan led course. Exercises, focus groups and discussion allowed for anxieties about the heterogeneous nature of the multidisciplinary participants to be considered and managed during the training programme.The Butabika Link East London Link obtained additional UK government funding for two smaller projects (2016\u201318) to assist the Ugandan Ministry of Health and CAMH professionals to develop, launch and implement a national CAMH Policy.The diploma is a 2 year modular programme with the six first year courses providing basic training that focus on practical skills in child and family assessments, and recognition and management of mental disorders in children and adolescents. The first year of the training serves as a foundation for the second year courses which focus on psychological therapies, clinical supervision, training, service development and research. Each module consists of 5 days of classroom teaching at the Butabika School for Psychiatric Officers followed by 5 days of clinical experience in the specialist children's ward at Butabika Hospital. The trainees are expected to focus on assessing and treating children and adolescents in their workplace between modules and to complete case studies, a logbook and a research or audit project. As well as written examinations for each course, clinical and teaching skills are examined. The programme provides training that equips trainees with the knowledge, clinical, teaching and managerial skills to provide care, develop child mental health services and to train others. The criteria for admission to the programme include commitment, professional mix and regional representation, and ability to teach others. Previous training/expertise and interest in child and adolescent mental health are key.Apart from assessment of the trainees' academic and clinical performance, M&E for the training projects consisted of evaluation of the quality of the course by trainees  together with evaluation of the impact of the training on service delivery and quality of clinical work over 6 years. Baseline activity data was collected at the four teaching hospitals at the start of the first project and as trainees joined the course from other locations an M&E coordinator collected the number of child attendances per month from a professional at each site by age group for out-patient attendances and admissions. This included a record of children seen by both CAMH and non CAMH staff. The number of dedicated clinics for children and of CAMH trained staff at each location was recorded.The quality of clinical work was assessed on an individual basis during clinical training and examined twice. A sample of the twenty most recent case notes for outpatient attendances or admissions were assessed annually at each of four main sites using a case note monitoring form. This recorded patient demographics, diagnosis, assessing professional (CAMH trained or not), indicators of quality of assessment , management and appropriate use of medication (no prescription when not indicated). For follow ups it recorded use of psychological treatments, reviews of diagnosis and management including medication side effects.The first two diploma cohorts funded by the projects completed their training in 2015 and 2017. Since then the first and second year courses have been running simultaneously allowing a new cohort to graduate each year with more efficient use of teaching resources. Fifty health workers from various medical backgrounds have been trained since 2012 and are working with children at various regional referral hospitals. These comprise two psychiatrists, one medical officer, ten psychologists, sixteen psychiatric clinical officers, twelve nurses, two occupational therapists, five social workers/counselors, one public health officer and one human resource officer . These new cohorts of trained CAMH professionals have been able to contribute to the training programme, provide peer \u2013 peer mentoring and supervision as well as providing clinical assessments and management of children with mental health and developmental disorders at their work places .Monitoring and evaluation of the training programme showed that following the training, the trainees developed increased confidence, knowledge and skills in assessment and management of mental health problems in children and adolescents and in teaching and presentation skills. All the trainees study together but different professional groups have varied levels of experience related to topics in the programme and share their knowledge and experience. The roles of specific professions are discussed in depth at the end of the programme (for example psychometric assessment for psychologists). Initially the professionals found learning in a multi-disciplinary group unfamiliar and some were uneasy about different educational levels, for example between doctors and nurses. The training groups quickly became cohesive and mutually supportive which was crucial for trainees working in isolation around the country. Individuals spontaneously commented how valuable it was to train with and learn from other professionals from social work, psychology, occupational therapy, counseling, and child health. This enriched trainees' knowledge and skills through shared experiences and they came to see the importance of developing a multidisciplinary and inter-professional environment in child mental health services.Some quotes from trainees following clinical placements includedI am building more relationship with my clients and they keep the appointments. I have noticed that the way we ask questions is indeed very important and that when you begin the interaction with your clients with a smile and have a smile during and at the end of the session it becomes more therapeutic. Please members let us try it!!!\u201d (CAMH Trainee)\u201cI did receive a child aged 13 yrs with history of shaking the right arm for about a month. I applied the skills that I had learnt including questioning skills, history taking, and genogram. I was amazed when the mother commented that she had never met a doctor who could ask her such questions. She was impressed and interestingly the girl left my clinical room when the shaking had stopped. The mother telephoned me yesterday thanking me and saying that the girl has been free from shaking for the last five days.\u201d (CAMH Trainee)\u201cI would like to thank you for all the efforts, work and time that you have dedicated to our training. Surely there is no enough thank you or reward that I can give, except results of the practice of the skills that I have learnt over this period of time. At my new workplace, all my colleagues know that I have speciality in CAMHS and have been booking patients for me which is a great start in a new place.\u201d \u201cThe course in child and adolescent mental health provided a deserving opportunity for the first trainees in Uganda to acquire knowledge and skills in this field so as to provide a service that was previously non-existent in most hospitals in this country. The course content effectively addressed the common mental health problems in children and adolescents in our community. In future trainings more emphasis should be placed on psychotherapies, family therapy and child protection. There is however, a huge need for child and adolescent mental health service in this country and therefore the need to train more child and adolescent mental health specialists.\u201d .\u201cThe final project was completed in 2019 and monitoring and evaluation for the projects demonstrated that, since the start of the Diploma course in 2012, the number of sites with a trained CAMH professional increased from 4 to 24 with all regions of the country represented. The number of children seen in their services increased from 2,184 to 31,034 .The development of multidisciplinary teams has so far been confined to the university hospitals while CAMH trained mental health and child health professionals provide much of the service to children in regional hospitals and health centres around the country as well as continuing to see adults. Despite there being just one or two CAMH staff at these units, most were able to set up specialist CAMH clinics by dedicating specific clinic days for children. The specialist multidisciplinary teams at the national referral hospitals in Kampala, Butabika, and Mulago, have been able to provide daily specialist CAMH outpatient services and a large children's inpatient service at Butabika, A few CAMH Diploma graduates have been employed by NGOs to work with refugee children mainly in Northern Uganda where their skills have also been utilized extensively in staff training.In addition to the substantial increase in children attending services, examination of clinical records showed more children were having thorough child centred assessments, and there were increased numbers and range of non-epilepsy diagnoses compared to baseline findings. The improved quality of assessments by CAMH trained staff compared with assessments by other mental health professionals included the recognition of co morbidity in epilepsy cases, less medication used, more appropriate medication used, increased use of psychological treatments and more revisions of diagnosis and management for cases seen by non CAMH professionals. For example, assessments now included observation of the child, child's views, their drawings, and observations of family relationships accompanied by a drawing of the family genogram. Less medication was being prescribed whereas before the training, most children with mental health problems were given psychotropic medication due to lack of adequate knowledge of psychological treatments. All pioneer graduates of the programme have been equipped with training skills through training the trainers courses and have been providing training for large numbers of health and primary care workers, teachers and community groups in their local areas.Peer support supervision has been piloted over 2 years around the country and has worked well to support CAMH workers in the regions and provide continued professional development for local health professionals. There has been great enthusiasm for continuing the 2 day events but sustaining them without funding for transport is a problem. Butabika Hospital already has a professional supervision system for PCOs working in the regional hospitals and funding has been sought from the Ministry of Health for a separate specialist supervision system for CAMH workers.In 2017 the Ministry of Health launched the Ugandan Policy for Child and Adolescent Mental Health . Other aThis training is timely, not just being academic but responding to one of Uganda's biggest public health problems. It is a speciality that needs to be recognised and embraced at all levels\u201d .\u201cResearch interest in the subspecialty has been generated and the development and launch of CAMH policy was a great achievement...... I hope that people will come from neighbouring countries as this training programme is the first of its kind in the region\u201d .\u201cAn independent value for money assessment of the first training project was commissioned by the Tropical Health Education Trust . It concDevelopment of the CAMH training programme in Uganda and a multidisciplinary service for most regions of Uganda has had a major impact on the numbers of specialist CAMH staff, attendances by children with mental health problems and the quality of treatment received but has not been without challenges. The extensive preparatory work, need for external funding, achievement of university accreditation and current challenges in relation to workload and sustainability are relevant to the development of specialist clinical training programmes in other LMICs , 22, 25.Following the strategic work that took place with the Ministry of Health in 2008, before the training programme could start in 2012, it was necessary to train four key staff in the UK on Commonwealth Fellowships, develop a curriculum to meet university regulations and secure funding for the first UK funded training project. The first two fully funded groups graduated in 2015 and 2017 but university accreditation for the Advanced Diploma in CAMH was not achieved until 2017.The Ministry of Health has recognized the diploma as the specialist qualification for child mental health posts in Uganda and this has been supported by the introduction of the MOH Policy for CAMH  and its Prior to the training programme very few children attended mental health services and those who did mainly suffered from epilepsy and intellectual disability. Training of local hospital and community health staff by CAMH professionals and public education through the media and community groups has resulted in increased recognition and referral of a range of mental health problems. This presented anticipated challenges , 28, witIn such overstretched services with few staff almost half of child cases were still seen by non CAMH staff although we found that younger children and new cases were more likely to be seen by CAMH staff. It has been important to prioritize new cases and young children for specialist CAMH assessment. Adult trained staff are familiar with the management of older adolescents with psychosis, affective disorders or substance misuse.Because of the large and growing child population in Uganda including many refugees with high levels of need, it is important to train more child and adolescent psychiatrists, accessible in rural areas, to support CAMH professionals working in isolation as well as pediatricians and child health workers who see many children with mental health problems. They can be recruited from both psychiatry and child health.General adult psychiatrists are eligible to undertake the training to become child and adolescent psychiatrists and we continue to lobby the MOH to support posting of medical officer special grade (psychiatry) to the regional and district hospitals. Those interested in providing CAMH services may then access the MOH scholarships for the Advanced Diploma in CAMH. Since the training programme was opened to child health professionals a medical officer and a clinical officer in child health have graduated. Pediatricians and medical officers in Uganda and sub Saharan Africa have shown interest in the training and some of these may then undertake psychiatric training in order to be eligible for consultant posts. To this end it will be important to publicize the training to attract international applicants from countries with few trained CAMH staff.In addition to trained doctors, a sustained increase in the capacity of the multidisciplinary CAMH workforce will be essential because of the growing volume of work and the unmet need for access to specialist CAMH services in all regions of Uganda. Priority for training and scholarships will need to be given to individuals from different professional backgrounds and from poorly served parts of Uganda. The provision of scholarships and the development of specialist CAMH posts will be essential for public health workers who so far have shown tremendous commitment to the specialty and have been very active in training their colleagues and community workers.The continued implementation of the national CAMH policy is crucial and, as part of this, CAMH professionals have provided training and held meetings with local directors of regional hospitals. Mental health services in the regions have many unfilled posts and the local promotion of child mental health awareness is vital to convince hospital directors of the need to appoint CAMH staff and to designate vacant posts for CAMH.Financial sustainability of the course has been a major challenge since the two UK funded training projects ended because public health workers for whom the course was designed, have low salaries and cannot afford the modest university fees, internet and travel costs. Provision of free residential accommodation at Butabika Hospital during the teaching modules has been invaluable for trainees outside Kampala. There were delays in securing scholarships for university fees through the Ministry of Health and in the transference of funds to the teaching institution affecting payment of course expenses and teaching fees. CAMH trainers experienced financial stress while balancing their teaching contribution with demanding service responsibilities. Long term reliable sponsorship for university fees is required otherwise the number of public health workers who can be trained will be limited.Like Uganda many LMICs have a young population with high percentages of children in need of specialist child and adolescent mental health services \u201317, 19. For LMICs planning to develop child mental health services through their own training programme we can make some recommendations drawn from our experiences over 12 years. It would be important to train a few key individuals in CAMH in advance to take both a training and strategic lead in order to develop a countrywide initiative, with support from and involvement of the ministry of health at an early stage. A teaching site ideally in proximity to a clinical training base where large numbers of children can be seen needs to be identified. Rather than a pure academic focus, the training programme needs to aim to develop a high level of clinical skills with associated knowledge and understanding for professionals working in public health services. Ideally it should be linked to a university as soon as possible as obtaining academic approval for such a specialist course was in our experience a long drawn out process. While the programme's demands meant that it could have been offered as a postgraduate master's degree, it was important to be able to recruit a multidisciplinary group including nurses from services throughout the country hence its designation as an advanced diploma. The modular design works well but thought needs to be given to the provision of accommodation and food with the possibility of scholarships to enable low paid health workers to attend. At the outset some seed funding and sponsorship would be likely to be required. We were fortunate to have UK government funding with UK volunteers to develop and evaluate the programme and associated government policy but we hope that other countries will be able to make use of our resources and experience to develop child mental health services themselves .The ongoing partnership with East London provided continued opportunities for long term volunteers from UK and other -high income countries to come to Uganda to support the CAMH programme contribute to training the trainers, deepen skills in psychological therapies and to further develop Butabika as a centre for clinical training. They have benefited from the opportunity to develop new skills in cross cultural working and project management and also to conduct research programmes. The relationships established have proved mutually beneficial with continued electronic and telephone communication to support the training programme.Initial steps to train a cohort of CAMH professionals in Uganda have yielded rewarding outcomes. With collaborative effort over time, it proved possible to develop multidisciplinary teams for both urban centres and rural areas through the national and regional referral hospital system. These multi-disciplinary professionals have been able to improve both access to and the quality of mental health services for children and to train others in their local hospital and community services even when working in isolation. The multidisciplinary nature of the programme implies that different categories of staff can be trained; and recently this has included some professionals providing general health care in rural health centres where they can easily be accessed by the rural communities. This means that communities can be trained to identify children with mental health problems as early as possible and refer to appropriate services within their communities or regional centres.grukundo@must.ac.ug.The data analyzed in this study is subject to the following licenses/restrictions: The raw data from which the article has been written will be available on request to the authors. Requests to access these datasets should be directed to Godfrey Zari Rukundo, Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent from the participants' legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.GR wrote the first draft of the article. The rest of the authors JN, PO, and AH contributed significantly to the writing of the final paper, improving on the draft. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Following publication of the original article , the autThis has since been corrected in the published article and the corrected names may be found in this correction.The publisher apologizes for any inconvenience caused."}
+{"text": "Ongoing innovative preclinical research and development provide a rationale for studying new diagnostic and treatment approaches in inflammatory and autoimmune diseases, diabetes, paralysis and other disorders. Bioelectronic Medicine, on the Springer/Nature BMC platform reflects the commitment to a necessary forum for publishing cutting edge primary research, timely reviews and other relevant publications. Here we comment on the recent content of Bioelectronic Medicine (published in 2018) that captured many important aspects of the current state of the field. Our aims are to trigger multidisciplinary discussions and to inspire future research efforts that will contribute to advancing the field.It is an exciting time for the expanding field of Bioelectronic MedicineBioelectronic Medicine by Giagka and Serdijn  Zhang et al. provided insight into the utility of wavelet decomposition as a method to extract neural features obtained from a microelectrode array implanted in the motor cortex of a human with tetraplegia (Zhang et al., Studies providing mechanistic insight into the CNS in health and disease are extremely important for Bioelectronic Medicine (Pavlov et al., Obesity and diabetes are pandemic and present significant challenges to modern society (Mokdad et al., Visual prostheses are medical devices designed to provide some degree of vision to individuals with blindness as a result of severe degeneration or damage to the retina, the optic nerve, or brain damage (Fernandez, It was estimated that in 2015, 36 million people were blind, and 217 million had moderate or severe vision impairment (Bourne et al., Bioelectronic Medicine will be the platform for innovative research and conceptual developments reflecting the progress in the field.A growing knowledge of mechanisms of neural regulation in disease pathogenesis will be instrumental for developing new bioelectronic technologies."}
+{"text": "In response to the protracted Ebola virus outbreak in the Democratic Republic of Congo, the international public health community called for increased attention, coordination, and resources to support the response. The use of real-time modeling and analytics to support public health decision-making  has been an important capability that has grown during previous outbreaks \u20133. DespiTo improve communication and create awareness of the efforts of modeling groups already studying the DRC Ebola outbreak, we\u2014an existing outbreak science working group\u2014convened an informal modeling research coordination group to align efforts around infectious disease modeling of the outbreak . Each moThe presentations throughout the seven months of this modeling coordination group meetings highlighted some of the ways this DRC outbreak differed to the prior 2014 West African outbreak. The impact of violence itself on epidemic growth and effective response was also a major focus of modeling efforts . Shifts This working group was not formally endorsed by any agency or formally tasked with supporting any specific public health activity in the DRC. It was not intended to replace formal modeling groups who had already been tasked to support the Ebola response and is distinctly different from epidemic surveillance sharing platforms such as the Global Public Health Intelligence Network or the Epidemic Intelligence Information System ,14. HoweThe Ebola modeling coordination group also highlighted the pervasive complexities of conducting research during epidemics. For example, there is a need to balance broad participation of scientists to study and help resolve the crisis while also deferring to the more urgent priorities of health authorities who are engaged in the critical public health response as well as respecting existing local and international research efforts already formally tasked with supporting the outbreak. It is also a priority to conduct equitable research by collaborating with locally-based scientists so that they are properly involved in and credited with the international scientific response, including data collection efforts. We propose that coordination groups, like the one described here, could help with that. Moreover, we have demonstrated how this model coordination framework could readily be adopted by other groups for future epidemics and indeed has been so in the current COVID-19 outbreak ."}
+{"text": "Physical conditions of living environments can impact risk of falls, however, prior work has focused typically on one domain at a time\u2014either neighborhood or home, capturing limited environmental boundaries of older adults. We extend prior work by considering both neighborhood and home as important residential contexts and examine their impact on the onset of falls over time. Data are drawn from two waves of the Health and Retirement Study . We used interviewers\u2019 report on outdoor and indoor dwelling conditions to assess environmental risk factors. One-third of respondents reported at least one fall years later. The presence of green space such as a park near the housing unit and clutter in the home appears to increase the risk of falls over a four-year period. This finding suggests that falls in old age may be determined by a combination of outdoor and indoor risk factors."}
+{"text": "HIV/AIDS is an infectious disease that has claimed the lives of millions of people worldwide. Currently, there is no vaccine that has been developed in a bid to fight this deadly infection, however, antiretrovirals (ARVs), which are drugs used in the treatment of HIV infection are routinely prescribed to infected persons. They act via several mechanisms of action to reduce the severity of infection and rate of infectivity of the virus by decreasing the viral load while increasing CD4 counts. COVID-19 pandemic has resulted in unprecedented events affecting almost all areas of humans' life including availability of medicines and other consumables. This paper analyses the availability of ARVs during COVID-19 era and offered recommendations to be adopted in order to prevent shortages. It was discovered in 2019 and has since become a global health crisis and was declared a pandemic on 11on (WHO) . Antireton (WHO) . Analysion (WHO) . The ripFactors responsible for the low availability of ARV medicines across borders include: inadequate human resources in manufacturing facilities due to physical distancing and lockdown; curtailing of sea and air transport dents the manufacture and distribution of raw materials and other products such as packaging materials pharmaceutical companies needs to in order to manufacture these medicines. Other factors include: increased overhead and transport costs, the need for an alternative source of key starting materials and active pharmaceutical ingredients coupled with fluctuation and weakened national currency caused by envisaged economic shock apparently pushed up the cost of some antiretroviral regimens . AdditioFirstly, HIV therapy should be promptly integrated into social health insurance scheme if not in totality at least to a greater percentage at all tiers of government such that a pool of funds is created thus, enhancing domestic resource mobilization without further pushing people into poverty. A coordinated action by government and private organizations is necessary for even distribution of ARVs to persons who need HIV treatment . Secondlit is vital that countries urgently make plans now to mitigate the possibility and impact of higher cost and reduced availability of antiretroviral medicines'. It is a call for global action by both suppliers and buyers to ensure smooth delivery and accessibility of ARV medicine for continue treatment by person living with HIV. Government should also pull concerted efforts and create policies that will enable this set of people gain uninterrupted access to antiretroviral in the midst of the current pandemic and beyond this global health crisis.The economic impact of COVID-19 pandemic indicates a possible shortfall in the availability and a rise in the cost of ARVs. We cannot let the COVID-19 pandemic undo the hard-won gain in the global response to this disease. In different occasion the executive director UNAIDS Winnie Byanyama said: '"}
+{"text": "In order to address the geropsychology workforce shortage, educators are trying to better understand the attitudes, interests, and needs of prospective students as well as expand educational opportunities and specialty competence. This symposium reports on several recent and ongoing research projects and educational initiatives which can together inform future efforts to recruit students into the field. King et al. discuss how concerns about adultist oppression might keep young adults from entering the field. This study describes a new adultism measure which positively correlates with ageism and negatively correlates with both experience and interest in working with older adults. Together with Strong and Graham\u2019s study looking at ageism among North American and non-North American students, these studies remind us of the continued effort needed to better understand and combat age-related oppression of individuals at both ends of the lifespan. Two studies share specific educational initiatives addressing areas of essential but undervalues areas of training for geropsychologists. O\u2019Malley and Graham report on the integration of health policy training into undergraduate education, while Jacobs et al. describing a new performance-based evaluation tool for training in the assessment of decision-making capacity. Postgraduate specialization continues to be crucial in establishing and growing the discipline of geropsychology. Mlinac and Smith report on the development of a mentorship program for professionals on the path to board certification."}
+{"text": "There are 5.8 million Americans living with Alzheimer\u2019s disease and more than 16 million Americans providing unpaid care for people with AD and related dementias. Since a treatment that can slow or stop progression of this disease has yet to be discovered, novel interventions are sorely needed to maintain cognitive function and quality of life among individuals with dementia, improve the health and well-being of caregivers, and provide assistance in caregiving duties. This symposium addresses novel interventions in the dementia care continuum ranging from social and leisure activities for improving cognition to incorporation of emerging technologies to assist with caregiving and provides recommendations and priorities for future studies. The first presentation introduces evidence that participation in an intergenerational choir can improve cognition, social connectedness, and quality of life among people with dementia and their caregivers. The second presentation systematically assesses recent randomized controlled trials of computerized cognitive training  aimed at improving cognitive function among individuals with cognitive impairment or dementia. The third presentation examines the evidence that interventions employing artificial intelligence such as robots may improve care for persons with Alzheimer\u2019s disease and caregivers\u2019 quality of life and provides suggestions for future studies to better assess the efficacy of these interventions. The session concludes with a presentation on a survey method used to build consensus among a panel of experts across academia and industry which identified the emerging technologies that are expected to become the most prevalent in dementia care and provides recommendations for limiting associated risks."}
+{"text": "Beckett et al  performeHowever, we are concerned that the authors excluded all scientific articles regarding the outcomes of human trials using the proposed dietary strategies due to fees for obtaining these articles and the assumed lack of ability of people with MS to interpret these types of articles. In our experience, people with MS who desire to incorporate diet into their personal treatment plans are often highly informed of the scientific literature regarding dietary strategies for MS. In addition, scientific journals often are open access and/or provide lay language summaries of the article; for these reasons, we disagree with the authors' justification for excluding these articles. Furthermore, the authors conclude that online dietary advice is often the result of an individual\u2019s experiences and has not been scientifically evaluated. However, at the time of the internet search November 2016) performed by Beckett et al 016 perfo and assoWe agree with Beckett et al  that theWe would like to thank the journal editors for allowing us to reply to Beckett et al , who con"}
+{"text": "The wide range of services needed to support a safe and quality life among people living with dementia at home is growing and extends beyond the bounds of traditional reimbursement models. Within the context of a health care system that is not designed to reimburse for these types of services, federal grants from the Alzheimer\u2019s Disease Programs Initiative (ADPI) funded by the Administration for Community Living (ACL) have supported the delivery of home- and community-based services (HCBS) for people with dementia and their care partners with a pragmatic emphasis on sustainability, such as establishing successful reimbursement pathways. Drawing lessons from ACL\u2019s ADPI program and from the Health Resources & Services Administration Geriatric Workforce Enhancement Program and Geriatrics Academic Career Award program, this symposium examines opportunities and strategies for providing services to people living with dementia in the community and highlights occupational therapy as a valuable dementia care service that has potential for sustainable delivery and opportunities for professional expansion. Papers address needed workforce development for delivering HCBS to diverse populations living with dementia and examine occupational therapy roles in delivering HCBS to persons with dementia and their care partners. Additionally, papers examine the implementation and outcomes of evidence-based occupational therapy and interprofessional interventions for persons living with dementia in the community. Reimbursement mechanisms for occupational therapy services delivered to people with dementia in the community are described. Discussion addresses how these innovative interventions and reimbursement mechanisms align with the recent surge of National Institute on Aging funding for pragmatic trials."}
+{"text": "The COVID-19 pandemic has in a matter of weeks fundamentally crippled health systems in many countries and is now threatening to cause a global economic depression [We wish to highlight two key natural experiments that it is important to focus attention on. The first is countries\u2019 responses to dealing with and mitigating the effects of the pandemic. There is considerable global variation in national responses ranging from immediate attempts to suppress the outbreak  to containment approaches aiming to promote the development of herd immunity  . These aA second major net of natural experiments that need to be undertaken is to establish on a global scale the impact of improvements in air quality on human and planetary health. The pandemic has resulted in the greatest restrictions in travel in human history, which have already led to very substantial reductions in ambient air nitrogen dioxide and particulate matter levels . Given tWhile still in the midst of the global turbulence caused by COVID-19, it is difficult to see any silver lining. We do however need to make the most of this adversity. We argue that mounting major international natural experiments to understand optimal approaches to national pandemic responses, and the effects of air quality improvements on human health represent very major opportunities to advance population health. Since such evaluations typically make use of routinely collected health care data -6, theseWe must collectively seize these opportunities to help achieve a lasting benefit of the global tragedy now unfolding."}
+{"text": "Refactoring is often needed to ensure that software systems meet their performance requirements in deployments with different operational profiles, or when these operational profiles are not fully known or change over time. This is a complex activity in which software engineers have to choose from numerous combinations of refactoring actions. Our paper introduces a novel approach that uses performance antipatterns and stochastic modelling to support this activity. The new approach computes the performance antipatterns present across the operational profile space of a software system under development, enabling engineers to identify operational profiles likely to be problematic for the analysed design, and supporting the selection of refactoring actions when performance requirements are violated for an operational profile region of interest. We demonstrate the application of our approach for a software system comprising a combination of internal  components and external third-party services."}
+{"text": "Humans combine incoming sensory and past information to deal with ambiguous and uncertain information  that uncertainty from the encoded stimulus is stored in short-term memory and (2) that knowledge about different statistical environmental regularities might affect how the brain integrate past information with current decisions. While the first should inform the development of models of short-term memory storage, specially those concerning short-term synaptic plasticity, a candidate mechanism to explain serial dependence (Barbosa et al., For downstream areas to have access to previous trial probability distribution of stimulus values, the brain must keep it in short-term memory. van Bergen and Jehee's  results If serial dependence relied only on averaging of previous and current information, one would expect response biases to increase as the difference between consecutive stimuli increase. However, as first shown by Fischer and Whitney , van BerInteresting predictions for future investigations of serial dependence can be generated by assuming that participants have at least an approximate knowledge of the natural temporal dynamics of the environment. For example, by having participants learn a new internal model of stimuli sequence (Chalk et al., Evidence that the brain uses past information and weight current and previous information based on uncertainty has been out there for a while. van Bergen and Jehee's  work proThe author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "As the caregiver ratio declines, technology will play an increasingly important role in supporting formal and informal caregivers. This presentation will report on the particular effects that frontier technologies may have on various tasks associated with caregiving, including assisting with basic Activities of Daily Living (ADLs) and Instrumental Activities of Daily Living (IADLs). The expert panel predicted that different technologies and new products will have varied effects on caregiving tasks, and that some tasks may be more impacted than others. Some of the key opportunities and barriers to integrating technologies into various tasks of caregiving will be discussed."}
+{"text": "Careful fidelity monitoring is critical to implementing evidence-based interventions in dementia care settings to ensure that the intervention is delivered consistently and as intended. Most approaches to fidelity monitoring rely on human coding of content that has been covered during a session or of stylistic aspects of the intervention, including rapport, empathy, enthusiasm and are unrealistic to implement on a large scale in real world settings. Technological advances in automatic speech recognition and language and speech processing offers potential solutions to overcome these barriers. We compare three commercial automatic speech recognition tools on spoken content drawn from dementia care interactions to determine the accuracy of recognition and the guarantees for privacy offered by each provider. Data were obtained from recorded sessions of the Dementia Behavior Study intervention trial (NCT01892579). We find that despite their impressive performance in general applications, automatic speech recognition systems work less well for older adults and people of color. We outline a plan for automating fidelity in interaction style and content which would be integrated in an online program for training dementia care providers."}
+{"text": "Older adults are often relying on a family member or other informal caregiver (friend or other) to jointly navigate the health care system and cope with the ramifications of serious illness; thus, the patient-caregiver dyad becomes the unit of care. The caregiving role becomes crucial in cases where patients are facing a condition that limits their cognitive and functional abilities and caregivers are called to act as proxy decision makers for significant treatment and symptom management decisions. Caregivers often report that they feel isolated and overwhelmed, and in some cases experience significant barriers in communicating with health care providers. It is important that clinicians communicate in a way that acknowledges and addresses caregivers\u2019 preferences, needs and perspectives. Caregiver centered communication can facilitate a more effective adaptation throughout the illness course with better adherence to recommended treatment plans and greater satisfaction with care for both patients and families, as well as a more comprehensive response to their psychosocial needs. While health care organizations often aim to increase caregiver engagement and involvement in care processes, there is a lack of tools or strategies not only to more actively engage caregivers but also to assess how ongoing approaches perform in terms of facilitating meaningful and inclusive communication. This symposium will review existing tools and a new instrument to measure caregiver centered communication, challenges and opportunities in measuring the quality of communication with caregivers and highlight empirical data of communication quality in various health care settings including home care and hospice."}
+{"text": "L-arginine by means of nitric oxide synthase enzymes. Recently, a novel pathway for the reduction of dietary inorganic nitrate to nitrite by the bacteria in the oral cavity and subsequently to vasodilatory nitric oxide within the body has been uncovered. Dietary nitrate is abundant in green leafy vegetables, including beetroot and spinach, and reduction of exogenous nitrate to nitrite by oral bacteria can increase nitric oxide in the vasculature, lessening hypertension. Supplements rich in nitrate may be an attractive choice for treatment due to fewer side effects than drugs that are currently used to treat hypertensive pregnancy disorders. Additionally, manipulation of the composition of the oral microbiota using pro- and prebiotics in tandem with additional dietary interventions to promote cardiovascular health during gestation may offer a safe and effective means of treating hypertensive pregnancy disorders including gestational hypertension and pre-eclampsia. The use of dietary inorganic nitrate as a supplement during pregnancy requires further exploration and large scale studies before it may be considered as part of a treatment regime. The aim of this article is to review the current evidence that oral microbiota plays a role in hypertensive pregnancies and whether it could be manipulated to improve patient outcomes.Chronic hypertension during gestation is associated with an increased risk of adverse pregnancy outcomes including pre-eclampsia, fetal growth restriction and preterm birth. Research into new chemotherapeutic regimes for the treatment of hypertension in pregnancy is limited due to concerns about fetal toxicity and teratogenicity, and new therapeutic avenues are being sought in alternative physiological pathways. Historically, generation of the vasodilator nitric oxide was believed to be solely from  Hypertension is a modern medical crisis in all nations across the globe due to its correlation with a poor, high calorie diet and minimal exercise, all of which are risk factors for cardiovascular disease and death  is crucial in maintaining vascular homeostasis within the host  is a vital signaling molecule in the cardiovascular system and has been implicated in numerous vascular processes including vasodilation and tissue protection .in vivo both in animal models  per oral administration; a high pharmacological dose] led to methemoglobinemia in a pregnant rat model  toward higher relative abundances of Neisseria and Veillonella following nitrate supplementation (Koopman et al., Research interest in the oral microbiota and its relationship with BP responses has become more prominent within the last few years (Bryan et al., Given the positive effects of nitrate supplementation in non-pregnant populations, and our preliminary findings in pregnant women, it remains possible that dietary interventions targeting the nitrate-nitrite-NO pathway could be used in future to improve outcomes in HPDs. Investigating whether differences in the oral microbiome are associated with HPDs, and determining the efficacy of BP responses to dietary nitrate supplementation amongst different groups of pregnant women, is the focus of our current studies. Future trials should explore and evaluate whether nitrate supplementation and/or probiotic supplementation can improve pregnancy outcomes in hypertensive pregnant women. Research should also be expanded to other maternal microbiotas which are known to be dramatically altered during gestation, such as the gut (Koren et al., All authors contributed to the writing of the manuscript and approved the final submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In the past decade, remote home monitoring has emerged to monitor surgical patients in the vulnerable period after hospital discharge.In this observational feasibility study,The results of this study provide a valuable contribution to the discussion on the feasibility of monitoring systems for older and vulnerable populations. Future home monitoring systems should measure a various range of parameters, yet remain usable and acceptable for older and vulnerable patients. This is necessary to ensure high compliance and completion rates of the population with the perceived greatest benefit of monitoring. Finally, the integration of monitoring systems into existing health care systems should be well explored to secure feasibility for health care professionals."}
+{"text": "With this notice, Frontiers states its awareness of concerns regarding the validity of the participant data in this study. An investigation is currently being conducted by Kashan University of Medical Sciences research ethics committee. This expression of concern has been posted while Frontiers awaits the outcome of that investigation and will then be updated accordingly."}
+{"text": "Oxford Medical Case Reports will contribute to increasing the available knowledge base through the submission of papers by medical staff in humanitarian settings sharing their experiences and challenges with the provision care for people living with complex medical conditions in similar resource-limited settings.As discussed by our colleague Wind , in a prNone declared."}
+{"text": "Following publication of the original article , the autResults for matched tests performed by BioFire and qPCR or rapid test and qPCR.The publisher apologizes for any inconvenience.The original article has been corrected."}
+{"text": "Cellular processes often decline with age and cells lose their ability to function optimally, which may lead to organ-specific dysfunction and the development of systemic age-related diseases. The cellular hallmarks of aging are associated with clinical signs and symptoms and can be termed Age Associated Cellular Decline. An expert consensus study group was convened to provide an initial framework for the development of a tool for adults over 50 years old, which identifies self-reported symptoms and observable signs likely to be early and/or surrogate markers of age associated cellular decline. A total of 16 potential early signs and symptoms of age associated cellular decline were identified and need to be validated in further research."}
+{"text": "The goal of ending preventable maternal and newborn mortality is achievable. Many maternal and newborn deaths can be averted through family planning services, and the timely provision of high quality care throughout pregnancy, childbirth, and the postnatal period. Yet, progress in increasing universal access to these life-saving interventions has been uneven and slower than we hoped. There are still approximately 2.5 million newborn deaths and 300\u2009000 maternal deaths per year, most occurring in countries with the highest resource constraints and weakest health care infrastructures ,2.The positive news is that these stark numbers have not gone unnoticed, and great strides have been made in identifying essential packages of care for saving the lives of mothers and their newborn babies. Global consensus has also been reached on a core set of indicators for assessing progress in scaling-up these essential packages. Targets for reducing maternal and newborn mortality are in the Sustainable Development Goal (SDG) Framework, and many of these core indicators are embedded within other global accountability frameworks such as the Global Strategy for Women\u2019s, Children\u2019s and Adolescents\u2019 Health (2016-2030), Countdown to 2030, Every Newborn Action Plan, and Ending Preventable Maternal Mortality.But, why does it matter if maternal and newborn health related indicators feature prominently in global accountability frameworks? The simple answer is the maxim we know so well: What gets measured gets done. And this translates into all of us doing our part to make it possible for every woman to have a healthy pregnancy and positive birth outcome for herself and her newborn baby.The inclusion of maternal and newborn health indicators in global accountability frameworks has spurred a surge of data collection efforts in recent years \u2013 new questions and modules have been added, for example, to large-scale population-based surveys such as the UNICEF supported Multiple Indicator Cluster Surveys (MICS) and the USAID supported Demographic and Health Surveys (DHS), and to health facility assessments such as MEASURE\u2019s Service Provision Assessment, and WHO\u2019s Service Availability and Readiness Assessment. There are also ongoing efforts to provide guidance to countries, through a set of modules (DHIS2 modules) produced under the umbrella of the Health Data Collaborative, on a standard set of indicators to collect through their routine health information systems.All these data collection efforts have greatly increased the availability of data on essential maternal and newborn health interventions. The aim of this supplement is to take stock of where we are now: Are these efforts enough to meet global and national monitoring needs for maternal and newborn health? What else needs to be done to improve the measurement of maternal and newborn health indicators so that we all can be held to account for achieving the ambitious SDG targets? This supplement is organized into three sections. The first provides an overview of the data landscape for essential maternal and newborn health interventions. The second section includes papers that focus on the policy and programmatic implications of accurately measuring and regularly monitoring key maternal and newborn health indicators. These studies demonstrate what can be learned from analyses of available data about progress in individual and in groups of countries. They highlight where improvements are being made, where more work is needed, and context specific opportunities for increasing both the supply of and demand for essential maternal and newborn care. The set of papers in the third section highlights methodological work completed or under way on improving the measurement of maternal and newborn interventions and how this work helps address existing data gaps.Several actionable messages emerge from the collection. These include a recommendation to increase data collection approaches that capture information about effective coverage and the quality of care. The study by Carvajal-Aguire et al., for example, revealed large data gaps in 20 countries in sub-Saharan Africa on the content of health services provided . One sucAlthough the escalation in data availability on maternal and newborn health interventions is a laudable achievement, studies in this collection show that further work is needed on harmonizing data collection efforts to improve comparability across them. The study by Amouzou et al., for example, found that the MICS and DHS use different questions and methodologies for capturing information on postnatal care which reduces comparability across the two survey programs and the ability to develop time trends . Other aThis supplement is timely given the ambitious global development agenda and the growing awareness of maternal and newborn survival as essential to its achievement. It shows the power of data to: 1) inform us about how well we are doing in improving coverage of essential maternal and newborn interventions within and across countries, and 2) why investments in the measurement agenda are critical for increasing our ability to know what we need to know about the success of policies and programs in saving maternal and newborn lives."}
+{"text": "Growing evidence indicates that residential contexts are implicated in the health and well-being of older adults. Operationalization of these contexts varies and includes psychosocial, physical and socioeconomic neighborhoods, and more proximal contexts . We aim to bring together a diverse set of papers focused on the living environment to understand how contextual factors are associated with individual outcomes. Mu\u00f1oz and colleagues applied a lifespan perspective by evaluating associations between current and childhood neighborhood perceptions on cognitive health. Their results indicated that the association between perceived neighborhoods and cognition in adulthood was moderated by childhood neighborhoods. Garc\u00eda and Ailshire contextualized the types of neighborhoods in which older Latinos live and how these influenced diabetes risk. They identified neighborhood clusters characterized by racial/ethnic and socioeconomic compositions and found that predominantly Latino neighborhoods with low SES were more likely to have diabetes compared to other neighborhood clusters. This symposium will also focus on the more proximal environment. Lee and Ailshire examined the neighborhood and home environment and found that the home\u2019s proximity to green space and level of clutter within the home was associated with increased fall risks in older adults. Fingerman and colleagues coded older adults\u2019 living spaces and found that personality type was associated with room conditions. Altogether, the presentations highlight the relevance of context measured across multiple levels of analyses and dimensions of well-being outcomes in aging individuals. Dr. Markus Schafer will provide a discussion of these findings and address the challenges and opportunities for future research."}
+{"text": "Surface modified bioactive virus-mimicking organic nanovesicles represent themselves as complex biomimetic structures that have abilities to dissect the functions of individual entities in a complex biochemical system. The customized surface of nanovesicles from (glyco)dendrimersomes has structural modifications that contribute to manifest the SARS-CoV-2 and host pathogenic molecular interactions that help the virus to evade the human immune system. Nanovesicles also have a potential role in dynamic biomedical applications such as designing galectin targeting drugs, evaluation of antibodies to design antiviral therapeutics or vaccines and targeted delivery of drugs.in vitro, biocompatibility and customized design that provides a better understanding of a particular function with safe handling. Designing spike-like oligomannoses of SARS-CoV-2 on the surface of (glyco)dendrimersomes play a significant role to translate host-pathogenic molecular mechanisms dendrimersomes with glycans and glycoproteins (oligomannoses) found on the surface of viruses including SARS-CoV-2 and other living cells or bacterial pathogens provide an opportunity to understand molecular interaction patterns between host and pathogen. This customized system helps to better understand the effects of one single molecular function at a time rather than to attain a synergistic response which becomes difficult to explain  receptor on the surface of the host cells and mediates entry inside cells dendrimersomes that have customized sequence of sugars or proteins and allow scientists to understand how host and pathogens interact? and How intercellular signaling changes during the process of disease? dendrimersomes also have abilities to act as an epitope of an antigen and to be recognized by the antibodies secreted by immune cells to generate an immune response and neutralize the future pathogenic attacks. These (glyco)dendrimersomes also act as a functional platform to screen antibodies to design and select vaccines. Empty lumen or pocket of the (glyco)dendrimersomes provide an advantage to use them as a carrier of antiviral therapeutics that can target specific virus particles because of their surface modifications and release drugs upon exposure to a particular physicochemical stimulus such as ultra-violet light. Surface targeting and controlled release of drugs have advantages to better manage patients' health and have profound treatment success rates dendrimersomes as nearly safe against human umbilical vein endothelial cells (HUVEC) and they were observed viable upon exposure to nanovesicles that require further toxicological investigations to use them as drug carriers dendrimersomes provide a multi-dynamic platform to understand host-pathogen interactions that help SARS-CoV-2 to evade the human immune system. Nanovesicles have the potential to be used as a vaccine having customized oligomannoses as terminal groups on their surface that represent the blueprints of spike S proteins. The empty lumen of organic supramolecular vesicles has abilities to carriage antiviral drugs or therapeutics to their targeted sites or pathogens and release drugs in response to a particular stimulus.BJ designed the study and wrote the manuscript.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Pediatric Reports was launched in 2009 and it has been published over the past eleven years by PAGEPress Publications [ications . ProfessPediatric Reports from PAGEPress and perpetuate the legacy of this journal, and ensure that we serve well the pediatrician community. Pediatric Reports complements very well the MDPI portfolio of medical journals [Children [International Journal of Neonatal Screening [We are delighted to take over the publication of journals , especiaChildren  and the creening .MDPI will publish the fourth quarterly issue of 2020 and will thereafter publish four quarterly issues as of 2021. Pediatric Reports [Enjoy publishing your work in  Reports !"}
+{"text": "The COVID\u201019 pandemic has exposed fragilities and reinforced the resiliency of different elements of our manufacturing and processing systems. Food processing, in particular meat packing, currently a very labor\u2010intensive operation, experienced significant disruption and the car industry implemented shutdowns which will ripple through supply chains in the coming months. It became clear that packaging supply chains are bottlenecks as producers tried to divert food stuffs from restaurants to consumer stores, and shifts in demand for paper products caused persistent consumer outages. The basic chemicals and fuels industry did not see significant disruption, but wild price fluctuations did occur as reduced demands and an unfortunately timed production increase caused available storage capacity to be strained. Recycling industries saw, and will continue to experience, both ends of the disruption as their consuming industries reduced demand and their providers stockpiled material or diverted it to trash. The beverage industry has significant inventory in public venues that has expired. Boutique level hand sanitizer production has resulted as these beverage production systems have been reconfigured and the rules surrounding the grade of alcohol relaxed.1 and we would like to encourage you to consider other ways in which our manufacturing systems will change in response to the pandemic. However, much as there is a need to address the short\u2010term disruptions caused by a pandemic, and to understand how research can respond to create advanced manufacturing and processing systems with flexibility and resilience in the future, we also need to continue to push forward with efforts that provide new foundations for those features and we have curated articles that we hope fulfill that goal.We are sure there are many of you who have worked long hours to innovate your manufacturing and processing systems to cope with the challenges of COVID\u201019 and we would welcome articles and commentaries on how advanced manufacturing can play a role in our collective response. In this issue of JAMP we share a commentary on the rapid manufacturing of vaccines as our contribution to understanding how our community might respond to COVID\u201019,2 and Process intensification remains a key approach to advanced manufacturing enabling more nimble and responsive systems. This issue provides two examples tackling a variety of processes: the epoxidation of vegetable oils and the manufacturing of butyl acrylate. show that by using a mesoscale oscillating baffled reactor the process can be converted from a batch operation to a continuous one and in the process they estimate that the new reactor is approximately 144 times smaller than the batch reactor operating at the same production rate.Rahim et al.3 show have combined this technology with membrane pervaporation creating a Simulated Moving Bed Membrane Reactor which reduces the number of operation sections for the manufacturing of butyl acrylate while reducing the eluent consumption and improving the productivity. A complete analysis of all process metrics is given in this paper.The Simulated Moving Bed Reactor (SMBR) technology has been an example for process intensification for a couple of decades. Constantino et al.4 have discusses the importance of protecting data as critical intellectual capital and how many in the AI vendor community do not understand the value of data to the process industry. The commentary offers insight on the need for chemical engineers and data scientists to work closely together to solve technical and operational problems that require analysis of data that is broader than process data and where fundamental models break down. This commentary takes on additional importance for resiliency in light of the social and economic impact of COVID\u201019.The use of Artificial Intelligence (AI) in the chemical process industry is being used in new ways that are challenging the way this industry should consider the adoption and deployment of Industry 4.0 that has become ubiquitous in other business sectors. Colegrove5 disc"}
+{"text": "Iran has witnessed one the fastest decline in the road traffic mortality in past decade. Despite this great achievement, the number of death toll has increased in past two years although in a small manner. The global situation is similarly alarming and recent figures show an increase in the number of fatalities and injuries despite the proclaimed goals for decade of action by the united nation. The current situation does not mean that there were negligence but it indicates more importantly the urgent need to combine the current engineering approach to more humanistic approach to this modern world preventable disaster. Risk perception insufficiency has been found to be a major driver of fatal events especially in younger victims. Although law enforcement and environmental support could initiate the change in behavior but there is need for a humanistic approach for persistent change in behavior.Humanistic Approach, Traffic Accidents"}
+{"text": "The steady rise of antimicrobial resistance is one challenge where the current research and development system does not provide the needed solutions. Two new World Health Organization (WHO) reports show that too few new antibacterial treatments are in development and that more interventions are needed.Clostridioides difficile. The 10 biological treatments in clinical development target Staphylococcus aureus (six treatments), Pseudomonas aeruginosa (two treatments) and Clostridioides difficile (two treatments).The 2019 WHO clinical antibacterial pipeline analysis describes all antibiotics and biological treatments that are currently in development against the WHO priority pathogens list.WHO also assessed the novelty of the antibacterials using four criteria: absence of known cross resistance, new class, new target and new mode of action as defined by the WHO expert group. Only six of the agents that target the WHO priority pathogens fulfil at least one of the four criteria.New derivatives of the same class can be superior than the first in class treatment by having a better safety profile, better efficacy or activity against resistant bacteria. However, resistance is likely to develop quicker against derivatives of the same class that share the same mode of action and target. Clinicians are reluctant to switch to new, more expensive treatments that are based on non-inferiority trials that only show that the new treatments are not worse than the standard of care. This reluctance and the conservative approach required towards using new antibiotics under stewardship programmes is translating into serious economic challenges. The recent bankruptcy of some of the small antibiotic research and development companies and the fact that most major pharmaceutical companies have left the antibiotic research and development space illustrates these economic difficulties.,How to tackle the lack of private investment in the research and development of new antibacterial treatments has been discussed in the G7, G20 and other international fora.Mycobacterium tuberculosis and Clostridioides difficile.WHO\u2019s first report and publicly accessible database on the preclinical antibacterial pipeline published in January 2020 captures 252 antibacterial agents being developed by 145 individual institutions against the WHO priority pathogens, More public investment is needed to ensure a viable economic environment for antibacterial treatments that are innovative and add significant clinical value. Major pharmaceutical companies also have to make a more sustainable financial contribution. Antibiotic developers together with regulatory agencies must find ways to better demonstrate the clinical advantages of new antibiotics over standard of care through clinical data. Maintaining the antibiotic research and development crisis high on the international political agenda is essential to push for further reforms and to ensure that bacterial infections do not become another field of neglected diseases.In line with WHO\u2019s mandate to promote and conduct research in the field of health,"}
+{"text": "Medical innovation awards stand out as an important means to focus public attention on what matters in medical advancement. Traditional awards typically focus on celebrating medical innovators with either a track record of proven successes in new treatments or promising basic science breakthroughs still years away from reaching patients. Perhaps one of the greatest challenges for medical innovation that is not sufficiently addressed by these traditional awards is celebrating translational research efforts on the cusp of major advancements where medical innovators are demonstrating success in bringing emerging transformative medical innovations to patients. As a part of its award process, the Sanford Lorraine Cross Award has developed a unique method to fill this gap in the landscape of medical innovation awards for ongoing translational research efforts by identifying promising medical innovations within a narrow spectrum of the research pipeline on the verge of having transformative impact for patients in the near term. The Sanford Lorraine Cross Award addresses the challenges of identifying emerging transformative medical innovations making their way through development by deploying a rigorous, analytically-based \u201cearly signals analysis\u201d to identify emerging transformative medical innovations in its selection process independent of the medical innovators who are succeeding in bringing them forward. It also stands apart from traditional medical innovation awards in focusing on identifying award candidates that have significant roles in bringing the emerging transformative medical innovation across the finish line to patients, and their efforts in overcoming challenges, forging collaborations, and ensuring a successful outcome. The data-driven award selection process used for the Lorraine Cross award ultimately inverts the standard medical award selection paradigm \u2013 truly innovative areas of discovery and breakthrough science are identified independently of candidates and used to then focus candidate selection on the areas with the most promising transformative potential for patients. This article sets out the details of how the Sanford Award makes use of leading tools and methods in identifying transformative innovations currently in translational research to provide another important focus of what matters in medical innovation.The Sanford Lorraine Cross Award identifies the most successful application of translational research that ultimately expedited the development of a treatment or cure of a disease. Medical research awards garner significant attention and prestige in recognizing research excellence and contributions to making a difference in advancing medical innovation. For instance, the NIH Almanac touts that \u201cThe National Institutes of Health (NIH) has a long, rich tradition of support for award-winning, cutting-edge research. Many of the world\u2019s most distinguished investigators have been honored with medicine\u2019s top prizes, including the Nobel Prize and awards from the Albert and Mary Lasker Foundation \u2013 \u2018America\u2019s Nobels\u2019 \u2013 honoring groundbreaking contributions to our understanding of the human disease\u201d . This paThese traditional medical innovation awards either celebrate those medical researchers and innovators with proven successes or transformative basic science breakthroughs still years away from reaching patients. Among the examples of major awards for proven successes are the Nobel Prize in Physiology or Medicine with an emphasis on \u201cdiscoveries that have changed the scientific paradigm and are of great benefit for mankind\u201d  and the While these traditional medical research awards are a critical component of celebrating foundational scientific research, there is not currently a focus on celebrating those medical researchers and innovators closing the translational research gap for emerging transformative medical innovations today as opposed to the past or in a distant future. Advancing current translational research is perhaps the most pressing challenge of today\u2019s age in medical research in terms of providing new health-care solutions to patient populations. As the groundbreaking Food and Drug Administration (FDA) report on the Challenges and Opportunity on the Critical Path to New Medical Products  brought to public attention that \u201cat a time when basic biomedical knowledge is increasing exponentially, the gap between bench discovery and bedside application appears to be expanding\u201d .The need to recognize and incentivize medical researchers and innovators having success in addressing today\u2019s translational research challenges calls for a new type of medical innovation award backed by an analytical process that leverages the holistic body of highly descriptive but unstructured data on medical research activities. The importance of translational research requires a new paradigm that incorporates means to assess the emerging transformative medical innovations that are making their way through the development process to reach patients. A medical innovation award process that embraces the context of translational research also needs to be able to identify the medical researchers and innovators making significant contributions in advancing these emerging transformative medical innovations by demonstrating ingenuity, perseverance, and commitment to its success in reaching patients.Developing a rigorous and repeatable method for creating an award for translational research is the vision and focus of the Sanford Lorraine Cross Award, which celebrated its inaugural award in emerging transformative medical innovations in December 2018 and is now preparing for its second award process for December 2020.This award is agnostic to individuals at outset. As depicted in Another unique aspect of the Sanford Lorraine Cross Award is the criteria used to select the award winners. Rather than primarily focusing on the significance of the contribution of a researcher or clinician, the Sanford Lorraine Cross Award is concerned about the role that the award candidate has played in bringing a new emerging transformative medical innovation across the finish line to patients, and their efforts in overcoming challenges, forging collaborations, and ensuring a successful outcome.A final distinguishing aspect of the Sanford Lorrain Cross Award is the \u201crigor\u201d it brings in focusing on emerging transformative medical innovations in its selection process independently of the pioneers who are succeeding in bringing them forward. In particular, the Sanford Lorraine Cross Award stands out in the development of an \u201cearly signals analysis,\u201d which applies a data-driven approach using advanced analytical techniques to capture the vision of the Sanford Lorraine Cross Award in targeting emerging transformative medical innovations. As explained in further detail below, the early signals analysis relies on machine learning approaches to enable Sanford to cast a wide net across an expansive portfolio of high-impact translational research activity indicators and identify those innovations that are on the cusp of realizing transformative impacts in bringing new treatments to patients.The early signal analysis functions as the first step in a four-step selection process for the Sanford Lorraine Cross Award, as depicted in Following the selection of the most promising emerging transformative medical innovation areas, the focus then shifted to identifying specific candidates who are advancing science in those areas and embody the spirit of the Sanford Lorraine Cross Award. Potential candidates were identified based on peer-reviewed sources detailing the research history and current status of those selected emerging transformative medical innovation areas, and data mining of recent online activity in medical innovation news and press releases related to those areas. Further, due diligence was carried out by Sanford Health, including discussions and in-depth background analysis of candidates to identify the top three candidates for consideration.The ultimate selection among the three final candidates, each of which was well-qualified, is the responsibility of the Sanford International Board to ensure the focus on a medical pioneer who has demonstrated ingenuity, perseverance, and commitment to bringing an emerging transformative medical innovation to fruition. The Sanford International Board offers both a strong patient-orientation along with a passion for supporting the improvement of the human condition through transformative medical treatments and care, and brings their expertise and life experiences as entrepreneurs, health-care leaders, business executives, and world-class competitive athletes to bear. This advisory group helps oversee Sanford\u2019s World Clinics, with current locations in Canada, China, Germany, Ghana, and the U.S. These Sanford World Clinics provide care to children, families, and underserved populations along with offering innovative approaches in areas as primary care services, regenerative medicine and diabetes, to improve the health and well-being tailored to the needs of each community it serves, using methods that surpass current practices of health-care delivery.This rigorous early signals analysis stands in contrast to other major medical innovation awards, which generally rely on the subjective vetting of a small set of highly accomplished and recognized scientific leaders  and reflet al. explained that when disruptive innovation occurs in this cascade of innovative development, it disrupts the existing paradigm and begins a new innovative cascade of ideas generated by the disruptive idea [The approach of using early signals to identify trends in innovation is rooted in the scientific literature of how innovations evolve over time and the \u201cbursts\u201d in innovative activity that typify emerging innovations. One way of describing trends in innovation is using the analogy of a cascade, shown visually in ive idea . These dAnalyses of this type of disruption rely on the linkages between ideas, and for this reason, the forward citation patterns, or citing of past work by future work, of research publications, and patents are often used to study shifts in patterns that indicate the onset of a disruptive idea. Other work on identifying and characterizing high-impact and transformative science metrics also relies on the idea that transformative ideas will rapidly generate various types of measurable recognition and forward citation activity as radical and high-impact ideas disrupt previously established citation patterns and generate new concepts .The concept of using the patterns related to short-term bursts of innovation activity that occurs just after a transformative or disruptive idea is introduced to characterize high impact areas through forward citation analysis is reflected in various ways using several different approaches and metrics through the work of a number of other researchers, and is particularly applicable to the biomedical innovation space -10.Since the Sanford Lorraine Cross Award is intended to recognize emerging transformative medical innovations making their way through development with a clear path to reaching patients, only signals that occur at the later stages of basic research up until just before product introduction to market are included to spotlight developing areas where the award can help propel emerging ideas to completion.The identification of early signals consistent with the focus of the Sanford Lorraine Cross Award requires tracking activities that take place across translational research. Translational research is the pathway in which basic research discoveries are advanced and developed into new innovative medical products to serve patients, and it reflects the critical interface of \u201cbench and bedside\u201d relationships which drives medical innovations forward. The U.S. NIH explains that: \u201cInformation flow at this interface is bi-directional, requiring close interaction between clinical and bench scientists\u201d . TranslaThe nature of translational research and the many steps involved in advancing bioscience innovation makes it difficult to establish a single metric intrinsically tied to its development. The early signals data sources considered in an analysis of innovative potential should represent a variety of milestones on the timeline of translational research as medical innovations go from initial discovery to market delivery to ensure maximum coverage, as transformative applications can occur at various points in the process of developing an initial breakthrough discovery into a market-ready product.For this reason, a mix of seven early signals was identified for the Sanford Lorraine Cross Award to consider, including:NIH transformative research grantsHigh impact scholarly activitiesHigh impact patent activitiesHigh potential venture-backed companiesHigh potential NIH small business innovation research grantsFDA expedited reviewTrending social media topics in medical innovationFrom the scientific literature, a critical way to identify those high impact innovations reflecting a \u201cburst\u201d of activity is through various measures of forward citation patterns. To the extent possible, this focus on forward citations patterns as an early signal of high volume, compressed innovation activity is used to process signals data (such as for publications and patents). However, this is not possible for all measures due to limitations in the underlying data. When forward citations are not available for identifying high potential innovation activities taking place in specific early signal measures, then the early signal measure itself is defined in a manner that reflects only highly innovative activities, such as only selecting innovations going through clinical trials approved for expedited reviews.Once filtered, the unstructured text content present in the early signals data describing the applications of each innovation is pooled for further analysis of the innovative technology platform themes present across the breadth of the various early signals measures. This unstructured text data takes the form of descriptive metadata attached to each record documenting an innovation and includes information such as patent and publication abstracts, grant award descriptions, early stage company descriptions, and social media posts describing innovative discoveries. The various early signals records are pooled without any weighting attached to individual records since later steps in the early signals validation process incorporate subject matter expert judgment and feedback in weighting the validity of different concepts. The complete process of selecting, filtering, and combining the early signals data for use in subsequent analysis phases .et al. of quantitative methodologies for identifying emerging technologies indicates that the two most commonly used types of analysis for characterizing the information structure of data rely on patterns formed by either keywords or citations [There are a wide variety of different quantitative approaches that are possible for analyzing the thematic makeup of early signals data, each of them with advantages and limitations. A comprehensive review by Cozzens itations . The metTo analyze the overarching themes present in the refined pool of early signals innovation data, a machine learning technique known as unsupervised latent topic modeling analysis is used to build out \u201cvocabularies\u201d based on the unstructured text content and then use them to identify distinct topics present across the data present in the descriptions. A text processing algorithm is used to clean the text data and then identify frequently appearing terms and multiword phrases through techniques such as word stemming and stop-word removal which are commonly used in natural language processing methods, which turn text content into data for analysis. Once key terms are identified for each record, weighted term frequency methods are used to assess the importance of each term or keyword phrase in describing the content held within an individual text record. The key terms identified for each body of unstructured text are then used as inputs to an unsupervised clustering technique known as latent topic modeling to identify key underlying concepts present in the text data based on the process of building out \u201cvocabularies\u201d of terms that are identified by the algorithm and evaluating their presence across the data. As opposed to more basic clustering algorithms which evaluate text content at the overall record level and then assign a unique theme to a data record, latent topic modeling estimates the mixture of topics present in an individual record to better approximate the structure of real-life text content which often contains multiple themes within a single record. In addition to identifying the underlying topic structure present across the body of text data, the algorithm also enables calculation of a measure of similarity, or \u201cdistance,\u201d between different text records documenting innovations so that all records in the refined pool of early signals data can be compared to one another to identify records that contain similar ideas and concepts. The steps for processing the early signals data for the next stage of review by scientific expert panels are shown in Even after identification of an initial set of topic clusters by the clustering algorithm, it is still necessary to evaluate the cluster groupings to determine cohesiveness and critical mass around a single relevant subject based on analysis of key terms appearing in cluster records. These validation steps filter out clusters that are not focused or are not relevant to the innovation areas that the Sanford Lorraine Cross Award process is designed to target.A total of 20,290 records were generated from the sources for the early signal analysis. This included 9218 records from standardized databases that document more formal stages of innovation involving: Publications, NIH grants, patents, early stage venture capital, SBIR Phase 2 awards, and FDA special approvals. Another 11,072 records came from web surveillance data across medical innovation and research news aggregators that offer insights on informally recognized areas of medical innovation that has new and exciting developments.The latent topic model identified approximately 100 underlying topics present in the body of early signals data. These initial topics were then interpreted through expert review validation and categorized as relevant or \u201cartifact\u201d topics based on how highly focused their themes were on biomedical innovation topics versus other subjects. This step identified 72 highly focused biomedical innovation topics for review by Sanford stakeholders to assess their relevance to the specific vision of the Lorraine Cross Award with respect to the maturity and ongoing research activity in the innovation area. From this grouping, a total of 57 medical innovation topics from the text records were identified and then underwent subsequent review steps with a group of internal Sanford scientific experts who identified a final set of 14 medical innovations to consider in the validation exercise with the external scientific expert panel.et al. note in their work outlining processes by which transformative research can be identified that there are many cultural and cognitive biases that can need to be considered. Further complicating the identification of medical innovations is a wide range of different attributes to innovations that must be considered and weighed, such as potential for impacts on scientific discovery, patients, clinical practice, and public health.In selecting among potential emerging medical innovations for those that stand out as having the highest transformative potential, there is no substitute for the inclusion of expert judgment in evaluating the transformative potential of medical innovation. As Huang et al. [There is an existing literature on retrospective analyses of transformative innovations in the medical space, which includes a variety of techniques that utilize subject matter experts to either critique or rank order sets of medical innovations based on present-day recognition of the innovative value of a set of innovations. For example, Kesselheim et al.  use a meet al.  ask a grFor the Sanford Lorraine Cross Award, the difference from retrospective studies is providing a rigorous approach to conducting the due diligence on emerging innovations identified through the early signals analysis that accounts for the role of uncertainty and the implied preferences of respondents in a forward-looking way. One way to do this is to use a decision theory framework known as multi-attribute utility modeling to capture expert opinions across the various defining characteristics of a particular innovation. Utility modeling techniques are used to assign preference rankings to choices across a set of uncertain outcomes, in this case, represented by the uncertain outcome of the ultimate future transformative impact for a group of candidate medical innovation applications areas.Multi-attribute modeling relies on two key pieces of information gathered from a survey process and a utility function to determine the \u201cutility\u201d of each medical innovation in the eyes of scientific expert evaluators with respect to its ability to cause transformative impacts. The information provided by expert survey respondents is comprised attributes or descriptive properties or characteristics of medical innovations that are measured or scored, and weights, or the importance of each attribute to the respondent in determining the transformative potential of a medical innovation. The combination of attribute scores and weights using a utility function produces a measure of the transformative potential of a given medical innovation, which can then be used to comparatively rank medical innovations on a consistent basis to determine the top candidate innovation areas to consider in identifying candidate inventors for award consideration. For this analysis, the utility function used to combine attributes and weights takes the form of a simple weighted average:whereU = the overall utility measure for a particular candidate medical innovationn = the number of attributes used to describe medical innovationsw = the importance weights of different attributesA = the scores for different attributesWhile other utility function forms are possible, this particular form of multi-attribute analysis is commonly used across a variety of technology areas to assess the market potential for products and services.A review of the literature describing the profiles of the past transformative medical innovations was used to outline a set of attributes describing a set of characteristics of transformative medical innovations. Attributes were identified within the context of four broad areas that describe the transformative impact of innovations on applications of medical science and refined with guidance from a scientific expert group composed of Sanford researchers and clinicians to validate their effectiveness in capturing the dimensions of what it means to have transformative effects. The final listing of broad impact areas that contain detailed attributes across which survey respondents were asked to evaluate candidate medical innovations is shown in An accomplished and broad-based panel of scientific leaders was organized by Sanford Health to participate in the multi-attribute survey process and came together as a group to consider the results and to help guide the focus of what emerging medical innovation areas held the highest transformative potential from which to consider candidates. The members of the Sanford Lorraine Cross Scientific Advisory Board are shown in Since transformative medical innovations identified in early signals data do not necessarily yet have a track record of creating impacts, the attribute evaluations relied on the expert judgment of transformative potential through relative scoring rather than measured outcomes criteria. A survey instrument was created and tested to validate this approach using the following process in two sequential steps:Scientific experts were first asked to weight their preferences toward the attributes shown above with respect to their relative importance in determining the transformative potential of any new medical innovation in the marketplace. To accomplish this, a \u201cbudgeting\u201d survey design was used to elicit implied preferences for the importance of certain areas through having respondents assign point values across the entire set of attributes shown above from a limited budget of total points. For this evaluation, a 100-point budget across the 13 attributes was used to determine importance weightings.Scientific experts were then asked to review a refined list of medical innovations identified from the early signals analysis using a Likert scale survey design to elicit measures for how they viewed the potential transformative impact of a given innovation in each attribute area. This took the form of a 0-5 rating system, where a score of 0 represents a predicted outcome of no transformative change relative to the current state of medical science and treatment, a score of 1 indicates a very insignificant transformative impact relative to current conditions in medical science and treatment, and a score of 5 indicates a very significant transformative impact relative to current conditions in medical science and treatment. In the survey, respondents are given the opportunity to include any additional attribute areas they feel are important to transformative impact in the medical space that is not present in the evaluation set provided as well as the opportunity to score the medical innovations along with those attributes.The results from the assessment of the early signal analysis by the Scientific Advisory Committee on which of the emerging medical innovations held the highest potential for transformative impacts set the stage for considering candidates for the Sanford Lorraine Cross Award. In doing so, we now have an award focused on the key issues of our time \u2013 celebrating transformative medical innovations of today and the researchers and clinicians playing a key role in overcoming scientific challenges, forging collaborations and ensuring that the emerging transformative medical innovation crosses the finish line to improving the lives of patients.To address the need for a new type of medical innovation award that celebrates those medical researchers and innovators demonstrating the determination and success in advancing translational research for emerging transformative medical innovations, the Sanford Lorraine Cross Award has developed a unique data-driven methodology that inverts the traditional medical award selection paradigm \u2013 truly innovative areas of discovery and breakthrough science are identified independently of candidates and used to then focus candidate selection on the areas with the most promising transformative potential for patients. This unique approach allows identification of medical innovations on the cusp of achieving breakthrough outcomes for patients and allows the award to target individuals leading those emerging transformative development efforts.For the inaugural award process, a robust set of different medical innovation areas were identified that are actively contributing to cutting edge science across a variety of medical disciplines. The area of emerging transformative medical innovation ultimately selected for the inaugural award from this grouping that had the highest potential for near term breakthroughs was centered around gene therapy applications. Alongside key advancements in the development of modified viral delivery vectors such as tailored adeno-associated viruses, recent activity in this space has addressed issues with the delivery of fragile DNA molecules without degradation or potentially dangerous immune responses.The pioneering innovators identified within this space leading activities that are having clinical impacts today that was considered as finalists for the Lorraine Cross award were as follows:Jean Bennett, M.D., Ph.D., and Katherine A. High, M.D., whose work with the RPE65 mutation has reversed an inherited form of blindness. Bennett and High pioneered gene therapy, took it to clinical trials, and then received FDA-approval for the treatment, the first FDA approval of a gene therapy for a genetic disease. High also cofounded Spark Therapeutics, a fully integrated, commercial gene therapy company working to accelerate the timeline for bringing new gene therapies to market. Bennett is a professor of ophthalmology at the University of Pennsylvania, and high is president and head of research and development at Spark Therapeutics.Brian Kaspar, Ph.D., whose lab discovered a gene replacement therapy approach that seeks to change the course of spinal muscular atrophy (SMA) by addressing its genetic cause. SMA is a devastating disease that robs babies of basic muscle functions, like breathing and swallowing, and in its most severe form (Type 1), usually leads to death by age 2 years. An initial clinical trial using the AAV9 vector to treat SMA Type 1 demonstrated a dramatic survival benefit and rapid improvement in motor milestones. Kaspar is the scientific founder and chief scientific officer of AveXis, a gene therapy company that was acquired by Novartis in 2018.James M. Wilson, M.D., Ph.D., whose work helped define the scientific and ethical standards for advancing gene therapies through FDA-approved clinical trials. He is the director of the Gene Therapy Program, the Rose H. Weiss Professor and Director of the Orphan Disease Center, and a professor of Medicine and Pediatrics in the Perelman School of Medicine at the University of Pennsylvania. In 2008, Wilson and the University of Pennsylvania cofounded REGENXBIO, Inc., a clinical-stage biotech company designing gene therapy products.After intensive consultation, the winner selected by the Sanford International Board of the first Sanford Lorraine Cross Award was Jean Bennett and Katherine High. The inaugural winner and other finalists exemplify the criteria outlined in the vision of the award and help to validate the methodology used to identify areas of innovation activity that is well-positioned within the translational research pipeline to have significant near-term patient impacts.Additional areas of potentially transformative medical innovation identified by the early signals process will be monitored for ongoing developments and can be included alongside an updated set of early signals data at later times to re-evaluate transformative potential relative to future activities. In addition to allowing the most relevant areas and individuals to be selected dynamically as research focuses and the state of medical science changes, this approach helps control for any bias toward certain areas of established science over time within the selection process."}
+{"text": "Joint mSocio-affective components of joint musical engagement have been postulated following empirical investigation of joint music-making and group music-listening  and practical  considerations for using computational techniques in social science research is covered in a review paper by Martinez . ConcernThis article has summarized recent developments in music psychology and related fields that may be applied to detecting emotional contagion in music. We have discussed this research in terms of how it may be incorporated into existing experimental paradigms in scientific studies of music. We hope to encourage further findings regarding the means by which various forms of musical engagement can result in positive prosocial consequences for a broader population.IH conducted literature reviews in order to gather necessary evidence and to generate initial drafts. MBK assisted argument development and expanded source material. Both authors approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The standard treatment for locally advanced rectal cancer (LARC) includes neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision (TME) and adjuvant chemotherapy.P\u2009<\u20090.01). The authors\u2019 proposed radiopathomics strategy and signature escaped the limitation of using only medical imaging to depict the whole tumor and decreased the potential risk of overlooking tumor heterogeneity by adding micro-scale pathologic information.In this study,This study provided evidence that the radiopathomics strategy of combing the images of both radiology and pathology is a potential strategy for predicting the variation in pathologic response before nCRT. More quantitative and multi-scale tumor information powered by the information fusion method was able to improve the heterogeneous description of tumors and enhance the performance of the model for restaging patients. As such, future studies should focus on the integration of gene and protein information to construct a more comprehensive tumor prediction model from the macro radiological information of tumor to the micro pathological information of tumor. The biologic interpretation between radiomic and pathomic features also should be central to future studies."}
+{"text": "Previous literature has analysed the effects of establishment regressors on different measures of restaurant financial performance  Specifications table\u2022This data set can be beneficial to analyze the factors that determine the profitability of corporations in the restaurant industry.\u2022This dataset can be used to conduct different studies on the heterogeneous pattern that profitability of European restaurant corporations presents at country level. These studies would benefit from the creation of company profiles within each country based on financial determinants of profitability.\u2022The data can be useful for business managers and public institutions with an interest in tourism. Understanding the causes of heterogeneity among countries provides useful insights for companies\u00b4 business growth and location strategies.\u2022The analysis is useful when discovering new and innovative sources of strategic competitive advantages.1Data were collected by using a multi-step approach to address their objectives with solvency. The first dataset was obtained through a sample consisting of 860 restaurant corporations selected from the total population of active restaurants in Europe in 2018. A random sampling technique was applied to stratify 18 European countries with a sample error of less than 1%. This dataset includes financial indicators obtained from the corporate financial statements from Amadeus Database by Bureau Van Dijk. The second dataset concerned contextual variables and shows macroeconomic and tourism indicators related to the countries in which the restaurant corporations in the sample are active.The data file spreadsheet accompanying this article consists of 860 rows and 20 columns of data. The first four columns collect the identification code of the company and the country where the company operates. The rest of the columns include financial indicators and contextual variables. In the group of financial indicators, two measures of corporate profitability are considered: Return on equity (ROE) is calculated as profits available to equity shareholders/equity shareholders\u2019 funds of corporate and Return of assets (ROA) is calculated as earnings before interest and tax/total assets. In addition, information is also included on other financial indicators such as Fixed assets ratio  2In general, the transnational analysis of the financial performance of restaurant corporations exhibits a hierarchical data structure, which does not match the statistical properties of a random sample. Specifically, companies from the same country share common economic and tourism environment conditions. Some of these characteristics are included in the dataset. However, other contextual variables may be unobservable and, although the coefficients estimated by standard regression remain consistent, standard errors may be biased The figures above demonstrate that country effects vary randomly but also that significant variance exists in the level of financial performance within and between countries. We can explain the causes of such heterogeneity between countries, adding contextual regressors, which could help to understand the impacts of economic conditions and the tourism environment on corporate profitability. For instance, Therefore, the dataset associated to this paper sheds light on an important issue still inadequately explored in the literature on companies\u2019 financial performance. Although traditionally, stakeholders have managed companies\u2019 financial performance based on their economic and financial indicators, the dataset shows additional indicators related to the country in which a company operates, which allows us to understand the causes of heterogeneity among countries in a context of internationalised companies and globalised markets. Future research using hierarchical linear models could facilitate the creation of company profiles based on both their financial variables and each country's specific economic and tourism environment. Moreover, the data included in this paper is also relevant to guide further research to improve knowledge of the determinants of corporates\u2019 profitability in the restaurant industry.The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper."}
+{"text": "Thymus regenerative therapy implementation is severely obstructed by the limited number and expansion capacity in vitro of tissue-specific thymic epithelial stem cells (TESC). Current solutions are mostly based on growth factors that can drive differentiation of pluripotent stem cells toward tissue-specific TESC. Target-specific small chemical compounds represent an alternative solution that could induce and support the clonal expansion of TESC and reversibly block their differentiation into mature cells. These compounds could be used both in the composition of culture media designed for TESC expansion in vitro, and in drugs development for thymic regeneration in vivo. It should allow reaching the ultimate objective - autologous thymic tissue regeneration in paediatric patients who had their thymus removed in the course of cardiac surgery. Thymus is an essential organ of the immune system since it is the main site of T lymphocyte production and the place of adaptive immunity regulation. The thymus significance for development and function of the immune system is the centre of hot discussions since the 1961, when thymus function was first discovered by Jacques Miller \u20137. AccorCurrent epidemiological data indicate that almost 1 in 100 children is born with a congenital heart defect , and theFoxn1 expression could be used to identify the human TEPC/TESC population(s)  for 2013\u20132017, the Scientific Centre of Excellence for Reproductive and Regenerative Medicine , Terry Fox Foundation and InnovaTRT project that was submitted for funding to the European Union\u2019s Horizon 2020 Programme for 2019\u20132024 . The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed."}
+{"text": "The TeleDementia Clinic is an interdisciplinary longitudinal telehealth dementia clinic providing care to rural Veterans in Western Pennsylvania with cognitive decline. The TeleDementia Caregiver Support group uses telehealth to provide caregiver support and education to those caregivers with the highest levels of caregiver burden in this population. The support group has caregivers participating in the session at different rural clinics while a multidisciplinary team of professional  are located at an urban VA medical center. All can interact via video telehealth connection. Each session provides a short educational session on caregiving topics that then provides a springboard for caregiver discussion about their own experiences. The multidisciplinary clinician team lend their expertise to the education and support of caregivers. Both quantitative and qualitative analysis of effectiveness of this model will be discussed."}
+{"text": "The authors wish to make the following corrections to this paper :In the Materials and Methods Section 2.2.1, part of the method was incorrect and instead ofEscherichia coli. After confirmation of the integration plasmid by restriction analysis and sequencing, purified plasmids were electroporated into the fusobacterial strains used in this study to generate the respective derivatives lacking target genes according to previously described protocols [29]\u201d.\u201cThe plasmid DNA of the recombinants were isolated with the Qiagen Mini prep kit  and the presence of construct was confirmed by restriction digestion and sequencing. The construct was further subcloned in the suicide vector pHS31 as follows: both the fusion construct and pHS31 were digested with EcoRI/BamHI and purified prior to ligation  and transformation into The method should be:\u201cThe plasmid DNA of the recombinants were isolated with the Qiagen Mini prep kit  and the presence of the construct was confirmed by restriction digestion and sequencing. Further, purified plasmids were electroporated into the fusobacterial strains used in this study to generate the respective derivatives lacking target genes according to previously described protocols  [29]\u201d.The authors would like to apologize for any inconvenience caused to the readers by these changes."}
+{"text": "The fastest growth of population living with cognitive impairment takes place in China. The estimated prevalence of cognitive impairment among older adults in China is between 13% and 20%. This study focused on persons with cognitive impairment (PWCI) and their spousal care partners to explore how spousal relationships impact dyadic experiences of living with cognitive impairment through a person-centered care lens. We conducted a longitudinal qualitative study of 10 dyads of PWCI and their care partners over three years with three data collection time points. Our findings suggest that the complexity of changing experience of living with cognitive impairment is interpreted in the dynamic nature of their spousal relationship and relationship with others, patterns of communication, daily activities and care during the extended period of cognitive decline. It is crucial to help them nurture the belief that there is a significant meaning in the journey of living with cognitive impairment."}
+{"text": "NIHR GOSH BRC. The corrected Funding Statement appears below.In the original article, we neglected to include the funder This work was supported by an Action Medical Research project grant (SN4051). Financial support for LH was provided through the regional agreement on medical training and clinical research (ALF) between Stockholm City Council and Karolinska Institute. TB was supported by the NIHR GOSH BRC.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "This presentation will focus on two projects that aim to inform and educate communities through community based intergenerational programs. An additional link is collaborating with community partner staff on the potential to improve health outcomes with the integration of generations in programming. Through inter-professional collaborations, these projects focus on two areas: reducing social isolation and loneliness among rural older adults through an intergenerational technology program with university students and modifying the implementation of an evidence-based preschool nutrition program for an intergenerational setting. This presentation will focus on the benefits of using community based intergenerational programs and experiential learning opportunities. Aims of this presentation are to highlight how issues related to social isolation and loneliness can be mitigated by incorporating experiential opportunities for university students while simultaneously supporting university students\u2019 preparation for engaging in an intergenerational workforce."}
+{"text": "The aim of this Special Issue on the deregulation of cell death in cancer is to bring together recent perspectives on the relationship between tumorigenesis and programmed cell death (PCD). According to the World Health Organization, cancer is the second leading cause of death worldwide, and in 2018 it was responsible for an estimated 9.6 million deaths. The human genome is exposed to mutations during the course of life, and while many have no impact on individual health, others (heritable or acquired) are responsible for carcinogenesis. It is becoming ever clearer that defects in intracellular signaling pathways lead to altered gene functions and malignant cellular transformation . The altThe reactivation of altered or silenced cell death pathways may improve outcomes in cancer. The development of new drugs able to modulate specific molecular targets involved in cell death mechanisms may provide more efficient therapeutic strategies for cancer treatment."}
+{"text": "Dear Editor, We would like to congratulate the authors for documenting this interesting phenomenon.We are writing to share our observations regarding the article \u201cMultiple pit defects of unknown etiology in a foldable hydrophobic intraocular lens\u201d by Thabit et al. Factors such as ocular inflammation and systemic comorbidities that affect ocular metabolism may contribute to the opacification of IOLs. Surgical interventions with the injection of different materials into the anterior chamber such as air or gas seem to increase the risk of IOL opacification, particularly in hydrophilic IOLs. The pits are limited to a more or less circular area of the anterior optical surface of the IOL corresponding to the zone of contact with the instilled air or gas.The authors mentioned no obvious reason for the formation of pit-like deposits on the anterior surface of the intraocular lens (IOL). We want to disagree with this statement in that IOL pit formation is a well-established phenomenon where opacification of hydrophilic acrylic IOLs occurs after corneal transplantations such as penetrating keratoplasty and Descemet's stripping endothelial keratoplasty (DSEK). It is our observation that opacification of hydrophilic IOLs develop in eyes that undergo DSEK and receive an air tamponade intraoperatively [Figures 1 and 2].Prolonged breakdown of the blood-aqueous barrier has been suggested as a contributory factor in IOL pit formation. The air in the anterior chamber causes dehydration of the anterior surface of the hydrophilic IOLs, and postoperative inflammation induces a metabolic change in the anterior chamber leading to an increase in aqueous proteins and calcium content that causes subsequent crystallization of the lens."}
+{"text": "The main objective of this article was to present some of the engineering noise control methods that are currently being used across the world in the mining industry, while at the same time interrogating noise control measures that could be applied to effectively reduce noise emissions from the equipment utilised within South African mines.A brief summary of the hearing conservation programmes used in South Africa is presented. Summarised research on the use of engineering noise control in South Africa is also presented, with an overview of the various engineering noise control methods applied across the world in dealing with occupational noise.For illustrative purposes, case studies were used to show how engineering noise controls could be used to reduce the noise levels and risks within this context.Some of the case studies used have cited a reduction in the noise intensity emitted by machinery from a range of 93 dBA \u2013 104 dBA to a range of 90 dBA \u2013 94 dBA, demonstrating quite a significant reduction in the noise emission of the equipment. This article further provides recommendations on how South African mines could contextualise these methods.One of the key recommendations is encouraging the South African mining industry towards the documenting and publishing of those engineering noise control methodologies that have proven to be effective for shared best practice. A need was identified for extensive research to be conducted and documented evidence to be made available to assist the South African mining industry with locating and assessing current engineering controls available in South Africa. Machines and processes that require noise control should be identified and, lastly, the current barriers to the use of engineering noise control methodologies should be identified, with the main goals of finding ways to overcome the noise challenges in the mines. Noise may be defined as an undesirable sound lacking musical quality  pillarsOverview of engineering noise control methodsSummarised research on the use of engineering noise control in South AfricaFor illustrative purposes, Case studies of engineering noise control methods currently being used across the world are used to show how engineering noise controls can be used to reduce noise levels in this context.Recommendations on how South African mines can contextualize the noise control methods used by the rest of the world.The engineering noise control methods can be divided into: Control of noise at source, control of noise propagation and receiver control as shown in Gumede, Blomerus, Coutts and De Beer  conducteSensogut  documentCase studies show how engineering noise controls can be used to reduce noise levels in this context. Nikola, Aleksandar, Dinko, Vladimir and Uros  proposedThe research by Sensogut , using aThe Peterson  proposedPeterson, Miller and Yantek (2014), working with the National Institute for Occupational Safety and Health (NIOSH), visited a collaborating mine and investigated a haul truck underground in a shop area using Source Path Contribution (SPC) techniques for Noise Source Identification (NSID) . Further studies were conducted in 2018, using dosimetry and time motion to determine when an operator accumulates the most noise dose (Peterson, Engineering noise controls that have been discussed may be implemented in the South African mines, for example, by enclosing noisy places, using correct sound barriers and using curtains and retrofitted noise control packages. There is limited published evidence from the South African mines that document how engineering noise controls have contributed towards a reduction in noise emission from equipment. Mining companies and research centres in South Africa should consider partnering with NIOSH because of their extensive documented research work on ONIHL in the mines, to extend and contextualise their research to South African mines. The South African mines should thereafter consider conducting research and the documented evidence should be made available to assist with locating and assessing current engineering controls in South African mines. This research work should also include identification of machines and processes that require noise control. Current barriers to the use of noise control should be identified with the main goals of finding ways to mitigate them.This article is not a systematic review paper; hence, not all engineering noise control methods currently have been applied. The engineering noise control method as a technique to mitigating noise in the mines has been presented. Case studies from around the world and how they can be contextualised to the South African mining industry have also been presented. A follow-up to this work would include the documentation of a strategic plan that would encourage the mining industry to publish the noise control interventions that have currently worked for them."}
+{"text": "Phytophthora cactorum) was duplicated in Phytophthora cambivora) and two representative images for cucumber damping-off symptom were overlapped in In the original article, there were mistakes in The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "Following publication of the original article , the autPlease be advised that the Acknowledgements are as follows:\u201cWe would like to thank Jacob Kroeker, Katie McKearney, Arthur MacDonald and funding support from the Atlantic Canada Opportunities Agency (Atlantic Innovation Fund) for the development of the working memory training protocol. RH is supported by a Guangzhou Planned Project of Science and Technology grant (2016201604030018).\u201dThe original article has now been corrected to include this declaration.The publisher apologizes for any inconvenience caused."}
+{"text": "Behavioral health and substance use disorders are significant problems among older adults who are experiencing homelessness. This presentation describes the components of a social work field education model for preparing practitioners to work effectively in community-based agencies using the Hartford Practicum Partnership in Aging Educational (HPPAE) model. A planned and systematic transition from one field setting to another with the goal of giving students a range of practice experiences with various service delivery systems to address social isolation and other social determinants of health. This exploration of demographic and social action factors that may impede or foster success among community-dwelling older adults offer insight and guidance for constructing a conceptual and theoretical model a social justice framework in geriatric social work practice and research."}
+{"text": "The authors report on results of a randomized prospective trial in comparable groups of patients with intrarenal stones treated by flexible ureteroscopy and laser lithotripsy   . PatienThey find no significant difference in OR times, hospital stay, postoperative pain, fluoroscopy times or stone free rates defined as 2mm or smaller fragments on non contrast CT one month post treatment.The sentinel finding in this study was an increased complication rate in the regional anesthesia group comprising patients with either bradycardia, mucosal tear or hemorrhage. They attribute the mucosal injuries and bleeding to a lack of good control of laser energy secondary to respiratory excursion of the kidney in patients under regional anesthesia. Moreover \u201csurgeon comfort\u201d which was subjectively measured during the procedure was also significantly less in procedures performed under regional anesthesia.While the numbers are small these results are interesting and emphasize the point that intrarenal surgery with a flexible ureteroscope and laser is an operation of millimeters. Both as regards the stone fragmentation and in avoiding tissue injury. Stones in the mid to distal ureter are relatively unaffected by significant respiratory excursion while those in the kidney can be subject to substantive movement especially in the awake patient. It would have been desirable to have more information on the detailed questions in the surgeon comfort questionnaire and whether this is a validated tool. Nonetheless this study does inform us of some of the pros and cons of differing anesthesia methods for retrograde intrarenal surgery and thus discussions with patients and our anesthesia colleagues."}
+{"text": "Through the theoretical framework of the Social Comparison Theory, the current study will examine general attitudes and perceptions of body image in senior adults who are currently participating in organized recreational activities. Participants between the ages of 50 years of age and older participating in organized recreational programs in the Southeast will be administered the Sociocultural Attitudes Toward Appearance Scale (SATAQ) to measure participants\u2019 body image as influenced by general media, athletic and sport figures, as well as pressure to conform to the media ideal. The Figure Rating Scale will be administered, and is composed of nine drawings of bodies that progressively increase in size from very thin to overweight. Pearson product moment coefficient of correlation will be used to determine the association of scores between the SATAQ and Figure Rating Scale."}
+{"text": "Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a disease first reported inSaudi Arabia in 2012 and it can be transmitted from human to human. This disease hasspread to several other countries, most confirmed cases have displayed symptoms of severeacute respiratory illness and many of these patients have died. This research is aimed toconstruct a mathematical model for the transmission of MERS-CoV in two areas by separatingthe human population into two groups; susceptible and infectious groups. The dynamics ofthe disease is studied by a compartmental model involving ordinary differrentialequations. The basic reproductive number of this disease is discussed to control theoutbreak of this disease. Sensitivity analysis of this model is performed to determine therelative importance of the model parameters to the MERS-CoV transmission."}
+{"text": "Economic inequality has grown rapidly in all age groups in the past several decades. In each successive cohort, the wealth gap grows for young people and seems to accelerate faster over the life course. While rising inequality has taken its toll on Baby Boomers, we have become acutely aware of the increasing economic pressures across the entire life course  that will manifest in the greatest degree of inequality in older adulthood seen to date. This session explores the forces that have shaped the degree of inequality among current older adults and are setting the stage for future cohorts of older adults. Presenters will explore several aspects of this issue: the growing state of the \u201crisk retirement,\u201d the impact of income inequality on later-life wealth and health, the structural racism written into economic policies intended to help Americans accumulate wealth and maintain health, and the market disadvantage for GED recipients compared to high school diploma recipients."}
+{"text": "GSA's Public Policy Advisor will lead a discussion of legislative activities related to elder abuse, neglect, and exploitation during the past year. The panel will examine successes and failures and what may still be possible in the lame duck session and the next Congress."}
+{"text": "Fear extinction learning is considered a key process for a successful treatment of anxiety disorders and the post-traumatic stress disorder (PTSD) A recent review The scientific literature has also shown that in the context of reward and aversion processing both chemical messengers work in antagonistic way Worthy of mention is also the necessity to clarify whether the role played by dopaminergic and serotoninergic systems in fear extinction learning is inexorably interdependent, or it is possible to identify a degree of autonomy in each system with regard to the process of fear extinction learning. A closer look at the process of fear extinction could add some timely insights in this regard.When speaking about fear extinction it is important to distinguish between learning and consolidation In conclusion, the current research leaves open the hypothesis that the effect of dopaminergic system on learning of fear extinction memories could reflects, at least in part, some interaction with serotonergic system. Therefore, both monoamine should be simultaneously considered when speaking about fear extinction. This is supported also at the neural level, as the serotonergic system of the dorsal raphe nucleus"}
+{"text": "The 2019 Minnesota Legislature requested the Department of Human Services (DHS) and Minnesota Board on Aging to develop and administer a report card for assisted living (AL), including conducting annual resident and family surveys in Minnesota AL settings. This presentation includes the perspectives of representatives from MN DHS and Vital Research, as well as the University of Minnesota team who worked together to develop survey items, carry out the cognitive testing, and conduct analyses. Survey items were developed from published literature and existing tools on assisted living quality and underwent testing with MN stakeholders and cognitive testing with MN AL residents. Pilot testing assessed any further changes that needed to take place for resident and family satisfaction with AL quality (n=400). Presenters will share lessons learned with implementing the new tools and different aspects of the of the report card development and implementation process as well as the survey findings."}
+{"text": "The study of gerontology across different generational cohorts is not static but rather dynamic. As we consider teaching gerontology to different age cohorts, what similarities and differences do exist? How do the educational needs within higher education differ across the different cohorts of the workforce? This presentation aims to identify and present specific learning needs and styles of the millennial cohort, as compared to other generational cohorts with the effort of building educational strategies for this workforce cohort. The presentation will also address the unique needs that a rural workforce faces and how to address these within the millennial cohort. Strategies such as online learning, flip classroom, experiential strategies and research projects/practicum will be addressed with a specific focus on the engagement of the millennial student. These strategies are all described within the context of teaching gerontology through a specific Certificate in Gerontology program located on a rural campus setting, but meeting the educational needs of people across the country."}
+{"text": "Increased survivorship and longevity have resulted in dramatic improvements in life quality for people with significant disabilities and impairments. However, the fields of rehabilitation and gerontology have tended to divide this phenomenon into people aged under 65 aging with lifelong and early onset disabilities, and those aged 65 plus who are aging into late onset disability. But for both groups, increased survivorship also translates into more years living with comorbidities associated with the underlying condition and increased risk for premature onset and higher rates of age-related chronic conditions. Despite these widely acknowledged trends, we have no national data systems that estimate the overall prevalence of the \u2018aging with long-term disability\u2019 population and monitor its status. Acknowledged is that the lack of national data and reliance on chronological age undermines our knowledge of the disablement experience across the life course and the needs for services and supports associated with diverse trajectories. Part of a symposium sponsored by the Lifelong Disabilities Interest Group."}
+{"text": "Loneliness is a risk factor for poor quality of life among older adults. Social media use provides a new dimension of communication for older adults to connect with people and to maintain social relationships. However, research has been inconclusive about whether social media use reduces loneliness among older adults, which is due in part to a lack of appropriate measures for capturing different types of social media use. Furthermore, little is known about the underlying mechanisms through which social media use is associated with loneliness. This study investigates the association between social media communication with close social ties and loneliness among community-dwelling older adults (65+), and further examines the mediating role of social contact and social support in the association. Data from the 2014 wave of the Health and Retirement Study (HRS) are analyzed to address our research questions . Path analyses are employed to examine the relationships among social media communication with close social ties , frequency of contact with social ties , perceived social support from social ties, and loneliness . The results show that a higher level of social media communication is associated with lower levels of loneliness through social contact and perceived social support. Moreover, the relationship between social media communication and perceived social support is partially mediated by social contact. These findings suggest that social media communication may be considered an intervention that may reduce loneliness among older people."}
+{"text": "Dear Editor,JournalRacial disparity in prevalence and incidence of atrial fibrillation (AF) are known to exist While the reported increase in AF prevalence in Thailand is in concordance with the previous projection in Asian countries Notwithstanding, epidemiological data of AF in Asian Pacific region is scare, high quality data similar to that from Suwanwela and colleagues is urgently needed to inform policymakers and clinicians in the allocation of limited health care resources.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."}
+{"text": "While the use of photographs is an emerging data generation method within phenomenology , research that incorporates photo elicitation to inform the understanding of the lived experience is limited. This presentation will describe the use of photo elicitation within a phenomenological approach to explore the lived experience of older learners in higher education. After an initial interview, six participants aged 50 years and older shared photographs that that they chose to depict experiences of being student at a regional comprehensive university in the Midwest. Photographs served as mode for participant reflection of their experiences and guided a second interview. Interpretative Phenomenological Analysis  with photographs and verbatim transcripts ensued and resulting findings included: complicated sense of belonging and community development and access. Implications for use and analysis of photographs within qualitative research will be discussed."}
+{"text": "Globally, people are living longer with the Human Immunodeficiency Virus (HIV) and older individuals are becoming infected. Menopause symptoms affect women\u2019s health and are associated with perceived declines in wellbeing. This study assessed and compared the menopause symptom experience and perceived wellbeing among HIV positive and negative older women in Ibadan Nigeria Focus group discussions were conducted among menopausal women attending the ARV and GOP clinics at the University College Hospital Ibadan. Opinions of discussants on knowledge and experience of menopausal symptoms, perceptions about the menopause and perceived health status were explored. A total of 90 HIV positive and 92 HIV negative women aged between 40 to 60 years were sampled. Knowledge of the cause of menopause was poor, with more HIV positive women opining that sexual promiscuity causes menopause. The majority of the discussants had adequate knowledge of menopausal symptoms with most of them reporting vasomotor and musculoskeletal symptoms. In both groups, perceptions about the menopause were generally positive as most of them opined that the menopause means freedom from sexual activity and child birth. More HIV negative women perceived themselves to be in good health compared to HIV positive women. Menopause induces many of the same metabolic changes that are being observed with HIV infection, and this may affect the health and quality of life of aging women with HIV infection. There\u2019s a need for health education and health promoting interventions that will help these women in coping with the double burden of HIV infection and menopause."}
+{"text": "The demographic bulge created by the baby boom generation has shaped American politics since they came of age in the 1960s. Over the next decade, aging issues will become more relevant as the oldest boomers reach 84 and the youngest boomers will be eligible for Medicare. This paper highlights three converging trends that will shape United States politics; including increased spending on \u201centitlement\u201d programs like Social Security and Medicare, growing mismatch in caregiving need and supply, and the heightened concentration of older adults in certain geographic areas. The next decade will see not only extraordinary demographic change but also unprecedented advances in technology and medicine, and cultural and societal shifts that were once unimaginable."}
+{"text": "Studies examining communication during clinical handovers involving paramedics are rare. A recent National Institute of Health Research (NIHR) report has noted a significant gap in our knowledge and understanding of what happens during clinical handovers between ambulance services and emergency departments. This PhD study has used a video analysis to understand issues in communication and teamwork during these clinical handovers by examining cases of good practice.24 Hours in A&E and The Real A&E, was conducted. This methodology emphasised the capturing of real-world practice, without the limitation of semi-structured interviews which are reliant on recall of events. These examples highlighted how interprofessional teamworking and communication were conducted during these high pressured and complex situations. The videos were transcribed verbatim and idiosyncratically to show variances in the style of communication as well as the non-verbal actions used by the staff during the exchange of patient information.A video analysis of 100 examples of handovers from different TV programmes, including The emergent findings demonstrate a variety of interactional strategies that paramedics use when conducting handovers. These strategies often involved a paramedic team member drawing attention to themselves by stating they were ready to do the handover or loudly introducing the patient\u2019s name. This was typically followed by an account of the treatment the paramedic team provided and ended with questions from those receiving the handover. The questions asked by the receiving team would be about the treatment provided and during this exchange the paramedic team would justify the methods used in assisting the patient. When handovers were being taken for high-risk patients, for example \u2018haemorrhaging of a femoral artery\u2019, the structure of the handover changed. In such examples, the paramedic team were found to dictate how the receiving team handled continuation of treatment for the patient.The variations in handover examples that have been captured and analysed have been beneficial in understanding the interactions between paramedics and the emergency care team. Initial findings have shown how the structure of communication during handovers can be altered due to situational or contextual factors. These results have highlighted where potential improvements in communication can be made during handovers, which would subsequently increase patient safety and experience."}
+{"text": "Journal of Cachexia Sarcopenia and Muscle, we read with great interest the article by Veltkamp et al. \u201cExperimental ischaemic stroke induces transient cardiac atrophy\u201dIn the recent issue of the In the present study, the authors investigated cardiac function in mice with experimentally induced acute cerebral ischaemia by middle cerebral artery occlusion (MCAO). Animal models have been well\u2010established to study pathophysiology of wide range of medical conditions including ischaemic stroke, cancer, cachexia and heart failure.The authors declare that they have no conflict of interests and certify that they comply with the ethical guidelines for authorship and publishing in the Journal of Cachexia, Sarcopenia and Muscle."}
+{"text": "Of the many changes to the OAA, the Modernizing Allotments for Vulnerable Elder Rights Protection Activities and Other Programs section included notable changes. This bill specifies that Title VII programs will receive a 7% increase in 2020 and a 6% increase in the following four fiscal years. It extends the Supporting Grandparents Raising Grandchildren Act for an additional year. The reauthorization ensures that ombudsman representatives can be reimbursed for costs incurred through their services. The Act requires that the Government Accountability Office study federal programs for home modification assistance for older adults and individuals with disabilities. The Act directs the Administrator of the Administration for Community Living to continue the 2017 requirement of disseminating and soliciting feedback on the Principles for Person-directed Services and Supports during Serious Illness. This reauthorization updates home and community-based best practices; and elder justice activities, including community outreach and education to bolster community partnerships."}
+{"text": "In the appropriate clinical context, bland urine sediment with little cellular activity and primarily hyaline or few finely granular casts suggests AKI is due to a functional decline in GFR from renal hypoperfusionThe utility of a urine sediment score based on RTECs and granular casts was demonstrated in 231 patients with hospital-acquired AKI from either prerenal azotemia or ATI--Urine microscopy can also predict important clinical end points. In the studies described in In this issue of the Brazilian Journal of Nephrology, Goldani and colleagues examine the utility of urine microscopy (urine sediment score based on RTE cells and granular casts) in identifying AKI in patients undergoing cardiac surgeryOne of the major negatives of this study is the low sensitivity of urine microscopy in identifying AKI, a finding noted in other studies. It is likely that a number of AKI patients in this study had prerenal azotemia as the majority of AKI was stage I, which recovered back to baseline in 24 hours. One would expect the urine sediment in these patients to be bland. Identifying these patients and separating those from patients with higher stage or persistent AKI (>48 hours) would have likely improved the sensitivity of the test, but may have reduced specificity.In summary, the authors are to be applauded for performing this study and adding to the literature supporting the continued use of rigorous examination of the spun urine sediment in the evaluation of patient with or at risk for AKI."}
+{"text": "This international symposium brings together leading occupational therapy researchers from around the world with a shared focus is on evaluating and improving the driving performance of older adults to decrease their crash risk and facilitate their community participation. In this session, five groups of international scholars will share their collective and individual research outcomes for driving as a means of community mobility. The first presentation will outline their collective international, cross-sectional study of 247 older adults from seven countries where the impact of driving on out-of-home mobility was compared. Each presentation that follows will then present results from innovative studies of ways in which to assess and address fitness to drive in older adulthood. Our discussant will summarize the potential expansion of the current work and engage the audience through interactive questions. Transportation and Aging Interest Group Sponsored Symposium."}
+{"text": "Children with intellectual disability are susceptible to poor experiences of care and treatment outcomes, and this may compound existing health inequities. Evidence to date indicates three priority areas that must be addressed in order to reduce these inequities in the safety and quality of care for children with intellectual disability. Firstly, we need reliable methods to identify children with intellectual disability so that healthcare organizations understand their needs. Secondly, we need to develop quality metrics that can assess care quality and unwarranted care variation for children with intellectual disability in hospital. Finally, for a comprehensive understanding of the safety and quality of care for these children, and how to improve, it is critical that healthcare organizations partner with parents/carers and enable children with intellectual disability to voice their experiences of care. Children with intellectual disability have higher healthcare utilization than their peers; yet, their voice is rarely sought to optimize the safety and quality of their healthcare experience. Patient experience narratives enhance our understanding of the genesis of adverse events. By addressing these priorities, children with intellectual disability will be identified, and health services will measure and understand the problematic and beneficial variations in care delivery and can then effectively partner with children and their parents/carers to address the inequities in care quality and create safer healthcare. Children with intellectual disability are susceptible to poorer quality of care than their peers when they are admitted to hospital, and this may compound existing health inequities for this group. To address this, we must identify these children when they access tertiary healthcare, meaningfully measure their quality of care and enable the patient voice to help optimize their healthcare experience.ICD\u201010 codes are not reliable for identifying children with intellectual disability when they are admitted to hospital; reliable identification of children with intellectual disability is the first step in understanding where and how clinical variation occurs.Understanding of the patient and system factors underlying unwarranted clinical variation for children with intellectual disability can enable healthcare organizations to adapt care delivery to ensure high\u2010quality services to meet the needs of the child with intellectual disability.Partnering with these children and their carers to hear their experiences of care will enable healthcare organizations to call attention to and emulate examples of good care quality experiences for these children.1People with intellectual disability have higher rates of health care utilization   with intellectual disability:\u2018Furthermore, the CYP PREMs are not suitable for CYP with moderate or severe learning disability, and further work is required to develop a PREM that is appropriate for their use in terms of both engaging them and eliciting their views.\u2019  Translational Research Fellowship Scheme [2019\u20132021] awarded to LM."}
+{"text": "There is a growing emphasis on diversity and its impact on health care. Our research has focused on migrants who are Mandarin speaking Chinese and Puerto Rican. Through a series of focus groups conducted in their native languages we discovered that barriers to service access differ across the two groups. In addition, many of these services are administered by individual states rather than the federal government. The diversity across migrant groups and state policies creates a challenge in using findings to establish national or international standards for best practices with older migrants. How then can we apply lessons about diversity and the impact of programs on a national and international scale? We propose the use of Social Interaction Modeling as a method for understanding patterns of behavior at both national and international levels, while preserving the unique character of each migrant group and the context within which they live."}
+{"text": "This multi-authored book is the real stimulus for interest in primary care and research. It starts with compelling discussions highlighting the merits and gaps to be addressed only via primary care research. It convinces one of the importance of contextually appropriate evidence for primary care. It further highlights epistemological position that may be unique for this setting, which may allow different methodologies that could have otherwise been applied individually in a different setting to be used to enrich findings.The Matrix cleverly sheds light on different lenses  that researchers can take whilst tackling primary care issues through research. The story also compels one to think harder not to disregard these positions before embarking on primary care research. This is the clever way of capturing graphically the readers into these concepts and I find them difficult to forget.The thoughtful weaving of the storyline in the film The book also dispels wrong assumptions and puts into perspective terminologies that are otherwise used loosely in research. The clear example of this is in chapters 4 and 5 where interdisciplinary approach is differentiated from mixed-methods approach. The examples used in these chapters are compelling and successfully drive the idea of interdisciplinary research home.The book is reader-friendly and practical whilst ensuring important themes of research in primary care are thoroughly explained. Multiple author nature allows the readers to see primary care research from different primary care contextual positions, even so through examples provided to discuss each subject. Although research terminology is used throughout the book, the key is application in the complexity of primary care setting.Another important subject described in this book is quality improvement in primary care, how it contrasts with traditional research and important gaps to be addressed through development of this field. This is an important area for African primary care practitioners whose systems are bugged with challenges requiring leadership in the area of clinical governance.It is also the strength of this book that the chapters are precise and not lengthy to guide individuals through important steps in primary care research. The resource boxes in each chapter are also very useful for individuals who want to learn deeper into certain aspects of their research that needs further reading.I find this book useful, practical and user-friendly. I recommend it as a resource for individuals who are starting their journey in research, especially young primary care researchers, residents and teachers of family medicine."}
+{"text": "In the Author Contributions, Catherine Longo should be listed as one of the persons who contributed to Conceptualization and Funding acquisition.The following information is missing from the Funding statement: CL received financial support from the Walton Family Foundation."}
+{"text": "This data article presents on the ectoparasites infestation on small mammals in Peninsular Malaysia. The dataset on ectoparasites infestation is important because it raises a major medical concern regarding the spread of potentially zoonotic disease from wildlife to human. Tick and chigger are the primary ectoparasites as reservoirs of vector-borne diseases found on small mammals in Malaysia. These small mammals that are infested with ectoparasites occupy various types of habitats, including human settlements, could be of community health risks as the carriers of potentially zoonotic diseases. Field samplings were conducted from February 2015 to February 2016 in three different ecological habitats of mixed dipterocarp forest, coastal forest and insular forest, in Terengganu, Malaysia. A total of 35 and 22 species of bats and rodents respectively were captured and examined for ectoparasites. Twenty-three species of bats and 16 species of small mammal were recorded as hosts for at least one species of ectoparasites. These findings show that the highest ectoparasite infestation occurred on bat community. Specification Table\u2022The data is useful in providing the information regarding the ectoparasite species composition and the relationship among the ectoparasites with their small mammal hosts.\u2022The data is valuable for further research to determine whether there are any spatial and temporal changes in ectoparasites composition due to ecological disturbances or climate change.\u2022The data on the occurrence of the ectoparasite-vector are useful in epidemiology study to predict the potential of presence of the zoonotic disease in the studied area.\u2022The data also provide information on the interaction of ectoparasites and small mammal hosts in term of the degree of the specificity and distribution of each ectoparasites species.\u2022The data is vital for the community health and wildlife authorities to monitor the host populations near rural villages and forest edges that maybe the cause of zoonotic diseases spillover.1Systematic field samplings were conducted in three different habitats that are mixed dipterocarp forest, coastal forest and insular forest of Terengganu from February 2015 to February 2016. 2Field samplings on small mammals were conducted in three different habitats in Terengganu including the mixed dipterocarp forest, coastal forest and insular forest off coast islands from February 2015 until February 2016. The description of these habitats has been described by A fine tooth-comb was used to remove all the ectoparasite that attached on the host animal coat. Ectoparasite dropped during combing were collected by using the wet sharpen applicator stick and preserved in the collecting vials containing 70 % ethanol separately for each host small mammals. The vials were labelled with sufficient information and brought back to the laboratory for species identification. The ectoparasites were prepared for mounting on slide and identified according to their taxonomic groups which are mesotigmatid mite ,10, chig"}
+{"text": "A specific feature in the Finnish pension system is rule-based preparation for mortality change. The earned pension capital is adjusted to life expectancy and the lowest age limit of the flexible retirement age will be adapted so that the ratio of expected years in employment and retirement is fixed after year 2030."}
+{"text": "Increases in the numbers of older adults with mental health and substance use concerns compel us to identify best practices in training to address these issues. Senior Centers are an ideal location for behavioral health education programs as they are the go-to place for many older adults. This session will describe a program funded by The Retirement Research Foundation and offered in collaboration with Center for Aging and Disability Education and Research at Boston University and NCOA to increase senior center staff knowledge and skills. Approximately 250 senior center staff in Illinois, Florida, and Wisconsin completed an online certificate in Behavioral Health and Aging. Results show that 100% of respondents felt that the training was useful for their job; 93% felt that they will be a more effective worker as a result of the training; and 97% felt that the information they learned in the training will make a difference with the people they serve. We held key informant interviews to assess the impact of training and participants stated that their knowledge, skills, and behaviors were influenced by the program. At the organizational level, leaders reported new programming related to behavioral health and revised practices and protocols. This presentation will cover: (1) the extent to which training participants mastered the competencies needed for effective practice; (2) knowledge and skills gained from the training program; (3) Senior Centers\u2019 capacity to identify and refer older adults to mental health services; and (4) organizational changes related to behavioral health programming with older adults."}
+{"text": "Biological membranes consist of lipid bilayer matrices enriched with integral membrane proteins and membrane-associated proteins. They not only define cells and cell organelles but also represent the main contact area for intercellular communication, for which membrane transport and signaling are indispensable. Because of their high physiological importance and unique physical and chemical properties, biological membranes have been intensively studied for over 100 years, and membrane physiology remains a flourishing and lively research field. Recent years have witnessed great progress in our understanding of the biophysical basis of membrane transport and its role in generating biological electricity and controlling the intracellular milieu. The workings of ion channels and transporters are understood in a degree of detail that was unimaginable when many of us started our scientific careers. Protein sequences and three-dimensional structures are now available for almost every major ion channel and transporter family  allow us to define protein ecosystems  for each membrane channel/transporter. Advanced cell culture methodologies also allow us to observe ion transport in intracellular organelles, and techniques are available to study signaling in almost every living cell or organ. Moreover, animal models permit studying the impact of changes in transport protein function or expression on cells and organs, and on the coordinated functions of an intact body.Frontiers in Physiology \u2013 Membrane Physiology and Membrane Biophysics will assist in these development by provide a platform for reporting and discussing novel results  with the ultimate aim of correcting membrane transport and organ function and developing hybrid devices that utilize membrane transport protein to link living cells with technical devices.The collaboration between scientists using different approaches and experimental systems will lead to a comprehensive and quantitative description of membrane function at the molecular, cellular, and systemic level in both health and disease in the near future. The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Dear Editor,Colonoscopy is a technically difficult procedure due to mobility and tortuous anatomy of the colon. It becomes more challenging in women because of deeper transverse colon and a broad pelvis. This challenge further deepens in patients with prior history of a hysterectomy because of multiple adhesions formation leading to acute angulation of sigmoid colon as well as the bowel dipping deeper into the pelvis.2The rate of moderate or severe discomfort varies significantly between women who had undergone a hysterectomy and those who had not. Mild discomfort was noticed in women without a hysterectomy and moderate to severe discomfort was noticed in women with a hysterectomy.3A meta-analysis by Clancy et al highlighted that colonoscopy completion rate appeared to be decreased in women with a history of hysterectomy in comparison to women without it.However, despite these maneuvers if endoscopists still find difficulty in negotiating the scope further in lumen together with increased patient discomfort, the procedure should be abandoned and the patient must get referred to a more experienced colonoscopist at a high volume center. Pre-procedure counselling with the patient explaining the above points is imperative.LK: Conceived the idea and did final editing and review of manuscript and approval.NB: Review of literature and revision of manuscriptHK: Writing of first draft of manuscript and review of literature"}
+{"text": "To examine how health system design and delivery can fail to support the needs of LGBT+ older adults.LGBT+ older adults face barriers in access to care, impacting their ability to receive person\u2010centred care in old age, which is central to the prevention and management of frailty, disability and disease.Using a conceptual framework of access to care, this commentary illustrates issues LGBT+ older adults may face in accessing health and social care services in Ireland, and provides examples of how access may be improved from the published international literature.Health policies, service design and delivery all impact on the ability of the health system to meet the needs of LGBT+ older adults across all levels and types of care.Heteronormativity and discrimination must be addressed across the whole health system to achieve the health policy goal of supporting all older adults to enjoy health and well\u2010being.We suggest nursing professionals use a systems perspective to address the multilevel issues relating to care for LGBT+ older adults. Researchers in gerontological nursing should include the experiences and outcomes of service utilization for LGBT+ older adults in their research agenda. For some LGBT+ older adults, prior experiences of discrimination or stigma within health services mean they may not view these services as inclusive spaces where they will be respected, and where their needs will be met  and types of care . We conclude that addressing heteronormativity and discrimination is needed across the whole system of care, to achieve the policy goal of supporting 7Nursing professionals are well placed to address these issues given their scope of practice across the whole system of care, their involvement in policy making and commitment to delivering culturally competent care. We suggest nursing management who are charged with mentoring, training staff and service improvement recognize the importance of taking a systems perspective to improve access and care services for LGBT+ older adults. Researchers in gerontological nursing should add the experiences of service utilization for LGBT+ older adults service users to their research agenda.This commentary is based on existing published literature and did not require ethical approval."}
+{"text": "As population aging is accelerating rapidly, there is growing concern on how to best provide patient-centered care for the most vulnerable. Establishing a predictable and affordable cost structure for healthcare services is key to improving quality, accessibility, and affordability. One such effort is the \u201cfrailty\u201d adjustment model implemented by the Centers for Medicare & Medicaid Services (CMS) that adjusts payments to a Medicare managed care organization based on functional impairment of its beneficiaries. Earlier studies demonstrated added value of this frailty adjuster for prediction of Medicare expenditures independent of the diagnosis-based risk adjustment. However, we hypothesize that further improvement is possible by implementing more rigorous frailty assessment rather than relying on self-report of ADL difficulties as used for the frailty adjuster. This is supported by the consensus and clinical observations that neither multimorbidity nor disability alone is sufficient for frailty identification. This symposium consists of four talks that leverage data from three CMS-linked cohort studies to investigate the utility of assessment of the frailty phenotype for predicting healthcare utilization and costs. Talk 1 and 2 use data from the NHATS cohort to assess healthcare utilization by frailty status in the general population and the homebound subset. Talk 3 and 4 use data from the MrOS study and the SOF study to investigate the impact of frailty phenotype on healthcare costs. Taken together, their findings highlight the potential of incorporating phenotypic frailty assessment into CMS risk adjustment to improve the planning and management of care for frail older adults."}
+{"text": "To learn about the imaging characteristics of pulmonary emboli caused by metallic mercury and be aware that an underlying psychiatric condition might exist when mercury poisoning is not caused by occupational exposure. To learn about the imaging characteristics of pulmonary emboli caused by metallic mercury and be aware that an underlying psychiatric condition might exist when mercury poisoning is not caused by occupational exposure. A 25\u2010year\u2010old asymptomatic woman was referred with diffuse, high\u2010density opacities in a chest radiograph Figure\u00a0 and dissMunchausen's syndrome is a factitious disorder imposed on the self and usually difficult to identify due to deceptive misrepresentation. Patients intentionally fake or cause symptoms of an illness and/or injury in themselves, even in the absence of obvious external rewards.None declared.WS: wrote the initial draft of the manuscript. YJ: critically appraised and revised the overall content of the manuscript. Both authors: read and approved the final manuscript.Our study has been granted an exemption from the review by the Institutional Review Board of Peking Union Medical College Hospital.Written informed consent was obtained from the patient's brother  for publication of this case report and any accompanying images."}
+{"text": "Health literacy assessment tools that are designed and validated specifically for East Asian older adults are limited. This session reviews the existing health literacy assessment tools and discusses possible applications in East Asian older adults. As an alternative to the population-level health literacy assessment, the general literacy measures and assessment approach in the Program for International Assessment of Adult Competencies (PIAAC) data are discussed. As a case demonstration, the PIAAC literacy measures in Japan and Korea are summarized and evaluated for the applicability in aging and health research with East Asian older adults."}
+{"text": "Clinics and Practice was launched in 2011 and it has been published over the past nine years by PAGEPress Publications [Clinics and Practice from PAGEPress and wish to ensure the reader that we will continue to serve health professionals and clinicians well. Clinics and Practice complements the MDPI portfolio of medical journals very well [Journal of Clinical Medicine [Medicina [Medical Sciences [We are delighted to take over the publication of ery well ,4, especMedicine , MedicinMedicina , and MedSciences , and strWe will regularly publish four quarterly issues from 2021.Clinics and Practice [We hope that you enjoy publishing your work in Practice !"}
+{"text": "Lassa fever outbreaks continue to be recurrent after fifty years of its identification. The true burden of the disease in Nigeria is unknown while gaps in knowledge about the infection still persist. Based on the Nigeria national Lassa fever research agenda and the World Health Organisation's roadmap initiative for accelerating research and product development which enables effective and timely emergency response to LF disease epidemics among other infectious diseases; a research pillar was added to the seven existing LF emergency operations centre response pillars in 2019. We describe lessons learnt from the integration of a research pillar into the LF national emergency response.Emerging and re-emerging infectious diseases are becoming more frequent and developing countries are especially at increased risk. A recurring infectious disease outbreak in Nigeria has been that of Lassa fever (LF), a disease that is endemic in Nigeria and other West African countries. Nigeria, between 1 Mastomys natalensis is distributed across this region [Emerging and re-emerging infectious diseases are becoming more frequent and advancing faster than ever before, predominantly in developing countries of Africa, South America and South Asia . Multipls region .st January and 27th October 2019, 743 confirmed cases of LF and 157 deaths in confirmed cases were reported [In West Africa, LF is estimated to affect 100,000-500,000 persons annually; with Nigeria bearing the most burden  recordinThe World Health Organization (WHO) developed a roadmap initiative for accelerating research and product development to enable effective and timely emergency response to LF disease epidemics among other infectious diseases . One of Overview of the national emergency response: a cardinal point in the coordination of any emergency response to a public health event is the activation of an emergency operations or coordinating centre. In 2019, the national EOC for LF in Nigeria was activated on the 22nd of January, following the declaration of the LF outbreak as an emergency by the NCDC due to high case numbers [ numbers . The EOCActivities of the research pillar: the NCDC LF research pillar commenced its activities by identifying and mapping ongoing research by various stakeholders across the country to avoid duplication of efforts. A 3-day capacity building workshop on the development of research proposals was also held for pillar members of the Lassa EOC. The research pillar participated in all meetings of the LF national EOC while also working closely with all the other response pillars to identify gaps from their operations which could be addressed by research. Reviewing daily and weekly reports from these other pillars of the EOC, gaps in knowledge, methods, response activities, assessments and challenges were identified as potential questions that could be addressed by research. Before the outbreak, WHO had supported the NCDC to prioritise its research areas with respect to LF and developed a research agenda. This was also used as a benchmark in the identification of potential research areas. During the outbreak, however, potential operational research that could immediately help to improve response were identified. These potential research areas spanned across case management, infection prevention and control, surveillance, contact tracing, laboratory, risk communication, environmental and vector control activities. The research pillar worked with the other response pillars concerned to develop concept notes around these gaps which would help inform their response subsequently. Those concept notes were prioritized based on the perceived impact on future prevention and response effects and a few of these concept notes were developed into research proposals for implementation by the rapid response teams (RRT) deployed to the field.Lessons learnt: outbreak response activities help to highlight gaps that can be addressed by research which otherwise may be either overlooked or not have been noticed. An example is the actual infection prevention and control practice of healthcare workers during outbreak periods as opposed to during routine care at other seasons. Also having a research pillar helped provide needed guidance on response research activities at national and subnational levels leading to streamlined research activities thereby avoiding duplication of efforts and optimising the available resources. An example was in the utilisation of the same checklist and methodology for household assessment by the RRT across various states and local government areas they were deployed to. Another lesson learnt is the need to have supportive teams with enough research methodology capacity to rapidly develop scientifically sound proposals based on identified gaps during an epidemic response. This was a challenge for the team as there were limited members in the research pillar and the other response pillars were more focused on outbreak response activities rather than on development of proposals. Also studies will need to be conducted in such a way as not to disrupt the much needed response being provided by the RRT and other members of the various response pillars. For implementation, the RRT were saddled with implementation of the operational research in addition to response activities and this led to non-completion of data collection by many due to distraction by response activities. We also learnt that there is need to have pre-dedicated funding such as a certain percentage of outbreak operational funds to support research prior to predictable outbreaks. Some of the studies could not be implemented due to paucity of funds for research during the period and this limitation was also reason for the use of RRT to collect data; obtaining the support of ethics committees for expedited approval is crucial to the implementation of research during outbreaks as it has been noted that epidemics tend to reveal vital knowledge gaps that could neither have been predicted nor prioritized for study before an outbreak occurs [k occurs . Prior tRecommendations: gaps identified during an outbreak should continue to generate research questions for high-priority study as both an integral component of the immediate response and if not possible immediately, could be for longer-term follow-up study. This hopefully would help in both understanding of the disease process and inform best practice for prevention and response activities [tivities ; countrytivities . Howevertivities ; the pertivities ; continuLessons learnt from the incorporation of a research pillar in the 2019 LF disease outbreak response provided an opportunity for both improvement and planning for research. This would inform future approaches to research-related response activities especially for predictable diseases like LF. This will ensure that we learn as much as we can from these significant public health events. The importance of utilizing research during an outbreak to evaluate and or improve our response and institute preventive programmes cannot be over emphasised; and this would go a long way in addressing knowledge gaps to improve prevention and control of outbreaks of infectious diseases such as LF."}
+{"text": "The development of RAPN enabled wider indication of nephron sparing surgery. For the bilateral kidney tumors, RAPN should be considered first to maintain the kidney function and minimum invasiveness. In performing RAPN for the both kidneys suspecting different histology, we must discuss about: What is the suspected histology based on the radiological examination? Is preoperative biopsy necessary? Do we operate sequentially or simultaneously? What is the appropriate interval? Which side should be operated first? Are there any options such as ablation therapy or active surveillance? There may be no concrete answer for these questions, however, we have to present many alternatives to the patients and inform them of the merits and demerits of each strategies. It is very difficult and time consuming effort but absolutely necessary. To treat the renal cell tumors we must have ability to perform many choices of procedures but it is impossible to experience every rare situation like this case. This case report will be very useful in the decision making in the similar circumstances.The author declares no conflict of interest."}
+{"text": "Although austerity was particularly strong in the aftermath of the economic crisis of 2008 and its consequences in the euro area, Italian fiscal policies have been characterised by tough consolidation periods ever since the 1990s."}
+{"text": "We examined the frequency of participation in cognitive and social type of leisure activities in association with dementia risk over 15 years of follow-up in 12,280 participants aged 50+ from the English Longitudinal Study of Ageing. Cox proportional hazards regression models were used to estimate the hazard of dementia in relation to the cognitive and social type of leisure activities as well as their interactions with sex and marital status. Medium and higher levels of engagement in cognitive leisure activities were associated with a lower risk of dementia. An analysis of the social type of leisure activities showed a similar pattern with protection for higher levels of engagement in a model adjusted for sex and marital status but further explained by wealth. This study shows a reduced risk of dementia for individuals with higher levels of engagement in cognitively stimulating activities, that may preserve cognitive reserve until later in life."}
+{"text": "To the Editor,We read with great attention the remarkable research letter by Yang and colleagues studying the utility of optic nerve sheath diameter (ONSD) in predicting sepsis-associated encephalopathy (SAE)  in critically ill patients . HoweverSystemic hypertension itself could be an independent risk factor for increase in ONSD and has been studied in the past . While pWe wish to congratulate the authors for this remarkable work in the critical care setting to risk stratify patients with SAE with the help of ONSD. However, providing further details about the clinical status of the patients in this setting (such as blood pressure readings) and details of past medical background (steroid use and history of endocrinopathies) will provide readers of this journal with much needed clarity and further credibility to this outstanding work."}
+{"text": "Communication and interactions are an integral part of care in long-term care settings. Resident variables, such as race and gender, shape communication and interaction between staff and residents. The Quality of Interactions Schedule (QuIS) was developed to measure the quality of verbal and nonverbal interactions among nursing staff and older adults initially for those in acute care and later used as well in a variety of long term care settings. A quantified measurement of the quality of interactions between residents and staff was created to quantify the QuIS. The purpose of this study was to describe the gender and racial differences in scored quality of interactions. Data for the present study was based on baseline data from the Evidence Integration Triangle for Behavioral and Psychological Symptoms of Dementia (EIT-4-BPSD) implementation study. A total of 535 residents from 55 settings were included in the analyses. An analysis of covariance was conducted to determine a difference in QuIS scores between males and females while controlling for age. The second model tested for differences in QuIS scores between blacks and whites while controlling for age and gender. There was not a statistically significant difference in QuIS scores between male and female residents. There was a significant difference in QuIS scores between those who were black versus white, such that those who were black received more positive interactions from staff than those who were white. Future work should focus on a deeper examination of resident factors and staff factors that may influence these interactions."}
+{"text": "Background: International policy is increasingly committed to placing interdisciplinary team-working at the centre of health and social care integration across the lifespan. The National Clinical Programme for Older People in Ireland has a critical role in the design and implementation of the National Older Person\u2019s Service Model, which aims to shift the delivery of care away from acute hospitals towards community-based care. Interdisciplinary Community Specialist Teams for older persons (CST-OPs) play an important role in this service model. To support the development of competencies for interprofessional collaboration and an interdisciplinary team-based approach to care integration, a culture shift will be required within care delivery.Design:This study builds upon a collaborative partnership project which co-designed a framework describing core competencies for interprofessional collaboration in CST-OPs. A realist-informed process evaluation of the framework will be undertaken as the competencies described in the framework are being fostered in newly developed CST-OPs under the national scale-up of the service model. Realist evaluation approaches reveal what worked, why it worked (or did not), for whom and under what circumstances. Three iterative and integrated work packages are proposed which combine multiple methods of data collection, analysis and synthesis. Prospective data collection will be undertaken within four CST-OPs, including qualitative exploration of the care experiences of older people and family carers.Discussion: The realist explanatory theory will provide an understanding of how interprofessional collaboration can be fostered and sustained in various contexts of care integration for older people. It will underpin curriculum development for team-based education and training of health and social care professionals, a key priority area in the national Irish health strategy. It will provide healthcare leaders with knowledge of the resources and supports required to harness the benefits of interprofessional collaboration and to realise the goals of integrated care for older people. International health system policy and operational models have increasingly identified interdisciplinary teamwork as critical for health and social care integration across clinical pathways . InternaInterdisciplinary team working is a core feature of common international models of older people\u2019s health and social care and is considered critical for comprehensive geriatric assessment and care planning . The EurThe ECLECTIC project  sought to address this gap by co-designing a competency framework that provides practical guidance for building competencies for interprofessional collaboration in the context of older people\u2019s integrated care . These CThe ECLECTIC framework was co-designed with healthcare professionals, from across thirteen disciplines involved integrating care for older people in community care settings. Five Public and Patient Representatives (PPRs) also joined the co-design team and were critical in the development and validation of the framework. Furthermore, in-depth qualitative research was undertaken with two interdisciplinary community-based teams integrating care for older people. The qualitative analysis was used to contextualise the core competencies described in the framework  and NCPOP that will enable team members to develop competencies for interprofessional collaboration. These resources will provide specific learning activities and materials aligned to relevant contexts-mechanism-outcome configurations and will be made available to all the CST-OPs supported by NCPOP.4.Contribute to the theoretical understanding of what works (mechanisms) in building proficiency for interprofessional collaboration and under what circumstances (contexts) through the development of a middle-range theory providing a detailed explanation of the dynamic relationship between varying context-mechanism-outcome configurations.Ethical review and approval will be sought from the relevant governance committee once the case-study sites are identified. Furthermore, ethical exemption will be sought from the UCD Life Sciences Ethics Committee.The study adopts a realist evaluation approach which is an interpretive theory-driven approach to evidence synthesis which uses multiple sources of evidence including published peer-reviewed studies, policy documents and grey literature. This evidence is combined with stakeholder theories and explanations of how interventions might work  will be included.3.Public and patient representatives (PPRs) of older people and family carers (our PPI advisory group).i.e., patterns of generative causation). These IPTs will support the evaluation of the implementation of the ECLECTIC framework within CST-OPs operating under the NCPOP (Work Package Two). The realist review will be guided by five steps adapted byThis review will focus on generating initial programme theories (IPTs) for the contexts and the mechanisms that are associated with the outcomes of interventions targeting interprofessional collaboration Finally, four validation workshops will be held with key stakeholders  to review, refine and prioritise the IPTs. This will result in a series of evidence based IPTs which are context specific theories in the form of statements which explain how and why teams build interprofessional collaboration and what the associated outcomes are.versus more established teams). Furthermore, case study site selection will be guided by the IPTs that were prioritised at the end of work package one for testing.The second work package will involve multiple methods to explore, evaluate and test the IPTs . ProspecDue to the given complexity of the system in which the ECLECTIC framework is being implemented, each of the four teams will likely be at different stages in their development proficiency for interprofessional collaboration. This will provide additional nuance and understanding of the role of context in the realist evaluation. Two of the nominated teams will be identified by the research team in collaboration with the project advisors for the collection of extensive process data and a more in-depth realist evaluation. This evaluation will primarily focus on testing and refining the emerging programme theory. The other two teams will provide prospective qualitative data that can be used to contextualise and support the emerging theory.Data Collection: Four case study sitesThe following prospective data will be collected from the four nominated CST-OPs: Structured interviews with team membersQualitative structured interviews will be conducted with members of each of the four nominated CST-OPs (N=24\u201332) at baseline (T1), six months (T2) and at 12 months (T3). The participants will be purposely selected to ensure representation from each discipline represented on the team as well as a support member such as operational manager (n=6\u20138 per team). We aim to interview the same team members at each time-point to enable prospective exploration of changes over time. The interviews will be guided by a structured format derived from the IPTs. The participants will review the IPTs and explore each of the configuration elements  from their own experience of interdisciplinary and interprofessional working. The participants will determine whether the interviews will be conducted either face-to-face or remotely using video conferencing technology as per their requirements and preferences.Semi-structured interviews with older people and family carersProspective qualitative interviews will be conducted with older people and/or their nominated family carer who are receiving integrated care from one of the four nominated care teams. Interviews will be conducted in two waves: following initial referral/assessment and following discharge from the CST-OP. We will aim to prospectively interview 16\u201320 older people and/or family carers across four team sites at each time point (n=4\u20135 per team). The focus of these interviews will be to explore the participants\u2019 care experiences and needs during their time with the CST-OP and to identify how needs change over time. The IPTs will inform the interview guide and will prompt discussion of the outcomes identified in the configuration statements from the perspective of older people and/or family carers. This discussion may also identify potential causal mechanisms for these outcomes. These interviews will be conducted face-to-face unless otherwise requested by the participant themselves.Quantitative outcome measurementThe quantitative outcomes associated with interdisciplinary collaboration identified from the systematic scoping review in work package one will be measured at three timepoints (baseline (T1), 6 months (T2), 12 months (T3) as above). Each of the CST team members (N=52\u201355) will complete an online questionnaire measuring outcomes that have been adopted from the mechanisms for evaluating team competency in interprofessional collaboration described in the co-designed ECLECTIC competency framework . Listed Other measures that may emerge from the evidence scoping and realist synthesis include attitude towards interdisciplinary working, knowledge of team roles, knowledge of each competency, trust, conflict, collective leadership/decision-making and sense of work engagement such as feelings of vigour, dedication and absorption. The measurements will be conducted online through individual scaled questionnaires. Previously validated and robust instruments will be used to measure outcomes, where available.Data collection: Two case study sitesIn collaboration with the project advisory committee, two of the nominated CST-OPs will be identified for more extensive data collection and realist evaluation. The following additional sources of data will be collected from these two teams. This will ensure the generation of rich and detailed explanatory programme theory for two case study sites. The data collected from the other sites will be used to support and refine the two case study programme theories.Observations of team meetingsStructured observations of a team meeting will occur at three timepoints (baseline (T1), 6 months (T2), 12 months (T3) as above). The focus of these team observations will be to identify the contextual conditions and related mechanisms which lead to outcomes associated with interprofessional collaboration. A bespoke observation template will be developed to support data collection to promote consistency in data capture across observations. This will be modelled on a tool developed by a member of the research team with colleagues (McAuliffe) for observation and measurement of psychological safety in healthcare teams  as well as standard operating procedures for interdisciplinary team communication and referral processes. The teams will be asked to record adverse events and indicators of care quality including episodes of missed care, duplication of care, declined care . These will be recorded by the team in anonymised format and will be collected for the purposes of tracking frequency of adverse events over the observation time frame (12 months).Data analysisNVIVO Pro 12 Software .Qualtrics XM will be used for the collection of quantitative data and data will be analysed using IBMSPSS Statistics 27. The analysis will be undertaken on an ongoing basis whereby each wave of data collection will iteratively inform the next wave of data collection in each case study site. Data analysis will be guided byQualitative data analysis of the interview transcripts, the documents and the team observational notes will be conducted usingThe focus of data analysis in this second work package will be to observe outcome patterns to inductively identify C-M-O configurations and to deductively test IPTs within each of the two case study sites identified for in-depth realist evaluation. The outcome from this work package will be a refined programme theory for each of the two case study sites nominated for in-depth realist evaluation. The additional case study data from the other two sites will be used to support or refine the theories. At the end of the evaluation period (12 months) data will be reported to each of the case study sites. This will ensure that the knowledge generated from the evaluation can inform the study sites and be used to improve their interprofessional collaboration.The third and final work package will involve the synthesis and sharing of the refined programme theories which emerged from the second work package across case study sites to develop a middle range theory. This is a higher order theory involving a synthesis of more granular programme theories to provide hypotheses about how different types of interventions might work in different types of contexts in realising overall programme outcomes . The metMiddle range theory developmentFindings from each case study will be collated alongside all their support evidence. The first step of analysis will involve combining the programme theories and C-M-O configurations from both cases. Commonalities within the combined PTs and C-M-O configurations will be identified and grouped into a framework. The next step of analysis will be to identify predictable patterns occurring across the data. The additional qualitative data extracted from all four case study sites will be deployed at this stage. Data from all four sites will be reviewed to identify explanatory information to facilitate the synthesis of patterns of causation. This will support and refine the theories that had arisen from each of the two case studies and help manage any discrepancies between the case study findings.In line with realist methodology, the focus of this analysis will be to develop an understanding of the generative causality between different contexts and the mechanisms which are linked to specific outcomes . The resThree final validation workshops will be held with the four key stakeholder groups . The purpose of these workshops will be to refine and validate the theories and to generate discussion on how this theory can support the workforce capacity development with specific reference to teaching and learning approaches.Translation of the middle range theory into operational guidance and curriculum developmentThe realist evaluation proposed for this application will identify guiding principles that can be applied in practice to support effective interprofessional collaboration in the delivery of quality integrated care for older people in the community setting. Through dissemination, it will offer practical guidance and insights for policymakers and health and social care providers as well as organisational leaders, and innovators to support successful implementation programmes across the health systems nationally and internationally.The proposed project will impact the national healthcare workforce planning and development and through the dissemination of outputs will influence international conversations concerning workforce capacity in health and social care. The implementation evaluation of the ECLECTIC framework will directly influence the development of professional standards and guidelines for clinical design to support the implementation of the national older person\u2019s service model. This will inform the recruitment strategy for the programme managers as well as continuing professional development for the integrated care teams established through the programme.We will work with the NCPOP to scale up the findings across the clinical programme for older people as well as translate these findings to other programmes which have been restructured to include a focus on interdisciplinary teams.The next element of work package three will involve the translation of the middle range programme theory into an interdisciplinary curriculum for the education and training of health and social care professionals. This will involve revision of the ECLECTIC framework  to incluA cross-disciplinary and institutional project team will be convened with representation from core health professional programmes  as well as regulatory bodies . The team will be supported by collaborators from the Australian Institute for Health Innovation at Macquarie University who will enable knowledge translation for broader health system impact. The team will also invite public and patient representatives from our PPI advisory group to become members. The aim of this project team is to co-design a curriculum framework which will map the knowledge and skills required for interprofessional collaboration. This framework will enhance interdisciplinary teaching, learning and assessment of interprofessional collaborative practice across health and social care professional curricula. It will be a resource for educators across health professional programmes as well as continuing professional development. It will support incremental learning of the appropriate knowledge and skills as well as provide recommendations for specific learning activities to scaffold competency among students. The middle range theory will be embedded into the framework ensuring that the curriculum is context specific and aligned to the mechanisms associated with measurable outcomes for interprofessional collaborative practice. This framework will be used to foster interdisciplinarity in the health and social care professional curricula and will form the basis for structured elective module development at both undergraduate and taught graduate levels.Members of the research team are academic champions of PPI as part of the UCD PPI Ignite program. The team have long established experience enabling patient, public and practitioner involvement in health system change such as co-designing frailty pathways in acute care settings  Older Persons Office, the HSE and the NCPOP will play a critical role in supporting the translation of the findings across the national integrated care programmes generally. The inclusion of the CST-OP clinical leads is critical for the translation of the findings into clinical design and practice as well as the operational guidelines and procedures within the National Clinical Programme for Older People. Associate Professor Harrison, a collaborator for this project, leads the healthcare engagement and workplace behaviour stream at the Australian Institute of Health Innovation, Macquarie University. The institute is focused on related areas of health services research, health informatics and health systems and safety. Harrison will work with co-applicant N\u00ed Sh\u00e9 who has an honorary appointment at the institute in enabling knowledge translation of the work in Australia.The research team will be in the UCD Centre for Interdisciplinary, Research, Education and Innovation (UCD IRIS) and will harness the knowledge and expertise of the centre in translating study findings into broader health systems research and education. This will ensure that the knowledge generated from this study will have immediate relevance for future workforce capacity development and ongoing professional education. This translation into ongoing professional development will also be facilitated through the creation of learning resources for integrated care teams that will be developed in collaboration with the HSE and NCPOP as a result of this study.The findings from this study will also be disseminated to the international research community through publications in open-access peer-reviewed journals as well as presentations in national and international conferences. UCD Library, as a member of the IReL consortium of Irish academic libraries, has entered into a few Open Access Publishing agreements with key scholarly publishers. The budget request for this study will also provide for publication of two research papers in international open access peer-reviewed journals. Finally, this study protocol and a final study summary will be submitted for publication in HRB Open Research.The results of the realist review will be reported according to the Realist and Meta-narrative Evidence Synthesis: Evolving Standards (RAMESES) quality and publication standards  revolved around person-centered values but this was not reflected in the figure. Third, when talking about IPC team members, it is relevant to provide a description of the health professionals involved and their roles in the team considering the healthcare landscape in Ireland.Is the study design appropriate for the research question?YesIs the rationale for, and objectives of, the study clearly described?YesAre sufficient details of the methods provided to allow replication by others?YesAre the datasets clearly presented in a useable and accessible format?Not applicableReviewer Expertise:Ageing, inteprofessional education and collaborative practice, quantitative research methodsI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. This is an excellently written paper outlining an extensive process to improve care of older people. Starting out by conducting a realist review will situate the subsequent study of 4 cases quite well. I appreciate the conducting of interviews and observations of team meetings initially, in six months and in a year as an important way to see differences in how teams develop and demonstrate competencies. Developing the mid-range theory to support how the competencies are applied to older adult care over different contexts will support the end goal of developing curriculum for interprofessional education. I look forward to further publications as this process unfoldsIs the study design appropriate for the research question?YesIs the rationale for, and objectives of, the study clearly described?YesAre sufficient details of the methods provided to allow replication by others?YesAre the datasets clearly presented in a useable and accessible format?YesReviewer Expertise:Nursing care of older adults, nursing education and interprofession practiceI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. This paper describes the methodology for a realist review to evaluate the implementation of the ECLECTIC framework for the development of competencies in interdisciplinary community-based teams for older people. The goals are clearly described with an appropriate methodology clearly described and suitable to answer the research question. There is a structured plan of work packages that is realistic and deliverable. The methodology clearly describes how different sources of information will be identified and used to inform the research.\u00a0 In particular, the explanation of the chosen methodology and rational for this choice is clearly presented. The plan for ethics review is appropriate. The plan for dissemination of results is also appropriate and hopes to influence policy meaningfully as well as to share learning from the research.Is the study design appropriate for the research question?YesIs the rationale for, and objectives of, the study clearly described?YesAre sufficient details of the methods provided to allow replication by others?YesAre the datasets clearly presented in a useable and accessible format?Not applicableReviewer Expertise:Geriatric Emergency Medicine, Medical EducationI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard."}
+{"text": "During the last few decades, the field of rehabilitation has experienced substantial development, growth and acceptance. Rehabilitation addresses the impact of a health condition on a person\u2019s everyday life by optimising their functioning and reducing their experience of disability. Rehabilitation expands the focus of health beyond preventative and curative care to ensure people with a health condition can remain as independent as possible and participate in education, work and meaningful life roles .We also now have a better understanding of the growing global need, demand and recognition of rehabilitation around the world. For example, it has been estimated that 2.41 billion people in the world could benefit from rehabilitation services. This means that at least one in every three persons in the world needs rehabilitation at some point during the course of their disease or injury  seeks to understand and improve how societies organise themselves in achieving collective health goals and how different actors interact in the policy and implementation processes to contribute to policy outcomes   invite researchers in the field of HPSR for rehabilitation to submit their manuscripts to our journals for peer review and possible publication, (2) create a special journal section, series or designation dedicated to HPSR for rehabilitation, (3) appoint editorial board members with expertise in HPSR for rehabilitation and (4) disseminate research articles among funding agencies and policymakers. These actions by our academic journals will help the WRA achieve its goal of strengthening rehabilitation services for all."}
+{"text": "It is known that the restrictions and clinical changes experienced during the pandemic period have negative effects on the care and treatment of psychiatric patients. However, insights on how the pandemic environment and the approaches of healthcare professionals serving during the pandemic affect the care and treatment of patients at risk of suicide are insufficient.This ethnographic study aimed to identify the approaches of psychiatric nurses in managing suicide risk during the pandemic period in relation with their work environment.This ethnographic research design used a sample of 13 psychiatric nurses in a psychiatric clinic in Ankara. Data were collected with in-depth interviews, participant observations and observant participations. Data were obtained from a total of 612 hours of observation and 13 planned nurse interviews. Data were analyzed using qualitative thematic analysis.The emergent main theme from data analysis is explained under the title of \u201cThe risk of loss of inauthenticity in suicide risk management\u201d. \u201cRisk of loss of inauthenticity\u201d means the fact that the individual suicidal risk factors and differences of the patients cannot be perceived/assessed by the nurses.Supposing all patients having the same suicide risk level by psychiatric nurses caused insensitivity to risky patients in the care process. Nurses\u2019 inadequate approach to patient personality disorder and limited social interactions due to the pandemic atmosphere made it difficult for nurses to have knowledge and understanding of how patients cope with suicidal ideations. These findings show the importance of the use of valid and reliable scales with risk formulations and the significance of triage in crisis periods such as current pandemic. In addition, creating available online consultancy service alternatives may have an important role in the management of suicide risk for patients who are disturbed by long-term hospitalization. Also these findings may contribute to the creation of qualified care and treatment guidelines on suicide risk management for crisis periods.None Declared"}
+{"text": "Balancing career and family is a hard job for everyone. Academic life with multiple and conflicting demands on our time necessitates prioritizing among responsibilities. This resonates especially for a woman academic who takes care of a baby. The speaker will address specific challenges of mothers who are in both academia and clinical practice, give reflections and elaborate on patterns and ways of dealing with this challenge. The talk is hoped to promote awareness and discussion on addressing the inner and outer sources and planning one\u2019s own way on a career path.None Declared"}
+{"text": "As one of main aim of broad mental health (MH) reform in Bosnia and Herzegovina (BH), quality of services and continuous improvement are priorities. In last decade network of community services-community mental health centers (CMHC) covered all the parts of the country and is connected with secondary and tertiary medical institutions as well as with broad network of centers for social welfare and growing number of user organizations.As a novel practice that will be involved in standards of quality for all MH services is joint planning of hospital discharge people with mental illnesses, supported by legislative and connected with other positive results of mental health reform in BHReview of implementation of results of MH reform in BH with focus on joint planning hospital discharge.In BH in last decade has been established broad spectrum of services that improved quality of care through multidisciplinary collaboration between sectors. Important role has given to users\u2019 organization. Quality standards are defined trough certification and accreditation. New services were developed or renewed and implemented . Entities\u2019 policies and strategies involved new services and improved MH legislative following the course of more involvement of patients as well as their families, representatives or persons of their trust in decision making and planning of multidisciplinary treatments in the CMHCs. Joint Planning of discharge from the hospital fund as important step in further improvement of quality of care for people with MH disorders, especially for those with severe mental illnesses.Last decade in BH gave important results in the better quality of MH care. Further plans will be focused on implementation of new MH user-oriented services.None Declared"}
+{"text": "Intraventricular hematoma includes massive clots spreading in all four ventricles and partial clots obstructing cerebrospinal fluid circulation in the foramen of Monro and aqueduct and foramen of Magendie. The authors have described in detail the characteristics of hematocephalus; however, its basic mechanism and clinical management have not been fully discussed, as indicated by the authors. I suppose that many neurosurgeons agree with the authors\u2019 opinion that simple intraventricular drainage is not always successful in the management of hematocephalus associated with massive intraventricular hematoma. Difficulties in management are as follows: the bleeding point is often unknown based on pre-operative imaging; emergent cases cannot allow conventional angiographical examination; even large drainage catheters can sometimes clog with clots of hematoma; intracatheter administration of fibrinolytic agents can cause rebleeding; the selection of neuroendoscopies is not simple; flexible- or rigid-type surgical devices for flexible neuroendoscopy for the removal of hematoma have not been fully developed; and hematocephalus includes variable causes of hemorrhage, which has complex pathological states. Moreover, clinical states often need emergent management, which can be challenging. The paper is of considerable interest to clinicians. The definition of hematocephalus is based on the report by Benes et al (2). The recent categorization of hematocephalus can provide new perspectives on pathological states and therapeutic strategies. The present paper is believed to contribute to the accurate categorization of the knowledge on hydrocephalus caused by intraventricular hematoma and development of new approaches to clinical management.Hematocephalus is a noncommunicating hydrocephalus caused by intraventricular hematoma, as described by Martin et al None"}
+{"text": "Besides selecting and developing (sub-) targets, evaluating target achievement  is an important aspect of the concept. This article discusses the methodological challenges for impact evaluation in addition to providing approaches to solve these issues.Experiences with the evaluation concept developed by the German forum  The collaboration is based on the principle of consensus. The members jointly develop national health targets, recommend measures to achieve the set goals and present recommendations for the practical implementation of measures. The forum ensures the results are made public and encourages the decentralised implementation of national health targets by stakeholders. The forum regularly evaluates and optimises target achievement rates and processes . GermanyExperiences with the evaluation concept, which was developed and implemented by academic experts, and the results it provides can be of use for prevention reporting. It is built around the following four areas:I. Target selection: Members of the health target forum name relevant fields of interest that are compiled to be assessed on the basis of a scientific catalogue of criteria . Based oII. Workgroups are established to elaborate the targets and sub-targets, guided by the following key points:\u25baTargets are directed at the population and the health and social systems and aim to respect the principles of equal opportunity  \u25baThey are based on the results of the scientific criteria analysis \u25baMeasures recommended to achieve targets should be evidence-based, their implementation feasible and impact measurable\u25baCriteria to quantify targets are also availableIII. Monitoring (sub-) target achievement will be based on the following questions: Has the (sub-) target been achieved? Which measures for target achievement have been implemented and how have they contributed to the achievement of targets? What conclusions do the results allow regarding the need to update targets?The complexity of measures provides methodological challenges at the different intervention levels which differ in extent and form. A broad range of stakeholders  help achieve targets in diverse contexts . Information is often scarce, in particular, concerning the effects of individual measures, the timespan during which such effects are visible and the mechanisms behind such effects, as well as the interplay between different measures in the achievement of targets.Possible steps to limit these methodological challenges include:\u25baSelection of sub-targets and initial measures (priority measures) for evaluation\u25baFocus on the national level (structures and population) or on larger units \u25baDevelopment of measurable indicators to monitor the implementation and effectiveness of initial measures at different levels\u25baUse of established sources of data\u25baDetection of gaps in the data \u25baIdentification of best practice models and relevant individual measures \u25baTheoretically grounded assumptions on the mechanisms that lead measures to be effectiveIV. Overall evaluation: a survey of the participating stakeholders was undertaken in 2013 that enquired about their experiences with and expectations of the process we had installed to establish targets. The survey focused on the strategies and model projects that members had developed to initiate and implement the established health targets and on recommendations on how to enhance the additional value provided by the forum. 49 out of the 69 surveyed stakeholders had defined fields of action for their organisation that were related to national health targets. 54 stakeholders could provide at least one example of a measure to implement these health targets [gesundheitsziele.de suggests that the experiences and results of the process to establish targets will be used by prevention reporting and that the evaluation committee and its expert academic members will thereby play an advisory role. Moreover, the results, methods and data that prevention reporting produces should be made available to the health target forum. We believe we should pursue the approach of impact evaluation and promote the methodological discourse on the evaluation of complex interventions as it is currently being discussed in public health research.The forum"}
+{"text": "In this issue of this journal, van Boxtel and colleagues  reportedLabelling of heart valve substitutes has been confusing since the introduction of the first man-made artificial heart valve, the Starr\u2013Edwards ball valve. That is the reason manufacturers provide them with sizers to measure the annulus where they are to be implanted. This labelling problem is not only with supra-annular bioprosthetic heart valves used for aortic valve replacement but also with mechanical heart valves that are implanted in all positions in the heart as well as with annuloplasty devices used for heart valve repair. This issue is so important that the 3 major European and American cardio-thoracic surgical societies endorsed a document prepared by a panel of experts on heart valve substitute sizing .The ideal prosthetic heart valve substitute should offer minimal impedance to blood flow and this can often be attained by knowing the estimated effective orifice area of each valve type and size and matching to the patient\u2019s body surface area. The initial problem is not the IOD but rather the mislabelling by the various manufacturers and the great variability in sizes for any given size and the effective orifice areas , 4. For The suggestions proposed by van Boxtel and Mariani  should b"}
+{"text": "After this article was published, similarities were noted between this article  and submIn response to queries about these concerns, the first author provided the underlying data in The authors commented on aspects of how data were collected and analyzed for this study, but overall their responses did not fully resolve the concerns.PLOS ONE Editors issue this Expression of Concern to notify readers of the unresolved concerns discussed above, and to provide the data received from the authors.The S1 File(ZIP)Click here for additional data file."}
+{"text": "CPT: Pharmacometrics and Systems Pharmacology showcases recent modeling and simulation examples to develop and assess complex generic drug products, with scientific achievements that are germane to new drug development.Approximately 90% of prescriptions dispensed in the United States are generic drugs.The GDUFA was enacted by Congress in 2012 as a partnership between the generic drug industry and the FDA to bring cost\u2010saving medicines to patients faster. Under the GDUFA, the FDA assesses generic industry user fees to improve diverse aspects of regulatory review and approval of generic drug applications. Across two re\u2010authorizations, the GDUFA has enabled expanded research and innovation for complex generic drugs. These products are the generic version of a drug containing complex active ingredients, formulations, routes of delivery, dosage forms, and/or drug\u2010device combinations and for which early interactions with the FDA may be beneficial to address scientific challenges to avoid delays in approval.Central to the success of the initiative is the burgeoning integration and adoption of model\u2010integrated evidence (MIE) by generic drug developers and the FDA. MIE integrates evidence from empirical studies with computational models, extending the continuum of knowledge acquired through model\u2010informed drug development (MIDD) for a new drug application (NDA) with emerging post\u2010NDA knowledge.The FDA has pioneered advancements in QMM for complex generics to offer developers MIE\u2010driven frameworks to establish BE. The widening impact of QMM and MIE to demonstrate BE and characterize drug delivery for complex generics is spotlighted extensively in this mini\u2010themed issue. In 2021, workshops led by the FDA and co\u2010sponsored by the Center for Research on Complex Generics (CRCG) showcased advanced applications of mechanistic modeling and simulation platforms for determining BE and their utility in addressing complex generic drug development challenges. An overview of the learnings from the locally acting and oral generic drug product workshops are presented by Babiskin et al.Under the GDUFA III (2023 to 2027), utilizing QMM for complex generics to establish BE in place of clinical end point BE studies has the potential to lower development costs and accelerate access to generic drugs. A recent rise in MIE alternative BE approaches in pre\u2010ANDA and ANDA interactions between the generic drug industry and the FDA is signaling an industry shift from MIE development to implementation; Yoon et al.As MIDD and MBBE become central tenants to innovator and generic product development, there are opportunities to hybridize learnings to advance QMM in both arenas. The MMF may find value across innovator drug development to accelerate new drug approvals as part of the MIE continuum. Curation of standards for data generation, dataset and input parameter assessment, modeling analysis and validation, and reporting to ensure consistency and harmonization across global development and regulatory decision making are pertinent to both new and generic drug development so that QMM approaches are not underutilized. The International Conference on Harmonization (ICH) M15 Concept Paper for new drug approvals provides a foundation to expand these best practices to both innovator and generic products."}
+{"text": "The corrected list of affiliations is as shown above.The authors regret that the email address for Muhammad Imran: imraniub86@gmail.com, was incorrectly listed under affiliation The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "Some evidence converges to consider that suicidal behaviour could be a separate diagnosis and emphasizes the relevance to identify specific biomarkers. Identifying the neural substrates of suicide attempt is key to understanding the etiology of suicide and might be helpful in reducing suicide rates among psychiatric patients by promoting the development of novel therapeutic strategies based on behavioral neuroscience and brain stimulation. Neuroimaging studies have reported structural and functional brain abnormalities located in the prefrontal cortex, insula and striatal regions as well as in the connections between these brain areas. Based on task related and resting state functional MRI studies, we will discuss original data showing the role of the ventral prefrontal cortex in suicide vulnerability.None Declared"}
+{"text": "Climate change and the need to reduce global carbon emissions drastically in upcoming years pose a challenge to physical activity (PA) promotion. Not only is PA more difficult in heat and people need to adapt, but also many physical activities come with a comparable high carbon footprint. While the field of PA promotion has so far utilized the health-enhancing physical activity (HEPA) concept to define and promote PA, this concept might need to be amended to account for the environmental impacts of PA. The aim of the presentation is to critically analyze the interconnections between PA and planetary health and suggest potential steps towards a concept of sustainable HEPA."}
+{"text": "In the published article, there was an error in the Ethics statement. The registries' institutional review boards of Kurashiki Hospital and St. Luke's Hospital were listed, not the institutional review board to which the first author belongs. \u201cThe protocols for the studies were approved by the Ethics Committees of Kurashiki Central Hospital  and St. Luke's International Hospital . Written informed consent for participation was not required for these studies in accordance with the institutional requirements.\u201d The correct Ethics statement appears below.\u201cThe protocols for the studies were approved by the Ethics Committees of Tokyo Bay Urayasu Ichikawa Medical Center . Written informed consent for participation was not required for these studies in accordance with the institutional requirements.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "In 2013 the Berlin Health Conference  implemented intervention reporting for the first time within a kindergarten setting. Results from the survey of LGK Berlin members on current measures in kindergartens in Berlin that are related to the child health targets enabled us to map socio-spatial interventions and subsequently identify needs. This article highlights the potential and limits of intervention reporting as an element in the wider field of health and prevention reporting. The LGK Berlin is a network of institutions and associations that actively partake in health policy at the federal state level in Berlin and/or hold health policy responsibility. In 2012 the LGK decided to begin internal intervention reporting. Intervention reporting aims to create an instrument to optimise the management of activities and will be based on the self-commitment of LGK members to transparency in the implementation of measures in the context of Berlin's health target process [Intervention reporting was implemented for the first time in 2013 referring to measures in a kindergarten setting. LGK members were asked which measures they were implementing in kindergartens that relate to the fields of activity for Berlin's child health targets. To judge whether offers meet the (estimated) needs, the locations of the kindergartens in which LGK stakeholders were implementing measures were projected onto a map providing information on Berlin's social structure [Most LGK stakeholders view intervention reporting as a useful tool to identify social spaces with a heightened need for measures and those where needs are already being satisfied. Reporting can help account for socially compensatory aspects in the planning of measures. One risk is the potential to misinterpret results: a high number of offers in a particular area does not automatically mean that health is being effectively promoted here and vice versa, particularly because whilst intervention reporting does provide information on the kind and number of measures, it cannot say anything about how effective these measures were. Because intervention reporting only collects information on activities by the members of the LGK, it also does not provide a full picture of the activities in a social space that are directed at promoting health.Generally speaking, intervention reporting is a potential element of prevention reporting. Meaningful prevention reporting should cover all phases of the Public Health Action Cycle  , 4. Heal"}
+{"text": "Editorial on the Research TopicImpact of COVID-19 on cancer care and rehabilitationThe pandemic of COVID-19 had a significant impact on healthcare worldwide, affecting the care of many high risk patients including those with cancer . ReferraFor example, short-course radiotherapy was used to delay the need for surgery in locally advanced rectal cancer and reduced attendance requirement in the hospital setting . This haA number of healthcare settings utilised technology in their outpatient clinics switching to virtual consultations thus further reducing hospital attendance whilst still providing a high quality level of care . StudiesThe British Oncology Pharmacy Association collated changes in oncology pharmacy services during the pandemic and provided a guide for its members on reviewing and evaluating these changes for consideration for future services in the endemic phase . An examThe purpose of this collection of papers is to showcase and share learning from those who have had experience of these changes including implementing the use of IT solutions and/or IT science to assist and improve clinical outcomes for patients.There are four articles in this research topic each providing insight into the affects COVID-19 has had on cancer care around the world and the initiatives that have been implemented. Each study had a unique angle to investigate with some focusing on the impact of mental wellbeing on treatment delays while others examining predictive models measuring the impact of the pandemic on hospital admissions.Cigarini et al. described the impact that the pandemic had on cancer care pathways in northern Italy and proposes a tool for providing high levels of quality care even in the most critical health situations.He et al. described factors influencing delayed treatment in people living with breast cancer. This study took place in Chengdu, China and described a cross sectional investigation of close to 400 patients living with breast cancer.Liu et al. report on an interrupted time series analysis investigating the impact of the pandemic on monthly hospital admissions for cancer patients in Henan, China. They also review the delays to diagnosis and recognise that telemedicine is not only a helpful IT solution for those that cannot visit a hospital but it can also be used to support reduction of the backlog caused by the pandemic.Jani et al. reviews the risk factors associated with worse outcomes from COVID-19 in cancer patients and understanding a suitable method to mitigate the risks of COVID-19 for this patient cohort.The final article submitted by The COVID-19 pandemic was disruptive to most health care services and healthcare professionals displayed resilience and agility in adapting the care they provided to their patients. The impact and resulting learnings were valuable and will help better prepare for any future similar disruptions.Both editors of this research topic wish to thank all submitting authors for their work. As the editorial team, we hope that this research continues to prove a useful resource to provide care to cancer patients during unprecedented times."}
+{"text": "To review the current state of diabetes treatment from a clinical and management perspective and explore the role that new biologic pharmaceuticals may offer patients who fail to meet or maintain glycemic goals with existing treatment options.Key clinical areas involve the role that insulin resistance and beta-cell dysfunction/failure play in the progression of type 2 diabetes as well as current treatment modalities and how they address those core defects. Management issues include a discussion of the economics of the disease and the implications of theUnited Kingdom Prospective Diabetes Study (UKPDS)\u2014that good glucose control reduces the occurrence of microvascular complications and improves quality of life for diabetic patients. While an intensive approach may be costly in the short term,statistics on the rising pandemic of the disease argue compellingly for early and aggressive treatment to delay fatal complications and improve the quality of life for persons suffering from type 2 diabetes. Current pharmaceutical regimens are not successfully enabling patients with type 2 diabetes to reach glycemic goals. The ramifications of this failure have profound repercussions in the managed care organization environment. Fortunately,new treatment modalities are in various stages of development. These will be reviewed with a more in-depth exploration of the potential of incretin mimetics, a new biologic, injectable class of drugs for the treatment of type 2 diabetes. Emphasis will be given to exenatide, an incretin mimetic that demonstrates particular efficacy for patients not achieving glycemic goal with oral medications and are insulin naive. Biologics are administered by injection or infusion and are generally costly. Apart from their cost, however, what is even more critical to managed care executives and decision makers is that these medications indicate a trend in pharmacotherapy,a groundswell of new medications. In addition, few practitioners and even fewer health care executives understand molecular medicine. The key message is that making formulary decisions about these pharmaceuticals will become more pressing every year.Managed care executives will be faced with the significant challenge of investing their limited resources in the most clinically and fiscally responsible manner within a milieu of ever increasing pharmacologic options that could significant lystrain budgets and result in less than optimal patient outcomes."}
+{"text": "ACS Sensors entitled \u201cSensing Technologies for Extravasation Detection:A Review\u201d1 and we appreciate theinterest it has generated in the scientific community.We recently received and checkedyour Comment about our latest Review in perse.2The authorsof the Letter pointed out remarkable observations aboutthe procedure of peripheral intravenous cannulation (PIVC) and citedinnovative and recent technologies that practitioners and cliniciansare learning to use. Since the main goal of our review is to providethe reader with an overview of the systems and strategies developedover the years to monitor the inserted catheter and possibly detectIntravenous Extravasation (IE) events, we did not go into the detailsof technologies realized for the placement of the device. Indeed,we believe that these technologies refer to a different topic (improvingthe placement and insertions of catheters in veins and arteries) anddo not really fall within the scope of our paper but could be treatedas a separate work, probably worthy of a review paper 6 The cited works are mainly related to the possibility of buildinga panel of guidelines and best practices for nurses and professionalsfor the prevention and management of IE events. This aspect is ofcourse extremely important in clinical practice and we thank the authorsof the letter for highlighting it, since these tools could be exploitedsynergistically with the technological devices we presented in ourreview and could support the human component.Some works reportedby the Comment\u2019s authors clearly demonstratethe growing interest and awareness of the need to continuously researchmethods for detection and treatment of extravasation.help themwith this. Indeed\u2014as the authors of the Comment also mentioned\u2014weshould be able to offer to the patient the best method of early detectionand identification of peripheral intravenous extravasation.This aspect isalso linked to the last comment raised by the Comment\u2019sauthors: we are aware that these technologies are not yet ready forclinical use, which is why in the last section Concluding Remarks,Challenges, and Perspectives we provided some considerations on whatwe believe are important features that an IE prevention device shouldhave. The ultimate goal was not to compare a practitioner\u2019sexperience with a technological device in detecting extravasationbut to find the best way technology can"}
+{"text": "Evidence suggests that green space use for physical activity significantly benefits to maintenance and improvement of public health. Settlements need to provide adequate access to public green spaces which enable and encourage physical activity. Provision of publicly accessible green spaces is therefore often included in different sectoral strategies and policies. However, to really meet goals and objectives, declared in these documents, appropriate and efficient actions need to be taken in spatial development practice on a local level.We present the approach, developed within the first year of the national research project PREZENCA, which aims at developing indicators for the assessment of the provision of settlements with green spaces for outdoor physical activity in Slovenian municipalities. The approach may be of interest to countries which have adequately developed strategic spatial planning of urban green spaces but lack useful tools to assess the current state and to monitor changes in the provision of quality green and other outdoor spaces to encourage physical activity.The approach is based on a comprehensive analysis of examples and possibilities for measuring presence and quantity of green spaces, defining green space types, and measuring citizens\u2019 accessibility and use of green spaces for physical activity. Content analysis of existing planning documents on a local level was carried out to elaborate: (1) whether the provision of green spaces in settlements in Slovenia is defined and how (2) which population groups are addressed and (3) where such content should be put into policy documents to support implementation in practice. Based on the results, the suggestions on relevant factors and indicators of green space provision and quality for physical activity were prepared to be further developed for evaluation and monitoring on the local level and included into spatial planning practice and policies.Furthermore, we discuss the importance of establishing local standards and possibilities to include them into planning documents to form the basis for long-term monitoring of the condition of publicly accessible green spaces for recreational use by residents."}
+{"text": "Cross-sectional data has shown that compassion for self and from others may be a protective factor for greater psychosocial wellbeing in the COVID-19 pandemic whilst fears of compassion act as a risk factor for experiencing mental health difficulties.The current study sought out to explore the natural fluctuation of compassion  and of fears of compassion  across time during the COVID-19 pandemic in a multinational community sample.Data from 4057 participants from 21 countries was collected at 3 time points during the pandemic . Other than demographic variables, participants completed the Compassionate Engagement and Action Scales and the Fears of Compassion Scales. Multilevel latent growth modelling was used to investigate the main aims.There was a significant increase in compassion for self and from others, whilst compassion for others remained unchanged throughout the 3 time points . Fears of self-compassion and compassion for others significantly reduced throughout the pandemic whilst fears of compassion from others remained stable .The findings from this study seem to suggest that in a period of shared suffering people from multiple countries and nationalities tend to become more compassionate and less afraid of and resistant to compassion for and from others.None Declared"}
+{"text": "In 2020 \u2013 2021 the Robert B. Greenblatt, M.D. Library at Augusta University implemented two projects leveraging virtual reality (VR) technology to provide immersive experiential learning opportunities for health sciences students. The projects shared some commonalities in spite of having differing objectives and desired outcomes. These common facets led to the success of both projects and will be helpful for other institutions considering implementing VR projects. This project is described in detail in a previously published article  and was The second project utilized virtual reality technology to create a VR escape room to introduce concepts of data literacy and research data management in a more engaging way. The primary objective of this project was to instruct graduate students in the health sciences disciplines how to ethically manage data. The scholarship and data librarian was inspired to find a way to gamify the information and decided to develop the virtual reality escape room. She and the allied health sciences librarian collaborated with the Department of Physical Therapy (PT) to launch a pilot project to develop the data literacy modules for the PT graduate students. The escape room game is an innovative component to engage students in a non-traditional way beyond the classroom setting. Students work their way through the escape room by finding clues, answering questions and following instructions related to data management principles. Research shows that game-based learning can increase student learning by incorporating elements of game mechanics with established learning theories .Both projects involved partnering with Augusta University's School of Computer and Cyber Sciences, in particular a faculty member who is an expert in virtual and augmented reality. His students chose to build out the VR experiences for the library's projects as capstone projects for their degree programs. This expertise proved invaluable as the library's faculty and staff did not have the skills to build the experiences themselves. The other common elements for both of these projects are that they both involved partnership and collaboration with other academic units on campus . They also both utilized the same equipment, allowing for interoperability see . Lastly,Both of the projects have been well-received. The virtual reality space in the Greenblatt Library is being utilized by at least three groups per week. The Physical Therapy students provided positive feedback about the virtual reality escape room as a method to learn data management principles."}
+{"text": "These results are noteworthy as they were obtained in patients with high degree of cartilage degeneration (Kellgren&Lawrence grades III and IV) although commonly HTO surgery is applied for patients with early and moderate OA with lower degree of cartilage degradation [I read with great interest an article by Dong et al. . The autradation . It is aradation \u20135 and deradation , we reporadation , 8 whereAnother concern about the article by Dong et al.  and otheIn conclusion, comprehensive studies of various orthobiologics associated with osteotomies including evaluation of functional outcomes at the molecular level such as analysis of proinflammatory environment and regenerative machineries should be encouraged in search for further improvement of treatment options for patients with OA."}
+{"text": "The distribution of these silver nanostars on the surface allowed excellent reproducibility of the detection with a low relative standard derivation (RSD) of SERS intensity of 8%. This work potentially builds a platform for an ultrasensitive detector where samples can be probed with little to no pre-processing and a range of pollutants can be detected at very low levels.Strategies for synthetic control of anisotropic metal nanostructures have grown in recent years in part due to their great potential for application as surface-enhanced Raman scattering (SERS) sensing substrates. It has been shown that SERS using silver substrates is a powerful tool for identification and qualification of trace chemical analysis on the basis of their unique molecular vibrations. In this work, we synthesized star-shaped silver nanostructures and fabricated SERS substrates to use the SERS enhancement of the Raman signal to detect neonicotinoid pesticides. These silver nanostar substrates were prepared by assembling the nanostar particles on a glass substrate surface using a self-assembly technique with various layers of silver nanostars film. The silver nanostar distribution on the solid substrate surface was found to have good reproducibility, reusability and were a stable SERS substrate giving SERS enhancements for pesticide detection at concentrations as low as 10 Technically, SERS occurs when conduction electrons of metal nanoparticles on the surface interact with electromagnetic radiation such as light waves, which can lead to an amplification of natural electronic oscillation. This phenomenon enhances the optical near fields to allow single molecule detection. Thus, the SERS technique is commonly used in chemistry and biology analysis because of the high sensitivity and the fact that the spectra of molecular vibrations provide a fingerprint to identify molecules .Joseph George Shapter was supported by Data will be made available on request.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."}
+{"text": "Oestrogen plays a vital role in maintaining a normal vulvovaginal epithelium, vaginal lubrication, as well as a healthy microbiome to ensure an acidic pH. The decrease in oestrogen levels in women going through menopause results in both physiological and physical changes of the genitourinary system, and more specifically the vulva. We conducted a literature review on the effects of low oestrogen levels on the physiology and function of the vulva and the vulvovaginal epithelium. \u2018Genitourinary syndrome of menopause\u2019 (GSM) is the term used to describe the signs and symptoms of a low oestrogen state. The symptoms and signs of GSM can overlap or coexist with other vulval dermatoses. Expert opinion is needed to diagnose and manage vulval dermatoses in menopause. This article will discuss the signs and symptoms of GSM, as well as the different management options available. Other vulval dermatoses that can be affected by hypo\u2010oestrogenism are also reviewed. The low oestrogen levels during menopause lead to physical and physiological changes to the female genitourinary tract. This can lead to the characteristic changes known as genitourinary syndrome of menopause (GSM). The symptoms and signs of GSM can overlap or coexist with other vulval dermatoses. Expert opinion is needed to diagnose and manage vulval dermatoses in menopause.here for the corresponding questions to this CME article.Click  This article reviews the effects of menopause on genital skin, by discussing the features and management of genitourinary syndrome of menopause (GSM), as well as other vulval dermatoses.The Cochrane Library, National Institute for Health and Care Excellence (NICE) Evidence database and the Turning Research into Practice database were searched from 2001 to 2021. In total, 116 original research articles were found on menopause in dermatology, 42 of which related to vulval conditions. Individual searches were performed for specific queries related to our paper.The embryological origin of the vulva is the primitive urogenital sinus, which is rich in oestrogen receptors, whereas the epithelium of the labia majora is derived from the ectoderm, which has more androgen receptors.Oestrogen is vital in maintaining a normal vulvovaginal epithelium, lubrication and microbiota.GSM is a constellation of symptoms and signs caused by low levels of oestrogen.A holistic and individualized approach is required to manage GSM. The aim of treatment is to relieve the symptoms and improve QoL. It is important to exclude other causes of vulvovaginal symptoms. Treatment can be classified into hormonal or nonhormonal. Nonhormonal topical therapy options are summarized in Table\u2009Vaginal and vulval lubricants and moisturizers are important first\u2010line management options to relieve the symptoms of GSM. They help to reduce the friction and discomfort caused by the dryness and atrophy of the genital tissues. A water\u2010based lubricant is generally preferred with minimal excipients to reduce vulval irritation.Hyaluronic acid (HA) is an important component of the extracellular matrix, and plays a role in the repair of the epidermis and dermis. Menopause causes a reduction of collagen and water retention of the vaginal epithelium. HA is available in various formulations, including gel, vaginal tablets, pessaries and oral tablets.The mainstay of treatment of GSM is topical oestrogen preparation. This has consistently been shown to be the most effective treatment for the symptoms of GSM, especially vulvovaginal atrophy.Topical testosterone (dehydroepiandrosterone) is also used to help with dyspareunia and urinary symptoms of GSM.Systemic HRT is an effective treatment for the symptoms associated with menopause including those of GSM.Selective oestrogen receptor modulators are a synthetic nonsteroidal class of drugs, which act on the oestrogen receptor.Lasers and radiofrequency devices have been used to treat the symptoms of GSM.Pelvic floor exercises for women who have pelvic floor dysfunction have shown to be effective as measured by improvement in QoL and GSM assessment scores.Vulval dermatoses that can present in any age group but can potentially be exacerbated by menopause include lichen sclerosus (LS), lichen planus (LP), irritant dermatitis, and vulvodynia and vulvovaginal candidiasis. Vulval malignancy is also more common with age, and therefore more common in post\u2010menopausal women.Vulval LS is an inflammatory scarring dermatosis that predominantly affects postmenopausal women. The true aetiology is unknown but an autoimmune cause and a genetic predisposition are implicated.LP is a mucocutaneous autoimmune condition. It can cause irreversible architectural change and significant morbidity.The different types of dermatitis that can affect the vulva are atopic dermatitis, irritant contact and allergic contact dermatitis. Urinary incontinence in postmenopausal women can make them susceptible to irritant dermatitis.Vulvodynia is a chronic pain syndrome in the absence of an identifiable cause.The low oestrogen state in menopause means that candidal infections are less likely, and studies have found that vulvovaginal candidiasis is more common in women taking HRT.Premalignant and malignant conditions that can affect the vulva are listed in Table\u2009Oestrogen is vital in maintaining a healthy female genitourinary system, and the low levels of oestrogen in menopause results in characteristic changes.Decreasing levels of oestrogen in menopause lead to physical and physiological changes in the vulva, which can present as vulvovaginal atrophy.GSM is the specific diagnosis given to the effects of the low oestrogen state of menopause on the genitourinary system.This review summarizes the effects of menopause on the vulva, including the specific changes associated with GSM, and giving an overview of the management of GMS, along with a discussion of other dermatoses affecting the vulva.The mainstay of treatment of GSM is topical oestrogen therapy, which is best used in conjunction with water-based lubricants and moisturizers; systemic HRT is not routinely indicated for the symptoms of GSM alone.Dermatoses affecting the vulva include LS, LP and irritant dermatitis; the symptoms of these can overlap with GSM.A holistic and multidisciplinary team approach is needed to improve QoL for postmenopausal women.Menopause and low oestrogen states lead to physical and physiological changes in the genital skin, leading to significant morbidity. It is important to recognize the changes associated with menopause in order to offer appropriate treatment and improve QoL for affected women. More research is needed on the role of hypo\u2010oestrogenism on vulval conditions and the potential role of HRT.The authors declare that they have no conflict of interest.None.Ethics approval and informed consent not applicable.To gain up\u2010to\u2010date knowledge on the female genitourinary system and disorders that can be associated with menopause.(a) The labia minora is derived from the ectoderm.(b) The ectoderm has more androgen receptors.(c) The labia majora originates from the primitive urogenital sinus.(d) The epithelium of the labia minora is lacking in oestrogen receptors.(e) An alkaline pH is ideal for the maintenance of a healthy vulvovaginal epithelium and microbiota.Which of the following is correct regarding the embryological origins of the female urogenital tract and the healthy vulvovaginal epithelium?(a) Atrophy of the vulval tissues is the only physical sign of GSM.(b) GSM affects a small minority of menopausal women.(c) Symptom severity usually correlates with physical findings.(d) The symptoms and signs of GSM can have a significant impact on patient quality of life (QoL).(e) The symptoms of GSM tend to get better with time.Which of the following statements about genitourinary syndrome of menopause (GSM) is correct?(a) Systemic hormone replacement therapy (HRT) is indicated for the management of the vulval symptoms of menopause alone in the absence of other symptoms of menopause such as vasomotor symptoms.(b) Topical lubricants and moisturizers are not routinely recommended for the relief of symptoms of GSM.(c) There is no evidence that hyaluronic acid (HA) preparations are useful in the management of the vulval symptoms of GSM.(d) Ospemifene acts on the progesterone receptors.(e) There is not enough evidence for laser\u2010based treatment to routinely recommend their use for the management of GSM.Which of the following statements about the management of genitourinary syndrome of menopause (GSM) is correct?(a) Topical oestrogen therapy should be continued as long as it is needed.(b) Regular monitoring of endometrial thickness is advised for women on long\u2010term topical oestrogen therapy.(c) Topical oestrogen therapy has rapid onset for the relief of the symptoms of GSM.(d) Topical oestrogen therapy is safe in women taking aromatase inhibitors for the treatment of breast cancer.(e) Gel\u2010based preparations are superior.Topical oestrogen therapy is first\u2010line management of the genitourinary syndrome of menopause (GSM); which of the following statements is correct?(a) It is easy to differentiate between the clinical findings of vulval lichen sclerosus (LS) and late genitourinary syndrome of menopause (GSM).(b) Genital candidiasis is more common in menopause.(c) Low oestrogen levels lead to impaired water retention in the epidermis and impaired skin barrier function.(d) Vulvodynia usually has a clear cause.(e) Menopausal women have the same risk as premenopausal women of developing a vulval malignancy.Which of the following statements about vulval dermatoses and menopause is correct?http://www.wileyhealthlearning.com/cedThis learning activity is freely available online at Read the article in print or online, paying particular attention to the learning points and any author conflict of interest disclosures.Reflect on the article.http://www.wileyhealthlearning.com/ced and answer the CPD questions.Register or login online at Complete the required evaluation component of the activity.Users are encouraged toOnce the test is passed, you will receive a certificate and the learning activity can be added to your RCP CPD diary as a self\u2010certified entry.This activity will be available for CPD credit for 2\u2009years following its publication date. At that time, it will be reviewed and potentially updated and extended for an additional period."}
+{"text": "The treatment of psychological trauma is an integral part of the health care provided to military patients in Tunisia. For patients with PTSD several therapeutic options are proposed to patients as EMDR but there are various barriers to the use of EMDR . It seems that being patients consider the therapy which necessitate recognition and expression of emotional distress as a weakness. Added to that patients may be judged negatively by others and experiencing social rejection and isolation which limited the use of EMDR in a military setting.The aim of this study is to study the contribution of the EMDR associated to pharmacological treatment in PTSD among military patients comparing to patients who received only medication .The study was conducted since 2021 during ten months at the military hospital concerned two groups of patients with PTSD the first one composed of four military patients with PTSD who received 11 sessions of EMDR associated to medication and the second one four patients exposed to the same trauma under medication only. The evolution oftroubles were assessed using PCL-5 scale and medication compliance was assessed by psychometric scale MARS .Other data was gathered from medical files .The first group of four military patients who were followed for PTSD since a year under pharmacological treatment presented sleep disorders with flaschbaks and nightmares , . The patients consulted for a depressive disorder and asocial isolation with feelings of insecurity about others. Psychiatrists proposed to associate 11 sessions of EMDR . At the end of sessions the evolution was interesting with regression of symptoms and remission comparing to the second group who presented relapses ten months later.To improve symptoms of PTSD The use of EMDR is not systematic in a culture where emotional expression is restrictive in an environment that favors the intellect over the emotions. However EMDR can help the military patients with PTSD to link cognition to the emotions. PsychiatristS should propose this therapy as well as possible to patient with severe trauma to avoid relapse .None Declared"}
+{"text": "In the published article, there was an error. A correction has been made to the Conclusion section.The Conclusion previously stated:\u201cBuilding resilience into a reformed health system will be key in ensuring Ireland's ability to respond to future threats such as pandemics. Operationalization of the EPHFs can help ensure the health system is prepared to meet the next challenge affordably and sustainably. The findings of the review have been utilized to support high level advocacy for the shift toward public health required to build and ensure health system resilience against future threats. Work is currently underway to utilize the EPHFs to define the operational scope of public health in Ireland and to identify the scope and functions of a new national public health institute and will help inform ongoing implementation of public health reform. Given the current focus on strengthening public health capacities globally, the findings in Ireland have applicability and relevance to policy audiences and key decision makers within Ireland as well as more broadly to other WHO regions and member states for health systems recovery and building back better, fairer and more resilient health systems.\u201dThe corrected section appears below:\u201cBuilding resilience into a reformed health system will be key in ensuring Ireland's ability to respond to future threats such as pandemics. Operationalization of the EPHFs can help ensure the health system is prepared to meet the next challenge affordably and sustainably. The findings of the review have been utilized to support high level advocacy for the shift toward public health required to build and ensure health system resilience against future threats. Given the current focus on strengthening public health capacities globally, the findings in Ireland have applicability and relevance to policy audiences and key decision makers within Ireland as well as more broadly to other WHO regions and member states for health systems recovery and building back better, fairer and more resilient health systems.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "The Government of Kerala in 2017 launched the Aardram Mission with the aim to revamp public health delivery in the State. A key strategy under the mission was its focus on comprehensive primary health care to achieve equitable health care delivery through the Family Health Centre (FHC) initiative. Given this, the current study aims to examine the primary health care policy discourse for their perspectives on caste-driven inequities.The study undertook a Critical Discourse Analysis (CDA) of the primary health care policy discourse\u00a0in Kerala. This included CDA of spoken words by senior health policy actors and policy texts on Aardram Mission and FHC.Though equity was a major aspirational goal of the Mission, related policy discourse around equity failed to acknowledge caste as a potential axis of health marginalisation in the State. The dismissal of caste manifested in three major ways within the policy discourse. One, the \u2018invisibilisation\u2019 of caste-driven inequities through strategies of (un)conscious exclusion of Dalit issues and \u2018obliteration\u2019 of caste differences through the construction of abstract and homogenous groups that invisibilise Dalits. Secondly, locating caste as a barrier to primary health care initiatives and health equity in the state, and finally through the maintenance of an \u2018apoliticised\u2019 social determinants discourse that fails to recognize the role of caste in shaping health disparities, specifically among Dalits in Kerala.Given Kerala\u2019s renewed commitment to strengthening its public health provisioning, the acknowledgment of caste-driven inequities is invariable in its path toward health equity and social justice. That Dalits (Scheduled Castes or SC in administrative parlance) are one of the most marginalised social groups in contemporary India is not something new to Indian academia and policymakers. While many countries have had similar hierarchisation of societies, none was as complex, pervasive, and long-lasting as the caste system that exists in India. The resilience of caste in the face of myriad historical changes including feudalism, colonial rule, and modern-day capitalism is proof enough of its adaptability and the complex grip it wields over Indian society , 2. ThisThe Indian state of Kerala despite its low economic performance is often hailed for its achievements within human development indices. The State is often considered a model, even for the third-world regions burdened with the history of colonialist exploitation and chronic developmental inequality. The developmental landscape of Kerala is marked by its impeccable achievements in the social sector reflected as high levels of life expectancy, literacy, and low levels of maternal and infant mortality . An achiThe continuing presence of health inequities along caste lines in the state is often argued as the product of deep-rooted and historically shaped caste norms leading to social exclusion and denial of opportunities of social development for Dalits including education, landownership, and employment amongst others, despite the strident growth in terms of poverty reduction and human development post the 1980\u2019s in Kerala . The expWhile Kerala achieved significant improvements over the years in human development indicators and in the domain of health, its achievements in health post the economic liberalisation of the \u201890\u00a0s have often been argued as unimpressive. Reflected through the reversal of its achievements within indicators like infant mortality rate, and childhood anaemia during the period between 2003 to 2012 . In additranslated as \u2018New Kerala\u2019) Mission conceived by the incumbent government (led by the Communist Party of India (Marxist)), that sought course corrections in terms of the historical exclusion of various social groups within the state\u2019s developmental trajectory. The Nava Kerala mission within its umbrella consisted of four key sub missions 1) The Aardram mission, 2) Life mission , 3) mission to revamp public education and 4) \u2018Haritha Keralam\u2019 mission . These missions were part of the Left government\u2019s aspiration to ensure a developmental model that is much more equitable and inclusive of the underprivileged and marginalised sections in the state [In full recognition of the widening gaps within the health landscape in terms of reduced public presence and growing distrust in the public health system, the Government of Kerala initiated the Aardram Mission in 2017 [he state .The Aardram mission through its approaches, therefore, also aligned itself with the new national policy roadmap set out by the National Health Policy, 2017 that sought to achieve Universal Health Coverage. These included initiatives such as \u2018Ayushman Bharat\u2019 that aimed at the transformation of Primary Health Centres and Sub-Centres as Health and Wellness Centres (HWCs) with the specific aim of delivering Comprehensive Primary Health Care that is easily accessible for communities at the grassroots , 23. On The policy affirmation on comprehensive primary health care through the Aardram mission along with the other three missions under the \u2018Nava Kerala\u2019 Mission, therefore, presents itself as a unique opportunity for the state to take cognizance of unaddressed health inequity gaps that continue to exist in Kerala. The current study, therefore, locates itself within this context of revived commitment on the part of the Government of Kerala on comprehensive primary health care, reflected through the Aardram and FHC initiative and aims to examine how it problematise the situation of Dalits and the ways to overcome their health challenges.Health policy and systems research (HPSR) has over the years gained substantially from its engagement with the construct of power and its analysis, specifically to gather a nuanced understanding of the mechanisms and structures that generate health inequities and disparities. Application of theories on power and deeper empirical examination of its dimensions does hold significance in the attempts to locate health policies as also a product of wider social, political, and historical contexts and to drive potential revisions and improvements to generate equitable health outcomes through them. Power here is defined as the capacity \u2018to do something or act in a particular way\u2019 and \u2018to direct or influence the behaviour of others or the course of events. Quite crucial, as power relations do hold the ability to shape societies and societal interactions and thereby also in the process shape health and related policies and subsequent health outcomes. The current study specifically draws from the idea of analysing power and how it may flow through societal expressions in the context of health policies and systems. To analyse how power manifests and expresses itself within health policies reflected through their unique positionalities and expressions of social relations and in turn how they may also engender health disparities .One of the suggestive methods to undertake the analytical examination of words both written  and oral  is using a Discourse Analysis approach. It facilitates a deeper examination of oral and written acts of communication to bring to the fore the subtle yet shared ways of perceiving the world around us and what may be considered normal , 27. DisThe application of CDA was guided in the current study using the four-phased approach to CDA Fig.\u00a0 suggesteThe formal policy documents related to Aardram and FHC were sourced from multiple sources. The Aardram document on FHC was collected from the office of the State Health Systems Resource Centre, Department of Health, Government of Kerala in Thiruvananthapuram. In addition, documents on the Aardram mission available from the website of the National Health Mission, Kerala were also sourced. The policy officials\u2019 narratives on primary health care and their ideas on various marginalised communities in Kerala were prepared through in-depth interviews with seniormost policy officials at the Directorate of Health Services (DHS), Department of Health, Government of Kerala (GoK). This involved interviews with officials from the Directorate of Health, District Medical Officers (DMO) as well as District Program Managers (DPM) under the National Health Mission and senior officials of the State Aardram mission Table . The finA central idea within CDA is the fact that social actors from different social locations see and express the world differently and exploring the use of language within discourse could be a way to bring out these differences . This isThe analysis of the policy discourse on primary health care in the current study primarily pivoted itself to the dimension of equity from a caste lens. Specifically, through the examination of how equity and its dimensions are being expressed within the policy discourse on Primary Health Care. This has been undertaken by examining how the policy discourse problematise health vulnerabilities in the state and subsequently examining the nature in which caste is being discussed within the discourse on health inequities in the State. The CDA of the policy discourse in this regard points to three related aspects. Firstly, the discursive strategies adopted by policy actors that aimed at Dalit \u2018invisibilisation\u2019 within the policy discourse. These include methods such as the overt exclusion of references to caste as a potential axis of health vulnerability and/or through subtle ways of obliterating caste differences and thereby mobilising health vulnerabilities to inexistent social groupings that further invisibilise Dalits. Secondly to locate caste as a barrier to effective primary health care strategies and thirdly through \u2018apoliticised\u2019 discourse on social determinants that is devoid of the consideration to caste-driven health disparities in the State.A common theme within the discourses on marginalised social groups was the ways in which they carefully avoided references to caste as a probable axis of marginalisation in Kerala, where dimensions of caste remained obvious through their unignorable absence. Discourse that excludes caste-related marginalisation also by extension remain blind to the situation of Dalits in the state and prioritised efforts in the context of primary health care initiatives in the State.The policy official Table , Quote 1Dalit exclusion was also found shaped within the policy discourse through their discursive subsumption under abstract and homogenous social categories.One of the ways in which the policy narratives discursively obliterated caste differences was through the construction of an abstract \u2018general community\u2019 and limiting ideas of marginalisation exclusively from the point of geographically and religiously tangible social groups Table , Quote 1A second way of discursively obliterating caste differences is through the forceful imposition of logics of economic inequality over caste-driven inequities in Kerala Table , Quote 2Yet another way caste was found subsumed within other categories is through the homogenous category of \u2018SC/ST\u2019 Table , Quote 3Within the policy document, the word SC appears 5 times, yet in all these instances it is never used or defined in its own right as a specific social class but always as \u2018SC/ST\u2019. Although a possible fallacy in the argument here would be the unique contexts in which these terms may be appearing within the policy document justifying the clubbing of SC and ST. While it may not be completely wrong to argue so, the document however without delineating the unique social realities and health needs of two completely different social groups, such homogenising narratives can only further reinforce the existing discursive patterns of subsuming caste groups under the abstract category of \u2018SC/ST\u2019. One that may do justice, neither to Dalits nor to Aadivasis in terms of recognising their differential health needs and thereby pre-empting the possibility of providing equitable primary health care services.To be read along with the patterns of caste invisibilisation achieved through its subsumption within constructed abstract social groups is the perception of caste as a barrier to novel primary healthcare strategies in the State. The discourses on marginalisation largely perceived caste as a fractural construct that can negatively influence the implementation of primary health care strategies, and by implication renders consideration of caste within primary health care modalities as a negative idea.The narratives related to primary health care innovations often tend to iterate the need to approach the community as a homogenous group Table , Quote 1The narrative also further considers the exclusion of certain social groups as normalised and a taken-for-granted requirement in the context of primary health care innovations anywhere. This is established through the statement that \u2018it is always difficult to consider only a small section\u2019 and \u2018there is always the barrier of some sections not accepting innovations.\u2019 This view by extension is also normalising and legitimising exclusions that continue to exist in the case of various marginalised sections of the community including Dalits in Kerala as a given within local primary health care-related projects.Yet another way caste was excluded and located as a barrier was through the relegation of caste as an irrelevant grouping when it comes to the idea of primary healthcare Table , Quote 2However, even this narrow take on social groups evidently turned problematic, upon pointed inquiries of caste as an axis of marginalisation Table , Quote 2The analysis of the State Government\u2019s Aardram Policy document too points to a discourse that is blind to the existing caste-driven disparities in the State. The policy document on Aardram and Family health centre specifically stood out in terms of its unique representation of Dalits and in its complete absence in terms of not recognising caste as an axis of inequity and a social determinant of health marginalisation in the State.Most striking is the way in which the FHC document locates the word Scheduled caste within its considerations for health care priority Table , Quote 1While the policy also suggests the idea of marginalised communities and specific care for them, here too it fails to speak explicitly about social groupings based on caste in its discourse on marginalisation in Kerala Table , Quote 3The Aardram mission and the FHC initiative clearly suggest Kerala Government\u2019s commitment to reviving the primary health care provisioning in the State. This is also reiterated by the fact that it pivots itself on comprehensive primary health care as its approach to achieve the larger goals of equity and social justice for the state. However, the analysis of the policy suggests the persisting gaps in its conceptualisation and articulation of equity and underprivileged specifically from a caste lens. The existing discourse on marginalisation within the primary health care policy in Kerala is characterised by a blindness to caste-driven inequities and the existing social realities of Dalits as a marginalised social group. One that is also curious given its acknowledgment of Adivasis and coastal communities as marginalised, groups which too are historically marginalised in the State , 37\u201339. A good place to start here would be, therefore, to problematise the nature of representation of caste as a possible axis of marginalisation in Kerala as well as the ways in which the policy engages with Dalits. The primary health care policy discourse examined in the study was evident in its dismissal of the caste question or in recognizing caste as a potential axis of marginalisation. The policy narratives were characteristically evident with an ominous reluctance to mention the word caste or scheduled castes related to discourses on marginalisation and health inequity in the state. Beyond the recognition of Adivasi and coastal communities, the marginalisation narratives in the current study almost exclusively existed along the axes of biomedical markers of age and sex, access to drinking water, and hygiene. The palpable need to dismiss any reference to caste within marginalisation discourses within the current study alludes to a conscious or unconscious yet strong repugnance towards discussions on caste. Quite similar to what sociologist Satish Deshpande argued in his thesis on \u2018castelessness\u2019, where he discusses how various historical legal, and policy decisions on the issue of caste and reservation in India have shaped a new \u2018common sense\u2019 of caste in India. He argues that the word caste is almost often immediately reinterpreted as \u2018lower castes\u2019 within the collective discourses. This also has parallels to similar recontextualizations within other universal categories of gender and race. Gender is almost often construed as women from a conventional patriarchal common sense and race as people of colour from a white supremacist sense .The reductionist logic of caste as \u2018lower caste\u2019 has significant relevance in the current study too, since dismissing caste also by extension suggests the exclusion of Dalits themselves as a marginalised social category. Through the avoidance of discussions on caste, there is an uncanny resemblance of the Brahminic logics of purity and impurity being carried over to the realm of social discourses on health and by extension exclusion of Dalits. An evident contempt to even discuss caste among the ruling elites, leading to the existing caste blindness within policies. This is also in line with the \u2018Social Nausea\u2019 argument by sociologist Awanish Kumar, where he argues that Indian policy today suffers from the potent combination of social isolation backed by the regressive notion of Brahminical caste and that of social nausea of elite castes towards utterances of caste and Dalits. The result is the inability of public policies on health to effectively address the real issues of the masses in India . The facThe discursive ostracization of Dalits also seems to have been facilitated by the differences in the geographical attributes of Aadivasis/coastal communities and Dalits in Kerala. Historically Aadivasi and fisherfolk communities have remained distinct from their non-Aadivasi/coastal counterparts in Kerala. Specifically, in terms of the almost exclusive geographical presence of Aadivasi communities along the Western Ghats and fisherfolks within the long coastal belts of Kerala with their own distinct socio-cultural identities , 47, oneth report of the Administrative Reforms Commission of the Kerala government, majority of the state\u2019s slum population is constituted by marginalised Dalit sections and is characterised by poor housing status, subpar infrastructural facilities, and sanitation services amongst a host of others [What\u2019s also not helping is the adversarial position historically adopted by the political left including Communist parties in India and in Kerala towards caste and caste-identity politics. The urgency in declaring caste-identity politics as an antithetical force to Marxian class politics has often contributed to the political left\u2019s inability to accommodate the struggles of various historically marginalised social groups in India including Dalits . The subf others . Besidesf others . The resf others . HoweverAn obvious corollary being the stark contradictions within the state\u2019s health policy that is adamantly caste blind despite chronic disparities both in terms of access to basic determinants of health as well as health outcomes among Dalits. A toxic contrast, arguably drawn from the \u2018Savarna (upper caste) gaze\u2019 that is relentless in its attempt to normalize Dalit invisibilisation within its discourse on health inequities. Achieved in this case through clandestine ways of shaping discourse on health inequities that is quick to deny the spotlight on caste-inequities either through dismissal or by \u2018mobilising health vulnerabilities\u2019 to amorphous social groupings that shall never have a Dalit focus as its priority. A rather lucid demonstration of how caste continuously arranges and rearrange itself to find ways and means to continue its status quo and maintain the social order of caste hierarchies in Indian societies . These pI, therefore, argue that as a first step it is important to deconstruct current policy discourses on development in the state by carefully breaking them down to their individual contradictions that constitute their exclusive positions and subjecting them to deeper understanding and subsequent problematisation . InsightWhile there is a renewed rhetoric against health inequities under the Aardram mission and FHC initiative, the Kerala health system\u2019s policy discourse on primary health care suggests the persisting presence of a \u2018Savarna gaze\u2019 that is quick to dismiss the role of caste-related social hierarchies in shaping health disparities among Dalits in the state. Through a discourse that is silent about existing caste-driven health inequities, the renewed policies on comprehensive primary health care under the FHC initiative also stand to engender social practices of primary health care at the grassroots in the state through various Local Self-Government Institutions (LSGIs) that are also similarly blind to caste inequities. This is crucial as a key anchor point for the implementation of the Aardram mission and FHC initiative is the ability of decentralised LSGIs across Kerala to pro-actively undertake and implement the strategies envisioned through the mission at the level of communities at the grassroots . The pol"}
+{"text": "Extensive research has demonstrated the effectiveness of physical activity interventions for middle aged and older adults (MAOA). Despite this effectiveness, the actual reach of the target population participating in these interventions in a real-world setting remains relatively low. This demonstrates the urgent need for further implementation research. In the Netherlands, this need has been recognized earlier, leading to the foundation of the ZonMW financed Implementation Network Sports and Physical Activity: the presenters in this symposium are all members of that network.The aim of this symposium is to describe barriers and facilitators regarding implementation that were determined by qualitative studies among MOAO and stakeholders. In addition, the development of a practical tool that stimulates implementation by stakeholders is presented. These studies were grounded in relevant scientific frameworks such as Consolidated Framework for Implementation Research (CFIR) and Implementation Mapping. This symposium also provides recommendations for future research and practice in the shape of potential strategies that can be applied when implementing interventions."}
+{"text": "Managed care pharmacists are faced daily with choices regarding how to deliver the best care with finite resources. Whether it is through encouraging appropriate utilization of medications via formulary management and drug utilization evaluation or through chronic diseasemanagement programs, pharmacists are guiding patient care with effectiveness, quality, and an eye toward value. It is with these goals in mind that pharmacists can benefit from the research produced by the Agency for Healthcare Research and Quality (AHRQ)."}
+{"text": "Klippel\u2013Trenaunay syndrome (KTS) is a very rare vascular malformation syndrome also referred to as a capillary\u2013lymphatic\u2013venous malformation with unknown aetiology. The aim of our paper is to highlight interesting images, regarding a rare case of foetal Klippel\u2013Trenaunay syndrome diagnosed prenatally in our department and confirmed postnatally with a favourable evolution during the gestation and neonatal periods. This case was diagnosed at 26 weeks gestation and characterised through ultrasound by the presence of superficial multiple cystic structures of different sizes spreading over the left leg with hemihypertrophy and reduced mobility. The cystic lesions were spreading to the left buttock and the pelvic area. The right leg and upper limbs had normal appearance with good mobility. There were no signs of hyperdynamic circulation or foetal anaemia, but mild polyhydramnios was associated. The ultrasound findings were confirmed postnatally, the left leg presented multiple cystic lesions and port wine stains, and there was hypertrophy and fixed position, with favourable evolution at 6 months of life, when the size of the lesions began to decrease and the mobility of the leg improved."}
+{"text": "The translation of evidence based practice to clinical care in rehabilitation settings has been limited , 2. It cDespite such challenges, the effective implementation of evidence based cognitive rehabilitation treatments is essential and the process of clinical implementation for cognitive rehabilitation has been specifically investigated \u20137. In anboth before and during the implementation of the intervention are integral to delivering flexible interventions in practice. Additional modifications that may occur in clinical practice include applying an intervention to a clinical population that was not included in the empirical research or to an individual who may not have met inclusion criteria in the research studies associated with the intervention  approach in inpatient stroke rehabilitation, was conducted at five rehabilitation hospitals in Canada . In thisIt is likely that increased integration of implementation science and knowledge translation paradigms in the area of cognitive rehabilitation will allow for increased communication and collaboration between cognitive rehabilitation researchers and practitioners and will contribute to increased development of flexible evidence-based protocols that can flow from the research lab to the more fluid demands of the treatment environment. Such flexibility will allow for guided modifications to evidence-based cognitive rehabilitation treatment protocols and data driven application of cognitive rehabilitation which aligns with clinical recommendations. Formal tracking and documentation of needed and implemented modifications, as well as improved dialogue between researchers and clinicians are necessities. Such dialogue will encourage a common language through which to communicate about cognitive rehabilitation concepts  and to d"}
+{"text": "Comprehensive sexuality education is a scientifically accurate global program that encompasses the variable aspects necessary for achieving healthy sexual and reproductive health in children of school-going age. It provides a holistic approach to developing sound knowledge and a positive attitude in a manner that does not blatantly refute the established sociocultural norms but rather delicately treads around them to bust unhealthy practices through age-appropriate measures. It is deemed necessary for health professionals to be appropriately trained to better convey sensitive information regarding sexual and reproductive well-being in a manner that is acceptable and effective, especially in the context of orthodox communities. The available guidelines of CSE help to explore the very sensitive aspects of sexuality without becoming flustered and without imposing ideas upon the recipient. The need for health professionals to receive formal training to be able to answer potential queries in an effective manner would help relieve the enormous health burden arising from mere ignorance.5In 2018 Comprehensive sexuality education (CSE) was defined by United Nation Educational, Scientific and Cultural Organization (UNESCO).6 Being thus backed up by the scientific community we felt much more confident in putting our plans into action.During our internship, we proposed to conduct a health awareness program in a local government school targeting school-going children between grades 8 and 10. At the end of our session, we hoped to better equip our target group with the basic information needed to make informed choices regarding their sexual behaviour, strengthen their relationships with their friends and family and respect and appreciate their interpersonal differences. Being medical students gave us a scientific edge in addressing the anatomical and physiological aspects of adolescence. But we understood a sensitive topic like itself would require us to be strong yet approachable to break the ice with our participants. It would be challenging to overcome reservation and shyness on both ends. There was also the risk of coming across as being \"vulgar\" or instigating risky behaviour by \"putting ideas in one's head\". We felt the need to find established and tested age-appropriate norms in communicating sexual information to the impressionable young minds of children. In doing so we discovered the CSE program by UNESCO along with several studies conceding to the efficacy of this program in perpetuating much of the same goals as ours. Opposed to the common misconception that such programs encourage young adults to engage in risky sexual acts studies showed that two in three CSE programs provided evidence of a decrease in risky sexual behaviour and encouraged responsible decision-making like the use of contraception.Before the main event, we decided to conduct a mock session amongst our own team to better apprehend the questions that could arise on an actual day. Surprisingly many of us had strikingly different views on the same topics. This instigated extensive debates and arguments among ourselves making us realise that it was necessary to recognize our goals clearly and not impose our personal beliefs or practices onto others in order to succeed. This persuaded us to seek formal training from certified CSE trainers. We felt it was important to avoid imprinting personal opinions particularly regarding grey areas into the minds of the young children and only deliver facts in the form of a clear message. Recalling our own school days brought to us the revelation that hardly any of us had any definite knowledge on a lot of sexual and reproductive topics as adolescents. Much of what young adults know is theoretical and the little practical knowledge they do have is borrowed from social platforms or from conversations with their peers. Even in medical school much of what is taught describes unhealthy sexual behaviour and hardly any literature is found painting a healthy sexual relationship. This later poses problems in the form of unclear concepts and inadequate vocabulary. Overcoming the uneasiness with our own friends and discussing openly during our training made us realize that knowing earlier what we knew then could have saved us from tremendous anxiety and uncertainty while growing up. The training proved very insightful and we realized that even after medical school there was much to learn.7We conducted our pilot program as a tutor-based peer-to-peer learning with two tutors, a male and a female, assigned to a total of 20 trainees. It comprised health education, demonstration, information exchange and active question-and-answer sessions. Young adults are naturally inquisitive and have the ability to soak up information like a sponge. But even so, as anticipated talking about anything even remotely associated with sex caused them to initially show inhibition and shyness. But once they overcame the awkwardness we found them to be remarkably inquisitive and brimming with queries. The open and casual discussion enabled us to unmask traditional firmly rooted beliefs like menstruation being a time of \"ridding body of impure blood\" and the lack of clarity regarding bodily processes like \"menstrual blood flows from the same opening as that for urine\". Busting myths in a delicate yet affirmative manner was the most challenging of all tasks but our formal CSE training had prepared us for that part. Above everything we had learnt that it was necessary to respect our subjects for them to reiterate our teachings. In several instances, we felt that the training had prepared us to avoid potential controversies and grey moral grounds while still providing an appropriate and acceptable response. The receptiveness and kindness that the children demonstrated were a fresh breath of air. We were truly overwhelmed with how fulfilled we felt towards the end of the program and this has only fuelled us to conduct more such programs thereafter. We understand that a limitation to CSE programs, especially in South Asian settings due to cultural normative patterns can be the elimination of dialogue regarding pleasure and sexual fluidity. This may be due to the portrayal of sex as problematic behaviour and not as a natural entity.Available literature from the last three decades offers strong evidence for the effectiveness of CSE. School programs can be framed to be initiated early on and delivered successively over increasing grades to build up knowledge in a manner that is age appropriate and essential. Health professionals should seek to be better informed regarding the aspects of CSE to delve better into prevention medicine. The need for formal training on CSE is necessary to better reiterate learning objectives without potentially harming the existing cultural sentiments and dissuading the participants. It would also help in acquiring clear concepts and an appropriate vocabulary to interact without becoming flustered while remaining respectful to the target audience. As medical professionals, we are capable of sending out enormous ripples of positive changes. Only through formal training and indulgence in research can we equip ourselves for the battle against ignorance. It is upon ourselves to seek to become adequate before we begin to address inadequacies. While there may be limitations to what can be comfortably included in our discussions, it is time we start where we stand and begin the climb to a better view."}
+{"text": "We thank the authors  for elevBecause meat intake is often at the crux of scientific debate on optimal healthy, sustainable diets for the population , this reThe DGA model dietary patterns that are intended to provide examples of healthy dietary patterns use food groups and subgroups rather than individual foods and beverages to avoid being prescriptive . The modWhile the authors  compare"}
+{"text": "We read the article by Theodoraki K and colleagues entitled \u2018Colloid Preload versus Crystalloid Co-Load in the Setting of Norepinephrine Infusion during Cesarean Section: Time and Type of Administered Fluids Do Not Matter\u2019 with interest . The aimThere are some possible related concerns worth being discussed further.1. The intraoperative use of hydroxyethyl starch (HES) solutions remain controversial regarding that the perioperative use of HES have increasingly been reported to both the US Food and Drugs Administration and the European Medicines Agency (EMA) . Accordi2. According to an international consensus statement, maternal hypotension following spinal anesthesia should be treated or prevented routinely with vasopressors . In this3. In a study aiming to determine the effects of in vitro hemodilution with HES on the coagulation status of women, it was concluded that an HES solution causes significant hypocoagulable changes in the thromboelastographic profile . From an4. The safety category of HES during parturiency and breastfeeding is C, which means \u2018the effects on fetus is unknown and adverse effects were obtained in animal reproduction studies on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks\u2019. There are not enough data to recommend the use of HES for children, and it is widely accepted that administration of HES to pregnant and breastfeeding women must be limited to emergency cases only .Given the abovementioned concerns and the relevance of coagulation abnormalities that might eventually result into extensive bleeding and a hysterectomy and the limitations provided by EMA, is it worth using HES instead of using vasopressors as the first-line therapy in patients undergoing cesaren delivery without any hemodynamic instability?We believe that clarification of these issues will result in better deductions and improve the anesthetic management of parturients with safety concerns."}
+{"text": "This is the authors\u2019 response to peer-review reports for \u201cInformation Technology Ambidexterity, Digital Dynamic Capability, and Knowledge Processes as Enablers of Patient Agility: Empirical Study\u201dComments and Responses by the Authors MethodsDescribe the study [Move the highlighted (in the reviewed manuscript) content under Data Collection Procedures to a new subsection under subsection heading Study Population (see comments in the reviewed manuscript)The highlighted content should be under a new subsection heading Study DesignProvide content on another two subsection headings:Sampling TechniquesSample SizeSeparate content under Data Collection Procedure into two new subsection headingsData Collection Tool and ProcedureData Analysis and ManagementMove Table 1 to Analyses & Results sectionProvide content under two new subsection headings: Inclusion and Exclusion CriteriaEthics ConsiderationsAuthors: The sections mentioned in this review  are esseInclusion and exclusion criteria were combined with sample size, as we described how we got the final sample and why we included respondents (and why not).AbstractDo not begin a sentence with abbreviation of figureUse past tense under Methods See comments in the reviewed manuscriptIntroductionUse physicians in lieu of doctorsUse health care providers not other medical professionalsKeep in-text citation to the end of sentenceAdd health information management professionals among the key stakeholdersConsider reducing the whole of section 2  to 1-2 paragraphs and keep it within the Introduction section just before your study objective. This is to reduce readers\u2019 boredom.Compress the content under research models and hypothesesResultsMake your findings more visible hereMake your writing more readable to known and unknown readersDiscussionPlausible and insightful discussion but not a reflection of the content under the Results. Make the Results section more readable and meaningful to your audience.FigureUse Fig not FigureAcknowledgement It is scientifically necessary that you acknowledge the numerous (n=107) participants, who are the major stakeholders in your research.ReferenceList at least 3 authors before et al Follow the Referencing Style consistentlyOthersUse participants not respondentsAuthors: We adjusted this accordingly.Thank you for the opportunity to review this paper on the lesser known topic of information and communications technology ambidexterity. The paper is well cited, uses appropriate methods, and discusses the concepts and findings in a clear and thorough manner. The paper should appeal to a broad audience. It is a good example of the underrepresented information and communications technology\u2013centered literature in health care.Authors: We would like to thank this reviewer for these kind words . We hopeWell thought out study design with specific hypotheses and methods of analysis spelled out. Interesting conclusions drawn out that would be fruitful for further discussion and analysis to replicate on a broader sample of hospital systems outside of the current reviewed sites.Authors: We would also like to thank this reviewer for these kind words . We agre"}
+{"text": "Reply to the Editor:The authors reported no conflicts of interest.Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.The We thank the author for his interest in our article titled \u201cConventional Versus Miniaturized Cardiopulmonary Bypass: A Systematic Review and Meta-Analysis.\u201dIt is well known that cardiopulmonary bypass induces a systemic inflammatory response due to the contact of the patient's blood with nonendothelial surfaces and air, which is accompanied by an increase in cytokine levels. The attenuation of this inflammatory response is associated with a reduction of morbidity and mortality after cardiac surgery.We note that the author reported the formation of a colloid film as an incidental finding during the administration of polygeline (Emagel) for volume integration in the establishment of cardiopulmonary bypass. The use of a colloid film as a solution to temporarily reduce air\u2013blood contact in optimized open circuits has both potential benefits and risks.,The elimination of the air\u2013blood interface reduces contact activation of blood components when exposed to air, especially with longer perfusion times . However,Colloid solutions are effective in increasing circulatory blood volume and maintaining colloid osmotic pressure in cardiopulmonary bypass. However, the use of such solutions increases the cost of cardiac surgery and may cause adverse reactions such as histamine release, resulting in hypotension, bronchospasm, and skin rash.The hemodilution effect caused by large amounts of colloids could result in an increased risk of stroke or other neurological events through cerebral hypoperfusion.Although the formation of a colloid film reduces air\u2013blood contact for a short period of time, the clinical benefits of this are not well investigated. The use of solutions to limit air\u2013blood contact in optimized open circuits is thought provoking, and more research is needed to fully evaluate its effectiveness and safety."}
+{"text": "BackgroundPost-operative complications present a challenge to the healthcare system due to the high unpredictability of their incidence. However, the socioeconomic factors that relate to postoperative complications are still unclear as they can be heterogeneous based on communities, types of surgical services, and sex and gender.MethodsIn this study, we conducted a large population cross-sectional analysis of social vulnerability and the odds of various post-surgical complications. We built statistical logistic regression models of postsurgical complications with social vulnerability index as the independent variable along with sex interaction.ResultsWe found that social vulnerability was associated with abnormal heart rhythm with socioeconomic status and housing status being the main association factors. We also found associations of the interaction of social vulnerability and female sex with an increase in odds of heart attack and surgical wound infection.ConclusionsOur results indicate that social vulnerability measures such as socioeconomic status and housing conditions could be related to health outcomes. This suggests that the domain of preventive medicine should place social vulnerability as a priority to achieve its goals.The authors would like to note that Mohamed Abdelhack and Sandhya Tripathi contributed equally to this work."}
+{"text": "A more dynamic school day that includes less sitting and more physical activity throughout the day may support health in primary school children. In this mixed methodologies study, we assessed which physical activity possibilities are incorporated in the school policies of Dutch primary schools and if this translates into more physical activity in pupils.Seven primary schools were included in the study. The head teachers completed a questionnaire on the incorporation of physical activity in the school policy. Physical activity policy was assessed for physical education, physical activity during breaks, scheduling of physical activity during lessons, after school physical activity and active transport to school. In each school, actual physical activity was objectively measured using accelerometers in pupils in two classes and planning and logging of PA by teachers.We will assess the impact of the school policy on physical activity in pupils using logistic regression. We will assess the impact of the several school policies on total physical activity in pupils, and on the three  modalities of physical activity.The results of this study will give us more insight in the current role of physical activity in Dutch primary schools. The potential impact of the school policy on physical activity levels in pupils can be used as a starting point for a more integral dynamic school day approach.This study was partially funded by \u201cStichting Westelijke Tuinsteden\u2019."}
+{"text": "Chicken breast meat is one of the most sustainable and affordable sources of animal protein making it one of the most popular protein sources globally. As such, maintaining consistency in product quality is of the utmost importance. Over the last decade three novel myopathies have been identified in broilers (White striping (WS), Wooden breast (WB) and Spaghetti breast (SB)) ; there hThe exact aetiology of the myopathies is still not fully understood however a wide range of studies have used gene expression , proteomGenetic selection for broiler performance traits such as bodyweight (BW) and breast yield (BY) has been a core theory as a cause of the myopathies. Published data of large populations of broiler pure lines have estimated low genetic correlation between the three myopathies and performance traits (BY and BW), this indicates there is little shared genetic background between the myopathies and broiler performance traits ; 2020. HThere are many non-genetic factors that can influence broiler growth rates such as incubation, brooding, nutrition, temperature and ventilation . A key aOxidative stress and hypoxia have been highlighted as a key feature of all three myopathies  thereforWhilst genetic correlations indicate that there are no significant links between the myopathies and bird growth at the genetic level, phenotypically it is often the larger birds in a flock which express the myopathies. This phenotypic relationship is not always the case however, as some studies report that WS and WB are not linked to bird weight . Wooden One approach to influencing growth is reducing nutrient intake by diluting or limiting the availability of feed; these methods ultimately impact upon the efficiency of production through poor bird growth or the birds compensate by eating more food and thus do not offer a suitable solution . By targvia the intermediate guanidinoacetic acid (GAA)   but thisid (GAA) . Exogenoid (GAA) ; 2018b.Increasing dietary antioxidants such as vitamin E and selenium have been used to reduce oxidative stress and myopathies but results have been mixed and may depend upon the quality of fat in the diet . A novelpost mortem, the authors stated that SB was not and thus not described fully due to the uncertainty; this raises the question of whether SB is present in the live bird (post mortem change in the muscle. Immediately post mortem, muscle pH drops as a result of lactic acid production which is accompanied by the release of proteolytic enzymes (post mortem changes in the muscle and thus increase SB incidence in a flock. The rate of cooling of carcases post mortem has an influence on the rate of lactic acid production and the activity of the proteolytic enzymes (Spaghetti breast is probably the least understood myopathy  and its ive bird  or only  enzymes . This pr enzymes  and, in  enzymes \u2014the slow enzymes . The useBreast myopathies remain an important focus for the poultry industry and the poultry science community, and it is clear that there is still a lot to understand. The reduction in breast myopathies relies on a holistic approach to control: Balanced breeding by poultry breeders can target the genetic component but the larger influence from non-genetic factors remains an important focus area. Understanding the biological needs of the muscle and ongoing physiology in the modern broiler provides key time-points for strategies to reduce the myopathies and gain more insight into their aetiology ."}
+{"text": "Due to a production error, an incorrect Conflict of Interest statement was provided. The correct Conflict of Interest statement appears below. The publisher apologizes for this mistake.\u201cThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u00ae. After investigation, the journal has no reason to believe that the scientific conclusions of the article are affected in any way.\u201dA reviewer of this manuscript, Devan Mehrotra, is a biostatistician at Merck & Co., Inc., known as MSD outside the United States and Canada. The pharmaceutical ivermectin studied in this manuscript is manufactured and marketed by Merck & Co., Inc. in the United States under the brand name STROMECTOLThe original article has been updated."}
+{"text": "It is much more important to know what sort of a patient has a disease, than what sort of disease a patient has.William Osler1Despite powerful narratives echoing a purported existence of meritocracy in our society, major racial and ethnic disparities in health and healthcare have persisted for hundreds of years. Yet a clear understanding of structural societal inequities and not innate group differences underlying the racial disparities in health was articulated nearly 200\u2009years ago by Dr. James McCune.It was not until the 1985 Report of the Secretary's Task Force on Black and Minority Health, led by Dr. Margaret Heckler, that the nation could accept such disparities as a problem worthy of consideration. Soon thereafter, the 2003 Institute of Medicine report entitled \u201cUnequal Treatment: Confronting Racial and Ethnic Disparities in Health Care\u201d sought to not only codify racial and ethnic group differences in health outcomes, but emphasized these were due to how people were treated and not due to innate attributes. It also identified how this mistreatment led to differences in the quality of and access to health care.AHRQ Equity Agenda and Action Plan that was created to help guide priorities to advance health equity. This commentary addresses two interrelated articles, written by Chisholm et al.The emerging focus on the quality of and access to health care at the turn of the 21st century was embraced by the Agency for Healthcare Research and Quality (AHRQ) who in 2003 started to formally track disparities in health care delivery as it relates to racial and socioeconomic factors in priority populations. This formal tracking of disparities played a critical role in developing the evidence base for health systems to improve and advance their ability to provide the best care to all of us. Spurred by the Coronavirus 2019 (COVID\u201019) pandemic and the 2020 murder of George Floyd, the US health care system faced a social and health equity justice movement. This movement emphasized the role of racism and the inequitable distribution of the social determinants of health (SDoH), the broad set of forces and systems shaping the conditions of daily life, as major driving forces in health disparities and major root causes in the racial and ethnic disparities in the access to and quality of health care. In 2022, AHRQ sponsored a Health Equity Summit to bring together multiple working groups from the 2021 2Chisholm et al.Jindal et al.Together, these articles reflect the importance of how addressing inequities in access to and quality of health care must be done with consideration of systemic racism and intersectionality, and emphasize the importance of high\u2010quality research to inform equitable health care delivery.These outcomes and recommendations from the AHRQ's 2022 Health Equity Summit help to more optimally position AHRQ to address inequities in access to and quality of health care, created and once again perpetuated by legal decisions during this time of potential new limits in tools we have available to achieve equity. The importance of a focus on the SDoH as a pathway through which racism works is critical given the potential implications of the new Supreme Court rulings, which state that universities can consider \u201can applicant's discussion of how race affected his or her life, be it through discrimination, inspiration, or otherwise.\u201d3AHRQ's Health Equity Summit was prescient in its timing, preceded two major landmark events with major implications for the health equity landscape\u2014the recent Supreme Court rulings , which have ended affirmative action in college admissions and yet allowed discrimination based on free expression despite public accommodation laws. These rulings do not mean that racial and ethnic or other identity\u2010based inequities no longer exist, particularly with regard to health. However, these rulings limit the approaches that can be used to address health inequities, particularly those focused on health workforce composition or regulations requiring equal provision of service. We will collectively need to innovate to ensure that health systems have the appropriate research findings and data to implement requisite solutions to reduce health disparities and improve health equity. This is why a focus by AHRQ explicitly on equity in access to and quality of health care will be critical, as AHRQ can be the driver for necessary health equity innovation through its research agenda and funding priorities.Some have argued that health care organizations are not well equipped to take on many of the root causes of health disparities such as inequities in the allocation of social determinants of health (SDoH).However, to truly reverse many of the structural and longstanding issues that underpin health inequities, AHRQ will need to directly partner more closely with affected communities.4Ensuring health equity is critical for all of us in the care we receive from health care delivery systems, especially the components that affect our ability to access care. Implementation of these proposed approaches for AHRQ to infuse its research agenda would be important steps toward achieving health equity.Dr. Ong receives relevant funding from the Agency for Healthcare Research and Quality (K12 HS026407) and the Department of Veteran Affairs Health Services Research & Development (CIN 13\u2010417). Dr. Norris receives relevant funding from the National Institutes of Health ."}
+{"text": "Rapid assessment of avoidable blindness (RAAB) is a population-based survey methodology that is designed to provide a simple and affordable \u2013 yet reliable \u2013 estimate of the prevalence and causes of vision impairment and blindness among people aged 50 years and older in a defined population. RAAB is therefore an important tool in achieving the global eye health priorities set out by the World Health Organization's World Report on Vision and the Lancet Global Health Commission on Global Eye Health.,RAAB surveys provide the majority of the data used to estimate the global and regional prevalence and causes of vision impairment, as well as data which are vital for tracking progress towards eye health within universal health coverage, such as effective cataract surgical coverage and effective refractive error coverage.www.raab.world) collates RAAB survey results and datasets and makes them available for secondary analyses; data from 118 of the 330 RAABs carried out since 2000 have has been made available for this purpose. We encourage more RAAB survey principal investigators and data owners to share their data via the repository, so that the global eye health community collectively can have a more comprehensive and powerful evidence base for research and advocacy.The RAAB repository ("}
+{"text": "In our study  we reconVariations in monsoon moisture supply are a crucial physical process to disentangle, and isolating the influence of atmospheric black carbon  is a welWhile the study of Yang et\u00a0al.  demonstrThe rapid decline of glaciers in the Southeastern Tibetan Plateau threatens the sustainability of its water resources, and understanding these two complementary drivers will help to design mitigation measures and refine projections of glacier and hydrological changes."}
+{"text": "Standardization Is Necessary in the Methods to Assess the Value of Electronic Prescribing Systems In the May 2005 issue of JMCP, we reported that an electronic prescribing system with integrated clinical decision support was effective at improving prescribing behavior and lowering prescription costs. In contrast, Ross et al. reported in the June 2005 issue of JMCP that a different electronic prescribing system  had no impact on generic drug utilization or formulary compliance."}
+{"text": "Individuals with schizophrenia exhibit severe speech and Theory of Mind (ToM) deficits creating substantial handicaps for them on the level of communication and interpersonal skills. Consequently, these individuals cannot adequately take part in social life, and are exposed to marginalization in all aspects of life. Hence, communication impairments associated with schizophrenia are a central issue to investigate in order to optimize their quality of life and functioning in society. The study being part of an interdisciplinary research is based on guided interviews related to a short story by Hemingway. The analysis of person deictic expressions related to social emotions and social interactions combined with the most frequently used mental state terms  identified in the corpus may not only describe the severity of linguistic disturbances indicating ToM deficits but can also help understand patients\u2019 social dysfunction and difficulties in the context of social cohesion.The primary task of the functional linguistic research is to identify and classify the occurrence of linguistic disturbances during mentalizing processes expressed via mental state terms. The study particularly focuses on interpersonal relations expressed with person deictic forms that may indicate the difficulties of this patient group with social cohesion.The End of Something. The interviews were digitally recorded and transcribed in Hungarian. The qualitative analysis was performed with Sketch Engine corpus analysis tool, which assisted in the identification and classification of collocations associated with the interviewees\u2019 mental processes directed at interpersonal relations expressed by person deictic forms.The corpus involves 40 guided interviews including 20 individuals with schizophrenia treated at the Department of Psychiatry of the University of P\u00e9cs and 20 controls. The interviews were conducted by a PhD student of Psychology in Hungarian and centred around Hemingway\u2019s short story entitled \u2018I don\u2019t know\u2019 combined with person deictic expressions revealed that individuals with schizophrenia have difficulty attributing mental states to a specific linguistic utterance during a social situation (e.g. \u2018I don\u2019t know why somebody said that\u2019). These examples show that their communicative and interpersonal skills are substantially impaired.Pragmatic processes including the communicative aspect showed severe deficiencies. The most commonly used mental state term The findings can offer some possible indications for psychotherapists how to detect pragmatic impairments in schizophrenic speech and interpret mental state terms with reference to social interaction, thereby contributing significantly to therapeutic success enhancing the social reintegration of individuals with schizophrenia.None Declared"}
+{"text": "Frontiers in Cell and Developmental Biology presents an exciting series of articles encompassing significant developments in the application of Pluripotent Stem Cells (PSCs) to the treatment of ophthalmological diseases. Diseases affecting the retina and its associated innervation present significant societal challenges since treatments are frequently limited to symptom management and slowing the progression of the disease rather than affecting a complete cure. Conditions such as Age-Related Macular Degeneration (AMD) characterised by declining functions of both the retinal pigment epithelium and neural retina, and Glaucoma which involves dysfunction of retinal ganglion cells and the optic nerve, currently affect approximately 280 million individuals worldwide. Without the means to repair the damage to retinal structures, the impact of these diseases will worsen as the numbers of older individuals in the global population increases; thus the costs of disease management are likely to rise significantly. In view of these sobering observations, the number research efforts aimed at increasing our understanding of retinal degeneration and developing methods to ameliorate the decline are encouraging.Rohowetz and Koulen in this Research Topic is exciting since it provides a highly informative review of the current state of the art in RPE transplantation. A key point arising from this publication is that the safety of RPE transplant seems to be promising and that adverse events arising during the procedure are more likely related to surgery induced damage or to the need for immunosuppression which indicates the need for more precise HLA matching; however, an alternative strategy to eliminate the need for immunosuppression might be to generate RPE cells from \u201chypoimmunogenic\u201d iPSC lines in which the assembly of the MHC-I major histocompatibility complex at the cell surface is inhibited by homozygous knockout of the gene encoding \u03b2-2-microglobulin . Of particular value is the light responsiveness of organoid photoreceptors (in vivo retinogenesis and restate disease phenotypes seen in patients (V\u00f6lkner et al. to this series is valuable because it further optimises the process of retinal organoid generation which will be of considerable use to other groups in this field. The last publication in this series published by Wahlin et al. explores early retinal development by introducing markers of eye field development that may be used to distinguish those cells that have committed to a retinal development fate from those that may be forming cells that contribute to other regions of the CNS.The remaining two papers in this series add to our understanding of pluripotent stem cell derived retinal organoid development. This is an important enquiry since many of the cell types generated in 3D retinal organoids show more advanced maturity than those generated by 2D differentiation protocols (with the exception of eceptors  which unpatients . NaturalOverall, we have enjoyed reading these incisive articles and we hope that the reader will draw the same level of inspiration and enjoyment from this special series highlighting the great contributions of pluripotent stem cells to the understanding and potential treatment of eye diseases."}
+{"text": "In a review of UK-supported clinical trials more than half of the investigators asked the funding agency for an extension and a third did not hit their recruitment targets . Study fPreviously we investigated the requirements of clinical and protocol development experts for a system to support trial design and recruitment. We developed a software architecture which addresses their primary concerns: preservation of consent for consent; improving the efficiency of the trial design process and automation of as much as possible of the recruitment workflow . The FARWe have worked with local clinical research organisations to evaluate FARSITE, running recruitment criteria for on-going clinical trials through FARSITE and comparing our estimates of numbers of patients eligible for the trial with the trials\u2019 actual recruitment rates. A strong correlation was observed between protocols with a low FARSITE recruitment estimate and trials struggling to recruit participantsWe have shown that FARSITE can improve the speed and efficiency of clinical trials feasibility, allowing researchers to quickly assess the feasibility of trials in advance."}
+{"text": "Crude and fractionated Xenopus egg extracts can be used to provide ingredients for reconstituting cellular processes for morphological and biochemical analysis. Egg lysis and differential centrifugation are used to prepare the crude extract which in turn in used to prepare fractionated extracts and light membrane preparations. Current Protocols in Cell Biology.The complete text protocol for this experimental approach is available in"}
+{"text": "This research is concerned with the peristaltic flow of third order nanofluid in an asymmetric channel. The governing equations of third order nanofluid are modelled in wave frame of reference. Effect of induced magnetic field is considered. Long wavelength and low Reynolds number situation is tackled. Numerical solutions of the governing problem are computed and analyzed. The effects of Brownian motion and thermophoretic diffusion of nano particles are particularly emphasized. Physical quantities such as velocity, pressure rise, temperature, induced magnetic field and concentration distributions are discussed. Peristaltic motion is now an important research topic due to its immense applications in engineering and physiology. This type of rhythmic contraction is the basis of peristaltic pumps that move fluids through tubes without direct contact with pump components. This is a particular advantage in biological/medical applications where the pumped material need not to contact any surface except the interior of the tube. The word \u201cperistalsis\u201d comes from a Greek word \u201cPeristaltikos\u201dwhich means clasping and compressing. The peristaltic flow has specific involvement in the transport of urine from kidney to the bladder, chyme movement in gastrointestinal tract, movement of ovum in the female fallopian tubes, blood circulation in the small blood vessels, roller and finger pumps, sanitary fluid transport and many others. Latham Heat transfer in cooling processes is quite popular area of industrial research. Conventional methods for increasing cooling rates include the extended surfaces such as fins and enhancing flow rates. These conventional methods have their own limitations such as undesirable increase in the thermal management system's size and increasing pumping power respectively. The thermal conductivity characteristics of ordinary heat transfer fluids like oil, water and ethylene glycol mixture are not adequate to meet today's requirements. The thermal conductivity of these fluids have key role in heat transfer coefficient between the heat transfer medium and heat transfer surface. Hence many techniques have been proposed for improvement in thermal conductivity of ordinary fluids by suspending nano particles in liquids. The term \u201cnano\u201d introduced by Choi The aim of present study is to venture further in the regime of peristalsis for fluids with nanoparticles. Therefore we examine here the mixed convective peristaltic transport of third order nanofluid in an asymmetric channel. Channel asymmetry is produced by peristaltic waves of different amplitude and phases. Mathematical modelling involves the consideration of induced magnetic field, Brownian motion and thermophorsis effects. Numerical solution of nonlinear problem is obtained using shooting method. Limiting case for viscous nanofluid in symmetric channel is also analyzed. Detailed analysis for the quantities of interest is seen.Extra stress tensor Consider third order nanofluid in an asymmetric channel of width To facilitate the analysis, we introduce the following transformations between fixed and wave framesThe dimensionless boundary conditions are given byOur main interest in this section is to examine the velocity (This subsection illustrates the behavior of emerging parameters The variations of or  and  \u201313.Effect of heat transfer on peristalsis is shown in the Influence of mass transfer on peristalsis is shown in the The variations of Trapping phenomenon is shown in the A detailed analysis is presented for peristaltic transport of third order nanofluid in an asymmetric channel with an induced magnetic field and mixed convection. The main findings of the presented study are listed below.Pumping rate increases with Velocity distribution is increasing functions of Deborah number at the centre of channel. Absolute value of axial velocity and pressure rise in third order nanofluid is larger than viscous nanofluid.Influence of Temperature distribution is an increasing function of Brownian motion parameter (Induced magnetic field increases with"}
+{"text": "The recent development and implementation of a catheter-based approach to denervate the renal sympathetic nerves in patients with resistant hypertension has ensured that the sympathetic nervous system (SNS) remains on center stage in cardiovascular medicine (Krum et al., Sympathetic neural drive is dependent on a range of factors including race, sex, and age. This idea is developed further in the review of Fu  who poinThree articles acknowledge the limitations of multiunit MSNA and emphasize the increased information associated with recording single unit MSNA. Single unit recording is technically more difficult; however, it provides a more precise description of the way vasoconstrictor neurons behave during a sympathetic burst. Upon our previous findings, we (Lambert et al., The SNS has long been recognized to play a central role in cardiovascular regulation, and targeting sympathetic activity is certainly a therapeutical approach in the treatment of many cardiovascular diseases. Thus, a reliable tool to assess SNS activity such as microneurography remains essential in order to comprehend the physiological mechanisms underlying disturbed SNS activity and to assess the effects of therapeutical strategies. It is anticipated that assessment of both multiunit and single unit will remain central in future investigations related to cardiovascular health."}
+{"text": "In humans the two cerebral hemispheres have essential roles in controlling the upper limb. The purpose of this article is to draw attention to the potential importance of ipsilateral descending pathways for functional recovery after stroke, and the use of non-invasive brain stimulation (NBS) protocols of the contralesional primary motor cortex (M1). Conventionally NBS is used to suppress contralesional M1, and to attenuate transcallosal inhibition onto the ipsilesional M1. There has been little consideration of the fact that contralesional M1 suppression may also reduce excitability of ipsilateral descending pathways that may be important for paretic upper limb control for some patients. One such ipsilateral pathway is the cortico-reticulo-propriospinal pathway (CRPP). In this review we outline a neurophysiological model to explain how contralesional M1 may gain control of the paretic arm via the CRPP. We conclude that the relative importance of the CRPP for motor control in individual patients must be considered before using NBS to suppress contralesional M1. Neurophysiological, neuroimaging, and clinical assessments can assist this decision making and facilitate the translation of NBS into the clinical setting. Reaching forward with the arm to manipulate objects with the hand is a quintessential function for higher order primates. Upper limb movements involve a fine balance between proximal stability and distal dexterity, presenting a unique motor control challenge to the central nervous system. There is a growing body of evidence that skilled upper limb function is under the control of both contralateral (cM1) and ipsilateral (iM1) motor cortices  provide objective information about corticospinal tract integrity. TMS and DWI can be used in combination with clinical measures to predict the potential for recovery of function with rehabilitation (Stinear et al., It is becoming increasingly clear that skilled function of the upper limb relies on the balance of excitability of cM1 and iM1 in healthy adults. In this article we propose a neurophysiological model of ipsilateral neural control of the proximal upper limb via the CRPP. The model highlights the importance of understanding how the degree of compensatory activity in the contralesional hemisphere after stroke contributes to paretic upper limb function across a range of impairment levels. It is proposed that NBS protocols are not \u201cone size fits all\u201d and should be carefully selected based on individual patient characteristics. Research has targeted the development of structural and functional biomarkers that can be combined with clinical tests to allow NBS to be individually prescribed as an adjuvant to therapy after stroke. These methods of patient stratification based on objective measures of impairment should be used to determine the optimum intervention in future studies of NBS in stroke. Individualization may increase effectiveness of NBS in clinical trials and expedite translation from research laboratory to the clinical setting.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "This article introduces the concept of \u2018cognitive comorbidity,\u2019 which lays emphasis on common cognitive deficits that cut across different disorders. The concept is illustrated with the help of two commonly reported overlapping conditions (autism and epilepsy). It is further explained by concentrating on two important cognitive processes of facial emotional recognition and emotional memory, shown to be compromised in both conditions; and their underlying neural substrates. Cognitive comorbidity is then contrasted with \u2018comorbidity,\u2019 a term which is more commonly used for describing cognitive disorders. The paper closes by providing directions for rehabilitative and theoretical efforts that could be inspired by the newly introduced concept. This article aims to introduce and understand the concept of \u2018cognitive comorbidity\u2019 and differentiate it from the more common usage of the term \u2018comorbidity\u2019. The current paper strives to achieve this aim by describing the overlapping symptoms of autism and epilepsy. These two disorders are chosen as examples because of the high rate of association between the two . This article is not an attempt to discuss the comorbidity between these two disorders in the technical sense of the word \u201ccomorbidity,\u201d as it is described in scientific literature but to discuss and highlight the overlap of cognitive deficits. All through, the focus will be on cognitive processes and references to brain/neural structures are provided to advance understanding of the concept. This way of explanation is hoped to be a better method from the viewpoint of theoretical formulations and would also help to throw light on the issue of \u201ccomorbidity,\u201d the way it is described in the scientific literature. Therefore, first the description of comorbidity is given, which is followed by a brief introduction to the disorders.Fried, Ferrucci, Darer, Williamson & Anderson (2004) explain comorbidity as, \u201cthe concurrent presence of two or more medically diagnosed diseases in the same individual, with the diagnosis of each contributing disease based on established, widely recognized criteria\u201d.The DSM-IV defines autism as a disorder with impairments in socialization, imagination and communication with stereotyped repetitive interests . Autism is a prototypical example of autism spectrum disorders (ASD). The term ASD is used to define life-long developmental disorders of the brain with variable severity . Approximately one-third of the children on the autism spectrum are shown to develop epilepsy .Epilepsy is defined as two unprovoked seizures of any kind that result from genetic defects, due to diffuse or focal pathology in the brain, or due to an unknown cause. Thus seizures due to trauma, infection or metabolic illness are not defined as epilepsy .et al. 2004; Beversdorf et al. 1998; Paesschen et al. 1996). Two most important tasks that have been conducted to demonstrate the cognitive deficits are facial emotion recognition and emotional memory task. Facial emotion recognition and emotional memory are hypothesized to be dependent upon the integrity of functional connections between amygdala and the fusiform cortex  and between amygdala and the hippocampus respectively . Consistent with the hypothesized relations, Brierley et al. (2004) showed inefficient performance by patients suffering from epilepsy and amygdala damage on the two tasks. Their emotion recognition task dealt with perception of affect from faces and voices while the emotional memory tasks dealt with narratives and novel word recognition. There was also a lack of association between the emotional memory and the emotion recognition tasks, thus showing that these two are different cognitive processes.The neurobiology of autism and epilepsy, especially temporal lobe epilepsy, can be similar; that is, the integrity of the amygdala has been found to be compromised in both the disorders; and various cognitive tasks conducted on people inflicted by both of these separately reflect this compromised integrity  also proposed two different neural connections responsible for supporting performance on the two tasks where deficits in facial emotion recognition could arise due to disruptions of connections from the amygdala to the fusiform cortex, and problems on the emotional memory task could arise due to disruptions of connections from the amygdala and hippocampus. Similar performance deficits are also shown by the autistic subjects of Beversdorf et al. (1998) on an emotional memory task. Beversdorf and colleagues presented emotional sentences and coherent/incoherent stories and word lists to their autistic and normal subjects. Autistic and normal individuals showed comparable performance on recalling coherent/incoherent word lists and stories but differed only with respect to recalling emotional sentences, with the autistics remembering lesser number of emotional sentences. Deficits of emotional facial recognition have also been observed for autistics where they showed normal performance on a facial discrimination task but impaired performance on emotional facial recognition task . These results put together show that the two cognitive processes can be disturbed in both the disorders.Brierley This paper makes an initial attempt to highlight the common cognitive processes that might be disturbed in both the conditions giving a possible clue to the comorbidity, in this case, cognitive comorbidity. The paper does not go into the details of different types of autistic spectrum problems or different types of epilepsies as the aim is to highlight broad cognitive processes that could be disturbed. It only concentrates on the common neural and cognitive substrates. By highlighting the issue of cognitive comorbidity, the paper is a step in the direction of encouraging researchers to investigate such issues by looking at the overlap of cognitive deficits between disorders and not to emphasize \u201ccomorbidity\u201d based on the incidence rate of the disorders.The previous sections show that emotional memory and emotional facial recognition could be disturbed in a similar manner in both the disorders despite the fact that these two disorders are totally different from each other. In order to provide direct support for the concept of cognitive comorbidity, we need studies that concentrate on examining the performance of both autistics and individuals with epilepsy on these tasks in the same study so that direct comparisons could be drawn. In its current state, the concept of cognitive comorbidity could only be indirectly supported with findings from separate studies and thus future studies need to be planned not only on these two disorders but other similar cases of disorders that have been reported in the literature as comorbid or associated disorders; for instance, attention deficit hyperactivity disorder (ADHD) and tics.Research directed at theories of cognitive disorders and cognitive rehabilitation would save precious efforts if guided by the concept of cognitive comorbidity as this would discourage separate research attempts focusing on different disorders and would definitely go a long way in encouraging coordinated efforts at understanding the overlapping cognitive deficits that cut across the different categories of disorders. It becomes a lot easier to explain the nature of cognitive functions that are disrupted in a similar manner across different disorders but it is difficult to explain these disruptions across two different disorders especially when the current thrust of the field is to place disorders into separate categories. Emphasizing on cognitive comorbidity also helps one apply precious successful attempts of rehabilitation designed to address an underlying cognitive deficit across the disorders but this can only be done when it is known that similar cognitive processes are disturbed. To come up with different rehabilitation programs for different disorders can be very costly, especially if one follows the strategy of placing these into different categories as this can happen at the cost of ignoring the common underlying cognitive substrates.Current article highlights the concept of cognitive comorbidity by elucidating the differences and similarities between autism and epilepsy. The hypothesis still requires direct comparison of patients suffering from both autism and epilepsy on the commonly disturbed processes that support emotional memory and emotional facial recognition. Direct comparison in this manner will not only be helpful in providing support for the cognitive comorbidity hypothesis but will also help us understand the common underlying symptoms that might be important and hence could be targeted commonly across the disorders. This will help us save previous time and resources deployed for treating different disorders separately. For instance, if research shows that emotional memory and facial emotional discrimination are commonly disturbed in both autism and epilepsy, one single intervention strategy (e.g. cognitive rehabilitation program) could be easily designed for autistics and patients of epilepsy. Providing support for cognitive comorbidity might not work well with researchers and clinicians who are looking for more discrimination among the disorders for the purpose of classification and distinction among various categories but this concept could potentially work well for therapists who deal with many patients and suffer from time constraints. Efforts directed at cognitive comorbidity will work well with patients and their families who are not happy to be tagged by some diagnostic label or the other.It is hoped that future work in this direction can be instrumental in stimulating research and highlighting other such overlaps that will be ultimately useful in constraining theories about cognitive processes and also trimming diagnostic criteria and saving precious resources geared towards interventions.This article makes an attempt to highlight the cognitive comorbidity between autism and epilepsy where the structural and the functional integrity of the amygdala is compromised. Hence, there are similar cognitive deficits in both the disorders observed on two tasks, namely, facial emotion recognition and emotional memory, which are supported by the amygdala. Work also shows that these two cognitive processes are not correlated with each other and either both or one of them can be disturbed in autismNone declared.This work or parts of it are not published anywhere else.How can the concept of cognitive comorbidity be extended to other cognitive disorders?How can clinicians save on precious resources by developing the concept of common disturbance among disorders and develop intervention techniques accordingly?How well can this concept of cognitive comorbidity be integrated into popular classifications like the DSM?Should we altogether abolish placing cognitive disorders into various classifications and only focus on overlapping cognitive profiles? http://www.jspsciences.org and as the editorial member of the New School of Psychology Bulletin www.nspb.netNeha Khetrapal is currently a graduate student at the Centre of Excellence \u201cCognitive Interaction Technology\u201d (CITEC) and the Faculty of Psychology and Sport Sciences, investigating the interaction of spatial processes and language and is supported by Deutsche Forschungsgemeinschaft (DFG) grant managed through the Graduate School of CITEC, Germany. She has been a holder of various awards, and the most important recognition earned by her is from Marquis Who\u2019s Who in the World for 2009. The author also serves currently as the reviewer for Journal of Social and Psychological Sciences"}
+{"text": "Tracheostomy is common in the acute care facility today. The care for these patients is challenging for the nurses in the ward where knowledge and skill is tested and often lacking resulting in emergency shift of these patients to ICU. As we found it difficult to care for this group in the wards inspite of continous training, we decided to have a dedicated tracheostomy ward for patient safety and better outcome. As a part of training, this module on tracheostomy care was developed by the medical ICU nurses.Tracheostomy is common in the acute care facility today. The care for these patients is challenging for the nurses in the ward where knowledge and skill is tested and often lacking resulting in emergency shift of these patients to ICU. Often chronic patients tend to be overlooked in Infection control practices (ICP)aspect. This leads increased Health care associated infections (HAI) along with increased morbidity & mortality.To reduce the HAI in tracheostomy patients by ensuring proper infection control practices implementation by effective training module.As we found it difficult to care for this group in the wards inspite of continous training, we decided to have a dedicated tracheostomy ward for patient safety and better outcome. As a part of training, a module on tracheostomy care was developed by the medical ICU(MICU) nurses. Infection control issues are discussed in these patients as they are patients on long term care All the sisters who take care of patients having Tracheostomy are educated with the help of this audio visual medium. Also hands on training is provided with the help of a mannequin.The care is improving in these patients. This is reflected in lower HAI rates and decrease in number of patients returning to the ICU\u2019s from wards with tube blocks and aspirations.Continuous training is the most important part for sustaining ICP in a healthcare setup. We identified the tracheostomy patients as those falling in the high risk category for HAI. We could successfully train our sisters and implement the tracheostomy care practices and bring down the HAI rates.None declared."}
+{"text": "Gloucestershire Learning Disability Partnership is a collaborative service of NHS Gloucestershire and Gloucestershire County Council. It serves over 2500 people with a learning disability and is currently working to incorporate telecare and telehealth into its mainstream services. We believe this proposed presentation would fit under the Developing Applications at Scale category. The Partnership Commissioners recognising the internal barriers to effecting telecare and telehealth applications commissioned a service from external providers which substantially improved service and reduced costs as compared with in-house telecare assessments and implementation. A new partnership was established with two external providers: Allied Health care/Tunstall. Their work is exemplified in the attached case study. The Learning Disability Partnership is now able to commission the evaluation of requirements, establishing the baseline and effecting the necessary changes in a continuous stream. This is now being rolled out across the county for learning disability services.The barriers to success: the internal barriers which prevented telecare and telehealth from happening. How we get in our own way to making change happen.How we commissioned around the barriers and achieved success.The case study and other examples of significant service improvements and savings.The next generation:At the front end of services the partnership is now actively using teleprompting, geofencing and GPS systems to facilitate the enablement of people with a learning disability and enhance their abilities to be independent. Service users express delight in having control of their own lives versus having \u2018support workers\u2019 follow them around (DVD available).Q and A. The main presenter would be Chris Haynes, an accomplished international speaker winner of the Queens Golden Jubilee Medal for Public Service and currently Joint Commissioner of Learning Disability Services.The presentation would follow the following format:There will be representatives from Allied and Tunstall on hand to discuss their involvement and how it works."}
+{"text": "The exhaled breath of more than four hundred patients who presented at the Environmental Health Center \u2013 Dallas with chemical sensitivity conditions were analyzed for the relative abundance of their breath chemical composition by gas chromatography and mass spectrometry for volatile and semi-volatile organic compounds. All presenting patients had no fewer than four and as many as eight co-morbid conditions. Surprisingly, almost all the exhaled breath analyses showed the presence of a preponderance of lipophilic aliphatic and aromatic hydrocarbons. The hydrophilic compounds present were almost entirely of natural origin, i.e. expected metabolites of foods. The lipophile, primarily C3 to C16 hydrocarbons and believed to have come from inhalation of polluted air, were, in all cases, present at concentrations far below those known to be toxic to humans, but caused sensitivity and signs of chemical overload. The co-morbid health effects observed are believed to be caused by the sequential absorption of lipophilic and hydrophilic chemicals; an initial absorption and retention of lipophile followed by a subsequent absorption of hydrophilic species facilitated by the retained lipophile to produce chemical mixtures that are toxic at very low levels. It is hypothesized that co-morbid conditions in chemically sensitive individuals can be predicted from analysis of their exhaled breath. All of these patients presented with between four and nine co-morbid conditions. It was anticipated that the chemical compositions and concentrations of these chemicals in the exhaled breath could be predictive of chemical sensitivity and other co-morbid conditions.Of the more than 400 patients, the records of thirty randomly chosen individuals were selected for detailed study. These individuals ranged in age from 12 to 86 years with a median age of 47.7, and 70% were female. Between 40 and 120 chemicals were identified in the exhaled breath of each patient. As the concentrations of all were low ( in the part per billion range), the top 20 in abundance were taken as significant for potential impact. The presenting patients who were analyzed for relative abundance all had between 4 and 9 distinct points of impact of the chemicals in their bodies and all had exhibited signs and symptoms of chemical sensitivity. The breath analysis samples were collected in a less polluted environmentally controlled room by the methods of Rea and Phillips Rea . Air colThe compounds found in the exhaled breath of these patients were almost exclusively exogenous lipophilic C3 to C16 aliphatic and aromatic hydrocarbons. Hydrophilic compounds were almost all endogenous. The concentrations measured were orders of magnitude lower than the known toxic levels of these species. The abundances of the top 6 at times were relatively high, in the 200\u20131000 part per billion (ppb) range, but still far below the known toxicity levels for these compounds.Since almost exclusively lipophilic exogenous compounds were identified in the analysis and because of the similar toxicological properties of these compounds, the lipophils were considered as additive and treated as such.et al., et al., et al., et al., All presenting patients had nervous systems and immune system impacts and most had respiratory, cardiovascular and gastrointestinal impacts as well. All had a minimum of 4 and a maximum of 9 different systems affected. et al., et al., It should be noted that lipophilic hydrocarbons are not known to attack any of the systems listed above with the exception of the nervous system, but the nervous system is not known to be impacted by these compounds at the low levels found  exhaled butane and one exhaled propane, despite the fact that those species were not present in ambient air.It was anticipated that certain organ/system effects could be associated with specific exhaled chemical species. Though all patients exhibited multiple system effects, this did not turn out to be the case. Essentially no exogenous hydrophilic chemicals were found in the exhaled breaths of the study group. Numerous lipophilic hydrocarbons, however, including the very low molecular weight propane and butane were exhaled by patients despite not being present in the air gradients of the room in which these individuals were studied.et al., et al., It is hypothesized that the finding of lipophilic hydrocarbons in the alveolar air of individuals with zero values recorded for their ambient less polluted room air gradients is indicative of relatively long term retention of these chemicals. This hypothesis is consistent with the known toxicology of these chemicals, i.e. that they are metabolized/eliminated much more slowly than hydrophilic species  and tobacco smoke. The results presented here suggest that chemically sensitive individuals should avoid exposures to these sources as much as possible.Members of the subject study group were found to have numerous systemic ill health effects triggered by chemicals and having one of their diagnoses as Chemical Sensitivity. Their exhaled breath analysis revealed the presence of a preponderance of low level lipophilic hydrocarbon species, that alone are believed to be of very low toxicity, and essentially no exogenous hydrophilic species. The ill health effects induced are believed to be caused by the establishment of a steady state lipophilic layer on body membranes and subsequent exposure to toxic hydrophilic species results in the lipophile facilitated absorption of hydrophilic species that would otherwise not be absorbed. This sequential absorption of chemical mixtures is believed to be responsible for the onset of environmentally induced systemic effects in people. The presence of exogenous lipophilic chemicals in the exhaled breath of chemically sensitive individuals is believed to be predictive of neurological, immunological, respiratory, cardiovascular, gastrointestinal and other health effects in such people.These findings point out the need to limit environmental exposures to lipophilic chemicals even at levels far below their current permissible exposure levels (PELs). It is also recommended that PELs for chemical toxicants be reduced by at least one order of magnitude and that air and water pollution allowable concentrations likewise be significantly lowered."}
+{"text": "The purpose of this viewpoint is to provide rationale for the cellular investigation of blood flow restriction (BFR) in the absence of exercise, as this may provide a novel insight into the mechanisms exclusive to the restriction stimulus itself. Most of the research on BFR thus far has been completed with BFR in combination with low intensity resistance training. To illustrate, BFR in combination with low intensity exercise has consistently been observed to result in improvements in muscle size and function  activity observed with low intensity resistance exercise combined with BFR are greater than those observed with resistance exercise alone (Takarada et al., Many hypotheses exist for the mechanism behind the beneficial effects observed with BFR; however it may be necessary to research the effects of BFR in the absence of resistance exercise in order to allow for a clearer picture of what is physiologically occurring with the BFR stimulus itself. We would like to suggest that acute muscle swelling may be the mechanism behind the reductions in muscle size and strength declines observed following surgery or cast immobilization. In addition, this swelling may also help explain the increases in muscle size and strength previously observed from slow walking in combination with BFR (Abe et al.,"}
+{"text": "Spigelian hernia (SH) is rarely seen in pediatric age group and is usually associated with cryptorchidism on the same side; termed as a syndromic association of the defect in the Spigelian fascia and absence of gubernaculum and inguinal canal. The absence of the inguinal canal has surgical implication as to placement of the undescended testis into the scrotum. A 3-month-old baby presented with spigelian hernia and ipsilateral impalpable testis. The spigelian hernia was repaired and undescended testis which was present in abdominal wall layers was brought to scrotum with cord structures anterior to external oblique muscle. SH is rare in children with only 59 pediatric cases reported up until 2012 since its first description in 1935.[1-4] The anatomical basis of SH is weakness in the SH belt arising from a transversus abdominis aponeurosis between the lateral edge of the rectus sheath and the semilunar line that stretches from the ninth rib to the pubic tubercle. Whereas adult SHs are considered to be acquired because of trauma or increased intra-abdominal pressure, pediatric cases are suspected to be congenital. Among male infants with SHs, 75% are associated with cryptorchidism.[6] The association of ipsilateral undescended testis and SH is being debated whether it is a cause or effect relationship. Raveenthiran suggested that a defect in the Spigelian fascia combined with ipsilateral cryptorchidism, may be a part of new syndrome.[7] Rushfeldt and others suggested that the additional lack of a gubernaculum and inguinal canal in similar cases, may be considered as two additional and closely connected elements of this new syndrome.[2] We have managed a 3 months old male child who presented with SH and ipsilateral undescended testis along with all the features of this new syndrome.A 3-month-old male baby was admitted with a swelling on the right side of abdomen and absence of testis on the same side. The swelling increased in size on crying. The swelling occupied right lower quadrant of the abdomen and was non-tender. On genital examination, the left testis was normally descended and right one was impalpable in scrotal pouch and inguinal area . Ultrasonography of the swelling revealed an echogenic tissue consistent with testis in the layers of abdominal wall along with small gut loops echoes. At operation a defect found on the lateral border of rectus abdominis muscle around the arcuate line with a hernial sac containing testis without any inguinal canal and gubernaculum .The sac was opened and the testis was separated from the sac. The defect in the abdominal wall was repaired by absorbable sutures and testis placed in the right sub-dartos pouch by placing the cord structures anterior to the external oblique muscle (subcutaneous route). In the post operative period child remained well and discharged home after 3 days.Cryptorchidism in children presenting with SH is considered to be a congenital condition. There has been considerable speculation and controversy regarding the possible mechanism of cryptorchidism in SH. According to the general viewpoint, SH is the primary defect and the undescended testis takes the path of least resistance to descend and lie in the hernial sac accounting for this association. Raveenthiran speculated an ectopic location of the testis is the primary abnormality, and it leads to formation of SH by dragging a peritoneal sac along with it.[7] Rushfeldt et al believed in failure of development of gubernaculum as an inciting event; [2] thus inguinal canal could not develop and the testis remain in their intra-abdominal position.Ultrasonography helps in assessing the size of the defect and contents of the hernia sac. The management of this anomaly includes repair of the hernia and scrotal placement of the undescended testis. While undertaking surgical repair of SH, one should look for an undescended testis, and expect it to be in the hernia sac. Furthermore, since an inguinal canal may not be found, one should be prepared to perform an orchidopexy either via a subcutaneous route or a new internal ring may be created through the abdominal wall medial to the inferior epigastric vessels and just lateral to the pubic tubercle.[4] However one should be careful in orchidopexy by creating neo internal ring as testicular atrophy has been reported in one patient.[4] The possible reported explanations for such an outcome include vascular damage, tension and compression of the cord and scrotal infection.Source of Support: NilConflict of Interest: None declared"}
+{"text": "We build a model of cuttlefish chromatophore excitation patterns due to environmental input. Specific inputs generate scripted chromtophore pattern responses on the surface of the skin. More complicated responses are then assembled from these templates as sequences of inputs arrive. We build a simplistic cuttlefish brain using neural architecture modeling tools written in MatLab which allow us to construct the brain model from individual modules using a vector addressing scheme  Figure .Inputs come into the sensory input module and are processed by the cuttlefish brain architecture into signals sent to the output module. The signals activate the individual chromatophores in the usual way giving an essentially binary on/ off pixel response. Different cues in the environment are mapped to known cuttlefish pigmentation overlays on the surface of the skin. Individual simple cues result in coarse patterns of chromotophore activation and upon receiving a sequence of simple cues, more complicated responses are constructed in a hierarchical fashion .The chromatophore visibility is known to be due to a brain signal which when received energizes a ring of muscle which contracts and pushes a dot of ink up to the surface of the skin. Hence, activation signals lead to visible dots and lack of activation signal can be inferred from the loss of the pigment dot. Our model therefore treats each chromatophore as a binary switch which moves from 1 to 0 or vice versa depending on the signal sent to the output module from our cuttlefish brain processing ,4."}
+{"text": "The percentage of sports and leisure shoes sold worldwide is gradually increasing. However, consumers have little or no objective information on the mechanical properties of the shoes. A justified selection protocol of sports and leisure shoes based on static and dynamic shoe properties considering the intended use is essential. Today, commonly accepted dynamic test protocols for (sports) shoes do not exist.The development of an artificial parametric foot as part of an innovative robot gait simulator is a tool to objectify shoe properties independently from possible compensations encountered during assessment of test persons. This contribution discusses the development of an artificial foot enabling objective testing of the mechanical and functional properties of sports and leisure shoes.An artificial foot consisting of the shank, the rear foot, the mid foot and the toes was designed based on a measurement protocol for barefoot running using 12 active markers sampled at 400 Hz [Based on measurements the design of this initial foot was optimized with respect to functionality and appropriate shoe fit. The multi segment design of this foot is shown in figure An improved artificial foot design with built-in springs and dampers for objective testing of shoe properties is realized. The design needs further elaboration with respect to geometry, foot axes and functional behaviour. This mechanical foot is a promising tool to help us understand mechanical properties of shoes using strictly standardised testing protocols using mechanical gait simulators."}
+{"text": "In October 2011 the Mater Child and Youth Mental Health Inpatient Unit developed and implemented the Mater CYMHS Program for the Management of Eating Disorders (the protocols). The protocols were developed to improve admission and discharge pathways for young people with restrictive eating disorders as well as to improve consistency and efficacy of inpatient treatment which supports various outpatient models of care. Currently there exists little evidence for best practice treatment of restrictive eating disorders in children and adolescents on a psychiatric inpatient unit. This presentation aims to fill in the gaps in the existing literature by presenting outcome data for young people treated under the protocols. These outcomes will then be compared with those patients who received \"treatment as usual\" prior to the implementation of the protocols. Furthermore, we will present data examining staff perceptions of patient care of those with restrictive eating disorders both before and after the protocols were introduced.Care in Inpatient and Community Settings stream of the 2013 ANZAED Conference.This abstract was presented in the"}
+{"text": "NaP) and an A type potassium current (IA), in combination with the passive properties [Mesencephalic trigeminal (MesV) cells are sensory neurons involved in the brainstem circuitry that generates and controls orofacial activities . Recentloperties . These cNaP and IA currents), is the waveform of the action potentials of these cells characterized by its high amplitude and short duration, with almost no after hyperpolarization and small interspike intervals. Despite the fact that those subthreshold mechanisms have been thoroughly studied [In an attempt to generate a model of a network of electrically coupled MesV neurons that reproduce these behaviors, as critical as the subthreshold active mechanisms responsible for the frequency selectivity of these contacts  , that wa"}
+{"text": "There is a growing body of literature examining the utility of behavioral treatment in primary progressive aphasia (PPA). There are, however, no studies exploring treatment approaches to improve speech production in individuals with apraxia of speech (AOS) associated with the nonfluent variant of PPA. The purpose of this study was to examine a novel approach to treatment of AOS in nonfluent PPA. We implemented a treatment method using structured oral reading as a tool for improving production of multisyllabic words in an individual with mild AOS and nonfluent variant PPA. Our participant showed a reduction in speech errors during reading of novel text that was maintained at one year post-treatment. Generalization of improved speech production was observed on repetition of words and sentences and the participant showed stability of speech production over time in connected speech. Results suggest that oral reading treatment may offer an efficient and effective means of addressing multisyllabic word production in AOS associated with nonfluent PPA, with lasting and generalized treatment effects."}
+{"text": "Radiation oncology practice is a collaborative effort that involves multiple clinical and technical specialists including physicians, medical physicists, dosimetrists, radiation therapy technologists, and nurses. The safe and efficient delivery of radiation therapy was never a simple matter and is now exceedingly complex.The growing complexity of radiation oncology procedures has been identified as a significant risk factor in potentially causing patient treatment errors. National and international standards have evolved to guide the safe and effective use of ionizing radiation for treatment and have been codified by leading professional organizations into accreditation requirements that necessitate rigorous documentation of performance for each aspect of the process of care. The process of care in radiation oncology refers to a conceptual framework for guaranteeing the appropriateness, quality, and safety of all patients treated with radiation for cancer and certain benign conditions.A primary objective of a Comprehensive Radiation Oncology Quality and Safety Program is the design and clinical implementation of approaches that will minimize the incidence of radiotherapy adverse events that could potentially have negative impacts on the quality of patient care.The papers in this Research Topic address multiple issues that should be considered to ensure managing the process of care with approaches that will ensure the optimal delivery of radiation therapy."}
+{"text": "Plant cell walls display a considerable degree of diversity in their compositions and molecular architectures. In some cases the functional significance of a particular cell wall type appears to be easy to discern: secondary cells walls are often reinforced with lignin that provides durability; the thin cell walls of pollen tubes have particular compositions that enable their tip growth; lupin seed cell walls are characteristically thickened with galactan used as a storage polysaccharide. However, more frequently the evolutionary mechanisms and selection pressures that underpin cell wall diversity and evolution are unclear. For diverse green plants (chlorophytes and streptophytes) the rapidly increasing availability of transcriptome and genome data sets, the development of methods for cell wall analyses which require less material for analysis, and expansion of molecular probe sets, are providing new insights into the diversity and occurrence of cell wall polysaccharides and associated biosynthetic genes. Such research is important for refining our understanding of some of the fundamental processes that enabled plants to colonize land and to subsequently radiate so comprehensively. The study of cell wall structural diversity is also an important aspect of the industrial utilization of global polysaccharide bio-resources. The first level consists of primary screens for cell wall polysaccharides based on carbohydrate microarrays probed with mAbs and CBMs  using microarray-based polysaccharide screening and lichenase treatments  and also having diverged prior to the gene duplication events associated with the evolution of flowering plants, cautions us not to generalize this principle excessively. The second reason why the number of GTs cannot be inferred from the number of different linkages is that the biosynthesis of some polysaccharides has turned out to be much more complicated than anticipated from the polysaccharide structure; xylan biosynthesis, reviewed by Box 1. The CAZy database is the most extensive database of GTs and contains GTs from all three kingdoms. By using a global approach including the whole CAZy database in the screen, more remote orthologies can be discovered, exemplified by the discovery of a mannosylglycerate synthase of GT78 in S. moellendorffii  of enzymes that degrade, modify, or create glycosidic bonds  genes as encoding putative extensin arabinosyl transferases. This annotation is not proven but was corroborated by Arabidopsis . A number of EST datasets ? Is this to be a paradigm for non-cellulosic wall polymers for which we currently have one or a limited number of probes such as pectic galactan and xyloglucan? The next few years will see more detailed systematic assessments of molecular architectures. This will be in conjunction with enzymatic and/or chemical pre-treatments that are in some cases required to optimize polysaccharide detection and in the case of polysaccharide masking (in which one polymer class blocks access to another polymer class) indicates important features of cell wall architectures reflecting protein access  the absence of pectic galactan from pit fields, we do not have a good understanding of the cellular distributions of all polymers for most plant cell types. Even for ectic HG  and alsoectic HG  where a renchyma . What isn access .Figure 2? How are these heterogeneities integrated into a functional whole in terms of wall properties and functions? In vitro analyses of composites formed from cellulose, pectins, and xyloglucans have yielded invaluable information about the properties of some wall components (in vitro approach cannot reasonably be applied to investigate the functional properties of the full diversity of extant walls. In vivo methods of investigating wall biomechanics, at the tissue and lower levels, have been developed (in situ analyses are combined with genetic and enzymatic interventions. Integrating this knowledge will be a major challenge and is an exciting frontier for cell wall biology.Clearly we face many challenges in understanding cell wall evolution not least of which include sufficient sampling followed by appropriate synthesis and interpretation of large data sets including diverse information such as gene and protein sequence data as well as sugar linkages and epitope distributions. However, as cell and tissue molecular architectures are documented another major issue that is brought into focus is the function of individual wall components and of the entire cell walls, which can vary enormously with respect to quantitative and qualitative composition. Why do some cell walls have xyloglucan, xylan, and mannan hemicelluloses in distinct spatial distributions as for example in the extensively studied tobacco stem system as shown in mponents . Howevereveloped  facilitaThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Populus tremulae) at the transcript level we inoculated clones of this species with a foliar rust on the leaves and a necrotroph in the bark. Leaf samples were collected from above the inoculation site to examine the long distance (systemic) defense responses and bark tissue around the site of inoculation examined for the local response as early as day1 post treatments. We performed microarray experiments on the biotrophic and necrotrophic interaction and between healthy controls of two SwAsp clones. Selected candidate genes were also examined in more detail by qRT-PCR and chemical analysis for phenols and tannins was also performed. We found that the two clones respond in a very different in fashion at the transcriptional level to both the biotrophic and necrotrophic pathogen. The more resistant clone responded systemically within 24 hours while little response at the transcriptional level was detected in the more susceptible clone in response to the biotroph, while indications of suppression in response to the necrotroph was found.Trees are exposed to a variety of pathogenic fungi. The defense response toward a biotroph may require a different strategy that toward a necrotroph. To understand the key processes of defense responses toward pathogenic fungi in aspen ("}
+{"text": "The inference of reaction rate parameters in biochemical network models from time series concentration data is a central task in computational systems biology. Under the assumption of well mixed conditions the network dynamics are typically described by the chemical master equation, the Fokker Planck equation, the linear noise approximation or the macroscopic rate equation. The inverse problem of estimating the parameters of the underlying network model can be approached in deterministic and stochastic ways, and available methods often compare individual or mean concentration traces obtained from experiments with theoretical model predictions when maximizing likelihoods, minimizing regularized least squares functionals, approximating posterior distributions or sequentially processing the data. In this article we assume that the biological reaction network can be observed at least partially and repeatedly over time such that sample moments of species molecule numbers for various time points can be calculated from the data. Based on the chemical master equation we furthermore derive closed systems of parameter dependent nonlinear ordinary differential equations that predict the time evolution of the statistical moments. For inferring the reaction rate parameters we suggest to not only compare the sample mean with the theoretical mean prediction but also to take the residual of higher order moments explicitly into account. Cost functions that involve residuals of higher order moments may form landscapes in the parameter space that have more pronounced curvatures at the minimizer and hence may weaken or even overcome parameter sloppiness and uncertainty. As a consequence both deterministic and stochastic parameter inference algorithms may be improved with respect to accuracy and efficiency. We demonstrate the potential of moment fitting for parameter inference by means of illustrative stochastic biological models from the literature and address topics for future research. The traditional approach to modelling of biological reaction networks is based on deterministic mass action kinetics in which the time course of the species concentrations averaged over the population is described by a set of coupled ordinary differential equations Parameter estimation in differential equation models is a classic nonlinear inverse problem that arises in a variety of scientific, industrial and financial applications and is approached both in deterministic and statistical ways for a multivariate normal distribution or a weighted sum of squared residualsfit higher sample moments derived from time series data, e.g., by computing the distance between the sample variance see In this paper we present a moment fitting approach to parameter inference in stochastic biological models from time series data that to the best of our knowledge has not been studied before. First, we suppose that the state variable vector of molecule numbers can be partially - both with respect to time and state variable components - and repeatedly, say that describe the time evolution of parameter dependent moment approximations We studied the concept of moment fitting for parameter inference in stochastic biological models from time series data by means of three reference examples, see Materials and Methods for all model details, and chose The Kolmogorov differential and implies the ODE systemfor the mean For the purpose of data generation we have simulated the true stochastic process In order to infer the rate parameters for a comparison of the sample mean with the analytic mean expression (2). Choosing the initial parameter guess The problem of non-identifiability is overcome if not only the first moment but also the second central moment is fitted to the available data, e.g., by minimizing the cost functionAgain starting from In a further test, we utilized the likelihood functiondoes not involve the error between which compares as priors for the parameters, the algorithm failed to yield acceptable marginal posterior density distributions due to the ignorance of the sample variance Based on the Fokker Planck the normal moment closure technique yields the nonlinear ODE systemfor the (approximative) mean We first only focused on the sample mean data by means of the MATLAB The linear noise approximation (14) yields a nonlinear ODE system describing the temporal development of the mean approximation with the initial guess Our numerical tests by means of reference models from the literature show that comparing sample moments with theoretical moments may enhance parameter identifiability and the performance of parameter identification algorithms in comparison to mean-only approaches. These observations can be explained by an examination of the cost functions that have been used for the parameter inference. In the linear birth death example the mean expression (2) shows that any parameter combination of of (5) evaluated at For the dimerisation example the level sets of the cost function (7) are shown in Similar conclusions can be drawn from the by differentiation with respect to which corresponds to a reduction of the eigenvalue ratio Based on accepted mathematical descriptions of stochastic reaction networks in well-mixed conditions we have introduced the concept of moment fitting for parameter inference from time series data of repeated measurements. In numerical tests for simple reference examples we observed that if the common comparison of sample mean data with the parameter-dependent mean expression derived from the model is augmented by consideration of higher moments such as covariance, improvements both with respect to parameter estimate accuracy and algorithmic efficiency are achieved.Our approach offers opportunities for extension and further research. In case of larger models and real data, then also affected by external noise, measures against data instability and overfitting become necessary. The regularization theory of nonlinear inverse problems see In our examples we used squared errors to build the distance functions. This not only allowed us to numerically demonstrate the advantages of moment fitting but also to give explanations of the results in terms of Hessian matrices which in the squared error case can be computed in a straightforward manner. Furthermore, the squared error approach enables the straightforward utilization of the adjoint method, see Materials and Methods, for providing gradient information to the optimizer. Still, as moments of different order may be correlated but then poses severe challenges with respect to an efficient computational realization.The moment fitting approach presented in this paper rests upon the availability of sufficient data for the estimation of higher moments as only then more traditional mean-only approaches may be outperformed. This raises the question of selecting the sample size see In well-mixed conditions a network of where the integers Let With where An alternative approximative description of the stochastic process is given by the linear noise approximation into a deterministic part and a stochastic process with the increment Finally, the deterministic modelling approach which corresponds to (15) with the setting Depending on the chosen modelling approach the state variable of a stochastic biochemical reaction network is described as a discrete or a continuous random quantity. In the discrete case associated to the Kolmogorov differential where In general, the and the with In case the state space of the biological system is modelled as a continuous random variable Based on the differential see holds only then. Another example is the time evolution of the The simple example exact differential equations for their time evolution impossible to solve analytically or numerically. The problem may be overcome by the technique of moment closure and implies the dependency of the ordinary differential equation for approximatively describes the time evolution of the true moments in which As an alternative to the moment closure approach, a closed form (21) for the approximative description of the moment time course for Here, A classic and illustrative reaction system widely studied in the literature is the linear birth and death process with the associated stoichiometric matrix In all simulations of the discrete stochastic dynamics of the model we chose the rate parameters With respect to the parameter inference problem we suppose that the state variablecan be only partially observed at the obtained from an  equidistant discretization of the time interval such that the partial state observation can be compactly described as A simple reaction system featuring a nonlinear rate function is the dimerisation process The conservation of the total number allows to formulate the stoichiometric matrix for a one-dimensional state space. In all simulations of the discrete stochastic dynamics of the model we chose the rate parameters For testing the practicability of our approach in case of partial state observations we have chosen a model for the In all simulations of the discrete stochastic dynamics of the model we chose the rate parameters andThe time observation parameters were chosen as All molecular copy numbers used in our tests have been generated by MATLAB A of data matrices. For each discrete time point while the empirical covariance matrix of the observables at time in which of length with sample mean vector If we split the state variable Then, in order to compare the parameter dependent solution component may be utilized where the time discretization operator Examples for where, in general, With respect to parameter inference the difference function (26) can be utilized in various manners. For instance, it can be minimized by deterministic or stochastic optimization routines, it can be incorporated as a cost function in approximate Bayesian methods or used in building Kalman filters or Luenberger type observers. In the context of gradient based optimization, the gradient information can be efficiently provided by means of the so-called adjoint technique whenever Supporting Information S1Moment Equations for Test Models.(PDF)Click here for additional data file.Supporting Information S2Adjoint Method for Gradient based Optimization.(PDF)Click here for additional data file."}
+{"text": "Prediction and competition mechanisms are here combined into a neuro-inspired computational model in order to enhance robustness for spatiotemporal tracking and pattern recognition tasks. The research presented in this abstract extends the initial experimental results and mathematical accuracy proof obtained with a single predictor  to a setThe performance and emergent attentional properties of the model were ascertained on a 2D visual tracking application with ambiguous and noisy signals. Results are synthesized in Table While the predictors improve tracking performance when they adequately anticipate the dynamics, their inadequacy simply leads to a fall back on the original CNFT dynamics. This allows the system to perform correctly while learning the predictors, but also to discriminate between trajectories, as the relative level of assimilation of the dynamics is updated in real-time."}
+{"text": "Patient diaries have the potential to support food allergy diagnosis. The time relationship between the consumed product and the experienced symptoms is of high value for diagnostics as well as for therapy control. The combination of a barcode reading handheld device and a dedicated electronic patient record is a unique method to support the diagnostic process.A Smartphone based Personal Allergy Assistant (PAA) allows patients to keep an electronic patient diary by scanning the barcode of the consumed food products. A catalogue of predefined symptoms as well as their medically justifiable time window during which a symptom can manifest itself after the ingestion has been defined. An Electronic Patient Record for Allergies (EPRA) stores results from patient investigations with allergy specific medical knowledge, provided by allergy experts . Data on the PAA is regularly synchronised with the electronic patient record and the food database. Diaries are evaluated by emphasising the association between food intake and occurred symptoms in order to calculate the relative risk (RR) of a specific food product or nutrition.The PAA provides patients with an easy to use device to create high quality diaries for food intake and symptoms by scanning the food package's EAN barcode. It sets automatic timestamps to reduce potential data tampering and increase the data quality and allows recording of food intakes from non-packaged food  as well as pharmaceuticals. For diagnostic purpose, the diary is regularly transmitted to the allergist's electronic patient record. Diaries are evaluated automatically providing measurement categories that are commonly used in medicine. To support the individual diet management, the PAA gives a warning before the consumption of allergenic food.During a pilot study with 35 participants the feasibility and patient acceptance has been proven. Information and Communication Technology has the potential to simplify the interdisciplinary exchange of patient information between patients and medical experts."}
+{"text": "Randomised control clinical trials of acupuncture have been hampered by the challenges of assessing it as a complex intervention. Controlling for and separating placebo effects whilst identifying its efficacy as a treatment can be difficult . The comThe objective of this pilot trial is to investigate the feasibility of undertaking a novel randomised cohort design study with a nested factorial RCT, investigating acupuncture alone versus manual therapy alone versus a combination of acupuncture and manual therapy versus usual care.The pilot will investigate recruitment rates to allow for planning a full-scale trial, identify any compliance issues and strategies for reducing these in a full-scale trial and assess patient\u2019s acceptance and therapist delivery of combined therapies for the treatment of their LBP.The study will follow a randomised cohort trial design and participants from the cohort will be selected to participate in the pilot trial. The use of this design as a recruitment method for nested trials is relatively new methodology but the cohort design has been suggested as an effective method for the use with chronic conditions  and its The factorial pilot RCT will investigate the treatment of low back pain with Acupuncture vs Manual Therapy vs Acupuncture and manual therapy vs Usual GP care. All interventions will be delivered by a chartered physiotherapist.Recruitment and retention rates will be presented. The acceptability and feasibility of the design for use with complex interventions and in a common musculoskeletal condition will be discussed."}
+{"text": "The purpose is to introduce the Lebanese Society for Infectious Diseases and Clinical Microbiology (LSIDCM).The Society was established in 1992.It includes 46 infectious diseases physicians as well as clinical microbiologists. The members are spread across the country. All physicians are involved in managing infection control programs in their respective hospitals. So far the Society has organized twelve national and regional congresses on infectious diseases and clinical microbiology. Over the last 4 years, a yearly course on infection control is offered during each congress and many national and international speakers are involved.The LSIDCM is currently working on developing national guidelines for the management and control of infectious diseases, national antibiotic usage monitoring, monitoring of antibiotic resistance on a national background and the establishment of a national registry of health care associated infections.None declared."}
+{"text": "Fracture healing is a biological process in continuum from fracture to healed stage. It involves a sequence of dynamic events which ultimately restores the integrity of the bone and its biomechanical properties.The severity of damage to the physical environment at the fracture site as a result of injury affects the biological potential for healing. The magnitude of injury decides the insult occurring at the fracture site. The disruption of soft tissues and network of vascular channels makes the bone ends devoid of circulation to a variable length. The more is the force of impact and disruption to the tissues the more is the devascularization. The repair process starts with demineralization of devitalised bone ends and subsequent revascularization. The pleuripotent cells get converted into cartilage cells and later osteoblasts to make a new bone on the scaffold of the devitalised bone and thus finally a woven bone is laid down which in due course gets trabeculated. The fracture ends first get temporarily stabilized by organized fracture hematoma, cuff of fibrocartilage followed by woven bone. The woven bone is seen as fracture callus which continues to remodel for many years. This in short is described as secondary  fracture healing which occurs in the majority of fractures. The primary bone healing occurs where there is a rigid internal fixation. This consists of cutting cones traversing through the devitalised bones which progress across the fracture site directly in a similar way to normal bone remodeling.The process of healing is a very slow process occurring at cellular levels hence the need to provide a temporary stability by plaster cast for a certain length of time which allows the cascade of events of fracture healing to take place unabated. The normal cascade of events is modified by open injuries, surgical intervention and instability at the fracture site. The length of immobility by plaster cast adds the effects of immobility such as stiffness of joints, secondary to fibrosis in the injured muscles and ligaments hence an exercise regimen is indicated till such time normal joint motions are regained. The stability at the fracture site is of paramount importance. The motion at fracture site within a permissible range (micromotion) stimulates the fracture healing potential while beyond a certain level retards the healing process. The rigid immobilization of fracture is considered unphysiological and micromotion occurring secondary to functional activities encourages osteogenesisThe objective of fracture care is to allow the biological process of healing to occur at a normal pace with minimal hindrance and damage to the injured limb. Since some of the fractures are not aligned by closed manipulation they are treated by open reduction and internal fixation by implants. The surgery has its impact on the natural cascade of fracture healing. The fractures ends are exposed surgically, manipulated and aligned anatomically and internally fixed (stabilized) by intramedullary or extramedullary implants. All this require exposure of bone to certain length and disrupts normal soft tissue with results and disruption of already damaged blood supply. The biological efforts needed for fracture healing are going to be more extensive than healing in a closed fracture. The healing process becomes further complicated when internal fixation fails to achieve relative stability at the fracture site or wide exposure leads to lifting of periosteum and consequent damage to its cambium layer or the fracture fragments are stabilized at the fracture site with a gap of 2 mm or more.The ideal objective of surgical treatment should be to achieve a better outcome than nonoperative treatment. The outcome of surgical treatment are going to be worse if surgery is not executed perfectly as prescribed by the surgical principles of fracture fixation technique. The open reduction and internal fixation (ORIF) in a closed fracture increases the risk of infection and consequent retardation of fracture healing. A good outcome following ORIF of fractures can only be achieved when the fracture is anatomically reduced, stably fixed, and there is no risk of infection, to allow early postoperative mobilization. When an implant is inserted a race starts between fracture healing and implant failure. In a successful osteosynthesis the fracture unites first before implant fails. The implant has to survive till the biological process of healing is over. The concept of minimal access or least invasive skeletal stabilization is being suggested to minimize the surgical insult to the fracture milieu during internal fixation.The bad results of ORIF are worse than the worst results of closed reduction. Multiple variables influencing sound osteosynthesis by surgical means include the nutritional state of patient (soil), severity of trauma, complexity of fracture configuration, choice of treatment method, ORIF or closed reduction and internal fixation, quality of instrumentations and implants available, quality of operating room and level of surgical training. If everything is good one can choose any method of treatment. However, if anything is wanting than the surgical treatment of fractures gives bad results than those of conservative treatment.On a review of the literature we encounter variable conclusions on a clinical problems from different studies and thus a controversy is created. The possible reason for the controversy is dissimilar variables considered for sound and successful fracture outcome. The clinical results are comparable and predictable if identical outcomes are reported by various studies. The evidence based guidelines are relevant when the conclusions drawn from a particular setup are implemented in identical clinical settings. This becomes particularly more relevant when conclusions drawn in a developed country are considered in a primary health centre of a developing country disregarding infrastructure, quality of instrumentation and implants and level of surgical training available at that centre, hence the outcomes of fracture management are different. By the time these differences in infrastructure are understood lots of complications are produced and reported. More nonunions and infected nonunions are being reported because various fractures are operated for relative indications in suboptimal theatre conditions with poor quality instrumentations and implants and surgical principles are not adhered to. Hence it is imperative to talk about rational treatment. It is justified to treat a simple closed fracture tibial by interlocked nailing on the pretext of early weight bearing when it is guaranteed that it would not produce any risk of infection. Even if there is a 1% risk of infection (100% for that poor patient) then closed reduction and functional treatment outweigh the surgical treatment. We should read and use the published literature keeping all variables in mind. The rational treatment of fractures is selection of a particular modality of treatment keeping in mind all variables to achieve a predictable and consistent outcome of fracture treatment. Grahm Apley once wrote \u201cthe indication for fixation are not immutable; this if the surgical skills or backup facilities  are of low order; internal fixation is indicated only when the alternatives are unacceptable . With average skills and facilities, fixation is indicated when alternative methods are possible but are very difficult or unwise (eg. multiple injuries) and with the highest levels of skills and facilities, fixation is reasonable if it saves time, money or bed\u201d.4We at Indian Journal of Orthopaedics attempt to appraise the readership with the best available evidence on controversies of fracture management. We provide guidelines5"}
+{"text": "The study team were advised by the independent oversight committees to stop recruitment to the trial and the delivery of the trial therapy due to a difference in the number of reported hospitalisations between the treatment and control group.There was a lack of guidance on how to proceed with implementation of the changes in a trial of this type and little precedent for cessation of trial treatment in a psychotherapy trial following a safety alert. Furthermore, there were concerns over the potential for distress and disruption to participants and clinical teams as a result of the trial changes and the potential risks of discontinuing treatment prematurely.A collaborative approach to the development of the process and supporting documents was adopted, with attention given to the impact on participants and clinical teams. The changes were implemented as an urgent safety measure.The following were developed:\u2022 Written process for implementation.\u2022 Written information for participants, potential participants and clinical teams.\u2022 Guidance documents for sites.\u2022 Arrangements for local and national telephone helplines.\u2022 Media response.The following key features were intended to reduce the impact on participants and clinical teams:\u2022 Prompt, but careful action.\u2022 Staged, allowing adequate time to inform and support participants and clinical teams, and ensuring feedback received could inform further development.\u2022 Clinically appropriate, with reference to national guidelines and accepted good practice.\u2022 Honest, concise and consistent information given to all concerned and follow-up support offered as appropriate.\u2022 Regular review and reflection."}
+{"text": "New advances in medicine often raise challenges, and none more so than those involving the manipulation of human oocytes and embryos. Issues around clinical need and ethical considerations must be taken into account, as well as the safety of the proposed technique. The discussion around the proposed mitochondrial replacement techniques to prevent the transmission of mitochondrial DNA disease has perhaps raised more challenges than most Mitochondrial DNA diseases are both common and, in their severest forms, devastating In the United Kingdom, the Human Fertilisation and Embryology Authority (HFEA) recently considered the safety issues after extensive expert and public consultation The authors raise an interesting evolutionary argument that the human mitochondrial genome co-evolves with the nuclear genome in females, raising the possibility of a conflict with the paternal nuclear genome. They suggest Leber's hereditary optic neuropathy (LHON) and male infertility could be potential examples of this in humans The studies in macaques are also highly relevant to the risks proposed in humans associated with mitochondrial replacement. There are now multiple reports of the health status of the offspring born after mitochondrial replacement, and all have shown no difference between these offspring and controls Some studies in laboratory mice have proposed a nuclear DNA\u2013mitochondrial DNA interaction, but there are others that have reported no defect despite the use of very divergent genomes Whilst we accept that any new technique is associated with risk, we think the lack of any reliable evidence of mitochondrial-nuclear interaction as a cause of disease in human outbred populations provides the necessary reassurance to proceed. The recent studies in macaques after mitochondrial replacement are also supportive that the possible harmful interactions are unlikely to occur in man"}
+{"text": "Clostridium difficile infection (CDI) and development of national prescribing indicators to support reduction of CDI.The Scottish Antimicrobial Prescribing Group (SAPG) was established by the Scottish Government in 2008 to lead the first national initiative to actively address antimicrobial stewardship. Healthcare associated infection (HAI) is a priority in Scotland and the work of SAPG contributes to the national HAI Delivery Plan. SAPG's early work has focused on restricting the use of antibiotics associated with a high risk of Scottish Antimicrobial Prescribing Group has developed prescribing indicators for hospital and primary care, which are measured and reported in all 14 NHS board areas. Improvement in compliance with the indicators has been demonstrated with resultant reductions in CDI rates and no adverse effect on mortality or antimicrobial resistance patterns.The establishment of a Scottish national antimicrobial stewardship programme has made a significant contribution to the HAI agenda, particularly in relation to CDI. The programme is supported by local antimicrobial teams, a national framework for education, surveillance of antimicrobial use and resistance and sharing of data for improvement. Antimicrobial stewardship has been integrated with other national programmes on patient safety and quality improvement. The Scottish Antimicrobial Prescribing Group (SAPG)  was formSAPG was established to lead the first national initiative to actively address antimicrobial stewardship. Collaboration with key stakeholders at national level and development of local (NHS board level) leadership through Antimicrobial Management Teams has been essential to develop national consensus and implement key stewardship interventions. This has been combined with the development of national and local systems and a framework for collecting and disseminating data on antibiotic prescribing and resistance surveillance and a framework for educational material to support the healthcare professionals in the workplace.Clostridium difficile infection (CDI) is a key objective for NHS Scotland and in 2009 a target was set for all NHS boards to reduce their rate by 30% (later increased to 50%) in patients over 65 years. Much of the focus of SAPG's early work has therefore been to reduce the use of antibiotics associated with a high risk of CDI across hospital and primary care settings. SAPG developed national prescribing indicators based on compliance with local antibiotic policies to support reduction of CDI:Healthcare associated infection (HAI) is a priority for the Scottish Government and the work of SAPG contributes to the national HAI Delivery Plan. Reduction of Indication for treatment recorded in the patient medical record and antibiotic choice is compliant with the local Antimicrobial Prescribing Policy - target \u2265 95%Seasonal variation in quinolone use, consumption of quinolones in winter months is \u2264 5% greater than consumption in summer months.National surveillance data confirm that there has been a progressive reduction in CDI throughout Scotland and that all NHS boards have exceeded the original target of 30% reduction. The national rate has fallen from 1.5 to 0.32 cases per 1000 acute occupied bed days [National results for the hospital and primary care CDI prescribing indicators are shown in Additional file There is a temporal association between this reduction and the introduction of restrictive antimicrobial policies in line with SAPG guidance. The true impact of this intervention is being evaluated using a time series analysis and results from one region (NHS Tayside) show a reduction in total CDI post-intervention of 54% in Medicine and 50% in Surgery [E. coli. Aminoglycoside-related toxicity is also being prospectively evaluated.National surveillance of antimicrobial resistance shows no significant increases in resistance to key Gram-negative organisms and reduced resistance to third generation cephalosporins in Crude 30-day all-cause mortality (from admission) was analysed for both NHS Tayside cohorts. No change was observed following the introduction of the restricted antibiotic policy. Subgroup analysis by age and Charlson Co-morbidity Index score showed no changes in mortality following the introduction of the policy. Further analysis using adjusted 30-day mortality in patients who have had blood cultures taken as an outcome indicator for sepsis management and antibiotic stewardship interventions is also being undertaken.The establishment of a Scottish National Antimicrobial Stewardship Programme has made a significant contribution to the HAI agenda, particularly in relation to CDI . ProvidiThe authors declare that they have no competing interests.All authors are members of the Scottish Antimicrobial Prescribing Group (SAPG). DN has been chair of SAPG since 2008 and JS has been Project Lead for SAPG since 2008. DN and JS have made substantial contributions to the conception and design of the SAPG work programme including development of the prescribing indicators to support reduction of CDI. AP is responsible for developing and maintaining the data management system for measuring and reporting the hospital prescribing indicators and for performing the analysis of data from NHS Tayside to confirm the impact of changes in antimicrobial use on CDI and mortality. WM made a significant contribution to development of the primary care prescribing indicator and is responsible for evaluation and reporting of the data for this indicator. All authors have read and approved the final manuscript.DN is Chair of SAPG and is a Consultant Physician in Infectious Diseases and Honorary Professor of Infection, Ninewells Hospital and Medical School, Dundee, UKJS is Project Lead for SAPG and has a hospital pharmacy background with a PhD in medicinal chemistry and an MSc in Clinical Pharmacy.AP is an Information Analyst with an MSc in Applied Statistics.WM is Pharmaceutical Adviser at Health Protection Scotland and has a background in pharmaceutical public health and primary care pharmacy.Table S1 Compliance with empirical prescribing in Medical Admission Units April - June 2011. Summary of data for national prescribing indicator for empirical prescribing in hospital.Click here for fileFigure S1 Primary care seasonal variation of quinolone use by NHS board 2008-2011. Annual data for national prescribing indicator for primary care.Click here for file"}
+{"text": "It has long been known that myeloid derived suppressor cells (MDSCs) inhibit the anti-tumor immune response. And recently a relationship between MDSC levels and patient outcomes to cancer immunotherapy was discovered. Studies conducted at the Memorial Sloan Kettering Cancer Center in New York showed that patients with reduced levels of circulating MDSCs were more likely to respond favorably to Ipilimumab, an immunotherapy approved for the treatment of melanoma. This raises the exciting prospect that baseline levels of MDSCs may help drug developers and physicians identify or select those patients who are most likely to benefit from immune-based cancer treatments. However the development of a robust and commercially available MDSC biomarker assay presents many challenges, from sample handling and logistics to an objective and reproducible definition of this elusive cell type. Here we present data from our MDSC assay development program and discuss the merits of applying this assay to biomarker studies as part of the clinical development of novel cancer therapies."}
+{"text": "The thesis examined three different research questions to help build a knowledge base for future intervention strategies by better understanding the reasons behind smoking among pregnant women in Nunavut. The first study focused more at the individual level and investigates clinical and socio-economic factors and their relationship to the readiness to quit smoking. The second article moved beyond the individual level to the broader social and structural environment to identify a broader range of barriers and facilitators to smoking and smoking cessation among Inuit women. This second article draws upon in-depth interviews focusing on perceptions of smoking, and perceived barriers and facilitators of smoking behaviours. Finally, the third article investigated the perspectives of health care providers regarding the barriers and facilitators of smoking cessation for pregnant women in the Baffin Region of Nunavut and describes perceptions of smoking cessation resources available to health care providers in the this Region. It is hoped that the findings from this thesis will help generate a knowledge base that can more appropriately address the smoking cessation needs of Inuit pregnant women."}
+{"text": "The Wirral Assistive Technology Programme (WAT) has operated across the whole population of the Borough for 3 years. It includes the installation of telecare technologies such as falls alerts and movement sensors to prolong users\u2019 independence and reduce use of secondary care. Qualitative evaluation of user and carer perspectives indicated a reduction in admissions as a result of the technology and we sought to demonstrate this at a population level.Secondary care episodes for A&E, admissions and outpatients were temporally analysed to identify changed trend in secondary care usage as a result of installation for 400 users. Primary diagnoses at point of secondary care engagement were categorised to discern those that might have been mediated by WAT  from those likely to be incidental (e.g. infection). The nature of the WAT service made the identification of a control group challenging and it was necessary to try and establish the counterfactual of secondary care usage in an equivalent group of patients not engaged with WAT. We used Patients at Risk of Re-Hospitalisation (PARR) scores which are routinely assigned to every patient discharge in Wirral to identify an equivalent group of patients not engaged with WAT and compared trends of secondary care usage as above. Controls were selected on the basis of an equivalent PARR score to an AT user on the same date as that user\u2019s final discharge before installation of AT.A&E and inpatient episodes showed regression to the mean around the point of AT installation, both for AT-related and unrelated diagnoses . Outpatient episodes showed a stable trend. We found no evidence that AT installation reduced the average number of secondary care episodes per patient, reduced the average PARR score or reduced the average length of hospital stay in comparison to controls.Although conceptually and qualitatively WAT should be impacting secondary care episodes, we could find no evidence of this. This has important implications for the way the programme is currently integrated with other local re-ablement schemes, how it is monitored and what incentives there are in the discharge system to promote its use. This paper will outline actions taken to embed the programme since the evaluation was completed (September 2011)."}
+{"text": "For the interventionalist, intracoronary thrombus remains an important marker for the presence of an acute coronary syndrome as well as a harbinger of potential complications during the percutaneous procedure. Acute complications include myocardial infarction either new and/or recurrent related to coronary embolization, slow coronary flow or acute closure and long term complications include sub acute and late stent thrombosis and possibly restenosis. Over the years, there have been several advances in the development of new and more potent antithrombotic and anticoagulant therapies as well as new interventional and pharmacologic approaches for dealing with intracoronary thrombus before, during and immediately after percutaneous intervention.The purpose of this symposium is at least three fold: 1. Define the pathophysiology of intracoronary thrombus and its relationship to acute and long term complications. 2. Describe the best antithrombotic and anticoagulant approaches in STEMI and NSTEMI. 3. Review the mechanical and pharmacological approaches available to the interventionalist for thrombus removal or/dissolution and/or treating its complications. All of these approaches and particularly for the antithrombotic and anticoagulant therapies must be balanced by the potential for side effects especially the possibility of increasing bleeding complications. I hope this symposium will provide you with important information as well as stimulate further investigation in this area."}
+{"text": "The second stage is currently being designed but will take the form of a RCT of probiotic vs. placebo administered alongside the antibiotic. These two studies are governed by separate laws and regulations in relation to mental capacity. PAAD stage 1 is covered by the Mental Capacity Act and, for those service users who lack capacity, personal consultees are able to give agreement to the service user\u2019s participation. PAAD stage 2 is covered by the Medicines for Human Use  Regulations and consent is given by a personal legal representative or a professional legal representative of the participant. The PAAD study also presents novel challenges in relation to advanced consent. We propose to explore some of the ethical and practical challenges of conducting these studies (and others like it) within the care home setting using qualitative methods. Our purpose is to optimise the informed consent process in a vulnerable population in preparation for stage two of PAAD.The PAAD Study (Probiotics for Antibiotic Associated Diarrhoea in care homes) involves 2 stages. The first stage is a prospective 12 month observational study to collect data on the amount and type of antibiotic prescribed episodes of Antibiotic Associated Diarrhoea and Cc.difficile circulating within the care home.We are conducting focus groups with staff within the 9 care homes who are participating in PAAD stage 1. We are also conducting face-to-face interviews with service users who have capacity, with relatives of service users, and with GPs who provide primary care to the care homes. Focus group and interview schedules focus on issues such as: the merits and problems associated with a number of models of consent for both stage one and stage two of PAAD, views about the feasibility and acceptability of taking advance consent/assent for research trial procedures, and views about potentially raising concerns about the possibility of Data collection is in early stages, and we will have data analysed by Autumn 2011.We anticipate that our data will not only optimise the design of our informed consent process for stage 2 of PAAD, but will also provide generalisable insights to guide other studies which plan to conduct clinical trials amongst vulnerable populations within care home settings."}
+{"text": "We have developed Oligopaints  along with a suite of scripts and documentation that will assist researchers with probe set design and allow our technology to be extended to any organism whose genome has been sequenced. Oligopaints robustly label chromosomes both in tissue culture cells and whole-mount tissue preparations and can be generated using standard molecular biology techniques and equipment at a price well below the cost of commercial FISH probes. The flexibility offered by our bioinformatic design platform has allowed us to perform complicated hybridizations, such as the simultaneous targeting of RNA and the genomic DNA flanking its site of transcription. Thus, we anticipate that Oligopaints will be a valuable tool for the study of nuclear architecture and the relationship between chromosome positioning and gene expression.Fluorescence gopaints , a PCR-b"}
+{"text": "The dynamics of synaptic plasticity and the encoding of spatial information have been extensively studied in the hippocampus. Yet few attempts have been made to investigate how the two combine to produce the most striking emergent function of this system, the cognitive map Toleman, .Here, Bush et al. present a neural network model describing how a cognitive map based on empirical findings from hippocampal electrophysiology could function in order to encode space and enable sequence learning. The model demonstrates how both functions could be accommodated within the same network architecture and using the same learning rule (Bush et al., The network employed by the authors is based on the recurrently connected CA3 region of the hippocampus, where individual \u201cplace cells\u201d fire maximally at specific locations within one, two, and three-dimensional space (O'Keefe and Dostrovsky, When the network experiences neural activity corresponding to a series of shuttle runs across a square arena, heteroassociative connections between activated place cells become potentiated, cells with overlapping place fields develop strong bidirectional connections and asymmetric connections between cells against the direction of motion become depressed. The elevated connectivity of the activated ensemble resembles the broad development of a \u201ccognitive map\u201d with bidirectional connections providing detailed information about the relative proximity of individual place fields. The firing patterns of cells with overlapping place fields satisfy the STDP rule and enable connections between such cells to become potentiated, as demonstrated in slices (Isaac et al., During simulated random exploration of an arena, a similar pattern of bidirectional connectivity develops between place cells encoding proximal place fields, with local asymmetric connections reflecting fragments of recent trajectories. Repeated traversals of a one dimensional route in a single direction through such a learned environment does not alter the gross structure of the map, but profoundly alters the connections of place cells that lie on the route. As before, connections following the direction of travel are significantly potentiated but those against it are depressed, suggesting information concerning recent trajectories can be embedded in the cognitive map.in vivo and in vitro data demonstrating the role of synaptic plasticity within the of development of the cognitive map and the encoding of episodic memory; it also prompts a number of predictions as to when and where plasticity may be induced during these processes (Sadowski et al., The model goes some way to supporting in vivo hippocampal recordings, where sequences of place cell activity are recapitulated during sleep or rest following behavior (Skaggs and McNaughton, One unexplored aspect of the paper relates to the \u201coffline\u201d dynamics of a network when such patterns of connectivity have been established. The phenomenon of place cell replay has been observed during in vivo and in vitro approach is necessary to test such predictions; recording from place cells during behavior and investigating the consequences of such activity on connectivity. In addition, robust empirical data regarding the influence of neuromodulators on STDP must be acquired in order to improve the physiological relevance of this promising model of plasticity and the cognitive map.Overall, the paper demonstrates how computational modeling can elegantly combine parallel strands of hippocampal electrophysiology and make defined predictions about how behavior might shape connectivity and therefore the function of neural networks. An integrated"}
+{"text": "I read with interest the study performed by Eizadi Mood et al. recently published in Critical Care Research and Practice . The autCan they provide more details on the types of the complications they meant and their correlation to the GCS and its components? Also, may they provide the rate of intubation in these two groups (with or without complications)? In other words, did they only intubate the complicated patients or was there any uncomplicated patient who was intubated from the beginning and developed complications afterwards ? Thanks"}
+{"text": "In September 2010, 9 months after empowerment of caring for patients with severe sepsis and septic shock and implementation of a cooperative sepsis management protocol between community hospitals and tertiary referral hospital in Phitsanulok, the Phitsanulok Co-operative Sepsis Management (PCSM) team announced the Saving 500 Lives Campaign. This campaign aimed to encourage the unity and importance of caring for patients with severe sepsis and septic shock.From October 2010 to September 2011, eight community hospitals and one tertiary referral hospital in Phitsanulok established and promoted a set of achievable goals and interventions for patients with severe sepsis and septic shock . The group of patients from community hospitals that can be admitted directly to the ICU from the emergency department using a sepsis fast-track protocol had the lowest mortality rate (19%).Setting a numeric goal using the 500 Lives Campaign was another way to support and empower the cooperation of sepsis care in Phitsanulok, Thailand."}
+{"text": "The poster is based on the in silico identification and analysis of the variation in the gene network related to the pancreatic cancer. Pancreatic cancer has been a major cause of death in Asia and European countries. This cancer is not easily detectable in its initial stages and at the later stages it becomes very hard to cure this disease. So the in-depth understanding of the variation in the genetic pathway of this disease is very important. We selected 5 candidate genes from various published journals which are involved in the pancreatic cancer pathway  in generating their interaction network using Agilent literature search plugin in cytoscape. The organic layout of interaction revealed the cross interaction between these genes and the other neighbour genes. Merging the expression profile data of the pancreatic cancer to the parent network helped us in understanding the variation of the network in the diseased state. Using the merged profile network we found out the importance of the KRAS & CDKN2A gene interaction with other 21 neighbour genes among which PIK3CA and TP53 interactions were showing major variation on their expression pattern. This study reveals the importance of change in expression level of candidate genes in causing pancreatic cancer. The results obtained in our study will be very much useful in detecting the disease in its initial stages and in finding the cure."}
+{"text": "Scotland has one of the highest liver cirrhosis mortality rates in Western Europe. The Scottish government has invested in a range of policies to address this and the wider harms from alcohol, including a national programme on alcohol brief interventions (ABIs). The initial focus of this work was primary care, accident and emergency care, and antenatal care but it was expanded in 2012 to include ABIs delivered in wider settings and with populations such as social work service users and young people. This process evaluation aims to explore the feasibility and acceptability of ABIs delivered to young people and in social work settings. The study involves two phases: one that maps existing projects providing ABIs in these areas and examines barriers and facilitators to their delivery, and a second that explores case study projects in depth and develops proposals for a potential future outcome evaluation. Phase 1 of the study involved conducting 24 semi-structured interviews with 28 professionals from 12 projects providing ABIs in the wider settings of social work and young people's services between December 2012 and April 2013. Two field visit observations were also completed and documentation/data gathered from all projects, including numbers of clients and ABIs delivered where possible. A framework approach was used for coding and analysis of data. In addition to a detailed thematic analysis, 10 project case summaries were produced to retain the specificity of information about the diversity and similarities across the cases studied. Results from Phase 1 of the study will be presented and implications for policy and practice will be discussed."}
+{"text": "To study frequency and associated factors for care giving among elderly patients visiting a teaching hospital in Karachi, Pakistan.A cross sectional questionnaire-based study was conducted at the Community Health Centre (CHC), Aga Khan University Hospital (AKUH) Karachi, Pakistan from September to November 2009. All individuals, visiting the CHC and aged 65 years or above were interviewed after taking written informed consent.A total of 400 elderly completed the interview. Majority were females, 65\u201369 years age, More than half of the individuals ie: 227 (85%) had received Care Giver experience for assistance and among these 195(72%) had care provided by an immediate family member. A large proportion of them stated that their Care Givers managed to provide less than four hours in a day for care giving. Around 37% showed substantial improvement in their relationship with the care givers. About 70% of the respondents stated that the care provided by the Care Giver improved their quality of life.Elderly care is provided by majority of the family members resulting in increased satisfaction level, however small number still not satisfied due to unfulfilled need of these older people. This demands that efforts should be made to strengthen the family support by increasing awareness regarding elderly care and arranging support system by the government. Elderly population particularly aged 65 years and more contributes to 380 million people globally and by the year 2020, this population is projected to increase to more than 690 million This older population is vulnerable to various disabilities as a consequence of stroke, dementia, heart diseases and trauma According to Center for Disease Control (CDC), about 80% of older Americans are living with at least one chronic condition, and 50% with two Care Givers can either be formal (paid volunteers associated with a service system) or informal which includes family, friends, neighbors or trust members who provides unpaid care out of love, respect, obligation or friendship to a disabled person In accordance with accepted social and cultural norms in Pakistan, people prefer to live in an extended family system as it is cost effective and has many other advantages including availability of support for the elderly by the family members There is serious scarcity of formal Care Givers and also non availability of Trusts and social projects to provide care to the elderly people in Pakistan, we designed this study to assess the problems faced by the people requiring support from Care Givers and the barriers faced by the care givers in providing support., so that proper intervention techniques could be devised to raise the quality of life of the elderly and to reduce the negative outcomes of care giving practices.This was a cross sectional survey conducted at the Community Health Centre (CHC), Aga Khan University Hospital (AKUH) located at Karachi from September 2009 to November 2010. AKUH is a tertiary level teaching facility in the private sector and caters to the medical needs of a large majority of patients coming from all over Karachi as well as from other parts of Pakistan. CHCalong with family medicine clinics also provides specialist services to a number of patients thus enabling a diverse assortment of patients from all backgrounds to be encountered.A total of 423 people who were 65 years or older presenting to CHC for consultation were approached out of which 400 agreed to participate in the study through non probability convenient sampling.Sample size was calculated through WHO sample size calculator by using following assumptions: since we do not have any prevalence data for the Frequency and associated factors for care giving among elderly patients visiting a teaching Hospital in Karachi, Pakistanhence a prevalence of 50% was assumed to observe a difference, with bound of error of 5% and level of significance of 5%, the estimated sample size was 385.After addition of 10% for non-response the final sample size was approximately 423 study participants.The initial questionnaire was designedbased on the prior experience of investigators, input fromcolleagues, peers as well as patients.The proforma was then pre-tested on 25 respondents and no changes were deemednecessary to be made in the questionnaire based on this pretesting.The questionnaire was initially prepared in English; then translated into Urdu, the national language of Pakistan, for the convenience of the respondents. The questionnaire was also back-translated into English by two non-medical personnel to check for any paraphrasing errors.The questionnaire was divided into four sections and included questions related to Socio demographic factors, needs of elderly people and their choices for Care Givers, perception of elderly people regarding their Care Givers and the impact of Care Giving on their life. And lastly characteristics of care giving among respondents based on gender.p-value of <0.05 was considered significant.Data was entered using Epi-data version 3.1 and analyzed through SPSS version 15. Frequencies were calculated for categorical variables (Gender), Mean and standard deviation for age. Cross tabulation was done and chi-square test was applied to compare different factors related to care giving on the basis of gender and Written informed consent was obtained from the subjects after explaining the study objectives. The subjects were free to withdraw at any time without giving any reason.Strict confidentiality was maintained throughout the process of data collection, entry and analysis. All efforts were made in this study to fulfill the ethical considerations in accordance with the \u2018Ethical principles for medical research involving human subjects\u2019 of Helsinki Declaration A total of 423 people were approached out of which 400 agreed to participate in the survey.The overall response rate was found to be 91%.Among these respondents, 165(41%) were male and 235 (59%) female with a mean age of 69\u00b15.95 years.On enquiring about the relationship of the care givers with the participants around three fourth of the care givers (72%) were their immediate family members whereas only (15%) were house Maids and (9%) their relatives. Relationship of the elderly with the care givers have improved in only (37%) cases while (59%) did not felt any change at all. Impact of care giving to respondents showed improvement as mentioned by majority of the respondents and .on specifying improvements areas majority responded for medical problem (37%) followed by improvement in financial (10%), social (12%) and emotional well being (16%).Problems in providing service was faced by (43%) of the care providers as mentioned by care recipients. Most common reasons responsible for slow down of taking care of elderly people/relatives included financial difficulty (30%) lack of time(30%) followed by job responsibility(22%),home responsibilities(10%) and, health reasons(6%)respectively.It is important to note that 290 (73%) respondents reported they provided care in their past life and among these 66% of them acted as a Care Giver for their family members. Regarding duration of care giving 54% of the participants recalled that they provided care for more than 3 years. About 68% of them accepted that they faced difficulty in providing care with majority having financial difficulty and lack of time as the main barrier.This study assessed frequency and associated factors of care giving among elderly population visiting a teaching hospital in Karachi. Numerous studies have been conducted worldwide but to the best of author's knowledge very limited data exist regarding trends of care giving in Pakistan.In this study majority of the participants were females probably females required more assistance of care givers in comparison to males and they have higher life expectancy as compared to males these results are consistent with studies in other parts of the world It was seen that majority of the elderly needed care givers for medical and physical reasons as large number of population in this age group suffers from multiple Co-morbidities Similarly financial needs were also reported by only small number of respondents probably because they belonged to educated and financially better placed group of individuals. It also is explained on the basis of support being available to those living in extended family model.Social needs were stated by small number of respondents because of their limited mobility as a consequence of multiple co-morbidities and physical limitations. A need exists to promote Senior Citizen Clubs and societies that may provide opportunities for socializing among elderly population and social interactions and exchanges.A majority of respondents reported immediate family members specially females as care providers similar to another study done in Thailand This will lead to a serious issue in future with the substitute of traditional extended family system with nuclear family system. On the other hand it was interesting to note that small numbers of respondents were using House Maid as care givers.Time provided by the care givers by half of the elderly population was less than four hours per day and only a small number were able to give up to eight hours of care giving which is required for minimum needs. Another aspect was that there were more than one Care Giver for a given patient and the added supported may be able to satisfy most of the patient requirements this is consistent with a study done in Spain which showed care givers spent around 14 hrs/day with more than one care givers It is also notified that a significant respondents required assistance from Care Giver for more than three years similar results of study done in Pakistan on care giving of cancer patients Relationship between patient and care provider has an important role to play in care giving as evident by a prior studies It was heartening to see that around one third of the respondents reported improvement after care giving. Major areas of Improvements were medical, physical, social and financial well being On further questioning one third of the respondents reported unfulfilled needs despite provision of care giving. Financial need was the most commonly reported unfulfilled need. These results are in contrary to findings of a study done in Japan on females with or without dementia and showed majority of the females without dementia were satisfied with their daily life and economic status Nearly two third of the respondents reported that their needs were fulfilled by care giving. Majority of the people had an impression that the care provided by the care giver improved their quality of life Majority of the respondents reported they provided care in their past life and more than half of them acted as a Care Giver for their family members. This shows that Care Giving is an accepted practice in Pakistani society. Half of these individuals recalled that they provided care for more than 3 years, again emphasizing long term and ongoing nature of care giving in the elderly.On further enquiring about difficulties which they faced while providing care more than half of the respondents faced difficulty in providing care with a majority having financial difficulty and lack of time as the main barriers these results are similar to a study done in Canada and Spain This study highlights the issues and problems encountered by elderly people and their care givers and also clearly demonstrate the level of satisfaction regarding their care. Elderly care is provided by majority of the family members resulting in increased satisfaction level, however small number still not satisfied due to unfulfilled need of these older people as a consequence of hindrance faced by the family members in the form of financial, mental and psychosocial issues. Lack of awareness among family members for elderly care is also an important area of concern. Pakistan lack social services or study respite centers or any support system for the elderly. This situation demands efforts to strengthen the family support by increasing awareness regarding elderly care and arranging support system by the government for these older population.This study was done on a selected population of elderly in a tertiary hospital which caters mostly educated people with good financial background so it cannot be generalized. However Community Health Centre caters people from all socioeconomic groups this fact helped us in offsetting this particular limitation of study."}
+{"text": "Studies have widely documented the socioeconomic inequalities in maternal and child health related outcomes in developing countries including India. However, there is limited research on the inequalities in advice provided by public health workers on maternal and child health during antenatal visits. This paper investigates the inequalities in advice provided by public health workers to women during antenatal visits in rural India.The District Level Household Survey (2007\u201308) was used to compute rich-poor ratios and concentration indices. Binary logistic regressions were used to investigate inequalities in advice provided by public health workers. The dependent variables comprised the advice provided on seven essential components of maternal and child health care. A significant proportion of pregnant women who attended at least four ANC sessions were not advised on these components during their antenatal sessions. Only 51%\u201372% of the pregnant women were advised on at least one of the components. Moreover, socioeconomic inequalities in providing advice were significant and the provision of advice concentrated disproportionately among the rich. Inequalities were highest in the case of advice on family planning methods. Advice on breastfeeding was least unequal. Public health workers working in lower level health facilities were significantly less likely than their counterparts in the higher level health facilities to provide specific advice.A significant proportion of women were not advised on recommended components of maternal and child health in rural India. Moreover, there were enormous socioeconomic inequalities. The findings of this study raise questions about the capacity of the public health care system in providing equitable services in India. The Government of India must focus on training and capacity building of the public health workers in communication skills so that they can deliver appropriate and recommended advice to all clients, irrespective of their socioeconomic status. Janani Suraksha Yojana (JSY) \u2013 under the National Rural Health Mission to promote births in the public health care system in the country. Further, maternal and child health services are provided free of charge in the public health care system. Another important step taken by the Government of India to improve accessibility of health services is to make certain primary health centres in the rural areas functional 24 hours a day.Prenatal care, skilled birth attendance and postnatal care strategies have been recommended for several years Despite all these efforts, the utilisation of care during pregnancy, at childbirth and during the postpartum period has been limited in India. Recent data from the National Family Health Survey 2005\u201306 suggests that only 37% of pregnant women made 4+ antenatal visits for their most recent pregnancy, 39% delivered their recent babies in a health facility, and only 42% of women reported receiving postnatal check-up after their most recent birth Advice and counselling are important components of the antenatal care package and key to improving health behaviour and care seeking during pregnancy, labour and delivery and in the post-partum period There are only a few studies that have examined inequalities in advice provided during the antenatal sessions. Recent studies in rural Tanzania reported that most recommended topics critical to improving maternal and newborn survival were rarely covered during the antenatal sessions The Government of India guidelines recommend that every pregnant woman have at least three antenatal visits and that the first visit is preferably in the first trimester. During the antenatal visits, pregnant women must undergo physical examination , interventions (such as iron folic acid supplementation and tetanus toxoid vaccinations), laboratory investigations, counselling , etc Our study is, therefore, an attempt to investigate the inequalities in advice provided by the public health workers to women during antenatal sessions in rural India using a recent and representative large-scale dataset that was particularly designed to monitor the performance of the Reproductive and Child Health (RCH) program in India. In particular, this paper examines the inequalities in advice according to the wealth status of the clients. The paper investigates the inequalities in advice separately for higher level and lower level health facilities. We restrict our analysis to rural areas as the rural population depends heavily on public health facilities for maternal and child health care services.The study is based on a secondary data set with no identifiable information on the survey participants. This dataset is available in the public domain for research use and hence no formal approval from the institutional review board is required. So, no ethics statement is required for this work.We used data from the \u2018District Level Household Survey\u2019 round three (DLHS-3) conducted in 2007\u201308 in 601 districts from 34 states and union territories of India. The DLHS-3 was designed to provide estimates on maternal and child health, family planning and other reproductive health indicators at the district level Dependent variables used in the analysis are the advice provided on seven essential components of maternal and child health care during antenatal sessions. These components include 1) breastfeeding, 2) keeping the baby warm, 3) spacing methods of family planning, 4) limiting methods of family planning, 5) nutrition, 6) institutional delivery, and 7) visiting a health facility in case of pregnancy complications. Advice and counselling during antenatal sessions play a critical role in preventing morbidity and mortality among the mothers and the newborn by enabling women and their family members to adopt health promoting behaviour and to identify and act on medical emergencies that may arise during pregnancy, delivery and post-partum periods The main explanatory variable of interest in the analysis is a measure of wealth \u2013 computed in order to investigate inequalities in access by poverty status. In the absence of direct data on income or expenditure in many surveys, a wealth index based on the ownership of household assets is widely used as a proxy for assessing the economic status of the households Wald test was used in the binary logistic regression models to examine whether or not wealth status was a predictor of receiving advice during the antenatal sessions.To assess the extent of inequalities in access to advice, we estimated rich-poor ratios , as well as concentration indices (CI). The CI measures the relationship between the accumulated proportions of individuals ranked by their socioeconomic status against the cumulative proportion of utilisation of healthcare The advice given to pregnant women on the seven components during antenatal sessions in India was far from universal and varied considerably across the type of advice . The advThe provision of advice on the seven components also varied by the level of public health facility; the chances of providing such advice being higher in higher level facilities compared to lower level facilities. For example, 75% of pregnant women who availed themselves of antenatal care in the higher level facilities were advised on breastfeeding compared to only 70% among those who availed of antenatal care in the lower level facilities. Likewise, 65% of women availing of antenatal care in the higher level facilities were given advice on keeping the baby warm compared to only 59% among those who availed themselves of antenatal care in the lower level facilities.The rich-poor ratios suggest enormous socioeconomic inequalities in the provision of the aforementioned advices. The rich-poor ratios were consistently above one, thus indicating that the rich were more likely than the poor to receive advice . MoreoveWald test was significant in all the models indicating that wealth status was indeed a predictor of receiving the seven sets of advice. Findings further suggest that women availing of antenatal care in the higher level facilities were significantly more likely to receive advice on breastfeeding, keeping the baby warm, spacing and limiting methods of family planning, and nutrition than women availing of antenatal care in the lower level facilities.The binary logistic regression results for providing advice on the seven components during antenatal sessions are shown in Wald test results suggest that wealth status was a predictor of receiving advice in only five out of seven components . In contrast, among those women who availed themselves of antenatal care facilities, the rich were 1.3 to 1.5 times more likely than the poor to receive advice on all the seven components in the lower level facilities  which also showed significant socioeconomic inequalities in the utilisation of postnatal care among facility births The World Health Report 2005 has particularly emphasized on the critical issues of exclusion and equity A few studies from the developed and developing world have shown that inequity is built in the health systems This study has some limitations. The information in DLHS-3 on advice during antenatal sessions was obtained from women and thus might be affected by recall bias. However, the chances of such bias are limited because we restricted our analysis to only those women who had four or more antenatal visits. By doing this, we included only those women in our analysis who were motivated enough to utilise the antenatal care services and thus recall the information provided to them. The analysis was also restricted only to the most recent birth that took place in the three years preceding DLHS-3. The survey format has been regularly used in the various rounds of DLHS and the findings are widely used to monitor the performance of policies and programs in India. Survey teams receive formal training and quality control measures are in place. Moreover, a study conducted in Indonesia, India and China has shown that while systematic reporting heterogeneity was significant, it was relatively small in magnitude and did not have a substantial effect on measured socio-economic inequality in health Our findings have important policy implications. The Government of India has taken a number of steps for improving maternal and child health in India. Promoting antenatal care, delivery care and postnatal care are some of the interventions. Studies have shown that there is a preference among the health workers for medical procedures during antenatal visits and advice and counselling are limited In addition, the Government of India is taking a number of initiatives to improve public health care infrastructure to provide quality care to the rural and socioeconomically deprived population under its most ambitious program, the National Rural Health Mission (NRHM) 2005\u20132012. The Government of India has also formulated Indian Public Health Standards (IPHS) and is trying to bring health care infrastructure especially in rural areas up to IPHS. A number of other architectural corrections have also been proposed to deliver quality care to the rural population. The Government of India is planning to launch the second phase of NRHM. So, it is high time that the Government of India focused more on training and capacity building of the health personnel so that they can deliver appropriate and recommended care to the clients. Special sessions must be organised to sensitize health workers towards the special needs of the socially and deprived classes of the population, who need more care and attention. The health workers must also be informed about the rising inequalities in maternal and child health and its negative consequences. These strategies are particularly needed for public health workers deputed to the lower level health facilities, as our findings clearly reveal higher inequalities in advice among women who availed of antenatal care from lower level health facilities compared to those who availed of antenatal care from higher level health facilities. Policy-makers and program managers should think seriously about improving the managerial skills of the health workers, so that they treat their clients equally irrespective of their socioeconomic status. If immediate attention is not given to these findings, there is every chance that the public health care system will improve in terms of infrastructure, but will fail in delivering the required services to those who need them the most."}
+{"text": "In less than 40 years of the first human gene being isolated, which involves putting isolated and manipulated DNA (genes) back into individuals for treatments of genetic diseases. Gene therapy is now more widely accepted to encompass all forms of therapeutic intervention in which DNA is used to alter the overall pattern of gene expression within an organ. Potential applications of gene therapy are widespread and implications for the management of various human diseases are becoming available. Approaches are being developed to overcome difficulties and identify a number of potential applications . The manIt is now relatively well accepted that much of human disease can and should be treated at the level of underlying genetic manipulation. Much of the theoretical basis of gene therapy are going to be worked out step by step . What weSeveral approaches have also been made to modify cell phenotype including inhibition of gene function associated with cell proliferation and to arrest the progress of atherosclerosis and restenosis, and the local production of growth factors to promote angiogenesis  to elicit regionally specific effects i.e., directed for to regions of hypoxia or other stress. Approaches most likely to succeed in gene therapy remain a subject for speculation and based on experimental findings. We should also take caution and not only overestimate the importance of gene therapy at this early, but promising stage. These are exciting times but it takes additional and substantial effort before gene therapy makes real impact in humans. What appears certain is that cardiovascular diseases will be a major of therapeutic applications."}
+{"text": "Case finding by using screening on frailty and physical activity among elderly and coaching them on lifestyle and to find appropriate activities in order to increase physical activity and well-being of elderly.Several stakeholders in community health services and social services, can detect signs of frailty and poverty of physical activity in their contacts with elderly clients. It is also known that adequate physical activity will positively affect the different area\u2019s of frailty like physical and mental abilities as well as social well-being.Therefore valid screening on frailty and physical activity and subsequent interventions are important to (positively) affect the negative spiral of becoming more and more frail and dependent on health and social services.In each municipality a local network of health care professionals and social workers came together in order to make agreements on the process of early screening and lifestyle coaching focused on physical activity and on the stakeholders which should be involved. For each municipality 20\u201340 elderly can be included in the process of lifestyle coaching with the following inclusion criteria:in the age of 55 years or olderliving independent frailty score of 4 or more or physical ability-score of 2 or morepoor physical activity and motivation to improve physical activity.Questionnaire among stakeholders in community health services and social services (for early screening) and among the lifestyle coaches. Structured interviews among elderly who are participating in this field project. Measurements using the GFI-scale for frailty and a scale for physical activity.During the period September 2011 until June 2012 the early screening will be performed using the validated Groninger Frailty index and the lifestyle coaches will select and reach them in order to start a coaching process.Starting up early screening by several stakeholders demands a good preparation; involvement in making the local appointments about the process of screening and lifestyle coaching is important. Having a coordinator with an important responsibility for communication is crucial. New connections are realized between social workers and health care professionals. To get other professionals involved for early screening is not easy. Focus on frailty in early screening is altered to physical activity. Success for including elderly differs among the municipalities.Results from structured evaluation are not available yet. In March 2012 some preliminary results will be presented."}
+{"text": "Patient and public involvement (PPI), inclusion of members of the public as active partners in the research process, can be a requirement of research funding. Limited evidence has suggested that clinical trials may be particularly likely to benefit from PPI. There is a lack of critical assessment of PPI and suggestions in the literature of selective reporting of its benefits. This study aims to increase the knowledge of PPI in clinical trials by systematically investigating how it is approached within a cohort of public funded randomised trials in the UK.Documentation from the application process for all randomised trials funded by the National Institute for Health Research Health Technology Assessment (NIHR HTA) programme between 2006 and 2010 were obtained. Data relating to PPI activity and how these plans were assessed within the peer review process were extracted.Documentation to allow details of planned PPI activity to be extracted were available in 107 RCTs. PPI representation was not described in 15% with representation on TSCs, DMCs, and TMGs described in 53%, 8%, and 12% of applications respectively. A consultancy approach was described in 26%.Of the 515 reviewers comments across the trials only 211(41%) commented on PPI plans. The majority repeated the PPI plans from the application rather than commenting on their suitability.Research applicants frequently describe PPI but reviewers seem unable to comment on suitability of the approach. Evidence of impact is needed to inform future approaches for applicants and peer reviewers."}
+{"text": "What mechanisms underlie this impact of emotion on perception? Evidence suggests that emotion-induced blindness may be distinguishable from closely related phenomena such as the orienting of spatial attention to emotional stimuli or the central resource bottlenecks commonly associated with the attentional blink. Instead, we suggest that emotion-induced blindness reflects relatively early competition between targets and emotional distractors, where spontaneous prioritization of emotional stimuli leads to suppression of competing perceptual representations potentially linked to an overlapping point in time and space.Emotional visual scenes are such powerful attractors of attention that they can disrupt perception of other stimuli that appear soon afterward, an effect known as  Most aspects of the environment resonate with emotional meaning, so an understanding of perception in the real world necessitates understanding how it is impacted by emotion. Evidence suggests that emotional stimuli themselves attract attention more robustly and are more readily detected than are non-emotional stimuli  of upright landscape and architecture photos at a rate of 10 images per second. They were instructed to search within each stream for a landscape or architecture photo that was rotated 90\u00b0 clockwise or counterclockwise and to report its orientation  was equally likely to appear in the same stream as the target or in the opposite stream. Results revealed that target perception was worse following an emotional distractor only when the critical distractor appeared in the same stream as the target . At the end of the experiment, the female participants were asked to rate their level of unease about the fact that their partner had been rating other women; in two separate experiments, there was a robust correlation between self-rated unease and emotion-induced blindness  perception of neighboring targets through relatively central, late-stage mechanisms as well . The evidence reviewed in the present discussion highlights potential spatiotemporal competition mechanisms; further characterization of the loci at which emotion can impact visual processing holds promise for more fully understanding the myriad ways that it can shape our conscious perception of the world.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Urachal remnant disease is uncommon in adults and can present with symptoms ranging from drainage near the umbilicus to a severe abdominal infection. Most cases are referred for treatment once diagnosed either clinically or radiographically with ultrasound or computerized tomography. We present a unique case of an infected urachal cyst visualized on a series of CT scans in an adult patient with abdominal pain over a period of years. A 33-year-old-male patient presented initially with lower abdominal pain in March 2006. He was diagnosed with appendicitis based upon his exam and history. A CT scan of the abdomen was performed at that time and demonstrated extensive inflammatory changes in the right lower quadrant with possible interloop abscess . Two nonThe patient presented again in August 2011 with right flank pain and urinary symptoms. A noncontrast CT scan of the abdomen was performed and demonstrated a right ureterovesicular junction calculus with mild right ureteral dilation . Again, He subsequently presented again 3 weeks later with severe abdominal pain and induration of his lower abdominal wall. CT imaging now demonstrated interval enlargement of a complex cystic mass inseparable from the anterior superior wall of the urinary balder and abutting the posterior margin of the abdominal wall . The radAt the time of surgery, cystoscopy did not demonstrate any abnormalities of the bladder. Exploratory laparotomy was performed and an indurated mass and abscess were encountered near the area of the anterior abdominal wall and bladder. The abscess was drained and a few small calcifications were encountered and removed for pathologic examination. A complete exploration was performed and the phlegmon appeared to be limited to the dome of the bladder. This area was excised and the dome of the bladder was closed primarily in layers with absorbable suture. Drains were placed and the abdominal wall was debrided and closed. He had an uncomplicated postoperative course. Final pathology demonstrated urachal remnants with no evidence of malignancy. The urachus is an embryologic tract that extends from the bladder to the umbilicus during development . RemnantOur case highlights the potential complications related to an urachal cyst disease in one patient who was treated for multiple causes of lower abdominal pain. The initial presentation of appendicitis was the first glimpse of the cystic remnant disease. The lower abdominal inflammatory changes were nonspecific and therefore it was impossible to differentiate perforated appendicitis with a fecalith from a less common cause of infection. Since the operative and pathologic findings were consistent with appendicitis at that time, consideration of a simultaneous condition was not considered.Later when the patient presented with a ureterovesicular stone and mild hydronephrosis, the CT scan demonstrated the proximity of the lower abdominal calcifications to the bladder. However, at that time there was no obvious inflammatory changes or infection associated with the bladder or abdominal wall and his symptoms were more consistent with nephroureter obstruction. Despite the radiographic presence of the urachal cyst each time the patient was evaluated for his symptoms, he was diagnosed with a potentially more common cause of pain each time. It was not until the patient developed a severe infection of his lower abdominal wall that the urachal cyst was finally treated surgically and excised. Urachal remnant disease should be considered in any patient with calcifications or cysts adjacent to the anterior abdominal wall or bladder dome. Urachal disease can be an incidental finding radiographically or it may present once infection or some other complication develops. Our case presentation highlights the potential for early diagnosis or potential misdiagnosis due to the frequent use of computerized tomography for patients with lower abdominal pain."}
+{"text": "The positioning of the patient on the fracture table is critical to the successful reduction and operative fixation of hip fractures which are fixed using the dynamic hip screw system (DHS). There is a standard setup which is commonly used with relative ease. Yet the positioning of patients with amputations either above or below knee of the affected side can pose a significant challenge. We describe a novel positioning technique used on a 51-year old patient with a right above knee amputation who sustained an intertrochanteric extracapsular hip fracture. Hip fractures are a common source of morbidity and mortality worldwide . The incThis standard setup is quick and is achievable with relative ease in patients with intact lower limbs. The positioning of patients with amputations either above or below knee of the affected side can pose a significant challenge. We describe a positioning technique used on a 51-year old patient with a right above knee amputation who sustained an intertrochanteric extr-capsular hip fracture.A 51-year-old male with a right above knee amputation presented to the emergency department with a painful right hip subsequent to a fall on that side. He had been mobilising with two crutches for the previous four weeks while awaiting new prosthesis for the right above knee amputation from previous infected total knee arthroplasty.Plain film radiographs revealed an undisplaced extracapsular intertrochanteric fracture of the right hip .As an active and mobile amputee with a functional prosthesis, the patient was scheduled for a DHS fixation of the right intertrochanteric hip fracture with spinal anaesthesia. Securing the amputated limb poses a challenge in patients with above knee amputations. Our setup involved the standard fracture table used routinely to position a patient for DHS fixation. Adhesive fabric tape  was used to secure the stump to the distal end of the fracture table in a similar manner to the application of skin traction. Combining a specially formulated porous adhesive and a superior woven cloth, Elastoplast now Tensoplast, provided satisfactory adhesion while remaining secure in place. Such adhesive fabric tape and a crepe bandage was used circumferentially around the distal stump to further secure the limb .The DHS fixation was uncomplicated and the patient's recovery was uneventful. The patient was mobilised full weight bearing as tolerated with physiotherapy and discharged two days postoperatively. The post operative radiographs were satisfactory  and at tThere is little in the literature regarding the management of intertrochanteric hip fractures in patients with ipsilateral above or below knee amputations. Securing the amputated limb to the fracture table poses a significant challenge. Al-Harthy et al.  describeLimbs that have undergone an above knee amputation can have short stumps that can be very challenging to position or apply traction to. To our knowledge, there is only one report on the positioning technique for patients with a fracture and an above knee amputation. Aqil et al.  describeOur technique is an alternative to those described above. While the skin traction facilitated positioning of the limb, it provided little rotation control. Our patient had an undisplaced fracture and our technique resulted in a timely and satisfactory fixation. Due to the size of the stump and the small area the skin traction is applied to, it cannot generate any significant amount of traction prior to it getting unravelled. It may be conceivably more useful in below knee amputees where adequate skin traction and therefore traction may be applied. The skin around the stump needs to be carefully inspected prior to application of this technique as any fragile areas may become prone to breaking down during the procedure if prolonged.Some level of rotation can be applied using a wooden stick or a metal bar placed within the crepe bandage limbs and applying rotation towards the desired direction. Yet if significant traction and rotation control were needed for the reduction and fixation of these fractures, the use of skeletal pin traction may be necessary. The application of such a pin carries with it the risk of injury to the soft tissues of the stump. The pin may pull out of the osteoporotic bone on application of traction.There is little in the literature regarding the intraoperative positioning of patients with a hip fracture and an above knee amputation. There is one previous report and we describe an alternative technique for the positioning of a patient with an extracapsular hip fracture and an ipsilateral above knee amputation."}
+{"text": "The objective of this study is to discuss some of the issues and give some examples of dealing with clustering in individually and cluster randomised trial sample size calculations.Clustering often occurs in individually randomised trials and is sometimes ignored when calculating sample sizes. Examples include practitioner effects in individually randomised trials with more than one practitioner or therapist effects from group interventions where clustering may be in one arm only. Additional levels of clustering may also occur in cluster randomised trials and estimating their effects can be difficult.Sample size calculations for several recent grant applications submitted by the South East Wales Trials Unit (SEWTU) have attempted to account for clustering or reduce inter-practitioner variation in different ways.Example 1: Clustering effects in an individually randomised trial of a group intervention for drug and alcohol detoxification based in prison were estimated for the intervention arm and the sample size of both arms inflated. Example 2: Clustering effects of anaesthetist were not estimated for a multi arm trial of 4 different airways devices but sample sizes were inflated to allow for small unknown effects. Sample size estimation used comparative and equivalence methods in three parallel multi arm trials. Example 3: Possible clustering in a trial of fissure sealant vs fluoride varnish at the school or family level was not accounted for in sample size calculations. All schools in the trial are Communities First schools and likely to be fairly homogeneous. Example 4: Unknown clustering effects of weight loss slimming groups were not accounted for in the intervention arm of a cluster randomised trials of a healthy lifestyle programme in obese pregnant women. Training has been implemented to reduce variability among group leaders.There appears to be no consensus regarding dealing with additional clustering effects and best efforts are made on a trial by trial basis for sample size estimation. Access to data for the estimation of intraclustering correlation coefficients and/or dissemination of the results will benefit all researchers designing trials with clustering issues."}
+{"text": "Two major neurological disorders \u2013 Parkinson\u2019s disease and dystonia \u2013 are believed to involve pathology in the activity of the basal ganglia, a subcortical brain structure, whose output nuclei  projects to thalamus and modulates thalamocortical relay. While these disorders may ultimately involve different network and cellular pathologies, some pathological physiology may be shared between them because surgical treatment of both conditions includes surgical lesion or electrical stimulation to GPi . This work compares the thalamocortical relay responses to inhibitory inputs from internal segment of GPi in Parkinson\u2019s disease and in dystonia.Experimental data suggest that both conditions are marked by stronger oscillatory activity. In dystonia this activity becomes pathologically strong in the theta and alpha bands ,2, whileThe results of the study of the \u201chybrid\u201d system  reveal a substantial similarity in the properties of relay in Parkinson\u2019s disease and in dystonia. TC relay fidelity is substantially impaired due to the pathological pattern of GPi signals in both conditions. The results are robust with respect to variations of the model details and the types of incoming excitatory synaptic input.The results suggest that even though the rhythmicity in Parkinson\u2019s disease and dystonia are confined to different frequency bands, their effect on the dynamics of downstream circuits is similar. Thus given the differences in dystonic and parkinsonian symptoms these results suggest the existence of mechanisms beyond pathological rhythmicity and thalamocortical relay in at least in one of the conditions. On the other hand, overlap in some motor deficits of dystonia and Parkinson\u2019s disease may be attributed to the existence of similar pathological rhythmicities and the resulting deficiencies of thalamic relay."}
+{"text": "The project focussed on two local services in Wales that have recently moved to  an integrated health and social care intellectual disabilities service.What are the advantages and disadvantages of service integration as viewed by parents with respect to care provision for young people with intellectual disabilities?We conducted a parental survey facilitated by nursing staff in both local services.Parents were generally skeptical of any positive impact of organisational changes on quality of care for children with LD. The main issues of concern for parents, however, did NOT relate to integration but to lack of resources and quality of care provision. This has serious implications for the way in which we should evaluate organisational changes such as health and social care integration for this user group.Parental concerns cover a wide range of issues. These issues reflect the unique needs of service users. Evaluating the impact of service integration for service users need to take account of different needs and abilities in this population group. The study also helps us to appreciate the limitations of parental surveys to measure service integration outcomes."}
+{"text": "Associated neurospinal dysraphism in combination with anomalies of the genitourinary tract is well known in children with imperforate anus. There is a broad spectrum of concomittant anomalies with the OEIS Syndrome as the most serious endpoint. OEIS is an acronym for omphalocele, exstrophy , imperforate anus and spinal defects. At present almost all cases of OEIS are diagnosed prenatally and the patients should be treated at a specialized center with a multidisciplinary team. The complex diagnostic procedures and surgical measures are addressed as well as the difficulties in achieving continence in these patients.We present data of six patients with imperforate anus and spinal dysraphism  currently managed in the spina bifida clinic of the Children\u2019s Hospital of Cologne. Two of them presenting the complete OEIS syndrome symptoms, another two with cloacal exstrophy without omphalocele and two with major renal malformations. Only two of six patients had hydrocephalus.The often difficult and multiple reconstructive surgical procedures in these patients are described . Especially the management of incontinence is extremely complex in these patients. For instance there is no sufficient bladder capacity in patients following initial closure of bladder exstrophy and there is only a weak or no function of the anal sphincter following pull-through procedures.OEIS syndrome is a devastating combination of anomalies resulting in a neurological deficit similar to myelomeningocele. In contrast to the functional problems arising in spina bifida patients, children with OEIS syndrome have functional impairment with additional problems due to the malformed urogenital tract and anorectal system. Management of children with OEIS syndrome demands a careful management plan starting already in the prenatal period and resulting in a life-long surveillance. Treatment of these patients should only be performed by a multidisciplinary team in a specialized center."}
+{"text": "Although there is a substantial literature about the effectiveness of psychological therapies such as relaxation for pediatric chronic pain and about mindfulness meditation (MM) for health and mental health conditions, there has been little systematic attention to the use of MM for pediatric chronic pain. This presentation will address lessons learned from our ongoing clinical trial of MM in a pediatric chronic pain service at a university clinic.We present case material from our ongoing pilot clinical trial of a manualized mindfulness meditation intervention, called Inner Resources for Coping with Chronic Pain . Participants are 30 patients diagnosed with chronic pain and aged 11 \u2013 17 receiving a 6-week, group-based meditation intervention that includes daily home practice of the techniques. Case material from two participants will be presented to illustrate effects and precautions.Our case material indicates that patients are able to learn and practice the MM techniques, with good adherence to the home practice. A male patient with multiple pain complaints was able to learn and practice the meditation techniques and use them to cope with stressors associated with his medical conditions. A 16 year old female patient with longstanding participation in pain management that primarily involved distraction found the concurrent use of mindfulness and distraction to be confusing and ineffective.MM shows promise as an intervention for helping children and adolescents to deal with chronic pain. The children and adolescents in our clinical trial have evidenced the ability to engage with the material and adhere to regular home practice of the techniques and application of them to presenting problems. However, a note of caution is raised by the possible incompatibility of mindfulness with concurrent therapies emphasizing the use of distraction for dealing with chronic pain."}
+{"text": "Clark's article provides a useful synthesis of theoretical and empirical work evincing the brain as a prediction machine and proposing bi-directional, prediction error estimation as a fundamental mechanism of adaptive brain function. Accordingly, in Bayesian terminology both cognitive and perceptual mental states can be understood as statistical posterior distributions formed by integrating encountered data (with specific likelihoods) with prior beliefs (in turn with their own prior distributions). In his discussion of this unifying framework, Clark elegantly describes how updating priors with the aim of minimizing prediction error can sometimes result in illusory experience. When faced with stimuli manipulated to have multiple possible hidden causes, ambiguity is resolved by selecting the most likely explanation given prior beliefs about those hidden causes. As such, in conditions such as those created for the sound-induced visual illusion  and delusional beliefs ; with a marked impact on social and occupational functioning. The underlying mechanisms giving rise to these phenomena remain unclear, and current treatment is largely based on medication to block sub-cortical dopaminergic receptors, allied to cognitive behavioral psychological approaches to reduce distress associated with these symptoms. Examination of individuals with schizophrenia demonstrates that they are less susceptible to perceptual illusions than healthy individuals. For instance, the McGurk phenomenon by which incongruence between certain lip movements and speech sounds produces the perception of alternative speech sounds appears to be exhibited to a lesser degree in individuals with schizophrenia (Pearl et al., Can the findings of reduced susceptibility to perceptual illusions be viewed as conferring a schizophrenia-related behavioral advantage? If so, is this outperformance of healthy individuals by those with schizophrenia best explained by a predictive failure? The findings of our own laboratory provide empirical evidence that predictive abnormalities are not restricted to passive sensation \u2013 in accord with Clark's suggestion of prediction as a universal neural mechanism \u2013 but extend to predictions made on the basis of self-generated movement. Individuals with schizophrenia differ from healthy individuals in their ability to estimate the level of force necessary to match a force applied directly to themselves (Shergill et al., Computational modeling has proven valuable in the characterization of behavioral and neurophysiological parameters relating to the updating of Bayesian processes during information processing in schizophrenia (for example, Averbeck et al., The study of wide-ranging illusions presents a potentially fertile means of understanding the intricacies of predictive failures in schizophrenia as each illusion draws on specific perceptual and cognitive priors. On the flip side, the study of illusion potentially provides a tantalizing model for the study of distorted reality in the healthy brain. Furthermore, given the efficacy of dopaminergic pharmacological neuromodulation in patients with schizophrenia, there is an urgent need for examination of the role of neurotransmitters in mediating predictive coding."}
+{"text": "Postgraduate training is a dynamic activity. Over the years it is undergoing increasing standardization. In the past programs have been haphazard and inconsistent but now structured curriculum are in place. Comprehensive details related to criteria of entry, duration of training, core knowledge areas, and competencies required can be found. How program is to be run is explicitly chalked down and log books developed to be completed by trainees. In Pakistan one such model is implemented by College of Physicians and Surgeons Pakistan (CPSP). The program was developed through a well organized activity with explicit guidelines, under supervision of medical educationists, who initially trained program directors through various educational workshops. Few medical universities have also developed curriculum related to pediatric surgery but how they are developed is not known. While CPSP training program is uniform throughout the country, university program varies. There is also a comprehensive evaluation system with CPSP program and evaluation strategies are accessible to both trainees and trainers and evaluators.The magic figure of three years of residency in pediatric surgery  in CPSP model is questioned by few program directors. In United States the total duration of training in pediatric surgery after general surgery residency, is two years. The 18 months training comprise of clinical pediatric surgery and the remaining six months may be spent in related clinical disciplines to enhance the educational experience, or get involved in scholarly activities. It raises question as to how general surgery residency in US model is beneficial to those seeking career in pediatric surgery. In this model the pediatric surgery resident spends only 25% of his total training in core curriculum of his own discipline. During this time period it is expected that trainee must document a total of 800 major pediatric surgery procedures as surgeon and the service providing training must cater for at least 1200 core surgical procedures per year. It is for pediatric surgeons to ponder for unique requirements for patient population and trainees [The magic figure of three years of residency in pediatric surgery  in CPSP model is questioned by few program directors. In United States the total duration of training in pediatric surgery after general surgery residency, is two years. The 18 months training comprise of clinical pediatric surgery and the remaining six months may be spent in related clinical disciplines to enhance the educational experience, or get involved in scholarly activities. It raises question as to how general surgery residency in US model is beneficial to those seeking career in pediatric surgery. In this model the pediatric surgery resident spends only 25% of his total training in core curriculum of his own discipline. During this time period it is expected that trainee must document a total of 800 major pediatric surgery procedures as surgeon and the service providing training must cater for at least 1200 core surgical procedures per year. It is for pediatric surgeons to ponder for unique requirements for patient population and trainees [Accreditation of the services for training in pediatric surgery is another painstaking assignment. An elaborate form has been developed by CPSP to be filled in by the program directors providing details of workload, facilities offered, number and expertise of teaching faculty etc. It is an observation that departments of pediatric surgery in the country are heterogeneous thus training imparted may not be uniform. Some services may get recognition even when facilities like ICU care, minimally invasive surgery etc are not optimal. Thus need of rotation to other centers where such exposure is guaranteed, must be looked into.The two important areas not addressed with CPSP model are, compliance with the residency program, periodic evaluation and need of changes that may be required in this era of rapid technological advancement with new evidence based data related to diseases. No study has been conducted by pediatric surgeons in this regard to objectively address the issue. The Association of Paediatric Surgeons of Pakistan may gather a multi-institutional data to get some inference and suggest changes, if deemed necessary.Another important issue is evaluation of trainees. In United States continuous periodic assessment is made and feedback given while in contemporary evaluation system with CPSP only end exam is the deciding point though residents do complete log books of their training and write dissertation or a scientific paper but these are not counted in the final examination. The training institutes thus play a passive role and may feel isolated. The input from supervisors must be acknowledged at some level for which integrity of trainers themselves is an issue. The role of trainers in residency program must be assessed periodically by respective institutes and monitoring body. In addition residents should be asked to write an annual confidential report of their supervisors. This two way accountability and evaluation helps in raising the standard of training program and evaluation of both trainees and trainers.A residency program in pediatric surgery intends to impart advance knowledge coupled with hands on training to aspiring young doctors caring for children. An optimal program thus aims at producing safe surgeons, competent enough to take care of pediatric surgical patients referred to them.Source of Support: NilConflict of Interest: None declared"}
+{"text": "The atomistic modeling of protein adsorption on surfaces is hampered by the different time scales of the simulation ( The interaction of proteins with different biomaterials plays a vital role in describing their biocompatibility. Depending on the surface the overall protein structure may vary from native to unfolded A major problem that arises when using MD to study protein adsorption is the limited time scale of only a few hundred ns. The experimental time scale when these processes are investigated usually ranges from Based on the work by Voter In the present work, a comparison between classical and accelerated MD is used to show differences in the sampling of conformational changes during adsorption on a hydrophobic graphite surface. To our knowledge, it is the first time that the technique of aMD is used to study protein adsorption. We note that interest in adhesion studies focuses on the final structure and adhesion forces of the adsorbed molecule, since this is where comparison to experiment is possible. The actual adsorption dynamics are not so relevant; this feature makes adsorption a good candidate for aMD.Our protein of interest is the bone growth factor BMP-2 (bone morphogenetic protein 2) which is used to improve osteointegration by functionalizing implant surfaces All the simulations were carried out using NAMD 2.8 ayer see .For all simulations periodic boundary conditions are used with Particle Mesh Ewald (PME) After energy minimization all systems were equilibrated for 100 ps at a temperature of 310 K and constant pressure of 1 atm with the protein backbone atoms restrained in order to prevent adsorption before equilibration. Following the equilibration classical and accelerated MD simulations were carried out for 20 ns with a time step of 2.0 fs enabled by the SHAKE In order to sufficiently sample the conformational space of adsorption the implementation of accelerated molecular dynamics (aMD) We also let these simulations run for The mass weighted radius of gyration is defined as:Furthermore, principal-component analysis using the cartesian coordinates of the protein atoms was performed with the GROMACS The adsorption snapshots were rendered using VMD During the first 100 ps both classical and accelerated simulations show a similar trend. The protein approaches the graphite surface driven by attractive van-der-Waals interactions. But very soon classical and accelerated simulations show quite a different adsorption behavior. In the case of aMD, conformational transitions start to occur instantly whereas cMD simulations show very little structural rearrangements after the protein got in contact with the surface. During the accelerated simulations not only the protein motions but also the solvent motions were affected. Since dehydration of the surface is an essential but time consuming step in the adsorption process The final adsorption snapshots after 20 ns, which compare cMD and aMD simulations , clearlyThe protein, in the case of aMD, has spread completely on the graphite surface and forms a flat peptide monolayer. This can be confirmed by the temporal evolution of the radius of gyration . Here, oteps see ; this feInterestingly, both orientations in the case of aMD show the same secondary structure content after adsorption as can be seen in When comparing aMD and cMD one can clearly recognize that the helical and Additionally, we performed cartesian principal component analysis to identify the conformational space during protein adsorption . In thisComparing our results obtained by classical and accelerated molecular dynamics simulations we conclude that sufficient sampling of the conformational space is key to understanding protein adsorption. Since adsorption phenomena take place in time scales extending from The advantages of this method are \u2013 among many others see  \u2013 (i) thThe easiness of use and computational efficiency make aMD an ideal candidate for studying adsorption processes in large systems. Other interesting sampling techniques such as conformational flooding Our results suggest that the monomeric form of BMP-2 does indeed unfold on a hydrophobic graphite surface as suggested by previous results Even though the dynamics of the adsorption process have been altered, the final adsorption state is most relevant in adsorption studies, since it can be compared with experimental results. From what we know from experimental results"}
+{"text": "Simultaneous oscillation of neuron groups could provide solution to the binding problem  and simuIn our experiments the Brian simulator  featurinThere might be some number of basic mechanisms that are responsible for processing and forwarding information in the brain, including a variety of synchronizing mechanisms. In this experiment we have shown how synchronized oscillations of neurons and decision making processes can be used for binding and forwarding information between the neuron groups."}
+{"text": "Adverse drug reactions are a common and important complication of drug therapy in children. Over the past decade it has become increasingly apparent that genetically controlled variations in drug disposition and response are important determinants of adverse events for many important adverse events associated with drug therapy in children. While this research has been difficult to conduct over the past decade technical and ethical evolution has greatly facilitated the ability of investigators to conduct pharmacogenomic studies in children. Some of this research has already resulted in changes in public policy and clinical practice, for example in the case of codeine use by mothers and children. It is likely that the use of pharmacogenomics to enhance drug safety will first be realized among selected groups of children with high rates of drug use such as children with cancer, but it also likely that this research will be extended to other groups of children who have high rates of drug utilization and as well as providing insights into the mechanisms and pathophysiology of adverse drug reactions in children. The recent interest in personalized medicine has highlighted the importance of genetic variability in the pathophysiology and outcome of human disease  or Type B (Unpredictable) Table  Rieder,. While TThe importance of enhancing drug safety in children is even more telling given the drug approval process Rieder, . The usuHistorically there have been five recognized risk factors for adverse drug reactions, of which several\u2014extremes of age and impairment of the organs of clearance\u2014apply to children; more recently, an additional two risk factors have been added, one of which\u2014certain genetic polymorphisms\u2014is a direct indication of the importance of pharmacogenomics in drug safety Table  Rieder,. Given tCancer is one of the commonest causes of death for children in developed countries, but also has been one of the major\u2014and often unsung\u2014success stories of pediatric pharmacotherapy. Over the past five decades, there has been remarkable overall success in terms of improved survival among children with cancer  is a key enzyme in the biotransformation of 6-mercaptopurine Figure  Pacific. 6-mercaThe fact that this observation was made three decades ago raises the question of why TPMT genotyping has not been a part of routine care for children with cancer for longer than it has  gene  and in the catechol-O-methyltransferase (COMT) gene (rs9332377) with severe cisplatin induced ototoxicity , poor metabolizer (PMs) and ultrarapid metabolizers (UMs) as the result of extensive polymorphisms for the gene encoding CYP2D6 . Thus, developing strategies to evaluate risk at the onset of therapy would be of obvious utility and as well would provide important insights into the pathophysiology of these adverse events, which remains unclear (Rieder, One of the most feared patterns of adverse drug reactions among children is drug hypersensitivity such as Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (Elzagallaai et al.,  Rieder, .*5701 has reduced the risk of serious skin rash from 3% to zero (Phillips et al., Initial pharmacogenomic studies in drug hypersensitivity have been somewhat disappointing Rieder, . Over thThe examples cited above should not be taken to mean they are the only care areas in which pharmacogenomics for children has the potential to improve drug safety. There are a number of other drugs commonly used in children for whom pharmacogenomic studies offer great potential in improving safety and efficacy (Downing et al., There is perhaps no area in which there is greater need for better defining therapy than pediatric psychopharmacology Arango, . While tWhen considering these studies there are serious questions that need to be asked, such as which should be priority drug targets for study? This issue has been given careful thought by a number of investigators and algorithms have been developed to identify targets for further study (Shaw et al., The use of pharmacogenomic information to inform diagnosis and guide therapy for children provides a series of interesting and unique ethical challenges. Implicit in therapy for children is the ethical conflict that the person giving consent\u2014a parent or guardian\u2014is not the one receiving the therapy. As an example, research conducting in the setting of childhood cancer demonstrated that when facing difficult therapeutic choices parents have difficulty in distinguishing their understanding of the situation from their child's experiences (Levi et al., A major additional challenge germane to pharmacogenomics is the concern that secondary information obtained during genetic testing may have a distant impact on access to insurance, employment or care (Netzer and Biller-Andorno, Our group has worked with parent groups in studying the ethical acceptability of genetic testing for their children and have found that their most important concerns were securing proper informed consent including ensuring that they had enough information to make a well informed decision. An additional concern was that their health care providers had the background and training to make appropriate decisions based on the results of genetic testing. This speaks strongly to the importance of patient and parent empowerment as well as to the need for including considerations on how to use genetic information for diagnosis and therapy in undergraduate and postgraduate health care professional training.One of the major directions that medical education and care has made over the past several decades has been in the development of evidence-based medicine and in clinical guidelines informed by evidence to enhance and optimize patient care. Our group and others are working to incorporate the use of genetic information into guidelines on the diagnosis and therapy of common and important conditions. One area in which this is most likely to take fruit in the short term is the area of pediatric oncology, where guidelines are being written to incorporate the results of pharmacogenomic analysis into the initial assessment, monitoring, and therapy of children with cancer. Cancer and chronic disease offer the potential for pharmacogenomic analysis as therapy is being planned, which provides the opportunity given real-time turn-around of genetic testing to be able to better define which children are at special risk for adverse drug events and to better plan how therapy might be more closely monitored or modified in these children.The potential of pharmacogenomics in improving therapy for children also applies in the development of new therapeutic agents, for which the potential for genetic variation impacting on efficacy and/or safety should be part of the research considerations and clinical trial design. Historically therapy for children has lagged behind therapy for adults\u2014it is important that this should not be the case in the era of personalized medicine.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The firing rates of neurons in primate motor cortex have been related to multiple parameters of voluntary movement. This finding has been corroborated by stimulation-based studies that have mapped complex movements in rodent and primate motor cortex. However, it has been difficult to link the movement tuning of a neuron with its role within the cortical microcircuit. In sensory cortex, neuronal tuning is largely established by afferents delivering information from tuned receptors in the periphery. Motor cortex, which lacks the granular input layer, may be better understood by analyzing its efferent projections. As a primary source of cortical output, layer 5 neurons represent an ideal starting point for this line of experimentation. It is in these deep output layers that movements can most effectively be evoked by intracortical microstimulation and recordings can obtain the most useful signals for the control of motor prostheses. Studies focused on layer 5 output neurons have revealed that projection identity is a fundamental property related to the laminar position, receptive field and ion channel complement of these cells. Given the variety of brain areas targeted by layer 5 output neurons, knowledge of a neuron's downstream connectivity may provide insight into its movement tuning. Future experiments that relate motor behavior to the activity of neurons with a known projection identity will yield a more detailed understanding of the function of cortical microcircuits. One of the great achievements in neuroscience is our detailed understanding of the circuitry and function of the visual system. A well-defined anatomical framework and an established parameter space for visual stimulation have expedited research on the computations performed by the visual cortex. A particularly productive approach has been to develop circuit models of the visual cortex based on its multiple input channels and to associate these microcircuits with the macroscopic functional areas of visual cortex  type corticostriatal axons synapse in the ipsilateral striatum before continuing on toward the spinal cord. This differentiates them from intratelencephalic (IT) type corticostriatal neurons which cross the midline to project to the striatum and contralateral cortex but do not leave the telencephalon. IT and PT type neurons preferentially innervate direct and indirect pathway neurons of the striatum, respectively (Reiner et al., Neurons forming the corticospinal tract are predisposed to possessing movement tuning, but other descending pathways such as the rubrospinal tract are also heavily involved in motor control Lemon, . Nor is Movement tuning is a well-documented yet controversial property of motor cortex that has been successfully exploited for direct cortical control of neural prostheses (Hochberg et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "This review is focused on discussing in some detail possible neuroprotective functions of microglial cells. We strive to explain how loss of these essential microglial functions might contribute toward the development of characteristic neuropathological features that characterize Alzheimer\u2019s disease. The conceptual framework guiding our thinking is provided by the hypothesis that microglial senescence accounts for impaired neuronal protection and consequent neurodegeneration. The role of CNS microglial cells in the development of Alzheimer\u2019s disease(AD) has been the subject of considerable interest since McGeer\u2019s initial description of reactive microglia in human AD brain in 1987 , and that it represents an immunologically subdued environment  or ferrous (Fe+2) ions. We propose that the sequestration of free iron in the CNS by ferritin in microglia constitutes an important neuroprotective mechanism that becomes most relevant when there is a breach in the BBB and the possibility exists of free iron entering the brain parenchyma. The evidence for this mechanism of microglial neuroprotection is as follows: we and others have previously reported that many of the dystrophic (senescent) microglia in human brain are positive for the iron storage protein, ferritin  A final aspect of microglial neuroprotection within the scope of this discussion concerns their emerging role in the regulation of the plasticity of neuronal circuits, that is, their involvement in the pruning/elimination and maintenance of synaptic connections. This aspect of the microglial functional repertoire was recognized for the first time more than 40\u2009years ago by Blinzinger and Kreutzberg , yet it via mitosis of resident cells undergo programmed cell death which reduces cell numbers back to baseline  and certainly to studies in human brain which reveal a lack of A\u03b2 phagocytosis by microglia. Thus, the relationship between A\u03b2, microglial activation, and/or neuroinflammation remains enigmatic and perplexing even after more than 20\u2009years of intense research. If one also considers the alleged causal connection between amyloid deposits and neurofibrillary degeneration the picture gets blurred even more as this connection seems to grow weaker and evidence is mounting against rather than in favor of it.Countless studies in laboratory animals involving experimental CNS lesions have shown that microglia become activated rapidly in response to neuronal injury (Kreutzberg, Yet another issue that complicates our understanding of neuroinflammation in AD is found in the fact that primary infections outside of the CNS influence the state of microglial cells. In particular, sepsis, which is more commonly found in elderly patients due to compromised immune function, will induce microglial activation within the brain (Lemstra et al., The discovery of dystrophic microglia in human brain represents a critical step in conceiving the microglial dysfunction hypothesis because it raises the possibility that microglia are subject to senescence and degeneration (Streit et al., The morphological abnormalities that characterize dystrophic microglia have been described in detail before (Streit et al., With regard to the aforementioned neuroprotective roles of microglia, there are a number of interesting points to consider in terms of how deterioration of these neuroprotective functions could be critically important in the development of aging-related neurodegenerative diseases. Phagocytosis of debris by microglia is an essential cellular activity that ensures maintenance of a clean, debris-free brain parenchyma, and is conducive toward facilitating optimal interneuronal electrochemical signaling. A substantial decline in microglial phagocytosis due to cell senescence and/or degeneration would almost certainly contribute to NDD development (Neumann et al., For quite some time now the presence of increased brain iron and/or a disturbance in iron metabolism has been seen as a major factor contributing directly to free radical mediated neuronal degeneration (Jellinger et al., As mentioned, there is an increasing number of recent studies that suggest significant involvement of microglia in synaptic plasticity (Tremblay et al., As the brain\u2019s innate immune system one might be inclined to think of microglia primarily as immunological defenders that fight invading microorganisms. However, in so doing one underestimates their importance as supportive and neuroprotective glial cells essential for helping to maintain neuronal functioning in the normal CNS and especially their crucial involvement in CNS repair and regeneration during injury and disease. We believe that microglial neuroprotection constitutes a most important aspect of the cells\u2019 biological significance because it defines a single common denominator that contributes to improved understanding of CNS development, normal adult brain function, as well mechanisms of injury, disease, and repair. Specifically, with regard to aging-related neurodegenerative diseases, which represent one of the greatest challenges for biomedical science in this day and age, we think that the concept of CNS immunosenescence has considerable potential for advancing progress in terms of new and improved approaches toward treatment and prevention.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Diagnostic reproducibility and accuracy in cytology and histology are the main issues in Oncologic Screening of cervix, breast and colorectal cancer : it can be achieved by programs for quality assurance (QA). The slides set standard represents the most used method to compare diagnostic proficiency, the chance of interpreting microscopic digital photographs provided an interesting alternative to read conventional microscope slides.The whole digital slide observed in a computer screen is a third, interesting, option to reach the goal. In fact all the information on conventional samples are transferred into a file, easily archived, catalogued, duplicated or advice for quality control, but is especially available at distance and from multiple locations simultaneously with drastic reduction of time needed to achieve proficiency test reproducibility ., educational programs with integrated digital slides are poorly developed or proficiency tests for continuing education and professional updating are easily accessible.The production of digital slides with modern scanners is relatively simple and quick. All suppliers offer services into private or public networks server in the literature  and softA project on Virtual Microscopy and Digital Pathology has been conducted in Emilia-Romagna Region  with the goal to promote quality in diagnostic cytology and histology in Screening programs by testing a different system involving pathologists and cytologists using digital slides, with a faster and reproducible program easier to manage than standard diagnostic sets and by distance for retraining of patrhologists with a final consensus meeting.The aim has been reached with the realization of a management system for cytological and histological whole-slides digital images and related clinical data and the building of a picture archive and communication system (PACS) among pathologists of our (and probably other) region. This must be backed by software for the realization of network slide seminars to perform periodic diagnostic reproducibility and proficiency test. The cases, collected and properly catalogued in an online, easily accessible and systemic digital archive of slides, with diagnoses discussed in clinical and pathologic audit meetings and validated by experts, can be used as diagnostic reference tools (case registry online ). The cataloguing and indexing is performed with NAP codes derived from SNOMED , which cThe cancer screening group of the Emilia-Romagna Region  set up a picture, archive and communication system (PACS) devoted to pathologists for cooperative diagnosis, teaching and training, teleconsulting, documentation of rare cases and pilot experiences; furthermore selected cases are catalogued in the PACS with the aim to check the diagnostic concordance in regional oncologic screening . The PACS system is made by two Aperio scanner and an adequate internet server where the described programs perform, . An e-learning platform (Docebo)  has beenNowadays the diagnostic reproducibility has been performed in colorectal and cervical cancer screening , and for breast cancer is ongoing (Bologna June 2012). In all three slide seminars a number of cases have been selected by a committee of pathologists working in regional anatomo-pathologic units.Colorectal cancer screening was the first retraining slide seminar for pathologists performed with these features in our region and probably in Italy.Three regional units  were involved by sending representative histological cases of all main diagnostic occurrences to test the diagnostic reproducibility; 28 histological cases were collected. A definite and limited time interval was indicated to study slides, then a consensus conference was organized in the same day.The second Seminar of QA to test the diagnostic reproducibility was performed in cervical cancer screening program; 30 cytological and 30 histological cases have been selected by a committee of pathologists among the cases proposed by the regional units. All main diagnostic occurrences were represented, basic clinical information and relevant follow-up information were available; the cases have been completely anonymized.A 30 days interval was indicated to study the slides, then a consensus conference has been programmed at the end of the evaluation to present the results and discuss cases. Before the meeting each participant received a report with the gold standard diagnosis performed buy the committee and her/his diagnosis and concordance result.colon-rectal QA and the diagnostic reproducibility have been evaluated matching their results with the final gold standard diagnosis reached during the consensus conference. The observed agreement was 69% and the overall performance of the participating pathologists was assessed with a statistical analysis using Cohen\u2019s kappa: the average value was 0.64 .15 pathologists of regional units attended the cervical cancer screening QA.95 cytologists and 32 histopathologists have been involved in the The diagnostic reproducibility has been evaluated using the final diagnosis reached in the consensus conference: in 2 out of 30 cytological cases the diagnosis was different from the diagnosis of the committee, while all histologic diagnoses were in agreement. The overall performance of the participating readers is reported in table Whole digital slide is suitable for proficiency tests and the internet e-learning platform allows to share cases and to get the answers from participants, in a easier way than by of a set of conventional slides.The quality of whole slides is very good, approaching optical microscopic resolution.In a cytological environment the bias is to get a perfect focus in all parts of the slide; the wider area of slide to examine and the higher number of diagnostic classes may justify a worse agreement of the pathologists and a poorer performance (lower Cohen\u2019s kappa) than histology.We have produced an integrated environment that includes many of the modern aspects of digital pathology that can be shared with the PACS system in many laboratories of the region, including quality promotion and control of image interpretation in cytology and histology applied to cancer screening."}
+{"text": "PopulatThe coding of single stimuli in population codes is relatively well understood , and in Theoretical studies  have thWe investigate the theoretical implications of these findings by comparing different encoding strategies and examine the decoding accuracy. The goal is to find the optimal encoding scheme for multiple stimuli.We investigate the theoretical implications of these findings by comparing different encoding strategies and examine the decoding accuracy. The goal is to find the optimal encoding scheme for multiple stimuli.In our current study, we focus on the simultaneous coding of visual stimuli representing overlapping movements of two groups of points in different directions. We investigate different ways of decoding these, among them a Maximum Likelihood decoder and estimate error rates made by these predictors, comparing to maximum rule to a linear rule."}
+{"text": "To the Editor: Wagner and colleagues report nosocomial dengue transmitted by needlestick and note that it is the fourth case of nosocomial dengue to their knowledge (nowledge . In the nowledge . Three onowledge \u20135.We have recently published a case of nosocomial dengue infection that was transmitted by mucocutaneous exposure to blood from a febrile traveler who had recently returned from Peru . During We agree that nosocomial transmission may become more common in temperate areas as more travelers return home with acute dengue fever. As Wagner and colleagues pointed out, travelers visiting Southeast Asia have the greatest risk of acquiring dengue infections because of the high endemicity of these viruses there. Our report further illustrates the occurrence of dengue infection in the Americas  and the"}
+{"text": "This article has been republished to address equation and symbol formatting errors and errors in figure citations. This republication addresses the errors referenced in the previous formal correction. The publisher apologizes for the errors."}
+{"text": "Type1 restriction modification system are intriguing multifunctional multisubunit molecular motors that can catalyze both restriction and modification activity. The type 1 RM enzymes binds to its target sequence and its activity as an endonuclease or methyltransferase is determined by the methylation state of the target sequence. If the target sequence is unmodified, the enzyme while bound to its target site is believed to translocate or pull the DNA towards itself simultaneously in both directions in an ATP dependent manner.The crystal structure of the motor subunit R has been determined by our group but the molecular mechanism by which these enzymes translocate and cleave the DNA is not fully understood.Our current research effort focuses on full-length three-dimensional structures of the R-subunit, utilizing computational and bioinformatics methods. Modelling of missing loops of residues of the crystal structure is done by Modeller9v2. Optimization of intersubunit contacts is performed by energy minimization followed by molecular dynamics simulations in solution at 300K. The dynamic behavior of WT and mutant holo and apo systems is explored by molecular dynamics simulation in GROMACS using the AMBER99SB force field. Conformational changes connected to coupling of translocation and endonuclease activity are observed and QM/MM methods are applied to calculate the contribution of the residue to the overall binding energy of ATP in the binding pocket."}
+{"text": "The goal of this Research Topic was to bring together articles representing the spectrum of current research aimed at understanding the functional organization motor cortex at the level of microcircuits.The original research articles in this collection address a wide range of aspects of motor cortex microcircuits. The monkey's motor cortex is an especially important model system because of the similarities to the human brain, and the ability to train monkeys to perform complex movements. However, information about the cellular composition of different primates has been limited; Young et al.  now descin vivo dynamic activity across motor cortical layers in relation to movement. Harrison and Murphy (The review-type articles provide new syntheses of current knowledge about different aspects of motor cortex function and dysfunction. Kaneko  focuses d Murphy  emphasizd Murphy  address d Murphy  discussed Murphy  review dd Murphy  review ed Murphy  review tWe are impressed not only with the diversity of contributions included here, but even more so we were delighted that researchers from all walks of motor cortex investigation enthusiastically steered their research toward the microcircuit theme pursued in this volume. More than ever it seems clear that we all are working toward a common goal, i.e., describing motor cortical function in terms of the transactions in identified cellular circuits. We thank the authors for their contributions, and are additionally grateful to the many reviewers who contributed their efforts."}
+{"text": "There has been a complete turnaround in scientific thinking about malnutrition as a protective factor to that of a major determinant of diabetes. Development of Type 2 diabetes is attributed to a combination of genetic susceptibility and precipitation factors in adult or early adult life. Current trials and preventive interventions are based on this gene-obesity model causing glucose intolerance necessitating food restriction for management. However when we compare the burden of low birth weight and intrauterine growth restriction with that of type 2 diabetes it can be hypothesised that good nutrition during intrauterine development and early childhood is more important. Foetal programming due to under nutrition can result in intergenerational transfer of long latency disorders.This hypothesis led to the establishment of the Pune maternal nutrition study and Pune children study involving cohorts. The Pune children study involving 400 children has completed 21 years of follow up and has shown an inverse relationship between birth weight and risk of diabetes mellitus measured by high glucose and high insulin levels. The maternal nutrition study which started with 2675 pregnant women in six villages has now completed 17 years. Both the mothers and children are being followed with very good follow up rates. The study involved consensus building among village leaders, consultation of experts, focus group discussions and training of local girls as Auxiliary Nurse Midwives (ANMs). The study involves assessment of weight and haemoglobin of young women, nutritional intake during pregnancy, foetal growth monitoring, biochemical assessments, storage of maternal and cord blood samples, detailed anthropometry at birth and continuing monitoring for cardiovascular disease risk markers. A steering committee of all stakeholders was constituted to oversee the study. The observations have shown that the intra abdominal fat content of Indian babies is higher. Low vitamin B12 levels, folate levels and high homocysteine levels are shown to be associated with low birth weight and insulin resistance in offspring. This demonstrates that maternal micro nutrient status influences risk of diabetes in the offspring and birth weight is a marker of intrauterine environment. Policy implications include ensuring the health of the young girl and addition of vitamin B12 along with folate for pregnant women. The biochemical estimation was made possible by storage of samples in biobanks which is a most useful resource for subsequent measurements, but there are ethical concerns and issues of subject approval."}
+{"text": "Docking is possibly the most widely used technique in structure-based drug design. It is recognized as extremely useful to guide the development of active molecules as well as in virtual screening to identify new leads. But docking is also notoriously imperfect and many aspects need to improve. In this talk I will present our work on two different sources of errors in the docking predictions: protein-ligand interaction potentials and internal energy of the ligands. The use of higher-level calculations offers an opportunity to obtain better quality results and offers a glimpse of the full potential of the technique, but introducing this information back into fast and general scoring functions remains a challenge."}
+{"text": "Several hypotheses have been proposed to explain the unexpected results of the first completed efficacy clinical trial of a vaccine against dengue virus C). This is distinct from vaccine efficacy against infection (VEI), and potentially a very important distinction.However, we believe that in addition to questioning the immune response elicited by the vaccine, it is important to discuss the interpretability of efficacy results for dengue vaccine trials that are based exclusively on clinical outcomes. The study by Sabchareon measured vaccine efficacy against clinically apparent infection  are equal in the control and vaccine groups.VEC and VEI. I would seem to be ineffective in a trial based only on clinical outcomes.Dengue disease is caused by four interacting viral serotypes. Risk factors for symptomatic disease have not been fully characterized. There is substantial evidence that preexisting, naturally acquired immunity against a heterologous serotype is a significant risk-factor for the development of clinical disease C and VEI under different assumptions of the impact of prior heterologous immunity on the probability of symptomatic disease, we developed an analytical framework  (C could lead to prematurely abandoning vaccines that could have promising population-level impacts or moving forward with an overly optimistic estimate of a vaccine's impact.To explore the agreement between VEdisease) . DiscardC and VEI also raises questions about one of the conclusion of this vaccine trial: that the \u201cabsence of any sign of disease enhancement\u2026in the presence of non-protective immune responses\u201d to DENV-2 serves as evidence against vaccine-induced enhanced severity of disease. With the inclusion of only clinical outcomes, it is impossible to know what number of individuals in the vaccine or control groups experienced infection and thus what fraction of infections experienced clinical outcomes. Tradeoffs between protective immunity and immunity that may predispose individuals to severe outcome again obscure the results.The discrepancy between VEC the primary measure of vaccines I will be necessary to determine the proportion of the population that needs to be vaccinated in order to control transmission. We acknowledge that measures of infection  are imperfect and resource intensive, but surveillance for infection has been performed routinely in other cohort studies While we agree with WHO guidance that clinical disease should be the primary end point of dengue trials and thus VEText S1C and VEI.Description of the analytical framework developed to explore the agreement between VE(PDF)Click here for additional data file."}
+{"text": "The aim of the workshop is to explore the effects of footwear design on lower limb motion and discuss research findings relevant to the clinic and physical activity. Delegates will be actively involved in a motion capture process where important lower limb joint stress variables will be displayed in real time. The University of Sydney researchers will raise footwear issues from a range of areas such as children physical activity, adult walking and running, specific footwear such as thongs (flip-flops), dance and experimental methodology.During or on completion of this workshop, participants will be able to:\u2022 Critically analyse footwear characteristics that are likely to influence lower limb function during physical activity.\u2022 Experience the use of state of the art technology to analyse lower limb mechanics.\u2022 Discuss the models and methods used to build knowledge about the effect of footwear on lower limb mechanics.\u2022 Recount clinical and research outcomes for the effect of footwear on lower limb biomechanics during physical activity.\u2022 Apply biomechanical principles to the effective choice of footwear for a range of physical activities."}
+{"text": "Eating disorders can be a life threatening illness not only due to the effects of starvation, but also the effects of impaired capacity. At Robina Hospital, patients admitted with a BMI < 14 are admitted to the Acute Medical Unit (AMU) for nutritional restoration and medical management before being transferred to a suitable mental health ward for ongoing treatment.The AMU at Robina has been managing patients with eating disorders, in particular Anorexia Nervosa for a number of years. The treatment plan implemented by the Acute Medical team is considered to be of a very high standard by the Eating Disorders Outreach Service (EDOS), a specialist consulting liaison service provided by the Royal Brisbane and Women's Hospital. The AMU prides itself on developing a cohesive multidisciplinary team approach, striving for best practice management by utilising protocols and guidelines developed by the EDOS service.This presentation will discuss the experiences of the Acute Medical Team in managing eating disorder patients. It will outline the team structure, current practices and guidelines used and identify areas of improvement recognised through lessons learned.The aim is to present information and experiences that may assist other acute inpatient medical settings in managing eating disorder patients discussing evidence based strategies developed to support and improve the management and physical health of patients with eating disorders.Care in Inpatient and Community Settings stream of the 2013 ANZAED Conference.This abstract was presented in the"}
+{"text": "For the past decade the field of proteomics has transitioned from a highly specialized research area into a conventional technique widely employed by plant biologists. This approach now encompasses basic protein identification to advanced comparative studies. The result has been an abundance of proteomics data, often not readily available to the research community  often represent the functional state of a protein and are a significant objective for many proteomic studies. A number of resources have been developed to interact with these phosphoproteomic datasets. Initial phosphoproteomic surveys involved Arabidopsis and one of the first phosphorylation-based databases created in any species was PhosPhAt (Arsova and Schulze, The proteomics community has created an array of online tools that can be used to support various technical approaches in mass spectrometry. The MRMaid utility was designed to facilitate the selection of peptides for targeted proteomic analyses (Fan et al., The range of proteome resources highlighted in this Research Topic reflect the diversity of proteomic-based applications in plant sciences. The principle objective for many these research groups has been focused on cataloguing or collecting data in an effort to capture information. Indeed, the creation of many data portals likely reflects an attempt to make sense of one's own data. This collection highlights the diversity and range of plant proteomic resources and utilities available to the plant research community."}
+{"text": "Information regarding the first and last authors is incorrectly omitted from the Competing interests statement. The Competing interests statement should read: \"One of the authors (Dr. Juhl) is affiliated with Indivumed, GmbH. A provisional patent application has been filed by Georgetown University related to the technology described in this paper. Drs. Wellstein and Shivapurkar are named as inventors on this provisional patent application.This does not alter the authors\u2019 adherence to all the PLOS ONE policies on sharing data and materials and does not provide a conflict of interest.\""}
+{"text": "More than 500 delegates and speakers from twenty countries gathered to hear about best practice and innovation in trauma care, pre-hospital care and major incident management. In addition the Norwegian Air Ambulance hosted a day devoted to air ambulance medicine and a parallel symposium examined key aspects of cardiac arrest. This produced to an expanded programme that appealed to a wide range of professional groups. This supplement describes some of the key points made by speakers and also focuses on two innovative aspects of training for penetrating trauma. Firstly resuscitative thoracotomy training for non-surgeons based on a one-day practical workshop held during the conference and secondly the training of young offenders to administer immediate care at the scene of injury \u2013 based on an abstract accepted for presentation. The posters and oral presentations submitted cover a wide range of subjects and the accepted abstracts are published at the end of this supplement. Dates for the 2013 conference can be found at http://www.londontraumaconference.com.The sixth London Trauma Conference was held at the Royal Geographical Society in London between 4"}
+{"text": "Information regarding a possible competing interest of the sixth author is incorrectly omitted from the Competing interests statement. The Competing interests statement should read: \"James A. Colbert was an editorial fellow at the New England Journal of Medicine. Navindra Persaud is an Associate Editor for the Canadian Medical Association Journal. Peter Gill is a member of the Editorial Advisory Board of the CMAJ. All other authors have declared that no competing interest exists. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.\""}
+{"text": "There is a growing amount of literature to support the view that active involvement in research by consumers, especially informed and networked consumers, benefits the quality and direction of research itself, the research process and, most importantly, people affected by cancer. Our exploratory project focuses on identifying their priorities and developing a process to assess the research needs of Australian cancer consumers which may be useful beyond the cancer scenario.This project was consumer initiated, developed and implemented, with the assistance of a leading Australian cancer consumer advocacy group, Cancer Voices NSW (CVN). Such direct involvement is unusual and ensures that the priorities identified, and the process itself, are not influenced by other interests, regardless how well-intentioned they may be. The processes established, and data collection via a workshop, followed by a questionnaire to confirm and prioritise findings, and comparison with a similar UK exercise, are detailed in this paper.Needs across five topic areas reflecting cancer control domains  were identified. Cancer consumers high priority research needs were found to be: earlier diagnosis of metastatic cancers; the extent of use of best practice palliative care guidelines; identifying barriers to cancer risk behaviour change; and environmental, nutrition and lifestyle risk factors for people with cancer. A process for identifying consumers\u2019 research priorities was developed and applied; this may be useful for further investigation in this under-studied area.The findings provide a model for developing a consumer derived research agenda in Australia which can be used to inform the strategic direction of cancer research. Consumers have been seeking a workable method to achieve this and have worked in collaboration with a major cancer charity, which funds research, to do so. Research is central to improving health and contributing to overall national development. Australia has made substantial investments in building and enhancing its health research capacity in recent years. Despite these efforts and some notable examples of success,2, the oNo public research funding program can afford to service all potential health research questions, each program must identify priority areas and questions. Within Internationally, there is an increasing call for public involvement in identifying health research priorities including distinguishing where and why resources should be allocated. GreaterThere is currently a limited understanding of the research needs of people affected by cancer in Australia. Moreover, published projects that specifically determine needs and gaps are few-21. TherA previous UK study found thThis project set out to investigate the views of those affected by cancer in New South Wales, Australia on what they consider should be the key priorities for future research in this area. The purpose of the paper is to provide information on the research needs of NSW cancer consumers and describe the priority setting process so that interested parties may duplicate the approaches used. The findings, key issues and challenges in the identification and utilisation of consumer research needs are discussed.This exploratory project adopted a participatory approach, where project ownership was shared with people affected by cancer. Cancer Council NSW (CCNSW), a leading non-government cancer charity and research funder, partnered with Cancer Voices NSW to design and implement an approach to capture cancer consumers\u2019 research needs. CVN, as a peak Australian cancer consumer group with members from all areas of the state of New South Wales had identified this work as a pressing need. Ethical approval was received from the CCNSW Ethics Committee.Constantly communicating with members is a critical, ongoing aspect of the work of CVN. The organisation routinely surveys its members to ensure an up-to-date understanding of the perceptions and experiences of cancer consumers and to support decisions that will best help people affected by cancer. CVN uses knowledge acquisition to support member empowerment and information, and inform broader policy and advocacy processes.Cancer consumers, including those impacted by the disease directly, or indirectly as friends or family members, were invited to participate through the following channels: (1) CCNSW website and constituent mail-outs, (2) CVN\u2019 s newsletter and networks, (3) cancer support group contacts and cancer care centres, and (4) via a range of cancer charities and consumer groups. The opportunity was also advertised in the volunteer section of a large, well known recruitment website.Global Cafe\u2019 approach, which had been recommended by CVN, was the main data collection method selected in this part of the project. The Global Caf\u00e9 process is a technique for harnessing group experience and views on a number of topics, and channelling this output into a usable data set[The methods used to capture consumer research needs were developed after careful deliberation of the support, funding and timeframe within which we were required to work. A workshop designed broadly on the \u2018data set.Data collected from CVN\u2019s own bi-annual survey on cancer research needs was included with an invitation to all participants. They were also asked to provide written input from their constituencies which was incorporated within the pre-workshop data to provide a robust list of consumer research needs.Prior to and at the commencement of the workshop, participants were provided with information to clarify their general understanding of cancer research across the cancer control spectrum from cancer prevention to screening, diagnosis, management, survival and end of life care. This was designed to focus thinking about cancer research and lead to more informed discussions of what should be researched. Each of these five topic areas became the individual focus of table discussions in the workshop. Participants at each table were asked to discuss the topic as a group, giving their rationale for research interests and then record those research topics they felt to be important on \u2018post-it\u2019 notes.Ideas and conversations of no more than eight participants at each table were linked and built upon as people moved to different tables, cross-pollinating ideas for each topic area and identifying research needs that mattered to their own lived experiences and/or those collected by their consumer network or group. The living network of conversations evolved through several rounds of exploration and research question identification until all participants had the opportunity to input into each of the five topic areas. A cancer researcher or CCNSW research program staff member acted as an advisor on each table for participants\u2019 questions, and if participants required information on research currently being undertaken in the area. The advisors brought discussions back to the issue of research needs if discussions began to go \u2018off track\u2019. A pre-selected consumer table host remained at each table and briefed new table arrivals on previous discussions to ensure each new group built on the topic in an iterative exchange process. The needs identified through the small group process were then fed back by the consumer host to the whole group and discussed. This enabled an effective summary of the discussion and also permitted any additional views not covered in the small group to be raised.To verify the workshop results and achieve higher quality results CVN canvassed their membership of over 300 consumers who had been affected by cancer or were interested in cancer control via a general postal questionnaire. A few had attended the workshop. The questionnaire, planned and developed by SC and CS, and tested for readability and ease of understanding by another member of CVN, invited personal reflection on the research needs of consumers. Included with the questionnaire was an explanation of the workshop process and results to ensure an understanding among members of the context within which the questionnaire was sent. CVN members were asked whether their needs reflected some or all of those identified in the workshop. Members were also asked to rate their research needs from 1 to 5, with 1 being their highest research priority. They were asked to identify 5 priorities in each section.Members were asked to send their responses back to CVN in the included stamped, return addressed envelope. Details of the process steps employed in the project are provided below.Steps in the consumer research needs and priorities identification process1. The requirement for cancer consumer involvement in identifying research needs is established by consumers and acknowledged by professional partners who commit resources and coordination support to the process.2. A project reference group is established to support the design and implementation of the consumer research needs identification process.3. Consumer research needs identification approach is clarified and agreed by all parties.4. Participant recruitment is planned and carried out.5. Global Caf\u00e9 workshop process is developed in detail by the project reference group.6. The information needed for the workshop is identified and assembled, such as on the cancer control research domains, to help inform participants\u2019 discussions during the workshop and help them build on existing knowledge during their exchanges.7. Pre-workshop input from members of each consumer group represented at the workshop and the results of previous Cancer Voices NSW survey results are collected for incorporation with the data and information obtained in the workshop.8. Workshop conducted as planned using the Global Caf\u00e9 process.9. The research needs of cancer consumers are confirmed at the end of the workshop. Follow-up via an emailed report of the workshop outcomes is undertaken to ensure that the final research needs truly reflect the views and advice expressed during the workshop.10. Workshop findings are strengthened via CVN postal questionnaire to members.11. The final identified priority issues are compared with a similar project to support the generalisability of the results and help ensure that the priorities are not just intrinsic to this project\u2019s particular process or participants12. A final report is disseminated to consumer groups, research funding and research organisationsPost-it note entries, which were automatically categorised within each of the five cancer control research areas discussed by the workshop table groups, were examined. Repeating issues were identified and summarised. An independent assessment of all data by two members of the project team (CS and SC) was undertaken to ensure consistency in the interpretation of the data.Member priorities were analysed using SPSS version 16 for Windows and are Thirty two people with direct experience of cancer across different cancer types responded to the invitation to participate in the workshop. This number was accepted as workable for the purpose and the process. Participants ranged in age from 18 to 72 years. More females (n=18) than males (n= 14) attended the workshop. Consumers identified needs across the five cancer control research domains with cancer treatment drawing the greatest number of identified issues. Needs across the domains  ranged from a better understanding of unhealthy behaviours such as smoking and sun exposure, to researching factors related to differences in cancer outcome due to personal and geographical inequity, and better understanding the cancer control needs of vulnerable groups such as older people, culturally and linguistically diverse and indigenous people. Improvements in health systems and professional capacity to better meet the needs of the population and quality of life issues for cancer patients, carers and significant others were also deemed to be important areas for inquiry.An overview of the identified needs within the cancer research domains from which they were raised are provided below.Prevention and risk\u2022 How can media improve understanding (and behaviour change) of cancer risk factors linked to personal behaviours, with attention to confused use of relative and absolute risk messages?\u2022 Definitive research into nutrition and other lifestyle risk factors and cancer development\u2022 What are the barriers to cancer risk behaviour change and how can positive behaviour change be encouraged?\u2022 What is the need in Australia for a rare cancer registry to increase volume of and ease of access to information about these cancers?\u2022 What are the perceptions of cancer in culturally and linguistically diverse (CALD) communities?\u2022 How can barriers to prevention be removed and cancer awareness raised amongst CALD groups?\u2022 How can young people be better supported to understand cancer risk?\u2022 Further research into cancer clusters\u2022 Further research into environmental risk factors for cancer development\u2022 What are the most effective interventions for dispelling myths and misconceptions about the causes of cancer in our community?\u2022 Impact of technology on cancer risk \u2013 eg mobile phones, CT scans, etc.\u2022 Degree of impact of multi risks in causing cancers\u2022 Do prevention messages cause unnecessary feelings of guilt and self blame?What is best use of public health dollars re cancer prevention?Screening and diagnosis\u2022 How can behaviour be changed to improve cancer screening rates?\u2022 What steps are needed to increase skin cancer screening?\u2022 What are the most effective channels for consumers to access information about cancer?+ age group\u2022 What is the cancer screening benefit for 70\u2022 What is the scale of exposure to diethylstilbestrol in the Australian communityWhat are the perceptions and barriers to cancer screening among different cultural groups?\u2022 What interventions work best to increase cancer screening in different cultural groups?\u2022 What interventions work best to increase cancer screening in indigenous groups?\u2022 What are the best approaches to meet the cancer information needs of different groups?\u2022 Investigate genetic testing services in Australia to determine and compare service effectiveness across different population groups and localities\u2022 What is the role and capacity of the general practitioner in encouraging patients to undertake cancer screening?Is general practitioner training to detect early signs and symptoms of cancer adequate?\u2022 What constitutes a supportive workplace when cancer is diagnosed?\u2022 How can metastatic cancers be diagnosed earlier, preferably before symptomatic?Treatment\u2022 More investigation into targeted therapies and personalised medicine for all cancers\u2022 Which cancers will benefit from development of immunotherapy?\u2022 Identify best practice treatment protocols and guidelines for all rare cancers\u2022 Overview of research relating to patient treatment profiling for all cancers\u2022 Which drugs available overseas but not to Australians should be fast tracked?Determine which advanced cancers have yet to have treatment guidelines and address\u2022 Are elderly Australians offered adequate cancer treatment & management?\u2022 What is the difference in cancer treatment decisions of those living in rural, regional and remote areas?\u2022 What are the preferred treatment choices of CALD and Indigenous groups in Australia compared with best practice management?\u2022 Is access to best practice cancer treatment determined by cost in Australia? What impact does this have on health outcomes?\u2022 Investigate the extent and causes for the under representation of particular groups in cancer clinical trials i.e. older people, rural, minorities etc.\u2022 What are the levels of access to cancer clinical trials for residents of rural Australia?\u2022 Is there equity in cancer treatment throughout Australia?\u2022 How can people living in rural areas be best supported emotionally and financially to receive best practice cancer management?\u2022 How can elderly cancer patients be best supported in self management?\u2022 What are the best approaches that health care providers can use to prevent or alleviate patient guilt at cancer diagnosis?\u2022 How can medical care providers be best trained to deliver a cancer diagnosis that is aligned with the patient and family\u2019s level of understanding, emotional and support needs?\u2022 How effective is the communication between different the medical specialists for those with cancer and unrelated co-morbid conditions?\u2022 To what extent are general practitioners \u2018kept in multidisciplinary care loop\u2019 of cancer patients?\u2022 What value does multidisciplinary care provide cancer patients?\u2022 What is the currency of cancer specialist and General Practitioner evidenced based knowledge?\u2022 What is the current and predicted need for additional geriatric oncologists in Australia?\u2022 More clinical trials investigating the effectiveness of complementary therapies in cancer control\u2022 How can greater awareness of clinical trials in patients and clinicians be better supported?\u2022 How user friendly and accessible is cancer patient prescription drug information?\u2022 How can we maximise knowledge transfer among researchers working on different cancer types and research disciplines?\u2022 What are the training needs of personal carers of cancer patients and the current availability of such training?\u2022 What are the variations in response to pain management?\u2022 Identify more effective pain management for cancer patients\u2022 Identify individualised pain management interventions\u2022 How can chemotherapy be made less toxic?\u2022 How can the side effects of treatment be better managed?\u2022 What are the different needs of men caring for women with cancer; and women caring for men with cancer?\u2022 What is the extent of carers of cancer patients who are socially isolated and what are their service and support needs?\u2022 What is the extent of carers of cancer patients who are depressed and what are their service and support needs?\u2022 Survivorship\u2022 How can the long term effects of chemotherapy be best addressed?\u2022 What are the particular needs and wants of people living with cancer who do not have adequate social capital?\u2022 What is the level of fear of cancer recurrence among survivors?\u2022 How can the normalisation process be supported ?\u2022 What are the long term effects of repeat diagnostic or prognostic scans for cancer survivors?\u2022 More studies on the effects of chemotherapy on long term cognition\u2022 What is the extent (and intervention availability) of male and female fertility issues post cancer treatment?\u2022 What are the best approaches that can be used to establish and sustain cancer support groups in rural areas?\u2022 Is cancer survivorship related to a greater chance of personal relationship breakdown?\u2022 How can children caring for adults with cancer be best supported?\u2022 What information to survivors need and who should provide it?End of life care\u2022 What is the extent of use of best practice palliative care guidelines \u2013 for patients, carers and family? Gaps?\u2022 What are cancer patients' attitudes to dying with dignity and control?\u2022 Is access to good information about end of life issues , adequate?\u2022 What are the most effective interventions to ensure palliative care service availability in rural and remote areas?\u2022 What is the acceptability and impact of a professional support person in improving the experience and outcomes of those with advanced cancer?\u2022 What extent do different social environments impact on end of life care?\u2022 What are the long term affects and counselling and support needs of carers after the death of a loved one?\u2022 What is it that people value about dying at home? What is it they fear about dying elsewhere?\u2022 What are the needs and areas of unmet needs for respite care for patients and families?\u2022 What is the impact of differing views about end of life, of patient and carer, if any?how can metastatic cancers be diagnosed earlier before they are symptomatic?\u2019 as their greatest research need. The second highest priority research questions (32%) were found to be \u2018what is the extent of use of best practice palliative care guidelines?\u2019 and \u2018more research into nutrition and lifestyle risk factors for people with cancer\u2019 Other high priority research areas include identifying the barriers to cancer risk behaviour change and research into environmental risk factors.Fifty seven (19%) of CVN members completed and returned the questionnaires. The majority of respondents were female (56%) aged between 61\u201370 years (41%). The large majority of respondents reported that the research needs identified at the forum reflected either all or some of their needs (98%) with almost 60% stating they reflected all their research needs. One third of members (33%) identified the research question \u2018The most common research priorities across all respondents\u2019 first to fifth selections were:\u2018How can the long term effects of chemotherapy be best addressed?\u2019 (selected in the top five priorities of 77% of respondents)\u2022 \u2018How can behaviour be changed to improve cancer screening rates?\u2019 (selected in the top 5 priorities of 75% of respondents) and\u2022 \u2018How can the normalisation process be supported ?\u2019 (selected in the top 5 priorities of 68% of respondents).\u2022 This exploratory project facilitated identification of cancer consumers' priority research needs over five topic areas reflecting major cancer control domains. These were found to be earlier diagnosis of metastatic cancers; the extent of use of best practice palliative care guidelines; identifying barriers to cancer risk behaviour change; and environmental and nutrition and lifestyle risk factors for people with cancer. A process for identifying consumers\u2019 research priorities was developed and applied; this may be useful for further investigation in this under-researched area.The findings of this project should not be considered in isolation. Consumer research priorities are neither better than nor a replacement for priorities identified by health researchers. They are made available via this project and a range of other published investigations to support researchers to both understand prevailing consumer concerns and needs, and to support and inform decisions on what to research. Ideally consumers and researchers should always work together to identify and detail research topics.The paucity of Australian research in this area necessitated the use of a broad exploratory approach. The main limitation is the generalisability of findings for a larger population of cancer consumers. However asking consumer organisation representatives to collect the research needs of constituents prior to the workshop is likely to have reduced this problem, as is the comparison of findings of this project with those of a much larger UK study. The similarity between our results and the UK study results suggests that our results are comparable to other populations of cancer patients.A further limitation is the low response rate (19%) to the postal questionnaire. However, we believe that this low number can be explained in part by the belief among numerous CVN members that they had already provided input on the topic in previous forums. We therefore believe that the views of non-responders are not substantially different from responders.The findings of this project provide the basis for developing a consumer derived cancer research agenda in Australia, and can be used to help inform the strategic direction of cancer research over the longer term. They also provide direction for cancer care, education and information funding. Australia does not have adequate channels through which community members can express their research priorities or through which they can receive information about the broad scope and success of research being made in the fields with which they are concerned. Lack of recognised processes and resources to collect and analyse relevant information from consumers represents an important obstacle to context and culturally sensitive research needs identification in Australia. At the same time, societal expectations of health and medical research are growing.Global Caf\u00e9 method is a user-friendly approach for generating meaningful and cooperative discussion within and between different groups.The study sought to harvest diverse input from cancer consumers on the issues they need addressed through research. Identifying research needs can be challenging. What processes should be used to determine needs? How can this be done in a systematic, ongoing and efficient manner? What timelines for action should be assigned? This paper adds to the small range of available successful approaches that can be used to capture the research priorities of those directly affected. The It has been argued that consumers do not have adequate understanding to identify useful research priorities. This maDecision makers in publicly funded research systems are under growing pressure to improve priority setting processes and to be more accountable for research funding decisions. There is currently no established structure or mechanism in Australian public research funding schemes that allows consumer research needs to be incorporated. Researchers require training to understand and appreciate what is happening in health and health care overall, and with those adversely affected by too few research answers. Long term partnerships with the end recipients of research provides experiential and contextual learning that are the key to ensuring research is of benefit to and is valued by society. Liaising with intellectual colleagues and attending scientific seminars and conferences alone are unlikely to provide insight into the experiences of those with health problems. Researchers need to be inspired by the individuals and families of those in need of the benefits of focussed research.Earlier diagnosis of metastatic cancers; an understanding of the extent of use of best practice palliative care guidelines; identifying barriers to cancer risk behaviour change; and environmental and nutrition and lifestyle risk factors for people with cancer, were found to be the most pressing needs of cancer consumers on the subject of cancer research. The findings of this study offer a workable process for identifying the research needs of health consumers and may be applicable to scenarios other than cancer.In an era where research is making important progress in our understanding of disease causation and avoidance, and identifying real and potential cures, hopes are pinned on every piece of research to drive more progress. Today\u2019s more informed society is eager and able to encourage a purposeful research culture and direction. Hence, we see the need to build and maintain a critical mass of researchers who are competent in partnering with consumer groups, which in turn can offer capable consumer representatives. This partnership will lead to joint needs identification and priority setting, and to performing quality research of societal relevance.Neither author has any competing interests to report.Both authors contributed to the design of the project. CS undertook the review of the literature, facilitated the workshop, undertook data analysis and was the main author of the manuscript. Representing Cancer Voices NSW, SC brought this consumer initiative to the CCNSW for possible implementation. SC was a working member of the key reference group, assisted in facilitation of the workshop, organised the postal questionnaire, undertook data analysis and contributed to the preparation and editing of the manuscript. Both authors have read and approved the final manuscript."}
+{"text": "Over the past several years there has been growing interest in the high prevalence of vitamin D deficiency in both the general population and among people living with HIV infection. Vitamin D deficiency in the setting of HIV infection is likely multi-factorial with contributions from environmental factors as well as possible associations with HIV therapy. This lecture will highlight recent data on the prevalence and possible consequences of vitamin D deficiency in the setting of HIV with a focus on the relationship between vitamin D deficiency and HIV disease progression and possible metabolic and inflammatory consequences of chronic vitamin D deficiency. Finally, the talk will attempt to shine a light on areas for further investigation."}
+{"text": "Uterine fibroids are the most common gynaecological tumours found in women. These tumours are said to be present in 80% of Caucasian women and are even more common in women of African origin. In 50% of women with fibroids symptoms usually occur, leading to complications from the presence of these fibroids. Although they are mainly a problem in the reproductive years, there are reports of problems from fibroids in postmenopausal women.The management of patients with fibroids is quite variable including conservative oral and parenteral treatment, conservative and radical surgery, and newer techniques such as uterine artery embolisation and radiofrequency ablation. All of these techniques can also cause complications for the patient, and as a result careful evaluation of patients must be done to decide on the correct treatment option for a particular patient.The focus of this special issue is to highlight the complications which are caused by fibroids and also those which can arise as a result of the treatment options available. This is intended to assist clinicians and their patients in making informed decisions about the management of this common problem. The journal is the effort of a truly international group of clinicians giving varied experiences from across the world.Complications of uterine fibroids and their management\u201d is from Jamaica and outlines the entire spectrum of complications of fibroids and their treatment. This is a good review of the modern methods available and should be helpful to clinicians to assist them in counseling their patients.The paper entitled \u201cInnovative oral therapy for uterine leiomyomas\u201d is a collaborative effort of clinicians from Egypt and the United States of America (USA) reviewing the use of oral therapy for the treatment of fibroids. This paper gives an update on the modern use of drugs to treat fibroids to avoid surgery.The paper entitled \u201cSurgical management of uterine fibroids at Aminu Kano Teaching Hospital\u201d is from Nigeria, and this paper discusses use of myomectomy versus abdominal hysterectomy in their setting. The authors have outlined their experience and given the reader an idea of their methodology and complication rates comparing the two procedures.The paper entitled \u201cIntrauterine adhesions following conservative treatment of uterine fibroids\u201d is from Sweden and Spain discussing the complication of intrauterine adhesions reminding readers how to diagnose and treat this often forgotten complication of surgical treatment of fibroids.The paper entitled \u201cIndications and outcomes of uterine artery embolization in patients with uterine leiomyomas\u201d is from Japan, and the paper entitled \u201cComplications associated with uterine artery embolisation for fibroids\u201d is from the United Kingdom. Both papers discuss their experience with uterine artery embolisation. The complications from both sites are outlined.The paper entitled \u201cRadiofrequency ablation for treatment of symptomatic uterine fibroids\u201d is from the United States and the United Kingdom and reviews the use of radiofrequency ablation to treat fibroids. This is an excellent review detailing older now archaic methods and outlining the more modern safer techniques used in their setting.The paper entitled \u201cOverall this journal is an excellent resource for physicians who wish to review uterine fibroids as well as all the methods available to treat them. The complications of fibroids are outlined in detail, and the different treatment modalities and possible complications are also outlined. This should become a standard compendium on fibroids for students and physicians for the benefit of increasing knowledge for examinations as well as the proper counseling and management of patients.Horace FletcherHorace FletcherCelia BurrellCelia BurrellBharat BassawBharat BassawEarlando ThomasEarlando Thomas"}
+{"text": "The aims of the study were to examine: (1) the relationship between parental income and schooling and using Complementary and Alternative Medicine (CAM) for their children; (2) the relationship between giving the recommended vaccines and usage of CAM for children; and (3) the frequency and characteristics of CAM usage in children from different socio-economic layers.The study was done via a self-reporting anonymous questionnaire by parents of 535 children, in 5 primary care pediatric clinics located in different areas in Israel, representing a population from different socio-economic classes.Twenty-seven percent of the respondents reported that they used CAM for at least one child in their family. Parents with higher education and income used CAM more than less educated parents and those with lower incomes. Parents who have tried CAM for themselves used it also for their children. Parents who have not vaccinated or partially vaccinated their children used CAM more than parents who gave their children all of the recommended vaccines. Parents tend to attach importance to the pediatrician notification for using CAM.A significant portion of the population use CAM for children. CAM use in children was more frequent among families in a high socio-economic level. Most of the parents who used CAM for themselves did the same for their children, due to their positive experience and their desire to improve the health of their children using other methods outside of conventional medicine. Parents who tend not to vaccinate or partially vaccinate their children were more likely to use CAM, because this treatment is perceived as more \u201cnatural\". The common use of CAM in children requires raising the awareness and knowledge of pediatricians to this phenomena and improving the communication between parents and pediatricians regarding CAM usage, for the benefit of the children."}
+{"text": "Storing chemical structures and reactions in relational databases with the aid of database extension modules usually called cartridges is an industry standard. Typically such cartridges provide a fixed set of functions to facilitate structure queries , chemistry data file import and export, sometimes structure manipulations or standardizations, and occasionally a defined set of property computations. We extend this model by transplanting a complete scriptable chemical information processing toolkit into a database extension. With the aid of this tool a new realm of custom chemistry data operations and queries can be accessed directly in the database, and by means of SQL functions that can be used in any SQL statement. We discuss the design of the software and prototypical solutions this it can deliver."}
+{"text": "Cerebral cortex is generally thought to provide the neural basis for higher cognitive and perceptual functions  and via an iPad or iPhone \u201capp.\u201d From the results, the authors were able to propose how particular groups of neural pathways centered around cerebral cortex might subserve specific cognitive functions. This article illustrates the importance of a comprehensive neuroanatomical assessment of a complete brain.A solution to this Neuroinformatics challenge is important for progressing the discovery of cortical wiring principles. In an ambitious study (Solari and Stoner, Overall, we think this Research Topic demonstrates the complexity and diversity of cortical organization and the wide variety of approaches that can and have been made to understand how we think and perceive. We hope the reader will find something here to stimulate their curiosity concerning a topic of considerable importance to the individual and society."}
+{"text": "Idiopathic toe walking (ITW) is a condition that commonly presents to podiatrists. This presentation aims to give an overview of the quality of literature focused on the treatment of ITW and determine if common podiatric treatment modalities are evidence based. 24 articles reporting treatment modalities were appraised against the National Health and Medical Research Council Levels of Evidence. There currently is no evidence of any single treatment option having long term effect on ITW gait. The highest level of evidence was in support of serial casting or surgery with some evidence supporting the use of Botulism toxin Type A.Footwear and orthotic intervention with or without stretching programs are reported treatments with no rigorous studies to support these modalities yet anecdotally these are reported effective. This article aims update the knowledge of podiatrists, to enhance how children who present with this gait style can be managed and highlight areas for future research."}
+{"text": "Strain of the myocardium is conventionally presented in the polar coordinate system since it adapts best to the morphology of the heart. Strain calculation would be facilitated considerably if the CMR tagging patterns were in the radial or circumferential direction. However, the CMR tagging is implemented mostly in the Cartesian coordinate system as it is prescribed by SPAMM technique in which the gradient fields create only parallel taglines. Radial tagging is not used widely due to SAR problem for tight radial pattern. Implementation of circular tagging, to the best of our knowledge, has not been reported yet. Here we introduce an approach that makes both patterns possible for tagging based on off-resonance excitation. Its theoretical basis and practical details as well as initial results in phantoms and human hearts are presented.A rotating excitation plane in combination with a continuous RF pulse results in substantial excitation on a patterned region using off-resonance effect. A spoiler gradient destroys the net transverse magnetization on the region and generates the tagging with the specified pattern. The actual implementation of these cine sequences was performed on a commercial imaging platform  by using developmental software .The developed sequences were tested on phantoms and applied on healthy volunteers Figure . Images New tagging sequences were theoretically described and actually implemented. The sequences have been successfully tested on phantom and also used to acquire short axis images of the left ventricle. The spatial resolution and density of taglines for the radial tagging are considerably higher compared to its previous schemes and allows for relatively simple derivation of myocardial shear rate and angular strain."}
+{"text": "The recommendations are presented with supporting evidence level.In this report, guidelines for the evaluation, medical and surgical management of renal cell carcinoma is presented. It is categorized according to the stage of the disease using the tumor node metastasis staging system, 7 Renal cancer represents the third common genitourinary cancer in Saudi Arabia after urinary bladder and prostate. It accouAll cases of renal cell carcinoma should preferably be seen or discussed in a multidisciplinary forumth edition was usedThe American Joint Commission on Cancer Staging TNM 7The Memorial Sloan Kettering cancer center risk classification for metastatic disease will be used: Risk facEach of the above gives a score of one. Patients will be classified according to the total score as follows:"}
+{"text": "To the Editor: The recent article by Louie et al. underscores a more general disparity between the need for autopsies in potential infectious disease deaths and our present national capacity  that prevent pathologists from enthusiastically performing autopsies on those who died of potential infectious diseases, including prion diseases. One potential solution is the creation of regional centers of excellence for infectious disease autopsies that could operate in conjunction with a mobile containment autopsy facility ,6. Such"}
+{"text": "Drosophila has a primitive yet effective blood system with three types of haemocytes which function throughout different developmental stages and environmental stimuli. Haemocytes play essential roles in tissue modeling during embryogenesis and morphogenesis, and also in innate immunity. The open circulatory system of Drosophila makes haemocytes ideal signal mediators to cells and tissues in response to events such as infection and wounding. The application of recently developed and sophisticated genetic tools to the relatively simple genome of Drosophila has made the fly a popular system for modeling human tumorigensis and metastasis. Drosophila is now used for screening and investigation of genes implicated in human leukemia and also in modeling development of solid tumors. This second line of research offers promising opportunities to determine the seemingly conflicting roles of blood cells in tumor progression and invasion. This review provides an overview of the signaling pathways conserved in Drosophila during haematopoiesis, haemostasis, innate immunity, wound healing and inflammation. We also review the most recent progress in the use of Drosophila as a cancer research model with an emphasis on the roles haemocytes can play in various cancer models and in the links between inflammation and cancer. Drosophila has undoubtedly been a powerful model organism for the study of nearly all essential and fundamental biological processes. What we have learned from the fruit fly has expanded our knowledge in life science at an unprecedented speed. This is in particular due to the recent availability of the complete annotated genome, a versatile array of genomic modifying techniques and powerful life imaging tools. Cellular and molecular mechanisms underlying many basic biological processes have been discovered to be highly conserved between Drosophila and mammals. For example, the Notch, Hedgehog (Hg) and Wingless (Wnt) pathways first identified in Drosophila embryogenesis and the Runt and Hippo signaling pathways conserved in the Drosophila haematopoiesis and tissue growth are also implicated in the progression of various human cancers  and innate immunity with such precision that the time is now ripe for us to look into the active dialogs between these fundamental processes in the context of mammalian inflammation and cancer. Drosophila has a primitive open blood circulation system with only three types of blood cells or haemocytes circulating in the haemolymph during a fly's life span. The majority of the circulating haemocytes in the haemolymph are macrophage-like cells that engulf and degrade apoptotic cells and invading pathogens. Haemocytes perform vital roles through their contribution both to cellular and humoral immune responses in the fly. In combination with the currently well-developed Drosophila tumor models, the roles of haemocytes in tumor regression and/or progression can be explored and important clues can be obtained to understand further the inflammatory responses in relation to tumors; the focus can be directed more at the molecular and cellular level by use of sophisticated genetic manipulation and live imaging tools. Tian Xu and colleagues have done pioneering work in this direction by using a Drosophila tumor model to investigate the role of haemocytes in the tumor growth control during a systemic inflammatory response  direct killing by Antimicrobial peptide (AMP) released into haemolymph from rapid de novo synthesis in the haemocyte and fat body; (2) direct killing by Hydrogen Peroxide (H2O2) or Nitric Oxide (NO) agents produced during melanisation; and (3) immobilization of opportunistic pathogens by blood coagulation at an open wound  Dizzy was also identified to be required for the embryonic haemocyte migration  signaling which is also used by the mammalian neurophils in response to chemotaxic cues  Basket (Bsk) and Rac1. Bsk is also found to regulate the turnover of focal adhesions in the circulating haemocyte in the larva  investigated the integrin adhesion activation and maturation in the migration of the sessile haemocyte population in the late larval stage into pupal stage  and also stress/danger signals  into the nucleus. Dorsal and Dif are homologs of mammalian p50 and p65. Apart from these secreted cytokines, a cytoplasmic lysosomal protein called Psidin has been found to be the link between the haemocyte phagocytosis and AMP activation in the fat body in the larval immune response  is the enzyme required in melanisation to catalyze the oxidation of mono- and di-phenols to ortho-quinones, which polymerize into melanin. PPO in normal physical conditions is enzymatically inert. A serine protease known as prophenoloxidase activating enzyme (PPAE) acts upstream to cleave and turn PPO into active phenoloxidase (PO). Like PPO, PPAE also exists as an inactive zymogen and it is processed by a tightly regulated serine protease cascade in a step wise way into enzymatically functional form leading to the final melanin formation. As in other invertebrates, a recent in vitro study on the Drosophila PPOs suggested a direct binding of PPOs to bacteria and fungi which might play a role to initiate their activation  mutant with aberrant crystal cells , Zir  and Fondue. Drosophila TF is the only mammalian blood coagulation factor homolog (Factor XIIIa) found in the fly and uses Fondue as its substrate to form the blood clot. Unlike hemolectin (hml) mutants shown to affect only coagulation  expressed mainly by plasmatocytes is required in blood coagulation. Blood coagulation led by plasmatocytes is independent of both melanin production and phenoloxidase activity, which is also part of the wound healing process   primary clot formation during blood coagulation: larvae bleed following the puncture wounding and the primary clot forms in the wound gap; (2) scab and syncytium formation: the primary clot is further cross-linked and hardened by melanisation to form a scab while epidermal cells surrounding the primary clot migrate toward it and then fuse to form a syncytium; and (3) central syncytium formation: more epidermal cells are attracted to the initial synticium and a larger central syncytium forms. JNK pathway is activated in the epidermal cells of the syncytium in a gradient manner to emanate signals for the epidermal cells to move along or through the wound clot to rebuild a continuous epithelium with its basal lamina and apical cuticle lining. Crystal cells are the haemocyte required in the formation of the scab. The scab stabilizes the wound site, establishes a physical barrier to the external microbes, prevents the over-activation of JNK pathway which can result in chronic wounding and provides a scaffold for re-epithelialisation. Scab forming and wound closure are controlled by independent genetic and signaling pathways as re-epithelialisation can still be activated at the wound gap though it never heals in the absence of a scab  and the remote internal tissues in a process similar to systemic inflammation in mammals.In a study to reveal the genetic and molecular networks in control of systemic wound response after physical wounding in Drosophila embryo laser wounding model and it is revealed not surprisingly that a coordinated process exists involving myosin, E-cadherin, Echinoid, the plasma membrane, microtubules and the CDC42 small GTPase which respond dynamically during wound repair  to larvae. The ROS stress in the gut induces NO expression and transduces the signal to haemocytes by a NO dependent pathway  which give rise to both the myeloid and lymphoid lineage. Mammalian HSC possesses the ability to self-renew and the pluripotency to differentiate into a great variety of blood cells in response to signals from its microenvironment, which has been termed the HSC niche  while the mammalian JAK/STAT can be activated by a large group of cytokines and growth factors. Dom is the only transmembrane receptor upstream of one JAK kinase (Hop) and the one STAT transcription factor (STAT92E). Therefore the misexpression of a dominant-active form of STAT92E can also promote tumorigenesis in the eye of the Drosophila adult flies and melanotic tumor formation in the larva , Sima, activates full length Notch receptor under conditions of normal oxygen availability and commits the prohemocyte to the crystal cell lineage  the role of Hippo signaling pathway in control of cell growth and survival together with Scrib/Dlg/Lgl signaling pathway in cell polarity to regulate organ sizes;  was isolated 70 years ago. However only recently has Lgl been identified as a component of a signaling circuit in the regulation of apico-basal polarity in epithelial cells: Scrib/Dlg/Lgl  in the Drosophila eye imaginal disk and screening for the entire Drosophila genome, Pagliarini and Xu indentified Scrib as the promoting factor for the metastatic transformation of the otherwise benign tumor caused by overexpression of Ras oncogene alone (Pagliarini and Xu, Drosophila eye as an in vivo \u201ctest tube\u201d to investigate genetic interactions during tumor progression has proved to be extremely fruitful in dissecting the Scrib tumor suppressor signaling pathway and Hippo pathway and human oncogenes and tumor suppressors such as Ras and PTEN. Critical reviews of the most recent progress in the use of Drosophila in cancer modeling and therapeutic potentials can be found elsewhere (Miles et al., Despite a very short life span, cancer research to investigate directly the tumor progression and invasion in Drosophila, the interplay of innate immunity mediated inflammation and tumor growth and invasion can be investigated accordingly. Of note is the establishment of Drosophila intestinal tumor model to study the molecular and cellular mechanisms linking inflammation and cancer pathogenesis (reviewed in Christofi and Apidianakis, Drosophila cytokines Upd1-3 have been reported to activate the JAK/STAT signaling in promoting intestinal stem cell proliferation upon enteric infection or JNK-mediated stress response and thus the innate immunity plays essential roles in gut tissue homeostasis (Jiang et al., Drosophila Ras oncogene in association with bacterial infection can result in the formation of intestinal dysplasia (Apidianakis et al., v12Scrib\u2212/\u2212 model in the Drosophila eye disks, which has been used to offer complementary views of systemic innate immunity to tumor growth and invasion. Under the condition of established tumor, the Drosophila haemocyte could be recruited to the tumor site and tumor associated haemocytes are the major source of Drosphila TNF\u03b1, Eiger, to promote the growth and invasion of the tumor cells into other tissues (Cordero et al., Drosophila eliminates cells deficient for the polarity tumor suppressors Scrib or Dlg to maintain the tissue homeostasis and keep any malignant growth in check (Brumby and Richardson, v12Scrib\u2212/\u2212 tumor was found to induce a systemic proliferation of haemocytes via the JNK-JAK/STAT signaling cross-talk conserved also in response to tissue injury. The disrupted tumor basal membrane recruited circulating haemocytes in a manner reminiscence of wound healing (Pastor-Pareja et al., Drosophila the anti-tumor effect of a systemic inflammation response induced by mechanical injury and provided critical insight into the cross-talk between the different signaling pathways in regulating the multiple step progression of tumor.Like other aspects of tumor progression that can be modeled and studied comparatively in Drosophila as the complementary genetic tool to dissect each of the hallmark processes and to offer fundamental insights into the underlying genetic and cellular basis of the disease. In future, the Drosophila model can continue to be used as the reductionist system to investigate more of the cross-talks between these fundamental cancer biological processes. For example, the contrasting roles of immunity to control tumor growth or to be hijacked by the tumor can be modeled in the fly in a temporal and spatial manner. The unique advantage of Drosophila to be used as a whole organism has started to show promising potential in cancer drug screening and testing recently (Dar et al., Cancer has a complex biology. As a rationalization, Hanahan and Weinberg identified six major successive changes in human tumor development (Hanahan and Weinberg, The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "A question that continues to be asked by Clinical Trials Units is \u2018Should we invest in commercial trials software or should we develop our own solutions?' The answer depends on the expertise available within the organisation, volume and diversity of work undertaken by the Unit and of course the resources available. The benefits of using electronic technologies are well known; they promote better access and analysis of data as well as providing study results electronically.There are many commercial solutions available. These are often prohibitively expensive, require extensive training, management and support. They are not flexible or adaptable as there is usually no access to the source code so it is difficult to customise or extend the functionality.Trials units conducting publicly funded trials who have access to an experienced programming team having knowledge and experience of good clinical practice and current legislation could consider developing their own generic software solution. The pros and cons of this approach will be explored in this presentation along with comparisons with some of the commercially available solutions.The requirements for trial administration, data management, data cleaning, checking and extraction for analysis will be understood through experience and collaboration with trials teams. A well-documented and tested standard solution developed in-house can provide the benefits of commercial software coupled with the flexibility and quick response offered by a resident programming team. The professional expertise brought to a trials unit by a programming team with trials experience cannot be easily replaced by purchasing a software solution."}
+{"text": "Manganese (Mn) is an essential metal and has important physiological functions for human health. However, exposure to excess levels of Mn in occupational settings or from environmental sources has been associated with a neurological syndrome comprising cognitive deficits, neuropsychological abnormalities and parkinsonism. Historically, studies on the effects of Mn in humans and experimental animals have been concerned with effects on the basal ganglia and the dopaminergic system as it relates to movement abnormalities. However, emerging studies are beginning to provide significant evidence of Mn effects on cortical structures and cognitive function at lower levels than previously recognized. This review advances new knowledge of putative mechanisms by which exposure to excess levels of Mn alters neurobiological systems and produces neurological deficits not only in the basal ganglia but also in the cerebral cortex. The emerging evidence suggests that working memory is significantly affected by chronic Mn exposure and this may be mediated by alterations in brain structures associated with the working memory network including the caudate nucleus in the striatum, frontal cortex and parietal cortex. Dysregulation of the dopaminergic system may play an important role in both the movement abnormalities as well as the neuropsychiatric and cognitive function deficits that have been described in humans and non-human primates exposed to Mn. Manganese (Mn) is an essential trace metal that is required for a number of enzymes important for normal cellular functions   imaging on 20 asymptomatic welders (exposed to welding fumes containing Mn), 20 subjects with idiopathic PD and 20 normal controls  but significantly lower level of [18F]-FDOPA uptake in the caudate nucleus relative to controls but no effect on the anterior or posterior putamen  with a smaller reduction in the caudate nucleus (~17%)  PET for vesicular monoamine trasnporter type-2 (VMAT-2) is more likely to represent structural changes in dopamine terminals than [18F]-FDOPA PET when it relates to studies with Mn.In the last decade there has been a great deal of debate in the scientific literature about the potential role of Mn on the etiology of idiopathic PD. Epidemiological studies indicate that long-term exposure (>20 years) to Mn is associated with idiopathic PD . Consistent with this hypothesis, several studies in early idiopathic PD patients show that reductions in [18F]-FDOPA uptake in the caudate nucleus are associated with deficits in working memory performance and executive function  in which there is extensive behavioral and neuroimaging assessment prior to (baseline) and at two different time points after initiation of Mn administration  with amphetamine challenge in order to measure both D2-dopamine receptor (D2R) levels and in vivo dopamine release  dopamine available for release. To answer this questions, a number of ex vivo neurochemical studies were performed in the caudate and putamen of the same animals in which PET studies were performed. The results show that when all control groups were combined (imaged-controls and na\u00efve controls) and used as a referent group, there were no significant differences on the levels of dopamine and metabolites in the caudate and there was only an effect of Mn on dopamine levels in the putamen when compared to the na\u00efve controls only  in frontal white matter  most studies on Mn-induced neurochemical and neuropathological changes have been focused on basal ganglia structures due to its association with movement abnormalities and parkinsonism, and (2) Mn accumulates to a high degree in the basal ganglia. Besides the suggestion from neuropsychological and cognitive tests of frontal cortex involvement in Mn-induced neurological dysfunction, a review of the literature brings to light a lack of neuropathological studies in which Mn effects on the cerebral cortex have been performed. It is only recently when neuroimaging studies have interrogated cortical regions to examine their susceptibility to Mn-induced neurotoxicity. In this context, our recent studies in non-human primates have reported proton MRS metabolite changes in Mn-exposed animals  decrease in NAA/Cr ratio in the frontal cortex white matter  and [18F]-fallypride (Kd = 0.14 nM) have made such studies possible. Several publications have now described the reliability of using [11C]-FLB 457 to measure in vivo dopamine release in the cerebral cortex of humans and non-human primates (Narendran et al., 11C]-FLB 457 binding potential reduction measured by PET was directly associated with the amount of extracellular dopamine release induced by the acute amphetamine administration (Narendran et al., in vivo dopamine release in the cerebral cortex using PET is an extremely valuable approach to understand the molecular basis of the working memory impairments observed in humans and non-human primates exposed to Mn. We are currently performing these types of studies in our Mn-exposed animals in order to make associations between in vivo dopamine in cortical regions and working memory performance.While the displacement of D2R specific PET ligands such as [In the last decade there has been significant progress using state-of-the-art neuroimaging and behavioral methodologies that have opened up a new understanding of Mn neurotoxicology. While historically the focus of Mn neurotoxicity has been associated with parkinsonism as a result of the high levels of exposure that occurred in the mining and processing of Mn ore and in other occupational settings, the last decade has brought about compelling experimental evidence that at lower cumulative doses of Mn that are likely to occur from occupational and environmental exposures, other non-motor neurological effects appear to be more prevalent and these seem to be associated with cognitive function deficits. The later may be the result of Mn producing brain chemistry and structural changes in cortical regions, and the frontal and parietal cortex appear to be sensitive targets. Lastly, because of its relevance to motor and cognitive domains, it is possible that dysfunction of the dopaminergic system could be a common mechanism by which Mn could have an impact on both cognitive and motor function deficits observed in humans and non-human primates.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The Village/Commune Safety Policy was launched by the Ministry of Interior of the Kingdom of Cambodia in 2010 and, due to a priority focus on \u201ccleaning the streets\u201d, has created difficulties for HIV prevention programs attempting to implement programs that work with key affected populations including female sex workers and people who inject drugs. The implementation of the policy has forced HIV program implementers, the UN and various government counterparts to explore and develop collaborative ways of delivering HIV prevention services within this difficult environment. The following case study explores some of these efforts and highlights the promising development of a Police Community Partnership Initiative that it is hoped will find a meaningful balance between the Village/Commune Safety Policy and HIV prevention efforts with key affected populations in Cambodia. On the 16th of August 2010, the Co-minister of the Ministry of Interior announced the Village/Commune Safety Policy as a priority policy for the Kingdom of Cambodia. The policy urged authorities at the commune level to ensure that there was no stealing, drug production or dealing, prostitution, child trafficking, domestic violence, gangsters, illegal gaming, use of illegal weapons or crime occurring at any commune in Cambodia [With regards illicit drugs the policy stated that authorities were to specifically:\u201cTake action to cut off and eliminate production, dealing and use of illegal drugs at the village commune/Sangkat by following the guideline No 052 National Department of the Police dated 21st 2006 on the implementation of a warlike approach to fighting any drug crime and to especially focus the law on drug control[.\u201dThe policy has had negative implications for HIV prevention among risk groups including harm reduction programs; a fact not lost on the Government of Cambodia who have acknowledged that the policy has made it much more difficult to access people who use drugs and has made \u201cservice provision for their benefit very difficult due to the misunderstanding of the law enforcement officers, especially at the commune level \u201d.Although the Village/Commune Safety policy has further highlighted the direct impact that law enforcement policy and practices can have on HIV prevention, many agencies have actively been trying to find a balance between law enforcement and HIV prevention efforts among most-at-risk populations (MARPs) in Cambodia over the last several years. Recognising that law enforcement practices were negatively affecting HIV prevention among sex workers, men who have sex with men and drug users, UNAIDS began working with the National AIDS Authority on a MARPs Community Partnership Initiative (MCPI). The MCPI was being designed as a standard operating protocol that could be implemented to decrease the impacts of law enforcement practices in HIV risk environments. Specifically the MCPI was designed to,Restore the enabling environment so as to allow the effective and smooth delivery of all forms of services to all MARPs\u201d \u2013 UN Official familiar with the MCPIUnder the MCPI and with support from USAID and the Global Fund to Fight AIDS, Tuberculosis and Malaria, Family Health International in Cambodia FHI360) has been piloting initiatives aimed at improving the enabling environments for HIV prevention among MARPs in Banteay Meanchey province. These pilot endeavours have been done in conjunction with the AIDS Secretariat of the Ministry of Interior and focus on strengthening a collaborative partnership among Provincial AIDS Committees/Secretariats, local authorities, police, military police, development partners, non-governmental organisations and members of the MARPs communities. During implementation of this pilot project the local authorities, health care providers and NGO staff conducted sensitisation information sessions to the police about the HIV prevention needs of MARPs and the role of the police in the HIV prevention enabling environment [60 has beThe police were made aware of the HIV programs working with these groups including the specific activities being implemented to support them. Early evaluations of these sensitisation efforts indicate that the police no longer use possession of condoms by sex workers as evidence for arrest and the police are discussing drug related arrests more carefully with other service providers resulting in them distinguishing drug dealers from drug users and then releasing drug users back to the community .These initial successes are building momentum and FHI360 is being funded by AusAID\u2019s HIV/AIDS Asia Regional Project (HAARP) to conduct a similar pilot program with police in Phnom Penh. Furthermore, officials from the Ministry of Interior involved with the work in Banteay Meanchey are reportedly looking to expand the effort into other provinces. Furthermore, UNODC are also working closely with its partners in Banteay Meanchey and other provinces to ensure that law enforcement officials are working collaboratively with other sectors to enhance the HIV prevention efforts among drug users.\u201cThere are key officials from the Ministry of Interior who have been providing local and national political support to these pilot program efforts and this is leading officials to want to expand these efforts into Phnom Penh and Sihanoukville.\u201d \u2013 UN Official familiar with the pilot projects.While the original efforts towards the development of a formal standard operating protocol for the MCPI were with the NAA, it became clear that ultimately the Ministry of Interior needed to be able to lead efforts that were being designed to work with law enforcement officials at the local level, especially in relation to HIV prevention among people who use drugs. The Ministry of Interior agrees and has now specifically requested that resources be redirected so that they can train and build the capacity of all of its law enforcement agencies to play a collaborative leadership role in HIV prevention among MARPs.\u201cThe Ministry of Interior are key players if we want to make a meaningful impact on the enabling environment for HIV prevention among drug users. There are currently renewed efforts being made to bring the Ministry of Interior further on board with HIV prevention efforts. We need to support these efforts with resources so that the Ministry of Interior can coordinate positive law enforcement efforts with the enabling environment for HIV prevention among MARPs.\u201d \u2013 UN official familiar with the increasing involvement of the Ministry of Interior in HIV preventionIn addition to work on the enabling environment on the ground, efforts are also being made to reform police education with regards harm reduction. With support from HAARP, FHI360 has developed and begun to implement a harm reduction training curriculum for the Cambodian Police training academy. In November of 2011, the National Harm Reduction Curriculum was officially approved by the Cambodian Deputy Prime Minister and early evaluation has demonstrated positive results.\u00b7 Training pre-post test results showed a 34\u2009% increase (at least 27 out of 33) in answers provided that favoured a law enforcement approach and support of HR programs.\u00b7 A comprehensive nine module curriculum on HIV, drug use and its link with HIV, harm reduction principles and practices and on the new drug laws is being adopted by six police academies around Cambodia .The MCPI project work being done in Banteay Meanchey is about to be reviewed by a delegation that includes the Ministry of Interior. With ongoing technical support from UNAIDS, UNODC, WHO, and FHI360 and in collaboration with the Ministry of Interior the lessons being learned in Banteay Meanchey are being used to develop a new Police Community Partnership Initiative protocol. The protocol may include the formation of Rapid Response Teams to be comprised of police, local authority, NGO representatives and other key stakeholders at the local level to refer MARPs away from police arrest and into HIV prevention services.It is clear that the Ministry of Interior in Cambodia is serious about improving the role of law enforcement in HIV prevention among MARPs groups and the development and implementation of the Police Community Partnership Initiative is a critical step towards the realization of this goal.The authors declare they have no competing interests.NT, KC, SL and NC discussed the initial concept of this case study presentation. KC and SL conducted background research into the issue of the village/commune safety policy in Cambodia. NT conducted interviews with key informants familiar with the issue in Cambodia and drafted the initial manuscript. GS and AW provided unique insights, guidance and information with regards to this issue in Cambodia. GS, AW and NC provided editing assistance to reach the final stage of this manuscript. All authors read and approved the final version of this manuscript."}
+{"text": "We give a new explanation for why some biological systems can stay quantum coherent for a long time at room temperature, one of the fundamental puzzles of quantum biology. We show that systems with the right level of complexity between chaos and regularity can increase their coherence time by orders of magnitude. Systems near Critical Quantum Chaos or Metal-Insulator Transition (MIT) can have long coherence times and coherent transport at the same time. The new theory tested in a realistic light harvesting system model can reproduce the scaling of critical fluctuations reported in recent experiments. Scaling of return probability in the FMO light harvesting complex shows the signs of universal return probability decay observed at critical MIT. The results may open up new possibilities to design low loss energy and information transport systems in this Poised Realm hovering reversibly between quantum coherence and classicality. Discovery of room temperature quantum coherence in the avian compass Quantum biology is dealing with open quantum systems closely coupled to their many degrees of freedom environment. The environment exerts time dependent forces on the system through the coupling. Some of these forces change very rapidly compared to the excitation frequencies of the system and look random from its point of view. This \u201cheat bath\u201d destroys quantum coherence and moves the system into a mixed state rapidly. The average effect of the random forces can be described as a non-unitary time evolution of the system's density matrix.The speed of environmental decoherence can be characterized by the decay rate of the off diagonal  point Merging the pieces of classical, semiclassical and quantum aspects a new picture emerges. Systems well below the critical point have non-chaotic dynamics with zero generalized Lyapunov exponents and quantum localization lengths extending only for few states. Decoherence in these systems is slow and purity follows a power law decay We demonstrate this on a simplified model of chromophores in light harvesting complexes and argue that it is very likely that biological systems use this mechanism to tune their parameters Next we show results for ion  see . The effAt criticality not only purity changes from exponential to power law decay but so does the population of the chromophores. In The findings support a new approach to quantum biological systems. They are not just under the influence of environmental decoherence due to random noise but also driven by waves of the incoming photons. The photons are absorbed by the chromophores which initiates an exciton on one of the chromophores in an initial state which is concentrated on the selected chromophore. The purity of the system becomes"}
+{"text": "Environmental Health Perspectives (EHP) established the Paper of the Year Award in 2008 to recognize high-quality papers published in the journal  determine whether these changes persist in children at 7 years of age, b) examine the role of timing of exposure, and c) explore whether epigenetic inheritance plays a role in these findings. The authors are also coordinating an effort to bring together studies with data from the same platform for a meta-analysis of the effects of maternal smoking on newborns. The findings of Joubert et al. support the possibility that epigenetic mechanisms seen by DNA methylation may be associated with effects of maternal smoking during pregnancy.It is well known that children whose mothers smoked during pregnancy are more likely to have health problems such as low birth weight and asthma. Joubert et al. addressed the hypothesis that the diverse effects of maternal smoking during pregnancy may involve epigenetic modifications such as DNA methylation. The investigators obtained cord blood samples from a pregnancy cohort in the Norwegian Mother and Child Study (MoBa), and they used the Illumina Methyl450K platform to examine whether methylation changes were associated with smoking during pregnancy. Joubert et al. found cord blood methylation of genes in a pathway important for the detoxification of chemicals in tobacco smoke. They also identified the methylation of novel genes not previously implicated in the response to tobacco smoke, one of which is involved in fundamental developmental processes. Work is now in progress to EHP congratulates all the authors of this paper for their contribution to the environmental health science literature. This research is important because it demonstrates the value of using this approach to study mechanisms of epigenetic effects of in utero exposures to chemicals and other environmental factors."}
+{"text": "Food security requires the development and deployment of crop varieties resilient to climate variation and change. The study of variations in the genome of wild plant populations can be used to guide crop improvement. Genome variation found in wild crop relatives may be directly relevant to the breeding of environmentally adapted and climate resilient crops. Analysis of the genomes of populations growing in contrasting environments will reveal the genes subject to natural selection in adaptation to climate variations. Whole genome sequencing of these populations should define the numbers and types of genes associated with climate adaptation. This strategy is facilitated by recent advances in sequencing technologies. Wild relatives of rice and barley have been used to assess these approaches. This strategy is most easily applied to species for which a high quality reference genome sequence is available and where populations of wild relatives can be found growing in diverse environments or across environmental gradients. Agriculture needs significant increases in productivity to satisfy the expected growth in demand for food in the next few decades. The impact of climate variability and climate change on agricultural productivity is likely to be a major constraint to achieving increased food production. This makes the development of crop genotypes with resilience to climate change an important strategy for food security. Innovations in crop improvement based upon application of advanced genomics tools may be a way to address this need. The delivery of these technologies will require significant efforts in coordinated development and delivery of improved germplasm . GenomicCrop evolution has been relatively rapid under human selection over the last 10,000 years of agriculture. However, it is built on a very much longer period of evolution of wild crop relatives and the plant groups from which they are sourced. Understanding the processes and history of crop domestication and the evolution of related wild species provides critical knowledge to guide the development of crop varieties that are resilient to climate change in the future.Analysis of wild plant populations provides evidence of factors contributing to success in periods of climate change. For example, hybridization between species may be an advantage in adapting to rapid climate change by providing new genetic combinations to cope with new environmental circumstances. Closely related species that can hybridize are more likely to survive than highly divergent species that cannot hybridize . AnalysiRecent fossil evidence suggests early diversification of groups of crop wild relatives such as the grasses . The cliDomesticated crop species are few in number compared to the total number of land plant species . A smallGenomics tools provide new options for accelerated domestication of new species to allow adaptation of agriculture to climate change .Domestication may have been a single genetic event with all the domesticated plants being descendent from the same wild parents or have involved a few or many independent domestication events with many wild plants contributing to the domesticated gene pool. This understanding may provide the opportunity to repeat the domestication of important crop species from a different or more diverse gene pool. Genome analysis may be used to guide this process.The center of origin of a crop species is the region from which the species is believed to have been domesticated. These are the environments that the crop plant was originally best adapted to survive at the time of domestication. Domestication from a different population selected by genome analysis may provide an opportunity to develop genotypes adapted to a new environment.Oryza sativa) was probably domesticated in China from wild O. rufipogon. The A genome clade of wild rice relatives is now considered to be most diverse further south with a center of diversity in New Guinea, Australia, and Indonesia. These locations may prove to be good sources of novel germplasm for rice improvement. Species from more temperate regions could be used to adapt rice to production in cooler climates.Genome analysis allows rapid identification of geographic centers of genome diversity. The center of diversity of a crop species is the region displaying the greatest genetic diversity of the crop species or its wild relatives. This may be distinct from the center of origin as plant species may have been domesticated in areas that are not those including the greatest diversity. Identification of these locations may provide new and diverse germplasm and define new environments for production of the crop now or in the future. Asian rice (The gene pools of crop species may be considered at several levels. Genomic analysis may have value at all of these levels. The primary gene pool is the gene pool of the plant found in domestication and usually the species from which the crop was domesticated. The primary gene pool includes those plants that are available for direct use in genetic improvement of the species. The secondary gene pool may include more diverse material from other species that can be accessed but with a greater degree of difficulty. This often includes other species in the same or a related genus . The terde novo assembly of sequence data may be necessary to detect all differences and advances in sequencing technology to make this routinely possible with large plant genomes will be a significant advance.Advances in DNA sequencing in the last few years have resulted in genomic sequence data becoming more readily available . Major eAnalysis of the genomes of plants growing along environmental gradients may provide a greater understanding of how plants adapt to climate variation under natural selection .Analysis of the genomes of plant genetic resources will become a key tool to enable their utilization in crop improvement for climate adaptation. Targeting of genetic resources from environments that match the one being breed for is an important strategy. Large scale sequencing of accessions in plant germplasm collections will provide a platform to enable these approaches .Increased utilization of wild crop relatives will remain a major strategy for adaptation of crops to the environmental factors associated with climate change. Many crop wild relatives remain poorly collected and are not yet represent well in seed banks. Climate change and human development risk loss of this genetic diversity making accelerated collection of crop wild relatives urgent. Rice illustrates this challenge. The closest wild relatives of rice are those from the A genome clade from which rice was domesticated . Recent The analysis of populations of wild relatives of barley  and riceIn these studies, wild plants were collected from diverse environments or along a sharp environmental gradient. Sampling of the same population over time as the climate changes could be simulated by this strategy. In only a few cases we can access samples that have been sampled from the same population over a significant period of time. Key findings were that adaptation to hotter or dryer environments was associated with increased diversity of biotic stress genes. Coping with abiotic stress may be confounded by overriding associated changes in the biotic environment .Productivity gains in crop production require elimination of constraints to utilization of more diverse germplasm. In some species the requirements of end uses are a major limitation. Market requirements for specific food or processing attributes that are complex or not well understood at the genetic level can greatly hamper attempts to use diverse adapted germplasm. Genomics tools that allow these traits to be readily selected for in breeding will assist by removing these as constraints to rapid climate adaptation . Food quHuman selection for quality may result in loss of environmental adaptation. Fragrance in rice is highly attractive to humans and adds significant value to rice. The sequencing of the rice genome allowed the identification of the genetic basis of this trait  due to tThe breeding of crops to cope with new pests and diseases will be a key strategy to allow plants to cope with new climates. Genes from wild populations will continue to be a major option but this may need to be complemented by the use of novel transgenes or genetic modifications.Technology advances will continue to be critical. Ultimately we need to be able to access whole genome information on all crop species and their wild relatives to be effective in rapid crop adaptation to climate. Ongoing developments in the chemistry of DNA sequencing and in information technology hardware and software will be required to allow these very large amounts of information to be captured and managed.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Whole genome and whole exome sequencing projects yield thousands of missense mutations with unknown functionality. Direct estimation of the sensitivity and specificity of bioinformatic algorithms predicting the impact of missense mutations on protein function requires a 'gold standard' or set of mutations with known functionality. In the absence of a gold standard, additional statistical methods are needed to estimate the accuracy of these algorithms. It has been shown informative predictions depend on the algorithm and sequence alignment employed and often algorithms disagree as to which mutations are predicted deleterious or neutral .n algorithms, there are 2\" disjoint categories employed by the ABM model, which includes 2n + 3 parameters, and the BM model is a special case of the ABM model that includes 2n + 1 parameters. We use the expectation-maximization algorithm for parameter estimation.To investigate the level of agreement, disjoint categories of sets of mutations are defined depending on which algorithms predict which mutations to be deleterious or neutral. We have developed two statistical models called Bernoulli mixture (BM) and augmented Bernoulli mixture (ABM) based on the capture-recapture technique that employs these disjoint categories. Application of these models allows us to jointly estimate the sensitivities and specificities of each algorithm considered without the use of a gold standard and to estimate the proportion of deleterious mutations in a given set. These estimates may then be used to calculate the posterior probability of a given variant being deleterious. When considering We apply the models to two types of predictions of functionality: simulated and real predictions. Using simulated predictions, we accurately recover the true sensitivity and specificity values and report confidence regions. We show example posterior probabilities of a given variant being deleterious. When a gold standard is available, we show the sensitivity and specificity estimates reported the BM and ABM models closely match the sensitivity and specificity estimated directly using the true functionality status. To test our models on mutations without known functionality, we apply the models to mutations obtained from the exomes of four individuals which were sequenced at the Human Genome Sequencing Center at Baylor College of Medicine to identify cancer susceptibility genes for acute lymphocytic leukemia and lymphoma in children. Within each individual, we estimate posterior probabilities for each variant being deleterious and apply an intersection filter to look for deleterious mutations shared by the three affected individuals, but not in the unaffected individual.The BM and ABM models may be used to estimate the sensitivity and specificity of algorithms predicting the functionality of mutations without the use of a gold standard and to calculate posterior probabilities of a given variant being deleterious which may be used downstream in application of finding causal variants in next-generation sequencing."}
+{"text": "Data models are used to capture and organise the elements of the data in a meaningful way so that they can be stored and utilised by computer systems and support clinical decision making. This paper presents the data modeling considerations within the \u2018Clinical Trial Methods in Neurodegenerative Diseases\u2019 (CTMND) project funded by the NIHR [The project adopts a holistic approach for the investigation of the suitability and efficiency of clinical observations in neurodegenerative diseases clinical studies. This ongoing research in novel clinical and surrogate outcome measures will be incorporated in an online data collection and analysis system to facilitate clinical trials and relevant research, taking into account, wherever possible, routinely collected NHS data.This paper presents ongoing research in the project\u2019s data modeling aspects with the following objectives:1. To review the current state of the art data models for capturing clinical information from the available literature.2. To compare and contrast their features against the data management requirements of the project and outline the key factors that affected the adoption of a specific model for the CTMND project\u2019s information system.A set of key papers and past reviews were collected from the currently available literature detailing the characteristics of standard data models used in healthcare such as CDISC\u2019s ODM, Health Level 7 and others. The data models and associated approaches were compared and contrasted with each other by taking into account best practices and guidelines emerging from organizations such as the Object Management Group (OMG). Finally, having concluded in a specific modeling approach we were also able to look forward at the possibilities that a particular solution enables and propose a flexible way to model clinical trial data.This review highlights a number of key data management and organization considerations that affect the adoption of a specific data model given the project specifications and resource constraints. The key factors were Current Resources, Interoperability (with current and future systems), Documentation and Reference Implementation availability.Given the dynamic environment of clinical trials as well as the project\u2019s objectives to propose novel outcome measures, we comment on the suitability of the Dual Model approach for the efficient organization of clinical study data but more importantly for its flexibility in modeling novel outcomes with minimal software maintenance. According to this approach, a handful of elementary data structures  are made available to a higher level model that is responsible for their ordering and semantics. Additionally we provide specific details regarding system implementation."}
+{"text": "Developing new therapeutic strategies to achieve a functional cure for HIV infection is a central objective for contemporary AIDS research. A key obstacle towards a functional cure for HIV/AIDS is the paucity of information regarding the establishment and maintenance of the persistent reservoirs of latently HIV-infected cells which support the rapid reactivation of virus replication when antiretroviral therapy (ART) is stopped. Given the many and important similarities between HIV-infection of humans and SIV infection of macaques, it is very likely that crucial information on the nature of HIV reservoirs may come from studies conducted in SIV or SHIV-infected macaques that are treated with ART. While this area of AIDS research is still in its early stages, it is important to note that these studies have now become possible due to the availability of antiretroviral regimens that successfully reduce SIV or SHIV replication below detectable limits. Specific advantages of the non-human primate models for HIV latency, reservoirs and functional cure include the following: (i) possibility to conduct extensive characterization of the virus reservoirs and pathogenic processes in tissues (including elective necropsy); (ii) performance of in vivo pilot trials of new therapeutic approaches can be conducted in a timely and controlled fashion; (iii) developing and testing of \u201crisky\u201d interventions  that may pose significant ethical challenges in humans; and (iv) possibility to control for various clinical parameters that are very hard to control in humans . On the other hand, current limitations to this type of studies are their cost and the lack of standardized research resources . In this presentation, the potential and limitations of animal models of functional HIV cure will be discussed together with selected examples of therapeutic approaches that could be developed and tested in non-human primates."}
+{"text": "The cell has an intricate quality control system to protect its mitochondria from oxidative stress. This surveillance system is multi-tiered and comprises molecules that are present inside the mitochondria, in the cytosol, and in other organelles like the nucleus and endoplasmic reticulum. These molecules cross talk with each other and protect the mitochondria from oxidative stress. Oxidative stress is a fundamental part of early disease pathogenesis of neurodegenerative diseases. These disorders also damage the cellular quality control machinery that protects the cell against oxidative stress. This exacerbates the oxidative damage and causes extensive neuronal cell death that is characteristic of neurodegeneration. Mitochondria are key molecular players in all cells performing many vital functions. They are the powerhouse of the cell, providing the cell with adenosine triphosphate (ATP) generated by oxidative phosphorylation (OXPHOS). Mitochondria have an important role in buffering calcium flux from the endoplasmic reticulum and the plasma membrane thus helping to maintain the spatiotemporal distribution of calcium in the cell. Mitochondria have enzymes essential for steroid synthesis and are the chief source of endogenous reactive oxygen species (ROS) which are produced by several mitochondrial enzymes including components of the OXPHOS system .Proper mitochondrial functioning is very important to neurons. Neurons have high energy requirements. They are terminally differentiated cells which consume a lot of ATP to maintain ion gradients across membranes for proper neurotransmission. Efficient mitochondrial transport and positioning are also critical because different regions of the neuron have different energy requirements. Active growth cones and presynaptic terminals need more ATP than other parts of the cell . Calcium\u03b1-ketoglutarate dehydrogenase; pyruvate dehydrogenase; glycerol-3-phosphate dehydrogenase; dihydroorotate dehydrogenase; the monoamine oxidases; and cytochrome b5 reductase ..69].Mitochondrial quality control is a relatively new field of research which has a lot of unanswered questions. A simple analysis of the events that follow when cells are treated with the commonly used mitochondrial uncoupler like CCCP clearly exposes the many caveats in our understanding of the functioning this organelle. On CCCP treatment, it is seen that the mitochondrial distribution changes from a spread out pattern to a cluster around the nucleus. Why do they cluster around the nucleus? Does this involve ROS mediated signalling between the mitochondria and the nucleus or between the clustered mitochondria themselves? On using a high resolution microscope it is seen that what appears to be a cluster of fused mitochondria is actually made up of many punctuate individual mitochondria. It is known that fission can segregate out damaged or depolarised mitochondria so that it can be removed but what determines the sites of this fission? How does the cell know how much of the mitochondria have to be removed from the electrically continuous mitochondrial network? Are there internal sensors which can sense the local membrane potential within the mitochondria which decide the sites for mitochondrial fission? Once the depolarised mitochondria are separated from the rest by fission, it can undergo mitophagy. How does the cell specifically direct the autophagy machinery to the damaged mitochondria without activating bulk autophagy? And finally, how does the cell decide when to switch from mitochondrial quality control to activation of apoptosis? in vivo magnetic resonance spectroscopy (MRS) based techniques to analyse mitochondrial function, mitochondrial research is progressing rapidly towards a clearer understanding of the mitochondria and their interaction with the rest of the cell.Our knowledge of oxidative stress and mitochondrial biology is still very rudimentary with a lot of unexplored questions. With the advent of sophisticated techniques like super resolution imaging, mass spectrometry based mitochondrial proteome analysis, and new"}
+{"text": "Antibiotic drug discovery is an indispensable process to combat aggressive ability of pathogenic microorganisms and emerging infectious diseases against health and well-being of people throughout the world. According to the updated and expanded data on natural products presented by Newman and Cragg , the utiStreptomyces griseus there has been a rapid escalation in antibiotic discovery from the genus Streptomyces (largest genus of Actinobacteria). Subsequently, members of this genus have become renowned as a prime source of natural antibiotics  are currently isolated from diverse environments and intensively studied for potential leads for antibiotic discovery programs. The rare actinomycetes are usually regarded as strains of actinomycetes whose isolation frequency by conventional methods is much lesser than that of streptomycete strains  apparently opine that these organisms nourish the current antibiotic drug discovery programs."}
+{"text": "The application of Personalized Medicine strategies of matching specific disease genotypes and phenotypes with specific pharmaceutical drug treatment has shown tremendous efficacy in several important diseases. The most successful example is the targeting mutations of the epithelial growth factor receptor by small molecule antagonists of the tyrosine kinase in non small cell lung cancer. The expansion of this treatment paradigm into other diseases has led to new thinking considering the diagnosis and treatment of disease, including \u201cPrecision Medicine\u201d, which seeks to provide a molecular taxonomy of disease that can be used for guiding targeted therapy in individual patients. Today we have only a cursory understanding of the patterns of actual uptake of drugs or their active metabolites at such targeted sites in the body. In the past such studies required extrinsic labeling of the parent drug (ie radioactivity in PET) that potentially changed the chemical and biological properties of the drug. New technologies such as MALDI-MSI mass spectrometry have revolutionized the label-less tracking of drugs within targeted disease tissue sites . A spect"}
+{"text": "Effective malaria control programmes prevent malaria transmission by promoting personal protection measures and effective vector control strategies, and providing appropriate case management with early diagnosis and effective treatment. The objective of the study was to understanding of malaria entomologist in relation to current malaria control in their area of activities and technical disciplines.A qualitative approach was adopted based on a semi structured interview with 30 individuals working at community-level in malaria endemic areas. Thematic content analysis was used to analysis the data.Although most of participants have been concern with the distribution and causation of problems of malaria control, few of them have addressed the issue of solutions. Participants had positive perceptions on their basic activities and opinions in relation to biologic and epidemiologic factors in their field work. In contrary, their perceptions in relation to malaria control policy and integrated management of vector control were rather negative.There was not feedback mechanism on malaria control activity among practitioners. Therefore, any problems due to the mismatch between the institutional tasks and individual role performance should be fed back into the health system and adjustment should be made. Greater emphasizes should be given to the choice of solutions."}
+{"text": "The most significant epigenetic alteration found in cancer cells is a global loss of DNA methylation. Recent analyses of cancer methylomes have suggested that methylation is specifically lost from Lamin-associated domains (LADs) which are associated with the nuclear periphery. This suggests that nuclear organisation is a key influence on epigenetic alterations in cancer but the relationship between nuclear organisation and demethylation has not been directly investigated.in-situ hybridisation (FISH) to determine how nuclear organisation in normal cells relates to alterations in DNA methylation levels in cancer.We have combined analyses of cancer methylomes with fluorescence Our analyses demonstrate that DNA methylation is lost from different regions of the genome in breast and colorectal tumours. Surprisingly, we find that the propensity to become demethylated in cancer is not correlated with localisation to the nuclear periphery in the corresponding normal cell types. While regions some breast cancer hypomethylated regions are localised to the periphery in normal breast epithelial cells, an equal proportion are found in the nuclear interior.Our observations decouple hypomethylation in cancer from a peripheral nuclear localisation and suggest that association with the nuclear lamina is not mechanistically involved in the loss of methylation in cancer."}
+{"text": "Knee malalignment and variations in foot posture and function affect the forces transmitted through the knee joint and are associated with knee pain and medial tibiofemoral cartilage damage . HoweverNineteen patients  diagnosed with predominantly medial compartment knee OA who were scheduled for TKR surgery participated in the study, and were tested prior to and 12 months after TKR. Foot Posture Index (FPI) and arch index were measured as well as motion of the tibia, rearfoot and forefoot using a 3D motion analysis system incorporating a multisegment foot model (Oxford Foot Model).Significant increases in tibial external rotation  and tibial transverse plane range of motion (ROM)  were observed following the surgery. An increase in rearfoot ROM in the frontal plane  and a decrease in rearfoot transverse plane ROM  were observed. No significant differences were found between pre and post-surgery in the FPI and or the arch index.Following TKR, there is an increase in the ROM of the rearfoot in the frontal plane, but no change in static foot posture suggesting that rearfoot motion compensates for changes in the alignment of the knee."}
+{"text": "Rare diseases are designated as affecting less than 200,000 individuals (US) and of the approximately 7000 designated rare diseases, the majority of these occur in pediatric patients, and across international boundaries. An example is pediatric ARDS (Acute Respiratory Distress Syndrome) which is not diagnosed until a previously healthy child presents in the pICU with severe symptoms and in which more children die each year than from cystic fibrosis and leukemia, combined. The Nathaniel Adamczyk Foundation (NAF) is focused on identifying risk factors and opportunities for prevention of this devastating disease. Boththe diagnosis and patient management are challenged by having to deal with a syndrome in a critical care situation in a heterogeneous patient population.NAF has undertaken the development of an (inter) national tissue and data repository to support both clinical research and enhanced clinical decision support for patient management. Creation of an analytical platform to integrate, access and analyze temporal clinical data ranging from the pICU to also incorporate neo-natal ICU and pregnancy history is underway with a prototype already in testing. Analytical methods are being evaluated in collaboration with Dr. Mike Quasney  and the Virtual Pediatric ICU and PALISI (Pediatric Acute Lung Injury and Sepsis Investigators). This effort is exploring expanded international partnerships in both Europe and China to increase the accessible data for analysis and to further participate in the development of better diagnostic standards.We will present the initial state of both the analytics and platform development to encourage extension of this international effort to interested clinicians and clinical researchers. We believe that this unique approach, which focuses first on addressing the critical need to improve patient management through disease stratification, will not only benefit pARDS but be extensible to many other pediatric rare disorders."}
+{"text": "The UK Department for International Development (DFID) is committed to investing in research to combat poverty, reduce high mortality and morbidity in resource poor contexts and support progress towards meeting the Millennium Development Goals. Research helps us to identify what works, what does not work and how to understand the local context when introducing new ways of working. There is no point doing research if the findings do not get into policy and practice. DFID strongly encourages all research programmes to consider research uptake activities as an integral part of the research.This special supplement draws on the work of the Sexual Health HIV Evidence into Practice (SHHEP) initiative. SHHEP is a collaboration across four DFID Research Programme Consortia (RPC) that undertake research and action on HIV and Sexual and Reproductive Health in resource poor contexts. Each consortium consists of 5 or more research, advocacy or service provider institutions from the south and the north working together over a five year period on critical areas of sexual and reproductive health. The essence of SHHEP is to share learning on research uptake and research engagement in Sexual and Reproductive Health, including HIV. The group has formulated a range of targeted mechanisms to communicate health research to different audiences and spearhead change, and were finalists for the British Medical Journal 2010 Getting Research into Practice (GRiP) prize.The papers in this special supplement focus on lesson learning on getting research into policy and practice. They highlight the range of methodologies and approaches researchers and communication specialists have used in different contexts to try to ensure research does not simply gather dust on library shelves but feeds into and is relevant to policy and practice in different contexts  and on a diversity of topic areas .The work reported in this supplement provides examples of approaches that have been tried and from which other researchers can learn. They demonstrate that getting research into policy and practice is complex, dynamic and multi-faceted; and a wide range of context and issue specific conceptual and practical approaches have to be used. I hope that the innovative approaches and promising ways forward, presented in these papers, will inspire and motivate others.Professor Christopher WhittyDirector Research and Evidence DivisionDepartment for International DevelopmentDr Sue KinnHead of Health ResearchDepartment for International Development The authors declare that they have no competing interests."}
+{"text": "The Pall Micro24 Bioreactor system is one of several microbioreactor systems that have been commercialised in recent years in response to the demand to reduce costs and shorten process development time lines.We have previously demonstrated that the Micro24 Bioreactor system can be integrated successfully into the later stages of cell line screening programmes and that the results correlate well with those from more conventional methods . FurtherThis work describes the use of the Micro24 Bioreactor system to identify improved process conditions for different cell lines and their subsequent validation in bioreactors.3.This system comprises 24 bioreactors (7 ml working volume) each capable of independent temperature, dissolved oxygen and pH control. The main limitation of the system is the lack of automation meaning that any feed additions or sample removal must be made manually and similarly, for mammalian cultures, upwards pH control is achieved by the manual addition of NaHCOEngineering characterisation studies carried out at UCL (data not shown) have shown how conditions within the individual Micro24 chambers compare with those in bioreactors and recent results also indicate that the selection of the Micro24 plate type is critical in ensuring good correlation with performance in traditional bioreactors.Within the Micro24 Bioreactor system cell cultures are carried out in presterilised polycarbonate mammalian cell culture cassettes which are inoculated manually in a laminar flow cabinet before sealing with Type A single use closures and incubation under experimental conditions.Chemically defined medium and feeds were used throughout this work. Unless otherwise stated standard experimental conditions were used. ). Viable cell numbers and viability were determined using a ViCell Cell Viability Analyser (Beckman Coulter) and antibody titres were determined using an Immage Immunochemistry System (Beckman Coulter).Typical process relevant factors that can be tested in the Micro24 include feed regime, pH, DO and temperature. The effects of these types of factors are best tested using a Design of Experiments (DoE) approach to assess the effects not only of different factors but also of the interactions between them. Such data can then be used to build predictive models of process performance to specify the appropriate operating conditions in larger scale bioreactors. We have already developed and are using a similar approach for microbial dAb processes.The data below shows examples of how we have used this system to identify improvements to platform processes for specific cell lines.In this experiment the effects of changes to the platform process pH and DO set points on the performance of a mAb producing cell line were assessed in the Micro24 using a DoE approach with different operating conditions in each well.This data demonstrated that although the dissolved oxygen level had little effect on viable cell numbers, titres and specific productivity, operating at a higher pH than the standard platform set point resulted in an increase in titre and in specific productivity. There was no significant interaction between the factors.The high pH process identified from the Micro24 was run in 2 litre bioreactors and compared to the standard platform process.At the high pH set point cell numbers during the later stages of the process were slightly reduced compared to the control and as in the Micro24 higher titres were produced under higher pH conditions. However, as in the Micro24 the greatest effect of increased pH was on specific productivity which in the bioreactors was increased by approximately 35% compared to the control.Similar results were achieved at the 50 litre scale for a different cell line running in the same platform process but producing a different molecule Figure . There wThe Micro24 can be used to investigate the effect of different feeding regimes on culture performance. We have already demonstrated that the effect of feed addition on culture performance in the Micro24 is similar to that in shake flasks ; the datOur previous work has demonstrated how the Micro24 system can be used for mammalian cell line selection  and the The validation of the Micro24 results in bioreactors suggests that the integration of this technology into mammalian process development could reduce significantly the numbers of bioreactors required to achieve process improvements which could result in reduced resource requirements and improved timelines."}
+{"text": "The meaning of correlated neural activity for the processing and representation of information in cortical networks is still not understood, but evidence for a pivotal role of correlations increases . Recent"}
+{"text": "Multiple sources of influenza surveillance data are becoming more available; however integration of these data streams for situational awareness of influenza activity is less explored.We applied multivariate time-series methods to sentinel outpatient and school absenteeism surveillance data in Hong Kong during 2004\u20132009. School absenteeism data and outpatient surveillance data experienced interruptions due to school holidays and changes in public health guidelines during the pandemic, including school closures and the establishment of special designated flu clinics, which in turn provided \u2018drop-in\u2019 fever counts surveillance data. A multivariate dynamic linear model was used to monitor influenza activity throughout epidemics based on all available data. The inferred level followed influenza activity closely at different times, while the inferred trend was less competent with low influenza activity. Correlations between inferred level and trend from the multivariate model and reference influenza activity, measured by the product of weekly laboratory influenza detection rates and weekly general practitioner influenza-like illness consultation rates, were calculated and compared with those from univariate models. Over the whole study period, there was a significantly higher correlation  for the inferred trend based on the multivariate model compared to other univariate models, while the inferred trend from the multivariate model performed as well as the best univariate model in the pre-pandemic and the pandemic period. The inferred trend and level from the multivariate model was able to match, if not outperform, the best univariate model albeit with missing data plus drop-in and drop-out of different surveillance data streams. An overall influenza index combining level and trend was constructed to demonstrate another potential use of the method.Our results demonstrate the potential use of multiple streams of influenza surveillance data to promote situational awareness about the level and trend of seasonal and pandemic influenza activity. Many public health agencies routinely monitor influenza virus activity to facilitate situational awareness of the degree of disease activity in the community During the 2009 influenza pandemic, situational awareness was hindered by the introduction of new \u2018drop-in\u2019 surveillance systems and potential changes in behavior in pre-existing systems The local Department of Health conducts influenza-like illness surveillance among a network of 50 private-sector sentinel general practitioners (GP) and 62 public-sector sentinel general outpatient clinics (GOPC) who report weekly proportion of outpatients fitting the surveillance definition of ILI  and trend (decreasing/stable/increasing) of the underlying influenza activity representing different phases of influenza epidemics.For each week since 2004, we estimated the latent level and trend, and calculated the overall influenza activity index based on all available GOPC, GP ILI, school absenteeism and DFC fever counts surveillance based on data available up to that week. The data along with the scaled inferred influenza level and trend from the dynamic linear model, and the reference influenza activity are shown in We fitted dynamic linear models to the individual surveillance data streams, and estimated the correlation of these individual models versus influenza activity. We compared this with the correlation between the multivariate models using all available data versus influenza activity . While tWe have demonstrated the use of a multivariate method to integrate information from multiple streams of influenza surveillance data to improve situational awareness of the current level of influenza activity, and how a combined use of both the inferred influenza level and trend or an integrated index that can be potentially used to indicate overall influenza activity currently. Our study showed the advantage of a multivariate model-based approach especially if some surveillance data streams are interrupted or supplemented by additional systems during certain critical periods such as the 2009 influenza pandemic. During the whole study period, the estimated influenza level from the multivariate model showed higher correlation with influenza activity and the estimated influenza trend stably reflected the change in influenza activity as good as the best individual surveillance data streams from which it was derived  & 2. In A potential caveat of the method is that historical data are needed to parameterize the model prior to estimation of the overall influenza activity. The statistical time series model may not be able to fully describe the evolution of an infectious disease such as influenza. In this study we did not try to optimize the parameters for combining the level and trend into the overall influenza index nor validate the index with respect to an objective function. The level or trend may have different importance in various contexts which can be easily adjusted according to specific purpose, and compared to the simple average there may be superior combinations of these two parameters to provide a single prospective estimate of the degree of influenza activity currently and in the short-term future. We used the product of laboratory influenza isolation rate and GP ILI rate as a proxy measure for the reference influenza activity, which may partly explain the high correlation between GP ILI and influenza activity during the pandemic with particularly high proportion of medical consultations due to influenza. While we have taken into account the elevated ILI consultations during the pandemic which may have affected the laboratory isolation rate, change in healthcare consultation behavior was not accounted for due to limited data.Text S1Description of the multivariate dynamic linear model.(DOC)Click here for additional data file.Text S2Example syntax for estimation of the latent level and trend by the multivariate dynamic linear model.(DOC)Click here for additional data file.Table S1Test of differences in correlations with influenza activity, between surveillance data and inferred influenza level from the multivariate models.(DOC)Click here for additional data file.Table S2Test of differences in correlations with changes in influenza activity, between surveillance data and inferred influenza level from the multivariate models.(DOC)Click here for additional data file."}
+{"text": "Bracovirus and IchnovirusTextbooks define viruses as infectious agents with nucleic acid genomes (RNA or DNA), which replicate inside living host cells to produce particles (virions) that can transfer the genome to other cells To appreciate the conceptual challenges PDVs present requires first an understanding of their life cycle. In wasps, PDVs persist in the germ line and somatic cells as an integrated provirus. Replication, in contrast, only occurs in pupal/adult stage females in the nuclei of specialized calyx cells that are located in the ovary . In the Recent studies show that BV genomes exhibit organizational and functional features unlike any other virus group, while also providing important insights into why the activity of PDVs differs between wasps and the hosts wasps parasitize So when did PDVs evolve? In the case of BVs, all associated wasps reside in a single family named the Braconidae and form a monophyletic assemblage named the microgastroid complex Insights into what BVs evolved from derive from comparing the conserved core genes of their proviral genomes to other viruses. This exercise reveals homologies with the core genes of another group called nudiviruses The organization of nudivirus genomes and the core genes they encode suggest three features of likely importance in the evolution of BVs into beneficial symbionts. First, nudiviruses package their genomes as a single circular dsDNA into virions, while integrating as a single large linear DNA into the genome of host cells Polydnaviridae because they both package multiple circular dsDNAs into virions and exhibit similar life cycles, albeit the former are associated with braconids and the latter are associated with wasps in another family named the Ichneumonidae BVs and ichnoviruses (IVs) were assigned to the Returning to the definition of what a virus is, PDVs clearly replicate inside living cells and produce particles that transfer genes to other cells. Similar to other families of large dsDNA viruses, like the Baculoviridae and Poxviridae, BV genomes also encode a conserved set of replication genes plus other virulence factors from diverse sources that vary among genera and species"}
+{"text": "The introduction of Highly Active Antiretroviral Therapy has transformed HIV-infection from an inevitably lethal disease to a chronic condition with a life expectancy comparable to that of people with diabetes mellitus.In recent years it has become evident that people living with HIV/AIDS have an increased risk of developing cardiovascular disease and it is expected that the prevalence of chronic kidney disease will rise accordingly. To investigate the prevalence of chronic kidney disease in patients with HIV we conducted a retrospective observational analysis using the clinical database of a large centre  in the urban area of Antwerp, Belgium. The prevalence of chronic kidney disease among HIV infected subjects was found to be 3.0%. The development of chronic kidney disease was associated with age above 50 years, lower CD4 cell counts and Caucasian origin. Screening for chronic renal disorders and prevention of evolution toward chronic renal failure is a crucial challenge in the management of people living with HIV/AIDS."}
+{"text": "Community Advisory Boards (CABS) have played an important role in ensuring community oversight of AIDS vaccine trials and are an accepted part of the ethical conduct of AIDS vaccine trials. China's political system limits community engagement in trial communities and wholesale application of western CAB approaches does not accomplish the intent of a CAB. We adapted the CAB concept to China's political system through a multi year process of research and pilot testing in collaboration with six provincial CDCs conducting AIDS prevention research studies.Using questionnaires developed by IAVI for a global CABS study, we carried out an assessment of existing CABS in six provinces in China. The questionnaire examined membership, process, and governance along with other aspects of CABS operations. The results were used to revise standard CABS guidelines developed by IAVI for use in Africa and India. The revised guidelines were pilot tested in three sites, in Yunnan, Guangxi, and Shanxi. In depth interviews were also conducted with CAB members and local CDCS.A revised version of Chinese CABS guidelines was published in October 2011 and publicized at China's AIDS Prevention Conference by China's AIDS Ethical Review Board and IAVI. The CABS guidelines are now being promoted as part of the ethical requirements for AIDS prevention clinical trial research by China's National Center for AIDS Prevention and Control.Developing and adapting ethical tools for ensuring community input and oversight of clinical trial research in China is necessary given China's political system. These newly adapted CABS guidelines provide a mechanism to accomplish the intention of a CAB even while different in form and governance from standard CABS elsewhere."}
+{"text": "The authors of guidelines provide 100 recommendations describing many intensively discussed issues. Among them is hepatotoxicity of PTU and limitation of PTU treatment mainly to the first trimester of pregnancy. Methimazole becomes first line ATD for patients with new onset of Graves\u2019 disease. Graves\u2019 orbitopathy (GO) is classified according to its clinical activity and severity. Deterioration of GO after radioactive iodine (RAI) treatment and beneficial effects of steroids to prevent RAI induced exacerbation of GO are described. All patients with subclinical thyrotoxicosis who are older than 65 years and those who are below age 65 and have risk factors or hyperthyroid symptoms should be treated. It is proposed to measure TSH receptor autoantibodies in pregnant women with a previous history of autoimmune thyroid disease. The information about thyroid ultrasonography with the colour-flow Doppler for the rapid differentiation between the two main types of amiodarone-induced thyrotoxicosis, and its help for accurate treatment of these conditions is provided."}
+{"text": "About 15 % of patients who have been undergone to a laparotomy may develope abdominal wall hernia and the risk increases with age. In last years the Laparoscopic treatment of ventral hernia (LVHR) is becoming increasingly widespread in surgical community thanks to the good outcomes of this technique . The aimBetween January 2001 and March 2013, 523 patients were admitted to the Specialistic Surgery Centers  and treated for abdominal wall hernia. Two groups (Open and Laparoscopic Repair), each one of 100 patients, with similar characteristics have been selected from these presents more advatages compared to Open procedures related to reduced global complications and hospital stay with better comfort of patients."}
+{"text": "It is now widely accepted that insects encode odor identity in terms of the stimulus specific rate patterning observed in the projection neurons of the antennal lobe (AL). Several studies have explored nonlinear dynamical frameworks in order to gain general insights into the mechanisms underlying the observed dynamical phenomena. The currently most popular framework is the heteroclinic orbit (HO) developed by Rabinovich and collaborators -3. This Despite its obvious appeal there has been little work on applying the HO framework to more detailed conductance based models of olfactory dynamics even though it is in principle possible to obtain HO dynamics from biologically plausible neurons . HoweverHere we describe an alternate nonlinear dynamical framework which provides an appealing account of both the origin and function of rate patterning dynamics. We start by analytically reducing a biologically plausible conductance based model of the AL to a quantitatively equivalent rate model and construct conditions such that the rate dynamics are well described by a single globally stable fixed point. We then straightforwardly describe the AL's response to an odor stimulus as rich transient trajectories between this stable baseline state and an odor specific fixed point. We show how this framework can account for a disinhibitory period observed immediately after the stimulus is removed, for the qualitative differences between the dynamics in the presence and the absence of odor and for the invariance of odor identity to both the duration and intensity of an odor stimulus, as reported in . We comp"}
+{"text": "Current cognitive models of social phobia converge on the view that negative imagery is a key factor in the development and maintenance of the disorder. Research to date has predominantly focussed on the detrimental impact of negative imagery on cognitive bias and anxiety symptoms, while the potential benefit of promoting positive imagery has been relatively unexplored. Emerging evidence suggests however that positive imagery could have multiple benefits such as improving positive affect, self-esteem and positive interpretation bias, and enhancing social performance. The present article defends the view that combining bias induction with a repeated practice in generating positive imagery in a cognitive bias modification procedure could represent a promising area for future research and clinical innovation in social anxiety disorder. People with social anxiety disorder (SAD) frequently report experiencing negative self-imagery of how they think they appear to others in feared social situations  may have favored the generation of observer perspective imagery. Encouraging the use of field perspective imagery  is likely to produce stronger effects on negative and positive emotions, and counteract the natural tendency among socially anxious individuals to imagine themselves from an observer perspective. A second caveat with regards to the methodology used is that it may be too challenging for individuals with clinical levels of social anxiety to recall and elaborate on a time when they had experienced a positive social situation. This possibility is supported by recent evidence showing that social anxiety is associated with an impairment in generating detailed imagery of past positive events  for people with high levels of social anxiety (Murphy et al., The present article defends the view that combining a repeated practice in generating positive imagery with a CBM-I intervention may be a helpful component in future treatment of SAD. A similar hypothesis has been suggested in the context of depression (Holmes et al., The effects of imagery-focussed CBM on depression have been tested using analog and clinical samples of depressed participants (Blackwell and Holmes, Lang et al.  addresseSAD is a highly prevalent condition that causes considerable distress and significant functional impairments (Kessler et al., The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Despite the huge progress in the understanding of the pathomechanism of thyroid orbitopathy (OT) done during recent years this extrathyroidal manifestation of Graves\u2019 disease still remains one of the most complex problems of clinical endocrinology. The outcome of the management is not satisfying neither for patient nor for physicians. Some likelihood of the improvement of the results may be expected from innovative treatment options basing on the progress in understanding of mechanisms of autoimmunity and inflammation. On the other hand an effort must be done for the progress in the existing treatment regimes.Glucocorticoids have been used in the treatment of severe OT for over 50 years but irrespectively of therapeutic regime any improvement in eye changes may be achieved only in ca. 70% of patients. Numerous schemes of glucocorticoid use should be validated, optimized and meet an individual approach as well as adhere to the local capabilities.The common adjuvant treatment with selenium in Graves\u2019 disease patients may prevent from a development of eye symptoms and possibly will improve the quality of life.The mode of management of hyperthyroidism has an influence on OT. Medical and surgical therapy seem not to deteriorate the course of OT while radioiodine therapy may worsen eye symptoms. OT patients at high risk should get the preventive glucocorticoid treatment.The access to a surgical treatment procedures as orbital decompression and rehabilitative surgery must be assured for OT patients and techniques of surgical procedures should be developed.The results of anticytokine therapy are promising and the progress in this field may be expected while the value of newly developed TSH receptor blocking molecules needs further observations.The frequency of circulating CD40(+) fibrocytes is markedly increased in patients with OT, suggesting that this receptor might represent a therapeutic target for OT.An increase in a local steroidogenesis documented within orbital tissues in an active phase of OT rises the idea of the use of 11\u03b2 hydroxysteroid dehydrogenase-1 inhibitors in OT patients. These drugs are under intensive clinical investigation for the treatment of type 2 diabetics.Since recommendations basing on EBM according to the pivotal problems of the management OT are still lacking, the system of care for OT patients should be based on centres of excellence with proper experience and multidisciplinary approach."}
+{"text": "DACS  was developed to design a HTS collection or focused libraries for the FMP Screening Unit. But the dramatically increase of unique compounds of one order of magnitude from less than 10 to around 30 to 40 million compounds currently and approximately hundred million compounds in the next years requires a reorganization and redevelopment of the storage and searching strategy. To manage such a massive amount of data a relational database for registration and normalization of vendor catalogs was developed. This database contains the highly redundant data of the vendor catalogs and is converted in a second step into the non-redundant Unique Structure Database which represents a data warehouse combining vendor data, structural descriptors and in-house classification tools including our earlier developed ADMET- and reactivity filters as well as our in-house fragment-based fingerprints used for library design tasks ["}
+{"text": "The current study by Won and colleagues concluded that patients undergoing revision ACL surgery have a greater incidence of significant varus alignment compared with patients undergoing primary ACL reconstruction. The authors also observed that this varus alignment was associated with meniscal pathology and degenerative changes of the knee. The report of varus alignment provides an interesting observation that goes a step beyond the findings of the Multi-center Anterior (C)ruciate Revision Study (MARS) , but leaThe strength of the manuscript is that it reminds us that varus malalignment is a potential variable to be mindful of. It also serves to warn surgeons they should be aware of possible failure of the graft, and continuing pain related to medial compartment degeneration. Won and colleagues\u2019 attention to detail in establishing an effective protocol for the long-leg films is important because standing long-leg radiographs are fickle in terms of being able to demonstrate consistently the true amount of coronal plane alignment.Kim and colleagues  reportedAnother MARS study  indicateWe need to perform a large prospective case-control study observing primary ACLs over a long period of time, and separately analyzing those who have initial varus with intraarticular pathology from patients who do not. We need to conduct followup analysis to determine whether the varus indeed increases the risk of ligament failure. Such a study should also observe the progression of osteoarthritis and secondary development of varus deformity so we could get a better picture of the natural history.Another study that would help fill in our current knowledge gap would be examining the existence of medial compartment osteoarthritis in an ACL deficient knee that has already had a failure of a primary ACL surgery. It should be determined, in the setting of a large randomized controlled trial, whether those patients who undergo a high tibial osteotomy at the same time as ACL revision surgery will fare better than those who have an ACL revision without an osteotomy.This should be a very well-defined study group with radiograph-based alignment protocol similar to the one used in the current study. How much varus is necessary to change the odds ratio for ACL revision alone? Is varus thrust indeed the only game changer? Will staging the stabilization and the realignment procedure provide the patient with a greater number of years of satisfactory function? These important questions remain unanswered."}
+{"text": "Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant, rare familial cancer syndrome in which affected individuals develop diffuse gastric cancer at a young age. Mutations in the E-cadherin gene (CDH1) have a 70% lifetime risk of becoming gastric cancer and women with the gene have a 20-40% risk of developing lobular breast cancer.This paper will report on a series of young adults who have undergone predictive genetic testing and been identified as carrying the CDH1 mutation known to be present in their family. The majority of these patients have been diagnosed with gastric cancer at their first screening gastroscopy.Individuals who are known to carry the mutation are provided with a personalised cancer risk management plan with the aim of reducing morbidity overwhelmed by the number of appointments they receive and by the variability of information given to them, as care often moves from and between several teams. A care pathway has been developed by the oncology/genetics nurse to ensure optimal communication between the genetics and oncology treatment team, to ensure the best outcome for the patients. The oncology/genetics nurse coordinator with her specialist knowledge of genetics plays a vital role in facilitating ongoing follow up of these individuals, coordinating screening, educating patients and their family on risk management strategies.This paper will provide a clinical update on this rare familial syndrome will describe the needs of patients and families affected by this condition and illustrate the contribution that expert nursing care makes to the outcomes of people affected by HDGC."}
+{"text": "SweTree Technologies is a plant and forest biotechnology company providing products and technologies to improve the productivity and performance properties of plants, wood and fiber for forestry and fiber related industries.Eucalyptus and Populus elite clones. Another crucial part of a practical tree biotechnology program is to test the GM trees with commercially interesting genes under field conditions. We have initiated field trials and plan to have over 35 different types of transgenic trees in field trials by the end of this year. These field experiments are performed by SweTree or in collaboration with academic partners. The importance and requirements for elite clone transformation and field trials will be discussed in the presentation.In the area of Biotech Trees, we have been testing and developing genes and biotech trees. Since 2002 we have successfully screened well over one thousand genes in our gene testing program. The program has been mainly directed towards increased growth, improved wood properties and stress tolerance. The current outcome of this program will be presented. The primary gene developing program is performed in hybrid aspen for which we have a very efficient transformation protocol. However for practical tree biotechnology the genes and DNA constructs have to be transformed into the best commercial clones. Therefore we have been setting up efficient transformation protocols for both"}
+{"text": "Atrial fibrillation (AF) is the most common arrhythmic complication in the postoperative period, occurring in about a third of patients undergoing coronary artery bypass graft surgery ,2. It isPharmacological interventions have been the mainstay of preventive therapy. Beta blockers have been shown to be the most effective preventive therapy and it is recommended now to continue or initiate beta blocker therapy for all patients in the perioperative period . AmiodarAtrial pacing is an attractive non-pharmacological intervention for the prevention of atrial fibrillation. Pacing in the postoperative period is easy to implement since it is only required for a short period and can therefore be performed using epicardial temporary pacing wires placed by the surgeon. The mechanisms by which atrial pacing is postulated to reduce the incidence of atrial fibrillation include reduction of bradycardia induced dispersion of atrial repolarization and overdrive suppression of atrial premature beats. Dual site atrial or biatrial pacing may result in additional benefit by promoting more synchronised atrial depolarization which results in reduced dispersion of atrial refractoriness and by altered atrial activation patterns that may prevent the development of intra-atrial reentry . ProphylIn this issue of the journal, Chavan et al  report o"}
+{"text": "Glyceryl trinitrate is a substance that causes vasodilation by donation of nitric oxide which causes relaxation of the endothelium of blood vessel walls. The vasodilatory effect of this substance has been known since 1870 and it has been used extensively in the treatment of angina via transdermal patches, sublingual tablets and sprays. Studies involving normal vasculature as well as diseased vascular states have been promising in terms of demonstrably consistent and significant vasodilatory effects on both systemic and peripheral systems. Podiatric application for this pharmacologic intervention seems to have received little attention in the literature to date. Its efficacy in equine treatment of laminitis, an ischaemic condition of the horses hoof has been well established and researched. It has been applied to other clinical problems involving perfusion of the extremities, such as treatment of inability to achieve penile erection and use in treatment of anal fissures. A literature search has produced information on this drug which suggests potential for greater application in clinical podiatry. This includes positive effects in digital perfusion, which holds promise for wound healing and shows potential for reducing amputations associated with peripheral vascular disease (PVD). This novel therapy has the potential to be useful in cases with borderline vascular supply that require a boost to perfusion to trigger the healing process and/-or relieve other symptoms of ischaemia. It has also been found to be of assistance in the management of painful diabetic neuropathy (PND). This finding is of particular interest as an adjunct to treatment for the prevalent and difficult clinical challenge of PND. The literature regarding its use in musculotendinous applications such as for Achilles tendinopathy will also be covered in this review. Potential issues with this drug including side effects and tolerance will be addressed. Further study of this treatment modality would be beneficial in terms of determining specific indications and limitations of its use, particularly for vascular insufficiency of the feet and healing of foot ulceration."}
+{"text": "Flexible bell margins are characteristic components of rowing medusan morphologies and are expected to contribute towards their high propulsive efficiency. However, the mechanistic basis of thrust augmentation by flexible propulsors remained unresolved, so the impact of bell margin flexibility on medusan swimming has also remained unresolved. We used biomimetic robotic jellyfish vehicles to elucidate that propulsive thrust enhancement by flexible medusan bell margins relies upon fluid dynamic interactions between entrained flows at the inflexion point of the exumbrella and flows expelled from under the bell. Coalescence of flows from these two regions resulted in enhanced fluid circulation and, therefore, thrust augmentation for flexible margins of both medusan vehicles and living medusae. Using particle image velocimetry (PIV) data we estimated pressure fields to demonstrate a mechanistic basis of enhanced flows associated with the flexible bell margin. Performance of vehicles with flexible margins was further enhanced by vortex interactions that occur during bell expansion. Hydrodynamic and performance similarities between robotic vehicles and live animals demonstrated that the propulsive advantages of flexible margins found in nature can be emulated by human-engineered propulsors. Although medusae are simple animal models for description of this process, these results may contribute towards understanding the performance of flexible margins among other animal lineages. Medusae are thought to be the first metazoans to evolve muscular swimming. The simplicity yet functionality of the biomechanics of their swimming make them an ideal organismal model for studying fundamental mechanisms of animal propulsion. Many medusan species swim using rowing propulsion Existing literature provides a conflicting picture of the potential interactions between propulsor flexibility and swimming thrust production. Empirical An important reason for the absence of design criteria guiding application of flexible propulsor tips or margins is that, despite an extensive body of work on flexible propulsors, the mechanistic basis for thrust augmentation by flexible propulsor margins remains unclear A recently developed robotic jellyfish vehicle  has provOur approach to determining the mechanistic basis of thrust augmentation by flexible propulsor margins was to compare propulsion by robotic jellyfish vehicles with and without flexible bell margins to each other and to live medusae . With thAurelia aurita. The other was modified to represent the Cyanea capillata morphology by excising portions of the bell to form gaps along the bell margin  to quantify vehicle kinematics as well as fluid motions x and y coordinates of the apex of the vehicle bell and the tips of the bell margin over time. Swimming speed was calculated from the change in the position of the apex over time ash/d where h represents bell height and d represents bell diameter.Swimming kinematics were quantified by using ImageJ software (NIH) to track the u is the Eulerian velocity field.Pressure field data was inferred from the measured velocity fields by numerically integrating the inviscid Navier-Stokes equation, or Euler equation:u. The pressure term was then determined to within a constant of integration by integrating The material acceleration term To reduce errors in the numerical integration of the measured velocity data, the procedure of Liu and Katz kt and subsequently advected to new positions kt+1. The initial velocity of each fluid particle is given by the measured DPIV velocity field at time kt . The velocity of each fluid particle at time kt+1 depends on the measured DPIV velocity field at time kt+1 and on the position of the fluid particle at the same instant in time. To determine the position of each fluid particle in the flow at time kt+1, we defined an advection velocity field in which the fluid particles are carried. The advection velocity field was taken to be the average of two successive DPIV velocity fields:ua was assigned to the first time instant kt by the present convention. The positions of the advected data grid points at time kt+1 are therefore estimated asi and j are unit vectors in the x- and y-directions, respectively. The material acceleration was then estimated asThe input to the version of the code used presently (kindly provided by X. Liu) took as input a time series of DPIV data on a 128\u00d7128 grid. Preprocessing of the DPIV data was completed in MATLAB to compute the material acceleration As a check of the dependence of the results on viscous stresses, which are neglected in The output of the code was a time series of pressure fields with scalar pressure computed at each of the 128\u00d7128 nodes of the corresponding DPIV fields.Live medusae originated from cultured collections of the New England Aquarium, Boston, MA. Video and DPIV methods were the same for both live animals and medusan vehicles except that the live medusae were video recorded in filtered seawater.Aurelia and Cyanea vehicles. While we did not treat the two vehicles as replicates, because of their different bell configurations, the flap and no-flap versions of each do provide repeatable validation of the effects of a flexible propulsor on the fluid interactions and swimming performance of the vehicles. Means and variability estimates on figures with error bars were calculated by averaging over three consecutive swimming cycles.Due to the intensive effort involved in manual manufacturing of robotic vehicles we were limited in terms of number of the Aurelia aurita and Cyanea capillata. The proficiency of swimming was quantified as the diameter-normalized swimming speed to account for differences in size between the live and robotic jellyfish, U/D where U is medusa velocity and D is relaxed bell diameter Cyanea flap version was less than that of both Aurelia versions (flap and no-flap).Biomimetic robotic jellyfish vehicles closely replicated the morphology  and apprAurelia robot during bell contraction demonstrates how the flexible margin contributed to the differences we observed in wake circulation and swimming performance. During bell contraction there were two sources of fluid momentum that contributed to the starting vortex circulation, the flow that was expelled, or pushed, from the subumbrellar volume and the flow that was entrained, or pulled, from outside the bell by the contracting bell margin  was strongly related to the distance between the tip of the bell margin and the inflexion point . Furthermore, the enhanced performance was due to both thrust augmentation during bell contraction and to more optimal spacing between consecutive starting and stopping vortex rings during bell expansion. The strong resemblance of vorticity patterns generated by the robotic vehicles with those of living medusae supports the notion that the flexible bell margins of medusae function to enhance thrust similarly to the flaps of the robotic vehicles. These observations enable us to suggest some mechanisms by which thrust augmentation by flexible propulsors may guide future studies on this topic.The utilization of robotic vehicles to examine biological propulsion has provided insight into just how important flexible propulsors are for some swimming animals. These vehicles, in combination with the simple body plan of medusae, have also enabled us to visualize the structural differences in the fluid interactions of flexible and rigid propulsors. Visualizations are necessary to begin to understand the mechanistic basis of the enhancement in propulsion provided by flexible propulsors and begin applying these principles more generally. To summarize what can be taken away from these more or less preliminary observations of propulsion by robotic jellyfish, we found that flexibility significantly enhances the swimming performance of both the robotic vehicles examined (Much of the performance differences between the flap and no-flap vehicles can be attributed to the higher vortex circulation generated by flexible bell margins during bell contraction. Higher circulation is expected to augment performance because thrust production of a propulsor is proportional to the circulation generated at the propulsor margin Rather than the previously reported explanations, we suggest that increased circulation characterizing flexible bell margins was more likely due to unique hydrodynamic forces generated by bending at the inflexion point connecting the flexible margin to the more rigid actuating structure of the vehicle's bell. During bell contraction, a low pressure region extended along the exumbrellar surface from the bell margin to the inflexion point of the flap vehicles. This low pressure region was larger and lower in magnitude in the flap vehicles than the pressure along the bell margin of the no-flap vehicles. Consequently, entrained flow in this low pressure region at the inflexion point initiated vortex formation and merged with flow expelled from the inside the bell at the margin edge. The larger volume and velocity of this flow is directly related to the low pressure field and resulted in larger starting vortex formation at the bell margins, and hence, greater overall thrust production by vehicles with flexible margins. Although we have focused on empirical visualization and quantification of fluid flows surrounding vehicle margins, these results are consistent with computational fluid dynamic models describing pressure gradients surrounding swimming bells of oblate medusae. Swimming by oblate medusae generates pressure differences at the bell margin due to formation of a high pressure region within the medusa bell and a lower pressure region outside the bell margin at the region of greatest bell displacement Aurelia aurita are consistent with the proposed mechanism by which flexible margins enhance swimming performance. Other mechanisms likely contribute to this simple pressure mechanism such as the angular motions associated with flexible flapping which may facilitate vortex formation These observations lead us to suggest that one way that flexible propulsors enhance performance of swimming jellyfish is by intensifying the low pressure region associated with the propulsor thereby increasing fluid flow and therefore overall thrust . The relIn addition to enhanced thrust generated during bell contraction, performance of the flap vehicles was also better during bell expansion. Vortex interactions during bell expansion appear to largely influence the overall swimming performance of the vehicles. The collision of the stopping vortex of the no-flap vehicle with the oppositely spinning starting vortex cancelled out the overall circulation in the wake and stopped the vehicle's forward progress. This observation suggests two things, first, that interactions between starting and stopping vortices play important roles in determining the medusan swimming performance. Consequently, adequate spacing of these vortices by propulsor kinematics appears to be essential for swimming. Second, the flexible propulsor spaced the vortices more optimally than the rigid propulsor. By increasing the spacing between the two vortices, the starting and stopping vortices did not cancel each other out and the circulation in the wake dissipated slowly due to viscous dissipation. Consequently, the flap vehicles continued their forward progression during bell expansion. Numerical simulations of other flexible propulsors support the notion that flexibility increases spacing between shed vortex rings by increasing the downstream advection of the vortices The absence of complicating fluid interactions, such as with additional fins or appendages, makes the simple morphologies of medusae useful for exploration of essential fluid interactions between a propulsor margin and surrounding fluids. Despite their simplicity, the fluid mechanical basis of enhanced vortex production by flexible medusan margins may have wider application to other biological propulsors. The suitability of the medusan bell margin model for comparison with other flexible propulsors is influenced by the extent to which a propulsor margin's bending creates an inflexion point near the margin. A variety of biological propulsors such as wings and fins fit these conditions and fundamental relationships between actuator force, margin dimensions, and flexural stiffness distributions may be important factors influencing the role that flexible margins play in propulsive force generation by propulsors of both natural and man-made design. A more full understanding of these interactions will allow us to appreciate the means by which animals convert the energetic liability that tip vortices present for fixed wing aircraft"}
+{"text": "Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-V) as a disturbance in attention and awareness according to several criteria  and the fact that the cytokine response can be confounded by many factors   is protective for the development of delirium while genetic polymorphisms in the receptor DRD2 and dopamine transporter genes, were associated with delirium   when nervous system damage occurs as a result of cerebral damage  has been reported to regulate differentiation of neural progenitor cells  and butyrylcholinesterase (BuChE) are involved in the production of inflammatory cytokines, and are hypothesized to play a role in PD development through this mechanism. One study found significantly decreased activity of these enzymes both preoperatively and postoperatively in patients experiencing PD (Cerejeira et al., The pathogenesis of PD is still poorly understood. Further elucidation and refinement of biomarkers to track the risk and progression of this disorder would help in the identification and treatment of patients at risk for this devastating disorder. Future research should focus on both identifying serum markers of delirium and understanding the genetic basis behind these processes. Hopefully, these efforts will make important strides in improving outcomes of patients experiencing delirium.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The trend towards universal access for HIV prevention and treatment that was initiated at the beginning of the 21st century  has been threatened by the 2008\u20139 economic crisis which currently translates in a fiscal crisis for most developed countries . Other advances such as the drastic drop in ARV drug prices are also threatened . The presentation will discuss the negative consequences of slowing down and delaying universal access on macro-economic growth in the most affected countries and suggest alternative sources of funding such as the financial transaction tax recently introduced by the French Parliament."}
+{"text": "Following SCI activated ependymal cells generate progeny cells which migrate to the injury site but fail to produce the appropriate type of cells in sufficient number to limit the damage, rendering this physiological response mainly ineffective. Research is now focusing on the manipulation of ependymal cells to produce cells of the oligodendrocyte lineage which are primarily lost in such a situation leading to secondary neuronal degeneration. Thus, there is a need for a more focused approach to understand the molecular properties of adult ependymal cells in greater detail and develop effective strategies for guiding their response during SCI.Spinal cord injury (SCI) is a major health burden and currently there is no effective medical intervention. Research performed over the last decade revealed that cells surrounding the central canal of the adult spinal cord and forming the ependymal layer acquire stem cell properties either  Neural stem cells (NSCs) are specialized progenitor cells that can self-renew and generate both neurons and glia in the central nervous system (CNS). The first isolation of NSCs from adult brain lunched a new field of studies in neuroscience  of the forebrain  are produced from OL progenitors (OLPs) scattered throughout the parenchyma Miller, . SeveralWhile all NSCs in the SVZ of the forebrain express the stem cell markers Nestin, Sox2 and GFAP, in the spinal cord only dorsally situated ependymal cells express Nestin/GFAP, while Sox2 is expressed in all ependymal cells . It is also intriguing that the Gata3 gene has never been found to be expressed in any CNS progenitors but only in some differentiated neurons. In the spinal cord, Gata3 is expressed in V2b interneurons and its expression is regulated by Notch signaling , an agent that promotes axonal regrowth, possibly by recruiting myelinating OLs [reviewed by Weishaupt et al. ]. More rIn parallel to pharmacological manipulation of specific type of cells to limit functional impairment, the modulation of endogenously recruited ependymal-derived cells toward the OL lineage either using genetic engineering or by pharmacological means has not yet been reported. The fast-growing knowledge on glial cell specification during embryonic development should aid in this direction. For instance, the study of the regulation of the expression of the transcription factor OLIG2 in adult spinal cord could prove very useful in this regard. OLIG2 is not expressed in ependymal cells but only in OLPs scattered throughout the parenchyma (Meletis et al., In summary, several studies on the properties and behavior of ependymal cells in models of SCI have converged on to a number of findings that could pave the way for more effective therapies. Of major importance is the recruitment of a large number of ependymal-derived cells at the injury site while at the same time maintaining the ontogeny of the canal. Equally important is the fact that the astrocytes produced are positioned in the center of the glial scar opening the way for a more targeted approach to manipulate the fate of activated ependymal cells. Crucial in these efforts is to develop strategies for initiating remyelination at the injury site by manipulating the fate of cells produced from activated central canal stem cells. Forcing these cells to initiate a pro-oligogenic pathway of glial specification should be at the center of future experimentation. Such effort should be aided through combined approaches using knowledge from embryonic development and cellular responses following tissue damage in SCI conditions. It is likely that in the next few years we will be confronted with exciting developments that will open the way for clinical trials to treat SCI.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Detrended fluctuations analysis (DFA)  is a tecWe derived analytical formulations for the bias and variance of the error committed when using the scaling exponent obtained by DFA on a given time-series to predict the scaling exponent of the same time-series but shifted by one sample . These results make it possible to define a Kalman filter for tracking fluctuations in scaling exponents over a longer time scale. Estimates for the measurement noise of the filter are obtained by pooling DFA estimates of the signal across a small number of time shifts. Robust estimates of the state vector are obtained by augmenting the filter with a smoothing procedure.Simulation results with surrogate time series demonstrate that this technique makes it possible to accurately recover changing scaling exponents even in the presence of rapid fluctuations (see Figure"}
+{"text": "Since mid 2011 the tragedy unfolding across the Horn of Africa following prolonged drought in the region has been a major focus for international relief operations and emergency aid. However, the most effective strategies for mitigating the effects of the drought have not been given sufficient media coverage or discussed critically enough in the public arena. Instead, while important and necessary, the focus has largely remained on emotive pleas for increased aid. This unfortunately, detracts from a considered discourse on the most effective interventions in the current circumstances and reduces scrutiny on performance of the primary agencies and bodies responsible for coordinating the relief effort. The authors present a personal perspective having recently returned from the Dadaab refugee camps where much of the relief effort has focused. The Dadaab refugee camps, located in the North Eastern Province of Kenya approximately 60 miles from the Somalia/Kenya border and about 320 miles from the capital, Nairobi highlight concerns around the delivery and distribution of relief and aid. The three original camps, Ifo, Dagahaley and Hagadera were established in the early nineties following the onset of inter-clan conflict in Somalia. The vast majority of refugees present are Somalis from Central and Southern regions of Somalia. While the populations in the camps remained relatively stable from 1994 to December 2006, this year in particular has seen hugely increased numbers of refugees arriving over the border as a result of the drought. With over 160,000 new refugees having arrived\u00a0in the first eleven months of\u00a02011 alone, the camp complex now (as of November 2011)\u00a0holds in excess of 460,000 refugees in total according to UNHCR - the primary agency mandated with coordinating relief activity within the camps.Using a combination of focus group discussions and one to one interviews with refugees and members of the host community and following detailed discussions of comprehensive assessments carried out by NGO service providers within and outside the camps the authors conducted a rapid needs assessment over July 2011. The following discussion draws from those results as well as from more recent assessments and developments in the months since.The paediatric age group continues to be the most badly affected in terms of severe acute malnutrition and global acute malnutrition rates amongst newly arriving refugees.Another major area of concern in Dadaab is equity in the distribution of relief aid and service provision within refugee camps and adjacent areas. In the surrounding districts of Dadaab, Liboi and Fafi, the Host Community has also been suffering the consequences of the same drought plaguing the rest of the Horn. They, however, do not have equal access to services and relief routinely available to refugees. Healthcare services in the region exemplify these inequalities in aid provision. The three main camps are serviced by three hospitals with a total of 320 inpatient beds, 3 operating theatres, specialist outpatient services manned by doctors and visiting specialists. A structured referral system for specialized surgery and medical care in Garissa-the provincial capital, and Nairobi is also available to refugees. The Host Community which is approximately 150,000 strong and of a similar ethnic background to the majority of refugees only have access to outpatient health facilities within the camps. The only in-patient hospital service the Host Community has access to is a 30 bed district hospital (open to both the Host and refugee community) with 1 operating theatre. The most senior routine medical staff providing clinical care at this hospital are 2 clinical officers . A single Kenya Red Cross ambulance serves all three districts. These disparities are mirrored across other service sectors with old and new refugees having access to free food rations, water, sanitation and housing in an impoverished area where host communities are not routinely provided any of these services by the government or the NGOs.A perversely functioning artificial city-state has thus developed supported entirely by international Non- Governmental Organizations (NGOs) where older refugee camp residents after years of free utilities and services have developed successful businesses and even rent out their refugee shelters to newer arrivals or Host Community members and who can undercut any Host Community business with lower overheads. Host Community Kenyans often register as refugees themselves in order to avail improved healthcare services and obtain rations when necessary. A jointly commissioned report by the Danish and Norwegian Embassies and the Government of Kenya in 2010 estimated that at least 40,500  host community members hold refugee ration cards.The long term key to resolving the situation in Dadaab lies in recognizing that pastoralist Somalis have ancient patterns of movement which involve crossing to and fro across the artificial line that divides Kenya and Somalia and that services designed to cater for this group should facilitate and take account of their nomadic lifestyle. NGOs, local or otherwise able to operate on both sides of the border should thus be supported in their efforts to provide this service. UNHCR itself should be encouraged to view the situation holistically and look beyond its remit of catering specifically to refugee needs by partnering with organizations with a wider mandate that includes the Host Community. This will ensure that Somalis that cross into the territory of Kenya are both willing and able to cross back into bordering Somali provinces and obtain equitably provided services there as well. The authors would like to thank the team at Doctors WorldWide in Kenya for facilitating the field assignment to the Dadaab camps in July 2011. N/A The authors have declared that no competing interests exist."}
+{"text": "Plants are constantly exposed to potential pathogens in their environment. The intimate associations involved in plant-microbe interactions have influenced the evolution of a multi-faceted surveillance system to detect and respond to both the presence of microbes at the cell surface as well as the presence of pathogenic effectors inside the cell. Here, we bring together 11 reviews that discuss current concepts in plant innate immunity with a focus on protein biology and proteomics  is closely connected to defense responses, both as a large intracellular store of calcium and as the site of immune receptor biogenesis. Eichmann and Sch\u00e4fer  review tAdapted pathogens must evade or suppress host immune responses in order to colonize tissues and cause disease, and they deploy numerous effector proteins to secure this objective. Wirthmueller and Banfield  focus onProteomic methods have facilitated the identification of key players involved in plant immunity and have shed light on the significance of post-translational modifications and protein interactions in the regulation and transduction of immune signaling. In future, the use of large-scale and highly sensitive quantitative proteomics in combination with emerging transcriptomic and imaging technologies will play a central role in uncovering the kinetics of immune signaling pathways, which currently remains a challenge. This is an exciting time to be involved in plant immunity research and we hope that this collection of reviews will inform and inspire our readers."}
+{"text": "Pharmaceutical industry consolidation and overall research downsizing threatens the ability of companies to benefit from their previous investments in translational research as key leaders with the most knowledge of the successful use of biomarkers and translational pharmacology models are laid off or accept their severance packages. Two recently published books may help to preserve this type of knowledge but much of this type of information is not in the public domain. Here we propose the creation of a translational medicine knowledge repository where companies can submit their translational research data and access similar data from other companies in a precompetitive environment. This searchable repository would become an invaluable resource for translational scientists and drug developers that could speed and reduce the cost of new drug development. There is a well known problem in big pharma, low productivity despite high costs. It has become clear that the pharmaceutical industry's business model is broken . ResearcCompanies have consolidated through mergers and acquisitions resulting in lay-offs for thousands of researchers and the closing of hundreds of laboratories to avoid perceived redundancies, focus on what is considered to be more productive or lucrative therapeutic areas and save costs . Just coTranslational Medicine and Drug Discovery was to provide a guidebook for current and future translational medicine scientists and to clearly describe successful strategies for early drug development that utilize biomarkers and state of the art technologies. This book partially addresses the issue described above. It includes sections and chapters describing successful translational strategies for early drug development, principles of biomarker qualification and utilization in drug discovery and development, in-depth examples of translational research in six different therapeutic areas, translational imaging technologies, modeling and simulation and examples of pre-competitive collaborations between companies in many areas including biomarkers and drug safety [Biomarkers in Drug Development, also attempts to serve as a \"handbook of practice, application and strategy\" for translational researchers [One of the reasons Littman and Krishna decided to create a textbook entitled g safety . Anotherearchers . HoweverWe believe that companies and other institutions involved in translational drug research need to foster the discipline of translational medicine, maintain a knowledge base of their work and, when it is not proprietary, share that knowledge through publication and pre-competitive collaborations. It is often easier to find the published results of translational research performed by others than it is to find the unpublished results of translational research done within your own institution, especially if the drug projects the research supported were discontinued. For this reason we advocate the creation of a searchable knowledge repository for human translational research. This database could be maintained by a consortium of drug companies that voluntarily submit data and it would include human biomarker data, translatable human pharmacology models and other types of clinical methods that have been used in humans to measure drug responses. A structured database like this could be initially populated by data from failed drug projects with no significant loss of competitive advantage to contributing companies and institutions. Also, time is not on our side. The opportunities to capture this type of information decreases almost monthly as companies continue to reorganize, downsize and consolidate. It can only happen if those involved in these projects are still employed and have access to their companies' data.Imagine the benefits if this human translational medicine database existed today and could be searched by drug target, pathway, biomarker, disease, therapeutic area, challenge agent and translational pharmacology model name or description. It would become the first place to look when developing a translational research plan for a new drug project. It could potentially prevent reinventing proven clinical methods and replicating past biomarker and human model qualification efforts. Often there are multiple choices for achieving proof of mechanism for new drugs and this database would simplify the choice when an acceptable existing method or biomarker can be easily found. Use of the database could also translate into reduced costs and reduced time for drug development and enable the comparison of results from newer drugs with those from past drug projects. These comparisons will also aid decision-making based on the data from existing projects compared to older failed or successful projects. We urge companies to strongly consider adopting this recommendation and finding a home for the database perhaps under the auspices of an existing consortium such as The Biomarker Consortium managed by the Foundation for the National Institutes of Health (FNIH) ."}
+{"text": "Journal of the American Heart Association (JAHA), the American Heart Association's new Open Access journal. The Scientific Publishing Committee created JAHA to align the American Heart Association with recent trends in the publishing industry as readers have moved away from the print version of journals and increasingly seek rapid electronic access to scientific articles. In addition, JAHA was conceived as a novel publication forum to represent the collective interests of the 16 Scientific Councils .6 This paper is important because of the need for more comparative effectiveness research to guide the management of peripheral arterial disease and the importance of publishing both positive and negative studies. Fonarow et al showed that the National Institutes of Health Stroke Scale (NIHSS) provides strong prognostic information about 30-day mortality risk in Medicare beneficiaries with acute ischemic stroke.7 The forthcoming editorial by Dr Edward Jauch, Chair of the American Heart Association Stroke Council, explains how these findings may be used to better evaluate the performance of centers that manage patients with ischemic stroke.8 Finally, Barkoudah et al provide an interesting analysis of published clinical trials in patients with Type 2 diabetes mellitus providing new information about the increasingly recognized links between renal disease and cardiovascular mortality.9Our launch includes a number of outstanding papers that exemplify our goal to publish a broad range of cardiovascular science. A translational study by Ammirati et al links a specific T-lymphocyte subset to the extent of atherosclerosis in human subjects and a murine dyslipidemia model.JAHA. The editors believe that the open access format represents the future of scientific publishing and we are excited and honored to oversee the American Heart Association's first open access journal. We look forward to working with our authors to speed the dissemination of high-quality science to our readers with the ultimate goal of increasing our understanding of the underlying mechanisms and improving the management of patients with cardiovascular disease and stroke.Our first articles and editorials demonstrate our commitment to publish a wide range of cardiovascular science in"}
+{"text": "Regulatory guidelines for assessing the safety of new food crops developed using biotechnology were published in the early 1990s, before the introduction of genetically modified (GM) crops. Many GM crops are now widely adopted as 77% of global soybean and 26% of maize production is from GM varieties. The early safety assessment guidelines seem to work as there are no proven cases of harm from these products. The greatest potential risk of food allergy would be the transfer of a gene encoding an allergen or protein sufficiently identical to an allergen to a different food crop so that unexpected reactions might occur upon ingestion. These risks can be evaluated using sera from subjects allergic to the source or with a sequence matched to an allergen based on FASTA or BLASTP. Some potential risk is also possible due to de novo sensitization as nearly every food may cause occasional allergies, yet only a few foods and proteins present great risk. The current paradigm considers stability of the protein in pepsin under fixed conditions, abundance of the protein in foods and the potential impact of heating and processing, features common to some major allergens. Those methods are not fully predictive and will likely be improved through experience. However, proposed revisions by the European Food Safety Authority (EFSA) as well as demands from some regulators to include the use of short-amino acid sequence matches, animal models and evaluation of potential changes in endogenous allergen expression using proteomics approaches could reduce the effectiveness of the assessment. The value of new tests should be rigorously tested. It is clear that absolute safety is not possible and that demands for these tests have never been applied to new crop varieties derived through inter-specific hybridization, mutagenesis or the introduction of a whole new food crop."}
+{"text": "Jim McCambridge and colleagues analyze industry submissions to a Scottish Government consultation on whole-population approaches to alcohol policy. We examine how research evidence is used in alcohol industry submissions made to a Scottish Government consultation in 2008 to advocate policies in line with their commercial interests.Industry actors consistently oppose the approaches found in research to be most likely to be effective at a population level without actually engaging with the research literature in any depth.Strong evidence is misrepresented and weak evidence is promoted. Unsubstantiated claims are made about the adverse effects of unfavoured policy proposals and advocacy of policies favoured by industry is not supported by the presentation of evidence.The potential for corporations with vested interests to interfere with the evaluation of scientific evidence by policy makers needs to be restricted for effective policies to be designed.Studies of the nature of alcohol industry and other corporate influences on public policies can be informed by work already conducted on the tobacco industry.Like tobacco, alcohol is responsible for approximately 4% of the global burden of disease Alcohol industry actors, defined as all those involved with the production, supply, or sale of alcohol We examine formal submissions to the Scottish Government's 2008 consultation on \u201cChanging Scotland's relationship with alcohol\" We retrieved 27 separate submissions by industry actors made during the public consultation process from the Scottish Government's website . We extrThe views articulated on the nature of the alcohol problem facing Scottish society and appropriate policy responses are consistent across submissions. This position is encapsulated in the Executive Summary produced by the Wine and Spirit Trade Association (WSTA) Commitments to the use of evidence in policy making are often articulated. For example, the Portman Group . Pre\u2013post comparison of 335 antisocial behaviour incidents in August to 196 in February yielded an overall reduction in antisocial behaviour incidents described as 42%. A decrease in alcohol-related litter at the skate park from 21 bottles and 86 cans on the first weekend of the project to 1 bottle and 8 cans on the final weekend produced a 92% decrease (the time periods differ from previously cited outcome measure).A community partnership in the small market town of St.Neots in Cambridgeshire was widely cited as a model initiative, for example being described as successful or effective by three of the four main supermarkets. The WSTA provided a detailed account of the initiative and evaluation data provided by the local police and trading standards officers. The project \u201caimed to improve recognition amongst enforcement authorities and the wider community that retailers are in fact often the victims of attempted under-age purchasing and should be seen as the front line of enforcement rather than the cause of the problem\" [WSTA  pages 34The attention-grabbing percentage decreases are provided as evidence of benefits, and cited elsewhere, for example by SAB-Miller [paragraph 18 in The submission documents contain a number of unsubstantiated claims about adverse, unintended consequences of the proposals. These claims are frequently repeated and are by their nature difficult to evaluate. ASDA Sainsbury's Portman Group SBPA WSTA SAB-Miller Industry actors present targeted harm reduction measures as the preferred alternative to the whole population approach. The latter is presented as being too simplistic and blunt an instrument. This is a false dichotomy, as these approaches are complementary and the actual evidence in favour of some targeted measures ASDA Diageo Portman Group SAB-Miller Tesco The policy preferences of industry actors, with the interesting exception of greater law enforcement, are for policies such as industry self-regulation, public information, and education, which are the least likely to be effective There are few studies of alcohol industry documents in the public domain, with the exception of investigation of ICAP Investigations of the strategies of alcohol industry actors may benefit from comparisons with other industries, and particularly with the tobacco industry. Access to internal tobacco industry documents offers researchers extensive knowledge of the political goals, strategies, and tactics of transnational tobacco companies In addition to co-ownership of alcohol and tobacco corporations Click here for additional data file.Text S2Twenty-seven alcohol industry submissions.(DOCX)Click here for additional data file.Text S3All sources cited in industry documents.(DOCX)Click here for additional data file."}
+{"text": "The Australian government has announced a major program of reform with the move to primary maternity care, a program of change that appears to be at odds with current general public perceptions regarding how maternity care is delivered.A critical discourse analysis of articles published in 'The Age', a newspaper with national distribution, subsequent to the release of the discussion paper by the Australian Government in 2008 was undertaken. The purpose was to identify how Australian maternity services are portrayed and what purpose is served by this representation to the general public.Findings from this critical discourse analysis revealed that Australian maternity services are being portrayed to the general public as an inflexible outdated service struggling to meets the needs of pregnant women and in desperate need of reform. The style of reporting employed in this newspaper involved presenting to the reader the range of expert opinion relevant to each topic, frequently involving polarised positions of the experts on the issue.The general public are presented with a conflict, caught between the need for changes that come with the primary maternity model of care and fear that these change will undermine safe standards. The discourse; 'Australia is one of the safest countries in which to give birth or be born, what is must be best', represents the situation where despite major deficiencies in the system the general public may be too fearful of the consequences to consider a move away from reliance on traditional medical-led maternity care. The Australian government has announced a major program of reform with the move to primary maternity care in line with the recommendations of the national review of maternity services released in 2009. The reform represents a program of change that appears to be at odds with current general public perceptions regarding how maternity care is delivered. Primary maternity services offer women continuity of primary carer with a midwife or general practitioner, reserving obstetric services for only those in clinical need ,2. AustrAlthough many women expect childbirth to be a potentially non-affirming event steeped in pain and fear , giving Many women know little about maternity care prior to becoming pregnant for the first time and are guided by the advice of health professionals, family and friends or the media when choosing the maternity care that best suits their needs. Information presented in the media can be highly persuasive as illustrated by two recent high profile expos\u00e8s on maternity care including the US based DVD 'the business of being born'  and the Implementation of the primary maternity care reforms represents a major change to the way maternity care has been traditionally delivered in Australia. Successful implementation requires the support of the general public for whom the service is intended. One source of influence on general public opinion is the newspaper media and the news feeds that spin off to television and radio from feature articles of interest. The powerful use of language in a headline is used to attract general public attention to reports on controversial topics affecting Australian maternity care. This study examines the newspaper articles published in 'The Age' newspaper subsequent to the release of the Government discussion paper 'improving maternity services in Australia' in 2008  that herA critical discourse analysis of articles published in the 'The Age' subsequent to the release of the discussion paper by the Australian Government in 2008  was undeCritical analysis of discourse as a methodology was chosen for this study because language takes on greater significance in the arena of providing and consuming services . ObstetrCritical social theory has greatly influenced the development of CDA bringing together a wide variety of critical social theories including the way power is conceptualized . ThroughAll research data consisted of articles featuring the topics of maternity services or childbirth published in 'The Age' newspaper. Articles were obtained from the public domain, accessed through an online search of 'The Age' newspaper website. Personal information was not retrieved from any source and there was no participant involvement.A search was conducted on 'The Age' newspaper website for articles including the search terms; maternity services, birth and childbirth. A total of thirty-eight articles were indentified and included in the study. The title of each article including date and section of publication is supplied in Table Fairclough's approach to CDA links textual and sociological analysis in a way that foregrounds issues of power, resistance and identity . In thisAnalysis undertaken at the socio-cultural level refers to an analysis of the social context in which the text under investigation is produced. Texts were analysed for each key stakeholder group presented in the news article to uncover the unspoken and unstated assumptions implicit within them which have shaped the very form of the text in the first place . This leAnalysis undertaken at the level of discourse practice is concerned with the production, distribution and consumption of the text . In thisAnalysis at the textual level is concerned with the minutiae of the text such as how it is formed and what particular vocabulary and style is used in order to produce meaning . This stCritical discourse analysis is an interpretive process and acknowledges the multiple interpretations that can emerge from the text. The source of text included in the study has been explained and matched to the aims of the research. Sufficient quantities of text have been included in the analysis to capture all that can be known or said on the topic. Rigour in this study was enhanced through careful selection of text ensuring the discourses of all key stakeholders were represented in the analysis, as illustrated in Table Critical analysis of articles published in 'The Age' generated a number of discourses exerting influence on general public opinion. By far the majority of articles were concerned with sensationalising the deficiencies of maternity services. The articles featured attention grabbing headings, highlighting issues pertaining to the state of maternity services, supplemented by a range of expert opinions including the relevant government authority, medical or obstetric experts, Australian College of Midwives (ACM) and consumer groups.Expert consumer opinion was sought by 'The Age' from organisations such as maternity coalition or future families, advocates for primary maternity care reform supporting natural birth options. These organisations are well organised publicity machines promoting their position on natural childbirth . What waIn the process of sensationalising the deficiencies of maternity services, a number of articles extensively reported on the findings of a survey of 2792 mothers highlighting the traumatic or unsatisfactory experiences of women giving birth. Discourses generated from a critical analysis of that study included; 'the interests of women and their babies must be the focus of maternity care, not the system and those who work in it', 'next please, feeling depersonalised in the queue'. These discourses imply that current maternity services operate in the interests of the institution and maternity care professions and not in the interests of the women receiving care. The woman's personal experience and special needs are dismissed in an overstretched system providing a 'one size fits all service'. Selected statements illustrating the meanings of these discourses included:'Women feeling like cattle being pushed through herding yards that put both their own and their babies' lives at risk. Hundreds of women felt that both public and private maternity wards are overcrowded, needed more midwives, performed too many unnecessary medical interventions and did not provide enough non-drug options for pain relief (quote article 18).'Nothing could have prepared me for my horrible birth experience - \"herding yards does not go nearly far enough in describing the way the hospital treats new mothers and babies (quote article 14).The safety of overcrowded and understaffed metropolitan maternity services is called into question in the majority of these news articles. It has been argued that maternity care in Australia is delivered in an outmoded 'hospital nursing' model  that has'A large public hospital means a huge variation in staff on different shifts, which leads to inconsistent care and the danger of falling through the cracks' (quote article 17).'The most concerning theme centres on the apparent shortage of resources in public hospitals, leaving many women feeling as if they and their infants are being exposed to unacceptable risk' (quote articles 18 & 21).'Because of workforce difficulties, care is fragmented. Women might see 12 or 13 diffent people during the pregnancy' (quote article 27).A number of the newspaper articles reported on the findings of the national review of maternity services released in 2009. One of the main messages highlighted in the articles is the need to respect women's right to choose, inferring that women are not being offered choice in the maternity care they receive. Some women in an attempt to investigate childbirth options find themselves labelled by the health professionals, on whom they rely, as being 'difficult' or 'untrusting' . Discour'Stop treating pregnancy as an illness and respect women's birth choices' (quote article 35).'Women seduced by the \"empowering\" idea that only a woman knows how to deliver her child forget that 100 years ago 1 in 10 women died from complications of childbirth and 1 in 10' (quote article 25).'Women do not have to prove to health professionals that their healthcare choices are good or worthy ones to have the right to decide' (quote article 1).Several newspaper articles question why Australian women are more anxious about their pregnancies despite Australia's safe record in childbirth. The chance of a women dying during childbirth in Australia is remote . Of conc'Many women are feeling more, rather than less, anxious about the birth process. Some blame this on our risk-averse society, saying the screens and tests and the increasing level of intervention in birth and pregnancy is geared towards making women fearful. Antenatal care has become antenatal scare' (quote article 7).'The woman's surgery was scheduled without her consent and she claimed she was bullied by hospital staff, who said her baby could die if she did not follow their advice. This new mother never wanted to birth at home - she wanted the support of the hospital but the system would not provide the care' (quote article 30).'In one Australian study, 62% of women who had a caesarean section in a private hospital said their health care provider had recommended it' (quote article 1).'There should be more continuity of care. Knowing your carer and trusting your carer removes the fear from childbirth and fear leads to more interventions' (quote article 19).The plight of rural maternity services was highlighted in a number of articles as a serious deficiency in current maternity service delivery , a situa'Since 1996, 40 maternity units had closed across the state and others were near closure. It's reflective of a general shortage of GP's across rural Australia. As a society we have not invested enough in GP proceduralists: doctors who provide obstetric care, anaesthetics or emergency' (quote article 26).'Urgent action is required to prevent women enduring \"roadside births\" as they travel hundreds of kilometres to dwindling maternity services in regional and rural Australia' (quote article 34).'Reopen my local maternity unit. Travelling while in labour is not only uncomfortable, but dangerous. .All articles retrieved for this study presented a range of expert opinion on the topic featured, usually including the relevant government authority, medical or obstetric experts, the ACM and consumer groups. Opinions represented a range of views often involving polarised positions on the issue. Consumers and midwives reinforced the position of natural birth and challenged increasing rates of medical intervention. Medicine or obstetrics highlighted the dangers of medically unassisted childbirth while the government defended the proposed maternity service policy direction. The main issue debated in the articles centred on contention surrounding government support for midwifery -led maternity services extending to including controversial home birth trials. As exemplified in the statement:'Victorian women will be able to give birth at home - with hospital back up for the first time - under a pilot project starting at three hospitals next year' (quote article 22).The safety record of home birth is reported in a number of newspaper articles as having received a boost with several large studies in recent years reporting no significant difference between planned hospital birth and planned home births, as long as the mothers have access to trained midwives ,35.'A Dutch study of more than 500,000 women reported that planning a home birth does not increase the risks of perinatal mortality and severe perinatal morbidity among low risk women provided they were supported by well trained midwives and a good transportation and referral system' (quote article 24).Medical or obstetric opinion reported in the newspaper articles reflect the position that they are the guardians of safety in childbirth in the belief that only they have the training and expertise for safe birth outcomes to be achieved . The exp'Of course, women might feel that sometimes the medical profession interferes too much in what is a natural process, but the reality is that if left to mother nature then the outcomes is not very good often. There needs to be a sensible balance struck between interfering in a natural process but judiciously intervening when things start to go wrong, or preferable before things start to go wrong' (quote article 7).'The trouble is we take safety for granted now and are arguing about quality issues, like maternal satisfaction, which is important. But I'm sorry not as, as a clinician, survival is the most important thing' (quote article 25).'If birth is a natural process so is getting cancer and dying' (quote article 12).'It's a myth to say that the most important thing is a healthy baby. Traumatic birth gets carried with you - you don't leave it at the hospital- and it can have the most profound consequences for both the mother and baby' (quote article 7).On the issue of expanding midwifery -led maternity services as part of the proposed primary maternity care reform agenda some medical and obstetric opinion reported in new articles became divergent as seen in the following statements:'I fear the introduction of a system where women are pressured into having a natural birth that puts them and their baby at risk' (quote article 18).'If we can have a patient seeing either the midwife or the GP depending on who is the appropriate person at the time, then that's going to benefit the patients and free the GP's up to be able to see other people. The GP's in rural area's providing birthing services know they can't do it by themselves' (quote article 23.1)On the issue of planned home birth there is strong resistance reported in news articles from medical experts a position supported in a recently published systematic review of the medical literature on the maternal and newborn safety . Finding'Any birth at home under the care of midwives was unsafe and should not be supported by governments (quote article 2).A source of confusion for the general public is evident in reports of obstetric opinion where midwifery services are only recognised as they relate to home birth, failing to acknowledge the work of midwives across the full range of maternity services. Discourse generated in this study; 'midwives act irresponsibly when attending a women birthing at home', 'home birth is a return to times past where mothers and babies died in vast numbers'. Selected statements illustrating the meanings of these discourses included:'Midwives do things in a home setting, that no maternity service around the developed world would think a good idea' (quote article 36).'Home births with or without midwife help, increase the risk of infant death three fold' (quote article 27).The opinions of consumers are varied. Consumers advocating for increasing services supporting natural birth project positivity around women's ability to give birth with minimum intervention in a safe environment. The consumers represented in 'The Age' survey appear fearful, unsure of what is best, placing their trust in health professionals to keep them safe. There is evidence to indicate the presence of the 'what is must be best' belief where the public values the status quo over options for which they have little experience ,41.Contrasting discourse were generated in this study; ''women are the experts in giving birth, trust our bodies to keep us safe', 'Australia is one of the safest countries in which to give birth or be born, what is must be best'. Selected statements illustrating the meanings of these discourses included:'While most mothers were generally satisfied with their experience of the maternity system, hundreds of women felt that both public and private maternity wards are overcrowded, needed more midwives, performed too many unnecessary medical interventions and did not provide enough non-drug options for pain relief' (quote article 18)'A lack of obstetricians available after hours means junior registrars are making critical decisions, often bad ones'. I was not supported well enough to have a vaginal birth. I felt like they were more concerned with getting me in and out quickly so they could free up the beds (quote article 19).Consumer opinion reported in newspaper articles on the issue of midwifery -led maternity services including home birth was sought from consumer organisations advocating for non obstetric -led services, supporting women to give birth safely with minimal intervention . Consume'Over 400 submissions to the national review from consumers, the majority requesting greater access to home birth cannot be ignored any longer' (quote article 24).'You seem to have left out the home birth option in your report. Provided the women is healthy, well informed and well supported, there is no reason she cannot give birth at home with the aid of a trusted midwife. My wife did so three times, 25 - 30 years ago (quote article 17).While most of the news articles are concerned with the exciting process of giving birth, consumer opinion raises the issue of private and public hospital care following birth. Traumatic experiences of new mothers left to care for their babies following caesarean surgery are described, as are distressing stories describing lack of support with breast feeding. Discourse generated in this study; 'recovering from the effects of surgery while struggling to mother my baby'. Selected statements illustrating the meanings of these discourses included:'Thirty per cent of women in postnatal care wards have had major abdominal surgery and they are expected to try and care for a newborn baby' (quote article 9).'Nurses are not caring for women after caesareans properly because of overcrowding. Unless you scream the loudest you don't get looked after' (quote article 19).Expert opinion supplied by the ACM strenuously challenges the obstetric position that only they have the training and expertise to safely care for pregnant women. In each article the midwifery professional body challenges current obstetric practices leading to rising rates of medical intervention and culminating in an alarmingly high rate of caesarean section in healthy young women having their first baby. Discourse generated in this study; 'rates of medical intervention in Australia are too high', 'medical intervention is not without risk it comes with the potential for serious complications'. Selected statements illustrating the meanings of these discourses included:'We (midwifery professor) have consistently found that 30% of women report that their birth was traumatic; that they feared for their life or their baby's life. This is a very high figure. We also know that about 6% go on to develop post-traumatic stress disorder' (quote article 7).'Babies born by caesarean section are more vulnerable to asthma, allergies and infection because they miss out on receiving their mothers' good bacteria during birth. Babies delivered vaginally received protective bacteria as they pass through the birth canal (quote article 8).Reported midwifery opinion reinforced the desirability of midwifery -led maternity services designed to meet the needs of women as mothers. The ability to build a relationship with a known carer based on mutual respect and trust is promoted by advocates of midwives as the panacea for being able to control levels of fear, maintain feelings of being in control throughout the birthing process and being satisfied with the outcome of the experience .The discourses identified and described in this critical analysis of articles published in 'The Age' national newspaper present the general public with a quandary, what to believe? Careful reporting, inclusive of the range of often divergent expert opinion relevant to each news item, leaves the general public and consumers to evaluate the evidence, forming their own conclusions. The right to decide what to think rather than being told what to think reflects the neoliberal values of modern consumerism a situation supported by the Australian government encouraging women to empower themselves through informed decision making regarding maternity care . The risThe general public has been inundated with headline grabbing reports outlining the deficiencies of maternity service. Obstetric practices that are insensitive and a maternity service that is inflexible resulting in women feeling traumatised by the experience of giving birth have been sensationalised. Evidence presented suggests that maternity services are not meeting the expectations of consumers. Consumer discourses identified in this study; 'the interests of women and their babies must be the focus of maternity care, not the system and those who work in it', and 'maternity care options need to be expanded to allow women choice in the care they receive' are reflected in the primary maternity care agenda for change. However expert medical discourses: 'modern medicine knows best and women would be best served to listen to the experts'; 'the demonization of women who choose to give birth naturally', and 'at least you have a healthy baby' convey a very different message positioning women seeking non obstetric -led care options at odds with maternity care providers.The discourses describing consumer experiences of maternity care in public and private hospitals: 'next please, feeling depersonalised in the queue'; 'feeling vulnerable in the care of a parade of strangers'; 'expected to place blind trust in those who know nothing about me and still feel safe' captures the consumer experience of a fragmented maternity service care and subsequent distress associated with finding themselves in territory they never dreamed possible . Women aDespite the poor performance of maternity services on many levels the general public is reassured by Australia's record of safety in childbirth, a success attributed to modern medical advances. A claim contested by the midwifery profession  through The discourses of women living in rural and remote communities and strong consumer organisations representing the interests of these women have featured strongly in the proposed reform agenda ,47-49. RFindings from this critical discourse analysis revealed that Australian maternity services are being portrayed to the general public as an inflexible outdated service struggling to meet the needs of pregnant women and in desperate need of reform. The style of reporting employed in this newspaper involved presentation to the reader the range of expert opinion relevant to each topic, frequently involving polarised positions of the experts on the issue. As a result the general public are presented with a conflict, caught between the need for the changes that come with a primary maternity model of care and fear that these change will undermine safe standards. The discourse; 'Australia is one of the safest countries in which to give birth or be born, what is must be best', represents the situation where despite major deficiencies in the system the general public may be too fearful of the consequences to consider a move away from reliance on traditional medical -led maternity care.The authors declare that they have no competing interests.MM was responsible for the study conception, design, review and analysis of the literature and drafting of the manuscript. KF and YC made critical revisions to the paper for important intellectual content. All authors have approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2393/11/47/prepub"}
+{"text": "Phalangeal microgeodic syndrome is a rare bone disorder affecting the fingers of young children, originally described by Maroteaux in 1970.The aim of this case series is to present the clinical and radiological manifestations of three affected pediatric patients, and to illustrate the redundancy of additional investigations if the physician is aware of the disease.The details of three patients with phalangeal microgeodic syndrome are summarized in the table. Three boys presented before the age of 2 years with swelling of the digits of one or both hands. Further clinical examination and laboratory evaluation were normal. On radiological examination multiple small osteolytic areas with sclerotic lining and periostal reactions were visible in the phalanges of the affected hands. All cases were treated with a conservative approach and spontaneous resolution occurred within weeks to months.Phalangeal microgeodic is a rare bone disorder presenting with swelling of multiple digits yet alarming radiological signs. These manifestations can be misinterpreted as caused by an infectious, inflammatory or osteolytic condition and prompt clinicians to expand the diagnostic process with MRI or scintigraphic imaging and even biopsy. Timely recognition of clinical and typical radiological signs may prevent unnecessary investigations for this benign condition."}
+{"text": "One major constraint upon the application of molecular crop breeding approaches is the small number of genes linked to agronomically desirable traits through defined biochemical mechanisms. Proteomic investigations of crop plants under abiotic stress treatments have identified many proteins that differ in control versus stress comparisons, however, this broad profiling of cell physiology is poorly suited to ranking the effects and identifying the specific proteins that are causative in agronomically relevant traits. Here we will reason that insights into a protein\u2019s function, its biochemical process and links to stress tolerance are more likely to arise through approaches that evaluate these differential abundances of proteins and include varietal comparisons, precise discrimination of protein isoforms, enrichment of functionally related proteins, and integration of proteomic datasets with physiological measurements of both lab and field-grown plants. We will briefly explain how applying the emerging proteomic technology of multiplexed selective reaction monitoring mass spectrometry with its accuracy and throughput can facilitate and enhance these approaches and provide a clear means to rank the growing cohort of stress responsive proteins. We will also highlight the benefit of integrating proteomic analyses with cultivar-specific genetic databases and physiological assessments of cultivar performance in relevant field environments for revealing deeper insights into molecular crop improvement. Figure 1).Analyses by agricultural researchers and humanitarian organizations have continually found that abiotic stresses such as drought, extreme temperatures, and unfavorable soil conditions are responsible for significant decreases in crop yield and can have adverse economic and nutritional consequences for local populations . Given tCellular physiology is underpinned by the composition and function of the proteome, and the power of proteomics techniques lies in their ability to quantitatively analyze large numbers of proteins in parallel, providing rich sets of information with which to explain the molecular mechanisms that underpin cellular function. The plant proteomics literature is characterized by two major threads. The first is the descriptive cataloging of which proteins are expressed in which tissue , localizHowever, the value of the above mentioned approaches as gene discovery and ranking strategies for future crop improvement is less clear. Many limitations of the approach and results derived from these experiments must be taken into account before committing to pursue any one protein in a molecular breeding program. First is the common observation that a small subset of the stress responsive proteins are repeatedly identified across a number of different stress experiments, the so called \u201cd\u00e9j\u00e0 vu\u201d phenomenon . While tWe propose that controlled environment experiments that attempt to mimic field conditions are best framed as a starting point to identify proteins of interest. The results of these studies then need to be added together and explored more widely by subsequent profiling experiments conducted under field conditions in the target environment, to determine which, if any, of the favorable molecular mechanisms uncovered in the laboratory hold true in the target environment and what are the relationships between them.Medicago  is highly suited to high sample throughput of a wider group or groups of proteins in a single analytical run, thus enabling a larger number of data points on different proteins to be gathered per unit of machine time. This is particularly useful for the assessment of protein changes in field-grown crop plants where the variation in the samples may be larger than those collected in the controlled laboratory environment. This also allows the relationships between changes in the abundance of different proteins to be explored in G \u00d7 T datasets. Usually within the lab, power analysis will reveal that three to five samples are sufficient for the experiment to be informative and this number is amenable to quantitative shotgun proteomic approaches. However, field analysis may require >20 samples for the experiment to be informative and this would led to prohibitively expensive and time-consuming analysis by shotgun proteomic approaches. In these circumstances SRM MS approaches provide an opportunity to quantitate a select group or groups of proteins from a larger number of samples relativity cheaply and quickly. For instance, research suggest that the proteins involved in reactive oxygen species (ROS) detoxification are strongly linked to abiotic stress tolerance , but a fThe central difference between SRM MS approaches compared to other proteomics methodologies is the necessity for prior knowledge of proteotypic peptides derived from a protein of interest. Therefore, the most pressing constraint upon SRM approaches in crops is the lack of proteotypic peptides which can be used to quantify proteins of interest in relevant species, meaning that the first step in any SRM investigation involves a long period of library generation, where discovery proteomics and database searching are conducted to define high-quality peptides which are suitable for subsequent SRM experiments. This contrasts with the current state of the SRM field in other species, where for example the SRMAtlas project is collating representative mass spectra for signature peptides derived from tens of thousands of proteins expressed in human, yeast, and mouse . This daDespite widespread interest in applying molecular techniques to phenotyping crop plants, difficulties in sequencing the large and complex genomes of many crop species have constrained the power of proteomics applied to crops. DNA sequencing technologies are increasing the speed and decreasing the cost of sequencing, with recent highlights being the generation of reference genomes for barley  and tomaProteomics research is typically conducted by scientists trained in the disciplines of biochemistry and molecular biology. Their emphasis upon molecular mechanisms is indispensable for understanding the biological meaning of proteomics data. However, due to the specialist knowledge and logistical difficulties inherent in designing and conducting meaningful field experiments, proteomics researchers will likely depend upon collaborations with agriculturally focused researchers in order to access tissue grown in the relevant field environment with appropriate spatial designs and checks. Therefore, building effective collaborations across discipline boundaries is crucial for proteomics researchers who wish to access field-grown material and contribute to crop breeding programs. It can be argued that a mutual appreciation of classical plant physiology is the key bridge between molecular and field researchers, as its emphasis upon dissecting a specific trait at the single plant level is a logical convergence point for ideas and hypotheses stemming from the two different scales . For insAs claimed by the introductory sections of many papers, as well as preambles to many grant applications, the strategic endpoint of much plant biology research at the molecular scale is to improve the abiotic stress resistance of crop species. However, much of the data produced by plant proteomics research is yet to be actually evaluated for its use in directing breeding programs. Although the initial identification of candidate proteins linked to stress tolerance will still utilize discovery proteomics workflows applied to plants grown under controlled environment conditions in the lab, the technical capabilities of SRM are a better match for validation studies which aim to quantify the abundance of selected target proteins. The ability of the SRM approach to accurately quantify the abundance of a range of target proteins against complex cellular backgrounds in a large number of field-grown samples is a key to its applicability and value. Therefore, we argue that the judicious development of this SRM approach will further our understanding of the causative links between cellular composition and whole plant stress tolerance, and bring the knowledge and skills of proteomics researchers closer to the stated goal of crop improvement for higher yields in harsh environments.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Neurons in the mammalian cortex have conduction latencies that can scale up an order of magnitude or more with myelination and axon radius. These latencies can be categorized into two groups: distance dependent latencies associated directly with axonic/dendritic length and distance independent latencies due to intrinsic delays on synapses themselves. This paper focuses on the distance dependence of conduction latency, attempting to elucidate its effects on the temporal ordering of the network activity patterns. We use various statistical measures to characterize the temporal patterning behavior of the networks: mean phase coherence, a pairwise measure of phase locking between neuron spike trains averaged over the network and synchronous bursting, which quantifies the coincidence of spikes as it deviates from a Poisson process.We find that distance dependent delays and distance independent delays can lead to significantly different spatio-temporal patterning of network wide activity. The introduction of distance dependent delays into the network can drive temporal dynamics toward a more synchronous state. This synchronization enhancement can decrease as the topology of the network shifts towards a random graph and as the conduction speed moves out of an optimal range."}
+{"text": "Alcohol consumption and affordability in the UK has increased over the last 50 years and is associated with a range of adverse oral health outcomes, the most serious of which, oral cancer, is also increasing in incidence. Despite this, routine alcohol screening and brief intervention (SBI) within general dental practice remains uncommon. This review of the literature examined the background and evidence base for undertaking alcohol SBI in general dental practice, including the rationale behind it and the range of issues related to it. Questions addressed include why alcohol consumption is of relevance to dental professionals; what policy context exists for the role of prevention and health promotion in dentistry; what screening tools are appropriate for use within a general dental practice; what evidence of efficacy is there for alcohol SBI in general dental practice; and what barriers and facilitators must be considered before alcohol SBI can be successfully implemented in this setting. We conclude that alcohol SBI in general dental practice, delivered as part of a multidimensional approach to tackling risky alcohol consumption, offer significant potential to improve the oral and general health of the population."}
+{"text": "The identification and analysis of repetitive patterns are active areas of biological and computational research. Tandem repeats in telomeres play a role in cancer and hypervariable trinucleotide tandem repeats are linked to over a dozen major neurodegenerative genetic disorders. In this paper, we present an algorithm to identify the exact and inexact repeat patterns in DNA sequences based on orthogonal exactly periodic subspace decomposition technique. Using the new measure our algorithm resolves the problems like whether the repeat pattern is of period"}
+{"text": "Over the last 40\u00a0years the assessment and treatment of chronic obstructive pulmonary disease has focused primarily on airflow obstruction with little significance given to the problem of cough. The reasons for this include a view that cough arises simply from the direct irritant and inflammatory effect of cigarette smoke or the presence of excess mucus in the airways. Doubt that cough is of any consequence to patients or responsive to current therapies has reinforced this opinion. At odds with this is the emerging evidence that cough impacts adversely on patients\u2019 health status and forms an important component of recently validated quality of life instruments. This article presents the arguments why the assessment and treatment of cough should have a more prominent place in the clinical management of COPD. Chronic obstructive pulmonary disease (COPD) is now recognised to be a condition of global importance in terms of its impact on the morbidity and risk of premature death of millions of people. The definition of COPD continues to be refined. HoweverThe role of cough in COPD has been well reviewed before. That reWe do not have good data about the frequency with which smokers cough. This reflects one of the major problems in cough research \u2013 the lack of simple metrics which describe coughing. How often should the subject cough and with what intensity before it is classified as significant? This Gordian knot was cut by the Medical Research Council in the 1960\u2019s when they developed an epidemiological definition of chronic bronchitis. They haThis analysis was accepted for much of the last 3 decades but there are now reasons to doubt it. Coughing is associated with airway inflammation in non-smoking asthmatics and there are objective data showing persistence of airway inflammation in ex-smoking COPD patients, likely The epidemiological definition of chronic bronchitis emphasised the association with sputum production and it seemed reasonable to assume that excess mucus accumulation was the main factor driving cough in COPD. This agreed with pathological observation by Reid and Heard of mucous gland hypertrophy in the central airways of patients dying with what we now term COPD. Loss ofThe realisation of the association between self-reported cough and deaths from bronchitis led to the \u2018British hypothesis\u2019 that disease progression in COPD was related to the presence of bronchitic symptoms. This was tested in the long term study of lung function, symptoms and mortality in British postal workers which failed to find any association with disease progression and bronchitis. CoupledWhile there is no doubt that breathlessness is the most dramatic and disabling symptom experienced by COPD patients, more recent data shows that cough is also a matter of concern. Danish data in a large population study found that the presence of chronic mucous hypersecretion increased the risk of having pneumonia and was associated with a faster decline in lung function in men. More reThe impact of cough on patient well being has now been evaluated. In a telephone survey of 2950 COPD patients Kessler et al. found that cough was reported by 55% of subjects with 20% rating it severe to extreme. These sCough is now considered, along with breathlessness and sputum production, to be one of the cardinal symptoms of COPD and whicAt present it is difficult to quantify the degree to which cough responds to treatment for COPD. In part this reflects the lack of focus on cough in clinical studies where most attention has been paid to the relief of breathlessness or the prevention of exacerbations. However the lack of a validated measure of cough intensity and frequency which is known to respond to interventions is also a factor. This situation may improve when newer instruments such as the CAT and EXACT questionnaires are studied in treatment trials.There is general agreement that COPD patients who stop smoking are less likely to report the symptom of cough although this change may be more evident in the earlier stages of the disease, when lung function improvement with treatment is more evident. The proportion of patients with mild-moderate COPD who report a chronic cough declines by about 5% over a 5\u00a0year follow up period but only 10% of similar patients who quit complain of cough 5\u00a0years after stopping. WhetherMany pharmaceutical studies of COPD treatment have recorded cough as a symptom in daily patient diary cards but have seldom analysed the resulting data. One example of this is presented in Table\u00a0In summary it appears that the presence of cough with or without sputum is an early feature of clinical COPD that helps identify people at risk of progressive disease. The cough reflex in COPD is increased to levels seen in current smokers even when the patient no longer smokes. Cough remains a key symptom in the diagnosis of COPD and its presence helps identify those patients at greatest risk of future exacerbations. Smoking cessation early in the natural history of the disease remains the most effective way of reducing cough but other therapies show some promise. Non-specific cough suppressants do not appear effective in COPD and should be avoided. What is really needed is a more systematic study of this important symptom in larger numbers of well characterised patients using validated ways of assessing the occurrence and impact of cough. Once we better understand the nature and variability of this symptom at a patient level then we will be able to develop more effective methods of managing it in clinical practice.COPD: Chronic Obstructive Pulmonary Disease; C2: Concentration of capsaicin inducing 2 coughs; C5: Concentration of capsaicin inducing 5 coughs; CAT: COPD Assessment Test; EXACT-PRO: EXAcerbations of Chronic Obstructive Pulmonary Disease Tool (EXACT): a patient-reported outcome (PRO) measure; TRISTAN: Trial of Inhaled Steroids and long-acting \u03b22 agonists Competing Interests.The author declares that they have no competing interests."}
+{"text": "The present issue focuses on the classic question of early vs. late selection and evaluates the current status of the perceptual load theory that has been offered as an intermediate solution. Several of the papers compare or contrast perceptual load with an alternative explanation- perceptual dilution. The first group of papers report evidence that is inconsistent with the perceptual load theory but is generally consistent with the dilution theory.Roper and Vecera  report tMevorach et al.  tested pChen and Cave  further In their opinion paper Linnell and Caparos  argue thMore evidence for a strategic component in the seemingly automatic processing of task-irrelevant information comes from Biggs and Gibson . They shThe review of Scalf et al.  presentsThe remaining papers use perceptual load theory as a direct or indirect context for studying other aspects of attentional selection. The role of working memory in regulating the degree to which distractors can be ignored is the focus of de Fockert's  review. Forster  takes thParks et al.  used SSVSwallow and Jiang  bring inFolk  makes anFinally, Moher et al.  tested sWe hope you will find this Research Topic interesting and informative. Enjoy your reading!"}
+{"text": "This reductionist approach has lead to many fundamental insights into how myosin powers muscle contraction. In addition, nature has provided scientists with an array of muscles with different mechanical properties and with a superfamily of myosin molecules. Taking advantage of this diversity in myosin structure and function has lead to additional insights into common properties of force generation. This review will highlight the development of the major assays and methods that have allowed this combined reductionist and comparative approach to be so fruitful. This review highlights the history of biochemical and biophysical studies of myosin and demonstrates how a broad comparative approach combined with reductionist studies have led to a detailed understanding of how myosin interacts with actin and uses chemical energy to generate force and movement in muscle contraction and motility in general.Striated muscle is an elegant system for study at many levels. Much has been learned about the mechanism of contraction from studying the mechanical properties of intact and permeabilized (or skinned) muscle fibers. Structural studies using electron microscopy, X-ray diffraction or spectroscopic probes attached to various contractile proteins were possible because of the highly ordered sarcomeric arrangement of actin and myosin. However, to understand the mechanism of force generation at a molecular level, it is necessary to take the system apart and study the interaction of myosin with actin using  The mechanism of muscle contraction has been one of the great biological questions and has occupied the attention of many scientists for much of the last half of the 20th century through to today Huxley, . With it2 cross sectional area along with the EM measurements of 500 thick filaments/\u03bcm2 muscle cross sectional area and about 150 myosin molecules per half sarcomere lead to a forces of about 4 pN per cross bridge. Since only one third to one half of the cross bridges were attached during an isometric tetani, the estimate of force per attached cross bridges about is 8\u201312 pN ? In which ways do the physiological ensembles of myosins affect the kinetics and production of force by the individual force generators?Historically, the muscles of frog and rabbit were primarily used for physiological and mechanical studies. These tissues were readily available and could be easily isolated from the animals. With the proper supply of metabolic energy in an oxygenated and buffered extracellular solution the contractile behavior of the muscle tissue could be reproducibly studied and maintained in a viable state for several hours. Comparative approaches were used to study the differences between fast and slow muscle fibers from within a single animal and between muscles of different animals Barany, . AlthougStudies to biochemically define muscle proteins in solution began with the purification of myosin and actin. Albert Szent-Gyorgyi showed that when an actomyosin solution at high ionic strength was exuded into a solution of lower ionic strength, \u201cthreads\u201d were produced which contracted upon the addition of ATP  and regulatory (RLC) light chain in 1993  to drive the expression of wild type and mutant myosins. The ability of these cells to express mammalian myosins was variable. Several myosins such as smooth muscle myosin II  residue in switch 1 that forms a hydrogen bond with a glutamic acid residue (E459) in switch 2 to close the nucleotide binding pocket to permit catalysis. Mutation of either of these residues to an alanine greatly inhibits the actin-activated ATPase activity and abolishes the ability of the myosin to move actin filaments  to even an alanine (replaced of R = H vs. R = CH3) uncouples actin-activated ATP hydrolysis from motility  was discovered by Montell and Rubin  showed it to be single-headed without a long tail  was but one member  of actomyosin complexes has provided a link between the crystal structures and the geometry of myosin bound to actin (Rayment et al., A working stroke in two sub-steps was first seen in single molecule optical tweezer experiments with unconventional myosin I (Veigel et al., in vitro. Despite this kinetic difference both myosin V and myosin II molecules cycle through weakly and strongly attached actin states during their cycle which helps validate the use of myosin V as a model to understand the function of myosin II.Many of the biochemical properties that we have described for skeletal muscle myosin II so far make it difficult to study its interactions with actin at a biochemical and electron microscopic level. In the presence of ATP a myosin II head spends most of its kinetic cycle detached from and interacting only weakly with actin so that the lifetime of its strongly bound states are short. However some of the unconventional myosins serve as cargo transporters and have evolved to spend most of their kinetic cycle bound strongly to actin. An example is myosin V which, in melanocytes serves to aid in the transport of pigment granules, termed melanosomes, to the tips of the dendritic processes (for review, see Hammer and Sellers, These biochemical properties make myosin V much more amenable to study biochemically, particularly at the single molecule level, than most other myosins and it can be argued that it is the best understood myosin in terms of its mechano-chemical properties (Sellers and Veigel, in vitro motility assay, actin filaments are bound to the coverslip surface and fluorescently labeled myosins are in the solution. When a labeled myosin V molecule contacts the actin filament a processive run ensues that can be followed to determine the run length and velocity (Sakamoto et al., The processivity of myosin V can also be observed in a variant of the sliding actin motility assay where one inverts the geometry of the proteins used in myosin II sliding filament assays. In the single molecule myosin V Electron microscopy of myosin V molecules trapped while moving along actin demonstrated that the molecule bound to actin via both heads and that the two heads were separated by 36 nm (Walker et al., Bifunctional attachment of fluorescent probes to a single calmodulin moiety in the lever arm of myosin V allows for detection of the lever arm angular position during processive movement (Forkey et al., Dictyostelium myosin mutant in which the native lever arm was entirely replaced with an artificial one made up of a rigid section of sequence from \u03b1-actinin (Ruff et al., Several mutagenesis experiments support the idea that the light chain binding neck region acted as a lever arm. In these studies the neck regions of smooth muscle myosin II and myosin V were engineered to be longer or shorter than wild type via manipulation of the number of IQ motifs (Warshaw et al., The question of chemo-mechanical coupling is a crucial one in muscle research. Although most researchers would agree that one ATP molecule is hydrolyzed per power stroke and that load affects the kinetics of the cycle, the details of the chemo-mechanical energy conversion are not fully characterized. Here again, a reductionist approach, often using myosins other than muscle myosin have provided critical information. These experiments revealed that the sensitivity to load is very different in different parts of the cross bridge cycle. Studies of the load dependence of the chemo-mechanical cycle have been performed on striated muscle and smooth muscle myosin II (Veigel et al., The question of whether there is a tight coupling between cross bridge performance and ATP utilization was addressed in several studies. Ishijima et al. used optical trapping combined with fluorescence detection of cy3-ATP and came to the conclusion that skeletal muscle myosin II S1 might not have a tight one-to-one coupling between the mechanical and chemical cycles (Ishijima et al., There are many outstanding questions still remaining to fully understand muscle fiber mechanics. How do disease states alter cross-bridge mechanics? What are the rate constants for cross-bridges in isometrically contracting skeletal muscle fibers? How do the rate constants in the isotonically contracting muscle change and by how much as shortening velocity is altered? How do the rate constants in eccentrically contracting muscle change with rate of stretch and to what extent are the various populations of attached cross bridges altered? How are rate constants in contracting muscle altered by the extent of calcium activation or is the only change a rate in which the cross-bridges attach to exposed actin filaments? Finally a broad question, to what extent is skeletal muscles contractility altered by changes in diet, hormones, exercise, age, use, and innervations? It is clear how reductionist methods can address some of these questions. Several labs are using biophysical methods to probe myosins bearing mutations corresponding to ones found in diseased hearts (Palmiter et al., To understand how muscle works the vertebrate skeletal muscle systems has many advantages. However, the inability to make mutations within the myosin molecule in muscle, coupled with the fast and low duty ratio kinetics has made it challenging to understand the system at a molecular level. Using a comparative approach with recombinantly expressed non-muscle myosins, combined with a host of biochemical and biophysical techniques applied to purified myosin has allowed researchers to unravel how muscle works at a molecular level.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The aim of this poster is to provide a rationale and critical overview of \u2018Autologous Blood Injection Therapy\u2019 a new and possibly superior treatment modality in the management of tendinopathy. The theoretical background will be appraised including its clinical application and perceived clinical effectiveness.literature review and critical appraisal of papersAutologous blood injection therapy has been shown to have a significant positive effect on both pain and joint function, with concomitant therapies not being demonstrated to be required in the management of tendinopathy. However, the majority of studies were representative of patients being treated for refractory epicondylitis with different procedure techniques being employed. No studies compared blood re-injection therapy with dry needling alone, with minimal data available from controlled studies preventing a placebo response from being ruled out.With current evidence on the efficacy of autologous blood injection therapy in the management of tendinopathy being insufficient in quantity and quality, the current National Institute for Health and Clinical Excellence guidelines state this procedure is to only be used with special arrangement. Future research should focus on randomised control trials that clearly describe previous or adjunctive therapeutic interventions with a minimum follow up of 1 year."}
+{"text": "The incidence of malignant melanoma (MM) continues to rise in the UK and Europe. Despite being a common form of skin cancer it is responsible for the majority of skin cancer related deaths. Around 3-15% of all cutaneous MM arise on the foot. However, lesions arising on the foot hold a poorer prognosis than melanoma elsewhere due to frequent misdiagnosis and late presentation. Initiatives to raise practitioner awareness to the problem would hopefully facilitate earlier referral and diagnosis.Following discussions with the Faculty of Podiatric Medicine and General Practice, a panel including Dermatologists (with an interest in skin cancer) and a Podiatrist was assembled and undertook a project to produce a guide for Chiropodists/Podiatrists on the early recognition of malignant melanoma arising on the foot.Following a systematic review of published evidence and existing guidelines it was concluded there was insufficient research to fully inform such a guide. Therefore using the available literature and case reports a paper was drafted using expert opinion and clinical experience. Evaluation of reported cases of misdiagnosis and clinical features lead to the development of a new acronym specific to foot malignancy with clinical information and suggested actions. In addition, specific advice has been drafted on nail melanoma highlighting common clinical features and differential diagnosis.The guide is currently being field tested amongst practitioners but should ultimately be available to all Podiatrists and Chiropodists to help raise awareness of this aggressive and often fatal disease."}
+{"text": "An algorithm to automatically identify and extract matched molecular pairs from a collection of compounds has been developed, allowing the learning associated with each molecular transformation to be readily exploited in drug discovery projects. Here, we present the application to an example data set of 11 histone deacetylase inhibitors. The matched pairs were identified, and corresponding differences in activity and lipophilicity were recorded. These property differences were associated with the chemical transformations encoded in the SMIRKS reaction notation. The transformations identified a subseries with the optimal balance of these two parameters. Enumeration of a virtual library of compounds using the extracted transformations identified two additional compounds initially excluded from the analysis with an accurate estimation of their biological activity. We describe how the WizePairZ system can be used to archive and apply medicinal chemistry knowledge from one drug discovery project to another as well as identify common bioisosteres."}
+{"text": "Whether the balance between integration and segregation of information in the brain is damaged in Mild Cognitive Impairment (MCI) subjects is still a matter of debate. Here we characterize the functional network architecture of MCI subjects by means of complex networks analysis. Magnetoencephalograms (MEG) time series obtained during a memory task were evaluated by synchronization likelihood (SL), to quantify the statistical dependence between MEG signals and to obtain the functional networks. Graphs from MCI subjects show an enhancement of the strength of connections, together with an increase in the outreach parameter, suggesting that memory processing in MCI subjects is associated with higher energy expenditure and a tendency toward random structure, which breaks the balance between integration and segregation. All features are reproduced by an evolutionary network model that simulates the degenerative process of a healthy functional network to that associated with MCI. Due to the high rate of conversion from MCI to Alzheimer Disease (AD), these results show that the analysis of functional networks could be an appropriate tool for the early detection of both MCI and AD. Graph theory provides valuable tools to describe the topological organization supporting cognitive processes On the other side, Mild Cognitive Impairment (MCI) is an intermediate state between healthy aging and dementia To our best knowledge, no previous characterizations of the topological properties of functional brain networks in MCI subjects with MEG were attempted so far. We here apply methods from complex networks theory to compute macroscopic and mesoscopic parameters of the functional networks in a group of nineteen MCI patients and a group of control participants of the same size. Brain activity was measured by means of MEG during a Sternberg's letter-probe memory task Materials and Methods in MEG scans were obtained from nineteen MCI patients and nineteen healthy volunteers during a Sternberg's letter-probe task (see The SL between the 148 sensors yields a (symmetric and weighted) 148As for the network parameters, the average degree of a node The node outreach In order to evaluate the deviation of the network parameters from their corresponding randomized versions, we have generated For each individual, we construct a probability matrix from the broadband signal The outreach parameter To compare the mentioned network parameters between the two groups, each parameter value was first averaged across epochs for each participant and channel pair. Then, nonparametric permutation testing From a holistic point of view, it is well known that the processing abilities of the brain rely on the segregation and integration of information Next, we have gone down to the lowest scale . We have used the classification of nodes introduced by Guimer\u00e0 et al. All previous results indicate that mild cognitive impairment is related to a random increase in synchronization between brain areas. In order to model this phenomenon, it is necessary to understand how weights are distributed within the network, since the disease modifies the correlations between nodes. Our model can be discussed as follows: a) we randomly select a link in the correlation network Finally, The effect of MCI on brain networks dynamics is related to a group of phenomena that are hallmarks of an atypical network functioning. The relevant difference between healthy and MCI subjects is the increase in synchronized activity between brain areas. The enhancement in overall synchrony is reflected as an increase of average connectivity Another indication that this synchronization profile might be related to a compensatory effort is the fact that the main differences between the control and MCI subjects are observed in the alpha band  in order to see if this tendency of communication based on long distance connections could be ultimately assessed as an early hallmark of cognitive impairment.Many spatially distant, but functionally integrated functional networks have been described with fMRI and fcMRI analyses Finally, it is interesting to highlight the differences between the findings on MCI and Alzheimer disease (AD), since patients suffering from MCI are prone to develop AD. In both conditions, the distortion of the functional network is related to an evolution towards random structures, as indicated by a clustering coefficient and shortest path length that is closer to the random configuration. Both results are in accordance with the influence of aging in the increase of the network entropy, a concept recently formulated by Drachman File S1Supporting Information.(PDF)Click here for additional data file."}
+{"text": "The needs for other modes of care apart from acute hospital care have long been realized but minimal integrated efforts have developed so far. Payment mechanism is a strong financing strategy to create favorable changes in the health systems.This session is to illustrate the rationale and progress of the developments of sub-acute and non-acute Casemix classification as a financing mechanism in Thailand.Review of literature of the last five years is the main data collection.The rehabilitative medicine has been an established discipline for over four decades in Thailand while psychiatry even longer. Complaints from health care providers of being underfunded activities have been around since the third revision of Thai Diagnosis Related Group since 2001. The fifth revision of TDRG set the goal of accomplishing other Casemix classifications apart from DRG for acute inpatient care, two Casemix systems for inpatient psychiatric and rehabilitative care were submitted to the National Health Security Office in 2011. The NHSO anticipated the difficulties of implementing the two new Casemix systems as initiative payment methods. Two separate streams of putting the Casemix products to the health systems were designed. Further follow-ups of these developments are needed to document knowledge generation related to health system outcomes via financing initiatives.Health finance and Casemix research need long-term commitment of a development team to refine results to find ways of implementing into health systems as well as to evaluate whether favorable changes happen."}
+{"text": "Cardiac involvement infrequently occurs in hypopituitarism, and lethal cardiac arrhythmias are rarely reported. We present a middle age female who died as a consequence of refractory ventricular arrhythmia whose medical history and previous laboratory investigation were consistent with hypopituitarism. We conclude that hypopituitarism may lead to electrocardiographic changes and malignant ventricular arrhythmia and should be included in laboratory investigation and differential diagnosis of patients presenting with long QT syndrome Hypopituitarism is considered when a defect in some of the anterior pituitary axes results in failure of one or more target gland. The insult to the pituitary and hypothalamic area may be acute or chronic hence the clinical presentation may vary accordingly and in the majority of cases, it intervenes with a normal quality of life and may decrease life expectancy secondary to atherosclerotic complications or cerebrovascular accidents . Among vA 58 year old female lost consciousness in her room while preparing for a wedding ceremony and was instantly brought to the emergency room in 28.10.2010.Her cardiac monitoring on arrival showed polymorphic ventricular tachycardia degenerating to ventricular fibrillation, which was unresponsive to prolonged CPR efforts, and she died one hour after arrival to ER(emergency room. Examinations including electrolytes and blood sugar was reported to be normal, retrospective questioning of close family members and reviewing the previous medical data revealed that during last 36 months she had frequent visit to her family physician complaining of weakness and vertigo, her work up on 12 March 2007, while taking Levothyroxin100 ug daily and occasional 5 mg Prednisolone tab  revealedHypopituitarism was first described in 1914 by the German physician Dr Morris Simmonds (since then an enormous growth of knowledge about the pathophysiologic and management of this condition have been developed but the vague clinical presentation is still an obstacle to timely diagnosis and proper management which sometimes leads to extreme and unusual morbid presentations as seen in our case.Sudden unexpected death  and CardWe described a case presented with refractory ventricular tachycardia unresponsive to medical therapy with subsequent laboratory finding in favor of neglected panhypopituitarism. It is concluded that cardiac arrhythmia as a rare presentation of neuroendocrine disorders should be considered in differential diagnosis of long QT syndrome and ventricular arrhythmia."}
+{"text": "Patients with systemic lupus erythematosus (SLE) have up to a 50-fold increased risk of developing atherosclerotic cardiovascular disease that cannot be explained by the Framingham risk equation. While both SLE-specific and nonspecific mechanisms have been proposed to play a prominent role in the induction of premature vascular damage in this disease, the exact etiology remains unclear. We have proposed that an imbalance between vascular damage and repair probably induced by IFN\u03b1 and other type I interferons could play a prominent role in the induction of accelerated atherosclerosis in SLE. Our group and others have recently elucidated the potential role that these cytokines play in the development and progression of premature atherosclerotic disease in SLE and, potentially, in other autoimmune diseases. More recently, a novel role for aberrant neutrophils in the development of autoimmune responses and vascular damage in SLE and other diseases has emerged; in particular, the role that neutrophil extracellular traps may play in the development of this disease and its vascular complications such as endothelial dysfunction and atherothrombosis. The recent description of a distinct subset of proinflammatory neutrophils isolated from lupus patients that induces vascular damage and synthesizes type I interferons has shed new light into a potentially important cell subset implicated in endothelial damage. Finally, novel discoveries pertaining to the interactions of lipoproteins and the immune system may prove quite informative in understanding how premature atherosclerotic plaque develops in lupus."}
+{"text": "In the last twenty years, several global targets for protection of marine biodiversity have been adopted but have failed. The Convention on Biological Diversity (CBD) aims at preserving 10% of all the marine biomes by 2020. For achieving this goal, ecologically or biologically significant areas (EBSA) have to be identified in all biogeographic regions. However, the methodologies for identifying the best suitable areas are still to be agreed. Here, we propose a framework for applying the CBD criteria to locate potential ecologically or biologically significant seamount areas based on the best information currently available. The framework combines the likelihood of a seamount constituting an EBSA and its level of human impact and can be used at global, regional and local scales. This methodology allows the classification of individual seamounts into four major portfolio conservation categories which can help optimize management efforts toward the protection of the most suitable areas. The framework was tested against 1000 dummy seamounts and satisfactorily assigned seamounts to proper EBSA and threats categories. Additionally, the framework was applied to eight case study seamounts that were included in three out of four portfolio categories: areas highly likely to be identified as EBSA with high degree of threat; areas highly likely to be EBSA with low degree of threat; and areas with a low likelihood of being EBSA with high degree of threat. This framework will allow managers to identify seamount EBSAs and to prioritize their policies in terms of protecting undisturbed areas, disturbed areas for recovery of habitats and species, or both based on their management objectives. It also identifies seamount EBSAs and threats considering different ecological groups in both pelagic and benthic communities. Therefore, this framework may represent an important tool to mitigate seamount biodiversity loss and to achieve the 2020 CBD goals. Deep-sea and open ocean waters are the largest and yet least understood environments on Earth One of the major challenges in designing and implementing governance and management strategies in these environments is the fact that deep seas and open oceans frequently fall in areas beyond national jurisdiction (ABNJ). Therefore, international commitments are necessary to undertake effective conservation actions. In the last twenty years, several global meetings on biological conservation and sustainable development have proposed to set aside for protection 10\u201330% of all the marine biomes  by the year 2012. The failure in meeting these objectives has been internationally recognized with just 1.17% of the world\u2019s oceans currently included in marine protected areas (MPAs) mostly located in coastal waters www.gobi.org). However, the patchy nature of biological and ecological data regarding deep and open ocean ecosystems hinders a systematic application of these criteria and implies a wide reliance on global models and remote sensed data The methodologies suggested by the CBD should not be restricted to ABNJ and could also be adopted and implemented within areas of national jurisdiction. Pilot studies have identified several potential EBSAs in different marine regions  that capture the most relevant pelagic, benthopelagic and benthic components of seamount ecosystems. The presence of such indicators can be assessed by both using real data coming from sampled features or global models which could complement data deficient sites.http://www.gobi.org/candidate-ebsas). The presence of endemic organisms to assess the level of faunal uniqueness has to be considered with extremely caution, since seamount endemicity has been recently questioned The presence of hydrothermal vents on seamounts was used as a proxy for uniqueness. In fact, vents host a number of special communities and organisms that are found nowhere else in the marine environment e.g. Areas containing breeding or spawning grounds, juvenile habitat and important habitats for migratory species are considered good examples of this criterion The IUCN red list provides a comprehensive list of threatened, endangered or declining species sensuThis criterion values the degree of risk that will be incurred from human activities or natural events The dynamics of marine production in the open and deep oceans are poorly understood. To date, the depth of submarine features represents the best indicator of seamount productivity. In fact, shallow seamounts may intercept the diel vertical migration of zooplankton and micronekton, trapping these vertically migrating organisms and/or aggregate small zooplanktonic animals horizontally advected. This could result in an increased prey availability, which may benefit resident and visiting animals enhancing secondary production and aggregating behaviors Reliable estimates of biodiversity for seamounts are difficult to obtain with the data currently available in the scientific literature. However, the presence of structural species may increase local biological diversity and be used as a proxy for this criterion e.g. These are areas with a comparatively higher degree of naturalness as a result of the lack or low level of human disturbance Ten indicators were used to identify seamount EBSAs : four beIndividual indicators were weighted based on the relevance they have in the assessment of the EBSA criteria. Factors used to verify more than one criterion had a higher weight in the analysis . For exaThe major human activity currently impacting seamounts is fishing Mineral exploitation is likely to pose a serious threat to seamount ecosystems in the near future The effects of fishing and mining on individual seamounts were quantified using an expert knowledge system. This system was adapted from two recent reviews where experts were asked to rate the impact of several fishing gears on different taxonomic groups and habitats using a scale ranging from very low to very high The \u201cthreats score\u201d of individual seamounts was determined by the anthropogenic activities occurring on that features. In fact, benthic, benthopelagic and pelagic seamount components will experience different levels of disturbance depending on the set of human related activities present. Among the set of fishing and mining practices present on a specific feature, it is possible to identify a subset of activities likely to pose the highest impacts to the different components considered . The final threat score was thus calculated as the average of the maximum impacts  posed toTo account for data uncertainty, data quality issues and the varying degree of knowledge regarding different seamounts and geographical area, a data uncertainty index similar to the one elaborated in Wallace et al. Two measures were incorporated in the index: a data quality index (DQ) and a data deficiency index (DD). Data quality reflects origin and nature of the collected data and was divided into three categories: low (scored as 1), medium (scored as 0.5), and high (scored as 0) data quality. Considering the wide nature of seamount studies, the definition of these categories was not very strict but was based on general guidelines. The high data quality category was designed to include information mainly derived from rigorous scientific surveys. Even though data included in this category should be predominantly quantitative, qualitative data may also be considered as high quality data if in great detail. Medium quality data are incomplete quantitative information or qualitative descriptions of EBSA indicators and human impacts present on individual seamounts. These data should always be specific to a particular feature and validated in the literature. Low quality data include undisclosed data regarding wide geographic areas which do not specifically address seamounts, information inferred from models or from different seamount properties or data not properly referenced. The detailed scoring standards used to assign the data quality scores to all EBSA and threat indicators are described in the supplementary information  and S3. The data uncertainty index is visualized as error bars in plots of the seamount EBSA likelihood scores versus human threats scores. Minimum and maximum values of each final seamount EBSA likelihood and human threats score are calculated by subtracting and adding the data uncertainty index. The error bars can therefore potentially range up to two units above and below the original score. In this manner, a seamount lacking data and/or with low data quality is shown as possibly belonging to different EBSA likelihood and threat categories, reflecting the uncertainty of the outcome.Protecting all seamounts is neither particularly rewarding nor practically feasible considering the high variation that exists in terms of their ecology, geophysics and potential human impacts and the large number of seamounts present in the world\u2019s oceans. Therefore, approaches that systematically highlight conservation priority areas for seamount ecosystems can constitute a valuable tool for marine management purposes. We hereby propose an approach that combines the likelihood of a seamount constituting an EBSA and the level of human impact posed to a submarine feature to locate priority areas for seamount conservation at global, regional and local scales. This methodology allows the classification of individual seamounts into four main conservation categories, which can help in optimizing management efforts toward the protection of the most suitable areas. The portfolio categories are: Low EBSA likelihood-Low threats; Low EBSA likelihood-High threats; High EBSA likelihood-Low threats; High EBSA likelihood-High threats. EBSA likelihood and threats for individual seamounts can be easily summarized and graphically compared.Additionally this approach is designed in a way that helps in visualizing what parts of the ecosystems  are contributing to the EBSA score or being threatened by human induced activities. This is of paramount importance in identifying seamounts that may be ecologically or biologically significant for both the benthic and pelagic components of the ecosystem and in complementing preexisting conservation strategies with the protection of underrepresented seamount components.In order to test the framework developed here, we have randomly assigned the presence or absence of the ten indicators developed in the EBSA scoring procedure and of the nine types of threats considered in the threats scoring procedure to 1000 dummy seamounts . In this way it was possible to assess the ability of our framework to assign real world seamounts to the different portfolio categories considered. In addition, a set of eight seamounts from different geographical areas were selected as case studies for applying the present framework, six located in the Atlantic Ocean  and two located in the Gulf of Alaska (Cobb and Bowie seamounts). Data for the evaluation process were obtained by reviewing the existing literature The dummy seamounts were assigned to all 4 portfolio categories with only 5.1% seamounts considered as highly likely to be identified as EBSA with low degree of threat and 3.6% seamounts with low likelihood of being identified as EBSA with low degree of threat. Most of the dummy seamounts fall in the category low likelihood of being identified as EBSA with high degree of threat (36.2%) or high likelihood of being identified as EBSA with high degree of threat (55.1%). These results indicate that the framework is adequate to assign seamounts to different portfolio categories. In For the 8 case study seamounts considered, seamount EBSA likelihood scores  ranged fOverall, the eight seamounts evaluated were allocated to three different portfolio categories of EBSA likelihood and threat exposure : high liOf the case studies considered, Sedlo and Gorringe are those with the highest EBSA likelihood scores and, therefore, they may represent the most suitable areas where to adopt conservation measures. These two seamounts are experiencing very different levels of human pressure, with Sedlo presenting lower chances of detrimental effects caused by human activities than Gorringe. However, given the large uncertainty associated with the Gorringe threat score, a further evaluation of the activities should be undertaken. Sedlo has already been proposed as a suitable site for a marine protected area In order to achieve the conservation goals established under the Convention on Biological Diversity, scientists from different fields were asked to define and apply criteria which can highlight marine areas of particular interest The framework proposed here was designed to set priorities in seamount conservation and to help developing spatially explicit seamount management policies. In order to avoid the location of protected areas in places that contribute little to preserve ecosystem structures and processes, the biological or ecological value of specific areas should always be considered as a primary criterion for the identification of conservation priorities Three aspects were central in the practical definition of the proposed methodology. Our first concern was to develop a system which could provide solid measures of the relative value and threat status of individual seamounts. The choice of the selected seamount EBSA indicators and the definition of the most relevant human activities to seamount ecosystems were based on an extensive review of the existing literature and through intense consultations with seamount experts. This approach constitutes, therefore, a complete synthesis of what is presently known regarding seamount ecosystems. Our second concern was to design a system compatible with the data currently available. The major constraint faced by this kind of analysis is generally the scarcity of information readily available. In fact, while a very small portion of submarine relief has a fairly detailed ecological and biological description and an accurate report of ongoing anthropogenic activities, the large majority of seamounts have either never been explored or even charted through direct scientific measurements or only partially described The outcomes of the dummy seamounts may serve as an indication of the robustness of our methodology. Since our analysis was based only on presence/absence data, conservative outcomes regarding the threat status of individual seamounts should be expected. This is reflected in the outcomes of the analyses, where the highest proportion of seamounts fell within the high threat score category. Moreover, the consistent allocation of the dummy seamounts into high and low EBSA likelihood categories, as shown in Another important characteristic of this framework is that allows the identification of seamount EBSAs and threats considering different ecological groups in the pelagic and benthic realms . In bold the most conspicuous cold-water taxa.(DOCX)Click here for additional data file.Table S2Scoring standards used to assess the data quality of the EBSSA indicators.(DOCX)Click here for additional data file.Table S3Scoring standards used to assess the information quality regarding the human activities occurring at a seamount.(DOCX)Click here for additional data file.Information S1Guidelines for scoring human-induced threats to individual seamounts.(DOCX)Click here for additional data file.Information S2Description of the information used to evaluate the seamounts\u2019 EBSA likelihood and threats.(DOCX)Click here for additional data file."}
+{"text": "We describe a novel method for analyzing neural data that uses a combination of Markov transition matrices and Kullback-Leibler divergence to characterize spike history and spike patterns. For this method, the interspike intervals (ISIs) are divided into bins by quantiles, and a Markov transition matrix is computed for the ISI sequence. This Markov transition matrix is then compared to another Markov transition matrix constructed under the assumption of independent spiking. We then compute the Kullback-Leibler divergence between the distributions of ISI transition probabilities for each bin. The purpose of this method is to quantify the effects of spike history on neuron output and to help better characterize the flaws associated with assuming independent spiking.We test this method on both simulated data and experimental data from primary visual cortex of cats, publicly available through CRCNS -3. InterThese results emphasize that the main shortcoming of simple spiking models, like the Poisson model, is a failure to account for spike history and spike patterns related to bursting and long periods of silence. This also suggests that neural systems can gain an advantage in computational efficiency by accounting for spike timing aspects of bursting and extended periods of silence within the neural code."}
+{"text": "Traumatic brain injury (TBI) represents one of the greatest unmet needs in medicine and public health ? Could this be perhaps that we still have insufficient knowledge of how degradation products from brain tissue are removed into the venous blood? Is this directly into the venous system, or indirectly by flow of the extracellular fluid draining via the cerebrospinal fluid into the sagittal sinus? Basic understanding of such mechanisms would be of great relevance toward optimal biomarker sampling. Whilst many studies on the prognostic value of biomarkers show clear prognostic effects, it should be realized that numbers in these studies in general are small and that the added value of biomarkers as prognostic indicators over and above other predictors has not yet been adequately shown in multivariable analyses. The concept of being able to differentiate between neuronal and glial injury based upon biomarkers is exciting. This topical issue will also address relations between laboratory markers and other biomarkers such as imaging modalities. By definition characterization and classification of brain injury is multidimensional. Better characterization with the aid of biomarkers can be expected to facilitate Precision Medicine, a concept recently advocated by the US National Academy of Science . Precisi"}
+{"text": "The costs of developing a probiotic or prebiotic ingredient have always been substantial. Ingredient characterization, evaluation of technological and physiological properties, and demonstrations of safety and clinical efficacy require expensive research. The demanding regulatory requirements imposed by EFSA raise the bar even higher so that the costs of acquiring the necessary clinical evidence to support labeling of these food ingredients is approaching that of pharmaceuticals. In order to justify investment in such expensive clinical development, companies require certainty that they can gain a return on investment. Patenting can provide some protection but is not always possible to patent ingredients, and the period of protection is limited. All ingredients eventually face the prospect of commoditization once patents expire. Branding strategies offer one means of maintaining adequate product differentiation to protect market share and margins over the long term."}
+{"text": "Developing a sense of hope is a foundation for recovery. How can we inspire hope and motivation in those who are suffering from an eating disorder and the struggles that ensue?The Eating Disorder Mentor Program is a collaborative project between The Eating Disorder service at Royal Melbourne Hospital (ED-RMH) and Eating Disorders Victoria (EDV).It's an opportunity for people with a lived experience of an eating disorder to tell their recovery story and share their insight with current patients. Research has shown the many benefits of peer support which include increased feelings of hope for patients and the learning of practical strategies to assist their recovery. Mentors gain skill and satisfaction from seeing their lived experience used as a valuable source of expertise in promoting recovery.This presentation will:\u2022 Give an overview of the program including the aims, processes and results\u2022 Explore the value achieved by collaboration between a community based mental health provider and a specialist tertiary health service\u2022 Highlight the benefit of combining the experience of both health professionals and consumersCare in Inpatient and Community Settings stream of the 2013 ANZAED Conference.This abstract was presented in the"}
+{"text": "Microarray data acquired during time-course experiments allow the temporal variations in gene expression to be monitored. An original postprandial fasting experiment was conducted in the mouse and the expression of 200 genes was monitored with a dedicated macroarray at 11 time points between 0 and 72 hours of fasting. The aim of this study was to provide a relevant clustering of gene expression temporal profiles. This was achieved by focusing on the shapes of the curves rather than on the absolute level of expression. Actually, we combined spline smoothing and first derivative computation with hierarchical and partitioning clustering. A heuristic approach was proposed to tune the spline smoothing parameter using both statistical and biological considerations. Clusters are illustrated a posteriori through principal component analysis and heatmap visualization. Most results were found to be in agreement with the literature on the effects of fasting on the mouse liver and provide promising directions for future biological investigations."}
+{"text": "Neuronal morphology plays an important role in the processing of spatiotemporal synaptic input patterns.We formulate a new cable theoretic model to study the output in a dendritic cable with many subtrees, both analytically and computationally. The model is an extension of the continuum spine model derived by Baer and Rinzel  and likeA multicompartment model with equally spaced discrete branches implemented in NEURON  is used For a passive membrane and uniformly distributed branches, this formulation provides analytic estimates of electrical parameters, such as the input resistance. Transforming the equations to the frequency domain, we examine the steady state response properties for periodic forcing, where the impact of structural properties on transfer properties and the phase shift at different locations are calculated directly. Based on calculations of the voltage response along the primary neurite, the continuum formulation performs much better than a simple cable as an approximation of the morphologically realistic model. Simulations of the continuum model are in good agreement with the realistic model for frequencies up to 1000 Hz.In insects neurons the spike initiation zone (SIZ) is usually located far away from the recording site. We use this model to investigate the impact of the location of the SIZ and morphology on spike initiation and spike shape at the recording site as well as on activation and inactivation curves of ion channels obtained by voltage clamp recordings.Also we investigate how structural properties impact the results found in a point model of MN5, where variations of ion channel densities in physiological ranges lead to different observed firing properties ."}
+{"text": "Hemolytic activity was within the acceptable range revealing low toxicity risk of nanoemulsion. The ex vivo release studies of the formulated nanoemulsions were carried out using sheep nasal mucosa in comparison with drug suspension in simulated nasal fluid. The results revealed that release rate was biphasic and faster from drug suspension as compared to nanoemulsions. It can be concluded that nanoemulsions were prepared successfully having low particle size and can be used to deliver curcumin and artemether intranasally for management of cerebral malaria. The efficacy of the developed formulations either alone or in combination was evaluated further for antimalarial efficacy in Plasmodium berghei ANKA murine model of cerebral malaria in comparison with pure drug suspension administered intranasally and intravenously and showed promising results.The objective of the present investigation was to explore the potential of nanoemulsion (NE) containing artemether-curcumin combination to accomplish the delivery of drugs to the brain via olfactory delivery system for management of cerebral malaria. The components for curcumin NE (C-NE) and artemether NE (A-NE) formulations were selected based on saturation solubility studies and were prepared by aqueous titration technique . The muc"}
+{"text": "Iranian Red Crescent Society is a charitable and non-profit organization playing an active role in public-benefiting and humanistic affairs and services offered for rescue operations. The prospect of this society has been mentions as Red Crescent Society should be accountable for all kind of events in all parts of Iran with the highest possible efficiency and with minimal time required for services. In the bSWOT as a guide can analyze factors affecting the competition between the organizations and companies while providing a prospect for the future. Therefor"}
+{"text": "Aspergillus fumigatus, an interesting and relevant morphotype beyond the conidial and hyphal stages has gained increasing attention: the multicellular biofilm. Such hyphal communities were first described for A. fumigatus in 2007   as important component of Aspergillus biofilms (Ramage et al., Aspergillus lifestyle but also provide perspective for improvement and new avenues in antifungal therapy or biotechnological applications.In the light of the clinical as well as industrial relevance of"}
+{"text": "Given the high prevalence and serious consequences of both CVD and mental disorders, associations between the two types of diseases would have a major impact on public health. If there is a causal link between CVD and mental disorders, the screening and early treatment of one of the two types of diseases is likely to have a preventive effect on the other pathology. The mechanisms underlying this co-morbidity is poorly understood, partially due to major limitations of existing studies such as the use of clinical samples, the lack of an appropriate comparison group, the use of psychiatric rating scales for a single psychiatric syndrome rather than structured diagnostic interviews, reliability on self-reported somatic information rather than objective measurements and a lack of simultaneous assessment of cardiovascular risk factors which does not allow the study of potential pathways from a specific mental disorder to cardiovascular disease.The CoLaus/PsychoLaus is a prospective follow up of participants in the CoLaus cohort to assess whether mental diseases increase vulnerability to cardiovascular disease/risk factors or vice versa and to identify common pathogenic processes involved. It also gives better knowledge about long term course of mental disorders and cardiovascular diseases and service utilisation patterns all of which can result in more effective strategies in prevention and treatment. Current evidence from CoLaus/PsyCoLaus suggests a significant role of a typical depression symptom, which are strongly associated to physical and behavioural cardiovascular risk factors."}
+{"text": "Wood has played an indispensable part in the rise of human civilization, evolution of modern plants and has cornerstone importance for the sustained long term health and stability of managed and unmanaged ecosystems. Despite its importance, the molecular mechanisms involved in wood formation are still poorly understood.Wood formation initiates in a lateral meristem known as vascular cambium which consists of meristem cells  organized in single-cell radial file that form continuous cylinder around the stem. Cambium initials divide to produce xylem, phloem, and ray mother cells that in turn undergo several rounds of divisions followed by differentiation into respective cell types. Because of their importance to regulation the quantity and quality of wood production these processes are of substantial theoretical and applied interest but are poorly understood and thus very difficult to manipulate. The progression from meristem to fully differentiated cells is a complex process requiring highly organized transition from different developmental states, most prominently, loosing the pluripotency of meristem cell and committing to a specific cell/tissue fate . Because of the importance of this transition plants establish developmental boundaries that insulate cells in different stages of this progression. We have recently shown that plant-specific transcription factors of the LATERAL ORGAN BOUNDARIES DOMAIN (LBD) family play key role in the establishment and function of these boundaries .PtaLBD1  with uncharacterized previously function in poplar and Arabidopsis, is primarily involved in differentiation of secondary phloem and ray cells. Transgenic gain and loss-of-function experiments demonstrated that PtLBD1 is a positive regulator of secondary phloem growth and development. Expression and localization experiments showed predominant expression in the phloem and localization of the transcript on the boundary between the differentiating phloem and the cambium zone. Genes encoding regulators of meristem identity genes like ARBORKNOX1 (ARK1) and ARBORKNOX2 (ARK2) were downregulated while key regulators of phloem initiation like ALTERED PHLOEM DEVELOPMENT (APL) gene was upregulated in the activation tagged mutant line. The phenotype, localization and misexpression of ARK1, ARK2 and APL genes indicate that LBD1 is a critical component in the establishment and function of the developmental boundary between the vascular cambium and the differentiating phloem. It shows that the boundary genes like LBD have dual function to repress meristem identity but promote proliferation and differentiation. We have also found that LBD1 is downregulated by auxin and is co-expressed with strong repressors of auxin response. Because auxin concentrations peak in the cambium and LBD1 is downregulated by auxin we hypothesize that part of the molecular mechanism that establishes the boundary is through auxin-mediated repression of LBD1 in the cambium zone.The discovery leading to the realization of the importance of LBD proteins in woody development was the identification and subsequent characterization of an activation tagged mutant that shows enhanced woody growth. We have found that the activation of a LBD encoding gene, Populus identified 57 members; microarray results display that four LBD genes  show predominant expression in stems undergoing wood production with two genes expressed in the phloem (PtaLBD1 and PtaLBD4) and two in the xylem . This suggests that a similar regulatory mechanism is in operation during xylem growth and differentiation.Vascular cambium of most extant plants is bifacial \u2013 producing xylem to the inside and phloem to the outside of the stem trunk. We then asked if the boundary on the xylem side of vascular cambium is organized and regulated in a similar manner. A broad preliminary survey of the LBD family in Vitis vinifera. There were 12 putative LBD1 orthologs. Vitis is vine and has a unique wood anatomy. Most notably, the rays are highly multiseriate and secondary phloem is well-developed with multiple growth rings. The intercalation of less-lignified tissues in the xylem of vines and lianas and proportionally more parenchyma tissues is an adaptive feature allowing more stem flexibility. The multiseriate rays and increased secondary phloem production in Vitis resembles the poplar transgenics with increased PtaLBD1 expression. Thus the putative increased LBD1 gene dosage in Vitis, well-corresponds to its wood anatomical features and suggests that LBD genes like LBD1 may have played important role in evolution of wood anatomy as an adaptive mechanism reflecting species biology and life habit.Our studies also shed light on possible mechanisms in the evolution of woodiness and wood anatomy. The LBD proteins are present in most genomes of the sequenced species from the plant kingdom with exceptions of algae. This suggests that the LBD gene family has evolved after the colonization of land plants. Comparative sequence analysis of putative LBD1 orthologs in several sequenced plant genomes, indicates a large and highly significant expansion of the LBD1 gene in Our findings have broad importance with respect to regulation and evolution of wood formation. They provide tools for manipulation of woody growth and development and provide clues for the mechanisms involved in evolution of wood anatomy with relation to plants\u2019 biology and ecology."}
+{"text": "Excess gestational weight gain (GWG) in pregnancy is a major clinical challenge affecting 55-75% of Canadian women who enter pregnancy overweight and about 40% women of normal weight. The adverse sequelae of excess GWG for both mother and child are well documented and include a number of adverse health outcomes , which impose substantive burden of our health system. The larger research program aims to conduct a randomized trial with a diet and exercise intervention for optimizing GWG. The project presented here is a preliminary phase in order to determine feasibility and patient preferences to the proposed intervention.This project uses a qualitative approach employing focus groups and interviews of participant women (pregnant or recently pregnant) and health care providers that aims to identify the preferred evidence-based strategies for women to effectively manage their GWG during and after pregnancy and how best to implement the selected intervention. Primary research question: What are the preferences of pregnant and post-partum women and their health providers for engaging in healthy eating and increased physical activity? Secondary questions include: What do pregnant or recently pregnant women and health providers identify as enablers or barriers that support or limit successful management of GWG? What are women\u2019s and health providers\u2019 perceptions of GWG in relation to their health and the health of the child? What approaches have women and health providers tried to manage excess GWG?Outcomes include an identified preferred diet and exercise intervention for the planned clinical trial and information, which enables refinement of a locally acceptable implementation plan for the intervention.Collectively information from women and service providers enabled a comprehensive understanding of barriers, enablers and opportunities for the successful implementation of an intervention for GWG management."}
+{"text": "Action potentials (APs) generated and sustained by ionic currents flowing through neural cell\u2019s membrane constitute the main way these cells communicate with each other. The most common, although not the only possible mechanism of generating APs, involves sodium influx that ensures cell depolarization and potassium efflux that ensures cell repolaroization. A sodium-potassium exchanger and leakage currents eliminate the ionic disturbance created by an AP. In a closely packed bundle of neuronal cells with fast diffusion of ionic species in the extracellular space (ECS) an AP generated in one axon could impact the excitability of nearby neurons. The ECS is similar in composition to the cerebrospinal fluid that baths the outer surface of the brain and is present in large internal cavities or ventricles and in the spinal canal. The ionic composition of ECS is mostly made of sodium and chloride dissolved in water with much smaller amounts of other substances, including potassium and calcium. Previous studies have considered the role of potassium in seizures by employing a computational model of potassium diffusion between periodically firing neurons . However"}
+{"text": "This correction will replace the previous correction made by PLOS ONE. There is more information that is missing from the Funding Disclosure.The first sentence in the Funding Statement should read:This research was supported in part by a National Geographic Society Discovery grant (awarded to DYY and DL), a SSHRC Partnership grant (awarded to DL), the Tula Foundation and Hakai Network for Coastal Peoples and Ecosystems."}
+{"text": "An association of Paroxysmal Hemicrania (PH) with Trigeminal Neuralgia (TN) was described in eight patients ,2 and haLEPs study supported the diagnosis of TN idiopathic. It is still debated if the rare association of TN and PH is a new entity or two distinct disease. Further investigations by neuroimaging might be useful to clarify this issue and to better understand the pathophysiology of these entities ."}
+{"text": "The establishment of European Reference Networks as laid out under the Cross Border Health Care Directive (CBHCD) is a major opportunity for the rare disease community. There have been many successful networks for rare disease groups, but their establishment has been ad hoc and funding streams variable. Sustainability has been a major challenge. Although the assessment of the quality of these networks has not been systematic, nonetheless networks have succeeded in establishing important infrastructure including disease specific registries, shared tools such as tele-expertise and the production of disease specific guidelines and training pathways.Within the CBHCD it is envisaged that European Reference networks will be established, and these will not only relate to rare diseases. These networks will primarily link nationally designated centres of expertise. Within the EUCERD a process is being followed to inform the CBHCD committee on the specific issues relating to ERNs for rare diseases. These recommendations relate to areas of designation and governance, capacity building and resources to support ERNs and quality assurance.The recommendations will be discussed in a series of meetings in 2012, with the aim of producing a EUCERD recommendation on ERNs for rare diseases by the end of the year in line with the timeline of the cross border health care directive."}
+{"text": "Rigid bracing has been the mainstay of orthotic intervention for children with neurological onset scoliosis. The use of rigid braces, however, often do not provide the expected outcomes clinicians are hoping for with Cobb angles curve increasing over time , linked This paper will discuss the use of dynamic elastomeric fabric orthoses (DEFO) in this client group and question whether rigid bracing is most appropriate for long term outcomes. It will also discuss whether waiting for the 25 degree Cobb threshold, before treatment, is prudent.This study will use single case presentations (n=5) to demonstrate the advantages of early intervention using both radiographs and pre and post intervention photographs to illustrate the outcomes possible. All of the children have neurological onset scoliosis and show short/ medium term outcomes.The use of DEFOs to control scoliosis has provided clinicians with an opportunity with which to reduce the number of children presenting for orthopaedic spinal surgery. Clinically the scoliosis clinic at the Norfolk & Norwich University Hospital has seen a declining number of children referred for scoliosis surgical management over the last ten years due to early intervention. The DEFO scoliosis suits appear to work by providing heightened proprioceptive input to the brain coupled with dynamic corrective forces to correct and re- align the spinal segments. The DEF"}
+{"text": "Since its publication by the European Society of Radiology (ESR) and the European Association of Nuclear Medicine (EANM), the Multimodality Imaging Training Curriculum has given rise to numerous discussions regarding its aims and applicability \u20134.Both societies therefore wish to clarify specifically the purpose and scope of the document. The aim of the Multimodality Imaging Training Curriculum as a joint European initiative is to advance the quality of performance and reporting of hybrid imaging by defining the scope of training for medical specialists in hybrid imaging. It outlines skills and knowledge requirements in nuclear medicine for those whose training background is in radiology and in radiology for those whose training background is in nuclear medicine.This training curriculum is intended to relate solely to the training of specialists in hybrid imaging from both radiology and nuclear medicine with the purpose of ensuring optimal use of this complex methodology for patient care. It by no means encompasses full training and/or qualification in imaging modalities unrelated to hybrid imaging techniques."}
+{"text": "Familial Adenomatous Polyposis (FAP) is a well described autosomal dominant syndrome, whereby individuals develop multiple (up to thousands) of adenomatous polyps in the large bowel, conferring an extremely high risk of bowel cancer if left untreated.If the family specific mutation is known, genetic testing can be offered to at risk individuals to determine the need for endoscopic surveillance. Guidelines suggest starting endoscopic surveillance from the early teens. Most individuals with FAP undergo colectomy between the ages of 15 and 25 years [Recent studies have shown that many adults with FAP want their children to undergo genetic testing before the age of 12 years, the approximate age at which genetic testing is usually offered in Australia .Health professionals working in cancer genetics in Australia and New Zealand completed a web based survey aimed at examining their attitudes and experiences regarding genetic testing for young people at risk of FAP.Findings from the survey provide an insight into the views and practices of health professionals working in this area, including: the age at which they believe testing young people is most appropriate; their experiences regarding parental requests for testing of younger children; and whether the option of prenatal testing and pre-implantation genetic diagnosis is routinely discussed with individuals who have FAP and are also of child bearing age. These have important implications for clinical practice within the Australian cancer genetics community."}
+{"text": "Epigenetic mechanisms have emerged as important contributors to cancer initiation and progression. DNA methylation of gene promoters has been extensively studied since the 1970s but the role of DNA methylation in the activity of distal regulatory elements (DREs) has only recently emerged. We have previously shown that tissue-specific differentially methylated regions overlap with DREs and that DNA methylation status correlates with their activity and the ability to bind transcription factors. We and others also demonstrated that such elements are dynamic and prone to demethylation. Our goal is to understand the role of DNA methylation and hydroxymethylation in the activity of DREs in cancer progression. OSCC, characterized by a double aetiology (exposure to carcinogens and HPV infection) and highly variable response to therapies, will be used as a model system.Herein, we present the preliminary data of genome-wide identification of DREs in HPV-positive and HPV-negative OSCC cell lines using Digital DNaseI-Seq method and the application of this method in detection of chromosomal alterations \u2013 insertions and deletions. Data obtained at this stage will be used to establish a new methodological workflow for the 5mC and 5hmC analysis at DREs using capture array for fragment enrichment followed by third generation sequencing."}
+{"text": "The lack of a mechanism that aligns financial flows for global health research towards public health priorities limits the impact of health research on health and health equity. Collaborative groups of health research funders appear to be particularly well situated to ameliorate this situation and to initiate discussion on aid alignment for global health research. One such group is the Heads of International Research Organizations (HIROs), which brings together a large number of major government and philanthropic funders of biomedical research. Surprisingly, there is hardly any information publicly available on HIROs' objectives, or on how it aims to achieve more harmonization in the field of research for health. Greater transparency on HIROs' objectives and on its current efforts towards addressing the gap between global health research needs and investments would be desirable, given the enormous potential benefits of more coordination by this group. Such waThe Global Ministerial Forum on Research for Health in Bamako in 2008, in line with the Paris Declaration and the Accra Agenda for Action , recogniIn discussing the need for increased coordination among funders of research for health, it is important to consider what exactly needs to be coordinated. Recent positive developments among funders include the identification of common approaches to monitoring and evaluation and sharing research data ,18. Howe\"Heads of International Research Organisations\" OR \"Heads of International Research Organizations\" OR \"Heads of International biomedical Research Organisations\" OR \"Heads of International biomedical Research Organizations\" OR HIRO[Title/Abstract] OR HIROs[Title/Abstract] returns no relevant results. HIROs is not the only group where funders collaborate that is sparing with information. Recently, IHP+ was criticized for its lack of transparency [Since HIROs brings together the heads of major funders of biomedical research, it appears to be particularly well suited to give rise to the major changes in health research governance that are called for by the Bamako call to action. Unfortunately, HIROs has made little information available on its goals or on how it aims to achieve increased harmonization, alignment and coordination. An internet search reveals only websites noting that a meeting has taken place, and a search on PubMed for sparency . Individsparency .An initiative like the HIROs group is most welcome in the crowded field of global health research funders. It is surely one of the few groups that could initiate discussion on aid alignment for global health research. Given the enormous potential benefits of more coordination by this group, the contents of its discussions are of great interest to the global health research community. More transparency on HIROs' intentions for achieving increased coordination and on its current efforts towards addressing the gap between global health research needs and investments would therefore be desirable.The authors declare that they have no competing interests."}
+{"text": "High-density microelectrode arrays (MEA) can measure neuronal activity in potentially thousands of units with a high spatial resolution . HoweverHere we estimate the quality of spike detection using correlations as an indicator to distinguish between neuronal activity and noise. First we use a threshold-based detection of putative spikes, with a deliberately low threshold to lower the number of undetected spikes. We estimate pairwise correlations between spike trains based on spike ranks rather than time in order to reduce the effects of nonstationarities in the recordings. We then assume that the frequency of spontaneous firing in the neurons is small compared to the evoked firing and check for each detected spike whether we can find correlated units which are active within a short interval around its spike time. For each unit, we compare the relative frequency of such correlated spikes to the frequency that would be obtained by doing the same analysis with a Poisson spike train.This yields a per unit estimate of the fraction of putatively falsely detected spikes and we validate the procedure using shuffled data and recordings of an empty MEA (see Figure"}
+{"text": "The 2008\u20132012 French Alzheimer plan is marked by the experimental implementation of \u201cHomes for Integration and Autonomy for Alzheimer patients\u201d with implementation of intensive case management process for people in complex situation. In 17 experimental sites, teams of case managers (CMs) have been implemented with a total of 67 case managers for performing an intensive case management.We conducted a qualitative study to develop a full understanding concerning the implementation of the case management process and the links with the interdisciplinary approach. Focus groups were conducted in 2010 to explore the perceptions of case managers six months after their recruitment.Interdisciplinary approach inside the case managers\u2019 team has been rapidly constructed to resolve the complex situations, homogenize practices and help to create the new competency. Multidisciplinary and proximity team, common training and difficulties to get the good fit with professionals increased the interdisciplinary approach inside the case managers\u2019 team. Interdisciplinary approach between case managers and clinical professionals was few implemented because of the high level of fragmentation and lack of case managers legitimacy.Implementation of intensive case management in an innovative integrated services delivery showed a stronger interdisciplinary approach between case managers compared to with clinical professionals."}
+{"text": "Infections with the hepatitis B virus (HBV) are one of the major global public health problems. HBV has been categorized into different genotypes and subgenotypes that are distributed distinctively around the world. These classifications provide important information as the genotypes differ with respect to the clinical course of disease as well as in their response to antiviral therapy, and subgenotyping allows relevant conclusions about transmission routes, global or local spreading of infections or phylogenetic relations between viral strains . SeveralThe latest of these studies (published in 2012) investigated HBV genotypes and subgenotypes among patients living in the Eastern Black Sea region of Turkey . The aut"}
+{"text": "To the Editor,The article by E. Yorgancilar et al.  presentsIn connection with the article let us ask some questions to the authors: Were all of the patients operated on primarily? Why were the extradural abscesses and the temporal lobe abscesses not evacuated during the mastoid surgery? Temporal lobe abscesses may be evacuated during ear surgery (by puncture and aspiration). In this method of temporal lobe abscesses evacuation neuronavigation is a very serviceable tool. Neurosurgical approach to the cerebellar abscess and to the abscess located in occipital area is preferred. In patients with LST treatment consists of canal wall down mastoidectomy, delamination of dura and puncture of sigmoid sinus. When perisinus abscess is absent and a patient does not present symptoms of sepsis the clot is not removed from sigmoid sinus . In pres"}
+{"text": "Hemodynamic single use devices (SUD) namely cardiac catheters are reused worldwide and in India, where cost and aggressive intervention take priority over infection prevention, is no exception. An important issue associated with the reprocessing of any SUD is the potential for subsequent transmission of infectious agents.The reprocessing and sterilization methodology of reuse of SUD is often left to the discretion of the nursing staff (the clinicians do not play any role).The concerned staff often put the process best they know or is passed on by the predecessors. Safety, sterility issues are overlooked.To evaluate reprocessing and sterilization methodology. To develop guidelines and oversee their implementations that result in standardized practices and improve the safety of hemodynamic device reuse.Infection Control team took over the responsibility of the process initially by a small pilot study. A robust cleaning and sterilization processes protocol based on basic microbiological principles was developed and tested for bacterial, viral and endotoxin reminants before using on patients. Initially twenty cardiac angiogram patients (consent was taken) were followed up for three months for any adverse events with reuse policy in place. Clinicians feedback was taken and modification made in the process at the end of study. It was extended it to a full fledged protocol and implemented.This system is in place for the past 5 years and there are no adverse events reported on follow up (over 8000 angiograms so far).The facility does 12 angiogram per day and reuse is 75%.The protocol implementation has resulted in determining the number of times each catheter can be reused. The process is continuously audited and compliance to the protocol is 100%.The steps for repossessing are easy, adaptable, outcome measurable, sustainable and cost effective in resource limited settings.SUD is reused rampantly. No standard guidelines are available .The reprocessing is left to the staff who are ill informed of the consequences of reuse. The reprocessing should be based on sound microbiological and infection prevention principles and implementable .Frequent audit and follow up of patients is essential.None declared."}
+{"text": "Sir,It is well known that contamination of the anaesthesia work area with potential bacterial pathogens and blood occurs intraoperatively followinWe propose the use of the plastic cover of the disposable PVC endotracheal tube to keep the contaminated laryngoscope blade to avoid soiling the top of the anaesthesia machine and work area. The laryngoscope blade can easily be kept inside this plastic cover which had been opened before intubation . The conThe complex intraoperative environment has been theoretically associated with the development of nosocomial infections and may contribute to the emerging pattern of increasing bacterial resistance in the hospital setting. Currently, there is no consensus regarding a satisfactory method for the routine cleaning, disinfection and sterilization of laryngoscope blades and handles. It has been shown that 33% of anaesthesia work surfaces Tobin MJOur method of safeguarding the anaesthesia work area from soiling with the contaminated laryngoscope blade is very simple, does not involve any extra expenditure and has the potential to reduce iatrogenic transmission of infection in the perioperative setting."}
+{"text": "Two institutions that provided for payment of the publication charges for the article- a funding organization and university with which authors are affiliated that disbursed the funding- were incorrectly omitted from the funding statement. The Funding Statement should read: \"The article processing charge was funded by the German Research Foundation (DFG) and the Albert Ludwigs University Freiburg in the funding programme Open Access Publishing.\""}
+{"text": "To determine whether the pattern of late presentation noted previously in 2007 and 2008 in all patients newly diagnosed with HIV in our regional unit  has decrA retrospective case-note audit was undertaken in the ID/GUM clinics for all patients who were newly diagnosed with HIV in 2009. Patients were characterised as late presenters if they presented with a CD4 count of less than 200 or an AIDS defining illness. Medical records were reviewed to determine whether the patients had previously been diagnosed with a clinical indicator disease as defined by the UK National HIV Testing Guidelines, 2008, which might have facilitated earlier diagnosis of HIV. These 2009 data were compared with previous 2007 and 2008 data.See table 1Significant numbers of patients  still present with advanced HIV disease in the North East of England in 2009 despite the publications of the National UK Testing Guidelines in 2008. The numbers of late presenters have not changed as compared to 2007 and 2008. This is despite that a large proportion having had previous indicator diseases that should have prompt clinicians to test for HIV. Further education and awareness of the UK National Testing Guidelines 2008 should be encouraged if this burden of late presenters is to be reduced."}
+{"text": "The vertebrate retina has a very high dynamic range. This is due to the concerted action of its diverse cell types. Ganglion cells, which are the output cells of the retina, have to preserve this high dynamic range to convey it to higher brain areas. Experimental evidence shows that the firing response of ganglion cells is strongly correlated with their total dendritic area and only weakly correlated with their dendritic branching complexity. On the other hand, theoretical studies with simple neuron models claim that active and large dendritic trees enhance the dynamic range of single neurons. Theoretical models also claim that electrical coupling between ganglion cells via gap junctions enhances their collective dynamic range. In this work we use morphologically reconstructed multi-compartmental ganglion cell models to perform two studies. In the first study we investigate the relationship between single ganglion cell dynamic range and number of dendritic branches/total dendritic area for both active and passive dendrites. Our results support the claim that large and active dendrites enhance the dynamic range of a single ganglion cell and show that total dendritic area has stronger correlation with dynamic range than with number of dendritic branches. In the second study we investigate the dynamic range of a square array of ganglion cells with passive or active dendritic trees coupled with each other via dendrodendritic gap junctions. Our results suggest that electrical coupling between active dendritic trees enhances the dynamic range of the ganglion cell array in comparison with both the uncoupled case and the coupled case with cells with passive dendrites. The results from our detailed computational modeling studies suggest that the key properties of the ganglion cells that endow them with a large dynamic range are large and active dendritic trees and electrical coupling via gap junctions. One of the many important features of the vertebrate retina is the capacity to respond to signals over a wide range of intensities with a dynamic range of several orders of magnitude spatially extended excitable systems whose nonlinear input-output transfer function endows the neuron with a large dynamic range. If this hypothesis is valid, most cells of the vertebrate retina do not benefit from this property because they have simple dendritic structures. The possible exceptions are the ganglion and amacrine cells, which are the most complex cells of the retina and have relatively intricate dendritic arbors A single neuron characteristic, which is claimed to be fundamental for enhancing the neuronal dynamic range in general is the size and complexity of the neuronal dendritic tree with active conductances versus stimulus current (F\u2013I) curve. These studies found strong correlations between the total somatic plus dendritic surface area of the cell and its electrophysiological class and F-I curve.There is evidence in favor of a relationship between properties of ganglion cell dendritic trees and their firing behavior, however not exactly as predicted by the above theory. Computational studies with morphologically reconstructed models of ganglion cells of the salamander retina From the point of view of network properties, a mechanism that may contribute to enhance the collective dynamic range of the network is electrical coupling between cells via gap junctions Ganglion cells of the vertebrate retina are coupled by electrical synapses via dendrodendritic gap junctions In this work we use morphologically reconstructed, multicompartmental models of ganglion cells of the vertebrate retina with realistic distributions of ion channels to perform two computational studies on the dynamic range of ganglion cells. The first is concerned with the dynamic range of isolated ganglion cells and its objective is to compare the effects of active and passive dendrites on the cells\u2019 dynamic range and to assess what measure of size of dendritic arbor correlates better with the ganglion cell dynamic range: total dendritic surface area or number of dendritic branches. We measure the correlation between dynamic range and these two measures of dendritic tree size for a population of cell models with either passive or active dendrites. Our results show that active dendrites enhance the dynamic range in comparison with passive dendrites and when dendrites are active the dynamic range of isolated ganglion cells is positively correlated with either measure of dendritic tree size, though more strongly with total dendritic surface area than with number of dendritic branches.The second study is aimed at assessing the role of ganglion cell coupling by gap junctions on the dynamic range of the ganglion cell population. We construct a network of ganglion cells by coupling them via dendrodendritic gap junctions with realistic conductance values. The network simulates a small area of the ganglion cell layer. We consider different configurations of the network, with passive/active dendrites and different values of the electrical synapse conductance. The dynamic range of the network is measured either directly, by the average firing rate of all neurons in the network, or indirectly, by the firing rate of a lateral geniculate nucleus pyramidal neuron model coupled by chemical synapses to all ganglion cells in the network. As far as we know, this is the first computational investigation of the dynamic range of a neural cell layer using reconstructed neurons with full morphologies and realistic ion channel distributions. Our results show unequivocally that electrical coupling, especially when dendrites are active, increases the dynamic range in comparison with the uncoupled case.Our two results put together imply that to maximize the dynamic range of a population of vertebrate ganglion cells the best configuration would be cells with large and active dendritic trees coupled by gap junctions.We worked with a sample of 20 morphologically and biophysically detailed models of ganglion cells from the tiger salamander (for details see Methods). Cells belonged to four different morphological groups (5 per group), based on the size and complexity of their dendritic trees 1 to 2.103 pA in steps of 10 pA. In The dynamic range of each cell in the sample was determined from its F-I curve (see Methods). To obtain the F-I curve of a cell model, we submitted it to somatic step current injections ranging from 10The transition from tonic firing to rest observed in versus number of dendritic branches , the dynamic range is only marginally larger when the compartment is active in comparison with when the compartment is passive. However, for larger areas the behaviors of the cases diverge dramatically: the dynamic range for the active case constantly increases with area while the dynamic range for the passive case constantly decreases with area. The difference \u0393 between the dynamic ranges for the active and passive cases is shown in The results of this experiment are given in The second study was designed to assess the effect of electrical coupling between ganglion cells on the collective dynamic range of the cells. We simulated a 3\u00d73 square array of ganglion cells coupled via dendrodendritic gap junctions as shown in 1 to 105 pA. This central neuron excites the other neurons via gap junctions so that we can relate the steady state firing frequency of each one of the nine neurons in the array to the amplitude of the applied current input. In our experiments, step current inputs were applied to the central neuron of the array with amplitudes varying from 10Each coupled cell exhibits a F-I pattern similar to the one of the single cell in Although the enhancement was similar for the simulations with passive and active trees, the maximum dynamic range was obtained for the coupled array of ganglion cells with active dendrites . This ref given in f was calculated as IA/IP, where IA is the maximum current amplitude for the indicated cell of the coupled array with active dendrites and IP is the maximum current amplitude for the same cell with passive dendrites. The calculated value of f\u200a=\u200a2.94 shows that when cells in the coupled array have active dendrites the chosen cell can respond to inputs almost 3 times higher before saturation when compared to the same cell in the same coupled array but with all cells in the array with passive dendrites.A quantitative estimate of the contribution of active dendrites to the further enhancement of the dynamic range of a cell in the coupled array is provided by factor An indirect way to assess the dynamic range of the coupled array of ganglion cells is by measuring the dynamic range of the pyramidal neuron that receives input from them. The main result of our simulation studies with morphologically reconstructed ganglion cell models is that active dendrites enhance the dynamic range of the cells. The other two important results are that (1) for isolated ganglion cells, the dynamic range has positive and significant correlation with the size of the active dendritic tree , and (2) by coupling ganglion cells via gap junctions the dynamic range of the coupled cells is further enhanced, being greater than the average dynamic range of the individual cells.Why a cell with active dendrites has a larger dynamic range than a morphologically similar cell with passive dendrites? Passive dendrites act as current sinks. Current injected at the soma escapes to dendrites reducing the efficiency of the input current in making the cell fire. Active dendrites, on the other hand, allow soma-generated spikes to propagate into the dendritic tree. These in turn generate dendritic spikes, which interact nonlinearly across the dendritic arbor leading to creation and annihilation of spikes and the consequent enhancement of the cell\u2019s dynamic range This explains the lower values of dynamic range for ganglion cells with passive dendrites in comparison with ganglion cells with active dendrites. It also explains the positive correlation between dynamic range and size of the dendritic tree for cells with active dendrites and the negative correlation between dynamic range and size of the dendritic tree for cells with passive dendrites. Since passive dendrites act as current sinks, the larger the dendritic tree, the more space for current to sink. On the other hand, larger dendritic trees have more active ion channels to support spike creation and summation.per area rather than per dendrite.And why dendritic surface area correlates better with dynamic range than with number of dendritic branches? The stronger correlation of dynamic range with dendritic surface area than with number of dendritic branches means that dendritic surface area is a better predictor of dynamic range than number of dendritic branches. As commented above, the critical factor for the enhancement of the dynamic range of a cell is to have active ion channels distributed over its dendrites. So, surface area correlates better with dynamic range simply because it is a better estimator of the number of ion channels in a dendritic tree than number of dendrites. This is because the number of ion channels in a dendritic tree is determined by channel densities A demonstration that the key factor to enhance the dynamic range of a ganglion cell is the number of active ion channels in its dendrites is given by the results shown in Our results show that when ganglion cells are coupled by gap junctions their dynamic range is much higher than the average dynamic range of isolated ganglion cells. Even ganglion cells with passive dendrites, when coupled by gap junctions, have a larger dynamic range than isolated ganglion cells with active dendrites. The average dynamic range of these latter is 11.30 dB and the dynamic range of the former is 31.9 dB. When the coupled cells have active dendrites, the dynamic range of the array is a little higher: 34.7 dB.Why coupled cells with passive dendrites have a larger dynamic range than isolated ganglion cells with active dendrites? The reason for this is that dendrodendritic coupling by gap junctions interlinks the somata of the cells, which have active ion channels, transforming the system into a spatially extended excitable medium. The mechanism responsible for the enhancement of the dynamic range of the coupled ganglion cells with passive dendrites is, therefore, the same one responsible for the enhancement of the dynamic range of an isolated ganglion cell with active dendrites, namely nonlinear summation of spikes Based on our results on the dynamic range of coupled ganglion cells we can make two predictions: (1) blockade of gap junctional coupling of ganglion cells in the vertebrate retina should strongly reduce (approximately by 40%) the output dynamic range of the retina; and (2) selective suppression of dendritic (but not somatic) spiking of coupled ganglion cells in the vertebrate retina should reduce the output dynamic range of the retina by a much smaller factor (approximately 9%). These reductions could be verified by simultaneous recording from lateral geniculate nucleus pyramidal cells.In a previous work, we used a detailed model of the scotopic pathways that convey information from rods to a single ganglion cell of the vertebrate retina to study the effect of coupling by gap junction at the first stages of these pathways on the dynamic range of the ganglion cell We further predict, based on our results, that it is unlikely that any type of ganglion cell would have a passive tree or a very low channel density at the dendrites. We also predict that, if there are uncoupled ganglion cells in the retina, these are distributed over the retina so that cells with large dendritic trees (which imply large dynamic ranges) are able to integrate signals from circuits mediated by rods and cones responding to dim and bright light conditions. On the other hand, ganglion cells with small dendritic trees should be specialized to photopic or scotopic conditions. These predictions could be experimentally confirmed in the future with a detailed study on the distribution of morphologically distinct ganglion cells over the vertebrate retina.Future investigations can provide a better understanding on the roles of cell connectivity and membrane properties on the dynamic range of the retina. The model can be further improved with a more realistic synaptic input distribution over the dendrites of ganglion cells and also extended to include the main circuits involved with dim and bright light processing in the retina.Ambystoma tigrinum) retina http://senselab.med.yale.edu/modelDB). The reconstructed neurons were classified into four groups: medium-complex (MC), medium-simple (MS), small-complex (SC), and small-simple (SS) We worked with a sample of 20 morphologically reconstructed, three-dimensional ganglion cell models from the tiger salamander (A), one calcium-dependent channel (KCa). The dynamics and parameters of the calcium current were able to fit the high-voltage activated component of the calcium current (L-type) described in a previous experimental work A channels have inactivation kinetics. The channel densities for each group of compartments are given in The same set of active ion channels were placed in all ganglion cell models. Each model has four voltage-dependent channels  was calculated as:Na and IK currents and the T-type calcium current. The values of the parameters used to model these channels can be seen at the original work The single compartment model of a lateral geniculate nucleus pyramidal neuron used to obtain We used experimental evidence of dendrodendritic bidirectional gap junctions connecting ganglion cells tbinding \u200a=\u200a0.2 ms, tunbinding \u200a=\u200a1.1 ms), activated by square-wave transmitter pulses of amplitude 1 mM and duration 0.3 ms The excitatory chemical synapse between the axon of a ganglion cell and the LGN pyramidal cell was modeled by a closed/open gating scheme (The network model consisted of 9 ganglion cells and a single LGN pyramidal cell. The ganglion cells were arranged in a 3\u00d73 square grid and connected by gap junctions as shown in 1 pA to 105 pA separated by steps of 10 pA. We consider 0.3 seconds a period sufficiently long for a reliable estimate of the ganglion cells\u2019 firing frequency and to obtain the dynamic range of the ganglion cells and the pyramidal neuron. The simulations were performed in NEURON 7.1 To obtain the average response of the ganglion cells and the pyramidal neuron for a given amplitude of current clamp, we stimulated the network with the current for 0.3 seconds and counted the number of spikes during this period. We used current amplitudes in the range from 10"}
+{"text": "The standardised mortality ratio (SMR) is a key parameter by which ICUs quantify their performance. We report the effect of increased ICU consultant numbers on mortality and SMR in a central London teaching hospital.The study was registered with the Clinical Audit Support System. Data were collected prospectively from March 2005 to date by a dedicated audit team and were analysed as part of routine audit.Table In this study we describe the remarkable reduction in both mortality and SMR that has occurred in the general ICU at King's College Hospital over the past 5 years. The improvement in outcomes was associated with a quadrupling of ICU consultant numbers. We hypothesize that this increase in intensivist numbers allowed the reinforcement of a closed model of ICU care. We are now further analysing these data to search for quantitative improvements in surrogate markers of quality of care over the same time frame."}
+{"text": "Most of our cognitive life depends on our brain's ability to generate internal representations of the external world. The hippocampus is a brain structure that supports the formation of internal representations of the spatial environment  could suggest that once sequentially active cell assemblies are bound into a temporal sequence during theta they no longer need the theta oscillation for them to be expressed at a later time. This scenario would be consistent with the third prediction that posits that compressed temporal sequences of novel place cells should not be expressed before the novel spatial experience. However, temporal firing sequences reflecting the future order of place cell firing and future novel trajectories can be expressed during sharp-wave ripple epochs occurring during sleep or rest in na\u00efve animals before they had any experience on long linear tracks (Dragoi and Tonegawa, We explored the role of synaptic plasticity of intrinsic hippocampal circuitry in the internal organization of the hippocampal network in sequential cellular assemblies (Dragoi et al., The existence of preconfigured cellular assemblies and the phenomenon of preplay lead to a novel concept that an animal's encounter with a novel spatial experience is encoded in the hippocampus, in part using blocks of pre-made cellular firing sequences rather than creating all the sequences de novo in response to the external cues. This mechanism may contribute to the role of the hippocampus in prospective coding (Schacter et al.,"}
+{"text": "HIV drug resistance has proved to one of the greatest challenges to effective and durable viral suppression. Selection of drug resistance mutations and widespread cross-resistance between agents of a class are a main obstacle when administering antiretroviral agents in clinical practice. This has been perhaps the greatest barrier to incorporating HIV care in to routine medical management administered by general practitioners. As opposed to many other disease states where the development of effective therapy allowed for simple widespread use as part of general care, HIV drug resistance has mandated cumbersome, resource consuming and demanding medical practice from both clinicians and even more so patients. Extremely demanding lifelong drug taking behavior by patients, high level clinician knowledge and expertise; and expensive monitoring technologies are all required for durable clinical benefit from antiretroviral therapy due to resistance.But knowledge and understanding of drug resistance has also brought great improvement in HIV care. Technologies to detect and identify resistance as well as rapid and reasonably accurate interpretation have been developed and refined. A far greater understanding of resistance and its consequences by providers and patients have molded our highly effective modern care. Development of improved drugs including those with unique mechanisms has greatly benefited from our growing knowledge.As we move forward to the next decade of HIV care, we need to revisit how we relate to and address HIV drug resistance. Old assumptions need to be challenged; data needs to be critically evaluated considering our new and improved drugs, and widespread treatment of patients in resource limited settings need to be specifically prioritized as challenges may not be identical. How should our much improved (but expensive) resistance assays be used? To what degree do we need to continue to closely monitor HIV drug resistance and in what settings? Is resistance still a high priority when designing optimal drug combinations for our patients \u2013 those naive and those drug-experienced? How can we minimize the barrier resistance presents to more simplified and widespread antiretroviral therapy? These are important issues we must address to guarantee the best care for the most patients in coming years."}
+{"text": "The authors would like to make the following corrections to their published paper:50 fold changes for the NAI-resistant viruses reported in There was an error in calculation of ICWe apologize for any inconvenience caused to the readers."}
+{"text": "We alsoet al.  . In thiThe autopsy lungs of severe asthmatics and controls were examined by immunohistochemistry to reveal the lymphatics and morphometry using an image analyzer system was applied to compare the distribution of airway lymphatics in the same level of airways among these asthmatics and controls. We also estimated the degree of airway smooth muscles and fibrosis around the airways which would interrupt or disrupt airway lymphatics.The total area of airway lymphatics in each lung was found to be positively correlated with the airway radius. The distribution areas of lymphatics in larger airways of both types of asthmatics were significantly decreased than controls, and the severe asthmatics with increased muscle layers only in larger airways were found to have less lymphatics in these airways than the other group of severe asthmatics with increased smooth muscles in whole airways. The lymphatics around smaller airways were also reduced in both phenotypes of asthmatics without statistic difference. The airway lymphatics of these severe asthmatics were interrupted by both thickened muscle bundle layers and fibrotic tissues developed in the airway walls.These results indicate disrupted airway lymphatics as a novel cause of mucosal edema in severe asthmatics."}
+{"text": "The implementation of National Digital Health project get a high opinion from leaders at all levels and domestic and foreign experts, its research get a tremendous impact on construction of health information, play a technical supporting role of boosting health care reform and servicing people health, and make important significance to promote the development of Chinese public health care."}
+{"text": "The Building Bridges initiative was designed to promote positive cross-cultural interactions among young people and improve the mental health of migrant and refugee populations by addressing race-based discrimination. The goal of the evaluation was to build the evidence and knowledge base for promoting mental health and wellbeing by reducing discrimination through promoting cooperative intercultural contact. The design of the evaluation was multi-level with data collected at the individual, organisational and community levels to evaluate change associated with program participation and examine barriers and enablers to implementation.The evaluation used a before and after design. It examined characteristics of participants, the environment for intercultural contact , attitudes to people from other cultures and Basic Psychological Needs . Both quBuilding Bridges was effective in reaching children and young people who were affected by discrimination and for whom improving intercultural relations was a priority. Building Bridges projects all scored highly on their ability to provide an environment for effective intercultural contact. The results suggest that performance against the Equal treatment and Shared goals/Co-operation is important for how participants feel about themselves and others. Institutional Support for intercultural contact may be critical for translating these gains into meaningful changes in intercultural relationships.The analysis of the impact of the intervention showed that attitudes to intercultural relationships remained the same or improved marginally for people with nationalities other than Australian over the course of the intervention. However, attitudes to intercultural relationships declined for people with Australian ethnicity bringing them in closer alignment with the attitudes of participants with nationalities other than Australian. There was also evidence of positive effects on mental wellbeing with particular improvements for people with ethnicities other than Australian. Overall, the results suggest of a shift in power relations between the populations involved which had positive health effects.Overall, Building Bridges is a pilot program that has benefited the individuals, organisations and community involved and has yielded important learnings about the implementation of pro-diversity programs. The evaluation findings challenged assumptions about the impact of living in a multicultural society on intercultural relations and make a significant contribution to our understanding of pro-diversity interventions."}
+{"text": "To the Editor: We have critically read the brief report by Dr. Taha et alUnfortunately, this study recruited only male medical students and hence lost an opportunity to explore simultaneously the water pipe smoking behavior of female medical students. This is a major caveat because a comparative study involving both genders might have substantiated or refuted already emerging findings; one of them is that water pipe smoking is more common among females. Another limitation of this study is that the authors designed a new questionnaire rather than using one of the most relevant standardized questionnaires developed jointly by international health organizations, including the World Health Organization, the Canadian Public Health Association and the US Centers for Disease Control and Prevention. In doing so, the authors fell short of assessing the specific and relative social and cultural beliefs of male versus female students in Saudi Arabia, as medical students in medical colleges often hail from different regions. Furthermore, this study did not add anything major or new to the existing literature on shisha smoking. However, one finding and related explanation is noteworthy: mothers of water pipe smokers had an advanced education compared with mothers of those of nonsmokers. According to this study this result was speculatively attributed to two factors including shisha smoking as a prestige behavior and an indication of a modern standard of living. However, the commentators feel that these explanations might not be true because mothers were not asked about the explanations underlying the linkage between their higher education and shisha smoking. This finding needs further study. There might be more plausible explanations: shisha smoking in modern times is merely a continuation of a very old traditional behavior of the Eastern world and it may not be a prestigious behavior at all; rather it may reflect low status. A study that recruits a larger sample representative of all Saudi medical colleges might truly shed light on this finding and a more detailed explanation must be included in the measurement tools.4Finally, shisha smoking is a global health problem of the young population and needs effective preventive strategies across the world, including health warning labels on water pipe tobacco products and related accessories.The author of the original report declined to respond"}
+{"text": "To review existing methods to specify condition specific prevalence of and experience of the use of CAM in children in the US and begin to specify a strategic data plan to support evaluation of pediatric integrative medicine.Qualitative  and quantitative methods were used to evaluate the National Health Interview Survey\u2019s Children\u2019s CAM Supplement (2007), the Medical Expenditures Panel Survey (2008) and the National Survey of Children with Special Health Care Needs (2009/10), and to compare findings and specify strengths and weaknesses of each.Using the NHIS Child CAM Supplement method for asking about reasons for the use of CAM in children, we would conclude that fewer than 15% of all children using CAM do so for specific health conditions. However, over 91.7% of all child CAM users had parents who indicated in the larger NHIS that their child had one or more of 59 health problems or conditions assessed and over half of these had 3 or more health conditions. Nearly 40% of all child CAM users met criteria for having a special health care need. Linkage of NHIS and MEPS datasets result in 2411 cases of data - insufficient to validly explore the many condition specific patterns and associations critical to better understanding the need for and impact of integrative medicine for children. NS-CSHCN findings reveal similar overall prevalence and patterns of use and offers alternative methods for consideration.NHIS Child CAM Supplement methods are not valid for assessing CAM use among children with specific health conditions. Alignment with methods used in conventional medical care will enable comparisons between and relationships among CAM and conventional medicine use in the care of children\u2019s health conditions. A strategic approach to ensuring sufficient and valid data are collected across all national surveys is indicated."}
+{"text": "Participant recruitment is understood to be one of the most difficult aspects of the research process. Researchers are now devoting increasing amounts of time and resources to understand how participants decide to take part in research and what researchers can do to make their work appeal to potential participants. The purpose of the study is to assess the problems experienced by researchers in Northern Ireland when recruiting human participants into trials and studies and to gain insight into how researchers handle and overcome these issues. The main research question being addressed by this research is to develop an understanding of the problems experienced by staff when recruiting human participants to research projects. Methods used to increase study recruitment were also examined. The participants in this research are investigators and other associated staff on research studies based in Northern Ireland. Potential participants were identified through contacts with research active organizations such as the academic researchers in Queen\u2019s University Belfast and research physicians and clinical trialists employed by the Belfast Health and Social Care Trust. Each organization forwarded on the survey request via email or newsletters. Researchers willing to take part accessed the questionnaire through the Survey Monkey website. This study utilised a cross-sectional questionnaire design."}
+{"text": "Secondary growth and the development of woody tissue is a key process in the formation of woody biomass. The gene family of Class III HDZip genes has been shown in the herbaceous Arabidopsis model to play a central role in regulating polarity and vascular development. While Arabidopis is a poor model for investigating processes of wood formation, in this project all poplar Class III HDZip genes were cloned and expressed in hybrid aspen as a tree model system. To circumvent an endogenous regulation mechanism involving microRNAs the sequences were also mutated to render them microRNA resistant. Lines expressing the mutated Poplar ortholog of the Arabidopsis Revoluta gene (Populus Revoluta PRE) show a spectacular phenotype with stunted growth, radialized and rolled leaves, and a double and at times triplication or quadruple layer of the xylem, suggesting the formation of multiple layers of cambium. ClassIII HDZip genes have thus been shown to be crucial for the formation of lignified tissue in trees."}
+{"text": "The recently occurred pandemic H1N1 has given lessons on the significance of a multisectorial approach in developing mechanism for responses and preparedness against the spread of communicable diseases. This approach can expand beyond the administrative jurisdiction of a country when there is transboundary movement of diseases when measures taken require cross-border coordination. In this notion, regional integration appears to be a mechanism to address this challenge.The Asia-Europe Foundation (ASEF) Network for Public Health launched in May 2009 was established as part of the wider initiative of Asia-Europe Meeting (ASEM) Foreign Ministers\u2019 Meeting in combating possible human influenza pandemic. Financially supported by the Government of Japan for a period of 5 years (2009-2013), the ASEF Network is part of the wider ASEM Initiative for the Rapid Containment of Pandemic Influenza which also includes a regional stockpile.The paper will highlight the three thematic working groups of the ASEF Network and their activities for the past two years and how these activities have contributed in building bridges among public health stakeholders in Asia and Europe."}
+{"text": "Whereas astrocytes have been in the limelight of scientific interest in brain energy metabolism for a while, oligodendrocytes are still waiting for a place on the metabolic stage. We propose to term the interaction of oligodendrocytes with astrocytes and neurons: NOA (neuron\u2013oligodendrocyte\u2013astrocyte) interactions. One of the reasons to find out more about metabolic interactions between oligodendrocytes, neurons, and astrocytes is to establish markers of healthy oligodendrocyte metabolism that could be used for the diagnosis and assessment of white matter disease. The vesicular release of glutamate in the white matter has received considerable attention in the past. Oligodendrocyte lineage cells express glutamate receptors and glutamate toxicity has been implicated in diseases affecting oligodendrocytes such as hypoxic-ischaemic encephalopathy, inflammatory diseases and trauma. As oligodendrocyte precursor cells vividly react to injury it is also important to establish whether cells recruited into damaged areas are able to regenerate lost myelin sheaths or whether astrocytic scarring occurs. It is therefore important to consider metabolic aspects of astrocytes and oligodendrocytes separately. The present review summarizes the limited evidence available on metabolic cycles in oligodendrocytes and so hopes to stimulate further research interests in this important field. The body of research from the last century has established the present view of contiguous neurons in continuous, dynamic interaction with several types of glial cells . The interactions between neurons and astrocytes characterized by the glutamate\u2013glutamine(\u2013GABA) shuttle have received considerable attention since its discovery in the 1970s  an increase in MCT1 was observed in the spinal cord  described above be extended to a tri-cellular one including oligodendrocytes? The lack of knowledge available on the metabolic role of oligodendrocytes in the brain was highlighted recently with two publications in Nature  has a tri-cellular compartmentation , NAA is then assembled and released from neurons and hydrolyzed to acetate and aspartate \u22121  for the synthesis of oxaloacetate? Aspartate is an essential member of the malate aspartate shuttle which is the major shuttle for reducing equivalents from NADH from glycolysis into the mitochondria  interactions. Well-designed experiments are necessary to find answers to these and other questions concerning the referred metabolic pathways and cycles in oligodendrocytes.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Clients across Hunter New England Area Health Service (HNEAHS) with complex diabetes foot complications traditionally had to travel to Newcastle to access multidisciplinary high risk foot services; with some travelling up to five hours each way to attend the High Risk Foot Clinic in Newcastle. Ideally rural clients should be able to access multidisciplinary high risk foot services close to their home.A six-month pilot Telehealth High Risk Foot Clinic was established between Newcastle and Tamworth, with clinicians in Newcastle providing Telehealth multidisciplinary input for clients attending the Tamworth Podiatry Clinic.Over the six month pilot phase (February \u2013 August 2010) a total of eight clients were seen through the HNEAHS Telehealth High Risk Foot Clinic; seven presented with foot wounds and one presented with an acute Charcot Neuroarthropathy. Two clients (25%) refused gold standard treatment; one was subsequently discharged from the High Risk Foot Clinic and the other did not return for follow-up treatment. Of the remaining six clients, four (75%) achieved successful resolution of their presenting complaint. Clients surveyed in the evaluation phase indicated that they would prefer to attend the Telehealth clinic at Tamworth as it is closer to home, meaning less travel time and expense as well as reducing the impact on their work and/or family commitments. None of the clients felt unsatisfied in any way about the Telehealth model and all felt very satisfied by the impact that the clinic made on their quality of life. A cost analysis of the pilot model showed that this type of service is of cost benefit and has the potential to prevent lower limb amputations in high risk clients residing in rural areas.The pilot clinic resulted in many positive benefits to high risk foot clients living in rural areas. Good clinical outcomes were achieved, the client\u2019s quality of life was improved and cost benefits were attained. Also of note, were the strong relationships that were formed between Newcastle and Tamworth; resulting in rural clinicians being empowered with knowledge of the management of the high risk foot."}
+{"text": "Patients with Complex Regional Pain Syndrome (CRPS) experience distressing changes in body perception. However representing body perception is a challenge. A digital media tool for communicating body perception disturbances was developed. A proof of concept study evaluating the acceptability of the application for patients to communicate their body perception is reported in this methods paper. Thirteen CRPS participants admitted to a 2-week inpatient rehabilitation program used the application in a consultation with a research nurse. Audio recordings were made of the process and a structured questionnaire was administered to capture experiences of using the tool. Participants produced powerful images of disturbances in their body perception. All reported the tool acceptable for communicating their body perception. Participants described the positive impact of now seeing an image they had previously only imagined and could now convey to others. The application has provided a novel way for communicating perceptions that are otherwise difficult to convey. Changes in body perception can occur following peripheral injuries, or central nervous system damage  the ability of the body perception tool to represent participant\u2019s experience, (ii) their reactions to using the tool, (iii) limitations and aspects for refinement.Reflecting the CRPS population, participants were predominantly female 10 female). Ages ranged from 24 to 64\u2009years (median 54), and CRPS duration ranged from 6\u2009months to 7\u2009years (median 14\u2009months). Ten had an upper limb affected and three a lower limb (one participant had both upper and lower leg on one side affected). The characteristics of each participant are listed in Table 0 female.The participants produced powerful images of the disturbances in body perception they experienced. Some examples supported with quotes of participants\u2019 verbal descriptions are given in Figure Alterations in scaling were common with participants feeling that limb parts were either larger or smaller than normal and these perceptions were illustrated on the computer model  in many cases. This was because he wanted responses first hand and initially it was to help train the nurse in using the tool. This lack of independence in the evaluation could have led participants to be more positive about the application than they might otherwise have been. However both the nurse and the software developer stressed their desire for the participant\u2019s honest opinions in order to establish the acceptability of the body perception application to patients and for identifying aspects that needed to be changed.Areas for improvement to the application were identified, for example animation of perceived involuntary movements and creating more sophisticated depictions of sensation. However future use of the application needs to be considered before adding greater levels of detail and complexity. With increasing use of telemedicine, future versions of the application could be made to enable the software to be used by patients independently of clinicians in their own homes over the internet. The participants tested seemed to like using the application with the nurse; perhaps because it was new to them and may have appeared complicated. One of the participants even expressed the view that she was likely to have been less honest if she had used it on her own. However with the increasing use of finger activated tablets development of the tool using touch screen operation that is intuitive and user-friendly is important for its future development. Manipulation using finger drags and taps to turn the avatar, enlarge and shrink parts, and drop on textures and color will need to be robust for use on these smaller screens. The operations will have to be easy to complete with the non-dominant hand, since in some individuals their condition will have affected dexterity in their preferred hand. Further careful evaluation of independent usability and comparison of results between methods of delivery will be needed to determine reliability.There is also further work to do in exploring the best form of the avatar for patients to represent their disturbed body perception. Previous research using body image morphing techniques with fit healthy people and with obese people has indicated that body perception is influenced by the form of the image presented (Stewart et al., Further development and evaluation is in progress to determine the use of the body perception application with people with stroke. A significant prevalence of phantom limb in the form of postural illusions of limb position has been found in people with stroke (Antoniello et al., Since there is potential to \u201crepair\u201d distressing body perception using rehabilitation interventions (Flor et al., Another potential function of the body perception application is to quantify changes in predominant features in response to treatment. Other investigators have taken measurements of scaling from photo software. Vector deviations of image manipulations of a patient\u2019s representation, relative to a reference photograph, were obtained to measure perceived size changes of one side of his face (Rode et al., This proof of principle study has shown that the body perception tool provides a powerful vehicle for communicating and representing changes in body perception.We envisage that this tool could extend beyond being a very useful communication device between patients and clinicians and also become a meaningful process measure and an interactive tool for intervention.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "DNA barcoding generates a unique identification tag for individual species based on the sequence of a short stretch of DNA. For this study we evaluated the potential of DNA barcoding methods for identification of medicinal plants using examples from the Lower Rio Grande Valley border region in Texas. Many plants that enter the supply chain are not evaluated for correct identification and better and faster methods are needed for identification of fragmented samples.We sequenced several genomic regions, both nuclear and chloroplast, in order to assess variability and ability to identify highly fragmented plant material or otherwise incomplete specimens. Unidentified samples were compared with data available in Genbank and with an extensive collection of known reference materials.We successfully used phylogenetic techniques for correct placement of the unidentified samples and potential applications for this method are discussed. We compare this method with the Genbank-BLAST search technique that is widely used for sequence matching.In conclusion, DNA barcoding can be effectively used as an identification method for medicinal plant preparations that allows fast and efficient control for distributors, provides information to customers, and, in case of a poisoning accident, might aide in determining correct treatment and countermeasures. Our studies also showed that comprehensive databases for reference materials need to be carefully assembled and curated to provide reliable information for comparisons. Currently existing databases do not fulfill this requirement leading to potential misidentifications."}
+{"text": "Most studies have analyzed the factors affecting paternity insurance and dominance tenure separately. We use a long term data set on Alpine marmots to investigate the effect of the number of subordinate males on both paternity insurance and tenure of dominant males. We show that individuals which are unable to monopolize reproduction in their family groups in the presence of many subordinate males are likely to lose dominance the following year. We also report that dominant males lose body mass in the year they lose both paternity and dominance. Our results suggest that controlling many subordinate males is energetically costly for dominant males, and those unable to support this cost lose the control over both reproduction and dominance. A large number of subordinate males in social groups is therefore costly for dominant males in terms of fitness.Paternity insurance and dominance tenure length are two important components of male reproductive success, particularly in species where reproduction is highly skewed towards a few individuals. Identifying the factors affecting these two components is crucial to better understand the pattern of variation in reproductive success among males. In social species, the social context ( The number of offspring sired per year and the length of reproductive life are two major components of lifetime reproductive success The social context which dominant males have to cope with may be a key element of reproductive success. Subordinates within and outside the social unit compete with dominants both to reproduce and to reach dominance Suricata suricattaPapio cynocephalusMarmota marmotaMandrillus sphinxi.e. few subordinates), while males facing highly competitive situations (i.e. a large number of subordinates) should be unable to insure paternity and should lose their dominant status rapidly. In other words, the males which lose control over reproduction, due to challenging social conditions, will also lose dominance in their social group rather rapidly.To date, most studies have analyzed factors affecting paternity insurance and dominance tenure separately. As expected, dominants do lose paternity when they are confronted by a large number of subordinate males, for example in meerkats The mechanisms by which the number of subordinate males reduces the ability of the dominant male to secure paternity and to maintain dominance are not well understood. One possible explanation is that it may be energetically costly for dominant males to control potential competitors present in the social unit The Alpine marmot is a mammalian cooperative breeder, socially monogamous, which lives in family groups of 2 to 14 individuals comprising a dominant reproductive pair, mature and immature subordinates of both sexes and pups of the year Here we use a 18-year data set to (1) examine the effect of the number of potential competitors on the probability of losing both paternity and dominance in the male Alpine marmot; (2) test the prediction that males unable to monopolize reproduction are also unable to maintain their dominant status over time. We examine whether the probability of losing dominance is correlated positively with the occurrence of extra pair paternity (EPP) in the previous reproductive event. Finally, we attempt to identify the underlying mechanisms by investigating the link between the number of subordinates and the body mass of the dominant animals. We thus (3) test the prediction that the number of potential competitors influences dominants' body mass; and (4) examine whether the dominant male body mass influences its probability of losing dominance.Both the probability of maintaining dominance  and the The likelihood that the dominant male would lose its dominance is multiplied by 2.16 [CI95%: 1.23\u20133.79] when an EPP occurred at the previous reproductive event  declines . A male with a large number of male subordinates is in lower body condition and may consequently be more likely to lose paternity and then dominance.How do social factors affect the ability of dominant males to monopolize reproduction and secure dominance? One explanation is that it is simply impossible for dominant males to control each of numerous subordinates with fighting abilities We suggest that the general process by which the number of subordinates imposes costs on the dominants is that controlling many subordinate males leads to an energetic cost for these males, and this leads to losing body reserves. This mass loss may in turn lower their capacity to guard their mate effectively, thus allowing other males to gain extra-pair paternity and lowering the dominant male's ability to win contests for dominance. The cost generated by the presence of competitors in social groups may counterbalance the benefits provided by social living Pr\u00e9fecture de la Savoie. Sophie Lardy is authorized for experimentation with animals, issued by the French Ministry of Agriculture and Fisheries (diploma n/0ETRY20090520). French law does not demand approval by an ethical committee.The field work conducted in the Alpine marmots was undertaken after acceptance of the project by the scientific committee of the Vanoise National Park, and after the deliverance of the permit number AP n 2010/121 by the Alpine marmots are cooperatively breeding rodents which live in family groups where only the dominant pair reproduces, as a rule. Both males and females may stay as dominants on the same territory for several years , until they die or get evicted by a competitor. Eviction is generally followed by death, for dominants of both sexes Taraxacum densleonis). Once captured, the animals were tranquilized with Zol\u00e9til 100  were used thereafter. An additional correction for body size  did not change the results, so we present only the results with RBM. The influence of RBM on the probability of losing dominance was investigated first. Generalized mixed models (GLMM) with male identity within territory as random factors, a logit link function and a binomial error distribution were used to account for repeated measures and for the binomial distribution of the dependent variable. To verify that the effect of the number of subordinates on male RBM was not an effect of resource limitation due to high densities of individuals in the territories, the effect of the number of subordinates on dominant female RBM was also studied with the same procedure as the one used for males. The RBM of males staying dominant was then compared to the RBM of males losing dominance using linear mixed models with male identity within territory as random factors to account for repeated measures. Finally we compared the RBM of a male (Statistical analyses were performed with R 2.10.1"}
+{"text": "The organization of networks of interacting species, such as plants and animals engaged in mutualisms, strongly influences the ecology and evolution of partner communities. Habitat fragmentation is a globally pervasive form of spatial heterogeneity that could profoundly impact the structure of mutualist networks. This is particularly true for biodiversity-rich tropical ecosystems, where the majority of plant species depend on mutualisms with animals and it is thought that changes in the structure of mutualist networks could lead to cascades of extinctions.We evaluated effects of fragmentation on mutualistic networks by calculating metrics of network structure for ant-plant networks in continuous Amazonian forests with those in forest fragments. We hypothesized that networks in fragments would have fewer species and higher connectance, but equal nestedness and resilience compared to forest networks. Only one of the nine metrics we compared differed between continuous forest and forest fragments, indicating that networks were resistant to the biotic and abiotic changes that accompany fragmentation. This is partially the result of the loss of only specialist species with one connection that were lost in forest fragments.We found that the networks of ant-plant mutualists in twenty-five year old fragments are similar to those in continuous forest, suggesting these interactions are resistant to the detrimental changes associated with habitat fragmentation, at least in landscapes that are a mosaic of fragments, regenerating forests, and pastures. However, ant-plant mutualistic networks may have several properties that may promote their persistence in fragmented landscapes. Proactive identification of key mutualist partners may be necessary to focus conservation efforts on the interactions that insure the integrity of network structure and the ecosystems services networks provide. While there is much to be learned about the dynamics of mutualisms from the study of pair-wise interactions et al.et al.Despite these advances, however, most studies of mutualist networks fail to consider the complexity of the landscape in which these communities are embedded Mutualisms between ants and specialized plants known as myrmecophytes are a defining feature of tropical forests We evaluated the effect of habitat fragmentation on the structure of mutualistic networks using the community of ant-plant partners found in an experimentally fragmented landscape in the central Amazon. By comparing these networks in continuous forest sites with those in forest fragments, we provide the first empirical test of the effects of habitat fragmentation on network structure that have been put forward in prior theoretical and empirical work. To do so, we begin by comparing the diversity of ants and plants in fragments and continuous forest. Because species diversity of both plants and animals decreases in tropical forest fragments All necessary permits were obtained for the described field studies. All research was conducted with the approval of Brazil's National Council of Scientific and Technological Development  and the Brazilian Institute of Environment and Renewable Natural Resources .et al.We conducted our study in the lowland tropical forests of Brazil's Biological Dynamics of Forest Fragments Project . From October 2001 to February 2002, we conducted surveys of the comprehensively described ant-plant mutualist community Azteca species as a single taxon because of unresolved taxonomy of this group. We also pooled all Pouruma (Cecropiaceae) into a single taxon because of the difficulty in classifying individuals to species with floral characters and no individuals were fertile during our surveys. Finally, difficulty in distinguishing among juvenile Tachigali trees led us to exclude smaller individuals found in two CF plots  and two FF plots , although all adult trees were readily identified.In each of our eight study sites we established a 100 m\u00d7100 m plot in which we mapped all ant-plants and recorded the presence and identity of ant colonies in their domatia; vouchers of plants and ants were collected to confirm identifications. Here we analyze the network connections between the 12 myrmecophytes we recorded in our surveys and the 10 obligate ant species associated with them reported in Hypotheses about network structure can be addressed using both qualitative and quantitative approaches. Qualitative metrics are calculated from binary interaction matrices while quantitative metrics include information on the frequency of individual interactions. Qualitative metrics are still commonly used to study networks, and hence they are useful for comparing the results of our work with those of other studies. However, the frequency of an interaction between species is an important measure of its strength and hence importance To determine if ant and plant species richness was lower in fragments (Hypothesis 1), we compared the number of ant and plant species in the networks. We then tested whether there were fewer realized interactions between ants and plants in fragments  by comparing the number of links per species, network connectance , and linkage density (quantitative) for each treatment with separate one-way ANOVAs. Because there is the potential for correlation among different metrics of network structure et al.Finally, to test if networks in fragments and continuous forest were equally resilient to disturbance (Hypothesis 4) we calculated the network robustness (R) to simulated extinction of ant or plant species . The quaWe censused N\u200a=\u200a322 myrmecophytic plants in forest fragments and N\u200a=\u200a653 in continuous forest; for a detailed description of these results see We found that networks in continuous forest had significantly more plant species than networks in forest fragments  were associated with only one ant species in continuous forest sites. Such associations formed isolated subwebs, which are common in symbiotic interaction networks It is also important to emphasize that ant-plant mutualistic networks have several unique properties that may promote their persistence in fragmented landscapes. Nested mutualistic networks are expected to be resilient to species losses if extinctions involve specialists that are involved in fewer interactions within the network In general, it appears that the resilience of mutualistic networks is enhanced by higher species richness, network connectivity, and through strong, symmetric interaction within highly nested networks Although our study was not designed to compare within-habitat variation in the structure of networks, it appears that replicates within a single habitat class were often quite variable. Within habitat heterogeneity is hypothesized to have a major influence on network topology Azteca remains challenging and has yet to be fully resolved for our study sites Azteca species in a single taxon for our analyses. Our ongoing molecular analyses are attempting to determine the number of Azteca species colonizing myrmecophytes, and including multiple Azteca species species will clearly alter the structure of networks. However, the overall conclusion that networks are similar in forest fragments and continuous forests will likely remain unchanged \u2013 with the exception of Cordia nodosa, plant species colonized by Azteca are relatively rare Three important caveats to our results bear consideration. First, the taxonomies of the ant genus Allomerus octoarticulatus and Hirtella myrmecophila in our network), it may be possible to focus conservation efforts on those species in addition to the more commonly targeted rare or endemic ones as a means of ensuring the integrity of network structure and ecosystem services these networks provide We conclude that the redundancy built into mutualistic networks and the limited number of 1\u22361 interactions in tropical ant-plant systems makes these networks inherently resistant to the effects of fragmentation, at least in the short term Table S1Tables for one-way ANOVAs of nine network metrics. The metric with a significant p-value  is in bold.(DOC)Click here for additional data file."}
+{"text": "PLoS Computational Biology we have tried to support this evolution through a collection of educational articles pertinent to the undergraduate level and beyond. It is only natural that we would take the next step Bioinformatics is now an integral part of biology and biological research. The field began with a few people from other disciplines teaching themselves and each other the techniques that are now considered commonplace. These pioneers then began graduate programs We now introduce a subsection of the Education section with articles devoted to teaching bioinformatics in secondary schools that is derived from the work of the Education committee of the International Society for Computational Biology (ISCB), who identified a need to address the issue of incorporating bioinformatics into secondary school biology classes. They also recognized the interest among researchers to build and participate in outreach programs at the secondary school level given that many funding agencies worldwide encourage such a component in grant applications.To move the ball forward on secondary school bioinformatics education, at ISCB's 2010 international conference, Intelligent Systems in Molecular Biology (ISMB), the ISCB Education committee organized a half-day tutorial aimed at secondary school biology and chemistry teachers in the Boston area interested in learning about bioinformatics and how to include it in their curricula. The tutorial also attracted researchers involved in organizing or formulating outreach programs in their community. The main focus of the ISMB tutorial was the presentation of lesson plans by a secondary school teacher  who has successfully incorporated bioinformatics into his courses for more than five years. His is one example of such an effort and is embraced in the Ten Simple Rules and its supplementary material found in this issue. Also in this issue we have an article by Suzanne Gallagher and colleagues on the experience of teaching secondary school level bioinformatics in Boulder, Colorado.There are many examples of outreach efforts to high school students that we would like to feature in coming months, which incorporate bioinformatics into their programs see .Briefings in Bioinformatics was dedicated to bioinformatics education There are many other examples of educators doing similar work in school districts worldwide. A recent issue of We encourage feedback of any form, including comments on this editorial, and hearing about your experience teaching bioinformatics to secondary school students."}
+{"text": "There is a significant body of research indicating having a genetic condition is emotionally burdensome for the individual and their family. One goal of cancer genetic counselling is to assist patients to adapt to the news that they and family members are at significantly increased risk of developing cancer. Numerous studies have shown that the majority of patients who attend cancer genetic services do not report significantly increased long-term psychological distress. However, a small number of patients present with pre-existing complex psychological issues or particular personality traits which are not readily apparent. This subgroup of individuals may experience adverse psychological responses and complex adjustment challenges following their participation in the genetic counselling process."}
+{"text": "Optimizing Delivery of Health care Interventions (ODHIN) is an ongoing European project  involving research institutions from 9 European countries using the implementation of Early Identification and Brief Intervention (EIBI) programmes for Hazardous and Harmful Alcohol Consumption (HHAC) in Primary Health Care (PHC) as a case study to better understand how to translate the results of clinical research into everyday practice. The Italian National Health Service (ISS) is the project leader of the Work Package 6 assessment tool. The aim of the ODHIN assessment tool is to formalise, operationalise and test the questionnaire developed under the PHEPA project in order to produce an update instrument to assess the extent of implementation of EIBIs for HHAC throughout PHC settings. The ODHIN assessment tool has been conceived as a semi-structured questionnaire for the identification of the state of the art, gaps and areas in the country that need further work and strengthening; to monitor the adequacy of brief intervention programmes for HHAC in order to provide recommendations to improve and optimize delivery of health care interventions. It analyses 24 questions distributed across 7 key sections. Data have been collected from 9 ODHIN collaborating countries  and from other 14 European countries who have agreed to share their national experience with the ODHIN partners . Preliminary data on the state of the art of the implementation and the extent of EIBI for HHAC throughout PHC settings across 23 European participating countries will be presented. Identified areas where services require development or strengthening across the participating countries as well as examples of good practices between countries will be also discussed."}
+{"text": "PLoS Medicine editors discuss new research studies on the risks associated with mode of childbirth following caesarean section.The  PLoS Medicine publishes two research articles with new data that should help women and clinicians make better informed decisions about childbirth This month, planned, as opposed to actual, birth mode, which therefore helps clinicians to counsel women on the outcomes associated with their choice.One study The second study this birth, but for subsequent births too. For example, as highlighted by Crowther and colleagues The bigger issue raised by these findings relates to how clinicians and women can work together to make the best possible decision when so many questions remain unanswered. The existing research presents an incomplete picture of the entire set of possible risks associated with the options that women and clinicians have; under-studied issues relate to the implications not just for"}
+{"text": "Identification of prognostic and predictive biomarkers is important for targeting treatments to patients and for the design and analysis of randomised controlled trials. Cox proportional hazards modelling is a standard method for assessing prognostic value of clinical biomarkers where time to occurrence of an event is the primary outcome of interest. An important issue in the analysis of prognostic factors is the functional form of the relationship between the factor and outcome specifically for continuous covariates. Continuous covariates are often simplified assuming a linear relationship with log-hazard or dichotomisation which may be inappropriate leading to loss of efficiency in statistical tests, bias and incorrect conclusions. The effects of important prognostic biomarkers may go unrecognised due to simplistic assumptions made in statistical modelling.Two polynomial based strategies, restricted cubic splines and fractional polynomials, are compared directly for determining the functional form of non-linear relationships between prognostic biomarkers and survival using two real datasets from randomised controlled trials in advanced pancreatic cancer and cardiac surgery. Fractional polynomials are an extended family of curves including non-integer and negative power terms. Spline functions are piecewise polynomials connected across intervals of a variable constrained to meet at the \u2018knots\u2019.Multivariable models were constructed based on Cox proportional hazards regression using backward elimination. Internal validation to directly compare the fit of the restricted cubic spline and fractional polynomial strategies was carried out by calculating the sampling distribution of the difference in AIC between the models using nonparametric bootstrap analyses. Further analysis recalculated the univariate fractional polynomial transformation within each bootstrap resample to compare directly against a 5-knot restricted cubic spline. The influence of the size of the bootstrap samples was also investigated.The fitted functions generated by splines and fractional polynomials were similar resulting in comparable models. The methods are generally different in the extremities where there is often a paucity of data. Larger differences were seen between the two methods when sample sizes were reduced due to the reduced power to detect small effects but also to detect nonlinearity.Multivariable fractional polynomial transformations are an alternative approach to restricted cubic spline transformations for multivariable model building of continuous biomarkers with non-linear relationships with outcome."}
+{"text": "This research is concerned with the mixed convection peristaltic flow of nanofluid in an inclined asymmetric channel. The fluid is conducting in the presence of inclined magnetic field. The governing equations are modelled.  Peristaltic motion is now an important research topic due to its immense applications in engineering and physiology. This type of rhythmic contraction is the basis of peristaltic pumps that move fluids through tubes without direct contact with pump components. This is a particular advantage in biological/medical applications where the pumped material need not to contact any surface except the interior of the tube. The word \u201cperistalsis\u201d comes from a Greek word \u201cPeristaltikos\u201dwhich means clasping and compressing. The peristaltic flow has specific involvement in the transport of urine from kidney to the bladder, chyme movement in gastrointestinal tract, movement of ovum in the female fallopian tubes, blood circulation in the small blood vessels, roller and finger pumps, sanitary fluid transport and many others. Latham Heat transfer in cooling processes is quite popular area of research in industry and medical science. Conventional methods for increasing cooling rates include the extended surfaces such as fins and enhancing flow rates. These conventional methods have their own limitations such as undesirable increase in the thermal management system's size and increasing pumping power respectively. The thermal conductivity characteristics of ordinary heat transfer fluids like oil, water and ethylene glycol mixture are not adequate to meet today's requirements. The thermal conductivity of these fluids have key role in heat transfer coefficient between the heat transfer medium and heat transfer surface. Hence many techniques have been proposed for improvement in thermal conductivity of ordinary fluids by suspending nano particles in liquids. The term \u201cnano\u201d introduced by Choi The aim of present study is to venture further in the regime of peristalsis for fluids with nanoparticles. Therefore we examine here the mixed convective peristaltic transport of nanofluid in an inclined asymmetric channel in the presence of inclined magnetic field. Channel asymmetry is produced by peristaltic waves of different amplitude and phases. Mathematical modelling involves the consideration of Brownian motion and thermophorsis effects. Numerical solution of nonlinear problem is obtained using shooting method. Limiting case for nanofluid in symmetric channel is also analyzed. Detailed analysis for the quantities of interest is seen.0 only. Let We consider mixed convective viscous nanofluid in an inclined asymmetric channel of width g the acceleration due to gravity, T the temperature, The equations governing the flow under consideration areThe transformations between fixed and wave frames are defined as follows:We now introduceF in the wave frame is related to the dimensionless time mean flow rate Employing transformation (8), dimensionless variables (9) and long wavelength and low Reynolds number u), temperature (Our main interest in this section is to examine the velocity (This subsection illustrates the behavior of emerging parameters u is decreasing function of M near the upper half of channel. The variations of Effect of heat transfer on peristalsis is shown in the Influence of mass transfer on peristalsis is shown in the Trapping phenomenon is shown in A detailed analysis is presented for magnetohydrodynamic peristaltic transport of nanofluid in an inclined asymmetric channel with heat and mass transfer. Numerical simulation is utilized for solution analysis. The critical cases from asymmetric to symmetric channel ("}
+{"text": "Understanding how the brain implements social behavior on one hand, and how social processes feedback on the brain to promote fine-tuning of behavioral output according to changes in the social environment is a major challenge in contemporary neuroscience. A critical step to take this challenge successfully is finding the appropriate level of analysis when relating social to biological phenomena. Given the enormous complexity of both the neural networks of the brain and social systems, the use of a cognitive level of analysis (in an information processing perspective) is proposed here as an explanatory interface between brain and behavior. A conceptual framework for a cognitive approach to comparative social neuroscience is proposed, consisting of the following steps to be taken across different species with varying social systems: (1) identification of the functional building blocks of social skills; (2) identification of the cognitive mechanisms underlying the previously identified social skills; and (3) mapping these information processing mechanisms onto the brain. Teleost fish are presented here as a group of choice to develop this approach, given the diversity of social systems present in closely related species that allows for planned phylogenetic comparisons, and the availability of neurogenetic tools that allows the visualization and manipulation of selected neural circuits in model species such as the zebrafish. Finally, the state-of-the art of zebrafish social cognition and of the tools available to map social cognitive abilities to neural circuits in zebrafish are reviewed. In social species animals interact frequently with their conspecifics and have to adjust the expression of their social behavior according to previous social experience and to social context. This behavioral flexibility in the social domain  differ from those involved in the interactions of the organism with its physical environment, and therefore the term social cognition has been created to refer specifically to cognitive processes involved in social interactions e.g., . Social In this paper, I propose a conceptual framework for comparative social neuroscience based on: (1) the identification of the functional building blocks of social behavior and the underlying cognitive mechanisms across different species with varying social systems, and (2) how these information processing mechanisms are inbuilt in the brain, which is viewed as an information processing organ. Following Krogh\u2019s principle, that \u201cfor many problems there is an animal on which it can be most conveniently studied\u201d , teleostTable 1 and Figure 1 for summary and selected examples in teleost fish, respectively).The first step of the conceptual framework proposed here is to identify the information processing problems posed by the social domain of the environment in order to identify the cognitive abilities underlying social skills. For instance, what are the mechanisms required for an individual to tolerate the presence of conspecifics, to recognized different classes of conspecifics and assess their behavior, to use public information available in social environments and to choose the appropriate responses from the available behavioral repertoire? Once we identify these building blocks of social competence we can investigate their phylogenetic distribution and how they map onto neural networks underlying behavior. The putative building blocks of social competence are identified and discussed below  and salience (on a low to high continuum) to social agents , such thGiven the wide array of social signals conveyed in multiple sensory modalities it is postulated that a general appraisal mechanism that assesses the valence and salience of social stimuli across different sensory modalities and functional domains must operate. According to this view the evaluation of valence and salience of social information is not just a result of direct effects of perceptual information , but rather a function of what that perceptual information means to the organism at that moment in time  and its reef fish clients, cleaners feed against their preference (ectoparasites instead clients\u2019 mucus) in order to secure the possibility for numerous future interactions . This behavioral synchronization and coordination of individuals within social groups has lead to the emergence of collective patterns that can be impressive, such as the aerial movements of bird flocks, or the spatial behavior of insect swarms, fish schools, ungulate herds, and even human crowds. In most of these cases complex collective patterns can be explained by individual decision-making rules and by the way information flows between group members . For exaMore complex social systems are predicted to impose a higher cognitive demand, hence recruiting quantitatively more resources of the abovementioned social skills or promoting qualitative progress of new social skills  and sheep . Functional evidence for the presence of the social behavior network is difficult to obtain since it requires the simultaneous recording of neural activity in multiple brain regions. Given the difficulty of obtaining large-scale electrophysiological recordings indirect measures of neural activity, such as the expression of immediate early genes  or the activity of cytochrome oxidase, in relation to the expression of different social behaviors, have been used to test this hypothesis. In recent years this type of studies has been accumulating evidence in favor of the social brain network hypothesis. In the African cichlid Astatotilapia burtoni subordinate males given the opportunity to rise in social rank show higher expression of immediate early genes in all nodes of the social behavior network when compared either to stable subordinate or dominant males (Anolis carolinensis) repeated exposure to video-playbacks of aggressive displays of conspecific males induced changes in functional connectivity within the network .A successful comparative research program in cognitive social neuroscience has two key requirements: (1) the possibility for cladistic research on the evolution of social behavior and cognition aiming to uncover how pre-existing cognitive modules may evolve quantitatively  and how networks may be reconfigured leading to the emergence of qualitatively new solutions to adaptive problems; and (2) the possibility for reductionist research on the mapping of cognitive function into neural networks, which requires model organisms with appropriate social behavior and with an available \u201ctool box\u201d for the analysis of neural circuits. Therefore, the combination of comparative behavioral work on selected species in naturalistic settings covering the expected diversity in cognitive abilities with neuroethological research on a phylogenetically related model organism is a promising approach. Teleost fish fulfill both requirements and therefore they offer an excellent opportunity to fulfill such a research program on comparative cognitive social neuroscience.Labroides dimidiatus) on the context of cleaning mutualism  for which neurobiological and genetic tools are becoming increasingly available. Among the current teleost model organisms zebrafish offers the best conditions for research in social neuroscience due to a combination of relevant social behavior with availability of relevant tools for studying brain function in relation to behavior.Zebrafish are highly social animals that live in groups with structured social relationships including shoaling, dominance hierarchies, and territoriality . FurtherThe sight of conspecifics has rewarding value in zebrafish and can be used as a reinforcer in an associative learning task . Given tAlthough conspecifics act as social rewards zebrafish are not equally attracted to all conspecifics, exhibiting shoaling preferences that emerge during the juvenile phase . These sAs mentioned before a prerequisite for individuals to express social preferences is the ability to recognize individuals or classes of individuals. Zebrafish use both visual and olfactory cues in social recognition. Studies on zebrafish reared in social isolation and on cross-reared intra-specific phenotypes showed that visually mediated species recognition is based on a mechanism of phenotype matching against a learned template early in life . OlfactiCognitive appraisal and cognitive bias are recent research areas that only now are starting to be explored in zebrafish. In our lab we have collected preliminary evidence suggesting that in dyadic agonistic interactions it is the perception that the individual has of the event rather than its objective structure that triggers the physiological and genomic responses differentially observed in winners and losers . These results are in accordance with previous work on cichlid fish that showed that ambiguous agonistic interactions between fish and their own image on a mirror  failed to elicit the physiological responses observed in winners and losers of real opponent fights .So far the use of public information in zebrafish has been documented mainly in the context of response to aversive stimuli. A first suggestion of social learning in zebrafish comes from data showing that groups of zebrafish learn an avoidance response to an electric shock faster than single individuals . HoweverTemporal discounting has not been studied in fish so far. However, spatial discounting  for social rewards has been recently demonstrated in guppies . Both tyDanio aequipinnatus). The average distance among zebrafish shoal mates is approximately of 20 cm, and it responds to environmental factors, increasing in the presence of food and predators to over 30 cm  commonly used as a criterion for shoal membership in cyprinid species; er 30 cm . Consideer 30 cm , 2011. Aer 30 cm , only reer 30 cm , therefoOreochromis mossambicus: Lates calcarifer: A significant number of genetic and neuroanatomy tools and resources are becoming available for zebrafish, making it a tractable species to study brain behavior relationships. Detailed brain atlases are now available for adult zebrafish , and homThe functional study of neural circuits in zebrafish has benefited from the development of optogenetic and transgenic techniques that together allow the close monitoring of activity in neural networks and experimental gain and loss of function manipulations to assess causal relationships between specific neural patterns and specific behaviors . Imagingin vivo in the juvenile phase. On the other hand, the repertoire of social behavior is very limited in larvae, whose ethogram is limited to locomotor action patterns involved in swimming and in prey capture The creation of a common cognitive lexicon and taxonomy so that clear concepts are shared \u2013 the occurrence of complex social behaviors does not necessarily request complex cognitive abilities; therefore functionally similar cognitive abilities that rely on different underlying mechanisms should be recognized .(2)Poecilia reticulata) that had an impact on cognitive skills within two generations  and easy to breed in the lab, can be successfully used in the future to address this question using experimental evolution paradigms, as suggested by a recent study on artificial selection for larger brains in guppies (erations .(3)The distributed nature of information processing in neural networks should be taken into account when trying to map cognitive processes onto brain activity; therefore comparative analyses should move beyond the comparison of brain sizes and focus on inter-specific convergence/divergence in functional connectivity in the social decision making neural network.In answering all these questions I foresee a relevant role for species that offer the possibility to integrate imaging of brain activity with relevant behavioral tasks, as is the case of zebrafish.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Insect and sting allergy in immunocompetent populations. A comparison.Observation made in diferent subsets of population who had insect and sting allergy .1) Immunocompetent population in the developing world engaged in farming and related activities regularly exposed to all gradient of allergens like dust molds, dander, pets, etc and when they are exposed to insect and mosquito bites, bees and wasps stings even scorpion bites they suffer to a lesser extent.2) Immunocompromised population in the developed world far away from natural gradient of exposure of nearly all the allergens and when they are exposed to scorpion bite or bees and wasp stings there are reports of fatal reactions and even mosquito and insect bites causes serious wheal and flare reaction, this observation was made specially on the second generation of children from parents of Indian origin now living in USA and other affluent countries, where there is minimal exposure to all the allergens.Based on the observation made on nearly 2 lakh patients it was observed that there is a direct relationship of levels of exposure to all the natural allergens and the immunotolerance achieved by this natural exposure or natural immunotherapy.After above mentioned observations we reached to the conclusion that exposure to natural gradient of allergens, insect bites mosquito bites is troublesome for the immunocompromised populations who follow avoidance of exposure to allergens as a rule and this is a disaster for them there are many deaths reported due to the above mantioned exposure, at the same time the immunotolerant population which is exposed to all sorts of allergens insect bites mosquito bites bees and wasps stings suffers to a lesser extent."}
+{"text": "Medication adherence has a cumulative effect on people\u2019s health and wellbeing and reduces the reliance on health and social care services. This paper reviews the London Borough of Lambeth\u2019s assistive technology service, which is occupational therapy led and includes the use of electronic medication dispensers as part of innovative intervention in support of medication adherence.The paper gives an appraisal of the key-factors in the successful implementation of medication adherence aids in social care settings and is supported by observational records that originate in practice and by a review of the current evidence base for the use of assistive technologies in medicines management. Key factors include interdisciplinary working as well as having needs-led and outcome focussed services.In the current economic climate there is increased pressure on local government to deliver services more efficiently and cost-effectively. The paper examines several case studies, which demonstrate how the use of assistive technology can support medication adherence, resulting in cost savings and cost avoidances. A guiding framework with practical recommendations for best practice in implementing medication compliance aids in social care settings is then offered.There is a need for health and social care workers and others to engage with medication adherence more widely. There is a large and growing new variety of strategies, interventions, technologies and services available which have the potential to aid, facilitate and motivate clients to adhere to their prescribed medications. The paper gives an overview of their practical application and outcomes."}
+{"text": "The NHMRC Partnership Project \u201cEvidence based targeting of state wide strategies for preventing falls among community dwelling older people in Victoria\u201d is a five component project examining the uptake of falls prevention strategies to better understand issues that might impact on the health and well-being of older adults in our community. From this data, information regarding drivers of footwear selection was determined and that is the focus of this study.Cross-sectional population based telephone survey of 394 men and women 70 years and over living in the community in Victoria. The survey was conducted over December 2010 to January 2011 and in a second wave between January 2012 to March 2012. Questions were asked regarding footwear worn indoors and outdoors and the reasons for this selection.The choice of footwear worn indoors was overwhelmingly enclosed slippers with comfort as the reason for this selection. The outdoor footwear of choice was walking shoes with comfort once again the main driver for selection.Understanding footwear selection of the elderly may assist health care providers when recommending falls strategies for this at risk population."}
+{"text": "The Program for Disordered Eating run at Headspace Gold Coast is a new intervention developed in September 2012 in response to an identified unmet need for a service for young people with eating issues. This program aims to provide screening, assessment and early intervention for those who are suffering from disordered eating at a distressing level but who do not meet the criteria for local public health eating disorder services. Headspace is an ideal organisation as it targets young people between 12 and 25 and the two peak risk periods for the onset of eating disorders are early adolescence and late teens . Funded under ATAPS a young person can access 12 individual sessions and 12 groups per calendar year.The paper will present the background and rationale for the program, an outline of the evidence based approaches offered and the preliminary data gathered which demonstrates the effectiveness of the interventions.Disordered Eating \u2013 Characteristics & Treatment stream of the 2013 ANZAED Conference.This abstract was presented in the"}
+{"text": "Ontologies encode the knowledge of human experts in order to allow computers to automate common tasks in a domain. They are hierarchically organised and backed by computational logic which allows automated inferences of the implicit consequences of explicitly stated knowledge. ChEBI is a database and ontology of chemical entities of biological interest . Within"}
+{"text": "Numerous amperometric biosensors have been developed for the fast analysis of neurotoxic insecticides based on inhibition of cholinesterase (AChE). The analytical signal is quantified by the oxidation of the thiocholine that is produced enzymatically by the hydrolysis of the acetylthiocholine pseudosubstrate. The pseudosubstrate is a cation and it is associated with chloride or iodide as corresponding anion to form a salt. The iodide salt is cheaper, but it is electrochemically active and consequently more difficult to use in electrochemical analytical devices. We investigate the possibility of using acetylthiocholine iodide as pseudosubstrate for amperometric detection. Our investigation demonstrates that operational conditions for any amperometric biosensor that use acetylthiocholine iodide must be thoroughly optimized to avoid false analytical signals or a reduced sensitivity. The working overpotential determined for different screen-printed electrodes was: carbon-nanotubes (360 mV), platinum (560 mV), gold  or cobalt phthalocyanine . It is interesting to note that this potentiometric method needs an electroactive compound in the solution [Acetylthiocholine iodide was used as substrate for biosensors based on AChE immobilized on platinum electrodes poised at 410 mV  . A potensolution  and, in 3.5.The difference between the potential of the oxidation peak of thiocholine at 110 mV and iodide at 675 mV is important  and suggDifferent potentials were reported in literature for the quantification of the analytical signals of biosensors developed by the immobilization of AChE on electrodes modified with cobalt phthalocyanine when acetylthiocholine iodide was used as substrate. A wide oxidation peak attributed by the authors to the overlap of the peaks of unknown species was obtained by differential pulse voltammetry recorded from 100 to 1,000 mV. An oxidation peak attributed to the thiocholine with maximum at 370 mV with a height approximately equal with one third of the previous wide peak was obtained when the differential pulse voltammetry was carried out in a narrower potential range between 100 and 500 mV. The optimum potential for amperometric measurements chosen by authors was 370 mV, but the enzymatic inhibition may be determined between 300 and 400 mV . The thi3.6.The experiments described above are useful to predict the behavior of biosensors constructed by the immobilization of AChE on the surface of similar electrodes. Nevertheless, the electrode surface is modified in the case biosensors and in consequence the electrochemical propertied may be modified. We have verified our results using biosensors obtain by the immobilization of AChE by reticulation with glutaraldehyde on the surface of platinum and cobalt phthalocyanine screen-printed electrodes and the analytical signals were recorded for the injection of 1 mM acetylthiocholine chloride and iodide, respectively. The biosensors based on platinum screen-printed electrodes were tested at 560 mV and 700 mV. The response measured at 560 mV was 132 nA for both chloride and iodide substrates. The response obtained at 700 mV was 531 nA using acetylthiocholine iodide much higher in comparison with 148 nA that were recorded for acetylthiocholine chloride. The immobilized enzyme was completely denatured by incubation for 3 min in a 1:1 water-methanol solution and the residual response was recorded in order to test the interferences. At 560 mV it was not measured any significant signal for the injection of both chloride and iodide, but at 700 mV the response measured for acetylthiocholine iodide is 389 nA while for acetylthiocholine iodide the signal is still insignificant. For the biosensors based on cobalt phthalocyanine screen-printed electrodes it was obtained at 110 mV an analytical signal of 156 nA for acetylthiocholine chloride that is statistically higher than 118 nA recorded for acetylthiocholine chloride. All these results confirm the conclusions reached using bare electrodes, but tests with chloride and iodide substrate must be carried out for every particular developed biosensor in order to avoid false signals.4.Our study demonstrates that it is possible to use acetylthiocholine iodide as pseudosubstrate for the quantification of the analytical signals of amperometric biosensors based on AChE only after a careful investigation of the electrochemical behavior of the electrode towards thiocholine in the presence of iodide. Iodide anions may interfere with the measurements in two different ways: (i) by the modification of the measurement sensibility of the thiocholine and/or (ii) by producing false analytical signal due to the oxidation. The influence of the iodide on the measurements and optimum potential must be determined experimentally for every developed biosensor because each layer deposed on the electrode surface modifies the overall electrochemical behavior."}
+{"text": "Plasmodium falciparum on the north coast of PNG are genetically isolated. If this fragmented population structure is found throughout PNG it will provide a unique opportunity for planning malaria control strategies and focusing efforts on regions where they are likely to have the greatest impact. We are working towards defining a high-resolution population genomic map of parasite networks and migration patterns throughout PNG using single nucleotide polymorphisms. Our approach, preliminary data and the practical implications of this research will be discussed in context with the national malaria control program.Malaria is being controlled in Papua New Guinea (PNG) where the epidemiology of the disease ranges from highly endemic in low-lying regions to epidemics in the highlands. Analyses of microsatellite haplotypes have revealed that populations of"}
+{"text": "BRCA1 make a significant contribution to the molecular pathology of familial breast and ovarian cancer and are potentially detectable by the CGH or SNP microarrays in common use.The use of microarray based molecular karyotyping for diagnostic testing is now common in clinical practice. A feature of this technology is an increased capacity to uncover genetic abnormalities unrelated to the original indication for the test. These incidental findings can involve the unexpected diagnosis of well recognised Mendelian genetic disorders through the rearrangement of a known disease genes. Large scale genomic rearrangements of BRCA1 gene locus. Analysis showed that the copy number variant resulted in the deletion of exons 2-17 and would be classified as a pathogenic mutation. Following discussion with a clinical geneticist the result was reported to the family by the pediatrician who facilitated their referral them to a familial cancer centre for further discussion.We describe the case of a 5 year old boy seen at the Peter MacCallum Familial Cancer Centre. The index case and his twin brother originally presented to their pediatrician for investigation of a history of an autistic spectrum disorder and a molecular karyotype was ordered. This array revealed an unexpected finding of a deletion on chromosome 17q21 involving the A detailed pedigree revealed no significant cancer history with only a single case of breast cancer in the wider family. The parents of the index described being surprised by the result but grateful for the information. Both parents elected to proceed with predictive testing to clarify the origin of the mutation and the potential cancer risks for them and their family in the future.The rapid expansion of genetic testing capacity through new technologies such as microarray testing or next-Generation-Sequencing are certain to be associated with increasing numbers of unexpected findings including familial cancer syndromes. Although an approach to this type of finding needs to be developed, the current case demonstrates that whilst unanticipated, this information can be welcomed by families."}
+{"text": "Our findings regarding the Breast Cancer and Environment Research Centers (BCERCs) in which Wolff and Barlow are involved represent a broad overview of all four centers and are meant to portray several dimensions of the collaborative aspects of the work. In our article , we aimeThe findings reported in our article  show a nOur analysis  does notOur research  providedOur article  and reco"}
+{"text": "Endogenous opioid peptides have been aligned with a diverse array of effects. Their activity is not only attributable to action the three main opioid receptors, mu (MOR), delta (DOR), and kappa (KOR) opioid receptors but their impacts appear to extend to activities at sodium channels, cytokine receptors  is one of the most prominent and is the prototypical endogenous peptide for the MOR class of opioid receptors and is found within the CNS and the immune system  are effective inhibitors for DPP IV, albeit di-isopropyl fluorophosphate has been shown to induce compensatory anticholinesterase activity producing tremors due to its irreversible nature. Spinorphin  (Sacerdote and Panerai, The search for the sites of action for the non-opioid effects of endogenous opioids has been largely focused on the immune system (Rittner et al., Increasing our understanding of the role of beta-endorphin and its biotransformation fragments provides an insight into the complexity of the endogenous opioid system. The current analgesics are targeted at the modulation of analgesia by directly binding to one or more of the opioid receptors, with the analgesic being predominantly designed as a MOP agonist. The above observations would suggest that this is solely one aspect of opioid pharmacology, albeit one that has been explored widely and utilized in therapy. Biotransformation is a process that produces an array of compounds having a plethora of specific actions which contribute to the body's and its biological systems response to disease or injury. Future therapeutic strategies should consider such actions in designing better treatments or disease modulators."}
+{"text": "We are describing a simple and innovative way of documenting tachycardia. This patient came with video recording of neck pulsation done with the help of mobile phone camera. No other documentation of this tachycardia was available as patient was living in a remote area away from even basic health facilities. It was during one of those bedside clinics, when one of my professors taught us that Wenckebach block was first diagnosed by Dr Karel F. Wenckebach in 1899 by observing jugular venous pulsation [In a country like India, where mobile phone industry has grown tremendously and made inroads into every nook and corners of the country, this kind of indigenous telemedicine is certainly a small filler in the big lacuna of health care."}
+{"text": "A descriptive embedded multiple case study research design is planned to provide an intense focus on a single phenomenon (the audit cycle) within its real life context . The measures to be included in the case study have been identified by the Balanced Patient Safety Measurement Framework. These include: audit and peer review activity, provider attitudes to patient safety, safety learning, action and performance. A purposive sample of 6 to 8 surgeons  from 3 to 4 specialities (cases) will undergo semi-structured interview. This will investigate: current audit tools and processes; attitudes; and behaviours of surgeons to the audit cycle. Similarities in and differences between the units of analysis will indicate which identified measures function as barriers or enablers of the audit cycle. Reliability and validity  will be assessed using established methods for case studies. The descriptive embedded multiple case study will reveal how and why foot and ankle surgeons participate in the audit cycle. This will inform further research to improve the outcomes of foot and ankle surgery through development of an audit tool.The direct costs of managing adverse outcomes from Australian health care are estimated to be $2 billion. The audit cycle is considered an important tool to assist in the preventive management of adverse outcomes.Australian guidelines for audit cycle design allow for comparison of data sets derived from similar surgical specialities. However a lack of data set standardisation inhibits meaningful comparisons of foot and ankle surgical audits. This research will assist development of a best practice model for auditing foot and ankle surgery. Data derived from this model will improve the safety and quality of foot and ankle surgery. The preliminary phase of this process is to identify and understand the attitudes and behaviours of"}
+{"text": "The regulation of metabolism in fed and fasted states is governed by hormonal and nutrient-derived signals that are mediated in part by nuclear receptors. Just as insulin and glucagon help the body store and mobilize energy through their membrane receptors, nutrient-derived lipids activate their cognate nuclear receptors  to govern transcriptional programs involved in energy storage and utilization during times of nutrient excess and privation. Recent work has revealed that many of the actions of these nuclear receptors are mediated by two atypical fibroblast growth factors (FGF19 and FGF21) that function as endocrine-like hormones. The characterization of these pathways in normal and metabolic disease animal models has led to an understanding of their physiologic and pharmacologic mechanism of action."}
+{"text": "Portal vein thrombosis (PVT) not associated with hepatocellular carcinoma is considered a frequent complication of liver cirrhosis but, unlike PVT occurring in non-cirrhotic patients, very few data are available on its natural history and management. The reduced portal blood flow velocity is the main determinant of PVT but, as in other venous thromboses, multiple factors local and systemic, inherited or acquired often can concur with. PVT has a variety of clinical presentations ranging from asymptomatic to life-threatening diseases like gastroesophageal bleeding or acute intestinal ischemia. It is usually diagnosed by Doppler ultrasound but computed tomography and magnetic resonance imaging are useful to study the extent of thrombosis and the involvement of the abdominal organs. The risk of bleeding mainly determined by the presence of gastroesophageal varices and clotting alterations causes concern for the treatment of PVT in cirrhotic patients. To date, anticoagulant therapy seems to be indicated only in patients awaiting liver transplantation. This review focuses on the definition of the subgroups of patients with cirrhosis that might benefit from treatment of PVT and examines the pros and cons of the available treatments in terms of efficacy, monitoring and safety, providing also perspectives for future studies. Liver cirrhosis is the most frequent underlying disease in patients with non-neoplastic thrombosis occurring in the portal vein (PVT). In a large autopsy series of patients with PVT, neoplasia was present in 67%, cirrhosis in 28% and in only 5% of patients PVT was considered primitiveHepatocellular carcinoma (HCC) is the most frequent cause of PVT in cirrhosis, being present in up to 44% of casesThis review deals with PVT occurring in patients with liver cirrhosis without HCC focusing on the necessity and/or the opportunity of management of this specific complication of liver disease.The occurrence of PVT in cirrhotic patients has been increasingly reported in recent years. This stems from the different procedures utilized for diagnosis and the different settings of cirrhotic patients studied. The presence of PVT was 0.6% when evaluated by old angiographic studiesMoreover, the prevalence of PVT increases with the age and severity of liver disease reaching 15% in patients awaiting liver transplantationFew studies have focused on the incidence of PVT. The de novo thrombosis within one year, in patients with liver cirrhosis, ranges from 7.4% to 16%It is generally thought that liver cirrhosis leads to a progressive bleeding tendency because of the complex alteration of the clotting system induced by liver failure but recent studies have demonstrated that liver cirrhosis, causing a reduced synthesis of either pro-coagulant or anticoagulant proteins is still associated with a balanced equilibrium of the clotting system set at a lower levelEpidemiological studies show a prevalence of venous thrombosis of 0.5% - 1%As in all venous thrombosisIn patients with cirrhosis the derangement of liver architecture leads to increased intrahepatic vascular resistance, development of porto-systemic collateral circulation and splanchnic vasodilatation and ultimately to a stagnation of the portal flow, which is considered the main predisposing factor to thrombosis.Zocco et al have recently demonstrated that the portal flow velocity, measured by Doppler ultrasound, is inversely correlated with the risk of PVTThe age, sex of the patient and etiology of liver disease have not resulted as risk factors for PVT in patients with cirrhosis, even if a lower prevalence of PVT was reported in PSC and PBC candidates for liver transplantationLocal risk factors may trigger thrombosis via endothelial damage as abdominal inflammatory diseases like diverticulitis, pancreatitis, cholangitis. Abdominal surgical interventions, particularly portal-caval shunts and splenectomy, are associated with PVTPrevious bleeding episodes from gastroesophageal varicesLocal ablative therapies, percutaneous ethanol injection and thermotherapy for HCC may induce thrombosis of portal branches close to the tumorOdds ratio of 5.9The G20210A mutation of the prothrombin is the main inherited clotting abnormality that has been associated with PVT development in liver cirrhosis with a prevalence ranging from 21.4% to 29% and an The contribution of FVL, and antiphospho-lipid antibodies to the pathogenesis of PVT in cirrhosis remains controversial. MTHFRTT677 mutation in the absence of hyperhomocysteinemia is not considered a risk factor of venous thromboembolismIn rare cases of PVT associated with recurrent venous thrombosis, or severe presentation with intestinal infarction an underlying myeloproliferative disorder can be suspectedIs it worthwhile performing a complete thrombophilic work-up in the presence of PVT in a cirrhotic patient?The identification of one or more thrombophilic risk factors in a single patient is interesting for research purposes and it useful in the clinical setting to plan the length of anticoagulant therapy. In fact in patients with \u201cstrong\u201d and persistent risk factors anticoagulation has to be prescribed lifelong. In the subgroups of patients with cirrhosis and PVT in which anticoagulation is indicated (see below) the presence of thrombophilia justifies a protracted therapy.From a patho-physiologic standpoint, PVT aggravates portal hypertension with increasing blood flow through collateral veins, which in turn favours bleeding from the esophageal and gastric veins. Even if thrombosis mostly occurs in the main portal trunk it may extend to its intrahepatic branches, splenic vein and into the superior mesenteric vein, leading to mesenteric ischemia or infarction, often lethal in these patientsMoreover, thrombosis of the smaller branches of hepatic and portal veins, frequently found in autopsy samples of cirrhotic livers, may induce hepatocyte apoptosis, contributing to the further deterioration of liver diseaseWhereas theoretically the occurrence of PVT may worsen either liver function or portal hypertensionIn clinical practice the influence of PVT has been evaluated only in the setting of liver transplantation where, even if PVT is not considered an absolute contraindication, it represents a complex challenge for the hepatic surgeon and is the cause of increased post-transplantation morbidity and mortalityPVT can have a variable clinical onset. In a study of 79 cirrhotic patients, PVT caused gastrointestinal bleeding in 39% and abdominal pain in 18%; seventy per cent of patients, admitted for acute abdominal pain, presented intestinal infarction due to the involvement of mesenteric vein .In 43% of cases PVT was a fortuitous finding during the scheduled ultrasound examination for the screening of hepatocellular carcinomaIn the previous studyThis is probably due to the earlier diagnosis of PVT and the less pronounced thrombophilic state in patients with cirrhosis.Nonetheless, the complete occlusion of the mesenteric vein is invariably associated with intestinal ischemia or infarction and the presence of a splanchnic vein thrombosis has to be investigated in cirrhotic patients with acute abdominal pain.PVT is usually diagnosed by abdominal ultrasound with pulsed and color Doppler examination but this procedure has sensitivity and specificity in detecting the thrombus variable from 66% to 100%, because it is affected both by operator expertise and patient characteristicsOverall in the presence of new diagnosis of PVT, the extent of the thrombosis and the clinical features of the patient have to be investigated for a correct evaluation of the prognosis and of the treatment.Studies in numerous series of patients with non-cirrhotic PVT have demonstrated that anticoagulation is safe and effective and represents the therapy of choiceDespite the high frequency of PVT in patients with liver cirrhosis, there are very few data on the treatment in this settingThe main concerns for anticoagulation in cirrhotics arise from the presence of a bleeding risk in these patients and the lack of evidence of a real clinical benefit from the therapy in patients with an advanced liver disease.In stable conditions the bleeding risk arises mainly from the presence of portal hypertension, in fact more than 50% of these patients have gastroesophageal varicesThe utility of the PVT treatment has been assessed only in patients awaiting liver transplantation in whom the presence of a partial PVT represents a cause of increased morbidity and mortality, while a complete thrombosis is a definitive contraindication to transplantation.In a preliminary study Francoz et al.These data, even if necessitating confirmation in larger series of patients, indicated that PVT arising in patients listed for liver transplantation is an indication for anticoagulation therapy.Since data available are not sufficient to make recommendation on PVT treatment, the following suggestions should be considered advice that can help in clinical practice. The choice of the best management should be evaluated case by case, at least to date.The presence of acute abdominal pain, due to intestinal ischemia for progression of thrombosis to the mesenteric vein, represents an absolute indication to anticoagulation in the attempt to prevent intestinal infarction. However, there remains to be evaluated whether the presence of mesenteric vein involvement in asymptomatic patients is an indication for treatment. Considering the likelihood of progression of the thrombotic process and the life threatening consequences of the complete mesenteric vein occlusion, treatment is advisable.- asymptomatic patients with a compensated liver diseaseIt is useful, for clinical purpose, to identify other specific groups of patients in whom PVT treatment needs to be evaluated:This group of patients should be treated according to the criteria of non-cirrhotic PVT either to prevent long term complications of the thrombosis or not to preclude a future liver transplantation option. Moreover, a complete assessment of risk factors is suggested in these patients since a thrombophilic state other than cirrhosis per se is likely.- patients presented with bleeding from portal hypertensionThe clinical onset with gastroesophageal bleeding of PVT should not be considered a contraindication to an anticoagulant therapy since the thrombosis may have triggered the bleeding by worsening portal hypertension. Preliminary data show that in these patients anticoagulation therapy is safe if they are adequately treated for bleeding recurrence by medical and endoscopic prophylaxisIn these patients an intrahepatic shunt (TIPS) could be considered as second line treatment because it can achieve the repermeation of the vessel and concomitant treatment of portal hypertensive complications when endoscopic therapies have failedLastly, the treatment of PVT is not to be recommended in patients with advanced liver disease, unsuitable for liver transplantation, since the improvement of survival is unlikely in this setting. Nor it is recommended in the presence of a well established cavernomatous transformation of portal vein in the absence of well defined risk factors.Studies addressing the issue in patients with PVTare lacking and it is currently advisable to apply to this group of patients the guidelines for the primary prophylaxis of bleeding followed for patients without PVTAs in non-cirrhotic PVT, anticoagulation therapy is the first line therapeutic strategy in patients with liver cirrhosis. Two main groups of drugs are available to this purpose Vitamin K antagonists (VKA), acenocoumarol and warfarin, and heparins.Francoz et al.Amitrano et al.The number of platelets did not change significantly in any patient during anticoagulation treatment and only two patients complained of mild anemia due to portal hypertensive gastropathy.-VKAs administered by mouth are more acceptable by the patients but they need periodical dose-adjustments by INR monitoring; in patients with advanced liver disease the INR value is often spontaneously close to or above 2.0 considered a therapeutic range for anticoagulation. Thus INR value as currently measured is inadequate to monitor anticoagulation for patients with severe liver disease- LMWHs have completely replaced unfractionated heparins since they have the same efficacy and do not necessitate monitoring for dose adjustmentIn absence of comparative studies, the choice of the anticoagulant therapy has to rely on the following considerations:These disadvantages of both anticoagulation strategies may be overcome by the new oral anticoagulant drugs such as thrombin inhibitors and anti factor XaCurrently VKAs may represent a therapeutic option in patients with compensated liver disease who require long term anticoagulation. LMWHs should be given to patients awaiting liver transplantation and to patients with a more severe liver disease.- patients who achieved a complete recanalisation can stop anticoagulant therapy in the absence of previous thrombotic events, or thrombopilic risk factors. They should be followed periodically for PVT recurrence.- patients with partial recanalisation or with a stable partial thrombosis should continue anticoagulant therapy if candidates for or suitable for future OLT in order to prevent a complete portal vein occlusion.- patients who failed to achieve any recanalisation of occlusive PVT should stop anticoagulant therapy. Nevertheless, in patients with deep vein thrombosis of the limbs, residual or persistent thrombosis is considered as a risk factor for recurrence requiring long-life anticoagulation- patients with recurrence of PVT should be considered for long-life anticoagulant therapy.The current guidelines for the treatment of venous thromboembolismLocal and systemic thrombolysis has been utilized in the setting of non-cirrhotic venous thrombosis and only rarely in cirrhosis as rescue therapy but high rate of major complications including bleeding has been reportedSo this therapeutic approach in a cirrhotic patient with PVT should be reserved only in the case of patients with ongoing intestinal infarction not responsive to anticoagulation therapy.Transjugular intrahepatic porto systemic shunt (TIPS) can be considered a second line treatment of PVT in patients with portal hypertensive complications not controlled by the common therapeutic approach particularly in patients awaiting liver transplantation. In preliminary experience Senzolo et al. reported a successful TIPS placement in a 69% of 13 cirrhotic patients with PVTPortal vein thrombosis is recognized as one of the complications of liver cirrhosis but many aspects still remain to be elucidated. The first is the impact of PVT on the natural history of liver cirrhosis and prospective studies addressing this issue are warranted and to identify subgroups of patients who could benefit from PVT treatment.The best treatment option in terms of efficacy and safety has also to be established. Furthermore, which anticoagulant treatment, the duration of therapy and the modality of monitoring need to be evaluated in future controlled trials."}
+{"text": "A key problem in neuroscience is understanding how the brain makes decisions under uncertainty. Important insights have been gained using tasks such as the random dots motion discrimination task in which the subject makes decisions based on noisy stimuli. A descriptive model known as the drift diffusion model has previously been used to explain psychometric and reaction time data from such tasks but to fully explain the data, one is forced to make ad-hoc assumptions such as a time-dependent collapsing decision boundary. We show that such assumptions are unnecessary when decision making is viewed within the framework of partially observable Markov decision processes (POMDPs). We propose an alternative model for decision making based on POMDPs. We show that the motion discrimination task reduces to the problems of (1) computing beliefs (posterior distributions) over the unknown direction and motion strength from noisy observations in a Bayesian manner, and (2) selecting actions based on these beliefs to maximize the expected sum of future rewards. The resulting optimal policy (belief-to-action mapping) is shown to be equivalent to a collapsing decision threshold that governs the switch from evidence accumulation to a discrimination decision. We show that the model accounts for both accuracy and reaction time as a function of stimulus strength as well as different speed-accuracy conditions in the random dots task. Animals are constantly confronted with the problem of making decisions given noisy sensory measurements and incomplete knowledge of their environment. Making decisions under such circumstances is difficult because it requires (1) inferring hidden states in the environment that are generating the noisy sensory observations, and (2) determining if one decision (or action) is better than another based on uncertain and delayed reinforcement. Experimental and theoretical studies In this paper, we derive from first principles a POMDP model for the well-known random dots motion discrimination task hidden state, belief (posterior probability distribution) over the set of possible states given the sensory observations seen so far: optimal policyWe model the random dots motion discrimination task as a POMDP. The POMDP framework assumes that at any particular time step, the environment is in a particular We now describe how the general framework of POMDPs can be applied to the random dots motion discrimination task as shown in In a given trial, neither the direction It can be shown Given the framework above, the task of deciding the direction of motion of the coherently moving dots is equivalent to the task of deciding whether The animal updates its belief after receiving the current observation Recall that a belief state A policy belief MDP, we need to define the transition probabilities One standard way Given the time-independent belief state transition Before we proceed to results from the model, we note that the one-step belief transition probability matrix We summarize the model variables as well as their statistical relationships in The optimal policy We compare predictions of the model based on the learned policy The performance on the task using the optimal policy The sequence of random variables Let The probabilities of making rightward or leftward eye movement are the marginal probabilities summing over all possible crossing times: The left panel of The right panel of There is essentially one parameter in our model needed to fit the experimental accuracy data, namely, the reward ratio From The above model makes two testable predictions about neural responses in LIP. The first is that the neural response to The second prediction concerns the buildup rate  Another advantage of a POMDP model is that the model parameters have direct physical interpretations and can be easily manipulated by the experimenter. Our analysis shows that the optimal policy is fully determined by the reward parameters The proposed model demonstrates how the monkey's choices in the random dots task can be interpreted as being optimal under the hypothesis of reward maximization. The reward maximization hypothesis has previously been used to explain behavioral data from conditioning experiments We showed through analytical derivations and numerical simulation that the optimal threshold for selecting overt actions is a declining function of time. Such a collapsing decision bound has previously been obtained for decision making under a deadline Instead of traditional dynamic programming techniques, the optimal policy"}
+{"text": "This includes maintaining skin integrity wherever possible, promoting healing in the non-healing wound and provision of expertise and specialist equipment to complex acute and chronic wounds.\u25cb The Podiatry Wound Care Service is a team of experienced podiatrists highly skilled to manage the high risk foot. The team works across both primary and secondary care forming a seamless service between the two working closely with all disciplines to provide a holistic approach to treatment and care planning.\u25cb The Lower Limb Service is run by experienced nurses who are proficient in the management of cellulitis, tissue viability and skin care related to the lower limb. Patients are provided with a variety of health education, clinical treatment and advice in different settings including community clinics, domiciliary visits and groups within the wider community.Each service has a different view of the patient and their wound.Working within an integrated team allows us to fast track urgent referrals and arrange joint visits between the disciplines with ease so wound care plans can be devised and implemented immediately. The 3 services complement each other well, each bringing a different skill mix to the treatment but with us all having the same goalJust as we view the patient holistically but assess individual systems, so the Integrated Wound Care Team is able to take a different view of the wound but collaborate together to provide high quality care which benefits the patient as a whole."}
+{"text": "Previous vaccine development has been driven mainly by policies and concerns around childhood, with the aim of preventing premature death amongst young children from infectious disease and stopping them from acting as carriers. Whilst this is important, the face of the world has changed recently and the problem has now to be extended to include the protection of a vulnerable aging population. Here we present the case for a need to develop a prophylactic regimen for older individuals which features vaccination at the center of a portfolio of treatments.Advances in medical, social, and economic conditions have resulted in human population growth and an ever-extending life expectancy such that for the first time in our history the world population will soon have more people over the age of 65 than under the age of 5. The development of antibiotic therapy, progresses in vaccine technology combined with mass vaccination programs and government schemes to improve economic and social well-being mean that the majority of individuals over the age of 65 are currently physically more active than their counterparts a few decades ago . Influenza is commonly thought to be a disease of limited duration, but in older individuals it may lead to a period of prolonged bed rest. Because long periods of bed rest are associated with a loss of aerobic capacity (1% per week whilst bedridden), a loss of muscle capacity (5% per week), and a loss of bone density (\u223c1% per week) this may leave a previously healthy older individual as a weak frail person dependent on assistance from others for their normal activities of daily living  is recommended for all adults over the age of 60\u201365 to combat transmission (Michel et al., The poor performance of the TIV in providing protection in older individuals has been known for some time, but to date there has been no satisfactory resolution of the issue. Several studies have been undertaken on possible reasons for this problem and these have produced a number of studies on age-associated changes in immunity which have identified problems with Langerhans cells (Shaw et al., One of the major challenges for vaccine development in this population is associated with identifying measureable surrogate markers which are acceptable readouts of immune protection (Lang et al., In a complex system such as the immune system with its multiple component overlaps, predicting individual responsiveness to influenza vaccination using a single method able to distinguish between a healthy and an immunosenescent state, would be very challenging. Especially as the ability of the immune system to respond to vaccination is further impinged upon by the impact of non-immune factors such as nutritional and metabolic status, and comorbidities from which adults increasingly suffer from as they age (Collerton et al., The presence of these multiple issues associated with vaccine ineffectiveness underlines the degree of diversity which exists amongst older individuals, which in turn is somewhat expected since aging is neither regulated nor programed. Although each individual ages differently and in a way, which in part is dependent on lifestyle choices and environmental factors, there are common threads (Murabito et al., Since there are currently no tests associated with defining an individual's ability or inability to produce a protective response to vaccination, a more valuable approach would be to measure several aspects of the immune response following vaccination within an individual and compare these not only with known benchmark levels but also to confront these with validated biological and clinical outcomes. This would entail some degree of classification of older individuals into specific trends of aging on the basis of defined characteristics or their absence. In the past efforts have been made to achieve this and define an immune risk phenotype which includes T cell phenotypes, subset numbers, function, CMV status, and cognitive impairment (Wikby et al., Such a move from the existing immunization menu toward a greater degree of personalized medicine could contribute to accelerating the development of new vaccines with higher efficacy and of specific combined therapeutic approaches than those currently available."}
+{"text": "In 2007, Kangan Institute commenced inclusion of Allied Health Assistant Certificate 4 - Podiatry Units delivered by a podiatrist. Different models have been delivered including external placement with private podiatrists, service specific units on site and external work based programs. Since then, a number of TAFE based AHA courses have been commenced including those at Swinburne and Gippsland. With National Registration, the recognised qualification for podiatry assistants is the Certificate III or IV Allied Health Assistant qualification that includes Podiatry Units.Clarification of the required training for podiatry assistants has offered TAFE services the opportunity to consider the way in which services are offered, and to review the barriers and enablers: (i) to podiatrists using AHA trained podiatry assistants in the work setting and (ii) to acceptance of AHA students for podiatry based clinical placements. This presentation will discuss these issues and present some of the current strategies used in the TAFE sector to enhance the enablers and reduce barriers to the benefit of the profession and its podiatry assistants. It will also discuss methods to expand the training in the future to benefit the podiatry industry."}
+{"text": "By living in a \u201cworld of water\u201d fishes are exposed to major osmotic challenges that are opposite in nature in the freshwater and marine environments. In both cases, obligatory water fluxes primarily due to osmotic gradients across respiratory surfaces are threatening to the internal milieu and must be compensated by bulk flows of water in the opposite direction. While the ionoregulatory mechanisms that generate the osmotic driving force for such water flows have been known for decades, the molecular pathways of compensatory water fluxes are still largely unravelled. Current models suggest that water passes hydrophobic epithelia by para- and/or transcellular pathways, the former being defined by the characteristics of tight junctions, the latter determined by the serial permeability of apical and basolateral cellular membranes. Transcellular water transport may occur by simple diffusion through lipid bilayers or become markedly improved by the insertion of integral channel proteins (aquaporins) in the plasma membrane. Thus, aquaporins can truly be conceived as the plumbing system of cells.In mammals, 13 aquaporin subfamilies are present and several of these have been investigated structurally and functionally in >6600 publications since their discovery in 1992 by Agre and colleagues. The first paper on aquaporins in fishes appeared in Cutler and Cramb  but surpAquaporins most certainly play distinct roles in fishes as they do in mammals\u2014both at the cellular, organ and organismal level. However, there is a considerable lack of information from the fish world on this topic, with only ca. 50 papers addressing aquaporins in fishes at the time of the call of this Research Topic in 2010. Most of these describe tissue expression patterns in various Teleosts, while Aqnathans and Chondrichthyes and the functionality of fish aquaporins have received very little focus. This ebook presents a collection of papers addressing the evolution and role of aquaporins during gametogenesis and embryonic development as well as for water transport across adult gill, kidney and intestinal epithelia using bony and cartilagenous fishes as models. Our aim is to stimulate new original research in this area as well as bringing together new collaborations across fields."}
+{"text": "Sir,We appreciate the keen interest in our cMycobacterium tuberculosis from kidney transplant recipients because the recipients may belong to diverse geographic locations where the prevalence of drug resistance may vary. Identifying drug susceptibility is all the more important in transplant recipients in view of the limited drug options available for them due to significant interaction of rifamycins with calcinurin inhibitors (CNIs) and mTOR inhibitors. The current recommendation for treatment of tuberculosis in kidney transplant recipient is to use the same treatment regimen as used in local general population who require therapy.[The KDIGO clinical practice guidelines for the care of kidney transplant recipients recommen therapy. Rifampic therapy.5 The duret al.[et al.[Aguado et al. has repol.[et al. reportedl.[et al. durationThe prostatic abscess in our patient was asymptomatic and was picked up only on imaging; he had no evidence of bladder outlet obstruction. Hence, an intervention for draining the same was not considered necessary. A repeat CT scan after 3 months of antitubercular chemotherapy showed complete resolution of the abscess."}
+{"text": "Simon Hay and colleagues discuss the potential and challenges of producing continually updated infectious disease risk maps using diverse and large volume data sources such as social media. Systems to provide static spatially continuous maps of infectious disease risk and continually updated reports of infectious disease occurrence exist but to-date the two have never been combined.Novel online data sources, such as social media, combined with epidemiologically relevant environmental information are valuable new data sources that can assist the \u201creal-time\u201d updating of spatial maps.Advances in machine learning and the use of crowd sourcing open up the possibility of developing a continually updated atlas of infectious diseases.Freely available dynamic infectious disease risk maps would be valuable to a wide range of health professionals from policy makers prioritizing limited resources to individual clinicians.It is perhaps surprising to state that we have an extremely poor knowledge of the global distribution of the vast majority of infectious diseases Here we argue that this information gulf has serious implications for global public health surveillance and that too little attention is given to spatial epidemiology in international preparedness planning. Stated simply, how can we gauge the risk posed by new infectious disease outbreaks if we have only the crudest understanding of their natural geographical range? Additionally, how do we prioritise useful intelligence in the growing deluge of Big Data To explore the factors hindering progress, we need to consider how traditional methods are used to map disease. We illustrate this in To complete the process illustrated in Canonically, the output risk surface is where the mapping process ends, which further compounds the problem of the paucity of infectious disease mapping. This is in part due to the very labour intensive nature of assembling  provides continually updated disease occurrence points but not continuous spatial data. Can we conceive of spatially continuous risk maps being updated in \u201creal-time\u201d\u2014as frequently as new occurrence data are assimilated? The conceptual bridge of imagining spatial modelling as a continuous process in time is achieved simply by linking the output risk map back to the data inputs to create a feedback loop. This is important as it facilitates the novel step of spatial triage of new occurrence information (see below) and critically, the potential for multiple iterations of the map with continuous improvement by adding a machine learning element. This conceptual shift towards evolving maps, in combination with the increased availability of novel digital data sources The process described above provides a continuous risk map in space that is static in time. Conversely HealthMap , frequency of update (velocity), or diversity (variety) It is well established that a huge amount of novel data are being generated that will make important contributions to temporal public health surveillance In the era of satellite sensors, a diversity of epidemiologically relevant environmental information can be sourced globally at daily intervals Perhaps the most important development in relation to Big Data is the conceptual move from static to improving and evolving risk maps. Taking further our example of dengue mapping , the firThe biggest obstacles to incorporating a continuous spatial mapping component to routine biosurveillance will be demonstrating the feasibility and sustainability of this undertaking and engaging the audience. We have focussed here on applications for biosurveillance but it is important to emphasise the wider audiences. First, one should never underestimate the value of risk maps in helping to illustrate the extent of a public health problem www.flunearyou.org) and Influenzanet in the EU (www.influenzanet.eu), which now boast nearly 100,000 volunteers combined. From the outset all infectious disease data and derived maps should be made freely available to ensure engagement. This will also facilitate the uptake of new resources and their consideration by policy makers. Once the primary investment in the software platform is complete, and the community established, sustainability increases because demands for user inputs decrease as the software learns and the mapped outputs become increasingly stable. The ultimate vision is to democratise the platform by providing the code to all interested authorities.We have already argued that this mapping ambition is made tractable by automating many of the laborious steps in primary data acquisition and positioning. The Big Data revolution is already underway and harnessing the useful information in these new data sources will involve collaborations with computer scientists at the forefront of machine learning and with those who have had success in engaging communities"}
+{"text": "The potential to discover unanticipated clinically significant genetic variants during the course of research has stimulated much debate about the obligations of researchers to communicate such findings to study participants. Published guidelines suggest that researchers have an obligation to communicate valid and significant results, especially if they are clinically actionable. I will present data on the practices and perspectives of investigators conducting genome-wide association studies (GWAS) and will caution against the establishment of a general obligation to return results in research. I will compare the role-specific responsibilities of researchers with those of clinicians and discuss emerging standards for genomic analysis and communication of test results in the clinical setting."}
+{"text": "Mediterranean Journal of Hematology and Infectious Diseases (MJHID) is a new open access, peer-reviewed, online journal, which encompasses different aspects of clinical and translational research providing an insight into the relationship between acute and chronic infections and hematological diseases. MJHID will be a topical journal on subjects of current importance in clinical haematology and infectious diseases. Every issue should have, beside the editor in chief, a guest editor. Both editor in chief and guest editor provide to invite experts in the selected topic to performe a complete update of the arguments readily available for practising phisicians. The journal will have also a section devoted to original papers, case reports and letters to editor and Editorial comment mostly focusing on the arguments treated in the previous topical issues. Reciprocal interdependence between infectious and haematologic diseases  is well known.27Splenectomy frequently performed autoimmune diseases as well in lymphoproliferative diseases is a further cause of immunodeficiency.28helicobacter pylori and B lymphoproliferative diseases are well known65Nevertheless, the main cause of immunodeficiency at present is due to HIV infection in developed as well in developing countries.Urgent pragmatic and efficient measures are needed both at international and national levels. Most of the peoples affected by neglected infectious diseases live in Central Africa, South Asia This should be possible bridging the health system gap between the south and the north borders sides of Mediterranean Sea while improving scientific collaboration.Case report should have educational character. Clinical trials of hematologic and infectious diseases present of Mediterranean area will have their natural home in this Journal. Also case studies relative to important health care intervention in developing countries of south Mediterranean areas will be accepted. All that should contribute to disseminate updated informations among physicians of developing countries on the more frequent diseases of the Mediterranean area.The results of relevant studies in the field should be made available to scientists and clinicians, in particular those in developing countries where the fight against pathogen related cancers is of the utmost importance.Every accepted manuscript will be available for reading on its date of acceptance by any person who has access to the web in web-friendly XML. Considering that every issue will be devoted to a topic, when all articles of the same topic will be available they will be formatted and the typeset PDF version will be available. The first issue of the MJHID has been dedicated to \u201cUpdate in Diagnosis and Treatment of Thalassemia and related Disorders\u201d Guest Editor Prof. Maria Domenica Cappellini."}
+{"text": "Partnership between service users and researchers is a cornerstone of the current research and development strategy for England\u2019s National Health Service and is considered by funders as essential throughout the entire research process. To promote and facilitate public involvement in the field of HCAI research, the HCAI Research Network (RN) formed a Service User Research Forum (SURF) to inform priorities and contribute to HCAI research. This paper shows how SURF is supported to develop its own research priorities into viable projects.The HCAI RN has developed a robust process with SURF to identify priorities and develop feasible research questions, facilitate interrogation to assess viability and ethics and ensure potential benefits are defined. This enables lay researchers to contribute to literature reviews and desk research; determine appropriate funding; work in partnership with academic/ clinical researchers and undertake research team roles. The HCAI RN provides training and support for this process.In 2010, SURF worked collaboratively with clinical and academic researchers to submit a proposal exploring patient experiences of MRSA screening for funding. The group is currently developing a user-led project evaluating health professional education in HCAI.Active service user involvement contributes diverse perspectives, ensures projects are relevant to patients and the public and empowers service users to make real contributions to the reduction of HCAI and drive change within healthcare settings. We continue to develop strategies to enable SURF involvement at all stages of research. Dedicated training and support ensures service users have the research skills and confidence to make their knowledge, experience and insights count in HCAI research.None declared."}
+{"text": "Thyroid gland disease of autoimmune origin presents wide spectrum of pathologies, Graves\u2019 disease from one side and chronic thyroiditis with fibrosis and atrophy of gland parenchyma from the other one. Among them the highest number of misunderstandings is observed in pathological reports of chronic thyroiditis in pre-operative cytological as well as in post operative histological examinations. There are numerous classifications of chronic thyroiditis, however they are not widely accepted. Histoclinical classification which correlates elements of microscopic examination with clinical course of the disease seems to be ideal but still does not exist. FNAB of thyroid gland is a method of the greatest importance in the diagnosis of chronic thyroiditis however that fact is not widely understood in every day routine of clinicians and pathologists."}
+{"text": "The world of pharmaceutical statistics has taken adaptive designs to its heart - at least in theory. However despite the very large number of methodological publications and presentations at conferences there are still very few examples of adaptive designs in the medical literature. In this talk I will discuss why this might be the case and will suggest areas where these approaches are likely to be of greatest value in the future."}
+{"text": "To the Editor: Recent articles in the professional literature (Neisseria gonorrhoeae (QRNG) is much more common in Asia  . Those partners who were identified were either not located or did not agree to speak with the disease intervention specialist.Sexual behaviors associated with travel can change the level of risks for STD transmission (Neisseria gonorrhoeae should serve as a model for STD prevention planning and programming. It highlights the importance of retaining the laboratory capacity to monitor antimicrobial susceptibilities of bacterial STD isolates. Treatment protocols should be adjusted in light of the prevalence of resistant strains of sexually transmitted pathogens. In cases in which symptoms associated with a bacterial STD persist after what is usually considered appropriate treatment, clinicians should obtain cultures and perform susceptibility tests on isolates. Nucleic acid amplification technologies do not provide critical antibiotic susceptibility information. In this situation, the public health STD program or laboratory should be contacted for guidance. Determining the sensitivity pattern of the pathogen in an expeditious fashion will ensure that appropriate and timely therapy can be initiated for the infected patient as well as enable more effective follow-up and treatment to sexual contacts. Asking patients who seek treatment for a possible STD about their own and their partner\u2019s travel histories is important to broaden the differential diagnosis (This experience with antimicrobial resistance of"}
+{"text": "Malaria is one of the major public health problems for low income countries, a major global health priority, one that carries a dramatic economic impact. Funding and consequently coverage of both preventive interventions and of case management for malaria control have been rising and both international donors and governments of malaria endemic countries need the tools and evidence to assess which are the best and most efficient strategies. To aid with these decisions we developed an open access malaria costing database that effectively summarizes an extensive body of literature on costing and effectiveness of malaria preventive interventions and case management. The database comprises 150 publications spanning from 1985 through 2012 from a total of 42 countries. We collected costs, detailed site and intervention data on insecticide residual spraying campaigns, insecticide treated net distribution and re-treatment campaigns, delivery of intermittent preventive treatment, and treatment of uncomplicated and severe malaria. Unit costs and other intervention data were coded into standardized categories and expressed in common 2008 international dollars allowing us to compare economic outlays across sites and interventions. We discuss findings from these descriptive analyses and illustrate how these data can be used to extrapolate costs to other countries."}
+{"text": "A poster presentation will be prepared to disseminate the result of research conducted to investigate the potential for the Health Belief Model as a tool to understand the factors affecting compliance with the use of prescribed footwear in diabetic foot disease.A self-completion postal questionnaire was developed and applied in a South Wales Valley community to investigate the health beliefs of 72 individuals provided with prescription footwear for advanced diabetic foot disease and to investigate the impact of these beliefs on their compliance with prescription footwear.46.6% of respondents were found to be compliant with their use of prescribed footwear at the 9.6 hours per day threshold. Prior history of ulceration was found to be associated with increased likelihood of compliance , which contests the finding of McFarlane & Jensen(2003). Recollection of advice to wear the prescribed footwear indoors was also significantly associated with compliance . Patients who perceived prescribed footwear as beneficial used them for a greater number of hours per day . Patients who perceived diabetic foot ulceration as serious were more likely to perceive prescribed footwear as beneficial  and patients who perceived prescribed footwear as beneficial were less likely to rate barriers to compliance as high . The correlation between the summary health belief scale and reported daily hours of prescription footwear was not significant . An improved health belief model has been constructed to enhance understanding of the factors affecting compliance in this context.It is recommended that the NHS provision of prescription footwear should be focused toward patients with a previous history of ulceration and those for whom ulceration is imminent. Patients with pre-ulcerative diabetic foot disease should be counseled to wear protective commercial footwear indoors as well as when walking outside."}
+{"text": "Being able to induce therapeutic tolerance for the treatment of immunological diseases was once considered by many to be an unattainable dream, but recent developments in our understanding of immune regulation and tolerance-compatible immunosuppressive drugs may be turning that dream into reality. Tolerance induction in many rodent models of autoimmune disease and graft rejection is now almost trivial, and the problem has become not how to achieve tolerance experimentally but how to translate this knowledge to real clinical applications in human disease. This volume brings together 17 articles that highlight some of the different approaches being investigated for translating potentially tolerogenic therapies to the clinic and the barriers that still need to be overcome.The first two articles review the current status of clinical trials that result from large networks of basic laboratories and clinical consortia coordinated by the International Tolerance Network  o et al.  discuss o et al.  focuses o et al.  make a cThe following six articles consider various novel approaches to tolerance induction. Becker et al.  argue thThe final six articles discuss in more detail some of the barriers that remain to clinical translation of tolerogenic therapies to the clinic. Pasquet et al.  questionIn summary, we have made considerable progress toward translating potentially tolerogenic therapies from rodent models into the clinic, to the point where we now have a much clearer understanding of the barriers that remain and how we may yet overcome them."}
+{"text": "Previous research has overwhelmingly established a relationship between sport participation and the development of positive body image (BI) (Richman & Schaffer (2000), Shaffer & Wittes (2006) and Greenleaf et al (2009). However a number of studies have indicated some women are particularly vulnerable to the development of poor BI in relation to sports participation . Due to the conflicting evidence, we have used an interpretive phenomenological framework to qualitatively explore women's experiences. Specifically we aimed to understand the perceived impact of sports participation and related commentary during childhood on adult body image. Participants were given the opportunity to suggest interventions which would improve their experiences of sports in relation to BI.Women indicated they started to think about their bodies from as young as 6 and 7. They remembered critical incidences that occurred during childhood sports which they perceived to influence their BI either in a positive or negative way. The awareness of their bodies has often come about through commentary from family or coaches, or through sporting uniforms. Suggestions for interventions have included mandatory education on overall health and food from as young as 6 in primary schools.Body Image stream of the 2013 ANZAED Conference.This abstract was presented in the"}
+{"text": "Measurements of membrane potential traces constitute the main observables to derive a biophysical neuron model; in particular, the dynamics of auxiliary variables and the model parameters are inferred from voltage traces, in a costly process that typically entails a variety of channel blocks and clamping techniques  and some"}
+{"text": "Often it is mentioned by participants that having peers speak out about their personal journey has instilled a sense of hope and been an inspiring experience. From this evolved the Mentor program. The Body Image and Eating Disorders Treatment and Recovery Service (BETRS) Mentor Program has been developed to complement the professional expertise within the team. Our Mentors share their lived experience of an eating disorder with current patients of BETRS. The invaluable contribution to the service by our mentors has been the following:- Supporting hopefulness and the recovery process by co-facilitating group sessions that focus on how they dealt with issues that are of particular concern to current patients.- Strengthen relapse prevention by giving firsthand accounts of occasions when lapses have not signalled a relapse but have been incorporated into the recovery process.- Mentors have been fostering motivation by encouraging behaviours that supported their own recovery and by assisting with the organisation and general care of the client group.- By sharing their experience of having an eating disorder and providing evidence of hope during the course of recovery mentors have given family and carers and better understanding.Care in Inpatient and Community Settings stream of the 2013 ANZAED Conference.This abstract was presented in the"}
+{"text": "Enviromental bioburdon is a potential source of healthcare associated infections (HAI) but there has been no evidence based science to authenticate this. Cleaning practices in healthcare environments is often set in place by the environmental service workers  and continued. Standard guidelines of cleaning process are lacking, and as there is no scientific standard to measure the effect of the process and the bioburden, it is often not addressed by medical community. Monitoring of cleanliness is by visual audit  which is a purely aesthetic parameter and subjective. We put in protocols for the cleaning of patient zone and high touch surfaces for the ICU after we had an outbreak of Acinetobacter baumanni infections. We added also an indigenous (detergent) mat at the entrance of the o ICU to decrease the biobuden.To implement a standard domestic hygiene protocol to prevent HAI. To make cleaning an integral part of infection control activity.We took up a pilot project in our 18 bedded medical intensive care unit when there was an outbreak of Acinetobacter baumanni infections. We prepared a protocol for cleaning of the ICU by defining all basic  parameters. Responsibility was delegated to the nursing staff for cleaning the bedside equipment (near patient hand touch surfaces) and the environmental service workers were accountable for the rest of the area. Infection control team gave hands on training to relevant staff. The process was monitored microbiologically (aerobic colony count) and by biochemical (ATP bioluminescence) means.Environmental follow up surveillance showed marked decrease in the colony forming units and biobuden.There has been no outbreaks of Acinetobacter baumanni infections after the implementation and monitoring of this protocol.Awareness and compliance of the protocol is high. A well designed cleaning protocol has been set to maintain clinical environment across hospital today.Environmental contamination is recognized as an important reservoir of the epidemic strains. High standards of domestic cleaning are essential intervention in the control of HAI. Simple hygiene is only solution in this end of antibiotic era to prevent HAI.None declared"}
+{"text": "Sir,Mansonella perstans and apologize for the inadvertent error. The only reported case of pleural effusion due to M. perstans was of Kahn in 1983.[This is in reference to the letter by an esteemed reader. I appreciate the interest shown by him regarding our case. We regret that the case reported by him was wrongly quoted in our article as caused by We did not consider pleural biopsy as the diagnosis was firmly established by repeated demonstration of microfilariae in pleural fluid, and the patient denied consent for pleural biopsy. The literature shows that pleural biopsy does not always demonstrate microfilariae.3The method used for demonstration of microfilariae in pleural fluid was hematoxylin and eosin stain on smears prepared from the sediment of pleural fluid after centrifuging at 2000 rpm for 15 min. Pleural fluid samples were collected at night time or in early morning."}
+{"text": "Facial asymmetry is a common condition and only becomes a problem if there is a significant difference between both sides. In the Asian community, the difference between the height and width of the palpebral fissures and the skin creases is usually the most apparent on photographs. There has not been any reports on the prevalence of such differences between the various racial groups in Malaysia. This study looks at the incidence of asymmetry of the palpebral fissue and upper eyelid crease in young Malaysians of Malay and Chinese origins of which form the biggest racial groups in Malaysia. Data obtained from such studies would be useful for reconstructive and aesthetic surgery as well as for counselling patients with dysmorphophobia.Malaysian students between the ages of 18 and 26 were randomly selected at University Malaysia Sarawak. These students comprised of 197 Malays and 198 Chinese. The following parameters of both eyes were obtained with a millimeter ruler: palpebral fissure width (PFW), palpebral fissure height (PFH), intercanthal distance (ICD) and upper eyelid skin crease height (UESC). The presence and absence of skin creases were also recorded. Data collected was analyzed with Microsoft Excel and SPSS.There is statistical significant difference between the different sexes and races for PFW and PFH but none between the two sides. There is statistical significant difference between the two eyes for UESC. Chinese males have the highest percentage of PFW and PFH asymmetry. Malay males have the highest percentage of UESC asymmetry.Eyelid asymmetry is common amongst Malaysians. Asymmetry of PFW, PFH and UESC is commoner in males than females. Of the three parameters, asymmetry of UESC is the commonest. PFW and PFH asymmetry is more common in Chinese than Malays but UESC asymmetry is more common in Malays. UESC is almost universally present in Malays whereas in the Chinese there is a significant percentage of subjects with asymmetry of presence of UESC  which gives rise to a more obvious eyelid asymmetry. This data is useful for oculoplastic surgeons who are keen on counselling patients who wish to undergo aesthetic procedures pre and post-operatively."}
+{"text": "The introduction of mandatory Continuing Professional Development (CPD) as a condition of podiatry registration has caused quite a deal of manic amongst the Podiatry population. What practitioners may underestimate is the amount of CPD that is undertaken as part of their everyday work practices. The podiatrists at Eastern Health are fortunate to have a supportive work environment that aims to foster learning opportunities and career advancement. This poster shows an audit of the amount and types of learning opportunities logged by the 12 member podiatry department for the first six months of the mandatory CPD period. The audit uncovered that many of the staff members had satisfied the Podiatry Board of Australia\u2019s mandatory requirements within a two-month period. It is hoped that this poster will inspire others to think about their ongoing CPD opportunities within their own workplace."}
+{"text": "I World Health Organization Global Malaria Action Plan sets out an ambitious plan for improved control, leading to regional elimination and includes as the ultimate goal the eradication of malaria. The ambitious goal of malaria eradication can however not be achieved with the tools and approaches currently available. Research and development of new tools must accompany and complement the Global Action Plan. We critically review and discuss the progress so far made to pursue the R&D agenda and about the key R&D issues where renewed attention and investments are required [Malaria elimination and eradication is back on the global health agenda. The Roll Back Malaria required . The folP. vivax: in vitro culture and study of the biology of hypnozoites.\u2013 The strengthened focus on \u2013 Drugs to be used for mass drug administration to clear infections and provide prophylaxis to prevent new infections Vaccines that aim at interrupting transmission.A. gambiae.\u2013 New vector control approaches for (i) outdoor biting / resting mosquitoes and (ii) achieving permanent reductions of vectorial capacity in areas where transmission is predominantly due to \u2013 New approaches for fast and accurate assessment of transmission at community level and strengthened diagnostic, monitoring, and surveillance tools/approaches that are linked and embedded in the health and social health systems.\u2013 New approaches in mathematical modelling to inform Target Product Profiles of tools, and predict expected outcomes of intervention strategies for elimination.\u2013 Tools to scientifically assess and determine health system readiness for moving from control to elimination.The review will conclude by pinpointing the challenges that are still ahead of us in the development of the science for elimination and application of its results to effectively complement the Global Action Plan."}
+{"text": "Annals exists in part to keep surgeons up to date with advances in surgical research. We also have a responsibility to inform our readers of research opportunities that they may wish to join. Professor John Scholefield heads the National Institute for Health Research (NIHR) National Surgery Specialty Group and he has asked us to publish regular updates of surgical research activity taking place across the UK. We are pleased to do so and provide some additional information below.The  The Comprehensive Clinical Research Network (CCRN) is one of eight NIHR networks in England that provide researchers with the practical support they need to make clinical trials happen in the NHS so that more patients can take part in clinical research in England. The devolved nations have similar arrangements in place to support clinical research.The Surgery Specialty Group is 1 of 24 specialty groups that provide national networks of topic-specific expertise. These groups are key to the success of the CCRN. They work at both national and local levels to ensure the successful delivery of research in their specialties. This means ensuring that studies are delivered to target and on time.>We offer opportunities for surgeons and other healthcare professionals to become involved in research as well as for existing researchers to access a network of skilled research support staff and wider patient populations.>Comprehensive Local Research Networks can provide: assistance with the research and development approvals process; research nurses to consent patients into studies and perform study-related procedures; support for services such as pharmacy, imaging and pathology; and access to training opportunities.>http://www.crncc.nihr.ac.uk/about_us/ccrn/specialty/) or you can email the CCRN specialty groups team .Detailed information about specialty groups including contact details for regional representatives can be found on the Clinical Research Network website  of the Chief Investigator.>Get in touch with the named contact>Click on the link for each trial (if viewing online)>http://public.ukcrn.org.uk/search/)Visit the website of the Clinical Research Network Study Portfolio (For further details:"}
+{"text": "Telehealth systems benefit from the rapid growth of mobile communication technology for measuring physiological signals. Development and validation of a tablet PC enabled noninvasive body sensor system for rural telehealth application are discussed in this paper. This system includes real time continuous collection of physiological parameters  and fall detection of a patient with the help of a body sensor unit and wireless transmission of the acquired information to a tablet PC handled by the medical staff in a Primary Health Center (PHC). Abnormal conditions are automatically identified and alert messages are given to the medical officer in real time. Clinical validation is performed in a real environment and found to be successful. Bland-Altman analysis is carried out to validate the wrist blood pressure sensor used. The system works well for all measurements. The population of elderly individuals is quickly expanding far and wide. The population of individuals of more than 65 years of age around the world will achieve 761 million by 2025, more than twofold of the 1990 figures \u20136.Hypertension and accidental falls are the two emerging public health problems and a barrier to active ageing . HyperteFall prevalence in India increases with age and is the highest in women and older adults . All perLatest developments in the field of wireless technology can be utilized for monitoring. Wireless body area sensor network (WBASN) is a developing technology that interconnects tiny nodes with sensing capabilities in, on, or around a human body . Recent Community Health Centers (CHC) and Primary Health Centers (PHC) are managing a heavy patient load with the shortfall of doctors as well as supporting staffs . So the This paper is organized as follows: A wearable wrist sensor worn by the patient is used in this work for real time implementation. An embedded platform is used for acquiring the biological information from the wrist sensor and transmitting to a mobile phone/tablet PC running on android platform which is monitored by a medical staff.The hypertension status of the person under test is immediately sent to the tablet PC and automatic alert facility for hypertensive patients is sent to the medical officer through short message service (SMS) facility. The proposed telehealth system architecture with remote monitoring facility is shown in The block schematic of the body sensor unit developed for this work is shown in The body sensor unit, connected to the patient at the health center, consists of the following sensor units.(a) Blood Pressure/Pulse Rate Sensor. Arterial pressure is defined as the hydrostatic pressure exerted by the blood over the arteries as a result of the heart left ventricle contraction [traction . Blood pA noninvasive blood pressure (NIBP) sensor working on oscillatory principle is connected at the wrist of the subject. Wrist sensor measures systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse rate (PR) of the subject under test. The proper cuff and bladder size used in the assessment of blood pressure is important for accurate measurement. The use of a cuff that is too short and narrow for a given arm results in erroneously high blood pressure measurement. Use of a cuff that is too large results in erroneously low blood pressure measures. Wrist blood pressure sensor used in this work has a cuff with a bladder that is 120\u2009mm wide and 250\u2009mm long.(b) Temperature Sensor. The LM35 series are precision integrated-circuit temperature sensors, whose output voltage is linearly proportional to the Celsius (Centigrade) temperature [perature . The LM3(c) Accelerometer Sensor. A wearable sensor system called Smart Wristlet, providing 24-hour fall detection service, is discussed in [x-, y-, and z-axes are experiencing free fall, 0\u2009g pin (6th pin) will generate a high voltage which can be used to detect person fall. This signal is given to the interrupt pin of microcontroller in order to give highest priority to this event.ussed in . The aboussed in . MMA 736Embedded technology is implemented to perform a specified task. The programming of PIC 16f877A microcontroller is done using embedded C . This isBluetooth wireless communication has the advantage of higher data rate and easy interfacing with personal digital assistant such as a smart phone or a tablet PC. JYMCU HC-05 Bluetooth Module is used in this work which connects to the embedded platform for wireless transmission. Bluetooth module is connected at the software serial port of the microcontroller.Android Studio IDE is used to develop the application for tablets/smart phones with Android Operating System . AndroidA low cost high performance tablet PC (Digiflip XT 811) with Kitkat 4.4 operating system is used in this work for real time implementation. Tablet PC has the advantage of large screen size and better functionality compared to a mobile phone. The android application receives the data transmitted from the body sensor unit via bluetooth communication facility. An android application developed for tablet PC is used for the purpose of real time acquisition of data, comparison with threshold value, storage in SQL database, and alert mechanism generation using SMS facility.The android application initiates GPS services provided by the mobile phone network. While executing the subroutine for fall alert the developed android application collects location information via services given by the network provider or GPS provider. Information such as latitude, longitude, and exact address are collected by proper subroutines. This information is sent along with the text of fall alert message.The examinations have been carried out in Rural Primary Health Center in Andoorkonam, Trivandrum district of Kerala, India. The measurements were authorized by the Office of the District Medical Officer. Patients having Blood pressure variations or under medication for hypertension were directed by the medical officer for measurement. Overall 291 patients including healthy staffs in the PHC have been included.The aim of the validation of the device is to understand the reliability of the data obtained using the wrist sensor. The study also aims to get the feedback of the patients under test about the wrist sensor for blood pressure measurement. The study was conducted at a rural Primary Health Center in Trivandrum and the procedures in this study were approved by the District Medical Officer (DMO) and the medical officer, Andoorkkonam. The study was conducted in accordance with guidelines provided by the medical officer and under the supervision of two trained staff nurses. All subjects were informed and got consent for this study.291 subjects suspected to have hypertension/under medication for hypertension were suggested for BP measurement by the medical officer. 113 male subjects and 178 female subjects were first measured by the sphygmomanometric method and then by the digital wrist sensor based on oscillometric method. Hardware setup  is shown in Age frequency plot of males and females in different age groups under study are shown in The same subject was asked to take measurements using the wrist sensor also. The sensor was suitably positioned at the heart level in order to eliminate errors caused by position artifacts. The pair of data were used for validation of the wrist sensor. The statistical analysis was done for systolic blood pressure and diastolic blood pressure using Bland-Altman method.The system was tested in a practical environment and found to be most successful. The information was transmitted successfully to the tablet PC and stored in the SQL database by the developed android application. Patients with hypertension  were correctly identified and automatic alert messages were generated and sent to the medical officer by the developed android application. Low blood pressure conditions (SBP below 90\u2009mm of Hg and DBP mm of Hg below 60) were also identified. Normal and high body temperature were identified and transmitted to the tablet PC via bluetooth module.Screen shots of outputs obtained are shown in The validations were carried out largely according to the recommendations of the Association for the Advancement of Medical Instrumentation (AAMI). AAMI recommends the inclusion of a larger patient number and a greater number of subjects in an older age group in order to test the monitors' performances over a wider range of patient characteristics. The criteria require device to observe discrepancy within 5 \u00b1 (8 s.d.)\u2009mm of Hg for mean difference and standard deviation.Bland-Altman analysis was carried out to show the agreement between the two tests. The scatter plot of difference and average of SBP and DBP taken by wrist sensor method and sphygmomanometric method of female population and male population are shown in The accuracy of wrist sensor is calculated by identifying true positives, false positives, true negatives, and false negatives. The obtained accuracy is shown in The aim of this comparison was the analysis for clinical suitability of the wrist blood pressure sensor for family and community health care application. A comparison was done with sphygmomanometric method, which served as a reference device because of its wide distribution and acceptance. The parameters under investigation were the systolic and diastolic blood pressure.The trials showed satisfactory acceptance from the patient side because of the low discomfort caused by the wrist blood pressure sensor. Bland-Altman analysis shows very good agreement between the two methods of measurement.Wrist blood pressure sensor is more suitable in subjects with obesity having large arm sizes. Wrist blood pressure sensor does not require patients to remove clothing while taking measurements and it provides less discomfort compared to arm cuff monitors during inflation.The measurement taken at any time is successfully transmitted to the tablet PC and is stored in the SQL database of the android phone/tablet by the developed application without any manual intervention. This enables the medical officer to ascertain whether a drug is effective or not. The developed system is less expensive and causes less inconvenience for the patients.The validation conducted for the oscillometric wrist technique yields good results which shows good correlation between the BP readings taken with a sphygmomanometer and oscillometric wrist sensor. Patient's opinion about wrist sensor was promising. The device passed the AAMI criteria for SBP and DBP measurement except for male systole data. This study suggests that wrist devices can produce reliable and accurate results. The principal easiness of wrist blood pressure sensor based on oscillometric methods offers the opportunity for wide spread use. This may ultimately lead to an improvement in common efforts to prevent hypertension.A modern approach of health monitoring and management is put into practice by the experiment conducted using the developed system. The ever-increasing workload of physicians can be significantly reduced by the use of such systems."}
+{"text": "Early and effective chest compressions have a well known pivot role in cardiopulmunary resuscitation (CPR) and 2010 International Consensus on Cardiopulmonary Resuscitation have strongly reinforced its importance.The efficacy of chest compressions depends on hands position and on compression technique.Medical education can improve chest compression technique, while the choice of thoracic landmark is always blind even if 2010 consensus indicated that it is reasonable to place the hands in the lower half of the sternum.Critical care ultrasound (CCUS) has changed the approach of critical ill patient and can identify potential reversible causes of cardiac arrest during CPR.Our challenge is to use CCUS to locate the most appropriate site for chest compressions.We planned a pilot study (in progress) to evaluate the capability of CCUS to improve the quality of chest compressions while CPR is taking place.We describe data of a small case series from 6 non traumatic cardiac arrests who was treated both in-hospital and in pre-hospital settings.In 3 out of 6 patients compressions were correctly performed while in the other 3 cases partials left ventricle compression or the narrowing of the base of the heart and aorta was observed. Ultrasound guided changes in hands position improved passive left ventricle contractility in the 3 incorrect CPR.Our study doesn\u2019t permit to estimate if the changes made in hands position would have affected the outcome of CPR.Anyway we think that the possibility to focus the power of the hands over the real position of left ventricle certainly improves the quality of our chest compressions."}
+{"text": "A 66-years old man suffering from coronary artery disease appeared without symptoms for routine follow-up in our clinic.The echocardiogram revealed a tumorous mass of the right atrium and right ventricle. In the past, coronary revascularization with venous grafts of the right coronary artery and circumflex artery as well as internal mammaria graft to the left anterior descending artery was performed 20 years before. The general clinicians presented the case to the surgeons and it was decided to perform cardiac MRI as a preoperative diagnostic modality.Following cardiac magnetic resonance imaging (MRI) showed a mass in the pericardium in the right atrioventricular groove with thrombotic material. Due to the MRI the patient underwent coronary angiography to confirm an aneurysm.The learning points from this case are that cardiac MRI is a very useful tool for further evaluation of suspected cardiac masses and should be performed for further characterization. Spontaneous bypass aneurysm is a rare complication of coronary bypass revascularization (Hiraoka et al. The learning points from this case are that cardiac MRI is a very useful tool for further evaluation of suspected cardiac masses and should be performed for further characterization and planning of therapeutical options, particularly after previous cardiac interventions (Hiraoka et al. Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal."}
+{"text": "Manual analysis of abundant behavioral data produced by automated systems for long-time monitoring of a group of animals is extremely inefficient and error prone. Some systems (like IntelliCage\u2122) are shipped with software enough for basic analysis of the data, however lacking flexibility for more advanced analyses.\"let the computer do the work\"), therefore reducing number of possible human errors. The other advantage of such approach is that modern computers are both faster and more precise than humans when dealing with numbers.To facilitate research reproducibility, same analysis of same data should always yield same results. One (possibly the best) way to achieve such robustness is to have the process automated  and a data abstraction layer - therefore shifting ones focus from the form the data is provided to the data itself. A simple analysis can be performed in just a few lines of readable source code (see Figure"}
+{"text": "The mechanisms that allow biological networks to recognize temporal patterns of spikes that encode sensory inputs are unclear. Here we extend our previous work , using aGReaNs implements a genetic algorithm to obtain the topology of the networks (and the weights of the synaptic connections), starting from a population of networks of neurons connected randomly. The encoding of the neural networks in the genome is inspired by the encoding of genetic networks in biological genomes; neurons in GReaNs are modeled as either leaky integrate and fire neurons with a fixed threshold (LIF) or adaptive-exponential integrate and fire neurons . The numIn the computational task we consider, the network has several input neurons and one output neuron. A spike or burst received by an input neuron corresponds to a certain symbol . The output neuron should be active only after the network receives a certain sequence of symbols .Our preliminary results with LIF networks with a fixed threshold networks suggest that the presence of recurrent connections in the network allows the interneurons to reach plateau subthreshold states that provide a memory of what symbols have been received thus far. Here we will investigate the robustness of this solution to noise in the network, and then discuss the possibility to extend the paradigm to evolve spiking networks to accept regular languages."}
+{"text": "Hearing loss\u2014ranging from mild to severe\u2014afflicts large numbers of individuals of all ages. It is estimated that 40\u201350% of adults over the age of 65 years have some degree of significant hearing loss, with this figure rising to 83% of those over the age of 70  model in which they stress the importance of working memory for online spoken language processing, especially under poor listening conditions  to assess white matter integrity (Rachakonda et al., Together, these collected articles reflect a valuable sample of current approaches to our understanding of the effects of hearing loss on neural and perceptual processing. A theme that emerges from both the human and animal studies in this collection is that of an adaptive plasticity in the sensory, perceptual and cognitive systems that regulates performance in the face of often seriously degraded input. Challenges for future research include better understanding the link between neural consequences of hearing loss and other modifications of acoustic input (Van Engen and Peelle, The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "We review some recent cognitive models based on generative networks, and we point out promising research directions to investigate neuropsychological disorders within this approach. Though further efforts are required in order to fill the gap between structured Bayesian models and more realistic, biophysical models of neuronal dynamics, we argue that generative neural networks have the potential to bridge these levels of analysis, thereby improving our understanding of the neural bases of cognition and of pathologies caused by brain damage.Connectionist models can be characterized within the more general framework of probabilistic graphical models, which allow to efficiently describe complex statistical distributions involving a large number of interacting variables. This integration allows building more realistic computational models of cognitive functions, which more faithfully reflect the underlying neural mechanisms at the same time providing a useful bridge to higher-level descriptions in terms of Bayesian computations. Here we discuss a powerful class of graphical models that can be implemented as stochastic, generative neural networks. These models overcome many limitations associated with classic connectionist models, for example by exploiting unsupervised learning in hierarchical architectures  Despite the enormous progress in the prevention and treatment of neuropsychological disorders, traumatic brain injury and stroke are still among the major causes of adult disability and death  models  investigated through this approach, many PDP models suffer from serious limitations. In particular, connectionist models are often trained in a supervised fashion using error backpropagation, but the assumption that learning is largely discriminative and that an external teaching signal is available at each learning event is implausible from a cognitive perspective  through feedback connections and Hebbian-like learning mechanisms ? How do learning regularizers  compare with respect to organizational principles of biological neuronal networks?Can we improve lesioning studies in PDP models by taking into account structural and functional properties of the network? Could deep learning systems exhibit the same universal resilience patterns observed in other types of complex networks (Gao et al., AT and MZ equally contributed to the conception and writing of the manuscript. AT and MZ are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Brain-computer interfaces (BCIs) can provide a means of communication for people with severe motor impairments . For peoThis abstract describes multimodal  P300 BCI communication attempts performed with a 42-year-old male who had an intracranial hemorrhage of the cerebellum and brainstem one year prior to the measurements. The participant is paralyzed except for residual eye blinking and movement as well as some movement of the left hand. This residual muscular control is used for communication .Many pitfalls were encountered when attempting to establish communication. The main aspect is that when we performed the same task at different time points the results varied considerably (see Figure Albeit the fact that the attempts with the brain-computer interface was not successful in establishing free communication, the classified responses were clearly above chance. This illustrates that the user understood the instructions and has the physiological capacities to generate the responses required to operate the system. The fluctuations of vigilance experienced by patients with disorders of consciousness must be taken into account when developing new generations of BCI systems."}
+{"text": "There is an error in the fourth sentence of the first paragraph of the Conclusions section. The correct sentence is: This pattern may be observed in other large lakes with spatial and temporal variation in vertical mixing patterns. There are few large lakes where time series of in situ observations encompass a wide enough range of locations to estimate spatial variation in warming rates."}
+{"text": "The K13 gene mutations have been found to be associated with artemisin resistance in Cambodia, although the relevance of these mutations on artemisinin resistance in other endemic areas have to be better documented. We present here new data on K13 mutations and on the artemisinin resistance outside Cambodia. We propose to open the discussion about how these new findings have to be interpreted regarding the emergence and spread of artemisinin resistance and their usefulness to identify and prevent the spread of resistant strains in order to reach the malaria control and elimination global program goal."}
+{"text": "Recombinant human growth hormone (GH) has been used as an effective treatment for short stature since the late 1980\u2019s. Although clinical trials were crucial in developing GH treatment strategies, database analyses have the potential to provide additional information with regard to treatment efficacy and safety. The OZGROW database was established in 1989 as an initiative of the Australasian Paediatric Endocrine Group (APEG) to allow monitoring of children receiving GH under the national Pharmaceutical Benefits Scheme (PBS). There are currently (June 2014) 1948 children receiving subsidised GH treatment in Australia and the OZGROW database contains records from 6959 individuals. This unique resource has allowed a number of clinically relevant questions to be addressed.Defining short stature and therefore eligibility for GH treatment relies on the use of appropriate growth standards. There has been debate as to whether the World Health Organisation (WHO) or the Center for Disease Control (CDC) growth charts best describe the heights of contemporary Australian children. There appears to have been a positive secular trend for height in Australian children such that both charts under-estimate the number of children eligible for growth hormone treatment.Ascertainment bias has been proposed as an explanation for the fact that more boys than girls receive GH treatment. Analysis of the OZGROW database demonstrated that ascertainment bias did not appear to be a major factor explaining the gender discrepancy. It is possible that biological factors influencing the tempo of growth and development may contribute to the greater number of boys receiving growth hormone.Another issue that has complicated comparisons of international studies of growth hormone response has been the different dosing schedules used. A simple method for converting weight and surface area based doses was therefore developed. Further analysis suggested that the surface area based protocol used in Australia may disadvantage older children, given that the dose per kilogram reduces over time even if the dose per meter squared remains constant.The importance of commencing GH treatment early and maximising height gain during the first year of treatment was also highlighted by analysing GH responsiveness in a number of conditions including Turner syndrome, Prader-Willi syndrome and idiopathic short stature. Ensuring that referring physicians are able to diagnose these conditions in a timely fashion therefore remains a priority.Although the OZGROW database has allowed clinically relevant questions to be studied there remain a number of challenges, particularly with regard to long term follow up."}
+{"text": "Community Care Centres (CCCs) represent an innovative response to the containment of infection and the care of those infected in the context of an an Ebola Virus Disease (EVD) outbreak of unprecedented scale. This paper describes the implementation of this response in the Port Loko district of Sierra Leone in the last quarter of 2014. CCCs were effective in encouraging EVD patients to come forward, thus removing risk of transmission to their families and communities however there is significant scope for improvement in care for patients in the centres if the model is applied in future outbreaks of infectious disease. Changes in lay out of the centres, in staff training and support, in logistics and patient education are recommended. Sierra Leone has borne a significant burden of the ongoing EVD outbreak in West Africa. As of 25th February, 2015 the country had reported a cumulative total of 11,301 cases and 3,461 deaths (CFR 31%) making it the worst affected country in the history of the disease [A CCC is a community-based Ebola isolation unit where suspected and probable cases of EVD are isolated and provided with basic health care as they await their confirmatory test results. They also serve as places where confirmed cases can commence early treatment as they await transfer to bigger ETCs. They are small, low technology, mainly staffed by nurses and community health workers and can accommodate 8 to 10 maximum 15) patients. They focus on supportive management of patients; invasive procedures (except for collection of blood samples for EVD confirmatory test) are discouraged to reduce the risk of health facility acquired infection. The objectives of CCCs are to among others complement conventional ETCs by early isolation of EVD cases as close as possible to their communities and to improve access to Ebola care among the general populations especially for those in rural areas. The basic package of care offered at CCCs include presumptive treatment for malaria, supportive therapy such as management of fevers, body pains etc., provision of Oral Rehydration Solution (ORS), food, water and psychosocial care among others [ patientsCCCs were of two forms; frequently they were improvised around existing permanent structures, for instance the CCC in Lunsar was established within a hospital. In other circumstances CCCs consisted entirely of temporary shelters (tents) constructed on a new site. The centres were clearly identifiable at a distance as CCCs, were peripheral to or outside of a village, they required access to a water source for cleaning and washing, and were well demarcated from the surrounding community by a perimeter fence usually made of plastic sheeting. The CCCs had separate access points for staff arriving for work and for patients presenting for assessment. The centres had triage areas constructed with at least one metre separation between patient and staff areas. The triage area opened into a patient area (red zone). Movement to and from the triage zone to the red zone was variably controlled and frequently allowed movement in both directions. The red zone consisted of two or more separate spaces, either rooms within existing permanent structures or tents which were intended as cohort areas for two different categories of patients, those most infectious and those likely to be less infectious. There was generally no effective barrier to movement between these cohort areas within the red zone. The red-zone included patient latrines and shower facilities. In some cases communal traditional thatched shelters were provided in each cohort area for patient comfort. The red-zone included soak pits for effluent from showers. There were three exits from the red-zone, one to a mortuary area, one for those discharged from the CCC to the community and one through a PPE doffing area for staff leaving the red zone. The staff entrance to the CCC opened into the \u201cgreen zone\u201d where there were staff facilities including latrines and changing area. These facilities were in existing buildings or temporary tents. The green zone also included storage areas and staff rest areas. There is an entrance, typically gated, from the green zone into the red zone. Typically close to the exit from the red zone there was a pit for disposal of used PPE and other waste.Patients presented to a triage area either on foot or by ambulance. Staffs were expected to assess patients presenting by application of a triage algorithm. Those assessed as requiring admission then entered the patient area (red zone). Patients were confined to the red zone until such time that a blood test for detection of Ebola virus was available. The interval from admission to receipt of a laboratory report varied from approximately three to seven days. Patients who were well enough could move freely within their cohort area, sometimes between different cohort areas within the red zone and sometimes between the red zone and the triage area. Typically staff entered the red zone 3 times per day  for periods of 30 to 60 minutes on each occasion. During the visits the condition of patients was observed, ORS, water and food was provided and cleaning performed. When patients\u2019 test reports were received those who tested positive were transferred to EVD treatment centres as soon as possible and those with reports of EVD not detected were given a certificate and allowed to leave or provided with transport home.The CCC model was implemented rapidly in response to unprecedented pressures with a view to controlling ongoing community spread of EVD. Despite concerns raised by several partners about conducting EVD case management in such low technology setting, recent scientific evidence and field experience showed that the strategy has considerable potential for EVD outbreak prevention and control. Kucharski et al. in their recently published article demonstrated that CCCs could reduce EVD transmission in the community if well managed and all things are equal . Logan eThe concept was however not without its challenges. The small size of the units meant that they could only admit limited number of patients whilst the use of cadres of health workers with lower levels of qualification such as community health workers meant that more intensive training, support supervision and monitoring of the infection prevention and control practices was required. Although training was provided on site before opening of CCCs, ongoing training and close supervision of their operation was limited by the relatively remote locations and by the limited number of available IPC specialists. There were also significant supply chain issues resulting in intermittent shortages of drinking water, oral rehydration solution and items of personal protective equipment. Observation of practice within the CCCs suggests that messages to health care workers regarding self-protection at work were well received but balancing this requirement with the need to provide an appropriate level of patient care was less satisfactory. Our observations indicated that even in full PPE many staff would still avoid even minimal physical contact with patients who were too weak to stand or walk and too weak to drink ORS. The force of the message regarding self-protection may also have contributed to the long periods during which no health care workers were present in the red zone leaving debilitated patients to care for themselves or dependent on informal care from other patients. In practice our observations showed that half or more than half of patients admitted to CCCs may not have had EVD at the time of admission. Thus an unintended consequence of the CCC model was that many patients who did not have EVD were potentially exposed to the risk of acquiring EVD in the CCCs for extended periods of up to seven days or more, however this was also the same in the conventional holding centres. The provision of staff supervision in patient areas (which in many cases included minors) and of delivery of an appropriate level of care for critically ill patients with the CCC model was problematic because of the limited time during which staff were present in the red zone and the over whelming emphasis on self-protection in training. Our observations are based on implementation of the CCCs in rural and semi-urban settings; its applicability to urban settings where the community structures are different and transmission (and patient load) are likely to be higher may be tricky due to two main reasons. Firstly since the strategy is based on the principles of community ownership and participation and given that such structures are not well defined in urban centres, community participation in the process may be limited. Secondly, the limited number of beds in the CCC may not be able to cope with the patient load in a high transmission outbreak in an urban area.In conclusion, there is some evidence that the use of CCCs to isolate EVD patients in defined areas may have contributed to control of transmission in Port Loko, however there were unintended consequences associated with its roll out. Furthermore, a recent rapid assessment of the CCC concept which was conducted in six districts of Sierra Leone also highlighted key benefits of the concept . The use"}
+{"text": "Health professionals need to be integrated more effectively in clinical research initiatives to ensure that research addresses key clinical needs and provides practical, implementable solutions at the coal face of care. The recent McKeon review of Health and Medical Research in Australia suggested that the best way to achieve practical and implementable solutions in healthcare is to involve the health-delivery workforce in research to ensure that research addresses key clinical needs . Through"}
+{"text": "Dear Sir:We thank Rebaudet and others for independently confirming the value of cholera DNA preservation on filter paper and its suitability for molecular analysis. These two studies highlight the benefits of being able to store samples at room temperature for extended periods without risk of specimen compromise, as well as the ability to transfer and ship samples without a cold-chain requirement or risk of biohazard. This reduces the need for advanced laboratory capacity in cholera-prone areas while eliminating transportation issues. Moreover, the methodology can be combined with the use of the cholera rapid dipstick test  to provide immediate results confirmed by subsequent detailed (but delayed) molecular confirmation. We are also exploring the use of the filter paper with fecal sample directly, and agree this further simplifies the process under field conditions."}
+{"text": "We observed that only 20% of the recorded neurons accounted for 80% of the total information flow in these networks (see Figure rich nodes. The rich nodes were characterized by a higher firing rate, and graph theoretic analysis revealed their participation in a number of highly non-random network features. The networks were highly clustered with small average path lengths and thus exhibited small world attributes and the sub-network formed by the rich nodes was more efficient than the rest of the network. The networks also exhibited a central core of rich nodes which persisted even when the rest of the nodes in the network were peeled away. The rich nodes were also connected to each other more strongly than expected by chance giving rise to the rich club effect, observed for the first time in effective connectivity networks of individual neurons (see Figure Elegans [Structural and functional connectivity of macroscopic brain regions has been very widely researched  in the l Elegans .Our find"}
+{"text": "Oxytocin is a key molecule in social behavior. A recent study reported lateralized oxytocin signaling specifically in left auditory cortex during pup-retrieval behavior of female mice.Brain asymmetry shows great advantage in evolutionary adaption to the environment  significantly facilitated the process 1 day). In single housed virgin female mice, oxytocin signaling was sufficient to induce the maternal behavior. Given the important roles of pup calls in triggering the maternal behavior, Marlin et al. examined the expression of oxytocin receptor (OXTR) in the auditory cortex. They then identified large population of OXTR expressing interneurons, suggesting for a potential role of oxytocin in disinhibiting the auditory cortex  is dominated in the right brain (Ross et al., Knowing that oxytocin signaling lateralization is important for maternal behavior raises a new set of questions. What determines the asymmetrical distribution of oxytocin receptor expression between left and right cortical areas? Which cortical area is crucial for each types of maternal behavior and how does oxytocin facilitate the learning process? What other signaling molecules or neural circuits might the brain use for maternal behavior in parallel? How are these maternal cues encoded in infant's brain? The answers to these questions will lead to the further understanding of the most generous love\u2014mother love.TY and GH designed the study and wrote the paper together.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "SUI is a common and distressing condition affecting 3 million women in the UK. As part of the multicentre NIHR HTA funded SIMS study  we are evaluating the acceptability and correlation of two patient tests of SUI -the objective 24hr pad test (PT) and the subjective home continence stress test (HCST).Participants (n=197) were given sufficient standardised, pre-weighted incontinence pads to wear for 24hrs (changing when necessary) and two large tissue sheets. Used pads were returned to the study team in sealed plastic bags on the day of surgery for weighing and disposal. The tissue sheets were used as part of the HCST conducted before and after the pad test. Participant feedback on both tests is being collected.Results will be presented reporting response rates to both tests and comparisons between responses to the PT and the HSCT.The acceptability to participants and the advantages and disadvantages of each test from a trial management perspective will be discussed. Data collection challenges will be considered including; issuing of pads to sites and participants, the receipt (including the handling and delivery) of used pads and the decision process around which data to use in analysis when responses are available to both tests. Cost implications of both tests will also be presented."}
+{"text": "Current available in vitro tests including the lymphocyte toxicity assay (LTA) and the lymphocyte transformation test (LTT) are cumbersome and expensive, and their predictive values are undefined. We have recently developed a novel in vitro diagnostic test for DHRs, the in vitro platelet toxicity assay (iPTA) to test patient susceptibility to DHS. The aim of this study was to evaluate the predictive value of the iPTA in diagnosis of DHRs to sulfonamide antibiotics.Drug hypersensitivity reactions (DHRs) are rare but potentially fatal types of adverse drug reactions (ADRs) that develop in susceptible patients following exposure to certain drugs including sulfonamides. The diagnosis of this type of ADRs is challenging and currently depends on clinical expertise. A safe and reliable We have recruited 66 individuals  to participate in the study. The DHR cases were referred and diagnosed based on rigorous internationally accepted criteria. Blood samples were obtained and both LTA and iPTA were performed independently. Results were then analyzed to determine the degree of agreement between the likelihood of the occurrence of the reaction as determined clinically and the performance of the two diagnostic approaches.in vitro toxicity (p<0.05).There was concentration-dependent toxicity in the cells of patients when incubated with the reactive hydroxylamine metabolite of sulfamethoxazole for both the LTA and iPTA (p<0.05) and toxicity was significantly greater for the cells of patients versus controls (p<0.05). The tests had a high degree of agreement (correlation coefficient: R2 = 0.97). The iPTA was significantly more sensitive than the conventional LTA test in detecting the susceptibility of patient cells to The novel iPTA has considerable potential as an investigative tool for DHS as it is cheaper to perform and requires no special reagents that make it an excellent candidate for wider use. The iPTA has also a greater sensitivity in detecting patients with predisposition to develop DHRs to sulfonamides and other drugs and thus can be used to screen for susceptible patients prior to drug prescribing and during drug development process."}
+{"text": "Biologic therapy has not made the breakthrough in the treatment of patients with systemic lupus erythematosus (SLE) that it has managed in patients with rheumatoid arthritis and psoriatic arthritis. However, there are distinct signs that this form of treatment is going to find a place in the pantheon of SLE therapy. Based on a better knowledge of the ethiopathogenesis of lupus drugs, which interfere with B cell activation notably, Benlysta and Atacicept have been reported in major clinical trials to be successful in terms of controlling disease activity and preventing flares respectively. In addition, although the formal clinical trials did not meet their primary endpoints  the use of B cell depletion in the form of rituximab is widely accepted and appears to be helpful and highly beneficial in aspects of lupus ranging from skin disease to severe proliferative glomerulonephritis.My colleagues and I have treated 120 lupus patients with rituximab and have reported that 90% of patients are in partial or complete remission at six months , though some questions remained unanswered. For example, why is it in some patients B cells return within two months and in other cases it may be many years? In addition, once the B cells have returned there is a highly variable length of time before the clinical features return. In spite of disappointing results with major clinical trials, at least two new clinical trials using rituximab, are about to start recruiting, the RING trial for patients with lupus nephritis who failed conventional therapy at six months and RITUXILUP which aims to treat lupus patients at the time of diagnosis with two infusions of rituximab followed by a low dose of mycophenolate the state of aim avoiding the use of oral steroids. In an open label study of 50 lupus nephritis patients given rituximab at the time of diagnosis followed by low dose mycophenolate, Condon et al (Ann Rheum Dis 2013. In press) have reported that just two out of 50 patients after two years have required oral steroids.None declared."}
+{"text": "The mammalian nervous system can adapt to the challenges of life through neural plasticity. The brain will undergo extensive reorganization following sensory deprivation or damage to afferent pathways Kaas, . This plAge at implantation plays a substantial role in performance with a CI. Research has shown the existence of an early critical period for brain development and demonstrated how deprivation-driven functional changes in the cortex are affected by age. Cats that were implanted after the fifth month of age had smaller activation areas of the auditory cortex, compared with cats implanted earlier, even when they had longer experience with implant (Kral et al., In humans, the latency and morphology of the P1 component of auditory-evoked potentials can serve as a biomarker for the development of the central auditory pathways (Sharma et al., Despite the dominant role of age at implantation, experience with a CI also induces functional changes in the auditory system\u2014at both peripheral and central level\u2014stressing the importance of a post-implantation rehabilitation period (Sandmann et al., Returning to the parallel between visual and auditory deprivation, studies on critical period and visual implantation are still not possible as retinal implants are currently only available to adults. However, several questions arise, for instance, can we observe a similar benefit when implanting during the sensitive period for retinal implants? As hearing aid use correlates with positive CI outcomes (Lazard et al., In sum, both the time spent in a deprived state and acquiring sensory experiences matter for the brain to cope with the challenges of change. Stimulating the impaired sense as much as possible and restoring it as soon as possible within the cut-off period shall maximize the benefits from implantation.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Recent review of Bidulescu and colleagues\u2019 article on the association between vitamin D and adiponectin and its relationship with body mass index in African-Americans, as compared to Whites, reinforced the value of conducting stratified analyses using more resolute subpopulation/subgroup data . AlthougThe author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Authors Wagner et al. in your journal demonstrated effectiveness of mechanical chest compressions in the coronary catheterization laboratory to facilitate coronary intervention and survival in patients requiring prolonged resuscitation efforts. We dare to comment on this article and advocate to use mechanical chest compressions only as a bridge to extracorporeal membrane oxygenation to completely substitute failed circulation and enable percutaneous coronary intervention or other procedures to treat the cause of cardiac arrest. In line with an increasing interest in rescuing patients from refractory cardiac arrest by means of routine implementation of mechanical devices, we have read with a great interest an article by Wagner et al.  in your"}
+{"text": "Patient and public involvement (PPI) in research involves the active contribution of members of the public in research studies and within research organisations. PPI is important in ensuring the relevance and quality of general health care research. Funders often now request evidence of prior and future planned PPI in health research.The impact of PPI on various aspects of study development and delivery has been described, from study design through to the dissemination and implementation of study findings. Research, however suggests that PPI is inconsistent in terms of levels of engagement, quality and reporting. Within clinical trials variations in intentions and plans for PPI and the experience and impact of such involvement have been identified. Additionally resources to support PPI in clinical trials are often not used in practice. The University of Liverpool Clinical Trials Research Centre PPI working group decided to design a web based toolkit designed to support the PPI activities in clinical trials. The toolkit will signpost chief investigators and trial teams to a range of tools. The tools are designed to facilitate meaningful and effective PPI at all stages of a clinical trial.The development of the toolkit involves:\u2022 Describing the PPI pathway through a clinical trial\u2022 Identifying existing internal and external resources to support PPI\u2022 Identifying additional required resources\u2022 Evaluating the use the resources\u2022 Disseminating information about the use and impact of the resources and making improvements and modifications to them based on our experience.The results of developing this toolkit will be presented."}
+{"text": "In this study we propose to investigate the effect of the neovascularisation and blood flow to the sternum and surrounding tissues in diabetic & non-diabetic patients by using a laser Doppler imager. The reasons for the delayed healing are not entirely clear, but are thought to include both mechanical factors such as poor wiring of the breastbone during surgery, and biological factors related to the interruption to the blood supply to the sternum and surrounding tissues associated with the procedure.To assess the role of neovascularisation in diabetic & non-diabetic following coronary artery bypass graft (CABG) surgery using Laser Doppler Imager.Patients were divided into two groups as diabetic & non-diabetic had undergone CABG (30 patients). Sternal microcirculation measurements were taken by using a Moor LDI laser Doppler imaging system, at ten time points (pre-induction to 96 hours after bypass). The regional blood flow was estimated by measuring the Doppler shift of laser light caused by blood cells passing within the laser light field. Blood samples were taken for the analysis of number of factors.Results: The neovascularisation and wound healing were comparatively faster in non-diabetic surgical patients than diabetic group. New vessel formation from the right internal thoracic and intercostal arteries to the left side confirmed that the vascular supply of the sternum on the left side following CABG surgery was not entirely depended upon the left internal thoracic arteries. This is due to secondary changes in diabetic patients on vascular system.There was a formation of new vessels from right side of the sternum following the mobilization of left internal thoracic artery in CABG surgical patients. The healing process was faster in non-diabetic CABG surgical patients."}
+{"text": "Careful attention to clinical phenotypes can identify new diseases which are now amenable to molecular genetic elucidation. In the late 1980's I met a family labelled as having Huntington's disease but with absence of dementia. Scanning revealed unusual cavitation of the basal ganglia. The pedigree was extended my connection to a second family using birth records. We mapped the gene to chromosome 19 and went on to identify an unusual mutation in the E helix of light chain ferritin. Staining for iron revealed huge accumulation of iron/ferritin complexes in the brain leading to neurodegeneration. We named the condition neuroferritinopathy and tested desferrioxamine without success. We have shown that accumulation of iron commences in childhood and are now preparing to test deferiprone as an iron chelator which crosses the blood brain barrier."}
+{"text": "Action Plan for the Prevention, Care, and Treatment of Viral Hepatitis  in the United States. Although care and treatment can be life-saving, many of the 3 million persons estimated to be living with hepatitis C virus (HCV) infection are unaware of their infection and are not receiving preventive services and medical management. In addition, an emerging epidemic of HCV infection among a new demographic of persons who inject drugs is unfolding in several areas throughout the nation. Guided by the goals of the 2014 U.S. Department of Health and Human Services 9 in the The first report shows that trends in new cases of HCV infection are highly correlated with trends in substance abuse treatment admissions for opioid dependency and opioid injection in four states in the central Appalachian Region. The second report describes strategies for integrating HCV testing into primary care settings. These reports demonstrate how data can be used to identify patterns of risk for HCV transmission among persons who inject drugs and how programs can be successfully implemented to identify persons disproportionately affected by HCV infection and ensure they receive appropriate medical care and treatment."}
+{"text": "Research on human brain development has seen an upturn in the past few years due to increasing use of noninvasive neuroimaging tools for studying the anatomy and function of the developing brain. Here we gathered innovative studies of human brain function and development using magnetic resonance imaging (MRI), near infrared spectroscopy (NIRS) and magnetoencephalography (MEG) with experimental paradigms suitable for pediatric research. These modalities are without significant risk to the developing brain, generally require minimal patient preparation, and are well tolerated by children when performed by experienced teams. A review of recent studies of human brain development using these advanced neuroimaging tools is quite timely, since we are witnessing advances not only in the instrumentation optimized for the pediatric population, but also in research focused on the human fetuses in utero, neonates, and older children. MRI methods such volumetric T1 imaging and Diffusion Tensor Imaging (DTI) are being used more frequently in children to determine the gross anatomy and structural connectivity of the developing brain. Functional MRI and NIRS are being used to assess the hemodynamics of neurovascular responses and functional localization in development (Govindan et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Monitoring of services in the National Health Service in England is framed around clinical outcomes, safety and patient experience.A system of dashboards is being developed to provide monthly information about specialised services. The initial pilot has included a set of key information about services to patients with haemophilia and cystic fibrosis, for example the proportion of patients on home treatment (haemophilia) or the proportion admitted to a ward with specialist staff (cystic fibrosis). Data items were agreed by clinicians as relevant and important. The information is available from every provider.In the highly specialised services for very rare disease  the dashboard runs annually, not monthly, and is based on long experience [Quality of life measures are used in some services such as epidermolysis bullosa and neurofibromatosis type 2 [Safety incidents such as \u2018never\u2019 events are rare; they are reported and investigated immediately.Patient experience is monitored through surveys and close contact with patient organisations.A key mechanism for monitoring quality in the highly specialised services is an annual meeting. Attendance by all providers of the service is mandatory. Clinical outcome data is presented on all patients treated, and interesting or informative cases are discussed by the clinical teams. The meeting provides an excellent forum for peer review, exchange of clinical experience and learning."}
+{"text": "From 1978 National Health System (NHS) primary care pediatricians (PdF) in Italy take care of infants and adolescents from birth until 14 (in selected cases 16) years of age . HoweverAnother objective of primary care pediatricians will be to structure shared programs with general practitioners (MMG) to favour the shift of care from the primary care pediatrician to the family doctor. It should be necessary to always support a well planned care transition between Pdf and MMG . This will enable the MMG to receive the complete information on the health of the patient as well as on social and relational aspects."}
+{"text": "From February 2012 until January 2014 an acute medical ward at a 600 bed tertiary hospital in Western Australia conducted an internal audit of youth and adult inpatient separations for patients admitted with complications of severe eating disorders. This cohort exhibited levels of severe malnutrition on par with or more severe than those managed in a specialist service in another state of comparable size,  and may reflect the fact that Western Australia is one of only two states / territories in Australia that does not have a publicly funded specialist adult inpatient eating disorders program.Proposals for development of a state wide comprehensive specialist eating disorders service for youths and adults in Western Australia must take into account a potential legacy of decades of under investment in this area of health care, and potential barriers to optimising nutritional recovery within the confines of an activity based funding framework.Service Initiatives stream of the 2014 ANZAED Conference.This abstract was presented in the"}
+{"text": "This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. It discusses the role of the clinical nurse specialist in the head and neck cancer patient journey and provides recommendations on the clinical nurse specialist led assessments and interventions for this group of patients receiving cancer care.\u2022 All cancer patients should meet a clinical nurse specialist at the point of diagnosis. (R)\u2022 Clinical nurse specialists must act as gate keeper to the patients' cancer pathway to provide a seamless journey. (R)\u2022 Holistic needs assessment should be completed at different stages of the patient's pathway to reflect the changes of the patients' needs. (R)\u2022 Clinical nurse specialists to be part of local and national initiatives for health promotion and raising awareness in the public domain. (G)\u2022 Clinical nurse specialists should lead in redesigning of services and policies to ensure they are responsive to patient's needs for the future. (G)\u2022 Treatment summaries should become part of practice to provide good communication between primary and secondary care to enable continuity of care for the patient. (G) A diagnosis of cancer leaves patients frightened and vulnerable, often unable to understand the full implication of the treatment they are being offered.Carers of patients with head and neck cancer are under considerable stress during and after treatment as a result of disruption to daily life, the financial and emotional strain of long-term treatment and in many cases, role reversal within the family unit. Patients and carers look to healthcare professionals to provide information to help manage the psychological and social elements of head and neck cancer.\u2013It is the function of the clinical nurse specialist (CNS) to give the patient and carer the wherewithal to cope with the diagnosis, treatment and long-term consequences through the use of empathy and experience.The National Institute for Health and Care Excellence Improving Outcomes Guidance\u2022Specialist technical knowledge of the cancer process and treatment options\u2022Acting as the patient\u2019s key worker for a specific part of the process and linking in with the MDT\u2022Utilising advanced communication skills to support the patient and carer psychologically through the disease process\u2022Lead on redesigning services to make them responsive to the patient's needs\u2022Health education and promotion to reduce the risk of recurrence and promote a healthy lifestyle\u2022Assisting in local and national initiatives to promote awareness and prevention.The CNS workload can be complex and varied dependent on the patient's needs, it can be categorised into themes:The CNS acts as the key accessible professional to the patient within this multiprofessional setting, and allows the CNS to influence the patient's pathway. They are well placed to support the patient at each stage of their pathway and promote integration within the team. The CNS should be recognised as the patient's advocate within the MDT meetings where they deliver patient-centred care tailored to the individual patient's needs. In acting as the patients' advocate, the CNS also plays a key role in ensuring that the multidisciplinary care is responsive to the patients' needs and preferences.Clinical nurse specialists increasingly take the lead role in shaping patient care pathways and refining systems to make a difference to the patient experience and their safety. By acting as the key worker,Patients and carers have always been at the centre of cancer services, but have not always been encouraged or empowered to help influence and shape them.The Cancer Planvs risks of treatment.Patients and carers now have a realisation that they have considerable influence in gaining access to treatments and medicines, can participate in the designing of clinical trials and influence the amount of money spent by central government on research.A diagnosis of cancer has far reaching effects beyond the patient to their loved ones. This life-changing experience means that relationships and roles and responsibilities can often be changed. Treatments for head and neck cancer can have devastating effects on the lives of patients, including disfiguration, speech and swallowing impairment.\u2022Holistic needs assessment\u2022Treatment summary\u2022Cancer care review\u2022Education and support events.\u2018The Recovery Package\u2019It also compliments stratified care plans, which enable individualised follow-up care and self-support. It facilitates urgent access back to the specialist team if needed or on-going support from healthcare professionals.\u2022All cancer patients should meet a cinical nurse specialist at the point of diagnosis (R)\u2022Clinical nurse specialists must act as gate keeper to the patient's cancer pathway to provide a seamless journey (R)\u2022Holistic needs assessment (HNA) should be completed at different stages of the patient's pathway to reflect the changes of the patients' needs (R)\u2022Clinical nurse specialists to be part of local and national initiatives for health promotion and raising awareness in the public domain (G)\u2022Clinical nurse specialists should lead in redesigning of services and policies to ensure they are responsive to patient's needs for the future (G)\u2022Treatment summaries should become part of practice to provide good communication between primary and secondary care to enable continuity of care for the patient (G)An HNA ensures that the patients' and carers' physical, emotional and social needs are met in a timely and appropriate way, and that advice and support is available from the right source at the right time.Different assessment tools are used, i.e. distress thermometer, concerns checklist and more recently the patient concerns inventory. The tools can be used at different stages along the patient trajectory, but with an emphasis being on assessing and eliciting patients' and carers' concerns and expectations. This leads to a discussion and care planning of the patients' needs and helps to manage expectations.Pre-treatment clinics provide an opportunity for patients and carers to meet the CNS and other allied health professionals prior to surgical or oncological treatment. It allows HNA assessment to take place, but also facilitates discussion of acute treatment and rehabilitation with the key professionals involved prior to commencement of such.A care plan is based on the diagnosis and holistic assessment of the patient.A key component to effective patient care is good communication between the primary and secondary care sectors. Making sure that general practitioners are fully informed about their patients\u2019 cancer journeys can ease the transition between acute and long-term care. For this to be effective, treatment summaries are provided at the end of any acute treatment by the MDT for the general practitioner and patient. The treatment summary describes the treatment that that person has received, including any adverse reactions, the side effects and signs and symptoms of recurrence. This treatment summary provides confidence to the patient that their care is continuing albeit in the community setting. Patients report feelings of abandonment and vulnerability once initial treatment is complete but with a treatment summary and care plan these feelings can be minimised. Patients' on-going self-management can be well supported through peer support groups and health and wellbeing events. The CNS is obliged to inform patients of what is available in the local area that may be accessed by the patient and carer.\u2022meet every patient at the point of diagnosis to assist in a smooth transition along the cancer pathway\u2022ensure effective communication within the MDT, with patient and carer and within the community setting\u2022be at the centre of the patient's pathway and make effective use of resources\u2022act as the patient advocate, utilising support groups to act as patient voices in the changing healthcare environment to make them patient-centred\u2022perform holistic needs assessment for all patients at diagnosis and specific points along their journey to ensure patient-focused care is being provided\u2022offer treatment summaries to all people involved in the patient's recovery to ensure effective communication\u2022offer individualised care plans to help patients take control of the recovery phase.Clinical nurse specialists should:"}
+{"text": "The past decades have witnessed tremendous growth in the use of biostimulants in agriculture and it is estimated that biostimulants will grow to $2 billion in sales by 2018  for biocontrol applications. The application of salicylic acid (SA) has been shown to have negative effects on plant productivity either as a result of direct toxicity or changes in allocation of assimilates to plant defense responses. This response was also observed by Ghazijahani et al. (Vergnes et al.  used foli et al.  who noteMany biostimulants contain simple and complex carbohydrates that when applied to plant may alter metabolism by directly acting as a source of energy for endophytic and non-endophytic microbial populations or acting as signaling molecules. The complexity of the roles of carbohydrates in plant immunity was reviewed by Trouvelot et al. , who sugThe great diversity of plant response to biostimulants highlights the challenges faced by researchers. Many plant responses to biostimulants cannot be explained by our current understanding of plant processes and while this represents a challenge, it also presents a great opportunity.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Rehabilitation care is fundamental to health and human dignity and a human right enshrined in the United Nations Convention on the Rights of Persons with Disabilities. The provision of rehabilitation is important for reducing the need for formal support and enabling persons with disabilities to lead an independent life. Increasingly scholars and advocacy groups voice concerns over the significant barriers facing people with disabilities in accessing appropriate and quality rehabilitation. A growing body of research highlights a \u201crespond-need\u201d gap in the provision of rehabilitation and assistive technologies and underscore the lack of indicators for assessing performance of rehabilitation systems and monitoring States compliance with human rights standards in rehabilitation service planning and programming. While research on human rights and health monitoring has increased exponentially over the last decade far too little attention has been paid to rehabilitation services. The proposed research aims to reduce this knowledge gap by developing a human rights based monitoring framework with indicators to support human rights accountability and performance assessment in rehabilitation.Concept mapping, a stakeholder-driven approach will be used as the core method to identify rights based indicators and develop the rehabilitation services monitoring framework. Concept mapping requires participants from various stakeholders groups to generate a list of the potential indicators through on line brainstorming, sort the indicators for conceptual similarity into clusters and rate them against predefined criteria. Multidimensional scaling and hierarchical cluster data analysis will be performed to develop the monitoring framework while bridging analysis will provide useful insights about patterns of agreement or disagreement among participants views on indicators.This study has the potential to influence future practices on data collection and measurement of compliance with human rights standards in rehabilitation service delivery and organization. The development of a valid and universally applicable set of indicators will have a profound impact on the design and implementation of evidence informed disability policies and programs as it can support countries in strengthening performance measurement through documentation of comparative information on rehabilitation care systems. Most importantly, the resulting indicators can be used by disabled people\u2019s organizations as well as national and international institutions to define a minimal standard for monitoring and reporting progress on the implementation of the Convention on the Rights of Persons with Disabilities in the area of rehabilitation. Disability is a major issue facing global health policy. It is estimated that one billion people around the world experience some significant degree of disability with 80\u00a0% of those living in low and middle income countries . FiguresRehabilitation \u2013 defined by the World Health Organization (WHO) as \u201ca set of measures that assist individuals who experience or are likely to experience disability to achieve and maintain optimal functioning in interaction with their environment\u201d  p.96] \u2013 \u20136]. AltDemographic and epidemiological trends suggest that the number of people who could benefit from interventions aiming to reduce dependency, optimize functions and promote social participation is set to increase due to, among other factors, population growth and ageing , thus puex-novo to drive the collection of data in consistency with the legal requirements set by the CRPD in areas where data are not available. Data collection on disability (and rehabilitation) is a key obligation of States stipulated in Article 31(1) of the CRPD, under which \u201cStates Parties undertake to collect appropriate information, including statistical and research data, to enable them to formulate and implement policies to give effect to the present Convention.\u201d [Health systems performance measurement and human rights monitoring require meaningful, objective and reliable indicators to quantify progress achieved. While it is true that the use of indicators depends critically on the availability and quality of data, in disability rights monitoring some indicators must be constructed ention.\u201d . At presention.\u201d \u201317. The ention.\u201d  which maDriven by this absence of a unified framework for estimating disability prevalence and measuring environmental barriers to social participation, WHO is undertaking research to harmonize and advance data collection practices. This research, which is mostly guided by the WHO Disability Action Plan 2014\u20132021 \u201cBetter health for all people with disabilities\u201d  aims at These aspects are sidelined in international initiatives to strengthen disability data and left out of States\u2019 monitoring priorities. The narrowed approach to disability data collection that dictates current technocratic agendas  is inappThus far, international efforts to strengthen data collection practices have limited their focus on survey based data and screening for disability through interview questions in population surveys ignoring other types of data from population based disease registries, hospital discharge records, and facility based reviews, all of which are essential for both evidence-based service planning and human rights reporting , 29. ThiGlobal health leaders, agencies and independent expert groups have increasingly been calling upon States to intensify their efforts to collect appropriate data suitable to monitor the human rights status and situation of vulnerable groups and enhance their collaboration with specialized agencies to build the technical capacity required for health monitoring and human rights assessment. These calls have led WHO and the World Bank recently to propose a global framework for monitoring universal health coverage across the entire spectrum of essential health services . The pilCurrently we lack a validated international set of indicators, especially process indicators , that coWhich indicators are appropriate for monitoring the implementation of the rehabilitation aspects of the CRPD?Which indicators are relatively more important and feasible and how the views of researchers, rehabilitation professionals and people with disabilities differ on the subject?What does a human rights monitoring framework for rehabilitation consists of, and how can it be put in practice?Seeking to cover this knowledge gap, this paper proposes a study to develop a monitoring framework with indicators to support countries to assess progress in the implementation of the CRPD in the area of rehabilitation. Specifically the study aims to provide answers to the following research questions:The general approach to answering these questions and the methodological details of this study are explained in the Methods section. But before describing the research process, it is essential to define what a human rights based indicator is and understand some of the challenges associated with their development.In general terms indicators can be defined as numerical or textual values that provide information about a phenomenon. Indicators are essential elements of monitoring and evaluation systems that allow for assessment of progress towards the achievement of goals, enabling comparisons of different units or comparisons of the same unit at different time intervals. Unlike development and performance indicators, which follow programming principles, human rights indicators are explicitly anchored in human rights values and standards . \u201cSuch iMethodologically, the development of human rights indicators is a challenging undertaking. In academic research, scholars have proposed and used many ways to accomplish the difficult task of indicators development, ranging from traditional research methods to more sophisticated approaches . CurrentRegardless of the method being used to develop human rights indicators, one of the major challenges lies in the conceptualization of the treaty provisions (what to measure) and the operationalization of qualitative or textual information into measurable entities (how to measure). A thorough legal analysis is therefore essential to delineate the attributes of the right under examination and identify the key obligations of signatories to a specific treaty. These obligations must be then mapped onto indicators for which data are available and reliable. But as Fukuda Par notes, the criterion of measurability cannot dictate the selection of indicators since not all aspects relevant to human rights can be quantifiable or captured with measurement tools such as, people\u2019s participation in the conduct of health affairs , 48. ThuFor developing the rehabilitation monitoring framework and identifying appropriate human rights-based indicators we propose to carry out a Group Concept Mapping study (GCM) that is underpinned by the methodological principles of structured conceptualization . GCM is Conceptually, the study will be guided by key international legal instruments pertaining to disability and rehabilitation, specifically the CRPD and particularly Article 25 , Article 26 (Rehabilitation) and Article 31 (Data collection and Statistics). An analysis of the obligations of States under the CRPD with respect to rehabilitation and its resulting framework will serve as a conceptual platform for identifying potential indicators in key human rights commitment areas . This pln\u2009=\u2009150 participants through purposive and self-selection from the following stakeholder groups: (i) n\u2009=\u200950 rehabilitation professionals and service managers, (ii) n\u2009=\u200950 researchers with expertise in various disciplines such as global health law, health services research and rehabilitation medicine, and (iii) n\u2009=\u200950 people with disabilities and representatives of disabled people\u2019s organizations. This will result in n\u2009=\u200927 participants sorting and rating the indicators which is above the minimum number recommended for ensuring the validity and reliability of the study results (n\u2009=\u200915) [There is no limit on the number of people who can participate in GCM. Based on a pooled analysis of 69 concept mapping studies Kane et al. found a range of 20\u2013649 participants with an average of 75 participants completing the rating phase . AssuminFor recruiting experts in the study the investigators will contact international professional organizations and societies, disabled people\u2019s organizations and individual academics and peers asking them to participate in the study and nominate additional experts for participation. A pool of participants who fulfil the criteria for participation  will then be stratified by stakeholder group. A random sample will be drawn from the experts pool for each stakeholder group and sent an email invitation to participate in the survey. Invitees who decline the invitation are replaced by other randomly drawn experts from the same expert pool.In GCM data can be collected either in paper form during pre-scheduled workshops or remotely through dedicated web based platforms. In this study data collection will be facilitated by the Concept Systems Global MAX\u2122, a web based software specifically designed to facilitate concept mapping activities . Data peBased on the principles of GCM  a sequen\u201cAn appropriate indicator for monitoring the implementation of the CRPD in the area of rehabilitation is\u2026\u201d Using this question, participants will brainstorm a wide array of measures which will result in a long unfiltered list of potential indicators. After the conclusion of the brainstorming session, the research investigators will review and content analyze the brainstormed indicators to remove duplicate or other irrelevant statements and agree with stakeholder representatives on a final set of measures for further elaboration.At this stage, a focus prompt \u2013 an incomplete sentence designed to invite people to complete it \u2013 will be used to elicit participants\u2019 best ideas and expertise on the topic. The focus prompt is: In the first data collection activity of this phase all participants will be invited by email to organize the indicators into categories in a way that makes sense to them and thus identify the conceptual building blocks for the rehabilitation monitoring framework. Participants will also rate the indicators for importance and feasibility, thus allowing patterns of agreement\u00a0and/disagreement among different stakeholder groups to be identified.Data analysis will be performed using special functions of the Concept Systems Global MAX\u2122 software . MultidiThese analyses will finally lead to a general discussion of the reasonability of the resulting monitoring framework and its implications for human rights compliance and rehabilitation systems performance assessment. Specifically, in the final phase of the GCM, stakeholder groups' representatives and experts in public health monitoring will be invited to review the clusters of indicators and the underlying relationships between them and to collectively interpret the results in a way that can drive evidence based action.Ethics review and clearance has been obtained for this project by the Ethics Commission for Northwest and Central Switzerland.This study aims to reduce the information gap in the assessment of performance of rehabilitation services and programmes for people with disabilities. It also has the potential to influence future practices on data collection and measurement of compliance with human rights standards in the delivery and organization of rehabilitation care. The development of a valid and universally applicable set of indicators will have a profound impact on decision making and implementation of evidence informed policies for rehabilitation at national and global level. Furthermore, the resulting monitoring framework can support the documentation of comparative information on national rehabilitation care systems and could be used as a minimal standard for monitoring and reporting progress on the implementation of the CRPD in the area of rehabilitation.A unique feature and major strength of the GCM is that it employs a truly participatory process for developing the indicators. Unlike other research methods the approach to data collection and elaboration is highly structured and under the control of the participants. Specifically and significantly, GCM allows stakeholders to contribute their expert knowledge by identify relevant metrics, participate in the interpretation of their perceptions and elaborate on their potential use of the resulting evaluation framework. An additional strength lies in the use of advanced statistical techniques to provide useful insights about the relationships of the ideas of different stakeholder groups, which provides rigor and enhances the credibility of information obtained during qualitative research processes. This results in visual representations of the indicators in the form of maps that are relatively easy to understand and interpret in the subsequent phases of the research process.Alternative approaches that have been used for the development or selection of indicators in health research either lack scientific credibility  or adoptAs with conducting on line surveys, GCM presents a number of challenges for the investigators to address when collecting, organizing and interpreting the data. Remote data collection in concept mapping may allow researchers to access large and geographically distributed samples of participants, but they carry with them specific limitations when compared to the traditional paper based collection of data. These include the risk of a low response rate and a resource intensive process for collecting and analyzing the data . In ordeThe results of this study are relevant to key stakeholders at both the national and international level in a variety of ways. First, the resulting indicators set will equip national public health and statistical authorities and human rights institutions with a valuable tool to monitor States\u2019 compliance with international human rights law standards in the organization and delivery of rehabilitation services. In so doing, competent authorities may choose to either adjust their own data collection and monitoring systems to include human rights based indicators or use the new metrics separately on an ad hoc basis during periodic country performance reviews. Second, the results will be relevant to researchers, policy analysts, advocates and global health stakeholders, providing them with an evaluation framework and menu of newly created, evidence based measures that can be used to standardize the assessment of rehabilitation services and programs and facilitate comparative evaluation research.In addition to satisfying the need for human rights monitoring and performance assessment, the rehabilitation indicators will be extremely valuable for UN agencies, Member States and other international stakeholders. The metrics proposed by this study will augment existing quantitative and qualitative measures thus offering a more comprehensive evaluation toolbox that WHO and other organizations can use in their programmatic activities, as for example to assess progress in the implementation of the WHO Global Disability Action Plan. Finally, the indicators set will be based on the legal requirements of the CRPD that represents a nearly universal consensus as it has been ratified by nearly 160 countries in the world. This makes the set of indicators applicable in all contexts and thus might be an appropriate start for the development of specific human rights monitoring guidelines for Article 25 and 26 by the UN committee responsible for the oversight of the CRPD.Lastly, from a consumer\u2019s perspective, the long standing misapprehensions surrounding the goals of rehabilitation and the contested role of health professionals in disability management make the results of this research even more important. Since people with disabilities have been traditionally excluded from decision making in rehabilitation care planning and programming, rights based indicators will prompt rehabilitation professionals and service designers to reconsider oppressing attitudes and approaches in their everyday clinical practice and pay more attention to human rights issues in patients care . More imThe results of this study will provide the global health and disability community with a preliminary set of cross-cutting indicators for assessing performance of and monitoring compliance with human rights standards in rehabilitation service planning and delivery. It will help identify gaps in quantitative data and other qualitative information that are essential for the comparative evaluation of national rehabilitation care systems. This will stimulate action toward the expansion of information gathering on rehabilitation services and further research on the development, testing and validation of indicators for various tracer conditions. The study described in this paper is a major step toward advancing the current practice of rehabilitation systems performance comparison and promoting evidence-based human rights monitoring and reporting."}
+{"text": "Sir, The response by The very interesting question is the reason for the more severe disease expressivity and complete penetrance in the patients reported (TTN (We attempted to find evidence for a modifier effect for kinase variants by screening a HMERF population of 33 patients, but our findings did not support this hypothesis ("}
+{"text": "Maternal mental disorders are associated with adverse psychological outcomes in children in countries of low and middle income , 2. AlthWomen with mental disorders sometimes perform self-interruption of medications during pregnancy, and then the self-interruption of medications sometimes deteriorates their state of mental disorders. They seemed to misunderstand that the medication leads to the adverse outcomes of pregnancy. In addition, the pregnant women impoverished economically may be liable to be as follows: 1) they have often received low education leading to their misunderstanding about the influence of medications on their pregnancies because their parents had been also poor; 2) there may be large time and/or economic burdens in their visiting of psychiatric and obstetrics; and 3) the stress of pregnancy may be easy to hunt down their psychological status because there is no room in their life. These may become negative chains in their lives and these may lead to the poverty and adverse psychological outcomes of their children. The Japanese HAP system aids their delivery costs only. Therefore, in Japan the proper education and sufficient financial support are needed for pregnant women who are impoverished economically to prevent the deterioration of their mental status during pregnancy."}
+{"text": "Resonance in the membrane potential enables a neuron to discriminate its inputs on the basis of their frequency content, so that oscillatory inputs near the resonant frequency produce the largest responses . RecentlThese results contribute to the understanding of the complex interactions between active and passive properties in MNs and how these interactions can produce membrane potential resonance and affect action potential generation. The relation we found between subthreshold resonance and the minimum firing rate merits further studies to better understand how firing rate may be affected by membrane resonances."}
+{"text": "In many countries around the world sex work is criminalised and its regulatory control is therefore often in the hands of the police. In addition to the impact of this criminalised legal environment, much literature describes the negative impact that certain police practices can have on the ability of sex workers and the programs that work with sex workers to access essential HIV prevention, treatment, care and support services. This situation has resulted in persistent concentrated HIV epidemics among sex workers in many countries of the world. The need for multi-sector partnerships between police and HIV programs is increasingly recognised in various UN declarations and resolutions yet descriptions of the process or key ingredients required to actually establish and sustain these necessary partnerships between police and sex workers [or the programs that provide essential services to sex workers] are sparse. The paper seeks to establish key considerations and critical processes that are required to foster partnerships that if further investigated and scaled up, could result in an enhanced enabling environment for the provision of essential HIV services for sex workers around the globe. This paper is based on a realist review that investigated isolated examples of partnership formation between law enforcement and HIV programs working with sex workers. This methodology research is designed to work with complex social interventions and is based on the emerging 'realist' approach to evaluation. A realist review methodology was chosen given the paucity of relevant literature in this vein and the authors\u2019 familiarity with the grey literature and relationships with experts who work in this sphere. The review found that political and police leadership, civil society strengthening and police reform in relation to HIV, are critical factors and key ingredients in changing the enabling environment in which sex work takes place to ensure that HIV prevention, individual and public health as well as HIV prevention and the promotion of human rights are the number one priority. Further research into this relationship is needed to provide evidence for effective HIV programming with police. In many countries the buying and selling of sex is illegal and criminal law is enacted to control the industry. Regulatory control of the industry is therefore often in the hands of police. However, even where sex work is legal, street-based sex work is often conducted outside of the law. This situation makes it difficult to provide essential services to sex workers and ensures that in many countries concentrated epidemics of HIV among sex workers persist. Decriminalisation is widely regarded as the evidence-based model of sex industry regulation that best supports effective health promotion, public health outcomes, the human rights of sex workers and is the best practice model for the prevention of HIV and STIs. 2] 3]  [3] 2] [  [3] 2] Decriminalisation is also espoused by WHO, UNAIDS, UNFPA, UNDP, sex worker organisations and human rights groups.11] Desp Desp11] Given the prevalence of criminalisation, there is a growing political realisation of the need to promote partnerships between sex workers and police is also encouraged by various UN political declarations including UNESCAP Resolutions 66/10 and 67/9  yet therThe aim of this review is to identify and highlight examples of positive police partnerships that work with sex workers and sex worker organisations to prevent HIV transmission and to examine the aspects of these partnerships that contribute to success.To best source and analyse emerging examples of partnerships between sex workers and police a realistic review methodology was chosen. This qualitative approach was chosen for its aptness for in depth analysis of a small number of cases and its flexibility with regard to sampling and is a methodology designed to work with complex social interventions based on the emerging 'realist' approach to evaluation. It provides an explanatory analysis to explore what works, when and how. A realist review does not seek to find simple solutions to complex issues but can provide a more in depth understanding of how an intervention can be made more effective.  A small There is a significant amount of documentation that describes the barriers that various law enforcement cultures and practices can create for sex workers\u2019 health and wellbeing, in particular the barriers they create for HIV prevention programs. These barriers are often compounded by the inherent legal environment in which sex work takes place but are also often the result of law enforcement cultures and practices that operate outside of legislated paradigms.The use of the threat of arrest and bribery by the police towards sex workers has been documented widely.18]19][[19][18][[[19][18]had the right to beat them. Thei Thei41] The harassment and arrest of peer educators and outreach workers by police, documented in India, Nepal and the Philippines severely compromises their ability to serve their constituency and provide condoms and safe sex information. IncarcerPolice harassment, violence and extortion have very real and serious consequences for the health and well being of sex workers. Violence is associated with unprotected sex and heightened risk of STI and HIV transmission. In many Despite criminalised environments, there are emerging examples of both sex worker programs working with police to create greater understanding of the sex industry within police ranks, to ensure better access to services and greater wellbeing for sex workers. In addition, there are also examples of police led interventions as well as reform measures taken by police institutions that are beginning to result in both better outcomes for sex workers and police. A selection of these programs are described in order to draw out the critical factors and key ingredients in changing the enabling environment in which sex work takes place to ensure that HIV prevention, individual and public health as well as HIV prevention and the promotion of human rights are the number one priority.Resourcing Health and Education in the Sex Industry (RhED) is a service for the sex industry in Victoria, Australia. RhED uses a social model of health that incorporates harm minimisation, health promotion, social inclusion and community participation approaches to promote physical, emotional and social health and wellbeing for sex workers. RhED\u2019s UThailand\u2019s Sex Workers in Network Group (SWING) provides services for male sex workers in Bangkok and has an intern program for police recruits that aims to build relationships of mutual respect to enable sex workers to access STI and HIV prevention and treatment without fear of arrest. Police cadets\u2019 internship gives them first-hand knowledge of the working lives of sex workers. The police cadets study English and take part in other SWING program activities such as outreach. The program aims to sensitise future police officers to the needs of sex workers to foster supportive environments for sex workers and to create a cadre of police officers within the Bangkok police ranks that share an understanding and empathy for sex worker\u2019s rights.Save the Children\u2019s Poro Sapot program works with police liaison officers and conducts peer education amongst police in various sites in Papua New Guinea  of India decided to target local police stations to talk about HIV awareness with operational police. Informal meetings with sex workers and police were held which proved to be a beneficial way to communicate issues of concern for sex workers. The police constables were sensitized to the problems facing sex workers and devised steps to lessen the harassment. Peer educators were introduced to police so they recognized them as a part of the program. Police constables are now informing VJT as soon as any sex workers have been arrested. The GateKeeping Alive Societies Hope (KASH) has worked with sex workers for over 7 years in the Nyanza province of Kenya. In Kisumu, Nyanza\u2019s largest city, 60% of sex workers are HIV positive. Police violence has been widely observed and documented as a determinant of HIV risk. In 2007, KASH initiated joint workshops for police and sex workers to discuss, share and learn about HIV and AIDS and Kenyan laws on sex work. KASH selected 10 police officers and 10 sex workers as peer educators. This core group developed a data collection system to document abuses against sex workers, held regular workshops for their peers, and reconvened bimonthly to discuss their findings and strategize on how to address emerging patterns of abuse. The programme is now supported by the provincial police administration who have made it an integral part of all police training programmes in Kisumu.55] Simi Simi55] The development of police strategy, instruction and standard operating protocols has been shown to have some impact in addressing HIV risk among key affected populations, including sex workers. In 2005 the Nepal Police released their HIV/AIDS Strategy and Work Plan that outlined the commitment of the Nepal Police to HIV prevention both among uniformed officers and the general population of Nepal including sex workers and other key affected populations. The document outlines the importance of collaborative partnerships between the police, public health and NGOs working with vulnerable groups. It also mentions the need for HIV training and sensitisation of high ranking police officers so that policy can translate to operational guidelines and practice on the ground.Specifically in relation to vulnerable groups, the overall objective of the Nepal police is to ensure the creation of an enabling environment for supportive behaviour with vulnerable groups. In addition to regular sensitisation meetings, internships and field visits, the HIV/AIDS Strategy of the Nepal Police also includes a joint monitoring mechanism between the police, civil societies and vulnerable groups to monitor the behaviour of the Nepal Police. Further supporting reforms from the Nepal Police included the establishment of a Human Rights Unit in 2003 in order to promote and protect human rights in Nepal by implementing a range of human rights promotion measures into the operations of the Nepal Police. The Human Rights Unit is represented in all levels of the Nepal Police to train police on relevant human right issues, to monitor Nepal Police in the maintaining of human rights standards and to investigate cases brought to their attention by individuals or members of a community or network.To the knowledge of the authors there are no rigourous peer reviewed studies that have examined the efficiency of police/sex workers collaborations or police led interventions or reforms on HIV risk behaviour or access to service. As a result there are limitations regarding the quality and quantity of data included in this review. While these programs are not extensively documented, a realistic review makes it possible to draw out common themes and key ingredients that can help foster better partnerships between police, sex workers and the programs that provide services to sex workers. It also highlights where research to further investigate this field is warranted. In promoting an environment where collaborations between police and sex workers can support enhanced HIV service provision it is clear that the following areas need to be considered.While political leadership at a national and international level is critical, many of the examples described have resulted from local level collaborations between police and sex worker groups. Inherent is the need to identify champions from both the policing and the civil society, community-based and non-government organisations. The pursuit of collaborative leadership efforts can bring a sense of ownership, responsibility and support for partnerships. The Australian Government\u2019s former aid agency, AusAID, supported senior police officials from Vietnam and Cambodia to Australia to partake in a three-week training program designed to develop and promote police leadership in responding to HIV in Asia. Further efforts to develop police leadership include the formation of the International Police Advisory Group (IPAG) under the secretariat of Law Enforcement and HIV Network. An IPAG delegation recently presented at the 2013 UN Commission on Crime Prevention and Criminal Justice and launched an International Statement of Police in Support of Harm Reduction and other evidence-based HIV Prevention Strategies for Key Affected Populations. It is clear that as civil society organisations, NGOs and community based organisations and networks gain strength, they are more able to represent the needs of the people they work with and more able to engage in discussions and collaborative program design with police. The ongoing support for these organisations is critical as is their need to articulate and develop advocacy and program design strategies that describe and outline how they will engage and work towards partnerships with the police. This paper briefly described the positive impact of these efforts in India and Kenya.Across regions with concentrated epidemics of HIV among sex workers there exist numerous reviews of the legal and policy environment in which sex work takes place and the changes in legislation that are required. This paper highlights that without an equal examination of the culture and practice of law enforcement, addressing the legal and policy environment is self-defeating. PartnersThe example of the Nepal Police in designing and implementing their HIV/AIDS Strategy effectively outlines a best practice response of police when working with key affected populations including sex workers. While acknowledging the need for further legal reform, resources and high level political will, the Human Rights Cell of the Nepal Police has been an important platform and link between civil society groups and the Nepal Police. Police reform in the context of responding to HIV among sex workers is being seen through the efforts of the Ukrainian Police Training Institute  and the Police partnerships are not a substitute for law reform and should not preclude advocating for a more human rights based legal framework for the sex industry. However given that criminalization of sex work and sex work activities persists in a majority of countries in the world, creating police partnerships is a pragmatic option in support of the health and wellbeing of sex workers. The authors acknowledge that the examples of the programs described here warrant a more in depth analysis into the essential elements of HIV prevention programs that work with police in order to improve the health, wellbeing and quality of life of sex workers. Documenting these best practice examples and promoting further analysis begins to build an evidence base for the design of programs that can redress the barriers that law enforcement create and help contribute to greater access to services [especially HIV and STI prevention] and quality of life for sex workers and freedom from repeated incarceration and violence. Unfortunately these examples remain the exception rather than the rule.At the intersection of policing and sex work and in pursuit of a more enabling environment for the provision of HIV services for sex workers it is clear that interventions need to be multi-layered, multi-sector and designed so that they can be scientifically evaluated. While these intervention and study designs are more complex, the research community and the institutes that fund HIV prevention research need to move beyond single interventions and prioritise the design of multi-faceted structural interventions that require a greater level of complexity and indeed a greater level of community and government involvement. This is really the last frontier of HIV intervention science: the science of the enabling environment. The very process of this type of research will lead to program designs that if enacted will contribute to the scale up of access to HIV prevention, treatment, care and support for sex workers and other key affected populations around the globe. In addition, it will also lead to the development of more humane and professional police services."}
+{"text": "Electronic data collection for randomised trials is attractive as it can, in theory, provide great financial advantages by reducing fieldwork costs and data inputting time, as well as increasing the accuracy of responses over and above paper based methods. For trials involving young people, electronic methods provide other advantages such as the ability to adapt questions to meet the needs of young people of differing ages and abilities. Researchers have also suggested that young people prefer electronic methods over traditional ones and have found equal validity across both methods. This presentation will discuss issues relating to the collection of sensitive information from young people in Northern Ireland, using electronic and paper formats. We will draw on experience gained across several research studies that have collected data on sexual risks and behaviours, particularly in school-based research; including a recent trial on adolescent pregnancy. We will examine the feasibility, reliability and validity of data collected along with an evaluation of the cost implications and ease of using both methods (including the merging of the resulting datasets if both methods are offered). The views of the researchers and participants will also be reflected upon."}
+{"text": "Monogenic diabetes (diabetes caused by a change in a single gene) accounts for around 2% of all diabetes but is not well recognised and is initially misdiagnosed in 80-90% of cases. This frequently leads to inappropriate treatment and advice including unnecessary use of insulin injections. This presentation illustrates how nursing research has increased our understanding of the impact of a genetic diagnosis of diabetes and treatment change from insulin injections to sulphonylurea tablets for individuals and their families.Rapid advances in genetic technology have resulted in the identification of 30 genes causing monogenic diabetes. Identifying a means of effectively translating these genetic findings into diabetes clinical care was clearly needed. Training experienced Diabetes Specialist Nurses as Genetic Diabetes Nurses across the UK has increased awareness and recognition of monogenic diabetes, leading to improvements in clinical care. The role of the Genetic Diabetes Nurse, in the education of other health care professionals and aiding identification of patients with monogenic diabetes, and how this could be used as a model for other areas is discussed."}
+{"text": "Thus, early reactivation might be necessary for Beyond clarification of neuronal mechanisms, the findings of Waldhauser et al. afford a number of future directions to strengthen the argument that extrastriate reactivation is functionally relevant to episodic memory. Extrastriate cortex has distinct upper visual field and lower-visual field representations that map onto more ventral and dorsal portions, respectively  from those that are familiar . Recollection and familiarity have unique neural correlates . SK is supported by the National Science Foundation Graduate Research Fellowship Program (NSFGRFP grant number DGE1258923).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Frontiers in Plant Science by Goolsby and Mason  acquired this property in the course of their evolution millions of years ago  most others growing in the same soil environment, and (ii) most others growing on less metalliferous soils. These concentration-based definitions serve the very useful practical purpose of drawing attention to a relatively rare plant response to particular elements. Identification of hyperaccumulator behavior in the natural environment can then lead to studies on plant physiology and molecular biology, and to practical applications in phytoextractive technologies. Next-generation sequencing can lead to a better understanding of the evolutionary path toward hyperaccumulation and extend knowledge to species other than model plants (Verbruggen et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "During the recent years, the scientific knowledge of the pathomechanisms and new therapeutic options in pediatric lung diseases has dramatically increased which is reflected by the more and more increasing number of publications in this important field. Additionally, major scientific efforts have been bundled within national and international research networks like the German Center for Lung Research (DZL), the platforms of the European Respiratory Society (ERS), and the different Cooperation in Science and Technology (COST) actions , 2. It wPediatric lung disease already starts early in utero when the highly orchestrated process of lung development gets disturbed \u20137. The bTo this end, the conclusions of the symposium pointed out that despite the heterogeneities between different pediatric lung diseases and even between different clinical phenotypes within one disease, the commonalities of major pathomechanisms highly encourage a comprehensive concept to elucidate the frontiers in science to the different pediatric lung diseases within a bundled interdisciplinary approach. Learning from the others\u2019 cohorts and experimental results cannot only broaden the horizon but speed up the development and introduction of new and more specific therapies into the clinics to all children with pediatric lung diseases. We want to thank all speakers for their excellent presentations during the symposium and for their important contributions to this special edition."}
+{"text": "The current research topic and eBook \u201cMechanisms of neuroinflammation and inflammatory neurodegeneration in acute brain injury\u201d was initiated as a reaction to the rapidly expanding literature on inflammatory mechanisms in the pathophysiology of acute brain injuries. The scope of this compilation of reviews, opinion, and original research articles was to give a broad overview of the diverse cellular compartments and mechanisms involved in the inflammatory response to brain tissue injury.Although a specific aspect of the pathophysiology of acute brain injuries, the immune system interacts in highly complex as well as diverse mechanisms with the damaged brain.On one side acute brain lesions, such as brain ischemia, hemorrhage or traumatic injury, induce a local neuroinflammatory reaction, wherein microglial cells represent the local immune cells (Benakis et al., In addition to an overview and discussion of basic mechanisms and involved pathways in secondary neuroinflammation after acute brain injury, our research topic also contains several reviews and original articles on novel therapeutic approaches to modulate the immune response. Rissiek et al.  introducIn summary this research topic gathered contributions from the leading laboratories working in the field of secondary neuroinflammation after brain injury with nearly 100 authors from 4 continents. We are confident that this compilation covers most established and emerging research questions in this specific research field and presents an up-to-date overview on inflammatory mechanisms and drug targets in acute brain injuries.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The authors wish to amend the Competing Interests Statement for this article, which should have included additional information in relation to potential competing interests relevant to this work. The authors apologize for this omission and revise the Competing Interests Statement to read as below.The University of Pittsburgh Medical Center has received grants from the National Football League and the Pittsburgh Steelers. Dr. Joseph Maroon is an unpaid consultant for the Pittsburgh Steelers football club. He has been the team neurosurgeon for the Pittsburgh Steelers since 1981 and the medical director for World Wrestling Entertainment Corporation since 2008 for the management of spine and brain-related injury. He also has served on the National Football League's Head, Neck and Spine Committee since 2007 and is currently a consultant to the committee. Dr. Maroon is a founder and shareholder in ImPACT (Immediate Post Concussion Assessment and Cognitive Testing), and the WWE has partnered with ImPACT to provide concussion management. Dr. Maroon has served as an expert witness in medical legal cases involving concussions. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.In addition, the authors would like to correct statements in the published article and provide additional clarification regarding the searches underlying the systematic review:Figure 1 indicates that the authors conducted a meta-analysis on 40 studies, which is incorrect. The text in the last box of the flow chart should read \"40 studies included in quantitative analysis.\" For the qualitative analysis of 58 studies, the authors gathered information on observed pathology, associated symptoms and suspected risk factors of chronic traumatic encephalopathy (CTE). The 18 qualitative studies that were excluded from the quantitative analysis did not present any pathologically confirmed case reports of CTE.The following statement in the third paragraph of the Discussion section is incorrect: \"This is also true for athletes of contact sports with risk for head impact but with no confirmed CTE cases to date, such as rugby or soccer players.\" There are both rugby and soccer players included in the authors' dataset of pathologically confirmed cases of CTE (Table S1).The article reports a review of published data from 1954 to August 1, 2013. Because the review data collected did not have consistent demographic identifiers, each subject reported required an exhaustive process to cross-match the entire database to determine duplicate reporting and identify unique individuals. After the data collection, the analysis of the data and their preparation for publication took 12 months. Since the closing of the data collection in August 2013, there have been a number of additional reports documenting athletes and others with pathologically confirmed CTE. This includes an article by McKee and Robinson (2014) that reported on four US veterans from the recent wars who had a history of blast exposure and were found to have CTE at autopsy [A related publication by McKee et al. 2014) published after the closure of our data collection 014 publi and were"}
+{"text": "Adequate assessment of (un)consciousness is not only of theoretical interest but also has a practical and ethical importance, especially when it comes to disorders of consciousness (DOC). Accurately determining the presence or absence of consciousness in patients with DOC allows informed decisions to be made about long-term care support, referral for rehabilitation, pain management and withdrawal of life support.In spite of significant progress in neuroimaging and the introduction of clear-cut clinical diagnostic criteria, determining the (un)consciousness still presents an important clinical problem: errors are common and have been shown to be as high as 37\u201343%  or increased (more consciousness), and thus considered to be gradual  and high (like in seizure) levels of synchrony among neuronal assemblies result in a dramatic loss of consciousness Flohr,  Figure .High strength of default mode network synchrony is required to support representational content integrated within the first-person perspective  offer a unique opportunity to study the neural basis of (un)consciousness due to the fact that impairment in awareness of self and environment is dissociated in such patients from preserved and stable wakefulness. We believe that an appropriate level of consciousness description should articulate the operational level of brain organization where the phenomenal/conscious phenomena reside  differ considerably in their level of operational architectonic dysfunction and that in turn translates into different expression of consciousness (Fingelkurts et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Just as John Snow used a branch of informatics, geospatial analysis, to identify the source of cholera in London and so prove the germ theory and revolutionise medicine in 1854, so too will the application of informatics and associated technology be instrumental to the next big change in healthcare. All countries with advanced economies are facing increased demand from ageing populations and increased chronic disease. Many also have shortages of skilled workers. Mounting evidence points to avoidable errors causing serious harm in health systems. Indeed optimal care only occurs about half the time in even the best performing health systems  that may"}
+{"text": "The ageing population is becoming a major concern in Hong Kong. According to population projections by the Census and Statistics Department , the numCustomer relationship management (CRM) is the strategic use of information technology and people to manage customers' relationships with companies  across the whole customer life cycle .Existing CRM technologies include databases, software  and security features . ResearcAn initial framework is developed by extensive literature review. The final framework is further supported and finalised by in-depth interviews with industry practitioners and academics. Content analysis is used to analyse the collected data.The results provide evidence that innovative technology  can reveal the business opportunities of the ageing population and provide better service to this segment. For example, the use of big data can provide a better understanding of the needs of the 'silver hair market' and the mobile business and online retail platforms can ease their purchasing processes.The research findings can be applied across a range of industries to improve CRM for the ageing population."}
+{"text": "One of the main challenges in critical patient management is to assess the blood volume and determine which patients will benefit from volume expansion and which patients will benefit from support with vasopressor and/or inotropic drugs. It is known that 40-72 % of critical patients respond to volume expansion with increased stroke volume or cardiac index.To search the literature for methods assessing fluid responsiveness in spontaneously breathing critically ill patients.The present study is a systematic literature review. We searched randomized clinical trials through a blind search performed by two independent authors in any language in the National Library of Medicine from 2009 to 2014.We selected three articles for full review and analysis, totaling 116 patients. The results are shown in Table This systematic review supports the beneficial effects of adopting maneuvers that amplify the hemodynamic changes, increasing the accuracy of methods to predict fluid responsiveness in spontaneously breathing critically ill patients."}
+{"text": "Translational research helps move basic science and clinical laboratory discoveries toward application in health and medicine. Through controlled experiments, basic scientists use animal models to reproduce disease characteristics caused by an agent\u2014in this case, excessively high exposure to alcohol. Through systematic study and observation, clinical research scientists identify symptomatic and physiological characteristics that define a disease. These bidirectional, complementary approaches enhance basic and practical knowledge about the biological basis of disease and hold promise for creating thoughtful, scientifically motivated solutions for improving public health.More than a decade ago, the National Institutes of Health (NIH) recognized the need for accelerating translation of research findings. In 2003, NIH developed the \u201cRoadmap for Medical Research,\u201d a collection of initiatives designed to find ways of motivating the translation of basic science into practice with the goal of transforming health care and outcomes. That vision was further crystallized in 2011 with the formation of the National Center for Advancing Translational Sciences (NCATS), which creates integrated translational and clinical research programs and fosters collaborations with community partners.NIH\u2019s attention to translational research demonstrates its quest to bridge the laboratory\u2013clinic divide. In this issue, we examine how current research in the alcohol field is setting the stage for translating clinical research findings to alleviate physical damage and restore neuropsychological function in individuals with alcohol use disorder (AUD).A highly promising area is the translation of cognitive neuroscience discoveries to gain a basic-science understanding of behavioral and pharmacological treatment outcomes. Findings from structural magnetic resonance imaging (MRI) and functional MRI (fMRI) studies, both in active and in abstinent alcoholics, are leading to a better picture of cognitive pathways that underlie behavior change in AUD (see the article by Naqvi and Morgenstern). A more complete understanding might be achieved by tracking the condition of the brain\u2019s communication networks through the cycle of alcoholism from sobriety to relapse and recovery. Indeed, anomalous brain circuitry is present in certain individuals with a genetic predisposition for alcoholism (see the articles by Kamarajan and Porjesz and by Cservenka and colleagues). Knowing more about these networks may enable us to identify people at high risk for developing an AUD. In earlier research, electrophysiological recordings obtained with scalp electroencephalography (EEG) first helped explain the genetic predisposition for AUD in individuals with a dense family history of alcoholism (see the article by Kamarajan and Porjesz). An extension of these studies could contribute to prevention and individualized treatment regimens.Research using fMRI to examine brain network connectivity suggests that alcoholism may be related to problems in maintaining balance between opposing networks. As Fein and Cardenas explain, it may be possible to treat AUD by altering selective brain network function with focused magnetic stimulation applied transcranially and with the use of neurofeedback. Neuroimaging studies also have identified neuronal changes that may be associated with drinking relapse. Underlying the chronic relapse risk may be negative neuroplastic changes in the brain, caused by the cycle of continued alcohol abuse, repeated brief alcohol abstinence, and alcohol withdrawal.In light of the multifactorial nature of AUD, we now know that factors such as stress affect brain circuitry in recovering alcoholics (see the article by Seo and Sinha). Hence, basic research through animal models of stress is critical for testing the effects of stress surmised from human studies. Lovinger and Kash review the effects of high alcohol exposure on two brain regions in a limbic pathway\u2014the striatum and bed nucleus of the stria terminalis (BNST)\u2014involved in long-term stress-related behaviors. This research should enhance our understanding of the mechanisms by which alcohol produces its long-lasting change in synaptic function  and their potential as new treatment strategies.Excessive alcohol consumption by pregnant women is particularly dangerous to the fetus. The timing of hazardous drinking occurring during fetal development dictates the locus and extent of neural and facial dysmorphology sustained, resulting in fetal alcohol spectrum disorders (FASD). Landmark studies of human FASD conducted by Riley and his colleagues and reviewed in their article  also demonstrate how animal models can enhance the role of neuroimaging in human studies and lead to advances in FASD diagnosis and treatment. Animal models of FASD have yielded essential information about normal brain development and the temporal and dosage parameters of alcohol exposure that produce significant dysmorphology (see the article by Wang and Kroenke). In turn, this knowledge has provided suggestions for treatment.Alcoholism is a complex human disorder with biomarkers for neural health dysfunction that are now detectable with neuroimaging methods. Clearly, alcohol researchers have led the way in applying these methods to identify\u2014in the living brain\u2014neural changes that occur with chronic, hazardous substance use. This accommodation of brain structure and function to the chronic presence of alcohol, that is neuroadaptation, seems to be either reversible or at least reduced with sustained sobriety. The promise of many of the functional imaging studies, then, is to identify neural circuits affected by and maladapted to alcohol, as well as those intact enough to undergo further neuroadaptation, but now in the direction of normalization. Knowledge about bidirectional neuroadaptation also might lead to the development of medications based on neural circuitry that expresses neuroplasticity (see the article by Johnson and Oslin) and identification of individuals with AUD who are treatment candidates because of their adequate neuroadaptive reserve. By fostering innovative collaborations across government, academia, industry, and the people we strive to treat, we can make the most of translational research findings and meet the growing need for specialized treatment (see the article by Batman and Miles). Research designs with both basic and clinical translational components hold promise for preventing and treating AUD and sustaining sobriety."}
+{"text": "Abdominal wall defects repair using prosthetic material is currently considered as the best available solution for most incisional hernias. Postoperatory suppuration remains the most frequent and fearful complication after this kind of intervention therefore imposing prevention methods. The aim of our study was to evaluate this serious yet controllable complication in the situation of a known pathogenic agent.This retrospective case series was carried on in the Surgery and Emergency Clinic III of the University Emergency Hospital Bucharest. It includes 14 cases of suppuration after abdominal wall reconstruction using prosthetic material during the last 15 years.In the situation of specific pathogenic agent, the use of specific antibiotic therapy and certain rather simple surgical techniques could guarantee therapeutic success for the doctor as well as the patient. A very good collaboration between the surgeon and the infectious disease physician was the key to therapeutic success."}
+{"text": "Translational research to discover therapeutic targets for stroke has not fared well in developing new treatments for patients. The three most pressing issues are the choice of therapeutic target, animal model, and timepoint of administration of treatment. This manuscript \u201cDifferent immunological mechanisms govern protection from experimental stroke in young and older mice with recombinant TCR ligand therapy\u201d provides a fresh approach toward developing stroke treatments (Offner et al., For a number of years, researchers have reported the entry of immune cells into the area of the infarct, which leads to further neurodegeneration. However, targeting this immune response as a treatment for stroke remains elusive (Iadecola and Anrather, This treatment reduced infarct volumes in both age groups by altering the immune response to this neurological insult. Most interestingly, the recombinant TCR ligand differentially affected components of the immune response in the elderly and young mice but still resulted in a blunted immune response reducing neurodegeneration. This study illuminated differences in the immune cell composition and inflammatory expression between these two age groups in response to stroke. This is one of the few studies that enlists elderly animals which begins to provide insight into the differences in the physiological responses to stroke between young and the aged animals. Such differences in young and elderly could be responsible for the failure to translate findings at the bench to those in the clinic since the vast majority of studies use greatly cheaper young ones. More studies using elderly rodents will further supply additional insight in translating stroke treatment from the preclinical research to the clinical setting. This study sets the basis for future ones to develop new therapeutic approaches for a treatment for stroke.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Anorexia Nervosa is a devastating disorder with the highest mortality in mental health. For some, it becomes a life long struggle with immense personal and social consequences and premature death. Severe and enduring anorexia is often synonymous with intractable disorder.This presentation challenges the common definition of treatment resistant disorder. It presents the case of a 60 year old woman who has lived with the disorder for over 30 years. The treatment went beyond weight restoration and resolution of the anorexic thinking; the main focus was on minimising harm and focusing on best possible quality of life as defined in a collaborative therapeutic relationship with the client. The presentation is not only about what went well but also trial and error and learning to be flexible and inventive rather than being stuck with pre-conceived ideas of \u2018successful\u2019 treatment goals."}
+{"text": "Given the characteristics of VR, we have to admit that imagery of \u201crotated head\u201d generated the same neural conditions associated with real head rotation, despite the subjects could not predict which neural circuits should be activated/inhibited and the studied reflex could not be voluntarily controlled. In other words, highs can transform into appropriate neural activations not only the mental images of voluntary movement and of selected perceptions  of the brachial artery (Green et al., highs and lows may exhibit NO-dependent different activation of sensory and associative regions such as those belonging to the salience and executive circuits, cerebellar inhibition of the motor cortex, internal model for postural control.In the cerebellum NO acts also as a negative regulator of granule cell precursor proliferation, promotes survival and differentiation of these neurons and regulates bidirectional plasticity at parallel fiber-Purkinje neuron synapses (Contestabile, In conclusion, our findings allow to include hypnotizability among the individual traits responsible for part of the variability in postural control and indicate that it may be involved in the construction of individual sensorimotor selves. They suggest a key role of the cerebellum in hypnotic responding and go beyond psychological theories by suggesting that the involuntariness in action reported after a few sensori-motor suggestions can be real rather than merely experienced.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Mental retardation (MR) is frequently the result of genetic mutations. Syndromic mental retardation is intellectual deficits associated with other medical and behavioral signs and symptoms. Non-syndromic mental retardation refers to intellectual deficits that appear without other abnormalities. The newly identified ARX  gene consists of five exons and encodes 562 amino acid proteins and is thought to regulate brain development. Mutations in the ARX gene are associated with a diverse spectrum of phenotypes ranging from severe developmental abnormalities of the brain to syndromic and nonsyndromic forms of X-linked mental retardation (XLMR) syndromes that can be associated with normal or abnormal brain morphology. Mutations in the human ARX gene are the major cause of developmental and neurological disorders.The present study was focused on screening of exon 2 of ARX gene in Indian families with mental retardation in order to obtain the relative prevalence of ARX mutations. Method adapted in present study was amplification of target exon by using polymerase chain reaction, qualitative conformation of amplicons by agarose gel electrophoresis and their use for conformation sensitive gel electrophoresis to find heteroduplex formation which is followed by sequencing.In present study we have found insertion mutation at genomic position 25031668, this change leads to loss of homeobox, OAR domains of ARX protein. The other mutation obtained was substitution of C to A/G is observed and does not affect protein functioning."}
+{"text": "The dataset originally included as The Data Availability statement for the article is revised to read: The authors have prepared a dataset that fulfills requirements in terms of anonymity and confidentiality of trial participants, and which contains only those variables which are relevant to the present study. Data are available as Supporting Information.S1 Dataset(DTA)Click here for additional data file."}
+{"text": "The interesting comments of Assistant Professor Cakir et al.  highlighOur study showed a relatively high incidence of mild forms of depression in both groups of patients (patients with diabetic foot versus diabetic controls ). SevereBased on our data, we will support further investigation of psychosocial assessments in patients with the diabetic foot to improve their standard of living and therefore their quality of life."}
+{"text": "Sodium channel blockers are used to control electrical excitability in cells as a treatment for epileptic seizures and cardiac arrhythmia, and to provide short term control of pain. Development of the next generation of drugs that can selectively target one of the nine types of voltage-gated sodium channel expressed in the body requires a much better understanding of how current channel blockers work. Here we make use of the recently determined crystal structure of the bacterial voltage gated sodium channel NavAb in molecular dynamics simulations to elucidate the position at which the sodium channel blocking drugs benzocaine and phenytoin bind to the protein as well as to understand how these drugs find their way into resting channels. We show that both drugs have two likely binding sites in the pore characterised by nonspecific, hydrophobic interactions: one just above the activation gate, and one at the entrance to the the lateral lipid filled fenestrations. Three independent methods find the same sites and all suggest that binding to the activation gate is slightly more favourable than at the fenestration. Both drugs are found to be able to pass through the fenestrations into the lipid with only small energy barriers, suggesting that this can represent the long posited hydrophobic entrance route for neutral drugs. Our simulations highlight the importance of a number of residues in directing drugs into and through the fenestration, and in forming the drug binding sites. The treatment of cardiac arrhythmia, epilepsy and pain usually involves blocking the protein channels responsible for initiating electrical activity in nerves and muscles. Current drugs block all such channels, but improved medication requires compounds that can differentiate between the channels present in different parts of the body. Achieving this goal calls for a better understanding of the interactions of current drugs with the proteins. Here we use computer simulation to understand where a local anesthetic and an anti-epileptic bind to a bacterial sodium channel and how they find their way to this position, helping to uncover ways to selectively target different human channels. Voltage-gated sodium channels (Navs) are transmembrane proteins that initiate action potentials in excitable cells by responding to small depolarizing signals to allow the rapid influx of Sodium channel inhibitors exhibit a wide range of chemical moieties, but common to most of them is the presence of a phenyl ring connected to a basic nitrogen, with some combination of aromatic and aliphatic decorations Humans have nine different types of voltage-gated sodium channels, which are preferentially expressed in different tissue Arcobactor Butzleri, called NavAb, shows the protein is a tetramer of four identical subunits, with the pore axis running down the central axis While there are no atomic resolution structures of eukaryotic voltage gated sodium channels (eNavs), the recent publication of a number of structures of homologous channels from bacteria (bNavs) Despite the similarities between bacterial and eukaryotic voltage gated sodium channels that may make bNavs good models for studying tonic block, there are also functional and structural differences. NaChBac exhibits far slower gating kinetics than eNavs In order to better understand the mode of action of sodium channel inhibitors, here we use molecular dynamics simulations to examine the route of entry and mechanism of binding in NavAb of two channel-blocking drugs: the local anesthetic benzocaine, and the anti-epileptic phenytoin. Both are small, neutral drugs that bind inside the pore of eNavs As described above, mutation studies strongly support the notion that local anesthetics bind to residues in the central cavity. For this reason we limit our search for possible binding sites to the channel cavity and fenestrations in order to more extensively sample potential binding pockets (meaning that we will not pick up any sites on the exterior of the protein.) To gain a first appreciation of where the drugs might interact with the protein and to observe drug behaviour inside NavAb, we start our investigation by placing phenytoin or benzocaine in the middle of the central cavity of both the closed and inactivated conformations and allow them to explore the interior of the pore without external influence. Although the size of the cavity is small and the drugs rapidly move about in this region, the timescale of our simulations is shorter than the typical time taken for drugs to block the channel, so it is possible that the drugs will not find their way to the most likely site in the pore. However, this approach does enable us to make a first identification of potential binding pockets which can be verified with the more exhaustive metadynamics search described below. As will be described later, the same binding positions found in these equilibrium simulations are found in two additional independent methods, lending support to them representing likely binding positions in the bacterial channel NavAb.One of the most commonly occupied sites is formed by the hydrophobic pocket above the intracellular activation gate, created by the confluence of the four S6 segments at the pore axis  are shown in Since both drugs are uncharged and there are no aromatic residues available for pi-pi stacking or cation-pi interaction in the NavAb channel lumen, nonspecific binding based on van der Waals attraction to hydrophobic pockets seems to be the dominant force behind drug association in our simulations. Both the identified binding sites involve significant interactions with residues at positions previously shown to be important for block in eukaryotic channels To assess the strength of binding relative to bulk in each of the two sites identified in the unbiased and metadynamics simulations we employed the method of free energy perturbation. Using this, the binding free energy of each drug in each site was determined, from which the dissociation constant was calculated for comparison to experimental measurements. As shown in For benzocaine, published values for the dissociation constant in closed eukaryotic channels range from 0.3\u20131.2 mM Experimental dissociation constants for phenytoin binding to the closed channel are rare, due to its low solubility and affinity to this state. In eukaryotic channels, phenytoin has been shown to bind to inactivated channels with a dissociation constant in the range of 4 \u2013 9 \u03bcM, with affinity up to 100-fold weaker in the closed state Drug passage through a hydrophobic pathway has long been hypothesized in sodium channels As shown in Movement of benzocaine and phenytoin through the fenestration is associated with extension of water chains from the channel lumen into the fenestration and possible retraction of resident lipid tails. Without the drug present, lipids extend into each fenestration for the majority of our simulations eg  as suspeMoving from the bulk lipid into the fenestration requires the drugs to move into the hydrophobic core of the membrane, something previously shown to be unfavourable Accurately converging the right hand side of the free energy profiles is difficult. Once the drug leaves the fenestration it can sample more positions at the given coordinate value and there are a number of slow motions that are hard to sample in the 30 ns of simulation we allow for each drug position. These slow motions include lipids entering/leaving the fenestrations, the drug moving between leaflets of the bilayer and the formation and breakage of water chains. Although the PMF does not change significantly when we extend our simulations  we have Using molecular dynamics simulations we have characterised the likely binding sites for benzocaine and phenytoin inside the central cavity of NavAb, with 3 independent simulation methods yielding consistent results. Both drugs are found to bind either in the hydrophobic pocket formed by the activation gate or at the entrance to the hydrophobic fenestrations. In both cases, the drugs interact with residues found to be important in binding in eNavs. But, we find this association is due to non-specific hydrophobic interactions meaning that binding occurs due to the overall architecture of the central cavity rather than interactions to specific residues. Although our simulations clearly identify the likely drug binding sites in the channel, it is not yet clear if the binding of more than one drug is necessary to occlude the pore or prevent channel opening. Our simulations also provide a plausible rationalisation for the differences seen between tonic and use dependent block, as interaction of cationic drugs with aromatic residues are essential in the use dependent case but not for resting state block Our results also show that the hydrophobic fenestrations seen in NavAb can serve as conduits for benzocaine and phenytoin to enter the central cavity and thus can form the long hypothesised hydrophobic entrance route The large degree of sequence similarity in the pore forming regions of eNavs makes the design of subtype selective channel blockers a difficult goal. Elucidating the mode of entry and binding of existing channel blockers is an important step toward achieving this aim. Here we have been able to do this for benzocaine and phenytoin in a bacterial channel, but it is not clear how much about binding in eukaryotic channels can be inferred from this given the significant differences between these families of proteins. For example, the nature of binding seen here is likely to be less specific than that in the eukaryotic homologues. Additional functional studies of drug block in bacterial channels, increased availability of structural information about the different functional states of bacterial channels, reliable models of eukaryotic channels and detailed investigations of specific drug-residue interactions in tonic and use-dependent block will all aid progress toward the design of subtype selective channel blockers.Two simulation systems were set up based on the NavAb sodium channel with coordinates obtained from the protein database: a closed/pre-open channel; PDB accession code 3RVY In order to gain a first idea of the likely position of drug binding in the central pore cavity, three simulations lasting 125 ns each were run for each protein/drug system . In each of these the drug was placed in the center of the cavity with a different random orientation. Once complete, the first 25 ns was excluded from further analysis to allow for equilibration of the drug in the channel, and the three trajectories for each protein/drug system were combined. Cluster analysis was performed on the drug position in the combined trajectory  using the quality threshold algorithm to locate the most commonly occupied drug positions. For this purpose we clustered according to RMSD of the drug coordinates using a cutoff of 3 \u00c5. To determine which residues the drug interacts with in potential binding sites, the NAMDEnergy plugin was used to measure the interaction between the drug and chosen residues for selected subsets of the trajectory corresponding to each cluster.To better assess if the equilibrium simulations had sampled the most likely drug binding poses, metadynamics Free energy perturbation The equilibrium constant of the drug binding to each site were calculated using the following relation The energy profile for drugs to pass through the lateral fenestrations from the channel cavity into the lipid bilayer was determined using umbrella sampling Figure S1Orientations of the drugs as a function of time during the metadynamics simulations.(PDF)Click here for additional data file.Figure S2Representative snapshots of the binding poses of benzocaine phenytoin.(PDF)Click here for additional data file.Figure S3Drug-protein interaction energy decomposition. The interaction energies for benzocaine and phenytoin and residues in NavAb are decomposed into van der Waals and electrostatic components.(PDF)Click here for additional data file.Figure S4Snapshots from umbrella simulations. These show benzocaine and phenytoin occupying a hydrophobic fenestration at the same time as a lipid molecule from the bilayer.(PDF)Click here for additional data file.Figure S5Convergence of the potentials of mean force (PMF).(PDF)Click here for additional data file.Figure S6Cross-section of the simulation system used in this study.(PDF)Click here for additional data file."}
+{"text": "Since the middle 1990s biologics have been available for rheumatic diseases. The initial experiments showed efficacy for symptoms and signs but concern was expressed about tachyphylaxis and absence of a true DMARD effect. Combining the antibodies with methotrexate answered some of these criticisms and since that time the number of agents available for rheumatoid arthritis, psoriatic arthritis and spondyloarthropathy has grown.It is clear these agents work, what is less clear is how they should be used to produce optimum cost benefit. The ever expanding market has attracted a large number of pharmaceutical players to this area and this shows no sign of abating. Also there are number of new drugs including oral synthetic DMARDs becoming available.None declared."}
+{"text": "Breast cancer is the commonest malignancy of women in many parts of the world and comprises 18% of all female cancers. There is one million new cases in the world each year. Neopterin which is a pteridine produced by activation of monocytes by IFN-\u03b3 may be used as a marker of immune system activation. The biological function of neopterin is still largely unknown and certain patho-physiologic roles have only recently been elucidated. Therefore, the aim of this work was to investigate the role of neopterin in females with primary and metastatic breast cancer. The obtained results were correlated with different clinicopathological data of those patients. The study population included females with primary and metastatic breast cancer as well as healthy age matched females were taken as a control group. Peripheral blood mononuclear cells were separated from each subject under study by Ficoll-Hypaque density gradient centrifugation technique. The isolated cells were cultured with and without PHA and neopterin levels were measured in serum and culture supernatants by ELISA technique. The results showed that neopterin levels were lowest in serum, followed by culture supernatants without PHA and highest in culture supernatants with PHA in each studied group. The mean neopterin values in serum and culture supernatants with PHA of metastatic breast cancer patients were significantly higher than in the primary breast cancer patients and the control group. Our results also indicated that neopterin levels positively correlated with the tumor grade, tumor stage and the presence of metastasis. From all mentioned data it is clear that, measurement of neopterin either in serum or in culture supernatants with or without PHA can give an indication about immunological status of breast cancer patients' response to therapy and early detection of metastasis. It gives an important and valuable prognostic information before surgical intervention is performed."}
+{"text": "Reducing human infectivity of malaria parasite through early and effective treatment amongst under-five children is a major concern of WHO & MDGs 4 & 6. Getting mothers to bring their children to the nearest facility early for malaria treatment remains a major challenge.To explore health seeking behaviours and cultural attitudes of mothers of under five children suffering from malaria in Ile Ife using moderate interviews and providing recommendation to the Ministry of Health of Osun State to serve as knowledge basis for developing appropriate intervention.The study employs a qualitative research with the aid of purposive sampling, 16 women who brought their under five children to hospital for malaria treatment were recruited. A moderate interview was used to explore the experiences of the mothers and the data generated was subjected to thematic content analysis.Five themes emerged from the study. All respondents recognized fever as the major feature of malaria but their knowledge of what causes it, symptoms and sign was poor. They all perceived malaria as a simple disease for which mothers should be comfortable to apply home based remedies such as herbal concoctions. Religious beliefs did not prevent mothers from seeking hospital care but some are aware of mothers that rely on Holy water and prayer to treat malaria. Poverty is seen as an impediment to seeking treatment mostly by women in a polygamous relationship. Fear of use of injection to treat malaria in hospital coupled with perceived poor attitude of hospital staff was considered by some mothers.The study observed that mothers had poor knowledge of malaria; cultural beliefs in home remedies and poverty are issues that affect malaria outcome. Health education of the malaria life cycle, treatment and prevention is necessary for mothers as well as empowerment of women."}
+{"text": "NZ is considered a bicultural society; Maori make up approx 15% of the population (NZ census 2013). Maori have strong cultural traditions and beliefs around food, with food not only determining physical health but also emotional, psychological and spiritual wellness (HRC report). Food is also strongly linked to customs and cultural values. The implications and understanding of eating disorders in this group are therefore complex.Mental Health services traditionally struggle to both engage and treat the Maori population. Eating disorders rates are low overall in the general population; research suggesting that there was a very low prevalence overall for eating disorders in Te Rau Hinengaro. However, the highest prevalence of eating disorders, particularly bulimia, was in M\u0101ori (BPJ 2010).With this in mind there are several challenges to consider when planning and offering services to treat eating disorders in this population.The CMDHB covers an area with high Maori population and provides a culturally specific service for both adults and young people. The rates of referral of Maori to the CMDHB Eating Disorders Service are low overall, despite this there is a recognised unmet need in terms of recognition and support for these difficulties. Often young people present with complex needs with eating issues part of this presentation. Traditional treatments pose dilemmas when considering the cultural aspects of engagement and working with maori families; as well as the explanatory models used to think about eating issues. This presentation will consider these challenges and use a case example to support ideas to improve services and outcomes in this population."}
+{"text": "Drosophila melanogaster and human cells. They also reported that Rab5 is required for the correct alignment of chromosomes at the metaphase plate, an important step for the proper segregation of chromosomes.Mitosis is a crucial event that controls the equal partitioning of the genetic information between the two daughter cells. Failure in this process can cause various human genetic diseases and can contribute to cancer onset and development. For many years cell division studies focused on the identification and analysis of the mechanisms and signaling pathways that control microtubule dynamics and chromosome behavior, however in recent years other important cellular and regulatory processes have been implicated in various aspects of cell division and our traditional view of mitosis has changed. In particular several studies have highlighted the importance of membranes   , the Drosophila counterpart of the nuclear mitotic apparatus protein (NuMA) (Bowman et al., Drosophila, human Rab5 was found to be required for chromosome alignment, but interacted with a different mitotic player, CENP-F required for chromosome congression (Liao et al., During mitosis, RNAi-mediated depletion of Rab5 induced chromosome alignment defects at the metaphase plate and delayed mitotic progression both in s Figure  and it wDrosophila and human cells employ Rab5 proteins to direct membrane trafficking involved in the regulation and transport of key mitotic regulators important for the fidelity of chromosome segregation (Lanzetti, Together, the findings of these papers indicated that incomplete disassemble of the nuclear envelope affected the release and localization of important proteins for spindle assembly and maintenance. They also showed that both In conclusion, these findings indicate that mitosis requires more than just microtubules and chromosomes, and increasing evidence over the last years has pointed out that a membranous system surrounding the mitotic spindle is important not only to confine important mitotic proteins around the spindle (Capalbo et al., The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Very few qualitative studies on cluster headache have been conducted. As a result we have little in-depth understanding of the perceptions and experiences of cluster headache patients and the health professionals who treat them. With this research we aim to rectify that gap.The overall objective of the project is to gain insight into the perceptions, experiences and understandings of cluster headache from the perspective of three key stakeholder groups: the cluster headache patients, GPs and neurologists. We present here the findings of our literature study and identify the emergent themes which we will use during the interview studies for this project.A qualitative study using semi-structured interviews with the three participant groups. A systematic qualitative methodology is applied to the transcribed interviews.This study runs from August 2014 to June 2015 and data collection is currently in process. Therefore all results are tentative. Early findings show that this study sheds new light on the following aspects: early detection and diagnosis; health education and promotion; effective treatment and management of cluster headaches.This study will identify the particular challenges for each stakeholder group\u2014patients, general practitioners and neurologists\u2014with respect to early detection of cluster headaches and ways in which treatment and management can be facilitated. We envisage this study will raise awareness about the importance of early diagnosis, health education and the need for effective treatment pathways for cluster headaches."}
+{"text": "The Micro Cellular Rubber (MCR) unit established in Vizinagaram, Andhra Pradesh in India by The Leprosy Mission Trust India (TLMTI) caters to the need of poor Leprosy affected patients with neuropathic feet within India and to countries nearby India. The MCR Unit till date has provided over a million pairs of MCR insoles to all with anaesthetic feet and still continues to do so.The MCR sheets manufactured with a shore hardness of 15' Shore 'A', has helped prevent high pressure points and thus avoid plantar ulcers in anaesthetic feet. Natural Rubber along with several other chemicals is used in optimum quantities to manufacture MCR. The unique manufacturing process gives MCR the ability to spring back to original shape when pressure is released while walking.The larger size (24\u201d X 20\u201d) coloured MCR sheets with 10mm thickness has become an ideal rubber to prevent stigma for deformed anaesthetic feet. The cost effectiveness in the production of the MCR rubber has helped the poor leprosy patients afford and use the MCR insoles for their footwear. Association and constant interaction with various shoe and footwear companies have led to experimentation and development of newer designs in MCR sandals. High quality and standards of the MCR insoles are maintained through periodic standardised quality tests carried out both within and outside the organisation.Although the initial purpose of the MCR unit was to cater to the needs of Leprosy affected people, in course of time, various Orthotic & Prosthetic centres realized the value and have started using MCR in their products, especially for Diabetic foot care. Since patients use and prefer protective MCR footwear to prevent ulcers, protect and cover their anaesthetic and deformed feet, it is essential for MCR production units to constantly upgrade and develop newer designs and give the patients and opportunity to choose. At present TLMTI uses 50% of its annual MCR production and the rest is used by other NGOs and Orthotic centres.With time there has been a rapid change and development in the design and manufacture of footwear, however there has been no alternative to MCR insole footwear. The constant strive of introducing and making use of MCR footwear in other general disabilities have reduced the stigma of MCR\u2019s in leprosy to a great extent."}
+{"text": "Disorders of consciousness (DOC) present a clinical challenge in diagnosis, prognosis and defining appropriate treatments that aim at improving the patient's care and quality of life. As there is no universally accepted definition of consciousness, DOC are difficult to define, elucidate and diagnose  have facilitated the integration of structural and functional methods enabling a greater understanding of the variation in different states and transitions of a DOC, as well as some individual differentiators within the spectrum (Laureys et al., EEG can measure brain signals of neuronal activity over bandwidths of frequency ranges recorded with dozens or hundreds of scalp locations over different timescales; it has particular relevance when considering brain dynamics and the mesocircuit model in DOC. Brain dynamics are measured through signal oscillations which act as communication connections integrating brain functions. They are important for the mediation and distribution of higher functional and synchronized processes in the human brain (Sauseng et al., The most accepted measure of interaction and connectivity is that of coherence, a generalization of correlation to the frequency domain. Coherence is used to study the relationship and interactions between EEG channels and between brain regions (Nolte et al., In DOC, coherence is used to study connectivity and synchronization between brain regions. Correlated activities amongst brain areas or electrodes can determine patterns of functional connectivity, which is known to be impaired in DOC (Noirhomme and Laureys, One of the main limitations of this approach is that coherence values must be interpreted carefully, as they can be contaminated by artifacts between electrodes caused by reference and by volume conduction which is pertinent to the DOC population. Volume conduction can impact interelectrode connectivity results due to the spatial autocorrelation between electrodes which measures connectivity between the two brain regions where the electrodes are placed, this is further impacted by skull injury and craniotomy following a TBI Cohen, . This haResearch using the modified imaginary coherence across difference frequency ranges and brain regions in DOC using resting state and diverse stimuli has expanded significantly over the last few years (e.g., Le\u00f2n-Carri\u00f2n et al., EEG studies of coherence can be used to assess the effects of auditory stimuli in DOCs. One of the most reliably tested methods is using salient auditory stimuli either through music therapy or music intervention that is meaningful or personal to the patient. DOC studies have identified that auditory stimulus with personal and/or emotional meaning produces meaningful results compared to unrelated auditory stimuli (e.g., O'Kelly et al., Music therapy is an established rehabilitation intervention in DOC (Magee et al., More research is needed on the mesocircuit model and thalamocortical synchronization to develop an EEG regional coherence methodology in order to analyse and compare cortical regional connectivity in response to rehabilitation interventions, including music therapy. The application of these models in a clinical setting could help develop an EEG regional coherence methodology to analyse and compare cortical regional connectivity in response to music rehabilitation interventions.It is important to understand if an increase in connectivity across the mesocircuit pathways could be an indicator of the conscious state and neuroplasticity, and whether such a change could monitor the functional recovery in line with the earlier works Schiff, . This apThe application of the mesocircuit and thalamocortical connectivty models using EEG coherence measures could lead to a more objective determination of the state of consciousness in patients with DOC and any transitions that may happen across the continuum within the different states through the trajectory of rehabilitation with the contribution of music therapy. It is hoped that the development and adoption of such clinically applicable and complementary tools across DOC patient populations will enhance the existing practizes to provide more translational and differential evaluation of post-injury diagnosis and throughout rehabilitation.VL is the lead author. Both VL and JO contributed to the conception and design of this work. VL drafted the manuscript and JO revised it critically for intellectual content. Both authors approved the final version of manuscript. Both VL and JO agree to be accountable for all aspects of the work.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "We report a case of Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) which illustrates the natural progression of disease in the absence of availability of an implanted cardiac defibrillator (ICD). Electrocardiograms and cardiac imaging show the progress of ARVC and these clinical milestones of disease are presented herein. ARVC is a largely inherited cardiomyopathy that affects mostly young otherwise healthy individuals and is associated with an increased risk of sudden death . The morAn 18-year-old Chinese man was sent to the hospital after suffering syncope while playing basketball. After a 12-lead ECG revealed ventricular tachycardia  and a suThe deterioration of parameters on ECG and ECHO indicates a poor prognosis. Such clearly illustrated progression from diagnosis to SCD on clinical testing allows for better visualization of disease progression and may heighten clinician suspicion of disease and recognition of an ominous course. The lifesaving therapy for ARVC is ICD placement and this case corroborates the diminishment of the prognosis in its absence."}
+{"text": "To the Editor: We would like to add some specification and clarification to the discussion regarding the diagnostics and case definitions for urinary schistosomiasis in travelers to Corsica, France  exhibited atypical morphology  that S. haematobium uses  is safe. Epidemiologic analyses should take into account the role of zoonotic S. bovis infection and supplement parasitological investigations with molecular analyses (We recommend that clinicians treat any suspected case of"}
+{"text": "In this study, we investigated the gene expression profiles between female and male mice using the sfx mouse model and BXD RI strains. The objective of this study is to identify sex differentially expressed genes in bone using the sfx model and BXD RI strains.Geber and Murphy  found thx) mouse  which lasfx mice. We then analyzed the potential gene network among those differentially expressed genes with whole genome expression profiles generated using spleens of female and male mice of a total of 67 BXD (C57BL/6J X DBA/2J) recombinant inbred (RI) and other strains.We first identified the genes that are differentially expressed in the femur between female and male sfx mice from either female or from male mice than we found previously using RNA of a mixture of female and male mice. It is obvious that the skeletal system is different between female and male. The female and male skeletal system is most likely to react to the VC deficiency in sfx mice differently. The comparison between disease and control samples using data of sex mixture suffers from neutralization of gene expression levels between the female and the male. This result suggests that in the study of genes that are potentially affected by the sex or the gender, data from female and male individuals should be analyzed separately. Many reports have been using the sex balanced data of mouse strains.By analyzing the female and male mice separately, we found many more differentially expressed genes between wild type and Our data posed a question about whether the balanced data should be used without understanding of the sex differences."}
+{"text": "Due to high resolution cytogenetic microarray (CMA) has replaced traditional karyotyping for evaluation of individuals with intellectual disability, autism and congenital malformations. The diagnostic yield of CMA is 10 to 12 % and is more than any other investigation for evaluation of developmental disabilities. Due to its high resolution CMA is also being used as a prenatal test for chromosomal anomalies. The diagnostic yield is about 3% whatever may be the indication. The yield is higher in cases with fetal anomalies. The main concern with CMA is its ability detection of copy number variations of unknown significance. This is a major problem in prenatal diagnosis and is a challenge for the counselor and dilemma for the family in concern. With accumulation of more and more data of pathological and polymorphic variations in genome the variations of unknown significance will decrease. CMA is also useful in delineating abnormalities picked up by karyotyping. Some cases with double segment rearrangement may point towards familial chromosomal rearrangement and hence, CMA is indicated in familial cases with developmental disabilities and birth defects.Cost and availability of clinical cytogeneticists for appropriate interpretation of CMA results are important concerns for wider application of the technique."}
+{"text": "The traThe unexplained repeated implantation failure (RIF) is still another unsolved and one of the principal problems to affect the outcome of assisted reproductive technology (ART). The successful embryo implantation requires accurate temporal regulation of maternal immune function  and endocrine system . The pasThe \u201cbest viable\u201d embryo selection and also the optimal implantation regulation, both are going to be solved by new diagnostics and treatment methods based on personalized omics profiling . MoleculThe goal of our effort is to point out new and potentially useful biomarkers that can be used for the improvement of pregnancy rates after the assisted reproduction techniques (ART) in near future and also to emphasize some of the novel molecular targets and biomarkers that have been reported recently and might contribute to new strategies of infertility management that will return a hope of natural conception for selected couples.Evaluation of such markers may help clinicians to predict pregnancy outcome and detect occult implantation deficiency. Moreover, these novel molecular targets are expected to apply to the clinical practice from bench to bedside and improve the implantation efficiency in ART."}
+{"text": "It has been proposed that one of the causes of stuttering is a deficit in brain timing networks Alm, . In stutNeural oscillations in the beta frequency band (15\u201330 Hz) are classically related to motor activity , are more likely to reflect anomalies related to the cause of stuttering rather than consequences of stuttering (see for review Chang and Zhu, If abnormal beta power arising from the striatum is causally related to stuttering, then fluency inducing manipulations should normalize beta power. This contention is supported by functional neuroimaging and electrophysiological studies. The finding that putamenal beta band oscillations are biased toward internal timing (Bartolo et al., hypoactive beta oscillations in the basal ganglia. DAF may have normalized the beta band oscillations in the basal ganglia thereby reducing the need for compensation via hyperactive beta in the cortex. This idea suggests both AWS and CWS should exhibit reduced beta band responses in the putamen when internalizing rhythms. The fact that fluency-inducing mechanisms reduce the hyperactivity of the beta band in the cortex has major implications for stuttering. Firstly, it implies that without regular external stimulation, AWS have abnormal beta oscillations in the cortex and possibly the striatum. Secondly, normalizing compensatory hyperactivity in the cortex as well as temporarily alleviating stuttering implies that DAF may act to normalize hypoactive oscillations in the striatum.It is unclear whether the hyperactivity of the beta band activity in stuttering (Rastatter et al., In summary, if stuttering is a disorder of internal timing and internal timing is represented by modulations of oscillatory power within the beta band in the striatum, then it is likely that the cause of stuttering is reflected in abnormal beta band oscillations in the putamen. This is consistent with the structural and functional abnormalities in CWS (Beal et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "We report the results of a simulation study in which we explore the joint effect of group absorptive capacity  and cognitive distance  on the emergence of collective rationality in groups. We start from empirical results reported in the literature on group rationality as collective group level competence and use data on real-life groups of four and five to validate a mathematical model. We then use this mathematical model to predict group level scores from a variety of possible group configurations . Our results show that both group competence and cognitive distance are necessary conditions for emergent group rationality. Group configurations, in which the groups become more rational than the most rational group member, are groups scoring low on cognitive distance and scoring high on absorptive capacity. As groups become ubiquitous information processing units in modern organizations, emergent group level cognitive properties received considerable attention in the literature Of particular interest for research advancement and practice is strong cognitive/rational synergy, reflecting the extent to which the group as a whole is more rational than the most rational member of the group. Previous research pointed towards the fact that strong synergy is not easily achieved An important antecedent of emergent group rationality is the initial configuration of group members\u2019 individual rationalities. Cognitive distance as reflected by the detachment of the most rational group member from the rest of the group has a nonlinear association with both weak and strong group synergy Therefore, average individual rationality is a form of group absorptive capacity likely to be beneficial for strong cognitive synergy. The concept of absorptive capacity originates in the general management literature and describes a social system\u2019s  capacity of acquiring, assimilating, generating and transforming knowledge in order to achieve a competitive advantage Groups composed of members varying in their task-related knowledge and cognitive competencies often face the issue of bridging these differences in order to reach consensus on a decision or problem solving approach. For disjunctive tasks, in which the task accomplishment depends on the most knowledgeable or competent group member, groups often have to bridge the cognitive gap between the most knowledgeable group member and the rest of the group. Previous empirical research tested models that predict a non-linear association between cognitive distance (defined as the cognitive gap between the most knowledgeable group member and the rest of the group members) and cognitive synergy Building on the above mentioned arguments, Meslec and Cur\u015feu Meslec and Cur\u015feu We argue here that groups with high absorptive capacity are better equipped to integrate effectively the knowledge shared by the most knowledgeable group member and as such they are more likely to successfully bridge the cognitive gap that separates the best performing individual in the group from the rest of the group. Such a claim is very difficult to test in real life settings, because it is extremely challenging to find enough groups to cover all possible group configurations in which both cognitive distance and absorptive capacity to vary. We therefore set out to develop a simulation model and test the effects of the interplay of cognitive distance and absorptive capacity on strong and weak cognitive synergy. Computational experiments can capture, starting from existing relations as identified in the empirical studies with real-life groups, relationships between variables and then extrapolate these relations for all possible configurations of the two variables explored. As argued, this extrapolation will never be possible in real life as it is close to impossible to gather data on groups that cover all the spectrum of possible combinations between cognitive distance and absorptive capacity. Starting from real life data reported in previous studies Specific approval from the university ethics review board was not required since this study reports a simulation based experiment and it did not involve additional data collection from human or animal subjects. Data for testing the mathematical model used in the simulation was obtained from previously published studies.With the consent of the authors we used real life data from previously published papers on group rationality The group data is split up by group size, and then groups of different sizes are treated separately in order to control for the co-varying of cognitive distance measure with group size. If we were to investigate groups of all sizes simultaneously, we would have had to contend ourselves with only averaged individual performance and the within group standard deviation, and perhaps the best individual performance in the group to ensure model fit \u2013 therefore rely on much less data than in the current approach. Afterwards, the columns for each group are sorted according to the individual performance. We then performed a linear regression of the group score based on the sorted individual scores. For a group of size five, we get five individual coefficients: Group absorptive capacity and cognitive distance were the independent variables in our simulation study. We used the average individual rationality within groups as a measure of groups\u2019 absorptive capacity and we used a heuristic method of computing cognitive distance. Based on the guidelines reported in Meslec and Cur\u015feu Our simulation was programed and ran in MATLAB version 8.1.0.604 (R2013a). In the supporting information folder  we preseAs illustrated in both figures, our simulation study replicated the empirical results presented in Meslec and Cur\u015feu Although common in behavioral ecology, simulation studies starting from real life data According to our simulation results, a necessary condition for achieving strong cognitive synergy is that individual group members score high on rationality. If groups are composed of irrational individuals, they do not have the potential to become more rational than their most rational member. This finding is somehow at odds with studies on animal collectives showing that groups composed of irrational agents can in fact make rational choices Another important result of our simulation study, refers to the association between cognitive distance and group rationality (as strong cognitive synergy). At very low levels of cognitive distance, there is a small positive association between group competence and strong synergy. This pattern of results suggests that low cognitive distance is yet another necessary condition for achieving strong cognitive synergy. To conclude, our simulation study identified two necessary conditions for reaching strong synergy in groups. One of the necessary conditions is high group competence (absorptive capacity) and the other is low cognitive distance. When at least one of these conditions is not fulfilled, groups have little chance of achieving strong synergy that is, becoming more rational than their most rational group member. Yet another configural characteristic conducive for strong synergy is group size and according to our simulation results, at high levels of group absorptive capacity, groups of five have a higher chance of reaching strong cognitive synergy than groups of four. Availability of cognitive resources varies with group size and it is possible that groups of five with high absorptive capacity have more cognitive resources they can use to achieve strong synergy as compared to groups of four. This pattern of results comes at odds with previously reported negative association between group size and strong synergy File S1In the supplementary material folder labeled (ZIP)Click here for additional data file."}
+{"text": "The earliest application of evolutionary theory, although unknowingly at the time, was artificial selection of crops and animals for food production. Ever increasing technical advances in breeding, genetic engineering and comparative genomics have since led to a rapid acceleration in the rate of such selection, although many of the basic principles underlying the process have remained the same over time. For example, whereas we used to inter-breed among genotypes and even species to generate standing genetic variation upon which to select, we can now introduce specific genes of interest directly into the preferred genetic background.Much of crop domestication historically has involved increased yield and size (for example of fruit or seed), and this has resulted in parallel and often convergent selection upon traits and even genes of interest. Recent work by Dorian Fuller and colleagues used archaeological plant remains from around the world to examine the parallel acquisition of so-called \u201cdomestication syndrome traits\u201d across both plant species and regions (Fuller et al. Improved understanding of the evolutionary process as well as major technological advances means the pace of artificial selection has intensified and our ability to respond to changes in both the abiotic and biotic environment has improved greatly. Our ability to translate understanding of plant genetics and genomics into meaningful applications in crop science is discussed in a new piece by Pamela Ronald Ronald . The worArabidopsis thaliana in order to determine the specificity and consequences of evolution on one host to infectivity on another. They use experimental evolution to show rapid increases in infectivity and virulence on the host background in which the virus has been adapted, but also demonstrate that some host types select for viral populations that are more generally infective to other types (Hillung et al. Given the rapid potential for adaptation, many predictions regarding pest or pathogen evolution can be directly tested in the laboratory in order to inform better disease management. Recent work by Julia Hillung and colleagues examined the adaptation of a plant RNA virus to various ecotypes of Importantly, the utility of evolutionary theory for agricultural practice is not limited to pest and pathogen interactions. The increasingly clear role of the microbiomes across the rhizosphere and phyllosphere suggest great potential for application of both community ecological and evolutionary thinking. Suzanne Donn and coauthors examined the changing soil microbiome of intensive wheat crops across years and found that, relative to soil in the absence of plants, rhizosphere communities changed substantially over time in the presence of plant roots and these temporal dynamics could be explained well based on the stage of plant development (Donn et al. Overall, although artificial selection has been central to agricultural practice since its dawn, we are still constantly improving our ability to speed up the selective process, incorporate adaptation across heterogeneous environments, and allow for a more responsive management program in the face of coevolving enemies and mutualists. As such, there remains great promise in our ability to increase crop yield and decrease the use of pesticides and fertilizers through the application of evolutionary thinking."}
+{"text": "Pathology of posterior horn of medial meniscus is common and often presents a difficult approach during arthroscopy for various reasons. We describe an easy maneuver to facilitate \u201cdelivery of the medial meniscus\u201d during arthroscopy. Treatment of medial meniscus pathology is one of the most commonly performed arthroscopic and often presents difficult access during arthroscopy , 2. TherWe describe a technique to improve medial meniscus posterior horn accessibility without use of additional portals or tools.Standard anterolateral and anteromedial portals are used to enter the knee joint. Lateral compartment procedures are completed as it can be easily enlarged by conventional techniques. Medial compartment is assessed and configuration of medial meniscus tear is established through the anterolateral portal. The degree of opening of the medial joint is assessed by valgus stress in extension and slight internal rotation of the knee. If the standard 4\u00a0mm shaver can enter the posteromedial corner of the knee the space is usually adequate to access the posterior horn. Stable flap tears in the posterior horn can easily be resected using a cutting punch and oscillating shaver. The peripheral portion or unstable flaps become difficult to reach due to \u201cposterior slipping away\u201d of the posterior horn of the meniscus especially in cases of menisco-capsular separation. In this scenario we use the technique of \u201cmeniscus delivery\u201d. With the knee in 20\u201330 degrees of flexion, valgus stress is applied and the medial joint is allowed to open as much as possible, then the assistant places the middle or index finger on the posterior knee surface just medial to the semimembranosus tendon at the level of the joint line, and applies anteriorly directed pressure towards the centre of knee joint . This deIt is often difficult to visualize the posterior horn of the medial meniscus during arthroscopy and struggling to enter this part of the compartment may lead to iatrogenic cartilage injury and/or instrument damage. The maneuver we describe uses routine tools and allows easy access to the posterior horn without the need for additional portals or special tools. The push to the posteromedial aspect of joint must be done in the valgus opened knee and this allows delivery of the posterior horn into view for easy accessibility. This technique takes no extra time and is especially helpful in tight knees and osteoarthritic knees. It is described for the medial meniscus only as the lateral meniscus is usually easy to approach by conventional methods.The authors declare no conflict of interest in relation with this paper."}
+{"text": "There is a lack of experience in implementing clinical guidelines in Norway and most guidelines are put into practice without an implementation plan. This presentation is part of a project dealing with developing strategies for implementing a clinical guideline for persons with concurrent mental disorders and substance use disorders. Purpose To describe the different tools that have been developed to implement the guideline and thereby bridge the gaps between current practice and clinical guidelines.We have put an emphasis on leaders, patients/ families and service providers. For leaders we have established a toolbox for managers including equipment for doing clinical Audits and a practical guide for how to change practice. Representatives from patients organizations have selected and promoted the 10 most important recommendations. An electronic version of the guideline has been developed which in addition to the national dual diagnosis competence training program, are important tools for service providers.The national training programme has gathered around 200 to 300 service providers, leaders and users on 17 locations in Norway. Unfortunately, mental health workers and leaders are more absent from the seminars than addiction workers. One important objective of our implementation efforts is that health care workers should participate in continuous training using our internet-based educational training packages like video lectures, instruction videos, screening tools etc. The 10 user selected recommendation have been widely distributed and might also be downloaded as Apps. The clinical Audits have been used in several institutions and departments and we are now developing a community and user Audit. We will present some finding on the use of our net tools and Apps during the presentation.In an effort to bridge the GAP between the guideline recommendations and current practice, several measures have been put in place targeting leaders, service providers and users. One of the hurdles we have faced in the implementation is security systems and data programs used by the health authorities making access to our net based tools difficult."}
+{"text": "Dang and colleagues recently reported in the journal that tumor response to definitive chemoradiation, as assessed using the RECIST criteria, and the risk of radiation pneumonitis were positively correlated in patients with non-small cell lung cancer (NSCLC). We had previously reported similar findings in a study that used positron tomography both to measure tumor response and to assess normal tissue toxicity in patients treated with chemoradiation for NSCLC. Taken together these reports suggest that radiosensitivity of normal tissues and tumors may be strongly linked in a proportion of patients with lung cancer. We read the recent article published in the journal by Dang and colleagues with interest . These a"}
+{"text": "The Editorial on the Research TopicMolecular Regulation and Therapeutic Potential of Thermogenic Fat CellsMuch of systemic metabolism depends on the activity and function of adipose tissue. Adipocytes in mammals fall into two categories classified by their primary functions: white fat cells that mediate energy storage and thermogenic fat cells that counteract hypothermia and obesity through adaptive thermogenesis. Whereas white fat and its function as an energy reservoir and endocrine organ have been studied for decades and are relatively well understood, until recently, many aspects of thermogenic fat biology have remained elusive.It has long been appreciated that the thermogenic brown adipose tissue that exists in the interscapular depots of small rodents, hibernating mammals, and human infants provides significant evolutionary advantages against cold stress . The lasPark et al.; Mueller; Bayindir et al.]. Reviews and a perspective article next explore how mitochondrial function, including redox homeostasis, is regulated within these thermogenic adipocytes . Central control of adaptive thermogenesis and other functions of thermogenic adipocytes are also highlighted . Importantly, several articles illustrate that interconnections exist between adipose tissue function and overall metabolic health, and how to increase the content and activity of these cells to ultimately fulfill their therapeutic potential in humans . As technology has advanced, novel interdisciplinary approaches have been developed to harvest the thermogenic capacity in fat tissue toward the control of obesity and metabolic diseases . We anticipate that all these articles will help the scientific community, both experts in the brown and beige fat area and newcomers entering the field to understand the molecular mechanisms of brown/beige fat development and induction, and appreciate the physiological impact of thermogenic fat activity. I would like to thank all the authors and reviewers for their contribution and discussion to put together this wonderful topic that may inspire further interest in this exciting new field.In this research topic, leading experts in the energy metabolism field provide an overview of our current understanding of these metabolically active fat cells. We begin our discussions with mechanistic insights on the transcriptional regulation of thermogenic fat cells [JW conceived and wrote the manuscript.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Casemix Grouper software is a tool to improve efficiency and quality of care in hospitals and medical centres. The utilisation of Casemix Grouper among hospitals is very limited and depends on their existing local machine and hardware. While Casemix Grouper provides a crucial output in the form of Casemix groups, the hardware machine should not be a limiting factor to hospital. Thus, the objective of this development was to provide the utility for end user to use the Casemix Grouper on web environment.The conventional way of providing Casemix Grouper service is by deploying standalone software at user\u2019s local machine. This will create problem when user\u2019s machine are diverse and does not meet the requirement for running the Casemix Grouper. The online Casemix Grouper will have 2 modules, which are for user and for the admin. The user module includes the authentication login and then uploading the input file. Developing a web based using Java Servlet Page (JSP) will provide access to all the available browsers on any operating system, so that end user can upload the Casemix input file. After the input file has been uploaded, online grouper will process the input file and generate an output file. The user will receive the output file via user-registered email. The admin module will also have authentication login and will be able to monitor the whole process for each users.With the implementation of Casemix Grouper as a web-based application, user can now avoid the stringent hardware requirement on their local computers for standalone Casemix Grouper. The end users can now focus only on generating the input file and will receive output file without extra effort. This usage of web application of Casemix Grouper software will facilitate the provision of efficient and quality care in hospitals and medical centres."}
+{"text": "When it comes to prevalidation, it is assumed that a higher preoperative level of physical activity leads to better postoperative recovery. However current literature is inconclusive about the effect of prevalidation on functional recovery of patients with primary osteoarthritis (OA) who underwent a THA or TKA. Therefore the aim of this study is to analyse one of the major assumptions underlying the potential effectiveness of prevalidation namely the relationship between preoperative physical activity level and postoperative recovery one year after THA or TKA in a group of 658 OA patients.From 2006 to 2012, 1061 patients underwent a primary THA or TKA at University Medical Center Groningen. Preoperative and one-year postoperative patients filled in the SQUASH questionnaire to get an impression of their physical activity level, and the WOMAC questionnaire to obtain insight into degree of recovery. Missing data were multiply imputed. No relationship was found between the preoperative total  and leisure-time physical activity level  neither for preoperative compliance with the Dutch Recommendation for Health-Enhancing Physical Activity , and the degree of recovery one year after surgery.The preoperative physical activity level had no relation with the degree of recovery one year after THA or TKA. The results do not support one of the major assumptions behind prevalidation, which assumes that a higher preoperative physical activity level will lead to a better recovery after THA or TKA. Based on the Dutch GP registries, osteoarthritis (OA) is the most common progressive disorder of the musculoskeletal system It is hypothesized that the amount of preoperative physical activity and thus the fitness level can have a positive effect on the postoperative recovery of patients undergoing THA or TKA. This assumption is based on the fact that physical activity, fitness and health are mutually influencing factors Objective of this study is to analyze one of the major assumptions underlying the potential effectiveness of prevalidation namely that the amount of preoperative physical activity and consequently the fitness level has a positive effect on the postoperative recovery of patients undergoing THA or TKA. Insight into this relationship can strengthen or weaken the arguments for using prevalidation as a tool to improve postoperative recovery. The main question in this research is: Is there a connection between preoperative physical activity level and degree of recovery one year after THA or TKA in patients with OA?This research question is divided into three sub-questions:Is there a connection between the preoperative total physical activity level and the degree of recovery one year after THA or TKA?Is there a connection between the preoperative level of leisure-time physical activity and the degree of recovery one year after THA or TKA?Is there a connection between preoperatively meeting the Dutch Recommendation for Health-Enhancing Physical Activity and the degree of recovery one year after THA or TKA?A retrospective cohort study of prospectively collected data was conducted. Patients were asked to fill in the SQUASH and WOMAC questionnaires preoperatively and one year postoperatively. Completion of the questionnaire was taken as consent to participate. The Ethics Committee of University Medical Center Groningen approved this study (METc 2013/259).All patients that underwent a primary THA or TKA at University Medical Center Groningen between 2006 and 2012 were included. Patients who got a THA or TKA because of primary OA and had no operation within the following year after surgery were included in this study.Level of physical activity and meeting the Dutch Recommendation for Health-Enhancing Physical Activity (NNGB) were measured with the SQUASH questionnaire Degree of recovery was measured with the WOMAC questionnaire. The WOMAC is a self-reported questionnaire that measures OA-caused constraints experienced by the patient in function and degree of pain and stiffness when performing daily activities. The total score is reproduced on a 100-point scale, where a higher score represents a lesser degree of perceived restriction in daily activities. The Dutch version of the WOMAC questionnaire is considered reliable and valid Statistical analyses were performed with SPSS20. Descriptive statistics were used to describe the main characteristics. Univariate linear regression analysis was performed to answer the research questions. A second forward stepwise linear regression analysis was performed, adjusted for several potential confounders: type of surgery (THA or TKA), sex, BMI, ASA class and age of the patient at the time of surgery. A p-value of <0.05 was considered statistically significant.From the 1061 patients who had undergone a primary THA or TKA, 658 were included (see The mean age was 68 years (SD 10.6), with more women than men (32%) and more THA than TKA (36%). The majority had finished a form of lower (22%) or secondary (50%) education see . One yeaThere was no significant connection between the total preoperative physical activity level and the degree of recovery one year after surgery , even after adjustment for confounders see .There was no significant connection between the leisure-time preoperative physical activity level and the degree of recovery one year after surgery either , even after adjustment for confounders see .No significant connection was found between preoperatively meeting the NNGB and the degree of recovery one year after surgery , even after adjustment for confounders see .The basis for this study is the lack of understanding of the connection between preoperative physical activity level and degree of recovery after THA or TKA. Available studies report conflicting results The results of this study are in accordance with recent reviews on the link between prevalidation and degree of recovery after THA or TKA A strength of this study is the relatively large group of 658 patients who had undergone THA or TKA. Because all THA and TKA patients in the registries of UMCG are included, no selection bias occurred. In many studies on the effect of prevalidation a relatively large number of patients drop out during the study. Rooks et al. Overall it can be concluded that in this study preoperative physical activity level is not related to the degree of recovery one year after THA or TKA in patients with primary OA. It must however be taken into consideration that in this study the level of recovery was measured at one single moment, namely one year postoperatively. Patients are generally considered to have completely recovered one year after THA or TKA, yet this offers no insight into the connection between preoperative physical activity level and speed of recovery. Whitney et al. S1 DataMultiple imputed dataset.(SAV)Click here for additional data file."}
+{"text": "The magnitude of the neural activation, and hence the force produced by a muscle, depend on the number of motor units activated (recruitment) and the rates at which motor neurons discharge action potentials (rate coding). Although the recruitment order of motor units (size principle) is similar for contractions during which the force is gradually increased (ramp contraction) and those during which the force is produced as fast as possible . An alternative way is to produce force as fast as possible but to relax the muscle immediately after the target force is reached. Such impulse-like contractions have been termed Desmedt and Godaux  were theThe discharge characteristics of single motor units during ballistic contractions can be modulated by the conditions under which the action is performed. For example, it has been observed that when a ballistic contraction with the ankle dorsiflexors was superimposed on a submaximal isometric contraction , the average discharge rate for the first three interspike intervals was significantly reduced by 22%  compared with ballistic contractions performed from a resting state  than in young adults (~20 year) (Klass et al., To further analyse the effect of a change in discharge rate on the maximal rate of force development, isometric force produced by single motor units was simulated from a model that contains a pool of 200 units (Fuglevand et al., Together, experimental and simulated data indicate that a high initial motor unit discharge rate at the onset of a fast contraction plays a critical role to reach a high rate of force development. Furthermore, and because the instantaneous discharge rates of motor units at the onset of ballistic contractions are much greater than those recorded during slow contractions and not yet influenced by history-dependent effects, ballistic contractions from a resting state can be used to assess the maximal motor neuron discharge rate in human. Nonetheless, as the acquisition of a simple motor task such as index finger abduction requires up to ~300 repetitions to reach maximal acceleration capability (Lee et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "This study aims to explore a unique resource of weight and health data for further studies on effects of body weight and body condition score on developmental degenerative and metabolic diseases in dogs.Our study-data on weight at 12 months of age for more than 100,000 dogs of various breeds from the dog database at the Swedish Kennel Club (SKK) have enabled us to:\u2013 provide a reference for further studies by characterizing distribution of adult body weights in various breeds, also stratified by other factors, e.g. sex.\u2013 explore how weight influences hip and elbow status recorded in the same database.\u2013 investigate how to combine these data with recording of body condition score and to merge them with diagnostic information as insurance claim data.There is a wide range of body weights within all analyzed breeds as well as between the sexes within breeds. There is a pronounced correspondence between body weight at 12 months of age and radiological status of hips and elbows. It is also possible to include body condition score in further analyses and also to merge the data with anonymized information from an insurance claim database.We showed that the available body weight data are well-suited for further studies on the role and effects of both weight and body condition score in various diseases in dogs."}
+{"text": "A binge eating episode is defined as an uncontrolled event of hyperphagia, in which people quickly eat a large amount of food while feeling a sense of loss of control over eating  pellet for 2 h  plays an essential role in the regulation of eating as it is highly sensitive to peripheral signal molecules of energy status , which project to the nucleus accumbens (NAc) in the ventral striatum and other areas such as the amygdala, medial prefrontal cortex, hippocampus, and hypothalamus Kenny, . The VTAThe homeostatic and hedonic circuits regulating eating are presumably integrated in the lateral hypothalamic area. This area contains orexin neurons highly innervated by hypothalamic and mesolimbic circuits that project widely within the brain (Schwartz and Zeltser, Clinical reports stress the complexity of assessing if an event of hyperphagia is actually a binge eating episode in humans (Wolfe et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "This text describes the process of development of the new Spanish Prehospital Advanced Triage Method (META) and explain its main features and contribution to prehospital triage systems in mass casualty incidents. The triage META is based in the Advanced Trauma Life Support (ATLS) protocols, patient\u2019s anatomical injuries and mechanism of injury. It is a triage method with four stages including early identification of patients with severe trauma that would benefit from a rapid evacuation to a surgical facility and introduces a new patient flow by-passing the advanced medical post to improve evacuation. The stages of triage META are: I) Stabilization triage that classifies patients according to severity to set priorities for initial emergency treatment; II) Identifying patients requiring urgent surgical treatment, this is done at the same time than stage I and creates a new flow of patients with high priority for evacuation; III) Implementation of Advanced Trauma Life Support protocols to patients previously classified according to stablished priority; and IV) Evacuation triage, stablishing evacuation priorities in case of lacks of appropriate transport resources. The triage META is to be applied only by prehospital providers with advanced knowledge and training in advanced trauma life support care and has been designed to be implemented as prehospital procedure in mass casualty incidents (MCI). Mass casualty incidents (MCI) are defined by World Health Organization as events which generate more patients at one time than locally available resources can manage using routine procedures . A recenMost of these triage methods are based in basic life support techniques and have been designed to be applied by rescue teams and firemen . The speModelo Extrahospitalario de Triage Avanzado) as well as its main features and field operating mode in a mass casualty incident. It should be noted that META is a method of advanced triage type to be used only by advanced prehospital providers with adequate training and education in advanced trauma life support protocols and techniques.The aim of this paper is to present the development process and design of the Spanish prehospital advanced triage method  during a MCI.During the second phase of the study the degree of perceived usefulness and feasibility of use in the setting of an MCI were analyzed for each of the selected parameters by a sample of health professionals of the Spanish healthcare system. To do this a survey was designed for doctors and nurses working in hospital emergency departments and prehospital emergency care systems in which they were asked to evaluate three dimensions for each parameter: (i) Ability to predict the patient\u2019s vital risk, (ii) Ability to prioritize patient evacuation and (iii) Feasibility of use of the parameter in the prehospital setting in case of MCI. To assess the relevance of each parameter a numerical scale from one (irrelevant) to ten (maximum relevance) was used in each of the three dimensions.Once studied the degree of perceived usefulness and feasibility of use of each parameter during the third phase of the study, a wide panel of experts from different backgrounds  finally decided the parameters to be included in the triage method and sequence of application of each parameter during the triage process.anatomical type parameters, 19 were physiological type parameters, nine were parameters related to the kind of injury and nine were related to other conditions or circumstances of the victim or the MCI different of those already mentioned. Forty-five parameters were identified in literature review as potentially usable in an MCI advanced triage method. Eight out of those 45 identified parameters were p <0.05) for potential inclusion in the META. Table\u00a0Seventeen out of the 45 parameters studied were found to be significantly relevant 3).Fig. 3Identification of need of urgent surgical care. The aim of this stage (applied at the same time as first stage) is to identify patients who do not benefit of complex prehospital care and needs rapid transport to a surgical facility. This creates a new flow of patients that will by-pass advanced medical post and will be directed to evacuation area with a minimum acceptable care. For these purpose we used the Guidelines for field triage of injured patients developed in 2011 by the National Expert Panel of Field Triage . These rAdvanced Trauma Life Support. All patients, once classified will be treated following advanced trauma life support protocols . Red patEvacuation triage. Once we have treated out of hospital emergencies on the field, we have to decide, in a scarced resources situation, which patient needs to be evacuated first. The first ones will be those with urgent surgical care need that have not been detected prior to evacuation. Then, we have define a new cathegory as \u201chight priority criteria\u201d for those who have severe injury with haemodynamic or respiratory instability and one of these: systolic blood pressure under 110\u00a0mmHg , motor GMETA triage is to be implemented during the medical prehospital response to an MCI and has four stages: 1) Stabilization triage, 2) Identification of need of urgent surgical care, 3) Advanced trauma life support techniques and 4) Evacuation triage (Fig.\u00a0The selection of the variables identified as potentially be incorporated to an advanced triage method is based primarily on well-known aspects of the clinical approach to prehospital treatment of patients with severe trauma, as well as in physiological, and anatomical aspects and the mechanism of injury. Once evaluated by doctors and nurses, parameters with higher scores are those related to physiological aspects. We decided to design a method based in the ATLS protocol but with an anatomical component that creates a new high priority category for those patients that benefit from rapid transport to a surgical facility.This new model of triage would be useful specially for EMS staffed by doctors or nurses, but also for EMS based in paramedics with an advanced education, knowledge and skills in the management of patients with acute severe trauma. Most of the well known triage methods do not fulfil the principles of the advanced trauma life support. In the above triage methods , for exaIn a MCI with overwhelmed healthcare resources the flow of patients at different stages of the medical response is often slow. This means that patient transportation may be delayed and for some patients this could be life threatening . This isOnce a patient is treated or stabilized should go to the evacuation point. In this point we go to stage four for evacuation triage. This last triage allows us to use available transport resources in the best possible way. In case of lack of transport resources patients classified as red have the highest priority for evacuation. These \u201chigh priority criteria\u201d allows us to distinguish different priorities among patients classified as red and are based in a combination of clinical elements and injury mechanisms in order to improve evacuation of severe patients. This new method of advanced triage is highly adaptable to future scientific findings related to prehospital care and organization of MCI.One of the strengths of triage META is that has been developed taking into account the perception of emergency services staff on the factors to be considered in a method of triage and this is an important aspect that influences the success in implementation in daily work. Also the varied background of the expert panel has made possible a broad discussion on the different aspects and perceptions of the management of trauma care in the prehospital heathcare of MCI. Triage research has many limitations and is very difficult to fulfil the best evidence recommendations . Our metTriage META is a model of advanced prehospital triage and is a tool to be used by doctors and nurses trained as providers of advanced trauma life support, but also by paramedics with advanced education, knowledge and skills in management of patients with severe acute trauma. It can be implemented into MCI procedures and one of the main contributions is the early detection of severe surgical patients that benefit from rapid transport to a surgical facility. This mean that two flows of patients are needed in order to avoid delays of transport in these patients.Anatomical ParamethersAmputation proximal to the wrist or ankleTear or crushing of limbsOpen or depressed skull fracturePelvic fractureProximal fractures of two or more long bonesPenetrating woundContused woundFlail chestPhysiological paramethersHeart RateRespiratory ratePrehospital intubationLevel of consciousnessParalysisCarotid PulseRadial pulseVentilationAirway obstructionOxygen saturationSystolic blood pressureStaringPediatric Evaluation TriangleSpotted, pallor or cyanosis of the skinRespiratory distressStridor, grunting or breathing soundSpeech disorder or cryingFlaring nostrilsInteractivityMechanism of injuryKnive njuryFirearmOutrageFallRescue time more than 20 minutesEjected from vehiclePresence of a died person in the same vehicleVehicle IntrusionMotorbike accidentOthersMedical CriteriaOvertriage if case of doubt regarding severity of the patientAge under 15 or over 55Pregnant more tan 20 weeksSevere kidney diseaseLimb injury time dependantBurnsSexHaemostatiuc disorder or anticoagulants treatment"}
+{"text": "Metabolic flux comprises the ultimate phenotypic readout of cell physiology, and it shifts toward anabolic or catabolic regimes in conjunction with the proliferative state of the cell. Many parallels exist between the metabolic profiles of normal dividing cells and cancer cells, for which uncontrolled proliferation is a hallmark. Much effort in the field of cancer metabolism has been directed toward identifying these similarities to target how tumors use biochemical resources for growth and survival.Many studies have approached this question by experimentally identifying major metabolic changes that become induced in response to expression of oncogenes or inactivation of tumor suppressor genes; however, in these circumstances, the generality of these changes beyond the system under consideration may be unknown. Other avenues have employed genome-scale models of tumor metabolism to determine enzymes through which flux is upregulated when biomass production is maximized, but the size of these networks limits routine analysis.All major components of macromolecules may be derived from a small set of central metabolites that originate from well-known metabolic pathways, and as a result, it is possible to determine the rates at which these precursors must be consumed to maintain a particular growth rate. We have therefore employed a method to reduce experimentally measured biomass components to this set of precursor metabolites to better understand the effects of growth on metabolism in mammalian cells. Our strategy enables generalization of biosynthetic demands in a manner that is not specific for any particular oncogenic genotype while using a limited biochemical currency that enables elementary calculations and predictions."}
+{"text": "Cold water immersion is a severe challenge for humans. Mathematical modelling of human thermoregulatory responses is an alternative approach to study cooling in water. Preliminary modelling prediction can be a useful tool for preventive steps that will help to decrease or even to avoid health hazard . The purThe complexity of multi-compartmental models for human thermoregulation is realised as Information Technology (IT) in Borland C++ Builder 2010 [Modelling Figure  showed tModelling showed that evaluation of the safe time of human immersion in cold water depends on what part of body is immersed. Head out of water has principal effect on core cooling rate . ModelliModelling prediction showed that thermoregulatory system is high sensitive to the immersion level of human in cold water. Surface out of water increases safe time of immersion. But head submersion has priority effect on core cooling. The results, when validated in all ranges, can be used for planning of rescue operations and development of protective clothing."}
+{"text": "Systems Biology & Systems Medicine represent those emerging sciences. The development of the \u201cVirtual Patient Avatar\u201d will change conventional medicine into \"predictive medicine\" that will have the capacity to develop solutions based upon understanding of the dynamic mechanisms and the quantitative logic of human physiology. Drug discovery and clinical trials in silico will improve the development of products with higher efficiency and safety while reducing cost. Thus strategy must occur in the European Union to bridge the gap between academic and industry in the following ways:The integration of molecular sciences and computational sciences is moving the world towards a new generation of life science where physiological information from the human can be quantitatively described \u2022 Validate and publish medical informatics data and technology models to accepted standards in order to facilitate adoption,\u2022 Transform electronic health records to make them more accessible and interoperable,\u2022 Encourage information sharing, engage regulatory agencies, and\u2022 Encourage increasing financial support to grow and develop translational biomedical informatics."}
+{"text": "It is believed that in many cases Food allergy (FA) develops due to the contact of the immune system with different allergens through affected skin and mucous barriers. Studies of the filaggrin mutations in atopic dermatitis showed informativity of the transepidermal water lost measurement (TEWL) in assessment of the skin barrier condition. Faecal calprotectin is marker of the inflammation that can be helpful in understand of the GIT mucous condition.To investigate a possible relationship between the TEWL and stool calprotectin level as markers of the barrier's deficiency with severity of the FA and treatment response.80 patients with skin symptoms of food allergy of different severity were under study. TEWL level, faecal calprotectin level were measured to identify the presence of the skin and mucous barrier's deficiency in children and it's change under treatment.High TEWL was associated with a more severe disease course and a poor response to treatment with antihistamines than in patients with less TEWL . Faecal calprotectin was elevated in 35/80 patients (43.7%) and was found to be significantly higher in patients with more severe FA symptoms (P<.05). Not all patients with positive stool marker (45.7% 16/35) noticed unsteady stool in anamnesis. In addition, the most effective influence on the severity of the TEWL had topical treatment with emollients, than oral intake of the antihistamines .TEWL and faecal calprotectin level measurement are simple and informative tests for FA course assess. Patients with FA and deficiency in skin and mucous barrier experience a more severe course of the disease and show a poor response to treatment with antihistamines. In this case it was proposed to use TEWL and faecal calprotectin level measurement as additional tests to reveal and predict possible ways of the further Atopic March in children. Topical treatment with emollients is more effective than oral intake of the antihistamines."}
+{"text": "In literature, the most effective timing for intercepting skeletal malocclusion is still widely debated. The aim of this study was to analyze the main orthodontic and occlusal problems needing correction in growing patients.Crossbite, open bite and Class III malocclusion were observed and compared each one with their own control groups with the same age and dentoskeletal characteristics. The statistical comparisons between the test and control groups were performed with independent sample t tests and chi-square tests (P <.05).The presence of posterior crossbite was significantly greater in growing subjects with oral breathing thus confirming the influence of these factors on skeletal development with constriction of the whole palate. Unilateral posterior crossbite is often associated with mandibular lateral displacement that is clinically characterized by deviation of the chin, facial asymmetry, dental midline discrepancy, and high prevalence of internal derangement of the temporomandibular joint. Children with anterior openbite presented with a greater prevalence rate of sucking habits. Hyperdivergency is a risk factors for negative overbite in mixed dentition subjects. The test group had significantly smaller maxillary intermolar and intercanine widths and greater posterior transverse discrepancy. Class III malocclusion is a complex clinical entity that entail the contraction of the maxilla and a narrowing of the base of the nose in addition to an increased mandibular total length.Treatment of orthodontic problems that do not improve with age may be started earlier to avoid worsening of the condition in permanent dentition. The objective of any treatment in pediatric subjects before eruption of all permanent teeth are to correct the skeletal discrepancy between the jaws and improve function and facial esthetics by allowing them to develop normally, to create an ideal overbite and overjet relationship, to align the anterior permanent teeth and reduce the chance of trauma to these teeth, to improve the width of the dental arches and to reduce the risk for extraction of permanent teeth and for surgery in severe cases.Morphologic and functional characteristics of unilateral posterior crossbite with mandibular lateral deviation should be clarified to correct and prevent this malocclusion. Children with mouth-breathing pattern and sucking habits showed a significant constriction of the maxillary arch and an increased palatal height when compared with control group. Early treatment of Class III malocclusion is able to produce significant and favorable long-term skeletal shape changes characterized by an anterior morphogenetic rotation of the mandible."}
+{"text": "Pilot and feasibility studies underpin much of current health related research, including randomised controlled trials. The number of reports in which authors describe their studies as pilot or feasibility studies is increasing and there is currently a lot of interest in this area. However, in spite of a number of papers that have recommended ways in which the reporting of these studies could be improved, reporting remains poor.Using CONSORT endorsed methodology including a large Delphi study (n=93) and an international consensus meeting (n=26) we have developed a CONSORT extension for randomised pilot and feasibility studies. Much of the existing CONSORT statement for randomised controlled trials does apply to these types of study. However, sometimes the application of the items is different from that in RCTs designed to evaluate the effect of an intervention or therapy and some CONSORT items are not applicable or have needed some alteration.We are currently writing the explanation and elaboration statement for this CONSORT extension. We will present the major issues in reporting these types of randomised studies and use examples to illustrate good and bad practice. This work is part of a larger programme of work on pilot and feasibility studies."}
+{"text": "Life course socioeconomic inequalities in heart disease, stroke and all-cause mortality are well studied in Sweden. However, few studies have sought to explain the mechanism for such associations mainly due to lack of longitudinal data with multiple measures of socioeconomic status (SES) across the life course. Given the population health concern about how socioeconomic inequality is related to poorer health, we aim to tackle obesity as one of the prime suspects that could explain the association between SES inequality and cardiovascular disease and consequently premature death. The aim of this study is to test which life course model best describes the association between socioeconomic disadvantage and obesity among 60 year old inhabitants of V\u00e4sterbotten County in Northern Sweden.t-test was used to compare BMI between advantaged and disadvantaged groups and one-way ANOVA was used to compare BMI among eight SES trajectories. We applied a structured modeling approach to examine three different hypothesized life course SES models  in relation to BMI.A birth cohort consisting of 3340 individuals born between 1930 and 1932 was studied. Body mass index (BMI) at the age of 60 and information on socioeconomic status at three stages of life  was collected. Independent samples We found sex differences in the way that late adulthood socioeconomic disadvantage is associated with BMI among inhabitants of Northern Sweden. Our study suggests that social adversity in all stages of late adulthood is a particularly important indicator for addressing the social gradients in BMI among women in Northern Sweden and that unhealthy behaviors in terms of smoking and physical inactivity are insufficient to explain the relationships between social and lifestyle inequalities and BMI.In order for local authorities to develop informed preventive efforts, we suggest further research to identify modifiable risk factors across the life course which could explain this health inequality. It is well-established that obesity is a major risk factor for mortality and morbidity and is on the rise globally . This toWhile the evidence for the contribution of life course SES to the development of weight change or obesity is generally strong , it remaThere has been a burgeoning literature in recent decades on the association between socioeconomic factors and total mortality and CVD risk factors in life course analysis using multiple measurements ,8. This Socioeconomic differences in mortality are well documented in most European countries including Sweden . People accumulation of risk model, the critical period model and the social mobility model. The most prominent model in the current literature is the accumulation of risk model, which assumes that cumulative adverse exposures during the life course increases the risk of CVD risk factors irrespective of the timing , as well as downward (D) adult SES mobility .The social mobility models (\u2018Late life mobility\u2019 and \u2018Any mobility\u2019) showed particularly poor fits as they were significantly different from the saturated model . The general social mobility model assumes that all downward changes are equally harmful to health and that all upward changes are equally beneficial . This meWe note that smoking and physical activity are only two lifestyle aspects that are included in the analysis. Unfortunately, data on energy intake and food habits was unavailable. Even though we used a validated instrument to measure physical activity, it would be more accurate if it were not self-reported. Unhealthy behaviors including lack of physical activity  and smokOur study suggests that social adversity at all stages of late adulthood is a particularly important indicator for addressing the social gradients in body mass index among women in Northern Sweden and that unhealthy behaviors in terms of smoking and physical inactivity are insufficient to explain such association. In order for local authorities to develop informed preventive efforts, we suggest further research to identify modifiable risk factors across the late adulthood which could explain this health inequality. Our results suggest that efforts should be concentrated on reducing the social inequality that is associated with obesity in women in mid-adulthood and that such efforts should not be limited to targeting unhealthy behaviors.The authors declare that they have no competing interests.MN and MP participated in the design of the study. MP performed the statistical analysis and drafted the manuscript. Both authors read and approved the final manuscript."}
+{"text": "This pictorial series illustrates four cases with interesting imaging presentations of some unusual primary and secondary breast malignancies and aims to exemplify the range of appearances of malignancy and stimulate discussion of atypical differential diagnoses in appropriate cases.We present a pictorial series of four patients with unusual breast pathology who initially presented to the triple assessment breast clinic in a tertiary university institution. For each case the imaging features and final diagnoses are critically appraised, along with a review of the literature. We illustrate a case reminiscent of bilateral invasive ductal carcinoma which, after further histological immune profiling, is confirmed to be the first presentation of a metastatic lung cancer. A sarcomatoid carcinoma presents as a densely calcified well-defined lesion on mammography accompanying a synchronous invasive ductal carcinoma and could initially have been seen as benign. We present the imaging features of a fibroadenoma which interestingly was shown to contain DCIS. We also highlight the appearances of a recurrent pleomorphic invasive lobular carcinoma within latissimusdorsi muscle following mastectomy and reconstruction.Interesting and unusual differentials for malignant breast lesions are presented pictorially with an emphasis on the initial presentation and imaging findings. It is hoped that this will both educate and stimulate discussion of differential diagnoses in the breast imaging setting."}
+{"text": "Dental professionals have not fully embraced opportunities for tobacco intervention. The aim of my presentation is to suggest new strategy of curriculum to enhance smoking cessation intervention based on the novel findings that may useful under the universal health insurance system in Japan.Reviewed literatures regarding tobacco interventions by dental professionals and recent studies regarding oral microbiology, and surveyed dentists and dental patients to clarify the possibility of our strategy.The literature review regarding progression of the global dental tobacco interventions identified significant barriers such as lack of reimbursement and training for implementation to dental practice and dissemination and undergraduate education. Recent findings regarding the effects of smoking cessation on oral biofilms and those of tobacco extracts on virulence factor of periodontal pathogens would break the ice to enforce dental tobacco intervention in Japan. The studies that was conducted in dental clinics revealed that tobacco intervention for prevention of progression of dental disease and improvement of the effects of dental treatments that have potential coverage of the universal health insurance system in Japan were strongly supported by dentists while intervention services for prevention of oral diseases was strongly supported by dental patients.Education for dental students regarding tobacco intervention based on the effects on dental treatments would be promising strategy that reinforces those for oral and overall health in Japan."}
+{"text": "While dissemination and implementation (DI) science has become a clear area of research focus with associated methodologies, grant programs, journals, and training programs, these are relatively recent developments which have created a gap in training and career development. Many large institutions with major research programs have some investigators who are carrying out DI research but these tend to be limited and many investigators whose work has relevance to the field are not trained adequately to take advantage of existing grant mechanisms. The University of Pennsylvania has taken the strategy of creating the Implementation Science Working Group (ISWG) with the goal of providing an opportunity for idea development, feedback, grant review, and review of key methodologic approaches and conceptual frameworks for the field. A key element of the ISWG has been to support pilot studies by faculty from across the university which focus on DI topics and which have potential for translation into NIH grant applications. In this presentation, we discuss current efforts of the Penn ISWG as an exemplar for other institutions, and present examples of pilot grant receipts who have received funding to conduct DI related work within the context of the university efforts to support DI capacity."}
+{"text": "The significance of arterial lesions in IgAN patients has not been investigated well and characteristics of renal vessels in this disease not been studied separately. More investigations is necessary to found the clinical significance of thrombotic microangiopathy in IgAN.et al. in a study on a group of IgAN patients found 53% patients had morphologic lesions of TMA  have been completely observed by the authors.None."}
+{"text": "Chronic inflammation in well-defined mouse models such as Gi\u03b12 knock out mouse has been shown to trigger formation and expansion of hypoxic niches and also leads to up regulation of NF\u0138B, offering cells which have adapted their genetic machinery to hypoxia a unique survival advantage. These adapted cells have been shown to acquire stem cell-like capabilities as shown by up regulation of stem cell markers. Such long lived cells become permanent residents in sub mucosa and acquire a malignant phenotype from long-term exposure to noxious environmental agents due to a barrier defect secondary to down regulation of barrier proteins such as Zo1 and Occludin. Indeed mitotic spindle disorientation in such mice has been proposed as another contributory factor to malignant transformation. Sterilization of bowel lumen of these mice through different techniques has prevented malignant transformation in the presence of chronic inflammation. These facts stand strongly against chronic inflammation as a true driver of carcinogenesis but clearly support its role in facilitating the emergence of the neoplastic clone. The malignant transformation as per the free energy concept necessitates a significant and permanent decrease in the free energy of the malignant cell as a result of breakdown of the fine balance of cellular energetics. WarburgThere are many examples in which chronic inflammation is associated with carcinogenesis. However in none of them there is solid proof of a driver role for chronic inflammation,7. In caViruses can directly induce malignancy by down-regulating tumor suppressor genes such as TP53 and Rb. Through this mechanism papilloma virus promotes the pathogenesis of malignancies such as squamous cell carcinoma of cervix and head and neck. The lisV617FJAK2 mutation in a hematopoietic stem cell is seen in the majority of patients with MPN. V617FJAK2 confers upon hematopoietic progenitors resistance to the suppressive actions of TNF. An environment with high levels of inflammatory cytokines (such as TNF) selects for cells which have mutated in such a way to avoid these suppressive cues (such as the V617FJAK2 neoplastic clone). The V617FJAK2 mutant clone then expands and leads to unrestrained expansion of mature myeloid cells. The V617FJAK2 neoplastic clone in MPN likely also induces an inflammatory state which further enhances its selective advantage. This inflammatory response elicited by the V617FJAK2 clone may also be required for clinical manifestations of the disease. Clones with leukemia-associated mutations (such as V617FJAK2) can be detected in a few percent of normal aged individuals[There is also evidence that chronic inflammation facilitates clonal evolution in myeloproliferative neoplasm (MPN), a chronic hematologic malignancy. Chronic inflammation is a characteristic feature of MPN and has been implicated as the cause of many of the debilitating symptoms associated with this disease. Emerging evidence suggests that inflammation may play a more central role in disease initiation and maintenance of the neoplastic clone16. Somatic acquisition of a There is evidence supporting inflammation as a tumor growth promoting but not initiating factor. One example is infiltration of glioma associated macrophage/microglia (MG). In CNS inflammation, MG have been shown to be capable of presenting antigens and activating T cells, thus playing a direct role in modulating brain inflammation. A signiOne could arbitrarily categorize malignant disorders into two major groups. The first group would be those malignancies that are driven down an inflammatory path, such as the examples mentioned above. The second group would be those malignant disorders that are driven down the non-inflammatory path, such as certain well defined syndromes including Li-Fraumini and Lynch syndrome, classical lung, breast and colon cancer among many others.Free energy was first described by the American engineer Willard Gibbs in 1873 as the amount of energy available to do non-volume increasing work in a system with constant temperature and pressure and that inversely correlates with the amount of entropy of that system on thermodynamics arrow of time.Biological systems including a living cell are well known for their unique capability to keep entropy at the lowest possible level dictated by the limits of the second law of thermodynamics. The breakdown of this fine balance which is the distinguishing hallmark of malignant disorders could be envisioned as the universal driving force capable of driving down both inflammatory and non-inflammatory roads of malignant transformation. The fine balance of the cellular energetics under normal condition is governing a broad spectrum of fundamental biological events extending from epigenome to Micro RNA network and incorporating dynamics of mitosis and homeostasis of cell cycle kinetics to DNA damage response and gene regulatory mechanisms,27. EvenInterestingly enough even the contemporary literature has started to appreciate the interplay of metabolomics and inflammation. LiteratAccording to the universal free energy concept normal inflammatory cells with normal metabolism and energetics get attracted to the tumor sites comprised of a significant number of cells with significantly lower free energy/lower in situ vibratory motion. This atAlthough chronic inflammation has been noticed and reported for a long time by many different observers both in the vicinity of malignant cells and at the premalignant lesions of a wide range of malignant disorders both of hematological and solid subtypes, assigning a driver role to chronic inflammation has faced insurmountable technical as well as evidence based barriers.CCL2 expression on the surface of glioma cells which attracts macrophages to the tumor site, with its ensuing activation of other components of immune system through secretion of humoral factors on one end and eradication of inflammation without any observable effect on tumor growth and progression on the other end, are among the examples that take away the designation of driver role from chronic inflammation in inflammation associated malignancies.Available evidence supports a promoting role for chronic inflammation following malignant transformation. Interestingly enough at times the malignant cell itself is the source of chemokines which attract the inflammatory cell to tumor site as mentioned above. Finally In other tumor types the malignant cells take advantage of the nurturing microenvironment of the immune system organ, namely lymph nodes before progressing into advanced stages. Melanoma and breast carcinoma are among such malignancies.The modern generation of immunotherapy, including CTLA4 and PD-1 antagonists, has enabled us to make clinical achievements and prolong the life of patients with metastatic melanoma.However the toxicities associated with these treatment modalities which originate in reacting against the self-antigens at times have proven prohibitive. The key question is if the immune system can recognize the difference between the energetics of the tumor cell and normal cell, why is it so incapable of destroying tumor cells and in addition why does it contribute to promotion and progression of malignant phenotype?The answer to this question might reside in the exceptional capability of the tumor cell to also change the energetics of the infiltrating immune cells in favor of a low free energy state which would disable these cells as a result of modification of the quaternary structure of its constituent functional proteins under low free energy condition, in addition to taking advantage of their growth promoting humoral factors. A new wave of improved understanding and design of delicate measurement devices of cellular energetics and the ability to reverse those differences offers hope for future cancer therapeutics modalities. Indeed even today we are witnessing a crude, however rewarding attempt at physical rather than chemical cancer therapy by alternating electrical fields in the treatment of recurrent Glioblastoma multiforme, called NovoTTF-100A system which has been misunderstood as only a change in electrical field of cancer cell without appreciating the induced transient increase in free energy of the cancer cell,33."}
+{"text": "Dear Editor,Chronic patellar tendinopathy is a common clinical condition that is managed by physical therapists and is common among athletes and non-athletes alike. Patellar tendinopathy is characterized by the absence of inflammatory cells and prostaglandins and an increased presence of fibroblasts and disorganized collagen . Therefo"}
+{"text": "The study proves that simple image and depth sensors can be used to efficiently record biomedical multidimensional data with sufficient accuracy to detect selected biomedical features using specific methods of computational intelligence. The achieved accuracy for non-contact detection of breathing rate was 0.26% and the accuracy of heart rate estimation was 1.47% for the infrared sensor. The following results show how video frames with depth data can be used to differentiate different kinds of breathing. The proposed method enables us to obtain and analyse data for diagnostic purposes in the home environment or during physical activities, enabling efficient human\u2013machine interaction.This paper is devoted to a new method of using Microsoft (MS) Kinect sensors for non-contact monitoring of breathing and heart rate estimation to detect possible medical and neurological disorders. Video sequences of facial features and thorax movements are recorded by MS Kinect image, depth and infrared sensors to enable their time analysis in selected regions of interest. The proposed methodology includes the use of computational methods and functional transforms for data selection, as well as their denoising, spectral analysis and visualization, in order to determine specific biomedical features. The results that were obtained verify the correspondence between the evaluation of the breathing frequency that was obtained from the image and infrared data of the mouth area and from the thorax movement that was recorded by the depth sensor. Spectral analysis of the time evolution of the mouth area video frames was also used for heart rate estimation. Results estimated from the image and infrared data of the mouth area were compared with those obtained by contact measurements by Garmin sensors ( Recently developed computational technologies enable the use of non-contact and non-invasive systems for monitoring breathing features, detecting heart rate changes and analysing facial features as important diagnostic tools for studying neurological and sleep disorders, assessing stress and evaluating fitness level ,5,6,7,8.Complex monitoring of selected biomedical features can be based on processing of data  recordedThe present paper is devoted to (i) the description of methodology for breathing and heart rate monitoring based on image, depth and infrared video sequences acquired by MS Kinect in the face and chest area; (ii) the visualization of the obtained data; and (iii) the comparison of biomedical features evaluated from data recorded by non-contact image and depth sensors.The proposed methodology assumes the use of digital filtering methods for data noise component rejection, resampling, data fusion and spectral analysis for detecting the required biomedical features. Specific statistical methods ,31 are aThe paper provides motivation for further studies of methods related to big data processing problems, dimensionality reduction, principal component analysis and parallel signal processing to increase the speed, accuracy and reliability of the results. Methods related to motion recognition can be further used in multichannel biomedical data processing for the detection of neurological disorders, for facial and movement analysis during rehabilitation and for motion monitoring in assisted living homes ,33,34. FThe sequence of separate images was recorded with associated time stamps indicating the video frame rate changing from 7 to 15 fps. Image resolution was 1920 by 1080 pixels while the depth and infrared camera resolution was 512 by 424 pixels. The video camera allowed following colour image components with selected results recorded at the mouth area of the individual as presented in Simple tests were limited by the data size that was obtained. By scaling the image data by a factor of 0.4, the 120 s record of data from the image, depth and infrared sensors occupy 1.2 GB of hard disk space. The overnight record of sleep activities requires about 250 GB of disk space and is dependent on the frame rate and resolution; specific methods of big data processing should be applied to reduce the evaluation time.Time stamps recorded with each video frame allowed resampling of the video sequence ,41 to a uisition .R rows and S columns that covered either the mouth or the chest area of the individual. For each matrix n, the mean values were evaluated by the following equation:The sequences of image and depth maps that were acquired by the MS Kinect were analysed over the selected rectangular area of N. To optimize the final algorithm, the resampling mentioned above was applied to this sequence only and not to the complete image frame in this case.In this way, the mean value of pixels in the selected area for each video and depth frame formed a separate time series M (=40) was then applied to each obtained signal to evaluate the new sequence Finite impulse response (FIR) filtering filtering of the selected order Spectral components in each recorded frame were then evaluated by a discrete Fourier transform forming the sequenceP using the least squares method to minimize summed squared differencesK values of spectral components The local polynomial approximation of evaluated spectral components was then applied in two specified frequency ranges corresponding to possible frequencies of breathing  in this record as presented in A general methodology for the estimation of respiratory rate and heart rate is presented in Analysis of the heart rate estimate based upon a 180 s infrared video sequence is presented in Different spectral components estimated in separate subregions over the whole period of 180 s are presented in The average range of chest movement in selected grid points and over the selected time of 120 s is presented in Final parts of each record in MS Kinect provides a cheap alternative to video monitoring of sleep abnomalities performed in sleep laboratories by polysomnography as the gold standard diagnostic tool. Polysomnography (PSG) records different biosignals, but it is an invasive method that may disturb natural sleep. In comparison with other efficient methods, including infrared video monitoring , it is pThis paper presents the use of MS Kinect image, depth and infrared sensors for non-contact monitoring of selected biomedical signals, evaluation of breathing and heart rate using recorded video frames, and verification of the obtained results. It is assumed that estimated features obtained from data retrieved from a natural environment will increase the reliability of such observations related to the diagnosis of possible neurological disorders and the fitness level of the individual. The purpose of this approach is to replace wired sensors by distance monitoring, allowing more convenient data acquisition and analysis.Obtained data were used for the analysis of biomedical signals recorded after specified body activity. The results show no significant difference between biomedical features obtained by different biosensors and non-contact MS Kinect technology. While breathing rate can be recorded with high reliability, non-contact heart rate detection depends upon the visibility of an individual\u2019s blood vessels in the case of video sensor use.Results show how the MS Kinect sensors and selected digital signal processing methods can be used to detect the heart rate and to analyse breathing patterns during different kinds of breathing. Processing of video frames acquired during interrupted breathing points to the possible use of these sensors for sleep apnea analysis as well.The methods described here form an alternative approach to biomedical data acquisition and analysis. Developing the abilities of different biosensors with possibilities of wireless data transmission increase the importance of remote data acquisition and signal analysis using computational intelligence and information engineering in the future. This approach has a wide range of applications not only in biomedicine but also in engineering and robotics. Specific applications based on analysis of depth matrices allow gait analysis and early diagnosis of locomotor system problems.Further research will be devoted to algorithms for more precise data acquisition and processing to detect biomedical feature changes for correct diagnosis and for proposing further appropriate treatment. It is assumed that infrared sensors will be used for non-contact analysis during sleep to detect sleep disorders."}
+{"text": "The increasing volume of existing information on biological processes and the use of large databases have significantly increased the accessibility of datasets to the scientific community. This has enabled performing an analysis to facilitate the extraction of relevant information or modeling and optimizing tasks in different processes. Parallel to the increasing volumes of information is the emergence of new or adapted distributed computing models such as grid computing and cloud computing. Together with new techniques of artificial intelligence, or more specifically knowledge discovery, these management systems are making it possible to perform a more efficient analysis of the information and are enabling the creation of adaptive systems with learning ability.In the area of distributed artificial intelligence models for knowledge discovery in bioinformatics, ten interesting proposals are presented. These models analyze different biological aspects and simulate the process or user behavior in the health care system. The main characteristics in these proposals are the use of artificial intelligence techniques to analyze the information and extract knowledge.\u201cBladder Carcinoma Data with Clinical Risk Factors and Molecular Markers: A Cluster Analysis\u201d provides interesting research about bladder cancer. The paper shows the hypothesis that the use of clinical and histopathological data with information about marker is useful to manage treatments of nonmuscle invasive bladder cancers (NMIBC). The authors apply data mining techniques such as hierarchical clustering to create molecular cluster and risk groups. In their experiments, the authors analyze 45 patients with a new diagnosis of NMIBC. They create four groups of patients and categorize the patients according to clinical characters and biological behavior.The authors of \u201cA Linear-RBF Multikernel SVM to Classify Big Text Corpora\u201d use data mining techniques based on classifiers to big text corpora. In particular, they implement a variant of support vector machine (SVM) to reduce the computational cost. The authors show a multikernel SVM with automatic parameterization to improve the results of SVM parameterized under a brute force search. The proposal is composed of a workflow with algorithms to process documents, reduce the dimensionality of the data, and to apply/provide clustering, training, and prediction. The proposal is analyzed according to the classification results and building time in the dataset TREC Genomics 2005 corpus. Pleurotus ostreatus to improve quality and production. In order to carry out the analysis of the factors, the authors include several IoT sensors to retrieve the information from the sensors. The information is then processed with data mining techniques in cloud system in order to predict plant growth and manage plant growth control.In \u201cAnalysis of Environmental Stress Factors Using an Artificial Growth System and Plant Fitness Optimization,\u201d the authors analyze how some environment conditions can accelerate the evolution process; in addition to modifying the environment conditions, it is possible to select genomic variants. The authors analyze several factors for\u201cRecRWR: A Recursive Random Walk Method for Improved Identification of Diseases\u201d proposes a new method to select the best disease targets for multiconcepts graphs. The proposal, referred to as recursive random walk with restarts (RecRWR), includes multilayer networks, graphs, and weights calculation and has been tested with the OMIM database with the area under ROC curves.\u201cGene Knockout Identification Using an Extension of Bees Hill Flux Balance Analysis\u201d is an interesting paper that presents an extension of Bees Hill Flux Balance Analysis (BHFBA) integrated within the framework of the OptKnock and Hill Climbing algorithm in a local search to extract gene knockout in order to maximize the production of the desired metabolite. The proposal has been analyzed with different databases and compares the execution time, growth rate, and production yield. The authors validate that the BHFBA improves the performance due to the inclusion of the Hill Climbing algorithm.In \u201cUsing the eServices Platform for Detecting Behavior Patterns Deviation in the Elderly Assisted Living: A Case Study,\u201d the authors present the eServices platform (Elderly Support Service Platform). The platform detects any deviation in the behavioral pattern followed by elderly people and is able to predict dangerous situations. The system was modeled with the CRISP-DM methodology and was tested with synthetic data based on real data and expert knowledge. The authors incorporate several data mining techniques such as decision trees, cluster, or ROC curves in order to validate the results.\u201cAgent-Based Spatiotemporal Simulation of Biomolecular Systems within the Open Source MASON Framework\u201d presents a tool for biomolecular reaction modelling in the multiagent simulator of neighborhoods framework (MASON). The tool describes the interaction among the molecules. The system is worth considering to analyze the effect of different factors in simulations. The system is tested in several scenarios based on enzymatic activity. The results area is compared with studies performed in laboratories.\u201cA Distributed Multiagent System Architecture for Body Area Networks Applied to Healthcare Monitoring\u201d presents an architecture based on a multiagent system to monitor the parameters of several users with biomedical sensors. The agents incorporate the BDI  model and data mining techniques to analyze the data of the sensors. The system is able to detect movements, activities, and postures. Its accuracy is confirmed and presented in the results taken from the tests performed in several cases.\u201cModelling the Longevity of Dental Restorations by means of a CBR System\u201d presents a case based reasoning (CBR) system to analyze dental restorations with different materials. The system applies the steps of the CBR cycle in which it integrates several data mining algorithms to perform in the retrieved phase. It also includes a mixture of experts with neural networks and Bayesian networks in the reuse phase to predict the longevity of dental restorations. The system is tested with the data of patients and the results are shown in the paper.Finally, \u201caCGH-MAS: Analysis of aCGH by means of Multiagent System\u201d proposes a multiagent system to analyze data of CGH (comparative genomic hybridization) arrays. The agents incorporate several layers to perform visualization and analysis and to manage information processes. The system proposes different visualizations to facilitate the visual analysis and to access the information in databases. Moreover, the multiagent system provides several data mining techniques to carry out the analysis. The system is tested with several kinds of CGH arrays and the results are shown in the paper."}
+{"text": "Despite a large and rapidly expanding literature on psychological trauma, many fundamental questions remain about its basic nature: Is it a psychological problem or a biological one?; Is it a past event somehow stuck in the present or is it something new which has been triggered and shaped by that event?; Does it reside only within the patient or does it live between the patient and other people (including within the therapeutic relationship)? This presentation will review the history of the concept of psychological trauma and explore the theoretical bases for current evidence-based psychotherapies for PTSD, each of which will be shown to describe psychological trauma as a problem in bringing the past and the present together in memory and cognition. These theories primarily differ on the question of whether a traumatic memory becomes pathogenic, because it cannot be biologically processed or because it must be psychologically avoided. Psychoanalytic concepts of transference and countertransference will be shown to be of practical importance regardless of the type of treatment chosen. If researchers and clinicians can build on what they hold in common rather than become divided by their differences, we can improve our ability to understand and alleviate the effects of psychological trauma."}
+{"text": "Scientific research into mental health outcomes following trauma is undergoing a revolution as scientists refocus their efforts to identify underlying dimensions of health and psychopathology. This effort is in stark contrast to the previous focus which was to characterize individuals based on Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnostic status  and allied methods such as Latent Class Growth Analysis (LCGA) for the identification of heterogeneous populations defined by their pattern of change over time will be presented ."}
+{"text": "Fukushima et al. recently published research on the relationship between cost sharing policies and medical spending by the elderly (Fukushima et al., One of the baseline results of the study claims: \u201clower cost sharing significantly increases medical spending.\u201d This actually follows the natural logic that a patient is likely to consume more care if it is effectively free at the point of usage. Three decades ago policy makers believed it should be possible for a cost sharing mechanism to contain costs and induce net savings (Keeler and Rolph, The article conveys an important message with regards to the role of cost sharing in prescribing and dispensing medicines (Johnson et al., There is a variety of measures used to increase the prescribing of generics vs. originators in Europe. These include compulsory substitution, e.g., in Sweden (Andersson et al., The phenomenon of a shrinking labor force and threatened financial sustainability of health care provision was recognized in the Japanese market a few decades ago Ogura, . The devMJ has solely designed and authored this Commentary article without any external engagements by other contributor or professional services.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Polythelia has been defined as the presence of supernumerary nipples without accessory glandular tissue. Usually, these growths follow imaginary mammary lines running from the armpits to the groin.Although the presence of dental anomalies may occasion only a simple cosmetic problem with specific clinical considerations, the association with familial polythelia has been scarcely reported. This paper reports on a case of polythelia that is associated with dental anomalies in an Argentine family and discusses suggestions for a thorough dental history and medical consultation to prevent possible pathological conditions or potential malignant transformation of mammary tissues. The in,,,Polythelia represents a typical example of atavism and the word means \"many nipples\",The genetic transmission of polythelia appears to be heterogeneous and the most common modes are: autosomal dominant with incomplete penetrance and a dominant X-linked chromosome. Each of these modes has demonstrated intrafamilial variability in their clinical manifestations.Tooth agenesis is the most common anomaly of dental development and may occur as an isolated entity or that composing well-documented syndromes. These clinical situations appear to be due to chromosomal defects or mutations of the genes responsible for organogenesis ,,,Although the presence of dental anomalies may suppose a simple cosmetic problem with specific clinical considerations, the scantly referenced associations with polythelia (in syndromes of greater diagnostic complexity"}
+{"text": "Animals and humans must behave efficiently in acoustically rich environments, where few sound sources are of interest out of many others that are considered background noise. How does the auditory system implement such robust processing is a topic of intense research. In this work I am interested in the neural mechanisms underlying detection of novel objects in auditory scenes, such as a novel sound source at a given location.It has been shown psycho-physically that the perception of a sound depends on the acoustical context in which it occurs. A basic example of such effect is called enhancement . A harmoI implemented on the Brian simulator and its auditory package  a model The present functional study of auditory enhancement suggests that such contextual effects could be critical for animal survival and for hearing in realistic conditions. The results show how simple neural mechanisms modulate a sensory pathway so that it adapts to its surrounding environment and suggest that bias in perception could have ecological advantages. The model could also inspire the design of speech processing devices in real environments."}
+{"text": "The combination of the acromion Open fracture to a section of the supraspinatus tendon is an exceptional situation. The author reports the case of a young patient with a wound of the posterolateral side of the right shoulder. Screwing was done for the fracture of the acromion after supraspinatus tendon suture with good clinical and radiological outcome after an appropriate rehabilitation. Open fracture of the acromion is an exceptional clinical entity and should be reported. A heavy stab wound was the cause of this exceptional lesion association in a young patient whose surgical exploration noted a supraspinatus tendon rupture with capsular break. The reconstruction of the acromial arch with rotator cuff repair was needed urgently under antibiotic cover and anti tetanus serum.The authors report the case of a 19 year old man; autonomous; right handed laterality; carpenter by profession; without medical or surgical particular history; victim of an accidental injury by a knife causing a wound from the outer side of the right shoulder. The clinical examination  objectifRadiographs  objectifA joint lavage was the first operative time. A careful closure of the joint capsule with absorbable suture followed by a suture supraspinatus tendon with a no absorbable suture by points X. An osteosynthesis of the acromion bone fragment by two 3.5 mm cancellous screws .The evolution marked by a consolidation of the fracture with complete functional recovery after a suitable rehabilitation shoulder started working early and the joint amplitudes and muscle strength .The literature review has not revealed a similar published case involving an open fracture of the acromion and supraspinatus tendon injury. The young person is more prone to this type of severe trauma to the shoulder and especially male , 2. The Scapula fractures are very rare; they represents only 1% of all fractures . In thisSeveral technics for fixation of fractures have been described acromion, including tension band wiring for more distal fractures, plate fixation for fractures that are more proximal or through the acromial base and spine, interfragment screw fixation, as the case of our patient, plate fixation supplemented with interfragment screws, and fixation with Kirschner wires. According to the DASH score functional outcome is very satisfying to 6 months after ablation materiel. No local complications were reported especially calcification or early or late infection.This is a very rare case that combined an open acromion fracture to a supraspinatus fracture. Care of this type of lesion should be emergency operated with a solid osteosynthesis and tendon suture for early and appropriate rehabilitation."}
+{"text": "In an individually randomised controlled trial (iRCT) where the intervention is delivered by a health professional/therapist it seems likely that the effectiveness of the intervention could depend on the skill of the therapist delivering it. This leads to a potential clustering of the outcomes for the patients treated by the same therapist.If outcomes are clustered then the usual statistical methods for analysing RCT data may not be appropriate as they assume that outcomes observed on different participants are independent.In some iRCTs there is clustering in only one arm; where the therapist only treats participants in one arm of the trial but there is no equivalent clustering in the control arm.Several strategies have been proposed for this problem: ignoring the clustering; imposing clusters in the control arm and fitting a fixed or random effects model, or using a partially clustered approach where only the clustering in the treatment arm is modelled.This talk will describe and compare the statistical methods for analysing continuous outcomes from an iRCT with some element of clustering in one arm. Four confirmatory case studies  will be analysed using each of the methods: specialist clinics for the treatment of venous leg ulcers , acupuncture for low back pain , cost-effectiveness of community postnatal support workers (CPSW) , and Putting Life in Years (PLINY) . Recommendations for the best and most practical approaches will be made."}
+{"text": "The primary bilateral macronodular adrenal hyperplasia or the independent adrenocorticotropic hormone bilateral nodular adrenal hyperplasia is a rare cause hypercortisolism, its diagnosis is challenging and there is no clear way to decide the best therapeutic approach. Adrenal venous sampling is commonly used to distinguish the source of hormonal production in patients with primary hyperaldosteronism. It could be a useful tool in this context because it might provide information to guide the treatment. We report the case of a patient with ACTH independent Cushing syndrome in whom the use of adrenal venous sampling with some modifications radically modified the treatment and allowed the diagnosis of a macronodular adrenal hyperplasia. Cushing syndrome is a rare disease caused in most cases (after steroid use has been excluded) by a pituitary ACTH-producing adenoma A 76 years-old woman with history of controlled hypertension (with losartan and amlodipine) presented to our hospital referring weight loss of 4 kg in two months, edema that progressed to anasarca and back lumbar pain. Besides the edema her physical examination was completely normal with no clinical signs suggestive of hypercortisolism. Among the studies requested, an abdominal tomography showed a right adrenal gland nodule of 14x9 mm and another one in the left adrenal gland of 23x18 mm , additioWith these results an ACTH (adrenocorticotropic hormone) independent form of hypercortisolism was diagnosed and because the scan of the abdomen had documented the presence of two adenomas, one in each adrenal gland larger than 10 mm, we found ourselves with a therapeutic challenge since the resection of one of the glands may not cure the hypercortisolism in case that the hormonal production came from both glands and the resection of both glands with leave the patient with a permanent hypoadrenalism. It was decided then to perform an adrenal venous sampling to try to determine the origin of the of cortisol production.A previously described protocol was used The patient did not have any postoperative complication and received replacement therapy with hydrocortisone 50 mg every 8 h during the first 48 h and subsequently received prednisolone 10 mg and 0.1 mg of fludrocortisone replacement with resolution of the hypokalemia.The macronodular bilateral adrenal hyperplasia or ACTH-independent macronodular adrenal hyperplasia (AIMAH), is one of the rarest causes of hypercortisolism and its true frequency has not been established. Less than 2% of all cases of hypercortisolism are explained by any form of bilateral adrenal hyperplasia either macro or micro nodular Adrenal vein sampling is used mainly in patients with hyperaldosteronism. Even in high volume centers with experienced radiologist the success rates are around 70 to 90%6. Adrenal vein sampling is rarely used for the study of hypercortisolism and this is probably due to the rarity of cases in which adrenal cortisol secretion and bilateral nodules present together, but it can be a useful test in this group of patients. It is proposed that some patients could be treated with a unilateral adrenalectomy as production of cortisol could be related to the size of the nodule Based on the above it was decided to perform the extraction of both adrenal glands and the result of the pathology confirmed the diagnosis of AIMAH.To our knowledge this is the first report of Adrenal vein sampling in a patient with hypercortisolism and bilateral adrenal adenomas in our country.We made some changes to the procedure reported in the literature, given the difficulty with the measurement of catecholamines we chose to perform verification of proper positioning of the catheter tip by the image from the venography and to correct the dilution difference by measuring aldosterone, the biochemical diagnosis was confirmed histological which allows us to conclude that the verification by venography was adequate.This technique allowed an accurate diagnosis and avoids the need for re-intervention in the case that the glandular size guided the treatment."}
+{"text": "With continually increasing global connectivity and wholesale change of landscapes, the need to understand and control the spread of invasive species has never been greater. To do so requires insight into the factors that allow particular species to become invasive to begin with as well as into the evolutionary trajectory those invasive populations follow after establishment in new ranges.One of the more prominent hypotheses explaining the success of invasive species relies on the idea that populations can disperse away from their natural enemies, and thus grow without the constraints of antagonist-mediated control. Recent work by Tiantian Lin et\u00a0al. builds on this idea by demonstrating parallel evolution of invasive plant populations across three geographically distinct regions towards decreased investment in defense and increased competitive ability. By comparing the competitive ability of native versus invasive genotypes of Common ragwort in either the absence of herbivores or in the presence of either a specialist or a generalist herbivore, the authors were able to show that invasive genotypes outcompete their native conspecifics in both the absence of herbivores and presence of the generalist herbivore, but have lowered defenses against the specialist herbivore  of most founding populations. The authors describe how environmental and genomic perturbations typical of invasion may favor activation of transposable elements, and therefore increase the rate of introduction of potentially beneficial alleles (Stapley et\u00a0al."}
+{"text": "To improve the ability to accurately report CT and MRI by learning to recognise benign findings that may mimic malignant pathology in the setting of scans performed on patients with known malignancy.CT and MR images will be displayed demonstrating benign abnormalities that are easily misinterpreted as metastases, recurrent tumour or residual tumour in patients with known malignancy. Examples of benign findings will be displayed next to the corresponding malignant abnormalities to demonstrate the potential error.The ability to accurately differentiate between benign and malignant disease can be challenging and can contribute to reporting discrepancies even amongst experienced radiologists. This can be especially demanding when imaging patients with known malignancy and is a concern for general and specialist radiologists. Being aware of abnormalities that mimic malignancy will help to increase the accuracy of CT and MR reports and ensure the correct treatment plans are implemented."}
+{"text": "Solar radiation is essential for photosynthesis and global crop productivity but it is also variable in space and time, frequently being limiting or in excess of plant requirements depending on season, environment and microclimate. Photoprotective mechanisms at the chloroplast level help to avoid oxidative stress and photoinhibition, which is a light-induced reduction in photosynthetic quantum efficiency often caused by damage to photosystem II. There is convincing evidence that photoinhibition has a large impact on biomass production in crops and this may be especially high in rice, which is typically exposed to high tropical light levels. Thus far there has been little attention to photoinhibition as a target for improvement of crop yield. However, we now have sufficient evidence to examine avenues for alleviation of this particular stress and the physiological and genetic basis for improvement in rice and other crops. Here we examine this evidence and identify new areas for attention. In particular we discuss how photoprotective mechanisms must be optimised at both the molecular and the canopy level in order to coordinate with efficient photosynthetic regulation and realise an increased biomass and yield in rice. As an example, regions such as Central Luzon in the Philippines and Central and East Java in Indonesia can receive accumulative annual solar irradiation of more than 2200 kWh m\u22122. In regions that are environmentally vulnerable, higher light intensities could result in damage to crops and a significant reduction in yield. Photoinhibition is usually considered as a short-term response to periods of high light although is affected by long-term responses to environmental conditions (acclimation). In order to place photoinhibition in context with agricultural productivity which occurs over longer time scales it would be beneficial to link it with long term weather data. In this short review we summarise the current evidence that high irradiance levels result in significant yield reductions in rice crops at the metabolic and canopy levels.As the only significant source of energy, incident solar radiation (sunlight) at the surface of the earth governs climate and the meteorological cycles and is essential for life. It has a major effect on the diurnal and seasonal temperature variations as well as the productivity of both terrestrial and aquatic plants by providing energy for the assimilation of carbon by plant canopies  within the thylakoid membrane. This creates resonance energy, which is then transferred through neighbouring chlorophyll molecules to photosystems. An excited chlorophyll a molecule can return to ground state after light absorption through several pathways \u2013 photochemistry (photosynthesis), thermal dissipation, chlorophyll fluorescence or formation of a reactive oxygen species (ROS). The latter two are much less likely than the former  resulting in a sustained decline in photosynthesis  low light episodes and can substantially limit photosynthesis (Ogren 2 and Pmax (light-saturated photosynthesis) under very high light. While it has been suggested that under certain circumstances it may occur subsequent to photosynthetic down regulation or damage possibly associated with high carbohydrate levels  proteins has been shown to accelerate photoinhibition under strong light  or non-photochemical (occur prior to photolysis in PSII). Non-photochemical quenching (NPQ) refers to the measurement of thermal dissipation of excess excitation energy in PSII  and photoinhibition. In fact, studies show a broad (negative) relationship that exists between the capacity to utilise light energy within photochemical sinks (carbon fixation and growth) and NPQ capacity   difficult. However, the continued development of high-resolution phenotyping platforms (with automated darkening and light treatment) is expected to overcome this and uncover the genetic basis of these traits used in breeding programmes  and less under others (low light or during periods of moderate but rapid high \u2013 low transition). The patterns of photoprotection required will be determined by the proportion of canopy surface area exposed to high radiation that induces photoinhibition and the properties of light fluctuations that limit photosynthesis. So how can this problem be solved? Existing models of canopy photoinhibition can predict the impact of \u03a6COThe genetic improvement of crop yield will need to be integrative and consider multiple stress and signalling pathways in the plant. In this review we focus on responses to high light, which will compound the effects of other stresses. We have highlighted the weak links between leaf level effects and field yield and explain the case for a better understanding of canopy level optimisation.Finally we note some novel and highly relevant climatic factors related to irradiance. Studies carried out since the 1990s found a decline in solar radiation at the surface of the earth between the 1950s and the 1980s (Wild and Wild"}
+{"text": "Over a thousand nerve, skin and salivary gland biopsies were performed in FAP patients during the last forty years in our centre. We will try to demonstrate the different biopsy approaches over the years and confirm that biopsy of different types of tissue are useful not just in the diagnosis but also in the study of the pathogenesis of the disease.Retrospective analysis of our database since 1973 till 2014 showed 253 nerve biopsies, 441 skin and 738 salivary gland biopsies. Some of these were combined biopsies, nerve and skin or muscle nerve and skin. Except for the salivary gland biopsies they were all performed by one of our neuropathologists.Until 1988, nerve and skin biopsies were commonly performed for diagnostic purposes, after that with genetic testing being available all tissue biopsies declined in number and were only needed in difficult diagnostic cases or when genetic testing was not available. Nerve biopsy became relevant again with the appearance of atypical clinical presentations or late onset or sporadic patients where the clinical diagnosis of FAP had not been considered. Nerve biopsy was also performed to establish the diagnosis of \u201cde novo\u201d amyloid neuropathy in recipients of domino liver transplants from FAP individuals, who started showing symptoms of neuropathy, and to rule out other causes of neuropathy.Since 2005, salivary gland biopsy has become our method of choice to demonstrate amyloid and is as effective as nerve or skin biopsies.During the last forty years biopsies of different tissues were used to demonstrate amyloid. Nerve biopsy is still a useful tool not just for diagnostic purposes in problematic cases but also to understand the pathogenesis of the disease. Salivary gland biopsy is now our favoured method as it is a minimally invasive procedure and amyloid is demonstrated in very early stages of the disease. Biopsy could also be a tool to monitor treatment with the new drugs available."}
+{"text": "Burnout in healthcare workers is deleterious both for the patients as well as for the healthcare workers themselves with consequences ranging from less job satisfaction to increased mortality rates. Burnout in intensivists is reportedly high with almost half of French intensivists having burnout symptoms.The present study was done to estimate incidence and prevalence of burnout in intensivists in the Netherlands and to identify risk factors for burnout.Two online questionnaires were sent: one to all intensivists in the Netherlands and one to the medical directors of Dutch Intensive Care Units (ICUs).A reply was received of 318 out of 664 intensivists (47.9%). Results of 272 intensivists were evaluable, 12 of whom (4.4%) were diagnosed with burnout at the time of the questionnaire. No association was found between working conditions or personal characteristics and burnout, except for the association between burnout and conflict with the hospital management and between burnout and having complaints filed against one. From the medical directors questionnaire it was found that 7.4% of intensivists suffered from burnout in 2013.Incidence and prevalence of burnout among Dutch intensivist was found to be unexpectedly low as compared to the literature. No firm associations were found between burnout and working conditions or personal characteristics. The low incidence and prevalence of burnout in Dutch intensivists might be explained be a lower workload for intensivists as compared to the literature.This study was done with support of the Dutch Society for Intensive Care"}
+{"text": "This presentation will focus on a UK Cochrane funded project that explored different ways of engaging patients, the public and health practitioners in the development of outcomes for systematic reviews. It is called 'Outcomes Most Important for Patients, Public and Practitioners (OMIPPP)'.http://www.healthtalk.org). Healthtalk researchers reanalysed the original data for clues to outcomes. These were shared, discussed and compared with existing outcomes used in systematic reviews of breastfeeding interventions.Working with three Cochrane Review Groups (CRG); Airways, Ear Nose and Throat (ENT) and Pregnancy and Childbirth we focussed on outcomes for reviews in Asthma, Rhinosinusitis and Breastfeeding respectively. For each group we used a different method to engage; for asthma we facilitated a full day workshop. Working in partnership with Asthma UK, we prepared for this by gathering perspectives of asthma via a Facebook survey, and reviewing existing core outcome sets. Working in partnership with evidENT we gathered perspectives in rhinosinusitis using an online survey and experimented with social media as a way of reaching out beyond their networks as there are no relevant patient groups. We compared survey findings with existing outcomes used for reviews of chronic sinusitis. For breastfeeding we worked with the National Childbirth Trust and the Breastfeeding Network to review an existing online collection of experiences of breastfeeding called Healthtalk (At the time of writing this abstract the project is not yet complete, however early results will be discussed. We are interested in the following aspects of evaluation; how relevant was the gathered data for systematic review outcomes? What were the cost and resource implications of each method? From a review group perspective how feasible are these methods? Has the project extended the reach of CRGs with interested public/patient and practitioner groups? How does our data compare with other outcomes exercises e.g. COMET?"}
+{"text": "Aspergillus fumigatus, and pre-existing conditions such as pulmonary functional abnormalities such as cystic fibrosis or chronic obstructive pulmonary disease provides a favorable environment for Aspergillus colonization and biofilm formation in the lungs  or during invasive aspergillosis  and are considered as an important virulence determinant for a pathogen. For a fungus specie, growing as multicellular community may confer biological advantages in the colonization of tissues and may also act as barrier to external aggressions  maintenance and stability of biofilms and (ii) biofilm resistance to antifungal drugs. Similar results were also observed for A. fumigatus biofilms, where the treatment with DNAse destabilized biofilm architecture integrity and concomitant treatment of biofilms with DNAse and amphotericin B or caspofungin improved antifungal susceptibility  which consist in masses of decondensed chromatin decorated with antimicrobial proteins and opsonins (McCormick et al., C. albicans (McCormick et al., in vitro models with Aspergillus showed that despite the fact that NETs formation leads to trapping the fungus conferring a fungistatic effect by containing the infection, it does not represent the major factor for killing this fungus since NET-dependent killing of Aspergillus hyphae was only moderated (Bruns et al., in vivo influence of NET's eDNA produced by lungs in Aspergillus biofilm development, which may lead to the combination of antifungal drugs with DNAse to manage pulmonary aspergillosis. Further studies could also explore the Aspergillus ECM physicochemical features and permeability to current antifungal drugs, and these findings may lead to molecular improvement of these drugs by conferring them the capacity to penetrate ECM Aspergillus biofilm and act in their respective molecular targets.Taken together these findings, the next steps would include the elucidation of the The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Online sexual health services are an emerging area of service delivery. Theory of change critically analyses programmes by specifying planned inputs and articulating the causal pathways that link these to anticipated outcomes. It acknowledges the changing and contested nature of these relationships.We developed two versions of a theory of change for an online sexual health service. The first articulated the theory presented in the original programme proposal and the second documented its development in the early stages of implementation through interviews with key programme stakeholders.The programme proposal described an autonomous and empowered user completing a sexual health check using a more convenient, accessible and discreet online service and a shift from clinic based to online care. The stakeholder interviews confirmed this and described new and more complex patterns of service use as the online service creates opportunities for providers to contact users outside of the traditional clinic visit and users move between online and clinic based care. They described new types of user/provider relationships which we categorised as: those influenced by an online retail culture; those influenced by health promotion outreach and surveillance and those acknowledging the need for supported access.Co-development of clinic and online services to support complex patterns of service use.Developing access to online services for those who could use them with support.Understanding user experience of sexual health services as increasing user autonomy and choice in some situations; creating exclusion and a need for support in others and intrusiveness and a lack of control in still others.This analysis of stakeholder views on the likely the impacts of online sexual health services suggests three areas for further thinking and research.This work has influenced the evaluation of this programme which will focus on; mapping patterns of use to understand how users move between the online and clinic based services; barriers to use of online services among some populations and how to overcome these; understanding user perceptions of autonomy in relation to online services. Increasing demand for sexual health services, limited resources for sexual health care  and new Online sexual health services are thought to be less expensive than similar services delivered in clinic settings  and to iIn 2013 we started developing and evaluating an online sexual health service linked to a telephone and clinic-based service in an area of South East London with a young, multi-ethnic population experiencing high levels of socio-economic deprivation and with very high levels of sexual ill health. This programme proposes a web based sexual health service with a linked telephone service and direct referral into local clinics when required. The service is planned to evolve through small-scale prototype development and testing. As recommended for the evaluation of complex interventions we sought to generate a conceptual model for the intervention, link this to the published evidence and the local context and then monitor its development during programme implementation .Identifying long term goalsBackwards mapping and connecting outcomesIdentifying assumptionsWe developed a theory of change to articulate the conceptual model underpinning the programme and its development. Theory of change critically analyses new programmes by articulating the causal pathways that link specified inputs to anticipated outcomes. It acknowledges the need to test these relationships for new programmes and their development during implementation \u201312. TheoThis process informed our evaluation strategy for the programme by identifying key outcomes, process indicators and assumptions that required testing.Van Belle et al.  recommenThe proposed long term goals of the programme were identified from the original funding bid, developed by the two London borough public health departments and two NHS foundation trusts providing specialist sexual health services. We (PB and JS) read and re-read this document to identify the planned inputs and anticipated outputs described in the document and the steps that connected them. We developed a series of diagrams to describe these linkages and the assumptions that underpinned them. We imported the document into qualitative data analysis software Nvivo  and coded this material using our coding frameworks based on early versions of our theory of change diagrams to check the relationship between our initial theory of change and the text of the bid. We completed several cycles of causal model development and modification to ensure that our diagram accurately reflected the information in the bid. Finally we identified the key assumptions that underpinned the linkages in our causal model as important areas for evaluation.Having developed an initial version of the theory of change from the programme funding bid we then repeated a modified version of this process during programme implementation using interviews with stakeholders as our data source.Four clinicians in local services Three senior managers within clinical servicesThree senior managers within local government, public health and commissioningFour potential service users sampled to include individuals from the populations most at risk of sexual ill health in the local area; men who have sex with men, young people, and those from black and minority ethnic groupsWe recruited our interview participants to reflect the full range of stakeholders for the project including;All of the 14 stakeholders who were invited to complete individual interviews accepted our invitation. Each participant provided written informed consent. Interviews began with the interviewer describing the planned service inputs . These were listed on the left hand side of a large sheet of paper. Participants were then asked to list all of the outcomes, both positive and negative that they anticipated from this input. These were listed on the right hand side of the paper. By asking what needed to happen for the input to lead to the anticipated outcome and why this needed to happen participants were encouraged to map this relationship and to reflect on the assumptions that underpinned it . As thisOur qualitative analysis used the framework approach , a matriEthical approval for this research was granted by King\u2019s College London research ethics committee (Ref: BDM/13/14-42).that potential users have private internet access and sufficient health literacy to use an online facilitythat the online service is more convenient and discrete than use of clinical services, at least for some people; that the pattern of service use replicatesthat online services cost less than clinic based servicesthat the loss of health professional contact associated with online services is acceptable to users.The theory of change developed from the programme funding application articulated a causal chain with more convenient and discreet sexual health testing leading to increased uptake of testing and treatment, coupled with consistent health promotion advice to generate the final outcome of reduced STI transmission Fig.\u00a0. It refeThe theory of change developed from the stakeholder interviews supported the idea of online services as more convenient and more discrete The participants predicted new patterns of service use and new forms of user/provider interaction. Rather than a straightforward shift of activity from one service to another they thought users would choose to move between services for example complementing a clinic visit with online information or an online sexual health check with a visit to the clinic for reassurance or support.\u2018I\u2019ve tried to find out information online, for clients here, and there is some information on NHS Direct, but unless you can actually spell chlamydia or gonorrhoea, or syphilis; it\u2019s actually quite hard to find information\u201d.This more complex view of how users might choose to use services questioned the simple cost effectiveness analysis proposed in the initial bid. Stakeholders described the additional responsibilities associated with self management, loss of support/reassurance/empathy that might be part of a clinical consultation and missed opportunities to identify additional unmet need, for example, advice and referral for those experiencing intimate partner violence.They described new roles for clinic staff with provider driven, technology mediated, contacts such as reminders to take treatment or notify partners or follow up offers of tests or support. They emphasised the potential inequity of access to online services and the possibilities for providing additional remote support for those who might be able to use the service with help. These new approaches to service use were associated with descriptions of user/provider relationship. We summarised these as an \u2018online retail approach\u2019 that emphasises patient autonomy and choice; a \u2018public health promotion/surveillance\u2019 approach that emphasises outreach to support behaviour change or monitoring of service access and a \u2018supported care\u2019 approach that references a need for health care professional mediated support during use of the online service Table .Based on the stakeholder interviews we developed a second theory of change that incorporates this thinking see Fig.\u00a0. This emThe development of these two versions of the theory of change for this programme contributes to service development, implementation and evaluation. It identifies the development of support packages to enable online service use as a priority for service development; the co-development of online and clinic based services as a priority within the implementation strategy and the need to document new patterns of service use as clients move between clinic and online options as a priority for evaluation.The rationale for the development of online services as described in the two versions of our theory of change is based on a number of key assumptions. The architects of the original bid assume; private internet access, health literacy, an online service that is convenient and discrete, online services that are cost effective and the acceptability of loss of a consultation. These are supported by evidence from both similar interventions and other relevant sources. National statistics show that 76\u00a0% of UK adults accessed the internet daily in the 2014 and 96\u00a0% of 16 to 24\u00a0year olds access the internet via mobile device  but a 20The modified theory of change has three further assumptions essential to these new causal pathways; that users are willing to take on new responsibility for their own sexual health care; that remote support will enable new online users and that clinic processes will adapt to the new online service provision. The stakeholder interviews echo issues raised in the published literature on the potential of internet services to disproportionately enable some users to take on increased responsibility for their own health care , 32. ThoThe stakeholder interviews document what is potentially lost through use of online services and while suggesting that everyone should have access also suggests that not everyone will want to have access. This echoes the critiques of telemedicine and e-health that describe the potential loss of agency that comes from allowing digital health technologies into the home . The revFinally the stakeholder interviews suggest that online service introduction should be considered as part of a dynamic sexual health economy and not a stand-alone service. The clinic is likely to experience changes in its users, the problems they present and the clinic staff and processes available to respond as clients move between the online, telephone and face to face service. This is not a bolt on service but a change to the whole system of sexual health service provision and close working between the different elements of the system will be essential. A 2014 review of the literature suggests that co-development of online and clinic based services has received little attention to date but is an emerging area of focus in the development of online health services , 40.Co-development of clinic and online services to support complex patterns of service use.Developing access to online services for those who could use them with support.Understanding user experience of sexual health services as increasing user autonomy and choice in some situations; creating exclusion and a need for support in others and intrusiveness and a lack of control in still others.By documenting the development of the theory of change during implementation we identified three elements of online services that would benefit from further research.This work has influenced the evaluation of this programme which will focus on; mapping patterns of use to understand how users move between the online and clinic based services; barriers to use of online services among some populations and how to overcome these; understanding user perceptions of autonomy in relation to online services."}
+{"text": "Jean-Paul Chretien and colleagues argue that recent Ebola and Zika virus outbreaks highlight the importance of data sharing in scientific research. The recent outbreaks caused by Ebola and Zika viruses highlighted the importance of medical and public health research in accelerating outbreak control and prompted calls for researchers to share data rapidly and widely during public health emergencies.Effective preparation for emergencies requires the routine practice of data sharing in scientific research.Key impediments to data sharing, such as long-standing academic norms and human and technical resource limitations, cannot immediately be surmounted when an emergency occurs.Ongoing research that does not directly relate to an emergency now may be critical for the next unpredictable outbreak.As part of emergency preparedness, the scientific community should support ongoing initiatives that address major obstacles to data sharing and should embrace open science practices in both emergency and nonemergency research.In February 2016, Wellcome Trust organized a pledge among leading scientific organizations and health agencies encouraging researchers to release data relevant to the Zika outbreak as rapidly and widely as possible pdm09) originating in Mexico\u2014and we can be sure there are more surprises to come. Opening all research provides the best chance to accelerate discovery and development that will help during the next surprise."}
+{"text": "It is hypothesised that intraerythrocytic malaria parasite metabolism is not just fulfilling the need for ATP generation, but is highly evolved to support rapid proliferation, similar to what is seen in other rapidly proliferating cells such as cancer cells. Evidence is presented that deregulated glycolytic activity coupled with impaired mitochondrial metabolism is a metabolic strategy to generate glycolytic intermediates essential for rapid biomass generation for schizogony.1 and dihydroorotate dehydrogenase-targeting drug development programmes and within the context of current target product profiles for the malaria elimination agenda.The role of the parasite mitochondrion during key stages of the parasite life cycle makes it an attractive target for the development of novel prophylaxis, treatment and transmission blocking drugs. Using a targeted pharmacometabolomic approach, additional mitochondrial targets with therapeutic potential are identified and the potential of the development of inhibitors against these novel targets is discussed in the context of recent experiences with bc"}
+{"text": "The systematic review by Bleich and colleagues contributes to the much needed evidence supporting management of patients with multiple chronic conditions \u2014 multimorbidity. Although the review\u2019s focus is the United States, it addresses an issue that is highly relevant to all health care systems and raises important questions about how we can design systems to address the needs of this vulnerable group . LiteratThe systematic review of Bleich et al provides evidence from 27 studies that examined 5 models of care and suggests that care management, case management, and disease management are promising models for people with multimorbidity. This finding seems to fit with our intuitive sense that care coordination will reduce the challenges experienced by people with multiple chronic conditions, related polypharmacy, and high use of health care services . In addiThe review of Bleich et al also highlights the heterogeneity within the population of people with multiple chronic conditions and their overlap with other patient groups in relation to disability and frailty. Definitions of multimorbidity and related constructs such as comorbidity continue to be debated , but theAn additional key issue that Bleich et al discuss is the need for appropriate comparison or control groups to allow for robust evaluation. Ideally, randomized trials would be employed that use cluster and stepped wedge designs where appropriate. Only 13 of the 27 studies included in this review were randomized controlled trials (RCTS), which may partially explain the differences between Bleich\u2019s review and the related Cochrane review. The Cochrane review included only RCTs and not less robust study designs, and the included studies were from a wider range of countries, including the United States . VariatiThe systematic review of Bleich et al highlights the need for further evidence to support policy and management of patients with complex multimorbidity. In the meantime, studies should be designed to allow robust evaluation of interventions and should build on the evidence from this and related reviews that suggest a health care focus on patient-centered outcomes for patients with multimorbidity."}
+{"text": "In Australia\u2019s War against Rabbits, Brian Cooke details the emergence of rabbit hemorrhagic disease (RHD) in Asia and Europe and subsequent efforts to introduce RHD virus into Australia and New Zealand for rabbit control in the 1990s. The book documents the ecologic adaption between a virus and its animal host and provides cogent examples of our inability to contain the spread of (what was thought to be) a well-understood virus after it escaped into the environment.The first failed containment effort ensued after the virus jumped from a quarantine compound on Wardang Island to the coast of South Australia 3 km away. Despite a program carefully designed to counter unplanned spread of RHD virus on the Australian mainland (Operation Garter), the virus prevailed. Uncontained spread also followed an intentional and illegal release of RHD virus in New Zealand in 1997 when a farmer with intractable rabbit problems allegedly smuggled the virus in from Australia. After the outbreak started, instead of helping the New Zealand government control RHD, farmers reportedly used blenders to make \u201crabbit smoothies\u201d and actively spread RHD virus by applying these slurries to carrot baits.The book is generally well written and heavily referenced and contains many anecdotes penned by a scientist obviously passionate about his work. The flow of the narrative can sometimes be erratic, however, veering from amusing personal stories to a didactic recounting of the taxonomy of rabbit parasites or legislation relevant to pest control in Australia. Australia\u2019s War against Rabbits is best suited for professionals with a keen interest in rabbits, fleas, and their pathogens."}
+{"text": "We were interested in exploring the use of timing or delays in learning in neural networks. The work was developed by wondering about the effects of glia on network learning in the human brain. To investigate this idea, we created a Multilayer Perceptron (MLP)-based  feedforw"}
+{"text": "RARHA (REDUCING ALCOHOL RELATED HARM) is a Joint Action (JA) (2014-2016) funded under the EU Health Programme and by EU Member States to address some commonly identified priorities to reduce levels of alcohol related harm in the EU. The work package 5 contributes towards increased understanding among public health policy makers of the scientific basis and practical implications of the use of drinking guidelines as a public health measure, and towards more aligned messages to the general population, subgroups and health professionals.The objectives are to evaluate the presence (or not) of guidelines on EIBI for HHAC on the basis of the existing and available EU projects/documents  (1-4) and by additional information based on ad hoc survey across European Union Member States.A country specific questionnaire has been developed by the National Observatory on Alcohol for confirming the available sources of EU projects or documents and for collecting and/or upgrading information on drinking guidelines used in the context of EIBI. The form has been submitted by email to the country representatives of the Committee on National Alcohol Policy and Action as members with qualified experience and competence. Participants have been asked to check the validity of the information provided by the country questionnaire reported as \"review of available sources\" and to provide the most updated and reliable information for their Country (The survey started on May 2014).Twenty-nine out of 31 European countries selected , replied to the RARHA questionnaire. Twenty countries have a governmental organization responsible for preparing clinical guidelines for managing HHAC; twenty-two countries have multidisciplinary guidelines approved or endorsed by at least one health care professional body or scientific society and 22 countries have guidelines or recommendations for BI/treatment.The collected information represent the scientific basis and practical implications of the use of drinking guidelines as a public health measure. It serves to clarify the science underpinnings and practical/policy implications concerning low risk drinking guidelines, and work towards consensus on good practice principles in the use of drinking guidelines as a public health measure to help reduce HHAC. This activity, finalized to provide a more aligned messages to the general population, subgroups and health professionals, is ongoing (Rarha Delphi survey)."}
+{"text": "Using interpolation and collocation techniques, a continuous scheme is developed and used to obtain discrete methods which are applied via the Block unification approach to obtain approximations to the resulting large system of ODEs. Several test problems are investigated to elucidate the solution process.In this article, the boundary value method is applied to solve three dimensional elliptic and hyperbolic partial differential equations. The partial derivatives with respect to two of the spatial variables ( The general three dimensional problem (without cross derivatives) is given asThe numerical approximation of  has recementclass2pt{minimy and z variable with mesh spacings The method of lines approach is commonly used for solving PDEs whereby the PDEs is converted into a system of ODEs by replacing the appropriate derivatives by finite difference approximations. Our objective is to convert the 3D PDEs into a system of ODEs by replacing two of the spatial derivatives by central difference approximations. The resulting system is then solved using the BVM. Specifically, we discretize the k and whose k additional conditions are not only imposed at the beginning of the integration process but also at the end so that they form a discrete analog of the continuous boundary value problems. Thus, they are used for the numerical approximation of both initial and boundary value problems. They have been used for the solution of first order 1D initial and boundary value problems and their convergence and linear stability properties have been fully discussed in Brugnano and Trigiante 7), we handitions  on 11),,\\documenThe coefficients given in  are specWe note that the method  is locald system  over thementclasspt{minimaWe discuss the convergence of the BVMs in the following theoremLet be an approximation of the solution vector for the system obtained on a partition from the method  is the local truncation error vector of the formulas in  for nonlinear problems.Step 4 The solution of  and with zero boundary values on the entire We consider the Laplace equation with non zero forcing term in Zhang  and whosmentclass2pt{minimmentclass2pt{minimNext, we consider the following Sine-Gordon equation given in Cui \\documententclass1pt{minimaentclass1pt{minimaWe also consider the following equation given in Cui \\documentWe also consider the singularly perturbed convection diffusion equation given in Mohanty and Singh \\documentThe singularly perturbed elliptic boundary value problem given in Mohanty and Singh \\documentIn this paper, we have developed a highly accurate 3D problem solver. This has been achieved by the discretization of two of the spatial variables and the construction of a continuous BVM via the interpolation and collocation approach for solving the resulting semidiscretized system. The results given in \""}
+{"text": "Whilst extant literature demonstrates the aetiology, incidence and outcomes of eating disorders in women, with evidence showing the impacts on pregnancy, the fetus and parenthood adjustment, there is a paucity of research regarding how women make meaning of the experience. A phenomenological study provided a description of the pregnancy experience as perceived by a cohort of women with diagnosed eating disorders. Data were collected via semi structured interviews with women with a known diagnosis of an eating disorder either in the past or present and who had been pregnant within the previous twelve months. Data were analysed using constant comparative approach seeking themes and patterns.The study identified fourteen key themes that describe the women's experience of living with an eating disorder while pregnant. These themes included a basic description of the pregnancy journey itself; the use of metaphor; perceptions of motherhood; concerns about the baby; and body image. In addition, eating disorder behaviour; eating disorder status; secrets; wishes; misconceptions; support; emotions; health professionals' interactions and healthcare improvements were also identified. It is important that healthcare providers have an awareness that pregnant women may be undergoing personal distress and to be sensitive to the specific needs of women with eating disorders. This study has raised awareness of this issue and provided a baseline for further research in the area.Learning from Consumers stream of the 2014 ANZAED Conference.This abstract was presented in the"}
+{"text": "The rapid advancement of sequencing technologies has not been without challenges. The extensive size of genomes as well as the need to comprehend the vast complexities of genomic information has fostered the need to utilize more robust computational methods and statistical analysis tools. In a gene expression study involving multiple treatments, a time series analysis of differentially expressed genes provides great insights into the replicates. Such information is useful in identifying the potential sources of variation that cannot be easily extrapolated from a generalized experimental approach. It is also essential to be able to group the identified gene expression patterns in order to attain meaningful interpretations.The experiment employs the use of R software to identify gene expression patterns in a dataset involving parathyroid tumor treatments . The tre"}
+{"text": "Approximately 80% of human food is composed of crops, which are dominated by cereals that collectively make up 50% of global food production , identification of stress proteins, and the analysis of post translational modifications (PTMs) of proteins Figure .Understanding how plant cells sense and respond to abiotic stress is not only fundamental to our understanding of stress tolerance, but has the potential to yield novel approaches to improve crop productivity. Cellular proteomics plays an essential role in determining the functions of cellular compartments and the mechanisms underlying protein/gene targeting and trafficking.Currently, numerous organ-specific proteomic analyses of abiotic stress in crops have contributed to our understanding of the response mechanisms of crops to abiotic stresses  from specific cells or tissues, an appropriate sampling method needs to be first developed to obtain relatively pure subcellular fractions from this material. A promising sampling method is laser capture microdissection (LCM), which can isolate specific cell types of interest from sectioned specimens of heterogeneous tissues under direct microscopic visualization with the assistance of a laser beam  will make it possible to use a systems biology approach to understand crop responses to abiotic stresses.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The death of a baby before or shortly after birth is associated with profound long lasting grief for parents, similar to any child death. The majoA recent metasynthesis of the qualitative literature surrounding parents\u2019 experiences of care highlighted the value of additional emotional and psychological support from healthcare providers in improving care in pregnancy after stillbirth or neonatal death. However,Interim findings of this programme raise the issue of equity in provision of appropriate and sensitive care for parents in subsequent pregnancies who utilise UK maternity services. Data suggests that many parents receive inadequate emotional and psychological support and therefore there is a need to improve the evidence base underpinning care. The findings of this study will directly inform the development of specific interventions to improve antenatal support and promote positive birthing experiences and the development of a clinical care pathway to improve the care of women and their families in pregnancy following perinatal loss."}
+{"text": "Optimal medical treatment and personalised holistic patient care in an even balance is the ultimate management vision of Europa Uomo, the European prostate coalition, for all patients diagnosed with prostate cancer.The professional advice and support given on evidence based medicine is the easiest part of the education. We always provide a short but clear overview of the three main prostate diseases: prostatitis, benign prostate hyperplasia (BPH) and prostate cancer (PCa) and their relationship to Prostate Specific Antigen (PSA). The emphasis that we diagnose far more BPH then PCa has an immediate calming effect on the patient concerning \u2018abnormal\u2019 PSA results. Extending on the urological impeccable track record on BPH treatment with zero mortality and excellent quality of life outcomes is a good introduction to a prostate cancer diagnosis. The second emphasis on PCa as a complex disease with different biological forms is complimentary information. Concluding with the knowledge that most forms are indolent or low risk as compared to intermediate or high risk disease leads to an optimistic dialogue on prognostic factors and primary treatments of PCa .Some optimism and clarity are needed as our increased knowledge on prognostic factors and the many forms of primary treatment ranging from active surveillance to combination treatments of surgery and radiotherapy make a shared treatment decision a complex issue in the doctor-patient dialogue. There are few facts and many uncertainties which require the expertise of teamwork focused on the individual patient. There is medical and societal consensus that cancer is best treated by a multidisciplinary team confirming the improved outcome results recorded in multidisciplinary clinical trials , 3. The There are obvious benefits in integrated cancer management for the patients in a one stop shop where a full state-of-the-art program provides not only a consultation with the different experts on your diagnosis and treatment but at the same time access to innovative, tested health technology.However it is possible that the physician loses some autonomy in turning into a team player with the danger of losing \u2018the colloque singulier\u2019, the personal bond of trust between doctor and patient. This loss is already present in our health management as a direct consequence of advanced health technology where the patient has to put blind trust in the hands of an acknowledged expert. It is part of our modern lifestyle when we board airplanes or call for cabs.Can we save our holistic patient-centered care in the development of PCU? The model should connect intra  and extra (civil society) mural services. The latter include all professional and lay stakeholders in community health care.Two factors facilitate the link between medical management and patient care. Health literacy is one of most underrated factors to improve outcomes . It is lWhile we expect our patient responsibilities to facilitate clinical trials, translational research and save scarce health resources we feel that all innovative treatment should report on quality of life and cost-efficiency next to the desired efficacy.Last but not least we want to emphasize the facilitating role that nursing and patient groups can play between the PCU and community health and social care. The development of PCU\u00b4s provides an opportunity for a best practice forum with transparent pathways and outcomes."}
+{"text": "Evidence demonstrated that many aspects of drug abuse and dependence involve changes in glutamate neurotransmission. Neuroadaptations of the glutamatergic system are critical in alcohol dependence, tolerance and withdrawal   regulates the majority of extracellular glutamate  rats to measure the effectiveness of ceftriaxone in reducing alcohol consumption. These rats naturally prefer drink alcohol to plain water. After 5 weeks of a constant free choice of alcohol, the rats develop alcohol dependence. We administered ceftriaxone to the rats each day for 5 days and measured their alcohol consumption. P rats treated with ceftriaxone reduced their alcohol intake as compared to rats treated with physiological saline solution  was found downregulated in animal consumed alcohol for 5 weeks (Alhaddad et al., Furthermore, studies have shown that adenosine plays an important role in regulating the activity of neurons and controlling neurotransmitters, including GABA, glutamate and dopamine (for review see Nam et al., Alcohol abuse and dependence continue to be significant public health concerns. Thus, a better understanding of their neurobiology would facilitate the development of interventions targeting prevention and/or treatment of these major health issues. Here, we focused on the glutamatergic system as therapeutic target for the treatment of alcohol dependence. We have identified potential therapeutic compounds that may have beneficial effects for treating alcohol addiction. We believe that a focus on the glutamatergic system as a prime candidate for mediating drug and alcohol dependence.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Revelations that the majority of the world's two billion Christians currently live in developing countries may have important implications for global neglected tropical disease control and elimination initiatives.In December 2011, the Pew Research Center's Forum on Religion & Public Life produced a landmark report titled \u201cGlobal Christianity: A Report on the Size and Distribution of the World's Christian Population\u201d Prior to the Pew Forum's findings, I reported on an unexpectedly high burden of disease resulting from neglected tropical diseases in Catholic-majority countries Shown in The latest information from WHO's Preventive Chemotherapy and Transmission Control (PCT) Databank allows us to superimpose onto the Pew Forum findings the number people who require treatment for either intestinal helminth infections For Chagas disease\u2014predominantly a disease of the LAC region, which is overwhelmingly Christian\u2014almost all of the cases (96%) are found in Latin American nations The findings confirm that approximately one billion Christians who live in developing countries of Africa, Asia, and the Americas are highly vulnerable to NTDs. These diseases, which are highly destabilizing and associated with chronic and debilitating effects, represent a major force that traps the world's poorest Christians in poverty.Today, both the intestinal helminth infections and schistosomiasis are being targeted through regular and periodic mass drug administration (\u201cpreventive chemotherapy\u201d), costing less than 50 cents per person; but WHO estimates that currently only 35% of the world's population eligible for preventive chemotherapy actually receives essential NTD medicines Christian institutions and organizations could have an important role in expanding the control or treatment of NTDs among the 1.3 billion Christians estimated to live in the Global South. As was pointed out earlier, both local archdioceses of the Catholic Church and Catholic charities have been involved in implementing deworming and other preventive chemotherapy strategies Today, the NTDs represent some of the most common afflictions of global Christianity. It is especially noteworthy that Chagas disease and HAT are today almost exclusively a disease of impoverished Christians. Through NTDs, a renewed dialogue with faith-based organizations that work in developing countries and elements of the hierarchy of the Christian Church could make an important difference in global Christianity and the lives of the world's poorest people."}
+{"text": "This review explores the natural products of seagrass that are to be exploited for their bioactive potential. Beside from portraying the presence of a wide array of secondary compounds such as phenols, flavonoids, sterols and lipids from different seagrass species, the focus is on novel natural products projecting towards their biological applications. Though there are a significant number of reports on the abundance of secondary metabolites from seagrass and their bioactive derivatives, only a small number of reports explore their functional and defensive characteristics. Efforts have been made to collate the available information on seagrass natural products and clarify their function and metabolic pathway\u2019s. It is emphasized that metabolic profiling of seagrass should be extensively progressed to obtain a deeper knowledge about the specific roles of each natural product. The investigation of seagrass natural products for their bioactive potential would most likely result in the detection of surprising and unexpected novel chemical structures and clinical leads that may be useful to mankind."}
+{"text": "Many papers have used fluorescent probe diffusion to infer membrane viscosity but the measurement is actually an assay of the free volume of the membrane. The free volume is also related to the membrane tension. Thus, changes in probe mobility refer equally well to changes in membrane tension. In complicated structures like cell membranes, it appears more intuitive to consider variations in free volume as referring to the effect of domains structures and interactions with the cytoskeleton than changes in viscosity since tension is a state variable and viscosity is not. Many papers have used fluorescent probe polarization or anisotropy to infer membrane viscosity \u20138] and  and 8] af by the relationA and B are constants, the latter being about unity. This approach successfully explained the data on temperature and pressure dependence of liquid viscosity. However, the free volume of lipid membranes is directly related to membrane tension so measures of probe mobility also reflect membrane tension  stu stu12] s"}
+{"text": "Understanding the factors affecting participant attrition in trials is essential for ensuring ethical and effective conduct, appropriate power of the study and successful completion of data collection.The purpose of this research is to explore factors affecting the retention of patients with mental health problems in non-pharmacological randomised controlled trials (RCTs). This paper reports on a qualitative study with staff working on trials aiming to investigate the processes and strategies employed in mental health RCTs.Trialists from universities and research centres in the UK were recruited to take part in this qualitative study. 30 semi-structured interviews were conducted to understand the experiences of staff working on trials, the processes involved in planning and running RCTs and specific issues relevant to clinical research in mental health. The data were analysed using a framework analysis approach.This paper will focus on what retention strategies are used in non-pharmacological mental health trials, how the issue of attrition is dealt with, and what trialists perceive to affect participants\u2019 decisions about staying involved or ceasing their involvement."}
+{"text": "Multicenter databases are useful tools for quality improvement programs. Most of this evidence is based on studies in North America and Europe and little is known in other regions. Since 2011, a Brazilian private cardiovascular center has joined an international registry of cardiac surgeries.To evaluate changes in quality indicators and clinical outcomes of cardiac surgery patients after a multifaceted educational program based on reports of an international database.A multifaceted and continuous educational program based on trimestral reports from the international database was implemented in a Brazilian cardiovascular center. A local team targeted reductions in the time of mechanical ventilation (MV), in length of stay and in the number of inappropriate transfusions. A pilot protocol for rational use of blood products based on guidelines was developed in 2011 [From January 2012 to December 2013, 667 CABGs were performed. The predicted risk of in-hospital mortality by the score of the Society of Thoracic Surgeons (validated in the hospital [These results indicate that quality improvement program based on international database reports can improve outcomes in a Brazilian private hospital. Global registries can be useful tools to overcome gaps in clinical practice in different countries."}
+{"text": "Stab wounds to the neck can be potentially lethal. They are often associated with vascular injury of the carotid artery and jugular vein. Injury of the vertebral artery is rarely seen. The injury can vary from severe bleeding after transection with hemorrhage into the surrounding soft tissues of the neck to dissection and separation of the intimal lining from the subjacent media of an artery and subsequent occlusion of the vessel. We report a case of traumatic vertebral artery transection managed by minimal invasive balloon occlusion. Injury to the cervical carotid arteries are a well-recognized phenomenon in sharp and even blunt neck trauma. Injury to the vertebral artery is less common. The deep location of the vertebral artery within the neck makes injury relatively less common. This deep location also makes it difficult to detect and manage  ending in a complete stop  if the vertebrobasilar circulation permits this. If the vertebrobasilar circulation is at risk, a covered stent can be placed if the transection can be traversed. If this is unsuccessful a temporary occlusion should be performed to control the bleeding and subsequent definite repair should be performed."}
+{"text": "The recognition of facial dysmorphism remains an important skill for clinical geneticists to acquire despite the expanding use of next generation sequencing tools for the identification of gene mutations and related anomalies. Phenotype-genotype correlations, for example, still have an important role to play in diagnosis and prognosis. Facial morphology can now be quickly captured in 3D and analysed with the support of appropriate computer software. This talk will describe how: 3D images of affected individuals can be combined to delineate characteristic facial features of genetic and related conditions; static and dynamic visualisations can help a clinician to identify what is atypical in an individual child\u2019s craniofacial development; quantitative analysis of face shape can assist with diagnosis and the study of phenotype-genotype correlations; links can be established between facial dysmorphism and neuro-cognitive disability arising from genetic anomaly and teratogen exposure."}
+{"text": "K-RAS oncogene would save at least US $600 million a year. On the other side, many papers in the course of biomarker discovery projects have been published yet, but only few clinically useful biomarkers have been patented and successful validated for routine clinical practice. The reasons for the limitation to bring biomarkers successful on the market are manifold. Regulatory and scientific hurdles as well as lack in the biomarker validation and lack in the technical validation have been cited as one of the main reasons for the slow growth in this area. Whilst the majority of the published biomarkers will not be translated into diagnostic tests, the growth of biomarker used in clinical diagnostics indicates that the future of the industry will lie in the CDx co-development. The first drug introduced using the CDx co \u2013 development \u2013 Herceptin  \u2013 has now been on the market for several years. Our study focus on some economics and technical factors that should be considered to successfully develop and market a companion diagnostic test, based on lessons learned from recent case studies. A proposed framework of considerations to be addressed at the various stages of developing effective companion diagnostic test is also presented.In view of an urgent need for novel therapeutics that have a positive impact on morbidity and mortality of chronic diseases, the field is now moving more quickly towards clinical translation from biomarker identification to the development of an companion diagostic (CDx) test. The implimentation of such CDx test is driven by smart preclinical validation, a better study design and improved surrogate readouts using currently available methodologies and diagnostic techniques. Moreover, upcoming novel biomarkers and diagnostic technologies will soon permit a more accurate and efficient assessment of disease progression and regression. The ability of biomarkers to improve treatment and reduce health-care costs is potentially greater than in any other area of current medical research. For example, the American Society of Clinical Oncology estimates that routinely testing people with colon cancer for mutations in the"}
+{"text": "Numerous studies have been conducted in the West on the educational needs of minority students. These studies indicate that students from particular ethnic backgrounds have unsatisfactory educational experiences and various learning difficulties , 2. AlthThis paper investigates South Asian students\u2019 learning experiences and addresses issues of further studies and career preparation through understanding of their educational and vocational aspirations. Semi-structured interviews were carried out with Secondary 4 and 5 South Asian students in one designated and one non-designated school during April and May 2013.The results reveal the diversity of needs among South Asian students during learning. The majority of the South Asian students interviewed aspired to \u2018mainstream\u2019 education and occupations, but they were acutely aware of their inability to fulfill their ambitions. Students\u2019 emphasis on making themselves work harder in the pursuit of their aspirations testifies to the entrenched ideology of competitive individualism in local society. Because a limited number of affordable educational services target South Asian students at senior secondary level in the community, this calls for increased investment of the government on after school educational services for South Asian students across all levels of schooling. However, some interviewees were not aware of other educational choices except for mainstream secondary schools and universities.Educators should recognize that academic education is not the best for everyone. There are alternative education programs available for those who do not cope well in the mainstream educational path, and vocational education and training (VET) is a way to improve students\u2019 employability. Schools serving ethnic minority students are recommended to strengthen their career guidance services and make information and knowledge of VET more available to students and parents. These include technical and vocational programs targeting Secondary 3 and Secondary 6 transitions."}
+{"text": "High throughput technology makes it possible to monitor metabolites on different experiments and has been widely used to detect differences in metabolites in many areas of biomedical research. Mass spectrometry has become one of the main analytical technique for profiling a wide array of compounds in the biological samples. Extracting relevant biological information from large datasets is one of the challenges. Missing values in metabolomics datasets occur widely and can arise from different sources, including both technical and biological reasons. Mostly the missing value is substituted by the minimum value, and this substitute may lead to different results in the downstream analysis. Different methods tend to give different results. In this study we summarize the statistical analysis of metabolomics data with no missing values and with missing values. With the missing values, we compare the different methods and examine the outcomes based on each method.Analysis was done on 276 metabolites from 10 samples (12 metabolites excluded due to not detected in either group). 204 metabolites had complete information in all samples[Zero gave the least number of significant metabolites whereas Mean gave the most. 55 metabolites were uniquely identified by all methods in the volcano plot; 28 metabolites were similar across all methods.We have shown that the selection of imputation methods to replace MVs may have a dramatic impact on the data. The handling of missing values is an absolutely crucial step in the data pre-processing. Metabolites such as adenylosuccinate, caprylate (8:0) and N-acetylalanine are only detectible by a specific method and may be important in their specific metabolic pathways and so choosing an appropriate method is critical. Also PLS-DA FAD is important for only kNN in predicting the class membership whereas adenine and adenylosuccinate is important only for Zero and Mean Methods. In future studies we will further examine MVs and model an appropriate method such that the correct significant metabolites are captured."}
+{"text": "Peripheral odontogenic lesions are considered to be rare within the classification of odontogenic tumors. They share the same microscopic characteristics of their central counterparts. Here, we report an ulcerated mass of the maxillary gingiva that on histopathological examination was diagnosed as peripheral developing odontoma or peripheral ameloblastic fibroodontoma. The diagnosis of this tumor is challenging and may lead to unnecessary treatment. An 8-year-old healthy girl was referred to the pathology department for examination of an isolated and ulcerated soft tissue mass of the palatal gingiva in the region of right canine and deciduous first molar, measuring 0.8 \u00d7 0.8\u2009cm with unknown duration. There was no history of trauma to the area. The periapical radiograph did not show any intrabony lesion. The mass was excised under local anesthesia with clinical diagnosis of reactive soft tissue lesion most probably pyogenic granuloma (PG) or peripheral ossifying fibroma (POF). The cut surface of the lesion was creamy solid . On histOdontogenic neoplasms are categorized into peripheral and central. The relative frequency of peripheral odontogenic tumors is rare and there is no valid information of their frequency in the literature . SaghravOdontoma and ameloblastic fibroodontoma belong to mixed odontogenic tumors group and are composed of odontogenic epithelium and ectomesenchyme . Some auThe etiology of odontogenic tumors is indefinite and their source is the remnants of dental lamina that reside in the gingiva (rests of Serres) and develop lingually to those of the primary teeth . TherefoThe clinical presentation of this case was similar to PG and POF because of an ulcerated surface and the gingival involvement. In the case described by Kintarak et al. , focal fThe presence of dental tissue outside the alveolar process may be associated with ectopic neural crest cells that are still able to differentiate into tooth germ . It is dThe treatment choice is conservative surgical excision . RecurrePeripheral odontoma and peripheral ameloblastic fibroodontoma are exceedingly rare benign odontogenic lesions that are treated by conservative excision. The proper diagnosis of these lesions is necessary to avoid confusion with true neoplasms especially odontogenic tumors and prevent extensive surgery. Therefore, it is essential for oral pathologists to be familiar with clinical and microscopic characteristics of peripheral odontoma."}
+{"text": "Coxiella burnetii will rise.Q fever is a disease with worldwide distribution. The real number of patients with this disease is underestimated due to its nonspecific symptoms and because of the difficulties associated with serological diagnosis. Some of the patients diagnosed in the first stage with Q fever later develop chronic disease. Endocarditis is the most frequent and severe form of chronic Q fever. In the National Institute for Infectious Diseases \"Prof. Dr. Matei Bal\u015f\" the number of patients diagnosed with Q fever has significantly increased in the last few years. The number of cases from the first half of 2014 almost exceeded the whole number recorded in 2013. In these circumstances we expect that the number of cases of endocarditis with Coxiella burnetii).We retrospectively analyzed the patients diagnosed with Q fever with endocarditis in the Matei Bal\u015f Institute between 2011 and 2014. Of 89 patients with Q fever, 4 patients met the inclusion criteria (endocarditis plus serologic diagnosis of Coxiella burnetii by ELISA was used as screening test for the etiologic diagnostic that was confirmed by dosing phase I and II IgM and IgG antibodies. All patients initially received empiric therapy with association between betalactams and aminoglycosides. After the etiologic diagnosis was established, the patients were treated with doxycycline in association with ofloxacin/rifampin.All the patients were males with a median age of 58.25 years. All of them lived in urban area and were admitted for prolonged fever. Three out of four patients presented hepatitis with ALT elevation and cholestasis at admission. All blood cultures taken during hospitalization were negative. Endocarditis diagnosis was established after echographic evaluation. In three cases the aortic valve was affected while in the other case the aortic valve was impaired. Detection of IgM antibodies for Coxiella burnetii must be considered as a possible etiologic agent in case of endocarditis with negative blood cultures especially in the context of increasing numbers of patients diagnosed with Q fever. The association between fever, hepatitis and interstitial pneumonia must be an additional argument for considering chronic Q fever with endocardial impairment a possible diagnosis."}
+{"text": "Hospitals are the most costly operational and really important units of health system because they consume about 50%-89% of total health resources. Therefore efficient use of resources could help in saving and reallocating the financial and physical resources.The aim of this study was to obtain an overview of hospitals' performance status by applying different techniques, to compare similarities and differences between these methods and suggest the most comprehensive and practical method of appraisal for managers and policy makers.This is a cross sectional study conducted in all hospitals of Ahvaz  during 2007 to 2011. Two kinds of data were collected through separate special checklists. Excel 2007 and Windeap 2.1 software were applied for data analysis.The present findings show that the average of bed occupancy rate (BOR) in the studied hospitals was about 65.91 \u00b1 1.16. The maximum number of inefficient hospitals in the present study happened in the years 2007, 2008 and 2010  but there were two hospitals in the third part of the present graph which had maximum level of efficiency and optimal level of productivity in the years 2007 and 2009. Data Envelopment Analysis (DEA) showed that the mean score of technical efficiency for the studied hospitals is 0.924 \u00b1 0.105 with the minimum of 0.585 \u00b1 0.905 for hospital number 1. Furthermore It shows that only five hospitals (31.25%) reach complete technical efficiency (TE) scores across all five years of 2007-11 (TE = 1).Results of the present and similar studies should be considered for the future planning and resource allocation of Iranian public hospitals. At the same time it is very important to consider need assessment results for each region according to its potentials, population under the coverage and other geographical and cultural indices. Furthermore because of potential limitations of each of the above models it is highly recommended to apply different methods of performance evaluation to reach a complete and real status view of the hospitals for future planning. Health is an absolute right of the all members of the society and health care sector is considered as one of the most significant service sections, so its indicators are considered as one of the main criteria developmental level and social welfare of any country . On the Hospitals are the most costly operational and really important units of health system because they consume about 50%-89% of total health resources . NationaRatio analysis as one of the non parametric technical-efficiency assessment methods, which includes the separate examination of various key measures such as average cost per inpatient day, bed occupancy rate, average length of stay, bed turnover ratio and so on . But as SFA is a parametric linear programming method that uses an integrated data set considering a special form of production function for assessing efficiency but because of some potential challenges, it is suggested to be used along with other techniques . DEA, a This study was conducted to present an overview of the efficiency of all hospitals in Ahvaz  applying Pabon Lasso, DEA and Malmquist indicators to compare similarities and differences between the results obtained by these methods and suggest the most comprehensive and practical ones for managers and policy makers.This cross sectional study was conducted in all 16 hospitals of Ahvaz , Ahvaz, Iran during 2007 to 2011. All of them were specialized hospitals. Hospitals No. 1-8 were affiliated with the Jundishapur University of Medical Sciences in Ahvaz and the rest were nonaffiliated. Two kinds of data were collected through separate special checklists, one for indicators of Pabon Lasso and the other for assessing efficiency according to DEA and both were designed based on the research goals. Pabon lasso is a graphical model for demonstrating hospital performance using three indicators: bed occupancy rate (BOR), bed turnover (BTO) and average length of stay (ALS). This graph compartmentalizes the hospitals into four divisions: The first part stands for those hospitals with low BTO and BOR implying a surplus in hospital beds against the existing demand, however the second sector shows the hospitals with high BTO and low BOR which indicates unnecessary hospitalizations, an oversupply of beds, or using the hospital beds for simply observing patients. The third segment indicates those hospitals with high BTO and BOR that simply means an appropriate level of efficiency, with relatively few vacant beds at any time and finally the last category presents the low BTO and high BOR that may emerge because of admitting patients with chronic diseases or unnecessarily long ALS , bed turn over (BTO), and average length of stay (ALS). The items of these checklists were filled for each of the studied years. Data achieved from the first checklists, was analyzed using Excel 2007 according to Pabon lasso model for presenting the related graphs. Then, another checklist was designed for obtaining the necessary data in order to form an input \u2013 oriented DEA model. Variables were categorized as inputs  and bed occupancy rate number of patients and number of operations were considered as outputs. The related data were collected from the statistic's center of the Jundishapur University of Medical Sciences and other hospitals for a total of 16 hospitals during 2007-2011. Windeap 2.1 software was applied for further analysis.Three determinant indicators constructing Pabon Lasso model are presented in In contrast, there were only two hospitals in the third part of the graph which stands for efficiency and optimal level of productivity in the years 2007 and 2009. This number has been increased to three hospitals in 2008 and 2010, and 4 hospitals in 2011 as fully efficient units. Another important finding of this graph is that most of the hospitals were located in the second and the forth zone during 2007 to 2011 which may be due to unnecessary hospitalizations, an oversupply of beds, using the hospital beds for simply observing patients (second zone) or admitting chronic patients with unnecessarily long ALS (forth zone). The aveBeing aware of the hospitals\u2019 performance and efficiency is one of the major concerns of health policy makers and health care manager\u2019, although applying a unique scientific technique for hospital performance evaluation, efficiency estimation and determination of the effective factors has not been achieved yet. All the above methods have their own restrictions alongside their strengths, for example despite DEA's advantages in calculating the relative and not absolute efficiency and incorporating multiple input and output factors and also determining optimum level of practice and performance targets , there aEven though Pabon Lasso gives an instant picture of the hospital, its related indices may be influenced by different factors that cannot be calculated applying this simple model . ConsideMoreover, the maximum number of inefficient hospitals in the present study belonged to the years 2007 and 2008  in contrast with another study on Ahvaz University of Medical Sciences hospitals demonstrating that two hospitals were situated in the first zone in the year 2009 . FurtherThese differences can be justified by the fact that the present study only included 16 hospitals in Ahvaz but Zahiri  includedThis study like other studies performed in Iran showed that there was a surplus in the studied hospitals\u2019 inputs  in the hospitals affiliated with the medical governmental universities . It is oThis finding are justified applying Malmquist index that showed hospital number 2 was presented as the best and hospital number 14 was achieved the worst performance level considering the rate of change in the productivity. So it is recommended to consider the the present results and results of similar studies for the future planning and resource allocation of hospitals. At the same time it is very important to consider need assessment results for each region according to its potentials, population under coverage and other geographical and cultural indices. Furthermore because of potential limitations of each of the above models it is highly recommended to apply different methods of performance evaluation together to reach a complete view of the real status of the hospitals for future planning."}
+{"text": "RSV is the main cause of childhood lower respiratory infections, globally, an important cause of childhood wheeze and may be responsible for a substantial burden of disease in the very elderly and in adults with chronic medical problems, such as COPD. It is thus responsible for substantial healthcare and social costs. There are currently many companies and academic groups developing and testing candidate vaccines and there is an expectation that these will lead to effective and safe vaccines which will be available to health systems globally in the short \u2013 medium term. Despite this, there is an incomplete understanding of RSV disease, especially in adult groups, and large scale data are only available from a few countries and settings leading to low levels of awareness of the importance of this pathogen. We discuss the need for widespread national sentinel systems of RSV surveillance and some means by which this could be achieved. These data will be needed by national policy makers and immunisation advisory groups to guide future priority setting and decision making. Journal of Global Health there is a short series of papers on respiratory syncytial virus infection (RSV). RSV is a major cause of morbidity and mortality worldwide and has been estimated to cause about 34 million episodes of acute lower respiratory infections (ALRI) in young children globally each year, with over 3 million severe enough to cause hospitalisation [In this issue of the lisation . These elisation .In 2015, the World Health Organization (WHO) Product Development for Vaccines Advisory Committee (PDVAC), which scans the horizon for likely important vaccine developments in the coming decade, highlighted RSV as \u201ca pathogen for which there is major vaccine pipeline activity, high technical feasibility, and major disease burden in low and middle income countries (LMICs)\u201d. They summarised the current status of vaccine research as of June 2014 , and thiCurrently, these developments are gaining momentum ahead of action to gather information to raise awareness and inform policy discussions globally. Although RSV disease accounts for very significant health care and social costs globally, there is a low level of recognition of this among government policy makers. Thus, to support these developments there is a need to assemble epidemiological data on RSV through national and other large scale surveillance systems. This could provide data on:\u2022 burden of RSV disease by age group, by key risk groups and by geographical setting;\u2022 RSV seasonality patterns across the world; and\u2022 RSV viral parameters such as subtypes and genotypes.They could also provide baseline data on hospitalisations from RSV ALRI against which the impact of a future vaccine could be assessed at national scale.RSV is not currently a notifiable disease and there are no well\u2013established ongoing surveillance systems in existence. A sophisticated Global Influenza Surveillance and Reporting System (GISRS) functions well with data from over 140 National Influenza Centres globally and with the sharing of over 1 million respiratory samples for influenza detection. The paper by Shi and colleagues in this edition of Journal of Global Health demonstrates that about 90% of ALRIs in children in which RSV is detected can be causally ascribed to RSV. Some of the GISRS sites conduct acute surveillance of Severe Acute Respiratory Infections (SARI) in all age groups and although case definitions and sampling procedures are designed to identify episodes of SARI due to influenza there is the potential to adapt this surveillance system to also identify episodes of ALRI due to RSV. Key issues to address in this adaptation would include the differing seasonal pattern of RSV, the different age pattern of RSV disease (with more emphasis on the first 2 years of life) and the differing clinical presentation of cases (with fever absent in up to 80% of cases in children) . Most seIt is not fully clear how the existing GISRS systems can best be adapted for RSV surveillance but this will at least require the development of separate case definitions and RSV\u2013specific standard operating procedures for identification of the target population, data collection, analysis and reporting. This will require specific study and the new scheme will need to be validated before wide adoption. The proposed global web\u2013based FLuMART platform for sharing epidemiological (FLuID) and virological (FluNet) data could serve as a base from which an RSV information and reporting system could be built. A major advantage of this approach would be the existing excellent linkages to national policy makers globally who already receive weekly reports from GISRS. These developments will need to be supported by RSV reference laboratories which can conduct external quality assurance of participating laboratories. It will be essential to ensure that this development does not degrade the quality, completeness or timeliness of data on influenza since the GISRS data represents a vital public health activity eg, in informing annual influenza vaccine composition and in pandemic preparedness. Thus, it would be prudent to start with pilot projects in a few countries in each global region supported by a few designated RSV reference laboratories and this is the approach currently being proposed by WHO .In high\u2013income countries, in addition to the approach noted above, other options could be feasible. These could include bespoke hospital\u2013based surveillance schemes focused on RSV or, as in Canada (in their Serious Outcomes Surveillance (SOS) and Immunization Monitoring Program ACTive (IMPACT) paediatric surveillance network ), be parReductions in mortality from childhood pneumonia have been the largest single contributor to global falls in post\u2013neonatal child mortality over the past decade and have been due to a variety of factors associated with socio\u2013economic development as well the introduction of new vaccine and other interventions. The development of effective new vaccines and other prevention strategies to tackle RSV have the potential to make major contributions to reducing severe disease and deaths from RSV in children globally. These developments may also have an important impact on cardio\u2013respiratory sequelae due to RSV associated with from the growing tide of non communicable diseases among middle aged and elderly adults globally. It is important that structured data gathering systems are put in place now to gather the essential data that will be required to provide a secure evidence base to guide national, regional and global policy decisions in the near future."}
+{"text": "The lack of vascularization in the tissue engineered bone results in poor survival and ossification. Tissue engineered bone can be wrapped in the soft tissue flaps which are rich in blood supply to complete the vascularization in vivo by microsurgical technique, and the surface of the bone graft can be invaded with new vascular network. The intrinsic vascularization can be induced via a blood vessel or an arteriovenous loop located centrally in the bone graft by microsurgical technique. The peripheral nerve especially peptidergic nerve has effect on the bone regeneration. The peptidergic nerve can be used to construct the neurotized tissue engineered bone by implanting the nerve fiber into the center of bone graft. Thus, constructing a highly vascularized and neurotized tissue engineered bone according with the theory of biomimetics has become a useful method for repairing the large bone defect. Many researchers have used the microsurgical techniques to enhance the vascularization and neurotization of tissue engineered bone and to get a better osteogenesis effect. This review aims to summarize the microsurgical techniques mostly used to construct the vascularized and neurotized tissue engineered bone. The seed cells such as bone marrow stem cells in the center of the bone graft will lack enough nutrition and finally die. The osteogenesis is influenced by the process of vascularization and this limits the clinical application of tissue engineered bone. Over the last few years, many researchers have used the microsurgical techniques to enhance the vascularization of tissue engineered bone and get a better reparative effect in bone defect [It is a big challenge for surgeons to repair the large bone defect caused by the trauma, infection, tumor, or other reasons. Autologous bone grafting is considered as the golden standard for the clinical treatment of bone defects \u20135, but te defect \u201310. Tisse defect \u201313. Besie defect . The pere defect \u201318. So ce defect \u201321. We aTissue flaps such as fascia flap, muscle flap, and peritoneum flap have rich blood supply and can be used as the vascular bed to enhance the vascularization of tissue engineered bone \u201324. BefoThere are several kinds of soft tissue flap that can be used to enhance the vascularization of tissue engineered bone. Fascia flap, muscle flap, and periosteum flap are the most commonly used to wrap the bone graft.Fascia flap has rich capillary network and excellent permeability as a most suitable soft tissue flap for enhancing the vascularization. Our group is the first to report the use of fascia flap to enhance the vascularization of tissue engineered bone in the large animal model of goat. We found that pedicled fascia flap could accelerate the revascularization and osteogenesis process of tissue engineered bone in large animal model . Liu et Muscle flap also has rich blood supply and is usually used to repair the soft tissue defect or infected wound in clinical patients. The latissimus dorsi muscle is the most commonly used to wrap the tissue engineered bone. Casabona implanted a porous hydroxyapatite ceramic scaffold with the human bone marrow stromal cells into the latissimus dorsi of athymic mice and found the presence of new spongious bone tissue . TerheydPeriosteum flap also has rich blood supply and can be used to induce bone regeneration. There are many reports about using the periosteum or cultured periosteal cells to enhance the osteogenesis and vascularization of tissue engineered bone \u201345. A vaAlthough tissue engineered bone grafts can be wrapped in the soft tissue flaps which are rich in blood supply to enhance the vascularization in vivo by microsurgical techniques, only the surface of bone graft can be invaded with new vascular networks and the pattern of the new blood vessels is random. The intrinsic vascularization of bone graft is still not achieved with this method of soft tissue flap wrapping.The intrinsic vascularization can be induced via a blood vessel located centrally in the bone graft by microsurgical technique. There are many reports about the use of the carotid artery, jugular vein, and saphenous vascular bundle in biomaterials resulting in splendid osteogenesis and vascularization of the bone grafts \u201350. SurgAlthough the method of embedding axial blood vessel is available for enhancing the intrinsic vascularization of tissue engineered bone, the clinical application may be limited by the length and anatomic location of blood vessel. So a new method of arteriovenous (AV) loop has been used to enhance the intrinsic vascularization. This AV loop has been proved to be superior compared to the axial blood vessel both in terms of neovascular density and capacity . This meLike autologous bone grafts, the new vascularized bone graft can be transferred to the bone defect site using the microsurgical techniques. This method of embedding blood vessel or AV loop will facilitate the clinical application of tissue engineered bone and offer new therapeutic strategies for reconstruction of large bone defects.Bone tissue is not only a highly vascularized tissue but also a highly neurotized tissue. By the anatomy study of the bone tissue, many researches have proved that there were dense and intimate networks of nerve in the bone tissue and the nerve networks had contact with bone cells \u201362. Our \u03b2-TCP scaffold to repair a 1.5\u2009cm femur defect in the rabbit. The values of bone mineral density and the neuropeptide were significantly higher in sensory nerve group compared with the motor never group and the blank group. But the ossification and nervalization effects of motor nerve group showed no significant difference compared with that of blank group [\u03b2-TCP scaffold. This method could make the neuropeptide, which was produced by the neurons, release from the distal end more easily, and it acted on the BMSCs via its receptors to regulate the metabolism of the bone.The ability of the peptidergic nerve fiber to regulate the function of osteoblasts and blood vessels can be used to construct the neurotized tissue engineered bone by embedding the nerve fiber into the center of bone graft \u201321. As wnk group . These rnk group . AlthougOur group also evaluated the different effects on the expression of calcitonin gene-related peptide (CGRP) and neuropeptide Y (NPY) between tissue engineered bone with blood vessel in vivo or with sensory nerve tract. We found implantation of blood vessel into tissue engineered bone could significantly improve the expressions of CGRP and NPY at the early 3 months compared with implantation of sensory tract into tissue-engineered bone, but the differences were not significant at 6 or 12 months postoperatively . We alsoAlthough sensory nerves can enhance the osteogenesis of tissue engineered bone, the neurocyte also needs the oxygen and nutrients. The neurotization of tissue engineered bone needs the vascularization as the preconditions. Masaki connected a silicone gel tube to the sciatic nerves of mice and then placed a small artery that was adjacent to the sciatic nerve into the silicone gel tube through a longitudinal incision to provide oxygen and nutrients to the regenerated nerve . The impThe lack of vascularization and neurotization within the tissue engineered bone results in poor ossification and limits the clinical application of tissue engineered bone. The vascularization of bone grafts can be promoted by soft tissue flap wrapping, blood vessel embedding, and arteriovenous loop embedding centrally in vivo by microsurgical techniques, but this method has the disadvantage of uncertain neurotization effect. The neurotization of bone grafts can be promoted by peptidergic nerve tract embedding centrally in vivo by microsurgical techniques, but this method also has the disadvantage of uncertain vascularization effect. So each method has the superiority and disadvantage. Combination of different methods will be necessary and useful to improve the reparative effect of tissue engineered bone in the large bone defect. We give the concept of constructing the highly vascularized and neurotized tissue engineered bone simultaneously by microsurgical techniques according with the theory of biomimetics. The microsurgical techniques will play a more and more important role in the development of bone tissue engineering and eventually achieve the wide clinical application of tissue engineered bone to repair the bone defect of patients."}
+{"text": "Large genomic segments spanning millions of nucleotides commonly differ between any two genomes, including between monozygotic twins  are a prevalent type of SV that make up an extensive portion of genetic diversity. Katju and Bergthorsson  contribuThe divergence of CNVs between populations may help identify candidate regions under selection. Bryk and Tautz  tested tThe evolutionary and functional consequences of CNVs in livestock are an important area of research with economic relevance and are reviewed by Bickhart and Liu . The autFocusing on the evolutionary implications of SVs, Keane et al.  review sGiven that SVs are important to consider when studying genetic diversity and genome evolution, as highlighted by the contributions to this research topic, improvements in SV detection and analysis should be a priority to better evaluate the impact of SVs. Most current methods are poor at defining breakpoints at a fine scale, making it difficult to determine the mechanism of SV formation\u2014an essential requirement for understanding the evolution of SVs. Moreover, the ability to accurately genotype SVs would allow a population genetic framework analysis that can make use of allele frequency changes to determine the evolutionary dynamics of SVs. Despite these limitations, essentially any organism can now be screened for SVs, which will lead to increasing our knowledge on the ecological and evolutionary implications of genomic SVs.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Student dietitians are often very interested in developing skills in the assessment and management of clients with eating disorders. This may be difficult; clients often decline student participation in their care due to the sensitive nature of their condition. Nourishing Networks, a self-directed health professional learning program, was developed to enhance clinician knowledge and management skills for individuals with disordered eating and assist with the formation of local networks of support. This program was adapted and piloted for dietetic students attending placement at the University of Newcastle Department of Rural Health Tamworth. The aim of the program was to enhance the students', knowledge and skills in the management of eating disorders. Students were offered the opportunity to participate in the 10 week program. Results showed all students furthered their knowledge, skills and attitudes towards eating disorders and were better able to determine appropriate treatment plans. This program allowed students to gain tools for working with clients that they would not otherwise be exposed to in their undergraduate degree and associated placements. Future plans include the presentation of an Eating Disorder Interprofessional Learning Module for nursing, medical and allied health students and subsequently offering this 10 week program to these students."}
+{"text": "Evolutionary forces shaped the molecular complexity of these natural products that contribute to the exquisite binding of these compounds to biological targets. Starting with the discovery of penicillin by Fleming, we have seen a rapid increase in the discovery and production of natural products and derivatives thereof as antibiotics and other drugs. But once the \u2018easy to access\u2019 bioactive compounds have been isolated, the drug discovery pipeline slowed down beginning in the 1990s. Pharmaceutical companies turned away from natural products as screening programmes led to the rediscovery of known structures and development of structurally complex natural products into drugs using synthetic methods proved to be challenging and too expensive if no reliable biological sources were available. Considering the urgent need for the development of new drugs to combat multidrug-resistant pathogens and overcome long-term side-effects and/or reduction in effectiveness of current drugs, unlocking nature's treasure trough of small-molecule chemodiversity will be crucial for next-generation drug development  and from complex microbial ecosystems. Recent work has shown that metagenomic libraries from microbial ecosystems can be successfully arrayed and screened for large biosynthetic gene clusters of interest based on homology to conserved regions of known biosynthetic genes such non-ribosomal peptide synthases or polyketide synthases  that can be grown in the lab will be crucial to develop algorithms for accurate structural annotation. High-resolution transcriptomics analysis of diverse species will enable the construction of gene co-expression networks built on physical distance to seed genes that are frequently associated with natural products biosynthetic pathways  could be a means for the discovery of novel pathways and sequences for broader"}
+{"text": "In low-income countries, and particularly those in Africa, there are two important landscapes that have changed profoundly in recent years. One is the architecture of global health with its resulting increase in both the volume and complexity of health financing at country level. The second is the accelerating health transition in such countries where the past decade has witnessed declines in child mortality and increases in life expectancy at paces that have never been seen before in any period of history in any society. These health gains are not just a result of improving socio-economic development, but are consequent to important changes in health services and systems that have improved access to and coverage of several efficacious and cost effective essential health interventions funded in part by global health initiatives.The dynamics of this health transition naturally result in very different and continually changing patterns of risk factors and attendant burdens of disease. Unfortunately the improvements in health systems in such countries have not yet included the necessary changes in, or even development of, appropriate means of monitoring the dynamics of the disease and risk factor patterns on a routine basis suitable for forward planning and policy making that will adequately steer development of the future health systems needed to respond to these dynamics. We remain too dependent on burden of disease modelling based on intelligent, but not sufficiently empirical real time data at country level on disease and risk factor dynamics. This is particularly so for cause of death data of acceptable coverage and quality in low-income countries where premature mortality still constitutes the largest share of disease burden DALYs. At the same time, the share of burden constituted by disability is rising rapidly from a much more varied set of causes and risks which are also changing due to demographic transition and other evolving phenomenon such as urbanization and globalization. These dynamics will require very different health systems and policies.This presentation will discuss the need for linking three critical health information sources: 1) radical new approaches to routine longitudinal civil registration and vital statistics for disease burden monitoring, coupled with: 2) periodic national risk factor surveys that link to: 3) new approaches to monitoring district level health service coverage of services needed in response to the changing burdens and risks. Integrating across these data sources would provide the missing information strategy for evidence to feed more responsive health system planning and policy making needed for achieving universal health coverage."}
+{"text": "It is widely acknowledged that allopolyploidy via hybridization and genome doubling can easily lead to speciation, as polyploid hybrids can be immediately isolated from diploid parental taxa due to high levels of sterility caused by uneven numbers of chromosome complements in their progeny  of either parent, given long term interaction between and adaptive evolution of flower characters of parental species and pollinators  by attracting hummingbirds due to large red flowers, while I. hexagona is mainly pollinated by bumblebees due to blue flowers, although other isolation barriers such as habitat and environmental isolation are also present  and Fundamental Research Funds for the Central Universities (15lgjc23).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Sepsis is an important cause of mortality and morbidity for preterm and hospitalized newborn babies. Today, no single test satisfies the criteria as being the ideal marker for the early diagnosis of neonatal sepsis. Analysis of the entire metabolome is a promising method for determining metabolic variations correlated with sepsis -6.Works on metabolomics concerning sepsis conducted on animals and humans of different ages (newborn and adults) have recently been published and are presented in Table Present-day methods and procedures for the diagnosis of systemic neonatal infections are hindered by low sensitivity and long response times. Metabolomics is showing promise of becoming a most effective method, even in neonatology and paediatrics."}
+{"text": "In this context we define spatial analysis to mean Statistical Inference which takes into account spatial data, including but not limited to spatial exploratory data analysis. Groups in a Cluster randomised trial (CRT) are often defined geographically, giving spatial structure to the data. Taking account of the spatial aspects in the design and analysis of such a trial is important as it may influence results. In addition, the hierarchical structure imposed by the design should be adjusted for in the analysis. Therefore selecting software for spatial analysis of CRTs necessitates the capacity to accommodate for both spatial and clustering effects.The range of spatial software available is broad in focus and capabilities, with a plethora of options to choose from determining what tool to use is not necessarily straight forward. In the last decade due to rapid development of spatial methods in Statistical packages and the expansion of Statistical toolboxes in Geographical Information Systems there is substantial overlap in abilities.This review provides a comparison of current software options offering spatial analytical and visualisation techniques. First giving a brief account of the numerous cartographic visualisation tools, then focusing on what differentiates the capabilities of the analytical software. In regards to the latter we'll give special attention to multi-level modelling in both a Frequentist and Bayesian framework. Therefore demonstrating the flexibility of the options now available for the Analysis of CRTs taking into account spatial aspects."}
+{"text": "With advancing age venous wall thickness increases going along with a loss of elastic properties, the arterioles curl and capillary density decreases leading to a reduction of cross sectional area . Even inSo far no biomechanical model exists that investigates the influence of macroscopic and microscopic changes of cerebral blood vessels. That is why we put a model up for discussion that simulates vascular pressure propagation and enables the investigation of altered vascular properties in the context of NPH.A Matlab Simulink model was developed reproducing each vessel section by a distensible compartment. Therefore the cerebral vascular tree was divided into 13 sections from carotid artery to venous sinuses and the pulsatile carotid artery and sinus pressure were inputted as Fourier series. The cross sectional area was varied according to literature data and flow resistance was implemented taking into account the rheological characteristics of blood. The Windkessel function and relaxation properties of vascular walls were integrated by a Voigt model, enabling the variation of wall properties for each section individually. Due to the distensible vessel walls each section interacts with the CSF compartment and autoregulation was implemented by a simple proportional controller. After parameterisation mean pressure and pressure amplitude in the vessel sections showed good accordance with literature values .We have proposed a model of vascular dynamics that is able to identify the impact of altered vascular wall properties and structural changes. Furthermore the effect of different arterial and venous input pressure profiles can be analysed. These parameter analyses are part of our ongoing research."}
+{"text": "The images for Figs There is an error in the last sentence of the Deducing Parental Contributions of Alleles at CTCF BS6 subsection under Materials and Methods. The correct sentence is: Comparing these results allows each parental contribution to be deduced, see The panel labels for Figs The publisher apologizes for the errors."}
+{"text": "Psychoactive substance addiction presents a challenging public health issue worldwide particularly targeting vulnerable adolescent population  are released at regular times by the National Medicines and Medicinal Devices Agency of Serbia  in comparison to \u20ac9,450,094 back in 2004. This finding is wholly justified by previous findings on heavily increased anxiety levels among resident addicts in the former Yugoslav region compared to traditional EU-15 market economies (Jakovljevic et al., Although the situation appears to implicate an extensive public debate in this region, we should be aware of the fact that a large portion of reported consumption is clinically justified with basic mental illness. It would be highly difficult and demanding rigorous methodological approach to exactly identify the proportion of overutilization of these drugs that is attributed to abuse and addiction. Nevertheless, vast net quantity gains in consumed addictive medications in definite ATC groups by far surpass extended burden of associated psychiatric morbidity in recent years (Ristic-Ignjatovic et al., The abuse of potentially addictive medicines correlates with clinicians' decision making principles (Bendtsen et al., The underlying studies providing evidence for this contribution where funded out of The Ministry of Education Science and Technological Development of the Republic of Serbia Grant OI 175014. Publication of results was not contingent to Ministry's censorship or approval.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Children's Health Queensland, Child and Youth Mental Health Service (CHQ CYMHS) Family Based Eating Disorder Clinic is staffed by a multidisciplinary team trained in Family Based Treatment for Anorexia Nervosa (FBT-AN). A diverse range of families present to the clinic for treatment, including families where parents have separated and re-partnered to form reconstituted family groups with shared parenting arrangements. This is an increasingly common presentation to the Clinic regardless of child age, and presents unique challenges in the context of the Family Based Treatment Model. Whilst the Family Based Treatment Model does not focus on family etiological factors, the family unit is viewed as a crucial tool in facilitating recovery from Anorexia Nervosa and central to treatment strategies.This presentation will discuss how Family Based Treatment is undertaken in the Clinic with reconstituted families committed to shared parenting. Case examples will be used to demonstrate the innovative strategies utilised throughout the treatment process. The task of adhering to the principals of evidence based treatment whilst responding to specific challenges for families will be examined. Critical junctures in treatment which require careful attention in order to engage both family systems whilst creating a cohesive team will be explored.Service Initiatives: Child and Adolescent Refeeding and FBT stream of the 2014 ANZAED Conference.This abstract was presented in the"}
+{"text": "The right therapy for the right patient at the right time is the most important approach for the provision of proper health care. The field of rare diseases is an excellent example, with patients taking a more central role in the discovery and development of treatments for their disease. Limited budgets coupled with high failure rates of medicine development lead us to public-private partnerships as a model to move forward and reduce cost; no stakeholder alone has all knowledge and expertise.The newly founded BioPontis Alliance Rare Disease Foundation presents a scientific and economic partnership model designed to unleash the potential to find cures for rare (pediatric) diseases. The non-profit Foundation has developed an innovation joint venture business and scientific development structure to fill the gap between discovery science and the biomedical industry. The Foundation will establish scientific bridges across the discovery/preclinical development gap as a partner to independent academic and/or patient organizations to develop medicine candidates. The BioPontis Alliance Rare Disease Foundation intends to also establish a financial bridge between the cures \u2018push\u2019 of philanthropic resources and the commercial \u2018pull\u2019 of private sector.The Foundation will provide a professional drug discovery operation in which the necessary scientific expertise for each product/discovery initiative can be selected and applied to each program. It has a virtual network of contract research companies and academic institutes where development work can be conducted as well as bringing central project management and industry experienced managers to each initiative. With novel licensing practices, the Foundation financially honors the seeding contributions of originating scientists, their host institutions and/or the Patient organization partner. Licensing agreements have already been signed with over 12 leading US academic institutions/hospitals, offering the originators a pro rata share of revenues that are generated from the full intellectual property estate, thus removing many of the misalignments of interests in traditional licensing and sponsored research agreements. Focus on a single goal of creating potential treatments for patients is therefore assured across the BARD Foundation\u2019s model.The BARD Foundation is currently setting up financing and is seeking donations for its operations. While operating for a global patient community and market, we seek contacts with potential financial, scientific and patient organization partners in Europe and other parts of the world."}
+{"text": "Key to the clinical management of melanoma is the development of new diagnostic tools that predict individual patient prognosis and select from potential treatments those which may be effective. Identifying individual biomarkers in tumour cells to predict susceptibility to apoptotic cell death has thus far been largely unsuccessful, as apoptosis pathways show a high degree of signalling redundancy.DR_MOMP  and ApopThe combined approach is found to outperform either individual model in predicting strong and weak responses to treatment with cell death inducing drugs.This work may provide a basis for the development of improved prediction tools for clinical treatment outcomes and treatment selection in melanoma."}
+{"text": "Critical Care, particularly the article by Gando and colleagues [We read with interest the recent issue of lleagues  about thlleagues  showed dlleagues  and the lleagues  may depeAlthough most patients were considered to be treated with ATT at the early stage of DIC in this study , those tSatoshi GandoWe appreciate the interest of Wada and colleagues in our recently published article studying the JAAM DIC scoring system in patients with severe sepsis . It is nATT: antithrombotic therapy; DIC: disseminated intravascular coagulation; ISTH: International Society of Thrombosis and Haemostasis; JAAM: Japanese Association for Acute Medicine.The authors declare that they have no competing interests."}
+{"text": "The presence of lymph node metastasis is a key prognostic factor in colorectal cancer and lymph node yield is an important parameter in assessing the quality of histopathology reporting of colorectal cancer excision specimens. This study assesses the trend in lymph node evaluation over time in a single institution and the relationship with the identification of lymph node positive tumours. It compares the lymph node yield of a contemporary dataset compiled from the histopathology reports of 2178 patients who underwent surgery for primary colorectal cancer between 2005 and 2012 with that of a historic dataset compiled from the histopathology reports of 1038 patients who underwent surgery for colorectal cancer at 5 yearly intervals from 1975 to 2000. The mean lymph node yield was 14.91 in 2005 rising to 21.38 in 2012. In 2012 92.9% of all cases had at least 12 lymph nodes examined. Comparison of the mean lymph node yield and proportion of Dukes C cases shows a significant increase  in lymph node yield while there is no corresponding significant trend in the proportion of Dukes C cases . This study shows that there is increasing yield of lymph nodes from colorectal cancer excision specimens. However, this is not necessarily associated with an increase number of lymph node positive cancers. Further risk stratifying of colorectal cancer requires consideration of other pathological parameters especially the presence of extramural venous invasion and relevant biomarkers. Detection of metastasis in tumour-associated lymph nodes has a highly significant effect on prognosis in patients with colorectal cancer. All patients with one or more lymph nodes displaying metastasis are upstaged to Dukes C/stage 3 disease. This has important therapeutic consequences for a patient, as all these patients are considered for treatment with adjuvant chemotherapy. It is generally considered and accepted that examining more lymph nodes in a colorectal cancer excision specimen increases the likelihood of identifying involved lymph nodes and thus upstaging the cancer. However, recent studies have provided some contrary evidence. Data collected from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database for 86,394 patients showed that while the number of lymph nodes being evaluated increased over time but that this did not significantly increase the detection of node positive cancers. These recent studies appear to contradict the hypothesis that examining more lymph nodes increases the detection rate of node positive disease. Nevertheless the studies by Parsons et al., Despite the variation in the published evidence, guidance and standards on lymph node yield have been introduced as a quality performance indicator for the histopathology reporting of colorectal cancer resections. Professional and regulatory bodies including The Royal College of Pathologists UK, Healthcare Improvement Scotland and American College of Pathologists have recommended the identification of a minimum number of lymph nodes from colorectal cancer resections as a standard and also as a quality performance indicator. This study assesses the trend in lymph node evaluation in a large cohort of over a thirty seven year period in a single centre and focuses on the trend in lymph node yield in comparison with the proportion of lymph node positive cases.This study included 3216 patients who had their colorectal cancer pathology reported by the Department of Pathology, Aberdeen Royal Infirmary from 1975\u20132012. The Department of Pathology at Aberdeen Royal Infirmary is the regional pathology centre serving three health authorities and four acute hospitals namely NHS Grampian , NHS Orkney  and NHS Shetland . Approximately 75% of the total volume of colorectal cancer surgery is performed at Aberdeen Royal Infirmary. Relevant pathological data was extracted from the pathology reports of the resected colorectal cancer excision specimens and two databases were constructed.The first database was compiled using prospectively collected histopathological data from colorectal cancers resected between 2005 and 2012. The information recorded in this database includes age, gender, year of operation, administration of neoadjuvant therapy, whether the tumour was screen detected, tumour site, tumour differentiation, tumour (T) stage, extramural venous invasion (EMVI), total number of lymph nodes examined, number of lymph nodes involved by metastatic tumour, nodal (N) stage and Dukes stage. Information for each parameter was available for every patient. This database is referred to as the contemporary dataset and the distribution of cases in this series is shown in The second database was compiled retrospectively from cases of colorectal cancers identified by searching the Department of Pathology computer database using the search terms \u2018colon\u2019, \u2018rectum\u2019 and \u2018carcinoma\u2019. Histopathology reports of colorectal cancers excised at 5 yearly intervals 1975, 1980, 1985, 1990, 1995 and 2000 were identified and reviewed. Information on patient age and gender, tumour site, tumour differentiation, T stage, N stage, total number of lymph nodes examined, total number of lymph nodes involved and Dukes stage were extracted from these reports (when stated) and used to assemble the database. When not explicitly stated Dukes stage was inferred from the information stated in the histopathology report regarding the depth of tumour invasion and lymph node involvement. This database is referred to as the historic dataset and the distribution of cases is shown in Both databases were compiled in Excel 2007 and then imported into IBM SPSS version 21 for Windows 7\u2122  to perform data analysis. Linear trends for changes in lymph node yield and proportion of Dukes C cases with time were determined using Excel 2007 .The project was carried out using anonymised data and within the remit of ethics approval (ref. nos. 08/S0801/81) from the North of Scotland research ethics committee.The clinico-pathological parameters collected for the contemporary and historic datasets are summarised in The lymph node yield in the contemporary series of colorectal cancers is summarised in The frequency distribution of tumour stage in both the historic dataset and the contemporary dataset is shown in In the contemporary data set comparison of mean lymph node yield and proportion of Dukes C cases shows a highly significant year on year increase  in lymph node yield in contrast there is no significant trend in Dukes cases . This is true both for all colorectal cancers and also when potential confounding factors are excluded from the analysis including administration of neoadjuvant therapy, bowel cancer screening detected cases . Figure This large study from a single centre assesses the trend in lymph node evaluation over a thirty seven year period. It utilises both a contemporary dataset and a historic dataset to compare the effect of time and recent advances in colorectal cancer treatment, screening and pathological reporting on lymph node yield and involvement. It examines in detail the effect lymph node yield has on the detection of lymph node positive disease and hence colorectal cancer staging. All the data has been compiled from one centre thus minimising potential data collection and reporting bias.Factors that influence lymph node yield include patient, surgeon oncologist and pathologist and in designing this study it was important to consider key confounding factors to allow meaningful comparison of data especially between the historic dataset and the contemporary dataset. Histopathological reporting of colorectal cancers has greatly improved over the last 15 years driven by the introduction of guidelines and datasets for the reporting of colorectal cancer excision specimens and the parallel requirement for high quality pathology reporting as adjuvant and neoadjuvant therapy became recognized and established therapeutic options in the treatment of colorectal cancer. One of the key quality parameter in colorectal cancer histopathology is lymph node yield. The current Royal College of Pathologists UK colorectal cancer dataset recommends a mean of 12 lymph nodes and Healthcare Improvement Scotland quality performance indicator for colorectal cancer pathology is that greater than 80% of colorectal cancers should have 12 or more lymph nodes identified. Our data from the historic database shows that from 1975 to 2000 there is a higher proportion of Dukes B tumours and a lower proportion of Dukes C tumours compared to the tumours excised between 2005 and 2012 and this reflects the low lymph node yield per case and supports the concept of understaging of colorectal cancers when there is a low yield of lymph nodes. However in the current data set while there is a significant trend to increase lymph node yield this has not been reflected in an increasing proportion of Dukes C cases even when the confounding factors of neoadjuvant therapy and bowel cancer screen detected cases have been excluded from the analysis. The reasons for this are not apparent and have been observed in other series. Age distribution and anatomical site distribution of tumours within the colon both of which are other potential confounding factors do not appear to have significantly altered with time. Over the period of time from 2005\u20132012 pre-operative staging protocols have also remained constant. This may suggest that there may be a threshold for lymph node yield above which there is marginal benefit in identifying further lymph nodes."}
+{"text": "Neocortex plays key role in diverse brain functions. Understanding this role involves the study of collective neural activity patterns under different situations, and how these patterns relate to the structural and functional organization of neocortex. Here we study the effect of synaptic plasticity on neural spiking activity patterns in a neocortical network model. We measure changes in neural spiking patterns due to changes in the strengths of the synapses connecting neurons and relate them to changes in the functional connectivity of the network as disclosed by graph-theoretic measures.Our neocortical network model was composed of excitatory and inhibitory neurons in the proportion of four excitatory cells for each inhibitory cell. Neurons were described by the Izhikevich model . The parWe determined a set of parameters for which the spiking activity generated in L4 by the external input propagated to the entire network. This network-wide activity was oscillatory, and we found that its mean frequency was higher for the network version with synaptic plasticity than for the version without synaptic plasticity. We also found that the formation of clusters of synchronous neural activity was facilitated in the case with LTS cells as inhibitory neurons. Our results suggest that synaptic plasticity may induce changes in the functional connectivity of the neocortical network with impact on its global activity."}
+{"text": "Percutaneous interventions for cardiac disease are on the increase worldwide. Acute complications of interventions include vessel dissection, total occlusion, thrombosis etc. Other than the complications associated with the disease process and the disturbances to the vascular endothelium mechanical complications due to mishandling of or mishaps with the device itself can occur. These complications, though rare do occur and the cardiac surgeon has to deal with them often on an emergency basis.To assess the safety and efficacy of emergent surgery in patients who develop device related complications of PCI.We present 4 patients with coronary artery disease who had complications during angiogram and attempted angioplasty/stenting. In 1 patients the stent was inappropriately deployed and the patient required urgent surgery for stent retrieval. In one the ring tip of the angiography catheter dislodged in the coronary artery requiring emergency surgery and in a further two patients the guide wire broke in the circulation and had to be retrieved along with coronary artery bypass graftingIn another group of 3 patients there was mishandling of the ASD device requiring urgent retrieval and ASD closure. Devices were\" lost\" in the LA, in the RA and the other in the Pulmonary arteryIn 1 patient undergoing device closure of PDA the device was deployed before proper positioning and was brought down to the femoral artery using a bronchoscopic biopsy forceps and then retrieved surgically. In a further patient a PDA coil was \"lost' in pulmonary artery, lodging in a small branch. The child underwent surgical closure of PDA. The coil could not be retrieved.In conclusion, urgent surgery is often required for device related complications of percutaneous devices. Surgery can be safely undertaken in these patients with gratifying results.Emergent surgery is lifesaving in patients with device related complications of PCI and can be safely carried out"}
+{"text": "Early phase trials of complex interventions currently focus on assessing the feasibility of a confirmatory RCT and on conducting pilot work. These trials are not designed to enable a formal assessment of potential efficacy. As a result, guidance recommends any statistical analysis of treatment effects conducted in these trials should be treated with extreme caution and not used in deciding if a confirmatory trial of the intervention is warranted. Phase II trial designs developed in the drug context offer a potential solution, providing methods for selecting sample size parameters for feasibility and pilot trials which will enable formal assessments of potential efficacy to be carried out. In this paper we will outline the challenges encountered in extending ideas developed in the phase II drug trial literature to the complex intervention setting. The prevalence of multiple endpoints and clustering of outcome data will be identified as important considerations, having implications for timely and robust determination of optimal sample size parameters. The potential for Bayesian methods to help to identify robust trial designs and optimal decision rules will also be explored."}
+{"text": "In this session I will review the clinical and imaging features of the most common pediatric bone and soft tissue sarcomas and several benign lesions that may mimic them. These malignancies often have unique features that can help narrow the differential diagnosis. The material will be presented in an informal manner and audience participation is encouraged. A review of the appropriate diagnostic work-up will also be presented, including the role of various imaging modalities to detect local-regional and distant metastatic disease. At the end of this session participants should be able to identify clinical features  and imaging features that are suggestive of the correct diagnosis."}
+{"text": "The main factor related to gingival/periodontal problems in disabled individuals is the inadequacy of the plaque removal from the teeth. Motor coordination problems and muscular limitation in neuromuscularly disabled individuals along with the difficulty in understanding the importance of oral hygiene in mentally disabled individuals have resulted in the progression of inflammatory diseases.This report describes a case of cerebral palsy child who developed gingival hyperplasia due to poor oral hygiene practices which remarkably improved by proper motivation and adaptation of oral hygiene measures.It is important that the caretakers especially mother is informed about the importance of maintaining proper oral hygiene and the harmful effects of not doing so. It forms our duty to guide them towards maintaining good oral hygiene and thereby help in improving overall health of these children. There are no differences in prevention of the diseases and the treatment modalities between these groups. The main factor related to gingival/periodontal problems in disabled individuals is the inadequacy of the plaque removal from the teeth. Motor coordination problems and muscular limitation in neuromuscularly disabled individuals along with the difficulty in understanding the importance of oral hygiene in mentally disabled individuals have resulted in the progression of inflammatory diseases.6Handicap is the loss or limitation of opportunities to take part in the normal life of the community on an equal level with others due to physical and social barriers.The following report describes a case of cerebral palsy child who developed gingival hyperplasia due to poor oral hygiene practices which remarkably improved by proper motivation and adaptation of oral hygiene measures.A male patient aged 6 years reported to Department of Pedodontics and Preventive dentistry, VS Dental College and Hospital, Bengaluru. Patient\u2019s mother complained of severe bleeding from gums from past 1 week and inability of the child to eat. The child is known case of cerebral palsy with microcephaly and mental retardation with developmental age of only a few months . PatientOn intraoral examination, erythematous gingival overgrowth was noted on labial and palatal aspects of 54  and labiA detailed case history was taken and it was noted that the patients teeth were cleaned once daily by mother by wiping with a wet cloth. No brushing or use of any dentifrice was done from the beginning.Depending on clinical examination and based on the oral hygiene status of the patient, a provisional diagnosis of inflammatory gingival hyperplasia due to poor oral hygiene was obtained.Pediatric opinion on general state of patient was obtained and after performing all the necessary blood investigations, excision of hyperplastic gingiva in relation to 54 was planned and done under local anesthesia . The excMeanwhile, mother was educated regarding the importance of oral hygiene, method of brushing and other oral hygiene practices. Chlorhexidine mouth rinse was also advised and the surgical excision of the tissue in relation to 64 was deferred till the final diagnosis was obtained.The histopathological examination confirmed the diagnosis of inflammatory gingival hyperplasia secondary to poor oral hygiene status.Patient was recalled after 1 week for excision on the other side, i.e in relation to 64 but it was observed that there was spontaneous healing of the gingival tissues probably due to the oral hygiene measures adopted  and 6. T7 Thus, poor oral hygiene is perhaps more prevalent among mentally retarded persons compared to other indi-viduals.8 Many studies have found an inverse relationship between the levels of mental retardation and oral hygiene status; the lower the IQ score, the higher the oral hygiene index score.910 The provision and/or supervision of oral hygiene by parents have been reported to be lower for disabled children than for nondisabled children.11 This may lead to various complications like gingival and periodontal diseases, dental caries thereby affecting the nutritional status of the child.Oral hygiene practices are voluntary physical activities that have at least two requirements: Motivation and manual dexterity.1213 and also the lack of parental education and motivation leads to the development of gingival and periodontal diseases which thereby affects the nutrition status of these children. In this case report, the parents were from low socioeconomic background and were unaware of the importance of oral hygiene practices. No oral hygiene measures were being used or have been used which can be accounted for the gingival hyperplasia.The mechanical control of dental plaque in disabled individuals generally causes some difficulties, is found to be time-consuming, and sometimes ineffective14 As a result, chemical plaque control has been recommended as an alternative and adjunc-tive to mechanical plaque control in these special patient groups.15 The effectiveness of chlorhexidine (CHX) have widely been investigated in various patient populations, including the disabled, and the results have led CHX to be defined as the \u201cgold standard.\u201d20 The combination of mechanical and chemical plaque control seemed to be even more beneficial than only using a mouthwash.2122Various studies have shown that the effectiveness of manual and electric toothbrushes is limited by the manual dexterity and skill of the user.In the present case, spontaneous healing of the gingival hyperplasia was noted in just 1 week after the adoption of chemical (CHX) and mechanical plaque control measures.Particularly the education and motivation of parents, especially mother can be considered to be the main factor for the adoption of oral hygiene measures and improved oral hygiene status of the patient.Oral health problems in mentally disabled children may be because of the parental belief of a reduced importance of oral health in comparison to the over all scheme of health management or maybe more time is devoted to assist these children in other daily activities which are seen to be more important compared to their nondisabled counterparts. It is important that the caretakers especially mother is informed about the importance of maintaining proper oral hygiene and the harmful effects of not doing so. It forms our duty to guide them towards maintaining good oral hygiene and thereby help in improving overall health of these children."}
+{"text": "Patient recruitment to clinical research is an important metric used to assess the effectiveness of research departments and decide resource allocation. The Mobile Workforce (MW) has been put in place to increase recruitment to haematology studies across the North Thames region.The NIHR North Thames division three has provided funding to employ a group of clinical trial practitioners and data managers. The team are employed by and based at large teaching hospitals and travel to other sites within the North Thames region to open and manage research studies with a high anticipated recruitment.The MW has recruited over 200 patients to research projects in its first year of operation. This has contributed to a rise in the North Thames LCRN's haematology recruitment from 512 in 2013-2014 to 851 in 2014-2015. The MW has encouraged senior clinicians to participate in research and has facilitated the set-up of new research projects. The MW has reduced the need for staff training and has allowed for greater flexibility in meeting staffing requirements.The MW has achieved a significant increase in study accrual during its first year. The MW has allowed previously unsupported sites to participate in research and has caused an increase in investigator interest in research. The NIHR seeks to replicate the approach across divisions and regions to provide an efficient and cost effective approach to study recruitment."}
+{"text": "Ever since the first hematopoietic cell transplantation (HCT) was performed in 1960s, thousands of studies have elucidated the impact of patient and donor factors  on outcomes after the procedure. Fewer studies have looked at the role of center specific factors such as procedure volume, center experience or accreditation status in influencing the outcomes . MacroecIn this issue of EBioMedicine, Baldomero et al. present a retrospective population level analysis that examines the interplay of patient-, center- and country level factors on outcomes of allogeneic and autologous HCT using data from the European Society of Blood and Marrow Transplantation (EBMT) database . The autThe findings about the differential impact of macroeconomic factors on survival after autologous and allogeneic HCT are novel, but not surprising as these are two different types of procedures with different degree of medical complexity, risk and resource requirement. Even though the study is about HCT in Europe, it has wider implications. An important question it raises is \u2018if one size fits all?\u2019 for worldwide practice of HCT or for that matter, any expensive medical technology. Should the benchmarks for assessing the success of an expensive technology be different amongst different countries at diverse stages of socioeconomic development with different resource capacity ? The authors suggest streamlining and consolidation of the transplant activity to help maintain the quality of care and strengthening the overall health infrastructure to provide optimal pre- and post-HCT care. This proposition and a long term vision for the growth and sustainability of a transplant program may be more important for the poorer countries than the richer countries to help optimize the best utilization of the scarce resources. This is because the spending on health care especially on high cost medical technology is more likely to strain the government as well as individual household budgets in poorer countries as opposed to affluent countries. The bigger question is if the poorer countries should spend their limited resources to improve outcomes of expensive procedures that benefit only a few or focus on providing basic necessities and preventive care for a larger population?The authors highlight the role of professional medical societies worldwide in improving the quality of care and scaling up transplant systems through education and training that fit within the economic framework of individual countries across the globe. This will need to be supplemented with other measures such as international aid, advocacy efforts, partnerships and investment in research in the affluent countries to develop affordable technologies. Bidirectional knowledge transfer is important because the evolution of a technology developed in a richer country may follow a more cost-effective route when implemented in developing countries. This may provide an opportunity for the affluent countries to learn a less expensive way to do things as long as it doesn't impact short- and long-term outcomes . Finally"}
+{"text": "Over the past two decades finite element (FE) analysis has become a popular tool for researchers looking to simulate the biomechanics of the foot in people with diabetes. The ultimate aims of these simulations have been to improve understanding of the complicated nature of mechanical loading and to inform interventions designed to prevent plantar ulceration. This review is intended to provide a systematic review of these FE analysis based computational simulations.PUBMED, ScienceDirect and Web of Science databases were searched for relevant peer reviewed articles using the keywords \u201cdiabetic foot\u201d, \u201cfinite element\u201d and related synonyms. This review considered original research studies that utilised FE models of the foot or part of the foot to simulate function, tissue behaviour, or structural deformities associated with the diabetic foot. In addition, studies using FE to study footwear, insoles or surgical interventions intended to reduce ulceration risk in the diabetic foot were eligible for inclusion.Thirty relevant articles were found covering three primary themes: investigations of the characteristics of the diabetic foot (10 articles); design of interventions to reduce ulceration risk (17 articles); and methodological aspects for modeling the diabetic foot (3 articles). Several FE studies have provided estimates of external and internal soft tissue loading, and suggested that internal stresses may often be considerably larger than those measured at the plantar surface and are proportionally greater in the diabetic foot compared to controls. A series of results that inform the design of insoles, footwear and corrective surgery have been presented with the goal of defining the modes of action for these intervention strategies. FE analysis has also been applied to simulate the effect of changes associated with the diabetic foot on factors such as blood supply to local tissues.Existing models have not yet adequately captured the complexity of foot anatomy or the changes in tissue properties and structural factors associated with diabetes. Further work is required to improve the validity and credibility, of FE models and to standardize reporting. The development of patient-specific models is an extremely time-consuming process and reported run times are long. Progress in these areas is needed to ultimately move the technique beyond the research domain to allow it to become a clinically relevant tool at the patient level."}
+{"text": "To discuss the practicalities of setting up MRgFUS service for uterine fibroids and in particular the challenges of formulating an effective business plan in a time of financial austerity and curtailment of health service budgets.The authors, an interventional radiologist and a gynaecologist, have worked together closely for 10 years delivering a comprehensive service for the treatment of uterine fibroids in both the state and private health sectors. Despite recognising the clinical potential of MRgFUS and its undoubted appeal to patients we encountered difficulty in engaging any hospital partner to make the necessary capital investment.We describe the business planning process and arguments put forward to support our strategy. Close interdisciplinary working between specialities is fundamental to success as is the nurturing of links in both healthcare management and industry. Challenges include not only the capital costs of equipment purchase but also the opportunity cost of lost scanning time on MRI scanners also used for diagnostic imaging. The requirement for a particular make of MRI scanner can also hinder business plan progress due to manufacturer representation within a particular national market. Reluctance of both government health services and private health insurers to reimburse innovative treatments is a further hindrance to overcome.We share our experience of several unsuccessful and one ultimately successful bid to set up a service with a hospital partner and to provide MRgFUS as an addition to our repertoire of minimally invasive fibroid treatment options. We outline the ground work and business planning processes and arguments in terms of clinical quality, patient choice and health economics used to support our service development strategy.There are undoubtedly logistical and economic obstacles to overcome in setting up a new MRgFUS service but these are not insurmountable. With clarity of purpose, perseverance, an understanding of the health economic arguments and a level of persuasive skills these obstacles can be overcome."}
+{"text": "Medical education is tedious and takes both a physical and psychological toll on medical students. Stress could lead to burnout which research has shown that is prevalent among medical students and can lead to other significant dangers if it continues into residency and beyond . Aims: AInterviews and a self-administered anonymous survey of 55 final year medical students by a 2 part questionnaire assessing demographics and support system were carried out.35 final year medical students responded equating to a response rate of 76%. 54% were male mirroring class demographics. The majority (69%) were more than 25 years old and unmarried (89%). We observed that majority of students relied on family, friends and classmates for support when stressed and very few relied on mentors, faculty and school administration for support.The major support systems relied upon by the students has been identified and a void of support from mentors, faculty and school administration discovered. Further research for the cause of this might be helpful to distinguish between the lack of support provision or lack of use on the part of students. This is important as healthy support systems are necessary to cope with the stress ahead in the field of medical practice."}
+{"text": "Recent physiological studies revealed that the strength of the synaptic connections changes in a short period of time with short-term plasticity (STP) mechanism; these synapse is called dynamic synapse . The synIn the present study, we further explore the dynamical properties of the associative memory network with stochastic binary neuron model. Changes in the synaptic transmission efficacy can be modeled with variables that represent the releasable neurotransmitter and the utilization parameter reflecting the calcium concentration on presynaptic terminal. We drive the dynamical mean field model that allows to analyze detailed bifurcation structure of network dynamics of the stochastic model. We evaluate the memory retrieve performance with applying external input.In the associative memory network with dynamic synapses, the network shows variety of dynamical state including memory retrieved states and transitive states among the memory patterns."}
+{"text": "Batson\u2019s venous plexus is a system of paravertebral veins that connect pelvic and thoracic vessels to the intraspinal  veins. It was first described in 1940 to explain a route for spread of metastases and infection that was separate to the lymphatic system. Its role in the retrograde venous spread of malignancy is now well-described, but not widely demonstrated on imaging.We present a detailed pictorial review of imaging of patients from our oncology centre showing retrograde venous spread to the paravertebral vessels specifically in cases of renal, rectal and breast carcinoma.We demonstrate expansion of the paravertebral vessels containing tumour and associated vertebral body metastases.We also review and illustrate the spinal venous anatomy.Radiologists should be aware of the implication of Batson\u2019s venous plexus as a route of metastatic dissemination. Our pictorial review highlights the importance of the paravertebral vessels as a review area."}
+{"text": "The human auditory brainstem faithfully represents the acoustic structure of sounds  ? Assessing both young and aging amusic populations who speak tonal or non-tonal languages will shed further light on this issue. Longitudinal studies are also needed to elucidate the time course of the mechanism that sharpens or detunes the brainstem response and more clearly dissect the relative contribution of cortical structures in driving this type of plasticity.If limited exposure to music listening or making can have negative effects, this would support the idea that music has a role in rehabilitation and in education more generally. Recent studies suggest that music training accelerates neuro-development in children (Skoe and Kraus, In summary, the inherent plasticity of the auditory system primes it for being sensitive to the acoustic environment in a way that can either positively or negatively affect how sound is encoded subcortically. We believe that experience-dependent detuning of the auditory system may explain variations in auditory acuity in both typical and atypical populations, making it a topic ripe for future investigations.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "As human genomics moves into a mass-scale era, whereby millions of genome sequences will soon become available, new opportunities are opening up to use these very large samples better to understand the relationship between genotype and phenotype.A fundamental problem for such studies in the past has been lack of standardization in the description of the phenotypes used. Not only have disease concepts often been confused with phenotypes , but the concepts used have at times been vague   approach, has been developed . It therefore provides an underpinning component for the computational study of genotype-phenotype relations in humans and model mammals. At the same time it provides a valuable set of terms and relations to facilitate more systematic annotation and searching of phenotype terms across human and model organism databases. This opens up exciting new opportunities for the unified analysis of human and mouse disease and phenotype data.An important addition to the armory of ontological frameworks that can be used to describe phenotypes is provided by Shimoyama et al.  who descThe author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Diabetic foot ulcers (DFU) are a leading cause of diabetes-related hospitalisation and can be costly to manage without access to appropriate expert care. Within Queensland and indeed across many parts of Australia, there is an inequality in accessing specialist services for individuals with DFU. Recent National Health and Medical Research Council (NHMRC) diabetic foot guidelines recommend remote expert consultation with digital imaging should be made available to people with DFU to improve their clinical outcomes. Telemedicine appears to show promise in improving access to diabetic foot specialist services; however diabetic foot telemedicine models to date have relied upon videoconferencing, store and forward technology and/or customised appliances to obtain digital imagery which all require either expensive infrastructure or a timed reply to the request for advice. Whilst mobile phone advice services have been used with success in general diabetes management and telehealth services have improved diabetic foot outcomes, the rapid emergence in the use of mobile phones has established a need to review the role that various forms of telemedicine play in the management of DFU. The aim of this paper is to review traditional telemedicine modalities that have been used in the management of DFU and to compare that to new and innovative technology that are emerging.Studies investigating the management of DFU using various forms of telemedicine interventions will be included in this review. They include the use of videoconferencing technology, hand held digital still photography purpose built imaging devices and mobile phone imagery. Electronic databases  will be searched using broad MeSH terms and keywords that cover the intended area of interest.It is anticipated that the results of this narrative review will provide delegates of the 2015 Australasian Podiatry Conference an insight into the types of emerging innovative diagnostic telemedicine technologies in the management of DFU against the backdrop of traditional and evidence based modalities. It is anticipated that the findings will drive further research in the area of mobile phone imagery and innovation in the management of DFU."}
+{"text": "Dear editorMehta et al recently reported removal of dystrophic calcification on the posterior surface of a silicone intraocular lens (IOL) in a patient with asteroid hyalosis.We have recently tried unsuccessfully to use PPV to treat an 86 year old patient with calcification of a silicone IOL in the presence of asteroid hyalosis. We chose to avoid IOL exchange due to a history of Fuchs endothelial dystrophy and glaucoma in the left eye, and a failed corneal graft in a rubeotic eye on the right. Our patient did not have an intact posterior capsule having been treated with Nd:YAG capsulotomy 2 years previously, before the calcification occurred. A 25 gauge pars plana vitrectomy was performed after attempting to remove the deposits unsuccessfully from the posterior surface of the IOL with Nd:YAG laser. It was felt that PPV would be less likely to cause corneal decompensation than IOL exchange. In contrast to the experience of Mehta et alMehta et al reported that initially their patient underwent an unsuccessful Nd:YAG capsulotomy, however it was not made clear whether the posterior capsule remained intact.A similar case of this condition has been published recently by Ullman and Gupta.We believe that vitrectomy and surgical capsulectomy should be considered as an alternative to Nd:YAG capsulotomy where IOL calcification is not yet established. It is likely that opening a significantly calcified posterior capsule by Nd:YAG capsulotomy in the presence of asteroid hyalosis will lead to significant future IOL dystrophic calcification. In established calcification of a silicone IOL we feel that vitrectomy is of limited value and IOL exchange should remain the standard treatment. We appreciate Drs Rainsbury and Lochhead sharing their experience and insight into the treatment of dystrophic calcification of silicone intraocular lenses (IOL). As they point out, it intuitively makes sense that the presence or absence of a posterior capsule changes the natural history and management options of this pathologic calcification.In our case,In the setting of monocular patients (as in our case) or those with compromised capsular support (as in the case described by Drs Rainsbury and Lochhead), we believe it is reasonable to attempt vitrectomy prior to IOL exchange in these cases of dystrophic calcification. Though vitrectomy might not be successful in every case, removing the vitreous alone may make subsequent IOL exchange safer, and prevent recurrence of dystrophic calcification."}
+{"text": "Brain-computer interfaces (BCIs), or brain-machine interfaces (BMIs) involve real-time direct connections between the brain and a computer Kubler, . BidirecThe user of a BCI can execute an intention to perform a motor task through changes in the system caused by electrodes detecting signals in, for instance, the motor cortex mediating the intention. Success in operating the system depends on a combination of unconscious operant conditioning of brain responses and conscious goal-directed expectation of the subject. These depend in turn on how effective the practitioner is in training the subject how to operate the system. As in other cases of traumatic brain injury, goal-directed thinking in some patients with tetraplegia may be impaired if there is significant damage to neural networks in frontal regions mediating planning and decision-making. This may also impair the subject's capacity to understand the benefits and risks of the technique and give informed consent to participate in BCI research and treatment , electrodes are implanted epidurally or subdurally (Leuthardt et al., EEG- and fMRI-based BCIs might enable individuals to reliably communicate when they are unable to communicate behaviorally (Birbaumer et al., Some investigators have claimed that fMRI-guided BCIs could enable minimally conscious patients with a high level of cognitive function to make these decisions (Peterson et al., This last point may be overly optimistic. Even advanced BCIs that could detect neural activity correlating with complex semantic processing might not be sufficient to show that the subject had the cognitive and emotional capacity to make an informed and autonomous decision about life-sustaining treatment. Some form of behavioral interaction may be necessary to confirm that the subject had this capacity. Medical professionals and caregivers must be cautious not to read too much into BCI-enabled responses and interpret them as having a meaning they lack.BCIs can benefit individuals by restoring varying degrees of motor control and possibly the ability to communicate. But expectations of some subjects and their caregivers may exceed what they can reasonably achieve with the technology and result in psychological harm. Selecting candidates with higher levels of preserved cognitive function for BCI research and treatment and educating them on the potential benefits and limitations of the technique is advisable to prevent or at least minimize harm. The fact that a particular BCI system is more invasive than others does not imply that it has an unacceptable degree of risk and may instead indicate a more favorable benefit-risk ratio if it does more to enable the execution of intentions in actions and promote neuroplasticity. Perhaps the most significant application of BCIs would be in enabling minimally conscious or completely locked-in patients to communicate. Yet it is questionable that even the most sophisticated system alone could demonstrate that these subjects have the ability to clearly and meaningfully communicate their wishes and make informed decisions about life-sustaining treatment. Decision-making capacity falls along a continuum correlating with a continuum of cognitive and emotional capacities, and there is no algorithm providing a definitive answer to the question of where the threshold at which one has a sufficient degree of these capacities lies. All relevant parties need to be cautious and not infer that a BCI indicating certain levels of brain activity and semantic processing in a subject is evidence of an understanding of the ethical magnitude of life-and-death decisions and the ability to make them.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Hierarchical processing is key to understanding vision. The visual system consists of hierarchically organized distinct anatomical areas functionally specialized for processing different aspects of a visual object  is missing. The advent of optogenetics and neuroimaging has provided additional remarkable investigative tools. How these recent techniques will contribute to the prevailing arguments of feedforward and feedback projections in vision is still open. We hope this issue will inspire the readers and act as a catalyst for future work on the issues of feedforward and feedback processes in vision.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Pain perception is subject to powerful modulatory influences that can increase or reduce subjective responses in the short and long term. Nociceptive circuits can become sensitised causing both innocuous and noxious inputs to be amplified and their intensity and other sensory characteristics to be increased. Both central and peripheral mechanisms of sensitisation are recognised. Nociceptive mechanisms are immature at birth, undergoing both structural and functional change during normal development that can have important consequences for the maintenance, management and prognosis of chronic pain in children.The neurophysiology of pain in children will be briefly described with special reference to sensitisation in the context of non-inflammatory musculoskeletal pain and pain amplification syndromes. A mechanisms based approach to the medical management of chronic pain in children will be discussed.None declared."}
+{"text": "In the final version of our article entitled, \" Lessons from sexual and reproductive health voucher program design and function: a comprehensive review\" the authors inadvertently failed to acknowledge the role of International Union of Scientific Study of Population (IUSSP). IUSSP colleagues kindly reviewed early drafts of the manuscript presented at an IUSSP workshop in Bangkok August 2012 and had specifically requested that we recognize their feedback. We therefore feel obliged to acknowledge IUSSP."}
+{"text": "Diabetes is considered as a risk factor for atrial fibrillation and patients with a co morbidity of diabetes and atrial fibrillation have an increased risk of cardio-vascular complications like stroke. However, paroxysmal atrial fibrillation often is not recognized and therefore stroke is a frequent and severe complication of diabetes and atrial fibrillation. The objective of the study is a screening of patients with diabetes mellitus type 2 for atrial fibrillation and as a consequence an individually adjusted risk management regarding glucoses levels, anticoagulation and blood pressure.To detect atrial fibrillation ECGs of diabetes patients will be evaluated by an automated AF episode detection algorithm that already has proven superiority in the detection of atrial fibrillation. The software uses an algorithm that detects QRS complexes of the ECG data and then classifies them as being of atrial or ventricular origin and finally creates a list of R-R-intervals. To detect episodes of AF, the software performs a time series analysis of multiple mathematical parameters that are typical for an absolute arrhythmia during AF. Based on this analysis, the system creates a report on whether episodes of AF are present . The proThe study is expected to give detailed information on the increased prevalence of atrial fibrillation in patients with type 2 diabetes and provides the data base for an optimized therapy regime in order to avoid cardio-vascular complications.The detection of atrial fibilation as a major risk factor for cardio-vascular complications of diabetic patients will have to be improved. This strategy can be combined with other strategies of detection of complication risks  and improve personalized treatment of diabetic patients."}
+{"text": "Dermatological conditions form a significant number of consultations seen by general practitioners on a daily basis. There is a lack of training and formal assessment of dermatology during medical school and we propose that there should be a mandatory component in OSCEs for dermatology during medical school to enhance one's diagnostic and clinical reasoning skills which will ultimately lead to better care for the patient and efficacious use of NHS resources. Dermatology forms an essential part of a medical student's specialty training. Inflammatory skin diseases  and infective diseases  are some of the most commonly encountered conditions in primary care; it is estimated that the prevalence of skin diseases in primary care setting is around 12.4%  target sThere are many different forms of assessment used in medical schools throughout the United Kingdom. The most popular forms of assessment which have shown great validity in a medical student's performance as a competent and safe clinician are EMQs (extended matching questions), SBAs (single best answers), and the OSCEs . These forms of assessment have been widely adopted by many medical schools across the United Kingdom , 5. The Tomorrow's Doctors\u2019 provides a clear framework for medical schools to design curricula. The fact that there has been a lack of practical clinical examination for dermatology considering the vast number of cases presenting in general practice on a daily basis itself is a cause for concern  and can have a significant impact on social and psychological wellbeing . The Gen concern .On the other hand, it could be argued that as most universities blueprint the quantity of questions going to be asked across all different types of examinations by the number of weeks of the specialty placement itself; it can be understandably difficult for examiners to test candidates in dermatology . At BartWe believe that practical training in dermatology should begin at an early stage in medical school, and that practical dermatological clinical examinations should be compulsory. It is paramount to implement the core skills required for a competent and confident diagnosis and management of dermatological problems leading to a better outcome for all patients and an effective use of the NHS resources . One of"}
+{"text": "Prevalence of allergenic plants varies by geographic region and climate, which affects the level of allergen exposure experienced by patients in different parts of the country. Because of these variations in exposure it is recommended that allergy practices use customized regional diagnostic panels based on the prevalence and significance of various aeroallergens. However, gathering this information can be difficult for new physicians. The purpose of these recommendations is to provide a foundation for new physicians to begin building a custom aeroallergen panel for all regions of Canada.Clinical, geographical and botanical references were evaluated and compiled to determine the prevalence and impact of various aeroallergens across Canada. These recommendations were discussed with regional allergy practices and other clinical authorities for consensus on recommendations.Aeroallergen recommendations were compiled into a prevalence map and table that was organized by the major geographic regions of Canada. Allergens were categorized as (1) high allergenicity & high prevalence, (2) high allergenicity & low prevalence, (3) low allergenicity & high prevalence, or (4) low allergenicity & low prevalence. A significant degree of allergen similarity across all regions was recognized although specific differences in species selection and general distribution patterns were identified for each region.Gathering clinical and botanical prevalence data for aeroallergens across different regions can be time consuming and difficult. These recommendations were compiled from many years of industry experience working with allergy specialists across the country and were verified by the literature. It is hoped that this knowledge can provide a foundation for new physicians trying to understand which aeroallergens to target for allergy diagnostic panels specific to their region."}
+{"text": "The arcOGEN Consortium should be listed as an author of this article. They contributed to the genome-wide association study results presented in this work. They should be listed in the author byline at position 292 and affiliated with The Arthritis Research UK Osteoarthritis Genetics Consortium. They should also be included in the footnote designating consortia which is underneath the author affiliation list in the PDF version of the article, and in the S2 Text(DOCX)Click here for additional data file."}
+{"text": "The rate of infection of health care workers in the recent Ebola Virus Disease (EVD) outbreak in West Africa, including Nigeria has shown that the disease can be transmitted and amplified in healthcare settings especially when infection prevention and control (IPC) procedures are ineffective or ignored.The aim of this study was to evaluate the level of infection control measures operating in health facilities in Rivers state as at the time of the Nigerian 2014 EVD outbreak.th and 11th 2014. Each response was scored between 0-3. An overall score of \u226575% was graded as good while <75% was poor. Data was analysed with SPSS Version 20. Ethical statement; this study was conducted during the outbreak of EVD in Nigeria as part of response activities by the members of the Ebola Emergency Operation Center.The descriptive cross sectional study was done in Rivers state one of the two states that experienced the EVD outbreak in Nigeria. Information on IPC materials and practices in health facilities in the state was collected using the Infection Control Assessment Tool (ICAT) between September 4Two tertiary, twenty four public secondary and sixty six private secondary health facilities were studied. Only one of the tertiary healthcare facilities had an IPC committee in place with a focal officer in charge. Only one hospital had an IPC policy which was not operational. None of the health facilities had a good score for both IPC materials availability and practice.Gaps existed in IPC in health facilities in Rivers State, Nigeria at the outbreak of EVD. It is recommended that appropriate policy for maintaining and sustaining infrastructure and supplies essential to IPC in health facilities be developed and implemented in all health facilities. Regular surveillance should be put in place to ensure that these items are always available, while hospital administrators and departmental heads must provide the necessary resources to facilitate compliance.None declared."}
+{"text": "Magnetic Resonance Imaging (MRI) and Computed Tomography (CT) scan are the two ubiquitous imaging sources that physicians use to diagnose patients with Cystic Fibrosis (CF) or any other Chronic Obstructive Pulmonary Disease (COPD). Unfortunately the cost constraints limit the frequent usage of these medical imaging procedures. In addition, even though both CT scan and MRI provide mesoscopic details of a lung, in order to obtain microscopic information a very high resolution is required. Neither MRI nor CT scans provide micro level information about the location of infection in a binary tree structure the binary tree structure of the human lung. In this paper we present an algorithm that enhances the current imaging results by providing estimated micro level information concerning the location of the infection. The estimate is based on a calculation of the distribution of possible mucus blockages consistent with available information using an offline Metropolis-Hastings algorithm in combination with a real-time interpolation scheme. When supplemented with growth rates for the pockets of mucus, the algorithm can also be used to estimate how lung functionality as manifested in spirometric tests will change in patients with CF or COPD. Patients with chronic obstructive pulmonary disease (COPD) or cystic fibrosis (CF) have chronic lung inflammation which causes airflow limitation and the scarring of lung tissues. Their airways are generally inflamed and produce excess amounts of mucus that impair the flow of air into and out of their lungs.Our hypothesis is that the scarring, and ultimate remodeling of a CF lung is mostly due to the contact between the lung lining and the mucus. Inflammatory cytokines induce scars in lung tissue Spirometry, the measurement of a patient's breathing, is the standard clinical tool for monitoring lung disease. The two most common spirometric indicators are the forced expiratory volume in one second, FEVMRI was first introduced as an alternative imaging tool for patients with CF in 1987 There have been research studies on mesoscopic modeling of Cystic Fibrosis one configuration is of this form. In fact, however, repeated MRI measurements separated by small challenges such as coughing or even just taking a few deep breaths reveal that mucus inside the lungs of CF patients show small but discernible movements in response to such challenges. Given this dynamic picture, the possibility that all of the configurations of mucus would avoid the configurations that can be realized the largest number of ways is extremely unlikely. We describe below how to construct such distributions that best represent the state of airways corresponding to the patients lung functionality test values , we first have to define how mucus is distributed in a voxel's binary tree structure. There is an astronomical number of configurations for filling a binary tree of 10 generations with a given amount of mucus. Approximately, it is given by Hence if a voxel contains In order to expedite the computational process; Dulcinea computing clusters from the Computational Science Research Center at San Diego State University were used for collecting almost 54 million samples. The Dulcinea computing clusters contains 12 workstations each with Dual-Quad Xeon central processing unit (CPU) (E5520 2.27GHz) and Dual Tesla graphic processing unit (GPU) (M1060) which provides the total of 96 CPU cores. The cluster system utilizes 3GB of memory per CPU core for nodes 1 to 10 and utilizes 6GB of memory per CPU core for nodes 11 and 12. After obtaining these samples the probability distributions for different amount of mucus are calculated. In order to spatially locate each bronchiole in a human airway tree we used Kitaoka et al.'s three-dimensional model At this stage we have mapped the voxels from imaging data into our model in a way that the total rate of airflow and the accessible alveoli of the lung model resemble the corresponding patient's FEVIn this section we use the mucus distribution and growth model presented in This method can even be applied to follow a patient's progress with out fewer imaging tests. Since most CF patients take spirometry test more often than any imaging tests, we can use our model without recourse to imaging data. This time the model takes only the FEVSince the mean mucus growth rate was estimated based on years of data from many CF patients, such predictions should work reasonably well for a patient between exacerbations. Our model can also be used to predict the progression during exacerbations, albeit with voxel specific growth rates informed by much more data than we currently possess. Using one mean mucus growth rate is a shortcoming not of our algorithm but rather of the paucity of data to which our predictions have been applied. There is every indication that soon we will have reasonable metagenomic We can improve the accuracy level of the model by extending the resolution of our PDFE-2D distributions. The current PDFEs were constructed with With current research studies about cystic fibrosis, CF treatment is poised for great strides. Non-genetic treatments such as Ivacaftor  only works on patients with a certain mutation of cystic fibrosis which accounts for 4\u20135% of cystic fibrosis cases While an eventual cure for the disease by replacement of the defective gene is likely, we expect such treatment not to be available anytime soon. Rather we anticipate that new observational tools such as metagenomics, transcriptomics, metabolomics and MRI imaging coupled with our modeling approach will give the clinician unprecedented ability to follow and treat the disease. The models will provide quantitative predictions of responses to various drug regimens and prescribe adaptively implemented optimal controls for treatment. Predicting the impact of mucus growth on lung functionality will correlate the current stage of the disease with how infection has been propagating throughout different generations of lung. This will enable the physician with a tool to track this propagation of infection.The various sub-models required here will soon be informed by data characterizing the microbial communities present. Such data comes from metagenomic and transcriptomics analyses of sputum samples and metabolomic analyses of exhaled air. In our current model we predict the dynamic distribution of mucus in a CF lung in the absence of treatment as a stepping stone for eventually eventual treatment and microbial community specific modeling of the treatment response.According to a research study done by Willner et al. 3 for the size of one voxel was for illustration. Any resolution scale however forces estimation of the distribution on spatial scales below this resolution. Since estimation of the distribution on finer spatial scales would perforce need the solution of an inverse problem with many possible solutions and since the movement of mucus hinted that the \u201cright answer\u201d would in any case not be a unique distribution, we were led naturally to using Monte Carlo estimation methods for the most likely distribution and the corresponding spirometric observables. The resulting models and algorithms form a clinically useful tool with which to reassess the various simplest possible sub-models and assumptions used in our work so far. These models can play a crucial role in future treatments of the disease.Our methods are completely scalable \u2013 the 1.0 cmFile S1The supporting file Psudo.pdf contains the psudo code of the algorithms and models mentioned in this manuscript.(PDF)Click here for additional data file."}
+{"text": "The diuretic bumetanide failed to treat acute seizures due to hypoxic ischemic encephalopathy (HIE) in newborn babies and was associated with hearing loss (NEMO trial, Pressler et al.,  The diuretic bumetanide is one such drug that specifically blocks the NKCC1 chloride importer thereby reducing (Cl\u2212)I levels and restoring GABAergic inhibition in many neuronal types in physiological and pathological conditions. The recent failure of the NEMO trial aimed at treating seizures in newborn babies with bumetanide  neurons GABA provides most of the inhibitory tone, in immature neurons it depolarizes and often excites due to higher levels of intracellular chloride ((Cl\u2212)I in immature and adult cochlear hair cells, and effects of hypoxic injury and toxicity of aminoglycosides that are aggravated by bumetanide I levels was found to be highly seizure history dependent. Bumetanide neither prevented the formation by recurrent seizures of an epileptogenic mirror focus nor efficiently reduced their generation I levels and attenuated electrical and behavioral parameters I levels and excitatory GABA I levels I levels notably oxytocin attenuate schizophrenia symptoms , striatal medium spiny neurons generated Giant GABAergic Currents that are readily blocked by L\u2013Dopa and lesions of the sub thalamic nucleus suggesting that they constitute relevant signatures of PD I levels in pain pathways I levels paving the way to a common therapeutic strategy to many disorders. Therefore, neither the severe side effects of bumetanide on the hearing system of newborn with hypoxic ischemic encephalopathy (HIE) nor its lack of efficacy in the NEMO study bear relevance to many other disorders. High (Cl\u2212)I levels and excitatory GABA play a fundamental role in the pathogenesis of many disorders, generating aberrant activities that perturb the operation of behaviorally relevant oscillations. Bumetanide and other drugs acting on chloride co-transporters can restore low (Cl\u2212)I levels in these disorders but may be contraindicated in newborns because chloride co-transporters are still operative.In several instances, encouraging preclinical data fail in clinical trials and the reasons for these failures are not always straightforward. They might also lead to the abandon of the animal model although heterogeneity of the clinical data might also be a factor. Yet, with bumetanide, the situation is of particular interest as the convergence of animal and human data is reinforced by a fundamental conceptual series of observations stressing the impact of a wide range of insults on (ClPD and EL contributed to the summary on Parkinson disease and autism respectively and YB performed the analysis of the literature and wrote the paper.Experimental work on autism of YB-A was financed by the Bettencourt-Schuller Foundation but grants rejected by the European Research Council. Clinical trials on autism were supported by the Simons Foundation but grants rejected by the Agence Nationale de Recherche.YB is CEO and share holder of Neurochlore 2 and B&A Therapeutics biotech companies dedicated to the development of treatments to autism and parkinson disease. EL and PD are respectively share holders of Neurochlore and B&A Therapeutics."}
+{"text": "Contemporary psychology does not question the existence of psychological processes that operate outside human conscious awareness, such as implicit stereotypes  used different exposure durations of affective primes as operationalization of salience of affective stimulation. Confirming the predictions, the results showed assimilation effect when the exposure duration of primes was shorter\u20144 ms\u2014and the contrast effect, with the longer duration of 16 ms  affective stimulation. Thus, the nature of nonconscious affective priming may be more complex that was originally assumed and may be mediated by automatic processes of implicit emotion regulation  emotion regulation may appear automatically and modify the influence of affect on subsequent processes, as when we observe the contrast effect. This is one more argument for the substantial role of implicit processes in human life.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Health Logistics Association (HLA) is an association of logistics professionals committed to humanitarian logistics effectiveness by creating opportunities for dialogue and cooperative relationships with its members and partners to build a community of practice for advancing the humanitarian logistics profession through the promotion of cross organisational learning and collaboration. IAPHL is a professional association dedicated to improving public health supply chain management by promoting the professional development and recognition of those who work with health supplies.Under the Enhanced Learning & Research for Humanitarian Assistance professionalization umbrella, the HLA has joined an inter-agency project to define a framework and system for recognising relevant humanitarian logistics experience and training. Initial research will be required to ensure that any framework is relevant, inclusive and aligned with other initiatives. The project will build on training program achievements in the humanitarian logistics (and emergency nutrition) sector and support the emerging suite of competence based qualifications.Humanitarian assistance partners recognize the importance of effective humanitarian logisticians in the planning and delivery of aid. More humanitarian assistance professionals and academics see the need to hone specific competencies and skills for these programs so certifications build a portfolio of evidence. A key challenge is to ensure that individuals successfully completing these and other relevant qualifications gain the recognition they require from aid agencies. There is also a need to define a recognised career pathway within the sector with clear routes for progression. IAPHL is investigating professional certification requirements and seeks to learn from HLA\u2019s experience.The current system for recognizing knowledge and skills of humanitarian workers strongly favours international staff. Limited professional development funding for national staff is often wasted, as there is no accepted system to measure competencies or training effectiveness. A new system to capture, recognise and certify the skills, learning and development of aid workers is needed. It\u2019s proposed that an internationally recognized Learning and Development Passport for humanitarian logisticians be development, and extended to include other related sectors such as public health logisticians.Given HLA\u2019s experience, the next steps for professionalizing the humanitarian logistics workforce are to stimulate greater advocacy, buy-in, recognition and endorsement for certification in the mainstream. HLA\u2019s experience can be applied to other sectors like public health; IAPHL and PtD can build on and formalize the methods for professional certification and standards that have worked for HLA."}
+{"text": "Herpes Zoster also known as Shingles is an acute viral infection which is an extremely painful and incapacitating ailment. It results from the reactivation of the varicella zoster virus. The triggering factors for the onset of an attack of Herpes Zoster include some form of immunosuppression. The diagnosis of Herpes Zoster can be made on proper medical history and a thorough clinical examination. Here is the report of a male patient affected by Herpes Zoster infection which followed after extraction of a lower first molar. Herpes Zoster is a painful acute infectious viral disease caused due to the inflammation of dorsal root ganglia or extramedullary cranial nerve ganglia, leading to vesicular eruptions of the skin or mucous membrane in an area supplied by the affected nerve. The most commonly affected dermatomes are the thoracic (45%), cervical 23%), and trigeminal 15%) 3%, and tThe primary infection of varicella zoster virus (VZV) is the chicken pox and, due to the characteristic of latency of the herpes group of viruses, VZV gets reactivated to cause Herpes Zoster infection in later age.The incidence of latent Herpes Zoster increases 5\u201310-fold after the age of 80 years .A male patient of 49 years reported to the Department of Oral Medicine and Radiology, C.S.I. College of Dental Sciences and Research, with the chief complaint of pain and ulceration on left side of face and mouth for four days. Patient gave the history of extraction of the tooth 5 days ago after which multiple vesicles formed on the left side of the face and inside the mouth which made him uncomfortable while ingesting food. He had visited a dentist who diagnosed the condition as angioedema and prescribed antihistamines for three days but they did not alleviate any of the symptoms and the pain and ulcerations worsened. He did not have any relevant medical history. He is not a smoker but occasionally consumes alcohol.On examination, unilateral multiple vesicles with few of them ulcerated were found on the left side of the face and facial asymmetry due to diffuse swelling which extended superiorly to the upper eyelid was evident . On intrUlcerations were also evident on left buccal mucosa and alveolar mucosa in relation to 36 . The ulcPatient was subjected to few investigations to rule out any immunocompromised status. The hemogram and serum glucose levels were within normal limits. ELISA for HIV was negative. Patient was referred to a general physician for hydration and ophthalmic evaluation. A dose of antivirals and steroids which included Valacyclovir 1000\u2009mg 3 times a day and Prednisolone 20\u2009mg 3 times a day and topical acyclovir for 1 week was prescribed.The patient responded to antivirals and steroids well within a week and showed considerable healing. Patient was evaluated every week and steroids were tapered over four weeks and stopped. Gradual healing was observed in phases Figures .By fourth week the patient was seen only with scars on the left side of face Figures  and 6.Systemic steroids could have prevented complications as it has been 3 months and the patient is apparently healthy at present.Herpes Zoster has an estimated life time incidence of 10\u201320% and gets reactivated with some form of immunosuppression. Herpes Zoster infection is common in elder persons, HIV-positive individuals, and patients affected by malignant blood dyscrasias or malignant tumours or undergoing immune suppressive therapy and radiotherapy .The most noted point of our case report was that there was no previous history of any herpetic simplex infection in childhood or recurrent herpes labialis in later stage. It is believed that the patient could have contracted chicken pox early in his life as the incidence of chicken pox in a tropical country like India is very high. Also the unilateral distribution of the erosions and the lesions pertaining only to the oral and maxillofacial region with involvement of ophthalmic, maxillary, and mandibular division of trigeminal nerve is suggestive of Herpes Zoster rather than a herpes simplex infection. The infection was triggered by a traumatic extraction of left mandibular lower first molar. El Hayderi et al. postulated that HSV reactivation occurs during surgical procedures involving trigeminal nerve in 50% of patients and an anaesthetic block may irritate the nerve leading to reactivation and recrudescence of herpes lesion , 7. ThisInvolvement of the second and third branches of the trigeminal nerve results in vesicular lesions in oral cavity. The vesicular lesions develop 2\u20134 days after prodromal period of fever, weakness, fatigue, and stiffness of the neck . Our patThe duration of healing of Herpes Zoster lesions and the severity of pain associated with the disease have been shown to be considerably less with prompt administration of antiviral agents. However these benefits have been found in patients who received antiviral agents within 72 hours after the onset of the rash . But ourThe early diagnosis of Herpes Zoster and prompt treatment can avoid further complications. Herpes infection following extractions has been reported very rarely. Herpes Zoster infection must also be considered as one of the complications after extraction. The patients must be asked to report to the dentist if there is any symptoms of the disease after extraction. The patient should be under medication and periodically reviewed. Misdiagnosis should be avoided as far as possible unlike this case where herpes infection was misdiagnosed as allergy."}
+{"text": "The superiority of the Intensive insulin regimen over the conventional split mix is very well established in Western centres, often considered a prelude to pump therapy. Developing countries find it a challenge to initiate Basal bolus therapy. The main problems include: lack of support systems in school environment to take up the injections and glucose monitoring at school, and difficulties in assessing carbohydrate content of native foods prepared at home (considering the variability in preparation of any given food item). The parental acceptance of five injections a day also remains a challenge. There are numerous extraneous influences and myths in minds of parents that discourage them from accepting this regimen. We present our experience in surmounting these challenges and establishing Intensive insulin therapy as a first line of insulin therapy and also share the advantages in terms of the glycemic control and growth of children on follow-up with us."}
+{"text": "Doctors are not short of advice about how to manage their patients. In the case of COPD (Chronic Obstructive Pulmonary Disease) there are a wealth of guidelines, strategies and position papers synthesising an increasing body of data from observational studies and clinical trials into schemes that should help the doctor care for their COPD patients more effectively. In recent years particular attention has been paid to the views of the joint ERS/ATS COPD guidelines  and the 1/FVC ratio of 70% or less to support the diagnosis of COPD and suggest instead that the lower limit of normal (LLN) for this ratio is a more reliable guide. There might have been a little more advice for the busy clinician on the best way of accessing appropriate LLN data and perhaps a little more caution on the usefulness of bronchodilator testing in patient evaluation [Appropriately this new document takes a very wide view of the problems of COPD. It emphasises the need for early accurate diagnosis supported when needed but supplementary physiological investigations such as the measurement of lung volumes and airway responsiveness. It points out the limitations of relying on a fixed FEValuation . HoweverThe authors have avoided some of the controversy and uncertainty surrounding the new GOLD severity assessment scheme , insteadThis new approach to COPD care is needed in Italy now. As the authors point out, COPD remains a major health problem despite much good work to increase smoking cessation rates and improve air quality. International guidelines offer an overview of COPD care in all settings but there is still a need to develop management strategies which work locally and reflect the needs and perceptions of local physicians and patients. This new initiative has achieved both of these goals admirably."}
+{"text": "The impact of the chronic pelvic inflammatory state on other organ systems and women's health is unclear. Endometriosis associated chronic inflammation and potential adverse health effects across the lifespan render it imperative for renewed research vigor into the identification of novel biomarkers of disease and therapeutic options. Herein we propose a number of opportunities for research and development of new therapeutics to address the unmet needs in the treatment of endometriosis  The causal relationship regarding which comes first may not be absolutely established  but resewe must develop novel biomarkers of endometriosis for diagnosis, response to treatment, and disease progression;we must ascertain whether the chronic inflammatory process in the peritoneal compartment incurs a significant risk for other systemic (remote) diseases \u201318;we must strive to identify novel preventative, modulatory, or therapeutic interventions that can take advantage of cellular and molecular mechanisms to mitigate both the primary disease process  and the consequent systemic inflammatory effects.No matter whether the disease etiology depends primarily upon the biomechanics of retrograde menstruation, sex hormone modulation of endometrial tissue proliferation, environmental exposures, genetics, oxidative stress, or inflammatory cell populations, we must address three key themes:A plethora of biochemical differences in the peripheral circulation, peritoneal fluid, and endometrial tissues of women with endometriosis versus healthy controls has been demonstrated \u201342 many Emerging areas of interest include nerve fiber density, microRNA (miRNA), and neurotrophins. Recent studies report the fact that nerve fiber density in the functional layer of the eutopic endometrium is greater in women with endometriosis compared to controls , 72. AltSeveral recent studies have documented aberrant expression of several different miRNAs in women with endometriosis \u201382. miRNProspects for development of improved diagnostic and disease-monitoring strategies for endometriosis have recently been advanced by the efforts of a major international research consortium, the international \u201cWERF EPHect\u201d initiative \u201388. In tContemporary biomarker techniques  are begi per se and systemic adverse effects with durability will mean either long-term continuing usage or repetitive episodic usage with convincing evidence of patient safety and tolerability. Accordingly investigators in this field need to consider the prospects for patient safety with chronic usage of any candidate agents along with evidence of efficacy and reduction in risks of other diseases associated with chronic inflammation [Current therapeutic drugs are primarily directed at suppressing the intraperitoneal activity of the underlying disease. As is the case for other chronic diseases, future novel therapeutics for endometriosis will need to be developed to treat the primary intraperitoneal process , the potammation . Whetherammation  or in teammation  aimed atBeyond the current set of hormonal and anti-inflammatory drugs used to treat endometriosis, what classes of compounds might be safe and effective in the sustained management of this chronic inflammatory process? A modest number of ideas have been suggested by various investigators and we shall consider them plus one new idea that we propose from some recent research in continuous ambulatory peritoneal dialysis (CAPD).Several classes of compounds  have bee\u03b1 in peritoneal fluid [The second group of compounds that merit research and development for potential application in endometriosis may potentially mitigate both the intraperitoneal and the systemic inflammatory consequences of endometriosis , 34\u201339. al fluid . Finallyal fluid  and sincIt is our view that there are ample opportunities to pursue research regarding the impact of endometriosis across the lifespan and to pursue development of a number of therapeutics that could plausibly be expected to be both safe and beneficial for women suffering with this disease. This is not an argument for taking our eye off the prize meaning endometriosis as the primary disease; rather we owe it to each of our patients to consider all of the impacts at all times in life that this disease may incur. We urge deeper and broader understanding of such risks and pursuit of safe and effective interventions for the care of our patients."}
+{"text": "From February 2012 a multidisciplinary group in a 600 bed tertiary public hospital in Western Australia have worked collaboratively to improve the care of adult patients admitted to an acute medical ward with complications of severe eating disordersThis clinical care journey has gone on to inform a program of staff development and strategic advocacy for a state wide approach to the care of adults with eating disorders.Via demonstration of parallel journeys of patients, staff and the state wide strategy, the authors have identified areas of unmet need, gaps in resourcing and barriers to improving care from a local context.This multidisciplinary collaborative process has now informed a business case for a comprehensive specialist eating disorders service for youths and adults in Western Australia's public health service.Service Initiatives stream of the 2014 ANZAED Conference.This abstract was presented in the"}
+{"text": "An effective capacity building process for healthcare workers is required for the delivery of quality health care services. Work-based training can be applied for the capacity building of health care workers while causing minimum disruption to service delivery within health facilities. In 2012, clinical mentoring was introduced into the Jigawa State Health System through collaboration between the Jigawa State Ministry of Health and the Partnership for Transforming Health Systems Phase 2 (PATHS2). This study evaluates the perceptions of different stakeholders about clinical mentoring as a strategy for improving maternal, newborn and child health service delivery in Jigawa State, northern Nigeria.Interviews were conducted in February 2013 with different stakeholders within Jigawa State in Northern Nigeria. There were semi-structured interviews with 33 mentored health care workers as well as the health facility departmental heads for Obstetrics and Pediatrics in the selected clinical mentoring health facilities. In-depth interviews were also conducted with the clinical mentors and two senior government health officials working within the Jigawa State Ministry of Health. The qualitative data were audio-recorded; transcribed and thematically analysed.The study findings suggest that clinical mentoring improved service delivery within the clinical mentoring health facilities. Significant improvements in the professional capacity of mentored health workers were observed by clinical mentors, heads of departments and the mentored health workers. Best practices were introduced with the support of the clinical mentors such as appropriate baseline investigations for pediatric patients, the use of magnesium sulphate and misoprostol for the management of eclampsia and post-partum hemorrhage respectively. Government health officials indicate that clinical mentoring has led to more emphasis on the need for the provision of better quality health services.Stakeholders report that the introduction of clinical mentoring into the Jigawa State health system gave rise to an improved capacity of the mentored health care workers to deliver better quality maternal, newborn and child health services. It is anticipated that with a scale up of clinical mentoring, health outcomes will also significantly improve across northern Nigeria. Increasing the number of skilled health workers to provide quality health services is a key health systems strengthening objective . Within classroom training [Within clinical practice in particular, work based training is a key part of professional development which has the capacity to develop health care workers in ways quite different from, but complementary to formal training . The keytraining ,9. Clinitraining ,11. Clintraining . A typictraining .Nigeria has an estimated population of over 140 million people . Howevercontinuous professional capacity development to effectively provide the right quality of healthcare services to improve maternal, newborn and child health outcomes. It was hypothesized that the implementation of clinical mentoring would assist in addressing the prevailing challenges to maternal, newborn and child healthcare service delivery within northern Nigeria. The objective of this study was to elicit the perceptions of stakeholders about clinical mentoring and its potential for improving maternal, newborn and child health service delivery within Jigawa State in northern Nigeria. The study highlights some successes as well as some challenges associated with the implementation of clinical mentoring within the context of the Jigawa State health care system.There is considerable evidence that work-based training approaches such as clinical mentoring has been successfully utilized to transfer knowledge and skills in several fields such as management of HIV/AIDS , neonataJigawa State is within the north western part of Nigeria and consists of 27 Local Government Areas . Accordiwere randomly selected and recruited to participate in clinical mentoring from different cadres of health workers that routinely work in the five selected health facilities in Jigawa State  health workers to be mentored were recruited through purposive sampling from tertiary health facilities i.e. the teaching hospitals and were allowed to travel from their places of primary assignment to the clinical mentoring health facilities. The clinical mentoring intervention involves collaboration between the Jigawa State Ministry of Health  and the Partnership for Transforming Health Systems Phase 2 (PATHS2) which provides support for the allowances of the clinical mentors. PATHS2 is a health systems strengthening project sponsored by United Kingdom\u2019s Department for International Development (DFID) and implemented by a consortium of partners led by Abt Associates. PATHS2 works in collaboration with the Government of Nigeria  and other stakeholders to improve the planning, financing and delivery of sustainable health services to Nigerians.The clinical mentors were identified through the professional network of PATHS2\u2019s consultant on clinical mentoring. The clinical mentors work full time at teaching hospitals in the surrounding States of Kano and Bauchi States. These clinical mentors Each of the different subgroups of study participants  were identified as stakeholders in the implementation of clinical mentoring and regarded as key informants for the study. In February 2013, interviews by the study team (led by the first two authors of this paper) were conducted with the stakeholders of the clinical mentoring intervention in Jigawa State. The interviews were documented using tape recorders. The qualitative data were transcribed, a pre-determined coding framework was applied and subsequently thematic analyses of the data were undertaken. Members of the study team who were involved during the data collection process also provided assistance in identifying relevant themes. Regular meetings were held by the study team in order to reach consensus on the interpretation of the data collected during the interviews.A qualitative approach was adopted for this study so as to provide detailed information and sufficiently elicit the opinions, experiences as well as perceptions of the different stakeholders with respect to the clinical mentoring intervention as opposed to a quantitative approach. The expectation of the study team was that any connections or contradictions between activities and perceived changes arising from the implementation of clinical mentoring will be adequately highlighted using a largely qualitative methodology.or otherwise of the clinical mentoring intervention within the context of the State-wide health system. The Jigawa State Government health officials were asked questions about the most challenging areas within the Jigawa State health system and how clinical mentoring has helped to address these challenges. Other questions were intended to assess the key lessons learnt, best practices, specific improvements that have been recorded as well as recommendations to improve the implementation of clinical mentoring within the State. The study team also organized structured interviews with the mentored health workers. The structured interviews included questions on the perceived effect/impact of clinical mentoring on health facility activities  were carried out using semi-structured interview guides to elicit their opinions and experiences vis-\u00e0-vis the implementation of clinical mentoring within the intervention health facilities. The interview questions for the departmental in-charges sought to obtain information about the activities carried out by the clinical mentors during their visits, benefits of clinical mentoring to the health facility and any improvements observed due to the implementation of clinical mentoring within the intervention health facilities. There were also in-depth interviews with Jigawa State Government health officials to get their perspectives on the effectiveness Ethical clearance for the study was obtained from the Jigawa State Ministry of Health. In addition, informed consent was obtained from all the study respondents before the interviews commenced. The verbal consent of the study respondents were documented using tape recorders. The objective of the study, respondents\u2019 right to refuse participation and freedom to terminate participation in the study at any time was discussed with each study participant. Study respondents were assured of the confidentiality of their responses.i.Inadequate numbers and capacity of the health workforce to provide adequate health care services to the State\u2019s population.ii.Lack of skilled health care professionals and inadequate training of the health workers within the State.iii.Attrition of key healthcare workers, including doctors and midwives.Two senior level healthcare officials of the Jigawa State Ministry of Health were interviewed as part of the evaluation of the clinical mentoring intervention within selected health facilities in Jigawa State. Government officials acknowledge that the human resources for health system within the State have multifarious challenges, including but not limited to the following:\u201c\u2026perhaps a key outcome of the implementation of clinical mentoring will be that Jigawa State better understands other ways to tackle the human resources for health situation and improve healthcare service delivery.\u201dWith the introduction of clinical mentoring visits, some of these challenges are being addressed as there appears to be an increase in the number of better trained health professionals providing health services to patients. These improved professional healthcare services have been provided through the expertise and contributions of the clinical mentors. The Gunduma Health System officials indicated that one of the key lessons learnt from the implementation of the clinical mentoring programme was the increased focus the mentoring visits have given to maternal, newborn and child health issues within the health care delivery system of the State. It was also reported that the clinical mentoring intervention has increased awareness about the need to explore other innovative approaches/strategies to address the critical health workers\u2019 situation within Jigawa State. A Gunduma health official remarked:Highlighting some challenges however, the Gunduma healthcare officials pointed out that the current approach whereby the clinical mentors visit health facilities, provide services and travel back on the same day naturally limits the time spent providing services and this invariably affects the quality of healthcare services provided. The financial implication of retaining and recruiting more clinical mentors is also a serious challenge and Jigawa State needs to make adequate budgetary allocations to address this challenge.\u201cThe main suggestion I have is on integrating clinical mentoring into the district health system within the State so that it works through an existing system.\u201dThe key suggestion from the Gunduma health systems officials is that clinical mentoring needs to be effectively integrated into the existing district health system within the State. This integration it was argued would ensure sustainability, greater ownership by the State government and could potentially give rise to more benefits to the State\u2019s health system. In connection with this suggestion, a Gunduma health official remarked:It was proposed that adequate temporary accommodation should be provided to enable clinical mentors to follow up on some cases as maybe appropriate. It was also argued that with the perceived increase in patient flow within the mentoring health centres, clinical mentors should spend more visiting hours and days providing services within their assigned health facilities or more clinical mentors should be recruited. Jigawa State needs to have a long term plan of developing a pool of consultants to sustain the clinical mentoring programme.\u201c\u2026my capacity has been built and I have gained in experience.\u201dThirty three (33) mentored health workers recruited across the five selected health facilities were interviewed as part of the study. Table\u00a0\u201cWe as mentors have introduced clinical protocols to guide the health workers in the conduct of their work e.g. protocols for magnesium sulphate, management of post-partum hemorrhage, and the management of the third stage of labour\u2026\u201dThe three obstetrics clinical mentors recruited into the clinical mentoring intervention were interviewed as part of the study. The obstetrics clinical mentors indicated that the preliminary assessment which was carried out at the start of the clinical mentoring intervention provided guidance and thus assisted in identifying weaknesses as well as specific areas for improvement among health workers working within the obstetrics department. Significant changes arising from the clinical mentoring intervention include updated treatment guidelines on basic emergency obstetric health care, pre-eclampsia and eclampsia, post-partum hemorrhage as well as the management of the third stage of labour. An obstetrics clinical mentor remarked:Clinical mentors report that as a result of the mentoring visits, infection prevention practices have been introduced into the health facilities where they visit. Such emphasis on infection prevention will tend to minimize the possibility of patients picking up \u2018hospital-based infections\u2019 while visiting the clinical mentoring health facilities.\u201cIn health facilities in which we visit, we have developed and introduced treatment protocols, some of which are on the notice boards in some wards\u2026\u201dThe three pediatrics clinical mentors participated in interviews as part of the evaluation of the clinical mentoring intervention. The pediatrics clinical mentors indicated that standard treatment guidelines for the management of different pediatric cases have been introduced following the mentoring visits. A pediatric clinical mentor enthused:\u201cWe have introduced the use of nasogastric (NG) tubes for feeding pediatric patients with severe malnutrition\u201d.There are other significant changes attributable to clinical mentoring as highlighted by a pediatric clinical mentor:\u201cThe practice of weighing pediatric patients during each visit which was not the case before the start of the clinical mentoring intervention has also been introduced\u201d.Another pediatric clinical mentor pointed out:\u201cWe have made significant efforts within the mentoring centers to ensure that weighing scales were acquired for use within the pediatrics department\u201d.This approach of measuring pediatric patients during each visit has most likely given rise to the appropriate calculation of dosages for pediatric patients in addition to effective growth monitoring as part of best practices towards managing pediatric cases. A pediatric clinical mentor indicated:\u201cA good part of the mentoring visits for me is seeing the improvement in the mentee\u2019s knowledge, skills and confidence\u2026\u201dGreater emphasis has also been placed on better record keeping by the health care workers. Alluding to the changes arising from the mentoring visits, a pediatrics clinical mentor remarked:to assign one mentor to cover a health facility and not one mentor covering more than one health facility as is currently the case. This will ensure that the clinical mentor concentrates on the cases and health workers to be mentored in just one assigned health facility. Another suggestion was that temporary accommodation should be provided for the clinical mentors to allow the mentors follow up on cases when and where necessary. The current set-up whereby mentors travel from their primary location, provide services and have to travel back the same day limits the quality and quantity of care provided to patients. It is also not advantageous to the patients who may need further monitoring such as those that have had surgeries.As a way to improve the effectiveness of clinical mentoring, a clinical mentor suggested that it would be more appropriate \u201cThere is need to create more opportunities and sensitize community leaders in the surrounding communities while also liaising with the health facility in-charges to assist in mobilizing community members so as to better utilize the expertise and services offered by the clinical mentors.\u201dIt was proposed that payment incentives could be introduced to increase the motivation of the clinical mentors. Furthermore, it was recommended that the benefits of the mentoring visits should be extended beyond the health workers in the mentoring centres, such that health workers working in surrounding health facilities could be invited on the days that the consultants visit to learn alongside the health workers in the mentoring centres. In addition, there should be proper community mobilization such that the communities within the catchment areas of the health facilities should be enlightened about the visit of the consultants to ensure that a larger proportion of community members access and utilize the services of the visiting consultants. A clinical mentor remarked:\u201cThe clinical mentors are responsible for the introduction of the use of magnesium sulphate as the standard treatment for pre-eclampsia and eclampsia within the intervention health facilities.\u201dHealthcare workers in-charge of obstetrics in each of the five intervention health facilities took part in interviews as part of the evaluation of the implementation of clinical mentoring. Healthcare workers in-charge of obstetrics indicated that clinical mentors have introduced new skills and updated the knowledge of the mentored health workers working in obstetrics:\u201cThere is an improvement in the management of post-partum hemorrhage as mentored health workers were trained on the proper use of misoprostol\u201d.In addition, a health worker in-charge of obstetrics in one of the intervention health facilities indicated:\u201cProper record keeping and improved charting of medications have also been observed\u2026\u201dAnother health worker in-charge of obstetrics pointed out:\u201cCaesarean section (C/S) deliveries are more likely to be routinely carried out for some pregnancies especially when there are abnormal conditions that complicate normal vaginal delivery\u201d.The health facility departmental in-charges mentioned that health workers appear more confident when handling cases and this was reflected in comments from a health facility departmental in-charge:\u201cThe clinical mentor is assisting the health facility in addressing high burdens of anaemia and malaria in pregnancy within the communities that utilize the services of the health facility\u201dThe obstetrics departments of the intervention health facilities suggest an increase in patient flow as well as a decrease in the number of referrals out of the health facility to higher level health facilities. An in-charge of obstetrics in one of the intervention health facilities pointed out:\u201cWe now record the expected due date (EDD) for prospective mothers as part of best practices for effective maternal healthcare\u2026and to help us with this the clinical mentor came with a calendar so that the EDD for clients can be easily calculated.\u201dAn obstetrics unit head within an intervention health facility also indicated:\u201cMore patients are coming\u2026a health worker at a nearby health facility referred a patient and insisted that the patient visits on the day the clinical mentor visits this health facility\u2026\u201dThe health workers in-charges of pediatrics department in each of the five clinical mentoring intervention health facilities were interviewed as part of the study. The health workers in-charge of pediatrics concur with the mentored health workers and suggest that there has been an increase in pediatric patients coming to access health services. It was implied by health workers in-charge of pediatrics that the mentored health workers tend to better manage patients, thus likely reducing the number of pediatric cases referred out of the health facilities. A pediatrics unit in-charge remarked:\u201cThe clinical mentor introduced the use of ambu-bags and these have been particularly useful for neonatal resuscitation and reducing neonatal mortality\u201d.Aligning with the responses from the pediatric clinical mentors, pediatric unit in-charges indicate that some notable best practices have been introduced by the clinical mentors; for e.g. weighing pediatric patients which is crucial for the appropriate calculation of pediatric dosages as well as for growth monitoring. An in-charge of pediatrics in one of the intervention health facilities also pointed out:\u201cThere have been some changes in the treatment protocols for e.g. malnutrition; we have been taught that we should be careful with the use of IV fluids and instead insert NG-tubes especially for severely malnourished pediatric patients.\u201dProper baseline investigations and tests are now more likely to be carried out as part of standard management of pediatric cases following the introduction of clinical mentoring. The pediatrics clinical mentors also introduced changes to the management of malnutrition such as the use of nasogastric (NG) tubes for managing malnourished children within the intervention health facilities. A health worker in-charge of the pediatrics remarked:\u201cClinical mentoring has introduced new clinical approaches\u2026resulting in improved standards of health care for our pediatric patients.\u201dWith the accessibility of the consultant pediatricians to health workers working in the intervention health facilities, it was reported that health workers tend to better manage clinical cases and if there is need, the clinical mentors could be contacted using a mobile telephone and thus the necessary guidance can be provided. This perception of an improved standard of pediatric care within the intervention health facilities was summarized by a health worker in-charge of pediatrics in one of the intervention health facilities as follows:This study set out to investigate stakeholders\u2019 perceptions of clinical mentoring as an innovation for improving maternal, newborn and child health service delivery within Jigawa State in northern Nigeria. The study explored the implementation of clinical mentoring from four unique perspectives: clinical mentors, mentored health workers, departmental in-charges of Pediatrics and Obstetrics within intervention health facilities as well as government officials from the Gunduma Health Board. Utilizing a qualitative study design, the study elicits the responses of key actors in the implementation of the clinical mentoring intervention, discusses the implications for improving health care service delivery and outlines some key policy recommendations.Poor performance among health workers is usually associated with the lack of adequate knowledge and skills . Howeverduring each visit to ensure the appropriate calculation of pediatric dosages, appropriate baseline investigations for pediatric patients as well as the use of ambu-bags for neonatal resuscitation to reduce neonatal mortality.The preliminary assessments conducted at the start of the clinical mentoring intervention provided useful pointers on specific areas to focus on during the capacity building process. The vast majority of mentored health workers suggest that clinical mentoring did not only strengthen health workers capacity but it also appears to have improved service delivery and health facility management within the intervention health facilities. The contributions of clinical mentoring to health facility management and service delivery were also reiterated by the healthcare workers in charge of both Pediatrics and Obstetrics: clinical mentors have utilized their expertise to update the knowledge and skills of mentored health workers. More importantly, best practices were introduced and are being institutionalized with the support of the clinical mentors such as the use of magnesium sulphate for eclampsia management, misoprostol for the management of post-partum hemorrhage, weighing pediatric patients However serious considerations should be paid to the recommendations proposed by the clinical mentors such as the provision of temporary accommodation to allow the mentors follow up on cases when and where necessary. As a solution, the government can provide some form of \u201cdoctors\u2019 lodge\u201d to provide overnight accommodation for the clinical mentors to address the challenge of temporary accommodation. Pay for performance incentives can also be introduced to further motivate the clinical mentors which will have direct consequences on the quality of services provided at the health facilities. Criteria for computing these financial incentives could be based for example on the number of complicated cases managed per week or month over and above a set target. Concerted efforts should also be invested to ensure that the benefits of the mentoring visits are fully exploited by the catchment populations of the intervention health facilities through employing effective community mobilization strategies. Community mobilization could involve the use of meetings in surrounding communities that utilize the services of the health facilities as well as the mass media such as radio to inform communities about the availability of expert healthcare in the clinical mentoring health facilities. The availability of more patients through community mobilization could lead to better mentoring because of the exposure of the mentees to a wider variety of clinical cases. In addition, increasing access to the expertise of the clinical mentors by providing mentoring opportunities for the majority of health workers working within as well as others working outside the current mentoring centers should be a priority.Another obvious recommendation is the scale up of clinical mentoring to health facilities outside the current mentoring centers. In carrying out such a scale up to other health facilities, careful consideration should be paid to a more holistic system strengthening approach to the health system including the provision of essential drugs, adequate financial resource mobilization and reliable health information systems in addition to proper governance and accountability mechanisms. This is important because as implied elsewhere , simply This study has some key limitations: there is the possibility of response bias particularly among the mentored healthcare workers and clinical mentors. In addition the study design excluded health workers not participating in this clinical mentoring approach but working within the intervention health facilities, who may have provided an entirely different perspective. Furthermore, since the study was conducted just about six months after clinical mentoring commenced, there is lack of evidence on the longer term impact of clinical mentoring on health workers\u2019 capacity and healthcare service delivery.This study suggests that the introduction of clinical mentoring into the Jigawa State health system has given rise to mentored health care workers with improved capacity to deliver better quality maternal, newborn and child health services. There is strong optimism that consequently there will be more emphasis placed on the need for and the provision of better maternal, newborn and child healthcare (MNCH) services. However this optimism needs to be matched with organizational support from the health facilities\u2019 management as well as managerial support from the State\u2019s Ministry of Health to improve health workers\u2019 motivation, service delivery and health outcomes. Finally as suggested by healthcare officials working in the Gunduma Health Board, integrating clinical mentoring into the existing district health system within the State will promote ownership by the Government as well as the sustainability of clinical mentoring within the Jigawa State health system."}
+{"text": "Application of pharmacogenetic knowledge with the help of quick and cheap companion diagnostics in the primary care setting is expected to deliver improved treatment and reduced heathcare costs. Warfarin and aspirin are the two most widely prescribed drugs for preventing cardiovascular diseases. Long term aspirin use has also been shown to reduce risk, recurrence and mortality from colorectal cancer. However, they both have narrow therapeutic windows and several genetic polymorphisms have been noted to influence their dose and efficacy. We therefore have launched two collaborative projects: first, to study the genetics of warfarin safety in the Gujarati Indian population and second, to identify further polymorphisms that modulates aspirin\u2019s colorectal cancer chemopreventive efficacy. Understanding the impact of polymorphisms on dose and efficacy for these drugs would lead to development of a combined panel of markers that would predict accurate therapeutic dose with minimal risk for adverse reactions. These markers will be deployed at the point of care settings using a novel handheld genotyping device which will use disposable microfluidic cassettes and silicon nanowires currently developed by QuantuMDx. Results, future work, opportunities and barriers will be examined.The increase in identification of putative biomarkers and opportunities to develop tailored treatments are due to emergence of"}
+{"text": "Hepatocellular carcinoma (HCC) is a malignant tumor with hepatocellular differentiation and one of the most common cancers in the world. This type of cancer is often diagnosed when the survival time is measured in months causing high death rates . For theWe enhanced the classification process presented in  by incluThe results of classification experiment are summarized in The combination of nuclear, trabecular, and other tissue features enables improved classification rate in HCC detection using SVM. Even though the image characteristics are different in biopsy and surgically resected samples, the same classification system gives good performance in both samples. The HCC classification scheme introduced in this paper is implemented in the prototype \u201cfeature measurement software for liver biopsy,\u201d and the probability of HCC is visualized for every ROI in the WSI. It will support pathologists in the HCC diagnosis along with the quantitative measurements of tissue morphology."}
+{"text": "Size Principle of motoneuron recruitment stated that for any net excitatory input to the motoneuron pool, motoneurons were recruited in an orderly fashion, always from small to large. Stein and coworkers demonstrated that the size principle generalized to voluntary isometric contractions in humans, which they called Orderly Recruitment  and contractile properties of the associated muscle units. Considering the range of motoneuron and corresponding muscle unit properties, the obvious question arose about how and which motoneurons were selected by the central nervous system for various types of contractions and movements. Elwood Henneman and his coworkers proposed an unequivocal simple pattern in a series of papers starting in 1957 from experiments conducted on reduced cat preparations  muscles. Likewise, an anatomically defined motoneuron pool may under certain conditions be compartmentalized into task groups (Riek and Bawa, What do orderly recruitment and selective recruitment really mean? The accepted narrative is that orderly recruitment of motor units from small to large twitch force, results in a more precise control of force and movement; this precision is more important for small and mid range forces. By maintaining the same order of recruitment, the central nervous system minimizes the computational load across a wide range of desired outputs (Henneman et al., Another factor that has contributed to a misunderstanding of the orderly recruitment is the expectation for precise rank ordered recruitment (Henneman et al., laboratory conditions with simple muscles and a limited set of contractions, recruitment is orderly in terms of force (Milner-Brown et al., size principle of orderly recruitment will generalize to movements of everyday life.The ultimate meaning of recruitment order lies in the force output of the entire musculoskeletal system for the purpose of behaviorally relevant movements. Clearly in The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "PLOS Biology Editors and the splicing does not affect the authors\u2019 conclusions.The authors would like to clarify the source of splice lines that can be detected in several figures where lanes from parts of the same gel were juxtaposed. To assure readers of the integrity of the data and demonstrate the source and relationship of the gel lanes, we present in S1 Raw Data(PDF)Click here for additional data file."}
+{"text": "In the past decade, remarkable change in malaria control and transmission has been documented in many  African nations and some countries are moving toward elimination. The malaria control community has long measured and tracked malaria transmission using a variety of methods from the highest to the lowest transmission areas. For program action across the spectrum of transmission between humans and mosquitoes, the balance between accurate measurement, sufficient detail to inform program decisions, and ease and simplicity of information collection, analysis and interpretation has always been challenging. A summary of historic and current efforts to measure parasites within and moving between people and mosquitoes will be provided with an emphasis on how the approaches and emphasis change as transmission intensity changes. The program decision needs for routine systems and for special studies to track transmission reduction will be discussed. The detection and verification of \u201czero\u201d infection and transmission will be discussed in terms of tools and sampling methods that will allow the designation of malaria-free areas."}
+{"text": "While historically viewed as an immune-privileged area fully isolated from the immune system, the central nervous system (CNS) is now appreciated to maintain dynamic bi-directional communication with the immune system across the blood\u2013brain barrier (BBB) , 2. In nIt is now accepted that there is a need for constant immune surveillance of the adult CNS as part of normal host defense, acknowledging that simultaneous mechanisms must keep local CNS inflammation strongly in check . Indeed,Streptococcus pneumoniae is an important pathogen because it is the main cause of both community-acquired pneumonia and meningitis induced by a bacterial pathogen in otherwise healthy older children and adults. Much has also been learned about host immune responses elicited by pneumococcal pneumonia or meningitis using mouse models  is an arenavirus to which both mice and humans are susceptible and that causes varying combinations of visceral  and/or CNS  involvement in adult hosts. Murine LCMV infection has served as a prototype experimental system to study immunity to viruses for many years . This paThe host responses provoked by these two naturally occurring pathogens are used here to compare how the immune system recognizes and responds to the same challenge in the periphery and the CNS Table . The avaBoth the afferent and efferent arms of the immune system are efficiently activated in the context of either pneumococcal or LCMV infection, and the kinetics, magnitude, and composition of immune responses elicited in adult hosts appear remarkably similar when either a visceral organ or the CNS is the main target of disease Table . Acute CThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Emergency contraception pills (ECP) are among the 13 essential commodities in the framework for action established by the UN Commission on Life-Saving Commodities for Women and Children. Despite having been on the market for nearly 20 years, a number of barriers still limit women's access to ECP in low- and middle-income countries (LMIC) including limited consumer knowledge and poor availability. This paper reports the results of a review to synthesise the current evidence on service delivery strategies to improve access to ECP.A narrative synthesis methodology was used to examine peer reviewed research literature (2003 to 2013) from diverse methodological traditions to provide critical insights into strategies to improve access from a service delivery perspective. The studies were appraised using established scoring systems and the findings of included papers thematically analysed and patterns mapped across all findings using concept mapping.Ten papers were included in the review. Despite limited research of adequate quality, promising strategies to improve access were identified including: advance provision of ECP; task shifting and sharing; intersectoral collaboration for sexual assault; m-health for information provision; and scale up through national family planning programs.There are a number of gaps in the research concerning service delivery and ECP in LMIC. These include a lack of knowledge concerning private/commercial sector contributions to improving access, the needs of vulnerable groups of women, approaches to enhancing intersectoral collaboration, evidence for social marketing models and investment cases for ECP. Universal access to sexual and reproductive health and rights is an essential component of a healthy society. There are 222 million women in the world who wish to prevent pregnancy but are not using effective, modern methods of contraception. This results in an estimated 86 million unplanned pregnancies, 33 million unplanned births Strengthening service delivery and demand generation are key strategies to achieving universal access to sexual and reproductive health (SRH), including access to Emergency Contraceptive Pills (ECP). ECP is included in the list of 13 essential commodities in the framework for action established by the UN Commission on Life-Saving Commodities for Women and Children (UNCoLS) Quality service delivery at primary health care level, in both public and non-state sectors, is dependent upon inputs into the health system including supportive policies, evidence-based guidelines, trained workforce, secure contraceptive procurement and supplies, and financing. Ensuring the availability and access to quality health services is one of the main functions of a health system In order to improve the service delivery of ECP, leaders in LMICs require evidence to inform country efforts to strengthen quality assurance mechanisms, build the capacity of the pharmacy/drug-selling sectors to provide high-quality service and advice, co-ordinate and scale-up service provision, and generate demand through interventions such as social marketing. Improving service delivery requires building the knowledge base at country level. However, there is a paucity of such knowledge, nor is there a synthesis of quality evidence from a number of nations available to decision-makers in their efforts to increase access to ECP.In order to provide evidence to contribute to strengthening ECP delivery channels and developing policy guidance and tools to expand access to ECP including among vulnerable groups, we undertook a narrative synthesis of current research. The aim of this review was to identify what service delivery opportunities and interventions in LMIC can facilitate increased access to ECP. The results of this review and related reviews into consumer and service provider experiences will provide evidence to assist the ECP Technical Reference Team that has been established to help carry forward the UNCoLS recommendations at the global and national levels A narrative synthesis methodology was employed to analyse selected literature. This method was chosen due to the range of qualitative and quantitative methodologies of the studies identified for the review, which did not allow the pooling of results that are achieved in other systematic approaches to synthesising evidence such as statistical meta-analysis The scoping exercise identified databases and website where ECP literature could be retrieved and potentially useful keywords identified. Seven bibliographic databases , meta-Indexes ; websites of relevant organizations ; Google Scholar and the reference lists of key papers were searched to retrieve research literature.A Population, Interventions, Comparators, Outcomes, Study design (PICOS) question was formed to guide this review as per guidelines Observational studies, quasi experimental and non-experimental descriptive studies were considered suitable for inclusion and a systematic search of the contemporaneous primary research literature published from 2003 to 2013 in English in LMIC was undertaken. Electronic databases and the internet were searched using Medical subject headings (MeSH) . The following terms were employed: \u2018Postcoital Contraception\u2019 and \u2019Health Services Accessibility\u2019 and \u2018Healthcare Delivery\u2019 and \u2018Contraceptive Distribution\u2019 and \u2018Developing Countries\u2019 and supplemented by the terms key words \u2018emergency contraception,\u2019 or \u2018emergency contraceptive pills\u2019 using the MESH terms, abstract and keyword options. This was modified as returns were poor. For example a search of ProQuest Health & Medical Complete  AND MeSH  AND MeSH  AND MESH (Contraceptive Distribution) AND MeSH (Developing Countries) AND ab((emergency contraception OR emergency contraceptive pills))returned no results. Searches that returned results are outlined in Retrieved records were first screened for their focus as per the PICOS question by the first author and duplicates removed. Discursive papers (papers without research data), those older than 10 years or whose focus was outside of the aim were removed. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used to report the review process Sixteen papers were identified as relevant in discussion with all authors. These papers were appraised by all authors using the Critical Appraisal Skills Programme (CASP) tool, a checklist developed for assessing the quality of qualitative evidence for use in policy and practice Six items were discarded: reviews that did not include primary data A narrative synthesis approach was conducted as per guidelines Ten documents were included in this study see . Five doECP service delivery to survivors of sexual assault was examined in four studies The study by Khan et al. also examined ECP service provision at police stations in India and Bangladesh and also found a lack of consistent protocols and low police knowledge of ECP An intervention study involving 20 purposefully selected police stations in urban and peri-urban study sites in Zambia demonstrated promising results of stocking ECP at police stations and training police officers to deliver ECP to eligible survivors of sexual violence and high rates of referral of women to health facilities Scaling up and mainstreaming ECP in national programs was the focus of three studies All three studies included provider training activities that were found to have improved knowledge. In Ethiopia Task shifting and sharing was the key focus of one intervention study from India that investigated the difference between ECP service provision by paraprofessionals  and physicians One intervention study in the review is concerned with examining the effectiveness of providing ECP to women on demand compared with in advance in Bangladesh Print and electronic media were used to communicate messages about ECP in studies included in the review. In Nepal an ECP brochure was developed for clients that were found to have been widely shared in the community This review has identified limited knowledge concerning service delivery interventions in LMIC that can facilitate increased access to ECP. Data showing the effects of interventions on reproductive health outcomes The findings of four descriptive studies included in the review indicate that considerable gaps exist in terms of service provision to survivors of sexual assault and rape. Despite one promising study more research is needed to determine how police and health workers can best collaborate to ensure survivors of sexual violence are treated with empathy and dignity and scale up the efficient quality care they require. Task shifting and sharing with cadres other than doctors was found to be a useful strategy to improve ECP access in four of the included studies, forming the focus of one study intervention More research is needed to better understand how mobile phone technologies and other forms of electronic communication can be used to disseminate ECP information and respond to consumers' questions and how this can be integrated with other social marketing and education interventions.There appears to be a dearth of comprehensive evidence of scale up and mainstreaming of ECP as only three studies were identified, none of which included evidence about all sectors that provide ECP. Evidence of workforce interventions is scarce particularly in terms of the types of workforce support and performance management initiatives that may be required across both the public and private sectors. This review highlighted that there is a paucity of evidence concerning what ECP data should be collected and best practice for commodity procurement and disbursement, financing for ECP, and ECP policy. As a result, there is little guidance for LMIC about how to prioritize the limited resources available for improving access to ECP. Little research learning has been documented and shared. This underlines the need to invest in strategic high quality research efforts to better understand what service delivery strategies work in specific contexts. There is also a need to identify lessons from successful (and unsuccessful) endeavours that can be applied by countries undertaking similar policy objectives as they relate to improving access to ECP.Despite the commercial sector providing a significant portion of SRH health services in LMIC This study may have been limited by an incomplete retrieval of research studies; however, efforts were made to search not only bibliographic databases but also meta-Indexes and the websites of international organizations. As a result more documents identified but despite meeting the appraisal criteria some of these may have been at a lower quality, as not all studies were published in peer reviewed journals. The application of a narrative synthesis to the results of the studies included in this review may have led to a loss of detail particularly of contextual factors that are important to the outcomes of the various interventions. However in this review textual descriptions of the studies provided a narrative that was maintained across all studies. The graphical elements included in the analysis were useful for identifying service delivery patterns and the tabulation of findings enabled structured comparisons across the interventions identified. A final limitation may have been our cut-off point of 10 years prior as more attention was paid to research on ECP introduction shortly after the dedicated product was made available, in the mid-late 1990s.ECP have been acknowledged as an essential commodity to prevent unwanted pregnancy and save women's lives; however women in LMIC face many barriers to accessing this contraceptive method. This review has identified a number of promising strategies to improving access including: advance provision of ECP; task shifting and sharing; intersectoral collaboration for sexual assault; m-health (the use of mobile devices such as mobile phones) for information provision and engagement of potential users; scale up through national family planning programs. However, the lack of high quality evidence resulting in few studies from which to glean comprehensive insights has led to the identification of a number of knowledge gaps. These gaps present a range of questions that should be the focus of research into how to best improve service delivery efforts for ECP. Checklist S1PRISMA checklist.(DOC)Click here for additional data file."}
+{"text": "Initial diagnosis and staging of gynaecological malignancy is often the remit of the local general radiologist. The \u201cincidentaloma\u201d is not infrequently encountered on pelvic imaging undertaken for other indications. It can be daunting to those without a solid knowledge of the female pelvis.To recognise the spectrum of female pelvic malignancy and appreciate relevant incidental findings.To identify the pearls and pitfalls of diagnosis, understand important points in staging and restaging disease.To identify potential complications of both tumour and treatment and discuss imaging strategies in suspected local recurrence.We provide an overview of imaging modalities used, review pertinent anatomy and cover the spectrum of malignancy specific to the female pelvis, incorporating common and uncommon tumours. Emphasis is placed on imaging features that are important in treatment planning and evaluating prognosis.This exhibit will enhance the confidence of general radiologist in a district hospital setting when encountering potential female pelvic malignancy at initial diagnosis or when assessing for complications of tumour or treatment in the acute setting."}
+{"text": "This paper discusses the contentious issue of reuse of stored biological samples and data obtained from research participants in past clinical research to answer future ethical and scientifically valid research questions. Many countries have regulations and guidelines that guide the use and exportation of stored biological samples and data. However, there are variations in regulations and guidelines governing the reuse of stored biological samples and data in Sub-Saharan Africa including Malawi.The current research ethics regulations and guidelines in Malawi do not allow indefinite storage and reuse of biological samples and data for future unspecified research. This comes even though the country has managed to answer pertinent research questions using stored biological samples and data. We acknowledge the limited technical expertise and equipment unavailable in Malawi that necessitates exportation of biological samples and data and the genuine concern raised by the regulatory authorities about the possible exploitation of biological samples and data by researchers. We also acknowledge that Malawi does not have bio-banks for storing biological samples and data for future research purposes. This creates room for possible exploitation of biological samples and data collected from research participants in primary research projects in Malawi. However, research ethics committees require completion and approval of material transfer agreements and data transfer agreements for biological samples and data collected for research purposes respectively and this requirement may partly address the concern raised by the regulatory authorities. Our concern though is that there is no such requirement for biological samples and data collected from patients for clinical or diagnostic purposes.In conclusion, we propose developing a medical data and material transfer agreement for biological samples and data collected from patients for clinical or diagnostic purposes in both public and private health facilities that may end up in research centers outside Malawi. We also propose revision of the current research ethics regulations and guidelines in Malawi in order to allow secondary use of biological samples and data collected from primary research projects as a way of maximizing the use of collected samples and data. Finally, we call for consultation of all stakeholders within the Malawi research community when regulatory authorities are developing policies that govern research in Malawi. Clinical research may sometimes involve exportation and importation of biological samples and data which serve as the back bone of viable scientific or biomedical research. As emerging innovations in the fields of genetics, genomics and biotechnology increase, the value of biological samples and data , 2 creatIn the United States of America (US), it is allowed to collect and store biological samples and data for future research. However, there are disagreements on the issue of informed consent. According to the US federal regulations \u201calso known as the Common rule\u201d or the Code of Federal Regulations (CFR), research on stored biological samples and data is explicitly exempt from review by institutional review boards (IRB) . This isn\u2009=\u2009504) found that for biological samples and data derived from research, the majority of research participants would not require their consent for identifiable samples and data and even less than 12.1 % of the research participants would require consent for anonymized samples [It is important to note that these guidelines are not based on empirical research done on research participants but mostly on the interpretation held by the different bodies on the principle of respect for persons or autonomy and informed consent . A studyIntention for collecting the sample/data.Justification for requiring a biological sample/data.Duration for storage of the sample/data and its justification.The place where the sample/data will be kept.OwnershipControl of the sample/data.AccessMost countries in Sub-Saharan Africa require researchers from both academic and research institutions to complete material transfer agreement forms (MTAs) before shipping biological samples and data collected from research participants to academic or research institutions overseas, and mostly to developed countries. In the MTA forms, the researchers are required to justify importation and exportation of biological samples and data to the institutions in the developed countries where the samples and data are sent for further analyses and tests . Though However, there are variations in regulations governing use of biological samples and data in Sub-Saharan Africa. The National Health Act of 2003 of South Africa requires that research participants must provide informed consent before donating biological samples and data but the Act does not have guidelines on reuse of such samples and data in research . The Stan\u2009=\u2009343) found that 95 % of the research participants would consent to reuse of samples and data without additional consent as long as the Institutional Review Board approved it [n\u2009=\u2009600), 44.3 % of the participants felt consent forms should include a separate section for storage and future use of samples [n\u2009=\u2009200), 77.5 % of the participants were comfortable with storage of samples while 12 % of the participants said they would require reasons for storage and would want to give separate consent for storage [The variations in national regulations and guidelines reflect the differing perspectives of research participants across several African countries. A study done in Uganda  as early as 1982 . The samn\u2009=\u2009200), over a third (39.5 %) of participants indicated that \u201cthey would mind if researchers or research organizations generated profits from the research in which they were involved\u201d [Malawi like other developing countries has limited capacity to conduct complex biomedical and genetic tests required to answer scientific and ethically valid questions. This has allowed researchers to obtain ethics approval from local ethics committees to export biological samples and data to countries where such biomedical and genetic tests are available. However, the regulatory authorities are concerned that these exported biological samples and data may be subject to abuse and exploitation by researchers. Indeed, international collaborative research has been subject to abuse and exploitation in the past and not only on issues of stored biological material . There hnvolved\u201d . Of thisnvolved\u201d .It should also be noted that while it is the duty of government and RECs to promote the interests of the research participants and prevent their exploitation, such efforts may amount to unnecessary paternalism if the affected research participants are not involved in such decisions . For exaJohn Rawls, one of the contemporary philosophers once stated that \"justice as fairness serves as a basis of informed and willing political agreement between citizens viewed as free and equal persons \u201c. Thus, wRestrictions on secondary use of biological samples and data imply that any tissue remaining at the completion of a particular study should either be kept in storage indefinitely or be disposed of. This amounts to wastage of valuable biological material that could be used to advance medical knowledge for better interventions and such a restriction is not cost effective. This restriction also subjects research participants to biological sample and data recollection in order to carry out secondary research. This exposes them to additional risk and contradicts the principle of non-maleficence.The restrictions set forth by Malawian regulations and guidelines also run the risk of selective justice which is another form of injustice. While being restrictive on biological samples and data derived from research, which is heavily controlled and closely monitored by research ethics committees, regulatory bodies are silent on samples and data derived from medical centers for clinical diagnosis that could end up in research centers. Therefore, we propose the introduction and utilization of a separate material transfer agreement which shall be called medical material transfer agreement (MMTA) for exportation of biological samples and data that are collected from patients in both private and public health facilities for clinical purposes.Both the National Health Sciences Research Committee and COMREC do require completion and approval of MTAs for biological samples and data collected in research settings. However, there is no data and material transfer agreement that is designed for biological samples and data collected in clinical settings that may later on be used for research purposes. This may create a gap for exploitation of biological samples and data collected for diagnostic purposes. Although comprehensive, the MTA in research settings does not address the issue of how samples and data will be handled after research activities are over. As such, there is still room for researchers to exploit biological samples and data collected for research purposes. Creating a bio-bank or bio-repository center in the country and requesting return of samples and data after a specified period may be a viable alternative to better regulate handling of human samples and data for medical research.However, we are of the opinion that broad consent for storage and future use of biological samples and data done at the time of sample and data collection may be the best model of consent to allow unspecified ethical research that will be reviewed and approved by an ethics committee . By defiThere are also other consent models which could be used. A multi-layered/tiered consent is a consent model in which research participants are given a set of options which allow them to select how they want to participate in the research. Multi-layered/tiered consent can used where researchers want to give options to research participants to choose whether they want their samples and data to be used in future studies or not . This emIn circumstances where the research ethics committee recommends re-consenting of research participants having obtained specific consent in primary research projects, researchers would then be obliged to do so but if it is not feasible to re-contact research participants for consent to use stored biological samples and data for other purposes, the research ethics committee may provide a waiver or may consent on behalf of the research participants. As Nienaber puts it, \u201cresearch in vulnerable populations is not by definition exploitative and unethical\u201d and \u201cpaternalistic attitudes are denigrating\u201d . TherefoThe current view held by the National Health Sciences Research Committee and COMREC are restrictive and may prove to be detrimental to health research in Malawi. As such, there is need for review of the policy stand at the national level. Research participants must be allowed to give informed consent if they so wish or to decline use of their biological samples and data derived from them for any other purpose including in future research. As an important component of medical research, research participants\u2019 autonomy should be respected by allowing them to decide what they feel is the best fate for their donated biological samples and data. This could either be biological sample/data reuse or destruction.Research ethics committees and regulatory bodies should continue doing vibrant reviews of medical research and put in place measures to avoid research participants\u2019 exploitation and abuse. To better address regulatory bodies\u2019 concern about exploitation of biological samples and data by researchers, further empirical social science research needs to be conducted locally to assess the views of research participants and the public on collection, storage and future reuse of biological samples and data and inform policy makers accordingly. There is also need to educate the public about the benefits of future use of biological samples and data.We also recommend that government and local research institutions should invest in developing infrastructure that will allow processing of biological samples and data locally. In the absence of local capacity, it is unfair to hinder exportation of biological samples and data for good biomedical research. This would allow better regulation of biological samples and data that are collected both for medical research and diagnostic purposes.There is also need to introduce a medical data and material transfer agreement document for biological samples and data derived in medical centers for clinical diagnostic purposes that could end up in research centers. The current policy is rigid and too strict on research derived samples and data but there is no strict control on biological samples and data derived from clinical investigations or procedures.The current framework is also silent on proof of destruction of biological samples and data when the research is over. Hence, we recommend the development of a local bio-bank in Malawi where biological samples and data should be returned after the agreed period of storage has passed. Since establishing a bio-bank is likely to take time, a remote site can keep the biological samples and data in storage while allowing Malawian researchers the right to access the biological samples and data.As genetic, genomic and biomedical research technologies become more advanced, biological samples and data collected for specific research objectives may be of great value to study other secondary outcomes. Where genetic and genomic studies are involved, we are aware that the National Health Sciences Research Committee is mandated to review them. However, in both clinical research and genetic/genomic studies, much emphasis should be placed on collection, storage and obtaining consent for future reuse of biological samples and data. This has the potential to greatly benefit the nation and the medical research community in Malawi. However, this can only occur if the guidelines governing such research are reasonable, fair and objective. It is therefore necessary to review existing guidelines and allow secondary use of stored biological samples and data. Asking research participants to donate a sample or data for each research question when new research questions could potentially be answered by already existing samples and data is unnecessary duplication and unfair. This underutilization of biological samples and data constitutes reckless wastage of valuable and scarce human biological samples and data. While we acknowledge the genuine ethical concern by the National Commission for Science and Technology that it is trying to avoid exploitation of biological samples and data collected in Malawi for research purposes, there is no empirical evidence that researchers can exploit samples and data they collect in primary research projects. In addition, the current regulatory framework is punitive to those who want to be efficient for other emerging research questions. Too much restriction may also undermine training of local researchers as most high technology research is currently conducted outside the country."}
+{"text": "Beilstein Journal of Organic Chemistry on natural products in 2011 and 2013 [Artemisia annua [Streptomyces avermitilis at the famous Kitasato Institute and for the development of derivatives that are used as highly potent anthelmintics both for animal and human welfare [As a continuation of the first two Thematic Series in the  welfare . Current welfare ), analyt welfare , gene sy welfare  offer an welfare  continueBeilstein Journal of Organic Chemistry and also the whole team at the Beilstein-Institut for their professional work. I wish the readers of the present Thematic Series joyful reading and hopefully new inspiration for their own research.I thank all contributors that participated in this third Thematic Series on natural product chemistry in the Jeroen S. DickschatBonn, February 2016"}
+{"text": "Preventing Chronic Disease (PCD) has issued a special call for student papers for our Student Research Paper Contest. This year PCD received 67 submissions from students throughout the world. We are very excited to recognize Kathleen Li and colleagues as the winners of the 2014 contest for their paper entitled \u201cEvaluation of the Placement of Mobile Fruit and Vegetable Vendors to Alleviate Food Deserts in New York City\u201d  and with the multiple rounds of review of the top 15 papers  also contributed countless hours reviewing and commenting on these manuscripts. I especially want to recognize Dr Deesha Patel, our 2013 student winner, who served as a reviewer this year. Congratulations and thank you for making the student contest a success!The Student Research Paper Contest is a great opportunity to recognize the outstanding work being done by the next generation of public health researchers and their mentors. In addition to the 67 students who submitted manuscripts, hundreds of mentors and colleagues supported these young investigators, and we want to recognize them. Without their contributions"}
+{"text": "A lack of social support and recognition by the environment is one of the most consistent risk factors for posttraumatic stress disorder (PTSD), and PTSD patients will recover faster with proper social support. The oxytocin system has been proposed to underlie beneficial effects of social support as it is implicated in both social bonding behavior and reducing stress responsivity, notably amygdala reactivity : BONDS standing for \u201cBoosting Oxytocin after trauma: Neurobiology and the Development of Stress-related psychopathology\u201d in acutely traumatized persons admitted to the emergency department  enhanced psychotherapy in PTSD patients."}
+{"text": "At 30 minutes the jacket and weighted rucksack are removed and at 45 minutes the remaining t-shirt is also removed. Patients continue to exercise for a minimum of 60 minutes or up to 90 minutes duration to determine whether thermal equilibrium  can be achieved. Patients achieving thermal balance are considered to show normal thermoregulation (and pass HTT), those who do not or have another medical issue identified are considered to be heat intolerant (fail). Those who do not pass the assessment are reviewed at least once a minimum of 8 weeks later. Measurements of rectal temperature, skin temperature, heart rate and sweat rate made during the HHT are used to determine whether an individual's heat intolerance relates to an abnormal level of heat production  or impaired heat dissipation mechanisms.Exertional heat stroke and heat illness (HI) continue to pose a significant threat to military training and operations in both temperate and hot climates. In 2001, the Institute of Naval Medicine (INM) established a formal protocol for Heat Tolerance Testing (HTT) and in 2003 it became UK Armed Forces Policy that personnel who have been diagnosed as having suffered from an episode of heat stroke or HI with a significant biochemical disturbance or multiple episodes of HI are referred to the Heat Illness Clinic (HIC) at the INM. Following a full medical examination and assessment of maximal aerobic fitness (VOPatient outcomes of the HTT reported for those who attended in 2014 were reviewed.In 2014, 140 patients were assessed in the INM HIC, assessment outcomes are shown in Table Only a small number of the HI casualties referred to the HIC demonstrate abnormal thermoregulation. Although the HTT appears to discriminate between individuals with normal and abnormal thermoregulation further work is required to confirm the specificity and sensitivity of the HTT."}
+{"text": "In 2014, the first national report providing surveillance data for antibiotic consumption in England was published by the English Surveillance Programme for Antimicrobial Utilisation and Resistance (ESPAUR) [Rx-info and IMS Health are commercial organisations specialising in the provision of prescribing data for healthcare. Data from IMS Health was used to collate information on antibiotic use in secondary care for the ESPAUR report. The report showed considerable variability in the extent of antibiotic prescribing across different areas within England. While IMS Health and Rx-info each have formal internal quality assurance processes, there has been no external validation of the data when used for the purpose of comparison or benchmarking. The National Health Service (NHS) England will include validation of hospital prescribing data as part of the antimicrobial quality premium  in 2015/16.To develop a national protocol for validating antimicrobial consumption data in acute NHS hospitals in England.A validation protocol was designed and piloted in acute NHS hospitals. Each was sent the protocol along with a workbook to enable each hospital to submit antimicrobial consumption data from their own pharmacy system. These data were analysed alongside that from IMS Health and Rx-info. Participating hospitals were also sent a questionnaire to gather feedback on the pilot validation protocol to help inform the final national protocol.Forty-five (out of acute 156) NHS Trusts participated in the pilot. The pilot protocol and questionnaire feedback enabled the development of a national validation protocol which was published in March 2015.All acute NHS hospitals in England will be encouraged to use the national protocol to validate antimicrobial prescribing data to ensure correct and meaningful data for the purpose of benchmarking and antibiotic stewardship.None declared."}
+{"text": "Pilot and feasibility studies underpin much of current health related research, including randomised controlled trials. The number of reports in which authors describe their studies as pilot or feasibility studies is increasing. In spite of recent attempts to define pilot and feasibility studies, the research community has differing views about these definitions.We will present a framework for defining pilot and feasibility studies conducted in advance of randomised controlled trials designed to assess the effect of an intervention. The framework was developed using: a Delphi consensus study (93 participants); an open meeting at the 2nd International Clinical Trials Methodology Conference in 2013 (15 participants); a review of definitions outside the health research context; an international expert consensus meeting (26 participants); and a review of published empirical studies described as pilot or feasibility (27 studies).The framework uses feasibility as an umbrella term with pilot studies as a subset of feasibility studies; it does not use mutually exclusive definitions of pilot and feasibility studies. The framework involves straightforward definitions and can be represented in a simple diagram. We will show how it is consistent with the common usage of these terms in the literature, and with the UK Medical Research Council framework for complex interventions. Additionally although the UK National Institute for Health Research does imply that feasibility and pilot studies are mutually exclusive, their definitions can be mapped onto the framework. This work is part of a larger programme of work on pilot and feasibility studies."}
+{"text": "Reelin is a neurodevelopmental protein important in adult synaptic plasticity and learning and memory. Recent evidence points to the importance for Reelin proteolysis in normal signaling and in cognitive function. Support for the dysfunction of Reelin proteolysis in neurodegeneration and cognitive dysfunction comes from postmortem analysis of Alzheimer\u2019s diseases (AD) tissues including cerebral spinal fluid (CSF), showing that levels of Reelin fragments are altered in AD compared to control. Potential key proteases involved in Reelin proteolysis have recently been defined, identifying processes that could be altered in neurodegeneration. Introduction of full-length Reelin and its proteolytic fragments into several mouse models of neurodegeneration and neuropsychiatric disorders quickly promote learning and memory. These findings support a role for Reelin in learning and memory and suggest further understanding of these processes are important to harness the potential of this pathway in treating cognitive symptoms in neuropsychiatric and neurodegenerative diseases. Neurodegenerative diseases are characterized by the progressive loss of synapses and neurons, accounting for cognitive deterioration. One molecular pathway that is well characterized in playing a role in adult synaptic plasticity and learning and memory is the Reelin signaling pathway  receptor insertion, and can contribute to the induction and enhancement of long-term potentiation  and Apolipoprotein receptor 2  and repeats 6\u20137  peptide, and neurofibrillary tangles composed of modified versions of the tau protein  of Reelin and its fragments has demonstrated significant improvements in models of Reelin deficiency (Rogers et al., ALL wrote the review and generated the figures. EJW and GWR edited the content and structure of the review. Each author contributed ideas of topics for inclusion.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "We study random strongly heterogeneous recurrent networks of firing rate neurons, introducing the notion of cohorts: groups of co-active neurons, who compete for firing with one another and whose presence depends sensitively on the structure of the input. The identities of neurons recruited to and dropped from an active cohort changes smoothly with varying input features. We search for network parameter regimes in which the activation of cohorts is robust yet easily switchable by the external input and which exhibit large repertoires of different cohorts. We apply these networks to model the emergence of orientation and direction selectivity in visual cortex. We feed these random networks with a set of harmonic inputs that vary across neurons only in their temporal phase, mimicking the feedforward drive due to a moving grating stimulus. The relationship between the phases that carries the information about the orientation of the stimulus determines which cohort of neurons is activated. As a result the individual neurons acquire non-monotonic orientation tuning curves which are characterized by high orientation and direction selectivity. This mechanism of emergence for direction selectivity differs from the classical motion detector scheme, which is based on the nonlinear summation of the time-shifted inputs. In our model these two mechanisms coexist in the same network, but can be distinguished by their different frequency and contrast dependences. In general, the mechanism we are studying here converts temporal phase sequence into population activity and could therefore be used to extract and represent also various other relevant stimulus features."}
+{"text": "Respondents were randomly allocated to one of the following three question formats: The dichotomous choice referendum, the dissonance minimizing referendum and the two-sided payment ladder. The data can be used to investigate the influence of alternative statistical approaches on the willingness to pay measures and their comparison across question formats.The dataset includes responses from a contingent valuation study about the national climate change mitigation policies in Germany. The online survey was carried out in the spring of 2014. It assesses the willingness to pay for an increase of the national CO Specifications TableValue of the data\u2022The data is designed for evaluating influences of different question formats on willingness to pay.\u2022Additionally the data contains a rich set of attitudinal variables.\u2022The data can be used to explore the influence of alternative statistical approaches on willingness to pay measures.\u2022The data facilitates evaluation of different methods to compare willingness to pay across dichotomous and continuous question formats.12 reduction goal. The sample is representative for the German population between 18 and 69 by sex and age. The data is used to estimate willingness to pay across different question formats in \"The Role of Question Format for the Support for National Climate Change Mitigation Policies in Germany and the Determinants of WTP\" The data set contains 1512 records obtained from a nationwide web-based survey of WTP for new or intensified climate change mitigation policies that are needed to reach Germany\u05f3s CO22 reduction target of 30% to 40% by 2020 compared to 1990. The target increase from 30% to 40% was selected for the contingent valuation (CV) scenario because it closely represents Germany\u05f3s climate change mitigation strategy.The questionnaire is designed to evaluate willingness to pay (WTP) in Germany for an increase in the COThe three versions of the questionnaire differed only by question format. The question formats employed are the dichotomous choice (DC) referendum, the dissonance minimizing (DM) referendum and the two-way payment ladder (TWPL). The DM referendum provides further categories to the standard DC referendum, which allow the respondent to express favour for the referendum without having to agree to pay the posted price The questionnaire is structured as follows: After a few introductory questions an information screen informed briefly about possible climate change mitigation measures that are prominent in the public discussion about the climate policy mix in Germany. After the information screen, subjects were presented a short cheap talk script and afterwards the CV scenario with the varying question formats."}
+{"text": "One key debate in memory research centers around the problem of representation. How is information represented in memory and how do the principles that govern memory representations change across the short and long term? One class of memory models  information from memory. Elhalal et al.  have intWe conclude by highlighting several venues for future research. Recent advances in neuroscience now enable powerful approaches that combine behavioral indices along with complementary neuroscience methods that can utilize univariate and multivariate analyses of neuroimaging data on healthy individuals, as well as transcranial magnetic stimulation and lesion studies to test and infer similarities and dissociations across the hypothesized states of memory. The literature would benefit from computational memory models that can account for the recent neural findings . A more in-depth investigation of the neural correlates of the FoA is also warranted. Recent neuroimaging work has implicated the posterior parietal cortex and the lateral inferior temporal cortex (\u00d6ztekin et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The vestibular system is crucial for postural control; however there are considerable differences in the task dependence and frequency response of vestibular reflexes in appendicular and axial muscles. For example, vestibular reflexes are only evoked in appendicular muscles when vestibular information is relevant to postural control, while in neck muscles they are maintained regardless of the requirement to maintain head on trunk balance. Recent investigations have also shown that the bandwidth of vestibular input on neck muscles is much broader than appendicular muscles (up to a factor of 3). This result challenges the notion that vestibular reflexes only contribute to postural control across the behavioral and physiological frequency range of the vestibular organ . In this review, we explore and integrate these task-, muscle- and frequency-related differences in the vestibular system\u2019s contribution to posture, and propose that the human nervous system has adapted vestibular signals to match the mechanical properties of the system that each group of muscles controls. The vestibular system senses linear and angular head motion in space. This sensory information is used by the central nervous system to elicit reflexes and control appendicular, axial and extraocular muscles that are crucial for posture and gaze. Vestibular reflexes vary across and within muscle groups and are modulated by spatial and temporal factors related to a muscle\u2019s contribution to the system dynamics, the different neural pathways innervating each muscle, and the congruency of sensory signals and motor commands for a given task. Recent findings from our lab indicate that these modulating mechanisms may be related to the frequency content of the vestibular signals impinging on the different muscles. Like many electromechanical systems, the vestibular system\u2019s input-output response varies with stimulus frequency, and like many biological systems, the bandwidth of this frequency response has evolved to match the mechanical system being controlled. This review examines the frequency response of the vestibular system\u2019s reflexive control of posture. More specifically, it focuses on the differences in the frequency response and task dependence of vestibular reflexes controlling appendicular and spinal muscles in order to better understand the neurophysiological principles governing how humans achieve stable upright posture of the head and body. We argue that the frequency response of vestibular reflexes is governed by the mechanical systems under their control, with the neck system exhibiting a broader bandwidth than the appendicular muscles. The higher frequency response in neck muscles can be modulated but not inhibited, and in contrast to the lower frequency response observed in the appendicular muscles, its contribution to muscle activity does not dependent on a neck muscle\u2019s contribution to postural control. Based on this evidence, we propose the higher frequency response of the vestibulocollic reflexes (VCR) is functionally similar to the vestibulo-ocular response for the coordination of eye-head movements as well as head postural control during gaze shifts.The frequency response of the vestibular system is governed by the electromechanical properties of the sensory organs and the various neural structures and pathways that then carry these sensory signals to motor neurons  exhibit head rotational velocity profiles containing frequency information approaching 20 Hz  of turtle otoliths during inertial stimuli reaches 500 Hz and resembles that of a linear second order system with a natural frequency at ~400 Hz . This processing depends on the afferent\u2019s intrinsic membrane electrophysiology and can differ within and across nuclei  response latencies  on the vestibular\u2014and more generally the sensorimotor\u2014control of standing has yet to be established. For instance, increased muscle stiffness, as experienced by Parkinson patients, could be simulated in healthy controls in order to understand its effects on sensorimotor processing during standing balance. Robotic balance simulators  short-duration biphasic waveform  response dynamics in the sternocleidomastoid muscle are insensitive to changes in vision, external support, stance width and posture  also varied little between isometric tasks involving different neck muscle activation patterns with equivalent activation levels. For example, similar VCR responses were observed in the sternocleidomastoid muscle during isometric contractions in flexion and yaw, as well as in the splenius capitis muscle during isometric contractions in extension and yaw. This low sensitivity to the combination of muscles being activated highlights the flexibility in neck muscle control, where the activation of a group of muscles does not have strong reciprocal (inhibitory or excitatory) connections to other muscles  is related to the bandwidth of the mechanical system under control, which for the head-neck system during voluntary movements and imposed force perturbations is up to 5 times wider compared to the whole body during standing balance . Although modulation of higher frequencies (up to 70 Hz) in neck muscles was observed in some conditions , this part of the neck vestibular reflexes frequency response were maintained even in conditions where the muscle did not directly contribute to postural control. The absence of a reduced high-frequency VCR response with the head fixed parallels the response of the electrically evoked VOR, which occurs regardless of the functional or postural state of the head and body (Aw et al., Furthermore, the VOR is subject to suppression during gaze shifts and gaze pursuit, where an intact VOR would be counterproductive to the intended change in gaze or ongoing tracking (see review, Cullen and Roy, The data reviewed here have important implications for understanding the role of the vestibular system in controlling posture and gaze. Indeed, studying separately individual effectors controlled by the vestibular system would lead to diverging conclusions regarding its role in a specific task. A similar statement could be made for the examined bandwidth of the vestibular reflexes. We instead propose an integrative approach that simultaneously examines the complete frequency response of vestibular reflexes in appendicular, spinal and extraocular muscles. Using combinations of robotic systems and electrical vestibular stimulation, it may be possible to evaluate the relative dependence or independence of vestibular input on axial and appendicular systems. The evaluation of vestibular input expressed in multiple motor systems will provide a more comprehensive understanding of how the vestibular system contributes to the complex behavioral tasks of daily living.G.P. Siegmund owns shares in a consulting company, and both he and the company may derive benefit from being associated with this work. All other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Dear Sir,The revolutionary forces at play in medical education are full steam ahead. From PBL, TBL and the flipped classroom, which has barely had time to cement itself we might add, we are now faced with the prospect of massive open online courses (MOOCs) and synchronous massive online courses (SMOCs).MOOCs or massive open online courses are still fairly premature in the field of medicine with limited courses currently available. Examples in present use include Introductory Human Physiology by Coursera and Fundamentals of Clinical Trials courtesy of edX. From a learning perspective we can only hypothesize the potential benefits of such a movement. For instance, students may gain an enhanced understanding of pathology not common to their resident country or gain further understanding of hard to grasp concepts by clinicians renowned in their field of expertise.Whilst medical schools are not currently offering academic credits for MOOC courses, the American Council on Education has certified four Coursera courses  so that However, just like the flipped classroom, the dust has been barely left to settle following the arrival of MOOCs as a result of the recently announced SMOCs which may hold greater promise . GoslingWhatever the future holds for medical education, it is sure to continue to amaze many an instructor and we for one feel it should be embraced wholeheartedly."}
+{"text": "Plain English summaries (PESs) are a valuable tool for making research findings available and accessible to patients and the public. They provide brief descriptions of research written in non-specialist language. The National Institute for Health Research Journals Library (NIHRJL) currently requires authors to provide a 250 word PES. This is published online as part of the final, open-access report. Practice varies among other funders and journals, some of whom employ independent external writers (IEWs) for this purpose.To compare ease of reading and understanding of PESs written by clinical trial teams and an IEW.Forty reports undergoing the editorial process for the NIHRJL will be included in the study. The PES for each report will be revised by authors in line with detailed guidance and edited by an IEW.Ease of reading will be measured using the Flesch Reading Ease score. Scores range from 0-100; higher scores indicate text that is easier to read. Ease of understanding will be assessed by asking public reviewers to read a selection of PESs and rate them from 1 (did not understand) to 4 . Statistical comparison of group scores will be reported.High quality PESs are a priority for dissemination of clinical trial results to patients and the public but it is currently unclear who is best placed to produce them. Results of this study will inform future practice for the NIHRJL and will be relevant to all agencies communicating trial findings to patients and the public."}
+{"text": "Given a perfect superposition of  Generation of non-classical states of light compatible with atomic quantum memory has been an outstanding challenge driven by various applications in quantum information processing On the other hand, several specific quantum algorithms have been discovered , we denote by We want to end with a summary and a discussion of a number of open questions related to the proposed algorithm and its possible applications to problems beyond the quantum memory. The underlying idea of the proposed algorithm is very general and consists of employing Hamming distance to transform the superposition state into a specific quantum state. The crucial advantage is that any required quantum state can now be exactly created using these simple operations. Novel type of applications can be formed in quantum storage protocols based on photon echo techniques. Also, because the dynamical model used here can be equally realized in multi-qubit models, an exponential propagation of quantum excitation along a large number of qubits is in principle possible."}
+{"text": "Diabetes mellitus is increasing, so it is relevant to plan services to prevent vision loss from diabetic retinopathy. There are 3 target groups to consider:the communitypeople known to have diabetes mellitus (DM)people with sight-threatening diabetic retinopathy (STDR)In order to provide the relevant services that each group needs, it is useful to undertake a situational analysis to set priorities and develop an action plan.We must work out how many people need the two key services required to address DR: case detection  and treatment of sight threatening retinopathy .Case detection. How many people with diabetes will need an annual eye examination?Treatment. How many people with sight threatening diabetic retinopathy will need treatment?In order to answer question 1, we need to estimate:The size of the population (over 20 years old) in the country or district proportion of the population (over 20 years old) with diabetes mellitus (available at www.diabetesatlas.org)The number of people with diabetes who will need an annual eye examination.Then it is straightforward to calculate the total In order to answer question 2, we need to estimate:The number of people over 20 years old with diabetes (the answer to question 1)proportion of people with diabetes who have sight-threatening DR (STDR). A reasonable estimate in low-income countries is 10% of all people with diabetesThe Summarise your answers to questions 1 and 2 in Knowing what the need for services is, estimate what is being done at present and summarise this in The following activities all help to ensure that everyone with diabetes and STDR are able to access screening and treatment services. They are ordered, starting with activities conducted by the eye health team and then radiating out into the general hospital and eventually into the community.Which of the following are currently being done, at local and national level?Diagnosing and treating patients with STDR attending an eye clinic (with/without outreach clinics)Examining all patients with diabetes for STDR at hospital diabetes clinics (with/without outreach clinics)Creating a register of all known people with diabetes mellitus and calling people for an annual eye examinationIdentifying people with undiagnosed diabetes and STDR in the communityEducating health professionals about diabetes and STDREducating the communityWho are the health professionals able to offer screening services?Who are the health professionals able to offer treatment for STDR?What equipment is available for diagnosis?What equipment is available for treatment?What management protocols are available?Is there a database of patient records?What is the financial support?What is the leadership for the service?What statistics and information are collected and monitored What patient information materials are available?Who are the stakeholders? Having completed this situational analysis, you can decide what are the next priorities and what are the important actions that need to be taken to improve the DR service."}
+{"text": "In Pakistan, Contraceptive Prevalence Rate (CPR) among married female youth is 17.4% and even lower in rural and slum areas leading to rapid population growth on one hand and poor health consequences on the other. The study was conducted to explore family planning service providers\u2019 perceptions regarding use of different contraceptive methods and to identify factors that are influencing their use amongst currently married youth aged 18-24 years in slum areas of Karachi.Qualitative exploratory study design was adopted and a total of ten in-depth interviews were conducted with family planning service providers of the area. For content analysis coding of transcribed interviews was done and then categories were made and furthermore themes were derived.Our findings revealed that family planning service providers perceived that there is low use of contraceptive methods amongst youth of study area and low usage could be due to side effects; myths and misconceptions; lack of proper knowledge about different contraceptives; unmet needs of contraceptives; socio-cultural and religious factors about different contraceptive methods and family planning service providers own biases against or for use of contraceptive methods amongst youth in the study area. However better education of youth and family planning service providers\u2019 improved knowledge about counseling and use of contraceptive methods was perceived to be associated with improved use of family planning methods amongst youth of the study area.Exaggerated side effects and socio-cultural factors could be important influences leading to low use of family planning methods amongst youth of Karachi. Some policy initiatives are the training of lady health Workers, lady health visitors, physicians and staff of the pharmacies for counseling youth in the correct use of family planning methods. Being one of the poorest and sixth populous countries of the world , PakistaTo date voluminous studies have explored the determinants towards the use of different contraceptives methods among married couples across the globe . FurtherThe study was conducted in Korangi town (UC 2 and 3), Karachi, Pakistan from July to September, 2010. Exploratory qualitative study design was adopted using in-depth interviews with family planning service providers. In order to capture as many aspects and views of family planning service providers, the participants were chosen purposively .The study participants included: Family Planning Service Providers from the 2 Union Councils of Korangi town. They included 2 physicians, 4 Lady Health Visitors, 2 Lady Health Workers and 2 medical store drug providers. Lady Health Workers working in the area facilitated the identification of family planning service providers. Inclusion criteria being family planning service providers of UC 2 and UC 3 of Korangi town, Karachi, Pakistan and those who gave consent for IDIs.A topic guide was used to guide the discussions . The entContent analysis was the strategy used for analyzing the transcribed interviews. We considered a meaning unit as words, sentences or paragraphs containing aspects related to each other through their content and context . TherefoStudy was approved by Ethical Review Committee (ERC) of Aga Khan University (AKU) Karachi, Pakistan. The hard copies of the interviews and all audiotapes were kept in lock and key. Verbal and written consent was sought from all study participants.Transcription was done on the day of the interview to ensure that there is minimum time lapse so that the data on tapes is transcribed to the paper with the fresh memory. All of the authors were competent in the local language and the cultural meaning of the content . Recordings and notes were also consulted for any verification at the end of the interview with the interviewees. Interviews were transcribed into Urdu and then translated to English by the Principal Investigator. Credibility was maintained by selection of context, informants and well-structured in- depth Interviews. Conformability was achieved through separate coding by the first and third author, whereby similarities and dissimilarities were discussed. Consensus on codes and categories was thereafter reached. During the analytical process, the first and third author thoroughly discussed the structure of codes, categories and themes. All authors read, discussed and agreed on the final categorization and themes. Two of the authors (NN and SA) agreed in the way the codes and categories were labeled and categorized, which in later stages were verified by the other two authors (FH & NS). Transferability was achieved through purposive selection of informants with different background characteristics such as profession  educational level and experiences. Dependability was enhanced by conducting the IDIs over 2 months, to ensure that the phenomena under study did not change. All IDIs were conducted in Urdu, moderated by local researchers well versed with the context, transcribed into English by the principal investigator and analyzed within a week. Verification of transcriptions was done by the first author who listened to the audio-tapes twice. The quotations given in the study are intended to facilitate the reader\u2019s evaluation of the creditability of results (JQM 2006).Results were obtained by content analysis keeping in mind objectives of the study. Two underlying themes emerged during the analysis: barriers of family planning methods use and facilitators of family planning methods use . For thiOn Content analysis, there appeared to be multiple determinants of use of contraceptive methods as shown in Exaggerated side effects of different contraceptive methods were considered as one of the main reasons for discontinuation of Family Planning methods.Family Planning service providers shared that Intra Uterine Contraceptive Device (IUCDs) has most of the side effects.\u201cMany women complain that IUCDs make their husbands uncomfortable during intercourse because of the thread that protrudes. Therefore, IUCDs are not well liked by the general population.\u201d (\u2026.interview 9)\u201cMost women taking OCPs complain of dizziness & nausea. Even if she convinces them to take the pills they, automatically, get turned off because of the side effects.\u201d (\u2026.interview 3)Likewise most of the family planning service providers were of the view that youth of the area think that vasectomy is causing physical weakness in males and tubal ligation is the causing weight gain in females as a side effect.Family Planning service providers of the area shared that myths and misconceptions about different contraceptive methods are also potential factors for not using contraceptive methods amongst youth in the study area.\u201cIn general, men do not realize or care for the problems that their wives are going through. They do not agree to undergo vasectomy as they are afraid it will make them impotent\u201d \u2026. (interview 2)\u201cMany of the women shun IUCDs because they believe that IUCDs can cause infections, destroy the uterus somehow & that is can travel up from the uterus into the abdomen.\u201d \u2026. (interview 7)\u201cUsually they don\u2019t have misconceptions about injections. If they have a big family, they frequently use injections\u201d \u2026. (interview 4)\u201cAfter using family planning method, the ovary of females will become dry and then they will not be able to have children \u2026. (interview 10)Majority of family planning service providers shared that youth of the area perceive that condoms cause inflammation, infections and ulceration in both males and females. Most of the Family Planning service providers said that none of the males in the area want to opt for vasectomy as they believe that vasectomy causes physical weakness and impotency.This also emerged as one of the probable determinants for non-use of Family Planning methods amongst youth of the area as some of the Family Planning service providers shared what youth of the area perceived\u201cPills are difficult to remember & these women become very upset often missing a dose & do not understand what to do next.\u201d \u2026 (interview 6)All the FP service providers were of the view that education is one of the most important factors in improving CPR. Moreover some of the FP service providers shared that certain ethnicities as Bengali and Sindhi believe that big family size is associated with more respect in the society.Most of the family planning service providers shared that Pakistan is a patriarchal society as shared in the quote by an interviewee.\u201cRole of mother in law and husbands is pivotal in decision making for the use of contraceptives.\u201d \u2026 (Interviewee 8)Family planning providers also shared that some people of the area believe that if someone prevents pregnancy, Allah makes them ill in some other way for example blood pressure and diabetes and there is a common belief that Family Planning is forbidden in our religion.One of a Family Planning service provider shared that\u201cYouth of the area thinks that their prayers will not be accepted if they use Family Planning methods\u201d \u2026 (Interviewee 5)Some of the family planning service providers have their own biases towards the use of contraceptive methods as stated by one of the interviewee.\u201cI don\u2019t recommend contraceptive methods like IUCD, injections and pills to youth females and maximum I council them for using condoms or natural family planning methods\u201d \u2026 (Interviewee 1)Better knowledge of Family planning service providers and improved education of youth are facilitating the use of family planning methods as discussed below.Some of the family planning service providers themselves identified that knowledge of the family planning service providers about counseling youth for use of contraceptive methods is very important in this aspect and facilitate the use of these methods amongst youth of the area.\u201cInjectables are not liked by women of the area; tend to cause excessive bleeding, due to hormonal imbalance. Therefore, does not prefer injectables to anemic women.\u201d\u2026 (Interviewee 8)\u201cMisconception is rampant among the females who come to her is that IUCD moves up to the stomach. I, myself believe that mostly what actually happens is that the IUCD is expelled during menstruation and these women do not realize it.\u201d\u2026 (Interviewee 1)All the interviewees unanimously agreed that mostly, if the client seeking family planning services is better educated at-least (uptill grade 10), they will understand the importance of family planning methods use and will be much more compliant to the use of contraceptive methods.This paper has tried to add to existing evidence on factors that support or constrain the use of family planning methods and two broad themes were identified as barriers to and supporters of the use of family planning methods amongst youth of study area. We have identified many demand side barriers to the use of family planning methods use as mentioned in the study where the author has shared that demand side barriers to health services access are abundant in low- and middle-income countries and there is a lack of evidence on ways to reduce them . In our In family planning service providers\u2019 perceptions, illiteracy was also identified as one of the constraining factor, whereas better education of youth were identified as a supporting factor towards the use of family planning methods use. It is thought that better educational completion operates through multiple factors to influence family planning service use, encompassing female decision-making power and increasing awareness of health services . Women with no education were most likely to report psychosocial barriers to the use of family planning services. A woman\u2019s involvement in education may also increase her exposure to the health system and improved use of services . ExploraThis study addresses the reproductive health issues of youth in a community setting and in depth interviews responses explicated from Family Planning service providers were valuable and based on their observations & experiences, which is one of the strength of this study. Moreover findings documented by this study would assist in planning and undertaking policy initiatives to streamline recommendations for improving the use of different contraceptive methods amongst youth in slums of Karachi. It was a not a large population study due to paucity of funds and time due to which it has certain shortcomings, the important of which are: few interviews with the respondents were not conducted in depth due to increase patient load at their offices; extreme hot weather in the month of data collection and some of respondents unwillingness to give more time for interview. One weakness of the study might be that the data were initially collected in Urdu, translated to English and analyzed in the English version. However, a multidisciplinary team with experienced qualitative researchers took part at all stages of the research process.In the light of findings of the study and suggestions by the interviewees during in-depth interviews, some of the recommendations to address the low use of contraceptives are that there is a need to disseminate correct information on the use of contraceptive methods. It will help in removing related misperceptions about Family Planning methods through easy to understand booklets in local languages. The initiative should also include other opinion leaders in the society such as prayer leaders, school teachers, local political and social workers. It would help change the societal mindset regarding many aspects such as baseless myths. It will also help to rectify religious and cultural misperceptions. Some urgently needed policy initiatives to improve the use of contraceptives are: lady Health Workers, lady Health Visitors, physicians and staff of the pharmacies are needed to be trained for proper counseling for correct use of family planning method. In conclusion, contraceptives use amongst youth is low in the study area; in addition lack of appropriate knowledge about contraceptives contribute for low CPR among the youth and side effects; some religious and socio-cultural beliefs about different contraceptive methods could be potential determinants contributing to low use of contraceptives."}
+{"text": "Gliomas, the most frequent tumours occurring in the CNS, are defined and graded on the basis of histological features to predict prognosis and management. Owing to biological heterogeneity, the histological diagnosis and expected clinical outcome do not match in a significant number of patients. The combination of imaging and gene expression, referred to as \u201cradiogenomics,\u201d has the potential to give insight into tumour biology that would be difficult to acquire from either technique alone.\u2022 Throwing light upon individual imaging feature and biological/ molecular alterations, analyses that may detect subsets of morphologically identical tumours with different clinical behavior (diagnostic markers).\u2022 Classification and grading of Gliomas as per Haarlem consensus.\u2022 Imaging features of glioblastomas may correlate with molecular mutations.\u2022 Identification of imaging parameters that has the potential as a non-invasive biomarker for common molecular mutations associated with gliomas and their associated clinical impact.\u2022 Review of current radiogenomics literature.\u2022 Given the noninvasive nature of medical imaging and its wide use in clinical practice this approach facilitates the association of complex molecular signatures with readily identifiable imaging characteristics.\u2022 As we move toward a more individualised approach to therapy for glioblastoma on the basis of its specific genetic and biochemical features, radiologists may contribute to the future development of targeted agents for treatment of glioblastoma."}
+{"text": "Good information on the harm of a drug is vital to inform risk-benefit decisions and undertake robust cost effectiveness analysis. Clinical trials reported in peer-reviewed articles are not useful for this purpose ,2. RegulInclusion: Antidepressants/antiepileptic brand drugs evaluated in randomised trials of neuropathic pain and marketed in the US and Europe. Documentation was obtained from the European Medicines Agency and Food Drug Agency.Twelve brand drugs with matching SmPC and USPI were included. The number of harms ranged from 56 to 265 for SmPC and 65 to 425 for USPI Table . On averIt is expected that the harm profile in the product information for the same drug should agree. This study found a lack of consistency for the same drug based on the same central data available to the pharmaceutical company, and demonstrates the overwhelming impact of using arbitrary rules for reporting and differing dictionaries to code harm data. This problem can only be exacerbated across drugs.The development of CORE harm outcome sets by drug class would improve the usability of this information by facilitating comparison of harm profiles across drug which would support informed risk-benefit decisions and allow robust cost effectiveness analyses."}
+{"text": "Every day seems to bring a new development in the treatment of chronic total occlusions (CTOs). The interest in this field is to be welcomed, given the rapidly increasing procedural success rates, in spite of attempting CTO percutaneous coronary intervention (PCI) in increasingly complex patients and lesions .Yet the barriers to treatment for this group remain formidable and include sometimes long procedure duration and cost , perceptGiven that angiographic markers of complexity predict longer procedures with higher incurred costs, it may be that the higher complexity  causes a reflection on the prognostic benefit of the procedure that does not seem to defer non-CTO PCI . Yet it This series of commissioned articles aims to review the evidence base of CTO PCI, define the evolution of techniques with particular reference to the pathophysiology of the disease and describe how techniques have evolved to meet the challenges referred to above. It defines the role for pre-procedure planning in treating this complex lesion subset, describing the role for adjunctive imaging both in planning and in ensuring optimal procedural results. The chronicity of these lesions carry specific challenges and newer techniques for treating coronary calcium and ensuring both equipment delivery and optimum stent deployment are also covered.It is clear that success in the CTO PCI environment can no longer be claimed by individual, relatively small series, but should be viewed more in terms of growth in the overall percentage of CTO PCI patients. The challenge is to ensure that anatomical factors do not deter physicians from percutaneous revascularization where clinical indications support it."}
+{"text": "Overcrowding in emergency departments is a global issue, which places pressure on the shrinking workforce and threatens the future of high quality, safe and effective care. Healthcare reforms aimed at tackling this crisis have focused primarily on structural changes, which alone do not deliver anticipated improvements in quality and performance. The purpose of this study was to identify workforce enablers for achieving whole systems urgent and emergency care delivery.n\u2009=\u2009102); a qualitative survey (n\u2009=\u200948); and a review of literature and analysis of policy documents including care pathways and protocols.A multiple case study design framed around systems thinking was conducted in South East England across one Trust consisting of five hospitals, one community healthcare trust and one ambulance trust. Data sources included 14 clinical settings where upstream or downstream pinch points are likely to occur including discharge planning and rapid response teams; ten regional stakeholder events  contains supplementary material, which is available to authorized users. Overcrowding in emergency departments is a global issue, which places pressure on the shrinking workforce and threatens the future of high quality, safe and effective care \u20134. DespiUrgent and emergency care refers to the range of healthcare services available to people who need medical advice, diagnosis and/or treatment quickly and unexpectedly . The risPressures arising from increased workloads and limited resources are diminishing the desirability of careers in emergency medicine. This is exemplified by fewer practitioners choosing to pursue a career in emergency medicine citing poor working conditions, work-life balance, a target-driven culture, and the lack of 24-hour consultant support as reasons for their lack of desire to engage in this work . As a reWhole system approaches to urgent and emergency care have garnered attention as strategies to alleviate overcrowding in emergency departments (ED) , 8 but tHow do we solve the current workforce crisis in emergency departments creatively to promote sustainable transformational change?What should the urgent and emergency workforce of the future look like?A descriptive multiple case study design was used to clarify gaps and pinch points in the various contexts of the urgent and emergency care pathway across primary/community, secondary and tertiary settings. This design facilitates empirical investigation of phenomenon within real life contexts to answer \u2018how\u2019 and \u2018why\u2019 questions, especially when the boundaries between the phenomenon and the contexts are not evident . A multiData collection and analysis were informed by systems thinking which provides a rational process for mapping and understanding relationships to address complex issues in a holistic way. Checkland defines a system as a complex entity at the core of which is the concept of a whole that can adapt and survive within limits in a changing environment . The whoThis study was based on the concept that achieving transformational change in complex systems also requires attention to patterns that drive thinking and behavior in order to promote a sense of shared responsibility that mirrors ways of working among interdependent partners . SystemsData were collected from multiple sources using the fourth generation stakeholder evaluation approach . The metWhat is urgent and emergency care?What are the redesign, innovation and policy issues?What are the required standards?What are the required competences?What factors enable or inhibit these?What are service user perspectives on urgent care?Four methods were used to gather qualitative data to gain clear understanding of issues emerging in urgent and emergency care. Firstly, a review of evidence relating to urgent and emergency care delivery including care pathways and protocols was undertaken to understand international and national workforce implications. The review was guided by six questions:Competence was defined as acquiring and using evidence-based scientific and humanistic knowledge and skill in the application of therapeutic interventions in the practice setting .Understanding of urgent and emergency careUltimate purpose of urgent and emergency careHow purpose is achievedCurrent urgent and emergency care pathwaysPotential or future urgent care pathwaysEnablers and inhibitorsKey competences required for current and future integrated urgent and emergency carePerceived gaps in pathway competenceKey roles in urgent and emergency careWhat would happen in an effective integrated urgent and emergency care system and how effectiveness would be recognized? This specific question drew on the concept of \u2018the miracle question\u2019 from solution focused approaches to envisage options for achieving an effective system in the future .Other considerationsSecondly data were collected from ten regional stakeholder events held in South East England across one Trust consisting of five hospitals, one community healthcare trust and one ambulance trust. The events were widely publicized using both electronic and paper flyers which included the research questions. The stakeholder events were facilitated using a claims, concerns, and issues approach  to pave At each stakeholder event, discussion points and other verbal contributions were noted on separate flipcharts for each question to enable collaborative data analysis. Some participants gave accounts of their experience with or within the service to demonstrate the gaps and pinch points in the service and or in the workforce. These accounts were themed but also maintained as case examples , acute services (n\u2009=\u200910), ambulatory care (n\u2009=\u200913), residential and nursing homes (n\u2009=\u20096), ambulance services (n\u2009=\u20094), clinical commissioning groups (n\u2009=\u20093), service user groups (n\u2009=\u200916), voluntary sector workers (n\u2009=\u20093), social services and enablement services (n\u2009=\u20096) and Higher Education Institutes (n\u2009=\u200911).Participants in the study were urgent and emergency care stakeholders including representatives of service user groups. The 102 participants that attended stakeholder events organized across the region included representatives from primary/ community services (13), accident and emergency departments (n\u2009=\u20098), community and hospital pharmacists (n\u2009=\u20091), specialists and allied health professionals (n\u2009=\u200930), Ambulance staff/ paramedics (n\u2009=\u20091), public/patient groups (n\u2009=\u20092) and residential and nursing homes (n\u2009=\u20096).Forty-eight respondents completed the online survey that targeted underrepresented groups at the stakeholder events. These included general practitioners 111 urgent care telephone advice service; hospices; minor injuries units; mental health services; rapid response teams; integrated care24; and hospital at home.The multiple data sources facilitated triangulation, enhanced the validity and reliability of the case study and provided holistic understanding of existing challenges in the urgent and emergency service and workforce.Primary data analysis involved collaborative thematic analysis with participants at each stakeholder event to empower participants to co-create a shared purpose . CollaboThe research team used a similar process to generate themes from the literature review, qualitative online survey and process mapping activity. Themes from each of the four datasets were maintained separately during primary level data analysis to enable cross data consistency checks .The research team completed secondary level data analysis by triangulating themes from all datasets and synthesizing them in relation to broad system components , 27. TheThe data analysis process entailed distinguishing characteristics of a whole system approach to urgent and emergency care and developing a representative framework of system and workforce development enablers and outcomes. Data were consciously organized using systems assumptions, into enablers (inputs) and desired outputs for whole systems urgent and emergency care delivery . The synThemes from the miracle question about an ideal effective integrated urgent and emergency care system yielded the criteria for whole systems urgent and emergency care. Participants characterized an urgent and emergency care whole system as one that is safe, sustainable and person-centered; based on best evidence and practice standards; integrates health and social care; focuses on quality and safety rather than targets; is tailored to meet needs in the local population; and involves interdependent partners working together towards the same purpose. Additional file fragmented working without clinical systems leadership causing duplication and waste;a lack of any integrating competence framework to enable staff recruitment, development and retention across all contributing partners; anda lack of team approach to the competences needed to cope with urgent and emergency care demands across the health economy.Gaps and challenges identified in the current service informed system and specific workforce enablers, building on what works and envisioning what is required for whole systems urgent and emergency care delivery. Three overarching themes prominent in the process mapping gap analysis matrix emerged from all datasets:We hypothesized that whole system enablers identified across datasets have implications for workforce development at every level ranging from provider-user interfaces; career development across urgent and emergency care; systems leadership; human resource management through to infrastructure development; public information systems, and commissioning.There is a lack of integrated pathways and too many clinical commissioning groups to work with.Participants perceived commissioners to be the gatekeepers for a common strategy that models integrated working at the commissioning level and works to dismantle barriers that drive silos across the system particularly around the use of budgets and information in acute and primary care settings. One urgent care clinician commented:Additional file Recruitment has been a real problem for our trust. staff are moving away from the trust towards general practice. Staff need to have acute experience and know how the systems and processes work in both the community and hospital setting. I often feel that I could facilitate early discharge if a discussion was held between ourselves and the ward staff.Core challenges across the whole health economy were identified as both recruitment and the retention of staff and that these need to be addressed in a joined up way through system and specific workforce enablers. For example, a lead for a community healthcare team stated:Three specific workforce enablers emerged as most significant not only for achieving a whole system approach to workforce transformation, but also for addressing issues pertaining to staff recruitment and retention. These were: i) clinical systems leadership, ii) an integrated career and competence framework and iii) facilitators of work based learning.\u201cIntegrate experienced clinicians into the system. Management needs to be much better in an integrated system. Currently ridiculously fragmented\u201d .At the moment there are many senior managers and I think their role and expectations should be reviewed. There always seems to be many meetings/discussions but there are few actions generated and these are not adhered to in a timely manner. There needs to be a greater emphasis on clinical skills and practice development so that new services/skills can be explored and supported in practice (emergency care nurse).Secondary analysis of data overwhelmingly indicated the need for a much stronger focus on leadership with less emphasis on management. Themes from all datasets denoted that clinical systems leadership would complement leadership for commissioning urgent and emergency care services. This is reflected in statements made by some of the participants:Clinical systems leadership is a concept we assigned to the leadership approach that drives integration across boundaries based on specialized clinical credibility working with shared purposes to break down silos and deliver person-centered, safe and effective care with continuity. Clinical systems leadership was linked to the ability to draw on expertise in a number of different areas to enable contributing partners to work together towards a shared purpose and to create a culture that values and retains staff. The required skill identified in the data encompasses: clinical expertise and credibility for a specific client group; consultancy functions that share expertise within the wider system; leadership for culture change; developing, improving and evaluating person centered care; and creating a learning culture that uses the workplace as the main resource for learning.There is a need to think productively, are the right resources in place, clear roles and responsibilities. Identify what skills and jobs could be done by administrative or healthcare support workers rather than removing a nurse or qualified healthcare professional from hands on care.Cross data analyses suggested that a single integrated career and competence framework would enable staff recruitment and retention and also empower staff to know how the systems and processes work in both the community and hospital settings. One emergency care doctor emphasized:Assess Treat (treat people appropriately and promptly for their urgent and emergency care needs within different contexts)SORT  people appropriately within or across the system and its different contexts in a timely way)Assess, Treat and SORT  constituted the single integrated career and competence framework we developed outlining key competences performed in any context by interdependent partners. Themes relating to competences required for current and future integrated urgent and emergency care from each of the datasets were triangulated to identify the key outcome competences. That is, what staff would be expected to do in the workplace underpinned by essential knowledge and understanding. We created three categories for the key competences to reflect the person\u2019s journey through the urgent and emergency care pathway.The key competences were mapped against national competence frameworks identified in the literature for professional groups working across the urgent and emergency care system to validate the themes generated for the single integrated career and competence framework. Additional file A multidisciplinary career and competence framework for urgent and emergency care demonstrates whole systems working in managing the patient pathway and experience in any context - promoting an interdisciplinary team approach underpinned by shared risk and integrated information and finance systems.Case example 1 illustrates how a learning disabilities consultant undertaking a program to develop expertise in the functions of clinical systems leadership  works collaboratively across boundaries to ensure that a person with learning disabilities and complex needs receives appropriate care and avoids hospital admission. This case example also illustrates effective use of resources in place, and attributes of systems leadership with a focus on person centered, safe and effective care. Case example 1 was an account of the participant\u2019s experience with the service shared at one of the stakeholder events.A nurse working with people with learning disabilities in the community and an aspiring clinical systems leader at the hospital have been corresponding for two weeks about a person with a learning disability and an autistic spectrum condition. The person had recently been discharged from hospital to a residential care home having had a fall and a fractured ankle. The community nurse contacted the hospital about the individual\u2019s loss of skills and mobility over the last four months along with disturbances in behavior that did not appear to be mental health related. A closer review of the records indicated that the individual had experienced two admissions and three visits to the emergency department not quite triggering the learning disability repeated admission pathway (people with learning disabilities admitted through the accident and emergency department three times or more). Diagnostics also suggested a possible malignancy. The aspiring clinical systems leader linked the community nurse with an orthopedic consultant and the general practitioner via email, encouraging coordinated discussion about the individual, which led to swift conclusion regarding the possible diagnosis of cancer and further discussions about interventions for behavior problems and loss of skills. The individual did not require another emergency admission due in part to the collaborative practice across several organizational boundaries and the individual\u2019s care being coordinated effectively.Case example 2 illustrates how the single career and competence framework can be used in everyday practice for diverse contexts and roles to facilitate work based learning and career development. Case example 2 was developed by the research team to illustrate how the Assess, Treat and SORT can be used to support career development.A community nurse working part of an integrated discharge team plays a vital role in preventing unnecessary hospital admissions by liaising with others to make sure that older frail people receive the care and treatment they require in a home setting. For example, pain management, treatment for urinary tract infections and end of life care planning, taking into account the individuals wish about their preferred place of death.Formerly an emergency care nurse, the community nurse in question uses the integrated career and competence framework to undertake a self-assessment and submit a portfolio of evidence to a local university in order to gain academic accreditation for prior learning and development in the workplace. The community nurse is able to pursue a blended Master of Science advanced practice program at the university tailored to development needs identified. By demonstrating advanced skills in clinical assessment, history taking and decision making in addition to a prescribing qualification, the community nurse gains 60 academic credits towards accreditation for prior experiential learning at advanced practitioner level.Teams from the different organizations involved are often very tribal in their behaviors, with a low level of trust. People often do not understand their colleague\u2019s role. This is counterproductive and negatively impacts on team working. The patient experiences disjointed care. Suggest more joint training across organizations and multidisciplinary events to build trust and understanding.Facilitators of work based learning emerged as an essential enabler for supporting the urgent and emergency care workforce competence and career development while using the workplace as the main resource for learning and development. Evidence from the data suggested that facilitating learning in the workplace would enable role clarity and a team approach to the competences needed for urgent and emergency care demands across the various contexts. A community matron working with people with long term conditions observed:Workplace mentors and supervisors that facilitate learning, development and improvement in a holistic way embrace the integration remit across the system and meet the learning needs of multi-disciplinary teams aligned to the single integrated career and competence framework. Participants evoked that this can be achieved through rotation opportunities which enable staff to become familiar with the whole system, and the talents and contributions of interdependent partners.Whole systems approaches to tackle overcrowding and promote collaborative working to improve people\u2019s experience and health outcomes are more compelling in an era of increased demand and finite budgets. The objective of this study was to identify workforce enablers for achieving whole systems urgent and emergency care. Aligning workforce planning and development with population healthcare needs is crucial but complex, especially in light of changing needs in an aging population that present with a complex range of mental and physical morbidities , 36. HowThe most consistent finding was the need for strong systems leadership capable of enabling the creative reshaping of urgent and emergency care services while coping with change. Systems leadership is often presumed to be the remit of commissioners of healthcare services  however Results of this study indicate that system redesign and successful implementation is facilitated through enabling the workforce to acquire competences needed to cope with complexity and changing models of care . In addiWorkplace facilitation spans a number of purposes including learning, development, improvement, inquiry, knowledge translation and innovation . ResultsThis study illuminates whole systems working which involves integrating all system elements including structures, processes and patterns that drive thinking and behavior in the workplace to achieve transformational change.The collaborative and inclusive approach used the study demonstrates a partnership drawing on providers\u2019 and users\u2019 experiences to achieve shared direction and valued outcomes. This approach is most likely to obtain and sustain positive change in the delivery of care.Nevertheless, it is probable that stakeholder events may have inhibited freedom of expression as opposed to user only groups. While this resulted in powerful case studies to illustrate an ideal system, the same drawback may have also influenced discussions with junior staff involved in delivering urgent and emergency care.In this study, participants agreed that whole systems urgent and emergency care allows for the design and implementation of care delivery models that meet complexity of population healthcare needs, reduce duplication and waste and improve healthcare outcomes and patients\u2019 experiences. For this to be achieved emphasis needs to be placed on holistic changes in structures, processes and patterns of the urgent and emergency care system. Often overlooked, patterns that drive the thinking and behavior in the workplace directly impact on staff recruitment and retention and the overall effectiveness of the organization. These also need to be attended to for transformational change to be achieved and sustained. We recommend further work to refine and validate the integrated career and competence framework by testing competences against all key roles in different contexts across interdependent partners contributing to the system; and to identify standards for integrated facilitation in the workplace to grow the capacity of work based facilitators and ensure consistency in quality and effectiveness of this role.NHS, National Health Service; SORT, support discharge, organize admission, refer and/ or transfer; UK, United Kingdom"}
+{"text": "Somatic integration of synaptic inputs relies on the propagation of currents arising from sources across the dendritic tree. Whilst active processes strongly contribute to current flow in most neurons, understanding the passive backbone to transmission allows a better intuitive grasp of dendritic function; the results of Rall in highlighting the properties of cylindrical dendrites are of fWe have derived an asymptotic approximation to the voltage in dendrites with an arbitrary taper profile using the insight that voltage attenuation is substantially faster than radius change in realistic morphologies Figure . This reA particularly interesting implication of these results is that the optimal taper profile to proximally transmit maximum voltages can be found by variational calculus, matching results from non-parametric numerical optimisation which predicted a quadratic form for the diameter taper Figure  3]..3]."}
+{"text": "Open access journals provide an opportunity to read quality research articles through internet across the world. Concern has been shown as to the standard of articles published in open access journals and their peer review process but same has been refuted by a study of Bj\u00f6rk and Solomon.[1] They have concluded that scientific impact of open access journal is now approaching that of subscription journals.In paediatric surgery, the impact of open access journals has not been evaluated presently but hopefully as they receive impact factor in future, this issue shall be addressed. There is encouraging trend towards addition of open access journals of paediatric surgery to international databases which in itself reflects quality of such publications. But unfortunately, most of the open access journals originate from developing countries. Few of these are \u201cElectronic-only\u201d publications. This takes care of cost of publication and therefore become economical and viable option on the longer run. The foremost issue is why journals from technologically advanced countries published by giants in the field of publications still charging huge amount both from the contributors as well as readers. The cost is huge not within the reach of researchers, students, residents etc from developing countries. This amounts to putting hurdles for researchers from developing world where the need of research is most. This gap is now being filled by open access journals and the number of manuscripts being sent to them and their quality has visibly improved. Same trend is apparent in our APSP Journal of Case Reports (AJCR). This is indexed with international databases and we hope to get impact factor soon. We have no conflict of interest as this is an official journal of The Association of Paediatric Surgeons of Pakistan (APSP). There are no subscription and publications charges thus researchers are encouraged to send their quality manuscripts for publication to this journal. Our peer review system further ensures that all submissions are seen by experts in the field to improve standard of the manuscript. We are thankful to all of our contributors and reviewers for their hard work.Source of Support: NilConflict of Interest: None declared"}
+{"text": "This article presents a historical review of the protein structure classification database CATH. Together with the SCOP database, CATH remains comprehensive and reasonably up-to-date with the now more than 100,000 protein structures in the PDB. We review the expansion of the CATH and SCOP resources to capture predicted domain structures in the genome sequence data and to provide information on the likely functions of proteins mediated by their constituent domains. The establishment of comprehensive function annotation resources has also meant that domain families can be functionally annotated allowing insights into functional divergence and evolution within protein families. \u2022We present a historical review of the protein structure database CATH.\u2022We review the expansion of the CATH and SCOP resources with sequence data and functional annotations.\u2022How functional annotation resources allow insights into functional divergence and evolution within protein families. Several studies had shown the extent to which protein structures are conserved during evolution which suggested that 3D structure was a valuable fossil capturing the essential features of an evolutionary protein family and making it possible to identify even very remotely related proteins through similarities in their structures.The first protein structure, myoglobin, was solved in 1958 and for the following three decades the number of structures solved and deposited in the Protein Databank Although global structural characteristics (ie the folds of homologous proteins) are largely conserved during evolution The development of structure comparison algorithms by Rossmann and Argos Pioneering studies of groups of related proteins, by Chothia and Lesk Lesk and Chothia also published a seminal study on the relationship between sequence identity and structural similarity These studies prompted the question of whether other general trends could be gleaned from reviews of protein families. Furthermore, the concurrent expansion of the PDB and development of more robust techniques for comparing structurally distant homologues led several groups to begin classifications of protein families based on structure. The domain was the focus of these studies as it was clear this represented the primary unit of evolution and proteins evolved through duplication, shuffling and fusion of domain sequences in genomes Early structure comparison algorithms exploited rigid body algorithms to superimpose the structures based on the 3D coordinates and the methods struggled to achieve an optimal superimposition between distant homologues. Generally, they failed to converge on a solution where substantial insertions/deletions (indels) and changes in secondary structure orientations had occurred. Therefore in the late 1980s, more sophisticated approaches were explored  could easily be confirmed using pairwise algorithms like BLAST This was a considerable task but arguably more reliable than relying entirely on completely automated approaches. Over the last decade or more, much more sophisticated sequence comparison techniques have been developed that can confirm homology even in the midnight zone of sequence similarity (<20% sequence identity). These are discussed in more detail below.In 1997 the SSAP algorithm was modified to increase the speed for large scale comparisons within the PDB, by employing a filter that only allows comparison of proteins having sufficiently similar secondary structure arrangements and connectivity in their common structural core The SCOP classification was largely constructed using manual evaluation of domain relationships although available algorithms such as BLAST Both SCOP and CATH further classified the domain superfamilies and fold groups according to their architecture, where architecture describes the orientation of the secondary structure elements in 3D regardless of their connectivity. However, in CATH this was a formal level in the hierarchy whilst in SCOP architecture was simply an annotation. Finally domains were assigned to protein classes depending on the composition of secondary structure elements ie whether they were all-alpha, all-beta, or mixtures of alpha and beta see  SCOP use3ab-initio methods . This is because the linking regions between domains can be quite small and the domain interfaces quite large and complex, especially if one of the domains is dis-contiguous. Therefore, it is difficult to optimize parameters in a way that doesn't lead to under-chopping or over-chopping of large complex multi-domain proteins. The difficulty in capturing the heuristic rules defining domains in an algorithm is illustrated by the fact that an analyses of the performance of these methods, judged using a manually validated benchmark set, showed that all three approaches only agreed about 10% of the time and that frequently there were considerable differences in the boundaries assigned SCOP employs the same physical criteria in recognising domains by expert curation. Furthermore, a putative domain must be found to occur in at least two different independent contexts ie with different domain partners. This means that some protein regions deemed to be domains in CATH are not recognized as such by SCOP until additional data confirms the existence of this domain fused to different domain partners.In 1995 both CATH and SCOP publicly launched their classifications via the web 4Perhaps the most interesting revelation to emerge from the structural classification data was the highly uneven distribution observed in the populations of the fold groups. In 1994 Orengo, Jones and Thornton reported the existence of ten \u2018superfolds\u2019 accounting for nearly 50% of all domain relatives in CATH Based on the number of diverse sequence families found across the SCOP classification and the proportion of all known sequence data that this represented, Chothia postulated that there could be fewer than 1000 fold groups in nature In fact these predictions appear to have been largely borne out by the current data. Twenty years on, there are still only 1300 folds identified in CATH, and sensitive structure prediction tools suggest that CATH and SCOP capture nearly 80% of all protein domains in completed genomes with the remaining 20% being largely membrane associated domains which are likely to adopt relatively few diverse structural arrangements because of the physical constraints imposed by their location. The remaining sequences suggest highly disordered proteins that are not expected to adopt globular folds.The structural classification data and large scale comparisons of domain structures also revealed novel folding motifs  common to a large proportion of alpha\u2013beta domain superfamilies in which structures comprise a central antiparallel beta-sheet covered by a layer of alpha-helices  a hypothesis that had been speculated as a \u2018russian doll effect\u2019 in the original CATH classification Development of faster structural comparison algorithms like GRATH 5The international genome initiatives which started in the late 1990s and exploited rapid sequencing techniques, enabled the completion of the human genome by the millennium, and resulted in an explosion of sequence data by the turn of the century. This expansion of the sequence data combined with much more sensitive tools for recognizing sequence similarities prompted the recruitment of sequence relatives into the domain superfamilies of SCOP and CATH. Both resources exploited powerful sequence profiles \u2013 known as Hidden Markov Models (HMMs) \u2013 which were built from multiple alignments of sequence clusters in domain superfamilies and used to recognize domain relatives in the genome sequences. Two sister resources were established \u2013 Gene3D These strategies brought about an \u223c100-fold increase in the number of domains assigned to CATH and SCOP allowing more detailed analyses of evolutionary relationships and in particular an understanding of the divergence of sequences and functions within particular superfamilies (discussed more below). Currently more than 50 million sequences are assigned to CATH superfamilies in Gene3D. SUPERFAMILY which has explicitly incorporated completed genome data not yet deposited in public repositories like UniProt and ENSEMBL, has more than 40 million sequences from 2500 completed genomes. This data is likely to expand further in the near future as the metagenome projects bring in millions more relatives from species in diverse environments from around the globe.By recognizing CATH or SCOP domains within protein sequences it was possible to trace the emergence of novel proteins resulting from different domain fusions or fissions. For example, Vogel and Chothia examined changes in domain partnerships in proteins linked to the immunoglobulin superfamily. In worm, expansions in multi-domain architectures were linked to the expansion of structural proteins whilst in fly, expansions involving related domains enhanced the immune system repertoire 6The expansion of CATH superfamilies with sequence data considerably increased the amount of functional data too, allowing large scale studies of the divergence of function within superfamilies during evolution. These studies showed that whilst relatives in most superfamilies shared a common function, in the most highly populated superfamilies considerable divergence of sequence and function had occurred. A detailed study of 31 such diverse superfamilies revealed the molecular mechanisms by which functions had changed Studies of enzyme superfamilies revealed that changes in function were usually associated with variations in the substrate specificity. Changes in chemistry were much less frequent presumably because it is harder to engineer a novel chemistry than to alter the binding site and change the compound on which that chemistry is performed More recent collaborations between the Thornton and Orengo groups have led to the establishment of a new resource, FunTree FunTree enabled much more comprehensive studies of functional divergence in domain superfamilies and confirmed the previously observed trends of conservation of chemistry between parent and child nodes in the phylogenetic tree but also highlighted frequent divergence in substrate specificity within some promiscuous enzyme superfamiles. However, significant changes in chemistry can still occur As regards the structural mechanisms mediating functional change, analyses of some structurally and functionally divergent CATH superfamilies revealed substantial insertion of residues often resulting in additional secondary structural features packed against the common structural core of the domain and appearing as embellishments to that highly conserved core. In some large CATH superfamilies, relatives differ in size by three-fold in the number of residues or more 7More recently, the extreme divergence of functional properties of relatives in some highly populated CATH superfamilies prompted the development of protocols to sub-classify superfamilies into functional families . Comparisons of interfaces across superfamilies showed that functionally diverse relatives were exploiting different surface patches on the structure ie distinct sites, depending on their interaction partner, and that paralogues shared few common interactors. However, quite frequently there was one location that was more frequently exploited by diverse paralogues Recent analyses of changes in catalytic residues in different functional families across 101 well annotated CATH enzyme superfamilies showed that in the majority of superfamilies (\u223c70%) at least two FunFams had significant differences in their catalytic machineries . Unsurprisingly, most of the time these led to changes in the chemistries of the relatives or the substrates being acted upon. However, in 25% of the cases examined the same chemistry was associated with completely different catalytic machineries. This may be a consequence of evolutionary drift from a common ancestor with a particular function, resulting in modified efficiency in one relative which is then compensated by further mutations to optimize the physico-chemical features of the active site 8The SCOP and CATH classifications organize the 3D structure of proteins into evolutionary classifications that have enabled detailed studies of the molecular mechanisms by which new protein structures and functions evolve. The sequence patterns and fold libraries that they provide have enabled prediction of structural relatives thereby providing structural annotations for more than 50 million domain sequences, available on their sister sites  and in InterPro Although \u223c20\u201325% of domain sequences in the genomes do not currently map to any structural superfamilies in CATH or SCOP, the analyses of structures solved by the structural genomics initiatives in the States \u2013 which targeted structurally uncharacterized domain families in Pfam for structural determination \u2013 showed that once the structures of these superfamilies had been solved they revealed a structural or evolutionary relationship with an existing fold group or superfamily in SCOP or CATH. In fact, nearly 98% of all new structures deposited in the PDB can be classified in an existing CATH superfamily Over the last few years collaborations between SCOP and CATH have led to mappings between these resources that help to confirm detection of very remote homologues"}
+{"text": "After publication of the original article  it was b\u2018The statements presented in this publication are solely the responsibility of the authors and do not necessarily represent the views of the Patient-Centered Outcomes Research Institute (PCORI), its Board of Governors or Methodology Committee\u2019.Also, author Joann Sorra was incorrectly included as Joanna Sorra. The correct spelling of Joann Sorra\u2019s name is included in the author list of this erratum."}
+{"text": "The Continual Reassessment Method (CRM) is not widely used in early phase dose finding trials partly because the logistics of development and implementation are perceived as complex and time consuming. Details are presented of the steps involved when designing such a trial using an adaptation of a Bayesian CRM calibration algorithm proposed by Cheung .In addition to clinician centred parameters including target toxicity probability and number of test doses, the Bayesian CRM requires specification of the prior probability of toxicity associated with each of the test doses and the prior SD of the single model parameter. Cheung\u2019s simple pragmatic approach is used to aid selection of these parameters.Competing designs are assessed in terms of risk-adjusted accuracy and trial specific requirements including the mean number of patients treated above the maximum tolerated dose. Performance measures are estimated by Monte Carlo simulation across a range of scenarios chosen solely upon the target toxicity level and the number of test doses.We demonstrate that following this pragmatic approach to CRM design calibration, design of CRM trials need not be overly complex or time-consuming."}
+{"text": "The external validity of RCTs, which provides evidence for major clinical guidelines, may be questioned if they are not representative of real-life populations in primary care.11\u201315 In the 2007 study by Travers et al, only 4% (range 0\u201336%) of participants with asthma in a population-based survey met the eligibility criteria to be included in 17 major RCTs cited in the GINA guidelines.14 The same study found that only 6% (range 0\u201343%) of participants receiving asthma treatment also met the eligibility criteria. The proportion of patients with asthma from primary care settings that would be eligible for the major RCTs is unknown. If the proportion is similar to that found in the study by Travis et al., then the generalisability of the conclusions and the clinical relevance of major RCTs may be questionable, and they have not been improved in the past decade. There is a need to explore the external validity of pharmacological RCTs in primary care populations. The UNLOCK (Uncovering and Noting Long-Term Outcomes in COPD and asthma to enhance knowledge) project15 of the International Primary Care Respiratory Group (IPCRG) covers a broad primary care population that may help clarify the external validity of these RCTs.There are concerns that current asthma treatment is based on research with subjects who are not representative of the patients seen in clinical practice.The aim of this study is to determine whether the inclusion criteria for patients with asthma in the major RTCs supporting GINA guidelines are representative of real-life primary care populations with asthma. The study will address the following research questions:What proportion of patients in primary care would be eligible for the major RCTs assessing patients at treatment step two heading for step three?What are the clinical characteristics of these patients when compared with participants in major RCT studies?1\u20138 The management and treatment of patients with asthma in primary care is a challenge, and many patients still suffer from poor asthma control.2 The major international clinical guidelines for the prevention and management of asthma are influenced by the empirical evidence and conclusions of RCTs.9\u201314 However, RCTs tend to be highly selective in terms of inclusion and exclusion criteria for people with asthma and may under-represent primary care populations with asthma. Smokers, for example, are usually excluded from registration RCTs assessing inhaled corticosteroids (ICS), as smoking is known to reduce the efficacy of ICS.16 Other common exclusion criteria are pregnancy, lactation, elderly patients and other chronic diseases such as ischaemic heart disease. A common inclusion criterion is a bronchodilator FEV1 reversibility of 12 or 15%, which is not a frequent clinical sign in real-life asthma patients, and in the Travers study, 71 (or 76%) of participants with asthma were excluded.14Asthma is a highly prevalent disease worldwide with variability and a large range of phenotypes.17 The assessment of the external validity of asthma RCTs is therefore needed to better understand the clinical relevance of their conclusions. There should be discussion on the need for effective studies, pragmatic trials and observational studies, as a complement to RCTs, to evaluate treatment outcomes in real-life clinical settings including the whole asthma population. The main weakness of these studies might be a lower internal validity, which needs to be addressed in the design of the studies. When developing guideline recommendations in the future, data from both efficacy and effectiveness studies should be evaluated with the strengths and weaknesses given.18RCTs are important in establishing the efficacy and short-term safety of new therapies, but there are limitations in evaluation of effectiveness of the therapies in the real world.16\u201320 Previous findings suggest that the level of representation of the population with asthma14 and chronic obstructive pulmonary disease (COPD)13 in RCTs may be lower than desirable. This study can inform not only the development of future clinical practice guidelines17\u201320 but also the way asthma clinical trials are being designed and implemented.10 The study will tell us more about the patients who are not eligible for these major RCTs, and it may also provide new insights into why the control of asthma in many patients does not appear to improve in spite of the implementation of the treatment strategies that are recommended in guidelines.This study will provide estimates of the proportion of real-life primary care populations that are eligible for RCTs. It will also present descriptive characteristics of primary care patients compared with patients included in RCTs. This will present relevant information for the adequacy and use of GINA and other major guidelines in primary health-care settings.The study will use an observational design for comparing baseline characteristics of asthma patients in primary care databases with the inclusion criteria in the pharmacological RCTs that support major international guidelines .Data collection will involve two steps:Step one will identify the major relevant RCTs used in GINA guidelines.Step two will identify the primary care data sets that contain the required variables to assess eligibility for participation in the major RCTs.In step one, a Systematic Review focusing the search on selected asthma international guidelines  will be conducted in order to identify all studies that fit the following criteria:Randomised controlled clinical trialPharmacological treatment at GINA management step 2 heading for step 3n>400RCT sample size Other criteria 21 statement guidelines and follow the steps identified in The systematic review will follow the PRISMAIn step two, members of the IPCRG UNLOCK group will be invited to participate in the study with primary care data sets that include the variables listed in Participants identified in the data sets will remain anonymous. Patient confidentiality will be assured in the collection and merging of the data sets.Data will be analysed according the defined criteria for the identification of RCTs. Statistical analysis of the data sets will provide summary descriptive statistics, means, measures of dispersion and proportions. The statistical analysis will focus on group classification values, and no individual statistical values will be computed or revealed.All included data sets will require approval by local primary care research ethics committees."}
+{"text": "The lack of clinical data for orphan drugs and the development of \u201cprecision medicines\u201d or advanced therapies have required a new regulatory approach to guarantee a marketing authorization for new and innovative medicines.What is actually changing in the scenario is the way Agencies are managing the regulatory procedures to ensure a rapid access to treatment for patients with unmet medical needs.In the last few years EMA and National Agencies have provided a lot of scientific advices (SA) to companies and applicants about orphan designation, CTs design, marketing authorisation procedures and HTA evaluations.Currently the global scenario is already changing as we are issuing licenses for marketing authorization under exceptional circumstances and conditional marketing authorizations. The legislative framework is also changing with the new Pharmacovigilance Directive and the new Regulation on Clinical Trials entering into force progressively by 2015.The new Pharmacovigilance Legislation supports a Progressive Patient Access Scheme  approach by expanding EMA authority to request mandatorily to Applicants a post-marketing evaluation of effectiveness in addition to safety.The basic principles of PPAS approaches are facilitating early access to an early medicine approval, by acknowledging and managing uncertainty about favourable and unfavourable effects. The result will be achieved through the conduction of optimised RCTs, the monitoring of risk-based SA and the harmonisation of RCTs platforms.Lots of effort is needed by everyone through a new level of cooperation, in particular regulators, companies and the CROs need to go down to patient level in order to evaluate how the trial is proceeding and by avoiding complex policies.Moreover, patients have to accept a certain level of uncertainty as the clinical studies are not completed and Clinical Trials investigators need a continuous talking to patients during the drug development to ensure the higher level of achievable safety.A successful PPAS pathway depends on the willingness of patients, regulators, health-care providers and payers to accept a greater level of uncertainty using the new medicine in the expectation of an improved benefit risk profile.Furthermore, PPAS approach could facilitate a more open and timely strong scientific dialogue and significant cooperation among stakeholders and a time reduction to full market approval resulting into a possible impact reduction on the overall cost of development."}
+{"text": "Health systems around the world are grappling with the difficult issue of how to allocate scare healthcare resources. Within Europe many different approaches to healthcare resource allocation exist, but it is clear that the formal techniques of cost-effectiveness analysis are becoming increasingly important. This presentation will first address the fundamental economic principles of scarcity and opportunity cost, before looking at how different European systems are attempting to address the economic challenge of providing healthcare for their population from a limited budget. The presentation will go on to consider general issues in health economic evaluation that are likely important for clinical community focused on HIV treatment: appropriate comparator treatments for defining opportunity cost, patient heterogeneity and the potential for personalized/stratified medicine to control costs and target treatment appropriately."}
+{"text": "The devastating toll of the Ebola epidemic in West Africa necessitates considerations of new approaches to research into new prevention technologies and treatments for Ebola Virus Disease (EVD). Research must be planned and delivered in consultation with civil society from the epicentre to prevent mistrust and misunderstanding. Ethical considerations include development of local research and regulatory capacity; negotiating the standard of prevention packages for research participants, including healthcare workers; and strengthening health systems in developing countries to ensure effective response to future EVD outbreaks in the region. Also, strategic consultation with local communities is an ethical imperative for EVD research, particularly where there is potential for differential access to prevention and care packages between trial staff and local hospital staff. The increasing incidence of cross-border infection exemplified by case detection in Nigeria, Mali, Senegal, England, United States and Spain, further necessitates consideration of new approaches to the evaluation and distribution of new treatment and prevention technologies. Despite possible remission of EVD symptoms following early detection and aggressive supportive care, mortality reported in the current epidemic has been estimated to be 73%  with morThe high case fatality may be connected to poor medical management of patients with EVD . ProvisiDevelopment of EVD treatment drugs and vaccines is very important, but glaringly, development of local capacity to provide care and support for patients with EVD is equally essential. Accordingly we will also address issues of local capacity in this paper, which will discuss and identify significant ethical considerations when planning the design and implementation of clinical trials for EVD treatment drugs and vaccines.Phase I trials for anti-EVD vaccines and therapeutics should happen in developed countries as is the norm with other drug and vaccine development process. This is because of the need to ensure optimum standards of clinical care and patients\u2019 monitoring during phase I trials while establishing baseline safety data. Phase II trials however may be conducted in developing countries with EVD outbreaks. This should not preclude efforts to build local capacity in Africa to conduct phase I clinical trials. Kanapathipilla et al  proposedFor EVD vaccine research, Kanapathipilla et al  proposedUnfortunately, countries affected by EVD in West, East and Central Africa have grossly inadequate health infrastructure and do not have a large pool of personnel with competency to conduct clinical trials . In addiWhile most if not all of the EVD clinical trials protocols for treatment therapies and vaccine are developed primarily by researchers in the developed countries, this research will be conducted in collaboration with partners in the local settings. For EVD treatment research, health care workers will be actively engaged with drug administration and data collection. Also, healthcare workers are to be targeted as study participants for EVD vaccine research due to their heightened risk for contracting EVD . It is tFor healthcare workers as care providers, the standard of prevention package should include providing effective personal protective equipment (PPE) and implementing evidence-based standardised protocols regarding working conditions . There is evidence that suggests a need to improve the quality of PPE  as the cIn addition, due consideration should be given to the PPE requirements of those who wear prescription glasses and the use of fluid resistant particulate respirators when carrying out procedures that could cause aerolisation of infectious particles . While EFurthermore, participants and researchers will need to be carefully prepared to deal with fever that could arise as a complication of EVD vaccine research. Fever is a common vaccination side effect and, not unexpectedly, has been seen in a small number of participants in the human safety trials of one of the candidate Ebola vaccines . Fever iAs healthcare workers face increased risk of Ebola exposure and infection in their daily lives, it is also likely that some healthcare workers who volunteer for the EVD vaccine trials will acquire EVD. This raises the issues of the standard of care for EVD trial participants who become infected. The long-standing debate on what constitutes appropriate standard of care in resource constrained settings  has onceThe standard of care package for trial participants will need to be carefully negotiated to optimise care not just for participants but also for their local communities. In the context of HIV prevention trials, negotiation of standard of care packages has also been proposed, especially in situations where the standard of care between developing and developed countries differ significantly, and where the institution of international gold standard of practice may involve differing standard of care between research participants and other community members . DiscussA further ethical imperative for trial conduct in countries with EVD epidemics hosting EVD research is the need to ensure technology transfers. It is very clear that the development of EVD therapeutics and vaccines can no longer be delayed. The corollary of this is that research teams need to think about how to develop not only the infrastructure but also the human and administrative capacities in proposed research sites to facilitate the conduct of the required phase II and III trials. There is a need for structured supportive systems that promote local capacity building for research staff in Ebola-affected countries in ways that enable them to design and implement future research studies that can address local EVD containment. Unfortunately, the lion's share of the funding for research on Ebola is currently spent in developed countries outside Africa, with very little focus on building the capacity of researchers in affected region been able to lead Ebola research initiatives . This paThe ethical complexities of conducting clinical trials during epidemics of such magnitude as the current West Africa outbreak make it imperative that decisions about compassionate access for therapy and clinical trial design for EVD therapeutics and vaccines are made in consultation with affected communities, including non-medical members of civil society. Building shared understandings of the epidemic and research strategies to help affected people and communities are critical to the success of research and access programs, making the involvement of civil society in EVD research planning and implementation crucial.In an epidemic setting where the prospect for compassionate access to new interventions is possible, decisions about the conduct of clinical trials of such interventions has to be weighed against compassionate access for those infected or at high risk of infection. Compassionate access is important for humanitarian reasons, and it may also assist with gaining compliance with public health measures. Access to an experimental vaccine should however be based on defined clinical criteria that allow for systematic data collection, without preferential treatment for people with particular roles in society, in order to avoid entrenching social inequalities .Compassionate access to experimental therapeutics and vaccines may however deplete the supply of experimental interventions and complicate evaluative processes, as patient deaths or recoveries may be wrongly attributed to the experimental substances. This and other possible challenges with evaluation of the efficacy of potential EVD therapeutics and vaccines should not preclude access of citizens in a country where EVD therapeutics and vaccines clinical trials are been conducted to compassionate therapy.In a health crisis like that been currently experienced with EVD in West Africa, civil society consultation may sound like an unaffordable luxury. The decisions that need to be made over the following months about how to distribute and test experimental therapeutics and vaccines in West Africa will necessarily involve complex choices based on values, however.Without meaningful input from civil society, and strong support from the media for disseminating accurate and unbiased information, there is the risk that EVD therapeutics and vaccine research and development could exacerbate social inequalities and breed social unrest. Perceptions about social injustice could arise from differential access of trial participants and trial support staff to prevention and care packages that dichotomise the populace.Decisions therefore need to be made with communities on research design and implementation plans including participant recruitment process, whether or not some communities are too vulnerable to participate, and how to ensure communication of key concepts to community members who participate in clinical research. The decision-making process should promote collaboration between researchers and community members as invested stakeholders in the management and control of the EVD epidemic. Dialogue between researchers and communities should therefore be bidirectional and continuous up till the point of research result dissemination. Community-research partnerships should be the ultimate goal of the community engagement process for EVD therapeutics and vaccine clinical research programmes. The Good Participatory Practice Guidelines  developeDevelopment of effective EVD treatment drugs and vaccines must be a global priority. Prevention however cannot be the only strategy for combatting this disease. Pictures and reports from countries affected by the EVD have shocked the world, with men, women and children suffering and dying in unspeakable conditions that attest to the parlous state of health infrastructure in areas stricken by the disease. The social and economic effects of the epidemic will further delay the development of infrastructure that is urgently needed to provide decent care to people in these countries. Strengthening the health systems of countries with low GDP needs to be given global priority while effective EVD therapies are been researched and developed. The next epidemic may hit another region in Africa outside the current know zones of the epidemic. The world cannot afford a repeat of the current EVD epidemic we are witnessing."}
+{"text": "Research into correlates and determinants  of fatigue has burgeoned in the past two decades. However the link between cortical activity and muscle force generation on fatigue that develops during exercise is not very well understood. While there is extensive evidence suggesting that the central nervous system can contribute to the inability of a human being to sustain a motor task, some questions are unsolved. Is fatigue a sensed variable? Could substantial progress in neurophysiological techniques have additional benefits in the understanding of fatigue? What have we learned and what happens next? Answers require likely the combined insights not only from physiologists, but of neuroscientists and psychologists. Recent research in this area presents three trends providing current interests and opinions in the field.The first issue concerns the fatigue state with respect to changes in motor performance. The picture of fatigue that emerges is the conscious perception of a sensation of fatigue according to the phenotypic traits of the individuals mediated by environment and culture  with sufficient ecological validity Mauger,  is a rapAdvances in functional neuroimaging techniques of the human brain with behavioral outcomes, such as electroencephalography (EEG) and near-infrared spectroscopy (NIRS), helped to generate first valuable data in human exercise research. Increased muscle recruitment as revealed by electromyographic activity was accompanied by a higher brain cortical activity (measured by EEG) localized mainly in the primary motor cortices during unilateral isometric knee extensions . The PFC involved in motivational and decision-making processes is an important candidate for acting as relay station in the central fatigue related network regulating central command. Development of fatigue at the highest force output during intermittent isometric upper limb contractions was attributed to reduced muscle oxygen availability rather than impaired prefrontal oxygenation  have also gained popularity owing to its potential to explore the neural processes underlying motor functions Mauger, . Recent Investigating the post-exercise recovery strategies could shed light on the contributions of the brain into the control of muscle force with fatigue development. Regarding the post-exercise recovery period, little or no data are available concerning central processes of performance  to understand cortical brain function during and after exercise in healthy humans should guide our future works.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Sibling recurrence data from the Baby Siblings Research Consortium (BSRC) recapitulate results from very large clinical family studies that demonstrate the absence of the Carter effect and provide clarification of the nature of the female protective effect in ASD. This legacy prospective data collection confirmed marked differences in the proportions of males versus females who lie along deviant trajectories of social development in the setting of inherited liability to autism\u2014a phenomenon which defines the female protective effect\u2014and demonstrate that among affected children, sex differences are modest and homologous to those observed among non-ASD children. I read with great interest the report and analysis of the extensive collection of data by the Baby Siblings Research Consortium regarding early sex differences . Given tnot observed for ASD in the Baby Siblings Research Consortium (BSRC) sample. But the absence of the Carter effect is not the same as the absence of a female protective effect.What the data suggested, replicating what has actually been previously reported by numerous prior studies , 3, is tThe manuscript describes the BSRC observation that across a number of developmental competencies, modest sex differences were observed, and the discrepancy between boys and girls with ASD was not different in magnitude from that between typically developing boys and girls. The authors conclude that therefore sex differences were \u201cnot autism-specific.\u201d Examining males and females within the category of the disease-of-interest is an important exercise in understanding sex differences, but there can be profound ASD-specific sex effects on a disease that render sex differences among affected subjects relatively minor and indistinguishable from those differentiating typical boys and girls. Conduct disorder provides an excellent example\u2014the differences between males and females who meet diagnostic criteria are minimal (by definition) and yet males are six times more likely to be affected than females. within any subject group was dwarfed by the magnitude of difference across groups (ASD versus non-ASD). Since the \u201cquantum leap\u201d from typicality to clinical abnormality  occurred over three times more commonly for male siblings than for female siblings (this was the second major clue generated by the study data), the data actually represent a remarkable manifestation of sex-specific modulation of inherited liability, which is the fundamental nature of the so-called female protective effect. The refocusing of the problem on contrasts across groups rather than within groups is represented by comparing the arrows and relative sample sizes in\u00a0Fig. In the case of ASD, the first major clue generated by these data was that the magnitude of sex difference for any given trait In prior published work, we have presented evidence for the manner in which a female protective effect might operate in the absence of the Carter effect, essentially via a categorical mechanism of protection by which most females are protected from most forms of ASD , 7\u20139. Thdefines the female protective effect\u2014and demonstrate that among affected children, sex differences are modest and homologous to those observed among non-ASD children.The BSRC data recapitulate results from very large clinical family studies that demonstrate the absence of the Carter effect and provide clarification of the nature of the female protective effect in ASD. The prospective data collection confirmed marked differences in the proportions of males versus females who lie along deviant trajectories of social development in the setting of inherited  liability to autism\u2014a phenomenon which"}
+{"text": "The evolution of intrauterine development, vivipary, and placentation in eutherian mammals has introduced new possibilities and constraints in the regulation of neural plasticity and development which promote neural function that is adaptive to the environment that a developing brain is likely to encounter in the future. A range of evolutionary adaptations associated with placentation transfers disproportionate control of this process to the matriline, a period unique in mammalian development in that there are three matrilineal genomes interacting in the same organism at the same time . The interactions between the maternal and developing foetal hypothalamus and placenta can provide a template by which a mother can transmit potentially adaptive information concerning potential future environmental conditions to the developing brain. In conjunction with genomic imprinting, it also provides a template to integrate epigenetic information from both maternal and paternal lineages. Placentation also hands ultimate control of genomic imprinting and intergenerational epigenetic information transfer to the matriline as epigenetic markers undergo erasure and reprogramming in the developing oocyte. These developments, in conjunction with an expanded neocortex, provide a unique evolutionary template by which matrilineal transfer of maternal care, resources, and culture can be used to promote brain development and infant survival.  Two major innovations have contributed to the evolutionary success of mammals. The first is the evolution of a foetally derived placenta which enables the foetus to influence its own destiny, whilst placing a considerable burden in terms of time and energy investment on an expectant mother. Hormonal cues provided by the developing foetus influence maternal neural function, increase maternal food consumption to compensate for increased energetic costs , suppresThe mammalian brain has undergone profound changes during its evolution. The huge expansion of the neocortex especially in primates has facilitated a shift in the complexity of social interactions and in primates complex social cues replace changes in hormonal states to promote maternal and sexual responses. Parturition is not required to initiate maternal behaviour which is therefore displayed towards a range of offspring in a social group and sexual interactions may occur out of oestrus and are used to reinforce social attachment. The most important phases of neocortical development and socialisation occur during periods of maternal attachment, among stable groups of females that extend over more than one generation. There are often complex social hierarchies within these groups and social rank is often inherited matrilineally from the mother .The developing mammalian brain can demonstrate remarkable plastic and adaptive responses many of which serve to adapt the brain to an environment that it will encounter when mature. This may account for the ease in which mammals have undergone adaptive radiation into a wide range of environmental niches, where evolution of the brain and neuronal phenotype has paralleled adaptations in physical structure. In this review we focus on the importance of a number of mechanisms that contribute to this and emphasise the importance of the matriline in these mechanistic processes. We also suggest that failure in these processes can result in the induction of deleterious neural and peripheral phenotypes that cannot be viewed as traditionally pathological but are phenotypes which are adaptive to the environmental conditions with which an individual or its mother interacted during early development. Subsequent shifts in environmental conditions during an organism's later development may leave it with a poorly environmentally adaptive phenotype and a propensity for health problems.The hypothesis of predictive adaptive responses or plasticity (PAR) was originally developed at a whole organism level to provide a mechanistic framework by which a developing organism can attempt to predict and modify its developmental phenotype to accurately match the environment that it will encounter when mature. It also incorporated a range of ideas that attempted to explain why early life experiences are associated with an increased risk of disease in later life, especially in contemporary human societies \u201323. TherMicrotus pennsylvanicus) born in late summer and early autumn have much thicker coats than those born in the spring. The proximal cue for this is a reduction in day length, which is transmitted to the developing vole in utero via melatonin signalling originating in the mother [A range of predictive adaptive responses involving the brain have been described in a number of mammalian species. One of the simplest and earliest related to the observation that vole pups  which provides a unique template by which a mother can transmit environmental information to her developing foetus and her potential grandchildren. The placenta is produced by the developing foetus and provides a mechanism by which it can attempt to control the physiology and neural function of its mother to its own advantage. Progesterone secreted by the placenta suppresses sexual activity , 3; its Placental hormones also prime the oxytocin system in anticipation of parturition where oxytocin release is required to support uterine contractions, milk ejection, and maternal behaviour in the mother , 6 and t in utero via placentation or postnatally via lactation and efficient maternal care [The developing foetus begins to exert considerable leverage on the neural function of its maternal hypothalamus during early placental development at the same time as it develops a hypothalamus of its own , 47, 48.nal care , 47, 48.Genomic imprinting refers to a form of monoallelic gene expression whereby the expression of an allele depends on its parental origin. The fact that genomic imprinting is absent in egg laying mammals and the fact that there are only 6 or so recorded imprinted genes in marsupials but around 150 imprinted genes in eutherian mammals have driven the development of over 14 interesting theories that explain their existence . Most ofPeg3) has provided a range of evidence that supports the role of imprinted genes in the development of coadapted responses between the hypothalamus and placenta. The Peg3 gene can be inactivated in the maternal hypothalamus but not the placenta or hypothalamus of offspring or be functional in the maternal hypothalamus but inactivated in the hypothalamus or placenta of offspring. Both of these paradigms produce remarkably similar deficits in hypothalamic cell number, maternal behaviour, and impaired suckling, which leads to impaired growth, onset of puberty, and reproduction [Many imprinted genes are coexpressed in the developing hypothalamus and placenta, and a range of studies using mice with an inactivated paternally expressed gene 3 , which are thought to be important for the regulation of monoallelic gene expression and disruption to these can be associated with Prader-Willi and Angelman's syndrome . ImprintThe development of the brain is by definition a complex epigenetic process; neural systems are designed to respond to environmental changes as the interactions of over a trillion synaptic connections both are activity dependent and can be subjected to epigenetic modification. This occurs throughout the life of an individual but at key stages of development, epigenetic modification of neural function is under disproportionate control of the matriline. The erasure and reprogramming of the epigenetic landscape in the developing oocyte, interaction of the developing brain and placenta with environmental cues, the ability of a developing brain to accurately assess present conditions and accurately anticipate the future, and programming of the postpartum brain via efficient maternal care and lactation are all disproportionately matrilineal processes. No two brains are ever alike and even monozygotic twins exhibit increasing differences in behaviour and predisposition to psychiatric disorders as they age , 55 whicThe evolution of paternally derived intergenerational effects on offspring fitness and phenotype may suggest one further mechanism by which adaptive traits can be passed rapidly through an expanding population. Beneficial genetic variations and epigenetic modifications of monoallelically paternally expressed genes will spread far more rapidly through a population than those of monoallelically expressed maternally expressed genes. This is because mammals typically have fewer ancestral fathers than mothers as in males freed from the energetic burden of placentation reproductive success is based on competing to impregnate as many females as possible. This means that many low status males fail to breed and yet high status males often have large numbers of offspring. In populations that are moving into novel environments, who then subsequently undergo a rapid expansion this reproductive asymmetry coupled with the evolution of paternally expressed  gene expression provides an elegant mechanism to rapidly distribute traits that are adaptive to neural function. Adaptive gene variants and epigenetic modifications of paternally expressed genes will spread extremely rapidly in such rapidly expanding population, especially in circumstances where there are few ancestral or founding fathers. This is an important adaptive trait when populations are moving into new environmental niches. There are animal examples of this gender asymmetry of ancestral influences but one rare but illustrative human example of this process relates to the amazing fecundity of Genghis Khan who was thought to have sired over 1,500 children. This productivity was also replicated by his sons and grandsons. As a consequence there are now over 16 million men in Asia who can trace their Y chromosome lineage to an extremely small number of reproductively successful men living in the 12 and 13th centuries .In circumstances where an organism's early life environment provides accurate predictive cues to the environmental conditions prevailing when adult, the ability of the developing foetal and neonatal mammalian brain to adjust its development to optimally match its function to the requirements of its adult environment confers profound advantages in terms of survival and reproductive fitness. One evolutionary development that elegantly facilitates this process in eutherian mammals is the development of a foetally derived placenta, by which the foetus can attempt to control its own destiny and hormonally regulate the maternal hypothalamus to leverage maternal resources for its own benefit. This is a unique situation that requires the interaction and coadaptation of three matrilineal generations and hence genomes interacting in one organism at the same time . This provides a template by which a mother can transmit adaptive information concerning present and potential future environmental conditions to the developing foetal brain over an extended period. When combined with the evolution of imprinted genes and disproportionate maternal control over the mechanisms of epigenetic inheritance, this provides a mechanism to ensure intergenerational coadaptation of the maternal hypothalamus, developing brain, and placenta, integrate potential maternal and paternal interests, and promote the optimal allocation of maternal resources and transfer of matrilineal cultural influences. In circumstances either where the early environment provides inaccurate cues to the environmental conditions prevailing when adult due to rapid environmental change or when disruptions to normal neural development occur, the mismatch between the environmental predictions made during early development and subsequent reality may mean that an organism may have a poorly adapted phenotype to its adult environment which may predispose it to health problems. An appreciation of these underlying evolutionary salient processes may provide a novel perspective on the casual mechanisms of a range of health problems. The concept of a brain that is not pathological in the classical sense but it is simply mismatched to its environment has been most extensively studied in the context of ancestral and early developmental nutrition , 40, 41."}
+{"text": "Finding the right dose of a novel treatment is one of the most important tasks in early drug development. However, there is often uncertainty about the form of the relationship between dose and patient response at the time that the dose-finding trials are designed. In this presentation we develop Bayesian adaptive designs for Phase II cross-over trials conducted to estimate the minimum effective dose (MED), that is, the dose corresponding to the minimum clinically relevant effect over placebo.We propose designs which stipulate that patients enter the trial in cohorts, and each cohort receives placebo and three active doses from a total of K active doses available for use. After each cohort of patients has been treated using a Williams square design an interim analysis is performed to identify which doses the next cohort of patients should receive. Bayesian model averaging is used to account for model uncertainty. Prior distributions will be based on pseudo data collected from experts by eliciting quantiles of the response distribution on placebo and a number of active doses to be used in the trial. A number of plausible models for the dose-response relationship are identified before the trial begins and accumulating evidence on the shape of this relationship is summarised by posterior model probabilities. Doses for the next cohort of patients are chosen adaptively to minimise the weighted average variance of the log(MED), averaging across all candidate models and weighting according to posterior model probabilities."}
+{"text": "ObjectiveHypotonia is a common clinical entity well recognized in pediatric age group, which demands experienced clinical assessment and an extensive array of investigations to establish the underlying disease process. Neuroimaging comes as great help in diagnosing the disease process in rare cases of central hypotonia due to structural malformations of brain and metabolic disorders and should always be included as an important investigation in the assessment of a floppy child. In this article, we discuss the MRI features of eight cases of central and two cases of combined hypotonia and the importance of neuroimaging in understanding the underlying disease in a hypotonic child. Hypotonia is a constant clinical sign associated with a wide variety of cerebral as well as systemic diseases in newborns and older infants. Causes can be common such as hypoglycemia and hypoxic ischemic injuries that do not pose many difficulties in diagnosis and could be rare Inborn Errors of Metabolism; which are difficult to diagnose especially in resource limited Nations. A thorough clinical examination by an experienced pediatrician is usually the first step necessary to determine the anatomical origin of hypotonia i.e., whether in the central or peripheral nervous system . CarefulIn this article, MRI brain imaging details have been discussed retrospectively in eight patients of central and two cases of combined hypotonia referred to the Department of Radiology of Dr. Rml Hospital, a Tertiary Care Institute for neuroimaging in northern India. We have excluded the more common systemic or acquired causes like sepsis or hypoxic ischemic encephalopathy and those cases where MRI was essentially normal. MRI was performed on a 1.5 Tesla Siemens Magnetom Symphony scanner with 4 mm thick slices and 2 mm interslice gap. All standard sequences were included including post contrast sequences and MR Spectroscopy in special situations as and when required.MRI findings in structural anomaliesVariable degree of posterior fossa abnormalities were observed in the present cases: Jouberts Syndrome, Chiari I, WalkerWarbug Syndrome (WWS) and Fukuyama. Small posterior fossa and tonsillar herniation was seen in Chiari I malformation , VermianMRI findings in metabolic disordersWhite matter signal abnormalities were observed in most of the cases with metabolic disorders with symmetrical involvement being the most common type. While the white matter signal changes were confined to the white matter of cerebral hemispheres, corona radiata in adrenoleukodystrohy and metachromatic leukodystrohy diffuse signal changes with involvement of posterior fossa was seen in Canavan\u2019s disease and in Maple syrup urine disease , 9. AmonMRI findings in combined hypotoniaIn Fukuyama disease, MRI revealed multiple subcortical small cysts in bilateral cerebellar hemisphere and polymicrogyric cortex with diffuse signal changes in white matter of brain . In WalkAdvances in neuroimaging have led to early recognition and diagnosis of rare congenital anomalies of brain and inborn metabolic disorders in floppy infants even before the full clinical manifestations of the disease sets in the later childhood. Present series was aimed at describing MRI features and its importance in the work up of floppy infants with congenital structural and metabolic basis of neurological disorders. Structural malformations and metabolic encepahalopathies produce profound hypotonia in infants and often in early months of life, this may be the sole manifestation of these rare diseases .These inIn Conclusion, Neurological evaluation of a floppy child is an extremely difficult and demanding task and the clinician may be clueless about the next correct investigation to choose among the wide array of highly specialized tests for the diagnosis of central hypotonia. Hence, neuroimaging should be considered for quick diagnosis and identification of potentially treatable cases."}
+{"text": "The brain-machine interface (BMI) used in neural prosthetics involves recording signals from neuron populations, decoding those signals using mathematical modeling algorithms, and translating the intended action into physical limb movement. Recently, somatosensory feedback has become the focus of many research groups given its ability in increased neural control by the patient and to provide a more natural sensation for the prosthetics. This process involves recording data from force sensitive locations on the prosthetics and encoding these signals to be sent to the brain in the form of electrical stimulation. Tactile sensation has been achieved through peripheral nerve stimulation and direct stimulation of the somatosensory cortex using intracortical microstimulation (ICMS). The initial focus of this paper is to review these principles and link them to modern day applications such as restoring limb use to those who lack such control. With regard to how far the research has come, a new perspective for the signal breakdown concludes the paper, offering ideas for more real somatosensory feedback using ICMS to stimulate particular sensations by differentiating touch sensors and filtering data based on unique frequencies. Limb loss and paralysis can have crippling consequences for those affected, severely hindering the ability of individuals to live normal lives. Work being done with prosthetics utilizing neural interfacing techniques for neural control may hold the answers to potentially restoring some of what these people have lost and significantly improving their overall quality of life , 2. WithRecently the importance of somatosensory feedback as a method for providing higher level cognitive control has become apparent \u20137. Ever This paper will review what is currently being done with prosthetics implementing BMI technology, focusing on the integration of proprioceptive and somatosensory feedback as a method to improve control. After delving into some of the basics behind BMI, the importance of sensory feedback and commencing with the review, a new perspective on methods for signal breakdown will be explored for the purpose of offering possible new insights and a unique perspective on what can be done moving forward in the field. Finally, the applications of neural prosthetics will be discussed.A brain-machine interface is a link between the mind and the physical world in which information can flow and allow the two to interact through an external device. The principals behind modern day prosthetic BMIs involve extracting motor control signals from pools of neurons and translating those signals into motor control of a device that control being fine-tuned through different feedback sources and assistance from computer algorithms . InformaDecoding is a huge component of being able to understand brain signals and translating them to the prosthetic device. Decoders use multiple mathematical functions to process a variety of neural signals recorded by electrodes into signal patterns that can be recognized and interpreted as relating to specific neural activity . The rigAlong with decoding, one of the most crucial challenges facing brain-machine interfacing is electrode design and lifespan. The electrode/electrolyte interface can cause unfavorable reactions, such as irreversible faradaic reactions, and chronic implantation in the central nervous system has been shown to elicit a typical response of electrode encapsulation by macrophages, microglia, and astrocytes, even in materials considered to be biocompatible . Less inDecoding signals from neural activity collected from these electrodes give rise to cognitive control. BMIs used in research involving monkeys have developed from giving them cognitive control of a cursor on a computer screen, in which they would perform tasks for a juice reward , to beinPatients suffering from paralysis and limb loss can theoretically benefit from two different types of prosthetics: motor-based prosthetics that read out information from motor cortical areas of the brain concerned with arm and movement and cognitive prosthetics that translate activity from various cortices related to sensory-motor integration involving higher level of cognitive processes that organize behavior , 20. EffThe idea of sending the information about the touch from the artificial hand to the brain is a new concept. It works by adding additional somatosensory feedback channel that can create tactile signals generated by real sensors placed in the robotic hand, directly to the somatosensory cortex. The goal of adding sensory signal makes the system closer to the real side and can also add a whole new experience of being able to feel the touch surface. BMI without somatosensory feedback only relies on visual feedback and thus could result in reduced quality of BMI-controlled movements , 5.Research has shown that integration of multiple sources of feedback significantly improves control when using BMIs, research that will be explored in the following animal study. Work done in 2010 by Suminski et al. using BMIs that incorporated feedback from multiple sensory modalities in monkeys found early on that using proprioception as a feedback mechanism aided in neural control [Two adult male rhesus macaques were trained to control a two-dimensional cursor using a robotic exoskeleton, moving the cursor to a series of random targets to receive a juice reward. The monkeys were then implanted with a 100-electrode microelectrode array in the primary motor cortex (MI) contralateral to the arm used for the task of controlling the cursor see , and mulThese results are the first to demonstrate the important implications of feedback modalities other than that provided by one's vision in cortically controlled brain-machine interface. The performance with proprioception also surpassed that reported in a clinical experiment involving two human patients with tetraplegia  and compSomatosensation, including proprioception, is an integral component of natural motor abilities. Losing proprioception will have significant detriments on the capacity to plan dynamic limb movements , and in Conveying somatosensory information via ICMS has also been shown to be viable in animal studies. Researchers at the University of California Berkeley tested whether rats could use artificial tactile percepts generated from ICMS to the barrel cortex to navigate around a virtual target . Rats weResearchers at the University of Chicago sought to convey information about sensory contact location on the hand and digits of a Macaque monkey by delivering ICMS to regions of S1 with particular receptive fields in the hand . Tabot aEarly experiments exploring sensory mapping along S1 via electrical stimulation by Penfield and Boldrey showed that S1 neurons organized into distinct columns, which represent regions of the body , and thaOne option being explored utilizes the brains ability to adapt, relying on its plasticity, instead of meeting the demands of complete biomimicry. By associating different stimulation patterns with various kinds of sensory information, it is hoped that patients will be able to learn the meaning behind each and use that information to operate better prosthetics. This method might also be warranted in the presence of cortical plasticity, or when the brain adapts unused areas to help control the functions used to compensate for that loss. Given time, areas not in use may have become completely devout to this other function, making new adoption out to be a more reliable option. The synergy between these adaptive methods and biomimicry may hold answers to improving patient control of cognitive neural prosthetics and BMIs that can integrate both afferent and efferent signals .BMI technology can aid tremendously in restoring function and patient rehabilitation in a clinical setting. Traditionally, the main forms of treatment for sensorimotor disorders involve pharmaceutical intervention for pain and clonus, and classic physiotherapy techniques focused on avoiding muscular hypotrophy by administration of passive movement sessions through manual interventions . HoweverThe idea of neural prosthetic control through functional electrical stimulation spans back from when one of the first FES systems employing implantable electrodes is inserted into muscular fibers to allow a hemiplegic patient to move a completely paralyzed limb again  to FES-BImplanted electrode arrays can produce excellent accuracy and complex motor routines; modern BMIs can detect and encode natural hand and finger motions performed by monkeys with the use of intracortical electrodes , 36. IntRaspopovic et al. at Ecole Polytechnique Federale de Lausanne set out to restore natural sensory feedback via stimulation of peripheral sensory nerves (median and ulnar nerves) through the use of transversal intrafascicular multichannel electrodes . They thFuture perspectives include incorporating the prosthesis into the body schema . Better brain-prosthetics integration must reduce the timing between motor information and sensory information, which has been found to be crucial for patient recognition and acceptance of the prosthetics . ExistinDealing with phantom limb pain as an application of ICMS offers a good example of the mechanisms and benefits of peripheral stimulation in the context of neural prosthetic replacement. Phantom limb pain is a mild to extreme pain whose seeming origin comes from a no longer existing extremity or which is felt from where a person's limb has been amputated , 42. ThiEven when a basic prosthetic device is attached to an upper limb injury the patient can still have these types of phantom pains because there is still no sensory information being sent to the primary somatosensory area of the brain. The sensory information received at the prosthetic device has shown a resultant decrease in the phantom pain experienced by these amputee patients , 44. RedAlthough most of the current research involves the use of ICMS to stimulate the somatosensory cortex; in future, the use of optogenetics might become more prevalent. Optogenetics is based on genetically modified ion channels that respond to light, and thus it could remove all the problems associated with the use of ICMS. It would also allow for finer control of spatial pattern of activation .The focus on improving control in this paper will be via proposing a stimulation method to provide full sensory information directly to the patient. The intent on conveying comprehensive somatosensory information will focus on providing information regarding multiple features of tactile perception rather than just one . Visual feedback has been predominantly used to modulate the output of BMI limbs, but this provides limited control of force and takes time for complicated spatial tasks . As mentCurrent ICMS techniques have demonstrated the capability to deliver localized activation of neurons . They caAs elucidated earlier, there has been much progress in the development of advanced decoding algorithms and research into the function and mapping of the motor cortex that has contributed to the capability of lending CNP arms to mimic much of the natural movement capabilities of a native arm. Given these developments and the demonstrable advantage of artificial sensory feedback , using tSince ICMS has been established as the preferred method of conveying somatosensory feedback, it is necessary to have a stimulation strategy that will successfully convey comprehensive somatosensory information. To accomplish this, the signals will first have to be acquired by the device and then converted into a form that can be conveyed via ICMS. The following proposed method of signal breakdown will only require information from one or two sensors preferably from a flexible array sensor with a high spatial resolution and small size accompanied by a larger normal force sensor to contrast related receptive fields in the hand. This combination of sensors is a possibility given previous applications in robotics .Next, the method of signal breakdown will be discussed. Since most of the information within contact events is contained within the event itself, we propose selecting certain features of the information out to be conveyed via existing somatosensory information streams in native arms. In the native arm, haptic information is conveyed via canonical mechanoreceptors of the skin and their slowly adapting (SA) and rapidly adapting (RA) afferent components . These mTo accomplish this, one approach would be to mimic the somatosensory afferents of the native arm. For providing comprehensive somatosensory information, this paper will focus on SA and RA information streams and their two subtypes. SA and RA refer to the response of the mechanoreceptor to a sustained stimulus; SA mechanoreceptor afferents maintain a high response throughout the stimulus duration, where RA mechanoreceptor afferents respond to changes in stimulus intensity. Furthermore, the SA and RA mechanoreceptors can be broken down into their respective subtypes based on their intrinsic response properties. The frequency range refers to the range of frequencies, to which the mechanoreceptor can respond. Sensitivity refers to the lowest amount of change in frequency that will cause a change in the firing of the mechanoreceptor, and the receptor field size refers to the area on the surface of the skin which one mechanoreceptor occupies , 13.  TaSensory information produced by the response to contact events could possibly be replicated by filtering out the appropriate information from the fewest amount of sensors needed to replicate tactile sensation in the fingers and hand. The electrical signals from these sensors could be filtered through appropriate frequency band selection via bandpass filters or low-pass filters , followed by the addition of processing to recreate the response properties of the native sensory afferent  according to their native physiological properties listed in The processed signals must be used to evoke sensory percepts via ICMS to their relevant regions of S1 .  FigureICMS pulse trains from the proposed method of signal processing could then be delivered to the respective areas of S1 for each receptive field of the hand and separated by their RA and/or SA stream components into the areas with these natural receptive fields. We hypothesize that using ICMS to deliver the same information processed by this method may improve the ability of a patient to interpret many details from elicited tactile percepts due to the existence of both RA and SA-like neurons in S1 .The goal of this perspective is to propose a technique that could convey multiple submodalities of somatosensory stimuli to a human patient operating a somatosensory BMI. This point of view could offer insight into the recovery of multiple submodalities of tactile information as well as a deeper insight into the relationship between natural cortical coding of somatosensory information and the somatosensory percepts that they elicit.Providing direct sensory feedback to amputees can be considered truly cutting edge research. A review of BMI and the superior control attained when incorporating somatosensory feedback into a device shows the possibility to restore natural function and the challenges that need to be addressed for this technology to reach a broad clinical setting. This paper offers a new perspective for improving tactile sensation in neural prosthetics with somatosensory feedback by separating the stimulus from the sensor into signals that resemble the sensory afferent sensation of a real hand. ICMS was discussed as a primary method for sending signals to the S1 in the postcentral gyrus of the brain. The applications of a feedback system range from reducing the cognitive burden of one sense to restoring vital sensations that are essential in allowing people the chance to interact with their surroundings and one another. The power that tactile sensation conveys is invaluable and completely necessary for restoring function. Moreover, it is certainly clear that research into creating prosthetic devices with sensory feedback will continue to evolve the scientific frontier, creating a new understanding of how the brain works and helping those suffering from the loss of limb use everywhere."}
+{"text": "Newborns from multiple pregnancies demonstrate a higher perinatal morbidity and mortality compared to singletons. Prematurity is more frequent in twins and therefore birth weight is significantly lower compared to singletons . Thus, tCareful analysis of both twins for a pathological condition is mandatory to address the most appropriate management. Twin discordance for the presence of a severe pathological condition raises serious concern in terms of bioethical and psychological impact on the parents and medical staff. DiffereThe management of multiple pregnancies is a very complex task for medical staff and requires parental support with adequate counselling and psychological help ."}
+{"text": "Virtual communities are emerging in many aspects of health activities and widespread in health management. Online health communities offer a virtual system where people with common interest, specific health needs can exchange information and experiences with other people with the same condition as well as getting support from peer and professionals. The objective of this study is to develop an ICT platform enhancing community resident participation involving in the chronic disease prevention and physical activities. The aim of this platform is to promote physical activity of community residents for health promotion and disease prevention goal attainment. Health promotion goals for enhancing physical activity were set by health care professionals based on scientific evidence. Instead of individual plan to set the goal by themselves, the platform offered them tailored goal with their conditions and then suggested them to participate in group shared their physical activity goals. The platform encouraged the active participation of community residents though adherence physical activity of health communities in which they were members.The ICT platform provides a place where community residents with chronic conditions or even healthy people who want to promote their health be able to find an appropriate group for together prevent disease and enhancing physical activity. The platform in the study allowed community residents to develop their own communities and invite other members to participate with them. This online community intended to empower community residents to increase their involvement in their self-management and pushing the active participation in phycial activities. Function such as reminder of activity participating was added. Future study will be conducted to evaluate changes in health promotion self-efficacy, health goal fulfillment, health-related quality of life, and shared decision-making after using the Health Community Platform among community residents. Extensive research initiatives are needed to determine the impact of virtual health communities on patient outcome, the overall process as well as quality and access of care."}
+{"text": "Subjective aging is interpersonal, it embodies processes of thinking about the self in relationship to others. We utilize data from the 100-day microlongitudinal Personal Understanding of Life and Social Experiences Project  to explore how self-perceptions of aging differentiate the processes by which older adults shape interactions with close social ties to support progress toward a meaningful health goal in everyday life. Those with more positive self-perceptions of aging identified more friends among their closest social ties and reported a higher levels of goal progress and support toward that goal during the study period. Further, multilevel random coefficient models showed that goal progress on a given day was more sensitive to received support on that day among those with more positive self-perceptions of aging. The implications for adult development and shared experiences of aging within friendship networks is discussed."}
+{"text": "Parker  The authors regret that the incorrect middle initial was given for Samantha Y. Chong in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "Impaired cognition is often overlooked in the clinical management of depression, despite its association with poor psychosocial functioning and reduced clinical engagement. There is an outstanding need for new treatments to address this unmet clinical need, highlighted by our consultations with individuals with lived experience of depression. Here we consider the evidence to support different pharmacological approaches for the treatment of impaired cognition in individuals with depression, including treatments that influence primary neurotransmission directly as well as novel targets such as neurosteroid modulation. We also consider potential methodological challenges in establishing a strong evidence base in this area, including the need to disentangle direct effects of treatment on cognition from more generalised symptomatic improvement and the identification of sensitive, reliable and objective measures of cognition."}
+{"text": "Pathogens initiated this Special Issue. Epidemiology is a field that combines specialist knowledge of many disciplines, considered a facilitator of communication and various diverse skills.One Health is a popular headline for an all-inclusive concept of our scientific work. It is not a new concept, but one along that we have been researching for many decades, if not centuries. Nevertheless, the term has become a keyword used worldwide for an inclusive approach to investigating issues such as pathogens in our various environments and host species. It was with this intention that We are very pleased with to present ten original publications covering the molecular properties, distribution and surveillance of pathogens and vectors. A few examples:A sampling methodology for the surveillance of mosquitos and arboviruses in Florida was more efficient when stratified by a vertical gradient;Genotyping parvoviruses of dogs and cats in Sri Lanka allowed identification of cats as possible source of the virus for dogs;A hitherto unknown zoonotic risk emerged from a study of illegally traded companion animals in Italy and Austria;A study in Barbados resulted in the identification of the seasonal and occupational distribution of human orthohantavirus infections among febrile patients;We now know that the majority of genotypes of equine herpes virus 5 from Poland clustered within two main groups and similar viruses circulated in geographically distinct locations without any apparent age predisposition;An investigation of re-emerging rabies virus in Southeast Asia demonstrated a need for collecting data in remote locations for detecting drivers of emergence.Leptospira spp., about virulence factors of the avian-pathogenic Escherichia coli (APEC) to inform antibiotic therapy, vaccine development and virulence inhibitors, and about the economic loss of the zoonotic Ross River virus (RRV) transmitted from horses to humans. A more confined investigation described an outbreak of canine distemper in a rescue centre.In addition, three reviews detail the merits and limitations of diagnostic assays for describing the diversity of This Special Issue intended to provide \u2018insights into the ecological behaviour of pathogens and their impact on human and animal populations and environments\u2019. We believe the ten publications have significantly contributed to achieving this goal. We would like to thank our colleagues and authors who collaborated and crafted articles describing their scientific thinking and outcomes."}
+{"text": "There is considerable interest by many stakeholder groups in developing new therapies in Alzheimer\u2019s disease (AD). Increasing interest in the treatment of pre-clinical disease and measurement of associated long term outcomes using RWD is being explored as the use of RCTs in this context can be limited. Many challenges exist in generating RWE to support regulatory submissions in this disease population including lack of important clinical variables such as disease severity and progression in existing data sources. We will discuss the AD RWD landscape with a focus on challenges and future directions for the use of RWD to generate RWE supportive of regulatory submissions for pharmaceutical products."}
+{"text": "The progressively lowered stress threshold model suggests that due to impairments in coping, persons living with dementia have a reduced threshold for stress and respond with more behavioral symptoms of dementia as stress accumulates throughout the day. While the propositions of the model have not been evaluated, this model serves as the basis of non-pharmacological interventions for behavioral symptom management aimed at modifying the environment to reduce stressors. These interventions have mixed success, which may be due to traditional longitudinal measurement models that don\u2019t account for the dynamic temporal nature of behavioral symptoms. This paper evaluates the progressively lowered stress threshold conceptual model as an explanation for behavioral symptoms of dementia and tests several of its hypothesized propositions using an intensive longitudinal design. A sample of N=165 family caregivers completed brief daily diary surveys for 21 days (n=2841) reporting on behavioral symptoms of their care recipients. Dynamic structural equation modeling was used as the analytic technique to examine the impact of caregiver and care recipient environmental stressors on the diversity of behavioral symptoms of dementia (number of different symptoms) to account for the nested data structure and autoregressive relationships. Results show direct relationships between environmental stressors and diversity of behavioral symptoms of dementia that same day and the following day. Findings provide support for the progressively lowered stress threshold model. Further, findings suggest an extension to the conceptual model is warranted given evidence of an exposure/recovery trajectory and the lagged effects of stress exposure on behavioral symptoms of dementia presentation."}
+{"text": "Older adults experiencing cognitive decline, including those with Alzheimer\u2019s disease and related dementias, are at-risk for social isolation and participation restrictions, especially given the COVID-19 pandemic. Previously examined research has primarily focused on reducing problematic behaviors and remediating cognition for individuals with cognitive impairments. In this symposium, we will discuss novel intervention approaches and under-studied aspects of lifestyle behaviors that minimize social isolation and maximize participation for older adults with Alzheimer\u2019s disease and related dementias. Information presented in this symposium is intended to inform future intervention research to achieve an optimal quality of life for those with cognitive impairments. The first presentation will describe an analysis of lifestyle behaviors and cognition in an older population. The second presentation will discuss the development of an intergenerational, active music intervention that is delivered virtually to individuals with dementia and their caregivers. The third presentation will describe the effects of an adaptive horseback riding program that is becoming increasingly prevalent and improves the quality of life of persons living with Alzheimer\u2019s disease and related dementia."}
+{"text": "Sleep quality has been considered as one of the most important parameters of good sleep health. A recent study  conducteThe strength of the study lies in the inclusion of various ethnicities and groups across the country. Similar studies with regional modifications need to be performed in other countries to find out the modifiable factors that can help in improving quality of sleep as well as overall health of the population. Inclusion of sleep medicine specialists at district/county-level hospitals would further enhance the health indices significantly in the coming years.The recent advancements in artificial intelligence based trackers and diagnostics bring a lot of hope for affordable sleep health improvement applications . Ethical"}
+{"text": "Funding statement. The corrected statement appears below and replaces the Acknowledgments.In the original article, there were errors in the \u201cThe authors extend their appreciation to the Deputyship for Research & Innovation, Ministry of Education in Saudi Arabia for funding this research work through the project number: IFP22UQU4331317DSR174.\u201dThe authors apologize for these errors and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "Recent years have provided unprecedented opportunities to advance translational science in obstetric and pediatric pharmacology. With our Insights 2021 Research Topic presented herein we also appreciate that there is still much to do. Previous works have pointed out some of the challenges in our domain; many of these relate to the still conservative nature of clinical research in obstetric and pediatric populations and sub-populations  but alsoKoch et al. remind us that there are opportunities for these newer quantitative approaches to be applied in perinatology, providing an excellent application in the treatment of jaundice in preterm and term neonates.An encouraging theme among these papers is that they not only that they address the aforementioned knowledge gaps, but they all represent building blocks by which future preclinical and clinical investigations in obstetric and pediatric pharmacology can proceed. DBS assays have been around for a long time with many illustrating the benefit in the clinical conduct in obstetric and pediatric clinical trials and still there is a reluctance to invest in the approach prospectively to support new drug research and development due to concerns about transitivity and cross-validation with traditional analytical methodologies and regulatory acceptance . LikewisTherapeutic proteins still represent a gap as a modality for pediatrics and pregnant women though new promising agents in this class provide an opportunity to fill these gaps in addition to benefit patients.Meibohm paper highlights the knowledge gaps and prioritizes efforts to reduce them for the purpose of accelerating new TP development in these at-risk populations.Their development however typically requires some manner of bridging from small molecule experience in these populations. Cell and gene therapy for obstetric and pediatric pharmacology populations continues to be an important therapeutic modality requiring additional study. Several critical therapeutic areas including cancer, ischemia, and several rare diseases  all reprThese papers are both timely and clinically relevant in their own right, but they are also likely to be foundational for future work to come. Obstacles remain for obstetric and pediatric pharmacology investigation."}
+{"text": "There is strong and consistent evidence that leisure-time physical activity (LTPA) improves cardiovascular health and reduces the risk of all-cause and cardiovascular mortality. Less is known about health effects of occupational physical activity (OPA), and results are not in favor of a beneficial effect on cardiovascular health. Several large-scale prospective studies have found that high occupational physical activity (OPA) is associated with detrimental or no effects on cardiovascular health and mortality. These contrasting associations with cardiovascular morbidity and mortality for LTPA and OPA have coined \u2018The Physical activity health paradox'. Although the underlying physiological mechanisms are not established, a theoretical framework was proposed by Holtermann and colleagues (2018). This framework suggests that due to the nature of OPA , it may not result in healthy adaptation to the same extent as LTPA, or even lead to unhealthy responses, such as elevated 24-hour heart rate and blood pressure and increased inflammation. Drawing on theoretical models and empirical findings, the aim is to summarize the literature regarding potential physiological mediators of the physical activity health paradox. This also includes a brief summary of our own research based on accelerometer measurements of physical activity with cardiovascular regulation assessed by heart rate and blood pressure in workers with low occupational class and manual work."}
+{"text": "This study aims to assess the impact of the relationship quality between parents and children on parents\u2019 cognitive function in later life, with an additional focus on variation by parents\u2019 gender. We analyze data from a nationally representative longitudinal panel survey of participants age 50 and older. We employ latent growth curve models (LGCM) to estimate how changes in parent-child relationship quality are related to cognitive trajectories over time. Maintaining frequent contact with children and receiving more support from children are associated with a slower rate of cognitive decline for older parents whereas experiencing relationship strain with children is associated with a faster rate of cognitive decline for older parents. These associations are stronger for mothers than fathers. This study highlights the importance of the \u201clinked lives\u201d of aging parents and their children. The findings have implications for the development of interventions and strategies to protect cognitive function in later life."}
+{"text": "It has been suggested that liberal values such as lack of autonomy and burden discourses shape the public\u2019s relation toward people with health problems. However, previous research on the role of such values on one\u2019s recovery and well-being is scarce.We investigated whether perceived autonomy mediates the impact of stigma and negative social experiences on life satisfaction and recovery.Our sample, drawn from a subsample of the Swiss Household Panel survey, consisted of 326 individuals reporting a mental health problem  and 354 individuals reporting a physical health issue . We tested a model where perceived autonomy, measured with four items drawn from the Acceptance of Illness Scale (AIS), mediates the impact of experienced stigma and negative social experiences on health satisfaction and self-reported recovery.Our analysis of direct and indirect paths confirmed our hypothesis. Our model showed a good fit to the data for persons with a mental health problem  and an adequate fit for persons with a physical health problem .Our results provide empirical evidence for the potentially self-stigmatizing role of the autonomy ideal for people with health problems and invite for the development of further research and practice regarding this role.No significant relationships."}
+{"text": "Multidisciplinary management of breast cancer patients has become standard of care. It has been shown that patients managed by multidisciplinary teams have better disease outcome and better quality of life. In a large retrospective cohort study analyzing outcome data of 13,722 breast cancer patients diagnosed between 1990 and 2000 at an NHS Hospital in Scotland, it was shown that after the introduction of multidisciplinary care, breast cancer mortality was 18% lower compared to hospitals performing traditional care  and first president of the Central and Eastern European Academy of Oncology (CEEAO).The development of the final version of the texts published in this Issue of Pathology & Oncology Research followed a methodology similar to the formulation of the Hungarian Consensus Documents; i.e., the Hungarian documents \u20137 were tThe set of documents published in this issue of Pathology & Oncology Research \u201313 comprIn the first document , standarThe second document on pathology workup and reporting  includesThe third text  includesThe fourth document  summarizThe fifth document on medical oncology  describeThe sixth document gives guidance for follow up, rehabilitation and psycho-oncology  and is a"}
+{"text": "This research focuses on a current social welfare problem: unemployment and the loss of employer-based health insurance among non-elderly adults aged 18 to 64. The literature covers this social problem in terms of health status, access to medical care, employed versus unemployed working-age adults, mitigating the risks of unemployment, and loss of health insurance via the Consolidated Omnibus Budget Reconciliation Act of 1985 (COBRA) and the Health Insurance Portability and Accountability Act of 1996 (HIPAA). As good as the findings are, they are methodologically limited by looking at only half the story. This research asks a different question: how might the humanities and arts-based perspective address the social problem? It aims at answering why the employment status is related to health and health insurance. Chinese poetry has a long rich tradition of expressing insights about the inner life since antiquity to the present. These reflections include practice wisdom and keen observations on aging. This poster presents case findings on the use of Chinese poetics to inform aging care in the West. Each case provides discussions on why social welfare system comes up short to solve the problem and how the social welfare system can be effectively changed. Researchers use survey data to compliment Chinese poetic insights about employment status and insurance status to illustrate the correlation between respondents\u2019 health status with versus without employment. Findings are hoped to interpret the role of family as a social unit where it consists in social welfare along with the speculative inquiry of poetry."}
+{"text": "Psychiatric disorders may be one of considerable contributing factors for dry eye symptoms and the severity of subjective symptoms of dry eye are often related to psychological factors.The aim of this research was to determine which of two chosen questionnaires for subjective symptoms of dry eye (Ocular Surface Disease Index and Schein questionnaire) is more reliable in the assessment of dry eye in patients with schizophrenia.Our research included 80 patients of both sexes with schizophrenia ranging between the age of 25 and 55 who have been taking antipsychotics  for five years and were in remission. All participants were required to satisfy all included and excluded criteria. They all filled out the Schein and OSDI questionnaires for assessment of subjective symptoms. Tear break-up time test (TBUT) for objective evaluation of tear film stability was also performed. In order to determine the correlation between two subjective and objective tests we calculated Spearmans correlation coefficients.A analysis shows that there are no statistically significant differences between the correlations. Both subjective questionnaires are statistically significantly and negatively related to the TBUT test, showing that an increase in the results on the OSDI and Schein\u2019s questionnaires led to the decreases in the results on the TBUT test.In patients with schizophrenia the OSDI and Schein questionnaires are equally reliable in the assessment of subjective symptoms of Dry eye disease. Considering that, OSDI is more common in clinical practice, it is recommended for use in patients with schizophrenia.No significant relationships."}
+{"text": "This paper first introduces major aspects of the Japanese Act on the Prevention of Elder Abuse, including trends in substantiated elder abuse cases in both institutional and domestic settings, definitions of elder abuse, and abusers and reporting systems. It then introduces the recent amendment of operational standards in institutional settings made by ministerial ordinance. The amendment includes a requirement to develop a committee to prevent occurrence and recurrence of elder abuse and to appoint a designated individual to establish guidelines and implement training. It is hoped to further prevent elder abuse in Japan."}
+{"text": "Currently anxiety and depression are the fourth leading cause of morbidity. Anxiety is the most common mental disorder from which 20% of the adult population suffer worldwide and has become a significant research area in the field of psychopharmacology . AnxietyMajor depressive disorder (MDD) is also one of the most common psychiatric disorders, posing serious public health problem . AccordiIn the last few decades have seen a significant rise in the use of natural remedies to treat various ailments including depression and anxiety. These products are perceived as safer alternatives to pharmacotherapy, with lower risk of adverse effects or withdrawal. Considerable efforts have been made in recent years to discover substances from natural sources particularly plants which can help prevent these serious mental disorders. Natural products are small molecules present in divergent natural sources. They are considered to possess one of the most coveted positions in the treatment of all human disorders including anxiety and depression. They are considered to be the most important source of novel drug leads . The impvia different mechanisms that may provide quick onset of action for relieving anxiety and depression symptomatology. Furthermore the newer agents may prevent the aforementioned adverse effects and provide effective treatment to the non-responsive patients to the conventional drugs.In view of the above, there is a dire need for the discovery and development of novel antidepressant agents acting This Research Topic focuses on original contributions for natural products being useful in various mental disorders particularly anxiety and their possible mechanisms of action."}
+{"text": "Good metadata, local ownership and fair reuse of genomic and outcome data can be sustained in partnership among well\u2010resourced and well\u2010peopled regions of the world.\u201cA Perspective in this issue recounts the endeavors of the collaborative Virus Outbreak Data Access Network (VODAN)\u2014AfricaGenome data is cheap, plentiful, and concentrated in a few wealthy places, even relative to the information web, where less than 1% of the world's servers serve over 99% of the web content.In contrast to genome data, personal experiences including exposures and clinical records are distributed across institutions, homes, families, and individuals. Lifelong trust that sharing this information brings better outcomes for the donors is essential if we are to use this living biobank of diverse experience to make sense of variation in both viral and human genomes. Information from affected and unaffected individuals is needed to understand the importance of even point mutations in small viral genomes\u2014such as the SARS\u2010CoV\u20102 variants that continue to cause so much disruption and disease worldwide. Yet this data has not been gathered from places where the disruption is occurring, largely because we do not yet have collection networks with the trust and capacity to sustainably return results within the region of study.There are now several related functional technologies for linked data to deliver the aspirational goals laid out in the principles of FAIR data and services. These working together would amount to a mercantile revolution in the global data trade rather than the gold rush metaphor of the Perspective.The VODAN project has contributed to capacity building through its active interdisciplinary cooperation informatics training plan and has greatly promoted the cause of equitable autonomous and secure data ownership. However, it may be some time before the participating sites will be able both to innovate and interoperate fully on the same network in a distributed fashion as the project was originally conceived. Problems inherent in the stability of each local datastore's query protocol service and the potential for inadvertent divergence in implementation led to a tactical decision instead to use centrally provided metadata templates and mirrored storage at a secure central site (CEDAR). This redesign shows that central providers may gain sufficient trust, and partner through secure hosting and open commitment to the storage, organization and ownership of data by the participating local informatics communities across the network. The dream of building distributed capacity together across data rich and resource rich regions remains alive and compelling as ever.Myles Axton: Writing\u2010original draft; writing\u2010review & editing."}
+{"text": "There is a critical need to grow and strengthen the pipeline of physician scientists who have expertise in sociomedical and behavioral research and are dedicated to addressing the nation's challenges posed by Alzheimer's disease and related dementias (ADRD). In 2021 The Indiana ADRD Medical Scientist Training Program (IADRD MSTP) was designed to meet this need and is built on the infrastructure of a robust portfolio of ADRD research, graduate training programs in medical neurosciences and sociology, and our existing MD-PhD program at Indiana University School of Medicine. The Aims of the IADRD MSTP are: 1) To recruit and train a competitive pool of diverse students who have an interest and commitment to social and behavioral research and patient care focused on ADRD; 2) To engage MD-PhD students early in mentored sociomedical and behavioral research that integrates IUs systems-based medical training curriculum with our cutting edge ADRD research that reinforces commitment and minimizes attrition of physician-scientists ADRD; and 3) To graduate students with dual MD-PhD degrees with strong methodological training in social and behavioral science and experts in ADRD who will be successful independent investigators at the best academic medical centers nationwide. The program includes rigorous didactic training in social, behavioral, and clinical research methods, with flexibility to allow students to focus their effort on one methodological area of interest; early initiation of ADRD research experiences with multidisciplinary teams of mentors and advisors; and the provision of educational experiences that enhance students' abilities to become independent researchers."}
+{"text": "A physicians work is closely related to patients and the understanding of their problems. The use of psychotherapeutic methods is a factor for successful care . At the same time burnout is a syndrome that can affect the health of doctors themselves thus reflecting on the quality of care they can provide .To investigate the use of psychotherapeutic methods in family physicians work in Latvia and the association between burnout rates and the use of these methods in practice as well as different demographic and work-related factors.A cross sectional study was carried out. An anonymous online form that contained questions about the demographic data, psychotherapeutic methods/techniques mastering and usage and questions from the Maslach Burnout Inventory was sent out to the publicly available email addresses of family physicians in Latvia. The collected data was analyzed using Microsoft Excel and IBM SPSS software.Together 54 responses were received from all regions of Latvia. The analysis found association between work hours per week, patients seen per week, usage of psychotherapeutic methods and burnout. More hours per week was associated with higher rates of depersonalization  and burnout . More patients per week was associated with higher rates of burnout . Being unsure if they were using any psychotherapeutic methods was associated with higher rates of depersonalization .The data obtained allows a better insight in to the usage of psychotherapeutic methods, everyday work and the association with burnout rates in family physicians."}
+{"text": "This article has been retracted: Aging has completed its investigation of this paper. We found overlap between some transwell assay images used for Figures 3G and 6E and data previously published by different authors. The authors confirmed the overlap and also raised a concern that the statistical methods used for some analyses were inappropriate. As a result, all of the listed authors agreed that the article should be retracted.The Administration of the First Affiliated Hospital of Xinxiang Medical University was notified about the retraction by Aging Journal. The Ethics Committee of The First Affiliated Hospital of Xinxiang Medical University agreed that this paper should be retracted because the errors in the statistical methods led to an insufficiently rigorous analysis of the results and because of the improper use of several pictures included in this manuscript. The authors deeply regret any inconvenience this publication has caused for the scientific community."}
+{"text": "Pogostemon cablin Benth) using a microwave air-hydrodistillation method as a new green technique\u2019 by Heri Septya Kusuma et al., RSC Adv., 2017, 7, 1336\u20131347.Expression of concern for \u2018The extraction of essential oils from patchouli leaves ( RSC Advances is publishing this expression of concern in order to alert our readers that we are presently unsure of the reliability of the data reported in the article.Periodica Polytechnica Chemical Engineering, 2017, 61, 82\u201392), which has not been cited in this RSC Advances paper. The reproducibility seen between the GCMS data in these two papers is very unlikely. The authors have been unable to provide raw GCMS data for the measurements presented in the RSC Advances article.The Royal Society of Chemistry has been provided with credible information suggesting that the GCMS results presented in the paper may not be reliable. The majority of the microwave hydrodistillation (MHD) GCMS data presented in Table 5 has been reproduced from a previously published paper by the authors (The Royal Society of Chemistry is currently seeking support from the affiliated institution in order to investigate this matter and establish whether the reported results are reliable. An expression of concern will continue to be associated with this manuscript until we receive information from the institution on this matter.Andrew Shore19th November 2018RSC AdvancesExecutive Editor,"}
+{"text": "Older adults living with chronic illnesses, such as diabetes, cancer and heart disease, have an increased risk of poor mental health outcomes. While a link between living with chronic illness and depression have been examined in previous studies, relatively little is known about factors that increase and decrease the risk of suicidal ideation among older adults living with chronic illness. Using data from the third wave of the Midlife in the United States (MIDUS) database, we examined the relationship between living with a chronic illness were more likely to endorse thinking about death in the previous two weeks . The analysis also revealed that the likelihood of suicidal ideation in the previous two weeks increased with the number of chronic conditions reported by participants . The results of this study are consistent with previous studies suggesting a relationship between older adults living with a chronic condition are at a higher risk of suicidal ideation. Findings from this study can help inform intervention development to support mental health of older adults living with chronic illness. Future studies are needed to examine additional psychosocial factors that may mediate the relationship between living with a chronic illness and suicidal ideation among older adults."}
+{"text": "Alzheimer\u2019s Disease and Related Dementias (ADRD) affect one in nine adults aged 65 and over. Past research has demonstrated the need for services that improve quality of care for those with ADRD and their caregivers. Those with ADRD are at a greater risk for negative health outcomes. Therefore, it is crucial that those with ADRD receive care consistent with their preferences. However, more research is needed to shed light on effective tools available and patterns of advance care planning (ACP) when it comes to those with ADRD and their caregivers. This symposium highlights the landscape of ACP communication among those with ADRD and their caregivers. The session begins with a study that explored experiences of apathy and preferences for dyadic-communication via mobile health  among adults with mild cognitive impairment and their care-partners. The second presentation demonstrates the feasibility and effectiveness of a palliative care education in assisted living program for nurses and administrators on increasing ACP discussions with family caregivers of residents with dementia. The third presentation investigates ACP among African Americans with ADRD and their caregivers and the critical role the community can play in facilitating communication. The final presentation explores how ACP differs by race, ethnicity and ADRD status using data from the 2018 Wave of the Health and Retirement Study. Future directions for implementation of these innovations for improving ACP communication among caregivers and persons with ADRD will be discussed."}
+{"text": "To continue to monitor trends in detentions under the Mental Health Act based on race, age, gender, and sexuality during the COVID-19 Pandemic to consider if there were any specific areas that would need to be addressed.We investigated available mental health detention documents stored in mental health legislative office, Birmingham and Solihull mental health foundation NHS Trust.We found that detentions under Section 3 of the Mental Health Act have increased very gradually over the last three years (2018 to2021). However, there has been gradual reduction in detentions under Section 3 within the white population beginning in 2019 and continuing with a marked acceleration in reduction during the two peaks of the pandemic. This is marked in the 66yrs plus age group. As the pandemic has eased this reduction has stopped and reversed with increased section 3 admissions in last few months in this population. The detentions in the black and Asian population have followed a reverse pattern, with marked increase during the pandemic peaks in 2020/2021 and a marked fall as the pandemic has eased.Mental health act detention data during the Pandemic shows that the pandemic has disproportionality impacted black and Asian population of all ages and Elderly white population.During the pandemic there has been a marked increase in detentions under Section 3 of the Mental Health Act (for treatment) in the Black and Asian population with a marked reduction in the white population. This difference is stark in the working age population.The need for a well-functioning community based health and social care offer to reduce detentions in the black and Asian population.Return of admissions under the mental health act of white elderly post vaccination (which are vast majority white) shows a reversal of the trend of this group not accessing inpatient treatment fully during the pandemic.This highlights:Community Treatment Order (CTO) detentions in the Black and Asian population continue to increase through the pandemic disproportionatelyThere is no material change during the pandemic, in short term detentions ) or other inpatient detentions under the Mental health actThere are no significant trend changes noted based on gender or sexuality or age during the pandemic in BSMHFT ."}
+{"text": "Cross-border health data sharing is essential to facilitate vital health research into new treatments and to improve patient care and safety across Europe. The flagship European Health Data Space (EHDS) aims to promote better exchange and access to health data through the creation of a European-wide infrastructure. However, significant barriers to cross-border data sharing must first be resolved in order to fully ensure the successful functioning of the Data Space. To this end, the European Commission established a Joint Action (TEHDAS), as the policy development tool for the development of the EHDS. This presentation will be based around the findings of the recent TEHDAS report \u2018Barriers to cross-border sharing of health data for secondary use and options to overcome them.\u2019 The report draws on the results of a dedicated literature review, 133 case studies from across 23 countries and expert interviews to identify the primary barriers to cross-border data sharing and options to overcome these from the perspective of European data users (research and policymakers). The session will start with a concise presentation of the report methodology. The research team will then deliver an interactive presentation, in which they succinctly outline each barrier and policy option and ask participants to vote for their preferred policy option to overcome each barrier identified. EUPHA participants votes will inform the final TEHDAS recommendations on mitigations and solutions for barriers to cross-border data sharing which will be submitted to the European Commission for incorporation in the European Health Data Space legislative proposal."}
+{"text": "As a part of continuous destigmatization of mental illness and paople with mental disorders significant importance has media reporting, especially in modern times.Media reports about mental health (MH) are still an issue of a great discussion concerning their content especially in ethical matters. Many initiatives in different countries resulted in various changes in attitudes and influenced on this topic. But the image of mental illness as well as psychiatry in general are still burdened with the shadow of stigma.To show development of one of initiatives in Bosnia and Herzegovina (BH) supported by policy makers through the creation and broad distribution of recommendations for ethical media reporting about mental disorders.In 2019 Task Force appointed by both entities\u2019 ministries of health in BH developed an publication with recommendation for ethical reporting about mental health topics with special highlights on specific mental disorders . It was widely distributed to media and health institutions in the country and was officially adopted as the recommendation of the national Regulatory Agency for Media. Trough five rounds of educational workshops in 2019 and 2021 more than 150 media and mental health professionals were introduced with the publication as well as practical implementation of this recommendations (as is exercises of giving statement).In BH is developed very useful tool for more quality media reporting about MH topics as one of important ways for reducing the stigma and discrimination of people with mental disorders as well as promotion of good mental healthNo significant relationships."}
+{"text": "There has been an increasing focus on the importance of national policy to address population levels of physical inactivity. It has been suggested that the four ?cornerstones' of policy comprise: 1) national guidelines on physical activity levels; 2) setting population goals and targets; 3) surveillance or health monitoring systems; and 4) public education. The aim of the current paper was to analyse the policy actions which have addressed each of these elements for children and youth in England and to identify areas of progress and remaining challenges.A literature search was undertaken to identify past and present documents relevant to physical activity policy for children and youth in England. Each document was analysed to identify content relevant to the four ?cornerstones' of policy.Physical activity guidelines for children and youth have been in place since 1998 and reviewed periodically to ensure they reflect the latest scientific evidence. The setting of physical activity targets has focused on the provision of opportunities for physical activity, particularly through physical education (PE) in schools, rather than in relation to the proportion of children meeting recommended physical activity levels. There has been much surveillance of children's physical activity but this has been undertaken infrequently over time, by a wide range of organisations, and with varying inclusion of different domains of activity such as school PE, leisure time activity and active travel. There has only been one campaign in England targeted at children and their intermediaries (Change4Life), which was an obesity campaign focussing on dietary behaviour in combination with physical activity. Most recently an infographic supporting the physical activity guidelines for children and young people was developed, but details of its dissemination and usage are unknown.There have been many developments in physical activity policy in England targeted at children and youth. The area of greatest progress is national physical activity guidelines. Establishing prevalence targets, streamlining surveillance systems, and investing in public education would strengthen national policy efforts to reduce physical inactivity."}
+{"text": "Digital infrastructure and connectivity is layered and requires a number of defined viewpoints in order for safe data flow and use to occur. To address context specific challenges to support communication in health and social care, health informatics standards supporting interoperability are key. In this skills building seminar we will introduce participants to a standards based roadmap for interoperability. We will provide examples of projects and resources detailing the process of engagement to optimise system design for sustainability through a use case based approach."}
+{"text": "Intergenerational relationships have been present features in texts from the American literary canon that often problematizes the intersections of age and gender. This paper investigates how representations of intergenerationality provide the opportunity to explore the concepts of relationality and intersectionality through a feminist lens. Maierhofer\u2019s concept of anocriticism was used in in the analysis of Julia Alvarez\u2019 In the Time of the Butterflies (1994) and Yaa Gyasi\u2019s novel Homegoing (2016) to validate individual experiences of gendered ageing. This paper presents ways in which this particular intersection can be viewed as a potential site of resistance towards what it means to grow old as a woman. Placing literature in a cultural, social, and political context, traditional paradigms can be reconstructed and heteronormative assumptions of age and gender can be deconstructed by focusing on the individual narratives and their potential for resistance."}
+{"text": "Owens  In order to avoid misleading readers, the sentence on page 35448 \u201cThe same clean disposable plastic nozzles have previously been used by Babel and Rudolph,The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "Cell cycle checkpoints are surveillance mechanisms in eukaryotic cells that monitor the condition of the cell, repair cellular damages, and allow the cell to progress through the various phases of the cell cycle when conditions become favorable. Recent advances in stem cell biology highlight a mitochondrial metabolic checkpoint that is essential for stem cells to return to the quiescent state. As quiescent stem cells enter the cell cycle, mitochondrial biogenesis is induced and mitochondrial stress is increased. Mitochondrial unfolded protein response and mitochondrial oxidative stress response are activated to alleviate stresses and allow stem cells to exit the cell cycle and return to quiescence. These processes are critically regulated by several sirtuin family members, which are NAD+-dependent deacetylases. Because loss of stem cell quiescence results in the depletion of the stem cell pool and compromised tissue regeneration, deciphering the molecular mechanisms that regulate the mitochondrial metabolic checkpoint in stem cells will increase our understanding of tissue homeostasis and how it becomes dysregulated under pathological conditions and during aging. More broadly, this knowledge is instrumental for understanding the maintenance of cells that convert between quiescence and proliferation to support their physiological functions."}
+{"text": "For the study, the animals were observed exclusively by video cameras and no manipulations of the animals were necessary. Therefore, ethical approval for animal experimentation by an institutional animal care and use committee was not considered necessary in our jurisdiction.\u201dThe animal ethics statement on page 218 should be revised as follows (addition in bold): \u201cThis study was conducted on a commercial Austrian dairy farm in May 2019. The farmer gave his informed consent to the use of the accelerometer data and video recordings of his animals."}
+{"text": "A thread common to all disasters is the effect on human health that results when the health care infrastructure and delivery of health services are disrupted. This view has reinforced the importance of an all \u201call-hazards approach\u201d to preparedness, whereby disaster response planning incorporates principles common to all events and can be adapted to specific contingencies. Preparing for and responding to a disaster in long-term care (LTC) requires a broad view of multiple events that can disrupt daily life and needed services for LTC residents . This symposium will examine the effects of varied emergency events on older adults residing in nursing homes (NHs) and assisted living communities (ALCs) using quantitative and qualitative methodologies. The first presentation will discuss morbidity and mortality of NH residents exposed to Hurricane Harvey (Texas). The second is an investigation of NH direct care staffing during the recent Winter Storm Uri (Texas). The third presentation qualitatively explores the challenges of providing care to residents living with dementia during the COVID-19 pandemic, based on interviews with Florida NH and ALC administrators. The fourth quantitatively and qualitatively explores issues related to resident-to-resident contact restrictions in Florida ALCs. Finally, we will discuss the application of the 4Ms Age Friendly framework  to disaster preparedness in LTC. This symposium will provide information that can be used to develop or revise public policies to improve preparedness for and response to a range of emergency events in NHs and ALCs."}
+{"text": "Cultural barriers and prejudices of mental healthcare professionals may promote inequalities in the provision of care to immigrant population and have a negative impact in provided service quality.To identify barriers and facilitators of immigrants\u2019 accessibility to mental health services.A literature review has been made through PubMed database.Immigrants\u2019 accessibility to mental health services may be related to social insurance problems, inadequate knowledge about their health rights, inadequate knowledge of the local language, as well as the bureaucracy of Greek State which may complicate mental health examination and treatment. The challenges faced by mental healthcare professionals in terms of diagnosis and treatment of migrants include communication difficulties due to linguistic and cultural differences as far as verbal presentation of symptoms and illness behavior is concerned. Culturally competent mental health professionals should work to erase racism and prejudice, to be familiar with cultural issues and have adequate knowledge related to cultural groups, to learn the life story of each patient separately and encourage patients to explain how their illness affects their lives, promoting a trustful communication environment in the context of healthcare provision.Exploring the specific needs of migrants as well as assessing the degree of satisfaction from their access to healthcare services are essential to providing integrated mental health care for people from different culture.No significant relationships."}
+{"text": "The authors have provided the original correct data for 0.03 MPa.The Royal Society of Chemistry has asked the affiliated institution (Tianjin University) to investigate this matter and confirm the integrity and reliability of the new data and figures provided.An expression of concern will continue to be associated with this manuscript until we receive information from the institution on this matter.Laura Fisher10th November 2022RSC AdvancesExecutive Editor,"}
+{"text": "This presentation gives a real world and compelling picture of the abuse of older adults, with authors representing three different World Health Regions  each locating the problem within an area\u2019s historic and present societal treatment of older persons. An actual and emblematic case study of the abuse of an older adult will frame each presentation. Presenters will synthesize empirical data and research on the problem, explaining its usefulness and limitations as well as guiding frameworks utilized to address the problem, highlighting efforts of leading figures in each area or region who are addressing the problem and explaining existing policies and future initiatives to address the abuse of older adults. Dr. Eniola Cadmus will present perspectives on elder abuse in Nigeria. Drs. Noriko Tskudada and Asako Katsumata and will present perspectives from Japan. Drs. Farida Ejaz and Mala Shankardass will present perspectives from India. Dr. Georgia Anezberger will tie together the differences and commonalities within each region drawing upon a holistic and person-centered picture of the issue and problem of elder abuse."}
+{"text": "Medical educators and representatives of medical student associations in Australia and New Zealand are collaborating on an initiative on climate change and health in medical educationClimate change and environmental degradation are harming the health of Australians and New Zealanders and pose a serious challenge to our health care systems.Australia and New Zealand have accreditation standards for the education of the regulated health professions. For the medical profession in Australia and New Zealand, standards are maintained by the Australian Medical Council (AMC), including for the 23 university medical schools offering medical programs.A Working Group on Climate Change and Health was formed when medical educators from several Australian medical schools submitted a proposal to the Medical Deans Australia and New Zealand Medical Education Collaborative Committee that it explore the development of model learning objectives and learning resources regarding the impact of climate change on health.\u25aathe evidence for anthropogenic climate change and how this relates to the environmental determinants of health;\u25aathe impact of climate change on health;\u25aathe impact of climate change on the health system;\u25aathe environmental impact of the health sector and the elements of environmentally sustainable health care; and\u25aacreating change, both intra\u2010 and inter\u2010sectorally, through practice, advocacy and leadership.To examine current environmentally sustainable health care education, the Working Group searched the literature, reviewed teaching experience, and benchmarked against relevant courses developed for medical students, including those developed by students for their peers.The current 2012 AMC graduate outcome statements were mapped against these five areas to determine whether they were sufficient or whether amendments or new statements were required. A minimal change approach was adopted, mirroring changes to the accreditation standards adopted in 2018 by the United Kingdom General Medical Council.The Working Group considered that, by focusing on the environment as a determinant of health, climate change would be addressed. As sustainable health care in Australia usually refers to financial sustainability, to avoid confusion, the term environmental sustainability is used. The amendments proposed by the Working Group also introduce the concept that decisions taken today in the care of patients and populations should not compromise the health of future generations.The proposed amendments to the graduate outcome statements represent modest changes to the existing statements. Fourteen statements were identified: ten were modified to be aligned and four did not require amendment. Statements have been identified in all four AMC domains of practice. The Box 1Learning objectives regarding climate change and health in medical and health professional education that support each statement have been identified from recently published literature.The proposed graduate outcome statements and learning objectives were circulated to the Deans of all medical schools in August 2018 for further consideration and as a potential curriculum resource when considering curriculum review. Resourcing changes to curricula is a major hurdle to the successful implementation of change.https://www.amc.org.au/review\u2010of\u2010accreditation\u2010standards\u2010for\u2010primary\u2010medical\u2010programs\u2010medical\u2010schools/). A submission has been provided to the consultation by the authors.However, the suggested amendments will only be sustained and embedded into practice across Australia and New Zealand if they are adopted by the AMC and become part of the Standards for Assessment and Accreditation of Primary Medical Programs. A review by the AMC of the accreditation standards for primary medical programs opened in 2021 and the consultation process for this review continues in 2022 (MJA\u2013Lancet Countdown report aims to report an indicator describing progress on the inclusion of environmental sustainability and the health impacts of climate change in medical curricula in Australia.From 2023, the annual Medical educators internationally and other health professions in Australia have shown strong interest in this collaborative approach to aligning the education of health professional graduates with environmentally sustainable health care.Through this initiative, the collaboration of medical educators and medical student associations in Australasia has shared with all medical schools an approach to incorporating the health effects of climate change and the environmental impact of health care within medical curricula. The work is stimulating a dialogue within faculties and among medical students. The process recognises the essential contribution of the AMC Standards to secure and drive these changes to prepare medical graduates to practise environmentally sustainable health care. Amending the AMC graduate outcome statements to frame curricula change, and working through the network of medical schools, enables system level change in medical curricula. New patterns of disease are already emerging and medical practice is evolving as health care systems are challenged to become more environmentally sustainable; doctors and other health professionals are increasingly using their influence to help society transition to an environmentally sustainable future. Health educators have an essential part to play in preparing future doctors for these roles.The statements or opinions expressed in this article reflect the views of the authors and do not represent the opinion or policies of Medical Deans Australia and New Zealand Inc.No relevant disclosures.Commissioned; externally peer reviewed."}
+{"text": "Dementia is one of the major age-related societal challenges and causes enormous demands for persons living with dementia (PlwD) and their families. We do not understand the origins of this multifactorial syndrome and there is still no cure for dementia. New thinking by the exploration of paradigms has scope to improve knowledge about this complex condition. Social health can be understood as a driver for stimulating the use of cognitive reserve through active facilitation and utilization of the individual\u2019s capacities. It allows to slow cognitive impairment or to maintain cognitive functioning in old age and therefore seems to be a promising approach to a better understanding of the developmental mechanism of dementia.In this international symposium we therefore aim to explore the role of social health in the onset and progress of dementia. The first presentation will present a new framework on understanding social health in dementia. The second presentation will describe convoys of care in a family based culturally sensitive ADRD caregiving intervention reducing care burden and family conflicts. The third presentation reports on the role of immune system and neurodegeneration markers in the association between social health and cognitive brain aging in older adults. The final presentation presents newly derived results from a mixed research synthesis on underlying mechanisms of the interrelation of social health and cognitive functioning, elaborated by the international SHARED-consortium. Our discussant will synthesize the research findings and lead a discussion of future directions for research and practice to successfully fight challenges in dementia care."}
+{"text": "Implantable hemodynamic monitoring may be considered a milestone in the management of patients supported by LVAD because monitoring may dramatically improve the prognosis of these patients.18.See Article page Heart failure is an advanced disease with an increasing influence\u00a0on patient quality life, and the health system. These patients become increasingly frail and hemodynamically more unstable.These factors are major causes of repeat hospitalizations and influence a patient's life by being associated with poor prognosis, poor quality of life, and reduced life expectancy. In advanced and extreme conditions (Intermacs stage 2 or 3), these patients no longer respond to medical therapy and are often kept hospitalized to undergo intensive medical treatment with intravenous inotropic drugs while waiting to undergo heart transplantation or left ventricular assist device (LVAD) implant. During the past decade, more and more attention has been paid to the use of continuous remote implantable hemodynamic monitor (IHM) to prevent both rapid deterioration of the hemodynamic parameters of patients with heart failure (HF) and to monitor continuously the course of patients assisted with LVADs. There is an increasing interest in the use of a wireless IHM  in these patients because the CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients randomized trial demonstrated an advantage of this device in reducing significantly the rate of readmission compared with patients without a device .,CardioMEMS is positioned in 1 pulmonary artery branch during right heart catheterization and measures the pulmonary artery pressure and the filling pressures. It works according to the hypothesis that filling pressures will increase before other signs of decompensated HF occur. In addition, the usefulness of CardioMEMS is also likely to be found in patients with an LVAD. A decrease in filling pressures recorded by the device is frequent in situations such as hypovolemia and hemorrhage, whereas an increase in filling pressures is often associated with increased pulmonary congestion  and in case of cardiac tamponade. Moreover, patients with fixed pulmonary hypertension before LVAD implant can be carefully monitored to verify the trend of pulmonary pressure during LVAD therapy to consider the patient eligible for heart transplant.Lampert and TeutebergCardioMEMS represents a promising tool and should be\u00a0considered a cornerstone in the continuous monitoring of patients with HF and those assisted with an LVAD, especially\u00a0because it could improve their prognosis."}
+{"text": "As people age, they find themselves living similar lives to those around them. This concept is often referred to as linked lives. Linked lives explains that individual lives are often interdependent. This is due to various elements such as social and historical influences. These influences can imprint networks of shared relationships. Researchers have found that the first point of socialization as humans are social relationships with family and friends. However, while the connections of linked lives are often attributed to early life course trajectories, little research has evaluated the interdependency that is created with disabilities in later life. Life course disability research is a key factor of gerontology because a majority of older adults encounter disabilities within later life. This attributed disability can often forge bound and interdependence within people and their own social networks. This paper theoretically examines different perspectives of disabilities research and how it relates to the fundamental principles of linked lives. This paper highlights the gap in the current gerontological understanding of the later life links among older adults with disabilities. This theory paper provides the needed information for gerontologist focusing on older people with disabilities to be able to evaluate allocations needed for providing adequate social support and services tailored towards the needs of these interdependent lives."}
+{"text": "Highlighting the intersectionalities between different markers of diversity and health inequities encourages the reconsideration of normativities in public health (PH). We developed an open access collection of syllabi on the relevance of intersectionality and diversity in PH together with the Association of Schools of Public Health in the European Region (ASPHER).We developed the syllabi in a participatory, iterative process guided by transformative teaching pedagogy. We reflect on this process and how this can inform the enhancement of the syllabi themselves, as well as future curriculum development.We recruited a core group of 9 PH researchers, teachers and professionals from all career levels from participants of introductory session presentations in different settings . The core group met once a month for one year online, and each meeting took the form of co-working sessions in breakout rooms to develop the syllabi based on interest and expertise. We designed a qualitative online survey to evaluate and ensure the scientific rigor and pedagogical value of the syllabi. We invited critical and constructive input from ASPHER member school professionals with expertise in intersectionality, diversity or curriculum development in PH in terms of content and pedagogy.Drawing from the expertise of the PH community we combined diverse professional and cultural backgrounds, experiences from different career levels and PH education systems, as well as specialisation in the PH field. The transformative pedagogical approach was considered particularly valuable in strengthening competences such as reflexive strategies and self-, social- and global awareness which are key to teaching on diversity and intersectionality issues. The peer-review structure supports the uptake in PH education and a sustainable implementation. The collection will also allow PH faculty to diversify their pedagogical approaches.\u2022\u2002Inclusion of health inequities, diversity and social injustice issues is crucial in public health curricula, since an intersectional perspective is increasingly acknowledged in public health research.\u2022\u2002The syllabi collection will equip public health teachers of all career levels to develop their own course material on social identities and their significance for public health."}
+{"text": "Social isolation is an important predictor of mortality and morbidity in older persons. The increase in social isolation is often a result of major life events such as retirement, leading to the loss of social connections. The effects of the pandemic have exacerbated the loss of social connectedness. Measures to ensure social distancing have made technologies like voice and video calling, text messaging, and other phone mediated communication important resources for connecting people. Measuring social isolation often requires periodic administration of a paper survey instrument, like the Lubben Social Network Scale (LSNS). The approach was taken by Lubben for predicting a person\u2019s social isolation level typically involves looking at their general frequency of interactions with family and friends along with the specific frequencies of private, tentative discussions happening during those interactions. This paper explores the process used to develop a tool to measure social isolation continuously and automatically by using an older person\u2019s frequency and tone of telephonic conversations. We categorized a person\u2019s family and friends into three sub-categories based on the self-reported level of closeness shared with them. We then analyzed the person\u2019s conversation (content and tones). Lastly, we trained the deep learning model (Watson) using these captured tone values to determine the social isolation index of the individual. Our preliminary results indicate that we are able to correctly predict their degree of social isolation as judged by Lubben\u2019s scale using their phone conversations. This technology may be promising for the assessment and intervention of social isolation."}
+{"text": "To analyse the linked dataset between England and Wales 2021 Census/Census Coverage Survey and the Demographic Index (DI), would provide insights on quality and coverage, enabling improvements of using admin data to form population/ household estimates for future linkages and to evidence additional admin sources needed to capture the population.The DI is a composite dataset made up of several linked admin sources. Therefore, the linked output is complex, made up of clusters where individual sources within the clusters have been linked to the Census using the different available information across sources. To carry out the analysis, a flagging strategy has been designed to enable analysts to form cuts of the linked dataset that are specific to their research needs. High level research questions have been designed to provide fast paced analysis to inform the National Statistician\u2019s 2023 recommendation on the need for a future Census.Providing insight into how to improve the current linkage methodology of the DIHow we use the DI to construct Statistical Population Datasets Identifying the extent of over and under coverage in the Statistical Population Datasets, allowing development of an appropriate estimation strategy to more accurately estimate the populationThe results will also inform how we utilise linked composite data sources in the future, as we can share the lessons learnt in how we planned to use the data, including our flagging strategy verses the reality faced when undertaking the analysis.This analysis will inform approaches to using linked composite data in the future but also provide a wealth of knowledge including: informing linkage methods, defining the population estimation challenge and providing insights into how we deliver admin based population estimates."}
+{"text": "Middleton reflects on ASPHER\u2019s achievements related to ensuring a vibrant multidisciplinary public health workforce now that he is reaching the end of his term as President for that organization. Finally, Barnhoorn and Busse describe the plenary programme of the European Public Health Conference that will take place 9\u201312 November 2022 in Berlin. Topics range from financial protection and the European Health Data Space to health system performance assessment and health promotion.In this edition of European Public Health News, we will reflect on past achievements and how we build on those for upcoming activities. In my first EUPHA office column I describe the busy yet exciting autumn the EUPHA team has ahead of them and highlight some of our main plans. Kluge"}
+{"text": "Covid-19 pandemic has affected early career psychiatrists (ECP) and psychiatric trainees significantly. Child and Adolescent Psychiatry (CAP) specialists and trainees have a particular position in the pandemic as redeployments to adult units are possibly more disorientating for these psychiatrists normally working in paediatric settings. Redeployments and abrupt but potentially permanent changes to the delivery of service and training are explored via the Covid-19 and Early Career Psychiatrists survey which was prepared and disseminated by the EPA ECP Committee and the European Federation of Psychiatric Trainees (EFPT). The CAP related data from the survey will be discussed in this presentation and the implications on the future of CAP will be considered with particular emphasis on training.No significant relationships."}
+{"text": "A considerable percentage of Health Care Workers (HCW) have experienced psychological distress during the COVID-19 pandemic. Data from previous pandemics suggest that HCW might develop psychiatric disorders. Psychosocial and workplace measures can improve mental wellbeing of the MHW. As part of the program of the Hospital to give support to the HCW, five support weekly open dynamic groups have been carried out with HCW from the COVID Areas of our Hospital including the ICUIdentify recurrent contents in the group that express areas ofconcern Identify HCW in risk of develop a psuchiatric disorder and refer them to their apropiate level oThe sessions were carried out in a freely open group and the contents expressed in the sessions were recorded and analyzed ina narrative way. Special attention was given to the the more stresfull activities identified, to Signs of overload and to the ability to seek relief, as well as signs of disruption of personal life outside of work. Four sessions of 90 minutes, with staff of the same area were established and after these four sessions booster sessions was offered through continuity groups to members with need of more long term care as well as individual care.The recurrent areas identified were Concern about inadequite Personal Protective Equipment Concern about spreading the infection in their own families Need for relief and avoid double turn Uncertainty about the course of the illness Exposure to patients suffering and dyingHCW need nor only psychological support but also pragmatic measuresNo significant relationships."}
+{"text": "Caring for an individual with dementia may result in caregiver stress and burden , which can lead to detrimental health outcomes if not managed with effective coping skills and support . Access to support and psychoeducation is limited in rural and frontier communities, and solutions are needed to reach caregivers across sparsely populated regions. Project ECHO  is an evidence-based model designed to improve patient outcomes through healthcare provider education. The Wyoming Dementia Together Caregiver Network is the first of its kind to adapt the ECHO model for family caregivers of persons with dementia. This presentation details evaluation results of 24 session across 52 weeks (n=162). Results suggest that adaptation of Project ECHO for family caregivers is feasible and palatable. In addition, the adapted program shows promise for improving caregiver outcomes such as depressive symptoms and caregiver burden."}
+{"text": "Schizophrenia (SCH) and bipolar affective disorder (BP) are complex disorders that overlapping both in their clinical symptoms and certain familiar characteristics. They share some common characteristcs but there are also key differences. The frequency of overlapping symptoms between these diseases could give us more information about the current validity of the diagnosis based on existing diagnostic criteria. Similarities within and between these two disorders in the future, can possibly redefine greater reliability of diagnosis.The aim of the study was to investigate the frequency of overlapping symptoms between BP and SCH.The sample included 159 patients diagnosed with SCH and 61 with BP who were followed over a two year period. The research was conducted at the UCCS Psychiatric Clinic. Assessment of clinical symptoms and diagnosis were performed using a structured clinical interview (SCID I), a list of operationalized criteria (OPSCRIT), a scale for the assessment of positive and negative symptoms (PANSS), a scale for the assessment of manic symptoms (YMRS).The overall PANSS score was significantly higher in patients with SCH compared to patients with BP, but on the general psychopatology there are no significant differences betwen SCH and BP. Symptoms of mania are significantly more pronounced in patients with BP compared to those with SCH.Our results of overlapping of individual symptoms between SCH and BP can speak infavor of the theory of disease continuum. And can also help us in understanding symptoms and guide us to develop optimal treatment strategies.No significant relationships."}
+{"text": "Due to the increasing costs of Medicaid and Medicare and concerns about how these two programs fail to work together to deliver quality care, there has been a growing enthusiasm for integrated care programs. The Financial Alignment Initiatives (FAI), implemented by the Centers for Medicare and Medicaid Services (CMS) in 2011 and tested in 13 states were designed to test the impacts of a program that offers Medicare and Medicaid services under one organization to individuals who are dually eligible for both programs. Previous studies of the expansion of managed long-term services have generated considerable interest over the last two decades however, research results have been mixed. There is also limited information about the implementation of these efforts, as demonstrations have served varying target populations with very different intervention strategies. The lack of conclusive results means that states, now faced with decisions about continued implementation of these initiatives do not have good information to make sound policy decisions. The national evaluation of the FAI states did not include Medicaid costs. Our study is designed to gain a better understanding of Ohio\u2019s FAI MyCare Demonstration. This symposium provides data from a comprehensive impact analysis that examined both Medicaid and Medicare claims data using a difference- in- differences treatment and comparison analysis  and an in-depth process evaluation (using interviews with 487 participants) to gain an understanding of program effects. After reviewing results the symposium will discuss the future of these and other reform efforts to integrate Medicaid and Medicare services."}
+{"text": "Incarcerated peers play a critical role in the provision of care for incarcerated older adults. Peer counsel is part of the culture in carceral settings and official and unofficial caregiving is a necessity for visually, mobility, and cognitively impaired residents of these institutions. Due to their experiences of exploitation by the prison system and research institutions, most older incarcerated people are reluctant to trust community partners or correctional staff members who conduct research in correctional settings. Many older residents who are offered participation in research do not believe any real systemic changes will occur with the publication of findings. This presentation will draw on autoethnographic experiences of a peer health worker in the palliative care setting. We will describe the role that peer health workers play in guiding patients in decision-making around research and interrogate a model of partnering with peer health workers to engage incarcerated older adults in research."}
+{"text": "Voluntary dropouts before completion of inpatient psychiatric treatment are common in patients with dual disorders. However, the socioeconomic profile and family structure of patients who undergo a therapeutic program may correlate with their motivation and participation in the treatment received, as well as with their subsequent recovery.To evaluate the family typology of patients with dual diagnosis according to the degree of intrafamily cohesion and adaptability correlated with the prediction of therapeutic success and the risk of voluntary abandonment of hospital detoxification treatment.A total of 211 patients admitted to an inpatient psychiatric unit with substance use disorders were studied. Data were obtained from two sources: (1) interview of participants, (2) review of participants\u2019 medical records using the Maudsley Addiction Profile (MAP) and the Family Cohesion and Adaptability Assessment Scale (FACES III).The 127 subjects who completed the hospital detoxification program had significantly lower MAP and FACES III scores at baseline than the 84 subjects who did not complete the study. Those who did not complete the admission reported greater addictive severity and poorer family functioning. Family cohesion and adaptability measured with FACES III and addictive severity assessed with MAP positively correlated with successful compliance with the hospital treatment program for dual diagnosis patients.These findings reveal the association of psychosocial and family determinants and addictive severity with treatment completion and subsequent prognostic evolution. Recognizing these predictive characteristics may allow early identification of patients at higher risk of early dropout and prevent it by increasing the intensity of treatment."}
+{"text": "The retraction has been agreed because none of the listed authors \u2010 Mohsen Shoja, Ali Jafarpour and Shahin Aghamiri \u2010 fulfil the journal's criteria for authorship for the research published in the article. The article was submitted for publication by Mohsen Shoja without the consent of the legitimate authors or attribution to the legitimate authors.The above article, published online on 19 August 2019 in Wiley Online Library ( The retraction has been agreed because none of the listed authors \u2010 Mohsen Shoja, Ali Jafarpour and Shahin Aghamiri \u2010 fulfil the journal's criteria for authorship for the research published in the article. The article was submitted for publication by Mohsen Shoja without the consent of the legitimate authors or attribution to the legitimate authors.The above article, published online on 19 August 2019 in Wiley Online Library ("}
+{"text": "The authors regret that there was an error in the author list in the original article. Thomas Shean Yaw Choong should have been listed as a corresponding author. The amended author list and contact details are shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "This paper describes the creation of a comprehensive, linked Australian population spine including name and address history. This spine was developed using four national datasets and linked to multiple State and Territory datasets. This enabled the creation of linkage maps which could then be used to produce de-identified linked datasets.Initially the spine was created using identifiers from Medicare Consumer Directory (MCD), Social Services data (DOMINO) and National Death Index (NDI). The COVID-19 vaccination program covering almost the entire Australian population provided the opportunity to add the Australian Immunisation Registry (AIR).Probabilistic linkage was used to link MCD and DOMINO with linkage rates of 97.3%. MCD and NDI data were also linked probabilistically. Most AIR identifiers shared IDs with MCD and were linked deterministically with the remainder linked probabilistically.Based on the linkage results, unique identifiers were created for everyone appearing in at least one of the four datasets. Only unlinked records with very incomplete information in NDI and AIR were excluded. All unique combinations of names and addresses for each individual were added to the combined spine. This allowed us to cover the data gaps of each dataset and create a comprehensive history not possible when using a single data source.Linkage maps were created between all contributing data sources. State and Territory datasets were also linked to the spine using probabilistic linkage. These linkages were then reused for multiple projects.Linkage to the combined spine increased linkage efficiency  as well as increased linkage accuracy and a reduction in the transfer of personal information to provide a better service to the Australian research community."}
+{"text": "Today the maternal death of black women is four times than the maternal death of white women. A lot has been written about the physical health of black women during pregnancy and childbirth however the perinatal mental health of this group of women is less well researched. I wanted to investigate if black and ethnic minority women in the UK had the same access to perinatal mental health services.To explore how the access to perinatal mental health services vary between white British and non-white British women.A literature review was conducted. Papers were selected based on their focus on perinatal mental health service access and differences in access based on ethnicities. Most research focused on the perinatal mental health service access of white British and non-white British groups of women.The literature review revealed that black African, Asian and minority white women had significantly lower access to community perinatal mental health services when compared to white British women. It was also found that that black African, Asian and minority White women had a higher percentage of involuntary admissions to psychiatric hospitals when compared to white British women.The literature would suggest that there is less access to perinatal mental health for non-white British women. This suggested that the disparities that exist within perinatal physical health extend into perinatal maternal health.No significant relationships."}
+{"text": "The case for perinatal psychiatry as a subspecialty is strong. In the context of perinatal mental illness consideration has to be given to; differences in presentation, the need to account for mother and baby and the risks associated with inadequate treatment. Specialist services improve outcomes, reduce risks and save money. Despite the government's agenda of preventative healthcare, service provision has been inequitable across the UK. Here we detail the journey towards the development of new Community Perinatal Mental Health Services in Northern Ireland (NI).In NI the first embers of a perinatal service were ignited by Dr Janine Lynch approximately 15 years ago when she established a small community perinatal team in Belfast Health and Social Care Trust (BHSCT). Her commitment and foresight regarding training inspired others, resulting in high levels of interest among trainees. From this grew a dedicated group of consultants committed to supporting service development across NI.A multidisciplinary regional perinatal mental health forum was formed leading the development of a Northern Ireland Care Pathway in 2012. In partnership with women with lived experience, this forum led the bid for perinatal service development across the province.Following years of campaigning the need for services was recognised in both the Bamford Review (2012) and RQIA Perinatal Review (2017). A commitment for funding for specialist teams, across all five health and social care trusts, was outlined in the Mental Health Action Plan in May 2020. Funding was finally approved in January 2021.Significant work has gone into training to ensure there is a workforce ready to deliver services with focus on upskilling all professionals who deliver care to mums during the perinatal period. A competency framework has been developed to compliment this.It is important to recognise the support and commitment of many members of the college Perinatal Faculty throughout this journey.Community perinatal mental health services are at an exciting juncture in NI. Each of the trusts have made a commitment to the development of services under the co-ordination of the Public Health Agency. Several have progressed to recruitment of key staff with the aspiration for services to go live before the end of the year. There will be an overarching, integrated approach, co-ordinated by the new Regional Perinatal Network.As newly recruited consultants we look forward to working in partnership to address this long-standing health inequality and improve the outcome for women and their babies in NI."}
+{"text": "Although the primary goal of self-directed programs providing long term services and supports (LTSS) is to maximize choice and control for service recipients, such programs may also benefit family caregivers by compensating them for providing supportive services. This study draws on qualitative data from research supporting the RAISE Family Caregiver Advisory Council, finding that family caregivers themselves see the expansion of self-directed programs as a policy priority due to their need for financial security. The request for compensation was the strongest finding, with respondents highlighting the incompatibility of work with caregiving and their inability to rely on the existing paid workforce due to supply and quality issues; the consequences of this loss of earned income were reported as severe. Ultimately, respondents saw payment for providing care as an issue of fairness. This evidence supports the policy case for expanding access to self-directed programs that permit the employment of family caregivers."}
+{"text": "Stark geographic variation in later-life health outcomes suggests that local built and social environments are critical in shaping disease and disability, physical and cognitive function, and engagement in everyday life among older adults. This paper presents a community-engaged mapping project aiming to depict the uneven distribution of hazards and amenities relevant to cognitive aging across the United States. Living in neighborhoods with opportunities for social interaction , intellectual stimulation  and physical activity  may slow rates of cognitive decline and reduce risk for Alzheimer\u2019s disease. We assembled a community advisory board to translate research findings into a pilot website and interactive map that assesses neighborhoods for cognitive aging resources and amenities. The objective is to increase public awareness and inform public health and policy efforts to ameliorate community barriers and create more equitable opportunities to promote healthy aging in place."}
+{"text": "Young people who are care experienced are overrepresented in the criminal justice system and in general have worse outcomes in education than their non-looked after peers . Recent evidence has reported that children who have a social worker (classified as child in need or those with a child protection plan), but who do not enter the care system, can have worse outcomes in education than those children who are looked after . There remains little research evidence about the extent to which children with a social worker become involved with criminal justice services or how the age, duration and nature of formal social care service involvement may impact on education and offending outcomes. Researchers have been challenged by the lack of a sufficiently sized quantitative data, that crossed social care, education and offending domains. In work funded by ADR-UK, the present research project uses the newly linked DfE-MoJ administrative dataset to explore how different forms of formal social care services involvement impacts on education and criminal justice outcomes. Multi-level models will explore the role of formal child social care services amongst other multi-systemic risk and protective factors for education and offending. The presentation of his work will include preliminary statistics and insights into the challenges and potential further use of the linked dataset for researchers."}
+{"text": "The harmful use of alcohol is an important risk factor for the health of the population around the world. The incidence of alcohol dependence in women is increasing and both its consumption pattern and its consequences have unique characteristics.To present a literature review focused on alcohol use disorder with a gender perspective.Literature review.- Women use to start using alcohol sooner than men and this seems to be a risk factor to become addicted. - Due to physiological and psychological factors women experience more negative health effects from excessive alcohol use than men and it occurs at lower levels of use. - Psychiatric comorbidity associated with alcohol abuse such as anxiety and depression is more common in women and this in turn worsens the alcohol use disorder. - Alcohol consumption increases the vulnerability of women on several levels, including an increased risk of physical abuse.Alcohol abuse among women deserves special attention and a specific intervention focused on the gender perspective.No significant relationships."}
+{"text": "Affective Disorders are on a clinical continuum in which temperaments and other coexisting or emerging mental conditions may cover the role of risk factors or determinants of specific dimensional aspects of Bipolar Disorder. Overall, it is important to better characterize the psychopathological conditions associated to the clinical picture of an affective disorder in order to perform more personalized and integrated approach for the assessment, diagnosis and treatment of individuals with dual disorder.No significant relationships."}
+{"text": "Disruptive medical events such as pneumonia and hip fracture occur more frequently among older adults with dementia than those without dementia. It is not well-understood whether these events increase the risk of mortality to a greater extent for people with dementia (PWD) compared to people without dementia (PWoD). Using data from the Health and Retirement Study linked to Medicare claims, we estimated the impact of hip fracture and pneumonia on risk of mortality among 700 PWD and 12,438 PWoD using a Cox proportional hazards model. PWD had a higher risk of mortality both in the case of hip fracture  and pneumonia  compared to PWoD who experienced those events. This study provides evidence that dementia may increase mortality after a disruptive medical event and suggests that the clinical course of dementia may not always be slow and gradual."}
+{"text": "Psychiatry is facing major challenges during times of a pandemic as illustrated by the current COVID-19 pandemic. The challenges involve its actual and perceived role within the medical system, in particular how psychiatric hospitals can maintain their core mission of attending to the mentally ill while at the same time providing relief to general medicine. Since psychiatric disorders are the top leading causes of global burden of disease, we need to strengthen mental health care in the wake of the massive onslaught of the pandemic. While nobody can deny the need to act decisively and swiftly and ramp up intensive care readiness, we believe that the immediate availability of psychiatric care is just as important. In order to provide the best possible treatment conditions for people suffering from mental illness but as well for those suffering from the immediate pandemic\u2019s consequences such as isolation, reduced social interaction etc. instant and comprehensive provision is inevitable.No significant relationships."}
+{"text": "The current social distancing directives have heightened the need for older adults to seek remote healthcare solutions. Telehealth robots could support home health by carrying out on-demand tasks for diagnosis and treatment at the user\u2019s home through remote teleoperation by the healthcare provider. Acceptability of such telehealth robots by older adults is critical to their successful deployment. The overall goal of this research was to investigate older adults\u2019 perceptions and attitudes towards a telehealth robot supporting health checkups at home. Specific objectives were to explore potential healthcare use cases for the robot; identify facilitators and barriers to its use; and elicit design requirements for use in healthcare contexts. We interviewed 5 men and 5 women (ages 66\u201373) after they viewed a series of videos demonstrating the potential uses of the telehealth robot. The older adults had positive first impressions towards the telehealth robot and were generally open to the idea of using it for telehealth tasks. They conveyed a high level of trust with the robot, especially if it were controlled by a healthcare provider, yet expressed concerns with privacy and security of health information that would need to be addressed in the design of security protocols. They described added value of the robot\u2019s healthcare support while suggesting potential improvements to the robot. This research provided insights into older adults\u2019 perceptions and attitudes towards a telehealth robot as well as identified potential healthcare use cases that would inform the design requirements for telehealth robots in different home healthcare contexts."}
+{"text": "There is a significant global lack of policy action on consumption of sustainable diets. Application of political science theories such as theories of the policy process can help in understanding policy inaction. Applying these theories could provide a more in-depth understanding of how various influences on the policy process shape decision making for consumption of sustainable diet policy.A systematic review to examine application of eight key political science theories of the policy process to research on consumption of sustainable diets was conducted.The review identified no papers applying a theory of the policy process although 17 papers did mention or discuss influences on the policy process that are common elements within theories of the policy process. Most notably these elements were the influence of coalitions/networks, evidence use, narratives and framing, institutional and political system factors, and the importance of value and belief systems and socio-cultural norms. However, in most papers these influences were not examined in a detailed or in-depth way and often presented as suggestions for lack of policy action without the support of empirical data or application of any theory.Most research discussing policy inaction on the consumption of sustainable diets fails to utilise political science theories of the policy process, although a small number of papers include mention of or discussion of influences on the policy process. Application of political science theories could provide a more in-depth understanding of how different determinants might shape decision making at various points in the policy process. This could help identify key reasons for policy inaction on the consumption of sustainable diets and suggest possible ways to increase attention and action on the issue from policy decision makers.The online version contains supplementary material available at 10.1186/s12889-022-13717-5. A systematic review of the environmental and health impacts of dietary change in high-income countries concludes there are clear environmental benefits to modifying current dietary practices towards more sustainable choices, and that environmental benefits are largely proportional to the extent by which meat and dairy consumption can be reduced . HoweverA number of possible reasons for this policy resistance have been put forward, with studies citing the complexities related to contemporary food production and consumption as being the major challenge for policy makers in taking action . The difAlongside these suggestions there have also been some recent attempts in the literature to examine the processes occurring around the creation and implementation of policies in support of consumption of sustainable diets. These studies have largely focused on describing the competing interests involved in the governance of sustainable diets such as between government, civil society, consumers, and private sector stakeholders , 14\u201319. how these determinants might shape decision making at various points in the policy process. For example the powerful influence of food and agricultural industry lobbying on policy makers has often been cited as a key reason for a lack of policy action, and the production and use of evidence highlighted as a significant factor in shaping policy decisions. Yet there is no research which examines critical questions such as how and on whom do policy actors exert influence in the policy process? And, how do policy actors form successful coalitions to influence policy decisions, and how are policies on consumption of sustainable diets informed by evidence?While studies which elucidate potential policy determinants have a role to play in contributing to knowledge about why there has been so little policy action on consumption of sustainable diets, they do not provide any in-depth understanding of The questions outlined above are not isolated to the area of sustainable diets and indeed in areas such as public health and environmental policy there has been increasing attention on the need to utilise theories from other disciplines, particularly political science, to help conceptualise and make sense of the many interactions and variables involved in complex policy areas \u201331. As BDistinct from the \u201cwhat have we done\u201d and \u201cwhat should we do\u201d questions of policy evaluation and analysis, policy process research asks questions about the why and how of policy making. For example policy process scholars seek to find out why certain policy issues capture the attention of governments, how coalitions or groups influence policy making, and how different institutional arrangements and history shape policy. As Breton and de Leeuw  identifyMeet the criteria of a theory .Is indicative of an active research program via recent theoretical development and empirical applications.Has a relatively broad scope that seeks to explain a substantial portion of the policy processDe Leeuw et al.  describeFor the purpose of this review \u2018Theories of the policy process\u2019 will refer to the eight key theories identified by Sabatier as meeting the minimal set of conditions. These will be the theories that are used to guide the systematic review and analyse the current gaps and limitations of current research into consumption of sustainable diets policy.Given the large body of literature espousing the need for policies to increase consumption of sustainable diets for both health and environmental reasons, there is a clear need to understand why there has been such a significant lack of policy action on this issue at a global scale. Increasing sustainable diet scholars\u2019 knowledge of how policy works could help make their work more relevant and targeted towards addressing policy barriers which could assist with uptake of sustainable diet policies. One way this knowledge could be increased is through the use of theories of the policy process that examine reasons for policy inaction. This study thus aimed to systematically review the literature on consumption of sustainable diets to determine if any research uses policy process theories from political science to explain the lack of policy action and if so what are these explanations?The systematic review was undertaken to broadly align with the guidelines laid out in the PRISMA  statement . These gThis systematic review examines the literature on consumption of sustainable diets to ask the question: Do sustainable diet consumption studies draw on or apply any political science theories of the policy process to help explain policy inaction? A systematic electronic search was conducted in June 2021 to identify relevant publications from the following databases: CINAHL, ScienceDirect, Scopus, Web of Science, ProQuest, PubMed, PLoS and JSTOR. The reference lists for included papers were also searched for relevant studies. Search terms for all databases included the following: (climate change OR greenhouse gas OR sustain*) AND (food OR diet* OR nutrition* OR meat) AND (policy OR policies OR govern*). These search terms were chosen to help include papers that linked diets to sustainability and included some mention of policy. The searched fields were keyword, title and abstract where available. Searches were limited to English language studies published until July 2021.Titles (and then abstracts where available) were screened for relevance to consumption of sustainable diets policy. Citations were categorized into two groups: i) possibly relevant studies; and ii) excluded studies. The full text of all candidate studies  was obtained, using a low threshold for inclusion if there was any doubt. These publications were then screened against the inclusion criteria (see Table\u00a0N\u2009=\u20090).Applies a theory of the policy process to analyse sustainable diet consumption policy to help explain policy inaction (N\u2009=\u200917).Includes mention of or discussion of influences on the policy process consistent with elements from theories of the policy process to help explain policy inaction but does not directly apply a theory of the policy process  . One theA number of papers made mention of dominant economic or neoliberal political ideology acting as a barrier to policies to encourage consumption of sustainable diets. This often has interactions with other influences on the policy process. For example in their examination of how livestock industry practices influence sustainable diet policy in the US Rose et al.  discusseThere is a large literature demonstrating the gap between production of evidence and a policy making response , 56, 57 Theories of the policy process recognise the importance of the public mood, and the values and beliefs of stakeholders in the way the policy process operates. Almost all theories of the policy process include these elements with some such as the Social Construction Framework and Narrative Policy Framework more specifically focusing on these influences. A number of papers in this review commented on the way meat consumption is associated with socio-cultural norms and beliefs. Beverland  argued tThis systematic review found no papers that applied a key political science theory of the policy process to help explain policy inaction on consumption of sustainable diet policy. However, a small number of papers did discuss or mention some influences on the policy process that are regularly included as elements within theories of the policy process. Most commonly mentioned was the influence of coalitions or networks on the way sustainable diet consumption policy is being made, with a focus on power imbalances between stakeholders\u2019 ability to influence policy. The power of the food industry and/or farming lobby groups in exerting political influence was mentioned in a number of papers  argue, recognising that policy makers have a tendency to base judgements on their well-established value and belief systems and make decision making shortcuts based on emotions and familiarity with information is a key understanding required for stakeholders advocating policy change. Without a focus on the way policy makers understand and react to problems those seeking to create policy change will find it much harder to exert any influence, and instead find themselves only responding to sudden demands from policy makers for evidence-based solutions to pre-defined problems . Greaterhow they can best influence future policy making and the best strategies for different political and socio-cultural contexts. Given the ample evidence on the need for a global shift to public consumption of more sustainable diets to help mitigate climate change and other environmental impacts, future research that applies political science theories of the policy process to help understand policy inaction is urgently needed.Given that food consumption is a complex and interconnected policy area that encompasses a vast literature including food security and production issues, a limitation of this review is that it may have missed studies which have used policy theories to examine other food sustainability policy issues. Never the less this review highlights that in the area of consumption of sustainable diets there is the need for greater use of political science theories of the policy process to help analyse the lack of meaningful policy action from governments across the world. This could provide greater clarity on how policy decision making is being made in this area, where there may be increased opportunities for policy advocacy efforts and to identify where barriers to policy adoption lie. Without application of such theories studies may be more limited in their ability to explain a lack of policy action and elucidate which policy options would be most likely to gain the attention of decision makers. Further, a greater understanding of how the policy process is operating for consumption of sustainable diet policy could help inform policy actors on This review examined the application of theories of the policy process to research on consumption of sustainable diets to help explain policy inaction. No papers were found that directly applied a theory of the policy process although a small number of papers were identified that did include some discussion of key influences on policy making that are commonly included elements within theories of the policy process. However, these were often only examined in a rudimentary way and most papers lacked empirical evidence to support suggestions for policy inaction. A lack of application of theories of the policy process means studies are more limited in their ability to explain the absence of policy action or to recommend strategies and leverage points which would help achieve future policy change. Given the urgent need to shift consumers towards more sustainable diets to help mitigate climate change and other environmental impacts we recommend more research utilising theories of the policy process to help explain this lack of policy action and provide greater insight into how to achieve increased attention and policy implementation by decision makers.Additional file 1: Appendix A. Summary of key themes of policy influence extracted from the data."}
+{"text": "The context of infodemic and necessity of preventive behavior  demands for studies of the role of news in compliance including health priming . Especially important is a topic the effect of news about traditional and alternative medicine  their impact on subjective compliance.The aim was to study the relationship to medicine and subjective compliance in people with hypochondriac beliefs after priming by negative news about traditional and alternative medicine.122 healthy adults  were randomized to conditions ; then they read and appraised four news ; filled changes in emotions after reading , Cognitions About Body and Health Questionnaire , checklist of relationship to medicine and compliance.Moderation analysis indicates that in people with higher hypochondriac beliefs negative news about alternative medicine lead to lower readiness to use these methods but also to comply with any medical recommendations (p<.01). In people with higher hypochondriac beliefs negative news about traditional medicine decrease readiness to use it but not alternative medicine (p<.01).Negative news about formal medicine situationally decrease readiness to use it while negative news about alternative medicine situationally decrease any readiness for treatment. Research is supported by the Russian Foundation for Basic Research, project No. 20-013-00799."}
+{"text": "The citizen\u2019 awareness about environmental health risks has been identified as an important determinant of citizens\u2019 choices for the adoption of pro-environmental behaviors, but for its study simple measures to be applied in population studies are still lacking. The Environmental Health Literacy (EHL), is a recent sub-cathegory of health literacy, including functional, critical and interactive dimensions, that can be applied in surveys on environmental health risk perception and behaviors. The aim of our study was to elaborate and validate an EHL Index (ELHI) using data from a large multicenter survey carried out among 4778 students of different disciplines in 15 Italian Universities, with a self-administered anonymous questionnaire investigating risk perceptions, attitudes and behaviors towards environmental health risks and including a simple Functional Health Literacy test (FHL). From the original questionnaire of 56 items three sets of questions were selected to represent the three dimensions of health literacy  and their outcomes were compared with the answers about FHL test and pro-environmental behaviors. The Principal Component Analysis was used to select the most representative questions that were then grouped in the EHLI. The index was significantly associated with both FHL test and behaviors questions. The ROC curve indicated a satisfying accuracy and was used to identify the best cut-off for ELHI. In conclusion the constructed ELHI can be considered reliable and useful for further population surveys in similar target people to plan communication interventions about environmental health risks and their prevention through individual choices.An Environmental Health Literacy Index is proposed as simple measure to be used in population surveys.This measure resulted associated with behaviors and can be considered accurate and reliable."}
+{"text": "Two rapid communications in this issue report on attempts to gauge the extent of the recently reported increase in acute hepatitis cases among children in several countries in Europe and on other continents. They show that at the start of a possible outbreak with a yet unknown aetiology but features suggestive of an infectious cause, it is challenging to establish a sound evidence-base and to measure increase against a baseline of a syndrome or disease which is not under systematic surveillance and governed by standard case definitions. The short communications by van Beek et al.  and de KVan Beek et al. set out to establish the incidence for acute hepatitis of unknown aetiology in children over the previous 5 years (2017\u250021) as comparison baseline to assess the increase and included data from the United Kingdom (UK). They further investigate geographical distribution of cases up to 26 April 2022. This year, of 24 countries with experts responding, five of 17 identified an increase in probable cases of unexplained acute hepatitis in European countries and in one of seven non-European countries. An increase in severe cases was noted in five European countries.De Kleine et al. establish estimates of paediatric acute liver failure (pALF) registered by specialised liver centres within the European Reference Network on Hepatological Diseases over 3 previous years (2019\u250021) that fulfil the definition of the Paediatric Acute Liver Failure Study Group [The results from these surveys show that the condition remains rare also in 2022. They do not provide a uniform picture but indicate that while in some countries or centres there are signals for an increase in cases, this is not evident in others. As examples of the former, Marsh et al. described the clear signal seen in Scotland and the initial investigation and clinical details of the first Scottish cases on 14 April .Despite acknowledged limitations, the two Rapid communications in this issue provide some useful information in the form of \u2018best available evidence\u2019 at this moment in time. International collaboration is needed to support robust and timely epidemiological and clinical investigations to establish if there is an excess of cases of severe hepatitis of unknown origin that demands targeted studies to determine the aetiological agent. Over the coming weeks we hope to see more data and results from ongoing investigations that should help to fill the present gaps."}
+{"text": "In the published article, there was an error in the Funding statement. This work was not supported by the Humanities and Social Sciences youth project of Liaoning Provincial Department of Education (WQ2020012). The correct Funding statement appears below."}
+{"text": "The relationship between behavioral changes and the menstrual cycle in women at a reproductive age has been investigated in several studies; women during every menstrual cycle experience noticeable changes in levels of sex hormones which are consequently reflected on their mood and behavior. The relationship between the menstrual cycle and the emotion recognition processing has been also studied.The aim of this study was to examine if differences exist between women with Premenstrual Dysphonic Disorder (PMDD) and women without PMDD in Emotion recognition processing across menstrual cycle.We examined 26 women with a PMDD and 30 women without PMDD, who have both visited the Mental Health Centre . Women were clinically interviewed (DSM-V); also the Emotion Recognition Task (ERT) was administered in the luteal and the follicular phase.Women with PMDD showed significant differences in emotion recognition depending on the the luteal and the follicular phase (according to estradiol and progesterone level) whereas women without PMDD did not present significantly different responses to the emotional stimuli.Our findings suggest that there is an effect of PMDD on emotional facial recognition across the two phases of the menstrual cycle. Thus, the importance of incorporating ERT in the formal clinical examination of PMDD is highlighted.No significant relationships."}
+{"text": "Family care partners face increased and more complex caregiving demands at the time of hospital discharge for persons living with dementia. This study examined family care partners\u2019 needs for preparation and factors associated with the degree of preparation for caregiving. Care partners who were younger , demonstrated anxiety  and depression , and were caring for a person in pain  had lower scores on the Preparation for Caregiving Scale. Care partners described the least preparation to care for the patients\u2019 emotional needs  and deal with the stress of caregiving . Content analysis of nurses\u2019 transitional care notes converged with these findings, while also describing a lack of preparation to advocate for information from medical providers. Findings suggest the need to attend to the psychological and informational needs of care partners, while considering patient well-being and comfort."}
+{"text": "A feeling of restrictiveness is often associated with coercive practices, such as seclusion or restraint. In addition to these obvious procedures more subtle practices can also feel restrictive. Its registration and monitoring is of special importance in forensic mental health care since feelings of restrictiveness can lead to adverse events like increased aggression and suicidal intentions.To enable the registration of the experience of restrictiveness in forensic mental health settings in Germany, the Forensic Restrictiveness Questionnaire was translated from English into German.Method: We used the TRAPD approach presented by Harkness (2003). This approach combined the expertise of professional translators and clinical experts and enabled adaptation at an early stage. The developed version underwent a cognitive pretest with a small patient sample to check for comprehensibility and interpretation of the questions in line with the original authors intention.A preliminary translation of the FRQ was developed. Translators combined their expertise from linguistic and clinical practice as well as their knowledge about English and German culture to produce a translation as close as possible to the original questionnaire with necessary adaptations. Remaining uncertainties, e.g., regarding comprehensibility of long phrases or uniform interpretation of certain wordings or questions, were addressed in the cognitive pretest with patients. The version produced can be used for validation.Conclusion: The TRAPD approach produced a comprehensible and well adapted German translation of the FRQ. This version underwent a cognitive pretest by a small patient sample and is now ready for validation.No significant relationships."}
+{"text": "Physical inactivity accounts for as many as 5 million deaths per year globally but has yet to be addressed effectively by most governments or the World Health Organization (WHO).Reasonable evidence for effective strategies exist, and several countries have implemented consistent public health policies and programs that have increased population prevalence of regular physical activity. In 2018 WHO launched a Global Action Plan for Physical Activity (GAPPA). However, most countries do not have effective public health policies in place for physical activity. Evaluating the history of national and global policies to understand how some countries have developed sound public health programs for physical activity while most have not requires monitoring and evaluating policy, programmatic, and perhaps even research indicators for physical activity. Only recently have there been systematic efforts to do so.Several key questions about physical activity policy, starting with an examination of the evolution of public health physical activity policy and policy research from when it was first explicitly identified in the 1990s to the present will be addressed. Key recommendations, global statements, research reviews and action plans will be summarized to provide a clear picture of the evolution of this important aspect of public health. Evidence on the implementation of policy at national and global levels will also be reviewed. We will examine whether it feasible to track physical activity policy at the global and country levels, if the existence of ?good? physical activity policy is associated with less physical inactivity, how policy indicators may be used for advocacy and guidance.Physical activity policy for public health is a relatively new concept that has evolved significantly in the last three decades with formal national and global policy statements, research, and evaluation efforts all increasing markedly since 1990.Despite notable growth in policy research and the development of sophisticated national and global policies and action plans, implementation of effective national and global policies and programs for physical activity remains limited."}
+{"text": "The traditional \u2018one size fits all\u2019 model within secondary care mental health (MH) settings of regular appointments scheduled by a clinician at defined intervals isn't always responsive to an individual's changing needs. Previous reviews have shown significant levels of patient and clinician satisfaction with Patient initiated models of review in a variety of healthcare settings but its use within secondary care MH settings has been relatively limited. We describe the development and implementation of a Patient initiated follow-up (PIFU) pathway within MH services in NHS Greater Glasgow and Clyde (GG&C).The pathway was developed by a small working group of clinicians with input from local management and eHealth colleagues with an emphasis on the principles of Realistic Medicine. There was input from peer support workers and the Mental Health network, a local service user organisation, into the development of the pathway. The pathway underwent a \u2018test of implementation\u2019 within three adult CMHT's with support from the development group. Feedback from the test sites was used to modify the pathway and ultimately support the wider rollout of the model across all seventeen CMHTs within NHS GG&C over the course of 2021. Formal evaluation of the pathway, including patient and clinician satisfaction, service utilisation as well as safety measures, is due to be undertaken at 12 months after full implementation.The tests of implementation identified a range of factors that needed to be considered as part of the introduction of a PIFU model into MH settings.Patient choice and shared decision making along with other clinical factors such as level of insight, availability of other supports, shared risk assessments and current clinical need were identified as relevant patient related factors. Clinician related factors included concerns about applicability within MH settings, perception of risk, increase in workload and appropriate identification of suitable patients. Regular meetings between the clinicians in the test sites and members of the development group as part of the implementation process helped address clinicians concerns and ultimately supported uptake of the model.Our experience highlighted the potential for a personalised approach to care planning in empowering patients have a more active role in the way they access services as part of their recovery journey. It also highlighted patient and clinician related factors that need to be considered for a successful adoption of the model."}
+{"text": "This clinical guideline is intended for use by orthopedic surgeons andphysicians who care for patients with possible or documented septicarthritis of a native joint (SANJO). It includes evidence and opinion-basedrecommendations for the diagnosis and management of patients with SANJO."}
+{"text": "This presentation provides an overview of factors that can cause symptom exaggeration and/or fabrication in chronic pain. It will explore how symptom and performance validity tests can be applied to chronic pain in the context of a malingering framework and the problems of implementing this in the UK through a case example.No significant relationships."}
+{"text": "A quality improvement project was undertaken to counteract obesity in patients with mental health morbidity. The exponential trend of increased antidepressant prescribing  has created a trend towards weight gain in patients. An audit of the Serious Mental Illness (SMI) register and depression registers was conducted in a population of 591 patients. Those patients identified as obese were offered referral to the local authority weight management services.Patients have a body weight and BMI calculation with their twice yearly mental health and medication review and those whose BMI met the obesity criteria were offered referral to the local authority for 12 weeks weight management services.Of the SMI and depression register 189 (32%) patients met the criteria for referral to the weight management program. Of these 154 (81%) patients accepted the local NHS weight management program, 35 (18%) of patients declined the NHS weight management program.Weight gain is a known side effect of antidepressant medication SSRI and SNRIs and Anti psychotic medication resulting in increased risk of obesity and cardiovascular and metabolic disease. The QI program was undertaken to counteract these changes with referral to weight management services to address the weight gain the patients were experiencing.This quality improvement service was done to help patients across three surgeries lose weight in an effective and educational manner. We found a high rate of acceptability of referral to weight management services when offered as patients themselves were aware of the weight gain. A review of positive changes in the BMI after referral to the weight management program will be undertaken at 6 and 12 months to evaluate its acceptability and effectiveness. We advocate sensitive counselling of the risks of weight gain and regular monitoring of body weight throughout the span of the prescribing of these weight gaining agents."}
+{"text": "Teaching Point: Infected urachal cysts are a rare cause of abdominal complaints and can be accurately diagnosed by abdominal ultrasound and computed tomography (CT). An abdominal ultrasound revealed a thick-walled heterogeneous cystic mass surrounded by fat stranding anteriorly in the midline on top of the bladder. The bladder dome was thickened, and the lesion was focally invading the left rectus abdominis muscle . The primary imaging modality for urachal cysts is ultrasound revealing a cystic mass in the midline anteriorly between the bladder dome and umbilicus. CT or MRI may be subsequently employed to help reach a definite diagnosis. Infection represents the most common complication of urachal anomalies and may present with nonspecific symptoms. Imaging findings that should prompt consideration of infection in the setting of an acute clinical presentation include the presence of a urachal remnant with complex echogenicity at ultrasound and heterogeneous attenuation of the content and contrast enhancement of the thick wall on CT. As in this case, it can be challenging to distinguish an infected urachal remnant from a malignant urachal neoplasm. Treatment consists of antibiotic therapy followed by complete excision to mitigate the 30% risk of infection recurrence and potential malignant degeneration ["}
+{"text": "The impact of racism on health and the quality of health care services for racialized patients have been the object of prior research. The experiences of racialized medical students and physicians, who operate in a field of tension between natural sciences and practical application and between a \u2018medical habitus\u2019 and exclusionary discrimination, have hardly been examined to date. The education of (future) physicians is an especially fruitful research area in the context of the study of institutional racism in the health care system, as informal everyday experiences come together with formal knowledge and normative learning.Based on expert consultations and preliminary interviews with civic stakeholders, teaching and learning materials in German medical studies were randomly sampled and used as a starting point for qualitative guided interviews with physicians and medical students in Germany who are themselves affected by racism. The first steps of the thematic analysis of these interviews are reflected upon and further developed in focus group discussions with the interviewees.The study is particularly concerned with the question of how certain dimensions of racism in the health care sector are related, and how racist normativity appears in this context. This is concretized in the relationship between formal and informal medical curricula as well as in the interweaving of everyday experiences and teaching materials.There are different dimensions of relation between a hegemonic normativity in the medical curriculum and the everyday experiences of racialized medical students and physicians in Germany. Politics, faculties, publishers, and civic society may be the target of several recommendations for action regarding those diverse dimensions, e.g. the line between omission and stereotyping of several patient groups.\u2022\u2002Hegemonic normativity in German medical education is an important and challenging issue. There are several institutional levels of medical knowledge reproducing racism in the health care sector.\u2022\u2002Both racialized physicians and racialized patients are affected by symbolic and material forms of racism in the German health care system, which are interweaving and crucial on diverse levels."}
+{"text": "The Global Council on Brain Health (GCBH) convened experts from around the world to examine the impact of cardiovascular risk factors on brain health. GCBH issue experts carefully considered how high blood pressure, diabetes and stroke, as well as lifestyle choices such as diet and exercise, influence brain health in adults age 50 and over. The GCBH concluded that the best evidence to date shows us \u201cwhat\u2019s good for the heart is good for the brain.\u201d Their consensus puts powerful tools in the hands of adults wanting to protect their brain as they age. The GCBH adopted 10 recommendations for individuals to incorporate into their lives to keep heart and blood vessels healthy and reduce the risk for cognitive decline and dementia. These recommendations and 16 practical tips are provided in the final report. Liaisons from numerous civic and nonprofit organizations with expertise in heart and brain health helped develop these recommendations for adults 50+ and their health care providers."}
+{"text": "Building upon the Scottish Safe Haven Network\u2019s (SSHN) collaborative experience to develop an exemplar dataset on Scottish national level laboratory tests within the SSHN. To test the feasibility of a federated safe haven network in Scotland for clinical laboratory data using existing federation solutions.Considerations were given to the clinical tests that are being commonly used across Scotland. An investigation of laboratory data structure was conducted using SQL with the assistance of White Rabbit which captures the metadata information from each safe haven. Data heterogeneity or commonalities were investigated in detail in R. We examined the inter-relationships among clinical laboratories from different regions of NHS Scotland. A common data structure was proposed to facilitate the sharing of clinical test results. We investigated multiple existing federation solutions to streamline access to data across the SSHN.A dataset of all laboratory tests for patients registered with the Scottish Health Research Register and Biobank (SHARE) from laboratory data sources within the network  were developed. An open-source toolkit that includes SQL scripts to harmonise laboratory data from multiple safe haven and R scripts to conduct heterogeneity investigation to streamline the sharing and the analysis was created. We have shown a working model for federation within Scotland for the first time with the view to expand into more routine projects. The project has developed a systematic concept mapping of data available across the SSHN to aid cohort discovery.The exemplar national level laboratory data together with the toolkit will help provide researchers with information such as which data are available to access. It will also support and improve national-level research studies at a faster pace. The work has demonstrated the feasibility of a common process for federated data discovery and sharing across the SSHN."}
+{"text": "Establishing broad spectrum of new mental health services in whole Bosnia and Herzegovina (BH) existing mental health laws in both entities needed to be upgrade according positive results of the mental health reform in the country. Previous laws were exclusivelly oriented on protection of rights of the people with mental health disorders in (mainly) psychiatric institutions and were progressive and new in the period of their implementation (2001-2004).Since 2010 main reform processes had direction to community mental health care and developed positive movement with implementing new services oriented to patients and their needs/continuity of care. For example case management and occupational therapy are part of daily work in whole country and standards established trough accreditation process lead to uniform approach in community work in the area of mental health.Comparative analysis of laws in BH concerning mental health.Carefuly and good preparation for pronounce of new Mental Health Law both in Republic of Srpska and Federation of BH were supported from both entities  and they are formaly supported in both entities parliaments in 2020 (prolonged since COVID-19 situation). In both laws is more emphasised role of commnity services, prevention, and post-hospital rehabilitation as continuity of care. Book of rules that follow the laws will be establish no longer than the end of 2020.New mental health laws in BH are path to better protection of mental health of all population in BH and rights of our patients\u2019 recovery."}
+{"text": "The youth and adult criminal justice systems in England and Wales disproportionately draw in individuals from ethnic minority backgrounds  and those who have been in care as children . While evidence suggests that there is likely to be considerable overlap between these two groups , there was previously little in the way of quantitative data to explore this. The newly linked MoJ/DfE datasets have provided a unique opportunity to investigate the intersections between ethnicity, care experience and justice systems involvement for the first time. This paper will draw on findings from an ADR UK (Administrative Data Research UK) Fellowship utilising the newly linked datasets. It will outline to what extent ethnic minority care-experienced people are over-represented in justice systems. It will also explore the nature of this involvement including offence type, frequency, and disposals. The findings will be contextualised within the wider literature on racialisation  and criminalisation in care  to enable a broader understanding of the issues. The paper will outline the challenges of conducting interdisciplinary research using linked data from across government departments as well as the possibilities for future research."}
+{"text": "Comparatively little is known about the ability of physical activity to improve or maintain cognitive function in older adults. Our Midwest Roybal Center uses social/behavioral theory to promote engagement in physical activity in order to improve this outcome. In 2019, we received funding to establish a Multimodal Connectomics Core that enabled investigators to examine concurrent changes in cognitive function and brain connectivity by providing access to fMRI imaging. The Connectomics Core enabled investigators for the first time to examine cognitive function and changes in brain connectivity simultaneously by providing access to fMRI imaging as well as MRI data storage and data analysis. It enabled measuring of standardized participant outcomes selected from the NIH toolbox. This Symposium describes findings from the first three completed pilots and discusses their implications for the field. The first pilot by Bronas examined effect of a 6-month home-based walking program in people chronic kidney disease on cognitive function and intervention induced neuroplasticity compared to usual care. The second pilot by Marquez adapted the Fit & Strong! program to test the combined impact of physical activity and interactive health education for managing mood on cognitive function among older adults with depression. The third pilot by Bhatt examined the effectiveness of 4 weeks of exergaming combined explicit cognitive training on behavioral measures of fall-risk  and their associations with brain integrity measures. The discussant will initiate discussion based on outcomes of these pilots and future directions for developing them into larger studies or clinical translation."}
+{"text": "The project aimed to test an alternative method to estimate the number of duplicate responses in the 2021 England and Wales Census. The method utilises information from all census records instead of relying on samples. It requires less clerical review than the original inverse sampling method used for overcount estimation.We used the Splink implementation of Fellegi-Sunter to match the 2021 Census to itself. The resulting linked dataset was filtered to retain only the top scoring record pair for each unique census record, giving a final dataset of around 71.5 million record pairs. These pairs were divided by score into 13 homogeneous buckets. Random samples of 1000 pairs per bucket were clerically reviewed to determine whether each pair was a true duplicate or not. The clerical results were used to assign an estimated probability of being a duplicate to each bucket and hence to every census record within the bucket.A dashboard was created which contained percentages of duplicates by region and \u2018overcount group\u2019 for the original and alternative methods. This enabled us to view the data side by side and create visualisations to aid analysis. The alternative method had higher average duplicate percentages in overcount groups for communal establishments and was also higher for 9 out of 10 regions in the armed forces overcount group. We found that both the original and alternative methods of overcount estimation followed the same pattern in terms of minimum and maximum duplicate percentages except for those in communal establishments where minimum and maximums were both higher than the original method. Additionally, the minimum was marginally higher for the student and armed forces overcount groups for the alternative method.On initial comparison, estimated rates of duplication resulting from the different methods are comparable. We plan to conduct further analysis on the similarities and differences of the two methods, and research whether the new method could be applied to estimate the duplication rate in other large datasets including administrative data."}
+{"text": "Digital home assistants  hold great potential for supporting older adults in completing a wide range of daily living activities and improving their overall quality of life. As these devices can wirelessly connect with other smart technologies to increase their capabilities , digital assistance technologies may benefit older adults who need support within their home such as those living with mobility disabilities. However, research is needed to better understand the facilitators and barriers of using these technologies by these individuals, as well as the resources that best support their onboarding and continued use. To assess the potential efficacy of integrating smart and connected technologies into the homes of older adults with mobility disability, we are conducting a field trial to understand how best to introduce these devices and support their use. Design considerations and initial findings are discussed."}
+{"text": "Few studies have explored the Central Nervous System (CNS) infection illness trajectory among older persons with dementia in sub-Saharan African (SSA) settings. This study explored the Caregiver\u2019s perspectives on the Central Nervous System infection illness trajectory among the older persons with dementia in Northern Uganda.This was a qualitative study conducted in Lira District northern Uganda in March 2022 amongst purposively selected 20 caregivers of the older persons aged 50\u2009+\u2009years with a positive history of CNS infection and later life dementia. Data were collected using an in-depth interview guide. Audio recordings and field notes of the interviews were undertaken. The interviews generated data on the CNS infection illness trajectory from onset to the current demented state of the older persons. The audio-recorded interviews were transcribed verbatim before manual reflective thematic analysis.Older persons with a positive history of CNS infection illness and later life dementia in rural northern Uganda presented with symptoms of early life CNS infection illness ranging from neck pain, back pain, chronic headache, and fatigue. There were also manifestations of comorbidities particularly road traffic accidents involving traumatic injury to the head, neck, and spine, high blood pressure, chronic headache, and or their medications in the older person\u2019s trajectory to later life dementia. A plurality of healthcare which included both formal and informal healthcare medicines was sought and utilized for the treatment and care of the CNS infection illness and dementia by the older persons amidst improper diagnosis and mismanagement.Older persons with early-life CNS infections illness and later-life dementia were reported to present with symptoms including neck pain, back pain, chronic headache, high blood pressure, and fatigue. The reported symptoms of CNS infection illness may be intertwined with co-morbidities particularly traumatic injury involving the head, neck, and spine, high blood pressure, and chronic headache. Healthcare professionals should integrate routine screening of older persons for the history of CNS infections, chronic headache, high blood pressure, trauma to the head, neck, and spine, and dementia and early treatment. Dementia is a syndrome in which there is deterioration in cognitive function beyond what might be expected from the usual consequences of biological aging . More thCentral Nervous System (CNS) infections have for decades been epidemiologically and sometimes mechanistically associated with dementia among older persons globally \u201311. InfeThe CNS infection may be spread from blood-borne infections, infections at sites adjacent or contiguous to the CNS such as the mastoid, sinuses or middle ear or from primary infections at more remote anatomic sites such as lungs, and heart, skin, gastrointestinal tract, or the kidneys , 12. CliTowards a Dementia Plan \u2013 A WHO guide, guidelines on risk reduction of cognitive decline and dementia, mdementia handbook, WHO mental health gap action program (mhGAP) and Towards a dementia-inclusive society \u2013 WHO toolkit for dementia friendly initiatives have insufficiently addressed CNS infection\u2019s considerations in dementia risk reduction, prevention and care.In Uganda, there is an increasing population of older persons , 19 who Worse still, fewer previous studies investigated the CNS infection illness trajectory among older persons with probable or possible, dementia especially from sub-Saharan African (SSA) context. The few available previous studies in the SSA focused on the prevalence and risk factors for HIV-associated neurocognitive disorders including HIV-associated dementia , 21\u201323.An CNS infection illness trajectory is defined as the occurrence of factors, events, signs, and or symptoms with or without causative\u2014outcome roles in the past and present life history of the older persons with possible or probable dementia. Investigations into CNS infection illness trajectory among older persons with probable or possible dementia are critical in risk reduction and prevention of severe forms of dementia through early screening, and diagnosis of persons with signs and symptoms of CNS infection illness.Lira district located in northern Uganda has an increasing population of older persons . HoweverThis study therefore explored CNS infection illness symptoms among older persons aged\u2009\u2265\u200950\u00a0years in Lira District northern Uganda with positive history of CNS infection illness who screened positive for probable or possible dementia with the BCSD. Notably, the definition of older persons from a seemingly early age of 50\u00a0years was used in a sister quantitative study upon which this qualitative study was piggybacked meant for screening possible or probably dementia including early onset cases as early as 50\u00a0years.This qualitative inquiry was prompted by a preceding quantitative survey which found a significant association between possible or probable dementia and positive history of CNS infection illness among older persons aged 50\u2009+\u2009years in northern Uganda. We conducted a descriptive qualitative study . The desThe study was conducted among the key informants who were the caregivers of the older persons aged\u2009\u2265\u200950\u00a0years with probable or possible dementia [from the Brief Cognitive Score for Dementia scale (BCSD) screening] and a positive history of CNS infection illness. Caregivers are defined as the spouse or relative providing general home-based care for the older persons with dementia by providing support in form of house cleaning, cooking, bathing, washing, shopping, grooming, walking support and or accompaniment to the healthcare facilities among other activities of daily living. We used the maximum variation purposive sampling method to recruited 20 participants who lived the experience of being caregivers of the older persons with the phenomena under scrutiny (i.e. CNS infection illness symptoms trajectory among their relatives or partners with probable or possible dementia). This being a qualitative key informant study the variations considered during the purposive sampling of the key informants were the caregiver\u2019s age, sex, educational level, and relationship with the older person with possible or probable dementia under their care rather than the CNS infection illness characteristics among the older persons with dementia Table . Only onThis qualitative study was piggybacked on the quantitative household survey which investigated for the association between CNS infection illness and dementia among older persons in the study setting and helped to identify participants with both positive history of CNS infection illness using a CNS infection questionnaire and probable or possible dementia using a Brief Cognitive Score for Dementia scale. From the preceding quantitative survey analysis, a total 49 older persons met the criteria of having possible or probable dementia and positive history of CNS infection illness and it provided the sampling frame for the selection of key informants for the qualitative research. The preceding quantitative household survey of older persons in northern Uganda for prevalence of dementia and its association with CNS infection illness was conducted in March 2022. It involved a sample of 434 older persons aged 50\u2009+\u2009years in Lira district northern Uganda. The quantitative household survey found a high prevalence of possible or probable dementia (23%) among older persons aged 50\u2009+\u2009years in northern Uganda. It also found a significant association between possible or probable dementia and positive history of CNS infection illness among older persons aged 50\u2009+\u2009years in northern Uganda at both bivariate and multi-multivariate analysis. The quantitative survey paper is under peer review for journal publication.The selection of the study setting for this descriptive qualitative study was informed by a preceding quantitative household survey of older persons in the aforementioned 20 villages in Lira district northern Uganda for dementia among older persons and its association with CNS infection ilness. Older persons who were found to have a positive history of the CNS infection illness and dementia from the quantitative household survey were eligible for this qualitative study. The Community health extension workers (CHEWs) also known as Village Health Teams (VHTs) who enlisted the households with older persons aged\u2009\u2265\u200950\u00a0years for the quantitative household survey also helped to identify and locate the residential addresses of the older persons with positive history of the CNS infection illness and later life dementia.The VHTs are community health volunteers who maintain registers of all residents including older persons in their respective villages . The VHTWe conducted the face-to-face in-depth interview using an interview guide. The interview guide comprised of open-ended questions to elicit the participants account of the CNS infection illness trajectory among older persons with probable or possible dementia who were their care receivers. The interview guide was developed by the research team members informed by literature. The items in the guide were pre-tested among caregivers of the older persons who were not included in the study and improvements were made accordingly. The interview guide had three sections. The first section comprised of the socio-demographic characteristics of the study participants. The second section comprised of items for confirming the prior CNS infection illness diagnosis or the history of CNS infection illness, the characteristics and hence the types of the CNS infection illness and dementia among the older persons. The third and last section of the guide comprised of items on the CNS infection illness trajectory from onset to the current demented state of the older persons. The Research Assistants with nursing and midwifery educational background who were trained on the research protocol asked the questions in an open-ended format to elicit responses and conversations for each section of the interview guide. The interviews were conducted in the local language Luo. Interviews were conducted in private spaces within the participants\u2019 homes. The interviews lasted for 30 to 60\u00a0min. Interviews were audio recorded. Field notes were also taken by the Research Assistants on the body language and unique circumstances around the participant at the time of data collection.The audio recorded data were transcribed verbatim by the Data Clerk. The transcripts were verified against the source audio recordings by a research team member to clarify any unclear data before permitting the Data Clerk to conduct the next transcription. Verbatim transcripts in the local language (Luo) were translated to English language before analysis. Two research team members independently coded the data and discrepancies in codes were reconciled through consultation with other research team members. We conducted a manual reflexive thematic analysis of data as they manifest from the participants in accordance with the six steps described by Braun and Clarke . FindingThe four principles of credibility, dependability, confirmability, and transferability of qualitative research were upheld to assure and maintain rigor and trustworthiness in the study. Credibility was assured by restating and summarizing points during the interviews and also by taking field notes from the interviews in addition to the audio recording . DependaWe approached the 20 purposively selected caregivers of the older persons aged\u2009\u2265\u200950\u00a0years to provide informed consent and all of them consented and participated in the in-depth interviews. The response rate was therefore 100%.The socio-demographic characteristics of the 20 caregivers of the older persons aged\u2009\u2265\u200950\u00a0years with a positive history of CNS infection illness and later life dementia in Lira District northern Uganda who participated in the study is shown in Table Some symptoms of the CNS infection illnesses surfaced at an earlier time or age of the demented person\u2019s life. These early symptoms in terms of their earlier time of manifestation in the demented person\u2019s life are therefore put together under the theme of presenting early symptoms of the CNS infection illness although they varied considerably in terms of the actual time of manifestations in the demented person\u2019s life ranging from childhood, adolescence, youthful age, middle age though a few years or months ago.\u201cThe problem she had especially now that you have come to make a follow up, her main problem she used to complain of pain. This complain went on until a point that it become worse to the extent that she started forgetting a lot of things. Her major complaint was that the pain would start from the lower limbs, radiates to the waist region then to the back through her spinal cord\u201d We explored the initially presenting symptoms of CNS infection illness among the older persons prior to being screened positive for probable or possible dementia. Many of the key informants (who were caregivers) narrated that the older persons with probable or possible dementia were always complaining of pain around the neck and the back. From these, it slowly progressed to memory loss and inability to carry on with daily activity. The experiences of neck and back pain was typified by a response from one of the study participants described below.\u201cit all started one day as she was here on the compound winnowing sorghum when she realized her energy was getting low and she decided to go and take some rest, when I went inside to check on her after sometime I found she was struggling with breath, I tried calling her she could not respond to me I then ran to my elder brother who came and picked her and she was taken to the hospital. And another thing I know is she subjects herself into too much worry\u201d Some key informants reported that the older persons with probable or possible dementia also complained of fatigue. This would also interfere with their ability to carry on daily activities and raised the suspicion that something was not right with their health. Some key informants went on to say that the feeling fatigue increased stress levels among the older persons. They thought the fatigue was the part of the reason as to why their relative with probable or possible dementia suffered from memory loss. One of the participants had the below to say.My relative always complained of having too much headache and sudden feeling of being very tired, it was then at that point we took her to the hospital and she was confirmed to be having illness which was said had started to affect her brain\u201d \u201cSome key informants pointed out chronic headaches as one of the complaints that were always raised by the older persons who were screened positive for probable or possible dementia. Chronic headache typically is due to the inflammation of the immune system secondary to the CNS infection. This continuous headache without concise remedy could have led to development of the dementia among the older persons. This was described by one participant below.The study also investigated prior conditions amongst the older persons with a positive history of CNS infection and dementia. These prior disease conditions or illnesses that co-existed in the demented persons with positive history of CNS infection illnesses were defined under the theme of manifesting co-morbidities and or their medications. The findings are presented below.\u201cHer condition started after she had suffered an accident and hit her head on the ground. suffered two accidents in a row and after the accidents, hit her head on the ground, she started experiencing memory loss, back and body pain, victim of Goiter, shock, suffered a stroke. Half of her body was completely paralyzed for some time, and she kept suffering from the brain infection which made her forget a lot of things. Keeps getting malaria infections\u201d Some of the key informants revealed that the older persons have been victims of road traffic accidents that led to shock and paralysis for some time. And from the accident they started experiencing signs of forgetfulness and memory loss. Traumatic tissue injury from road traffic accidents are often entry point for some of the pathogenic microbes that infect the central nervous system as many of the participants also reported that from the time their relative were involved in two rows of the accidents they started suffering from episode of CNS infection illness. This was typified by one of participants below.\u201cWhat I can tell you according to my understanding about how this problem begun is she was taken to the hospital and was diagnosed with pressure and she was given medication to help control the condition, it was then when she started on medication when we realized she started having episodes of forgetfulness but this was not happening before she was put on medication. And so people started telling us it could be the side effects of the medication that she is taking to control pressure which is causing her to be acting that way\u201d Other key informants reported that their relatives (the older persons) started experiencing episodes of forgetfulness following treatment for high blood pressure. They related the forgetfulness to the side effects of the medications they gave their relatives (the older persons) as treatment for high blood pressure. The thiazide diuretic and a calcium channel blocker (nifedipine) the two widely available and commonly prescribed antihypertensive drugs in Ugandan public health facilities were implicated by the key informants. This was exemplified by one of the key informant\u2019s comment below.My relative always complained of having too much headache and sudden feeling of being very tired, it was then at that point we took her to the hospital and she was confirmed to be having illness which was said had started to affect her brain\u201d \u201cSome key informants also pointed out chronic headache as one of the complaints that were always raised by these older persons indicated for probable dementia. This could be due to the inflammatory response of the immune system to the CNS infection that triggered the headache. This continuous experiencing of headache with no concise remedy for the infection-related CNS illness could have led to development of signs dementia among the older persons aged\u2009\u2265\u200950\u00a0years. This is quoted by one participant.\u201cShe looks young though already aged than I am, my sister was once diagnosed with an underlying condition of high blood pressure, which I hope has made her weak and very vulnerable to CNS infections and forgetting things\u201d Many of the key informants reported of their relatives (the older persons) being ever diagnosed with high blood pressure in addition to the diagnosis of CNS infection and dementia. The participants believed having hypertension weakened their immune system and made them vulnerable to CNS infections and developed dementia. This was exemplified by a narrative from one of the study participants below.The study explored the diagnosis, treatment and care sought and given to the older persons when experiencing the signs and symptoms of illness before the diagnosis of CNS infections and the positive screening test for dementia. Therefore, this theme of seeking and receiving of series of treatment and care without thorough checkup for CNS illnesses consolidates all the missed diagnosis, unsuccessful treatment and care sought and received by the demented persons.When the pain first started she kept visiting the hospital time and again to get medical help, she was given drugs without any thorough checkup to find the origin of the illness\u201d \u201cMost of the key informants reported of ever taking the older persons for medical professional care at nearby health facilities. They further narrated that during the time no clear diagnosis was done on their patients (the older persons) as the health workers provided treatment for the prevailing signs and symptoms. The delay in definitive treatment could have given time for the infections to disseminate further to CNS region and cause further pathology including dementia. The narrative was typified by a participant by the saying below.She was discharged from the hospital after spending about three weeks, and advised to continue with her treatment from home. \u201cThe doctor said that my mother was much better but needed to continue taking some medication, and as said by the doctor, to-date my mother mostly suffers only from the effect on the brain, which causes her to lose memory quite often and fail to talk or make sense out of what people are saying, this is all that she is still going through once in a while\u201d \u201cSome key informants narrated that their patients would get admitted in the hospitals but could not stay longer because of the treatment expenses they could not sustain admitted in the hospitals to receive the desired treatment and so gets discharged to receive further treatment from home. This prompted discharge of patients before full recovery from hospitals and receive the rest of care while at home without follow up from the health workers to assess improvements in the conditions of the patient.\u201cThe only treatment she received was local herbs that was given to her from the village and prayers that the church pastor came home and prayed when we told him of what was happening to her. We could not raise the money to pay for the drugs the doctors had prescribed for her\u201d Some key informants also reported of their relatives (the older persons) sometimes used local herbs to treat themselves. They related this to the high financial constraints that their families could not raise to meet the cost of biomedical care. They also attached the condition of CNS infection and dementia to spirituality that did not require biomedical care and thus opted for spiritual care. This was exemplified by a narrative from a participant below.\u201cShe had only used the painkillers and antibiotics which helped her to reduce the pain. These drugs used to help her reduce the pain but was unfortunately just helping her temporarily and after sometime the pain gets triggered again and kept on increasing overtime\u201d Some key informants reported that their patients the older persons were being treated mostly with pain killers and antibiotics. Such presumptive treatment without specificity on the type of infection the medicines are targeted at instead escalated the condition. Participants reported that the presumptive treatment would palliate temporarily and then the patient\u2019s condition reoccurs. This was exemplified by a narrative of a participant below.We explored the challenges faced by the caregivers or family of the older persons with a positive history of CNS and probable or possible dementia while seeking the desired health care. This theme of Facing a Multitude of challenges to optimal diagnosis, treatment and care therefore consolidates all the diagnosis, treatment and care related challenges or difficulties encountered by the demented persons, their caregivers or family. The findings are described below.\u201cShe faced financial constraints and couldn\u2019t start medication. She spent a lot of money in the tests and because of this, purchasing the prescribed medication became a little challenging for her\u201d Many of the participants expressed the lack of money was the main reason for the failure of their patients the older persons to receive the desired care. The lack of money for care could probably be due to limited the financial support for the elderly persons in the community. The lack of money hindered them from receiving quality care from quality health facilities which offered specialized care for CNS infections. The above narrative was typified by a participant in the saying below.When the pain first started she kept visiting the hospital time and again to get medical help, she was given drugs without any thorough checkup to find the origin of the illness\u201d \u201cSome key informants also reported that the older persons lacked proper diagnosis in the initial stages of the infection. The inadequate or lack of diagnostic equipment\u2019s in health facilities led to treatment of the presenting signs and symptoms without definitive understanding of the causative agents of the infection. This led to reoccurrence of the infection and long stays in hospitals. One participant narrated it as below.Old age is one problem I can say is affecting her memory because at this time she needs special attention they used to get but now they are not getting. The need someone to keep around and do for him most of the work, you can see he is even weak\u201d \u201cSome key informants also reported that because of the forgetful nature of these patients, if not helped and reminded to take their drugs they end up missing taking the drugs in the right time. Therefore, their patients need a full time person to take care of them, since even their treatment take longer durations. One participant had the description below to narrate.Our study explored the Central Nervous System (CNS) infection illness trajectory to dementia among the older persons with positive history of CNS infection illness and later life dementia in northern Uganda. The themes that emerged were four and they were the presentation of early symptoms of illnesses, manifestations of co-morbidities and or their medications, seeking and receiving of series of improper diagnosis, treatment and care and facing of a multitude of challenges to optimal diagnosis, treatment and care.The early symptoms of CNS infection illness among older persons with dementia that emerged from interviews of key informants included chronic headache, neck pain, back pain and fatigue. These findings concur with the findings from a previous study conducted in the United States (US) where elderly patients with CNS infection illness presented with headache, fever, neck stiffness and altered mental status . The impInterestingly, our study found the existence of comorbidities of high blood pressure, CNS infection illness and dementia among older persons with positive history of CNS infection illness and later life dementia. There is limited literature on the comorbidity of high blood pressure, CNS infection illness and dementia. Whereas previous studies have shown separate associations between CNS infection illness and high blood pressure, high blood pressure and dementia, CNS infection illness and dementia , 14, theOur study also found that some of the older persons with positive history of CNS infections and later life dementia were once victims of road traffic accidents involving traumatic injury to the head, neck or spine  developed CNS infections later in life. The road traffic accidents involving traumatic injury to the head, neck, or spine have the potential to cause breakage in surface barriers such as the skin and bones allowing pathogens from the external environment to gain entry into the CNS and cause CNS infections. These findings agree with a previous study conducted in the US where CNS infection was also found to result from trauma and fractures involving the CNS . These fThe treatment and care modalities received by the older persons with positive history of CNS infections and later life dementia in this study included a mix of biomedical care, home-based care, and local herbs. This finding concurs with findings from previous studies conducted in southwestern Uganda where caregivers or families of older persons with dementia were found to be seeking healthcare for their patient with dementia from both formal and informal care providers . The simOur study also found that pain killer was among the treatment for pain management among the older persons with probable or possible and positive history of CNS infections. This could be as a result of pain being reported to be among the symptom of CNS infection the older persons with possible or probable dementia experience. This finding is in conformity with previous studies were analgesic were also reported among the medication for pain management among older patients with dementia , 17. TheOur study in northern Uganda further found that older persons with history of CNS infection and dementia in later life used local herbs as one of the treatment and care modality for the neurological conditions. These results is in conformity with the previous studies were plant-based medicines were found to be the most frequently sought and used mode of treatment for a number of CNS disorders , 19. TheOur study found that poverty was one of the challenges hindering the older persons from obtaining timely and optimal health care for both the early CNS infections and the dementia in later life. As many of the caregivers made mention of their family\u2019s inability to raise funds for carrying out diagnostic tests and procuring the drugs as prescribed by the healthcare professionals. This result concurs with the previous study conducted in South Africa where poverty and financial stress were highlighted as the most common barrier to providing care for older persons with dementia \u201322. ThesOur study in northern Uganda also revealed that patients with positive history of CNS infections and later life dementia encounter a series of missed diagnosis and mismanagements of their neurological conditions. This was probably due to the lack of equipped medical laboratories in most of the healthcare settings in northern Uganda being a post armed conflict area. These results conforms with findings in previous studies, were late diagnosis and syndromic approaches are used to treat CNS illness among older persons . The finLastly, our study in northern Uganda unearthed the need for government and partners to consider policies and mechanisms of care for older persons including those with the positive history of CNS infections and later life dementia to address their long course of treatment and care needs. The long time for treatment and care needs of the older persons with a positive history of CNS infections and later life dementia put their families not only in financial distress but also in emotional discomfort. Our findings conform to the findings of previous studies where caregivers were faced with similar challenges of a long course of treatment and extended hours of caring for the persons with dementia , 23. TheThe current study in northern Uganda did not conduct laboratory investigations on the participants to confirm the positive history of the CNS infection illness. This was however addressed by obtaining additional data on the CNS infection illness from the past medical discharge forms of the participants. The natures of the CNS infection illnesses were written in the medical records as laboratory results or medical diagnosis for example \u2018Cryptococcal meningitis\u2019 although some of them were based on clinical history and physical examinations. Also, control for potential confounders for the association between CNS infection illness and dementia such as traumatic injuries were not possible in the qualitative research design but are well controlled for in the preceding quantitative study in the same setting which investigated the prevalence of CNS infections among older persons and its association with dementia among older persons in northern Uganda. Additionally, key informants who were caregivers of the index participants were the ones involved to provide data about the CNS infection trajectory to dementia of the index participants. The concurrent manifestations of multiplicity of symptoms in older persons made it not possible to examine what symptoms or comorbid conditions led to which type of treatment seeking. The reflexive thematic analysis of data as they manifest from participants resulted in multiple symptoms and factors with or without proven causative relations to possible or probable dementia.Older persons with the positive history of CNS infection illness and later life dementia in rural northern Uganda were reported to present with symptoms of early life CNS infection illness ranging from neck pain, back pain, chronic headache, and fatigue. There were also reports of comorbidities particularly road traffic accidents involving traumatic injury to the head, neck, and spine, high blood pressure, chronic headache, and or their medications in the older person\u2019s trajectory to later life dementia. A plurality of healthcare which included both formal and informal healthcare medicines were reported to be sought and utilized for the treatment and care of the CNS infection illness and the dementia without thorough checkup for the CNS infection illness. Sticking out were the reported challenges of poverty, and long course of treatment and care for the older persons with positive history of CNS infection illness and dementia which requires government interventions in the form of policies and mechanisms for funding of institutions or agencies to facilitate care for the older persons. Health professionals should conduct routine screening of older patients for history of CNS infection illness, chronic headache, high blood pressure, history of traumatic injuries to the head, neck and spine and their proper management to reduce the likelihood of dementia in later life. Further research with case\u2013control or retrospective cohort design is recommended to characterize the trajectory of CNS infection illness to dementia including the time, duration and comorbidities among others."}
+{"text": "In 2020, Afghanistan supplied around 85% of the world's heroin. The recent Taliban takeover and political upheaval seems highly likely to impact the supply chain, but how? This literature review aims to explore the background of heroin production and possible consequences of the recent conflict, both for suppliers and for end users.In addition to recent mainstream media news articles on the Afghanistan conflict, PubMed search terms \u201cheroin adulteration\u201d were used to find 202 results. Only results published from the year 2000 onwards were examined for relevance, leaving 160 results. These were reviewed for relevance and led to suggestions of similar PubMed articles to arrive at the final 23 sources used.Studies of previous heroin shortages in Australia and the UK are discussed to gain insight into the potential effects of a future shortage. A reduction in heroin exports from Afghanistan would cut down the supply to most nations excluding North and South America. Sources of evidence for our current understanding of the supply chain are examined. Specific US and UK policy failure which led to the current situation is also provided for context.Methods of production in Afghanistan and smuggling routes are also examined to help predict impending changes.Given the number of factors involved it is difficult to anticipate with much certainty how the Taliban takeover of Afghanistan will affect the global heroin trade, but based on the available literature it seems more likely that this will cause shortages rather than an increased supply.Clinicians should be aware that in line with previous shortages, this may cause a shift towards increased rates of polysubstance use in regular heroin users. We may also see a rise in incidents of harm from heroin adulteration with substances other than the currently widespread paracetamol and caffeine."}
+{"text": "The authors regret that the title shown in the original article was incorrect. The correct title should read as follows:Preparation of superhydrophobic surfaces with micro/nano hierarchical structures by nanoimprinting using anodic porous alumina molds.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "Housing security is a likely indicator of loneliness  but there are few studies that focus specifically on the relationship between the two. This paper presents findings from a New Zealand Ageing Well National Science Challenge research programme that presents findings on the impacts of housing and living standards on loneliness and social exclusion. Method: This presentation will provide results from a study of 200+ M\u0101ori  aged 50 years and over. Key questions around loneliness and social isolation were co-created with the participants and responses compared with standard international scales to help identify both universal aspects of loneliness and culturally specific aspects. Questions relating to housing security, affordability, living standards and neighbourhood safety were also asked. Regression analysis was used to test the statistical significance of the various relationships between differing aspects of housing and loneliness.The results demonstrate statistically significant relationships between housing quality, affordability, living standards and neighbourhood suitability with both the universal and culturally specific scales of loneliness. Overall greater housing security and quality was shown to be negatively associated with loneliness, which suggests it contributes to the reduction of loneliness.Addressing the quality of social connections has often been seen as the key way to address loneliness. The results of this study suggest housing security and living standards play an important role in people\u2019s perception of loneliness and their experience of it, as well."}
+{"text": "This article has been corrected to fix a typo in the first sentence of the Results section:\"A total of 177 patient files were reviewed during the study period, of which 87 patients met the inclusion criteria.\"The correct amount of patients meeting the inclusion criteria was in fact 89, not 87. This sentence has been amended to reflect this. The journal sincerely regrets that this typo was not caught and corrected prior to publication."}
+{"text": "Emotional support has been consistently identified as a mechanism through which socioeconomic resources influence mental health outcomes. Despite emerging evidence that compassionate love has a beneficial effect on mental health, its distribution across levels of financial strain and subsequent role in mediating the effect of financial strain on later life mental health have yet to be examined.Based on our nationwide web-based survey of adults aged 50 years and older (n=1751), we conducted a mediation analysis to estimate the direct and indirect effects  of financial strain on depressive symptoms and anxiety.We documented a statistically significant overall effect of financial strain on depressive symptoms  and anxiety . We found a statistically significant path-specific effect  through compassionate love alone on depressive symptoms  and anxiety , but did not find effects for paths through emotional support. There was also a significant direct effect of financial strain on both depressive symptoms and anxiety. Discussion: Our study advances a new line of research by looking at the role of compassionate love in transmitting the effects of financial strain on mental health in later life. Findings suggest that the detrimental effect of financial hardship on mental health operates through its negative effect on the receipt of compassionate love, rather than by its impact on emotional support."}
+{"text": "Incorrect corresponding authors were indicated in the published article while the correct version is shown above; Wei Zhang rather than Weilong Liu is the co-corresponding author.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "As the number of older incarcerated persons grows, evaluating changes in their physical and mental health over time may be important for appropriate planning and needs assessment. Based on findings from the Aging Inmates\u2019 Suicidal Ideation and Depression Study (Aging INSIDE), we will provide recommendations for assessing both objective and subjective physical function in older incarcerated persons. We will also discuss our experiences with assessing depression and suicidal ideation in this population and describe how the processes for collecting data needed to be modified during the COVID-19 pandemic. Those attending this session will learn about the pros and cons of using face-to-face assessments and mailed surveys to assess physical function and mental health among older persons in the prison setting and will learn how these outcomes may differ between those who have a life sentence versus those expecting to be released from incarceration in late life."}
+{"text": "The pandemic further exacerbated racial and ethnic health disparities with BIPOC  communities experiencing significantly higher infection rates and higher hospitalization rates compared to White populations. Underlying medical conditions that disproportionately affect BIPOC populations  and social determinants of health  can account in large part for increased rates of morbidity and mortality. Within the long term services and supports (LTSS) continuum, health disparities exist in both who receives and provides care. The four papers in this Social Research Policy and Practice Presidential Symposium will highlight factors that result in health disparities across the LTSS continuum and propose possible policy and practice solutions to address the disparities. The first paper presented will be an overview of existing nursing home workforce issues that continue to impact disparities in the quality of resident care. The second paper presented examines nursing home resident quality of life disparities from a measurement perspective. The third paper will highlight issues on elder abuse and mistreatment of rural elders, American Indian and Alaskan Natives. The fourth paper will present recommendations from key stakeholders of the RAISE Family Caregiving Advisory Council on how to meet the needs of underrepresented groups  of family caregivers. Policy and practice solutions to reduce disparities will be discussed."}
+{"text": "Our public health system is advancing activities to prioritize the health and well-being of older adults and recognizes the importance of policies to support us all as we age. Faculty will discuss national efforts underway to inform and support an age-friendly ecosystem."}
+{"text": "Animatronic pets can improve psychosocial outcomes among older adults, but little is known about in-home use by Veterans living with dementia and the perceptions of informal caregivers regarding these tools. This quality improvement project examined the usability and acceptability of animatronic pets by community dwelling Veterans living with dementia from the perspective of informal caregivers. Usability and acceptability were examined through a structured telephone interview with 17 caregivers. Usability was operationalized as frequency of: pet use by the Veteran , and reminders provided by caregivers . Acceptability was defined as perceived benefit  and satisfaction (measured using acceptability tool with close and open-ended response items) as reported by caregivers. Results indicated high usability (71% of Veterans used the pet daily with reminders provided by 30% of caregivers) and acceptability ; Satisfaction: 94% of caregivers would continue to encourage use of the animatronic pet by the Veteran and recommend one to others). Open-ended responses suggest that they may be less satisfying to those who lost a real pet or did not have an affinity for pets earlier in life. Animatronic pets can be used with minimal assistance by Veterans with dementia and are acceptable to informal caregivers. As VA initiatives support provision of these pets, additional research is needed to examine their broader impact on Veterans living with dementia specifically."}
+{"text": "Innovation distinguishes between a leader and a followerThis quote by Steve Jobs has defined the most admired surgeons in our discipline. Innovation fueled by surgical intelligence can expand the reach and performance of surgery beyond what was once considered possible. Endonasal surgery has shepherded skull base surgery into an era in which some of the radical open skull base exposures have been replaced with minimally invasive endonasal corridors, resulting in the concept of operative space being replaced by operative angle.Neurosurgical Focus: Video demonstrates an effort to push the boundaries of endonasal surgery for resection of an intradural lateral brainstem tumor. Although the retromastoid approach would have provided reasonable exposure of this lesion and potentially more aggressive resection while placing the VI nerve at less risk, the authors chose the endonasal route and were able to achieve a good result. In this video, the limitations of microsurgical instrumentation in carrying out intradural microsurgery within lateral trajectories in this operative space are evident. The angles of freedom become progressively more restrictive and challenge the microsurgical prowess of the surgeon to achieve maximal resection.The video titled the \u201cEndoscopic Transnasal Resection of the CP Angle Schwannoma\u201d by Kiyofuji and colleagues in this issue of Pushing the boundaries of minimally invasive surgical approaches at the expense of increased technical difficulty and its yield of resection frequently haunts us. Our ability to resect brainstem lesions via endonasal approaches is at its early stages and requires further evolution of endoscopic microinstrumentation and development of objective selection criteria. Ultimately, the operation is not only about how to get there but also, more importantly, about what to do when you are there. I am thankful to Dr. Kiyofuji and colleagues for their thought-provoking video."}
+{"text": "The main challenges after getting started with a podcast will be growth and sustainability. This presentation will focus on promotion tactics for digital health podcasts, including the pros and cons of different hosting platforms and the use of social and academic networks for promotion. The importance of sustainability and consistency for growth will also be discussed, including some practical tips on productivity and team management for content producers."}
+{"text": "Physical activity across the life course contributes to physical function and health in later life. Here we characterize a measure of physical activity history, newly implemented in participants of the Baltimore Longitudinal Study of Aging (n = 690). Participants selected one of four levels to describe activity during each decade of life from age ten to the present. Recalled levels of physical activity are positively associated with activity assessed in current and prior decade study visits, suggesting that the recalled estimates are consistent with historic activity. A summary measure based on ranking activity patterns was associated with measures of physical performance, muscle and fat areas quantified from computed tomography images as well as some indicators of homeostatic dysregulation (p <.05). The observed associations suggest that an estimate of physical activity across decades provides complementary information to estimates of current activity and reemphasizes the importance of consistently engaging in physical activity."}
+{"text": "The U.S. is experiencing a demographic shift characterized by a significant segment of the population entering older age groups and beginning to require specialized eldercare, however little is known about the influence of demographic characteristics on individuals\u2019 involvement with long-term care institutions. I use data from the Health and Retirement Study and logistic regression models to examine how the identities and resources people bring to the later stages of their lives influence their use of nursing homes. I find that individuals\u2019 levels of human capital \u2013 measured through their educational attainment \u2013 have the strongest influence on their use of nursing homes, with individuals with college degrees having significant increases in the odds of \u200breporting any nursing home stay and in the expected count of nursing home stays. I posit multiple pathways by which education could increase the likelihood of using institutionalized care, including through the social mobility of other family members as well as the ability to navigate healthcare resources and evaluate eldercare options. This detailed examination of the intersection between older ages, individual characteristics, the accumulation of different kinds of capital over the life course, and the involvement with formal care facilities provides valuable insight into the relationship between individuals and institutions across older ages and can inform policies attempting to prepare the landscape of formal care institutions for the influx of possible consumers."}
+{"text": "Community-based health enhancing physical activity (PA) initiatives often lead to important mental health and wellbeing outcomes beyond improvements in physical activity levels. However, identifying what outcomes to measure and how to measure them is a challenge in community-based work. There is a lack of practical guidance on how to strengthen mental health and wellbeing outcomes within the context of PA initiatives. This presentation will share the work on a project with community based practitioners and mental health/physical activity experts which is being led by the HEPA Europe Working Group on HEPA promotion in socially disadvantaged groups, supported by WHO Europe.The presentation will engage participants in discussions around the following questions:What are the most important mental health and wellbeing outcomes of community-based health enhancing physical activity initiatives in Europe, and how can these best  be assessed for evaluation purposes?What are the needs of practitioners  working in communities to promote mental health through physical activity?"}
+{"text": "In Response: We thank McNamara and colleagues for their commentary (We believe that underestimations of the number of cases in France can be improved by increasing awareness of healthcare professionals through publications describing the risk factors associated with NTM HAI and by triggering clinical and microbiological vigilance through networks and registers. We hope that our article ("}
+{"text": "Mycobacterium tuberculosis antigens using immunodiagnostic testing. It is recommended that TB exposed children and adolescents and those living with HIV receive TB preventive treatment (TPT) to reduce the risk of progression to TB disease. Several TPT regimens of similar effectiveness and safety are now available and recommended by the World Health Organisation.The burden of tuberculosis (TB) in children and adolescents remains very significant. Several million children and adolescents are infected with TB each year worldwide following exposure to an infectious TB case and the risk of progression from TB infection to tuberculosis disease is higher in this group compared to adults. This review describes the risk factors for TB infection in children and adolescents. Following TB exposure, the risk of TB infection is determined by a combination of index case characteristics, contact features, and environmental determinants. We also present the recently recommended approaches to diagnose and treat TB infection as well as novel tests for infection. The tests for TB infection have limitations and diagnosis still relies on an indirect immunological assessment of cellular immune response to  Mycobacterium (M) tuberculosis complex transmitted by inhaling bacilli contained in droplets expelled by a TB contagious individual : d: d106]: Despite the recent advances in the development of shorter TPT and the pragmatic WHO approach for high TB incidence and resource limited countries to reduce barriers such as chest X-ray to rule out TB disease and TBI testing before TPT initiation, there is still a low uptake of TPT among child contacts and children and adolescents living with HIV . The GloSystematic TB screening of child contacts and children living with HIV including adolescents is essential to early detect and treat those with TB and prevent others from develop TB. This is likely to contribute to reduce the burden of TB. Any innovation that is adapted to the limited resources of most high TB incidence countries will support these efforts but the lack of tools such as chest X-ray and TBI testing should not be a barrier to prescribe TPT to these children. Innovative decentralised, child and adolescent centred approach are also essential to ensure acceptability and access to treatment."}
+{"text": "The authors regret that the affiliation details for Mohamad Pezeshki-Modaress were incorrect in the original article. The correct author affiliations are as presented above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "Plants form complex interaction networks with diverse microbiomes in the environment, and the intricate interplay between plants and their associated microbiomes can greatly influence ecosystem processes and functions. The phyllosphere, the aerial part of the plant, provides a unique habitat for diverse microbes, and in return the phyllosphere microbiome greatly affects plant performance. As an open system, the phyllosphere is subjected to environmental perturbations, including global change, which will impact the crosstalk between plants and their microbiomes. In this review, we aim to provide a synthesis of current knowledge of the complex interactions between plants and the phyllosphere microbiome under global changes and to identify future priority areas of research on this topic. Global agricultural production is expected to increase by 70% by 2050 to feed the increasing human population . It has beenreported that organic farming increased fungal alpha diversity in the wheat phyllosphere, compared with conventional management  with increasing surface temperature of 2\u00b0C, Aydogan et\u2009al. (Sphingomonas spp. and Rhizobium spp.) and enhancement of potentially pathogenic bacteria  in the phyllosphere may indicate that warming increases the potential transmission of pathogens in grassland ecosystems   , warming negatively affected putative fungal pathogens   phyllosphere  showed that rain events did not have a significant effect on the richness or evenness of its phyllosphere bacterial community  showed different abilities in shaping the soil microbiomes.As the outcome of past evolutionary history, the phylogenetic relationship between plant species has been found to be able to interact with climate change to modify plant microbiomes  What are the mechanisms within and across plant hosts that underpin host\u2013microbe interactions? (2) What are the major microbial taxa in the phyllosphere that control or mediate plant performance ? (3) How does the phyllosphere microbiome interact with other plant microbiomes? (4) How can we manage the phyllosphere microbiome to increase plant health and performance in a changing world? (5) How will host and the phyllosphere microbiome evolve in response to global changes, and what impacts will this ecoevolution have on ecosystem functions? Therefore, we argue that advancing our fundamental understanding of the impacts of global changes on the phyllosphere microbiome and related ecosystem functions requires interdisciplinary investigations. We need to shift the focus from the level of community ecology to ecosystem ecology for a better understanding of the mechanisms underlying responses of the \u2018holobiont\u2019 (assemblage of a plant and its microbiome living in or around it) to global changes. A systems approach is needed to understand the complex interactions between the phyllosphere microbiome and host fitness, and the ecological functions of these microbes for plant nutrition uptake, growth and survival under global climate change."}
+{"text": "Cancer and its treatment often impose physical and psychological consequences. Children with cancer are not only at a risk of adverse events resulting from medical procedures but also severe effects on their social and mental health as a result of its treatment. Depression being one of the most common psychiatric disorders associated with cancer in children and adolescents. The current study aims to provide evidence of an easy and inexpensive intervention that can be used in oncology patients in a low resource setting to help maintain mental health stability in pedriatric patients..To examine the effectiveness of therapeutic group art therapy, in reducing depression scores in children with cancer.The study is quasi experimental, through convinient sampling data of fifteen children in initial stage of thier treatment were selected. They were divided into two groups experimental and controlled through random allocation. Three sessions of forty minutes of group art therapy was given in experimental group, in control normal treatment was provided excluding group art therapy. Childhood Depression Scale (CDI) was used in both group as pre and post test to determine the depression level.The results shows a positive change in the level of depression in experimental group as compared to controlled group.Group art therapy is an effective and inexpensive way of reducing depression level of paediatric leukemia patients that can be used by oncology healthcare centres worldwide with trained mental healthcare professionals in order to maintain positive treatment results of cancer."}
+{"text": "The authors regret that an incorrect affiliation was given for co-author Mehdi Bazarganipour in the original article. The correct affiliations are as shown here.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "There is a significant problem of unidentified and unaddressed reading disabilities leading to psychiatric problems in children and adolescents because of not having proper tools of assessments in schools. This research proposal can be a revolutionary paradigm in identifying, classifying, modeling, and benefitting children and adolescents with a specific learning disorder (SLD).The objective of the current research proposal is to provide a framework of our reading program and collect data over time as cohorts to reflect the positive outcomes of the reading program.After a reading assessment, students with specific reading disabilities will be registered in the program for 10 weeks. Every student will have reading training and CBT on different days of the week via video conference. Data will be collected retrospectively from the initial cohort and subsequent cohorts will be added to the data collection process for a final analysis when 60 students have completed the program.Initial two weeks of reading training and CBT shows positive and promising results so far.Children need to be screened at a young age for a reading disability before they struggle academically, and develop psychiatric issues later in life.The aim of this research proposal is to help us understand, evaluate and benefit children with Specific Learning Disorder (SLD) with our newly setup reading program at RUSH University Medical Center, Department of Child and Adolescent Psychiatry."}
+{"text": "In the originally published article, the provided supplemental figures and tables were erroneously missed in being uploaded to the Supplementary Data file. The figures and tables have now been added to the Supplementary Data file online."}
+{"text": "This is easily verified by consulting PubMed, a free search engine of biomedical scientific literature online since 1996. By entering \u201cpsychology\u201d and \u201cvirtual reality\u201d (VR) as search keywords, it is possible to verify a progressive growth in the number of articles in the sector that in a few years it has gone from a few dozen to several hundred articles per year .An important field of application of VR is clinical psychology. The use of computer screen-displayed clinically relevant scenarios for therapy has a limited impact in the field, due to the relatively low ecological validity of these experiences. VR technology offers a solution to this limitation by allowing the opportunity to actively perceiving one's own body within a simulated environment, letting individuals to experience reality-like situations Talking about clinical practice, VR is becoming an increasingly established and widespread method alternative to in-vivo exposition for the treatments of several mental disorders. Recent studies have shown that this approach provides better results compared to traditional therapies for mental disorders Advanced applications of VR for the treatment of anxiety and fear could refer to an integrated human-computer system Insights supporting the importance and efficacy of VR in the clinical field is also provided by research on the rehabilitation of neurological disorders. For example, a recent review article investigating the relevance of VR in stroke rehabilitation found that this technology can be more effective than standard therapies in improving upper limb function and activities of daily living function when used in addition to usual care Finally, VR can be useful for creating experimental settings relevant for the study of clinical symptoms through the involvement of healthy participants. This is the case of Pavlovian conditioning protocols  In conclusion, the current state of the art suggests that the use of VR technology has great potential in boosting clinical practice by promoting therapeutic efficacy, especially when combined with other well established therapeutic methods such as mindfulness and NIBS. The community of clinical psychologists and clinical neuroscientists should look with enthusiasm and genuine interest in VR technology as it could make a difference in psychotherapy and neurorehabilitation."}
+{"text": "Rural and remote communities in Australia are characterised by small but widely dispersed populations. This has been proven to be a major hurdle in access to medical care services with screening and treatment goals repeatedly being missed. Telemedicine in ophthalmology provides the opportunity to increase the availability of high quality and timely access to healthcare within. Recent years has also seen the introduction of artificial intelligence (AI) in ophthalmology, particularly in the screening of diseases. AI will hopefully increase the number of appropriate referrals, reduce travel time for patients and ensure timely triage given the low number of qualified optometrists and ophthalmologists. Telemedicine and AI has been introduced in a number of countries and has led to tremendous benefits and advantages when compared to standard practices. This paper summarises current practices in telemedicine and AI and the future of this technology in improving patient care in the field of ophthalmology. However, one of the most targeted diseases is diabetic retinopathy. Despite improvements in diabetic care, diabetic retinopathy remains the leading cause of visual impairment in working\u2010age adults.2A number of formal telemedicine programs in ophthalmology exist in rural and remote communities across Australia. A recent systematic review of current telemedicine programs in ophthalmology identified five general eye care programs, three emergency care programs and five diseases specific models of care.An program run in Mt Isa, Queensland, allowed for ophthalmologists working in Townsville to remotely assess patients attending the emergency department, who would have otherwise been required to travel significant distances.Lions Outback Vision has provided telemedicine service to rural and remote regions of Western Australia for over a decade. These regions continue to have workforce shortages and telemedicine has enabled increased access for populations dispersed across a vast geographic area.The uptake of telehealth in remote and regional services remains underwhelming given the potential for improving equity in eye care access. The challenges of coordination between outreach optometry and ophthalmology services as well as availability of specialists for on call integration into daily workflow are logistical hurdles.3There are a number of different forms of telemedicine within ophthalmology currently in use, all of which have different logistical and technological requirements Table\u00a0. The mos4Within Australia and internationally Indigenous people have poorer health and social outcomes compared to their non\u2010Indigenous counterparts. This includes a shorter life expectancy, increased infant mortality and morbidity and lower educational attainment.Although resources have been committed to improving screening and treatment rates for ophthalmic conditions in Indigenous populations, between 2008\u20132009 and 2019\u20132020 screening rates for diabetic retinopathy only increased by 4%.5The COVID\u201019 pandemic saw a marked expansion of existing telehealth services and the creation of new of telemedicine programs to maintain both patient and clinician safety. Of great concern during this expansion period was patient safety both from a COVID\u201019 perspective and existing chronic health conditions. To minimise the infectious disease risks for both patients and clinicians in Australia, a temporary expansion of Medicare funding for telemedicine during the COVID\u201019 pandemic saw the introduction of Medicare benefits to cover the use of audio only consults and the use of telemedicine in metropolitan regions which had previously been unfunded. The lack of funding is often listed as a key reason for a limited uptake of telemedicine. During the COVID\u201019 epidemic, ophthalmology saw one of the largest decreases in case volume, with one US study reporting a drop of 81%,Of concern during this period of transition was the effect on patient outcomes and safety. Concerns were raised that deteriorating ocular health would be missed and that both patients and clinicians would fail to engage with a telemedicine service. A number of studies have been conducted in order to address this concern and measure any potential impact that a change in patient care may have had. One large meta\u2010analysis of just under 1000 primary studies, including one on ophthalmology, found that telemedicine in a number of forms was not inferior to conventional care.6Clinician triage and assessment is still integral to current models of telemedicine in Australia for rural and remote populations Figure\u00a0. The incThese DLS are able to triage and assess patients for eye diseases and overcome the initial hurdle of accessing a clinician for assessment which has been identified as a barrier particularly in rural areas. This type of artificial intelligence diabetic retinopathy screening model has been trialled in Indigenous communities in Australia. A trial from our group in a number of specialist and primary care clinics including an Aboriginal Medical Service clinic in Western Australia demonstrated that the sensitivity and specificity were above the above that required by Food and Drug Administration sensitivity and specificity endpoints, 96.9  and 87.7 , respectively.Any form of telemedicine is not without its limitations, either in technology and access to clinicians. The introduction of artificial intelligence overcomes the initial hurdle of access to clinicians for screening however these systems are limited by the quality of camera accessible for assessment and the original training image dataset used which tends to be primary of Caucasian descent. This limits the generalisability of artificial intelligence algorithms with area under the curve lower in Aboriginal and Torres Strait Islanders compared to Chinese, Malay and Caucasian populations.7Alongside the benefits of improved and more timely access to care there are economic benefits associated with the use of telemedicine and AI. There is a well\u2010established evidence base for the cost\u2010effectiveness of telehealth systems in multiple settings globally.A common theme to these economic analysis is that with greater uptake, the cost\u2010effectiveness increases. Any new telemedicine program must therefore effectively identify the needs of the population they are serving and integrate into any existing health\u2010care system in order to maximise the cost benefit both at an individual and government level.8A maldistribution in Australia's eye health clinical workforce means rural and remote populations have chronic issues with eye healthcare access. Therefore, the role of ophthalmologists will be in the management and treatment of surgical management or complex eye diseases. Current telemedicine programs integrate optometrists, nurses and general practitioners; however, further technological advances in ocular imaging and data sharing mean that this can be augmented further and, in some cases, conducted by patients themselves using artificial intelligence.Telemedicine with the addition of artificial intelligence provides many advantages in an aging population with increased healthcare needs, with artificial intelligence screening systems becoming more effective and their integration into telemedicine cheaper. This enhances primary care screening and ensures patients are well triaged for specialist clinician input as required and in an appropriate time frame for optimal visual outcomes.9There are numerous benefits provided by telemedicine ophthalmology programs. These include the increased access to screening and treatment, which is especially important in rural and remote areas which have continue to lag in access and uptake of screening and treatment goals. These telemedicine programs both with and without artificial intelligence enhancements allow for the prompt and early detection of disease, allowing for better patient outcomes. By augmenting screening with integrated artificial intelligence algorithms, further efficiencies may ensure appropriate referrals, reduced travel time and timely triage. A number of studies have already demonstrated the cost effectiveness of telemedicine programs, especially within diabetic retinopathy and these cost savings are likely to increase with the increased expansion and adoption of telemedicine programs. The COVID\u201019 pandemic saw the rapid introduction of expanded telemedicine programs in many areas of medicine including ophthalmology. This may serve as an impetus to embrace telemedicine to provide high quality and timely access to healthcare for all Australians no matter their geographic location."}
+{"text": "ACS Applied Materials & Interfaces,1 which was not cited in this RSC Advances paper. The RSC Advances paper is a valuable and necessary supplement to the publication in ACS Applied Materials & Interfaces and focused on the reduced gas sensing performance of the devices instead of film characterization and film conductive performance.The authors wish to draw the reader\u2019s attention to their previous related study, published in RSC Advances paper, which should be attributed to The authors regret not giving correct attribution to Fig. 1\u20136 which duplicate data from The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "To demonstrate the methodology and results for linking measures of neighbourhood walking-friendliness or \"walkability\" to Canadian health surveys and Canadian health surveys linked to administrative health care records. We linked multiple measures of neighbourhood walkability to hundreds of thousands of 6-digit postal codes of respondents to three large Canadian surveys using geographic information systems and anonymized banks of postal codes.Long term exposure to walkable neighbourhoods was associated with increased reporting of walking for utilitarian purposes. Moving to a high walkable neighbourhood from a low walkable neighbourhood was associated with a full unit decrease in the body mass index of Canadian men over a 12-year follow-up. In a linkage of walkability measures to respondents who wore biosensors for a one-week period in several Canadian cities, we found that neighbourhood walkability was associated with increased reporting of utilitarian walking but not overall physical activity and step counts as measured by biosensors.There is potential for walkable neighbourhoods to influence physical activity and body weight of Canadians which is more evident when individuals are followed for long periods of time."}
+{"text": "The assumption that \u201cnormal\u201d or typical sexual behavior exists is important for research and practice . The definition of normal sexual behavior is multifaceted, that is why its adequate understanding by students in the course of sexuality requires some effort.The focus of the research was the students\u2019 understanding of complicated normal sexual behavior.24 students  completed adapted and modified questionnaire  consisting 30 items concerning sexual behavior by deciding whether or not they consider each item as normal. Then the evaluations by each student on all items were generalized and discussed and summarized in this general form among all participants.Only 2 items were considered by all students as a normal: concerning sex somewhere other than a bed and masturbation after marriage. Some items were evaluated as normal by the half of participants: fantasizing about a person other than one\u2019s partner during sex; becoming aroused by peeping; dressing of the clothing of the other sex; having rape fantasies. Many items were characterized as normal by less or more than a half of the participants. Trying to answer the question of what elements of sexual behavior can be considered as normal, students aware the ambiguity of these assumptions and observe the variability in the opinions of other participants.Evaluation of different elements of sexual behavior and subsequent group discussion demonstrates for students some difficulties and uncertainty in defining normal sex behavior.No significant relationships."}
+{"text": "Advance care planning (ACP) is an important process to enable individuals to make their preferences known in the event of dementia onset. Racial and ethnic minorities have an increased risk of developing dementia. Understanding more about ACP differences by race and dementia status will help improve ACP communication among minority populations. For the current study the 2018 wave of the Health and Retirement Study  to test the relationship between dementia status and ACP and if there were differences by race. Findings indicated that both African Americans and Hispanics are less likely to have completed ACP than non-Hispanic Whites. In unadjusted models, having a dementia diagnosis indicated a lower likelihood of completing ACP; dementia was not significant in the final model when controlling for predisposing and enabling factors. More research on the predisposing and enabling factors that influence ACP among minority and dementia populations is needed."}
+{"text": "While we may not be able to predict with certainty whether any particular individual can prevent dementia, we are now able to talk about dementia risk reduction at the population level. The Public Health Center of Excellence on Dementia Risk Reduction reviews and synthesizes the state of the science on modifiable risk factors for cognitive decline and dementia. The Center translates that science into public health action \u2013 identifying interventions and best practices to address those risk factors \u2013 and develops tools and resources for public health agencies. The Center disseminates this information and works with public health to undertake community-level actions to address risk factors. The Center also works with public health agencies to: (a) address the social determinants of health with respect to dementia risk; (b) build capacity to enable smaller agencies to engage in risk reduction activities; and (c) partner with health systems to advance risk reduction."}
+{"text": "The authors regret that the email address was not included for one of the three corresponding authors, Guang-ji Wang. Contact email addresses for all three corresponding authors are presented here.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "Dramatic changes in family life may have altered the structure and quality of social ties to family and friends. However, little is known about whether and how social relationships vary between older adults from different cohorts. Using data from the National Social Life, Health, and Aging Project, we compared social network composition and social support between older adults at ages 57 to 67 from the Silent Generation cohort  and the Baby Boom cohort . Compared with the Silent Generation cohort, the Baby Boom cohort had significantly higher odds of not listing any kin in their core discussion network. There were no cohort differences in proportion of friends in the network. The Baby Boom cohort also reported lower levels of family and friend support than their counterparts. Results suggest that the Baby Boom cohort is more socially disconnected from friends and particularly family compared with the Silent Generation cohort."}
+{"text": "Refugees have been shown to be a vulnerable population with increased psychiatric morbidity and lack of access to adequate mental health care. By establishing cooperations between psychosocial centers and psychiatric clinics the state funded project refuKey by NTFN e.V. and DGPPN aims to improve access to and quality of mental health care for traumatized refugees pursuing a stepped-care model.As part of a larger project evaluation study four focus-groups among experts were conducted to explore the impact of refuKey on refugees\u2019 mental health care.Data analysis was conducted using Mayring qualitative content analysis as well as an additional quantitative survey with state refugee reception centers\u2019 employees.The results indicate that refuKey faciliated the access to mental health care for refugees in terms of systematic identification of mental disorders, eased transitions and increased networking between the mental health care institutions and sectors. Planning and implementation of treatment is described as being more coordinated, solution oriented and sustainable due to multiprofessional collaboration and regular use of qualified interpreters. Reduced distress as well as increased transcultural expertise was found for professionals.The persisting barriers for refugees in access to mental health care, especially to psychotherapeutic treatment and the emotional burden for professionals underlines the need for further support and research. The experts highly endorse the continuance of refuKey. Furthermore, they call for expansion of the project in terms of staff and new sites and changes of health policies to guarantee the access to adequate health care for traumatized refugees.No significant relationships."}
+{"text": "The authors are retracting \u201cAssessing the Dissemination of COVID-19 Articles Across Social Media With Altmetric and PlumX Metrics: Correlational Study\u201d :e21408) in alignment with COPE guidelines and based on an honest error that invalidates the results.Authors\u2019 statement:We sincerely regret our honest misunderstanding of the Altmetrics variables as it was discussed in our manuscript. As a team that values honest and ethical research, we are grateful to JMIR for bringing this grave error to our attention and appreciate our fellow peers for holding us to the highest standard of research. We strive to uphold integrity in our research and agree with the decision of the editors of JMIR to retract our original manuscript. We look forward to the opportunity to edit our work so our research accurately reflects the intention behind the Altmetrics variables."}
+{"text": "Pregnancy is associated with profound changes in pharmacokinetic processes. This is an important - and until recently neglected - area of research since the majority of women take drugs during pregnancy in addition to vitamin and dietary supplements. Recent evidence has emerged that the changes do not only include absorption, distribution and excretion but also drug metabolism, such as modifications in the regulation of hepatic metabolism and conjugation. Oestradiol is known to have an important role in the expression of cytochrome P450 isoenzymes and glucuronosyltransferase that are involved in the metabolism of psychotropic drugs. Recent studies of different psychotropic drug classes have shown that this can result in profound changes of plasma concentrations that commence early in pregnancy and gradually increase towards delivery. In this presentation pregnancy-induced metabolic changes that have been found so far for several psychotropic drugs will be discussed and the question addressed whether and how we should monitor plasma levels in our pregnant patients.No significant relationships."}
+{"text": "There are many definitions for polypharmacy used within clinical practice and research and many factors contributing to this problem. Definitions vary from being based on the number of medications the older adult is taking to a more qualitative evaluation of the appropriateness of medication based on the benefit of the drug for a specific problem. For research purposes the definition is more commonly conceptualized as being equivalent to taking five or more medicines. Polypharmacy is noted to be presented in about 40% of older adults living in the community. Limited research has focused specifically on polypharmacy in assisted living settings. In addition to concerns about polypharmacy in assisted living there has also been a focus on the use of psychotropic medication and opioids in these settings as prevalence ranges from 53% to 68%. Although there are not regulations related to decreasing polypharmacy via deprescribing or to decrease use of psychotropics or opioids in assisted living, there are currently major initiatives in geriatrics to focus on these areas. This symposium will provide current data on medication use and polypharmacy among a large sample of 781 assisted living residents from 85 communities across three states and address the impact of a Function Focused Care approach on decreasing polypharmacy and use of psychotropics and opioids. Lastly data will be provided on the value of Deprescribing Networks to help decrease polypharmacy within these settings. The findings from this symposium will provide recommendations for future research as well as guidance for clinical practice."}
+{"text": "The largely rural setting of Northern New England offers unique challenges to implementing improved acute care for the growing geriatric population. Northern New England is one of the United States\u2019 most rapidly aging regions, with Vermont and New Hampshire being the second and third oldest US states respectively by median age (U.S. Census 2017). There is a need to expand innovations in geriatric emergency medicine to reach older adults in rural areas such as Northern New England. Dartmouth-Hitchcock Medical Center and the West Health are collaborating on a project leveraging telehealth to extend the reach of a GED to rural hospitals, as well as investigate the opportunities for scaling and sustaining this concept to other rural facilities across Northern New England and throughout the country. This symposium will focus on our experience implementing a hub and spoke model to achieve our goal of improving the care of older adults in rural emergency departments."}
+{"text": "The aim of this research topic is to give the opportunity for clinicians and researchers from around the world to contribute with their experience and knowledge around challenges and solutions in the sphere of translational research in neuromuscular diseases (NMD). This is with reference to study design, outcome measures and what we have learnt from both successful trials and those that did not meet their primary endpoints. Resulting publications around this topic offer exciting and valuable insight which we hope can help guide future clinical trials as well as clinical practice. Lessons learned will benefit those developing research methodology to help improve trial outcomes and therefore clinical care for patients with neuromuscular diseases.Duong et al.). Traditionally, assessments have been performed in person with direct contact with the research subject. Recent global events have created additional pressures for industry in delivering face to face consultations. A number of industry sponsors quickly introduced amendments to their study protocols to enable remote evaluations. There may be many complications when utilizing a scale initially validated to be performed in person through a remote platform which may potentially impact the scale validity. Here a global network of physiotherapists report on methods for adapting current practices to accommodate remote testing and considerations for remote evaluations . Insight from these two manuscripts may provide valuable knowledge for considerations in study design and set up.Many factors may contribute to clinical trials not meeting their primary endpoint. One of the identified reasons is the lack of robust data to support the validity of a measure and poor-quality data collection. Significant efforts have been made to ameliorate these issues and one manuscript has provided a framework to guide the learning process for clinical outcome assessments (COAs) for use in both clinics and clinical trials. The process of teaching and learning COAs is necessary to maximize reliability of the measure and validity of the data collected. Evaluators involved in collecting data must do so in a standardised manner and must use clinical judgement and knowledge to accurately perform and score the COA. This manuscript is a consensus-based guideline to assist in the required training that must be employed for study start up for all evaluators regardless of experience . And finally, but not insignificantly are the implications of the use of social media in and around clinical trials. Can they be a force for good as well as perhaps their more usually perceived negative impact? In this paper they provide an overview of the guidance that has been published and muse the pros and cons of the use of social media in trials for rare disease (Nelson and Iannaccone). The knowledge based on past experiences may be extremely valuable as we continue to advance clinical trials and clinical care for patients with NMD.Prior experience in clinical trials has provided us another important tool for moving the field forward in these rare diseases. For example, in the last three\u00a0decades, several compounds have been assessed preclinically and within clinical studies for their ability to restore functional dystrophin levels or to modify pathways involved in Duchenne muscular dystrophy (DMD) pathophysiology. However, there has been a significant attrition rate of early and late phase trials. Here they present data from 16 compounds that failed to complete clinical development, despite positive results in the early phases of development . The autThe success of a clinical trial in the rare disease community may be based on many factors. The manuscripts within this issue have touched on some of the aspects that researchers must take into consideration. Furthermore, we must also remember that clinical outcome assessments utilised in clinical trials need to be robust measures  based up"}
+{"text": "At a time of growing enrollment among adult learners, student bodies are increasingly age diverse. Identifying and reducing age-related bias on campus may be multipurpose in supporting those who experience ageism while promoting professional skills to combat ageism in students' future careers. The extant literature has primarily focused on ageism in the workplace and ageism experienced by faculty and staff in higher education while less has focused on ageism experienced by adult students and the possible disruption this creates to feeling included as part of the campus community. We present data from a mixed methods study of adult learners assessing the extent to which they experience and are impacted by age-related bias on campus. Data are used to justify faculty and student training to improve intergenerational contact in the classroom and beyond under the broader umbrella of DEI initiatives."}
+{"text": "In the second phase, semi-structured interviews will be conducted via selective sampling to record participant opinions, experiences and expectations of using cancer-related health services.We expect to identify and explain important personal barriers and facilitators related to the use of cancer screening and treatment offers. Further interviews with stakeholders in cancer healthcare, such as physicians, nurses and self-help groups will be conducted to complement data from the service-providers\u2019 point of view. The results will be analyzed with behavioral and sociocultural theories to gain a deeper understanding of perceived and experienced barriers in accessing cancer care in Germany and to formulate recommendations for prospective targeted approaches and interventions.Our findings will be useful for facilitating knowledge transfer and policy dissemination to increase public awareness about cancer offers and improve participation rates. The results will be also used to develop an interprofessional teaching module in the medical curriculum as well as prepare and implement advanced training courses for medical professionals certified by the State Medical Association.This study is funded by Strube Stiftung Stuttgart."}
+{"text": "Chorioretinitis is a serious ocular complication of congenital syphilis (CS) that can cause permanent vision loss. While antibiotic use and public awareness have helped dramatically reduce the incidence of syphilis in the twentieth century, the US incidence of syphilis has more than tripled from 2000 to 2018 [The Stanford University Network for Diagnosis of Retinopathy of Prematurity (SUNDROP) study is a telemedicine screening platform for retinopathy of prematurity (ROP) used by member hospitals that lack access to quaternary pediatric retina specialists. The SUNDROP platform has been used in expanded indications beyond ROP to provide hospitals with pediatric retinal screening including the transmission of retinal images in infants with known or suspected CS. We retrospectively analyzed the SUNDROP database to examine a more recent incidence of chorioretinitis among cases of CS. This index study was conducted in accordance with the Health Insurance Portability and Accountability Act and the tenets of the Declaration of Helsinki and with local approval of the Institutional Board Review (IRB 8572).Thirty-seven confirmed and seven probable cases of CS were identified from 2015 to 2020 following Centers for Disease Control case definitions . An addiThese preliminary findings suggest that even as the incidences of CS have risen, chorioretinitis remains a rare complication. While these results are specific to CS in neonates, they are consistent with a recent study that found hospital admissions for syphilitic uveitis have not increased despite a growing incidence of admissions for syphilis . Althoug"}
+{"text": "Building a health data pipeline is an opportunity not only to review the efficiency of data flows and organisational processes but also to guarantee that the resulting data system incorporates data protection and fairness principles by design. This session will cover some key aspects of data protection and the principles of data fairness and ethics:Transparency, simplicity and fairnessThe importance of a diverse team with diverse expertiseKeeping the business objectives in mind and purpose limitationCompliance with data protection directives (GDPR)"}
+{"text": "After this article was published, similarities were noted between this article  and submIn response to queries about these concerns, the corresponding author provided the underlying data in The authors commented on aspects of how data were collected and analyzed for this study, but overall their responses did not fully resolve the concerns.PLOS ONE Editors issue this Expression of Concern to notify readers of the unresolved concerns discussed above, and to provide the data and updated figure received from the authors.The S1 File(ZIP)Click here for additional data file."}
+{"text": "Background: A large healthcare system in Georgia implemented an enhanced electronic infection surveillance system that is incorporated into the electronic medical record (EMR). Prior to the implementation of this electronic infection surveillance system, the infection prevention (IP) team performed healthcare-associated infection (HAI) surveillance through a locally created system that did not interface with their EMR. Each HAI identified undergoes a robust analysis for opportunities depending on the infection type by manual abstraction from the EMR, which is stored in a spreadsheet. One disadvantage of this spreadsheet is that only 1 person can enter data at a time. The coronavirus disease 2019 (COVID-19) pandemic has presented many challenges for healthcare facilities including shifting resources from HAI prevention programs. These programs include the investigations performed to identify risk factors that can aid in preventing future infections. Due to the necessity to increase efficiency in the current pandemic, the IP team proposed using technology to automate our HAI investigation process. Method: The IP team and the business intelligence (BI) team met to determine whether data completed in the electronic infection surveillance system could flow into an interactive data visualization software that is currently used for other HAI prevention dashboards. The existing spreadsheet was reviewed to select variables essential for HAI investigations and for which the data existed in the EMR. The BI team worked to find the correct data tables within the EMR so that the data could automatically refresh daily in the data visualization software. Result: The BI team was able to correctly identify variables used in the previously manual HAI investigation process within the EMR to interface with the data visualization software. This automation of investigations allows quick analysis of trends and areas of opportunity to prevent future HAIs. Conclusion: This utilization of technology can be applied to other healthcare facilities with similar software systems to streamline IP workflows. The automation of quickly and efficiently recognizing areas of opportunity allows IPs more time to facilitate the prevention of HAIs in other ways.Funding: NoDisclosures: None"}
+{"text": "The last decade has seen a remarkable resurgence of interest in psychedelic drugs such as psilocybin (from magic mushrooms) LSD and DMT (dimethyl tryptamine \u2013 the active ingredient of ayahuasca). This has been driven by the discovery that these psychedelics all act agonists of 5-HT2A receptors. Human imaging studies have revealed this action leads to profound alterations in brain measures of activity particularly in terms of increased entropy of EEG MEG and fMRI signals and reduced within-network, but increased between-network, connectivity. In addition they all can increase synaptic growth and brain plasticity. These findings not only explain the subjective nature of the psychedelic experience but also have implications for the treatment of internalising disorders such as depression addiction anorexia and OCD that are characterised by increased within network connectivity especially of the default mode network. Subsequent trials, particularly of psilocybin, in these disorders has revealed significant clinical benefits from even just a single administration. A number of companies have now been set up to extend these discoveries with regulatory-level trials that could result in market authorisations within a few years. My talk will explore these brain mechanisms and clinical data and discuss the potential place of psychedelic medicine in the future of psychiatry.I am an advisor to Compass pathways and Beckley Psytec two companies that are developing psychedelics for depression and other psychiatric indications. Several members of my research group receive support from these companies and also from Small Pharma."}
+{"text": "Although the primary goal of self-directed programs providing long term services and supports (LTSS) is to maximize choice and control for service recipients, such programs may also benefit family caregivers by compensating them for providing supportive services. This study draws on qualitative data from research supporting the RAISE Family Caregiver Advisory Council, finding that family caregivers themselves see the expansion of self-directed programs as a policy priority due to their need for financial security. The request for compensation was the strongest finding, with respondents highlighting the incompatibility of work with caregiving and their inability to rely on the existing paid workforce due to supply and quality issues; the consequences of this loss of earned income were reported as severe. Ultimately, respondents saw payment for providing care as an issue of fairness. This evidence supports the policy case for expanding access to self-directed programs that permit the employment of family caregivers."}
+{"text": "Frontiers in Psychology on Environmental, Social, and Corporate Governance (ESG) and Sustainability. After a thorough blind review procedure, we are pleased to announce that 19 articles have been selected for publication in the Research Topic. We believe that all of these articles address important aspects of ESG in this Research Topic according to the background detailed below.Welcome to this Research Topic of We are currently witnessing dramatic changes in the business environment  when they recall altruistic anxieties associated with COVID-19. Considering ESG also mediated the moderating effects. By introducing the nature of COVID-19 fears as a critical factor, this study made a worthwhile contribution to the literature on pro-environmental behavior.The fifth paper by Lee and Jeong confirmed that the compatibility and authenticity of social responsibility activities affect a firm's brand trust, thereby improving corporate sustainability management. The results of this study provided strategic implications for the performance of social responsibility activities necessary for the continuous growth of firms and for building brand trust.The sixth paper by Qing and Jin investigated whether CSR can affect sustainability through the economic and social performance of social enterprises (SEs). It also attempted to verify the moderating role of innovativeness in the relationship between CSR and SE performance. The results suggest that, while CSR can improve sustainability through economic and social performance, innovativeness has no moderating effect on the relationship between CSR and SE performance.The seventh paper by Bae et al. presented a new theoretical perspective on the relationship between the strength of environmental regulations and foreign direct investment (FDI), which is currently attracting increased scholarly attention. We argue through this new perspective that we should observe the strength of environmental regulations, which has been overlooked by previous literature, and the distance between countries in the FDI relationship. This will make it possible to obtain fresh insights and new ideas regarding the relationship described above.The eighth paper by Wang and Liu addressed two important research questions: \u201chow may various types of green innovation strategies matter in explaining the variation of firm performance?\u201d and \u201chow may various types of green innovation strategies interact with supply chain risks in illustrating firm performance variation?\u201d Using primary data collected from a sample of 337 firms in China, the study uncovered that the effects of green innovation strategies were statistically significant in elucidating the heterogeneity of firm performance, and their interactions with supply chain risks were also noteworthy and economically important.The ninth paper by Wang and Teng was motivated to address two major research questions: \u201cwhat contributes to the development of supply chain management (SCM) capability?\u201d and \u201chow does SCM capability matter in explaining the environmental performance variation of firms operating in large emerging economies?\u201d Using survey data collected from 272 firms in China, the study discovers that specific forms of digital innovation play a positive role in driving the development of SCM capability. The results of the empirical analyses provide further supportive evidence indicating that SCM capability functions as an important role by either partially or fully mediating the relations between the effect of digital innovation and firm environmental performance.The tenth paper by Yang and Yang examined the association between dynamic capabilities (DCs) and corporate performance in ESG management. This empirical study tested this as an alternative method using topic modeling with Word2Vec. The findings imply that DCs can enhance corporate performance under uncertainty and pursue a balanced way of sensing-seizing-recofiguring capabilities through ESG management.The eleventh paper by Son and Kim attempted to examine the relationship between ESG management and financial performance and the role of socially responsible investment by the National Pension Fund (NPF), Korea's largest institutional investor. Their primary discoveries are that Korean firms with good financial performance actively participate in ESG. NPF has a propensity to invest in firms with high financial and ESG performance.The twelfth paper by Lee and Yang investigated the impact of CSR performance feedback on future CSR performance to answer the following research questions: First, how does positive CSR performance feedback affect future CSR performance? Second, how does negative CSR performance influence future CSR performance? By performing generalized least squares (GLS) regression analysis based on Korean company data from 2012 to 2019, their empirical findings document that positive social and historical performance feedback positively affected CSR performance.The thirteenth paper by Liang et al. explored the role of DCs for ESG strategies as well as sustainable management performance. A research model was established by using DC theory, thereby integrating sustainable management and ESG literature. According to the results of their statistical analyses, both absorptive capability and adaptive capability have considerable effects on sustainable management performance through implementation of the ESG strategy as a mediating factor.The fourteenth paper by Wu and Kuang began with its anticipation that key subordinate executives would play a role linking superiors and subordinates within the top management team (TMT). Based on their recognition of the heterogeneity of TMT preference, data from Chinese listed firms from 2010 to 2019 were used. Their empirical results exhibited a positive relationship between key sub-level executives' governance and accounting conservatism. They also indicated that CEO overconfidence could positively modulate this relationship.The fifteenth paper by Li and Qamruzzaman examined the nexus of tourism-driven sustainable human capital development (HCD) in emerging economies from 1984 to 2019. In this process, they observed a statistically substantial and long-lasting favorable correlation between tourism and HCD.The sixteenth paper by Park and Oh identified the different types of information used by investors to make investment decisions based on the UTAUT (Unified Theory of Acceptance and Use of Technology) model. This paper figures out how ESG information affects the decisions of individual investors regarding investments and the factors that affect such behaviors.The seventeenth paper by Park et al. used text scraped from Twitter. It polished the data to identify trends in ESG themes and their sentimental value over time. This paper informs us how the general public feels about ESG through sentiment analysis.The eighteenth paper by Lee et al. addressed that ESG at the host country level significantly impacts the implementation of clean development mechanisms (CDM). Moreover, the results of zero-expansion Poisson regression extended the ESG pillar based on institutional theory and emphasized the importance of sustainable development.The nineteenth paper by As a final remark, the guest editors would like to thank all the reviewers and all those who submitted papers to this Research Topic. The editor-in-chief of Frontiers in Psychology, Axel Cleeremans, also deserves special gratitude. We are incredibly appreciative of the participants' kindness and efforts, both of which have made this special edition possible.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.This work was supported by the Soonchunhyang University Research Fund.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Pharmaceutical treatment and psychotherapy constitute the most common treatment methods for depression and anxiety. Physical training has been shown to have comparable effect to cognitive behavioral therapy in treatment of mild to moderate depression and anxiety. Physically active individuals also show lower risks to develop depression and relapse in depression.The objectives are to evaluate how physical activity can affect depressive and anxiety symptoms, by examining biomarkers in the blood and from the gut and also by measuring cognitive functions. Hopefully, this can lead to new treatment strategies for patients with depression and anxiety.102 patients are randomized to two groups and undergo 12 weeks intervention as add-on to standard outpatient psychiatric treatment. The first group will participate in physical training three times per week and the other group will receive relaxation therapy on a weekly basis. Daily activity intensity will be measured before and at the last week of intervention with an accelerometer. Blood and faeces sample collection, symptom grading by clinician together with self-rating scales and cognitive screening will be performed at baseline, week 12 and one year of follow-up. The cognitive screenings are performed digitally in cooperation with Mindmore.The RCT is currently recruiting patients at the Department of Psychiatry of \u00d6rebro University Hospital.The project aims to be holistic in its approach, combining the defining clinical psychiatric symptoms in patients who have both depression and anxiety with the finding and evaluation of new biomarkers from blood and gut to improve cognitive functions.No significant relationships."}
+{"text": "Ageing world populations and increases in life expectancy have facilitated an interest in developing ageing models that promote inclusivity and positive perceptions of ageing. This scoping review examines how and to what extent research that utilizes successful, active, productive, and healthy ageing framework(s) include death or dying. The study followed Joanna Briggs Institute\u2019s methodological standard for scoping reviews and PRISMA guidelines and conformed to Arskey and O\u2019Malley\u2019s five-stage framework. A thematic analysis was used to identify how research utilizes the concepts of death and dying in the context of positive ageing models. The analysis identified five core themes: (a) the critique that death and dying dimensions in positive ageing models are absent; (b) older adults\u2019 outlooks on death and dying while ageing well; (c) religious and spiritual dimensions of ageing well; (d) negative consequences of positive ageing models without death and dying dimensions; and (e) the future of death and dying in positive ageing models. The results bolster support for a paradigm shift that redefines what it means to age successfully without denying death. Incorporating the topics of death and dying into ageing conversations encourages individuals to ponder their end-of-life preferences and proactively participate in their advanced care plans. Death and dying conversations help care providers support people to live and die in a manner that is meaningful to them and inspire those receiving care to live fully and deeply and to think about the legacy that they want to leave."}
+{"text": "Under the skin is an intricately woven tale of Professor Alex Anstey's career as a junior doctor then general practitioner and ultimately academic dermatologist working in the NHS. Personal memoirs are punctuated by amusing clinical vignettes, key moments in recent British political history and chapters devoted to heroes in health care. These influential and inspirational men and women range from military nurses to the founding father of evidence\u2010based medicine to pioneering Oxford Regius Professors and giants of medical education. These heroes have been well researched, and the quirky details the author has uncovered will delight readers.The book provides valuable insights into the history, the machinations and struggles of the NHS both in the early days and during the pandemic. Anstey details his inspiration and journey to improve clinical efficiency in his corner of Wales. In 2000, his efforts ultimately led the Gwent Healthcare NHS trust in winning the UK Dermatology Team of the Year. The foundation of repairing a strained hospital system he details is based on consultation with all team members and connecting with the local GPs through personal interactions, education, triage and telehealth. This is a thoughtful book on how health services run and how clinicians must be in tune with both their support team and their managers, with lessons applicable beyond dermatology.Other chapters are devoted to academia, research, scientific journal stewardship and politics. Contemporary themes of teledermatology (even more relevant post\u2010COVID\u201019) and patient partnership or empowerment are discussed. The charming Welsh personalities and stories only augment the tale. I enjoyed this beautifully written book very much and would recommend it to not only dermatologists but all healthcare workers with an interest in hospitals and health management. If you have worked in the NHS or aspire to building a better team, equally this is essential reading.No conflict of interest to declare."}
+{"text": "Autism is a neurodevelopmental disorder that is considered more common in males; however, ascertainment estimates of ASD in the UK population suggest a significant proportion of female cases of ASD go unrecognised and undiagnosed. This review examines whether the apparent underdiagnosis of girls may be attributed to gender sampling bias in the validation of diagnostic instruments routinely used to diagnose autism.To compare the gender ratio in validation samples of commonly used diagnostic tools for autism to estimates of the gender distribution of children with autism in the UK populationA review of diagnostic tool manuals and a targeted literature search identified the gender of sample participants used to validate tools used by Scottish ASD services. Analysis of validation samples compared the mean percentage of female participants with ASD to estimates of the proportion of girls with ASD in the UK population.Data on 7 tools was extracted. The mean percentage of female sample participants with ASD was significantly lower than the ascertainment estimate of females with ASD in the UK population =-3.67) and significantly lower than the mean percentage of females in comparison groups =-3.06).There is low representation of females in validity samples of tools, which may reduce their sensitivity to the female phenotype and contribute to diagnostic disparities. Future research is warranted on why instruments are poorer detectors of ASD in girls and how female features of ASD could be better represented in their structure."}
+{"text": "RCP is defined as the \u2019ratio of the activity of a radionuclide in a stated chemical species in a material over the total activity of all species containing that radionuclide in this material\u2019  and/or Instant Thin-layer Chromatography (ITLC) under the same experimental conditions for cross validation . The rules of Good Radiopharmacy Practice (GRP) dictate that RCP of an injectable radiopharmaceutical The paucity of purified actinium materials combined with the lack of stable isotopes and measurable spectroscopic properties for this element has prevented the isolation and structural investigation of authentic samples of its coordination compounds and made it arduous to determine their chromatographic properties (Deblonde et al."}
+{"text": "The last decade has witnessed huge technological advances in genomics, particularly in DNA sequencing. Here, we review the actual and potential application of genomics in supporting in situ conservation of crop wild relatives (CWRs). In addition to helping in prioritization of protection of CWR taxa and in situ conservation sites, genome analysis is allowing the identification of novel alleles that need to be prioritized for conservation. Genomics is enabling the identification of potential sources of important adaptive traits that can guide the establishment or enrichment of in situ genetic reserves. Genomic tools also have the potential for developing a robust framework for monitoring and reporting genome\u2010based indicators of genetic diversity changes associated with factors such as land use or climate change. These tools have been demonstrated to have an important role in managing the conservation of populations, supporting sustainable access and utilization of CWR diversity, enhancing accelerated domestication of new crops and forensic genomics thus preventing misappropriation of genetic resources. Despite this great potential, many policy makers and conservation managers have failed to recognize and appreciate the need to accelerate the application of genomics to support the conservation and management of biodiversity in CWRs to underpin global food security. Funding and inadequate genomic expertise among conservation practitioners also remain major hindrances to the widespread application of genomics in conservation. It is estimated that there are about 50,000\u201360,000 CWR species globally, out of which 700 need to be prioritized for conservation  and its CWRS, thus resolving the gene pool classification in this genus which has remained inconsistent and contradictory  was developed with the aim of providing a globally coordinated and harmonized system of biodiversity monitoring  Walp landraces and wild relatives has provided insights on the crops domestication suggesting a divergent domestication process   which is a perennial CWR of wheat  (Zs\u00f6g\u00f6n et al., Domestication marks a major deliberate effort of promoting the use of wild plants by manipulating their genetic and phenotypic traits in order to suit the needs of human kind. Genomics presents tools, resources and knowledge to accelerate domestication of new species thus potentially enhancing food and nutritional security (Brozynska et al., 9.2Provisions that allow utilization of in situ CWR genetic diversity should be tempered with appropriate laws and regulations that prohibit illegal harvesting and over\u2010exploitation that could threaten the survival of the CWRs. Such regulatory frameworks should have sufficient and enforceable safeguards that helps prevent bio\u2010piracy. Molecular analysis is aiding law enforcement and regulatory authorities in detecting cases of illegal harvesting and trade of wild populations (Aubriot et al., It has been argued by Wambugu et al.  that adv9.3Solanum demissum Lindl and stem rust from wild wheat Aegilops tauschii Coss into the respective cultivated gene pool (Prescott\u2010Allen & Prescott\u2010Allen, Climate change currently poses the single largest threat to world agriculture and global food security. Although CWR populations are facing immense threats in the wild due to climate change, those populations that will successfully withstand these threats will be a useful source of genes for breeding for increased climate resilience. Genomics is providing tools to dissect the genetic basis of important traits and understand the functional trait diversity that is available in CWRS. Information on candidate genes and trait associated genetic markers is important in accelerating the use of CWRs in breeding programmes. The use of CWRs in crop improvement is particularly important in crops where genetic gain has been low as a result of inadequate variation in the domesticated gene pool for key target traits. Genomic data has enabled identification of regions that have lost important genetic diversity during the domestication process (Wang et al., 10One of the major challenges facing in situ conservation is that the majority of CWRs are poorly studied and may not have a lot of genomic information and resources which may be required to guide conservation management. For species with limited genomic information, there have been considerable advances in genomic technologies allowing genome wide marker discovery, even for poorly studied taxa. Genotyping by sequencing is a powerful marker technology which is suitable for species with no reference genome sequence (Elshire et al., The cost, computational requirements and necessary bioinformatic expertise for deploying genomics is high and may be beyond the reach of most conservation practitioners thus hindering its real world application (Flanagan et al., In future, genome editing might offer an opportunity to support PGR conservation by introducing novel alleles that confer adaptive capacity against climate change as well as removing deleterious ones that reduce fitness (Breed et al., The authors declare no conflict of interest.Peterson W. Wambugu wrote the first draft. Both authors contributed to the editing of the manuscript."}
+{"text": "This study uses data from the 2017-2018 National Health and Aging Trends Study and the 2017 National Study of Caregiving to examine whether caregiving network configuration factors  and caregiver supports  are associated with consequences of unmet needs among older adults. Findings from this study will provide greater understanding of how caregiving contexts shape the quality of care and health of older adults who rely on help from family caregivers."}
+{"text": "Youth radicalization is an ongoing and growing challenge worldwide , 2. AdolRadicalization Among Adolescents authors from various countries address this issue and illustrate how youth are disproportionately represented in radicalized networks across different continents. Now more than ever it is essential scholars and policymakers attempt to better understand the underlying mechanisms and factors driving youth radicalization and formulate effective policies and interventions. In addition to addressing this priority, this Research Topic also considers the role that psychopathological factors play in individual processes of youth radicalization and examines how young people who hold extremist views and experience psychological vulnerabilities, can be best supported by professionals.In the Frontiers for Psychiatry Research Topic: Miconi et al.); to social networks and psychological manipulation , mental health and trauma , and psychopathology . Several papers show that that the relationship between psychopathology and violent extremism is not straightforward or one-dimensional and that it interacts with other factors. One of several articles by French scholars illustrate that psychological trauma can create vulnerabilities to radicalization amongst youth. In such cases treatments targeting psychological trauma may be one way to prevent violent radicalization.A number of articles in this Research Topic, explore various underlying mechanisms of youth radicalization ranging from the influence of personal uncertainly and negative outlooks about life . This can increase the risk of biased and incorrect interpretations of what places youth at risk of radicalization. Prevailing public and political assumptions about the causes and manifestations of violent extremism can reinforce particular viewpoints and lead to inappropriate counseling and treatment options for radicalized youth across different ideological spectrums. How best to intervene with radicalized youth is a developing field of knowledge and experience is in its infancy. As Australian experience highlights, pluralistic, non-punitive multidisciplinary approaches can be used to address various developmental and psychosocial vulnerabilities, in addition to violent extremist risk factors amongst young offenders (Barracosa and March). These approaches should be supplemented by youth-specific practitioner expertise, and a range of violent extremism case management and risk assessment measures. In another paper by French scholars, the authors conclude that professionals must consider individual risk factors and vulnerabilities, but also need to tap into existing strengths, resilience and coping strategies that youth at risk of radicalization can possess and implement forms of psychotherapeutic support for this group .Among practitioners there can be a lack of specialist knowledge with regards to psychopathology and extremism among young people. A demonstrated by a Dutch paper such knowledge and expertise is not always available  and all raise important questions about youth radicalize and what can be done about it. This includes whether young people involved in violent extremism differ in their risks and vulnerabilities compared to adults who have radicalized or other \u201cordinary\u201d delinquents? Does this therefore require different forms of tailored treatment? Findings from papers in this Research Topic are derived from cohort studies and individual case studies and all draw attention to overlapping and divergent factors and processes. While the evaluation of youth specific deradicalization programs is lacking [, BarracoAll authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "To gain an understanding of the attribution of patients to newly introduced Ontario Health Teams (OHT). OHTs are responsible for organizing and delivering health local care based on established connections between patients, their primary care providers, and hospitals. Furthermore, we aim to identify areas with poor geographic access to care.We used GIS analyses and maps to depict the attribution of patients to OHTs based on their uptake of primary care and hospital referral patterns. Residents of a specific local area can be attributed to different OHTs based on their prevailing health seeking choices. This leads to a creation of non-unique OHT \u2018capture zones\u2019, which may pose challenges in primary health care planning and delivery.The range of spatial analyses and maps used in this study helps to overcome some of these limitations and provides healthcare administrators with important geographic layer of information not available through other data summary methods.We used GIS analyses and maps to depict the attribution of patients to OHTs based on their uptake of primary care and hospital referral patterns. Residents of a specific local area can be attributed to different OHTs based on their prevailing health seeking choices. This leads to a creation of non-unique OHT \u2018capture zones\u2019, which may pose challenges in primary health care planning and delivery.The range of spatial analyses and maps used in this study helps to overcome some of these limitations and provides healthcare administrators with important geographic layer of information not available through other data summary methods.These attribution maps and data tables are an essential resource for planners and decisions makers in identifying priorities within the regional provision of primary care. This knowledge is essential to a better understanding of health care needs of local populations, and to implementing improvements in health care access."}
+{"text": "Joy in Motion is a nationwide physical activity and well-being programme aimed at early childhood education and care (ECEC) launched in 2015 in Finland. The aim is to enable every child to be physically active and enjoy physical activity every day. Latest updates of the Finnish recommendations for physical activity in early childhood was published in 2016. The key message in the recommendations is Joy, play and doing together. Daily physical activity is just as important for children's well-being as healthy nutrition and sufficient sleep and rest. Presentations discuss the current state of the programme with more than 2200 registered early education units and provides concrete examples of the promotion work in practice."}
+{"text": "The authors regret that the author contributions were incorrect in the original article. Two co-first authors were originally indicated, however Fangfang Zhao should be the only first author as indicated here.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "This paper outlines a mixed methods research study conducted at three independent boarding schools  that all focus on sport and physical activity. In total independent boarding schools attracts more than 30.000 students per year, which makes it a very popular choice for young people. Interestingly, this particular type of schools have not been researched much.This study aims to provide an insight into the special qualities of Danish independent boarding schools and explore how a focus on sport and physical activity in relation to personal development of young people plays a role at three of these schools.The analyses are based on an online survey distributed to 1020 students at the participating schools in March 2019. In total, 865 students answered the survey. The purpose of the survey was to collect quantitative data on background issues, the students' motives for choosing independent boarding school life and to gain an insight into what the students' perceived as the special qualities of living on such a school - typically for one year. The quantitative findings are enriched by empirical findings and conclusions from qualitative data generated via six MSc theses.The survey results show that students to a great extent choose an independent boarding school based on the sports program (73%), facilities (69%) and sport performance levels (51%). The students point out getting new friends (92%), being a part of a community (92%), learning to collaborate (91%) and solving conflicts (88%) as some of the special qualities of life at independent boarding schools. The qualitative analyses reveals that sense of community, social interaction with fellow students and the relationship between teachers and students are perceived as the main qualities of this type of school life. Furthermore, the analyses points out that sport and physical activity can both hinder and promote qualities as the ones mentioned.The study contributes to new and important insights into a popular and unique type of school in Denmark, but more research is undoubtedly needed."}
+{"text": "The corrected images for Figure The authors regret that the original version of our paper, unfortunately, contained incorrect pictures in Figure The correction made in this erratum does not affect the original data and conclusions. The authors apologize for any inconvenience that the errors may have caused."}
+{"text": "Health systems are the central part of infrastructure in societies and their smooth operation is important for the continuation of a wide range of critical operations in any country. The COVID-19 pandemic has actualised questions on health system resilience defined as the system's ability to prepare for, manage  and learn from external shocks.. However, economic recessions as well as long- and short-term stresses related to aging, climate change and migration, and most recently a war have underlined that also in Europe the governments need to prepare their health systems to face different types of threats in order to guarantee effective protection to population health in their countries. The importance of the task to strengthen health system resilience has been comprehended at national and international level. International actors including WHO, OECD and World Bank have designed policy advice on strengthening health systems against external shocks, the European Union has launched programmes for preparing for future health emergencies, and individual countries are designing policy and system reforms allowing for health crises. In the workshop we address policies to strengthen health system resilience drawing on the experiences in three countries: Ireland which entered the COVID-19 pandemic with a legacy of the recent economic crisis hitting hard health care financing, Finland which has been implementing a major health care reform concomitantly with the pandemic, and Denmark which offers a case study on organisational learning from the pandemic within the hospital sector and chronic patient care. Based on these three case studies the workshop also contemplates whether learning from shocks is always helpful in terms of system transformation or whether they can also create path dependencies that weaken the systems\u2019 ability to prepare for unknown threats. The workshop will broaden the view by discussing the trends of health system reforms in European countries and considering international advice on system and policy reforms to strengthen health system resilience.\u2022\u2002Shocks create opportunities for reform and better performance and challenges through overloaded systems and fast decision-making.\u2022\u2002Assuming all shocks are like the last weakens preparedness and adaptability."}
+{"text": "There are development and advancement on concepts and methods for applications in neurorobotics that are continually achieved and published. This Research Topic provides a mini collection of up-to-date technologies and methods which address challenges and tackle limitations in neurorobotics. Those technologies and methods collected in this Research Topic involve various applications in neurorobotics ranging from human machine interface, rehabilitation, and treatment.Assessment methodology for human-exoskeleton interactions: Kinetic analysis based on muscle activation . A new assessment protocol on human-exoskeleton interaction that requires a fewer number of instruments and leads to an easier process was proposed.Kinetic parameters and effects associated with the interaction between human and exoskeleton based on electromyogram (EMG) and muscular activities were evaluated in Influence of proprioceptive training based on ankle-foot robot on improving lower limbs function in patients after a stroke . The experimental results suggest that the motor function and walking ability in patients after a stroke can be effectively improved from the proprioceptive training based on an ankle-foot robot.The influence of proprioceptive training on lower limb function in patients after a stroke was examined and presented in ClueDepth Grasp: Leveraging positional clues of depth for completing depth of transparent objects , a deep learning technique was developed for improving a perception on transparent objects for machines and robots. The better accuracy and successful employment of a humanoid robot grasping were achieved. The ClearGrasp dataset that is a set of images of transparent objects is made publicly available at https://sites.google.com/view/~cleargrasp/data?authuser=0.In Blind detection of circular image rotation angle based on Ensemble Transfer Regression and fused HOG  is another work that develops a deep neural networks model for improving a perception of machines and robots. The improved performance on accuracy of rotation angle estimation can be achieved using the ensemble transfer learning regression networks model.The comparison of electroencephalography power and event related potential in success and failure during multitask game . A significant difference in EEG power associated with a theta band (4\u20137 Hz) was evidenced. This finding thus implies that the theta power of EEG acquired from the frontal area of the brain can be applied for predicting the success or failure of the Go trial.A video game has been adopted as a part of treatment for children with attention-deficit hyperactivity disorder (ADHD). The brain activity of subjects during playing and interacting with a multitask game in virtual reality (VR) was focused in The author confirms being the sole contributor of this work and has approved it for publication."}
+{"text": "Most of the lectures and workshops were offered via the Microsoft Teams platform. Student presentations were delivered virtually as well. Due to social distancing requirements, practical junior peer teaching opportunities were not available. We were surprised to observe high levels of enrolment during the virtual offering of the elective, with no decline in participant numbers.,,,Previous studies have evaluated the perceptions and experiences of student participants of similar teaching electives offered at institutions across North America.Future studies will be needed to examine the impact of the elective offered in the virtual format during the COVID 19 pandemic \u2013 and a shift in focus from observing and evaluating bedside and physical examination skills to evaluating virtual didactic presentations. Presently, 50% of medical schools in the United States (and only our institution in Canada) offer a dedicated fourth-year medical school elective in clinical teaching.The authors declare that they have no conflict of interest."}
+{"text": "Assessing the performance of health systems is essential to initiate policy processes that further strengthen health systems to improve population health. Starting with WHO's World Health Report of 2000, Health System Performance Assessments (HSPA) gained increasing attention in research and policy. By now, several comparative HSPA initiatives of international organisations  and country specific HSPA  were implemented in Europe. Further countries are currently in the process of developing or piloting an HSPA . The objective of the workshop is to foster and strengthen the interchange of different HSPA initiatives in Europe and beyond. While each health system has its specifics, initiatives likely face similar challenges in the implementation and ongoing development, which holds a lot of potential for learning from each other. The workshop is supposed to be a platform for the exchange of and about HSPA initiatives and related topics by bringing together stakeholders of different countries and professions. Participants are supposed to gain new insights into recent activities in Europe and will be able to discuss challenges and lessons learned. The presentations give insights into recent activities of selected HSPA initiatives in Europe. One presentation originates from the Belgian HSPA which is well established. This presentation will focus on the transversal dimension of equity, on which a separate report was recently published. The second presentation is about the German HSPA which is still in development and currently tested in a pilot study. Both presentations represent HSPA initiatives at different stages, which provides a good basis for the following panel and discussion with all workshop participants. The two presentations of about 20 minutes each will be combined with a panel discussion. Afterwards, there will be room for exchange and discussions between all participants and presenters.\u2022\u2002Recent developments of HSPA initiatives in Europe will be presented along two examples from Belgium and Germany and lessons learned and challenges will be discussed.\u2022\u2002The workshop provides a platform for the exchange of and about HSPA initiatives and related topics by bringing together stakeholders of different countries and professions."}
+{"text": "Over time the prevalence of methamphetamine associated psychosis (MAP) has increased globally including Asia and Europe. Shoptaw et al looked at an RCT and concluded that olanzapine is superior to haloperidol in terms of tolerability and the side effect profile as it causes fewer extrapyramidal symptoms. Another study by Xue et al compared the efficacy of olanzapine and haloperidol and found that they had comparable effects but the onset time in the olanzapine group was significantly earlier than the haloperidol group. Srisurapanont et al analyzed 6 RCTs and concluded that quetiapine and olanzapine are probably superior than aripiprazole and risperidone.The purpose of this review is to find out if olanzapine is better than other antipsychotics in treating methamphetamine-induced psychosis.PubMed, SCOPUS, and Web of Science literature databases were screened and filtered by using specific search terms, inclusion/exclusion criteria. Texts of the selected articles and trials were reviewed and the search terms generated a total of 248 results from the databases. After applying the criteria 200 citations were left and 15 papers were reviewed.The literature review concluded that olanzapine can be used as an effective treatment for methamphetamine-induced psychosis. Olanzapine can help to reduce the psychotic symptoms in MAP with a quicker onset and lesser side effects.Olanzapine can help in the treatment of methamphetamine-associated psychosis and can be considered as the first-line therapy. Research is further needed with a higher pool of candidates in the future to compare the efficacy and tolerability of different typical and atypical antipsychotics.No significant relationships."}
+{"text": "Dementia is a progressive, irreversible neurological disorder that causes changes in cognitive function and behaviour. While at least 5% of people who develop dementia every year are under the age of 65, dementia in the workplace is currently not well recognised or supported. The changes associated with dementia present multiple challenges for individuals who wish to continue with their employment. Many lose their positions before receiving a diagnosis, whilst others take sick or disability leave or early retirement. The process of understanding what is happening and coping with this new situation is highly individualistic and involves several transitions. The MCI@work project is an international initiative taking place in Canada, Finland, and Sweden where we examine these transitions through the personal narratives of individuals who have either currently or recently gone through the experience of developing dementia whilst in the workforce. From these data, we have developed a framework for understanding the transitions experienced by people who develop dementia whilst in the workforce. The aim is to assist individuals and their employers to better understand the needs of people living and working dementia as well as engage in appropriate actions that support choices and dignified transitions either within the context of employment or out of the workforce."}
+{"text": "This document is written on behalf of the two professional bodies in the United Kingdom that represent genetic counsellors (the Association of Genetic Nurses and Counsellors) and clinical geneticists  and aims to support multidisciplinary working of these professional groups highlighting within a quick-reference format, areas of shared practice and the distinctions between role profiles for a Consultant Clinical Geneticist, Principal/Consultant Genetic Counsellor and the new support role that we have termed \u2018Genomic Associate\u2019, see AGNC career structure . This bu In the United Kingdom clinical geneticists are medically qualified Members/Fellows of the Royal College Physicians or equivalent, where Clinical Genetics is an affiliated medical specialty. Genomic or genetic counsellors are allied health professionals with Masters level accreditation from the Genetic Counsellor Registration Board included in the Academy for Healthcare Science register and clinical scientists  accredited by the Health and Care Professions Council.We acknowledge there is currently variability in these roles between NHS trusts and exceptions where the scope of practice for one professional group exceeds what is provided below in Fig.\u00a0In Fig."}
+{"text": "The Sage Resource Project\u2019s goal was to prepare researchers to use the Sage Resources to create Sage Model boards in order to continue to expand and amplify the voice of older adults in aging PCOR/CER research. Training researchers is essential to amplify the voice of older adults in research. This project culminated in the creation of a training manual as well as critical lessons learned for the advancement of engaged research with older adults receiving Long Term Services and Supports (LTSS). After developing a series of webinars for national dissemination, 5 research centers were identified as potential sites for intensive and tailored training on The Sage Model and, ultimately, two research centers completed the training with quite different approaches and results. This session will review the training that was developed as well as the lessons learned from training researchers on creating research advisory boards with older adults."}
+{"text": "The COVID-19 pandemic has exposed Public Health system weaknesses due to chronic underinvestment in Public Health. In this context, Essential Public Health Functions (EPHFs) have been revitalized as an integrated, cost effective and sustainable approach to operationalising Public Health. The World Health Organization's recent position paper on building health systems resilience towards universal health coverage and health security recommended investing in EPHFs as a key mean for countries\u2019 health systems recovery and transformation during COVID-19 and beyond. There is a need for conceptual and operational clarity of EPHFs to support countries to build back better, fairer and more resilient health systems.A rapid review of peer-reviewed and grey literature regarding the EPHFs was conducted to identify different actors\u2019 understandings of EPHFs and key lessons of applying the EPHFs at the global, regional and national levels, in order to identify the added value and key enablers to operationalising EPHFs. A crosswalk analysis of different authoritative lists of EPHFs was conducted to develop a common list of EPHFs as a reference for countries in response to Public Health challenges.A consolidated list of 12 EPHFs derived from the crosswalk analysis of different authoritative lists is presented, underpinning the consideration of health systems components and pressing health challenges. Six key enablers are identified from evidence and experience. These enablers are fundamental for countries to build holistic and strong Public Health capacities.The EPHFs provide a clear and integrated framing to operationalise Public Health in countries that can be adapted to country contexts to build resilience. Health authorities and other Public Health stakeholders must seize the opportunity brought by COVID-19 recovery to continue advocating for and strengthening Public Health as a priority in health systems\u2019 reconstruction and reform."}
+{"text": "It is now widely accepted that most microorganisms live within communities and not as single cells. The interaction between species within the community drives the behaviour of the population and its adaptation to various ecosystems and hosts. This relatively recent concept has triggered the emergence of a whole research field in Microbiology aiming at understanding the structure and organisation of bacterial biofilms combined with the detail of microbiome composition and evolution. Researchers also joined forces in what is a multidisciplinary field of investigation calling for knowledge from basic microbiology to surface chemistry and all the way to advanced omics and microscopy methodologies. The National Biofilms Innovation Centre was launched in 2017 to address the impact of biofilms on global challenges from antimicrobial resistance and food safety to water security by bringing together UK research and businesses to drive the translation of biofilm research into innovative solutions. Since its creation, NBIC has built a national partnership with 63 UK research institutions and more than 250 companies and an international partnership with biofilms centres across the world including the Centre for Biofilm Engineering (CBE) in the United States (Montana) and the Singapore Centre for Environmental Life Sciences Engineering (SCELSE).npj Biofilms and Microbiomes has been created to review the impact of biofilm across sectors, illustrate some translational research on biofilm carried out by NBIC partners and highlight key issues on the successful translation of biofilm research. The collection addresses the four interventional pillars of NBIC: prevent, detect, manage and engineer.This special collection in 1, with biofilms being central to some of the most important global challenges. Addressing these challenges through the above interventional pillars opens endless opportunities for growth by harnessing and controlling the biological activities of complex biofilms.Biofilms have an economic impact of 5Tn USD ($) per year across multiple sectors, as detailed in perspective by Camara et al.Prevent theme focuses on the prevention of early stage microbial adhesion and colonisation events at surfaces and interfaces and curtailing the development and maturation of early stage biofilms. The two main approaches used to prevent biofilm formation are through early microbial killing or preventing the establishment of the biofilm in the first place. This collection shows two examples of these approaches. The work from Barbieri et al.2 uses a simple way to functionalise a common silicon-based polymer utilised in biomedical and industrial applications for the slow release of antimicrobials already approved for human use. This modified polymer can drastically reduce the ability of bacteria to colonise these surfaces providing a scalable new alternative for the functionalisation of catheters, dressings and in-dwelling medical devices to existing strategies, such as the in situ generation of silver nanoparticles3. In another study, Pentland et al.4 show that C. albicans uses CO2 found in the host environment to promote its ability to colonise and compete for nutrients. These findings reveal that the design of therapeutic interventions targeting CO2 utilisation could be used as a new approach to prevent C. albicans biofilm formation in high CO2 environments paving the way for new therapeutic approaches against infections caused by this organism.The Detect theme focuses on the requirement for accurate, quantitative biofilm detection and also measurements across multiple scales through innovative sensing, tracking and diagnostic technologies. The detection and quantification of morphological changes in a biofilm is frequently done using confocal microscopy. However, there have been issues with regards to the reproducibility of image analysis across laboratories due to some of them not reporting the full exact imaging methods and parameters used. This is essential when biofilm interventions are compared across laboratories using techniques such as LIVE/DEAD\u00ae staining. Mountcastle et al.5 have developed an automated image analysis approach which has shown reproducible and robust results in a range of bacterial species biomass and cell viability measurements. This method is highly accessible to researchers from different disciplines supporting their biofilm translational studies. There is also a need not only to visualise and quantify biofilms but also to develop novel technologies which enable scientists to visualise changes in a biofilm in real time such as viability and metabolic changes. A study by Wang et al.6 shows the use of resonant hyperspectral imaging to monitor in real-time bacterial cell attachment and micro-colony formation. With this technique the authors were able to focus on the underside of the biofilm providing a very clear picture of the early stages of biofilm formation and the fate of biofilms in response to antibiotics treatment. Another study by Hollmann et al.7 show the development of ratiometric fluorescent pH-sensitive nanosensors which enable the visualisation of pH changes in biofilms. Here the authors demonstrated that these nanosensors could be used to detect sugar metabolism in real time. The use of alternative dyes in these nanosensors will generate powerful tools to monitor wider microniche changes within biofilms at high resolution.The Manage theme is to kill, remove or control established biofilms by exploiting the knowledge gained from understanding the mechanisms governing biofilm life cycle dynamics and development, their physicochemical properties, and levels of complexity across a range of environments. Biofilms can adapt quickly to changing environmental conditions and rapidly select for mutants that increase their fitness. This poses a serious issue in the clinic with the adaptation of biofilms to antibiotic use. Some of these biofilms, and the cells sitting within different regions of such an environmentally heterogenous structure, are frequently exposed to sub-inhibitory concentrations of antibiotics yet, there is limited understanding of how they adapt to these levels of antibiotics. Trampari et al.8 show that biofilms from Salmonella Typhimurium exposed to sub-inhibitory concentrations of three antibiotics rapidly evolve resistance to them. This adaptation resulted in a deficit in biofilm formation but strains forming the least biofilms were more virulent in a Galleria mellonella infection model resulting in the lowest survival rates. This is supporting both the concept of lifestyle switch and trade-off when gaining novel function/feature. The resilience of biofilms to the action of antibiotics has also led to a search for novel approaches to eradicate them. One of these approaches is based on the use of phage components such as endolysins. In a study by Arroyo-Moreno et al.9 the authors show that endolysins can disrupt Gardnerella vaginalis both in single species and polymicrobial biofilms with no effect on microorganisms from the commensal vaginal flora nor the emergence of resistance, offering a promising strategy to combat bacterial vaginosis. An alternative approach to identify novel antimicrobials is to search from them in microbiomes as they are a great resource for bioactive molecules which has been very much unexploited. In the study by Mulkern et al.10 the authors used antimicrobial peptides form rumen microbiome that show high effectiveness against Pseudomonas aeruginosa biofilms with low cytotoxicity and hence therapeutic potential. Finally, when designing new antimicrobials, it is important to understand their impact on different components of the biofilm such as the extracellular matrix, especially if the drug interacts with it like polymyxin B. One of the most common ways to visualise changes in this matrix requires the use of dyes which can frequently alter its physicochemical properties preventing an accurate visualisation of the changes. To overcome this limitation, Powel et al.11 have used multiple particle tracking (MPT) to characterise the physical and mechanical properties of antimicrobial resistant (AMR) bacterial biofilms and quantify the effects of antibiotic treatment. Using nanoparticles (NPs) of varying charge and size they were able to quantify the diffusion and mechanical effects of antibiotic therapies within the AMR biofilm matrix as a result of changes in the viscoelasticity of the biofilm. The authors found that this approach offers a valuable tool for the pre-clinical screening of new antibiofilms.The mission of the Engineer theme is the control of biofilms in industrial environments and large-scale infrastructure, and the engineering of bespoke biofilms for targeted applications.The vision of the 12 reveals that microbes in lower abundance could have a key role in anaerobic digestion maintaining the stability and functionality of microbial communities. Therefore, the ecological role of low-abundance taxa should be further investigated in bioreactors with significant environmental impact. Biofilms can also be engineered to reduce the impact of global warming by contributing to the reduction of CO2 levels. A range of approaches, including electrochemical methods, have been developed to reduce CO2 to valuable chemicals. As such, microbial electrosynthesis (MES) offers an alternative for the sustainable conversion of CO2 into valuable organic chemicals at the cathode of bio-electrochemical systems where microorganisms are used as biocatalysts. A major bottleneck with MES lies with the development and scale up of the technology due to the slow development of CO2-reducing biofilms on the cathodes. Izadi et al.13 showed a strategy which can potentially bypass this issue by modifying the potential applied and the inorganic carbon source used as these can enhance the efficiency of the system by affecting the development of the biofilm during MES and its microbial composition. Keeping biofilms under control in drinking water systems is also paramount to maintain water quality standards. Phosphate dosing has been regularly used to prevent plumbosolvency in water supply networks; however, the impact this may have on polymicrobial communities in these networks had not been studied. Del Olmo et al.14 have studied the effect of phosphate on the growth of polymicrobial biofilms from drinking water grown on lead and PVC. They found that changes in phosphate levels can induce changes in the structure of biofilms and affect the level of chlorine in the water. Their studies will help improve the management strategies to control microbial growth in drinking water pipelines helping to increase its quality.Engineering biofilm communities for more effective anaerobic digestion has great potential in organic/wastewater treatment as it offers the opportunity to recover biogas as energy whilst reducing risks to human health and the environment. For the engineering of these systems the core microorganisms have traditionally been considered. However, the study by Guo et al.15 who have created a two-dimensional framework they have termed the Biofilm Research-Industrial Engagement Framework (BRIEF). This framework enables the organisation of current biofilm technologies relevant to biofilms across sectors, based on their accuracy to current science knowledge and industrial application, enabling to predict the chances of evolving through Technology Readiness Levels (TRLs). They also introduce some advisory guidelines to enhance the translational impact of future biofilm research.For all the above findings to be successfully translated from the academic research lab into the industrial environment it is paramount to have a cross-sectorial engagement at the conception of the technology to facilitate its evolution along a Translationally Optimal Path (TOP). This is highlighted by Highmore et al."}
+{"text": "Reviews suggest that family interventions including family therapy are effective for a range of disorders in youth. Family sculpting is used in different clinical settings to help young patients, their parents and siblings when words are not enough.Participants will be able to understand the clinical relevance of family sculpting: shifting from discussions about family problems to physical representations of family dynamics and how to apply in their practice.There will be a brief overview of the general principle of family sculpting followed by clinical vignettes of patients combined with videos of the intervention. These examples will guide the discussion on how relevant in our clinical work this therapeutic practice may be. This variation on sculpting incorporates theater warmup exercises and therapists joining the family experience.Family sculpting captures an immediate picture of the family dynamics that is a therapeutic turning point for families and gives voice to the children. The clinical cases and videos will guide clinicians on how to integrate into their own practice.This presentation will make possible integrating family sculpting into your own practice, providing an engaging alternative modality for complex cases.No significant relationships."}
+{"text": "The corrected graphical abstract now appears with the article online, and the original and corrected graphical abstract appear here.Cell Press and the authors regret this error."}
+{"text": "Informal caregiver support has been defined as different types of interventions. However, it has not been well explained in the social context and not well discussed as an integrative concept for dementia caregivers who are Asian Americans. Therefore, the aim of this study was to conduct a dimensional analysis--a type of evidence synthesis--to explore caregiver support in the context of Asian American dementia caregivers. A synthesis of 40 articles produced four interrelated dimensions of caregiver support: Individual ; Family ; Community ; and Professional healthcare system . The findings provide guidance for future studies on this population in promoting caregiver\u2019s health and developing caregiver interventions."}
+{"text": "Nervecentre is an application that can be used on mobile devices and desktop computers to record and view physical observations amongst other tools. An audit had been done previously assessing the practice of recording observations using paper documentation. That audit had recommended the use of Nervecentre to improve the recording of observations. This audit was undertaken following the introduction of Nervecentre for documentation of physical observations. The aims were to evaluate if the transition to electronic documentation of NEWS  observations on Nervecentre has improved practice in comparison to paper documentation and to evaluate if our practice could be improved by implementing electronic observations for psychiatric observations in addition.Data were collected over a 10-day period looking at all the documented observations from all inpatients on the MHSOP wards that met the inclusion criteria. Data were collected on the recording of psychiatric observations (recorded on paper charts) and physical observations (recorded on Nervecentre). The data were collated and analysed. The new data were compared to the original data from prior to the introduction of NerveCentre and the findings were presented at a local meeting.This audit has highlighted that the documentation of physical observations on MHSOP wards has greatly improved since Nervecentre was introduced. There was an improvement in recording of physical observations in almost all domains measured. NEWS scores were correctly documented 100% of the time compared to 87% previously. Raised NEWS scores were correctly escalated to a senior and reviewed 80% of the time compared to 0% previously. It has also highlighted that the quality of documentation regarding psychiatric observations could be improved as we are not currently meeting local or national guidance.The most likely cause for the improvement in the recording of the physical observations is the implementation of Nervecentre. Nervecentre prompts users when observations are due, removes the risk of calculation errors and allows for observations to be directly escalated. Implementing Nervecentre for psychiatric observations may similarly improve the quality of these observations therefore improving patient safety."}
+{"text": "Older, rural adults have limited access to quality geriatric specialty care for several reasons including relatively few geriatric specialists in rural areas and lack of transportation options or patient ability to travel to more urban centers. GRECC Connect is a promising telehealth-hub and spoke model that provides rural patients access to teams of multidisciplinary geriatric specialists in more urban medical centers primarily by video connection with affiliated community-based outpatient clinics (CBOCs). This model provides a viable option for increasing access to geriatric specialty care for rural patients but is not used to the extent it could be. To date, much of our understanding of this model has come from the experts at the hub medical centers. To learn more about the experience of this model from the field we interviewed CBOC staff and providers as well as Veterans and their caregivers about geriatric specialty telehealth services. In this symposium we will discuss facilitators and barriers to implementing this model from the perspective of the field and then explore more deeply both the context of the CBOC environment and the older patient population served by rural CBOCs to further understand the challenges that are faced in attempting to connect older patients with telehealth services. Finally, we will share the perceived value of the service and alignment with local needs. This deeper understanding of the experience of the \u2018spoke\u2019 may help enhance access to much needed geriatric specialty care for rural veterans."}
+{"text": "A case report of two patients who underwent auxiliary liver transplantation and two staged hepatectomy was recently published in BMC Surgery. The surgical technique utilised is described as novel but has been published previously also in the setting of chronic liver disease. A new name for this surgical approach therefore seems redundant. The importance of careful hemodynamic monitoring of pressure and flow in the portal vein and artery of the auxiliary graft as well as optimizing venous outflow is paramount to ensure graft regeneration and avoid small for size syndrome. The relevant surgical considerations to ensure optimal safety has also been reported in previous literature. This brief letter to the editor of BMC Surgery gives an overview that put the article content in context with published literature on this transplant surgical technique. We have read the case report from S. Brunner et al. in the recent issue of BMC Surgery  and beliProgress and improvement in clinical medicine is reliant on original and novel scientific contributions as well as stepwise improvements of existing published treatments and concepts. Brunner and co-workers choose to term the described surgical technique as \u201ca new treatment concept for patients with end-stage liver disease\u00bb and propose a dedicated acronym for it. We believe this to be incorrect and contributing to confusion in the terminology of the HPB surgical literature .The technique of combining liver resection with auxiliary liver transplantation has been known since 2015 as the RAPID technique  in deceased and living donation respectively , 3. UtilThe original RAPID protocol includes the relevant portal modulation procedures, and successful performance of the RAPID technique in patients with cirrhosis through careful modulation of portal vein perfusion has been published previously . In the Selective attention to the published literature and introduction of established surgical techniques as novel concepts may limit the collective stepwise improvement of surgical techniques. The authors experienced a range of serious complications that certainly are of great concern, and suggest some modifications based on an \u201coptimized technical approach\u201d. The main learning experiences stated in the current paper are already described in other publications such as end to side anastomosis of the graft portal vein to the main portal trunk, the need to resect segments 1\u20133 as opposed to 2\u20133, risk of venous outflow obstruction with increasing graft regeneration necessitating endovascular stenting . ModulatNo other report on this technique have found it necessary to delay the biliary reconstruction to a separate day, pack the liver graft, or mandate a second-look procedure, thus making the patients undergo three laparotomies in the course of three weeks. In our experience, this is not justified and increases both the risk and the complexity of the procedure.On this background, we believe that the paper in its current form provides a somewhat skewed presentation of the RAPID technique and therefore think the readers of BMC Surgery should be made aware of this. We cannot see any justification or added value for the proposed acronym \u201cASPIRE\u201d apart as a designated naming of a prospective trial. There is however no citing of ethical approval or study registration in this paper to suggest that this is the case."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "The approach to providing long-term services and supports (LTSS) has changed dramatically over the last three decades in both the financing and delivery arenas. In the U.S., long-term strategies have varied by state in organizational structure, scope of delivery and administrative practices. In the past two decades an additional change has emerged with over half the states adopting some form of managed LTSS. This shift has deepened the divide in state approaches to LTSS system design and delivery. The shift to managed LTSS has been largely fueled by ideological expectations and concerns about growing Medicaid costs: Empirical research findings have played a minimal role. For example, the large CMS evaluation conducted in this area did not include Medicaid data or encounter data from the managed care plans as part of the study efforts. However, the managed LTSS experiment does create an opportunity to compare costs and outcomes of these different models of financing and delivery. This symposium will present preliminary evaluation findings from two states, Ohio and Pennsylvania, which are generating data to assess both the implementation and outcomes of these alternative LTSS models. To set the context an initial paper will discuss the expansion of managed LTSS programs across the nation and examine how these efforts compare to the development occurring in the European LTSS systems. The third presentation will discuss the results of the Community Catalyst dual eligibles\u2019 managed care demonstration program monitoring project."}
+{"text": "The National Institute for Health and Clinical Excellence (NICE) recommend that renal and thyroid function must be checked before lithium is prescribed and for all patients who are prescribed lithium should have their renal and thyroid function checked every six months, and their serum lithium checked every three months. The aim of this audit is to ascertain whether or not routine blood monitoring for bipolar disorder patients, taking lithium is in keeping with the guidelines.Lithium has been a mainstay in the management of bipolar disorder since the 1970's; indeed, lithium carbonate was first used in the early 1880's for the treatment of mania. Despite its usefulness however, the drawback of lithium treatment remains its very narrow therapeutic index, toxic side effects and as such its need for close therapeutic monitoring.A list of patients with a diagnosis of bipolar disorder being treated with lithium was collated from an electronic database of psychiatry patients in Cumbernauld Community and inpatients at Glencairn unit Coathill Hospital and Cleland Hospital. A retrospective analysis using Clinical Portal was conducted looking at blood results; Lithium levels checked 3 times a year and Kidney functions and Thyroid function checked twice a year, over the previous year. Our results were then compared to the NICE Guidelines for lithium monitoring to see if they complied with the expected routine monitoring schedule. We may have missed patients open to Community Psychiatric Nurses (CPN) but not open to Consultant psychiatrists. Other group that might have been missed could be open to General Practitioners but not to secondary care. We attempted to contact them but this was unsuccessful.Total of 690 patients were studied. Of 690 patients 51 patients had the diagnosis of Bipolar Affective Disorder. 49 percent of them were prescribed Lithium. 48percent had their Lithium bloods checked and 60 percent had their Kidney function and thyroid functions checked according to the guidelines. There were no data available for around 7 percent of patients but their Lithium levels were indicated only in Clinical notes.This audit has demonstrated that Lithium monitoring falls short of conforming to accepted standards. Data obtained by this audit have prompted an electronic alert system for patients on Lithium endorsing primary care, mental health and laboratory staff to work together to ensure supporting recommended Lithium monitoring."}
+{"text": "In South Australia (SA), there were 27 deaths of Aboriginal infants between 2005 and 2014 attributed to SUDI, which often occurs after an infant is placed to sleep (Child Death and Serious Injury Review Committee 2014).The first sentence of the second paragraph is incorrect. It should instead read as follows:The Authors would like to apologise for this mistake."}
+{"text": "As much as 40% of dementia cases can be attributed to modifiable risk factors . Much of that risk-reduction can be accomplished by changing behavior in midlife. In light of the emerging evidence that dementia may be preventable, UsAgainstAlzheimer\u2019s convened a workgroup of national experts to develop new recommendations that primary care clinicians and general neurologists can use to initiate primary prevention conversations with their patients about cognitive decline. Few resources address steps that clinicians can take in their routine care to help patients reduce risk. Some relevant resources provide excellent guidance but tend to be more focused on early detection or slowing disease progression rather than primary prevention. The Risk Reduction Workgroup (RRWG) was convened to help address the need for clinicians to know how to discuss cognitive decline with their patients. The workgroup aligned on 11 recommendations for primary care clinicians and general neurologists. In addition the RRWG provide considerations for implementing the recommendations in clinical practice. The recommendations are mindful of social determinants of health, account for cultural differences, and are designed for general accessibility. This effort is part of a broader initiative by UsAgainstAlzheimer\u2019s to address risk-reduction for cognitive decline and early interventions. Under the guidance of a multidisciplinary Provider Leadership Group consisting of representatives from some of the nation's largest health provider serving organizations, three independent workgroups are developing guidance and tools to assist providers in their clinical practice and improve health outcomes for patients at-risk for Alzheimer's and related dementias."}
+{"text": "This project was designed to evaluate the use of PRN medication and PRN monitoring charts on an adult learning disability ward. These charts had been designed by the trust to provide us with a way of monitoring the use of psychotropic PRN medication to ensure monitoring of treatment response, physical health and side effects.The data were collected from PRN monitoring charts, electronic case notes and electronic prescribing chart records for all patients on an adult learning disability inpatient unit. The sample consisted of 7 patients who had been prescribed and/or received PRN psychotropic medication over a five week period. Quantitative data were derived by simple calculation for the total amount of PRN medication used and number of PRN monitoring charts completed. Qualitative data were collected of prescription charts and PRN protocols which is supposed to guide treatment.Out of all the incidences where PRN medication was administered, only 64% of monitoring charts were completed. Out of the 7 patients on the ward, 6 had PRN protocol charts and for only 5 patients these were followed.Clinical practice must be improved. The results were presented to ward staff and doctors to discuss the implications for patient care and ways to improve clinical practice by ensuring full monitoring of the use of PRN medication to help reduce the overmedication of people with learning disability by improving the use of the PRN charts. NICE guidelines and The Royal College of Psychiatrists have published guidelines on the prescription of psychotropic drugs for people with learning disabilities. NHS England have also published an article to discourage over-medication of people with learning disabilities. There is a risk that doctors are prescribing medication to treat behaviour that is an expression of distress or a mode of communication rather than a mental disorder. Doctors have a responsibility to ensure they have fully assessed the person's potential to benefit from medication before they prescribe. The audit would serve to provide a baseline for this team prior to any audits in the future."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "There is a long-standing literature that has documented the importance of both the immediate and distal context in impacting mental and physical health across the adult lifespan. The goal of this symposium is to bring together a collection of papers that target the extent to which the immediate and distal context as measured through objective and subjective indicators relate to pertinent outcomes of mental and physical health. Staben and colleagues use an intensive longitudinal design in middle-aged adults to show that objective and subjective indicators of the neighborhood are associated with higher levels of and are protective against the impact of monthly adversity on mental health and well-being. Munoz and colleagues evaluate associations between objective and subjective early-life neighborhood contexts and whether they play a role in cognitive function at midlife. They find that poorer age-five self-report conditions were associated with lower working memory. Osuna and colleagues examine how both neighborhood and housing conditions play a role on psychological well-being. They find that housing and neighborhood safety conditions are associated with depressive symptoms over time. Piazza and colleagues examine associations between daily financial thoughts, SES, and indices of emotional and physical health. They find that individuals who reported more daily financial thoughts also reported more negative affect and physical symptoms. The discussion by Crimmins will integrate the four papers by highlighting the importance of how different forms of context can impact development in adulthood and old age, particularly in relation to health and well-being and consider future routes of inquiry."}
+{"text": "To improve postgraduate psychiatry education and training in Northern Ireland.Historically within Northern Ireland there has been a postgraduate Member of the Royal College of Psychiatrists (MRCPsych) teaching programme delivered to core trainees in preparation for MRCPsych examinations. There has been no official teaching programme for higher trainees. Northern Ireland Medical and Dental Training Agency (NIMDTA), in collaboration with the Royal College of Psychiatrists in Northern Ireland and all five Trusts developed the novel idea of introducing Postgraduate Education Fellows, to oversee and improve core training, and to develop a bespoke higher training programme.The Postgraduate Education Fellows met to collate information from various sources in relation to issues within the current teaching programme and address these along with the development of new initiatives. The fellows further act as a point of contact for all trainees within their Trust to provide advice and support with education if needed.One higher trainee was appointed to the role of Postgraduate Education Fellow in each Trust within the NIMDTA deanery for a term of 1 year.The starting point was delivering the pre-established teaching timetable and gaining feedback from core trainees to identify areas for improvement. The next phase involved piloting traditional and contemporary methods of feedback. A further development was designing a mock paper A delivered under exam conditions. Two mock Clinical Assessment of Skills and Competencies (CASC) exams were organised under exam conditions, offering other trainees the opportunity to act as simulated patients and examiners.The third aspect of this role involved creating a programme of higher trainee seminars. Baseline data were collated and identified key areas that higher trainees felt they needed further training and guidance in.Using baseline data on the current teaching programme and from higher trainees as well as incorporating quality improvement methodology, we have been making small changes to each aspect of the teaching programme and evaluating the changes made. The feedback from trainees has been positive as evidenced by quantitative and qualitative feedback. 8 candidates sat our first mock CASC with a 100% pass rate in their MRCPsych CASC examination. There has been a positive response to the higher trainee seminar programme.This programme has produced good outcomes to date and sets foundations for the future development of post graduate psychiatry education in Northern Ireland."}
+{"text": "The Covid pandemic brought to the forefront the crucial role of social interactions for society at large and in gerontological practice. Social interactions play a paramount role in preserving cognitive reserve in older adults. They rely on neurobehavioral processes that are complex . Pitch mimicry is a well-known and spontaneously arising social phenomenon that requires the integrity of numerous processes of the brain, and we hypothesize that it constitutes a potentially sensitive behavioral marker of neurodegeneration in Alzheimer\u2019s Disease and Related Dementias (ADRD). We developed and validated a series of algorithms to parse verbal exchanges between people and quantify the level of mimicry that each exhibit with their partners. Those algorithms are based on silence thresholding, carefully parametrized CEPSTRAL algorithms for automatic pitch estimation and Synchrosqueezing Transform for validation. We introduce a theoretical model to compare our estimates of pitch mimicry with model\u2019s expectations based on the null hypothesis that its neurobehavioral pathways retain their integrity. Our method will allow researchers to study the evolution of pitch mimicry in aging individuals and its sensitivity to diverse social contexts, including those preserving lasting social engagement. Our method will also allow us to test the hypothesis that Pitch Mimicry is a sensitive behavioral marker of dementia, a condition characterized by a breakdown in social relatedness."}
+{"text": "Undergraduate programs  and continuing education programs in gerontology prepare students for entry-level careers in aging and increase competitiveness for graduate work in a variety of fields. Job growth in the field of gerontology is high, especially for positions requiring a bachelor\u2019s degree and less. Gerontology education at this level is essential for meeting the growing demand for workers in social services and health services who understand the opportunities and challenges that come with increased longevity and global aging. This presentation will highlight the new recommendations for competency-based gerontology education for undergraduate and continuing education credentials outlined in the latest edition of AGHE Standards and Guidelines. Whether you are developing a new curriculum or revising an old one, we will offer suggestions for using the AGHE competencies and guidelines to ensure that your program adequately prepares students and offers them a competitive edge in today\u2019s job market."}
+{"text": "Family members of persons diagnosed with dementia or a traumatic brain injury (TBI) are often relied upon to provide daily support to their care recipients. However, research on the differing experiences of caregivers based on care recipient diagnosis is limited. The aim of this study was to examine the impact of worry and feelings of vigilance among caregivers of people with cognitive impairment due to either TBI or dementia. This sample included 61 caregivers  of persons with either a TBI (n = 32) or dementia (n = 29). Worry was assessed with the Penn State Worry Questionnaire and Vigilance was assessed with the Caregiver Vigilance Scale. Linear regressions revealed that after controlling for age, care recipient diagnosis moderated the relationship between worry and caregiver vigilance. Specifically, worry was significantly associated with caregiver vigilance in those caring for someone with dementia; however, a similar relationship was not seen in those caring for someone with a TBI. This suggests caregivers of people with TBIs have a different experience of worry and vigilance than caregivers of people with dementia. These findings demonstrate the need for more research on the unique needs of caregivers of people with TBIs. Additionally, this research suggests interventions targeting worry may be particularly effective in supporting caregivers of people with TBIs."}
+{"text": "Throughout our lifespan we experience the culture of our families and communities. Our cultural selves guide our understanding of health and illness. However the health care system often ignores our culture in the delivery of care. This can have devastating effects on individuals and particularly the elderly. This presentation reviews a case study of a tribally owned and operated nursing home. The emphasis on maintaining cultural activities, feasting on traditional foods, offering sacred practices led to high satisfaction of the health care experience by residents and staff. Creating this environment was difficult and barriers in culturally responsive care delivery will also be discussed."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "The Year 2020 has proved to be a great success for Pakistan Journal of Medical Sciences as we achieved yet another landmark of crossing the Impact Factor of one as per the Journal Citation Report released by Clarivate Analytics for the Year 2020. Our current Impact Factor is 1.088.A critical analysis of the year under review shows that the number of new submissions from Pakistan as well as overseas has also significantly increased. The total submissions in 2020 was 1781. While the number of submission are increasing but our acceptance rate has remained almost static about 20%. The number of manuscripts received from Pakistan during 2020 were 854. Majority of them being from Karachi 261, Lahore 226, Islamabad 101, Peshawar 62 and Rawalpindi 43. The number of submissions and publications from Turkey was increasing during the Years 2013-2018 but decreased in 2019 but has again increased in 2020. However, the number of papers accepted for publication after peer review has not increased much due to strict peer review Researchers are under great pressure to publish their research work as soon as possible to meet deadlines for the completion of their research projects or to defend their PhD thesis but editors of biomedical journals in Pakistan are also faced with a dilemma due to human resource and financial constraints. Publications overseas in Impact Fact journals which the regulatory bodies in Pakistan as well as overseas demand is very expensive which many researchers cannot afford while the number of Impact Factor medical journals published from Pakistan so far remains just three. A few more journals have applied but it may still take some time and the authors who are always impatient will continue to suffer. The situation can be eased if the regulatory bodies in Pakistan like Higher Education Commission can accept Only Online Journals which will reduce the cost of production to a great extent and also enable the editors to accommodate more papers as there will be no page constraints. It will also reduce the publication charges for the authors which is expected to increase further in view of the devaluation of the Pakistani currency. 3However, going for only Online Journals does involve some challenges as well in view of the increasing number of predatory journals. Hence, to check this menace, the authorities can give this permission of Only Online Journals to those publications which have earned Impact Factor, or indexed in Medline, and are covered by important databases like PubMed Central and Scopus. The regulatory bodies should also facilitate the journals to get IF and indexation in international databases. (PAME) on its behalf has taken an initiative in collaboration with University of Health Sciences (UHS) Lahore to start Certificate Course in Medical Editing (CME) to build professional capacity of the editors . This has helped many editors whose journals have now been recognized by the Higher Education Commission as per the latest revised list released last month.5While we would like to thank our valued members of the Editorial Board and Reviewers who have played a vital role in the enhancement of our Impact Factor and improving the quality of manuscripts accepted for publication, we are mindful of our weaknesses as well. We need to increase our presence on Social Media which at present is not satisfactory. Accelerating the peer review system shortening the time from submission to acceptance and publication is also being looked into. We also need understanding by the authors whose papers are not accepted for various reasons and hope situation will improve in the days to come. Repeated lockdowns due to Covid19 Pandemic has also adversely affected our working. However, we were lucky to publish a special issue on Medical Imaging in collaboration with Wuhan Institute of Technology during September 2021 thereby further improving the academic collaboration and cooperation between the healthcare professionals and medical institutions of Peoples Republic of China and Pakistan.Yet another important step that Pakistan Journal of Medical Sciences has taken during the Year 2021 is collaborating with PharmEvo Pharmaceuticals to establish PharmEvo Research Forum with the main objective of promoting research culture and the art of medical writing and scientific publishing.We have also offered Internship facility to one Fellow who is getting training for the last few months. We offer special prize, scholarships in the name of our founder Chief Editor late Dr. Maqbool H. Jafary to junior editors every years and some of the brilliant candidates in the CME Course by UHS are also picked up for this award. At the certificate distribution ceremony of CME Batch-2 held at UHS Lahore on June 23, 2021, four junior editors were presented this prestigious prize/award. This is our humble effort to promote the cause of medical journalism in Pakistan."}
+{"text": "Medicaid is the largest payer of long-term services and supports and millions of older Americans rely on the means-tested program for health care coverage. There has been longstanding concern that wealthy older adults are taking advantage of the program by divesting assets in order to qualify for coverage. The existing research on the issue is somewhat dated, does not focus on the question of asset transfer, and often lacks a significant longitudinal view. Thus, questions remain about whether states need to tighten asset eligibility rules to prevent the wealthier older adults from accessing the program. This analysis explores longitudinal data from the Health and Retirement Study (1998 to 2016) to determine the extent to which wealthier Americans age 50 and older engage in asset transfer to access Medicaid. Our findings demonstrate that this may occur among a relatively small proportion of wealthy older adults, and that tightening Medicaid eligibility criteria would likely have a small to modest impact on the financial status of the program."}
+{"text": "Most African immigrants report that they had never heard about dementia until their arrival in the United States. Conversations and insights from project advisory board meetings of the African Immigrant Memory Loss and Dementia Education projects (5 conversations and 8 meetings in the Minneapolis area) reveal unique cultural and immigrant characteristics surrounding dementia terminology and awareness. Dementia is often lumped together with mental illness which is associated with stigma. In addition to the fear of bad news and death, mental health issues are often considered a result of witchcraft, spiritual attack or punishment. Additionally, there are no traditional or cultural words for dementia in many African languages and current terms used are related to mental illness and all have negative connotations. There is a need to identify appropriate words for dementia in many tribal and immigrant dialects that can facilitate dementia awareness and education programs in African communities."}
+{"text": "These chosen topics covered common significant challenges to patient health in psychiatry. Sessions were delivered to proactively address these important health related issues in a group visit setting.Baseline and post intervention feedback including telephone interviews were conducted to evaluate the effectiveness of the intervention.The qualitative data and the positive feedback obtained from participants indicate the intervention was highly valued and deemed effective in promoting positive health and lifestyle changes. Participants valued the educational and co-production aspects as well as the social and peer support elements of the groups. They appreciated the level of access they had with the clinicians involved, to explore their health and wellbeing in more detail without being limited by the usual 30 minute clinic follow-up sessions.The clinicians involved found the sessions rewarding and more engaging than most of routine 1:1 clinic sessions as they were able to spend quality time exploring important issues and not just educate the patients but also be educated by their questions and feedback about their lived experiences.The project aim was met and we believe this intervention can be successfully incorporated into the identified service provision gap within the CMH T model. There is potential to build on and embed this innovation with roll-out to a wide range of service users in different settings.In line with existing literature from GP settings, the consensus was that the amalgamated group visits/consultations model could be successfully modified to meet the needs of patients in the Mental Health arena who have a range of physical health and lifestyle concerns.We planned to obtain more information about improvement in patient self-management but this was affected by the pandemic. However, we believe it is a cost effective and helpful innovation which warrants further promotion and evaluation."}
+{"text": "Even though Germany has a mandatory health and long-term care insurance with no or only very low co-payments, immigrants and the native population differ in their health and social services use. Differences in cultural traits and a lack of knowledge about the institutional setting are frequently mentioned as contributing factors. Relying on the epidemiological approach in the economic literature, this empirical study shows that both cultural traits that prevail in older immigrants\u2019 country of origin and older immigrants\u2019 knowledge about the host country\u2019s institutional setting affect their health and social services use in Germany. We distinguish foreign-born immigrants and their descendants as both groups differ in their connection to the home and the host country. The results will be used to discuss immigrants\u2019 access and potential barriers to the use of health and social services in comparison to the native population."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "Practical Uses of Bioelectric Stimulation. Here you will find six examples of the use of imposed or modified electric fields to greatly influence tissue functions. This is only a very small sampling of the thousands of practical uses of bioelectricity today, and many more examples of this subtopic will appear regularly in this journal.It has been a great honor to be a guest editor for this special issue on the + on the immune system. In contrast, this issue of Bioelectricity focuses on the use of imposed electric fields to modify cell and organism functions.The discipline of bioelectricity encompasses both endogenous ionic currents and electric fields used by living organisms in their daily functions as well as the use of imposed electric fields to influence or modify these functions. The endogenous ion channels and currents associated with cancer cells was highlighted in the September issue that contained eight articles focused on the bioelectricity of cancer and covered many characteristics of cancer cells that are intimately associated with bioelectricity, including the control of metastasis, the localization of specific ion channels, and the influence of extracellular KThe common theme of four of these bioelectricity applications is the use of pulsed electric fields to influence cell permeability. The first article is a broad review of the past 5 years of electrochemotherapy, the use of microsecond-domain electric fields that trigger transient or reversible permeabilization to locally enhance the uptake of drugs that kill dividing cancer cells. This approach has been used extensively in Europe but is not yet approved for use in the United States. In human oncology electrochemotherapy is fully recognized as a local therapy for cutaneous tumors and metastases and its effectiveness is also being explored in combination with immunomodulatory drugs.The second article reviews irreversible electroporation (IRE), the use of larger pulsed electric fields in the microsecond domain that generates permanent pores in the plasma membrane resulting in the loss of homeostatic equilibrium leading to necrosis within minutes to hours. This technique has been approved for human use in both the United States and Europe for soft tissue ablation. It has established a clinical niche as an alternative to thermal ablation for the eradication of unresectable tumors, particularly those near critical vascular structures. IRE clinical data have shown promise in treating tumors in the prostate, pancreas, and liver.The third article describes the use of much shorter electrical pulses to treat skin lesions called Nano-Pulse Stimulation. This is a nonthermal technology that has been used to eliminate several types of skin lesions in clinical trials approved as nonsignificant risk trials supervised by IRBs and has not yet been approved for human use. These pulses generate reversible nanopores in all membranes exposed to them that are much smaller than the pores generated by the longer microsecond pulses. In addition, they have been shown to penetrate into cells and permeabilize the organelles as well as the plasma membrane resulting in the initiation of regulated cell death when a sufficient number of pulses are applied.The fourth article describes a very new application of Nano-Pulse Stimulation, cardiac defibrillation. The standard method for defibrillation uses much longer millisecond pulses that often cause long-term damage to the heart. Nano-Pulse Stimulation requires only about 12% as much energy to defibrillate so will probably result in less tissue damage.The fifth article is an exception to the increased permeability theme and instead provides a review of tissue inflammation and regeneration responses to imposed sinusoidal magnetic fields. In addition, some new data are presented showing that 5 and 15\u2009Hz sinusoidal magnetic fields can induce very weak electric fields that can modulate inflammation and tissue regeneration. The mechanisms by which such low sinusoidal fields affect inflammation are likely to be very different from those used by much higher amplitude pulsed fields. We have much to learn about the targets of and mechanisms used by these weak oscillating electromagnetic fields.The final article in this special issue utilizes a light-activated ion channel to modify the membrane potential of brain tissue and reverse the abnormal brain and eye morphologies created by ethanol exposure. This is a striking demonstration of the critical role of membrane potential in the development of the brain that was not possible before optogenetics came on the scene. It is an amazing example of the signaling power of bioelectricity brought to light through the use of technological advances."}
+{"text": "This paper reviews 63 policy documents in four Canadian jurisdictions that guide long term residential care staff on how to enhance 11 resident quality of life in Canada. We found guidance in each jurisdiction that provide clear language to support staff discretion and flexibility to navigate regulatory tensions and enhance resident quality of life. Newer policies tend to reflect more interpretive approaches to staff flexibility and broader quality of life concepts. We argue that if interpreted through a resident quality of life lens and with the right structural supports, these promising texts offer important counters to the rigidity of long term residential care policy landscape and can be leveraged to effectively broaden and enhance quality of life for residents in long term residential care."}
+{"text": "This research tested whether performing an action themselves leads young and older adults to have difficulty remembering which of a number of other people had performed that same action. It also tested whether observing another person perform an action leads to false memory for self-performance of that action. Young adults and healthy older adults 62 to 88 years of age viewed videos of actors performing actions. After viewing some of the actions, participants were instructed to perform those same actions themselves. Participants were tested one week later on their memory for their own actions and for the actions of the actors in the videos. Older adults were more strongly influenced by self-performance than were young adults when asked whether the actor in a test item had performed the same action previously. Young adults performed better than older adults at discriminating the correct and incorrect actors in the videos, although both groups showed reduced discrimination for actions that they had also performed themselves. The two groups were equally likely to falsely remember having performed an action that had only appeared in the videos, but young adults were better able than older adults to correctly identify the actions that they had in fact performed. Older adults thus have greater difficulty than young adults at distinguishing self-performed actions from actions performed by other people. This suggests the existence of common representations for the actions of oneself and others that must be bound to identity information to specify the correct source of the actions."}
+{"text": "The aim of this audit was to look into patients on high dose antipsychotics who had developed complications of constipation in the PICU setting .Antipsychotics are usually used in the treatment of Schizophrenia and other psychotic illnesses. Drug such as Clozapine mainly has a higher risk profile due to gastrointestinal hypo motility. It could present as constipation, fecal impaction or a bowel obstruction and could even lead to death.During ward rounds enquired on bowel habits and diet.Physical examination of patients complaining of abdominal pain.Screened notes in past to see how many patients complained of constipation and interventions suggested and used.I65.3 of the 10 patients on PICU were on high dose antipsychotics and 2 of them had reported constipation. Of which one required daily review and vigorous treatment with laxatives and dietary changes.RecommendationBristol stool chart introduced as part of care plan for all patients.Teaching presentation of constipation and its treatment management was given to the PICU team.Involving medical team early on for assessment and prophylactic laxatives prescription.Liaison with the pantry team to include more options of fruits and vegetables into daily meal plan for patients.Data and material handed over to next trainee to Re-audit and complete audit cycle.Appropriate prevention and early management of side effects can enhance the benefits of antipsychotics. Bowel function monitoring and the use of prophylactic laxatives for patient on high dose antipsychotics such as clozapine is advisable to prevent complications related to it."}
+{"text": "Ever since the establishment of Indus Hospital Health Network (IHHN) by Dr. Abdul Bari and his colleagues, they have made a commendable progress and practically demonstrated that provision of free tertiary care is possible with the help of philanthropists and donors. It only becomes possible once an institution has earned credibility and the donors are confident that their contributions are being used judiciously for the purpose they are made.Starting with a major hospital at Karachi, IHHN has now expanded its network in the country and this institution has emerged as an important non-governmental player in health sector. It offers treatment facilities in almost every discipline of medicine with a multidisciplinary team approach with exceptional results. Apart from providing healthcare, it also realized the importance of documentation and publication for which they established a Research Department. Hospitals in Pakistan are considered as goldmine of data offering innumerable opportunities for research but most of them lack proper record keeping hence the data needed for research publications is not easy to find. However, IHHN knowing its importance managed to install the Health Information Management System which makes their researcher\u2019s job easy. Since the researchers are also lucky to get help, guidance and assistance from the Research Department, IHHN faculty members and postgraduate trainees have managed to complete numerous research project thus showcasing their research work at international conferences which IHHN holds regularly and much of this research work is also published.We in Pakistan Journal of Medical Sciences published a special issue at the time of their last conference ICON 2021. This year too, we were approached and after initial discussions on working modalities, the project was started in March 2021.As agreed IHHN provided us manuscript after peer review by two reviewers which were then finally reviewed and edited by our editorial team before they were accepted for publication in this \u201cOnly Online Edition\u201d. The workshop that we organized at Indus Hospital on Medical Writing and Peer Review during 2020 was very helpful and the experience which the IHHN Research Department gained while working with us last year proved very helpful with the result that this time it was mostly a smooth sailing.This special issue covers some very important subjects. Faiza Ahmed and colleagues in their write up has highlighted the knowledge and perceptions of sepsis among doctors. Sepsis, they have concluded remains a challenge to treat, it is often misdiagnosed. Early diagnosis and prompt management is the key to improving the outcome. 1Asthma severity and hospital admissions measured by PRAM score have been discussed by Kazi et al. Their conclusions are that this score is the best predictor for the need for hospitalization for these patients suffering from asthma. They have suggested that this should be put to use in clinical practice in paediatric emergency departments. They suggest better facilitation of intensive therapy of patients at triage which will decrease the need for hospitalization.2Obstructive lung disease is an important NCD. According to Saima Saeed and colleagues the OLD programme at IHHN uses capacity building, gold standard diagnostic and management strategies in primary care. This enables early diagnosis of suspected patients which improves the morbidity and mortality. 3Drug resistant tuberculosis remains yet another important problem in Paksitan. Nazia Khursheed and colleagues have identified in their study a number of such cases. They have advocated development of new strategies to reduce the spread of this disease.4Safety and efficacy of Remdesivir on mortality and length of stay in hospitalized Covid19 patients has been studied by Quratulain Shaikh et al., in this prospective cohort study which enrolled two hundred sixty eight patients. The findings of this study showed that there was no difference in in-hospital mortality while length of stay was longer in these patents. In addition more patients had severe ARDS in the RDV group. 5Ensuring privacy and confidentiality while examining a patient is extremely important but unfortunately practically it is not possible in overcrowded Out Patients Departments of public hospitals. Syed Ghuzzanfar Saleem et al studied the patient\u2019s perceptions on this issue who visited the emergency department of Indus Hospital Adult Emergency Department. They found out that despite overcrowded and busy environment patients generally felt that privacy and confidentiality were maintained which must be very satisfying for the hospital administration.6There are numerous other studies covered in this special issue which shed light on many important subjects which the researchers have discussed which make an important reading. We are delighted to be a part of this project and by offering highly concessional publication charges despite the massive devaluation of the currency, we have contributed our share to promote and project the image of this remarkable institution of which the country should be proud of. In future too, we will be delighted to help, assist and cooperate with IHHN to showcase its research work thereby making significant contribution to the world medical literature from Pakistan.We are extremely grateful to the management of IHHN for providing us this opportunity and the two Guest Editors Dr. Farhana Amanullah and Dr. Naila Baig Ansari for their hard work in compiling, this special supplement."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "Ambulatory assessment methods offer new possibilities to study cognitive, emotional, and social processes in the setting in which they naturally occur, namely in the daily life of individuals and couples. This allows to zoom into processes with great relevance for healthy aging and well-being over the lifespan. Research on daily psychological processes opens the door for investigating the interplay with contextual  and stable factors  that are known to shape these dynamic processes. This symposium will present and discuss innovative contributions investigating daily emotional and cognitive functioning and their interplay with social and individual characteristics over the adult lifespan. The first study by Haas and colleagues will present experience sampling data on daily prospective memory performance in couples. Haas et al. will offer a dyadic perspective on cognitive functioning by examining how prospective memory performance is co-regulated in the daily lives of younger and older couples. Meier et al. will present another study from the same couples project; here the focus is on age differences in couples\u2019 \u201cwe-ness\u201d and its relationship with daily positive emotional experiences and how they are shared with the partner. The series of talks will be completed by Zavala et al. who examined associations between stress and emotional health in daily life and its interplay with prior discrimination experiences of an age-diverse sample of BIPOC adults. After these individual contributions, Christina Roecke will discuss the presented studies and provide her reflections on the results and their implications."}
+{"text": "This poster reflects how the experience of staying with people of diverse nations and cultural background helped the stranded IMGs cope with this agony in a foreign land during an unprecedented tumultuous situation. The aim is to show that despite diversity among people, the hard times made them unite and overcome countless difficulties.The COVID 19 pandemic has been a period of global health crisis and has exponentially affected mental health issues in the world population. In these difficult times, several International Medical Graduates (IMGs), who had come to the UK to attend their PLAB exams, were left stranded as the exams were postponed, flights cancelled and borders sealed. Faced with huge uncertainty their mental health was of great concern.At this time the British Association of Physicians of Indian Origin (BAPIO) came forward to help this cohort of stranded doctors in terms of accommodation, finances, mental health support, preparation for exams to the extent of liaising with General Medical Council (GMC) and Home Office. The virtual support group provided a platform for IMGs from different nations and cultures to get in touch with each other helping overcome mental burden and stress.The stories presented in the poster show how unity in diversity helped these young doctors deal with mental trauma amidst the Pandemic.276 doctors from 27 countries were looked after by BAPIO. From those excerpts taken from 26 IMGs, personal narratives was used as a method for qualitative assessment.The percentage of IMGs clearing their exams and getting jobs in the NHS has been used for quantitative assessment.Qualitative: The personal narratives of the IMGs show how they were positively impacted by staying together albeit different nationalities and cultural background.Quantitative: A total of 21 IMGs out of the 26 cleared their PLAB 2 exams and got registration under General Medical Council giving a percentage of 81.7%. 20 IMGs have successfully joined the NHS in various posts giving a job success rate of 95.2%.The experience of living and sharing housings with people from different nationalities, has increased appreciation and also prepared them to work in the NHS which has a diverse work force. This learning experience has been integral for all of us in shaping our life in the UK making everyone more compassionate."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "Up to 35% of Dutch elderly patients still receive an ostomy after colorectal cancer (CRC) surgery.We performed a nationwide comprehensive analysis on the postoperative results and survival after CRC surgery in elderly Dutch patients (\u2265 75 years), comparing the outcomes of patients with primary anastomosis (PA) with those with end ostomy (EO).The pace of population aging is much faster than in the past; elderly and frail patients are rapidly becoming the new challenges in the future of colorectal surgery. In contrary to popular belief, those elderly patients might not necessarily benefit from a stoma. More information is needed regarding how frailty combined with a stoma impacts postoperative outcomes and survival. Our hopes for the future are vested in the development of a surgical prediction model for colorectal surgery for elderly patients, focusing on which patients would benefit from conservative therapy and which patients would benefit from an ostomy. This is important for our clinical practice; it will change our surgical decision making and hopefully reduce the number of unnecessary elderly ostomy patients."}
+{"text": "Racial and socioeconomic disparities are prevalent in long-term services and supports (LTSS). There is a need for innovative research with practical application informing aging and disability policies to reduce health care disparities for older adults and people with disabilities using LTSS. This presentation will provide an overview of the career trajectory of Dr. Chanee Fabius, whose research agenda is informed by applied care management experience, where she helped older adults remain at home and delay the need for nursing home care. She will also present findings from work that (1) examines networks of care used by older adults  and how they vary by race and socioeconomic status and (2) describes the effect of LTSS utilization on quality of life and health service utilization across diverse groups of older adults."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "Introduction. This paper examines regulations which govern procedures for reporting incidents other than accidents or serious incidents related to unmanned aircraft system (UAS) operations. The regulations are discussed in the context of available data and the paper included an analysis of them from both a European and national perspective. The goal of the paper is to provide a series of recommendations with regard to the procedures for reporting and analyzing UAS incidents in order to improve the safe integration of unmanned and manned aviation. This article also explores the legal consequences that arise from the midair collision between a UAS and a manned aircraft. Material and methods: The method of study comprises a content analysis of existing legislations. The current doctrine was confronted with existing regulations, documents and materials. Results: The results of the study show that there is a practical problem of objectively identifying operators of a UAS as well as in defining what exactly constitutes an \u201cincident\u201d. It can be reasonably concluded that reporting and analyzing UAS-related incidents allows for the assessment and development of strategies for integrating manned and unmanned aviation. It is worth mentioning that drones and UAS technology requires refinement, especially in technological terms. It is reasonable to take action aimed at raising awareness amongst UAS users of the need to report incidents, as well as engaging UAS users in the investigative process which follows such occurrences."}
+{"text": "Behavioral and psychological symptoms of dementia are increasingly being reconceptualized as expressions of distress and unmet needs. Measures that evaluate context are needed to increase our understanding of factors that influence these expressions. This review evaluated measures for two common behavioral states that are experienced as challenging for caregivers: apathy and resistance to care. A systematic literature search identified measures of apathy or resistance to care for people living with dementia. Eight measures of apathy and three measures of resistance to care were identified. Reliability and validity of these measures were evaluated using the COSMIN framework, as well as reported contextual factors within which the behavior occurs. The identified measures had fair to good reliability and validity in people living with dementia. However, available measures need to move beyond symptomatic constructs for this complex paradigm, and toward the varied interpersonal and contextual factors associated with behavioral expression."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "We read with interest the review by Dastoorpoor and colleagues , highligWe would like to highlight the importance of contrasting work related to the prevalence of sexual dysfunction in MS against broader community samples when considering this research, given that sexual dysfunction in men is prevalent and increases with age and common ageing-related comorbidities (e.g. diabetes and cardiovascular disease) . For exaWhile a systematic review and meta-analysis are limited to available data from the original studies, we believe there is a need to consider sexual dysfunction across the spectrum of severity from mild through severe. The current review aptly pointed out the differences in measurement tools used across studies, but some discussion about the measurement of severity and its impact on prevalence estimates is warranted. A Danish community study found that 11% of male respondents reported sexual dysfunction (frequent and perceived as a problem), while 68% of males reported less severe sexual difficulties . Many ofWe again wish to thank the authors for bringing this research together and summarising information about the prevalence of sexual dysfunction for men with MS to date. We hope to have encouraged a follow-up article detailing some of the above aspects and that future reviews on this topic will be considered from the perspective of sexual dysfunction in men more broadly, across the severity of dysfunction and potential causal aspects to contextualise knowledge in this area. A more detailed understanding of this important clinical issue would assist with appropriate clinical attention and management, as well as referral for support to maximise the quality of life for men with MS who experience sexual dysfunction."}
+{"text": "Following the publication of the original article  the authDNA2 gene [18].\"\"Another special IBDD patient, with a severe lack of speech development and lack of social interactions, was reported to be associated with autism that was genetically confirmed in the The correct sentence should read:\"Another special IBDD patient, with a severe lack of speech development and lack of social interactions, was reported to be associated with autism [18].\"The original article has already been corrected as above."}
+{"text": "The Coronavirus disease 2019 (COVID-19) pandemic has introduced numerous challenges to the global scientific community and has been particularly disruptive to the conduct of ongoing clinical trials. Gerontological studies that focus on older adults with cognitive impairments have endured additional challenges ranging from increased vulnerability of this group to COVID-19, thereby prohibiting study participation, to difficulties in participant engagement as a product of a worsening Digital Divide. The purpose of this talk is to describe the pandemic-related factors that have influenced recruitment and enrollment of older adults with mild cognitive impairment and mild dementia in an ongoing feasibility study of a physical activity smartphone app. We discuss the changes we made to recruitment procedures and the impact those changes have had on the success of enrolling individuals in the study. We conclude with a discussion of feasible strategies and procedural alterations moving forward that may facilitate achievement of enrollment goals."}
+{"text": "Following publication of the article , it cameThe figure has been updated in the published article and the correct values may be found in this correction article.The authors thank you for reading and apologize for any inconvenience caused."}
+{"text": "Family members of persons diagnosed with dementia or a traumatic brain injury (TBI) are often relied upon to provide daily support to their care recipients. However, research on the differing experiences of caregivers based on care recipient diagnosis is limited. The aim of this study was to examine the impact of worry and feelings of vigilance among caregivers of people with cognitive impairment due to either TBI or dementia. This sample included 61 caregivers  of persons with either a TBI (n = 32) or dementia (n = 29). Worry was assessed with the Penn State Worry Questionnaire and Vigilance was assessed with the Caregiver Vigilance Scale. Linear regressions revealed that after controlling for age, care recipient diagnosis moderated the relationship between worry and caregiver vigilance. Specifically, worry was significantly associated with caregiver vigilance in those caring for someone with dementia; however, a similar relationship was not seen in those caring for someone with a TBI. This suggests caregivers of people with TBIs have a different experience of worry and vigilance than caregivers of people with dementia. These findings demonstrate the need for more research on the unique needs of caregivers of people with TBIs. Additionally, this research suggests interventions targeting worry may be particularly effective in supporting caregivers of people with TBIs."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "The is session will demonstrate how to use the Canvas learning management system (LMS) to organize and facilitate interprofessional education experiences (IPE) amongst students and faculty. Emphasis will be placed on the use modules as a way to organize content and facilitate requirements associated with IPE. In addition, the session will include demonstration on how to assign disciplines to sections to aide in faculty abilities to review of student submissions."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "The study highlighted that the integration of new FPs into the healthcare team requires active management, including the need for role clarification and supporting role maturation over time.Interviews with district managers to understand the impact of family physicians (FPs) on the South African health system confirmed several benefits, including their ability to increase access to a more comprehensive and coordinated health service, to improve clinical care, to capacitate the healthcare team and facilitate clinical governance activities.3 A survey was held amongst South African Academy of Family Physicians (SAAFPs) members to explore the needs and suggestions for activities for this special interest group, which is named Next5 (see At the April 2021 meeting of the South African Academy of Family Physicians education and training committee (ETC), it was agreed to set up a working group to look at an initiative on how the academy can assist newly qualified FPs within their first 5 years of qualifying, similar to the First five concept of the Royal College of General Practitioners and the Young Doctors Movements of WONCA (World Organization of Family Doctors).1 By encouraging existing FPs to support new FPs in their transition from registrar to expert generalist trained to work in both public and private healthcare sectors, we trust that this new Academy initiative will assist with creating an ongoing \u2018sense of belonging\u2019 in the SAAFP community and tangible membership benefits for all newly qualified FPs. We encourage all registrars to continue their full membership of the SAAFP after graduation and become involved with the Next5 activities. If you are keen to learn more about this initiative and wish to become involved, please email to admin@saafp.org.As part of the August 2021 ETC presentation, we reviewed the number of registrars who became SAAFP members after graduation . Reassur"}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "Unpaid work carried out inside the home has increased in the pandemic, and evidence points to women\u2019s share in care responsibilities and domestic tasks remaining higher than those of men in the pandemic, continuing the gender divides of past decades."}
+{"text": "The main aim of this audit was to determine the prevalence of HDAP in Havering Community Recovery Team (CRT). The secondary aim was to determine how well HDAP has been monitored and documented - specifically, whether discussions around the reasons for continuing and the risks and benefits have been discussed.There is a focus to reduce high dose antipsychotic prescribing (HDAP) due to the lack of evidence that it is efficacious and that smaller doses have an equivalent effect and are better tolerated. Similarly, the consensus by the Royal College of Psychiatrists is that any prescribing of high dose antipsychotics should be an 'explicit, time-limited individual trial\u2019 with a distinct treatment target. There should be a clear plan for regular clinical review including safety monitoring. The high-dose regimen should only be continued if the trial shows evidence of benefit that is not outweighed by tolerability or safety problems.' Following a CQC inspection in 2014 of NELFT which found that the trust was failing to comply with the relevant requirements of the Health and Social Care Act 2008 with regards to safe use of medicines, yearly audits of inpatient HDAP have been undertaken. Although improvements have been made in the inpatient setting, no such audits have been performed in the community setting and consequently there is no data in NELFT regarding community services compliance with the above regulations.All 349 patients in Havering CRT clinical records were screen by either using RIO or GP letters from recent CPA reviews. A data collection and analysis tool was created using Microsoft Excel. Data collection and analysis was carried out by the project lead and checked by a fellow project member.16 (4.58%) of patients were prescribed a high-dose antipsychoticOf the 16 prescribed high dose antipsychotics:0 out of 16 had the high dose antipsychotic monitoring form available12 (75%) had well documented evidence of review of HDAP.4 (25%) had no documented evidence of review of HDAP.Of the 349 patients included for analysis:There is a small group of patients receiving high dose antipsychotic therapy for which better monitoring is needed. This should include education of staff regarding HDAP, better documentation in their care plans and working with pharmacy to make HDAP monitoring forms available widely in the community."}
+{"text": "Concerns about loneliness and social isolation for older adults were already evident but have been exacerbated during the pandemic. Home and Community Based Organizations (HCBOs) provide support for their older clients in the community and need to support their staff, who may be working remotely. We are exploring the potential of video chat technology to connect older adults with their friends, families, and other support. We review the technologies available to older adults in the community and staff working with older adults to promote social engagement. We are collaborating with OneClick.chat to identify the needs of the HCBOs through a literature review and qualitative interviews of staff members from different senior living environments. Their challenges and successes of engaging older adults through video chat technologies will provide guidance for design of an HCBO dashboard for OneClick.chat that will support diverse needs."}
+{"text": "Nemeth et al. have sought to collect and collate the current knowledge generated on IPF disease development and progression through a review on the cellular heterogeneity during the progression and development of fibrotic lung disease and how these single cell studies provide insight toward identifying novel therapeutics for the treatment of IPF.This Research Topic titled \u201cFrom Development to Senescence, Bridging the GAP in Pulmonary Fibrosis\u201d sought to clearly define the role of developmental and senescence pathways that are abnormally regulated during the progression of interstitial lung diseases (ILDs). In contrast to the progress made in reducing the mortality in several other diseases including cancers, ILD mortality rates have remained constant over the last decade. ILDs are characterized by the loss of normal lung regions that are replaced by fibrotic tissue that replace normal alveoli leading to progressive respiratory failure and potentially death. The term ILDs is associated with several lung diseases including cystic fibrosis, scleroderma, sarcoidosis, and one of the most common forms of ILD, Idiopathic Pulmonary Fibrosis (IPF) . IPF is Gokey et al. One of the major pathways identified through genetic studies in mice has been the transforming growth factor-beta (TGFb) pathway. Al-Mudares et al. have sought to clarify the potential role of a TGFb pathway member growth differentiation factor 15 (GDF15), a protein that is ubiquitously expressed, that appears to play a role across the lifespan, as it has been implicated in early life diseases such as bronchopulmonary dysplasia to diseases associated with increased age such as COPD and IPF. The potential role of GDF15 in senescence points to another established risk factor of pulmonary fibrosis, increased age. The link between aging, exposure to injury, and senescence is further explored as a driving factor in onset of pulmonary fibrosis, which is increasingly critical as the world's population ages. Venosa defines the loss of normal cellular \u201cfitness\u201d through the progression of cellular senescence and discusses how as the patient ages, a major indicator of pulmonary fibrosis prognosis, the threshold of injury required to generate an irreversible phenotype is lowered, thereby increasing the potential for abnormal lung regeneration and onset of fibrosis. The link to chronic injury, and potential to treat the source of certain injuries is further explored by Duckworth et al., who collated current data on the role of herpes viral injury in the development of IPF and seek to clarify discrepancies as to whether herpes virus injury is a contributing factor. The potential mechanisms by which herpes virus induces fibrotic progression and whether treatment of viral injury may be beneficial in delaying fibrotic progression are discussed. In the current global environment, the potential role of viral infections leading to onset of pulmonary fibrosis is of eminent concern. The role of lung injury driven by Severe Acute Respiratory Syndrome coronavirus 2 that causes COVID-19, that leads to fibrotic remodeling in some patients is further explored by Kiener et al. The authors explore the various potential models available to study lung fibrosis in-vitro in human samples including the use of precision cut lung slices and organoids to study alveolar regeneration.Several pathways have been implicated in driving development and progression of pulmonary fibrosis. Single cell sequencing has identified that the Hippo/YAP pathway is aberrantly activated in IPF. The recently identified role for YAP during normal alveolar development and repair, as well as aberrant activation leading to abnormal repair that induces atypical cell phenotypes associated with pulmonary fibrosis. Open questions surrounding the function of Hippo/YAP signaling in both normal and pathologic alveolar repair and fibroblast activation have been summarized by Lopez-Rodriguez et al. have generated a novel study by which enhanced repair is capable in the bleomycin induced lung injury model. Instillation of primary AT2 cells into the lung 7 days post injury enhanced lung physiology compared to animals that did not receive AT2 cells when assessed at 14 days post injury.Understanding the mechanisms regulating alveolar repair, and determining ways to enhance alveolar regeneration, are beneficial approaches to identify potential efficacious treatments to delay or resolve pulmonary fibrosis. The most utilized model of pulmonary fibrosis is the use of bleomycin injury in mammalian models. Collectively these manuscripts collate and clarify the current literature in the field that defines the role of developmental and senescence pathways in the onset and progression of pulmonary fibrosis. This collection of timely and insightful reviews greatly assists the field in quickly organizing the current literature and providing novel insights that facilitates the advancement of the understanding of pathways and tools that may provide efficacious targets for delaying, preventing, or resolving pulmonary fibrosis and provide hope for patients diagnosed with this disease and its bleak prognosis.The author confirms being the sole contributor of this work and has approved it for publication.This work was made possible by the Pulmonary Fibrosis Foundation, by an independent grant from Boehringer Ingelheim Pharmaceuticals, Inc. who provided the financial support. The author meets criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE) and was fully responsible for all aspects of the trial and publication development.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Aging is the major risk factor for many diseases but the mechanisms are poorly understood. The risk of developing hepatic steatosis increases with age and the health impact of this disease is negative and high. When challenged with high fat diets, long living Ames mice withstand the detrimental metabolic effects that occur in normal mice. We examined transcriptomic and epigenomic profiles of Ames and wild type hepatocytes in the presence or absence of fat to demonstrate that the epigenomic profile drives transcription factor and downstream gene expression resulting in susceptibility or resistance to fatty liver disease. We found that markers of steatosis are related to gene expression in wild type and Ames mice, and dwarf mice retain fewer lipid droplets compared to wild type mice. These studies will provide data to guide our understanding of mechanisms leading to hepatic disease and define factors that provide protection from age-related metabolic disorders."}
+{"text": "Modern bioinformatics requires the use of many field-specific file formats. Two of the most prevalent formats for representing biological sequences are FASTA  and FASTfqfa is a pure Python package that aims to fill the needs of bioinformatics and computational biology researchers who want a simple and efficient solution for working with files in FASTA and FASTQ formats. It has no dependencies outside of the Python standard library (with the exception of backported dataclasses  for PythAlthough fqfa is written in pure Python, its performance is comparable to modules using C extensions like pyfastx  for taskfqfa is released under the BSD 3-Clause License and is available from GitHub and PyPI."}
+{"text": "In their prospective multicentre study Stumpf et al. report on the humoral and cellular immunity to SARS-CoV-2 vaccination in the so far largest cohort of dialysis patients However, when looking in detail at the quantity of the antibody titre their humoral response is significantly lower than in health care workers or non-dialysis patients . More thIn addition to this apparent diminished antibody response in dialysis patients, concerns also remain about faster waning of antibody levels after vaccination in this group, as is described after natural infection Sandra Hasmann and Ulf Sch\u00f6nermarck designed the letter; all authors contributed significantly to the content of the letter and have accepted the final version.This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.The authors have nothing to disclose."}
+{"text": "Mexican immigrants make up an increasing proportion of the US population 65 and older. Estimating outcomes for this population is complicated by return migration. Due to data limitations, theoretical frameworks and empirical evidence fail to provide clear indication of the economic selection mechanism of return migration, especially at older ages making it difficult to estimate economic determinants of return. Here two waves of data from the US based Health and Retirement Study and the Mexican Health and Aging Study are combined to create a novel dataset that enables a comparison of assets at older ages for those who stay in the US, those who return before age 50 and those who return at 50 and older. Unadjusted results show no difference in total net wealth at older ages between the three groups, with higher business assets among returnees and higher concentration of wealth in home equity among stayers. With evidence of higher inequality among stayers, lower median wealth in Mexico, and asset advantages operating through citizenship, older age return can be interpreted as a means to acquire a higher standard of living in retirement for non-citizen immigrants. Comparing assets between 2000 and 2012 reveal the vulnerability of stayers during the US housing crisis. These findings are novel because they point to return migration as a retirement strategy and expose a source of vulnerability among those Mexican immigrants who remain in the US into older ages."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "Aboriginal people face challenges on several fronts when it comes to the health and wellbeing of their community, compared to the rest of the Australian population. This is no different in urban areas such as Australia\u2019s largest urban Aboriginal community located in Blacktown, NSW, where sexually transmitted infections (STIs) remain an issue of concern. Across Australia, rates of infectious syphilis, human immunodeficiency virus (HIV), and hepatitis C infection have increased by 400, 260, and 15% respectively while gonorrhoea decreased 12% in the 5-year period from 2013 to 2017. This study explores how to address the barriers that prevent young Aboriginal people under 30 years of age from accessing STI treatment through Government Sexual Health Services.This qualitative study will use purposeful sampling to recruit 20 male and 20 female health consumers, 10 Aboriginal elders and 10 sexual health clinicians. This recruitment will be undertaken with the assistance of the local Government Health Services and local Aboriginal organisations. One-on-one semi-structured interviews will be undertaken by someone of the same gender in order to address cultural preferences. Data will be entered into NVivo and thematically analysed.This study will seek to add to the literature that explores why young Aboriginal people do not access sexual health services. This study seeks to understand the experience of clinicians, Aboriginal elders and Aboriginal young people to provide practical policy and clinical redesign evidence that can be used to improve the experience and cultural safety of sexual health services in urban areas of Australia. The results of the qualitative research will be disseminated with the assistance of participating local Aboriginal organisations, and the findings will be published through peer-reviewed scientific journals and conference presentations.The study is approved by the Western Sydney Local Health District Human Research Ethics Committee (HREC/16/WMEAD/449) and the New South Wales Aboriginal Health and Medical Research Council\u2019s Human Research Ethics Committee (1220/16). The Closing the Gap report delivered the Australian Parliament a stark picture of the health of Australia\u2019s first people [In 2008, t people . The scat people . Over tht people . Of partt people . The medt people . There iNSW STI Strategy 2016\u20132020 also identifies Aboriginal people as a priority population in the strategy and in particular focuses upon young people [Whilst the Aboriginal population across Australia represents 3% of the total population, incidence rates of STIs can range anywhere from 3 to 30 times higher than that of the non-Aboriginal population . AccordiAboriginal people in urban communities are often not the focus of research because the funding priorities of the Commonwealth Government tend to direct significant funding towards remote communities and leave state and territory governments to address health needs in urban areas . AborigiOne of the barriers to accessing sexual health services appears to be shame and stigma \u201310. The There is a significant gap in the published literature in terms of studies that seek to understand the issues that prevent Aboriginal people participating in sexual health care through the collection of directly obtained evidence. Many of the studies reviewed, including those undertaken by Bailie et al., Nattabi et al., Buhrer-Skinner et al. and Richmond et al., rely on the response of clinicians in quality improvement processes to guide the conclusions of their research \u201314. ThesThe status of sexual health amongst young Aboriginal people in Western Sydney is an area that has not been explored in any great depth within the published literature. The study undertaken by Biggs et al. provides a cross-sectional view of Aboriginal people attending public sexual health services in Western Sydney through an incentive-based program called \u2018The Deadly Liver Mob\u2019 . The DeaThis study will seek to add to the literature by exploring why young Aboriginal people do not access sexual health services. This study seeks to understand the experience of clinicians, Aboriginal elders and Aboriginal young people to provide practical policy and clinical redesign evidence that can be used to improve the experience and cultural safety of sexual health services in urban areas of Australia.This qualitative study will utilise content analysis design and undertake semi-structured one-on-one interviews with up to 40 health consumers , 10 clinicians and 10 community elders or until a saturation point is reached. Inclusion criteria for health consumers will be that they need to be between 18 and 29 years of age at the time of enrolment into the study. The semi-structured interview guide was developed with feedback from Aboriginal staff and Clinical Staff with specialist knowledge of sexual health. Wherever possible, we will be using Aboriginal interviewers to create culturally safe spaces for study participants to respond to questions. All cohort groups will be interviewed using a semi-structured interviewer-assisted questionnaire with the aim of answering the following questions:What prevents Aboriginal people in Western Sydney from accessing government sexual health services?What would enable Aboriginal people in Western Sydney to access mainstream services?Would changes in service modality make services more accessible?What do participants see as the most important things that could be implemented to improve sexual health services in Western Sydney?A target number was purely set to ensure gender equity amongst study participants, and data collection will cease once saturation has been reached. The study investigators have adequate qualifications and experience to undertake a qualitative study in the area of sexual health and have significant expertise in community engagement and co-design. The questionnaire is worded in plain English to ensure that potential participants with low literacy can also participate. Interviews will be audio recorded, and results of this study will be analysed using the software program, NVivo , so that major themes can be identified and thematically analysed.This data will create translational research that will assist service delivery models in publicly funded Sexual Health services in Western Sydney and perhaps more widely.Study participants will be free to withdraw from the study at any point up to where audio files are destroyed, post the transcription process. Participants will not be able to withdraw after this point because individual transcripts will only be coded with the participant\u2019s interview cohort, gender and a sequential number; therefore, any individual submission will not be able to be identified for withdrawal.This study will be conducted in a manner that safeguards the anonymity of participants by ensuring that interview responses do not contain any identifying marks apart from an indication of age and sex. This will assist in protecting the privacy of Aboriginal people who choose to participate in the study. The value of Aboriginal interpretation is integral to this project\u2019s success, and this will be achieved through the engagement of Aboriginal research assistants, consultation about the study design and through the engagement of Aboriginal people in the analysis of data and the final conclusions of the study. Involvement in the governance of the study is also of paramount importance, and every effort will be made to ensure participation.NSW Children and Young Persons (Care and Protection) Act 1998, the matter will be immediately reported to the NSW Department of Families and Communities, and referrals would be offered to relevant support services [The investigators anticipate that some risks may be posed by participants disclosing sensitive information particularly around the conduct of illegal activities, a history of sexual or physical abuse or need to have sexual health conditions treated. Should a disclosure of illegal activity be made, the interview would be immediately terminated in order to ensure that the participant did not further incriminate themselves. If the disclosure relates to any form of abuse that falls under the definitions of Section 27 of the services . In ordeThe results of this study will be disseminated through several different media including meetings with study participants, local elders and Aboriginal groups, peer-reviewed publications, presentation of results at conferences, and through summaries presented via social media.The contribution of local Aboriginal people will be acknowledged in all publications to reflect the unique contribution that they provide, and co-authorship of academic papers will be offered, consistent with University of Sydney policy on the matter. The research will be conducted in accordance with the National Health and Medical Research Council (NHMRC) guidelines for ethical research with Aboriginal people . Plain EThis study will provide benefits to Aboriginal people by enabling local health services to better understand and allocate resources to meet the needs of young Aboriginal people through the acquisition of more robust study data concerning how Sexual Health Services may best be delivered.The results of this study will be significant in informing urban health services on the needs of young Aboriginal people in terms of how they prefer to access public sexual health services and the barriers that currently exist that may prevent them from using existing services. Much of the research based both in remote areas and urban areas relies on the experiences of clinicians rather than the lived experience of young Aboriginal people themselves and may miss important aspects of interpretation that only occur when Aboriginal people share their insights. These insights will be deepened in this study by involving local Aboriginal people in the interpretation of the de-identified results of the study.This engagement project will provide a set of documents that will be informed by the local community and provide policy makers with practical measures that can be implemented to improve the cultural appropriateness and clinical care of young Aboriginal people. This study will also address important policy questions and directly inform on the delivery of healthcare to young Aboriginal people in urban settings."}
+{"text": "We read with great interest the study by Poncette et al  on the dThe paper  illuminaA survey found high levels of satisfaction among students participating in the elective module. Confidence levels, as well as the acquisition of knowledge and skills in digital health, were reported to be high. However, this analysis is subjective as it is based on the student\u2019s own opinion of their knowledge. In order to obtain more objective results, we recommend the assessment of individual skills by a standardized exam before and after participating in the module. Supplementing the opinion-based survey with exam performance may shed light on the actual perceived level of student competence while reducing selection bias. This would highlight the effectiveness of the course and give medical departments and universities more confidence to adopt digital health competencies in their curricula.We commend Poncette et al  not onlyThe introduction of digital health competencies into the medical curricula remains key to the success of future physicians as shown by Poncette et al . Therefo"}
+{"text": "Cavernomas are rare cerebrovascular malformations that usually occur in sporadic forms with solitary lesions located most often in the hemispheric white matter, but also in the infratentorial or spinal region. Multiple lesions at different CNS levels are considered a hallmark for the familial form of the disease. The diagnostic modality of choice for cerebral cavernous malformations (CCMs) is magnetic resonance imaging (MRI). We present an intriguing case of a 65-year-old male admitted to our hospital with tetraparesis and cognitive impairment where highly sensitive MRI sequences identified many cerebral cavernous lesions at the supra-, infratentorial and cervical\u2013thoracic spine levels, some of them with recent signs of bleeding in a patient with oral anticoagulant therapy due to atrial fibrillation. The mechanism of cognitive impairment in this patient is most probably the interruption of strategic white matter tracts, as it is known to happen in other subcortical vascular pathologies. MRI can be helpful not only in mapping the anatomical distribution of lesions, but also in weighing the risks and making decisions regarding whether or not to continue oral anticoagulant therapy."}
+{"text": "Younger Onset Dementia (YOD) and Mild Cognitive Impairment (MCI) are relatively prevalent conditions globally which can affect the job performance of individuals in their working lives. This presentation considers the existing research documenting actual, stated or intended approaches taken by employers to managing and supporting employees with these conditions. Nine relevant research projects were identified based on an extensive exploration of the peer reviewed literature. These show that employers have some knowledge of dementia, but do not recognise this as a possible explanation when performance changes occur in the workplace. Employees typically leave or are removed from the workplace before a formal diagnosis or soon after. The literature shows both supportive and unsupportive behaviours toward employees. Drawing from this literature recommendations for increasing the quality of support provided to employees are offered: awareness training to foster earlier detection, clarification of these conditions as a disability, and application of methods to support employees to continue to contribute to the workplace while this is feasible and desirable from both the employer and the employee\u2019s perspective."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "Population aging will inevitably bring an increasing burden of poor cognitive function. The risk factors for cognitive decline have been widely studied. Even though environmental hazards have the greatest adverse impacts on older adults and the existing evidence has shown that green space, air pollution, and weather have an impact on cognitive function, most of the studies were conducted in developed countries and limited to cross-sectional analyses. China has the largest aging population in the world so the research evidence from it can offer an insight to the study in other developing countries facing similar issues and inform future public health policy and disease control. Using the data from a nationally representative sample of adults aged 45 years and older from the three waves of China Health and Retirement Longitudinal Study (CHARLS 2011-2015) and China City Statistical Yearbook, this study estimated multilevel growth curve models for the effects of green space coverage, air pollution, and weather conditions on cognitive function and cognitive decline. It showed that after controlling for sociodemographic characteristics, built area green coverage rate was positively associated with cognition score at baseline, and higher annual minimum temperature was associated with faster decline in cognitive function. These effects did not substantially change after weekly total hours of physical activities and levels of social engagement were added and the interaction effects were examined between environmental conditions with them, respectively. More research on the mechanisms of the effects of environmental factors on cognition is needed such as the subgroup analyses."}
+{"text": "Lycopene is a C40 tetraterpene that is composed of eight isoprene units joined by regular head to tail bindings, except in the middle of the molecule, where tail to tail binding forms an asymmetric structure  . Its abThis work was supported by the Incheon National University Research Concentration Professors Grant in 2021.The authors declare no conflict of interest."}
+{"text": "Adherence to Cumbria Northumberland Tyne and Wear NHS Foundation (CNTW) Trust physical health monitoring guidelines for a caseload of community forensic psychiatry patients residing at Westbridge supported accommodation was audited to identify areas for improvement in practice. It was also our aim to highlight the delay in obtaining non-urgent investigations due to the need to minimize COVID infection transmission risks.Data were collected from mental health and acute trust electronic records (Rio and ICE) of all patients taking antipsychotic medications currently care coordinated by the Westbridge Forensic Community Mental Health Team (FCMHT) between January 2020 and January 2021 (8 patients). Analysis of compliance with standards set by Trust guidelines was made.In the chosen audit period, compliance with physical health monitoring standards was below target of 100% . Reasons for non-compliance were unexpected restrictions in service availability  and one omission of sending a prolactin levels request.The need for practice adaptation and advance planning by team in anticipation of potential delays was identified. Request for routine bloods and ECGs will now be made two months before the annual due dates to compensate for delays in the new process with plan to continue re-audit yearly."}
+{"text": "This study targeted junior high school kendo club members who have practice experience with elderly kendo practitioners and examined the image of the elderly and the related factors that intergenerational exchange through kendo brings to the junior high school members. Kendo is one of the traditional Japanese martial arts. The subjects in this research were 193 players who practiced with the elderly kendo practitioners in Osaka prefecture. As a result of factor analysis to clarify the structure of the image, the \"evaluation\" factor and the \"activity / competence\" factor were extracted as in the previous research, and it was suggested that the junior high school players generally had positive image regarding the elderly practitioners. As a result of logistic regression analysis to clarify the factors related to the high/ low scores in the image of elderly kendo practitioners, \"evaluation\" factor showed a significant relationship between \"intimacy with elderly practitioners\" and \"empathic interest\", and \"activity / competence\" factor indicated a significant relationship between \"gender\" and \"intimacy with elderly kendo practitioners.\" Although it is pointed out that the traditional style of kendo and the image of elderly kendo practitioners have a negative impact on children, it may be possible to control these factors through an appropriate guidance and approach depending on the children's stage of growth ."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "Stigma towards psychiatry feels rife within medical school and this extends from university life into clinical placements. Mental health remains an unattractive area of medicine and is frequently regarded as subpar by other specialists. Against existing literature, this study compares the authors first hand experiences over the last five years within medical school to evaluate how representative their experiences of stigma in psychiatry are for the wider community and published literature. The study aims to inform the wider discussion on this topic and offer areas where intervention may yield a better perception and hence uptake of this specialism.Literature review relating to the topic was completed. Studies pertaining to medical students and/or educators views and experiences of psychiatric medical education and clinical placement were included for discussion. A reflection on the first author's specific experiences to date of psychiatry and his intent to pursue psychiatric career was conducted, with careful reference to existing literature. This allowed validating personal experiences in light of shared experience within the medical community in various national and international settings.Arguably, some non-psychiatric clinicians do inadvertently set the scene early in medical school for the stigma that is to be thrust upon students. This builds upon prospective students ranking psychiatry low for satisfaction, prestige and stating it to be a \u2018pseudoscience\u2019 or words to that effect. The lack of understanding from junior medical students of the role of the psychiatrist sees them associating psychosocial education as equivalent to psychiatry. This reinforces the idea of psychiatry being grounded in sciences other than anatomy, biochemistry, physiology and pharmacology. On clinical placement, there is little cross-speciality support for those students who want to be psychiatrists and sometimes even lost opportunities for those publically aspiring towards psychiatry. Placements in psychiatry give students a better understanding of psychiatry but this does not seem to significantly change their career aspirations and this is rather defined from the admission stages.After comparing experience with literature, stigma towards psychiatry appears to be universal. It may be important to consider the types of students who are being attracted to medical school as currently students seem to have an intrinsic disinterest in psychiatry despite later becoming better informed through psychiatric placement. Culture is notoriously hard to change, particularly within medicine. This stigma exists both in the lay and medical communities with early potentially inaccurate lay views of psychiatry being validated and reinforced throughout medical school."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "The tendency of caregiving alone is increasing, and these solo caregivers often perceive caregiving responsibilities as a burden. Still, literature on positive aspects of caregiving shows that not all caregivers experience severe distress. Little is known on which factors make a difference in experiencing caregiving distress among solo caregivers. We focused on the empirical findings on the negative impact of social isolation on caregiver\u2019s mental health, examining if and how the intersection of solo caregiving and social isolation is related to severe caregiving stress among caregivers of older adults in Korea. We analyzed 501 family caregivers of older adults in Korea using survey data from the Care Work and the Economy research project (2018). We conducted ordinal logistic regression analysis. The findings show that solo caregivers with a lack of social time fall under the most at-risk group of caregivers in terms of experiencing severe stress  whereas solo caregivers with enough social time did not show significantly higher stress compared to the reference group . Being socially isolated caregivers still had high levels of stress despite the division of care , implying the need to provide caregivers more time for social interaction with others. The current public long-term care insurance in Korea provides limited hours of in-home care aide services to enable aging in place of older adults. To reduce the social isolation of caregivers, it is necessary to extend the service hours and provide support, such as creating online caregiver networks."}
+{"text": "The 8th International Cancer Metastasis Congress through the Lymphovascular System: Biology & Treatment, was held from October 25\u201327, 2019 in San Francisco, California. This international conference was inaugurated in 2005 and has been successfully held biennially with several publications summarizing the biology and treatment of cancer metastasis. The last conference in 2017 was summarized in a special issue by Clinical and Experimental Metastasis , 4 with Cancer heterogeneity is discussed in the context of Breast Cancer Disparities in Outcomes; Unmasking Biological Determinates Associated with Racial and Genetic Diversity  and CancThe diversity of cancer biomarkers further validate that cancer is heterogeneous as represented by several review articles on Detection of Cancer Metastasis: Past, Present and Future ; SentineBased on the heterogeneous array of biomarkers, personalized cancer therapy is developed against specific biomarkers for more accurate targeted therapy as represented by the two review articles on Precision Oncology for Breast Cancer through Clinical Trials  and BrinThe role of cancer microenvironment exerts a selective force akin to Darwin\u2019s natural selection \u201318 in thCancer clones may escape the primary site and spread initially to the sentinel lymph node as summarized in the Donald L. Morton\u2019s Memorial Lecture: The Legacy of Donald Morton: Past, Present and Future  to suggeThe molecular mechanism of cancer metastasis through the lymphatic versus blood vessels is still not well understood. An attempt has been made to summarize what we know to date relating to the mechanisms of cancer metastasis in the following review articles on Mechanisms of Breast Cancer Metastasis ; The LymThe role of lymph node dissection and systemic treatment for a positive sentinel lymph node biopsy are discussed in depth using the model of melanoma, entitled Current Management of Melanoma Patients with Nodal Metastases . In-tranAdditional novel imaging of cancer is illustrated by Emerging Photoacoustic and Thermoacoustic Imaging Techniques for Detecting Primary and Metastatic Cancer and Guiding Therapy . Novel rFurther, innovations in radiotherapy are described in Innovations in Radiotherapy and Advances in Immunotherapy for the Treatment of Brain Metastases . Check pSecondary Lymphedema Related to Cancer Treatment by Surgery or Radiotherapy is an important topic relating to the treatment complication of cancer .The biological events of cancer development with mutation and cancer evolution\u00a0as well as the molecular mechanisms of cancer metastasis may be more accurately correlated and\u00a0defined\u00a0by the adoption of artificial intelligence as summarized in the review article on Empowering Study of Breast Cancer Data with Application of Artificial Intelligence Technology: Promises, Challenges, and Use Cases .This Special Issue: Novel Frontiers in Cancer Metastasis emphasizes that cancer is a heterogeneous disease resulting from genetic mutations or epigenetic changes . Such he"}
+{"text": "The Eastern and Western Mediterranean are separated by an elevated plateau that regulates water exchange between these two basins. The Maltese archipelago, situated atop this topographic high, offers a unique window into the evolution of this plateau in the lead up to the Messinian Salinity Crisis. The Upper Coralline Limestone Formation was deposited between the late Tortonian and the early Messinian and was probably terminated by palaeoceanographic events related to the Messinian Salinity Crisis. It represents the youngest Miocene sedimentary deposits outcropping in the Maltese archipelago. This shallow\u2010water carbonate unit can be used to trace palaeoenvironmental changes atop the sill between the Eastern and Western Mediterranean and to explain the possible water flow restrictions to the Eastern Mediterranean that could have preceded the Messinian Salinity Crisis. Here field surveys, and analysis of the depositional environment within the Upper Coralline Limestone in Malta, are combined with recently acquired multichannel seismic reflection profiles between Malta and Gozo, to reconstruct the depositional sequence in the Malta Plateau during the late Miocene. The Upper Coralline Limestone consists of multiple coralline and larger benthic foraminifera dominated facies, extending from subtidal to intertidal environments. These accumulated in two depositional cycles observed in both outcrop and seismic reflection data. Each cycle exhibits an early aggradation\u2013progradation phase followed by a progradation phase and a final aggradation phase. These manifest themselves in the outcrops as shallowing and deepening upwards phases. These were deposited above a deep water unit and are indicative of a preceding uplift phase followed by filling of the accommodation space through the deposition of the Upper Coralline Limestone Formation in shallow marine depths. The presence of this highly elevated sill during the late Miocene could have restricted circulation to the eastern basin. The Upper Coralline Limestone formation in Malta offers a unique look at the gateway between the West and East Mediterranean in the period before the Messinian Salinity Crisis (MSC). Here we revisit this unit using both field bases sedimentological analysis and seismic imaging to document the evolution of this sequence. The findings illustrate the ongoing uplift of the barrier between the basins before the MSC. This mineral assemblage suggests that material had been recrystallised at some point post\u2010deposition. The absence of dolomite suggests an open system that allowed removal of the Mg. The implication of this would be that any geochemical analysis would inform of the diagenetic rather than the primary conditions , and the known eustatic sea\u2010level patterns (Miller et al., The emplacement of two cycles of shallow\u2010water deposits in the UCL formation, terminating near sea level, indicates that accommodation space was available for the establishment of two depositional cycles and topography fill by a carbonate factory. The fact that a C\u2010type factory is dominant in Malta at this time, while in other regions of the Mediterranean T\u2010type factories are still dominant Follows, , does su6Over the late Miocene, the area around the Maltese Archipelago has experienced a significant uplift. The uplift raised the Maltese Islands to a water depth that allowed the emplacement of a shallow\u2010water carbonate unit in the form of the UCL Formation. This unit was deposited during two depositional cycles, with both cycles characterised by a strong tendency towards filling the available accommodation space typical of C\u2010type carbonate factories. The mode of emplacement and overall geometry suggests a very shallow position of the Malta Plateau, conforming to an existing tectonic structure already present in the late Miocene. This uplift appears to have played a role in restricting connectivity of the water masses between the east and the west Mediterranean prior to the onset of the MSC and could have played an important role in triggering halite deposition in the larger Eastern Basin prior to salt deposition in the Western Basin. This uplift would have restricted flow to the Eastern Basin at a time when the Western Basin was still relatively well\u2010connected to the Atlantic Ocean and probably played a pivotal role in the observed differences in deposits between the two basins during the MSC.Figure S1Figure S2Figure S3Click here for additional data file."}
+{"text": "Gratitude is foundational to well-being throughout the life course, and an emerging body of work suggests that older adults may be more inclined to attribute gratitude to a non-human target (God). Drawing on life course theory and Erikson\u2019s lifespan development framework, we use data from a national sample of Christian older adults from the United States  to examine whether gratitude towards God buffers the noxious health effects of the death of a loved one or personal illness. Results suggest that gratitude towards God tends to predict better age-comparative and global self-rated physical health in the aftermath of stress, a moderation effect which is partially mediated by stronger beliefs in God-mediated control . We conclude by proposing some interventions for clinicians and counselors centered around gratitude and religiosity that may assist older adults in coping with major life stressors."}
+{"text": "From December 2020 \u2013 February 2021 we conducted 32 semi-structured interviews with Veterans who responded to our initial and follow-up surveys and agreed to discuss their cannabis use. We coded and themed the interviews using inductive thematic analysis. We found that many Veterans are using cannabis in place of other medications such as opioids and benzodiazepines and often do so to avoid the negative side effects. However, barriers such as Veterans Administration policies and cost of medical cannabis affect Veterans ability to obtain medical cannabis. Our results inform clinicians and policy makers on the use of cannabis as an alternative to prescription medications for treating chronic pain and other conditions in older Veterans."}
+{"text": "We discuss a stepwise approach using properties of the conduction system to diagnose the patient\u2019s tachycardia. The presenting ECG is shown in Figure 2The ECG in Figure The most challenging part of interpreting a WCT is determining whether the mechanism is due to aberrant conduction versus VT, especially in light of a history of prior myocardial infarction. While there are numerous algorithms to help differentiate between the two,Shortly after the ECG in Figure The authors have nothing to disclose."}
+{"text": "The importance of Public Involvement (PI) is increasingly being recognized in the field of dementia research. In 2012, Alzheimer Europe set up the European Working Group of People with Dementia (EWGPWD) which provides advice and input for all activities of the organization including several large European-funded research projects. The German Center for Neurodegenerative Diseases (DZNE) created a research advisory patient board in 2020 with the intention of supporting the board in strategic research decisions. Both groups are composed of people with dementia and act independently. With the aim of finding out whether PI in research is mutually rewarding and beneficial, members of both groups were asked about their motivation to be involved in PI research activities and the value this had for them. This was collected either through narrative interviews or during meetings. People with dementia described several reasons for being involved in PI activities in dementia research."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "I am delighted to announce this new Methods X Article Collection on Groundwater on the occasion of the World Water Day 2022 dedicated this year to highlight the importance of this water resource.Groundwater constitutes about 30% of the world's freshwater resources. From the other 70% nearly 69% is captured in the ice caps and mountain snow and glaciers and only 1% is located in rivers and lakes. The thing is that according to these figures, groundwater is one of the keys to sustainability of world water resources and there is an urgent need to apply better management practices. Groundwater is extensively used worldwide for domestic, industrial, and agricultural purposes. In this sense both urban and rural areas rely on groundwater resources to meet their water demands. Over-exploitation of groundwater resources reduces water availability and results in negative impacts on groundwater-dependent ecosystems, such as springs and wetlands. In short, the main negative impacts to groundwater quality are caused by saline intrusion, the entrance of chemicals by diffuse sources, i.e., agricultural practices, by point sources such as the leaking of city sewage pipelines and lastly by inefficient waste management practices originated in landfills and other industrial activities like mining.-Conceptual model to include a broad range of emerging contaminants groundwater monitoring programs-Advances in mass spectrometric instrumentation to determine emerging organic contaminants and arsenic in groundwaters-Health risk assessment of nitrate leachates from agriculture and its impact on groundwater resources in mountainous catchments and as a source for drinking water-Hazard assessment models to predict and manage the impact of different types of landfills in groundwater resources-Water quantity and hydrological investigations using numerical and mechanistic models to investigate the groundwater potential zone of the aquifers-River and groundwater model algorithms for simulating the response of river water temperature to urban greeningBased on everything has been said groundwater quality and quantity issues are the major challenges identified and are discussed in the twelve papers selected in this article collection. These papers were published in the last few years in Methods X and evaluate practical aspects and state of the art methodologies such as:Examples reported here describe many different aspects related to groundwater research challenges. The first example discusses the need to develop a conceptual model that integrates various monitoring programs covering a broad range of organic wastewater contaminants like pesticides, pharmaceuticals and personal care products among others. The following two papers report mass spectrometric (MS) methods such as the use of liquid chromatography-MS coupled to solid phase extraction for the analysis of ubiquitous pesticides like atrazine and metolachlor or the application of inductively coupled plasma-MS for the determination of arsenic species. Nitrate contamination of groundwaters is a global problem not only in catchment level but also for drinking water purposes and it also part of this article collection. A drinking water quality index that includes nitrates and other anions and cations has been proposed in one of the papers selected. The impact of landfill leachate plumes on ground water has been in the environmental agenda for quite some time. Examples reported here include industrial and municipal waste and sanitary landfills as well as models for landfills selection sites according to a comprehensive list of criteria such as land use, protected area, surface water and groundwater resources in the potential landfill location. The last examples reported in this collection are related to water quantity and hydrological investigations. Needless to say that stochastic and mechanical models are generally used to predict groundwater availability considering aquifer recharge and evapotranspiration among other variables. Location of groundwater potential zones is of great importance in order to unequivocally identify the quantity of ground water resources in certain geographical area. A river and groundwater model algorithm that captures the warming and cooling impact of urban development and restoration through a water and energy budget is described in the last paper of this article collection.That being said I would like to thank all authors of these twelve contributions to Methods X in compiling such a timely article collection. Needless to say that this groundwater collection papers will be of help to environmental scientists, specially hydrologists as well as newcomers, PhD students and those senior researchers who consider groundwater as one of the world resources that needs protection.Ultimately I have the pleasure to announce a Virtual Special Issue on Groundwater to celebrate this World Water Day 2022. This will allow authors who had not the opportunity to be part of this VSI that is now released as well as to previous authors who contributed to this Methods X article collection to update and publish their recent methods. Submission window will be open from March 20 till October 31st 2022.As always, thanks for reading and stay safe and healthy!"}
+{"text": "Sexual dysfunction should be enquired about as a symptom of mental health disorders and as side effects of commonly used psychotropic drugs. We audited against NICE guidelines the record of sexual dysfunction discussion at initial assessment and follow-up by the community mental health recovery service (CMHRS).Research reports that sexual dysfunction occurs more often in individuals with serious mental illnesses including depression and schizophrenia. Sexual dysfunction is also a reported side effect of antidepressant and antipsychotic medications. NICE guidelines recommend assessment of biological symptoms of mental health disorders and discussion of potential side effects of treatments being considered prior to initiation and at follow-up.Our sample consisted of 71 patients, all new patient assessments from referrals made to CMHRS between January 1st and March 31st 2019.We reviewed all initial assessment and follow-up electronic notes and any correspondence generated from these meetings.Our results showed that no record was made of sexual dysfunction as present or absent by health care professionals (HCPs) completing initial assessment or follow-up.We surveyed the HCPs from the team and observed a high level of confidence in discussing sexual dysfunction and high self report of this discussion being conducted.Our audit results show no records of the discussion of sexual dysfunction, we held to the principal that in absence of record the discussion did not take place. Our survey results suggested that HCPs were confident they do assess for sexual dysfunction. We wondered, therefore, if HCPs would be less likely to make record in the event that symptoms are denied, recognizing that the list of potential symptoms and side effects is extensive and documentation of all negative results would be time consuming.Our audit results may show then, that sexual dysfunction is not present in any of the sample; however this would contrast to research findings of higher than average rates of sexual dysfunction in groups with serious mental illness and those using antidepressants or antipsychotics.We propose further assessment is needed for the disparity between our and recognised rates of sexual dysfunction.We propose the standard that recording \u2018absence of biological symptoms\u2019 of mental health disorders or recorded supply of medicine information leaflets are adequate record. We also made suggestions for training and recording to assist HCPs initial assessment."}
+{"text": "Ottawa Charter for Health Promotion provided a template that has fundamentally re-shaped public health practice in the past 35\u2009years . WHO\u2019s priorities include achieving Universal Health Coverage (UHC): responding successfully to global health emergencies (including COVID-19); and creating healthier populations .Shanghai Declaration by exploring law and urban governance through the paper by Burris and Lin; and the future evolution of health literacy by S\u00f8rensen and colleagues    as a worThe paper by Hancock and colleagues examines a further key challenge emerging from the task of positioning health promotion methods and strategies at the heart of actions required to achieve the UN SDGs by advancing planetary health promotion through local-level actions (Finally, we have two papers that explore emerging issues in health promotion examining evolving concepts in health and wellbeing by Corbin and colleagues; and Digital Health Promotion by Lim and colleagues (et al. examines the potential benefits and challenges of digital technology for current and future health promotion strategies. The benefits include expanding access to health information and health-promoting services, as well as lowering the cost of scaling up activities to reach larger populations. It also highlights key challenges including the growth of misinformation and disinformation through digital media; and ensuring widespread accessibility and affordability to digital technology in ways that minimize social inequities.The paper by Lim Taken together this set of papers provides an overview of several key transformations facing the global community and suggests pathways for the application of health promotion methods and strategies to meet these challenges. This collection of papers reflects the evolving local and global contexts and emerging priorities for health promotion. Insofar as promoting health is one of the three strategic priorities for the WHO\u2019s 13th General Programme of Work, the papers point to the evolution of our paradigm about health\u2014i.e., shifting from disease to risk factors to determinants, and from individual, through social to planetary health and wellbeing. Research, policy and practice in health promotion will need to similarly evolve to keep up with these emerging health challenges and changing contexts.The authors alone are responsible for the views expressed in this article and they do not necessarily represent the views, decisions or policies of the institutions with which they are affiliated."}
+{"text": "I am reading the paper of Sanoglioni et al. aiming to to identify to evaluate the usefulness of left atrial (LA) reservoir strain for risk stratification of asymptomatic patients with moderate aortic stenosis . In rece"}
+{"text": "Many studies show that cultural perspective is an important factor in caring for elderly tribal adults. To understand the level of attention that the Cultural Health Station of Indigenous People attaches to culture during its operation, this study selected Taitung County as the region of study. A qualitative focus group research method and quantitative questionnaire, we try to understand \u201cWhat are the demands of elderly tribal adults?\u201d \u201cDo services provided by the Tribal Cultural Health Station satisfy the demands of elderly tribal adults?\u201d and \u201cWhat are the gaps between the service demands and provided to elderly tribal adults?\u201d The results showed that service providers believe that culture is markedly important to elderly tribal adults, that culture-based care designs offered by the Tribal Cultural Health Station is currently insufficient, and that to enhance the capacity of the multiethnic Tribal Cultural Health Station, the cognition and understanding of policy makers and enforcers must be elevated."}
+{"text": "The number of people in the United States with dementia is increasing, with nearly six million people living with Alzheimer\u2019s disease and related dementias. It is the fifth leading cause of death for those aged \u226565 years. Over 95% of people with dementia have another comorbid chronic condition. The Healthy Brain Initiative\u2019s State and Local Public Health Partnerships to Address Dementia: The 2018-2023 Road Map notes that public health agencies should raise awareness of the link between brain health and physical health, and specifically calls out tobacco prevention and control, cardiovascular health management diabetes prevention and management, obesity prevention and control, and injury prevention as intervention points. The National Association of Chronic Disease Directors developed brain health messages targeted to reduce risk for cognitive decline through the prevention and control of comorbid chronic conditions. These messages can be leveraged for public health action by integrating them into existing chronic disease programs."}
+{"text": "The aim of this study was to explore experiences of consultations with non-specialist health professionals in a group of young people with ASD and their parents and what they considered would help to improve these interactions.Research has shown that general awareness around autism is poor among the general medical community and this can result in poor communication during medical consultations.An opportunistic group of 4 young people with ASD and 8 parents from a local support group in Exeter were interviewed in an informal environment about their experiences of healthcare consultations after seeking verbal consent.Among the 8 parents interviewed the themes emerging were a deep lack of understanding and awareness among medical staff of the challenges faced by individuals with autism, the importance of the doctor-patient relationship to allow children to open up to healthcare professionals, and the need for all children to be respected as individuals.Among the 4 young people (13 to 19 years) with ASD interviewed they identified significant anxiety around waiting for appointments and expressed a desire for a distractor to relieve stress, questions posed by clinicians were often vague and should be clearer, 3D models/mannequins could be useful to support understanding of anatomy and physiology, patience and a calm demeanour were vital with a quiet clinical environment to avoid distraction, time for mental preparation is important and efforts should be made to avoid delays or cancellation of appointments where possible.An interactive website was generated in the light of feedback from the client group and their parents, aiming to educate clinicians regarding the challenges faced by this client group and provide a guide suggesting how to facilitate effective consultation through the use of simple techniques to promote engagement/reduce anxiety in the clinical environment.Simple changes to the approach to consultation with clients with ASD - a quiet consultation space, no delays and better communication - could reduce stress and promote positive interactions with a beneficial effect on healthcare delivery for this client group."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "The number of older adults with intellectual and developmental disabilities (IDD) in the U.S. is expected to double and potentially triple by 2030. Despite this demographic urgency, there continues to be a lack of research directly addressing aging of people with IDD. Individuals with IDD have on average twice as many health problems than others without IDD, experience earlier age-related declines in health and function than the general population and are more likely to develop secondary conditions as they age. The increase in the number of people aging with IDD and the challenges experienced by this population have demanded new directions for research, practice and policy that promote social justice and improve this population\u2019s health and well-being. This symposium brings together research that critically examines and calls for a \u201cnew normal\u201d of supports for healthy aging provided to the population aging with IDD. The first presentation consists of a systematic review of healthy aging interventions for adults with IDD. The authors conclude that such interventions for adults with IDD remain scarce, incipient and sporadic. The second presentation critically reviews an interprofessional education model aimed to address the complex and unique needs of older adults with IDD and dementia. The authors provide recommendations for the future development of interprofessional education in this field. In the third and final presentation the authors offer further transformation toward a new normal as they outline future directions for research on aging with IDD that is informed by positive psychology and disability studies theory."}
+{"text": "During the recovery, investing in gender equality is essential: it will lead directly to higher GDP and indirectly to increase human capital and promote a sustainable society.Or Women as economic agents may themselves have an impact on policies: the changing role of women in families and societies and their greater representation in decision making positions contribute to focusing and redirecting the policy agenda toward items that ultimately reduce gender gaps."}
+{"text": "The psychodynamic approach views human behavior from the standpoint of unconscious motives that influence personality functioning. In contrast with a nosological approach, the emphasis is on tracing behavior to its origins, fostering a deeper understanding of what is \u201cbehind\u201d the overt signs and symptoms of disorder (Vaillant, The impact of a dynamic approach in psychotherapy is largely documented (Midgley et al., The health emergency we are experiencing due to COVID-19 has strongly influenced not only physical health but also the mental health of the general population as well as collective behavior (Gray et al., Due to uncertainty surrounding COVID-19, collective distress and individual suffering, the psychodynamic approach may be able to consistently identify and manage stressful life-event dynamics (Afari et al., In this opinion article the relevance of the implementing psychodynamic approach in the prevention of individuals' mental health during the ongoing COVID-19 crisis has been highlighted. In accordance with Mar\u010dinko et al. , the incad hoc effective interventions. The systematic assessment of unconscious psychological aspects of personality should be promoted for the early detection of vulnerable individuals and for improving research and clinical practice toward a personalized therapeutic approach (Lingiardi and McWilliams, Understanding how the ongoing pandemic is influencing human reactions to such a stressful event is essential for developing The author confirms being the sole contributor to this work and approves it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Stress distribution pattern around dental implants is an important determinant for rate of bone resorption around them. During planning the treatment for most prosthetic rehabilitations, the surgeon uses a software to virtually plan the dimension, position and angulation of the implants considering only the quantity of available bone in the area of interest but does not usually consider the strain generated around the implants after prosthetically loading them. We hence hypothesise that dental implants not be subjected to abnormal strain they should be positioned and angulated not only based on volume of bone available but also based on the vector of occlusal load. The virtual FEA model to analyse the stress distribution would hence require alveolar bone with future tooth/ teeth in centric relation to be modelled. This paper proposes a simple innovative technique to develop a 3D FE model of occlusal loading surface by using a radio-opaque malleable lead foil to generate a patient specific FE model. This would greatly minimise modelling errors and also help determine the best position of the dental implant based on both the volume of bone in the CT scan and the results of FE analyses.  Specifications table*Method detailsThe dental implants are often positioned in the jaws using 3D printed implant positioning surgical guides. The surgeon uses the software to plan the angulation and position of the implants considering only the quantity of available bone in the area of interest but not the strain which would be generated around the positioned dental implants, a vital factor for long-term success of the treatment executed.During the replacement of a single missing tooth, loading vectors are usually along the long axis of the implant Hence, we hypothesise that dental implants not be subjected to abnormal strain, it should be positioned and angulated not only based on volume of bone available but also based on the vector of occlusal load.The problem though is to relate the loading vector to the strain generated around the implants. The only logical way is to relate the position of teeth (loading point) and the available bone for implant placement. When there is a single tooth or multiple teeth missing, it is not possible to model load application point. It requires a patient specific FEA analyses of a virtual model of the alveolar bone with future tooth/ teeth in centric relation, which is a customised position of teeth in the patient's upper and lower jaw at rest.This paper proposes a simple innovative technique to develop a 3D FE model by delineating the occlusal loading points using a radio-opaque malleable lead foil and then generate a patient specific FE model to determine the best position of the dental implant based on both the volume of bone in the CT scan and the results of FE analyses.The proposed process is executed after an informed consent from the patients requiring functional rehabilitation. Practical clinical prosthetic problems for functional rehabilitations of jaws are of two kinds. One rehabilitating a single missing tooth and other multiple missing teeth/completely edentulous patient. This novel method of generating FE model using this lead foil is a versatile technique and is applicable to both scenarios. The current proposed procedure has been clinically applied in 4 patients requiring single tooth replacements in the four quadrants of the mouth  and one patient requiring full maxillary arch rehabilitation. The material properties assigned during creation of FE model is given in The entire concept behind the generation of this technique is to reduce the modelling errors as much as possible. It mimics the reality by incorporating the real material properties and as much architectural features as possible so that results achieved after FE analyses would mimic real-time biomechanical scenario and hence highly reliable. The masticatory apparatus of every human is unique and hence it generates anatomically specific loads of varying magnitude and direction. Every point load on the facial skeleton be it on the maxilla, mandible or surface of teeth, generate unique stress pattern, based on which rehabilitation is to be planned.The precision with which the FE models are generated by this method is very much appreciable. The occlusal surface models depict accurate anatomy mimicking reality. Hence it gives an opportunity for the researcher to customise load application points to individual teeth cuspal levels so that loading conditions can also be modified by altering the design of cusps of individual teeth in case of increased strain noted around the dental implants on loading on specific occlusal points. The technique is inexpensive, does not require high skill or training. It is reproducible under various scenarios with similar clinical problems, requiring biomechanical 3D FE model generation for customised load application points.A possible disadvantage of this current proposed procedure is the requirement of 2 CBCT examinations during the complete treatment. An improvisation of the current proposed protocol would be to take a CBCT using the existing removable prosthesis for generation the FEA model of the occlusal loading points using the lead foil crown delineation technique along with assessment of bone volume and custom fabricate surgical stent to position the implants in accordance to the FEA results. This would hence reduce the requirement from 2 CBCT to a single CBCT as proposed in the current protocol.The success of any functional rehabilitation is measured in terms of its precision, longevity and efficacy. Surgeon planning for rehabilitation, should be aware of the biomechanical perspectives of treatment planning. The biomechanical engineer should understand the bone biomechanics from macro and micro perspectives so that rehabilitation withstands multidimensional load. The proposed patient specific FE model generation of occlusal load application points using lead foil crown delineation technique is a precise, inexpensive, versatile and simple solution in scenarios requiring complex virtual simulations of varied loading points to mimic reality. Thus, the accuracy of finite element analyses would increase with customised patient specific model generation.Even though the proposed technique aims to optimise loading around dental implants based on FE analyses to minimise bone loss during function, a study is required to compare the results of the proposed procedure to conventional implant based on volume of bone alone.Additional material:Biomechanical considerations in functional treatment planning using dental implantsFor a patient requiring maxillofacial functional rehabilitation with dental implants, its architectural complexity should be seen from both the surgeon's and bioengineer's perspective. Such multidisciplinary approach would provide a customised comprehensive rehabilitative solution. Precision, efficacy and longevity of functional rehabilitation of jaws are dependent on both primary mechanical stability of a dental implant and osseointergration. The position and angulation of a dental implant determines the stress distribution pattern for a given load around it which over a period of time determines the pattern of bone resorption around it and hence the stability of an implant The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "The African Immigrant Dementia Education project is a community-university partnership with the goal of developing a culturally tailored dementia education program with African immigrants in Minnesota. In collaboration with our community partner , a project advisory board that features professionals and family members from the African immigrant community was assembled and its first meeting was held in February 2021. Preliminary discussions about content, mode of delivery and cultural considerations of an eventual dementia education intervention have begun. This presentation will offer details on the process of working with an advisory board and community partner to identify and culturally tailor an evidenced-based dementia education curriculum for a unique cultural group. Also, we will present challenges encountered during this process and offer suggestions and strategies to promote successful researcher-community partnerships."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "The parasacral TENS has been used to treat OAB in children however, the periodicity with which it should be carried out has not been yet standardized. This is a randomized clinical trial designed to compare two and three times weekly TENS (20 sessions of 20 min each at 10 Hz.) in children with OAB. The study included children of at least four years of age with a diagnosis of pure OAB based on ICCS definition (Sixteen children were included in the twice-weekly group and eighteen in the three times weekly group . There wBoth groups experienced an improvement in symptoms of urgency and urge incontinence. Evaluation of the bladder diary showed no difference in mean urinary frequency, mean urine volume voided or maximum urine volume voided between the two groups.Based on the results, the study suggested that it is possible to administer parasacral TENS twice a week, since there was a significant reduction in lower urinary tract symptoms in both groups.Parasacral TENS has emerged as an effective non invasive treatment for OAB in view of its success rates in improving lower urinary tract symptoms without direct side effects. However, periodicity and comparison between applications conducted at home or an outpatient basis have not been yet defined. Considering that issues of cost effectiveness and adherence must be considered and put on the table in light of the evidence, more randomized clinical trials with a larger number of patients are necessary for better standardization of the technique."}
+{"text": "The link between the migration of cancer cells and the spread of cancers has been established for many years. Tumour invasion and metastasis was labelled as one of the original Hallmarks of Cancer in the seminal paper written by Hanahan and Weinberg at the turn of the century . The defThe tumour microenvironment (TME) is made up of complex mixture of tumour cells and stromal derived cells but also containing a modified extracellular matrix (ECM). The ECM is the major structural component of the body comprised of proteins, glycoproteins, glycosaminoglycans and other polysaccharide in a network which would be able to host tumour cells (seed and soil theory) and control whether the tumour will be able to grow and metastases or not be able to move freely through a tissue ,4. ModulModulation of the ECM can also initiate the release of cytokines and growth factors that can stimulate pathways that allow for cells to migrate whether in single cells or as sheets . Growth n = 279 where 172 have a tumour of the oral cavity and most likely to be oral squamous carcinoma) indicates several signalling pathways such as Akt/PI3K that are up-regulated in these patients [Growth factors and ECM can both modulate cell signalling pathways. Analysis of genomes from Head and Neck Cancer patients  and how this translates into the clinical environment. We are also interested in research involving the studies of novel therapies or novel therapeutic approaches which may block cell migration and leading to possible new treatments."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "The international health community has set ambitious goals for health: eliminating or reducing communicable and noncommunicable diseases, ensuring appropriate use of antibiotics, increasing the uptake of vaccines and other preventive measures, and responding appropriately to epidemics, among others. Behavioural science can help in achieving these goals;The global health community should adopt multidisciplinary approaches to changing behaviours and integrating behavioural and social science into public health. Behavioural science is one of several disciplines that can help us understand and address behaviours that affect health \u2013 together with social sciences, anthropology, social psychology, behavioural economics, systems thinking, social marketing, human-centred design and implementation science. Each one of these disciplines is uniquely equipped to contribute to this understanding \u2013 and action \u2013 while sharing the goal of developing and implementing policies and programmes designed around people\u2019s needs and life experiences.Bulletin of the World Health Organization focuses on behavioural science and its application to understand individual and community behaviours through the analysis of cognitive, social and environmental drivers and barriers. Traditionally, public health efforts addressing risk behaviours have often focused on knowledge and awareness. Behavioural science analyses influencing factors within the environments around individuals and how insights can be used to design and make discrete changes in the environment to impact behaviours.This theme issue of the The systematic use of behavioural science to address longstanding and emerging public health challenges can provide an opportunity to improve the impact of programmes and policies, but behavioural science is still underutilized in public health. Ineffective behaviour change techniques continue to be used, while effective ones are not used or are difficult to replicate because both practitioners and researchers often do not capture, describe or understand their mechanisms of action.,Such underutilization may also arise because systematically adopting behavioural science can be challenging for practitioners and policy-makers.Bulletin explores some of these practical and theoretical challenges with the objective of advancing the use of behavioural science within public health. We hope to do so by raising the profile of the debate on these issues and including public health experts in this discussion. Only when these practical and theoretical challenges get beyond discussions held exclusively or mostly among behavioural and social scientists will there be meaningful progress towards the systematic inclusion of behavioural science into public health.This theme issue of the This theme issue targets the global community of public health experts, providing examples of the benefits of incorporating behavioural science in our work. The articles show how behavioural science has been used successfully around the world in support of programmes addressing a variety of risk behaviours and health issues, from iron deficiency"}
+{"text": "While hypertension is an important predictor of cardiovascular disease (CVD),In an earlier analysis of the Systolic Blood Pressure Intervention Trial (SPRINT)Journal provides several new insights into the relationship of two VVV parameters (the variability independent of the mean [VIM] and the difference of maximum minus minimum [MMD]) with all\u2010cause mortality in the 7996 hypertensives from SPRINT.The paper by Cheng and coworkersThe first key finding is that VVV SBP was an independent predictor of all\u2010cause mortality after adjustment of conventional risk factors or FRS.The second key finding was that VVV SBP and FRS were both significant risk factors for all\u2010cause mortality, and that higher VVV SBP combined with higher FRS conferred an increased risk for all\u2010cause mortality..Wide oscillations in BP have been considered to increase the extent of oscillatory shear stress in the macrovascular system,While VVV was shown to be associated with artery remodeling in a cross\u2010sectional analysis,It is not completely clear whether the increased VVV is a cause or simply an index of increased arterial stiffness. One major determinant of BP variability is the sensitivity of baroreceptor function.A recently proposed novel disease entity, systemic hemodynamic atherothrombotic syndrome (SHATS),Until now, there have been few reports assessing the relationship between VVV and unfavorable outcome according to the severity of FRS. The data presented in the manuscript reported by Cheng and coworkersK. Kario has received research grants from Omron Healthcare and A&D Co. outside the submitted work. The other author declare no conflict of interest."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "Prior research has suggested that poor neighborhood and housing conditions can lead to worse psychological wellbeing. Most studies examine either neighborhood or housing conditions, but not both. Since neighborhood and housing conditions may be correlated it raises the question of whether one is a proxy for the other. We use data from the 2006 and 2008 waves of the Health and Retirement Study to examine associations between perceived neighborhood and housing conditions in 2006 and depressive symptoms (CES-D 8) score in 2008. We find that worse housing conditions and neighborhood safety are associated with more depressive symptoms two years later, even when controlling for prior depressive symptoms. Furthermore, housing and neighborhood conditions are independently related to increased depression symptoms over time. Our research contributes to a deeper understanding of the relationship between home and neighborhood environments and psychological wellbeing in older adults."}
+{"text": "The use of medical cannabis  to treat chronic pain is increasing globally, although such use is not approved by any national regulatory authority such as the US Food and Drug Administration and is not supported by replicated, high-quality controlled clinical trials. The absence of data generated by the standard drug development process leaves clinicians with a substantial knowledge gap regarding appropriate dosing regimens. The article by Bhaskar et al.  attempts"}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "A 2009 independent review commissioned by the UK government to review the use of antipsychotic medication in patients diagnosed with dementia produced the Time for Action report, often referred to as the Banerjee Report. It highlighted the common practise of using antipsychotics in the treatment of Behavioural and Psychological Symptoms of Dementia (BPSD) and the clinical issues this could raise especially when these medications were not being regularly reviewed. The audti was therefore carried out to determine whether patinets with BPSD in a Community Mental Health Team for Older adults (CMHTOA) in Mid Surrey, who had been diagnosed with BPSD, were being adequately assessed and managed in line with the current guidelines.Patients with a diagnosis of dementia open to one of three teams in the CMHTOA during the months of October and November 2019 were identified, those being prescribed antipsychotic medication were selected and data from their electronic records collected and analysed to determine if clinicians: a) identified and documented the target behaviours, b) carried out a structured assessment using an ABC chart before commencing medication, c) reviewed the antipsychotic medication 6 weeks after it was commenced.Of the 87 patients with a diagnosis of Dementia from October to November 2019, 18 were on antipsychotic medication. 100% of these had target behaviours identified and clearly documented, a sixth had a structured assessment prior to starting medication and 61% had been reviewed after the first 6 weeks of starting antipsychotics.The findings showed that a good proprotion of patients did not have the required structured assessment before commencement of treatment and that more needed to be done by way of improving regular reviews after antipsychotic treatment is commenced."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "The aims of this quality improvement project were to determine if Nicotine Replacement Therapy was being prescribed correctly in Shannon Clinic in Northern Ireland and also to improve the rates of correct prescribing of Nicotine Replacement Therapy in the aforementioned unit.There are several different types of Nicotine Replacement Therapy currently available. Shannon Clinic is a smoke-free clinical environment therefore patients who smoke are offered Nicotine Replacement Therapy on admission. When I was working at Shannon Clinic I became aware that there was no clear guidance available to medical staff on the wards regarding prescribing Nicotine Replacement Therapy and therefore I decided to carry out this quality improvement project.An audit of drug charts was done on the patients who were under the care of the consultant that I worked with. In total nine drug charts were included in the audit. After the audit was complete, I produced a poster to show how to correctly prescribe Nicotine Replacement Therapy. A copy of this poster was placed on each ward in Shannon Clinic. After a period of time the drug charts were re-audited to see if there had been an improvement in the rates of correct prescribing of Nicotine Replacement Therapy.In total, 22% of the drug charts which were included in the audit had Nicotine Replacement Therapy prescribed incorrectly on them. After the inclusion of a poster outlining how to prescribe Nicotine correctly on each ward in Shannon Clinic, 0% of drug charts had Nicotine Replacement Therapy prescribed incorrectly on them. This was an improvement of 22%.This quality improvement project was successful at reducing the rates of incorrect Nicotine Replacement Therapy in Shannon Clinic. In the future it is my hope that this quality improvement project should lead to the correct prescribing of Nicotine Replacement Therapy for all patients in Shannon Clinic. It should also lead to an increased awareness regarding the different types of Nicotine Replacement Therapy for medical staff working in this clinical unit."}
+{"text": "The pandemic exposes policymakers to fundamental uncertainties about future economic scenarios. While policymakers have to act forcefully to mitigate the impact on the economy, these conditions call for policy strategies that are also robust to uncertainty. This article compares two concepts of robust strategies: robust control and robust satisficing. It argues that a robust satisficing strategy is preferred and shows that the crisis responses of governments and central banks in Europe share features of robust satisficing in several dimensions."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "The association between socioeconomic position (SEP) and dementia is well studied. However, scant attention has been given to the relationship with mild cognitive impairment (MCI), often considered a transient state between normal cognition and dementia. The purpose of this study was to determine the role of various SEP markers such as education and wealth on transitioning to MCI and dementia over a four-year period using data from the English Longitudinal Study of Ageing, a national representative sample of the English population aged 50+. We ascertained MCI and dementia over four years, using a validated algorithm based on physician diagnosis and lower cognitive performance (1 standard deviation below the mean) on multiple standardised tests adjusted for age and education. A Multistate Markov survival model was utilised to investigate whether different SEP markers increased the risk of specific transitions between normal cognitive performance and MCI or dementia, with the latter being considered an absorbing state. During the study period, a quarter of participants progressed to MCI from the normal state. Being in the lowest quintile of wealth was associated with a lower probability of transitioning back to a normal cognitive state from MCI, compared with those in the highest quintile. Greater wealth was weakly associated with a lower risk of transitioning from normal cognitive state to MCI and from MCI to dementia. The overall results imply that socioeconomic advantage might be protective against rapid progression from mild to more severe neurocognitive disorders such as dementia in later life."}
+{"text": "The session will focus on new and existing innovative ways that Community Colleges are effectively addressing workforce needs resulting from a rapidly aging population; the ever-expanding career pathways available to students in the field of gerontology; as well as the continuing higher education needs of students transferring to bachelor\u2019s and graduate-level gerontology programs. A panel of Community College and University gerontology professionals, representing both the GSA Community College and Aging Workforce Interest Groups, will share the innovative ways that they are working to address the three focus areas of this symposium. We will also include opportunities for discussion with participants about their experiences with and ideas for addressing these issues."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "The adulteration of plant based products is a global problem and one that cannot be addressed without combined efforts from industry, academia and regulators. This research topic focused on the problems of quality in the broadest sense as well as looking at specific established and new techniques to help improve the detection of sub-standard products. The issues investigated included species authentication, adulteration and contamination, value chains, agricultural practices and sustainability. Authors and reviewers contributed from Asia, the Americas and Europe, with a high percentage of published papers coming from Chinese institutions.Ichim and Booker in their review assessed the scale of the problem globally and found that 37 countries had significant adulteration problems. An opinion piece provided by Palhares et al., the authors described the situation in Brazil and particularly in relation to sustainability and the protection of minority groups and their traditional knowledge. Luo et al. looked specifically at the on-going and increasing problem of heavy metal contamination in Chinese herbal products, something that is often affected by increased industrial pollution of the land and rivers as well as being due to cultivation or collection in areas where they are naturally occurring e.g., in cinnabar containing rock, risking mercury contamination in crops.Of the fourteen papers that were accepted for publication, three papers focussed on documenting and highlighting the scale of the problem. Kum et al. used Salvia miltiorrhiza as an example of how incorrect species might enter the supply chain and how different processing and storage techniques can affect the end quality of products. Whereas Bi et al. investigated the value chains of Astragalus membranaceus var. mongholicus and assessed the quality in relation to the geographical origin of the material and the effects of using different systems of production and suggested sustainable cultivation as a workable alternative to wild Research Topic. Cultivation may be a viable sustainable option to uncontrolled wild collection, however start up costs and lack of infrastructure can inhibit this process and more governmental and industrial support is needed for these practices to be established long-term.There were several papers that explored the value chains of medicinal plants and Woodley et al. conducted a review of chemical methods and described how mitochondrial activity could be used as a new measure for assessing the biological potency of herbal products and gave detailed methodology on how this could be achieved. Ichim and De Boer described the variation in Ginseng quality and how there were other problems apart from incorrect species, including the wrong part of the plant used and incorrect age of the plant at the time of harvesting (ginseng should be at least 5\u00a0years old prior to harvesting in order to obtain the desired amounts of metabolites). There were three papers on shotgun metabarcoding and Yu et al. presented this as a powerful tool for the molecular identification of biological ingredients. This was endorsed by Liu et al. who described how adulterating fungi could be detected in complex herbal mixtures using this technique. Xie et al. showed how shotgun metabarcoding could overcome biased PCR amplification and be used to authenticate herbal mixtures with distinct variation of dosages of individual ingredients. Similarly Yu et al. described specific mini- DNA barcode techniques for use with highly processed herbal products.Other researchers provided new ways to assess the quality of herbal products. Yu et al. described how a method was developed for the analysis of Ophiopogon japonicus that incorporated quantitative microscopy. This allowed for the differentiation of quality within the same species and highlighted the concept of da di  herbs in the Chinese herbal supply chain. Ichim et al. also looked at how microscopy could be used as a cost-effective and rapid method to identify impurities within mixtures although with the caveat that it was difficult to use with highly processed materials e.g., extracts. Zhao et al. described vector control quantitative analysis as a new method for analysing complex formulations. A PCR strategy was explained that rapidly generated the integrated DNA fragments needed from multiple targeted species. A technique with much potential for future use within the industry.Some of the new techniques (or known techniques repurposed) focussed on single plants and It is clear that there are global initiatives in place to improve the detection of poor quality and adulterated material in herbal medicines and there has been advances in many analytical techniques in an effort to overcome the difficulties encountered in analysing complex mixtures of medicinal plants. There appears to be growing emphasis on investigating quality problems along the length of the value chain as opposed to focussing on the finished products and with this comes an increased awareness of good collection and cultivation practices and a greater resolve to tackle issues of sustainability. Overall the papers emphasise the need for effective quality management along the length of the supply chain and the continued application of well known and new techniques to improve herbal quality and safety."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "The quality of maternal healthcare training is the most optimal degree of health in the delivery of effective, efficient and quality healthcare in midwifery discipline. Student accoucheurs studying at the Free State School of Nursing are faced with resistance, discrimination, rejection and unacceptability by pregnant women during their clinical placement at the Free State maternal healthcare institutions. This results in poor quality of training of student accoucheurs in maternal healthcare. Considerable studies have been conducted on males in midwifery nursing, but no guidelines have been developed to facilitate student accoucheurs' acceptance and improvement of the quality of training in maternal healthcare, hence the purpose of this study.n\u00a0=\u00a032) were conducted through purposeful sampling method. Data was analysed thematically.A descriptive, explorative qualitative design was used in this study. Qualitative focused group discussions (Three main categories emerged: student accoucheurs' related factors with social interactions and relations as a theme; maternal healthcare users\u2019 related factors with transcultural diversity and socio-economic status as themes; nurse training institutions and maternal healthcare institutions service providers-related factors with gender inequality in the work place as a theme. Ultimately, the guidelines to facilitate acceptance and improvement of quality training of student accoucheurs in maternal healthcare institutions were developed and recommended for implementation.The paper developed guidelines to facilitate acceptance and improvement of quality training of student accoucheurs in Free State maternal healthcare institutions. The quality of education and training of nurses, midwives and accoucheurs are low and poor in many countries including South Africa, resulting in a health workforce ill-prepared to effectively respond to rapidly changing and complex existing, and future health systems including maternal healthcare challenges. The training of males in nursing specifically in midwifery has met various challenges worldwide.Over time, however, nursing and midwifery evolved to include males, men have been prominent in the nursing profession during the Middle Ages and Renaissance, the modern image of an \u201cideal nurse\u201d is feminized. This is primarily because of the Nightingale system for nurse training, wartime and economic factors . The auMidwifery, however, may be one of the most exclusively and disproportionately female specialties in the field of nursing, it is time to acknowledge the presence of accoucheurs, the challenges they face and the positive attributes they bring to the profession . This cIn the eighteenth century, childbirth in most parts of the world remained informal and exclusively managed by women, and in the nineteenth century respectively, midwifery began to change based on the revised curriculum which allowed men to enter into maternal healthcare discipline . R.425 In South Africa, chapter 2 of the Constitution stipulates the upholding of gender equality at all times. Hence, the percentage of student accoucheurs training in midwifery has steadily risen and continues to do so in the country. Although the numbers of men who choose nursing midwifery as a profession have increased significantly, it remains difficult for men to practice in this area of nursing despite being trained as accoucheurs.Gender diversity and inequality occurring in the nurse training institutions and clinical workplace contributes towards the phenomena. Segregation, rejection and discrimination projected by pregnant women towards student accoucheurs during their clinical placement in maternal healthcare institutions have a negative impact towards goal achievement to become accoucheurs . SimilaAccording to the World Health Organization (WHO), 800 women die per day globally owing to pregnancy-related complications . While The nurse training institutions are constantly producing registered midwives/accoucheurs on an annually basis to enter the working force in a healthcare sector. According to the policy on gender in Malawi, an equal number of males and females should enter tertiary education. However, this is not the case with nursing due to the historical background of nursing being \u201cfeminine,\u201d and the challenges men face in nursing, impact negatively on those intending to enter the profession . PredomIt is evident that student accoucheurs are faced with difficulties during their training specifically in midwifery discipline. These difficulties maybe contributed by rejection, segregation, discrimination by pregnant women based on their gender including lack of support from their lectures and midwives in maternity units among other factors contribute to these difficulties. This was confirmed byA descriptive explorative design was used to explore the views of student accoucheurs' experiences encountered during their third and fourth levels of training in maternal healthcare institutions. The main focus of this study was on the acceptance of student accoucheurs by pregnant women during their clinical placement in the maternity units. Therefore, a descriptive explorative design was chosen to invent the full nature of the phenomena, the way it is manifested and establishing the clear picture of the situation as it is naturally happening without manipulation of any variables . The inThe total of 32 student accoucheurs between the ages of 20 and 24 years studying in the Free State School of Nursing were purposively selected to be included in the study. Purposive sampling is a method often used when the researcher wants a sample of experts . FurtheAll student accoucheurs registered at the Free State School of Nursing at their fourth year of training placed at post-natal units were purposively selected.All student accoucheurs over the age of 18 years at their fourth year level of training who were willing to participate in the study and who signed the consent form were purposively selected.All student accoucheurs not studying at the Free State School of Nursing and not in their fourth-year level of their study and who are below the age of 18 years of age.All student accoucheurs who meet the inclusion criteria but not willing to participate in the study.Five focus group discussions consisting of four to five members in a group were conducted. Additional two focus group discussions were added to ensure that data has been saturated. The focus group discussions were conducted with the fourth year student accoucheurs only based on the aim of the study which was to explore the experiences of student accoucheurs regarding their acceptance by pregnant women during their clinical placement at maternal healthcare in the Free State Province. Ground rules and information about the scope of discussion which assisted the participants to understand what is expected from them were laid . All foAs outlined inQualitative data was transcribed from the voice-recorder into a written format, organised and stored using Atlas TI 8. version programme. This programme helped the researcher to systematically organised data into themes and sub-themes with codes to evaluate and interpret qualitative texts . Tesch'Lincoln and Guba criteria of credibility, transferability, dependability and conformability were used to establish trustworthiness . ConforPrior to the commencement of the study, the approval of the study was obtained from the University Ethics Committee (IREC Number: 10/17) and the Free State Department of Health. Information letters detailing the purpose of the study were given to the participants. Confidentiality was assured, anonymity guaranteed and participants were allowed to withdraw from the study at any point. All participants gave informed consents agreeing to take part in the study.The analysed data was grouped into three categories of factors from which four major themes and six sub-themes emerged . These As males, we are challenged on how to build good relationships with women in maternity units. Most women come with preconceived ideas that they expect to be treated by female midwives that's how they were socialised [\u2026] .Most procedures are invasive such as vaginal examination [\u2026] and women refuses to be examined by us. I need help and support to interact and gain women's trust [\u2026] .Most participants stated that the quality of their training in midwifery is based on good interactions with pregnant women. According to them, such interaction alleviates woman's preconceived ideas and fears about pregnancy, labour, delivery and the midwife that will be assisting them. Hence building a nurse\u2013patient relationship was important in the maternity units, but this could be a challenge because most women are socialised into building sound relationships with other females. Therefore, the provision of quality training by the training institutions will empower them with knowledge, skills and support to build good nurse\u2013patient relationships with pregnant women:Sometimes I feel shy to ask a woman to push in SeSotho as this word sound vulgar if used by male to a female [\u2026] .I need to be taught how to give instructions to women without embarrassing them [\u2026] .Moreover, participants associated lack of communication skills as a contributing factor to women not accepting maternal healthcare rendered by them. Vernacular words used to give instructions to women during delivery could sound vulgar and embarrassing when are said by a male to a female:I was denied the opportunity by a Muslim family to assist during delivery as this was seen as taboo. I had to respect the patients' rights you know [\u2026] .Married women do not want to be seen naked by another man other than their own husbands. Despite this, culturally it is unacceptable to undress for a younger person of opposite gender [\u2026] .Some women will tell you that in their culture, men should wait for the period ten days before they can be allowed to see them during and after delivery [\u2026] .Most participants stipulated that the training institutions should empower them with transcultural nursing in midwifery. Participants said women who are from traditional rural areas are religiously, socially and culturally sensitive regarding pregnancy as this is regarded as sacred to them hence, they become sceptical about maternal healthcare services rendered by males:I have forfeited the chance of learning and fulfilling my required objectives other day when I was refused to deliver a lady teacher whose husband was a taxi owner [\u2026] and the Unit Manager did not intervene [\u2026] .Whereas financially unstable women are forced to attend public hospitals. Although some women do not express their views about student accoucheurs' presence in maternity units. Their resistance and non-co-operation can be detected when taking care of them which contribute to poor quality of their training in midwifery while increasing risks of maternal mortality:Some women who are unemployed do not actually tell you that they do not want you as a male to assist them depriving us from quality training in midwifery, but they will resist your commands during examination and during labour putting themselves and the babies at risk [\u2026] .It emanated from the participants that financially stable women are at liberty to choose the midwife of their preference, whether to attend private or public hospital for maternal healthcare services. Their voices in a public hospital regarding their choice of care is more respected. Therefore, they indicated that the training institutions should capacitate them with skills and knowledge in managing women attending their maternal healthcare services in the public hospitals irrespective of their financial statuses:Accoucheurs are allocated in casualty, intensive care, theatre and other general wards except in maternity units [\u2026] .Student accoucheurs indicated that in clinical areas where they were allocated for maternal healthcare services in the province, no accoucheurs were placed in maternity units:In some other few institutions you will find one or two community service accoucheurs working for either a week to a month [\u2026] and they are constantly taken to assist in other units if there is shortage of staff [\u2026] .Most participants attested that even community health service accoucheurs were placed for the short period of time in this units. Therefore, women have limited exposure to maternal healthcare services rendered by accoucheurs; hence they reject and unaccepting to be taken care by them during their clinical placement in maternity units:I have never saw even a single male Unit Manager or Assistant Director Nursing Manager where I was placed for my maternal healthcare rotation for the past two years [\u2026] and all our lecturers are females .Moreover, all Unit Managers, Assistant Director Nursing Managers responsible for maternal healthcare units were females including Lecturers teaching midwifery at the Free State School of Nursing. Although they render quality services in students training in midwifery, but gender diversity is not represented:I like midwifery nursing [\u2026] and I prefer to work in maternity units rather than in other units [\u2026] .Most student accoucheurs chose midwifery nursing science as their preferred discipline:The study finding was based on the categories emerged during data analysis. The first category was based on student accoucheurs' related factors. The nurse training involves an active social interactions and relations with the patient. This enhances building a good nurse\u2013patient relationship which promotes effective communication and provision of quality maternal healthcare to pregnant women. According to the Department of Health as cited byA gap was identified from the student accoucheurs discussion that they lack communication skills in assessing women and giving instructions effectively during delivery without causing discomfort to them and feeling embarrassed. The key facets of constructive communication in maternity care include an empathetic communication style, willingness to respond to questions and allowing enough time to discuss the woman's concerns . The NGT gathers information by asking the participants to respond to questions posed by the researcher and then asking the participants to prioritise the ideas of all group members .Table A policy which incorporates cultural or religious sensitivity of pregnant women to student accoucheurs' presence in the maternal healthcare institutions should be developed and implemented.A policy that integrates cultural and religious sensitivity in maternal healthcare in the curriculum of the Free State School of Nursing to ensure that student accoucheurs are taught about pregnant women's religious and cultural diversity.The policymakers in the Free State Department of Health need to ensure that maternal healthcare services rendered at the maternal health institutions cater for all pregnant women despite their cultural or religious backgrounds, whilst ensuring effective and quality training of student accoucheurs in midwifery. Therefore, the following recommendations for the implementation of this guideline should be taken into consideration:Nurse Managers should allocate accoucheurs on a rotational basis in the maternal healthcare units to improve the visibility of accoucheurs in these units.Nurse Managers should consider accoucheurs when vacant positions for Unit Managers in maternal healthcare become available to ensure gender equity in the work place.Placement of accoucheurs in maternal healthcare units will improve the quality of student accoucheurs' training by providing support and encouragement in midwifery discipline.The Nurse Managers places accoucheurs in all other nursing units within the organisations except in the maternal healthcare units' despite being trained to work in this discipline. This deprives pregnant women an opportunity to experience the maternal healthcare services rendered by accoucheurs. Hence the recommendations for implementation of the developed guideline by Nurse Managers.Nurse Managers should ascertain accoucheurs' preferred discipline and negotiate placement on a rotational basis with them to promote gender equity in maternal healthcare institutions.Accoucheurs requesting to be placed in maternal healthcare units should be granted the opportunity to practice midwifery.Accoucheurs who have an interest in improving their career by furthering their studies in advanced midwifery should be given the relevant opportunities by Nurse Managers.Accoucheurs should be given opportunities to mentor and supervise student accoucheurs in the maternal healthcare institutions to improve the quality of their training in midwifery discipline.Nursing Managers need to consider how accoucheurs are allocated in the Free State healthcare institutions. The random allocation of accoucheurs in general units except for maternity units, despite their preference, deprives them of the opportunity to explore and grow their careers in maternal healthcare. It is recommended that the developed guideline should be implemented by Nurse Managers:A programme designed to teach pregnant women in ANC, labour wards and postnatal wards about gender and its importance in nursing, and to equip pregnant women and their families with knowledge about the nursing profession.Involve the relevant training stakeholders in the implementation of the teaching programme about gender diversity and equity in nursing to ensure correct implementation of the programme at the Free State maternal healthcare institutions.Involve student accoucheurs in teaching pregnant women and their families about their roles in maternal healthcare to promote gender diversity and equity in nursing.Encourage pregnant women to verbalise their concerns and uncertainties about student accoucheurs in maternal healthcare and to give clear and accurate responses.Student accoucheurs undergo the same training as their female counterparts' despite being rejected and discriminated by women in maternal healthcare units due to their gender. It is recommended that a career exposure programme that will focus on teaching pregnant women and their family members about career choice and the contribution of student accoucheurs in maternal healthcare is required. Hence the researcher made recommendations to implement the developed guideline:Lecturers at the Free State School of Nursing should develop and integrate communication skills in their teaching objectives to equip student accoucheurs with effective communication skills in maternal healthcare.Translation of culturally sensitive terminologies, used in midwifery, into a less embarrassing and non-offensive form so that student accoucheurs and pregnant women are not embarrassed.Lecturers should encourage student accoucheurs to implement the taught communications skills, acquired in their training, during their clinical placement at the Free State maternal healthcare institutions.Student accoucheurs should give feedback regarding the effectiveness of implemented communication skills programme to lecturers on a regular basis.The development of a programme that will integrate communication skills specifically in maternal healthcare for student accoucheurs in their third- and fourth-year level of training is necessary. This programme will facilitate effective communication skills for student accoucheurs as the key facets of constructive communication in maternity units (Create, advertise and approve posts with specific requirements for clinical instructors while considering gender diversity and equity to be allocated in various maternal healthcare institutions in the Free State Province, employed by the Free State School of Nursing.Enrolment of clinical instructors in a simulation course for health professionals to equip them with needed skills and knowledge on clinical accompaniment of students including student accoucheurs to improve the quality of training in maternal healthcare.Allocation of clinical instructors in the Free State maternal healthcare institutions accredited for placement of student accoucheurs in midwifery discipline to ensure prompt and active supervision of student accoucheurs to improve the quality of their training.Clinical instructors should actively utilise the simulation skills laboratory at the Free State School of Nursing in demonstrating skills and feedback from student accoucheurs to ensure quality of training in midwifery discipline.Clinical instructors at the Free State maternal healthcare institutions should frequently give feedback to lecturers about challenges, progress and proposed solutions regarding student accoucheurs placed in these institutions.The Free State School of Nursing should consider hiring clinical instructors to be stationed in the maternity units. The developed guideline and the proposed implementation is aimed at improving the supervision of student accoucheurs by clinical instructors stationed at the Free State maternal healthcare institutions. It is imperative that the Free State School of Nursing consider the recommendations below for implementing the developed guideline:A designed programme with stipulated time frames for clinical skills demonstrations and feedback for student accoucheurs to improve the quality of training in maternal healthcare.Compulsory attendance and supervision of student accoucheurs during clinical practice in the skills laboratories.Use simulated patients in the skills laboratory for maternal healthcare history taking to teach student accoucheurs effective communication skills improve their confidence in maternal healthcare.Giving constructive feedback, either negative or positive to student accoucheurs after the performance of their clinical tasks to encourage them to improve their skills and knowledge.Debriefing sessions after each clinical task should be conducted to ensure that student accoucheurs express their fears and concerns which should be addressed by clinical instructors.Counselling sessions and referrals to student counsellors those student accoucheurs with difficulty in maternal healthcare clinical practice in the skills laboratory.Compulsory briefing sessions by lecturers for student accoucheurs on what to expect and how to deal with rejection by pregnant women prior to their clinical placement in the Free State maternal healthcare institutions.The Free State School of Nursing should design and equip clinical skills laboratory with the high and low fidelity manikins designed for midwifery teaching purposes. This skills laboratory should be fully utilised for midwifery clinical practice to enhance skills and knowledge of student midwives and student accoucheurs enabling them to render quality maternal healthcare services. The Free State School of Nursing academia should consider the following recommendations for implementation of this guideline:The study was conducted in the Free State Province maternal healthcare institutions accredited by SANC for student nurse training purposes which may restrict transferability.The study is in line with nursing education in the midwifery discipline and human resource management. The developed guidelines are intended for implementation by the policymakers in the Free State Department of Health, Free State School of Nursing and the Nurse Managers in their respective maternal healthcare institutions in the Free State Province including to other relevant maternal healthcare institutions involved in midwifery student nurse training. The researcher contends that this is the first comprehensive study that has researched and developed guidelines regarding the phenomena. According toThe literature review and data analysis from the study participants confirmed that there were gaps in the training of student accoucheurs and that there were no developed guidelines with respect to improving the quality of training and support of student accoucheurs during their clinical placement in maternal healthcare institutions. The main aim of the current study was realised in that the guidelines to facilitate acceptance and improve the quality of training of student accoucheurs in midwifery clinical practice at the Free State maternal healthcare institutions were developed. Recommendations for implementation of the developed guidelines were suggested for stakeholders involved in the training of student accoucheurs in midwifery discipline."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "There is an error in the Funding statement. The new statement should be: \u201cSupported by the national social science fund project Research on Path Design and Policy Support for Rural Tourism in Ethnic Areas to Consolidate the Achievements of Poverty Alleviation (20BSH062), the Fundamental Research Funds for the Central Universities (SWU2109207).\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "There is a large gender gap in critical care medicine with women underrepresented, particularly in positions of leadership. Yet gender diversity better reflects the current critical care community and has multiple beneficial effects at individual and societal levels. In this Viewpoint, we discuss some of the reasons for the persistent gender imbalance in critical care medicine, and suggest some possible strategies to help achieve greater equity and inclusion. An explicit and consistent focus on eliminating gender inequity is needed until gender diversity and inclusion become the norms in critical care medicine. Medicine has traditionally been a male-dominated profession. Despite women medical trainees outnumbering men medical trainees in many countries, there are still more men than women in clinical and academic leadership positions around the world . Recent Publication of research is considered essential for academic career advancement in medicine, and the number of publications influences the authors\u2019 visibility as researchers, their success as grant applicants  and theiThe reasons for the persistent gender imbalance in critical care medicine have been studied extensively over recent years. Societal ideas pertaining to the roles traditionally occupied by men and women have likely contributed. In a survey of 115 faculty and 122 undergraduate students at large, research intensive universities, agentic traits  were thought to be more important than communal traits  for success in science . Other bParsons Leigh and colleagues described institutional (lack of flexibility and limited job prospects) and interpersonal (bias against women) factors as key drivers of the gender gap in critical care medicine . At the Another important area that needs to be addressed is the tension that many women experience between the different roles they hold at work and at home. The challenges of taking time away from medicine for maternity leave have been widely recognized and discussed , 18. TheWithin national and international critical care societies, several initiatives have been introduced to encourage gender balance, including selective endorsement of meetings that have gender diverse speakers. The Canadian Critical Care Society Diversity Policy strives to achieve at least 30%  women speakers. A similar policy developed by the Australia New Zealand Intensive Care Society aims to include 50% women speakers by 2022. The European Society of Intensive Care Medicine (ESICM) has introduced several task forces to address gender inequality. In the absence of international registries, it remains challenging for critical care societies to benchmark or compare their diversity metrics to those of others.The focus of this Viewpoint has been to highlight the need to promote gender equity and inclusion in critical care medicine and suggest some possible strategies to help achieve greater equity and inclusion. It is our collective responsibility, as a critical care community, to identify and address barriers that perpetuate inequities in critical care. Diversity and code of conduct policies have been adopted by several critical care societies and the World Federation of Societies of Intensive and Critical Care Medicine. Widespread adoption of such policies will help eliminate inequity and enhance inclusion. Training and mentorship programs for women intensivists will enable promotion of women to higher academic ranks and leadership positions. Acknowledging the existence of implicit and explicit biases is an essential first step. We believe that an explicit focus on eliminating gender inequity will help to gradually change societal views of the roles played by women and men critical care physicians so that it will become the norm for women and men to be both critical care physicians and leaders in critical care."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "With our work we want to support better, evidence\u2010based decisions by: (a) supporting rigorous synthesis of evidence on key questions; (b) further improving the quality of climate change research through critical appraisal of primary research; and (c) improving the efficiency of the scientific process through enhanced oversight of, and less duplication in, secondary research efforts. We further believe that our work strengthens the IPCC and other climate change assessments by supporting the completion of its evidence pyramid  in resource constrained contexts like the Global South. Our aim is, therefore, to provide accessible and functional training in climate evidence synthesis that works across settings .3It is an exciting and important task to build a thriving  community that tries to learn what climate solutions work under what conditions, for whom, and why, using rigorous systematic review and evidence (gap) map methodologies. Beyond the core remit of the group to promote rigorous evidence synthesis as an important pathway to more evidence\u2010informed climate policy, CSCG will further try to advance evidence synthesis methodology more generally in four priority areas.Promote the adaptation and application of qualitative and mixed methods evidence synthesis methodologies: The social science of climate change provides a very diverse body of evidence. Only a small part of this literature is directly on impact evaluations of climate solutions based on experimental or quasiexperimental research designs IPCC,\u00a0. In partEncourage the development and application of novel evidence synthesis technology: Climate change is not only one of the most pressing policy issues of our time, but also a very prolific area of research with tens of thousands of studies being published every year. In such an age of big literature with a vast and fast\u2010growing evidence base, traditional manual tools of evidence synthesis are being pushed to their limits (Callaghan et al.,\u00a0Integrating the evidence synthesis traditions of the climate and the systematic review communities: It is clear that comprehensive learning on climate solutions must be rooted in a systematic exploration of alternative future pathways as well as systematic evaluation of past policies. The CSCG brings together two evidence synthesis communities with complementary strengths in ex\u2010ante and ex\u2010post assessments of climate solutions. We are convinced that there is great scope for mutual learning and that sharing and integration of these distinct traditions will ultimately lift evidence synthesis and the resulting scientific policy advice to a higher level.Promote the application of formal assessment of confidence in evidence within syntheses of climate solutions: Assessment of uncertainty and confidence in evidence is a critical component of climate change assessments (Janzwood,\u00a0Climate change is one of the most pressing problems that humankind faces. We need to urgently and rapidly learn from the best available evidence on climate solutions. The CSCG warmly invites registrations and submissions to Campbell Systematic Reviews from climate experts across diverse disciplines and evidence synthesis practitioners."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "The aim of the study was to assess the attitudes and perceptions of parents towards child and adolescent psychiatric consultation, diagnosis and treatment.The hypothesis of the study was there are significant problems in the domains of attitude and perceptions of parents towards child and adolescent psychiatric consultation, diagnosis and treatment.Parents are an important stake holder in child and adolescent psychiatry and mental health care service models. There is scarce literature from developing countries regarding attitudes and perceptions of parents towards child and adolescent psychiatric consultation, diagnosis and treatment.This study was conducted at the Child and Adolescent Psychiatry Clinic, Department of Psychiatry at a Tertiary Care Institution. Eligibility criteria comprised of parents of children and adolescents who had come for consultation. The parents were provided information of the study and those willing to participate were included in the study. A convenience sample of 100 parents was considered for the study. The parents were interviewed using a specially designed survey comprising 30 questions with Yes/No response developed by the authors for the purpose of the study. Informed consent and Institutional Ethics Committee Clearance was obtained. Data were analysed using SPSS.We found that the majority of parents were from urban area (72%) and mothers comprised 68%. We found that 46% of parents did not want a psychiatric diagnosis and 35 % parents felt stigmatized for seeing a psychiatrist for their child. Sixty nine percentage of parents preferred counseling as the first line of treatment and 31% preferred medicines as the first line of treatment. We found that 33 % felt additional psychological tests could be useful and 54% of parents felt brain imaging and blood tests could be useful for their child. Majority of parents expected basic improvement for their child within 1 week(32%) and expected full improvement by 1 month(82%). Fifty three percent of parents had searched online information prior to consulting and found useful information. However, 38% of the parents felt confused after reading online information and 69 % of parents were more worried about giving medications after referring online information.Our study provides useful key insights from parent's perspective in child and adolescent psychiatric services. Implications exist for future research as well as policy perspectives on the role, attitudes and expectations of parents as vital stake holders in child and adolescent psychiatry."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "The Competing Interests statement published incorrectly. The publisher apologizes for the error. The correct statement is as follows: The authors have read the journal\u2019s policy and the authors of this manuscript have the following competing interests: JT discloses a consulting relationship with Genetika, and JKW discloses paid employment with the Center for Translational Bioethics and Health Care Policy at Geisinger during the conduct of this study but no active competing interests at the time of publication. The authors have declared that no other competing interests exist and that the authors have no financial interests  related to this study to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials."}
+{"text": "The review by Hurst et al.  is a comProgressive vision loss in adults is escalating worldwide, as the incidence of macular degeneration and diabetic retinopathy are expected to exceed 300 million and 642 million, respectively, by 2040 (Mitchell et al., in vitro and organotypic platforms have been developed to examine native stem cell behaviors within microscale environments (reviewed in Greene et al., Contemporary cell replacement therapies offer exciting promise to restore vision by replacing damaged neurons with transplanted stem cells. Numerous platforms have been developed to elucidate the cellular mechanisms able to promote stem cell integration within mature retinal hosts (Wu et al., Initial hybrid models  culturedSM developed and wrote the manuscript. MV wrote and provided edits to the manuscript. All authors approved the final manuscript version for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "The COVID-19 crisis has revealed the deep technological and production dependencies of the EU on third countries in sectors deemed as particularly strategic and has thus fuelled the debate on (the lack of) European technological sovereignty in critical fields. This article argues that in the light of a renewed interest in relaunching a European industrial policy, technological sovereignty considerations must be fully incorporated into policy objectives and instruments."}
+{"text": "Somaliland is a de facto state in the horn of Africa. It unilaterally declared independence from rest of Somalia in 1991. Medical education in Somaliland started in the year 2000.Aim of the study is to explore the feasibility of teaching program for the country by its future potential psychiatry educators. The initiative started in 2019 to seek trainees with interest in academic psychiatry and support them with medical education skills. This is intended to prepare them for leading future teaching roles in both undergraduate and residency/fellowship in psychiatryAmoud University wanted to empower junior doctors at the university to have teaching skills needed to set up residency program. The Somaliland government asked Ethiopian ministry of health to offer psychiatry residency program for general practitioners in Somaliland to have future residency and fellowship in psychiatry. Several psychiatry trainees worked with the visiting professor from the United Kingdom who joined Somaliland medical school as visiting professor in psychiatryThe visiting professor supported the trainee in setting up a psychiatry undergraduate training curriculum in line with Somaliland medical school curriculum. Before the teaching methods were didactic and role play based. The faculty introduced different teaching methods including flipchart, small/large group teaching which was student centered education. Students received a online survey to reflect on psychiatry teaching they received. post course survey was conducted at the end of the teaching to evaluate the teaching initiative.Survey revealed interesting pattern that students preferred class room based teaching in comparison to online teaching. 90 percent of the attendees showed interest in flipchart teaching compared to didactic model. They expressed increasing understanding of the subject matter when they read and discuss among themselves instead of lectures. 70% of students prefer more clinical teaching compared to online sessions.52% liked the new teaching module compared to the lecturing sytle.Supervision of early career psychiatrists to undertake future academic psychiatry roles is an important step in building psychiatry faculty in medical schools. As the case of Somaliland this retains trainees in teaching roles in the future to teach undergraduates mental health courses. The other benefit is empowering them to set up psychiatry training program to close the service delivery gap with skilled psychiatrists in the future. Somaliland plans to set up its psychiatry residency/fellowship programs soon after this initiative."}
+{"text": "We need a Green Tax Reform which focuses on the Pigouvian approach and can correct the distortions of different climate hurting activities. Through tax policy tools, the price structure should be drastically changed and serious incentives should be provided to change the behaviours of the consumers and producers to achieve green policy goals.Climate crisis is becoming higher on the agenda of the decision makers of the world. A huge amount of resources have been dedicated to green projects, however far less emphasis has been put on tax policy opportunities. Carbon pricing can increase the burden of CO"}
+{"text": "One emerging dyadic concept is the experience of family caregivers when their care partner dies and their dyadic relationship comes to an end. This study qualitatively examined and characterized the loss of the dyadic experience for the caregiver after the death of their care partner. Data was accrued as part of a randomized clinical trial in 29 older hospice caregivers. Iterative thematic analysis focused on dyadic processes before, during and post death. Using two relational parameters from Relational Turbulence Theory resulted in a preliminary characterization of a new concept - dyadic dissolution as a cognitive and affective process whereby a remaining member of a dyad experiences relational uncertainty and partner interference while adapting (or not) to the death of their care partner. Findings suggest that asking several open-ended questions about the dyadic relationship will enable assessment for any continuing impact of relational uncertainty and partner interference on bereaved caregivers."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "This study assesses the relationship between indicators of early childhood disadvantage and later-life multimorbidity within a nationally representative sample of Brazilians aged 50 and over . Data come from the baseline assessment (2015/2016) of the Brazilian Longitudinal Study of Aging (ELSI). We employed survey-weighted Ordinary Least Squares regression to estimate the effects of individual and combined measures of childhood disadvantage on the total number of chronic conditions in later life. Mediation analysis assessed whether adult socioeconomic status (SES) mediated the relationship between childhood disadvantage and chronic conditions. We found that individual and combined measures of childhood disadvantage were associated with the total number of chronic conditions, even after controlling for potential confounders. Mediation analysis suggested that part of the effect of childhood adversity is mediated by higher SES in adulthood (~10%). A formal strategy of sensitivity analysis showed that omitted variable bias is extremely unlikely. To rule out the observed effect, an unobserved hypothetical confounder would need the explanatory power of the residual variance of both the independent and the dependent variables that is at least 30 times larger than that of BMI or 5 times larger than the explanatory power of age. Results should inform efforts to strengthen interventions targeting early childhood development and to improve other key inputs (such as education) to enhance adult SES and lessen the impact of early life stressors on health in older adulthood."}
+{"text": "Plant life cannot exist without programmed cell death (PCD). Both plant developmental processes and responses to environmental factors are modulated by highly controlled, localized cell death events  and the proteases involved in execution of cell death process . Burke et al. highlights the role of transcription factors (TFs) in the regulation of plant PCD occurring in response to abiotic and biotic environmental triggers, complementing a recent publication by Cubr\u00eda-Rad\u00edo and Nowack  and degradation of cellular components (effector caspases) . We expect that the application of increasingly accessible proteomics-based approaches will test this hypothesis in the near future.The two review articles of this Topic discuss critical aspects of plant cell death pathway: its transcriptional control . These authors used the root hair assay (Kacprzyk et al., The Earth's changing climate is leading to increased frequency of extreme weather events that may lead to severe crop damage. Thankfully, plants have developed diverse strategies to deal with environmental stresses, and PCD is part of this defense repertoire (Kacprzyk et al., Collectively, the contributions from the Research Topic emphasize the progress in the field of PCD research and its potential to deliver solutions from the laboratory to the farm. They also highlight the still unanswered questions about the death of plant cell\u2014and hence the exciting opportunities for further research!All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Surgical procedures alter tissue integrity; are associated with pain and activation of the sympathetic nervous system; and sometimes, cause exposure to foreign materials used during the surgery or implanted perioperatively. Those factors have been demonstrated to induce a number of inflammatory reactions ,2,3. DepCardiovascular risk stratification has become an essential dimension in the standardization of clinical pathways and has significantly improved the overall quality of care . HoweverThis Special Issue aims to provide insights in current developments and mechanistic discoveries regarding the impact of surgical and interventional procedures on organ systems and the potential of specifically monitoring biomarkers and cellular responses in perioperative medicine."}
+{"text": "Conduct an environmental scan of Marion County (Indianapolis) neighborhoods using electronic medical record data, state health data, and social and economic dataDevelop strong network of community collaboratorsConduct a thorough assessment for each targeted neighborhood by listening and understanding the pressing health issues in the community and working together to design and deliver solutionsOBJECTIVES/GOALS:Identify measures in the 3 domains of vulnerability, health and assets for the targeted neighborhoods and conduct bivariate descriptive statistics and multivariable regression analyses to investigate association between measures of vulnerability and health outcomes.Initiate relationships with leaders and residents in targeted neighborhoodsLocate organizations working in targeted neighborhoods through online mapping software and word-of-mouth at neighborhood events, and created a spreadsheet with contact information.Conduct multidisciplinary assessment  of the targeted neighborhood.Iteratively synthesize assessments to develop areas of interest and relevance to the community.Develop a road map for solutions identified by the community.METHODS/STUDY POPULATION:RESULTS/ANTICIPATED RESULTS: The results from the environmental scan conducted will be displayed in a report and visual \u201cmap\u201d of health outcomes and health determinants, including assets and barriers for the targeted neighborhoods. The research team will use results from the environmental scan coupled with listening activities including attendance at community events, key informant interviews and focus groups to develop relationships and strong collaborations with the targeted neighborhood stakeholders. The relationship building between the research team and community will provide increased trust and engagement that will further enhance the effectiveness of the assessments completed with the targeted neighborhood. The assessments will help to empower communities to develop sustainable solutions and drive future work that will lead to future grant applications and larger-scale implementation in other community impact hub neighborhoods. DISCUSSION/SIGNIFICANCE OF IMPACT: Through the community impact hub work, we will develop collaborative efforts with targeted neighborhoods with the greatest health inequities in the Marion County area. In partnership with these neighborhoods, we will build a foundation \u2013 a network of community collaborators and a focused plan \u2013 upon which we will improve the health outcomes of residents while learning best practices on how to do so."}
+{"text": "The implications of the COVID 19 pandemic signal both tragedy and possibility.This reflective paper considers the amplification of the concurrent pandemics ofviolence against women and children and anti-black racism during the responsesto COVID 19 and renewed calls to action. The enforced \u2018pause\u2019 as a result ofsocial isolation or distancing measures in response to COVID-19, has led manypeople to re-imagine a different world and ignited social movements across theglobe. Education must inspire a vision of what our world could be and definewhat action is needed and the steps required to implement change. The criticalreflection that characterizes most social work educational programs can provideopportunities to harness such imaginings in redefining \u2018the possible\u2019 in thequest for a more equitable and safer world. This article describes the potentialof the pandemic to subvert the pervasive influence of neoliberalism by promotingcollective notions of care. The implications of the COVID 19 pandemic signal both tragedy and possibility. Thisreflective paper considers the amplification of the concurrent pandemics of violenceagainst women and children and anti-black racism and renewed calls to action. Theenforced \u2018pause\u2019 as a result of social isolation or distancing measures in response toCOVID-19, has led many people to re-imagine a different world and ignited socialmovements across the globe. The critical reflection that characterizes most social workeducational programs can provide opportunities to harness such imaginings in redefining\u2018the possible\u2019 in the quest for a more equitable and safer world. At no other time inrecent history has the call for social justice been so insistent.During the first few months of the pandemic the media posted news stories of the largestmass shooting in Canadian history, depicted images of global marches against anti-blackracism and described marked increases in violence against women and children all whilesocial isolation or distancing measures were enforced. These early months of thepandemic were characterized by hoarding and fear and at the same time acts of generosityand a swiftness of innovative responses unimagined before the pandemic. Examplesincluded new housing options for the homeless, releasing inmates from prisons and arenewed call for equitable access to a living wage for all. This article describes theseinnovative responses as disruptions and discusses the potential of the pandemic tosubvert the pervasive influence of neoliberalism by promoting collective notions ofcare.The guiding political philosophy in Canada since the 1980\u2019s has been neoliberalism. It has been described as a regime change that facilitated a transitionto corporate rule in which it is assumed that increased productivity and economic growthwill improve human well-being . RelyingIt is difficult to quantify the pervasive influence of neoliberalism and the myriad waysin which it gets \u2018under our skin\u2019 to order our thoughts about what constitutes oursuccess and in turn influence our behavior; monitoring our appearance, employment andaccumulation of possessions. As one student shared in class this past year, she feltpressure to be perfect and believed this pressure contributed to high rates of anxietyamong her peers. But how is perfection defined? If we turn to Foucault\u2019s concept ofpanopticism, in which he described the ways inmates in prison are constantly visible,subjected to surveillance and controlled seemingly by invisible authority figures, itcan serve as an analogy regarding the impacts of neoliberalism. Facebook, twitter andother forms of social media comprise mechanisms of visibility evident in the consumerculture spaces, images and screen culture . InvisibGlobally, at least one third of women experience physical or sexual violence . Over haThe call to end anti-black racism also includes the subversion of neoliberal ideologiesand practices to redress years of neglect and indifference by providing support andresources to African Canadian communities. Canadian Senator Wanda Thomas The murder of African American George Floyd by police officer Derek Chauvin has awokencollective rage that demands action. As the fall university term begins it is moreimperative than ever that the individualism that marks neoliberalism be replaced bycollective concern and action. Education should inspire a vision of what our world couldbe and define what action is needed and the steps required to implement change. Thepairing of reflection followed by implementation of action is required. This moment ofsubversion of neoliberalism compels a re-imagining of what our social and community lifecould be if a more just and peaceful world was the measure of success."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "Family caregivers of hospice patients faced additional challenges in the context of the COVID-19 pandemic where social isolation and loneliness that are often observed among those taking care of a loved one at the end of life, were exacerbated by social distancing rules and workflow changes introduced by hospice agencies. The use of telehealth technologies has the potential to facilitate the delivery of supportive services for family caregivers. We conducted a study examining the use of telehealth for the delivery of a supportive intervention based on problem solving therapy and positive appraisal theory designed specifically to support family caregivers of hospice patients during the COVID-19 pandemic. We recruited 248 caregivers who each participated in three telehealth sessions over a month; caregivers reported higher levels of quality of life and lower levels of anxiety post intervention. Specific recommendations for inclusive telehealth design are discussed based on lessons learned."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "Resilience is described as the ability to respond to acute forms of stress and recover to normal homeostasis. There is growing evidence that biology of resilience is entwined with the biology of aging. With increasing age, resilience decreases and is a likely contributor to increased morbidity, frailty and susceptibility to death with age. Conversely, increased resilience across numerous physiological markers of function is associated with longevity and healthy aging. The variation in resilience in populations suggests biological and molecular regulatory mechanisms that might provide insight into interventions to improve resilience, healthy aging and longevity. In this session, speakers will provide insight regarding short-term assays of resilience in animal models that prove useful both in delineating these biological mechanisms as well as inform on potential translational models to better understand biological resilience in human populations. The sessions focus is on defining these assays and discussion of the biological relevance each resilience assay in terms of the regulation of aging. The goals of these studies range from identifying potential predictors of individual lifespan within markers of functional resilience to leveraging geroscience to define whether markers of resilience can be modified through interventions to the aging process. Moreover, better understanding of the biology of resilience could assist in defining novel interventions that improve resilience and thereby enhance longevity."}
+{"text": "Rupture of ascending thoracic aortic dissection mimicking pulmonary thromboembolism due to pulmonary artery occlusion is rare and should be considered in hypoxic patients with aortic dissection. We describe a case of an 88-year-old male who presented with shortness of breath and hypoxia. Chest radiograph demonstrated airspace opacification in the right lung mainly involving the mid and lower zones . TransthCT demonstrated a dissection flap at the ascending thoracic aorta extending caudally to the aortic root and cranially to the origin of left common carotid artery . The braUnfortunately, the patient deteriorated soon after the CT scan and passed away within 24\u2009h after the CT.The ascending thoracic aorta and the PT are invested in a common sheath of serous visceral pericardium. Occlusion of the RPA from rupture of ascending aortic dissection into the common sheath shared by the aorta and pulmonary artery is rare. It can mimic pulmonary thromboembolism and it is important to distinguish from this as anticoagulation is contraindicated.1 had similar imaging findings mimicking thromboembolism. They describe the susceptibility of compression of the RPA by pathology of the ascending aorta due to the anatomical relationship with the aorta at this level and the common tunica adventitia shared by the aorta and PT. Buja et al2 described medial rupture of an ascending aortic aneurysm resulting in adventitial haematoma compressing the PT. A case of pulmonary hypertension caused by compression of the pulmonary arteries by dissecting ascending aortic haematoma was reported by Kim et al3 Another case of transient pulmonary hypertension caused by extrinsic compression of the pulmonary trunk was reported by Okiwelu et al4, due to a contained rupture of proximal ascending aorta, likely from a penetrating atherosclerotic ulcer.One case of an ascending aortic dissecting aneurysm causing RPA occlusion described by De Silva et alIt is important to consider rupture of ascending aortic dissection into the common sheath as a cause of pulmonary artery occlusion. Occlusion can mimic pulmonary thromboembolism and it is important to distinguish from this, as anticoagulation is contraindicated.CT should be considered in cases of dissection, even when a dissection flap is clearly visible on TTE. CT will demonstrate extension of the dissection in the ascending aorta, aortic root and possible involvement of pulmonary artery, which cannot be assessed on TTE."}
+{"text": "To gauge the breadth of current inflation and prospects for inflation returning to target, we consider disaggregated measures of CPI infl ation to evaluate trends and then consider diff erent scenarios for the realisation for wages and prices."}
+{"text": "The authors regret that in the original article an incorrect email address was given for the corresponding author Sang-Wha Lee. The correct email address is shown here.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "COP cells have been identified as having a potential role in the pathogenesis of tissue loss syndromes such as osteoporosis and frailty. This is based on the hypothesis that their dysregulation may cause a decrease in bone and muscle formation, which also increase the risk of adverse outcomes such as frailty and disability. Whereas high numbers of COP cells have been associated with osteoporosis and fracture healing, a low percentage of COP (%COP) cells have been associated with frailty and disability. In addition, low expression of lamin A (a protein of the inner nuclear envelope) in COP cells has also been associated with frailty and disability in older persons. In this session, the evidence on quantification methods for COP cells in clinical settings and the potential clinical use of COP cells in tissue loss syndromes will be discussed. This discussion will include current evidence supporting the use of COP cells as a biomarker or as a novel therapeutic approach to these age-related conditions."}
+{"text": "Health technology has the potential to support behavior change by measuring performance and providing users with visualizations of this performance as feedback. Such visual feedback has had limited success in changing health behaviors, but it is not clear why. We conducted a systematic review of the visual feedback literature to develop an organizational framework representing the visual feedback-action process. We identified the components that have been investigated in the context of visual feedback. These components are classified into four categories: visualization types  and variables ; feedback characteristics ; psychological processes  and action . The insights will inform the design of feedback visualizations in a smartphone application to support medication adherence for older adults. More broadly, this integrative perspective will yield principles of feedback visualization techniques and components that influence the behavior change process and develop a roadmap to facilitate the design."}
+{"text": "The National Institute for Health and Care Excellence (NICE) has been applying the principles of evidence-based medicine to public health problems for over twelve years. This application is in effect the practice of evidence-based public health (EBPH) . NICE asInfrequently is it practical to assess the effectiveness of interventions for complex public health problems by traditional gold standard randomised control trials. The importance of context, wider determinants, subpopulation variability and the role of the non-human biology element often mean that specific high quality evidence is unavailable. There is often a lack of good outcome studies answering the specific \u2018what works\u2019 question. There are often fewer studies still that answer the questions what works for whom and under what circumstances? The evidence is also often too imprecise to determine the relationship between the intervention and the outcome.The public health evidence base is rarely perfect, if it were it would likely negate the need for, or change the approach and role of organisations such as NICE. Perhaps more importantly the question asked in the evidence interrogation at NICE is \u2018What is the best available evidence to answer the specific question being addressed?\u2019 We know public health questions may benefit from exploration of a broader range of evidence including that which is further down the hierarchy of evidence. By taking a transparent and systematic approach and pulling from evidence from a range of disciplines, NICE has been able to review and synthesise evidence for complex public health problems .The evidence used to generate NICE guidelines is diverse and consists not only of the traditional scientific published evidence but also stakeholder comments, grey literature, real world evidence and expert testimony . The defThis presentation will aim to describe the approach taken by NICE in interrogating the evidence base to develop national public health guidelines. The key challenges and some solutions will be illustrated through examples from evidence synthesis to support guidelines for non-communicable diseases."}
+{"text": "Brandenburg\u2019s federal state framework agreement (LRV) on the implementation of the national prevention strategy according to section 20f of Book 5 of the German Social Code specifies the structural and organisational bases for the further development of prevention and health promotion strategies. The targets and fields of action defined by the federal framework recommendations form part of the established structures of health target processes. The Alliance for Growing up Healthy in Brandenburg (BGA) therefore defines health targets with regard to the objective Growing up healthy stated in the federal framework recommendations. LRV partners thereby have agreed to develop activities sustainably and uphold the current quality standards. This includes a commitment to answering the needs revealed by health and social reporting.In 2018, the roundtable Starke Kinder \u2013 Starke Familien  focused on \u2018child health and poverty\u2019. This year the thematic focus will be on applying the LRV as a basis for co-operative strategies to improve health equity for children and adolescents at the district and municipal levels.The planned report on the health and social conditions of children in Brandenburg aims to reveal the causes of health inequality and provide a basis for measures. To evaluate health and social conditions, the report will build on previous reports on child health in Brandenburg. This combined form of health and social reporting references multiple activities in Brandenburg and in addition to the efforts in the context of the Strong children, strong families roundtable, aims to further develop integrated municipal level prevention strategies, as well as implement Germany\u2019s National Prevention Strategy. The report matches health findings to the health targets of the growing up healthy alliance. The Koordinierungsstelle Gesundheitliche Chancengleichheit Brandenburg  accompanies the establishment and implementation of co-operation projects at the district and municipal level.Brandenburg\u2019s health and social reporting provides comprehensive data and thereby a basis for monitoring the health and social conditions of children and adolescents. A key challenge remains improving the implementation of these findings in municipal level health planning."}
+{"text": "The concern relates to the provenance of this article as brought to our attention by Faisal Alhawaj, who denies authorship of this article and others published in Cureus. These articles were submitted and subsequently published purportedly as an effort coordinated by Imam Abdulrahman Bin Faisal University to ensure all medical interns publish at least one peer-reviewed article in order to qualify for enrollment in a postgraduate residency program as stipulated by The Saudi Commission for Health Specialties (SCFHS).The journal has not been presented with enough evidence to warrant the formal retraction of these articles as both Imam Abdulrahman Bin Faisal University and The Saudi Commission for Health Specialties have failed to respond to numerous communications requesting additional information regarding these allegations. While we acknowledge that the provenance of these articles is very much in question, we cannot act until these claims have been investigated by the appropriate institutions with the results of said investigation communicated to Cureus.The concern and this note will remain appended to the above-mentioned article until Cureus is provided with official confirmation from Imam Abdulrahman Bin Faisal University or The Saudi Commission for Health Specialties."}
+{"text": "In the UK, people with severe mental illness at a greater risk of poor physical health and have higher premature mortality than the general population, highlighting the importance of responding to physical health problems among patients suffering from psychiatric conditions. However, training for staff on inpatient psychiatric units to meet patients\u2019 physical health needs is sometimes overlooked and has not always been effective.According to NICE Clinical Guideline 25 (2005) and NPSA Rapid Response Report (2008/RRR010), staff on any psychiatric inpatient setting must be capable of monitoring, measurement, and interpretation of vital signs. They must have both adequate information and skills to identify signs indicating worsening of patients\u2019 health and respond effectively to severely ill patients.Hence, we aim to re-audit the results of a similar audit carried out in 2016 to review the level of medical emergency training (in terms of life support training) of clinical staff across the inpatient psychiatric wards at our local hospital - Stepping Hill Hospital- in Stockport.Our hypothesis is that there will be a gap in meeting the required standards for training.A questionnaire including 6 questions  was given to staff on acute inpatient psychiatric units in Stepping Hill Hospital.The sample included 49 staff members from all the 3 wards included in the audit. The level of training of nursing staff on the 3 wards was meeting standards except for nursing staff who were new to the wards or coming back to work from prolonged leaves. There was also a gap identified in the level of training of other staff members on the ward as well as on the remaining standards measured by the audit.A gap was identified in meeting the required standards of training on the inpatient psychiatric units. Reasons identified for this gap are mainly due to the fact that new or bank staff are asked to cover the wards without providing them with appropriate training and without orientating them about the location of different equipments and policies on the ward."}
+{"text": "Residents of care homes across the globe are affected by the spread of SARS-CoV-2 as they have been identified as a high-risk group and because they experienced strict social isolation regulations during the first wave of the pandemic. Social isolation of frail older people is strongly associated with negative health outcomes. The aim of this research project was to investigate how residents in care homes experienced social isolation during the first phases of contact ban in Germany. This paper draws on structured interview data collected from 22 residents in two care homes during early June 2020 in Frankfurt/Main. The findings show that their experiences were shaped by three factors: care home staffs\u2019 approach to handling the contact ban; biographical sense of resilience; and a hierarchy of life issues. The findings highlight the importance of locally specific response mechanisms in care homes, and the need to contextualize residents\u2019 experiences."}
+{"text": "The origin and cell lineage of stromal cells in the bone marrow is uncertain. Whether a common stem cell exists for both haemopoietic and stromal cells or whether these cell lines arise from distinct stem cells is unknown. Using in situ hybridisation for detection of the Y chromosome, we have examined histological sections of bone marrow from seven patients who received marrow transplants from HLA-matched donors of the opposite sex. Stromal cells  were identified in these recipients as being of host origin. This result is consistent with the concept of a distinct origin and separate cell lineage for cells of the haemopoietic and stromal systems. It also shows that engraftment of marrow stromal cell precursors does not occur and that host stromal cells survive conditioning regimens for marrow transplantation. With the exception of one case, with a markedly hypocellular marrow, mixed chimaerism was seen in haemopoietic cells, indicating that this is not a rare event after marrow transplantation."}
+{"text": "The in vitro activity of the novel chloroethylating agent, Clomesone, was investigated in a panel of established murine and human tumour cell lines. In vivo anti-tumour activity was examined against three transplantable adenocarcinomas of the mouse colon and in vivo bone marrow toxicity was assessed using a spleen colony forming unit assay. The pharmacokinetic behaviour of the drug in vivo and drug stability in vitro was analysed by gas chromatography with electron capture detection. Clomesone exhibited no activity in vitro against the majority of cell lines derived from solid human colorectal carcinomas. Anti-tumour activity against the murine tumours in vivo was not impressive and was accompanied by myelosuppression. Pharmacokinetic data suggested that the lack of in vivo activity was due to the failure to achieve effective anti-neoplastic drug concentrations at the tumour site. It was concluded that this study found no evidence to suggest that Clomesone was toxicologically more selective than the chloroethylnitrosoureas."}
+{"text": "The haemodynamics of the uterine arteries and myometrium were assessed using Doppler ultrasound in forty consecutive patients requiring treatment for invasive mole and choriocarcinoma. The investigations were performed prior to the commencement of chemotherapy and the subjects followed prospectively. The Doppler waveforms from the uterine arteries were analysed using the pulsatility index. It was found that patients with a pulsatility index of 1.1 or less were significantly more likely to develop drug resistance than those with a higher value (P < 0.04). There was no significant association between the pulsatility index and metastatic disease or uterine bleeding. Five out of eight patients who developed drug resistance could have avoided initial inadequate treatment if the Doppler findings were included in the scoring system for selecting chemotherapy for these tumours. It can be concluded that assessment of the uterine arteries using the pulsatility index prior to the treatment of patients with invasive mole and choriocarcinoma is of help in predicting those who will develop drug resistance."}
+{"text": "We measured immunoreactive EGF and TGF alpha in prostate tissue extracts obtained from 19 patients with benign prostatic hyperplasia (BPH) and 19 with cancer of the prostate (CaP). Whilst both BPH and CaP expressed EGF  and TGF alpha  in equal concentrations, the levels of EGF in any tissue extract were on average twice those of TGF alpha. Furthermore analysis of the individual growth factor data revealed a direct correlation between EGF and TGF alpha in both BPH  and CaP . When the tumours were classified according to their Gleason score, a slight but significant increase in growth factor concentrations was noted as the tumour became less differentiated. We also measured the concentrations of testosterone and dihydrotestosterone (DHT) in prostate extracts with a view of elucidating the relationship between androgen and growth factors in this gland. There was a small positive correlation only between testosterone and EGF  and testosterone and TGF alpha  in CaP. The absence of any similar correlation in BPH where DHT becomes the predominant hormone may suggest an indirect role for testosterone in the regulation of growth factor production."}
+{"text": "Study of the distribution of the p21 ras oncogene product as demonstrated by monoclonal antibody Y13-259 shows this protein to be apparently present in all epithelial populations of both premalignant and malignant tumours and throughout the normal foetal and adult epithelial crypt population in the colorectum. Metastatic tumour in liver shows a similar staining pattern which is less intense however than in the surrounding normal hepatocytes. Our results suggest that the presence of this protein is a widespread feature of normal cellular metabolism in certain cell types and is not restricted to those actively involved in cellular proliferation. It appears, furthermore, that neither cells at different stages of carcinogenesis nor those representing variants of a malignant phenotype can be identified using this particular antibody."}
+{"text": "Neither testis nor epididymis was found to be invaded by L1210 leukaemic cells in spite of widespread dissemination through other organs and tissues. The same applied to animals in relapse after protracted remissions induced by cyclophosphamide. Prior damage to the gonadal vascular endothelium by Cd++ did enable leukaemic cells to enter the testicular interstitium, but not the depleted seminiferous tubules. Injection of cells into the lymphatic sinus system of the testis led to rapid peritubular proliferation and systemic dissemination but the seminiferous tubules were not penetrated. The histological appearance resembled that of human ALL. The results suggest that the L1210 system, using the intratesticular route for inoculation can be used to examine the susceptibility to drugs of leukaemic cells in this environment. The potential of drugs to damage the vascular endothelium of the gonad and perhaps contribute to the development of testicular relapse could be assessed following intramuscular inoculation of cells."}
+{"text": "The pattern of spontaneous screening for cervical cancer by general practitioners and gynaecologists in The Netherlands is compared with an efficient screening policy resulting from a cost-effective study. Spontaneous screening tends to start and stop too early in a woman's life, and leaves too many women overscreened or unprotected. The combination in young age of a low incidence of invasive cancer and a high incidence of regressive lesions explains relative ineffectiveness and harmfulness of present screening practice. When screening would take place between ages 30 and at least 60, with intervals of about 5 years, as many lives could be saved for half the costs and with only 60% of the unnecessary referrals and treatments. Much attention should be paid to the coverage of the target population. Therapeutic follow-up policies for dysplastic lesions should be restrained."}
+{"text": "The prone leg extension (PLE) is commonly used to identify dysfunction of muscle recruitment patterns. The prone leg extension is theorized to identify proximal muscle disturbances which are a result of distal injury or dysfunction (i.e. an ankle sprain). This case study compares the trunk and hip muscle  timing during a PLE of a 27 year old female runner during a healthy state (pre ankle sprain) and 2 and 8 weeks post ankle sprain.The gluteus maximus muscle onsets at 8 weeks post injury appeared to occur earlier compared with 2 weeks post injury. The Right Erector Spinae at 8 weeks post injury was also active earlier compared with the participant's non-injured state. A large degree of variability can be noted within trials on the same day for all muscle groups.An acute ankle injury did not result in a delay in gluteus maximus muscle activation. The utility of the prone leg extension as a clinical and functional test is questionable due to the normal variability seen during the test and our current inability to determine what is normal and what is dysfunctional. The prone leg extension (PLE) test is used by therapists who manually palpate the posterior muscles and observe trunk kinematics in an attempt to identify deviations from a supposed optimal. A dysfunctional firing pattern is assumed to exist when postural muscles (hamstrings and erector spinae) initiate the movement and a delay in gluteus maximus firing is evident . As wellBullock-Saxton et al  investigcause of disturbances in the muscle firing pattern during the PLE. Presented in this case study is a longitudinal quantitative assessment of the muscle onset timing of posterior trunk and leg muscles during the prone leg extension following an acute lateral ankle sprain. This case study will specifically address whether an acute ankle sprain precedes a delay in the muscle activation of the ipsilateral Gluteus Maximus muscle.The Bullock-Saxton study  was a crThis case study is a product of serendipity. A 27 year old female runner was initially part of an experimental study documenting the muscle onset timing of the posterior leg and trunk muscles during the prone leg extension. At the time of the study the participant had no leg or spine injuries. The participant was part of the asymptomatic control group. Five months after the completion of the study this participant suffered an inversion right ankle sprain during a rainstorm while leaping into a camping tent filled with children. At 2 and 8 weeks post ankle sprain the PLE extension test was performed while recording the posterior muscle activation EMG to determine if an ankle injury influences the timing of muscle activation during the PLE as compared with an injury-free PLE onset timing pattern.Twenty seven year old female distance runner  suffered a right ankle inversion sprain. X rays revealed no fractures. Informed consent to participate in this study was received from the subject. In the initial study the participant read and signed an information and consent form that was approved by the Research Ethics Board of CMCC. For the second half of the study the subject was notified of the risks and benefits of the study which complied with the World Medical Association declaration of Helsinki on the ethical conduct of research using human participants within a private practice and agreed to have her results published.No passive therapy was received by the participant. The participant was encouraged to perform daily weight bearing exercise and range of motion exercises. The participant was running within two weeks of the injury with pain and not at her pre injury level. At two weeks post injury the participant reported that she felt she was functioning at 60% of her optimum. At 8 weeks post injury the participant reported that she was running 95% pain free with little loss of function.An identical testing protocol was used across the 3 experimental days . The muscle activity of the right gluteus maximus, bilateral lower erector spinae, and right hamstring muscle groups was recorded during right prone leg extension while lying prone on a manual therapy table. The position of the leg was controlled in all planes  visually by the experimenter. A rig restricting movement or a kinematic analysis system to ensure an identical movement across trials was not used as this is not similar to what occurs during practice. The control of proper form was limited to a visual assessment as this most resembles clinical practice.Disposable bipolar Ag-AgCl disc surface electrodes with a diameter of one cm were adhered bilaterally over the five muscle groups with a centre to centre spacing of 1 cm. Raw EMG was amplified 5000 times. The amplifier has a CMRR of 10,000:1 . Raw EMG was band pass filtered (10 and 1000 Hz) and A/D converted at 2000 Hz using a National Instruments data acquisition system.The prone leg extension exercise was performed five times during each experimental session. The task required the subject to lie prone at complete rest with no movement while the EMG from each muscle was collected for 5 seconds. The subject then extended their straight right leg approximately six inches off the table. The leg was held isometrically for 3 seconds then lowered to the table.The data from each PLE trial was processed in the same manner. The aim of the processing for this study was to determine the order and timing of muscle activation. To determine muscle timing, it is necessary to determine when a muscle is considered active or \"on\". A muscle was considered \"on\" when the level of muscle activity was greater than 10% of the peak muscle activity during the prone leg extension. This method of determining muscle onset was used in the previous study by Bullock-Saxton et al . The ordThe data was processed in the following manner: The raw EMG signal was first full wave rectified, then smoothed using a moving average technique which averaged every 100 points of data with an overlap 98 points. The bias was removed from the signal to allow resting activity to be at 0. The peak muscle activity was found and each data point was divided by this peak muscle activity. In this way, muscle onset could be determined by determining the time when the myoelectric signal exceeded 10% of the maximum. The signal was visually inspected to ensure that no artefact occurred or that the results were biologically feasible.Table To the knowledge of the author this is the only prospective case documenting the longitudinal influence of an inversion ankle sprain on muscle activation patterns during the prone leg extension test. The results from this one participant failed to support the idea that lower limb injury leads to a delay in gluteus maximus firing as suggested by the cross sectional study of Bullock-Saxton et al .Conversely, at 8 weeks post ankle sprain there was a decrease in the latency of the gluteus maximus muscle (the muscle fired earlier). This earlier firing is similar to the differences in onset timing of the gluteus medius during lateral ankle perturbations between groups with chronically sprained ankles and controls . BeckmanThe lack of support from this case study and previous research questions the utility of the PLE in determining dysfunctional muscle firing patterns. There is little support in the research literature for the use of the PLE test in assessing muscle onset dysfunction. Further evidence against the use of the PLE in adequately assessing muscle function is found in the conclusions of Pierce and Lee  and Lehmwas not associated with a delay in the gluteus maximus activity. The Gluteus Maximus at 8 weeks post injury fired earlier than 2 weeks post injury and showed a trend to firing earlier than in a healthy state.An interesting trend in changes in muscle activation was earlier muscle activation of the erector spinae activity. Before the injury both erector spinae were active after the hamstring group. Eight weeks post injury the erector spinae preceeded hamstring activation by more than 130 ms. This earlier activation was also seen in the contralateral Erector Spinae at 2 weeks post injury (56.2 ms before hamstring activation). Bullock-Saxton et al [Another weakness of the PLE test is the high variability between trials within one individual (as seen in the current case study) and across individuals. This variability appears normal and limits the use of EMG in producing data which can identify individuals with dysfunction ,4. Last,While this case study failed to support the proposal that distal dysfunction may result in proximal dysfunction manifesting as aberrant muscle onset timing of the gluteus maximus during the PLE, the PLE as a clinical assessment test may still have value. The only means of assessing the PLE has been via muscle onset timing with electromyography. As stated earlier the trunk and hip kinematics of the participant are observed during the performance of the movement. No research to date has measured the kinematics with the aim of identifying and quantifying optimal and dysfunctional movement patterns (as opposed to the motor patterns assessed with electromyography). Quantifying these kinematics may lead to determining the discriminant ability of this test for the identification of dysfunction. The PLE may have more clinical utility as a crude test of function \u2013 minor differences in muscle onsets may have no clinical value and may not be easily detected by observation; however, major dysfunctions in muscle activation (i.e. no observable gluteus maximus contraction) would be more easily detected and may be of more clinical value. For example, during the test a patient's buttock may remain flaccid. This is easily seen and may be indicative of inhibition and possible dysfunction. The use of the PLE as a gross detector of dysfunction may be more supportable than being used to questionably detect subtle differences in firing patterns that are within 200 ms of each other.An acute ankle injury did not result in a delay in gluteus maximus muscle activation. The utility of the prone leg extension as a clinical and functional test is questionable due to the normal variability seen during the test and our current inability to determine what is normal and what is dysfunctional.The author(s) declare that they have no competing interests."}
+{"text": "The value of the inclusion of doxorubicin hydrochloride (dox) in Cooper type regimens in advanced breast cancer was assessed by performing an overview employing summary statistics derived from published papers of randomised clinical trials comparing Cooper type regimens that contain dox with regimens in which dox was replaced by one or more compounds. Trials were selected which published data on survival, time to treatment failure and response rate. This study suggests that dox confers advantages on all of these endpoints and that the size of such benefits needs to be taken into account when deciding whether to use dox."}
+{"text": "Transvenous pacemaker lead implantation is the preferred method of pacing in adult patients. Lead performance and longevity are superior and the implantation approach can be performed under local anaesthetic with a very low morbidity. In children, and especially in neonates and infants, the epicardial route was traditionally chosen until the advent of smaller generators and lead implantation techniques that allowed growth of the child without lead displacement. Endocardial implantation is not universally accepted, however, as there is an incidence of venous occlusion of the smaller veins of neonates and infants with concerns for loss of venous access in the future. Growing experience with lower profile leads, however, reveals that endocardial pacing too can be performed with low morbidity and good long-term results in neonates and infants. Cardiac pacing in infants and children has evolved considerably since the initial implants over half a century ago. Pacemaker generators have become smaller and are now easily accommodated subcutaneously or submuscularly either in the chest or the abdominal wall in the smallest of infants. Improvements in lead technology have enabled lower chronic thresholds with greater mechanical and electrical integrity and longevity of the leads and the pacemaker system. While endocardial leads have consistently proven to be superior to epicardial leads both mechanically and electrically, the development of steroid eluting epicardial leads has improved the effectiveness of epicardial systems . The chiThe choice of the method of permanent pacing is determined by the patient\u2019s size, and presence of structural heart disease. While a large body of opinion holds that neonates and infants should receive epicardial pacing systems -4, experEndocardial leads are increasingly preferred for small infants in other centres as well -16. The Studies specifically comparing pacing via the endocardial route versus the epicardial route in small infants are lacking. The incidence of venous obstruction and occlusion has rarely been addressed. Venous obstruction due to endocardial leads in a small group of newborns and infants was assessed by Stojanov et al . In 12 cStojanov et al promote a cephalic vein cut down rather than a subclavian puncture approach in the very small . It may Endocardial pacing in neonates is not for the faint-hearted as lead replacement is likely to be needed in at least some of the patients. While extracting 11 leads uneventfully in nine patients , Kammeraad et al [Although epicardial leads do not carry a risk of venous thrombosis, there is an increased perioperative morbidity . PatientNeither the epicardial nor the endocardial approach in permanent pacing is free from complications. The experience reported with endocardial pacing in neonates and infants while encouraging is limited and no directly comparative data with epicardial pacing are available. Although the clear advantage of endocardial pacemaker implantation over the epicardial approach has yet to be demonstrated, the growing experience indicates that endocardial pacing is feasible and effective even in neonates and small infants - and it is an acceptable alternative to epicardial systems. The current disadvantages of endocardial leads may be overcome in the future by downsizing of the leads and extraction systems. The ultimate approach in very small children currently will depend on the facilities and experience of the surgeons and cardiologists in each centre."}
+{"text": "Fogel's suggestion of a grading system according to the level of peer review (reminiscent of grading systems for \"level of evidence\" of primary studies) is interesting, but further study is required to determine to what degree the proposed ratings actually correlate with quality or peer review rigor. My suggestion  was to r"}
+{"text": "Male and female age standardised mortality and incidence rates of colorectal cancer have increased over the most recent 30 years in New Zealand. Among men and women aged 40 to 74, age standardised mortality and incidence rates increased 18 to 105%. However, age standardised mortality and incidence rates among younger men and women have declined from 14 to 69%. Analysis of trends in age specific mortality and incidence rates indicates that the occurrence of colorectal cancer has been declining equally for men and women in successive cohorts born about 1943 to 1953 in New Zealand. This decline in the frequency of colorectal cancer among recent generations was apparent for both the right and left sides of the colon and the rectum. Age-specific trends in coronary heart disease and breast cancer differed from those apparent for colorectal cancer, suggesting that the factors producing the reduction in colorectal cancer risk may affect these diseases among different age groups or may not be of major aetiological importance in these diseases. These trends provide empirical evidence that the occurrence of colorectal cancer can be reduced by at least 50% with a substantial component of the risk being determined before the age of 30. Further study is needed to establish whether changes in risk factors at older ages contribute to the prevention of the disease."}
+{"text": "On most common microarray platforms many genes are represented by multiple probes. Although this is quite common no one has systematically explored the concordance between probes mapped to the same gene.Here we present an analysis of all the cases of multiple probe sets measuring the same gene on the Affymetrix U133a GeneChip and found that although in the majority of cases both measurements tend to agree there are a significant number of cases in which the two measurements differ from each other. In these cases the measurements can not be simply averaged but rather should be handled individually.Our analysis allows us to provide a comprehensive list of the correlation between all pairs of probe sets that are mapped to the same gene and thus allows microarray users to sort out the cases that deserve further analysis. Comparison between the set of highly correlated pairs and the set of pairs that tend to differ from each other reveals potential factors that may affect it. High density DNA microarrays are extensively used by biologists in order to gain information about the expression levels of thousands of genes simultaneously. The advantage of the genomic approach is that it allows the study of cell behavior on the systems level rather than on the gene specific level . One of A related issue which has been studied extensively in recent years is the question of cross platform comparisons in which researchers try to compare results obtained for the same gene on different microarray platforms. Overall there is only limited agreement between experiments performed on different platforms . ManyIn order to compare RNA measurements from two different regions of a gene on the same array, we chose to explore the Affymetrix U133a platform since it is a very popular platform with thousands of publicly available datasets. The U133a platform contains 20,267 probe sets which are mapped to 12,942 distinct genes with 4,552 of them represented by multiple probe sets .In order to asses the overall agreement within pairs of probe sets, we decided to look at the Pearson correlation between the set of measurements for each of the probe sets in each dataset. We chose the Pearson correlation as our metric since it is not sensitive to differences in scaling and average expression levels but rather compares the degree of linear relationship between the two probe-sets which is a better indication for the overall similarity. We calculated the correlation coefficient of all the informative pairs in each dataset. Histograms of these correlations and correlations obtained by a random list of pairs are shown in figure Comparison of the correlation values obtained in the different datasets revealed a high degree of correlation between them figure , suggestOne of the main purposes of our analysis was to guide microarray users in cases of genes that are represented by multiple probe sets. The users would like to know when the multiple measurements can be combined and when they should be handled with caution. In order to achieve this goal, we wanted to define a list of pairs which show overall good agreement between them. This list should be based on the combination of the correlation values calculated in each dataset. Thus for each pair, we combined the individual P values obtained for each dataset in which it was informative, resulting in a single combined P value for each pair. A list of all the pairs along with their combined P values is included in Microarrays users frequently ask themselves what to do when a gene is represented by multiple probes. Our analysis provides a partial solution to this problem by mapping all the pairs of probe sets on the Affymetrix U133a platform and providing a significant measurement  as to whether the transcription levels reported by the two different probe sets correlates. In order to demonstrate that the combined P value may be useful in analyzing microarray data, we calculated the number of cases in which averaging the intensity reported by a pair of probe sets is misleading. The clear dependency between the error rate level and the P value  and pairs which did not show a significant concordance between them .Intra array repeats are printed on the same array and therefore they share all the external conditions  and differ from one another only in the particular sequence chosen to be printed on the array. Thus multiple probe sets printed on the same array serve as an excellent case for exploring the contribution of sequence effects to the overall deviation of the transcription values reported by each probe set. To this end we defined two large sub groups of pairs (each containing approximately 1500 pairs) \u2013 pairs that were highly correlated  for the s_at and x_at suffixes in the \"good\" pairs figure , suggestMicroarray users frequently encounter the problem of different values for the same gene resulting from multiple probe sets. Without clear guidelines from the manufacturers, each investigator deals with this problem in a different way, some are not aware of it and therefore either use the first appearance of the gene or use the probe set that fits their expectations better. Alternatively, users may use the average of all probe sets without validating that all indeed report similar transcription rates. In order to help microarray users to chose the right approach for multiple measurements of a gene in the Affymetrix U133a GeneChip we examined all such cases and developed a statistical method to asses the agreement between the measurements in each of these cases. Our method is based on the calculation of the Pearson correlation between all the measured values of a pair of probe sets along all the experiments in a data set. The Pearson correlation gives a good estimation of the overall agreement between such pairs without being sensitive to variability in the average expression level reported by the probe sets. We excluded from the analysis probes that were non informative either because their expression level was below detection or because their expression level did not change (>2 folds) along the experiments. As expected the correlation values obtained between probe sets from the same gene were much higher than those obtained from randomly chosen pairs of probe sets with 77% of the pairs reporting similar values. The pairs of probe sets where sorted according to the statistical significance of the Pearson correlation between them and a list of all the pairs together with their P value is provided see . This liThe division of the pairs of probe sets into those that tend to agree (\"good\") or disagree (\"bad\") allows us to examine the factors affecting it. The deviation between two probes that are mapped to the same gene may be due to several reasons including alternative splicing, mistakes in the annotation and differences in the efficiency each probe set reports the transcription. We found no evidence for the contribution of alternative splicing to the disagreement between probe sets figure . On the Recent studies about cross platform comparisons found that the best results are obtained if the comparison is done on the probe level rather than on the probe set level ,18,19, sThe observation that non unique probe sets perform better than unique ones figure  is surprOur analysis suggests that in most cases (77%) pairs of informative probe sets report similar transcription levels. However, it should be noted that our decision to concentrate only on informative probe sets may influence those results. By excluding from the analysis the most problematic cases in which one probe set is informative and the other is not we elevated the percentage of cases with good correlation see . These cThe analysis of the differences between the \"good\" and the \"bad\" pairs suggests that biological differences such as alternative splicing have a very limited contribution to the disagreement between probe sets. This conclusion was derived from the current knowledge of the genome sequence and of splicing variants (using fairly strict criteria). Updates of the genome sequence and advancements in the technology of measuring splice variants (such as the use of exon microarrays) may change this conclusion. Although those changes may affect the reasons for the disagreements between probe sets it will not change the definition of \"good\" and \"bad\" pairs. Only updating the probe set definition according to the new sequence information  may solvAn important internal control for microarray experiments is multiple array spots that are mapped to different regions of the same genes. In the ideal world these different probe sets should give similar measurements for expression of the gene. Our analysis tested whether this is true using four data sets that used the Affymetrix U133a platform. We found that in the majority of such cases both measurements agree and thus using the average value of the probe sets would be appropriate. However in a significant number of cases this approach is not suitable and our results can guide the user in deciding about each case. Further analysis is needed to define guidelines for choosing better regions in the gene that will represent the transcription level more accurately.For our analysis we downloaded the data of four large experiment series from the gene expression omnibus database . We chosIn order to define intra array repeats, we used Affymetrix annotation and defined 11,722 pairs of probe sets in which both members were mapped to the same gene. In order to compare the RNA levels reported by the two probes in each pair we calculated the Pearson correlation between the expression values (log transformed) reported by each probe set in all the experiments in each dataset. We also performed Spearman correlation and the results see  are verySince we were interested only in the correlations between probe sets of active genes we looked only on probe sets that passed two filtering criteria \u2013 they got a present call (P) in at least 10% of the experiments in a dataset and they showed at least 2 fold changes in their expression level over the average in at least 10% of the experiments. This filtering resulted in a different number of informative pair of probe sets for each dataset , pairs with only one informative probe set (red) and pairs in which both probe sets are informative (red). See methods for the definition of informative probe set.Click here for fileExcel file containing information about the Spearman correlation values of all pairs of probe sets in all the four datasets.Click here for file2 values. The only dataset with spots that are not along the diagonal is GSE1133 in which ~5% of the spots deviate from the diagonal by >2 folds, the remaining spots gave R2 = 0.93.Scatter plots showing the Pearson correlation values (X axis) against the Spearman correlation values (y axis) of all the informative pairs in the 4 data sets. Note that the spots are arranged along the diagonal with high RClick here for file"}
+{"text": "Eighty-one patients with advanced breast cancer completed the Hospital Anxiety and Depression Scale (HADS) and Rotterdam Symptom Checklist (RSCL) to determine how well these questionnaires identified patients suffering from an anxiety state or depressive illness, compared with an independent interview by a psychiatrist who used the Clinical Interview Schedule. A threshold score was defined for each questionnaire which gave the optimal sensitivity and specificity. Seventy-five per cent of patients were correctly identified as suffering from an affective disorder by both the Rotterdam Symptom Checklist and by the Hospital Anxiety and Depression Scale. Twenty-one per cent of 'normal' patients were misclassified by the Rotterdam Checklist and 26% by the Hospital Anxiety and Depression Scale. When the HADs anxiety and depression subscales were analysed separately, the performance of the anxiety items was superior to that of the depression items. Both questionnaires were found to have good predictive value and could be used in patients with advanced cancer to help screen out those with an affective disorder."}
+{"text": "The presence of cellular aggregates in cell suspensions derived from human solid tumours often complicates subsequent evaluation of colony formation in primary soft agar cultures . In the present study, performance of a conventional colony formation assay was observed to lack sufficient sensitivity to identify growth and active chemotherapeutic agents in the majority of specimen cultures. Modification of conventional methodologies to include filtration of cell suspensions, use of \"proliferation control\" and \"cytotoxicity control\" cultures as well as vital staining were found to be essential for the valid assessment of primary soft agar cultures in our laboratory. In addition, application of drugs to culture surface in place of culture incorporation appeared to facilitate culture performance and drug sensitivity testing."}
+{"text": "The effect of the synthetic progesterone, megestrol acetate, on weight loss induced by both tumour necrosis factor alpha (TNF) as a model for the cachexia accompanying the acquired immunodeficiency syndrome and by a cachexia-inducing tumour (MAC16) has been studied in NMRI mice. Megestrol acetate was effective in preventing weight loss in both model systems with treated animals having an increase in intake of both food and water. Megestrol acetate was unable to prevent loss of body weight in animals pair-fed with TNF treated animals, suggesting that the increase in food and water intake was responsible for the increase in body weight. Analysis of body composition showed that the major contribution to the increase in body weight in animals treated with megestrol acetate was an increase in water content, although there was also an increase in carcass fat in animals bearing the MAC16 tumour given the high dose of megestrol acetate. Animals bearing the MAC16 tumour had a significant increase in tumour weight after treatment with megestrol acetate, possibly owing to the increased plasma glucose levels. These results suggest that an increase in appetite and weight gain alone are not sufficient to justify the anticachectic effect of a particular agent and that body composition analysis and tumour growth rate are very important parameters."}
+{"text": "The effects of different doses of hydralazine and prostacyclin on the 31P magnetic resonance spectra of the LBDS1 fibrosarcoma were investigated and related to their effects on mean arterial blood pressure (MABP) and heart rate. The effect of reducing MABP by bleeding the animals, via the tail artery, was also investigated. Tumour spectral changes following high dose drug treatment  were consistent with nutrient deprivation. These changes were dose dependent. Changes in MABP and heart rate were consistent with vasodilatation in normal tissues. However, for the same fall in MABP, hydralazine produced a greater rise in tumour inorganic phosphate (Pi) and a greater fall in tumour pH than did prostacyclin. Controlled bleeding was effective in reducing MABP. It also reduced tumour pH but had no significant effect on tumour Pi. The clinical application of the two drugs for reducing tumour blood flow and pH for therapy is likely to be limited by the large degree of hypotension necessary to produce an effect. The differential effect of the two drugs for the same fall in MABP may be related to different degrees of direct tumour vasodilatation or to a direct effect of hydralazine on tumour energy metabolism. The observation that controlled bleeding does not change tumour Pi is further evidence indicating that the degree of arterial hypotension is not the sole factor in determining tumour energy status."}
+{"text": "In order to assess whether exposure to stress was associated with an increased risk of breast cancer, 100 women presenting with carcinoma of the breast completed a standard life events inventory documenting life stresses experienced during the previous three years. The same questionnaire was completed by 100 women presenting with benign breast lumps and 100 apparently healthy controls. Both groups of patients with breast disease also completed the Eysenck personality inventory. There was no difference in the number of stressful life events experienced by the patients with benign and malignant breast lesions and the nature and severity of those stresses encountered were similar for both groups. The personality indices were also the same for both groups. The controls, however, recorded significantly higher levels of stress exposure than the patients with breast disease. On the basis of this series, there is no evidence to support the hypothesis that stress predisposes to breast cancer development."}
+{"text": "Paragangliomas of the head and neck (glomus tumours) can occur in a hereditary pattern and may be hormonally active as well as being associated with paragangliomas elsewhere. A number of these tumours may be present without symptoms. To detect the presence of subclinical paragangliomas we screened 83 members of a family at risk of developing hereditary paragangliomas using whole body MRI and urinary catecholamine testing. In eight previously diagnosed members, eight known glomus tumours of which one functioning, and two unknown glomus tumours and one unknown pheochromocytoma were present. Six unsuspected members showed ten glomus tumours and one pheochromocytoma. It has been suggested that the manifestation of hereditary glomus tumours is determined by the sex of the transmitting parent. There were no tumours in the descendants of female gene carriers. Comparing the likelihood of inheritance with genomic imprinting versus inheritance without genomic imprinting we found an odds ratio of 23375 in favour of genomic imprinting."}
+{"text": "It is now recognised that the breast exhibits a circadian rhythm which reflects its physiology. There is increasing evidence that rhythms associated with malignant cells proliferation are largely non-circadian and that a circadian to ultradian shift may be a general correlation to neoplasia.Cancer development appears to generate its own thermal signatures and the complexity of these signatures may be a reflection of its degree of development.The limitations of mammography as a screening modality especially in young women with dense breasts necessitated the development of novel and more effective screening strategies with a high sensitivity and specificity. Dynamic thermal analysis of the breast is a safe, non invasive approach that seems to be sensitive for the early detection of breast cancer.This article focuses on dynamic thermal analysis as an evolving method in breast cancer detection in pre-menopausal women with dense breast tissue. Prospective multi-centre trials are required to validate this promising modality in screening.The issue of false positives require further investigation using molecular genetic markers of malignancy and novel techniques such as mammary ductoscopy. Breast cancer is one of the most common cancers, it is estimated that one in eight women in the USA will develop breast cancer during their lifetime -4. FurthIn addition to mammography, non invasive new modalities have been developed to allow the early detection of breast cancer in all age groups and more importantly in young women with dense breast tissue and women who have high risk of developing breast cancer such as, women with strong family history and carriers of BRCA1 and/or BRCA2 genes.Currently, magnetic resonance imaging (MRI) is being studied for the early detection of breast cancer. Its sensitivity in high risk women has been found to be much higher than mammography but with a lower specificity ,6. KriegElectrical impedance scanning (EIS) is another modality under development for breast cancer detection especially in young women with dense breasts . The basFurthermore, mammary ductoscopy (MD) and visualization of mammary ducts and proteomics of nipple aspirate fluid (NAF) and serum are promising screening modalities that require further evaluation ,10.The limitations of mammography as a screening modality especially in young women with dense breasts necessitated the development of novel and more effective screening strategies with a high sensitivity and specificity.This article focuses on the dynamic thermal analysis as an evolving non invasive and a safe method in breast cancer detection in pre-menopausal women with dense breast tissue and women at high risk due to family history or genetic predisposition.It is now recognised that the establishment and growth of a tumour depend on neovascularization. This successful recruitment of new blood vessels into a tumour; also known as angiogenesis is dependent on angiogenic growth factors produced by the tumour cells . Such neEarlier technology for assessing thermal abnormalities in the breast focussed on the presence of the abnormal temperature as a crucial marker -17. In aThe superficial thermal patterns measured on the surface of the breast seem to be related to tissue metabolism and vascularization within the underlying tissue. Such thermal patterns change significantly as a result of normal phenomena including menstrual cycle, pregnancy and more importantly the pathologic process itself. Additionally, cancer development represents the summation of a large number of mutations that occur over years, each with its own particular histologic phenotype -23.Such changes appear to generate their own thermal signature and the complexity of these signatures may be a reflection of their degree of development -28.Temperature in a normal breast increases from the skin into the deep tissue and heat conductivity in the healthy breasts is constant in most cases and generally can be characterized in terms of circadian rhythm periodicity . In contFurthermore, the unique relationship between the thermal circadian rhythm and mitotic activity could be considered as a first warning of tumour development, which can be detected using a safe and non-invasive technology. The genes that drive the circadian rhythm are emerging as central players in gene regulation throughout the organism, particularly for cell-cycle regulatory genes and the genes of apoptosis .Recent technological advances have facilitated the recording of circadian rhythm variations of the breast and analysing the recorded data using highly complicated computer statistical software. A miniaturized microprocessor has been developed to record and store thermal information collected from eight separate sites of each breast. Sensors are placed in anatomically critical positions elicited by data obtained from tumour registries as to where cancers are most likely to develop.In the First Warning System , thermal data are collected every five minutes for a period of 48 hours during which time women are encouraged to maintain their daily activities. 9000 pieces of data are recorded by microprocessors during the test period and analysed using specially developed statistical software. Temperature points from each contralateral sensor are plotted against each other to form a thermal motion picture of a lesion's physiological activity.Such a technology was first used by Farrar et al who examined a cohort of 138 women who had been scheduled for open breast biopsies based on the finding of physical examination and mammography . A totalOne of the main challenges to this technology is the false positive cases; confusion could be created in these women who are characterized as being positive or high risk by dynamic thermal analysis in the absence of physical and mammographical signs. This group of women may or may not have cancer in its earliest stages. Further retrospective analysis of the thermal data using a refined neural net algorithm may increase the sensitivity and reduce the number of false positives. Also this group of patients may well benefit from the new advances in the nipple aspirate fluid analysis and proteomic profiling technologies. Research is currently ongoing on this subject and the initial results are promising .Dynamic thermal analysis of the breast is a safe, non invasive approach that seems to be sensitive for the early detection of breast cancer especially in young women where the conventional mammography is of limited value. Such a technology could become the initial breast screening test in pre-menopausal women and those who are classified as positive can then be selected for anatomical imaging with mammography, MRI and/or ultrasonography. Further refinement of the neural net algorithm is required in order to shorten the period of data recording and improve specificity. Prospective multi-centre trials are then required to validate these promising observations. The issue of false positives require further investigation using molecular genetic markers of malignancy and novel techniques such as mammary ductoscopy .Finally, a better understanding of the circadian rhythm biology ,30 and c"}
+{"text": "In 1999 the membership of the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) formed a multisector consortium to address challenges associated with the integration of genomics data into risk assessment . FollowiIn 2004 we have seen considerable progress in many of the areas mentioned above, particularly in our technical ability to execute microarrays and to analyze and interpret the resultant data. The experimental program of the HESI Genomics Committee clearly demonstrated that it is possible to replicate data on biologic pathways across laboratories and technical platforms . The comThe efforts of the HESI Committee on Genomics regarding experimental collaboration and toxicogenomics database development  suggest The risk assessment community is also striving both to harness the collective power of publicly available data sets and to facilitate exchange of single data sets for safety evaluation. As such, numerous formats for the capture and exchange of microarray and toxicology data have become available and/or are under development . DiversiThe HESI Committee on Genomics looks forward to an ongoing role as a multi-stakeholder consortium committed to facilitating discussion on the scientifically sound use of genomics for risk assessment."}
+{"text": "Dopamine acts as neurotransmitter in the central and peripheral sympathetic nervous system. Determination of dopamine (DO) was performed by spectrophotometric analysis depending on the formation of new colored compound. The proposed procedure was efficient in quantitative determination of DO as pure material in pharmaceutical preparations and in urine samples. DO concentration in urine sample of patient confirms the affection with schizophrenia and the proposed procedure was used to facilitate diagnosis and followup of schizophrenic patients. It is recommended to apply the proposed procedures as routine analysis in pharmaceutical companies for quality control and in analytical laboratories to diagnose and follow up schizophrenia."}
+{"text": "Standard (UICC) crocidolite was subjected to ball milling to reduce the length of the fibre. These milled materials and the original standard sample were injected into the pleural cavity of rats to determine their ability to induce mesothelioma. Previous in vitro work on the same materials had suggested that biological activity was related to fibres greater than 6.5 microns in length and that the material milled for 4 and 8 h did not contain fibres in this range and was biologically inactive. The results of the animal work, however, did not follow this pattern; mesotheliomas occurred in rats in all treatment groups including the 4 and 8 h milled samples. Examination of the tissues and the dust recovered from them showed the presence of fibres greater than the suggested threshold. Attention is drawn to the problems associated with drawing conclusions from size distributions and in vitro studies without considering in vivo mechanisms."}
+{"text": "Programmes of education in breast self-examination with specialist clinics for self-referral were introduced in two health districts around 1980. Combining the results from the two centres showed no reduction in mortality from breast cancer over the following 10 years but the mortality was low in one of the centres whilst in the other it was higher than in four geographically separate comparison centres in which there was similar careful monitoring of breast cancer incidence and mortality. Because this was not a randomised controlled trial and lacked a uniform treatment protocol, biases may be responsible for the differences observed, but it is also possible that BSE education with annual reinforcement contributed to the breast cancer mortality reduction seen in one district. The overall conclusion however is that the value of breast self-examination remains unproven."}
+{"text": "In this issue of the Journal of Medical Internet Research, the reader is presented with two important studies that focus on the challenges of integrating patient participation and partnership in medical informatics. Both studies address the enormous potential of information technology to effect change in health by influencing patient behavior.The study by Ross et al is a randomized controlled trial of SPPARO (System Providing Patients Access to Records Online), a patient-accessible electronic patient records (EPR) system implemented at the University of Colorado, measuring its impact on health outcomes and patient satisfaction . SPPARO The SPPARO study also serves to illustrate two key dilemmas facing clinical informatics researchers. In defining the unit of analysis, is \"access\" the antecedent for change in outcomes, or is it more appropriate to look for some kind of behavioral change, like technology acceptance or actual system utilization ? FurtherThe second study by Kim and Johnson observes the contributory role of format on the subsequent accuracy of data entry by patients in personal health records (PHR), and vividly illustrates the most important challenge facing developers: how to make the PHR useful for patients . The intIn conclusion, medical informatics research must continuously develop the capacity to demonstrate that information technology can effect positive change for patients . These t"}
+{"text": "To explain the possible effects of exposure to weather conditions on population health outcomes, weather data need to be calculated at a level in space and time that is appropriate for the health data. There are various ways of estimating exposure values from raw data collected at weather stations but the rationale for using one technique rather than another; the significance of the difference in the values obtained; and the effect these have on a research question are factors often not explicitly considered. In this study we compare different techniques for allocating weather data observations to small geographical areas and different options for weighting averages of these observations when calculating estimates of daily precipitation and temperature for Australian Postal Areas. Options that weight observations based on distance from population centroids and population size are more computationally intensive but give estimates that conceptually are more closely related to the experience of the population.Options based on values derived from sites internal to postal areas, or from nearest neighbour sites \u2013 that is, using proximity polygons around weather stations intersected with postal areas \u2013 tended to include fewer stations' observations in their estimates, and missing values were common. Options based on observations from stations within 50 kilometres radius of centroids and weighting of data by distance from centroids gave more complete estimates. Using the geographic centroid of the postal area gave estimates that differed slightly from the population weighted centroids and the population weighted average of sub-unit estimates.To calculate daily weather exposure values for analysis of health outcome data for small areas, the use of data from weather stations internal to the area only, or from neighbouring weather stations , is too limited. The most appropriate method conceptually is the use of weather data from sites within 50 kilometres radius of the area weighted to population centres, but a simpler acceptable option is to weight to the geographic centroid. A study of the possible effect of temperature and precipitation on gastroenteritis inspired an assessment of different methods for small area population exposure estimation techniques. The health data were obtained from a survey with respondents from Australia conducted between September 2001 and August 2002 . Microsoft Access was used to join the concordance table of POA-to-monitoring station proximity polygons to the daily observations, and averaged these whilst grouping by POA code and date in Options 1 and 2. Options 3 and 4 used \"joinby\" and \"collapse\" commands in STATA 8  to join Individual station files of daily meteorological data for 1990\u20132005 were parsed for integration in MS Access databases using visual basic code written by Melissa Goodwin at the National Centre for Epidemiology and Population Health.The CD populations from the 2001 census were obtained from the ABS . These dSome postcodes don't exist as POA and for these the locality names were found using the online postcode finder from the electronic telephone directory . These lMultipart POA were assessed by first using the ArcGIS multipart to single-part tool (features toolbox) and then counting the number of parts per feature (using the frequency tool).Internal stations were found using the intersect tool in the ArcGIS Spatial Analyst extension. This information was joined to the meteorological data using Microsoft Access.Nearest neighbour concordances were calculated by first creating proximity polygons of the appropriate stations (using the coverage tools), then overlaying and intersecting these with POA .Centroids were calculated using the Visual Basic for Applications script from the ArcGIS help menu. Then distances were calculated using the coverage toolbox \"point-distance\" tool. The projection was set to Albers South Asia Conic (metres) projection. This is necessary to avoid the distortion of length inherent with other cartographic projections .The author(s) declare that they have no competing interests.IH carried out the GIS analysis and drafted the manuscript. GH conceived the study, conducted the health analysis and helped to draft the manuscript. KD provided theoretical and conceptual guidance and helped to draft the manuscript. All authors read and approved the final manuscript."}
+{"text": "The multivariate lognormal survival model can be used to determine the relationship of prognostic covariates to two important parameters of malignancy. Cured fraction and median survival time among uncured patients. Analysis with this model revealed that cured fraction is primarily a function of histologic type and node status, while median survival time is primarily a function of age and node status. Patient sex was also related to likelihood of cure, but this association was of marginal significance. The symmetric impact of node status on both cured fraction and median survival time is consistent with known biologic principles. The strongly asymmetric relationships of histologic grade to cured fraction and age to survival time suggest, however, that likelihood of cure and survival time may not operate by identical biologic mechanisms."}
+{"text": "We read with special interest the article by We would like to focus on the potential neuroprotective role of iron against the deleterious effect of lead on the development of ADHD symptoms.Although the mechanisms underlying ADHD remain unclear, both genetic and environmental factors have been implicated. In a recent review on the implication of the dopaminergic system in the etiology of ADHD, Lead in the central nervous system may contribute to dopaminergic dysfunction inducing alteration of dopamine release and dopamine receptor density . MoreoveIn a controlled comparison group study, we  showed tGiven that lead exposure may contribute to ADHD and iron deficiency may exacerbate deleterious effects caused by lead, we recommend systematically seeking for iron deficiency in children with ADHD. We also think that controlled studies assessing the potential effectiveness of iron supplementation on ADHD symptoms should be encouraged. Such studies could aid the understanding of the complex pathophysiology underlying ADHD and provide effective therapeutic strategies for this disorder."}
+{"text": "Pathology observer agreement studies are clearly important in the development of new pathology assessments and in the quality control of those assessments in common use. Setting up such studies, and reporting and interpreting their results requires careful thought and statistical expertise. Investigators are advised to seek collaboration with a statistician before embarking on these studies. Pathology reference panel reviews in multicentre studies are useful for checking eligibility when there is a high level of disagreement on the eligibility criterion between local pathologists and the reference panel members, but good agreement between members of the panel. However, such situations are uncommon."}
+{"text": "PLoS Medicine for initiating a students' forum [We congratulate and acknowledge s' forum  and for PLoS Medicine, which is composed of articles selected by student representatives across the world. The unique integration of student associations with PLoS Medicine, and the journal's policy of not publishing advertisements for drugs or medical devices, will also enlighten students about the influence of drug companies in medical practice and enable students to realize their priorities in poorer countries for the future. Thereby, students may focus their attention on becoming professionals in developing new strategies to combat killer infectious diseases like malaria and tuberculosis, and malnutrition\u2014such as vitamin deficiencies among children and iron deficiency among pregnant women\u2014that are dreaded and very common in poorer countries.It will be really motivating for students from developing countries to actively take part in debate through the Student Forum of"}
+{"text": "There is ample evidence of the efficacy of cytological screening in the prevention of cervical cancer but disagreement on the form which screening programmes should take. Simulation models have been used as a convenient and rapid method of exploring the outcome of different screening policies and of demonstrating the importance and interrelationships of the variables concerned. However, most such models are either too abstract or too simplistic to be of practical value in planning screening programmes. A model is described which reproduces demographic events in a female population  over a 30 year period, and onto this superimposes the natural history of cervical carcinoma, using data derived from published studies. A microsimulation approach--each individual in the population being retained as a unit--allows factors such as disease onset and screening uptake to be dependent upon personal characteristics and past events. Screening can be offered as part of a routine programme, or incidentally--for example during pregnancy or hospital attendance. The model allows quantitative evaluation of the complex patterns of screening that are actually observed and the relative importance of the different components of such screening programmes. Assumptions about natural history can thus be studied."}
+{"text": "Health Assessment (HA) items were introduced in 1999 for Aboriginal and Torres Strait Islander people aged at least 55 years and all Australians aged over 75 years. In 2004 a new item was introduced for HAs among adult Aboriginal and Torres Strait Islander people aged 15\u201354 years. The new item has been applauded as a major policy innovation however this enthusiasm has been tempered with concern about potential barriers to its uptake. In this study we aim to determine whether there are disparities in uptake of HA items for Aboriginal and Torres Strait Islander people compared to other Australians.The analysis was based on Health Insurance Commission data. Indigenous status was ascertained based on the item number used. Logistic regression was used to compare uptake of HA items for older people among Aboriginal and Torres Strait Islander people compared to other Australians. Adjustments were made for dual eligibility. Uptake of the HA items for older people was compared to the uptake of the new item for Aboriginal and Torres Strait Islander people aged 15\u201344 years.Our analyses suggest a significant and persistent disparity in the uptake of items for older patients among Aboriginal and Torres Strait Islander people compared to other Australians. A similar disparity appears to exist in the uptake of the new adult Aboriginal and Torres Strait Islander HA item.Further engagement of primary care providers and the community around the uptake of the new HA items may be required to ensure that the anticipated health benefits eventuate. The introduction of Medical Benefits Scheme (MBS) item numbers to reimburse health assessments (HAs) represented a major shift in support for access to health promotion and preventive care in primary care settings. The HA items provide reimbursement for doctors to evaluate patient's physical, psychological and social function in order to optimise health care and education. HA items were first introduced for older patients in 1999. [The uptake of the HA items and other items introduced as part of the Enhanced Primary Care (EPC) program from 1999\u20132001 has been rigorously evaluated. HA items had the highest uptake of the Enhanced Primary Care items with around 18% of the eligible population using them.  No inforIn May 2004, a new item item 710) was introduced for HAs among adult Aboriginal and Torres Strait Islander people aged 15\u201354 years. ,9 Adult  was intrIn this study we aim to establish whether there are likely to be barriers to the uptake of the new HA item by comparing the uptake of the HA items for older people among Aboriginal and Torres Strait Islander people and the rest of the community. We also examine differences in uptake over time and differences between States and Territories. Finally we compare uptake of the HA items for older people to the uptake of the new items for Aboriginal and Torres Strait Islander people aged 15\u201344 years in the first three quarters after their introduction. It would be expected that structural barriers to the introduction of HAs should have decreased over since 1999 because of the introduction of the HA items. Accordingly it might be expected that the uptake of the new item might be more rapid than the uptake of the items for older Australians.Data on the use of item numbers  by year and by State and Territory were obtained from the Health Insurance Commission statistical reports.  Data on Data on the use of item numbers  in the first three quarters of their introduction was also obtained from the Health Insurance Commission statistical reports.  These daIn addition to the other eligibility requirements, only one claim could be made per person in a 12 month period. Accordingly quarterly and annual data reports should only contain one observation per person. Data are available for smaller geographic areas than State and Territory, such as general practice divisions, however low numbers and a high level of suppressed data made small area analysis problematic.Population estimates for the Aboriginal and Torres Strait Islander population aged at least 55 years and aged 15\u201344 years by State and Territory were obtained for the Australian Bureau of Statistics (ABS) projections from the 2001 census for the years 2001 to 2004.  PopulatiA logistic regression was conducted to analyse differences in the uptake of consulting room  and non-consulting room  HA items according to Indigenous status and year taking into account variation due to State and Territory. Consulting room and non-consulting room items were analysed separately because there is geographic variation in their use which may be potential source of confounding. The dependent variable was coded dichotomously using service use data to estimate the number of people who used the service and population data to estimate the number of people who did not. Year was coded to enable linear trends in uptake to be tested. Indigenous status was coded dichotomously based on whether the items were only available to Aboriginal and Torres Strait Islander people or available to all Australians.The 12.2% of Aboriginal and Torres Strait Islander people aged at least 75 years would be eligible for the general population items as well as the Aboriginal and Torres Strait Islander specific items. All analyses were conducted twice to explore whether dual eligibility could have an impact on the results. The first set of analyses was based on observed service use. Service use among Aboriginal and Torres Strait Islander people would be underestimated in these analyses if people with dual eligibility were using general population items. The data were also analysed assuming that Aboriginal and Torres Strait Islander people aged at least 75 years accessed HAs through general population items at the same rate as the rest of community. These instances of service use were then attributed to Aboriginal and Torres Strait Islander people rather than to other Australians. Service use among Aboriginal and Torres Strait Islander people would be overestimated in these analyses because some of the people using the Aboriginal and Torres Strait Islander items are likely to be aged at least 75 years and therefore would be counted twice. Some overestimation would also be expected to occur because the observed rate of service use among Aboriginal and Torres Strait Islander people aged over 75 years is likely to be less than that for the general population.Differences in rates of consulting room and non-consulting room service use for Aboriginal and Torres Strait Islander people and the rest of the community were calculated for each State and Territory.A logistic regression was conducted to compare the uptake of older all Australian (700), older Aboriginal and Torres Strait Islander (704) and adult Aboriginal and Torres Strait Islander people (710) HA items. The HA item for adult Aboriginal and Torres Strait Islander people (710) was used as the reference category for comparisons. Quarter was coded to enable linear and quadratic trends in uptake to be tested. The dependent variable was coded dichotomously using service use data to estimate the number of people who used the service and population data to estimate the number of people who did not.The result of the logistic regression for use of consulting room HA items  was lower than for the uptake of the general population item (700) but was higher than uptake of the item for older Aboriginal and Torres Strait Islander people  declare that they have no competing interests.Margaret Kelaher conceptualised the paper and conducted the analysis. David Dunt, Ian Anderson and David Thomas collaborated in drafting the paper."}
+{"text": "Three hundred and sixty-nine patients in an MRC study of combination chemotherapy and radiotherapy for small-cell lung cancer of limited extent were asked to complete a Daily Diary Card which enabled an assessment of their quality of life to be made during and after treatment. The information derived from the card suggests that although cytotoxic chemotherapy has an adverse effect upon quality of life, this impairment only affects the first 2 or 3 days following each course of treatment, although there is also a small deterioration which may be associated with the 'nadir' effect of the blood counts about 10 days after each course. These results should assist physicians in counselling patients about the likely effects of treatment. Just over half of the patients (196) were subsequently randomised to either a further six courses of maintenance chemotherapy or no further chemotherapy, and it is also shown that the patients allocated to no maintenance chemotherapy experienced a gradually deteriorating quality of life, as opposed to the brief but more severe adverse effects which occurred following each course in the maintenance chemotherapy group; this supports the hypothesis of a palliative effect in this latter group. The findings demonstrate that the Daily Diary Card is a sensitive instrument capable of yielding useful information."}
+{"text": "Although the need for a method of measuring the quality of life of patients undergoing therapy for cancer has been widely recognised, no adequately evaluated or feasible method has been established. We describe a method in which 31 items were assessed by patient self report using linear analogue scales. Eighteen items inquiring about general health problems were derived from the Sickness Impact Profile, an established method of assessing the effect of health upon behaviour and function. Thirteen items inquiring about major problems associated with breast cancer were derived from clinical experience and the opinions of patients with this disease. Each item of the measurement method (instrument) has been evaluated for content, feasibility, reliability and validity by methods that are widely used in psychometry but less familiar in medicine. It appeared easy to use, acceptable and reliable in these assessment. Validity was evaluated indirectly since no standard measurements of quality of life exist for comparison. Most items appeared valid when compared to alternative measurement methods including the Sickness Impact Profile and evaluation by a physician in a structured interview. The correlations between items in the instrument were analysed by factor analysis and seemed to fit with the clinical features of breast cancer. The method distinguished between clinically distinct groups of patients and detected changes with time. The study illustrates the possible approaches to the scientific evaluation of methods for measuring subjective features of patients lives. This method appears suitable for some purposes to measure quality of life in breast cancer and is intended to be flexible enough to be modified for other diseases. However, further evaluation, development and refinement will be needed before routine clinical application can be recommended."}
+{"text": "In vivo nuclear magnetic resonance 31P spectroscopy was used to demonstrate different patterns of high energy phosphate metabolism in a group of malignant tumours of glial origin. In some of the more malignant tumours a decrease in adenylate energy charge was found. This was associated with a decline in phosphocreatine and an increase in sugar phosphate and inorganic phosphorus."}
+{"text": "A seasonal variation in the month of initial detection of breast cancer has been previously observed in pre-menopausal women, and it has been proposed that this may be due to cyclic changes in tumour growth mediated by the effects of melatonin on ovarian function. To investigate this possibility serum melatonin concentrations have been measured every 2 h for 24 h at the summer and winter solstice in 20 pre-menopausal women with previous breast cancer and nine controls. Twelve women had detected their tumour in winter and eight in summer. Overall melatonin secretion assessed by either amplitude of the nocturnal melatonin pulse or the area under the 24 h melatonin curve (AUC) was not different between breast cancer women or controls. However, the amplitude and AUC fell in winter in breast cancer patients , whereas the winter minus summer values were significantly positive in controls compared with cancer patients. The abnormal fall in winter values in the women with previous breast cancer was confined to the group of women who had been winter detectors  whereas there was no significant seasonal alteration in these measurements in summer detectors. The acrophase of the nocturnal pulse of serum melatonin was significantly advanced in both groups of women with previous breast cancer  with a similar although nonsignificant trend in control women. The abnormal reduction of serum melatonin seen in wintertime in winter detectors of breast cancer could promote tumour growth at this season and so contribute to the decreased survival previously observed in this group compared with summer detectors. The relatively normal seasonal profile of melatonin observed in summer detectors could allow increased ovarian steroidogenesis in spring/summer with a resulting increase in tumour growth and consequent rise in tumour detection rate at this time."}
+{"text": "To our surprise we also found that acute perfusion of low concentrations of lead onto brain slices from control animals resulted in reduction of long-term potentiation, suggesting that the effect is more pharmacologic than developmental. The results of In their article about blood lead and IQ in older children,"}
+{"text": "We examined the ability of primary human tumour cells to secrete diffusible factors capable of stimulating anchorage independent growth of normal rat kidney fibroblast (NRK) cells. Conditioned media (CM) prepared from cells derived from 31/43 patients with adenocarcinoma of the breast, colon, ovary or lung were found to induce growth of NRK cells in soft agar. The ability of the CM to induce anchorage independent growth was enhanced in 25/35 cases by the presence of epidermal growth factor (EGF). The CM did not compete with EGF for binding to the EGF receptor site. CM from cells derived from nonmalignant effusions also supported the growth of NRK cells in soft agar. There was no significant difference in the ability of the CM derived from malignant or normal cells to support NRK colony growth. The ability of primary human tumour cells to clone in soft agar was compared to the ability of these cells to produce diffusible colony stimulating factors for NRK cells. No correlation was observed between the ability of the primary human tumour cells to clone in soft agar and their ability to induce anchorage independent growth of NRK cells. The secretion of substances with TGF like activity may be a property of many types of primary human cells."}
+{"text": "Disabling fatigue is the main illness related reason for prolonged absence from school. Although there are accepted criteria for diagnosing chronic fatigue in adults, it remains uncertain as to how best to define disabling fatigue and Chronic Fatigue Syndrome (CFS) in children and adolescents. In this population-based study, the aim was to identify children who had experienced an episode of disabling fatigue and examine the clinical and demographic differences between those individuals who fulfilled a narrow definition of disabling fatigue and those who fulfilled broader definitions of disabling fatigue.Participants (aged 8\u201317 years) were identified from a population-based twin register. Parent report was used to identify children who had ever experienced a period of disabling fatigue. Standardised telephone interviews were then conducted with the parents of these affected children. Data on clinical and demographic characteristics, including age of onset, gender, days per week affected, hours per day spent resting, absence from school, comorbidity with depression and a global measure of impairment due to the fatigue, were examined. A narrow definition was defined as a minimum of 6 months disabling fatigue plus at least 4 associated symptoms, which is comparable to the operational criteria for CFS in adults. Broader definitions included those with at least 3 months of disabling fatigue and 4 or more of the associated symptoms and those with simply a minimum of 3 months of disabling fatigue. Groups were mutually exclusive.Questionnaires were returned by 1468 families (65% response rate) and telephone interviews were completed on 99 of the 129 participants (77%) who had experienced fatigue. There were no significant differences in demographic and clinical characteristics or levels of impairment between those who fulfilled the narrower definition and those who fulfilled the broader definitions. The only exception was the reported number of days per week that the child was affected by the fatigue. All groups demonstrated evidence of substantial impairment associated with the fatigue.Children and adolescents who do not fulfil the current narrow definition of CFS but do suffer from disabling fatigue show comparable and substantial impairment. In primary care settings, a broader definition of disabling fatigue would improve the identification of impaired children and adolescents who require support. Disabling fatigue in children and adolescents is an important clinical problem given that it is associated with severe functional impairment that has an impact upon the child's education and social development ,2. It isThere have been several attempts to define disabling fatigue as a disorder in adults and perhaps the most accepted is the Center for Disease Control (CDC) definition . This reA number of authors have raised the concern that the current criteria for CFS were designed for use in adults and that there has been relatively little work in assessing how appropriate these criteria are for children and adolescents -14. AlthThe importance that these associated symptoms play in CFS and whether they contribute to defining a homogenous group of individuals with disabling fatigue has been increasingly questioned . As the Given the current discussion about the role of the associated symptoms in CFS in adults, the lack of empirical testing about the appropriateness of the adult CFS criteria in children it seems pertinent to examine whether the clinical and demographic features of children and adolescents differ in those who fulfil CFS criteria and those who fulfil broader criteria for disabling fatigue. Evidence that those individuals with \"adult like CFS\" did differ significantly would give credence to the idea that adult CFS criteria do identify a specific group of fatigued individuals.There is also evidence to suggest that the majority (two thirds) of adults who attend GP clinics regarding disabling fatigue lasting more then 6 months do not fulfil the CDC definition of CFS, but do have substantial associated impairment . Given tIn this paper, we set out to identify children and adolescents with a lifetime ever episode of disabling fatigue in a population-based sample and test whether those who fulfilled a narrow definition were more severely impaired and different in terms of clinical and demographic characteristics than those who only fulfilled broader definitions of chronic disabling fatigue. Specifically, three groups of individuals with disabling fatigue were defined; those who had a similar symptom profile, duration and impairment as the CDC operational criteria for CFS in adults (\"adult like CFS\"), those who also had a similar symptom profile and impairment but whose fatigue, at time of interview, had lasted for a period of between 3\u20136 months disabling fatigue (\"child like CFS\") and those that did not fulfil the symptom profile for operationally defined CFS but who had had more than 3 months disabling fatigue (\"3 months plus disabling fatigue\").Cardiff Study of All Wales and North West England Twins). Previous studies have shown that the register is representative of the local population [Participants were identified from the population based twin register CaStANET . The duration of the fatigue at the time of interview was used to classify the twins into the different categories regardless of whether the fatigue was currently ongoing. The nature and degree of impairment associated with the fatigue was assessed by enquiring about whether the twin needed to rest for at least 1 hour daily, and whether there was interference with school attendance, and/or usual leisure activities and with family and peer relationships. To be classed as suffering from \"disabling fatigue\" the twin was required to need to rest for at least 1 hr daily and for there to be a report of some interference in at least one of these areas.Individuals who did not fulfil the associated symptom requirement but had experienced a period of disabling fatigue of greater than 3 months at the time of interview were classed as suffering from \"three months plus disabling fatigue\". Those who did fulfil the associated symptom requirement but had only experienced a period of between 3\u20136 months of the disabling fatigue at the time of interview were classed as suffering from \"child like CFS\" and those who has experienced a period of more than 6 months disabling fatigue were classed as suffering from \"adult like CFS\"Information was also sought about the age of onset of the fatigue, the number of days per week affected by the fatigue, the number of hours per day that the affected child required to rest/sleep, whether the child or adolescent was absent from school due to the fatigue, and whether they were taken to visit a General Practioner with regard to the fatigue. A global measure of impairment was created by asking whether the fatigue had interfered with the following 4 areas; i) the child's schoolwork, ii) peer relations, iii) family relations and iv) their usual leisure pursuits. The possible response's to these questions were on a discrete adjective scale consisting of \"Not much\", \"A little\" or \"A lot\" and were scored as 0, 1, or 2 respectively. The answers to these questions were then summed to give the overall score which ranged from 0 to 8.Parents were asked whether any diagnoses or explanation for the disabling fatigue had been offered by GP's or hospital specialists, when these had been visited. Their responses were recorded verbatim. This information was then reviewed by one of the authors (PD) who was blind to other information from the data collection and who determined those cases where the diagnosis could entirely explain the chronic fatigue in the twin. These cases were then excluded from further analysis.The second part of the interview consisted of the depression section of the parent version Child and Adolescent Psychiatric Assessment (CAPA) . This isAs it was determined that the most important analysis to undertake was to assess whether those individuals who fulfilled just the broad definitions of disabling fatigue (\"child like CFS\" and \"3 months plus disabling fatigue\") differed from those who fulfilled the narrow definition (\"adult like CFS\") and to reduce multiple testing no comparisons were made between individual classed as suffering from \"child like CFS\" and those who had \"3 months plus disabling fatigue\". Two sets of comparisons were therefore made, the first between those individuals who had \"adult like CFS\" and those who had \"child like CFS\", the second between those individuals who had \"adult like CFS\" and \"3 months plus disabling fatigue\". Independent t-tests and chi-square tests were used as appropriate.However, although the twin register is population based, each twin pair could potentially contributes two observations, and where this is the case the individual twin cannot be classed as statistically independent. Reduced variance due to the correlation between twins' scores can cause high false positive rates . To adjuParents from 1468 families returned questionnaires (65% response rate). There were no significant socio-demographic differences between the responding and non-responding families . The scrTwins classed as suffering from \"3 months plus disabling fatigue\" had an average duration of fatigue of 25.8 months  of which 27% still had ongoing fatigue at the time of interview. Twins classed as suffering from \"adult like CFS\" had an average duration of 23.5 months of fatigue (SEM 6.1) with 41% with ongoing fatigue at the time of interview. Those classed as suffering \"child like CFS\" had by definition between 3\u20136 months disabling fatigue, of which 27% had ongoing fatigue at the time of interview. Table The results of the statistical analysis suggested no significant difference (P > 0.1) between the groups. The only exception to this was the number of days that the child was affected during the episode of fatigue, for which there is a significant difference between individuals who were classed as suffering from \"adult like CFS\" and those classed as suffering from \"child like CFS\" . These analyses were repeated using non-parametric tests, however there was no difference in results.The descriptive statistics suggested that there was greater variability in individuals classed as suffering from \"3 months plus disabling fatigue\" than in individuals in the other two groups, particularly for the age of onset and number days per term absent from school. Less individuals from this group had visited a GP with regard to the fatigue. Although no significant differences or trends were found between individuals classed as suffering from \"3 months plus disabling fatigue\" and those classed as suffering from \"adult like CFS\" for these 3 variables, because of the descriptive statistics, a post hoc set of analyses was also conducted. For the post hoc analyses individuals classed as suffering from \"adult like CFS\" and \"child like CFS\"  were combined into one group and compared to those classed as suffering from \"3 months plus disabling fatigue\". However no significant differences were found between these groups for age of onset, number of days absent from school per term or visits to the GP. As in the previous statistical analyses, these tests were also repeated using non-parametric tests however there was no difference in the pattern of results.The results indicate that the clinical and demographic characteristics and level of impairment of children with narrowly defined disabling fatigue and more broadly defined fatigue are similar. There was no significant difference in gender ratio, the average age of onset or the rate of comorbidity with depression between the groups. Likewise affected young people seemed to spend a similar number of hours resting and/or sleeping, there was parental report of similar levels of global impairment, they were absent for a similar number of days from school during the term in which they were most affected by the fatigue and a similar percentage of individuals were contacting their GP about the fatigue.A lack of significant findings cannot necessarily be interpreted as meaning there is no differences between these groups but there are still a number of implications of these results. Specifically, the results suggest that a longer duration of fatigue and accompanying symptoms are not necessary in defining disabling, impairing fatigue in children and adolescents. Children who present with shorter histories of fatigue and/or in the absence of CFS associated symptoms have high levels of parent reported impairment, both in terms of family and peer relationships and school work. They also appear to be absent for a substantial number of days from school and it causes enough worry for the parents to take the majority of these children and adolescents to a GP. Even though their was a significant difference for the number of days affected by the disabling fatigue between those individuals classed as suffering from \"adult like CFS\" and \"child like CFS\", all groups reported that they were affected by the disabling fatigue for most days of the week.The descriptive statistics also suggested the possibility that individuals within the \"three months plus disabling fatigue group\" may be more heterogeneous, given that there is a relatively large amount of variance in this group in comparison to the other groups. Although this may have nosological implications it does not negate the high level of impairment this group also appears to be experiencing.One important limitation of this study is that the individual's symptoms were identified by telephone interview rather than medical examination. Although every effort was made to exclude individuals who may have had an alternative diagnosis that would explain the fatigue this does not guarantee that if an in depth medical assessment were undertaken with these individuals that a number would not be classed as fulfilling the CDC definition of CFS. This may in some way explain why over half individuals in this population based sample showed a similar symptom profile to the CDC criteria for CFS whereas in the adult population only one third were categorised as fulfilling this criteria , althougA further possible limitation is that parent report of disabling fatigue was used to identify individuals for further data collection and the analysis is based on information from parental interview only. There are often low levels of agreement between parent and child/adolescent report of behavioural/psychiatric symptoms  and therThese findings have clinical significance in that they imply episodes of fatigue in children and adolescents which last at least 3 months warrant investigation regardless of whether or not a diagnosis of CFS can be made. This is because the degree of impairment is substantial in terms of interference with usual activities, family and peer relationships, school absence and school work, and the impairment does not appear to differ from the level of impairment found in more narrowly defined disabling fatigue.There was no indication that the group of children with shorter periods of fatigue differed on a number of associated characteristics  or in terms of impairment from the group of children who had a symptom profile similar to the CDC criteria for CFS. Although this does not prove that there is no differences between individuals in these groups it does indicate that within a primary care setting it may be appropriate to consider a broader definition of disabling fatigue in children for clinical and research purposes.The author(s) declare that they have no competing interests.TF interviewed the families, performed the statistical analysis and drafted the manuscript. PM provided clinical advice when conducting the analysis and helped drafted the manuscript. AT participated in the design and coordination of the study. AF conceived of the study, and participated in its design and coordination.The pre-publication history for this paper can be accessed here:"}
+{"text": "Epidemiological and environmental surveys in the Cappadocian region of Turkey have linked the high incidence of pleural and peritoneal mesothelioma in the occupants of some villages with the zeolite fibres released from the locally occurring volcanic tuff. In view of the low ambient fibre concentrations and the extraordinary incidence of mesothelioma a study to test the hypothesis of high biological activity for the zeolite fibres was required. Experimental studies using both intrapleural inoculation and inhalation techniques have been undertaken with the erionite from this region and from Oregon in the United States. Additionally a non-fibrous zeolite from Japan and a synthetic non-fibrous zeolite of similar chemical composition to erionite have been included in the experiments. In these studies the samples from Oregon and Turkey produced a very high incidence of tumours. All the rats inoculated intrapleurally with Oregon erionite and almost all those inoculated with the Turkish fibre died with a mesothelioma. Inhalation of the Oregon erionite induced a similar effect. No other dusts we have investigated have produced this high incidence of tumours particularly following inhalation. These studies demonstrate that we now have a valuable new fibre for experimental study and a possible hazard to man in regions other then Turkey."}
+{"text": "The psychometric properties of a method of measuring the quality of life of cancer patients based on multiple linear analogue scales have been assessed in a group of 294 patients with breast cancer attending one clinical unit. The method was found to be readily managed by patients although a small number of scales presented difficulties of understanding to patients and difficulties of analysis. The scales distinguished readily between patients of different disease and treatment status. Factor analysis revealed a 5 factor structure which we interpret as relating to physical activities of everyday living, emotional disturbance, alimentary disturbances, appearance and cosmetic problems and a fifth factor which is more difficult to interpret and includes impairment of speech, writing and concentration. We feel the essential factors determining quality of life in cancer patients have been demonstrated in this and our earlier studies and there is now a substantial level of agreement in the factors that have been identified by groups taking quite different approaches. The major factors determining quality of life in cancer patients are now known and should be assessed in clinical research and clinical trials. The method by which they should be assessed is not as yet so clear."}
+{"text": "Molecular monitoring by the polymerase chain reaction was used to detect and follow minimal disease in working formulation category B and C on non-Hodgkin's lymphoma. Rearrangement of the bcl-2 gene served as the target for gene amplification. Thirty patients were studied. Bone marrow histology was compared to PCR analysis of bone marrow aspirate and blood. PCR upstaged disease status in approximately 50% of patients. Results are shown from a patient whose disease was followed with PCR during chemotherapy from initial remission to relapse. We conclude that PCR of bone marrow and blood can be used to upstage disease status in low grade lymphoma and PCR of blood may be used to monitor response to treatment with obvious patient benefit. The general approach of molecular monitoring provides a means for appraising therapies in the setting of subclinical disease."}
+{"text": "We evaluated a new ultrasound microhandpiece (Dissectron PenstyleWe used under magnifying lenses the ultrasound microhandpiece to decalcify 30 explanted aortic valves. In the cases with embedded calcifications the thin top of the probe could be introduced into the thickness of the leaflet preserving covering layers.The leaflets were totally decalcified and flexible, and surrounding structures were preserved as assessed by histological examination.This new approach of ultrasonic aortic valve decalcification gives good in vitro results which allow to consider a clinical evaluation of this procedure. This probe is more handy and more precise than the previous ones. Therefore the reintroduction of valve decalcification by ultrasound is envisageable.The aortic valve debridement by ultrasound in degenerative-calcific aortic stenosis appeared to be an alternative treatment for severe calcified aortic stenosis , but was\u00ae Penstyle  used in neuro and general surgery but never used in cardiac surgery. This ultrasonic system consists of a control console with a handheld aspirator that contains a magnetostrictive transducer which converts electrical energy into mechanical motion (piezoelectric technology). The handpiece  to perform the process and the operating surgeon determined the adequacy of decalcification by inspection and palpation of the leaflets. A preliminary study on 10 other valves had allowed us to familiarise with the device and to adjust the settings. The completeness of the leaflet decalcification was studied by palpation and by histopathological examination with the help of a nonparametric grading system (from 1+ to 4+).We used ultrasonic energy to decalcify 30 aortic human tricuspid valves after they had been surgically removed during an aortic valve replacement. The valves had not been selected and were severely calcified in accordance with the necessity of the valve replacement. Ultrasonic decalcification was performed with the Dissectrone Figure  has a ho\u00ae handpiece was very ergonomic. The calcium was disintegrated in about 15 minutes in all the 30 cases. At the end of the process all the leaflets were observed as flexible again by palpation assessment. In 26 cases leaflets were totally decalcified (4+)  we performed the decalcification by introducing the probe through the aortic surface and directing it inside the thickness of the valve in contact with the calcification  declare that they have no competing interests.SA did all the research and wrote the paper.EV had been involved in the research.LC had been involved in the anatomopathology examination.FF had been involved in the analysis of the data.OJ had been involved in the final approval of the version to be published."}
+{"text": "The effect of adriamycin on human and mouse CFUGM was examined at concentrations and times suggested by plasma clearance data derived from the results of a number of published studies. Our results suggest that the high concentrations of drug present in the plasma for short periods of time following infusion are only weakly cytotoxic towards the CFUGM when incubated for similar times. In contrast, there was a considerably greater cytotoxic effect when the drug was examined at low concentrations for periods similar to those described for the terminal phase of adriamycin clearance. The principal metabolite, adriamycinol, was poorly cytotoxic."}
+{"text": "We have assessed the effects of clodronate  in 17 episodes of hypercalcaemia and osteolysis due to carcinoma. Clodronate reduced serum calcium in 14 episodes and bone resorption in all patients. These remained suppressed for the duration of treatment, but recurred promptly when treatment was stopped. Clodronate may be a useful measure for controlling hypercalcaemia and osteolysis in patients with carcinoma."}
+{"text": "With increased emphasis being placed on the importance of environmental health comes the need for an expanded variety of environmental health care practitioners. Nursing is one of several professions that are augmenting and advancing the capabilities of their practitioners to meet this need. Now the Community Outreach and Education Program (COEP) of the University of New Mexico\u2019s Center for Environmental Health Sciences has partnered with the New Mexico Environment Department to create an environmental health nursing internship as a component of its outreach program.In cooperation with the university College of Nursing, the partners recruit nursing students who are interested in implementing environmental health care initiatives in the surrounding community. For four years, the program has taken nursing students beyond the traditional curriculum and shown them firsthand how interaction with environmental factors affects human health. The program also gives students valuable experience in taking measures to abate hazardous exposures in communities.The interns are currently working on a number of projects that will affect different community members. They are helping to develop surveys and compiling data for a project investigating uranium exposure and subsequent kidney damage among the Navajo Nation, whose members live near and work in uranium mines. They are gathering and assembling materials for a community education and survey project on mercury in surface waters and other environmental health concerns among the Cheyenne River Sioux Tribe. They are helping COEP staff write and field-test an integrated environmental health curriculum on diabetes for middle school students. And in a fourth project, they are helping to develop a best-practices manual for applying farm waste fertilizer to croplands in a way that minimizes human exposure to aerosolized waste.The local ties of some of the nursing interns have enhanced the program\u2019s role as an effective community advocate. Intern Krystyn Yepa is a Native American from the Pueblo of Jemez who became interested in environmental health nursing because she wanted to understand some of the health effects in her tribe resulting from exposure to different pollutants in the environment. \u201cLearning about the different environmental health problems that exist in New Mexico has given me the willpower to finish nursing school to ultimately achieve my goal of improving the health and lifestyles of my people by placing importance on the environment,\u201d she says.Yepa explains further, \u201cAs a Native American, I was raised to respect and appreciate the environment, and working at the COEP has only strengthened my values related to the environment.\u201d She also credits the internship with teaching her important assessment tools that lay emphasis on the environment when completing a health history on patients, something a traditional nursing internship would not likely provide.\u201cThe nursing interns have been an incredible asset to our COEP,\u201d says staff member Stefani Hines. \u201cIt is a mutually beneficial situation on many levels\u2014the student nurses gather valuable real-world experiences in environmental health; the nursing school has access to additional, unique placements for their students; we have additional support for projects, which helps make them better; and the communities we work with benefit from the students\u2019 efforts as well.\u201dDedicated, enthusiastic environmental health nursing interns will only continue to play an important role in advancing the COEP mission. One project currently in development will help community members get involved in city and county zoning processes, which will both encourage a healthy community mindset and minimize exposures to pollutants."}
+{"text": "Rat mammary tumour cells were grafted to parietal bones as an experimental model to study the nature of bone resorption around metastatic carcinomas in the skeleton. After periods of growth of from 6 to 56 days bones and tumours were removed and embedded in epoxy resin. The appearances were compared with those found when whole parathyroid glands were grafted in similar positions. Tumours were evident in all animals at the time of death and some were palpable five days after grafting. In 15 of the 21 animals with tumour, osteoclasts and resorption were found, and in only two of these were the tumour cells not separated from the bone surfaces. In 6 animals killed between 6 and 12 days after grafting there was new bone formation without resorption. There were osteoclasts and resorption under the grafted parathyroid glands which were always separated from the resorbing cells by fibrous tissue. The appearances of the bone surfaces under the tumours and the parathyroid glands suggested that the resorption in both situations was similar, was brought about by the secretion of a locally active agent and mediated by osteoclasts. This is further support for the role of osteoclasts in bone resorption around metastatic carcinomas."}
+{"text": "The outcome of treatment by age and socio-economic status was examined for 1,588 women with invasive cancer of cervix resident in the West of Scotland and diagnosed between 1980 and 1987. There was no difference in prognosis according to either variable once analysis was controlled for stage at presentation, treatment type and tumour grade. Tumour histology, date of treatment and health board of residence had no significant effect on survival independent of other variables. A strong correlation was found between socio-economic status and the incidence of cervical cancer in the West of Scotland. Women aged 45 and over and living in deprived areas were more likely to present with later stage tumours and to survive less well than younger patients from the more affluent parts of the region. Any additional resources which may be made available for cervical cancer screening should be directed more effectively towards those most at risk."}
+{"text": "Mothers of a population-based series of young adults with bone and soft tissue sarcoma were traced and their cancer risks estimated. No overall excess of cancers compared with expected numbers calculated from population rates was seen but mothers of patients with synovial sarcoma had significantly more cancers than expected and this was accounted for mainly by an excess of breast cancer. In addition there were strong indications that a proportion of cases were members of families with inherited cancer-prone syndromes, in particular with neurofibromatosis or with the Li Fraumeni cancer family syndrome."}
+{"text": "The hepatic perfusion index, the ratio of hepatic arterial to total liver blood flow, was measured in 50 consecutive patients with colorectal cancer using radiolabelled colloid with high administered activity. In patients with proven liver metastases the diagnostic sensitivity of the HPI was 96% and the predictive value of a negative test was 92%. Dynamic hepatic scintigraphy is of value in the management of patients with colorectal cancer."}
+{"text": "In the economic evaluation section of the protocol , we statA further issue is that the Office of Scottish Health Statistics does not provide cost estimates for different types of delivery. Although costs in Scotland have been estimated using data collected in the early 1990s , we consThe pre-publication history for this paper can be accessed here:"}
+{"text": "Ninety-two consecutive adult patients admitted with acute life-threatening complications of haematological malignancy were studied to determine long term outcome. The quality of life was evaluated in seven long term survivors who are currently alive more than 1 year after hospital discharge using three validated methods: the Nottingham Health Profile, the Hospital Anxiety and Depression Scale and the Perceived Quality of Life Scale. Patients were also asked whether they had returned to work, whether their daily activities were limited and whether they would be willing to undergo intensive care again under the same circumstances. The in-hospital mortality rate was 77%. Median duration of long term survival was 23 months (range 6 weeks to 8 years). Long term survival did not appear to be related to either the aetiology or the severity of the acute illness, but seemed to be determined solely by the nature and progress of the underlying malignancy. The quality of life of six of the seven long term survivors is good, while that of the other is acceptable. None of the patients reported any increased limitation of their daily activities, five had returned to full time employment and all seven stated that they would be willing to undergo intensive care again under the same circumstances."}
+{"text": "The inhibition of 3H-thymidine incorporation into the DNA of mitogen-stimulated lymphocytes from patients with chronic lymphocytic leukaemia by chlorambucil was measured in vitro and the results related to clinical drug resistance. The assay proved to be both sensitive and specific showing a clear separation of those patients with responsive disease from those with disease resistant to treatment. There was evidence of primary drug resistance in untreated patients. In almost all patients who received treatment this led to increasing resistance to chlorambucil in vitro. The assay is predictive of clinical responsiveness and provides a potential means whereby new therapeutic agents and treatment modifiers may be investigated."}
+{"text": "Since the publication of our article on counterfeit artesunate in June 2006 , furtherIn addition, we would like to bring readers' attention to the newspaper reports of counterfeit artesunate and dihydroartemisinin seized from ladies' handbags at Lagos airport ."}
+{"text": "Improving the quality of health care requires a range of evidence-based activities. Audit and feedback is commonly used as a quality improvement tool in the UK National Health Service [NHS]. We set out to assess whether current guidance and systematic review evidence can sufficiently inform practical decisions about how to use audit and feedback to improve quality of care.We selected an important chronic disease encountered in primary care: diabetes mellitus. We identified recommendations from National Institute for Clinical Excellence (NICE) guidance on conducting audit and generated questions which would be relevant to any attempt to operationalise audit and feedback in a healthcare service setting. We explored the extent to which a systematic review of audit and feedback could provide practical guidance about whether audit and feedback should be used to improve quality of diabetes care and, if so, how audit and feedback could be optimised.National guidance suggests the importance of securing the right organisational conditions and processes. Review evidence suggests that audit and feedback can be effective in changing healthcare professional practice. However, the available evidence says relatively little about the detail of how to use audit and feedback most efficiently.Audit and feedback will continue to be an unreliable approach to quality improvement until we learn how and when it works best. Conceptualising audit and feedback within a theoretical framework offers a way forward. A range of strategies exist to promote the uptake of clinical research findings into the routine care of patients. They seek to change the behaviour of healthcare professionals and thereby improve the quality of patient care Table . For eacAll healthcare systems are concerned with improving the quality of care that they deliver as demonstrated by their establishment of structures  and high profile reports. Across cThe strategies in Table While rising prevalence and changing patterns of service delivery diabetes mellitus increasingly contributes to the primary care workload  and therThe UK NHS has produced a framework and set of measurable criteria by which to judge the quality of care for patients with diabetes mellitus. The National Service Framework (NSF) for Diabetes was launched in 2002. It suggePrinciples for Best Practice in Clinical Audit [We informed the study with two definitions of audit and feedback Table . The sysal Audit  which ofWe explored the extent to which a systematic review of audit and feedback could provide practical guidance about whether audit and feedback should be used to improve quality of diabetes care and, if so, how audit and feedback could be optimised. Based upon discussions with those responsible for conducting audit and feedback at a local level as well as our own experiences of doing so, we identified several questions which would be relevant to any attempt to operationalise audit and feedback in a healthcare service setting.\u2022 Does audit and feedback work for this condition and setting, specifically improving the care of patients with a chronic disease \u2013 diabetes mellitus \u2013 in primary care?\u2022 Does it work equally across all dimensions of care \u2013 from simple recording of cardiovascular risk factors to more complex areas of care such as glycaemic control? The latter requires a greater number of actions to achieve which include measuring blood glucose levels, reviewing the patient, checking compliance with drug and dietary therapies and checking patients' understanding of the condition.\u2022 How should it be prepared? Should data be comparative and if so, what should the comparator group be? Should data be anonymised?\u2022 How intensive should feedback be? Intuitively, providing more and personalised feedback on a recurrent and regular basis should have a greater impact on practice than a one-off report of (say) PCT-level aggregated data. However, it is uncertain whether the extra time and costs of ongoing data collection and preparing more frequent feedback would be matched by additional benefits.\u2022 How should it be delivered \u2013 by post or by a messenger in person? And if by a messenger who should this be? Professionals might be more convinced by a message delivered by a colleague with a recognised interest in diabetes care rather than a non-clinical facilitator.\u2022 What activities, if any, should accompany feedback? The likely costs and possible benefits of (say) educational meetings or outreach visits need to be weighed up against providing feedback via paper or computerised formats alone.\u2022 What should be done about the poorest performers detected by the audit? Targeting such practices may help close the gap between the poorest and best performers. Alternatively, spreading effort to improve quality more equally amongst all practices may improve average performance for the whole PCT.We identified a systematic review of audit and feedback that identified and appraised 85 randomised trial.[\u2022 audit and feedback can improve professional practice, although the effects are generally small to moderate\u2022 effectiveness varies substantially among different studies\u2022 variation may be related to different methods of providing feedback or contextual factors, such as targeted behaviours and professionalsThe review identified only five direct (head-to-head) comparisons of different methods of providing feedback Table . One comThe review also evaluated 14 direct comparisons of audit and feedback alone compared to audit and feedback combined with other interventions (multifaceted interventions). There was no evidence that multifaceted interventions worked better than audit and feedback alone. A multivariate analysis explored potential causes of heterogeneity in the results . Only low baseline compliance was associated with greater effect sizes for multifaceted interventions. There was no evidence of larger effects with increasing intensity of feedback.Fifteen studies relate to chronic disease management . Just over half of comparisons indicated that audit and feedback was more effective than doing nothing Table . Using mFour studies evaluated audit and feedback in diabetes care, three set in primary care. Two comparisons addressed one of our key questions (Does audit and feedback work for this condition and setting?) and showed that audit and feedback, with or without other interventions, was more effective than doing nothing.,13 A UK Two studies partially addressed three of our key questions about how to conduct audit and feedback . In US secondary care, there was no difference between continuing feedback against withdrawal of feedback in the accuracy of capillary blood glucose monitoring. An AustrThe review evidence was of limited use in informing the operationalisation of evidence based audit and feedback. A number of issues contributed to this \u2013 the heterogeneity of the studies in the overall review, the problems of interpreting sub-groups of studies within the larger review, and the lack of direct evidence (particularly from head-to-head comparisons) to answer key questions.It is unclear how to use the review to extract generalisable lessons about how audit and feedback achieves its effects. For example, individual level feedback could reasonably be assumed to be more personally relevant and persuasive and thus more effective than feedback at a group level; there are no such direct comparisons available. Four out of 10 studies using individual feedback for chronic disease management reported no effect whilst both studies using group feedback reported positive effects. Therefore group feedback might be more effective than individual feedback, possibly by promoting peer pressure, consensus and subsequent action. Unfortunately this must all remain conjecture given the paucity of data to test different hypotheses about the causal mechanisms that make audit and feedback work.a priori, reasons as to why these studies should be examined separately from others in the review.Based upon a limited number of comparisons, audit and feedback appears to work better for diabetes than for other conditions. It is unclear whether this is because there is something intrinsically different about diabetes (or the audit methods used in diabetes) compared to other conditions, or whether this is an unreliable sub-group analysis of four studies selected from the 85 available. It is hard to have confidence in the findings of the diabetes studies in the absence of good, preferably Similar pitfalls exist in judging the relative effectiveness of different feedback methods. This is mainly because of the limited number of head-to-head comparisons comparing audit and feedback alone against combined interventions or variations in providing feedback. Across all studies, audit and feedback alone appears similarly effective to multifaceted strategies. However, the lack of difference in effect size could have occurred because multifaceted strategies were used in situations where investigators judged them necessary to overcome greater obstacles to improving care. In the absence of primary studies, the review cannot address some of the key questions such as whether intensive feedback would improve more complex outcomes (gylcaemic control) at an acceptable cost.Mapped back onto the principles for good clinical audit, the evidence only supports doing audit if there is low baseline compliance Table . This evThe issues of external validity of randomised controlled trials  have been aired in the context of clinical studies.,16. HoweA rational approach to this situation is to develop a conceptual framework within which to describe common elements of settings, individuals, targeted behaviours and interventions -20. ThisReview evidence was of limited use in informing the operationalisation of evidence based audit and feedback. This is mainly because of the heterogeneity of the studies in the overall review, the problems of interpreting sub-groups of studies within the larger review, and the lack of head-to-head comparisons to answer key questions. Audit and feedback will continue to be an unreliable approach to quality improvement until we learn how and when it works best. Conceptualising audit and feedback within a theoretical framework offers a way forward.UK NHS United Kingdom National Health ServiceNSF National Service FrameworkGP General PractitionerNICE National Institute for Clinical ExcellenceHbA1c Glycosylated haemoglobinPCT Primary Care TrustThe author(s) declare that they have no competing interests.Principles for Best Practice in Clinical Audit. ME suggested the idea for this paper. RF wrote the first draft and is guarantor. All other authors helped draft the manuscript and have approved the final manuscript.GJ and JY undertook the Cochrane Review of audit and feedback. RB co-authored The pre-publication history for this paper can be accessed here:"}
+{"text": "This data article along with original article provide the basic data required for ideal characterization of BCP and other bioceramics in an attempt to provide basic standardized protocols for future studies.The data presented in this article are related to the research article entitled \u201cBiphasic calcium phosphates bioceramics (HA/TCP): Concept, physicochemical properties and the impact of standardization of study protocols in biomaterials research\u201d  Specifications TableValue of the data:\u2022To provide basic standard data for proper characterization of BCP and other bone substitutes.\u2022To encourage researchers to standardize their study protocols.\u2022To help in reducing the discrepancies among the findings of future studies.1This paper presents the required data and examples on proper characterization of BCP. This can be applied to other similar materials in the field of bone tissue engineering 2An electronic data base search on PubMed was performed to recruit related literature on BCP including data on basic biomaterials science, synthesis and characterization. Interested readers are referred to full text of this review paper for comprehensive review and recommendations"}
+{"text": "As a team of workforce analysts and academics with an interest in workforce planning, we are aware that the data available to support primary care workforce planning are disorganised and overwhelming. This makes it difficult for General Practice to extract meaningful and relevant information. We deliver workforce planning workshops across England. Participants at our workshops regularly express their frustration with the quantity of information they are required to produce and the quality of information they receive from other parts of the system. We are dismayed at what we sense to be growing cynicism with data generation and information analysis and are interested in stimulating a conversation about what data matter and how primary care teams can extract data that are useful.Bottom up ownership of information and local benchmarking is needed to underpin workforce planning in primary care.As with other parts of England, primary care in London faces considerable challenges in terms of recruiting and retaining staff. It is highly dependent upon locum, interim and agency staff. In London the challenge is less about recruitment of staff and more about retaining experienced, qualified staff. As well In 2015 Health Education England London teams (HEE) commissioned the University of West London to deliver training for CCG and practice staff. One element of this support was the development of CCG regional profiles so that the eight CCGs of North West London (NWL) and the 12 in North Central and East London (NCEL) could benchmark workforce performance against one another and against average performance in England. We used one of the largest English healthcare databases available, the NHS benchmarking database, for this exercise. The database (available from the corresponding author) combines 1400 workforce planning and development data sets from around 20 sources into one easily accessible location. Organisations, localities and regions can use the database to benchmark their performance against best practice organisations . This database has been used extensively in secondary care settings for over a decade. It clearly predicted one failing Trust\u2019s demise in 2008 (though results were ignored) and has consistently demonstrated the link between an investment in staffing  and mortality rates.Is Primary Care service-quality related to staffing? How does my practice compare with \u2018best practice sites? The answers to these lie in Figure We used this to help London CCGs and GP practices to consider the questions: Is patient satisfaction the best differentiating variable?Is London so different that a national average becomes unhelpful?Figure Demonstrate many system relationships; for example the relationship between failing primary care services and ED admissions: - important evidence for a primary care community arguing for additional resources or different ways of working.Scrutinise and defend variation: The Carter report  states tTake ownership of decision-making at a local level. Primary care staff attending our workshops report that much of the data they are sent is used not for service and systems improvement but rather for micro management of performance. We concur with the views of Nigel Edwards of the Nuffield Trust that plans \u2018to impose benchmarks from the top down risks turning into another round of the kneejerk centralisation that has served the NHS badly in recent years\u2019. Open resBetter use of openly available strategic datasets will enable primary care to:t.houston@nhs.netThe Workforce Transformation team at HEE are developing a free, user-friendly interface for the NHS Benchmarking database to enable healthcare providers across the capital to benchmark what matters most to them. The trial version of this interface is available from Tom Houston, Healthy London Partnership at This will be the first of a series of brief papers and in future editions we will identify where London staff really do provide \u2018best practice\u2019 care\u00a0\u2026\u00a0and where there is room for improvement.All three authors deliver commercial workforce planning education and training courses commissioned by HEE for primary care organisations working across West, North, Central and East London. Keith Hurst develops and maintains the NHS Benchmarking Database and this tool is used to support a range of training and education programmes delivered by the University of West LondonNo potential conflict of interest was reported by the authors."}
+{"text": "The focus of this research was to present a data article for analyzing the cost of displacing a drilling fluid during the drilling operation. The cost of conventional Spud, KCl and Pseudo Oil base (POBM) muds used in drilling oil and gas wells are compared with that of a Reversible Invert Emulsion Mud. The cost analysis is limited to three sections for optimum and effective Comparison. To optimize drilling operations, it is important that we specify the yardstick by which drilling performance is measured. The most relevant yardstick is the cost per foot drilled. The data have shown that the prices for drilling mud systems are a function of the mud system formulation cost for that particular mud weight and maintenance per day. These costs for different mud systems and depend on the base fluid. The Reversible invert emulsion drilling fluid, eliminates the cost acquired in displacing Pseudo Oil Based mud (POBM) from the well, possible formation damage (permeability impairment) resulting from the use of viscous pill in displacing the POBM from the wellbore, and also eliminates the risk of taking a kick during mud change-over. With this reversible mud system, the costs of special fluids that are rarely applied for the well-completion purpose (cleaning of thick mud filter cake) may be reduced to the barest minimum. Specifications TableValue of the data\u2022These data describe the volume and material estimate needed for each hole section and the type of mud necessary to achieve smooth drilling operation in each hole section.\u2022The data showed the cost, the quantity of materials and sequence at which these materials are applied to achieve optimum displacement.\u2022These data can be used to study the economic analysis of new mud systems proposed by researchers and also help to compare if these mud systems are economically viable.\u2022These data can also be used to analyze and predict prices and/or build cost for drilling mud systems for a certain mud weight and daily maintenance expense.\u2022The data reveals that cost varies according to the different mud types and are dependent on the base fluid phase.1The type of drilling fluid systems and the volume of drilling fluid needed for each hole section is summarized in The volume of drilling fluids needed for three sections was estimated and presented in The cost for drilling a typical well may be constant when drilled without any instability case. Instability during a drilling operation in wells can quickly escalate cost dramatically The build cost for a drilling fluid system is the price for the individual components and mixing requirements. The total build cost includes purchasing the initial drilling systems materials and the expenses involved with conditioning the drilling mud system in the well as it is drilled.2The water-based mud in the wellbore from the previous hole section is displaced and replaced with POBM drilling fluid. The first step is to lower the viscosity and gel strength of the water-based mud. The suggested method is to dilute the fluid with water to obtain a low rheology After drilling and prior to running completion hardware, the fluid in the borehole is often displaced to a water-based completion fluid, usually a solution of various salts. During this displacement, chemical washes and viscous spacers are placed in the solution to make surfaces water- wet, while helping to remove oil mud and residual oil-wet material from the borehole The viscosity and gel strengths of the POBM are low prior to displacement. The suggested method was to dilute the fluid with premix, base fluid or a thinner to obtain the low rheology if this is necessary. The optimal thinning of the POBM fluid will dictate how easy the mud will be displaced out of the hole.ID = Hole Internal Diameter, inchD = Hole Depth, ftThe volume of drilling fluid needed for each section was obtained using the equation below:Eqs. sxs = Sackslb/bbl = Pound per barrelbbl = BarrelEq."}
+{"text": "Tumor metastasis is challenged by its resistance to microenvironmental stress infringed during escape from the primary tumor and the colonization of a foreign secondary tissue. Because of its great metastatic potential and its strong resistance to anticancer drugs, pancreatic cancer is regarded as a paradigm of the adaptation of cancer cells to microenvironmental stress. Thus, to understand how pancreatic cancer cells adapt to the different endogenous and therapy-related stresses is crucial for understanding their etiology and for the development of new efficient anticancer strategies. This review summarizes the multiple functions accomplished by one major factor of pancreatic cancer cell stress response, the stress protein p8."}
+{"text": "The aim of this review is to highlight emerging trends about Chinese people and gambling addiction over the last 15 years, and to provide a discourse on the potential link between gambling and Chinese culture and history. The authors reported on the phenomenon of gambling among Chinese people using relevant research studies and reports and traditional Chinese literature. Chinese people have elevated levels of gambling addiction compared to their Western counterparts. These elevated rates are coupled with the rapid expansion of gambling venues within the Pan-Pacific region. While there is an accumulated body of research on Chinese and gambling, a systematic cultural analysis of Chinese gambling is still under development. We undertook a brief comparison between two ancient civilizations, China and Rome, in order to gain better understanding about gambling among Chinese people. To effectively deal with gambling addictions among Chinese people, it is imperative to develop culturally responsive interventions."}
+{"text": "Although the role of intense psychological distress in psychopathology has been recognized for centuries, the metaphorical use of the word \u2018trauma\u2019 to indicate intense psychological distress only became popular in the midst of the industrial revolution  may point to innovative strategies for the treatment of trauma-related psychopathology and medical conditions (Lanius & Olff,"}
+{"text": "Over recent decades, the numerous coronary revascularisation procedures performed either by percutaneous coronary intervention (PCI), or coronary bypass surgery has led to an increasing number of patients who are no longer eligible for additional revascularisation procedures. This number of patients is expected to rise even further in view of an increase in life expectancy in patients with coronary artery disease.In a recent issue of the Netherlands Heart Journal, the investigators from the University Medical Center Utrecht report interesting findings on the use of a\u00a0coronary sinus device in patients with refractory angina in whom there were no options for conventional revascularisation procedures . This deThe principle of improving myocardial perfusion by elevating coronary venous pressure was introduced as early as 1954 when the coronary sinus was partially ligated in patients with angina pectoris . The pubThe implantation of the balloon expandable stent into the coronary sinus creates a\u00a0focal stenosis and, as a\u00a0result, an increase in coronary venous pressure. It is remarkable that none of the aforementioned clinical studies verified this supposed increase in venous pressure by using either fluid-filled catheters or pressure guidewires. There are several postulated mechanisms that may explain the improvement in angina status, although they have not been proven in the clinical setting. First, the increase in venous pressure may lead to the enhancement of collateral blood flow to ischaemic regions , 5. AddiCoronary back pressure can also be increased intermittently and this modification of the technique has recently been tested in the setting of reperfusion in primary PCI . It has The authors are to be commended for conducting this trial and for their tenacity in using this device in patients with refractory angina. Previous clinical trials and the promising results of the present study encourage further exploration of this novel mode of therapy for the increasing number of patients who are not eligible for current revascularisation therapies. The relative simplicity of the implantation techniques and their documented efficacy and safety warrants further evaluation in larger sized trials to verify these interesting findings. We must await the long-term clinical outcome of the patients enrolled in the trials, including their safety, to show if implantation of this coronary sinus device adds to the armamentarium of the coronary interventionalist for the treatment of patients with refractory angina who are no longer candidates for current coronary revascularisation procedures."}
+{"text": "An elective course for PhD students in cardiovascular and respiratory sciences was modeled and developed by a team of faculty at the Aga Khan University, Karachi. This course dealt with the multidisciplinary integrated concepts of heart, circulation and respiration components of human physiology. The understanding of basic science concepts enables students to better understand problems to derive solutions. Only those who understand how the healthy human body functions can recognize changes in diseased body to interpret the investigation rightly for an effective treatment. This forms the basis of dialectical imagination and experimentation.This was a unique course of its kind where the concept of \u2018lecture debate\u2019 was introduced. Students and faculty indulged in mutual learning and difficult concepts were dealt with thought provoking visual cues e.g. elucidating data in the form of graphs and tables instead of textual slides.The student\u2019s feedback was encouraging. They remained highly motivated and committed throughout this course as being active team learners. They took active part in session discussions, execution of experimental work and tutorials. Their status of pre-knowledge enabled them to understand problems in light of application of currently grasped multidisciplinary integrated concepts. This offered a unique opportunity of turning teaching into learning mode.Students at the end of the course were found to have developed the curiosity for learning and were able to think in response to challenges. This was evidenced by critical analysis of concepts through experimentation.The following concepts of cardiovascular and respiratory system forms the content of this course while integrating morphology, biochemistry and physiology. This integration forms the basis of physiological sciences.*Cardiac Mechanics*Cardiac Cycle*Cardiac Rhythm*Cardiac Electricity*Hemodynamics*Micro-circulation*CVS Control System*Pulmonary Mechanics*Gas Exchange*Gas Transport*Respiratory Control SystemCardiovascular and respiratory concepts were continuously developed in interactive learning sessions. This was supplemented with experimental lectures and tutorials. The course was of 12 weeks duration with two lectures, one tutorial and one laboratory work per week. This was supplemented with take home assignments of reading articles associated with the topics. The analysis of current scientific literature on the topics covered was critically debated in the context of premises and conclusion. This new model enabled the students to transform their imagination into experimentation to test the correlation between the two variables in order to arrive at an evidence based conclusion. Such a strategy of experimentation based learning could be possible through a horizontal enabling environment. Thus, this enabled to unfold the creative energy of students.The assessment was based on the following distribution of marks. It included 30% Continuous assessment (CAT), 20% student presentation and 50% formal written examination. CAT was based on the students\u2019 performance in the lecture debate and laboratory sessions. Student presentations during tutorial sessions were peer-reviewed by faculty involved in the module. Comprehensive written examination contained Best Choice and Extended Matching Questions and short integrated essay questions which included analysis and interpretations of data.This course was a unique model of how active thinking driven by curiosity for knowledge enhanced the learning experience of students. How thinking oscillates between a group and an individual and how critique enhances learning. One is winged with the ability of going back and forth with imagination and experimentation to be enlightened and nurture the learning curve of consciousness."}
+{"text": "The possible occurrence of metabolic acidosis in patients with intestinal ileus is not well recognized. We describe a patient with acute alcohol-induced pancreatitis and a large transverse colon ileus in which plasma bicarbonate dropped rapidly in the absence of an increase in the plasma anion gap. The urinary anion gap and ammonium excretion were consistent with an appropriate renal response to metabolic acidosis and against the possibility of respiratory alkalosis. The cause of the falling plasma bicarbonate was ascribed to intestinal bicarbonate sequestration owing to the enhancement of chloride-bicarbonate exchange in a dilated paralyzed colon."}
+{"text": "Effective site supervision plays an important role in construction project delivery. This situates site supervisors in taking the responsibilities of coordinating and controlling all physical aspects of the day-to-day task in construction projects. A cross-sectional design approach was adopted by administering a well-structured questionnaire to selected built environment professionals. Descriptive statistics was performed on the data obtained and are presented on figures and tables. The data was also subjected to inferential statistics using Kruskal Wallis test to analyze the perceptions of respondents on effects of site supervision of construction works on completion time and quality respectively. The significance of the analyzed data is on identifying the effects of site supervision on project completion time and quality delivery. The analyzed data will also guide project stakeholders in selecting competent personnel in executing construction projects. Specifications TableValue of the data\u2022The data reveal cogent roles of site supervisors in construction projects towards elimination of reworks, minimization of waste and ensuring conformity to standards.\u2022The impacts of site supervision on project accomplishment of time and quality will be a contribution provided by the data.\u2022The identification of the effects of site supervision will provide basics for local construction sector to equip themselves for future selection of site supervisors.\u2022The data will also guide academia in fulfilling their teaching requirements hence producing competent hands that can handle construction works.1A total of 78 online well-structured data instrument was administered to various built environment professionals comprising of Architects, Builders, Quantity Surveyors and Civil Engineers. The demographic features of the selected built environment professionals are presented in 2The collected data was based on the survey of selected construction practitioner's perception on the effects of site supervision on project completion time and quality delivery. Several literatures have reported similar accounts of the subject matter and can be found in"}
+{"text": "An exact probabilities method is proposed for computing the confidence limits of medical binomial parameters obtained based on the 2\u00d72 contingency table. The developed algorithm was described and assessed for the difference between two binomial proportions . The behavior of the proposed method was analyzed and compared to four previously defined methods: Wald and Wilson, with and without continuity corrections. The exact probabilities method proved to be monotonic in computing the confidence limits. The experimental errors of the exact probabilities method applied to the difference between two proportions has never exceeded the imposed significance level of 5%."}
+{"text": "Cost and availability of a database often impede research while the lack of compatibility inhibits collaboration by making merging of databases difficult or impossible. The Global Pregnancy Collaboration (CoLab) has promoted harmonization of studies and standardized data collection to facilitate pregnancy and placental research. Its online database, COLLECT, allows collection of minimal and optimal clinical datasets to accompany basic and applied science studies and provides a placental sample inventory system. COLLECT is available free of charge in LMIC and for $100 per month in HIC. Data is the property of the investigator but with permission can be combined into larger studies across centers and countries. \u2022High quality clinical data can usefully assist basic placental research studies.\u2022Designing a database is expensive and existing databases are usually incompatible.\u2022CoLab has designed and made available a tried and tested database at low or no cost.\u2022Data is the property of the investigator but can be easily combined with permission. Increasing amounts of evidence indicates that these syndromes, and preeclampsia in particular, are heterogeneous disorders with more than one subtype including those with involvement of the placenta. The burden of these disorders falls disproportionately on low and middle income countries (LMIC) where we know less of their pathophysiology and characteristics which indeed may be different from high income countries (HIC). Recent large scale studies of up to 5000 subjects have failed to accurately predict the occurrence of preeclampsia The Global Pregnancy Collaboration (CoLab) was established with support from the Bill & Melinda Gates Foundation as an international consortium of investigators and centers to enable sharing of data and biological samples worldwide with the objective of facilitating collaborative research studies of adverse pregnancy outcomes and ultimately improve the health of women and their infants. As part of this objective the members of CoLab have published position papers which outline standards they feel are necessary for data collection, including minimal and optimal datasets 2CoLab has designed and built a database, initially to facilitate preeclampsia studies worldwide. The database has been adapted by MedSciNet from that they designed for the international SCOPE study, ensuring it is tried, tested and robust. The database will be available free for use for investigators in LMIC with limited resources and available in HIC at a nominal charge ($100 per month). This is much less than that incurred for designing and operating one's own database. The database contains the minimal and optimal datasets as specified by Myatt et\u00a0al., 2014 3COLLECT is an opportunity for members of the clinical and basic science placental research communities to use a high level comprehensive clinical database where none existed before. This will enable harmonization of data collection to facilitate later merging with other studies if desired and help elucidate the role of the placenta in the great obstetric syndromes dickensonke2@mwri.magee.edu or Tel 412 641 1427.COLLECT is available now via The Data Manager of the Global Pregnancy Collaboration, email Bill & Melinda Gates Foundation (OPP1119324).The Global Pregnancy Collaboration is funded by the"}
+{"text": "The data article provides the factors that influence the cost; time performance of the Industrialized Building System (IBS), its prospects and challenges. A survey technique was used for this research. Structured Questionnaires were administered to occupants of prefabricated buildings and interviews were conducted with the professionals in the building industry. Statistical Package for Social Sciences (SPSS version20) was used to analyse the data obtained from the questionnaires. The variables were ranked based on Relative Importance Index (RII) calculation. The Data indicated that IBS would be more economical if used for mass production. Specifications TableValue of the data\u2022This data provides a benchmark for further studies on the performance of the precast concrete system in the construction industry.\u2022This data shows the significance of using Industrial Building Systems (IBS), its impact and valuable benefits of incorporating it in the industry.\u2022This data shows cost- time effectiveness and perception of the implementation of the building system for policy making.\u2022This data can be used to compare findings from other countries where this type of construction method is prevalent.1The data article provides the factors that influence the cost; time performance of the Industrialized Building System (IBS), its prospects and challenges.22.1Data was obtained from building professionals involved in the construction of precast concrete structures and 60 questionnaires were distributed to occupants of already constructed precast buildings in Lagos state. Data was also collected from secondary sources which include information from published journals, articles and thesis 2.2Data collected from the questionnaires administered to respondents were analysed and presented as follows."}
+{"text": "Viruses are highly abundant in aquatic environments  to illustrate how sequencing technologies and associated bioinformatics tools can be utilized to trace aquatic viruses, and (ii) to discuss the new opportunities they offer for understanding the emergence of viral diseases and controlling their spread.Mutoloki et al.). In the second paper, Abbadi et al. looked at the evolution of two viruses that cause high mortalities in rainbow trout farms, the infectious haematopoietic necrosis virus (IHNV) and the viral haemorrhagic septicaemia virus (VHSV). They analyzed the glycoprotein (G) gene sequences of many isolates collected over a period of nearly 30 years and concluded that the two viruses have distinct evolutionary rates. Integration of these molecular data with high-quality epidemiological information led to propose different patterns of virus spread among trout farms.The two first articles of this topic show how sequencing a single gene of a virus may help understand the ways it propagates between aquaculture settings. Sequence comparison of VP2 gene from infectious pancreatic necrosis virus isolates showed the existence of two clades that differed by a distinct signature motif in the hypervariable region, each motif being associated with a different level of infection . Likewise, metagenomics has greatly accelerated the pace of virus discovery in the recent years, and also appears valuable to design proactive diagnostic tools able to identify novel viruses before they cause disease outbreaks .The following two articles discuss the ability of metagenomics to uncover the environmental factors that influence virus spread in aquatic environments and to identify novel pathogenic viruses. Most of our knowledge on the epidemiology of viral diseases in aquaculture so far is derived from studies carried out on infected aquatic organisms. Metagenomics offers the possibility to study the epidemiology of viral diseases outside their host species by the direct analysis of environmental samples, which in turn enables to follow the environmental factors that influence the composition of viral communities . WGS not only enables to resolve micro-evolutionary distances, but it also has the power to discover new and rare variations, including polymorphisms that arise during an outbreak or that evolve in vivo during an infection. It thus offers the possibility to track the emergence and spread of a given variant, while it may also provide predictive information concerning key phenotypic traits  represents the \u201cultimate\u201d typing methodology in terms of discriminatory power emergence: the potential role of fish endogenous retroviruses. While several exogenous retroviruses have been clearly identified as etiological agents of some fish diseases data. Besides, both metagenomics and WGS are facing technological challenges when applied to aquatic viruses, which the third and fourth generations of sequencing will probably only partly overcome (Nkili-Meyong et al., The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The current Ebola outbreak in West Africa and the large scale wild Polio virus outbreak in several countries are the top most issues among international public health and scientific communities' debates and concerns. These two outbreaks were judged to be declared as Public Health Emergency of International Concern (PHEIC) during 2014. This is the first time ever to have such circumstance of two PHEICs at the same time.PHEIC, which has to be declared by WHO Director General after a recommendation of IHR Emergency Committee; is observed to start in countries with fragile health system and conflict areas. Then it rapidly spread to threaten the global public health. The year 2014 has uniquely witnessed declaration of two events as PHEIC according to IHR (2005); Polio and Ebola Virus Disease (EVD). Both outbreaks are caused by viruses such as H1N1 which was previously declared as PHEIC in 2009.Public Health Emergencies of International Concern in 2014 occurred in countries with weak health systems and conflicts and threatening the whole globe. International collaborative work is required to contain the event and to mobilize resources/capacities between countries. Moreover, public health surveillance systems as core capacity for IHR (2005) should be strengthened in all countries with focus on those with limited capacity and ongoing conflicts. The ultimate aim is timely detection of potential PHEIC events in the future along with early preparedness and response plans. This was due to international spread of Wild Polio Virus (WPV) particularly during the known low virus transmission season (January\u2013April/May) 2.0) of EVD is 2  While it is 6 For WPV-basic reproductive number is an epidemiological parameter that indicates the average secondary cases attributed to the index case of a communicable disease The year 2014 has uniquely witnessed declaration of two PHEIC events according to IHR (2005); Polio and EVD are on the top of global public health and international scientific communities' debate and agenda. Both outbreaks are caused by viruses such as H1N1 which was previously declared as PHEIC in 2009 In 2014 WPV was actively transmitted within at least ten countries with a risk of exportation and infection to others. Eastern Mediterranean Region is shouldering the greater portion of this burden particularly due to \u201cPakistan to Afghanistan\u201d and \u201cSyria to Iraq\u201d exportations. While, \u201cCameroon to Equatorial Guinea\u201d and \u201cEquatorial Guinea to Brazil\u201d are the other documented exportations in the rest of world during 2014 EVD in 2014 started and propagated in western Africa. Guinea was the index country which exported the infection to Sierra Leone and Liberia initially, and later to Nigeria, Senegal and Mali in addition to Spain and United States of America.WHO had made case specific recommendations based on IHR (2005) to cope with current states of Polio and EVD. These recommendations are generally temporary and are subject to the day to day progress and developments. For Polio, recommendations in infected and exporting countries included official governmental declaration that Polio transmission is a national public health emergency. In addition to vaccination for travelers and documentation with international vaccination certificate as per IHR PHEIC in developing countries that are represented in this discussion by Afghanistan, Pakistan and Sudan carries and tells several stories and lessons that need to be well taken. These countries like other several developing countries have been subject to long standing civil wars and turmoil. Two of these countries are directly involved in the current declared PHEIC related to Polio in the epidemiological block that includes both Afghanistan and Pakistan with a common viral circulation pattern and exporting the virus to each other. While Sudan is an African country that been affected by major disease outbreaks during the recent years such as Rift Valley fever outbreak in 2007 and Yellow fever outbreak in 2012. Within these countries we notice that classical index areas for spreading these outbreaks are the most vulnerable and security compromised areas. In Afghanistan, the Southern region including Kandahar and Helmand is persistently being the reservoir for WPV. The same is true for the tribal areas in northern part of Pakistan that remain as major contributor in terms of Polio related outbreaks. In Sudan, the index cases of Rift Valley fever outbreak started in the previous conflict border between Sudan and the republic of South Sudan. In 2012, the yellow fever outbreak started and spread from security compromised areas in newly formed central Darfur state in the western part of the country.Eastern Mediterranean Region Office for WHO that including theses three countries had recently conducted an assessment for country preparedness to EVD potential case importations. It revealed that countries have very low capacity to respond and control potential outbreak despite the fact that technical guidance have been provided to these countries. It is now clear more than any given time before that health systems should be adequately built in all such countries. National governments of these countries are required to prove the commitment to implementation of IHR (2005). Availing adequate or even the minimally required capacities to cope with any PHEIC in a country is the major determinant of the final outcome. This also could be concluded from the recent experience of response to current PHEIC. Despite the huge efforts that paid by international community represented by the United Nation Mission for Ebola Emergency Response 3.In this brief discussion, it is clear that Public Health Emergencies of International Concern occurs in countries with weak health systems and internal conflicts then threatening the whole globe. International collaborative work is required to contain the event and mobilize resources/capacities between countries. Public health surveillance systems as core capacity for IHR (2005) should be strengthened globally aiming for timely detection of potential PHEIC events in the future. Building capacities for implementation of IHR in war/turmoil stricken countries with low resources, weak and fragile health systems will guarantee early detection, response and control and PHEIC in other parts of the world."}
+{"text": "The purpose of this paper is to demonstrate the relationship between food preservation and reducing consumer waste is of value in developing sustainable meal options. The research reports insights into Austrian marketplace for frozen and fresh foods that have been obtained from a consumer survey.The consumer survey methodologies indicate how preservation can change meal planning and lower food waste across frozen and fresh and ambient food purchases using freezing preservation methods.The results show food waste can be reduced by six-fold when frozen foods are compared with fresh foods.This study highlights the requirement for a greater understanding of the probability that specific foods will be wasted with respect to the frequency of purchase. This is a limitation of the current study that has been investigated by other researchers.This research has enabled the identification of different food waste amounts for different food product categories. The data presented could be used to guide food product development so that less consumer waste is produced.The research suggests a decision matrix approach can be used to can guide new product development and a model of this matrix is presented so that it may provide fit-for-purpose food preservation options for consumers.This paper will continue to highlight the overlooked value of food preservation during processing and manufacturing of foods and their preparation in households. Consumers produce the greatest amount of food waste and loss in the food supply chains of developing and developed economies .Previous food waste reduction initiatives have typically focussed outside of this consumer arena and they have focussed on manufacturing and retail food losses. They have been successful at designing out food waste using the right-weighting of food products (portion control) and light-weighting of packaging . Their success has been made possible through cooperative actions across the food industry that have developed joint responsibility for food waste. It is essential that these initiatives now act to reduce the food that consumers purchase but do not eat . While tThere has been an emergence of re-distribution schemes and community focussed actions that have been successful at removing food waste from supply chains. Redistribution of foods that are close to shelf-life limits and schemes that facilitate providing food to consumers such as \u201ccommunity fridges\u201d have an exceptionally important role to play in waste reduction particularly where communities experience limited accessibility and affordability of foods. The redistribution of foods from retailers and manufacturers that are close to shelf life limits or charitable donations has also seen the impact of using on-line communication technologies that connect providers with consumers of redistributed foods . A more Schemes that engage and redistribute resources to reduce food waste do not fully address the issue of food and drink products being wasted by consumers because they are not designed to reduce food waste. They redistribute food that would otherwise be waste; the study reported here focusses on reducing the wastage of food that is purchased with the intention of using it. The preservation of foods and types of food preservation methods available to consumers can facilitate this because it reduces food degradation and improves the utilisation of food in the domestic environment. This is a principle that has remained largely unconsidered even though the production of food waste increases greenhouse gas emissions or the carbon footprint of food consumption . It is cIn this study, it is demonstrated how frozen preservation can provide greater utilisation of food by consumers and reduce household food waste. It is not intended to show frozen is the only option for reducing consumer food waste. It is hoped that the research will highlight the use of preservation methods in reducing consumer food waste and that there are several factors that must work together in food waste reduction is to be successful. Previous research carried out in the UK market compared fresh and frozen food use in households and the amount of consumer food waste was dependent on food preservation method. The study showed a 47 per cent reduction in household food waste for frozen products compared to fresh products .Frozen food in this study is defined by all food that is frozen via quick freezing; this ensures the cell intactness and preserves the nutritional value of the food. The process of freezing food in this household focussed study is defined as non-frozen food which gets frozen via a standard freezer (at home), as such this is slow freezing where cell structure is not maintained and it is less beneficial than quick freezing but adds to shelf life significantly. The definition of fresh food in this study is all non-frozen and non-freezing food.Working with frozen foods not only gives us an opportunity to consider the value of food preservation in households but we must also consider manufacturing factories providing efficient use of resources and continual availability . This prFrozen foods have played a pivotal role in enabling the global food supply chain to evolve and without that food losses would be increased in agriculture and processing. Many of the food supply chain issues highlighted in current food loss and food waste research do not exist with frozen foods because quick freezing leads to the extended shelf life gains that many waste reduction initiatives seek . The \u201cclThe Austrian market research reported in this paper allows us to extend current understanding of the utilisation of frozen foods. It also leads us to consider the broader issue of what incentivises consumers to eat a more sustainable diet. Austrian households currently produce around 369,000 tons of packed and unpacked food waste each year and there is over 23.4 million tonnes of food waste produced by households across the EC member nations . The datThe Austrian market data was collected via an online survey carried out by the Institute of Marketing & Innovation, University of Natural Resources and Life Sciences, Vienna (BOKU) and Gesellschaft f\u00fcr Konsumforschung (GfK SE) during July 2015 . The surThe survey participants were selected to represent the typical Austrian population with regard to age and educational level. The selection made for geographic distribution across the Federal States was proportional to the population in each Federal State. The selection to the panel of 2,800 was made using the GfK market survey methods used for market research. GfK are a commercial and international company that provided the survey panel of 2,800 households. GfK\u2019s services are routinely used by the food sector by manufacturers and retailers to develop business activities and identify food and drink trends. The participants used in this survey bought food and drink for their household and were asked how much food they wasted across six food groups as a percentage of the total amount of the food they purchased. The six food groups were selected because they were important food categories in Austria that have both frozen and fresh options. Notably this included bread where the offer and purchasing of frozen bread rolls is typical for Austrian consumers.What percentage of fresh food from your household purchases do you throw away?What percentage of the frozen food from your household purchases do you throw away?What percentage of fresh food from your household purchases do you throw away per following product groups?What percentage of frozen food from your household purchases do you throw away per following product groups?The participants of the survey were asked to consider their household food waste in a week from the food they purchased, partly utilised food, leftovers (plate waste) and preparation residues. The core questions of the survey that asked participants to report their proportion of food purchased that was wasted as a percentage were as follows:The food groups were fruit; vegetables (including specific questions for potatoes and spinach); bread (fresh only); pasta; meat; and, fish . The core questions were developed in terms of what food product groups were wasted in households. The survey also collected demographic information so that the 2,800 participants reflected a typical sample of the Austrian population and this was determined using GfK\u2019s demographic methods.The amount of food waste produced in the sample of 2,800 Austrian households is shown in The goal of the research reported is to show how food waste behaviours connect many sustainability issues across the complex food choices consumers make when meals are prepared. Our research shows food manufacturers and food retailers occupy critical points in supply that can determine how these food consumption behaviours can be transformed into more sustainable ones. An important way of achieving this is through reducing the food waste associated with every meal.Notably, the fresh to frozen ratio of specific food products , includeThe reduction of food waste and correct meal portioning of specific food products are important because when they align and work together they can reduce food waste. This means data collected from consumers regarding what they consider to be the correct portion size in a meal is exceptionally valuable in waste reduction actions and it is rarely done. Obtaining such data is a challenge future research into food waste will need to address so that it can be transferred to food product development operations for maximum impact. The data collected here does not consider correct portion size data specifically but it does indicate its importance. The Austrian research reported here has shown that the fresh food thrown away per household per person for this sample was 37.48\u2009kg each year while the frozen food thrown away per household per person was 6.46\u2009kg and per year. The nutritional losses associated with food waste have yet to be fully characterised but they are an important component of food waste projections (While we can determine the environmental impact of consuming foods in terms of their carbon footprint, it is the impact of wasting foods as an outcome of consumption that concerns us here. This is important because assessment of the environmental value of foods requires considerable investment of finance, knowledge and skills. It seems futile to make this investment if the assessed foods are wasted downstream in the food supply chain as they are prepared and consumed. New supply chain models are required to promote the value of reducing food waste and guide processes such as freezing that can reduce food waste. The data presented in Current carbon footprinting methods show us that agri-production and global distribution can be the least of our problems because food wastage can be up to 20 per cent of food purchases and food losses across the supply chain can be far greater than this (These ideas lead us to summarise the research presented here as a decision matrix model . The decThe research reported here shows purchased fresh foods have a six-fold greater food waste compared to purchased frozen food in a survey of 2,800 Austrian households. The research supports previous research conducted in the UK where a 47 per cent food waste reduction was demonstrated for frozen foods compared to fresh foods. This relationship shows maximal resource use is achieved for frozen food products that are manufactured for the convenience of being included in meals. The conclusion is that food manufacturers, food retailers and policy makers must consider the role of food preservation in delivering a sustainable diet. The decision matrix approach here provides initial guidance in new product development a basis for doing this and it is supported by data sets that have now been obtained in the Austrian and UK markets."}
+{"text": "Thinking the roof will collapse because you feel anxious). Exaggerated use of negative feelings as source for judging danger  has been demonstrated to have clinical relevance both as maintenance factor  and thinking  have always been viewed in interaction. One way our feelings interact with our thinking is through judgments we make about external situations based on how we feel about them rather than on objective facts. We may conclude that we will get a salary raise because we feel good about the letter we received rather than on the facts that suggest the raise  which serves as input for further thinking . In other scenarios, only objective danger information was presented. After being presented scenarios that included information about feelings, participants judged the probability of danger as higher than after scenarios without information about feelings. Arntz and colleagues also asked participants to \u201cevaluate these events as if they are happening to you.\u2026try to identify yourself with the description as much as possible\u201d . Furthermore, if simulations of feelings are important for the effect of feelings on higher cognition, then the properties resulting from FaEI  will both be recognizable and necessary to see such an effect.Affective forecasting refers to estimations of how one will feel in the future . The results showed that people who were depressed and had higher pre-treatment EMG zygomatic values when they imagined positive feelings respond better to antidepressant treatment  in emotional disorders. Analogous to measures of vividness of kinaesthetic imagery (in which participants are asked to rate the clarity of imagining the sensation of movement), studies may measure the vividness of imagining feelings by asking participants to rate the clarity of imagining emotional states.In line with studies that have investigated the imagery of emotional events (Holmes et al., The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "C. elegans  are kinds of reactive chemicals mainly formed in mitochondria as byproduct of normal metabolism of oxygen  is known as the herbicide and is often used as ROS inducer in biomedical studies (Castello et al., The excessive response may be a preparation for unpredictable and harder conditions forthcoming. If the extent of the response is only appropriate but not excessive, the organism will be killed immediately by worse environmental factors before it has time to motivate stronger protective mechanisms. Such kind of response may also exist in other cellular processes besides ROS metabolism. It is well known that physical activity is beneficial for health in terms of prevention of heart disease and cancer, fat control, and maintenance of mental function (Berra et al.,"}
+{"text": "The high service burden for acute admissions and referrals via rapid access chest pain clinics for evaluation of possible coronary artery disease means that many patients are now undergoing an investigation such as stress echocardiography as part of their evaluation. We aimed to see if the reassurance provided by negative stress echocardiography correlates with long-term event free survival.A cohort of all patients who were referred at a single centre for stress echocardiography for diagnosis of coronary artery disease between January 1st 1999 and December 31st 2000 were followed up at least 10 years following theirs stress echocardiogram for further major cardiovascular events and mortality.A total of 64 patients were identified where records could be obtained for analysis. There were 16 positive scans, 37 negative scans and 11 inconclusive scans. The indeterminacy rate of scans was 17%, the sensitivity rate for detecting significant disease as indexed to invasive angiography was 88 % and the specificity rate compared with angiography was 75%. There were no myocardial infarctions or new diagnoses of heart failure in the negative echocardiogram group. There were seven deaths in the total population and only one death from cardiovascular causes in the negative echocardiogram group.Stress echocardiography even in this small group predicts long-term outcomes as well as invasive coronary angiography. Stress echocardiography was initially developed approximately 20 years after the initial introduction of cardiac ultrasound in 1979 and was limited by poor technical apparatus [Since then there has been rapid development in terms of techniques, indications and the accuracy of the test with thousands of people undergoing stress echocardiography each year. This rapid expansion in testing has rested on numerous works showing that stress echocardiography has evidence in predicting cardiovascular outcomes .More specifically what has been shown in a meta-analysis of available work with a follow up period of approximately 33 months is that a negative stress echocardiogram, very strongly confers a low likelihood of future major adverse cardiovascular events  and theyThe role of imaging in cardiology is increasing year on year and the current recommendations from the European society of Cardiology suggest usages for echocardiography which covers a very large proportion of patients .In the United Kingdom (UK), the recently published guidance from the national institute for clinical excellence (NICE) has clarified the role for stress echocardiography in the assessment of people with stable chest pain . As streMost hospitals in the United Kingdom are unlikely to have access to cardiac magnetic resonance imaging or myocardial perfusion single photon emission computed tomography, which are the two other recommended options in the moderate risk group. We therefore felt that as our centre is a non-specialist centre as our the majority of centers in the UK, we needed to clarify how useful a negative a result would be for the people seen and assessed by stress echocardiography.What we aimed to establish with this audit was whether the strong negative predictive value of stress echocardiography for future events in the short term was replicated in the long term.The patient list was formed from a list of patients kept by the department of cardiology who underwent stress echocardiography between January 1st 1999 and December 31st 2000. All patients were referred for stress echocardiography from within Aintree University Hospitals NHS Foundation Trust to a single operator. All patients who were referred for the assessment of possible ischaemic heart disease were included, patients with known disease undergoing viability assessments or those with valvular pathology being further assessed were not included in the analysis.As part of the ongoing service evaluation and audit process, it was not felt that this work required referral to the national ethics system. This work was however formally approved by the audit department university hospital Aintree NHS foundation trust.Patients were admitted to the department following the omission of all rate limiting drugs or caffeine containing products for 48 hours. Patients were put on continuous electrocardiographic monitoring and regular blood pressure monitoring. Patients were given a pharmacological stressor either arbutamine  in standAn examination was considered to have reached the required heart rate for examination at the discretion of the operator but normally a level of at least 85% of age related maximum was used. The images were then analysed offline by a single experienced operator (AA-consultant cardiologist). Examinations were considered diagnostic of ischaemia and therefore positive when 2 or more adjacent regions became hypokinetic with stress in line with published guidelines .Results were collated in terms of the age, sex and risk factor distribution of the patients scanned. We then collated the number of positive, negative and inconclusive echocardiograms recorded and then the sensitivity and specificity of the test by comparing the echocardiograms where there was an invasive coronary angiogram after and if that showed significant flow limiting disease. We also made a record of the percentage of age predicted maximum heart rate that was achieved where that information was available.We then collated how many patients went on to develop myocardial infarctions, heart failure and who died from all cause and cardiovascular causes . Follow up was performed using the patient\u2019s casenotes, electronic data and if needed by correlation with the general practitioner\u2019 s records.In all we found 64 patients who had stress echocardiography performed in the period from the 1st of January 1999 to the 31st of December 2000 for the attempted primary diagnosis of myocardial ischaemia.The average age of patients presenting was 56 (95% CI 54 to 58) with fifty one percent being female.The average heart rate as a percentage of the age predicted maximum reached for all stress echocardiograms performed was 83% (95% CI 81 to 85).The risk factor profile of the patients involved in the study is shown below in In our cohort of 64 patients there were16 positive scans, 37 negative scans and 11 inconclusive scans.The indeterminacy rate in our collection of echocardiograms was 17% and the sensitivity of stress echocardiography in our cohort was 88% and the specificity 75% using the standard method.The primary outcome measurements were in all cause and cardiovascular mortality and major adverse cardiovascular events .In all there 7 deaths, 2 in the positive echocardiogram group from cardiovascular causes, 1 in the inconclusive echocardiogram group from cardiovascular causes and four in the negative echocardiogram group.In this negative echocardiogram group there were 2 deaths not related to cardiovascular causes and 1 death from cardiovascular causes (witnessed ventricular fibrillation- with no obtainable post mortem report). The cause for one patient could not be determined due to a lack of correct address and general practitioner details.This equates over the minimum ten year follow up to a 0.27% per year risk of death from a cardiovascular cause following a negative stress echocardiogram.The results for the patients developing major adverse events such as heart failure and myocardial infarction are shown below .Using a Mid P exact test, there was no significant difference between the all cause and cardiovascular mortality rates in the positive and negative echocardiogram groups, owing to the low numbers involved.Using a Yates corrected Chi-Squared test there was a significant difference between myocardial infarction and rates of heart failure between the positive stress echocardiograms and the negative stress echocardiogram (P < 0.001).What this studies expands on compared to previous work is that high reassurance provided by a stress echocardiogram in the short term  is repliWhen compared to a negative invasive coronary angiogram the per year risk of cardiovascular death rate of 0.51% [Our sample is a small sample with a single operator and as such is open to biases associated with smaller studies. We also assumed invasive coronary angiography to be the gold standard and that luminographical analysis when negative excluded significant disease. There is more and more work using intravascular ultrasound that suggests that unstable plaques and varying plaque morphology may be more significant than operators may appreciate with traditional angiography . This maThe final limitation to our study is that because all the echocardiograms were analysed by one highly experienced reader, there is an inherent expert bias in terms of the accuracy of the results. It maybe that when replicated with less experienced readers that the interpretation of the echocardiograms may not be as accurate and the outcomes not as favourable.As our results fit in broadly with in terms of sensitivity, specificity and previously reported mortality rate and adverse event rates published in the shorter follow up period for new referrals , we feelAs ever cost effectiveness is a major aspect of all work performed in the national health service and stress echocardiography has been shown to a very cost effective way of reducing the need for invasive angiography  and now It would of course be interesting to repeat this work in a larger group with more operators to see if our results are replicated. With improvements in the scanner technology behind stress echocardiography, we expect the accuracy and the predictive value to improve. We suggest also that correlation between positive echocardiograms and apparently normal angiography be repeated with intravascular ultrasound or optical coherence tomography to more accurately visualise vessels and plaque.Negative stress echocardiography is as good a negative predictor of cardiovascular mortality."}
+{"text": "The increasing demand for energy and the need for clean and affordable energy in Nigeria have necessitated the need for renewable energy resource assessment and subsequent determination of suitable sites within the country. One of the promising renewable energy resources with good potentials of meeting the energy requirements is wind. One of the main challenges of wind power development in Nigeria is lack of scientific data for policy formulation and decision making that will aid the development of wind power utilization. The data presented in this article were obtained with proper evaluation of the wind resource while taking into consideration environmental, social, and economic factors. The information from the data could be useful for taking optimal site selection decision by the policy makers, government, engineers etc. This will ensure optimal investment and return on investment for wind farm developers. Specifications TableValue of the data\u2022Discoveries from the data set could draw the attention of the government to the most suitable states for wind farm establishment for grid integration.\u2022The data set could serve as a tool for estimating wind energy potential in the country and development of renewable energy map.\u2022The data set could serve as a reference for the utilization of wind resource for energy generation by investors and energy companies.\u2022The data and findings could serve as a reference for government policies and planning.\u2022The data set could be used for educational and instructional purposes.1The data contained in this paper comprises of proposed wind farm sites data obtained from wind farm site evaluation in Nigeria. The data includes wind farm suitability map for Nigeria , maps of2The average annual wind speed data for 28 locations obtained from Nigeria Meteorological Agency (NIMET), Oshodi, Lagos, Nigeria was gotten from a previous work The criteria weights generated , togethe"}
+{"text": "The authors of a recently published article entitled, \u201cAdverse childhood experiences and risk for suicidal behavior in male Iraq and Afghanistan veterans seeking PTSD treatment\u201d by Carroll et al.  examinedResearch on psychiatric disorders and suicide risk among active duty personnel and military veterans tends to focus on traumas related to the military service \u20137. HowevThe results of studies by Blosnich et al.  and AfifThere are a lot of research observations of the effects of ACE on the psychobiological development of children and adolescents. Considerable evidence suggests that the brain development of children is likely to be affected in by their ACE \u201321. EarlMilitary service may subject individuals with a history of trauma to additional trauma such as combat, which may additively increase risks of psychiatric disorders and suicidal behavior. If some military recruits have trauma-related psychological abnormalities that predispose to psychiatric disorders when they enter the military, then we have to seriously question the screening that goes into allowing persons to enter the military . PossiblIt is important to address early trauma histories in addition to more recent traumatic experiences because the psychobiological impact of early trauma is different from psychobiological effects of trauma during adulthood , 33. StuClinicians, researchers, and health policy makers should work to reduce the stigma of revealing ACE and apportion funds for epidemiologic studies and the development of new treatment modalities to tackle problems related to ACE among military personnel and veterans .The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Prefrontal cortex (PFC) has long been known to be a region of the brain crucially important for cognitive processes. Major progress has been made in understanding the functions of this part of the brain however when it comes to brain organization there are still unanswered questions. In particular, if we compare known prefrontal cortex organization to that seen in sensory cortices, it is not currently clear whether PFC organization is essentially the same or different. This research topic focuses on the structural and functional organization of the prefrontal cortex in rodents and primates and makes a contribution to current research and debate within this field of neuroscience.Bedwell et al.; Bedwell et al., neuroanatomical tracers were employed to investigate PFC cortical connections. These studies illuminate a connectional feature common to PFC and other cortical regions: topological/topographical organization of connections. In addition, these studies provided evidence at a fine microscopic resolution for both reciprocal and non-reciprocal PFC connections. The finding of fine-scale non-reciprocity is unexpected, especially when one considers that other cortical regions (such as sensory cortices) are well-known for their detailed reciprocity. The study by Nguyen et al. uses electrophysiological approaches to explore important functional questions about the anatomical connections between PFC and primary visual cortex. Such links may be important for mediating attentional and other top-down signals. The experiments provided evidence for a functional link between infralimbic and prelimbic cortex and V1, but they found that this link was not mediated strongly via basalo-cortical cholinergic projections. Another feature of anatomical organization is the columnar organization present in PFC and in other regions of the mammalian cerebral cortex. Several previous anatomical studies have provided evidence for columnar or modular organization within PFC, in this topic Opris et al. investigated the functional aspects of this organization during exposure to cocaine. The results help to show how cocaine interrupts complex cognitive processing within columns and layers of the monkey prefrontal cortex.In the articles by Funahashi in this research topic, the interpretation of delay period activity in relation to visual memory tasks in primates is explored. The article presents previous and historical findings on the subject and discusses different interpretations of these important results. Another important function ascribed to the PFC is fear processing. PFC is known to have strong anatomical links with the amygdala, which is an important structure for mediating fear responses. This research topic features two articles which indicate that PFC plays a role in the processing of fear-related stimuli . Sharpe and Killcross investigated how cues modulate conditioned fear using inactivation of the rat prelimbic cortex. The authors found evidence for a prelimbic cortex role in the processing of these behavioral cues so that responses can be modulated accordingly. Shiba et al. explored how PFC lesions alter innate fear in the primate brain. Here the authors found that lesions to either ventrolateral PFC and orbitofrontal PFC caused heightened fear in response to predatory stimuli.Prefrontal cortex is perhaps best well-known for its role in cognitive function. The classic experiments of Funahashi and colleagues in the late 1980s and early 1990s  in reorienting attention was investigated. In this study a patient with MFG resection was compared to healthy volunteers and the results showed that, in certain tasks, the patient found it difficult in switching to top-down attentional control. In the review article by Cassaday et al., PFC studies involving attention are discussed in relation to the methodology employed and the results from different regions of PFC. This article covers studies of both rodent and primate PFC and outlines the evidence for distinct PFC regions having a role in both attention and executive processes. Remaining on the subject of methodology is the field of optogenetics which has become an increasingly important approach used in the arena of cognitive neuroscience. In the review article by Riga et al., the subject of how optogenetic tools have been used to study the prefrontal cortex in animal models is explored and discussed. The article highlights how these tools have been used to effectively study the functional circuitry of PFC in rodents. Optogenetics continues to be developed rapidly and successfully combined with existing techniques, such as fMRI (Liang et al., Another crucial cognitive function is attention and there is substantial and increasing evidence for the role of PFC in attention. In the imaging case study by This research topic provides a snapshot of current PFC research and highlights some of the progress made in understanding PFC anatomy and function. Many of these studies also point to the important role of PFC microcircuitry in cognitive processing. Clearly there are still important and fundamental gaps in our understanding of PFC structure and function. There are many similarities between the anatomical organization of PFC and other cortical regions yet functionally PFC may be unique, possibly having a multifunctional role which is difficult to define Duncan, . We stilThe author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Hemispatial neglect refers to the defective ability of patients to explore or act upon the side of space contralateral to the lesion and to attend to stimuli presented in that portion of space. Evidence from animal models suggests that many of the behavioural sequelae associated with visual neglect may result not solely from the size of the lesion, but also from a pathological state of increased inhibition exerted on the damaged hemisphere by the contralesional hemisphere. On the basis of these potential mechanisms underlying neglect, in this review we discuss therapeutic approaches, focusing particularly on recent research using transcranial magnetic stimulation (TMS). This technique, besides representing an ideal tool to investigate visuo-spatial attentive mechanisms in humans, has shown promising beneficial effects that might have an impact on clinical practice."}
+{"text": "This paper reports a case study of acquired surface alexia in Spanish and discusses the most suitable tests to detect this syndrome in a writing system that is very regular for reading at the segmental and supra-segmental levels. Patient MM has surface alexia characterized by quantitatively good performance in reading words and pseudowords; accurate but slow and syllabic reading of words, nonwords and sentences; good performance in lexical decision tasks including words and nonwords; errors in lexical decision with pseudohomophones; and homophone confusions. This pattern of reading can be interpreted as a disorder in the lexical reading route and overdependence on the non-lexical route. We discuss nonlexical impairments and the interpretation of alexia and suggest tasks to identify surface alexia in a shallow orthography."}
+{"text": "Pelvic and lower abdominal pain constitutes more than 30% of the referrals to our adolescent medicine and gastroenterology clinics. These cases are responsible for numerous school absences and significant cost to the healthcare system. This article will review the most common causes of lower abdominal and pelvic pain in adolescents, diagnostic and management issues, as well as prevention."}
+{"text": "Obesity is associated with increase in mortality and morbidity due to renal dysfunction. Adipocyte cells are able to secrete different protein named adipokines. In obese subjects, the production and secretion of adipokines alter and these may affect renal homeostasis. More study in the effect of adipokines in progression of chronic kidney disease can help us to understand the pathophysiology and better management of kidney disease in obese patients.Journal of Nephropathology\u201d discussed the relationship between obesity and renal function  have been completely observed by author.No funding from any source is directly associated with this manuscript."}
+{"text": "The remodelling of the NHS requires a strong general practice nurse (GPN) workforce within general practice. The challenges facing general practice nursing are set within the current policy context and recent available evidence and illustrated by drawing upon the experience of a current GPN working in London. It is argued that there is a need to support the professional development of GPNs and nurture the next generation of potential GPNs if the current shortage of GPNs is to be addressed. General practice nurses (GPN) are integral to effective primary care but they are often neglected in discussions about the development of primary care and its workforce. There is a current shortage of GPNs in London and elsewhere and a third of current GPNs are expected to retire by 2020. The issues affecting the general practice nursing workforce are long standing and need addressing urgently so that its capacity and capabilities are maximised and the current shortfall remediated.The working conditions and professional development of GPNs require attention.The world of general practice nursing is changing. This article will draw on the experiences of a general practice nurse (GPN [CWB]) gained over the last five years through working in ten different general practices within London. GPNs are an essential component of primary care  and withFive Year Forward View  sets outThe Queen\u2019s Nursing Institute (QNI)  surveyedThe QNI  survey aBaird et al.\u2019s  recent sLike many GPNs, CWB\u2019s entry from hospital nursing was serendipitous. CWB was confident and competent in cardiovascular disease and health promotion with her accident and emergency background and recent experience as a Borough smoking cessation advisor but she needed additional training in diabetes, asthma and chronic obstructive pulmonary disease.  A generaThere is little incentive for GPN nurses to do more courses especially independent prescribing which requires practice support and time to complete the required assessments. Independent prescribing would take a GPN to the next level of working as an Advanced Nurse Practitioner (ANP) but there is no guarantee of financial reward. Currently contracts do not routinely reflect the role and responsibilities of the GPN although they should be reviewed with the post-holder as the workload changes.  The exteSupport for continuing professional development (CPD) can be problematic with CW-B\u2019s access to study days in the different practices varying from 0 to 4 while many of the better courses are 4\u201312\u00a0days in length. Further mandatory courses often compete with CPD both with their scheduling and approved absence for study/training. In 2014 the local Health Education England (South London HEE) sponsored free places on the postgraduate Train the Teachers course together with mentoring/coaching to support newly qualified nurses and student nurses in primary care but without recognising the constraints facing GPNs which included attendance at CGC mandatory and core role training before the end of March. The training included safeguarding in childhood and travel vaccinations study days, and updates in cervical cytology, diabetes, asthma, cancer, leg ulceration and mental health including Depot treatment. A GPN\u2019s CPD may be further impeded by the October\u2013March focus on the delivery of the QOF targets with the new national childhood immunisation schedule adding to the workload throughout the year.In order to become a practice teacher (to support student nurse learning) in primary care , a certified nurse teaching qualification must be completed which CWB undertook in her time. But like other CPD, because the GPs contend that as they have not asked for her to do the courses, there is no financial reward despite using her enhanced skill set at every available opportunity such as managing asthma patients. Additional constraints are the costs and scheduling of the courses. There are relevant e-learning courses and those offered through the Local Medical Committees but their cost is more than \u00a3500 which GPNs cannot afford. The timetabling of university based courses between October and March is also unhelpful. Few universities run courses over the summer months when GPNs have most availability and their course regulations are inflexible to the needs of those working in overstretched primary care where requirements for supervision of new skill development and certification of attained proficiency is challenging. The lack of accessibility to learning opportunities  underminMany GPNs are lone practitioners in their general practice and working part-time  adds to In some general practices the GPN may undertake minor injury work or surgery such as the removal of lumps and tags following Patient Group Directives. In another general practice the GPN may develop and support Expert Patient groups while in another practice the GPN may undertake work associated with district nursing such as visiting patients with the GP and sometimes on their own if the Patient Group Directives permit lone visits. Some GPNs have an ANP qualification and forget or lose their GPN skills so that an ANP will not test a urine sample referring their patients to the GPN!An added complexity is the power of the receptionist staff who may operate with or without the consent of GPs and may be relatives of key individuals making the organisational politics challenging for an \u2018unrelated\u2019 GPN. Indeed Hammond et al.  observedBeing a GPN is a challenging role because it is complex compared to many other nursing roles based in hospitals and other institutional settings. The role exists within an often hidden and mysterious general practice hierarchy with plenty of titles to confuse patients and sometimes the GPNs themselves. The new role of nursing associate  will onlThe time has come for GPs and policy makers to recognise the value of GPNs and establish a system which rewards them appropriately and nurtures their development. Many nurses become GPNs having worked as established hospital nurses with a wealth of knowledge but were unable to combine childcare and other caring responsibilities with hospital shift work. At a time of workforce shortages primary care cannot afford to waste opportunities to recruit a new generation of GPNs to replace those retiring by 2020 nor can primary care afford to \u2018squander\u2019 the potential talents of the current GPN workforce. Perhaps supporting ageing GPNs to mentor and provide placements for nursing students  so that The authors have no conflict of interest to declare."}
+{"text": "The Trail Making Test and Digit Span are neuropsychological tests widely used to assess executive abilities following stroke. The Trails B and Digits Backward conditions of these tests are thought to be more sensitive to executive impairment related to frontal lobe dysfunction than the Trails A and Digits Forward conditions. Trails B and Digits Backward are also thought to be more sensitive to brain damage in general. Data from the Stroke and Lesion Registry maintained by the Washington University Cognitive Rehabilitation Research Group were analyzed to compare the effects of frontal versus nonfrontal strokes and to assess the effects of stroke severity. Results showed that the performance of patients with frontal and nonfrontal strokes was comparable in each condition of both the Trail Making Test and Digit Span, providing no support for the widely held belief that Trails B and Digits Backward are more sensitive to frontal lobe damage. Further, Trails A was as strongly correlated with stroke severity as Trails B, whereas Digits Backward was more strongly correlated with stroke severity than Digits Forward. Overall, the Trail Making Test and Digit Span are sensitive to brain damage but do not differentiate between patients with frontal versus nonfrontal stroke."}
+{"text": "Advances in tactile cognition and haptics have increased our understanding of the multimodal nature of touch. Haptic data is mostly confined to human performance arising from the flexibility and dexterity of the fingers used to discriminate shapes and objects. Studies with infants indicate that recognition of objects either seen or held in the hand is possible during early periods of infancy. Evidence indicates performance differences between the hands decrease over periods of development, reflecting maturation of the cortical brain system supporting motor skills. Thus ability is not confined to the preferred hand. Tactile process and haptic cognition reflect hand ability. Studies examining manual performance must consider the relevance of haptics in research. Knowing about the evolution of the hands controlled by the cerebral hemispheres is of interest because it is a major contribution to the repertoire of human hand actions. The emergence of RDBM  is an important shift in the development of infant manual skills. Between 4 and 7 months of age, infants begin to manipulate objects using RDBM where one hand stabilized an object while the other hand manipulated the object. Understanding the affordance of a tool is an important cognitive milestone in early sensorimotor period that develops during the second year in full-term infants. This ability has also been demonstrated in preterm infants indicating the emergence of handedness during prenatal periods. Thus a multimodal approach that incorporates studies of tactile processes and hand actions may reveal their interactions with task demands and haptic ability. The subject of cognition in Psychology has evolved from Gestalt views of brain isomorphism to attributing information processing capacities and mental rotation abilities in the brain . StudiesThe study of haptics or active movement in touch , 2008 haFurthermore evidence indicates preattentive sensory processes during tactile searches as in vision, when stimulus characteristics such as sharp edges or angles pop out during contact . PlaisieKnowing about the evolution of hand use is important because it is a major contribution to existing lateralization and the repertoire of human hand actions. It is now established that brain lateralization is no longer confined to the human brain but exists among animals or the vertebrate species  and amonThe division of labor by the two hemispheres predates humankind by half a billion years . These aRecent studies show that there may be subtle functional differences between the hands . These aBy 4 months of age there is a division of labor between the hands, revealing better right hand performance for fine motor movements and left hand performance for spatial arrangement and haptic processing . These fThe emergence of RDBM is an important shift in the development of infant manual skills. In bimanual tasks differing in the precision of the movement required to remove pieces of paper from a stalk, the right hand was used more often than the left not only to grasp the object but also to remove pieces. Though infants do not anticipate the need of their preferred hand to remove pieces, they showed handedness in these coordinated bimanual tasks to a greater degree on those requiring precision grips than whole hand grip, indicating handedness develops early and is related to the precision required from the active hand . UnderstIn summary a multimodal approach that incorporates studies of tactile processes and hand actions may clarify interactive processes in the sense modality of touch. Task demands require interactive processes that are a combination of thought, movement and hand actions to produce the required response. Although tactile sensations are perceived during contact, lateralization and ability of the hand is reflected in the nature of the grip and force applied to the object by its fingers. The problem of producing devices that function like the human hand is mixed with challenges and insights. Since haptics has recently become important in robotics the results of such human-centered studies could be revealing.The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Biometrics has become an emerging field of technology due to its intrinsic security features concerning the identification of individuals by means of measurable biological characteristics. Two of the most promising biometric modalities are iris and retina recognition, which primarily use nonionizing radiation in the infrared region. Illumination of the eye is achieved by infrared light emitting diodes (LEDs). Even if few LED sources are capable of causing direct eye damage as they emit incoherent light, there is a growing concern about the possible use of LED arrays that might pose a potential threat. Exposure to intense coherent infrared radiation has been proven to have significant effects on living tissues. The purpose of this study is to explore the biological effects arising from exposing the eye to near infrared radiation with reference to international legislation."}
+{"text": "The purpose of the data presented in this article is to use it in ex post estimations of interest rate decisions by the European Central Bank (ECB), as it is done by Bletzinger and Wieland (2017)  Specifications TableValue of the data\u2022Real-time data of key macroeconomic variables of the euro area which allows an empirical assessment of monetary policy decisions based on data available to policy makers at the time of the decision.\u2022Data is not distorted by later revisions based on hindsight information.\u2022Either the raw data or the constructed data are constant-horizon forecasts of macroeconomic variables which allows an assessment of forward-looking monetary policy decisions.\u2022Two different sources to construct the same set of forecast variables allows to check which data performs better in empirical assessments of policy decisions.1Bletzinger and Wieland 2One important aspect of the analysis by Bletzinger and Wieland The benchmark model in Bletzinger and Wieland The alternative model of Bletzinger and Wieland The full dataset containing the final data for the interest rate, inflation rate (SPF and ECB staff), real output growth rate (SPF and ECB staff) and potential output growth rate which are used in the estimation of Bletzinger and Wieland The projection exercises in Bletzinger and Wieland"}
+{"text": "To our knowledge, this is the first case of an arterial bleeding as a late complication 3 months after nephron sparing surgery of renal cell cancer, presumably originating from an arteriocalyceal fistula. Superselective embolization of the feeding arterial branch was chosen for treatment of the hemorrhage and proved successful. The high efficacy of superselective embolization as a minimally invasive procedure in this and other cases of bleeding Vessels should be the preferred method instead of open surgery."}
+{"text": "The development of durable ventricular assist devices (VADs) has improved mortality rates and quality of life in patients with end stage heart failure. While the use of VADs has increased dramatically in recent years, there is limited experience with VAD implantation in patients with complex congenital heart disease (CHD), despite the fact that the number of patients with end stage CHD has grown due to improvements in surgical and medical care. VAD use has been limited in patients with CHD and end stage heart failure due to anatomic  and physiologic constraints (diastolic dysfunction). The total artificial heart (TAH), which has right and left sided pumps that can be arranged in a variety of orientations, can accommodate the anatomic variation present in CHD patients. This review provides an overview of the potential use of the TAH in patients with CHD. Ventricular assist devices (VADs) have been shown to improve mortality and quality of life in adults with refractory heart failure. This has led to a dramatic increase in VAD use among adults over the last decade , AbioCor , and CARMAT . The history of these devices and their clinical use has recently been reviewed  was developed for use in adults with end-stage heart failure who had a contraindication to LVAD or biventricular VAD (BiVAD)  or congenitally corrected transposition of the great arteries (ccTGA) carry a life-long risk of systemic right ventricular dysfunction  but does so with a low CVP, something rarely seen with VADs or even early after transplantation. It is this immediate improvement in cardiac output in the environment of a decongested venous system that may allow recovery of renal  and adolescents who are too small for the 70 cc TAH. Syncardia\u00ae has now developed a 50 cc pump which is 30% smaller by volume and is now enrolling children and adults in a bridge to transplant clinical study Figure . The stuThe last few decades have seen a dramatic improvement in clinical outcomes among patients with CHD. These improvements are most pronounced in young children and those with severe CHD (Moons et al., CV provided conception/design of the review, contributed to critical drafting and revision of the manuscript and provided final approval for the manuscript. DM provided conception/design of the review, contributed to critical drafting and revision of the manuscript and provided final approval for the manuscript.DM has served as a consultant for Syncardia. DM is also a consultant for HeartWare and Berlin Heart.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "There is an error in the last sentence of the Results section. The correct sentence is: Although PTSD was not significantly associated with injury group in the overall models, early amputation had a statistically significant  reduction in the likelihood of PTSD relative to limb salvage only during the first year after injury."}
+{"text": "This data article represents academic performances of undergraduate students in a select Nigerian Private Tertiary institution from 2008 to 2013. The 2413 dataset categorizes students with respect to their origins (ethnicity), pre-university admission scores and Cumulative Grade Point Averages earned at the end of their study at the university. We present a descriptive statistics showing mean, median, mode, maximum, minimum, range, standard deviation and variance in the performances of these students and a boxplot representation of the performances of these students with respect to their origins. Specifications TableValue of the data\u2022The data provided will shed more light on students learning outcomes based on ethnicity; by providing sample data reflecting students\u2019 academic performance based on ethnic groups.\u2022The data will provide empirical evidence confirming or refuting the impact of culture on students learning outcomes \u2022The data will be useful to advise education stakeholders in Nigeria and West Africa on the influence of ethnicity on students learning outcomes.1The data presents a sample of students with respect to their origins from the six (6) geopolitical zones as identified by 2The data was retrieved from the department of records and the Center for systems and information services at Covenant University."}
+{"text": "In this study, we describe an fMRI version of the verbal fluency test. This is the second in a series of fMRI adaptations of classical neuropsychological tests, for which normative samples of functional activation have been collected from unimpaired control subjects and structured in a manner that makes individual patient evaluation possible in terms of familiar z-score distributions. This fMRI protocol is shown to have strong convergent validity with the FAS phonemic fluency test and to elicit activation patterns highly consistent with a large body of previous neuroimaging studies of verbal fluency. We also present a case study, in which we report concurrent data from a patient with selective deficits in verbal processing, using both conventional neuropsychological and fMRI approaches. These analyses reveal striking correspondences between the deficits present in this patient on cognitive performance tests and the equally selective patterns of deviation present in his fMRI data."}
+{"text": "The anorexia of aging was first recognized as a physiological syndrome 30 years ago. Its major causes are an alteration in fundal compliance with an increase in antral stretch and enhanced cholecystokinin activity leading to increased satiation.This anorexia leads to weight loss in aging persons and is one of the component causes of the aging related sarcopenia. This physiological anorexia also increases the risk of more severe anorexia when an older person has an increase in inflammatory cytokines such as occurs when they have an illness. This results in an increase in the anorexia due to cachexia in older persons. Anorexia is an important component of the cachexia syndromeFigureThe physiological anorexia of ageing places the older person at increased risk of severe anorexia and weight loss when they develop an illness associated with an increased in inflammatory cytokines or an increase in tumours producing lactate.The central regulation of feeding is a very complicated process.Sarcopenia is defined as the decline in function due to the loss of muscle mass.Persons with the anorexia of ageing are at risk of developing severe anorexia when exposed to high levels of inflammatory cytokines as occurs in the anorexia\u2013cachexia syndrome.The data presented here support the concept that the anorexia of ageing is a major risk factor for older persons developing sarcopenia and/or cachexia. In addition, weight loss together with sarcopenia are major causes of the physical frailty syndrome.The author has no conflict of interest regarding this work."}
+{"text": "Postoperative pseudoaneurysm formation is one of the most feared complications of pancreatic leak following pancreaticoduodenectomy (PD). Surgical repair may be compromised due to a persistent enzymatic insult on the repaired vessel; therefore, preventive measures should be adopted. We report a case of ruptured hepatic artery pseudoaneurysm occurring 12 days following PD in a patient with a postoperative pancreatic fistula. Emergency surgery revealed that the pseudoaneurysm was situated at the point of surgical transfixation of the gastroduodenal artery. The pseudoaneurysm was successfully managed by under-running of the bleeding point combined with the direct application of hemostatic products to the bleeding surface (TachoSil and Tisseel to act as a barrier from the pancreatic secretions."}
+{"text": "Volume transmission (VT) is the diffusion through the brain extracellular fluid of neurotransmitters released at points that may be remote from the target cells with the resulting activation of extrasynaptic receptors. VT appears to play multiple roles in the brain in normal and abnormal activity, brain plasticity and drug actions. The relevance of VT to pain perception has been explored in this review."}
+{"text": "To characterize the velocity slip at the fibrous porous media, data on the anisotropic slip length has been fully analyzed through direct simulations for various geometrical aspects of fiber architecture [2] ). This data article provides detailed slip lengths and slip coefficients in dimensionless form as a function of various geometrical parameters of fibrous porous media including the fiber volume fraction, the dimensionless void length and the normalized permeability. The data is presented for three different fiber packing structures  in both the fiber and normal to fiber directions. Finally a set of curves from the complete fitted equation set are also provided in a single figure that can be used to estimate the slip length and the normalized permeability for a given fibrous porous media. Specifications TableValue of the data\u2022The data provided herein can be used to demonstrate the anisotropic interfacial slip in fibrous porous media in liquid composite molding.\u2022The data provided here can be used to obtain two important characteristic parameters for flows in fibrous porous media: the anisotropic normalized permeability and the anisotropic interfacial slip length (or slip coefficients).\u2022The data provided here can be used to construct the slip length tensor of the Navier-slip model, which replaces actual corrugated fibrous surfaces by an effective smooth boundary at the interface between fibrous porous media and fluid.\u20221\u22121] of Beavers and Joseph 2]. For the quadrilateral packing structure, Data in this article provides the dimensionless slip length f fibers . The fib d*=d/L1 , and the2Pressure-driven channel flows between a no-slip wall on the top and a fibrous porous media on the bottom were solved to estimate the slip length and slip coefficient, which is the most important parameter in describing flows within the dual-scale porous media. The Navier\u2013Stokes equation is solved for the two problems: one is the computational solution for the actual fiber arrangement on the bottom and the other is the analytical solution with the effective slip boundary condition on the bottom. The slip length and slip coefficient can be evaluated by comparison of the two solutions. Extensive numerical simulations were performed to obtain the slip coefficient in the longitudinal (fiber) and transverse  directions are presented as a function of various geometrical parameters of fibrous porous media including the fiber packing structure, the fiber volume fraction, the dimensionless void length and the normalized permeability. By the mesh refinement study, the accuracy more than three significant digits were ensured in estimating the slip length and slip coefficient. The three different fiber packing structures are presented in As was discussed in Ref. From the data on the slip length and slip coefficient presented in The normalized permeability in both directions can be fitted also as follows:In the above equations, the symbols"}
+{"text": "Vetiveria zizanioides) growing on an abandoned terrace slopes in Spain. The results comprise tables showing the resistance of each tested vetiver plant to pullout forces applied to it at various angles. The dataset also contains the measurements of the displacement at each pullout force increment. The dataset also includes the plots of the pullout resistance of each vetiver plant against the measured displacement.The data set presented in this article includes the results of pullout tests carried out on vetiver grass ( Specifications TableValue of the data\u2022This data set provides an insight into the behavior of vetiver grass grown in semi-arid climate during potential erosion or shallow landslide event\u2022This data set can be used to develop a reinforcement models for vegetated soils\u2022This data set can be combined with published data on root distribution of vetiver to derive the strength that vetiver root systems can impart on soil\u2022This data set can be combined with published data on above-ground vetiver plant morphology to derive the sediment retention capacity of vetiver plants\u2022This dataset can serve as a benchmark for measurement and presentation of parameters required for derivation of root reinforcement models and soil-root interaction1Vetiveria zizanioides) growing on row on an abandoned terrace slopes in Spain is shown on The data set of the results of pullout tests carried out on vetiver grass (2In order to investigate the pullout resistance of vetiver grass, 24 plants were randomly chosen from a plantation on an abandoned terrace near Almudaina, Spain and were used as a test sample"}
+{"text": "Dopamine neurons of the substantia nigra compacta (SNc) and ventral tegmental area (VTA) are critical components of the neuronal machinery to control emotion and movement in mammals. The slow and gradual death of these neurons as seen in Parkinson's disease has triggered a large investment in research toward unraveling the molecular determinants that are used to generate these neurons and to get an insight in their apparent selective vulnerability. Here, I set out to summarize the current view on the molecular distinctions that exist within this mesodiencephalic dopamine (mdDA) system and elaborate on the molecular programming that is responsible for creating such diversity. Regulation of behavior and more specific emotion is critically regulated by dopaminergic neurons located in the mesodiencephalon. These dopaminergic (DA) neurons can be sub-classified within their own groups by specific molecular features  to follow the developmental trajectory  enriched in the SNc of the mdDA population, were it was proposed to have a major function in local retinoic acid synthesis and was suggested to play a role in disulfiram (Antabuse) induced neurotoxicity leading to parkinsonism and catatonia  , also known as paternal expressed gene 1(Peg1), is a is a member of the divergent alpha-beta hydrolase protein family. In the liver, Mest inhibits Lrp6 glycosylation through enhancing ubiquitination of beta-catenin and therefore is able to regulate balancing of canonical and non-canonical Wnt signaling (Jung et al., Based on initial gene expression comparison studies performed on human PD patients and controls, NeuroD6 was identified to be enriched in VTA neurons (Chung et al., The first data that hinted toward subset specific molecular coding involved in the generation of mdDA neuronal subsets was published at least a decade ago (Smidt et al., The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "We report on a patient with visual agnosia for line drawings and silhouette pictures following cerebral infarction in the region of the right posterior cerebral artery. The patient retained the ability to recognize real objects and their photographs, and could precisely copy line drawings of objects that she could not name. This case report highlights the importance of clinicians and researchers paying special attention to avoid overlooking agnosia in such cases. The factors that lead to problems in the identification of stimuli other than real objects in agnosic cases are discussed."}
+{"text": "Although the semantic memory impairment has been largely documented in Alzheimer's disease, little is known about semantic memory in the preclinical phase of the disease (Mild Cognitive Impairment). The purpose of this study was to document the nature of semantic breakdown using a battery of tests assessing different aspects of conceptual knowledge: knowledge about common objects, famous people and famous public events. Results indicate that all domains of semantic memory were impaired in MCI individuals but knowledge about famous people and famous events was affected to a greater extent than knowledge about objects. This pattern of results suggests that conceptual entities with distinctive and unique properties may be more prone to semantic breakdown in MCI. In summary, results of this study support the view that genuine semantic deficits are present in MCI. It could be useful to investigate the etiological outcome of patients failing or succeeding at such tests."}
+{"text": "Current treatment options for men with early localized prostate cancer are either some form of radical therapy or active surveillance. Radical therapy is usually associated with significant adverse effects that might jeopardize a man's quality of life. Some observers believe that PSA screening has resulted in the over diagnosis and over treatment of prostate cancer. Many men are being diagnosed with an early stage, small volume, unifocal or unilateral prostate cancer but are reluctant to accept watchful waiting or active surveillance. Focal cryoablation is the less than complete ablation of the gland with ice. Based on review of the limited amount of material available in the current literature, focal cryoablation can provide acceptable cancer control while preserving sexual potency and urinary continence. Focal cryoablation may fill a void in the therapeutic options available to patients with unifocal or unilateral prostate cancer who have a strong desire to maintain their quality of life."}
+{"text": "Now, VariZIG is also available from a second distributor .In July 2013, CDC published updated recommendations for the use of VariZIG for postexposure prophylaxis of varicella for persons at high risk for severe disease who lack evidence of immunity to varicella and for whom varicella vaccine is contraindicated ("}
+{"text": "The \u201cpsychic tonus\u201d model or PTM [1] of hemispheric specialization states that the left hemisphere is a psychic and behavioral activator and that the right hemisphere is an inhibitor. The PTM predicts that the tonus of visual representation ought to manifest hemispheric specialization in the occipital lobes. Specifically PTM predicts that pathological positive visual tonus  ought to be associated more frequently with right occipital lesions. PTM also predicts that pathological negative visual tonus  ought to result more often from left occipital lesions. We reviewed 78 cases of post lesion hallucination and 12 cases of post lesion loss of evocation of images, all following a unilateral lesion. Analyses of these relevant previously published cases support the predictions. In accordance with previously published demonstrations of hemispheric specialization for auditory tonus in the temporal lobes and for somesthetic tonus in the parietal lobes, the present findings extend the psychic tonus model of hemispheric specialization to vision in the occipital lobes."}
+{"text": "In B\u00e6rentsen , variousAs indicated by Patanjali, there are types of mental fluctuations  that one has to overcome to reach a stable meditative state (which are discussed in detail elsewhere; Woods, The various techniques and modalities of meditation suggested in the respective traditions involve clearing out the fluctuations caused by numerous faculties. A deeper insight into various types and stages associated with each of these techniques reveal that each different type of meditation involves a process to reduce any of the noise components and gradually takes through different stages of evolvement to reach the same and ultimate experiential state Woods, . Such anThe dynamics of how an individual responds and benefits from meditation practice depends on his current evolutionary state which is driven by both the inherent and acquired personality traits and external influences etc. (Fingelkurts et al., From this viewpoint, all the data emerging from different studies on meditation are essentially indicating various levels and extent of noise. That is the reason why each type of meditation involves different levels of coherence and neural patterns (Travis et al., JR came up with an idea to write comments and extend the original article. Both JR and SR analyzed and wrote the article.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "None of the authors have any commercial associations or financial disclosures that might pose or create a conflict of interest.We describe a simple technique for excision of rhinophyma using equipment found commonly in theatre. The nose is infiltrated with lignocaine and adrenaline, and a colposcopic loop electrode  is used to shave excess tissue in smooth planes while providing simultaneous haemostasis. The burr  is then used to soften the nasal contours into the desired appearance. Additional haemostasis is performed with loop diathermy before the wound is dressed.Excision of rhinophyma is typically a bloody and time consuming affair. Our technique creates a smoothly contoured appearance and simultaneous haemostasis with only a few passes of the loop cautery tip."}
+{"text": "This letter is written in response to a review recently published in the journal. The aim is to highlight a potential methodological limitation common to many studies comparing bipolar patients with few previous episodes versus those with multiple episodes, and in which the results are interpreted as indicating the longitudinal course of the illness. Dear Editor,We read with great interest the recently published review by Joyce et al.  entitledIn addition to the limitations described very accurately in the review, we would like to highlight an unconsidered aspect that could be critical for interpreting the results. BD is a very heterogeneous illness in terms of severity, with some patients experiencing a few recurrences and complete functional recovery throughout their lifespan and others showing multiple episodes and marked functional impairment despite treatment (Goodwin and Jamison Joyce et al.  proposedClinical staging and neuroprogression proposed for BD are very attractive and potentially useful models (Berk et al."}
+{"text": "Asymptomatic hematuria is very common in pediatric and adolescent patients. In contrast to painless hematuria in adults, the differential diagnosis and investigative modalities in the pediatric population is vastly different. This article presents the major diseases that may cause hematuria in children and suggests an evaluation algorithm for the pediatric urologist."}
+{"text": "Salmonella enterica serovar Typhimurium is one of the most common isolated serovars. Here, we reported the draft genomes of 40 S.\u00a0Typhimurium strains isolated from humans and food in Brazil. These draft genomes will improve phylogenetic analysis and will help enhance our understanding of strains of this serovar isolated in Brazil.Salmonellosis is an important health problem worldwide and  Salmonella enterica is recognized as one of the most common pathogen causes of foodborne disease worldwide   . The numSalmonella Typhimurium strains isolated from humans and food in Brazil. It will also provide phylogenetic insights into their evolution. A more detailed report of these genomic features will be addressed in a future publication.The data provided will help in understanding the molecular epidemiology of Salmonella Typhimurium isolates are available in GenBank and are listed in The draft genome sequences for these 40"}
+{"text": "Vsto vesicles of blood transfusions have been shown to deliver glycosylphosphatidylinositol-linked proteins to recipient erythrocytes, to display prothrombotic activity, and to have an inhibitory effect on macrophages. The interaction of Vsto vesicles with and their effect on neutrophilic granulocytes has not yet been studied in detail. Fluorescentlylabeled Vsto and calcium-induced vesicles were preparedin order to study the uptake of labeled vesicular components by neutrophils as compared to the process of phagocytosis of zymosan using flow cytometry and confocal microscopy. The activating effect of Vsto vesicles on neutrophils was addressed by a luminometric assay for stimulated radical oxygen species (ROS) generation. Coincubation of vesicles and neutrophils results in a transfer of vesicular components to the cells. This uptake is different from a phagocytotic process and is enhanced upon interference with the cellular actin cytoskeleton. Preincubation of neutrophils with Vsto vesicles results in an enhanced ROS generation by neutrophils, which is further increased upon fMLP stimulation and during zymosan phagocytosis. The activating effect of Vsto vesicles on neutrophils might be due to the specific accumulation of lysophospholipidsin Vsto vesicles and should be considered as a possible contributor to the pathogenesis of transfusion-related acute lung injury.Erythrocytes are known to shed vesicles"}
+{"text": "It is possible to modulate the amount of AL loaded into the nanospheres up to a maximum value of about 17 wt %. In vitro tests were performed using a human osteosarcoma cell line (MG63) and a murine monocyte/macrophage cell line as osteoclast model (RAW 264.7). The results indicate that even the lower concentration of alendronate provokes decreased tumor cell viability, and that osteoclast activity exhibits an alendronate dose-dependent inhibition. The data suggest that nMBG can act as a suitable support for the local delivery of alendronate, and that the antiresorptive and antitumor properties of the functionalized mesoporous nanospheres can be modulated by varying the amount of alendronate loading.In this work we synthesized mesoporous bioactive glass nanospheres (nMBG) with the aim to utilize them as substrates for loading one of the most potent amino-bisphosphonates, alendronate (AL). The results of the chemical and structural characterization show that the nMBG display a relatively high surface area (528 m In detail, Oscar is an OCLs\u2019 associated receptor, its expression follows TRAP during osteoclasts differentiation ; CtsK isin vitro tests prove that the proposed multifunctional system is a promising platform for controlled regulation of osteosarcoma cells and osteoclast activity, providing a new tool for OS treatment.The approach developed in this study allows mesoporous bioglass nanospheres to be loaded with increasing amounts of alendronate up to about 17 wt % and yields materials where the ability to promote mineralization of the nanospheres is coupled with the antiresorptive and anticancer properties of alendronate. The results of"}
+{"text": "The European Society for the Study of Tourette syndrome (ESSTS) was established in Denmark in 2000 by Mary Robertson and Anne Korsgaard. The aims of the organisation are to foster research activity and raise awareness of Tourette syndrome throughout Europe. The organisation went into abeyance in 2002 but was resurrected in 2007 in Bari, Italy. Since that time ESSTS has grown and prospered. We have established elected officers and a constitution. We have successfully applied for three large scale European research grants and have members throughout the European Union. We have held yearly meetings across Europe including two training schools and we have developed successful alliances with patient support groups. ESSTS has developed and published the first European guidelines on assessment, diagnosis and treatment of Tourette syndrome."}
+{"text": "Sexual health is an important global public health concern. Planning effective strategies to improve sexual health requires a high degree of attention to the local epidemiological trends and cultural context where the strategy is to be implemented. The paper by Chemtob et al. describes the process to develop a plan that aims to reduce the burden of Sexually Transmitted Infections in Israel by 2025. This commentary argues that increased attention to planning and implementation of sexual health policy is required in order to address the real burden of disease. Sexual health should not be merely addressed from a communicable disease control perspective but should comprehensively address health and wellbeing of all population groups through a positive approach in line with the WHO current definition of sexual health. As even traditionally culturally conservative societies are experiencing rapid changes in attitudes and practices towards sexual lifestyles, the challenge is to ensure that sexual health strategies combine evidence-informed measures and good practices with culturally appropriate communication and implementation approaches. The paper by Chemtob and colleagues  \u201cA natioThe authors clearly demonstrate the large variation in reported epidemiology and practice that exists between countries in Europe pointing to the need for a more robust evidence base for policy making in the area of sexual health. They rightly highlight the issue of underreporting which may be a key factor explaining the degree of variation observed and reach the conclusion that different approaches to better capture the real epidemiological situation are necessary.Estimation of the burden of STIsThe paper focusses primarily on estimation of the burden of STIs, screening for STIs and implementation of strategies to reduce the burden of STIs.Various countries have different systems of collection of data. This is essential for each individual country to have a good picture of trends in order to have a clear picture of the situation including the risk groups to be targeted as well as monitoring of progress being made. Robust and reliable surveillance systems are critical in order to inform relevant stakeholders in an accurate and timely fashion. The epidemiology of STIs including HIV is constantly evolving and information on new cases, routes of transmission and patient outcomes are important needed to monitor the epidemiology of infection. Surveillance systems therefore need to keep pace with the changing nature of epidemics at national and European levels.Passive surveillance, which collects information from laboratories, clinics and STI control programmes and serviceBehavioural surveillance collects data from behaviours of specific target groupsSentinel which identify specific centres and they report on their practice eg that seen in GermanyPeriodic cross sectional surveysThere are various forms of surveillance systems for STIs which include:In many countries, the number of reported STIs represent only the \u201ctip of the iceberg\u201d for various reasons. The commonest reason is because most infections are asymptomatic or else they are not diagnosed. There could also be unreported symptomatic cases due to stigma and discrimination, fear of potential conflict with sexual partner especially in the married group, self-prescription of medicines from pharmacies or empirical treatment in the community. Many countries have legal frameworks which mandate notification by doctors to notify cases of infectious diseases. Some countries also have a legal obligation for the notification of positive samples from laboratories .Screening of STIsUnderreporting for STIs can be tackled through the development of a sentinel surveillance system focusing on a selected primary care doctors who will report on the cases they see in their practice and this is extrapolated to the general population. Enhanced surveillance of STI in Europe is essential to outline the distribution of disease and evaluate the public health response to control the transmission of infections . The EurImplementation of strategies to reduce the burden of STIsScreening individuals to determine if they have been infected with or exposed to an infectious disease is a core public health strategy. Early identification of cases and early linkage to treatment has important public health benefits. In the area of STIs, early treatment reduces the risks of transmission to others and also reduces the risks to health of the patient including long term effects such as infertility. Early diagnosis for HIV and linkage to care through a treat all approach is one of the UN targets for ending HIV/ AIDS. Routine, voluntary HIV testing benefits both affected individuals and their intimate partners by facilitating early access to prevention, care and treatment services.A comprehensive approach to disease prevention, testing and care is a basic public health strategy. The European Centre for Disease Prevention and Control commissioned a project with the aim of increasing the understanding of how HIV and STI can be prevented among vulnerable groups in the broader context of sexual health and health promotion . The maiThis paper by Chemtob et al. outlines the components of the Israeli strategy to control STIs. The strategy covered the main aspects which are evidence based. One crucial element in strategy formulation is the identification of vulnerable groups based on the national epidemiology of the people being affected. Combination STI and HIV prevention measures are more cost effective if taken through a comprehensive approach.The focus on social determinants of sexual health is unfortunately a missing element in many strategies. Yet social determinants have an impact on health of vulnerable populations. Such groups may have barriers such as preventing high risk individuals from accessing services offering preventive services. These barriers include national legislation such as laws governing sexual conduct. One of these laws includes age of sexual consent which affects the age of first start of sexual encounters. Sex between same gender sex is now legal in several countries and so no legal barriers are identified in this area. Accessibility of service provision and fear of stigma and marginalisation are other reasons which may keep persons from coming forward to access services.This paper has a second important contribution. It raises the issue of different epidemiological patterns between religious groups. As societies in Europe and elsewhere become more ethnically heterogenous due to increased migration, the way in which these demographic changes affect sexual lifestyles needs to be taken into account in planning sexual health policy.The authors place a specific emphasis on groups at risk such as men who have sex with men (MSM) and commercial sex workers. However, the wider implications of changing sexual attitudes and practices amongst the general population are somewhat overlooked. The importance of regular population surveys complemented by in-depth qualitative research with specific groups needs to be given more importance. The value of the numbers and trends of STIs achieved through passive and active surveillance needs to be placed in the broader context and narrative of societal attitudes and practices. These are often difficult to extract and confront in conservative and religious countries. Yet, evidence points towards rapid societal change leading to fast changing sexual health practices. These are often least well addressed by those countries not typically used to dealing with such a situation and the Israeli approach is to be commended in this regard.In 2016 the World Health Organisation published its strategy on Sexually Transmitted Infections (STIs) for the period 2016\u20132021 . This isHowever if each country takes steps to define the specific populations that are most affected by sexually transmitted infection epidemics including populations most likely to have a high number of sex partners, such as sex workers and their clients as well as other populations such as men who have sex with men, transgendered people, and people with an existing sexually transmitted infection, including people living with HIV this is a good start. Other groups considered to be particularly vulnerable to sexually transmitted infections include young people and adolescents, women, mobile populations, children and young people living on the street, prisoners, drug users and people affected by conflict and civil unrest.In our view, the key element to ensure success in addressing sexual health at country level is that the response is one which is firmly rooted in epidemiological evidence but which gives due attention to the social context. Planning and implementing sexual health strategies is a challenging policy area for public health. The rising trends in STIs combined with rapidly changing societal norms and sexual lifestyles and practices make the need to address sexual health at both individual and population levels an urgent one. Public health professionals and policy makers need to use the whole array of health promotion tools ranging from legislation, effective communication, empowerment of individuals and communities as well as strengthening health services in order to make positive progress to improve sexual health and well-being."}
+{"text": "The impact of type 2 diabetes on ageing societies is great and populations across the globe are becoming more diverse. Complications of diabetes unequally affect particular groups in the UK older people, and people with a South Asian background are two population groups with increased risk whose numbers will grow in the future. We explored the evidence about diabetes care for older people with South Asian ethnicity to understand the contexts and mechanisms behind interventions to reduce inequalities. We used a realist approach to review the literature, mapped the main areas where relevant evidence exists, and explored the concepts and mechanisms which underpinned interventions. From this we constructed a theoretical framework for a programme of research and put forward suggestions for what our analysis might mean to providers, researchers, and policy makers. Broad themes of cultural competency; comorbidities and stratification; and access emerged as mid-level mechanisms which have individualised, culturally intelligent, and ethical care at their heart and through which inequalities can be addressed. These provide a theoretical framework for future research to advance knowledge about concordance; culturally meaningful measures of depression and cognitive impairment; and care planning in different contexts which support effective diabetes care for aging and diverse populations. Although longevity in the UK is increasing, average increases mask important differences within the population \u20133. FurthThe purpose of this research was to review the evidence to guide a programme of applied research to address the key areas and processes for reducing inequalities in diabetes care for older people from ethnic minority groups. We focussed in this instance on South Asians in the UK as this group has an established history in the UK (making up fifty percent or more of the population in some UK locations) and so would be likely to feature in the relevant research literature.We define ethnicity as a consciousness of belonging to a particular group based on commonality of family origin and culture of shared values and beliefs which is socially constructed  and loosThe term \u201colder people\u201d is used variously according to context and different age-related dimensions: chronological, biological, functional, psychological, and social. In western societies, it broadly aligns with age of retirement 60 or 65+ , 8 but tThis study's principal interest was diabetes care and prevention in relation to inequality, ethnicity, and the older population rather than the aetiology of diabetes per se, although this was necessarily touched on where it related to clinical practice and management of older people who are living with diabetes. Diabetes care in the UK is a context specific and complex activity because it takes place across NHS settings through consultations in primary and secondary care and in people's home through self-management and care support.Inequality was the main lens through which the literature review was conducted. The starting point was that our previous research in related areas had found inadequate care of older people with diabetes particularly those being cared for in residential settings ; that prAlthough familiar with some of the concepts associated with reducing inequalities in access to diabetes care, such as cultural competency and concordance , we had The review had two parts: Part 1, a mapping phase where we thematically synthesised the relevant studies into the main areas of research evidence; and Part 2, a theory building phase where we hypothesised, by abstracting from the evidence, a theoretical framework for moving forward from this base. As the work was early stage the emergent theory raised further questions which will help test and refine the theory in the future. As it stands however the review highlights a number of issues for policy makers, providers, and researchers concerned with reducing and preventing inequalities in diabetes care and these are summarised at the end of this paper.We reviewed literature at the intersection of three areas: quality diabetes care, older people, and ethnicity see . The revFollowing an initial exploratory phase we decided to apply a realist approach to review the literature. This methodology was considered the most appropriate because it accommodated the broad research question; was compatible with the complex and context related nature of diabetes care; was sympathetic to the usage of a multimethod, multidisciplinary evidence base; and would facilitate the exposition of theory through emerging and generalisable mechanisms . This coThe search would be limited to the previous 30-year timeframe and to studies from the UK. The period 1985 to 2015 spanned several changes of UK governing parties and associated health policies some of which addressed health inequalities in relation to diabetes care, the impact of which would be captured in literature published during this time.The search would focus specifically on the UK population. Ethnic minorities and health systems are different in different countries and diabetes care is context related. Literature on ethnicity, access, and cultural competency from other countries such as the US, Canada, and Australia was drawn on where appropriate in the analysis and discussion of mechanisms.The search would focus on the UKs' South Asian population rather than other or all ethnic minorities living in the UK. Previous research by members of the team provided insight into some of the inequalities that people with a South Asian background experience . As thesThe search would use common age descriptors for older people as well as specific age categories from 55 years upwards. In the context of diabetes and care for minority groups age as a descriptor could be relative and variable depending on the population and phase of care .The search would use descriptors for diabetes that included the key complications: diabetic neuropathy, retinopathy, and nephropathy. Terms for the latter would be expanded as studies of diabetic nephropathy and end stage kidney disease would be likely to include the older South Asian population because of the links between ethnicity, diabetes, chronic kidney disease, and longevity , 15.The search would be inclusive of research using qualitative and quantitative methods as well as grey literature in line with the realist methodology to prioritise relevance and contribution to theory building . The quaWe conducted an initial scoping phase in which we hand-searched for research publications and tested different search strategies with available electronic databases. We made a number of decisions about the search strategy which are listed as follows:A combination of hand searching and electronic searching of publication databases was carried out.\u2009\u2217 OR hypoglycem\u2217 OR non insulin dependent diabetes mellitus OR NIDDM OR insulin OR insulin resistance OR glucose level OR glucose regulation OR haemoglobin A1c OR HbA1C OR metabol\u2217 OR foot problems OR amputation OR lower extremity OR lower limb OR complications OR nephropathy OR retinopathy OR kidney disease OR chronic kidney disease OR renal OR renal impairment OR kidney damage OR albuminuria OR proteinuria OR microalbuminura OR renal replacement therapy OR CKD OR ESRD OR ESRF OR ESKD OR ESKF OR RRT OR end stage renal disease OR end stage kidney disease OR end stage kidney failure OR end stage renal failure OR dialysis OR primary care AND Older people OR older persons OR elder\u2217 OR old age OR ageing OR aging OR late life OR frail\u2217 OR non frail OR end of life OR geriatrics OR gerontology OR post menopausal OR over 55 years OR over 60 years OR over 65 years OR over 70 years OR over 75 years OR over 80 years OR over 85 years OR over 90 years OR over 95 years OR over 100 years OR end of life OR functional disability OR functional decline OR mortality AND Ethn\u2217 OR race OR culture OR BAME OR BME OR minorit\u2217 OR ethnic minority OR asia\u2217 OR Indoasia\u2217 OR south asia\u2217 OR Indian OR Pakistani OR Bangladeshi OR Sri Lankan OR racial OR black\u2217 OR culturally and linguistically diverse group OR CALDDiabetes OR diabetes mellitus OR type 1 diabetes OR T1DM OR type 2 diabetes OR T2DM OR hyperglycemThe following databases were searched: Academic Search Elite, CINAHL Plus with Full Text, MEDLINE, MEDLINE with Full Text, PsycARTICLES, PsycINFO, SocINDEX with Full Text, and Global Health. Publication abstracts were searched using keyword criteria as follows:Electronic search results were screened for duplication and relevance to the review area and question. Copies of the full publication were obtained for included abstracts which were screened and those considered relevant included in the analysis. This process was conducted by EW and MW jointly, with assistance from an information specialist and with input and oversight from the other members of the author team.The research question \u201cWhat are the key mechanisms for reducing inequalities in diabetes care in the UK for older people with a South Asian background?\u201d was the basis of capturing learning from the published literature. In realist terms it was conceptualised as a complex intervention comprising government policy, applied research, and evidence based practice from the UK which addressed inequalities in diabetes outcomes and care for older people with diabetes from ethnic minorities and spanned the diabetes care system as a whole. We drew on the RAMESES guidance  for repo\u2009Part 1: the overview and mapping of literature relevant to the research question and search criteria.\u2009Included studies were analysed thematically into broad areas.\u2009Part 2: the building of a theoretical framework for research in response to the question.\u2009For each mapped area we considered the context, mechanisms, and outcomes and considered how these related to common concepts also emerging from the literature that could be explanatory in terms of observed inequalities in diabetes care and interventions to reduce them see .The realist programme theory developed iteratively through the scoping, mapping, and theory building stages of the literature review and the findings are reported in two parts in The results of the literature search are summarised in Following thematic analysis the included literature was following broad areas.There were very few studies which specifically investigated diabetes, older people, and ethnicity, and even fewer (none) which specifically addressed diabetes care for older South Asian people in the UK. Although studies which included South Asian people with diabetes often stated in their background that diabetes was a leading cause of mortality and morbidity and South Asians were the largest ethnic minority in the UK, the majority of studies identified by our literature search concerned prevalence and incidence of diabetes, diabetes related complications, and associated conditions particularly cardiovascular disease. Exceptions to this were the UK Asian Diabetes Study (UKADS)  and the In South Asians, the prevalence of type 2 diabetes is 4 times greater than that of White Europeans . Most ofWhere ethnicity was discussed in relation to inequalities in the research literature it was mainly to explain variations in outcomes or patterns of distribution within a given population and there was a dearth of studies which analysed inequalities as it related to diabetes care specifically for older people with a South Asian ethnic background. There were very few studies about diabetes and diabetes care which explicitly included older South Asian people as participants and a similar number of papers which discussed the lack of participation of older people and ethnic minorities in studies as a research issue , 28.Studies of diabetes which include an analysis by ethnicity invariably noted the earlier onset of diabetes in South Asians compared to White Europeans as an important factor in understanding both aetiology and disease progression as well as indicating a timeframe for intervention and prevention which is different to the majority population. South Asians experience diabetes approximately 10 years before White Europeans and show signs of more rapid progression of complications , 30. ResTogether, key UK government guidelines, the Quality Outcomes Framework and the National Service Frameworks for Diabetes and Kidney Disease, have encouraged GPs to consider ethnicity as a factor for earlier diagnosis and targeted care. These quality initiatives have gone some way to redress inequalities in diabetes care  but therSeveral of the studies which detail South Asian ethnicity describe the heterogeneity within the broad South Asian descriptor for the UK's diverse South Asian population and some, depending on the data source, were able to break down their results across the main South Asian groups  in the UK . EthniciThe complicating associations between diabetes and cardiovascular disease (CVD) were the subject of over half the studies identified through our electronic search. These were seeking to understand the aetiology of morbidity and mortality of CVD and included diabetes and ethnicity as established risk factors in the analysis . SimilarDifferences in diabetes related mortality and morbidity between different ethnic groups outlined in a small number of publications point to different mechanisms through which ethnicity exerts influence. For example, South Asian and Black groups both have increased risk of diabetes, CVD, and Stroke  comparedStudies which focus on diabetic nephropathy show that South Asians also experience complications at an earlier age and their progression is faster than in White Europeans. South Asians' risk of diabetic nephropathy is 13 times that of the White European population . As a grOther diabetes complications, retinopathy and neuropathy, have a similar association with ethnicity; that is, they have been found to be associated with increased risk factors  and are As the South Asian population is ageing and as longevity is main risk factor for comorbidities in older people, the incidence of end stage renal failure and dementia are set to increase in South Asian ethnic group . Both thDepression as a comorbid condition for people with diabetes is associated with both increased risk of developing cardiovascular problems as well as being secondary to cardiovascular complications and increasing risk of mortality . It is aIndividualised assessment of need and cultural sensitivity are included within the national service frameworks for diabetes, kidney disease, and care of older people \u201324 as meResearch into the extent of how well healthcare services are able to meet the needs of South Asian people who have diabetes has found that whilst services have implemented the organisational element of quality improvement policy such as the Quality Outcomes Framework and shifts of diabetes care from secondary to primary care they may not have resulted in quality of care from the patient perspective , 57 nor The small number of trials testing culturally appropriate self-management programmes  and struPilots of integrated diabetes care such as the North West London Integrated Care Pilot for people over 75 years of age considered ethnicity in their design and analysis , 62. ThePatient experience research with South Asian people with diabetes in primary care identified barriers one of which was a need for information and health education to be delivered in a culturally appropriate way that matches an individual's understanding of health and disease, as well as taking into account the broader social context for ethnic minority groups and common psychological responses \u201368. FindA care pathway approach to exploring patient experience of diabetes care across primary care and specialist renal care found that South Asian patients referred to renal care lacked awareness of kidney complications of diabetes despite familiarity with diabetes over more than 10 years. Furthermore reflecting back on diabetes care patients felt there had been missed opportunities for information and self-management support .The small number of studies of South Asian patients' experiences of care in secondary care kidney services also tells us more about the care of older South Asian people with diabetes as nearly half the South Asian patients requiring renal replacement therapy also have T2DM . CommuniThe exploratory mapping of the literature in this review created a context for the second part of our analysis. Explanatory concepts which emerged from the literature alongside the observational data were cultural stratification and comorbidities, cultural competency, and access. The relationship between these concepts and the CMO analyses in each mapped area is shown in As diabetes complications are associated with longevity and length of time with diabetes as well as South Asian ethnicity, it is common that older South Asian people with diabetes will have multiple comorbidities requiring some sort of prioritisation and integration of treatment and care according to which conditions are of most concern or life limiting. Stratification of patients by risk, comorbidities, patient experience, and diagnosis is therefore a key part of informing effective care , 73 and The fact that South Asian people develop diabetes earlier and experience the complications younger means that in the context of diabetes care the descriptor \u201colder\u201d age needs to be brought forward relative to the White European population. The changing demographics of the UK mean that there will be more older South Asian people in the future and half will have developed diabetes by age 80 .Studies which identified the cardiovascular risk and outcomes associated with diabetes and South Asian ethnicity and the small number breaking it down further into the predominant South Asian groups in the UK provide evidence for the high risk that South Asians with diabetes have for cardiovascular disease mortality and morbidity and persisting inequalities . This fiDetection of prediabetes, incident diabetes, and diabetes complications is important for prevention of the onset and progression of complications through the provision of appropriate and timely care which may need to be more aggressive for South Asians because of the greater risk for cardiovascular  complications. Measures to detect complications which are culturally mediated, that is, dependent on language or ideas of dependency and quality of life, such as depression and cognitive impairment, need to be sensitive enough to identify complications in heterogeneous populations , 76.The range of complications which are associated with older age and diabetes may contribute to frailty which results in vulnerability to sudden changes in health states and increased risk of falls, disability, long term care, and death . A recogResearch Question. How can knowledge about diabetes comorbidities and associated impacts for older people with a South Asian background improve care that maximises quality of life and NHS resources?Whereas stratification on the basis of disease, comorbidities, and symptoms dictates the context for clinical care, the way that information is conveyed and discussed to people with diabetes is important for supporting self-management and decision making in patient care.Understanding the importance of social and cultural influences on patients' health beliefs, and behaviours; considering how these factors interact at multiple levels of the health care delivery system ; and finally, devising interventions that take these issues into account to assure quality health care delivery to diverse patient populations. Research which investigated ethnicity and quality of diabetes care in South Asian patients in primary and secondary care identified the importance of individualising care within a culturally competent approach to support concordance in the care process [The opportunities for prevention of diabetes and complications are an important part improving outcomes for older South Asian people with diabetes because of the earlier and extended timeframe that they are living with diabetes. The focus on primary care and integrated care as a means of delivering patient centred outcomes, if supported by systemic knowledge and awareness of culture within the NHS, aligns with the concept of culturally competent care: process . For indTo achieve this one on one with patients requires the resources within the system to be in place and a full understanding of the challenge. The evidence as it stands suggests that although it is possible to target diabetes interventions  and makeThe concept of cultural intelligence takes the theory of cultural competency further , 86 by sResearch Question. What are the most effective communication methods for promoting concordance in diabetes care with older people with a South Asian background?A person has access to quality care when the care they experience is meaningful and effective , 88. As Whilst the national quality improvement frameworks for diabetes and kidney services have improved diabetes care in terms of the infrastructure for monitoring in primary care with incentives for practices to do this, the evidence suggests that these do not support access to all aspects of diabetes care and that it can be fragmented and variable for all patients particularly for South Asian groups for whom there can be more barriers \u201391.It has been estimated that a quarter of care home residents are likely to have diabetes  and whilOur review of the literature highlights there is a dearth of research studies which have considered access as a collective function of providers within local systems and which include older patient and carer participation in diabetes care at local and individual levels. This is despite the growing awareness of the diabetes epidemic and observations that older age is when cultural differences and sensitivities can be most acutely experienced ; healthcThe prevention imperative to reduce levels of diabetes and complications requires intervention to raise public awareness of the issues of diabetes care for older people from ethnic minority groups and to shift attitudes of patients and clinicians towards a more empowered approach  to care Whilst evaluation of on-going programmes such as integrated care initiative, National Diabetes Audit with Patient Experience of Diabetes Services, and House of Care  will conResearch Question. What are patients and their informal and formal carers experience of involvement in care planning and how can these inform service improvement for older people living with diabetes who have a South Asian background?Current policy and interventions to reduce inequalities in diabetes care in older people with South Asian ethnicity have not resulted in a knowledge base of what works to reduce complications and the poorer outcomes for this population. This exploratory synthesis of the literature is the first to put forward a theory based framework for doing so.The lack of a body of research evidence which addresses inequality and quality of diabetes care for older South Asian people with diabetes reflects many and complex relationships between diabetes and macro- and microvascular complications; the different settings where care is provided; the lack of specific inclusion of older South Asian people in research; and the heterogeneity within ethnic and age descriptors. Studies which, by default, have included this group highlighted that the ethnic specific and ageing effects of diabetes require further enquiry.Limitations of this review relate to complexity; diffuse literature; a broad research question; and the multidimensional influence of ethnicity and culture on health. We mitigated any shortfalls in capturing relevant literature via electronic databases by hand searching and including grey literature and including broad age descriptors which was in line with the exploratory nature of this study. The realist approach taken helped to expand the knowledge base by identifying common mechanisms across different contexts which together contributed to a theoretical framework for policy, research, and practice.It is both a strength and a limitation that our review was conducted by a team with familiarity with particular areas of the literature, that is, diabetic nephropathy and end stage renal failure in South Asians, and frailty in relation to diabetes and older people. Whilst it helped inform the search strategy and theory building it could constitute bias as published research of inequalities in diabetic kidney disease and kidney care made an important contribution and the subsequent analysis applied some of the concepts from diabetic nephropathy research previously published by two of the authors . To mitiTeam composition comprised public health researchers and senior academics who have been involved in guideline development, some of whom are practicing clinicians, strengthened our analysis and interpretation in policy and practice terms. Theory building from such a broad question and diverse literature base identified mechanisms which were \u201cmid-level,\u201d conceptual, and compatible with a systems viewpoint, and interpretation into practical questions for policy makers, clinicians, and researchers was a useful element of this review see .Although this piece of work was limited to a UK perspective and a focus on one  ethnic grouping, the rationale, realist methodology used, and the resulting theoretical framework could equally well be applied to other groups and other diverse populations in other countries. The focus of the review was on understanding the mechanisms which could be useful for reducing inequalities in diabetes care and because the work was exploratory the theoretical ideas are at an early stage and conceptual so also relevant to other health systems.Our theory building went further to identify submechanisms: concordance; the use of culturally meaningful measures for comorbidities affecting older people such as depression and cognitive impairment; and care planning, in particular understanding ways that older people with diabetes can be involved to ensure that it is as person centred as possible. These submechanisms, articulated as future research questions, were at the next level of abstraction from the evidence reviewed. Addressing these will enable us to revisit and refine this early theoretical framework to further improve understanding of how to ensure equitable care at the intersection represented with a \u201c?\u201d in Underpinning individualised care and pertinent to understanding these mechanisms is the ability of the healthcare system to work with the intersectionalities of individuals and groups within a population. The heterogeneity within broad ethnicity and age descriptors is lost in much of the research literature and a more nuanced approach to understanding individual identity and influences on health  will be Research with diverse groups of older people and their care providers in different clinical and community settings requires a culturally intelligent approach by researchers , 102. CoIn practice terms too the awareness of multiple identities and individual experiences affecting diabetes care including, but not exclusive to ethnic group and age, requires closer involvement between patients and practitioners in negotiating care in order for it to be truly person centred . AlthougIn a similar way the relevance of this review in policy terms should be seen in the context of other influences on health inequalities, that is, the psychological, sociological, economic, and life course factors , 105. AlThis review has found that there are very few studies which address care of older people with diabetes who have a South Asian background. As policy makers need evidence to help them respond to the changing demographic profile of the UK to commission effective services to prevent avoidable mortality and morbidity and maximise resources, this is an important limitation in the existing evidence base.There is commissioning guidance for diabetes services and integrated care which by default covers care for chronic conditions and older people and points to earlier onset, need for services to consider ethnicity , but it South Asian people experience diabetes earlier than White Europeans and have a greater risk of complications and faster progression so that care providers and patients would benefit from a better informed and targeted approach to intervention.For policy, practice and research to make an impact on reducing inequalities in diabetes care for older people with diverse backgrounds we suggest attention is given to all three of the mid-level mechanisms: access, comorbidities, and stratification and cultural competency.Research that specifically includes older people with a South Asian background would go some way to providing knowledge about the best way to do this.The definition of \u201colder\u201d people needs to be redefined in the context of diabetes care and South Asian ethnicity and the influence of intersectionalities require more attention to understand and apply these mechanisms for reducing inequalities in diabetes care."}
+{"text": "CHDs affect approximately one in 100 births every year in the United States and are the most common type of birth defect .CDC-funded research recently reported associations for certain CHDs in infants of mothers who were exposed to pesticides at work ("}
+{"text": "Renal cell carcinoma (RCC) is comprised of several distinct histologic subtypes many of which have characteristic cytogenetic abnormalities. The molecular pathogenesis of some of these neoplasms is beginning to be elucidated. Yet renal cell carcinoma is often discovered at an advanced clinical stage and effective pharmacologic therapies for this disease remain to be discovered. For these reasons, renal cell carcinoma is ideally suited to the genome scale investigation made possible by DNA microarrays. A number of DNA array studies of renal cell carcinoma have been published. Renal cell carcinomas have also been studied by array based comparative genomic hybridization. The purpose of this review will be to summarize these studies, to compare the results of the different studies, and to suggest future areas of investigation with a particular emphasis on clinically relevant advances."}
+{"text": "The modeling and simulation of Switched Reluctance (SR) machine and drives is challenging for its dual pole salient structure and magnetic saturation. This paper presents the input data in form of experimentally obtained magnetization characteristics. This data was used for computer simulation based model of SR machine, \u201cSelecting Best Interpolation Technique for Simulation Modeling of Switched Reluctance Machine\u201d  Specifications TableValue of the Data\u2022Flux data is useful for determination of steady state and transient performance of machines\u2022The presented data is obvious for switched reluctance modeling irrespective of how it is obtained i.e. through experiments or computer softwares.\u2022This data shows evidence of nonlinear characteristics of the machine.\u2022Once having this data, remaining data tables are obtained easily and it is easier to find missing data points by interpolation techniques.\u2022Accurate simulation in different areas relating SR machine is possible with this data if current and torque of the machine counted.1The data of flux linkage presented in this article is useful for modeling and simulation of existing SR machine especially when phase current, and phase instantaneous torque profile of SR machine are discussed. Furthermore; an ample picture of this data in 3-D is given for purpose of illustration.22.1Electrical machines are judged from its electrical and more importantly the magnetic circuit. The data of flux linkage presented in this paper actually epitomizes the magnetic behavior of the existing machine  The experiment setup is shown in The obtained data of induced EMF and data of flux after integration is shown in graphical form in Measured data of flux for different current values and different rotor position is graphically represented in Additional data of static torque is also experimentally obtained by locked rotor test by allowing current to flow through motor winding and measuring toque on dynamometer. The set of measured data in graphical representation can be seen from"}
+{"text": "Recognition memory can be supported by both the assessment of the familiarity of an item and by the recollection of the context in which an item was encountered. The neural substrates of these memory processes are controversial. To address these issues we applied repetitive transcranial magnetic stimulation (rTMS) over the right and left dorsolateral prefrontal cortex (DLPFC) of healthy subjects performing a remember/know task. rTMS disrupted familiarity judgments when applied before encoding of stimuli over both right and left DLPFC. rTMS disrupted recollection when applied before encoding of stimuli over the right DLPFC. These findings suggest that the DLPFC plays a critical role in recognition memory based on familiarity as well as recollection."}
+{"text": "We will also discuss how these negative findings can help to design future clinical trial using tDCS to treat individuals with chronic pain.In a recent clinical trial we demonstrated the analgesic effects of anodal transcranial direct current stimulation (tDCS) in patients with spinal cord injury (SCI); however, the positive impact of tDCS on pain was not paralleled by an improvement in quality of life or other related clinical scales. Here we discuss the reasons of such tDCS is an alternative but relevant therapeutic option to manage pain and stimulate motor recovery in patients with SCI. This non-invasive neuromodulation technique has been shown to significantly and sustainably reduce pain if applied repeatedly in various pain syndromes  M1 may not be an appropriate target to modulate mood or satisfaction with life; (2) the primary outcome was pain and therefore this study was not designed to specifically detect change in such scales; (3) the SWLS and PHQ-9 may not be accurate or sensitive enough to detect changes due to tDCS treatment.a priori hypothesis and to select the appropriate clinical scale(s) accordingly. A recent framework developed by researchers from National Institute of Mental Health (NIMH), called the research domain criteria (RDoC) is useful for such analysis.Based on the current tDCS literature and the present understanding of pain sensitization mechanisms, the sensorimotor cortex is the most relevant area to target when aiming at treating pain , anodal M1 tDCS has been shown to activate ipsilateral motor areas  as well as contralateral or long-distance areas  and subcortical areas (anterior cingulate cortex) in healthy controls  targeting the same cortical network should be tested in addition to tDCS in order to prime its effects.Regarding the selection of the main outcome measure(s), especially when it concerns clinical scales, it is of an upmost importance to choose a sensitive tool that accurately evaluates the symptoms being treated and/or the mechanisms of the therapy. In our case, the mental states evaluated by the selected scales  are unrelated to modulation of the motor cortex excitability. The expected improvements would have been related to the indirect effects of pain relief on patients' quality of life and satisfaction. Despite the fact that many studies have demonstrated a correlation between pain levels and quality of life (Wahl et al., AT and FF: wrote the manuscript. RZ and LM: significantly reviewed the manuscript for intellectual content and approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "For humans, activity during the night is correlated with multiple pathologies that may reflect a lack of harmony among components of the circadian system; however, it remains difficult to identify causal links between nocturnal activity and different pathologies based on the data available from epidemiological studies. Animal models that use forced activity or timed sleep deprivation provide evidence of circadian disruptions that may be at the core of the health risks faced by human night and shift workers. One valuable insight from that work is the importance of changes in the distribution of food intake as a cause of metabolic imbalances associated with activity during the natural rest phase. Limitations of those models stem from the use of only nocturnal laboratory rodents and the fact that they do not replicate situations in which humans engage in work with high cognitive demands or engage voluntarily in nocturnal activity . Temporal niche switches by rodents have been observed in the wild and interpreted as adaptive responses to energetic challenges, but possible negative outcomes, similar to those associated with human eveningness, have not been systematically studied. Species in which a proportion of animals shows a switch from a day-active to a night-active  when given access to running wheels provide a unique opportunity to model human eveningness in a diurnal rodent. In particular, the mosaic of phases of brain oscillators in night-active grass rats may provide clues about the circadian challenges faced by humans who show voluntary nocturnal wakefulness. Our contemporary global society has created demands that require many of us to be active during the natural rest phase of our species, the night. This is exemplified by increasing number of individuals who work nights and thus are awake and engaged with the environment at least for part of the time normally dominated by human sleep. There is a rich, albeit mostly correlational, literature linking night and shift work to a multitude of pathologies including higher risk of cancer , metabolvia direct retinal projections from melanopsin-containing retinal ganglion cells  , 8 that on cells . Outputson cells . Night oon cells , 11. HowAnimal models of shift work have used almost exclusively laboratory rodents  is remarkably different if the animals are forcibly kept awake at night compared to when they show unconstrained night wakefulness ] rhythms in the SCN  or the nAvailable models using constrained (forced activity and timed sleep deprivation) or unconstrained (wheel running availability) activity during the natural rest phase of a species do not incorporate the effect of the type of engagement with the environment that goes on during the new active phase. In particular, these models do not replicate instances of human nocturnal activity with significant attentional and cognitive demands, e.g., nurses in hospitals or technicians working at nuclear plants. Experiments in which nocturnal laboratory rats are trained and tested during the day on tasks that demand enhanced attentional performance provide evidence of clear circadian effects that include a shift to a predominantly diurnal chronotype with salient anticipatory activity that persists for days after the training is discontinued , 47. ActThe work from our group discussed here was carried out in accordance with the recommendations of the Michigan State University All University Committee on Animal Use and Care, and the National Institute of Health guide for the Care and Use of Laboratory Animals. All protocols were approved by the Michigan State University All University Committee on Animal Use and Care.The ideas presented here stem from discussions among the three authors, AN wrote the first draft and LS and LY edited and expanded the initial version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The epigenome is a set of heritable modifications and tags that affect the genome without changing the intrinsic DNA sequence. These marks include DNA methylation, modifications to histone proteins around which DNA is wrapped and expression of noncoding RNA. Alterations in all of these processes have been reported in patients with COPD. In some cases these differences are linked to disease severity and susceptibility and may account for the limited value of genetic studies in COPD. Animal models of COPD suggest that epigenetic modifications and processes are linked to COPD and may be tractable targets for therapeutic intervention"}
+{"text": "We present an overview of the current literature and management techniques for vaginal extrusion or urinary tract erosion of graft materials used in pelvic floor reconstruction. A MEDLINE search was performed to identify literature pertaining to the incidence and management of vaginal or urinary tract exposure of graft materials commonly used in anti-incontinence and pelvic floor reconstructive procedures. Dependent on the type of mesh material used, a vaginal extrusion rate of up to 77% has been reported. The currently accepted, loosely woven, monofilament type I polypropylene meshes appear to have acceptable lower exposure rates in the range of 1\u20133% for slings, but with the larger area of mesh used in prolapse repairs, the rate increases to up to 10%. With the current widespread use of graft materials to reinforce pelvic floor reconstructive techniques, it is imperative for surgeons to be familiar with potential complications related to the materials and proper management of these complications. Although it is beginning to appear that the benefit of using some synthetic materials may outweigh the risks, proper management and understanding of the risks is important in order to counsel our patients appropriately and responsibly prior to their surgeries."}
+{"text": "Viruses are master molecular manipulators, and evolved to thrive and survive in all species. Key to their continuing success has been the ability to subvert host cell defence systems to ensure viral survival, replication and proliferation. Amongst the diverse arsenal of defence mechanisms deployed by multicellular hosts are those that rely on rapid activation of programmed cell death or apoptosis pathways, to trigger premature cell death of infected host cells. Apoptosis of an infected host cell has been identified as a powerful mechanism to curtail viral spread, and consequently, viruses have evolved sophisticated molecular strategies to subvert host cell apoptotic defences.This special issue is devoted to the interplay of viruses and host cell apoptotic signalling pathways. Many viruses manipulate apoptosis for their own purpose, and Zhou et al. review the interplay of viruses with death receptor mediated apoptosis . This coI hope that the research articles and reviews that were assembled for this special issue will shed light for both experts and interested bystanders on the complex and sometimes unexpected interplay between viruses and host cell apoptosis signalling pathways, and inspires researchers to investigate the many unresolved questions about the ways and means utilized by viruses to manipulate life and death of an infected cell."}
+{"text": "Integrating social client relationship management (CRM 2.0) in the built environment can enhance the relationship between construction organizations and client towards sustaining a long and lasting collaboration. The data exploration analyzed the e-readiness of contracting and consulting construction firms in the uptake of CRM 2.0 and the barriers encountered in the adoption of the modern business tool. The targeted organizations consist of seventy five (75) construction businesses operating in Lagos State which were selected from a pool of registered contracting and consulting construction firms using random sampling technique. Descriptive statistics of the e-readiness of contracting and consulting construction firms for CRM 2.0 adoption and barriers limiting its uptake were analyzed. Also, inferential analysis using Mann\u2013Whitney U statistical and independent sample t-test was performed on the dataset obtained. The data generated will support construction firms on the necessity to engage in client social relationship management in ensuring sustainable client relationship management in the built environment. Specifications tableValue of the data\u2022Clients are the most important entity in the construction business, therefore managing their needs is paramount to the success of construction organizations.\u2022The dataset will enable researchers to advance on the subject of social client relationship management in the built environment as there is a dearth of studies in this area as it relate to the construction industry \u2022An understanding of the data when analyzed compared with existing data on client relationship management can help ascertain the sustainable route to managing client relationship in the built environment.\u2022The dataset can help construction stakeholders understand the barriers militating against the uptake of client social relationship management so as to develop a framework that can successfully increase the uptake of ICT tools and other relationship management tools in the built environment.\u2022Clients are the most important entity in the construction business, therefore managing their needs is paramount to the success of construction organizations.1p-value at .40 and .36 which is higher that the alpha value of .05 depicts that there was no significant difference between contracting and consulting firms on barriers militating against the adoption of social media in social client relationship management (CRM 2.0) in their construction business.Social client relationship management (CRM 2.0) is a business strategy that uses internet and social media platforms to enhance traditional, one-dimensional interactions between companies and their existing and potential customers by giving clients greater control over how they communicate with the firms they do business with and providing them with the tools needed to form the foundation of the relationship. In order to measure the relationship management that exist between clients and construction organization, the data exploration covered contractor and consultant construction firm's readiness to uptake social client relationship management (CRM 2.0) in the built environment and barriers militating against its uptake. The necessity of the data on Client Relationship Management uptake is due to the slow rate of adoption of the modern client management tool in the built environment compared to other industries like telecommunication and logistic enterprise 2The population for the data exploration is the summation of construction organizations which comprises of consulting and contracting firms in Nigeria. The dataset collected is more specific to construction business of contracting and consulting firms operating in Lagos State. Lagos State has many head offices of construction organizations within the state. The contracting and consulting construction firms used to generate the data were selected randomly from the pool of the record of registered construction organizations in the study area. A cross-sectional research survey design was used in selecting the sample size of seventy-five (75) construction organizations. Questionnaire instruments were directed to managerial staff that deal with client and client organizations. Similar field surveys that have obtained dataset in like manner include"}
+{"text": "Now, the time required to replace a field light is up to seven times faster and the time to realign a reticule is reduced to the order of three times faster. Only one quality control (QC) check is required after these adjustments. Removal of excess heat within the gantry head has eliminated two major problems: (A) the metal rod supporting the mirror assembly for the field light no longer expands and contracts causing a misalignment of the field light projection, and (B) the damage to the bearing in the cooling fan assembly has been eliminated. The simulator is now more functional and these improvements have reduced downtime significantly, making repairs and adjustments much more convenient and efficient.The modifications made to a radiotherapy simulator that improve its functionality and minimize its downtime are described. Functionality was enhanced with some simple effective improvements. Decreasing the frequency and time spent on repairs reduced downtime. These \u201cin\u2010house\u201d improvements were made to a Varian Ximatron simulator at the Tom Baker Cancer Center. Now there is easier access to the field light and optical distance indicator (ODI). Projections of the field light and ODI are much brighter and ODI adjustment is more reproducible. A crosshair was etched onto the clear PACS number(s): 87.53.Vb, 87.53.Xd Conventional radiotherapy simulators are still the workhorses for treatment simulation even with the popularity of CT\u2010simulators and virtual simulation. Almost all treatment facilities use conventional simulation for tumor localization and treatment simulation for many treatment sites. They are much less expensive and simpler and cheaper to repair and maintain than the more complicated CT\u2010simulators.Some conventional simulator designs do not allow convenient or timely repair and replacement of components within the gantry simulator head. The compactness of all of the various systems makes it difficult to gain access to the affected component and not adversely affect other nearby components unintentionally. Thus, seemingly simple routine servicing that should be quick to complete are made difficult and untimely.The replacement of burnt out light bulbs for the field light and optical distance indicator (ODI) assemblies require immediate replacement usually during a busy clinical day. On the average replacement occurs once or twice a year and there have been years where light bulb replacement occurred up to four times. The proximity of these lights is so close to other crucial components that any tampering with them may adversely affect the others. Again what should be simple tasks are manifest into inordinate amounts of time during the useful clinical day causing an increase in downtime that should be preventable or reducible.All improvements have been made to the components in the head of the simulator gantry with the intent of making convenient and more efficient adjustments and major savings in downtime. Before modifications downtime from these components ranged from 5.5 to 22.5 h per year, and after the improvements downtime was reduced to the range of 3.5 to 5.5 h. The time to plan trouble shoot, and implement the modifications took approximately one week of nonclinical time. Duplicate original equipment manufacturer's (OEM) components were modified externally allowing continued clinical use of the simulator. Final implementation of the completed modules was efficient and also performed outside of clinical time (see Table II). The importance of the field light, ODI, and reticule alignment see Fig.  in the sSeven major improvements have been made to deal with the following problems:(i) Gaining access to the affected device in a timely manner within a tightly compacted and confined space. Many components are within very close proximity to one another within the simulator head. In fact, some systems block access to others and some systems cannot be handled without simultaneously touching and adversely affecting another.(ii) Heat buildup caused by the burning bulbs of the field light and ODI. This heating and eventual cooling causes the metal rod supporting the mirror to expand and contract. The mirror, which is then a moving target, changes the optical projection of the reticule crosshair causing a perceived misalignment. In the cooled state, this misalignment disappears.(iii) The cooling fan bearing wears down with latent heat originating from hot light bulbs causing premature failure.(iv) Alignment mechanism for ODI lacks reproducible control using only one screw to control tilt. Thus, trial and error is used in positioning.(v) Projections of the field light and the ODI are dim enough that they are difficult to read on the patient.(vi) Damaged or loose reticules have been time consuming to realign.(vii) Quality control checks after any of the above mentioned repairs have been very time consuming and may have to be repeated in an iterative repair procedure causing further delay to clinical service. Reducing repetition of these or eliminating them altogether is desirable in reducing downtime.The lamp assembly was modified with fiber optics  to make the manipulation of the assembly more convenient and timely. It was relocated to share the housing  with the ODI and the cooling fan that is shown in Fig. A special tilting mechanism was added to the fiber optic inputs for the field light and ODI  shown in Fig. The ODI mechanism for alignment was controlled from a single screw or pivot  It was modified to allow movements using two independently placed screws. This allows a push\u2010pull dynamic facilitating more reproducible movements for alignment. Figure All of the improvements have produced a reduction of downtime and more convenient repairs and maintenance (see Table II). The components requiring the most frequent servicing, namely the field light and ODI, were improved significantly. The modified design facilitates easier access to these components while minimizing or eliminating the potential for adverse effects to other components nearby. This increases efficiency by eliminating needless adjustments and the accompanying QC checks.3 Replacing the light bulb for the field light for example will no longer affect the bulb positioning since it is fixed within the new housing and this eliminates the lengthy amount of time that was required previously to reposition the bulb. Now the QC afterwards is done only once for the affected component only.The heat that builds up from the field light and the ODI light was concentrated and made the assembly too hot to touch. The conduction of this heat caused the expansion of the mounting rod see Fig.  that supThe tilting mechanism for the field light and ODI is a very simple but significant improvement. This feature locks the corresponding light bulb into a position eliminating the fiber optic input falling on the optical shadow created by the apex of the bulb. A significant increase in brightness is achieved for both systems.Any positioning adjustment of the ODI can now be done in a reproducible manner with the new dual screw push\u2010pull mechanism. A large increase in efficiency is realized over that of the previous single screw trial and error mechanism.x\u2010ray center coincides with the optical center and the collimator axis of rotation.The addition of the optical crosshair markings on the previously clear acrylic exit window facilitates an effective starting point for realignment and replacement of the reticule. The reticule crosshair is aligned optically with the projection from the acrylic window crosshair. Then centering of the crosshair is tested optically followed by a fluoroscopic test to verify that the optical and fluoroscopic crosshair images match.A Varian Ximatron simulator has been improved with regards to utility and the reduction of downtime. The field light and ODI assembly have been combined into one housing together with the cooling fan which now runs continually to remove any heating problems from the lights. This design makes these components more accessible and their adjustment independent of other components in the simulator gantry head. The field light has been modified to include fiber optics and any light bulb replacement occurs at a fixed position within the housing, eliminating time\u2010consuming optical maneuvering. Increased brightness to both the field light and ODI has been achieved with a tilting mechanism that fixes the bulb into a shadow\u2010free position within the assembly. The continuously running cooling fan reduces the heat enough such that it disallows the previously occurring displacement of the mirror. This saves much time and frustration in repair. Premature failure of the fan is also avoided. The ODI adjustment mechanism has been converted from a trial and error device utilizing a single screw into a dual screw push\u2010pull dynamic allowing reproducibility. A permanent optical crosshair that overlaps optically with the reticule crosshair has been added to the clear acrylic sheet composing the exit window. This allows an efficient reticule replacement or adjustment. All of these improvements have significantly reduced downtime of repair, replacement, and repositioning. The frequency of QC after routine adjustments has been greatly diminished with the added confidence of the design."}
+{"text": "Haematopoiesis is the term used to describe the production of blood cells. This is a tightly regulated hierarchical system in which mature circulating blood cells develop from a small population of haematopoietic stem (HSC) and progenitor cells within the microenvironment of the bone marrow. Molecular and genetic abnormalities arising in these stem cells lead to a block in the normal programme of proliferation and differentiation and result in the development of the blood cancers known as the leukaemias and lymphomas. Recently the regulatory role of the bone marrow microenvironment or niche has also become increasingly recognised. The interface between the bone and bone marrow (endosteum) and the region surrounding the blood vessels (perivascular) provide distinct niches harbouring quiescent HSC or proliferative HSC respectively. Current chemotherapeutic regimes can often successfully target the proliferative HSC but disease relapse occurs due to residual quiescent HSC. Understanding these developmental and regulatory processes and the associated cell communication mechanisms are thus crucial to the development of new treatment strategies. The CCN family of proteins have been recognised to play a key role in all aspects of haematopoiesis. Normal adult blood cell production (haematopoiesis) takes place mainly within the bone marrow. It is now acknowledged that this microenvironment plays a key role in maintaining the balance between proliferation and differentiation  with insulin-dependent diabetes mellitus (IDDM) and CD34+ cells from 100 cord blood samples  is also a recognised source of haematopoietic progenitor cells although these cells differ subtly from those found in bone marrow  is characterised by the accumulation of malignant plasma cells in the bone marrow (BM) leading to the overproduction of monoclonal immunoglobulins, osteolytic bone lesions, renal disease and immunodeficiency. MM is usually preceded by the premalignant conditions monoclonal gammopathy of undetermined significance (MGUS) and/or smouldering multiple myeloma (SMM). Interactions between MM cells and the BM microenvironment are well-established to play a role in supporting the growth and survival of MM cells, as well as enhancing bone resorption through increased osteoclast activity and suppression of osteoblast activity  is a term used to represent a group of leukaemias in which there is a block in differentiation in the myeloid lineage of cells. These leukaemias are the result of malignant transformation in haematopoietic stem or progenitor cells and are characterised by the presence of 20 % or more immature blast cells in the blood or bone marrow at diagnosis. AML is classified into specific subtypes based on cytogenetic and molecular characteristics defined by the World Health Organisation. This classification provides prognostic information regarding poor, intermediate and favourable risk groups  study  is from the MILE (Acute Lymphoblastic Leukaemia (ALL) is the most common leukaemia found in children but it is also found in adults where it has a poor prognosis. Research in this field is focussed on finding new prognostic biomarkers and alternative therapeutic targets  compared to non-Hodgkins (32 patients) lymphoma  is the only blood cancer which is characterised by a single specific genetic marker, the Philadelphia chromosome. This is caused by a reciprocal translocation between chromosomes 9 and 22 and leads to the formation of the bcr-abl fusion protein associated with elevated tyrosine kinase activity. Tyrosine kinase inhibitors have been developed as targeted therapy for CML and have been successful in obtaining long term remissions in patients. Nevertheless, many patients become resistant to these inhibitors and it is acknowledged that the leukaemia initiating cell remains. Efforts are now being made to find targets other than the kinase activity and to understand the relationship of the leukaemic stem cell with the surrounding microenvironment (Hughes and Ross CCN3 expression is dys-regulated at both the RNA and protein level in CML and there is a reciprocal relationship between CCN3 and BCR-ABL expression (McCallum et al. The mechanism of action of CCN3-induced growth regulation has been investigated using a number of cell line models. In the FDCP-MIX CML cell line model it was shown that BCR-ABL kinase activity not only regulates transcriptional activity but also enhances CCN3 secretion by the cells (McCallum et al. CCN3 is a non-canonical NOTCH ligand which is known to be a core signalling pathway in the haematopoietic system (Bigas et al. With the advent of high throughput technologies it is possible to screen for expression of thousands of genes in both cell lines and primary clinical material. CCN family members are now included on many microarray platforms and information on expression profiling is increasing exponentially. Two large online datasets discussed in this review, BloodSpot and MILE, are prime examples of information which suggests a wider involvement of CCN family members in blood cancer than currently appreciated but has not yet been validated (Kohlmann et al. This review has focused on the role of CCN members in haematological malignancies where there is more than simply basic expression data available. The haematology research community is currently focusing on targeting the microenvironment in addition to the malignant stem cell to improve therapeutic efficacy. It is clear the CCN family will play a key part in these future developments."}
+{"text": "This review will discuss the importance of sequencing long chondroitin sulfate and dermatan sulfate chains specifically derived from decorin. Decorin is a member of the small leucine-rich repeat proteoglycans and ubiquitously expressed primarily in the skin. Sequence information and diverse function of glycosaminoglycans is further influenced by variable expression through the core protein indicating the importance to analyse glycosaminoglycans from specific proteoglycans."}
+{"text": "The electroactivity of purine and pyrimidine bases is the most important property of nucleic acids that is very useful for determining oligonucleotides using square wave voltammetry. This study was focused on the electrochemical behavior of adenine-containing oligonucleotides before and after their isolation using paramagnetic particles. Two peaks were detected\u2014peak A related to the reduction of adenine base and another peak B involved in the interactions between individual adenine strands and contributes to the formation of various spatial structures. The influence of the number of adenine bases in the strand in the isolation process using paramagnetic particles was investigated too. The limits of detection  were calculated, whereas N was expressed as standard deviation of noise determined in the signal domain unless stated otherwise [The mathematical analysis of the data and their graphical interpretation were analyzed by software Matlab . The results are expressed as mean \u00b1 standard deviation (S.D.) unless noted otherwise  and changes in analytical parameters . It seems that the separation processes based on magnetic materials could change the properties of biomolecules and influence especially their usage in"}
+{"text": "Neurodegenerative disorders encompass a range of medical conditions which primarily affect the neurons in the human brains. Such conditions result in the disorders of the central nervous system which eventually lead to the progressive loss of neural tissues including death of neurons . An insight into the prospective roles of haptoglobin (Hp) (an endogenous hemoglobin-binding protein) in traumatic brain injury and other acute brain injuries is discussed in another report which portrays to be helpful in understanding the inconsistency in outcomes of clinical studies regarding the importance of Hp phenotypes in such brain injuries . This study is a step forward to develop and progress with new therapeutics in the prevention of cerebral hemorrhage which is a common feature of traumatic brain injury and its associated chronic disabilities . Furthermore, important and significant biomarkers for neurodegeneration have been investigated and studied for their sensitivity and specificity in this e-book that sheds new lights in treatment of irreversible cognitive deficit and dementia in elderly population. Biomarkers represent important molecular diagnostic tools and thus the development of novel biomarkers could bring significant breakthroughs in an early diagnosis of neurodegeneration .This e-book showcases important and significant reports that cover a wide range of areas in neurodegeneration research and treatment. These include diagnosis and prognosis; role of neuroactive drugs in regulating central nervous system; advances in novel biomarkers; brain injury induced neurobehavioral outcomes and also connectivity between spinal muscular atrophy and loss of \u03b1-motors neurons among other reports. One of the reports investigates the origin and potential function of corpora amylacea (CA) which are found in large numbers in the central nervous system of the patients with neurodegenerative diseases. Immunohistochemistry analyses were employed to reveal fungal proteins present in CA from patients diagnosed with Alzheimer's disease . In another review, adropin is discussed as a biomarker for the diagnosis of central nervous system disorders and is considered as a potential therapeutic candidate in central nervous system injuries . It is believed that hyper excitability in neuronal network possibly contributes to the cognitive deficits in Alzheimer's disease and this is addressed in a research report that sheds light on the mechanism of aberrant neuronal networks in Alzheimer's disease . To this end, researchers conducted investigations on the excitability in cultured pyramidal neurons from APP/PS1 mice using patch clamp recording techniques. This provides an important insight into the pathogenesis of Alzheimer's disease that could be helpful in developing new therapeutic avenues in the future . This e-book covers another area of neurodegeneration: spinal muscular atrophy, which is an early-onset, autosomal recessive neurodegenerative disease that is characterized by the loss of spinal \u03b1-motor neurons leading to infant deaths (Butchbach). The author highlights why a better understanding of the underlying mechanism causing spinal muscular atrophy and the accurate measurements thereof are crucial to control such neurodegenerative disease in infants (Butchbach). The molecular mechanisms of C9orf72 gene causing amyotrophic lateral sclerosis, frontotemporal dementias and atypical parkinsonian syndromes are also discussed (Munteanu and Lynch).In a particular review, the application of stem cells and induced pluripotent stem cells in combating neurodegeneration is discussed that addresses the issues of diagnosis, modeling, and therapeutic transplantation strategies (In concluding our thoughts and deliberations, we do hope that this discussion forum in the form of an edited e-book will advance our further understanding to have an enhanced insight of neurogenesis and eventual cure for neurodegenerative diseases. Future research directions might involve multifunctional biomolecular diagnostic markers and technology platforms that would significantly enhance and augment the accuracy, specificity and sensitivity that would drive an early diagnosis and prognosis of various neurodegenerative disorders.Both authors have made substantial intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The data presented in this article are related to the research article entitled \u201cThe Influence of Atrium on Energy Performance of Hotel Building\u201d   Specifications TableValue of the data\u2022The detailed thermal loading data provided for design alternatives of atrium type hotel buildings in Belgrade would give designers a better understanding of hotel energy demands.\u2022The building energy modeling and simulation is performed using EnergyPlus simulation software, and could be compared to other studies that used different simulation techniques.\u2022The data presented in this article could be used for analyzing the facilities located in the climatic conditions similar to Belgrade climate.\u2022Atrium design alternatives could be used as a basis for further research and development of hotel building envelopes.1The data in this article present input data and schedules for the building energy simulation of design alternatives of atrium type hotel building .The research method includes the creation of a hypothetical model for the analysis, design of alternatives, application of numerical simulations using computer software, and comparative analyses of the selected results. The building energy simulation is carried out by OpenStudio SketchUp PlugIn \u2013 an interface that integrates with EnergyPlus simulation engine. Certain parameters in the particular model are changed  so that the observation of how the changes influence energy performance of the building could be conducted."}
+{"text": "This data presented herein are the research summary of \u201cmechanical behavior and durability performance of concrete containing recycled concrete aggregate\u201d   Specifications TableValue of the data\u2022The influence of replacement of recycle concrete aggregate in production of new structural concrete is discussed here\u2022This data set can also be used as a guideline for others to scrutinize the properties of recycle concrete aggregate\u2022The research data presented herein may be useful to manufacture different commercial elements using recycle concrete aggregate\u2022This data set may also encourage to recycle other wastes to minimize the dependency on natural resources1This dataset reported herein were obtained from the experimental studies conducted on the different percentages of recycle concrete aggregate (RCA) replacement in the concrete mix and relate them to the influence of physical, mechanical and durability properties. The detailed of the dataset can also be found in 2The materials compositions for different RCA mixes used in the research are shown in The RCA was collected from the different sources of construction and demolition waste (C&DW) sites in the Western Cape region of South Africa. Concrete was then made by replacing different percentages  of NA by RCA as they are assigned RCA0 to RCA100 in The physical properties of aggregates such as relative density of aggregates, aggregate crushing value, flakiness index, and water absorption capacity were also measured and presented in"}
+{"text": "The data presented herein are compilations of the research summary of \u201cAssessment of the Quality of Steel Reinforcement Bars Available in Nigerian Market\u201d  [1]. This data article provides information on the properties and cost of steel rebars used in reinforced concrete in Lagos, Nigeria. The data is based on the properties of 12\u202fmm rebar brands which are the most used steel diameter in construction and they include actual diameters, yield strengths, ultimate strengths, ultimate/yield strength ratio, ductility and the cost of each brand. This data also contains the limiting standard properties of the highlighted properties in this data. Specifications TableValue of the data\u2022This data will assist in assessing the role of steel rebars in the quality of our reinforced concrete properties and form a basis on how to prefer solutions to managing the challenges the state of the steel might pose to construction and durability of building structures.\u2022The data can be used in collaboration with other related research outcome to develop a local factor of safety for the steel rebar as used in the design of reinforced concrete.\u2022This data can form a basis for the standard regulatory bodies or agencies to query erring steel rebar manufacturing brands with a view to improving their quality or appraising complying brands.1Over 90% of storey building in Nigeria are of structures made from reinforced concrete 2The method of sampling these rebars is by market survey to identify the steel brands used in this data, purchased three cuts of 12\u202fmm diameter rebars for each identified steel brand from three different merchants. The cuts were labeled and sent to the laboratory for tests. 12\u202fmm diameter bar size was chosen because it is the most used in structural design work in Nigeria Reinforced concrete is designed according to a recommended standard procedure"}
+{"text": "Most often the newspapers and bulletin come out with voluminous cases of deaths due to drowning. At the same time an ample section of such cases encompass entomological evidences, that can be scrutinized as a very useful parameter in estimating post mortem interval (PMI). This research database is an outcome of a 2 years reflective study, based on an assessment of records related to human deaths due to drowning. The drowned bodies from various districts of Haryana are sent to PGIMS , Rohtak. The study took the data of year 2015\u20132016 into consideration. All the cases were reviewed and summarized in terms of monthly occurrence of total cases, age differentiation, gender differentiation and month wise occurrence of entomological evidences on the dead bodies through detailed study of post mortem findings. This data will lead to an insight into the magnitude of drowning deaths in Haryana along with the usage of entomological data for determining Post Mortem Submersion Intervals (PMSI). Specifications TableValue of the data\u2022Routine monitoring of deaths due to drowning in an aquatic environment is very important for medicolegal and forensic purposes around the world.\u2022Little is known about the trend of drowning related death in an aquatic habitat with respect to entomological evidence, so the present data emerge of immense value since no data is available on this important aspect from Haryana.\u2022The information provided in this data set bring about new ideas for forensic experts and police officers about the trend of drowning deaths in an aquatic habitat with respect to the presence or absence of any entomological testament.\u2022This kind of data is also useful for scientists and researchers working in the field of forensic medicine, aquatic entomology and forensic entomology. It administers detailing to the inhabitance of entomological specimen in this particular area.\u2022Entomological facts generated in the study provide a pandora of information which can be useful for future efforts in the discipline of forensic entomology.\u2022The details contributed here would be the first of its kind for the readers to fully understand the types and trends of drowning deaths with a special emphasis on entomological knowledge in an aquatic environment.\u2022The present data shows the presence of entomological specimen with most of the recovered drowned bodies. The neglect of this evidence is no more possible.\u2022This data will also provide means of determining PMI in aquatic environments, when the initial signs of decomposition have passed off.\u2022This data serves as a source of information for the research institutes as well as for the forensic science community. It can be further used to correlate the significance of entomological specimen present in drowned bodies for future research in this particular area.1The data provided in this article explain about the trend of deaths in an aquatic environment and the significance of entomological evidence in drowning deaths from Haryana, India . There h2Experimental design consists of frequencies based on the distribution patterns of death due to drowning in an aquatic system. These patterns were evaluated in the context of location, year, month, gender and age wise variations. The present database comprises of drowning death cases reported in the Department of Forensic Medicine, Post Graduate Institute of Medical Sciences (PGIMS), Rohtak from 1st January, 2015 up to 31st December, 2016. All the drowning related death cases were surveyed and filtered from the Post-mortem Reports (PMRs) , Table 5"}
+{"text": "Action research (AR) has an important role to play in educating physical therapists. Increasing efforts should be encouraged to instigate AR programs in physical therapy practice and clinical education. Such programs commonly require considerable effort and understanding by clinical instructors, and require adoption of new educational methods. AR programs can lead physical therapists and clinicians to be more questioning and reflective in evaluating practical questions regarding patient therapy and education. The purpose of this article is to educate the readers on the importance of AR and to provide a few relevant references on that topic. A specific study is described in this paper in which physical therapy clinical instructors participated in a structured workshop designed to demonstrate the values of AR and how such values can be incorporated in teaching their students. AR can lead to improved therapist-patient interaction and help solve specific practical problems arising during therapy sessions."}
+{"text": "For genomic medicine research to be fully translated into clinical care, it is critical for researchers to engage stakeholders who ultimately regulate the use of genomic technologies and therapeutics within healthcare practice. Herein, we describe an example of how this might work. Notwithstanding the historical hype of genomic medicine , there iProducing the evidence is but the first step toward implementation of genomic medicine. Efforts to engage with target communities and patient stakeholders are now a frequent component of clinical genomics research protocols . Successhttps://cser-consortium.org/), Implementing Genomics in Practice , and Clinical Genome Resource . A primary aim of these public-funded projects is to elucidate whether and how genomic technologies can be utilized to improve patient outcomes and optimize healthcare for the population and individual. In other words, much of research is focused on the analytic and clinical validity as well as clinical utility of genomic technologies. Researchers\u2019 definitions of these concepts may vary considerably from that of regulatory groups, however. Rather than producing scientific evidence with the assumption that it will meet the evidence requirements for policy development, it is important to engage individuals making both coverage and regulatory decisions to understand the evidence needs and assessment processes of these stakeholders. Such engagement may facilitate understanding between researchers and regulators and help ensure study designs and outcomes achieve their intended goals.Currently, many of the research programs producing the growing body of evidence for healthcare applications of genomic medicine are associated with or directly linked through large-scale consortia funded by the National Human Genome Research Institute (NHGRI), under the purview of the National Institutes of Health (NIH). Examples include Clinical Sequencing Exploratory Research  in genomic medicine and their evidence/data needs for policy development and decision-making. Key questions may include the following: (1) What is each regulatory group\u2019s role(s) in genomic medicine and how can research efforts contribute to their specific aims? (2) What types of evidence are needed to support each group\u2019s regulatory decisions? (3) Do the research aims align with the evidentiary needs and/or can the study protocol be amended in response to the required data/evidence? (4) Are there mutual benefits to establishing a relationship? (5) Is it feasible to build and sustain a relationship of transparency, communication, and dissemination?The US Food and Drug Administration (FDA) proactively expressed interest in ClinGen\u2019s approach to curation of genes and variants. Based on this interest, ClinGen sought to establish a process of engagement with the FDA as the first stakeholder. The interactions to date between ClinGen researchers and the FDA described here are presented as an example of how such engagement could work. To facilitate the development of this stakeholder relationship, a small workgroup of key program contacts/liaisons from the relevant organizations  met monthly via conference calls. At the outset, roles and interests were defined as summarized in Fig.\u00a0The open dialogue generated by establishing this relationship has provided a means through which to clarify and/or contextualize confusing or misunderstood jargon and concepts in terms of the research and the regulatory processes. Acknowledging the need for shared learning is essential to building a mutually respectful relationship. The formal development of a dedicated liaison and workgroup tasked with engaging regulatory groups has allowed broader contextualization of overarching goals and minimized the possibility for ambiguous messages or distorted perceptions.The relationship has allowed ClinGen researchers to understand the potential uses of ClinGen resources for FDA regulatory purposes and to align curation processes to produce a resource consistent with FDA draft guidelines on regulatory-grade databases . The accThrough this experience, it has become evident that engaging with regulatory stakeholders, such as the FDA, can not only be helpful in the development of the ClinGen resource, but is essential to guiding appropriate utilization of the generated evidence to support improved health through genomic medicine Fig.\u00a0. This exThe need for continued and increased regulatory engagement activities among genomic medicine research is great, and the potential impact of these types of interactions to further clinical genomic medicine may be well worth the effort."}
+{"text": "Sickness absence rates in the UK continue to exceed those in much of the developed world, with an annual cost to employers of \u00a329 billion. Rates of sickness absence in the public sector are higher than those in the private sector, with the exception of the fire service where they are consistently lower.To understand the influences that increase attendance among operational firefighters.A series of semi-structured interviews undertaken with operational staff to explore their attitudes to sickness absence.Review and analysis of participant responses identified a number of key themes, namely employee well-being, including physical fitness and mental health; employee engagement with the fire service as manifested by culture, experience, nature of the job and leadership; organizational factors including the staffing model and relationship with occupational health services and policy, which describes both refinements to and implementation of targeted policies.Previously observed factors such as improved fitness and the distinct firefighter culture play a role, yet other factors emerged that could explain the differences. These include the greater work\u2013life balance offered by their shift patterns, the terms and conditions of employment and perhaps most importantly the evolution of precisely targeted policies that understand the unique nature of the operational fire service. The rates of sickness absence in the UK, where workers take an average of 9.1 sick days per year, costing employers around \u00a329 billion in sick pay and employees \u00a34 billion in lost earnings  and a nuAt first glance, these figures may appear incongruous considering the hazardous nature of operational firefighting and the risk of physical injury and exposure to psychological stress ,9. TheseThe study took place within WMFS, the second largest UK Fire and Rescue Service (UKFRS) and one that provides emergency services to 2.7 million residents of the seven local authorities within the West Midlands metropolitan county. The workforce consists of some 1500 operational and 500 non-operational staff. Operational staff are made up of firefighters or fire officers, organized into groups known as \u2018watches\u2019, working either day or night shifts typically in a pattern of 4 days on and 4 days off. Non-operational staff work in fire control and are responsible for handling emergency calls to the service, with shift patterns similar to operational staff, or in specialist and administrative roles such as human resources or finance where staff typically work more conventional office hours.All those invited to participate in the study were operational staff directly employed by WMFS and purposively sampled to reflect a range of rank, gender and length of service. The intention was not to sample proportionate numbers of each rank but instead for our sample to incorporate maximum variance, i.e. to reflect the range of seniority of operational employees. Written invitations were issued to all six operational watches from occupational health. Semi-structured interviews by the second author, a member of the occupational health unit at WMFS, were used to capture individual experiences of operational staff regarding their motivation to attend and the factors that influence this motivation. These include attitudes to their role and to their colleagues and the current management of sickness absence within the service . CollectWhat emphasis do you place on the importance of physical health?What emphasis do you place on mental health?Are there any aspects of your role that encourage you or your colleagues to attend work?Are there any aspects of your work environment that encourage you or your colleagues to attend work?Are there any aspects of the way your work is organized that encourage you or your colleagues to attend work?What impact if any have management policies had on whether you or your colleagues attend work?A total of 16 interviews were conducted with staff who had served between 8 and 28 years and ranged in rank from station commander to firefighter. The response rate was low at 24%, although the requisite job titles and watches were represented in the group interviewed. Only two of the participants were female which though small is indicative of the lower numbers of female operational staff. The characteristics of those interviewed are summarized in The first theme of \u2018employee health\u2019 describes the attitudes of operational staff to physical fitness and mental health. This included how they related to exercise and their attitudes to mental health and the reluctance to use the word stress. Quotations illustrating these findings are contained in The second theme was \u2018employee engagement\u2019 which describes the connection staff felt with their colleagues and their organization . It appeThe third theme identified, \u2018organizational factors\u2019 describes the structure of the organization and how resources are utilized . SpecifiFinancial incentives were also described and reference made to the continuing professional development (CPD) payment of up to \u00a3900 per annum available to operational individuals as part of their National Joint Council terms and conditions of employment. This payment can be withheld if sickness absence exceeds stated limits (quotation 18). However, potential drawbacks in the form of presenteeism were also recognized as one consequence of using these financial rewards (quotation 19). Whatever the policy, there was an understanding that they were only successful if implemented correctly and the importance of raising awareness in senior staff of the content of the policy and how it should be executed was noted (quotation 20).A number of potential influences on attendance among operational fire service staff emerged. These included the physical and mental resilience borne of their training and the engagement that comes from the distinct role and culture of the fire fighter. However, there appeared other important factors such as the shift system that provides a better work\u2013life balance and changes to policy that helped reduce the sense of entitlement to sick pay, encouraged responsibility for attendance and introduced the potential for financial penalties. We present what are to our knowledge the first detailed insights into the factors that underlie the low sickness absence rate of these public sector employees. Staff with a range of experience and rank were interviewed, reflecting the broader operational workforce. We further point out the advantages of an interviewer within the same organization, a role as occupational health advisor providing both understanding of the organization and trust within it, both of which are recommended characteristics when gathering qualitative data . That saPreviously research has shown how improved physical fitness can help reduce sickness absence  and the Engaged employees take less sickness absence  and charThe impact of correctly implementing a precisely worded attendance management policy has long been recognized and a number of successful policy adjustments were described by our participants. These included more robust policies to reduce the sense of entitlement and the requirement of colleagues to cover for absent team members, potentially a persuasive factor when considering the camaraderie of firefighter culture. One further policy change that appeared effective, though not without prompting concerns of presenteeism, was linking continual professional development payments to attendance. Previous research has also described the positive impact of financial incentives on work attendance  particulOur study has identified a number of factors that appear to contribute to continued low levels of sickness absence observed in the operational fire service. Future work might attempt to quantify some of our findings and determine further their relative importance both alone and in combination. Our qualitative work now needs underpinning with quantitative data to help determine which interventions and occupational settings would be most effective. A starting point would be to pilot interventions based on the influences we have identified in isolation across non-operational staff groups within the fire service and begin to build an evidence base of demonstrable efficacy.This is the first study of its kind to try to identify and understand the factors determining why sickness absence rates observed among operational firefighters are the lowest in the public sector.Though physical fitness and firefighter culture play a part, other factors came to light including the positive work\u2013life balance afforded by fire service shift patterns and the evolution of precisely targeted policies that understand the unique nature of the operational fire service.The relative importance of the factors identified and how they combine should be explored further in view of the potential benefits of reducing sickness absence in other groups of public sector workers.P.H. was employed directly by WMFS as a senior occupational health advisor. I.L. declares no conflicts of interest. The findings and conclusions in this work are those of the authors and do not necessarily represent the official position of WMFS."}
+{"text": "Cytotoxic chemotherapy brings routine cures to only a small select group of metastatic malignancies comprising gestational trophoblast tumours, germ cell tumours, acute leukemia, Hodgkin\u2019s disease, high grade lymphomas and some of the rare childhood malignancies.We have previously postulated that the extreme sensitivity to chemotherapy for these malignancies is linked to the on-going high levels of apoptotic sensitivity that is naturally linked with the unique genetic events of nuclear fusion, meiosis, VDJ recombination, somatic hypermutation, and gastrulation that have occurred within the cells of origin of these malignancies.In this review we will examine the cancer stem cell/cancer cell relationship of each of the chemotherapy curable malignancies and how this relationship impacts on the resultant biology and pro-apoptotic sensitivity of the varying cancer cell types.In contrast to the common epithelial cancers, in each of the chemotherapy curable malignancies there are no conventional hierarchical cancer stem cells. However cells with cancer stem like qualities can arise stochastically from within the general tumour cell population. These stochastic stem cells acquire a degree of resistance to DNA damaging agents but also retain much of the key characteristics of the cancer cells from which they develop. We would argue that the balance between the acquired resistance of the stochastic cancer stem cell and the inherent chemotherapy sensitivity of parent tumour cell determines the overall chemotherapy curability of each diagnosis.The cancer stem cells in the chemotherapy curable malignancies appear to have two key biological differences from those of the more common chemotherapy incurable malignancies. The first difference is that the conventional hierarchical pattern of cancer stem cells is absent in each of the chemotherapy curable malignancies.The other key difference, we suggest, is that the stochastic stem cells in the chemotherapy curable malignancies take on a significant aspect of the biological characteristics of their parent cancer cells. This action includes for the chemotherapy curable malignancies the heightened pro-apoptotic sensitivity linked to their respective associated unique genetic events.For the chemotherapy curable malignancies the combination of the relationship of their cancer stem cells combined with the extreme inherent sensitivity to induction of apoptosis from DNA damaging agents plays a key role in determining their overall curability with chemotherapy. Despite the introduction of a significant number of new cancer therapeutics that target specific molecular pathways within malignant cells, the use of DNA damaging cytotoxic chemotherapy currently remains the mainstay in the management of most malignancies .In the majority of metastatic malignancies, DNA damaging cytotoxic chemotherapy can reduce the disease bulk, improve symptoms and extend life . HoweverBeginning in the 1950s and fully established by the 1980s there has been the development of routine curative chemotherapy treatment for most patients with acute leukemia, high grade non-Hodgkin\u2019s lymphoma (NHL), Hodgkin\u2019s disease, testicular and ovarian germ cell tumors, the gestational trophoblast tumors and for many cases of the rare childhood malignancies , 4. In cThere is clearly a significant clinical and biological divide between these rarer malignancies that can be routinely cured with cytotoxic chemotherapy and the majority of the more common cancers that are incurable in the metastatic setting and only relatively rarely cured even in the adjuvant setting. The biological explanation for this divergence presents a significant challenge to both understating of the cellular processes involved and to the development of more effective approaches to care , 7.With such a routine but dramatic and reproducible divide in chemotherapy sensitivity and treatment outcomes between these differing tumor cell types, the conventional explanations that ascribe chemotherapy resistance to the two main continuous variable parameters of the rate of tumour cell growth and the development of genetic mutations that lead to resistance are perhaps worthy of an updated review.Historically the concept of the inherent chemotherapy sensitivity of tumour cells and the concept of \u2018log kill\u2019 originated in early models that used murine leukemia as the model , 9. As wWe have recently suggested an alternate biological explanation for the extreme chemotherapy sensitivity of the chemotherapy curable malignancies. The theory centres on the close association between the cells of the chemotherapy curable malignancies and the occurrence of their unique genetic events of nuclear fusion, meiosis, variable-diversity-joining (VDJ) recombination, and somatic hypermutation (SHM) each of which has naturally upregulated apoptotic pathways as shown in Table\u00a0th century [The existence and important role of cancer stem cells appears to support many of the clinical observations on malignant cells and their responses to treatment. Whilst their existence was originally suggested in the 19 century , cancer  century , 12. Fur century \u201317. Over century .The importance of tissue specific somatic stem cells on cancer biology and therapeutics is twofold. Firstly, the existence of tissue specific stem cells allows for cells to be sufficiently long lived to be able to accumulate the number of mutations required to develop the malignant phenotype . The secThe resistance to chemotherapy of the normal tissue specific somatic stem cells appears to be routinely shared by the stem cells that have undergone malignant transformation and have become cancer stem cells . It is bThe main cancer stem cell model relates to cancer stem cells that form a hierarchy in giving rise to the tumour cells, following the linear progression from somatic stem cell to cancer stem cell and then to cancer cell. However there is also evidence that cells with some similar properties of stemness can arise from within the tumour cell pool in the stochastic cancer stem cell model. However these cancer stem cells having a different aetiology to hierarchical stem cells and the potential to have different biological characteristics. These two approaches to cancer stem cells are not mutually exclusive with stochastic cancer stem cells being reported in colon cancer that is also supported by a hierarchical cancer stem system .By definition the development of the malignant phenotype dramatically affects the biology of the cell with a major impact on the inhibition of normal patterns of cellular differentiation, senescence, ageing and programmed cell death . The resThe most dramatic impact of the onset of the malignant phenotype on altering cellular development can be seen in B and T cell malignancies which arise at a number of differing points along the normal but complex linear lymphocyte development pathways. In these malignancies, the malignant cells appear to become developmentally frozen with no further progression in the normal inear development of these cells from the time of the onset of the malignant phenotype . As a reMore recently we have postulated how the impact of the onset of malignancy on freezing the cells normal developmental progression may leave malignant cells developing at certain normally transient but key developmental points with fixed heightened physiological pro-apoptotic potential . For eacAlongside the major contribution made to chemotherapy responses of the chemotherapy curable malignancies by the apoptotic sensitivity associated with their associated unique genetic developments, the ABC transport proteins also plays an important role in determining chemotherapy responses , 29.A number of studies have indicated that the expression of this family of molecules is associated with a reduction in the efficacy of chemotherapy as a result of the increased efflux of drugs from cancer cells , 31. HowThe relationship between stem cells, the cancer cell of origin, the expression of the ABC system and the response to chemotherapy treatment in the chemotherapy curable malignancies helps to define the unique biology of these cells.The ABC protein system is widely expressed in conventional tissue specific stem cells, where it plays a key role in protecting these cells from genotoxic stress . SimilarHowever, as previously discussed, in the chemotherapy curable malignancies, there are no standard hierarchical cancer stem cells derived from the tissue specific stem cells and each of these malignancies arises from a transient developmental cell. It is apparent that these transient developmental cells have very differing patterns of ABC protein expression compared to tissue specific stem cells and this status appears to impact significantly on the expression of ABC proteins in malignancies derived from them.In normal trophoblast cells, assessment of the expression and functional activity of ABC transporter genes in murine embryos indicate that activity of these efflux systems is not present immediately post nuclear fusion but only becomes active by day 6 . PatholoThere is less data on the expression of the ABC family proteins in choriocarcinoma and placental site trophoblast tumours, however the limited data indicates that the majority of cases of choriocarcinoma or PSTT do not express ABCB5 .B and T cell malignancies arise from differing transient cell types occurring along the lymphocyte development pathways . The levData suggests that this variation in ABC protein activity during normal B cell development is reflected in the various malignancies arising along the course of lymphocyte development. A number of studies have indicated that there the expression of ABC family members is significantly lower in both B cell and T cell ALL than in HSCs . This reIn Hodgkin\u2019s lymphoma which is believed to arise from germinal centre B cells, the majority of cases do not express ABC proteins. Of note a more recent study has indicated that the approximately 30% of Hodgkin\u2019s cases that do express the ABCC1 protein have a tendency to a worse prognosis . SimilarIn contrast in CLL, levels of ABC proteins are higher than in DLBCL  and myelIn testicular cancer characteristically the majority of ABC proteins are expressed at only very low levels, with significant levels of expression only seen in tumours that have demonstrated chemotherapy resistance . The preReviewing the chemotherapy curable malignancies as a group it is apparent that they have this additional shared characteristic of generally low levels of ABC protein expression. This finding is intrinsically linked to particular cells of origin of these malignancies being transient developmental cells. Each of these developmental cells themselves have low ABC expression, rather than the high levels that are seen in hierarchical cancer stem cells. The relative role that these low levels of ABC expression plays compared to the impact of the unregulated apoptotic pathways associated with the unique genetic events occurring in these cells is an area to debate and hopefully one with interesting data to come.In the common epithelial malignancies the conventional structure of the cancer stem cell is the hierarchical system as shown in Fig.\u00a0In contrast in the chemotherapy curable malignancies the role and relationship of potential cancer stem cells appears to be significantly different in both the hierarchy of the cancer stem cell/cancer cell relationship and also of crucial importance in the characteristics of the cancer stem cell with regards to sensitivity to chemotherapy. Cancer stem cells in the chemotherapy curable malignancies have proven to be challenging to study but cells with stem like properties have been reported in most of these diagnoses. As discussed below it appears that in each case of the chemotherapy curable malignancies they do not have standard hierarchical cancer stem cell structure, however they do have a population of cells that have developed cancer stem cell qualities when arising from the malignant cells themselves in a stochastic or non-hierarchical model.The origin of the cancer stem cells in these malignancies may have a dramatic impact on their characteristics. Whilst the hierarchical stem cells will share many characteristics with the tissue specific somatic stem cells from which they arise, the stochastic stem cells arising from within the cancer cell pool whilst taking on some of the acquired characteristics of stemness, will also take on some of the primary biological properties of the malignant cell . We woulALL characteristically arises in pro-B cells that have or are undergoing VDJ recombination of their immunoglobulin genes . B cellsResearch into the existence and potential characteristics of cancer stem cells in acute lymphocytic leukemia (ALL) has been an area of considerable endeavour. A number of studies have indicated that there is no cancer stem cell hierarchy in ALL , 55, 56 Lymphoma presents a range of diagnoses of B cell malignancies arising from mature B cells that have completed VDJ recombination. Cells with stem like properties have been identified in a number of types of mature B cell malignancies including chronic lymphocytic leukemia (CLL), follicular lymphoma and myeloma \u201360. In kWe have previously hypothesised that the relationship to the onset of malignancy and the relationship with the VDJ or SHM activity determines much of the sensitivity of the malignant cells to chemotherapy and would argue that this degree of sensitivity is maintained in the stochastic cancer stem cells arising from these malignancies. The malignancies closely linked to VDJ and SHM, ALL, DLBCL, Hodgkin\u2019s disease and Burkitt\u2019s lymphoma are routinely curable with chemotherapy. However in contrast in malignancies arising distant from these genetic events; CLL, mantle cell lymphoma and multiple myeloma are not chemotherapy curable. We would argue that the apoptotic sensitivity linked to VDJ and SHM is absent in these cells distant from these events so determining the lack of extreme chemotherapy sensitivity in both the malignant cells and their counterpart stochastic stem cells.The pregnancy associated malignancies of post molar pregnancy trophoblast tumour and gestational choriocarcinoma are rare but highly curable with chemotherapy treatment , 63. TheGerm cell tumours are rare and predominantly arise from the pre-malignant precursors carcinoma in situ (CIS) in men and gonadoblastoma in women , 66. BotThe childhood malignancies have less clear developmental pathways but are generally believed to arise from embryological cells with blocked and failed development. We have previously postulated that the high apoptotic potential and chemotherapy curability of these rare malignancies is linked to the development of the malignant phenotype and blocked development occurring soon after gastrulation .In neuroblastoma the malignant cells are primitive cells with blocked embryological development that prevents normal cellular differentiation . Cells wThe finding that these other potentially chemotherapy curable malignancies do not arise in the conventional hierarchical manner from cancer stem cells related to standard tissue specific stem cells, also helps explain why these tumours frequently do not relapse after successful chemotherapy treatment.In the chemotherapy curable malignancies, the cells of each diagnosis arise from a cell which would normally have a transient passage through a complex developmental stage during which they become malignant. In health, a normal cell does not persist long term as a new trophoblast cell, or as a pro-B cell or germinal centre B cell, similarly the process of meiosis occupies only a relatively brief step in the complete pathway of production of sperm from sperm stem cells. In health cells passing through these developmental stages, do so for a relatively short length of time, and then exit to either the next stage in their development after their unique genetic event successfully occurs or naturally undergo apoptosis in response to event related DNA damage or an absence of positive selection.In the common solid malignancies the hierarchical relationship of the tissue specific somatic stem cell, the cancer stem cell and the cancer cells is relatively simple with the tissue specific stem cell giving rise through mutation to the cancer stem cell and the cancer stem cells in turn giving rise to the more rapidly growing standard cancer cells .In contrast in the chemotherapy curable malignancies the relationship and role of cancer stem cells is more complex and at present less clearly defined. The biological difference is most easily seen in the B cell and T cell malignancies where there is a very differing relationship with their stem cells than most conventional malignant cells. Here the stem cell that is the original source of cells for all lymphoid and myeloid malignancies is the haematopoietic stem cell (HSC). However this cell, which is very resistant to chemotherapy, only acts in the conventional stem situation for the initial lead off into B cell, T cell and myeloid cell development. After this point the B cell and T cells undergo the complex genetic recombinations of V(D)J genes and for the B cells somatic hypermutation and class switching that lead to their specific clonal identity. These processes in which DNA is cut, rearranged, mutated, rejoined and repaired contain much of the risk of DNA damage that leads to leukamagenesis and lymphomagenesis  but alsoThe malignancies that arise further along these pathways and more distant from the HSC are physiologically very different cells and now clonally and mutationally only very distantly related to the original HSC. Whilst HSC that carry mutations have been recognised to confirm a risk of development of CLL, these cells are not directly clonally related to a current diagnosis of CLL and cannot serve to repopulate the pool of established CLL cells after chemotherapy treatment . Whilst In a similar fashion there is a similar lack of conventional hierarchical cancer stem cells for the other chemotherapy curable malignancies. In the gestational tumours the malignant cells arise from the primitive trophoblast cells, which are present for only short time after conception and nuclear fusion. Similarly the malignant germ cell tumours have no healthy counterpart and are believed to arise from arrested gonocytes that having ongoing meiosis/mitosis stresses. These cells are not present in health and the malignant germ cell tumour cells are not supported by stem cells arising from the spematogonial stem cells.These biological observations suggests that the chemotherapy curable malignancies share a common theme in that they do not have conventional hierarchical cancer stem cells. In each case their cancer stem cells appear to arise either from within the cancer cell pool in the stochastic model, as in ALL, lymphoma and choriocarcinoma, or from a persistent embryonal cell with blocked development as in the childhood malignancies and germ cell tumours. In Table\u00a0This observational model on the relationship between the chemotherapy curability of cancer cells and their stem cells is complicated in that some types of B cell and T cell malignancies including CLL, follicular NHL, multiple myeloma and the mature T cell malignancies also will share the same non-hierarchical stem cell model, frequently respond well to chemotherapy treatment but are not curable with chemotherapy.In this situation we would argue that the characteristics of the stochastic stem cells with regard to DNA damage and induction of apoptosis is not determined solely by the process of their development of stem cell characteristics but is also very significantly affected by the intrinsic characteristics of the malignant cell from which they arise . Figure\u00a0The ability of simple cytotoxic DNA damaging chemotherapy drugs used as single agents or more commonly in combination to cure a select group of relatively rare malignancies has been one of the great achievements from the early days of cancer therapeutics in the 1950\u201370s. However since then, despite enormous endeavour, no additional metastatic malignancy has been added to the short list of routinely curable metastatic cancers.This dramatic divergence in responsiveness between different malignancies to chemotherapy treatment and how to improve it, has been one of the major areas of oncology research. In this paper we have reviewed how the cancer stem cell structure associated with these malignancies may impact on this divergence.Our observations indicate that each of the chemotherapy curable malignancies arise in a cell type that has a transient passage through a complex developmental stage involving complex DNA manipulation. The conventional hierarchical cancer stem cell system is absent in each of the chemotherapy curable malignancies and these factors are likely to be an important associations with the dramatic and divergent responses seen to chemotherapy. Additionally each of the chemotherapy curable cancers arises from a parent cell that has much lower levels of ABC transporter protein expression than hierarchical cancer stem cells have is also likely to lead to a further increase in efficacy of chemotherapy treatment.In the chemotherapy curable malignancies the cancer stem cells where present, generally arise in a non-hierarchical or stochastic method from within the pool of tumour cells itself. In each malignancy these cells are either developmentally isolated from their originating tissue specific somatic stem cells or have no conventional hierarchical cancer stem cells. As a result of the absence of a hierarchical cancer stem cells, the chemotherapy curable malignancies can only have cells with stem cell like properties that have arisen from with the cancer cell pool. These cells will take much of their properties from the cancer cells rather than having the propertices of a conventional cancer stem cell that is closely related to the damage and chemotherapy resistant somatic stem cells.We have previously postulated the potential importance regarding the presence of the key cellular pro-apoptotic sensitivity associated with the unique genetic events of nuclear fusion, VDJ recombination, somatic hypermutation, meiosis and gastrulation. Normal healthy cells undergoing these activities are exceptionally sensitive to the action of chemotherapy drugs, as seen in the action of methotrexate in producing pregnancy loss , of chemWe would argue that this association also directly impacts on the chemotherapy sensitivity of the non-hierarchical or stochastic cancer stem cells associated with these varied malignancies. In this situation the responsiveness to chemotherapy of the stochastic cancer stem cell will be determined by both the acquired characteristics of stemness but also significantly impacted by the underlying apoptotic sensitivity of the malignant cell. As a result, in the chemotherapy curable malignancies the degree of chemotherapy resistance that the adoption of stemness gives to these stochastic cancer stem cells, is functionally outweighed by the apoptotic sensitivity and allows the chemotherapy to kill the stem cells. In contrast in the similar malignancies of CLL/mantle cell lymphoma/myeloma/low grade NHL which also have stochastic stem cells and no hierarchical stem cells, their stochastic stem cells do not have this extreme apoptotic sensitivity and their stem cells are able to survive the chemotherapy, in a similar fashion to standard hierarchical cancer stem cells.In this debate section, it is clear that there is a great deal of data needed to confirm or repudiate this new hypothesis. To date there has been only limited research on these natural apoptotic pathways, their mechanisms and the controls occurring in these cells. Additionally there has been also limited work on the differential apoptotic responses of the chemotherapy curable malignancies compared with the incurable. However whilst this paper may serve as a prompt to explore these areas in more depth it should also serve to remind that the genes that can give rise to overwhelming apoptosis in response to chemotherapy are present in every cancer cell and in their respective cancer stem cell. The key of how to unlock this potential is awaited."}
+{"text": "Since the signing of the Oslo Ministerial Declaration in 2007, the idea that foreign policy formulation should include health considerations has gained traction on the United Nations agenda as evidenced by annual General Assembly resolutions on global health and foreign policy. The adoption of national policies on global health (NPGH) is one way that some member states integrate health and foreign policymaking. This paper explores what these policies intend to do and how countries plan to do it.White Paper on Global health in foreign and development policy and the Swiss Health Foreign Policy using Schneider and Ingram's policy design framework. After replicating analysis methods for each document, we analysed them side by side to explore the commonalities and differences across elements of NPGH design.Using a most similar systems design, we carried out a comparative study of two policy documents formally adopted in 2012. We conducted a directed qualitative content analysis of the Norwegian Analyses indicate that NPGH expect to influence change outside their borders. Targeting the international level, they aim to affect policy venues, multilateral partnerships and international institutions. Instruments for supporting desired changes are primarily those of health diplomacy, proposed as a tool for negotiating interests and objectives for global health between multiple sectors, used internally in Switzerland and externally in Norway.Findings suggest that NPGH designs contribute to constructing the global health governance system by identifying it as a policy target, and policy instruments may elude the health sector actors unless implementation rules explicitly include them. Research should explore how future NPGH designs may construct different kinds of targets as politicised groups of actors on which national governments seek to exercise influence for global health decision-making. The adoption of global health strategies by some governments in European countries over the past decade represents a formalised approach to health and foreign policymaking at the national level.Case studies on the development of the UK's and Germany's global health strategies have contributed to understanding the motivations and interests for their production in those countries.Little is known about the content of these documents regarding what they propose to do from a public policy perspective.Actors at the international level that make policy are targets for countries to influence change related to global health;Health diplomacy is an instrument countries use either domestically or internationally for supporting the desired change related to global health;The specification of rules for implementing NPGH varies between these policy documents.Based on a comparative analysis of formally adopted national policy on global health (NPGH) documents in Norway and Switzerland:Actors in the global health governance system are the target population intended to benefit from change as a result of implementing NPGH.When policy instruments are unfamiliar to or outside of the mandate of actors in the health sector, the implementation of NPGH may exclude structures from the health sector unless rules specifically include them.An empirically informed definition of NPGH is proposed for researchers and policymakers.The Oslo Ministerial DeclarationWe define NPGH as policies that aim to organise and co-ordinate a state's action on global health across more than one sector of public administration, as part of a coherent approach to policy development and implementation between relevant ministries involved in improving health on a global scale.24By questioning what NPGH intends to change and how it plans to accomplish this, we aim to better understand the multilevel and multisectoral empirical characteristics of such policies. First, NPGH requires domestic actors to collaborate to improve health globally, but it remains unspecified where change is expected . Second, NPGH demands that the health sector collaborates with the foreign affairs and the development sectors, but we do not know whether the goals and methods of intervention will be those of the health sector or of another sector. To this end, we study NPGH with tools of health political science, a field of research that uses theories from political science in health policy research to generate knowledge about policy change in matters related to public health.25In policy science, policy design is generally conceptualised either procedurally  or substantively .We conducted a comparative study of the content in cases of NPGH policy design from two countries. In this study, we define a case of NPGH policy design as a formally adopted policy document at the highest level of government.Using three criteria , we selected cases of NPGH policy design adopted in 2012 by Norway and Switzerland from a group of four countries in Europe who have adopted such policies.In line with other studies on health and foreign policies that identify a single policy document as a country's policy framework for its national global health strategy,We manually coded text of the two policy documents using Schneider and Ingram's six elements of policy designWhite Paper on Global health in foreign and development policySwiss Health Foreign PolicyNorway's The Norwegian and Swiss policies aim to act on the global health governance system by influencing change in policy venues, international institutions, networks and partnership structures where decisions about global health policy and programmes are made. The main targets for the Norwegian policy are international policymaking arenas where political and economic support are mobilised for global health such as United Nations agencies ), the World Bank, Global Health Initiatives (GHI) , Global Fund to fight AIDS, Tuberculosis and Malaria (GFATM)), financing mechanisms , Global Environment Facility (GEF)) and multilateral partnerships )  support information sharing across the entire Swiss public administration and the coproduction of policy guidance , the document's section 6 \u2018Perspectives on the future\u2019 explores the challenge of further developing \u2018a coherent Norwegian global health policy\u2019 see ref.  p. 46 thThe rules for implementation in the Swiss policy are administrative because they provide the procedures for working across federal departments . The rules define how the co-ordination of the interdepartmental structures is part of a collaborative process for overseeing implementation of policy-related activities . A plurality of actors representing competing normative frameworks vie for policy attention and resources to support respective agendas for global health action in the global health governance system.52\u201354Both NPGH designs portray WHO, UN agencies, the World Bank, health-related multilateral organisations, and GHI and public\u2013private partnerships  as key institutions for health and arenas for political mobilisation to support technical advancements in global health. Schneider and Ingram propose that groups targeted by public policy are depicted in normative terms because policy design contributes to the social construction of policy targets.Second, the implementation of NPGH may be elusive to health sector actors. Although both NPGH designs construct similar target populations, different instruments to reach them relate to who is responsible for implementation and according to what rules. Policy instruments are technical and social devices representing knowledge about how to coerce or enable a change in the target population.health and foreign affairs sectors are not homogenous groups of actors or expertise; diverse subgroups compose each sector . One caveat of conducting directed qualitative content analysis of policy documents is limitation for understanding the policy processes, negotiations between sectors and subsectors, and trade-offs in the content's production.These results and their implications for public health must be considered within the methodological and theoretical limitations of our analysis. The narrow concept of policy design we used confines the scope of policy content to texts of adopted NPGH strategy documents. This is an incomplete picture of content as theorised by Schneider and Ingram. Symbolic forms of content could be collected through interviews and other materials, but our analysis focused on single policy documents from two countries. Our deductive approach to using Schneider and Ingram's policy design elements also imposed limits. By applying generic categories of design elements to explore the content of NPGH documents, we might have omitted issues of focus in global health policy. For example, our analysis excludes discussion pertaining to the meaning of global health in NPGH and global health priority topics promoted by states for attention in the system of global health governance . Research has explained why certain policy issues receive political attention over others in the global health agenda,Global health policy and governance research generally focuses on how different frames of global health construct policy problems and legitimise the knowledge, actors and resources associated with their solutions.While there is no consensus on the understanding and use of the term global health governance in scholarship or practice,"}
+{"text": "Rana pipiens), is cytostatic and cytotoxic to variety tumor cell lines, inhibits growth of tumors in model animals and advanced to clinical trials as anticancer and antiviral drug [Onconase , a 12 kD ribonuclease from oocytes of northern leopard frogs (ral drug .et al., [In this issue of Oncotarget Vert et al.,  report oet al.,  explorinet al., .via decreasing resistance to apoptosis [The findings that ATF3 is the Onc target are in accordance with earlier reports that activation of ATF3 by other than Onc means triggers signaling pathways that lead to apoptosis in different types of cancers. Of particular interest are observations that overexpression of ATF3 increases cell sensitivity to variety of anticancer drugs. Thus, there is a remarkable correspondence between the mentioned above effects of ATF3 and Onc as factors increasing sensitivity of cancer cells to other treatments. Namely, dozens of papers describing ability of Onc to sensitize cancer cells to different anticancer drugs are recorded in PubMed. In some of these publications Onc is proposed to be used as an adjunctive therapy to amplify effectiveness of the primary treatment. The suppression of NF-kB by Onc was advanced to explain its ability to sensitize cancer cells poptosis . The invpoptosis .The noncoding RNA that provides regulation of genes activity via RNAi appears to be the potential primary target of this Onc. It was already demonstrated that Onc is able to attack siRNA within the cell and activate the siRNA-suppressed gene . It is pvia RNAi by Onc does not preclude the eventuality that other RNA species are targets of Onc as well. Both rRNA and tRNA have been shown degraded by Onc. Our early data on human submaxillary carcinoma A-253 and colon adenocarcinoma Colo 320 CM cells indicated that in addition to reduced clonogenicity the size of individual cells as well of cell clones was substantially smaller in the Onc treated cultures [Activation of ATF3 cultures  however"}
+{"text": "To evaluate the success of ultrasonography directed renal access in entering the target calyx from proper entry site and in the direction of renal pelvis during percutaneous nephrolithotomy (PCNL).PCNL cases who were operated on by one fellow from May-June 2014 were included in this study. A vertically placed ultrasound probe on the patient flank in prone position was used to identify the preselected target calyx. Needle was advanced through needle holder and fluoroscopy was used to document the entered calyx, site and angle of entry.Successful entering to the target calyx was achieved in 43 cases (91%). Successful entry with appropriate entry site and angle was observed in 34 cases (72%). Reasons for failure were minimal hydronephrosis, upper pole access and high lying kidneys.Although it is feasible to access a preselected calyx by ultrasonography guidance during PCNL, but entry to the calyx from the appropriate site and direction is another problem and needs more experience. In cases of minimal hydronephrosis, superior pole access or high lying kidneys, ultrasonography is less successful and should be used with care. Percutaneous nephrolithotomy (PCNL) is now the treatment of choice for surgical management of large renal stones. Fluoroscopy has traditionally been the method for obtaining access to the pelvicalyceal system. Later ultrasonography access to the pelvicalyceal system has been introduced and popularised by some researchers \u20138. It haA perfect percutaneous access tract to the pelvicalyceal system should be made through the tip of renal papilla in the targeted calyx and to be along the axis of renal calyx  so that The aim of this study was to access the effectiveness of ultrasonography guided PCNL renal access in entering the targeted calyx and in the direction of renal pelvis.Patients who were candidate for PCNL in Labbafinejad Hospital and were operated by one fellow during May-June 2014 were included. PCNL cases included patients with large renal stones (>2cm) or patients with renal stones >1.5cm in horseshoe kidneys. No specific exclusion criteria were applied and typical cases for PCNL within the study period were included. The operating fellow had prior experience in fluoroscopy guided PCNL (>400 cases) and in ultrasonography guided PCNL (>50 cases). PCNL was done according to the standard protocol described before . In brieIn this study proper entry site into renal calyx was defined as entry from the surface of renal papillae and not from the lateral walls of the calyx or any other entry sites. Proper entry direction was defined as the direction or angle that leads to renal pelvis . Tract wPlacement of nephrostomy or removal of ureteral catheter was done according to the judgement of the attending surgeons.The ethics of this study was approved by the local committee institutional board review. All patients were informed about the study and informed consent obtained.52 patients were enrolled during the study period. 5 patients were excluded from the study and their data is not presented in the below sections. Reasons for exclusion from the study were: fat body resulting in poor ultrasonic view of the kidney (1 patient), ectopic kidney with poor ultrasonic view (1 patient), high lying kidneys with poor longitudinal ultrasonic view because of rib shadows or stones in superior calices making ultrasonic view of the stone by ultrasonic probe in longitudinal view difficult (3 cases).Details of the 47 remaining patients and their operations have been outlined in A perfect access for PCNL should pass from the papillae into the collecting system and direction of the needle path should be coincident with the long axis of the target calyx . There hIn this study, we observed a high success rate for entering targeted calyx by ultrasonography guided renal access. Reasons for failure were: 1) minimal/no hydronephrosis in the target calyx. The absence of hydronephrosis makes identification of the stone and its surrounding calyx difficult on ultrasonography especially by less experienced urology surgeons. We usually inject normal saline through ureteral catheter in patients with nil-minimal hydronephrosis to augment the magnitude of hydronephrosis during the access phase of the operation. Another alternative can be injection of diuretic agents before the access phase so that the access time is roughly in the peak action duration of the diuretic agent 2). Failure to enter the preselected calyx was less often observed in lower calices in comparison with middle to upper calices. Therefore, in difficult or borderline cases, selection of lower calyx for entry especially in equivocal cases may be associated with a higher success rate. As illustrated in the methods section, appropriate entry site in this study was defined as the convex area of the tip of the calyx and not its lateral walls . ReasonsIn univariate analysis, right side PCNLs were associated with more frequent false entry sites . After pIn order to use ultrasonography for taking access in PCNL, there should be a clear view of the kidney calices on ultrasonography monitor. In situations in which this image is not clear, the success of ultrasonography in properly targeting the access calyx, its entry site or entry angle can be impaired. In our limited experience, this scenario happened in the following situations 1). A very fat patient with normal lying kidney with a 2cm stone in the lower calyx, 2) One muscular patient with body mass index of 27 with low lying mal-rotated kidney with a pelvis stone, 3) Three patients with stones in middle or upper kidney calices so that when the ultrasonography probe was placed longitudinally beneath the ribs, the view of the whole kidney or the segment containing the stone was not clear. In a few cases we tried to overcome this problem by angling the ultrasonography probe end caudally and pressing it on the patient back below the ribs but in these cases, this simple manoeuver could not solve the problem. Nevertheless, in such cases it is possible to obtain access to lower calyx without the need to observe the calices containing stones on ultrasonography monitor and then perform PCNL. In the protocol of the current study, we requested to have the image of kidney calices and containing stones which was not possible in the above cases but just for the sake of performing PCNL, it is enough to obtain ultrasonography guided access through a lower calyx and then perform PCNL by rigid or flexible nephroscope. Having mentioned these solutions, we think it is still safer to have fluoroscopy equipment at hand in such cases in case of failed ultrasonography guided access.We do acknowledge the operator dependency of ultrasonography a limitation of the results of this study. The experience of the operator can influence the obtained results. Nevertheless, there has been a publication by Japtag et al. in which the guidance of access by fluoroscopy versus ultrasonography yielded similar outcomes in hands of a trainee urologist with little prior experience in PCNL . It is nAlthough it is feasible to access a preselected calyx by ultrasonography guidance during PCNL, but entry to the calyx from the appropriate site and direction is another problem and needs more experience. In patients with minimal hydronephrosis, upper pole access or high lying kidneys this success rate is lower or the entry site into the calyx is less perfect. In such cases, it is advisable to have fluoroscopy equipment at hand."}
+{"text": "General practitioner attitude questionnaires were sent in May 1987 to 525 general practitioners (GPs) within Avon. A year later a section dealing with the management of clinical situations was sent to 198 Avon consultants, to determine how they would ideally expect a GP to respond to these situations.The majority of both the GPs and consultants held a common viewpoint, but significant differences were noted between the consultants and GPs in six out of the ten situations. Consultants with more than six months' GP experience had fewer significantly different views than their colleagues with little or no GP experience. GPs and specialists under the age of 45 years also had fewer significant differences in management than older GPs and specialists. The differences seem to reflect the clinical focus and interests of each professional group. We believe vocational training is a contributory factor to the differences and support the General Medical Council's proposal of a broader post registration training for all doctors."}
+{"text": "The complex nature of studying health and healthcare disparities in general, and in the context of the Israeli healthcare system in particular, is depicted in two recent IJHPR articles. The first examines Emergency Department (ED)\u00a0waiting times in a tertiary children\u2019s hospital and the second examines disparities in the health care for people with schizophrenia of an ethnic-national minority. Contrary to other Israeli studies on wide disparities in health and healthcare, these studies show no disparities -\u00a0 ED waiting times did not differ among Arab and Jewish children and report no differences in performance of Hemoglobin A1C tests or in surgical interventions in patients with cardiovascular\u00a0disease between Arabs and Jews with schizophrenia. Thus, the studies reflect areas of equitable health care delivery within the Israeli healthcare system.Future studies should account for the fact that the phenomena of health and healthcare disparities is complex and should utilize rigorous methodologies to take into consideration the various factors that may affect the manifestation of differences amongst population groups. As a result, they may help detect disparities which may otherwise be missed. Two recent Israel Journal of Health Policy Research articles depict the complex nature of studying health and healthcare disparities in general and in the context of the Israeli healthcare system in particular. Feldman and colleagues  studied The two papers present an impressive platform for the study of ethnic disparities within vulnerable population groups, namely children  and patiThese findings should be evaluated in light of the multifaceted makeup of the Israeli society and its healthcare system, within a comprehensive approach that accounts for the various types of interrelated social determinants of health  and the Despite universal coverage and a national health insurance law in Israel since 1995, a wide-array of gaps in health care service use have been extensively documented, including, as also exemplified by Gal and colleagues , lower rThe null findings regarding disparities in most of the indicators reported by Gal and colleagues  may reflHowever, it is not possible to rule out that the lack of disparities reported by Gal  and collThe lack of disparities reported by Feldman and colleagues  presentsAdditionally, Feldman and colleagues address a potential reason for disparities in waiting times by differentially examining waiting times by ethnic concordance. Contrary to other studies, concordance between providers and patients was not related to differentiated waiting times. For example, in a study on patient-provider language concordance and the quality of transitional care in oncology patients at the same hospital , Rayan et al. report that language concordance was associated with higher ratings of the care transition experience by Arab and immigrant minority groups compared with the general Hebrew speaking population .To conclude, the findings on the mainly lack of differences amongst Arabs and Jews in treatment of chronic comorbidities in schizophrenia patients  and in pThe phenomena of health and healthcare disparities is complex and should utilize rigorous methodologies to account for the various factors that may affect the manifestation of differences amongst population groups. Rigorous methodology may help detect disparities which may otherwise be missed."}
+{"text": "The majority of these designs have reused naturally occurring protein structures as \u2018scaffolds\u2019 onto which novel functionality can be grafted without having to redesign the backbone structure. The incorporation of backbone flexibility into protein design is a much more computationally challenging problem due to the greatly increased search space, but promises to remove the limitations of reusing natural protein scaffolds. In this review, we outline the principles of computational protein design methods and discuss recent efforts to consider backbone plasticity in the design process.The computational algorithms used in the design of artificial proteins have become increasingly sophisticated in recent years, producing a series of remarkable successes. The most dramatic of these is the  No new data was created during the course of this research.The Authors declare that there are no competing interests associated with the manuscript."}
+{"text": "We thank Morfeld and Erren for their continued interest in the WHO Health risks of air pollution in Europe (HRAPIE) report (WHO Regional Office for Europe The HRAPIE report itself clearly spells out the limitations of calculating \u2018premature deaths\u2019, on pages 15 and 16 (WHO Regional Office for Europe Appreciating the limitations of death counts as a metric for quantifying disease burden due to exposure to air pollution and other risk factors, the widely cited global burden of disease exercises have since their inception quantified such burdens both in terms of the number of deaths in a given year attributable to past exposure and in terms of lost years of healthy life, or DALYs (Murray and Lopez We appreciate the opportunity for clarification of the HRAPIE report, article, and first response and agree with Morfeld and Erren that estimated burdens of disease attributed to air pollution need to be correctly interpreted in the context as explained in more detail above and in the quoted references."}
+{"text": "Imprinted genes are a subset of genes that are expressed from only one of the parental alleles. The majority of imprinted genes have roles in growth regulation and are, therefore, potential oncogenes or tumour suppressors. Cancer is a disease of aberrant cell growth and is characterised by genetic mutations and epigenetic changes such as DNA methylation. The mechanisms whereby imprinting is maintained in somatic cells and then erased and reset in the germline parallels epigenetic changes that cancer cells undergo. This review summarises what we know about imprinting in stem cells and how loss of imprinting may contribute to neoplasia."}
+{"text": "The use of non-invasive brain stimulation (NBS) such as transcranial magnetic stimulation (TMS) and direct current stimulation (tDCS) has significantly advanced our understanding of the mechanisms underpinning motor and cognitive processes in the brain. Repetitive TMS (rTMS) and tDCS have the potential to induce bidirectional changes in cortical excitability and lasting neuroplastic effects that are dependent on the nature and parameters of the stimulation used  . For insIn particular, the application of interventional forms of NBS in neurological disorders such as Parkinson\u2019s disease (PD) has been viewed with great interest. PD is a chronic neurodegenerative condition that stems from a loss of dopamine-producing neurons in the substantia nigra within the basal ganglia (BG) . While tApart from changes in intracortical excitatory and inhibitory neural circuitry, PD is associated with pathological neural oscillations that are thought to underpin motor dysfunction . While mInterventional forms of NBS can have a positive effect on motor and cognitive function that is likely to be driven by a change in cortical excitability of specific brain areas . To dateOf interest, variant forms of NBS, which are frequency specific such as transcranial alternating current stimulation (tACS), are gaining increasing interest for their ability to induce lasting neuroplastic and functional change . tACS isWhile there is some evidence to support the concept that neural entrainment using tACS improves motor function in healthy individuals , 36, theTo this end, we acknowledge that the scarcity of information surrounding the effects of tACS on neural entrainment limits our interpretation of early studies in healthy individuals and people with PD. Research into the therapeutic potential of tACS is still in its early days, and there is much that is not known about the causal relationship between dysfunctions in neural oscillations and specific motor and cognitive deficits in PD. While studies by Brittain et al.  and KrauAll the authors  contributed equally to the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Staphylococcus aureus infection  as well as replication studies in well-characterized patient cohorts may improve our understanding of the potential role of inflammation in disease pathogenesis and open up new avenues of therapeutic intervention.The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In April 2013, a case of wild polio virus (WPV) was detected in the Somalia capital Mogadishu. This inaugurated what is now referred to as the 2013-2014 Horn of Africa Polio outbreak with cases reported in Somalia, Kenya and Ethiopia. By the notification of the last polio case in August 2014, 223 cases of WPV had been reported in Somalia, Kenya and Ethiopia of which 199 in Somalia alone. The outbreak response required timely exchange of information between the outbreak response coordination unit (in Nairobi) and local staff located in multiple locations inside the country. The need to track and timely respond to information requests, to satisfy the information/data needs of polio partners and to track key outbreak response performance indicators dictated the need to urgently set up an online dashboard. The Somalia Polio Room dashboard provided a graphical display of the polio outbreak data to track progress and inform decision making. The system was designed using free and open sources components and seamlessly integrated existing polio surveillance data for real time monitoring of key outbreak response performance indicators. In this article, we describe the design and operation of an electronic dashboard for disease surveillance in an outbreak situation and used the lessons learned to propose key design considerations and functional requirements for online electronic dashboards for disease outbreak response. Polio is a disease targeted for elimination since 1988 when the World Health Assembly voted to eradicated polio . In ApriIn a management and information system standpoint, a dashboard is \u201can easy to read, often single page, real-time user interface, showing a graphical presentation of the current status (snapshot) and historical trends\u201d . StephenPolio outbreak response is data and information intensive. Timely and accurate information from field activities are required 1) to monitor key performance indicators to measure progress towards planned goals and timely identified deviations from planned goals and implement corrective measures; and 2) to assess the impact of outbreak response activities. Dashboards are not new in public health; however, their use in disease outbreak response at country level by national programs is not very well documented. Notable examples of the use of dashboards include multiscreen displays of disease and outbreak information at the Centers for Disease Control Emergency Operation Centers  or at thData inputs: the system was designed to use acute flaccid paralysis (AFP) data as the primary data source. AFP describes a sudden onset of weakness or paralysis, affecting mostly motor muscles of lower limbs in children. AFP is the main clinical presentation of poliomyelitis disease [ disease . PatientThe AFP database served as the primary source of data for the dashboard to avoid interfering with ongoing AFP surveillance and data entry processes; no new data source was created or required. A tab-separated text file containing selected AFP data elements  was generated from the AFP main database and imported into the system. On upload, the text file was processed and the key data elements stored in a table in the MySQL database. To accommodate for early notification of cases, a user protected area allowed for the manual entry of AFP cases by surveillance officers located in districts through a customized online form. Additional data streams used by the system are shown on Geo-mapping: the systems integrates Google Map API to display the location of AFP cases. Since geolocation information of AFP cases are not available, we used the latitude and longitude coordinates of the capital city of district of residence of the AFP case as a proxy to the geolocation of the AFP case. The altitude and longitude data of all district city capitals were extracted from the geo-name server table [er table  for SomaGraphical display: the visual interface of the system was specifically designed for display on high resolution/large monitors in the outbreak control room located in the WHO Somalia Liaison Office in Nairobi. Six rich individual displays existed and combined maps, graphs and tables summarizing the current status of outbreak response and AFP surveillance activities. During its 15 months of existence (July 2013 to Oct 2014), the Somalia Polio Room Dashboard, by integrating various outbreak and surveillance response data sources into rich graphical interfaces provided an easy-to-read information to polio outbreak response managers, responders and immunization partners located in various areas inside and outside of the organization. A polio outbreak response involves a multitude of players at various levels of the same organization or outside of the organization. The ongoing analysis and sharing of information with all these players can place an undue burden on surveillance staff and data managers. With the Somalia Polio Room Dashboard, we were able to reduce the need of daily analysis and sharing of outbreak information, thereby release surveillance staff from the need to response to multiple information requests from various sources.The methodological innovation of the system can be viewed at various levels: 1) we demonstrated the possibility of designing, at country level, an effective data visualisation tool using available and free technology in a limited amount of time; 2) we demonstrated that the use of a visualisation tool accessible to all partners can significantly reduce the time spent on routine analysis and other reports.Lessons learned on key considerations for dashboards for outbreak response In his 2006 essay on dashboard design, Stephen Few provided 13 pitfalls for dashboard design [d design . These pThe need for a dashboard is established: are existing data visualization, analysis and sharing mechanisms and tools sufficient or is there a clear need for additional or expanded data visualization tools? Knowing who has interest in accessing the dashboard should be the main determinant of whether or not to pursue the project of developing a dashboardcritical advantages over existing data exchange mechanisms and formatsThe dashboard should provide The need of the dashboard should be established for a reasonable period of time: establishing that the need for a dashboard will be sustained for an acceptable period of time should help decide whether investing time and efforts into the development of a dashboard is warrantedStructured and regularly updated data streams exist: to feed the need to constantly update the rich visual display of the dashboard; a dashboard that is not updated regularly loses its appeal. The dashboard should use existing data and should not require new data collection processesThe workload and skills required to update and operate the dashboard should be nil to minimal on the outbreak response staff: during an outbreak, the surveillance staff including data managers and data entry clerks are overburdened and should not be distracted by new processes or long trainings on how to operate the dashboardThe dashboard should be designed for scalability and flexibility: and should easily accommodate the changing information requirements of the outbreak response; it should be easy to add, remove or modify the visual display or other processesopen sources or free technology and web-services to minimize the cost of the dashboard developmentUse of available, preferably We have demonstrated that it is possible to develop an online electronic dashboard for outbreak response using existing open source and free tools. The development of such dashboard requires technical expertise but should also be carefully examined in the light of the considerations we identified. The Somalia Polio Room Dashboard clearly demonstrates the usefulness of electronic dashboard in outbreak response through their ability to improve information sharing and minimize the time spent on multiple information requests; their use should therefore be encouraged. The technical expertise in computer programming, data management and software design required to set-up functional and useful electronic dashboards remains a limitation. To address these limitations, technical partners including WHO should develop and avail ready-to-use/easy-to-setup dashboards for outbreak response.The authors declare no competing interests."}
+{"text": "In this study we used a model of adult learning to explore undergraduate students\u2019 views on how to improve the teaching of research methods and biostatistics.This was a secondary analysis of survey data of 600 undergraduate students from three medical schools in Uganda. The analysis looked at student's responses to an open ended section of a questionnaire on their views on undergraduate teaching of research methods and biostatistics. Qualitative phenomenological data analysis was done with a bias towards principles of adult learning.Students appreciated the importance of learning research methods and biostatistics as a way of understanding research problems; appropriately interpreting statistical concepts during their training and post-qualification practice; and translating the knowledge acquired. Stressful teaching environment and inadequate educational resource materials were identified as impediments to effective learning. Suggestions for improved learning included: early and continuous exposure to the course; more active and practical approach to teaching; and a need for mentorship.The current methods of teaching research methods and biostatistics leave most of the students in the dissonance phase of learning resulting in none or poor student engagement that results in a failure to comprehend and/or appreciate the principles governing the use of different research methods. Research is globally recognised as a major output of universities and other institutions of higher education. On the other hand the teaching of research methods has received a limited amount of attention , 2. AlsoPlease suggest any ways in which your undergraduate teaching in research methods and statistics could have been more useful?\u201d. It is important to note that the pharmacy and nursing programs have a research project as a requirement for the award of the degree at all the three universities. The students\u2019 responses were previously captured verbatim in Epidata and then exported to Microsoft word for editing before being saved as a single text file for analysis. The responses were then subjected to qualitative phenomenological data analysis informed by the model of adult learning proposed by Taylor and Hamdy (2013) [This was a secondary analysis of undergraduate student's survey data from three purposively selected public medical schools in Uganda namely: Makerere University College of Health Sciences (MakCHS), Gulu University (GU) and Mbarara University of Science and Technology (MUST) . All they (2013) , using ay (2013) , 19. The\u201cSometimes we carry out research and fail to analyse or understand it because of very little or no information on biostatistics\u201d2nd year Female Medical Radiology student.There were 600 respondents to this survey of whom 516 responded to the open-ended question. \u201cUndergraduate teaching in research methods provides a unique opportunity to follow your interest in an area of research to focus on this for several years and make an impact\u201d 3rd year Male Medical Radiology student. The items coded under relevance pointed to the students desire to understand why they were learning the research methods now. In summary the students thought the teaching of research methods would make the teaching of other subjects more relevant, promote the use of a common scientific language, impact the communities from which the students came from and make journal reading easier. Also under relevance the students wanted to see the societies they got the information from benefiting from the research findings as captured in this quotation: \u201cIt could be more useful if the statistics obtained were used to improve health in the regions from which the statistics were obtained\u201d 2nd year Male Medical Radiology student. The next code was on teaching with 44 codings. In this code student concerns on who was teaching the course were identified. The concerns ranged from the level of expertise of the teacher to how the teachers presented their material. Some of the students desired to learn the material under less stressful learning conditions for example in the morning as opposed to before lunch as seen in this quotation. \u201cIf only they (lectures) can be before lunchtime with more vibrant lecturers and a bit practical it would help\u201d 4th year medical student The next frequently cited code in this item was the courses with 41 codings. The students thought that the course material should be delivered as a stand-alone mandatory course with clear course content and examination leading to credits that appear on their transcript. Some of the student even suggested that a department should be created in the university to handle the teaching of research methods and biostatistics. The last code under dissonance was content with 28 codings. In this code student's suggestion for additional content in the form of exams, books available, software and scheduling were captured. The students also suggested that the exposure to this content should be repeated with increasing detail for deeper learning as they matured in their academic programs (see \u201cIf we had data collection practically immediately after studying the theory and not wait for years\u201d 1st year female medical student.The next most frequently identified code in this theme was time with 76 codings see . In thisrams see . The nexrams see . The opp\u201cLecturers who understand that field\u201d 3rd year male medical student The last theme was that corresponding to the consolidation phase of the adult learning model [\u201cBiostatistics learning should be gradual right from year 1 semester 1 and should be applied more prominently in COBES\u201d 2nd year female pharmacy student.The next code group in this theme was mentorship with 24 codings. In mentorship students identified the need for opportunities for guided practical learning through involvement in departmental research, or engagement in the activities of different research organizations as a form of mentorship. Learning to do research in an area of interest to the mentor would result in greater mentor engagement in the learning process. This engagement is driven by the quality of feedback the mentor provides. The students linked the quality of feedback to the level of interest the mentor had in the area of research. ng model . In thisThis study set out to explore students\u2019 views on how to improve the teaching of research methods and biostatistics at three Ugandan public universities. The students who participated in the study appreciated the importance of learning research methods and biostatistics as a way of understanding research problems and appropriately interpreting statistical concepts during their training and post-qualification practice. They also identified the limited time allotted to teaching and inadequate educational resource materials as the main impediments to effective learning of research methods and biostatistics. They proposed several suggestions on ways to improve the teaching and learning of research methods and, ways of effectively utilizing the little time allotted to this course with a strong emphasis on putting what is learned into immediate practice as expected according to the principles of adult learning . Health \u201cBiostatistics learning should be gradual right from year 1 semester 1 and should be applied more prominently in COBES\u201d. Some of the shortcomings of this study included the use of inherently biased qualitative approach for the analysis of short open-ended responses to the probe question. Whereas the results of the analysis are very context specific, the number of respondents created an opportunity to do tallies that can be used as a rough indicator of where the institutions represented in the study lie with respect to the used adult learning model. Future studies may need to use more in-depth approaches involving more stakeholders. Despite the shortcomings the study findings are relevant at both the institutional and individual levels. For the student, it is important to foster student interest in research methods. The ease of understanding statistical and research concepts is directly dependent on the student's interest in the subject [Another example of the students identifying adult approaches to learning is seen in suggestions to increase learning and developing durable skills in critical appraisal and statistical interpretation. Students proposed early and continuous exposure to research methods throughout the course of their academic programs. This they suggested should be complemented with; additional web based educational resource materials; and more hands-on practical teaching approaches such as case study interpretation, participation in research and publication writing. As students mature they become more independent and self-directed. Thus, they have to practice as this is the most effective way of teaching and mastering statistical skills . Some au subject . Since m subject .This study has highlighted several challenges faced by students in public universities in learning research methods and biostatistics. In view of the large number of suggestions clustered under the dissonance phase of learning we conclude that the current teaching of research methods is not adequately engaging students in the learning process. This has resulted in the students\u2019 failure to comprehend and appreciate the underlying principles governing the use of the various research methods. There is thus a need for the participating institutions to make individual learner and institutional adjustments to align the teaching of research methods with their vision and mission statements.Health professional training curricula have increasingly become congested leading to the allocation of inadequate time to hands-on teaching of research methods and related research statistical approaches;Much of the university teaching on research methods focuses more on knowledge transfer, while giving little or no attention to context and application of the acquired knowledge;Students\u2019 research outputs count greatly to research related status of most institutions of higher education, thus keeping track of student\u2019 research related expectations and performance is a key quality control measure.The current methods of teaching research methods leave most of the students in the dissonance phase of learning resulting in none or poor student engagement that results in a failure to comprehend and/or appreciate the principles governing the use of different research methods;Research methods and biostatistics should be delivered as a stand-alone mandatory course with clear course content and examination leading to credits that appear on academic transcript;Individual learners and academic institutions should make adjustments to align the teaching of research methods with their vision and mission statements."}
+{"text": "Primary emotional systems and personality Christian Montag and Jaak Panksepp analyze how emotional systems are involved into the development of basic personality into an evolutionary framework. They also stress the importance of such investigation for the promotion of human welfare in the context of psychiatric research and practice . Sentiments and character do not exactly overlap with emotions and personality because they are the product of social interactions, civilization processes, and reflective activities . Highlighting the mechanism underlying personality development and its link to emotions can offer a solid ground for empirically tenable views on moral education. The interest of this last topic is not purely theoretical, but progress in this field could foster human welfare (as recommended by Montag and Panksepp themselves). Here it is not possible to argument, but it is very likely that an empirically informed sentimentalist view would strongly discourage rigoristic views of moral education and would confirm Hume's ideas about the so called \u201cmonkish virtues\u201d Davie, . A scienThe author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The objective of this study was to compare performance on different versions of the running span task, and to examine the relationship between task performance and tests of episodic memory and executive function. We found that the average capacity of the running span was approximately 4 digits, and at long sequence lengths, performance was no longer affected by varying the running span window. Both episodic and executive function measures correlated with short and long running spans, suggesting that a simple dissociation between immediate memory and executive processes in short and long running digit span tasks may not be warranted."}
+{"text": "Physical activity promotion has met with limited success across a range of demographic indicators, largely due to our poor understanding of how drivers of physical activity behaviours vary by context and setting . DespiteNine articles focused on physical activity among children and adolescents. Best and colleagues addressed the methodological issue of measurement heterogeneity by exploring predictors of children\u2019s physical activity that emerge regardless of whether objective or self-reported physical activity data are considered. Enjoyment, parent support and availability of sport facilities emerged as consistent predictors, suggesting that these factors should be prioritized as intervention and policy targets. The challenges of integrating physical activity options into school curriculum were addressed in a qualitative study reported by van den Berg and colleagues who interviewed primary school teachers and principals in The Netherlands. The battle for curriculum time, also reported elsewhere  was evidThe majority of studies of adult physical activity focused on aspects of the built environment, with two studies examining this from a socioeconomic perspective. Zandiah and colleagues used Geographic Positioning System technology to compare high and low SES neighborhoods in The Netherlands on components of walkability for older adults. Disparities in walking across SES gradients could be related to availability of green spaces and recreation centres. Highlighting the need to consider influences of physical activity in context, Micklesfield and colleagues reported that the influence of SES on physical activity among young South African women depended on whether they lived in urban or rural areas. In accord with this observation, Berry and colleagues found that neighbourhood walkability was directly associated with walking behaviour in urban but not rural Australian adults. The authors suggested that context-specific measures of walkability need to be developed to better understand the environmental influences that seem to be unique to rural settings. The challenges of promoting physical activity in rural areas of the USA were investigated by Lo et al., with residents\u2019 preferences for structured and socially supportive settings discussed against a backdrop of limited resources to effect rapid change in these communities. The authors suggested that small, staged improvements to existing features were key to meeting substantial longer term targets. Costigan and colleagues identified features of public parks that should be targeted for improvement in their study of park use for recreational physical activity among Australian adults. Ease of access, provision of shade, safety and regular maintenance were strongly supported. Interestingly, the availability of recreational dancing in public parks was associated with overall physical activity among Colombian women, as reported by Sarmiento et al. All but one of the studies of built environment influences on physical activity were cross-sectional in design and therefore unable to identify the impact of changing salient environmental features on consequent physical activity behaviours. McCormack and colleagues\u2019 elegantly designed study tracked Canadians who changed residence in the previous 12 months, and confirmed a relationship between changed neighbourhood walkability and changes in active commuting. The only study of social influences on adult physical activity came from Westgarth and colleagues who provided intriguing evidence for a \u2018mutualistic\u2019 association among dog owners and their dogs during walking. Dog walkers were strongly motivated by the sense that the dog also enjoyed the experience, much more so than other potential influences such as exercise benefits and social interactions while walking.This collection of studies confirms that physical activity behaviours are shaped by all levels of the social ecological framework as well as interactions among these levels, resulting in a complex causal web of factors. To advance our understanding to the point that interventions targeting social and physical environmental influences on physical activity can be designed with confidence, research efforts need to continue to focus on context- and setting-specific factors that are amenable to change within demographic groups differentiated by age, gender, social disadvantage and geographic location."}
+{"text": "Robotic radical prostatectomy (RRP) has become an effective modality in the treatment of localized prostate cancer. We detail the experience at our institution and provide a perspective for future considerations of RRP with respect to improved preoperative imaging and surgical instrumentation."}
+{"text": "Paliperidone palmitate is a 2nd generation long-acting injectable (LAI) antipsychotic which is increasingly prescribed for patients with chronic schizophrenia. However, it is more expensive than 1st generation LAI antipsychotics and little is known about its effectiveness in a real world clinical setting. We sought to address this issue by analyzing a large electronic case register of patients with schizophrenia treated with LAI antipsychotics.Data were obtained from 1,281 patients in the South London and Maudsley NHS Foundation Trust (SLaM) Biomedical Research Centre (BRC) Case Register who were treated with an LAI antipsychotic between 1st April 2011 and 31st January 2015. The number of days spent as a psychiatric inpatient and the number of admissions to a psychiatric hospital were extracted using the Clinical Record Interactive Search tool (CRIS) and analyzed in each of the 3 years before and after LAI prescription using multivariable regression.Patients who received paliperidone palmitate  spent more time in hospital  and were admitted to hospital more frequently  in the year prior to treatment than those treated with other LAI antipsychotics . However, there were no significant differences between paliperidone and the other LAI antipsychotics in the 3 years after initiation with respect to the number of days spent in hospital  or frequency of hospital admissions .Paliperidone palmitate was more likely to be prescribed in patients with more severe illness, as indicated by a history of more frequent and lengthy hospital admissions prior to initiation. The absence of differences in outcomes after initiation indicates that the effectiveness of paliperidone palmitate was similar to that of other LAI antipsychotics. However, paliperidone palmitate may be better tolerated than other 1st generation LAI antipsychotics with a lower rate of discontinuation. These findings merit consideration in relation to the high cost of paliperidone palmitate compared to other LAI antipsychotics."}
+{"text": "One the most fundamental aspects of the human motor system is the hemispheric asymmetry seen in behavioral specialization. Hemispheric dominance can be inferred by a contralateral hand preference in grasping. Few studies have considered grasp orientation in the context of manual lateralization and none has looked at grasp orientation with natural prehension. Thirty right-handed adults performed precision grasps of a cylinder using the thumb and index fingers, and the opposition axis (OA) was defined as the line connecting these two contact points on the cylinder. Subjects made ten consecutive grasps with one hand (primary hand movements) followed by ten grasps with the other hand (trailing movements). Differences between primary and trailing grasps revealed that each hemisphere is capable of programming the orientation of the OA and that primary movements with the right hand significantly influenced OA orientation of the trailing left hand. These results extend the hemispheric dominance of the left hemisphere to the final positions of fingers during prehension."}
+{"text": "This paper concerns the ethics of human neuromodulation using transcranial magnetic stimulation (TMS). We examine the challenges of modulating the brain with TMS through the research ethics lens and in clinical medicine for treating frank pathology, primarily in psychiatric diseases. We also consider contemporary issues raised in the neuroethics literature about managing unexpected findings, and relate these to TMS and to other frontier neurotechnology that is becoming openly available in the public domain. We argue that safety and informed consent are of paramount importance for TMS, but that personal values and sociocultural factors must also be considered when examining the promise of this technology and applications that ought to be highlighted for extra precautions."}
+{"text": "Specifications TableValue of the data\u2022The data provided allows comparison of screening test results with previous editions, as they have been weighted for traffic intensity at selected sites.\u2022The large sample size of this survey means that results can be considered stable, and as representativeness was pursued in the sampling procedure, the data can be used for comparisons.1In this document we provide new data derived from 2015 roadside screening tests. Published results from previous editions of surveys conducted in Spain in 2008 and 2013 following the methodology set up in the framework of the European Union DRUID project (Driving Under the Influence of Drugs) 2Methodology for the three surveys has been already published. Detailed information about sample planning , driving recruitment, data collection and toxicological aspects can be found elsewhere 3Results from the 2015 survey are presented with the same format as used in the 2008 and 2013 survey publications Data is provided in"}
+{"text": "Persons with Down syndrome (DS) are at risk for a life of inactivity that can result in a multitude of medical problems including heart and vascular diseases. This review presents findings regarding the physical status of individuals with DS, as well as proper interventions found to improve the physical fitness and general health for this population. This review was written with the intent to suggest practical directions in planning and implementing quality physical intervention programs for this population."}
+{"text": "Complete avulsion of the ureter is one of the most serious complications of ureteroscopy. It requires open or laparoscopic intervention for repair. This case report emphasizes its management and presents recommendations for prevention in current urological practice."}
+{"text": "A large proportion of the vertebrate body is made of epithelial tissues; these provide organized barriers between organ compartments and also differentiate into glandular, secretory specializations  , Wnt, fibroblast growth factor (FGF), and Notch (Kahata et\u00a0al., et\u00a0al., Important areas that remain open to investigation relate to the translation of the basic knowledge on EMT on various aspects of oncology. Are the EMT and MET truly important for cancer progression and metastasis or are they, as some studies have suggested (Fischer By combining the expertise of founders of the EMT field with younger investigators, this compendium aims at leading the research front and illuminating both scientists and the wider public that are interested in fundamental problems of oncology. Studies on EMT provide exciting clues about the evolution and adaptations that human tumors undergo through their history, a history that represents the awakening of embryonic developmental scenarios taking place in adult bodies over the trajectory of unpredictable genetic and environmental insults that characterize normal human life."}
+{"text": "Formation of urinary tract concrements is a common disease and steps should be taken in order to elucidate the underlying mechanisms and to give the patients appropriate advice and medical treatment. This present article summarizes the principles for recurrence preventive measures in patients with uric acid, infection, cystine and calcium stone disease. Categories of stone formers are identified with the aim of providing a basis for an individualised treatment with a reasonable patient's compliance. The recommendations are in line with those given by the EAU guideline group for urolithiasis."}
+{"text": "Pregnancy induces a variety of physiologic changes in the urinary tract. When such changes become accentuated the physiologic becomes the pathologic and symptoms arise, at times of significance enough to threaten the well being of mother and/or fetus. This article intends to describe the basis for urinary physiology and its pathologic counterparts during pregnancy. Such a background may then facilitate a rational management protocol for various urologic problems in the gravid state."}
+{"text": "We read with interest the study by Andrews et al.  and the These findings raise questions regarding our understanding of the decision-making process of LMIC clinicians in the detection and management of the acutely unwell patient. Clinicians may be utilising additional cues in a manner different to their HIC contemporaries; such as the presence of relatives as carers at the bedside or a nursing decision to place a patient in a specific location in\u00a0the ward. Work done to evaluate the impact of setting-adapted practical training on the management of common emergencies in LMICs has highlighted the limited priority given to practising such skills in existing training programmes for both doctors and nurses , 5. It iGreater understanding is essential if we are to better influence the processes that contribute to acute and critical care mortality in LMIC settings. Mixed-method approaches combining qualitative techniques to capture clinicians\u2019 perceptions of the importance of clinical assessment alongside setting-adapted electronic tools to improve the capture of granular information of the patient journey\u2014currently being undertaken by our group in multiple LMIC settings\u2014could enrich our understanding of the management of acutely unwell patients. Greater understanding of these clinical priorities and their importance in acute care in diverse settings would offer valuable insights to inform subsequent trial design and the end points selected for evaluation."}
+{"text": "The construction site provides an unfriendly working conditions, exposing workers to one of the harshest environments at a workplace. In this dataset, a structured questionnaire was design directed to thirty-five (35) craftsmen selected through a purposive sampling technique on various construction sites in one of the most populous cities in sub-Saharan Africa. The set of descriptive statistics is presented with tables, stacked bar chats and pie charts. Common occupational health conditions affecting the cardiovascular, respiratory and musculoskeletal systems of craftsmen on construction sites were identified. The effects of occupational health hazards on craftsmen and on construction project performance can be determined when the data is analyzed. Moreover, contractors\u2019 commitment to occupational health and safety (OHS) can be obtained from the analysis of the survey data. Specifications TableValue of the data\u2022The dataset provided showed the empirical evidence of health challenges in the cardiovascular and respiratory systems including the musculoskeletal disorders experienced by craftsmen on construction sites.\u2022The understanding of the dataset sheds light on the effect of occupational health hazards on the well-being of the craftsmen and construction project performance.\u2022The dataset gives insight into the level of contractors\u2019 commitment to occupational health and safety (OHS).\u2022Construction activities and materials are crucial entities that can impact the body system when not handled in the standardized way, therefore, the dataset can guide policies on reducing occupational health hazards among craftsmen on construction sites.\u2022The structured questionnaire can be adopted or modified for similar research in a larger context in sub-Saharan Africa and other parts of the world. In addition, comparison can be drawn with other sectors where workers are more prone to be affected by working conditions and severe exposure to toxic materials.1The cardiovascular, respiratory and musculoskeletal systems are essential parts of the human body that could be severely affected by the un-friendly working conditions of construction sites and exposure to some chemical and toxic building materials 2This dataset is based on previous research conducted on occupational health hazards of craftsmen on construction sites"}
+{"text": "The data presented in this article are related to the research article entitled \"Plant richness enhances banana weevil regulation in a tropical agroecosystem by affecting a multitrophic food web \" [1]. It provides information about plant species richness, weevil corm damage and the abundance of different arthropod groups, including the banana weevil and its potential natural enemies and alternative preys. Specifications TableValue of the data\u2022The data is valuable for other researchers working on this pest or in similar scientific field because it offers them the opportunity to compare with their own datasets and/or to independently verify or extend statistical analyses.\u2022This data is a contribution to the effort of the scientific community to quantify ecosystem services and in particular ecosystem services in agroecosystems associated with plant diversification.\u2022The data is valuable as it comes from an original experimental design using an existing plant richness gradient to study the continuous relationship between plant richness and response variable related to pest regulation service.\u2022This data does not focus solely on the effect of plant richness on abundance or damage of the pest, but also on potential alternative preys or predators of the pest.1Cosmopolites sordidus. In addition to the dataset, we present the outputs of statistical models that quantify the effect of total plant species richness on the abundance of each arthropod group and on corm damage. The dataset presented in this article, in 2The experimental design is described in details in 2.1In 2.2"}
+{"text": "We read the article Critical care ultrasonography in acute respiratory failure  by Vigno We thank Dr. Balthazar and coworkers for pointing out the erroneous figure legend and annotation in our recently published manuscript describing the clinical value of critical care ultrasonography in both the diagnostic work-up and management of patients admitted to the intensive care unit with acute respiratory failure . Massive"}
+{"text": "Green tea (Camellia sinensis) is a popular herbal remedy worldwide. Polyphenols in green tea have attracted much attention as potential compounds for the maintenance of human health due to their varied biological activities and low toxicities. Camellia sinensis) is a popular herbal remedy worldwide. Polyphenols in green tea have attracted much attention as potential compounds for the maintenance of human health due to their varied biological activities and low toxicities. Recently the antioxidant properties of green tea on injury protection caused by oxidative stress have been on focus  have been completely observed by the author.None.SH was the single author of the paper."}
+{"text": "Staying current with the literature is of paramount importance to the pharmacist engaged in an evidence-based clinical practice. Given the expanding roles and responsibilities of today\u2019s pharmacists combined with exponential growth in new medical and health sciences literature, staying current has become an extremely daunting task. Traditional journal clubs have focused upon their role as a training vehicle for teaching critical reading skills to residents. However, schools of pharmacy are now required to provide instruction in biostatistics, research design, and interpretation. We present a paradigm shift in the traditional journal club model whereby a collection of periodicals is screened and a short synopsis of the pertinent articles is provided. The associated tasks for screening and presenting of the primary literature are shared among a group of clinicians and trainees with similar practice interests resulting in a more reasonable workload for the individual. This journal club method was effective in identifying a significant majority of articles judged to be pertinent by independent groups of clinicians in the same practice arenas. Details regarding the shared core practice and knowledge base elements, journal club format, identification of journals, and evaluation of the success of the journal club technique are provided. Journal clubs are commonplace in academic medical centers and hospitals in various fields of clinical practice including pharmacy. The first record of a medical journal club was attributed to Sir William Osler at McGill University in 1875 . The purStaying current with the literature is an essential requirement for the pharmacist engaged in an evidence-based clinical practice. It has been suggested that the gap between implementation of new knowledge into clinical practice is a primary reason for the suboptimal provision of quality health care for some institutions . HoweverFive clinical faculty members with direct patient care responsibilities and three second post-graduate year (PGY2) pharmacy residents comprise the core of the journal club group. All faculty are within the same department at the University of Tennessee College of Pharmacy and are based at the same university-affiliated hospital . Advanced clinical pharmacist activities are required via a contractual agreement between the College of Pharmacy and the hospital. Two faculty members have clinical responsibilities and coordinator duties for the Nutrition Support Service (NSS), another two faculty members provide critical care pharmacy services, and one faculty member shares responsibilities for both services. The NSS faculty members provide clinical services to adult patients throughout the entire hospital that require parenteral nutrition and to select complicated patients who require enteral nutrition. The critical care faculty members provide pharmacotherapy services to a Level 1 Trauma Intensive Care Unit (TICU) and its associated step-down unit. Most of the patients managed by the NSS are also trauma and surgical intensive care unit patients that frequently coincide with the population followed by the TICU faculty. The PGY2 pharmacy residents are required to complete four months of NSS experience and four months of TICU clinical pharmacy services with the remaining months dedicated to elective experiences, research, and miscellaneous activities. Thus, all clinical faculty and PGY2 trainees share a common thread of required knowledge and reading sources necessary for optimal performance of their respective duties. It would be intuitive that both NSS and TICU clinical pharmacy services could streamline their ability to stay current with the literature by sharing reading sources and communicating findings from pertinent articles with each other.The primary intent of our journal club is to stay current with new literature that may confirm, alter, or augment conventional practice in pharmacy nutrition support or pharmacy trauma intensive care. A second objective is to accomplish the task of screening and compiling pertinent studies on a consistent basis without burdening a sole person with the excessive workload. Third, this journal club methodology provides a forum for training pharmacy resident mentees via dialogic teaching of emerging innovative therapies, where perspective on the paper\u2019s application to clinical practice and what is currently known in the field can be provided. This model exemplifies one method on how to facilitate continued growth in knowledge of current literature for trainees to potentially emulate upon completion of their training.The journal club process and organization are overseen by five clinical pharmacy faculty mentors. In addition to the faculty mentors, other active participants are also expected to screen journals, prepare materials for the journal club, and present papers at each session. These other participants include our three PGY2 critical care pharmacy residents and PGY1 pharmacy residents  enrolled in an elective NSS or TICU rotation. Students on Advanced Pharmacy Practice Experience (APPE) rotations for the month with the clinical faculty are also required to attend as non-presenting participants. Most journal club sessions are comprised of 12\u201315 attendees.Journal club meetings are scheduled twice monthly on the second and fourth Tuesday of every month at 3 P.M. and is to last no longer than 1 h. This time was found to be conducive for attendance as the NSS and TICU pharmacy services tend to complete most of their clinical activities for the day by that time as clinical service responsibilities usually begin at 6 or 7 a.m. for each service. In addition, a consistent time and day facilitates the development of a routine, whereby the session is unlikely to be inadvertently forgotten and missed. The location of journal club meetings is also kept consistent and held in a conference room at the College of Pharmacy building, which is located adjacent to the hospital. The tables and chairs are arranged in a rectangular format to facilitate interactive communication among the participants. The presenter may be located within any location in the rectangle.It has been suggested that journal clubs can encourage residents to regularly and critically read the medical literature but will not succeed if the journal club suffers from poor attendance or periodic abandonment . AttendaTwenty-nine journals are screened monthly . The jouThe scheduled presenter must screen the assigned journals and develop a packet of materials consisting of a face sheet, the table of contents for all assigned periodicals for the month, the first page of selected articles containing the abstract of the paper, and sometimes an entire article if the presenter considers the paper of pivotal importance. A truncated example of the journal club packet is provided in Reviews, guidelines, and position papers are not reviewed but may be provided on the face sheet and mentioned during the presentation to alert journal club attendees of its presence. The following month\u2019s presenters use the current month\u2019s face sheet to ascertain what issues of the assigned journals have already been evaluated so that a lapse in coverage in evaluating journal content can be avoided.Our journal club\u2019s current periodicals identified for screening and presentation are listed in To evaluate the success of our journal club in identifying articles pertinent to our practice, we examined a series of publications which was intended to identify the most significant articles for pharmacy nutrition support and critical care pharmacy practice published from 2013 to 2017 ,16,17,18Eighty-seven papers significant to pharmacy nutrition support practice were identified by the author group over the four-year observation period. Seventy-five articles were from periodicals included in our journal club. An additional three articles were from a journal that was not included in the screening list of periodicals but all faculty and PGY2 residents receive as part of their membership of the journal\u2019s sponsoring organization . SeventyStaying current with the literature is a daunting but essential task for the pharmacist who is engaged in an evidenced-based clinical practice. Presented in this review is a method for redesigning journal clubs from the traditional technique of an in-depth analysis of one or two articles to a screening tool that effectively keeps pharmacists informed of current literature. This technique reduces workload of the individual by sharing duties among multiple pharmacists and provides a forum for faculty and senior clinicians to mentor their trainees. This methodological redesign of the traditional journal club is offered to others for consideration."}
+{"text": "Following relevant reader's comments and Editor's request, my co-authors and I would like to add some references which have been unintentionally omitted in some sections of the review. We thank the readers and the Editorial Office for pointing this out and helping us to improve the manuscript.After surgery, radiation therapy (RT) has long been an integral component of cancer care. It is usually employed to locally eradicate tumor cells as well as alter tumor stroma with either curative or palliative intent  family as collagen receptors represents a new paradigm in the regulation of collagen-cell interactions and regulation of tumor progression  and fibroblast growth factor receptor (FGFR) which display a rapid and transient activation, DDR1 and DDR2 are unique in that they exhibit remarkably delayed and sustained receptor phosphorylation upon binding to collagen  undergo negative regulation such as receptor/ligand internalization and subsequent degradation or dephosphorylation by phosphatases . CS is recipient of PhD fellowships from the French Ministry of Higher Education and Research.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Implantable devices utilizing bioengineered tissue are increasingly showing promise as viable clinical solutions. The design of bioengineered constructs is currently directed according to the results of experiments that are used to test a wide range of different combinations and spatial arrangements of biomaterials, cells and chemical factors. There is an outstanding need to accelerate the design process and reduce financial costs, whilst minimizing the required number of animal\u2010based experiments. These aims could be achieved through the incorporation of mathematical modelling as a preliminary design tool. Here we focus on tissue\u2010engineered constructs for peripheral nerve repair, which are designed to aid nerve and blood vessel growth and repair after peripheral nerve injury. We offer insight into the role that mathematical modelling can play within tissue engineering, and motivate the use of modelling as a tool capable of improving and accelerating the design of nerve repair constructs in particular. Specific case studies are presented in order to illustrate the potential of mathematical modelling to direct construct design. Copyright \u00a9 2016 The Authors Journal of Tissue Engineering and Regenerative Medicine Published by John Wiley & Sons Ltd. These parameters have the potential to impact clinical efficacy, and currently are investigated predominantly via experimental techniques. The use of mathematical modelling could speed up and streamline the process of identifying optimal design parameters, provided that the models can be parameterized effectively. The search for a bioengineered solution to the problem of peripheral nerve regeneration, in the form of nerve repair construct (NRC) design, offers a prime opportunity to demonstrate the potential of theoretical techniques in tissue engineering.in vivo and in vitro  to Rachel Coy. Rachel Coy is also supported through the UCL CoMPLEX doctoral training programme.The authors declare no conflicts of interest."}
+{"text": "Background:  Health promoting schools (HPS) projectis currently being used in Iran but many challenges still lie ahead. Thepresent study aimed, to test feasibility of implementing a comprehensiveadvocacy program (CAP) to overcome the obstacles and problems associated withthe consummation of school health programs based on the HPS framework. Methods: This quasi-experimental study was performed throughrecruiting all schools that were enrolled in the national HPS program andlocated in Jolfa as the intervention group and all of the schools situated inthe East Azerbaijan province as control. In order to collect data, IranianMinistry of Health\u2019s checklists and external audit guidelines for HPS wereutilized. In addition, to plan a CAP required data for coordinating fundraising activities including current rules and regulations regarding implementationof local health promotion interventions were collected. Results:  Findings of the study revealed that the implemented CAPhad improved all HPS dimensions\u2019 mean score in the intervention group. Theobserved change in the pre- and post-test score in the intervention group wassignificant (P < 0.05). The intervention was also successful inencouraging signing of an agreement among the participated organizations to becommitted to pursue the adopted policies in facilitation of progress towardsfull implementation of the local HPS project. Conclusion: Commencingchanges in the recruited schools\u2019 structure through coordinated multi-levelactivities is feasible and this must be considered as a priority wherecontextual determinants exist to motivate progress towards providing healthiereducational settings for school aged children in Iran. Health promoting schools (HPS) therefore are communities\u2019 asset for countries\u2019 sustainable development especially when limited resources are allocated for children\u2019s wellbeing in larger societies or families.4 All these acquirements should be considered along with cost savings that communities may gain by decreasing education dropouts or preventing low educational attainments due to reasons such as illnesses or related disabilities.3A health promoting school not only improves school aged children\u2019s health through encouraging healthy behaviors and thus prevention of diseases or high risk practices but it may also improve students\u2019 educational performance and achievements.5 It is also recommended to be one of the effective strategies in filling health gaps among population subgroups and in a larger scale among rural/urban and developed/less developed regions.6Antecedence of required revisions in current schools\u2019 environments even goes beyond the local and national boundaries. Therefore it was incorporated into several international health policies including health for all (HFA).8The health promoting school initiative was introduced in the Ottawa Charter (1980) and addressed as a proper strategy to promote health and empower communities through executing coordinated activities across all sectors (1995). The objectives could be achievable by encouraging communication and collaboration among community sectors and training for better team work.10 The initiative targets both health and educational activities through mobilizing resources as a framework for collaborative and outcome based efforts to reach HFA goals in schools and larger communities.A health promoting school is by definition a school in which continuous efforts are organized to improve students, schools\u2019 staff and members of communities\u2019 health through composing healthy environments, providing required services and dietary recommendations along with maintaining opportunities to improve physical activities and also receive of required mental health counseling.13 including Iran.12 However, there are challenges in executing the HPS project in several countries. Mobilization of human resources and facilities that are required for execution of the initiative, attracting inter-sectoral collaborations especially between private and governmental organizations and persuading students\u2019 parents and teachers active participations are among the important ones.10 Weak or lack of collaborations among responsible organizations, absence of a baseline structure to direct performed activities in a designated route and insufficiency of funding are amongst the important existed barriers in front of the HPS implementation in Iran. Ambiguity of rules and regulations regarding assessment and monitoring of students and school personnel\u2019s health in addition to the scarcity of the health training programs for students\u2019 parents or school personnel have made the current situation even more complicated. All these obstacles along with shortage of human resources such as health counselors and psychologists and current sub-standard physical environments of a considerable number of schools in Iran represent importance of HPS for Iranian students, their parents, schools\u2019 staff and whole country.14The idea was introduced and supported by the World Health Organization (WHO) in the past decade in many countries of the worldConsidering the spectrum and nature of the challenges that need to be overcomed to have HPS in Iran, multidimensional interventions are required in local and national levels. These interventions should be planned for lower level stakeholders e.g. students, families and schools\u2019 staff to higher level stakeholder who might be top level policy makers or managers.Comprehensive advocacy programs (CAPs) could create the required enthusiasm among all stakeholders to work collaboratively in upgrading existent schools to health promoting ones.16To reach the goal changes in policies and practices will be required. Without policy makers and high, middle and lower level managers\u2019 commitment to overcome current barriers in front of the necessary changes that should be planned in the schools, little success must be expectable.This study was designed and carried out to examine feasibility of implementing a CAP and creating stable changes in the schools recruited within the study location  and to learn lessons for implementation of the planned advocacy program possibly in a wider area or whole country.This is a quasi-experimental study which utilized pretest-posttest nonequivalent control group design. The study sought to investigate effectiveness of a CAP in promoting the recruited schools towards HPS from February 2011 to October 2013 in Jolfa, North West of Iran. All schools that were determined by the local authorities and compromised to participate in the national level HPS project (n=26) in Jolfa and those schools that had been determined to participate in the national HPS program and located in Tabriz  (n=1041) were assigned to intervention and control groups respectively.12 The instrument covers eight dimensions including Health Education (8 items which includes 4 one point questions and 4 two point questions); Health Services (11 items which include 5 two points questions and 6 one point questions); Healthy School Environment ; Nutrition Services ; Physical Education and Physical Activity ; Staff Health and Wellness ( 8 items including 5 one point questions and three 2 point questions) and Counseling, Psychological, and Social Services . In addition; Family and Community Involvement in the HPS\u2019 programs were asked using 8 items that were 6 one point and 2 two points questions. To collect required data for planning of a CAP in the area, several dimensions like allocated funding, published national rules and regulations that support HPS program and official policy documents both in the national and local levels were scrutinized. Using audit checklists, the organized audit teams consisting of health care centers\u2019 staff who were blind to the objective of the study carried out the primary and final assessment of the studied schools regarding the changes that were assumed to take place following the advocacy program.The study data were collected using the introduced checklists for external audit according to the guidelines recommended for assessment of HPS by the Iranian Ministry of Health and Medical Education (MOHME).14A baseline assessment was carried out to recognize the current problems and challenges in successful implementation of the HPS program using the primary assessment checklists. Findings of this stage were used to plan a CAP considering the recommendations were given for conducting a CAP by Sprechmann and Pelton including two steps and in each step the instruments and work sheets introduced by Sprechmann and Pelton were used in the following order.(1) Activities prior to conduction of the comprehensive advocacy program Main purpose of this phase was to minimize risk of failure and also maximum use of all potentials to achieve success. To accomplish activities of this stage policy documents at local and national scales were checked, key responsible persons in the local organizations, decision makers and those who have capabilities and chance to lobby these policy makers and other important authorities were identified. The identified individuals were contacted consequently to publicize the idea behind the HPS program. Understanding the dominant policy climate in the organizations, all efforts were made to ensure provision of reliable information by credible individuals that included a short list of priorities required to be focused in the planned CAP.(2) Planning for comprehensive advocacy programActivities of this phase were conducted in the following four stages: analysis of policies, development of strategies for a CAP, making decision on most suitable strategies and program implementation. The performed activities that had been carried out in every stages of this phase were displayed in t test and independent t test were applied for comparison purposes. The test results considered to be significant if P<0.05.To examine effectiveness of the implemented advocacy program the collected pre and post intervention data were compared against the data collected in the provincial level following the implementation of baseline HPS program. Data analysis was performed using the statistical package for the analysis of social science (SPSS) version 16. Mean and standard deviation for quantitative data were estimated and inferential statistics of paired The study results revealed that 26 (25%) out of 104 schools that were located in Jolfa area covered by the provincial HPS program and only 3 (11.53%) of them were located in rural areas. Among the 4463 schools that were listed to be working in East Azerbaijan province, 1041 (23.22%) were included in the provincial HPS program of them, 146 (14%) schools were located at rural areas. In the city of Jolfa; 15(57.69%) of the schools were primary schools, 7 (26.92%) were junior high schools and 4 (15.38%) were senior high schools that decided to be included in the provincial HPS program. In East Azerbaijan province, 557 (83.81%) primary schools, 302 (29.17%) junior high schools and 176 (17%) senior high schools were covered by HPS program.The obtained data regarding the areas of \u201cgeneral policies\u201d and \u201ceffective policies\u201d and also in each of the eight mentioned dimensions of the pilot CAP project in Jolfa were summarized in Tables P<0.001)  . Additio18 Multi-level involvement of stakeholders including families, schools, policy makers and health care providers could increase chance of success to reach the program objectives16 and should be regarded as a pivotal principle in implementation of a CAP. Based on the community participatory project for development of HPS in Zhejiang province, China,17 considerable improvements in knowledge and behavior of students, staffs, and parents about healthy nutrition were observed. Huang et al also reported that integration of local resources and close cooperation among all collaborators within local communities could greatly help development of HPSs and overcoming challenges stemmed from incongruous activities.18 It seems, a participatory approach to HPS would be more than the improvement of the health and would have multidimensional outcomes beyond the schools\u2019 environments.Findings of this pilot field test indicated feasibility of implementing an effective CAP to pursue the proposed polices with regard to execution and development of the HPS project in Jolfa, Iran. The study results were also revealed that  the agre20 Winkleby et al, based on implementation of a CAP, have reported a considerable decrease in cigarettes consumption in their study\u2019s intervention group.19 Goodkind, reported that through a CAP, satisfaction of the Hmong refugees about assessment process of their required resources, living standards and stress level had improved.20Results of other studies were also indicative of the effectiveness of CAPs in improving and sustaining health programs.25 In spite of the importance of inter-sectoral collaboration in success of community wide programs, the required level of cohesion that is especially required in developing countries was not seen due to partially rigid and patchy definition of organizational responsibilities and priorities.26While the conducted CAP had considerable outcomes for development of HPS project in the study location, but various challenges were also encountered including lack of full cooperation of responsible organizations that interfered with expected achievements. Failure in achieving full cooperation of all stakeholders in the HPS programs were also reported in other studies.27 with potential to influence the program results. In this study, the principal encountered challenges in implementation of CAD program were as follows: instability of directors and managers in their position in the relevant organizations, resisting against the required changes in the organizations\u2019 responsibilities, higher priority of the short term benefits compared to long term organizational achievements, lack of culture of team work and full cooperation to achieve organizational goals and objectives and deficiencies in financial resources that are needed for coordinated activities. Consistent with the findings of this study, Abdulmalik et al27 have pointed to the facing challenges in implementation of CAP such as lack of full support from the policy makers side due to a narrow level of expertise they may have and reluctance of official staff to input new activities or objectives into their organizational routines that may expand their current responsibilities beyond the existent frameworks.27Implementation of CAP may face same common route barriers and challenges in the developed and developing countriesWhile there is no explicit blueprint to reach success in advocacy programs all efforts were made to use current research evidence in planning phase of the study. An unequivocal hybrid of professional skills to fascinate partnership was applied to build local capacity for supporting the initiative. Thus; local planning skills for HPS were improved but we believe that overall capacity to sustain the required support for long term planning remained inconsistent. A part of this paucity was related to bureaucracy of decision makings in the local organizations, hierarchy of the agreements\u2019 approval in the upper level managerial settings and divergent priorities within the participant organizations.To achieve advocacy programs\u2019 goals proactive collaboration of all stakeholders is indispensable but financial impediments were amongst the most alleged considerations by the local level managers to intimate participation with the scheduled advocacy program. The current top-down centralized planning and budgeting mechanisms in Iran prohibits creativity in local level decision makings and prioritization of the health problems.Another limitation of this study was abstaining of a number of local stakeholders from full engagement in the designed HPS reinforcement project.Another limitation of this study was assuming of existent baseline data in provincial level suitable for comparison purposes. This is while; inherent differences actually might exist between the study location and other socio-economic milieus. We were aware of importance of selecting a socio-economically and demographically homogenous control field but due to logistical restraints it was impracticable. Despite all these impediments the study results could provide advices for better planning and implementation of HPS programs in at least socio-culturally and economically similar settings.This study used the strategy of CAP as an attempt to overcome the potential challenges and obstacles in front of implementing a local version of the HPS program in a typical national level setting. The study findings indicated that using a well-organized CAP and implementation of a sustainable HPS program could greatly improve the current programs and overcome many challenges. The employed strategies and lessons learnt in this local CAP may help other local or even national level programs in progressing towards healthier schools and thus healthier next generations. While, the identified barriers and applied strategies could be applicable in other national and even international levels, special attention must be paid to the inherent differences that might exist and interfere with the CAP implementation in culturally, socially or organizationally heterogeneous settings.Based on the study findings advocacy activities for boosting national level HPS initiatives should consider more effective routes to engage all organizations and administrative sectors in public health activities as one of their national and even international missions that need to be followed for a safer and promising planet for all. Secondly, ministries of health and relevant organizations should clarify their expectations about how other organizations can engage and collaborate in improvement of school health programs and help them to move in line with health promotion programs in a sustained manner. Next, all organizations are encouraged to have a clear and documented policy to help local and national level health promoting programs to overcome national health related challenges since; weak or lack of inter-sectoral cooperation might hamper accurate implementation of community based health promoting programs.The ethical approval was obtained from the Human Research Ethics Committee (HREC) of the Tabriz University of Medical Sciences. In line with the ethical guidelines for implementation of the study, its purpose was clearly explained to the participants i.e. involved organizations and groups. The participants\u2019 rights to withdraw from the study at any time for any reason and without any obligation in giving reasons for their refusal to continue participation in the study were also clarified. In the implementation phase of the study during negotiations and convincing study participants their views, times and preferred schedules for spending time to answer questions or give their opinions were considered respectfully. All efforts also were made to build mutual trust with the respondents and carefully concede issues like organizational benefits, sensitivity of the managerial tasks and other considerations.None of the authors has any conflict of interest.TB helped in drafting the article and data analysis, BF major role was conceptualization and design of the study, data collection and interpretation and drafting the article, ASH and HA helped greatly in conceptualization and design of the study, data analysis and interpretation and revised several drafts of the article critically for major intellectual content. All authors have read and approved the submitted and revised final version of the manuscript.This research was supported by a grant from the Tabriz University of Medical Sciences. The authors would like to appreciate all local organizations\u2019 support in execution of this study."}
+{"text": "The technique of transtympanic electrocochleography was initially developed as an objective hearing threshold test by Eggermont. Gibson et al.  claimed  Electrocochleography (EcochG) is a method of directly recording electrical activity of the cochlea and the acoustic nerve in response to acoustic stimulation. The three components measurable are the cochlear microphonic (CM), the action potential (AP), and the summating potential (SP). In contrast to the earliest studies, new computer averaging techniques have enabled routine testing of these components in humans.This review will briefly summarize the useful components of the EcochG used in the diagnosis of Meniere's disease. The effects of electrode placement on the size of the AP and SP and the merits of tone burst stimuli will be discussed. New international criteria for the symptomatic diagnosis of Meniere's disease make no allowance for any diagnostic test for a disorder which always begins in the cochlea, even though objective testing can confirm or exclude it.The CM, originally called the cochlear potential, was recorded in cats by Wever and Bray . It is tThe response from the acoustic nerve is the AP and was first demonstrated in the cochlear nerve and brainstem of cats by Saul and Davis . BecauseA 100 ms click stimulus stimulates the whole basilar membrane. Frequency selective masking experiments suggest that the major contribution from a click is from the basal turn of the cochlea  there is a need for alternative diagnostic certainty, particularly for investigational studies, and to unequivocally distinguish Meniere's disease from other causes of recurrent vertigo attacks.The term clinically certain Meniere's disease can be defined as a diagnosis based on the 1995 AAO-HNS symptomatic criteria  could confirm a diagnosis of superior canal dehiscence syndrome other diagnostic applications for VEMPs have been sought, including for Meniere's disease with numerous publications employing cVEMPS and ocular VEMPs (oVEMPs) to diagnose hydrops in the vestibule. These have produced conflicting interpretations as to the diagnostic sensitivity. In 18 patients with a clinically certain diagnosis in one ear, Johnson et al.  measuredConfirmation of visible inner ear hydrops on MRI scanning with intratympanic gadolinium (Nakashima et al., Hornibrook et al.  comparedThe initial promise of a click response SP/AP ratio as a sensitive test for endolymphatic hydrops has not been realized (Hornibrook et al., ET electrodes are significantly inferior for measuring tone burst responses. Until the signal-to-noise ratio problem of ET electrodes is solved, TT recordings are of greater magnitude and accuracy.An analysis of 128 Meniere's disease studies (Thorpe et al., cochlear hydrops to confirm a diagnosis of Meniere's disease. There is agreement that a response of not < \u22123 mV is diagnostic for endolymphatic hydrops (Dauman and Aran, Of all investigative tests transtympanic tone burst EcochG remains the simplest, and most sensitive test to diagnose As was once for electrocardiography there is an urgent need for universal agreement on equipment specifications (Hohmann et al., The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Delivering in health facility under the supervision of skilled birth attendant is an important way of mitigating impacts of delivery complications. Empirical evidence suggests that decision-making autonomy is aligned with holistic wellbeing especially in the aspect of maternal and child health. The objective of this paper was to examine the relationship between women's health decision-making autonomy and place of delivery in Ghana. We extracted data from the 2014 Ghana Demographic and Health Survey. Descriptive and logistic regression techniques were applied. The results indicated that women with health decision-making autonomy have higher tendency of health facility delivery as compared to those who are not autonomous . However, those who have final say on household large purchases  and those having final say on visits  were less probable to deliver in health facility than those without such decision-making autonomy. Consistent with existing evidence, wealthier, urban, and highly educated women had higher inclination of health facility delivery. This study has stressed the need for interventions aimed at enhancing health facility delivery to target women without health decision-making autonomy and women with low education and wealth status, as this can play essential role in enhancing health facility delivery.  The World Health Organisation (WHO) estimates that 536,000 women die yearly owing to pregnancy and delivery related complications. At the same time, over the past two decades, maternal mortality ratio has declined by 45 percent whilst prevalence of maternal death declined from 532,000 to 289,000 as of 2015  and this persisted even after controlling for the sociodemographic variables  as displayed in Women in all age categories were less probable to deliver in health facilities as compared to those aged 15\u201319 years . The modAgain urban residents were noted to have higher odds of health facility delivery as compared to their rural counterparts . Women who had subscribed to the NHIS were more likely to deliver in health facilities compared with unsubscribed counterparts . With the Western region as a reference, women from Upper East stood out as having five times likelihood of health facility delivery  as displayed in Previous studies have demonstrated that some women in Ghana are less empowered and have limited decision-making rights. This study was carried out to examine the relationship between women's health decision-making power on their place of delivery.It was revealed that women with autonomous health decision-making power were more likely to utilise health facility for delivery as compared to those without. This presupposes that autonomy of women in relation to health is important to enhancing health facility delivery which guarantees skilled birth attendance. To a greater extent maternal health and child health are inherent in the level of empowerment and autonomy exercised by women because autonomous women would make right choices and access quality healthcare at all times particularly during delivery.This observation is consistent with some prior studies which also noted that when women are autonomous and have much influence on decisions that affect their wellbeing, their access to and utilisation of healthcare improves \u20139. As woDelivery in health facilities increased with higher wealth quintile whereas home deliveries characterised poor women. This finding highlights the influence of cost on utilisation of healthcare in the country and this might pose threat to the health status and maternal wellbeing of poor women. This is particularly critical because cost can also deter them from accessing quality healthcare for themselves and their children even after delivery and this might constitute severe threat to their health status and their children. Similar findings were noted in a study conducted in Nepal where it was realised that home delivery was dominant among poorer than wealthier women  whilst aIn line with wealth status and utilisation of health facilities, health insurance is a cost cutting intervention that enables people to have easy access to healthcare. The finding that insured women had high propensity of delivering in health facilities indicates that indeed subscription to the insurance scheme immensely influences decision on place of delivery. This observation conforms to a study conducted in the Ga-East Municipality of Ghana which noted higher rate of health facility delivery among NHIS subscribers .It was observed that respondents aged 15\u201319 years were more probable to deliver in health facilities as compared to those aged 45\u201349 in Ghana. Maternal age has been linked to parity and various aspects of life , realisiIt was noted that higher educational attainment was highly related to health facility delivery which affirms the plethora of studies \u20138 that hThe study has indicated that health facility delivery is more probable among urban residents as compared to those in rural settings. This might be owing to the relatively less availability of health facilities in rural settings as compared to urban areas in the country. If a woman in rural area has to ply several miles before accessing the nearest health facility, such a person might not have the urge to consistently access health facility as compared to those in urban areas where health facilities relatively abound. At the same time, urban areas have relatively better road networks, which enhances their easy to access health facilities for deliveries. Analysis of trend and pattern of institutional delivery in Bangladesh from 1993 to 2007 in relation to residency and education also revealed low utilisation of health facility among women in rural settings . On the Women in the Upper East region were noted to have the highest likelihood of health facility delivery in the country. The high presence of CHPS in the region may be contributing substantially to the observed pattern. The relevance of CHPS in improving maternal and child health in Ghana has been highlighted previously , 36, sugSince the study dwelt on preexisting data, it could not explore the motivation for the use of place of delivery among women. Again, the cross-sectional nature of the survey does not permit identifying cause and effect. Amidst all these, the results present a true reflection of the relationship between health empowerment and place of delivery and thereby provide insights into public health interventions worth instituting to promote health facility delivery in Ghana.The study has indicated that Ghanaian women with healthcare decision-making autonomy are more likely to deliver in health facilities and this persisted even after controlling for sociodemographic factors. It is also evident that higher wealth status is aligned with health facility delivery. The study therefore recommends that government and nongovernmental organisations concerned with maternal and reproductive health should target women who do not independently decide on their own healthcare with mass media campaigns advocating health facility delivery. Additionally, incentive packages required to inspire health facility delivery must be geared towards women with low education and wealth status, as this can play essential role in enhancing health facility delivery."}
+{"text": "The endocannabinoid (eCB) system (ECS) plays a prominent role in regulating brain reward function and modulating emotional homeostasis  has been implicated as a critical component of long-lasting neural maladaptation underlying addictive behaviors  receptors were downregulated by chronic ethanol administration  and its application to other drugs of dependence or other prenatal stresses remain to be determined. Moreover, the extent of the excitatory pathway linked to the widely-studied inhibitory GABAergic pathway on the VTA DA neurons should be investigated. The CB1 receptors examined by Hausknecht et al.  were at These considerations notwithstanding, the observations of Hausknecht et al.  advance The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "ARPANSA) collect reported incidents for inclusion in the Australian Radiation Incident Register (ARIR), a database of radiation incident reports that occur within Australia. While the information on previous radiation incidents is available, there is little information on the lessons that can be learned from those past incidents to help prevent the same errors reoccurring. The aims of the study were to investigate what radiation incident registers are publicly available in Australia and to utilise the information contained within the ARIR and any other state or territory radiation protection authority registers to make recommendations for radiographers and radiation therapists to prevent future adverse events.The Australian Radiation Protection and Nuclear Safety Agency  of the adverse events. A vast majority of the incidents were a failure to comply with time\u2010out protocols .There are several radiation adverse event registers publicly available to utilise in Australia. All departments need to adopt and strictly adhere to time\u2010out protocols. This in conjunction with the other recommendations in this article has the potential to dramatically reduce radiation adverse events. When adverse events occur in the medical radiation science (MRS) profession, the incident is investigated and the incident along with the findings of the investigation is reported to the relevant state or territory government radiation protection authority. The Australian Radiation Protection and Nuclear Safety Agency (ARPANSA) collect reported incidents for inclusion in the Australian Radiation Incident Register (ARIR), a database of radiation incident reports that occur within Australia.(p12) For the ARIR to be an effective tool to reduce radiation incidents, the information from past experiences contained within the annual summary reports must be utilised as a learning tool to change systems and behaviours.The Australian Radiation Protection and Nuclear Safety Agency compile radiation incident reports to produce annual summary reports of the ARIR. The World Alliance for Patient Safety states: \u2018The primary purpose of patient safety reporting systems is to learn from experience. It is important to note that reporting in itself does not improve safety. It is the response to reports that leads to change\u2019.Any diagnostic procedure other than as prescribed by the medical practitioner.Any diagnostic procedure resulting in an observable acute radiation effect.Any therapeutic treatment delivered to either the wrong patient or the wrong tissue or using the wrong radiopharmaceutical.(p37)When during administration of a therapeutic dose of radiation from a radiation apparatus or a sealed radioactive source, the dose delivered differs from the total prescribed treatment dose by more than 10%.Schedule 13 of the National Directory of Radiation Protection specifies the incidents that must be reported to ARPANSA for inclusion in the ARIR. Radiographers and radiation therapists have to report incidents in the following circumstances:(\u00b64) The annual summary reports are the only documents to be released by ARPANSA from the information contained within the ARIR. Summary reports from 2012 onwards contain additional information on the causes of the incidents but are not detailed enough to draw recommendations for improvements in safety. ARPANSA plan to include more detailed information in future annual summary reports on post\u2010incident follow\u2010up and lessons learnt.One of the objectives of the ARIR when it was established was \u2018through appropriate publications, to provide feedback and guidance to users of radiation on preventing or limiting the consequences of radiation accidents\u2019.\u00b6 The annuTo investigate if any radiation protection authority incident registers within Australia are available to the public.Utilise the information contained within the ARIR and any state or territory radiation protection authority registers to make recommendations for radiographers and radiation therapists to prevent future adverse events.The aims of the study were:keywords: \u2018Radiation\u2019, \u2018Radiation incidents\u2019, \u2018Radiation accident\u2019) to locate what radiation incident registers within Australia were available to the public. Authorities responsible for radiation in each state and territory were contacted via e\u2010mail to confirm if radiation incidents data were publicly available.As this study involved publicly available anonymised data, ethics approval was not required. A search was conducted from January 2015 until March 2015 of all state and territory health department's, environment authority's and radiation authority's websites (All diagnostic radiography (DR) and radiation therapy (RT) adverse events available from the state and territory registers along with those in the ARIR that occurred between 2003 and 2014 were compiled into a spreadsheet for analysis. Incidents were excluded if the researchers concluded there was inadequate information to determine a cause or were deemed to be no fault of the MRS personnel involved , South Australia (SA), Tasmania (TAS), Victoria (VIC) and Western Australia (WA). These incident registers are contained within annual reports of the relevant state government authority Table . IncidenA total of 356 adverse events were derived from the incident registers between 2003 and 2013 that the researchers determined a cause could be concluded . There were 35 incidents  determined to be duplicated in both a state authority register and the ARIR, so these were considered to count as one incident for the purposes of this study. This left 321 incidents  being subject to further scrutiny.DR represented 76% of the 321 adverse events. A vast majority of the incidents were a failure to comply with time\u2010out protocols (77%) and half of those were due to non\u2010compliance where the time\u2010out protocol was not carried out. The categorisation of the total number of incidents included in the study is detailed in Table It is not surprising that DR errors outnumber those of RT by approximately 3:1. Radiation therapists often work in pairs checking each other's work and the procedure times are longer resulting in fewer procedures performed. RT also has more quality assurance checks due to the higher risks associated with greater radiation doses.(p2) and the correct patient, correct site and correct procedure protocol is a way of meeting the mandatory requirements of that standard.The use of the \u2018correct patient, correct site and correct procedure\u2019 protocol for operating theatres was mandated by Australian health ministers in 2004.Underreporting of incidents has been well documented in medicineThis study identified several other publicly available radiation registers apart from the ARIR. Causes of incidents are easier to determine the more information that is made available; the NSW register generally contained more information than the ARIR, while the WA and VIC registers contained far more detailed information on each incident that makes those registers an invaluable learning resource. The Radiology Events Register (RaER) is a voluntary radiology incidents database that contains case studies that are also useful learning resources.Several trends were identified in the analysis of the incidents to draw recommendations from. Almost 39% of the adverse events were due to non\u2010compliance in which the description of the incident clearly stated the time\u2010out protocol was not performed. All facilities must develop, practice, perfect and monitor the use of time\u2010out protocols appropriate to the organisation. The implementation of this one recommendation addresses numerous error classifications in this study, such as the use of closed questions, and has the potential to drastically reduce the rate of adverse events that occur in DR and RT.Booking procedures also had several reoccurring causes identified. There were numerous incidents in DR of two requests being submitted for the same examination and being completed twice. Incidents in both DR and RT of examinations being cancelled and performed anyway. Examinations in DR were also rescheduled and performed on both occasions. All practices need to examine their clerical procedures to look for deficiencies of this kind. Many patient scheduling software packages incorporate warnings for duplicated examinations within preceding time frames to assist with this. Another reoccurring cause of incidents in DR was the use of faxed request forms and the examination being performed again with the original form. Strict policies and procedures for the use of faxed request forms need to be implemented to reduce these types of errors occurring.There were several RT incidents that involved the use of proposed instead of actual prescriptions or fields for treatment. These errors can be prevented by having clearly defined protocols where the radiation oncologist signs off all information/scans to be used for the patient treatment at predefined stages throughout the simulation and planning process, and any preliminary data not utilised should be deleted or filed in non\u2010clinical folders so it cannot be confused with the actual treatment plan.A number of incidents occurred in DR where the incorrect patient identification label was affixed to the request form. A considerable portion of identification errors are due to the use of stickers and this is unlikely to be eliminated with the use of electronic requesting,The sub\u2010category of Failure to Comply with Time\u2010Out Protocols: Procedure: Human Error had numerous causes but some reoccurring causes were identified. The reoccurring causes along with the recommendations to prevent them are detailed in Table Although the aims of the research have been achieved, there are limitations to this study. The authors acknowledge they are not experts in the field of occupational or nuclear safety and the recommendations are those from people working in and understanding the processes of the profession. Many more incidents from the ARIR could have been analysed if anonymised data were sought from ARPANSA instead of the brief descriptions in the annual summary reports; however, the authors set out to use publicly available data throughout Australia to determine if MRS professionals could utilise the data to make useful suggestions to prevent future adverse events.As MRS professionals, we have an obligation to minimise and prevent adverse events when interacting with our patients. One way to achieve this is to learn from previous errors that have occurred and there are several radiation adverse event registers publicly available in Australia that can be utilised for that purpose. The knowledge obtained from these registers can help prevent future adverse events occurring.An overwhelming percentage of adverse events in radiography and radiation therapy occur due to the failure to comply with time\u2010out protocols. All departments need to adopt and strictly adhere to the protocols mandated by organisations Australia wide. This in conjunction with the other recommendations in this article that has the potential to dramatically reduce radiation adverse events and improve safety for staff, patients and members of the public alike.The authors declare no conflict of interest."}
+{"text": "To the Editor: We read with interest the article by Furuya-Kanamori et al. on the proportion of influenza virus infections that are asymptomatic or subclinical . It is not considered good practice to present pooled estimates in instances of massive heterogeneity (In another systematic review of the asymptomatic fraction of influenza virus infections ("}
+{"text": "The main aim of collecting the data was to assess the climate smartness, profitability and returns of soil protection and rehabilitation measures. The data were collected from 88 households. The households were selected using simple random sampling technique from a primary sampling frame of 180 farm households provided by the ministry of agriculture through the counties agricultural officers. The surveys were administered by trained research assistants using a structured questionnaire that was designed in Census and Survey Processing System (CSPro). Later, the data was exported to STATA version 14.1 for cleaning and management purposes. The data are hosted in an open source dataverse to allow other researchers generate new insights from the data ( Specifications TableValue of the data\u2022The data allows researchers to compute cost benefit indicators of climate-smart soil practices in Western Kenya in order to understand the perceived benefits and cost from a private and social point of view.\u2022The data can help researchers to understand what explains farmers' decision to implement climate-smart soil (CSS) practices while allowing comparisons with soil management practices from other countries in sub-Sahara Africa.\u2022This data can provide a significant contribution to the literature on economic assessment of climate-smart agricultural (CSA) technologies on the costs that accrue to the stakeholders in both the short- and long-term.\u2022The data can be used to identify barriers to adoption and implementation of different soil practices at the micro level and macro level.1This article presents data collected by CIAT with an aim of assessing the climate smartness, profitability and returns of soil protection and rehabilitation measures. The data was collected using a structured questionnaire by means of Computer Aided Personal Interview (CAPI) technique to make the collection process effective and to minimize errors such as outliers and missing values. It is estimated that researchers spend about 80% of their time cleaning and organizing data Data were collected with the help of six local enumerators\u2014two from each of the three counties\u2014who were fluent in both English and the local language. These enumerators trained intensively for five days in English language to ensure a thorough understanding of the research questions and to control loss of information during translation. They were also trained on using CSPro entry android application and how to record geographical positioning coordinates using a GPS. To maintain consistency during the interviews, each enumerator had a hard copy version of the questionnaire to serve as a reference point throughout the survey period and to act as a backup in case of power failure, although data were to be entered directly into the laptops if hard copy questionnaires were used. Each enumerator was given CSPro data entry application on their laptops to facilitate data entry.Immediately after the training, a reconnaissance was done to test enumerators\u2019 ability in collecting reliable data and time taken to interview one farmer for logistical planning. This served as an important exercise for enumerators to familiarize well with the questionnaire and also for the engaged CIAT staff to have prior knowledge of the field challenges. Enumerators were instructed to interview the household head because they are more conversant with farming activities. In the absence of the household head, however, the enumerators were requested to interview any other household member above 18 years old as long as the member had more than 10 years of farming experience. We defined household head as a person who was the main decision maker as far as farming was concerned and participated in most of the agricultural activities of the household. CSPro was linked to a CIAT staff drop box account that aided data backup and daily checking of the quality of the data. A CIAT research associate in Nairobi office was tasked to check for consistencies in the data using predesigned Stata do files.2This data was collected from three counties of western Kenya, namely Bungoma, Kakamega, and Siaya . Siaya cStep two involved identification and listing of the already existing (and new) CSS practices that are applicable in the different farm typologies through focus group discussion. Step three involved evaluation of the listed practices using ten indicators in the CSA goals of productivity, resilience, low emission and development. The main goal of step three was to generate a short list comprising three high-interest CSS practices for each farm typology . Step fo"}
+{"text": "The cellular origins of cancer have long been debated. Work indicating the existence of a rare stem cell for acute leukemia was followed by a number of reports of relatively rare stem cells for a number of cancers. Other work has challenged the concept of cancer stem cells being a rare repopulating cell for cancer or providing a promising target for chemotherapy or immunotherapy. A balanced view here may be that there may be a continuum of \u201cstemness\u201d with early cancers having rare stem cells while with progression , i.e. most solid tumors, most of the cancer cells are in fact stem cells. In this latter case there would be no advantage to defining these cells. Thus far therapeutic application of cancer stem cell directed therapy has been disappointing. There is also longstanding and abundant information on the role of microenvironment in carcinogenesis. This bring up the issues of whether cancer cell mutations or micro environmental influences are predominant in carcinogenesis.The area of aging and stem cells interfaces with carcinogenesis as the latter progressively increases with age. The increasing clonal nature of blood stem cells with aging is pertinent here. Many studies have suggested interesting changes in hematopoietic stem cell numbers and function but have not taken into account the issues of the stem cell continuum and baseline stem cell hematopoiesis. Major issue are whether aging effects can be reversed or manipulated and what role the systemic effects of aging have on neoplastic hematopoietic diseases.The definition of cancer stem cells;The characterization as to total phenotype of putative cancer stem cells;The model systems available for study;The regulation of putative cancer stem cells:-the therapeutic implication of cancer stem cells;The changes in hematopoiesis and hematopoietic stem cells with aging;The nature of clonal hematopoiesis with aging;The study of different stem cell models with aging;The capacity to modulate aging effects of hematopoiesis;The implications for hematologic malignancies with regard to aging hematopoietic stem cells;The therapeutic implications of aging hematopoietic stem cell populationsThe section on Cancer stem cells and Aging provides a forum for the exchange of ideas and results from areas pertaining to cancer stem cells and carcinogenesis in general and the impact of aging on stem cell number and function and neoplastic potential. We will emphasizeWe look forward to receiving your high-quality submissions to our journal and also welcome your feedback and opinions on the new structure and other future changes."}
+{"text": "During the last decade, OMICs techniques have conquered the field of oral microbiology. This has resulted in an exponential growth of publications on microbiome related to different stages of caries process, as well as on primary and recurrent root canal infections. But have these technological advances brought us any groundbreaking insights that would help a clinician in choosing the right treatment or prevention strategies? In this presentation the current knowledge on microbiome related to Cariology and Endodontology fields will be critically assessed. Then the potential pitfalls and shortcomings of the studies using OMICs approaches will be discussed and future directions will be highlighted."}
+{"text": "Nutrients Editorial Office has recently been made aware that the figures in the title paper [The le paper  are takele paper  (rat) isle paper  (mouse),le paper  (rat) isle paper , and Figle paper  is identle paper . Given tle paper  will be Nutrients is a member of the Committee on Publication Ethics (COPE) and strives to uphold the highest ethical standards; misuse of images is not acceptable and we are committed to taking appropriate action when such cases are reported. We apologize to readers of Nutrients and wish to thank the reader who first reported this case."}
+{"text": "The freight rail systems have an essential role to play in transporting the commodities between the delivery and collection points at different locations such as farms, factories and mills. The fright transport system uses a daily schedule of train runs to meet the needs of both the harvesters and the mills  [1]). Producing an efficient daily schedule to optimise the rail operations requires integration of the main elements of harvesting, transporting and milling in the value chain of the Australian agriculture industry. The data utilised in this research involve four main tables: sidings, harvesters, sectional rail network and trains. The utilised data were collected from Australian sugar mills as a real application. Operations Research techniques such as metaheuristic and constraint programming are used to produce the optimised solutions in an analytical way. The results in this research can be used to compare the performance of the proposed mathematical methods in optimising complex systems such as rail systems in many prospective studies.\u2022The data of the produced schedules of the train runs can be used for many different types of the freight systems such as the sugarcane or coal rail systems 1Based on the feedback from our industry partners, the data utilised in this research are created in four main tables: Sidings , Trains 2A case study was examined to validate the constraint programming models and metaheuristic techniques. Constraint programming (CP) is one of solution techniques to find a near optimal scheduler for the sugarcane rail systems. The proposed mathematical model considers the siding and train capacity constraints, daily allotment constraints of each harvester, train passing constraints where each train cannot occupy more than one rail section at a time or two trains can occupy one section at a time. Constraint programming that deals with problems defined within the finite set of possible values of each variable is the main technology used for solving mathematical formulation problems through the search trees. Metaheuristic techniques such as Simulated Annealing and Tabu Search are integrated with CP to improve the CP\u2019s solutions"}
+{"text": "This article comments on:Regente M, Pinedo M, San Clemente H, Balliau T, Jamet E, de la Canal L. 2017. Plant extracellular vesicles are incorporated by a fungal pathogen and inhibit its growth. 68, 5485\u20135495Journal of Experimental Botany . Extracellular vesicles (EVs) are secreted by organisms from all forms of life. In the mammalian field they are intensively studied due to their importance in disease and potential for therapeutic use. However, there has been little research in plants and thus the paper by) is a valuable addition to a small but hopefully growing body of data. The authors conducted proteomic analysis on purified sunflower EVs and demonstrated that they are enriched in defence-related proteins. They found that fungal spores treated with fresh EV preparations are damaged and show reduced growth.In addition to being a means to unconventionally secrete proteins to the apoplast, extracellular vesicles (EVs) are presumably being secreted by plant cells for communication with neighbouring plant cells and for interaction with microbes and other organisms. Indeed, it is conceivable that the latter might be more important as it could be argued that plasmodesmata can take care of the bulk of protein and RNA exchange between neighbouring plant cells. On the other hand biology loves complexity and redundancy.There are several potential pathways for the production of EVs and different classes of EVs are recognized, such as microvesicles and exosomes  proteins enter the endoplasmic reticulum (ER) co-translationally then pass through the Golgi body and are packaged into transport vesicles that fuse with the plasma membrane. For unconventional secretion several routes have been proposed. Classically, unconventional secretion describes how proteins without signal peptides, which are presumably therefore synthesized in the cytoplasm (black stars), are secreted into the extracellular milieu (the apoplast in the case of plants). This may be via invagination into multivesicular bodies  (2) or direct budding from the plasma membrane (3) followed by degradation of the vesicle membrane in the apoplast (4). The vesicles that emerge via these routes have an alternative fate, however, which is to stay as extracellular vesicles (EVs) and be taken up by another cell. It is possible that some of them fuse directly with the target cell\u2019s plasma membrane (5) but the evidence favours endocytosis of the majority. The endocytosis may be preceded by recognition of the vesicle components by receptors on the target cell  or by recognition of proteins, carbohydrates or lipids on the target cell by components of the vesicle membrane . Once endocytosed the vesicle contents could be released by degradation of the vesicular membranes (8) or through retrograde trafficking to the late endosome (orange arrows), which is largely equivalent to the MVB, and fusion of the vesicular membrane with the bounding membrane (9).The picture is complicated by unconventionally secreted proteins that do have signal peptides (red stars). It is not difficult to understand how they could end up within the bounding membrane of the exosome positive organelle (EXPO), which is probably a form of autophagosome and may thus form from a cup-shaped ER extension that engulfs cytoplasm and potentially organelles. It is also possible that there are transient connections between the ER and MVBs (10) by which means the protein could enter the MVB without passing through the Golgi apparatus. These proteins would then be released into the apoplast or could perhaps associate with the exterior of EVs and make their way inside the target cells then to be released by vesicle degradation, or possibly by trafficking all the way to the target cell ER and hijacking the unfolded protein response pathway to exit from the ER (11). It is more difficult to envisage whether there could also be routes by which these proteins end up inside EVs (question marks).In The treatment of fungal spores by in planta or in a culture system) of EVs carrying highly effective biocides or RNAs that are specifically taken up by economically important pathogens or pests. Host-induced gene silencing is a method shown to provide crop protection . Bacterial pathogens have specific structures such as the type 3 secretion system to deliver their effectors but no such structures have been identified for eukaryotic pathogens. Botrytis cinerea has been shown to produce RNAs that are destined for host cells (Cuscuta to host cells but plasmodesmata are formed between Cuscuta and their hosts. Thus mRNAs may move symplastically, though of course this does not rule out an exchange of EVs between Cuscuta and its host.A further exciting area of study will be characterization of RNA populations in pathogen- and plant-derived EVs. The delivery of small RNAs to control gene expression within the host or mRNAs to ensure the production by the host of specific proteins helpful to the establishment of infection are both possible through EVs as they can protect the vulnerable RNAs from the apoplastic environment. The proteomics of plant EVs has only been published by The analysis of EVs involved in plant\u2013pathogen interactions is only just beginning but their potential for increasing our understanding of the exchanges determining disease outcomes and the potential for the development of new strategies to combat disease in economically important crops will ensure the rapid expansion of this field."}
+{"text": "This study focused on a comparative analysis of exposure to pollution in Ota and Ewekoro Township where we have concentration of industries that emits pollutant to the air. This was with a view to proffer solution to the negative effects of industrial activities on residents within industrial location. The study involved empirical observation and interview of residents. About 652 questionnaires were administered randomly on the residents. Analysis involved descriptive statistical tools including chi-square techniques. The results suggest that air pollution was most frequently reported in Ewekoro and Ota and this can help in the prediction of stringent factor in which industrial activities could pose to society. Value of the data\u2022The given data will show author in the field of environmental management and urban renewal the trend of pollution as it relate to industrial activities.\u2022The data obtained can be used as inference to understand clearly the percentage distribution of respondents by socio-economic and physical characteristics\u2022The data can be used to examine the relationship between the different levels of disposition to various environmental hazards.1In an attempt at appreciating the respondents perception on pollution generated from the industries, residents were asked to indicate their perceived causes in the study settings. More so analysis shows that 89% of the respondents reported industrial causes as the major sources of pollution within their neighborhood while 7% of the study sample indicated other causes as presented in 2Quantitative data collection method was used for this study. This strategy includes the use of questionnaire, direct interviews, personal observation and the use of photographs"}
+{"text": "The data presented in this article are related to the research article entitled \"Child and adult exposure and health risk evaluation following the use of metal- and metalloid-containing costume cosmetics sold in the United States\"  Specifications TableValue of the data\u2022Provides an exposure assessment on realistic exposure scenarios and for multiple age use categories\u2022Risk assessment based on multiple routes of exposure, including dermal uptake and hand to mouth which have previously not been published\u2022Intra-lab comparison using two similar methodologies to evaluate how the sensitivity of the method impacts the ability to calculate an assessed risk\u2022Data from creams, sticks and lip products can be compared against other existing data for similar cosmetic products to estimate cumulative exposures\u2022Serves as a benchmark for other researchers to evaluate the exposure potential and risk for similar cosmetic products with chemicals not tested in our assessment, including organic chemicals1The dataset of this article provides the concentration of the metals and metalloids in the various products from the three different methods used to measure concentration S3, alon2Each cosmetic sample was pre-screened for metal content with the use of an X-ray fluorescence analyzer. If there was any metal detected in a cosmetic then it was purchased in order to do further analysis. Each cosmetic sample purchased was analyzed a second time with the X-ray fluorescence analyzer in a controlled environment and the data is shown in"}
+{"text": "To improve quality and personalization of oncology health care, decision aid tools are needed to advise physicians and patients. The aim of this work is to demonstrate the clinical relevance of a survival prediction model as a first step to multi institutional rapid learning and compare this to a clinical trial dataset.Data extraction and mining tools were used to collect uncurated input parameters from Illawarra Cancer Care Centre's  oncology information system. Prognosis categories previously established from the Maastricht Radiation Oncology (training cohort) dataset, were applied to the clinical cohort and the radiotherapy only arm of the RTOG-9111 .Data mining identified 125 laryngeal carcinoma patients, ending up with 52 patients in the clinical cohort who were eligible to be evaluated by the model to predict 2-year survival and 177 for the trial cohort. The model was able to classify patients and predict survival in the clinical cohort, but for the trial cohort it failed to do so.The technical infrastructure and model is able to support the prognosis prediction of laryngeal carcinoma patients in a clinical cohort. The model does not perform well for the highly selective patient population in the trial cohort. Laryngeal carcinoma has a recorded incidence of 606 2009) with 255 reported mortalities 2010) in Australia  to create well defined semantically interoperable data stores and secure messaging systems to facilitate multi institutional rapid learning.In both the previous study  and in tIn clinical practice TNM staging is used to estimate the prognosis for larynx patients and there is some evidence of additional single variable prognosis predictors , 28. To We were able to use a data mining system to automate the collection of model parameters in a totally different clinical cohort in a different country and healthcare system and predict 2-year survival for their patient population using uncurated clinical data. The study shows that routine clinical data contains valuable information that could be harvested to improve and personalize patient care and even more so if recorded in a detailed, structured manner. The results demonstrate that further investigations into the difference between clinical trial cohorts and clinical cohorts is necessary with the potential for rapid learning systems to provide evidence for patients who do not fit clinical trial criteria."}
+{"text": "A burgeoning question in understanding literacy development is whether engaging in musical training directly transfers benefits to reading-related skills. Although, there is considerable data examining transfer effects of musical training on literacy skills, results from these studies have been largely inconclusive (Anvari et al., Initial results from Gordon et al.'s  meta-anaGordon and colleagues propose that the way forward is to focus on what is transferred from music to language and how it is being transferred. With this goal in mind, they plausibly argue that rather than a direct transfer between music and literacy, improved reading fluency is the gradual result of enhanced auditory discrimination leading to improved rhyming skills that in turn facilitates phonological awareness (see also Besson et al., In conclusion, continued examination of positive transfer effects from musical training to literacy skills furthers our understanding of the complex connections between music and language, and their shared neurocognitive features. By outlining longitudinal studies that would address study design factors and further the examination of the neural mechanisms underlying musical training driven learning and plasticity, Gordon and colleagues provide us with a compelling example of and future direction toward such research.The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "DMD gene and results in progressive wasting of skeletal and cardiac muscle due to an absence of functional dystrophin. Cardiomyopathy is prominent in DMD patients, and contributes significantly to mortality. This is particularly true following respiratory interventions that reduce death rate and increase ambulation and consequently cardiac load. Cardiomyopathy shows an increasing prevalence with age and disease progression, and over 95% of patients exhibit dilated cardiomyopathy by the time they reach adulthood. Development of the myopathy is complex, and elevations in intracellular calcium, functional muscle ischemia, and mitochondrial dysfunction characterise the pathophysiology. Current therapies are limited to treating symptoms of the disease and there is therefore an urgent need to treat the underlying genetic defect. Several novel therapies are outlined here, and the unprecedented success of phosphorodiamidate morpholino oligomers (PMOs) in preclinical and clinical studies is overviewed.Duchenne muscular dystrophy (DMD) is caused by defects in the  DMD gene that lead to premature termination of translation and a complete loss of dystrophin protein in muscle cells. Dystrophin is a key regulator of mechanical stability within cells, providing a vital link between the sarcomeric cytoskeleton and the extracellular matrix via a complex of transmembrane proteins (dystrophin associated protein complex) ..mdx miceDuchenne muscular dystrophy is underpinned by a complex pathophysiology involving numerous signalling cascades. The extent to which the cellular disease mechanisms differ between skeletal and cardiac muscle remains unknown, but changes in calcium handling and mitochondrial dynamics are critical in establishing the phenotype. Corticosteroids have been successfully used to ameliorate the skeletal muscle phenotype for a limited time, and death from respiratory failure is declining due to the advent of better supportive strategies such as mechanical ventilators and management of respiratory tract infections with antibiotics and cough assistance. The therapeutic focus has therefore shifted towards developing treatment for dystrophic cardiomyopathy. Patients with better motor and pulmonary function are living longer, and engaging in activities that exert a greater cardiac load. Whilst pharmacological interventions such as ACE inhibitors and beta blockers can stabilise cardiac function to some extent, morbidity and mortality from heart failure in DMD patients remains high and there is an urgent need to develop treatments that prevent both motor, pulmonary and cardiac decline. Promising results from the eteplirsen study are at the current forefront of this field, and it is anticipated that minor modifications to the existing chemistry that improve uptake of the compound into the heart may greatly delay death from cardiorespiratory failure in DMD boys with the relevant mutation."}
+{"text": "There are more than 200,000 end stage renal disease (ESRD) patients who are potential transplant candidates and more than 100,000 previously transplanted renal recipients with functioning allografts in the United States . Fifty-seven percent of these patients are male and forty percent are greater than 50 years of age . Diabetes is the most common cause of kidney failure. It is evident that many patients are at high risk for development of urologic problems and thus it is estimated that the average urologist will care for up to ten of these patients yearly. Thus a review of the genitourinary (GU) evaluation and management of these patients is timely."}
+{"text": "In a normal pregnancy, decidual spiral arteries are transformed into wide diameter, non-vasoactive vessels capable of meeting the increased demands of the developing fetus for nutrients and oxygen. Disruption of this transformation is associated with PE and FGR. Very little is known of how these first trimester changes are regulated normally and even less is known about how they are compromised in complicated pregnancies. Interactions between maternal and placental cells are essential for pregnancy to progress and this review will summarise the challenges in investigating this area. We will discuss how first trimester studies of pregnancies with an increased risk of developing PE/FGR have started to provide valuable information about pregnancy at this most dynamic and crucial time. We will discuss where there is scope to progress these studies further by refining the ability to identify compromised pregnancies at an early stage, by integrating information from many cell types from the same pregnancy, and by improving our methods for modelling the maternal-fetal interface  \u2022Pathology of PE/FGR begins in the first trimester.\u2022Investigating pregnancies with increased risk of PE/FGR is giving valuable information.\u2022This will improve further with advances in identifying compromised pregnancies. Trophoblast invasion and remodelling of the uterine vasculature occur in the first trimester of pregnancy and are tightly regulated in both a temporal and spatial manner. Information on the maternal-fetal interface in the first trimester can be gained from immunohistochemical studies however this does not give an indication of which dynamic cellular and molecular interactions are of functional importance in regulating these crucial events. In this review we will discuss some of the strategies taken to investigate the field, how they have informed what we know about the cell biology of normal pregnancies and those with placental complications and where the scope for future development lies.2Trophoblast invasion occurs in a tightly regulated manner, influenced by signals from the surrounding decidual environment. During the decidualisation process maternal immune cells are recruited to the uterus in significant numbers, with approximately 70% being decidual natural killer (dNK) cells, 20% macrophages and the remaining 10% T cells. During placentation, extravillous trophoblast (EVT) cells invade into the decidua and interact with this enriched environment of specialised immune cells. Cross-talk between the immune cells, stromal cells and the fetal EVT will contribute to regulating EVT invasion and the accompanying changes to the spiral artery structures required for successful pregnancy.Spiral artery remodelling involves the loss of vascular cells and matrix proteins and occurs in an orchestrated fashion. The initial steps involve activation and vacuolisation of endothelial cells (EC), hypertrophy and disorganisation of vascular smooth muscle cells (VSMC) and fibrinoid deposition EVT invasion can be either interstitial or endovascular with endovascular EVTs interacting directly with the EC while interstitial EVT interact first with the VSMCs. Invasion by either route will influence vascular structure via disruption of the heterotypic interactions between EC and VSMC known to be important for maintaining a healthy differentiated vessel There is increasing evidence that maternal immune cells in addition to the fetal EVT play important roles in the remodelling process. In humans all of the immune cell types are located around actively remodelling vessels The ability to investigate during the timeframe in which these changes are actively occurring is hindered by the difficulties inherent in studying human pregnancy. A wide-ranging evaluation of the cellular and molecular cross-talk at the maternal-fetal interface, at what is the most critical time in the first trimester, therefore remains to be performed. Being able to develop strategies to try and address this would advance our understanding of both normal human pregnancy as well as pregnancies complicated by PE and FGR.3Investigating vascular changes at a molecular or cellular level in early human pregnancy is restricted by ethical issues and while animals model some aspects of human pregnancy, they lack deep trophoblast invasion and comparable spiral artery transformation Access to human tissue is limited in ongoing pregnancies to that obtained during chorionic villous sampling (CVS) for genetic screening in the first to early second trimester, or that obtained following parturition. Some highly informative gene array studies have been carried out on tissue obtained from CVS suggesting that the decidual environment may be key in the establishment of placental pathology Placental tissue obtained at term comes from a pregnancy where it is known whether the woman developed PE or another placental complication and has the advantage that tissue is plentiful as the whole placenta can be studied. However this represents a time many months after active remodelling has occurred and any differences in the placentas of PE/FGR pregnancies may represent a consequence of the disorder rather than inform causative pathology. To investigate the decidua and myometrium, uterine biopsies can be taken at the time of delivery and histochemical studies carried out or cells and vessels isolated. This approach has proven useful in developing models of spiral artery remodelling where non-placental bed vessels are obtained and used in co-culture with EVT Tissue samples can also be obtained following termination of pregnancy in the first trimester. The approach taken by our group and others has been to focus on events occurring in the first trimester as this is the most informative time to study EVT invasion and vessel remodelling. Most studies using first trimester tissue have been done without any additional information to inform whether that pregnancy was developing normally. Herein lies the challenge as the clinical symptoms of conditions such as PE are not apparent until after 20 weeks gestation. How can we look at first trimester tissue and know whether it is from a normal or pathologic pregnancy? We have started to address this by using uterine artery resistance index (RI) measurements obtained by Doppler Ultrasound screening to identify women who would have had an increased risk of pregnancy complications had the pregnancy progressed, allowing us to divide the first trimester placental and decidual tissue into two study groups; that from pregnancies with a higher risk and a very low risk of developing PE/FGR. A disadvantage of this approach lies in the fact that many of the pregnancies designated higher risk in the first trimester would have ended up progressing normally despite the probable initial impairment. This will be addressed in the future studies section below. Even given this limitation we have reported fundamental differences in the behaviour of cells isolated from the fetal-maternal interface of high resistance index (RI) compared to normal RI pregnancies which will be described in the following section.4Studies of approximately 10,000 ongoing pregnancies showed that cases with a resistance index obtained from uterine artery Doppler scanning of >95th percentile (high RI) had a 5-fold increased risk of that pregnancy developing placental complications compared to those with a normal RI (<95th percentile) We have shown that primary trophoblast cells isolated from the hRI pregnancies are more sensitive to apoptotic cell death than those from nRI pregnancies, and this may be a contributing factor to impaired invasion Differences in how the maternal immune cells behave between these patient groups is also starting to become clearer with dNK cells from pregnancies with impaired remodelling showing abnormalities in secreted proteins and functional interactions with other decidual cells There is evidence for the involvement of dNK cells directly in spiral artery remodelling in\u00a0vitro, has increased our knowledge of how placentation in the first trimester develops normally and pathologically. There is however scope for much development of these areas in the future, which will be addressed in the following section.It is clear that studying the uterine artery Doppler screened patient groups, combined with improved techniques for isolating pure cell types and modelling events 5Improvements in early diagnostic tools are proving valuable clinically, for example reliable serum or metabolic biomarkers that more accurately predict development of PE before the clinical symptoms become apparent in\u00a0vitro culture systems are needed to look at dynamic multi-cellular interactions. Some of the general processes involved in spiral artery remodelling have been reported by a number of groups, including our own, using monolayer co-cultures in\u00a0vivo allowed us to determine which genes were differentially expressed following stimulation by trophoblast and show VSMC de-differentiation The complexities of modelling cellular interactions in a more 3-dimensional (3D) environment also provide challenges and potential for development. Immunohistochemical studies can provide much information about early human pregnancy however Advances in isolation and culture methods for primary cells means that multiple cell types can be isolated from first trimester tissue from an individual pregnancy. We routinely isolate stromal cells, dNK cells and macrophages as well as endothelial cells  from decidual tissue of the uterine artery Doppler screened women. From the placenta we can isolate trophoblast, stromal, endothelial and macrophages. In the future the ability to look at multiple cell types across an individual pregnancy (with a known risk of developing complications) provides an opportunity for some complex profiling integrating information about genes, microRNAs, proteome and secretome with readouts from functional and biochemical cell based assays. This will allow us to start to get an overview of the maternal-fetal interface in an individual pregnancy. Determining whether this complex information can be integrated to model both normal and PE pregnancies will require strong collaborations with the bioinformatics and mathematical modelling fields. We will then be able to interrogate these models asking questions such as the importance of particular cellular or molecular interactions to successful placentation. The ultimate aim of developing robust models of the maternal-fetal interface would be to help in the identification of novel targets and the safe design of therapies.There is no conflict of interests."}
+{"text": "This article contains data related to the research article entitled \u201cA survey analysis of the wood pellet industry in Finland: Future perspectives\"  [1]. The dataset include information about the importance of wood pellets on the global bioenergy development and role of wood pellets on the Finnish bioenergy development. Data leads to an expansion of knowledge and discoveries of new possibility for wood pellets industry analysis. Specifications TableValue of the data\u2022The data show opportunities and challenges of Finnish wood pellets development.\u2022It allows predicting the future wood pellets markets in Finland.\u2022Data helps to make future actions and managements for improving the development of wood pellets within the country and outside.\u2022Data leads to an expansion of knowledge and discoveries of new possibility for wood pellets industry analysis.\u2022The data can be used to analyze the wood pellets markets for other countries, similar opportunities and challenges can exist in many other European countries.1The shared data describes the role of wood pellets in bioenergy development in Finland 2The data analysis of the Finnish wood pellet industry was done using a qualitative approach. It based on literature reviews combined with the results of a questionnaire, which is a typical qualitative research method"}
+{"text": "Sepsis is an umbrella syndrome created by clinicians to identify patients with an acute infection and a high risk of death. The Sepsis-3 definition group recognized new organ dysfunction as the key indicator determining whether a patient falls into the group with a high risk of death or not . The samIn a recent issue of the Annals of Intensive Care, Sacha et al.  reportedDue to the retrospective nature and the fact that the database contained only a limited set of variables, the authors could not report other hemodynamic parameters than MAP, catecholamine requirements and lactate levels. Given the striking difference in the response to AVP therapy, it is obvious that the two patient groups (AVP responders and AVP non-responders) relevantly differed in their hemodynamic status and hence their response to infusion of a strong vasoconstrictor drug such as AVP. This result underlines the common oversight of both intensivist and researchers that arterial hypotension and increased lactate levels in patients with sepsis would be signs of a uniform circulatory pathology. Basic physiology and recent research , 9 indicIndependent of these pathophysiologic speculations, the results of this study clearly underline that arterial hypotension alone is an inappropriate trigger for vasopressor or AVP therapy in critically ill patients (with sepsis). Instead of continuing our quest for a single therapeutic intervention miraculously capable of improving the mortality of a highly heterogeneous patient population, future clinical studies must elucidate the different and unique phenotypes hidden under the umbrella syndrome of sepsis and septic shock. Only with an improved understanding of the various pathophysiologic phenotypes presenting with arterial hypotension and elevated lactate levels in sepsis can adequate resuscitation strategies be developed and tested. Such resuscitation strategies must take these phenotypes with their specific time sensitivities to and indications for therapeutic interventions as well as appropriate resuscitation endpoints into account. In light of the missing answers to these fundamental questions of septic shock resuscitation, the current search for the ideal type of fluid, vasopressor, or inotropic agent appears of only minor relevance."}
+{"text": "Although the pathogenesis and clinical significance of cerebral white matter lesions remain controversial, it is well established that age and hypertension are the most important factors related to the presence of these lesions. Hypertension is known to be the most important factor for developing stroke and vascular dementia. In addition, the presence of cerebral white matter lesions is an important prognostic factor for the development of stroke, and also for cognitive impairment and dementia. The mechanisms underlying hypertension-related cognitive changes are complex and are not yet fully understood. Correlations between cerebral white matter lesions and elevated blood pressure provide indirect evidence that structural and functional changes in the brain over time may lead to lowered cognitive functioning when blood pressure control is poor or lacking.Some authors have suggested that the presence of white matter lesions in hypertensive patients could be considered an early marker of brain damage."}
+{"text": "Schizophrenia and bipolar disorder are severe mental disorders with unknown etiology. Our research group has studied biomarkers in the cerebrospinal fluid (CSF) of twins with schizophrenia and bipolar disorder to be able to determine the genetic and environmental influences. In brain disorders, CSF is the most appropriate substrate to study as it may reflect the brain biochemistry better than blood. In this presentation I aim to give an overview of our findings and their relation to psychotic disorders. I intend to present our most recent preliminary finding and to discuss future prospects.We studied CSF-markers from a cohort of 50 monozygotic (MZ) and dizygotic (DZ) twins with schizophrenia or bipolar disorder. The twins have gone through diagnostic assessments and have been extensively phenotyped with questionnaires, symptom scales for psychiatric symptoms as well as neuropsychological testing. We have analyzed monoamines, microglia-, neurodegenerative-, kynurenine-, and inflammatory markers using immunoassays and high-performance liquid chromatography techniques. We have also studied microscopic structures with scanning electron microscopy.One of our main findings was that soluble cluster of differentiation 14 protein (sCD14) was higher in twins with schizophrenia or bipolar disorder compared to their not affected co-twins. A later analysis showed that the difference within the discordant twin-pairs was higher in the DZ twin pairs  compared with the MZ twin pairs  suggesting that genetic components along with unique environmental effects have an influence on the higher sCD14 levels in patients with schizophrenia and bipolar disorder. We also found that sCD14 was higher in those patients with more psychotic symptoms.In our study on microscopic structures in CSF we found that the structures were prevalent not only in the patients with schizophrenia and bipolar disorder but also in their not affected co-twins. The finding suggests that genetic factors may be partly involved in the formation of the structures.We have analyzed inflammatory and neurodegerative markers in the CSF of twins with psychotic disorders to be able to study genetic and environmental influences. Our results indicate that sCD14 may have an influence on microglia activation in psychosis. We have continued with analyses on the correlations between all the markers, the monoamine metabolites and associations with symptoms and cognitive ability and the preliminary results from these analyses will be presented.To conclude CSF analyses for biomarkers in twins may result in extended knowledge regarding the genetic and environmental relationships. Our unique twin data gives us the possibility to study CSF-markers in relation to psychiatric symptoms and cognitive measures. For future studies it would be of interest to assemble twin-samples from several research groups to be able to study research questions regarding gene and environment interactions."}
+{"text": "Understanding exactly how disparity is processed from binocular views of the world is a long standing problem in vision. It has been hypothesised that an important first step in visual processing is to generate an energy efficient sparse coding of visual inputs. This reduces both noise and redundancy. Mathematical models of such codings have been found to produce components that resemble the responses of simple cells in V1. Similar results with binocular inputs suggest that these methods can be used to build hypothetical models of early binocular visual processing. In our study we have used Independent Components Analysis in the vein of work by Hyv\u00e4rinen and colleagues to find components that form an efficient coding of binocular visual inputs. The distribution of these components was analysed. We found statistical evidence for a bimodal distribution of interocular differences in phase tuning, further strengthening the summation/difference channels theory of Li and Atick (1994). We have also found components tuned to detect mixtures of phase disparity and position disparity in each view similar to the physiological findings of Anzai et al. (1997). This is consistent with the arguments of Read and Cumming (2007) that both phase disparity and position disparity are necessary for stereopsis."}
+{"text": "Laboratory mouse strains are known for their large phenotypic diversity and serve as a primary mammalian model in genotype-phenotype association studies. One possible attempt to understand the reason for this diversity could be addressed by careful investigation of the unique evolutionary history of their wild-derived founders and the consequence that it may have on the genetic makeup of the laboratory mouse strains during the history of human fancy breeding. This review will summarize recently published literature that endeavors to unravel the genetic background of laboratory mouse strains, as well as give new insights into novel evolutionary approaches. I will explain basic concepts of molecular evolution and the reason why it is important in order to infer function even among closely related wild and domesticated species. I will also discuss future frontiers in the field and how newly emerging sequencing technologies could help us to better understand the relationship between genotype and phenotype."}
+{"text": "Many biomedical studies of the past seven years have failed in giving a sound picture of what hookah  smoke and smoking are. The reasons are many: from the widespread use of a confusing neologism (\u201cwaterpipe\u201d) instead of the few clear and natural words used for centuries by indigenous and non-indigenous people in their real life, to the use of artificial smoking (machines) instead of relying on quantitative and qualitative analysis of toxicants directly performed on real hookah smokers."}
+{"text": "The ideal size of intramedullary device to fix corrective osteotomy of proximal femur in abnormal bone in children and small patients may not be easily available. We report the successful use of Rush rod in combination with multiple Kirschner wires to fix the corrective osteotomy of coxa vara and shepherd crook deformity in two patients with osteogenesis imperfecta and fibrous dysplasia. The union was achieved on time, neck shaft angle and rotation were maintained. It is especially common in abnormal bone like fibrous dysplasia and osteogenesis imperfecta. Correction of these deformities will improve limb length discrepancy. It will also improve the hip abductor mechanism by correcting the working length of abductor muscle thus correcting Trendelenburg gait. Fixation for corrective osteotomy for coxa vara or shepherd\u2019s crook deformity in abnormal bone like osteogenesis imperfecta and fibrous dysplasia in children and small patients is challenging due to difficulties to obtain appropriate size of intramedullary nail to fit a small bone. Plates and screws are not the preferred method due to stress points on both ends that may lead to fractures. We report the successful modification of the technique described by Fassier The first patient was a 14-year old boy with fibrous dysplasia who presented with limping due to worsening deformity of the left femur . The TreThe second patient was a 14-year old girl with osteogenesis imperfecta who presented with inability to ambulate without walking frame since sustaining a fracture of the proximal femur six years prior to presentation . She hadWe performed the procedure in both patients in the supine position with standard lateral exposure. Transverse osteotomy was carried out at the subtrochanteric level. The proximal segment was reamed retrograde from the osteotomy site using cannulated drill to ensure it started at the lateral most and exited at the greater trochanter. Next, a few Kirschner wires sized 1.6mm were inserted from the lateral femur at subtrochanteric level to the neck. These wires acted as joy-sticks during manipulation of the proximal femur to the required neck-shaft angle (NSA). The distal segment was also reamed using cannulated drill bit to ensure no penetration of the cortex. In the first patient, a Rush rod of selected length and diameter was inserted antegrade from the greater trochanter to the osteotomy site. The Rush rod was then passed through the osteotomy side to distal femur while the NSA was maintained by the Kirschner wires . In the An ideal implant for fixation of osteotomy for this deformity of abnormal bone would be an intramedullary nail with proximal locking screw to the neck to maintain the correction of NSA and distal locking screw to provide stability. Inability to obtain correct diameter and length of intramedullary locking nail at the time of the surgery prompted us to look for an alternative method.2. In 2003, Fassier improved this technique by combining Wagner\u2019s method with Finidori\u2019s technique which used telescopic rods to fix the subtrochanteric corrective osteotomy1. Fassier et al in 2008 showed satisfactory outcome with this technique in 18 hips with osteogenesis imperfecta and three hips with fibrous dysplasia 3. There was a complication rate of 12% which was largely implant related.One of the early methods in correcting coxa vara is the Wagner method that involves passing two Kirschner wires through the femoral neck and the external portion of the wires moulded and fixed to the femoral shaft by cerclage wireset al3, we modified the technique by using Rush rods as the intramedullary fixation device. Apart from its low cost, it is also a strong solid nail. The Rush rod can be cut according to the desired length as opposed to either intramedullary locking nail or Fassier-Duval nails. Furthermore, in proximal lesions, we were able to control the length of the rod so that it did not breach the distal femur growth plate, as seen in our first patient.Instead of using telescopic rods, as reported by Fassier 4. This modified method provides intramedullary load sharing fixation to the osteotomised bone for long term support. The Kirschner wires that are placed through the neck with the distal half bent and held to the side of the shaft by cerclage wire maintain the NSA as well as prevent rotation. Rotational instability is the limitation faced by the FassierDuval telescopic rod5. In order to achieve an acceptable NSA and rotational alignment, the position of cerclage wires must be distal to the osteotomy site. This method provides relative stability to facilitate union. When the nail is properly positioned with a snug fit in the proximal fragment, as seen in the second patient, two Kirschner wires are adequate to maintain NSA and rotation. In case of fibrous dysplasia, the implant may be removed once the lesion has completely healed. In the case of osteogenesis imperfecta, we propose not to remove the implants unless complications arise.Another difference from the original procedure described by Fassier, was that we did not penetrate the lateral cortex of distal of proximal fragment. Instead, we used cannulated drill bit to create canal in the lateral most part of the shaft. This is possible in an abnormal bone that has big lateral diameter in mal-united fibrous dysplasia bone (first patient) and oval shape osteogenesis imperfecta bone (second patient). If greater valgus correction is required, the penetration through lateral cortex should be chosen. The use of cannulated drill bit is an important step to avoid cortex penetration at unwanted locations especially in deformed and soft osteogenesis imperfecta bone. This method ensures the desired direction of canal to maintain the NSA and avoids the piriformis fossa which might cause injury to important retinacular vessel to the femoral head in immature patientsWe would also like to highlight that in the second patient with osteogenesis imperfecta, the Rush rod was inserted in a retrograde manner through the knee joint. A retrograde entrance from the knee allows protection of the whole femur from the intercondylar notch where the hook of the Rush rod sits firmly, through the shaft till proximal penetration in the piriformis fossa. We think that it is worth taking the risk of causing joint stiffness with the benefit of reducing the risk of recurrent fracture in osteogenesis imperfecta patients. This patient did not develop any limitation of knee motion. However, the patient should still be warned regarding the possibility of joint stiffness and long term complications.Based on the experiences gained from these two cases, we are of the opinion that our modified method can be an alternative when an appropriately sized interlocking nail is not available for correction of coxa vara or shepherd\u2019s crook deformity in abnormal bone."}
+{"text": "Proteinuria is common in diabetic patients and usually reflects the presence of diabetic glomerulosclerosis. This paper reviews the differential diagnosis of proteinuria in diabetic patients and discusses the role of renal biopsy examination in identification and management of minimal change disease in this cohort. Identification of nondiabetic glomerular disease requires careful correlation of clinical history and renal biopsy findings and may have important implications for prognosis and therapy."}
+{"text": "Ion mobility spectrometry was first introduced to the analytical community in 1970 as an ultratrace organic technique under the name of plasma chromatography. Using highly sensitive ionization methods commonly employed in electron capture detectors coupled with an atmospheric pressure drift region to separate ions produced, it had the potential for widespread application in the separation and detection of trace quantities of organics.As researchers began to investigate the method, a number of serious problems rapidly became evident: Competitive ion-molecule reactions which occurred in the ionization region of the detector limited its use as a quantitative instrument when complex mixtures were introduced into the spectrometer. Long residence times (sometimes measured in hours) in the spectrometer prevented practical application to a large number of samples. Often spectra for a single component were found to contain multiple ion peaks, hopelessly complicating true multicomponent interpretation.We designed and constructed an ion mobility spectrometer that was specifically suited for the detection of trace organics after separation by high resolution gas chromatography . Using aMore recently, our work has led to investigation of the mobility of ions produced from organic compounds with molecular weights higher than those that can be conveniently eluted from a gas chromatograph. One approach to achieve this goal has been to use supercritical fluid chromatography as the introduction method for IMS ,9. BesidNow that interfaces and operational modes for the ion mobility detector have been developed for both gas and supercritical fluid chromatography, the methodology is being investigated for application to real samples. The real challenge for ion mobility spectrometry as a chromatographic detector, however, lies in the detection of compounds separated by liquid chromatography. A significant step toward achieving this goal is the recent development of an electrospray ion source for IMS. By introducing the effluent from a liquid stream into the spectrometer via an electrically charged capillary, we have been able to capture ion mobility spectra from nonvolatile compounds dissolved in the mobile phase. The practical utility of this method of ionization is currently under investigation."}
+{"text": "There is debate over the mechanisms that govern the orienting of attention. Some argue that the enhanced performance observed at a cued location is the result of increased perceptual sensitivity or preferential access to decision-making processes. It has also been suggested that these effects may be the result of trades in speed for accuracy on the part of the observers. In the present study, observers performed either an exogenous or an endogenous orienting of attention task under both normal instructions (respond as quickly and as accurately as possible) and speeded instructions that used a deadline procedure to limit the amount of time observers had to complete a choice reaction time (CRT) task. An examination of the speed-accuracy operating characteristics (SAOCs) yielded evidence against the notion that CRT precuing effects are due primarily to a tradeoff of accuracy for speed."}
+{"text": "Severe corneal complications associated with the use of anti inflammatory drugs (NSAID) eye drops are known. We report the case of a patient of 57 years treated for rheumatoid arthritis with a central corneal perforation of the right eye following the use of indomethacin eye drops in the postoperative period following cataract surgery. The image shows a paracentral corneal perforation with iris prolaps. The course was favorable with improvement in visual acuity and complete healing of the corneal perforation after stoping indometacin and using of bandage contact lens. The anti inflammatory drugs should be avoided in cases of rheumatoid arthritis because they increase the risk of perforation. Indomethacin, like other molecules in the same therapeutic class should be used with caution in patients with general risk factors of suffering from ocular surface."}
+{"text": "Human hantavirus disease cases, caused by Puumala virus (PUUV), are mainly recorded in western and southern areas of Germany. This bank vole reservoir survey confirmed PUUV presence in these regions but its absence in northern and eastern regions. PUUV occurrence is associated with the presence of the Western bank vole phylogroup. Myodes glareolus  causes most hantavirus disease cases in Central and Western Europe and is the only human pathogenic hantavirus in Fennoscandia  revealed 79 positive and 361 negative samples  Table. AIncluding results of previously published studies  Table. Acytochrome b PCR was performed and used for determination of the bank vole evolutionary lineages as described previously  according to manufacturer\u2019s guidelines. The cytochromeb\u2013based typing revealed the presence of the bank vole Western, Eastern, and Carpathian evolutionary lineages  is preferentially associated with the presence of the Western evolutionary lineage of the bank vole, but the virus was also detected in sympatric animals of the Eastern or Carpathian lineage. Future studies will have to determine if the current distribution of PUUV can be explained by the postglacial colonization of Germany by bank voles of the Western evolutionary lineage from western refugia through southern Germany (The observed limited geographic distribution of PUUV in bank voles has important implications for public health measures and development of early warning modules for hantavirus outbreaks. These public health measures of monitoring local bank voles for PUUV strains (Serologic and molecular Puumala virus detection in bank voles from Germany and bank vole evolutionary lineage, and Puumala virus phylogenetic tree reconstructed with novel and published partial small segment sequences."}
+{"text": "Chemokines are a family of polypeptides that direct the migration of leukocytestoward a site of infection. They play a major role in autoimmune disease and chemokine receptors have recently been found to mediate HIV-1 fusion. In this short review we examine the role of chemokines in host defence and in the pathophysiology of autoimmune diseases. We conclude by discussing various therapeutic approaches that target chemokine receptors and that could be beneficial in disease."}
+{"text": "To the editor,We read with interest the recent case of an unusual intravesical foreign body reported by Bansal et al. . A case The authors allude to the array of intravesical bodies that have been reported and mention the psychological reasons for self insertion . It shouThe important role of radiology in determining the luceny, location and size of foreign bodies is discussed and the preference for endoscopic management is mentioned . The incThe authors conclude by discussing urogenital fistulae as a consequence of foreign body insertion. Recent reports have highlighted the additional acute complication of urethral avulsion following polyembolokoilamania necessitating emergency urethroplasty .Finally, it should be acknowledged that not all cases of self embedding behaviour require intervention as some patients deliberately request no intervention  and repo"}
+{"text": "A retrospective detailed study of 272 cases of breast carcinoma treated by radical mastectomy was published by Hamlin (1968). An extended analysis of the material for 258 of these cases is now reported.Data for 21 prognostic factors from 258 patients have been subjected to multiple regression analysis to determine the independent effect and thus the relative importance of each factor. The findings confirm previous single factor analyses and demonstrate that nine of the factors are independently associated with survival.Mathematical manipulation of the information obtained in this analysis allowed a risk score to be allotted to each patient. Grouping of patients by the prediction scores is found in this series to be more closely related to survival than is clinical staging of the same patients."}
+{"text": "A bioluminescence technique involving single photon imaging was used to quantify the spatial distribution of the metabolites ATP, glucose and lactate in cryosections of various solid tumours and normal tissue. Each section was covered with an enzyme cocktail linking the metabolite in question to luciferase with light emission proportional to the metabolite concentration. The photons emitted are imaged directly through a microscope and an imaging photon counting system. In some cases, good agreement was observed between the distribution of relatively high concentrations of ATP and glucose in viable cell regions of the periphery, while the reverse was seen in more necrotic tumour centres with comparatively high lactate levels. In general, lactate was distributed more diffusely over the sections while ATP was more highly localised and glucose assumed an intermediate pattern. In contrast to the large degree of heterogeneity seen in tumours, distribution patterns of metabolites were much more homogeneous in normal tissue, such as heart muscle. Mean values for metabolite levels in cryosections using bioluminescence are in good agreement with those obtained from the same tumour by conventional methods."}
+{"text": "A single treatment of adult animals with the potent carcinogen NMU was known to induce tumours in a wide variety of organs, with the notable exception of liver. Administration of NMU after partial hepatectomy gave rise to the first liver cell adenomata ever observed in rats due to this carcinogen. The tumours were induced when NMU was given during the period of increased DNA synthesis but not when given early in the pre-replicative period. Although tumours were induced in other organs, the incidence of these did not correlate with the timing of NMU administration. It is suggested that replication of damaged DNA may be a relevant event in carcinogenesis."}
+{"text": "Distress associated with attendance at a radiotherapy department was assessed in 80 consecutive patients. All patients were interviewed within 24 h of their first fraction of radiotherapy; 31 patients were also interviewed at the end of treatment. The problem identified at first interview as causing the most distress was worry about the effects of disease and its treatment upon the patient's family. At second interview the dominant complaint was of not being allowed to wash. Psychological problems, including anxiety and sleep disturbances, caused more overall distress than did physical symptoms. The method used in this study for eliciting information on the side-effects of therapy is straightforward and has yielded data that are provocative and suggest interesting avenues for further investigation."}
+{"text": "A novel tumour system has been used to study the effect of natural killer cells on tumour growth by using agents which modify natural killer cell activity. The tumour cells are hybridoma cells which secrete antibody specific for red blood cells so that tumour growth can be quantitated by a haemolytic plaque assay. Spleen-seeking variants have been derived from original hybrids which are sensitive to natural killer cells. Treatment of mice with polyinosinic-polycytidylic acid substantially enhanced natural killer cell activity and correlated closely with a reduction in the growth of the hybridoma tumour cells in the spleen and life extension. Conversely, a single injection of anti-asialo GM, antibody resulted in a substantial increase in the number of plaque forming splenic tumour cells and virtual elimination of natural killer cell activity. These data demonstrate the important role of natural killer cells in constraining the growth of a tumour of B cell origin and establishes the usefulness of this tumour model in studying the biology of effects on tumour growth."}
+{"text": "An audit was carried out of 51 oncology patients referred to a clinical psychology service to identify the characteristics of patients selected for referral and to assess change following psychological intervention. A survey was conducted of an unselected sample of oncology patients representative of the workload of the oncology department from which the referrals came, to determine the prevalence of comparable psychosocial problems among patients who were not referred for help and to assess whether doctors were aware of the problems patients reported. Data were collected using the Hospital Anxiety and Depression (HAD) and Mental Adjustment to Cancer (MAC) scales and a problem checklist devised for this study. Referred patients were significantly more anxious and depressed (P < 0.001) and showed poorer adjustment on MAC scales than the surveyed sample, but 30% of the latter group warranted assessment for anxiety and 23% for depression. The number of psychosocial problems of their severity. Intervention was clinically significant mood disorder irrespective of the specific problems of their severity. Intervention was associated with a significant improvement in distress and problems for referred patients by the time of discharge. Psychosocial problems were often undetected by staff even in referred patients. The checklist is a feasible screening method for potentially remediable problems which are cumulatively a significant contributor to cancer patients' distress."}
+{"text": "Across the pharmaceutical industry, there are a variety of approaches to laboratory automation for high throughput screening. At Sphinx Pharmaceuticals, the principles of industrial engineering have been applied to systematically identify and develop those automated solutions that provide the greatest value to the scientists engaged in lead generation."}
+{"text": "Drosophila species Dobzhansky and Sturtevant provided the first view of the molecular basis of species identity in their 1938 seminal study classifying the chromosome rearrangements that distinguish two PLoS Genetics, Lucia Carbone et al. Nomascus leucogenys leucogenys) to address a fascinating problem in evolutionary biology: why are some groups of organisms characterized by a high frequency of chromosome change while others are karyotypically stable?The view that has emerged over the last decade, with a sharp acceleration since the publication of the human genome sequence, is of a fluid genomic landscape that is dotted with evidence of both large- and fine-scale chromosome rearrangements. What has remained a mystery are the mechanisms responsible for chromosome rearrangements that karyotypically define species. In this issue of Gibbons are members of the Hominoidea superfamily, which includes humans and great apes, but they are unique among Hominoidea, and indeed rare among mammals, in having experienced an extraordinarily high rate of karyotypic change Building on their previous work defining the synteny map for the northern white-cheeked gibbon with respect to its human cousin, these authors used a comparative genomics approach to analyze sequences spanning breaks of synteny for repeat distribution and genomic signatures that would lend some insight into the mechanism of interchromosomal rearrangement. Corroborating data from other studies on a smaller set of gibbon breakpoints Rather than simply quantifying the repeat classes at the gibbon-specific breaks of synteny, Carbone et al. took this study one step further by asking whether the epigenetic signatures of specific repeat classes may be an important distinguishing feature in highly divergent genomes. Previous work has shown that gibbon Alu elements are more active than their human counterparts The epigenetic alteration of genomic sequences by DNA methylation is appreciated as a major regulatory force in the evolution of genome structure and expression, and is known as a potent regulator of mobile DNA activity. Through bisulfite sequence analysis, the authors show that the gibbon Alus are undermethylated compared to their human orthologues. The authors suggest these epigenetic differences between human and gibbon as a possible mechanism to account for the disparity in the number of chromosome rearrangements between the gibbons and old world primates.The proposal that mobile DNA itself participates in DNA rearrangement is not new to biology. Mobile elements, such as transposons and retrotransposons, were first implicated in DNA rearrangements in studies of maize by McClintock The novelty in this study is that there is hypomethylation of the gibbon Alus at evolutionary breakpoints, and thus the epigenetic architecture of these regions may have facilitated the rearrangements in the gibbon karyotype. The lower levels of methylation in these repeats may lead to an open chromatin configuration that increases the opportunity for double-strand breakage and repair mechanisms such as intrachromosomal non-allelic homologous recombination and non-homologous end joining . HoweverMcClintock first implicated transposable elements in the speciation process when she stated that \u201cspecies crosses are\u2026a potent source of genomic modification\u201d and that \u201cmajor restructuring of chromosome components may arise in a hybrid\u201d Exciting advances in sequencing technology will now afford full genome-scale methylation studies  that can offer insight into the diversity of elements that may be differentially methylated between gibbons and humans, and whether Alus are the sole target. Additionally, testing for a similar association between mobile DNA and methylation state at breaks of synteny in other species groups that have experienced rapid karyotypic change  are exciting areas of future work that may finally shed light on the mechanisms responsible for the chromosome diversity observed in a broad range of species."}
+{"text": "Corresponding dose-effect curves obtained for growth of the primary tumour (Pr) and its metastases in unirradiated tissues showed that local irradiation of Pr caused an exponential decrease in growth of metastases due to any dissemination occurring after irradiation, but was also responsible for stimulating growth of metastases already established before treatment in lymph nodes and in lungs. This stimulating effect was most marked when Pr was larger at the time of treatment and when high doses were given to eradicate Pr. This effect is attributed to the liberation of growth stimulating substances (GSS) from a pool of GSS produced in the irradiated Pr by sterilized, but metabolically active and growing tumour cells (HR cells). This effect of HR cells on tumour growth and metastases was also demonstrated when rats were inoculated with viable tumour cells and subsequently treated by injecting large doses of HR cells prepared The systemic effects of GSS on metastases were most clearly seen after immunosuppression of recipient hosts by sublethal whole body irradiation, since immunosurveillance in unirradiated rats resulting from a rapidly developing allogenic tumour-host incompatibility caused marked reductions in clonogenicity of the tumour which tended to overshadow the GSS effect. The latter was also masked in immunosuppressed hosts when excessively high rates of dissemination were due to growth of large Pr inocula for sufficiently long to \u201csaturate\u201d the capacity for growth of metastatic tumour in lymph nodes and lungs.The relevance of these findings to clinical radiotherapy is discussed."}
+{"text": "Immunofluorescent tracing by rabbit antiserum with specific reactivity against intestinal mucosa revealed cross-reaction with human ovarian mucinous cystadenoma epithelium and not with epithelium of any of several other human mucous epithelia. The mucinous cystadenoma epithelium apparently contains at least one but not all of the specific intestinal mucosal antigens. The findings support the view that such tumours are histogenetically of intestinal type, as might occur for example by unilateral intestinal development of a teratoma."}
+{"text": "Since PLA2 carry out their catalytic function at membrane surfaces, the kinetics of these enzymes depends on what the enzyme \u2018sees\u2019 at the interface, and thus the observed rate is profoundly influenced by the organization and dynamics of the lipidwater interface . In this review we elaborate the advantages of monitoring interfacial catalysis in the scooting mode, that is, under the conditions where the enzyme remains bound to vesicles for several thousand catalytic turnover cycles. Such a highly processive catalytic turnover in the scooting mode is useful for a rigorous and quantitative characterization of the kinetics of interfacial catalysis. This analysis is now extended to provide insights into designing strategy for PLA2 assays and screens for their inhibitors.Several cellular processes are regulated by interfacial catalysis on biomembrane surfaces. Phospholipases A"}
+{"text": "This is my third year working for the Kuru Research Project and I have been assigned to take charge of the fieldwork. Our fieldwork is based in Waisa village and we have nine field patrol officers who make five teams for kuru surveillance right around the four corners of Okapa District. There are two technical officers based in the field transcribing interview tapes recorded by Jerome Whitfield, Sena Anua and myself.five suspected kuru patients have \u2018recovered\u2019 and are well;five suspected kuru patients are still sick with no change of symptoms and are diagnosed as not having kuru; andfour suspected kuru patients have died from other disease.One patient, a man aged 62 years, died of kuru in March 2005. There were 14 suspected cases of kuru from January 2005 to September 2007:Arrange field patrols for kuru surveillance of villages in remote parts of the kuru-affected region every quarter and prepare a report.Assist Jerome Whitfield in conducting interviews on the cultural and mortuary practices of the Atigina and Pamusagina people.Diagnose and film suspected kuru patients and compile reports for Jerome and Michael Alpers.Check and regularly report on the sickness status of suspected kuru patients.Transcribe recorded tapes from the Fore language into English.The other responsibilities in the field are:"}
+{"text": "In comparison with normal controls the number of colony forming cells (CFC) is moderately increased (about three-fold) in the bone marrow and enormously increased in the peripheral blood of untreated patients. In the peripheral blood their number in general is related to the total leucocyte count. In patients whose blood counts have been restored to normal by the use of cytotoxic drugs the number of CFC in the peripheral blood is very greatly reduced. In the marrow of treated patients CFC are present in approximately normal numbers. When used as feeder layer sto support the culture of normal bone marrow cells, the peripheral blood leucocytes of untreated patients are a uniformly poor source of colony stimulating factor (CSF) and fractionation experiments suggest that this is not due merely to a relative scarcity of monocytes. After treatment the peripheral blood has normal CSF activity and this is associated with the monocytic cell component. The last data may be explained in either of two ways: it is possible that restoration of the blood of patients with CGL to normal values removes a homeostatic factor suppressing the formation of CSF by functionally normal monocytes, or alternatively treatment with cytotoxic drugs leads to the replacement of defective monocytes by a population of relatively normal CSF producing cells.We have used the technique of human haemopoietic cell culture in agar to study the peripheral blood and bone marrow colony forming capacity of 23 patients with Ph"}
+{"text": "The VX2 carcinoma has been used extensively as an experimental model for different aspects of tumour behaviour and is usually maintained by serial intramuscular injections of tumour cells. The tumour grows rapidly, infiltrating between muscle bundles into the fibrous tissue replacing ischaemic muscle and into the vascular tree. The most interesting method of spread occurs within the sarcolemma and this may be responsible for the rounded cell nests described in this tumour."}
+{"text": "Sir,Intravenous drug therapy is the corner stone of patient management in today\u2019s hospital practice and the discipline of pediatrics is no exception. The drug dosage in pediatrics is usually calculated according to the body weight or surface area leading to less cumulative dose when compared to adults. Unfortunately there are no separate pediatric drug dose formulations for most of the commonly used drugs. It is a Intravenous drug dosage for pediatric use is often limited by the strength of the drugs available commercially, especially in developing countries. Most druSince in developing countries like India where sepsis is the leading cause of mortality necessitating the use of antibiotics, it is high time the medical fraternity realizes this potential lacuna in treating pediatric patients. We feel that the pharmaceutical majors should realize the urgent need to introduce commonly used drugs, especially life-saving medicines in doses suitable for pediatric use so that the basic right of every child to receive safe medication is not jeopardized."}
+{"text": "We show that, from the earliest morphologically recognisable stages of development, mouse skin papillomas induced by a chemical initiation-promotion regime are polyclonal. We have demonstrated polyclonality directly by immunohistochemical staining of the mosaic cell populations in embryo aggregation chimaeras, a method which removes some of the uncertainties of previous conclusions based on analysis using electrophoretic polymorphisms. The findings may imply that initiation within a single cell and promotion of its clonal descendents is not a sufficient explanation for the origin of these tumours and that interaction between cells of more than one clone is involved."}
+{"text": "Current data from in vitro and in vivo animal models indicate that fibronectin-binding integrin receptors expressed by colon cancer cells may regulate tumour growth. While individual members of the beta 1 subfamily of integrins have now been clearly identified in colorectal cancer, little information exists with respect to the alpha V subfamily. In the present study we show that alpha V can associate with multiple and different beta subunits capable of binding fibronectin in this tumour type. This is likely to have functional implications for growth and spread of colorectal cancer."}
+{"text": "Adrenocortical activity has been assessed in patients with inoperable carcinoma of the bronchus or with disseminated malignant disease of other organs. The mean basal plasma cortisol level was higher in the former than in the latter and both were higher than the controls. Each had abnormally high midnight levels, particularly those with oat cell carcinoma of the bronchus. After the administration of a single dose of dexamethasone both groups suppressed poorly compared with the controls. Failure to suppress was associated with a poor prognosis."}
+{"text": "The method of measuring changes in the structuredness of cytoplasmic matrix (SCM) in single cells is described. Data on SCM distributions and fractions of human lymphocyte populations which respond to stimulations with PHA and CaBP in healthy donors and patients with malignant disorders are presented."}
+{"text": "It has been shown that lymphocytes isolated from the peripheral blood of patients with chronic lymphocytic leukaemia do not modify the mustard group of chlorambucil, as has been demonstrated previously in Yoshida ascites cells. However, lymphocytes from patients with an unsatisfactory clinical course or poor response to treatment were able to modify the aromatic region of the drug molecule; little change occurred in the aromatic absorption of intracellular chlorambucil in patients who responded to treatment. This simple test may provide a rapid assessment of a patient's potential response to chemotherapy."}
+{"text": "The liver is morphologically and functionally modulated by sex hormones. Long-term use of oralcontraceptives and androgenic steroids can induce benign and malignant hepatocellular tumors.Hepatocellular carcinoma (HCC) is more prevalent in men than in women. The role of sex hormonesand their receptors in the development of HCC was reviewed. Some HCCs may be androgen dependentbut others may be estrogen or even both dependent. Further studies are mandatory in order to utilizesuch characteristics of HCC for an effective prophylaxis and therapy of this tumor."}
+{"text": "We investigated cases of shigellosis in San Francisco and Alameda Counties identified during 1996 by active laboratory surveillance to assess the role of HIV infection as a risk factor for shigellosis. Dramatically elevated rates of shigellosis in HIV-infected persons implicate HIV infection as an important risk factor for shigellosis in San Francisco."}
+{"text": "This study was completed as part of a project for the Quality Assurance Agency on the enhancement theme of 'Research teaching linkages: enhancing graduate attributes' in the disciplines of Medicine, Dentistry and Veterinary Medicine. The aims of this investigation were to elucidate a list of desirable research related graduate attributes for the disciplines of Medicine, Dentistry and Veterinary Medicine and provide evidence as to how they could be covered within such curricula.Semi structured interviews, symposium breakout sessions and conference workshops were used to define and rank attributes suggested by curricula design experts from the three disciplines. Students graduating from a BSc Medical Science degree program were surveyed to determine how well they felt the curriculum and associated final year project equipped them with the identified attributes.A list of seven high level attributes which were desirable in graduates wishing to pursue either a professional or research career were identified. 105 students reported that a final year project was particularly effective at developing an understanding of the need to have an inquiring mind and critical appraisal skills whilst other components of their degree course covered team working skills, core knowledge and an understanding of ethics and governance.This study identified desirable attributes from graduates from medical, dental and veterinary degree programs and provides evidence to support the case for student projects helping to achieve both clinical and research related graduate attributes in medical undergraduates. The project also provides a focus for debate amongst those involved in curriculum design as to whether the attributes identified are those desirable in their graduates and to examine their current curriculum to determine coverage. The study reported here was part of a project funded by the Quality Assurance Agency (QAA) Scotland Enhancement theme programme investigating 'Research teaching linkages: enhancing graduate attributes' in the disciplines of Medicine, Dentistry and Veterinary Medicine . One comThere has been debate regarding the shortfall in graduates from professional degrees who opt to include research in their career plans. The Selborne Report raised concerns over the future of Veterinary Medicine research , whilst Professional attributes should already be covered within the curriculum as required by the governing bodies the General Medical Council (GMC) , the GenAlso of interest is the opinion of students graduating from such professional/vocational programs as to whether the courses do cover the attributes discovered. The BSc in Medical Sciences at St Andrews is a three year Honours degree program, after which graduates move on to their clinical years at other Medical Schools. The program itself is designed to provide 'an excellent scientific foundation for clinical practice'  and therThe first aim of this study was to identify what research related graduate attributes were desirable in graduates from Medical, Dental or Veterinary degrees. A secondary aim was to determine whether such research related attributes can be covered in a curriculum whose content is governed by regulating bodies. The third and final aim was to investigate student opinion as to whether a course designed to provide a scientific foundation in Medicine would equip graduates with the identified attributes.Semi structured interviews were carried out with key staff members responsible for curriculum design from all Medicine, Dentistry and Veterinary Medicine schools in Scotland. Interviewees were purposively selected as being involved with curriculum design within their school. Further interviews were carried out with selected staff from English schools. These schools  were selected to provide a wide range of views from different teaching and learning environments. The interview was structured around the Quality Assurance Agency enhancement theme 'Research-Teaching Linkages: enhancing graduate attributes' aims, and was piloted with two participants from different Medical schools, after which minor revisions were made.A total of 24 interviews were completed, either in person or over the telephone. Sampling was concluded once all Scottish schools and the selected English school representatives were interviewed. Interviews were recorded and transcribed. Of interest to this study was the question: 'Can you name 10 key research attributes that graduates from your course should have?'Qualitative analysis of the transcripts was carried out using a grounded theory approach . Two of Quote 1: 'Asking questions, as in a method of learning an enquiring mind'Quote 2: 'Encouraging aspects of the personal and professional behaviour such as being interested in a problem enough to try and find out more about it'Delegates (n = 58) at the symposium 'Research Teaching Linkages in the disciplines of Medicine, Dentistry and Veterinary Medicine',  discussed the list of attributes during small group breakout sessions. Group composition was balanced to ensure they contained representatives from each discipline. Using a variation of nominal group technique, participants were asked to discuss and define the predefined list of attributes and rank them in order of preference from a professional standpoint and then again from a research standpoint. Groups were invited to discard any attributes they thought were not vital. During collation of the results from all groups, attributes ranked by less than three out of the five groups at the symposium were discarded. Attributes that were deemed vital by three or more groups at the symposium had their average ranks calculated. This provided a final list of attributes, the definitions of which were provided by the groups. The definitions were further refined at a QAA Enhancement Themes conference  workshop aimed at the three disciplines.Final year students (n = 104) of the BSc Medical Sciences degree program at the University of St Andrews were asked to complete a questionnaire to evaluate the course as part of the curriculum review process. The part of the questionnaire relevant to this study focussed on how well equipped they felt with the graduate attributes defined previously in the study. For example questions asked whether completion of either the degree program or the final year project module had given them 'an understanding of the evidence base for practice', or 'has made you aware of the need for an inquiring mind' (1 = agree - 5 = disagree).The data was investigated for normality and statistical analysis was carried out using appropriate tests in SPSS v 14.Ethical approval was granted by the Bute Medical School Ethics Committee.Interviews with 24 staff members from Medical, Dental and Veterinary schools yielded 122 graduate attributes, an average of five per interviewee. There were no differences between the three disciplines in terms of the attributes suggested by faculty members. Qualitative analysis (described above) of the interview transcripts resulted in 16 higher level attributes.Discussion at the Research Teaching Linkages symposium breakout sessions resulted in nine attributes being thought to be vital for a professional career and 10 for a research career. Table As can be seen from Table Response rate of the student questionnaire was 100%. Table Degree program average scores for all attributes were significantly higher than 2, which would be a 'neutral' response . The final year project was also thought to equip students well with all attributes, apart from team working where the average score was lower than neutral .It can be seen from Table Interviews with faculty members with responsibility for curriculum design from all three disciplines and ranking by further experts in the area resulted in two lists of attributes, one desirable in a graduate pursuing a professional career, the second in a graduate pursuing a research career. The definitions agreed in the study Table  provide Interestingly the top seven attributes in both lists were the same, although not ranked in exactly the same order of preference. This suggests that such graduate attributes are high level skills which would be applicable to both research and professional situations. This finding has implications for curricula design in Medical, Dental and Veterinary degree programs. Curricula in all three disciplines are prescribed by guidelines issued by the governing bodies, the GMC , GDC 5]5] and RCA BSc program in Medical Sciences may not have precisely the same aims as the standard five year MBChB and this is one limitation of this study, as graduates may have a slightly different focus in their careers. The course at the University of St Andrews provides the basis for entrance to the third year of an MBChB course, but also attempts to deliver an understanding of the scientific basis of Medicine and therefore should be equipping its graduates with the research related attributes determined in the previous part of the study. The results show that the final year students considered that the degree program as a whole, did provide them with the opportunity to develop all of the top seven attributes identified in this project as being common to both professional and research careers. The final year project component of the course was viewed as being particularly effective at equipping students with the ability to understand the importance of having an inquiring mind and developing their critical appraisal skills. Similar outcomes for research projects were shown in a qualitative study in science undergraduates and their faculty advisors by Seymour et al . They noOther limitations of this study include the sample of interviewees, which included individuals from all Scottish Medical, Dental and Veterinary schools and a selected sample from English schools. The English schools were selected for participation on the basis of achieving representatives from a wide range of curriculum types although it is not an exhaustive sample. We acknowledge that this may have impacted on the views that were obtained.Data analysis employed both qualitative and quantitative methods. The development of the list of refined attributes from the interview suggestions utilised NVivo software which may have affected coding and clustering of data and therefore the emerging themes. The process was however carried out by two authors (AL and JS) who achieved consensus.This study is timely as the Higher education sector becomes ever more globalised. Many Veterinary schools in the UK comply with European Association of Establishments for Veterinary Education curriculum guidelines . The TunCurriculum designers in Medicine, Dentistry and Veterinary Medicine can utilise the seven graduate attributes identified in this study as a means of ensuring that they produce graduates who are equally well equipped for either a professional or research career. By mapping these core attributes to current learning activities they can ensure that there are opportunities within their curriculum for students to develop and practice these skills. The definitions of these attributes will allow a focus for discussion on the opportunities available within the different curricula.Results of the student study confirmed the belief that involving students in a research project was an excellent way to equip them with many of the identified attributes. Students completing a BSc Medical Sciences reported that the final year project was particularly effective in developing an inquiring mind and the skills of critical appraisal.The authors declare that they have no competing interests.AL was a member of the original project team, carried out interviews, facilitated symposium breakout sessions and drafted this article. SG derived the initial QAA project proposal and recently presented some of the results of the project at the AMEE conference, Prague. JS was project director of the original QAA project, carried out interviews, facilitated symposium breakout sessions and commented on drafts of this article. All authors read and approved the manuscript.The pre-publication history for this paper can be accessed here:"}
+{"text": "An expert working group of the European Association for Palliative Care has revised and updated its guidelines on the use of morphine in the management of cancer pain. The revised recommendations presented here give guidance on the use of morphine and the alternative strong opioid analgesics which have been introduced in many parts of the world in recent years. Practical strategies for dealing with difficult situations are described presenting a consensus view where supporting evidence is lacking. The strength of the evidence on which each recommendation is based is indicated. \u00a9 2001 Cancer Research Campaign"}
+{"text": "To determine diagnostic value of magnetic resonance urography in cases of duplex renal system.Twenty cases between five month to nine years with suspected or known duplex renal system were evaluated by ultrasound (USG), micturating cystourethrography (MCU), intravenous urography (IVU) and magnetic resonance urography (MRU). The findings of these diagnostic imaging studies were then compared with each other and against the results of final diagnosis established at surgery.Duplex renal system could be identified in two of these cases on USG, was diagnosed in four in IVU and could be diagnosed in all cases with MRU.MRU is superior and far accurate than IVU, MCU and USG in diagnosing duplex renal system. Conventional radiological investigations are commonly being used for the diagnosis of duplex renal system. However, each of them has limitations and hence multimodality workup is required in their evaluation.It may be possible to avoid it with its associated cost, if similar information were available from a single imaging modality which will reduce the time and will give better diagnosis using magnetic resonance urography (MRU) for its diagnosis. This article describes our initial experience using MRU for the diagnosis of duplex renal system and comparing its findings with other conventional radiological investigations.et al.[The concept of MRU has been introduced since 1986 by Henning et al. and is bThe purpose of the study was to confirm the efficacy of MRU and comparing its findings with other radiological investigations.This was a prospective study done over a period of one year from 2006 to 2007. At the outset of the study the patients with diagnosed or suspected duplex renal anomalies on routine radiological investigations or those not picked on conventional investigations as intravenous urography (IVU), micturating cystourethrography (MCU), ultrasound (USG) and nuclear scintigraphy and having persitant urogical symptoms underwent MRU using gadolinium contrast after obtaining proper consent for the procedure. IVU, MCU were performed using standard protocols of the procedure and USG was done in all the cases. Nuclear scintigraphy study was done using technetium T99 labeled diethylenetriaminopentaacetic acid (DTPA) and dimercaptosuccinic acid (DMSA) with lasix at 10 min of study.MRU was done using heavily T2-weighted images, contrast enhanced T1-weighted MR sequences and maximum intensity projection (MIP) after proper hydration in 1.5T MR scanner imaging.Very young and uncooperative patients were given oral sedation. These patients were given as per body weight to maintain proper hydration. Intravenous gadolinium contrast was used for the study for image acquisition using abdominal or body coil, with patient in supine position and coil positioned over upper abdomen and centered on kidneys. After initial localizing images were obtained in the following sequences:T2 HASTE single sliceT2 HASTE multislice3D GRE T1TRUFI 2DFL2D 80TSE FS T2Post contrast images in T1 sequences were obtained.Total twenty cases were subjected for MRU after they were either diagnosed to have duplex on conventional radiological investigations or were suspected to be having duplex renal system and routine radiological investigations failed to pick the condition.USG was suspicious in two cases and IVU showed four cases to be having duplex renal system including these two cases. MRU successfully picked up duplex moiety in either of the side in all of these patients. Fourteen were female patients and rests were male. Three patients had bilateral duplex renal system. Ten patients underwent upper pole heminephrectomy for nonfunctioning upper moiety. One patient had both the moieties functioning and hence underwent upper pole ureteric reimplantation for the refluxing moiety. Two patients had pathological single unit on one side and normally functioning duplex unit on the other side and underwent nephrectomty of the pathological single unit of the opposite side. Two patients are under regular follow up and are asymptomatic and on chemoprophylaxis and doing well and two patients did not turn up for further follow up. One patient had unilateral duplex with ureterocele of the upper mioty which was normally functioning and incision of uereterocele was done. We compared the sensitivity and specificity of the IVU and MRU in the diagnosis of the duplex system and compared it with operative findings. MRU showed the sensitivity and specificity of 100% as compared to only forty percent sensitivity of the IVU. But specificity of IVU was 100% here.Duplication is the most common congenital anomaly in the urinary tract, a 0.7% incidence in one series. During iMCU can diagnose associated refluxing unit in cases of duplex moity and ureterocele however as a single investigation cannot diagnose duplex system.IVU which is considered as a standard investigation for morphological assessment of renal parenchyma fails to identify nonfunctioning upper moieties of duplex system.Abnormal alignment of upper pole calices of lower moity because of pressure effect of dysplastic upper moity can be seen on IVU which may give clue to the diagnosis.Renal scintigraphy is necessary to know the differential functional status of the duplex moieties which influences the treatment. It however gives poor anatomical delineation.et al. described the concept of computed tomographic urography (CTU) as a diagnostic method in renal diseases. Multislice computed tomography (CT) with contrast and 3D reconstruction also gives excellent anatomical details but has high radiation exposure and risk of allergy to the contrast.[In 1996, Pearlman We found that, MR urography as a single investigation gives excellent anatomical description of the duplex renal moieties even when they are nonfunctioning. MRU is a noninvasive examination method that does not entail ionizing radiations and does not require iodinated contrast as in IVU or CTU and safer in children. It is excellent in identifying nonfunctioning or poorly functioning duplex system.The heavily weighted T2 images best pick up the dilated non functioning moieties using static fluid as hyperintence images . This teBut there are studies where this is calculated and found to be almost 99% sensitive and more than ninety five percent specific for the diagnosis of the duplex renal system.6We attribute the reasons for failure of IVU to diagnose the duplex system where operative intervention was not required to presence of ectopic moity superimposed on the bony structures and could not be seen in IVU in three cases, borderline functioning in these same cases, poor patient preparation in another two cases and where the pressure from the dilated lower moity was obstructing the drainage as well as compromising the perfusion of the duplex moity and hence was appearing like non functioning moity on IVU. In one case, the anatomical arrangement of the calyses was so close to each other that on IVU they resembled as calyses of the single unit and misinterpreted by the radiologist and only MRU could detect the duplex in this.It is obvious that conventional radiology cannot singly pick up duplex renal anomaly and hence there is no single gold standard conventional investigation for its diagnosis and here the role of MRU appears to be superior to all conventional investigations and also gives better anatomical and functional accuracy in diagnosing duplex system which surpasses its disadvantages of cost, time, and need of sedation for the procedure.591059Moreover, the time of examination for MRU is lesser than for scintigraphy done for quantification of function.In our cases, MRU successfully picked up duplex renal system and in the cases where operative intervention was required, also helped in deciding the plan of management which was not possible by conventional investigations.In our initial experience, MRU may become the single investigative modality compared to other conventional radiological investigations in cases of duplex renal system.\u201314"}
+{"text": "The possibilities of clustering between those electoral wards which display higher than expected incidences of cases of the lymphomas occurring between 1978 and 1982 are examined. Clusters are defined as being those wards with cases in excess (at a probability of less than 10%) which are geographically adjacent to each other. A separate analysis extends the definition of cluster to include high incidence wards that are adjacent or separated by one other ward. The results indicate that many high incidence lymphoma wards do occur close together and when computer simulations are used to compute expected results, many of the observed results are shown to be highly improbable both in the overall number of clustering wards and in the largest number of wards comprising a 'cluster'."}
+{"text": "Sir,The only study to assess prevalence of dementia in elderly in Sri Lanka has reported a prevalence of 3.98% in a semi urban population. There isWe conducted a preliminary study to assess cognitive impairment and depression in a sample of geriatric patients presenting to the University Medical Unit of the National Hospital of Sri Lanka . This prospective study included all patients over 65 years, who were admitted over four weeks. The Mini Mental State Examination  and the geriatric depression scale (GDS) were used to screen for cognitive impairment and depression respectively.P>0.05).. The percentages of gender and ethnicity did not differ significantly from the population average (P>0.05).We also assessed the impact of educational level and social support on cognitive impairment with a statistical model. It was hypothesized that better education and family support will protect against cognitive impairment. However (holding age and gender constant), the cognitive impairment did not correlate with either factor, alone or in combination  and cognitive impairment (>50%) was very highThe assumption that better education and family support leads to less cognitive impairment could not be validatedThe symptoms of depression may be due to illness itself. Yet it underscores the lack of psychiatric input in medical wards as none of these patients were referred to a psychiatrist. The second observation may be due to:Errors in variables that defined family support (frequency of visits by relations and living with family), which may not indicate coherent family functioningPathology of dementiaDepressive pseudo dementiaSampling errorsThe findings of this preliminary study are significant and indicate theImportance of improving mental health among geriatric patientsNeed for coordinating psychiatric and medical care to reduce disease burdenNeed for routine screening of elderly patients for cognitive impairmentNeed for a large multi center hospital-based study to assess the interaction of socioeconomic factors, depression, dementia and disease burden"}
+{"text": "The evolution and structure of adenomatous polyps and adenocarcinomata of the colon in NMRI mice induced by dimethylhydrazine are described. Severe toxic reactions in the liver and other organs are produced by dimethylhydrazine (DMH), but tumours are induced only in the colon and around the anus. The 100% incidence and growth characteristics of the tumours make it potentially a good model system, but investigators should take into account the widespread nonspecific cellular injury induced by this carcinogen."}
+{"text": "The weights of mouse sarcoma 180 differed according to the varieties of mouse. In two varieties in which both sexes were studied the tumour weights were lower in females. In three varieties the tumours weighed less at lower environmental temperatures than at higher ones. At three environmental temperatures in the physiological range the surfaces were cooler than the adjacent skin, and the tissues of tumours were cooler than the surrounding subcutaneous tissues. These differences were greater in cooler than in warmer environments and increased as tumours grew larger. There were no histological changes to account for the different tumour weights at different environmental temperatures and it seems probable that tumours are unable to maintain their temperature and their metabolism in cool environments. In mice of the same breed kept at room temperature the smallest animals had the largest tumours in a weight range of 18-28 g."}
+{"text": "This study has examined cells from naturally-occurring murine mammary tumours to ascertain whether cell surface glycoproteins play a significant role in colonisation of the lungs after intravenous inoculation. It was found that gel electrophoretic analysis of membrane extracts and lectin adsorption studies did not reveal any consistent differences in glycoprotein composition of cells from tumours which can heavily colonise the lungs relative to ones from tumours which cannot do so or to cells from pulmonary metastases. Also, alteration of structural and functional properties of surface glycoproteins by treatment with succinylated lectins or with drugs such as tunicamycin and swainsonine, which inhibit glycosylation of membrane proteins, had no specific effects on metastatic colonisation of the lungs. Tunicamycin apparently decreased capability to form experimental metastases but also diminished tumourigenicity on subcutaneous inoculation, although it did not affect tumour cell viability in vitro. This information supports earlier studies from this laboratory involving enzymic digestion of the surface of living tumour cells before inoculation and demonstrates that the pulmonary colonisation capability of these mammary tumour cells can withstand global disorganisation of membrane glycoprotein structure and composition. This implies that either the surface glycoproteins are not important in the colonisation process, or that these tumour cells have great capability for rapid repair of their surfaces. It is concluded that a clear answer to whether surface glycoprotein composition has a decisive role in pulmonary colonisation by these mammary tumour cells requires introduction of stable heritable traits into tumour cell populations by genetic manipulation."}
+{"text": "High throughput screening has significantly contributed to advances in drug discovery. The great increase in the number of samples screened has been accompanied by increases in costs and in the data required for the investigated compounds. High throughput profiling addresses the issues of compound selectivity and specificity. It combines conventional screening with data mining technologies to give a full set of data, enabling development candidates to be more fully compared."}
+{"text": "The discovery of effective cancer treatments is a key goal for pharmaceutical companies. However, the current costs of bringing a cancer drug to the market in the USA is now estimated at $1 billion per FDA approved drug, with many months of research at the bench and costly clinical trials. A growing number of papers highlight the use of data mining tools to determine associations between drugs, genes or protein targets, and possible mechanism of actions or therapeutic efficacy which could be harnessed to provide information that can refine or direct new clinical cancer studies and lower costs. This report reviews the paper by R.J. Epstein, which illustrates the potential of text mining using Boolean parameters in cancer drug discovery, and other studies which use alternative data mining approaches to aid cancer research. The discovery of effective treatments for cancer represents a key goal for pharmaceutical companies who wish to identify drugs that can prolong survival time and even reverse cancers, while having an acceptable toxicity profile. However, the average cost of bringing a drug to the commercial market in the USA is now estimated at $1 billion per FDA approved drug, and many factors have compounded the expense of these developments such that cancer drug discovery is now both extremely slow and costly even for a potential blockbuster. Among the many factors contributing to the cost are the high price of clinical trial organisation and the bench research hours required to validate the efficacies and toxicities associated with a drug despite the use of time saving technologies such as high throughput screening to determine efficacies and genomic analyses of drug effects. A growing number of papers highlight the use of data mining tools to determine associations between drugs, genes or protein targets, and possible mechanism of actions or therapeutic efficacy which could be harnessed to provide information that can refine or direct new clinical cancer studies.One common method of data mining is referred to as text mining. Richard EpsteinEpstein also provides examples of how text mining can determine associations between types of cancers and a particular gene for example, AKT.5However, there are a few known limitations to text mining. Associations are based on the use of constant terminology for a drug or gene, whereas this may not be the case for example, where drug names are changed by companies. Also there is restricted access to full text journals and also restriction to abstract publications and some chemical and physical science journals in databases such as pubmed so that data associations need to be retrieved from a more limited source of overall citations. Text mining may therefore be better utilized by combining it with other data mining tools such as microarray database mining. This uses microarray gene data from experiments which have analysed genomes or sets of genes of particular cells or tissues.The power of data mining has now been harnessed by a growing industry specialising in the production of databases which can utilise text or gene or protein data. A selection of databases with direct application to cancer drug or target molecule discovery are presented in The tools that these databases provide for both the drug industry and academia can maximise the mining process compared to manual mining techniques. Whereas data mining has not yet resulted in blockbuster discovery on its own merit, the use of this technology harnessed with the power of dedicated databases and bench top research, has already contributed to deciphering mechanisms of action of genes and drugs and should allow a much more rapid progress toward discovery of effective cancer therapies in the future."}
+{"text": "Objective: The purpose of this study was to evaluate the possible association between Lewis phenotype status in pregnant women and preterm labor (PTL) or preterm rupture of the membranes (PROM).Methods: Red blood cell (RBC) Lewis phenotype was determined in 113 pregnant women admitted for PTL or PROM and in 121 controls. The results were controlled for the influence of race on Lewis phenotype.Results: Pregnancy was associated with a higher frequency in women with the a\u2013b\u2013 phenotype. There was no association between RBC Lewis phenotype and the occurrence of PTL or PROM.Conclusions: A susceptibility to PTL or PROM is not due to a lack of Lewis antigen expression onthe plasma membrane of the vaginal mucosa."}
+{"text": "Two cases are described, one with proven lymphosarcoma and doubtful autoimmune disease, and the second with the reverse situation, in which circulating abnormal mononuclear cells showed PHA responsiveness and an abnormal chromosomal constitution . These findings are discussed in the light of previous cytogenetic studies of lymphoreticular neoplasia and autoimmune disease and the relationship between these two conditions."}
+{"text": "The system could be adapted to the clinical determination of oestrogen receptor content in biopsy material from mammary and endometrial tumours and would be of value in predicting hormone dependency.A thin-layer gel filtration system for the assay of oestrogen receptors in target organ tissue samples as small as 50 mg is presented and compared with the sucrose gradient centrifugation method. Only specific high-affinity binding of ["}
+{"text": "The exact cause of liver failure occurring after long standing biliary obstruction is not known.Impairment of hepatic mitochondrial respiration was postulated in some studies. Sodiumthiosulphate (STS) is known to have a protective effect on liver function during administration ofhepatotoxic chemotherapy. In the present experimental study the effect of treatment with STS inthe presence of obstructive jaundice was studied by determination of the survival rate of ratssubjected to biliary obstruction and by polarographic determination of the hepatic mitochondrialfunction. Treatment with STS was found to result in a significant improvement in rats'survival rate (p < 0.05). Polarography demonstrated significant preservation of mitochondrialrespiratory capacity after treatment with STS. The results of the present study show that thedeterioration in liver function in the presence of biliary obstruction is probably caused byimpairment of mitochondrial respiration. This may be preserved by treatment with STS. Theexact explanation of its effect is not yet clear."}
+{"text": "Sir,One cannot but agree with the pitch for substantial changes in the current pharmacology curriculum. TraditioCurrent medical graduates learn their first lessons in rational and appropriate prescribing in busy out patient departments during their internship. Their knowledge about practical drug dosing and modifications to be made in various clinical scenarios leaves much more to be desired. The new guidelines for teaching pharmacology must be radical in scraping what is useless and in recommending a practical patient-based learning. This will bring the interest of medical students back into pharmacology classes."}
+{"text": "Vaccination against influenza is currently recommended for patients with rheumatoid arthritis (RA). The safety and efficacy of vaccination in patients suffering from rheumatic diseases is still a matter of debate. This review summarizes the studies performed on the safety and immunogenicity of influenza vaccination in patients with RA as well as the rheumatic complications of the vaccine in otherwise healthy persons. Several trials have shown that the vaccine induces an adequate humoral response and does not induce clinical exacerbation of RA. Rheumatic complications (mainly vasculitis) following influenza vaccination in the general population are scarce."}
+{"text": "The activities of certain enzymes in the tissus of mice infected with Friend virus have been studied. Progressive increases in LDH, G6PDH and 6PGDH have been observed in the spleen and liver concomitant with malignant transformation. Plasma LDH activity was also observed to increase over the period of study, but changes in the isoenzyme distribution probably resulted from contamination of the Friend virus preparation with lactic dehydrogenase virus. The tissue enzyme changes are similar to those observed in human malignancies."}
+{"text": "Research on biological data integration has traditionally focused on the development ofsystems for the maintenance and interconnection of databases. In the next few years,public and private biotechnology organisations will expand their actions to promote thecreation of a post-genome semantic web. It has commonly been accepted that artificialintelligence and data mining techniques may support the interpretation of huge amounts ofintegrated data. But at the same time, these research disciplines are contributing to thecreation of content markup languages and sophisticated programs able to exploit theconstraints and preferences of user domains. This paper discusses a number of issues onintelligent systems for the integration of bioinformatic resources."}
+{"text": "Experiments are described in which dose-response data have been obtained for EMT6 mouse tumour cells growing in vivo and exposed to various cytotoxic agents. A comparison has been made of the response of solid tumours in the flank and of rapidly growing lung nodules. The results are discussed with regard to their cell kinetic implications and compared with our results for the chemosensitivity of EMT6 cells in exponential and plateau phase growth in vitro."}
+{"text": "The role of the vagus nerve in liver regeneration after partial hepatectomy was studied by comparing theeffects of hepatic branch vagotomy with those of hepatic branch sympathectomy in rats. The liver weight as a percentage of body weight decreased significantly 7 days after vagotomy compared with the controls and this was associated with a reduction in food intake. There was no difference in the liver weights between the control rats and the pair-fed vagotomized rats. Hepatic sympathectomy had no significant effect on the liver weight. The serum scores indicating hepatic function showed no difference between the control and the vagotomized rats except alkaline phosphatase. The concentration of insulin was unchanged. The number of mitotic hepatocytes remained high at 7 days after vagotomy: Theseobservations led us to conclude that the vagus nerve stimulates liver regeneration, and its effect depends on vagal factors directly and specifically."}
+{"text": "Because two authors were added to the author byline, the funding statement should also include the following: SF was supported by a studentship from the French Ministry of Research. JYG was supported by Programme Amazonie du CNRS and ANR through Projet MIRETTE."}
+{"text": "A survey of all hospital pharmacies in the former North Western Regional Health Authority has revealed that hospital personnel continue to prepare cytotoxic drugs in suboptimal conditions, despite the widespread introduction of pharmacy cytotoxic reconstitution services. Other concerns include the lack of formal training for medical staff in the administration of these agents and the frequent absence of written procedures for dealing with extravasation and chemotherapy errors."}
+{"text": "However the existence of chronic inflammatory conditions that do not have an established infective cause and are associated with the development of tumours strongly suggests that the inflammatory process itself provides the prerequisite environment for the development of malignancy. This environment includes upregulation of mediators of the inflammatory response such as cyclo-oxygenase (COX)-2 leading to the production of inflammatory cytokines and prostaglandins which themselves may suppress cell mediated immune responses and promote angiogenesis. These factors may also impact on cell growth and survival signalling pathways resulting in induction of cell proliferation and inhibition of apoptosis. Furthermore, chronic inflammation may lead to the production of reactive oxygen species and metabolites such as malondialdehyde within the affected cells that may in turn induce DNA damage and mutations and, as a result, be carcinogenic. Here it is proposed that the conditions provided by a chronic inflammatory environment are so essential for the progression of the neoplastic process that therapeutic intervention aimed at inhibiting inflammation, reducing angiogenesis and stimulating cell mediated immune responses may have a major role in reducing the incidence of common cancers. \u00a9 2001 Cancer Research Campaign"}
+{"text": "DNA samples obtained from 29 testicular germ cell tumours have been screened for instability at nine different microsatellite sequences consisting of dinucleotide, trinucleotide and tetranucleotide loci. Overall, in tumours from six (21%) patients we found abnormalities in at least one of the loci examined. Mutation was most frequently found in tetranucleotide and trinucleotide repeats with only a low proportion of alterations in dinucleotide repeats. This pattern of instability is distinct from that reported in colorectal cancer and other cancers that have a high level of alterations in dinucleotide repeats."}
+{"text": "Leucocytes containing a high proportion of blast cells were obtained from 11 patients with acute myeloid leukaemia, and leucocytes were also obtained from 2 normal subjects. Ferritin was partially purified from leucocyte extracts and subjected to anion-exchange chromatography and isoelectric focusing. The Fe content of leucocyte ferritin was low, and in all but one case the preparations contained isoferritins corresponding to those found in normal tissues or serum. Only some of the preparations contained the relatively acidic isoferritins which have been described as \"carcinofoetal\", but which are also present in normal heart and kidney. Ferritin from one patient contained isoferritins of lower isoelectric point than heart ferritin. These results show that there does not appear to be any specific isoelectric focusing pattern for leukaemic cells, and that assays for acidic isoferritins are unlikely to be of use in the diagnosis of leukaemia and in monitoring treatment. However, the very acidic protein found in one preparation suggests that the search for abnormal subunits of ferritin may be fruitful in acute leukaemia."}
+{"text": "The cumulative radiation effect (CRE) is one of several empirical scalar descriptions of biological effect which enable corrections to be made for gaps in radiotherapy treatment. Predictions of this theory were tested using mouse crypt regeneration and mouse skin as biological models. These experimental results are discussed in terms of the dependence of tissue regeneration potential during a gap on the biological effect achieved before the gap, and on gap length. A hypothesis is proposed to reconcile the apparent conflict between the two experiments. While the simple exponential gap formulation of the CRE is seen to be inadequate, insufficient data are available at present to modify it."}
+{"text": "A simple method has been developed which facilitates the detailed cytogenetic analysis of proliferating tumour cells within clusters and colonies arising from clonogenic tumour stem cells in biopsy samples of human cancers. The method uses a simple agar cloning technique for human tumours, which provides marked enhancement in the number of cases with observable mitotic activity and the number of mitotic figures available for detailed karyotypic assessment. The frequency of mitotic figures in cluster and colony samples is much greater than is attainable with standard chromosomal techniques. This novel approach should prove to be a powerful tool for the study of human tumour karyology."}
+{"text": "Three outbreaks of Ebola hemorrhagic fever have recently occurred in Gabon. Virus has been isolated from clinical materials from all three outbreaks, and nucleotide sequence analysis of the glycoprotein gene of the isolates and virus present in clinical samples has been carried out. These data indicate that each of the three outbreaks should be considered an independent emergence of a different Ebola virus of the Zaire subtype. As in earlier Ebola virus outbreaks, no genetic variability was detected between virus samples taken during an individual outbreak."}
+{"text": "Despite several years of implementation, prevention of mother-to-child transmission (PMTCT) programmes in many resource poor settings are failing to reach the majority of HIV positive women. We report on a data driven participatory quality improvement intervention implemented in a high HIV prevalence district in South Africa.A participatory quality improvement intervention was implemented consisting of an initial assessment undertaken by a team of district supervisors, workshops to assess results, identify weaknesses and set improvement targets and continuous monitoring to support changes.The assessment highlighted weaknesses in training and supervision. Routine data revealed poor coverage of all programme indicators except HIV testing. Monthly support to all facilities took place including an orientation to the PMTCT protocol, review of local data and identification of bottlenecks to optimal coverage using a continuous quality improvement approach. One year following the intervention large improvements in programme indicators were observed. Coverage of CD4 testing increased from 40 to 97%, uptake of maternal nevirapine from 57 to 96%, uptake of infant nevirapine from 15 to 68% and six week PCR testing from 24 to 68%.It is estimated that these improvements in coverage could avert 580 new infant infections per year in this district. This relatively simple participatory assessment and intervention process has enabled programme managers to use a data driven approach to improve the coverage of this important programme. UNAIDS estimates that approximately 370 000 children were infected with HIV in 2007. More thProgramme evaluations from a number of countries in Africa have found deficiencies in various components of PMTCT programmes including uptake of antenatal HIV testing,7, receiIntegrating PMTCT programmes into an already overburdened health system has been identified as a common reason for the sub-optimal performance of PMTCT programmes as they scale up to achieve national coverage. There is little documentation of how these challenges have been/are being addressed in routine (programmatic) settings where PMTCT programmes are taken to scale but evidence suggests that 'one size fits all' clinical guidelines are not leading to the desired changes. This paThe package of care for the PMTCT programme at the time of this intervention included routine offer of antenatal voluntary counselling and testing (VCT), infant feeding counselling, single dose nevirapine to mothers and infants, infant PCR testing at six weeks and six months of free formula milk to women choosing not to breastfeed. The PMTSouth Africa has a district health system in which comprehensive primary health care (PHC) clinics provide primary level care, referring patients to district and regional hospitals for secondary level care. PHC services are nurse driven. Clinic nurses are responsible for the diagnosis and management of infectious diseases such as tuberculosis, HIV and sexually transmitted infections, preventive care such as childhood immunisations and growth monitoring, antenatal care, as well as providing an acute curative service and attending to chronic conditions such as hypertension and diabetes.The intervention was carried out in one district in KwaZulu-Natal province, Amajuba. In 2006 the district was estimated to have a total population of 585 858 and a population under one year of 13 259. The antth year[Routine maternal and child health indicators for the district are good with an antenatal care coverage rate of 94%; 92% of deliveries undertaken by trained health professionals (midwives or doctors) and an immunisation coverage rate under one year of 83%. PMTCT wth year. Anthropth year has idenThe intervention consisted of a participatory assessment phase followed by a feedback and planning phase and then an implementation and monitoring phase. Each phase of the intervention had a focus on using routine data for problem identification, target setting and monitoring Table .During the participatory assessment phase a task team consisting of programme managers for HIV, PMTCT, maternal and child health (MCH), unit managers for hospital labour and postnatal wards and PHC clinic supervisors was formed to improve the performance of the PMTCT programme. The purpose of the participatory assessment phase was to build the capacity of local programme managers to conduct a simple assessment of maternal and child health services in their district. The process was introduced at a workshop held with this team in May 2007. During the workshop the team was oriented to the assessment framework, introduced to the assessment tools and supported in a short phase of piloting. An evaluation guide was developed to give step by step instructions about how to plan, prepare for and undertake the assessments.Three data collection tools were developed for the assessments; a structured interview tool for facility managers, an observation tool for PHC clinics and a structured interview tool for lay counsellors. These tools are described in Table Assessment teams consisted of three to four people (district and sub-district co ordinators and PHC supervisors) who visited facilities over a one week period. Each facility visit took approximately 3-4 hours. Assessment of the entire district took 7 days. Routine district PMTCT data from the district information officer was also collected in order to assess performance of key PMTCT indicators.The feedback and planning phase and the intervention and monitoring phase are described in the results section of the paper as these were developed following review of the findings of the participatory assessments.All eighteen comprehensive PHC clinics were visited in the assessment phase. At three facilities the facility manager was not present at the time of the assessment due to meetings or training resulting in a total of 15 facility manager interviews. Sampling of lay counsellors was determined by their availability but at least half of the total number assigned to each facility were included resulting in a total of 35 lay counsellor interviews.Interview and observation tools were submitted at the end of each day to the project facilitator who entered the data into excel. Epi-Info was used to generate basic frequencies for all tracer indicators as shown in Table Clinics had on average 7 full time clinical staff who were mainly nurses; only two clinics had doctors on site. Whilst there are no national norms for doctors in PHC it is expected that 10-15% of patients in clinics will be seen by a doctor and therefore clinics are expected to have a visiting doctor once a week. Coverage of PMTCT training was found to be sub-optimal with less than a third of clinical staff trained in PMTCT and HIV and infant feeding Table . InterviThe median number of clients seen per lay counsellor per day was 9 (range 2-30). This is slightly less than would be expected of a full time counsellor (10-12) but is dependent on the size of the facility and the number of nurses available to perform rapid HIV testing. Less than half of the lay counsellors reported having their own dedicated counselling room and 56% reported having to wait for a room to become available before they could counsel a client. 48% reported that this occurred on a daily basis.Management of drugs and supplies was good with only one clinic found to be out of stock of rapid HIV test kits and one facility did not have nevirapine tablets. Documentation and record keeping was generally found to be good with all clinics having an HIV testing register and a nevirapine drug register which were up to date. All clinics had guidelines for HIV testing, however, a quarter did not have a PMTCT manual on site.Supervision systems however were found to be poor. Forty seven percent of facilities had been visited by the district MCH supervisor in the previous six months and 33% had been visited by the district PMTCT supervisor in the previous six months. Supervision from the PHC clinic supervisors was better with a median of 3 visits per clinic (range 0-7) in the previous six months. These fall far short of the national norm of one visit per month to each facility.All of the clinics visited were open 5 days a week until 4 pm, however, a third of the clinics did not take first antenatal bookings every day of the week. Three clinics did not take blood for CD4 testing on site but referred clients to another facility. The South African PMTCT policy states that a CD4 cell count should be taken on the same day that the HIV positive status is established, and preferably at the first ANC visit therefore all clinics should be drawing blood for the CD4 test. The median turn around time for CD4 results was one week (range 1-5 weeks). This is better than the nationally recommended turn around time of two weeks. All of the clinics except one provided infant PCR testing and the median turn around time for PCR results was 6 weeks (range 1-24 weeks). National PMTCT guidelines state that all facilities should have the capacity to collect dried blood spots for PCR testing of infants. There is no South African norm for turn around time however WHO recommends a turn around time (from collection of sample to return of results) of no more than four weeks.The review of routine PMTCT data for the period January to June 2007  were receiving a PCR test.Assuming 4837 births to HIV positive women per year in the district and 12% A common complaint amongst programme managers is the large amount of data they have to collect and process. The development of a comprehensive health systems framework, key tracer indicators and relatively simple data collection tools in this intervention enabled middle level managers to feasibly collect relevant data rapidly and to identify possible bottle necks to optimal programme performance.The results of the assessment showed that the district is clearly performing well in terms of HIV testing within antenatal care and this has been achieved through adequate human resource provision in terms of lay counsellors and a philosophy of making HIV testing a routine component of antenatal care. Areas of weakness identified include inadequate coverage of training amongst clinical staff, inadequate infrastructure in terms of counselling rooms, infrequent supervision by district supervisors, low coverage of CD4 testing, nevirapine to mother and infant and infant PCR testing. These weaknesses are due to the complex interaction of client and health systems factors. Client factors include lack of information and fear of disclosing HIV status, health systems factors include lack of ownership of the PMTCT programme amongst nurses, unclear roles and responsibilities, lack of knowledge of the protocol, poor recording systems and continuity of care.The process of identifying weak areas and implementation of a participatory approach to problem solving together with regular, data driven, facility level support resulted in large increases in key programme indicators over the period of one year.An intervention in Zimbabwe to improThis intervention used a participatory approach which has both advantages and disadvantages. The disadvantages are that it relies on support and buy in from senior district management to allow mid level managers the time to participate in the workshops and to actually undertake the assessments. Without this support, the participatory approach would not succeed. It is also possible that there is some loss of data quality by utilising health workers to collect assessment data instead of trained research data collectors however the aim of the project was not to be a rigorous research study but rather to develop the skills of mid level managers to conduct assessments of their own programmes and to interpret and act on the findings. The advantages of a participatory approach are that the process of conducting the assessments enables mid level managers to see first hand how well their facilities are functioning and to take ownership of the findings since it is data that they themselves have collected.This operational research study has several limitations which deserve discussion. Firstly the assessment of the intervention relied on routinely collected primary health care data. Routine health system data for PMTCT in South Africa has been found to suffer from problems of completeness and accuracy and thisSecondly the operational research design did not include a control or comparison group hence the findings cannot be causally attributed to the intervention. However, the intervention was adopted and supported by the district management team as something that would be conducted across the entire district and during its implementation there were no other large scale efforts by NGOs or the district health department to address the quality of the PMTCT programme. The changes reported here were observed over a period of approximately 18 months prior to the introduction of the new PMTCT regimen when no media activities or health system changes were occurring. It is therefore plausible that the effects seen are due to this intervention.Improving PMTCT programmes is vital if the worsening under five mortality in high HIV burden countries such as South Africa is to be reversed. This is unlikely to be achieved through resource intensive generic health-system interventions (e.g. training courses and development of protocols and guidelines). The impact of these, in terms of programme functioning and health outcomes, has been disappointing; this has been attributed to their failure to link with specific programme activities. We propThis study was undertaken in one district with a relatively well functioning basic PHC system. The findings therefore cannot be generalised to every district in South Africa. All districts in the country do however have similar district management structures that would be applicable to this form of intervention. The addition of a facilitator for the duration of the intervention does add to the cost however it has been found to be essential at least in the initial stages of the intervention to encourage motivation and focus on the improvement targets. This approach of providing ongoing support through an external facilitator has recently been adopted as part of a national government accelerated plan for PMTCT. Several large NGOs have entered into performance contracts with the government which includes provision of external support for quality improvement.The development of a comprehensive programme evaluation framework, identification of key indicators and relatively simple data collection tools in this intervention enabled district and sub-district level managers to collect relevant data rapidly on the individual effectiveness of each programme component, as well as identifying possible efficiency gains and missed opportunities for improved programme performance. This approach could be scaled up as a model for participatory programme improvement.The authors declare that they have no competing interests.TD, MC and DN participated in the design of the study, conducted training and drafted the manuscript. TD and DN analysed the data. DM participated in the coordination and implementation of the study and helped to draft the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:"}
+{"text": "Alterations of microsatellites have been found at relatively high frequency in hereditary and sporadic colorectal cancer and gastric and pancreatic cancers and at lower frequency in some other cancers. We determined the frequency of instability at 39 poly-CA microsatellite loci in 20 squamous cell carcinomas and 26 Barrett's adenocarcinomas of the oesophagus. None of the tumours presented instability for a high percentage of the tested loci. Four squamous cell carcinomas and six Barrett's adenocarcinomas showed microsatellite instability at one locus, and three Barrett's adenocarcinomas showed microsatellite instability at two loci. The presence of few loci showing microsatellite instability could be due to an instability background. We conclude that genetic defects in the DNA mismatch repair system do not play an important role in oesophageal cancers."}
+{"text": "We used a link between cancer  and AIDS  registries in the United States to study whether nasopharyngeal carcinoma (NPC) was increased in the population with AIDS. There was no indication of a significantly increased risk up to or after the AIDS diagnosis, which argues against progressively failing immunity being important in the development of this malignancy."}
+{"text": "The distribution of iron and iron binding proteins (IBP) have been compared with control spleen tissue in an attempt to establish a pattern of staining restricted to Hodgkin's disease (HD). All but one of the HD spleens examined stained for ferritin, which was largely present in red pulp dendritic macrophages (DM). In spleens histologically involved with HD heavy deposits of ferritin were seen around tumour nodules. Staining for ferritin increased with involvement of the spleen in HD but DM still represented the bulk of positive cells. However, ferritin positive DM were frequently seen in control spleens, and often in large numbers. Staining of ferric iron by Perls technique was less prominent than ferritin but this observation was also true of the non-HD spleens studied. Patterns of staining with transferrin were equivalent in both groups of spleens with DM being the most frequently positive cell type. Polymorphous macrophages showing erythrophagocytosis were present in the red pulp sinuses of all groups of spleens and although these cells have been considered as precursors of the Reed-Sternberg cell their presence seemed related to total splenic ferritin regardless of the disease process. These cells marked as macrophages and their presence was not restricted to HD. The results show that there is no particular appearance of iron or IBP distribution which is restricted to HD spleens. However, staining for ferritin and iron increased in HD spleens with tumour involvement and could contribute to circulatory abnormalities in this disease."}
+{"text": "DNA flow cytometry was performed on formalin fixed, paraffin embedded melanocytic naevi. DNA aneuploidy was detected in all three types of naevus but was significantly more frequent in those naevi accepted as precursors of malignancy: that is, dysplastic and congenital pigmented hairy naevi. It may be that the presence of DNA aneuploidy has prognostic significance in these naevi. Technical problems were encountered in the analysis of data from melanocytic lesions so that caution is recommended in interpretation of studies using formalin fixed tissue."}
+{"text": "Despite the 1991 reforms of the health system in Zambia, mental health is still given low priority. This is evident from the fragmented manner in which mental health services are provided in the country and the limited budget allocations, with mental health services receiving 0.4% of the total health budget. Most of the mental health services provided are curative in nature and based in tertiary health institutions. At primary health care level, there is either absence of, or fragmented health services.The aim of this paper was to explore health providers' views about mental health integration into primary health care.A mixed methods, structured survey was conducted of 111 health service providers in primary health care centres, drawn from one urban setting (Lusaka) and one rural setting (Mumbwa).There is strong support for integrating mental health into primary health care from care providers, as a way of facilitating early detection and intervention for mental health problems. Participants believed that this would contribute to the reduction of stigma and the promotion of human rights for people with mental health problems. However, health providers felt they require basic training in order to enhance their knowledge and skills in providing health care to people with mental health problems.It is recommended that health care providers should be provided with basic training in mental health in order to enhance their knowledge and skills to enable them provide mental health care to patients seeking help at primary health care level.Integrating mental health services into primary health care is critical to improving and promoting the mental health of the population in Zambia. Over the last decade, Zambia has embarked on a radical transformation process aimed at creating a well functioning, cost effective and equitable district-based health care system . Such reMental health was not amongst the ten priority areas for health services in the BHCP. In fact, none of Zambia's strategic health plans and policy documents have addressed and incorporated mental health . AlthougMental health services appear to have been inadequately incorporated into the primary health care in Zambia, a problem shared with many other low-income African countries -9. AlthoThere has been widespread recognition of the benefits of and need for low and middle income countries to better integrate mental health within primary health care ,14. InteThere is a dearth of research on mental health generally in Zambia ,13,5 witA survey was devised and conducted in order assess the knowledge, attitudes and practices (KAP) regarding mental health of general and mental health care providers' in Zambia. The main objective behind this survey was to guide and inform the training that would be carried out amongst general and mental health care practitioners to better identify and manage common mental illness.Data collection took the form of a questionnaire with both open and closed ended questions. The questionnaires were administered to selected health care providers who worked in Out-Patients departments. Seventy six questions were asked covering three topics namely: Knowledge, Attitudes and Practices. Knowledge and Practice included the following sub-headings; knowledge about causes of mental illness, knowledge about mental disorders and ability to treat, prescribe, and administer drugs while Attitudes involved; stereotypes, separatist and discriminatory attitudes, restrictiveness. The questions on which this paper is based formed part of the 'attitudes' component of the survey instrument which included questions on attitudes towards training, and attitudes towards integration. The guiding questions are shown in table 1The questionnaire was piloted on fifteen health workers in Kafue District that was not part of the survey sites. Based on the findings from this pilot, the questionnaire was adapted and revised.The data were collected from two purposively selected sites: Lusaka, representing an urban setting, and Mumbwa, representing a rural setting. These sites were selected as Ministry of Health pilot districts for integration of mental health into primary health care as well as for the purpose of representation of rural and urban scenarios. A total of 111 participants drawn from health facilities in the mentioned areas took part in the survey. Purposive sampling technique was used to select participants. Health workers from Out-Patients departments were selected because they see all incoming patients and refer them to respective departments depending on the patient's condition.Participants were recruited from more than half the number of health centres in Lusaka. In Mumbwa they were recruited from health centres that were accessible. However, the health centres and clinics that participated were typical of all clinics in the sense that they are government financed and supervised health centres, and being served through the same basic health care package. The clinics also recruit categories of staff with similar levels of qualifications and training. In addition, almost all the health centres in Lusaka are placed in low density areas catering for similar characteristics of the population. The same applies to the rural health centres. Therefore the sample was representative of the districts from which participants were drawn. The data were collected between March and April 2009.The quantitative data were entered into the excel data entry programme where numeric data were aggregated. Descriptive statistical analyses of relevant items were conducted.The qualitative data were analysed using thematic analysis informed by Braun and Clarke  in orderPermission to conduct this study was obtained from the Ministry of Health Directory of public health and research, and the District Directors of Health for the respective districts. Detailed information was provided to participants concerning participation and the consequence of the study. Participation was voluntary, and informed consent was obtained. For the purpose of anonymity, participants' names were omitted from the questionnaire.One hundred and one participants were took part in the survey. The age ranged between 19 and 65 years with the majority (41.4%) of them aged between 35 and 45 years. All participants were health care providers working in out-patients departments. Their work experience ranged from the newly graduated to those almost reached their retirement.Table The results revealed a high degree of favorable attitudes towards the proposed integration of mental health into primary health care. As indicated in table The reasons different respondents gave for why mental health should be integrated into primary health care can be categorized into three main themes: Better detection and management of mental health problems; stigma reduction; and human rights.\"early intervention\", \"early detection\" and that \"Early diagnosis of mental illness patients will be facilitated\" .A key theme advanced by most of the participants that supported integration was that integration of mental health services into primary health care will facilitate early detection of mental health problems and prevent complications. Many respondents indicated that integration would aid It was indicated further by many health care providers that many people avoid or delay seeking care and treatment at Chainama, the main mental hospital, as the institution is a major source of stigma. It was indicated that people with mental disorders would be more willing to access care and treatment at primary health care clinics, which do not have the same negative connotations attached:'Mental illness will not be let to reach advanced stage since early detection and treatment will be effected by both health facility and community, since some family members fear/avoid being associated with Chainama Hospital and end up delaying seeking attention' .Similarly, another health care provider indicated:'People usually have a negative perception about Chainama and mostly people don't even go there if they are referred from health centres so by bringing this service nearer to their community and also being treated in the same facility just like any other patient, then people can be willing to get treatment from the centres without being stigmatized and discriminated against. Other problem can be identified apart from mental illness'.As alluded to in this last remark, integration of mental health with primary health care would also improve the general health care of persons with mental disorders.Many participants also indicated that integration would facilitate the detection and management of mental disorders as mental health care would be brought closer to the communities. Numerous health care providers highlighted that many people have to travel long distances, and incur great costs to seek care at Chainama mental hospital. This was particularly emphasized by health care providers in rural areas. It was argued that mental health care would be more accessible and available if it was integrated into primary health care:'It will enable the mentally ill to receive care within easy reach in our community and lessen the cost of transport to other institutions like Chainama'.In addition, it was indicated that mental health workers are in short supply in comparison with other types of health workers. It was thus suggested that integration would mean that there would be many more staff available for the management and treatment of mental disorders, as general health care workers would be able to attend to patients. This was most aptly revealed by the following two statements:'All health care providers would receive training and will be ready to handle mental illness cases in the community and at health centre level, so there would be many more staff available' and'Patients will be receiving professional case management from all health workers'.The rationale behind this was summarised by one participant as follows:'Primary health care system is the only health framework can bring health as close as possible to the communities'.less congestion at Chainama Hospital\" as \"'People with simple mental illness could be handled within the clinic instead of sending them to Chainama'.There was also widespread agreement that integration would aid better detection and management of mental health problems because less people would go to Chainama mental hospital, and Chainama would be less congested and overcrowded. This would ensure that those patients who are admitted to the main mental hospital, would receive better and more comprehensive care. Many respondents indicated that integration will create \"once integrated they come out of stigma\" and integration would \"lessen stigma\") and \"reduce negative attitudes\". It was suggested that stigma would be reduced because people would start to \"regard mental illness as a disease like any other because they would be treated in the same facility just like any other patient\". Furthermore, one respondent indicated:The issue of stigma and discrimination appeared to be prominent in many participants' responses around integration of mental health into primary health care. Numerous respondents who supported integration stated that stigma would be reduced if people with mental health problems were treated at primary health care units. It was not uncommon to hear statements such as \"'The community attitude will gradually change as they see mental patients are cared for and recover, rather than being locked away'.Many respondents shared this view that stigma would be reduced as many people would be able to receive care within their communities, rather than being institutionalized far away in Chainama.Numerous participants stated that the government has made a clear commitment to providing health care to the population at the primary health care level. Some respondents said that over and above the benefits of integration, people with mental health problems possess an intrinsic right to treatment at this level of care, just like any other person seeking help for a health problem. They thought that integration of mental health at primary health care level would serve to uphold the human rights that people with mental health problems are thus equally entitled to. As one respondent indicated when stating that he supported integration:'Because mentally ill patients like any other patients deserve treatment and care from the primary health care system, in health centres'.This view was shared by another health care worker who stipulated:'The patients are all important and need equal rights and attention as early as primary care level'.\"right to receive care at the primary level\", and the \"right to care without segregation\".Indeed, many respondents spoke about how people with mental disorders have the Although respondents who were against integration were not asked directly why they held such attitudes, some of the reasons could be hypothesized based on respondents responses to other questions such as the one asking about the importance participants attached to integrating mental health into primary health care. As such, it seems that fear and negative attitudes towards people with mental disorders may underlie some health care providers reservations regarding integration. Table It thus seems that such attitudes may be informing certain reservations around potential integration between mental health and primary health care.There was widespread agreement amongst respondents that better integration of mental health into primary health care required increased training in the identification and management of mental disorders. Responses are shown in Table It was indicated that a lot of mental health problems currently go undiagnosed at the primary health care level because of inadequate knowledge and skills to identify and treat mental health problems. As one respondent indicated:'Most cases go unidentified and undiagnosed, so training in mental health at the primary level is long overdue'.It was indicated that training would equip general health care workers with necessary skills to manage cases of mental illness appropriately. The rural population indicated that training in mental health would also prevent them from referring uncomplicated cases to Chainama hospital. As the following remark indicates:'Training will equip us to manage mental illness cases at clinic level and give adequate support'.This study explored integration of mental health into primary health care from the perspective of health care providers in two districts in Zambia. It documents their attitudes towards integrating mental health into primary health care, as well as some of the possible reasons for such attitudes. It also highlights health care providers' recommendations regarding integration. One of the key barriers around integrating mental health into primary health care that has been identified is that the views and concerns of health care providers around integration have not been fully taken into account . This stThe results revealed a general willingness amongst health workers to have mental health added to their list of care responsibilities, and integrated with primary health care. A multitude of reasons were highlighted as to why integration would be beneficial. These included improving the detection and management of mental health problems as people would be more willing to access care, care would be brought closer to the communities, there would be more human resources and Chainama would be less congested. Furthermore, it was indicated that integration would help reduce the stigma surrounding mental illness, as people would receive care in the same facilities as other patients, rather than being institutionalized. Finally, some respondents indicated that integration was a human right for people with mental disorders.Integrating mental health into primary health care has been shown to improve the diagnosis of mental disorders and uptake of treatment, as health care at the primary level is generally more accessible, available and less stigmatizing . FurtherHowever, while most respondents favoured integration, most also said that people with mental health problems should not be treated in the same health centre as general patients. Although it was not explored fully, it seems that resistance to integration may stem from the fear and negative attitudes some health care providers may have towards mentally ill persons. Indeed, fear and stigma, which are common amongst general health care providers -25, haveThe World Health Organisation has been encouraging nations to have a deliberate policy to integrate mental health into primary health care since the Alma Ata International Conference on Primary Health Care in 1978. Despite the numerous health sector reforms that have taken place in Zambia that have been situated within a primary health care philosophy, mental health has been largely overlooked in these reforms. Indeed, the Zambian health service's priority is placed on communicable diseases, at the expense of non-communicable diseases. Jenkins and Stratdee  emphasizIt is with the above background in mind that the present study suggests restructuring of mental health services through its integration into primary health care and involvement of the community in the management of mental health problems and promotion of mental health . ResearcBearing in mind the commitment by government contained in the Zambian mental health policy  that menThe recommendations of this study are consistent with Orley and Sartorius'  suggestiIn this way, the health system would be upholding the holistic concept and person centred approach to care that WHO has recommended in its mental health programmes. Given the current inadequacy in human resource in Zambia in general and at primary health care level in particular, it is appropriate to build capacity so that people with mental health problems can be seen and cared for by health care providers who are not specialised in mental health but have basic knowledge and skills.It is thus clear that in principle, primary health care workers in Zambia appear to support integration of mental health into primary health care, but many still have stigmatising attitudes towards the mentally ill. Consequently, further work is needed, not only in the provision of clinical skills, but also in providing education to change attitudes and beliefs. Integrating mental health into primary health care is however ultimately going to require increased consensus, commitment and political will within government to place mental health on the national agenda and secure funding for the sector. This is essential if the country is to realize the many of the ideals enshrined in the progressive health reforms undertaken over the last decade. As indicated by the World Health Organization, ultimately, there is \"no health without mental health\" .The authors declare that they have no competing interests.AF and CL conceived of the study, and participated in its design and coordination and helped to draft the manuscript. LW and SC drafted the manuscript. AS, AK and AS were involved in revising the manuscript critically for important intellectual content. All authors read and approved the final manuscript."}
+{"text": "We were very interested to read the article by The potential carcinogenic risk of nano-materials that are structurally similar to asbestos and have been used in many industrial fields in the last few years has been highlighted by In addition to mesothelioma  or lung cancer, asbestos can cause other types of cancer. On the basis of our clinical experience, we hypothesize that at least a portion of bile ducts cancers  are caused by exposure to this known carcinogenic agent.From 2002 to 2008 we treated 258 patients with cholangiocarcinoma at our institute. Over the previous year, we carefully interviewed 66 consecutive patients using a standardized questionnaire asking about their exposure to asbestos and other known risk factors linked to bile duct carcino genesis . We collAsbestos fibers cause cancer through chronic inflammation, amplifying the production of oxygen radicals, cytokines, growth factors, and proinflammatory factors responsible for both impaired antioxidant and control cell proliferation and apoptosis mechanisms in target cells . In contThe putative increased risk of bile duct cancer in subjects exposed to asbestos may be due to different mechanisms. The asbestos fibers cross the alveolar barrier by inhalation or penetrate the gastrointestinal mucosa by ingestion. They then reach the interstitial environment and circulatory system through lymphatic vessels and are finally delivered to all tissues, namely the liver and bile ducts , where tIn the near future we may have to consider asbestos as another factor accounting for the etiopathogenesis of cholangiocarcinomas that may explain the otherwise mysterious increasing incidence of intrahepatic cholangio carcinomas in Western countries."}
+{"text": "Constuction of the obturator prostheses and providing the patient's comfort with them are very difficult. Primary and the most important stage for these prostheses is to perform a proper impression.A 55-year-old edentulous Turkish female patient with a congenitally maxillary defect was rehabilitated with an open hollow obturator prosthesis. After the preliminary impression was completed, a metal frame suitable with the maxillary defect was constructed manually and used for making the impression of the defect area. After the first part of the obturator was finished, second part which separates nasal cavity and oral cavity was constructed by the aid of the bulb.When constructing an obturator prosthesis, making a detailed impression from the defect area can be performed by the aid of a metal frame, and an intraorally shaped extension that separates oral cavity from nasal cavity might be more effective for adaptation of the prosthesis. Maxillary defects can be sourced by congenital malformations or the acquired defects resulting from surgeries . The maxThis clinical report describes the prosthetic rehabilitation of an edentulous patient with congenital maxillary defect with an obturator made by a modified technique to restore the defect and separate the oral and nasal cavities from each other.A 55-year-old edentulous Turkish female patient was referred to the Department of Prosthetic Dentistry in Karadeniz Technical University for examination and treatment. The patient had a history of congenital palatal defect with an opening between oral and nasal cavities. Detailed case history revealed that the oronasal opening was present since year of birth and the defect was not treated surgically. The patient's major complaint was being edentulous after looosing her natural teeth because of periodontal diseases. She had never had obturator prosthesis until she lost her last teeth. Construction of obturator prosthesis was decided for the rehabilitation of the patient after clinical examination.Local anesthetic spray  was used for the palatal and post palatal region before making the impression. A tampon covered with Vaseline and anesthetic solution was placed in the defect cavity to protect the area from the residual impression material Figure  It was tThe prosthetic rehabilitation of an edentulous patient with congenital maxillary defect with an obturator has some difficulties at the stages of impression and construction. Even the defect area is filled with a tampon before the impression, protecting the soft tissues from the residual impression materials and making a detailed impression is not easy. In this respect, recording the tissue borders with modeling wax around a metal frame intraorally may be more protective and still an effective method. Separating nasal and oral cavities from each other helps to form speech voices better and to protect nasal cavity from the food escape during chewing, and swallowing. Constructing a second part which extends to the palatal defect cavity on previously constructed bulb using an intraorally shaped modeling wax, helps the second part to cover the defect area without any damage to the soft tissues even during the functional movements. Fabricating method of this open hollow obturator provides better initial record base retention, which is also compatible with the oral tissues. And the design of this obturator prosthesis has also some advantages as: better phonation and protection of food escape to nasal cavity.Fabricating a successful obturator prosthesis used for the prosthetic rehabilitation of congenital or acquired defects in maxilla depends on making a detailed impression and constructing the prosthetic parts compatible with the oral tissues. This clinical report describes an intraoral technique for impression making and fabrication of open hollow obturator prosthesis.The authors declare that they have no competing interests.BB performed for the case and prepared the manuscript. EA helped at the some steps of constructing the prosthesis and to draft the manuscript. UH supervised the case and reviewed the manuscript. All authors read and approved the final manuscript.Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal."}
+{"text": "The report contrasts the ascertainment of cases by the regional cancer registry with a specially designed search for records and pathology material which was then submitted to critical review irrespective of the original diagnosis. Boundary changes over the intervening years were accounted for and the results contrasted between time periods and with the cancer registry records. A large proportion of cancer registry cases were never subjected to histopathological diagnosis and comparisons between the new data and records are not easy to undertake. The study describes a probable true rise in the incidence of follicular non-Hodgkin's lymphoma in certain parts of Yorkshire over the last 20 years; there is less evidence of a similar change in Hodgkin's disease incidence over the same period of time."}
+{"text": "The recognition of genital chlamydial infection as an important public health problem was made first by the recognition of its role in acute clinical syndromes, as well as in serious reproductive and ocular complications, and secondly by our awareness of its prevalence when diagnostic tests became widely accessible. The recent availability of effective single dose oral antimicrobial therapy and sensitive molecular amplification tests that allow the use of noninvasive specimens for diagnosis and screening is expected to have a major impact in reducing the prevalence of disease in the next decade. Clinical manifestations associated with Chlamydia pneumoniae infection continue to emerge beyond respiratory illness. In particular, its association with atherosclerosis deserves further investigation. Chlamydia pecorum, a pathogen of ruminants, was recently recognized as a new species. The continued application of molecular techniques will likely elucidate an expanding role for chlamydiae in human and animal diseases, delineate the phylogenetic relationships among chlamydial species and within the eubacteria domain, and provide tools for detection and control of chlamydial infections."}
+{"text": "The inability to assess the extent of tumour damage immediately following treatment is a major clinical obstacle to improving the management of cancer patients. Normally, the effectiveness of chemotherapy or radiation therapy cannot be determined for at least several weeks after treatment. We studied the increase in mRNA of the growth arrest and DNA damage-inducible gene GADD153 in human 2008 ovarian carcinoma cells in vitro and in vivo to determine whether treatment-induced increases in the level of GADD153 mRNA could be used as a marker of the extent of tumour damage. GADD153 mRNA was increased in a transient, dose-dependent manner by cisplatin (DDP) when the tumour cells were grown both in vitro and as tumour xenografts in nude mice. The magnitude of induction of GADD153 mRNA did not vary significantly between different 2008 xenografts treated with equal doses of DDP, and GADD153 mRNA induction correlated with the degree of in vitro cytotoxicity for two different schedules of drug exposure. DDP increased GADD153 mRNA levels in melanoma and head and neck xenograft models as well. We conclude that the increase in GADD153 mRNA can be used to detect tumour injury at time points as short as 24 h after administration of DDP."}
+{"text": "This issue of the MEAJO journal mainly containing original and educational articles on uveitis is compiled from the uveitis course and symposium organised during the last MEACO meeting in Bahrain in March 2009 by the Society for Ophthalmo-Immunoinfectiology in Europe (SOIE). Although the course was held on the last day of the meeting and consisted of a full day course, sustained attendance indicated that considerable interest exists in the Middle-East for uveitis. Together with Ahmed Abu El Asrar, the local organiser of the SOIE course and Deepak P. Edward, the Chief-Editor of MEAJO, we decided to publish a theme based issue on uveitis.SOIE is an association oriented towards educational activities in the field of uveitis in Europe but is also organising activities beyond Europe, especially in the Middle East and North Africa. The society has organized educational courses in Saudi Arabia in 2005 and 2008 and in Bahrain in 2009. SOIE symposia were held in Krakau, Poland in 2007, in Ancona, Italy in 2008, in Cappadoccia, Turkey in 2008 as well as in Tunisia in November 2009, with significant attendance at each venue. Our group is willing to collaborate with any local partner to organise courses or symposia on uveitis. We are interested in working interactively and exchange information with the local organisers and ophthalmologists and provide educational content on the practical aspects of uveitis taking into account local specificities. We are open to all viable propositions to promote the recognition and management of uveitis and ophthalmic infectious disease.For this MEAJO issue, the instructors of the SOIE Bahrain course were asked to contribute articles either on original ongoing uveitis research or to summarize their course presentations for didactic and educational purposes in a manuscript. A significant number of instructors made contributions so that an attractive theme oriented issue on uveitis could be produced.In his tutorial article on the differential diagnosis of anterior uveitis Carl P. Herbort gives a practical method for the appraisal and work-up of anterior uveitis based on clinical examination. He emphasizes the simplicity of the diagnostic steps of uveitis cases as long as investigations are based on clinical signs and not on random endless lists that are published in uveitis textbooks.The article on angiography in uveitis puts forward a comprehensive approach of angiographic investigation indicating the need for dual fluorescein and indocyanine green angiography (ICGA) in most cases where performing angiography is deemed necessary. By demonstrating lesions not shown by any other means, ICGA shows its pre-eminence over fluorescein angiography that merely gives more precision on superficial fundus lesions and RPE changes usually already identified by fundus observation, optical coherence tomography or other means.The two articles by Professor Ahmed Abu El Asrar and his group from Riyadh touch upon two important topics in uveitis. The first article has the merit to reassess the role of tuberculosis in present day uveitis. The second article is gives an excellent summary on the difficult clinical question of retinal vasculitis. The article includes a practical approach to the diagnosis of retinal vasculitis and provides precious information for the clinician.Who better than Professor Ilknur Tugal-Tutkun from Istanbul University could write a review article on Beh\u00e7et's uveitis? This reknowned specialist who is recognized globally for her expertise in ocular Beh\u00e7et's disease has put all her experience and expertise to give an overview on what the clinician should know about Beh\u00e7et's uveitis. In this article the author also presents the latest developments in the management of Beh\u00e7et's uveitis including laser flare photometry which has become an essential tool for non invasive follow-up of intraocular inflammation in most uveitis entities.We have the opportunity to publish a very important and interesting review article on emergent causes of infectious uveitis; thanks to Professor Khairallah from Monastir University in Tunisia who has been at the origin of several reports on emerging agents causing uveitis. He certainly is the most appropriate person to write this report on rare and unknown etiologies of uveitis which should nevertheless be known by all practicing ophthalmologists in this era of increased travel and migration.The last review article relates to inflammatory choroidal neovascularization, a complication of uveitis which is of rare occurence but that however has devastating consequences on visual function. Piergiorgio Neri, being both a specialist in medical retina as well as in uveitis, the review he and his team are presenting here is based on a very longstanding experience in the management of this feared complication of uveitis. So far treatment has been unsatisfactory but the availability of intra-vitreal anti-VEGF therapies seems to have drastically changed the outcome of inflammatory CNV although this statement still relies on an accumulation of cases as the authors indicate. In such rare diseases however, where controlled studies are impossible, medical treatment should be based on common sense which in this case points to the use of anti-VEGF treatment.The theme based part of this issue is completed by an original article on Fuch's uveitis, the publication of which is especially appropriate in the MEAJO journal, as the readership mainly comes from areas where irises are predominantly brown. This article indicates that heterochromia should not be considered as a preponderant feature. Indeed in brown iris geographical areas heterochromia will rarely be seen and iris texture changes should be evaluated instead. The authors therefore recommend abandoning the term Fuch's heterochromic cyclitis and to resort to the simple eponym of Fuchs' uveitis. The main message of this article however is the importance and relevance of posterior segment involvement that has been scotomized in the last decades although it was clearly described in Ernst Fuchs' initial reports. The failure to associate posterior signs such as vitritis with Fuchs' uveitis was identified as the single most important reason for misdiagnosis or delay in the diagnosis of Fuchs' uveitis.It is always a great pleasure for the SOIE to collaborate with our colleagues from the Middle-East where several successful projects have been conducted so far. We hope that the present project resulting in this theme based issue will be appreciated and are looking forward to future collaborations and projects."}
+{"text": "The following information was omitted from the funding statement: This study was supported by NIH grants NS39089 and NS35962 to NS and MSMT CR grants LC06044 and 002162080 to JP and DV."}
+{"text": "The intensifying pressure on reducing the development time for new pharmaceutical products is resulting in an increasing need for laboratory automation. A key element for the successful implementationof robotics for drug product analysis is the establishment of a reliable process for interaction of the automation team with its various customers, for example development product team and manufacturing group. The reduction of cycle time for product development appears to be resulting in more stability studies to support NDA/MAA filings for several reasons. Key clinical information may not be available before initiation of the stability studies and simultaneous world-wide development may result in an increase in the number of product strength and pack options."}
+{"text": "Percutaneous Transvenous Mitral Annuloplasty for mitral regurgitation is in early stages of development and involves a complex intervention which can not be done in patients with left ventricular leads. Since functional mitral regurgitation is common in low ejection fraction states, we propose a device which can serve for annuloplasty in addition to cardiac resynchronization therapy and simplifying the intervention. Treatment of dilated cardiomyopathy has evolved considerably over years leading to marked improvement in quality of life and survival. This has been possible by intervening at the various biochemical, hemodynamic and electrical abnormalities by drugs and  use of  various devices. The role of cardiac resynchronization therapy (CRT) is an established one resulting in improvement in quality of life and survival and lately studies have shown  its benefit even in patients with  moderate fall in ejection fraction.One important accompaniment of dilated heart is functional mitral regurgitation secondary to mitral annular dilatation, apical displacement of papillary muscles and reduced transmitral closure force  secondary to LV systolic dysfunction.Cardiac resynchronization therapy helps by synchronizing the contractions of the postero-lateral wall and the interventricular septum and thereby improving the ejection fraction and by decreasing the functional mitral regurgitation by its presumed effect of synchronizing the motion of two papillary muscles and increasing transmitral closure force.Percutaneous  transvenous mitral  annuloplasty (PTMA) for ischemic or functional mitral regurgitation is in its evolution. The procedure involves cannulation of coronary sinus via subclavian or internal jugular  vein and delivering  a hemispherical  structure from coronary sinus ostium posteriorly to the anerior interventricular branch of the  great cardiac vein anteriorly. As the coronary sinus  forms  the lateral half of the mitral annulus, the device alters  the geometry of the mitral annulus  thereby causing better apposition of two valve cusps  and decreasing mitral regurgitation. Three such devices under investigation include Viacor PTMA device, CARILLON contour system and MONARC (previously VIKING) PTMA system all utilizing the various modifications of the same principle. These PTMA devices cannot be placed in patients who have coronary sinus leads of CRT devices. Since low ejection fraction states are usually associated with functional mitral regurgitation hence to produce a device which can address both issues seems compelling.Although the left ventricular leads of CRT devices are soft and may not significantly bring about conformational changes in the mitral annulus, part of reduction of mitral regurgitation can be expected by left ventricular lead especially once the lead is distally nicely fixed and under some tension. However  left ventricular lead is placed in the  lateral most  vein  which may include  only one fourth of the mitral annulus. If  left ventricular lead is modified in such a way that it is rendered  stiff in its distal part and part of the stiff end projects anteriorly upto anterior interventricular groove  it can serve as well for annuloplasty in addition to CRT. Otherwise a stiff  annuloplasty hemisphere can be delivered over the left ventricular lead hence simplifying the procedure and simultaneously addressing both issues."}
+{"text": "Sir,We thank Dr Chaouachi for his interest in our study. Dr Chaouachi suggests that the association of hookah and oesophageal cancer observed in our study ("}
+{"text": "Growth curve measurements on the EMT6 tumour following treatment with cyclophosphamide indicate a growth delay of about 3 days for each 100 mg/kg of the drug. Tumours treated whilst still microscopic show a rather longer delay for the same dose. Data for the surviving fraction of cells in the tumours measured by in vitro plating at 2 h after cyclophosphamide are not compatible with the measured growth delay and realistic values for the doubling times of surviving clonogenic cells; It is concluded that there is considerable \"repair of potentially lethal damage\", and that there is probably no single time after cyclophosphamide treatment at which the surviving fraction of cells can be correctly measured by the in vitro plating technique. Cell loss from cyclophosphamide-treated tumours is increased only slightly over that from untreated tumours, and the regeneration of surviving cells is very rapid. In this situation, only marginal regressions in tumour volume are caused by the highest doses of the drug."}
+{"text": "The recurrent synaptic activity may arise in a negative feedback loop between a bipolar cell and an amacrine cell that exhibits resonant behavior and oscillations in membrane potential when the normal balance between excitation and inhibition is disrupted by the absence of photoreceptor input.Here we review evidence that loss of photoreceptors due to degenerative retinal disease causes an increase in the rate of spontaneous ganglion spike discharge. Information about persistent spike activity is important since it is expected to add noise to the communication between the eye and the brain and thus impact the design and effective use of retinal prosthetics for restoring visual function in patients blinded by disease. Patch-clamp recordings from identified types of ON and OFF retinal ganglion cells in the adult (36\u2013210 d old)  Retinitis pigmentosa (RP) refers to a number of related diseases that result in the death of rod and cone photoreceptors causing blindness in about one in 3,500 people, nearly 2 million people worldwide. Not surprisingly, PubMed lists more than 7,000 papers on RP that provide an abundant source of information about the genetic, biochemical, physiological, and therapeutic characteristics of the disease. The goal of much recent work on RP has been to develop methods to restore vision by resuscitating the retina using gene therapy to repair the mutation that gives rise to the dystrophy  or by drrd1 mice that was not present in normal animals. The patterned spike activity was reversibly abolished by temporarily occluding blood flow to the eye, providing evidence of its retinal origin. The frequency of the persistent discharge was dependent on the anesthetic and ranged between 9\u201314\u2009Hz. These findings were confirmed subsequently using autocorrelgrams to demonstrate the rhythmicity of maintained spike activity in units recorded from the SC in dystrophic but not nondystrophic Royal College of Surgeons (RCS) rats [c-fos-like immunoreactivity in the superior colliculus and lateral geniculate nucleus in rd1 mice and RCS rats that is eliminated by intraocular injection of TTX or optic nerve transection [c-fos expression was attributed to the generation of rhythmic input from retinal ganglion cells. Out of the several thousand publications on RP, less than a dozen have addressed questions about the effects of retinal degeneration on RGC firing properties. The responses of individual cells cannot be evaluated using the electroretinogram (ERG), which is the widely employed standard method for assessing the functional changes in the retina resulting from loss of photoreceptor input. An early study by Drager and Hubel  based onCS) rats . There ansection , 19. Therd1 mouse [The changes in RGC spike activity during the progression of photoreceptor degeneration has been documented more directly using extracellular single RGC recording in the RCS rat  as well d1 mouse  and the d1 mouse . In agred1 mouse , 21 in ad1 mouse . Taken tIt is important to understand the properties of the ongoing spike activity that is present in RP because it represents an undesirable noise source that degrades the communication between the eye and the brain that the aforementioned strategies to restore vision in patients blinded by degenerative disease depend upon. Here we review experiments designed to investigate the cellular mechanisms responsible for the increase in maintained spike activity and explore the retinal circuitry that may give rise to it.rd1 retina [\u03bcm)\u2014which, by virtue of their large size, are referred to here as alpha cells [To determine whether RGC hyperactivity was caused by changes in the intrinsic properties of RGCs, such as ion channel function or distribution, or by altered synaptic input, intracellular recording was used to study the effect of photoreceptor loss on the electrophysiological properties of selected types of ganglion cells in 1 retina . RGCs wiha cells \u2014were tarha cells  were useha cells . The useha cells , 26.rd1 alpha RGS retained the characteristic differences in the weights of excitatory and inhibitory synaptic inputs that ON and OFF cell types receive. They also continued to generate rebound excitation in OFF cells and gave rise to voltage-evoked dendrite calcium signals that were similar to those recorded from the dendrites of RGCs in non-dystrophic retina [rd1 alpha RGC activity are triggered by oscillatory synaptic inputs as shown by the fact that they persist under voltage clamp recording conditions and are eliminated by CNQX, a glutamatergic blocker (Unlike ganglion cells from normal animals, which generate resting spike activity with no obvious temporal periodicity, the rate of spontaneous spike discharge in alpha RGCs from animals blinded by degeneration is increased and consists of continuous rhythmic bursts of spikes  with a bc retina . The rhy blocker .rd1 ON and OFF RGCs retain their normal distinguishing differences in the strengths of the excitatory and inhibitory inputs they receive, in spite of the ongoing oscillations in maintained synaptic activation, suggests that the organization and distribution of RGC contacts with presynaptic neurons have not been remodeled. The extensive changes in retina morphology that have been reported in this and other models of RP [rd1 animals where it appears that functional changes have occurred but massive remodeling of the inner retina has not taken place.The presynaptic source of the synaptic inputs that give rise to rhythmic firing is not known. That ls of RP , 29 emerls of RP . While trd1 retina show no evidence of having intrinsic pacemaker activity that gives rise to spontaneous fluctuations in membrane potential [Single cell recordings from bipolar cells isolated from dissociated otential . This inotential . This isotential , wide fiotential  and dopaotential , 35 amacrd1 retina, it might be expected that oscillations in spike discharge would not be confined to local spatial areas, but would instead be rather widespread. Stasheff [\u03bcm spacing of the electrode array that the study made use of.This hypothesized mechanism for oscillatory spike discharge could be tested by recording from bipolar cells in an intact dystrophic retina to determine if rhythmic changes in membrane voltage are present and sensitive to inhibitory synaptic blockade. Note that the proposed circuit cannot be rejected solely on the basis of finding no evidence of periodic fluctuations in baseline voltage in recordings from bipolar cells in retinal slices . In suchStasheff , howeverIn the proposed circuit the oscillations that give rise to rhythmic RGC spike discharge originate in an unidentified amacrine cell as a result of photoreceptor death and deafferentation. In this scenario, it is the loss of photoreceptor synaptic input that unbalances the circuitry of the normal retina and in so doing exposes the resonant membrane properties of an amacrine cell that is normally held in check in the functionally intact retina. Resonance is a consequence of the interactions between the active and passive membrane properties of a cell  that effrd1 mice were also present in single unit recordings in the visual cortex. Thus it is likely that the increased level of spontaneous activity that has been described in animals models of RP is also be present in patients with degenerative retinal disease and may participate in the generation of the phantom visual images that are reported by some RP patients [rd1-modified CNS circuitry gives rise to discontinuous visual sensations. In any case uncontrolled spontaneous spike activity would be expected to degrade the action potential encoded messages RGCs send to the brain and thus hinder attempts to restore vision using electrical or optical prosthetics designed to directly evoke RGC spike trains that the brain can interpret as meaningful visual information. The RP retina retains functional connections with the brain as shown originally by Drager and Hubel  who founpatients \u201341. ThesResearch designed to evaluate the treatment of RP using electronic or optical retinal prosthetics has not considered the influence that increased spontaneous RGC spike discharge might have on the successful use of prosthetics. While electrical stimulation of the retina in blind subjects can evoke the sensation of light and provide a rudimentary means of detecting motion, it has not been possible to use this approach to elicit the complex pattern percepts that are associated with more robust visual function . Whether"}
+{"text": "Dear Sir,et al.,[I read with interest the recent case report submitted by Bhartia et al., which deet al., While thet al.,With their report, the authors added to the growing number of reports of patients with right paraduodenal hernia managed safely and effectively using a laparoscopic technique and reminded the astute surgeon to expedite diagnosis and possibly shorten length of stay in the hospital by entertaining the diagnosis of paraduodenal hernia. This is particularly true in adults who present with acute symptoms associated with small-bowel obstruction. For surgeons with significant experience in minimally invasive techniques, physical examination and abdominal radiographs followed by diagnostic laparoscopy and definitive laparoscopic repair is a viable option for patients with acute and chronic presentation of right paraduodenal hernia."}
+{"text": "It would be interesting to be able to quantify the extent of ROS formation. We investigated if histamine which is present at the inflammation site can serve as an endogenous marker for the formation of OH.. We found that histamine after incubation with OH. gave two distinct products in our HPLC system. One of the products gave the same characteristics as the synthesized 2-imidazolone derivative of histamine. This suggests that this derivative will be formed when histamine is incubated with OH..During inflammation an influx of neutrophils and release of mediators from mast cells (such as histamine) take place. The stimulated neutrophils can produce reactive oxygen species (ROS). One of these ROS is the highly reactive hydroxyl radical (OH"}
+{"text": "Intensity Modulated Radiation Therapy (IMRT) is a means of delivering radiation therapy where the intensity of the beam is varied within the treatment field. This is done by dividing a large beam into many small beamlets. Dose constraints are assigned to both the target and sensitive structures and computerised inverse optimization is performed to find the individual weights of this large number of beamlets. The computer adjusts the intensities of these beamlets according to the required planning dose objectives. The optimized intensity patterns are then decomposed into a series of deliverable multi leaf collimator (MLC) shapes in the sequencing step.One of the main problems of IMRT, which becomes even more apparent as the complexity of the IMRT plan increases, is the dramatic increase in the number of Monitor Units (MU) required to deliver a fractionated treatment. The difficulty with this increase in MU is its association with increased treatment times and a greater leakage of radiation from the MLCs increasing the total body dose and the risk of secondary cancers in patients. Therefore one attempts to find ways of reducing these MU without compromising plan quality.The design of inverse planning systems where the beam is divided into small beamlets to produce the required intensity map automatically introduces complexity into IMRT treatment planning. Plan complexity is associated with many negative factors such as dosimetric uncertainty and delivery issues A large search space is required necessitating much computing power. However, the limitations of the delivery technology are not taken into consideration when designing the ideal intensity map therefore a further step termed the sequencing step is required to convert the ideal intensity map into a deliverable one.Many approaches have been taken to reduce the complexity. These include setting intensity limits, putting penalties on the cost function and using smoothing filters Direct Aperture optimization (DAO) incorporates the limitations of the delivery technology at the initial design of the intensity map thereby eliminating the sequencing step. It also gives control over the number of segments and hence control over the complexity of the plan although the design of the segments is independent of the person preparing the plan. Intensity Modulated Radiation Therapy (IMRT) is an advanced form of 3D radiotherapy. The non-intuitive nature of IMRT planning can sometimes lead to very complex plans. This review highlights the difficulties of overly complex plans and evaluates Direct Aperture Optimization (DAO) as a potential means of reducing this complexity.Intensity Modulated Radiation therapy (IMRT) is a means of delivering radiation therapy where the intensity of the beam is varied within the treatment field. It is an advanced form of 3D conformal radiotherapy (3DCRT) which allows for more precise shaping of dose to the target and reduced dose to normal tissues. For example, in a study of 57 nasopharyngeal patients. IMRT sta3D conformal radiotherapy is forward planned requiring the expertise of the planner to decide on the weights, beam orientation, use of wedges or compensators to achieve the desired dose distribution. IMRT, in contrast, is inverse planned in that the planner inputs the desired tumour dose and dose limits and the computer adjusts the beam intensities to achieve as close as possible to this desired outcome. With inverse planning, the dose distribution is broken up into different beamlets, with the computer tracing each beamlet through the patient producing the initial dose distribution. By altering the weights of individual beamlets the computer can accept these changes if it results in an improved distribution. This process is repeated for all beamlets during a single cycle. This is repeated until no further improvements are seen. At present this computerised process is very lengthy as the adjustments required to produce an acceptable plan are not intuitive as with forward planning.IMRT can be delivered in many different ways; segmental, dynamic, arc or tomotherapy. Segmental IMRT (sIMRT) is where modulated field intensity is achieved by summing all the segments. The radiation is only turned on when the segment is in position, and is often known as step and shoot delivery. Dynamic MLC-IMRT is where the leaves are in continuous motion during each field. Although this method produces a more conformal dose distribution, a larger number of MU are required and there is more leaf transmission increasing the integral dose to normal tissue. As the The complexity of a plan is linked to the rate at which the fluence varies across each field. It is important however to avoid overly complex plans for several reasons.First, IMRT requires more treatment fields than conventional radiotherapy and therefore a larger volume of normal tissue is exposed to low doses of radiation. Second, IMRT treatments are inefficient with respect to the number of MU which are necessary to deliver daily fractional dose leading to an increased leakage exposure. The more complex the intensity patterns, the higher the number of MU will be required to deliver the prescribed dose. It has The increase in the number of monitor units relative to 3DCRT has led to concern about secondary malignancies with IMRT. Depending on the treatment energy IMRT treatments require 3.5\u20134.9 times as many MU to deliver a specified dose as compared to conventional treatments. From thHowever there is much uncertainty in these calculations of risk of secondary malignancies from the increase in MU. In factThe average number of MU per segment becomes very small for complex plans. This maTreatment planning algorithms are less accurate in more complex IMRT treatments. Treatment fields which contain highly modulated intensity regions will be affected by low resolution pencil beam kernels. This was apparent in a study which compared two commercial planning systems. One of the systems not only underestimated the dose of the high intensity peaks by over 13% but it also overestimated the horizontal spread of the dose at the sides of the peak. This inadequacy of this treatment planning system was only relevant in highly modulated fields.High dose rate, multiple beam segments, and low dose per segment have also been associated with the overshoot effect which generally occurs in the first and last beam segments due to the dose servo control system and causes an over and under dosage respectively. It occuIMRT plans can result in hot spots distant from the tumour, from crossing high intensity beamlets. This can be counteracted by drawing 'help structures' at the area of the crossing but this may result in the hot spot appearing elsewhere. A positive side effect of controlling the intensity variation may be that these distal spots are less prevalent.Decreasing the number of cycles in the optimization process has been shown to reduce dose dumping and MU. This maThe intensity distribution for each field is non-intuitive in highly complex plans and the complexity in general may increase the likelihood of human error. For example the verification of anatomical position through traditional imaging becomes difficult for multiple static segments of small size and varying intensity encompassing very little distinctive anatomy. This wilIn addition to the dosimetric uncertainty and less intuitive nature of complex plans there is also increased machine and resource allocation required which may increase treatment times  and thusA limitation in planning IMRT treatments is the time the optimization process takes. This can be reduced by decreasing the search space or number of variables. A common procedure would be to input set gantry angles for this reason. As computing power improves this will be less of an issue, but an important consideration is to use the computer power and time available appropriately. For example it may be more productive to use a more accurate dose calculation algorithm than using computer power calculating very complex plans, which may lead to inaccuracies.IMRT can be forward planned or inverse planned. With forward planned IMRT the beams are first of all shaped to the target volume. Additional beam segments are then added and weightings are distributed between the larger beams and the segments in order to shape the isodose distribution. Forward planning IMRT has been shown to be superior to conventional forward planned tangential techniques in intact breast cancer although it is inferior to inverse planning techniques Aperture-based inverse planning IMRT adopts some of the features of forward planning and incorporates inverse planning into the process. Apertures are designed from the anatomical shape of the targets and conformal apertures are also designed that exclude critical structures. An inverse optimization is then performed to optimise the weights of the apertures within the provided dose constraints. This method therefore is a development of forward planning by using inverse planning software to optimise the weights of individual segments.Direct Aperture optimisation (DAO), sometimes termed Direct Machine Parameter Optimisation, is another IMRT optimisation technique where similarly to aperture based inverse planning the apertures are identified during the planning process. However with this technique the apertures are not selected by considering the anatomical relationship between the target and critical structures. The planner inputs the dose constraints, beam angles, energies and number of apertures. With DAO the planner can also put a constraint on the minimum size of each aperture and place a lower bound on the weight . The ape2. Dose constraints are assigned to the targets and sensitive structures. Computerised inverse optimization must be performed to find the individual weights of this large number of beamlets. The computer adjusts the intensities of these beamlets according to the required planning dose objectives. Plans frequently fail to achieve the desired dose constraints and so clinical decisions have to be made as to which are most important and which can be relaxed. Once the optimal fluence map is decided upon there is a further leaf sequencing step. The optimized intensity patterns are decomposed into a series of deliverable MLC shapes made up of a number of basic beamlets with mathematically related weights/intensities. This typically results in a total number of leaf segments ranging from 60\u2013100 in prostate only IMRT plans[Beamlet based optimization divides a large beam into many small beamlets of about 1 cmMRT plans.In converting the plan from the computer generated solution to deliverable segments, the dose distribution will degrade from that originally decided upon. In comparing beamlet based sIMRT for three commercial inverse planning similar performance was found in all three systems and IMRT plans tended to converge. The main differences in the IMRT plans concerned dose gradients outside the target, MU and segment number; demonstrating the impact of the sequencing step. In anotDAO differs from beamlet based optimization in that it does not rely on the use of a segmentation routine (sequencing step) to select the initial leaf sequence as this step is incorporated into the original optimisation. Therefore with DAO the planner has direct control over the complexity of the IMRT plan. With DAO the treatment plan is optimized using a deliverable treatment solution. This avoids the plan degradation which can occur during the conversion of the ideal intensity map into a deliverable one at the end of optimization. The main purpose of direct aperture optimisation is to reduce the number of segments and MU required to treat a complex arrangement of targets and surrounding structures. The problems with large numbers of segments and high total MU have been discussed earlier.Many of the dosimetric concerns associated with IMRT such as low MU per segment, high overall MU, and dosimetric uncertainties can be improved by controlling plan complexity. Direct aperture optimization is a method of controlling complexity that provides a significant reduction in the number of beam segments and MU required. However it also has the advantage over other methods of complexity reduction in that it eliminates the sequencing step which is associated with plan degradation. Studies which evaluated the use of DAO in the clinical setting are illustrated in table When DAO was compared to 3D conformal radiotherapy, and beamlet based IMRT in 15 breast cancer patients it was found that DAO plans were equal to or better than those generated with 3D-CRT and standard beamlet IMRT. DAO IMRIn another study which compared DAO and beamlet based IMRT plans of 12 breast cancer patients  the doseJones at al. comparedIn a study of 10 hypopharyngeal patients, acting as their own control, no statistically significant difference was found for compliance to the dose volume constraints although the mean dose to the parotid was lower with the beamlet based plans compared to the DAO plans. Dose homogeneity within the PTV was superior for the DAO plans and they also required significantly less MU to deliver .Ludlub et al. comparedThe use of pencil beam algorithms when calculating IMRT treatments can lead to inaccuracies in difficult to calculate treatment geometries. To address this problem, Monte Carlo (MC) simulated dose data can be used with DAO in the optimization step. The optimized plan then undergoes a final dose calculation using MC. This is referred to as a MC DAO plan. This technique would be useful for planning small field IMRT cases for PTVs located within or adjacent to tissue inhomogenities. The optimized DVHs generated by the MC_DAO software are already a faithful representation of the final MC forward calculated doses as there is no leaf sequencing step required.DAO can also be applied with collimator rotation, termed rotating aperture optimisation (RAO). Plans generated with RAO were found to be as good as or better than DAO, while maintaining a smaller number of apertures and MU than beamlet based optimization. RAO is less sensitive to tongue and groove effects than DAO. However delivery time is increased due to the collimator rotation speed.Reducing the complexity of IMRT has been the focus of this review, but it has to be noted that there is a limit to the degree which the complexity of the plan can be reduced before severely affecting plan quality. This was demonstrated in prostate patients where it was found that for DAO plans with 20 segments the conformal indices values dropped drastically when compared to plans with 40 or greater segments confirming the indication for a threshold for the minimum number of segments. It was The smallest width of any aperture is the width of an MLC leaf and the minimum length of any aperture is determined by the minimum step size along the direction of travel of the MLC leaves. The quality of an IMRT plan can be improved by increasing the number of degrees of freedom. Therefore increasing the number of apertures per beam should improve plan quality. Reducing the step size from 10 mm to 1 mm demonstrated continuous improvements in the objective function value and led to steeper dose gradients between the target and critical structures. HoweverOther methods have been suggested to increase delivery efficiency and reduce MU without significantly affecting plan quality. In a study of 9 patients (including head and neck prostate and brain) it was found that by using intensity limits during inverse planning it was possible to reduce the total MU without compromising the clinical acceptability of the plan. MU reductions up to 38% were observed.Matuszak et al. looked aSmoothing parameters as either part of the optimization process or post optimization have been used to reduce the complexity in IMRT. Although those applied post optimization usually result in degradation of the plan quality, it has been shown that a smoother fluence can result in a reduction in dose to the healthy tissue and again that a reduction in fluence complexity is strictly correlated with a reduction in MU. Increasing the smoothing parameter has been shown to have an impact on the accuracy of delivery,30.It is important to reduce the complexity of IMRT plans as much as possible as overly complex plans deliver unnecessarily high MU and excessive radiation leakage. There is also more dosimetric uncertainty associated with highly complex plans as well as increased pressure on resources. Therefore a balance needs to be found between plan complexity and optimal dosimetry. Forward planning provides better dosimetry than 3D but is inferior in general to inverse planning approaches. Aperture based planning takes on some of the elements of forward and inverse planning. DAO differs from aperture based planning in that it is an entirely inverse planned approach which incorporates the restrictions of the treatment machine into the optimisation process. Many approaches have been taken to reducing the complexity of IMRT plans such as setting intensity limits, putting penalties on the cost function and using smoothing filters. DAO incorporates the treatment machine restrictions into the optimisation process thereby eliminating the sequencing step which has been associated with plan degradation. DAO has been associated with a reduction in MU in a number of clinical situations but further research needs to be conducted to establish the optimum number of segments for targets and OARs of varying geometry as it may not be possible to reduce segment number and MUs in the more difficult geometries.Due to increased pressure on resources, dosimetric uncertainties and leakage of radiation, treatment plans with very small fields, low MU per segment and high overall MU are not optimal. It is necessary therefore to look at ways of reducing the complexity of beamlet based IMRT treatment plans. It is also desirable to reduce the discrepancy between the optimal treatment solution and the deliverable treatment solution following segmentation. Many approaches have been taken to addressing these issues. This review discusses the potential role of DAO in attempting to reduce the number of field segments while achieving a similar dose distribution.IMRT: Intensity Modulated Radiation Therapy; MLC: Multi leaf collimator; MU: Monitor Units; DAO: Direct Aperture optimization; 3DCRT: 3D conformal radiation therapy; sIMRT: segmental IMRT; sMLC: static MLC; TLD: thermo luminescent dosimeters; MC: Monte Carlo; RAO: Rotating Aperture optinization; OAR: Organ at riskThe authors declare that they have no competing interests.MB conceived and drafted the manuscript. ML critically reviewed/revised the article. MC drafted the abstract. All authors read and approved the final manuscript."}
+{"text": "The occurrence of organ-specific antigens on the surface of cells freshly isolated from normal adult rat liver and from liver cell lines cultured as monolayers for up to 6 months is demonstrated. Enzyme treatment used to disaggregate parenchymal cells from liver tissue did not result in appreciable changes in the antigen profile of the cell surface membrane."}
+{"text": "Incompleteness of ascertainment of new cases of any disease leads to underestimation of its incidence rate and may result in false assumptions about incidence trends if incompleteness varies over the course of time . We report an attempt to assess the completeness of ascertainment in a cancer registry in the North-Western Region of England using a method based on independent comparison with accurate morbidity data. A total of 1955 verified cases of cancer from 5 independent sources covering 11 sites were used in the study. The corrected mean level of overall registration completeness was found to be 94% but this varied appreciably with site and source of data. Independent comparison is recommended as an effective method for estimating the completeness of cancer registration."}
+{"text": "Support for family carers is a core function of palliative care. Family meetings are commonly recommended as a useful way for health care professionals to convey information, discuss goals of care and plan care strategies with patients and family carers. Yet it seems there is insufficient research to demonstrate the utlility of family meetings or the best way to conduct them. This study sought to develop multidisciplinary clinical practice guidelines for conducting family meetings in the specialist palliative care setting based on available evidence and consensus based expert opinion.The guidelines were developed via the following methods: (1) A literature review; (2) Conceptual framework; (3) Refinement of the guidelines based on feedback from an expert panel and focus groups with multidisciplinary specialists from three palliative care units and three major teaching hospitals in Melbourne, Australia.The literature review revealed that no comprehensive exploration of the conduct and utility of family meetings in the specialist palliative care setting has occurred. Preliminary clinical guidelines were developed by the research team, based on relevant literature and a conceptual framework informed by: single session therapy, principles of therapeutic communication and models of coping and family consultation. A multidisciplinary expert panel refined the content of the guidelines and the applicability of the guidelines was then assessed via two focus groups of multidisciplinary palliative care specialists. The complete version of the guidelines is presented.Family meetings provide an opportunity to enhance the quality of care provided to palliative care patients and their family carers. The clinical guidelines developed from this study offer a framework for preparing, conducting and evaluating family meetings. Future research and clinical implications are outlined. Palliative care is expected to be holistic and multidisciplinary; it is provided to both the patient and their family . EffectiHowever despite the promotion of family meetings as an essential tool for information sharing and goal clarification in specialist palliative care settings, it has been reported that sparse evidence exists to demonstrate the process for training staff to conduct or participate in them . It has We set out to develop practice guidelines for conducting family meetings within the context of the specialist palliative care setting, based on the best available evidence and complemented by consensus based expert opinion. For the purposes of these guidelines we define a specialist palliative care setting as a health care environment or service that specifically focuses on the care of patients with an advanced incurable disease and their family. An evaluation of the effectiveness of these guidelines in clinical practice will be reported separately.Key questions guiding the development of the guidelines were: (a) How should family meetings be convened and structured? (b) What content is essential? and (c) Who should attend and lead them?Development of the guidelines was based on the following three methods: (1) A literature search using MEDLINE (1995 \u2013 2007), CINAHL (1995 \u2013 2007), and PsycINFO (1995\u20132007) databases. The principal search terms used either singly or in combination, were: family, carers, case, conference, meeting, hospice and palliative care. Key palliative care textbooks (eg ) and theData from the expert panel and focus groups were audiotaped and transcribed verbatim. These data were then content analysed in accordance with the structured questions set by the research team.The literature search revealed only three published articles in peer reviewed journals specifically related to family meetings in the specialist palliative care setting ,3,7. DueOne palliative care related article acknowledged that most health professionals do not receive sufficient training to conduct family meetings . The autThe opinion based family meeting guidelines for health professionals advocated suitable planning and an overt purpose in order to conduct an effective meeting. Other key recommendations included giving consideration to who should attend, a meeting place that ensures privacy and a method for disseminating outcomes of the meeting.Similar recommendations on how to conduct a family meeting exist in the aged care setting . While tA practice model for nurses working with families has been developed . It inclThe conduct of family meetings has also been described in the context of training medical practitioners . Two relOur review identified several studies that explored family meetings within the context of the intensive care unit (ICU) -20. EvenA study involving qualitative analysis of 51 family conferences across four ICUs in the USA and a survey of 169 family members regarding their satisfaction with communication found that increasing the frequency of three types of clinicians' statements during family conferences was associated with increased family satisfaction. These sLilly and colleagues examined the effectiveness of a proactive patient and family centred communication strategy within the ICU . The intA study conducted in France aimed to measure the amount of time physicians in ICU spent with patients' families by examining contact over a 24 hour period with 951 patients . The medA cross sectional study involving audiotaping family meetings in the ICU concluded that family satisfaction with communication was increased when they were given ample opportunity to voice their concerns, rather than just listening to the medical staff . LautretIn summary, from our review of the literature, while family meetings are promoted as a common and valuable tool within the context of specialist palliative care there is limited evidence related to how they should be conducted and indeed whether they are valuable, most evidence being extrapolated from other settings. Furthermore, despite the apparent support for family meetings, there is limited evidence from the literature that explores ways of preparing or educating health professionals to conduct them . While tThe conceptual foundation for the family meeting guidelines for palliative care was derived initially by the research team from the available literature and then with input from the expert panel. Research team and panel members drew upon their knowledge of various conceptual and theoretical models which appeared to be applicable to underpinning the guidelines. The final conceptual foundation was informed by: (1) The transactional model of stress and coping, (2) Single session therapy, (3) Family consultation model and (4) Therapeutic communication principles. A brief overview of each is now provided.The diversity of responses related to end-of-life issues from patient and family carers can be understood from a psychological perspective based on a transactional model of coping in which cognitive appraisals are made to determine the possible impact of a potentially stressful event -23. The The psychologist, Moshe Talmon is most often associated with the development of Single Session Therapy which he articulated in his texts in the early 1990s in the United States . Talmon Over time the practice of Single Session Therapy has developed into an approach and set of techniques that emphasizes both the client and the therapist approaching their single session with an attitude of trying to make the most of each meeting (even if further sessions are needed). It also sees Single Session Therapy as part of a process that begins with initial contact and includes phone contact after the session with the client. An advantage of the single session method is that it has been used in combination with a range of counselling approaches with differing theoretical orientations.More recently, there have been attempts to integrate Single Session approaches, including the types of questions used, into existing work roles; for example, as part of intake or assessment processes in mental health settings. In other contexts it has been used to inform meeting practices with families, where ongoing treatment and contact occurs with an individual but where professional contact with their family may be occasional or episodic. Family meetings in palliative care typically occur only once . The tenets of single session therapy therefore seem relevant to the development of family meetings clinical guidelines. Although we contend that conducting a routine family meeting should not be considered as 'therapy', some principles of single session therapy appear applicable.Family Consultation is a model of family intervention that emerged in the mental health field in the United States in the late 1980s . It arosThe model assumes a position of family competence and seeks to cultivate a respectful and reciprocal relationship between health professionals and families . In pracGuidelines for therapeutic communication and psychosocial support for adults with cancer  offer stThe research team developed the initial draft of the clinical guidelines based on their clinical experience, the aforementioned literature review and the conceptual framework. The guidelines were then refined by an expert panel comprising: family therapist, social worker, psychologist, clinical nurse consultant, pastoral care consultant, consumer representative, and a palliative care medical consultant.After several iterations a penultimate version of the guidelines was presented at two focus groups for feedback to inform the final version of the guidelines. The first focus group consisted of multi-disciplinary team members from three metropolitan palliative care in-patient units. There were seven participants in this focus group. The health professionals represented the following disciplines: medicine (2); nursing (2); social work (1); occupational therapy (1); and pastoral care (1). The second focus group consisted of consultative palliative care service representatives from three major metropolitan hospitals. Eight participants contributed to this focus group including palliative care medical consultants (3); clinical nurses consultants (4); and social worker (1). Commensurate with the focus group questions (developed by the research team) the results were categorised in the following content areas: (a) description of current practice related to family meetings; (b) recommended core elements of family meetings and (c) feedback on the draft version of the family meeting clinical practice guidelines.A summary of the results is now outlined. In relation to current practice regarding family meetings it was reported that:\u2022 Meetings were typically offered based on need and not routinely;\u2022 Meetings were typically convened and chaired by a social worker;\u2022 The treating team usually determined who attended the meeting;\u2022 Formal training in conducting family meetings does not occur as part of general training;\u2022 Some units use a family meeting guide that they had developed internally;\u2022 The typical purpose of meetings was to find out what a family already knows about patient's prognosis and whether there are any gaps in knowledge;\u2022 Relevant health professionals generally try to meet before the meeting to clarify the goal of the meeting;\u2022 The social worker (who is commonly the chairperson) usually documents the outcomes of the meeting in the patient' medical record;\u2022 Documentation of the meeting discussion and outcome is not usually provided to the family;\u2022 Meetings are not formally evaluated as part of a quality improvement strategies.In relation to recommendations regarding core elements of family meetings it was reported that:\u2022 Good communication skills were considered essential;\u2022 A friendly and comfortable environment should be promoted;\u2022 Common goals and objectives should be established for the meeting;\u2022 Only key health professionals should be present at the meeting;\u2022 A designated chairperson is required for the meeting;\u2022 An agenda, specified aims and objectives should be confirmed at the start of the meeting;\u2022 The meeting should also be used as a forum to provide and gather information;\u2022 Allowing time at the beginning of the family meeting for introductions was considered essential.In relation to feedback regarding the draft version of the clinical guidelines for family meetings there was general consensus that the guidelines were applicable to the clinical setting and contained the aforementioned key elements. However the following points were considered important to be included in the guidelines:\u2022 Clarification of some terms throughout the protocol to reduce ambiguity was recommended;\u2022 Limiting the number to 'one or two' family members and/or friends was highlighted as a potential challenge in practice;\u2022 Ensuring that each discipline represented at the meeting has an opportunity to contribute was considered important;\u2022 Where pertinent and if possible (resources permitting), offer a family meeting via teleconference.The guidelines for conducting family meetings are outlined in Table \u2022 Family meetings can be a useful way to assist patients and family members to clarify goals of care, consider site of care options, and to share information. Ideally they provide a safe environment where issues and questions can be raised and appropriate strategies agreed upon.offer family meetings based on need.\u2022 Strategies to support family carers are a core component of palliative care; hence service providers have a responsibility to \u2022 Service providers should view family meetings as mutually beneficial. They are not only potentially valuable for patients and family carers; they may also provide a resource effective way to explain what the service can and cannot offer. Such meetings provide an opportunity to triage priority issues and a way to make referrals to other health professionals or other institutions early in the care planning phase.not be used as an opportunity for health care professionals to debate a patient's medical status; in this situation, a case conference should be convened prior to the family meeting.\u2022 Family meetings should \u2022 Family meetings should not be saved for 'crisis' situations. Instead, a preventative approach is advocated where issues are anticipated before they become major dilemmas. Hence a proactive rather than reactive approach to care is fostered.offered routinely on admission, and conducted at a pertinent time thereafter.\u2022 Ideally, family meetings are \u2022 Facilitators of family meetings require appropriate skills in group work, therapeutic communication and palliative care. We contend that the decision about who (i.e. which discipline) should convene and facilitate a family meeting is best determined on pragmatic grounds  and not based on hierarchical reasons (i.e. based on authority). Hence the multidisciplinary team should determine who conducts the family meeting and presumably this may change depending upon skills, knowledge of the family and resources.\u2022 Occasionally, family members may want to withhold details of the patient's prognosis from the patient; there may be incongruent wishes about the site of care; 'desire to die' statements may have been made by the patient; or there may be conflict within the family or difficulties regarding the transition from curative treatment to palliative care. In these circumstances we recommend the key resources and references to support therapeutic communication outlined in Table \u2022 Pre-planning for the actual meeting is imperative as outlined in Table \u2022 Suitable resources should be available to patients and family members who attend the meeting in order to complement the verbal information .Family meetings provide an ideal avenue to inform, deliberate, clarify and set goals for future care, based on discussions between health professionals and the patient and family. While there is consensus in the literature that family meetings are necessary and valuable, our study identified an absence of empirical evidence, within the context of specialist palliative care settings, to guide when they are required, who should attend, how they should be conducted and whether or not they are beneficial. Evidence from the intensive care context appears to offer the best guidance to date. While these data are important, caution is needed when considering their applicability to specialist palliative care settings where the population is somewhat different.The feedback from clinicians involved in the focus groups in this study also complemented other claims that most palliative care health professionals receive little or no preparation to conduct family meetings . Focus gThe clinical guidelines described herewith (based on a multidisciplinary research based approach) aim to assist health care professionals working in specialist palliative care to convene and conduct family meetings. Nonetheless, our study had several limitations and consequently more research is required. The clinical guidelines presented were in the most part based on expert opinion owing to the paucity of available research evidence. Accordingly, a formal evaluation of the benefits (or otherwise) of family meetings conducted using the guidelines is required. Furthermore, it would be advantageous to know whether the guidelines are applicable to other palliative care settings such as home care and aged care. Moreover, testing the utility of the guidelines in other countries is warranted. Our literature review included studies undertaken after 1995, hence there may have been evaluations of family meetings in palliative care conducted prior to this period. However, if so, the relevance of research findings almost 15 years on may be questionable. Evaluating strategies to prepare health care professionals to conduct family meetings would also be valuable .The essence of palliative care provision is effective communication amongst health professionals, patients and their family carers. Family meetings are one potential method of interaction that may facilitate optimal care planning and support and seem to be commonly used in palliative care. To our surprise however, according to our review, there have been no research studies within specialist palliative care settings that have examined: when meetings should be convened, how they should be conducted; who should attend and whether or not they are effective. It is intended that the clinical guidelines presented here will aid health care professionals to plan, conduct and evaluate family meetings. However, we recommend that the utility of these guidelines undergo additional examination.The authors declare that they have no competing interests.PH was the principal investigator for the study and was awarded a Postdoctoral Research Grant to undertake the project. He oversaw the grant application, management of the research project and was responsible for drafting the manuscript and preparing the final submission and responsible for coordinating feedback regarding reviewer and editorial queries. KQ was a chief investigator for the project and assisted with design, data collection, project oversight and provided input into the manuscript focusing on the literature review. BO'H was a consultant for the project focusing on the areas of single session therapy and assisted primarily with the conceptual framework and literature review sections of the manuscript. SA was a chief investigator for the project and helped conceptualise the study design and provided feedback on draft versions of the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:"}
+{"text": "Attempts to identify particular aspects of psychosocial work conditions as predictors of sickness absence remain inconclusive. A global measure has previously been suggested to be an efficient way to measure psychosocial work conditions in questionnaires. This paper investigates whether satisfaction with specific aspects of psychosocial work conditions explains sickness absence beyond its association with a global measure of psychosocial work conditions.The participants were 13,437 employees from 698 public service workplaces in Aarhus County, Denmark. 33 items from a questionnaire fell in groupings around six aspects of psychosocial work conditions: skill discretion, professionalism, management, decision authority, workload and cooperation. A global measure rating satisfaction with psychosocial work conditions on a scale from 0 to 10 was also included in the questionnaire. Individual ratings were aggregated to workplace scores. Analysis of variance and multiple linear regression was used to compare the average number of days of yearly sickness absence with different levels of satisfaction with six aspects of psychosocial work conditions. The covariates included were gender, age, occupation, size of workplace, contact to hospital, civil status and children below 13 living at home.Dissatisfaction with each of the six aspects of psychosocial work conditions was associated with an increase in sickness absence. When all aspects were simultaneously included in the model, only skill discretion and professionalism were negatively associated with sickness absence. When a global measure of satisfaction with psychosocial work conditions was also included in the model none of the specific aspects showed a statistically significant association with sickness absence.Low global satisfaction with psychosocial work conditions is associated with increased levels of sickness absence. Including specific aspects of psychosocial work conditions in the model does not provide further information regarding the nature of this association. Many studies have attempted to establish the association between specific aspects of psychosocial work conditions and sickness absence. -10 Most In a previous study we examined the association between a global measure of psychosocial work conditions and sickness absence. We found a positive correlation between the level of satisfaction with psychosocial work conditions and the amount of sickness absence across different occupations and types of work places. A global measure is a parsimonious way of measuring psychosocial work conditions, assuming that the overall concept of psychosocial work conditions is conceived in a more homogenous way across heterogenous populations than separate aspects of psychosocial work conditions.The purpose of the present study was to investigate the relationship between specific aspects of psychosocial work conditions and sickness absence in a large sample of public services employees. Additionally it examines whether specific aspects of psychosocial work conditions explain sickness absence beyond the association found regarding the global measure. The study includes aspects of psychosocial work conditions evaluating professionalism and management that are not commonly included in studies regarding psychosocial work conditions.Two specific questions raised are i) do specific aspects of psychosocial work conditions function as independent predictors of sickness absence beyond a one-dimensional global measure of satisfaction with psychosocial work conditions? And ii) does the character of the association between psychosocial work conditions and sickness absence vary across different occupations?From April 2002 through April 2005 Aarhus County in Denmark conducted a general survey of the psychosocial work conditions among all employees, with the intent to use the results to improve psychosocial work conditions. . The surThe study population included 13,437 employees from 698 different workplaces in Aarhus County who received a questionnaire in one of the surveys  can be evaluated by a simple correlation matrix Table .Four of the scales were closer correlated than the others  with coefficients between 0.51 and 0.67. The same four aspects were also closer correlated to the global measure than skill discretion and workload. Workload and skill discretion were least correlated to the other aspects (Pearson's correlation coefficients between 0.29 and 0.50).The content validity was evaluated by two occupational psychologists. They were asked to place the original 40 items under headings with aspects commonly regarded as key aspects of psychosocial work conditions . The questionnaire was found to include measures of all of these aspects.th was chosen as the start date of measurement of sickness absence.Data regarding sickness absence were obtained from the salaries administrative system of the County of Aarhus. Reporting of sickness absence is compulsory and necessary to obtain wage reimbursement. The data are produced by each workplace and submitted to the administrative system each week. The data contain a record for each day of absence for every employee. Only the instances explicitly coded with illness as the reason for absence were included, thus excluding maternity leave and other reasons for absence. Data regarding sickness absence could only be linked to data regarding psychosocial work conditions at the workplace level, as the latter were not available at the individual level. The outcome measure was the number of days of sickness absence through one year for each employee. The number of spells of sickness absence was also examined. The distribution of spells was similar to the distribution of the number of days and the association to psychosocial work conditions was also similar. Choosing spells of sickness absence as our outcome measure would thus have lead to the same conclusions. The time period used was 6 months before and 6 months after the time of measurement of psychosocial work conditions. As only the month of measurement of satisfaction with psychosocial work conditions was known the 15The covariates included in the adjusted analyses were: gender ; age (continuous); occupation ; the size of the workplace unit ; marital status ; children ; and registered illness during the year of measurement of sickness absence .The responses to the items of each aspect were added using equal weights and scaled from 0 to 100. The global measure was also transformed to a 0 to 100 scale. The aggregated workplace unit scores from each of the 698 workplace-units were assigned to each employee for all of the aspects.The aggregate scores where divided into septiles. A low level of satisfaction was defined as the lowest septile, medium satisfaction as the 5 middle septiles and high satisfaction as the highest septile. The levels were defined to satisfy a trade off between the size of the groups and the magnitude of contrast between the groups. No absolute cut off point could be used across the 6 aspects as the distributions cover different spans of the 0 to 100-scale.Analyses were performed using the workplace unit scores on the 6 aspects of psychosocial work conditions as predictors of the individual number of days of sickness absence throughout a one-year period. In the first step of the analyses we compared the number of sickness absence days during a year for the three levels of satisfaction for each aspect and the global measure. Analysis of variance was used to test differences between mean values of sickness absence across the three levels of the scores. In a second step we used multiple linear regression to estimate the effect of a one-unit increase in the satisfaction with psychosocial work conditions on sickness absence.Estimates were calculated including the covariates with and without control for the other aspects in order to investigate how much the individual aspects contributed to prediction of sickness absence.The SAS 9.13 statistical package was used for all statistical analyses. Analysis of variance and multiple linear regression was performed using the MIXED procedure with the repeated option account for the workplace clustered nature of the data on satisfaction with psychosocial work conditions. All covariates were included in the model regardless of their contribution to the explanation of sickness absence variation. The distributions of the scores on the 6 aspects and of the global measure of psychosocial work conditions are presented in figure Distribution of 6 aspects and a global measure of psychosocial work conditionsTable The results from the first step of the analyses showed a statistically significant association between increasing satisfaction and decreasing sickness absence for all aspects except workload. For the 5 other components the decrease in sickness absence was statistically significant between the lowest and the medium level of satisfaction with psychosocial work conditions while the difference between the medium and the highest level was not statistically significant. Skill discretion, professionalism and decision authority were most closely associated with sickness absence. A 10 points increase in satisfaction with psychosocial work conditions on each of these 3 aspects was associated with a 1 \u2013 1.5 days decrease in sickness absence per year.In the second step of the analyses, when all 6 aspects were included in the model only the skill discretion-aspect was statistically significantly associated with sickness absence ). The professionalism aspect had an equally high but not statistically significant regression coefficient ).In a third step we tested whether any of the aspects could independently predict sickness absence when a global measure of satisfaction with psychosocial work conditions was also included in the model. Only decision authority had a statistically significant, independent association with sickness absence ) and the effect was in the opposite direction than expected. Regression coefficients were positive (but non-significant) for all other aspects except skill discretion. The global measure was consistently negatively associated with sickness absence regardless of which of the 6 aspects were included in the model and it also had the strongest explanatory power in itself .The effect of poor satisfaction with psychosocial work conditions on sickness absence could not be further explained by including specific aspects of psychosocial work conditions in the model. The overall results from the model with all 6 aspects did not apply generally across all occupations included in the study. For some occupations other aspects than skill discretion or professionalism were closer associated with sickness absence. None of these associations were statistically significant when all 6 aspects were included in the model. For most occupations none of the aspects were associated with sickness absence (results not shown).We found that all aspects of psychosocial work conditions included in the study, except workload, were individually negatively associated with sickness absence. The amount of sickness absence was notably lower in the group with medium satisfaction with psychosocial work conditions than in the most dissatisfied group. When all aspects were included simultaneously in the model, skill discretion and professionalism showed the strongest association with sickness absence. The meaning of work, development opportunities and the deployment of personal and professional resources, which are inherent in the skill discretion aspect thus provide the best target for improving psychosocial work conditions in order to reduce sickness absence. Skill discretion was not highly correlated with the global measure, thus rendering an independent explanatory power on sickness absence possible.The negative association between professionalism and sickness absence (regression coefficient -0.11) was not statistically significant. Professionalism was more closely correlated to the global measure than skill discretion.When a global measure of psychosocial work conditions was included in the model, only one of the six aspects of psychosocial work conditions, namely decision authority, was associated with sickness absence. Surprisingly, an increase in decision authority was associated with increased sickness absence. The reason for this independent explanatory contribution could be that decision authority is not always contributing to enhance the psychosocial work conditions. Increased decision authority means increased responsibility and new ways of working can lead to a blurring of work and private life. The result could also be an artifact due to inclusion of overlapping variables in the analysis.Specific aspects of psychosocial work conditions have not explained sickness absence beyond its negative association with the global measure found in our previous study.Most previous studies have implicitly assumed that psychosocial work conditions can be divided into a number of clearly distinguishable aspects that can be consequently identified as latent variables across heterogeneous populations and thus measured with the use of generic questionnaires.Typically studies took offset in Karasek's demands, control (and support) model  or SiegrThe use of a global measure provides the opportunity to examine the explanatory power of specific aspects as compared to the global measure. This study suggested that psychosocial work conditions may be more of a one dimensional concept than previous studies have hypothesized, because the global measure explained more of the negative association between psychosocial work conditions and sickness absence than any of the aspects included in this study.If the specific aspects of psychosocial work conditions do not have any independent explanatory power when a global measure is included, then the aspects do not explain the association beyond the association found between sickness absence and the global measure.When only a limited number of items or aspects are included in a study, they could all account for the effect of the common latent aspect \"psychosocial work conditions\" and could lead to false conclusions. Furthermore, even when the association between a global measure of psychosocial work conditions and sickness absence is consistent across subpopulations, the combination of aspects of psychosocial work conditions responsible for this association may be different across subpopulations. The inconsistent results of earlier studies suggest that this indeed may be the case.Subpopulations are typically divided according to gender, occupation or type of institution. It also remains unclear whether specific dimensions of psychosocial work conditions are associated with sickness absence in the same manner across all of these subpopulations. Particular characteristics of the workplace amounting to a workplace \"culture\" may be more important for the association than e.g. different occupational categories.The strengths of this study are that it is based on a large and heterogeneous study sample and in the independent measurement of exposure and outcome. Our data on sickness absence are highly reliable, as the Danish legislation requires accurate registration for reimbursement of expenses. Equally the response rate in the surveys of psychosocial work conditions was high (81.0%). The validity of the 6 scales used in this study was evaluated through measurements of internal consistency, convergent, discriminant and content validity. On these criteria they performed adequately. The inclusion of the global measure of psychosocial work conditions allowed for further testing of the discriminant validity. However, the study also has some limitations: important predicting variables such as physical demands, shift wIndividual data regarding sickness absence could only be linked to workplace levels of psychosocial work conditions. This is both a limitation, possibly responsible for weakening the association found in the study but also a strength as the use of workplace unit scores may minimize the effect of individual characteristics not related to the workplace as the effect of these variables may be expected to be randomly distributed across workplaces in our study sample.Our design provides a better background to believe that our results represent an association truly related to satisfaction with psychosocial work conditions as it avoids the triviality trap of personal characteristics associated to both proneness to sickness absence and reporting of low satisfaction with psychosocial work conditions.We have earlier found a strong and consistent association between general satisfaction with psychosocial work conditions and sickness absence. The present study indicates that this association is not further explained by including measures of specific aspects of psychosocial work conditions as management, cooperation, skill discretion, professionalism, work load and decision authority.Instead it is a general dissatisfaction with psychosocial work conditions that is associated to sickness absence rather than a specific combination of different aspects of the psychosocial work conditions. No particular aspects can be identified as associated clearly to sickness absence neither in the total study population nor in occupational subgroups.A general recommendation for workplaces with poor psychosocial work conditions would be to focus particularly on the items and aspects with low scores in their own local survey results instead of pointing to specific aspects as being generally associated to sickness absence across all subpopulations. It can also be recommended to focus particularly on workplaces with low satisfaction with psychosocial work conditions because the difference in amount of sickness absence is most notable between the groups of workplaces with low and medium levels of satisfaction.Across large and heterogenous populations associations between psychosocial work conditions and sickness absence we find it appropriate to use a single global question as a screening to spot workplaces with particular problems regarding psychosocial work conditions. In a forthcoming study concerning interventions to improve psychosocial work conditions we argue, that only at workplaces with poor psychosocial work conditions (the lowest septile) there is an effect on sickness absence of intervening to improve psychosocial work conditions. At the workplaces spotted through the screening it will make sense to make a more detailed survey of psychosocial work conditions to clarify the aspects of psychosocial work conditions most in need for improvement and as indicators for measurement of the effect of subsequent interventions.The authors declare that they have no competing interests.TM was the main author of the manuscript and has contributed to all phases of it.  JW and JPB contributed substantially to the conception, design, analysis and interpretation of data and the drafting and revision of the manuscript.  EA and NW contributed substantially to the analysis and interpretation of data and to the revision of the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:Characteristics of 13,437 participants.Click here for fileSix aspects of psychosocial work conditions and the items used to measure them .Click here for file"}
+{"text": "Sentinel lymph node (SLN) detection and biopsy is gaining popularity in the treatment of Head and Neck cancer. Various methods in this regard have been described, each with their respective advantages and disadvantages. The aim of this paper was to evaluate the potential application of Indocyanin Green (ICG) in the mapping and detection of sentinel lymph nodes (SLN) in cancers of the head and neck.Patients with oropharyngeal cancer and N0 neck who were scheduled for primary tumor ablation as well as a neck dissection were selected. One milliliter of Indocyanin green was injected around the tumor and the sentinel node detection was performed by aiming the infra red video camera on the cervical area. When no detection was possible transcutaneously, a cervical incision was made, a sub-platysmal flap raised and further detection was done to visualize the fluorescing lymph nodes.Detection of cervical SLN was only possible when 5 mm or less tissue covered the sentinel lymph node. Accurate and clear detection of the lymph drainage pattern and SLN was possible. There is some uptake in other tissues such as the submandibular gland which is easily distinguishable from lymphatic tissue.Indocyanin green fluorescence is a potential valuable potential tool in the detection of SLN in patients with oropharyngeal cancer which warrants further investigation. It is well known that poorer prognosis prevails in head and neck cancer patients that develop metastatic lymph nodes and even more so if there is evidence of extra capsular spread. This is one of the reasons why elective neck dissections are frequently performed even in patients with N0 necks .There are no clear and accurate guidelines regarding the decision to perform a neck dissection concurrent to the ablation of the primary tumor in the N0 neck. Clinical staging of the neck by manual examination is notoriously inaccurate, especially in patients with more voluminous necks. Radiological staging with either CT or MRI has improved the sensitivity for identifying nodal metastatic disease and has contributed to the upstaging of necks in a significant number of patients, resulting in a more accurate selection of patients requiring a neck dissection. With size alone as one of the more important criteria in this regard it has been shown that an important group of patients at risk for occult lymphatic metastasis may be missed ,3.The potential benefit of CT-PET in the pre operative evaluation of patients with a negative CT or MRI is still controversial and probably plays a bigger role in detecting second primary tumors and follow up ,5.Ultrasound with simultaneous fine needle aspiration cytology is probably the most accurate method to date in staging the neck, but requires skill and solid ultrasound and cytology knowledge to reach good levels of accuracy .Currently there is thus no accurate way of determining the presence of occult lymphatic metastasis for cancers of the head and neck. It is clear that the gold standard for detecting involved lymph nodes is accurate pathological analysis of the nodes. This is traditionally done in a retrospective manner by sending the neck dissection specimen for analysis. In the normal pathological processing there is a possibility to miss micro metastases as the specimens are not as accurately examined as with a sentinel node protocol. In such a protocol stepwise serial sectioning as well as immunohistochemistry will be able to find occult microscopic deposits that would be missed with routine pathology examinations .Many factors determine the propensity of a tumor to disseminate its cells to spread via the anatomical lymphatic system. Tumor cell motility as well as lymphatic vessel density is factors that may contribute to the enhanced spread along lymphatic pathways .The principle of sentinel lymph node (SLN) identification and biopsy is to identify the first station of drainage of a particular anatomical area in which the tumor lies ,10.SLN detection was first used in other anatomical areas like the breast and soon skin cancer as well as gastric cancers followed. In many centers SLN detection has become standard clinical practice.Benefits for the patients are the more selective removal of the first drainage lymph nodes from a particular anatomical site with lower morbidity and by closer histological examination of the nodes a higher detection rate of micro metastasis is possible.The anatomical basis of head and neck cancer nodal drainage has been well established and is in use on a daily basis . On thisSLN identification and biopsy has increased its role in detection of the first nodal drainage in an attempt to either limit surgical damage, or to more accurately stage the patient by more accurate examination of the sentinel node or nodes. Koch et al (1998) was the first to describe the use of technesium-99 m (99T cm) labeled sulfur colloid in the quest for accurate sentinel node biopsy .The use of lymphoscyntography with 99T cm colloid as well as a following SLN biopsy with possible concurrent blue dye injection can be regarded as the current gold standard with regards to identification of the SLN . With thThe use of ICG in the diagnosis of SLN in areas other than that of the head and neck region has well been described. Reports of its use in gastric, breast, lung as well as skin cancer are found in the literature with good success -22A total of 8 Patients with oropharyngeal head and neck cancer and N0 neck status and where resection of the primary tumor as well as a neck dissection was planned were used to evaluate the use of ICG in the identification of the sentinel lymph node. Only unilateral elective neck dissections were performed according to the clinical indication. In no way was the treatment of the patients altered or influenced by the additional use of ICG or sentinel node detection. Patient's informed consent was obtained before surgery.\u00aeICG-Pulsion, Pulsion medical Systems AG, Germany)is supplied as a sterile, water-soluble powder dye  was then directed to the cervical area within 3-5 minutes and an attempt was made to identify the sentinel lymph node.  alone or in combination with methylene blue is probably the most widely used as it allows one to quantify the radioactivity picked up on the gamma probe and further to have a pre operative picture of the identified SLN. Injection of 99 mTcSC around the primary tumor site is performed at least 2 hours before or even the afternoon before surgery the next morning. The injection is reported to be painful as local anesthesia in the vicinity should be avoided. Another advantage is the possibility to perform a scintigraphy beforehand to identify and localize the SLN before surgery. This may be of great help where the SLN isolated in an unexpected area.Technesium 99 labelled sulfur colloid : Indocyanin Green; (SLN): Sentinel lymph node; (SNB): Sentinel Node Biopsy; (IHC): Immuno histochemistry.The authors declare that they have no competing interests."}
+{"text": "Skin and soft tissue infections are increasingly prevalent clinical problems, and it is important for health care practitioners to be well trained in how to treat skin abscesses. A realistic model of abscess incision and drainage will allow trainees to learn and practice this basic physician procedure.We developed a realistic model of skin abscess formation to demonstrate the technique of incision and drainage for educational purposes. The creation of this model is described in detail in this report.This model has been successfully used to develop and disseminate a multimedia video production for teaching this medical procedure. Clinical faculty and resident physicians find this model to be a realistic method for demonstrating abscess incision and drainage.This manuscript provides a detailed description of our model of abscess incision and drainage for medical education. Clinical educators can incorporate this model into skills labs or demonstrations for teaching this basic procedure. Staphylococcus aureus infections.[Skin abscesses are commonly encountered clinical problems, and the incision and drainage of an abscess is a treatment that is often performed in both emergency and outpatient practice settings. The goal of this project was to develop a model of abscess incision and drainage for educating clinicians about this minor surgical procedure. The importance of educational models for this procedure is evident in the recent resurgence of skin infections and abscesses associated with community acquired methicillin-resistant fections.,2 While fections.-5Our abscess model was developed in the human anatomy lab at our medical school using a donated human cadaver. The use of fresh cadaveric specimens without traditional preservatives allowed manipulation of dermal structures in a life-like fashion. Areas of erythema on the skin were often already present but were also simulated by application of a lipstick moulage.Tapioca pudding was diluted 30% with water to simulate purulent material for the abscess contents. Tapioca pudding was the appropriate consistency and color with individual particles to accurately simulate purulent abscess contents. Initial attempts to create a subcutaneous abscess with this simulated purulent material were unsuccessful as intradermal or subcutaneous injections rapidly diffused under the skin and did not create localized collections to correctly simulate an abscess.A Word catheter  , was idein situ using subcutaneous tunneling from a distant incision site [see Figure This filled catheter was surgically implanted into the cadaveric skin The size and firmness of the abscess was varied by changing the amount of simulated purulent material that was injected into the catheter, and this created a realistic model ready for an incision and drainage procedure. Draping of the area allowed for concealment of the incision site and the terminal end of the Word catheter to enhance the realistic appearance of the model, and the model was then used to practice incision and drainage [see Figure Digital video and still photography was used to demonstrate appropriate techniques for the incision and drainage procedure [see Figure The effectiveness of this model as a realistic way to demonstrate key components of the incision and drainage procedure was evaluated by creating a multimedia video presentation using this model. This vidThis project developed a model for incision and drainage of skin abscesses to teach clinicians this important clinical procedure. This model is realistic, which is demonstrated by physician review and the use of this technique to create a peer-reviewed and published teaching video. TeachingWhile the realism of our model is evident in the video and still photographs that have been produced using these methods, use of tThe authors declare that they have no competing interests.All authors participated in the conception, design, and implementation of the abscess model. MTF drafted the manuscript and all authors participated in the writing and revising of the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:"}
+{"text": "Bronchial dehiscence in lung transplantation is still a significant and threatening cause ofmorbidity, even if several progresses have been made in this field. In the present report wediscuss a case of incomplete dehiscence of the right bronchial anastomosis in a patient whounderwent sequential double lung transplantation for bronchiectasis. This complication hasbeen successfully treated with endobronchial stent positioning, with the aim to allow thehealing of the anastomosis around a rigid endobronchial support and to prevent the airwaystenosis. The usefulness of 3D spiral CT reconstruction of bronchial tree is also underlined,for its capacity to detect the dehiscence and to monitor the healing of this complication."}
+{"text": "Clonogenic survival of HeLa, Chinese hamster and HaK cells after treatment with a range of cisplatin concentrations and exposure times was determined and cellular platinum concentrations were measured by PIXE. It was demonstrated that cisplatin cytotoxicity of the three cell lines varied considerably as a function of drug exposure dose. These differences are related to differential cellular drug uptake."}
+{"text": "Numerous case-control studies have suggested a link between the oral contraceptive pill and liver cancer. The secular trends in liver cancer mortality rates for England and Wales from 1975 to 1992 were examined to determine whether an effect of the pill was apparent. Liver cancer mortality has remained constant in women in the age groups that have had major exposure to the pill."}
+{"text": "The behaviour of the normal epidermis of mice on the first 5 days of exposure to a single application of carcinogens and cocarcinogens has been investigated by simple quantitative measurements of cell population, size of cells and thickness of the epidermis. Irritant substances and promoting agents both produce cellular hypertrophy but the respective responses can be distinguished by the much greater incidence of degenerate cells associated with irritant treatment. Urethane treatment is characterized by induction of a transient hypoplasia which is not in agreement with the level of cellular division. This response has also been demonstrated after treatment with mild carcinogens or low doses of potent carcinogens. Higher dose levels are followed by a reduction in the mitotic index after about 27 hours. The possibility of developing a preliminary screening test for carcinogenic substances is discussed in the light of these observations."}
+{"text": "In confirmation of other studies it has been shown that antibody directed against the tumour specific transplantation-type antigens (TSTAs) cannot be detected in rats with a tumour growing intramuscularly but appears within a few days after excision of the tumour. Circulating antibody is found in the serum of rats with lymph node metastasis following excision of the primary. Absorption by the intramuscular tumour of circulating antibody does not account for the absence of antibody since the antibody levels in thoracic duct lymph in rats with tumours in the leg are also very low and rise rapidly after tumour excision. Antibody is released by the draining nodes directly into the lymph and must pass through the thoracic duct before entering the blood. Under these conditions low levels of antibody activity in lymph cannot be ascribed to absorption by the tumour.It is postulated that TSTA is released from the tumour into the lymph. Following injection of tumour cells into immunized rats the level of antibody falls and this is attributed to release of TSTA from the injected cells. The possible role of antigen release from tumours in determining the host reaction to the tumour is discussed."}
+{"text": "A substance capable of inducing tumour cell aggregation, which is supposed to be a glycoprotein showing noncytotoxicity, was separated from rat ascites hepatoma cells and partially purified by chromatography. Adhesiveness of rat ascites hepatoma cells induced by this substance was characterized by gradual development of known binding structures during a period of 24 h after contact with the substance; simple apposition and intermediate junctions developed in the early stage, and desmosomes and focal tight junctions in the later stage. It was assumed that the substance might be involved in the development of such binding structures as a triggering mechanism of tumour cell adhesiveness."}
+{"text": "Hydatid disease is caused by the larval stage of the cestode, Echinococcus granulosus. Man is the intermediate host in its life cycle. The most common organ involved is liver followed by lung. Although surgery remains the definitive treatment for symptomatic lesions, it is associated with considerable morbidity. Other less invasive treatment strategies as an adjunct to medical treatment that have been tried in various case series include percutaneous aspiration, instillation and reaspiration of scolicidal agents (PAIR), and thoracoscopic removal of cysts located subpleurally. Here we report the case of a 58 year old gentleman with hepatic and pleuropulmonary hydatid disease who was subjected to medical thoracoscopy and instillation of hypertonic saline (3%), followed by medical management with albendazole with which complete resolution of the pulmonary cysts was achieved. A 58 year old male working in Saudi Arabia in an aquarium shop for more than 15 years was referred to our institute with complaints of breathlessness and vague abdominal discomfort of 8 months duration with worsening dyspnea and cough with scanty mucoid expectoration 1 month prior to admission. At his workplace, he had contact with aquatic creatures in the shop in which he was working. There was also occasional exposure to cats which was imported for sale and distribution to nearby places. The patient denied any addictions and there were no significant past medical or surgical illness. At the time of admission he was comfortable at rest, vitals were stable and respiratory system examination revealed features of left sided hydropneumothorax. Examination of other systems was within normal limits. Complete blood count, random blood sugar, renal and liver function tests were all normal. Chest X-ray taken at the time of presentation  revealedMost of the case reports regarding hydatid lung disease published from India are from the northern states where it is relatively common. Similar case reports are scarce from southern regions. Also thoracoscopic instillation of scolicidal agents in the treatment is reported only in a few case series, although percutaneous aspiration, instillation and reaspiration (PAIR) is commonly employed for treating hepatic hydatid cysts. Sarai et al68The use of minimally invasive technique like medical thoracoscopy under conscious sedation in the management of pulmonary hydatid located in the subpleural region as well as those with pleural complications seems promising and needs to be promoted in those patients who refuse surgery or in whom surgery is contraindicated due to various reasons. However, it should be stated that the optimum management of asymptomatic cysts which are diffusely distributed in thorax (that are difficult to access by thoracoscopy) as well as in liver  remains controversial and poses challenge to the treating clinician. A trial of prolonged treatment with albendazole may be tried as in our case which could be fruitful in certain cases."}
+{"text": "The effect of the anabolic steroids nandrolone decanoate and oxymetholone on the peripheral blood haemoglobin, total leucocyte and platelet counts was studied in a controlled trial in which patients received standardized chemotherapy for one form of malignant disease. The results indicate that these agents have no protective effect on bone marrow suppression during cytotoxic chemotherapy. It was observed that the time interval between the initial nadir total leucocyte count and the return to pre-treatment values in those patients receiving the anabolic steroids was significantly shorter than in the control group."}
+{"text": "We present a tool for tracking coronary vessels in MRIscans of the human heart to aid in the screening of heartdiseases. The vessels are identified through a single click insideeach vessel present in a standard orthogonal view. The vesselidentification results from a series of computational stepsincluding eigenvalue analysis of the Hessian of the MRI imagefollowed by a level set-based extraction of the vessel centerline.All identified vessels are highlighted using a virtual contrastagent and displayed simultaneously in a spherical curvedreformation view. In cases of over segmentation, the vessel tracescan be shortened by a click on each vessel end point. Intermediateanalysis results of the vessel computation steps can be displayedas well. We successfully validated the tool on 40 MRI scansdemonstrating accuracy and significant time savings over manualvessel tracing."}
+{"text": "Karyotyping and marker analysis of G- and C-banded metaphases from a metastatic bronchial carcinoma revealed a dominant stemline with five markers and four sidelines with additional markers. One to three minute bodies were noted in the majority of cells and these were classified as markers. On the basis of this analysis it was possible to postulate an evolutionary pathway within the tumour whereby the stemline was derived from existing sidelines."}
+{"text": "These observations are relevant to current proposals for adjuvant immunotherapy of human malignant disease where conditions of minimal residual disease are not being fulfilled.Growth of syngeneic transplants of a 3-methylcholanthrene induced rat sarcoma was suppressed when tumour cells were injected in admixture with BCG. Rejection of these mixed inocula resulted in the suppression of growth of a simultaneous challenge with cells of the same tumour at a contralateral subcutaneous site and conditions for immunotherapy were evaluated with respect to the maximum tumour cell challenge rejected and the optimum time of treatment. These studies established that viable tumour cells were more effective than radiation attenuated cells for the immunizing stimulus. Also, the maximum tumour challenge totally rejected in this way was of the order of 10"}
+{"text": "Antisera to extracts of a variety of bronchogenic carcinoma were raised in rabbits and extensively absorbed with immunoadsorbents prepared with normal lung extracts cyanogen bromide linked to Sepharose 4B, and glutaraldehyde insolubilized normal lung extracts. The antisera were tested by immunodiffusion against a panel of extracts from a variety of bronchogenic carcinoma, foetal lung extracts and pools of normal lung extracts. The results indicate that two distinct antigenic components are associated with bronchogenic carcinoma; one which is present in a high percentage of the tumour extracts tested and appears to have partial identity with a foetal lung component, and one (or more) which is not foetal and appears to have higher cross-reactivity (but not exclusively) with tumours of the same pathological type. Attempts to detect either antibody or antigens relating to these components in the serum of patients with bronchogenic carcinoma by these techniques were unsuccessful. The foetal cross-reacting component was neither carcinoembryonic antigen and alpha1-foetoprotein."}
+{"text": "The Proteomics Standards Initiative (PSI) aims to define community standards for data representation in proteomics and to facilitate data comparison, exchangeand verification. Initially the fields of protein\u2013protein interactions (PPI) and massspectroscopy have been targeted and the inaugural meeting of the PSI addressed thequestions of data storage and exchange in both of these areas. The PPI group rapidlyreached consensus as to the minimum requirements for a data exchange model; anXML draft is now being produced. The mass spectroscopy group have achieved majoradvances in the definition of a required data model and working groups are currentlytaking these discussions further. A further meeting is planned in January 2003 toadvance both these projects."}
+{"text": "Two hundred and ninety-nine oral leukoplakias were examined by exfoliative cytology; 83 of these lesions were biopsied because of clinical or previous histological features. Epithelial atypia was found in 16 of these biopsies, exfoliative cytology detecting epithelial atypia in only 6 of these cases. Thus exfoliative cytology used alone would have led to a false negative diagnosis in 10 out of 16 (62%) of the cases with epithelial atypia verified by histology. In addition, in no instance was exfoliative cytology responsible for the detection of an epithelial atypia that had been overlooked by consideration of clinical or previous histological features. Exfoliative cytology was successful in the detection of atypia only in those cases in which the surface of the lesion was either ulcerated or not keratinized; all keratinized lesions with atypia yielded negative cytology. The results of this study lead to the conclusion that exfoliative cytology is not to be recommended as a routine diagnostic or screening procedure for the detection of possibly pre-malignant features in oral leukoplakias."}
+{"text": "Two cases of portal hypertension due to hydatid cysts of the liver are reported. In one of the patients,symptoms were secondary to obstruction of inferior vena cava and hepatic outflow tract. The other patientwas operated on with a diagnosis of extrahepatic presinusoidal portal hypertension caused by extrinsiccompression of the liver by an hydatid cyst. Although hydatidosis is a benign disease, it can produce seriouscomplications as in these reported cases. Therefore hydatidosis should be remembered amongst the causes ofportal hypertension in countries where the disease is endemic."}
+{"text": "The effects of various chemotherapeutic agents on alpha-fetoprotein (AFP) secretion and growth of human hepatocellular carcinoma and hepatoblastoma cell lines were investigated in vitro. It was found that there was a high correlation between hepatoma cell number and AFP secretion after treatment and that the amount of AFP secreted per cell per 72 h was not affected with therapeutically achievable concentrations. These results suggest that serum AFP level in patients with hepatomas does not correlate with the size of whole tumour but with that of viable tumour mass, and that AFP-secreting capacity of tumour cells in the mass is kept unchanged after chemotherapy."}
+{"text": "Exposure to the fibrous mineral erionite is known to induce mesothelioma in man and laboratory animals. Previous studies demonstrated the presence of a trypsin-like protease associated with tumour cells. This protease could be demonstrated by the use of fluorescent probes which located cells possessing this enzyme. We have employed this fluorescent probe technique to follow the early events in the lungs of rats exposed to erionite. The evidence presented shows that the mesothelial cells initially lack this enzyme but the enzyme can be detected within hours of exposure of the rat to erionite. The number of mesothelial cells possessing the enzyme steadily increased after a single exposure to the mineral until the animal finally died with a massive pleural tumour. This is the first study of such fluorescent probes in the early stages of tumour induction."}
+{"text": "Healthy Schools programmes may assist schools in improving the oral health of children through advocating a common risk factor approach to health promotion and by more explicit consideration of oral health. The objectives of this study were to gain a broad contextual understanding of issues around the delivery of oral health promotion as part of Healthy Schools programmes and to investigate the barriers and drivers to the incorporation of oral health promoting activities in schools taking this holistic approach to health promotion.Semi-structured telephone interviews were carried out with coordinators of Healthy Schools programmes in the Northwest of England. Interview transcripts were coded using a framework derived from themes in the interview schedule.All 22 Healthy Schools coordinators participated and all reported some engagement of their Healthy Schools scheme with oral health promotion. The degree of this engagement depended on factors such as historical patterns of working, partnerships, resources and priorities. Primary schools were reported to have engaged more fully with both Healthy Schools programmes and aspects of oral health promotion than secondary schools. Participants identified healthy eating interventions as the most appropriate means to promote oral health in schools. Partners with expertise in oral health were key in supporting Healthy Schools programmes to promote oral health.Healthy Schools programmes are supporting the promotion of oral health although the extent to which this is happening is variable. Structures should be put in place to ensure that the engagement of Healthy Schools with oral health is fully supported. The World Health Organisation (WHO) advocates using Health Promoting Schools/Healthy Schools (terms used interchangeably in this paper) to promote general and oral health ,2. HealtWHO guidance on Health Promoting Schools has been translated into policy in many countries. In England, the National Healthy Schools Programme (NHSP) provides strategic leadership to local Healthy School programmes (LHSPs) by endorsing a whole-school approach focused on common risk factors (CRFs); risk factors such as diet, tobacco and exercise, which are shared by the major non-communicable diseases . CurrentThe NHSP requires schools to achieve 'Healthy School' status by addressing the CRFs through focusing on four strands :Personal, Social & Health Education \u2022 Healthy Eating\u2022 Physical Activity\u2022 Emotional Health & Wellbeing\u2022 Oral health is not discussed within the NHSP, although the English oral health strategy suggests that oral health should be promoted using the CRF approach within settings such as Healthy Schools . LHSPs mA recent study in Scotland reported an association between Healthy School status and twice-daily toothbrushing for some children attending Healthy Schools in deprived areas . The autA study in Brazil has also reported oral health benefits for children attending schools engaging with the Health Promoting Schools philosophy . Schoolshow the Healthy Schools programme translates into interventions influencing oral health. Therefore the research questions being addressed were:Whilst these studies point towards Healthy Schools having a positive impact on oral health, nothing is known about What are the areas of the Healthy Schools programme which might impact on oral health? To what extent are these areas pursued within Healthy Schools programmes in the North-West of England? What are the barriers and drivers to the incorporation of oral health promoting activities within Healthy Schools programmes?Approval to carry out the study was obtained from the Central Office for Research Ethics Committees (COREC) (06/MRE/63), the Department of Health and employers of participants.. Each region of the NHSP consists of several LHSPs that operate as partnerships between local education and health agencies. Coordinators of the 22 LHSPs in the North-West of England  were identified as key informants for this study. These individuals have responsibility for managing LHSPs and as such, were considered to have the potential to provide both strategic and practical insights for the current study.The English NHSP is organised into 9 regions. The North-West region incorporates 2 large conurbations and some rural areas. Parts of the North-West region are among the most deprived areas in England, others are among the most affluent A qualitative rather than quantitative study design was selected because of the lack of previously reported data in this field. Semi-structured interview rather than focus group methodology was selected because of the difficulty in arranging for the participants to gather in one place. Interviews can also assist respondents in speaking freely . The intOral health promoting activities suitable for incorporation into the NHSP were identified from a literature search, followed by consultation with a range of senior personnel working in the field of dental public health by means of a questionnaire. A panel with expertise in the field of oral health promotion (OHP) reviewed the activities identified and thus finalised the interview schedule Table .The schedule contained questions around three themes:A. The concept of promoting oral health as part of Healthy SchoolsB. The delivery of OHP in Healthy SchoolsC. Drivers for oral health to be promoted as part of Healthy SchoolsCoordinators of the 22 LHSPs in the Northwest of England were mailed to invite them to participate and to give them information about the study. Participants who did not reply were contacted by telephone and/or email to establish whether they were willing to take part. All 22 LHSP coordinators consented to participate in the study. Participants were assured that their responses would be anonomised. Interviews were audio-taped and transcribed.A coding framework based on the themes in the interview schedule was designed. Transcripts were examined manually to identify codes using thematic content analysis and a system of constant comparison ,14. ThisThis study referred to qualitative research review guidelines to ensure its quality . SystemaAll the respondents felt that it was appropriate to promote oral health within Healthy Schools. All respondents placed OHP within the Healthy Eating strand of the NHSP. Six respondents also recognised the appropriateness of locating OHP within other strands of the programme:(numbers in brackets after each quote refer to the participant)'it goes hand in hand with the Healthy Eating standard' (9)'It's also an important part of the emotional health and ... the sex and relationship education' (22)All respondents felt that oral and general health were linked. Three participants conceptualised oral health as an indicator of general health:'the health of the gums etc is an indicator in terms of heart disease' (11)Other respondents felt that there was no distinction between oral and general health for the purposes of promoting oral health within Healthy Schools. There was also recognition that oral health had historically been separated from general health, but that it should now be included as part of general health, and the Healthy School approach was therefore a positive thing in this context:'I think the key thing is ... the linkage. Oral health has sat on its own for so long' (9)Eight participants gave schools or school nurses the responsibility for OHP, others felt that the responsibility lay solely with specialist OHP teams or jointly between Healthy Schools teams, schools and OHP teams:'it's part of what schools teach young people' (10)'It's got to be a partnership thing' (12)Many respondents acknowledged the necessity for the involvement of personnel with specialist oral health expertise.This code categorised oral health promoting activities within the main strands of the NHSP.All participants reported that schools addressing healthy eating as part of their Healthy Schools work were expected to have a healthy eating policy and to be acting on that policy. Irrespective of engagement with Healthy Schools, all schools were expected to conform to minimum nutritional standards . There wFormal oral health education and education about alcohol and tobacco fall within the PSHE strand . Although participants did not tend to make unprompted links between tobacco and alcohol and oral health, once prompted they were aware of the relevance of targeting these areas to promoting oral health. Tobacco interventions were being directed through national legislation e.g. The Smoke-free (Premises and Enforcement) Regulations (2006), as well as through Healthy Schools. Healthy Schools programmes required schools to have policies covering tobacco, alcohol and drugs. School interventions and education around these topics were more variable with some participants reporting smoking cessation workers visiting schools. In other areas schools-based smoking cessation was viewed as being inappropriate because it was felt that smoking cessation should be instigated by an individual's desire to quit.Nine respondents recognised the relevance of oral health to this Healthy Schools strand:'there's a very nice project ... about the effect of your teeth on your whole face, and your own personality ... that's about self-esteem as well' (11)Respondents were asked about two aspects of physical activity that could prevent oro-facial trauma: the use of cycle helmets and sports mouthguards. Cycle helmets were commonly being promoted either directly by the LHSP, or by their partners. Sports mouthguards were less commonly promoted and one respondent raised concerns raised about the appropriateness of promoting mouthguard use:'because of the chance of choking' (16)This code related OHP activities to the five core features of a whole school approach.Participants were generally positive about oral health being taught within schools, with most expressing that it should be taught either within PSHE or science. Not all participants were aware of precisely what was taught in relation to oral health. Some respondents expressed concerns about timetabling constraints.The physical environment of the school has the potential to impact on oral health because of its links to health and safety, accident prevention and emotional health and wellbeing. The extent to which it was being considered differed between localities. Some areas considered the physical environment of their schools as an area for schools to address after they achieved 'Healthy School' status. Others conceptualised assessing the physical school environment either as a part of ensuring that schools were using the whole school approach or as linked to the emotional health and wellbeing strand of the NHSP.All the participants except one were unaware of schools in their area having specific oral health policies; it was generally felt to be more appropriate that references to oral health should be embedded within more general policies:'it's also explicit in in you know the whole school food policy which we've modelled for them ...erm which which sort goes through ... DMFT figures ... so its sets the context of ...why it is important about healthy eating' (18)Pupil participation may impact on oral health through promoting psychological health and wellbeing. In one area pupil participation was being used to promote oral health specifically:'we ... use some of the older children to be peer educators ... we've trained the children ...and they then have gone to work with some of the nursery children' (11)Involving parents and staff in Healthy School programmes is a vital part of the whole school approach. Parents were more commonly involved in OHP in the primary than the secondary sector:'we're ... trying to educate parents of primary school children ... we emphasize that a lot more ...than we do with secondary children' (10)This code described the resources, personnel and partners involved in the delivery of OHP.Personnel involved with OHP in Healthy Schools sometimes included individuals working as core members of local Healthy Schools teams. In the majority of areas personnel also included people working for partner agencies such as OHP teams, local sports partnership teams, school nurses and drug education teams. OHP teams are generally dental nurses, hygienists, and therapists trained in oral health education and employed by the local salaried dental service. Only one participant reported that the LHSP was not working in partnership with an OHP team. The role of local OHP teams varied considerably between areas:'the OH  team come in and run a programme ... supporting the curriculum ... they've done something in terms of leaflets on resetting teeth, if they've been knocked out they ... support the work right throughout all Key Stages' (16)'they do like puppet plays as well ...around the theme of OH' (4)In one area, the issue of expertise was addressed differently; the Healthy School team had recognised that they had more expertise about delivering interventions in schools than the local OHP team. They worked with the OHP team to ensure that OHP messages were provided in the most appropriate ways:'oral health were working ... quite independently of us .... they were too focused on oral health ... there was actually a jarring happening so that when Health Promoting Schools were going in as well ... it was beginning to be seen as a bit of a nanny state .... so what we decided to do was because we had more expertise about delivering in schools ... is to make the health messages education friendly ... we started working more closely with oral health ... one of their workers actually joined our team ' (22)OHP interventions were sometimes targeted to either the primary sector and/or to those schools with the worst dental health. One reason for targeting the primary sector related to lack of uptake by secondary schools although other areas targeted the primary sector because of the perceived importance of establishing healthy behaviours at a young age.This code described challenges identified in promoting oral health in Healthy Schools.This problem emerged in relation to schools being able to choose the extent to which they engaged with their local Healthy Schools programme or with OHP interventions:'all our schools are signed up, it doesn't necessarily mean they're doing anything' (2)Seven respondents discussed that lack of expertise was a challenge in delivering OHP:'we don't go into the secondaries ... we haven't got enough medical knowledge' (22)Many of the challenges in delivering OHP in Healthy Schools discussed by participants were logistical:'if you give them water in classes, they'll just mess about with it' (10)Participants noted that there was evidence of mixed messages occurring in schools, for example with unhealthy food being served at some school events.The problem of outside vendors (ice cream vans at the school gates etc) was common to several localities. There was evidence of work going on to address the issue in six areas, by involving vendors themselves, trading standards and/or environmental health. Participants expressed a wish for guidance on this issue.The low profile of oral health was discussed by twelve respondents as a potential barrier to promoting oral health in Healthy Schools. Interviewees cited the exclusion of oral health from National Healthy Schools guidance, although they did recognise that oral health may be promoted as part of the CRF approach, despite the lack of national guidance:'it's hard because there's no specific reference to it within Healthy Schools ... at the moment the focus is on Healthy Schools status' (2)'it's almost implicit in the healthy eating work that you do. I don't think it's perhaps given as high a priority as it might do' (18)There were also comments made relating to the low profile of oral health on the local agenda:'oral health hasn't been targeted as a priority this time' (2)Respondents were also unsure if schools would make the link between Healthy Schools and oral health and recognised that this may depend on circumstances within individual schools.Problems identified specific to the secondary sector included accessing parents, engaging schools and the tight curriculum.Seventeen participants considered that oral disease in their area was a problem:'we've got the worst OH erm data in the country' (8)A few respondents did not think that oral disease was a local problem or recognised that although local levels of oral disease were high, the problem had not been prioritised:'as far as I'm aware it isn't' (19) 'it hasn't been deemed to be (a priority), .... that's not saying that it isn't' (2) In some areas oral health was a local priority:'we've specifically said good practice is linked to dental health' (15)Respondents were unaware of the existence of any national strategies or directives that would support the promotion of oral health as part of Healthy Schools:'we've not got any sort of directives, not sort of nationally' (17)Historical ways of working emerged from the data as a way to explain how many local Healthy Schools programmes had come to be so involved with oral health:'we've always done it in this area' (17)Recent evidence of an association between periodontal disease and systemic diseases such as coronary heart disease and diabetes , has broWhen interpreting the data generated from evaluations of health promotion interventions it is difficult to disentangle the intervention being studied from other interventions . In the Care is necessary in extrapolating the results of this study to wider national and international contexts. However, there is no evidence that the North-West region is different from other English Healthy School regions, in the way in which its Healthy Schools programmes engage with OHP. Further, because local Healthy Schools programmes work within the NHSP framework  and towaResults showed that some Healthy Schools programmes were relying largely on the promotion of oral health through the CRF approach, whilst others were more explicit in promoting oral health. Explicit OHP tended to be related to historical ways of working, and often involved input from local OHP teams using dental personnel. In some areas OHP teams were offering specific schools-based interventions. In other areas, OHP teams were more involved in providing advocacy and training, roles which have been recommended for oral health experts working within general health promotion frameworks -25. The OHP was most often related to the healthy eating and PSHE strands of the NHSP. Whilst it is easy to envisage the positive impact of the promotion of healthy eating within the school on levels of dental caries, it is more difficult to see how Healthy Schools programmes might impact on levels of toothbrushing, as indeed they appear to . It is wlocal Healthy School coordinators seem to have made linkages between Healthy Schools and oral health, Healthy Schools policy makers at a national level have excluded oral health from guidance. National guidance on OHP in Healthy Schools would legitimise the promotion of oral health in Healthy Schools and secure its future against the threats identified by participants in this study. The authors suggest a national document based on the WHO publication on OHP in Health Promoting Schools [The integration of OHP within Healthy Schools programmes was occurring despite participants' lack of awareness of international and national guidance in relation to oral health ,8. Curre Schools . The autThe authors declare that they have no competing interests.ES designed the study, carried out the fieldwork and drafted the manuscript. CMP and RVH assisted in the design of the study and advised on the preparation of the manuscript. All the authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:"}
+{"text": "Journal of Experimental and Clinical Cancer Research although this article had been accepted and previously published by Cancer Biotherapy & Radiopharmaceuticals [Nucleosides, Nucleotides and Nucleic Acids [Journal of Experimental and Clinical Cancer Research. The authors are deeply sorry for any inconvenience this may have caused to the editorial staff and readers.The corresponding author submitted this article  to Journeuticals . The artic Acids . Since i"}
+{"text": "This is the first report of a case-control epidemiological study on lymphomas and leukaemias occurring in Yorkshire during 1979-84. This paper deals with the results of the Hodgkin's disease analysis comprising 248 cases and 489 controls. The results indicate support for previous work with respect to small family size and past history of infectious mononucleosis. Positive observations made in a previous pilot study are also confirmed and extended with respect to associations with certain chronic skin lesions, dental anaesthesia and familial factors. Negative associations are described with respect to X-ray exposures and cigarette smoking. It is proposed that these results fit into a general hypothesis that these conditions are the result of interaction between infectious agents and altered immunity in those persons genetically predisposed."}
+{"text": "The risk of nodal metastasis is higher in women with bigger breast. It is not clear if this increase is due to the size of the breast (largely related to obesity) or is the result of larger tumour size at presentation (due to delayed diagnosis). It is hypothesised that women with large breasts are more likely to have node positive disease mainly attributable to their breast size.\u00ae computer programme.One hundred and twenty consecutive patients who underwent mastectomy during the year 2004 and 2005 for primary breast cancers in a large Teaching Hospital were included in the study. Patient's variable and tumour variable were collected and analysed by SPSSIt was found that big breasted women (those patients with mastectomy weight greater than 800 g) had a significantly greater tumour size than those with smaller breasts  but there was no significant difference in grade  or lymph node positivity  between the two groups. Although, the tumour size was significantly greater in those with lymph node metastases (p < 0.001) but mastectomy weight was not found to be significantly greater in those with lymph node metastases (p = 0.11). For patients with similar tumour sizes mastectomy weight was not significantly greater in those patients with lymph node metastases (p = 0.28).It is concluded that increased incidence of lymph node positivity at presentation big-breasted women is because of larger size of the primary tumour and not due to the size of the breast alone. The present literature on the large size of breast and the stage of breast cancer is controversial. The larger size of the breasts is more common in obesity which is associated with poor prognosis of breast cancer in both pre and postmenopausal women. It is aOne hundred and twenty primary breast cancers operated at a large Teaching Hospital were included in the study. These were consecutive patients who underwent mastectomy during the year 2004 and 2005. Patient's variable and tumour variable were collected and analysed by SPSS computer programme.Spearman correlation was used to measure association between continuous variables, the Mann Whitney test for the comparison of continuous variables between two groups and Kendall's tau-b statistic to analyse ordinal variables such as grade and lymph node positivity. Binary logistic regression analysis was used to determine whether, for patients with similar tumour sizes, mastectomy specimen weight was a significant predictor of the presence of lymph node metastases.A large breast was defined as a breast with mastectomy specimen weight of 800 grams or more. It was found that increasing weight of the mastectomy specimen was associated with increasing risk of large tumour . The tumour size was significantly greater  in those with mastectomy weight greater than 800 g  have larger tumours reported that patients with bigger breasts had larger tumours in both symptomatic and screen detected group . In a laIt is concluded that Increased lymph node positivity at presentation of breast cancer in big-breasted women is because of larger size of the primary tumour and not due to the size of the breast alone.ARC conceived the idea and coordinated the data collection and analyses, participated in all stages of the study and drafted the manuscript, CS collected the data and PN participated in the performed the statistical analysis. All authors read and approved the final manuscript."}
+{"text": "The expectant management of high grade renal injuries in hemodynamically stable children has gained increasing acceptance amongst paediatric surgeons. However, patients with grade 1V injury with complete renal transection have been identified as a subgroup with a poor outcome that may benefit from early operative intervention.Interestingly, both internal and external drainage have been independently utilised as part of the expectant approach. The former is more widely practiced and was first suggested by Haas et al who used it successfully in 5 patients with grade 1V renal trauma. Yet to be clearly established in this context is the value and timing of external drainage, particularly, when used in combination with internal stenting.Described is a child with complete renal transaction who was successfully managed with a combination of internal and external drainage. A 5 year old Caucasian male patient was admitted to a tertiary paediatric surgical centre within 1 hour of coming off a quadbike, sustaining blunt trauma to the right chest and the right upper quadrant of abdomen. Initial assessment confirmed hypovolaemic shock which responded to aggressive resuscitation as well as a tender right flank with macroscopic haematuria. Once stabilised a Computarised Tomography (CT) scan and IVP were performed which confirmed contusion of the right lower lung, fracture of several overlying ribs and complete right renal fracture with distraction of upper and lower poles (Grade1V),  scan Fig The kidneys in children are proportionally larger and have much less perirenal fat and costal protection than in adults which predisposes them to injury after blunt abdominal trauma (10% of cases) . Prompt However the management of grade IV renal injury in children is controversial, particularly with regard to the management of urinary extravasation. Grade IV trauma is defined as parenchymal laceration extending through the corticomedullary junction and into the collecting system . This reGrade 1V renal injuries with complete fracture and separation of the poles but with intact blood supply constitutes a special group with a decreased likelihood of spontaneous resolution and where early intervention may be necessary [There is currently no consensus on the optimal timing of these interventions. However from the experience of this case where a policy of early aggressive management with a combination of internal and external drainage was successfully utilised would lead us to support this approach to improve renal salvage. It would appear that reconstitution of the distracted but viable renal poles into a solitary functioning unit is possible provided the urinoma is adequately managed. Successful drainage also ensured that there was no significant residual scarring on late DMSA scanning.The expectant management of isolated high grade renal injuries with complete fracture in the haemodynamically stable patient is evolving and both internal and percutaneous drainage are crucial to the success of this approach. It seems the advances in interventional radiology are facilitating a less invasive approach to the management of these significant injuries in the paediatric population. The experience of this case reinforces a strategy which is leading to kidney salvage with minimal complications and is advocated.Consent was obtained from both parents and the involved institutions for publication of the case report.The authors declare that they have no competing interests.CH prepared the manuscript, MH provided the clinical details of the case, AM managed the case and edited the paper."}
+{"text": "The current guidelines of the European Resuscitation Council (ERC) for advanced cardiac life support recommend that endotracheal intubation \"should be attempted only if the healthcare provider is properly trained and has adequate ongoing experience with the technique.\"  One woulWithout adequate skills, not only in intubation but also in the verification of tracheal tube position, following advanced life support guidelines may not be possible without considerable risks for the patients. When German HEMS physicians assessed the tube position in patients who were initially intubated by other emergency physicians, the percentage of oesophageal intubations 6.7%) was unacceptably high . Many of.7% was uWhile the new guidelines of the Scandinavian Society for Anaesthesiologists and Intensive care medicine (SSAI) for prehospital airway management continue to recommend intubation by anaesthesiologists to secure the airway in emergencies, the importance of personal experience and skill level is pointed out as critical, in addition to the fulfillment of formal qualifications . These nConsulting and lecturing fees from VBM and Ambu."}
+{"text": "The serum ferritin concentration is increased in both acute myeloblastic leukaemia and Hodgkin's disease. In acute leukaemia the mean concentration is about ten times the normal level and is associated with a high concentration of transferrin-bound iron. In Hodgkin's disease abnormal ferritinaemia is associated with a low concentration of transferrin-bound iron and appears to result from a block of reticuloendothelial iron release. Increased concentrations of circulating ferritin have also been observed in a few cases of chronic leukaemia and myelomatosis."}
+{"text": "In \"Reframing School Dropout as a Public Health Issue\" , FreudenIt is time to include school dropout rates  among the national health objectives for 2010  to the sUniform national measures of school readiness  should also be included among current national health objectives and tracked through No Child Left Behind. Such measures would underscore the relevance of children's emotional and cognitive health to academic achievement . It would also provide schools with baselines for assessing students' academic growth, beginning in kindergarten. Most importantly, it would offer a national benchmark for assessing progress toward the national goal of ensuring that every child starts elementary school with the necessary skills to succeed and eventually graduate from high school by age 18.To the list of recommendations cited by the authors  for reduEarly childhood interventions are critical to reducing school dropouts over the long term. These programs are highly cost effective  and may Read the author's reply"}
+{"text": "The object of this study was to measure some of the differences between normal squamous epithelial cells and cells from invasive squamous carcinoma of the uterine cervix. A total of 107 patients were studied; only those specimens which when assessed by a histopathologist were thought to show classic normal features or undoubted invasive carcinoma were included in the quantitative analysis. In addition, any specimens which at the electron microscope level, showed faulty sampling or preparation were discarded, leaving us with 16 carcinoma and 15 normal specimens for detailed study.The nuclei of tumour cells had a greater area than those of normal cells; histograms of the size distribution of nuclei showed a distinctly different pattern in the 2 groups. Tumour cells had fewer ribosomes in each cubic micron of cytoplasm than had the normal cells and showed a reduction in the amount of intercellular space; in addition, the malignant cells had a smaller surface density and fewer tonofibrils in their cytoplasm. Some tumour cells had a smaller percentage of cell membrane specialized as desmosomes than the corresponding normal cells but all tumour cells had desmosomes of shorter length than normal.Discriminatory analysis, carried out with the help of a computer, allowed all of these variables to be assessed with respect to each other in order to arrive at a numerical score for each specimen. When expressed graphically, these scores showed that the populations of normal and carcinomatous cells fell into 2 separate groups. The significance of these results is discussed."}
+{"text": "The 'unopposed oestrogen hypothesis' for endometrial cancer maintains that risk is increased by exposure to endogenous or exogenous oestrogen that is not opposed simultaneously by a progestagen, and that this increased risk is due to the induced mitotic activity of the endometrial cells. Investigation of the mitotic rate during the menstrual cycle shows that increases in plasma oestrogen concentration above the relatively low levels of the early follicular phase do not produce any further increase in the mitotic rate of endometrial cells. A modification of the unopposed oestrogen hypothesis which includes this upper limit in the response of endometrial cells to oestrogen is consistent with the known dose-effect relationships between endometrial cancer risk and both oestrogen replacement therapy and postmenopausal obesity; it also suggests that the mechanism by which obesity increases risk in premenopausal women involves progesterone deficiency rather than oestrogen excess, and that the protective effect of cigarette smoking may be greater in postmenopausal than in premenopausal women. Detailed analysis of the age-incidence curve for endometrial cancer in the light of this hypothesis suggests that there will be lifelong effects of even short duration use of exogenous hormones. In particular, 5 years of combination-type oral contraceptive use is likely to reduce a woman's lifetime risk of endometrial cancer by some 60%; whereas 5 years of unopposed oestrogen replacement therapy is likely to increase her subsequent lifetime risk by at least 90%; and even 5 years of 'adequately' opposed therapy is likely to increase subsequent lifetime risk by at least 50%."}
+{"text": "An enzyme activity with the characteristics of reverse transcriptase was detected in marrow from patients with leukaemia in relapse and in firm haematological remission. The endogenous enzyme activities increased following culture, and in remission patients the enzyme activities reached levels equal to or exceeding those found in relapse."}
+{"text": "A method of comparing differences in growth rates of tumours in small groups of animals is described. A common slope can be fitted to the growth curves of a given tumour in a group of isogeneic animals. Differences between growth potentials can be demonstrated by comparing the common slope for a given tumour against that of another tumour (or the same tumour at a later stage of development).A highly significant difference is shown between the growth potential of an A-strain mammary carcinoma after 7 or after 28 days' growth in isogeneic animals. Since this increase in autonomy is reflected in the tumour's subsequent growth rate in secondary hosts, it is suggested that it involves adaptation of the tumour rather than progressive immunodepression of the primary host."}
+{"text": "Comparison of the growth of normal bone marrow cells in CDCs and in ADCs suggests that cell proliferation in diffusion chambers may result from the same precursor cell as detected by colony formation in agar culture in vitro. This proposal is supported by the suicide of approximately 46% of the ADC colony precursor cells following incubation with 3H-labelled thymidine.The conventional diffusion chamber (CDC) as described by Benestad (1970) had been modified to assay the colony forming capacity of RFM bone marrow and spleen cells in agar diffusion chambers (ADCs). The colonies are morphologically identical to those formed by the CFUc in agar culture Colony formation by haemopoietic cells taken from leukaemic mice appears to be due to the proliferation of a remaining normal cell population alone, while the leukaemic cells in the inoculum form a background of uniformly distributed blast cells. In the case of leukaemic cell culture, there are differences in the results from CDCs and ADCs, and data from colonies in leukaemic ADC cultures are similar to those from normal ADC colonies. These comparisons imply that the ADC technique may be used to monitor the functional capacity of normal bone marrow, by its ability to form colonies, during the development of leukaemia. A humoral effect of a leukaemic environment on the growth of normal bone marrow cells in ADCs has also been detected."}
+{"text": "We tested the hypothesis that Cache Valley Virus (CVV), an endemic North American bunyavirus, may be involved in the pathogenesis of human neural tube defects. This investigation followed a 1990 and 1991 south Texas outbreak of neural tube defects with a high prevalence of anencephaly and the demonstration in 1987 that in utero infection by CVV was the cause of outbreaks of central nervous system and musculoskeletal defects in North American ruminants. Sera from 74 women who gave birth to infants with neural tube defects in south Texas from 1993 through early 1995 were tested for CVV neutralizing antibody. All tested sera did not neutralize CVV. These data suggest that CVV is not involved in the induction of human neural tube defects during nonepidemic periods but do not preclude CVV involvement during epidemics. Other endemic bunyaviruses may still be involved in the pathogenesis of neural tube defects or other congenital central nervous system or musculoskeletal malformations."}
+{"text": "Histological sections of the primary tumour from 496 women with operable breast cancer have been examined for purposes of histological grading by two observers working independently. Each found a similar distribution of grade through the series, and a virtually identical influence of grade on prognosis. This close agreement occurred despite a 30% disagreement as to grade in individual cases. It is suggested therefore, that this technique while of relevance to analysis of groups of cases is of very limited reliability in individual patient prognosis."}
+{"text": "Although echinococcal disease of the liver is common in some parts of the world, it is rarely seen in theUnited States. Even from endemic areas, few reports deal with its treatment during pregnancy. A 25 year old18 week pregnant Italian woman presented with pruritis and right upper quadrant pain. Ultrasoundrevealed a cystic lesion in the left lobe of the liver. The cyst was treated by operative insertion of hypertonicsaline and capsulorrhaphy. The patient and her fetus had no postoperative complications. We believe thatthe pregnant patient with symptomatic hepatic echinococcal disease should be treated operatively and thatinsertion of hypertonic saline and capsulorrhaphy is the safest and most effective technique for both themother and fetus."}
+{"text": "Anxiety is common in cancer patient populations, and must often initially be recognized and managed by cancer care professionals. This article reviews the recent oncology and mental health literature on anxiety. The aim is to help those involved in cancer patient care who are not specialists in mental health to understand the nature of anxiety, and discriminate morbid from normal anxiety. We review recent research into the association of anxiety with events during diagnosis and management of cancer, highlighting the importance of the meaning of events to an individual as an important factor in making people anxious. Lastly we review management strategies which might be used by cancer care professionals, in particular the importance of an awareness of specific patterns of communication which may alleviate or maintain anxiety for some cancer patients. \u00a9 2000 Cancer Research Campaign"}
+{"text": "Selection of cytostatic agents for intrathecal administration is the subject of this paper.Both the toxic side effects\u2014destruction of blood-brain barrier and change of body weight\u2014and the cytostatic effects on intracranially transplanted Yoshida ascites sarcoma were investigated of intrathecal administration of various cytostatic agents. As a result, it may be concluded that Methotrexate and Endoxan and lower dose of mitomycin C are suitable drugs for intrathecal chemotherapy.Based on these findings, clinical cases of malignant brain tumours were treated with intrathecal chemotherapy.Grateful acknowledgement is made to Professor Dennosuke Jinnai for his constant interest and guidance in this investigation."}
+{"text": "The second edition of Essentials of Dermatology has come out with a new look and high standard of cover page, color illustrations and printing. Three new chapters on skin in systemic disease, skin changes of pregnancy and old age and anti retroviral therapy (ART) have been added giving a wider dimension to its contents. The existing chapters have also been revised and updated to keep pace with newer developments in dermatology.This handbook has incorporated all basic principles of diagnosis of skin diseases and provided a brief update and essential information on disease processes. An algorithmic approach to diagnosis would have added color to it. This brief but essential information on the diseases and high standard color photographs will make dermatology more accessible to new entrants Post Graduate Trainees (PGTs), general physicians as well as senior dermatologists. It is worth carrying, preserving in any library and is also recommended for all sections of the medical fraternity.One may have some reservations regarding selection criteria of most influential persons in Dermatology, Venereology and Leprosy in India but that does not necessarily undermine the quality of the book."}
+{"text": "Baculoviruses are widely used both as protein expression vectors and as insect pest control agents. This video shows how lepidopteran larvae can be infected with polyhedra by droplet feeding and diet plug-based bioassays. This accompanying Springer Protocols section provides an overview of the baculovirus lifecycle and use of baculoviruses as insecticidal agents, including discussion of the pros and cons for use of baculoviruses as insecticides, and progress made in genetic enhancement of baculoviruses for improved insecticidal efficacy. Springer Protocols to learn more about the engineering baculovirus as an insecidical agent and the oral infection techniques used in this assay.Please visit"}
+{"text": "Background: Isolated caudate lobectomy is a challenging surgical procedure for which safe and reliable techniques have yet to be developed.Methods: Isolated caudate lobectomy was performed by initial inflow control of the caudate lobe, full mobilization of the liver from the inferior vena cava by dividing all short hepatic veins, and parenchymal division dorsal to the major hepatic veins with a clockwise rotation of the liver while the liver was selectively devascularised by Pringle's maneuver and occlusion of the confluence of the major hepatic veins flush with the inferior vena cava.Results: Two patients with cirrhosis underwent this procedure successfully without intraoperative hemodynamic instability or postoperative liver dysfunction.Conclusions: This technique allows safe and truly selective excision of the caudate lobe without the need for occlusion of the inferior vena cava or venovenous bypass."}
+{"text": "Resource Allocation during an Influenza Pandemic To the Editor: Planning for pandemic influenza is accepted as an essential healthcare service and has included creation of national and international antiviral drug stockpiles and novel approaches to emergency vaccine development (Even when clear societal goals are established, much work remains to ensure that the healthcare community is equipped to steer healthcare resources to deliver these effectively (The third component of our preparation for optimally deploying standard care in a pandemic is being able to change our approach quickly as new knowledge emerges. In the so-called Spanish influenza pandemic of 1918\u201319, the unfamiliar clinical course meant that influenza was not even considered when the first cases appeared ("}
+{"text": "Parental smoking data have been reabstracted from the interview records of the Oxford Survey of Childhood Cancers (deaths from 1971 to 1976). Reported smoking habits for the parents of 2587 children who died with cancer were compared with similar information for the parents of 2587 healthy controls . Maternal daily consumption of cigarettes and paternal use of pipes or cigars were unimportant, but there was a statistically significant positive trend between paternal daily consumption of cigarettes and the risk of childhood cancer (P < 0.001). This association could not be explained by maternal smoking, social class, parental ages at the birth of the survey child, sibship position or obstetric radiography. Relations between maternal consumption of cigarettes and birth weights suggested that  smoking data were equally reliable for case and control subjects. About 14% of all childhood cancers in this series could be attributable to paternal smoking. These data were combined with smoking data from two previously published reports from the Oxford Survey  to obtain further information on risks for different types of cancer and different ages at onset of disease. Paternal cigarette smoking emerged as a potential risk factor both for the generality of childhood cancer and for all ages at onset."}
+{"text": "A previous case-control study which utilised the occupational information available on the New Zealand Cancer Registry found an increased risk of multiple myeloma in agricultural workers consistent with previous findings in the United States. The findings are now presented for the second phase of the study which involved interviewing 76 cases of multiple myeloma (who had been included in the previous study) together with 315 controls with other types of cancer. The previous finding on an excess of farmers in the case group was confirmed by the interview data . There were no significant differences between cases and controls regarding potential exposure to phenoxy herbicides or chlorophenols. There were also no significant differences regarding activities involving potential exposure to other agricultural chemicals, although the odds ratio for fencing work, which may involve exposure to arsenic and sodium pentachlorophenate, was 1.6 . The odds ratios were significantly elevated for sheep farming  and exposure to beef cattle . The odds ratio was also elevated for persons reporting a history of hay fever . Overall, these findings suggest that the search for the causes of elevated mortality in farmers from multiple myeloma should be directed to potential causes other than pesticide exposure."}
+{"text": "Human herpesvirus (HHSV) and human cytomegalovirus (HCMV) infections during pregnancy are a major concern of public health because of the risk for severe sequelae for the fetuses and the neonates and because primary infections, reinfections and reactivations can be asymptomatic. The risk for neonatal herpes is mostly congenital, while the risk for HCMV infection is either prenatal or congenital. Screening exposed women has not brought definite solutions but is currently being evaluated. Among pregnant women with active infection, evaluation of the fetus for contamination and thus for the risk for severe immediate or long-term sequelae for neonates is the major goal. Diagnostic tools are available, cell culture still being the gold standard, and polymerase chain reaction (PCR) being currently evaluated for its contribution to diagnosis of active infection. Consensus for screening pregnant women as well as achievement of antiviral vaccines are the most urgent intervention strategies to develop in the near future."}
+{"text": "Water is used in vast quantities in health-care premises. Many aquatic microorganisms can survive and flourish in water with minimal nutrients and can be transferred to vulnerable hospital patients in direct  and indirect ways . Many outbreaks of infection or pseudoinfection occur through lack of prevention measures and ignorance of the source and transmission of opportunistic pathogens."}
+{"text": "A new study described in a set of three articles provides the first comprehensive characterization of DBPs in an indoor pool environment and offers initial evidence of cellular-level effects of these chemicals in swimmers in an indoor chlorinated pool The authors assessed short-term changes in 49 healthy adults after they swam for 40 minutes in a public indoor chlorinated pool. They observed increases in two biomarkers of genotoxicity relative to the concentration of brominated trihalomethanes (THMs) in exhaled breath, which were used as a proxy of the swimmers\u2019 total DBP exposures. Those biomarkers were micronuclei in blood lymphocytes  and urine mutagenicity (a biomarker of exposure to genotoxic agents).The team also took detailed measurements of THMs in air around the pool and in exhaled breath of the swimmers before and after swimming. The investigators measured several biomarkers of respiratory effects after swimming and found changes in only one\u2014a slight increase in serum CC16, which suggests an increase in lung epithelium permeability. However, they found no evidence that DBP exposure affected lung function.In vitro assays showed the swimming pool water was mutagenic at levels similar to that of drinking water but was more cytotoxic (could kill cells at a lower concentration) than drinking water.The research team identified more than 100 DBPs in the water of the chlorinated pool as well as another indoor pool disinfected with bromine. Some of these compounds had never been reported previously in swimming pool water and/or chlorinated drinking water. The researchers acknowledge the need for further research on a variety of swimming pools under various conditions of maintenance and use as well as more complete evaluations of the uptake and potential effects of the compounds present in pool water. They also note the importance of timing in the collection of biological samples\u2014a parameter for which there was no precedent, given the lack of previous studies of this type with swimmers. Above all, they emphasize that positive health effects of swimming can be maintained by minimizing pool levels of DBPs."}
+{"text": "Randomised controlled trials (RCTs) represent the gold standard methodological design to evaluate the effectiveness of an intervention in humans but they are subject to bias, including study publication bias and outcome reporting bias. National and international organisations and charities give recommendations for good research practice in relation to RCTs but to date no review of these guidelines has been undertaken with respect to reporting bias.National and international organisations and UK based charities listed on the Association for Medical Research Charities website were contacted in 2007; they were considered eligible for this review if they funded RCTs. Guidelines were obtained and assessed in relation to what was written about trial registration, protocol adherence and trial publication. It was also noted whether any monitoring against these guidelines was undertaken. This information was necessary to discover how much guidance researchers are given on the publication of results, in order to prevent study publication bias and outcome reporting bias.Seventeen organisations and 56 charities were eligible of 140 surveyed for this review, although there was no response from 12. Trial registration, protocol adherence, trial publication and monitoring against the guidelines were often explicitly discussed or implicitly referred too. However, only eleven of these organisations or charities mentioned the publication of negative as well as positive outcomes and just three of the organisations specifically stated that the statistical analysis plan should be strictly adhered to and all changes should be reported.Our review indicates that there is a need to provide more detailed guidance for those conducting and reporting clinical trials to help prevent the selective reporting of results. Statements found in the guidelines generally refer to publication bias rather than outcome reporting bias. Current guidelines need to be updated and include the statement that all primary and secondary outcomes prespecified in the protocol should be fully reported and should not be selected for inclusion in the final report based on their results. Randomised controlled trials (RCTs) are planned experiments, involving the random assignment of patients to interventions, and are seen as the gold standard of methodological designs to evaluate the effectiveness of a treatment in medical research in humans .However, empirical research consistently suggests that published work is more likely to be statistically significant P < 0.05) than unpublished research, and significant results have a higher probability of being published than non-significant outcomes . Evidenc than unpOutcome reporting bias (ORB) has been defined as the selection on the basis of the results of a subset of the original variables recorded for inclusion in publication of trials . Recent The registration of RCTs before initiation, on clinical trial registries , is one Organisations that fund clinical trials often issue research guidelines to aid trialists in the conduct of their study. A review of these guidelines has been conducted to discover how much guidance research funders give concerning the publication of results. That review is the focus of this report.Particular international guidelines [ICH Harmonised Tripartite Guideline for Good Clinical Practice (E6) , The EU The International Conference on Harmonisation Good Clinical Practice (ICH GCP) guideline came into effect in 1997 and \"is an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve the participation of human subjects .\" It wasRegarding the primary outcome of a trial, the ICH GCP guidelines state \"The primary measurements and endpoints used to determine efficacy should be clearly specified. There should generally only be one primary variable. The primary variable should be specified in the protocol, along with the rationale for its selection. Redefinition of the primary variable after unblinding will almost always be unacceptable, since the biases this introduces are difficult to assess.\" The guidelines also state that \"The results of a clinical trial should be analysed in accordance with the plan prospectively stated in the protocol and all deviations from the plan should be indicated in the study report. In the statistical section of the clinical study report the statistical methodology should be clearly described including when in the clinical trial process methodology decisions were made.\" This indicates that the primary outcome should usually not change between protocol and publication of the trial report; if there is a change, it should be documented and explained in the trial report.The Declaration of Helsinki  was firsThe CONSORT  Statement is intended to improve the reporting of a randomised controlled trial . It compThe EU Clinical Trials Directive 2001 (updated in 2005)  was tranA survey of major research organisations and UK charities  and 2 charities have been incorporated into Epilepsy Research UK (Epilepsy Research Foundation and Fund for Epilepsy).Data from all organisations and charities were entered into a Microsoft Access database with data entry screens in the form of the original questionnaire  This would cover the issue of ORB as any legitimate changes to changes of outcomes should be reported. Under \"trial publication\" we sought any statement referring to publication . For \"monitoring against guidelines\" we looked for a reference to monitoring for adherence to the published guidelines.Descriptive results from the questionnaire are presented. Data are tabulated and excerpts found in the guidelines relating to the issue of outcome reporting are used to support statements made.Twenty five organisations were contacted of which 17 were eligible. There were 115 charities listed on the AMRC website  of which 56 were eligible , while others proved more difficult to find. The websites for Health Technology Assessment (HTA) and National Institute of Health (NIH), for example, provided a lot of information making it difficult to find the required guidelines.Fifty two charities and 14 organisations had guidelines for RCTs or sent the terms and conditions of a grant. There was limited contact with one charity and two organisations (and there was no relevant information on their websites), one charity and one organisation said they had no guidelines and two charities would not send their guidelines/terms and conditions due to confidentiality. Eight of the charities and three of the organisations did not respond when we asked them to check the information we had extracted.The guidelines were requested as per Appendix 2  organisations/charities stated that the guidelines were sent by post/email (11 (37%)), supplied with the grant application (11 (37%)) or researchers were referred to their website (8 (26%)).Table Of the guidelines issued by the organisations and charities, 19 (26%) stated explicitly that a trial should be registered although a further 29 (40%) referred to trial registration implicitly through their reference to other guidelines such as AMRC, MRC or the Department of Health Research Governance Framework. Protocol adherence and protocol amendment were discussed explicitly in 32 (44%) and implicitly in 26 (36%) of the guidelines although not specifically in relation to outcomes; they state only that the protocol should be followed, all major amendments need ethics committee approval (or similar) and minor amendments need to be recorded. Publication was explicitly referred to in 49 (67%) and implicitly in 14 (19%) of the guidelines/terms and conditions. They state that trials should be monitored with regards to the guidelines (47 (64%) explicitly and 12 (16%) implicitly). Publication of negative and positive findings were explicitly referred to in 11 (15%) and implicitly in 27 (37%) of the guidelines/terms and conditions. The large majority refer to other guidelines  or ORB (selective non-publication of outcomes). The empirical evidence of publication bias was first seen in the early 1990's  and muchOrganisations tended to have their own guidelines whereas the charities mostly had terms and conditions but referred to some of the organisations' guidelines. This may reflect some of the charities being small and that some had only recently begun to fund RCTs.p-value only), and in addition may help identify outcomes that have not been reported, these recommendations alone will not prevent the selective reporting of outcomes. The CONSORT statement does not state that all outcomes that were included in the protocol should be stated in the methods section and reported in the results section of the final report. It also does not state that outcomes should not be upgraded or downgraded between the protocol and final report, or that new outcomes should not be added or old outcomes deleted based on their results. Therefore even when trialists follow the CONSORT Statement, it would be impossible to determine whether all outcomes in the protocol are reported in the final report. However, these concerns will be addressed in the revision of CONSORT that is under way. The CONSORT Statement  addresseSince this work has been completed, the members of the WHO Registry Platform Working Group on the Reporting of Findings of Clinical Trials have proposed that \"the findings of all clinical trials must be made publicly available .\"In the USA legislation is in place so that legally researchers are required to make their findings publicly available within a specific timeframe . The legOutcome Reporting Bias in Trials (ORBIT) project [This review forms part of the  project . It has Our review indicates that there is a need to provide more detailed guidance for those conducting and reporting clinical trials to help prevent the selective reporting of outcomes. Current guidelines need to be updated, as many include statements regarding the publication of 'negative' studies to prevent publication bias but do not go as far as mentioning ORB. In the MRC guidelines the statement 'all outcomes stated in the protocol should be fully analysed' needs to be extended to specify that prespecified primary and secondary outcomes should be fully reported and that outcomes should not be selected for inclusion in the final report based on their results. Recommendations for text to include in research funders' guidelines are suggested (see Additional file The next step is to conduct a systematic review of empirical studies that have compared protocols to publications, to assess their adherence to specified guidelines. It would then be important to conduct a survey of trialists to see which guidelines they follow and their adherence to them, to assess their understanding of the issues discussed in this paper.AMRC: Association for Medical Research Charities; CONSORT: Consolidated Standards of Reporting Trials; HTA: Health Technology Assessment; ICH GCP: The International Conference on Harmonisation Good Clinical Practice; MHRA: The Medicines and Healthcare products Regulatory Agency; MRC: Medical Research Council; NIAID: National Institute for Allergies and Infectious Diseases; NIH: National Institute for Health; ORB: Outcome Reporting Bias; RCT: Randomised Controlled TrialThe authors declare that they have no competing interests.DGA conceived the idea for reviewing guidelines following the DAMOCLES project. All authors contributed to the design of the study.KD contacted all organisations and charities, read through the guidelines obtained and drafted the manuscript. PRW did a random check of the guidelines to ensure all relevant details had been extracted and also provided comments on drafts of the manuscript. DGA and CG provided comments on all drafts of the manuscript.Appendices for review of guidelines. A list of charities and organisations that were contacted and questionnaires that were completed.Click here for fileTable 3 Summary of organisation guidelines. A table of findings for organisations that issue guidelinesClick here for fileTable 4 Summary of findings for charities that issue guidelines or terms and conditions. A table of findings for charities that issue guidelinesClick here for fileText box 1: Recommendations for text to include in research funders' guidelines. Recommendations for text to include in research funders' guidelines.Click here for file"}
+{"text": "Dear Sir,I read with interest article by Sarin and Manchanda.Correction of chordeeI think authors had been lucky to correct the chordee by simple penile degloving. In my experience such patients of mid-penile and proximal penile hypospadias with hypoplastic urethra of 1.92 cm have significant chordee which is unlikely to be corrected by penile degloving. The authors have not mentioned whether they performed Gitte's test or not which is a sure way to confirm correction of chordee. Mobilization of hypoplastic and proximal urethra along with corpus spongiosum is my preferred choice for correction of chordee in such cases or alternatively plication procedures can be performed. The added advantage with mobilization of urethra and corpus spongiosum is easy and tension-free tubularization of urethral plate.Rational approach in utilization of hypoplastic urethraThis thin distal urethra is devoid of corpus spongiosum as spongiosum is spread lateral in \u201cY\u201d manner and is attached to the glans. HypoplasThe issues which need to be resolved in the preservation of hypoplastic urethra:Preservation of hypoplastic urethra depends on the type of hypospadias, degree of chordee and type of repair chosen. The thin urethra can easily be preserved and utilized in urethral plate preservation procedures like TIP in distal hypospadias with minimal or no chordee. Spongioplasty in these cases will reconstruct the near normal urethra and will help in correction of chordee. It is reThe authors have come across one case with chordee without hypospadias but which type, has not been mentioned. But by the description it looks like type III, where corpus spongiosum is well developed, but only dartos fascia is deficient and chordee correction is possible by penile degloving. Though some authors have advised reconstruction of the entire dysplastic urethra when the paper-thin urethra of type I chordee without hypospadias is associated with an abnormal meatus. But with"}
+{"text": "The majority of human anti-tumour monoclonal antibodies (Mabs) isolated to date have been disappointing. Firstly, they react or cross react with intracellular cytoskeletal proteins or nuclear antigens and therefore are of limited value as blood borne agents. They are also generally of the IgM isotype and show relatively low intrinsic affinity for the primary epitope. Secondly, such Mabs can be generated from normal, non tumour bearing subjects at a frequency comparable to their production from tumour patients. This latter observation is true also for common autoantigens such as DNA and IgG since Mabs to these can also be generated from normal subjects in addition to autoimmune individuals. This article rationalises these observations in the context of the requirement for clinical use for human Mabs. It discusses the evidence that there is a potentially useful B cell response to be immortalised, and examines the consequences of the newly recognised phenomenon of monoclonal antibody multispecificity both on the methodology of their generation and on their subsequent use as imaging and therapeutic tools."}
+{"text": "Gravimetric and histological studies of lymphoreticular tissues during growth of a syngeneic squamous cell carcinoma in Wistar rats show that the regional lymph node anergy reported previously in this system is associated with replacement of paracortical small lymphocytes by large blastoid cells. The regional node continued to gain weight throughout the period of anergy and showed no atrophy and minimal necrosis. Over the same period the spleen increased in both weight and cytotoxicity."}
+{"text": "Gastrointestinal stromal tumour (GIST) is the commonest mesenchymal tumour to affect the gastrointestinal tract.Appropriate management requires accurate diagnosis and the skills of a multidisciplinary team. Surgery is the only curativetreatment option and should be performed whenever feasible, by experienced personnel. For patients with advancedunresectable or metastatic disease, the receptor tyrosine kinase inhibitor imatinib offers effective therapy and can provideeffective palliation for the majority of patients with this disease. The background to this recent development and aguideline for the management of GIST is proposed."}
+{"text": "This approach is thought to be of greater promise than the antiproliferative screens which discovered cytotoxic agents and dominated cancer drug discovery for 60 years. However, one cannot lose sight of the fact that these targets exist in the cellular environment consisting of many additional influences on target function, and that effective drug treatment will take into account drug uptake, metabolism and elimination at the level of the cell as well as the organism. A key goal is to define for the new millennium a path to cancer drug discovery and development which accounts for the cancer cell phenotype in its totality rather than as arising solely from single molecular targets. The US National Cancer Institute maintains a cell-based drug discovery screen which can define a context for drug action in the milieu of more than 300 molecular targets and thousands of gene expression patterns which have been measured in the 60 human tumour cell lines which comprise the screening panel. The challenge of the millennium will be addressed by molecules active against defined targets but with selectivity of action occurring in the milieu of deregulated cancer cell biology in all its aspects. \u00a9 2000 Cancer Research Campaign"}
+{"text": "Recent investigators have used several indications to incorporate laparoscopy in the management of patients with cervical cancer. This manuscript reviews the current literature on the role of modernoperative laparoscopy in early cervical cancer and recommends a simple approach for its use in thesepatients."}
+{"text": "A study of parental cancer in 326 children referred to a single Paediatric Oncology Unit found a significant increase in breast cancer in mothers of children with solid tumours. The 5 tumours found were 8.9 times the expected number. This increase could not be accounted for by any of the known risk factors for breast cancer. The incidence of cancer in mothers of leukaemic children and in all groups of fathers was not significantly raised. Further prospective studies in the mothers of young children with soft tissue tumours are needed to clarify the groups at risk and to determine whether counselling and surveillance of these mothers is appropriate."}
+{"text": "Bronchogenic carcinoma is an uncommon neoplasm in the Nigerian. Endocrine manifestations of pulmonary neoplasm are even more uncommon in Nigerians or elsewhere. The association of gonadotrophin activity with an anaplastic carcinoma of the lung in a 25-year-old Nigerian housewife forms the basis for this communication. The successful removal of a left lower lobe neoplasm in the patient who had manifested with menometrorrhagia and abnormal breast lactation was followed by a normal pregnancy and delivery of a normal baby boy within 12 months following the lobectomy."}
+{"text": "Tobacco use is the largest global threat to public health and is anticipated to kill 1000 million people prematurely this century . This exSubstantial research by health professionals, and public health policy advocates have indicated different avenues through which adolescent smoking can be prevented at a population based level, key points which are depicted in the Tobacco Control Funnel in Figure One of the most discussed ways of reducing tobacco use among adolescents is by increasing the price of tobacco products, through a regulated rise in taxation . AdolescRestricting smoking areas also play a key role in promoting the populations health, not only by reducing the negative ramifications of exposure to second hand smoke but also by reducing cigarette consumption by restricting the smoker's ability to smoke under certain situations. Furthermore, smoke free legislations are also associated with a increased rate of smoking cessation . This enIndustry advertising and brand imagery are also associated with smoking susceptibility among adolescents, with the implementation of advertising bans a core element of comprehensive tobacco control measures and a central part of the Framework Convention on Tobacco Control (FCTC) .Tobacco Induced Diseases by Wilson N et al., who indicated an abnormal distribution of such graphic warning labels within a Canadian community [Research has indicated that adolescent smoking rates are higher in areas with a higher density of tobacco advertisements, thus increasing the community and social acceptance of smoking as part of daily life . In addiommunity .The third aspect of the Tobacco Control Funnel for preventing adolescent smoking is to educate the adolescent, the parent and the community. School based educational programmes that focus on health promotion and tobacco use, are a key element of this avenue and their importance in health education has been stressed by previous researchers . As closTobacco Induced Diseases strongly supports.Taking all the above into account, the need for collecting translational research at a national level is imperative. This community oriented research is needed to provide the society and public health advocates with the original national data required so as to de-normalise tobacco use and prevent adolescent smoking on a country to country basis, an action which"}
+{"text": "The evidence base for head and neck cancers is low with relatively few randomized controlled trials of the two main treatments, surgery and radiotherapy. The aim of the study was to investigate the patterns of surgery and radiotherapy treatment for head and neck cancers in three large areas of England and to investigate their effects on survival. This was a retrospective study of 13 510 cases of head and neck cancers  diagnosed and treated from 1984 to 1992 in England. We undertook multivariate analyses of survival using a step-wise Cox proportional hazard model and Kaplan\u2013Meier analysis. There were regional variations in the treatments given to patients. Four in ten patients did not receive currently recommended treatments. In multivariate analyses treatment content and timing had an independent effect on survival. Better survival was associated with surgery for mouth cancers, radiotherapy for laryngeal cancers and combined treatment for pharyngeal cancers independent of tumour and demographic factors. Further research is needed to investigate the findings of this study through large randomized controlled trials and multi-centre audits. \u00a9 1999 Cancer Research Campaign"}
+{"text": "Aminoglutethimide has been used in combination with hydrocortisone in patients with advanced prostatic cancer with the rationale that it causes a 'medical adrenalectomy'. Both objective and subjective responses have been recorded. We have examined the effect of AG and HC alone and in combination on plasma androgen levels throughout the day in two studies on 11 such patients. Whilst AG combined with HC led to a significant suppression of both testosterone and androstenedione levels, the suppression with HC alone was significantly greater, indicating that any beneficial clinical effects of AG in these patients is not due to its suppression of adrenal androgen secretion."}
+{"text": "Gross cystic breast disease is a common condition. Women with apocrine breast cysts may be at higher risk of breast cancer than women with cysts which are lined by flattened epithelium. Apocrine cysts have been shown to be associated with higher intracystic levels of dehydroepiandrosterone sulphate and intracystic sodium to potassium ratios of less than 3. In this study we measured the concentrations of epidermal growth factor, dehydroepiandrosterone and its sulphate in breast cyst fluid. The concentrations of all three analytes were significantly higher in cysts with intracystic Na+/K+ ratios of less than 3 than in cysts with electrolyte ratios of greater than or equal to 3 (P less than 0.001). The higher levels of EGF in cysts with low intracystic electrolyte ratios may provide an explanation of why women with apocrine cysts may be at greater risk of breast cancer. Positive correlations were obtained between concentrations of EGF and DHAS and between EGF and DHA, compatible with the view that intracystic EGF levels may be androgen-modulated. A positive correlation was also obtained between DHA and DHAS concentrations which supports the view that DHA in cyst fluid may be derived from the metabolism of DHAS in the breast cyst wall."}
+{"text": "Inocula of cultured sheep cells that had been transformed with FeSV were injected into the legs of sheep so that the changes in the cellular and humoral composition of the efferent lymph from the regional node could be studied throughout the immune responses. The times at which immunoblasts and specific antibodies appeared in the lymph were similar to those recorded during responses to conventional antigens. The antiboides were mainly 7S, G1 immunoglobulins directed against virion antigens on the membranes of the transformed cells."}
+{"text": "First and foremost, our data from Nevada  should np = 0.05 , thus indicating the temporal correspondence between elevated tungsten in Fallon and the childhood leukemia cluster.The comparison of real interest was between Fallon and other towns of west-central Nevada. Tree-ring tungsten in Fallon was not significantly different from that of other towns of west central Nevada during the tree-ring period centered on 1991 [Figure 4 in our article ], beforeThe Centers for Disease Control and Prevention (CDC) conclusion that tungsten is not mathematically associated with the leukemia cases of Fallon  is basedOur environmental research in Fallon has followed an ecologic approach with the philosophy that greater variability in exposure between different towns is more important than the minor variability in exposure within communities . The entEven with this preponderance of evidence showing spatial and temporal patterns of airborne tungsten in Fallon, we still have not concluded in any of our reports on Fallon that exposure to tungsten causes leukemia. Quite the opposite: We have acknowledged that environmental data alone cannot lead to such a conclusion and that direct biomedical testing is needed to establish a causal linkage between tungsten and leukemia.Years ago in an article on disease cluster research,"}
+{"text": "The cytolethal response to treatment with prednisolone was investigated in vitro in eight human lymphoblastoid cell lines containing varying concentrations of specific cytoplasmic glucocorticoid receptors. A similar response was observed in seven of the lines irrespective of their concentration of cytoplasmic receptors and pharmacological doses of steroid, well above those required to saturate receptors in cell-free extracts, were required for a massive lethal response. One cell line derived from Burkitt's lymphoma was refractory to lethal effects even with pharmacological doses of steroid. A similar unresponsiveness to the cytolethal effect of prednisolone in vitro was observed in fresh lymphoblasts derived from patients with acute lymphoblastic leukaemia despite evidence of a satisfactory clinical response to therapy which included steroid. The resistance of human lymphoblastoid cells to treatment with glucocorticoids in vitro may result from a defect in activation subsequent to the binding of steroid to cytoplasmic receptors."}
+{"text": "The cylindrical/polygonal mouse holder has semitransparent rainbow bands on its side surface forthe acquisition of spectrally resolved data. Numerical studies and experiments are performed to demonstratethe feasibility of this system. It is shown that bioluminescent signals collected using our system can producea similar BLT reconstruction quality while reducing the data acquisition time, as compared to the sequential dataacquisition mode.We describe the system design of the first bioluminescence tomography (BLT) system for parallel acquisition of multiple bioluminescent views around a mouse in a number of spectral channels simultaneously. The primarycomponent of this BLT system is a novel mirror module and a unique mouse holder. The mirror module consists ofa mounting plate and four mirrors with stages. These mirror stages are right triangular blocks symmetricallyarranged and attached to the mounting plate such thatthe hypotenuse surfaces of the triangular blocks all make 45"}
+{"text": "Four human and 4 rat astrocytomata and mammalian adult brain and spinal cord were examined by indirect immunofluorescence with human serum containing smooth muscle antibody. Cryostat sections of astrocytomata showed staining of the tumour cell cytoplasm and processes while in normal adult brain and spinal cord the entire astrocyte stained. Impression film and tissue culture monolayers of astrocytomata showed staining of cell processes and a fine, filamentous network in the cell body. The reaction with astrocytoma tumour cells was stronger than that with the corresponding normal astrocytes. Specificity of the staining reaction was established by its prevention on neutralization absorptions of the serum with extracts or homogeneous of smooth muscle. The presence of smooth muscle-associated antigen in astrocytes and astrocytomata is indicative of contractile protein providing a mechanism of cell movement in vivo."}
+{"text": "Noradrenaline induced changes in the distribution of blood flow in implanted tumour and normal liver tissue was measured using blood flow tracer microspheres. The ratio of embolised microspheres in tumour compared to normal tissue was determined before and after the intravenous infusion of noradrenaline, propranolol and a combination of the two drugs. The ratio was significantly decreased by noradrenaline alone but significantly increased when propranolol was added to the infusate. Propranolol had no effect on the ratio. The drug combination increased the tumour to normal ratio by approximately 69% and also doubled the proportion of microspheres entering the internal tumour circulation. This represents an enhanced relative blood supply to tumour and would provide a means of preferential carriage of blood borne cytotoxic agents to tumour tissue rather than normal tissue."}
+{"text": "The effect of exogenous sex hormones on the cell mediated response in male and female mice has been studied by measuring the subcutaneous growth of HeLa tumour nodules and the variation in the total lymphocyte count. It was found that oestrogen treated male and female mice experienced a profound lymphopenia which was vary rapid in onset. Concurrent with the lymphopenia there was prolongation of HeLa tumour nodule growth in female mice, but not in males. A lymphopenia occurred in androgen treated male mice with subsequent prolongation of HeLa tumour nodule growth, and a lymphocytosis in female mice, with reduction of HeLa tumour nodule growth."}
+{"text": "The role in which electronic endoscopy plays is important in EMR. It is useful in diagnosis and treatment of gastric cancer from a clinical viewpoint. EMR with use of electronic endoscopy allows bettercoordination between the operator and assistants, and thus improves the results further."}
+{"text": "The use of cryotherapy for the treatment of some unresectable liver tumours has been clearlyestablished as a therapeutic option. Intra-operative ultrasound has enhanced the process by enablingthe surgeon to identify hepatic lesions and to allow visualisation of the freezing process to ensure thatthe cryolesion will include the tumour mass. The purpose of this paper is to provide a practical guide tosurgeons who wish to perform cryotherapy of liver tumours. Patient selection and anaestheticconsiderations are important. The surgeon should be able to deal with the complications ofcryotherapy, particularly the intra-operative haemorrhage which may arise from cracking of thehepatic parenchyma as the iceball thaws. Follow-up is based on tumour marker assay and imaging ofthe liver and repeat cryotherapy can be considered for selected cases."}
+{"text": "Background. Metastatic spread of soft tissue sarcomas to the digits is            extremely rare and metastasis of MFH to the fingers and toes has not been documented.            Purpose. We present two case reports of metastatic spread from a giant            cell rich malignant fibrous histiocytoma to the digits and discuss their management."}
+{"text": "D. latum and the closely related sea gull tapeworm, D. dendriticum, have well-established endemic life cycles in a series of glacial lakes that dot Region XIX and Region X in northern Chilean Patagonia. Infections with these parasites have been detected in this geographic area since the 1950s in persons who ingested uncooked fish from these lakes and also in animals (\u2013D. latum is transmitted to humans by plerocercoid larvae present in fish meat and visceral organs (\u2013\u2013\u2013During the past 55 years, work by Chilean parasitologists has demonstrated that native species and introduced salmonid fish are infested with Diphyllobothrium plerocercoids in these lakes (\u2013\u2013,\u2013The Brazilian studies did not detect Diphyllobothrium plerocercoids in several samples of Chilean salmon tested after the first human cases of diphylobothriasis appeared (\u2013,\u2013Traditionally in Europe and North America, infections with fish tapeworms were incurred during the preparation of gefilte fish by Jewish women who tasted bits of uncooked freshwater fish and thus ingested plerocercoids (\u2013Thus, to avoid new human outbreaks of fish tapeworm in other geographic areas where this parasite does not exist, salmon originated from aquaculture should not be eaten raw, at least not until it has been frozen under the conditions discussed above. Assuming the epidemiologic information presented here explains the appearance of the fish tapeworm outbreak in Brazil, it would be preferable, in terms of sanitation, for the Chilean aquaculture industry to stop growing salmon smolt in the lakes in the areas where diphyllobothriasis is endemic in humans and animals (,This epidemiologic event may also be understood as cautionary tale, and 1 more example of the dangers entailed by the globalization of food supply and of the rapidly changing global eating habits that facilitate the distribution of human and animal pathogens worldwide. The expansion of diphyllobothriasis-endemic areas in Chile may, in turn, facilitate the appearance of future outbreaks of this disease as the aquaculture industry expands to these new infested areas and the market for Chilean salmon enlarges worldwide. The increased popularity of eating uncooked fish in sushi and ceviche will also be a factor in the emergence of future outbreaks of this disease ("}
+{"text": "The choice of calibration policy is of basic importance in analyticalchemistry. A prototype of the practical calibration problem isformulated as a mathematical task and a Bayesian solution of theresulting decision problem is presented. The optimum feedbackcalibration policy can then be found by dynamic programming. Theunderlying parameter estimation and filtering are solved byupdating relevant conditional distributions. In this way: thenecessary information is specified ; the relationship of the information gained from acalibration experiment to the ultimate goal of calibration, i.e., tothe estimation of unknown samples, is explained; an ideal solutionis given which can serve for comparing various ways of calibration;and a consistent and conceptually simple guideline is given forusing decision theory when solving problems of analytical chemistrycontaining uncertain data. The abstract formulation is systematicallyillustrated by an example taken from gas chromatography."}
+{"text": "In order to predict the metabolic fate of an arbitrary compound based solely onstructure, it is useful to be able to identify substructural \u2018functional groups\u2019 that arebiochemically reactive. These functional groups are the substructural elements thatcan be removed and replaced to transform one compound into another. This problemof identifying functional groups is related to the problem of classifying compounds.The research presented here discusses the state of the art in biochemical databasesand how these sources may be applied to the problem of classifying compounds basedsolely on structure. We describe a biochemical informatics system for processingmolecular data and describe how 100 255 compositional (hasA) relationships areinferred between 835 abstractions and 9500 metabolites from the KEGG Liganddatabase. Specifically, we focus on the identification of amino acids and consider waysin which the inference of biochemical ontologies for metabolites will be improved inthe future."}
+{"text": "An attempt has been made to construct an assay potentially suitable for use with primary cultures of human tumours to measure the survival of exponentially growing monolayer cultures after exposure to anti-neoplastic drugs. Cell survival was assessed using their protein synthetic capacity after removal of drugs. HeLa cells were employed to avoid the ingerent variability and heterogeneity of primary cultures from human tumours, and an assay has been constructed using microtitration trays to provide large numbers of replicate cultures without the requirement of a large number cells. An increase in the duration of the exposure to drug increased sensitivity in nearly all cases examined. Similarly, an increase in the period of culture following drug removal produced increased sensitivity to alkylating agents but allowed recovery from exposure to certain cycle-dependent drugs. Some of the drugs used were shown to be unstable under culture conditions and vinblastine was actively metabolized, although this instability was not necessarily reflected in the time course of the drug's effect. Mustine sensitivity was shown to be reduced by an increase in cell density at a level where density limitation of 3H-thymidine incorporation becomes apparent. These variations and possible methods of minimizing their effects are discussed."}
+{"text": "We surveyed physicians and veterinarians in Wisconsin about the risk for and prevention of zoonotic diseases in immunocompromised persons. We found that physicians and veterinarians hold significantly different views about the risks posed by certain infectious agents and species of animals and communicate very little about zoonotic issues; moreover, physicians believe that veterinarians should be involved in many aspects of zoonotic disease prevention, including patient education."}
+{"text": "The blastogenic response to a crude cell extract of ovarian cancer cells has been studied in 48 patients with ovarian cancer , in 26 female controls matched for age and in 18 female patients with other types of cancer in remission from disease. The responses in ovarian cancer patients in remission and relapse were considered separately. The blastogenic responses to cell extracts of foetal ovary, foetal lung, foetal liver and normal adult ovary were also assessed in a proportion of all 3 groups. The blastogenic responses to ovarian cancer and foetal ovary cell extracts were found to be significantly greater in the ovarian cancer patients in remission than in the controls, but the responses to ovarian cancer extract were not greater in the relapse group or in patients with other cancers. As a blastogenic response to normal ovarian extract was also present in some of these patients, the data so far do not support the hypothesis of a tumour specific antigen. This tumour associated response may be occurring to determinants in foetal or adult ovarian tissue to which the patient becomes sensitized in malignant disease. The response is complex and the nature of the antigen requires further analysis."}
+{"text": "Metastatic melanoma of the common bile duct (CBD) is very rare, with only 18 cases reported so far.. A compuThe first case of a metastatic melanoma to the bile duct was described by Spigelberg in 1895 and the second by Duval in 1908. The melaIt seems reasonable to perform radical surgical resection in patients with potentially curable disease and isolated deposits in the bile duct. If there is a concurrent metastatic disease elsewhere, it is prudent to adopt a less-aggressive approach in order to relieve obstructive jaundice, such as the bypass procedure or stenting.Patients with gastrointestinal symptoms and a history of melanoma should be investigated for the presence of gastrointestinal metastases even if the original primary malignancy was diagnosed years before the patient presentation."}
+{"text": "Sir,Chlamydia trachomatis infection also lies in the fact that it is the most common reportable infectious disease in the United States of America.[Chlamydia trachomatis infection. This change occurred because of recent evidence supporting azithromicin as safe and effective during pregnancy.[We agree with the readers of our article \u201cApproach to Urinary Tract Infection\u201d when they point out that it is important to treat both gonorrhoea and Chlamydia in a patient of urethritis simultaneously. Gonorrhoea need not be treated if excluded after proper testing and investigation. Importance of  America. Azithromregnancy.Both Gonococal and Chlamydial infections are sexually transmitted diseases (STDs) and the standard practice is to recommend treatment of sex partners of the patients of these infections to decrease the risk of reinfection. The primary goal is for the patient\u2019s sex partner to be examined by a physician for testing, treatment and education. However, there may be clinical situations in which this cannot be accomplished . In these circumstances, the Center for Disease Control recommends that physicians consider using \u201cexpedited partner treatment.\u201d This is the practice of treating sex partners of persons diagnosed with an STD without medical evaluation or prevention counseling by providing the patient with appropriate treatment to administer to his or her partner."}
+{"text": "The T lymphocytes populations of 22 young healthy adults, 21 healthy middle aged and older blood donors, 35 non-pregnant women of child bearing age and 14 patients with advanced malignant disease were assessed and compared. It was found that the mean T cell counts in the middle aged and older controls were significantly lower than in the healthy young adults and were further reduced in the patients with malignant disease. The addition of the proteolytic agent brinase (protease 1 obtained from Aspergillus oryzae) to the rosetting test increased the T cell counts signficantly in all groups. This was mot marked in the older age groups and the patients with malignant disease. The proteolytic agent is shown to exert its effect on the lymphocytes in the test. Slow intravenous infusion of either brinase or streptokinase into patients with malignant disease is shown to result in increased T lymphocyte counts pari passu with a restoration of skin allergy. The significance of these findings and possible mode of action of the proteolytic agents in increasing T cell activity are discussed."}
+{"text": "Insecticide resistance has been a problem in all insect groups that serve as vectors of emerging diseases. Although mechanisms by which insecticides become less effective are similar across all vector taxa, each resistance problem is potentially unique and may involve a complex pattern of resistance foci. The main defense against resistance is close surveillance of the susceptibility of vector populations. We describe the mechanisms of insecticide resistance, as well as specific instances of resistance emergence worldwide, and discuss prospects for resistance management and priorities for detection and surveillance."}
+{"text": "The cytocidal properties of metronidazole against hypoxic mammalian cells are described. This chemotherapeutic action has been shown to be dependent on drug concentration and duration of exposure. The x-ray TCD50 for a murine anaplastic carcinoma was reduced from 6081 rad to 4643 rad when animals were given metronidazole orally for 36 h before radiation treatment. The effect is attributed to the direct killing of hypoxic tumour cells by a mechanism analogous to that proposed for the action of the drug on anaerobic micro-organisms. It is concluded that further work with metronidazole as a cytotoxin specific for hypoxic cells is warranted, particularly in view of the reported lack of toxicity associated with the preliminary clinical use of the drug as a radiosensitizer in man."}
+{"text": "Should a medical practitioner be aware of ethics? Does knowledge of ethics make you a thoughtful and competent doctor? The society expects medical practice to be based on sound ethical principles. But then what are these principles? Who decides what is unethical? Does ethics vary among different groups, societies or countries? Why more and more medical trials are now being conducted in the third world countries? Does the poor unsuspecting population of the third world become a guinea pig for the multinational companies? To what extent can learning ethics in a medical school produce a caring physician? How many of us put ourselves or our near and dear ones in the position of the patient before making a medical decision, more so in a difficult situation.Surgical workshop is the order of the day and has become very popular among surgeons. Are there any ethical guidelines to govern them? How often does a new surgical procedure go through proper checks and balances before being adopted widely in medical practice? This has led to see one, do one and teach one principle and has resulted in an undisciplined introduction of laparoscopy and many other similar surgical procedures in Urology and General surgery and has earned dubious distinction of the biggest unaudited free for all in the history of surgery. The terminology of surgical learning curve has gained popularity due to the mishaps, which have occurred during the learning of laparoscopy. I am sure that the aviation industry that trains pilots would be in for a rude shock if they knew how we are trained before we adopt these new procedures.Medical Ethics and Legal Issues may not necessarily discuss the above issues but if we want to salvage the reputation and integrity of our profession, we certainly need to think and draw our own \u201cLakshman Rekha.\u201d Ethics should be taught in medical schools by senior medical/paramedical faculty who are either practicing (or have practiced) medicine and have the experience of making difficult medical decisions and have learnt from their mistakes.This symposium on Dr. Joseph Thomas, Professor and Head of Urology at KMC, Manipal, who has a special interest in this field and holds a degree in medical law has guest edited this symposium. I am optimistic that it would sensitize all of us toward these important issues and provide an opportunity for further deliberation. I thank Dr. Thomas and his team for their efforts.By the time you all receive this issue you would be aware of the sudden demise of Dr. Atul Thakre. He was a brilliant urologist and the rising star in the field of Pediatric Urology. He took keen interest in the activities of the IJU. We are all deeply saddened by this loss and I feel a fitting tribute to Dr. Atul Thakre would be development of Pediatric Urology in India."}
+{"text": "The interpretation of time trends in disease rates can be facilitated using estimable contrasts from age-period-cohort models. Cohort and period trends in breast cancer incidence and mortality rates in Scotland were investigated using contrasts that measure the changes in the linear trends. These contrasts were compared with estimates obtained from mortality rates in the USA and Japan. A significant moderation of both breast cancer incidence and mortality rates was observed in Scotland, associated with cohorts of women born after the Second World War compared with women born between the two world wars. The moderation of breast cancer mortality among cohorts born after 1925 compared with cohorts born before 1925 that was observed in the USA and Japan was also observed in this study. This moderation is not present in the incidence rates. The relative decline in the risk of breast cancer seen in younger cohorts seems to be contradictory to the temporal pattern present among breast cancer risk factors. It may well be that the alteration of eating patterns as a result of rationing in the wartime and immediate post-war period, and the subsequent influence on certain breast cancer risk factors probably produced by such changes, may have had some influence on the development of healthier girls and women. Such speculation could be addressed in a well-designed epidemiological study. There have been no changes in the mortality rate trends with period in Scotland, although the changes in the incidence rate trends with period are consistent with an increase in registration coverage."}
+{"text": "Two patients with stricture of the extrahepatic biliary tree are described. Both patients presented with aclinical picture of obstructive jaundice one to two years following radiotherapy for a malignantcondition. As no recurrent tumour was detected in either of the patients the strictures were consideredto be the result of radiation therapy. Bilio-enteric decompression was performed in both patients whoare well at follow up one and ten years after the procedure."}
+{"text": "Mycobacterium tuberculosis and dysregulation of the heat shock response results in increased immune recognition of the bacterium and reducedsurvival during chronic infection. In this study we use a whole genome spottedmicroarray to characterize the heat shock response of M. tuberculosis. We also begin a dissection of this important stress response by generating deletion mutants that lackspecific transcriptional regulators and examining their transcriptional profiles underdifferent stresses. Understanding the stimuli and mechanisms that govern heat shockin mycobacteria will allow us to relate observed in vivo expression patterns of HSPsto particular stresses and physiological conditions. The mechanisms controlling HSPexpression also make attractive drug targets as part of a strategy designed to enhanceimmune recognition of the bacterium.The regulation of heat shock protein (HSP) expression is critically important to pathogens such as"}
+{"text": "The articles in this special issue reflect a convergence of developments in the fields of bioinformatics and plant genomics. Bioinformatics has its roots vaguely seated in the early 1980s, a time when personal computers began appearing in research laboratories and researchers began recognizing that those computers could be used as tools to organize, analyze and visualize their data. In the ensuing years bioinformatics tools began appearing at various sites including the European Molecular Biology Laboratory, the Molecular Biology Research Resource at the Dana-Farber Cancer Institute in the mid 1980s, the National Center for Biotechnology Information (NCBI) in 1988, the Genome Database Project at Johns Hopkins University in early 1989, and in countless laboratories throughout the world. These last efforts resulted in the development of many of the tools described in this special issue.Arabidopsis thaliana was published. Since then many genome sequencing projects have been undertaken that include poplar (Populus), grape (Vitis), the moss Physcomitrella, the biflagellate algae Chlamydomonas and several globally crucial crop plants such as corn (Maize) and rice (Oryza). However, as we have witnessed on numerous occasions, determining the sequence of a genome is only the first step toward understanding genome organization, gene structure, gene expression patterns, disease pathogenesis and a host of other features of both scientific and commercial interests. Computational tools of genomic annotation and comparative genomics must be applied to gain a useful understanding of any genome.Progress and interest in plant genomics have been accelerating since the time in late 2000 when the genome of In this special issue we present a collection of papers that together describe a powerful and impactful toolbox of applications and resources for plant genomic analysis. Among those articles you will find a description of research performed by the Mexican headquartered Generation Challenge Programme (GCP) which led to the GCP Platform . This research support tool supports a number of data formats and web services and provides access to high performance computing facilities and platform-specific middleware collectively designed to support crop science research.Probably one of the most promising empirical tools for investigating gene expression developed in the last 15 or so years is that of microarray technology. While the technology has become commonplace, with tools for generating and hybridizing arrays available to all, the analysis of microarray-derived data has been challenging. Many laboratories have struggled not only with this challenge but also with the task of sorting through the plethora of analytical tools available in an effort to find the ones that may be best suited to their own work. In this issue there are two reviews by Page and Coulibaly which examine and describe bioinformatics tools for inferring functional information from plant microarray data. Together these papers step the reader through a collection of tools, and their applications, for analyzing the expression of single and multiple gene expression profiles.This theme of microarray analysis is continued in the description of the cross chip probe matching tool (CCPMT) by Page et al. Indeed it expands the readers horizons beyond the analysis of individual microarrays with the ability to associate probes across species. And of course, microarray analysis is facilitated by careful experimental design from the start so Robert Tempelman provides a review of statistical methods used to design efficient two-color microarray experiments. Taken together, these microarray papers provide an overview of the design of microarray experiments and the interpretation of the complex results of those experiments that will be informative for new and experienced laboratorians alike.Several other novel tools are described herein. One, Blast2GO is a suite of tools for the analysis and functional annotation of plant genomes (Conesa and Goetz). It provides an intuitive interface for identifying functional regions within DNA sequences. Another sequence analysis tool described by da Maia et al. is the SSR locator. That tool enables researchers to identify suitable targets for binding PCR primers in order to ensure that those targets are unique within the genome. It also assists with primer design and has a PCR simulator which facilitates comparisons of hypothetical amplification products among different species.Another challenge facing scientists today is the need to stay abreast of advances in a field that is progressing rapidly as a consequence of newly available technologies. In order to address this challenge there are two review articles that together provide insights into the discovery of relationships among a varied array of plant species. The first article, by Abdurakhmonov and Abdukarimov, describes the application of association mapping to understanding traits in crop species. Their work is directed toward novices within the crop breeding community in order to expose them to potential problems that they may face and solutions they may employ to overcome those problems. The second article describes the tools available for phylogenetic analyses and the increased use of Bayesian methods in those tools (Aris-Brosou and Xia). Constructing phylogenies has traditionally been a challenge to even the most experienced researcher but modern bioinformatics tools are lowering the bar for those interested in detecting adaptive evolution and estimating divergence among species.Zea mays which includes genomic sequences as well as functional information and the tools to explore both.The wealth of information available to researchers today can be overwhelming. In order to address this potential, two papers describe information resources which consolidate and organize related information. PPNEMA is a database resource for those interested in plant-parasitic nematode ribosomal genes . That resource allows the user to browse, search and generally explore phytoparasite ribosomal DNA. A second database described in these pages is the MaizeGDB . This resource contains information about The body of the papers in this special issue represents the leading edge of plant genomics research. Together they provide the reader with descriptions of the tools and resources necessary to understand and promote advances in this important field.Gary R. SkuseGary R. SkuseChunguang DuChunguang Du"}
+{"text": "The inhibitory effect of the protease inhibitor aprotinin (Trasylol) on the invasion of mouse kidney explants by polyoma virus transformed BHK21 cells was investigated using a mixed cell/organ culture technique. The extent of invasion was monitored by following the changes in LDH isoenzyme pattern in the explants and by histological assessment. The kidney explants containing aprotinin were found to maintain a normal kidney LDH pattern and to suffer considerably less invasion than the explants not containing the drug. These results support the idea that proteolytic enzymes are associated with invasion and that inhibitors of protease activity could possibly be useful in the management of clinical cancer."}
+{"text": "The level of galactosyltransferase activity was measured in the serum of 220 patients with a variety of solid tumours. There was a significantly greater proportion of patients with elevated galactosyltransferase in the group with metastatic disease (43%) than for the group with localised disease (16%). Galactosyltransferase was elevated in 69% of patients with liver metastasis compared to 32% of patients with metastatic disease at sites other than liver and this difference was also significant. High resolution agarose isoelectric-focusing was used to determine the 'isoenzyme' pattern of serum galactosyltransferase of 6 patients with liver metastasis and 2 patients with primary hepatoma and these were compared to those of 6 patients with similar primary tumours without liver involvement. There were no qualitative differences in the patterns from the two groups. The average peak height for each of the 19 peaks of activity identified was generally higher in the group with liver involvement, except for those peaks known to contain little or no attached sialic acid. Liver involvement appears not to contribute in any specific way to the altered pattern of serum galactosyltransferase often seen in patients with solid tumours. The tumour rather than the liver is therefore the most likely source of these alterations."}
+{"text": "To describe early cancerous and precancerous lesions of the laryngeal vocal folds as well as of themost common differential diagnoses, based on a series of microlaryngoscopic photographs. Someintroductory remarks about terminology and the classification of epithelial lesions of the vocal foldsare included. The paper ends with some comments as to the management of epithelial thickenings(or leukoplakias) of the vocal folds. Malignancy should be suspected as long as it has not been ruledout by histologic diagnosis on adequate biopsies, which is the only way to correctly evaluate the characterof such lesions. Precancerous lesions should be controlled by regular follow up examinationsas carefully as invasive carcinomas (posttreatment), because there is a high tendency for recurrencesor for later development of malignancy in these cases."}
+{"text": "The growing consensus that most valuable data source for biomedical discoveries is derived from human samples is clearly reflected in the growing number of translational medicine and translational sciences departments across pharma as well as academic and government supported initiatives such as Clinical and Translational Science Awards (CTSA) in the US and the Seventh Framework Programme (FP7) of EU with emphasis on translating research for human health.The pharmaceutical companies of Johnson and Johnson have established translational and biomarker departments and implemented an effective knowledge management framework including building a data warehouse and the associated data mining applications. The implemented resource is built from open source systems such as i2b2 and GenePattern.The system has been deployed across multiple therapeutic areas within the pharmaceutical companies of Johnson and Johnsons and being used actively to integrate and mine internal and public data to support drug discovery and development decisions such as indication selection and trial design in a translational medicine setting. Our results show that the established system allows scientist to quickly re-validate hypotheses or generate new ones with the use of an intuitive graphical interface.The implemented resource can serve as the basis of precompetitive sharing and mining of studies involving samples from human subjects thus enhancing our understanding of human biology and pathophysiology and ultimately leading to more effective treatment of diseases which represent unmet medical needs. The effective management of knowledge in translational research setting ,2 is a mMerck has developed a system which enables sharing of human subject data in oncology trials with the Moffit Cancer Center and Research Institute . This syThere is a growing set of data being deposited in NCBI GEO , EBI ArrThese databases enforce standards for some of the elements of the experimental metadata . In geneThe computational experiments can lead to validation of the primary findings or to novel discoveries such as in the case of meta-analysis of multiple datasets. The burden of deconvoluting the phenotypes from source files downloaded from these primary sources and coding them in a standard to enable large-scale meta-analyses makes these types of discoveries very costly and in fact quite rare -13.Data curation is a way to tackle some of these issues. Typically, derived databases of omics experiments are curated to create comparisons for specialized mining with specific questions in mind. For example, there are multiple resources being developed to integrate and analyze gene expression and other omic data and create contrasts (A vs. B comparisons) or signatures ,15. The The treasure trove of high-content data derived from human samples can be much more effectively mined if standard dictionaries applied to all these studies and each subject's clinical and the associated sample's genomics data is stored and analyzed through a system which enables efficient access and mining. An example of such standardized infrastructure and potential for pre-competitive sharing is presented below.Johnson & Johnson has invested in translational research by establishing within its pharmaceutical R&D division a set of translational and biomarker groups and focusing also on the management and mining of the data emanating from integrative settings crossing the drug discovery and development stages. One of the deliverables of this enhanced governance structure was the development of a translational medicine informatics infrastructure. This infrastructure is a combination of dedicated people, robust processes and informatics solution - tranSMART.We have established a strong cooperation across the R&D of the pharmaceutical companies of Johnson & Johnson and an open innovation partnerships with the Cancer Institute of New Jersey and St. Jude Children's Research Hospital . The R&DAn important aspect of successfully introducing a paradigm shift within a large pharmaceutical organization is change management. From the start we have recruited biologists, pharmacologists and physicians from various therapeutic areas to help champion the adaptation of the newly developed translational infrastructure but also to guide us through the development of the application in an agile environment.The translational medicine data warehouse - tranSMART - was developed in partnership with Recombinant Data Corporation Fig.  and detaData is stored in an Oracle 11 database which is fully auditable. We selected a set of open-source components to assemble the application in contrast to the strategy followed by Merck. A user interface providing a biological concept search of analyzed data sets and an i2b2  based coClinical trial and experimental medicine study data sets were transformed by curators and ETL  developers into an i2b2  EAV  of this complex query. In subset one (denoted by S1_... sample ids) most of the samples have low expression of the gene of interest (denoted by blue color) whereas in subset two (denoted by S2_... sample ids) most of the samples have high expression of the gene of interest (denoted by red color).Queries can use Boolean operators such as OR and AND as illustrated in Figures EGFR gene with k = 2 can stratify the subjects into high and low expressors.Cross-study meta-analyses are also available in the application Figure . In thisThe tranSMART system allows clinicians, translational scientists and discovery biologists to interrogate aligned phenotype/genotype data to enable better clinical trial design or to stratify disease into molecular subtypes with great efficiency. Initial successes of applying this system point towards the high value of translational data in proposing indications for drugs with new mechanism of actions  and selecting biomarkers for stratified medicine.The system has been in wide use across multiple therapeutic areas within the pharmaceutical companies of Johnson and Johnson. Comparing biological processes and pathways between multiple data sets from related disease or even across multiple therapeutic areas is an important benefit of such a system. Through the examples presented above we have shown that the tranSMART system allows scientist to quickly re-validate hypotheses or generate new ones with the use of an intuitive graphical user interface. The use cases supported by tranSMART have been developed in close collaboration with key users and the solution was built from many open source systems making the adaptation of the system straightforward.We have implemented a fine-grained, role-based authorization model throughout the application so that study level permissions are enabled and can be controlled by the study owners. During curation the study owners are actively involved in reviewing and approving the loading and standardization of the data from their studies. This approach greatly enhanced the cooperation of the study owners and the ultimate success of the data warehouse.A well-constructed system can enable scientist to test but also generate new hypotheses using well-curated, high-content translational medicine data leading to deeper understanding of various biological processes and eventually helping to develop better treatment options.Active curation and enterprise data governance have proven to be critical aspects of success. The capability of the system to query both internal and public data and that during the development and implementation full organizational alignment was ensured turned out to be crucial.Because large part of tranSMART is built from open source systems it is much more amenable for being shared with academic institutions in a pre-competitive setting enabling collaborations aimed at developing deeper understanding disease biology.The tranSMART system is under active development including active curation of additional studies, implementing new modalities and adding novel workflows. Future development may include connection to the internal biobank. By the established system and the robust processes our research and development organization can now effectively manage not just the complex and multimodal data but can also unlock the potential of the data by transforming it into actionable knowledge.SS, VK and EP are employees of Johnson and Johnson.SS and EP conceived and designed the study. VK and TK assisted with the experiments. SS drafted the manuscript. All authors read and proofed the final manuscript."}
+{"text": "Although serologic evidence suggests the presence of Q fever in humans and animals in Saudi Arabia and the United Arab Emirates, acute Q fever has not been reported on the Arabian Peninsula. We report the first two cases of acute Q fever in Oman."}
+{"text": "A high-performance continuous flow analyser is described, based on gas pressure driven carrier and reagents controlled by computer switched solenoid valves. The principal characteristics of the analyser are discussed and examples of its performance are provided in the form of results obtained using a standard procedure for the determination of Cr(VI). The system was also tested in use with real samples using an ammonium ion analysis on potable and effluent water samples, and the results compared with those obtained using a segmented continuous flow method operated at the Laboratory of the Government Chemist."}
+{"text": "The increased focus on the epistemology\u2014the theory of knowledge\u2014that underlies both healthcare improvement and patient safety has brought a fresh vitality to the scholarly healthcare improvement literature.2Quality and Safety in Health Care in 2005 as draft guidelines to advance the scholarship of improvement and to address the underlying theory of experiential learning that is central to much of healthcare improvement research.QSHC supplement.2SQUIRE was originally promulgated by Davidoff and Batalden in Colleagues who labour daily at improving health care in their clinical and institutional settings do not necessarily have incentives or the inclination to publish their original improvement work. Indeed, healthcare improvement is often its own reward. Academics, on the other hand, have strong incentives to publish their original work because publication provides a measure of professional productivity, one of the criteria by which they are judged by their peers and by academic institutions. Improvement researchers may use methods\u2014for example, qualitative techniques, particularly those that reflect critical experiential learning that are less commonly used in biomedical research.SQUIRE was preceded by concise guidelines for quality improvement reports (QIR), which provided guidance for reporting local improvement projects.\u2013Authors and editors will find that SQUIRE and QIR both emphasise the central importance of context and of the effective communication of improvement strategies.3QSHC website by over 15\u2009000 unique viewers. Authors who were early adopters7\u2013After the initial publication of the draft SQUIRE guidelines in 2005, their theory and utility underwent considerable scrutiny. The original draft guidelines were accessed online via the Now that the revised SQUIRE guidelines are available, what are potential unforeseen and unintended consequences of SQUIRE\u2019s wider application to healthcare improvement reports? An example of the more worrying questions include: is there a risk that improvement scholars\u2014in their commitment to the unique epistemology of improvement science\u2014have created potentially controversial theory that could contribute to possible isolation of this scholarly field? Might initiatives to consider deeper underlying issues of epistemology discourage valuable reporting by clinicians, administrators and scholars for whom improvement is not a first or primary discipline? The authors of SQUIRE hope it will offer guidance that, in fact, serves to circumvent these concerns and contribute to the development of a lively community of scholarly inquiry and practice about the improvement of healthcare.2Nevertheless, these questions highlight the importance and value of the \u201cExplanation and Elaboration\u201d (E & E) document that accompanies the publication of SQUIRE in this supplement.In addition, a SQUIRE website has been established for its promulgation and systematic evaluation.Authors and editors can readily test the utility of the SQUIRE guidelines for making healthcare improvement research more accessible to a wider audience, and the opportunities they provide for increasing the clarity of improvement research reportsQSHC and other scholarly journals. Finally, we encourage active interaction, specifically on the SQUIRE website and directly with the editors of QSHC, as the healthcare improvement community endeavours to enhance the rigour and utility of the scholarly healthcare improvement literature.We encourage authors to consider the use of either SQUIRE or QIR\u2014based on the nature of their healthcare improvement activity\u2014as they craft their reports for"}
+{"text": "The clinical features of 19 patients with malignant infiltration of the retroperitoneal tissues are described. These patients usually presented with unexplained uraemia and nonspecific symptoms; only a few had other evidence of malignancy. The diagnosis was resolved only by histological examination of multiple biopsy specimens. Since the prognosis is usually very poor it is essential to distinguish this condition from non-malignant causes of retroperitoneal fibrosis."}
+{"text": "The Epithelial Membrane Antigen (EMA) has until now only been described in immunological terms and has been shown immunohistochemically to be present on a variety of human non-squamous epithelial surfaces. It is a valuable marker in diagnostic tumour pathology and enables the detection of small deposits of malignant cells in organs such as liver and bone marrow. Its discovery in soluble form in human milk has enabled a purification of the antigen from this source. The antigenic activity in the milk is spread over a wide range of mol. wts and although purification causes a general reduction in size, the antigen remains heterogeneous. Carbohydrate forms the major component of the antigen with galactose and N-acetylglucosamine as the two major sugars. The protein content of EMA is low and shows considerable variation in amino acid composition from one sample to another. A high content of inorganic material has also been found in EMA but is not due to high sulphate or phosphate levels."}
+{"text": "With progressive growth of syngeneic sarcomata in rats there was a rise in serum levels of lysozyme which correlated with their immunogenicity and their macrophage content. By an examination of lymph/blood differences in normal and in tumour bearing rats and of the production of lysozyme by cells obtained from the tumours and maintained in vitro, it is apparent that the macrophages resident in a tumour mass make a massive contribution to the elevation in serum lysozyme concentrations. Tumour cells did not release detectable lysozyme activity. Tumour amputation led to a rapid fall in lysozyme levels. Irradiation of the host rats abolished the lysozyme response and the subsequent development of metastases in these rats was associated with a rise in serum lysozyme. The serum concentration of this enzyme reflects the macrophage content of a tumour mass and the draining lymph nodes. We conclude that under well defined conditions serum lysozyme activity may be a useful marker of macrophage mediated host responses to a tumour."}
+{"text": "Records of approximately 310,000 patients admitted to the 10 hospitals in Botswana between 1960 and 1972 have been studied and details of 1445 patients with malignant tumours abstracted. For the 894 tumours for which there was some supporting evidence--at best histological proof and minimally a clinical description of symptoms--proportional frequencies have been calculated for all sites and comparison made with the findings of other surveys. Cancer of the cervix uteri is overwhelmingly the most commonly occurring malignant tumour and the proportional frequency is among the highest observed in Africa south of the Sahara. Skin tumours are unusually common for Southern Africa in both sexes. In males, penile and prostatic tumours have a relatively high frequency whilst the frequencies for liver and lung are lower than in other parts of Southern Africa. Oesophageal cancer in males has a moderate frequency. Other tumours which show a marked variation of frequency within Africa--Kaposi's sarcoma and cancers of the stomach and bladder--are all low in frequency in Botswana. Tumours which are rare throughout Africa but common in Western Europe and North America--cancers of the colon, rectum and corpus uteri--are also rare in Botswana."}
+{"text": "Atherosclerosis is nowadays generally accepted as an inflammatory disease             but the mechanism of its origin and development have not yet been fully clarified.              The present review focuses on the role of the local immune system as one of the              key players in the pathogenesis of the complex process. Its part represented by               vascular-associated lymphoid tissue (VALT) within the arterial wall participates               directly in the vascular wall's homeostatis. Its inordinate activation during               ontogenic development of an individual, this formerly defensive and physiologic               mechanism transform into a pathological process resulting in an impairing                inflammation. Hsp60, CRP and oxidized or otherwise modified LDL are serious                 candidates for triggering these pathological changes. The principal role is played                 by anti-Hsp60 antibodies and by shear stress originating on the surface of                 endothelium due to blood flow. The experimental and clinical data             supporting this immunological hypothesis of atherosclerosis are discussed."}
+{"text": "This paper describes a PC  based titrator which was developed for gradient flow titrations. Concentration gradients were generated electrolytically or volumetrically in small tubes. Complete titration curves can be recorded on-line and evaluated automatically. The titrator can be used with all liquid flow detectors with low axial dispersion. The titrator was evaluated for the titration of thiosulphate with electrogenerated triiodide and for the titration of ammonia with electrogenerated hypobromite after continuous gas dialytic separation of ammonia from the sample solution."}
+{"text": "After surgery for hepatic injury as a result of blunt abdominal trauma from a motorcycleaccident, an external biliary fistula developed in a young patient. The authorsdescribe the rapid and complete healing of the fistula by use of a nasobiliary catheter.These findings emphasize the importance of endoscopic operative technique for postoperativeand traumatic external biliary fistulas."}
+{"text": "Endothelial cells play an important, active role in the onset and regulation of inflammatory and immune reactions. Through the production of chemokines they attract leukocytes and activate their adhesive receptors. This leads to the anchorage of leukocytes to the adhesive molecules expressed on the endothelial surface. Leukocyte adhesion to endothelial cells is frequently followed by their extravasation. The mechanisms which regulate the passage of leukocytes through endothelial clefts remain to be clarified. Many indirect data suggest that leukocytes might transfer signals to endothelial cells both through the release of active agents and adhesion to the endothelial cell surface. Adhesive molecules (such as PECAM) on the endothelial cell surface might also \u2018direct\u2019 leukocytes through the intercellular junction by haptotaxis. The information available on the molecular structure and functional properties of endothelial chemokines, adhesive molecules or junction organization is still fragmentary. Further work is needed to clarify how they interplay in regulating leukocyte infiltration into tissues."}
+{"text": "The possibility of detecting pre-clinical ovarian carcinoma by ovarian cytology taken at the time of laparotomy has been studied in 472 patients. Malignant cells have been recovered from ovarian carcinomas but never from macroscopically normal ovaries. It is suggested that this simple, inexpensive technique of sampling cells from the ovarian surface should be continued to be practised on all occasions at which ovaries present such as at laparotomy or at laparoscopy, as with further experience this technique may prove to be of help in the early diagnosis of ovarian carcinoma."}
+{"text": "Histological sections of the primary tumour and of homolateral axillary lymph nodes from 500 women with operable invasive breast cancer have been examined. The tumours have been graded and the degree of round cell infiltration assessed. These features, together with clinical palpability and pathological involvement of axillary nodes, have been related to survival.It was found that prognosis was worse in patients with a high grade tumour and in those with histological evidence of axillary node spread. Round cell infiltration of the primary tumour did not confer improved survival.The clinical state of the axillary nodes was associated with prognosis in so far that palpable nodes were twice as commonly the seat of metastatic spread as were impalpable nodes."}
+{"text": "A squamous cell carcinoma of spontaneous orgin in a WHT/Ht mouse was used to study the frequency with which the regional axillary lymph nodes draining subcutaneous or intradermal tumours gave rise to tumours after their isogeneic transplantation as whole nodes. This frequency (similar to 40%) was found not to vary significantly with the size or duration of the tumour drained and not to be increased by coincident infective, traumatic or antigenic stimuli acting at the tumour site or in adjacent tissue. Because tumour growth occurred in only 2/55 (4%) nodes which were left in situ in mice whose tumours were radically excised, it was concluded that tumour forming node transplants reflected a small and limited content (estimated to be about 13) of transnodally passing tumour cells destined to pass on to the blood; separate experiments showed that tumour cells reaching the blood survived for only a few hours. Nodes from tumour-excised mice gave rise to tumours as frequently when autografted as when isografted to mice with no previous expose to the tumour. A review of the finding reported here and of previous quantitative data for this system enabled us to exclude any implication of anti-tumour immunity from our interpretation of the results of the experiments."}
+{"text": "Induction programme for trainee doctors in the UK generally do not focus on the surgical aspects of their jobs. In this context we decided to conduct a telephonic survey among the hospitals belonging to three orthopaedic training regions in the UK from the point of view of the diversity of instrumentations and implants used for index procedures.We chose four index trauma & orthopaedic procedures . A telephonic survey was done in six NHS trust hospitals which were part of an orthopaedic training rotation . In total there were 39 different instrumentation systems for these 4 index procedures in the 6 trusts (see table In view of this we feel that more focused theatre based induction programmes for higher surgical trainees is advocated in each hospital trust so trainees can familiarise themselves with the tools available to them. This could include discussion with the consultants and senior theatre staff along with representatives from the companies supplying the implants and instrumentation systems. Hospital induction programmes are a standard part of the commencement of new posts for junior doctors . It has To emphasise the scale of this problem a telephonic survey was done in six NHS trust hospitals which were part of an orthopaedic training rotation . In our survey we used 4 index operations commonly performed in all hospitals with a trauma and orthopaedic intake. For each trust we contacted (by telephone) the theatre manager to identify the instrumentation and implant systems used for total hip replacement (THR), total knee replacement (TKR), and fixation of tibial or femoral fractures with either intra-medullary nailing or external fixation.In total there were 39 different instrumentation systems for these 4 index procedures in the 6 trusts (see table This representative survey we conducted shows no uniformity in the orthopaedic instrumentation used between the different regions. This is hardly surprising as currently there is a vast array of instrumentation systems available in the market for use in orthopaedic surgery. Considering that this data only represents 4 particular index operative procedures the actual amount of different implants and instrumentation systems for each trust is likely to be significantly higher.We recommend mandatory theatre induction as a part of the specialist registrars' departmental induction programme. This could include discussion with the consultants and senior theatre staff along with representatives from the companies supplying the implants and instrumentation systems. Ideally it would include practical/video demonstrations of the commonest systems used, as well as a booklet for each trainee containing the operative technique for the instrumentation systems.The authors declare that they have no competing interests.AJSK designed the survey and wrote the article, JO and SKSW conducted the survey and the literature search, SP revised the manuscript and gave final approval for publication"}
+{"text": "The effect of varying the numbers  of weekly applications of DMBA to the dorsal skin of intact and castrate male and female rats on the induction of basal and squamous celled epitheliomas and of sarcomas has been investigated.Basal celled tumours originate mainly in hair follicles and squamous celled neoplasms in the interfollicular regions of the epidermis and differ in their progression to malignancy. Penetration of the panniculus carnosus is neither a sufficient nor necessary criterion of malignancy since growing hair follicles pass through the muscle layer and carcinomas and sarcomas which are still confined to the dermis, spread along the perineural lymphatics and metastasise to the lungs.Sex and castration do not affect carcinogenesis of epitheliomas in the dorsal skin at any dose level. Significantly more sarcomas result from 20 weekly paintings in male than in female or castrate rats.The induction period for all tumour types is shortened in sensitive individuals only by an increase from 5 to 10 weekly applications. For less sensitive animals the rate of oncogenesis is accelerated with number of administrations up to 20, but slowed down from this level by 40 paintings. The optimal dose for speed of induction of all tumour types, for maximal yield of basal celled epitheliomas and for that of sarcomas in male rats is 20 weekly applications.The progression to malignancy varies with tumour type: it is fast for sarcomas and slow for basal celled neoplasms. Of the 336 rats at risk only 1% have fibromas or other precursor lesions, while 40% have sarcomas; animals with squamous celled papillomas account for 12%, but those with carcinomas for 66%; there are, however, 64% of rats with basal celled papillomas and only 9% with carcinomas.The optimal dose phenomenon in carcinogenesis is discussed."}
+{"text": "An in vitro agar colony technique has been developed for the growth of tumour cells taken directly from human tumours grown in immune-suppressed mice. The novel feature of the technique is the addition of a replenishable liquid phase which permits the maintenance of relatively slowly growing cells. A number of different xenografted tumours have been cultured successfully in this system, with red blood cells added to the agar and using 5% O2 in the gas phase. The technique has been used to assay cell survival in tumours treated in vivo with cytotoxic agents, and examples are given of survival curves obtained from a pancreatic tumours irradiated with gamma-rays and a colonic tumour from mice treated with cyclophosphamide. The results obtained by this in vitro method are in agreement with those from the agar diffusion chamber technique. This culture method has also been successfully used for the growth of cells taken directly from human tumour biopsy samples obtained in the clinic."}
+{"text": "In drinking water supplies the intake of the toxic heavy metal lead is commonly due to metal corrosion in the peripheral water distribution system, especially the user\u2019s plumbing or lead service lines. Recently, the problem again received attention in the United States when testing data of drinking water at schools was published . In EuroLead exposure from drinking water has been a topic of public health prevention programs in several parts of Germany before, for example, Hamburg  and FranA moderately higher percentage of households with elevated composite water samples was found in the geographic area of the city of Berlin using two composite water sampling methods  can have a substantial effect in elevating lead . Flushin"}
+{"text": "A crisis exists in medical education. Changes in methodology have diverted attention from synthesisto mass accumulation of factual data. The response to this crisis has been largely focused on a shellgame involving new pathways and curriculum changes without addressing the critical issue of whatconstitutes education. The ultimate problem in medical education is a crisis of leadership. Untileducation is given a priority status and the obligations to teach on the part of medical educators andto learn on the part of students are translated into a creative policy by those who can lead, the wheelsof learning will continue to spin without significant progress."}
+{"text": "The early changes induced by a carcinogenic nitrosoquinoline compound (NTDQ) have been studied in the subcutaneous tissues of 88 rats. An initial acute infiammatory response is quickly replaced by a distinctive granuloma which is established by 10 days and persists indefinitely\u2014a sequence which takes place both in adult and in newborn animals. Its main components\u2014histiocytes, multinucleate giant cells and granulation tissue\u2014are described in detail and the formation of giant cells by fusion from adjacent histiocytes has been traced. Autoradiographic studies with tritiated thymidine show heavy nuclear labelling in the histiocytes and fibroblasts during the first 10 days; this later declines but raised levels of nuclear labelling persist up to the end of the experiment. No proliferative activity is seen in the giant cells and these cells show only feeble phagocytic activity, tested by their ability to take up carbon particles. The experiments in which colloidal carbon was injected locally also provided some information on the lymphatic vessels in the vicinity of NTDQ-induced granulomata. It appears that, initially, the lesions contain large dilated lymphatic vessels. Later, a dense connective tissue barrier develops and lymphatic connections with the surrounding dermis are progressively reduced.The properties of granulomata induced by NTDQ are discussed and some possible relationships between the formation of granulomata and eventual tumour developed are considered. Particular emphasis is given to two related features: the sustained proliferative activity of the fibroblasts and the resulting semi-isolation of the injection site lesion by the formation of a dense connective tissue barrier."}
+{"text": "Fluorescence probes for the active centre of an enzyme associated with tumour cells have been used to locate leukaemia cells in a model rat system. These fluorescent techniques are inexpensive and rapid to carry out. The leukaemic cells can be located by fluorescence microscopy in frozen sections, wax embedded sections and resin embedded sections. The technique is illustrated with reference to sections of leukaemic rat kidney, epididymis and testis. These studies confirm earlier histological findings employing conventional staining techniques and have the advantage that individual leukaemia cells can be detected in leukaemic animals undergoing drug therapy. The evidence suggests that these techniques will be of value in further studies of the design of drugs directed to leukaemia cells."}
+{"text": "Cell survival was investigated in an intraocular retinoblastoma-like tumour 30 min to 48 h after photodynamic therapy. The survival of the cells was assessed by an in vivo to in vitro colony forming assay, estimated by either the plating efficiency of the treated tumour cells compared to non-treated cells or the number of clonogenic cells per mg excised tumour. Curves showing cell survival as a function of the time between light irradiation and excision of the intraocular tumours were biphasic. This suggests more than one PDT tissue destruction mechanism in vivo (i.e. an early direct cell damage plus a subsequent late damage occurring in the tumour tissue left in situ after treatment). The delayed mechanism may be due to changes in the environment of the tumours probably caused by vascular damage. Tumour cells sensitised by Photofrin II in vivo and excised from the eyes were damaged by light when irradiated in vitro and this was dependent on the light energy dose. This showed that cellular Photofrin II uptake in the eye tumours was sufficient for direct cell damage and thus supports the suggestion that direct and indirect tumour destruction occurs in this eye tumour after photodynamic therapy."}
+{"text": "The serum concentrations of the radiosensitizer metronidazole have been determined in mice for both oral and intraperitoneal doses of the drug and these have been related to radiosensitization studies in murine tumour systems. In preliminary work before a possible clinical trail the serum metronidazole concentration/time curves have been determined in 7 patients using single doses of metronidazole of up to 15 g. The data suggest that a linear relationship exists between the metronidazole dose expressed in mg/kg and the peak serum concentration. The possibility of achieving radiosensitization of tumours in patients after tolerable doses of metronidazole is discussed in relation to enhancement ratios determined for in vitro and in vivo systems. It is concluded that predictions from in vitro systems give values that are probably too optimistic."}
+{"text": "The alkylamines and their related boron derivatives demonstrated potentcytotoxicity against the growth of murine and human tissue culturedcells. These agents did not necessarily require the boron atom topossess potent cytotoxic action in certain tumor lines. Their abilityto suppress tumor cell growth was based on their inhibition of DNA andprotein syntheses. DNA synthesis was reduced because purine synthesiswas blocked at the enzyme site of IMP dehydrogenase by the agents. Inaddition ribonucleotide reductase and nucleoside kinase activities werereduced by the agents which would account for the reduced d[NTP] pools.The DNA template or molecule may be a target of the drugs with regard tobinding of the drug to nucleoside bases or intercalaction of the drugbetween DNA base pairs. Only some Of the agents caused DNAfragmentation with reduced DNA viscosity. These effects wouldcontribute to overall cell death afforded by the agents."}
+{"text": "Resistance to FCE 24517 is not related to the emergence of any of the most frequently observed phenotypes. We have found that two resistant cell lines (L1210/24517 murine leukaemia and LoVo/24517 human colon adenocarcinoma) present congenital modifications in tyrosyl phosphatase and kinase activities. Moreover, the cytotoxic activity of FCE 24517 is increased in combination with a tyrosine phosphatase inhibitor and decreased in combination with protein kinase inhibitors, this being in agreement with the hypothesis that the activity of this drug is strictly dependent on the presence of tyrosine phosphorylated protein(s)."}
+{"text": "Laboratory robotics has been firmly established in many non-QClaboratories as a valuable tool for automating pharmaceuticaldosage form analysis. Often a single project or product line is usedto justify an initial robot purchase thus introducing robotics to thelaboratory for the first time. However, to gain widespread acceptancewithin the laboratory and to justify further investment in robotics,existing robots must be used to develop analyses for existing manualmethods as well as new projects beyond the scope off the originalpurchase justification. The Automation Development Group inAnalytical Research and Development is a team of analystsprimarily devoted to developing new methods and adapting existingmethods for the robot. This team approach developed the expertiseand synergy necessary to significantly expand the contribution ofrobotics to automation in the authors' laboratory."}
+{"text": "Data from the Los Angeles County Cancer Surveillance Program (CSP) from 1972 to 1975 were used to study the descriptive epidemiology of testicular cancer and prostatic cancer. The very high black/white ratio and late age peak of cancer of the prostate contrasted sharply with the very low ratio and early age peak of testicular cancer. However, both sites had higher rates among upper occupational and social class groupings. Avalable descriptive and analytical research suggests that the etiology of prostatic cancer is most probably related to hormonal influences rather than to a horizontally transmitted agent, while the etiology of testicular cancer is most probably related to endogenous or exogenous hormonal influences in utero or in infancy, or to in utero exposure to other exogenous agents."}
+{"text": "Similar animals were also treated with local hyperthermia . The marked increase in median survival time following the combination of drug and local hyperthermia indicates that the combined treatment has a synergistic effect in the control of solid tumours. The median survival time of animals receiving the two treatments in immediate succession was higher than in animals with 30 min between treatments. This has important implications for the therapy of human cancer."}
+{"text": "The author discusses the implications of a new study that used data from The Netherlands to simulate the annual and lifetime medical costs attributable to obesity. PLoS Medicine, Pieter van Baal and colleagues used data from The Netherlands to simulate the annual and lifetime medical costs attributable to obesity . Governments need to understand that public-health policies affect more than merely the sum of individual health, and sadly require greater courage to implement than does treating the sick."}
+{"text": "The potential of plants to replace fossil oil was evaluated by considering the scale of production required, the area of land needed and the types of plants available. High yielding crops (50 tonnes/ha) that have a high conversion efficiency (75%) would require a global land footprint of around 100 million ha to replace current (2008) oil consumption. Lower yielding or less convertible plants would require a larger land footprint. Domestication of new species as dedicated energy crops may be necessary. A systematic analysis of higher plants and their current and potential uses is presented. Plant biotechnology provides tools to improve the prospects of replacing oil with plant-derived biomass by increasing the amount of biomass produced per unit area of land and improving the composition of the biomass to increase the efficiency of conversion to biofuel and biomaterials. Options for the production of high value coproducts and the expression of processing aids such as enzymes in the plant may add further value to plants as bioenergy resources. Biomaterials and bioenergy have long been produced from plants. The development of oil from fossil fuel replaced many of these traditional uses during the twentieth century. The prospect of oil supplies being exhausted and concern about the impact on the atmosphere of adding the carbon in fossil fuels have resulted in renewed interest in the use of plants as direct sources of bioenergy and biomaterials .Humans domesticated plants more than 10 000 years ago largely for food . Use of The first generation of biofuel production has been based upon the conversion of the storage carbohydrates (sugars and starch) in the plants into fuel . Oil froA major question we need to ask is how much land do we need to grow plants to replace oil. The global consumption of oil in 2008 was around 3930 million tonnes. The area of land required can be calculated if we assume different levels of efficiency in converting plant biomass to biofuel  at any given yield of biomass per hectare. The next question we need to address is what species of plants do we have with yields that would allow production on a reasonable land footprint. The yields of crops used as biomass sources need to be achievable on a sustainable basis with minimal energy inputs for crop production including cultivation, planting, nutrient production and application, harvesting and transport. This requirement limits the choice of crop species and production environments.Panicum virgatum) has been widely evaluated as an energy crop option  are C4 plant with high yield potential. Sugarcane and related species are probably the grasses with the highest yield potential identified to date. Sugarcane has potential to yield in excess of 100 tonnes dry matter/ha/year . Switchgrass  conservation. The amount of arable land in the world has been estimated at more than 4000 Mha. The amount of land available by continent is given in Discovery of the best options for use as energy crops in specific environments requires an analysis of available species and their suitability in available production environments. A systematic analysis of plant options for food, energy, conservation and other uses should include all plant species. Those that do not have a current specific human use may have one in the future and all species contribute to biodiversity. Selection of new plants for energy production or even diversified food production requires a systematic analysis of the available options. Many of the species currently being promoted for use as energy crops have not been a product of such analysis and are in many cases not good options. For example, many oil-producing species are promoted because of the ease of using the oil produced in the plant with minimal processing. However, the environmental cost (land and water requirements) of growing these species will often not compete with many other species with much greater potential for biomass production. Application of appropriate selection criteria should focus attention on species with good potential for sustainable production. Following are some general criteria  for use high suitability for genetic improvementhigh biomass accumulationhigh harvest indexhigh fraction of biofuel in harvested biomassnutrients partition to nonharvested partsbeing able to be grown on marginal landsharvested material able to be stored in the fieldhigh bulk densityhigh water use efficiencyhigh N use efficiencylow potential as a weedhigh coproduct potentialoptimal biomass compositionlarge-scale potential productionlow cost of harvestBoth algae and seed plants are actively being investigated as potential energy crops. The growth of higher plants is a well-established process, and the risks and likely outcomes of research in this area are more predictable. However, research aiming to develop technology to grow algae on a large scale is more uncertain but may produce a highly efficient energy production system. Analysis of specific plant families is a useful level for systematic analysis of options for plants and their current and potential uses. All plants in a family will not have the same utility, but they often share common biochemical features that make the family a useful level for analysis. Modern DNA analysis methods have greatly improved the rigour and utility of higher plant taxonomy. The variation in the composition of plants in relation to their utility can now be analysed against this taxonomy. For example, the distribution of the major components of plant biomass, the major structural and nonstructural carbohydrates in these families, deserves re-evaluation. A good example of how plant taxonomy and biochemical composition relate is found in the plant families reported to contain fructans (polymers of fructose that serve as reserve carbohydrates). Current DNA-based systematic analysis suggests many other related families that should be examined for the presence of fructans. The presence of nonstructural carbohydrates in the form of fructans has implications for food use and for energy production from these species. The type of structural carbohydrate  can also be very important in determining the utility for food, feed or energy. The monocotyledonous plant families in the commelinoid group (including the grasses and related families) have cell walls rich in arabinoxylans and mixed linkage \u03b2-glucans . These cMany plants have been developed as food crops, and this suggests that we may need to domesticate many species to produce the biomass required to replace oil. Plants adapted to a wide range of available production environments are needed. The grasses (Poaceae) represent a major option having been domesticated for food production; they will probably repay screening efforts aiming to discover potential bioenergy crops. Many more plant families are probably able to contribute to the development of woody bioenergy tree crops. Some limited new options for domestication of food plants could also be identified by systematic analysis.Plant biotechnology provides tools that may allow rapid development of domesticated genotypes with growth and composition characteristics optimized for energy production ."}
+{"text": "We use wavelet-type discrete transforms for signal analysis on strings of finite length.We apply these transforms for edge and hidden Markov process detection. We alsopresent new approaches for string matching and for measures of the diversity ofchaotic strings."}
+{"text": "Improvements in the performance of a laboratory computer systemdo not necessarily require the replacement of major portions of thesystem and may not require the acquisition of any hardware at all.Major bottlenecks may exist in the ways that the operating systemmanages its resources and the algorithm used for timesharingdecisions. Moreover, significant throughput improvements may beattainable by switching to a faster storage device if substantial diskactivity is performed. In this study the fractions of time used foreach of the types of tasks a laboratory computer system performs aredefined and measured. Methods for reducing the time fractions ofthe various types of overhead are evaluated by doing before and afterstudies. The combined results of the three studies indicated that a50% improvement could be gained through system tuning andfaster storage without replacement of the computer itself"}
+{"text": "The peripheral blood lymphocyte count has been measured in 74 cases of histologically proven carcinoma of the gastrointestinal tract. The count has been correlated with the pathological stage of tumour spread and the patient's delayed hypersensitivity response to 2.4 dinitrochlorobenzene (DNCB). A statistically significant correlation was found between the peripheral blood lymphocyte count and the response to DNCB. There was linear association between the extent of spread of the tumours and the lymphocyte count. Those patients with low peripheral blood lymphocyte counts tended to have more advanced tumours and a poor response to DNCB. The possible causes of this lymphopenia are discussed."}
+{"text": "Beilstein Journal of Organic Chemistry. The series now embeds the subject firmly as a special interest area of the journal. The first series in 2008 presented contributions representing a wide range of organic fluorine chemistry [It is a pleasure to be able to introduce this second Thematic Series on \u2018organo-fluorine chemistry\u2019 within the hemistry \u201310 and tThe introduction of fluorine remains an important specialism in organic chemistry for modulating the physical properties of molecules involved in programmes ranging from bioorganic chemistry to performance materials. Consequently fluorinated organics are of major commercial significance to the pharmaceuticals, agrochemicals, materials and polymer industries with the fluorine fine chemicals industry servicing these industrial sectors. New innovations and insights into the synthesis and the nature and behaviour of organo-fluorine compounds continue to intrigue and this Thematic Series offers a glimpse into the level of activity in the area.I am delighted that all of the authors have agreed to submit such high quality contributions to render this Thematic Series substantial and make it such a success.David O'HaganSt. Andrews, April 2010"}
+{"text": "Peter Stastny and Peter Lehmann's Alternatives beyond Psychiatry offers a comprehensive and up to date account of the alternatives to mainstream psychiatry that are being developed by service consumers and survivors across the world. As psychiatry moves into a new age less dominated by a biomedical paradigm many of the approaches described in this book may be adopted by mainstream health services. This is a hugely readable and accessible book for professionals and consumers alike. Paul Hammersley is the Programme Director for Post Graduate Studies in cognitive behavioural therapy for psychosis at Manchester University's COPE Initiative in The United Kingdom. He is also an active therapist specialising in CBT for individuals experiencing severe psychological problems following traumatic life events. He has been widely published and has lectured extensively. 2006 along with Professor Marius Romme from Holland and The UK Hearing Voices Network, he founded CASL (The Campaign for the Abolition of the Schizophrenia Label.)The author declares that they have no competing interests."}
+{"text": "Critical to the effective implementation of high throughput methods of synthesis is the necessity for a significant supporting level of automation. There are a number of critical issues associated with the successful introduction, and supporting role, of automation of small molecule chemical synthesis. Clearly there are needs for automation to increase drug candidate synthesis throughput. Automation of repetitive and laborious tasks associated with the synthesis process can release skilled chemists to apply their talents to the more challenging investigational aspects of developing new synthetic protocols. This provides continuity in the compound supply pipeline and ensures an optimal use of the automated platform for compound production. The very high fidelity of performing repetitive processes that can be managed through automation also removes some of the limitations and errors associated with more fallible human operators. This can include very difficult tasks associated with tracking data, and general information and inventory management. Taken collectively, these attributes associated with automation can lead to greater efficiencies, throughputs and improved allocation of human resources with concomitant reductions in costs associated with current day and future drug discovery. In our library development/synthesis paradigm, we feel that automation support must be invoked early in the process and that this automation support must continue throughout the project."}
+{"text": "Germinal centers (GC) are an essential part of the humoral immune response. They develop a clear structure during maturation: Centroblasts and centrocytes are separated into two zones, the dark and the light zone. The mechanisms leading to this specific morphology as well as the reason for zone-depletion during a later phase of the GC reaction have not clearly been revealed in experiment. We discuss and weigh possible mechanisms of dark and light zone development in the framework of two mathematical models. In a comparative approach we formulate constraints on typical lymphocyte velocities in GCs which are characteristic for the different proposed mechanisms."}
+{"text": "The evolution of metastatic colorectal cancer in patients who have had surgical treatment for a primary lesion was studied in relation the progressive changes in the blood levels of carcinembryonic antigen (CEA), to gamma glutamyl transpeptidase (GGT) and routine liver function tests (LFTs). Involvement of the liver could ofter be reliably predicted many weeks in advance of clinical diagnosis while metastases to other sites were less likely to be detected early by this test. The association of the extent of disease with the patterns of biochemical changes is discussed with reference to several illustrative examples."}
+{"text": "A study of granulocyte function in myeloblastic leukaemia is reported. Function was assessed by the ability of peripheral blood granulocytes to ingest and kill Candida albicans in bitro. Depressed cidal activity was observed in 11 patients with smouldering leukaemia and in 19 patients with acute myeloid leukaemia. Cidal activity was lowest in the untreated acute disease; this improved during cytoreduction therapy and was maintained when remission occurred. Leukaemic plasma depressed the function of control granulocytes; the possible role of a plasma \"factor\" is discussed."}
+{"text": "A fluorescence imaging system (Xillix LIFE \u2013 Lung Fluorescence Endoscopy system) usingfluorescence for the accurate diagnosis and early detection of lesions through an endosocopehas been developed. This system has applied an optical diagnostic technology to functionallydiagnose lesions which have been difficult to morphologically recognize or are occult withconventional endoscope. The benefit of this system in the diagnosis of lung cancer has alreadybeen confirmed in the US and Japan, and feasibility of the system in the gastric intestinal fieldhas also been evaluated."}
+{"text": "The expression of thymidine kinase--an enzyme of the DNA precursor pathway--is strictly regulated during the normal cellular cycle, but is much higher and permanently expressed in malignant growing cells. We used this fact to detect neoplastic cells in samples freshly taken from leukaemia patients and kept frozen in liquid nitrogen until analysis. Using a new cytofluorometric assay for thymidine kinase in single cells, we were able to identify leukaemic cells in a surplus of normal ones. Our results demonstrate the benefits of this assay for leukaemia diagnosis."}
+{"text": "Emerging infectious diseases and the growth of information technology have produced new demands and possibilities for disease surveillance and response. Increasing numbers of outbreak reports must be assessed rapidly so that control efforts can be initiated and unsubstantiated reports can be identified to protect countries from unnecessary economic damage. The World Health Organization has set up a process for timely outbreak verification to convert large amounts of data into accurate information for suitable action. We describe the context and processes of outbreak verification and information dissemination."}
+{"text": "One hundred and ninety-one adults with acute myelogenous leukaemia were treated with combination chemotherapy consisting of daunorubicin and cytosine arabinoside (Barts III). Sixty-three patients achieved remission and were admitted to one of 3 trials of active immunotherapy: immunotherapy alone, immunotherapy and maintenance chemotherapy or neither of these. All patients had weekly clinical and blood examination and monthly marrow examination. Reinduction chemotherapy was given as soon as relapse was diagnosed in the marrow. The most striking observation was that immunotherapy was associated with easy and repeated reinduction of remission and marked prolongation of survival after first relapse when compared with immunotherapy plus chemotherapy. The possible reasons for this and the value of immunotherapy are discussed in relation to the third trial still in progress which includes 2 maintenance arms, immunotherapy alone and surveillance only."}
+{"text": "Background: Impairments in oral word production are common at the onset of stroke. The identification of factors that predict early recovery has important implications for identifying those at greater risk of continued impaired functioning, and the management of the patient's care following discharge.Aims: To identify patterns of performance that are predictors of acute recovery of oral word production abilities following stroke;to identify any association between early and more chronic recovery.Method and procedures:Acute stroke patients were administered oral word production tasks within 1\u20132 days of hospitaladmission, with repeat testing by 7 days; a subset of patients had repeat testing between three weeks to one year later. Performancewas examined for error rate and type to identify potential predictors of early recovery.Outcome and results: The proportion of circumlocution and no response errors at initial testing were associated with the magnitudeof recovery of language functioning within the first week following stroke. Patient characteristics of age and gender were foundto have no influence on the degree of early recovery observed. None of the examined factors predicted late recovery. The degreeof early recovery was not associated with the degree of later recovery.Conclusions: The current study identified patterns of task performance that increase our understanding of how oral wordproduction recovers following acute stroke. The finding that the degree of early recovery does not predict the degree of laterrecovery is consistent with the hypothesis that early and late recovery are due to different mechanisms ."}
+{"text": "Epidemiological studies of active smokers have shown that the duration of smoking has a much greater effect on lung cancer risk than the amount smoked. This observation suggests that passive smoking might be much more harmful than would be predicted from measures of the level of exposure alone, as it is often of very long duration frequently beginning in early childhood. In this paper we have investigated this using a multistage model with five stages. The model is shown to provide an excellent fit to data on the incidence of lung cancer among smokers, ex-smokers and non-smokers in a cohort of male British doctors. Contrary to our expectation the model predicted only a slight increase in relative risk with increasing duration of passive exposure. Allowing for exposures early in life does not therefore explain the discrepancy between the relative risk of about 1.5 calculated from epidemiological studies of lung cancer and the low levels of exposure indicated by cotinine measurements in those passively exposed."}
+{"text": "In order to assess the importance of the intensity of administration of chemotherapy in the management of advanced germ cell tumours we have calculated indices of chemotherapy. These have been used to compare the treatment given to patients who subsequently relapsed with matched controls who did not relapse. Two of these indices  are derived from the doses of drugs whose dose is varied . These indices showed significant variation between cases and controls. Indices gamma and delta are derived from drugs whose dose is not varied. They showed no significant differences between the two groups. These results emphasise the importance of ensuring that patients with these curable cancers receive adequate doses of chemotherapy."}
+{"text": "Orthopedics had become a separate specialty within whole field of medicine about 50 years ago.The demands of the orthopedist have increased tremendously during the last 30 years because of changes in the demographic profile of population, increase in life expectancy, rapid urbanization and increasing speed of mobility. In developed countries the burden of orthopedic disease is because of aging population and social emphasis on the welfare of elderly. In low income countries it is because of increasing population, rapid urbanization and using high speed vehicles with poor road safety and driving standards. The abysmal health and living standards continue propagation of infective conditions. The increased life expectancy has added aging population.The advances in medicine have largely been empirical. The intuition has guided development through trial and error. Science has explained what was observed by clinicians.2Most of the orthopedic surgeons repair deficiencies in musculoskeletal system by established surgical methods2Orthopedic practices till now were guided by the research conducted in the West since the disease profile was more or less the same. In the present times the disparity between disease profiles has widened. The affluent nations have better living standards and health infrastructure. As a result the infective diseases are practically eliminated and degenerative problems are in plenty. Most of the research direction and funding is towards their needs while the low income countries which have 2/3 of world population still see the natural history of disease. They see the continued pathogenesis of osteoarticular infection.The research includes a clinical research and basic science research. Not many clinical problems can be solved by clinical research alone.We must resolve that basic and clinical research are two sides of one coin; both inseparable. Both require similar commitment and both must be integrated in the same clinical setting. Basic research is largely being conducted by nonphysicians world wide with a gradual decline in orthopedic surgeons as researchers. Basic scientists bring skill to the research proposal but find it difficult to appreciate the clinical relevance. Sarmiento believed, and rightly so, that an orthopedic surgeon who is trained as a clinician-scientist and who understands the capabilities and limitations of the basic science approaches is a superior collaborator.The number of clinician scientists has taken a steep decline in the last 30 years in America and Europe in spite of the state of art research facilities and adequate funding.On the contrary, low income countries have not yet started thinking about region specific basic research. They have very little infrastructure for research. The attitude of health planners is to support patient care. The education and research is left to the interest of orthopedic clinicians. Hence all research in these countries is conducted by clinicians because of their love towards research. The end result is that there is a very little contribution from these countries to the pool of knowledge. Even society does not recognize the researchers, while clinicians are recognized well. The low income countries should devote resources and part of health budget towards need based research. This has to be realized by teachers, orthopedic associations (whether of countries or region) and government health planners.Training programs on research methodology should be arranged. We should equip young clinicians with the skills to understand and appreciate the musculoskeletal biology and perhaps conduct serious research on locally relevant issues.7Low income countries have high income countries as an example. The progress in the field of research in orthopedics, the obstacles faced and solutions suggested by them are available. We should ensure credible research programs keeping all these lacunae and matching limited research facilities and heavy disease burden in mind. We should attract the best students in orthopedics for research by providing a structured research curriculum, appropriate funding and reward good outcome and support financial loss which they occurred by not practicing orthopedic surgery.8Indian Journal of Orthopaedics is making a step in this direction. We have three invited write ups in the Perspectives section from well established clinician-scientists from USA, South Africa and India to give their opinion on the (a) need and scope of basic research (b) prospects of basic research in their countries and (c) infrastructure needed for basic research. This is an attempt to sensitize the orthopedic community and Government in this direction."}
+{"text": "Recent reviews of the management of hilar biliary cancer suggest that radical resection is the preferredtreatment option. It seems true that most of the long term survivors are treated this way, but it is equallytrue that most patients receive palliative rather than curative treatment. Before we go too far in ouradvocacy of radical treatment, we need to develop methods for quantifying palliation because that is intruth what we usually achieve. A method of quantifying palliation is described. Surgeons are encouragedto use methods of this kind in order to allow valid comparison of the results of different methods oftreatment."}
+{"text": "It has been reported that decreased numbers of dendritic cells (DCs) are correlated with poor prognosis in some types of malignancy, such as gastric cancer. However, factors that determine the density of DCs have not been characterized. It was recently reported that vascular endothelial growth factor (VEGF) inhibits the functional maturation of DCs from CD34+ precursors. In this study, we analysed the relationship between the expression of VEGF and the density of DCs in gastric carcinoma tissues by immunohistochemical staining. The extent of infiltration by DCs was graded from marked to slight on the basis of the mean densities of DCs. The prognosis of patients with marked infiltration was significantly better than that of patients with slight infiltration among patients who had undergone curative resection. Multivariate analysis showed that infiltration by DCs was an independent prognostic indicator. Furthermore, there was an inverse correlation between the density of DCs and the expression of VEGF Our results suggest that expression of VEGF might be associated with tumour progression and poor prognosis not only because VEGF stimulates angiogenesis, but also because it allows tumours to escape from attack by the immune system in patients with gastric carcinoma."}
+{"text": "The elevated levels of ras-related cellular RNA in a series of colorectal carcinomata (n = 12) was correlated with conventional staging criteria (tumour morphology and Dukes' staging) and with clinical outcome with particular reference to the development of metastatic disease. No direct relationship was evident between these parameters suggesting that although abnormal expression of ras oncogenes may be critical in the development of malignancy, variations in the level of their expression do not appear to be directly related to clinically evident phenotypic differences."}
+{"text": "Metastases to axillary lymph nodes is an important factor in predicting prognosis and survival in primary operable carcinoma of the breast. A series of post mastectomy lymph nodes (150 cases) was selected in this retrospective study, in which the initial diagnosis had been no metastases by light microscopy and in which a long follow-up was available (average 10 years). The original H&E sections from these cases were immunostained to detect metastases which might not have been previously appreciated. The study was performed using a cocktail of 5 monoclonal antibodies directed against epithelial antigens. The object was to explore the possibility of detection of occult micrometastases by immunohistochemistry and to evaluate their prognostic significance. Micrometastases with individual cells and cell clusters were readily detected by this technique in 14% of all cases. It also became apparent towards the end of the study that micrometastases could be detected with equal sensitivity by any one of the 5 monoclonal antibodies. Positive staining of malignant cells was found to be more frequent in invasive lobular carcinoma (ILC) than in invasive ductal carcinoma (IDC). However, for the IDC group a striking association was found between micrometastases and both recurrence and survival rate. The ILC sample was considered too small for meaningful interpretation. We recommend the use of immunohistochemical techniques using monoclonal antibodies for the detection of occult metastases in lymph nodes to improve the prediction of recurrence and survival in invasive ductal carcinoma of the breast."}
+{"text": "EHP 116:1071\u20131076; Akre et al.][.Hypospadias is a male birth defect in which the opening of the urethra is located on the underside of the penis instead of the tip. Although the defect is common and increasing in prevalence , the causes of most cases are unknown. Some studies suggest that reduced levels of the placental hormone human chorionic gonadotropin (hCG) may play a role; others suggest associations between hypospadias and conditions such as low birth weight, preterm birth, and preeclampsia that could be caused by malfunction of the placenta and subsequent abnormalities in hormone regulation and nutrition provided to the fetus . A new study now presents additional evidence that hypospadias has its origins in malfunction of the placenta Data on 292 cases of hypospadias and 427 controls were collected as part of a joint Danish\u2013Swedish study of both hypospadias and cryptorchidism (undescended testes). In Sweden, hypospadias cases were recruited at a pediatric surgery clinic, and data were collected via self-administered questionnaires. In Denmark, cases were from the Danish National Birth Cohort, a population-based cohort of women and children. Mothers were interviewed while pregnant and twice after delivery. Matched controls were born within at least 6 months of each case and within the same county, and were randomly selected from national birth and population registries.The investigators found several conditions independently associated with increased hypospadias risk, most of which they say could be explained by impaired production of hormones by the placenta. Mothers without first-trimester nausea were twice as likely to bear sons with hypospadias, as were mothers who had a prepregnancy body mass index of 30 or greater. These findings support the theory that placental insufficiency contributes to hypospadias. Nausea is believed to be caused by an early surge of pregnancy hormones, and the absence of first-trimester nausea is associated with low hCG levels. A previous study showed that obese women have lower levels of a family of proteins called plasminogen activator inhibitors, some of which are derived from the placenta.The team also determined that a maternal diet lacking both fish and meat was associated with more than a fourfold increased risk of hypospadias in baby boys. This finding complements a 2000 study by other authors that showed a strong positive association between maternal vegetarian diet and hypospadias in offspring. The authors of the current study conclude that exclusion of animal proteins could increase the risk of a transient deficiency of some nutrient that\u2019s essential for formation of the organs or the placenta. Another explanation is that some protein sources in vegetarians\u2019 diets (such as soybeans) contain compounds with hormonal effects that may affect the development of the urogenital organs in humans."}
+{"text": "Therapeutic response in patients with advanced breast cancer is conventionally assessed with reference to criteria devised by the International Union Against Cancer. Evidence to date suggests, however, that assessments of equivalent quality may be obtained at lower cost from the use of serum markers. The paper presents estimates of potential cost savings resulting from the use of serum markers in place of conventional assessment and argues that the size of these savings merits the establishment of a randomised controlled trial."}
+{"text": "The cellular content of receptors for epidermal growth factor (EGF) was measured in different histological subgroups of human mammary carcinomas. EGF receptors were detected in 36% of the ductal and all the medullary carcinomas. In contrast lobular and pure colloid tumours did not contain measurable amounts of the receptor. The receptor was found both among tumours with an euploid and aneuploid DNA pattern. The EGF receptor is thus found in carcinomas with a varying degree of differentiation as judged by the cellular DNA pattern. There was no correlation between the proliferative activity of the tumours as measured by thymidinekinase activity and the amount of EGF receptors in the tumour. Tumours with detectable EGF receptor often had low levels of oestrogen receptor. This finding could only partly be explained by the menstrual status of the patients."}
+{"text": "Electron spin resonance studies have been made of caeruloplasmin and iron transferrin levels in whole blood of healthy controls and patients with a variety of malignant conditions receiving various forms of treatment. A small difference was found in caeruloplasmin level between normal males and females, although normal females receiving contraceptive steroids had an elevated level. No difference was found in iron transferrin level. Various conditions increased the caeruloplasmin and some also decreased the iron transferrin level in patients with malignant disease. These included surgery and the approach of a terminal phase of disease. Once allowance for these factors was made, the remaining small differences in Cu and Fe between patients with either squamous cell carcinoma or breast cancer and controls appeared to have no clinical significance."}
+{"text": "Thymectomy effectively prevents the development of spontaneous lymphoma in the AKR but how this effect is achieved remains to be determined. One possible mechanism, namely suppression of genomic expression of the oncogenic murine leukaemia virus now seems unlikely since levels of the group specific MuLV antigen were in comparision with their sham operated controls unaltered in both neonatally and adult thymectomized AKR."}
+{"text": "The important paradigm shift for asthma care that focuses on clinical control has revolutionized the understanding of the disease and its optimal pharmacological care. UnfortunThe February 2010 new release from the U. S. Food and Drug Administration (FDA) requires new safety measures and warnings for the use of inhaled long-acting beta agonists (LABAs) in asthma control .[2] SuchCertainly, this new FDA safety release on the use of LABAs will create some confusion among asthma care workers, patients and related drug companies. However, the bright side of such warnings is that it will for sure reinforce the tendency of asthma care workers to revisit the stepwise (whether up or down) approach of pharmacotherapy recommended by most recent national and international asthma guidelines.\u20136 The maSome of these FDA warnings for LABA inhalers can be considered as fine-tuning and reinforcement of the already comparable recommendations stated in most recent asthma guidelines.\u20136The use of LABAs as monotherapy and as a reliever medication is strongly discouraged because of potential health hazards.LABAs may be used in combination with ICs in the stepping up of treatment for the long-term management of only such asthma that is uncontrolled by controller medications.Patients should be maintained on an asthma controller medication once asthma control is achieved.A combination product of ICs and LABAs should be used only to ensure compliance with both medications.Surprisingly, among these FDA warnings, the new recommendations are to shorten the period of use of LABAs even if in combination with ICs and to discontinue its use, if possible, once asthma control is achieved. These new advices are somewhat welcome as true phenomena of stepping-down in the treatment of well-controlled asthma.These recommendations might open the gate for the use of other alternative controller agents that can optimize asthma control. They have also stressed the implementation of non-pharmacological measures for achieving the control of asthma. These include the identification and avoidance of triggering and exacerbating factors  to minimize the overall use of any unnecessary pharmacological agents in order to avoid their potential future hazards for health. These meFurthermore, I would also like to take these warnings to share a personal view about similar safety requirements that may be needed for the solo use of short-acting beta agonists (SABAs), which is recommended in asthma guidelines as reliever inhalers.\u20136 Such cIn conclusion, this new FDA safety release on the warnings for the use of inhaled LABAs is very well saluted. It will motivate the asthma care workers to revisit the stepwise pharmacotherapy approach recommended by most current asthma guidelines. It recommends the use of LABAs to be limited to the combination with ICs for cases with uncontrolled asthma and to be administered for the shortest possible duration. The solo use of LABAs might soon become history in the management of asthma. Extension of similar cautions for solo use of SABAs is a personal vision that will be challenged further by benefit/ risk profile in future clinical investigations."}
+{"text": "Dear Editor,et al.[I read with interest the brief report by Parija et al. and apprThe clinical presentation was suggestive of raised intracranial pressure, with the diagnostic workup pointing to cerebral venous thrombosis (CVT). CVT is a relatively common presentation of polycythemia vera. When we This report highlights the diagnosis of an uncommon hematological condition which primarily presented to an ophthalmologist. CVT is often under diagnosed even by neurologists. It should be remembered that almost 40% of CVT patients present with signs and symptoms suggestive of isolated intracranial.4 A thoroVisual loss in CVT maybe due to thrombotic ischemia of any structure of the visual pathway or due to pressure on the optic nerve due to the transmitted raised intracranial pressure (ICP). All cases of CVT with visual loss require visual field analysis and measurement of optic nerve sheath diameter using B-scan ultrasonography (USG). Visual loss in patients with CVT due to transmitted raised ICP (indicated by increased optic nerve sheath diameter on USG) not amenable to medical management is an indication for optic nerve sheath decompression (ONSD). ONSD as a treatment option for the visual loss in the left eye should have been offered to the patient in this case, as it has been shown to be effective even in the presence of optic disc pallor.5 Moreove"}
+{"text": "Many marine coastal ecosystems are threatened by increasing waste discharge, and bioassays are needed because chemical and physical tests alone are not sufficient to assess potential effects on aquatic biota. In light of the fact that larval metamorphosis of benthic invertebrates is usually very sensitive to environmental changes, this paper reviews sensitivity comparisons of larval metamorphosis with other common bioassays in different species and those in different developmental stages of the same species, and it discusses the potential use of larval metamorphosis as an indicator of marine environmental quality."}
+{"text": "An analysis of past and present Australian legislation for managing and regulating contaminated sites confirms that such legislation must deal with a number of specific matters.Australian legislation is effective in some of these areas but poor in relation to others. The analysis will assist other countries and jurisdictions to create effective legislation more speedily by avoiding identified problems."}
+{"text": "The American College of Surgeon\u2019s Coalition for Quality in Geriatric Surgery will formally launch a national initiative aimed to improve the quality of surgical care for all older adults in July 2019. The first-year goal will be to recruit and successfully verify 100+ medical centers. This presentation will provide an overview of dissemination efforts for the standards set for providing high quality surgical care for older adults as well as processes to measure the quality of care provided to older adults at these medical centers. It our vision that this national initiative will lead the effort to the improvement of surgical care of all older adults."}
+{"text": "There are errors in the Funding statement. The correct Funding statement is as follows: The current study is funded by Iran National Science Foundation with grant ID 940007 and 95824986 to Sima Rafati. Also Farnaz Zahedifard received funding from Pasteur Institute of Iran as part of her Ph.D studentship. She also got Calmette and Yersin training scholarship from RIIP foundation from Institut Pasteur International Network for her training period in South Korea. The founders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript."}
+{"text": "The authors noticed that the cartoons in Both the HTML and PDF versions of the article have been corrected. These errors appear only in print and PDF versions downloaded on or before August 21, 2018."}
+{"text": "Alzheimer\u2019s disease (AD) and temporal lobe epilepsy (TLE) are the most common forms of neurodegenerative disorders characterized by the loss of cells and progressive irreversible alteration of cognitive functions, such as attention and memory. AD may be an important cause of epilepsy in the elderly. Early diagnosis of diseases is very important for their successful treatment. Many efforts have been done for defining new biomarkers of these diseases. Significant advances have been made in the searching of some AD and TLE reliable biomarkers, including cerebrospinal fluid and plasma measurements and glucose positron emission tomography. However, there is a great need for the biomarkers that would reflect changes of brain activity within few milliseconds to obtain information about cognitive disturbances. Successful early detection of AD and TLE requires specific biomarkers capable of distinguishing individuals with the progressing disease from ones with other pathologies that affect cognition. In this article, we review recent evidence suggesting that magnetoencephalographic recordings and coherent analysis coupled with behavioral evaluation can be a promising approach to an early detection of AD and TLE.Highlights\u2013Data reviewed include the results of clinical and experimental studies.\u2013Theta and gamma rhythms are disturbed in epilepsy and AD.\u2013Common and different behavioral and oscillatory features of pathologies are compared.\u2013Coherent analysis can be useful for an early diagnostics of diseases. It is known that theta and gamma oscillations are closely related to cognitive processes. The theta rhythm (4\u201312 Hz) is prominent oscillations recorded in the hippocampus and surrounding limbic structures during exploration and REM sleep  or \u201cnested\u201d oscillations  evoked a firing of hippocampal neurons, which reflects an integrated representation of spatial and temporal information  during the performance of cognitive tasks  complex of rats and guinea pigs revealed that normally theta oscillations were relatively synchronous in these brain regions  compared to healthy control was revealed , an impairment of cross-frequency gamma amplitude modulation by hippocampal theta rhythm was observed  suggests that these diseases have some common properties and, probably, at least partially similar mechanisms of their development.The potential relation between TLE and AD has been supported by experimental and clinical data. Thus, aging is a common and well-established risk factor for epilepsy and AD (Armon et al., Many clinical evidence indicates an increased comorbidity of seizure pathology in AD: it is becoming clear that AD is associated with neuronal hyperexcitability as well as network hypersynchronicity, which is the main reasons of epilepsy development (Eichler and Meier, At the same time, neurodegenerative processes peculiar to dementia can play a central role in the development of epilepsy in the patients predisposed to cognitive deficit. Adult-onset epilepsy of unknown cause could thus represent a risk factor for the ongoing neurodegenerative damage, even when epileptic manifestations and clinically recognized dementia are separated by long time (Cretin et al., The facts of cognitive impairment in animals with epileptiform activity were derived from different studies devoted to the role of the tau peptide (Roberson et al., In the hippocampus, one of the main foci of cell death in TLE and AD brains, the network hypersynchronicity and epileptiform activity can be the result of formation of extensive aberrant neuronal connections. This aberrant remodeling was revealed in epileptic rats and in APP transgenic mice (Harris et al., It is known that the main problem in diagnosis of neurodegenerative diseases is the detection of neuronal abnormalities at early stages of their development. At present significant achievements have been made in the development of methods for the detection of some biomarkers of AD and TLE, including cerebrospinal fluid and plasma measurements and glucose positron emission tomography (Shiihara et al., At present, the methods for detection of theta\u2013gamma coherence during cognitive loading are still not absolutely perfect. Thus, changes in theta\u2013gamma coupling may simply reflect memory-related increases in gamma power and phase synchrony (Montgomery and Buzs\u00e1ki, The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The population of persons aging with disabilities is growing. Being able to segment aging with disability sub-populations within national data sets is becoming increasingly important in order to understand the relationship of aging with disability to a range of outcomes in later life including health and wellness, economic security, and health and long-term service and support need and use. This symposium includes four examples of how existing data can be used to draw conclusions about the experience of old age for persons with intellectual or developmental disabilities. In addition, the symposium offers insights into the limitations of these data and the presentations lend themselves to a discussion of how measurement across disability sub-population can be ope rationalized. Two of the presentations focus on understanding mortality trends of adults with cerebral palsy and down syndrome--including an understanding of the health conditions facing these populations. A third presentation will focus on cardiovascular risk factors and co morbidity among adults with cerebral palsy. Finally, a fourth presentation will focus on pairing qualitative understanding with quantitative trends to offer a deeper understanding of the health management challenges for adults with disability as they age. Through a deeper understanding of the experience of health in later life for adults with disability, ideas about interventions and supports can be better aligned with the needs of these populations."}
+{"text": "The exact neurophysiological mechanisms of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) for treating patients diagnosed with depression are still not clear. Results of previous structural and functional MRI studies showed an aberated functional connectivity in major depressive disorder (MDD)  which induces very mild sensations in the skin  stems from obsolete medical point of view that the stimulating electrodes do not enter the crania . The real effect of \u201cnon-invasive\u201d electromagnetic stimulation (rTMS and tDCS) cannot be measured directly due to their non-invasive nature. Opitz stated in recent research, that the important point is in interpretability of stimulation effects  can decrease the complexity of electrophysiological signal (\u010cuki\u0107 et al., Several researchers who used various non-linear measures of complexity of EEG confirmed that physiological complexity is elevated in MDD (Ahmadlou et al., Bestmann et al.  demonstrAlthough it can seem impossible to compare the two non-invasive brain stimulation techniques that are so different in the sense of their electromagnetic properties and the level of power they can induce in the living tissue, we can still recognize the same functional pattern. In many review papers exploring the efficiency of both rTMS and tDCS in clinical applications (Brunoni et al., For all electromagnetic stimulation treatments, the effect is of temporary nature. The rationale is that they can at least ameliorate the symptoms for a limited time; after which they need to be repeated. The common advantage of non-invasive brain stimulation techniques over medications is that there are no foreseeable harmful side-effects (Antal et al., Although study of physiological complexity changes is still in the realm of research and mainly not in use in clinical setting, it is expected that soon clinicians would start using varying electromagnetic modalities of stimulation with better understanding of how they work\u2014as means to decrease complexity characteristic of depression. Further research based on empirical data is necessary before making the final conclusion that non-invasive brain stimulation treatments may work through changing physiological complexity.To conclude, after all above mentioned results of various lines of research that tried to bring us closer to understanding various aberrations of depression, both rTMS and tDCS might be efficient because of their ability to decrease characteristically elevated levels of physiological complexity in depression.M\u010c conceived the idea about the article, performed a literature research and wrote entire text.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "We offer a novel perspective on the burgeoning literature focused on loneliness later life by examining the language(s) used to describe, define and depict loneliness. We have an extensive body of work describing the prevalence of , \u2018vulnerability factors\u2019 and consequences of loneliness in later life. These activities start with pre-defined concepts of what loneliness is and often use scales and questions which may/may not use the term loneliness. How well does the contemporary language of loneliness used in research, policy, practice and the media really capture the depth and complexity of what people are experiencing? Do the terms and words use in our measurement scales and quantitative research resonate with this vocabulary? In qualitative research interviews how do older adults talk  about loneliness? How does the media talk about loneliness and what images does this convey about later life? We will address these three issues in our seminar. Using data from qualitative interviews undertaken as part of a mixed methods study of temporal variations in loneliness, Thomas uncovers the strategies participants used to talk or avoid talking about loneliness. Victor uses qualitative data from 12,000 adults aged 60+ collected as part of the BBC loneliness experiment to examine the terms used to describe loneliness and to identify both the opposite of loneliness and the positive aspects of loneliness. Sullivan exposes how loneliness is constructed in print and digital media over a 10-year period in the UK and Canada and its role in framing the loneliness problem."}
+{"text": "Resilience has been examined in various age groups, initially focused on vulnerable children and more recently in enhancement of resilience in various age groups and in response to trauma. Based on studies of resilience in Holocaust survivors and intergenerational engagement to promote resilience in former gang members and isolated older adults, Corley\u2019s 3E model of Experience, Expression and Engagement is discussed in terms of multiple studies and the implications for forming and strengthening networks in communities at risk. This includes initiating creative coalition-building endeavors to address loneliness in residential settings for older adults evolving from a project funded to the Motion Picture and Television Fund in Los Angeles from the AARP Foundation."}
+{"text": "The global prevalence of sensorineural hearing impairment was first reported by the World Health Organization (WHO) in 1985.\u2013At the individual level, the burden of hearing loss over the life course is substantial and can be exacerbated by negative societal attitudes and prejudice towards affected people. In general, hearing loss has adverse consequences on interpersonal communication, psychosocial well-being, quality of life and economic independence.,,The main drivers for the rising trend in hearing loss include demographic changes attributable to global population growth and improved life expectancy.,,,Since 2007, WHO has promoted increased public awareness of hearing loss through World Hearing Day, held every March. Actions required to curtail the growing number of people with hearing loss and to improve quality of life for those with hearing loss have also been extensively reported.The sustainable development goals explicitly recognize the need for a better quality of life and opportunities for optimal well-being throughout the life course of all people with disability."}
+{"text": "Sound and movement are perceived through the vibration of modified ciliary bundles located on the apical surfaces of specialized mechanosensory hair cells. These hair cells derive from specific regions of the otocyst that become determined to develop initially as sensory epithelia and ultimately as either hair cells or supporting cells. The number of hair cells in an individual vertebrate is surprisingly small and the ability to replace these cells varies among different classes. The molecular and cellular factors that specify hair cell identity are not known, but the results of recent experiments have begun to identify some of the signaling pathways that play important roles in hair cell development. This review will describe recent findings related to the factors that influence the final choice of a progenitor cell to develop as a hair cell and discuss their implications for the overall development of the auditory and vestibular systems."}
+{"text": "Concerns have been raised that the transplants performed in the local context at the time of procedures reported in this article  may haveThis article  reports PLOS ONE Editors retract this article.International ethics standards call for transparency in organ donor and transplantation programs and clear informed consent procedures including considerations to ensure that donors are not subject to coercion. Owing to the lack of documentation to demonstrate this study had prospective ethical approval, insufficient reporting, concerns about the use of prisoners as transplant donors, and unresolved concerns around the informed consent procedure used for organ donors, and in compliance with international ethical standards for organ/tissue donation and transplantation, the The first author notified the journal that all authors agree with the retraction. The other authors either could not be reached or did not respond directly."}
+{"text": "Recent findings from longitudinal followup studies of adolescents and adults with fetal alcohol syndrome (FAS) indicate that the deficits associated with this disorder are long lasting and pervasive. In addition, followup data from several large, prospective studies of cohorts representing a broad range of alcohol exposure levels have confirmed that although FAS represents the severe end of a continuum of birth defects, moderateAccumulating evidence shows that many FAS deficits can be detected at infancy and remain through adolescence into adulthood. In particular, an abnormally small head circumference  and intellectual problems persist as an affected child matures, whereas behavioral, emotional, and social problems can become more pronounced e.g., . In addiIn a recent long-term followup study of a Seattle cohort of adolescents and adults with FAS, This article aims to demonstrate the need to differentiate the impact of prenatal drinking from the impact of the environment in which the child is raised when assessing neurobehavioral and other outcomes in children whose mothers drank both during and after pregnancy. In the 20 years since FAS was first identified, a major body of research has been compiled on the effects of prenatal alcohol exposure as well as the impact of being raised by an alcoholicAn association between drinking during pregnancy and neurobehavioral function in infants and children normally is interpreted as teratogenic . The specific body systems affected by alcohol exposure and the resultant outcomes depend on when exposure occurs during the prolonged period of CNS sensitivity to alcohol see . For exaOne alternative explanation\u2014that an observed deficit is attributable to the socioenvironmental consequences of being raised by a drinking mother\u2014can be evaluated by examining the relationship of the deficit to postnatal maternal alcohol use. In cases where the mother drinks both during and after pregnancy, however, it may not always be possible to determine the degree to which observed deficits are attributable to teratogenic versus socioenvironmental factors. Statistical analyses that include variables related to both prenatal and postnatal drinking behavior may sometimes obscure true prenatal effects and result in the failure to recognize a true effect or in an understatement of the magnitude of the effect .Two analytical approaches have been used to assess the impact of prenatal versus postnatal drinking on the child. One approach was used in a prospective longitudinal study  conducte(1) the Fagan Test of Infant Intelligence , (2) a tAs seen in A second analytical approach for assessing the effects of drinking during and after pregnancy was used in a longitudinal study conducted in Atlanta, Georgia . The defA similar pattern of results was seen when The data from these studies are consistent with findings demonstrating that cognitive performance is less affected by alcohol exposure in infants and children whose mothers stop drinking in early pregnancy, despite the mothers\u2019 resumption of alcohol use after giving birth e.g., . Thus, tThe impact of being raised by an alcoholic parent has been examined extensively in the research on children of alcoholics (COA\u2019s), but few studies have compared the effects of being raised by an alcoholic father versus an alcoholic mother. Most COA research has focused on children whose fathers have problems with alcohol abuse or alcoholism, but whose mothers do not, in order to exclude the effects of alcohol exposure attributable to maternal drinking during pregnancy. Little is known about the impact of these nonalcoholic mothers\u2019 drinking habits on their children. As previously noted, however, recent findings  have detThe studies cited in this article illustrate the need to distinguish the effects of drinking during pregnancy from the consequences of being raised by a drinking parent. The methods described here reflect some of the advances in this research area that have enabled investigators to better distinguish between the harmful effects of prenatal alcohol exposure and the additional impairment that may be incurred in an environment in which one or both parents drink heavily. Current research is beginning to explore complex models and is attempting to identify specific factors  that may buffer or increase the magnitude of the damage incurred by alcohol exposure."}
+{"text": "Radiographers have been providing their opinion on radiographic findings to referring physicians in Australia in an informal capacity for some time. Evidence has shown improved outcomes for patients when radiographers and referring clinicians work collaboratively as part of a multidisciplinary healthcare industry.A number of barriers have been identified to the implementation of formalised radiographer abnormality detection systems in Australia which include the following: lack of education, lack of confidence and lack of support from radiologist colleagues.In recent times, Logan Hospital in Queensland has set the standard for radiographers to fulfil full scope of practice with the implementation of a formalised PIE system. The prospective longitudinal study by Brown et\u00a0al."}
+{"text": "This finding highlights how junior doctors, whether in a formal training programme or not, are particularly vulnerable to the adverse effects of a patient suicide, with potential effects on recruitment and retainment in psychiatry.2 The projects involve annual events to promote knowledge and discussion about quality and safety; discussions about the process of serious incident investigations and the support available at each junior doctor induction; and the development of a written resource on formal and informal sources of support for junior doctors involved in a serious incident investigation. These projects are under constant review in order to respond to trainee feedback.In our mental health trust in South East London, trainee-led initiatives in collaboration with the postgraduate training department have been making changes to the learning and support offered to junior doctors who are involved in a serious incident investigation in the past 5 years.We thank the authors for the valuable work exploring how suicide can affect doctors of any grade. We hope that mental health trusts and postgraduate training departments continue working to develop formal and informal support structures for doctors experiencing this difficult event."}
+{"text": "Concerns have been raised that the transplants performed in the local context at the time of procedures reported in this article  may haveDetails as to the donor sources and methods of obtaining informed consent from donors were not reported in this article , and wheThe authors state that no vulnerable populations were involved in their research and all organs were obtained voluntarily but did not provide ethics approval documentation or consent forms to support their claim or clarify whether organs had been procured from prisoners.The authors did not respond to inquiries about the availability of underlying data supporting this study.PLOS ONE Editors retract this article.Owing to the lack of documentation to demonstrate this study had prospective ethical approval, insufficient reporting, unresolved concerns around the source of transplanted organs and whether they included organs from prisoners, and in compliance with international ethical standards for organ/tissue donation and transplantation, the The corresponding author notified the journal that all authors disagree with the retraction. The other authors either could not be reached or did not respond directly."}
+{"text": "This paper presents the process by which we adapted an existing Alzheimer\u2019s Disease and Related Dementia (ADRD) caregiver support intervention that is directed at multiple family caregivers and culturally-responsive to the needs of the Arab American community. Three focus group discussions with Arab American families caring for a family member with ADRD were organized in partnership with the Arab Community Center for Economic and Social Services (ACCESS). Focus group discussions included two members from each family to gather data on needs of Arab American ADRD caregivers, role of family in caregiving and use of technology for caregiving information. Results underscored the lack of and desire for knowledge around ADRD, and the perception by Arab Americans that they differ from non-Arab Americans in approaches to caregiving . These data confirm the need for caregiving interventions responsive to Arab American needs/preferences."}
+{"text": "Evidence is mounting that patient-reported experience can provide a valuable indicator of the quality of healthcare services. However, little is known about the relationship between the experiences of people with severe mental illness and the quality of care they receive. We conducted a study to examine the relationship between patient-reported experience and the quality of care provided to people with schizophrenia.We calculated a composite global rating of quality of care for people with schizophrenia using data from an audit of 64 mental health providers. We then examined associations between these ratings and mean patient satisfaction and patient-rated outcome using data from a survey of 5608 schizophrenic patients treated in these services.r\u2009=\u20090.33; p\u2009=\u20090.01) but not with patient satisfaction . Patient-rated outcome was also positively correlated with patient involvement  and the quality of prescribing practice . High patient satisfaction scores were significantly associated with the extent of use of care plans within each organisation .Global rating of quality of care was positively correlated with patient-rated outcome (Among people with schizophrenia, patient-rated outcome provides a better guide to the quality of care than patient-rated satisfaction. Greater use of patient-reported outcome measures should be made when assessing the quality of care provided to people with psychosis. Improving the quality of care that patients receive is a key objective for healthcare providers across the world. As well as safety and clinical effectiveness, patients experience of care is a key component of most definitions of quality of healthcare .In recent years evidence has begun to emerge that patient-reported experience can offer a reliable indicator of the quality of care that services provide \u20134. A sysSmall scale studies have examined the relationship between patient-reported experience and other measures of quality of care. For instance, Shipley and colleagues  investigThe second round of the National Audit of Schizophrenia conducted between 2013 and 2014 assessed the quality of care provided to patients with schizophrenia across all the Mental Health Trusts in England and Health Boards in Wales. As the audit provided data on a wide range of outcomes of care for patients with schizophrenia around the county, we set out to use data from this audit to examine whether patient-reported experience provides an indication of the services\u2019 overall quality of care in a nationwide cohort of patients with severe mental health illness.The National Audit of Schizophrenia provided an in-depth examination of service performance against 16 standards of care derived from national guidelines for the treatment of people with schizophrenia in England . These sA total of 64 NHS Mental Health Trusts in England and Health Boards in Wales (referred to collectively as \u2018Trusts\u2019 in the remainder of this report) participated in the audit. Data were collected via an audit of practice tool and a contemporaneous patient survey. The audit of practice tool was developed specifically to measure standards of care and the relevant data were obtained from the patients\u2019 case records .The quality of patient involvement (e.g. whether there was shared decision making process in the selection of medication).Compliance with recommended prescribing practice (e.g. extent of polypharmacy and prescribing above BNF recommended maxima).Access and uptake of evidence-based psychological treatments.Provision of a care plan jointly developed with the patients to meet their needs.For each Trust, we calculated the proportion of patients for whom each individual standard was met and the mean percentage of compliance for each standard relative to the total national sample. We then calculated a global trust rating score based on the mean percentage of compliance of each Trust across all standards assessed with the audit of practice tool. We also calculated five sub-scores from standards relating to:The patient-reported experience measures we used included a measure of patient satisfaction with care and a patient-rated outcome measure. The question on patient satisfaction with care asked: \u201cTaking everything into consideration, are you pleased with the care you have received from the service so far?\u201d Responders had to indicate their answer by using a four-points Likert scale from 1  to 4 (very satisfied). The question on patient-rated outcome asked: \u201cTo what extent have services helped you to achieve good mental health in the last year?\u201d and patients responded using a four-point Likert scale ranging from 1 (made me worse) to 4 (helped a lot). We calculated the mean trust scores for these two questions and converted them into a 100-point scale.We carried out Pearson product-moment correlations to investigate associations between patient satisfaction and patient-rated outcome scores with the global trust performance and subgroups of care scores .The National Audit of Schizophrenia (NAS) was commissioned by the Healthcare Quality Improvement Partnership (HQIP) as part of the National Clinical Audit Programme (NCA). As part of NCA, all Mental Health Trusts in England and Wales were expected to take part in NAS. Consent was not required from the patients to publish the audit data in the audit\u2019s main report or for research purposes and the data were collected by the audit team in such a manner that the patients could not be directly identified.The audit team received 5733 returns from the audit of practice, of which 5608 were used in the analysis after data cleaning with a mean of 88 SD\u2009=\u200917) returns per Trust. In total, 3379 patients submitted a survey form with a mean of 53 (SD\u2009=\u200919) per Trust and a response rate of 26.4%. Table\u00a07 returnsp\u2009<\u20090.01). In Table\u00a0There was a positive significant correlation between the patient satisfaction and the patient-rated outcome measure (rs\u2009=\u20090.582, The results relating to the five subgroups of patient care we examined are also presented in Table Secondary analysis of data from this national audit of care for people with schizophrenia found that patient-rated outcome was positively associated with an independent rating of the global quality of care provided by these services. In contrast, we did not find an association between global quality of care and the patients\u2019 satisfaction with the service they received. High scores on patient-rated outcome were also correlated with high patient involvement in the decisions about their care and with high compliance of the services with the recommended prescribing practice. In contrast, high levels of patient satisfaction were associated only with the provision of a care plan tailored to the patients\u2019 needs. Nonetheless the strength of these associations are not strong and caution needs to be exercised in interpreting the results of this analysis.While the previous work of Doyle and colleagues  demonstrThe main strength of this study is that we were able to examine the relationship between patient experience and quality of care across a large number of providers of mental health services throughout England and Wales. However, the study also has a number of limitations which need to be considered when interpreting the results. Firstly, the audit used two different samples for collecting case note data and for the patient survey, which did not allow us to determine whether individual patient ratings related to the quality of care provided to them personally by their Trust. The use of aggregate data from different samples of patients within each Trust may have underestimated the strength of the associations we might have seen, had both sets of data come from the same patient sample.A second limitation of the study was that the measures of patient-rate experience and the global trust rating we used have not been validated. The global rating of trust quality of care was developed from standards for the treatment and management of people with schizophrenia published by the National Institute for Health and Clinical Excellence following a systematic review of published literature and extensive consultation with patients and providers . HoweverWhile we found a moderate degree of association between patient satisfaction and patient-reported outcome in our analysis, only the latter was correlated with the independent rating of global quality of care provided Trusts. This suggests that patient-rated outcomes might be a better indicator of the quality of care that a service provides than patient-rated satisfaction with care. We also found that the two measures of patient-rated experience were associated with different elements of care delivered by participating Trusts. The more the services promoted the patients\u2019 involvement in decisions about care and higher levels of compliance with recommended prescribing practice were associated with patients being more likely to state that services were improving their mental health. On the other hand, services that had higher compliance with recommendations that patients should have a care plan that was jointly developed to meet their needs had higher ratings on patient satisfaction with care.These results support previous research in other healthcare settings which indicate that patients rate their experience and outcomes of care according to different criteria and highlight the importance of both in assessing the overall quality of care that healthcare services provide , 12.In recent years concerns have been expressed about the burden that providers of healthcare services face in assuring the quality of care they deliver , 14. TheIn summary our findings highlight that, feedback from patients with severe mental disorders can provide important information about the quality of care they receive. Therefore, greater use of patient-reported experience measures should be made when assessing the quality of care provided to people with psychosis. Future work should focus on exploring the best way to combine patient views with audit data to obtain a comprehensive picture of the quality of care that services provide."}
+{"text": "The fruits of this collective endeavour include an understanding of the genetic architecture of the disease, an appreciation of its complex pathophysiology, and much progress in clinical management. However, many challenges remain, particularly with respect to disease prevention and the management of progressive heart failure.The first description of hypertrophic cardiomyopathy (HCM) can be attributed to any number of great anatomists and physicians working from the 17th century onwards, but the modern era is often said to have begun with Donald Teare\u2019s landmark paper of 1958HCM differs in several important aspects from other conditions associated with left ventricular failure and cardiac hypertrophy. From a clinical perspective it has a well-known association with sudden cardiac death but it also represents an important prototype for diastolic heart failure. The natural history of heart failure in HCM is notably longer than that of ischaemic heart disease with symptom evolution and remodelling occurring over decades. In about one third of patients the presence of intra-cavity or left ventricular outflow tract obstruction provides an additional haemodynamic burden and endothelial and microvascular dysfunction are present from an early stage and contribute to the genesis of symptoms and disease progression. The prognosis of HCM is also highly variable with sudden death the major cause of mortality in younger patients and heart failure and stroke the major causes of death in older individuals. Earlier diagnosis within families has also led to a growing number of healthy carriers of pathogenic mutations that offer opportunities for early intervention to prevent disease.Global Cardiology Science and Practice, we present a unique series of papers that review the aetiology, clinical presentation and management of HCM from childhood to old age. The series reveals how the simple notion of HCM as a disease defined by hypertrophy unexplained by loading conditions, encompasses a remarkably complex spectrum of genetic and acquired disorders. Sudden death prevention with implantable cardioverter defibrillators and the management of left ventricular outflow tract obstruction are comprehensively reviewed, but attention is also given to the management of rare but important phenocopies. The nuances of management in particular sub-phenotypes are also discussed and illustrate the need for systematic and expert evaluation of this and other complex heart muscle disorders.In this special issue of\u00a0For many decades, the diagnosis and management of HCM has run in parallel with technological developments that permit more precise and timely diagnosis but not necessarily greater insight into pathogenesis or novel therapies. In 2018, however, there are signs that a new and exciting chapter in the story of HCM and other cardiomyopathies has begun with the transition of molecular genetics into the clinic and a growing number of randomised clinical trials designed to ameliorate and perhaps even prevent disease. It is our sincere hope that this expert series will spur readers to learn more about this fascinating group of diseases and to contribute to this landscape of therapeutic opportunity."}
+{"text": "Enigmatically, mitochondrial disease can affect individuals at any age and in any tissue (Lightowlers er et\u00a0al  use mous To assemble much of the chain of enzyme complexes that perform oxidative phosphorylation (OXPHOS) requires coordinated expression and assembly of gene products from both the nuclear and the mitochondrial genome. The catalogue of diseases associated with mitochondrial dysfunction continues to increase, and in many cases, the ubiquity of exome or whole genome sequencing has enabled the identification of the genetic mutations responsible for these pathogenic defects  occurred early on, whilst the axonal and locomotor degeneration only developed later, and were not the consequence of generalised brain atrophy. The tandem knockout of both YME1L and OMA1 restored the dynamic mitochondrial network, but despite this restoration of L\u2010OPA1, not only did the combination of eye defects persist but both the neuroinflammation and axonal degeneration became more severe, with an earlier onset. The combination of models used in these investigations brings us a little closer to understanding pathogenic mechanisms and that disruption of mitochondrial proteostasis alone can be a driver for disease.What is the relationship between this change in mitochondrial morphology, eye defects and axonal degeneration with age? Sprenger The authors declare that they have no conflict of interest."}
+{"text": "Akkermansia muciniphila and Anaerotruncus colihominis are swapped. A revised There is an error in As stated in the Competing Interests statement on the original article, all authors have patents pending in relation to this work. The following sentences are added to the Competing Interests statement as an additional clarification: The healthy reference ranges reported in this article were used in the development of a commercially available test product developed and marketed by uBiome. This does not alter our adherence to PLOS ONE policies on sharing data and materials."}
+{"text": "This symposium presents early results on epigenetic, transcriptomic and other aging biomarkers such as telomere length and mitochondrial DNA copy number from the Health and Retirement Study that allows a detailed examination of the biological pathways through which socioeconomic conditions influence the human aging process. In 2016 HRS collected 6 tubes of blood from people who completed the 2016 interview, had been in the sample at the prior wave and were not in a nursing home  to maintain a nationally-representative sample. These blood samples were analyzed for novel biomarkers of aging that included global methylation arrays, whole transcriptome sequencing, telomere length and mitochondrial DNA copy number among other biomarkers that were shown to be related to both social and economic circumstances and health outcomes at older ages. This level of integration of biological data to address social disparities hasn\u2019t been accomplished before on a large nationally-representative sample of Americans and will provide a unique opportunity to understand the biological mechanisms through which social disparities affect human health. The symposium will describe the utility of measuring novel age related biomarkers in a nationally representative population study such as HRS and the potential research opportunities that can be pursued using this publicly available resource. It will provide an overview of the measurement and distribution of epigenetic, transcriptomic and telomere length and mitochondrial DNA copy number as novel aging biomarkers. It will also describe the utility of these biomarkers in further understanding the biological underpinnings of socioeconomic differences in health and mortality."}
+{"text": "To effectively deliver child and adolescent mental health (CAMH) services in resource-constrained settings, it is vital to be smart in utilizing such resources efficiently, and this requires strategic planning. Of paramount importance is in-service training of primary care professionals aimed to consolidate existing knowledge and employ evidence-based strategies to manage child mental health care and to successfully integrate further these services into other mainstream healthcare facilities.\u2022Enthusiasm from health professionals/ CAMHS team lead by a child psychiatrist and CAMHS team as the service provider is a key determinant of sustainability\u2022Perseverance and patience are the salient qualities necessary to secure commitments and resources from relevant authorities\u2022Liaising effectively and cultivating cooperative and communicative networks between primary care professionals, educators, child-care and social care professionals, as well as non-governmental organisations is essential for effective service network\u2022In-service education and training as well as \u2018task-shifting\u2019 methods to optimise human resource development can be potent strategies to sustain CAMH service in limited resource environmentsThe establishment of CAMH services in Terengganu and the East Coast of Malaysia has resulted in better skills in assessing and managing young people with mental health problems by medical practitioners and mental health workers. It has had a positive impact on young people with mental health issues and their families around the East Coast and particularly in Terengganu.The implementation of CAMH services in Terengganu has served to facilitate numerous improvements such as promoting and increasing awareness of young people with mental health problems within their general practices. Furthermore, planning and implementing fully integrated child mental health service in Terengganu and the East Coast of Malaysia has served to enhance our understanding and yielded valuable insights which include:Child psychiatry services in Terengganu, Malaysia were initiated in 1997 as part of services provided by the department of Hospital Sultanah Nur Zahirah Hospital (HSNZ) which has been gazetted to manage psychiatric patients in Terengganu since early 70\u2019s. The service was led initially by a general psychiatrist who has a deep interest in working with young people with mental health problems. A specific day was allocated for children and adolescents with mental health issues to attend the general psychiatric clinic.The service development has progressed with the integration of child psychiatric unit specially designed and included during the planning of Day Treatment Complex in the 8th Malaysian Plan. This complex which also housed the psychiatric clinic was finally completed in April 2003. Sadly, the service was temporarily discontinued when the specialist was transferred to serve a different hospital. All children and adolescent patients were then relocated to the general adult clinic to be managed by medical officers and general psychiatrist.In December 2004, the child psychiatry clinic was re-established and re-branded with a new name Child and Adolescent Mental Health service (CAMHS) and managed by a child and adolescent psychiatrist who was posted to the hospital. The CAMHS was moved to the existing Day Treatment Complex. There were, however, multiple challenges faced during the initial implementation of CAMH service. Among those, we encountered various constraints involving inadequate funding to provide effective training and crucial posts to set up a multidisciplinary team to facilitate the assessment and management of mental health needs of children and adolescents. Inadequate support received including a vague understanding to allocate appropriate staff namely occupational and speech therapists, clinical psychologist/counsellor dampened the proper assessment and effective interventions upon arriving at the diagnosis. It was more of \u2018a one-man show\u2019 type of approach; i.e. existing occupational therapist focused mainly on the physical deformities while speech therapists are based in the ORL department; primary health care providers were not managing the cases adequately.\u2022Encouraged more specialists to subspecialise in child psychiatry with ongoing training of Masters in child psychiatry as well as a training base for those planning to subspecialize in child psychiatry abroad\u2022Provided an opportunity for staff to further their study or doing an attachment in child and adolescent mental health programmes and activities\u2022Made sure that all training modules, guidelines and protocol on child and adolescent mental health have been made available to all schools, primary care clinics and communities.\u2022Collaborated with the Education Department in organising courses and workshops related to mental health for school children and teachers in Terengganu.Since 2005, great efforts were made. A series of training courses and workshops were carried out both by the department and by other agencies. Specific issues were identified and funding was appropriately explored to materialise such plans. The primary focus was on improving knowledge and useful skills among mental health practitioners in the care of children and adolescent mental health patients. We have:Despite such constraints and being the only CAMH service in Terengganu, the team has endeavoured to provide an efficient service that will give an impact to the state of Terengganu and East coast. As demonstrated in Table CAMH service in Terengganu and the East coast of Malaysia has resulted in better skill reinforcement in areas of assessment and management of young people with mental health problems among medical practitioners and primary health care workers. Through receiving continuous funding and appropriate training, staff have achieved more confidence and are more able to care for their clients in their settings. This CAMHS establishment is believed to have an encouraging impact in the improvement of mental health among children, young people and their families in the East coast particularly Terengganu.To date, there is no standardised service evaluation in our CAMHS to assess patient clinical and service outcome measurement that may indicate the impact of CAMHS to the population of Terengganu and also the east-coast. This standardised routine outcome measurement is still mostly unexplored not only in Terengganu but Malaysia in general. These future research findings may help us to provide useful information for improvement in the quality of treatment planning as well as the implementation of standardised outcome measurement for local and national benchmarking of CAMHS service in this country.National Institute of Health (NIH), Ministry of Health (MOH), Malaysia.Application of approval for publications and presentations from Director General (DG) of Health Malaysia has been submitted to the NIH .No potential conflict of interest was reported by the authors."}
+{"text": "Not surprisingly given their multi-component nature, initiatives to improve integrated care often evolve to find the best way to bring about change. This paper provides an example of how an evaluation evolved alongside such an initiative designed to better integrate care across primary, community and hospital services in South Auckland, New Zealand.Using the explanatory power of a realist evaluative approach, theories of new ways of working that might be prompted by the initiative were explored in: (i) interviews with stakeholders in 2012 and 2015, (ii) online surveys of general practices and local care organisations, and (iii) a purposive sample of ten general practices.The results highlighted the institutional contexts that led to difficulties in implementing population health initiatives. They also revealed that changes in work practices focussed mostly on activities that improved the coordination of care for individuals at risk of hospital admissions.Multi-component complex interventions can vary in their delivery and be vulnerable to one or more components not being implemented as originally intended. In the case of this intervention, the move towards strengthening local relationships arose when contractual arrangements stalled. Realist evaluative approaches offer a logic that helps unpick the complexity of the relationships and politics in play, and uncover the assumptions made by those developing, implementing and assessing health service changes.Given the multi-component and evolving nature of initiatives seeking to better integrate care, the realist evaluative emphasis on surfacing early the theories to explain how change is expected to occur helps overcome the challenge of evaluating \u201ca moving target\u201d. In recognition that the projected demand for the local hospital was going to outstrip supply, a District Health Board in South Auckland, New Zealand introduced a major change programme focused on shifting the balance of care away from the hospital towards the community . Rather In 2012, in the context of a long standing interest in delivering care better designed around the needs of the local community, Counties Manukau District Health Board in South Auckland, New Zealand grouped a number of interventions together into a major change programme in order to deliver more care outside of the local hospital. An earlier initiative involving case management of patients who were high users of the hospital was extended to primary care to increase the management of patients in the community . Under tInternationally, efforts to better integrate health care have taken many forms  often fu81011The changes being put in place to increase the role of primary care by this District Health Board were informed by evidence that a greater focus on primary care is associated with better health, a more equitable distribution of health in populations, and lower health costs 1415. Fur1417An independent evaluation was commissioned to track progress and evaluate the outcomes achieved from a Strategic Locality Partnership Agreement signed between Counties Manukau District Health Board and the five providers of primary health care within the district. In New Zealand, Primary Health Organisations represent the interests of groups of general practices that generally operate as independent businesses receiving a proportion of their funding from government capitation, and the remainder from patient co-payments. In this district, five Primary Health Organisations representing particular enrolled populations were in operation. In many cases these enrolled groupings cut across the geographical boundaries set up by the Localities initiative.The Partnership between the five Primary Health Organisations and Counties Manukau District Health Board established a global budget for each locality centred on the expectation that if each locality was able to reduce demand across an agreed set of shared services then the savings would be directed towards innovative primary care services. The partnership agreement was the founding document of the Localities initiative.Reviews of new contracting arrangements designed to create savings and reduce utilisation have found mixed outcomes. Potential savings can be limited by the time taken to design and implement new contracts, pricing services and agreeing how performance will be assessed . NeverthThe evaluation team undertook an initial assessment of the outcomes expected to be attributed back to the Localities initiative and were struck by the variety of routes being put in place to achieve an outcome concentrated on reducing demand for secondary health care. These routes included new financial incentives via a risk/gain share contract,Recognising that the Localities initiative was not a fixed thing involving an unchanging set of interventions amenable to a closed system investigation, the following evaluation questions were agreed with the specially created Localities Evaluation Advisory Group:What were the initial theories of how the Localities initiative would achieve change?How is the Localities initiative being implemented, and what are the implications for the initial theories of change?What projects/events/interventions to improve integration most characterise the Localities initiative in health providers\u2019 minds?Using claims made in planning documents and governance meetings, as well as insights from relevant literature 23242526,232425networks theory. When health providers are included in local decision-making networks (context), their knowledge about local issues enables them to improve the design and integration of local services (mechanism), which in turn leads to a reduction in demand for secondary services (outcome).The The early parallels between the Localities initiative and clinical commissioning groups in the NHS, led us to theorise that the proposed risk/gain share contract would employ a similar mechanism of using general practitioners\u2019  frontline knowledge about patient experiences to improve service redesign .planned proactive care theory. When local health providers are resourced to undertake more local coordination activities (context), their confidence in working in a planned proactive way for patients increases (mechanism), resulting in better outcomes for patients and a reduction in demand for secondary care services (outcome).The The District Health Board had a long-term concern with those adult patients who were very high intensity users of hospital emergency departments  and havi26relationships theory. When relationships are strengthened between primary and secondary care health providers, and with social care providers as a result of localities-linked events and activities (context), then increased awareness of who to contact (mechanism) improves the coordination of care for individual patients (outcome).The A growing theme in the integrated care literature stresses the importance of the softer issues of relationship building  in orderBox One). Guidance on developing realist theories suggests that formal theories drawn solely from the literature can end up being too abstract :\u201cAs a doctor I can say OK book 30 minutes with me and I spend that time with the patient and then pass on to the practice nurse \u2026 it doesn\u2019t reduce the time I spend having the nurse involved but it increases the quality of what patients receive\u201d .Larger practices reported adapting to the At Risk Individuals model of care demands by appointing nurse leads, sharing caseloads across nurses and experimenting with different ways of \u201cpulling nurses off the floor\u201d to cover the extra time involved. These staff were also able to draw on a team-based approach to delivering care in partnership with the doctors in the practice. While the At Risk Individuals model of care did involve more work for the nurses, with the right team dynamic they were able to argue for changes to the way the practice allocated time:\u201cWhen it first started we were all lost \u2026 we did not know what to do \u2026 but now as we are going ahead it is more work for us but we are getting more time allocated to do that work as well. We are getting set times. As it is going when we do need more time we are speaking out and we are getting an allocation\u201d (Large-size practice participant).As being part of a new locality network was expected to influence practices to work in a more planned proactive way for those with long-term conditions, the focus group results revealed different locality contexts had much less influence than the team dynamic within each practice. Those practices prepared to change their organisational processes in order to support nurses to confidently take on new responsibilities for those with long-term conditions, were those most likely to embrace the opportunities to work in a planned proactive way.The changes put in place by the Localities initiative were collectively expected to shift the balance of care from the hospital to the community by better integrating services between primary and secondary care, moving from a more reactive to proactive model of care and encouraging the provision of more services in primary care settings. However, an assessment of the high-level trends in secondary care demand across the Auckland region found no evidence of change that could be confidently attributed back to the Localities initiative.Confirming that integrated care \u201cis not a fixed thing but instead is a fluid state that requires constant amending and adapting\u201d , the LocThe original Strategic Locality Partnership Agreement was yoked to an ambitious target of a 20% reduction in the projected standardised use of acute medical in-patient bed days and emergency department services over five years. When the Strategic Locality Partnership Agreement was reshaped into a series of enabling activities across the four localities, the policy target remained. However, using the theory-driven realist approach the evaluation sought to assess progress through the intermediate measures of: (i) whether primary care practices were working more proactively for those with long-term conditions; and (ii) the ways in which relationships were improving in order to deliver more integrated care. It is worth reflecting that this smaller scale of experimentation involving a series of enabling activities was forced on the District Health Board by the different power dynamics between the state  and the non-state .This experience adds weight to broader calls to acknowledge the power dynamics within integrated care  and the Box One outlined ten original propositions of how the initiative was supposed to work. These propositions included both actions that reshaped services for different local populations and actions that improved the coordination of care for individual patients. As time progressed, the Localities initiative became distinguished by the attention paid to the introduction of a new case management programme  and the opportunities to build new working relationships. This finding suggests that of all the propositions in play the ones gaining the most traction were those aiming for improvements for individual patients. Smith\u2019s 2011 analysis of New Zealand\u2019s Primary Health Care directions pointed to unresolved tension between population and patient perspectives within New Zealand primary care. Her assessment was that reform emphasis was placed on the population health gains expected from capitated funding, and less management and policy attention was paid to the development of more integrated primary care services for individual patients [From the beginning, the Localities initiative encompassed a bundle of interventions. patients . Adaptiowhat was happening to drive change. The key recommendations from the evaluation were to:Multi-component complex interventions can vary in their delivery and be vulnerable to one or more components not being implemented as originally intended . Recent Temper the expectation that the creation of four localities would reduce demand for secondary care and be more targeted about which local relationships need to be improved in order to benefit which groups of patients. The experience confirms the challenges of the field of integrated care, which can easily be saddled with ambitious business cases claiming significant effects when the reality is that behavioural changes are much more nuanced .Acknowledge the different contexts for local general practices compared to local care organisations. Local care providers were looking to be affirmed as an advocate and coordinator of care for their clients, while general practices wanted to be confident their time was being spent strengthening the local connections most likely to improve individual case management for their patients. These organisational contexts were more influential than the local contexts in each of the four geographical localities.Strengthen the implementation of the At Risk Individuals programme by supporting the growth of team-based cultures within primary care practices. Further research is planned on how patients are reasoning differently in order to support decisions on who is enrolled in the programme.The strength of this evaluation centres on the application of the realist approach. Recognising that the Localities initiative is a social programme involving human decisions and actions, attention was paid to identifying how change is expected to occur, and then testing the extent to which these theories were borne out. A recent realist evaluation of two integrated care initiatives tried to retrospectively identify the context, mechanism and outcomes in play but struggled to identify the relationships between them . This evThe Localities initiative demonstrated an agility in adapting to the complex web of incentives around primary health care in New Zealand, but the consequence was that attributing what was done to earlier defined metrics of success was difficult. The realist logic of enquiry regards programmes as \u201ctheories incarnate\u201d . Surfaci"}
+{"text": "Renal cell carcinoma, particularly the most common clear cell type, is one of the most aggressive of urological cancers with significant risk of metastatic spread. It also has a propensity for venotropism with a proportion of tumors developing thrombi up to the right atrium. The response with newly adopted targeted therapy has been considered to be in the evolutionary stage with no clear role with respect to debulking or reducing the size of the inferior vena cava (IVC) thrombus. We describe a case of a right-sided metastatic RCC with Level IV thrombus initially managed with Pazopanib followed by Nivolumab and Adalimumab followed by cytoreductive nephrectomy and IVC thrombectomy in the post-targeted therapy setting with complete curative response. Renal cell cancers (RCC) comprise 3.8% of all new cancers in the United States with 90% of renal tumors being RCC and about 80% being clear cell type , 2. The A 57-year-old woman with good performance status was detected to have a large right renal mass with adrenal extension and tumor thrombus extending to the right atrium Figures  and 3. SShe was started on Pazopanib 800 mg orally once daily which was later switched to Nivolumab after she developed upper gastrointestinal bleeding secondary to a duodenal ulcer.Interval imaging 6 months after targeted therapy revealed a decrease in the size of the primary renal mass, although the thrombus extension into the IVC still persisted with development of new hilar lymphadenopathy and segmental pulmonary embolism. Nivolumab was continued and 3-month PET/CT showed further reduction in the size of the renal mass with thrombus extension now to the level of liver. There were new enhancing masses in the liver suspicious for metastases with subcarinal, precarinal, and bilateral hilar mediastinal lymphadenopathy.She was initiated on Cabozantinib in addition to the Nivolumab in view of new lymphadenopathy. She tolerated the new regimen very well and was completely symptom-free with this therapeutic combination . New imaBased on the imaging, it was decided to proceed with posttherapy right cytoreductive nephrectomy with IVC thrombectomy. The anticoagulant was stopped and bridging was done with Heparin prior to the surgery. Intraoperative findings were that of a large renal mass with an infiltrating IVC thrombus in the retrohepatic location (using TEE assistance) with no gross evidence of metastases. Open radical nephrectomy with IVC thrombectomy and caval reconstruction was carried out with complete tumor thrombus resection . The patRadical nephrectomy specimen examination showed a necrotic nonviable carcinoma consistent with an RCC with complete response measuring 7 cm in size with perinephric extension. The tumor was extensively sampled and no viable carcinoma was detected . The necShe was fully back to her activities of daily living with no complaints at the time of her first follow-up visit to the clinic at the postoperative visit at 3 weeks. She will continue to follow up with both the Urological Oncology and Medical Oncology teams. She has not been planned for adjuvant targeted therapy at this stage in view of no evidence of residual disease.The management of metastatic RCC with Level IV IVC thrombus is complex and requires multimodality treatments. Current available literature supports the potential increasing role of targeted therapy in the neoadjuvant setting for the management of metastatic RCC and advanced RCC. The therapy does seem safe and feasible with no significant complications. The priority in this case from our standpoint was to achieve substantial downgrading of the tumor and to ensure control of metastatic disease. When this had been accomplished, the next step was posttherapy cytoreductive nephrectomy with IVC thrombectomy.Pazopanib is a preferred Category 1 option for first line treatment of patients with relapsed or medically unresectable Stage IV clear cell RCC. This is supported by the results of the COMPARZ and the PISCES trial which showed a comparable oncological control with fewer side effects reported \u20137.The data for first line Nivolumab in combination with Ipilimumab for favorable risk patients has been mixed. The Checkmate 214 trial showed that the combination of Nivolumab and Ipilimumab produced a higher objective response rate  and a higher complete response rate  compared to Sunitinib monotherapy [Patients treated with Cabozantinib as a primary treatment modality showed a significantly increased median progression free survival (PFS) compared to those treated with Sunitinib. They also showed a significantly higher objective response rate (ORR) compared to Sunitinib 46% vs 18%) [% [8].One of the benefits of preoperative systemic treatment is the possible reduction in the size of the primary tumor to make it resectable. This has received variable reporting in literature with wide variation in the treatment protocols and adoption. Despite this, there does seem to be some evidence to achieve downstaging in truly unresectable tumors. Thomas et al. reported a series of 19 patients with unresectable or bilateral tumors who received neoadjuvant Sunitinib. 15 patients were able to undergo radical nephrectomy thereafter with mean reduction in tumor size by 16% and significant reduction in tumor burden .The commonly used RECIST criteria to look for response to standardized treatment may not be effective as antiangiogenic therapy may not affect the size of the tumor but effectively produces intratumoral necrosis which is not assessed at all . FurtherPreoperative therapy to produce a reduction in the level of IVC thrombus has remained ineffective with IVC thrombectomy alone remaining the standard of care. Much of the existing literature on the use of preoperative therapy in the setting of an IVC thrombus comes from single center studies. The study by Cost et al. demonstrated there was minimal clinical effect on RCC thrombi with only one case of thrombus level regression from Level IV to Level II .There have been data in the form of randomized controlled trials to demonstrate that overall survival does not increase with a cytoreductive nephrectomy in intermediate and poor risk patients. However this data is not robust for favorable risk patients . Our patDownstaging the advanced primary tumor, tumor thrombus, and metastases provides an option of radical nephrectomy. Although current literature does not advocate neoadjuvant therapy for downstaging the level of IVC thrombus, we found a significant downstaging in the level of the thrombus from Level IV to Level II. Although the standards for neoadjuvant therapy have still not been established due to paucity of literature, more research is required to shed light on management of such tumors."}
+{"text": "Infectious diseases can be manifested by a spectrum of clinical signs and resultant clinical courses that range from acute to chronic and possible persistence in the victim in a latent form. Until recently, the origins of this kind of biodiversity were poorly understood, but advances in immunology \u2014 especially in identifying the constitutional mechanisms of immunity \u2014 have contributed to our understanding of the origins of biodiversity in infectious diseases. Infectious diseases affect only focal areas in the affected organisms, and the amounts and distribution of infectious lesions vary from patient to patient. In a population attacked by an infectious agent, individuals can be conveniently divided into three categories: totally resistant organisms which contain no susceptible structures and are not affected; mildly susceptible organisms in which a few foci appear and in which the infection runs a benign course; organisms in which the number of constitutionally susceptible structures is high and the infectious process develops in a severe form. The diversity is determined by the differences in susceptibility of various parts of the organism under consideration."}
+{"text": "Shale gas is considered by many to have the potential to provide the UK with greater energy security, economic growth and jobs. However, development of a shale gas industry is highly contentious due to environmental concerns including the risk of groundwater pollution. Evidence suggests that the vertical separation between exploited shale units and aquifers is an important factor in the risk to groundwater from shale gas exploitation. A methodology is presented to assess the vertical separation between different pairs of aquifers and shales that are present across England and Wales. The application of the method is then demonstrated for two of these pairs\u2014the Cretaceous Chalk Group aquifer and the Upper Jurassic Kimmeridge Clay Formation, and the Triassic sandstone aquifer and the Carboniferous Bowland Shale Formation. Challenges in defining what might be considered criteria for \u2018safe separation\u2019 between a shale gas formation and an overlying aquifer are discussed, in particular with respect to uncertainties in geological properties, aquifer extents and determination of socially acceptable risk levels. Modelled vertical separations suggest that the risk of aquifer contamination from shale exploration will vary greatly between shale\u2013aquifer pairs and between regions and this will need to be considered carefully as part of the risk assessment and management for any shale gas development.The online version of this article (10.1007/s10040-018-1737-y) contains supplementary material, which is available to authorized users. One such use of the subsurface, the production of natural gas from shales, or shale gas, has received growing attention in the last few years, with recognition of the range of potential threats to groundwater  are shown in Fig.  are showA methodology is presented here for evaluating the vertical separation between shales and aquifers across England and Wales. Its application is demonstrated for two important principal aquifer\u2013shale combinations\u2014the Cretaceous Chalk Group aquifer and the Kimmeridge Clay Formation, and the Triassic sandstone aquifer and the Bowland Shale Formation . The Chalk Group and the Triassic sandstone aquifers are the most important aquifers for water supply in southern and northern England respectively  are established as part of the EU Water Framework Directive and applied to groundwater bodies. The UK Technical Advisory Group (UKTAG) have issued guidance on the definition and delineation of groundwater bodies UKTAG , recommeThe UKTAG recommendation is consistent with the zone of active exploitation of groundwater in England based on the distribution of borehole depths within a given aquifer. Most exploitation of groundwater takes place at depths of a few tens of metres below groundwater level\u2014Fig. S1 of the electronic supplementary material . HoweverThe first extensive review of shale gas prospectivity in the UK  National Geological Model (NGM) of Great Britain  of contaminants migrating between shales and aquifers Myers . NumericImportantly, these numerical models of contamination transport do not consider the likelihood of particular geological conditions existing  out of a possible 25 aquifer\u2013shale combinations identified in the UK have been presented and discussed. In general, the vertical separation for the Chalk Group and Kimmeridge Clay Formation is much smaller than for the Triassic sandstone and Bowland Shale Formation though both pairs show quite large variability, reflecting the complex geological history and basin development of the UK. Safe vertical separation distances are difficult to determine due to large uncertainties in geologic parameters and determination of socially acceptable risk levels and aquifer depth limits. Modelled vertical separations suggest that the risk of aquifer contamination from shale exploration will vary greatly between shale\u2013aquifer pairs and between regions.ESM 1(PDF 1622 kb)"}
+{"text": "The Paediatric Rheumatology European Society (PReS) has over many years, developed a portfolio of educational activities to address increasing educational needs of workforce and support young clinicians to acquire skills to develop new knowledge and deliver clinical care in the future. These educational activities aim to facilitate growth of paediatric rheumatology and ultimately improve the clinical care for children and families. This article describes the current portfolio of PReS educational activities and their relevance to the international paediatric rheumatology community. The Paediatric Rheumatology European Society (PReS) has an overarching aim to promote paediatric rheumatology as a sub-specialty across Europe and also further afield through the expanding international membership. PReS aims to improve the lives of children with rheumatic diseases through collaborative networking to raise awareness, facilitate high quality research to create new knowledge, support education and training, promote advocacy and \u2018best care \u2019 based on evidence, consensus and active consumer engagement. The importance of education and training activities to achieve these aims and address unmet need within Europe has been highlighted following the SHARE initiative . This new syllabus ensures that rheumatology training is compliant with the revised European Syllabus structure and format. The educational activities of PReS reflect the roles of the paediatric rheumatology specialist; namely \u2018life-long\u2019 scholarly clinician, researcher and teacher. These roles have foundations firmly embedded in the European Syllabus which sets out the minimum requirements for training to cover knowledge , skills  and professional roles . In the context of education and training, the 2016 European syllabus for paediatric rheumatology has the following aims:Harmonise training programmes across European countries.Establish defined standards of knowledge and skills required to practice paediatric rheumatology at the tertiary care level.Foster development of a European network of competent specialist centres to facilitate collaborative research and training opportunities.Improve the clinical care of children with chronic and acute rheumatic disorders within Europe.Enhance European contribution to international scientific progress in the field of paediatric rheumatology.Promote teaching of paediatric rheumatology at undergraduate and postgraduate levels to raise awareness about the importance of early diagnosis, prompt referral to specialist care and facilitate potential recruits to fellowship programmes and the future workforce.The educational activities of PReS are overseen by the PReS Education and Training Committee (ETC), currently led by one of us [TA]. The PReS ETC represents rheumatology within the European Academy of Paediatrics and has contributed to the recent 2016 European Syllabus for Training in Paediatrics  through \u2018state of the art\u2019 lectures and presentations. There are active allied health and consumer parallel programmes. The annual scientific meeting has become one of the most important educational events in the paediatric rheumatology international calendar and provides a platform to disseminate knowledge, opportunities to network and foster new collaborations. The annual Young Investigators Meeting (YIM) is held over the two days preceding the annual scientific meeting and is organized with support from PReS to facilitate attendance by young researchers  and trainee doctors. The YIM aspires to nurture the PReS research ethos and aims to promote networking and foster opportunities for international collaboration; young investigators are encouraged to present their work to an international audience with feedback and guidance from PReS & YIM senior faculty. Over recent years the number of young investigators attending the YIM meeting has increased significantly with a substantial number of trainees from non-European countries . Proceedings of future meetings and how to apply for YIM bursaries are available on the PRES website (https://www.pres.eu).The annual scientific meeting of PReS disseminates advances in knowledge and research (http://www.pres.eu). The aim is to have one of either the Basic or Advanced course per year and to reach audiences who may not otherwise have access to education and training. PReS members are encouraged to contact the ETC for further information if they wish to consider organizing a Basic or Advanced course in their country and seek PReS support.The ETC oversees a \u2018rolling programme\u2019 of courses which are financially supported by grants from PReS. Details of future courses and how to register for them are available. , Sao Paulo (Brazil 2015), Budapest (Hungary 2015) and Cape Town (South Africa 2017) with future courses planned in the Ukraine and South East Asia. The aim is to promote the specialty, facilitate networking and ultimately improve patient care. The model includes an organising committee led by a local paediatric rheumatologist with faculty drawn from local and national colleagues as well as international faculty who are PReS members. Examples of previous Basic Courses are available from the ETC and it is envisaged that lectures from courses will be archived on the PReS website. The Basic Courses have a similar format  and up to 100 delegates, with interactive lectures and workshops. Case presentations are encouraged from delegates. Workshops focused on joint examination have been included since 2015 with practical demonstrations of pGALS (paediatric Gait Arms Legs and Spine)  website (octors [  Smith ethttps://www.printo.it/pediatric-rheumatology/). The importance of patient and family advocacy and engagement in clinical care, service delivery and research has been highlighted [ [Patient and parent information - Further to the SHARE initiative there has been a complete revision of the freely available information leaflets covering a broad spectrum of conditions and including translations into several languages  and through a bimonthly newsletter highlighting activities and opportunities for members (contact emerge.pres@gmail.com). The PReS EMERGE fellowship programme (https://www.pres.eu/activities/young-investigators/fellowship-programs.html) was launched in 2017 with financial and practical assistance for clinical trainees who are members of PReS and younger than 40\u00a0years, to facilitate placements of up to 6-months within a European Paediatric Rheumatology Centre. In addition to gaining clinical knowledge and skills, the trainee is expected to participate in a research project. From 2018, the programme is open to basic science trainees (pre-PhD to five years post-PhD) working in paediatric rheumatology. It is envisaged that the programme will enhance both clinical and basic collaborative research, foster a network of emerging and established paediatric rheumatologists and allow sharing of ideas and practices between different countries to harmonize paediatric rheumatology training.PReS EMERGE (EMErging RheumatoloGists and rEsearchers) encompasses young paediatric rheumatologists and researchers working together to improve clinical and research opportunities for trainees, participating in organisation of PReS educational events  and liaising with other young investigator groups . The group was set up following the 2016 YIM and currently includes trainees mainly from Europe but also from all other continents. Further details are available through an active social media network (The Standards of care for Juvenile Arthritis Management in Less Resourced countries (JAMLess) is a collaborative effort with funding and support from International League Against Rheumatism (ILAR) and PReS to develop consensus based guidelines relevant to challenging health care contexts; these highlight the importance of education and training being integral to the delivery of clinical care. This project was initiated by PReS colleagues from South Africa, Argentina and India and has resulted in a consensus document [  Scott C The activities of the PReS ETC aim to improve access to, and provision of, high quality clinical care delivered by an appropriately trained workforce and ultimately improve outcomes for children and families. The emergence of Basic and Advanced courses, specialist courses, online resources and the EMERGE fellowship programme, supplement the annual scientific meeting of PReS and YIM as a means to facilitate advances in knowledge being implemented into high quality evidence-based clinical care. We recognize that more work is needed to enable and support the expanding paediatric rheumatology community both in Europe and Internationally. The uptake and implementation of the new 2016 European syllabus into training programmes needs to address the accreditation of training centres, a proposed European sub-specialist examination and certification in paediatric rheumatology.There is now an overarching structure to the education and training activities of the PReS ETC to address the expanding needs of the broad paediatric rheumatology community with the content based on the 2016 European Syllabus for training. The format and structure of the PReS educational portfolio, much of which is free and open to all, serves as a template relevant to the wider international paediatric rheumatology. There is clear synergy between the educational and training activities of PReS and other initiatives led by paediatric rheumatology organisations elsewhere in the world . Through working with colleagues around the world, the aim has been to \u2018reach out\u2019, raise awareness and facilitate growth of paediatric rheumatology relevant to the local context."}
+{"text": "Background: Pharmacy has utilised the changes in legislation since 2000 to increase the range and supply function of services such as travel health to travellers. With the number of travellers leaving the UK and trying new destinations there is an increasing need for more travel health provision. Working models: The models of supply of a travel health service vary according to the size of the corporate body. The large multiples can offer assessment via a specialist nurse or doctor service and then supply through the pharmacy. Others will undertake an onsite risk assessment and supply through the pharmacist. The sole Internet suppliers of medication have been reviewed and the assessment standards questioned following survey and inspection. Education: There is no dedicated pharmacist-training programme in advanced level travel health. As a consequence one academic institution allows pharmacists to train on a multidisciplinary course to obtain an academic membership. With training for travel health not being mandatory for any travel health supply function the concern is raised with standards of care. Future: There is a consultation paper on the removal of travel vaccines from NHS supply due to be decided in the future. If these vaccines are removed then they will provide a greater demand on pharmacy services. Discussion: The starting of a travel health service can be made without any additional training and remains unregulated, giving cause for concern to the supply made to the traveller. Conclusions: Pharmacies in the UK offer a range of options for supplying travel health services; however these need to be with improved mandatory training and supply. This is a review of the development of the practice of pharmacy in the UK developing from the legal changes that occurred in the 2000s to include modern working models and specialist eduction that is available to pharmacists.In the UK, prior to 2000 the role of the pharmacist was that of the traditional supply function against the supply of a prescription and the sale of over the counter products (OTC). Within the UK the legislation is defined in 3 legal categories of medicines, prescription only (POM)\u2014only supplied against a doctors or dentists prescription ); pharmacy only medicines (PM)\u2014only supplied from a licensed pharmacy in the presence of a pharmacist and OTC products. At this time there was no legislation that allowed pharmacists to provide routine or travel vaccinations or to supply POMs without a relevant prescription.With changes to both the legal supply of POMs and the increasing requirement to use pharmacist\u2019s clinical skills then evolvement of influenza vaccination was introduced. This led onto the consideration of travel health health services from a pharmacy, by a pharmacist, to become established.The changes to a nationally funded travel health service remain under scrutiny and with increasing numbers of patients travelling abroad annually (+5%) and +27% intending to to travel a country they have never visited before  the NHS In 1998 the NHS reviewed the medicines that where be allowed to be supplied on a prescription. This review included the removal of chloroquine for malaria prophylaxis and the change to PM status allowing it to be purchased from pharmacies, . The NHSIn 2000 following lobbying from the Royal College of Nurses (RCN) for group protocols to supply national immunisation services, the law was changed to allow the supply of medication by healthcare professionals using Patient Group Directions [At the same time-work was underway to allow a new category of prescribers to be formed. This became known as supplementary prescribing, which was originally given to practice and district nurses working alongside a doctor to reduce the workload . A supplWith the increase in clinical knowledge and skills being taught and applied to other healthcare professions the role of independent prescriber was created in 2006, which included pharmacists . This roA major change in the law occurred in 2012 with the introduction of the Human Medicines Regulations . This alWith the UK Government reviewing the impact of annual influenza absences and the pressure for new roles to be allowed to pharmacy the first pharmacy flu vaccination services were introduced in 2007 as a private service utilising PGDs. This continued until 2015 when it was extended and included as a pharmacy NHS funded service.Alongside the provision of seasonal influenza vaccinations other vaccination services supplied by PGDs and Pharmacist Independent Prescriber (PIPs) evolved such as travel vaccinations and the supply of antimalarials for prophylaxis. With the austerity measures imposed on public spending private clinical services were considered as a part solution to maintaining financial solvency.In late 2017 the PHE was tasked with a consultation between professionals to consider if the total withdrawal of all vaccines for pre-travel should be removed from the NHS [The significance of the changes to practice working at a faster rate than legislative changes has led to the introduction of support networks for pharmacists providing travel health service using telemedicine or at distance triage services completed by a nurse or doctor .Within the pharmacy population in the UK, 49.2% of pharmacies are owned by groups and termed large multiples. Examples of these include Boots, Lloyds, Well, Rowlands and the supermarket groups of Asda, Morrisons and Tesco. Other smaller independents provide 12.4% and the remainder is made up small chains (<3 outlets) and independents 38.4% of the market [Access to travel health or medicine services is varied and one type of model includes a risk assessment being completed externally by a doctor, nurse or pharmacist and then the vaccination or anti-malarial supply being authorised by either a private prescription or directed to a pharmacist through a Patient Specific Direction (PSD). .Other pharmacies, allow an online booking service to be made with one of its selected stores  for a risk assessment lasting up to 40 min. The clinical support and backup is provided by a nurse led service to which the pharmacist can refer. The pharmacist can administer the vaccinations and supply the medication at the appointment.The UK legislation differs at this point regarding the regulation of the standards of practice between solely organised pharmacist clinics and those by other healthcare professions. The regulating body in England, the Care Quality Commission (CQC)  regulateA small independent survey study in 2018 concluded that a pharmacy travel health service was well accepted by patients and met their needs, providing a value for money service .With the supply of POM medication made by pharmacists either under a PGD or as an Independent Prescriber the professional expectation is that the standard of training to use these preparations should be of the a similar standard at an advanced level. Within the UK there is no legal requirement to have received any formal advanced level training before using a PGD and whilst an Independent Prescriber qualifies in a defined area of competence, they are legally allowed to prescribe any medicinal product outside of their competence, including controlled drugs.To ensure that basic immunisation is practiced correctly the GPhC in alliance with the Royal College of Nursing and Public Health England have published a document that lists the national minimum standards and core curriculum for immunisation training for registered healthcare practitioners .For those pharmacists who do elect to undertake extended training there are ranges of courses in travel health that are shared with other professions allowing an equality between practitioners. Examples of this can be found at the centres of excellence of in London, Liverpool and Glasgow. Details of the courses available to pharmacists are seen in Additionally an external representative body, the British Global Travel Health Association (BGTHA) has produced its own e-learning programme that is currently awaiting accreditation.The Association of British Travel Agents travel trends report  indicateWithin the UK the changes in national legislation have provided wider and more extensive powers for pharmacists to supply POM medication. The term travel health is undefined and yet to be recognised by the General Medical Council as a medical speciality. The consequence is that a pharmacist can initiate a travel health service and the levels of service being offered can vary from the supply of antimalarial medication to specialists who have completed an extensive level of training. To become competent in travel health, pharmacist practitioners should consider the need to complete an independent prescribers course, a recognised formal qualification in travel health and membership to a medical Royal College. This has been accomplished by a small number of pharmacist practitioners, however the practice of travel health without all of the additional skill sets, relies on the pharmacist to understand the limits of their competency when assessing and providing a clinical service.As highlighted before, the supply function of POMs can be made using a PGD, however no mandatory training on the use is required to use these. The other supply function is using an independent prescriber that trains in a specific area of competency but are legally allowed to prescribe any POM. A consequence of this is that pharmacist independent prescribers can supply travel health medication without being specifically trained in the specialist clinical area.The professional guidelines advise that independent prescribers should only practice within their competency and that PGDs are only used following specific training. Due to the complex nature of travel health a review is required of the supply provision and training and that should include arrangements for referral of complex patient cases to specialist pharmacists. The need of specialist, mandatory training is supported by the Faculty of Travel Medicine who have published a statement indicating that there is no licensing or checks on the level of care and that travellers are at risk .By comparison in Alberta, Canada pharmacist provided travel health services are supplied by suitably trained pharmacists with basic life support skills and prescribing skills. The additional requirement is the completion of a formally recognised qualification in travel health, such as the Certificate of Knowledge of the International Society of Travel Medicine .Travel health provision through UK community pharmacies is well advanced due to changes in national legislation. The supply of POM medications using PGD and independent prescriber services allows any pharmacist to privately supply travel health medication; however the minimum skill base to provide these services remains undefined and not legally required. To ensure the ongoing safety of travellers then the UK licensing authorities need to consider working with the specialist education providers to define minimum standards of competence for pharmacists. The formal training of advanced level services available to pharmacists is supplied through a single awarding institution, with other institutions selectively offering to medical practitioners and nurses only. To match the demand of pharmacist level travel health services more formally certified post-graduate courses in travel medicine would need to be made available. The future would indicate that with more people travelling there would be an increased demand on travel health services in the UK."}
+{"text": "Humans are influencing the global carbon (C) cycle due to the combustion of fossil fuels and due to changes in land use management. These activities are fostering the manmade greenhouse effect and thus global climate change. Negative effects for life on earth are accounted for.Among others the international climate debate focused attention on forests and forestry, knowing about their considerable influence on global climate change. Whilst the global C budget is described fairly well, there is a lack of regional data describing the C reservoirs and flows in detail. This has to be constituted especially for forests in developing countries.This paper presents an investigation at regional scale of the C reservoirs in a South American forest ecosystem. The investigation puts emphasis on the area and stand volume estimation and the development of expansion and reduction factors. Vegetation types are classified and stratified, determining the corresponding areas and estimating the stand volume. Converting factors are developed to calculate C in branches and roots as a percentage of standing wood measured by inventories."}
+{"text": "Voice-activated digital assistants  are an emerging technology that have great potential to provide support for adults aging with a long-term mobility disability. Digital assistant technologies allow the user to perform a variety of everyday tasks and activities through voice interactions. Such tasks may include environmental control ; supporting self-health management ; and fostering opportunities for social engagement . This presentation will focus on the perceived facilitators and barriers to digital assistant use in the home among adults aging with mobility disabilities. The findings provide design guidelines and insight for intervention implementation for the use of these technologies for the target population."}
+{"text": "Despite being discovered over 50 years ago, and its close association with the development of several important human cancers being well-documented, Epstein Barr Virus (EBV) continues to be a source of important information on how viruses can contribute toward the development of human cancer. EBV is known to be an important carcinogen, but because of its large genome (around 172 kb), much still remains to be discovered about its normal viral life cycle and how it drives malignancy at different anatomical sites.In a recent study in PLoS Pathogens (Lyu et al., Studies such as this are exciting because they begin to define how these viral miRNAs can both contribute toward malignant development and provide favorable environments for viral replication. It will now be very interesting to determine whether blocking the function of these miRNAs has any potential therapeutic applications.In contrast to EBV, two viruses that have only more recently gained notoriety are Dengue and Zika, which belong to the family of Flaviviruses. These viruses are mosquito-borne and represent major and growing health problems in many parts of the world. Whilst a great deal of attention has been placed on understanding the immunology underlying clearance of infection with these viruses, much less is known about the underlying mechanisms by which the viral gene products interact with components of the host cell.In a proteomic tour de force published in the recent issue of Cell (Shah et al., Since Shah et al. provide data on both the mosquito and human viral interactomes, this opens the way for studies to specifically characterize the functions of different viral proteins in the two different hosts and may offer leads for the development of novel therapies or preventative measures.The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Colijn et al.). Quantifying patient similarity is an important challenge that is critical in predicting patients' disease trajectories  patient similarity concept has been introduced as a paradigm shift in optimizing personalisation of patient care.Appropriate mathematical tools and methodologies are critical for ensuring robust and reliable computational model predictions based on medical and healthcare data in the era of the digital health revolution  of statistical learning in the model space for Attention-Deficit Hyperactivity Disorder medication response prediction at individual patient level. Mental health is intimately related to neurological diseases and brain modeling for neurological disease treatments .Applications of mathematics in healthcare are achieving unprecedented growth at vertiginous speed in a vast number of areas. Mental health presents a formidable challenge in our modern society and computational psychiatry has recently emerged  as well as type 1 diabetes . Chronic diseases are often extremely complex leading to computational models formulated in high-dimensional space, which poses a challenge for characterizing the pathways of disease progression or patient-specific disease progression trajectories as discussed in Colijn et al. Computational cardiology encompasses mathematical modeling and computer simulation of dynamical processes in the heart and the cardiovascular system in health and disease . Computational cardiology applications could help in improving clinical decision support systems in cardiac ablation therapy for example . Moreover, the use of collections of patient-specific models could provide a tool for pre-clinical and clinical assessment of disease pathology such as atherosclerosis and associated calcification .Non-negligible effort is currently being devoted to capturing disease progression, a real challenge in this field. Disease progression modeling involves simulations of disease evolution based on available biomarkers or other time-dependent measures of disease status. This is particularly important in the case of chronic (non-communicable) diseases as demonstrated in this special issue in the case of hypertension  presents a network-based statistical methodology for cancer biomarker selection. Computational and mathematical pharmacology is becoming increasingly relevant for drug development. Mechanistic models has become more and more widely used and our understanding of the models' qualitative and quantitative behavior has improved  as well as the estimation of drug absorption profiles in-vivo .Computational oncology broadly refers to computational modeling and simulations of biological process underlying tumors' development and progression as well as cancer therapy including cancer biomarkers and drug effects . This special issue presents several examples of such methodological developments in the case of quantifying: the biomechanical properties of human gallbladder ; the forces involved in abrasion damage to skin ; and intracellular calcium signals .Robust quantitative methods for identifying biologically/physiologically relevant computational model parameters from experimental data are critical for the successful applications of computational medicine in precision healthcare  that are necessary for implementation of precision healthcare  as well as to inform public policies related to vaccination, for example see .Infectious disease modeling including the underlying mechanisms is becoming increasingly important in the face of the anti-microbial resistance and its associated clinical and public health burden (de Kraker et al., By no means the topics included in this special issue are exhaustive. They are rather indicative of a wider range of problems specific to computational medicine that not only can be tackled by available mathematical approaches but also inspire the development of novel tools and techniques. Examples of methods that have not been included are machine learning and artificial intelligence for electronic health records analysis and usage (Callahan and Shah, KT-A and VD-Z conceived and wrote the editorial.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The Journal retracts the 20 September 2016 article cited above. Following publication, the authors discovered through further analysis that the species of bacteria discovered in this study was resolved in error.This retraction was approved by the Field Chief Editor of Frontiers in Microbiology."}
+{"text": "An error was found in the first and second sentence of the original article's abstract.It had originally been published as:Hereditary inclusion body myopathy (HIBM) is a rare autosomal recessive adult onset muscle disease which affects one to three individuals per million worldwide. This disease is autosomal dominant and occurs in adulthood.The corrected sentences should read:Hereditary Inclusion Body Myopathy (HIBM) is a rare autosomal dominant or recessive adult onset muscle disease which affects one to three individuals per million worldwide. This disease is autosomal dominant or recessive and occurs in adulthood.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.The original article has been updated.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "This paper is a commentary on the training of Chinese Primary Health Care Doctors to reduce chronic illness and its burden. First, we will consider the policy position of the Chinese government concerning the development of a competent and enlarged primary physician workforce to deliver the proposed primary health care system reforms. We then turn to a review of the drivers of the high burden of chronic illnesses especially in older people in China. We argue that the curriculum for the training of primary health care medical practitioners should match the demonstrated high prevalence chronic illnesses and their risk factors and that there needs to specific competencies in prevention and mitigation of the diseases and their risk factors. The various policy statements from the Chinese State Council  and the China has also recognized the need for expansion of its primary care physician workforce and has set ambitious targets for the growth in this workforce . Its phyIn designing training systems for the Chinese primary care physician workforce it is necessary to understand the health needs of the people that the workforce is intended to service . The popThe United Nation's Sustainable Development Goals for 2030  include The China Joint Study Partnership comprising the World Bank Group, the World Health Organization, the China Ministry of Finance, the National Health and Family Planning Commission, the Ministry of Human Resources and Social Security  recentlyHowever, the Deepening Reform report  differs Shaping a tiered health care delivery system in accordance with People-Centered Integrated Care modelsImproving quality of care in support to People-Centered Integrated CareEngaging citizens in support of People-Centered Integrated CareReforming public hospitals and improving their performanceRealigning incentives in purchasing and provider paymentStrengthening health work force for People-Centered Integrated CareStrengthening private sector engagement in production and delivery of health servicesModernizing health service planning to guide investment.https://www.cochranelibrary.com/ which at the time of writing had 162 systematic reviews of patient centered care with almost universally successful results). A further key feature of the Deepening Reform report is its evidence-based philosophy. The report focusses on what can be done to improve the efforts in the delivery of services that address the demonstrated health needs of the Chinese people.The central inclusion of the concept of People-Centered Integrated Care reflects best global health care practice . This isWhile all the identified \u201clevers\u201d are certainly worthy of attention, our focus as educators of primary health care physicians in this commentary is on delivering the required numbers of appropriately trained doctors to participate in the new reformed Chinese system. This raises the question of what should be included in an appropriate Chinese primary care physician curriculum?We have made substantial progress in the development of the Shenzhen standards for primary care physicians. We have critically analyzed the major Western General Practice clinical standards. The new Shenzhen standard was developed using rigorous modified Delphi procedures with a large expert panel building on a detailed analysis of relevant international standards. Embedded in the standards are assumptions about what doctors will and should do in their everyday practice. We have separately reported the Shenzhen standards development in another publicationThe major illnesses associated with China's disease burden have been studied in detail by many government bodies and academic researchers. The same lists emerge from these analyses. The Deepening Reform Study  and the Stroke (35.9 million DALYs)Malignant neoplasms (30 million DALYs);Ischaemic heart disease (22.6 million DALYs);Respiratory diseases (16 million DALYs);Diabetes mellitus (5.6 million DALYs);Mental health conditions such as depression, suicide and dementia (5.3 million DALYs);Hypertensive heart diseases (3.6 million DALYs); andFalls (3 million DALYs).Thus, it is evident that primary health care physicians require a substantive knowledge of these conditions and their prevention and management. This is how many medical curriculums are organized with a list of key conditions to be covered.However, we consider that the second key focus is the need for primary care physicians to identify and to mitigate and control the risk factors that exacerbate the main diseases. To mitigate these risk factors requires a quite specific skill set. The same analyses have identified risk behaviors amongst the Chinese population that exacerbate the above list of diseases. For example, smoking is a key health risk for most of the above list of diseases/ conditions. But there are others that the WHO analysis  has idenDietary risksHigh blood pressureSmokingHigh fasting glucose levelsExposure to air pollution andPhysical inactivityWhile our focus for this paper is behavioral risk factors that can be mitigated in the primary health care setting, in order to address behavioral risk factor mitigation in China we recognize that multi-level approaches are needed including a systematic approach to chronic illness management within the health system, public health interventions, as well as primary health care physician training in behavior change approaches. In China, as discussed previously, the Deepening Health Reform in China monograph , developIn the United Kingdom and Australia, chronic illness management systems have been strongly influenced by the Wagner Chronic Care Model  and a foIn Australia, General Practitioners (GPs) are funded by the national health insurance system and government to provide longer consultations and care planning for patients with chronic illnesses . A recenMedication management in primary care in people with chronic illnesses has been a particular focus in Australia and world-wide. Polypharmacy, the prescription of potentially inappropriate conflicting medications has been recognized a potential risk to patients with chronic illness and the typical pattern of multimorbidity. However, the effectiveness of polypharmacy reduction programs \u201322 and tChronic illness management also needs to address mental health co-morbidities. Since 2006 the Chinese Government policy has promoted the detection and treatment of mental illness in primary care settings through integrated mental services . Yet traPublic health approaches are also an important part of addressing behavioral risk factors at the population level. Smoking is an example of the need for combined regulatory, public health and primary care approaches. For example, to reduce smoking rates, strategies such as increasing excise on tobacco, regulating smoking advertising, banning smoking in public places, public health education and health promotion programs and plain paper packaging have been used in Australia and other western countries to reduce smoking levels . In ChinAddressing physical inactivity is another important risk factor for poor health and chronic illness prevention and management that requires primary care and public health interventions as well as legislative approaches. In a review of national policies to increase Health Enhancing Physical Activity (HEPA) in seven European countries, Bull et al.  reportedThe Chinese National Fitness Plan (2016-2020) aims to increase physical activity and population health . The plaThere has been significant Chinese work in clinical trials and systematic reviews of this issue. For example, we examined the therapeutic effects of motivational interviewing on blood pressure control by conducting a meta-analysis of randomized controlled trials . The revThere is widespread agreement about the need to appropriately train general practitioner physicians so that they may deliver high quality and effective care to their patients. There is also strong evidence that there is a global shortage of skilled practitioners and China has particular needs to develop the talent pool to support its ambitious primary care reform agenda. We have argued that primary care physician training needs to be informed by rigorous analysis of the causes and underlying risk factors for high burden of disease conditions. These conditions and their treatments have been well-researched and there is a strong evidence base. We propose that to effectively prevent and mitigate the many chronic conditions and diseases that are caused and exacerbated by lifestyle factors requires high level behavior change skills, mental health detection and management skills and other patient management skills that need to be included in the Chinese primary care physician curriculum.http://datatopics.worldbank.org/world-development-indicators/Publicly available datasets were analyzed in this study. This data can be found here: All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Based on rapidly increasing numbers of older adults and growing populations of culturally diverse citizens, we developed and provided an interprofessional education program for graduate nursing and social work students that focused on the delivery of care to older adults and veterans with multiple chronic conditions. The students participated in multiple activities together over a year long period. Activities included an introductory IPE day with all students together and simulated patient cases that had required roles for the students\u2019 specialties. Knowledge and skills of interprofessional collaborative practice were measured with the Interprofessional Self Assessment Competencies (IPEC) and Assessment of Interprofessional Team Collaboration Scale (AITCS). We also measured attitudes toward cultural differences using the Cultural Awareness Scale (CAS). The entire project was repeated a second year with a second cohort of students. Overall, our students were better able to understand and work collaboratively with other health care professionals after participating in this program. Regarding cultural awareness, both NP and SW students were more aware of and comfortable with cultural differences after participating in the program. After one year of experience, we wanted to know more about our students\u2019 skills and attitudes. Focus groups were added to the design to dive deeper into the students\u2019 perceptions about which activities were most impactful and recommendations for future IPE activities. This paper will describe these data and implications for future planning of more effective interprofessional and cultural programming for students caring for older adults and veterans."}
+{"text": "In addition to the broad panel of aging related biomarkers available in HRS, we will describe measurement of novel aging biomarkers such as telomere length and mitochondrial DNA copy number in 4000 HRS participants. Both these biomarkers were measured in DNA obtained from whole unsorted blood using quantitative real time polymerase chain reaction (PCR) and were adjusted for individual cell composition measured from flow cytometry. We will describe the relationship between these two biomarkers and other measures of biological age available in HRS. Differences in these two novel aging biomarker by socioeconomic status, race/ethnicity, and exposure to early life hardships will be presented to clarify the value of the data to further unravel how social factors get under the skin to affect the process of aging."}
+{"text": "In order to provide effective mental health care to older adults with major neurocognitive disorders  within outpatient mental health clinics, mental health practitioners must possess a basic understanding of these disorders, the needs of and challenges faced by people living with dementia and their families, and effective treatment approaches for this population. The Mental Health Gero-Champions Program was established in 2015 at a large Veterans Affairs medical center with the aim of providing clinical support and opportunities for training to multidisciplinary mental health providers to enhance skills in assessing and treating older adults with neurocognitive disorders. This presentation will provide an overview of the Mental Health Gero-Champions Program, describe the development and implementation of this program, and discuss challenges and successes in sustaining this transformative initiative over time."}
+{"text": "Chlamydomonas to the addition of acetate during day/night cycles\u201d  icl mutant, a null mutant of the isocitrate lyase gene, and its control are summarized and the FPKM values are listed. The data were analysed using surprisal analysis and the genes contributing the strongest to the mutant and wild type phenotype are listed. The raw data are accessible at BioProject PRJNA437393 with SRA accession number SRP136101 (experiments SRX3824204\u2013SRX3824249). The raw data set and expression values used for surprisal analysis are made public to enable critical or extended analyses.The data presented in this article are associated to the research article \u201cSurprisal analysis of the transcriptomic response of the green microalga  Data shared concerns the reads information for each biological replicate (The dataset of this article provides information on raw RNA-seq reads obtained from the eplicate , the FPKeplicate , the numeplicate , the liseplicate .List of shared data is found in the 2Chlamydomonas to the addition of acetate during day/night cycles\u2019 by Willamme et al. The experimental design has been described in the accompanying research paper (\u2018Surprisal analysis of the transcriptomic response of the green microalga"}
+{"text": "We consider the human genetic targets of many proven and hypothesized pharmacologic interventions meant to promote healthy-aging and explored not only how polymorphic these targets are in the human population, but also whether these polymorphisms have been shown to impact longevity and age-related phenotypes in general. We also determined if polymorphism in the genes or proteins modulated by healthy-aging interventions have been shown to also modulate the expression levels of those genes and proteins  and whether they have been subjected to mediation analyses testing their potential causal relationships to aging and longevity phenotypes. We compare our results to studies of other classes of drugs used to treat specific conditions, such as hypertension."}
+{"text": "A radiographer has the unique advantage of directly seeing the patient and presenting injury at the time of imaging. Extending this skill set to further evaluate the image acquired and document the findings may be helpful in reducing diagnostic errors in emergency department. Since the invention of X\u2010rays, medical imaging has played a prodigious role in the field of medicine, with it being an important and at times the only diagnostic tool amongst an array of investigative methods available to a healthcare practitioner. Emergency departments (ED) form the frontline defence for a healthcare system, and with increasing activity seen throughout Australian departments,Due to the constant rotation of junior doctors in and out of the ED, coupled with the spectrum of skills that junior doctors are required to develop, the consultant group in my ED are always considering new processes/initiatives that assist in mitigating error. One such initiative is radiographer preliminary image evaluation (PIE). The introduction of a PIE system in 2016 into my ED has seen an extra layer of safety implemented for patients whose radiographic images are interpreted by referring healthcare practitioners such as medical doctors, nurse practitioners and physiotherapists. Healthcare practitioners are advised to initially review the radiographic images and make an assessment before checking their assessment against the radiographer PIE. This workflow assists referrers in developing their image interpretation skills by having an immediate second opinion.A radiographer has the unique advantage of directly seeing the patient (and presenting injury) at the time of imaging. This scenario along with their knowledge and expertise of radiography promotes the acquisition of high\u2010quality X\u2010ray imaging. This also provides the radiographer with an extra edge at interpreting the radiographic images when compared to the referring practitioner and the reporting radiologist. Radiographers in a public healthcare system may form a stable workforce when compared to junior doctors who tend to rotate between multiple specialities, and training a radiographer would be more cost\u2010effective and may result in consistent image interpretation.In reference to the study by Brown et al.Following review of the findings of this audit, an additional process was employed to reduce errors that may have occurred from the radiographer's incorrect PIE. This process involves the reporting radiologist flagging examinations where a discrepancy exists between the radiographer's PIE and the radiologist's report. These discrepancies are reviewed by a senior radiographer who compares the radiologist report to the ED diagnosis. If a true discrepancy exists, the senior radiographer notifies an ED consultant and requests the case to be reviewed. I believe this additional process improves the overall diagnostic accuracy of our service, thus reducing error.Some ED radiographs such as obvious dislocations or fractures, or injuries of fingers and toes may not require formal reporting by a radiologist. The adoption of a selective reporting policy may reduce the reporting workload of the radiology department without compromising patient careRadiographer PIE is likely to benefit both the patients and ED in reducing missed injuries and reducing recall rates. For any ED who is planning on implementing such a system, it is important to clearly advertise and communicate the process prior to implementation with regular reminders of the availability of such a process. Regular audits on efficiency and a robust verification platform are crucial to the effective functioning of PIE by radiographers. Further research into comparing the accuracy of ED referrer interpretation and radiographer evaluation of radiographic images and also the combined accuracy of the ED referrer and radiographer versus radiologist's interpretation will give better understanding of the future direction of the radiographer image interpretation role to improve patient outcomes in ever\u2010demanding ED.The author declares no conflict of interest."}
+{"text": "Parkinson's disease (PD) is a neurodegenerative disease caused by a reduction in dopaminergic neurons in the substantia nigra  or rate of perceived exertion (RPE). Prescribing intensity using heart rate responses should not be recommended, as many individuals with PD exhibit autonomic nervous system (ANS) dysfunction  and are prescribed medications that can interfere with heart rate responses and heart rate variability  within the National Institutes of Health (NIH) has called for research scientists to consider sex when designing study protocols to allow for both men and women to receive the full benefit of medical research (National Institutes of Health, All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Early definitions of ageism as prejudice, attitudes and discrimination tend to stress the cognitive aspects of the processes where groups of people are being marginalized and/or excluded because of their age. This differ from recurrent studies which emphazise social categorization such as age and gender as a dynamic social positioning practice and as a complex form of doing age as marginalization and exclusion. Based on qualitative interviews with eleven men between the ages of 56 and 74, who work with manual labour at a steel company in Sweden, this paper discusses the processes where age normality and ageism are constructed in parallel. Departing from the concept age coding; distinctive practices associating a context or a phenomenon with demarcated ages, it shows the disciplining dimension of ageism. The paper concludes with a reflection on the central position which ageism can have in neo-liberal governance by creating social insecurity among older workers."}
+{"text": "This paper examines the effect that a man\u2019s retirement has on his wife\u2019s mental and physical health. I exploit the large increase in the probability of retirement at the legal retirement age for urban male wage earners in China as a natural experiment, using data from the China Health and Retirement Longitudinal Survey (CHARLS). I have implemented a fuzzy regression discontinuity design to compare the health outcomes of women whose husbands recently retired with those whose husbands are close to retire. My findings indicate that the retirement of her spouse improves physical and mental well-being of the woman, most likely by increasing the frequency of her social interactions and exercising. Although income and marital quality are less likely to be the main channels through which this positive spillover effect operates, decreased marital satisfaction or severe income constraints can be binding."}
+{"text": "This is not surprising since PCMO often resolves spontaneously and can be compatible in mild to moderate cases with good vision. Further, there is no standard means to diagnose PCMO and thus definitions and incidence vary widely among published studies. We agree with the authors' suggestion that confusion surrounding the use of NSAIDs may have arisen from the lack of an accepted diagnostic criteria for PCMO.The article by Donnenfeld et al has also been included as evidence that PCMO was lower in groups where NSAIDs were commenced between 1 and 3 days preoperatively.The review article does allude to the challenges faced in providing advice on prophylaxis of PCMO when citing the report by the American Academy of Ophthalmology. A subsequently published editorial by the same author however questioned how prescribing NSAIDs for routine cataract surgery had become popularized without compelling evidence of visual benefit to patients.The authors have provided a significant review of a complex topic. However, the statement that topical NSAIDs remain the mainstay in the prophylaxis and treatment of PCMO is not supported by the literature reviewed. We hope that this letter may raise awareness of these issues to the readership.None declared."}
+{"text": "To the Editor: We read with interest the article by Olesen and Grad  by antimicrobial-resistant bacteria. The New Zealand study found that dispensing rates of topical antimicrobial agents (predominantly fusidic acid) for Pacific and Maori children were approximately twice those for children of other ethnicities and suggested that these high dispensing rates might have contributed to the higher proportion of staphylococcal infections caused by methicillin-resistant (and fusidic acid\u2013resistant)"}
+{"text": "Following in the footsteps of the first JND special issue in 2018, highlighting the work of the Eunice Kennedy Shriver Intellectual and Developmental Disabilities Research Centers (IDDRCs), this year again showcases the work of the IDDRCs and honors the distinguished career of Dr. Jean de Vellis, world-renowned scientist in the study of white matter pathophysiology and long-standing director of the UCLA IDDRC. As eloquently described in the dedication [Much of the promise in studying white matter comes from the potential this neural structure has for developing new treatments. In a review of both mouse models and clinical work , the novIn addition to investigations of white matter morphology, a key aspect of thinking about novel treatments has come from thinking about inflammation and the negative impact this may have on neurodevelopment. Investigators at the Children\u2019s Hospital of Philadelphia IDDRC present exciting work demonstrating that inflammation caused by Th2 cytokines during early brain development can be rescued with the application of IL-4 antibody treatment in the newborn rat . This woAs may be evident by work focusing on these neurodevelopmental disorders, a key benefit of approaching treatment stems from an ability to change developmental trajectories by acting early through specific interventions. In a comprehensive study examining motor neurons in a Down syndrome mouse model (Ts65Dn), the investigators demonstrated clear changes in the spinal white matter composition across the lifespan . This woThe articles included in this special issue highlight the advances made in understanding white matter in neurodevelopmental disorders that investigators across the IDDRCs strive to tackle daily. By approaching these questions from both clinical (human) and basic neuroscience perspectives, both sides gain knowledge and move forward to the goal of better interventions. We hope that the work showcased in this special issue underscores the promise for developing targeted treatments in neurodevelopmental disorders that comes from these investigations. Many of the IDDRCs contain researchers influenced and inspired by the groundbreaking work Jean de Vellis began. We hope that this special issue also serves to honor his legacy to the field."}
+{"text": "The protracted war in South Sudan has led to severe humanitarian crisis with high level of malnutrition and disruption of the health systems with continuous displacement of the population and low immunization coverage predisposing the population to vaccine preventable diseases. The study aimed at evaluating the effect of integrating immunization services with already established nutrition services on immunization coverage in resource-constrained humanitarian response.A community and health facility based interventional study involving integration of immunization into nutrition services in two Outpatient Therapeutic Program(OTP)centers in Bentiu PoC between January-December 2017. The main hypothesis was that inclusion of immunization services during nutrition services both at the OTP and community outreaches be an effective strategy for reducing missed opportunity for immunizing all eligible children accessing nutrition services. Data analyzed using STATA version 15 and bivariate analysis using logistic regression was conducted to identify predictor of missed vaccinations.Integration of immunization into the nutrition services through the OTP centres increased the number of children immunized with various antigens and the dropout rate was much lower and statistically significant among children who received immunization at the OTP centers than those in the Primary Health Care Centers (PHC Centers) in the study sites. Children who were vaccinated at the OTP centre in sector 2 were 45% less likely to miss vaccination than those vaccinated at the PHCC , p<0.05 while those vaccinated at the OTP sector in sector 5 were 27% less likely to miss vaccination than those vaccinated at the PHCC  p<0.05).This study indicated that immunization coverage improved effectively with integration with nutrition services as a model of an integrated immunization programme for child health in line with the Integrated Management of Childhood Illnesses (IMCI) and the Global Immunization Vision and Strategy (GIV). Expanded Program on Immunization (EPI) has become one of the most successful public health programmes, reaching over 85% of the world's children . HoweverWHO and UNICEF developed the Global Immunization Vision and Strategy (GIVS), in 2005, to expand the reach of EPI, and prevent more disease . One of Justification for the study: The OTP centers are located few meters to the PHC centers where immunizations are being conducted and mothers were usually asked to go to the PHCC after being attended to at the OTP centers for their children immunization. However, it was observed that most of the children referred from the OTP centers to the PHCC for immunization services didn't go. During a focus group discussion conducted among the mothers/care givers some of the reasons given by the mothers/care givers for not taking their children for immunization at the PHCC when referred from OTP centers included being tired after spending some considerable time at the OTP centre and the need to go back home to continue their work or household chores. Some caregivers reported that on few occasions they went, the vaccinators were not around to provide the services or being asked to queue up again on getting to the clinic instead of being attended to immediately while others reported they forgot the immunization cards and had to go back home but late to go back to the clinic for that day leading to missed opportunity to improve immunization coverage in the camp.This was a community and health facility based interventional study during which immunization services were integrated with nutrition services in OTP centres and nutrition outreaches where immunization was previously not provided. All children under 5 years seen at the OTP centres and during nutrition community outreaches were all assessed for their immunization status and provided with appropriate immunization needed during the course of the study between January-December 2017. In the 2 OTP centers where the intervention was implemented, vaccinators were recruited to join the nutrition team to provide immunization in the OTP centre. During community outreaches and at the OTP centers the client flow as arranged so that all children who visited the centre either on follow up visit or new cases or during mass nutrition screening conducted by the Community Nutrition Volunteers were first assessed for immunization status before being screened or and enrolled into the nutrition program. The community nutrition volunteers were trained and supported to include health education and promotion messages on immunization in addition to the routine nutrition education and counselling being provided. In addition, during mass screening for malnutrition using MUAC tape being done and Infant and Young Child Feeding (IYCF) counselling the immunization status of all children were assessed and appropriate vaccination provided by the vaccinators who was part of the team. The community nutrition volunteers tracked children who defaulted from both the nutrition and immunization programs using the facility records and child health cards. The defaulter tracking was incorporated as part of the community outreaches so any child who had missed any immunization session was appropriately vaccinated. The main hypothesis was that inclusion of immunization services during nutrition services both at the OTP and community outreaches be an effective strategy for reducing missed opportunity for immunizing all eligible children accessing nutrition services.Study site: The study was conducted in Bentiu Protection of civilian (PoC) site in Rubkona County, Unity State established in December 2013. There were 112,140 IDPs and 20,219 households seeking protection in the site and is divided into 5 sectors (sector 1-5) [tor 1-5) . There aSampling: Purposive sampling was used in the selection of the two OTP centres out of the 3 OTP centres in the camp used for the study. The two OTP centres (the only one in sector 2 and one out of the two in sector 5) were those the nutrition implementing partner agreed to integrate immunization into nutrition activities at OTP centres and community outreaches.Data collection and analysis: All immunised children were routinely tallied and recorded in the national immunization registers to ensure accuracy during immunization sessions both in the OTP and during outreaches and all children had their vaccination status recorded in the child health card every time immunized which was used to determine the next vaccines and identify any child who had missed any immunization sessions during defaulter tracking in the community. The immunization coverage for various antigens were analysed and the immunization coverage among children receiving nutrition services both through the OTP and outreaches was compared with the immunization coverage for various antigens in the primary health care centres which routinely provide immunization services. Data were entered and analyzed using STATA version 15 and excel analysis software. The primary outcome measure was receipt of appropriate antigens by children assessing nutrition services and the secondary outcome measure was dropout in vaccination. Proportions were calculated for categorical variables and summarized into tables and figure for univariate analysis. Bivariate analysis using logistic regression was conducted to identify predictor of missed vaccinations. Odds Ratio (OR) and 95% Confidence Interval (95% CI) were used to estimate the strength of association between independent variables and the dependent variable. The threshold for statistical significance was set at p < 0.05. The dropout rate was calculated as a percentage of the difference between first and third pentavalent vaccine dose.Ethics approval and consent to participate: The State Ministry of Health, Liech State reviewed and cleared the use of data, contents and publication of this manuscript.The comparison analysis of the immunization data showed that more children were immunized with various antigens in 2017 than in 2016. In sector 2 in 2016, the total number of children immunized with BCG vaccine was 985 compared to 1366 vaccinated with BCG vaccines in 2017, likewise the number of children who received third dose of Oral polio vaccine was 987 in 2016 compared with 1653 in 2017. The number of children vaccine with third dose of pentavalent vaccine and measles were 1002 and 2693 respectively in 2016 which were less than 1783 and 3357 children vaccinated with third dose of Penta valent vaccine and measles respectively in 2017. Similarly, in sector 5 in 2016, the total number of children immunized with BCG vaccine was 1721 compared to 2045 vaccinated with BCG vaccines in 2017, likewise the number of children who received third dose of Oral polio vaccine was 1463 in 2016 compared with 2131 in 2017. The number of children vaccinated with third dose of pentavalent vaccine and measles were 1103 and 2987 respectively in 2016 which were less than 1917 and 3916 children vaccinated with third dose of Penta valent vaccine and measles respectively in 2017 .rd dose of Oral polio vaccine and Pentavalent vaccine respectively. A total of 1721(43.9%) and 743(30.3%) of children immunized in Sector 5 with measles and injectable polio vaccine respectively were immunized through the OTP centre  of them immunised with BCG vaccines while 502(30.5%) received the third dose of Oral Polio Vaccines, 687(41.2%) were vaccinated with the third dose of pentavalent vaccines and 1482(90%) vaccinated with measles vaccines. In sector 5 OTP centre, a total of 2712 malnourished children were enrolled into the nutrition program during the study with 934(34.4%) of them immunised with BCG vaccines, 951(35.1%) received the third dose of Oral Polio Vaccine, 1096(40.4%) vaccinated with the third dose of pentavalent vaccines and 1875(69.1 %) were vaccinated with measles vaccines . The anaP centre .rd dose of pentavalent vaccine ( Penta 3) and those who received 1st dose of the pentavalent vaccine(Penta 1) showed that in sector 2, among those children who received the first dose of pentavalent vaccine through the OTP centre, 8.9% did not return for their third dose of pentavalent vaccine while 26.8% of children who received the first does of pentavalent vaccine through the PHCC did not return for the third dose of pentavalent vaccines. In sector 5, among those children who received the first dose of pentavalent vaccine through the OTP centre, 12% did not return for their third dose of pentavalent vaccine while 35 % of children who received the first does of pentavalent vaccine through the PHCC did not return for the third dose of pentavalent vaccines. The acceptable limit is 10%  and the Global Immunization Vision and Strategy (GIV) and with adequate planning, integration can improve coverage, combine costs and create synergies. In order to deliver on the promise of Sustainable Development Goals 2 and 3 and dramatically reduce child mortality by 2030 we must ensure that every child has access to life-changing vaccines that not only provide protection against the leading causes of death in children under five, but also contribute to decreasing vulnerability to malnutrition.Limitation of the study: this study is based on review of clinic records and subject to the limitations associated with studies utilizing routine data. In addition, the study did not evaluate the possible impact of immunization status on the nutrition outcome among malnourished children who completed their immunization and those who dropped out.A child who is borderline nourished will tip into malnutrition if he or she contracts an infectious disease such as measles. As part of an integrated health approach, immunization plays a critical role in curbing the devastating impact of malnutrition;Immunization and Nutrition services are mostly vertical program in most countries.The number of children immunized through the integration in the nutrition services contributed greatly to the coverage of all immunization antigens in the project sites;Integration reduced greatly the missed opportunity for immunization services among the vulnerable population.The authors declare no competing interests."}
+{"text": "The article presented an integrated data on talent management practices and innovation performance of academic staff in a technology-driven private university in Nigeria. The study adopted a quantitative approach with a survey research design to establish the major determinants of talent management practices. The population of this study included academic staff and the use of questionnaire was adopted to elicit from the study population. Data was analysed with the use of structural equation modelling and the field data set is made widely accessible to enable critical or a more comprehensive investigation. The findings identified talent development and retention strategies as predictors for facilitating innovation performance in the sample University. It was recommended that management of the sampled university will consistently need to adopt reliable range of strategies to attract and retain people for excellence performance. Talent management is a major determinant of organisational success but highly misconstrued in a competitive and demanding environment like the educational sector. Today, institutions especially the private universities in Nigeria are becoming more conscious of how and why talents need to be identified and managed. Several strategies have been put in place by many private universities to stimulate these practices, but despite the efforts, the issue of turnover, brain drift and low performance still become worrisome especially in the Nigeria\u05f3s context.2The study is quantitative in nature and data were retrieved from staff (teaching and non-teaching) of Covenant University. This paper adopts the talent management measurement proposed by Winfield After validating the data collected from the survey, we further evaluated the structural relationships in the research model. We first use our data to test the benchmark model of Lee and Choi\u05f3s \u03c72 is within the acceptable range of 1 and 3 as suggested by Browne and Cudeck Results in 3An empirical study was conducted to test the proposed research model. Survey instruments were distributed to 350 staff of the leading private university in Africa and has also emerged the winner of the Best Use of Technology Award 2016 among the private universities in Nigeria. The same University among others was awarded the Centenary ICT Driven University of the Year in 2014, the Overall Best University in Nigeria and West Africa and number 15 in Africa on the Webometric Ranking (February 2015) as well as African Private University of the Year (2015), by African Leadership Magazine Group in March, 2016.All participants were selected based on their substantive amount of work experience with the institution; as such they were able to provide useful information regarding the survey questions. Of those surveyed, only 313 respondents filled out and returned the questionnaire without missing or invalid data. Data were gathered from academic staff and non-academic staff directors, and other categories of employees across the institution with the aid of a researcher- made questionnaire based on the works of The collected data were coded and analysed using SPSS version 22. Data was analysed applying descriptive and inferential statistical tests. Importantly, the study participants were selected based on the following inclusion criteria:Inclusion criteria:\u2022Participants were employees of the sampled technology-driven university.\u2022Participants signed the consent form provided and have worked with the firm for a minimum period of 2 years.\u2022Participants were accessible as at the time of the survey and interviews.This paper adopts the measurement proposed by Ueno Even though emerging issues in HRM have received much attention in the management literature over the last decade, only limited research has established how talent management practices can be used to drive on growth and prosperity for many organisations empirically. Motivated by a critical synthesis of literatures and consistent with prior research, our study shows that talent management practices improve innovation performance, which subsequently results in superior organizational performance. The researchers ensured that respondents were well informed about the background and the purpose of this research and they were kept abreast with the participation process. Respondents were offered the opportunity to stay anonymous and their responses were treated confidentially."}
+{"text": "This letter has been written by the components of the European Milk Bank Association (EMBA) Working Group on Human Milk Fortification in response to a recent paper published by Mathes et al. :154) with the aim of drawing attention to the importance of the use of a metabolic marker to adapt protein intake in preterm infants. EMBA Working Group on Human Milk Fortification clarifies further the terminology and some specific aspects regarding individualized human milk fortification. There are two types of individualized human milk fortification: Adjustable human milk fortification and Targeted human milk fortification. Advantages and disadvantages of these methods are summarized. Dear Editor,We read with great interest the paper from Mathes et al.  which unWe appreciate the attempt of Mathes et al.  to searcOn the other hand we would like to remind them that there is a type of individualized HM fortification method, namely \u201cadjustable fortification,\u201d proposed in 2006 and comprises twice weekly assessments of blood urea nitrogen (BUN) as a marker of protein intake , 4.We are also aware that there is some confusion regarding the terminology around individualized human milk fortification, as we noticed previously , 6. TherThe nutrient and energy requirements stated in the international recommendations refer to the populations not individuals. We know that some infants will require more than the recommended intakes and some less. To find out how much protein an individual infant requires it is important to monitor the physiological response of each baby to the amount received and respond accordingly. In addition, protein and energy requirements may be particularly high in subgroups of infants for example those with bronchopulmonary dysplasia or extra-uterine growth restriction. Therefore fortification of HM should be adapted to specific nutrient needs of each individual infant. Adjustable human milk fortification in this sense is a good compromiseEuropean Milk Bank Association (EMBA) Working Group on Human Milk Fortification We greatly appreciate the clarification by the colleagues from the European Milk Bank Association and we agree to their comments.According to the data we were able to present in our original article (Ref ), it see"}
+{"text": "A critical approach in rural gerontology has led to a better understanding of the complex interplay between older adults unique aging experiences and the multidimensional and dynamic communities in which they live. The evolution of critical rural gerontology will be explored, outlining why a similar approach is needed in rural gerontological health. In particular, rural gerontological health literature must expand beyond a deficit focus that homogenizes older adult health experiences and recognize the complexities of negotiating older adult health within multidimensional rural spaces. Inherent in this approach is recognizing the intersectionality of older adult health as well as the need to study rural gerontological health as an experience enhanced and inhibited by interactions within and across formal health services, informal social services and informal care. This approach will contribute to innovations in policy and practice addressing the burgeoning interest of how to effectively care for older adults in rural settings."}
+{"text": "Pediatric anesthesia has evolved as a subspecialty because the needs of infants and young children are fundamentally different from those of adults: they differ anatomically, physiologically, pharmacologically, emotionally and socially. Children who undergo anesthesia have special needs and all children have the right to receive the highest attainable standard of health in the right environment. The pediatric patient subjected to anesthesia is burdened by a significant increase in perioperative severe critical events that require unplanned immediate intervention to prevent the occurrence of disability or death. A recent pan-Europe multicentre studyThese important and recent data invite us to be aware that anesthesia for children should always be delivered by competent and appropriately experienced anesthesiologists and care teams. Children aged less than 3 years, ASA physical status \u2265 III , with underlying congenital and metabolic diseases and/or undergoing major or complex surgery are those at highest risk for perioperative complications and poor outcome. It is recommended that these children should receive care by an anesthesiologist with specific education, training and ongoing experience in pediatric anesthesia. Anesthesiologists with mixed practice can deliver pediatric anesthesia for healthy children aged >3 years simple and routine procedures provided they have the adequate expertise and regular practice in pediatric anesthesia. They should maintain their competence and skills with regular exposure to pediatric lists and keep their knowledge up-to-date. The practice of pediatric anesthesia should be accompanied by continuous professional development (CPD).How to become a pediatric anesthesiologist? There is still no recognized framework for common and homogeneous pediatric anesthesia training in Europe. In the 90\u2019s FEAPA (Federation of European Association of Pediatric Anesthesia later became ESPA European Society of Pediatric Anesthesia) made recommendations to certify training in pediatric anesthesia which were transposed unevenly in various European countries.However still today there are so many legislative differences among European countries that regulate the statutes of postgraduate training and also in the countries where pediatric anesthesia is recognized as a subspeciality  the duration of the fellowship, the supervision and the quality of training are different. There are currently only four national programs for maintenance of anesthesia certification, and these are available only in three countries In Italy, during postgraduate training we have pediatric anesthesia as part of compulsory professional activity  in the area core specialistic skills, but the duration and the quality of this training is very different among the University Postgraduate School. So SARNePI  and SIAARTI  have recently drafted a document in which they define who does what in the field of pediatric anesthesia.Children should receive pediatric anesthesia care in children\u2019s hospitals or in general/district hospitals with dedicated pediatric areas. The pediatric population is too small to allow maintenance of sufficient skills for every anesthesiologist. Care of children undergoing anesthesia should ideally be regionalized in specialized pediatric settings staffed by pediatric anesthesiologists and pediatric nurses. In particular, the most vulnerable pediatric population, such as neonates and infants, those with co-morbidities and with underlying congenital and metabolic diseases as well as children undergoing major or complex surgery require referral to appropriately resourced multidisciplinary pediatric environments. Anesthesia for elective routine operations in otherwise stable and healthy children can be performed in district hospitals by teams with sufficient expertise in pediatric anesthesia. This requires appropriate staffing, equipment, facilities and support services.The most of pediatric surgery is performed in a healthy population, has a short duration and a recovery with few complications, so infants and children are well suited for ambulatory surgery. The frequency of pediatric ambulatory surgery has exploded such that 80\u201390% of pediatric surgery are now performed as ambulatory surgeryThe data we have available requires us centralizing children in the structure of reference with appropriately experienced anesthesiologists and care teams, but can we centralize all healthy children who undergo minor surgery? The answer is NO but the maximum competence of the personnel must be assured by guaranteeing a certain volume of activity. An adequate environment suitable for children with safety standards that must absolutely be present and centralize the most complex cases for pathology, for age and for comorbidity."}
+{"text": "Explore associations between dietary patterns and maternal agePopulation based cohort studyMaternity department of a large hospital in northern EnglandWomen delivering a singleton at Bradford Royal Infirmary between March 2007 and December 2010 .Survey data including maternal dietary patterns derived from food frequency questionnaire data using principal component analysis (PCA) were compared by maternal age using one-way ANOVA and chi-squared as appropriate.Dietary pattern PCA scores, supplement use, familiarity and compliance with 5-a-day fruit and vegetable recommendations, consumption of cola, maternal BMI.Three distinct dietary patterns were derived from the data; snack and processed foods, meat and fish and grains and starches. Mean PCA score for snack and processed foods was higher among women aged \u226419  than women aged 20\u201334  and those aged 35\u2265 . Women aged 35\u2265 had a significantly higher mean PCA score for the grains and starches dietary pattern  compared to both the 20\u201334 years  and the \u226419  groups. No differences were observed between groups in mean PCA scores for the meat and fish dietary pattern. Adolescent women also had higher intakes of sugar sweetened cola  and reported lower levels of fruit and vegetable and supplement intake. Women aged 35\u2265 had a higher mean BMI  and higher prevalence of overweight (36.8%) and obesity .Significant differences were observed between age groups both in terms of diet quality and BMI. Interventions targeted by age group may be advantageous in improving maternal nutrition and contribute to healthy pregnancies. Nutrition during pregnancy is a well-established modifiable factor which has the potential to impact upon the health and well-being of both mother and child. Study oOne such factor is the age of the mother during pregnancy. Adolescence is a time of substantial physiological change during which the nutritional needs of adolescent women are likely to differ from those of older women. Previous work examining the impact of maternal growth on outcomes in adolescent pregnancies suggested that nutrient partitioning between mother and child in growing adolescents negatively affected foetal growth and prematurity. A furthA recent systematic review of nutritional status of pregnant adolescents in developed countries found that intakes of energy, fibre and a number of micronutrients were below recommended levels in this population. The stuSimilar results were however reported in two reviews which were not confined to adolescent populations\u20137. This These previous works suggest that there may be nutritional issues that may impact on the health of both mother and child which vary by maternal age. This study therefore aims to assess differences in dietary pattern by maternal age in the Born in Bradford cohort.Born in Bradford is a largely bi-ethnic cohort of approximately 13,500 children with high levels of socio-economic deprivation. Pregnant women who were booked to deliver at Bradford Royal Infirmary were invited to join the cohort between March 2007 and December 2010. A detailed profile of the cohort has been published elsewhere. This stThe following demographic characteristics of the sample reported in the baseline questionnaire were explored; ethnicity, marital status, parity, education, smoking during pregnancy, alcohol and illegal drug use during pregnancy and index of multiple deprivation (IMD) score . Body maDue to the focus of this study being on detecting differences between age groups the study population was categorised into three groups for analysis according to maternal age; \u226419, 20\u201334 and 35\u2265 years, with women aged 20\u201334 being considered as the reference group. Statistical analysis was undertaken using SPSS 24.In order to evaluate nutrition in this population a series of statistical analyses were conducted using responses to the FFQ and applying principal component analysis (PCA) to identify distinct patterns of food types consumed. The FFQ was completed at 26\u201328 weeks gestation and refers to food intake during the preceding 4 weeks. There were a total of 37 items included in the FFQ, details of which are given with the results of the PCA. Since the original objective of the FFQ was to characterise the intakes of key food items only, it was not appropriate to derive an estimate of total energy intake. Responses to the food frequency questionnaire were given on either an eight  or five  point scale, these responses were therefore transformed to give an estimation of frequency per day in order to standardise questions asked in different formats.Individual items on the FFQ were then grouped by type and total frequency of consumption of different food groups estimated. The grouped nutritional variables were then used as the basis for a PCA in order to examine the dietary patterns which exist within the data set. PCA was selected as it allows for a larger number of variables to be reduced and underlying factors exposed.Differences between maternal age groups in both the demographic and nutrition related variables were explored using Chi-Square for categorical data and one-way ANOVA for continuous data; categorical variables are presented as percentages and continuous variables as means and 95% confidence intervals. Logistic regression analyses were used to compare the rate of each of the categorical nutrition related variables by age group and differences between groups estimated using odds ratios. Multivariate logistic regression models were then used to adjust these comparisons for confounding variables.Crude and adjusted odds ratios (OR and aOR) are therefore presented with 95% confidence intervals. Index of multiple deprivation (IMD) score and maternal ethnicity  were included as covariates in the adjusted analysis, due to the association of these variables with dietary pattern identified in the literature\u201312. WherIn the multivariate regression models for this study there is no clear logical or theoretical basis for assuming any variable to be prior to any other, either in terms of its relevance to the research goal of explaining phenomena, or in terms of a hypothetical causal structure of the data. For this reason a simultaneous method of including independent variables in the multivariate regression models was considered to be most appropriate, as opposed to a stepwise method.Due to the assumptions required to produce statistical models not being met for the dietary pattern scores  it was not possible to adjust the analysis of these variables for potentially confounding variables.Data were available for 5,083 pregnancies for this analysis; demographic characteristics of the participants included in the study are shown in Analysis of the nutrition related variables  showed tAdjustment for ethnicity and IMD score in the regression analysis produced similar results as shown in Several combinations of food groupings were explored to see which gave the most sensitive output in the PCA. These included loading all of the food items in separately, separating whole grains from other grains and starches, analysing all proteins as one group and separating proteins by type . The groupings outlined in When the analysis was completed without stipulating the number of factors to be retained two factors were retained which explained 43.8% of the total variance. On closer examination of the output, including examination of the inflection point of the scree plot, it was considered that a third and fourth factor with Eigen values of 0.971 and 0.939 respectively should be considered for inclusion. The analysis was therefore run with both 3 and 4 factors stipulated and the results compared with the initial analysis. The inclusion of a third factor presented a distinct dietary pattern which added to the logical understanding and interpretation of the data. The inclusion of a fourth factor did not however add to the understanding of the data. The decision was therefore made to retain 3 factors from the analysis, the inclusion of these 3 factors would then account for 55.9% of the total variance. Details of the retained factors and factor loadings are given in The analysis showed that there was an association between both the snacks and processed foods pattern and the grains and starches pattern and maternal age group . The meaThe results show an association between two of the dietary patterns in this analysis and maternal age. Strongest associations were seen in the snack and processed foods pattern where women aged \u226419 were found to have the highest mean PCA score reflecting a higher intake of foods that are typically viewed as snack items  and moderate intake of processed meat. Adolescent women also reported consuming higher levels of sugar sweetened cola compared to older women; no differences were observed in levels of consumption of artificially sweetened cola.There were no differences by age group in women's awareness of recommendations to eat five portions of fruit and vegetables per day; however adolescent women were less likely to say they achieve this recommendation. Adolescent women in the sample also reported the lowest use of nutritional supplements.Adolescent women had a higher prevalence of underweight (BMI <18.5) and older women a higher prevalence of overweight or obesity (BMI >25).These results are largely consistent with findings from the latest wave of the National Diet and Nutrition Survey (NDNS). ResultsThe findings of these studies are consistent with those of the present study however neither specifically addressed adolescent women or older women as distinct groups. As discussed in the introduction, the nutritional needs of adolescent women in particular may differ from those of older women due to the continued growth of the mother meaning that understanding the nutritional intake of young women during pregnancy is important. This study helps us to start to understand the dietary patterns associated with this group, however further work based on more robust dietary surveys is needed in order to improve understanding of this complex topic. A particular strength of this work is that it utilises well-established, ethnically diverse, UK based cohort data in a way which is unique to this study. This cohort includes a large number of participants meaning that analysis by maternal age including an adolescent group is both possible and robust.There were limitations in the dietary data available for this study. The number of items included in the FFQ was limited meaning that there is potential for the dietary patterns identified to be lacking in detail, or that additional patterns which might be present in the population could have been missed. This issue also resulted in the distribution of dietary pattern scores being significantly skewed, meaning that it was not possible to use statistical modelling to predict the extent to which maternal age influences dietary pattern, only that there appears to be an association. There was also no definition of portion size in the collection of data meaning there is likely to be significant variation between participants self-defined portion sizes. The FFQ was completed at 26\u201328 weeks of pregnancy and related to the preceding 4 weeks, meaning that the dietary patterns identified are only reliably relevant to the second trimester of pregnancy. Women's diet may change over the course of pregnancy meaning This study assesses dietary patterns ascertained by principal component analysis. Dietary patterns have been defined as \"foods that are actually consumed in various characteristic combinations\". The stuThe results suggest that there may be some cause for concern regarding the quality of adolescent pregnant women's diet, despite reporting similar levels of knowledge of recommendations to older women. This suggests that factors other than knowledge may be important in developing behaviour change interventions. There are a number of different theoretical models discussing the process of translating knowledge into action in public health. For example the health belief model is basedThe adolescent women in the sample also reported less use of nutritional supplements compared to the reference group. This suggests that any gaps in the nutritional profile of young women during pregnancy as a result of a sub-optimal diet may not be being filled by supplementary vitamins and minerals and may therefore leave women in this group with nutrient deficiencies.Consumption of sugar and artificially sweetened cola in this cohort has previously been examined with resEnergy intake was not available for analysis in this dataset meaning that maternal BMI at booking appointment is a useful indicator. Individual differences in total energy intake are largely determined by a combination of body size, physical activity and metabolic efficiency. Measurements of energy intake and physical activity in epidemiology are often crude and suffer from under or over reporting, and metabolic efficiency is essentially impossible to measure in this setting. For these reasons height and weight measurements are often considered a suitable alternative to measures of energy intake. The resThe results of this study are consistent with previous work assessing maternal obesity in the UK. This woThere may be some cause for concern with regard to diet quality in adolescent women and obesity among older women during pregnancy. Further work using more comprehensive methods of dietary data collection would be advantageous in assessing the nature of these relationships.The impact of dietary pattern on birth outcomes is also an important area for further work, particularly in light of evidence presented previously that there is a higher risk of extremely low birthweight babies and extremely pre-term delivery among adolescent women in this cohort.Interventions targeted to specific age groups to facilitate behaviour change may be useful due to differences identified in the types of nutritional issues affecting pregnant women at different ages. There is a need to further understand the barriers to healthy eating during pregnancy in order to develop successful interventions."}
+{"text": "Several studies have investigated longitudinal changes in health status and functional ability but few have examined whether inequalities in healthy ageing varied across different countries. The aim of this study is to investigate trajectories of health metric scores (generated in previous symposium abstract) over the ageing process and examine the impact of education and wealth on the trajectories across eight cohorts in the ATHLOS consortium  using multilevel regression modelling. After adjusting for age, gender and study, higher levels of education  and wealth  were associated with higher baseline scores but had minimal impacts on decline rates. These effect sizes varied across different cohort studies and the inequality gradient was found to be strongest in the Health Retirement Study from US. Future research may investigate potential mechanisms which might explain the differential impact of education and wealth in different societies."}
+{"text": "According to the \u201cuse it or lose it\u201d hypothesis of cognitive aging, cognitive enrichment and cognitively engaging activities are associated with the maintenance of high levels of cognitive functioning in old age. Similar ideas have been brought forward with respect to characteristics of individuals\u2019 work environment, with more cognitively enriching work demands providing an optimal environment for cognitive development and maintenance. The goal of this research group is to showcase new developments in research on work, retirement and cognitive aging. H\u00fcl\u00fcr et al. examine the role of perceived work environment for cohort differences in trajectories of cognitive change based on 56-year longitudinal data from the Seattle Longitudinal Study. Andel et al. use data from the Swedish Adoption/Twin Study of Aging to examine trajectories of cognitive aging before vs. after retirement with two-slope growth curve models. Zulka et al. conduct a systematic literature review on the association between retirement and cognition and examine the role of factors such as occupational experiences and the cognitive domain studied. Burzynska et al. investigate the relationship between stressful and stimulating occupational exposures and structural brain health and cognition in older age. The discussion by George Rebok will focus on how these findings contribute to our understanding of the role of occupational experiences for cognitive and brain aging and how they can be utilized to promote maintenance of cognitive functioning in old age."}
+{"text": "Osteoporosis is largely undetected and untreated in older men who are at-risk, with even lower rates of detection and treatment in rural communities. In this presentation we report the consequences for primary care providers (PCPs) of the implementation of an osteoporosis telemedicine clinic that targeted rural patients and is purposefully designed to minimize PCP workload. Analysis of qualitative interviews with PCPs who co-managed patients with the telemedicine clinic confirmed that implementation strategies used by the telemedicine clinic were successful at minimizing workload and had a positive impact on PCPs\u2019 work. However, the clinic\u2019s seamless approach may have contributed to unintended consequences of low PCP awareness of program care processes and selection criteria and a missed opportunity for PCPs to reinforce osteoporosis care goals in the primary care setting."}
+{"text": "The creation and maintenance of sustainable data archives can be challenging but it offers clear advantage. Properly curated data can be used by multiple researchers, testing a variety of hypotheses and increasing the return on investment to the expensive process of data collection. Having an internally managed archival system also provides greater control and autonomy in the equitable distribution of data resources, insuring all researchers have full use of the data for original research, teaching and new directions once the data leaves the control of the local investigator\u2019s control. This poster reviews the advantages of having a local strategy geared toward the preservation and sharing of gerontological research data. Using the National Archive of Computerized Data on Aging (NACDA) as a working example, the poster offers an overview of collections at NACDA. Using our metadata tools and variable search database, NACDA can identify studies in its collections that examine aspects of aging and health among adults during their lifecourse. Many of the studies are longitudinal or repeat measure cross-sectional studies. We are also able to identify studies which focus on aging that are not maintained by NACDA but which are available to interested researchers. Using a strategy of archival preservation combined with a strong focus on productive research and outreach, NACDA has amassed data and metadata covering a wide array of studies worldwide that address the aging lifecourse. Because our collections are multinational, we share these data at no cost to interested users worldwide"}
+{"text": "In the original article, there was an error. The statement of the written informed consent procedures was incorrect because of inappropriate wording.Materials and Methods, subsection Subjects, paragraph two:A correction has been made to the \u201cThis study was approved by the Ethical Committee of Tianjin Medical University General Hospital and written informed consent was obtained from all subjects or their guardians.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "Concerns have been raised that the transplants performed in the local context at the time of procedures reported in this article  may haveDetails as to the donor sources and methods of obtaining informed consent from donors were not reported in , and wheThe authors state that no vulnerable populations were involved in their research and all organs were obtained with informed consent but did not provide ethics approval documentation to support their claim or clarify whether organs had been procured from prisoners.The authors did not respond to inquiries about the availability of underlying data supporting this study.PLOS ONE Editors retract this article.Owing to the lack of documentation to demonstrate this study had prospective ethical approval, insufficient reporting, unresolved concerns around the source of transplanted organs and whether they included organs from prisoners, and in compliance with international ethical standards for organ/tissue donation and transplantation, the The corresponding author notified the journal that all authors disagree with the retraction. The other authors either could not be reached or did not respond directly."}
+{"text": "There has been a long tradition of wayfinding and orienteering studies in humans but these have mostly neglected possible age-related differences in navigation. This field of inquiry is experiencing something of a resurgence of interest due to the development of VR technology which has brought the systematic study of large scale navigation into the laboratory and into the MRI scanning environment. Empirical studies to date identify navigation as an aspect of cognition that is vulnerable to the aging process. Functional and structural neuroimaging studies in humans suggest that age-related changes in the brain\u2019s \u201cnavigation circuit\u201d may underlie these behavioral age differences. Older adults also adopt unique spatial strategies and knowledge of these strategy preferences could enlighten both basic science research in spatial cognition and also inform the development of age-specific technological assistance that may extend functional independence of older adults into later life."}
+{"text": "This study investigated whether perceived neighborhood quality was associated with chronic loneliness for adults 60 and older in the United States. Although loneliness can be episodic and overcome, chronic loneliness has been identified as a social determinant of health. Utilizing ecological systems theory we hypothesized that higher levels of neighborhood social cohesiveness would be associated with lower odds of chronic loneliness. We postulated that the networks available to people in the proximal area where they live could provide social opportunities for reducing loneliness. This idea was consistent with prior findings indicating the salience of neighborhoods for retirees, but inconsistent with research indicating the importance of a confidant in reducing loneliness. Data from the 2008 and 2012 Health and Retirement Study Psychosocial Surveys were used (n = 3530). Loneliness was measured using the 3-item scale developed by Hughes and colleagues in 2004. Findings from unadjusted logistic regression indicated that loneliness was inversely related to neighborhood cohesion as measured by an index of the trustworthiness, friendliness and helpfulness of neighbors and cleanliness, occupancy, lack of graffiti, and sense of belonging in the area . When demographic and health-related factors were entered into the model the odds of being lonely were significantly lower for those with higher ratings of social cohesion . These findings were consistent with the idea that neighborhoods are an important social place for older persons and interventions at the neighborhood level may be more effective than individualized treatment plans."}
+{"text": "Systematic reviews of clinical trials aim to include all relevant studies conducted on a particular topic and to provide an unbiased summary of their results, producing the best evidence about the benefits and harms of medical treatments. Relevant studies, however, may not provide the results for all measured outcomes or may selectively report only some of the analyses undertaken, leading to unnecessary waste in the production and reporting of research, and potentially biasing the conclusions to systematic reviews. In this article, Kirkham and colleagues provide a methodological approach, with an example of how to identify missing outcome data and how to assess and adjust for outcome reporting bias in systematic reviews. Bias arises when trialists select outcome results for publication based on knowledge of the results. Hutton and Williamson first defined outcome reporting bias (sometimes termed selective reporting bias) in 2000: \u201cthe selection on the basis of the results of a subset of the original variables recorded for inclusion in a publication.\u201dof systematic reviews.Empirical research provides strong evidence that outcomes that are statistically significant have higher odds of being fully reported than non-significant outcomes (odds ratios ranging from 2.2 to 4.7).The aim of this article is to show, with an example, how systematic reviewers can minimise the amount of missing data in reviews of healthcare interventions, and use ORBIT methods to detect and classify the suspicion of outcome reporting bias in benefits and harms reported in included studies. The paper also provides details of a statistical approach to assess the robustness of meta-analysis conclusions on this potential source of bias that non-methodologists can implement on a web based platform.Outcome reporting bias occurs when trialists select for publication a subset of the original recorded outcomes based on knowledge of the results. Outcome reporting bias is a threat to evidence based medicine and contributes to waste in researchEmpirical evidence suggests that statistically significant outcomes have higher odds of being fully reported than non-significant outcomes (odds ratios ranging from 2.2 to 4.7)The ORBIT  research programme offers tools for systematic reviewers to identify missing outcome data, and assess and adjust for outcome reporting bias. A tutorial is provided to show how these tools could be used in a systematic reviewOne way to streamline the process of systematic reviews and to help reduce outcome reporting bias is for reviewers to use outcomes considered as core for all trials in a particular topic area.We recommend that systematic reviewers consider core outcome sets when registering their topics with Cochrane review groups or PROSPERO . Systematic reviewers can identify if relevant core outcome sets exist for their review area by searching the publically accessible COMET  database.Reviewers should not exclude studies from their review on the basis of whether the outcomes of interest were reported, because non-reporting does not necessarily mean that the outcomes were not measured.We strongly encourage systematic reviewers to include relevant studies in their review irrespective of whether the studies reported any of the review outcomes of interest, and to assess those studies in accordance with the methods described below.An outcome matrix was proposed to help identify missing study outcome data.For trials that do not or partially report on outcomes, the matrix allows reviewers to assess the risk of outcome reporting bias according to the ORBIT classification system (see next section below). In the epilepsy example in We strongly encourage systematic reviewers to include an outcome matrix in their reviews. The ORBIT matrix generator, available on the ORBIT website,Sources for obtaining unpublished information on clinical trials for use in systematic reviews have previously been described.When no usable missing outcome data can be obtained from the sources given above, the ORBIT researchers developed classification systems to help systematic reviewers detect outcome reporting bias in reviews. The method relies only on information in the published trial report , expert clinical judgment, and an assessment of the outcomes that researchers usually report across a set of trials in a review.For the epilepsy review, the classifications given for each outcome with missing or partially reported data are presented in the outcome matrix , with a To assess the risk of bias due to selective reporting, we recommend that the ORBIT classification system is used by systematic reviewers as a framework to determine whether there is a high or low risk of outcome reporting bias when review outcome data are missing or partially reported. We also recommend that the assessment is completed by at least two independent researchers and differences discussed to agree on an overall classification .Copas and colleagues developed new statistical sensitivity approaches for assessing the robustness of review meta-analysis conclusions when outcome reporting bias is suspected.We return to our epilepsy example given earlier, for which the outcome matrix of the ORBIT classification is shown in After applying the Copas bias adjustments for partially reported or unreported outcomes , the revWhen outcome reporting bias is suspected, we recommend that the quality of evidence is lowered in relation to the standard GRADE  assessment applied in reviews. We also recommend that sensitivity analyses are performed for important outcomes to assess the robustness of conclusions to outcome reporting bias.Empirical evidence suggests that outcome reporting bias is a threat to the validity of the evidence base and contributes to research waste. We have highlighted up-to-date approaches and recommendations for detecting this problem and adjusting the results when performing sensitivity analyses in systematic reviews. We anticipate continued application of these methods and methodological research into the assessment and adjustment of outcome reporting bias in the years to come. The ORBIT website is a useful resource, providing researchers with tools to detect outcome reporting bias and methods for sensitivity analysis; it is also a repository for important publications in this field."}
+{"text": "Aging is the product of numerous dynamic processes that span multiple domains of functioning , multiple levels of analysis, and multiple time-scales. Scientific inquiry in many fields has benefited from articulation and analysis of complex systems. This symposium brings together a collection of papers that illustrate how dynamical systems modeling is contributing to both theory and understanding of aging. Yang and colleagues apply Boolean network approach to intensive longitudinal data to identify sequences of emotion and behavior that lead to a stable equilibrium, and suggest how that information can be used to design interventions that push individuals toward a healthier equilibrium. Rector and colleagues illustrate use of dynamic indicators and multiscale entropy measures as indicators of resilience and explain how those measures may be used in prediction of physical recovery. Brick highlights how sequence mining methods can be used to identify commonalities and differences in dynamic change, and how those patterns characterize and distinguish groups with respect to aging trajectories. Moulder and colleagues demonstrate how latent maximum Lyapunov exponents can be used to study sensitivity of individuals\u2019 developmental trajectories to initial conditions. Boker and colleagues provide a general overview of how dynamic models, including an adaptive equilibrium regulation model, distinguish resilience to acute versus chronic stressors and patterns of regulation. Together these papers highlight the value complex system thinking can add to our understanding and optimization of aging."}
+{"text": "Following publication of this work , questioThe Ethics Committee at Ghent University have clarified that authors received specific approval for this study. The published ethics statement was incomplete, however, and is hereby corrected to the following:Patients consulting at the department of orthopaedics and traumatology are asked to sign a generic informed consent giving permission to use their medical data for retrospective research purposes  of patients who needed meniscal surgery in the past. All data were generated from the patient files and put anonymously in a dataset (used for this manuscript). Only the data from the patients with meniscal allograft transplant surgery were collected out of the general database (B670201317873) and added to the dataset (used for this manuscript)."}
+{"text": "The successful results of the program have led domestic and foreign governments to consider the application of cap and trade to address other air quality issues. Certain analyses are particularly important in determining whether or not cap and trade is an appropriate policy tool. This paper offers a set of questions that can be used as criteria for determining whether or not cap and trade is the preferred policy approach to an environmental problem.The use of emissions trading (cap and trade) is gaining worldwide recognition as an extremely effective policy tool. The U.S. Sulfur Dioxide (SO"}
+{"text": "The data presented in this research show the results of the experimental study of acoustic behaviour of coconut fibre-reinforced concrete (CFRC). The CFRC was added in percentages of 0.25%, 0.5%, 0.75% and 1% of cement. The acoustic test was conducted to determine the amount of sound that can be absorbed by the fibre. The data showed that the concrete reinforced with coconut fibre had the highest sound absorptive power, of which fibre treated absorbed more sound than other fibres, this is because washing of fibre increase the lignin content which is responsible for the sound absorbing property. The data also showed that the curing time had no effect on the absorbing property of the CFRC. The data presented will be useful in the construction of sound proof reinforced concrete slabs, walls and other elements. Specifications tableValue of the data\u2022These data will be useful to researchers working on incorporating coconut fibre on concrete.\u2022The data presented show that incorporating fibre in concrete improved the slump because the fibre absorbed some of the water during mixing.\u2022The data are valuable because they show that coconut fibre absorbed some amount of sound. Also, distance of propagation should be considered in further studies.\u2022The data obtained in this study solve the issue of noise affecting the occupants of buildings located in urban and rural areas.\u2022The data presented in this study provide an affordable and functional replacement for sound proof materials as opposed to importing of sound absorbing materials.1Composite material is defined as a unique combination of the fibre and the concrete matrix where function of the fibre is to withstand load and make the composite stiffer meanwhile matrix is a binder which holds the fibre in place 2Portland cement of the Dangote brand in conformity with"}
+{"text": "Trust and reciprocity are cornerstones of human nature, both at the levels of close interpersonal relationships and economic/societal structures. Being able to both place trust in others and decide whether to reciprocate trust placed in us is rooted in implicit and explicit processes that guide expectations of others, help reduce social uncertainty, and build relationships. This review will highlight neurobehavioral mechanisms supporting trust and reciprocity, through the lens of implicit and explicit social appraisal and learning processes. Significant consideration will be given to the neural underpinnings of these implicit and explicit processes, and special focus will center on the underlying neurocomputational mechanisms facilitating the integration of implicit and explicit signals supporting trust and reciprocity. Finally, this review will conclude with a discussion of how we can leverage findings regarding the neurobehavioral mechanisms supporting trust and reciprocity to better inform our understanding of mental health disorders characterized by social dysfunction. Racial bias can be particularly pervasive: an individual\u2019s implicit bias  relative to the bottom line outcome \u2014may be particularly diagnostic when deciding whether to trust a partner  differential weighting of reciprocity (or defection) as a function of the strength and valence of an initial impression of a partner; and (2) for initial impressions and experienced outcomes to influence each other in order to learn about a partner. In other words, whether a partner reciprocates or violates trust informs the updating of an impression, which then feeds forward to differentially weight subsequent instances of reciprocity/violation of trust  in ways that are consistent with prior impressions of others as \u201cgood\u201d or \u201cbad\u201d: reciprocity from someone initially perceived as trustworthy contributes more heavily to subsequent choices to a violation of trust from that same partner, and vice versa  based on whether we have priors about their tendency to cooperate , which may be quantified as the trade-off in value between outcomes for the self vs. outcomes for others  the monetary amount that a trustee thinks that an investor would expect them to send back ; and (2) the amount that the trustee actually sends back. This difference is weighted by a guilt aversion parameter which indexes sensitivity to feeling guilt , which may underlie the propensity for re-victimization in this population  involved in trust and reciprocity, our understanding of neural and behavioral mechanisms of trust and reciprocity will be bolstered by integration with advanced neuroimaging approaches. Recent efforts linking individual differences in computational strategies supporting reciprocity  with differential patterns of brain activity assessed by inter-subject representational similarity analysis (van Baar et al., DF wrote the manuscript.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The goal of this study was to leverage data from two environmental regulatory initiatives, Ontario\u2019s Toxics Reduction Act (TRA) and Canada\u2019s National Pollutant Release Inventory (NPRI), to assess their ability to monitor trends in the use and emission of carcinogens by industry sector in Ontario.Data reported to the TRA and NPRI by industrial facilities in Ontario were retrieved from 2011 to 2015. Twenty-six known and suspected carcinogens were identified (IARC) and the trends in the use and emission were evaluated by industry sector. The locations of industrial facilities that used and released carcinogens were mapped by Public Health Unit (PHU).Chemical manufacturing and primary metal manufacturing sectors accounted for 84% of all reported industrial use of carcinogens during the period 2011\u20132015. The largest source of carcinogen emissions came from facilities in the primary metal manufacturing and paper manufacturing sectors. The largest number of industrial facilities that reported the use and release of carcinogens were located in the City of Toronto and Peel Region PHUs. Overall, the use of carcinogens across all sectors appeared to decrease by 8%, while emissions increased by about 2%.The results of this study show the need to reduce the use and emission of select carcinogens in priority industry sectors. Environmental reporting programs, such as the TRA and NPRI, can serve as important tools in cancer prevention by tracking potential carcinogen exposures in the environment and in the workplace. About one out of every two Canadians will be diagnosed with cancer in their lifetime  , particulate matter less than 10\u00a0\u03bcm (PM10), and total particulate matter, only releases of PM10 were selected for analysis in this study as they were reported more frequently. IARC has classified all particulate matter as a known human carcinogen  Industrial facilities in Ontario that report their releases to the NPRI must report their use of toxic substances to the MOECC\u2019s TRA program from a list of substances prescribed by the program. Of the 322 substances prescribed under the TRA, those classified as known human carcinogens (group 1) and probable human carcinogens (group 2A) by the International Agency for Research on Cancer (IARC) were selected for analysis in this study , in order to geographically analyze the data for industrial facilities in both datasets. There are 36 PHUs in all of Ontario  by its intercept and multiplying by 100%. The same method was used to calculate trends for releases. All data analyses were performed using the statistical software SAS 9.4 .The total estimated use and release of carcinogens by industrial sector summed for all years from 2011 to 2015, the mean number of employees for each sector and the top three known and suspected carcinogens by amount used and released are shown in Table Facilities in the chemical manufacturing sector ranked first among all sectors for reported carcinogen use, using more than 10 million t in the 5-year period analyzed  and the transportation equipment manufacturing sector   located in the City of Toronto PHU, followed by Peel Region PHU (n\u2009=\u200951)  and Sudbury and District Health Unit (n\u2009=\u20092650\u00a0t), respectively (data not shown). The chemical manufacturing and petroleum and coal product manufacturing sectors are prominent industries in Lambton Health Unit and were likely responsible for the carcinogen use observed in that PHU. In Sudbury, nickel mining remains an important industry contributing to the large quantity of carcinogenic emissions.Of the 326 industrial facilities reporting the use of carcinogens in 2015, the City of Toronto PHU and Peel Region PHU contained the largest number of industrial facilities that reported the use of carcinogens, with each containing 34 facilities . A more detailed analysis of use and emission trends by carcinogen were previously discussed (Slavik et al. In addition to analyzing carcinogen use and emission by industry sector, this study examined the distribution of industrial facilities by PHU to explore potential geographic patterns in industrial sites. The largest number of industrial facilities reporting the use and release of carcinogens were observed in the city of Toronto, Ontario\u2019s most populous city. This finding is consistent with previous research that identified significant sources of industrial pollution in Toronto, where neighbourhoods with higher emissions of toxic contaminants were also characterized by populations who were racialized or socio-economically disadvantaged (Kershaw et al. Lung carcinogens are among the most used in industrial facilities in Ontario (Slavik et al. One limitation of this study is that the amount of toxic substances used and emitted by facilities is self-reported in both the NPRI and the TRA, though some consistency between volumes of self-reported pollutant releases by industrial facilities and pollution monitoring data have previously been found (De Marchi and Hamilton In addition, there are limitations in the reporting requirements of the TRA program for toxic substance use. The program allows for the reporting of use quantities by industrial facilities as ranges as opposed to absolute quantities, which limits the analysis to estimates. Another limitation of most environmental reporting programs is the fact that only larger industrial facilities meeting specific use and release thresholds are required to report (Dolinoy and Miranda There are also limitations in applying carcinogen use and release as indicators of potential exposure since numerous other factors impact a worker\u2019s exposure to chemicals. These other factors, including exposure controls such as safe work practices and personal protective equipment, were not examined in this study. It should also be noted that high sector emissions do not necessarily equate to high cancer risk since contaminants are dispersed and are often transported across large distances in the environment (Li and Ma Databases like the TRA and NPRI can be used for surveillance to provide estimates of industrial carcinogen use and release when detailed exposure assessments and routine environmental monitoring are not feasible. A major strength of the approach used in this study is the combination of descriptive and quantitative approaches to assess industrial trends in the province by both characterizing potential exposures in sectors of concern and quantifying changes in carcinogen use and release. The methods are also highly transferable to other jurisdictions where similar environmental reporting databases exist and concerns over toxics use and emission are present.There remain opportunities to reduce the use and release of carcinogens in many Ontario industries. The TRA program is still in its infancy and future analyses drawing from more datasets will be able to better indicate longer-term trends in carcinogen use and release. The findings from this study may inform future efforts to quantify levels of exposures in particular industry sectors or geographic regions where those industries are present. While this study does not attempt to draw conclusions on the risk of developing cancer in workers and populations residing near certain industries, it demonstrates the need to prioritize exposure prevention strategies in particular sectors where the most carcinogens are used and emitted."}
+{"text": "The published article  containsPatients attending Kasr Al Ainy hospital sign a consent form at admission to agree to use of their clinical data for research. The authors were involved in patients' care and management during their clinical course, but data were de-identified when extracted from the clinical database for use in this study. The Cairo University Research Ethics Committee confirmed that this study was exempt from the requirement for approval. As per the University\u2019s regulations, retrospective data analysis and other research that does not include interactions with or collection of identifying personal data from living human subjects, is exempt from Research Ethics Committee continuous review."}
+{"text": "AARP will introduce research on rural residents from the 2018 Home and Community Preferences Survey of Adults Age 18 and Older that shows the importance of making communities places where rural residents can successfully age throughout all stages of life. This data will provide useful insights regarding what adults who live in rural areas want and need in their communities to positively contribute to their overall health and well-being and keep them actively engaged and involved in their community. The survey data can serve as a key tool for communities to understand what rural residents view as important for successfully aging in place and strategies that communities might employ to create community supports and services conducive for older rural residents."}
+{"text": "Home- and Community-Based Services (HCBS) are increasingly important for older adults who want to maintain their independence and remain in their communities. Although HCBS systems have been developed widely in many western countries and in some countries in Asia, China is just beginning to grapple with its rapidly aging population by offering HCBS in a limited fashion. The purpose of this study was to investigate the relationship between structural  and cognitive  social capital and HCBS utilization among older Chinese adults. The study also examined the mediating effect of structural social capital for the the relationship between cognitive social capital and HCBS utilization. We frame the study within the Andersen behavioral model of health services utilization and argue that within this framework social capital is an enabling factor. We analyzed survey data from 456 community-dwelling older adults living in the Gusu district of the city of Suzhou, China in 2015. Structural equation modeling was used to test the hypothesized relationships. The results showed that both cognitive and structural social capital were significantly associated with HCBS utilization. Structural social capital also served as a mediator between cognitive social capital and HCBS utilization, even after controlling for sociodemographic characteristics and other relevant covariates. The findings supported the utility of employing Andersen\u2019s behavioral model and social capital theory for better understanding older Chinese adults\u2019 utilization of HCBS. Interventions for increasing social capital may be useful for improving HCBS utilization in Chinese urban communities."}
+{"text": "Diagnostic imaging pathways are developed to ensure that medical imaging examinations are appropriately selected and referred by clinicians with the aim of justifying the use of imaging modalities for clinical diagnosis. Failing to comply with the imaging pathways or guidelines results in exposing patients to unnecessary ionising radiation due to malpractice of imaging referrals. This editorial provides a comment on a recent study reporting very high percentage of general x\u2010ray imaging referrals which did not or partially met the imaging pathways in an emergency department. Advances in medical imaging technologies over the past number of decades have resulted in an increase in the sensitivity and specificity of imaging examinations, thereby improving diagnostic accuracy and the opportunity to deliver more accurate and personalised care. Parallel to these improvements, defensive medicineIn Australia, the Western Australia (WA) Government has developed the Diagnostic Imaging Pathways, which provide evidence\u2010based medicine to guide health professionals in the judicious use of imaging modalities for diagnosis of various pathologies. This presents the most appropriate diagnostic examinations in a desirable sequence for a wide range of clinical scenarios.Journal of Medical Radiation Sciences, Rawle and PighillsP\u00a0<\u00a00.001).In the current issue of the Similarly, a review of 140 medical records which did not meet the pathway or were unclear , a high percentage of medical records (65.5%) did not meet the imaging pathway criteria. Further analysis of the data was performed by combining these imaging referrals with medical records, and their results showed improvement with unjustified examinations reduced to 49%. Results of this study indicate that an excessive high percentage of clinically unjustified x\u2010ray imaging examinations were performed in the emergency department. They concluded that referring clinicians were not providing adequate relevant information and that the radiographers were not complying with justification requirements.There are several aspects from Rawle and Pighills\u2019 studyThe WA pathways are intended to help medical practice by improving the efficiency of health service delivery and promoting fair and cost\u2010effective care; however, its use as a reference brings some limitations. As individual patient circumstances vary, each pathway is neither a rigid set of rules nor a substitute for clinical assessment. It is also acknowledged that diagnostic practice may vary from one healthcare provider to another. Other variables include local availability of equipment and available expertise as previously stated. The 173 individual scenarios available cannot cover all possible patient presentations and for that reason, a divergence from the proposed pathway may be acceptable in certain circumstances.Another important issue to consider is the lack of research to identify the reasons behind whether it is due to the quality or absence of provided training or is a result of the availability of equipment and expertise in the fields that were explored or the communication between all individuals involved. The information provided to patients and the consent obtained from them to perform an examination may also influence the ultimate approach to diagnosing the patient's condition.In summary, one strategy that can be considered to reduce the number of unjustified examinations being performed is to develop criteria that are adapted to each context to guide the respective clinical community and to simultaneously introduce high quality education and training sessions across healthcare departments. The aim of these sessions would be to improve knowledge of radiation exposure in medical imaging, associated risks and appropriate examinations available for main pathological conditions based on clinical audits."}
+{"text": "This opinion article highlights the importance of targeting critical brain regions during reconsolidation to gain insight into the brain mechanisms of memory dynamics and modulating existing memories.Accumulating evidence has shown that reactivated existing memories become sensitive to modification during reconsolidation   have a role in modulating plasticity (Nitsche et al., Since NIBS techniques are promising interventions for treating declarative memory impairments that are often the first symptoms of dementia, the combination of NIBS with pharmacological interventions could prove to be an important symptomatic therapy for subjects with MCI due to AD (Albert et al., Finally, future research should address the issue of inter-individual variability in the effects of NIBS during reconsolidation. In particular, the possibility that variations in the presence of specific genetic polymorphisms (e.g., brain-derived neurotrophic factor gene; Chaieb et al., In conclusion, a better understanding of these basic and clinical issues will be instrumental to the development of NIBS clinical interventions for improving memory and symptoms through reconsolidation.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The re-emergence of Zika virus in Brazil and other contiguous countries is a source of anxiety for pregnant women on account of its association with microcephaly. Adverse pregnancy outcome has huge mental health implications. It is essential for health providers to incorporate psychosocial care as part of pre and postnatal care for women in all countries affected by the Zika virus infection. The resurgence of Zika virus in Brazil and the dire medical implications for the populace and pregnant women, in particular, led to its declaration as a public health emergency in November 2015 . SusceptThe WHO and the Brazilian health authorities must be commended for recognizing and declaring the Zika virus outbreak a public health emergency and forming a multidisciplinary committee but so much needs to be done and lessons drawn from the recent Ebola outbreak. Ultimately, all-inclusive health systems approach that combines flexibility with effectiveness is needed to achieve the health objectives. A three-pronged approach is recommended:Strengthening of the health facilities in Brazil and other neighboring countries on emergency preparedness and proactive handling of the Zika virus through adequate testing, surveillance and case management: There should be an aggressive contact tracing and provision of requisite equipment for laboratory testing and diagnosis of all suspected cases of Zika Virus. Psychosocial support is very essential and the long term effects of anxiety and trauma (post-traumatic stress disorder (PTSD) must be expected in the women that lost their pregnancy or babies during the outbreak. Psychotherapy for pregnant women and families affected is essential. Clinical psychologist and psychiatrist should be included in the high-level team set up by affected countries to address the health challenges. The WHO guideline on the provision of psychosocial support for women and families affected by Zika virus [ka virus  should bCommunity engagement and participation by all stakeholders: Productive dialogue and information channels must be created to serve as a two-way information link between the communities, women the health authorities. Community engagement would foster understanding and dispel the atmosphere of misinformation and fear that subsist in similar epidemics [pidemics . AggressAdequate prevention and Vaccine development of a vaccine is essential: The proactive prevention guidelines set up by the Public Health England (PHE) and the Royal College of Obstetrics and Gynaecology is recommended for health care providers everywhere [erywhere . Zika vierywhere -11. Timeerywhere .Zika virus is major public health issue with implications for women of reproductive age. From the health systems perspective, it is important to adequately allocate resources, build capacity, and develop appropriate clinical protocols for the healthcare workforce for diagnosis and treatment. Emergency response preparedness in virus outbreaks is glaringly sub-optimal and the mental health needs of affected individuals must be made a priority."}
+{"text": "Despite a global consensus that nurses and midwives constitute the majority and are a backbone of any country\u2019s health workforce system, productive capacity of training institutions remains low and still needs more guidance. This study aimed at developing a middle-range model to guide efforts in nursing education improvements.To explore challenges facing nursing education in Malawi and to describe efforts that are being put in place to improve nursing education and the process of development of a model to improve nursing education in Malawi.The study used a qualitative descriptive design. A panel discussion with eight nursing education and practice experts was conducted guided by core concepts derived from an analysis of research report from a national nursing education conference. Two focus group discussions during two quarterly review meetings engaged nurse educators, practitioners and clinical preceptors to fill gaps from data obtained from a panel discussion. A qualitative abductive analysis approach was used for the development of the model.Transforming and scaling up of nursing education emerged as the main concept of the model with nursing education context, academic practice partnership, regulation, competent graduate and nursing workforce as sub concepts. Key main strategies in the model included curriculum reforms, regulation, transformative learning, provision of infrastructure and resources and capacity building.The model can be used to prioritise nursing education intervention aimed at improving quality of nursing education in Malawi and other similar settings. Malawi is among countries with the most strained health systems in sub-Saharan Africa characterised by a heavy burden of disease  , nurse educators (n = 12), nursing managers (n = 8) and nursing clinical preceptors (n = 8) from teaching hospitals who participated in two NEPI quarterly review meetings. Theoretical sampling shaped further data collection as the researcher pursued developing conceptual ideas and participants helped to clarify understanding  for nurse educators to share best practices in enhancing nursing education in Malawi . During Data from the study were analysed based on grounded theory approach  and the Malawi National Health Research Ethics Committee (NHSRC 1154). Permission was sought from NEPI project manager to conduct quarterly review sessions for data collection. Informed consent was obtained and participants voluntarily took part in the study. No data were linked to individual participants to ensure anonymity. Data were treated with confidentiality.Four core concepts emerged from an analysis of research reports that were presented at the national nursing education conference. These were nursing education context, academic\u2013practice collaboration, competent graduate and transformative strategies .These core concepts formed the basis for a panel discussion and subsequent focus group discussions with nurse educators, practitioners and clinical preceptors, which resulted in the emergence of five themes.Participants of both the panel discussion and focus group discussions highlighted the need to have curricula that respond to the healthcare users. Findings show that there is a mismatch between the type of nurses and the expectations of the service users. Some participants reported that:\u2018we still train a lot of nursing midwifery technicians than registered nurses and midwives. That\u2019s an issue of quality of nurses.\u2019 \u2018the country should target having registered nurses who are primary health care oriented because most users access health services at this level.\u2019 Participants noted that curricula should be formulated in accordance with the actual health needs of the users.Participants reported:\u2018Our country needs nurses and midwives who are deliberately trained for the rural areas. Nurses who will serve the neglected communities.\u2019 \u2018as a country we have not embraced interprofessional training of health workers yet. We need training programs that will foster inter-professional approach to healthcare problems and demands.\u2019 Findings have shown that nursing education contributes substantially to the reduction of the healthcare workforce shortage. Some extracts from panel discussion include:\u2018our nursing programs no longer produce nurses whom the healthcare delivery system could rely on to deal with the challenges among our communities.\u2019 \u2018\u2026 there are too few nurses to serve the increasing number of patients in the health centres and health posts in remote areas.\u2019 \u2018\u2026 the HSSP drives the agenda for all of us, be it education, practice or regulation.\u2019 Findings of the study show that there is a well-established system of regulation and accreditation of nursing education in Malawi. The nurses and midwives council ensures that all nursing programmes being offered in the country are approved and accredited. Participants urged therefore that the nurses and midwives council should therefore be well conversant with the nursing care needs of the service users. Participants highlighted the importance of strategic leadership with the regulatory body in order to increase the number of competent nurses and midwives.Participants highlighted that:\u2018nurses and midwives council prescribes curricula content for nursing programs. It should be well informed of the healthcare needs in order to provide relevant nursing curricula.\u2019 Participants also noted that the nurses and midwives council regulates licensure of nursing personnel.\u2018nurses and midwives write licensure examination before they can practice in this country. How come then we talk about poor quality of nurses when they have been evaluated whether fit or not to practice.\u2019 \u2018we need to rethink how we want to regulate licensure systems for our nurses and midwives.\u2019 Participants highlighted that national standards of nursing education are key to ensure quality health services.\u2018\u2026 various nurses and midwives council standards help to keep nurse education in Malawi in good order.\u2019 \u2018\u2026 a joint evaluation exercise should be done with the Nurses Council to assess if programs have been formulated according to the needs of the national health system.\u2019 Findings of the study indicate that there is a growing number of students being enrolled in the training institutions. All participants concurred that there is overcrowding of students in the clinical area and this challenges clinical teaching of students. Some participants indicated:\u2018teaching students in classroom and clinical practice is a challenge now with increased student intakes. We need to find better ways of teaching these students.\u2019 \u2018\u2026 individualized teaching is more important now than ever. You need to ensure that each student\u2019s learning needs are met if you are to ensure quality students.\u2019 Findings of the study show that need for more space, infrastructure and resources cannot be ignored owing to the increasing number of students. Infrastructure and resources to support transformative methods are needed at both educational and practice institutions. Participants noted that in the absence of adequate infrastructure, distance learning is becoming an option in many countries to avert challenges with space owing to increasing number of students. Participants highlighted that:\u2018\u2026 massive investment is needed to provide educational institutions with adequate infrastructure and resources in order to accommodate changing number of students and need for innovative way of teaching them.\u2019 \u2018\u2026 we have increased the nursing intakes to the extent that we cannot accommodate or trace them in the clinical sites.\u2019 Participants of the study reported that there are problems with capacity among nursing faculty in terms of clinical competences. Participants noted that over time, faculty members lose their practice competences. Findings show that there should be deliberate continuous professional development for nurse educators. Participants highlighted that improving educational capacity through nursing faculty development could be one of the several strategies to address a complex human resource problem. Participants reported that:\u2018There should be deliberate effort to equip educational institutions with capacity to handle growing number of students and more importantly changing health care landscape.\u2019 \u2018\u2026 mutual collaboration among academic and practice staff increases their chance to share expertise thereby building each other\u2019s capacity.\u2019 Chinn and Jacobs  highlighThe model for improving quality, quantity and relevance of nursing education was created on assumptions derived from World Health Organization framework for transforming and scaling up health professionals\u2019 education and training (World Health Organization Transforming and up-scaling of nursing education should be responsive to the health needs of societies and ensure universal coverage.Teaching and learning process should prepare a graduate who is ready to address the health system\u2019s needs and demands.National, institutional and programme leadership commitment drives positive transformation when implemented using a collaborative and partnership approach.A nurse graduate who is competent, relevant to the needs of a society, builds a strong health system.The middle-range model presented in this article is aimed at guiding efforts to improve quality, quantity and relevance of nursing education in Malawi. This is a planning model and aims at providing guidance to planners to match strategies with situational determinants within the nursing education context. Planning models are developed to prevent the common practice of using one strategy to solve all problems. Although the model was developed in the Malawian context and within nursing education, it can be used in any country with similar nursing education context and in a variety of health professionals\u2019 education.Chinn and Kramer  stated tTransformative and scale-up of nursing education refers to a sustainable expansion and reform to increase quantity, quality and relevance of health professionals (World Health Organization Curriculum reform is central to transform the quality and relevance of nursing education. The recent focus on competency-based curriculum calls for identification of critical nursing activities and general competencies (Ten Cate & Scheele Interprofessional education has been recognised worldwide as a key component in strengthening healthcare and overcoming practice challenges by teaching students the necessary skills to become part of the collaborative practice-ready health workforce (Thistlethwaite & Moran Regulation is one important strategic direction in the roadmap for scaling up health workforce. The function of regulation is to ensure that each individual has some level of understanding of accountability to his or her professional discipline. Regulation can be enforced at different levels. Institutions can be regulated through accreditation to ensure they meet expected standards to train nurses or for student practice in case of clinical institutions. Individuals are also regulated to ensure that they possess the relevant competences to be safe practitioners. Quality assurance in nursing is important for healthcare services users\u2019 safety. The regional professional regulatory framework for nursing and midwifery reported that efforts to improve nursing and midwifery tend to ignore regulation (World Health Organization With the growing number of students being recruited into nursing programmes, there should be innovations in methods of teaching and learning. In common instances, despite the growing number of students, the number of clinical practice sites have remained the same (Msiska, Smith & Fawcett Infrastructure and resources to support transformative methods are needed at both educational and practice institutions. In the absence of adequate infrastructure, distance learning is becoming an option in many countries to avert challenges with space owing to the increasing number of students Graber .Capacity building as a sub-concept spurs around three dimensions. Firstly, studies have reported that the productive capacity of training institutions in many sub-Saharan countries is low. Training institutions cannot recruit adequate number of students. Appiagyei et al.  highlighMandatory continuous professional development is needed for faculty (Breakey et al. Nursing education context in this model refers to the present situation in the country serving as an antecedent for developing a model that will enhance nursing education in the country in terms of quantity, quality and relevance.Malawi like many other sub-Saharan African countries still reports poor health indicators. Several factors have been attributed to the situation including inadequate financing of the health systems (Lu et al. The structure of the model shows that the need for transformation should overlap within all levels of strategic implementation. Transformation needs to take place at national, institutional and programme levels guided by policy and frameworks that define national agenda for health. The national health needs are central and provide policy direction.Political agenda and strategic direction refer to governments\u2019 and nursing education stakeholders\u2019 plans with regard to nursing education improvement, expansion or reforms. Malawi is a United Nations member state and it abides by conversations and protocols set by United Nations through its agencies to improve the well-being of humanity. The political agenda and strategic direction is propagated down the system from national, institutional to programme levels. The National Health Sector Strategic Plan 2011\u20132016 highlighted the importance of transforming nursing education. The main goal of the Government of Malawi is to have the highest possible level of health and quality of life for all Malawians. Institutions and programmes have to set their agenda to be responsive to the national goal. Lu et al.  noted thNational health policies, strategies and plans play an essential role in defining a country\u2019s vision, priorities, budgetary decisions and course of action for improving and maintaining the health of its people (Dahlgren & Whitehead Partnership refers to a deliberate arrangement between parties to cooperate to advance mutual interest. In this model, academic practice partnership is defined as a well-defined strategic relationship between educational and clinical practice settings in the area of practice, education and research. Student nurses generally rotate between blocks of theory and clinical practice. The model advocates for formal structured relationships towards achieving the country\u2019s health sector objective of health for all. The model is also built on the assumption that a health system consists of all organisations, people and actions whose primary interest is to promote health, in which collaboration is critical (World Health Organization The complexity of the healthcare environment demands collaboration between academia and practice setting in preparing an effective healthcare workforce (Frenk et al. Competency refers to the expected level of performance integrating knowledge, skills and attitudes. In the model, a competent graduate is one who demonstrates the ability to perform based on this expected level after training. Kajander-Unkuri et al.  identifiThe nature of the curricula and amount of time students engage in putting theory into practice determine competence levels of students (Rahmati et al. The poor rural communities are most often neglected (De Kock & Pillay Nursing workforce in this model refers to a system of qualified and licensed nurses that form part of the healthcare workforce. Malawi has nurse midwife technician and registered nurse cadres. Enrolled nurses are trained to a minimum of college diploma while registered nurses are trained from the level of university diploma or higher.Healthcare workforce is a key building block of health systems Essack . It affeThe model was evaluated in accordance with the criteria proposed by Fawcett  for modeThe study was conducted to guide implementation and evaluation of transformative and scale-up of nursing education in the local context of Malawi. Guidelines provided by key stakeholders like the World Health Organization remain relevant to the implementation of the model.For nursing education \u2013 The model has been developed to guide implementation and evaluation of strategies to improve the quality, quantity and relevance of nursing education.For research \u2013 More research is needed to explore the impact of specific strategies using the model through comparative studies between Malawi and other countries with a similar context.The design and assumptions of the model were discussed followed by a description of concepts and relationship among concepts. Nursing education transformation and scale-up should take place within a collaborative environment that fosters mutual strategic and operational planning within the framework of willing and committed leadership. Leadership cuts across approaches at national, institutional and programme levels among all nursing education stakeholders."}
+{"text": "Recently, Noorani  suggesteNoorani  opinion With these models in mind, some aspects of Noorani  opinion TIMER-RIDER model has several advantages. It explains normal and pathological behaviors in paradigms in which movement cancellation is required or not . The modThe author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Any density gradient for the isolation of nonmammalian organelles should ideally only expose the sedimenting biological particles to an increasing concentration of the gradient solute. Thus they will experience only an increasing density and viscosity, other parameters such as osmolality, pH, ionic strength and the concentration of important additives (such as EDTA and DTT) should remain as close to constant as possible. This Protocol Article describes the strategies for the dilution of OptiPrep\u2122 in order to prepare such solutions for organelles and membranes from nonmammalian sources such as yeast."}
+{"text": "Epilepsy in Sudan accounts for 1.6 annual mortality rates and 238.7 disability adjusted life years per 100 000. These figures are higher among females; children and young adults. It is associated with notable stigma and social burdens. Patients of epilepsy are subjected to various forms of social discrimination that affect their quality of life. They are isolated, neglected and deprived of their education and employments rights and not able to achieve normal social and family life. Aiming at highlighting social implications of epilepsy among Sudanese patients, this study found that social encumbrances due to epilepsy in Sudan are more prevalent among highly vulnerable groups like women, children and poor populations living in remote areas. Lack of trained medical personnel in neurology and the medical equipment's required for proper diagnosis and treatment of epilepsy in Sudan are key reasons aggravating social and health burden of epilepsy both among patients and their caregivers. Epilepsy is a chronic disease characterized by episodes of seizures that may vary from brief undetectable to long periods of vigorous shaking and could be accompanied by physical injuries like bone fractures . Eighty Epilepsy in Sudan is associated with notable stigma, social burden and generally affects the quality of life of patients . SubjectEpilepsy also affects the health services, inequality and the treatment gap. A simple definition of treatment gap in epilepsy is the number of people with a condition or disease who need treatment for it but do not get it. In the developing world, this gab is either arising from difficulty in accessing biomedical services or lack of adherence to anti-epileptic drugs . In SudaIn the other hand the marked impact in the education, employment and daily life activities is attributable to lack of education and awareness raising programs about epilepsy any of which Sudan lacks to help incorporate these patients into their social roles. In addition to health services centralization in metropolitan areas, depriving remote areas inhabitants from their goods. The findings of Women and children marked impediment by the diseases are consistent with similar results reporting lower parameters for quality of life in same social groups in Nigeria and Egypt . They reThe authors declare no competing interests."}
+{"text": "The VA Geriatric Scholars Program is a workforce development program to integrate geriatrics into primary care in all VA clinics. The program has increased career satisfaction among clinicians, improved quality of care for aging Veterans, changed provider prescribing behaviors and improved patient outcomes. The core curriculum is an intensive course in geriatrics, an intensive workshop in quality improvement (QI) and a micro QI project to demonstrate application of new knowledge to local needs of patients and clinic processes; this is a longitudinal program and alumni continue to develop skills over time through a series of elective activities that tailor learning to self-identified gaps in career development and training. The program is a collaboration among the Geriatric Research Education and Clinical Centers (GRECC), centers of excellence that have been leveraged to create a network of expertise and creativity to develop the core and elective educational activities. This symposium focuses on recent outcomes of three educational components that improve quality of care for older Veterans. The Palo Alto GRECC developed an intensive course in gerontological psychology to enhance the skills and competencies of psychologists leading to greater job effectiveness. The Bronx GRECC developed an interdisciplinary training program for all clinical and non-clinical staff in rural clinics, leading to improved recognition of functional and safety concerns among older veterans. The Tennessee Valley GRECC developed the core QI component and many of these micro-QI projects have been sustained, spread or recognized by VA as Promising Practices."}
+{"text": "Although more than 300 different techniques for hypospadias repair do exist, successful outcome depends mainly on the surgeon's skills, availability of adequate tissue for urethral reconstruction and choice of the best suitable technique in each case. Significant advancements in the management of hypospadias occurred over the last few decades but there remains great controversy on how to select the best technical options . The genWe acknowledge that such proposal lacks evidence support but it is an objective and consistent measurement that may be useful to surgeons deciding to graft or not the incised plate.TA has come up with the suggested UPR ratio. JP has validated the point and both wrote this manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The updated American Heart Association (AHA)/American Stroke Association (ASA) Guidelines for the Early Management of Patients with Acute Ischemic Stroke were published in January 2018.Debate with regard to deciding the optimal diagnostic and treatment strategy for patients is healthy and anticipated with the release of new medical literature or recommendations. However, what is somewhat puzzling and unanticipated with the release of these new guidelines is that within two months of their release the AHA/ASA rescinded its recently released guidelines, publishing a \u201ccorrection\u201d in which several parts of the document have been deleted. The American Heart Association (AHA)/American Stroke Association (ASA) has released a correction to its \u201c2018 Guidelines for the Early Management of Patients with Acute Ischemic Stroke: A Guideline for Healthcare Professionals from the American Heart Association/American Stroke Association.\u201dAlthough the correction document reports continued support for the corrected version of the guidelines and its support for clinical decision-making, the rescinding of sections of the guidelines was done without the agreement of the Guideline Writing Committee.3Although with several new recommendations, there are a few new updates that bear particular relevance to emergency healthcare providers working in the prehospital and emergency department setting. One of the updates purported to have a significant impact on the initial evaluation and management of patients with suspected acute ischemic stroke is the window of time to perform endovascular thrombectomy, being increased to up to 24 hours in carefully selected patients. These recommendations are based on the results from the DAWN and DEFUSE 3 trials, which evaluated the effectiveness of endovascular therapy (thrombectomy) plus standard care vs. standard care alone in patients with large vessel occlusion acute ischemic stroke who had last been known to be well 6 to 24 hours (24 for DAWN and 16 hours for DEFUSE 3 studies) earlier with specific findings on advanced neuroimaging.5The extension of the window of thrombectomy for ischemic stroke patients up to 24 hours is particularly significant as this new extended window can increase the proportion of patients who may benefit from this intervention. Noting that the inclusion criteria is selective and only a subset of the acute ischemic stroke population will benefit, this extended therapeutic window for this intervention has tremendous implications for the prehospital care environment where systems are designed to transport patients to healthcare facilities that can optimize the likelihood of positive patient outcomes. Regionalization of diagnosis-specific care through specialty centers and transporting patients to those centers equipped with the human and capital resources to achieve optimal patient outcomes takes a tremendous amount of time, energy, effort, planning, and resources at the organizational level of any emergency medical services (EMS) system. These changes also have implications for protocols and procedures at the hospital and provider level. This may be one of the reasons why so much consternation over the new recommendation commenting on bypassing intravenous (IV) alteplase-capable hospitals to transport to a higher level of stroke care may have been deleted. Specifically, Section 1.3 EMS Systems, recommendation 4 stated that when several IV alteplase-capable hospital options exist within a defined geographic region, the benefit of bypassing the closest to bring the patient to one that offers a higher level of stroke care, including mechanical thrombectomy, is uncertain.2 target 30\u201334 millimeters of mercury) for patients with acute severe neurological decline from brain swelling as a bridge to more definitive therapy.The use of telemedicine evaluation of acute ischemic stroke patients is also a new recommendation that supports a service to assist community physicians who do not have access to on-site neurological services. Telemedicine allows physicians and patients in resource-poor  communities to benefit from the expertise of a neurology consultation via live audio/video communication or simply by phone. The recommendations report that the administration of IV alteplase guided by telestroke consultation for patients with acute ischemic stroke may be as safe and beneficial as that of stroke centers.The AHA/ASA has released a correction to the 2018 Guidelines for the Early Management of Patients with Acute Ischemic Stroke: A Guideline for Healthcare Professionals from the American Heart Association/American Stroke Association since its initial online publication in January 2018."}
+{"text": "Background: Most previous studies consider advance directives as one single outcome, which conceals possible variations of individuals\u2019 decisions on two different advance directives documents\u2013living will (LW) and durable power of attorney for healthcare (PA). To advance the knowledge on advance planning among older adults in the US, this study examined how health status and education are associated with completions of LW and PA and whether such associations vary by age and race. Methods: Data are from the 2016 wave of Health and Retirement Study. Health status was indicated by chronic condition and ADL and IADL functional limitations. Logistic regression model was used to examine how the completions of LW and PA are associated with health and education variables respectively. Interaction terms were created to test the moderating effects of race and age. Results: The analysis results show that older adults with higher IADL functional limitation and more education were more likely to complete completing PA or LW. Being white and higher age will increase the probability for an older adult to complete PA, whereas the older adults with heart problem were more likely to complete LW. The association between IADL/ADL and PA was stronger in white than other racial groups, and the association between IADL and LW was stronger in young-old than the oldest-old. Conclusion: The findings highlight the importance of examining the completions of two advance directive documents respectively and indicate the necessity of developing distinct and concrete strategies to promote the completions of PA and LW."}
+{"text": "Ever since mandatory long-term care insurance was introduced in Germany there has been concern about staffing of nursing homes. As attempts to introduce the Canadian PLAISIR system failed today staffing ratios between federal states differ by more than 20 % and perceived understaffing is a major reason for the lack of nurses. Against this background the reform act from December 2015 commissioned the development of a new instrument to identify necessary staffing ratios. The University of Bremen was mandated to develop this instrument, and will present the final product in August 2019 to the Commissioner. The contribution will describe the methods applied in developing the instrument and the resulting instrument itself which translates the number and characteristics of any given nursing home into staffing requirements according to certain degrees of qualification, thus replacing general quotas of registered nurses to auxiliary staff by individual ratios for each nursing home."}
+{"text": "Colombia has the highest level of income inequality among Latin American countries, which likely translates into disparities in the aging experience. This study uses data on adults ages 60 and older from the 2017 National Survey of Quality of Life to examine socioeconomic stratification in physical health and psychological well-being. Colombians are assigned to estratos that reflect their residential location as well as social and economic position. Compared to those in the lowest estrato, older adults in the middle and high estratos are less likely to report having sensory impairment or difficulty with daily activities. They are also 1-2 times more likely to report feeling happy and calm. Those in the highest estratos are less likely to report feeling worried. Results suggest there is tremendous variation in the aging experience across socioeconomic strata and that older adults in the lowest strata are particularly disadvantaged with respect to health and well-being."}
+{"text": "Concerns have been raised that the transplants performed in the local context at the time of procedures reported in this article  may haveDetails as to the donor sources and methods of obtaining informed consent from donors were not reported in , and wheThe authors state that no vulnerable populations were involved in their research and all organs were obtained voluntarily but did not provide ethics approval documentation or consent forms to support their claim or clarify whether organs had been procured from prisoners.The authors did not respond to inquiries about the availability of underlying data supporting this study.PLOS ONE Editors retract this article.Owing to the lack of documentation to demonstrate this study had prospective ethical approval, insufficient reporting, unresolved concerns around the source of transplanted organs and whether they included organs from prisoners, and in compliance with international ethical standards for organ/tissue donation and transplantation, the The corresponding author notified the journal that all authors disagree with the retraction. The other authors either could not be reached or did not respond directly."}
+{"text": "Jun Wang was not included as an author in the published article. The corrected Author Contributions Statement appears below:\u201cAT performed or assisted with all experiments and wrote the paper. AK performed the phase-separation characterization and helped write the paper. RA helped analyze data and edited the paper. NT helped analyze data and edited the paper. JW contributed to the initial concept of this work and assisted with experimental planning. JF oversaw all experiments and edited the paper.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "Althougact test . Surprisact test  reached The authors stated that their data may have potential implications in clinical practice of acutely ill patients. According to our results, critical care clinicians should be wary of basing decisions about conservative or liberal oxygen therapy on the available information from this meta-analysis  includinFurthermore, these results came from fragile and not statistically significant RCTs. Maybe it is time to add the FI and/or statistical significance of the considered outcome as criteria for the evaluation of the quality of evidence."}
+{"text": "This article examines the implementation of fish farming as an innovative and economic strategy for promoting food security and dietary diversities among vulnerable households in drought risk areas of Zimbabwe. The declining climatic conditions and lack of economic opportunities in Mwenezi district of Zimbabwe attracted the attention of three non-governmental organisations (NGOs) to implement fish farming as an innovative mechanism to stimulate food security and generate employment in the district. The article used a qualitative research approach that includes semi-structured interviews and secondary data. The purposive sampling technique was adopted to interview participants in Mwenezi district who were involved in fish farming to assess and explore the experiences and benefits they derive from such development projects. Results for the article revealed that fish farming was well embraced by local communities as it led to improvements in food security, household income and employment regeneration. The local government including traditional leadership (Chiefs and Headmen\u2019s) supported the NGO activities as they benefited local communities. The article concludes that although fish farming was instrumental in regenerating employment, some participants still fail to participate because of laziness and desire to maintain dependency syndrome. The article recommends the NGOs to launch awareness campaigns in rural communities and increase networking with the donor community which is fundamental in attracting sustainable funding. The government can also promote fish farming in vulnerable rural communities by providing funding and capacity building programmes. The theory is fundamental as it draws on the remembrance of ways and strategies which had been used over time to try and cope with challenges affecting the livelihoods of rural people in drought risk regions Lin . ResilieGupta, Bartley and Acosta  state thIn sub-Saharan Africa, fish farming has quickly gained momentum as an innovative and economic mechanism for generating employment and increasing household income. According to FAO , TanzaniAt the launch of Zimbabwe Fish Producer\u2019s Association (ZFPA) at Exhibition Park on 17 March, aquaculture or fish farming was integrated into agriculture as part of the livestock sub-sector. Fish farming was regarded as a livestock enterprise that has the potential to be developed into a full-fledged agricultural industry in Zimbabwe  and collect information from them  from this project is sold to local markets and some even exported beyond international boundaries. The article observes that the fish farming projects involve the farming of aquatic organisms, including fish, molluscs, crustaceans and aquatic plants. Fish farming as a poverty alleviation technique was very successful as food security and household income greatly improved. Kawarazuka  confirmeThe field officer interviewed remarked that:The day we launched the fisheries project many villagers became eager to join the fishing clubs within our project. The fisheries project was flooded since many people saw the benefits that were going to come out this project. Food security greatly improved as the produce (fish) was sold to the local markets and some exported at highly competitive prices. The project members were able to sustain their families and send their children to school. It can be deduced from this project that employment was created which improved the economic lives of the people in Mwenezi. However, a study by Brummett  shows thThe implementation of fish farming and other food security programmes in Mwenezi district was incapacitated by limited funding from the donor community. Findings reflected that donor agencies failed to adequately fund local NGOs which results in the selective implementation of fish farming projects as some communities were left marginalised. The challenges emanated from the high level bureaucracy in the donor community which requires strong accountability to boards of directors and government ministries that release funding.One participant states:Fish farming is a good poverty alleviation programme which is helping us in our villages. But ever since we joined the programme, we do not have adequate funding as the NGOs are running many fish farming projects resulting in us being underfunded. We appeal to the government and well-wishers to assist with funding to buy more materials and vehicles to transport our produce to nearby markets. Based on the financial challenges to fund fish farming, there is a need for NGOs to network and foster relations with other business people and financial institutions which can fund development programmes.The three NGOs under study admit to the shortage of financial resources which affect them in conducting Monitoring and Evaluation (M&E) on fish farming projects. The article affirms that M&E was regarded as an expensive exercise that required excessive funding to undertake; hence, the three organisations chose to ignore it on grounds of poor revenue base. The findings revealed that the shortage of funds hindered the NGOs from hiring external evaluators that could have bankrupted their already bleeding accounts. The findings highlighted on the shortage of technology (i.e. computers) and technical expertise among NGOs\u2019 employees which could have posed serious challenges in implementing M&E strategies. The participants from all NGOs openly state that many NGO staff members were technologically inefficient which shows weaknesses in managerial leadership or. Based on these scenarios the NGO top management was supposed to initiate training programmes which help to equip their staff with the necessary skills to cope with the trends in the economic and technological environment. A study by Belton and Little  endorsedThe success of NGOs in Zimbabwe rests on their ability to earn legitimacy with the people and government. The article revealed that legitimacy and political interference from government have been two major setbacks affecting fisheries and food security projects in Mwenezi district. NGOs indulging in fish farming projects are required to seek approval from traditional leadership  and local municipality which often derails this poverty reduction strategy.One NGO Programme Officer states that:Before we started fish farming projects we sought permission from the Council and Local Leaders to hold community meetings with the people. The reason was to earn legitimacy so that local people can understand and believe in our mission. We had to wait for some days whilst our application was being processed. The long period of waiting disappoint some communities who were waiting for the fish farming projects to start. These findings augur well with a ban imposed on NGOs in Masvingo province in 2013 by the Provincial Governor who accused them of being Western Imperialists who are driving an anti-government agenda under the mask of development aid The above assertions clearly show that participants embraced fish farming which was fundamental for employment creation, improving food security and household income to meet basic needs. Findings reflected further that NGOs in Mwenezi undertook an active role in mitigating high poverty levels in the district although there is a need to instil a sense of complete ownership among community members so that full participation is achieved for sustainable development.The success of any viable entrepreneurial venture rests on the availability of markets to export the produce. The article establishes that the lack of market opportunities and low cash injections hindered fish farming in Mwenezi district. The growing competition of fish farming in Zimbabwe saw markets becoming flooded owing to the decline in the economy, and so the businesses are fast losing their profits. The shortage of ready markets led to fish farmers selling fish to local neighbourhoods and businesses at a relatively low price because of unavailability of the external markets. Failure to obtain ready markets constrained fish farmers to expand into a more commercialised business; hence, they remain small at subsistence level. The majority of participants pointed to the lack of credit facilities to finance labour and technologies as NGOs often took time to provide the needed equipment to use in fish farming projects.One of the participants laments:After harvesting fish we face challenges in terms of transport and markets to sell our produce. The local businesses and growth points what are our main target are always full since the competition is very high in our district. We end up selling our fish to individuals such as teachers, business owners at low prices which is discouraging since fish farming is hard work and we sometimes get little. We do not have enough knowledge about where to sell our fish as other towns are very far and we do not have enough money to hire trucks to transport the fish to other big towns. The reason is that the participants who are of rural origin lack collateral security to solicit loans from local banks such as Agricultural Bank (AGRIBANK). The lack of borrowing power often exposes rural people to donor dependency syndrome. This limited access to markets was acknowledged in a study by Wetengere  where fiThe trends in the technological environment globally require organisations to adopt and cope with a wave of transformation which can improve the viability and profit margins of a business. The participants cited the limited technology application in the fish farming projects. This reduces the opportunity of fish farming to flourish into a more commercialised sector. On the issues of technology usage in fish farming, the participants lacked proper storage facilities, hatchery and improved fish feeds among others. The article points out further that fish farming in Mwenezi district has shown the need for extension services; however, there is inadequacy or non-viability of the extension services to disseminate information on the proper use of medicines, suitable fish farming technology and good management practises for fish farming. Research by Adinya, Offem and Ikpi  supportsAccording to Myer , ethics The findings of the article show that NGOs in Mwenezi district have been playing a vital role in fish farming projects that were regenerating employment and increasing household income and food security. Nonetheless, limited technological application hinders the transformation of fish farming into a more commercialised income generating venture. NGOs are often regarded as the third sector in the economy of the country and have been advancing several innovations and new models that have been adopted by various stakeholders in developmental circles. Because of their generally flexible organisational structures and characteristics such as organisational autonomy and participatory structures, NGOs have added value to fish farming projects in Mwenezi district as they have abundant time to engage relevant stakeholders such as community members to discuss and teach them the nature and way to self-sustain in the drought risk district. Therefore, fish farming as an innovative mechanism for improving food security in the drought stricken district led to socio-economic improvements in most rural areas under study. Nevertheless, NGOs need to improve their managerial capacities to achieve effective food security and employment creation among vulnerable households in Mwenezi district.The article observes that the implementation of fish farming projects by three NGOs in Mwenezi district has been widely embraced as it helped reduce the dependency syndrome among rural communities by generating employment for sustainable food security. Various factors such as poor infrastructure, limited market opportunities, shortage of finance, lack of research training extension, M&E and legitimacy affect the NGOs in the district. However, the study has shown a positive relationship between employment regeneration and improved food security through fish farming. As a drought prone area, fish farmers in Mwenezi district have since improved their household income; hence, fish farming can be regarded as an innovative and economic mechanism for transforming rural livelihoods.The study faced various challenges ranging from the remoteness of the study area, time constraints and limited financial resources as it involves traveling to fish farming projects within the district. The other main constraint was the reluctance by other participants to respond to interview questions. To mitigate these challenges, some friends and family assisted with funding to be able to finish this study.Based on the conclusions drawn from this article, NGOs need to improve on their research culture to widen the scope of fish farming, for instance implementing cage fish farming which is easy to manage. Public-Private Partnerships (PPPs) are vital for NGOs to subsidise fish farming and offer incentives to feed production and processing industries as fish farming as an economic sub-sector improves food security, nutrition and creates employment. The government needs to support fish farmers with access to credit facilities to finance aquaculture projects. NGOs need to provide skills training on fish farming to rural communities to bridge the technology skills gap. The contribution of fish farming to the economy of Zimbabwe needs to be embraced by including it the national budget as a viable poverty alleviation technique."}
+{"text": "This paper explores the associations of depressive symptoms with social supports and social networks among dementia caregivers. It has been well documented that dementia caregivers are at greater risk of experiencing negative mental health and poorer physical health than non-caregivers. This paper describes a collaborative process between two universities and a community-based provider in designing a Social Network Analyses to examine the network structures used by dementia caregivers participating in a community-based support program. The relationship between the caregiver support networks and depressive symptoms, were analyzed using multivariate regression models. Given the small sample size and missing data multiple imputation was applied to the data. The findings suggest the effects of a variety of supports in the caregiver network on mental health and depressive symptoms. Among the findings it was found that the presence of financial support  and frequency of contacts  support resulted in a decrease in depressive symptoms and better mental health than for caregivers without similar supports in their networks. This paper will conclude with a discussion of potential uses of social network analysis to better understand how the structure of caregivers\u2019 network can address the concrete physical, emotional and financial needs of dementia caregivers."}
+{"text": "Nature and Science ran completely different news line-ups this week. But their lead stories agreed on one thing: patients matter. Nature led with a story about a group of patients who will share in a patent after giving blood and tissue samples to scientists. Science chose to lead with the controversial World Medical Association decision to recommend restricting the use of placebos in certain clinical trials."}
+{"text": "The number of people above 60 years old will double by 2050. There is a considerate variability in the health status of older people. The identification of the different trajectories that people follow as they grow older constitutes one of the aims of the ATHLOS project. In the current study, we created a metric of health in the four available waves  of the Mexican Health and Aging Study (MHAS) by employing Bayesian multilevel Item Response Theory. Growth mixture modelling indicated that older Mexicans  age by following four distinct pathways . Adherence to healthy lifestyle behaviours  was associated with better health trajectories. Preliminary analyses in the ATHLOS harmonised dataset also suggest that older people age by following four distinct pathways. The impact of lifestyle behaviours within the harmonised dataset will be investigated and also presented."}
+{"text": "Animals have evolved a dramatic diversity of aging rates with lifespans ranging from 2 years to 200 years. This natural diversity of lifespan can be exploited to understand the mechanisms of longevity and develop anti-aging interventions. Our goal is to identify mechanisms that allow such exceptionally long-lived animals to live long and healthy lives and then use these mechanisms to benefit human health. Naked mole rat is the longest-lived rodent with the maximum lifespan of 32 years. We discovered that the mechanism of longevity and cancer resistance in the naked mole rat mediated by high molecular weight hyaluronan. I will discuss the mouse model we generated that mimics the naked mole rat and shows increased healthspan and lifespan. I will also the role of SIRT6 in mediating longevity across mammals and in human centenarians by improving DNA repair and silencing transposable elements."}
+{"text": "Most academic institutions welcome partnerships with industry and state government. These collaborations can lead to interventions to create social and environmental changes on a broad scale. Along with the opportunities, some challenges are inherent with these working relationships. The Kansas State University Center on Aging and the Kansas Department for Aging and Disability Services has been working together for more than 15 years on the Promoting Excellent Alternatives for Kansas nursing homes (PEAK) program. This collaboration has led to beneficial changes for nursing home residents and provided fertile ground for researchers wanting to examine these environments. This symposium will offer researcher insights as well as to elucidate process and procedures related to developing and maintaining collaborations with a state agency."}
+{"text": "This symposium addresses the issue of extended working life policy by considering the influence of gender and health on the experiences of older workers. In response to population ageing, policies designed to extend working life have been introduced in many countries. These policies include raising state pension age and linking the amount of state pensions more closely to years spent in paid employment. Such policies tend to be undifferentiated by gender or health status \u2013 in most countries, state pension age has been raised to the same age for men and women. Yet, research evidence indicates that women in all countries are disadvantaged in relation to employment at older ages and pensions. There are also health inequalities for older workers, depending on their occupation and whether they are in precarious or secure employment. Extended working life is of pressing societal concern. This symposium brings together the work of a group of leading international scholars who have been researching and reflecting on its implications in a forthcoming book on the topic across 34 countries. The symposium begins with an overview and analysis of the empirical landscape of older employment and pension policy by Martina Rasticova and Jim Ogg; Paper 2 offers a discussion of the theoretical perspectives and policy debates across 34 countries by Clary Krekula; there will be an analysis of extended working life policy in Ireland by Aine Ni Leime and a final presentation synthesising policy recommendations and mapping future research directions in extended working life by Debra Street."}
+{"text": "Materials [The authors have found two errors in the paper published in aterials . The errThe authors wish to make the following corrections (in both formulas of the paragraph) to this paper:\u201cIn the two-dimensional space, the maximal packing density for identical circles is given by These changes have no material impact on the conclusions of the paper. The authors would like to apologize for any inconvenience caused to the readers by these changes."}
+{"text": "Frontiers in Chemistry features papers that utilize phenolic compounds such as catechols for designing functional coatings and materials. Recently, scientists worldwide have incorporated catechols and various phenolic compounds in designing advanced and multifunctional materials with unique properties  , on the polymerization process of dopamine to form a polydopamine coating. HMDA promoted intermolecular crosslinking between the oxidized form of catechol and subsequently promoted film deposition. This article further confirmed the use of resorcinol as an inhibitor to polydopamine formation.The formation of polydopamine coatings involves the autoxidation and crosslinking of dopamine to form an adhesive primer for additional surface functionalization  when the coating was hydrated in an aqueous solution. H2O2 is generated as a byproduct during catechol autoxidation  and coated onto various elastomers commonly used to fabricate urethral catheters. The coating significantly lowered the friction coefficient of the elastomers. Additionally, incorporation of silver nanoparticles into the coating enhanced the antimicrobial property of the coating.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In medicine, we still cannot objectively assess who will recover from health stressors imposed by disease or its treatment. If resilience, the dynamic ability to respond to and recover from health stressors, is considered as an emergent feature of a complex system, then methodology from complexity science may help us quantify the health-promoting features that support the recovery process. This presentation describes ongoing work aimed at empirically testing the concept and predictive value of resilience by examining the extent to which small-scale responses of bodily systems  to natural (micro)perturbations and indicators of loss of complexity are related to physical functioning and recovery throughout the journey of 120 geriatric inpatients. Dynamic indicators of resilience  and multiscale entropy measures were estimated from continuous heart rate and accelerometer data and compared to measures of patients\u2019 physical functioning  at admission, discharge and 3 months later."}
+{"text": "The authors of the paper originally entitled \"Sources of Information and Behavioral Patterns in Online Health Forums: Qualitative Study\" :e10) wish to correct the title of their publication. The subtitle \"Qualitative Study\" is misleading because the analysis was primarily quantitative. The title has now been changed to read \"Sources of Information and Behavioral Patterns in Online Health Forums: Observational Study\". This error has been corrected in the online version of the paper on the JMIR website on January 31, 2014, together with publishing this correction notice. There are no changes to the contents of the paper. A correction notice has been sent to PubMed.\u00a0This was done before submission to Pubmed Central and other full-text repositories."}
+{"text": "Despite global trends in rural population ageing, relatively little attention within research and policy has been directed to understanding what it means for rural people, communities and institutions to be at the forefront of twenty-first century demographic change. To build understanding of rural ageing, this symposium draws together papers from four countries to provide insights in the gaps in rural ageing research \u2013 specifically the in context of productive and active rural ageing by examining rural work, retirement and volunteering through the critical perspectives of citizenship, contestation and complexity. Winterton and Warburton will explore how active citizenship trends among rural older adults support or hinder the capacity of rural settings to support health ageing. Colibaba and Skinner will discuss the contestation of rural ageing by examining a volunteer-based rural library and the emergent \u2018contested spaces of older voluntarism\u2019 whereby older volunteer negotiate their rights and responsibilities associated with ageing and volunteering in rural communities. Duvvury and Ni Leime will examine the interactions between the twin phenomena of feminisation of agriculture and the feminisation of ageing in the consequent implications for rural women\u2019s work and retirement. Skinner and Joseph offer a critical perspective on voluntarism in ageing rural communities by examining volunteer leadership biographies as another means of understanding the contribution of older rural adults."}
+{"text": "Impact Factor (IF) of academic journals continues to gain further importance with not only science community but also academic institutions, funding agencies as well as the Editors of academic journals the world over with every passing day. Despite lot of criticism IF has attracted over the last decade in particular and lot of drawbacks, it is still considered as the best available Scientometrics to judge the standard of an academic journal.It may be mentioned here that Impact Factor is a citation based metrics based on the average number of times an article published in a particular journal has been cited by authors in other journals.ISI has about 34,171 journals published in academic disciplines which includes 12,271 journals covering medical and social sciences.4Faced with this new situation the Editors and Publishers have started using different strategies to increase their Impact Factor i.e by refusing to publish supplements, encouraging authors and reviewers to cite papers published in their journals. Ensure early publication of papers which are likely to be cited early in the year and making the papers electronically accessible through their websites as early as possible.8San Francisco Declaration on Research Assessment (DORA) issued in December 2012 during the American Society of Biology meeting was considered almost a fatal blow to Impact Factor. DORA emphasized to stop the use of \u201cJournal Impact Factor\u201d in judging the scientists\u2019 work.13The increasing importance of Impact Factor is evident from the fact that many publishers and Editors who fail to get indexed by Web of Sciences feel proud to decorate the title of their journals with various fake Impact Factors. Some of these commonly known fake IF include the following:The twelve academic journals from Pakistan which includes three medical journals which enjoy Impact Factor are shown in Table-IIWhile the editors should concentrate on improving the quality of the manuscripts they accept for publication and accelerate their efforts to improve the standard of the journal, manipulating and artificially boosting their Impact Factor is highly unethical. They should follow author friendly policy, help and guide them to improve their manuscripts with the help of members of the editorial board and peer reviewers. It is nice for the editors to know their rights but they must also remember their duties and responsibilities which include teaching and training through workshops. Many journal editors and bodies of Editors including World Association of Medical Editors (WAME), Eastern Mediterranean Association of Medical Editors (EMAME), Asia-Pacific Association of Medical Editors (APAME), Pakistan Association of Medical Editors (PAME) and editor\u2019s bodies in many other countries are already doing this by organizing workshops and these efforts should not only be continued but also accelerated in collaboration with other professional specialty organizations and medical institutions."}
+{"text": "Recruitment of African American (AA) participants into clinical research trials in the area of aging and dementia is a major problem facing the field. Although AAs are at a significantly elevated risk of developing Alzheimer\u2019s disease (AD), they are underrepresented in clinical trials and research studies. While previous research has identified a number of barriers to participation, relatively little is known about how to overcome these barriers and engage AA individuals in research. Photovoice may provide a novel approach to advance our understanding of AA perceptions in regards to barriers and strategies to increase AA engagement in brain aging research. The purpose of this project is to add to existing understanding of barriers and facilitators and identify strategies to enhance engagement. Three AA research advocates served as community facilitators to identify and guide groups of AA adults though an 8-10 session photovoice project. Group sessions involved discussions and sharing of images pertaining to various prompts in the area of brain health and research participation. Sessions were audio-taped and transcribed verbatim and photos were uploaded. Participants identified four categories of barriers to AA research participation: Mistrust, the belief that all research involves medication, avoidance and fear of acknowledging problems, and seeing the risks of research but not the need. Participants had various suggestions and approaches for ameliorating each of these barriers. This photovoice community engagement process revealed unique insights into barriers and opportunities for increasing AA engagement in brain aging research."}
+{"text": "In the original article, there was an error. The statement of written informed consent procedures was incorrect because of inappropriate wording.Materials and Methods, subsection Participant Selection, paragraph two:A correction has been made to the \u201cThis study was approved by the Ethical Committee of Tianjin Medical University General Hospital and written informed consent was obtained from all participants or their guardians.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "Almost 25% of US military veterans live in rural areas and over 70% of these are age 55 years or older. The physical, cognitive, and functional declines common to aging coupled with accumulated physical and psychological traumas often incurred through military service make caring for older Veterans an especially difficult challenge. Furthermore, the geographic distances associated with rural living pose a significant barrier to timely access to care for aging Veterans and caregivers living in remote communities. Significant gaps remain in VA\u2019s understanding of the needs of this population, which is essential for developing adequate models of care. This symposium highlights various aspects of the rural older Veteran experience and will suggest opportunities for improving access to care for this population. The first presentation estimates the differential impact of rural status on mortality rates among older Veterans using mortality data from the General Social Survey . A second study is an analysis of urban/rural differences in PTSD symptoms as function of multiple co-factors and accounting for geographic location . Seaman et al present qualitative data regarding the experience of Veterans with head and neck cancer to understand how rurality impacts cancer survival . The final presentation will highlight a model to address mental health problems in older Veterans in primary care  and will specifically highlight how this VA program may be adapted to address such needs the needs of older Veterans in rural areas."}
+{"text": "Bionic Radiologist is a concept that combines humanity and digitalization for better health care integration of radiology. At a practical level, this concept will achieve critical goals: (1) testing decisions being made scientifically on the basis of disease probabilities and patient preferences; (2) image analysis done consistently at any time and at any site; and (3) treatment suggestions that are closely linked to imaging results and are seamlessly integrated with other information. The Bionic Radiologist will thus help avoiding missed care opportunities, will provide continuous learning in the work process, and will also allow more time for radiologists\u2019 primary roles: interacting with patients and referring physicians. To achieve that potential, one has to cope with many implementation barriers at both the individual and institutional levels. These include: reluctance to delegate decision making, a possible decrease in image interpretation knowledge and the perception that patient safety and trust are at stake. To facilitate implementation of the Bionic Radiologist the following will be helpful: uncertainty quantifications for suggestions, shared decision making, changes in organizational culture and leadership style, maintained expertise through continuous learning systems for training, and role development of the involved experts. With the support of the Bionic Radiologist, disparities are reduced and the delivery of care is provided in a humane and personalized fashion.Radiology images and reports have long been digitalized. However, the potential of the more than 3.6 billion radiology examinations performed annually worldwide has largely gone unused in the effort to digitally transform health care. The  This provides the opportunity for greater involvement of radiologists in shared decisions making with patients, which in turn is a solution in itself to avoid poor work satisfaction,es Table .34 For instance, neural networks can be used to predict the probability of brain injuries in elderly patients presenting with head injury after a fall which may be used for guiding testing decision.38 Natural language processing of clinical information provided by referring physicians and demographic data can be used to predict the protocol and priority of brain MRI examinations.39 Clinical prediction models can provide probabilities for instance of pulmonary embolism which has shown to improve the yield of imaging and avoid imaging in those not needing it.40 It is also know that patients with stable chest pain and low-to-intermediate clinical probability of coronary artery disease (7\u201367%) benefit most from coronary CT angiography.41 This information can readily be integrated into decision making about further testing in patients presenting with chest pain. An important barrier to implementation of such decision support systems in clinical practice is the hesitation of physicians to refrain from diagnostic testing in patients who are actually suggested to not need further imaging tests.42 Another practical challenge is that the half-life of clinical data for training decision support systems is just four months indicating that most recent data are needed and continuous updating is crucial.43There are already at present several examples for guiding decision making about imaging tests with the help of other clinical information for instance from the medical records or laboratory tests.15 The potential of this becomes clear when noting that present-day artificial neural networks are as accurate as radiologists in detecting breast cancer on a mammogram.44 However, there are also more false positive findings using current deep learning image analysis techniques for instance for detection of critical findings in head CT,45 which may lead to radiologists\u2019 fatigue posing a safety risk and should thus be avoided using better technology. The Bionic Radiologist as a combined approach to leverage both the consistency of automatic analysis and individual nuances of human image analysis would possibly have greater value for clinical practice. This however implies considerable changes in the work flow and will require a revolutionary shift in how radiology is practiced today: data science and artificial intelligence will be practically and physically integrated into the workplace of radiologists and interrelated functions. The Bionic Radiologist will be a radiologist supervising the results generated by machine learning algorithms and integrating them with other clinical data for the final interpretation.14 Interestingly, such a hybrid approach might also be most acceptable to patients according to a survey at Charit\u00e9 among 100 patients clinically referred to computed tomography; 85% preferred an analysis by radiologists and computers compared to either of them alone.A true augmented radiologists\u2019 image analysis by machine intelligence may increase consistency and avoid perception and interpretation errors when reviewing patients\u2019 radiology images.Bionic Radiologist approach would be similar to the situation in the airplane cockpit where the autoflight system is used most of the time, but for the situations in which human interaction cannot be replaced one prefers to have a pilot on board. Interestingly, the human pilot can better control for anomalies than the autopilot46 and shared control architecture should thus be considered for medical use. We also need to continue to advance the currently rather basic information technology infrastructure in health care so that it can integrate multifaceted information from all disciplines including radiology.47 This will allow radiologists more time for what should be their two primary roles in addition to interpreting images: talking empathetically to patients who are undergoing procedures and consulting with referring physicians. In general, this effect has potential to revitalize the patient-physician relationship. However, if the role shifts toward only supervising results generated by artificially intelligence a decrease in image perception and interpretation skills among physicians has to be expected to occur in the future. Expertise should thus be maintained through training that includes automated and individualized feedback systems to the human reader about his or her cases which is fed by patient events and outcomes  as well as efforts leading to more widespread use of quantitative imaging biomarkers such as the Quantitative Imaging Biomarkers Alliance (www.rsna.org/QIBA) and global health data sharing from pivotal clinical trials in radiology.75The 77 This can be addressed\u2014in analogy to the interplay between human pilot and autopilot\u2014by e.g. a greater role of humans in quality control and oversight of any treatment decisions before they are put into effect (Table 78 Job design and job development have to face the criteria which are related to such a role development and open mindset for new forms of human-computer collaboration.31Structured reporting will thus transform the culture of radiology reporting practice from prose text documents towards structured reports which have greater standardization and enable searchability. This requires acceptance on the human side for changes in the workplace which affect the culture of radiology as a clinical discipline. This includes overcoming the perception that patient safety and trust may be at stake if treatment recommendations are automatically generated by algorithms based on integration of imaging findings with other clinical information using computer-led systems.ct Table . This gr72 Similar electronic solutions are available for breast,79 coronary artery,80 and prostate imaging. There are also IT solutions that standardize radiology reports of abdominal aortic aneurysms and facilitate communication of results and patient follow-up.81 Importantly, natural language processing methods now allow to automatically extract and characterize the clinical significance of findings in radiology reports82 and convolutional neural networks have better accuracy for radiology text report classification than rule-based models,83 which holds potential to facilitate linking treatment recommendations with findings provided that a sufficient level of standardization is present in reports.73Several examples of structured reporting for improved linking of imaging findings with treatment suggestions exist. For instance, structured reporting of multiphasic CT of pancreatic cancer improves the completeness of reports while structured rectal cancer MR imaging reports reduce the need for further treatment planning consultations.Bionic Radiologist about whether or not to do an imaging test depends on a consistently obtained patient history and clinical background, clinical prediction rules, and models for decision making. To implement this integration of human and machine decision making in medical care requires uncertainty quantifications for decisions and predictions in order to obtain acceptance by the human radiologists. Integration of artificial and individual intelligence will also benefit from the digital transformation as a socio\u2013technical system with dynamics that balance interests on all sides.84 Using the opportunities of artificial intelligence for image analysis in clinical practice requires a seamless integration with human image analysis. This will also provide the radiologist with greater freedom for involvement in shared decision making with patients which will increase work satisfaction.85 This is in line with a recent survey of radiologists who expect an increase in the time spent with patients as a result of artificial intelligence implementations as well as a lower risk of imaging-related medical errors.86 Acceptance by human radiologists will be further increased by automated and individualized feedback systems to the human readers about outcomes of his or her patients and thus enhancement of the expert role. Bionic radiologists will use structured reports that include automatically generated reminders about imaging findings that require follow-up as well as treatment recommendations to avoid missed care opportunities and increase patient safety and trust of all stakeholders involved in health care by oversight of treatment decisions. The overall goal is to provide better integrated health care through the Bionic Radiologist combining digitalization with human input at all stages. Success in the implementation will ensure that advances in artificial intelligence and digital medicine benefit diagnostic management decisions by providing calculated disease probabilities to avoid disparities and provide humane and personalized health care universally. The implementation of the Bionic Radiologist depends on the interplay between the new technological potential, individual behavior and institutional organizational properties whether the positive outcome in terms of better decisions and medical care can be attained.88 The most critical influencing factors are summarized in Fig. Enabling better decisions by the Bionic Radiologists promises better outcomes and lower costs through better integration of diagnostic imaging in clinical care processes. In this perspective we outlined the characteristics and facilitating factors with respect to the technology development itself, the surrounding institutional conditions and resistance due to the required change in culture as well as the prerequisites for individual acceptance and adaptation (see Fig. The see Fig. . FurtherIt is an issue of future research to further analyze what the interaction between these fields can look like and what the specific characteristics of relevant variables are for gaining better outcomes in terms of appropriateness, completeness, and timeliness. A longitudinal socio\u2013technical system analysis with time-series analysis of health care data which are related to the characteristics of the workplace is supposed to be a suitable approach. This also implies that medical technology research could and should be further aligned to organizational studies and that the question of trust in AI-assisted medical imaging should play a central role in future research."}
+{"text": "Empirical applications of cumulative dis/advantage primarily focus on accumulative processes within an individual life course as a mechanism generating growing intracohort inequality with age. However, adult health reflects the accumulation of exposures to advantages and disadvantages across the individual life course as well as the transmission of resources and practices across generations within one\u2019s family of origin, which forms the foundation from which children are launched and inequality is reproduced. In analyses using two panel studies , we integrate literature on the early-life origins of health with the concept of linked lives and the intergenerational transmission of resources to examine the relationship between parents\u2019 health and the health of their children in adulthood. Results indicate an intergenerational persistence in health and demonstrate the importance of looking beyond the individual life course to better understand cumulative dis/advantage in health as a process operating across generations within families."}
+{"text": "Vaccines. [The authors wish to make the following corrections to this paper due to a typesetting error in the conclusion of this article which was recently published in accines. . The conBifidobacterium breve) as an adjuvant therapy for the modulation of chemotherapy efficacy and toxicity has been reported [87].\u201cStudies that investigate the relationship between the intestinal microbiome and the development and function of the immune system continue to demonstrate novel concepts that increase knowledge-based concepts for disease treatment. Cancer immunotherapy is such an example where for more than a decade in the field of oncology, the objective to harness the patient\u2019s immune system to kill tumours has remained a key goal . Recent research strongly suggests and shows that the intestinal bacterial cohort can significantly facilitate the efficacy of checkpoint inhibitor immunotherapies in cancer treatments [83\u201386]. As a consequence of this research activity, the administration of probiotics  and autoimmune pathologies . There is hence a logical step established for the inclusion and administration of probiotic formulations in the treatment of cancers with immunotherapies [88] as well as an adjuvant for vaccines in early and late life.\u201dThe authors would like to apologize for any inconvenience caused to the readers by these changes."}
+{"text": "Dutch nutrient policy aims at reducing leaching of agricultural nutrients by internalizing the negative externalities associated with inefficient nutrient use. This is done by taxation of nitrogen and phosphate surpluses that exceed a hectare-based threshold of maximum-allowed surpluses. One management strategy farmers may use to reduce the nutrient surpluses on their farms is to improve the nutrient efficiency of the agricultural production process. This study employs Data Envelopment Analysis (DEA) to calculate nitrogen and phosphate efficiencies and an overall nutrient efficiency measure for a 3-year panel of 114 Dutch dairy farms. Subsequent analyses show the impact of both farm intensity and nutrient efficiency on the nitrogen and phosphate surpluses. It appears that farm intensity has a positive effect on efficiency, but efficiency and intensity exert opposite influences on nutrient surpluses. This is especially the case for nitrogen. The magnitude of a possible reduction of nitrogen surpluses through a strategy of efficiency improvement is therefore limited by the intensity of the farming system, unless the technology with which nutrients are used by the farming system can be further improved or input/output ratios will be altered."}
+{"text": "Data in Brief comprises the curated data and species overlaps in the mentioned prioritization schemes. It aims to facilitate further critical and extended analysis and to highlight the importance of record keeping and management of aquatic species in zoological institutions across the globe for the conservation of these species.The data presented in this article are related to the research article entitled \u201cAssessing the Conservation Potential of Fish and Corals in Aquariums Globally\u201d. This article unveils the number of fish and coral species held by members of the Species360 network, from records in the Zoological Information Management Systems (ZIMS). Furthermore, we provide data for species in ZIMS that are under the following global prioritization and conservation assessments: i) the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES), ii) the International Union for Conservation of Nature (IUCN) Red List of Threatened Species, iii) Vulnerability to Climate Change, iv) Evolutionary Distinct and Globally Endangered (EDGE) and v) the Alliance for Zero Extinction (AZE). The material in this  Specifications tableValue of the data\u2022This is the most comprehensive overlap of 3511 species of fish and corals with five global species conservation assessments and prioritization schemes. We aim to inform how many of the species in aquariums members of the Species360 global network registered in ZIMS align with those schemes.\u2022ex situ populations for species of conservation concern.These data will assist further research on \u2022These data could support the decision-making process of aquariums and zoological institutions on captive management and collection planning.\u2022The dataset may also assist in further assessments by identifying existing gaps and opportunities for conservation.1The data incorporates 3511 species in aquariums with five conservation assessments and prioritization schemes.2The creation of this dataset is based on an extensive analysis of six online datasets: i) species holdings from the Species360\u05f3s Zoological Information Management System (ZIMS) R package taxizemerge function from R. We identified the species currently managed in a studbook in the European Association of Zoos and Aquariums (EAZA) The species names were standardized according to the accepted scientific name in Catalogue of Life (CoL) In"}
+{"text": "Oryza sativa) was domesticated in Asia many thousands of years ago and more recently independently in Africa. Wild rice populations are found around the tropical world. The extensive production of rice in many areas has displaced the wild populations that were the basis of the original domestications by humans. Recent research, reviewed here, has identified wild rice species in northern Australia that have been isolated from the impact of domestication in Asia. Wild rice populations contain novel alleles that are a source of desirable traits such as erect habit, disease resistance, large grain size, and unique starch properties. These populations include the most divergent genotypes within the primary gene pool of rice and more distant wild relatives. Genome sequencing also suggests the presence of populations that are close relatives of domesticated rice. Hybrid populations that demonstrate mechanisms of ongoing evolution of wild Oryza have been identified in the wild. These populations provide options for both new domestications and utilization of novel alleles to improve or adapt domesticated rice using conventional or preferably new breeding technologies. Climate change and growing food demands associated with population and economic growth are major challenges for agriculture including rice production. The availability of diverse genetic resources to support crop adaptation and new crop domestication is critical to continued production, and increased efforts to support in situ and ex situ conservation of wild Oryza and related species are warranted.Rice is one of the most important food crops contributing to the diet of large numbers of people especially in Asia. Rice ( Oryza genus is distributed around the tropical world. Domesticated rice has been cultivated in many of the areas that would have been native habits for wild Oryza species. Australia is a region that has escaped from the impact of rice domestication until very recently resulting in the persistence of many extensive populations of wild Oryza  includes the two domesticated species and six wild relatives. The genus has 11 genome types with the AA, CC, and EE genomes types found in Australia. Other members of the Oryzeae tribe are also found in Australia . The indica and japonica types correspond to distinct chloroplast sequences in wild populations indicating capture of these in separate domestication events. The aus type was found to include individuals with either wild chloroplast types  in the domesticated rice gene pool , making Oryza species, Oryza officinalis, and Oryza australiensis and other species from within the tribe Oryzeae such as Potamophila  has been reported only in the extreme north of Australia on the mainland and on Moa Island in the Torres Strait. Collect of this species has not been reported recently, and the status of the Australian populations is uncertain. The author was unable to locate populations on Moa Island during a visit in 2016. This species is part of the CC genome group of Oryza species. Populations reported in Australia may not be permanently established and may be the result of occasional migration from Asia suggesting that the current presence of this species in Australia requires confirmation.O. australiensis .Potamophila parviflora; Zizania of North America than to Oryza. Cold adaptation and the presence of separate male and female flowers are potentially useful traits. This species grows just south of the border between Queensland and New South Wales but has not been reported in Queensland despite some searching by the author and others.River grass  is found throughout temperate Australia demonstrating adaptation to cooler climates. Attempts have been made to domesticate this species as a cool climate dryland rice crop. Mutagenesis  had high amylose contents and gelatinization temperatures. Pasting properties varied. Analysis of starch structure suggested the presence of shorter chain amylose in O. australiensis . Specific descriptors were developed for sensory evaluation of these rices. The Australian wild rice was similar to the red rice and red basmati having a mild aroma and flavor but without the lingering aftertaste. The wild rice had a firmer texture and required a longer cooking time. The overall cooking profiles, sensory, and physical attributes suggest and that Australian wild rice has potential for commercialization in the colored rice market and may be a useful genetic resource for rice breeding.Sensory evaluation of Australian wild rice has indicated acceptable eating qualities . AustralProduction of domesticated Asian rice in northern Australia has been limited by a high incidence of disease relative to rice production further south in Australia. The southern production areas have been well outside the natural range of rice and rice pathogens. Rice and associated rice pathogens  are natiThe wild populations are extensive in the extreme north but are threatened by developments including the improvements of roads and the resulting more rapid spread of invasive weeds into new areas, associated with increased traffic. Aquatic weeds are displacing wild populations at some locations including protected areas such as national parks. Greater awareness of the presence of these populations and their potential to contribute to global food security is necessary to ensure adequate measures are taken to protect the wild populations.The Australian landscapes in which rice is found in Australia have been inhabited by humans for a very long time. The way in which rice was used as food is not well documented. It is possible that human use has impacted on the genetics of wild rice populations in Australia. The large grain size of some Australian populations  might reOryza could be targeted for direct domestication as new rice types. The key trait to be overcome in domestication is probably shattering, with wild populations all demonstrating high shattering characteristics. The option of domestication needs to be considered along with the potential to source many genes for useful traits in these populations for transfer into domesticated rice. The traits that are most desirable are disease resistance, grain size, grain color, and grain quality (starch properties). The strategy of new domestication may be especially useful in developing rice varieties adapted to new climates with advancing or rapid climate change especially with the availability of extensive genomics resources for rice (In addition to their use in rice improvement, the Australian for rice .ex situ collections in seed banks need to be supplemented by much more extensive collections. The in situ conservation of these species would be aided by greater awareness of the populations and their importance and may involve efforts to control weeds invading the aquatic habitats of the wild Oryza. Revision of the taxonomy of the A genome species is suggested by the available molecular evidence. Clarification of the taxonomy may aid conservation efforts by ensuring efforts to conserve rarer populations, including suspected hybrid populations. The growing genomic resources for the Oryza genus (Wild rice populations in Australia include species at varying distances from domesticated rice. These provide a rich resource for use in rice improvement. Both novel alleles and novel traits might be sourced from the Australian wild genotypes. Increased efforts to conserve these genetic resources would be justified. The current very limited za genus  would beThis manuscript is the work of the author.The Australian Research Council provided support for much of the research reviewed here.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Concerns have been raised that the transplants performed in the local context at the time of procedures reported in this article  may haveInternational ethics standards call for transparency in organ donor and transplantation programs and clear informed consent procedures including considerations to ensure that donors are not subject to coercion. Details as to the donor sources and methods of obtaining informed consent from donors were not reported in . In respThe first author expressed that they stand by the results reported in this article but the individual-level data underlying the study\u2019s results are no longer available.PLOS ONE Editors retract this article.Owing to the lack of documentation to demonstrate this study had prospective ethical approval, insufficient reporting, unresolved concerns around the source of transplanted organs and whether they included organs from prisoners, and in compliance with international ethical standards for organ/tissue donation and transplantation, the The authors did not respond to express whether they agree with the retraction decision."}
+{"text": "How does the integrated and unified conscious experience arise from the vastly distributed activities of the nervous system? How is the information from the many cones of the retina bound with information coming from the cochlea to create the association of sounds with objects in visual space? In this perspective article, we assert a novel viewpoint on the \u201cbinding problem\u201d in which we explain a metastable operation of the brain and body that may provide insight into this problem. In our view which is a component of the Default Space Theory (DST), consciousness arises from a metastable synchronization of local computations into a global coherence by a framework of widespread slow and ultraslow oscillations coordinated by the thalamus. We reinforce a notion shared by some consciousness researchers such as Revonsuo and the Fingelkurts that a spatiotemporal matrix is the foundation of phenomenological experience and that this phenomenology is directly tied to bioelectric operations of the nervous system. Through the oscillatory binding system we describe, cognitive neuroscientists may be able to more accurately correlate bioelectric activity of the brain and body with the phenomenology of human experience. Phenomenology is the reflection on and analysis of the essential structure and form of conscious experience Husserl, . An undeThe Default Space Theory (DST; Jerath et al., There still exists a debate as to whether neural oscillations play a functional role in cognition and consciousness, if they arise simply as a epiphenomenal byproduct of spiking activity, or even if they interfere with normal processing (Koepsell et al., The binding problem is a considerable mystery in cognitive science which ponders how a unified experience could arise from the distributed and disparate activities of the nervous system (Revonsuo and Newman, The temporal binding model proposes neurons responding to identical sensory objects or scenes in space synchronize in the millisecond range while this synchronization does not exist between neurons representing separate objects in external space (Singer and Gray, In our perspective shared by a subset of consciousness researchers, the most fundamental aspect of human experience is a subconscious Damasio, , unifyinWe share the view that consciousness is an emergent phenomenon resulting from a functional representation or simulation of the external world and that the ontology of our phenomenological space-time is a direct replication of the dimensional nature of the physical universe Siegel, . This alWhile there is significant support for a phenomenological space-time coordinate matrix as a foundation of experience, not much research has been invested in how this is reflected neurophysiologically. Our novel interpretation of this bridge between the material and experiential may provide great insight into binding and multisensory integration. This interpretation includes the notion that this subconscious space-time matrix is isomorphic to an ongoing, global, dynamic architecture of harmonious oscillatory activity (Jerath and Beveridge, via synchronization. Other theories of consciousness have also correlated higher frequency activity with consciousness and lower frequency with unconsciousness such as the Dynamic Core Hypothesis (Murphy and Brown, We propose this underlying, global, operational structure provides a coherence mechanism for all sensory modalities to unify based upon their spatial coordinates in external space and may provide an explanation for baseline neural activity. Baseline activity was traditionally considered noise (Emadi et al., Our perspective that the global cognitive architecture consists of multiple oscillatory layers (Jerath and Crawford, According to most perspectives in phenomenology, qualia must have structure, composed of several experiential distinctions such as visual color, a location, or sound Husserl, . The lowvia spatial attention (Sasaki et al., via inter-hemispheric connectivity provide a more sound explanation (Corbetta, Synchrony of Alpha oscillations in addition may mediate the rise of these frameworks into conscious awareness via the base oscillatory layer ultra-slow oscillations responsible for the spatial coordinate matrix we have described. The integration is primarily accomplished by binding and entrainment through similarity in space and time (Molholm et al., via synchrony and filled into their respective phenomenological frameworks which are themselves filled into the 3D coordinate virtual matrix.Imagine yourself along a busy street while you attempt to cross. Auditory and visual stimuli from passing cars provide reciprocal information on passing cars allowing you to safely cross, however these distinct categories of information must be integrated and unified for effective perception of crossing safety. Research has shown that different sensory modalities are indeed spatially and temporally integrated so that different qualities belonging to the same object are registered in the same space and time (Treisman, The dynamic nature and functional importance of audiovisual integration is demonstrated in a pioneering study showing incongruent auditory-visual speech signals result in a fused speech percept (Mcgurk and Macdonald, Gamma band activity is shown to increase when auditory and visual signals are presented close in time (~25 ms; Senkowski et al., via corticothalamic connections (Tyll et al., In our view, the thalamus and the thalamocortical oscillations are additional key coordinators of oscillatory activity among the cortex and among the cortex and sensory receptors [our novel proposition (Jerath et al., In asserting our perspective on phenomenal space-time and its isomorphic bioelectric structure, we have endeavored to provide insight into the binding problem regarding multimodal integration. We have focused on audiovisual integration in this article to provide an important instance of how this underlying oscillatory structure may entrain and organize multisensory streams into a unified whole resulting in the integrated experience. We have put forth a hierarchical view on oscillatory cognitive frameworks which include a basal, unconscious virtual coordinate matrix characterized by slow oscillations and the subconscious sensory frameworks characterized largely by Alpha oscillations. The sensory frameworks are bound to the space-time framework upon which qualia are further bound represented by even higher frequency oscillations. This hierarchy is supported by research revealing functional baseline activity and the fact that slow oscillations underlie and entrain faster ones. By describing how the slow oscillations produce a virtual space-time matrix, we describe a means for disparate sensory modalities to be integrated. In addition to empirically identifying a global oscillatory framework underlying sensory frameworks, further research should investigate the role of different frequencies in multisensory integration.Theory developed by RJ with some writing with majority of the manuscript written by CB.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "This study by Lieber and colleagues published in 1975 is one of a few seminal articles written in the past 25 years that has made a critical impact on the subsequent direction of research conducted on the mechanism of alcoholic liver disease (ALD), which usually progresses from fatty liver to hepatitis (inflamed liver with dead liver tissue) to liver fibrosis (scarring liver) to cirrhosis (severe and irreversible scarring of the liver). To comprehend fully the significance of this article, it is helpful to have a good historical perspective on the controversy that dominated the field at the time it was published. At the center of the controversy was this question: Does alcohol itself or do other factors such as dietary deficiency cause ALD? Not only was this issue scientifically important, but it also had serious practical implications.Because patients with ALD often have accompanying malnutrition, deficiencies of key nutrients were thought to be a primary cause of this disease. This view was exemplified by the early studies of In their study, Lieber and colleagues fed a liquid diet containing alcohol that was originally developed for rats to a species related more closely to humans\u2014the baboon. The researchers chose baboons because an earlier study had shown that, as a result of their aversion to alcohol, rats fed this liquid diet derived no more than 36 percent of their total calories from alcohol and failed to reproduce liver disease beyond fatty liver. Lieber and colleagues hypothesized that baboons might overcome this limiting factor and consume enough alcohol to induce more advanced ALD. Indeed, their study demonstrated that the baboons\u2019 alcohol consumption reached 50 percent of their total calories, a percentage approximating the calorie amount that many human alcoholics derive from alcohol. In addition, these animals exhibited the sequential development of the whole spectrum of ALD, ranging from fatty liver and hepatitis to cirrhosis. Because the liquid diet was designed to provide adequate nutrition, the baboons\u2019 development of liver disease was interpreted as evidence supporting alcohol\u2019s causal role in the development of ALD.Epidemiological studies of alcoholic patients by Over the past two decades, Lieber and colleagues\u2019 findings indicating that alcohol is a primary causative agent for ALD inspired more aggressive studies on the biochemical basis for alcohol\u2019s injurious effects on the liver. As a result, several hypotheses emerged, all of which linked the chemical breakdown of alcohol  to the development of ALD. Alcohol metabolism generates harmful chemical products and byproducts  and creates deleterious metabolic and physiologic conditions that make the liver more susceptible to injury. Lieber continues to play a leadership role in much of this research.Lieber and colleagues\u2019 article described the first animal model for the spectrum of progressive and advanced ALD. The baboon model offered great potential for investigations examining the biochemistry, cell biology, and molecular biology of ALD. Further research by Lieber demonstrated the following:Fibrosis surrounding a vein in the middle of a small anatomical unit of the liver  signals the beginning of progressive alcoholic liver fibrosisTransformation of the liver cells that store vitamin A (hepatic stellate cells) to the cells involved in scarring (myofibroblasts) is the cellular basis of the development of alcoholic liver fibrosisThe role of acetaldehyde in stimulating production of fibrous proteins by hepatic stellate cellsThe effectiveness of using polyunsaturated lethicin  as a therapy in alcoholic liver cirrhosis.Most of these findings would not have been possible without the baboon model.Although the baboon model has produced an enormous volume of new information concerning the mechanism of ALD, this model has not been reproduced by others . The pos"}
+{"text": "Research in the field of embodied cognition is occupied with a variety of research questions stemming from the idea that cognition is deeply connected with bodily aspects such as perception and action  categorization in reference to the dimensions of embodied learning research that hinges upon the two dimensions bodily engagement and task integration. They define low levels of bodily engagement as tasks with only minor bodily movement that occurs while sitting (Skulmowski and Rey, incidental manipulations are said to be reliant on cues that alter cognitive variables while Skulmowski and Rey (integrated manipulations to be strongly intertwined with tasks.Skulmowski and Rey  presente and Rey  state inAlthough the taxonomy of Skulmowski and Rey  is mainlBesides embodiment studies that are focused on tasks, others revolve around metaphor-based effects and priming (Wilson and Golonka, Lakens  reviews Fay and Maner  recentlyIn addition, it should be noted that some types of measures are more appropriate for embodied cognition research than others (Meier et al., In light of the current controversy surrounding the replicability of psychological science, we wish to emphasize a variety of aspects that may warrant a higher sample size or other amendments to embodied cognition study designs. One method of assessment concerns the degree of bodily engagement and the extent to which an embodiment manipulation affects how a task can be solved as described by Skulmowski and Rey . AnotherAS and GDR drafted and revised the article and approved the submitted version for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The authors are testing the hypothesis that hybridization is more common between species that are sufficiently genetically similar so that they can cross, but also genetically distinct enough to prevent homoeologous chromosome pairing and multivalent formation during meiosis in offspring, which can lead to sterility or reduced fertility in the gametes  were employed for detection of hybridization. To provide a time frame for the evolutionary events, a molecular clock was calibrated using *Beast (Heled & Drummond, Artemisia.To assess genomic divergence and traces of hybridization, Leucanthemum are clearly more divergent among each other than those in Rhodanthemum. The data also showed that the diploid species of Leucantheumum carried more genomic signatures of past interspecific hybridization events than did those of Rhodanthemum. The importance of genetic divergence as a stimulus for hybridization had been proposed by Darlington (et\u00a0al., et\u00a0al., The data revealed that the diploid species of rlington , and it Leucanthemum hybridize so frequently? A map of present distribution of the genus reveals localization in many of the previous refugial areas in Europe during the Pleistocene. As Rhodanthemum southward in the Atlas mountains of Morocco would have been much less affected by Pleistocene climatic changes, and this, plus the lower genetic divergence among species, may explain the absence of polyploids in this lineage.The remaining question was why did the species of The important conclusion by"}
+{"text": "We read with interest the study by Liu and coworkers in which they have addressed the role of hemodynamics in the development of aortopathy in bicuspid aortic valve (BAV) patients  between BAV and TAV patients by using a new matric integrating the magnitude and angular distribution uniformity of the local WSS vector. We however do not completely agree with their suggested direct correlation between hemodynamics and aortopathy in BAV patients. As the main issue is that only a proportion of all BAV patients develop aortopathy, whereas Liu et al. performed calculations on a whole cohort.all BAV patients, it could not select those patients with an increased risk for aortic complications. In search of predictive factors for aortopathy, several studies have searched for serological and immunohistochemical factors  (Grewal et al., In search of rheologic markers, several studies revealed helical blood flow in BAV patients as compared to TAV patients, with eccentric outflow jet patterns disrupting laminar flow and flow impingement zones along the greater curvature of the ascending aorta (Girdauskas et al., Recent literature further focused on the hemodynamic influences for the different raphe positions in the BAV population. Normalized flow displacement is a reliable quantification of flow eccentricity as compared to systolic flow angle (Mahadevia et al., An obvious increase in \u03b1 smooth muscle actin positive VSMC was seen in the outer intima, whereas the inner media shows a significant decrease in expression of \u03b1 smooth muscle actin of the VSMCs (Grewal et al., We further observed a trend in transition of squamous endothelial cells in the non-jet specimen to more cuboidal endothelial cells in the jet specimen of both BAV and TAV patients. Although the 2D magnetic resonance is not appropriate to describe wall shear stress features as the flow is observed in a flat plane, we could correlate the maximum jet stream in the ascending aorta to the histopathological findings in the aortic specimen.The main limitation of the findings of the hemodynamic studies published till date is that the WSS is observed is all BAV patients. Whereas, 20\u201340% of BAV patients do not develop aortic complications, implicating that the development of aortopathy in BAV cannot be explained by hemodynamic influences alone. WSS, together with the intrinsically immature aortic media which is also seen in all BAV patients, increases the vulnerability of the ascending aorta (Grewal et al., Thus, with the currently available data, a hypothesis of WSS causing aortopathy in BAV patients is hardly sustainable without ruling out the contribution of additional genetic influences.NG: first draft of article; AG-dG: revision of article. All authors conception and design of the paper and contributed to manuscript revision, read and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The commentary by Luyck and colleagues on our paper provides many stimulating viewpoints and interpretations of our original study on dissociable responses in the amygdala and bed nucleus of the stria terminalis in threat processing. Here, we reply to some of the points raised and while agreeing with most of the comments also provide some alternative viewpoints. We end by putting forward a research agenda for how to further investigate the roles of these regions in threat processing, with an emphasis on studying their roles in defensive action. We thank Luyck et al.  for a thIn our original publication . While Luyck and colleagues\u2019 interpretation rests on a solid theoretical framework linking the BNST to temporal unpredictability , which was greater in the second sample. While this is an interesting suggestion, we would like to point out that interpretation of the differences in results between our two samples lacks solid ground without a formal statistical test demonstrating that numerical differences in the mean group response are robust relative to the variance observed within each group. A direct comparison of amygdala and BNST responses to threat anticipation and confrontation with an aversive outcome between our two samples failed to reach significance  function of emotions is to invigorate the propensity of appropriate behavioral responses Frijda, . When thPhilosophers, psychologists and behavioral neuroscientists alike regard conflict between approach and avoidance motivational tendencies as central to anxiety (Kierkegaard, Finally, as described above, conflicting motivational tendencies might be central to anxiety and therefore it will be highly informative for a better understanding of clinically relevant mechanisms to include conditions of conflicting motivational tendencies in research on defensive-reactions. As opposed to the majority of previous work on defensive reactions, daily life rarely involves situations with unambiguously optimal behavioral reactions and including these conflicting motivational conditions in threat studies would thus allow more accurate modelling of pathological avoidance (Pittig et al.,"}
+{"text": "Any density gradient for the isolation of mammalian cells should ideally only expose the sedimenting particles to an increasing concentration of the gradient solute. Thus they will experience only an increasing density and viscosity, other parameters such as osmolality, pH, ionic strength and the concentration of important additives  should remain as close to constant as possible. This Protocol Article describes the strategies for the dilution of OptiPrep\u2122 in order to prepare such solutions for mammalian cells."}
+{"text": "The emotional state of the learner is an important factor that must be taken into consideration during evaluating learning process and managing learning flows in computer based learning environments. This factor has a significant impact on the process of interaction between the learner and the learning environment. Enriching this type of interaction make the learning flow more dynamic based on emotional and mental responses of the learners. This approach can manage various learning flows based on learner's capabilities which lead to enhance the learning process outcome. This article provides data on learners' emotional states during their interaction with learning environment and other data that describe their learning activities and learning flows. The learning activities data is a combination of data that represents summary of learners' emotional states and data that represents the mental responses per learning session. All of emotional states data and mental responses data are used to provide the next learning level for each learner using fuzzy rules. The datasets are hosted in the Mendeley Dataset Repository . First type of data describes the features of learners\u2019 emotional states as emotional responses, while the other type of data describes the combination of data that represents summary of learners' emotional states and mental responses per learning session.The emotional response of the learner is represented by seven classes of expressions which are angry, disgust, fear, happy, neutral, sad, and surprise. While the mental response is represented by other factors which are managed by the learning environment; these factors are learner id, learning activity id, answer validity ratio, test elapsed time, current learning level, and desired learning level.answer validity ratio describes the validation degree of learner's answer to all the test questions. The test elapsed time describes the time that spent by the learner to finish a provided test. The current learning level represents the learner's learning level at the start of the learning activity. The desired learning level represents a value that is generated by a fuzzy system to redirect the learner to the next learning level based on the level and degree of emotional and mental responses of the learner.The \u2022Learners' emotional states dataset describes the learners' emotional states during their interaction with the learning environment. The description of this dataset is explained in Table 1\u2022a.Aggregated emotional states of five learners across four learning activities for each learner as shown in Fig.\u00a01b.Learning paths for five learners during their learning sessions and the impact of summarized emotional states using mean on the learning flows as shown in Fig.\u00a03Learning activities dataset using mean describes the summarized emotional states using mean and its impact on the value of the next learning level of the learner which is generated by a fuzzy system. The description of this dataset is explained in \u2022a.Aggregated emotional states of five learners across four learning activities for each learner as shown in Fig.\u00a02b.Learning paths for five learners during their learning sessions and the impact of summarized emotional states using median on the learning flows as shown Fig.\u00a04Learning activities dataset using median describes the summarized emotional states using median and its impact on the value of the next learning level of the learner which is generated by a fuzzy system. The description of this dataset is explained in The collected data are divided into three datasets 2We developed a dynamic learning environment integrated with real time facial expressions detection model using deep learning to detect the learner's facial expressions and fuzzy system to provide the learning environment with the next learning level based on learner emotional and mental responses.To test our approach we prepared a test with six levels of difficulties on English language to represent a learning curriculum to a sample group consisted of twelve volunteer people with different ages between 25 and 35 years old, and have different learning background in English language. The sample members have been selected randomly with different ages to verify our approach on different learning levels across different ages, as well to obtain different emotional responses during their interaction with our learning environment. They have participated in the collected data with 72 learning activities represent different learning flows and 1735 data rows of vary emotional states.We logged all detected facial expressions during the learning sessions except emotional states data records those total value equal to zero in order to provide a consistent and meaningful emotional states data set.In order to summarize the detected set of emotional states to provide a meaningful crisp value for each facial expression  we used two different statistical methods. These statistical methods are mean and median to determine which statistical processing on the detected emotional states during the learning sessions is more accurate and realistic to prepare crisp values of emotions for the fuzzy system. The emotional states crisp values were combined with other captured factors  to represent the crisp inputs to a fuzzy system to provide the next learning level which draws the learning flow."}
+{"text": "There has been increasing pressure on farmers in Europe to reduce the emissions of ammonia from their land. Due to the current financial climate in which farmers have to operate, it is important to identify ammonia control measures that can be adopted with minimum cost. The planting of trees around farmland and buildings has been identified as a potentially effective and low-cost measure to enhance ammonia recapture at a farm level and reduce long-range atmospheric transport. This work assesses experimentally what fraction of ammonia farm woodlands could potentially remove from the atmosphere. We constructed an experimental facility in southern Scotland to simulate a woodland shelterbelt planted in proximity to a small poultry unit. By measuring horizontal and vertical ammonia concentration profiles within the woodland, and comparing this to the concentration of an inert tracer (SF6) we estimate the depletion of ammonia due to dry deposition to the woodland canopy. Together with measurements of mean ammonia concentrations and throughfall fluxes of nitrogen, this information is used to provide a first estimate of the fraction of emitted ammonia that is recaptured by the woodland canopy. Analysis of these data give a lower limit of recapture of emitted ammonia, at the experimental facility, of 3%. By careful design of shelterbelt woodlands this figure could be significantly higher."}
+{"text": "OBJECTIVES/SPECIFIC AIMS: Identify the impact of the provision of clinical and translational research training awards on investigators\u2019 pursuit of clinical and translational research careers. METHODS/STUDY POPULATION: Propensity score matching and qualitative analysis/investigators receiving MICHR\u2019s KL2 research training awards. RESULTS/ANTICIPATED RESULTS: While the evaluations of the impact of this service have shown participants find them to be valuable it is expected that participation in the workshop may be more beneficial to investigators with certain types of prior research experiences and who utilize more CTSA research support. DISCUSSION/SIGNIFICANCE OF IMPACT: Because this evaluation of a research service incorporate data representing investigator\u2019s receipt of different CTSA resources, the findings can be used to inform the ongoing coordination of these services in ways that optimize their impact on the production of clinical and translational research. There is an enduring need for evaluations of CTSA programs to account for investigators\u2019 use of different constellations of research services in order to identify what combinations of services over time are most effective at fostering successful clinical and translational research careers."}
+{"text": "The authors are to be commended for adding to our fund of knowledge for this burgeoning field. Characterization of at\u2010risk elite athletes is important because of the risk of arrhythmias and consequently, sudden cardiac death as these may be preventable. A risk prediction model should be established incorporating LA volumetric and strain data from the present study, myocardial fibrosis from the imaging studies, and other established criteria. Future studies should also aim to provide a risk prediction clinical tool to decrease the arrhythmia related morbidity and mortality in elite athletes.The authors declare no potential conflict of interests."}
+{"text": "We use self-reported and behavioral data from the HomeLab to comment on the theoretical and methodological implications of integrating objective and subjective measures of experience. To illustrate, we will focus on two domains that vary in the nature of objective and subjective measurements examined. One domain will be decision making where subjective measures include subjective probability and utility and the respective objective measures include probability and actual outcomes. The second domain will be activities of daily living where the subjective measure is perceived effort and the objective measures include various data from sensor such as EDA  and EMG (muscle contraction). The presentation will discuss the benefits of conducting such research in a realistic standardized context such as the HomeLab, which is a fully connected, fully functioning apartment set up as a standardized lab in order to study activities of daily living."}
+{"text": "Thirty three states have legalized marijuana for medical or recreational use. This increased access to cannabis products has heightened interest in its use among family caregivers. Clinicians anecdotally report frequent questions from families about the use of these products, but lack sound information to provide an informed response. Some studies suggest cannabis could help to manage behavioral symptoms of dementia,. No studies to date have explored marijuana or cannabis product use by caregivers for themselves or for the person with dementia. Caregivers of persons with diagnosed dementia were invited to take part in a study that included completion of a survey and participation in a focus group that explored self care practices, including the use of marijuana and cannabidiol (CBD) products for themselves and the person with dementia. Results of the survey and trends from the focus groups will be presented, with a comparison between English and Spanish speaking individuals."}
+{"text": "It is the basic step in the discovery of new drugs or studying the pharmacological actions of already developed one using both preclinical and clinical study designs in a stepwise phase of investigations. However, the investigations in the first phase of experimental pharmacology are usually concluded with assumption hypothesis without any adequate validation of the scientific evidence. Single dose acute toxicology had been conducted on Balb c mice with three different level of doses prepared from each of three different test chemicals  with known median lethal dose (LDThe methods used for data collection were: procurement of test chemicals, investigation of single dose acute toxicity on Balb c mice and quantitative immunoglobulins test. Data was thematically compiled for validation of the findings from each of the sources.The result showed that the dose had never limited the toxic property of tested chemicals but the magnitude of adverse effect and length of time at which adverse effect was manifested on treated Balb c mice. The toxicity of tested chemicals was however limited by the toxic reaction rate of a dose in the biological process of exposed Balb c mice. The toxic effect of tested chemicals became magnified within a short period of time when large amount administered orally. It also remained after a long period of time when small amount administered in the same route.Adequate investigation time for acute toxicity study was therefore essential for comprehensive analysis of pharmacological property of tested chemicals at different level of doses. Experimental pharmacology is a study through experimental design in controlled situations which involves testing of pharmacologically unknown substance and pharmaceutical products in human and animal . It dealExperimental pharmacology is the basic step in the discovery of new drug or studying the pharmacological actions of already developed one using both preclinical and clinical study designs in a stepwise phase of investigations . It is aDifferent species of laboratory animals are used in experimental pharmacology to investigate dose \u2013biological response relationship and pharmacokinetic of different test substances. The laboratory animals mostly used are, Mice, Rat, Guinea pig and Rabbits . ExperimAcute toxicity is the adverse effect produced after administration of a single dose of test substance using one of the routes of drug administration within a period of not exceeding 24\u2009h . It is uAcute toxicity study is routinely conducted in experimental pharmacology as a regulatory requirement in order to avoid infiltration of harmful pharmaceutical products for public consumption . But theIf the objective of acute toxicity study in animal is to provide the primary safety data to aid in the selection of a compound for clinical development, the toxicity study should be well designed to assess dose- biological response relationship and pharmacokinetics in the treated subject through adequate length of investigation time. Clinical and histopathology need to be evaluated at the earlier and termination time of acute toxicology for adequacy of public health safety .d)Administered dose (t) for adverse effect manifestation andElapsed time (\u0394Ig)The immune response  had been calculated and documented. The biological responses as toxic severity and toxic reaction rate of each doses administered to lab Balb c mice were finally determined using mathematical formula s is toxic severity, r is toxic reaction rate, d is the administered dose, t is the length of time at which adverse effect manifested and \u0394Ig is change in concentration of serum immunoglobulins at four hour after dosing. The computed result of toxic severity and toxic reaction rate were used to answer the research questions mentioned earlier which may help to define the fundamental principles in experimental pharmacology.An integrated biological approach  was employed in this study to evaluate the different biological responses to test chemicals administered to Balb c mice. First, acute toxicity study was conducted in the biomedical laboratory of pharmacology and therapeutics during which the time elapsed for the manifestation of significant adverse effect on treated Balb c mice was determined and recorded in note book. The immune response had also been evaluated using quantitative immunoassay before dosing as reference test and at four hour after dosing for comparison from which changes in concentration of serum immunoglobulinsus study  where s Three data collection methods were used. These were, procurement of test chemicals, investigation of single dose acute toxicity on laboratory Balb c mice and quantitative immunoglobulins test.50 [. Three different doses from each test chemicals  were prepared using micropipette and stored in separate and sterile, disposable test tubes which were pre-labeled with number and concentration of test chemical. The prepared doses have been stored at room temperature until it was tested on laboratory Balb c mice.Three toxic chemicals  with different LD50 , 11 were.Data collection in acute toxicology has been conducted in the biomedical laboratory of department of pharmacology and therapeutics from 14th to 28th June 2018. First, fifteen female Balb c mice at the age of 10\u2009weeks were procured from college of veterinary medicine, Makerere University and transported to the department of pharmacology and therapeutics where they have been kept in a cage by providing them food (bread and layer\u2019s mash) and water in a daily basis. Even though, the toxicity of prepared test chemicals has been planned to be evaluated on 15 Balb-c mice, six mice were attacked and killed by a rat which was escaped from its cage at night during the experiment. As a result the experiment was evaluated on nine Balb c mice by dividing them in three groups by which three mice were selected by non-probability sampling, labeled at the head, back and thigh with different colours i.e. black, blue and red and kept them in separate cages. After acclimatising them in cages under standard environmental conditions of light and dark cycles for two weeks, about 1\u2009ml of blood specimen for reference quantitative immunoglobulins test was drawn from the tail and facial veins of each Balb c mice using micro test tubes pre-labeled with number corresponding with the label of Balb c mice. After blood specimens drawn for reference quantitative immunoassay, three days have been given to all lab Balb c mice to restore normal bio-physiological state. And then, all sampled mice have been starved for overnight before weighing them and calculating the right dose. The mice from each group weighed separately using an electronic balance. First, the mouse picked from the cage by holding its tail and put in a plastic bottle with its tail off which was already measured. The weight of each mouse has been recorded in note book from which the right dose per body weight was calculated. Three different level of doses which were less than the LD50 [The calculated doses of prepared test chemicals were also measured using micropipettethe LD50 , 11  for content. Subject matters of the study were identified and organized into meaningful categories and sub\u2013categories. For comprehensiveness, data from different data collection methods was compiled to validate and complement the findings from each of the sources.The analysed data from each of the sources presented in form of tables, graphs and use of descriptive statements under the themes mentioned in the result and discussion sections.The researcher was given an introduction letter from the department of pharmacology and therapeutics, and ethical clearance from Internal Review Board of School of Biomedical Sciences, Makerere University to seek permission and conduct research. Heads of departments, where different sections of the study has been conducted, were contacted. The norms and rules of each department has been highly observed. Laboratory Balb c mice have been treated according to the universal declaration on animal welfare (UDAW) to prevent cruelty and reduce suffering .Aristolochia elegns mast but the length of time at which undesired effect was clearly manifested on treated Balb c mice [50) and effective dose (ED50) of test extracts precisely [r) and toxic severity (s) of each doses administered into Balb c mice in the oral route were calculated using mathematical formulation Doses of test chemicals prepared from Dichlorvos, Chlorpyrifos and Cypermethrin pesticides at three different level of doses  had been administered into laboratory Balb c mice at 10\u2009weeks old and monitored for a maximum period of 5\u2009days. The length of time at which undesired biological effect manifested in treated Balb c mice was inversely related to the amount of dose administered in the oral route. The higher the dose of administered test chemical, the shorter the length of time at which adverse effect manifested on treated Balb c mice  were developed slow respiration and hypo-activity immediately after oral administration Table .Table 5TThree Balb c mice treated with three different level of doses at 10, 50 and 90\u2009mg/kg of Chlorpyrifos pesticide were also evaluated with acute toxicity trial for five days Table . The maiThree Balb c mice treated with three different level of doses at 10, 50 and 90\u2009mg/kg of Cypermethrin pesticide developed signs and symptoms of toxicity within about 9 to 23\u2009min depending on the amount of dose administered orally Table . The BalIgG (immunoglobulin G) and IgM (immunoglobulin M) quantification tests had been conducted to evaluate the immune response against test chemicals administered to Balb c mice in the oral route. Except Balb c mice treated with the highest dose at 90\u2009mg/kg of Dichlorvos which was died at 1:36\u2009h after dosing orally, about 1\u2009ml of blood specimen had been collected from each Balb c mic using micro test tubes before treatment as reference test and at four hour after treatment for comparison Table . QuantitThe negative value of computed toxic severity and toxic reaction rate in Tables The dose literally refers to the amount of a substance, medicine or drug in the field of nutrition, medicine and toxicology respectively to be utilized at a particular time for certain biological or pharmacological purposes \u201316. The 50) and effective does (ED50) of test substance has no scientific ground to declare at a point of time that the lower dose is safe and the higher dose is unsafe for life. Even if the adverse effect of the lower dose is not significantly manifested at the organismal level within a short period of time, its adverse effect is significantly manifested at the cellular level which could cause impact on the life of an organism in the long run. In the previous study, for instance, the test extract at 500\u2009mg/kg body weight killed treated Balb c mice in the 9th day and the highest dose (5000\u2009mg/kg body weight) killed them in the 4th day after dosing orally [r) is the administered dose (d) over the length of time (t) at which signs and symptoms of adverse effect is manifested minus concentration of serum immunoglobulins change (\u0394Ig) as counter response to the toxic effect of test chemical on treated study animal [t was considered four hours at which blood specimens for immunoassay were collected after dosing. The toxic reaction rate of test chemical was higher in the higher administered dose and the shorter the length of time at which adverse effect manifested in treated Balb c mice and Vic versa. The length of time in the investigation of acute toxicology was an essential factor to determine the toxicity of a test substance. The longer the period of time at which the undesired biological effect of test substance manifested on treated organism, the smaller the dose and its toxic reaction rate.The different structure of the body of living things  is the metabolic by-product of ingested dose of substances from the environment that involves different metabolic pathways in which one chemical is bio-transformed into another chemical with multiple bio-transformation mechanisms . Metaboly animal . It coul\u0394Igmg/sec. In thiss) of test chemical is the toxic reaction rate (r) over the administered dose (d) multiplied by one hundred which is expressed in percent per unit time [The toxic severity (nit time . It coul0) %/sec . The higr) indicated safety limit of test chemicals whereas the value of toxic severity (s) predicted the length of time at which adverse effect of test materials could probably be manifested on treated organism. The laboratory Balb c mice treated with the amount of dose whose toxic reaction rate was less than zero survived from death whereas those sampled Balb c mice treated with the amount of dose that had toxic reaction rate more than zero died at different length of time after treatment depending on the toxic severity of tested chemicals.During this study where the toxicological effect of three test chemicals  were evaluated on Balb c mic at the age of 10\u2009weeks, the toxic reaction rate and toxic severity of each tested chemicals were calculated and recorded in different tables as presented under subsection 3.2 in the result section. The value of toxic reaction rate (r) is less than or equal to zero. This means that the administered test substance is successfully neutralized and harmonised with the biological process of treated organism. The result of toxic severity (s) of each administered doses showed that treated Balb c mice with different dose had no equal opportunity to exist in life but equal fate for death at different lifespan depending on the amount of test chemical administered orally. This means that the higher the toxic severity of test substance the shorter the lifespan of treated organism and Vice versa. At the same time, the higher the toxic reaction rate of test substance in the biology of treated organism, the higher toxic severity of test material will be which shortens the lifespan of an organism.It could be a scientific fact to declare that a test substance is safe when the value of toxic reaction rate , is most likely to have a higher risk of health problem in the long run. There is no scientific ground to categorise a single test material as safe dose (ED50) and lethal dose (LD50) at a point of time during the experiment, in other words, the lower dose could not be safe for life when the higher dose is lethal. It might not be manifested at the organismal level like does the higher dose but it could be significantly manifested at the cellular level which perhaps impact the health of treated organism in the long run. It is most likely to be a waste of time and resources to categorise a single test substance as effective dose (ED50) and lethal dose (LD50) and proceed to the next phase of preclinical trial with inadequately validated data.All the three different level of doses prepared from three different test chemicals mentioned earlier  manifested the toxic effect with different magnitude at different length of time depending on the amount of dose administered in the oral route. If the higher dose kills treated organism, the lower dose which is referred to as effective dose (EDThe term immunoglobulin refers to any of a class of proteins present in the serum and cells of the immune system which function as an antibodies . ImmunogThe immune system is made up of a network of cells, tissues and organs that work together to provide protection to the organism from environmental agents such as microbes or chemicals, thereby preserving the integrity of the organism. The specific immunity is further divided into humoral immunity, the one involved with antibody, and cellular immunity, which is orchestrated by T cells . ThroughThe normal biological component of the immune system is therefore the overall indicator of the wellbeing of an organism whereas the abnormality in the immune system is the indicator of unhealthy conditions of an organism. What is going wrong in the biology of an organism is ultimately reflected as a quick counter response from the immune system that could be detected as abnormal temperature, supressed appetite, and abnormal immunoglobulin concentration in the plasma, physical and biological disintegration and many more to mention depending on the antigen detected by the immune system .When the administered test substance is absorbed and interacted with the biological system of an organism, it is not only the subjective effect but also other multiple effects that could be triggered in the body which is ultimately detected by the immune system. The administered test substance becomes harmful to the life of treated organism when the biological systems of the body has failed to neutralize and harmonise the chemical component of test substance with the molecular counter part of an organism. Thus, an integrated biological analyses in the earliest stage of preclinical trial is crucial to make adequate assessment about the general safety of test material which may help to avoid progressive trail of harmful test chemicals.The study revealed that the dose had never determined the toxicity of tested chemicals but the magnitude of adverse effect and length of time at which adverse effect manifested in treated Balb c mice. The adverse effect of tested chemicals was rather determined by the toxic reaction rate in the biological process of treated Balb c mice. Adequate length of investigation time in acute toxicology was essential to determine the toxic nature of tested chemicals at different level of doses. Finally, the three different level of doses prepared from each test chemicals disproportionately suppressed IgM depending on the amount administered orally."}
+{"text": "The central role of primary care within the field of mental health is a global phenomenon with policymakers actively encouraging primary care to take a lead role in developing and delivering mental health services.Involving patients actively in research represents a significant culture change. Public and patient involvement (PPI) describes a whole variety of ways that researchers engage with people for whom their research holds relevance. The challenge is to mainstream PPI in all aspects of research, health policy and structures going forward, which will require significant political leadership and a new overall strategy."}
+{"text": "Sir,It has been a general acceptance that early stage of diabetic kidney disease (DKD stage 1) has been underrecognized, and therapeutic prevention of the diabetic kidney disease at this stage has never happened. The significance and importance of the physiologically defensive mechanism and vascular homeostasis in the early stage of diabetic kidney disease has recently been identified . TherefoThe preceding information renders support that DKD stage 1 can be recognized in the early stage with alternative diagnostic markers than creatinine clearance. The most important issue of early recognizing DKD stage 1 is that it is the golden period for implementing the therapeutic strategy to restore the renal microvascular disease as well as renal function, inasmuch as the mechanism of vascular repair and homeostasis is still adequately functioning in this stage. Treatment at this stage has been vulnerable to correct the renal ischemia, and restore the renal function, and effectively prevent the progression toward end-stage renal disease ."}
+{"text": "Cardiovascular complications are extremely frequent in patients with chronic kidney disease (CKD) and death from cardiac causes is the most common cause of death in this particular population. Cardiovascular disease is approximately 3 times more frequent in patients with CKD than in other known cardiovascular risk groups and cardiovascular mortality is approximately 10-fold more frequent in patients on dialysis compared to the age- and sex-matched segments of the nonrenal population. Among other structural and functional factors advanced calcification of atherosclerotic plaques as well as of the arterial and venous media has been described as potentially relevant for this high cardiovascular morbidity and mortality. One potential explanation for this exceedingly high vascular calcification in animal models as well as in patients with CKD increased systemic and most importantly local (micro)inflammation that has been shown to favor the development of calcifying particles by multiple ways. Of note, local vascular upregulation of proinflammatory and proosteogenic molecules is already present at early stages of CKD and may thus be operative for vascular calcification. In addition, increased expression of costimulatory molecules and mast cells has also been documented in patients with CKD pointing to a more inflammatory and potentially less stable phenotype of coronary atherosclerotic plaques in CKD. Patients with chronic kidney disease (CKD) and chronic renal failure (CRF) develop early on in the course of the disease structural and functional alterations of the heart and the vascular tree that represent a major clinical problem in these patients. In addition, cardiovascular diseases are a major contributor to the high incidence of cardiovascular complications and particularly death from cardiovascular causes in this population , 2. AparIn addition to the cardiac alterations specific structural changes of the extracardiac arteries and veins are present which consist of vessel thickening Figures  but moreAlthough the exact pathogenesis of increased vascular calcification in CKD is not fully understood there are some very plausible hypotheses and candidates: from the very beginning disturbances in the phosphorus (P) and calcium (Ca) metabolism , 26, altThe above-mentioned recent study by Viegas and coworkers  more empAdvanced stages of atherosclerotic plaques particularly with plaque and vessel calcification are specific features in patients with CKD that might contribute to the high cardiovascular morbidity and mortality in these patients. Our findings of a more inflammatory phenotype of coronary atherosclerotic plaques and particularly of a potential role of MCs for advanced atherosclerosis in CKD might be particularly important in view of recent experimental findings in the animal model of the ApoE knockout mouse  where ph"}
+{"text": "During the ongoing water crisis in Flint, Michigan, residents continue to express their voices in community meetings. In this study of older adults, the research team conducted participant observation of such meetings in addition to interview older adults. This presentation highlights themes of trauma and resilience as found in the collective; we illustrate the knowledge gained by researchers about the challenging environmental contexts in which study participants are navigating and how narratives that are both personal and collective co-emerge. We examine how these narratives illustrate concerns of health and wellbeing from a life course perspective and index relationships of residents to their spaces. We conclude by offering lessons learned on investigating community meetings as a way of ensuring research is \u201ccommunity based.\u201d"}
+{"text": "This symposium addresses debates around the theme of precarity and its implications for understanding social and economic changes affecting the lives of older people. To date, the concept of precarity has been applied to several subpopulations by various academic disciplines but has yet to be systematically applied to later life. The symposium will give particular attention to the extent to which the lens provided by precarity can illuminate different types of inequalities experienced through the life course and reflected in public policies directed at older people. Chris Phillipson reviews theoretical perspectives relating to precarity, examining their potential contribution for the development of critical gerontology. His paper also considers the extent to which the concept of \u2018precarious ageing\u2019 offers a competing or complementary view to theories of \u2018active\u2019 and \u2018successful ageing\u2019. Larry Polivka examines the growing precarity of life for older Americans emanating from austerity budgets and privatization of public services. The paper suggests that policies such as health care and long term care are in jeopardy, creating a glide path toward the extension of precarious employment into a precarious retirement for millions of older people. Wenxuan Huang examines how the focus on agency and other individual-level foci obscure understanding of social dynamics. Finally, Amanda Grenier draws on a scoping review of precarity to outline conceptual distinctions between frailty, vulnerability, and precarity. She presents reflections on what these concepts offer in terms of understandings of late life the study of disadvantage across the life course."}
+{"text": "The \u201caging\u201d of populations in the developed world is rapidly altering demographics and presents a number of challenges for science and medicine. Foremost among these challenges is the need to enhance the quality of life for this \u201caging\u201d majority. Paradoxically, improved prevention and treatment of diseases will only increase the number of individuals who will lose quality of life because of cognitive deficits in learning and memory. Such cognitive deficits are particularly vexing in societies where the ability to deal with information technology has become an increasing necessity. Understanding how the human brain encodes and stores information becomes critical in designing required therapeutic strategies."}
+{"text": "Vaccine clinical trials in low\u2010resource settings have unique challenges due to structural and financial inequities. Specifically, protecting participant and caregiver autonomy to participate in the research study can be a major challenge, so understanding the setting and contextual factors which influence the decision process is necessary. This study investigates the experience of caregivers consenting on behalf of paediatric participants in a malaria vaccine clinical trial where participation enables access to free, high\u2010quality medical care.II or III malaria vaccine clinical trial in Uganda, Tanzania and Kenya. Interviews were qualitative and analysed using a thematic framework analysis focusing on the embodied caregiver in the political, economic and social reality.We interviewed a total of 78 caregivers of paediatric participants previously enrolled in a phase Caregivers of participants in this study made the decision to enrol their child based on economic, social and political factors that extended beyond the trial into the community and the home. The provision of health care was the dominant reason for participation. Respondents reported how social networks, rumours, hierarchal structures, financial constraints and family dynamics affected their experience with research.The provision of medical care was a powerful motivator for participation. Caregiver choice was limited by structural constraints and scarce financial resources. The decision to participate in research extended beyond individual consent and was embedded in community and domestic hierarchies. Future research should assess other contexts to determine how the choice to participate in research is affected when free medical care is offered. Vaccines play a major role in public health and their development is dependent on clinical trial testing in human populations. Transnational clinical trials operate through collaborative partnerships that involve a wide array of stakeholders and participants from varying sociocultural backgrounds. Each stakeholder enters into clinical trial research with varying degrees of inequity linked to its role in the clinical trial and resource context Phase II and phase III vaccine clinical trials establish the safety of a vaccine and determine its efficacy This study investigates the community context, communication needs and decision\u2010making processes of the caregivers of participants in a phase II and phase III paediatric malaria vaccine clinical trial. Each of these trials operated in low\u2010resource settings in multiple African countries. The phase II vaccine trial involved GMZ2 malaria vaccine and was conducted at five clinical trial centres in four African countries The phase III RTS,S clinical trial investigated here has led to the regulatory registration and the roll\u2010out of the RTS,S vaccine in a phase IV study, making it the first licenced malaria vaccine. These phase IV studies will take place in three different countries, including the Kenyan research centres investigated here While community engagement has been recognised as necessary in ethical transnational research, there is no clear consensus as to its definitive application in different community contexts In order to better understand the experiences and decision\u2010making processes of caregivers during the paediatric malaria vaccine clinical trial, we conducted a series of in\u2010depth interviews between March 2017 and March 2018 with caregivers of children who participated in a malaria clinical trial.Interviews were held across four clinical trial sites in Uganda (Iganga), Kenya (Siaya and Kombewa) and Tanzania (Bagamoyo) with caregivers of participants. We used purposive sampling to recruit respondents and in the majority of the cases the mother was the primary caregiver. Participants were selected based on having had a child enrolled in a paediatric malaria vaccine clinical trial. Interviews were conducted until saturation was reached, were semi\u2010structured and held in the home of the respondent.The RTS,S phase III malaria vaccine trial took place between March 2009 and January 2014 in seven African countries  and spanned 11 clinical trial centres This was a qualitative study that used in\u2010depth interviews to capture the perspective of the caregiver who had a child enrolled in a malaria vaccine clinical trial. The fieldwork consisted of a scoping trip to the research sites to introduce the study, recruit participants and meet with community leaders. Field visits took place in March 2017 (the scoping visit), and the interviews were conducted between May 2017 and March 2018 with the help of local research assistants. The research assistants from Tanzania were fluent in Swahili . In Uganda, all three female research assistants were fluent in Luganda and conversational in the related Lusoga language of the community investigated. In Kenya, all three research assistants  were fluent in Dholuo. None of the research assistants lived in the community investigated, all were fluent in English and had post\u2010secondary education. Interviews were semi\u2010structured and had a focused discussion on the vaccine trial, leaving room to explore concepts as they emerged, such as community dimensions and domestic relationships in the context of the trial. Interviews began by asking open questions and were then funnelled into more specific questions about the respondent's views and experiences within the health system, interaction with researchers, and challenges faced in the community. The interviews were recorded with the informed consent of the respondent and conducted in the local language. They were then transcribed verbatim and translated into English by the research assistant. The interview guide was first piloted in each country and then changed and developed throughout to best explore unanticipated replies as they emerged.The study protocol, informed consent forms and interview guide were reviewed and approved by the following bodies: in Tanzania, National Health Research Ethics Review Committee for the National Institute for Medical Council (NIMR), Ifakara Health Institute IRB (IHI\u2010IRB), Tanzania Commission for Science and Technology (COSTECH); in Uganda, Uganda Council for Science and Technology (UNCST), the Makerere University School of Biomedical Sciences Higher Degrees Research and Ethics Committee (SBS\u2010HDREC); in Kenya: Strathmore University IRB (SU\u2010IRB).The analysis was based on the approach described by Strauss and Corbin 1998) 98 19. Fin\u00a0=\u00a018), Kombewa, Kenya (n\u00a0=\u00a020) and Siaya, Kenya (n\u00a0=\u00a017). Interviews lasted around 31\u00a0min on average, with the longest being 56\u00a0min and the shortest being 19\u00a0min. Seven interviews could not be included in the time calculation due to logistical limitations of the recordings.Of the 78 interviews, 23 were with parents of children enrolled in the GMZ2 Phase IIb trial in Iganga, Uganda. The remaining 55 in\u2010depth interviews were with parents of children enrolled in the RTS,S phase III study across three sites in Bagamoyo, Tanzania  and is intricately connected to the political, social and economic reality that a caregiver occupies at a given time. Below, we move through these themes and discuss the role local values and beliefs play in research participation.vs. benefit communication in transnational clinical trials What is most striking about our results is the dominance of free medical care as being the prevailing motivator for participation. Limited capacity of local medical services has been raised as a challenge in transnational research when the medical services in the clinical trial significantly surpass local services the village life we are in\u2019. The respondents are embedded in communal lives where other members of the community would suggest their child was going to be killed or face the consequence of a stigmatised condition if they enrolled in the malaria vaccine clinical trial. Failing to recognise the contingency of community and individuality and to overlook the historical experiences that contributed to the generation of these beliefs can derail research studies Beyond the individual, the provision of accessible medical care was also highlighted as the trial component most highly valued by the community. Health care was framed as a community value by respondents. The political leadership which influenced community acceptance of the research suggests a locus of decision\u2010making that is communal. The leadership decided its position on the research study and then passed this approval down into the community, driven by the desire to promote the health of the children. The provision of health care within the community context in combination with the structural constraints impacts decision\u2010making structures in clinical trials and provides challenges for the consent process The final analysis of the domestic context also brought the value of healthcare provision to the forefront as the dominating motivator for trial participation. Having a sick child in the home leads to difficulties for others sharing that same domestic setting, whereas having access to health care to treat the sick child leads to greater domestic harmony. Respondents reported that enrolling in the research trial often occurred as a result of the difficulty in accessing medical care and trial enrolment has been reported to be lower in areas with better medical services joy\u2019 in the home. Having a sick child in the home can burden the relationship and make parents more likely to participate in research than when their child is healthy How parents weigh the risks and benefits of participation differed and was related to the structural constraints around healthcare access for the child rumours\u2019 by respondents and those believing them were referred to as a distant third party. Respondents repeatedly emphasised the gratitude they experienced from trial enrolment and the accompanying care. Concerns around potential adverse events outlined in the informed consent documents associated with vaccination did not come up as a significant concern during the interviews. While therapeutic misconception was also evident in some interviews, the offer of medical care overshadowed it in its ability to influence the caregiver's risk perception.The absence of risk in the interviews conducted was also of note. Sceptical beliefs or concerns were often framed as \u2018Designing vaccine clinical trials in low\u2010resource settings such that the communication of risk and benefits is done in a way that is comprehended by participants and their communities is a challenging task. Ethical design of research requires the communication of trial proceedings not to be overshadowed by the provision of free care in resource\u2010limited settings. To address this in future trials and taking the first step towards more ethical communication means placing the community at the forefront of research design Understanding and addressing the local context will reduce inequalities inherent in transnational clinical trials in low\u2010resource settings Limitations of this study include the sampling strategy, which recruited caregivers who enrolled their child and therefore would have been more likely to have a reduced risk perception due to the provision of care than caregivers who were approached and refused to enrol their child in the clinical trial. Future work investigating the perception of caregivers in the community who refused to enrol their child could shed further light on this topic. We also did not interview and male caregivers, which is indicative of the traditional caregiving roles where the mother or grandmother has the primary responsibility for the child's health.Through mapping how contextual realities interplay with the decision\u2010making process of caregivers of paediatric clinical trial participants, this study can strengthen clinical trials in low\u2010resource settings. Our work shows that individual consent in clinical trials is intricately linked with community consent and family dynamics. Based on this, future research needs to investigate how this interplay varies across contexts and the role free medical care plays in consent in these settings."}
+{"text": "The plating efficiency of neurons in culture is highly dependent on the concentration of cells used to establish the monolayer. A discontinuous iodixanol gradient permits both the production of a viable concentrated suspension of neurons and purification from other brain tissue elements. The gradient that is described in this Protocol Article is applicable to brain tissue from rat and also from human biopsy specimens."}
+{"text": "This dataset conducted a comparative analysis of sustainable construction practices of foreign and indigenous construction firms in Lagos state, Nigeria using a structured questionnaire survey. The dataset contains the level of awareness and consistency of practice of sustainable development on construction projects between the foreign and indigenous construction firms and the impact of implementing sustainable development practices. Descriptive analysis such as frequencies, percentage and mean score were used to present the quantitative data in form of tables. Further analysis of the dataset highlight the practices of indigenous and foreign construction firms in sustainable development which can be beneficial to stakeholders in environmental protection and mitigating climate change issues. Specifications TableValue of the data\u2022The dataset highlights sustainable strategies that can be implemented for creating safe construction activities which are environmentally friendly by construction firms and stakeholders \u2022The dataset is useful for policy makers in enforcing sustainable practices by construction firms.\u2022The dataset can be replicated in other sectors to understand the sustainable practices used and the level of awareness in those practices.\u2022With rising population and the needs to provide adequate housing, high waste generation by the construction needs to be curtailed. Construction clients through this dataset can set limit on waste generation through efficient sustainable development practices.\u2022Further analysis of the dataset can reveal the rationale of investing in sustainable development practices by indigenous and foreign construction firms.1The dataset presented in this context described a comparative analysis of sustainable construction practices of foreign and indigenous construction firms in Lagos state, Nigeria. The dataset gives a summary of the construction firms\u2019 information, level of awareness, consistency of practice and the impact of implementing sustainable development practices. The dataset was obtained on a firm-level basis using a primary instrument. 2The dataset was obtained from primary sources using the questionnaire instrument. The data article follows the works of previous studies in"}
+{"text": "The increase in availability of actinobacterial whole genome sequences has revealed huge numbers of specialised metabolite biosynthetic gene clusters, encoding a range of bioactive molecules such as antibiotics, antifungals, immunosuppressives and anticancer agents. Yet the majority of these clusters are not expressed under standard laboratory conditions in rich media. Emerging data from studies of specialised metabolite biosynthesis suggest that the diversity of regulatory mechanisms is greater than previously thought and these act at multiple levels, through a range of signals such as nutrient limitation, intercellular signalling and competition with other organisms. Understanding the regulation and environmental cues that lead to the production of these compounds allows us to identify the role that these compounds play in their natural habitat as well as provide tools to exploit this untapped source of specialised metabolites for therapeutic uses. Here, we provide an overview of novel regulatory mechanisms that act in physiological, global and cluster\u2010specific regulatory manners on biosynthetic pathways in Actinobacteria and consider these alongside their ecological and evolutionary implications. Streptomyces genome sequence, the genus was estimated to have the potential to produce in the region of 150,000 bioactive compounds  in actinobacterial genomes that encode for the production of potentially useful metabolites which are not actively expressed under commonly used laboratory conditions. Prior to the sequencing of the first et al., et al., et al., et al., et al., et al., et al., Streptomycesantibiotic regulatory protein (SARP) protein family to be identified  synthesis and the regulation of antibiotic production in actinomycetes has long been established. ppGpp is a key intracellular signalling molecule, which links nutrient starvation sensing with adaptive responses in a wide range of bacteria including actinomycetes. Under conditions of nitrogen limitation, ppGpp is synthesised by the ribosome bound protein RelA . Moreover, MtrA binds to the promoters of the streptomycetes\u2010specific cell division genes ssgA and ssgB  of the particular biosynthetic gene cluster in which they are located. Traditionally in actinomycetes, this type of regulation is conducted by either transcriptional activators/repressors or two component regulatory systems  sigma factors are a group of small regulatory proteins normally bound (when inactive) to a cognate membrane\u2010associated anti\u2010sigma factor. Once the appropriate inducing signal is detected, the anti\u2010sigma factor is inactivated either through modifications, conformational changes or proteolysis. This inactivation leads to the release of the ECF and enables it to be recruited by the RNA polymerase core enzyme, therefore allowing transcription initiation from ECF\u2010specific target promoters. Actinomycetes contain a large number of ECF sigma factors within their genomes compared to other bacterial groups /PKS) assembly line. The M. corallina is initiated by ppGpp synthesis (see above). This precursor is then exported, and once outside the cell, it triggers the release of the cluster specific ECF sigma factor MibX from the membrane\u2010associated anti\u2010sigma factor MibW. MibX can now activate transcription of the whole biosynthetic cluster to reach high levels of production of the fully modified and active form of microbisporicin . In this case, planosporicin itself is responsible for the release of the sigma factor to activate transcription of the biosynthetic cluster . For example, the production of a much less active precursor form of the lantibiotic microbisporicin in et al., et al., Given that the specialised metabolite producing Actinobacteria are a widely distributed group of organisms that occupy a wide range of environmental niches with an enormous repertoire of specialised metabolites, it is unsurprising that they have also evolved a vast array of mechanisms with which to coordinate and regulate the expression of molecules with adaptive function. The biosynthesis of specialised metabolites clearly has a larger evolutionary cost to the producing strain than carrying the resistance mechanism to a specialised metabolite where tens of kilobases of DNA are required to encode BGCs whereas only hundreds of bases are required for many resistance mechanisms (Traxler"}
+{"text": "The dataset contains financial indicators from the financial statements of 250 banks operating in Europe which are collated for the 2015 accounting year. First, the dataset is split into input and outputs measures. Then the preferred number of inputs and outputs in relation to the total number of data is selected according to the rule of thumb in data envelopment analysis (DEA). The dataset is related to the research article entitled \u201cRobust optimization with nonnegative decision variables: A DEA approach\u201d  [1]. The dataset can be used to evaluate the performance of banks and bank efficiency under uncertainty. The nu[5,All the raw data are scaled for uniformity and to reduce round-off errors from excessively large values prior to analysis."}
+{"text": "Any density gradient for the isolation of mammalian organelles should ideally only expose the sedimenting biological particles to an increasing concentration of the gradient solute. Thus they will experience only an increasing density and viscosity, other parameters such as osmolality, pH, ionic strength and the concentration of important additives (such as EDTA and DTT) should remain as close to constant as possible. This Protocol Article describes the strategies for the dilution of OptiPrep\u2122 in order to prepare such solutions for mammalian organelles and membranes."}
+{"text": "The main objective of this survey is to present data on the perception of the influence of faculty support initiatives on efficacy of job responsibilities using six private university in Nigeria as case study. The population of the study included all faculty members of selected private universities with a total of 1912 faculty members. A sample size of 500 were selected to participate in the survey based on the outcome of the sample size determination formula suggested by Falola et al. (2016)  Specification TableValue of the data\u2022University management can have insight into which of the faculty support initiatives mostly predicts efficacy of faculty responsibilities.\u2022If the data is properly analysed, it can provide a platform upon which universities take decisions that will completely restore the dignity of Nigerian Universities. See \u2022The data provided here can be used for decision making purposes.\u2022This can be used as a platform upon which management of the universities and other stakeholders in the education sector formulate policies.\u2022The questionnaire can be adopted or adapted for a similar studies.1The data presented in this study is quantitative in nature. It comprises raw statistical data on the influence of faculty support initiatives on the efficacy of job responsibilities. The study is descriptive in nature. Statistical Package for Social Sciences (SPSS) was used for the coding of the data collected. The population, sample size and response rate of questionnaire administered as well as demographic characteristics of the respondents are depicted in 2Six best private universities as ranked by National Universities Commission, and webometric ranking were selected from Southwest Nigeria. What informs the choice of the best six private universities in southwest Nigeria was because of their outstanding performance when it comes to research and innovation. The researchers wanted to find out the institutional supports given to the Academic Staff that might be responsible for their performance. Data were collected from the sample of four hundred and forty three faculty members across all the colleges with the aid of structured questionnaire designed by the researcher based on the similar studies of"}
+{"text": "The cell membrane provides a functional link between the external environment and the replicating DNA genome by using ligand-gated receptors and chemical signals to activate signaling transduction pathways. However, increasing evidence has also indicated that the phospholipid bilayer itself by altering various physical parameters serves as a sensor that regulate membrane proteins in a specific manner. Changes in thickness and/or curvature of the membrane have been shown to be induced by mechanical forces and transmitted through the transmembrane helices of several types of mechanosensitive (MS) ion channels underlying functions such as osmoregulation in bacteria and sensory processing in mammalian cells. This review focus on recent protein functional and structural data indicating that the activation of bacterial and yeast osmosensors is consistent with thickness-induced tilting changes of the transmembrane domains of these proteins. Membrane thinning in combination with curvature changes may also lead to the lateral transfer of the small lipid-anchored GTPases Ras1 and H-Ras out of lipid rafts for clustering and signaling. The modulation of signaling pathways by amphiphilic peptides and the membrane-active antibiotics colistin and Amphotericin B is also discussed. Lippa et al., has found that the periplasmic protein DsbA facilitates the oxidation of the MgrB cysteine residues blocking PhoQ/PhoP signaling activity  is flanked at both the cytoplasmic and at the periplasmic side with two consecutive aromatic residues. This preferential location of aromatic Trp and Phe residues at the membrane/water interphase has been predicted to allow large movements of the TM domain perpendicular to the membrane by acting as a membrane \u201cfloat\u201d that minimizes energy costs  signaling pathway in fungal cells is known to be activated under a hyperosmotic shock by the rapid loss of cell volume due to water efflux , but the two hydrophobic Ile residues that are present at the periplasmic side, are followed by a segment containing two positively charged Lys residues (KLAK). These positively charged aminoacids upstream of TM2 may be interacting with negatively groups of membrane phospholipids, potentially playing a role in modulating membrane thickness as observed for the TMs of the Ca2+-ATPase  domains that are formed in model lipid membranes . In the Sho1-P120L mutant, the substitution of Pro by a hydrophobic Leu amino acid residue may enhance the interaction of any of the two positively charged lysines with the negatively lipid head groups at the membrane surface. Consequently, the TM4 helix of Sho1 may be forced to tilt with respect to the membrane normal, as it is expected to occur upon the reversal of the membrane thinning induced by the loss of turgor. Similar displacements of a TM domain by a positively charged-lipid anchor at the membrane surface has been demonstrated to play a role in the activation of mechanosensitive bacterial ion channels     to fungal cells exerts an opposite effect that turgor by inducing the loss of salt and water produced via the aqueous pores formed  pathway is another membrane-based signaling mechanism present in fungal cells that is capable to sense turgor pressure Levin, . Thus, mWsc and Mid2 proteins contain a large extracellular o-mannosylated serine-threonine region (STR) that is connected to a single TM domain  of the TM within the bilayer, leading to a conformational change that brings the cytosolic domain closer to form functional multimers that triggering the CWI pathway activation. Consistent with the localization of the CWI pathway sensors in specific lipid rafts, it was found that the CWI pathway is activated by inhibitors of fatty acid synthase (FA), acetyl-CoA carboxylase and myriocin, an inhibitor of sphingolipid synthesis , a higher fungal species, there are two Ras isoforms (Cn Ras1 and Cn Ras2) that share overlapping functions, but also play distinct signaling roles  and the cytoskeleton to regulate specific functions during cell growth and pathogenesis processes. In addition, the increasing evidence that supports the role of biophysical membrane properties in the localization of the Ras and Rho family members into specific lipid nanodomains makes it possible to define new innovative approaches for improving the therapy of fungal and cancer diseases. Efforts in this direction are driven by the remarkable progress made in the use of multiscale computer simulation approaches to understand protein dynamics and its impact on events that can be propagated over long distances such as signaling via Ras and its downstream effectors Papaleo, . HoweverThe author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
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+{"text": "Pieridae is a large group of butterflies which plays an important role in evolutionary biology and contains many potential pests , was discovered for the first time, which comprises the first record of the genus Belenois in China and the highest altitude record of this species.The family al pests . PieridaB.aurota  is the first record of the genus Belenois from China. The specimen was collected at an altitude of about 3,000 m in Tibet Autonomous Region. Relevant details are presented for the species.The species  Pieridae, which is a cosmopolitan family, includes over 1,000 species in 83 genera  that is distributed in the Oriental and Australian Realms. China is a country with mega-biodiversity, with new taxa and new records of butterflies discovered nearly every year in recent times  has been collected from Tibet Autonomous Region. The migration of the African colonies of this species almost every year has received lots of attention. The biology of B.aurota is also well studied. B.aurota larvae feed on plants of the family Capparidaceae, in particular the genus Capparis. Under some circumstances, the population erupts at local scale and defoliates the entire bush of Capparis; for example, in the Rwenzori National Park in Uganda, it has been a regular pest on C.decidua (Chandra 1985). The specimens collected in this contribution are the first record of the genus Belenois from China.In this contribution, a well-known migratory species Photographs of the adult were taken with an interchangeable lens digital camera Olympus E-M1 with the lens M. ZUIKO DIGITAL ED 60 mm F2.8 Macro. After removal, the abdomen was soaked in 10% potassium hydroxide solution at room temperature for about 24 hours and was dissected under a Nikon SMZ18 microscope. The genitalia preparation was photographed by a Nikon D7500 digital camera attached to the microscope. Final plates were prepared in Adobe Photoshop CC . The specimen examined is deposited in the insect collection, Department of Forest Protection, Beijing Forestry University (BFU), Beijing.1D570FA8-EC16-50B9-8F38-C650FC7A78EFType status:Other material. Occurrence: recordedBy: Sixun Ge; individualCount: 1; sex: male; lifeStage: adult; disposition: in collection; Taxon: scientificName: Belenoisaurota ; kingdom: Animalia; phylum: Arthropoda; class: Insecta; order: Lepidoptera; family: Pieridae; genus: Belenois; subgenus: Anaphaeis; specificEpithet: aurota; taxonRank: species; verbatimTaxonRank: sp.; scientificNameAuthorship: ; vernacularName: Pioneer White; taxonomicStatus: accepted; Location: country: China; stateProvince: Tibet Autonomous Region; county: Zanda County; locality: East of Diya township; verbatimElevation: 2983 m; verbatimCoordinates: 31\u00b078'83\"N, 78\u00b087'88\"E; Identification: identifiedBy: Sixun Ge; dateIdentified: 2019; Event: samplingProtocol: sweep net; year: 2019; month: 7; day: 17; habitat: Desolate valley beside the road; Record Level: basisOfRecord: PreservedSpecimenMale Belenoisaurota is found both in Asia and Africa, this species is migratory, the migration of the species in South Africa has received considerable attention in previous studies . We are more inclined to recognise this specimen as a stray butterfly based on its location \u2014 far from the known distribution area and a single record for several decades.Interestingly, although there has been no official publication of this species in China, we found a specimen labelled \u201cChina, Sichuan, Mt. Kintushan, [probably Jinfo Shan in Chongqing] (ohne Datum) [no date], ex coll. A. SCHULTE. M\u00e4nnchen [male].\u201d on a European butterfly website (B.aurota were mainly distributed in areas below 1,800 m, the highest altitude recorded for the distribution of this species being 2,400 m in Nilgiris, India (B.aurota was collected at an altitude of about 3,000 m which is the highest altitude record of this species. Colonies of an undetermined Capparis species were also found around Diya Township (Fig. Capparishimalayensis, which could be a suitable host plant for B.aurota larvae. Due to the existence of the host plant, we believe that our B.aurota specimen, collected in the Diya Township, was highly likely from a local population rather than a stray butterfly.In previous studies, the Himalayan populations of s, India . However"}
+{"text": "To determine whether location-linked anaesthesiology calculator mobile application (app) data can serve as a qualitative proxy for global surgical case volumes and therefore monitor the impact of the coronavirus disease 2019 (COVID-19) pandemic.We collected data provided by users of the mobile app \u201cAnesthesiologist\u201d during 1 October 2018\u201330 June 2020. We analysed these using RStudio and generated 7-day moving-average app use plots. We calculated country-level reductions in app use as a percentage of baseline. We obtained data on COVID-19 case counts from the European Centre for Disease Prevention and Control. We plotted changing app use and COVID-19 case counts for several countries and regions.A total of 100\u2009099 app users within 214 countries and territories provided data. We observed that app use was reduced during holidays, weekends and at night, correlating with expected fluctuations in surgical volume. We observed that the onset of the pandemic prompted substantial reductions in app use. We noted strong cross-correlation between COVID-19 case count and reductions in app use in low- and middle-income countries, but not in high-income countries. Of the 112 countries and territories with non-zero app use during baseline and during the pandemic, we calculated a median reduction in app use to 73.6% of baseline.App data provide a proxy for surgical case volumes, and can therefore be used as a real-time monitor of the impact of COVID-19 on surgical capacity. We have created a dashboard for ongoing visualization of these data, allowing policy-makers to direct resources to areas of greatest need. Many health-care systems have responded by cancelling or delaying elective surgical procedures.,\u2013Assessing the volume of global surgical care is notoriously difficult. Prior work in this area has relied on estimations based on modelling and labour-intensive retrospective analysis of data from nations where such information is routinely recorded and available.We previously developed a free anaesthesia calculator mobile application (app) for the Android platform, called Anesthesiologist.Our aim is to determine whether utilization of the app, aggregated over the large existing international user base, could serve as a real-time qualitative proxy for surgical case volume, and therefore be used to monitor the impact of, and recovery from, the COVID-19 pandemic.,,,Data collection using the app has been described in previous publications.We also queried the electronic data warehouses of the University of Washington and the Seattle Children\u2019s Hospital for aggregate surgical case counts for the period 1\u00a0October\u00a02018 to 18\u00a0April\u00a02020, a time period capturing the relevant drops in surgical case volumes associated with holidays in the USA. We used publicly available data to classify World Health Organization (WHO) regions.,We analysed raw data in R using RStudio v3.6.2 ;We performed change point detection in time-series data using the cpm package.The study was reviewed and approved by the Emory University Institutional Review Board (study no.\u00a000082571), and there is a reliance agreement in place with the University of Washington Institutional Review Board. The approval includes a waiver of written informed consent. Participants gave electronic consent anonymously before participating in any data collection. The app is a medical device that falls into the category of enforcement discretion as per the United States Food and Drug Administration.From 1 October 2018 to 30 June 2020, we collected and analysed 4\u2009827\u2009263 data points from 100\u2009099 unique users in 214 countries and territories . ApproxiBox\u00a01India: 12\u2009374; United States of America: 4259; Germany: 4092; Russian Federation: 3630; Indonesia: 3352; Italy: 3304; Mexico: 2888; Pakistan: 2844; Brazil: 2155; Poland: 2052; Turkey: 2003; Egypt: 1709; Algeria: 1679; Spain: 1625; Colombia: 1520; Malaysia: 1353; France: 1267; Ethiopia: 1249; Ukraine: 1218; Nigeria: 1204; Kenya: 1156; Romania: 1136; Philippines: 1112; Iran (Islamic Republic of): 1097; Sudan: 1085; United Republic of Tanzania: 1067; Peru: 1032; Ghana: 1031; Yemen: 1019; Portugal: 1010; Libya: 997; Iraq: 961; United Kingdom: 926; Saudi Arabia: 924; South Africa: 903; Argentina: 732; Cuba: 724; Ecuador: 720; Bangladesh: 705; Democratic Republic of the Congo: 678; Belarus: 628; Viet Nam: 614; Netherlands: 610; Afghanistan: 567; Morocco: 565; Hungary: 561; China: 535; Chile: 507; Czechia: 507; Bolivia : 505; Israel: 468; Nepal: 462; Slovenia: 453; Madagascar: 450; Australia: 446; Croatia: 437; Austria: 436; Cameroon: 434; Venezuela (Bolivarian Republic of): 434; Belgium: 420; Uzbekistan: 392; Canada: 389; Bulgaria: 386; Greece: 363; Tunisia: 360; Rwanda: 354; Serbia: 350; Myanmar: 327; Uganda: 315; Kazakhstan: 310; Switzerland: 305; Syrian Arab Republic: 298; C\u00f4te d\u2019Ivoire: 297; Dominican Republic: 295; Slovakia: 272; Sweden: 272; Thailand: 270; Jordan: 264; Somalia: 256; Republic of Korea: 245; Mali: 241; Zimbabwe: 236; United Arab Emirates: 230; Georgia: 221; Angola: 220; Bosnia and Herzegovina: 199; Burundi: 198; Lithuania: 197; Zambia: 197; Paraguay: 194; Ireland: 187; Norway: 186; Sri Lanka: 178; Azerbaijan: 175; Lao People's Democratic Republic: 173; Haiti: 161; Lebanon: 161; Kuwait: 154; Cambodia: 146; Liberia: 145; El Salvador: 144; Niger: 142; Latvia: 139; West Bank and Gaza Strip: 138; Taiwan, China: 135; North Macedonia: 130; Mauritius: 129; Papua New Guinea: 124; Chad: 120; Nicaragua: 117; Republic of Moldova: 117; Mozambique: 114; Oman: 112; Senegal: 110; Honduras: 104; Tajikistan: 98; Fiji: 97; Albania: 91; Trinidad and Tobago: 91; Burkina Faso: 90; Guatemala: 90; Turkmenistan: 89; Mongolia: 87; Japan: 85; Qatar: 84; Namibia: 81; Guinea: 78; Guyana: 76; Singapore: 76; China, Hong Kong SAR: 74; Kyrgyzstan: 74; Uruguay: 74; Panama: 73; Denmark: 72; Estonia: 71; Jamaica: 71; Finland: 69; Sierra Leone: 68; Armenia: 67; New Zealand: 67; Congo: 64; Gambia: 62; Malawi: 62; Kosovo: 56; Benin: 55; Costa Rica: 54; Mauritania: 54; Cyprus: 48; Puerto Rico: 45; South Sudan: 45; Bahrain: 39; Botswana: 38; Djibouti: 37; Lesotho: 36; Comoros: 33; Bhutan: 32; Gabon: 31; Togo: 29; Montenegro: 28; Maldives: 26; Luxembourg: 21; Belize: 20; French R\u00e9union: 19; Seychelles: 17; Suriname: 17; Bahamas: 16; Malta: 16; Sao Tome and Principe: 15; Barbados: 14; Iceland: 14; Antigua and Barbuda: 13; Central African Republic: 13; Solomon Islands: 13; Eswatini: 13; Timor-Leste: 12; Equatorial Guinea: 11; Cabo Verde: 10; Tonga: 9; Brunei Darussalam: 8; New Caledonia: 8; Guadeloupe: 7; Guinea-Bissau: 7; China, Macao SAR: 6; Tuvalu: 5; Vanuatu: 5; Aruba: 4; Martinique: 4; Monaco: 4; Anguilla: 3; Cayman Islands: 3; Kiribati: 3; Micronesia (Federated States of): 3; Saint Lucia: 3; Saint Vincent and the Grenadines: 3; American Samoa: 2; Eritrea: 2; French Polynesia: 2; Mayotte: 2; \u00c5land Islands: 1; Andorra: 1; Bermuda: 1; Cook Islands: 1; Cura\u00e7ao: 1; Dominica: 1; Faroe Islands: 1; Greenland: 1; Grenada: 1; Isle of Man: 1; Liechtenstein: 1; Palau: 1; Saint Martin (French part): 1; Samoa: 1; San Marino: 1; United States Virgin Islands: 1.App: mobile application; SAR: Special Administrative Region.Note: A small number of users (44) had country codes that were not standard ISO\u00a03166 \u03b1-2 codes, meaning that their country of origin could not be reliably determined.\u2013We demonstrate in ,We also observed an expected variation in app use by the day of the week, consistent with known data demonstrating that surgical case volumes are highest during the middle of the week and much lower over weekends (data repository).We illustrate the impacts of COVID-19 on app use in We further used this data to illustrate variability in app use relative to counts of COVID-19 cases. Overall, app use declined as COVID-19 cases increased during the study period . We founWe generated a map of the global impact of COVID-19 on app use (available in the data repository),Many people in low- and middle-income countries are already without adequate access to safe anaesthetic and surgical care at baseline.,The benefits and challenges associated with the collection of health-care data using mobile technology have been discussed in previous publications.A specific strength of our work is the practical use of the app from which data were gathered and analysed. Users download and use the app for the clinical care of patients. The app has never been advertised or its use encouraged via notifications or other mechanisms, meaning that use of the app reflects stochastic clinical care events. This same stochasticity highlights a limitation of the work, however; data from individual regions or countries with a small user base reduce the confidence we can assign to the association between app use time-series data and surgical case volume. By excluding many more high- and middle-income countries than low-income countries with zero app use during the relevant periods in our calculation of median app use reduction, we have probably underestimated the global impact of COVID-19 on surgical case volumes.Another important limitation is that the app is used primarily for the care of paediatric cases (about 75% of app uses are for patients aged 12 years and younger), and this predominance may drive greater use of the app in low- and middle-income countries where (i)\u00a0subspecialty training in paediatric anaesthesia is less prevalent compared with in high-income countries; and (ii)\u00a0as much as 50% of the population in low- and middle-income countries may be younger than 16 years. Notably, these needs in low- and middle-income countries are not trivial: 1.7 billion children lack adequate access to surgical care and an estimated 85% of children will need surgical care by the age of 16 years.Finally, we acknowledge that many factors may drive changes in patterns of app use, and hence the relationship between app use and surgical case volume for a given country or region. For example, users are more likely to consult the app during emergencies,http://globalcases.info). Longer term, our app could be combined with other data to assist with measurement of global surgical capacity as part of the Global Surgery 2030 initiative. In conclusion, we present a real-time qualitative monitor of the impact of COVID-19 on global surgical volumes, particularly in low- and middle-income countries. Combined with other information sources, our app provides governments, global health organizations and philanthropic groups access to data providing markers of recovery \u2013 or otherwise \u2013 of surgical capacity, as well as the opportunity to direct resources to the areas of greatest need. To ensure the ongoing accessibility of this information, we have developed a near real-time dashboard ("}
+{"text": "Correction to: BMC Pediatrhttps://doi.org/10.1186/s12887-017-0844-6Following the publication of article by Cauble et al. , typograThe paper lists the Deierlein equation as:The correct Deierlein equation is:The paper lists the Lingwood equation as:The correct Lingwood equation is:"}
+{"text": "Following publication of the original article , the autThe Funding section originally read:This work was funded by Grants #82070034, #81970033, #31900424, #81570026, #81670002 and #3167188 from the NSFC; Grants #2017JJ2402, #2019JJ50760 from the Hunan Natural Science Foundation; Grant #20K142 from open Foundation of Hunan College Innovation Program and Grants #2018zzts813, #2018zzts812, #2019zzts327, #2019zzts1008 from the Fundamental Research Funds for the Central Universities of Central South University.The Funding section should read:This work was funded by Grants #82070034, #81970033, #31900424, #81670002 and #31671188 from the NSFC; grants #2020JJ4776, #2020JJ4688, #2019JJ50760 from the Hunan Natural Science Foundation; grant #20K142 from open Foundation of Hunan College Innovation Program and grants #2019zzts327, #2019zzts1008 from the Fundamental Research Funds for the Central Universities of Central South University.The original article  has been"}
+{"text": "Objective: This study aims the perspectives of older adults on their sexual well-being. For this purpose, a qualitative research was carried out, which analyzes older adults\u2019 perspectives on indicators of sexual well-being in Portugal and Romania. Methods: Forty seven older participants aged 65 to 91 years, were interviewed. Participants lived in the community. All the interviews went through content analysis. Results: Preliminary results of content analysis generated 5 themes for the Romanian sample: Supportive relationship ; positive financial situation ; good health ; education ; and family support ; and five themes for the Portuguese sample: Supportive relationship ; demonstration of love ; sharing joint activities ; positive attitude and good humor ; and open communication ; Conclusions: This study highlighted the perspectives of Portuguese and Romanian older adults concerning sexual well-being. For both samples, showing a supportive relationship with a partner was the more frequent theme. Keywords: Content analysis; cross-national; older adults; qualitative study; sexual well-being."}
+{"text": "The authors of \u201cTreatment Adherence and Secondary Prevention of Ischemic Stroke Among Discharged Patients Using Mobile Phone- and WeChat-Based Improvement Services: Cohort Study\u201d :e16496) noticed several errors in their published article. The following corrections have been implemented:In the Abstract, the sentence:Of the platform registry participants, 88.9%  adhered to inputting information into WeChat for 8-96 weeks.Has been corrected to:Of the platform registry participants, 89.7%  adhered to inputting information into WeChat for 8-96 weeks.This change does not impact the findings of the paper.The following additional changes have also been made within the manuscript. The caption of Figure 3 has been corrected from \u201cUntitled.\u201d to:Synchronous web terminal of the WeChat information platform part 1.Figure 4 was formerly captioned:Synchronous web terminal of the WeChat information platform.This has been revised to:Synchronous web terminal of the WeChat information platform part 2.Figure 6 was formerly captioned:Flowchart of the study design. PUSH: Peking University Shougang Hospital; PUTH: Peking University Third Hospital; ITT: intention-to-treat.This has been revised to:Selection bias analysis of the WeChat platform registry population. DM: diabetes mellitus; HLP: hyperlipidemia; HP: hypertension; TIA: transient ischemic attack.Figure 7 was formerly captioned:Selection bias analysis of the WeChat platform registry population. DM: diabetes mellitus; HLP: hyperlipidemia; HP: hypertension; TIA: transient ischemic attack.This has been revised to:Participants' usage of the WeChat-based modules.Figure 8 was formerly captioned:Participants' usage of the WeChat-based modules.This has been revised to:Survival functions: Kaplan-Meier analysis of the rate of endpoint events during the 1-year follow-up.Finally, Figure 9 was formerly captioned:Survival functions: Kaplan-Meier analysis of the rate of endpoint events during the 1-year follow-up.This has been revised to:Demographics of the participants with good and poor adherence.The correction will appear in the online version of the paper on the JMIR website on April 29, together with the publication of this correction notice. Because this was made after submission to PubMed, PubMed Central, and other full-text repositories, the corrected article has also been resubmitted to those repositories."}
+{"text": "There is an error in the Competing Interests statement. The correct Competing Interests statement is as follows: Co-author K. Nakayama is a co-founder and shareholder of Cyfuse Biomedical KK. and an inventor/ developer designated on the patent for the Bio-3D printer. Patent title: Method for Production of Three-Dimensional Structure of Cells; patent number: JP4517125. Patent title: Cell Structure Production Device; patent number: JP5896104. The other authors have declared that no competing interests exist. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials."}
+{"text": "Prevalence of mental health conditions, sensory impairments and physical disability in people with co-occurring intellectual disabilities and autism compared with other people: a cross-sectional total population study in Scotland. BMJ Open 2020;10:e035280. doi: 10.1136/bmjopen-2019-035280.Dunn K, Rydzewska E, Fleming M, This article was previously published with an error. The funding information in the published article was incomplete. The updated funding information is stated below:This work was supported by the UK Medical Research Council, grant number: MC_PC_17217) and the Scottish Government via the Scottish Learning Disabilities Observatory."}
+{"text": "The following information is missing from the Data Availability statement: The plasmids described in this study are available from Addgene:plasmid pBDC, Addgene ID: 135188plasmid pBDK, Addgene ID: 135190plasmid pCNA, Addgene ID: 135191plasmid pSNA, Addgene ID: 135192plasmid pSNK, Addgene ID: 135193There is an error in S2 Table(DOCX)Click here for additional data file."}
+{"text": "The online article and PDF will be updated in due course.In this research article by Dagens and colleagues (BMJ 2020;369:m1936, doi:"}
+{"text": "Metformin blunts muscle hypertrophy in response to progressive resistance exercise training in older adults: A randomized, double\u2010blind, placebo\u2010controlled, multicenter trial: The MASTERS trial. Aging Cell. 2019; 18:e13039. c mean (SD) were incorrect. The correct data is shown as follow:In Table In addition, related measures presented in Appendix S2 under Supporting Information have been updated online.The authors would like to apologize for the inconvenience caused."}
+{"text": "Correction to: BMC Infect Dis (2020) 20:897https://doi.org/10.1186/s12879-020-05605-3Following publication of the original article , the autThe incorrect caption is: \"Admission early in the epidemic versus later in the epidemic\".The correct caption is: \"Multivariate analysis of risk factors for death versus hospital discharge\".The original article  has been"}
+{"text": "Scientific Reports 10.1038/s41598-019-56360-8, published online 27 December 2019Correction to: In the original version of this Article, Parastoo Mojtahed Zadeh-Ardabili and Sima Kianpour Rad were omitted as equally contributing first authors. Therefore, the below equal contribution statement has been added:\u201cThese authors contributed equally: Parastoo Mojtahed Zadeh-Ardabili and Sima Kianpour Rad.\u201dIn addition, the author contribution statement has been updated from:Designing of experiments: Abolfazl Movafagh, Parastoo Mojtahed Zadeh-Ardabili and Sima Kianpour Rad; Consultation: Abolfazl Movafagh; Experimental works: Parastoo Mojtahed Zadeh-Ardabili and Sima Kianpour Rad; Acquisition of data: Sima Kianpour Rad; Analysis and interpretation of data: Sima Kianpour Rad; Drafting of manuscript: Parastoo Mojtahed Zadeh-Ardabili, Sima Kianpour Rad and Soheila Kianpour Rad; Critical revision: Sima Kianpour Rad and Abolfazl Movafagh. All authors contributed toward data analysis, drafting and critically revising the paper, and agree to be accountable for all aspects of the work.to:Parastoo Mojtahed Zadeh-Ardabili and Sima Kianpour are considered as first authors in this publication. Designing of experiments: Abolfazl Movafagh, Parastoo Mojtahed Zadeh-Ardabili and Sima Kianpour Rad; Consultation: Abolfazl Movafagh; Experimental works: Parastoo Mojtahed Zadeh-Ardabili and Sima Kianpour Rad; Acquisition of data: Sima Kianpour Rad; Analysis and interpretation of data: Sima Kianpour Rad; Drafting of manuscript: Parastoo Mojtahed Zadeh-Ardabili, Sima Kianpour Rad and Soheila Kianpour Rad; Critical revision: Sima Kianpour Rad and Abolfazl Movafagh. All authors contributed toward data analysis, drafting and critically revising the paper, and agree to be accountable for all aspects of the work.These errors have now been corrected in the PDF and HTML versions of the paper."}
+{"text": "The online version has been amended.This paper by Weedon and colleagues (BMJ 2021;372:n214, doi:"}
+{"text": "Additionally, focal mechanism solutions of the main Mw 6.5 and its biggest triggered aftershock Mw 5.2 events were acquired. Such datasets could provide a basis for further seismology analysis, including seismic tomography, source mechanism analysis, and further seismic hazard analysis in the Ambon and Seram islands. This paper and its dataset are a companion for a published article in the Tectonophysics under the title \u201cSource Mechanism and Triggered Large Aftershocks of the Mw 6.5 Ambon, Indonesia Earthquake\u201d This article presents earthquake catalogs of the 2019 Ambon aftershocks compiled from regional the Agency for Meteorology, Climatology, and Geophysics of Indonesia (BMKG) and local seismic networks deployed in  The second sheet includes the velocity model used in locating the aftershocks in The first dataset contains station coordinates and velocity model for determining the hypocenter location of 2019 Ambon aftershocks. This is a Microsoft Excel worksheet consisting of two sheets. The first sheet contains the coordinates of the eleven local seismographic stations used for monitoring the 2019 Ambon aftershocks A: YEAR; B: MONTH; C: DAY: date type variables indicating the date for each earthquake.D: HOUR; E: MINUTE; F: SECOND: date type variables indicating the time for each earthquake.G: LONGITUDE; H: LATITUDE: double type variables  indicating the location (longitude and latitude) for each event.I: DEPTH: double type variable  indicating the depth of each individual earthquake.J: MAGNITUDE: double type variables indicating the reported magnitudes  for the included earthquakes. The type of the magnitude is ML  for regional BMKG catalog K,L,M: UNCERTAINTY: double type variables indicating the calculated uncertainty  for each event. This information is only available for aftershock catalog determined using local seismic network The second Microsoft Excel file in the Mendeley Data repository includes earthquake catalogs of 2019 Ambon aftershocks. The files contain a total of 1009 and 1764 earthquakes taken from BMKG catalog A\u2013I: similar with the format of the aftershock catalog mentioned earlier.J: MAGNITUDE: double type variable  indicating the final considered moment magnitude for each earthquake included.K: Strike 1; L: Dip 1; M: Rake 1; N: Strike 2; O: Dip 2; P: Rake 2: these columns represent the two nodal planes for the focal mechanism solution for each earthquake; each column contains a number for each mentioned individual parameter .Q: SOURCE: string variables indicating the source of the focal solutions.The third file in the repository is the focal mechanism of the 2019 Ambon aftershock main event and its biggest M 5.2 triggered event. The focal solutions of the main M 6.5 event were taken from Global CMT http://ds.iris.edu/ds/nodes/dmc) under the network codes II, IU, G, IC, dan RM. This file consists of two tables, i.e. represent each focal solution plane. Each table consists of four columns: X and Y location, seismic moments, and rake of each node. The header describes the reference point (X=0 km and Y=0 km) used in the inversion scheme.The fourth Microsoft Excel file is the slip model of the main 2019 Ambon earthquake derived using teleseismic data. The teleseismic dataset of the M 6.5 event was gathered from the Incorporated Research Institutions for Seismology (IRIS) Data Management Center (DMC) (2o and 128.60o and latitudes between \u22123.70o and \u22123.30o and occurred between October 18th to December 15th, 2019 were considered during the dataset compilation. During this monitoring period, 1009 and 1764 events were compiled from the BMKG 2019 Ambon aftershocks located in the spatial region spanning longitudes between 128.15Focal mechanism solutions of the 2019 Ambon main event and its largest M 5.2 triggered event were obtained from gCMT The related article has been submitted to the Tectonophysics under the title \u201cSource Mechanism and Triggered Large Aftershocks of the Mw 6.5 Ambon, Indonesia Earthquake\u201d.DPS, ADN, AM, AAR and SR: Conceptualization, Methodology, Software; ZZ, SW, NTP and AP: Writing-Original draft preparation; AL, DK, AA, YH and AWB: Visualization, Software and Validation; HAS: Software, Slip Model.The authors declare that they have no known competing financial interests or personal relationships which have or could be perceived to have influenced the work reported in this article."}
+{"text": "Coleoptera: Cucujidae) is a small insect family with only about 70 species. Most of the species are distributed in Holarctic, Oriental and/or Australasian realms, while in South America, only six species have been recorded, including a single one known from Peru.The flat bark beetles  and Cusco and Jun\u00edn (P.nicaraguae) Regions of Peru, based, in part, on data collected through the iNaturalist citizen science database. Habitats of both species are presented in photographs for the first time. A country-level checklist to Cucujidae species currently known from South America is provided.Two cucujid beetle species,  Coleoptera: Cucujidae) form a small insect family which includes five genera and almost 70 species and is distributed worldwide, except for Africa, Antarctica, most of the oceanic islands and the greater part of the Arctic  fall within the tropical and subtropical climatic zones, with a mainly temperate climate in the southern regions. The western part of the continent is characteristically arid , while a cold, polar climate is present only in southern regions of Argentina and Chile . As a coPalaestesabruptus from Peru  in a photo published on the iNaturalist website . The iNaturalist site allows observers from around the world to post images of organisms on the website, while others provide identifications. Although the observer of the Palaestesabruptus photograph  was unable to send the material for study, he provided information that allowed RJ to contact Mr. Pavel Udovichenko, an insect dealer in Russia, who had additional material of this species. Subsequently, two male specimens were received from this seller. Moreover, Mr. Andrey Azarov sent us a pair of Palaestesnicaraguae adults for study. These specimens are currently deposited in the first author\u2019s collection (RJC). Three further specimens from Peru were examined by JM from loan material from the Florida State Collection of Arthropods, Gainesville, Florida, USA (FSCA), provided by the late Michael Thomas.This project was prompted from viewing a single male The specimens examined in this study were identified, based on the original species descriptions  and by cSharp, 189964FD53F4-FE8A-5EB8-8A94-53CE3A5B658EType status:Other material. Occurrence: sex: 2 males; lifeStage: adult; Taxon: higherClassification: Animalia; Arthropoda; Insecta; Coleoptera; Cucujidae' Palaestes; kingdom: Animalia; phylum: Arthropoda; class: Insecta; order: Coleoptera; family: Cucujidae; genus: Palaestes; specificEpithet: abruptus; Location: higherGeography: South America; Peru; Pasco Region; Oxapampa Province; Pozuzo District; Pozuzo; continent: South America; country: Peru; countryCode: PE; stateProvince: Pasco Region; county: Oxapampa Province; municipality: Pozuzo District; locality: Pozuzo; verbatimElevation: 750-1430 m; Identification: identifiedBy: Radomir Jasku\u0142a; dateIdentified: 2020-12; identificationReferences: Sharp 1899; identificationRemarks: Pictures of type material were used to confirm identification; Event: eventDate: 2019-11; year: 2019; month: 11; habitat: mountain rain forest; eventRemarks: col. Alexander Sokolov; Record Level: collectionID: RJC ; ownerInstitutionCode: RJC/CUC-0008; RJC/CUC-0009; basisOfRecord: PreservedSpecimenSmall beetles with strongly flattened bodies; body length (measured from the top of clypeus to the end of elytra) of two studied Peruvian males: 14.7 mm ; ownerInstitutionCode: RJC/CUC-0010; RJC/CUC-0011; basisOfRecord: PreservedSpecimenType status:Other material. Occurrence: sex: male; lifeStage: adult; associatedOccurrences: NCBI BioSample ID: SAMN10963593; associatedSequences: MK614522GenBank: No. ; Taxon: kingdom: Animalia; phylum: Arthropoda; class: Insecta; order: Coleoptera; family: Cucujidae; genus: Palaestes; specificEpithet: nicaraguae; Location: higherGeography: South America; Peru; Cusco Region; Sancurtambo; Santa Isabel; Cosnipata [Kos\u00f1ipata] Valley Rain Forest Alt. 5525 ft.; continent: South America; country: Peru; countryCode: PE; stateProvince: Cusco Region; locality: Cosnipata [Kos\u00f1ipata] Valley Rain Forest Alt. 5525 ft.; Identification: identifiedBy: Mengjie Jin; dateIdentified: 2019; identificationReferences: Sharp 1899; identificationRemarks: Pictures of type material were used to confirm identification; Event: eventDate: 1951-12-14; year: 1951; month: 12; day: 14; eventRemarks: col. F Woytkowski; Record Level: collectionID: FSCA ; basisOfRecord: PreservedSpecimenType status:Other material. Occurrence: sex: male; lifeStage: adult; Taxon: higherClassification: Animalia; Arthropoda; Insecta; Coleoptera; Cucujidae' Palaestes; kingdom: Animalia; phylum: Arthropoda; class: Insecta; order: Coleoptera; family: Cucujidae; genus: Palaestes; specificEpithet: nicaraguae; Location: higherGeography: South America; Peru; Cusco Region; Sancurtambo; Santa Isabel; Cosnipata [Kos\u00f1ipata] Valley Rain Forest Alt. 5525 ft.; continent: South America; country: Peru; countryCode: PE; stateProvince: Cusco Region; locality: Cosnipata [Kos\u00f1ipata] Valley Rain Forest Alt. 5525 ft.; Identification: identifiedBy: Mengjie Jin; dateIdentified: 2019; identificationReferences: Sharp 1899; identificationRemarks: Pictures of type material were used to confirm identification; Event: eventDate: 1951-12-14; year: 1951; month: 12; day: 14; eventRemarks: col. H. L. Dozier; Record Level: collectionID: FSCA ; basisOfRecord: PreservedSpecimeType status:Other material. Occurrence: sex: female [genitalia dissected]; lifeStage: adult; Taxon: higherClassification: Animalia; Arthropoda; Insecta; Coleoptera; Cucujidae' Palaestes; kingdom: Animalia; phylum: Arthropoda; class: Insecta; order: Coleoptera; family: Cucujidae; genus: Palaestes; specificEpithet: nicaraguae; Location: higherGeography: South America; Peru; Cusco Region; Quiroz; Rio Paucartambo; continent: South America; country: Peru; countryCode: PE; stateProvince: Cusco Region; locality: Quiroz, Rio Paucartambo; Identification: identifiedBy: John W.M. Marris; dateIdentified: 2020-12; identificationReferences: Sharp 1899; identificationRemarks: Pictures of type material were used to confirm identification; Event: eventDate: 1933-11-23; year: 1933; month: 11; day: 23; Record Level: collectionID: FSCA ; basisOfRecord: PreservedSpecimenSmall beetles with strongly flattened bodies; body length (measured from the top of clypeus to the end of elytra) from 10.2 mm . The specimens from Peru share the following distinctive characteristics: head, mandibles and prothorax orange-brown, scutellum orange-brown, legs with femorae orange-brown and tibiae and tarsi black, tarsal claws brown-orange and elytra with black colouration extending apically from about the basal 1/3 to 2/5. The only notable difference is that, in the specimens from Peru, the antennomeres dark brown to black, except for the last two apical segmenta, which are red-brown. In contrast, the holotype has three apical segments that are red-brown.The Peruvian specimens match closely with the holotype of Previously, this species was known only from Nicaragua . The locP.abruptus, the larvae and adults of P.nicarague are presumed to live under the bark of dead trees, where they most probably prey on small insects and larvae. There are no published accounts of the ecology and biology specifically for P.nicaraguae.As noted for Coleoptera: Cucujidae) of South America has never been intensively studied and only a few papers have focused on the insect family in South America. For Palaestes Perty, 1830, original species descriptions were provided by P.freyreissi (described as Cucujus), by P.bicolor, by P.mandibularis and P.freyersi (both noted as Cucujus) and by P.dejeani (described as Cucujus) from Brazil  , one from Venezuela  and one from Ecuador (T.macclarini). Two species of Palaestes: P.nigriceps Waterhouse, 1880 and P.tenuicornis Waterhouse, 1880, were erroneously recorded from Peru by loci typici (and the only currently known locations) for these species are in Ecuador, from Chiguinda and Sarayacu [Sarayaku], respectively, as stated by Palaestes) and three species of Cucujidae in Peru, but later stated that only P.tenuicornis was present. P.nigriceps from Peru by P.tenuicornis. They also recorded P.freyreissi  and P.nigriceps from South America, but absent from Peru (P.freyreissi are published in the GBIF database (www.gbif.org).The flat bark beetle fauna ( [1827])  and by Wrom Peru . In addiP.abruptus and P.nicaraguae from South America, as well as the first confirmed data for the genus Palaestes from Peru. Discovery of one of these species was possible thanks to the data collected through the iNaturalist database, which confirms the high value of citizen science in studying biodiversity. Summarising all data mentioned above, we can conclude that the flat bark beetle fauna of South America comprises one subfamily (Platisinae), two genera  and at least eight species  has not been recorded from Brazil for almost one hundred years.This paper provides the first records of es Table , Fig. 5.Cucujidae in South America and for the genus Palaestes over its wider distributional range . Most of the published distribution information for Palaestes is from the original species descriptions, the most recent of which dates back to 1899. Since that time, the only publications discussing Palaestes were reliant on the same locality data as given in the descriptions . It is highly likely that further, targeted collecting in appropriate habitats will yield new taxa. This likelihood is emphasised by the recent discovery (the first specimen was collected in 1997) and description of the new genus, Thesaurus, with three new species from South America. It is remarkable that, despite more than 220 years of collecting on the continent, these relatively large and distinctive beetles had evaded discovery. Similarly, the state of taxonomy of Palaestes species is overdue for revision and there are no keys or modern identification aids available for the genus. The identifications of the two species recorded here are based solely on the original descriptions and photographs of the type material. Examination of existing collection material and detailed, critical analysis of the genus will likely show that new species are present. Both species, recorded here, have been identified as species otherwise known only from localities in Central America, separated by more than 2000 km in a straight line and crossing major geographical barriers. Hopefully, with more emphasis given to surveying for these beetles across Central and South America, more will be revealed about the ecology and biology of both the larvae and adults, as well as providing more information on the range of these distinctive and remarkable beetles.The two new species records, reported here, highlight the poor state of knowledge of ons viz. . Various"}
+{"text": "The family Tortricidae includes approximately 11,500 species of small moths, many of which are economically important pests worldwide. A large number of tortricid species have been inadvertently introduced into North America from Eurasia, and many have the potential to inflict considerable negative economic and ecological impacts. Because native species behave differently than introduced species, it is critical to distinguish between the two. Unfortunately, this can be a difficult task. In the past, many tortricids discovered in North America were assumed to be the same as their Eurasian counterparts, i.e., Holarctic. Using DNA sequence data, morphological characters, food plants, and historical records, we analyzed the origin of 151 species of Tortricidae present in North America. The results indicate that the number of Holarctic species has been overestimated by at least 20%. We also determined that the number of introduced tortricids in North America is unexpectedly high compared other families, with tortricids accounting for approximately 23\u201330% of the total number of moth and butterfly species introduced to North America. This suggests that introduced tortricids have a greater potential of becoming economically important pests than moths in other families, and why distinguishing Holarctic from introduced species is critical to American agriculture.Acleris ferrumixtana , stat. rev.; Acleris viburnana , stat. rev.; Acleris pulverosana , stat. rev.; Acleris placidana , stat. rev.; Lobesia spiraeae , stat. rev.; and Epiblema arctica Miller, 1985, stat. rev. Cydia saltitans , stat. rev., is determined to be the valid name for the \u201cjumping bean moth,\u201d and Phiaris glaciana , comb. n., is placed in a new genus. We determine that the number of Holarctic species has been overestimated by at least 20% in the past, and that the overall number of introduced species in North America is unexpectedly high, with Tortricidae accounting for approximately 23\u201330% of the total number of Lepidoptera species introduced to North America.In support of a comprehensive update to the checklist of the moths of North America, we attempt to determine the status of 151 species of Tortricidae present in North America that may be Holarctic, introduced, or sibling species of their European counterparts. Discovering the natural distributions of these taxa is often difficult, if not impossible, but several criteria can be applied to determine if a species that is present in both Europe and North America is natively Holarctic, introduced, or represented by different but closely related species on each continent. We use DNA barcodes (when available), morphology, host plants, and historical records (literature and museum specimens) to make these assessments and propose several taxonomic changes, as well as future areas of research. The following taxa are raised from synonymy to species status:  Lymantria dispar , Erebidae) being among the most notorious. Examples of important lepidopteran pests that have been introduced recently to new regions around the globe include the fall armyworm, Spodoptera frugiperda (J. E. Smith) (Noctuidae), a native of the New World that has spread to much of Africa and Asia ), a native of Europe that was inadvertently introduced to the wine-growing regions of Argentina, Chile, and California )DNA barcode sequences were obtained from BOLD. All records for a particular taxon, usually at the genus level, were selected with the option \u201cinclude Public\u201d records. Records were filtered to exclude contaminants, records with stop codons, and records flagged as misidentifications or errors. Only sequences \u2265400 bp were used because of random alignment issues with shorter sequences. Sequences were aligned in BOLD using the BOLD amino acid-based HMM Aligner, and neighbor-joining trees were constructed in BOLD using the Kimura 2 Parameter (K2P) distance model.The \u201crevised status\u201d of each taxon was determined by examining how the specimens clustered in the distance tree, the identity and origin of the specimens, the specimens themselves , the relevant literature, and additional statistics in BOLD. In many cases, the average and maximum p-distance for each of BOLD\u2019s Barcode Index Numbers (BINs) and the p-distance between the nearest neighbors were examined; these are reported in the results when relevant. We did not use a specific percentage cut-off for species delimitation. We also did not rely exclusively on BOLD\u2019s BIN assignments, although in most cases, the placement of more than one taxon in a single BIN or the splitting of one taxon into multiple BINs did indicate there was an issue, either with the taxonomy or identifications. In some cases, the DNA data was completely ambiguous, either due to a lack of data, too many potential misidentifications, or the apparent sharing of DNA barcodes across multiple taxa.Each of the following species accounts includes five components: (1) the previously concluded status of the species with regards to its biogeographic origin (\u201cPrevious status\u201d), usually as listed in Pohl et al. ; (2) ourFamily TORTRICIDAESubfamily TORTRICINAEAcleris forsskaleana Previous status: Introduced from EuropeRevised status: No changeSupported by DNA in BOLD: YesBINs: BOLD:AAA8796A. forsskaleana group into a single BIN (BOLD:AAA8796) with representatives from North America  and Europe . Many of the specimens from both continents share identical barcodes. Acleris forsskaleana was first recorded from North America by Klots  pattern or genitalia between the two. DNA barcodes indicate that C. cespitana is not present in North America. It is not known if North American C. cespitana and O. baccatana in BIN BOLD:AAA7669 are indeed the same species or if barcodes are not sufficient to separate taxa in this group. If they are synonyms, C. instrutana would be the senior name, with Sericoris poana Zeller, 1875 being an additional junior synonym.Heinrich  synonymiArgyroploce aquilonana Karvonen, 1932Previous status: HolarcticRevised status: No changeSupported by DNA in BOLD: YesBINs: BOLD:AAB9941A. aquilonana, with specimens from Canada , Greenland, and Finland. Jalava and Miller [Olethreutes aquilonanus) from the Ogilvie Mountains in the Yukon, which was the first North American record. They also synonymized this taxon with Olethreutes kononenkoi, extending the distribution of A. aquilonana into Russia. Nedoshivina [There is a single BIN (BOLD:AAB9941) in BOLD representing d Miller  reportedoshivina  records Argyroploce externa Previous status: HolarcticRevised status: No changeSupported by DNA in BOLD: YesBINs: BOLD:AAI3239A. externa are placed in a single BIN (BOLD:AAI3239) with representatives from Europe  and Canada . Jalava and Miller [Olethreutes dalecarlianus\u201d in North America, from the Ogilvie Mountains in the Yukon and Wellington, British Columbia. This name was synonymized under the Palearctic Argyroploce externa by Nedoshivina [Specimens of d Miller  reportedoshivina , making Hedya atropunctana Previous status: HolarcticRevised status: No changeSupported by DNA in BOLD: YesBINs: BOLD:ABZ7645H. atropunctana are placed in a single BIN (BOLD:ABZ7645) that includes specimens from Europe  and a single specimen from Alaska. Jalava and Miller [Hedya atropunctana (which was previously placed in Metendothenia).In BOLD, sequences of d Miller  reportedd Miller  lists mad Miller  reviewedHedya ochroleucana Previous status: Holarctic Revised status:Hedya ochroleucana ; North American cryptic spp. (Nearctic)Supported by DNA in BOLD: YesBINs: BOLD:AAC0586 (Europe); BOLD:ACE9334 (British Columbia); BOLD:AAC0585 H. ochroleucana are placed in three BINs in BOLD: BOLD:AAC0586 contains specimens from Europe , and the other two BINs  contain specimens from North America. The North American BINs are separated by 3.10% (p-dist), and both are separated from the European BIN by 7.35% (p-dist).Specimens of Hedya ochroleucana was described from Germany. DNA barcode data indicate that it is Palearctic, and that specimens identified as this species from North America represent different taxa. Three closely related taxa, currently considered synonyms, are described from North America: nimbatana Clemens, 1860, from Massachusetts; contrariana Walker, 1863, from Nova Scotia; and consanguinana Walsingham, 1879, from California. It is uncertain whether these North American names are indeed all synonyms, or to which of the North American BINs the names should be applied.Hedya nubiferana Previous status: Introduced from EuropeRevised status: No changeSupported by DNA in BOLD: YesBINs: BOLD:AAA4552A single BIN (BOLD:AAA4552) in BOLD contains nearly 100 specimens from the U.S., Canada, and Europe. The majority of specimens share a single identical barcode. This species was first reported from North America in 1913 from Nova Scotia and in 1914 from British Columbia . It is cHedya salicella Previous status: Introduced from EuropeRevised status: No changeSupported by DNA in BOLD: No (no specimens from North America in BOLD)BINs: BOLD:AAD6484H. salicella (BOLD:AAD6484), represented only by specimens from Europe . Sabourin et al. [BOLD contains a single BIN with sequences of n et al.  reportedAncylis comptana Previous status: HolarcticRevised status:Ancylis comptana ; North American cryptic sp. (Nearctic)Supported by DNA in BOLD: YesBINs: BOLD:AAB2712 (North America); BOLD:AAB2713 ; BOLD:ABX5131 ; BOLD:ADI5033 A. comptana are placed in four main BINs in BOLD; there are other single specimens placed in other BINs that are likely misidentified. BOLD:AAB2712 contains specimens from the U.S.  and Canada . The other three BINs contain specimens from Europe: BOLD:AAB2713 Austria, Finland, Italy, United Kingdom); BOLD:ABX5131 ; and BOLD:ADI5033 .Specimens of Ancylis comptana was described from Germany. Although the European representatives of this species in BOLD fall into three separate BINs, these form a single cluster separate from the North American BIN. Thus, it appears that A. comptana is restricted to the Palearctic, and there is a separate unrecognized species in North America. Numerous junior synonyms of A. comptana from North America are currently associated incorrectly with that species, and it is likely that one of these would apply to the Nearctic populations . However, more extensive research is needed to determine the taxonomic status of this group in North America and to examine the multiple BINs in Europe. Ancylis are notoriously difficult to identify, and there are many serious taxonomic issues to resolve in this genus.Ancylis unguicella Previous status: HolarcticRevised status: No changeSupported by DNA in BOLD: YesBINs: BOLD:AAB3498Ancylis. They determined that A. unguicella is Holarctic, with a distribution that includes Western Europe east to Siberia and Japan in the Palearctic, and from Alaska and British Columbia east to Ontario and south to Colorado in the Nearctic [The BIN assignment listed here is from Gilligan et al. , who resNearctic .Ancylis uncella Previous status: Holarctic Revised status: No changeSupported by DNA in BOLD: YesBINs: BOLD:AAA7191A. uncella is from Gilligan et al. [Ancylis uncella was previously thought to be a Palearctic taxon, but Gilligan et al. [A. carbonana, making it Holarctic. This species is distributed from Europe east to Siberia and Japan in the Palearctic and across southern Canada and the northeastern U.S. in the Nearctic [The BIN assignment for n et al. , who resn et al.  determinNearctic .Eucosmomorpha albersana Previous status: Palearctic Revised status: PalearcticSupported by DNA in BOLD: YesBINs: BOLD:AAF2360E. albersana in BOLD are placed in a single BIN (BOLD:AAF2360) representing Austria, Finland, Germany, The Netherlands, and Norway. This species was included by Pohl et al. [E. nearctica. We are unaware of any valid records of the European E. albersana from North America.Sequences of l et al.  as introl et al. ,128, Mill et al.  subsequeEnarmonia formosana Previous status: Introduced from EurasiaRevised status: No changeSupported by DNA in BOLD: YesBINs: BOLD:AAC5227Enarmonia formosana sequences are placed in a single BIN in BOLD (BOLD:AAC5227), which contains specimens from the U.S., Canada, and Europe. Enarmonia formosana is widely distributed from Western Europe and northern Africa to Asia Minor, Russia, and Siberia [ Siberia . The fir Siberia ; it was  Siberia . The \u201cch Siberia .Rhyacionia buoliana Previous status: Introduced from EuropeRevised status: No changeSupported by DNA in BOLD: YesBINs: BOLD:AAD1611 ; BOLD:ACE8290 (France and Spain)R. buoliana are placed in two BINs. BOLD:AAD1611 contains specimens from Europe , Canada (Ontario), and the U.S. (Maryland). BOLD:ACE8290 contains specimens from France and Spain. These BINs form a single cluster and are less than 1% (p-dist) different, indicating that they represent a single species.Specimens of Rhyacionia buoliana was first recorded in North America in 1913 in New York [New York . It was New York . The \u201cEuNew York .Spilonota ocellana Previous status: Introduced from EurasiaRevised status: No change; possible cryptic species in CanadaSupported by DNA in BOLD: YesBINs: BOLD:ABZ4399 ; BOLD:AAA6641 (Canada)S. ocellana in BOLD are placed in two BINs: BOLD:ABZ4399, with specimens from Europe and North America, and BOLD:AAA6641, with specimens from Canada . It is not known if this second BIN represents a possible cryptic species or genetic variation.Sequences of Spilonota ocellana was introduced to the Nearctic likely before 1840, with the first report from Massachusetts in 1841 [ in 1841 . It beca in 1841 . This is in 1841 .Spilonota laricana Previous status: Introduced from EuropeRevised status: No change; possible cryptic species in EuropeSupported by DNA in BOLD: YesBINs: BOLD:AAA7738 ; BOLD:AAA7739 (Finland)S. laricana are placed in two BINs in BOLD: BOLD:AAA7738 contains specimens from Europe  and Canada , while BOLD:AAA7739 contains specimens from Finland. These BINs are separated by 4.1% (p-dist).Sequences of S. ocellana [Historical records of this species in North America likely refer to ocellana ; thus itEucosma cana Previous status: Palearctic Revised status: Holarctic or Introduced?Supported by DNA in BOLD: YesBINs: BOLD:AAB4296E. cana in BOLD are placed in a single BIN (BOLD:AAB4296) with representatives from Europe  and Canada, which includes records from Cape Breton Highlands National Park in Nova Scotia, Sable Island National Park in Nova Scotia, Forillon National Park in Quebec, and Gros Morne National Park in Newfoundland. Records from Canada date back to as early as 2009. This is the first report of E. cana in North America.Specimens of Eucosma hohenwartiana Previous status: HolarcticRevised status: No changeSupported by DNA in BOLD: No (no specimens from North America in BOLD)BINs: BOLD:AAB4295E. hohenwartiana in BOLD are placed in a single BIN (BOLD:AAB4295), with all of the specimens from Europe. Ferris et al. [Sequences of s et al.  recordeds et al.  were unaPelochrista adamantana Previous status: HolarcticRevised status: NearcticSupported by DNA in BOLD: YesBINs: BOLD:AAF2211P. adamantana with sequence data in BOLD are from the U.S., and are placed in a single BIN (BOLD:AAF2211). This species has been listed as potentially Holarctic in some checklists because of the statement in the original description that it was described from \u201cex Lapponia (?),\u201d which could refer to Lapland in Finland. However, it has been excluded from European checklists since Rebel [The three specimens of ce Rebel  determince Rebel  appendedce Rebel  were unaPelochrista medullana Previous status: Introduced from EuropeRevised status: Not established in North AmericaSupported by DNA in BOLD: No (misidentifications and/or DNA barcodes do not separate species)BINs: BOLD:AAE7175P. medullana are placed in a single BIN (BOLD:AAE7175), along with specimens identified mostly as P. caecimaculana and a few other Pelochrista species from Europe. It is likely that the mixed species assignments to this BIN are the result of misidentifications. Pelochrista medullana was introduced into western North America for the biological control of Centaurea species (knapweed). This species was released in Idaho, Montana, Oregon, and British Columbia, but there is no evidence that it established in these locations [In BOLD, two specimens labeled as ocations ,136.Epiblema simploniana Previous status: HolarcticRevised status:Epiblema simploniana ; Epiblema arctica Miller, 1985, stat. rev. (Nearctic); other potential cryptic speciesSupported by DNA in BOLD: YesBINs: BOLD:ACO4599 ; BOLD:ACO4600 ; BOLD:AAF2136 ; BOLD:AAF2135 ; BOLD:ACJ7207 E. simploniana and its former junior synonym, E. arctica, are placed in five different BINs in BOLD: BOLD:ACO4599 contains specimens identified as E. arctica from the Ogilvie Mountains in the Yukon Territory, Canada; BOLD:ACO4600 contains specimens identified as E. arctica from the British Mountains in northwestern Yukon; BOLD:AAF2136 contains specimens identified as E. simploniana from Finland and Norway; BOLD:AAF2135 contains specimens labeled as E. simploniana from Finland; and BOLD:ACJ7207 contains specimens labeled as E. simploniana from Austria and Italy.Sequences of E. arctica from specimens collected in Alaska. He later [E. arctica was conspecific with E. simploniana, a Palearctic species recorded from the mountains of Central Europe, Scandinavia, western Russia, Siberia, and Mongolia [E. arctica in the Nearctic and E. simploniana in the Palearctic. In addition, we found what appear to be subtle but consistent morphological differences between E. arctica and E. simploniana that could be used to separate the two taxa (unpublished). Further research is necessary to determine why there are two separate BINs for E. arctica and three separate BINs for E. simploniana; this could indicate the possibility of one or more cryptic species in this group. Regardless, there is sufficient evidence to elevate E. arctica Miller, 1985, stat. rev., back to species status and restrict the distribution of E. simploniana to the Palearctic.Miller  describeHe later  determinMongolia . DNA barEpiblema sticticana Previous status: Palearctic Revised status: Holarctic or Introduced?Supported by DNA in BOLD: YesBINs: BOLD:AAC0719E. sticticana from Europe. It appears that this taxon is either Holarctic or newly introduced to North America.Specimens of this species are placed in a single BIN (BOLD:AAC0719) with representatives from Europe  and a single specimen from Canada. The specimen from Canada was collected in Gros Morne National Park in Newfoundland in 2009. It shares a 100% identical DNA barcode with 15+ specimens identified as Notocelia rosaecolana Previous status: Introduced from EuropeRevised status: No changeSupported by DNA in BOLD: YesBINs: BOLD:AAC1134 N. rosaecolana in BOLD are placed in a single BIN (BOLD:AAC1134) with representatives from Europe , Canada , and the U.S. . There is little genetic variation in this BIN, and many specimens share nearly identical DNA barcodes. A single specimen from the United Kingdom is placed in a separate BIN by itself (BOLD:AAC1135), but the DNA sequence is short and likely accounts for placement of this specimen.Specimens of N. rosaecolana, N. trimaculana, or both species were introduced to North America. The earliest record is from Smith [Eucosma suffusana (a junior synonym of N. trimaculana) from New Jersey. Various other publications refer to N. trimaculana or N. rosaecolana as being the introduced taxon. Miller et al. [N. rosaecolana is the only species of the two present in North America, and that prior literature records referring to N. trimaculana were likely incorrect.There has been a long history of attempting to determine if the European om Smith , who repr et al.  resolvedNotocelia cynosbatella Previous status: Introduced from EuropeRevised status: No change; potential cryptic species and/or misidentificationsSupported by DNA in BOLD: YesBINs: BOLD:AAC3245 (Canada); BOLD:AAC9709 (Europe); BOLD:AAC3246 (Europe and Canada)N. cynosbatella are placed in three separate BINs in BOLD: BOLD:AAC3245 contains specimens from Canada ; BOLD:AAC9709 contains specimens from Europe ; and BOLD:AAC3246 contains specimens from Europe and Canada. The last BIN also contains some specimens labeled as N. illotana. BINs are separated by 2.4\u20133.4% (p-dist).Sequences of N. cynosbatella in North America from specimens collected near Vancouver, British Columbia in 1978. Pohl et al. [Notocelia cynosbatella is very similar to N. illotana, which is native to North America. Although Mutuura [N. illotana, or that DNA barcodes in BOLD are not sufficient to separate these two species. It is also possible that there are cryptic species in this group.Mutuura  documentl et al.  list the Mutuura  providesGypsonoma parryana Previous status: HolarcticRevised status: No changeSupported by DNA in BOLD: No (misidentifications and/or DNA barcodes do not separate species)BINs: BOLD:AAB1285Gypsonoma, including G. parryana, G. nitidulana, G. fasciolana, G. salicicolana, and G. nebulosana. The sequences cluster into several groups, but it is not clear if many of the specimens in this BIN are misidentified or if these DNA data are not sufficient to separate out species. Pohl et al. [The BIN BOLD:AAB1285 contains specimens identified as several different species of l et al.  list thil et al. .Gypsonoma nitidulana Previous status: HolarcticRevised status: PalearcticSupported by DNA in BOLD: No (misidentifications and/or DNA barcodes do not separate species)BINs: BOLD:AAB1285G. parryana, G. nitidulana, G. fasciolana, G. salicicolana, and G. nebulosana). It is not known if many of these are misidentifications or if DNA barcodes are not able to separate species in this group.Sequences of this species are placed in BIN BOLD:AAB1285, along with sequences of the previous taxon and several other species Previous status: Introduced from EuropeRevised status: No changeSupported by DNA in BOLD: YesBINs: BOLD:AAB0379G. aceriana in BOLD are placed in a single BIN (BOLD:AAB0379) with specimens from Europe  and Canada. This species was first reported from North America in western Washington by Miller and LaGasa [G. aceriana that were collected in southwestern British Columbia as early as 1980. Subsequent collecting by LaGasa and Humble et al. [Sequences of d LaGasa . Severald LaGasa  reportede et al.  confirmeCrocidosema plebejana Zeller, 1847Previous status: HolarcticRevised status:Crocidosema plebejana ; potentially several other species, none with a Holarctic distributionSupported by DNA in BOLD: YesBINs: BOLD:AAA7083 ; BOLD:ABY9664 (Africa); BOLD:ACE9795 ; BOLD:AAA7084 C. plebejana in BOLD are separated geographically into several BINs. BOLD:AAA7083 contains specimens only from Australia; BOLD:ABY9664 contains specimens only from Africa; BOLD:ACE9795 contains specimens from Europe and Egypt; and BOLD:AAA7084 contains specimens from California, Texas, and Costa Rica. There is seemingly no regional overlap in the BOLD data, suggesting that each of these BINs might be a separate taxon. Distance between BINs varies from 1.4% (p-dist) between BOLD:AAA7083 and BOLD:ACE9795 to 4.3% (p-dist) between BOLD:AAA7084 and the other three BINs.Sequences of Crocidosema plebejana was originally described from Europe, and an additional 13 names, described from various parts of the world, are currently considered synonyms, including several from the New World. Some other species described from Hawaii and South America are closely related [C. plebejana is currently treated as a cosmopolitan species, it has been suggested that several of the synonyms are valid species [C. synneurota Meyrick  as a valid species and suggested other potential changes. The DNA data in BOLD suggest that at least populations on each continent might be separate taxa. Similarly, Lincango [C. plebejana, and the specimens of C. plebejana from Europe did not group with those from South America. Moreover, there is extreme variation in both male and female genitalia. A more comprehensive molecular analysis is necessary to clarify the identity of the species involved. For now, we believe C. plebejana should be restricted to the Palearctic, and that none of the taxa involved in this complex are Holarctic in distribution. related ,144. Alt species . Razowsk species  resurrecLincango  in a mulCrocidosema lantana Busck, 1910Previous status: Holarctic?Revised status: Neotropical; introduced elsewhere for biocontrolSupported by DNA in BOLD: Yes BINs: BOLD:AAH5763 C. lantana in BOLD are placed in a single BIN (BOLD:AAH5763), with specimens from Costa Rica, Jamaica, Australia, Madagascar, and Kenya.The sequences of Lantana [Crocidosema lantana has been introduced to Kenya [C. lantana is found in Florida.This species was introduced to Hawaii from Mexico in 1902 to control Lantana . It was Lantana . Crocidoto Kenya , and is Rhopobota naevana Previous status: HolarcticRevised status: No changeSupported by DNA in BOLD: YesBINs: BOLD:AAA9812In BOLD, the nearly 700 sequences representing this species fall into a single BIN (BOLD:AAA9812), with representatives from Canada, Europe, Japan, Pakistan, and the U.S. There is no evidence of any cryptic taxa.This species is most likely Holarctic, being recorded from North America as early as 1863 and 1869 based on junior synonyms described from Hudson Bay, Canada and Massachusetts. Gillespie and Gillespie  state thEpinotia trigonella Previous status: HolarcticRevised status: No changeSupported by DNA in BOLD: YesBINs: BOLD:AAB2504E. trigonella fall into a single BIN from Europe  and Canada . Sequences are clustered into three groups, with one consisting of mostly specimens identified as E. indecorana from Finland and Norway. Two specimens from Alaska identified as E. trigonella are placed in other BINs and most likely misidentified.Specimens identified as jasperana Brown, 1980 [E. trigonella. Aarvik [E. indecorana and E. trigonella as separate species, and Karsholt et al. [E. indecorana clustering separately from those of E. trigonella.DNA data support a Holarctic distribution for this species. Pohl et al.  include wn, 1980 , describ. Aarvik  treats Et et al.  follow tEpinotia solandriana Previous status: HolarcticRevised status: Holarctic?Supported by DNA in BOLD: No (sequence clustering is ambiguous)BINs: BOLD:AAA6716E. solandriana in BOLD are placed a single BIN (BOLD:AAA6716). However, sequences within this BIN are divided into two distinct clusters, with one representing North America  and the other representing Europe . This clustering of sequences could suggest that the European and North American populations represent different species, but more study is needed to determine the genetic variability of this species.Sequences of Epinotia solandriana is currently considered to be Holarctic [olarctic ,149. Marolarctic  suggesteEpinotia abbreviana Previous status: Introduced from EuropeRevised status: No changeSupported by DNA in BOLD: No (no specimens from North America in BOLD)BINs: BOLD:AAE1784Epinotia abbreviana is represented in BOLD with specimens from Europe placed in a single BIN (BOLD:AAE1784). This species was first recorded from North America by Dang [E. abbreviana reared from St. John\u2019s, Newfoundland in 1981 and 1988. by Dang , who docEpinotia nisella Previous status: Holarctic Revised status: No changeSupported by DNA in BOLD: YesBINs: BOLD:ABZ1141 ; BOLD:AAA7530 ; BOLD:AAA7528 E. nisella is placed in three BINs: BOLD:ABZ1141 containing specimens from Austria and Germany; BOLD:AAA7530 containing specimens from Europe and Alaska; and BOLD:AAA7528 containing specimens rom Canada and Alaska. Mutanen et al. [In BOLD, n et al.  providesE. cinereana). Epinotia nisella has a long list of synonyms, owing to its variable forewing pattern. This species is currently distributed throughout Europe and Russia to China and Japan, and has even been recorded from Iceland [Mutanen et al.  resolved Iceland . In NortEpinotia cinereana Previous status: HolarcticRevised status: No changeSupported by DNA in BOLD: YesBINs: BOLD:AAA7532 ; BOLD:AAA7529 ; BOLD:ABX4876 E. cinereana represented in BOLD are placed in three BINs: BOLD:AAA7532 containing specimens labeled as E. cinereana from Europe; BOLD:AAA7529 containing specimens labeled as E. criddleana from Canada; and BOLD:ABX4876 containing specimens labeled as E. cinereana from Europe and E. criddleana from Canada. Mutanen et al. [The specimens of n et al.  provide E. nisella. They determined (based on morphology) that the North American E. criddleana is a junior synonym of E. cinereana, resulting in a Holarctic distribution. Epinotia cinereana is widely distributed across Europe, with scattered records through Russia to Japan and China [Mutanen et al.  resolvednd China . In Nortnd China .Epinotia columbia Previous status: HolarcticRevised status: Nearctic; potential cryptic species in North AmericaSupported by DNA in BOLD: YesBINs: BOLD:AAF0407 ; BOLD:AAE1754 (Canada)Epinotia columbia is represented in BOLD with two BINs: BOLD:AAF0407 contains specimens from California and British Columbia, and BOLD:AAE1754 contains specimens from Canada . Both are separated from the BIN containing E. crenana (former senior synonym) from Europe (BOLD:AAE1756). It is not known which BIN represents E. columbia, although it was described from British Columbia, and the historic distribution has been limited to western North America. Thus, it is likely that BOLD:AAE1754 represents an undescribed cryptic species.columbia with E. crenana based on similarities in genitalia. In his unpublished Master\u2019s thesis, R. L. Brown [E. columbia back to species status; this change was formalized by J. Brown [E. columbia includes much of Canada west to British Columbia, Arizona, Nevada, Utah, and along the Pacific Coast to southern California [E. crenana.Heinrich  synonymiL. Brown  elevatedJ. Brown  in the tlifornia . There iEpinotia nanana Previous status: Introduced from EuropeRevised status: No changeSupported by DNA in BOLD: YesBINs: BOLD:AAA8628 ; BOLD:ACF5528 (Europe)E. nanana fall into two BINs in BOLD. BOLD:AAA8628 contains specimens from Canada , the U.S. (Connecticut), and Europe . BOLD:ACF5528 contains specimens from other locations in Europe . Both BINs cluster together and are separated by only 1.09% (p-dist). As such, it is likely they represent a single taxon with some geographic structuring.Sequences of Epinotia nanana was originally described from Germany, and in the Palearctic, it is widely distributed across Europe, ranging into Siberia and Mongolia [E. nanana by Heinrich [Eucosma domonana  was described from Framingham, Massachusetts, and Epinotia piceafoliana  was described from Essex County Park, New Jersey. The first record of E. nanana in western North America is from a single specimen collected in British Columbia at some point prior to 1965 [E. nanana established in British Columbia.Mongolia . The firHeinrich . Eucosma to 1965 . This spEpinotia medioplagata Previous status: HolarcticRevised status: No changeSupported by DNA in BOLD: No (no specimens from outside North America in BOLD)BINs: BOLD:AAB6354BOLD contains sequences of specimens from the U.S. and Canada placed in a single BIN (BOLD:AAB6354). There are no specimens from the Palearctic represented in BOLD. However, this species is also recorded from Magadan Region in the Russian Far East , and wasEpinotia cruciana Previous status: HolarcticRevised status: No change; potential cryptic speciesSupported by DNA in BOLD: YesBINs: BOLD:ABX2894 (Canada); BOLD:ACE9994 ; BOLD:AAC2644 E. cruciana fall into three BINs: BOLD:ABX2894 contains specimens from Canada ; BOLD:ACE9994 contains specimens from Canada  and two specimens from Italy; and BOLD:AAC2644 contains specimens from Europe  and much of Canada. The first BIN containing specimens only from Canada is more distant (2.2% p-dist) from the other two BINs, which are only separated by 1.2% (p-dist). It is likely that one or both of the BINs containing specimens from Europe represent the true E. cruciana.Sequences of Epinotia cruciana ssp. alaskae was described from Alaska; cockleana was described from western Canada; direptana was described from Hudson Bay, Canada; E. cruciana ssp. lepida was described from New Hampshire; and vilisana was described from Hudson Bay, Canada. This species was described from Sweden and has at least 15 junior synonyms, several of which are from North America . EpinotiEpinotia seorsa Heinrich, 1924Previous status: Holarctic?Revised status: NearcticSupported by DNA in BOLD: No (this species not present in BOLD)BINs: N/AE. seorsa includes western Canada  and California [blanchardi [The known distribution of lifornia . There alifornia  includedanchardi  as a junEpinotia salicicolana Kuznetsov, 1968Previous status: Introduced?Revised status: Holarctic or Introduced?Supported by DNA in BOLD: No (no specimens from North America in BOLD)BINs: N/AEpinotia salicicolana was described from the Kuril Islands in the Russian Far East and has been also recorded from Korea, Japan, China, and Taiwan [www.efauna.bc.ca). Pohl et al. [d Taiwan ,155. It l et al.  listed tDichrorampha vancouverana McDunnough, 1935Previous status: HolarcticRevised status: No changeSupported by DNA in BOLD: YesBINs: BOLD:AAC1223D. vancouverana are placed in a single BIN, BOLD:AAC1223, with specimens from Europe  and Canada . As the name suggests, D. vancouverana was described from Vancouver Island, British Columbia. Miller [D. vancouverana was the same species as the European D. gueneeana  and synonymized the two names.Sequences of . Miller  recognizTortrix politana from Austria (now a junior synonym of Lathronympha strigana). Guenee [Dichrorampha (now vancouverana) in Europe as politana; however, this was clearly a misidentification. Obraztsov [gueneeana as a replacement name for Guenee\u2019s misidentified politana. Because Guenee\u2019s reference to politana was simply a misidentification, it is likely that Obraztsov\u2019s gueneeana is invalid, because this was assigned as a replacement name and was not a new species description. Regardless, the species previously referred to as D. gueneeana in Europe can now be correctly referred to as the Holarctic D. vancouverana.The taxonomic history of this species is somewhat confusing. Denis and Schifferm\u00fcller  describe. Guenee  referredbraztsov  assignedDichrorampha sedatana Previous status: HolarcticRevised status: Holarctic?Supported by DNA in BOLD: No (misidentifications and/or DNA barcodes do not separate species)BINs: BOLD:AAA8637 ; BOLD:AAA8636 Dichrorampha sedatana can be problematic to separate from similar species such as D. aeratana, D. acuminatana, D. plumbana, and D. dana based only on wing pattern. A genitalic dissection is necessary to confirm identity in this group, and even then, identification is difficult due to variation. The majority of Dichrorampha in BOLD are not dissected, and thus, species identifications are sometimes questionable, especially when multiple species are assigned to the same BIN. Sequences of D. sedatana in BOLD are placed in two BINs. BOLD:AAA8636 contains specimens labeled as D. sedatana from Canada and specimens labeled as D. acuminatana from Europe. BOLD:AAA8637 contains specimens labeled as D. sedatana from Europe, specimens labeled as D. aeratana from Europe and Canada, and specimens labeled as D. tarmanni from Italy. Relatively low genetic diversity in both BINs suggests that multiple names in each BIN are a result of misidentifications, or that multiple species within this group share nearly identical DNA barcodes. It is not possible to determine the status of these taxa without extensive examination of the specimens from this group represented in BOLD.Dichrorampha sedatana is currently treated as Holarctic [D. sedatana specimens identified in Europe seem to be different from those identified in North America . However, the BOLD data are currently not sufficient to support this conclusion because of apparent issues with species identifications. Pohl et al. [D. plumbana  for North American populations is erroneous.olarctic . It has l et al.  noted thDichrorampha odorata Brown and Zachariades, 2007Previous status: Introduced?Revised status: Probably native to southern Florida/CaribbeanSupported by DNA in BOLD: No (this species not present in BOLD)BINs: N/AThis species was described from Jamaica in 2007, but was found in Florida in 2014 feeding on weeds. There is no evidence it is introduced, and thus, it is probably native to the region and simply not detected in Florida until recently. This species is not represented in BOLD.Dichrorampha petiverella Previous status: Introduced from EuropeRevised status: No changeSupported by DNA in BOLD: YesBINs: BOLD:AAC9827D. petiverella in BOLD are placed in a single BIN (BOLD:AAC9827) representing Europe  and North America .Specimens of D. petiverella is also present in Ontario, Quebec, and Washington. Pohl et al. [Roberts  documentl et al.  recordedDichrorampha acuminatana Previous status: Introduced from EuropeRevised status: No changeSupported by DNA in BOLD: No (misidentifications and/or DNA barcodes do not separate species)BINs: BOLD:AAA8637 ; BOLD:AAA8636 D. sedatana for a discussion of the DNA data for this group of species. Dichrorampha acuminatana was first discovered in North America in 2001 in Washington County, Maine [See y, Maine . This spy, Maine , and they, Maine  recordedDichrorampha montanana Previous status: Introduced from EuropeRevised status: No change; cryptic species in EuropeSupported by DNA in BOLD: YesBINs: BOLD:AAE0714 ; BOLD:AAE0715 Dichrorampha montanana is represented in BOLD in two BINs: BOLD:AAE0715 contains specimens from Europe , and BOLD:AAE0714 contains specimens from Europe  and Canada (Newfoundland). It is assumed that BOLD:AAE0714 is the \u201ctrue\u201d D. montanana because it contains a specimen from Canada that was verified via dissection. Huemer [D. montanana for the first time from North America with specimens from Newfoundland that were confirmed via genitalic dissection.. Huemer  stated t. Huemer  recordedDichrorampha aeratana Previous status: Palearctic Revised status: Introduced from EuropeSupported by DNA in BOLD: No (misidentifications and/or DNA barcodes do not separate species)BINs: BOLD:AAA8637 ; BOLD:AAA8636 D. sedatana for a discussion of the DNA data for this group of species. Sabourin [D. aeratana from North America with specimens first collected in 1992 in Vermont. Sabourin [See Sabourin  reportedSabourin  also repGrapholita molesta Previous status: Introduced from AsiaRevised status: No changeSupported by DNA in BOLD: YesBINs: BOLD:AAB0523G. molesta fall into a single BIN (BOLD:AAB0523) with a worldwide distribution. The earliest records of G. molesta in North America are from Washington, D.C., where it was apparently introduced in flowering cherry from Japan in 1912 or 1913 [In BOLD, specimens of  or 1913 . It has Grapholita delineana Walker, 1863Previous status: Introduced from AsiaRevised status: No changeSupported by DNA in BOLD: No (no specimens from North America in BOLD)BINs: BOLD:AAY2279 ; BOLD:ABW6517 (South Korea)G. delineana in BOLD are placed in two BINs: BOLD:AAY2279 contains specimens from Pakistan and Japan, and BOLD:ABW6517 contains a single specimen from South Korea. It is possible the South Korean specimen is misidentified.Specimens of Grapholita delineana is a native of East Asia that spread into Europe, Asia Minor, Transcausasia, and North America with the commercial production of hemp [G. delineana to be present in hemp fields in eastern Colorado in 2017\u20132018, and it is likely that this species will continue to spread with expanded industrial hemp production. of hemp ,165. The of hemp ,165. Cra of hemp  found G.Grapholita aureolana Previous status: HolarcticRevised status: No changeSupported by DNA in BOLD: YesBINs: BOLD:AAE7252Grapholita aureolana fall into a single BIN in BOLD (BOLD:AAE7252), with specimens from Europe  and Canada. Pohl et al. [Sequences of l et al.  were theCydia coniferana Previous status: Introduced from EuropeRevised status: No change; potential cryptic species in western North AmericaSupported by DNA in BOLD: YesBINs: BOLD:AAC6167 (Europe and Canada); BOLD:AAC6168 (western U.S.)Cydia coniferana is represented in BOLD by sequences that fall into two BINs: BOLD:AAC6167 contains specimens from Europe  and Canada (Ontario), and BOLD:AAC6168 contains specimens from the western U.S. .This species was first reported from North America by Schaffner  for seveC. coniferana did establish in eastern North America, with one specimen collected in 2015 from Peterborough in Central Ontario represented in BOLD. It is likely that the populations in the Pacific Northwest and elsewhere in western North America (New Mexico) represent a cryptic species. There are also records of this species from the Russian Far East [C. coniferana. Based on the DNA sequence data, it seems that a population of Far East ; these aCydia nigricana Previous status: Introduced from EuropeRevised status: No change; potential cryptic species in North AmericaSupported by DNA in BOLD: YesBINs: BOLD:AAA7614 (Europe and Canada); BOLD:AAE7682 (North America)C. nigricana in BOLD are placed into two separate BINs: BOLD:AAA7614 contains specimens from Europe  and Canada , and this BIN likely represents the true C. nigricana, which was described from Great Britain; the second BIN (BOLD:AAE7682) contains specimens from only North America , and represents either a group of misidentified specimens or a potential cryptic species. There are two junior synonyms of C. nigricana that were described from the U.S. , and it is possible that one or both of these names could be applied to specimens in BOLD:AAE7682. Cydia nigricana was introduced from Europe, and first found in North America in eastern Canada in 1893 and in British Columbia in 1933 [Sequences of  in 1933 .Cydia pomonella Previous status: Introduced from EuropeRevised status: No changeSupported by DNA in BOLD: YesBINs: BOLD:AAA3532C. pomonella in BOLD are placed into a single BIN (BOLD:AAA3532) that consists of specimens collected throughout the world. There is no evidence of any cryptic species. The earliest record of C. pomonella in North America is a report of wormy apples and pears in the vicinity of Boston in 1819 [Sequences of  in 1819 . The \u201ccoCydia saltitans , stat. rev.Previous status: IntroducedRevised status: Neotropical; not present in the U.S.Supported by DNA in BOLD: YesBINs: BOLD:AAA0992Cydia deshaisiana Lucas, 1858 in most modern publications. Although this name was published by Lucas in November, 1858 [deshaisiana is a nomen nudum. The behavior of this insect (\u201cjumping seeds\u201d) had actually been described a year earlier by Westwood in 1857 [Carpocapsa saltitans [The name for the \u201cMexican jumping bean\u201d moth has traditionally been cited as er, 1858 , his acc in 1857 , althougaltitans ,172.C. saltitans, unless we simply use the June 7, 1858 date when the paper was first read and assume it was published in the next issue of the Proceedings in July. Regardless, the correct name for the \u201cMexican jumping bean\u201d moth is Cydia saltitans , stat. rev.Determining the exact date this description was published is difficult. The Proceedings of the Entomological Society of London were published on an irregular basis, most often quarterly. Wheeler  listed dC. saltitans appears to be restricted the northern states of Sinoloa and Sonora in Mexico.The only specimens in BOLD are from Costa Rica in (BOLD:AAA0992), and there is no evidence of this species occurring north of Mexico. \u201cMexican jumping beans\u201d are routinely imported into the U.S. and adult moths eventually emerge from the seeds. However, there are no records of this species being found in the wild in the U.S., and the distribution of Cydia cornucopiae Previous status: Holarctic?Revised status: No changeSupported by DNA in BOLD: No (no specimens from North America in BOLD)BINs: BOLD:AAF7704This species was first reported from North America in Alaska by Ferris et al. . It is oThaumatotibia leucotreta Previous status: IntroducedRevised status: Not established in North AmericaSupported by DNA in BOLD: YesBINs: BOLD:AAE7729This species is native to Africa. A single male specimen was found in a pheromone trap in Ventura County, California in July, 2008 . AlthougConiostola isabelae Razowski and Landry, 2008Previous status: Neotropical Revised status: No changeSupported by DNA in BOLD: No (this species not present in BOLD)BINs: N/AThis species was described from the Galapagos Islands. Razowski and Becker  reportedSubfamily CHLIDANOTINAEAuratonota dispersa Brown, 1990Previous status: Exotic, not established Revised status: No changeSupported by DNA in BOLD: No (insufficient records in BOLD)BINs: BOLD:AAJ9640This species is native to Central America, e.g., Guatemala to Panama . It has Determining whether a species is natively Holarctic or a relatively recent immigrant to North America from Eurasia is often difficult, even with the assistance of DNA data. Based on an established set of criteria, we evaluated 151 species of Tortricidae putatively documented from North America and hypothesize their origin. A summary of the data is presented in The overall number of tortricids introduced to North America is similar to those recently reported by other authors, e.g., Pohl et al. . A totalThe overall importance of introduced taxa cannot be overstated, and the environmental and economic costs from invasive species continue to increase. Hence, it is critically important to recognize these pests and distinguish them from species that are natively Holarctic. Based on the entire order Lepidoptera, the superfamily Tortricoidea has the third highest number of economically important species , trailing only Noctuoidea, with 1034 pests, and Pyraloidea, with 748 pests . Further"}
+{"text": "There is an error in the Competing Interests statement. The correct Competing Interests statement is as follows: Co-author K. Nakayama is a co-founder and shareholder of Cyfuse Biomedical KK. and an inventor/ developer designated on the patent for the Bio-3D printer. Patent title: Method for Production of Three-Dimensional Structure of Cells; patent number: JP4517125. Patent title: Cell Structure Production Device; patent number: JP5896104. The other authors have declared that no competing interests exist. This does not alter the authors\u2019 adherence to PLOS ONE policies on sharing data and materials."}
+{"text": "Bathytoshialata, Dasyatismarmorata, Dasyatispastinaca, Dasyatistortonesei, Himanturauarnak, Pteroplatytrygonviolacea and Taeniuragrabata. Papaconstantinou (2014) listed four species of Dasyatidae occurring in Greece . However, the marbled stingray (D.marmorata) was not amongst them. Here, the presence of D.marmorata was examined for the first time in Greece.Currently, seven dasyatid species have been described in the Mediterranean Sea: D.marmorata in the Eastern Mediterranean Sea. A juvenile male stingray was captured in February 2019, during an onshore survey in Maliakos Gulf, located in the central Aegean Sea, Greece. The ray was examined at the Fisheries laboratory of the Hellenic Centre for Marine Research (HCMR) in Athens and was identified as D.marmorata. Morphological characters were recorded and DNA barcoding was applied to confirm the species identification. The combination of the two methods verified the occurrence of the marbled ray in the Greek waters. This is the first record of D.marmorata from the Aegean Sea.The present study provides updated information on the geographical distribution of  Dasyatidae have been described in the Mediterranean Sea, which is the result of considerable updating of species occurrence in the region; for example, the roughtail stingray, valid as Dasyatiscentroura Mitchill, 1815, that was previously reported inhabiting the Mediterranean Sea, is now considered to be solely distributed along the Western coasts of the Atlantic Ocean, whereas its closely related species, the brown stingray Bathytoshialata Garman, 1880, occupies the Mediterranean and the eastern coasts of Africa  for males and females, respectively and the gestation period lasts around three to four months, with litter size of two to four embryos   Fig. . The occea) Fig. . The spe2 (1.5 mM), 200 \u03bcM of each deoxyribonucleotide triphosphate , 0.5 \u03bcl (300 \u03bcM) of each primer, 1 U GoTaq G2 Flexi polymerase (Promega) and 14.5 \u03bcl molecular grade water. Subsequently, the PCR product was sequenced commercially .Genomic DNA was extracted using the Chelex resin protocol . DNA barhttp://blast.ncbi.nlm.nih.gov/Blast.cgi) and the BOLD database .The sequence was compared with those available in GenBank using the standard nucleotide BLAST (blastn) against the nucleotide collection (nr/nt) database A39C719A-0311-5D12-B498-3FA2DAB02AE9Type status:Other material. Occurrence: occurrenceRemarks: collected dead in fishing nets; recordedBy: Stefanos Kavadas; individualCount: 1; sex: male; lifeStage: juvenile; reproductiveCondition: non-reproductive; preparations: whole animal, photographs, DNA extract; associatedSequences: MT044303GenBank: ; Taxon: kingdom: Animalia; phylum: Chordata; class: Chondrichthyes; order: Myliobatiformes; family: Dasyatidae; genus: Dasyatis; taxonRank: species; vernacularName: marbled stingray; Location: continent: Europe; waterBody: Aegean Sea; country: Greece; countryCode: GR; municipality: Central Greece; locality: Maliakos Gulf; verbatimLatitude: 38.882326; verbatimLongitude: 22.592301; verbatimCoordinateSystem: decimal degrees; Identification: identificationID: 371208; identificationReferences: Cyclostomata from the North-eastern Atlantic and the Mediterranean. Iglesias 2013\".\"Rays of the world. Last et al. 2016\". \"Chondrichthyans and ; identificationRemarks: blue blotches on pectoral fins, disc length vs. disc width; Event: samplingProtocol: trammel net; samplingEffort: 27 sampling hours; eventDate: 2019-02-09T09:00+0200; startDayOfYear: 39; endDayOfYear: 40; year: 2019; month: February; day: 9; habitat: muddy bottom; fieldNumber: 1902MLGT/T1H1/CM1; Record Level: type: By-catch entanglement; language: en; rightsHolder: Hellenic Centre for Marine Research; institutionCode: HCMR; basisOfRecord: Dead specimenThe collected specimen was a juvenile male measuring 330 mm in total length, 160 mm in disc length and 188 mm in disc width and weighing 171.8 g . Additionally, twenty six morphological characters were also recorded Table  and the D.marmorata (1.5 times) than that from D.pastinaca (1.8-2 times) (MT044303). The barcode search on GenBank produced clear top matches with 100% similarity to Dasyatismarmorata records reported in the database. Additionally, BOLD comparisons showed similar matching rates. The molecular results obtained verified the macroscopic identification of the species.Morphological measurements were expressed as percentage of DW as previously proposed for sting rays  and are 2 times) b. PrevioD.marmorata, collected in Greek waters, extending its distribution further into the Eastern Mediterranean Sea. Morphological measurements and molecular tools were combined to identify the species in the studied area. This is consistent with recent records of D.marmorata along the Turkish coast (Bilecenoglu in D.marmorata). Species records from the latest book of fish fauna in Greece do not include the marbled ray , in collaboration with the Fisheries Research Institute . Priority should be given to rare and vulnerable species occurring in the Eastern Mediterranean, to improve their conservation and restrict further biodiversity loss. Furthermore, this study highlights the utility of DNA barcoding in assisting species identification and its role to accurately determine the occurrence and distribution of species."}
+{"text": "Comparison of different surgical approaches for pediatric cataracts: complications and rates of additional surgery during long-term follow-upIn the article Figure 1 for:Replace"}
+{"text": "Colorectal carcinoma (CRC) is among the most common cancers with high morbidity and mortality among all malignancies, and the most common CRC is colon adenocarcinoma (CA).Overall, we obtained genome\u2010wide sequencing data from a cancer genome atlas of 319 patient cohorts . Lili Yan: Data curation . Yang Lu: Software . Dongfeng Liu: Methodology . Jia Niu: Writing\u2010original draft . Liyong Yin: Writing\u2010review & editing ."}
+{"text": "The online version has been amended.In this paper by Harriet Forbes and colleagues (BMJ 2021;372:n628, doi:"}
+{"text": "Plasmodium vivax, the most widespread Plasmodium species in the world. This species has been neglected and understudied for a long time, due to its lower mortality in comparison with Plasmodium falciparum. A renewed interest has emerged in the past decade with the discovery of antimalarial drug resistance and of severe and even fatal human cases. Nonetheless, today there are still significant gaps in our understanding of the population genetics and evolutionary history of P. vivax, particularly because of a lack of genetic data from Africa. To address these gaps, we genotyped 14 microsatellite loci in 834 samples obtained from 28 locations in 20 countries from around the world. We discuss the worldwide population genetic structure and diversity and the evolutionary origin of P. vivax in the world and its introduction into the Americas. This study demonstrates the importance of conducting genome-wide analyses of P. vivax in order to unravel its complex evolutionary history.More than 200 million malaria clinical cases are reported each year due to  Plasmodium species infecting humans, P. vivax is the most prevalent parasite outside Africa. To date, there has been less research on this species than for Plasmodium falciparum, a more lethal species, principally because of the lack of an in vitro culture system and also because P. vivax is considered relatively benign. Nevertheless, P. vivax is responsible for severe and incapacitating clinical symptoms with significant effects on human health. The emergence of new drug resistance and the discovery of severe and even fatal cases due to P. vivax question the benign status of P. vivax malaria. In recent years, there has been increased interest in characterizing the distribution of genetic variation in P. vivax. However, these studies either generated genetic information from a regional geographic scale or combine genetic datasets generated in different molecular platforms, which is known to generate biased results. In this study, we used a single genotyping platform to genotype 14 microsatellite markers in 834 samples of P. vivax obtained from 28 locations in 20 countries from around the world, including several populations from East and West Africa. We discuss the worldwide population genetic structure and the evolutionary origins of P. vivax, as well as its introduction into the Americas.Among the five  Plasmodium parasites are the agents responsible for malaria, one of the worst scourges of mankind, with almost 600,000 infant deaths and about 200 million clinical cases reported each year)ilibrium . In contilibrium . P. vivar others  Tables. observed , indicatulations , which cAt a worldwide scale, populations tend to group together according to their geographic locations but the relationships between populations of different geographic origins are far less obvious Figs  and 4. OP. vivax as well as the effect of more recent demographic events like population contraction, expansion or founding events.The variations of genetic diversity and genetic differentiation observed among populations at a worldwide scale are likely the consequence of the history of colonisation of the world by P. vivax and its spread throughout the world: the \u201cOut of Asia\u201d scenario and the \u201cOut of Africa\u201d scenario. Although these two hypotheses were based on different lines of evidence, the \u201cOut of Africa\u201d hypothesis has enjoyed renewed interest in recent years following the discovery of parasites closely related to P. vivax in African apes (named P. vivax-like) and the observation that human P. vivax diversity appears to be nested within that of the P. vivax-like parasites. This discovery has led some researchers to suggest that human strains of P. vivax originated following the transfer of parasites from African great apes to humans [P. vivax in sub-Saharan human populations, associated to the absence at the surface of their red blood cells of the Duffy antigen (i.e. Duffy negativity), suggesting that the Duffy-negative mutation was selected a long time ago in response to P. vivax infection [P. vivax was inferred from just a few nuclear genes and partial mitochondrial genomes and is consistent with several alternative scenarios. Indeed, such phylogenetic patterns can also be obtained because of incomplete lineage sorting or because of a lack of phylogenetic signal for the sequences used, two phenomena that are frequent when species have recently diverged (which is the case for P. vivax and P. vivax-like). We recently showed, comparing P. vivax-like genomes to those of P. vivax, that incongruent phylogenies may be obtained when one limits the analyses to a single or a couple of genes [P. vivax, with the high genetic diversity obtained in current Asian P. vivax parasite populations in comparison to the rest of worldwide P. vivax parasites? This pattern of genetic diversity is the opposite for P. falciparum, which has a well-established African origin [P. vivax [P. vivax among Plasmodium parasite species infecting mostly wild Asian monkeys (about fifteen monkey species\u2019) also calls into question the \u201cOut of Africa\u201d hypothesis.Two scenarios have been proposed to explain the origin of o humans ,33. The nfection . Howeverof genes . Second,n origin . Indeed,P. vivax . FinallyP. vivax at a worldwide scale, then our results based on microsatellite markers, would be more congruent with an Asian origin and a spread from Asia of the current populations of P. vivax found worldwide in humans. Genetic diversity and allelic richness are highest in South-East Asian P. vivax populations and decrease from South East Asia to East Africa  are clearly insufficient to disentangle the impact of recent and ancient demographic events on the distribution of P. vivax genetic variability. More extensive analyses of the population genetic structure of these parasites, using whole genome data and some tests of demographic scenarios, might be necessary to resolve the origin and evolution of these parasites.One may nevertheless advocate that some of these genetic patterns (e.g. the decrease of genetic diversity from Asia to Africa) could also be the consequence of the current differences in population size of the P. vivax populations from South America  and Central America (Mexico and Honduras)  appear to be more closely related to some African populations (the Mauritanian P. vivax population), thus suggesting a double origin of P. vivax in America (Asian and African). Moreover, we found that American P. vivax populations harbour low levels of genetic variation. These results are consistent with a scenario in which American P. vivax populations were introduced from multiple sources. This possibility of introduction from multiple locations has already been mentioned in several recent studies based on the analysis of different kinds of genetic markers [P. vivax populations contributed to the current diversity of P. vivax observed in South America [P. vivax dated between 1942 and 1944 that European isolates were closely related to the most common present-day American haplotype [P. vivax likely entered the American continent during the post Columbian contact [P. vivax parasites seem to be characterized by a recent history through multiple introductions and the next steps will be to identify the sources of introduction and to date such events.Within the Americas, a separation is observed between onduras) . When coonduras) , it seem markers ,38. Rodr America . Gelaberaplotype . This su contact . To concP. vivax populations. The highest genetic diversity is again observed in South East Asian P. vivax populations in comparison to the populations of the rest of the world, which argues again the suggested African origin of current human P. vivax. Concerning the colonization of the American continent, results obtained in our study seem to suggest a double origin from Africa (or Europe) and Asia, as already suggested by different studies [P. vivax are needed, including the study of ancient European P. vivax strains.This study confirmed the worldwide genetic structure of  studies ,37\u201339. IS1 FigFST computed using an island model. Red: area including the highest 5% neutral FST. Yellow: area including the lowest 5% neutral FST.The microsatellite markers suspected to be under positive selection (MS3 and MS6) are displayed. Grey: area including 95% of the neutral (PDF)Click here for additional data file.S2 FigRed and orange dots indicate the bootstrap values, ranging from 0.9 to 1, and from 0.6 to 0.89 respectively. The only difference detectable is that the AFR+MRT cluster is associated to the Central American populations when considering the full microsatellite markers set, whereas it is distinct when getting rid of the two markers detected under positive selection (MS3 and MS6). AFR: Central African Republic + Cameroon + Togo; ARM: Armenia; AZE: Azerbaijan; BAN: Bandarban; BAY: Bay Islands; CAM: Camopi; CAY: Cayenne; COX: Cox\u2019s Bazar; ETH: Ethiopia; HLF: New Halfa; HND: Honduras; IND: India; IRN: Iran; KGR: Khagrachari; KHA: Khartoum; MEX: Mexico; MRT: Mauritania; PAK: Pakistan; PER: Peru; STG: Saint Gorges de l\u2019Oyapock; THA: Thailand; TMY: Thailand/Myanmar; TUR: Turkey; VEN: Venezuela. In yellow are represented Asian countries, in purple Middle-east countries, in grey African countries and in green American countries.(PDF)Click here for additional data file.S3 FigIn yellow are represented Asian countries, in purple Middle-east countries, in grey African countries and in green American countries.(PDF)Click here for additional data file.S4 FigIn yellow are represented Asian countries, in purple Middle-east countries, in grey African countries and in green American countries.(PDF)Click here for additional data file.S5 FigST). A. Asian/Middle East continent and B. American continent. Mantel tests gave P-values < 0.05 for both continents tested.Pairwise geographic along landmasses plotted against pairwise genetic differentiation (F(PDF)Click here for additional data file.S1 TableAll isolates were genotyped by us for the 14 microsatellite loci. NA: non-available information.(DOCX)Click here for additional data file.S2 TableFor markers on the same chromosome, distances are enough to limit any physical linkage: MS2, MS5 and MS6 are at a minimum at 0.15Mb apart from each others; MS7 and MS8 are 1.14Mb appart; MS12 and MS15 are 1.04Mb appart.(DOCX)Click here for additional data file.S3 TableFor microsatellite genotypes, blank cases correspond to the absence of readable amplification/genotype.(DOCX)Click here for additional data file.S4 TableAFR: Central African Republic + Cameroon + Togo; ARM: Armenia; AZE: Azerbaijan; BAN: Bandarban; BAY: Bay Islands; CAM: Camopi; CAY: Cayenne; COX: Cox\u2019s Bazar; ETH: Ethiopia; HLF: New Halfa; HND: Honduras; IND: India; IRN: Iran; KGR: Khagrachari; KHA: Khartoum; MEX: Mexico; MRT: Mauritania; PAK: Pakistan; PER: Peru; STG: Saint Gorges de l\u2019Oyapock; THA: Thailand; TMY: Thailand/Myanmar; TUR: Turkey; VEN: Venezuela.(DOCX)Click here for additional data file.S5 TableARM: Armenia; AZE: Azerbaijan; BAN: Bandarban; BAY: Bay Islands; CAM: Camopi; CAY: Cayenne; COX: Cox\u2019s Bazar; ETH: Ethiopia; HLF: New Halfa; HND: Honduras; IND: India; IRN: Iran; KGR: Khagrachari; KHA: Khartoum; MEX: Mexico; MRT: Mauritania; PAK: Pakistan; PER: Peru; STG: Saint Gorges de l\u2019Oyapock; THA: Thailand; TMY: Thailand/Myanmar; TUR: Turkey; VEN: Venezuela.(DOCX)Click here for additional data file.S6 TableP-value < 0.008 (Bonferroni correction).*(DOCX)Click here for additional data file.S7 TableAll significant values are indicated in bold . AFR: Cantral African Republic + Cameroon + Togo; ARM: Armenia; AZE: Azerbaijan; BAN: Bandabar; BAY: Bay Islands; CAM: Camopi; CAY: Cayenne; COX: Cox\u2019s Bazar; ETH: Ethiopia; HLF: New Halfa; HND: Honduras; IND: India; IRN: Iran; KGR: Khagrachari; KHA: Khartoum; MEX: Mexico; MRT: Mauritania; PAK: Pakistan; PER: Peru; STG: Saint Georges de l\u2019Oyapock; THA: Thailand; TMY: Thailand/Myanmar; TUR: Turkey; VEN: Venezuela.(DOCX)Click here for additional data file."}
+{"text": "In \u201cRecommendations From the Twitter Hashtag #DoctorsAreDickheads: Qualitative Analysis :e17595), the authors noted three errors.In the originally published manuscript, the fourth sentence of the second paragraph of the Introduction section read:The term originated from a professional YouTube video maker, who posted a video on Twitter explaining that she had been diagnosed with Ehlers-Danlos syndrome and postural orthostatic hypotension syndrome (POTS).This has been changed to:The term originated from a professional YouTube video maker, who posted a video on Twitter explaining that she had been diagnosed with Ehlers-Danlos syndrome and postural orthostatic tachycardia syndrome (POTS).a originally read:In Table 2, footnote POTS: postural orthostatic hypotension syndrome.This has been changed to:POTS: postural orthostatic tachycardia syndrome.The Abbreviations section originally included the following:POTS: postural orthostatic hypotension syndrome.This has been changed to:POTS: postural orthostatic tachycardia syndrome.These corrections will appear in the online version of the paper on the JMIR Publications website on November 9, 2020, together with the publication of this correction notice. Because this was made after submission to PubMed, PubMed Central, and other full-text repositories, the corrected article has also been resubmitted to those repositories."}
+{"text": "Correction to:Movement Ecology (2023) 11:2010.1186/s40462-023-00378-1Following publication of the original article , the autThe statement in the \u2018Availability of data and materials\u2019 section originally read: We will make our data publicly available upon publication.The statement should read: The datasets generated for this study are available on request to the corresponding author.The original article  has been"}
+{"text": "In the manuscript \u201cIsolated and combined association of excessive screen time and physical inactivity with negative self-rated health in adolescents\u201d, DOI: 10.1590/1984-0462/2023/41/2022077, published in the Rev Paul Pediatr. 2023;41:e2022077:On the top of the first page:Where it reads:Jean Carlos Parmigiani de MarcoIt should read:Jean Carlos Parmigiani De Marco"}
+{"text": "Correction to: BMC Health Services Research (2023) 23:71110.1186/s12913-023-09725-9Following publication of the original article , the autThe incorrect author name is: Zahra Hadian ShiaziThe correct author name is: Zahra Hadian ShiraziThe author group has been updated above and the original article  has been"}
+{"text": "There are errors in the Funding section. The correct Funding statement is: Specific grant number: GST03 Initials of authors who received award: AvS Specific grant number: EDU/0500057415 Initials of authors who received award: AvS, HYFull names of commercial companies that funded the study or authors: no commercial company funded the study or authors.Work preparatory to this meta-analysis was funded by the Organization for Economic Cooperation and Development (Contract Reference: EDU/0500057415).The systematic literature search and the coding for this meta-analysis was funded by the Global TIES for Children Research Center at New York University Abu Dhabi (GST03).https://nyuad.nyu.edu/en/research/faculty-labs-and-projects/global-ties-for-children.htmlURL to sponsor\u2019 website: The funders (other than the named authors) had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."}
+{"text": "J Pediatr 2022;241:203; Open Forum Infect Dis 2022;9(2):ofac492.626) that residents trained in a structured communication strategy called AIMS  demonstrated specific behaviors of interest during live and virtual encounters with standardized patients (SPs) portraying vaccine-hesitant parents. The current study was conducted to determine if those behaviors were prioritized long after completion of training.We previously showed  or standard of care training ; blinding was maintained after training and until the time of the current study. Subjects were invited to complete an online survey wherein 10 possible communication behaviors were ranked from highest priority to lowest priority . Respondents were considered to have prioritized AIMS behaviors if they ranked each of the 3 AIMS items in the top 5; the ability of this measure to detect prioritization of AIMS behaviors was assessed by surveying unblinded residents who underwent AIMS training in the prior 2 weeks . Differences between groups were assessed using Chi-square tests for proportions. We hypothesized that a higher proportion of subjects in the AIMS Group would prioritize AIMS behaviors compared to subjects in the Control Group.p-value = 0.003). However, only 19% of the 32 residents in the AIMS Group met criteria for prioritization of AIMS behaviors .Characteristics of study participants are shown in Figure 3. Seventy-seven percent of the 31 residents in the Validation Group met criteria for prioritization of AIMS behaviors, compared with only 38% of the 32 subjects in the Control Group (AIMS communication behaviors are ranked highly shortly after training, but this prioritization is not retained over time. Future studies of the utility of structured vaccine hesitancy communication strategies should incorporate repetition and spaced retrieval to enhance retention and ensure deployment in practice.Shanna M. Barton, MD, M.Sc., Sanofi Pasteur: Grant/Research Support Gary S. Marshall, MD, GSK: Advisor/Consultant|GSK: Grant/Research Support|GSK: Honoraria|Merck: Advisor/Consultant|Merck: Grant/Research Support|Merck: Honoraria|Moderna: Advisor/Consultant|Moderna: Grant/Research Support|Moderna: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Pfizer: Honoraria|Sanofi: Advisor/Consultant|Sanofi: Grant/Research Support|Sanofi: Honoraria|Seqirus: Advisor/Consultant|Seqirus: Grant/Research Support|Seqirus: Honoraria"}
+{"text": "Journal of Pharmaceutical Health Care and Sciences (2023) 9:1310.1186/s40780-023-00281-2The original publication of this article contained an incorrect title.The correct and incorrect title are listed below, the original article has been updated.Rhabdomyolysis caused by interaction between rosuvastatin and vadadustat: a case control studyRhabdomyolysis caused by interaction between rosuvastatin and vadadustat: a case report"}
+{"text": "Correction: Journal of Orthopaedic Surgery and Research (2022) 17:544 10.1186/s13018-022-03434-5Following publication of the original article , the autThe incorrect author name is: Jingxing ZhaoThe correct author name is: Jingxin ZhaoThe author group has been updated above and the original article  has been"}
+{"text": "Caption: Section of the digestive gland of a cockle infected with Marteilia cochillia.Credit: Dr. Antonio Villalba."}
+{"text": "To the editor,We thank Dr. Sasaki, Dr. Suzaki, and Dr. Ueki for their interest and comments on the letter entitled \u201cPredictive significance of Charcot\u2010Leyden crystal structures for nasal polyp recurrence\u201d,However, we readily acknowledge that detection of CLCs by H&E staining has some issues as proposed by Ueki et\u00a0al. First, we believe that the most critical factor determining staining success is the optimal eosin pH value. Actually, many commercial eosin solutions could detect eosinophils perfectly but not CLCs. It should also be noted that CLCs identified by H&E staining may be interfered by other eosinophilic components, which can be improved by optimizing the eosin solution pH value. Second, CLCs count may vary depending on the different fields of view. In fact, CLCs are preferentially detected in the nasal mucosa tissue that is in close proximity to denuded epithelium and eosinophil degranulation.Yurong Bai: Data curation (lead); Formal analysis (lead); Methodology (lead); Writing \u2013 original draft (lead). Wenyi Chen: Data curation ; Methodology ; Validation . Weifeng Kong: Methodology (supporting); Software; . Xin Luo: Methodology (supporting); Software (supporting). Jingyuan Chen: Methodology (supporting); Software . Xinyue Wang: Methodology (supporting); Software . Qingwu Wu: Methodology (supporting); Software . Jianning Chen: Methodology (supporting); Resources . Qintai Yang: Funding acquisition (supporting); Investigation ; Project administration ; writing \u2013 review & editing . Yana Zhang: Conceptualization (lead); Funding acquisition (lead); Investigation ; Project administration (lead); Resources (lead); Supervision (lead); writing \u2013 original draft (supporting); writing \u2013 review and editing (lead).None.The National Natural Science Foundation of China (NSFC), Grant/Award Numbers: 8217114, U20A20399, 82271148; the Natural Science Foundation of Guangdong Province, Grant/Award Number: 2022A1515011787; the Science and Technology Program of Guangzhou, Grant/Award Number: 202201020402; the Key\u2010area Research and Development Program of Guangzhou Province, Grant/Award Number: 2020B0101130015; Fundamental Research Funds for the Central University, Sun Yat\u2010sen University, Grant/Award Number: 23qnpy141"}
+{"text": "Penicillium roqueforti.Caption: A slice of a French Termignon blue cheese naturally colonized by Credit: Tatiana Giraud."}
+{"text": "Correction: Journal of Medical Case Reports (2023) 17:434 10.1186/s13256-023-04160-0Following publication of the original article , an erroThe section currently reads:FundingNo fund received for this article.The section should read:FundingFunding Open Access funding provided by the Qatar National Library.The funding section has been updated above and the original article  has been"}
+{"text": "Septic shock studies have identified that delay to the initial antimicrobial administration is the strongest predictor of survival. With every hour of delay mortality increases by 7.6%. The time from the written antibiotic order to intravenous administration or \u201chang-time\u201d can be several hours due to logistics within the hospital. As the optimization of the antibiotic administration involves the participation of a team in the ICU, Antimicrobial Stewardship Programs (ASP) play an important role in reducing this gap. The present study sought to determine the time between the prescription and the infusion of the antibiotic in 7 Latin American ICU that are implementing ASPs.Prevalence study between 2021-2022 in 7 hospitals . Hang-time was defined as the time elapsed from the written antibiotic order to actual IV administration. Hang-time compliant was defined as antibiotic administration within an elapsed time of 1 h from the written antibiotic order. Any patient with a suspected infection in the ICU , who had a first dose of the antibiotic was included. Patients with incomplete medical records or who died before the administration of the first dose were excluded. For the descriptive analysis, the average of the time difference between the formulation versus the administration of the treatment was determined, as well as the adherence to the administration of the antibiotic in the first hour after being formulated.1207 prescriptions were evaluated. The most common diagnose was sepsis and septic shock from urinary and pulmonary source. Hangtime adherence was 38.5% (22.5%-74.0%). The time range was 2 to 1080 minutes.HANGTIME RESULTS BY COUNTRYThe administration of antibiotics during the first hour in ICU patients was not an adherent practice despite being a risk factor for mortality. A stewardship process improvement protocol with physicians, pharmacists, and nursing collaboration has been developed to improve the hang-time of antibiotics in patients with sepsis. ASPs with limited resources should consider implementing hang-time protocols. Phase 2 will measure compliance of the hang-time protocol and mortality.Christian Pallares, MD, MSc, 3M: Advisor/Consultant|3M: Honoraria|MSD: Advisor/Consultant|MSD: Grant/Research Support|MSD: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Pfizer: Honoraria|Westqu\u00edmica: Advisor/Consultant|Westqu\u00edmica: Grant/Research Support|Westqu\u00edmica: Honoraria Jorge Chaverri, n/a, Pfizer: Advisor/Consultant|Pfizer: Honoraria Mar\u00eda Virginia Villegas, n/a, MSD: Advisor/Consultant|MSD: Grant/Research Support|MSD: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Pfizer: Honoraria|Westqu\u00edmica: Advisor/Consultant|Westqu\u00edmica: Grant/Research Support|Westqu\u00edmica: Honoraria"}
+{"text": "Correction to: Current Hypertension Reports 10.1007/s11906-023-01264-2The article \u201cDoes Renal Denervation a Reasonable Treatment Option in Hemodialysis-Dependent Patient with Resistant Hypertension? A Narrative Review\u201d, was originally published electronically on the publisher\u2019s internet portal on 6 September 2023 with error on the tagging of the author names (first names and last names were interchanged) and affiliation of the third author.First Name: AlbertoLast Name: MazzaAuthor 1First Name: FabioLast Name: Dell'AvvocataAuthor 2First Name: GioiaLast Name: TorinAuthor 3First Name: FrancescaLast Name: BulighinAuthor 4First Name: YuriLast Name: BattagliaAuthor 5First Name: FulvioLast Name: FioriniAuthor 6The correct tagging of the author names are as follows:Gioia Torin (third author) should be affiliated to ESH Excellence Hpertension Centre and Dept. of Internal Medicine, Santa Maria della Misericordia General Hospital, AULSS 5 Polesana, Rovigo, Italy.The original article has been corrected."}
+{"text": "Correction to: BMC Health Services Research (2023) 23:106910.1186/s12913-023-10066-wFollowing publication of the original article , the autThe incorrect author name is: Branden McCormack.The correct author name is: Brendan McCormack.The author group has been updated above and the original article  has been"}
+{"text": "Details of correction: reverse order of first and second authors.Existing text: Federica Turati, Marta RossiCorrected text should read: Marta Rossi, Federica Turati"}
+{"text": "Correction to: Acta Neuropathologica Communications (2023) 11:11110.1186/s40478-023-01609-7Following publication of the original article , the autThe incorrect author names are: Laura Kuhlman and Andrew Mackling.The correct author names are: Laura Kuhlmann and Andrew Macklin.The author group has been updated above and the original article  has been"}
+{"text": "Caption: An infant of Macaca mulatta vestita is groveling on adult\u2010female monkey's back in Jiacha Gorge on the Yarlung Zangbo River, Tibet, China.Credit: Dayong Li."}
+{"text": "Following publication of the original article , we haveOriginally published phrase:From top left: All-cause deaths; deaths from external causes; deaths from neoplasms; deaths from diseases of the nervous system and the sense organs. From bottom left: Deaths from circulatory diseases; deaths from mental and behavioural disorders; deaths from diseases of the respiratory system; deaths from other causes.Corrected caption phrase:Panel a: all-cause deaths; Panel b: deaths from external causes; Panel c: deaths from neoplasms; Panel d: deaths from diseases of the nervous system and the sense organs; Panel e: deaths from circulatory diseases; Panel f: deaths from mental and behavioural disorders; Panel g: deaths from diseases of the respiratory system; Panel h: Deaths from other causes.The original article has been corrected."}
+{"text": "BJS Open 2023;7: https://doi.org/10.1093/bjsopen/zrad024This is a correction to: Bin Li and others, Surgical treatment of hilar cholangiocarcinoma: retrospective analysis. Fig. 2. This is the correct version:In the originally published version of this article, there were errors in the use of \u2018>\u2019 and \u2018<\u2019 symbols in the RLV/TLV presentation of the site area in instead of:The figure has been emended in the article."}
+{"text": "There were multiple errors in the Author Contributions statement. The Author Contributions statement should read: \"Conceived and designed the experiments: SJD LAS DPB CJK. Performed the experiments: SJD LAS DPB CJK.Analyzed the data: SJD TP LAS DPB CJK. Wrote the paper: SJD MIT TP LAS DPB CJK.\""}
+{"text": "HLA genes. In this study, we sought to use SNP genotyping in a large patient collection to identify sJIA susceptibility loci.Systemic juvenile idiopathic arthritis (sJIA) is a complex inflammatory disease whose etiology remains unknown. sJIA is distinguished from other forms of juvenile idiopathic arthritis (JIA) by its characteristic features including requisite quotidian fever and salmon-colored, evanescent skin rash, but also by an absence of autoantibodies. Based on its unique phenotype among JIA subtypes, it has been suggested that sJIA may be autoinflammatory rather than autoimmune in nature, and consistent with this, sJIA is distinct among JIA subtypes for its inconsistently detectable association with p below 0.001, producing a dataset of 690,672 SNPs in 576 cases and 426 controls. To address population stratification, we employed principal components (PC) analysis to identify and exclude samples with differing genetic backgrounds. We excluded 60 sJIA samples on this basis, reducing the size of the collection for final analysis to 516 cases and 426 controls. After correcting for the top 10 PCs, the genomic inflation factor reflected minimal population stratification (\u03bbGC = 1.01).We genotyped 576 children fulfilling ILAR criteria for systemic arthritis and 366 control subjects free of sJIA or autoimmune disease. The collection included 205 cases and 210 controls from Cincinnati Children\u2019s Hospital, 185 cases from the repository at University of Manchester, 56 cases and 60 controls from University of Genova, 54 cases from Hacettepe University, 42 cases from the University of Utah, 34 cases from Stanford University, and 96 controls from Istanbul University. SNP genotyping was performed using Illumina Omni1M Quad v1.0 beadchips and iScan platform. Omni1M beadchip data from 60 unrelated CEU HapMap individuals were obtained through Illumina\u2019s iControlDB. SNP associations were evaluated using SNP & Variation Suite 7, excluding SNPs with call rates below 95%, minor allele frequencies below 0.05, or Hardy-Weinberg Equilibrium HLA-DRB1 with PC-corrected associations that exceeded a stringent threshold for genome-wide significance (p < 5 x 10-8). These SNPs were part of a larger group of 45 SNPs with p < 5 x 10-5 in the MHC class II gene cluster. The effect size of the sJIA-associated SNPs ranged from odds ratios of 1.45 to 1.65. Notably, the effect size of this association is modest, relative to the effect of associated HLA genes in other JIA subtypes and other autoimmune diseases. Figure We identified 12 SNPs within MHC of sJIA patients, albeit with more modest effect sizes than those detected in other JIA subtypes. This suggests at least some contribution of autoimmunity to the pathogenesis of this complex disorder.A large collaborative effort to identify sJIA patients and a careful genetic matching strategy have allowed us to clearly detect an association signal within the class II region of the Michael Ombrello: None; Elaine F. Remmers: None; Alexei A. Grom: None; Wendy Thomson: None; Alberto Martini: None; Marco Gattorno: None; Seza Ozen: None; Ahmet Gul: None; John F. Bohnsack: None; Andrew S. Zeft: None; Elizabeth D. Mellins: None; Jane L. Park: None; Claudio Len: None; Colleen Satorius: None; Ricardo A.G. Russo: None; Terri H. Finkel: None; Rae S.M. Yeung: None; Rayfel Schneider: None; Sampath Prahalad: None; David N. Glass: None; Roger C. Allen: None; Nico Wulffraat: None; Pierre Quartier: None; Maria Odete E. Hilario: None; Kevin Murray: None; Sheila Oliveira: None; Jordi Anton: None; Anne Hinks: None; Eleftheria Zeggini: None; Carl Langefeld: None; Susan Thompson: None; Jeffrey Chaitow: None; Justine Ellis: None; Davinder Singh: None; Andre Cavalvanti: None; Blanca Bica: None; Flavio Sztajnbok: None; Hakon Hakonarson: None; Katherine A. Siminovitch: None; Kirsten Minden: None; Peter Haas: None; Tobias Schwarz: None; Daniel L. Kastner: None; Patricia Woo: None."}
+{"text": "AbstractTettigettalnamariae Quartau & Boulard 1995 is recorded for the first time in Spain. Thought to be endemic to Portugal (occurring in the southern province of Algarve), the present paper adds its distribution to southern Spain, being an Iberian endemism. The acoustic signals of the new specimens collected were recorded in different localities of Huelva province, in Andalusia during August 2012. According to their present known distribution, specimens of Tettigettalnamariae tend to be sparsely distributed in small range populations in southern Iberian Peninsula, favouring wooded areas with Pinuspinea. Hemiptera: Cicadoidea) constitute a successful group of insects where males typically communicate during pair formation and courtship through acoustic distinctive signals  have been described and recorded so far in Portugal only . Identification was based on the collection of specimens and the recording of male acoustic signals typical of the species.As an outcome of intensive fieldwork in Portugal and Spain for species of the genus The field survey was conducted daily from 10:00 h to 19:00 h during sunny weather with temperatures ranging from 29\u00b0 to 32\u00b0 C. Searches were conducted by car while driving at a reduced speed, allowing the detection of the songs of calling males. Their acoustic signals were recorded at the collecting site using a Marantz PMD 661 Portable SD recorder (20 Hz \u2013 24 kHz) connected to a Telinga Pro 7 Dat-mic microphone (Twin Science) following the procedures given in Faculty of Sciences, University of Lisbon (FCUL). Collected specimens were stored dry and a front leg was preserved in 100% ethanol for DNA isolation.Geographical coordinates were determined with a GPS  for each site where male songs were heard and where specimens were collected. Species confirmation was accomplished with time and frequency analysis of sound recordings using the software Avisoft Sas-Lab Pro  as in prQuartau & Boulard, 1995Type status:Other material. Occurrence: recordedBy: Raquel Mendes; individualCount: 3; sex: male; Location: country: Espana; stateProvince: Andaluzia; verbatimLocality: Cartaya; verbatimLatitude: 37\u00b015'44.2\"N; verbatimLongitude: 7\u00b007'48.9\"W; Event: samplingProtocol: Acoustic recording; eventDate: 2012-08-15T17:00Z; Record Level: collectionID: 3372;3373;3374; institutionCode: FCUL; collectionCode: Entomology_PCSType status:Other material. Occurrence: recordedBy: Raquel Mendes; Vera Nunes; individualCount: 3; sex: male; Location: country: Espana; stateProvince: Andaluzia; verbatimLocality: Cartaya; verbatimLatitude: 37\u00b015'44.2\"N; verbatimLongitude: 7\u00b007'48.9\"W; Event: samplingProtocol: Acoustic recording; eventDate: 2012-08-15T18:00Z; Record Level: collectionID: 3375;3376;3377; institutionCode: FCUL; collectionCode: Entomology_PCSType status:Other material. Occurrence: recordedBy: Vera Nunes; individualCount: 1; sex: male; Location: country: Espana; stateProvince: Andaluzia; verbatimLocality: Cartaya; verbatimLatitude: 37\u00b015'44.2\"N; verbatimLongitude: 7\u00b007'48.9\"W; Event: samplingProtocol: Sweep net capture; eventDate: 2012-08-15T17:45Z; Record Level: collectionID: 3378; institutionCode: FCUL; collectionCode: Entomology_PCSType status:Other material. Occurrence: recordedBy: Raquel Mendes; Vera Nunes; individualCount: 1; sex: male; Location: country: Espana; stateProvince: Andaluzia; verbatimLocality: Moguer; verbatimLatitude: 37\u00b012'30.7\"N; verbatimLongitude: 6\u00b046'46.1\"W; Event: samplingProtocol: Acoustic recording; eventDate: 2012-08-16T11:50Z; Record Level: collectionID: 3379; institutionCode: FCUL; collectionCode: Entomology_PCSType status:Other material. Occurrence: recordedBy: Raquel Mendes; Vera Nunes; individualCount: 1; sex: male; Location: country: Espana; stateProvince: Andaluzia; verbatimLocality: Moguer; verbatimLatitude: 37\u00b012'30.7\"N; verbatimLongitude: 6\u00b046'46.1\"W; Event: samplingProtocol: Acoustic recording; eventDate: 2012-08-16T14:40Z; Record Level: collectionID: 3380; institutionCode: FCUL; collectionCode: Entomology_PCSType status:Other material. Occurrence: recordedBy: Vera Nunes; individualCount: 1; sex: male; Location: country: Espana; stateProvince: Andaluzia; verbatimLocality: Almonte; verbatimLatitude: 37\u00b013'43.0\"N; verbatimLongitude: 6\u00b033'51.1\"W; Event: samplingProtocol: Acoustic recording; eventDate: 2012-08-16T15:45Z; Record Level: collectionID: 3382; institutionCode: FCUL; collectionCode: Entomology_PCSTettigettalnamariae specimens in Spain.Our analysis of the morphological and acoustic data confirmed the presence of Tettigettalnamariae tending to favour wooded areas of Pinuspinea near the sea in the southern Iberian Peninsula (Figs Specimens were collected and recorded in different locations from Huelva province in Andalusia around the following localities: Cartaya, Aljaraque, Moguer, Mazag\u00f3n, Almonte and Hinojos Table . Recordsula Figs , 2.Tettigettalnamariae specimens have a broad spectrum near 6 - 16.5 kHz with maximum energy around 12 kHz. For time domain variables, our results indicated an echeme duration ranging from 0.02 to 0.10s, with an average value of 0.06s. For the echeme period we found a range of 0.16 to 0.54s and average of 0.32s.Acoustic analysis Table , Fig. 3 Tettigettalnamariae was a Portuguese endemic cicada, seeming to be confined to central Algarve, close to the sea (Tettigettalnamariae given the restricted habitat range of the known populations. The discovery of Tettigettalnamariae populations in Spain means that the species is not confined to the central wooded area of Algarve, close to the sea, having instead a wider distribution extending to Andalusia. The new populations of Tettigettalnamariae reported here constitute an important addition to the scarce knowledge of this rare species. However, Tettigettalnamariae distribution remains heavily fragmented and discontinuous. Consequently the species is still vulnerable to habitat loss caused by changes in land use or forest fires that often jeopardize Pinuspinea woods during the summer, when cicada adult males are active. These threats may cause the decline and eventual extinction of local populations of cicadas and are especially worrying for small range species such as Tettigettalnamariae (Previous studies suggested that  the sea  which isamariae .With the present data, obtained through our 2012 fieldwork, a new cicada species is listed for Spain and a new endemism for Iberia.Cicadetta (e.g.Moreover, the current species list available for the cicadas from Iberian Peninsula are likely to still be incomplete. As the male acoustic signals in cicadas are highly diagnostic for the separation of closely related species , it is qetta e.g.. All thi"}
+{"text": "Several authors were omitted from the contributions to the \"Wrote the paper\" section. The correct Author Contributions are: Conceived and designed the experiments: CMC APM DAE EAW KEWJ. Performed the experiments: CMC PMW APM WKR AB. Analyzed the data: ERG CMC PMW RD WKR KEWJ. Contributed reagents/materials/analysis tools: APM WKR DAE KEWJ. Wrote the paper: ERG RAD EAW KEW."}
+{"text": "The word \"arsenal\" was misspelled in the title of the article. The correct title is: \"Molecular Evolution of Vertebrate Neurotrophins: Co-Option of the Highly Conserved Nerve Growth Factor Gene into the Advanced Snake Venom Arsenal.\" The correct Citation is: Sunagar K, Fry BG, Jackson TNW, Casewell NR, Undheim EAB, et al. (2013) Molecular Evolution of Vertebrate Neurotrophins: Co-Option of the Highly Conserved Nerve Growth Factor Gene into the Advanced Snake Venom Arsenal. PLoS ONE 8(11): e81827. doi:10.1371/journal.pone.0081827."}
+{"text": "There were errors in the name of the thirteenth author. The correct name is: Nhu Thi Quynh Nguyen.On two occasions in the Abstract, the letter \"M\" was dropped from words.Introduction: icroscopic Observation Drug Susceptibility (MODS)...\" should be \"Introduction: Microscopic Observation Drug Susceptibility (MODS)...\"\"Conclusion: ODS is a sensitive...\" should be corrected as \"Conclusion: MODS is a sensitive...\" \""}
+{"text": "T. harzianum are well known for their biocontrol activity against many plant pathogens. However, there is a lack of studies concerning its use as a biological control agent against F. solani, a pathogen involved in several crop diseases. In this study, we have used subtractive library hybridization (SSH) and quantitative real-time PCR (RT-qPCR) techniques in order to explore changes in T. harzianum genes expression during growth on cell wall of F. solani (FSCW) or glucose. RT-qPCR was also used to examine the regulation of 18 genes, potentially involved in biocontrol, during confrontation between T. harzianum and F. solani.The species of T. harzianum growth on FSCW or glucose. We identified various genes of biotechnological value encoding to proteins which function such as transporters, hydrolytic activity, adherence, appressorium development and pathogenesis. Fifteen genes were up-regulated and sixteen were down-regulated at least at one-time point during growth of T. harzianum in FSCW. During the confrontation assay most of the genes were up-regulated, mainly after contact, when the interaction has been established.Data obtained from two subtractive libraries were compared after annotation using the Blast2GO suite. A total of 417 and 78 readable EST sequence were annotated in the FSCW and glucose libraries, respectively. Functional annotation of these genes identified diverse biological processes and molecular functions required during T. harzianum expressed different genes when grown on FSCW compared to glucose. It provides insights into the mechanisms of gene expression involved in mycoparasitism of T. harzianum against F. solani. The identification and evaluation of these genes may contribute to the development of an efficient biological control agent.This study demonstrates that  Trichoderma harzianum is a soil-borne filamentous fungus that protects crop plants from attack by a range of pathogenic fungi \u2009\u00d7\u2009100 [ng Phred . Only se program . The fil)]\u2009\u00d7\u2009100 .T. harzianum grown in FSCW, and T. harzianum grown in glucose medium. Both conditions were sampled at three different time points . Statistical tests  were performed when appropriate. Eighteen genes potentially involved in biocontrol were selected from the FSCW-library and 10 genes from Glc-library . Amplification efficiency was then calculated from the given slopes in the IQ5 Optical system Software v2.0 [The expression levels of 28 genes were estimated from the threshold cycle using the 2T method . In ordeare v2.0 . All calF. solani cell wall library; Glc-library: Glucose library.asm: acid sphingomielinase; aoc: amine oxidase; aqp: aquaporin; cfem: eight cysteine-containing domain; chk1: checkpoint-like protein; chit: chitinase 33; cpox: coproporphyrinogen oxidase; CWDE: Cell Wall Degrading Enzymes; Duf: duf895 domain membrane protein; Endo: Endochitinase 42; Eno: Enolase; Exo: Exo-rhamnogalacturonase; Gapd: Glyceraldehyde 3- phosphate dehydrogenase; Glyc: Glycosyl hydrolase; hsp98: heat shock protein; ht: hexose transporter-like protein; mbl2: mbl2-like secreted; norA: norsolorinic acid reductase; ptr2: peptide transporter; psd: phosphatidylserine decarboxylase family protein; pld: phospholipase d; pdc: pyruvate decarboxylase; qid: QID74 protein; sag: senescence-associated protein; ser: serine protease; sck1: serine threonine-protein kinase; c2h2: zinc finger domain protein; zt: zinc-regulated transporter; bgn: \u03b2-1,3-endoglucanase; FSCW-library: No competing financial interests exist.PMV, ASS and SJLS performed the construction of the cDNA gene libraries and sequenced the ESTs. PMV and ASGC designed the bioinformatics analysis. PMV and RNS performed the RT-PCR analyses and evaluation of the data. PMV drafted the manuscript. ASGC and CJU were responsible for the experimental design and revised the manuscript. All authors approved the final version of the paper.Relative expression profiles of genes identified in Trichoderma harzianum (FSCW and Glc libraries) at different times of exposure to Fusarium solani cell wall. The data is presented with log scale for better visualization.Click here for fileRelative expression profiles of genes identified T. harzianum during interaction with F. solani. The data is presented with log scale for better visualization.Click here for file"}
+{"text": "This study describes the natural history of Barth syndrome (BTHS).The medical records of all patients with BTHS living in France were identified in multiple sources and reviewed.TAZ mutations were observed in 15 pedigrees. The estimated incidence of BTHS was 1.5 cases per million births (95%CI: 0.2\u20132.3). The median age at presentation was 3.1 weeks , and the median age at last follow-up was 4.75 years . Eleven patients died at a median age of 5.1 months; 9 deaths were related to cardiomyopathy and 2 to sepsis. The 5-year survival rate was 51%, and no deaths were observed in patients \u22653 years. Fourteen patients presented with cardiomyopathy, and cardiomyopathy was documented in 20 during follow-up. Left ventricular systolic function was very poor during the first year of life and tended to normalize over time. Nineteen patients had neutropenia. Metabolic investigations revealed inconstant moderate 3-methylglutaconic aciduria and plasma arginine levels that were reduced or in the low-normal range. Survival correlated with two prognostic factors: severe neutropenia at diagnosis (<0.5 \u00d7 109/L) and birth year. Specifically, the survival rate was 70% for patients born after 2000 and 20% for those born before 2000.We identified 16 BTHS pedigrees that included 22 patients. This survey found that BTHS outcome was affected by cardiac events and by a risk of infection that was related to neutropenia. Modern management of heart failure and prevention of infection in infancy may improve the survival of patients with BTHS without the need for heart transplantation. T studies ,14,22-27database . AllelicNotably, both in our cohort and in other BTHS patients , 3-methyFinally, the natural course of this disease illustrates the benefits of an interdisciplinary approach. In particular, a diagnosis of cardiomyopathy in a newborn or infant should lead to repeated tests to determine whether low ANC is present. The reverse is also true: It may be worth adding cardiac evaluation to the workup of the diagnosis of a chronic neutropenia suspected to be congenital. This diagnostic work-up should be performed in close cooperation with geneticists and metabolic disease specialists.TAZ gene; UPN: Unique patient number; WBC: White blood cell countACE-I: Angiotensin-converting enzyme inhibitor; ALC: Absolute lymphocyte count; AMC: Absolute monocyte count; ANC: Absolute neutrophil count; BSF: Barth Syndrome Foundation; BTHS: Barth syndrome; CBC: Complete blood count; CL: Cardiolipin; DCM: Dilated cardiomyopathy; GCSF: Granulocyte colony-stimulating factor; G6PC3: Glucose-6-phosphatase catalytic subunit 3 gene; Hb: Haemoglobin; HCM: Hypertrophic cardiomyopathy; IUGR: Intrauterine growth retardation; LV: Left ventricle; LVEDD: Left ventricle end diastolic diameter; LVEF: Left ventricle ejection fraction; LVNC: Left ventricular noncompaction; MLCL: Monolysocardiolipin; PCR: Polymerase chain reaction; QTc: Corrected QT interval; SD: Standard deviation; SF: Shortening fraction; TAZ: The authors declare no competing interests.A steering committee that included JD, DB, ASL, CO, AC and MR planned the study. ASL and RT carried out the molecular genetic studies, and CO and AC carried out the metabolic studies. DB analysed the data pertaining to the cardiac evaluations. CR collected the data and drafted the manuscript. JD was responsible for the statistical analysis and for the organization of the French SCN registry. All authors read and approved the final manuscript.Review of all published studies about Barth syndrome patients.Click here for fileFamily trees showing the 16 Barth syndrome pedigrees reported in this study.Click here for file"}
+{"text": "There were errors in the Author Contributions section. The correct contributions are: Conceived and designed the experiments: WS JF. Performed the experiments: WS. Analyzed the data: WS. Interpreted the data: JF. Designed the simulations: CK WL. Performed and analyzed the simulations: CK. Wrote the paper: WS CK JF."}
+{"text": "During early vertebrate development, various small non-coding RNAs (sRNAs) such as MicroRNAs (miRNAs) and Piwi-interacting RNAs (piRNAs) are dynamically expressed for orchestrating the maternal-to-zygotic transition (MZT). Systematic analysis of expression profiles of zebrafish small RNAome will be greatly helpful for understanding the sRNA regulation during embryonic development.We first determined the expression profiles of sRNAs during eight distinct stages of early zebrafish development by sRNA-seq technology. Integrative analyses with a new computational platform of CSZ  demonstrated an sRNA class transition from piRNAs to miRNAs as development proceeds. We observed that both the abundance and diversity of miRNAs are gradually increased, while the abundance is enhanced more dramatically than the diversity during development. However, although both the abundance and diversity of piRNAs are gradually decreased, the diversity was firstly increased then rapidly decreased. To evaluate the computational accuracy, the expression levels of four known miRNAs were experimentally validated. We also predicted 25 potentially novel miRNAs, whereas two candidates were verified by Northern blots.http://csz.biocuckoo.org.Taken together, our analyses revealed the piRNA to miRNA transition as a conserved mechanism in zebrafish, although two different types of sRNAs exhibit distinct expression dynamics in abundance and diversity, respectively. Our study not only generated a better understanding for sRNA regulations in early zebrafish development, but also provided a useful platform for analyzing sRNA-seq data. The CSZ was implemented in Perl and freely downloadable at:  Small non-coding RNAs (sRNAs) of about 20\u2009~\u200930 nucleotides (nt) play an essential role in a variety of animal developmental processes, such as embryonic, neuronal, muscle, and germline development -3. Microet al. quantitatively analyzed sRNA expression profiles in 256-cell (2.5 hpf), sphere (4 hpf), shield (6 hpf), and 1 dpf (days post fertilization) stages of early zebrafish development . The most widely used radial basis function (RBF) was chosen. The penalty parameter C and RBF kernel parameter \u03b3 were exhaustively searched as 8.0 and 0.03125, respectively.The LIBSVM package was used for training , while others are called false positives (FP). Among the predicted negative results obtained by ZmirP, real negatives are called true negatives (TN), while the others are called false negatives (FN). In a classification problem, the specificity (Sp), sensitivity (Sn), accuracy (Ac) and Mathew\u2019s correlation coefficient (MCC) are most widely used to evaluate the prediction system. They are defined as:Among the predicted positive results obtained by ZmirP, the real positives are called true positives  (AB type) were maintained under standard library conditions and the embryonic stages in this study were as described .k-nearest neighbors; ZmirP: Zebrafish miRNA prediction; CSZ: Characterization of small RNAome for zebrafish; RBF: Radial basis function; TP: True positive; FP: False positive; TN: True negative; Sp: Specificity; Sn: Sensitivity; Ac: Accuracy; MCC: Mathew\u2019s correlation coefficient; ROC: Receiver Operating Characteristic; qRT-PCR: quantitative real-time PCR; RPM: reads per million; Non-repeat-associated piRNAs: piRNAs that were not annotated as repeat sequences; Repeat-associated piRNAs: piRNAs that could be mapped to repetitive sequences.sRNAs: small non-coding RNAs; miRNAs: MicroRNAs; piRNAs: Piwi-interacting RNAs; pri-miRNAs: primary miRNA molecules; dsRNAs: double-stranded RNAs; RISC: RNA-induced silencing complex; hpf: hours post fertilization; MZT: Maternal-to-zygotic transition; NGS: Next-generation sequencing; dpf: days post fertilization; triplet elements: local structure-sequence features; SVMs: Support vector machines; RF: Random forest; MFE: Minimum of free energy; kNN: The authors declare that they have no competing interests.YX and HJ designed the project; YY, YX developed the algorithm and analyzed data; QY, LM and QJ performed experiments; WD, ZL, YZ and JR extensively shared and discussed data; YX, YY and QY wrote the manuscript. All authors read and approved the final manuscript.The detailed data statistics for different type of reads in eight libraries.Click here for fileThe 218 known zebrafish miRNAs identified from the sRNA-seq data, with corresponding mappable reads.Click here for fileThe 25 predicted miRNAs.Click here for fileThe secondary structures of 25 potentially novel miRNAs.Click here for fileThe piRNA clusters identified from the sRNA-seq data.Click here for fileThe distribution of different types of sRNAs in data from Wei\u2019s data . (A) TheClick here for file"}
+{"text": "There were errors in the published Author Contributions. The correct Author Contributions are: Conceived and designed the experiments: WAB AV TLH DJG. Performed the experiments: WAB MS HZ. Analyzed the data: WAB AV TLH DAK DJG. Contributed reagents/materials/analysis tools: TLH DAK DJG. Wrote the paper: WAB."}
+{"text": "AbstractCasuarinicolaaustralis Taylor, 2010 is reported for the first time, based on new material from Auckland. This is also the first record of the genus from New Zealand.The presence in New Zealand of the triozid  Casuarinicolaaustralis Taylor, 2010 was described from Australia, where it is the most common and widespread member of its genus, being widely distributed in New South Wales, Queensland, South Australia, Victoria and Western Australia. Like its congeners, it is restricted to host trees of the genus Casuarina. Casuarinicolaaustralis occurs on all Australian species of Casuarina, including Casuarinacunninghamiana and Casuarinaglauca. Both these species of Casuarina are exotic and present in the wild in New Zealand, according to the New Zealand Organisms Register (NZOR), as well as present in cultivation. Casuarinicola has not been reported (by name) previously from N.Z.Taylor, 2010Type status:Other material. Occurrence: recordedBy: Stephen Thorpe; sex: 1 male, 1 female; Location: country: New Zealand; verbatimLocality: Mechanics Bay, Auckland City; verbatimElevation: 0-5 m; verbatimLatitude: 36.8474938105S; verbatimLongitude: 174.7869624545E; Event: eventDate: 6 January 2013; Record Level: institutionCode: Auckland MuseumType status:Other material. Occurrence: recordedBy: Stephen Thorpe; individualCount: 1; sex: female; Location: country: New Zealand; verbatimLocality: Felton Mathew Avenue, Saint Johns, Auckland; verbatimLatitude: 36.8741794382S; verbatimLongitude: 174.8506522179E; Event: eventDate: 2013-02-20; Record Level: institutionCode: Auckland MuseumType status:Other material. Occurrence: recordedBy: Stephen Thorpe; individualCount: many; sex: males, females; Location: country: New Zealand; verbatimLocality: Thomas Bloodworth Park, Auckland; verbatimElevation: 0-5 m; verbatimLatitude: 36.8652411423S; verbatimLongitude: 174.7900235653E; Event: eventDate: 2013-02-26; Record Level: institutionCode: Auckland MuseumCasuarinaglauca trees growing in the vicinity of Ports of Auckland at Mechanics Bay. A few psylloids were observed, including a pair in copula, which I collected. The specimens will be vouchered in Auckland Museum. They are easily identified as Casuarinicolaaustralis Taylor in Casuarinicolaaustralis therein, except only that the second and third bands on the female fore wings of my specimen are narrowly joined. Such minor variation is entirely expected for insect colour patterns, and the pattern is still by far closest to that of typical Casuarinicolaaustralis than it is to any other species of Casuarinicola. I can find no other differences. I therefore recommend that Casuarinicolaaustralis be added to the New Zealand Organisms Register (NZOR) as present in the wild. Its \"origin\" is \"exotic\". Subsequently, on 20 Feb 2013, a further female specimen was found on a Casuarina tree in the Auckland suburb of Saint Johns. The second and third bands on the fore wings are separated, though narrowly (Fig. Casuarina trees at Thomas Bloodworth Park, Auckland. Several pairs were observed in copula. One female was collected. It has the second and third bands of one forewing joined, and of the other narrowly separated. On Casuarina in Auckland, there is also an apparently undescribed Australian species of Trioza, which is more common and widespread than Casuarinicolaaustralis.On 6 Jan 2013, I examined some"}
+{"text": "AbstractMicrogasterdeductor Nixon (1968) are recorded from the Nearctic (Canada and the United States) and the Palaearctic (Sweden), expanding significantly the range of the species. Microgasterdeductor seems to be widely distributed in boreal areas of the Holarctic, and it is characterized by unique morphological  and molecular (COI) traits. Preliminary evidence, to be corroborated when more data is available, suggests that the species might have shifted northwards between 1950 and the present day.Four new localities for the species  Microgasterdeductor Nixon (1968) is a very distinctive microgastrine wasp , and can be easily separated from all Holarctic species of Microgaster based on its tarsal claws, which have a lobe (Microgasterdeductor could be more widely distributed in sub-Arctic or Arctic areas of the Holarctic (Europe and North America).e a lobe  Fig. 2)Microgaste a lobe . Howevere a lobe . That loMicrogasterdeductor is recorded from four additional localities, three in the Nearctic and one in the Palaearctic, which expand significantly the known range of the species. Morphological and molecular data that serve as diagnostic tools are presented, and the potential of a shift northwards of the species distribution is briefly discussed.Here http://www.boldsystems.org/).All the specimens studied for this paper are deposited in the Canadian National Collection of Insects (CNC), Ottawa, Canada. The only exception is one female deposited in the Biodiversity Institute of Ontario, which was not examined directly. Instead it was studied based on a single photo  and associated DNA barcode, both freely available as public data in the Barcode of Life Data Systems (BOLD)  were examined, although no specimen of Microgasterdeductor was found in those samples.Additionally, 40 specimens of The historical data on the distribution of the species was extracted from the original references  and compNixon, 1968Type status:Holotype. Occurrence: individualCount: 1; sex: female; Location: country: Finland; stateProvince: Lapland; verbatimLocality: Ivalo; Record Level: institutionCode: BMNHType status:Paratype. Occurrence: individualCount: 2; sex: 1 female, 1 male; Location: country: Finland; stateProvince: Lapland; verbatimLocality: Ivalo; Record Level: institutionCode: BMNHType status:Paratype. Occurrence: individualCount: 1; sex: female; Location: country: Sweden; stateProvince: Lapland; verbatimLocality: Tornetr\u00e4sk; Record Level: institutionCode: BMNHType status:Other material. Occurrence: recordedBy: Jose Fern\u00e1ndez-Triana; individualCount: 3; sex: 1 female, 2 males; Location: country: United States; stateProvince: Alaska; verbatimLocality: Unalakleet; verbatimLatitude: 63.878889; verbatimLongitude: -160.789722; Event: eventDate: 27 Jun 1961, 28 Jun 1961, 4 Jul 1961; Record Level: institutionCode: CNCType status:Other material. Occurrence: recordedBy: Jose Fern\u00e1ndez-Triana; individualCount: 4; sex: females; Location: country: Sweden; stateProvince: Lapland; verbatimLocality: Abisko; verbatimLatitude: 68.35; verbatimLongitude: 18.816667; Event: eventDate: 29 Jul 1951, 9 Aug 1951, 15 Aug 1951; Record Level: institutionCode: CNCType status:Other material. Occurrence: recordedBy: Jose Fern\u00e1ndez-Triana; individualCount: 1; sex: female; Location: country: Sweden; stateProvince: Lapland; verbatimLocality: Abisko; verbatimElevation: 400 m; verbatimLatitude: 68.35; verbatimLongitude: 18.816667; Event: eventDate: 31 Jul 1960; Record Level: institutionCode: CNCType status:Other material. Occurrence: recordedBy: Jose Fern\u00e1ndez-Triana; individualCount: 1; sex: female; Location: country: Canada; stateProvince: Northwest Territories; verbatimLocality: Tuktoyaktuk; verbatimLatitude: 66.4445; verbatimLongitude: -133.032; Event: samplingProtocol: Sweeping; eventDate: 14 Jul 2010; Record Level: institutionCode: CNCType status:Other material. Occurrence: recordedBy: Jose Fern\u00e1ndez-Triana; individualCount: 1; sex: female; Location: country: Canada; stateProvince: Yukon Territory; verbatimLocality: Herschel Island; verbatimLatitude: 69.571; verbatimLongitude: -138.902; Event: eventDate: 29 Jul 2008; Record Level: institutionCode: BIOType status:Other material. Occurrence: recordedBy: Jose Fern\u00e1ndez-Triana; individualCount: 35; Location: country: Canada; stateProvince: Manitoba; verbatimLocality: 23 km E of Churchill; verbatimLatitude: 58.734; verbatimLongitude: -93.82; Event: eventDate: 12 Jul 1952, 18 Jul 1952, 23 Jul 1952, 28 Jul 1952, 29 Jul 1952, 3 Aug 1952, 5 Aug 1952; Record Level: institutionCode: CNCType status:Other material. Occurrence: recordedBy: Jose Fern\u00e1ndez-Triana; individualCount: 6; Location: country: Canada; stateProvince: Manitoba; verbatimLocality: Warkworth Creek nr. Churchill; verbatimLatitude: 58.375; verbatimLongitude: -93.875; Event: eventDate: 29 Jun 1952, 7 Jul 1952, 3 Aug 1952; Record Level: institutionCode: CNCMicrogasterdeductor in the Nearcitc include three localities: Unalakleet, Alaska (United States), and Tuktoyaktuk, Northwest Territories and Herschel Island, Yukon Territory (Canada). They expand considerably the distribution of the species in the Holarctic, and the Alaskan record suggests the possibility that the species might also be in Siberia, Russia . The new record in the Palaearctic is from Abisko in Sweden, a locality very close to that of Tornetr\u00e4sk, where one of the paratypes, included by Nixon  but in others the pale spot is reduced  differed from Microgasterdeductor by 46 base pairs (7%). Full data of the sequences and specimens can be freely accessed in BOLD from the public projects with codes CNCAS, HARC and WOMIA. The nucleotide sequence of the full barcode of Microgasterdeductor, in FASTA format is:The two specimens recently collected (2008 and 2010) rendered full DNA barcodes \u2013 a section of 658 base pairs of the mitochondrial COI gene. Among the material collected in Churchill in 1952, one specimen rendered about half a barcode (320 base pairs), and for another 33 specimens short sequences of 129-144 base pairs were obtained. All sequences were identical, with the shorter ones perfectly matching the corresponding section of the full barcode obtained from the two recent specimens. The closest sequences in BOLD  species that this wasp parasitizes.Based on the studied molecular and morphological data, Microgasterdeductor, seems to suggest that its range might have shifted northwards recently. For example, the species was the most commonly collected Microgastrinae in Churchill during a period of intense study of insects in the area around the 1950's. However, it has never been found there again, in spite of even more intense collecting efforts carried out in the same locality between 2006\u20132011 , this project has not recovered the species either]. Conversely, the only two recent records of Microgasterdeductor correspond to Canadian localities at 69\u201370\u00b0N, which had similarly been sampled in the 1940\u20131960 without finding any record of the species. These two localities are 6\u201310\u00b0 north of the Canadian collections from the 1950\u20131960.The relatively scarce information about historical (1950\u20131960) and present (2008\u20132010) distribution of 006\u20132011 . Similardeductor ; also, bHowever, both historical and current day distribution patterns are likely to be biased by incomplete sampling efforts. The study of more specimens and more localities will be necessary before reaching any conclusions on this topic."}
+{"text": "There was an error in the Author Contributions. The correct Author Contributions are: Designed the experiments: JRK RKK SB. Performed the experiments: SB. Analyzed the data: JRK RKK SB. Contributed reagents/materials/analysis tools: SB RKK JRK. Wrote the paper: JRK RKK SB. This research work is the part of PhD thesis (SB) under the supervision of JRK RKK."}
+{"text": "There was an error in the Author Contributions Statement. The Author Contributions Statement should read: \"Conceived and designed the experiments: WG SD LP. Performed the experiments: WG HY SD. Analyzed the data: WG DW. Contributed reagents/materials/analysis tools: WG HY. Wrote the paper: WG HY.\""}
+{"text": "Clostridium sticklandii belongs to a cluster of non-pathogenic proteolytic clostridia which utilize amino acids as carbon and energy sources. Isolated by T.C. Stadtman in 1954, it has been generally regarded as a \"gold mine\" for novel biochemical reactions and is used as a model organism for studying metabolic aspects such as the Stickland reaction, coenzyme-B12- and selenium-dependent reactions of amino acids. With the goal of revisiting its carbon, nitrogen, and energy metabolism, and comparing studies with other clostridia, its genome has been sequenced and analyzed.C. sticklandii is one of the best biochemically studied proteolytic clostridial species. Useful additional information has been obtained from the sequencing and annotation of its genome, which is presented in this paper. Besides, experimental procedures reveal that C. sticklandii degrades amino acids in a preferential and sequential way. The organism prefers threonine, arginine, serine, cysteine, proline, and glycine, whereas glutamate, aspartate and alanine are excreted. Energy conservation is primarily obtained by substrate-level phosphorylation in fermentative pathways. The reactions catalyzed by different ferredoxin oxidoreductases and the exergonic NADH-dependent reduction of crotonyl-CoA point to a possible chemiosmotic energy conservation via the Rnf complex. C. sticklandii possesses both the F-type and V-type ATPases. The discovery of an as yet unrecognized selenoprotein in the D-proline reductase operon suggests a more detailed mechanism for NADH-dependent D-proline reduction. A rather unusual metabolic feature is the presence of genes for all the enzymes involved in two different CO2-fixation pathways: C. sticklandii harbours both the glycine synthase/glycine reductase and the Wood-Ljungdahl pathways. This unusual pathway combination has retrospectively been observed in only four other sequenced microorganisms.C. sticklandii genome and additional experimental procedures have improved our understanding of anaerobic amino acid degradation. Several specific metabolic features have been detected, some of which are very unusual for anaerobic fermenting bacteria. Comparative genomics has provided the opportunity to study the lifestyle of pathogenic and non-pathogenic clostridial species as well as to elucidate the difference in metabolic features between clostridia and other anaerobes.Analysis of the  Clostridium consists of a large group of Gram-positive, anaerobic bacteria which belong to the Firmicute phylum . The genome annotation and features are available at http://www.genoscope.cns.fr/agc/microscope/Anaeroscope.The genome sequence reported in this article has been deposited in the EMBL database [EMBL:Rhodobacter capsulatus nitrogen fixation; Sec: selenocysteine; SLP: substrate-level phosphorylation; THF: tetrahydrofolate; WGS: whole genome shotgun.ATP: adenosine triphosphate; CoA or CoASH: coenzyme A; ETP: electron-transport phosphorylation; fd: ferredoxin; FMN: flavin mononucleotide; gcv-system: glycine cleavage system; LC-MS: Liquid Chromatography-Mass Spectrometry; MaGe: Magnifying Genomes; NADH: reduced nicotinamide adenine dinucleotide; NADPH: reduced nicotinamide adenine dinucleotide phosphate; Ppase: pyrophosphatase; Rnf: protein involved in AK, NF and GNC performed genome and comparative analysis and coordinated experimental procedures. SC carried out the growth experiments. ST analysed amino acid utilization by LC-MS. NP contributed to the experimental procedures. AL contributed to elaboration of the clostridial database Anaeroscope. MG constructed shotgun library for sequencing. VB carried out the assembly and finishing of the genome. EP performed bioinformatic analyses. ST, AL and VB participated in writing sections of the manuscript. MS, DL, and JW critically reviewed the manuscript. GNC and JRA contributed to writing of the manuscript. AK and NF wrote the manuscript. All authors read and approved the final manuscript.C. sticklandii compared with other clostridiaGenomic and metabolic features of . All data are extracted from the MaGe annotations except those of Clostridium sporogenes, which are from the NCBI database. C.stick: Clostridium sticklandii DSM 519; C.acet: Clostridium acetobutylicum ATCC 824; C.beij: Clostridium beijerinckii NCIMB 8052; C.botu: Clostridium botulinum A Hall; C.diff: Clostridium difficile 630; C.kluv: Clostridium kluyveri DSM 555; C.novy: Clostridium novyi NT; C.perf: Clostridium perfringens ATCC 13124; C.phyt: Clostridium phytofermentans ISDg; C.teta: Clostridium tetani E88; C.ther: C. thermocellum ATCC 27405; C.spor: C. sporogenes ATCC 1557; A.meta: Alkaliphilus metalliredigens QYMF; A.orem: Alkaliphilus oremlandii OhILAs; M.ther: Moorella thermoacetica ATCC 39073. *2-ketoacid ferredoxin oxidoreductases.Click here for fileC. sticklandii synteny conservation and Bidirectional Best Hit percentages with the most closely related clostrial species. Synteny conservation is given by the percentage of CDS in synteny between C. sticklandii and the complete sequenced genomes.Click here for fileC. sticklandii, their protein symbols and their corresponding labelsCharacteristic gene products of . This is a listing of all genes/proteins that are discussed in the text.Click here for fileComparative analysis of amino acid degradation pathways in several clostridial species. Blast searches (criteria: 30% identity over at least 80% of the length of the reference protein) were performed to determine the presence of the key enzymes in the microorganisms. All protein sequences were taken from C. sticklandii with two exceptions: the sequence of methylaspartate mutase was from Clostridium cochlearium, and that of 2-hydroxyglutaryl-CoA dehydratase from Acidaminococcus fermentans. C.stick: Clostridium sticklandii DSM 519; C.acet: Clostridium acetobutylicum ATCC 824; C.beij: Clostridium beijerinckii NCIMB 8052; C.botu: Clostridium botulinum A Hall; C.diff: Clostridium difficile 630; C.kluv: Clostridium kluyveri DSM 555; C.novy: Clostridium novyi NT; C.perf: Clostridium perfringens ATCC 13124; C.phyt: Clostridium phytofermentans ISDg; C.teta: Clostridium tetani E88; C.ther: C. thermocellum ATCC 27405; C.spor: C. sporogenes ATCC 15579; A.meta: Alkaliphilus metalliredigens QYMF; A.orem: Alkaliphilus oremlandii OhILAs; M.ther: Moorella thermoacetica ATCC 39073; C.coch: Clostridium cochlearium; A.ferm: Acidaminococcus fermentans DSM 20731. The genome of Clostridium cochlearium is not yet sequenced.Click here for fileLC-MS analyses of amino acid utilization during growth. For each amino acid, its presence in the medium was checked at different growth phases (colour graphs). The growth kinetic is represented by a yellow graph. Citrulline, ornithine, alanine and aspartate (indicated by a black frame) were not added to the medium. They appeared as intermediates or products of metabolism from other amino acids. Since the utilization of methionine was not discussed in the article, the graph for this amino acid is not shown.Click here for fileC. sticklandii in three types of media with different amino acid compositionCell growth of . Graph 1: medium containing amino acids that are catabolized in the exponential phase ; Graph 2: medium containing amino acids that are catabolized in the exponential and stationary phase ; Graph 3: the amino acid combination of this medium is equivalent to the second medium, complemented with amino acids apparently not metabolized . Tyrosine was added to each medium.Click here for fileComparison of the D-proline reductase gene cluster from different clostridial species. White arrows indicate hypothetical proteins or those presumed not to be involved in the D-proline reductase reaction. The letter \"U\" indicates the presence of selenocysteine. In Clostridium botulinum A Hall, a part of the cluster is duplicated.Click here for filePresence of characteristic enzymes of the glycine synthase (Gcv proteins)/glycine reductase (Grd proteins) and Wood-Ljungdahl (CODH proteins) pathway in microbial genomes. Complete and WGS microbial genomes  were scanned for some selected characteristic orthologous genes coding for carbon monoxide dehydrogenase/acetyl-CoA synthetase (Wood-Ljungdahl pathway), glycine reductase (Stickland reaction), and the glycine synthase (gcv-system) using a blastx search with stringent criteria (40% of positive residues over at least 80% of the length of the reference protein). For each target genome, the presence/absence of each protein was summarized in a 1/0 vector. Those WGS microbial genomes which do not contain all genes of both pathways are omitted.Click here for file"}
+{"text": "Representing species-specific proteins and protein complexes in ontologies that are both human- and machine-readable facilitates the retrieval, analysis, and interpretation of genome-scale data sets. Although existing protin-centric informatics resources provide the biomedical research community with well-curated compendia of protein sequence and structure, these resources lack formal ontological representations of the relationships among the proteins themselves. The Protein Ontology (PRO) Consortium is filling this informatics resource gap by developing ontological representations and relationships among proteins and their variants and modified forms. Because proteins are often functional only as members of stable protein complexes, the PRO Consortium, in collaboration with existing protein and pathway databases, has launched a new initiative to implement logical and consistent representation of protein complexes.http://pir.georgetown.edu/pro/.We describe here how the PRO Consortium is meeting the challenge of representing species-specific protein complexes, how protein complex representation in PRO supports annotation of protein complexes and comparative biology, and how PRO is being integrated into existing community bioinformatics resources. The PRO resource is accessible at PRO is a unique database resource for species-specific protein complexes. PRO facilitates robust annotation of variations in composition and function contexts for protein complexes within and between species. Logical and semantic access to related protein forms is critical for advancing bioinformatics approaches to representing, modeling, and reasoning about complex biological systems at the genomic and cellular level . The Prointeractions in that they are continuant entities, i.e. they endure or continue to exist through time. Interactions, in contrast, are occurrent entities, i.e. they occur in time through successive temporal phases. The explicit representation of protein complexes in PRO--defining each member of the complex at the level of its isoform, variant, or modified form--provides the ability to represent complex biological knowledge as it is emerging in the experimental research community in structures that are both human readable and accessible to algorithmic approaches.The PRO has three components informally referred to as ProForm, ProEvo, and ProComp . ProFormspecific classes of protein complexes, while GO, in most instances, represents the species-independent classes of protein complexes; within PRO, the latter are referred to by using GO identifiers. The UniProt Knowledgebase (UniProtKB) comment: Category = organism-complex. Entities of this type are disposed to have the enzymatic activity described by EC:6.4.1.4.synonym: \"beta-methylcrotonyl-CoA carboxylase (mouse)\" EXACT synonym: \"MCC (mouse)\" EXACT is_a: GO:0002169! 3-methylcrotonyl-CoA carboxylase complex, mitochondrialhas_part PR:000025354 {cardinality = \"1\"} ! methylcrotonoyl-CoA carboxylase subunit alpha, mitochondrial (mouse)relationship: has_part PR:000025357 {cardinality = \"1\"} ! methylcrotonoyl-CoA carboxylase beta chain, mitochondrial (mouse)relationship: relationship: only_in_taxon taxon:10090 ! Mus musculusSerine palmitoyltransferase  catalyzes the key reaction in the biosynthesis of sphingolipids. In many eukaryotic species, this enzyme is a heterodimer consisting of two subunits, SPTLC1 and SPTLC2. Recently, it was shown that in human cells, SPTLC1 and SPTLC2 form a complex with a third subunit, SPTLC3, with a resulting molecular mass of 480 kDa . SPTLC1 A serine palmitoyltransferase complex is also found in gram-negative sphingolipid-containing bacteria. Unusually, the outer membranes of these bacteria contain glycosphingolipid (GSL) instead of lipopolysaccharide, and SPT catalyzes the first step of the GSL biosynthetic pathway in these organisms. But, as opposed to the human SPT complex, bacterial SPT complex is homodimeric -21. In shas_part relation to the corresponding classes of protein components. The functional human complex classes have an is_a relationship to the serine C-palmitoyltransferase complex class in GO (GO:0017059). The complex core has an is_a relationship to GO:0043234 (protein complex) as there is currently not a more specific complex class in GO.The representation of SPT complexes in PRO shown below and illustrated in Figure [Term]id: PR:000026144name: serine palmitoyltransferase complex core 1 (human)def: \"A serine palmitoyltransferase complex that is heterodimeric consisting of one subunit of serine palmitoyltransferase 1 and serine palmitoyltransferase 2. These components are encoded in the genome of human.\" [PRO:CNA]is_a: GO:0043234 ! protein complexrelationship: has_part PR:000026141 {cardinality = \"1\"} ! serine palmitoyltransferase 1 (human)relationship: has_part PR:000026142 {cardinality = \"1\"} ! serine palmitoyltransferase 2 (human)relationship: only_in_taxon taxon:9606 ! Homo sapiens[Term]id: PR:000026155name: serine palmitoyltransferase complex A (human)def: \"A serine palmitoyltransferase complex consisting of an unknown combination of the serinepalmitoyltransferase subunits 1-3. The stoichiometry is a tetramer composed of the serinepalmitoyltransferase core complexes 1 and/or 2.\" comment: Category = organism-complex. Entities of this type are disposed to have the enzymatic activity described by EC:2.3.1.50.is_a: GO:0017059 ! serine C-palmitoyltransferase complexrelationship: has_part PR:000026141 {cardinality = \"4\"}! serine palmitoyltransferase 1 (human)relationship: has_part PR:000026142 ! serine palmitoyltransferase 2 (human)relationship: has_part PR:000026143 ! serine palmitoyltransferase 3 (human)relationship: only_in_taxon taxon:9606 ! Homo sapiensThe protein complex stanza for the bacterial SPT complex PR:000026169) is shown below. The bacterial and human complexes differ in composition def: \"A homodimeric serine palmitoyltransferase complex that is composed of bacterial serine palmitoyltransferase encoded in the genome of Sphingobacterium multivorum.\" comment: Category = organism-complex. Entities of this type are disposed to have the enzymatic activity described by EC:2.3.1.50.is_a: GO:0002179 ! homodimeric serine palmitoyltransferase complexrelationship: has_part PR:000026168 {cardinality = \"2\"} ! bacterial serine palmitoyltransferase isoform 1 (Sphingobacterium multivorum)relationship: only_in_taxon taxon:28454 ! Sphingobacterium multivorum+ as a cofactor in the oxidative decarboxylation of isocitrate and one utilizes NAD+. The NAD+-dependent IDH is a mitochondrial protein complex in the citric acid cycle; it consists of three subunits , each of which is encoded by a single gene. The mouse alpha subunit gene encodes two different protein isoforms by alternative splicing. ProComp can distinguish between complexes that differ in the isoform of one of the constituents. As illustrated below (in bold), the protein complex stanzas from PRO describe two types of IDH complexes that differ only in the type of isoform of the alpha subunit. Both classes of isoform-specific protein complexes shown below (PR:000026072 and PR:000026073) are subclasses of the mouse-specific protein complex class (PR:000026071) which, in turn, is a subclass of the species-independent complex class defined in GO (GO:0005962).There are three types of isocitrate dehydrogenases (IDHs) in mammals; two IDHs utilize NADP[Term]id: PR:000026071name: mitochondrial isocitrate dehydrogenase complex (NAD+) (mouse)definition: A mitochondrial isocitrate dehydrogenase complex using NAD+ whose components are encoded in the genome of mouse [PRO:hjd]is_a:GO:0005962 ! mitochondrial isocitrate dehydrogenase complex (NAD+)relationship: has_part PR:000025358 ! isocitrate dehydrogenase [NAD] subunit alpha, mitochondrial (mouse)relationship: has_part PR:000025359 ! isocitrate dehydrogenase [NAD] subunit beta, mitochondrial (mouse)relationship: has_part PR:000025360 ! isocitrate dehydrogenase [NAD] subunit gamma, mitochondrial (mouse)relationship: only_in_taxon taxon:10090! Mus musculus[Term]id: PR:000026072name: mitochondrial isocitrate dehydrogenase complex (NAD+) A (mouse)def: A mitochondrial isocitrate dehydrogenase complex using NAD+ whose components are encoded in the genome of mouse containing isoform 1 of subunit alpha\" [PRO:hjd]is_a:PR: 000026071! mitochondrial isocitrate dehydrogenase complex (NAD+) (mouse)relationship: has_part PR:000025355 ! isocitrate dehydrogenase [NAD] subunit alpha, mitochondrial isoform 1 (mouse)relationship: has_part PR:000025359 ! isocitrate dehydrogenase [NAD] subunit beta, mitochondrial (mouse)relationship: has_part PR:000025360 ! isocitrate dehydrogenase [NAD] subunit gamma, mitochondrial (mouse)relationship: only_in_taxon taxon:10090 ! Mus musculus[Term]id: PR:000026073name:mitochondrial isocitrate dehydrogenase complex (NAD+) B (mouse)def: A mitochondrial isocitrate dehydrogenase complex using NAD+ whose components are encoded in the genome of mouse containing isoform 2 of subunit alpha\" [PRO:hjd]is_a:PR: 000026071! mitochondrial isocitrate dehydrogenase complex (NAD+) (mouse)relationship: has_part PR:000025356 ! isocitrate dehydrogenase [NAD] subunit alpha, mitochondrial isoform 2 (mouse)relationship: has_part PR:000025359 ! isocitrate dehydrogenase [NAD] subunit beta, mitochondrial (mouse)relationship: has_part PR:000025360 ! isocitrate dehydrogenase [NAD] subunit gamma, mitochondrial (mouse)relationship: only_in_taxon taxon:10090! Mus musculushas_part statements that refer to \"either-or\" classes of proteins are used to represent uncertainty in a compact form with no loss of information. The union_of statement (highlighted by bold text in the stanza below) indicates which genes could code for a particular protein component. The union_of tag appears in the appropriate protein component stanzas, not in the protein complex stanza. These tags are shown below (as comments) for illustration purposes only.Cytochrome c oxidase, also known as Complex IV (EC 1.9.3.1), is a large transmembrane protein complex located in the inner mitochondrial membrane. Its function is sequestration of free radicals, coupled to the transport of protons across the inner mitochondrial membrane, which creates the proton gradient used by mitochondrial ATP synthase during ATP production. Although the function of Complex IV is well understood, the exact composition of the complex is not certain due to apparent genetic redundancy. Complex IV is composed of 13 polypeptides: three encoded in the mitochondrial genome, and ten encoded in the nuclear genome . The unc[Term]id: PR:000026295name: respiratory chain complex IV (mouse)def: A mitochondrial respiratory chain complex IV whose components are encoded in the genome of mouse. is_a: GO:0005751 ! mitochondrial respiratory chain complex IVrelationship: has_part PR:000025364 {cardinality = \"1\"} ! cytochrome oxidase subunit 1, mitochondrial (mouse)relationship: has_part PR:000025366 {cardinality = \"1\"} ! cytochrome oxidase subunit 2, mitochondrial (mouse)relationship: has_part PR:000025367 {cardinality = \"1\"} ! cytochrome oxidase subunit 3, mitochondrial (mouse)relationship: has_part PR:000026286 complex IV component 4 (mouse)! union_of: PR:000025368 ! Cox4i1! union_of: PR:000025369 ! Cox4i2relationship: has_part PR:000026294 {cardinality = \"1\"} ! cytochrome c oxidase subunit 5A, mitochondrial, transit peptide removed form (mouse)relationship: has_part PR:000025371 {cardinality = \"1\"} ! cytochrome c oxidase subunit 5B (mouse)relationship: has_part PR:000026287 {cardinality = \"1\"} ! complex IV component 6a (mouse)! union_of: PR:000025372 ! Cox6a1! union_of: PR:000025373 ! Cox6a2relationship: has_part PR:000026288 {cardinality = \"1\"} ! complex IV component 6b (mouse)! union_of: PR:000025374 ! Cox6b1! union_of: PR:000025375 ! Cox6b2relationship: has_part PR:000025376 {cardinality = \"1\"} ! cytochrome c oxidase subunit 6C (mouse)relationship: has_part PR:000026289 {cardinality = \"1\"} ! complex IV component 7A (mouse)! union_of: PR:000025377 ! Cox7a1! union_of: PR:000025378 ! Cox7a2! union_of: PR:000025379 ! Cox7a2lrelationship: has_part PR:000027496 {cardinality = \"1\"} ! complex IV component 7B (mouse)! union of PR:000027491 ! Cox7b! union of PR:000027489 ! Cox7b2relationship: has_part PR:000025383 {cardinality = \"1\"} ! cytochrome c oxidase subunit 7C, mitochondrial (mouse)relationship: has_part PR:000026290 {cardinality = \"1\"} ! complex IV component 8 (mouse)! union_of: PR:000025380 ! Cox8a! union_of: PR:000025381 ! Cox8b! union_of: PR:000025382 ! Cox8crelationship: only_in_taxon taxon:10090 ! Mus musculusWhile not illustrated in the use cases above, many PRO complexes have species-specific protein types of modified isoforms. A few examples are: (i) PR:000025933 smad2-smad4 protein complex 1 (human), which contains active phosphorylated form of smad2 (MAD homolog 2), (ii) PR:000026035 myc-max acetylated complex (human), where both myc (myelocytomatosis oncogene) and max (Max protein) are acetylated, and (iii) PR:000027084 IRF3-P:IRF7-P complex (human), which contains the active phosphorylated forms of IRF3 (interferon regulatory factor 3) and IRF7 (interferon regulatory factor 7).http://purl.obolibrary.org/obo/PR_000026144 is shown in Figure The web display of the ProComp stanza for the human SPT complex described above in Use Case 2 http://www.geneontology.org/GO.format.gaf-1_0.shtml. The PAF format consists of a standard header and 20 tab-delimited columns .The ProComp ontology provides species-specific, accessioned protein complex entities that support robust, context-specific annotation of protein biology . ComprehMCC; EC 6.4.1.4). Knowledge that mutations in human genes that encode the protein components of the MCC complex: MCCC1  and MCCC2 (subunit beta), cause methylcrotonylglycinuria type I (OMIM #210200) and methylcrotonylglycinuria type II (OMIM #210210), respectively, are represented in the PAF file  subunit is required for their proper functioning ,28. In mhttp://obi-ontology.org/) group on the development and application of an evidence code ontology to describe the evidence used to support protein complex assertions in ProComp, and with developers of the curation tools to enable capturing such evidence with appropriate granularity. Second, our current work records only protein monomer components of complexes facilitated by an interface that makes selection of the monomers and their identifiers manageable. However, as we note, protein complexes (such as Complex IV in Use Case 4) are known to have lipid, heme, and other co-factors as components. Extensions to our curation tools will be developed in order to select and include such components, identifiers for which are provided by, e.g., the Chemical Entities of Biological Interest (CheBI) ontology [has_agent and is_agent_in relations in our annotations to connect, provisionally, proteins with representation of sequence variation from the Sequence Ontology. However this does not agree with the formal definition in which these relations connect processes with their participants [has_part to relate a protein complex to its components and uses cardinality restriction to represent stoichiometry. However, because has_part is a transitive relation, the ontology falls outside OWL2-DL making it not possible to use standard reasoners. Thus, we are evaluating the possibility of replacing has_part with a new relation that is a non-transitive sub-property of the has_part relation. Finally, we will implement closure axioms that would more clearly define the number and kind of complex components. For example, our representation of Complex IV allows that there might be additional protein components because of the open world assumption. A closure axiom would assert that exactly 13 of the components of this complex are proteins, while still allowing that there might be other kinds of components.Improvements in the PRO ontology and annotation have come to light by our work on the use cases described in this manuscript. We outline a number of known issues that serve as the basis for future work. First, while the assertions in stanzas within PRO are intended to be backed by evidence, the distinction between experimental and inferential evidence (both legitimate) is not yet captured clearly. This is especially true in cases where the evidence for composition and stochiometry for protein complexes is derived from orthologous proteins and complexes in other organisms. Usefully recording such information, as we recognize is important, was hampered by deficits in our curation tools that made it impossible to record evidence for individual relations or, more specifically, cardinality. We are working with the Ontology for Biomedical Investigations  or text . Searches can be restricted to specific modified forms , database, or membership in a complex. PRO entries can also be accessed via hypertext links on gene detail pages in the Mouse Genome Informatics (MGI) database and from MouseCyc, Reactome, and EcoCyc. PRO (Release 20) contains 168 complexes drawn from Reactome (human), MouseCyc (mouse), EcoCyc (E. coli) and direct submissions from collaborating research groups. OBO Edit, an open source ontology editing tool http://oboedit.org/[The Protein Ontology resource can be accessed on-line edit.org/, can be http://purl.obolibrary.org/obo/pr.owl).Existing conversion tools allow for OBO-formatted ontologies to be converted into Web ontology language (OWL) ,33. The The authors declare that they have no competing interests.CJB, HD, AE, AR and PD researched and created protein complex stanzas for mouse and human. DN CA, and AR validated the ontology stanza formats and created the appropriate records in the PRO database. NR built software infrastructure to facilitate semi-automated acquisition of protein complex data from contributing databases. All authors contributed to the development of the formalisms to represent the classes of protein complexes illustrated in this manuscript. All authors participated in the writing of the manuscript. All authors read and approved the manuscript."}
+{"text": "The 7th author's correct name is: Diane Wallace Taylor.The correct author contributions are: Conceived and designed the experiments: KLS ALC RGFL RJIL PG MEM DWT SJR KCK. Performed the experiments: KLS ALC. Analyzed the data: KLS ALC. Contributed reagents/materials/analysis tools: RGFL DWT MEM SJR KCK. Wrote the paper: KLS ALC KCK. Constructive review of manuscript: DWT MEM SJR."}
+{"text": "The CIGS NCs of approximately 17 nm in diameter were homogeneously blended with P3HT layer to form an active layer of a photovoltaic device. The blend ratios of CIGS NCs to P3HT, solvent effects on thin film morphologies, interface between P3HT/CIGS NCs and post-production annealing of devices were investigated, and the best performance of photovoltaic devices was measured under AM 1.5 simulated solar illumination (100 mW/cm2).This work presents the systematic studies of bulk hybrid heterojunction solar cells based on CuSe Photovoltaic (PV) devices, converting photon into electricity as an elegant and clean renewable energy, have attracted tremendous attentions on research and developments. Among emerging PV technologies, organic photovoltaic devices (OPV) composed of polymer matrices can be considered as promising third-generation solar cell due to its exceptional mechanical flexibility for versatile applications ,2. Moreo2-Phenyl-C61 butyric acid methyl ester; PCE: Power-conversion efficiency; PEDOT/PSS: Poly-poly(styrenesulfonate); XRD: Powder X-ray diffraction; FTIR: Fourier transform infrared spectroscopy; HRTEM: High-resolution transmission electron microscopy; PL: Photoluminescence; FWHM: Full width at half maximum; Jsc: Short-circuit current; Voc: Opened circuit voltage; FF: Fill factor; OLA: Oleylamine; PYR: Pyridine.CIGS: CuSeThe authors declare that they have no competing interests.YKL carried out the device fabrication and drafted the manuscript; SHC synthesized the CIGS nanocrystals; HFH provided useful solutions to the experimental issues and helped to revise the draft; HYT participated in the design of the study; YTY participated in the sequence alignment and helped to draft the manuscript; YLC carried out the TEM analysis, conceived the study, and organized the final version of the paper. All authors read and approved the final manuscript."}
+{"text": "The author contributions provided in the HTML and PDF versions of the article contain author initials from a different paper. The following are the correct author contributions for this article:Conceived and designed the experiments: BZ YYH QY. Performed the experiments: BZ YYH QY SWZ YW YXC DRX. Analyzed the data: YYH QY SWZ YW YXC DRX. Contributed reagents/materials/analysis tools: YYH QY SWZ YW YXC DRX. Wrote the paper: YYH QY."}
+{"text": "There was an error in the author contributions section of the article. A correct version of the section is available below.Conceived and designed the experiments: AC JD LY. Performed the experiments: AC. Analyzed the data: AC. Wrote the manuscript: AC JD LY."}
+{"text": "AbstractChilopoda) is proposed. Terms are selected from the alternatives used in the English literature, preferring those most frequently used or those that have been introduced explicitly. A total of 330 terms are defined and illustrated, and another ca. 500 alternatives are listed.A common terminology for the external morphological characters of centipedes ( Chilopoda).This contribution is intended to propose a common terminology for the external morphological characters of centipedes , because they have been documented only recently, by histology and scanning electron microscopy, so that a consistent terminology is available , 2008. OWe considered all publications in English dealing with centipedes since PageBreakTo maximize future applicability, alternative criteria of selection have been discussed with authors who are either currently the most active centipede systematists publishing descriptions in English and/or have already addressed issues of terminology standardization. In order to identify and recommend a single term for each character, we applied the following criteria: (i) we selected a term already used in the literature, except when all alternatives are either ambiguous or inconsistent with other selected terms; (ii) among alternatives, we selected either the term used most frequently (by most authors and/or in most publications) or the one explicitly introduced and defined by an influential author; (iii) we applied minor emendations to selected terms  when necessary for consistency and uniformity. We refrained from revising the terminology based on homology hypotheses with other arthropods , becauseMajor anatomical differences exist between the six centipede orders, five extant - Scutigeromorpha, Lithobiomorpha, Craterostigmomorpha, Scolopendromorpha, and Geophilomorpha - and one extinct, Devonobiomorpha. Morphological and taxonomical investigations by different authors have sometimes been and still are limited to single orders, leading to different terminological traditions. While we propose a consistent terminology for the entire class, we specify the order(s) to which each term is applicable to facilitate usage by students interested in single orders; when no orders are specified, it is meant that the term is applicable to all orders; when an order is specified, it is meant that the term is applicable to at least some taxa in the order.After reviewing the relevant literature as explained above, we retrieved roughly 830 terms that apply to 330 anatomical features. By applying the criteria described above, we obtained the recommended terminology presented herein.PageBreakby a slash; listed alphabetically, without an implicit ranking). An alphabetical index of all recommended and synonymous terms is provided in the additional file: Analytical index. Abbreviations for orders are: Cra (Craterostigmomorpha), Dev (Devonobiomorpha), Geo (Geophilomorpha), Lit (Lithobiomorpha), Sco (Scolopendromorpha), and Scu (Scutigeromorpha).Terms for surface depressions and projections are provided in cephalic capsule: integument of the head to the exclusion of its appendages. cephalic plate:  dorsal side of the cephalic capsule. median sulcus:  mid-longitudinal sulcus on the anterior part of the cephalic capsule.  transverse suture: transverse suture on the anterior part of the dorsal side of the cephalic capsule.  anterior projection/projections of the transverse suture: [Scu] one of the paramedian sutures projecting anteriorly from the cephalic transverse suture. Fig. 3antennocellar suture/sutures:  one of the paired sutures on the antero-lateral parts of the cephalic capsule. antennal branch/branches of antennocellar suture:  part of the antennocellar suture, anterior to the cephalic transverse suture. Syn.: anterior portion/portions of antennocellar sutureocellar branch/branches of antennocellar suture:  part of the antennocellar suture, posterior to the cephalic transverse suture. Syn.: posterior portion/portions of antennocellar suture, posterior limb/limbs of  transverse suturefrontal plate: anterior part of the dorsal side of the cephalic capsule, delimited posteriorly by the cephalic transverse suture. ocellar area/areas:  one of the paired antero-lateral parts of the cephalic capsule, bearing compound eyes or ocelli when present, and delimited mesally by the antennocellar suture. compound eye/eyes: [Scu] faceted vision organ, composed of similar units known as ommatidia. Fig. 3ocellus/ocelli:  simple vision organ, appearing as a single convex lens. Fig. 5posterior ocellus/ocelli: [Lit] the most posterior ocellus on each side of the head. seriate ocellus/ocelli: [Lit] one of the ocelli other than the posterior ocellus. ocellar series/series: [Lit] one of the sub-horizontal rows in which the seriate ocelli can be arranged. Syn.: ocellar row/rowsposterosuperior ocellus/ocelli: [Lit] the most posterior ocellus of the most dorsal row of seriate ocelli. Fig. 5PageBreakPageBreakT\u00f6m\u00f6sv\u00e1ry\u2019s organ/organs:  hygroreceptor sensory organ at the side of the head. paramedian suture/sutures: [Sco] one of the paired paramedian sutures on the cephalic plate. Fig. 6 paramedian sulcus/sulci:  one of the paired paramedian sulci on the posterior part of the cephalic plate.  marginal ridge:  narrow ridge along the lateral and posterior margins of the dorsal side of the cephalic capsule.  marginal sulcus/sulci:  sulcus between the marginal ridge and the remaining part of the dorsal side of the cephalic capsule. Fig. 1 lateral marginal interruption/interruptions : [Lit] notch on the lateral margins of the cephalic plate. basal plate/plates: [Sco] one of the paired sclerites at the posterior corners of the cephalic plate. Fig. 6 cephalic pleurite/pleurites:  one of the pleurites lateral to the clypeolabrum. transverse suture/sutures : [Geo] transverse suture on the cephalic pleurite. stilus/stili: [Geo] sclerotised ridge on the mesal margin of the cephalic pleurite. anterior incision/incisions (of stilus): [Geo] notch on the mesal side of the stilus. spiculum/spicula: [Geo] sclerotised, pointed projection on the anterior part of the cephalic pleurite. maxillary complex: whole of first and second maxillaeantenna/antennae: one of the paired most anterior appendages on the head. Fig. 1article/articles: one of the rigid sectors along the antenna.  scape/scapes: [Scu] set of the two most basal antennal articles. Fig. 10annulation/annulations: [Scu] short antennal article.  PageBreakPageBreakflagellum/flagella: [Scu] one of the sections along the antenna composed of annulations. node/nodes: [Scu] elongate antennal article between two flagella along the antenna. Fig. 11 first flagellum/flagella: [Scu] the most basal flagellum along the antenna. second flagellum/flagella: [Scu] the second flagellum along the antenna. third flagellum/flagella: [Scu] the third flagellum along the antenna. shaft organ/organs: [Scu] sensory organ on the first antennal articleclypeolabrum: antero-ventral part of the cephalic capsule, posterior to the antennae and between the cephalic pleurites. Fig. 7clypeus: sclerite on the antero-ventral part of the cephalic capsule, to the exclusion of the labrum. Fig. 12paraclypeal suture/sutures: one of the lateral margins of the clypeus. scute/scutes: area on the cuticle, corresponding to the external face of a single epithelial cell. areolate part: [Geo] anterior part of the clypeus that is evidently areolate.  plagula/plagulae: [Geo] one of the non-areolate areas on the posterior part of the clypeus. mid-longitudinal areolate strip: [Geo] mid-longitudinal areolate band separating two paired plagulae. clypeal insula/insulae: [Geo] non-areolate area inside the areolate part of the clypeus. Fig. 9clypeal area/areas: [Geo] small, subcircular, median area on the areolate part of the clypeus, with distinctly finer or indistinct areolation. clypeolabral suture: suture between clypeus and labrum. Fig. 12labrum: posterior part of the clypeolabrum, sometimes delimited from the clypeus by a suture. mid-piece: median sclerite of the labrum.  PageBreakintermediate part: [Geo] median part of the labrum, when not a sclerite distinct from the lateral parts.  mid-piece tooth: sclerotised tooth on the labral mid-piece. Fig. 13 side-piece/side-pieces: one of the paired lateral sclerites of the labrum.  lateral part/parts: [Geo] one of the paired lateral parts of the labrum, when not sclerites distinct from the intermediate part.  ala/alae: [Geo] one of the two sclerites composing the labral side-piece. Fig. 8 anterior ala/alae: [Geo] the anterior of the two sclerites composing the labral side-piece. Fig. 8 posterior ala/alae: [Geo] the posterior of the two sclerites composing the labral side-piece. Fig. 8 transverse thickened line/lines: [Geo] sclerotised ridge between the anterior and posterior ala of the labral side-piece. Fig. 8 median arc: [Geo] concave posterior margin of the labral intermediate part.  bristle/bristles: hair-like, sometimes branching, projection along the posterior margin of the labrum.  denticle/denticles: [Geo] subtriangular, flat projection along the posterior margin of the labrum.  tubercle/tubercles: [Geo] subconical, stout projection along the posterior margin of the labrum.  paralabial sclerite/sclerites:  one of the paired sclerites posterior to the clypeus and lateral to the labral side-pieces. tentorium/tentoria: Y-shaped sclerite whose three limbs are attached to the labral lateral parts, the cephalic pleurite, and the mandibular condyle, respectively. mandible/mandibles: one appendage of the first pair of the mouth-parts. Fig. 13mandibular condyle/condyles: condyle of the mandible serving the articulation with the tentorium. Fig. 15gnathal edge/edges: distal margin of the mandible. manubrium/manubria: slender projection of the mandible opposite to the gnathal edge with respect to the mandibular condyle. PageBreaktrunk/trunks: main part of the mandible, to the exclusion of the manubrium and the gnathal edge. (mandibular) cruciform suture/sutures: [Sco] pair of crossed sutures on the mandibular trunk. (mandibular) lamina/laminae manubrii: [Sco] part of the mandible between manubrium and cruciform suture. lamina/laminae triangularis/triangulares: [Sco] part of the mandible between the lamina manubrii and the lamina dentifera, opposite to the lamina condylifera with respect to the cruciform suture. lamina/laminae dentifera/dentiferae: [Sco] part of the mandible between apical ridge and cruciform suture. lamina/laminae condylifera/condyliferae: [Sco] part of the mandible between the lamina manubrii and the lamina dentifera, including the mandibular condyle and opposite to the lamina triangularis with respect to the cruciform suture. molar plate/plates: [Scu] sclerotised, flat area on the gnathal edgepulvillus/pulvilli: array of dense short scales on the dorsal end of the mandibular gnathal edge. acicula/aciculae: one of the slender long projections on the ventral end of the mandibular gnathal edge. (mandibular) pinnule/pinnules (of acicula): one of the branches of a mandibular aciculabranching bristle/bristles: [Lit] hair-like, branching projection fringing the mandibular teeth and aciculae(mandibular) accessory denticle/denticles:  one of the denticles arranged in rows on the mandibular teeth(mandibular) lamella/lamellae: one of the flat projections on the gnathal edge of the mandible. (mandibular) dentate lamella/lamellae: mandibular lamella bearing teeth. (mandibular) tooth/teeth: sclerotised, large, subconical, projection on a mandibular dentate lamella. Fig. 15(mandibular) tricuspid tooth/teeth: tooth with three tips on a dentate lamella. Fig. 16(mandibular) block/blocks: one of the sclerotised distinct parts of a dentate lamella, each bearing one or more teeth. Fig. 17(mandibular) pectinate lamella/lamellae:  mandibular lamella bearing poorly sclerotised, subcylindrical, slender projections. (mandibular) basal tooth/teeth: [Geo] subconical projection at the base of the first mandibular lamella(mandibular) PageBreakPageBreakfirst maxillae {plural only}: pair of appendages and associated basal sclerites between the mandibles and the second maxillae. sternite: most basal part of the coxosternite, associated with the first maxillae(first maxillary) coxa/coxae: part of the coxosternite corresponding to a coxa, of the first maxillae(first maxillary) coxosternite: entire sclerite corresponding to sternite and coxae of the first maxillae. (first maxillary) lateral incision: [Geo] notch on the lateral margin of the first maxillary coxosternite. (first maxillary) coxal projection/projections: one of the paired projections on the anterior margin of the first maxillary coxosternite, mesal to the telopodites. (first maxillary) telopodite/telopodites: one of the paired projections, usually articulated at the base, on the anterior margin of the first maxillary coxosternite, lateral to the coxal projections. (first maxillary) basal article/articles: the most basal article of the first maxillary telopodite. (first maxillary) distal article/articles: the most distal article of the first maxillary telopodite. (first maxillary) plumose bristle/bristles: [Lit] one of the feather-like projections on the distal article of the first maxillary telopodite. Fig. 21(first maxillary) pad/pads: [Sco] array of short, dense projections on the distal article of the first maxillary telopodite. Fig. 22(first maxillary) lappet/lappets: [Geo] projection on the lateral margin of the first maxillary coxosternite or telopodite. (first maxillary) coxosternal lappet/lappets: [Geo] lappet on the first maxillary coxosternite. (first maxillary) telopodital lappet/lappets: [Geo] lappet on the basal article of the first maxillary telopodite. (first maxillary) PageBreakPageBreaksecond maxillae {plural only}: pair of appendages and associated basal sclerite/s, posterior to the first maxillae. coxosternite: entire sclerite corresponding to sternite and coxae of the second maxillae. (second maxillary) isthmus: median part of the second maxillary coxosternite. Fig.\u00a024(second maxillary) setigerous insula/insulae: [Geo] one of the nonareolate areas, bearing setae, inside the areolate part of the second maxillary coxosternite. Fig. 20(second maxillary) metameric pore/pores: one of the paired pores of the maxillary glands on the second maxillary coxosternite. foraminal process/processes: [Geo] marginal projection of the second maxillary coxosternite surrounding the metameric pore. Fig. 20statumen/statuminia: [Geo] sclerotised elongated ridge mesal to the metameric pore. parastatuminial suture/sutures: [Geo] suture along the statumen. circumforaminal ring/rings: [Geo] sclerotised ring partially surrounding the metameric poreinner process/processes (of second maxillary coxosternite): [Geo] one of the paired projections on the anterior margin of the second maxillary coxosternite, mesal to the telopodites. postmaxillary sclerite/sclerites:  one of the paired sclerites adjacent to the posterior corners of the second maxillary coxosternite. telopodite/telopodites: part of the appendage of the second maxillae, distal to the most basal articulation. (second maxillary) trochanter/trochanters: [Scu] first article of the second maxillary telopodite. Fig. 25(second maxillary) prefemur/prefemora: [Scu] second article of the second maxillary telopodite. Fig. 25(second maxillary) femur/femora: [Scu] third article of the second maxillary telopodite. Fig. 25(second maxillary) tibia/tibiae: [Scu] fourth article of the second maxillary telopodite. Fig. 25(second maxillary) tarsus/tarsi: [Scu] fifth article of the second maxillary telopodite. Fig. 25(second maxillary) PageBreakarticle/articles 1:  first article of the second maxillary telopodite. (second maxillary) article/articles 2:  second article of the second maxillary telopodite. (second maxillary) article/articles 3:  third article of the second maxillary telopodite. (second maxillary) plumose seta/setae: [Lit] one of the setae with apical branches, on article 3 of the second maxillary telopodite. Fig. 26(second maxillary) dorsal brush/brushes:  longitudinal row of hairs on article 3 of the second maxillary telopodite. (second maxillary) pretarsus/pretarsi:  terminal element articulated to the most distal article of the second maxillary telopodite. (second maxillary) claw/claws:  second maxillary pretarsus in shape of a claw. (second maxillary) digit/digits (of second maxillary claw):  one of the short projections on the second maxillary claw. Fig. 26comb/combs (of second maxillary claw):  row of projections along the margin of the second maxillary claw. filament/filaments (of second maxillary claw):  one of the slender projections of the comb of the second maxillary claw. Fig. 18forcipular segment: segment bearing the forcipules. forcipular pretergite:  short sclerite anterior to the forcipular tergite. forcipular tergite: main tergite of the forcipular segment. forcipular pleurite/pleurites: lateral sclerite of the forcipular segment. scapula/scapulae: [Geo] dorsal ridge of the forcipular pleurite. Fig. 27(forcipular) scapular point/points: [Geo] projecting anterior tip of the forcipular scapula. (forcipular) PageBreakcollar: [Lit] ventral transversal bridge connecting the forcipular pleurites. (forcipular) coxa/coxae: [Scu] one of the paired sclerites basal to the forcipules, bearing spine-bristles on the anterior margin. (forcipular) coxosternite:  entire sclerite corresponding to sternite and coxae of the forcipular segment. (forcipular) coxopleural suture/sutures: suture between the forcipular pleurite and the forcipular coxae or coxosternite. (forcipular) coxosternal condyle/condyles: condyle of the forcipular coxa or coxosternite serving the articulation with the trochanteroprefemur. cerrus/cerri: [Geo] one of the paired groups of setae on the dorsal side of the forcipular coxosternite.  condylar process/processes: [Geo] one of the paired projections of the forcipular coxosternite, close to the dorsal coxosternal condyles shoulder/shoulders (of forcipular coxosternite): [Lit] one of the paired obtuse projections on the anterior margin of the forcipular coxosternite. median diastema:  median concavity on the anterior margin of the forcipular coxosternite.  tooth/teeth:  sclerotised, short, subconical projection on the anterior margin of the forcipular coxosternite.  tooth-plate/tooth-plates:  one of the paired sclerotised, flat, teeth-bearing projections on the anterior margin of the forcipular coxosternite.  denticle/denticles: [Geo] one of the paired small, subconical projections on the anterior margin of the forcipular coxosternite.  porodont/porodonts: [Lit] one of the paired large setae usually placed lateral to the forcipular coxosternal teeth. porodont node/nodes: [Lit] basal structure from which the porodont arisesmedian cleft: [Lit] mid-longitudinal suture on the ventral side of the forcipular coxosternite.  chitin-line/chitin-lines: [Geo] one of the paired paramedian sclerotised narrow stripes on the ventral side of the forcipular coxosternite. PageBreakSyn.: chitinous line/lines, pleurogram/pleurograms,  (subcondylic) sclerotic line/linesPageBreakmedian embayment:  median notch at the posterior margin of the forcipular coxosternite.  forcipule/forcipules: telopodite of the forcipular segment. trochanteroprefemur/trochanteroprefemora: first article of the forcipule. (forcipular) trochanteral suture/sutures: trace of suture on the forcipular trochanteroprefemur. Fig. 29(forcipular) intermediate article/articles: one of the second and third articles of the forcipule. Syn.: intercalary article/articles, intermediate joint/joints(forcipular) femur/femora: second article of the forcipule. (forcipular) tibia/tibiae: third article of the forcipule. (forcipular) tarsus/tarsi: [Scu] fourth article of the forcipule. (forcipular) ungulum/ungula: [Scu] terminal articulated element of the forcipule. tarsungulum/tarsungula:  ultimate article of the forcipule. (forcipular) process/processes of (forcipular) tronchanteroprefemur:  large projection on the mesal side of the forcipular trochanteroprefemur. denticle/denticles: [Geo] small subconical projection on the mesal side of the forcipule. (forcipular) proximal denticle/denticles (of trochanteroprefemur): [Geo] the most basal of two denticles along the mesal side of the forcipular trochanteroprefemur. distal denticle/denticles (of trochanteroprefemur): [Geo] the most distal of two denticles along the mesal side of the forcipular trochanteroprefemur. Fig. 27basal denticle/denticles (of tarsungulum): [Geo] denticle at the base of the forcipular tarsungulum. spine comb/combs: [Scu] row of spines on the forcipular tarsus(forcipular) PageBreakleg-bearing segment/segments: segment of the trunk bearing paired walking appendages. tergite/tergites (of leg-bearing segment): sclerite on the dorsal side of a leg-bearing segment. stomatotergite/stomatotergites: [Scu] tergite bearing a stoma. Fig. 35stoma/stomata: [Scu] elongate opening of the respiratory organs on the posteromedian part of a stomatotergite. stoma-saddle/stoma-saddles: [Scu] domed region of the stomatotergite surrounding the stoma. margination/marginations (of tergite):  marginal ridge on a tergite. posterior triangular projection/projections (of tergite): [Lit] angulated projection on each posterior corner of a tergite. pretergite/pretergites:  anterior sclerite of the two dorsal sclerites of a leg-bearing segment. metatergite/metatergites:  posterior sclerite of the two dorsal sclerites of a leg-bearing segment. paramedian sulcus/sulci or suture/sutures (of tergite):  one of the paired paramedian longitudinal sutures or sulci on a tergite. transverse sulcus/sulci or suture/sutures (of tergite): [Sco] transverse suture or sulcus on the first trunk tergite. (anterior) cruciform suture/sutures (of tergite): [Sco] pair of crossed sutures on the first trunk tergite. Fig. 33oblique suture/sutures (of tergite): [Sco] one of the paired oblique sutures on some anterior trunk tergites. lateral longitudinal suture/sutures (of tergite): [Sco] one of the paired longitudinal sutures close to the lateral margins of a tergite. lateral crescentic sulcus/sulci (of tergite): [Sco] one of the paired curved, sublongitudinal sulci on a tergite. eupleurium/eupleuria: the whole of pleurites on a side of a leg-bearing segment. pleural membrane/membranes: arthrodial membrane between pleuritesparatergite/paratergites: [Geo] pleurite contiguous or almost contiguous to a tergite. Fig. 36intercalary paratergite/paratergites: [Geo] paratergite lateral to a pretergite. primary intercalary paratergite/paratergites: [Geo] the most mesal of two intercalary paratergites. secondary intercalary paratergite/paratergites: [Geo] the most distal of two intercalary paratergites. principal paratergite/paratergites: [Geo] paratergite lateral to a metatergite. scutellum/scutella:  pleurite in antero-ventral position with respect to the stigmatopleurite. spiracle/spiracles:  one of the paired openings of the tracheae on the lateral sides of a leg-bearing segment. stigmatopleurite/stigmatopleurites:  pleurite bearing a spiracle. catapleurite/catapleurites: pleurite between the scutellum and the coxa. eucoxa/eucoxae superior/superiores: [Lit] pleurite dorsal to the coxaeucoxa/eucoxae inferior/inferiores: [Lit] pleurite ventral to the coxapleurocoxa/pleurocoxae: [Geo] pleurite between coxa and metacoxasubcoxa/subcoxae:  pleurite anterior or posterior to the coxa. Syn.: subcoxal pleurite/pleuritesprocoxa/procoxae:  subcoxa anterior to the coxa. metacoxa/metacoxae:  subcoxa posterior to the coxa. sternite/sternites (of leg-bearing segment): sclerite on the ventral side of a leg-bearing segment. presternite/presternites:  anterior region of the single sternite of a leg-bearing segment, or anterior sclerite of the two ventral sclerites of a leg-bearing segment. metasternite/metasternites:  posterior region of the single sternite of a leg-bearing segment, or posterior sclerite of the two ventral sclerites of a leg-bearing segment. transverse sulcus/sulci (of sternite): [Sco] transverse sulcus on a sternite. median longitudinal sulcus/sulci (of sternite): [Sco] mid-longitudinal sulcus on a sternite. cruciform suture/sutures (of sternite): [Sco] the pair of transverse and median longitudinal sulci on a sternite. trigonal suture/sutures (of sternite): [Sco] pair of crossed sutures on the posterior part of the sternite. endosternite/endosternites:  posterior projection of a sternite, covered by the sternite of the following segment. carpophagus peg/pegs: [Geo] median projection on the posterior margin of a sternite, in the carpophagus-structure. carpophagus pit/pits: [Geo] median socket on the anterior margin of a sternite, in the carpophagus-structure. carpophagus-structure/carpophagus-structures: [Geo] whole of a carpophagus peg and the associated carpophagus pit. Fig. 37ventral pore/pores: [Geo] glandular pore on the ventral side of a leg-bearing segment. pore-field/pore-fields: [Geo] an area of clustered pores on the ventral side of a leg-bearing segment.  sternobothrium/sternobothria: [Geo] median horseshoe-like pit on the metasternite. Fig. 40transverse fossa/fossae (of sternite): [Geo] transverse, ellipical depression on some trunk sternites. fungiform fovea/foveae: [Geo] median T-like pit on the metasternitevirguliform fossa/fossae: [Geo] comma-like pit at each of the anterior corners of a sternite. lateral gutter/gutters (of sternite): [Geo] longitudinal groove along the lateral margin of a sternite. leg/legs: one of the paired appendages of the trunk to the exclusion of the forcipules and the gonopods. cursiped/cursipeds: [Lit] a leg of the pairs 1\u201313. tenaciped/tenacipeds: [Lit] a leg of the pairs 14\u201315. PageBreakarticle/articles: one of the articulated elements of a leg. (leg) coxa/coxae: the most basal article of a leg. Fig. 38(leg) trochanter/trochanters: small, basalmost article of a telopodite. Fig. 38(leg) prefemur/prefemora: second article of a telopodite. (leg) femur/femora: third article of a telopodite. Fig. 43(leg) tibia/tibiae: fourth article of a telopodite. (leg) tarsus/tarsi: fifth article of a telopodite, when ultimate. Fig. 43(leg) tarsal article/articles: one of the articles of a biarticulated region of the leg corresponding to the tarsus. Syn.: tarsalium/tarsalia, tarsomere/tarsomerestarsus/tarsi 1: the basal article of two tarsal articles. tarsus/tarsi 2: the distal article of two tarsal articles. annulation/annulations:  each part of a tarsal article, between two contiguous constrictions.  carina/carinae: [Scu] longitudinal ridge on a leg article. tarsal papilla/papillae: [Scu] relatively short, stout projection with a rounded tip, on the ventral side of tarsus 2. resilient sole-hair/sole-hairs: [Scu] one of the paired hairs thickened at the base, on the ventral side of the leg, originating near the posteromedian margin of each tarsal papilla. spur/spurs:  spur on legs. (leg) distal spinose projection/projections (of tibia): [Lit] spinous process at the distal end of the tibia of a leg. pectinal seta/setae: [Lit] one of the decumbent setae arranged in rows along the tarsal articles of legs. pecten/pectines: [Lit] row of pectinal setae.  pretarsus/pretarsi: apical element articulated at the tip of a leg. claw/claws: pretarsus in shape of a claw. PageBreakfundus/fundi (of claw): basal, swollen part of a claw. unguis/ungues proper: distal, slender part of a claw. accessory spine/spines: slender, pointed projection at the base of the claw. anterior accessory spine/spines: the anterior accessory spine of two of a claw. posterior accessory spine/spines: the posterior accessory spine of two of a claw. posteroventral spine/spines: [Lit] the largest of a pair of spines emerging on the ventro-posterior side at the base of a claw, close to the posterior accessory spine.  subsidiary spine/spines: [Lit] the smallest of a pair of spines emerging on the ventro-posterior side at the base of a claw, close to the posterior accessory spine.  fibulunguis/fibulungues: [Geo] pretarsus with a large projection flanking the unguis proper. penultimate leg/legs: leg of the penultimate pair. ultimate leg-bearing segment: leg-bearing segment bearing the ultimate pair of legs. ultimate pretergite: [Geo] pretergite of the ultimate leg-bearing segment. Fig. 50intercalary pleurite/pleurites: [Geo] pleurite contiguous to the ultimate pretergite. pleuropretergite: [Geo] entire sclerite corresponding to the ultimate pretergite and the two intercalary pleurites. Fig. 49(ultimate) tergite (or metatergite) of the ultimate leg-bearing segment: main tergite of the ultimate leg-bearing segment. ultimate presternite: [Geo] presternite of the ultimate leg-bearing segment. Fig. 51sternite (or metasternite) of the ultimate leg-bearing segment: main sternite of the ultimate leg-bearing segment. PageBreakPageBreakultimate leg/legs: one of the legs of the ultimate pair. coxopleuron/coxopleura:  basal element of the ultimate leg, corresponding to coxa and pleurites. coxopleural process/processes: [Sco] posterior process of the coxopleuron. spine/spines: [Sco] spine on the coxopleuron.  side spine/spines: [Sco] spine on the posterior margin of the coxopleuron mesal to the coxopleural process.  coxal pore/pores:  one of the pores of the coxal organs on posterior legs. macropore/macropores: [Geo] coxal pore that is distinctly larger than the other pores. Fig. 51gutter-like depression/depressions: [Lit] depressed area on the coxopleuron containing the openings of the coxal organs. Fig. 53 pit/pits: [Geo] pit on the coxopleuron, containing the openings of the coxal organs.  fossa/fossae: [Geo] longitudinal pouch close to the mesal margin of the coxopleuron, containing the openings of the coxal organs. Syn.:  cavity/cavities,  fossula/fossulae pore-field/pore-fields:  part of the surface of the coxa or coxopleuron of the ultimate legs containing the coxal pores.  prefemoral spine/spines: [Sco] spine on the prefemur of ultimate and/or penultimate legs. prefemoral (spinous) process/processes: [Sco] process, usually bearing spines, on the prefemur of the ultimate legs. corner spine/spines: [Sco] spine on the distal end, on the mesal side, of the prefemur of ultimate legs. saw tooth/teeth: [Sco] one of the bluntly pointed projections arranged in rows on the tibia and tarsus 1 of ultimate legs. ultimate pretarsus/pretarsi: pretarsus of the ultimate leg. Fig. 56PageBreakPageBreakpostpedal segments {plural only}: part of the trunk posterior to the ultimate leg-bearing segment. intermediate tergite: [Lit] tergite posterior to the tergite of the ultimate leg-bearing segment, corresponding to the intermediate sternite. intermediate sternite: sternite between the sternite or metasternite of the ultimate leg-bearing segment and the first genital sternite. Fig. 54intermediate pleurite/pleurites: [Geo] one of the two pleurites flanking the intermediate sternite. Fig. 54first genital tergite: [Lit] tergite posterior to the intermediate tergite, corresponding to the first genital sternite. Fig. 57first genital sternite: sternite between the intermediate sternite and the second genital sternite, usually associated with gonopods. first genital pleurite/pleurites: one of the two pleurites flanking the first genital sternite. first genital pleurosternite: entire sclerite corresponding to the first genital sternite and the relevant pleurites. Fig. 58first genital coxite/coxites: [Scu] one of the paired sclerites lateral to the first genital sternite. Fig. 59second genital sternite: sternite posterior to the first genital sternite. gonopod/gonopods: one of the paired appendages usually associated with the first or the second genital sternite. style/styles: [Scu] styliform male gonopod. Fig. 60 proarthron: [Scu] basal part of the complex of the paired female gonopods, composed of the basal contiguous parts of the basal articles of the gonopods. Fig. 59depression/depressions of proarthron: [Scu] one of the paired depressions on the proarthron. Fig. 59mesarthron: [Scu] median part of the complex of the paired female gonopods, composed of the distal separated parts of the basal articles of the gonopods. Fig. 59sinus of mesarthron: [Scu] concave median posterior margin of the mesarthron. Fig. 59metarthron: [Scu] terminal part of the complex of the paired female gonopods. Fig.\u00a059syntelopodite: [Scu] coalescent pair of female gonopod telopodites. Fig. 59 first article/articles:  basal article of the gonopod.  telopodite/telopodites: [Lit] articles of the gonopod other than the first article. Fig. 61 third article/articles: [Lit] third article of the gonopod.  claw/claws: [Lit] apical claw of the female gonopod. Fig. 61 spur/spurs: [Lit] spur on the female gonopod.  plinth/plinths: [Lit] swollen projection bearing a gonopodal spur. Fig.\u00a061 papilla/papillae: [Lit] relatively short, stout projection with a rounded tip, on the gonopod supplementary spur/spurs: [Lit] spur on the female gonopod other than those invariantly present lateral denticle/denticles : [Lit] one of the denticles on one or both sides of a gonopodal claw. gonopodal lamina: [Geo] entire median projection, corresponding to the paired female gonopods. penis: median projection bearing the male genital pore. postpedal tergite: the most posterior tergite of the trunk. lamina adanalis: [Sco] median dorsal flat projection on the posterior tip of the female body. lamina subanalis: [Sco] median ventral flat projection on the posterior tip of the female body. Fig. 63subanal plate/plates: [Scu] one of the paired ventrolateral sclerites in the telson. Fig.\u00a059anogenital capsule: [Cra] terminal, capsule-like part of the trunk. anal pore/pores:  one of the pores of the anal organs, on the ventro-lateral sides of the telson. anal valve/valves: one of the paired rounded flat projections on the ventral side of the telson. Fig. 58Conventional abbreviations recommended for describing particular elements and patterns of elements are described below.Antennal articles in Geophilomorpha. Each article is indicated by a Roman number, from the most basal article (I) to the most distal one (XIV).PageBreakArrangement of ocelli in Lithobiomorpha. The number of ocelli in different rows are indicated from the most dorsal row to the most ventral row, separated by commas .Pattern of teeth on the anterior margin of the forcipular coxosternite in Lithobiomorpha and on the tooth-plates in Scolopendromorpha. The number of teeth is indicated for the right and the left side, separated by a plus [nright + nleft].Leg-bearing segments and pairs of legs. Each leg-bearing segment, or the corresponding pair of legs, is indicated by an Arabic number, from the most anterior one (1) to the most posterior one.Tergites and sternites of the leg-bearing segments. Each tergite and sternite is indicated by T and S respectively , followed by an Arabic number, from the most anterior ones (T1 and S1) to the most posterior ones.Arrangement of spurs on the legs in Lithobiomorpha  are indicated in parentheses. Spurs that could be present on one side only are marked by an asterisk. Additional spurs are indicated by the abbreviation of their position  typed as a superscript to the corresponding spur . Legs with the same plectrotaxy in both ventral and dorsal side can be indicated in distinct rows or in a single, common line. This convention was first proposed by Pattern of coxal pores on the legs in Lithobiomorpha. The number of coxal pores is indicated from anterior to posterior legs, without separation between the numbers [\u2026n13n14n15]."}
+{"text": "Following the publication of our article, an erroThe GenBank accession number was incorrectly stated as:EX721840Forward primer: CCCTGTGGAAGTGGCTGAAGReverse primer: CATCCAAGGGTCCGTATCTCTTThe correct GenBank accession number should be:EX722124 Forward primer: CGGTATCCTCAAGCCCAACA Reverse primer: GTCAGAGACTCGTGGTGCATCTWe apologise for any inconvenience this may have caused."}
+{"text": "The SLE Subcommittee of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) is developing standardized treatment plans for proliferative lupus nephritis (LN) in childhood-onset SLE (cSLE) which will serve as the basis for future comparative effectiveness studies. The Initial Delphi survey revealed wide variability in the treatment of LN in cSLE. This abstract decribes the process of developing standardized evidence-based induction treatment plans for LN in cSLE by using consensus methods.A consensus conference attended by 12 trainees and 42 voting members of the CARRA SLE Subcommittee was conducted to discuss the components of the LN treatment plan for which there was wide variability and poor agreement. After the face-to-face conference, a second online survey focusing on management aspects of the induction therapy for LN was sent to the 42 voting members of the SLE Subcommittee of CARRA to resolve remaining issues. Consensus was defined at 70%.[see Figure A] Consensus was attained on: a) inclusion and exclusion criteria; b) primary and secondary outcome measures; and c) time-points for assessing patient response. No consensus was reached on the following points: a) age cut-off for the definition of childhood-onset SLE; b) need for SLE-specific quality of life measure; and c) measures of adherence to be utilized. These are being addressed through subsequent surveys.At the conference, two immunosuppressive treatment options for the 6-month induction phase, cyclophosphamide and mycophenolate mofetil, were selected. Three steroid regimens  with corresponding tapering schedules were developed to reduce variability in steroid exposure Several important consensus points were achieved in the development of induction treatment plans for proliferative lupus nephritis in childhood-onset SLE. Further refinement of these treatment plans and development of plans for maintenance therapy are needed to allow their use in future studies aimed at optimizing therapy for lupus nephritis.Rina Mina: NIH, 2; Hermine Brunner: NIAMS-NIH, 2; Barbara Anne Eberhard: None; Marilynn G. Punaro: None; Stacy P. Ardoin: None; Marisa S. Klein-Gitelman: None; Linda Wagner-Weiner: None; Lakshmi N. Moorthy: None; Joyce J. Hsu: None; Eyal Muscal: None; Suhas M. Radhakrishna: None; Laura E. Schanberg: Pfizer Inc, 2; Carol A. Wallace: None; Norman T. Ilowite: None; Emily Von Scheven: None."}
+{"text": "Following the publication of our article  we becamDMAJNCHD: Date of above (days elapsed from randomisation)DSIDED: Date of above (days elapsed from randomisation)DRSISCD: Date of above (days elapsed from randomisation)DRSHD: Date of above (days elapsed from randomisation)DRSUNKD: Date of above (days elapsed from randomisation)DPED: Date of above (days elapsed from randomisation)DALIVED: Date of above (days elapsed from randomisation)DDEADD: Date of above (days elapsed from randomisation)FLASTD: Date of last contact (days elapsed from randomisation)FDEADD: Date of death (days elapsed from randomisation)FU1_RECD: Date discharge form received (days elapsed from randomisation)FU2_DONE: Date 6 month follow-up done (days elapsed from randomisation)FU1_COMP: Date discharge form completed (days elapsed from randomisation).http://datashare.is.ed.ac.uk/). Both this corrected and the erroneous version of the dataset are available to allow comparison with any previous analyses of the data. The corrected submission states clearly that it supersedes an earlier one.These errors, that were introduced in the process of anonymisation, have now been corrected in the final, double checked version of the dataset, which is also available at the University of Edinburgh repository (see"}
+{"text": "The involvement of particulate matter (PM) in cardiorespiratory diseases is now established in developed countries whereas in developing areas such as Africa with a high level of specific pollution, PM pollution and its effects are poorly studied. Our objective was to characterize the biological reactivity of urban African aerosols on human bronchial epithelial cells in relation to PM physico-chemical properties to identify toxic sources.Size-speciated aerosol chemical composition was analyzed in Bamako  and Dakar  for Ultrafine UF, Fine F and Coarse C PM. PM reactivity was studied in human bronchial epithelial cells investigating six biomarkers (oxidative stress responsive genes and pro-inflammatory cytokines).PM mass concentrations were mainly distributed in coarse mode (60%) and were impressive in BK1 due to the desert dust event. BK2 and DK samples showed a high content of total carbon characteristic of urban areas. The DK sample had huge PAH quantities in bulk aerosol compared with BK that had more water soluble organic carbon and metals. Whatever the site, UF and F\u00a0PM triggered the mRNA expression of the different biomarkers whereas coarse PM had little or no effect. The GM-CSF biomarker was the most discriminating and showed the strongest pro-inflammatory effect of BK2 PM. The analysis of gene expression signature and of their correlation with main PM compounds revealed that PM-induced responses are mainly related to organic compounds. The toxicity of African aerosols is carried by the finest PM as with Parisian aerosols, but when considering PM mass concentrations, the African population is more highly exposed to toxic particulate pollution than French population. Regarding the prevailing sources in each site, aerosol biological impacts are higher for incomplete combustion sources resulting from two-wheel vehicles and domestic fires than from diesel vehicles (Dakar). Desert dust events seem to produce fewer biological impacts than anthropogenic sources.Our study shows that combustion sources contribute to the high toxicity of F and UF PM of African urban aerosols, and underlines the importance of emission mitigation and the imperative need to evaluate and to regulate particulate pollution in Africa. A number of epidemiological studies have now established associations between exposure to particulate pollution and increased morbidity and mortality for respiratory and cardiovascular diseases . Toxicol2, SO2 and particles) observed in African cities being at same levels as in Asian megacities pyrene) with 14%. 85% of total PAH were heavy PAH (5\u20136\u00a0cycles). This distribution profile and especially the relative abundance of BghiP were typical of diesel exhaust sources fluoranthene; BghiP: Benzo[ghi]perylene; BK: Bamako; C: Coarse; CHR: Chrysene; COPD: Chronic obstructive pulmonary disease; CYP1A1: Cytochrome P450 1A1; DK: Dakar; ELISA: Enzyme linked immunosorbent assay; F: Fine; FLUA: Fluoranthene; GM-CSF: Granulocyte macrophage-colony stimulating factor; HO-1: Heme oxygenase 1; IARC: International agency for research on cancer; IL-6: Interleukin 6; IncdP: Indenopyrene; UV: Ultraviolet; IR: Infrared; NHBE: Normal human bronchial epithelial; NQO-1: NADPH quinine oxydoreductase 1; OC: Organic carbon; PCR: Polymerase chain reaction; PHE: Phenanthrene; PM: Particulate matter; POLCA: Pollution des capitales africaines; POM: Particulate organic matter; PYR: Pyrene; UF: Ultrafine; RPL-19: Ribosomal protein L19; TC: Total carbon; WSOC: Water soluble organic carbon; XME: Xenobiotic responsive element.The authors declare no conflict of interest.SV performed the biological analyses, interpreted the results and contributed to write the paper. CL designed the research and with EHTD performed field experiments, analyzed the data and drafted the paper. CGL designed the research and performed field experiments with EG. HC contributed to the interpretation of the data. EHTD, HC, NM, EGand AS performed the chemical analysis. AB provided advices for statistical analysis. ABS directed the joint project and contributed to write the paper. All authors read and approved the manuscript.Correlation coefficients (Pearson) between biomarker responses induced by Parisian PM exposure. Correlations were calculated with results of Val et al. [l et al.  for UF aClick here for file"}
+{"text": "There is an error in the author contributions. KMB should be listed in \"wrote the paper\" rather than DME. The correct author contributions are: Conceived and designed the experiments: KMB CLE DME. Performed the experiments: KMB JMT MDD. Analyzed the data: KMB. Contributed reagents/materials/analysis tools: KMB. Wrote the paper: KMB. Edited the manuscript: CLE DME."}
+{"text": "In the Author Contributions statement, the last author (HRB) was incorrectly omitted from the list of those authors who wrote the paper. The Author Contributions statement should read: \"Conceived and designed the experiments: RLK HRB BS. Performed the experiments: RLK CS MR BS. Analyzed the data: RLK AG. Contributed reagents/materials/analysis tools: CS MR JS RF RKW. Wrote the paper: RLK RKW CJ EB NT SEH HRB.\""}
+{"text": "Bacillus licheniformis, an important industrial enzyme producer. Thereby, valuable insights which help to understand the complex interactions during such processes are provided.Industrial fermentations can generally be described as dynamic biotransformation processes in which microorganisms convert energy rich substrates into a desired product. The knowledge of active physiological pathways, reflected by corresponding gene activities, allows the identification of beneficial or disadvantageous performances of the microbial host. Whole transcriptome RNA-Seq is a powerful tool to accomplish in-depth quantification of these gene activities, since the low background noise and the absence of an upper limit of quantification allow the detection of transcripts with high dynamic ranges. Such data enable the identification of potential bottlenecks and futile energetic cycles, which in turn can lead to targets for rational approaches to productivity improvement. Here we present an overview of the dynamics of gene activity during an industrial-oriented fermentation process with B. licheniformis DSM13. Since a significant amount of genes in Bacillus strains are regulated posttranscriptionally, the generated data have been confirmed by 2D gel-based proteomics. Regulatory events affecting the coordinated activity of hundreds of genes have been analyzed. The data enabled the identification of genes involved in the adaptations to changing environmental conditions during the fermentation process. A special focus of the analyses was on genes contributing to central carbon metabolism, amino acid transport and metabolism, starvation and stress responses and protein secretion. Genes contributing to lantibiotics production and Tat-dependent protein secretion have been pointed out as potential optimization targets.Whole transcriptome RNA-Seq has been performed to study the gene expression at five selected growth stages of an industrial-oriented protease production process employing a germination deficient derivative of B. licheniformis to changing conditions over the course of a typical fermentation process in such extensive depth.The presented data give unprecedented insights into the complex adaptations of bacterial production strains to the changing physiological demands during an industrial-oriented fermentation. These are, to our knowledge, the first publicly available data that document quantifiable transcriptional responses of the commonly employed production strain  Bacillus subtilis group -1-propanesulfonate; CoA: Coenzyme A; Da: Dalton; DHAP: Dihydroxyacetone phosphate; DTT: Dithiothreitol; F6P: Fructose 6-phosphate; FBP: Fructose 1,6-bisphosphate; FDR: False Discovery Rate; g: Gravitational constant; G6P: Glucose 6-phosphate; GADP: Glyceraldehyde 3-phosphate; GDH: Glutamate dehydrogenase; GO: Genome ontology; GOGAT: Glutamate synthase; GS: Glutamine synthetase; H: Hours; H2O2: Hydrogen peroxide; HCl: Hydrogen chloride; IEF: Isoelectric focusing; IPG: Immobilized pH gradient; kVh: Kilovolt hour; M: Molar; m/z: Mass-to-charge ratio; MALDI: Matrix-assisted laser desorption/ionization; min: Minute; mL: Milliliter; mM: Millimolar; mm: Millimeter; NPKM: Nucleotide activity per kilobase of exon model per million mapped reads; Oxo: Oxoglutarate; P: Phosphate; PEP: Phosphoenolpyruvate; Pyr: Pyruvate; RK motif: Twin-arginine motif; RNA-Seq: RNA sequencing; Rrpm: Revolutions per minute; RR motif: Arginine-lysine motif; s: Second; S/N: Signal-to-noise ratio; SDS: Sodium dodecyl sulfate; SRP: Signal recognition particle; Tat: twin-arginine translocation; TAXI: TRAP-associated extracytoplasmic immunity protein; TCA: Tricarboxylic acid; TOF: Time-of-flight mass spectrometer; TRAP: Tripartite ATP-independent periplasmic dicarboxylate transporter; V: Volt; v/v: Volume per Volume; Vh: Volt hour; W: Watt; w/v: Weight per volume.The authors declare that they have no competing interests.SW performed the experiments, analyzed data and wrote paper, BV supervised proteomics experiments and analyzed data, DA performed mass spectrometry analyses, JB and SE provided industrial fermentation facilities and organized fermentation and sampling, MH granted access to facilities for proteome analysis, RD wrote paper and provided research facilities, HL wrote paper, designed research and analyzed data. All authors read and approved the final version of the manuscript.Figure S1: Protease production and process parameters. Figure S2: Proteome of the amino acid metabolism \u2013 Part I. Figure S3: Proteome of the amino acid metabolism \u2013 Part II. Figure S4: Amino acid transport. Figure S5: Proteome of the central carbon metabolism. Figure S6: Carbohydrate transport. Figure S7: Acetoin utilization operon acuABC. Figure S8: Most abundant proteins. Figure S9: Lichenicidin gene cluster. Figure S10: Cell envelope stress response. Figure S11: Sporulation. Figure S12: Iron starvation. Figure S13: Heat shock response. Figure S14: Phosphate stress response. Figure S15: Putative Tat signal peptide of Subtilisin Carlsberg.Click here for fileTable S1: k-means clustering of expression profiles. Table S2: GO term enrichment analysis of k-means clusters. Table S3: Proteome data.Click here for file"}
+{"text": "Please view Figure 2a in its original size here: The legend for Figure 4b refers to left and right panels rather than top and bottom panels. The correct legend for Figure 4b should read:The shapes of the binding pockets in the free and the antigen bound states: The top panel (apo form) and the bottom (METH complex) show identical cross sections. The entrance of the binding pocket is broader in apo structure, compared to the METH complex. Color code: Top panel: heavy chain -magenta and light chain -light pink. Bottom panel: heavy chain- blue light chain-light blue."}
+{"text": "AbstractCheiloneurusflaccus  is reported from New Zealand for the first time. Cheiloneurusflaccus a distinctive species of encyrtid found widely in the New World, and also Australia Type status:Other material. Occurrence: recordedBy: Stephen Thorpe; individualCount: 2; sex: female; Location: country: New Zealand; verbatimLocality: Tamaki Campus of University of Auckland; verbatimLatitude: 36.88661S; verbatimLongitude: 174.85253E; Event: eventDate: 20 April 2013; Record Level: institutionCode: Auckland MuseumCheiloneurusflaccus, using the redescription by Cheiloneurusflaccus is a distinctive species, quite different to the two congeneric species already known from N.Z. The antenna, in particular, is distinctive, with the first segment of the funicle much longer than the pedicel  also occur on the campus. I recommend that Cheiloneurusflaccus be added to the New Zealand Organisms Register (NZOR) as exotic, present in the wild.On 20 April 2013, while looking for insects in swards of long grass on the Tamaki Campus of the University of Auckland, I noticed two specimens of an unusual looking encyrtid. I collected one of the two specimens (see Figs"}
+{"text": "There were errors in the Author Contributions section. The correct version of this section is available below.Conceived and designed the experiments: VA UV EK LKV. Performed the experiments: FBF MS EK LKV, Analyzed and interpreted the data: VA UV SG JH EK LKV. Contributed reagents/materials/analysis tools: MS JH EK. Wrote the paper: VA UV LKV EK. Rose the funding: VA EK."}
+{"text": "Assam is very rich in plant biodiversity as well as in ethnic diversity and has a great traditional knowledge base in plant resources. It is inhabited by the largest number of tribes and they lead an intricate life totally dependent on forest plants. The Mising is the major section and second largest tribal community of Assam and have a rich tradition of religion and culture. Their religious practices and beliefs are based on supernaturalism. A study of the plants related to magico religious beliefs in Dobur Uie of Mising is carried out. The results revealed the use of 30 plants belonging to 23 families. All plant species are used both in religious purpose as well as in the treatment of different ailments. Details of the uses of plants and conservational practices employed in Dobur Uie are provided. Our findings on the use of plants in Dobur Uie ritual reflect that some plants are facing problems for survival and they need urgent conservation before their elimination. Because this elimination may threat the rich tradition of Mising culture. Most of the plants that are domesticated for different rituals are almost same in all Mising populated areas. Plants are used in many ways including worshipping gods and goddesses for the protection and betterment of human life. In every human society worship is performed with traditional rituals for well-being. Many tribal communities preserve this tradition through folklore and worship their deities right from the occasion of birth to mourning death. They perform specific worship with pressie offerings.In India various gods and goddesses are worshipped in different religions throughout the country. Various plant parts like bark, twigs, leaves flowers, fruits and seeds are offered to gods. There are many plants grown near the different religious institutions are regarded as sacred plants by different ethnic groups of the country. They preserve the plants by all means which are used in different rituals. At a time when ecological degradation and deforestation have been taking place at an alarming rate throughout the globe, in India thousands of pockets of natural vegetation scattered throughout the country are preserved almost in pristine condition -5. AlmosTribal folklore is rich in magico-religious beliefs and taboos. They believe that some gods and deities reside on the trees in the forest. If they do not show mark respect to them their full clan will be destroyed. So they preserve the plants which they regard sacred for social, cultural and religious purposes. Their taboos, festivals, rituals and other cultural aspects are closely associated with the surrounding vegetation preserved on religious ground. The fear of getting attacked by the forest spirits or getting cursed by the deities eventually makes the local communities to resort to worship the spirits and making sacrifices and offerings to pacify them. Although the taboos, self imposed restricted and extra care exhibited by the community have significantly contributed in preserving the religious plants intact and in good shape thereby conserving a whole range of biodiversity that is housed in it. There is an inextricable link between indigenous and biological diversity. All over the world the indigenous people have protected the biodiversity with which they have symbiotic relationship . It has Assam is situated in the North eastern region of India lying between 24\u00b0- 28\u00b0 N and 90\u00b0- 96\u00b0 E Figure . The entThe Misings are one of the tribal communities of Assam. By faith they are the worshippers of 'Dony'(The Sun) and 'Polo' (The Moon) Figure . They clPhragmites karka), a kind of wild reed, its stems and bamboo to indicate prohibition against the entry of the outsiders into the village. After the completion of the prohibitory indicators at the entry points they come back to the village and they form a group consisting of 20 members approximately and start visiting the house holds of the village. Usually the visit starts from the eastern corner of the village. The members of the visiting group carry rods, sticks etc.in their hands and enter the courtyard of the houses. On entering they shout \"Ajenge! Ajenge!Bilangka\"  and at the same time they strike the platforms, walls etc of the house with rods and sticks. On hearing this the house wife comes out with food materials (Ajenge dues)  - a type of wild fern, a 'Tabong' (Imperata cylindrica) - a sharp grass and a split bamboo are placed on the altar facing the rising sun. Then the sacrifices of the animals like pigs and fowls are done. The heads, wings, legs of the poultries are mounted on specially designed sticks and erected them on the side of altar  for Dobur ritual considering all relevant aspects and convenience. In early morning of the 'Dobur day' some selected male folks proceed to the main entry points of the village. There they erect some structure specially designed braided leaves of 'Piro' plant  Figure  like ricr Figure . Rice, AAreas analyzed: Research was carried out in these eight districts - Sonitpur, Lakhimpur, Dhemaji, Dibrugarh, Tinsukia, Sibsagar, Jorhat and Golaghat. These areas of Assam rich with traditional knowledge and a good vegetation cover were selected based on mopping up surveys during 2009-2010. The potential Mising areas were selected based on whether they still practice own social customs, beliefs, religious rites, taboos, totems, food habits, medicinal and agricultural practices, as it was observed that the utilization and conservation practices of the Mising tribes are intertwined with these. Also this kind of life style has created a proper understanding between them and nature, which has resulted in enormous amount of knowledge available with them. Exploration trips were conducted periodically and data on religious and conservation practices revealing information about their informal innovation were recorded with details. Initially, the stay in Mising areas was shorter periods, as the initial trips were aimed at establishing rapport with the Mising people. They will not pass the information to others so easily unless a cordial and social relationship with them is established. After making several trips to these areas good rapport could be established with them. Frequent field surveys were made. Headmen and Mibus of the hamlet were consulted to have easy access to the people and also to get uninhibited flow of information. Mising healers both men and women were invited for interview. They demonstrated about the different use of the medicinal plants : English; (Ass): Assamese; (Mis): Mising; (Nep): Nepali; (San): Sanskrit; (Hin): Hindi; (Ben): Bengali.Acorus calamus L.(Acoraceae)Vernacular names: Sweet flag (Eng), Bos(Ass); Alokoni (Mis); Bojho (Nep.) Bach: (Ben)Vacha (San)DCH 5063Description: A marshy, rhizomatous perennial herb.Parts used: RhizomeReligious virtue: People believe that spirits, devils cannot enter due to its odour. They put the rhizome at the four corners of the altar or at he entrance of the ritual site.Medicinal use: It cures bronchitis, rheumatic pain, diarrhoea, flatulence, Pneumonia and cough.Local status: RareAgeratum conyzoides L. (Asteraceae)Vernacular names: Eng: Goat weed; San: Visamustih; Hin: Visadodi; Ben: Uchunti; Ass, Mis: Gendelabon; Nep: Ilame jhar; Man: Khonjainapi DCH 5001Description: A hairy annual weed, 5 m-1 m tall; leaves opposite, hairy on both sides; margin toothed; flowers pale in heads.Parts used: The flowers, leaves, rootsReligious virtue: Flowers are used in the preparation of ApongMedicinal use: Infusion of roots is used as appetizer and ophthalmic; leaves are used to stop bleedingLocal status: AvailableAlpinia allughas (Retz.) Rosc. (Zingiberaceae)Vernacular names: Ass, Mis: Tora DCH 5006Description: Rhizomes tuberous, perennial, Leafy stem 1-2 meter highParts used: Leaf and rhizomeReligious virtue: The leaves of the plant are used as food wrappers or dishes in every Mising religious festival. The people regard the plant as sacred one.Medicinal use : Rhizomes are used in gout and colicLocal status: RareAlpinia malaccensis Rosc. (Zingiberaceae)Vernacular names.: Ass: Kaupat, Mis: Lisin DCH 5010Description: Rhizomes tuberous, perennial, Stems 1.5-3 meter highParts used: Leaf and rhizomeReligious virtue: Same as in A.allughasMedicinal use :Rhizomes are used for treatment of sores.Local status: RareAnanas comosus (L.) Merr. (Bromeliaceae)Vernacular names: Eng: Pineapple; San: Anamnasam; Hin: Ananas; Ben: Anaras; Ass: Matikathal; Nep: Bhui Katahar; Man: Keehom; Kar: Parokjongphong; Ngl: Yeangkong Peyong. Mis: Anaras DCH 5311.Description: A herbaceous perennial plant; leaves many, spirally arranged, linear-lanceolate, toothed on margins; inflorescence small, reddish, terminal, ovoid.Parts used:Tender leafReligious virtue: Tender leaf base is used in Apong preparationMedicinal use: Leaf base is crushed and the extract is given one time daily for amoebic dysentery and intestinal wormsLocal status: AvailableArtocarpus heterophyllus Lamk. (Moraceae)Vernacular names : Eng : Jack fruit; San : Panasah; Hin : Kathal; Ass, Mis : Kathal; Ben : Kathal; Nep : Katahar; Man : Theibong. DCH 6331Description : An evergreen tree, 18-25 m in height; leaves simple, alternate, coriaceous, entire, shiny; male flowers crowded on cylindrical receptacles; female flowers crowded on globose receptacles; fruits fleshy, many, oblong or round, covered with tubercles.Parts used : Roots, seeds.Religious virtue: Matured leaves are used in Apong preparation. Leaves are also used as dish in religious festivals.Medicinal use: Roots are used for diarrheaLocal status: AvailableAsparagus racemosus Willd (Liliaceae)Vernacular names:Eng: Wild Asparagus; San: Shatavari: Hin: Satawari;Nep: Kurilo, Mis: Otmul;Ass: Satmul; Ben: Satamuli; Man: Nunggarei. DCH 6019Description: A climbing slender plant with curved spines; leaves reduced to scales, leaf like cladodes succulent and green, flowers white in simple recemes; fruits three lobed, mature fruits are red in colour.Parts used: Tuberous roots, whole plantReligious virtue: In Lakhimpur district many people use whole plant near the entry of Dobur Uie venue. They believe that this plant will guard the people from the bad spirits.In Dhemaji district the tuberous roots are used in the preparation of Apong.Medicinal use: Root decoction is used as health tonic, it is diuretic, ophthalmic, galactagogue, aphrodisiac and carminative.Local status: Very rareBambusa tulda Roxb. (Poaceae)Vernacular names Jati banh (Ass); Peka (Hin); Taru Bans (Nep); Jati dibang (Mis)DCH 5054Description: Tufted bamboo reaching 30-50 meters in height.Parts used: Root, stem. leavesReligious virtue: Bamboo sticks and leaves are used in the main entrance of the Dobur Uie and in the four corners of the altar. The head and the feathers of the sacrificed chickens are hung on the bamboo sticks near the altar.Medicinal use : The decoction of roots taken internally to promote flow of urine.Local status: AvailableCentella asiatica (L.) Urban (Apiaceae)Hydrocotyle asiatica L.)Vernacular Names: Eng: Indian cassia lignea; San: Tamala patra; Hin: Tezpat; Ben: Tezpat; Ass, Mis: Tezpat; Nep: Tezpat; Man: Tezpat; Kar: Tezpat; Miz: Hnahrimtui DCH 6103Description: A small evergreen tree 4.5 m in height; leaves simple, opposite, lanceolate, glabrous, entire; flowers pale yellowish, in axillary panicle.Parts used: Leaves.Religious virtue: Leaves are used in Apong preparation and are offered in Ajenge DuesMedicinal use: The leaves are useful in gonorrhoea, rheumatism, diarrhea, enlargement of spleen and diabetes.Local status: RareClerodendrum colebrookianum Walp. (Verbenaceae)Vernacular names. Pakkom (Mis); Nephaphu (Ass) DCH 5019Description: Shrub with foetid smell; 1.5-2 meters high, Leaves ovate, Flowers white.Parts used: LeavesReligious virtue: The leaves of the 'Pakkom'are included in the Ajenge DuesMedicinal use: The leaves are used to kill the intestinal worms. Tender leaves are boiled and the soup is used for reducing blood pressure.Local status: AvailableDillenia indica L. (Dillenniaceae)Vernacular names. Elephant apple (Eng), Outenga (Ass): Sompa: (Mis), Nep: Chalta, Bhavya: (San) DCH 5013Description: A big tree; leave 10-15 cm broad, Flowers large, white, the fruits are used as vegetablesParts used: Sepal of the fruit.Religious virtue: The fruits are included in 'Ajenge Dues'. The sepals are sometimes used as 'Diya'or oil lamp Medicinal use: Fleshy calyx is used for stomach disorder. The jelly like pulp of the fruit is applied to scalp for curing dandruff and falling hairs.Local status: AvailableFicus racemosa L. (Moraceae)Vernacular names.: Eng:Cluster fig; Mis: Tajjig; San: Udumbarah); Ass: Jagnya dimaru); Nep: Dumri, Hin: Gular; Ben:Dumur DCH 5057Description: A middle sized deciduous tree, fruits are in large cluster on short leafless branches, leaves elliptic, ovate or ovate lanceolate.Parts used: Leaves, latexReligious virtue: The tender leaves are given in 'Ajenge Dues'. In all religious festivals of Mising people the leaves are used as the primary curry item.Medicinal use: The latex is used for piles and diarrhoea; Powdered dry leaves are mixed with honey and given in bilious affections.Local status: AvailableGomphostemma parviflora Wall. (Lamiaceae)Vernacular names: Ass, Mis: Bhedaitita DCH 6434Description: A stout undershrub with quadrangular stem covered with glandular hairs; leaves simple, opposite, short petioled; flowers zygomorphic, in axillary, double row of cymes, the pairs forming false whorls and are in sessile clusters round the stem, flowers fade yellow.Parts used: Leaves.Religious virtue: The tender leaves are used in Apong preparationMedicinal use: Leaves are used in Malaria.Local status: Very rareImperata cylindrica (L.) Raeusch. (Poaceae)Vernacular names: Eng: Thatch grass, San: Darbha, Mis: Kase, Tabong: Ass: Ulu kher: Nep: Siru: Hin, Ben: Ulu DCH 6336Description: Erect perennial grass, 1-2 meter in height. Leaf blades are very sharpParts used: Leaf and rootReligious virtue: The leaves are tied with fronds of Thelypteris multilineata at the south corner of the altar made for Dobur Uie. It symbolizes that no any other spirits can come and disturb people of the village.Medicinal use : Root is used for wounds and piles. It is anthelmintic. Decoction of root is taken in diarrhea and dysentery.Local status: AvailableKaempferia rotunda L. (Zingiberaceae)Vernacular names : Eng: Indian crocus; San: Bhumi champaka; Hin: Bhuichampa; Ben: Bhui champa; Ass: Bhumi champa; Nep: Bhuichampa; Man: Yai-Thamna-manbi; Kar: Michove; Miz: Tuktinpar DCH 5999Description: A small, erect plant with perennial rootstock and very short stem; leaves simple, erect, oblong or ovate-lanecolate, acuminate, variegated green above, tinged with purple below; flowers in crowded spikes fragrant, white, lip purple.Parts used: TubersReligious virtue: Tuber of the plant is used in Apong preparation. The Mising of Lakhimpur district believes that growing the plant brings peace in the family.Medicinal use: The tubers are used for wounds, ulcers, tumours, swellings and gastroenteritis.Local status: Very rareLeucas plukenetii (Roth) Spreng. (Lamiaceae)Vernacular names: Eng: Thumbe; San: Dronapuspi; Hin: Chota halkusa; Ben: Sada halkusa; Ass, Mis: Boga Doron; Nep: Dronapuspa; Man: Mayanglambum. DCH 6312Description: Small hairy, square stemmed, annual herb found in open fields and waste lands. The leavesof the plants are ovate-lanceolate, lobed, thin and hairy with a tapering base; flowers white, small, in dense terminal clusters, sessile.Parts used: Leaves.Religious virtue: The leaves are used in Apong preparation. It is not used by all MisingMedicinal use: The leaves are used as vegetables. Leaf juice is used in sinusitisLocal status: AvailableMicrosorum punctatum (L.) Copel (Polypodiaceae)Vernacular names: Eng: Climbing bird's nest fern, Ass: Kapau dhekia; Mis: Ising Okang DCH 6216Description: Terrestrial or epiphytic, Fronds sre sessile, leaf blades simple, reticulate venation, sori are irregularly scattered on the abaxial surface.Parts used: LeavesReligious virtue: Leaves are used in Apong preparation in Dhemaji and Lakhimpur district.Medicinal use: Leaf juice used as purgative, diuretic and healing wounds.Local status: RareMusa paradisiaca L. (Musaceae)Vernacular names. Ass: Kach kol; Nep: Kera, Hin: Kela; San: Kadali; Mis: Kopak. DCH 5091Description: Stoloniferous plant; leaves with sheathed petiole up to 9 meter long, flowers in a terminal spike.Parts used: Leaves, fruitsReligious virtue: Leaves and leaf sheaths are used as plates or dishes in the ritual. The materials required for observing Dobur Uie are kept in the leaf or leaf sheath dishes.Medicinal use: Fruits are used for chronic dysentery.Local status: AvailableNaravelia zeylanica (L.) DC. (Ranunculaceae)Vernacular names: San: Dhanavalli; Ben: Chagalbati; Ass: Goropchoi, Nep: Ras gagri; Meg: Jyrmailasam, Behalisham (Garo) DCH 6636Description: A woody stout climber; leaves opposite, 2-foliate, terminal leaflet ending in tendril, leaflets ovate-lanceolate;flowers yellow, in axillary and terminal panicles.Parts used: Leaf.Religious virtue: Leaves are used in Apong preparation. The Mising of Dhemaji believe that if they grow this plant inside their compound the bad spirits can not disturb them.Medicinal use: The leaves are anthelmintic; they are useful for wounds and ulcers.Local status: Very rareOldenlandia corymbosa L. (Rubiaceae)Vernacular names: Eng: Diamond flower; San: parapatah; Hin: Daman Pappar;Ass: Bonjaluk DCH 6212Description: A much spreading, annual herb, erect or spreading; leaves simple, opposite, sessile, flowers white, pedicelled, solitary.Parts used: whole plantReligious virtue: It is commonly used in Apong preparation. In Sibsagar district it is given in Ajenge Dues.Medicinal use: The plant is diuretic, stomachic, carminative and used as liver tonic. It is also used in jaundice.Local status: AvailableOryza sativa L. (Poaceae)Vernacular names: Eng: Rice; Ass:Dhan; Mis: Aam. DCH 6001Description: Annual cereal, Stem erect, cylindrical, hollow except in nodes, leaf blade long, lanceolate, acuminate, inflorescence is partly covered by leaf sheath, Spikelets are borne either singly or in cluster, flowers bracteates.Parts used : Seed, StrawReligious virtue: Rice is indispensable item in Apong preparation. Straw is burnt and used in 'Chhai Mod' (Ash liquor). The colour of commonly used Apong is white but the colour of 'Chhai Mod' is smoky in colour. Chhai Mod is prepared only in the special occasion or any religious festivals. Important guests are entertained by offering 'Chhai Mod'. The straws are also used to filter the Apong.Medicinal use: Rice-wash water (water used to wash rice before cooking) is used in diarrhea and dysenteryLocal status: AvailablePhragmites karka (Retz.) Trin.ex Steud. (Poaceae)Vernacular names.: Eng: Wild reed; Mis:Piro; Ass: Nal Khagari; Nep:Narkat; Ben: Khagra DCH 5066Description: Perennial, stem cylindrical, 2-3 meter high, leaves alternate, lanceolate.Parts used: whole plant, rootReligious virtue: The plant is mostly used by the Mising community in religious festivals like Dobur Uie and Ali Ai Ligang. In Dobur Uie four 'Piro' plants are transplanted at the four corners of the Dobur Uie altar' Mising regard this plant as the most sacred plant.Medicinal use: Roots are cooling, diuretic and very useful in Diabetes.Local status: RarePsidium guajava L. (Myrtaceae)Vernacular names: Eng: Guava tree; San: perala, Perukah; Hin: Amrud; Ben:Peyara; Ass: Madhuriam; Nep: Ambak; Man:Pungdol. DCH 6010Description: A small tree; leaves simple, opposite, elliptic-oblong, glabrous above; flowers white, fragrant, in axillary cymes.Parts used: Tender leaves.Religious virtue: It is very commonly used by the Mising in Apong preparation.Medicinal use: Tender leaves are used in Amoebic dysenteryLocal status: AvailablePueraria tuberose (Roxb.ex Willd.)DC (Papilionaceae)Vernacular names: Eng: Indian Kudzu; San: Vidari, Bhumi Kusmandah; Ass: Bhuin Komora; DCH 6455Description: A large, herbaceous twiner with very large tuberous roots; leaves 3 foliolate, leaflets broadly ovate; flowers blue or purplish blue, in raceme; fruits membranous, flat, jointed clothed with long, silky, bristly brown hairs.Parts used: Tuberous roots.Religious virtue: Tuberous roots are used in Apong preparationMedicinal use: Tubers are used for fever.Local status: Very rareSarcochlamys pulcherrima (Roxb.) Gaud. (Urticaceae)Vernacular names. Eng. Duggal fibre tree; Mis :Ombe; Ass: Mesaki DCH 5101Description:A small evergreen branched tree or large shrub upto a height 5 meter, Stem brownish, rough and warty, leaves in dense clusters at the apex of the branches, 12-20 cm long, dorsal surface shining green and ventral surface white.Parts used: LeavesReligious virtue: Mising people consider the plant as sacred plant. They make special food item from the tender leaves of the plant in any religious festivals, given in 'Ajeng Dues'.Medicinal use: Leaves are useful for diarrhea and dysentery, they are carminative and digestive.Local status: RareScoparia dulcis L. (Scrophulariaceae)Vernacular names: Eng: Sweet broomweed; Ass : Seni bon; Man : Maipuipin.DCH 6135Description: A much branched, herbaceous plant of about 70 cm height; leaves opposite, lanceolate, dentate, flower four lobed, white with staminal hair, fruit a dentate margined small globular capsule with free central placentation.Parts used : Leaves.Religious virtue: Leaves are used in Apong preparationMedicinal use: Leaves are used for fever, cough and diabetes.Local status: AvailableSpilanthes paniculata Wall.ex DC (Asteraceae)Vernacular names. Eng: Brazil cress, Toothache plant; Mis: Marsang; Ass: Jati malkathi DCH 5045Description: Herb upto 40 cm. in heght; leaves opposite, dentate, petiolate, elliptic-lanceolate; flowers in capitulum, yellow.Parts used: Whole plant, flowerReligious virtue: The plant is very popular among the Mising community; special food item is prepared from this plant in religious festival. The poor people offered this plant along with the 'Ajeng Dues' in Dobur UieMedicinal use: The inflorescence relives toothache, bronchial trouble and ulcers inside the mouth, it has strong local anaesthetization and also used for dysentery.Local status: AvailableThelypteris angustifolia (Willd.)Proctor (Thelypteridaceae)Vernacular names: Mis: Ruktak; Nep: Koche DCH 5111Description:Terrestral fern, Fronds large, pinnate, sessile, found in marshy place.Parts used: Whole plant, rhizomeReligious virtue: The entire plant is placed ine corneer of the altar. The tip of the plant and tip of the leaves of 'Piro' are tied together near the altar of the Dobur UieMedicinal use: Juice of the rhizome about four teaspoons three times a day given for indigestion or any stomach problem.Local status: RareZanthoxylum nitidum (Roxb.) DC (Rutaceae)Vernacular names: Eng: Toothache tree; San:Tumburuh; Hin: Tezbal; Ass: Tezmooi DCH 6020Description: A large, scandent, ever green shrub with prickles, shrubs or woody climbers, leaves compound, flowers yellow, fruits reddish, subglobose.Parts used: Leaf, stem barkReligious virtue: Leaves are used in Apong preparationMedicinal use: Stem bark is used for toothache or any gum problem, it is carminative and stomachic.Local status: Very rarePueraria tuberose, Zanthoxylum nitidum, Naravelia zeylanica, Gomphostemma parviflora, Asparagus racemosus, Kaempferia rotunda are not found easily in those areas where the research work has been carried out. Previously these plants were said to be found abundant but now they are in 'very rare' condition. In this way they categorized the plants in different status. They can easily identify the plants which are locally threatened or abundant, rare or very rare depending on the availability of the plants and accordingly they take special care to conserve such threatened species in their garden. So there is an urgent need of conservation of their rich traditional knowledge before their extinction. The old village heads or elderly persons of the research areas were interviewed. They expressed about their constrains for leaking out the information about the medicinal plants at the beginning but later on we somehow could motivate them and collected few information. They strongly believe that if they leak the information the efficacy of the drugs will be lost. If this trend continues their rich traditional knowledge will be lost along with their death. So the need of conservation of their knowledge is very essential. The status which they mentioned may not be applicable in other places. It is strictly confined to their areas only and therefore the word 'Local status' is mentioned. They collected many important plants from the forest and transplanted in the gardens. The authors personally visited some of their gardens and found some important plants like Pueraria tuberose, Zanthoxylum nitidum, Naravelia zeylanica, Gomphostemma parviflora, Asparagus racemosus, Kaempferia rotunda etc.Mising people have a rich tradition of religion and medicinal practices. They collect the plants from wild state and conserve them around their residences. They have good knowledge about the status of the plants. This knowledge has been acquired by their long experiences. They have been using the plants for different purposes since time immemorial. So they have good knowledge about the use and availability of the plants. Here the 'availability' means the 'status'of the plants. Some plants like Zanthoxylum nitidum, Asparagus racemosus, Sarcochlamys pulcherrima, Pueraria tuberose, Phragmites karka, Naravelia zeylanica, Gomphostemma parviflora, Ficus racemosa, Dillenia indica, Clerodendrum colebrookianum, Cinnamomum tamala, Acorus calamus, Alpinia malaccensis, Alpinia allughas have been domesticated. They sometimes sell the vegetable parts in the local market for their livelihood. These benefits coming out from the market will typically go to improving living standards of their families. This makes a clear link between conservation and development. Communities can contribute to biodiversityby collecting and propagating indigenous seeds, planting and tending both indigenous and plantation trees in their forests and their private farms and policing against illegal harvesting of animals and tree products. These plants seem to be threatened to get eliminated in their natural habitats due to the over exploitation. Because other tribal communities also collect the plants from the same source. So the domestication of these plants is a need for conservation. Keeping this in view the plants used in Dobur Uie, Apong preparation or vegetables are locally categorized in three divisions rare, very rare and available. Eight rare plants and six very rare plants have been identified to be used in Dobur Uie celebration. Very rare plants like Zanthoxylum nitidum, Pueraria tuberose, Naravelia zeylanica, Gomphostemma parviflora, Asparagus racemosus, Kaempferia rotunda and need urgent conservation for their sustainable use. The plants locally found and used in Dobur Uie in rare status are Thelypteris angustifolia, Sarcochlamys pulcherrima, Phragmites karka, Microsorum punctatum, Cinnamomum tamala, Alpinia allughas, Alpinia malaccensis and Acorus calamus. For different ritual purposes these religious plants are frequently used by the Mising people so the Mising people are trying their best to protect the plants in situ or ex situ condition from elimination. The rest 16 plants though are found locally available but due to lack of awareness of the people for sustainable use of the plants many such plants like Spilanthes paniculata, Clerodendrum colebrookianum, Dillenia indica, Centella asiatica though are found in available status but due to unsustainable use and over exploitation the number of these plants is decreasing gradually and therefore they need an urgent protection. As the Mising culture and plants have inseparable linkage so to protect the rich Mising culture the plants need to be conserved.In the Dobur Uie day the Mising people will take wild vegetables with their meal. In the previous day of the ritual the Mising women go to the forest for collecting wild vegetables for the next day. 20-30 varieties of wild vegetables were collected in the earlier time but this number comes down to 10-15 at present. On the other hand the alarming decrease of Apong plants from 50 to 10-15 is becoming a serious concern. As stated by the informants many plants got eliminated from the locality may be due to wanton felling of the trees or may be indiscriminate collection of the plants. Moreover other tribal people except the Mising also use the same plants for Apong preparation resulting over exploitation of these plants. The informants stated that if this trend of decreasing the number of plants used in different ritual practices continues then the situation of cultural threat may arise one day or other. This situation is found in all Mising populated areas undertaken for this study. In this paper altogether 30 plants under 23 families were discussed. Plants used for wild vegetables, Apong preparation and for Dobur Uie celebration are found in wild state and many of them like The strong motive behind observing Dobur Uie is the sense of fear or reverence shown by the Mising people towards god or deities. Be it a patch, a single or cluster of sacred trees a lot of conservation concern has been imbibed into the Mising communities. Irrespective of the motivating force behind conferring the sacred or religious status to a plant, it may be said that this process saves the plants from wanton felling. Through this project an attempt has also been made to make them aware of the status and sustainable use of the plants.A number of folk medicinal claims used by Mising people in Dobur Uie are reported in this communication. Among these, some interesting and new claims relate to the treatment of different ailments of human beings such as diarrhea, dysentery, malaria, indigestion, gastroenteritis, high blood pressure, intestinal worms etc. About 34 diseases have been described for the treatment of different ailments. Diarrhoea, dysentery, indigestion, flatulence, stomach problems, liver problems are found very common among the diseases. Information on the effectiveness to cure the ailments by using these species is based on continuous use by succeeding generations of Mising people. However these claims need to be further tested using standard scientific methodologies. Local names are given in different regional languages for the easy identification of the species.Gomphostemma parviflora, Clerodendrum colebrookianum, Ficus racemosa, Sarcochlamys pulcherrima etc. in their gardens for consumption and sale. These plants can help overcome the deficiency of nutritional constituents, especially in rural areas. It is important to promote consciousness about the food habits and accept wild food plants like the cultivated ones. Thus they become conscious about conserving their surrounding plant resources. Though the use of plants in Dobur Uie varies from place to place but some plants like Alpinia allughas, Alpinia malaccensis, Imperata cylindrica, Thelypteris angustifolia, Phragmites karka are found common to all places. We suggest that the traditional knowledge of the Mising people could provide useful information in finding new drugs that contribute to human welfare. So the most urgent need is to rescue and record the traditional knowledge on plants in the form of digitized database before its extinction.In the present study 30 plants belonging to 23 families have been identified as medicinal plants used by the Mising people of Assam in Dobur Uie ritual. These plants are used in the treatment of some very common ailments like diarrhea, dysentery, indigestion, flatulence, stomach problems, liver problems etc. All these diseases are water born and this can be explained that the water taken from ponds or from other free sources in rural areas are not hygienic and so the children are easily infected by these diseases. The Mising people believe that all big trees are abodes of gods and deities and therefore they are sacred and should not be harmed, they try to save these plants by all means This perception of nature plays a positive role on the protection of the vegetation around their dwelling places. That is why many scholars advocate that people living in modern society learn from the minority people to respect the environment rather than depredating it ,14,20,21Permission was granted by the Mising people shown in figures The authors declare that they have no competing interests.US conducted field survey, interviews with the healers, village heads, head of the religious institutions, elderly men and women. Herbarium specimens were identified and finalized with SP. SP helped to take the photographs and to collect and analyze data. Both the authors examined the manuscripts minutely and approved as final manuscript"}
+{"text": "There were errors in the Author Contributions. The correct contributions are: Conceived and designed the study: ST. Performed the study and contributed reagents/materials/analysis tools: ST MB GB. Analyzed the data: ST. Wrote the paper: ST GB."}
+{"text": "The scope of our understanding of the evolutionary history between viruses and animals is limited. The fact that the recent availability of many complete insect virus genomes and vertebrate genomes as well as the ability to screen these sequences makes it possible to gain a new perspective insight into the evolutionary interaction between insect viruses and vertebrates. This study is to determine the possibility of existence of sequence identity between the genomes of insect viruses and vertebrates, attempt to explain this phenomenon in term of genetic mobile element, and try to investigate the evolutionary relationship between these short regions of identity among these species.Some of studied insect viruses contain variable numbers of short regions of sequence identity to the genomes of vertebrate with nucleotide sequence length from 28 bp to 124 bp. They are found to locate in multiple sites of the vertebrate genomes. The ontology of animal genes with identical regions involves in several processes including chromatin remodeling, regulation of apoptosis, signaling pathway, nerve system development and some enzyme-like catalysis. Phylogenetic analysis reveals that at least some short regions of sequence identity in the genomes of vertebrate are derived the ancestral of insect viruses.Short regions of sequence identity were found in the vertebrates and insect viruses. These sequences played an important role not only in the long-term evolution of vertebrates, but also in promotion of insect virus. This typical win-win strategy may come from natural selection. The interaction between viruses and animals is quite profound and complex. Precious studies have deeply increased the depth of our understanding of their long-term evolutionary history in terms of genome sequence. Viruses have a highly host-associated life circle. As a result, they infect and occasionally integrate into the germ line cells chromosome and are inherited vertically as host alleles ,2. A groHowever, most of these discoveries were merely addressed in an aspect of virus-host interaction and may narrow our prospective to probe the links between viruses and animals.Here in a broad sense, we aimed at to identify the possible regions identity between the genomes of vertebrates and non-retroviral families of insect viruses and the possible role(s) of the identical sequences in evolution of the corresponding animal(s). Moreover, we reported phylogenetic analysis of these identical sequences. In this paper, we showed that at least some of the sequences identity in vertebrates chromosomes identified here are likely to come from insect viruses and exapted during their long-term evolution.NW_002197778.1] with respective E-values 4e-23 and 1e-14.We screened several hundreds of insect viruses including DNA viruses and RNA viruses against 21 vertebrates. Of interest, dozens of short regions of sequence identity were found between animals and viruses including double stranded DNA viruses and double stranded RNA viruses  of the regions identity as described in Methods.Figure Table A screen of vertebrate genomes has unexpectedly exhumed short regions of sequence identity to insect viruses leading us to speculate about the evolutionary relationship among these sequences. And then phyogenetic comparisons of these sequences identity were performed as described in Methods.Significant blast hits to Adoxophyes orana NPV were sequences from species including mammalian, virus, fungi and bacteria Figure . SequencSequences matching Choristoneura occidentalis granulovirus were all identified in insects Figure . In phylWe identified high-level significant matches to Culex nigripalpus baculovirus in the genomes of plant, mammalian, insect Figure . PhylogeSignificant matches to Cydia pomonella granulovirus are short regions identified in a broad range of lineage genomes including chordate, fungi, insects, vertebrates, protozoa and plant Figure . CuriousMatches to Leucania separata were sequences from different species ranging from fungi, mammalians, bacteria and protozoa as well as insects Figure . InteresIn order to broaden the scope of people's understanding of the interaction between virus and animals, We searched genomes of 21 currently available vertebrates for sequences identity to that of insect viruses with expectation that possible sequences identity may exist, and unearthed lush short regions of sequence identity in diverse animals. The chance matches of the search were ruled out by performing reciprocal BLAST. With sequence length from 28 to 124 bp, most of them are non-functional, however, with exceptional occasions, some are within exon.The mechanism that nucleotide sequences flowed from ancestral insect viruses to vertebrates is still unclear. A possible explanation for the phenomenon is due to genetic mobile element such as virus and phage as well as plasmid. Earlier study shows that viruses move between different biomes and the total number of viruses largely exceeds the number of cells . In our The fate of most acquired nucleotide sequences in the chromosomes of animals has been to undergo deletion due to homologous recombination , howeverNo discussion of short regions of sequence identity would be complete without mention pseudo-genes. Pseudo-gene which is known for non-functional, gene-like sequences due to a high mutation rate is harbored by mammalian genomes . LackingWe have investigated the evolutionary radiation of some of the identified short regions of insect viruses and demonstrated a broad history of interaction between insect viruses and vertebrates. It is interesting to speculate that short regions of identity occurred across a brand species. According to our data, at least some short regions of identity identified in vertebrates are derived from insect viruses. And the initial gene flow from Cydia pomonella to the ancestor of the Mus musculus at least post dated the divergence of Mus musculus and Rattus norvegicus about 10 million years ago. However, due to the limited samples, it is hard for us to know whether some sequences identity of the insect viruses and that of vertebrates shared the same ancestral lineage or not. Since the evolution of some viral sequences is more rapid than that of animals, it may mask any two nucleotide sequences which actually derived from the same ancestor .Our study established that the genetic material derived from insect viruses can flow to vertebrates and play a significant evolutionary role for the development of vertebrates and the survival of the viruses. This win-win strategy may be the result of natural selection.The genomes of non-retroviral families of insect viruses were screened against chromosome assemblies and whole genome shotgun assemblies of 21 vertebrate species in silico approach using BLASTn with the resources of NCBI. Insect viruses sequences with a high-level identity  of matches to vertebrates nucleotide sequences were acquired. Then the acquired animal sequences were used as queries to screen the GenBank non-redundant (nr) database in a reciprocal BLASTn search. Significant matches to retroviruses and non-insect viruses were discarded, while the remaining matches were considered as regions of identity to non-retroviral families of insect viruses.Regions of identity were located in corresponding genome shotgun assemblies of vertebrates precisely. If pseudo-genes were found near regions of identity (i.e. 2000 kb within their 5' and/or 3' ends) distance was calculated between the nearby pseudo- genes and 5'site and/or 3's site of regions of identity.For understanding the distribution and possible origin of sequences identity, BLASTn was run with virus sequences as queries to screen the GenBank non-redundant (nr) database. Significant hits with over 95% identity and blast E-values of 10-7 or lower were identified as regions of sequence identity. And representative sequences were extracted. These nucleotide sequences were aligned using ClustalX program Mammals: Primates (= 5): Callithrix jacchus (white-tufted-ear marmoset); Homo sapiens (human); Macaca mulatta (rhesus macaque); Pan troglodytes (chimpanzee); Pongo abelii (Sumatran orangutan); Rodents (= 2): Mus musculus (laboratory mouse); Rattus norrvegicus (rat)Monotremes (= 1): Ornithorhynchus anatinus (duck-billed platypus) Marsupials (= 1):Monodelphis domestica (opossum) Other Mammals (= 8): Ailuropoda melanoleuca (giant panda); Bos taurus (cattle); Canis lupus familiaris (dog); Equus caballus (horse); Felis catus (cat); Oryctolagus cunniculus (rabbit); Ovis aries (sheep); Sus scrofa (pig) Other Vertebrates (= 4): Danio rerio (zebrafish); Gallus gallus (chicken); Taeniopygia guttata (zebra finch); Xenopus tropicalis (Silurana) (western clawed frog)NC_005137]; Agrotis segetum granulovirus [GenBank:NC_005839]; Helicoverpa armigera NPV G4 [GenBank:NC_002654]; Orgyia pseudotsugata MNPV [GenBank:NC_001875]; Mamestra configurata NPV-A [GenBank:NC_003529]; Cydia pomonella granulovirus [GenBank:NC_002816]; Spodoptera exigua MNPV [GenBank:NC_002169]; Bombyx mori NPV [GenBank:NC_001962]; Bombyx mandarina NPV [GenBank:NC_012672]; Spodoptera frugiperda MNPV virus [GenBank:NC_009011]; Lymantria xylina MNPV [GenBank:NC_013953]; Mamestra configurata NPV-B [GenBank:NC_004117]; Lymantria dispar MNPV[GenBank:NC_001973]; Epiphyas postvittana NPV[GenBank:NC_003083]; Xestia c-nigrum granulovirus [GenBank:NC_002331]; Autographa californica NPV [GenBank:NC_001623]; Helicoverpa armigera NPV NNg1[GenBank:NC_011354]; Pieris rapae granulovirus[GenBank:NC_013797]; Pseudaletia unipuncta granulovirus [GenBank:NC_013772]; Agrotis segetum NPV [GenBank:NC_007921]; Spodoptera litura granulovirus[GenBank:NC_009503]; Chrysodeixis chalcites NPV [GenBank:NC_007151]; Neodiprion abietis NPV [GenBank:NC_008252]; Neodiprion lecontii NPV[GenBank:NC_005906]; Cryptophlebia leucotreta granulovirus [GenBank:NC_005068]; Adoxophyes orana granulovirus[GenBank:NC_005038]; Helicoverpa armigera NPV [GenBank:NC_003094]; Rachiplusia ou MNPV[GenBank:NC_004323]; Phthorimaea operculella granulovirus [GenBank:NC_004062]; Spodoptera litura NPV [GenBank:NC_003102]; Culex nigripalpus NPV [GenBank:NC_003084]; Plutella xylostella granulovirus [GenBank:NC_002593]; Heliothis zea virus 1 [GenBank:NC_004156]; Clanis bilineata NPV [GenBank:NC_008293]; Neodiprion sertifer NPV [GenBank:NC_005905]; Trichoplusia ni SNPV [GenBank:NC_007383]; Choristoneura fumiferana MNPV [GenBank:NC_004778]; Helicoverpa zea SNPV [GenBank:NC_003349]; Euproctis pseudoconspersa NPV [GenBank:NC_012639]; Agrotis ipsilon multiple NPV [GenBank:NC_011345]; Orgyia leucostigma NPV [GenBank:NC_010276]; Helicoverpa armigera granulovirus [GenBank:NC_010240]; Ecotropis obliqua NPV [GenBank:NC_008586]; Anticarsia gemmatalis NPV [GenBank:NC_008520]; Choristoneura occidentalis granulovirus [GenBank:NC_008168]; Adoxophyes honmai NPV [GenBank:NC_004690]; Hyphantria cunea NPV [GenBank:NC_007767]; Antheraea pernyi NPV [GenBank:NC_008035]; Spodoptera litura nucleopolyhedrovirus II [GenBank:NC_011616]; Helicoverpa armigera multiple NPV [GenBank:NC_011615]; Adoxophyes orana NPV [GenBank:NC_011423]; Maruca vitrata MNPV [GenBank:NC_008725]; Plutella xylostella multiple NPV [GenBank:NC_008349]; Leucania separata nuclear polyhedrosis virus [GenBank:NC_008348]Baculoviridae: Choristoneura fumiferana DEF MNPV [GenBank:NC_002520]; Melanoplus sanguinipes entomopoxvirus [GenBank:NC_001993] Ascoviridae: Spodoptera frugiperda ascovirus 1a [GenBank:NC_008361]; Diadromus pulchellus ascovirus 4a [GenBank:NC_011335]; Heliothis virescens ascovirus 3e [GenBank:NC_009233]; Trichoplusia ni ascovirus 2c [GenBank:NC_008518] Polydnaviridae: Hyposoter fugitivus ichnovirus ; Microplitis demolitor bracovirus ; Cotesia congregata virus ; Cotesia congregata bracovirus ; Campoletis sonorensis ichnovirus [GenBank:NC_007985~ NC_008008]; Glypta fumiferanae ichnovirus ; Campoletis sonorensis ichnovirus  Reoviridae: Southern rice black-streaked dwarf virus [GenBank:NC_014708~ NC_014717]; Great Island virus [GenBank:NC_014522~ NC_014531]; Stretch Lagoon orbivirus ; Raspberry latent virus[GenBank: NC_014598~ NC_014607 ]; African horsesickness virus ; Epizootic hemorrhagic disease virus [GenBank:NC_013396~ NC_013405]; Kadipiro virus ; Fiji disease virus [GenBank:NC_007154~ NC_007163]; St Croix River virus [GenBank:NC_005997~ NC_005998]; Operophtera brumata reovirus segment 1 [GenBank:NC_007559]; Mal de Rio Cuarto virus[GenBank:NC_008728~ NC_008737]; Eyach virus [GenBank:NC_003696~ NC_003707]; Aedes pseudoscutellaris reovirus [GenBank:NC_007666~ NC_007674]; Heliothis armigera cypovirus [GenBank:NC_010661~ NC_010670]; Yunnan orbivirus [GenBank:NC_007656~ NC_007665]; Rice ragged stunt virus ; Nilaparvata lugens reovirus [GenBank:NC_003652~ NC_003661]; Trichoplusia ni cytoplasmic polyhedrosis virus ; Homalodisca vitripennis reovirus [GenBank:NC_012535~ NC_012546]; Rice gall dwarf virus [GenBank:NC_009241~ NC_009252]; Banna virus ; Rice dwarf virus ; Rice black streaked dwarf virus [GenBank:NC_003728~ NC_003737 ]; Lymantria dispar cypovirus1[GenBank:NC_003016~ NC_003025]; Cypovirus 14 [GenBank: NC_003006~ NC_003015] Birnaviridae: Drosophila x virus  Dicistroviridae: Black queen cell virus [GenBank:NC_003784]; Triatoma virus [GenBank:NC_003783]; Drosophila C virus [GenBank:NC_001834]; Kashmir bee virus [GenBank:NC_004807]; Aphid lethal paralysis virus [GenBank:NC_004365]; Cricket paralysis virus [GenBank:NC_003924]; Rhopalosiphum padi virus [GenBank:NC_001874]; Israel acute paralysis virus of bees [GenBank:NC_009025]; Himetobi P virus [GenBank:NC_003782]; Acute bee paralysis virus [GenBank:NC_002548]; Plautia stali intestine virus [GenBank:NC_003779]; Solenopsis invicta virus 1 [GenBank:NC_006559]; Homalodisca coagulata virus-1 [GenBank:NC_008029] Tetraviridae: Euprosterna elaeasa virus [GenBank:NC_003412]; Boolarra virus ; Pariacato virus chromosome [GenBank:NC_003691~ NC_003692]; Nodamura virus [GenBank:NC_002690~ NC_002691]; Black beetle ; Macrobrachium rosenbergii nodavirus RNA-2 [GenBank:NC_005095]; Flock house virus [GenBank: NC_004146~ NC_004144 ]Entomopoxvirinae: Amsacta moorei entomopoxvirus 'L' [GenBank:ChchNPV: Chrysodeixis chalcites NPV; SfMNPV: Spodoptera frugiperda MNPV; SeMNPV: Spodoptera exigua MNPV; MaviMNPV: Maruca vitrata MNPV; AdorGV: Adoxophyes orana NPV; GflV: Glypta fumiferanae ichnovirus; TnAV-2c: Trichoplusia ni ascovirus 2c; MdBV: Microplitis demolitor bracovirus; HfIV: Hyposoter fugitivus ichnovirus; CcBV: Cotesia congregata bracovirus; CuniNPV: Culex nigripalpus NPV; ChocGV: Choristoneura occidentalis granulovirus; CpGV: Cydia pomonella granulovirus; EcobNPV: Ecotropis obliqua NPV; LsNPV: Leucania separata NPV; PoGV: Phthorimaea operculella granulovirus; CsIV: Campoletis sonorensis ichnovirus; NLRV: Nilaparvata lugens reovirus; FDV: Fiji disease virus; RBSDV: Southern rice black-streaked dwarf virusThe authors declare that they have no competing interests.Conceived the experiment: JL, Designed the experiment: GF; Performed the experiment: GF; Analyzed the data: GF; Wrote the paper: GF; Revised the paper: JL; gave the final approval of the version to be published: JL. Both authors read and approved the final manuscript."}
+{"text": "During cellulosic ethanol production, cellulose hydrolysis is achieved by synergistic action of cellulase enzyme complex consisting of multiple enzymes with different mode of actions. Enzymatic hydrolysis of cellulose is one of the bottlenecks in the commercialization of the process due to low hydrolysis rates and high cost of enzymes. A robust hydrolysis model that can predict hydrolysis profile under various scenarios can act as an important forecasting tool to improve the hydrolysis process. However, multiple factors affecting hydrolysis: cellulose structure and complex enzyme-substrate interactions during hydrolysis make it diffucult to develop mathematical kinetic models that can simulate hydrolysis in presence of multiple enzymes with high fidelity. In this study, a comprehensive hydrolysis model based on stochastic molecular modeling approch in which each hydrolysis event is translated into a discrete event is presented. The model captures the structural features of cellulose, enzyme properties , and most importantly dynamic morphological changes in the substrate that directly affect the enzyme-substrate interactions during hydrolysis.Cellulose was modeled as a group of microfibrils consisting of elementary fibrils bundles, where each elementary fibril was represented as a three dimensional matrix of glucose molecules. Hydrolysis of cellulose was simulated based on Monte Carlo simulation technique. Cellulose hydrolysis results predicted by model simulations agree well with the experimental data from literature. Coefficients of determination for model predictions and experimental values were in the range of 0.75 to 0.96 for Avicel hydrolysis by CBH I action. Model was able to simulate the synergistic action of multiple enzymes during hydrolysis. The model simulations captured the important experimental observations: effect of structural properties, enzyme inhibition and enzyme loadings on the hydrolysis and degree of synergism among enzymes.The model was effective in capturing the dynamic behavior of cellulose hydrolysis during action of individual as well as multiple cellulases. Simulations were in qualitative and quantitative agreement with experimental data. Several experimentally observed phenomena were simulated without the need for any additional assumptions or parameter changes and confirmed the validity of using the stochastic molecular modeling approach to quantitatively and qualitatively describe the cellulose hydrolysis. Lignocellulosic biomass is a complex matrix of three biopolymers: cellulose (20-50%), hemicellulose 15-35%) and lignin (5-30%) 5-35% and-6, folloHydrolysis of cellulose and hemicellulose into sugar monomers is a critical step in the biochemical conversion of cellulose into ethanol. Cellulose is the most abundant biopolymer on earth with about 100 billion tons produced by terrestrial plants every year . Trichoderma reesei (earlier known as T. viride), comprising endoglucanases EGI, two exoglucanases CBHI and CBHII and \u03b2-glucosidase. Cellulase system of T. reesei, a soft-rot fungi, has been extensively studied [T. reesei were assumed as 0.4, 0.8, and 1.6\u00a0IU/mg of EG I, CBH I and CBH II respectively [All model simulations were performed for four main classes of cellulase enzymes: Non-processive endoglucanases with CBM, processive CBH I with CBM and processive CBH II with CBM and \u03b2-glucosidase. These enzymes are similar to enzyme system of  studied ,3,18,20.ectively . Zhang aectively  calculatectively -68.Data from model simulations were compared with two sets of experimental results from literature to validate the model.T. reesei, provided by Novo Nordisk A/S, Denmark), at various enzyme: substrate loadings at 40\u00a0\u00b0C in 50\u00a0mM citrate buffer (pH\u00a04.8) for 47\u00a0h.Experimental details for the experimental data are detailed in Bezerra et al. -47. BrieT. reesei . For model simulations, activity of EG II enzymes used in experiments were assumed to be same as EG I enzyme (0.4\u00a0IU/mg protein).For model validation, cellulose conversion results were extracted from Figure\u00a0th\u2019 enzyme; BC: Bacterial cellulose; BG: \u03b2-glucosidase; C: Cellulose fraction of the solid; CBH: Cellobiohydrolases; CBM: Carbohydrate binding module; CBP: Consolidated bioprocessing; CD: Catalytic domain; CGlu: Concentration of glucose (g/L); CG2: Concentration of cellobiose (g/L); CG6+: Concentration of high DP molecules (g/L); CrI: Crystallinity index; DP: Degree of polymerization; DS: Degree of synergism; EF: Elementary fibril; EG: Endoglucanses; Ei: Amount of 'ith' enzyme used per unit of cellulose during hydrolysis (mg/g cellulose); fj: Fraction of hydrolysable bonds for 'jth' microfibril; Gactual: Number of glucose molecules in actual sample; Gsim: Number of glucose molecules simulated in the model; IU: International unit of enzyme activity; MF: Microfibrils; n: Number of microfibrils simulated; Nhij: Number of maximum bonds broken by ith enzyme on jth microfibril; Nhi_max: Maximum number bonds broken by an enzyme per minute; Ninhib: Increment in counter due to inhibition; Ninhib _G2: Increment in counter due to cellobiose encounter/inhibition; Ninhib _G: Increment in counter due to glucose encounter/inhibition; Nnb: Increment in counter when no binding occurs; Nnp: Increment in counter in case of non-productive binding; NNRj: Number of non-reducing end in jth microfibril; NRj: Number of reducing ends in jth microfibril; Nsj: Number of glucose molecules on the surface of elementary fibrils in jth microfibril; NSLj: Number of soluble oligomers produced from jth microfibril; ODE: Ordinary differential equations; R2: Square of the Pearson product\u2013moment correlation coefficient; S: Fraction of solids in the solution; Si: Stability of 'ith' enzyme under current hydrolysis conditions; SMM: Stochastic molecular modeling; T. reesei: Trichoderma reesei; Ui: Activity of 'ith' enzyme (IU/mg enzyme); Vactual: Volume of solution (mL); Wsample: Weight of total solution during hydrolysis (g)\u2206Cmixed: Cellulose conversion by action of mixture of \u2018n\u2019 enzymes; \u2206Ci: Cellulose conversion by individual action of \u2018iThe authors declare that they have no competing interests.DK developed the model, carried out the process simulations and wrote the paper. GM conceived and designed the study, helped in the development of the model, and reviewed the results and manuscript. All authors read and approved the final manuscript.1Graduate Student, Biological and Ecological Engineering, 116 Gilmore Hall, Oregon State University, Corvallis, OR-97331. 2Assistant Professor, Biological and Ecological Engineering, 116 Gilmore Hall, Oregon State University, Corvallis, OR-97331.This file includes seven sections (A1 \u2013 A7) as follow: Section A1: Parameters associated with glucose molecules in the model. This section illustrates the properties associated with glucose molecules in the model. Section A2: Binding and action of endoglucanase and cellobiohydrolase enzymes. This section explains the action pattern of cellulase enzymes on cellulose. Section A3: Values of parameters used for EG I, CBH I and CBH II action. This section provides the values of parameters (such as increment on productive or non-productive binding) used in model simulations. Section A4: Calculations of concentrations of soluble and insoluble sugars. Equations used to calculate concentration of soluble and insoluble sugars during hydrolysis are presented in this section. Section A5: Cellobiose production during hydrolysis of Avicel by CBH I action. This section presents the data from model simulation from hydrolysis of Avicel at various enzyme:substrate ratios. Simulations were performed three times at each condition and standard deviations are provided in the table. Section A6: Endoglucanases action on substrates with different crystallinity. This section illustrates effect of crystallinity on the hydrolysis profile of cellulose by endoglucanases action. Section A7: Effect of enzyme loading on the hydrolysis rate of cellulose. This section presents the data from model simulation from hydrolysis of Avicel at various enzyme loadings .Click here for file"}
+{"text": "There were multiple errors in the Author Contributions statement. The Author Contributions statement should read: \"Conceived and designed the experiments: RKL. Performed the experiments: JMP AMT. Analyzed the data: JMP AMT HJHC ASU. Wrote the paper: RKL.\""}
+{"text": "The terms \"PKA\" and \"EPAC\" are not appropriately capitalized in the article title. The correct title is: \"Opposing Roles of PKA and EPAC in the cAMP-Dependent Regulation of Schwann Cell Proliferation and Differentiation.\" The correct Citation is: Bacallao K, Monje PV (2013) Opposing Roles of pka and epac in the cAMP-Dependent Regulation of Schwann Cell Proliferation and Differentiation. PLoS ONE 8(12): e82354. doi:10.1371/journal.pone.0082354."}
+{"text": "The fourth author was incorrectly omitted from the list of those authors who wrote the paper in the Contributions Statement. The Author Contributions section should read: \u201cConceived and designed the experiments: EG LHS WLG. Performed the experiments: LHS WLG. Analyzed the data: GCS. Contributed reagents/materials/analysis tools: EG. Wrote the paper: GCS EG.\""}
+{"text": "There was an error in the name of the second author.The correct name of this author is: Michael G. FriskThe correct citation is: Karimi R, Frisk MG, Fisher NS (2013) Contrasting Food Web Factor and Body Size Relationships with Hg and Se Concentrations in Marine Biota. PLoS ONE 8(9): e74695. doi:10.1371/journal.pone.0074695The correct version of the Author Contributions section is: Conceived and designed the experiments: RK MGF NSF. Performed the experiments: RK. Analyzed the data: RK MGF. Contributed reagents/materials/analysis tools: MGF NSF. Wrote the paper: RK MGF NSF."}
+{"text": "There was an error in the Author Contributions. The correct version of this section is available below.Conceived and designed the experiments: BSC MS AJ AG TJ PGK CW. Performed the experiments: BSC MS AJ CRB AG. Analyzed the data: BSC MS AJ AG TJ PGK CW. Wrote the paper: BSC CRB TJ MS PGK CW."}
+{"text": "In Figure 1B, the figures for girls and boys in the primary analysis should be reversed. Please see the corrected version of Figure 1B here: There were multiple errors in the author contributions. The updated author contributions are as follows:Conceived and designed the experiments: AE PBo DE VM CF RL PBh.Performed the experiments: RL PBh. Analyzed the data: VM CF PBo AE DE. Contributed reagents/materials/analysis tools: RL AE PBh DE CF PBo VM. Wrote the paper: RL AE DE CF PBo VM PBh."}
+{"text": "There was an error in the Author Contributions section. The second contributions category should read: \"Performed the experiments: GC MG MZ; GC and MG contributed equally to this work.\""}
+{"text": "To the Editor: The recent publication by Habibzadeh and Shashok discussed the importance of direct verbatim textual plagiarism (agiarism . Indeed,agiarism . However"}
+{"text": "CMLLite is a collection of definitions and processes which provide strong and flexible validation for a document in Chemical Markup Language (CML). It consists of an updated CML schema (schema3), conventions specifying rules in both human and machine-understandable forms and a validator available both online and offline to check conformance. This article explores the rationale behind the changes which have been made to the schema, explains how conventions interact and how they are designed, formulated, implemented and tested, and gives an overview of the validation service. There is an on-going need for formal, computable representations of scientific data and documents which are also accessible to humans -3. The cThe strengths and weaknesses of CML have been recently analysed by Dumontier  and we qChemical Markup Language, backed by a controlled vocabulary, has been rather successful in specifying most aspects of chemistry, from small molecules and their connectivity to polymers and crystal structures.Unfortunately, while most elements of this specification can be parsed out using one of the many XML libraries, certain elements do not render themselves to facile interpretation. Consider the sample CML specification of a water molecule [...]. In order to identify the member atoms in a given bond, it is necessary to carry out string processing as an intermediate step. Further, while many of the elements of CML are defined in a controlled vocabulary, the lack of explicit, consistent, and formal axiomatization of the involved concepts gives rise to difficulties in inferring connections between chemical concepts where no such connections are stated explicitly, something that is possible in formal ontology-backed RDF-based information specifications. Although CML specifications have been increasingly evolving to incorporate elements of the Semantic Web, the lack of widespread adoption of the format, and the limited availability of large-scale CML-based chemical knowledge repositories, have somewhat limited CML-assisted federation of the world of chemical data. Furthermore, the implementation of coverage of additional chemical concepts in most chemical representations requires a formal, rigorous representation specification, complicating the incorporation of data represented using domain-specific representation extensions. We believe that an ideal chemical representation would require no specialized wrapper or interpreter, would be generic such as to allow for facile and conflict-free extensions, would be based on a formal ontology, and would be encoded in a machine-understandable  manner and therefore facilitates automated reasoning and data integration.This article addresses these points and describes a system we have built for managing explicit and implicit semantics. It was initially developed during the Chem4Word (C4W) project   thenmolecule@formalCharge: = =sum  +sum ) is missing on a molecule, calculate it by recursively summing its descendants. This is more complex in practice as we have to apply semantics for atoms without formalCharge.)etc.). This article describes how their combination with unit tests and other validation procedures creates strong accessible semantics.CML has thousands of relationships like this, and they are relatively straightforward to implement through procedural code  , Open BaIt is commonly believed that the (perceived) ease of use of a new technology will affect its adoption by communities . A succe\u2022 Accessibility for humans\u2022 Proven infrastructure\u2022 Authoring tools\u2022 Reading tools\u2022 Editors\u2022 Domain libraries\u2022 Critical mass of content\u2022 Agreed concepts and vocabularies\u2022 Critical mass of users.Postel's Law  > 1)can be decomposed into a set of steps which define a set of elements to query over and the query itself:etc.).\u2022 ancestor::cml:molecule selects any molecule element of which the current atom is a descendent .\u2022 The count(...) > 1 expression forms the query and evaluates the number of atoms left in the set. If this is greater than 1 then multiple atoms in the same ancestor molecule have the same id.The conventions in CMLLite have built-in rules which are generally not explicitly stated in the specification of conventions:\u2022 A convention is applied through an element carrying the convention attribute. The convention applies to that element and all its descendants.\u2022 The value of the convention attribute MUST be a QName that expands to the URI identifying the convention to be applied.\u2022 A convention can require other conventions which must be explicitly specified on appropriate elements.\u2022 If no conventions are declared a warning is issued.We do not intend conventions to replace the CML schema and they are not a general schema language.mode-name\" > limits subsequent validation to templates with mode = \"mode-name\". An apply-templates call without a mode will only call those templates without a mode (i.e. not governed by a convention in the document).CMLValidator uses normal XSLT processing rules but makes special use of the mode attribute to allow validation of different conventions within the same document. < apply-templates mode = \"The current conventions contain many hundreds of validatorTest and to illustrate them we create a very simple sub-convention: simpleUnit. There is already a mature convention for units using the schema3 elements unitList and unit.  simpleUnit explores a small portion of this.http://www.xml-cml.org/convention/simpleUnit namespace.1 The simpleUnit convention is specified with the 2 The simpleUnit convention MUST be specified on a cml:unitList element using the convention attribute.3 A cml:unitList element MUST contain at least one cml:unit child element.4 A cml:unitList element MAY contain other child elements from the CML namespace or from foreign namespaces.There are no constraints on where in a document the unitList element may appear.We start by creating an exhaustive set of tests against which the validator will be developed. These tests (Appendix B) are independent of the actual implementation of the validator. We can be confident that any validator that passes all these tests is likely to be useful in determining whether any of a wide range of documents is valid or invalid against the simpleUnit convention.Figure We now address the purpose of each of the templates in the validator in detail.Template 1: creates the root report:result elementTemplate 2: match = \"*|@*|text\" matches any element, attribute or text node when not in simpleUnit mode. The match expressions for the three node types are the most general possible and will therefore be overridden by any more specific matches. This template takes no action but allows recursive traversal to find elements covered by the simpleUnit conventions arbitrarily deep in the input document.Template 3: carries out the same operations as template 2 but only when in simpleUnit mode. Non-CML elements may be interspersed with CML in the text document and will not cause the validator to emit warnings.Template 4: Only elements from the cml namespace will be matched; the element MUST have a convention attribute, with namespace http://www.xml-cml.org/convention/ and the local name simpleUnit. The schema enforces that the value of the convention attribute must be a namespaceRefType.If the element matched is cml:unitList this triggers mode = \"simpleUnit\" which remains in scope for all descendants.If the element matched is not cml:unitList the validator informs the users that it is an error to specify the simpleUnit convention and apply-templates is called but not in simpleUnit mode.Template 5: matches any cml:unitList element. If this does not have at least one cml:unit child element then an error is reported. Any child nodes are then processed in simpleUnit mode.Template 6: matches any cml:unit element in simpleUnit mode. XSLT rules dictate that it has higher priority than template 7.Template 7: matches any element from the CML namespace in simpleUnit mode. The match is more specific than template 3 but less specific than templates 4, 5 and 6. This will therefore catch any CML namespaced elements other than unitList and unit. The elements matched by this template are covered by rule 4-they are allowed but they are not really part of the convention, hence the output contains information to this effect.This template is primarily for information, not errors-it is therefore appropriate to warn when CML elements might be ignored. Note that the presence of report:info elements in the report document does not mean that the input document is invalid.i.e. they do not overlap .http://www.xml-cml.org/convention/compchem has been developed as part of the Quixote project. It requires that the initialization module contains exactly one molecule and that all the atoms in this molecule MUST have three dimensional coordinates. Rather than create a new convention for molecules it was decided that these requirements were compatible with the molecular convention but required a tightening of some constraints.The compchem convention Some of the rules from the compchem convention are shown below:http://xml-cml.org/dictionary/compchem/).\u2022 There MUST be an initialization module which is a module element with a specific value of its dictRef attribute .\u2022 molecules MUST declare that they conform to the molecular convention by declaring this in the convention attribute  and tests that an atomArray is present and that all the child atoms of this have 3D coordinates. Note that we do not need to check whether or not the molecule has child molecules or other atomArray children because this will be done by the molecular convention.Following the W3C validation tools   and produces a ValidationReport. If input is an InputStream the program checks that it is well-formed XML (this is not necessary for a xomDoc as it is necessarily well-formed). A xomDoc is built from the InputStream and further processing is identical regardless of input format.1. It is well-formed XML. The control class can takes as input either an 2. The xomDoc conforms to the CML schema3.3. Deprecated constructs are not used. The use of deprecated constructs will give a VALID_WITH_WARNINGS result.4. Any conventions specified in the document are obeyed.5. All the prefixes used in namespaceRefTypes (effectively QNames) have been bound to namespaces and are resolvable URLs.etc. publicly available. The workflow is shown in Figure The final check has been put in place as a reminder to users that sharing information is preferable and they can only \"code to the green bar\"  by makinhttp://validator.xml-cml.org/validate which returns a ValidationReport. This must then be queried by the user to determine whether the overall validation resulted in VALID, VALID_WITH_WARNINGS or INVALID. Informal feedback from users indicated that it was more useful to send the complete ValidationReport rather than just a ValidationResult as feedback as this would allow the calling tool to do more.The RESTful webservice implementation is accessed by POSTing the XML/CML document to The website is effectively an instance of a tool that uses the RESTful implementation to do the actual validation but then interprets the results and displays them in the most human-user friendly fashion. Figures conventions which can be as rigid or fluid as they wish. The conventions can be rigorously unit tested using CMLValidator.We have developed an approach to extensible semantics for Chemical Markup Language, where we assume that the current schema (schema3) is stable and expressive. There is enough software and data that this approach has been widely deployed and tested, even if it is not yet mainstream. Semantics are defined in the XSD schema, with additional natural language and validated using a unit test approach (Java and .NET). It works in the main fields of chemistry for which CML has been developed . The approach encourages sub-communities in chemistry to create The convention-based approach is intermediate between natural language and formal systems. It relies, in part, on the wider community agreeing the semantics in schema3 . Sub-communities are starting to build their extensions of which the compchem convention being developed by the Quixote project is a prime example.We believe the convention-based approach will help developers to create better software quicker. The tests/conventions define clear, testable APIs and these are essential for any distributed development.The system interoperates fully with RDF-based systems. Many elements  can be algorithmically translated to RDF. A few core elements  can be held in a more atomic form with bespoke semantics and software . By using this mixture of approaches we believe this is a cost-effective approach to interoperability within chemistry for those who wish to interoperate.http://bitbucket.org/cml/cmllite-validator-code and the web-based implementation is available at http://bitbucket.org/cml/cmllite-validator-ws both under an Apache 2.0 licence.The CMLValidator and associated tests are available at The authors declare that they have no competing interests.JAT developed the CMLLite approach, created the CMLValidator and the test corpus, and wrote the manuscript. PMR is the original author of CML, created the test corpus and wrote the manuscript.The attributes in CML are defined in attributeGroups which must have unique names allowing them to be disambiguated within the schema. The attributeGroup defines an attribute, its datatype/allowed values, and the name of the attribute in the document (these do not have to be unique).Element declarations in the schema specify which attributeGroups are allowed on them (which in this case caused polymorphism).Table etc.) of the convention, the validator is run against this test set to verify that its behaviour still conforms to expectations.The documents below are a subset of the documents used to test the behaviour of the simpleUnit convention validator. After every alteration <cml:unitList convention = \"conventions:simpleUnit\"><cml:unit/></cml:unitList>This produces the following ValidationReport:http://www.xml-cml.org/report/\"><report xmlns = \"<well-formed-test><valid >xml is well formed</valid></well-formed-test><schema-validation-test><valid>document conforms to the schema</valid></schema-validation-test><convention-validation-test><valid>document conforms to all the conventions specified</valid></convention-validation-test><uris-reachable-test><valid>All appropriate URIs were reachable</valid><valid>all dictRefs are resolvable </valid></uris-reachable-test></report>The subsequent inputs produce exactly the same report and we therefore choose to explain what the document is testing for rather than show the output.(ii)http://www.w3.org/1999/xhtml\"><x:p xmlns:x = \"<cml:unitList convention = \"conventions:simpleUnit\"><cml:unit/></cml:unitList></x:p>Tests that simpleUnit convention can be declared on a unitList that is not the root element of the document and is a child of a foreign namespaced element.(iii)<cml:module><cml:unitList convention = \"conventions:simpleUnit\"><cml:unit/></cml:unitList></cml:module>The simpleUnit convention can be declared on a unitList that is not the root element of the document and is a child of a CML element (module).(iv)<element-in-default-namespace><cml:unitList convention = \"conventions:simpleUnit\"><cml:unit/></cml:unitList></element-in-default-namespace>Tests that simpleUnit convention can be declared on a unitList that is not the root element of the document and is a child of an element from the default-namespace.(v)http://www.w3.org/1999/xhtml\"><x:p xmlns:x = \"the unitList need not be the root element<cml:unitList convention = \"conventions:simpleUnit\"><cml:unit/></cml:unitList></x:p>Test that although CML does not have a mixed content model the unitList can occur within non-CML mixed content.(vi)http://www.w3.org/1999/xhtml\"><x:p xmlns:x = \"there are multiple instances of the simpleUnitconvention in this document<cml:unitList convention = \"conventions:simpleUnit\"><cml:unit/></cml:unitList><cml:unitList convention = \"conventions:simpleUnit\"><cml:unit/></cml:unitList></x:p>Test that there can be multiple disjoint simpleUnit convention declarations in the same document.(vii)<cml:unitList convention = \"conventions:simpleUnit\"><cml:unit/>http://www.w3.org/1999/xhtml\"><x:p xmlns:x = \"non cml child-this is fine</x:p></cml:unitList>Tests that the unitList element can contain foreign namespaced elements without giving rise to info reports.(viii)<cml:unitList convention = \"conventions:simpleUnit\"><element-in-default-namespace/><cml:unit/></cml:unitList>Tests that the unitList element can contain elements from the default namespace without giving rise to info reports.(ix)<cml:unitList convention = \"conventions:simpleUnit\"><cml:unit>http://www.w3.org/1999/xhtml\"><x:p xmlns:x = \"non cml child-this is fine</x:p></cml:unit></cml:unitList>Tests that the unit element can contain foreign namespaced elements without giving rise to info reports.(x)<cml:unitList convention = \"conventions:simpleUnit\"><cml:unit><element-in-default-namespace/></cml:unit></cml:unitList>Tests that the unit element can contain elements from the default namespace without giving rise to info reports.(xi)<cml:unitList convention = \"conventions:simpleUnit\"><cml:unit/><cml:unit>http://www.w3.org/1999/xhtml\"><x:p xmlns:x = \"multiple cml:unit elements are allowed</x:p></cml:unit></cml:unitList>Tests that a unitList may contain more than one unit child.The input documents below should all result in a ValidationResult of VALID and the ValidationReport should contain a single info element and MUST NOT contain either error or warning elements. info elements are used to give information about rules in a convention involving the MAY clause. Note that the complete ValidationReport is given for the first example but subsequent examples only contain the error message for brevity.(i)<cml:unitList convention = \"conventions:simpleUnit\"><cml:unit/><cml:molecule/></cml:unitList>Produces:http://www.xml-cml.org/report/\"><report xmlns = \"<well-formed-test><valid > xml is well formed </valid></well-formed-test><schema-validation-test><valid > document conforms to the schema </valid></schema-validation-test><convention-validation-test>http://www.xml-cml.org/schema'] [http://www.xml-cml.org/schema'] [<info location = \"/*[local-name = 'unitList' and namespace-uri = 'schema'] /*[local-schema'] \">http://www.xml-cml.org/convention/simpleUnit convention and may be ignored by some processors.molecule is not a part of the </info><valid>document conforms to all the conventions specified</valid></convention-validation-test><uris-reachable-test><valid > All appropriate URIs were reachable </valid><valid > all dictRefs are resolvable </valid></uris-reachable-test></report>(ii)<cml:unitList convention = \"conventions:simpleUnit\"><cml:unit><cml:atom/></cml:unit></cml:unitList>http://www.xml-cml.org/convention/simpleUnit convention and may be ignored by some processors\"Produces: \"atom is not a part of the (iii)<cml:unitList convention = \"conventions:simpleUnit\"><cml:unit/><cml:unit><cml:bond/></cml:unit></cml:unitList>http://www.xml-cml.org/convention/simpleUnit convention and may be ignored by some processors\"Produces: \"bond is not a part of the e.g. order = '1') the test result would be VALID_WITH_WARNINGS because numeric bond orders are deprecated.Note that if the bond specified a numeric bond order ((iv)<cml:unitList convention = \"conventions:simpleUnit\"><cml:unit>http://www.w3.org/1999/xhtml\"><x:p xmlns:x = \"this is still going to be processed inunitList mode.<cml:bond/></x:p></cml:unit></cml:unitList>http://www.xml-cml.org/convention/simpleUnit convention and may be ignored by some processors\"Produces: \"bond is not a part of the (v)http://www.w3.org/1999/xhtml\"><x:p xmlns:x = \"the unitList need not be the root element<cml:unitList convention = \"conventions:simpleUnit\"><cml:molecule/><cml:unit/></cml:unitList></x:p>http://www.xml-cml.org/convention/simpleUnit convention and may be ignored by some processors\".Produces: \"molecule is not a part of the The documents below should all result in a ValidationResult of INVALID. The ValidationReport should contain a single error element and should not contain either info or warning elements.(i)<cml:molecule convention = \"conventions:simpleUnit\"><cml:unitList><cml:unit/></cml:unitList></cml:molecule>Produces the following ValidationReport:http://www.xml-cml.org/report/\"><report xmlns = \"<well-formed-test><valid > xml is well formed </valid></well-formed-test><schema-validation-test><valid > document conforms to the schema </valid></schema-validation-test><convention-validation-test>http://www.xml-cml.org/schema'] [<error location = \"/*[local-name = 'molecule' and namespace-uri = 'schema'] @*[local-the only valid cml element that can specify the simpleUnit convention is \"unitList\"</error></convention-validation-test><uris-reachable-test><valid > All appropriate URIs were reachable </valid><valid > all dictRefs are resolvable </valid></uris-reachable-test></report>(ii)http://www.w3.org/1999/xhtml\"><x:p xmlns:x = \"<cml:molecule convention = \"conventions:simpleUnit\"><cml:unitList><cml:unit/></cml:unitList></cml:molecule></x:p>Produces: \"the only valid cml element that can specify the simpleUnit convention is 'unitList'\". (Illustrating that the document is still being correctly traversed.)(iii)<cml:unitList convention = \"conventions:simpleUnit\"/>Produces: \"A unit list MUST contain child cml:unit elements\".(iv)<cml:unitList convention = \"conventions:simpleUnit\"><!-- not valid, a unitList must have at least one unit child --></cml:unitList>Produces: \"A unit list MUST contain child cml:unit elements\".(v)<cml:unitList convention = \"conventions:simpleUnit\">http://www.w3.org/1999/xhtml\"><x:p xmlns:x = \"no unit child of unitList</x:p></cml:unitList>Produces: \"A unit list MUST contain child cml:unit elements\".(vi)<cml:unitList convention = \"conventions:simpleUnit\">http://www.w3.org/1999/xhtml\"><x:p xmlns:x = \"<cml:unit/>This unit is not a direct child of unitListand therefore should cause an error.</x:p></cml:unitList>Produces: \"A unit list MUST contain child cml:unit elements\".(vii)<cml:unitList convention = \"conventions:simpleUnit\"><cml:unitList><cml:unit>http://www.w3.org/1999/xhtml\"><x:p xmlns:x = \"the outer unitList does not have at leastone unit child</x:p></cml:unit></cml:unitList></cml:unitList>Produces: \"A unit list MUST contain child cml:unit elements\"."}
+{"text": "Simian immunodeficiency virus (SIV) infection of Indian-origin rhesus macaques (RM) has been widely used as a well-established nonhuman primate (NHP) model for HIV/AIDS research. However, there have been a growing number of studies using Chinese RM to evaluate immunopathogenesis of SIV infection. In this paper, we have for the first time reviewed and discussed the major publications related to SIV or SHIV infection of Chinese RM in the past decades. We have compared the differences in the pathogenesis of SIV infection between Chinese RM and Indian RM with regard to viral infection, immunological response, and host genetic background. Given AIDS is a disease that affects humans of diverse origins, it is of importance to study animals with different geographical background. Therefore, to examine and compare results obtained from RM models of Indian and Chinese origins should lead to further validation and improvement of these animal models for HIV/AIDS research. The antAlthough the published data have demonstrated that Chinese RM is a suitable macaque host for studies of HIV disease, more extensive investigations on testing of current HIV vaccine approaches in Chinese RM are needed in order to determine if efficacy of these approaches in humans can be predicted in Chinese RM. These future studies should provide further support for the use of Chinese RM for the investigation of HIV disease.AGM: African green monkey; AID50: 50% animal infectious doses; AIDS: Acquired immunodeficiency syndrome; CCL: Chemokine ligand; CCR5: C-C chemokine receptor 5; CD: Cluster of differentiation; Ch RM: Chinese rhesus macaques; CMV: Cytomegalovirus; CTL: Cytotoxic T Lymphocyte; DC: Dendritic cells; HIV: Human immunodeficiency virus; HLA: Human leukocyte antigen; HMBPP: (E)-4-Hydroxy-3-methyl-but-2-enyl pyrophosphate; IFN: Interferon; IL: Interleukin; LN: Lymph node; I.R: Intrarectally; I.V: Intravenously; IVAG: Intravaginally; MHC: Major histocompatibility complex; mtDNA: Mitochondrial DNA; NHP: Nonhuman primate; PMN: Polymorphonuclear neutrophils; SHIV: Simian-human immunodeficiency virus; SIV: Simian immunodeficiency virus; SNP: Specific single nucleotide polymorphisms; TCID50: 50% tissue culture infective dose; TDF: Tenofovir disoproxil fumarate.The authors declare that they have no competing interests.YZ wrote the manuscript. RB collected information for tables. NH, YP and WZH reviewed and edited the manuscript. All authors read and approved the final manuscript."}
+{"text": "Scientific Reports6: Article number: 2721710.1038/srep27217; published online: 06022016; updated: 07042016The original version of this Article contained typographical errors in the spelling of the author Alexandra Christina Isabelle Depelsenaire which was incorrectly given as Alexandra Christina Isobel Depelsenaire. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports5: Article number: 1521910.1038/srep15219; published online: 10152015; updated: 12142015The original version of this Article contained typographical errors in the spelling of the author Alice Mado Proverbio which was incorrectly given as C.A. Alice Mado Proverbio. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "AbstractGraminoids, including grasses, are frequently described in the botanical literature as being wind-pollinated. This paper offers visual evidence for insect pollination of a grass. Three of the bees involved were found to have 100% grass pollen in their pollen sacs. In reviewing the literature for this paper, it was evident that those working with bees are well aware that these insects often pollinate graminoids. It is not clear why this information has not been incorporated into the botanical literature. Eremochloaophiuroides)  Figs , 7 is a es) Figs . The popApismellifera, or honey bees, were introduced to North America by European settlers in the 1700's and are not native to the North American continent. They are now best described as being ubiquitous worldwide. Agricultural necessity has fostered this expansion as bees help to pollinate crops. Their evolutionary and phylogenetic origins appear to be multiple radiations out of Africa, with later expansions to Asia and Europe  (Fagaceae) (Sarcocornia)  , oaks (Fagaceae) , and eveocornia) .Supplementary material 1Climatological Data for Louisiana, June 2013Data type: PDFBrief description: Flat file for June 2013 precipitationFile: oo_6602.pdfNational Oceanic and Atmospheric AdministrationSupplementary material 2Climatological Data for Louisiana, July 2013Data type: PDFBrief description: Flat file for July 2013 precipitationFile: oo_6603.pdfNational Oceanic and Atmospheric AdministrationSupplementary material 3Climatological Data for Louisiana, August 2013Data type: PDFBrief description: Flat file for August 2013 precipitationFile: oo_6600.pdfNational Oceanic and Atmospheric AdministrationSupplementary material 4Climatological Data for Louisiana, September 2013Data type: PDFBrief description: Flat file for September 2013 precipitationFile: oo_6599.pdfNational Oceanic and Atmospheric AdministrationSupplementary material 5Climatological Data for Louisiana, October 2013Data type: PDFBrief description: Flat file for October 2013 precipitationFile: oo_6601.pdfNational Oceanic and Atmospheric AdministrationSupplementary material 6Derived wet summer data from NOAAData type: xlsBrief description: \"How-did\" converting inches to centimeters across three weather points in Baton Rouge, La., from manual NOAA PDF amalgamationFile: oo_6604.xlsxNOAA and Tim Jones"}
+{"text": "Scientific Reports6: Article number: 2004810.1038/srep20048; published online: 01282016; updated: 05232016.In the original version of this Article, Affiliation 1 was omitted for Zhiming Ma. This error has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "The correct reference is: AntifilariasisCampaign (2013) Annual reports. Ministry of Health, Sri Lanka Available at"}
+{"text": "Scientific Reports6: Article number: 1953710.1038/srep19537; published online: 01182016; updated: 04202016.The original version of this Article contained typographical errors in the spelling of the author Guodong Yuan, which was incorrectly given as Gongdong Yuan. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports5: Article number: 1234910.1038/srep12349; published online: 08262015; updated: 02082016.The original version of this Article contained an error in the spelling of the author Kohei Fujikura, which was incorrectly given as K. Fujikura. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports6: Article number: 21694;10.1038/srep21694 Published online: 02152016; Updated: 05092016The original version of this Article incorrectly listed \u2018College of Chemistry and Environment, Minnan Normal University, Zhangzhou, China, 363000\u2019 as a present address for Bang-Qin Huang rather than Shun-Xing Li.This error has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports5: Article number: 18366;10.1038/srep18366 published online: 12172015; updated: 03302016The original version of this Article contained a typographical error in the spelling of the author Lee D. Roberts, which was incorrectly given as Lee D. Robert. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports6: Article number: 20118; 10.1038/srep20118 published online: 01292016; updated: 03102016The original version of this Article contained typographical errors in the spelling of the author Terry G. Coursey, which was incorrectly given as Terry Coursy. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Asbestos exposure is related to various diseases including asbestosis and malignant mesothelioma (MM). Among the pathogenic mechanisms proposed by which asbestos can cause diseases involving epithelial and mesothelial cells, the most widely accepted one is the generation of reactive oxygen species and/or depletion of antioxidants like glutathione. It has also been demonstrated that asbestos can induce inflammation, perhaps due to activation of inflammasomes.The oxidation state of thioredoxin was analyzed by redox Western blot analysis and ROS generation was assessed spectrophotometrically as a read-out of solubilized formazan produced by the reduction of nitrotetrazolium blue (NTB) by superoxide. Quantitative real time PCR was used to assess changes in gene transcription.Here we demonstrate that crocidolite asbestos fibers oxidize the pool of the antioxidant, Thioredoxin-1 (Trx1), which results in release of Thioredoxin Interacting Protein (TXNIP) and subsequent activation of inflammasomes in human mesothelial cells. Exposure to crocidolite asbestos resulted in the depletion of reduced Trx1 in human peritoneal mesothelial (LP9/hTERT) cells. Pretreatment with the antioxidant dehydroascorbic acid (a reactive oxygen species (ROS) scavenger) reduced the level of crocidolite asbestos-induced Trx1 oxidation as well as the depletion of reduced Trx1. Increasing Trx1 expression levels using a Trx1 over-expression vector, reduced the extent of Trx1 oxidation and generation of ROS by crocidolite asbestos, and increased cell survival. In addition, knockdown of TXNIP expression by siRNA attenuated crocidolite asbestos-induced activation of the inflammasome.Our novel findings suggest that extensive Trx1 oxidation and TXNIP dissociation may be one of the mechanisms by which crocidolite asbestos activates the inflammasome and helps in development of MM. Malignant mesothelioma (MM) is a deadly cancer arising from the mesothelium and its etiology usually involves asbestos exposure. MM is aThioredoxin is a small ubiquitously expressed redox active protein that is important for maintaining the reducing milieu of the cell, in part by reducing protein disulfide bonds that occur in response to oxidative processes. During reduction of disulfide bonds Trx1 itself becomes oxidized and in turn reduced by thioredoxin reductase (TR) using electrons from reduced nicotinamide adenine dinucleotide phosphate (NADPH). Trx1 is2 and grown to 80\u201390% confluency as described previouslyethanesulfonic acid; ARE: Antioxidant response element; zYVAD-fmk: Carbobenzoxy-tyrosyl-valyl-alanyl-aspartyl-[O-methyl]- fluoromethylketone; Chry: Chrysotile asbestos; Croc: Crocidolite asbestos; DHA: Dehydroascorbic acid; DMSO: Dimethyl sulfoxide; DTT: Dithiotreitol; Dox: Doxorubicin; EV: Empty vector; EDTA: Ethylenediaminetetraacetic acid; ERK2: Extracellular signal regulated kinase 2; GB: Glass beads; HBSS: Hank\u2019s balanced salt solution; HMGB1: High mobility group box 1; LP9/hTERT (LP9): hTERT- immortalized human peritoneal cell line; HPRT: Hypoxanthine phosphoribosyl transferase; IAA: Iodoacetic acid; LDH: Lactate dehydrogenase; MM: Malignant mesothelioma; MnSOD: Manganese superoxide dismutase; NAC: N-acetylcysteine; NADPH: Nicotinamide adenine dinucleotide phosphate; NLRP3: NLR family pyrin domain containing 3; PBS: Phosphate-buffered saline; qRT-PCR/qPCR: Quantitative real time PCR; ROS: Reactive oxygen species; shERK2: Short hairpin RNA against ERK2; shCon: Short hairpin RNA non-targeting; SDS PAGE: Sodium dodecyl sulfate polyacrylamide gel electrophoresis; TBST: TBS-Tween; Trx1: Thioredoxin 1; TXNIP: Thioredoxin interacting protein; TR: Thioredoxin reductase; TBS: Tris-buffered saline.Authors declare no competing interests.JT, performed experiments and wrote the manuscript with the help of AS; CW, performed NAC and inflammasome related studies; MM, performed statistical analysis and made final figures for the publication. MM also provided technical assistance with many experiments; BM, conceived the initial idea and provided intellectual input; NH, provided all the plasmids used in the study and insightful discussion; PS, helped with redox Western blots; AS, conceived the idea, designed experiments, supervised the study, interpreted data, and helped JT in writing the manuscript. All authors have read and approved the manuscript."}
+{"text": "There are errors in the Author Contributions. The correct contributions are: Conceived and designed the experiments: ALC CRM RP FG EFS. Performed the experiments: ALC AG. Analyzed the data: ALC CRM RP. Contributed reagents/materials/analysis tools: FC FG EFS. Wrote the paper: ALC CRM RP FG EFS FC."}
+{"text": "Nature Communications7, Article number: 11317 10.1038/ncomms11317 (2016); Published: 04282016; Updated: 0526201615.13155/ncomms11317. This has now been corrected in both the PDF and HTML versions of the Article.The original version of this Article contained an error in the doi number, which was incorrectly given as"}
+{"text": "Scientific Reports6: Article number: 2529710.1038/srep25297; published online: 04292016; updated: 05312016The original version of this Article contained a typographical error in the spelling of the author Genyue Fu, which was incorrectly given as Genyu Fu. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Nature Communications 6: Article number: 788610.1038/ncomms8886 (2015); Published: 08072015; Updated: 10072015The original version of this Article contained an error in the phrase \u2018single electron spins' in the title. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Nature Communications 7: Article number: 1164110.1038/ncomms11641 (2016); Published: 05182016; Updated: 06242016.The original version of this Article contained an error in the spelling of the author Somenath Bakshi, which was incorrectly given as Somenath Bakhsi. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Nature Communications 6: Article number: 741410.1038/ncomms8414 (2015); Published: 06162015; Updated: 02182016.The authors inadvertently omitted Kimiora L. Ward, who managed and contributed data, from the author list. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports5: Article number: 14570; 10.1038/srep14570published online: 09282015; updated: 10292015The original version of this Article contained a typographical error in the spelling of the author Hoe-Yune Jung which was incorrectly given as Hoe-Youn Jung.This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Citation: Inderjit. 2015. Introduction to the Special Issue: The role of soil microbial-driven belowground processes in mediating exotic plant invasions. AoB PLANTS7: plv052; doi:10.1093/aobpla/plv052One of the articles in the special issue  was not included in the previous version of the introduction. A revised version which includes the missing article has been published, and we apologize for the omission."}
+{"text": "AbstractCales\u00a0has been extensively revised recently and divided into two species groups, the\u00a0noacki- and\u00a0spenceri-groups\u00a0The genus\u00a0Calesmotterni Polaszek, Shih & Ward sp. nov. is described from two females reared from the whitefly Bemisiapongamiae from Taiwan. The species belongs to the spenceri- group, and has a characteristic and unusual antennal clava. A key to the four\u00a0species currently known from the spenceri-group is provided. CalesCalesnoacki\u00a0Howard from eggs of Lepidoptera , C.orchamoplati Viggiani & Carver and C.berryi Mottern & Heraty .A series of surveys was undertaken from 2004 to 2014 for the collection of parasitoid host whiteflies, scale insects and aphids in Taiwan. Whiteflies were identified by C.C. Ko, National Taiwan University, where the holotype and paratype are deposited. Collection and rearing methods during this survey are detailed by Morphological terminology and the format for species descriptions follow NTU: National Taiwan UniversityPolaszek, Shih & Ward, 2015sp. n.urn:lsid:zoobank.org:act:81A93438-A9A8-45D3-9091-1EB842972CCAType status:Holotype. Occurrence: recordedBy: Y.T. Shih; individualCount: 1; sex: female; previousIdentifications: Bemisiapongamiaeex ; Location: country: TAIWAN; stateProvince: Xindian District; locality: Wulai; locationRemarks: Acer sp.on ; Event: eventDate: 10.xii.2010; Record Level: type: on slide; institutionID: NTUType status:Paratype. Occurrence: recordedBy: Y.T. Shih; individualCount: 1; sex: female; previousIdentifications: Bemisiapongamiaeex ; Location: country: TAIWAN; stateProvince: Xindian District; locality: Wulai; locationRemarks: Acer sp.on ; Event: eventDate: 10.xii.2010; Record Level: type: on slide; institutionID: NTUColour: pale brown; vertex of head and ante\u00adrior half of mesoscutum orange; posterior half of mesoscutum and scutellum brown; face and legs pale, almost white.Head with transverse sculpture, face ventral to antennae with scattered slender setae Fig. Unknown.Calesmotternisp.n. can be distinguished from other species in the genus by the following combination of characters: antennal clava with several multiporous plate sensilla attached throughout their lengths; each side lobe of mesoscutum with one seta; fore wing with setae rather evenly distributed; a single row of small campaniform sensilla on dorsal surface of basal cell, just posterior to submarginal vein.The species is named for Dr Jason Mottern, formerly of the University of California, Riverside, USA in recognition of his major contribution to our understanding of this unusual genus.TAIWAN: Xindian District, Wulai.Bemisiapongamiae (Hemiptera: Aleyrodidae). No parasitoids have been recorded to date from this host (A primary endoparasitoid of his host .Calesmotterni is an unusual species in several ways. Morphologically, the clava shows vestiges of having developed from a 2-segmented condition. This, plus the assumed plesiomorphic state of the wing setation, suggests it may be the most morphologically basal species known in the genus.The single female paratype is identical in all respects to the holotype. Calesmotternisp.n. is the only species of the genus currently known from Taiwan."}
+{"text": "Scientific Reports6: Article number: 2928510.1038/srep29285; published online: 07082016; updated: 08192016.The original version of this Article contained a typographical error in the spelling of the author Baoqiang Du which was incorrectly given as Baoqing Du. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Correction to:Corrigendum: British Journal of Cancer (2015) 113, 1641\u20131641; doi:10.1038/bjc.2015.391; published online 1 December 2015British Journal of Cancer, the authors noted that author KM Matula had been placed in the incorrect position on the author listing. The publishers would like to apologise for this mistake. The full and correct author listing is reproduced above.Upon publication of the above corrigendum in the"}
+{"text": "Scientific Reports5: Article number: 1424510.1038/srep14245; published online: 09182015; updated: 02082016.The original version of this Article contained typographical errors in the spelling of the authors Jaeyune Ryu, Hyoung-Juhn Kim and Jong Hyun Jang, which were incorrectly given as Jae Yoon Ryu, Hyung Juhn Kim and Jong Hyung Jang. These errors have now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports6: Article number: 2584410.1038/srep25844; published online: 05162016; updated: 06102016.The original version of this Article contained an error in the spelling of the author Asfa Alli Shaik which was incorrectly given as Alli Shaik Asfa. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Nature Communications6, Article number: 7879 10.1038/ncomms8879 (2015); Published: 07292015; Updated: 08282013.The original version of this Article contained a typographical error in the spelling of the author Matthew Gilliham, which was incorrectly given as Matthew Gillham. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports5: Article number: 1399410.1038/srep13994; published online: 09142015; updated: 12162015The original version of this Article contained a typographical error in the spelling of the author Takahiro Masaki which was incorrectly given as Takahiro Masaski.This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "A reference is omitted from the figure caption for The reference is: Forsman J, Van den Bogaard M, Linder C, Fraser D (accepted for publication 2014). Considering student retention as a complex system: a possible way forward for enhancing student retention. European Journal of Engineering Education."}
+{"text": "Nature Communications 6: Article number: 723110.1038/ncomms8231 (2015); Published: 06042015; Updated: 08272015.The original version of this Article incorrectly named the author Shuxin Han as Sean Han. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Three authors were omitted from the author contributions section in the \u201ccontributed to the writing of the manuscript\u201d sub-section. Please refer to the correct author contributions here:Conceived and designed the experiments: LC GB AB. Performed the experiments: LC GB GLP. Analyzed the data: LC GB FP GLP. Contributed reagents/materials/analysis tools: CD AB GLP. Contributed to the writing of the manuscript: LC FP GB.GLP CD AB"}
+{"text": "Scientific Reports5: Article number: 1428810.1038/srep14288; published online: 09232015; updated: 12142015Review-only material was inadvertently published with the original version of this Article as Supplementary Movie 1. This has now been removed."}
+{"text": "AbstractMyotisalbescens occurs from Mexico southward to Uruguay and Argentina. The species is known for all South American countries except French Guiana and Chile.Myotisalbescens occurs in the Guiana Shield with other four congeners, from which it can be distinguished by external and skull traits. As an aid to future identifications, we provide a key to this assemblage.Based on one specimen recently collected in French Guiana we fill part of the gap in the distribution of the species in South America.  Myotisalbescens was described by Etienne chauve-souris douzi\u00e8me (or chauve-souris brune-obscure) from Paraguay , on 31 July 2011 at an elevation of 42 m. The specimen was caught by hand, inside a hollow log. It is preserved in spirit, with skull prepared separately. The basicranium is broken, which prevented us from taking several measurements, but the rostrum and braincase\u2014structures useful in identifications\u2014are intact.The MHNG 1990.017 is an adult female  collected by M. Dewynter  at Rivi\u00e8re des Cascades, municipality of Montsinery, about 27 km SW of Cayenne, French Guiana  from Paraguar\u00ed, Paraguay. This set of specimens covers the entire distribution range of the species, and comprises most  of the morphological variation currently known for M.albescens.This specimen was directly or indirectly compared with more than 3,800 vouchers of New World Measurements are reported in millimetres (mm) and are from adults only. Dimensions were taken using digital callipers accurate to 0.02 mm, and craniodental measurements were taken under binocular microscopes with low magnification . Measurements include forearm length (FA), third metacarpal length (3MC), braincase breadth (BCB), interorbital breadth (IOB), postorbital breadth (POB), breadth across canines (BAC), breadth across molars (BAM), maxillary toothrow length (MTL), length of the upper molars (M1M3), and mandibular length (MAL). These measurements are defined in Type status:Other material. Occurrence: catalogNumber: MHNG 1990.017; occurrenceRemarks: caught by hand, inside a hollow log; sex: female; lifeStage: adult; preparations: Ethanol 70o GL; disposition: in collection; Taxon: scientificName: Myotisalbescens; kingdom: Animalia; phylum: Chordata; class: Mammalia; order: Chiroptera; family: Vespertilionidae; genus: Myotis; specificEpithet: albescens; taxonRank: species; scientificNameAuthorship: ; vernacularName: Silver-tipped myotis; nomenclaturalCode: ICZN; taxonomicStatus: accepted; Location: higherGeography: French Guiana; Montsinery; Rivi\u00e8re des Cascades; continent: South America; country: French Guiana; stateProvince: Cayenne; municipality: Montsinery; locality: Cayenne, 27 km SW; verbatimElevation: 42 m; verbatimCoordinates: 04\u00b045'01\"N 52\u00b029'08\"W; verbatimLatitude: 04\u00b045'01\"N; verbatimLongitude: 52\u00b029'08\"W; verbatimCoordinateSystem: degrees decimal minutes; Event: eventDate: 2011-07-31Presence of a fringe of hairs along the trailing edge of uropatagium, long and silky pelage with frosted appearance on the dorsum, ears 9\u201314 mm in length, broad interorbital and postorbital constrictions, and globular braincase.Southern Veracruz, Mexico, southward through Central America to Uruguay and Argentina.Myotis, there is no one single character distinguishing M.albescens from its congeners. However, the species can be easily identified based on the following set of traits: presence of a fringe of hairs along the trailing edge of uropatagium, long and silky pelage with frosted appearance on the dorsum, ears 9\u201314 mm in length, broad interorbital and postorbital constrictions, and globular braincase. Although this set of traits is not fully present in some specimens, the presence of a fringe of hairs along the trailing edge of the uropatagium has been recorded in 99.4% of the specimens examined (500 out of 503) throughout the entire distribution range of the species, and is useful to distinguish it from all Neotropical species but M.atacamensis  and M.levis . Myotisatacamensis occurs from western Peru to northern Chile  for French Guiana and for all South American countries except Chile, from which the species is possibly absent. Its southernmost record on the west side of the Andes is in the semideciduous forests of north-western Peru  field identification that are likely erroneous. This stresses the importance of vouchered and carefully identified specimens to appropriately record species occurrences in such difficult taxonomic groups as the Neotropical Myotis  of which occur in French Guiana (Although this record does not add any biological information for the species, it is useful to more accurately describe the spectacular biodiversity of French Guiana, and emphasizes its rich biota, which is taxonomically and ecologically highly diversified for bats. Paracou in French Guiana concentrates one of the highest species diversity in the world, with ca. 78 species see . About 1h Guiana ."}
+{"text": "Scientific Reports6: Article number: 2930910.1038/srep29309; published online: 07072016; updated: 08242016The original version of this Article contained a typographical error in the spelling of the author Amitava Banerjee, which was incorrectly given as Amitava Banarjee. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports5: Article number: 15578; 10.1038/srep15578 published online: 10232015; updated: 01202016.The original version of this Article contained a typographical error in the spelling of the author Gal Richter-Levin, which was incorrectly given as Gal Richter-Levine. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "AbstractTelotheta Warren found in Ecuador and Bolivia are described. The paper focuses on the morphological description and illustration of the wing pattern and genitalia structures of the typus generis Telothetamuscipunctata Dognin and the newly identified species Telothetaunoi and Telothetafresei. The distinguishing characters of the genera Telotheta and Paromphacodes are also briefly discussed.Two new species of the lophochoristine genus  Geometramuscipunctata.\u00a0Telothetachlorostigma), discussing the similarity of the species he discovered and Dognin's Geometramuscipunctata, highlighting the differences observed in the colour of the frons, and of the venation of the forewing.A delicate, bluish green moth from Southern Ecuador was described by\u00a0Telotheta for the first time, presented a comparative morphological characterization and synonymized the two species.\u00a0Telotheta\u00a0 with the tribe Lophochoristini. She characterized the male and female genital structures of the monotypical genus Telotheta. The genus-level characteristics of Telotheta include: hind tibia with one pair of  spurs, the absence of the frenulum in females, the absence of usual transverse lines on wings, the absence of fields of modified scales on the male abdominal sternite A3. Pitkin described the female antennae as being filiform or dentate and mentioned the similarity of the genera Oospila Warren, 1897 and Telotheta, while the latter differs from the former by lacking the characteristical lophochoristine abdominal crests, which are composed of specialized, long, erect and curled scales.Telotheta are described below.Two further species of the genus The present study was initiated by attempts to identify moths found in the collections of the Estonian Museum of Natural History  and in the IZBE insect collection which is deposited at the Estonian University of Life Sciences (Tartu). The material is collected by Aare Lindt.Telothetamuscipunctata (see the description of Telothetafresei\u00a0 below). Moths were mostly photographed prior to investigation of the genital structures using a Canon 300D digital camera, while genital slides were photographed with an Olympus SZ60 microscope and Leica M165C digital camera. The obtained photographs were augmented using Adobe Photoshop Elements v7 in order to improve their resolution.The mounting of emerald green moths is a complicated process and the method that was used required injecting some water into the thorax, followed by keeping the moth in a container with a high air moisture environment for about 2 hours, and finally desiccating the mounted sample at around 60\u00b0C for about 12 hours. Palpi, antennae, legs and details of wing venation were measured using an ocular micrometer and binocular microscopes, using 40\u00d7 magnification. The genital slides of males and females were treated using established procedures , inspectLindt & Viidaleppsp. n.urn:lsid:zoobank.org:act:DA996931-3FEE-4EF9-8DEE-E4D6FAE4AE0DType status:Holotype. Occurrence: sex: male; Location: country: Ecuador; stateProvince: Napo; verbatimLocality: Carlos Julio; verbatimElevation: 950 m; verbatimLatitude: 01\u00b015'33\"S; verbatimLongitude: 77\u00b049'27\"W; decimalLatitude: -1.259167; decimalLongitude: -77.824167; Event: samplingProtocol: UV light sampling; eventDate: 2008-02-10; Record Level: institutionCode: EMNHType status:Paratype. Occurrence: sex: 4 males; Location: country: Ecuador; stateProvince: Napo; verbatimLocality: Carlos Julio; verbatimElevation: 950 m; verbatimLatitude: 01\u00b015'33\"S; verbatimLongitude: 77\u00b049'27\"W; decimalLatitude: -1.259167; decimalLongitude: -77.824167; Event: samplingProtocol: UV light sampling; eventDate: 2008-02-10; Record Level: institutionCode: EMNH; collectionCode: IZBEHead, thorax and abdomen. Male: The wing span of males is 15\u201317 mm . The costal edge of the forewing is lined light brown (slightly rosy in Telothetamuscipunctata). The hindwing distal margins are evenly rounded, not slightly angulated at the middle.Male genitalia Type status:Other material. Occurrence: recordedBy: Aare Lindt; individualCount: 1; sex: male; Location: country: Ecuador; stateProvince: Pichincha; verbatimLocality: El Transito; verbatimElevation: 1080; verbatimLatitude: 00\u00b018'59\"S; verbatimLongitude: 78\u00b054'54\"W; Event: samplingProtocol: UV light sampling; eventDate: 2008-02-03; Record Level: institutionCode: ENHMBoth original descriptions by P. Dognin and W. Warren (see Introduction) refer to the pale bluish green moths with large green discal blotches on both wings. The colour of the frons was described as yellowish ochreous by Dognin, and as brick red by Warren.Telothetamuscipunctata has a row of about 20 stout curved setae to the distal margin of valva, and the thorn-like projections of the sternite A8 appear slightly diverging . The forewing costal edge is lined light brown (slightly rosy in Telothetamuscipunctata).ngs Fig.  are densMale genitalia . The aedeagus is about 1.3 mm long. The distal process of the uncus is reduced, the gnathos arms are short hooked. In Telothetafresei the juxta and the transtilla together constitute a long anellar complex. The juxta is broader than in the two other species. The valva is apically bilobed, the apical lobe as in Telothetamuscipunctata (more slender in Telothetaunoi). The dorsal margin of the apical lobe bears about 8-10 scattered, stout, curved setae,\u00a0and about 20 such setae in a row in Telothetamuscipunctata. The ventral margin of the subapical lobe of the valva is straight. Sternite A8 distal projections are flat and triangularly rounded, completely different from the slender, rigid projections in Telothetamuscipunctata and Telothetaunoi.lia Fig. c. The maTelothetamuscipunctata  and therefore treated as conspecific.\u00a0Telothetamuscipunctata males by the presence of two rod-like processes to the posterior edge of the last abdominal sternite and females by having a large roundish sclerotization in\u00a0 the sterigmal area, a membranous bursa copulatrix, provided with a \"small signum with two tapered prongs\" (Telothetamuscipunctata and Telothetafresei are clear. prongs\" : 408. ThTelothetafresei from Ecuador and from Bolivia differ slightly in the shape of the eighth sternite of male abdomen. The sternite has triangular projections to its posterior edge in the populations of Ecuador, and more rounded projections in the\u00a0 populations from Bolivia. This phenomenon requires further investigation: the differences are slight and, possibly, clinal.The series of This new species is named in honour of the former lutherian pastor in L\u00e4\u00e4ne-Nigula, West Estionia, Theodor Alexander Benedict Frese. His insect collection, consisting of several thousands of mounted and labelled local butterflies, moths and other hexapods, was donated in 1864 to the Eestimaa Provintsiaalmuuseum, the precedor of the Estonian Museum of Natural History. The 150th anniversary of the Museum will be celebrated 2014. The gender is masculine.Telothetafresei is described from Eastern Ecuador and Bolivia.Telothetafresei is collected in tropical forests between about 500 m and 2000 m elevation.Telotheta species are to be separated as follows:The three Telothetamuscipunctata\u00a0 moths have a slender frons, pale green, semidiaphanous wings and a bicornute sternite A8 in male;Telothetafresei moths have frons broad, both wings similarly pale green, the male sternite A8 flat with two broad projections distally;Telothetaunoi\u00a0 has frons broad, forewings dark green and dense scaled, and the male sternite A8 bicornute like in Telothetamuscipunctata."}
+{"text": "In the Funding section, one grant number from the funder Papes VI/FIOCRUZ/Brazilian National Council for Scientific and Technological Development (CNPQ) is missing. The grant number is: 407582/2012\u20136."}
+{"text": "Nature Communications 6: Article number: 805610.1038/ncomms9056 (2015); Published: 08202015; Updated: 09232015.In Fig. 5d of this Article, a shaded box was inadvertently placed over the lower part of the panel during the final stages of production. The correct version of the figure appears below.Figure 5"}
+{"text": "Nature Communications7: Article number: 11826 10.1038/ncomms11826 (2016); Published: 06072016; Updated: 08162016The original version of this Article contained an error in the spelling of the author Frances Eun-Hyung Lee that was incorrectly given as Francis Eun-Hyung Lee. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports5: Article number: 1122810.1038/srep11228; published online: 06102015; updated: 09022015.In the Supplementary Information file originally published with this Article, the primer sequences for cloning the constructs were omitted. This error has now been corrected in the Supplementary Information that now accompanies the Article."}
+{"text": "Nature Communications 6: Article number: 786610.1038/ncomms8866 (2015); Published: 07222015; Updated: 02102016.The original version of this Article contained an error in the spelling of the author Edda Kloppmann, which was incorrectly given as Edda Kloppman. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports6: Article number: 2577810.1038/srep25778; published online: 05122016; updated: 07202016The original version of this Article contained a typographical error in the spelling of the author Qingjian Wu, which was incorrectly given as Qingjiang Wu. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports5: Article number: 13532; 10.1038/srep13532 published online: 09012015; updated: 05202016.The original version of this Article contained a typographical error in the spelling of the author Karen Vanhoorelbeke, which was incorrectly given as Karen Vanhoorelbeeke. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "BMC Medical Genomics [Following the publication of the article in Genomics , it was Given names: Herman M.J.Surname: SontropGiven names: Marcel J.T.Surname: ReindersGiven names: Perry D.Surname: MoerlandWe apologize for the inconvenience this may have caused."}
+{"text": "Nature Communications6: Article number: 8745 10.1038/ncomms9745 (2015); Published: 10262015; Updated: 11272015The original version of this Article contained an error in the spelling of the author Gilbert Di Paolo, which was incorrectly given as Gilbert D. Paolo. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Nature Communications 6: Article number: 868710.1038/ncomms9687 (2015); Published: 10222015; Updated: 01112016.The original version of this Article contained an error in the spelling of the author Tomislav Ilicic, which was incorrectly given as Tomislav Illicic. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports6: Article number: 2132310.1038/srep21323; published online: 02182016; updated: 04132016Supplementary Datasets 2\u20135 were inadvertently published with the original version of this Article. These have now been removed."}
+{"text": "Nature Communications6: Article number: 888410.1038/ncomms9884 (2015); Published: 12022015; Updated: 01212016.The original HTML version of this Article contained an error in the spelling of the author R. Elizabeth Sockett, which was incorrectly given as Elizabeth R. Sockett. This has now been corrected in the HTML. The PDF version of the Article was correct from the time of publication."}
+{"text": "Nature Communications6: Article number:681910.1038/ncomms7819 (2015); Published 04142016; Updated 06142016The original version of this Article contained an error in the spelling of the author Hugh P. Possingham, which was incorrectly given as Hugh P. Posssingham. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports6: Article number: 21817; 10.1038/srep21817 published online: 02242016; updated: 05202016.In Figure 2 of this Article, the upper left graph is a duplication of the upper right graph. The correct Figure 2 appears below as"}
+{"text": "Scientific Reports6: Article number: 1931910.1038/srep19319; published online: 01132016; updated: 04132016In the original version of this Article, the symbol \u201cIn addition, the HTML version of the Article incorrectly listed Venkata Jayasurya Yallapragada, and not Venu Gopal Achanta, as corresponding author.These errors have now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports6: Article number: 23499; 10.1038/srep23499 published online: 03232016; updated: 04292016.In the Supplementary Information file originally published with this Article, references 31 and 32 were incorrectly given as references 44 and 45 respectively. These errors have been corrected in the Supplementary Information that now accompanies the Article."}
+{"text": "AbstractMilichiidae are often myrmecophilic. We document the first record of a fly from this family interacting with an ant of the genus Polyrhachis. In lowland riparian rainforest in Sabah, Malaysia, we observed a female of the genus Milichia following an ant of the species of\u00a0P.illaudata, and repeatedly attempting to make close contact. Our observation suggests that the dipteran may have been attempting to feed kleptoparasitically from the Polyrhachis\u00a0worker, since members of this ant genus often feed on liquid carbohydrate-rich food resources. This is the first time an interaction has been observed between a fly of this family and an ant of this widespread old world tropical genus.Flies in the family  Milichid flies often interact with ants, with either adults feeding kleptoparasitically from foraging ant workers, or larvae feeding on detritus in the nest . Howeverth 2014, in an area of regularly inundated riparian forest 100m from the river  close to the field centre, we observed an ant of the genus Polyrhachis traversing the top of a plastic sheet c. 50 cm in height, which was being used as a vertical barrier to trap amphibians on the forest floor during the field course. The single Polyrhachis worker was being followed closely (c. 3 cm above and behind) by a hovering dipteran, which frequently attempted to make closer contact with the ant, in particular when the ant stopped moving. The ant was not behaving normally, but appeared to be attempting evasion of the dipteran. We observed this for approximately thirty seconds before collecting both ant and dipteran into a plastic container. The dipteran was initially not disturbed by its collection, and continued for some time with attempts to make close contact with the ant. We were unable to directly observe the outcome of these attempts (either kleptoparasitism or oviposition). Both insects were then preserved in 95% ethanol and point mounted for identification. To identify the ant we first used a key to the ant genera of Borneo . To identify the fly we used the key to genera at http://milichiidae.info/content/key-genera-milichiidae, based on that of Field observation and collection was conducted during a field course organised by the Naturalis Biodiversity Center at Danau Girang Field Centre on the lower Kinabatangan river, Sabah, Malaysia. On March 4f Borneo . We thenf Borneo \u00a0and finaMeigen, 1830Type status:Other material. Occurrence: individualCount: 1; sex: female; lifeStage: adult; behavior: following an ant; preparations: whole animal point\u00a0mounted; disposition: In collection; otherCatalogNumbers: DIP 00713; Taxon: scientificName: Milichia; parentNameUsage: Milichiinae; originalNameUsage: Milichia\u00a0Meigen 1830; Location: higherGeography: Asia; Malaysia; Sabah; Kinabatangan River Floodplain; continent: Asia; country: Malaysia; stateProvince: Sabah; locality: Kinabatangan River Floodplain; verbatimLocality: Kinabatangan River Floodplain ~10km downstream from Lahad Datu - Sandakan road crossing; verbatimElevation: 30 m; verbatimCoordinates: 5.4115, 118.0395; verbatimLatitude: 5.4115; verbatimLongitude: 118.0395; verbatimCoordinateSystem: decimal degrees; decimalLatitude: 5.4115; decimalLongitude: 118.0395; Identification: identifiedBy: Irina Brake; dateIdentified: 13-09-2014; identificationReferences: Brake (2000); identificationRemarks: Milichia females to species.Not possible to assign ; Event: samplingProtocol: Manual collection into plastic pot.; samplingEffort: Single collection event.; eventDate: 2014-03-04; habitat: Riparian lowland rain forest.Walker, 1859Type status:Other material. Occurrence: individualCount: 1; sex: female; lifeStage: adult; behavior: foraging; preparations: whole animal point mounted; disposition: in collection; otherCatalogNumbers: HYM\u00a00003736; Taxon: scientificName: Polyrhachis (Myrma) illaudata\u00a0Walker 1859; parentNameUsage: Formicinae; Location: higherGeography: Asia; Malaysia; Sabah;\u00a0Kinabatangan River Floodplain; continent: Asia; country: Malaysia; stateProvince: Sabah; locality: Kinabatangan River Floodplain; verbatimLocality: Kinabatangan River Floodplain ~10km downstream from Lahad Datu - Sandakan road crossing; verbatimElevation: 30 m; verbatimCoordinates: 5.4115, 118.0395; verbatimLatitude: 5.4115; verbatimLongitude: 118.0395; verbatimCoordinateSystem: decimal degrees; decimalLatitude: 5.4115; decimalLongitude: 118.0395; Identification: identifiedBy: Tom M. Fayle; dateIdentified: 2014-06-20; identificationReferences: www.antbase.net; The BORNEENSIS collection at the Institute for Tropical Biology, Universiti Malaysia Sabah; Dorow 1995.; Event: samplingProtocol: Manual collection into plastic pot.; samplingEffort: Single sampling occasion.; eventDate: 2014-03-04Milichia . The ant was identified as belonging to the species Polyrhachisillaudata\u00a0, and P.beccarii, which is morphologically similar, but much larger than P.illaudata.The dipteran was identified as a female of the genus hia Fig. , in the ata\u00a0Fig.  in the sMilichiidae being associated with an ant in the genus Polyrhachis. The only other record of an ant in the tribe Camponotini being associated with this family of flies is that of Camponotusacvapimensis, with a fly of the species Milichiasavannaticola being found with the ant, although it was not clear whether the two species were interacting (Formicinae including Lasius (Formica (Milichia female was attempting to feed kleptoparasitically from the P.illaudata\u00a0ant, since many other species of diptera in this family are known to conduct such attacks, either feeding on regurgitated liquid food or through licking anal secretions (Polyrhachis ants, and indeed other genera in the Camponotini, are known to feed extensively on liquid carbohydrate-rich food sources at extrafloral and floral nectaries, and also to attend homopterans (To our knowledge, this is the first record of a fly in the family eracting . Howeverg Lasius \u00a0and Form(Formica . Althougcretions . Polyrhaopterans , and henopterans . Howeveropterans , and so"}
+{"text": "Scientific Reports6: Article number: 2089810.1038/srep20898; published online: 02162016; updated: 04132016The original version of this Article contained a typographical error in the spelling of the author Josef Andreas Weber, which was incorrectly given as Josef Andreass Weber. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "AbstractNeossos Malloch contains three Nearctic and one western European species. Most known specimens have been collected from bird nests. Two specimens of an undescribed species of Neossos were collected by sweeping in subarctic tundra and a mesic meadow in the Yukon Territory, Canada. This represents a significant northward extension of the known Nearctic range of the genus.The rarely collected genus Neossostombstonensissp. n. is described from the Yukon Territory. This represents the fourth described Nearctic species of Neossos. Although the type specimens were collected by sweeping, the species is predicted to be associated with bird nests, based on habits of other members of the genus. A revised key to the Nearctic species of Neossos is provided. Neossos Malloch, 1927 is a rarely collected genus of acalyptrate Diptera primarily associated with bird nests, where the larvae are apparently saprophagous in nest material. Neossos and recognized three species in the region: Neossosmarylandicus Malloch, 1927 (associated with cavity-nesting passerine birds in eastern North America); N.californicus Melander, 1952 (associated with raptors in western United States and southern British Columbia); and N.atlanticus Gilbert & Wheeler, 2007 . In the course of a large-scale study of arthropod diversity and ecology in northern Canada, we collected two specimens of Neossos from the Yukon Territory, far north of the documented geographic range of Nearctic Neossos species. Those specimens are described here as Neossostombstonensissp. n.Field-collected specimens were preserved in 95% ethanol and subsequently chemically dried using Hexamethyldisilazane. Type specimens are deposited in the Lyman Entomological Museum, McGill University, Ste-Anne-de-Bellevue, QC, Canada (LEMQ) and have been assigned unique specimen identifiers in the format LEM0000000. Genitalic dissection of the male holotype was made by detaching the posterior part of the abdomen, and heating it in 85% lactic acid on a heating plate for 10 minutes. Cleared genitalia were transferred to glycerin for examination and drawing, then stored in glycerin in a plastic microvial pinned with the specimen.Solecki & Wheeler, 2015sp. n.urn:lsid:zoobank.org:act:A7C54472-8048-461F-8C58-5DE8413622E4Type status:Holotype. Occurrence: recordedBy: NBP Field Party; sex: male; Taxon: class: Insecta; order: Diptera; family: Heleomyzidae; genus: Neossos; specificEpithet: tombstonensis; scientificNameAuthorship: Solecki & Wheeler, 2015; Location: continent: North America; country: Canada; stateProvince: Yukon Territory; verbatimLocality: Dempster Hwy nr North Fork Pass; verbatimElevation: 1200 m; decimalLatitude: 64.57942; decimalLongitude: -138.28212; geodeticDatum: WGS84; Event: samplingProtocol: sweeping; year: 2011; month: 6; day: 24; habitat: wet tundra; fieldNumber: wet replicate 3; Record Level: datasetID: LEM0110624; institutionCode: LEMQType status:Paratype. Occurrence: recordedBy: TA Wheeler; sex: female; Taxon: class: Insecta; order: Diptera; family: Heleomyzidae; genus: Neossos; specificEpithet: tombstonensis; scientificNameAuthorship: Solecki & Wheeler, 2015; Location: continent: North America; country: Canada; stateProvince: Yukon Territory; verbatimLocality: S Klondike Hwy, 18.2 km S Alaska Hwy, Robinson Road House; decimalLatitude: 60.44839; decimalLongitude: -134.84961; geodeticDatum: WGS84; Event: samplingProtocol: sweeping; year: 2012; month: 7; day: 9; habitat: mesic meadow; Record Level: datasetID: LEM0110625; institutionCode: LEMQGeneric characters as described by Epandrium brown, rounded, wider than high; hypandrium pale brown, ventral hypandrial process with 9 setae; surstylus with outer lobe roughly triangular, narrowing distinctly in basal half; postgonite large; distiphallus with fine setulae for most of length except distally; epiphallus clavate Figs , 3.The species is named for the Tombstone Mountains and Tombstone Territorial Park, where the holotype specimen was collected.Known only from the southern and central Yukon Territory, Canada.Neossos are rarely collected. Of approximately 130 specimens studied by Neossos, N.nidicola , known from Great Britain and Finland (N.tombstonensis by sweeping was surprising, the rarity of specimens was not. Multiple years of intensive sampling at the two localities from which types were collected, as well as other similar sites in the Yukon, have not produced another specimen.Because they are apparently obligate associates of bird nests, specimens of  Finland  is closeN.tombstonensis were collected in two distinct habitats. The North Fork Pass site is a wet tundra meadow north of treeline in the Ogilvie Mountain ranges. Dominant vegetation includes sphagnum mosses, grasses, sedges and ericaceous shrubs over a substrate with extensive permafrost. In contrast, the Robinson Road House site is a mesic meadow with a diverse assemblage of herbaceous plants dominated by Asteraceae, Fabaceae, and Poaceae, on a sand substrate in a clearing surrounded by spruce-pine-aspen forest.The types of Neossos, it is likely that N.tombstonensis is also a nest associate. Each of the other three Nearctic species exploits a different microhabitat and host group: Neossosmarylandicus in association with cavity-nesting passerines; N.californicus in raptor nests; and N.atlanticus in nests of cliff-nesting seabirds (N.tombstonensis was collected, so it is impossible to speculate on the identity or nesting habits of the hosts.Based on the known habits of the other described species of seabirds . Several"}
+{"text": "Scientific Reports6: Article number: 21282;10.1038/srep21282 Published online: 02172016; Updated: 06022016The original version of this Article contained errors in the spelling of the authors Anis Allagui, Mohammad Ali Abdelkareem, Hussain Alawadhi and Ahmed S. Elwakil which were incorrectly given as Allagui Anis, Ali Abdelkareem Mohammad, Alawadhi Hussain and S. Elwakil Ahmed respectively.These errors have now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports6: Article number: 24628; 10.1038/srep24628 published online: 04192016; updated: 06272016.An incorrect Supplementary Information file was inadvertently published with this Article. In addition, Supplementary Movies 1\u20135 were omitted. The correct Supplementary Information and Supplementary Movies now accompany the Article."}
+{"text": "Scientific Reports6: Article number: 2009010.1038/srep20090; published online: 01292016; updated: 04132016The original version of this Article contained an error in the spelling of the author Yan Huang, which was incorrectly given as Yanhuang. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports5: Article number: 1731910.1038/srep17319; published online: 11302015; updated: 03292016The original version of this Article contained a typographical error in the spelling of the author Mikhail A. Livshits, which was incorrectly given as Mikhail A. Livshts. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "There are errors in the Funding section. The correct funding information is as follows: This work was supported by Chang Gung Medical Research Program CMRPG 3C1441: HSC; CMRPG 391201\u20133: HSC; CMRPD 1A0302: WJS; CMRPD 190173: WJS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."}
+{"text": "Scientific Reports5: Article number: 17094; 10.1038/srep17094 published online: 11252015; updated: 01192016.The original version of this Article contained a typographical error in the spelling of the author Ben Murrell which was incorrectly given as Ben Murrel. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports5: Article number: 17568;10.1038/srep17568 published online: 12032015; updated: 04282016The original version of this Article contained a typographical error in the spelling of the author Marc B. Bissonnette, which was incorrectly given as Marc B. Bissonette. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "There are errors in the Author Contributions. The correct contributions are: Conceived and designed the experiments: GS SA AM LF. Analyzed the data: GS. Wrote the paper: GS. Revised paper: SA AKW FM AM LF"}
+{"text": "Nature Communications7 Article number:1147910.1038/ncomms11479 (2016); Published: 05102016; Updated: 06062016.The original version of this Article contained an error in the spelling of \u2018refine' in the title of the paper. This has now been corrected in both the PDF and HTML."}
+{"text": "AbstractCoccidohystrixinsolita (Green) (Hemiptera: Pseudococcidae), is recorded from the island of Guam in the Mariana Islands for the first time. Factors indicating that this introduced mealybug has the potential to become a pest of economic importance for agriculture and horticulture on Guam are discussed.The eggplant mealybug,  Coccidohystrixinsolita (Green) is broadly distributed in the tropics and subtropics and well known as a agricultural and horticultural pest  for diagnosis. A total of seven adult female specimens were selected and prepared on three microscope slides using the method given by Type status:Other material. Occurrence: catalogNumber: AM20131204.002; occurrenceRemarks: on eggplant leaves; recordedBy: Jesse Bamba; sex: 7 slide-mounted adult females were examined; Location: islandGroup: Mariana Islands; island: Guam; municipality: Dededo; locality: near Swamp Road; decimalLatitude: 13.539981; decimalLongitude: 144.83435; Identification: identifiedBy: Gillian W. Watson; dateIdentified: 2013-12-13; Event: samplingProtocol: eggplant leaf samples; eventDate: 2013-12-04; Record Level: collectionID: ESUG; institutionCode: UGUAM; basisOfRecord: LivingSpecimen; source: http://guaminsects.myspecies.info/node/26239-segmented; posterior ostioles present, anterior ostioles absent; cerarii on margins numbering 17 pairs, numerous dorsal cerarii present also, each cerarius consisting of 1\u201315 large conical setae situated on a sclerotized prominence, without any associated trilocular pores; legs well developed, each claw with a denticle present on plantar surface; circulus absent; anal lobes well developed, each with a sclerotized ventral bar; quinquelocular pores numerous on venter; multilocular disc pores numerous on venter of abdominal segments III-IX, a few also present on the venter of segments I and II and on the dorsum of segment VII; ventral oral collar ducts present on submargins of abdominal segments V-VIII; oral rim ducts absent entirely.Coccidohystrixinsolita.Diagnosis was based Coccidohystrixinsolita has been recorded in the literature from the following regions and countries:Afrotropical: Kenya, Madagascar, Rodriques Island (Mauritius), South Africa, Tanzania, Zanzibar; Australasian: Western Samoa; Oriental: Bangladesh, Burma (=Myanmar), India, Laos, Pakistan, Philippines, Sri Lanka, Thailand, Vietnam; Palaearctic: China, Saudi Arabia (i Arabia .Coccidohystrixinsolita on Alternanthera (Amaranthaceae) imported from Singapore ; Hyperaspismaindronia; Nephusregularis; Lepidoptera:Lycaenidae: Spalgisepeus . Experience has shown that invasive species which originate from outside of the U.S., such as this one, are harder to deal with than those accidentally imported from the U.S. mainland or Hawaii. For invasive insect species already present in the U.S., control resources are usually readily available. Often research has been done, control methods have been developed, biological control agents have been identified, an exploratory entomologist has been sent out to collect candidate species, and these have been imported, cultured and tested, and are available for use on Guam. However, resources are scant when it comes to responding to invasive species of non-U.S. origin.Rapid Response Capacity. There is currently a critical lack of capacity to deal with entomological problems on Guam and in the rest of Micronesia. The number of Ph.D. level entomologists practicing on Guam and in the rest of Micronesia has decreased from nine during the mid-1990s to only three at present.Biological Control Agent Import Permits. Guam is required to comply with U.S. Department of Agriculture regulations for importing biological control agents. These requirements are far more stringent for organisms originating outside of the U.S. than for those imported from within the U.S. Delays in the permitting process and a lack of capacity to comply with permit conditions sometimes impede rapid progress towards establishment of biological control in time to prevent major economic and environmental damage. Often, there is a pest population explosion prior to implementation of biological control. During this initial outbreak, risk of accidental export to trading partners is high."}
+{"text": "There are currently no agreed recommendations on how to investigate children for gastrointestinal (GI) involvement in Juvenile Systemic Sclerosis (JSSc). The aim of screening is to detect disease early to facilitate early aggressive therapy and improve outcomes. GI involvement at diagnosis incurs a worse outcome [1]. Most deaths occur early in the disease course .To develop recommendations for investigation of GI involvement in JSSc, based on paediatric evidence and where this was lacking, consensus expert agreement.Members of the PRES Scleroderma Working Group were invited to participate; additionally a paediatric gastroenterologist was invited. A nominal group technique was used. 75% consensus was defined as agreement.Table N-terminal pro-brain natriuretic peptide; GORD: gastro-oesophageal reflux disease.BP: blood pressure; ECG: electrocardiogram; ECHO: echocardiogram; MRI: magnetic resonance imaging; HRCT: high resolution computerised tomography; PFT: DLCO pulmonary function tests with diffusion capacity of lung for carbon monoxide; 6MWT: 6 minute walk test; NT BNP: JSSc has a significant mortality particularly early on in the disease course. The objective of an aggressive screening program is to identify GI involvement at a stage which may be amenable to treatment. The recommendations developed by this group aim to standardise care and improve outcomes in this rare disease.None declared."}
+{"text": "Scientific Reports5: Article number: 1243910.1038/srep12439; published online: 07272015; updated: 09212015The original version of this Article contained an error in the spelling of the author Paul R. Bessell, which was incorrectly given as Paul B. Bessell. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "AbstractTipula (Vestiplex) hugueniniana Alexander, 1971 is proposed as junior synonym of Tipula (V.) wahlgrenana Alexander, 1968. The new synonymy is based on similarity of male genitalia.Based on examination of type specimens a crane fly species  Tipula (Vestiplex) Bezzi, 1924, are characterized by an ovipositor with the cerci powerfully constructed, heavily sclerotized with outer margins serrate, smooth in several Asiatic species; hypovalvae small to rudimentary  includes 170 valid species and subspecies level taxa, which are distributed throughout the Nearctic, Palaearctic and Oriental Regions .TMMP, program Immage-Pro Express 6.0. (Media Cybernetics).Specimens were studied with an Olympus SZ51 microscope. Pictures were taken with an Olympus SZX10, camera EvolutionTerminology of morphological features generally follows that of Alexander, 1968Tipula (Vestiplex) wahlgrenanaTipula (Vestiplex) wahlgrenanaTipula (Vestiplex) hugueninianasyn. n.Type status:Holotype. Occurrence: recordedBy: Schmid; sex: male; preparations: antennae, leg, wing and genitalia on slide mounted; Taxon: genus: Tipula; subgenus: Vestiplex; specificEpithet: wahlgrenana; scientificNameAuthorship: Alexander, 1968; Location: country: India; stateProvince: Kumaon; verbatimLocality: Khumyara, Pauri Garhwal; verbatimElevation: 4300-5000 feet [1311-1524 m]; Event: eventDate: 28 May 1958; Record Level: institutionCode: USNMType status:Holotype. Occurrence: recordedBy: Schmid; sex: male; preparations: antenna, legs, wing and genitalia on slide mounted; Taxon: genus: Tipula; subgenus: Vestiplex; specificEpithet: hugueniniana; scientificNameAuthorship: Alexander, 1971; Location: country: India; stateProvince: Sikkim; verbatimLocality: Nanga; verbatimElevation: 5000 feet [1524 m]; Event: eventDate: 11 May 1959; Record Level: institutionCode: USNMType status:Paratype. Occurrence: recordedBy: Schmid; sex: male; preparations: antenna, leg, wing and genitalia on slide mounted; Taxon: genus: Tipula; subgenus: Vestiplex; specificEpithet: hugueniniana; scientificNameAuthorship: Alexander, 1971; Location: country: India; stateProvince: Kumaon; verbatimLocality: Duldhar, Pauri Garhwal; verbatimElevation: 4500 feet [1372 m]; Event: eventDate: 2 June 1958; Record Level: institutionCode: USNMTipula (Vestiplex) recorded in India. Three species were described by Edwards  .Tipula (V.) wahlgrenana Alexander, 1968  hugueniniana Alexander, 1971  wahlgrenana, the other male was collected somewhat east of the previous locality, but two weeks earlier in the following year. These two males are also the only known specimens for the described species  hugueniniana, Tipula (V.) gandharva Alexander, 1951 and Tipula (V.) tuta Alexander, 1936, without mentioning its similarity to Tipula (V.) wahlgrenana. After detailed analysis of the two holotype and one paratype specimens of Tipula (V.) wahlgrenana and Tipula (V.) hugueniniana, we found that they cannot be distinguished from each other positively; differences concern only quantitative characters, without qualitative differences. The original description of the morphological details of Tipula (V.) hugueniniana in essence repeats the morphological characters of Tipula (V.) wahlgrenana. The only difference, according to Alexander\u2019s descriptions, is the general coloration of the mesonotal prescutum, which is obscure yellow in Tipula (V.) hugueniniana and light grey in Tipula (V.) wahlgrenana. Based on our observation, the coloration of the prescutum varies depending on the angle at which light strikes its surface.The types of both species were examined. It was found that all the specimens are very similar. In the original description of The new synonymy is based on the structure of the male genitalia. All the three examined specimens have the hypopygium as in Fig. Female unknown."}
+{"text": "Nature Communications 6: Article number: 7390 (2015); 10.1038/ncomms8390 Published: 06162015; Updated 08212015.The original version of this Article contained a typographical error in the spelling of the author Jae-Ho Cheong, which was incorrectly given as Jae-Ho Jeong. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports5: Article number: 850210.1038/srep08502; published online: 02172015; updated: 09182015This Article contains an error in Fig. 5e, where the p-Akt immunoblots depicted for the Cerebellum are a duplication of the p-Akt immunoblots depicted for the Hippocampus. The correct Fig. 5e appears below as"}
+{"text": "Scientific Reports6: Article number: 21838;10.1038/srep21838 Published online: 02242016; updated: 05092016The original version of this Article contained a typographical error in the spelling of the author Xianzhen Yin, which was incorrectly given as Xianzheng Yin. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Nature Communications4: Article number: 186710.1038/ncomms2886 (2013); Published: 05212013; Updated: 04202016The financial support for this Article was not fully acknowledged. The Acknowledgements should have included the following:Huang-Ge Zhang is supported by a Research Career Scientist (RCS) Award."}
+{"text": "The following information is missing from the Funding section: Grant name: Using Fossil Proteomics for Resolving Phylogenetics of Extinct Mammalian Orders in Ancient Biodiversity Hotspots Principal. Investigator: Dr M Buckley, The University of Manchester, Life Sciences. Grant held at: The University of Manchester, Life Sciences. NERC Reference: NE/K000799/1"}
+{"text": "Some of the author contributions for Melissa S. Anderson were omitted. The following are the correct author contributions for this paper:Conceived and designed the experiments: ENW DHK. Performed the experiments: ENW MSA MSL. Analyzed the data: ENW MSA DHK. Contributed reagents/materials/analysis tools: MSA. Wrote the paper: ENW DHK"}
+{"text": "There are errors in the Author Contributions. The correct contributions are: Conceived and designed the experiments: IG. Performed the experiments: IG. Analyzed the data: IG OS. Wrote the paper: IG OS."}
+{"text": "It should be corrected as follows:incorrect: November 26, 2013correct: December 13, 2013This correction has been completed on the electronic file of the present paper available at J-STAGE.The editorial board expresses sincere apology for the misprinting.Microbes and Environments editorial board"}
+{"text": "The sixth author's name is spelled incorrectly. The correct name is: Bidhan Chandra Chakraborty.The seventh author's name is spelled incorrectly. The correct name is: Sukanta Ray.The second sentence of the \u201cCell culture and Transfection\u201d section of the Materials and Methods incorrectly references Xtremegene. It should read X-tremeGENE HP.In the Acknowledgements, Bidhan Chandra Chakraborty should also be listed as having a registered PhD with the West Bengal University and health sciences.There are errors in the Author Contributions. The correct contributions are: Conceived and designed the experiments: KD GKD AC SB. Performed the experiments: Somenath Datta S. Roychoudhury Alip Ghosh DD Amit Ghosh BCC AKS. Analyzed the data: Somenath Datta SB. Contributed reagents/materials/analysis tools: S. Ray SG Simanti Datta. Contributed to the writing of the manuscript: SB."}
+{"text": "There are errors in the Author Contributions. The correct contributions are: Conceived and designed the experiments: TFK MP. Performed the experiments: MP. Analyzed the data: KAM. Contributed reagents/materials/analysis tools: KAM MP TFK. Wrote the paper: KAM TFK."}
+{"text": "Scientific Reports5: Article number: 1514510.1038/srep15145; published online: 10192015; updated: 01212016The original version of this Article contained a typographical error in the spelling of the author Jakob Goldmann which was incorrectly given as Jakob Goldman. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports6: Article number: 2660310.1038/srep26603; published online: 05252016; updated: 06202016The original version of this Article contained errors in the spelling of the author Hemanta K. Majumder which was incorrectly given as H. K. Mazumdar. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Prevention plays a fundamental role: if these disorders are diagnosed and treated precociously, the risk of infertility is considerably reduced.Andrological disorders in paediatric age are important: they may cause serious repercussions on normal fecundity  and someThe authors suggest a new prevention model based on an Andrological Form to be included in the periodical medical examination by the family paediatrician. If the paediatrician detects an andrological disorder during periodical checks, he/she should refer the patient to the paediatric andrologist or paediatric surgeon. The Andrological Form consists of 11 sections to be filled by the family paediatrician . The first section consists of the patient's records, weight and height included. Second: patient's pubertal development. Third: testicular volume according to Prader. Forth: testicular position. Fifth section: the presence of varicocele. Sixth: penis disorders . Seventh: gynecomastia . Eight: occurrence of other associated genito-urinary disorders. Ninth: previous andrological surgery interventions. Tenth: previous medical therapies. Eleventh: sport practicing. The Andrological form should be filled at the following ages: 1) 6 months ; 2) 1 year old ; 3) 5 years old ; 4) 10 years old ; 5) at 11, 12, 13 and 14 years old .The periodic compilation of the Andrological Form , therefo"}
+{"text": "AbstractEuphydryas (Hypodryas) maturna (L.) is included in the Habitats Directive's Annexes II and IV(a). Therefore, it is crucially important to be able to define the habitat and breeding places of E.maturna in a correct and unbiased way.The scarce fritillary Melampyrumsylvaticum L.), of Euphydryasmaturna in Finland is presented.Data on a previously unknown pre-diapause main host plant, the small cow-wheat ( Euphydryas (Hypodryas) maturna  is a high-profile species within the European Union, as it has been included in the Habitats Directive's  Annexes II and IV(a). Based on the Annex II, special conservation areas (i.e. Natura 2000 areas) need to be designated for E.maturna. The Annex IV lists species in need of strict protection, and those species and their breeding and resting places are protected by national legislation, which also applies to Finland. Therefore, the ability to define the habitat and breeding places of E.maturna in a correct and unbiased way is crucially important for both protecting the species effectively and not making uninformed administrative decisions which may be economically very costly. Euphydryasmaturna is a wide-spread species in SW Finland, and it has been assessed as Least Concern by the IUCN criteria in Finland  has been recorded as the main host plant (Melampyrumsylvaticum L.), of Euphydryasmaturna in Finland.The species of the tribe iridoids . Iridoidiridoids . Larval se Table  and/or psee e.g. . In Finlst plant . Here, IE.maturna were systematically searched from an area of ca. 3.5 km2 within the municipalities of Sipoo and Pornainen in southern Finland . All larval groups were georeferenced with GPS and photographed, and a sample of each host plant was collected for identification. Plant samples were identified by Henry V\u00e4re . Fieldwork was made by MN and Kari Nupponen between August 27 and September 11 in 2014.Larval groups of Type status:Other material. Occurrence: occurrenceRemarks: number of larval groups counted (with unknown number of larvae per group); recordedBy: Marko Nieminen; individualCount: 120; lifeStage: larva; Taxon: scientificName: Euphydryas maturna; order: Lepidoptera; family: Nymphalidae; genus: Euphydryas; specificEpithet: maturna; taxonRank: species; Location: country: Finland; stateProvince: Uusimaa; municipality: Sipoo; locality: Brusas; verbatimElevation: 60 m; verbatimCoordinates: 60\u00b026.73'N 25\u00b017.95'E; verbatimLatitude: 60\u00b026.73'N; verbatimLongitude: 25\u00b017.95'E; decimalLatitude: 60.4455; decimalLongitude: 25.2992; Identification: identifiedBy: Marko Nieminen; dateIdentified: 2014; Event: samplingProtocol: visual search; eventDate: 2014-08-27/09-11; Record Level: language: en; basisOfRecord: Photographed; source: marko.nieminen@faunatica.fiType status:Other material. Occurrence: occurrenceRemarks: number of larval groups counted (with unknown number of larvae per group); recordedBy: Marko Nieminen; individualCount: 23; lifeStage: larva; Taxon: scientificName: Euphydryas maturna; order: Lepidoptera; family: Nymphalidae; genus: Euphydryas; specificEpithet: maturna; taxonRank: species; Location: country: Finland; stateProvince: Uusimaa; municipality: Pornainen; locality: M\u00e4kel\u00e4; verbatimElevation: 60 m; verbatimCoordinates: 60\u00b027.32'N 25\u00b017.94'E; verbatimLatitude: 60\u00b027.32'N; verbatimLongitude: 25\u00b017.94'E; decimalLatitude: 60.4554; decimalLongitude: 25.2991; Identification: identifiedBy: Marko Nieminen; dateIdentified: 2014; Event: samplingProtocol: visual search; eventDate: 2014-08-27/09-11; Record Level: language: en; basisOfRecord: Photographed; source: marko.nieminen@faunatica.fiType status:Other material. Occurrence: occurrenceRemarks: number of larval groups counted (with unknown number of larvae per group); recordedBy: Kari Nupponen; individualCount: 24; lifeStage: larva; Taxon: scientificName: Euphydryas maturna; order: Lepidoptera; family: Nymphalidae; genus: Euphydryas; specificEpithet: maturna; taxonRank: species; Location: country: Finland; stateProvince: Uusimaa; municipality: Pornainen; locality: Honkasenkalliot; verbatimElevation: 60 m; verbatimCoordinates: 60\u00b026.51'N 25\u00b019.27'E; verbatimLatitude: 60\u00b026.51'N; verbatimLongitude: 25\u00b019.27'E; decimalLatitude: 60.4419; decimalLongitude: 25.3211; Identification: identifiedBy: Kari Nupponen; dateIdentified: 2014; Event: samplingProtocol: visual search; eventDate: 2014-09-10/11; Record Level: language: en; basisOfRecord: Photographed; source: marko.nieminen@faunatica.fiMelampyrum spp.  M.sylvaticum. In addition, three larval groups have been found in the same area in the autumn of 2013, all on M.sylvaticum .Due to the dry conditions in July and August, many or even all host plants had withered especially in open rocky areas. Therefore, reliable identifications based on plant morphology were possible for 121 samples. Of the identified samples, 30 plants (25%) were E.maturna is highly variable throughout its range (Table Fraxinus is the most regularly used oviposition-plant genus in the Central Europe (e.g. Veronicalongifolia are often used in the eastern areas (e.g. Plantagolanceolata is frequently used after diapause in Austria (M.sylvaticum in a study performed about 200 km to the northeast of this study area (M.pratense and M.sylvaticum still remain uncertain throughout Finland.The regional host plant use of ge Table , but is ope e.g. , whereaseas e.g. . Howevereas e.g. , for exa Austria . There mudy area . MoreoveM.sylvaticum as a host plant (Fig. E.maturna and the amount of resources available for it. In the study area, the increase in both of these variables must be manyfold, but remains to be quantified. Melampyrumpratense is much more vulnerable to desiccation and withering because it grows in drier sites than M.sylvaticum. The ability to use both of these Melampyrum species is extremely important in dry summers such as 2014, when more than 90% of host plants had withered in several sites. That high rate of dry host plants has likely increased mortality of groups of small larvae and may also decrease overwintering success due to starvation of larvae, which are common phenomena in another larval group-forming species Melitaeacinxia in Finland (e.g. The use of ant Fig.  considerand e.g. .Vacciniummyrtillus had been eaten within some larval webs. Even though I could not confirm that E.maturna larvae had eaten them, it is, however, likely because other herbivorous larvae were not observed and Melampyrum individuals were almost completely dry in and around these larval nests. Therefore, larvae may have used V.myrtillus to rescue themselves from starvation. The same explanation may apply to the odd observations of larvae feeding on e.g. Fagus, Populus and Salix regularly referred to in the literature (e.g. Some leaves of ure e.g. . A furth"}
+{"text": "Scientific Reports5: Article number: 1043410.1038/srep10434; published online: 05222015; updated: 10052015The original version of this Article contained a typographical error in the spelling of the author Kaori Ishikawa, which was incorrectly given as Kaori Iashikawa. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports5: Article number: 1737810.1038/srep17378; published online: 11272015; updated: 02082016.This Article contains a typographical error in Affiliation 2. The correct affiliation is listed below:Department of Radiation Oncology, The Fifth Affiliated Hospital of Sun Yat-sen University, People\u2019s Republic of China"}
+{"text": "Nature Communications6: Article number: 8510 10.1038/ncomms9510 (2015); Published: 10142015; Updated: 03042016The original version of this Article contained a typographical error in the spelling of the author Zhenyi Liu, which was incorrectly given as Zenhy Liu. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports6: Article number: 2402710.1038/srep24027; published online: 04132016; updated: 05312016The original version of this Article contained an error in the spelling of the author Esaki Muthu Shankar, which was incorrectly given as Shankar Esaki Muthu. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "There is an error in the corresponding author designations. Christoph Buettner should be listed as a co-corresponding author. The correct corresponding authors are:mlamerrill@ucdavis.eduMichele La Merrill christoph.buettner@mssm.eduChristoph Buettner There are errors in the Author Contributions. Christoph Buettner should be listed as one of the persons who conceived and designed the experiments, analyzed the data, contributed reagents/materials/analysis tools and contributed to the writing of the manuscript. The correct contributions are:Conceived and designed the experiments: MLM and CB. Performed the experiments: MLM EK CL MLF. Analyzed the data: MLM EK EM CL MLF JN and CB. Contributed reagents/materials/analysis tools: MLM JN CB. Contributed to the writing of the manuscript: MLM EK EM CL MLF JN CB."}
+{"text": "Although molecular tools are increasingly employed to decipher invertebrate systematics, earthworm (Annelida: Clitellata: \u2018Oligochaeta\u2019) taxonomy is still largely based on conventional dissection, resulting in data that are mostly unsuitable for dissemination through online databases. In order to evaluate if micro-computed tomography (\u03bcCT) in combination with soft tissue staining techniques could be used to expand the existing set of tools available for studying internal and external structures of earthworms, \u03bcCT scans of freshly fixed and museum specimens were gathered.GigaDB and are publicly available for download.Scout images revealed full penetration of tissues by the staining agent. The attained isotropic voxel resolutions permit identification of internal and external structures conventionally used in earthworm taxonomy. The \u03bcCT projection and reconstruction images have been deposited in the online data repository The dataset presented here shows that earthworms constitute suitable candidates for \u03bcCT scanning in combination with soft tissue staining. Not only are the data comparable to results derived from traditional dissection techniques, but due to their digital nature the data also permit computer-based interactive exploration of earthworm morphology and anatomy. The approach pursued here can be applied to freshly fixed as well as museum specimens, which is of particular importance when considering the use of rare or valuable material. Finally, a number of aspects related to the deposition of digital morphological data are briefly discussed. The present dataset constitutes the first attempt at comparative micro-computed tomography (\u03bcCT) scanning of earthworm (Annelida: Clitellata: \u2018Oligochaeta\u2019) specimens. When used in combination with staining techniques that permit enhancing soft tissue contrast , \u03bcCT couThe aim of the present report is to provide the earthworm research community with a reference dataset for future analyses of soft-bodied organisms based on non-destructive imaging techniques. In addition, uninhibited data access and enforced data deposition, as practiced here, are briefly discussed.i.e. Aporrectodea caliginosa  and Aporrectodea trapezoides . All four specimens were stained using an ethanol-based phosphotungstic acid (PTA) solution, which was adapted from protocols described previously . This would result in large morphological taxon sampling, one of the prerequisites for broad taxonomic and systematic studies. Furthermore, non-invasive imaging techniques such as \u03bcCT leave specimens intact and generate digital data suitable for online dissemination, an important condition for effective data mining.GigaDB and has a citable digital object identifier (DOI) [The dataset is available at er (DOI) . Each ofDataset name: MicroCT scans of freshly fixed and museum earthworm specimensOperating system: Platform-independentLicense: Creative Commons 0 (CC0) public domain dedication (https://creativecommons.org/publicdomain/zero/1.0/)http://imagej.nih.gov/ij/). In addition, numerous other 2D and 3D visualization tools are available for free [Following download, the reconstructed images can, for example, be rapidly visualized using the \u2018File:Import:Image Sequence\u2019 command chain in the Java-based imaging software ImageJ (for free . Given tGigaDB[The dataset presented here permits full open access both to \u03bcCT-derived raw data (here: the projection images) as well as derivative data (here: the reconstructed image stacks). The availability of \u03bcCT raw data files has been deemed important, primarily due to the rapid increase in the performance of reconstruction algorithms, which in the future could lead to improved data reconstruction . FurtherGigaDB. DespiteGigaDB, and metGigaDB.GigaScience Database online repository [The dataset supporting the results of this article is available in the pository .2D: Two-dimensional; 3D: Three-dimensional; BMP: Bitmap image file; CC0: Creative Commons 0 1.0 public domain dedication; DOI: Digital object identifier; FTP: File Transfer Protocol; GigaDB: GigaScience Database; GNU: GNU\u2019s not unix; gzip: GNU zip; MCZ IZ: Museum of Comparative Zoology Invertebrate Zoology; \u03bcCT: Micro-computed tomography; PTA: Phosphotungstic acid; RAM: Random access memory; ROI: region of interest; TIFF: Tagged image file format; VOI: Volume of interest.The authors declare that they have no competing interests.Conceived and designed the experiments: JL SK RF AZ. Performed the experiments: JL SK RF. Analyzed the data: JL SK RF AZ. Contributed reagents/materials/analysis tools: JL SK RF GG AZ. Wrote the paper: JL SK RF GG AZ. All authors read and approved the final manuscript."}
+{"text": "There is an error in reference 71. The correct reference is: Abele, AE. The dynamics of masculine-agentic and feminine-communal traits: Findings from a prospective study. Journal of Personality and Social Psychology. 2003; 85: 768\u2013776."}
+{"text": "AbstractCamponotusparabarbatus sp. n. Presence of dense, short setae on gena and ventral surface of head resembles it most to Camponotusbarbatus Roger, 1863 distributed in Southeast Asia. A regional identification key of Camponotus species is provided from the Shivalik hills of Indian Himalaya.A new species of carpenter ant, collected in the Shivalik range of Himalaya is described and illustrated based on the worker and gyne castes under the name  Camponotus are known worldwide  software. These images were processed with Adobe Photoshop CS5. Holotype and paratypes have been deposited in PUPAC, Punjabi University Patiala Ant Collection, Patiala. One paratype will be deposited at BMNH, Natural History Museum, London, UK and one at California Academy of Sciences, San Francisco, USA. Morphological definitions for measurements (accurate to 0.01 mm) include:  \u2013 HL+ML+PL+GLTL; (Head Length) \u2013 length of head, excluding mandibles, measured in a straight line from anteriormost point of median clypeal margin to midpoint of occipital margin in full-face viewHL; (Head Width) \u2013 maximum width of head, measured in full-face viewHW; (Eye Length) \u2013 maximum length of eye as measured in oblique view of the head to show full surface of eyeEL; (Scape Length) \u2013 straight-line length of antennal scape excluding condylar bulbSL; (Mesosoma Length) \u2013 diagonal length of mesosoma in lateral view from the point at which pronotum meets cervical shield to posteroventral corner of mesosomaML; (Pronotum Width) \u2013 maximum width of pronotum in dorsal viewPW; (Petiole Length) \u2013 In profile, the maximum length of the petiole node, measured in a straight horizontal line from immediately above the dorsal base of the anterior petiolar tubercle to the posterior marginPL; (midtibia Length) \u2013 maximum length of midtibia in lateral view, with tibial base and apex in the same plane of focus, and with tibia at right angle to femurmTbL; (hindtibia Length) \u2013 maximum length of hindtibia in lateral view, with tibial base and apex in same plane of focus, and with tibia at right angle to femurhTbL; \u2013 length of the gaster in lateral view from the anteriormost point of first gastral segment to the posteriormost point of the last segmentGL.Bharti & Wachkoo, 2014sp. n.urn:lsid:zoobank.org:act:2A5E348D-3C27-4194-B147-9CACF67854CFType status:Holotype. Occurrence: recordedBy: Aijaz A. Wachkoo; individualCount: 1; sex: worker; Location: country: India; stateProvince: Himachal Pradesh; locality: Rewalsar; verbatimElevation: 1360 m; verbatimLatitude: 31.6345\u00b0N; verbatimLongitude: 76.8343\u00b0EType status:Paratype. Occurrence: recordedBy: Aijaz A. Wachkoo; individualCount: 5; sex: 2 workers, 3 gynes; Location: continent: Asia; country: India; stateProvince: Himachal Pradesh; locality: Rewalsar; verbatimElevation: 1360 m; verbatimLatitude: 31.6345\u00b0N; verbatimLongitude: 76.8343\u00b0EType status:Paratype. Occurrence: recordedBy: Aijaz A. Wachkoo; individualCount: 6; sex: workers; Location: continent: Asia; country: India; stateProvince: Uttarakhand; verbatimElevation: 640 m; verbatimLatitude: 30.3416\u00b0N; verbatimLongitude: 77.9903\u00b0E; Record Level: institutionCode: Forest Research InstituteType status:Paratype. Occurrence: recordedBy: Aijaz A. Wachkoo; individualCount: 8; sex: workers; Location: continent: Asia; country: India; stateProvince: Uttarakhand; locality: Rajaji Forest Area; verbatimElevation: 660 m; verbatimLatitude: 30.2483\u00b0N; verbatimLongitude: 77.9878\u00b0EDescription of worker .Head: Head subtriangular, longer than wide in major worker , with arched margins laterally, posterior margin shallowly concave .As in major worker, with modifications expected for caste and the following differences: head more elongate, sides relatively straight, occipital margin convex; mandible, clypeus and gena brownish. Head narrower than in conspecific major workers; mandible 7 toothed; scape barely reaches the posterior margin of head. Reticulate sculpture more pronounced on head; scutum with scattered wide, shallow punctures. Propodeum dorsum forms right angle with declivity.parabarbatus is a compound word meaning \u201csimilar to barbatus\u201d.The species epithet This species seems to be rare in the Shivalik range of Northwest Himalaya although collected from both forested and non-forested areas of the region. Most workers were collected from vegetation while gynes and some workers were found under a large stone.Camponotusparabarbatus resembles to the Camponotusbarbatus distributed in Southeast Asia (Camponotusparabarbatus is subtriangular with a shallowly concave posterior margin, the eyes well within the lateral cephalic margins, and the scape barely touches the posterior margin of head, while in Camponotusbarbatus majors the head is subrectangular with gently convex posterior margin, eyes almost touching the lateral cephalic margins, scape surpasses the posterior margin of head by about 0.25 of its length. In Camponotusparabarbatus minor workers, the scape surpasses the posterior margin of head by about 0.33 of its length, whilst in Camponotusbarbatus the scape does so by half its length. Additionally, Camponotusparabarbatus is uniformly jet-black whereas Camponotusbarbatus is red brown in color.ast Asia  but can"}
+{"text": "There are errors in the Author Contributions. The correct contributions are: Conceived and designed the experiments: ANJ. Performed the experiments: ANJ. Analyzed the data: ANJ CPU. Contributed reagents/materials/analysis tools: ESG. Wrote the manuscript: ANJ."}
+{"text": "Scientific Reports5: Article number: 1601910.1038/srep16019; published online: 11022015; updated: 01072016.The original version of this Article contained a typographical error in the spelling of the author Mengtao Sun, which was incorrectly given as Mentao Sun. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Nature Communications 6: Article number: 894810.1038/ncomms9948 (2015); Published: 11132015; Updated: 06062015.Imin using a simple parabolic \u03ba(E) WKB approximation, one would extract a much smaller bandgap since Imin is severely underestimated.'This Article contains an error in the penultimate sentence of the penultimate paragraph. This sentence should read: \u2018In other words, if one would analyse the minimum current level"}
+{"text": "Scientific Reports5: Article number: 1121710.1038/srep11217; published online: 06162015; updated: 09212015The original version of this Article contained a typographical error in the spelling of the author Huanyang Chen, which was incorrectly given as Huangyang Chen. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Nature Communications6: Article number: 8963 10.1038/ncomms9963 (2015); Published: 11252015; Updated: 02012016The original version of this Article contained a typographical error in the spelling of the author Chang-Hsiao Chen, which was incorrectly given as Chiang-Hsiao Chen. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "AbstractLaonastesaenigmamus Jenkins, Kilpatrick, Robinson & Timmins, 2005 was originally discovered in Lao People's Democratic Republic in 2005. This species has been recognized as the sole surviving member of the otherwise extinct rodent family Diatomyidae. Laonastesaenigmamus was initially reported only in limestone forests of Khammouane Province, Central Lao. A second population was recently discovered in Phong Nha Ke Bang National Park (PNKB NP), Quang Binh Province, Central Vietnam in 2011. The confirmed distribution range of L.aenigmamus in Vietnam is very small, approximately 150 km2, covering low karst mountains in five communes of Minh Hoa District, Quang Binh Province, at elevations between 250 and 400 m asl. The Laotian Rock Rat inhabits the lower part of steep karst towers with many rock boulders and crevices under tall limestone evergreen forest. They use small rock crevices for their dens. The natural habitat of this species in PNKB NP has been affected by selected timber harvesting, however, a complex 3-4 layer forest structure is retained. The Laotian Rock Rat is omnivorous, feeding on parts  of 18 plant species and also some insects . The population of this species in PNKB NP is seriously threatened with extinction due to its very restricted distribution, high hunting pressure, and habitat disturbance. Laonastesaenigmamus is listed in the IUCN Red List as endangered and in the Wildlife and Aquatic Red List of Lao, however, this species has not been listed in the Red Data Book or any conservation legislative documents of Vietnam.The Laotian Rock Rat  Laonastesaenigmamus, was first discovered in 2005 in Lao People's Democratic Republic  of Minh Hoa District, Quang Binh Province. These communes were selected because only these communes contain primary or little affected limestone forest as preferable habitat of the Laotian Rock Rat and are situated close to locality where the first Vietnamese specimens of Laotian Rock Rat were collected in 2011. During the village interview survey, all previously trapped animals of Laotian Rock Rat or their remains were collected for further laboratory studies.Based on the results of our village interview survey, 12 areas where local villagers have previously trapped the Laotian Rock Rat were selected for targeted field surveys using cage traps and box traps. After taking morphological characters, all live-trapped animals were released back into the wild at the place where they were trapped. Study of Laotian Rock Rat habitat was carried out in the same 12 areas using transect survey and plot survey techniques. Plots of 10 x 10 m were used for inventory of all trees with height more than 3m, plots of 4 x 4 m for inventory of bush trees of height from 0.5 m to 3 m, and plots of 1 x 1 m for inventory of herbs and tree seedlings less than 0.5 m high.Food items of the Laotian Rock Rat were identified by examining the stomach contents of 10 preserved specimens, food remnants found in the species dens, and observation of live specimens in semi-wild conditions in natural habitat. Food identification was conducted by taxonomic experts based on morphological characters of food item remains. Threats to population and habitat of Laotian Rock Rat were evaluated based on interviews of local villagers and direct observation of threat signs  in the species distribution area.Jenkins, Kilpatrick, Robinson & Timmins, 2005Type status:Other material. Occurrence: recordedBy: Nghia Xuan Nguyen; individualCount: 1; sex: male; Location: country: Vietnam; stateProvince: Quang Binh; verbatimLocality: Thuong Hoa Commune, Minh Hoa District; verbatimElevation: 200-350m; verbatimLatitude: 17\u00b040\u201939\u2019'N; verbatimLongitude: 105\u00b057\u201922\u2019\u2019E; Event: samplingProtocol: trapping; eventDate: 6 Sept 2011; habitat: Karst forest; Record Level: collectionID: PNKB-NXN21; institutionCode: IEBR; collectionCode: RodentiaDVZ-Type status:Other material. Occurrence: recordedBy: Nghia Xuan Nguyen; individualCount: 1; sex: unkown; Location: country: Vietnam; stateProvince: Quang Binh; verbatimLocality: Thuong Hoa Commune, Minh Hoa District; verbatimElevation: 200-350m; verbatimLatitude: 17\u00b040\u201905\u2019'N; verbatimLongitude: 105\u00b056\u201927\u2019\u2019E; Event: samplingProtocol: trapping; eventDate: 3 Sept 2011; habitat: Karst forest; Record Level: collectionID: PNKB-NXN232; institutionCode: IEBR; collectionCode: RodentiaDVZ-Type status:Other material. Occurrence: recordedBy: Nghia Xuan Nguyen; individualCount: 1; sex: unkown; Location: country: Vietnam; stateProvince: Quang Binh; verbatimLocality: Thuong Hoa Commune, Minh Hoa District; verbatimElevation: 200-350m; verbatimLatitude: 17\u00b040\u201955\u2019'N; verbatimLongitude: 105\u00b054\u201940\u2019\u2019E; Event: samplingProtocol: trapping; eventDate: 7 April 2012; habitat: Karst forest; Record Level: collectionID: PNKB-NXN231; institutionCode: IEBR; collectionCode: RodentiaDVZ-Type status:Other material. Occurrence: recordedBy: Nghia Xuan Nguyen; individualCount: 1; sex: unkown; Location: country: Vietnam; stateProvince: Quang Binh; verbatimLocality: Thuong Hoa Commune, Minh Hoa District; verbatimElevation: 200-350m; verbatimLatitude: 17\u00b040\u201932\u2019'N; verbatimLongitude: 105\u00b057\u201952\u2019\u2019E; Event: samplingProtocol: trapping; eventDate: 22 December 2013; habitat: Karst forest; Record Level: collectionID: PNKB-NXN181; institutionCode: IEBR; collectionCode: RodentiaDVZ-Type status:Other material. Occurrence: recordedBy: Nghia Xuan Nguyen; individualCount: 1; sex: Male; Location: country: Vietnam; stateProvince: Quang Binh; verbatimLocality: Thuong Hoa Commune, Minh Hoa District; verbatimElevation: 200-350m; verbatimLatitude: 17\u00b040\u201907\u2019'N; verbatimLongitude: 105\u00b056\u201906\u2019\u2019E; Event: samplingProtocol: trapping; eventDate: 12 April 2014; habitat: Karst forest; Record Level: collectionID: PNKB-NXN219; institutionCode: IEBR; collectionCode: RodentiaDVZ-Type status:Other material. Occurrence: recordedBy: Nghia Xuan Nguyen; individualCount: 1; sex: Female; Location: country: Vietnam; stateProvince: Quang Binh; verbatimLocality: Thuong Hoa Commune, Minh Hoa District; verbatimElevation: 200-350m; verbatimLatitude: 17\u00b040\u201927\u2019'N; verbatimLongitude: 105\u00b055\u201905\u2019\u2019E; Event: samplingProtocol: trapping; eventDate: 15 April 2014; habitat: Karst forest; Record Level: collectionID: Released to the wildType status:Other material. Occurrence: recordedBy: Nghia Xuan Nguyen; individualCount: 1; sex: Female; Location: country: Vietnam; stateProvince: Quang Binh; verbatimLocality: Thuong Hoa Commune, Minh Hoa District; verbatimElevation: 200-350m; verbatimLatitude: 17\u00b040\u201903\u2019'N; verbatimLongitude: 105\u00b056\u201927\u2019\u2019E; Event: samplingProtocol: trapping; eventDate: 15 April 2014; habitat: Karst forest; Record Level: collectionID: PNKB-NXN223; institutionCode: IEBR; collectionCode: RodentiaDVZ-Type status:Other material. Occurrence: recordedBy: Nghia Xuan Nguyen; individualCount: 1; sex: Female; Location: country: Vietnam; stateProvince: Quang Binh; verbatimLocality: Thuong Hoa Commune, Minh Hoa District; verbatimElevation: 200-350m; verbatimLatitude: 17\u00b040\u201903\u2019'N; verbatimLongitude: 105\u00b056\u201927\u2019\u2019E; Event: samplingProtocol: trapping; eventDate: 18 April 2014; habitat: Karst forest; Record Level: collectionID: PNKB-NXN224; institutionCode: IEBR; collectionCode: RodentiaDVZ-Type status:Other material. Occurrence: recordedBy: Nghia Xuan Nguyen; individualCount: 1; sex: Female; Location: country: Vietnam; stateProvince: Quang Binh; verbatimLocality: Thuong Hoa Commune, Minh Hoa District; verbatimElevation: 200-350m; verbatimLatitude: 17\u00b040\u201939\u2019'N; verbatimLongitude: 105\u00b057\u201934\u2019\u2019E; Event: samplingProtocol: trapping; eventDate: 5 May 2014; habitat: Karst forest; Record Level: collectionID: PNKB-NXN225; institutionCode: IEBR; collectionCode: RodentiaDVZ-Type status:Other material. Occurrence: recordedBy: Nghia Xuan Nguyen; individualCount: 1; sex: Male; Location: country: Vietnam; stateProvince: Quang Binh; verbatimLocality: Thuong Hoa Commune, Minh Hoa District; verbatimElevation: 200-350m; verbatimLatitude: 17\u00b041\u201913\u2019'N; verbatimLongitude: 105\u00b053\u201951\u2019\u2019E; Event: samplingProtocol: trapping; eventDate: 27 June 2014; habitat: Karst forest; Record Level: collectionID: PNKB-NXN230; institutionCode: IEBR; collectionCode: RodentiaDVZ-Fig. 1Fig. 217\u00b040'28\u201dN; 105\u00b055'05\"E). This low trapping success can be explained by very low density of the Laotian Rock Rat in the survey area and because of dry season weather. As reported by local villagers, small mammal trapping success is always very low in dry season (from January to June). The live animal was released into the wild after taking its body measurements and monitoring it for a few days in semi-wild conditions. In total, during the period from the first reports of the Laotian Rock Rat in PNKB NP in September 2011 to October 2014, we collected 12 specimens of the species  and checked coordinates of all these localities for the species distribution mapping. The distribution map of the Laotian Rock Rat was established based on data from the village interview surveys comprising 35 localities reported by villagers and 12 localities confirmed by our field surveys. The map showed that the distributional range of the Laotian Rock Rat in PNKB NP area covered about 150 km2 of limestone evergreen forests belonging to five communes  of Minh Hoa District, Quang Binh Province , Hoa Son commune  and Dan Hoa commune  , Dracontomelonduperreanum (Anacardiaceae), Toonasurenii (Meliaceae), Paviesiaanamensis (Sapindaceae), Pterospermumgrewiaefolium (Sterculiaceae), Mahuca sp., Hopea sp., Streblusasper (Moraceae), Litsea sp. (Lauraceae), Sumbaviopsismacrophylla (Euphorbiaceae), Actinodaphne sp. (Lauraceae), Pometiachinensis (Sapindaceae), Choerospondiasaxillaris (Anacardiaceae), Alangiumridleyi (Alangiaceae), Knema sp. (Myristicaceae); etc.The canopy tree layer consists of trees 20-25 m high with stem diameter 0.5-0.8 m. The most common trees species are: Knemacorticosa (Myristicaceae); Streblustonkinensis, Streblusasper (Moraceae), Xylopiavielana (Annonaceae), Diospyros sp. (Ebenaceae), Caryotamitis (Arecaceae), Arengapinnata (Arecaceae), Camelia sp. (Theaceae), Actinodaphne sp. (Lauraceae), Pterospermum sp. (Sterculiaceae), Litsea sp.(Lauraceae), Ormosialaoensis (Fabaceae), Nepheliumlappaceum (Sapindaceae), Sumbaviopsismacrophylla (Euphorbiaceae), Paranepheliumspirei (Sapindaceae), Alangiumridleyi (Alangiaceae), Baccaurea sp. (Euphorbiaceae), Aglaia sp. (Meliaceae), etc.The middle tree layer consists of trees 10-15 m high with stem diameter of 0.3-0.5 m. The most common species are Euphorbiaceae, Theaceae, Myrtaceae and Verbenaceae. Some dominant species are Antidesma sp. (Euphorbiaceae), Trevesiapanmalta , Litseavaliabilis (Lauraceae), Arengapinnata (Arecaceae), Excoecariacochinchinensis (Euphorbiaceae), as well as seedlings of trees from higher layers.The scrub layer consists of trees 3-7 m high, mostly with twisted stems, many branches, and several stems rising from one base. The most common species are from the families Araceae, the genera Calamus and Caryota (family Arecaceae), and many herb species from various families . Some of the most common species are Homalomenaocculta (Araceae), Aglaonemasimplex (Araceae), Aglaonemasiamensis (Araceae), Taccachantrieri (Taccaceae), Aspidistratypica , Piper sp. (Piperaceae), Corymborkisveratrifolia (Orchidaeceae), etc.The herb and fern layer is about 0.5-3 m high, with trees of 0.2-3 m high from family Local villagers reported that the Laotian Rock Rat feeds exclusively on plant parts  of various plant species. Stomach content analysis, examination of food remains dropped in dens, and observation of a live Laotian Rock Rat in semi-wild conditions showed that the species feeds mostly on plant parts, but also some insects, as follows:Aglaonemasimplex (Araceae), Streblusasper (Moraceae), Dracontomelonduperreamum (Anacardiaceae), Pometiachinensis (Sapindaceae), Ficus sp. (Moraceae), Acanthopanaxtrifoliatus , Perillafrutescens (Lamiaceae), Psidiumguajava (Myrtaceae), Zeamays (Poaceae), Prunuspersica (Rosaceae)Young leaves and buds of Streblusasper (Moraceae), Ficus sp. (Moraceae), Dracontomelonduperreamum (Anacardiaceae), Alangiumridleyi (Alangiaceae), Lythocarpusfenestratus (Fagaceae), Musaparadisiaca, Musauranoscapos (Musaceae)Ripe fruits of Zeamays (Poaceae)Seeds of Manihotesculenta (Euphorbiaceae) and Aglaonemasimplex (Araceae)Roots of Cicadidae), Mantis (Mantidae), Grasshopper (Acrididae)Insects: Cicada (2) and located close to the villages of ethnic minorities . These minority groups are very poor and their livelihood depends on wildlife and forest products. Wildlife hunting is a long tradition of the local people, and a practice that remains extensive currently. Most men 15 to 60 years in age in these villages are engaged in wildlife hunting. Their hunting season lasts about eight months per year (from July to February). The most widely used means for trapping the Laotian Rock Rat and other small animals is a metal spring snare, which has a high trapping success and can trap animals of various body size, such as rats, civets, large birds, and snakes. Snap traps are also used because they are easily made in the forest from bamboo and small trees. Each hunter usually keeps 30-100 active snares in forests; some hunters keep up to 300-500 active snares. It is estimated that 30-35 specimens of the Laotian Rock Rat are trapped by local villagers each year in the survey area. Other threats to the natural habitat of the Laotian Rock Rat include forest clearance for agricultural fields, removal of timber trees, collecting firewood and other forest products that lead to degradation of forest quality, and habitat modification. At present, no specific conservation measures are being undertaken aside from awareness education for local villagers.The distribution range of the Laotian Rock Rat in PNKB NP is very small  of Lao. It is expected that this area harbors the Laotian Rock Rat, but no surveys on rodents in this area were carried out.The confirmed distribution of the Laotian Rock Rat population in PNKB NP comprises roughly 150 km2. The species was most abundant in Phou Hin Boun NBCA, while in two nearby limestone areas (Nam Kading NBCA to the north and Hin Namno NBCA to the east) there are no reports of the species. The distribution of the Laotian Rock Rat in PNKB NP, Vietnam is small and far away from Phou Hin Boun NBCA as well as the species distribution range in Khammuoane province. This implies that the population of the Laotian Rock Rat in PNKB NP may be genetically isolated from other populations in Lao and conservation measures for the Vietnamese population should be of high priority and urgency.In Lao, HabitatPNKB NP is located along the eastern slope of the Great Annamite Range which has a wetter climate. The forest habitat of PNKB NP is characterized by dense moist evergreen forest with different types such as evergreen forest on limestone above 700 m asl, montane evergreen forest on hills above 700 m asl, evergreen forest on limestone under 700 m asl, evergreen forest on hills under 700 m asl, degraded evergreen forest on hills, tree and scrub savanna on limestone, tree and scrub savanna on hills, agricultural land, and plantations and other land uses . HoweverThreats and conservationDiatomyidae that was formerly believed to have been extinct for more than 11 million years (Conservation of the Laotian Rock Rat is a high priority not only because the species is the only surviving member of the otherwise extinct family on years  but alsoon years  and in ton years  for cons"}
+{"text": "Scientific Reports5: Article number: 9847; 10.1038/srep09847 published online: 06032015; updated: 12182015.The original version of this Article contained a typographical error in the spelling of the author Yeon-Gil Kim which was incorrectly given as Yeun Gil Kim.This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports5 Article number: 10179; 10.1038/srep10179 published online: 07102015; updated: 12182015.The original version of this Article contained an error in the spelling of the author Wen-cai Ye, which was incorrectly given as Ye Wencai.This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports5: Article number: 17487; 10.1038/srep17487 published online: 12032015; updated: 02172016.The original version of this Article contained a typographical error in the spelling of the author Corrado Corradi-Dell\u2019Acqua which was incorrectly given as Corrado Corradi-Dell\u2019 Acqua. This error has been corrected in both the PDF and HTML versions of the paper."}
+{"text": "Scientific Reports6: Article number: 25763; 10.1038/srep25763published online: 05102016; updated: 08252016In the original version of this Article, Affiliation 1 was incomplete. The correct affiliation is listed below:State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.This error has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports1: Article number: 18510.1038/srep00185; published online: 12072011; updated: 09182015The original version of this Article contained a typographical error in the spelling of the author Lesego Busang which was incorrectly given as Lesogo Busang. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports5: Article number: 1291410.1038/srep12914; published online: 09032015; updated: 09302015The original version of this Article contained a typographical error in the spelling of the author Xavier Rocquefelte, which was incorrectly given as Xavier Rocquelfelte. In addition, Affiliation 2 was omitted for this author. These errors have now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "The following information is missing from the Funding section: The study also used resources from the Department of Pathology/Comparative Medicine, Wake Forest University Health Science which were supported by NIH grant RR019963/OD010965 (PI: Jay R. Kaplan)."}
+{"text": "Scientific Reports6: Article number: 18970; 10.1038/srep18970published online: 01062016; updated: 03042016The original version of this Article contained a typographical error in the spelling of the author Bharati Tudu, which was incorrectly given as Bahrati Tudu. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Nature Communications7: Article number: 11521 10.1038/ncomms11521 (2016); Published: 0592016; Updated: 06072016The HTML version of this Correspondence was previously published with an incomplete title. This has now been corrected in the HTML; the PDF version of the paper was correct from the time of publication."}
+{"text": "There are errors in the Author Contributions. The correct contributions are: Conceived and designed the device: DMassai GC GI DG UM. Conceived and performed the computational multiphysics modeling: GI DMassai UM DG. Conceived and performed the biological tests: DMadeddu AF CF FQ DMassai GC. Analyzed the computational multiphysics modeling data: GI DMassai UM DG MAD. Analyzed the biological data: DMadeddu CF AF FQ. Contributed reagents/materials/analysis tools: FQ AA GFDL UM. Conceived and wrote the manuscript: DMassai GI UM DMadeddu FQ. The publisher apologizes for the errors."}
+{"text": "Scientific Reports6: Article number: 21413;10.1038/srep21413 Published online 02252016; Updated: 05092016A marked-up version of the Supplementary Information was inadvertently published with the original version of this Article. In addition, Supplementary Software 1 was omitted. These errors have now been corrected."}
+{"text": "In November 2013, CEGMR continued its leading role in genomics and organized its 2nd IGMC. The conference was well received and attended by 505 international and national participants. Among the international participants was Professor Erwin Neher, a Nobel laureate with Bert Sakmann in 1991 in Physiology or Medicine, who gave the keynote talk on the first day of the conference on his discovery of \u201cThe function of single ion channels in cells\u201d with notes on their function and role in disease. His presence and talk was an excellent opportunity for junior and senior national researchers in Saudi Arabia to meet and learn from a scientific pioneer.Centre of Excellence in Genomic Medicine Research  , is a lend IGMC scientific committee led by Dr Muhammad Abu-Elmagd worked tirelessly hard and managed, for the first time ever for the conference, to publish 98 IGMC abstracts and more than 24 peer-reviewed full articles in two separate special supplements in a high impact factor (IF) journal in the field, the BMC Genomics (IF: 4.04) [The 2nd IGMC program, Table . Abstracts of all oral presentations are now published in BMC Genomics special supplement [Oral presentation sessions started with a talk given by Dr Abdulaziz Al-Swailem from KCAST who elaborated on Saudi national science, technology and innovation plans towards knowledge based economy. After Dr Al-Swailem\u2019s presentation, the conference participants enjoyed attending a series of 17 two days excellent talks presented by Thomson Reuters\u2019s ranked highly distinguished scientists who came from various institutions around the globe to deliver presentations in different topics. The latter mainly covered five genomics and genomic-related areas including oncogenomics, genomics and environment interactions, systems biology and computational genomics, immunogenomics, and omics of cell signalling and reproductive biology , where we not only enjoyed tasty and spicy Saudi food, but also had a chance to inspect his remarkable facility for keeping desert wildlife.''APC: Adenomatous Polyposis Coli; BMC: BioMed Central; CEGMR: Center of Excellence in Genomic Medicine Research; ChIP-Seq: Chromatin Immuno-precipitation Sequencing; CIPM: Centre of Innovation in Personalized Medicine; CMV: Cytomegalovirus; CRC: Colorectal Cancer; ENCODE: Encyclopedia of DNA Elements; IF: Impact Factor; IGB: Integrated Gulf Biosystem; IGMC: International Genomic Medicine Conference; KAU: King Abdulaziz University; KACST: King Abdulaziz City for Science and Technology; KIFs: Kinesin superfamily proteins; Kras: Kirsten rat sarcoma viral oncogene homolog; KSA: Kingdom of Saudi Arabia; MOH: Ministry Of Higher Education; MTNR1B: Melatonin Receptor 1B; STSs: Sequence-Tagged SitesThe authors disclose no competing interests."}
+{"text": "Scientific Reports5: Article number: 1420010.1038/srep14200; published online: 09232015; updated: 02042016In this Article, an additional affiliation for Qian Liu and Xinyi Zhu was omitted. The correct affiliation is listed below:University of Chinese Academy of Sciences, Beijing 100101, China"}
+{"text": "The correct listing for corresponding author contact information in the PDF should be: *Email: licy_60@163.com (CYL); liuqiyong@icdc.cn (QYL).The email address for one of the corresponding authors, Cheng-Yi Li, is listed incorrectly. The correct email address should be"}
+{"text": "The correct name is: Bertrand Raynal. The correct citation is: Alexandre T, Raynal B, Munier-Lehmann H (2015) Two Classes of Bacterial IMPDHs according to Their Quaternary Structures and Catalytic Properties. PLoS ONE 10(2): e0116578. doi: There is an error in the Author Contributions. The correct contributions are: Conceived and designed the experiments: HML. Performed the experiments: TA BR HML. Analyzed the data: TA BR HML. Contributed reagents/materials/analysis tools: BR HML. Wrote the paper: BR HML."}
+{"text": "Nature Communications7: Article number: 1146310.1038/ncomms11463 (2016); Published: 05102016; Updated: 08042016.The source of reagents for this Article was not fully acknowledged. The Acknowledgements should have included the following:https://www.cellhub.org) for patient fibroblasts.'\u2018We thank Professors Robin Goland and Dieter Egli ("}
+{"text": "Scientific Reports5: Article number: 984610.1038/srep09846; published online: 04202015; updated: 10052015This Article contains an error in the affiliation of Daesung Yoon. The correct affiliation is listed below:Department of Bio-convergence Engineering, Korea University, Seoul, Korea"}
+{"text": "Nature Communications 7: Article numbber:1069910.1038/ncomms10699 (2015); Published: 03072016; Updated: 07192016.Technical support for this Article was not fully acknowledged. The Acknowledgements should have included the following: We are also grateful to Dr Alexei Barinov for his kind help during our beamtime at the spectramicroscopy beamline of the Elettra synchrotron."}
+{"text": "In a Belgian pilot study honey bee wax combs from ten hives were analyzed on the presence of almost 300 organochlorine and organophosphorous compounds by LC\u2013MS/MS and GC\u2013MS/MS. Traces of 18 pesticides were found and not a single sample was free of residues. The number of residues found per sample ranged from 3 to 13, and the pesticides found could be categorized as (1) pesticides for solely apicultural (veterinary) application, (2) pesticides for solely agricultural (crop protection) application, (3) pesticides for mixed agricultural and apicultural (veterinary) application. The frequencies and quantities of some environmental pollutants bear us high concerns. Most alarming was the detection of lindane (gamma-HCH) and dichlorodiphenyltrichloroethane (including its breakdown product dichlorodiphenyldichloroethylene), two insecticides that are banned in Europe. The present comprehensive residue analysis, however, also reveals residues of pesticides never found in beeswax before, i.e. DEET, propargite and bromophos. Varroa destructor with synthetic chemicals, like pyrethroid and organophosphate acaricides, naturally occurring organic acids and essential oils  [Regulation (EC) No 396/2005]. Although the contamination of honey is widely documented in the scientific literature . It should allow us to narrow the scope of future nationwide surveys.During hive control in spring 2012, wax combs were sampled from ten honey bee hives at apiaries located in Flanders at Heist-op-den-Berg (six samples), Leuven (three samples) and Ghent (one sample). As at least 100\u00a0g beeswax was required for the multiresidue analysis, we took two empty wax combs from each hive. The sampled bee colonies seemed healthy, with no clinical signs of infectious diseases or acute intoxication.The beeswax was analyzed on the presence of 293 organochlorine and organophosphorous compounds at Intertek Food Services GmbH  according to the European EN 15662 method CEN . The pesThe LC\u2013MS/MS procedure enables to determine the following agents: Abamectin; Acetamiprid; Aldicarb; Aldicarb sulfone; Aldicarb sulfoxide; Amitraz; Azoxystrobin; Benalaxyl; Bitertanol; Boscalid; Bromacil; Bromuconazole; Bupirimate; Buprofezin; Cadusafos; Carbaryl; Carbendazim; Carbofuran; Carbofuran (3-Hydroxy-); Chloroxuron; Clofentezine; Clomazone; Clothianidin; Cymiazole; Cyproconazole; Cyprodinil; Demeton-S-methyl; Demeton-S-methyl; Diethofencarb; Diethyltoluamid (DEET); Difenoconazole; Diflubenzuron; Dimethoate; Dimethomorph; Dimoxystrobin; Diniconazole; Diphenylamine; Disulfoton; Disulfoton-PS-sulfone; Disulfoton-PS-sulfoxide; Ditalimfos; Diuron; Dodine; EPN; Epoxiconazole; Ethiofencarb; Ethoprophos; Ethoxyquin; Famoxadone; Fenamiphos; Fenarimol; Fenazaquin; Fenbuconazole; Fenhexamid; Fenoxycarb; Fenpropimorph; Fenpyroximate; Fenthion; Fenthion-oxon; Fenthion-PO-sulfone; Fenthion-PS-sulfone; Fenthion-sulfoxide; Fluazifop-P-butyl; Fluazinam; Fludioxonil; Flufenoxuron; Fluquinconazole; Flusilazole; Fonofos; Hexaconazole; Hexythiazox; Imazalil; Imidacloprid; Indoxacarb; Iprovalicarb; Isofenphos; Isofenphos-methyl; Isoproturon; Kresoxim-methyl; Linuron; Lufenuron; Malaoxon; Malathion; Mecarbam; Mepanipyrim; Mepronil; Metalaxyl; Metamitron; Metazachlor; Methiocarb; Methiocarb; Methiocarb; Methomyl; Methoxyfenozide; Metobromuron; Metolcarb; Metribuzin; Monolinuron; Myclobutanil; Nitenpyram; Nuarimol; Omethoate; Oxadixyl; Oxamyl; Oxydemeton-methyl; Penconazole; Pencycuron; Pirimicarb; Pirimicarb (Desmethyl-); Prochloraz; Propamocarb; Propargite; Propiconazole; Propoxur; Propyzamide; Pymetrozine; Pyraclostrobin; Pyridaben; Pyridaphenthion; Pyrifenox; Pyrimethanil; Pyriproxyfen; Quinoxyfen; Rotenone; Spinosad; Spirodiclofen; Spiromesifen; Spiroxamine; Tebuconazole; Tebufenozide; Tebufenpyrad; Teflubenzuron; Terbutylazine; Tetraconazole; Thiabendazole; Thiacloprid; Thiametoxam; Thiodicarb; Thiophanate-methyl; Triadimefon; Triadimenol; Trichlorfon; Trifloxystrobin; Triflumizole; Triforine.The GC\u2013MS/MS procedure enables to determine the following agents: Aclonifen; Acrinathin; Alachlor; Aldrin; Benfluralin; Bifenthrin; Binapacryl; Bromophos (-methyl); Bromophos-ethyl; Bromopropylate; Captan; Carbophenothion; Chlordane ; Chlordane (Oxy); Chlordane ; Chlorfenapyr; Chlorfenson; Chlormephos; Chlorobenzilate; Chloroneb; Chloropropylate; Chlorothalonil; Chlorpropham; Chlorpyrifos (-ethyl); Chlorpyrifos-methyl; Chlorthal-dimethyl; Chlorthion; Chlorthiophos; Chlozolinate; Coumaphos; Cyanofenphos; Cyanophos; Cyfluthrin; Cyhalothrin (lambda-); Cypermethrin; DDD ; DDD ; DDE ; DDE ; DDT ; DDT ; Deltamethrin; Diazinon; Dichlobenil; Dichlofenthion; Dichlofluanid; Dicloran; Dicofol; Dieldrin; Endosulfan ; Endosulfan (beta-); Endosulfan-sulfat; Endrin; Esfenvalerate; Ethion; Etofenprox; Etridiazole; Etrimfos; Famphur; Fenchlorphos; Fenitrothion; Fenpropathrin; Fenson; Fensulfothion; Fenvalerate; Fluchloralin; Flucythrinate; Fluvalinate,; Folpet; Formothion; Halfenprox; HCH ; HCH (beta-); HCH (delta-); Heptachlor; Heptachlor epoxide ; Heptachlor epoxide ; Heptenophos; Hexachlorobenzene (HCB); Hexaflumuron; Iodofenphos; Iprobenfos; Iprodione; Isazofos; Isocarbofos; Isodrin; Isoxathion; Leptophos; Lindane (gamma-HCH); Methacrifos; Methidathion; Methoxychlor; Mevinphos; Mirex; Monocrotophos; Nitrapyrin; Nitrofen; o-Phenylphenol; Paraoxon-ethyl; Paraoxon-methyl; Parathion-ethyl; Parathion-methyl; Pendimethalin; Pentachloroaniline; Pentachloroanisole; Permethrin; Phenthoate; Phorate; Phorate-sulfone; Phosalone; Phosmet; Phosphamidon; Piperonyl butoxide; Pirimiphos-ethyl; Pirimiphos-methyl; Procymidone; Profenofos; Profluralin; Propetamphos; Prothiophos; Pyrazophos; Quinalphos; Quintozene; S 421 (octachlorodipropyl ether); Sulfotep; Sulprofos; Tecnazene; Tefluthrin; Terbufos; Tetrachlorvinphos; Tetramethrin; Tetradifon; Tetrasul; Thionazin; Tolclofos-methyl; Tolylfluanid; Triallate; Triazophos; Trichloronat; Trifluralin; Vinclozolin.Both procedures enables to determine the following agents: Acephate; Azinphos-ethyl; Azinphos-methyl; Chlorfenvinphos; Dichlorvos; Fipronil; Methamidophos.Traces of 18 pesticide residues were found in the beeswax samples and not a single sample was free from pesticide residues   and Perizin . However, illegal sales of prescription drugs or the use of home-made preparations based on the agrochemical formulations cannot be excluded.Amitraz was found in two out of ten samples and could originate from both apicultural and agricultural applications in the past. Both applications are presently no longer allowed in Belgium. Since this acaricide was proven to be unstable in beeswax and honey  with no MRL required in food from these animals [Commission Regulation (EU) No 37/2010]. In theory piperonyl butoxide could be allowed to be used in beekeeping upon prescription of a veterinarian under \u2018cascade\u2019. The use of this pesticide in beekeeping cannot be excluded: it is sometimes used in insect and bee repellents which are on the market for use in beekeeping and some authors claim that piperonyl butoxide is enhancing the toxicity of fluvalinate to control All other found pesticides originate from a pollution of outside the beehive and their frequencies and quantities bear us high concerns. We have found several fungicides and crop protection agents that are highly toxic for honey bees Table\u00a0. All of Just like two other Belgian studies we failed to find traces of neonicotinoids in beeswax (Nguyen et al. Worker bees of all ages are susceptible to the effects of pesticide exposure (Rortais et al. Given the contamination of beeswax one may consider to take actions in the field, aimed at lowering the pesticide contamination of beeswax in Belgian apiaries, as stated also before in other countries (Pettis et al."}
+{"text": "Nature Communications7, Article number: 11290 10.1038/ncomms11290 (2016); Published: 04122016; Updated: 05062016The original version of this Article contained an error in the spelling of the author Mark Hatherill, which was incorrectly given as Mark Hatheril. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports5: Article number: 9813; 10.1038/srep09813 published online: 05112015; updated: 03042016.The Acknowledgements section was omitted from the Article. It should read:AcknowledgementsThis work was supported by the Center for Nanoscale Science, an NSF Materials Research Science and Engineering Center, under the award DMR-1420620."}
+{"text": "There are errors in the Author Contributions. The correct contributions are:Conceived and designed the experiments: RKF MAG LAD-M RK AMVCS. Performed the experiments: RKF TFB DRR HAB. Analyzed the data: RKF MAG RK. Contributed reagents/materials/analysis tools: RK AMVCS. Wrote the paper: RKF AMVCS RK. Software used in analysis: MAG."}
+{"text": "It should be corrected as follows:incorrect: November 26, 2013correct: December 13, 2013This correction has been completed on the electronic file of the present paper available at J-STAGE.The editorial board expresses sincere apology for the misprinting.Microbes and Environments editorial board"}
+{"text": "Nature Communications7: Article number: 11106 10.1038/ncomms11106 (2016); Published: 04262016; Updated: 06032016The original version of this Article contained an error in the spelling of the author Milka Koupenova, which was incorrectly given as Milka Koupenova-Zamor. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "The authors would like to correct an error in the Author Contribution section. Jeffery L. Dangl (JLD) should be listed as one of the persons who wrote the paper.The correct author contributions are:Conceived and designed the experiments: GFW JJ JLD GJ PJBK. Performed the experiments: GFW JJ FEK. Analyzed the data: GFW JJ FEK GJ PJBK. Contributed reagents/materials/analysis tools: GFW PJBK. Wrote the paper: GFW FEK JLD PJBK."}
+{"text": "Scientific Reports5: Article number: 14557; 10.1038/srep14557published online 09282015; updated: 10292015The original HTML version of this Article incorrectly listed Ameeta Kelekar as being affiliated with \u2018College of Biological Sciences, University of Minnesota, Minneapolis, MN 55455\u2019. The correct affiliation is listed below:Department of Laboratory Medicine and Pathology and Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455.This has now been corrected."}
+{"text": "BMC Medicine 2015, 13:111 indicating the correct name for one of the authors.This is an Erratum to http://www.biomedcentral.com/1741-7015/13/111Please see related article:  Authors\u2019 corrected note:Jan NM IJzermans last name was incorrectly spelled in the author list and was indicated as Jan NM IJermans in our published article . The errCorrected text:Jan NM IJzermans"}
+{"text": "Scientific Reports6: Article number: 22867 10.1038/srep22867; published online: 03112016; updated: 04222016The original version of this Article contained a typographical error in the spelling of the author Yves De Repentigny, which was incorrectly given as Yves De Repentingy. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports6: Article number: 22020; 10.1038/srep22020 Published online: 02252016; Updated: 04072016The original version of this Article contained a typographical error in the spelling of the author Ariane Kaeppeli, which was incorrectly given as Ariane Kaeppli. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports5: Article number: 1346510.1038/srep13465; published online: 08272015; updated: 10162015In the Supplementary Information file originally published with this Article, Table S15 was truncated. This error has been corrected in the Supplementary Information that now accompanies the Article."}
+{"text": "There are errors in the Author Contributions. The correct contributions are: Conceived and designed the experiments: RT TCB. Performed the experiments: GPM TCB. Contributed reagents/materials/analysis tools: JRD TCB. Wrote the manuscript: TCB GPM.The publisher apologizes for the error."}
+{"text": "Scientific Reports5: Article number: 937810.1038/srep09378; published online: 03232015; updated: 03312016This Article contains an error in Figure 3, where the numbers of genes are incorrectly indicated in the 24-hour and 48-hour sections. The correct Figure 3 appears below as"}
+{"text": "Scientific Reports5: Article number: 16953; 10.1038/srep16953 published online: 11202015; updated: 04152016.In this Article, an additional affiliation for Keith L. March was omitted. The correct affiliation is listed below:Krannert Institute of Cardiology and the Indianapolis VA Center for regenerative medicine"}
+{"text": "Scientific Reports6: Article number: 2898710.1038/srep28987; published online: 07072016; updated: 08242016The original version of this Article contained a typographical error in the spelling of the author Gerald Fontenay, which was incorrectly given as Gerald Fonteney. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Nature Communications6: Article number: 866710.1038/ncomms9667 (2015); Published: 10202015; Updated: 11172015.The original version of this Article contained an error in the spelling of isomerism in the title of the paper. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "AbstractMacrotrachelianigronitens  (Heteroptera: Anthocoridae) is permanently present in the wild in Auckland (AK), New Zealand. It should therefore be added to the New Zealand Organisms Register (NZOR). It is a specialised predator of thrips inside leaf-roll galls. It has been present in New Zealand since at least the 1980s. Aspects of its biology, distribution, biosecurity status and history in New Zealand are discussed. The first detailed specimen records from New Zealand are provided, and a biological association is noted for the first time with Teuchothripsdisjunctus on Callistemon, probably its main association in New Zealand, where only two species of thrips cause leaf-roll galls. It has not been found associated with other thrips in New Zealand. Macrotrachelianigronitens is not known to be present in Australia, but the poorly known Anthocorisaustropiceus Gross, 1954 has been reported, in an easily overlooked publication, to be associated with Teuchothripsdisjunctus on Callistemon in Canberra. This led to an early tentative identification, by the author, of New Zealand material of Macrotrachelianigronitens as Anthocorisaustropiceus, in collections. This likely misidentification can now be discounted, but further research in Australia is required to determine the true identity of both Anthocorisaustropiceus, and whatever species of anthocorid was found in Canberra. Macrotrachelianigronitens   has recently been submitted by Bioforce Limited to the Environmental Protection Authority (EPA) to have Macrotrachelianigronitens declared as \"not new\", so that it can be legally propagated and/or distributed for the purposes of biological control of pest thrips. In fact, it shall be argued herein that Macrotrachelianigronitens ought never to have been classified as a \"new organism\" (under the Hazardous Substances and New Organisms (HSNO) Act = not present in New Zealand before 29 July 1998) in the first place, had its biosecurity status been properly assessed. An AMNZ record from 1997 is presented, and an even earlier record from the 1980s is indicated to be held in NZAC. Notes are provided on the biology, distribution and history in New Zealand of Macrotrachelianigronitens.ns St\u00e5l, 860 https://species.wikimedia.org/wiki/Macrotrachelia_nigronitensAnthocorisnigronitens St\u00e5l, 1860: 43 [Original description]Type status:Other material. Occurrence: recordedBy: Keith A. J. Wise; individualCount: 1; sex: female; Taxon: scientificName: Macrotrachelianigronitens ; Location: country: New Zealand; stateProvince: Auckland (AK); verbatimLocality: 15 Kingdale Road, Henderson, New Zealand, AK; verbatimElevation: 10 m; decimalLatitude: -36.86036; decimalLongitude: 174.62549; coordinateUncertaintyInMeters: 32; Identification: identifiedBy: Stephen E. Thorpe; Event: samplingProtocol: Swept; eventDate: 1997-05-09; habitat: Garden; fieldNumber: L5751; Record Level: institutionCode: Auckland Museum; collectionCode: AMNZ 59842Type status:Other material. Occurrence: recordedBy: G. Robertson; individualCount: 3; sex: females; Taxon: scientificName: Macrotrachelianigronitens ; Location: country: New Zealand; stateProvince: Auckland (AK); verbatimLocality: Auckland Regional Botanic Gardens, Manurewa, New Zealand, AK; verbatimElevation: 40m; decimalLatitude: -37.00879; decimalLongitude: 174.90646; coordinateUncertaintyInMeters: 570; Identification: identifiedBy: Stephen E. Thorpe; Event: eventDate: 2005-08; habitat: Callistemon sp. infested with Teuchothripsdisjunctus (Hood)In leaf-roll galls on ; fieldNumber: L14594; Record Level: institutionCode: Auckland Museum; collectionCode: AMNZ 73644, 73645, 73646Type status:Other material. Occurrence: recordedBy: John W. Early; individualCount: 5; sex: 3 females, 2 immatures; Taxon: scientificName: Macrotrachelianigronitens ; Location: country: New Zealand; stateProvince: Auckland (AK); verbatimLocality: Auckland Airport, Mangere, New Zealand, AK; decimalLatitude: -37.00019; decimalLongitude: 174.79505; coordinateUncertaintyInMeters: 400; Identification: identifiedBy: Stephen E. Thorpe; Event: eventDate: 2011-04-17; habitat: Gynaikothripsficorum in rolled leaves of FicusmicrocarpaWith ; fieldNumber: L19131; Record Level: institutionCode: Auckland Museum; collectionCode: AMNZ 85334 (immature), 85335 (immature), 85336 , 85337 , 85338 Type status:Other material. Occurrence: recordedBy: Stephen E. Thorpe; individualCount: 1; sex: male; Taxon: scientificName: Macrotrachelianigronitens ; Location: country: New Zealand; stateProvince: Auckland (AK); verbatimLocality: 25 Felton Mathew Ave, suburb of Saint Johns, New Zealand, AK; verbatimLatitude: -36.87246; verbatimLongitude: 174.84731; coordinateUncertaintyInMeters: 5; Identification: identifiedBy: Stephen E. Thorpe; Event: eventDate: 2014-03-01; habitat: Callistemon sp. In leaf-roll galls of TeuchothripsdisjunctusOn ; fieldNumber: L17240; Record Level: institutionCode: Auckland Museum; collectionCode: AMNZ 87996Type status:Other material. Occurrence: recordedBy: Stephen E. Thorpe; individualCount: 1; sex: male; Taxon: scientificName: Macrotrachelianigronitens ; Location: country: New Zealand; stateProvince: Auckland (AK); verbatimLocality: 2 Farringdon Street, suburb of Glen Innes, New Zealand, AK; verbatimLatitude: -36.87164; verbatimLongitude: 174.85883; coordinateUncertaintyInMeters: 0; Identification: identifiedBy: Stephen E. Thorpe; Event: eventDate: 2014-03-02; habitat: Callistemon sp., growing over fence into Paddington Reserve. In leaf-roll gall of TeuchothripsdisjunctusOn ; fieldNumber: EN17241; Record Level: institutionCode: Auckland Museum; collectionCode: AMNZ 87997Macrotrachelianigronitens is present in at least the vicinity of Auckland City and suburbs (AK). The genus Macrotrachelia consists of 6 currently recognised Central American species, with only Macrotrachelianigronitens extending  into South America , and possibly also adventive in California  are responsible for such galls in New Zealand, both of them adventive. One is Gynaikothripsficorum on Ficusmicrocarpa (Moraceae). The other is Teuchothripsdisjunctus on Callistemon (Myrtaceae). Ficusmicrocarpa is rare in New Zealand, present only in cultivation as an ornamental. Callistemon is far more common, and probably represents the main habitat of Macrotrachelianigronitens in New Zealand. Note that Gynaikothripsficorum in New Zealand appears to occur only on Ficusmicrocarpa, and not any of the other, more common species of Ficus. Note also that Macrotrachelianigronitens has not been found feeding on any other thrips, at least not in New Zealand.Macrotrachelianigronitens is present in New Zealand as a permanent wild population in suburban gardens and parks. It should therefore be added to the New Zealand Organisms Register (NZOR), as exotic and present in the wild.The data presented herein strongly indicates that Macrotrachelianigronitens into New Zealand is unknown. It may have arrived here directly from the Americas, associated with Gynaikothripsficorum, and then shifted host to the much more locally abundant Teuchothripsdisjunctus on Callistemon. It is not known to be present in Australia, where both Teuchothripsdisjunctus and Callistemon are native.The pathway of entry of Teuchothripsdisjunctus) in leaf-roll galls on Callistemon sp. The species was subsequently found by the author in the same habitat in Auckland Domain. In the then absence of a clue to the identity of the species, the author noticed a published reference by Anthocorisaustropiceus Gross, 1954. It had been found in leaf-rolls of Teuchothripsdisjunctus on Callistemon, in Canberra, Australia (see p. 83.) The author tentatively identified the New Zealand species as Anthocorisaustropiceus, based purely on the biological association. The identity of Anthocorisaustropiceus remains somewhat unclear from the original description in Anthocorisaustropiceus (AMSA K.67861) is apparently mounted on a microscope slide , and has not been examined by the author. Macrotrachelianigronitens has not been reported from Australia. Therefore, Australian entomologists are encouraged to double check the true identities of both Anthocorisaustropiceus Gross, 1954, and whatever species of anthocorid was collected in Canberra , as it is not impossible that one or other of them could turn out to be Macrotrachelianigronitens. Note that Anthocorisaustropiceus is the only known native Australian member of the tribe Anthocorini (see http://www.environment.gov.au/biodiversity/abrs/online-resources/fauna/afd/taxa/ANTHOCORINI/checklist), the tribe to which Macrotrachelia is also assigned , which was collected in the Auckland suburb of Henderson in 1997. Subsequently, Dr. Jocelyn Berry (then hymenopterist at NZAC) gave the author some material collected from Auckland Regional Botanic Gardens in August 2005, and given to her privately by the collector. This material was associated with thrips (assigned . It therhttps://commons.wikimedia.org/wiki/File:Anthocoris_austropiceus.jpg), as Anthocorisaustropiceus, an image of a specimen from Teuchothripsdisjunctus leaf-rolls on a Callistemon tree in Auckland Domain. On 31 March 2011, an email was received from David Horton (USDA research entomologist) suggesting that the imaged specimen was in fact a species of Macrotrachelia, which he suggested was probably Macrotrachelianigronitens, but with some reservations as the genus has not been taxonomically revised in recent times. Meanwhile, the author noted a specimen in NZAC collected in the 1980s (1986?), by entomologist Dr. Beverley A. Holloway, on a clothes line in her garden at Lynfield, Auckland. The specimen had an identification label on it reading \"near Maoricorisbenefactor\", det. M.-C. Larivi\u00e8re. The specimen was with the other material of Maoricoris (an unrelated endemic monotypic genus). Full details are currently unavailable to the author, but it is important for this specimen to be tracked down and confirmed as the likely first New Zealand record of Macrotrachelianigronitens. The issue is therefore highlighted herein for others to follow up. Until September 2007, the author deposited several other specimens into NZAC, tentatively identified as Anthocorisaustropiceus. In 2008 the species was independently discovered in New Zealand , associated with Gynaikothripsficorum leaf-rolls on Ficusmicrocarpa . Macrotrachelianigronitens in California and elsewhere. The Ministry for Primary Industries  treated this as a new incursion, which resulted in the current biosecurity status of Macrotrachelianigronitens as a new organism in New Zealand. Regrettably, none of the people involved or officially consulted by MPI during the incursion investigation took into account the all of the relevant material in AMNZ and NZAC, material which clearly demonstrates that Macrotrachelianigronitens has been present in N.Z. since at least 1997 and almost certainly at least since the 1980s.On 27 March 2010, the author collected and uploaded to Wikimedia Commons  Note that the present author had already sent New Zealand material to Horton, who carefully examined it, including dissections of both male and female genitalia, and he determined it as Macrotrachelianigronitens, based on the published literature. Larivi\u00e8re and Larochelle 2014 formally published the identification after 'comparison between specimens from NZAC and MACN', but without giving details how the comparison was made, or upon what the identification of the MACN material is based. Nevertheless, the present author accepts the determination as being certain enough to run with, in lieu of future taxonomic and/or molecular studies.David Horton initially intended to publish the New Zealand record of"}
+{"text": "Nature Communications7: Article number: 11146 10.1038/ncomms11146 (2016); Published: 03312015; Updated: 04262015In Fig. 3 of this Article, data in panel \u2018a' were inadvertently partially obscured during the production process. The correct version of Fig. 3 now appears in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports5: Article number: 869710.1038/srep08697; published online: 03032015; updated: 12182015This Article contains a typographical error in the Introduction section.16,17.although the existence of a such a transition below the upper critical dimension is still under debateshould read:16,17.although the existence of such a transition below the upper critical dimension is still under debateIn addition, there are errors in the following equations.In Equation (14)should read:In Equation (15)should read:In Equation (16)should read:"}
+{"text": "It came to our attention after our manuscript was published that the caption of Table 1 was incomplete. We provide below the missing information, which is essential to the correct interpretation of the referred table.a Species names and authors are as specified in the original text.b Setation formulae of the first (P1), second (P2) and fourth (P4) swimming legs are summarized as follows: Re /Ri , where Re: exopod, Ri: endopod. F: adult female; M: adult male; TL: total length (mm); Ur1 to Ur5: urosome segments; Fu: furca; CR: caudal rami. nd: no data.PageBreak* Character not explicitly stated in the original but taken from accompanying drawings for comparison purposes.\u00a7 Most likely Crisafi (1959) described a late juvenile C5 as an adult male. In addition to the non-geniculated antennule, the urosome is 4-segmented with the last two segments fused ."}
+{"text": "Scientific Reports5: Article number: 1589510.1038/srep15895; published online: 10282015; updated: 12142015In the original HTML version of this Article, Li Yue-Chun was incorrectly listed as being affiliated with \u2018Department of Pediatrics, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China\u2019. The correct affiliation is listed below:Department of Cardiology, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, ChinaThis has now been corrected."}
+{"text": "There are errors in the Author Contributions. The correct contributions are: Conceived and designed the experiments: MR AO MW MJ. Performed the experiments: MR MJ CS MG MM. Analyzed the data: MR AO MJ MM. Wrote the paper: MR AO MW."}
+{"text": "There are errors in the Author Contributions. The correct contributions are: Conceived and designed the experiments: SW EC. Analyzed the data: SW EC. Contributed reagents/materials/analysis tools: SW EC. Wrote the paper: SW EC."}
+{"text": "Scientific Reports5: Article number: 1215610.1038/srep12156; published online: 07172015; updated: 09222015The original version of this Article contained a typographical error in the spelling of the author Seulki Roh, which was incorrectly given as Seulki Rho. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "The correct contributions are: Conceived and designed the experiments: SNF MZ. Performed the experiments: JB SC. Analyzed the data: SC MZ JB. Contributed reagents/materials/analysis tools: SNF JB SC. Wrote the paper: SC MZ JB SNF. Designed the computational analysis: MZ SC.There is an error in the penultimate sentence of the second paragraph of the \u201cThe least-dependent components are statistically nearly independent\u201d subsection of the Results. The correct sentence is: The distribution of this null estimate calculated from 100 flight segments (12000 pairs of LDCs) is shown in Fig. 7B (red dashed line)."}
+{"text": "Scientific Reports6: Article number: 2421010.1038/srep24210; published online: 04132016; updated: 06202016In the original version of this Article, an additional affiliation for Taek Dong Chung was omitted. The correct affiliation is listed below:Advanced Institutes of Convergence Technology, Suwon-Si, Gyeonggi-do 16229, Korea.This error has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "AbstractHomotrysismacleayi  in New Zealand. Evaluation of this evidence clearly indicates that the species is fully established in the wild in New Zealand. It is therefore recommended that the species be added to the New Zealand Organisms Register (NZOR), as exotic and present in the wild. Some general comments are offered on the importance of data and evidence in faunistics.The first detailed specimen records are presented for the Australian beetle  Homotrysismacleayi . Although I immediately recognised it as a species of alleculine tenebrionid unknown in New Zealand, it was not identified until I found others in 2012. These were identified as Homotrysismacleayi by Australian tenebrionid expert Dr. Eric Matthews . The species was validated new to N.Z., based on this material identified by Matthews, by Homotrysismacleayi (tenebrionid beetle), Acacia sp. (wattle), Auckland, General Surveillance). Nothing more has been published regarding the presence of this beetle in New Zealand. There is currently no record of it on the New Zealand Organisms Register (NZOR). It is therefore somewhat unclear what the status is of the species in New Zealand. Is it a permanently established member of the New Zealand fauna? Faunistics is the study of the presence/absence of species in a given area, such as New Zealand. Since we are scientists, and not stamp collectors, the presence of a given species in a given area should be stated with specification of the associated evidence for its presence. Presence/absence can change over time. Presence could be based on a single, possibly mislabelled and/or misidentified specimen, or by many independent specimen records taken over a long period of time. It is important to specify, but it is not often done. Similarly, presence could be based on a specimen or specimens representing only post border interceptions, without a breeding resident population. Only the systematic accumulation of data can establish the facts.In 2004, I collected what is probably the first New Zealand specimen of the Australian beetle https://species.wikimedia.org/wiki/Homotrysis_macleayiAlleculamacleayi Borchmann, 1909 Alleculaflavicornis Macleay, 1887 (objective synonym)Type status:Other material. Occurrence: recordedBy: S.E. Thorpe; individualCount: 1; Taxon: scientificName: Homotrysismacleayi ; Location: country: New Zealand; stateProvince: Auckland; verbatimLocality: Auckland Domain; verbatimLatitude: 36.86385S; verbatimLongitude: 174.77501E; Identification: identifiedBy: Stephen E. Thorpe; Event: samplingProtocol: On trunk of Eucalyptus tree at night; eventDate: 2004-04-28; Record Level: institutionCode: Auckland Museum; collectionCode: AMNZ57969Type status:Other material. Occurrence: recordedBy: S.E. Thorpe; individualCount: 3; Taxon: scientificName: Homotrysismacleayi ; Location: country: New Zealand; stateProvince: Auckland; verbatimLocality: Tamaki Campus (East), suburb of Saint Johns, Auckland; verbatimLatitude: 36.88615S; verbatimLongitude: 174.85258E; Identification: identifiedBy: Eric G. Matthews; Event: samplingProtocol: Under loose bark of chopped up wattle tree (possibly Paraserianthes lophantha); eventDate: 2012-03-08; Record Level: institutionCode: Auckland Museum; collectionCode: AMNZ86134 (1 specimen)Type status:Other material. Occurrence: recordedBy: S.E. Thorpe; individualCount: 1; Taxon: scientificName: Homotrysismacleayi ; Location: country: New Zealand; stateProvince: Auckland; verbatimLocality: Tamaki Campus (East), suburb of Saint Johns, Auckland; verbatimLatitude: 36.88216S; verbatimLongitude: 174.85331E; Identification: identifiedBy: Stephen E. Thorpe; Event: samplingProtocol: Under bark of Pittosporum eugenioides stump, at edge of carpark.; eventDate: 2013-05-05; Record Level: institutionCode: Auckland Museum; collectionCode: AMNZ87636Type status:Other material. Occurrence: recordedBy: S.E. Thorpe; individualCount: 1; Taxon: scientificName: Homotrysismacleayi ; Location: country: New Zealand; stateProvince: Auckland; verbatimLocality: Tamaki Campus (East), suburb of Saint Johns, Auckland; verbatimLatitude: 36.88100S; verbatimLongitude: 174.85310E; Identification: identifiedBy: Stephen E. Thorpe; Event: samplingProtocol: On dead tree fern frond, on ground, by pond; eventDate: 2014-01-09; Record Level: institutionCode: Auckland Museum; collectionCode: AMNZ87720Homotrysismacleayi is easily recognised as an alleculine tenebrionid. Fig. Homotrysismacleayi on four separate occasions, spread over a number of years , at two sites in the vicinity of metropolitan Auckland . Figs I have now collected Homotrysismacleayi. I have collected it on a trunk of a Eucalyptus tree at night, under the bark of a chopped up wattle tree , under the bark of a stump of the native tree Pittosporumeugenioides at the edge of a carpark, and on the ground on a dead tree fern frond. I have only collected the species from anthropogenic habitats in metropolitan Auckland.Little or nothing is known of the ecology of Homotrysismacleayi was proposed as a new replacement name by Alleculamacleayi) for Alleculaflavicornis Macleay, 1887 , which is a junior homonym of Alleculaflavicornis Kolbe, 1883 (West Africa). It therefore makes no sense that Homotrysisflavicornis (Macleay 1887) and Homotrysismacleayi , with different associated data!There is some published confusion regarding this species in Australia. Homotrysismacleayi is present in the wild in metropolitan Auckland, and has been present there for some 10 years. The identification has been validated by Ministry for Primary Industries (MPI). I therefore recommend that Homotrysismacleayi  be added to the New Zealand Organisms Register (NZOR), as exotic and present in the wild.The available data clearly indicates that a breeding population of"}
+{"text": "Critical Care, Oshiro and colleagues describe the profile of acute coagulopathy of trauma-shock (ACOTS) using viscoelastic techniques [In an interesting and original article in a recent issue of chniques . The autchniques \u20134]. How. HowCritchniques . In thischniques . RegardlSatoshi GandoWe appreciate the interest of Egea-Guerrero and colleagues in our article regarding DIC in trauma . We agreACOTS: Acute coagulopathy of trauma-shock; APC: Activated protein C; DIC: Disseminated intravascular coagulation; PAI-1: Plasminogen activator inhibitor-1.The authors declare that they have no competing interests."}
+{"text": "Scientific Reports6: Article number: 1951710.1038/srep19517; published online: 01222016; updated: 02252016.in vivo: A Biomarker for LDH Activity\u201d was incorrectly given as \u201cLactate Chemical Exchange Saturation Transfer (LATEST) Imaging in vivo A Biomarker for LDH Activity\u201d. This has now been corrected in the PDF and HTML versions of the Article.The original version of this Article contained an error in the title of the paper, where \u201cLactate Chemical Exchange Saturation Transfer (LATEST) Imaging"}
+{"text": "There is an error in the funding statement. Please refer to the correct funding statement below.The authors received funding for this study from the following sources.http://www.sdcz.gov.cn/; Funding institution: Shandong Province Finance Bureau; Authors that received the funding: HZ;Grant number:Lu Cai Jiao Zhi (2013) 171;URL:\u00a0http://www.nsfc.gov.cn/; Funding institution: National Natural Science Foundation of China; Authors that received the funding: WG;Grant number:81400573; URL:\u00a0http://www.nsfc.gov.cn/; Funding institution: National Natural Science Foundation of China; Authors that received the funding: WG.Grant number:61471384; URL:"}
+{"text": "Computer Aided Diagnosis (CAD), which can automate the detection process for ocular diseases, has attracted extensive attention from clinicians and researchers alike. It not only alleviates the burden on the clinicians by providing objective opinion with valuable insights, but also offers early detection and easy access for patients.We review ocular CAD methodologies for various data types. For each data type, we investigate the databases and the algorithms to detect different ocular diseases. Their advantages and shortcomings are analyzed and discussed.We have studied three types of data  that have been commonly used in existing methods for CAD. The recent developments in methods used in CAD of ocular diseases  are investigated and summarized comprehensively.While CAD for ocular diseases has shown considerable progress over the past years, the clinical importance of fully automatic CAD systems which are able to embed clinical knowledge and integrate heterogeneous data sources still show great potential for future breakthrough. Patients with ocular diseases are often unaware of the asymptomatic progression of the said disease  until atOwing to the fast pace of technological advancements in both hardware and software, many CAD systems have been developed for the diagnosis of ocular diseases over the past years, though most of them are still undergoing evaluation or clinical validation. For example, Fujita et al.  discusseThough such fully automated systems are not yet on the market, semi-automated and manual computer systems incorporating these CAD systems are relatively widely used, with several clinical publications already reporting on their usage. Examples of the development of such systems include IVAN  from UniThis survey covers three types of data for CAD systems: clinical data, image based data and genetic data. Clinical data refers to a patient\u2019s demographic information  and data acquired from clinical laboratory tests or exams, e.g. intra-ocular pressure (IOP), but excludes data acquired from digital imaging or genomic tests . Image based data refers to images captured using an imaging device for observing the pathology in the affected part of the eye . Genetic information refers to any data obtained from an individual\u2019s DNA, genes or proteins (Section \u201cResult: predicting ocular diseases based on genetic information\u201d). These definitions are specific to this paper and may vary depending on context. Of the three data types, CAD systems using clinical data has already been widely studied in the clinical field -10. As fThere have been surveys on retinal imaging in the area of ocular research ,13. HoweIn this work, we review research and development on automatic ocular disease diagnosis in the light of three data types, viz. clinical, image and genetic. For each data type, we investigate the algorithms and available databases developed for different ocular diseases. The associated publications were retrieved from two literature databases, PubMed and IEEEXplore. Considering the works which use images as data, to understand the major image modalities used for CAD applications and the trends of research areas, we summarize the statistics of image-based studies conducted on various ocular diseases. We examine the biomedical databases to extract the known genetic information regarding ocular diseases.The results of the review are presented in three sections: Sections \u201cResult: CAD of ocular diseases based on clinical data\u201d and \u201cResult: CAD of ocular diseases based on imaging\u201d describe the CAD of ocular diseases based on clinical data and ocular imaging respectively. Section \u201cResult: predicting ocular diseases based on genetic information\u201d concerns studies relating genomic informatics to disease prediction. Furthermore, in Section \u201cDiscussion\u201d we discuss the observed trends in the field and the possibility of CAD systems based on integrated data sources.One of the pioneer research works on Clinical Decision Support Systems (CDSS), CASNET   or through a cultural sample of bacteria from the eye tested in a laboratory 31], a meResearch on CAD of PM has mainly relied on DFP but recently there have been efforts to explore the use of SS-OCT for PM analysis.An observable sign for PM detection is PPA, an atrophy of pre-existing retina tissue. The APAMEA system proposed by Liu et al.  was the Different features have been extracted from DFP for PM detection. APAMEA extracted a texture feature obtained through entropy analysis. In  BIF was \u03bcm range, which has improved their ability to penetrate deeper into tissues than the conventional SD-OCT instruments [SS-OCT uses a frequency swept laser as a light source  and, in truments . Though truments  reportedA brief review of cataract grading and CAD for corneal opacity is given below.Cataract is characterized by a cloudiness (opacity) in the eye lens which obstructs vision and can even lead to blindness. Cataract can be categorized into three types based on the location of opacity within the lens structure: nuclear, cortical and Posterior Sub-Capsular (PSC) . NuclearFigure\u00a0Typical features used for grading CC and PSC include enhanced texture features , intensiCorneal haze describes the condition when the cornea becomes cloudy or opaque. The cornea is normally clear, so corneal haze can greatly impair vision. Although the haze can occur in any part of the cornea, it is most often found within the thicker, middle layer of the cornea, called the stroma. Corneal haze is most often caused by inflammatory cells and other debris that are activated during trauma, infection or surgery. Corneal haze sometimes occurs during laser vision correction procedures.Slit lamp imaging has been used to clinically estimate corneal haze manually by physicians but not automatically. For example, it was used to observe the cornea haze after excimer laser ablation of cornea ,287. SliThe above imaging modalities have been used in clinic with manual detection but till now, as far as we know, there is no automatic method based on these modalities. Currently, the existing automatic method is based on the most straightforward way: examining frontal photograph of eye ,291. In AMD: Age-related macular degeneration; AM-FM: Amplitude modulation-frequency modulation; BM: Bruch\u2019s membrane; BMO: Bruch\u2019s membrane opening; CAD: Computer aided detection; CASNET: Causal association network; CC: Cortical cataract; CCT: Central corneal thickness; CDR: Cup-to-disc ratio; CDSS: Clinical decision support systems; CME: Cystoid macular edema; CNV: Choroidal neovascularization; CSLO: Confocal scanning laser ophthalmoscopy; DH: Disc haemorrhage; DR: Diabetic retinopathy; FBIF: Focal biologically inspired feature; GRI: Glaucoma risk index; GWAS: Genome-wide association studies; HALT: Histogram based adaptive local thresholding; HE: Hard exudates; HRT: Heidelberg retina tomography; ICA: Independent component analysis; IOP: Intra-ocular pressure; LASSO: Least absolute shrinkage selector operation; LDA: Linear discriminant analysis; MGG: Mixture of generalized Gaussian; MLP: Multilayer perceptron; MOG: Mixture of Gaussian; MRA: Moorfields regression analysis; MRI: Magnetic resonance imaging; MTA: Major temporal arcade; NC: Nuclear cataract; NCO: Neural canal opening; NRR: Neuro-retinal rim; OCT: Optical coherence tomography; OMIM: Online Mendelian inheritance in man; PCA: Principal component analysis; PM: Pathological myopia; PPA: Parapapillary atrophy; PSC: Posterior sub-capsular; QDA: Quadratic discriminant analysis; RNFL: Retina nerve fibre layer; RNFLT: Retina nerve fibre layer thickness; ROI: Region of interest; RPE: Retinal pigment epithelium; SAP: Standard automated perimetry; SD-OCT: Spectral domain-optical coherence tomography; SEAD: Symptomatic exudate-associated derangements; SIFT: Scale-invariant feature transform; SLIC: Simple linear iterative clustering; SLP: Scanning laser polarimetry; SNP: Single-nucleotide polymorphism; SNR: Signal to noise ratio; SS-OCT: Swept source-optical coherence tomography; SVDD: Support vector data description; SVM: Support vector machines; TCA: Topographic change analysis; VCD: Vertical cup diameter; VDD: Vertical disc diameter.The authors declare that they have no competing interests.ZZ conceived topic of this survey, did the review for ocular genomic data, and image related PM research and wrote the concerned parts of the manuscript. RS surveyed and wrote on Cataract and DR and consolidated the final manuscript. HL surveyed and wrote on the topics of AMD detection and corneal opacity detection. XC surveyed and wrote about Glaucoma screening and also enriched the section on CAD of ocular diseases based on clinical data. LD clarified the motivation of this survey and wrote the conclusion. JL, CKK and DWKW conceived of the survey and participated in designing it. TYW provided clinical advice. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6947/14/80/prepub"}
+{"text": "Scientific Reports5: Article number: 1042210.1038/srep10422; published online: 05282015; updated: 10282015.The original version of this Article contained a typographical error in the spelling of the author Martin Nors Pedersen, which was incorrectly given as Martin Nors Perdersen.This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports5: Article number: 16577; 10.1038/srep16577published online 11122015; updated: 01272016The original version of this Article contained a typographical error in the spelling of the author Chae-Myeong Ha which was incorrectly given as Chae-Myung Ha. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Nature Communications 6: Article number: 784110.1038/ncomms8841 (2015); Published: 07312015; Updated: 10222015.The original version of the Supplementary Information attached to this Article did not contain Supplementary Tables 1\u20137. The HTML has now been updated to include a corrected version of the Supplementary Information."}
+{"text": "Scientific Reports6: Article number: 24396; 10.1038/srep24396published online: 04182016; updated: 08252016The original version of this Article contained a typographical error in the spelling of the author Paola Bolognesi, which was incorrectly given as Paolo Bolognesi. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports5: Article number: 17665; 10.1038/srep17665 published online: 12072015; updated: 01202016.The original version of this Article contained a typographical error in the spelling of the author Konstantinos Karakostis, which was incorrectly given as Kostantinos Karakostis. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports6: Article number: 23213; 10.1038/srep23213 published online: 03182016; updated: 04292016.The original version of this Article contained a typographical error in the spelling of the author Ana C. Glembotsky, which was incorrectly given as Ana C. Glembostky. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Nature Communications7: Article number: 10268 10.1038/ncomms10268 (2016); Published: 01082016; Updated: 03032016The financial support for this article was not fully acknowledged. The Acknowledgements should have included the following:This work was supported by the intramural research program of the NIMH (ZIA-MH-002498-24)."}
+{"text": "Nature Communications6, Article number: 7131 10.1038/ncomms8131 (2015); Published 05192015; Updated: 08262015.The original version of this Article contained an error in the spelling of circulation in the title of the paper, and in"}
+{"text": "The seventh and eighth authors\u2019 names are spelled incorrectly. The correct names are: Flavia de Lima Alves and Juri Rappsilber.The authors contributions with the corrected initials are provide here:Conceived and designed the experiments: JG FT SCL BH JR. Performed the experiments: SCL BH PP FdLA SMG JG SY HT EdL. Analyzed the data: FdLA KS GVJ JG FT. Wrote the paper: JG FT EJF BH SCLThe 7th author\u2019s current address is missing. Flavia de Lima Alves\u2019 current address is: Centre for Microbial Chemical Biology, Department of Biochemistry, McMaster University, Ontario, CanadaThe affiliation for the 8th author is incomplete. Juri Rappsilber is affiliated with: Department of Bioanalytics, Institute of Biotechnology, Technische Universit\u00e4t Berlin, Berlin, Germany in addition to the listed affiliation: 3. Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, United KingdomThe following information is missing from the Funding section: The Wellcome Trust generously funded this work through a Senior Research Fellowship to JR (103139), a Centre core grant (092076) and an instrument grant (108504)."}
+{"text": "Scientific Reports6: Article number: 22440;10.1038/srep22440 Published online: 03012016; Updated: 06022016The following statement has been omitted from the \u2018Additional Information\u2019 section of the HTML version of this Article:\u201cData Availability: The images and spectra on which this paper is based may be publicly accessed and are stored at 10.17639/nott.35\u201d.The PDF version of this Article was correct at the time of publication."}
+{"text": "Nature Communications6: Article number: 10063 10.1038/ncomms10063 (2015); Published: 12212015; Updated: 04202016Staphylococcus aureus accession codes is incorrect, as follows:In Supplementary Data 3 of this Article, one of the SRR2101499 should be ERR1197981."}
+{"text": "Scientific Reports6: Article number: 2907310.1038/srep29073; published online: 07012016; updated: 08192016.The original version of this Article contained a typographical error in the spelling of the author Daniela Fernandois, which was incorrectly given as Daniela Fernadois. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Nature Communications 6: Article number: 6756 (2015); 10.1038/ncomms7756 Published: 04092015; Updated: 08212015.The affiliation details for Lin Xu and Xintian Hu are incorrect in this article. The correct affiliation for these authors is given below. Kunming Institute of Zoology, CAS Center for Excellence in Brain Science, Chinese Academy of Sciences, Kunming 650223, China."}
+{"text": "There are errors in the Author Contributions section. The correct contributions are: Conceived and designed the experiments: HM MK. Performed the experiments: HM. Analyzed the data: HM JT MK. Contributed reagents/materials/analysis tools: MK. Wrote the paper: HM MK JT."}
+{"text": "Scientific Reports5: Article number: 11699;10.1038/srep11699 Published online: 07012015; Updated: 05092016This Article contains an error in Figure 2: the arrow depicting the electric field should point right to left. The correct Figure 2 appears below as"}
+{"text": "Scientific Reports6: Article number: 22027; 10.1038/srep22027 published online: 02232016; updated: 06102016In the original version of this Article, an additional affiliation for Lin Chen and YiMing Zhu was omitted. The correct affiliation is listed below:Cooperative Innovation Center of Terahertz Science, Chengdu 611731, China.This error has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Description: Due to errors introduced in the production process, the Supporting Informationfiles were excluded. They can be found here:Table S1:  [^]"}
+{"text": "Scientific Reports6: Article number: 2186410.1038/srep21864; published online: 02232016; updated: 05042016In this Article, Figure 4 is incorrect. The Figure legend is correct. The correct Figure 4 appears below as"}
+{"text": "Nature Communications6: Article Number: 744610.1038/ncomms8446 (2015); Published 07012015; Updated 12142015The financial support for this Article was not fully acknowledged. The Acknowledgements should have included the following:ST acknowledges financial support from Grant-in-Aid Research S No. 26220710."}
+{"text": "There are errors in the Author Contributions. The correct contributions are: Conceived and designed the experiments: PLA JS JM. Collected data: ELV JLR KG JS. Interpreted images: ELV JLR. Analyzed the data: ALGB ELV OJA. Wrote the paper: ALGB ELV BM."}
+{"text": "Scientific Reports5: Article number: 950210.1038/srep09502; published online: 03302015; updated: 09212015et al. (reference 31), but in that paper the relevant data are not shown.The results presented in Fig. 1B were produced by Wei Wang, Kun-Liang Guan and Michael Karin. The authors neglected to indicate that the same results were also reported by Parmigiani"}
+{"text": "Scientific Reports5: Article number: 1591510.1038/srep15915; published online: 11032015; updated: 02052016In the Supplementary Information file originally published with this Article, the details of the beta testers in Supplementary Table S11 were incorrect. These errors have been corrected in the Supplementary Information that now accompanies the Article."}
+{"text": "There are errors in the Author Contributions. The correct contributions are: Conceived and designed the experiments: GL LX TF YC GJ HZ JW XC CW. Performed the experiments: GL LX TF JW. Analyzed the data: GL LX TF. Contributed reagents/materials/analysis tools: GL. Wrote the paper: GL.Additionally, there is an error in the legends for Further, there is an error in the footnotes for"}
+{"text": "Scientific Reports5: Article number: 1741310.1038/srep17413; published online: 11272015; updated: 01292016The Acknowledgements section in this Article is incomplete.\u201cThis study was supported by National Natural Science Foundation of China .\u201dshould read:\u201cWe thank Min Zhao , Zhu Ba , Zhaoxia Zhang , and Xinbo Song  for helpful sample collection.This study was supported by National Natural Science Foundation of China .\u201d"}
+{"text": "Scientific Reports6: Article number: 2012710.1038/srep20127; published online: 02162016; updated: 04202016.The original version of this Article contained an error in the spelling of the author Maha Al-Asmakh, which was incorrectly given as Al-Asmakh Maha. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "The affiliation for the seventh author is incorrect. Ajit Varki is not affiliated with #4 but with #3 University of California, San Diego, CA, USA.The following information is missing from the Funding section: This work was also supported by NIH grants R01GM32373 and U01 CA199792 (to AV).There are errors in the Author Contributions. The correct contributions are: Conceived and designed the experiments: GFG YS HS JQ. Performed the experiments: HS JQ SD. Analyzed the data: HS JQ YS ZK. Contributed reagents/materials/analysis tools: HS JQ YS HY XC. Wrote the paper: HS AV YS GFG. Collected the X-ray data and solved the structures: JQ. Array analysis and interpretation: ZK SD AV. Synthesis of glycans for array: HY XC."}
+{"text": "There are errors in the Author Contributions. The correct contributions are: Conceived and designed the experiments: LFT EMF. Performed the experiments: LFT WAdG EAJC. Analyzed the data: NAW. Contributed reagents/materials/analysis tools: CNW SG PD LJSH EMF. Wrote the paper: NAW LFT PMA WAdG EAJC CNW SG PD LJSH EMF"}
+{"text": "Scientific Reports6: Article number: 2266110.1038/srep22661; published online: 03032016; updated: 05042016In the Supplementary Information file originally published with this Article, references 32, 33 and 37 were incorrectly given as references 25, 26 and 35 respectively. These errors have been corrected in the Supplementary Information that now accompanies the Article."}
+{"text": "Following publication of the original article , the autSuperficial venous thrombosisas a possible consequence of ChAdOx1 nCoV-19 vaccine: two case reports.The incorrect title is:Superficial venous thrombosis as a possible consequence of ChAdOx1 nCoV-19 vaccine: two case reports.The correct title is:The title has been updated above and the original article  has been"}
+{"text": "Donacaulaniloticus  is known from south-eastern Europe, Middle East and Turkey to Central Asia, northern India and China and widely distributed in North Africa .Donacaulaniloticus (Zeller 1867) is recorded for the first time from the Iberian Peninsula and the first DNA barcode sequence is published and compared with other European and North American Donacaula species. Crambidae  currently includes 10,343 species in 15 subfamilies worldwide of which 239 species in 29 genera belong to the subfamily Schoenobiinae , S.xanthopygataSchoenobiusgigantellus  collected from the saltmarshes of Adventus in Trebujena . The specimens collected have some consistent morphological features which differ from the other Donacaula species. In addition, mtDNA sequence(COI) were used to assess genetic divergence between the Donacaula species from Europe and North America.In this article, we provide the first record and DNA barcoding of During the sampling, one female specimen with a white discocellular spot and unpointed apex traits was collected Fig. a. AdditiThe specimen was pinned, wings spread and dried. Their external characters were examined in order to evaluate possible differences in colouration and wing shape. Furthermore, it was dissected using standard procedures  with minMZ920225).For DNA extraction, two legs were removed from the specimen in order to sequence the 658 base-pair long barcode segment of the mitochondrial COI gene . The tissue samples were submitted to the Canadian Centre for DNA Barcoding  to obtain DNA barcodes using the high-throughput protocol described in Donacaulaniloticus and the Donacaulaother  species from Europe and from North America, we included all sites with the pairwise deletion option. The public sequences of Donacaulaforficella , D.mucronella  from Europe and D.longirostrallus , D.maximellus , D.melinellus , D.sordidellus  and D.unipunctellus  from North America were obtained from the public database in BOLD. We selected Scirpophagapraelata , which is systematically related into subfamily Schoenobiinae as outgroup to root the trees.Voucher data, images, sequences and trace files are publicly available on the Barcode of Life Data System (BOLD) . Sequencstrallus  BA57C87D-617C-568C-BEB0-08E4550B3C75Schoenobiusniloticus Type status:Other material. Occurrence: recordedBy: J.J. Guerrero; individualCount: 1; sex: female; lifeStage: adult; disposition: in collection; Taxon: scientificName: Donacaulaniloticus ; kingdom: Animalia; phylum: Arthropoda; class: Insecta; order: Lepidoptera; family: Crambidae; genus: Donacaula; specificEpithet: niloticus; taxonRank: species; verbatimTaxonRank: sp.; scientificNameAuthorship: ; taxonomicStatus: accepted; Location: country: Spain; stateProvince: Andalusia; county: Cadiz; locality: Trebujena, Saltmarshes of Adventus, Seno de la Esparraguera; verbatimCoordinates: 36\u00b053'31.20\"N 6\u00b015'36.00\"W; verbatimLatitude: 36\u00b053'31.20\"N; verbatimLongitude: 6\u00b015'36.00\"W; Identification: identifiedBy: J.J. Guerrero; dateIdentified: 2020; Event: samplingProtocol: light trap; eventDate: 08/09/2020; year: 2020; month: 9; day: 8; Record Level: institutionCode: ZAF-UMU; collectionCode: RCBA; basisOfRecord: PreservedSpecimenDonacaulaniloticus according to the diagnosis in Donacaula, are for the male: forewing with dark brownish line from the costal margin to approximately the centre of the wing, parallel to the outer margin; and for the female: forewing with white discocellular spot and apex non-pointed. Integrating the evidence from COI mitochondrial DNA sequences and adult morphology, we conclude that the D.niloticus specimen collected in the saltmarshes of Adventus (C\u00e1diz) is genetically different to other species included in the genus Donacaula from Europe and North America.The Iberian specimen showed morphological traits Figs , 2 typicDonacaulaniloticus and seven Donacaula species from Europe and North America, including Scirpophagapraelata as additional Schoenobiinae species, are presented in Table The COI divergences between All trees presented the same topology and were practically identical; therefore, only the ML tree is presented here with the branch tips collapsed since each of the groups of sequences correspond to a single BIN Fig. . The comDonacaulaniloticus in the riparian vegetation near to the mouth of the Guadalquivir River into the saltmarshes of Adventus  is confirmed by integrating the evidence from COI mitochondrial DNA sequences and adult morphology and is genetically different to the other two European and six North American Donacaula species. Molecular data indicate significant divergence with large mean distances amongst Donacaula species (13.0%) with maximum distance between D.sordidellus and D.longirostrallus and minimum distance between D.melinellus and D.mucronella (7.6%). In the case of D.niloticus, the distance to the European Donacaula species was 13% to D.forficella and 11.8% to D.mucronella, while the genetic divergence amongst D.forficella and D.mucronella was 13%. .The presence of  species 3.0% with%. Table . AlthougDonacaula is associated with various semi-aquatic and marsh plants where their larval stages live in stems or roots or on exposed and non-submerged leaves of Phragmitesaustralis, Glyceria spp. and Carex spp. These lepidopterans have developed various strategies and adaptations that have allowed them to stay in close proximity to water  which forms estuaries, salt marshes and marshes with a mixture of salty and fresh waters which is represented by the communities Cistancho-Arthrocnemetum macrostachyi, Polygono-Limoniastretum monopetaliSpartinetum maritimae, Puccinellio-Sarcocornietum perennis, Halimiono-Sarcocornietum alpini,  and, on the edge of the estuaries, the halonitrophilic community, Cistancho-Suaedetumverae. Sometimes, a plantation of Polygono-Tamaricetumafricanae may appear. The land use bordering the habitat are mainly agricultural fields  of the Data typeMaximum Likelihood tree (ML)Brief descriptionDonacaula species rooted with Scirpophagapraelata. Branch supports are represented by SH-aLRT/aBayes/UFBoot.Maximum Likelihood tree (ML)  including 99 sequences of selected File: oo_607849.pdfhttps://binary.pensoft.net/file/607849Antonio S. Ortiz"}
+{"text": "Many flies have specially evolved feeding mechanisms to imbibe liquids of specific viscosities. Observations of feeding on atypical liquids are notable because of their rarity.Philolicherondani.We report the first record of intrusive fluid feeding on vertebrate carrion by  Diptera constitute one of the five taxonomically megadiverse insect orders 19FAFF98-8D86-5F61-BD1E-029FBC8D2480Type status:Other material. Occurrence: individualCount: 1; sex: female; lifeStage: adult; behavior: feeding; occurrenceStatus: present; preparations: photograph; Taxon: scientificName: Philolicherondani; acceptedNameUsage: Philolicherondani; parentNameUsage: Tabanidae; kingdom: Animalia; phylum: Arthropoda; class: Insecta; order: Diptera; family: Tabanidae; genus: Philoliche; specificEpithet: rondani; taxonRank: species; scientificNameAuthorship: ; nomenclaturalCode: ICZN; taxonomicStatus: accepted; Location: higherGeographyID: 7017573; higherGeography: Africa: South Africa: Limpopo: Mookgophong: ASDIA Wild Game Farm; continent: Africa; country: South Africa; countryCode: ZA; stateProvince: Limpopo; locality: ASDIA Wild Game Farm; verbatimLocality: ASDIA Wild Game Farm, Mookgophong region; locationAccordingTo: Getty Thesaurus of Geographic Names; verbatimCoordinates: 24\u00b026'S 28\u00b025'E; verbatimLatitude: 24\u00b026'S; verbatimLongitude: 28\u00b025'E; verbatimCoordinateSystem: degrees minutes; decimalLatitude: -24.43333; decimalLongitude: 28.41666; Identification: identifiedBy: John Chainey; Event: eventDate: 2014-12; startDayOfYear: 334; endDayOfYear: 365; year: 2014; month: 12; verbatimEventDate: December 2014; habitat: savanna; eventRemarks: about 18 hours post mortem; Record Level: type: StillImage; modified: 2014-12; rights: Content licensed under Creative Commons Attribution 4.0 International; rightsHolder: R Boon; basisOfRecord: HumanObservation24\u00b026'S, 28\u00b025'E) in the Mookgophong area of Limpopo, South Africa, a female of Philoliche (Philoliche) rondani  was photographed visiting the carcass of a blue wildebeest ) cow that had died during calving  rondani specimens was taken from the KwaZulu-Natal Museum entomology collection (n = 15) and the average ratio of proboscis length  to head height  was measured using vernier calipers.A random selection of Tabanidae.Measurements of preserved specimens found the ratio of proboscis to head height to be 1.59:1 (n = 15). The minimum observed ratio was 1.15:1. In Fig. P. (P.) rondani is needed to establish the ability of these secretions to reverse the coagulation of blood. The reversal of coagulation is a likely explanation for this feeding observation, given the morphological specialisation in Philoliche.The average night time temperature in Mookgopong in December is 17.4\u00b0C, which is not low enough to delay decomposition or blood coagulation. Given the depth that the proboscis has penetrated and the time since death, intrusive feeding on coagulated blood is the most likely explanation for this observation. Further investigation into the oral secretions of Tabanidae at carcasses, but these observations have largely been dismissed as incidental (Tabaninae (three), Pangoniinae (one) and Scepsidinae (one). The variety in distribution and diversity of these observations indicates that more attention needs to be given to potential carcass feeding in Tabanidae and the potential range of viscosity in their food.Several authors have noted cidental . This maTabanidae provide evidence for their presence on a corpse and could show that a corpse has been moved after death (This behaviour is relevant to the field of forensic entomology and further investigation into the frequency of this behaviour is warranted. In future, known post-mortem bite marks should be documented, as the physiological response is likely to be different from that in pre-mortem bites. Post-mortem bite marks indicating feeding by er death ."}
+{"text": "Following publication of the original article , the autIncorrect: Kullbeck.Correct: Kullback.The original article has been corrected."}
+{"text": "RSC Advances article due to a significant amount of unattributed text overlap with The Royal Society of Chemistry hereby wholly retracts this Somayeh Sohrabi, Nour kassir and Mostafa Keshavarz Moraveji have not agreed to the retraction.RSC Advances Executive Editor.Signed: Laura Fisher, th November 2022.Date: 25"}
+{"text": "Following publication of the original article , the autGivenName: MshunqaneFamilyName: NombekoThe incorrect author\u2019s name is:GivenName: NombekoFamilyName: MshunqaneThe correct author\u2019s name is:The author group has been updated above and the original article  has been"}
+{"text": "Consent was added to this article: The patient provided consent (by signing on a consent document) at the time of tumor tissue and blood sample collection stating willingness to: Provide the required sample for tumor molecular profiling.Research use of deidentified data including publication of (deidentified) findings.4358-4363. https://doi.org/10.18632/oncotarget.27809Original article: Oncotarget. 2020; 11:4358\u20134363."}
+{"text": "Due to a publishing error the article: \u201cThe effect of cooling procedures on monomer elution from heat-cured polymethyl methacrylate denture base materials\u201d, published at Journal of Applied Oral Science 2022;30:e20220161 was printed with the following error:Where it reads:It should read:Where it reads:It should read:"}
+{"text": "The seventh author\u2019s name is spelled incorrectly. The correct name is: Shira Gur-Arieh. There is also an error in affiliation 6 for author Shira Gur-Arieh. The correct affiliation 6 is: The Leon Recanati Institute for Maritime Studies, University of Haifa, Haifa, Israel."}
+{"text": "The original version of the above article contains errors that need to be corrected. Incorrect ALP staining images for Fig.\u00a0Additional file 1: Fig. S3. The original gel images of BSP and ALP results in fig.3c. a The original gel image of BSP. b The original gel image of BSP with labels and marks. c The original gel image of ALP. d The original gel image of ALP with labels and marks. PDLSCS: periodontal ligament stem cell sheet; JBMMSCS: jaw bone marrow-derived mesenchymal stem cell sheet; CSCS: composite stem cell sheet; Yellow arrows: the blots displayed in fig.3c (BSP and ALP)."}
+{"text": "The correct name is: Simon Traub. The correct citation is: Traub S, Pianykh OS (2022) An alternative to the black box: Strategy learning. PLoS ONE 17(3): e0264485."}
+{"text": "Following publication of the original article , the autThe incorrect heading is: Transmittance electron microscopyThe correct heading is: Transmission electron microscopyThe incorrect name of the electron microscope is: Zeiss EM900The correct name of the electron microscope is: EM-10, Zeiss, GermanyThe original article  has been"}
+{"text": "Analysis of broad-spectrum antibiotic use in pneumonia revealed that 60% of patients were overtreated, highlighting the need for effective antibiotic stewardship practices.Systems such as the Drug Resistance in Pneumonia (DRIP) score select patients who are more likely to need broad spectrum antibiotics but still leads to overtreatment as it does not target specific pathogens. Rapid diagnostics such as the Unyvero Lower Respiratory Tract Panel (LRTP) can identify specific pathogens to narrow antibiotic use even further when combined with the DRIP score.max and DRIPmin were calculated assuming all missing elements were positive or negative respectively. The sensitivity and specificity of the DRIP score vs culture and LRTP were determined. An algorithm for antibiotic selection based on the results of the DRIP score combined with the LRTP was applied to each patient  .Using an existing patient pool from a clinical trial of the LRTP (NCT01922024) a DRIP score was determined for each patient. When data elements of the DRIP score were unavailable a DRIPStenotrophomonas maltophilia Applying the algorithm to each patient based on the DRIP score and the LRTP improved antibiotic choices by reducing broad spectrum antibiotic and by more selectively targeting the identified pathogens earlier and eliminating use of multiple empiric antibiotics.The sensitivity of the DRIP score vs culture in this population was 91.2% and the specificity was 65.1%. DRIP score vs culture + LRTP combined had a sensitivity of 86.6% and a specificity of 66.3%., the lower sensitivity was mainly due to Using an antibiotic stewardship algorithm combining DRIP score with LRTP rapid diagnostic data, which results in 5 hours, can lead to improved prediction of the presence of drug resistant pathogens and aid in narrowing antibiotics. The LRTP compensates for the DRIP score only predicting presence of antibiotic resistant pathogens, not specific pathogens. The DRIP score can compensate for the LRTP only having limited antibiotic resistance markers on panel and not supplying phenotypic antibiotic resistance testing. Further study using a prospectively collected cohort with antibiotic adjustment in real time is needed for validation of our results.Matthew Sims, MD PhD, Astra Zeneca: Grant/Research Support|ContraFect: Grant/Research Support|Crestone: Grant/Research Support|Diasorin Molecular LLC: Grant/Research Support|Epigenomics Inc: Grant/Research Support|EUROIMMUN US: Grant/Research Support|Finch Theraputics: Grant/Research Support|Genentech USA Inc: Grant/Research Support|Janssen Research and Development LLC: Grant/Research Support|Kinevant Sciences GmBH: Grant/Research Support|Leonard-Meron Biosciences: Grant/Research Support|Lysovant: Grant/Research Support|Merck: Grant/Research Support|OpGen: Grant/Research Support|Prenosis: Advisor/Consultant|Prenosis: Grant/Research Support|Qiagen: Grant/Research Support|Regeneron Pharmaceuticals: Grant/Research Support|Seres Therapeutics Inc: Grant/Research Support|Shire: Grant/Research Support|Summit Therapeutics: Grant/Research Support."}
+{"text": "Following publication of the original article , the autsection.The corrected Author contributions should read:The idea and design of project: MA; designed the experiments: HST, FF, PM; performed the experiments: HST; Analyzed data: HST, FF, PM; Wrote the paper: HST; Comprehensive reading and editing of the manuscript: MA, FF, PM.The authors affiliation has been updated above and the original article  has been"}
+{"text": "This series lists a pictorial quiz pertaining to identification of normal and abnormal anatomical structures and landmarks at a given level on computed tomography (CT). Readers are expected to identify and appreciate the changes from normal anatomy and variations of a given pathology. It is anticipated that this series will enhance the understanding of sectional anatomy of the brain to aid in brain CT interpretation. AnswersA: Frontal (anterior) horn of left lateral ventricleB Septum pellucidumC: Right lentiform nucleusD: Head of left caudate nucleusE: Right thalamusF: Posterior limb of the left internal capsule G: Occipital (posterior) horn of the left lateral ventricleH: Splenium of corpus callosum  The image is at the level of level of the basal ganglia which is group of paired deep grey matter nuclei including caudate and lentiform nucleus. Thin linear high density seen in the occipital horns of the lateral ventricles is due to calcification of the choroid plexus. Acute subdural hematoma characteristically appears as a crescent shaped high density area.Sub-acute subdural hematoma can be isodense to the normal brain parenchyma makings its detection difficult on CT. Chronic subdural hematoma is lower in density compared to the brain parenchyma.rd Ed. New York: Elsevier Health Sciences; 2011.1. Ryan S, McNicholas M, Eustace SJ. Anatomy for diagnostic imaging e-book. 32. Currie S, Kennish S, Flood K. Essential Radiological Anatomy for the MRCS. Cambridge University Press. 2009.3. Moeller T, Reif E. Pocket atlas of sectional anatomy. Computed tomography and magnetic resonance imaging. Vol. 1 Head and neck. Stuttgart: Thieme; 2013."}
+{"text": "Due to a publishing error the article: \u201cPreemptive analgesia with ibuprofen increases anesthetic efficacy in children with severe molar: a triple blind randomized clinical trial\u201d, published at Journal of Applied Oral Science 2022;30:e20210538 was printed with the following error:Where it reads:Title: Preemptive analgesia with ibuprofen increases anesthetic efficacy in children with severe molar: a triple blind randomized clinical trialThe sentence should read:Title: Preemptive analgesia with ibuprofen increases anesthetic efficacy in children with severe molar hypomineralization: a triple-blind randomized clinical trial"}
+{"text": "The Sharr Mountains are one of the most important hotspots of terrestrial and freshwater biodiversity in the Balkan Peninsula, with many endemic and rare species. The caddisfly studies in this area increased during the past years, although insufficiently investigated areas still remain.Potamophylaxhumoinsapiens sp. n. from the Sharr Mountains in the Republic of Kosovo, which is morphologically closest to Potamophylaxidliri Ibrahimi, Bilalli & Ku\u010dini\u0107, 2022 and Potamophylaxjuliani Kumanski, 1999. The males of the new species differ from all known species of the Potamophylaxwinneguthi Species Group by their uniquely-shaped parameres, which are long, bulbous in their basal half and thin in the remaining length, with a bunch of very thin and long, hair-like spines, grouped uniformly at the apex. The new species further differs from its most similar congeners by its very wide distance between the dorsal and ventral edges of the apical part of inferior appendages in lateral view. The new species was found at three localities from 1416 to 1505 m a.s.l.In this paper, we describe a new species, Potamophylaxwinneguthi Species Group, which have very narrow distribution areas, we posit that Potamophylaxhumoinsapiens sp. n. is a microendemic of the Sharr Mountains. The new species is the second known caddisfly species occurring only in the Kosovan part of the Sharr Mountains.Similar to the other species of the  The knowledge about the caddisflies of Kosovo has increased significantly over the past decade. Only few species were known before 2011 e.g.  and the The Sharr Mountains are one of the most important hotspots of freshwater and terrestrial biodiversity in the Balkan Peninsula, with many endemic and rare plant and animal species e.g. . This moPotamophylaxwinneguthi Species Group from the Sharr Mountains in Kosovo and also discuss morphological, molecular and ecological features of the Potamophylaxwinneguthi Species Cluster.In this paper, we describe a new species of the Fieldwork, identification and taxonomic work. We collected adults of the new species with ultraviolet light traps. Nocturnal light trapping followed Potamophylaxhumoinsapiens sp. n., we used specimens of Potamophylaxjuliani Kumanski, 1999, Potamophylaxwinneguthi Malicky, 1999  and Morphological characteristics of male terminalia of the new species were examined in specimens cleared in 10% potassium hydroxide (KOH). Nomenclature of male terminalia follows Potamophylaxhumoinsapiens sp. n. were analysed from 12 male specimens by using the Olympus SZX16 stereomicroscope. Illustrations were prepared in Adobe Illustrator (version Creative Cloud 2018) by digitising pencil templates drawn in the pictures taken with Olympus SC50 camera.Morphological features of genitalia of Specimens of the new species were collected at three localities in the Sharr Mountains, belonging to the Sht\u00ebrpce and Prizren Municipalities Fig. Ibrahimi & Bilallisp. n.721160E4-BE2A-5F10-A8A4-8B4BA1A0840895A49795-937A-419F-BA72-A85AD2C1C98EType status:Holotype. Occurrence: recordedBy: Halil Ibrahimi, Astrit Bilalli; individualCount: 1; sex: male; lifeStage: adult; occurrenceID: 6E91A186-F8FF-5E67-A55C-F4BF514BD704; Taxon: class: Insecta; order: Trichoptera; family: Limnephilidae; genus: Potamophylax; nomenclaturalCode: ICZN; Location: continent: Europe; waterBody: Aegean Sea Basin; country: Kosovo; countryCode: XKS; municipality: Sht\u00ebrpce; locality: main road towards Prevall\u00eb; verbatimLocality: sidestream of the Lepenc River; verbatimElevation: 1416; decimalLatitude: 42.172804; decimalLongitude: 20.969464; Event: samplingProtocol: UV light trap; year: 2021; month: 11; day: 12Type status:Paratype. Occurrence: recordedBy: Halil Ibrahimi, Astrit Bilalli; individualCount: 12; sex: males; lifeStage: adults; occurrenceID: 89E22BF4-8039-5F0B-A92B-6620CF80DFB8; Taxon: class: Insecta; order: Trichoptera; family: Limnephilidae; genus: Potamophylax; nomenclaturalCode: ICZN; Location: continent: Europe; waterBody: Aegean Sea Basin; country: Kosovo; countryCode: XKS; municipality: Sht\u00ebrpce; locality: main road towards Prevall\u00eb; verbatimLocality: sidestream of the Lepenc River; verbatimElevation: 1416; decimalLatitude: 42.172804; decimalLongitude: 20.969464; Event: samplingProtocol: UV light trap; year: 2021; month: 11; day: 12Type status:Paratype. Occurrence: recordedBy: Halil Ibrahimi, Astrit Bilalli; individualCount: 20; sex: males; lifeStage: adults; occurrenceID: 97FDA7E5-5061-50AA-9C21-CE0ADE296551; Taxon: class: Insecta; order: Trichoptera; family: Limnephilidae; genus: Potamophylax; nomenclaturalCode: ICZN; Location: continent: Europe; waterBody: Aegean Sea Basin; country: Kosovo; countryCode: XKS; municipality: Sht\u00ebrpce; locality: 2 km away from the main road Sht\u00ebrpce - Prevall\u00eb; verbatimLocality: Lepenc River; verbatimElevation: 1505; decimalLatitude: 42.176299; decimalLongitude: 20.984170; Event: samplingProtocol: UV light trap; year: 2021; month: 11; day: 20Type status:Paratype. Occurrence: recordedBy: Halil Ibrahimi, Astrit Bilalli; individualCount: 7; sex: males; lifeStage: adults; occurrenceID: 68CC6836-CFAE-5D3A-8226-FA10865B105E; Taxon: class: Insecta; order: Trichoptera; family: Limnephilidae; genus: Potamophylax; nomenclaturalCode: ICZN; Location: continent: Europe; waterBody: Aegean Sea Basin; country: Kosovo; countryCode: XKS; municipality: Sht\u00ebrpce; locality: few kilometers before Brezovica ski center; verbatimLocality: tributary of the Lepenc River; verbatimElevation: 1457; decimalLatitude: 42.185053; decimalLongitude: 21.006089; Event: samplingProtocol: UV light trap; year: 2021; month: 11; day: 12Male. General appearance  in lateral view very long paramere shaft, bulbous in basal half, thin in the remaining length; (2) median ventral incision on paramere shaft in lateral view; (3) parallel set-up of the basal 2/3rd of parameres on ventral view, with distal thirds diverging greatly from each other; (4) 30-40 very thin and long apical hair-like spines on parameres, grouped uniformly, curved and directed mesad in lateral view, almost reaching apex of the aedeagus in ventral view; (5) very wide distance between the dorsal and ventral corners of the apical part of inferior appendages, 2.1 times wider than in P.coronavirus, 1.4 times wider than in P.idliri and 1.2 times wider than in P.juliani; and (6) longer ventral edge of inferior appendages. The P.idliri male has long shaft of parameres, very narrow mesally, wide apically on lateral view; ventral incision on paramere shaft is located right after the basal third on lateral view; parallel set-up of the basal 1/3rd of parameres, with the remaining length gradually diverging from each other on ventral view; 10-15 medium long and very thick apical spines of different sizes on parameres, grouped irregularly, directed mesad; longer ventral edge of inferior appendages on lateral view. The P.juliani male has a short shaft of parameres with wider basal half on lateral view without any incision; parallel set-up of parameres, only with apices diverging from each other on ventral view; medium long 5-10 medium thick apical spines on parameres; ventral and dorsal corners of inferior appendages parallel to each other, directed mesad on lateral view. The P.coronavirus male has a short shaft of parameres, slightly wider on basal half on lateral view; ventral margin of paramere shaft straight, without any incision on lateral view; parallel set-up of parameres, only with apices diverging from each other, on ventral view; short, thick 5-10 apical spines on parameres; ventral and dorsal corners of inferior appendages parallel to each other, directed mesad on lateral view.Males of the new species are most similar to those of ies Figs , 8. The The species epithet is a combination of two Latin words, \u2018humo\u2019, which in English means \u2018to cover with soil, to bury\u2019 and \u2018insapiens\u2019 meaning \u2018unwise\u2019 and refers to the unwise and careless treatment of habitats of the new species, degraded greatly during the past years by hydropower plants and other activities. In some segments, the whole parts of the Lepenc River are \u2018buried\u2019 in large pipes.Potamophylaxhumoinsapiens sp. n. was found at three localities during 2021 in the Sharr Mountains, in the tributaries of the Lepenc River. All sampling sites are located inside a forested area. The substrates of streams close to the sampling sites were dominated by meso- to macrolithal substrate, surrounded by dense riparian vegetation. The species was captured only by ultraviolet light traps. The species was collected during October and November, implying it has an autumn flying period. All sampling sites are located in upstream sections of streams and rivers.Potamophylaxhumoinsapiens sp. n. have been found during 2009 in tributaries of the Lepenc and Lumbardhi i Prizrenit Rivers. The genetic distinction, calculated based on sequencing of the barcode region of the cytochrome c oxidase subunit I gene (COI) between Potamophylaxhumoinsapiens sp. n. and other species of the Potamophylaxwinneguthi Species Group, was found to be on par with those of the other morphologically recognised species in the group and especially the other five species of the P.winneguthi Species Cluster (Potamophylaxhumoinsapiens sp. n. is Potamophylaxidliri from the Jastrebac Mountains in Serbia, with the p-distance of 4%. However, due to the low number of specimens, we refrained from describing it as a new species at that time. During 2021, we collected a large number of male specimens and, based on a large scale analysis of more than 40 male specimens, we realised that the differences in paramere shape, spine pattern, inferior appendages and other characters are stable and easily distinguishable from all other species of this Species Group.Two male specimens of  Cluster . These mPotamophylaxwinneguthi Species Cluster contains six species, all of them confined to certain mountains of the Balkan Peninsula. Species of this cluster have diversified in several characters of the male terminalia, the most visible being paramere shaft shape and size, paramere spine pattern and length and inferior appendages shape. Paramere shaft varies in length, width of basal and apical parts, as well as the curvature. Paramere spine pattern is especially diverse in this species complex. Spines vary from being very thick in P.winneguthi, medium thick in P.juliani, P.idliri and P.coronavirus and very thin and hair-like in P.humoinsapiens sp. n. Length of paramere spines varies from very short as 1/5th of the total paramere shaft lengh in P.juliani and P.coronavirus, as 1/3rd of paramere shaft in P.idliri, as half of paramere shaft in P.humoinsapiens sp. n. and as long as paramere shaft in P.winneguthi. In P.haidukorum Malicky, 1999 spines are lacking completely and paramere shaft is long and slender. The level of divergence in the female terminalia remains to be studied, as currently only females of P.juliani, P.winneguthi and P.haidukorum are described (Currently the escribed .Potamophylaxwinneguthi Species Group are all found at isolated habitats at different mountain ranges of the Balkan Peninsula, usually at upstream segments of streams and rivers. These habitats have deteriorated heavily during the past decades by illegal logging, pollution and water extraction. Considering the fact that all species of this cluster up to now are known to be microscale endemics of certain mountain ranges, we posit that other new species will be found in the Balkans in future.Species of the Potamophylaxhumoinsapiens sp. n. is the second known endemic caddisfly species occurring only in the Kosovan part of the Sharr Mountains, the first one being Drusussharrensis Ibrahimi, Ku\u010dini\u0107 & Vitecek, 2015. This part of the Sharr Mountains represents the spring and upstream area of two rivers, namely Lepenc and Lumbardhi i Prizrenit. During the past decade, both rivers have deteriorated heavily, primarily by construction of dams and hydropower plants, illegal logging and pollution. Some of these activities occur in the very vicinity of the freshwater ecosystems where the new species is found. During the sampling of 2021, the new species was not found at one of the localities where it was sampled during 2009. Although large areas of upstream segments of both rivers are within the borders of the protected area, more law enforcement activities in the field are needed in order to protect unique freshwater diversity of this part of the Sharr Mountains, including the newly-described species Potamophylaxhumoinsapiens sp. n."}
+{"text": "Abstract: ; Results: 9678 participants .There were some errors in the original publication in the Abstract and Results sections . AbstracAbstract, line 6: ; Results, Paragraph 1, line 1: 9775 participants .A correction has been made to The authors state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."}
+{"text": "The Department of Acute Kidney Injury (IRA) of the Brazilian Society of Nephrology prepared this document for the purpose of standardizing AKI terminology and dialysis modalities in the Portuguese language for Brazil. Several terms with similar meanings have been used in AKI and its dialysis modalities, causing confusion and disparities among patients, nephrologists, health institutions, private care companies, insurance companies and government entities. These disparities can impact medical care, hospital organization and care, as well as the funding and reimbursement of AKI-related procedures. Thus, consensual nomenclature and definitions were developed, including the definitions of AKI, acute kidney disease (AKD) and chronic kidney disease (CKD). Additionally, we addressed all dialysis modalities and extracorporeal procedures related to AKI, currently approved and available in the country. The Brazilian Society of Nephrology hopes that this Consensus can standardize the terminology and provide technical support to all involved in AKI care in Brazil. Acute kidney injury (AKI) is a frequent complication in hospitalized patients, especially in ICUs, still causing high rates of morbidity and mortality. AKI can also occur in outpatients and in the community, often related to socioeconomic and cultural conditions. Several terms with similar meanings have been used in AKI and its dialysis modalities, causing confusion and disparities among patients, nephrologists, healthcare institutions, private care companies, insurance companies and government entities. These disparities can impact medical care, hospital organization and care, as well as the funding and reimbursement of AKI-related procedures. Thus, we worked on the terminology and consensual definitions, including the definitions of AKI, acute kidney disease (AKD) and chronic kidney disease (CKD). Additionally, all dialysis modalities and extracorporeal procedures related to AKI, currently approved and available in the country, were addressed in this document by the AKI Department of the Brazilian Society of Nephrology.. An additional advantage of using the term \u201cinjury\u201d is that it encompasses initial cases with cellular and tissue functional alterations to cases of established anatomical lesions. Therefore, it is suggested to avoid the term acute kidney lesion (AKL), which would be restricted to cases of anatomic kidney lesion.Preferably, use the term Acute Kidney Injury, in order to maintain the acronym AKI, which is well established and widespread in our country. In addition, the term was also approved in the Ibero-American Consensus on the Uniformity of Nomenclatures, observing the deliberations proposed by the Kidney Disease: Improving Global Outcomes (KDIGO) panelWe must also avoid the term \u201cfailure\u201d, as it denotes a more advanced stage of renal failure.2 or when dialysis is required .- Single-pass albumin dialysis. Single-pass albumin dialysis (SPAD).- Hemoperfusion to remove bilirubin and bile salts (uses the same system as hemoperfusion to remove medium molecules).Note: Therapeutic plasma exchange may be considered as artificial liver support.2). Extracorporeal CO2 removal (ECCO2R).- Extracorporeal removal of carbon dioxide  and high partition (high cutoff).- Dialysis solution: polyelectrolytic concentrate for hemodialysis.- Anticoagulation: heparin (unfractionated or low molecular weight), citrate or without anticoagulation.- Place of treatment: preferably in individualized rooms, rooms for hemodialysis or in intensive and semi-intensive care units.- Duration: up to 6 hours.- Technique: hemofiltration.- Removal mechanism: convection.- Equipment: hemodialysis machine and machines capable of performing ultrafiltration alone.- Device: membrane filters with biocompatible polymer.- Filter type: low flow, high flow, medium partition (medium cutoff) and high partition (high cutoff).- Dialysis solution: not applicable.- Anticoagulation: heparin (unfractionated or low molecular weight), citrate or without anticoagulation.- Place of treatment: preferably in individualized rooms, rooms for hemodialysis or in intensive and semi-intensive care units.- Duration: up to 6 hours.- Technique: hemodialysis and hemofiltration.- Removal mechanism: diffusion and convection.- Equipment: hemodialysis machine with module for hemodiafiltration.- Device: membrane filters with biocompatible polymer.- Filter type: high flow.- Dialysis and replacement solution: polyelectrolytic concentrate for hemodialysis.- Anticoagulation: heparin (unfractionated or low molecular weight), citrate or without anticoagulation.- Place of treatment: preferably in individualized rooms, hemodialysis rooms or in intensive and semi-intensive care units, with ultrapure water criteria.- Duration: 6 to 12 hours.- Technique: hemodialysis.- Removal mechanism: diffusion.- Equipment: hemodialysis machine.- Device: membrane filters with biocompatible polymer.- Filter type: low flow, high flow, medium partition (medium cutoff) and high partition (high cutoff).- Dialysis solution: polyelectrolytic concentrate for hemodialysis.- Anticoagulation: heparin (unfractionated or low molecular weight), citrate or without anticoagulation.- Place of treatment: preferably in individualized rooms, rooms for hemodialysis or in intensive and semi-intensive care units.- Duration: 6 to 12 hours.- Technique: hemofiltration.- Removal mechanism: convection.- Equipment: hemodialysis machine and machines capable of performing ultrafiltration alone.- Device: membrane filters with biocompatible polymer.- Filter type: low flow, high flow, medium partition (medium cutoff) and high partition (high cutoff).- Dialysis solution: not applicable.- Anticoagulation: heparin (unfractionated or low molecular weight), citrate or without anticoagulation.- Place of treatment: preferably in individualized rooms, rooms for hemodialysis or in intensive and semi-intensive care units.- Duration: 6 to 12 hours.- Technique: hemodialysis and hemofiltration.- Removal mechanism: diffusion and convection.- Equipment: hemodialysis machine with module for hemodiafiltration.- Device: membrane filters with biocompatible polymer.- Filter type: high flow.- Dialysis and replacement solution: polyelectrolytic concentrate for hemodialysis.- Anticoagulation: heparin (unfractionated or low molecular weight), citrate or without anticoagulation.- Place of treatment: preferably in individualized rooms, rooms for hemodialysis or in an intensive and semi-intensive care unit, with ultrapure water.- Duration: > 12 hours.- Technique: hemodialysis, hemofiltration or hemodiafiltration.- Removal mechanism: diffusion, convection and adsorption.- Equipment: continuous hemodiafiltration machine with autonomy for uninterrupted operation for more than 24 hours.- Device: membrane filters with biocompatible polymer.- Filter type: high flow and high partition (high cutoff).- Dialysis and replacement solution: specific electrolyte solutions for continuous hemodiafiltration.- Anticoagulation: heparin (unfractionated or low molecular weight), citrate or without anticoagulation.- Place of treatment: intensive and semi-intensive care units and surgical center.- Duration: > 12 hours.- Technique: hemofiltration.- Removal mechanism: convection.- Equipment: continuous hemodialysis machines and specific equipment for isolated ultrafiltration, with autonomy for uninterrupted operation of more than 24 hours.- Device: membrane filters with biocompatible polymer.- Filter type: low or high flow.- Dialysis and replacement solution: not applicable.- Anticoagulation: heparin (unfractionated or low molecular weight), or without anticoagulation.- Place of treatment: intensive and semi-intensive care units and surgical center.- Duration: up to 12 hours.- Volume: up to 12 L.- Technique: peritoneal dialysis.- Removal mechanism: diffusion.- Equipment: not applicable.- Solutions: hypertonic glucose or icodextrin.- Anticoagulation: not applicable.- Place of treatment: preferably in individualized rooms, rooms for hemodialysis or in intensive and semi-intensive care units.- Duration: > 12 hours.- Standard volume: up to 12 L.- Technique: peritoneal dialysis.- Removal mechanism: diffusion.- Equipment: not applicable.- Anticoagulation: not applicable.- Solutions: hypertonic glucose, icodextrin.- Place of treatment: preferably in individualized rooms, rooms for hemodialysis or in intensive and semi-intensive care units.- Duration: up to 12 hours.- Standard volume: up to 12 L.- Technique: peritoneal dialysis.- Removal mechanism: diffusion.- Equipment: cycling machine.- Solutions: hypertonic glucose or icodextrin.- Anticoagulation: not applicable.- Place of treatment: preferably in individualized rooms, rooms for hemodialysis or in intensive and semi-intensive care units.Note: the term \u201cautomated\u201d implies the need for a specific machine for this therapy.- Duration: > 12 hours.- Standard volume: up to 12 L.- Technique: peritoneal dialysis.- Removal mechanism: diffusion.- Equipment: cycling machine.- Solutions: hypertonic glucose.- Anticoagulation: not applicable.- Place of treatment: preferably in individualized rooms, rooms for hemodialysis or in intensive and semi-intensive care units.- Duration: > 12 hours.- Standard volume: > 12 L up to 42 L.- Technique: peritoneal dialysis.- Removal mechanism: diffusion.- Equipment: cycling machine.- Solutions: hypertonic glucose.- Anticoagulation: not applicable.- Place of treatment: preferably in individualized rooms, rooms for hemodialysis or in intensive and semi-intensive care units.- Duration: 2-6 hours.- Technique: hemofiltration.- Removal mechanism: convection limited by the size of the molecule.- Equipment: hemodialysis or continuous hemodiafiltration machine with plasmapheresis module.- Device: membrane filters with biocompatible polymer.- Filter type: plasma filter.- Replacement solution: solution with human albumin, fresh frozen plasma or cryoprecipitate.- Anticoagulation: heparin (unfractionated or low molecular weight), citrate or without anticoagulation.- Place of treatment: preferably in individualized rooms, rooms for hemodialysis or in intensive and semi-intensive care units.- Duration: 2-6 hours.- Technique: centrifugation.- Removal mechanism: sedimentation by specific gravity.- Equipment: centrifuge machine.- Device: not applicable.- Filter type: not applicable.- Replacement solution: solution with human albumin, fresh frozen plasma or cryoprecipitate.- Anticoagulation: heparin (unfractionated or low molecular weight), citrate or without anticoagulation.- Place of treatment: preferably in individualized rooms, rooms for hemodialysis or in intensive and semi-intensive care units.- Duration: 2-24 hours.- Technique: hemoperfusion.- Removal mechanism: adsorption.- Equipment: hemodialysis machines, continuous procedure machines or specific machines for hemoperfusion, or cartridges connected to the extracorporeal circulation circuit or to the extracorporeal membrane oxygenation (ECMO) circuit, in these situations without the need for specific equipment.- Device: cartridges with resins or microspheres.- Filter type: not applicable.- Dialysis and replacement solution:- In case of use of a specific machine for hemoperfusion: not applicable.- If using a hemodialysis or hemofiltration machine: specific electrolyte solutions.- In case of use of continuous hemodiafiltration machine: specific electrolyte solutions for continuous hemodiafiltration.- Anticoagulation: heparin (unfractionated or low molecular weight), citrate or without anticoagulation.- Place of treatment: preferably in individualized rooms, rooms for hemodialysis, intensive care unit, semi-intensive care unit and surgical center.- Duration: 2-4 hours.- Technique: hemoperfusion.- Removal mechanism: adsorption.- Equipment: specific machine for hemoperfusion, hemodialysis machine or continuous hemodiafiltration connected in series with the pre- or post-filter extracorporeal circuit.- Device: cartridge with synthetic resins with specific adsorptive capacity.- Filter type: not applicable.- Dialysis and replacement solution:- In case of use of a specific machine for hemoperfusion: not applicable.- If using a hemodialysis or hemofiltration machine: specific electrolyte solutions.- In case of use of continuous hemodiafiltration machine: specific electrolyte solutions for continuous hemodiafiltration.- Anticoagulation: heparin (unfractionated or low molecular weight), citrate or without anticoagulation.- Place of treatment: intensive and semi-intensive care unit.- Duration: 6-8 hours.- Technique: hemodialysis and perfusion for regeneration of the albumin solution.- Removal mechanism: diffusion and adsorption by albumin.- Equipment: specific machine coupled to a continuous hemodiafiltration or hemodialysis machine.- Device: membrane filters with biocompatible polymer, with parallel circuit of activated carbon cartridge and ion exchanger cartridge, for recirculation of solution with albumin.- Type of filter: low flow  and high flow .- Dialysis and replacement solution: specific electrolyte solutions for continuous hemodiafiltration. Human albumin solution for the parallel circuit.- Anticoagulation: heparin (unfractionated or low molecular weight), citrate or without anticoagulation.- Place of treatment: intensive and semi-intensive care unit.- Duration: 6-8 hours.- Technique: hemodialysis.- Removal mechanism: diffusion.- Equipment: continuous hemodiafiltration machine with autonomy for uninterrupted operation for more than 24 hours.- Device: membrane filters with biocompatible polymer.- Filter type: high flow and high partition (high cutoff).- Dialysis solution: specific electrolyte solutions for continuous hemodiafiltration with the addition of human albumin.- Anticoagulation: heparin (unfractionated or low molecular weight), citrate or without anticoagulation.- Place of treatment: preferably in individualized rooms, rooms for hemodialysis or in intensive and semi-intensive care units.- Duration: 2-24 hours.- Technique: hemoperfusion.- Removal mechanism: adsorption.- Equipment: hemodialysis machines, continuous procedure machines or specific machines for hemoperfusion, or cartridges connected to the extracorporeal circulation circuit or to the extracorporeal blood oxygenation (ECMO) circuit, in these situations without the need for specific equipment.- Device: cartridges with resins or microspheres.- Filter type: not applicable.- Dialysis and replacement solution:- In case of use of a specific machine for hemoperfusion: not applicable.- If using a hemodialysis or hemofiltration machine: specific electrolyte solutions.- In case of continuous hemodiafiltration machine use: specific electrolyte solutions for continuous hemodiafiltration.- Anticoagulation: heparin (unfractionated or low molecular weight), citrate or without anticoagulation.- Place of treatment: preferably in individualized rooms, rooms for hemodialysis, intensive care unit, semi-intensive care unit and surgical center.- Duration: >48 h.- Technique: hemodialysis.- Removal mechanism: diffusion of gases.- Equipment: specific machine for hemoperfusion, continuous hemodiafiltration machine coupled to the oxygenating membrane.- Device: oxygenating membrane.- Filter type: not applicable.- Sweep gas: oxygen.- Dialysis and replacement solution:- In case of use of a specific machine for hemoperfusion: not applicable.- In case of use of continuous hemodiafiltration machine: specific electrolyte solutions for continuous hemodiafiltration.- Anticoagulation: heparin (unfractionated or low molecular weight) or without anticoagulation.- Place of treatment: intensive care unit.The AKI Department of the Brazilian Society of Nephrology prepared this document in order to standardize the terminology and definitions related to AKI.Terminology and consensual definitions were addressed, including definitions of AKI, acute kidney disease (AKI) and chronic kidney disease (CKD). All dialysis modalities and extracorporeal procedures related to AKI, currently approved and available in the country, were described. The Brazilian Society of Nephrology hopes that this Consensus can standardize the terminology and provide technical support to all sectors involved in AKI assistance in Brazil."}
+{"text": "Glycinemax) is a major source of edible oil and protein. A novel species of the genus Pythium, Pythiumhuanghuaiense, isolated from soybean seedlings in China, is described and illustrated on the basis of morphological characters and molecular evidence.Soybean (Pythiumhuanghuaiense sp. nov. is closely related to species of the genus Pythium in clade F, as evidenced by the presence of hyphal swellings and its relatively rapid morphological growth. However, it differs by having relatively small sporangia and plerotic or nearly plerotic and thin-walled oospores. A pathogenicity test confirmed the newly-identified species as a pathogen of soybean. Pythium Pringsheim are diverse, occupying a variety of habitats , wheat (Triticum spp.) and corn (Zeamays)  . Some Pyic fungi . To datein China .Pythium in the Huang-Huai Valley, a novel species of clade F was identified, based on morphological characters and molecular phylogenetic analyses of internal transcribed spacer (ITS) and cytochrome c oxidase subunit I (Cox1) sequence data. The novel species is described and illustrated in this work. Moreover, comparisons of the novel species with morphologically and phylogenetically related species are also provided.Huang-Huai Valley is one of the main areas of soybean farming in China, covering an enormous area in Shandong, Anhui, Jiangsu and Henan Provinces between the Yellow River and the Haihe River. During the studies on the diversity of During April and August 2016, 60 plants of soybean cultivar 'Hefeng 47' exhibiting seedling blight, damping off and root rot were collected from three fields in the Huang-Huai region of China. 'Hefeng 47' is commonly grown in the Huang-Huai Valley. The fields were located in Jining of Shandong Province, Suzhou of Anhui Province and Nanjing of Jiangsu Province, which are representative geographic locations in the Huang-Huai region. Soybean plants were sampled from fields at approximately 10 m intervals along a 150 m transect laid out in a \u201cW\u201d pattern.Soybean plants were washed three times with sterile water and six sections of 0.5\u20131 cm length were cut from the roots of each plants using a sterile scalpel. One section was taken from the root tip, one from the interface between the hypocotyl and soil and the others at either the middle of the root or a symptomatic area along the length of the root. The sections were blotted dry and embedded in selective V8 juice agar (V8A) containing rifampicin (50 mg/l), ampicillin (50 mg/l) and pentachloronitrobenzene (50 mg/l) and incubated for 2\u20133 days in the dark at 25\u00b0C. When mycelial growth was observed, cultures were purified by transferring a small piece of medium with mycelium at the edge of a colony to fresh medium or by transferring a single hyphal tip on to water agar three times.The cultures studied were deposited in the Herbaria of the Institute of Microbiology, Beijing Forestry University (BJFC), Beijing, China; the College of Plant Protection, Nanjing Agricultural University (NJAU), Nanjing, China; and the College of Landscape Architecture, Jiangsu Vocational College of Agriculture and Forestry (JAFLA), Zhenjiang, China. Purified isolates were examined after incubation for 2\u20133 days at 25\u00b0C on V8A in the dark. Colony patterns of the representative isolate of the novel species were examined after incubation for 3 days at 25\u00b0C on corn meal agar (CMA), potato carrot agar (PCA) and V8A media . IsolateDNA extraction, amplification, sequencing and sequence alignmentA cetyl trimethylammonium bromide (CTAB) rapid plant genome extraction kit  was used to extract total genomic DNA from purified isolates and the polymerase chain reaction (PCR) was performed according to the manufacturer\u2019s instructions . PCR amphttp://purl.org/phylo/treebase; submission ID S24209).Sequences, generated in this study, were aligned with additional sequences downloaded from GenBank Table  using ClPhylogenetic analysesSaprolegniaparasitica Coker were used as outgroups ; language: enType status:Paratype. Occurrence: recordedBy: Jiajia Chen; Taxon: scientificName: Pythiumhuanghuaiense; class: Oomycetes; order: Pythiales; family: Pythiaceae; genus: Pythium; Location: country: China; stateProvince: Jiangsu; locality: Nanjing, Jiangning District, Pengfu Village; Identification: identifiedBy: Jiajia Chen & Xiaobo Zheng; Event: year: 2016; month: 4; day: 1; habitat: Glycinemaxon seedlings of ; Record Level: type: Chen 95  & Chen 96 ; language: enType status:Paratype. Occurrence: recordedBy: Jiajia Chen; Taxon: scientificName: Pythiumhuanghuaiense; class: Oomycetes; order: Pythiales; family: Pythiaceae; genus: Pythium; Location: country: China; stateProvince: Anhui; locality: Suzhou; Identification: identifiedBy: Jiajia Chen & Xiaobo Zheng; Event: year: 2016; month: 7; habitat: Glycinemaxon seedlings of ; Record Level: type: Chen 99 ; language: enType status:Paratype. Occurrence: recordedBy: Jiajia Chen; Taxon: scientificName: Pythiumhuanghuaiense; class: Oomycetes; order: Pythiales; family: Pythiaceae; genus: Pythium; Location: country: China; stateProvince: Shandong; locality: Jining; Identification: identifiedBy: Jiajia Chen & Xiaobo Zheng; Event: year: 2016; month: 8; habitat: Glycinemaxon seedlings of ; Record Level: type: Chen 100 ; language: enType status:Other material. Occurrence: recordedBy: Jiajia Chen; Taxon: scientificName: Pythiumhuanghuaiense; class: Oomycetes; order: Pythiales; family: Pythiaceae; genus: Pythium; Location: country: China; stateProvince: Jiangsu; locality: Nanjing, Jiangning District, Pengfu Village; Identification: identifiedBy: Jiajia Chen & Xiaobo Zheng; Event: year: 2016; month: 4; day: 29; habitat: Glycinemaxon seedlings of ; Record Level: type: JAFLA 94, NJAU-JN11 ; language: enPathogenic on soybean. Colonies submerged, with a cottony pattern on CMA, a rosette pattern on PCA and a cottony pattern on 10% V8A Fig. . CardinaWith reference to the distribution of the species in the Huang-Huai area of China.Pythiumhuanghuaiense can be distinguished morphologically from its closest relatives, including P.mamillatum Meurs, P.paroecandrum Drechsler, P.spiculum B. Paul and P.wuhanense Y.Y. Long, J.G. Wei & L.D. Guo, by its narrower hyphae and relatively higher maximum growth rate. Additional differences between the novel species and other related species are listed in Table Pythium , representing an unknown species of Pythium, were obtained from soybean plant samples collected from three fields in three cities during April and August 2016.Five cultures of Pythiumhuanghuaiense, showed the best phylogenetic matches with species of clade F in Pythium , indicating that they are phylogenetically distinct from other species of clade F in Pythium  significantly stunted and reduced the growth of soybean seedlings compared with uninoculated controls ; mostly monoclinous, sometimes hypogynous antheridia; sub-globose, club-shaped or fist-shaped antheridial cells; and plerotic or nearly plerotic and thin-walled oospores (0.5\u20131.5 \u00b5m).Pythium can be split into 11 clades (A-K), of which clade F is composed of species with either globose, non-proliferating sporangia or globose hyphal swellings (only P.irregulare Buisman develops both) and a fast growth rate  was highly pathogenic on soybean and wheat (Pythium spp. associated with soybean in China, the novel species, P.huanghuaiense, was identified and described in this study on the basis of morphological characteristics and ITS and Cox1 sequence data. Additional pathogenicity tests and studies on the economic impact of P.huanghuaiense on soybean and other crop plants will be conducted in the future.Soybean is a major source of edible oil and protein and plays an important role in the human diet. Many species of  such as . Howevernd wheat . As part"}
+{"text": "Publisher Correction to: BMC Biol 9, 44 (2021)https://doi.org/10.1186/s12915-021-00980-yFollowing publication of the original article , the autThe correct tagging of the author name is:Given name: Hye InFamily name: KaThis results in the correct citation information for this author on Pubmed as: Ka HI.The metadata of the original article  has been"}
+{"text": "Diptera: Cecidomyiidae) inducing leaf bud galls on MagnoliakobusDC.var.borealis Sarg. (Magnoliaceae) was found in Hokkaido and northern Honshu, Japan.A gall midge species . The species is herein described as Pseudasphondyliasaohimea Matsuda, Elsayed and Tokuda sp. n. The new species is easily distinguishable from its congeners by the number of adult palpal segments and the shape of the male terminalia and larval spatula.Based on its morphology, the species is regarded as an undescribed species of the genus  Pseudasphondylia (Diptera: Cecidomyiidae: Asphondyliini) includes 11 species associated with various plant families (P.elaeocarpi Tokuda and Yukawa on Elaeocarpuszollingeri K.Koch (= E.sylvestrisvar.ellipticus Hara) (Elaeocarpaceae), P.kiritanii Tokuda & Yukawa on Cornuscontroversa Hemsl. ex Prain (Cornaceae), P.matatabi (Yuasa & Kumazawa) on Actinidiapolygama (Siebold et Zucc.) Planch. ex Maxim. (Actinidiaceae), P.neolitseae Yukawa on Neolitseasericea (Blume) Koidz. (Lauraceae), P.rokuharensis Monzen on Viburnumdilatatum Thunb. (Caprifoliaceae) and P.tominagai Elsayed & Tokuda on Eleutherococcusspinosus (L.f.) S.Y.Hu   . They haliaceae) . In addiliaceae)  and otheliaceae) .MagnoliakobusDC.var.borealis Sarg. (Magnoliaceae) in Tomakomai, Hokkaido and Aomori Prefecture, Honshu, Japan. Based on morphological comparison, we concluded that the gall midge is a member of Pseudasphondylia. We describe the species as new to science and discuss the phylogenetic relationships amongst Japanese congeners on the basis of molecular analysis. We also compare its life history strategy with those of the Japanese congeners.In recent years, we found an undescribed species of asphondyliine gall midge that induces leaf bud galls on M.kobusvar.borealis . A 472 bp fragment of the mitochondrial gene cytochrome oxidase subunit I (COI) of the species from leaf galls of M.kobusvar.borealis and P.tominagai was sequenced and aligned following P.elaeocarpi was sequenced using the primer set: COIS (5\u2019\u2013GGA TCA CCT GAT ATA GCA TTC CCA TAT TGG\u20133\u2019) and COIA (5'\u2013CCC GGT AAA ATT AAA ATA TAA ACT TC\u20133\u2019)  . The seqT TC\u20133\u2019)  and depoPseudasphondylia and four species of Asphondylia were downloaded from the GenBank and used as ingroup taxa: P.rokuharensis (LC538357), P.kiritanii (LC538356), P.matatabi (AB085873) (P.neolitseae (AB334237) (Asphondyliatojoi Elsayed and Tokuda (LC373200) (A.aucubae Yukawa & Ohsaki (AB238595) (A.yushimai Yukawa and Uechi (AB194473) (A.sphaera Monzen (AB197945) (Ampelomyiaconicocoricis Elsayed and Tokuda (LC422091) (Gephyrauluszewaili Elsayed and Tokuda (LC270942)  , P.neolB334237) , AsphondC373200) , A.aucuB238595) , A.yushB194473)  and A.sB197945) . GenBankC422091)  and GephC270942) . These sC270942) .Matsuda, Elsayed & Tokudasp. n.34B09DDF-9268-5078-8309-13576CB34083C7679EFB-7E8C-4157-A5AE-C618D2D82B28Type status:Holotype. Occurrence: sex: male; lifeStage: adult; Taxon: order: Diptera; family: Cecidomyiidae; genus: Pseudasphondylia; specificEpithet: saohimea; taxonRank: species; nomenclaturalCode: ICZN; Location: country: Japan; stateProvince: Aomori; locality: Ashizaki, Mutsu City; Event: samplingProtocol: Magnoliakobusvar.borealis (Magnoliaceae) collected on 10.v.2015 by S. Yamauchireared from a leaf bud gall on Type status:Paratype. Occurrence: individualCount: 7; sex: males; lifeStage: adult; Taxon: order: Diptera; family: Cecidomyiidae; genus: Pseudasphondylia; specificEpithet: saohimea; taxonRank: species; nomenclaturalCode: ICZN; Location: country: Japan; stateProvince: Aomori; locality: Ashizaki, Mutsu City; Event: samplingProtocol: Magnoliakobusvar.borealis (Magnoliaceae) collected on 10.v.2015 by S. Yamauchireared from leaf bud galls on Type status:Paratype. Occurrence: individualCount: 8; sex: females; lifeStage: adult; Taxon: order: Diptera; family: Cecidomyiidae; genus: Pseudasphondylia; specificEpithet: saohimea; taxonRank: species; nomenclaturalCode: ICZN; Location: country: Japan; stateProvince: Aomori; locality: Ashizaki, Mutsu City; Event: samplingProtocol: Magnoliakobusvar.borealis (Magnoliaceae) collected on 10.v.2015 by S. Yamauchireared from leaf bud galls on Type status:Paratype. Occurrence: individualCount: 3; lifeStage: mature larvae; Taxon: order: Diptera; family: Cecidomyiidae; genus: Pseudasphondylia; specificEpithet: saohimea; taxonRank: species; nomenclaturalCode: ICZN; Location: country: Japan; stateProvince: Aomori; locality: Ashizaki, Mutsu City; Event: samplingProtocol: collected on 19.v.2019 by S. Yamauchi at the type localityType status:Paratype. Occurrence: individualCount: 4; lifeStage: pupal exuviae; Taxon: order: Diptera; family: Cecidomyiidae; genus: Pseudasphondylia; specificEpithet: saohimea; nomenclaturalCode: ICZN; Location: country: Japan; stateProvince: Aomori; locality: Ashizaki, Mutsu City; Event: samplingProtocol: Magnoliakobusvar.borealis (Magnoliaceae) collected on 10.v.2015 by S. Yamauchireared from a leaf gall on Type status:Paratype. Occurrence: individualCount: 3; sex: females; lifeStage: adult; Taxon: order: Diptera; family: Cecidomyiidae; genus: Pseudasphondylia; specificEpithet: saohimea; taxonRank: species; nomenclaturalCode: ICZN; Location: country: Japan; stateProvince: Hokkaido; locality: Takaoka , Tomakomai City; Event: samplingProtocol: collected on 31.v.2015 by M. LibraType status:Paratype. Occurrence: individualCount: 1; sex: male; lifeStage: adult; Taxon: order: Diptera; family: Cecidomyiidae; genus: Pseudasphondylia; specificEpithet: saohimea; taxonRank: species; nomenclaturalCode: ICZN; Location: country: Japan; stateProvince: Hokkaido; locality: Takaoka , Tomakomai City; Event: samplingProtocol: collected on 31.v.2015 by M. LibraHead .Pseudasphondyliasaohimea is univoltine. Third instars and pupae were found in the galls in mid-May and adults emerged directly from the galls in mid- to late May. All mature galls collected in July were empty, indicating that no individuals had entered long-term diapause. In rearing conditions, adults emerged in the morning and mated around 11:00 h, suggesting that the gall midge is a diurnal species. The adults are supposed to oviposit into host buds. First instars were found in undeveloped bud galls in late September. They possibly overwinter in the undeveloped bud galls and develop to the second and third instars in the following spring.MagnoliakobusDC.var.borealis Sarg. (Magnoliaceae), \u201cKita-kobushi\u201d in Japanese.Pseudasphondyliasaohimea induces hairy leaf bud galls on Magnoliakobusvar.borealis (Magnoliaceae). The galled buds remain closed and indistinguishable in appearance from ungalled buds until the following spring and rapidly grow with bud burst. Mature galls are 2.7\u20136.0 mm in diameter and 5.1\u201313.7 mm in length (n = 45). Galls are multi-chambered and each chamber contains a single gall midge larva.Pseudocatolaccus sp.  from Hokkaido and Aomori, Torymus sp. (Torymidae) from Hokkaido and Eurytoma sp. (Eurytomidae) from Aomori.The following three species of hymenopteran parasitoids were reared from the mature galls: P.neolitseae and four in P.rokuharensis, P.kiritanii and P.tominagai. Although P.matatabi and P.elaeocarpi have three-segmented palpi, they are easily distinguished from the new species by their cerci which are shorter than the hypoproct. The larval spatula of the new species has four lobes of which the outer two are longer than the inner two. However, the larval spatula of P.neolitseae has only two lobes anteriorly and the other species have four lobes of which the inner two are longer than the outer two. In the pupa, five pairs of long abdominal spiracles are present in the new species, while only three pairs are present in P.rokuharensis, P.kiritanii, P.elaeocarpi and P.tominagai and four pairs in P.matatabi. The pupa of P.neolitseae, which has five pairs of abdominal spiracles, is otherwise similar to the new species, but it can be distinguished by dorsal abdominal spines that are markedly shorter than in P.saohimea.The new species is distinguishable from most of its other congeners in Japan by the number of palpal segments: three in the new species, but two in Pseudasphondylia species in P.saohimea will run to couplet 5 that separates P.matatabi and P.elaeocarpi. In order to update the key and include P.saohimea, couplet 5 is amended and a sub-couplet is added as in Table In the key to the males of world Pseudasphondylia species constructed a monophyletic clade relatively supported by 65% bootstrap value. Although P.saohimea constructed a clade with P.rokuharensis, their bootstrap support was lower than 50%. Genetic divergence of P.saohimea and the other Japanese Pseudasphondylia species was high and ranging between 15% to 21% .In the ML tree Fig. , PseudasP.saohimea is distinct from its congeners in Japan, although phylogenetic relationships amongst Pseudasphondylia species were not revealed in the analyses, except for the sister group relationship of P.kiritanii and P.tominagai. Pseudasphondylia was hypothesised to be an ancient clade within the subtribe Asphondyliina  oviposit into axillary overwintering buds of Styraxjaponica Siebold and Zucc. (Styracaceae) and its larvae spend summer, autumn and winter as the first instar in the host buds; then, galls and larvae rapidly grow, coinciding with host bud burst , overwinters as the first instar in inconspicuous overwintering buds, although this species is multivoltine and repeatedly uses axillary buds throughout the year , Procontarinia on Mangifera (Anacardiaceae), Rabdophaga on Salix  and Semudobia on Betula (Betulaceae)  . Pseudases level ."}
+{"text": "Specifically, the order of the bar graphs was incorrect: Sigmoidal input; No input; Linear; Quadratic. Instead, the correct order is: No input; Sigmoidal input; Linear; Quadratic. The corrected version of this figure now appears in the paper."}
+{"text": "N/A C.iwatai was collected from Yunnan: Baoshan, instead of Yunnan: Menglian Dai; C.kaihuanus was collected from Yunnan: Jinghong, instead of Yunnan: Guangnan county; and C.filippovi was collected from Sichuan: Mount Emei, instead of Sichuan: Emeishan city.It has come to our attention that in the work referenced above, Figure"}
+{"text": "Following the publication of the original article , the autThe incorrect author name is: Julia Klensney-Tait.The correct author names is: Julia Klesney-Tait.The original article  has been"}
+{"text": "After publication of the original article , the autThe incorrect authors\u2019 names are:Danielle da Costa: given name.da Palacio: family name.Camila Monteiro: given name.Nascimento: family name.The correct authors\u2019 names are:Danielle: given name.da Costa Palacio: family name.Camila: given name.Nascimento Monteiro: family name.The author group has been updated above and the original article  has been"}
+{"text": "Following publication of the original article , the autThe incorrect and correct Figure 9 are published in this Correction article. The original article has been updated.Figure 9 before correction: :Corrected Fig."}
+{"text": "The correct name is: Agata Sielska. The correct citation is: Sielska A (2021) Determinants of hospital inefficiency. The case of Polish county hospitals. PLoS ONE 16(8): e0256267."}
+{"text": "There is an error in the second author\u2019s affiliation. The correct affiliation is: European Commission, Joint Research Centre (JRC), 21027 Ispra (VA), Italy."}
+{"text": "The online version has been amended.In this paper by Jasper Tromp and colleagues (BMJ 2021;372:n461, doi:"}
+{"text": "Corrigendum to: Drivers of stunting reduction in Peru: a country case study. Am J Clin Nutr 2020;112:816S\u2013829S.In the originally published version of this article, there was an error in the author, Aviva I Rappaport's full name. This has now been corrected online."}
+{"text": "The authors wish to correct the Funding statement of their article  to:Wellcome Trust; BBSRC. Funding for open access charge: Institutional award from Wellcome (103857/Z/14/Z) and RCUK (BB/R002851/1).This change does not affect the results, discussion and conclusions presented in the article. The published article has been updated."}
+{"text": "In the original article, Mueller et al.  and Muel(A) zebrafish (B) mouse and (C) human brains. Am: amygdala; Ce: cerebellum; Ctx: cortex; Dp: dorsal pallium; Hip: hippocampus; Lp: lateral pallium; Mp: medial pallium; Th: thalmus; Vp: ventral pallium. Zebrafish image in (A) adapted from Mueller et al. (Figure 1. Comparison of homologous regions of the r et al.  and Muelr et al. .The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "Micronecta (Micronecta) griseola Horvath, 1899 is a representative of water bugs of the family Corixidae. It is expanding its range eastwards according to our observations in Russia. In the last decade, the species has become more common in Western Siberia.M.griseola from the territory of the Middle Urals (Russia). The distribution of the species and the features of its biology are considered.The article presents the first records of  Corixidae family and two species of the Gerridae family in the Polar Urals is given by A.N. Corixidae are mentioned. In a later work by A.N. Corixidae family for the Orenburg Region and adjacent areas of the middle reaches of the Ural River. In the generalising work of A.N. Corixidae are given for the Urals. However, information on the species of the subfamily Micronectinae Jaczewski, 1924 in all these works is absent. This article presents the first records of Micronecta (Micronecta) griseola Horvath, 1899 from the Middle Urals (Sverdlovsk region).Water bugs of the Urals and Cis-Urals have not been sufficiently studied to date. Information on the finding of two species of the Sirotinina, who worked at the Volga biostation near Saratov. All specimens of Micronecta were determined by her as M.minutissima , according to the European literature existing at that time. These data were repeated in our country by many faunists before the publication of the key to the European part of the USSR , despite the fact that the real M.minutissima was reliably recorded from Russia only in Karelia and the Leningrad Region.In connection with the development of the national economy of the country in the 1920s , the employees of biological stations carried out an intensive study of water bodies and their inhabitants - the fodder base of fish. Extensive material on water bugs from the Volga, Oka, Kama and other water bodies, collected by A.L. Benning  and othethe USSR . The keyountries . A subseountries  showed tM.minutissima from the Southern Urals from the Orenburg Region , with the preparation of male parameres and comparison with the collection.The collection of material in the Middle Urals was done in the eastern part of the Sverdlovsk Region in the spring-summer period of 2020. Small rivers of the Pyshma and Tura River Basins (Ob-Irtysh Basin) were investigated. The material was collected with a hydrobiological net, by catching water near the coast and mowing aquatic vegetation. The determination was made at the Horvath, 189984D76BB6-21E2-56C9-B86F-153896819731Type status:Other material. Occurrence: recordedBy: Vitaly Stolbov; lifeStage: 1 larva of the last instar; Taxon: kingdom: Animalia; phylum: Arthropoda; class: Insecta; order: Hemiptera; family: Corixidae; genus: Micronecta; subgenus: Micronecta; specificEpithet: griseola; scientificNameAuthorship: Horvath, 1899; Location: country: Russia; stateProvince: Sverdlovsk region; county: Slobodo-Turinsky district; locality: vicinity of the village Bobrovskoe; verbatimLocality: Bobrovka River, backwater, slow current, silty ground, depth 1 meter; verbatimElevation: 60 m a.s.l.; decimalLatitude: 57.498944; decimalLongitude: 64.148056; Identification: identifiedBy: Elena Kanyukova; Event: eventDate: 28.05.2020; Record Level: basisOfRecord: PreservedSpecimenType status:Other material. Occurrence: recordedBy: Vitaly Stolbov; lifeStage: 2 males, 9 larvae of the last instar; Taxon: kingdom: Animalia; phylum: Arthropoda; class: Insecta; order: Hemiptera; family: Corixidae; genus: Micronecta; subgenus: Micronecta; specificEpithet: griseola; scientificNameAuthorship: Horvath, 1899; Location: country: Russia; stateProvince: Sverdlovsk region; county: Irbitsky district; locality: vicinity of the village Chernovskoe; verbatimLocality: Kirga River, depth more than a meter, fast current, sandy-silty soil, stones; verbatimElevation: 60 m a.s.l.; decimalLatitude: 57.609778; decimalLongitude: 63.382833; Identification: identifiedBy: Elena Kanyukova; Event: eventDate: 28.05.2020; Record Level: basisOfRecord: PreservedSpecimenType status:Other material. Occurrence: recordedBy: Vitaly Stolbov; lifeStage: 1 larva of the last instar; Taxon: kingdom: Animalia; phylum: Arthropoda; class: Insecta; order: Hemiptera; family: Corixidae; genus: Micronecta; subgenus: Micronecta; specificEpithet: griseola; scientificNameAuthorship: Horvath, 1899; Location: country: Russia; stateProvince: Sverdlovsk region; county: Artyomovsky district; locality: vicinity of the village Antonovo; verbatimLocality: Sparganium sp.Borovaya River, depth 50 cm, fast current, muddy soil with separate stones, thread algae, ; verbatimElevation: 95 m a.s.l.; decimalLatitude: 57.544000; decimalLongitude: 62.361556; Identification: identifiedBy: Elena Kanyukova; Event: eventDate: 28.05.2020; Record Level: basisOfRecord: PreservedSpecimenType status:Other material. Occurrence: recordedBy: Vitaly Stolbov; lifeStage: 1 male, 252 1-2 instar larvae, 2 last instar larvae; Taxon: kingdom: Animalia; phylum: Arthropoda; class: Insecta; order: Hemiptera; family: Corixidae; genus: Micronecta; subgenus: Micronecta; specificEpithet: griseola; scientificNameAuthorship: Horvath, 1899; Location: country: Russia; stateProvince: Sverdlovsk region; county: Talitsky district; locality: Pripyshminskie Bory National Park; verbatimLocality: bypass channel of the Urga River, depth 30 cm, clay-sandy soil, fast current; verbatimElevation: 86 m a.s.l.; decimalLatitude: 56.976389; decimalLongitude: 63.681250; Identification: identifiedBy: Elena Kanyukova; Event: eventDate: 30.07.2020; Record Level: basisOfRecord: PreservedSpecimenM.griseola for the first time in the Sverdlovsk Region. Species of the genus Micronecta are the smallest representatives of the Corixidae family, the body length of the species ranges from 1.5 to 2.4 mm . In cold countries, one generation was recorded each summer (According to Wroblewski (1958), h summer . The larh summer .In a previous work , we discM.griseola. The date of collection of imagos and young larvae in the rivers of the Middle Urals on 30 July 2020, makes it possible to think that these adults belong to the second (summer) generation, which, after laying eggs, gives rise to wintering larvae. Although, like many insect species, Micronecta's breeding times are extended during the summer and may overlap.Finds of older larvae and some imagos in the last ten days of May in the Middle Urals make it possible to attribute them to overwintered individuals and to consider this time as the date of the appearance of the first generation of adults of ConclusionM.griseola was recorded in the Novosibirsk Region in 2010. All records from the southwest of Western Siberia in the Tyumen Region were made by authors within several years after 2017. Findings of M.griseola in large numbers in four rivers of the Sverdlovsk Region in 2020 suggest that this species has been actively spreading in recent years over the territory of the West Siberian Plain (Ob-Irtysh Basin).For the first time beyond the Urals, in Western Siberia, M.griseola in different countries have also been published (In Europe, in recent decades, data on new finds of ublished , which iM.griseola is also evidence of the ecological plasticity of the species. Often, the expansion of the ranges of aquatic organisms is associated with human economic activities - unintentional introduction and transformation of water bodies (M.griseola range requires additional research.The expansion of the ranges of a number of species in recent years has been noted in many regions, including Siberia. Often, in the case of terrestrial animal and plant species, this phenomenon is associated with global climate change . The sitr bodies . Identif"}
+{"text": "We regret the unprofessional behavior of the authors involved.hongruiyan001@163.com> (new email)Correspondence: Ruihong Yan: <"}
+{"text": "Museums and other institutions curating natural history collections (NHCs) are fundamental entities to many scientific disciplines, as they house data and reference material for varied research projects. As such, biological specimens preserved in NHCs represent accessible physical records of the living world's history. They provide useful information regarding the presence and distribution of different taxonomic groups through space and time. Despite the importance of biological museum specimens, their potential to answer scientific questions, pertinent to the necessities of our current historical context, is often under-explored.The currently-known wild bee fauna of Luxembourg comprises 341 registered species distributed amongst 38 different genera. However, specimens stored in the archives of local NHCs represent an untapped resource to update taxonomic lists, including potentially overlooked findings relevant to the development of national conservation strategies.Andrenalagopus , Nomadafurva , Hoplitispapaveris  and Sphecodesmajalis . Additionally, the presence of Nomadasexfasciata , which inexplicably had been omitted by the most current species list, can be re-confirmed. Altogether, our findings increase the number of recorded wild bee species in Luxembourg to 346. Moreover, the results highlight the crucial role of NHCs as repositories of our knowledge of the natural world.We re-investigated the wild bee collection of the Zoology Department of the National Museum of Natural History Luxembourg by using morphotaxonomy and DNA barcoding. The collection revision led to the discovery of four species so far not described for the country:  Natural history museums are important research and educational institutions, with a crucial role in the production and communication of scientific knowledge. Their associated natural history collections (NHCs) document what is known about the world\u2019s bio- and geodiversity, provide resources and reference material for scientific research and outreach and contribute to the very basis of formal educational programmes . ArchiveIn this study, we followed this approach and performed a revision of the wild bee collection material curated at the Zoology Department of the National Museum of Natural History Luxembourg  to produce an updated species checklist of the wild bee fauna of Luxembourg. Additionally, specimens collected in 2019 during the pilot phase of the ongoing \"Atlas of the wild bee fauna of Luxembourg\u201d project were integrated in the analysis to evaluate the presence of potential new findings.Relevant entries of 5,908 wild bee voucher specimens stored in the database of the MNHNL  were downloaded as spreadsheets to evaluate the presence and distribution of Luxembourgish and non-Luxembourgish species in the collection . SpecimeSpreadsheets were manipulated using R version 3.6.2  to identFrom the pilot phase of the wild bee atlas project, 16 specimens were selected for molecular identification via DNA barcoding. The BF2/BR2 primer pair  was usedPotential new species discoveries originating from either the revised museum collection entries or the fieldwork material were inspected with a Keyence VHX-S660E digital microscope, using various morphological keys to evaluate diagnostic traits Table .11409551-665C-5A11-98D1-1B559156557BNomadafurva Common names: Nomade funeste (French), Schw\u00e4rzliche Wespenbiene (German)Type status:Other material. Occurrence: catalogNumber: MNHNL39915; recordedBy: Fernand Feitz; sex: male; lifeStage: adult; Taxon: scientificName: Nomadafurva ; order: Hymenoptera; family: Apidae; genus: Nomada; specificEpithet: furva; taxonRank: species; scientificNameAuthorship: ; vernacularName: Nomade funeste (French), Schw\u00e4rzliche Wespenbiene (German); Location: country: Luxembourg; locality: Remerschen; decimalLatitude: 49.4837; decimalLongitude: 6.3475; Identification: identifiedBy: Andrea Jakubzik; Event: samplingProtocol: Net; eventDate: 16-07-2004; Record Level: institutionCode: MNHNL; basisOfRecord: Preserved SpecimenNomada presenting yellow maculations in the margin of labrum, malar area, apex of clypeus and in front of the eyes  dark coloured yes Fig. a and b. yes Fig. c. The dayes Fig. d. The layes Fig. e and theyes Fig. f.Voucher specimen (MNHNL39915): Adult male. Body length of 4.7 mm.Lasioglossum, with a flight season that extends from the end of April until mid-September \u201d, meaning that there is a lack of scientific information to assess extinction risk 67382451-6A9B-5F81-8BA9-F874E30E9C0FHoplitispapaveris Common names: Osmie du Coquelicot (French), Mohn-Mauerbiene (German).Type status:Other material. Occurrence: catalogNumber: MNHNL21866; recordedBy: Svenja Christian; sex: male; lifeStage: adult; Taxon: scientificName: Hoplitispapaveris ; order: Hymenoptera; family: Megachilidae; genus: Hoplitis; specificEpithet: papaveris; taxonRank: species; scientificNameAuthorship: ; vernacularName: Osmie du Coquelicot (French), Mohn-Mauerbiene (German); Location: country: Luxembourg; locality: Mertert; decimalLatitude: 49.70359; decimalLongitude: 6.48171; Event: samplingProtocol: Caught by hand; eventDate: 04-06-2015; Record Level: institutionCode: MNHNL; basisOfRecord: Preserved SpecimenMale: A medium sized (9-11 mm) mason bee with a black body covered in yellow-brown hair and short antennae Fig. a. TergitVoucher specimen (MNHNL21866): Adult male. Body length of 8.8 mm.Papaverrhoeas) to line the brood cells \u201d (rn (LC)\u201d , but it rn (LC)\u201d .61DAE441-E835-587B-8939-D61C404ED6DCNomadasexfasciata Common names: Nomade six-bandes (French), Langkopf-Wespenbiene (German), Six-banded Nomad Bee (English).Type status:Other material. Occurrence: catalogNumber: MNHNL25076; recordedBy: Fernand Feitz; sex: female; lifeStage: adult; Taxon: scientificName: Nomadasexfasciata ; order: Hymenoptera; family: Apidae; genus: Nomada; specificEpithet: sexfasciata; taxonRank: species; scientificNameAuthorship: ; vernacularName: Nomade six-bandes (French), Langkopf-Wespenbiene (German), Six-banded Nomad Bee (English); Location: country: Luxembourg; locality: Remich; decimalLatitude: 49.5479; decimalLongitude: 6.36037; Identification: identifiedBy: Andrea Jakubzik; Event: samplingProtocol: Net; eventDate: 05-05-2000; Record Level: institutionCode: MNHNL; basisOfRecord: Preserved SpecimenNomada species. Yellow maculations are present in the pronotal lobes, tegula, as two small spots on the scutellum and as large yellow spots on the sides of tergites 1-3, that become bands in tergites 4-5  black and yellow  mm blackVoucher specimen (MNHNL25076): Adult female. Body length of 12 mm.Eucera nests, with a flight season spanning from late April until late July on the European continent (An univoltine species that parasites ontinent .Nomadasexfasciata is classified under the IUCN category \u201cLeast Concern (LC)\u201d (rn (LC)\u201d , but it rn (LC)\u201d .F86547C4-1DF0-5E0D-BFBD-11E2FF45A4DBAndrenalagopus Common names: Andr\u00e8ne deux-cellules (French), Zweizellige Sandbiene (German).Type status:Other material. Occurrence: catalogNumber: MNHNL100056; sex: female; lifeStage: adult; associatedSequences: BOLD: MNHNL162-21; Taxon: scientificName: Andrenalagopus ; order: Hymenoptera; family: Andrenidae; genus: Andrena; specificEpithet: lagopus; taxonRank: species; scientificNameAuthorship: ; vernacularName: Andr\u00e8ne deux-cellules (French), Zweizellige Sandbiene (German); Location: country: Luxembourg; locality: Kehlen; decimalLatitude: 49.671931; decimalLongitude: 6.046718; Identification: identifiedBy: Fernanda Herrera-Mes\u00edas; Event: samplingProtocol: pan trap (passive sampling); eventDate: 20-05-2019; Record Level: institutionCode: MNHNL; basisOfRecord: Preserved SpecimenAndrena : Adult female. Body length of 9.23 mm.Andrenalagopus from France , collected in Alsace and Indre et Loire.The taxonomic annotation is supported by DNA barcoding data. The best percentages of sequence identity were achieved with two specimens of Brassicaceae) for pollen collection \u201d (rn (LC)\u201d  as it isrn (LC)\u201d .A68A4ADA-245F-5A6A-8572-B7C6269E7294Sphecodesmajalis Common names: Sph\u00e9code de mai (French), Kortsnuitbloedbij (Dutch), Mai-Blutbiene (German).Type status:Other material. Occurrence: catalogNumber: MNHNL100057; sex: male; lifeStage: adult; associatedSequences: BOLD: MNHNL163-21; Taxon: scientificName: Sphecodesmajalis ; order: Hymenoptera; family: Halictidae; genus: Sphecodes; specificEpithet: majalis; taxonRank: species; scientificNameAuthorship: ; vernacularName: Sph\u00e9code de mai (French), Kortsnuitbloedbij (Dutch), Mai-Blutbiene (German); Location: country: Luxembourg; locality: Manternach; decimalLatitude: 49.710039; decimalLongitude: 6.430916; Identification: identifiedBy: Fernanda Herrera-Mes\u00edas; Event: samplingProtocol: pan trap (passive sampling); eventDate: 28-04-2019; Record Level: institutionCode: MNHNL; basisOfRecord: Preserved SpecimenSphecodes species (6-8 mm)  Fig. a and b. mm) Fig. c. The himm) Fig. d. The pumm) Fig. e. The gomm) Fig. f.Voucher specimen : Adult male. Body length of 7.19 mm.Sphecodesmajalis from France , collected in Loir et Cher.The taxonomic annotation is supported by DNA barcoding data. A perfect match of genetic sequence similarity was achieved with a specimen of Lasioglossumpallens , its only known host in Europe \u201d (ed (NT)\u201d . Recordsed (NT)\u201d .Andrenidae, Apidae, Colletidae, Halictidae, Megachilidae and Melittidae). Exact sampling sites and detailed information for each museum specimen are available at the Species Observation Database Service of the museum. From the 218 wild bee species listed in the database, 194 were present in previous species checklists, confirming that at least some individuals have been found in Luxembourgish territory. The remaining 24 species did not figure as present in the country in the literature sources consulted. These species were represented in the collection exclusively by individuals collected in other countries, except for five species, whose annotations linked them to at least one voucher specimen from a gathering site placed in modern Luxembourgish territory: Colletesfodiens , Hylaeusstyriacus , Nomadafurva , Nomadasexfasciata  and Hoplitispapaveris . In three of these cases, previous taxonomic annotations of the analysed voucher specimens and our morphological re-examinations were in agreement .The 5,908 wild bee specimens registered in the MNHNL collection were distributed amongst 33 genera from six families  in the collection. The results of the morphological re-evaluation of both specimens were inconclusive. The female specimen (MNHNL41840), which was collected in 1999, lacked the conspicuous white-haired face and those hairs across the dorsal surface of the first tergite that characterise C.fodiens , which was collected in 2013, had the hairs of the sternites glued together and partially covered by sand grains. The genitalia were contracted inside the abdomen, obscuring visualisation of the crucial characters described in the taxonomic keys. As a more conservative approach, we thus do not recognise C.fodiens as a potential new finding for Luxembourg.However, in the remaining two cases, the taxonomic annotations showed conflicting results. In the case of ns sensu . Some au females . HoweverH.styriacus, there were eleven female specimens in the collection. In all cases, the shape of the facial fovea matched the one of Hylaeus from the subgenusParaprosopis  presented the tridentate mandible and pronotum with pointed edges that characterise Hylaeusclypearis . In the rest of the cases evaluated, the characteristics of the specimens matched the description of Hylaeuspictipes : facial lateral yellow spots, punctures on tergites/mesopleura and the overall shape of the head. For the aforementioned reasons, the original annotation and the presence of H.styriacus in Luxembourg remains to be confirmed.In the case of is sensu  to whichAndrenalagopus  and Sphecodesmajalis , respectively. Both species have no previous records in the country, rendering those two entries the first documented findings.Finally, the DNA barcodes of two of the specimens from the pilot phase of the wild bee atlas project had a 100% genetic similarity in BOLD with sequences annotated as Therefore, the morphological and molecular evidence indicates the presence of five wild bee species that are missing in the most current checklists . The fifth species, Nomadasexfasciata, is missing in N.sexfasciata for Luxembourg as well. Moreover, two specimens  were collected in the country in 1997 . It is worth mentioning that the most important morphological traits used to separate species within the subgenusParaprosopis, according to the key of Hylaeus bees (~ 4 mm), distinguishing similar species without such a level of magnification and optical performance might not be straightforward, as it may be hard to observe the most subtle details in the head and face. The importance of this factor as a potential error source in the morphological identification of Hylaeus bees and other wild bees of similar size remains to be determined.In the case of the potential of 2.17% , DNA barAndrenalagopus and Sphecodesmajalis require a special ecological discussion. Both were collected in 2019 during the pilot phase of a wild bee atlas project. In particular, the discovery of the ground nesting bee, A.lagopus, is locally relevant. This species is described as an oligolectic, warm-habitat-loving bee with an Atlanto-Mediterranean distribution , Sinapsisarvensis, Barbareavulgaris and Cardaminepratensis  in Turkey  might be a consequence of the particular relationship this cuckoo bee has with its host. Unlike most other blood bees, which visit different nests and kill or expel their occupants, it has been observed that S.majalis females do not drive away its host, showing no aggressive or defensive behaviour towards L.pallens females  were added to the national checklist of Luxembourg. Additionally, we found evidence that supports the current presence in the country of a fifth species (N.sexfasciata), which was omitted during past inventories. With the addition of these findings, the number of wild bee species registered in Luxembourg has increased to 346. The wild bee collection curated at the National Museum of Natural History Luxembourg is preserved under suitable conditions, which will allow future generations of researchers to use, re-examine and debate it in order to answer scientific questions pertinent to their own historical time. As such, our results represent just a small fraction of the exceptional value that NHCs have as repositories for the documentation of the bio- and geodiversity of the world. Despite this great potential, the current decrease in the available funds to keep and curate NCHs threatens the future of several collections, especially the smaller ones, affecting our possibilities to continue profiting from them in the years to come. Therefore, support from the scientific community and funding bodies is imperative, so biological collections can keep growing, documenting and ultimately, fulfilling their role in society.Our results highlight the importance of NHCs as sources for discoveries and critical re-interpretations of scientific knowledge. In combination with recent fieldwork material, four new wild bee species Data typeSpecies listFile: oo_530987.xlsxhttps://binary.pensoft.net/file/530987Fernanda Herrera-Mes\u00edas, Alexander Weigand71958FD8-B10A-5BD2-A63F-E05C3E4550B210.3897/BDJ.9.e64027.suppl2Supplementary material 2Additional species suggested by the westpalbees database for Luxembourg.Data typetaxonomicFile: oo_532963.xlsxhttps://binary.pensoft.net/file/532963Alexander Weigand, Fernanda Herrera-Mes\u00edas"}
+{"text": "We regret the unprofessional behavior of the authors involved.fuyan0059@sina.com>Correspondence: Yan Fu: <"}
+{"text": "Arctiini is a species-rich tribe of the subfamily Arctiinae of the family Erebidae. The genus Olepa Watson, 1980 is distributed in the Oriental and Palearctic Regions and the diversity reaches its peak in south Asia.The tribe Olepa from China and re-describe Oleparicini , together with illustrations of its adult and male genitalia. Furthermore, based on an analysis of 658-bp COI barcoding sequences, together with morphological studies, we consider that Olepaschleini Witt et al., 2005 syn. n. is a new synonym of O.ricini.We herein describe the first record of the genus  Olepa was originally established by Alope Walker, 1855  with Alopeocellifera Walker, 1855 as the type species. Oleparicini Fabricius, 1775 species group, restored the specific status of O.ocellifera Walker and O.clavatus Swinhoe and described four new species from southern India and Sri Lanka. Subsequently, Olepa into two species groups, based on differences in male genitalia. Subsequent studies revealed three additional species from western Asia, India and Indochina . Two species, namely O.neumuthi and O.toulgoeti, were treated as the synonyms of O.ricini and O.clavatus, respectively. Recently, Kalawate et al.  solution for examination of male genitalia, photographs of which were taken under a Keyence VHX-5000 digital microscope. Terminology of adult and genitalia follows Olepa as the ingroup and, for the outgroup, we used Trischalisaureoplagiata and Cyclosiellaspiralis (two species of the tribe Lithosiini of the subfamily Arctiinae). We sequenced four specimens from China and the remaining sequences were obtained from GenBank and Bold Systems. DNA was extracted from two or three legs of dried adult specimens using a TIANamp Genomic DNA Kit  following the manufacturer\u2019s instructions. We amplified a single mitochondrial gene (a 658-bp fragment of COI) using the general primers 1490-2198 7F131776-AEE6-57B1-A7C1-524B2EEEE8C9BombyxriciniAlopericini Moore, 1882: 70Pericalliaricini Hampson, 1901, 350Oleparicini Watson, 1980:133Olepa (Ricinia) ricini ; Singh & Singh, 2013:276Olepaneumuthi Orhant, 2012:61, synonymised by Singh & Singh, 2013Olepaschleinisyn. nov. Witt et al., 2005:102 , Type status:Other material. Occurrence: recordedBy: S.Y. Huang; sex: 1 male; lifeStage: adult; occurrenceID: SCAU:Ole02; Taxon: scientificName: Oleparicini ; order: Lepidoptera; family: Erebidae; genus: Olepa; taxonRank: species; taxonomicStatus: accepted; Location: country: China; stateProvince: Guangdong; county: Guangzhou; locality: campus of South China Agricultural University; Event: eventDate: 14-Sep-2021Type status:Other material. Occurrence: recordedBy: S.Y. Huang; sex: 1 male; lifeStage: adult; occurrenceID: SCAU:Ole01; Taxon: scientificName: Oleparicini ; order: Lepidoptera; family: Erebidae; genus: Olepa; taxonRank: species; taxonomicStatus: accepted; Location: country: China; stateProvince: Guangdong; county: Guangzhou; locality: campus of South China Agricultural University; Event: eventDate: 24-Sep-2020Type status:Other material. Occurrence: recordedBy: Y.X Hou; sex: 1 males; lifeStage: adult; occurrenceID: SCAU:Ole03; Taxon: scientificName: Oleparicini ; order: Lepidoptera; family: Erebidae; genus: Olepa; taxonRank: species; taxonomicStatus: accepted; Location: country: China; stateProvince: Guangdong; county: Guangzhou; locality: campus of South China Agricultural University; Event: eventDate: 1-Oct-2021Type status:Other material. Occurrence: recordedBy: L.P. Zhou; sex: 1 males; lifeStage: adult; occurrenceID: SCAU:Ole04; Taxon: scientificName: Oleparicini ; order: Lepidoptera; family: Erebidae; genus: Olepa; taxonRank: species; taxonomicStatus: accepted; Location: country: China; stateProvince: Hainan; locality: Yinggeling Natural Reserve; Event: eventDate: 13-Jul-2020Type status:Other material. Occurrence: recordedBy: P. Qin; sex: 1 male; lifeStage: adult; occurrenceID: SCAU:Ole05; Taxon: scientificName: Oleparicini ; order: Lepidoptera; family: Erebidae; genus: Olepa; taxonRank: species; taxonomicStatus: accepted; Location: country: China; stateProvince: Guangdong; county: Guangzhou; locality: campus of South China Agricultural University; Event: eventDate: 14-Oct-20212; marginal line serrate, extending from apex to vein CuA1. Venation , Thailand, India, Israel.Olepa is morphologically similar to O.schleini and O.ricini. These two species were supposed to be distinguished from each other mainly by the differences in the tip of the valva, i.e. tip rounded in the former and more acute in the latter, together with a great genetic difference in COI sequences (O.ricini (GenBank accession numbers AM050280-AM050284) used by Witt et al. (2005) in GenBank, we found that these sequences are actually closer to those of certain species in the family Geometridae rather than other members of Arctiinae of the family Erebidae. It is very likely that these COI sequences of O.ricini are wrong and are not the true ones of this species. This result can also explain why the genetic difference between O.ricini and O.toulgoeti was also as large as 18.2% to 18.5%, but the difference between O.schleini and O.toulgoeti was only 1.6% to 1.8%, despite the fact that O.schleini and O.ricini are morphologically closer. Based on our analysis, the genetic difference between Chinese Olepa sp. and Israeli O.schleini is 0%, the difference between two true Indian O.ricini (GenBank accession numbers KX371816 and KY559102) and Israeli O.schleini varies from 0.3% to 0.9% and the difference between Chinese Olepa sp. and Indian O.ricini also varies from 0.3% to 0.9%. Considering the fact that the genetic difference between the morphologically dissimilar O.ricini and O.toulgoeti is only 1.6% to 1.8% and the difference found between Indian O.ricini and Israeli O.schleini is smaller than 1%, we believe that all the three populations of O.ricini and O.schleini mentioned above should be regarded as conspecific. As for the difference in wing pattern, according to Orhant (1986), the lectotype of O.ricini housed in the Natural History Museum of Denmark is a female without abdomen  and the holotype of O.schleini is a male deposited in Museum Witt Munich, but the adult of this specimen was not specified in the plates in Witt et al. (2005). By comparing the female lectotype of O.ricini and illustrations of males of this species from various publications with males and females of O.schleini figured in Witt et al. (2005), we found no significant difference between these individuals and, interestingly, the pale rings are mostly reduced in the lectotype of O.ricini, similar to the situation in O.schleini. Hence, we concluded that this character is most probably due to individual variation. Thus, we herein present the following synonym: Olepaschleini Witt et al., 2005 syn. n. = Oleparicini  and the Chinese Olepa sp. should be also identified as O.ricini.The Chinese population of equences . In addi"}
+{"text": "In \u201cA Patient Journey Map to Improve the Home Isolation Experience of Persons With Mild COVID-19: Design Research for Service Touchpoints of Artificial Intelligence in eHealth\u201d :e23238) the authors noted one error.In the originally published manuscript, Multimedia Appendix captions incorrectly appeared as follows:Multimedia Appendix 1: Patient journey map of persons with mild COVID-19 during home isolation.Multimedia Appendix 2: Visual summary.Multimedia Appendix 3: Video purpose and comments coding trees.Multimedia Appendix 4: Personal video story coverage and experienced symptoms during home isolation.In the corrected version of the manuscript, Multimedia Appendix captions have been corrected to:Multimedia Appendix 1: Personal video story coverage and experienced symptoms during home isolation.Multimedia Appendix 2: Patient journey map of persons with mild COVID-19 during home isolation.Multimedia Appendix 3: Video purpose and comments coding trees.Multimedia Appendix 4: Visual summary of design research.The correction will appear in the online version of the paper on the JMIR Publications website on May 4, 2021, together with the publication of this correction notice. Because this was made after submission to PubMed, PubMed Central, and other full-text repositories, the corrected article has also been resubmitted to those repositories."}
+{"text": "Lycaenidae is the second-largest group of butterflies which contains about one third of the known species of Papilionoidea. The genera Tajuria Moore, [1881] and Drupadia Moore, 1884 are both mainly found in the Oriental and Australian realms. In a very recent expedition to south-west China in Xishuangbanna (Yunnan Province), specimens of T.sekii Saito, 2005 and D.scaeva  were collected for the first time, a new subspecies of the former: T.sekiisisyphus ssp. nov., is described and illustrated and the latter species comprises the first record of the genus Drupadia in China.The family T.sekii Saito, 2005, T.sekiisisyphus ssp. nov., is described and illustrated. The species T.sekii Saito, 2005 and D.scaeva  are first recorded in China and the latter comprises the first record of the genus Drupadia in China. Relevant details are presented for the species.A new subspecies of  Lycaenidae is the second largest family of butterflies, which includes over 6,000 species  were first collected in Yunnan Province and a new subspecies, T.sekiisisyphus ssp. nov., is described and illustrated.In this contribution, specimens of Photographs of the adults were taken by an Olympus E-M1 digital camera with a M. ZUIKO DIGITAL ED 60 mm F2.8 Macro lens. To examine the male genitalia, the abdomen was removed and soaked in 10% potassium hydroxide solution at room temperature for about 24 hours and was dissected under a Nikon SMZ18 stereoscope, following D9D8C9F4-C372-5584-9389-C7C2C4618AC3Type status:Other material. Occurrence: recordedBy: Si-Xun Ge; Zhuo-Heng Jiang; individualCount: 3; sex: 3 males; lifeStage: adult; Taxon: scientificName: Drupadiascaeva ; kingdom: Animalia; phylum: Arthropoda; class: Insecta; order: Lepidoptera; family: Lycaenidae; genus: Drupadia; specificEpithet: scaeva; taxonRank: species; scientificNameAuthorship: ; Location: country: China; stateProvince: Yunnan Province; county: Mengla Country; locality: Menglun township; maximumElevationInMeters: 800 m a.s.l.; verbatimCoordinates: 21\u00b09629\u2032 N, 101\u00b02073\u2032 E; Identification: identifiedBy: Shao-Ji Hu; dateIdentified: 2021; Event: samplingProtocol: sweep net; year: 2021; month: 4; day: 24; habitat: Rain Forest; Record Level: basisOfRecord: PreservedSpecimenMale cooperi, with the bluish scales in the centre of fore-wings absent and a relatively limited violet area on hind-wings.We tentatively identified specimens collected in this study as ssp. Ge & Jiangn.566CA7A0-CD39-5557-A79A-2406410BBD0669624BFA-969D-44FC-9ED6-CFC6BEB9E2B5Type status:Holotype. Occurrence: recordedBy: Si-Xun Ge; individualCount: 1; sex: male; lifeStage: adult; disposition: in collection; Location: country: China; countryCode: CN; stateProvince: Yunnan; county: Mengla Country; locality: Menglun township; verbatimElevation: 800 m; verbatimCoordinates: 21\u00b09629\u2032 N, 101\u00b02073\u2032 E; Identification: identifiedBy: Si-Xun Ge; dateIdentified: 2021; Event: samplingProtocol: sweep net; year: 2021; month: 4; day: 24; habitat: Rain Forest; Record Level: basisOfRecord: PreservedSpecimenType status:Paratype. Occurrence: recordedBy: Si-Xun Ge; Zhuo-Heng Jiang; individualCount: 4; sex: 4 females; lifeStage: adult; disposition: in collection; Location: country: China; countryCode: CN; stateProvince: Yunnan; county: Mengla Country; locality: Menglun township; verbatimElevation: 800 m; verbatimCoordinates: 21\u00b09629\u2032 N, 101\u00b02073\u2032 E; Identification: identifiedBy: Si-Xun Ge; dateIdentified: 2021; Event: samplingProtocol: sweep net; year: 2021; month: 4; day: 24; habitat: Rain Forest; Record Level: basisOfRecord: PreservedSpecimenMale Fig. : Fore-wiMale genitalia Fig. : Highly Female Fig. : Fore-wiTajuriasekiisisyphus ssp. nov. can be distinguished from the nominotypical subspecies by the combination of the following characteristics: 1) Blue areas of both sexes are more reduced, especially in female, 2) Hindwing with tornal black spot in space 2 on the upperside of females, while absent in nominotypical subspecies and 3) Compared to the nominotypical subspecies, females of the new subspecies with both wings broader and more rounded.The Myth of Sisyphus. The process of scientific research is just like the act of rolling the boulder up the hill. However, the description of each new taxon is exciting enough. \"Each atom of that stone, each mineral flake of that night-filled mountain, in itself forms a world. The struggle itself toward the heights is enough to fill a man's heart. One must imagine Sisyphus happy.\" The subspecies name is treated as a noun in apposition.The subspecies name is derived from the name of a man in Greek mythology, who also appears in sisyphus is only known from China.The nominotypical subspecies can be found in Thailand, Vietnam and Laos, while ssp. China is a country with mega-biodiversity of butterflies, especially the southwest mountainous part . Yunnan D.scaeva had already been taken by nature lovers in Xishuangbanna Prefecture, while there has been no official publication of this species in China. In this expedition, specimens of D.scaeva were collected and it was confirmed that the species is, indeed, present in China.Before this contribution, photos of Tajuria has a high diversity in Oriental and Australian Realms. However, systematic studies on this genus are still very limited, even in recent years; therefore, the definition of some species is still unresolved. We speculate that there should be more species of Tajuria to be found in China.The genus"}
+{"text": "We regret the unprofessional behavior of the authors involved.joethomas5725@gmail.com>Correspondence: Wenhao Zhang: <"}
+{"text": "Quasipaa is a genus of frogs that belongs to a relatively poorly known group. Most of the species distribution has been recorded in China; however, a few incidences of identification have occurred in the eastern part of Indochina. To date, only one species (Quasipaafasciculispina) of Quasipaa has been recorded from Chanthaburi and Trat Provinces in south-eastern Thailand.Spiny Frog Quasipaaverrucospinosa from Doi Phu Kha National Park, Nan Province at an altitude of 900\u20131000 m a.s.l. Our study has demonstrated that populations of this species are paraphyletic and has revealed deep genetic differences. Therefore, it is recommended that a comprehensive study be undertaken to clarify the taxonomic and geographic distribution of this species for its suitable protection and conservation.Based on recent fieldwork conducted in northern Thailand, we report a new record of  Dicroglossidae is a diverse group of amphibians in Thailand. As a direct result of the increasing amounts of attention and effort being devoted to herpetological research studies, the species diversity of this family in Thailand has remarkably increased from 31 species in the year 2011, to 38 species at present . To date, official records are comprised of 12 recognised species of this genus, of which only one species, namely Q.fasciculispina, was reported from south-eastern Thailand (Frost 2021). The Granular Spiny Frog Quasipaaverrucospinosa (considered to be at the \u2018Near Threatened\u2019 level on the IUCN Red List) was first described by Ren\u00e9 Bourret in 1937 and was collected from Chapa and Fansipan (now Sa Pa) in Lao Cai Province and Tam Dao National Park in Vinh Phuc Province, northern Vietnam. Currently, the distribution of this species ranges from northern and central Vietnam; southern China; and northwest Laos  and Fejervaryalimnocharis (Gravenhorst) which were used as the outgroup  and Maximum Likelihood (ML). JMODELTEST v.2.1.7  was used65BF7EC1-909C-58BE-AE2D-9A7B3157EDF3Type status:Other material. Occurrence: catalogNumber: AUP-00392; individualCount: 1; sex: female; lifeStage: adult; Taxon: scientificName: Quasipaaverrucospinosa; class: Amphibia; order: Anura; family: Dicroglossidae; genus: Quasipaa; specificEpithet: verrucospinosa; Location: country: Thailand; countryCode: TL; stateProvince: Nan; locality: Doi Phu Kha; verbatimElevation: 900\u20131000; verbatimLatitude: 21\u00b019.66'N; verbatimLongitude: 103\u00b036.26'E; verbatimCoordinateSystem: WGS84; Event: eventRemarks: collected by C. Suwannapoom, P. Pawangkhanant; Record Level: basisOfRecord: preserved specimeType status:Other material. Occurrence: catalogNumber: AUP-00393; individualCount: 1; sex: female; lifeStage: adult; Taxon: scientificName: Quasipaaverrucospinosa; Record Level: basisOfRecord: preserved specimen; dynamicProperties: collection date, collector and location as the AUP-00392Type status:Other material. Occurrence: catalogNumber: AUP-00530; individualCount: 1; sex: female; lifeStage: adult; Taxon: scientificName: Quasipaaverrucospinosa; Record Level: basisOfRecord: preserved specimen; dynamicProperties: collection date, collector and location as the AUP-00392Type status:Other material. Occurrence: catalogNumber: AUP-00531; individualCount: 1; sex: male; lifeStage: adult; Taxon: scientificName: Quasipaaverrucospinosa; Record Level: basisOfRecord: preserved specimen; dynamicProperties: collection date, collector and location as the AUP-00392Type status:Other material. Occurrence: catalogNumber: AUP-00532; individualCount: 1; sex: male; lifeStage: adult; Taxon: scientificName: Quasipaaverrucospinosa; Record Level: basisOfRecord: preserved specimen; dynamicProperties: collection date, collector and location as the AUP-00392Type status:Other material. Occurrence: catalogNumber: AUP-00533; individualCount: 1; sex: male; lifeStage: adult; Taxon: scientificName: Quasipaaverrucospinosa; Record Level: basisOfRecord: preserved specimen; dynamicProperties: collection date, collector and location as the AUP-00392Type status:Other material. Occurrence: catalogNumber: AUP-00534; individualCount: 1; sex: male; lifeStage: adult; Taxon: scientificName: Quasipaaverrucospinosa; Record Level: basisOfRecord: preserved specimen; dynamicProperties: collection date, collector and location as the AUP-00392Type status:Other material. Occurrence: catalogNumber: AUP-01609; individualCount: 1; sex: female; lifeStage: adult; Taxon: scientificName: Quasipaaverrucospinosa; Record Level: basisOfRecord: preserved specimen; dynamicProperties: collection date, collector and location as the AUP-00392Morphological characteristics of the specimens (n = 10) obtained from Nan Province agreed with the descriptions of Skin. Dorsal surface with very rough back covered by short, thick, ridges and round tubercles. Sides covered by oval tubercles with dark spines; ventral surface smooth. During the breeding season (May to October), males have black spikes on finger I, chin, chest and underarms. Colouration of dorsum is grey-brown with dark brown spots; ventral surface cream-coloured, except for the chin with dark markings; iris dark green Figs , 3.This species is known to be from northern and central Vietnam, southern China and northwest Laos . This isLimnonectestaylori Matsui, Panha, Khonsue & Kuraishi and L.bannaensis Ye, Fei, Xie & Jiang. Advertisement calls of the males can be heard within or beside rocky streams from May to October  to 7.1% (with Q.shini) , was 0.2%. Furthermore, both ML and BI analyses placed the Nan population in one clade along with topotypic Q.verrucospinosa in conjunction with strong node support  of 16S rRNA data for Quasipaa are distinguished from each other mainly by the pattern and number of genital spikes in the areas of the first finger, chest, chin and underarms of males during their breeding season. Therefore, it can be considerably difficult for herpetologists to identify this species. Consequently, the taxonomic status of the species in this group is both controversial and unclear. Additionally, there has been a notable lack of interest in and integrated research  conducted on this species. However, this species has been determined to be especially widespread ; Paaboulengeri ; Paaspinosa  and Paa spp.  and Tam Dao NP. (Vinh Phuc Province). These two locations are situated on opposite sides of the Red River. Q.verrucospinosa sensu stricto. Specimens previously placed in other groups should be assigned to groups Q.cf.verrucospinosa in order to more accurately correspond with specimens in groups B, C and D .Sequences and voucher specimens of Data typeTable of sequences and voucher specimens of Quasipaa and outgroup taxa used in molecular analysesFile: oo_592305.docxhttps://binary.pensoft.net/file/592305Suwannapoom et al.FECF5CBD-031A-5187-912F-4A426C20EA2210.3897/BDJ.9.e70473.suppl2Supplementary material 2Quasipaa.The pairwise uncorrected p-distance (%) of 16S rRNA gene between species of Data typep-distanceFile: oo_554712.docxhttps://binary.pensoft.net/file/554712Suwannapoom et al.4B07CD53-2032-5B61-904D-4E72DA05A73C10.3897/BDJ.9.e70473.suppl3Supplementary material 3Quasipaaverrucospinosa in Thailand. .Measurement (in mm) and proportions of the series of Data typeMeasurement of Quasipaa verrucospinosa in ThailandFile: oo_554755.docxhttps://binary.pensoft.net/file/554755Suwannapoom et al."}
+{"text": "Facilitators include: tension for change for low-cost, accessible IDs; relative advantage over existing tools; development of partnerships; and identification of implementation champions. Barriers include: need for educational strategies to encourage clinical provider acceptability; lack of evidence of the optimal beneficiary. DISCUSSION/SIGNIFICANCE OF IMPACT: Tools for therapeutic OF self-management could be integrated into comprehensive OF programming. Employing the CFIR as an overarching typology allows for comparison across contexts and settings where OF care occurs and may be useful for clinicians, researchers, and policy-makers interested in implementing IDs for OF self-management in LMICs. CONFLICT OF INTEREST DESCRIPTION: I am working with colleagues at the non-profit Restore Health on developing an insertable cup for therapeutic self-management of obstetric fistula in LMICsOBJECTIVES/GOALS: Insertable devices (IDs) for obstetric fistula (OF) management are feasible, acceptable, but not accessible; implementation determinants in low and middle-income countries (LMICs) are unknown. Thus, the purpose of this study was to understand pre-adoption facilitators and barriers among global stakeholders for a therapeutic ID for OF in LMICs. METHODS/STUDY POPULATION: Stakeholders, including researchers (n = 11), clinicians (n = 4), government officials (n = 2), and administrators (n = 4), were purposefully identified from various sectors involved in understanding and addressing the needs of women with OF: clinical care, academia, international health, civil society, and government. Twenty-one individuals were interviewed about their perceptions of IDs for OF self-management and their implementation. Interviews were audio-recorded and transcribed. The Consolidated Framework for Implementation Research (CFIR) guided data collection and analysis. Thematic analyses were carried out within Nvivo v.12. RESULTS/ANTICIPATED RESULTS: Determinants of implementation of an ID for OF self-management (by CFIR domain) include: (1) intervention characteristics\u2014"}
+{"text": "Anoplura), some of their common, Eurasian or even cosmopolitan species still lack complete taxonomic descriptions, especially those for their nymphal stages. This applies especially to the most common rodent parasites: the lice of the genus Hoplopleura. In Europe, only two of the five most common Hoplopleura species have full taxonomic characteristics with a description of the nymphal stages. This study enriches the current state of knowledge for another species, Hoplopleuralongula and presents the first description of its nymphal stages.Despite the widespread belief that an extensive body of knowledge exists for the sucking lice  of H.acanthopus, H.affinis, H.captiosa, H.edentula and H.longula) have been given full taxonomic descriptions, including immature stages. This paper presents a description of the nymphal stages of H.longula (described for the first time).Only two of the five species found in Eurasia ( Psocodea: Anoplura) are obligatory, permanent ectoparasites of mammals. Lice complete their entire lifecycle on their host and it includes: egg, three nymphal stages  and an adult stage (imago). Some past research on this group has focused on their relationship with humans (e.g. Sucking lice (ans e.g.  or livesans e.g.  and theians e.g. . In compAnoplura are associated with rodents (Rodentia), the most abundant group of mammals in terms of species (Hoplopleuridae (Psocodea: Anoplura) is the most speciose group parasitising the Rodentia. Amongst the family, most representatives are in the genus Hoplopleura, which contains 154 species distributed around the world. The following five are most widespread in Europe - four of them being common in Eurasia: H.acanthopus , H.affinis , H.edentula and H.longula Neumann, 1909 and one is probably cosmopolitan: H.captiosa Johnson, 1960 , obtained from the Scientific Collection of the Mammal Research Institute Polish Academy of Sciences in Bialowieza . These were isolated from four  Eurasian harvest mice  Pallas, 771, obtaza Table .Lice were collected from dead rodent specimens by combing the fur with tweezers and the specimens were fixed and preserved in 70% ethyl alcohol. The specimens, intended for analysis of morphological traits, were immersed in polyvinyl-lactophenol to develop total preparations for light microscope examination .Topographic preferences were observed. The entire body surface area of the test hosts was analysed and all locations were marked; this allowed for a complete (intensive) analysis of the topography.The names and abbreviations of individual setae or body parts are provided following Abbreviations of head and thorax:ADHS accessory dorsal head setae;AHS apical head setae;AS antennal setae;CS clypeal setae;DAHS dorsal anterior head setae;DMsS dorsal mesothoracic setae;DMtS dorsal metathoracic setae;DPTS dorsal principal thoracic setae;DPtS dorsal prothoracic setae;ISHS inner sutural head setae;MHS marginal head setae;AMHS anterior marginal head setae;MMHS middle marginal head setae;PMHS posterior marginal head setae;OS oral setae;OSHS outer sutural head setae;PAS preantennal setae;PCHS posterior central head setae;PDHS posterior dorsal head setae;VMHS ventral marginal head setae;VPHS ventral principal head setae.Abbreviations of abdomen:AnS anal setae;MAS major abdominal setae.Neumann, 1909D8E3045B-4432-5473-9A0D-8B006A12B951Type host: Micromysminutus Other hosts: Micromysglareolus Schreber, 1780 in MicrotusarvalisSorexaraneus Linnaeus, 1758 in Wegner (1966b) Pallas, 1778 and Type status:Other material. Occurrence: lifeStage: 1 nymph first instar; Taxon: scientificName: Hoplopleuralongula Neumann, 1909; kingdom: Animalia; phylum: Arthropoda; class: Insecta; order: Psocodea; family: Hoplopleuridae; genus: Hoplopleura; Location: continent: Europe; country: Poland; locality: area of the Bialowieza National Park; verbatimCoordinates: 52\u00b045'23.3\"N 23\u00b052'23.6\"E; georeferenceProtocol: GPS; Identification: identifiedBy: Kozina P.; Event: samplingProtocol: Micromysminutushost ; eventDate: 20-09-1949; Record Level: institutionCode: UGDIZPMMmHHl1N1Type status:Other material. Occurrence: lifeStage: 1 nymph first instar and 1 nymph second instar; Taxon: scientificName: Hoplopleuralongula Neumann, 1909; kingdom: Animalia; phylum: Arthropoda; class: Insecta; order: Psocodea; family: Hoplopleuridae; genus: Hoplopleura; Location: continent: Europe; country: Poland; locality: area of the Bialowieza National Park; verbatimCoordinates: 52\u00b045'23.3\"N 23\u00b052'23.6\"E; georeferenceProtocol: GPS; Identification: identifiedBy: Kozina P.; Event: samplingProtocol: Micromysminutushost ; eventDate: 08-12-1949; Record Level: institutionCode: UGDIZPMMmHHl2N1, UGDIZPMMmHHl1N2Type status:Other material. Occurrence: lifeStage: 2 nymph third instar; Taxon: scientificName: Hoplopleuralongula Neumann, 1909; kingdom: Animalia; phylum: Arthropoda; class: Insecta; order: Psocodea; family: Hoplopleuridae; genus: Hoplopleura; Location: continent: Europe; country: Poland; locality: area of the Bialowieza National Park; verbatimCoordinates: 52\u00b045'23.3\"N 23\u00b052'23.6\"E; georeferenceProtocol: GPS; Identification: identifiedBy: Kozina P.; Event: samplingProtocol: Micromysminutushost ; eventDate: 07-10-1949; Record Level: institutionCode: UGDIZPMMmHHl1N3, UGDIZPMMmHHl2N3Nymph I . MAS four in number; AnS present, two in number.h I Figs , 3 . Legh I Figs . Head. ANymph II . Ventral side: large, concave scales around the mouth; head margins covered imbricately with scales (U-shaped); VMHS, OS and AHS present; VPHS constituting 50% of the head length. Dorsal side: AHS, DAHS and PAS present; ISHS and OSHS closely arranged; PCHS visible; ADHS and PDHS (reaching second segment of the abdomen) present; MHS minute. Thorax. Dorsal side: DPTS reaching beginning of the abdomen; pronounced border between the thorax, head and abdomen. Abdomen. Disproportionately large relative to the rest of the body, barrel-shaped, densely covered with U-shaped scales; traces of segmentation visible; MAS eight in number. After x-ray, structure of nymph III visible. II Figs , 5 . Bod II Figs . Head. WNymph III .III Figs , 7 . BodIII Figs . Head. WThe lice demonstrated topographic preferences - a tendency for congregating along the sides of the host\u2019s body and on both sides of the head (between the ears and on the neck) Fig. Table 1)1).H.longula was found amongst the lice. Despite the fact that there are also other species parasitising M.minutus, for example, of the genus Polyplax given in literature (In the present study, only terature , they weM.minutus is considered to be the main host of H.longula; it has not been recorded in any other hosts to date (The harvest mouse  to date .H.longula are easily identifiable. Nymph I possessed four major abdominal setae and an elongated, ovoid abdomen. Nymph II possessed eight MAS and a barrel-shaped abdomen. Like nymph II, nymph III possessed eight MAS; however, its abdomen is elongated and ovoid. In addition, like nymph I, the body of the adult individual can be seen inside the nymph.Individual nymphs of H.longula-M.minutus relationship. Despite this, similarities can be found with the distribution of H.acanthopus on Microtusarvalis (H.longula appeared to have a wider distribution on the sides and the dorsum on its rodent hosts. Similarly to H.affinis in Apodemusagrarius (H.longula was also found on the dorsal portion of the head and on the nape of the animal. In both of the previous studies, Dubinin did not observe lice on the ventral portion of the head; this was also confirmed in the present study.Regarding the location of the lice on the host, no comparative data are available in previous studies regarding the arvalis : in bothagrarius , H.longH.longula is a rare species associated with only one, also rare host, M.minutus. This is the first description of all three nymphal stages of H.longula. This characteristic will support other researchers working on lice to make positive identifications which will benefit future research examining host-parasite associations.Current research indicates that"}
+{"text": "The prognosis of breast cancer has radically changed in recent years and continues to improve due to the broad application of effective therapies. New targeting strategies including targeted delivery of cytotoxic drugs via receptor-targeting agents have been developed. We summarize recent publications and developments of novel antibody-drug conjugates (ADCs) used to control breast cancer. Cancer is the second main cause of mortality worldwide . Breast ADCs are a new class of protein-based therapeutic agents which bring together the targeting capabilities, high selectivity, and stability of mAbs with the cancer-killing potential of highly potent payloads to increase precise drug delivery in cancer cells, while sparing healthy tissues and/or cells from chemotherapeutic damage. This ability of discrimination between normal and cancerous cells would not have been achieved without decades of development of mAbs , 14\u201318.In order to achieve the desired results, each ADC must contain three parts  19]::19]:Monoclonal antibody: it binds the ADC to a specific tumor cell surface protein . The antLinker: it is a chemical spacer between the cytotoxic drug and the monoclonal body. It is usually stable in the circulation, but most of the linkers are easily displaced inside the cells. However, if the linker stays stable inside the cell, it requires degradation to release the drug. The linker must allow the release of the drug in its active form within or close enough to the target cells, because early release of drugs in the circulation can result in systemic toxicity and a lower therapeutic index , 25. TheCytotoxic drug: cytotoxic compounds are divided into two main categories: microtubule inhibitors and DNA-damaging agents. There are also other small molecules under investigation , 28. AllThere are three generations of ADCs: first, second, and third. The monoclonal anti-HER2 binds to the HER2 expressed on the cells of the tumor and gets internalized by endocytosis. The proteases in the lysosomes cleavage the linker, releasing the payload and starting the cytotoxic effects.This effect happens when the ADC is designed that the antibody releases the payload before internalization so that the surrounding cells get affected by its cytotoxic effects even if they do not express the receptor.Monoclonal antibody: a human epidermal growth factor receptor 2  targeting monoclonal antibody.Payload: an undisclosed cytotoxic agent with potential antineoplastic activity.Development status: first in human phase I/II.Monoclonal antibody: an engineered version of the humanized monoclonal antihuman epidermal growth factor receptor 2 (HER2) immunoglobulin G1 (IgG1) trastuzumab.Linker: cathepsin B-cleavable valine-alanine linker.Payload: DNA cross-linking pyrrolobenzodiazepine (PBD) dimer-based drug tesirine.Development status : phase IMonoclonal antibody: trastuzumab biobetter HM2.Payload: monomethyl auristatin E (MMAE).Development status : phase IMonoclonal antibody: a human epidermal growth factor receptor 2 (HER2) site-specifically targeting monoclonal antibody.Linker: cleavable valine-citrulline- linker.Payload: an analog of dolastatin 10, auristatin-0101.Monoclonal antibody: a human epidermal growth factor receptor 2  site-specifically targeting monoclonal antibody.Linker: para-acetyl-phenylalanine .Development status : preclinMonoclonal antibody: a human epidermal growth factor receptor 2  targeting monoclonal antibody.Payload: undisclosed maytansine derivative.Development status : BAT8001Monoclonal antibody: a monoclonal antibody targeting human epidermal growth factor receptor 2 .Payload: a DNA minor groove cross-linking agent pyrrolobenzodiazepine monoamide (PBD-MA).Development status : first-iMonoclonal antibody: a monoclonal antibody targeting human epidermal growth factor receptor 2 .Linker: a cleavable maleimidocaproyl-valyl-citrullinyl-p-aminobenzyloxycarbonyl  type linker.Payload: monomethyl auristatin E (MMAE).Development status: phase I and phase II .Monoclonal antibody: a monoclonal antibody against human epidermal growth factor receptor 2 (HER2) site-specifically.Payload: monomethyl auristatin F (MMAF).Development status: LegoChemistry\u2122 and ADC platform technology ConjuAll\u2122.Monoclonal antibody: hertuzumab.Payload: monomethyl auristatin E (MMAE).Development status: phase I and phase II.Monoclonal antibody: a bispecific antibody against the extracellular domain of human epidermal growth factor receptor 2  comprised of the single-chain variable fragment (scFv) of the anti-HER2 monoclonal antibody trastuzumab, fused to the heavy chains of the anti-HER2 monoclonal antibody 39S.Payload: tubulysinDevelopment status : phase IMonoclonal antibody: trastuzumab.Linker : it has Payload: PM050489.Development status : preclinMonoclonal antibody: a monoclonal antibody against the human epidermal growth factor receptor 2 (HER2).Payload: the antineoplastic anthracycline antibiotic doxorubicin encapsulated within liposomes.Development status : phase IMonoclonal antibody: a monoclonal antibody targeting human epidermal growth factor receptor 2 .Linker: a tetrapeptide linker, Gly-Phe-Leu-Gly (GFLG).Payload: deruxtecan, a derivative of the camptothecin analog exatecan ; a DNA topoisomerase 1  inhibitor, with antineoplastic activity.Development status : FDA appMonoclonal antibody: trastuzumab, a monoclonal antibody targeting epidermal growth factor receptor 2 (HER2).Linker : a cleavPayload: the duocarmycin prodrug.Development status : phase IMonoclonal antibody: trastuzumab.Linker : noncleaPayload: the microtubule-inhibitory agent DM1.Development status : approveMonoclonal antibody: HT-19, a monoclonal antibody directed against the human epidermal growth factor receptor 2  that binds to domain IV of HER2 to an epitope that is distinct from the trastuzumab-binding sitePayload: proprietary auristatin-derived payload molecules.Development status : in JanuMonoclonal antibody: sactizumab, an anti-Trop-2 humanized antibody.Payload: the topoisomerase-I inhibitor SN-38.Development status : phase IMonoclonal antibody: the zinc transporter LIV-1 targeting humanized antibody.Payload: monomethyl auristatin E (MMAE).Development status: phase I.Monoclonal antibody: anti-EGFR antibody.Payload: DM1 (derivative of maytansine).Development status: phase I.Monoclonal antibody: an anti-HER3 antibody.Payload: a topoisomerase I inhibitor exatecan derivative (DXd).Development Status: phase I/II.Monoclonal antibody: receptor tyrosine kinase-like orphan receptor 2 (ROR2) targeting antibody.Payload: an undisclosed payload.Development status: phase I/II.Monoclonal antibody: a humanized DS6 antibody directed against tumor-associated sialoglycotope CA6.Payload: the maytansinoid DM4.Development status: phase I.Breast cancer has become the most common cancer in the world; a lot of treatment methods and technologies were used in order to control it, but all of them did not achieve the required goal, until the invention of the antibody-drug conjugates. The concept of targeted delivery of anticancer drugs helped the oncologists to improve the tumor selectivity of anticancer drugs and to lower their systemic toxicity. Meaning that these drugs could be administered at higher doses, providing better therapeutic benefit to their patients. The tumor selectivity of antibodies offered a chance to achieve this goal by using them as guide for the drug towards the tumor. This seemingly simple concept had great attention from researchers at academic institutions and in the pharmaceutical industry. The current breed of ADCs uses antibodies that are humanized, not immunogenic, and linkers that are designed to be stable in circulation, but are cleaved upon delivery into a cell. The recent FDA approvals of new ADCs have generated tremendous excitement. There are a lot of ADCs currently in clinical evaluation and almost every major pharmaceutical company has embraced this technology. There is active research by medicinal chemists to develop new linkers and discover new potent effector molecules suitable for use in ADCs, while biologists have focused on identifying cell-surface targets suitable for antibody development."}
+{"text": "We regret the unprofessional behavior of the authors involved.li06yh@126.com>Correspondence: Yinghao Li: <"}
+{"text": "Moderate or severe burns are potentially devastating injuries that can even cause death, and many of them occur every year. Infection prevention, anti-inflammation, pain management and administration of growth factors play key roles in the treatment of burn wounds. Novel therapeutic strategies under development, such as nanotherapeutics, are promising prospects for burn wound treatment. Nanotherapeutics, including metallic and polymeric nanoformulations, have been extensively developed to manage various types of burns. Both human and animal studies have demonstrated that nanotherapeutics are biocompatible and effective in this application. Herein, we provide comprehensive knowledge of and an update on the progress of various nanoformulations for the treatment of burn wounds. HighlightsThe recent progress of various nanotherapeutics for the management of burn wounds and their therapeutic mechanisms are systematically reviewed.Assessment of burn wounds treated with nanotherapeutics is briefly summarized.Skin is the most active immune system organ and the largest organ of the body, as well as the main barrier between the environment and the internal organs . Acute sToday, we have a deep understanding of the pathogenesis of burn wounds. The main factors determining burn wound progression include bacterial infection, excessive inflammatory reaction and low expression levels of various growth factors (GFs). Of these, bacterial infection is the most serious complicating factor . In acco to treat burn wounds . I. IOther feration . By conteceptors . The res lesions . Importae models ,119.in vitro and in vivo models have been extensively employed to evaluate the therapeutic efficacies of nanotherapeutics. Anti-bacterial, anti-inflammatory and cell proliferation experiments have been mainly used to assess in vitro therapeutic efficacies of nanotherapeutics. However, many studies have focused on the animal models to evaluate the in vivo therapeutic efficacies of nanotherapeutics. Animals such as mice [et\u00a0al. have synthetically reviewed the establishment of various types of burn wounds  in animals [Both  as mice , rats [1 as mice , rabbits as mice ,112, dog as mice , and pig as mice  bearing  animals . The cli animals . AntibacA wide range of NPs have been explored for management of burn wounds. Using nanotherapeutics to treat these wounds has some advantages, such as increasing antibacterial effect, overcoming bacterial drug resistance, facilitating cell proliferation and decreasing drug administration frequency. The therapeutic efficacy of nanotherapeutics has been evaluated in various animal models on different types and degrees of burns. Some nanotherapeutics exhibit satisfactory therapeutic effects in patients with burn injuries, making them promising candidates for further studies of their role in the management of these wounds. Although gratifying therapeutic effects have been achieved, the toxicity of nanotherapeutics due to their particular physicochemical properties cannot be ignored. How to prepare multifunctional nanotherapeutics with good biocompatibility and efficacy for the treatment of burns needs further investigation. In particular, the systemic toxicity of nanotherapeutics should be investigated in various animal models before proceeding to patient applications. How to prepare nanotherapeutics for clinical practice on a large scale must also be considered. Although some problems must be overcome before this can happen, we believe that more burn patients can profit from nanotherapeutics in the future.sn-glycero-phosphatidylcholine; DNA: Deoxyribonucleic acid; DOTAP: 1,2-Dioleoyl-3-trimethylamonium propane chloride; EC: Endothelial cell; ECM: Extracellular matrix; EGF: Epidermal growth factor; EGF CDLs: EGF cationic deformable liposomes; FBS: Fetal bovine serun; FDA: Food and Drug Administration; FGF: Fibroblast growth factor; FN: Fibronectin; GFs: Growth factors; GM-CSF: Granulocyte macrophage colony stimulating factor; HA: Hyaluronic acid; HaCaT: Human immortal keratinocyte cell line; HB-EGF: Heparin binding epidermal growth factor; hFBs: Normal human fibroblast; HM-PA: Heparin-mimetic peptide; HUVECs: Human umbilical vein endothelial cells; ICAM-1: Intercellular adhesion molecule-1; IGF: Insulin-like growth factor; IGF-BP: Insulin like growth factor binding protein; IL: Interleukin; KGF: Keratinocyte formation growth factor; MMP: Matrix metalloproteinase; MRSA, Methicillin-resistant Staphylococcus aureus; MSC: Mesenchymal stem cell; NGF: Nerve growth factor; NPs: Nanoparticles; PBS: Phosphate buffer saline; PC: Phosphatidyl choline; PCL: Poly(caprolactone); PDA: Polydopamine; PEG: Polyethylene glycol; PEO: Polyethylene oxide; PDGF: Platelet-derived growth factor; PSIS: Porcine-derived small intestinal submucosa; PLA: Poly(lactic acid); PLGA: Poly(lactic-co-glycolic acid); PVA: Poly; ROS: Reactive oxygen species; SG: Silver nanoparticle gel; SF: Nanosilver foam; siRNA: Short interfering ribonucleic acid; TGF-\u03b2: Transforming growth factor beta; TIMP-1: Tissue inhibitor of metalloproteinase-1; TNF-\u03b1: Tumor necrosis factor alpha; TRA: All-trans retinoic acid; TRA DLs: All-trans retinoic acid loaded deformable liposomes; TSP: Thrombin-sensitive protein; VEGF, Vascular endothelial growth factor.AgSD: Silver sulfadiazine; \u03b1-SMA: Alpha-smooth muscle actin; BAC: Benzalkonium chloride; bFGF: Basic fibroblast growth factor; C: Collagen; CINC: Cytokine-induced neutrophil chemoattractant; Col1a1: Collagen type 1 alpha 1; CPC: Cetylpyridinium chloride; CXCL-1: Chemokine (C-X-C motif) ligand 1 protein; CRP: C-reactive protein; CTAB: Cetyltrimethyl ammonium bromide; CTGF: Connective-tissue growth factor; DMPC: Dimyristoyl-This work supported by the Open Project Program of the State Key Laboratory of Trauma, Burn and Combined Injury, Third Military Medical University .R.H. drafted the manuscript. J. H. and D. Z. designed this project and revised the manuscript. W. Q. prepared the revised manuscript. L. C. prepared some figures and tables. All authors read and approved the final manuscript.The authors declared that they have no conflicts of interest to this work."}
+{"text": "Correction to:Mol Syst Biol (2021) 17: e10179. DOI: 10.15252/msb.202010179 | Published online 30 March 2021et\u2009al  LacI variants include the following: a study of temperature\u2010sensitive variants (Sadler & Novick, Besides the sentence quoted above, this mistake does not impact the findings of the study. The authors apologize for this error."}
+{"text": "Following publication of the original article , the autThe incorrect author name is: Brandon P. Luke-WoldThe correct author name is: Brandon P. Lucke-WoldThe author group has been updated above and the original article  has been"}
+{"text": "Nature Communications8: Article number: 15732; DOI: 10.1038/ncomms15732 (2017); Published: 06092017; Updated: 03122018In the original version of this Article, the affiliation details for Yan Fang were incorrectly given as \u201cZJU-UoE Institute, Zhejiang University School of Medicine, Hangzhou 310058, China\u201d. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Nature Communications8: Article number: 14969; DOI: 10.1038/ncomms14969 (2017); Published: 04252017; Updated: 06202017In the original version of this Article, which was received on 04 November 2016, the received date was incorrectly given as 04 November 2017. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Nature Communications6: Article number: 7143; DOI: 10.1038/ncomms8143 (2015); Published: 05152015; Updated: 03262018The original HTML version of this Article had an incorrect article number of 8143; it should have been 7143. This has now been corrected in the HTML; the PDF version of the Article was correct from the time of publication."}
+{"text": "Nature Communications8: Article number: 14715; DOI: 10.1038/ncomms14715 (2017); Published: 03092017; Updated: 04242017In Fig. 2 of this Article, the inset image in the bottom panel was inadvertently omitted during the production process. The correct version of the Fig. 2 is shown below as"}
+{"text": "Scientific Reports6: Article number: 3960910.1038/srep39609; published online: 12202016; updated: 01232017This Article contains a typographical error in the Affiliation of the author Tingyong Feng. The correct affiliation is listed below:School of Psychology, Southwest University, Chongqing, China."}
+{"text": "Scientific Reports5: Article number: 991810.1038/srep09918; published online: 04212015; updated: 03192018Correction to: The original version of this Article contained a typographical error in the volume number \u20185\u2019 was incorrectly given as \u20184\u2019. This error has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports6: Article number: 2552310.1038/srep25523; published online: 05102016; updated: 05172018The original version of this Article contained an error in the indexing of the author Anang A. Shelat. This error has now been corrected."}
+{"text": "Nature Communications8: Article number: 13708 ; DOI: 10.1038/ncomms13708 (2016); Published: December162016; Updated: march042017The financial support for this Article was not fully acknowledged. The acknowledgements should have included the following:The European Community FP7 grant no. 602239 (ATECT)."}
+{"text": "Nature Communications7: Article number: 13903; DOI: 10.1038/ncomms13903 (2016); Published 12132016; Updated 01202017The original version of this Article contained a typographical error in the spelling of the author Stephen F. Price, which was incorrectly given as Stephen A. Price. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports6: Article number: 3316810.1038/srep33168; published online: 09092016; updated: 01232017The original version of this Article contained an error in the order of author names, which were incorrectly given as \u2018Naeime Karamipour, Mohammad Mehrabadi & Yaghoub Fathipour\u2019.These errors have now been corrected in the HTML and PDF versions of this Article."}
+{"text": "Nature Communications8: Article number: 13804; DOI: 10.1038/ncomms13804 (2017); Published: 01052017; Updated: 05032017In Fig. 7b of this Article, traces depicting the average MUA response evoked by the target (red) and distractor (blue) were inadvertently omitted during the production process. The correct version of Fig. 7 appears below as"}
+{"text": "Scientific Reports6: Article number: 35429; 10.1038/srep35429 published online: 10202016 updated: 01112017.The Supplementary Information file originally published with this Article contained incorrect Figures for the \u2018NMR spectra of all new compounds\u2019. This error has now been corrected in the Supplementary Information file that accompanies the Article."}
+{"text": "Nature Communications8: Article number:15137 ; DOI: 10.1038/ncomms15317 (2017); Published: 06052017; Updated 06302017In the original HTML version of this Article, which was published on 5 June 2017, the publication date was incorrectly given as 5 July 2017. This has now been corrected in the HTML; the PDF version of the paper was correct from the time of publication."}
+{"text": "Scientific Reports6: Article number: 2842210.1038/srep28422; published online: 06222016; updated: 01122017A supplementary dataset containing 3411 genes and their expression profiles from 303 microarrays available in the public domain, Gene Expression Omnibus (GEO) was omitted from the original version of this Article. This has been corrected in the HTML version of the Article; the PDF version was correct at time of publication."}
+{"text": "Scientific Reports6: Article number: 37810; 10.1038/srep37810 published online: 11252016; updated: 04062018.The original version of this Article contained an error in the indexing of the author Shaymaa Mohamed Mohamed Badawy. This error has now been corrected."}
+{"text": "Scientific Reports6: Article number: 37908; 10.1038/srep37908 published online: 11292016; updated: 02102017.The original version of this Article contained an error in the spelling of the author Pankaj Ror which was incorrectly given as Pankaj Kumar. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Nature Communications7: Article number: 13611; DOI: 10.1038/ncomms13611 (2016); Published 12052016; Updated 12172017The original version of this Article contained a typographical error in the spelling of the author S.A. Cannas, which was incorrectly given as S. Cannas. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports7: Article number: 44794; 10.1038/srep44794 published online: 03202017; updated: 12222017.The original version of this Article contained a typographical error in the spelling of the author Jack van Horssen, which was incorrectly given as Jack Van Horsen. This has now been corrected in the PDF and HTML versions of the Article, and in the accompanying Supplementary Dataset File."}
+{"text": "Nature Communications7: Article number: 12951; DOI: 10.1038/ncomms12951 (2016); Published 11252015; Updated 12172017The authors inadvertently omitted Richard Bianco, who provided consultation for the experimental surgical services, from the author list. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports6: Article number: 3616810.1038/srep36168; published online: 11032016; updated: 11302016The original version of this Article contained errors in the name of the author Deepika, which was incorrectly given as Deepika Goyal.These errors have now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports7: Article number: 45919; 10.1038/srep45919 published online: 04042017; updated: 05162017.The original version of this Article contained an error in the spelling of the author Cagla Ozgit-Akgun, which was incorrectly given as \u00c7agla Ozgit-Akgun. This error has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports6: Article number: 3713710.1038/srep37137; published online: 11162016; updated: 03132017This Article contains errors in Figure 6c. The Pearson correlation values for the automated and manually prepared samples were inadvertently switched. The correct Figure 6c appears below as"}
+{"text": "Scientific Reports6: Article number: 3578810.1038/srep35788; published online: 10202016; updated: 02242017The original version of this Article contained a typographical error in the spelling of the author Wenguang Xu, which was incorrectly given as Wengguang Xu. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Nature Communications8: Article number: 14944; DOI: 10.1038/ncomms14944 (2017); Published: 04212017; Updated: 06062017The HTML version of this Article previously published had an incorrect publication date of 20 April 2017; it should have been 21 April 2017. This has now been corrected in the HTML; the PDF version of the paper was correct from the time of publication."}
+{"text": "After the publication of this article  it was nAquatic Biosystems 2012, 12:33, which should be: Hayman et al. BMC Geriatrics, 2012, 12:33.An incorrect heading at the top of each page: Hayman et al. 2.The citation at the end of the article which was:This affected:Hayman et al.: Life and Living in Advanced Age: A Cohort Study in New Zealand -Te Pu\u0101waitanga o Nga Tapuwae Kia Ora Tonu, LiLACS NZ: Study protocol. Aquatic Biosystems 2012 12:33.This was incorrect and should be:Hayman et al.: Life and Living in Advanced Age: A Cohort Study in New Zealand -Te Pu\u0101waitanga o Nga Tapuwae Kia Ora Tonu, LiLACS NZ: Study protocol. BMC Geriatrics 2012 12:33."}
+{"text": "Scientific Reports7: Article number: 44894; 10.1038/srep44894 published online: 03202017; updated: 08292017.This article was published twice in error during a change in production systems. The publisher apologizes to the authors and readers for the error. When citing this work, please refer to the original version.1"}
+{"text": "Scientific Reports6: Article number: 25462; 10.1038/srep25462 published online: 05052016; updated: 10102016.In this Article, the values given in the column labeled \u2018compound\u2019 of Table 1 are incorrect. The correct"}
+{"text": "Scientific Reports7: Article number: 4300010.1038/srep43000; published online: 02232017; updated: 05122017This Article contains an error in Figure 8: the oxygen percentage for the black columns is incorrectly labeled as 21% instead of the correct value of 5%. The correct Figure 8 appears below as"}
+{"text": "Nature Communications8: Article number: 15845 ; DOI: 10.1038/ncomms15845 (2017); Published: 06202017; Updated: 07112017An incorrect version of the Supplementary Information was inadvertently published with this Article which included incorrect figure references in Supplementary Table 4. The Article has now been updated to include the correct version of the Supplementary Information."}
+{"text": "Scientific Reports7: Article number: 40259; 10.1038/srep40259 published online: 01112017; updated: 08242017.In the Supplementary Information file originally published with this Article, References 1\u20135 were omitted. This error has been corrected in the Supplementary Information that now accompanies the Article."}
+{"text": "Nature Communications7: Article number:13707 ; DOI: 10.1038/ncomms13707 (2016); Published: 12192016; Updated: 06302017The original version of this Article contained an error in the gene ID for TimRhom I, cited in the Methods, which specified an unrelated gene. The correct gene ID for TimRhom I is Tb927.9.8260. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Nature Communications7 Article number: 10144 ; DOI: 10.1038/ncomms10144 (2016) Published: 01112016; Updated: 08042017The original version of this Article contained an error in the spelling of the author Giorgos Gouridis which was incorrectly given as Giorgos Guoridis. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports5: Article number: 1026310.1038/srep10263; published online: 06232016; updated: 09072016In the Supplementary Information file originally published with this Article, Figures S1 and S2 were omitted. These errors have been corrected in the Supplementary Information that now accompanies the Article."}
+{"text": "Scientific Reports6: Article number: 3580510.1038/srep35805; published online: 10262016; updated: 03132017A glitch in the authors\u2019 reference-management software led to extensive errors in the reference list and in-text citations. These errors have been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports7: Article number: 4100910.1038/srep41009; published online: 01202017; updated: 04062017In the original version of this Article, the link to the Supplementary Information file was omitted. This has now been corrected in the PDF and HTML versions of the paper."}
+{"text": "Scientific Reports6: Article number: 39511; 10.1038/srep39511 published online: 12222016; updated: 10202017.A Supplementary Information data file and Supplementary Mathematica notebook file were omitted from the original version of this Article. This has been corrected in the PDF and HTML version of the Article."}
+{"text": "Nature Communications7: Article number: 10427 ; DOI: 10.1038/ncomms10427 (2016); Published: 01292016; Updated: 03092016The original version of this article contained an error in the spelling of the author C. Martijn de Sterke, which was incorrectly given as de Sterke C. Martijn. This has now been corrected in both the PDF and HTML versions of the article."}
+{"text": "Scientific Reports7: Article number: 44888; 10.1038/srep44888 published online: 03202017; updated: 08292017.This article was published twice in error during a change in production systems. The publisher apologizes to the authors and readers for the error. When citing this work, please refer to the original version.1"}
+{"text": "Nature Communications8: Article number: 14112; DOI: 10.1038/ncomms14112 (2017); Published: 07152015; Updated: 02162017The original version of this Article contained a typographical error in the spelling of the Author Preetam Janakirama, which was incorrectly given as Preetam Jankirama. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "There are errors in the Author Contributions. The correct contributions are: Conceptualization: MG EB. Data curation: MG ET EB. Formal analysis: MG ET EB. Methodology: MG EB. Supervision: MG CM EB. Writing-original draft: MG CM ET EB.There are errors in the Funding section. The correct funding information is as follows: This study was conducted when Massimo Grassi was supported by the grant CPDA123458 (\"Progetto di ricerca di Ateneo\"), and Chiara Meneghetti by the grant CPDA140302 (\"Progetto di ricerca di Ateneo\") awarded by the University of Padova. The Department of General Psychology financially supported Erika Borella for this study."}
+{"text": "Scientific Reports5: Article number: 1651110.1038/srep16511; published online: 11102015; updated: 01082018The original version of this Article contained a typographical error in the spelling of the author Maisoon Al-Jawad, which was incorrectly given as Maisoon AI-Jawad. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports6: Article number: 3817110.1038/srep38171; published online: 11022016; updated: 03162017The original version of this Article contained errors in the spelling of the authors Chung-Yuh Tzeng and Hsueh-Yao Chu, which were incorrectly given as Chung-Yuh Tseng and Shueh-Yao Chu respectively. These errors have now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Nucleic Acids Res (2017). doi: 10.1093/nar/gkx695The name of Hediye Erdjument-Bromage was misspelled in the original version of this paper. This has now been corrected online and in print."}
+{"text": "Scientific Reports6: Article number: 3811310.1038/srep38113; published online: 11292016; updated: 05262017The original version of this Article incorrectly included Haibing Chen as a corresponding author. This error has now been corrected in the PDF and HTML versions of this Article."}
+{"text": "Nature Communications8: Article number:15745 ; DOI: 10.1038/ncomms15745 (2017) Published: 06072017; Updated: 06302017The financial support for this Article was not fully acknowledged. The Acknowledgements should have included the following:The publication charges for this article have been funded by a grant from the publication fund of UiT The Arctic University of Norway."}
+{"text": "There are errors in Table 4. The correct version of Table 4 can be seen here:Part 1: Part 2: In the supplemental PDF download of this article, the Table 4 is correct, but missing the footnotes. The missing footnote information is: RSA values for proteins marked with * were determined from homology models (SWISS MODEL repository) and the PDB code given is that of the template (T) used for the model. Buried residues (RSA < 20 %) are in bold. Secondary structure information for residue determined by DSSP: Alpha helix (H), extended strand participating in beta ladder (E), 310-helix (G), hydrogen bonded turn (T), bend (S), loop/irregular (-)."}
+{"text": "Scientific name: Pimoa delphinicaSpecies authority: Mammola, Hormiga & Isaia, 2016Kingdom: AnimaliaPhylum: ArthropodaClass: ArachnidaOrder: AraneaeFamily: PimoidaeTaxonomic notes: Pimoa delphinica is a medium-sized spider , with slender legs and a brown-reddish coloration . The species\u2014previously misidentified with P. rupicola \u2014was described in 2016. It is readily distinguishable from the other species of European pimoids by morphological characters in male and female genitalia .Region for assessment: GlobalBiogeographic realm: PalearcticCountries: ItalyMap of records (image): Fig. 2Map of records (Google Earth): Suppl. material 1Basis of EOO and AOO: Known habitat extentBasis (narrative): During relatively intense speleological research studies in the Western Alps, we collected Pimoa delphinica in a few caves and military bunkers in the municipalities of Casteldelfino, Sampeyre and Sant'Anna di Bellino . Specifically, the species occurred in four small wild caves and a few subterranean military bunkers in Casteldelfino and Sant'Anna di Bellino and an abandoned house in the hamlet of Becetto (Sampeyre). Two additional localities reported in Isaia et al. (2011) and Mammola et al. (2016b)\u2014Buco del Nebin 1 [Speleological Cadastre: Pi 1158] and Buco del Nebin 2 [Pi 1159] caves\u2014are in need of verification, since only juvenile specimens were collected. However, even if confirmed, these additional localitites would fall within the known extent of occurrence of the species . Despite our extensive study of Pimoa specimens from Italy and France\u2014including material stored in Museums or private collections and original records\u2014we have not been able to find additional records of Pimoa delphinica outside this small area .We used the verified occurrence records of the species to calculate the extent of occurrence (EOO) as the minimum convex hull and the area of occupancy (AOO) through a 2x2 km2 grid, as implemented in the red R package (Cardoso 2016).Min Elevation/Depth (m): 1230Max Elevation/Depth (m): 2242Range description: Pimoa delphinica is a stenoendemic species with a restricted Western Alpine distribution. The species is recorded in seven nearby localities, in the high Varaita valley. Its distribution range represents a small enclave (ca. 20 km2) within the range of distribution of the sister species P. graphitica Mammola, Hormiga & Isaia, 2016.Type status:Other material. Occurrence: recordedBy: Stefano Mammola, Alessandro Girodo; individualCount: 2; sex: female; lifeStage: adult, juvenile; Taxon: scientificName: Pimoadelphinica; kingdom: Animalia; phylum: Arthropoda; class: Arachnida; order: Araneae; family: Pimoidae; genus: Pimoa; specificEpithet: delphinica; scientificNameAuthorship: Mammola, Hormiga, Isaia, 2016; Location: country: Italy; stateProvince: Piedmont; county: CN; municipality: Casteldelfino; locality: Military bunker 1 near the road to Casteldelfino; verbatimElevation: 1280 m; minimumElevationInMeters: 1280; maximumElevationInMeters: 1280; locationRemarks: Abandoned military bunker (II World War); verbatimCoordinates: 44\u00b035'07.21\"N, 7\u00b004'40.02\"E; georeferenceProtocol: GPS; Identification: identifiedBy: Stefano Mammola, Marco Isaia; dateIdentified: 2016; Event: samplingProtocol: hand collected; eventDate: 12 Dec 2016; Record Level: basisOfRecord: PreservedSpecimenType status:Other material. Occurrence: recordedBy: Stefano Mammola, Alessandro Girodo; individualCount: 3; sex: female; lifeStage: adult, juvenile; Taxon: scientificName: Pimoadelphinica; kingdom: Animalia; phylum: Arthropoda; class: Arachnida; order: Araneae; family: Pimoidae; genus: Pimoa; specificEpithet: delphinica; scientificNameAuthorship: Mammola, Hormiga, Isaia, 2016; Location: country: Italy; stateProvince: Piedmont; county: CN; municipality: Casteldelfino; locality: Military bunker 2 near the road to Casteldelfino; verbatimElevation: 1288 m; minimumElevationInMeters: 1288; maximumElevationInMeters: 1288; locationRemarks: Abandoned military bunker (II World War); verbatimCoordinates: 44\u00b035'07.70\"N, 7\u00b004'40.15\"E; georeferenceProtocol: GPS; Identification: identifiedBy: Stefano Mammola, Marco Isaia; dateIdentified: 2016; Event: samplingProtocol: hand collected; eventDate: 12 Dec 2016; Record Level: basisOfRecord: PreservedSpecimenType status:Other material. Occurrence: recordedBy: Alessandro Girodo, Paolo Bertacco; individualCount: 2; sex: females; lifeStage: adults; Taxon: scientificName: Pimoadelphinica; kingdom: Animalia; phylum: Arthropoda; class: Arachnida; order: Araneae; family: Pimoidae; genus: Pimoa; specificEpithet: delphinica; scientificNameAuthorship: Mammola, Hormiga, Isaia, 2016; Location: country: Italy; stateProvince: Piedmont; county: CN; municipality: Casteldelfino; locality: Miniera di Casteldelfino, galleria Auriol (Borgata Ciampanesio); verbatimElevation: ca. 970 m; locationRemarks: Mineshaft; verbatimCoordinates: 44\u00b035'10.3\"N, 7\u00b007'06.6\"E; verbatimCoordinateSystem: WGS84; decimalLatitude: 44.5862; decimalLongitude: 7.1185; georeferenceProtocol: GPS; Identification: identifiedBy: Stefano Mammola, Marco Isaia; dateIdentified: 2016; Event: samplingProtocol: hand collected; eventDate: 16 Dec 2016; habitat: Subterranean; Record Level: basisOfRecord: PreservedSpecimenEOO (km2): 26Trend: UnknownJustification for trend: The species is troglophile (sensu Sket 2008), showing a preference for dark and moisty habitats. Yet, the species exhibits a moderate plasticity in its ecological requirements, being able to colonize both cave and extra-cave environments, such as forests in high altitude habitats. The distribution range of Pimoa delphinica is enclosed within the range of the more widespread P. graphitica, which is apparently competing with the former thus limiting its expansion . The subterranean habitats colonized by P. delphinica are as yet not threatened by direct human activities. However, biogeographic studies and genetic data suggested that past climate change determined strong contraction in the distribution ranges of the species of alpine Pimoa . It is thus plausible that anthropogenic climate change may determine reduction or habitat shift for this species. In order to confirm this hypothesis statistically, a deeper study of the detailed occurrence of this species in its distribution range is required.Causes ceased?: UnknownCauses understood?: UnknownCauses reversible?: UnknownExtreme fluctuations?: NoTrend: UnknownJustification for trend: See paragraph \"Extent of Occurrence\".Causes ceased?: UnknownCauses understood?: UnknownCauses reversible?: UnknownExtreme fluctuations?: NoAOO (km2): 12Number of locations: Trend: StableExtreme fluctuations?: NoNumber of individuals: Unknown.Trend: UnknownJustification for trend: No information about population size are currently available.Causes ceased?: UnknownCauses understood?: UnknownCauses reversible?: UnknownExtreme fluctuations?: NoPopulation Information (Narrative): A census of the population has never been attempted. According to our observations, populations are locally abundant. In two caves in which Pimoa delphinica was found in syntopy with the congeneric P. graphitica, mixed nuclear alleles between the two species have been found, indicating the existence of unidirectional introgression of males of P. graphitica into females of P. delphinica .Number of subpopulations: 2Trend: StableJustification for trend: Examining the known range of distribution and taking into account habitat connectivity, it is possible to identify two subpopulations within the range. The first subpopulation includes the localitites from Casteldelfino and the Bellino valley, which are more connected through alpine scree and larch woods, acting as potential route of dispersal. The other subpopulation is found on the other slope of the Varaita valley, in the nearby of the hamlet of Becetto . The subpopulation are as yet not threatened.Extreme fluctuations?: NoSevere fragmentation?: NoJustification for fragmentation: System: TerrestrialHabitat specialist: YesHabitat (narrative): The species primarily lives in the twilight zone of wild caves and other similar sheltered habitats, in high alpine environments . Healthy populations were also observed in artificial subterranean habitat (military bunkers and mines), offering suitable cool climatic conditions . Further individuals of P. delphinica were collected in pitfall traps placed within the rocky debris on the floor of the cellar of an abandoned cottage . During summertime, we observed juveniles\u2014tentatively classified as P. delphinica\u2014in an epigean environment, near the locus typicus , in a larch (Larix decidua) wood. Accordingly, it is possible that juveniles of P. delphinica may be able to disperse trough epigean habitats under suitable climatic condition. Extra-cave dispersal was also documented for the congeneric alpine species P. graphitica and P. rupicola, as justified by occasional catches of juveniles and males in pitfall traps placed in the leaf litter of broad-leaved woods at mid-altitudes .Trend in extent, area or quality?: StableHabitat importance: Major ImportanceHabitats: 7. Caves and Subterranean Habitats (non-aquatic)Habitat importance: MarginalHabitats: 1. ForestSize: Total length (leg excluded) = Male: 7 mm, Female: 10.5 mmGeneration length (yr): 1Dependency of single sp?: NoEcology and traits (narrative): Little is known about the ecology of Pimoa delphinica. We report the result of our sporadic observations, which are not supported by specific studies or statistical inference. Like other Pimoa species , P. delphinica exhibits a moderate ecological plasticity. In caves, it is found preferentially in the twilight zone. We observed adult males and females during the summertime. Adults display thanatotic behaviour when disturbed, possibly as a protection against predators . Depositions of cocoons occurs in July and cocoons are guarded by females. Females affix substrate particles to their cocoons .Justification for threats: See \"Extent of occurrence\".Threat type: FutureThreats: 11.1. Climate change & severe weather - Habitat shifting & alterationJustification for conservation actions: A portion of the distribution range of Pimoa delphinica falls within the border of the Natural Park \"Parco del Monviso\".The installation of information panels educating the visitors about this peculiar endemic species would positively increase the awareness of the caves as a natural heritage deserving protection.Conservation action type: In PlaceConservation actions: 2.1. Land/water management - Site/area managementConservation action type: NeededConservation actions: 4. Education & awarenessResearch needed: 1. ResearchJustification for research needed: Supplementary material 1PimoadelphinicaExtent of Occurrence of Data type: Geographic rangeFile: oo_102120.kmlMammola S., Hormiga G., Isaia M."}
+{"text": "Scientific Reports6: Article number: 3578910.1038/srep35789; published online: 10212016; updated: 12232016The original version of this Article contained a typographical error in the name of the author Dan Zheng, which was incorrectly given as Zheng Dan. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Nature Communications8 Article number: 15909 ; DOI: 10.1038/ncomms15909 (2017); Published 06262017; Updated 07272017.An incorrect version of the Supplementary Information was inadvertently published with this Article where the wrong file was included. The Article has been updated to include the correct version of the Supplementary Information."}
+{"text": "Scientific Reports7: Article number: 3997810.1038/srep39978; published online: 01052017; updated: 03092017This Article contains an error in the order of the Figures."}
+{"text": "Scientific Reports6: Article number: 20077; 10.1038/srep20077 published online: 01292016; updated: 06302017.The original HTML version of this Article listed an incorrect volume number. This has now been corrected in the HTML version; the PDF version was correct at the time of publication."}
+{"text": "Nature Communications8: Article number: 14014; DOI: 10.1038/ncomms14014 (2017); Published 01102017; Updated 05192017cains@hotmail.co.uk. The error has been corrected in the HTML and PDF versions of the Article.The original version of this Article contained an error in the email address of the corresponding author Sarah Cains. The correct email is"}
+{"text": "Scientific Reports7: Article number: 4333810.1038/srep43338; published online: 02232017; updated: 04062017The original HTML version of this Article contained formatting errors in the \u201cGravimetric water (ice) content (%)\u201d row. The correct This error has been corrected in the HTML version of the Article; the PDF version was correct at the time of publication."}
+{"text": "Scientific Reports6: Article number: 3337010.1038/srep33370; published online: 09262016; updated: 11242016This Article contains an incorrect version of Figure 4. The correct version of Figure 4 appears below as"}
+{"text": "Nature Communications5: Article number: 3562; DOI: 10.1038/ncomms4562 (2014); Published online: 04152014; Updated: 04102018The original HTML version of this Article had an incorrect article number of 4562; it should have been 3562. This has now been corrected in the HTML; the PDF version of the Article was correct from the time of publication."}
+{"text": "Nature Communications8: Article number: 15987; DOI: 10.1038/ncomms15987 (2017); Published: 07112017; Updated: 03132018In the original version of this Article, financial support was not fully acknowledged. The PDF and HTML versions of the Article have now been corrected to include the following:\u2018This work was supported by grant I10-0095 from the STARR foundation.\u2019"}
+{"text": "In the original publication  one authWrong: Miro, ZupcicCorrect: Zupcic, Miro"}
+{"text": "Scientific Reports6: Article number: 32096; 10.1038/srep32096 published online: 08242016; updated: 01192017.The original version of this Article contained a typographical error in the spelling of the author Kathleen Cheng, which was incorrectly given as Katherine Cheng. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Nature Communications8: Article number: 14530; DOI: 10.1038/ncomms14530 (2017); Published 02212017; Updated 03212017The financial support for this Article was not fully acknowledged. The Acknowledgements should have included the following:The research was funded by a grant from the Medical Research Council (MR/N004299/1) and the German Research Foundation (DFG) through the priority programme 1608."}
+{"text": "AbstractMantispidae are a distinctive group of Neuroptera known for the adults\u2019 possession of raptorial forelegs. There are four recognised, extant subfamilies of Mantispidae: the Mantispinae, Symphrasinae, Calomantispinae and Drepanicinae. The life history and larval behaviour of the subfamily Mantispinae is best known: the immatures are spider egg predators. Among the three remaining subfamilies, larval Symphrasinae and Calomantispinae most likely predate on other small arthropods, while the immature life history of Drepanicinae, until now, remained completely unknown.The Ditaxisbiseriata (Westwood), within a well-established Macadamia orchard in northern New South Wales, Australia. A female deposited fertile eggs, allowing this first report of egg batch and first instar morphology. The mass emergence of mobile pharate adults from the ground was observed in the same month in two consecutive years. The pharates climbed tree-trunks for a distance before undergoing eclosion. The newly-hatched first instar larvae are campodeiform and prognathous; a typical morphology among Mantispidae. After hatching, they drop to the ground and burrow into soil. They are unpigmented and appear to lack stemmata. Together, the observations infer that the immature component of the life cycle takes place underground in forested habitats. If this feature is common among the Drepanicinae, it might explain why so little is known of the biology of the immature stages.Here we provide observations of annual, near-synchronised, mass emergences of adults of the drepanicine,  Neuroptera is one of the most ancient orders of insects that show complete metamorphosis. Larvae are typically predaceous with elongate, slender mouthparts that are adapted for piercing and sucking , based on the raptorial forelimbs and elongated prothorax  have been reared in the laboratory on immature Lepidoptera, Hymenoptera and Coleoptera  between 11th and 16th September 2015. This appeared to have no effect on subsequent emergences of pharate adults.The study site was a th to 22nd September 2015 and from 17th to 24th September 2016. Mature adults and pharate adults were collected on and after 5th September 2015.Observations of adult eclosion were made between 5Some adults were kept in captivity (in petri dishes or insect containers) while others were killed and pinned. Pharate adults were preserved in ethanol.Both field and studio photographs were taken, with studio images being of both live and preserved specimens. To record larval morphology, ethanol-preserved first instars were washed in water and cleared in KOH before slide-mounting and photomicroscopy.For the timelapse observations of adult eclosion, a Canon EOS 60D dSLR camera with 100 mm macro lens was mounted on a tripod and focused on a pharate adult and 759 images were taken over a period of 43 minutes. The camera was controlled by an external remote control and a canon speedlite 580EX II was used to light the specimen. A video was produced comprising of all 759 images played at 25 frames per second.Type status:Other material. Occurrence: catalogNumber: JD1DB; recordedBy: James B Dorey; individualCount: 1; lifeStage: adult; associatedMedia: http://www.jamesdoreyphotography.com.au/Nonpublic-galleries/Mantispids/n-s3NpJH/; Taxon: taxonID: urn:lsid:biosci.ohio-state.edu:osuc_names:275502; scientificName: Ditaxisbiseriata; kingdom: Animalia; phylum: Arthropoda; class: Insecta; order: Neuroptera; family: Mantispidae; genus: Ditaxis; Location: country: Australia; stateProvince: New South Wales; locality: Newrybar; verbatimElevation: 11 m; locationRemarks: label transliteration: \"Newrybar, NSW, 28\u02da43'52.0\"S 153\u02da33'18.8\"E, J.B.Dorey, 05/09/2015, JD1DB\"; verbatimCoordinates: 28\u02da43'52.0\"S 153\u02da33'18.8\"E; decimalLatitude: -28.731111; decimalLongitude: 153.555222; georeferenceProtocol: label; Identification: identifiedBy: Kevin Lambkin; dateIdentified: 2017; Event: samplingProtocol: sweeping; Record Level: language: en; collectionID: JD1DB; collectionCode: Insects; basisOfRecord: PreservedSpecimenType status:Other material. Occurrence: catalogNumber: JD2DB; recordedBy: James B Dorey; individualCount: 1; lifeStage: adult; associatedMedia: http://www.jamesdoreyphotography.com.au/Nonpublic-galleries/Mantispids/n-s3NpJH/; Taxon: taxonID: urn:lsid:biosci.ohio-state.edu:osuc_names:275502; scientificName: Ditaxisbiseriata; kingdom: Animalia; phylum: Arthropoda; class: Insecta; order: Neuroptera; family: Mantispidae; genus: Ditaxis; Location: country: Australia; stateProvince: New South Wales; locality: Newrybar; verbatimElevation: 11 m; locationRemarks: label transliteration: \"Newrybar, NSW, 28\u02da43'52.0\"S 153\u02da33'18.8\"E, J.B.Dorey, 05/09/2015, JD2DB\"; verbatimCoordinates: 28\u02da43'52.0\"S 153\u02da33'18.8\"E; decimalLatitude: -28.731111; decimalLongitude: 153.555222; georeferenceProtocol: label; Identification: identifiedBy: Kevin Lambkin; dateIdentified: 2017; Event: samplingProtocol: sweeping; Record Level: language: en; collectionID: JD2DB; collectionCode: Insects; basisOfRecord: PreservedSpecimenType status:Other material. Occurrence: catalogNumber: JD3DB; recordedBy: James B Dorey; individualCount: 1; lifeStage: adult; associatedMedia: http://www.jamesdoreyphotography.com.au/Nonpublic-galleries/Mantispids/n-s3NpJH/; Taxon: taxonID: urn:lsid:biosci.ohio-state.edu:osuc_names:275502; scientificName: Ditaxisbiseriata; kingdom: Animalia; phylum: Arthropoda; class: Insecta; order: Neuroptera; family: Mantispidae; genus: Ditaxis; Location: country: Australia; stateProvince: New South Wales; locality: Newrybar; verbatimElevation: 11 m; locationRemarks: label transliteration: \"Newrybar, NSW, 28\u02da43'52.0\"S 153\u02da33'18.8\"E, J.B.Dorey, 05/09/2015, JD3DB\"; decimalLatitude: -28.731111; decimalLongitude: 153.555222; georeferenceProtocol: label; Identification: identifiedBy: Kevin Lambkin; dateIdentified: 2017; Event: samplingProtocol: As pharat adult; Record Level: language: en; collectionID: JD3DB; collectionCode: Insects; basisOfRecord: PreservedSpecimenDitaxisbiseriata, is provided by A description of the subject of this study, Ditaxisbiseriata was distinguished from its sister species, Ditaxismeridiei, by characters of the adult vertex and colouration of the sclerites  and emergence was observed simultaneously in nearby regenerated rainforest, suggesting that emergence is highly seasonal over the local area, perhaps through detection of photoperiod or some attribute of their yet-unknown food source, and that the life cycle covers a single year. Further, the presence in rainforest as well as in a location within the orchard with high soil moisture, dense canopy cover and numerous epiphytes hints at a rainforest association. The much higher prevalence of emergence in the Macadamia orchard compared to nearby regenerating rainforest could be due to more favourable conditions in the Macadamia orchard. It is possible that the coordinated emergence of D.biseriata facilitates mating because at least one of the females collected at the site produced fertile eggs. The species might not just be associated with rainforest; reports suggest that it is also common at the same time of year in open eucalyptus forest.As far as the authors are aware, mass, near-synchronous emergence of mantispids is a previously unreported phenomenon. It is uncertain if the emergence in such large numbers is a natural occurrence or an artefact of monoculture farming. Adults and exuviae were observed in other local Mantispidae, pupation generally takes place within a silken cocoon in a concealed location and the pharate adults leave the cocoon and walk some distance away before eclosing  . Larval morphology was not detailed but it was noted that they lacked stemmata  . In one stemmata , an obsetispidae  and the rothidae . Comparitispinae , the ovetispinae . Distincrothidae , whose lrothidae . The antrothidae .D.biseriata are subterranean. If this life history was common to all or most Drepanicinae, it could explain the lack of historical knowledge about the immature stages of the subfamily. The larval diet remains unknown; they could be subterranean arthropod predators like the subfamilies Symphrasinae and Calomantispinae or spider-egg predators like their sister sub-family, Mantispinae. A clue, at least in this species, might lie in the apparent preference for moist soil and the rainforest association. Future studies could focus on taking soil samples in the orchard to determine what potential prey or host species are present and possibly to detect larvae or pupae in situ.Together, the behaviour and morphology of larvae, including their lack of stemmata, their tendency to drop from the egg and burrow into soil, and the subterranean origin of the pharate adults, support the premise that the larval and pupal stages of"}
+{"text": "Scientific Reports7: Article number: 46474; 10.1038/srep46474 published online: 04122017; updated: 12222017.This Article contains errors in Figure 3 where the authors calculated the probability of survival instead of the probability of mortality. The correct"}
+{"text": "Nature Communications5: Article number: 5446 ; DOI: 10.1038/ncomms6446 (2014); Published: 11172014; Updated: 08212017Because two of its three major findings have been invalidated, the authors wish to retract this Article3The symmetry error"}
+{"text": "Scientific Reports6: Article number: 3701610.1038/srep37016; published online: 11212016; updated: 02152017The original version of this Article contained referencing errors, where multiple instances of reference 5 were incorrectly given as reference 1. The publishers regret introducing these errors during final typesetting.This has now been corrected in the HTML and PDF versions of this Article."}
+{"text": "Nature Communications8 Article number:14632 ; DOI: 10.1038/ncomms14632 (2017); Published: 03082017; Updated: 03312017The original version of this Article contained an error in the spelling of post-transcriptional in the title of the paper. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports7: Article number: 4112510.1038/srep41125; published online: 11242017; updated: 03162017The original version of this Article contained a typographical error in the spelling of the author Armand Bensussan which was incorrectly given as Armand Benssusan. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports6: Article number: 2724810.1038/srep27248; published online: 06062016; updated: 09212016While this paper was under review, a correction was published to reference 17, which indicated that the reported dosage rate was incorrect. Therefore, points 2\u20134 in the Supplementary Information of this paper cannot explain the reported discrepancy in metabolic rates. The authors apologize for this oversight."}
+{"text": "Scientific Reports7: Article number: 4081510.1038/srep40815; published online: 01192017; updated: 03232017The original version of this Article contained an error in the spelling of the author Xuan Qin, which was incorrectly given as Xun Qin. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports6: Article number: 3134710.1038/srep31347; published online: 08112016; updated: 05112018In the original version of this Article, the Supplementary Information files containing the supplementary figure and datasets were omitted. This error has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports7: Article number: 4504010.1038/srep45040; published online: 04282017; updated: 05262017The original version of this Article contained a typographical error in the spelling of the author Martin H. de Borst, which was incorrectly given as Martin de Borst. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports6: Article number: 22834; 10.1038/srep22834 published online: 03092016; updated: 04262017.The Supplementary Information file originally published with this Article omitted Reference 1, and a number of equations contained errors. Therefore,now reads:now reads:now reads:These errors have been corrected in the Supplementary Information that now accompanies the Article."}
+{"text": "Scientific Reports6: Article number: 36161; 10.1038/srep36161 published online: 11022016; updated: 01192017.The original version of this Article contained an error in the spelling of Fatemeh Seyednasrollah, which was incorrectly given as Fatemeh Seyednasrollah sadat.This has now been corrected in the HTML and PDF versions of this Article."}
+{"text": "Nature Communications7 Article number:13702 ; DOI: 10.1038/ncomms13702 (2016); Published 12022016; Updated 02272017The financial support for this Article was not fully acknowledged. The acknowledgements should have included the following: The authors acknowledge Nano-Tera.ch for financial support."}
+{"text": "Scientific Reports6: Article number: 1996810.1038/srep19968; published online: 01292016; updated: 04052017The original HTML version of this Article listed an incorrect volume number. This has now been corrected in the HTML version; the PDF version was correct at the time of publication."}
+{"text": "Scientific Reports6: Article number: 29905; 10.1038/srep29905 published online: 10232016; updated: 10102016.In the Supplementary Information file originally published with this Article, Reference 1 was omitted. This error has now been corrected in the Supplementary Information that now accompanies the Article."}
+{"text": "Scientific Reports6: Article number: 2330510.1038/srep23305; published online: 03162016; updated: 01122017In this Article there is a plotting error in Figure 1b and c, due to the data sorting technique. The correct figure appears below as"}
+{"text": "Nature Communications8: Article number:15238; DOI: 10.1038/ncomms15238 (2017); Published: 05032017; Updated: 06272017An incorrect version of the Supplementary Information was inadvertently published with this Article. The HTML has now been updated to include the correct version of the Supplementary Information."}
+{"text": "Scientific Reports7: Article number: 4015710.1038/srep40157; published online: 01142017; updated: 05312018In the Corrigendum published 28 April 2017, the author Schalk van der Merwe was incorrectly indexed. This error has now been corrected."}
+{"text": "Nature Communications8: Article number:15559 ; DOI: 10.1038/ncomms15559 (2017); Published 05302017; Updated 07042017The original version of this Article contained an error in the email address of the corresponding author Daniel I. Simon. The correct email is Daniel.Simon@UHHospitals.org. The error has been corrected in the HTML and PDF versions of the article."}
+{"text": "Scientific Reports7: Article number: 4334010.1038/srep43340; published online: 02272017; updated: 03282017The original version of this Article contained an error in the spelling of author Tian Jian Lu, which was given as Tian Jain Lu.This has now been corrected in the HTML and PDF versions of this Article."}
+{"text": "Scientific Reports6: Article number: 39026; 10.1038/srep39026 published online: 12152016; updated: 01312017.The original version of this Article contained an error in the spelling of Sin-Hyeog Im, which was incorrectly given as Sin-Hyeog Lm. This has now been corrected in the PDF and HTML versions of this Article."}
+{"text": "Scientific Reports7: Article number: 4364710.1038/srep43647; published online 03132017; updated on 04242017This Article contains an error in the legend of"}
+{"text": "Scientific Reports7: Article number: 4552210.1038/srep45522; published online: 04032017; updated: 03192018Correction to: In the original version of this Article, the authors Maximilian P. J. de Courten and Barbora de Courten were incorrectly indexed. These errors have now been corrected."}
+{"text": "Scientific Reports6: Article number: 3388010.1038/srep33880; published online: 09272016; updated: 12092016The original version of this Article contained a typographical error in the spelling of Jianfang Chen, which was incorrectly given as Jian Feng Chen.This has now been corrected in the HTML and PDF versions of the Article"}
+{"text": "Scientific Reports6: Article number: 3386010.1038/srep33860; published online: 09202016; updated: 02172017The original version of this Article contained a typographical error in the spelling of the author Geoffrey R. Oxnard, which was incorrectly given as Geoffrey G. Oxnard.Additionally, the original version of this Article contained an error in Figure 4A, where an asterisk was omitted in error. The correct Figure 4 appears below as These errors have now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Nature Communications7: Article number: 12554; DOI: 10.1038/ncomms12554 (2016); Published: 09132016; Updated: 11232017.x and y axis labels of the scatter graph were inadvertently inverted. This error has been corrected in both the PDF and HTML versions of the Article.The previously published version of this Article contained an error in Figure 1. In panel b the"}
+{"text": "Nature Communications7: Article number: 12597; DOI: 10.1038/ncomms12597 (2016); Published: 08312016; Updated: 05032017The authors inadvertently omitted Christine H\u00e4ger, who was involved in the initial characterization of Notch mutant mice presented in this Article, from the author list and Author contributions statement. These errors have now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports6: Article number: 2672010.1038/srep26720; published online: 06072016; updated: 10192016In this Article, there is an error in Figure 6. The arrows in the right-hand portion of the image are misplaced. The correct Figure 6 appears below as"}
+{"text": "Scientific Reports6: Article number: 3953510.1038/srep39535; published online 12232016; updated on 04242017The original HTML version of this Article listed an incorrect volume number. This has now been corrected in the HTML version; the PDF version was correct at the time of publication."}
+{"text": "Nature Communications7: Article number: 13660; DOI: 10.1038/ncomms13660 (2016); Published: 12162016; Updated: 04102018The original HTML version of this Article had an incorrect volume number of 8; it should have been 7. This has now been corrected in the HTML; the PDF version of the Article was correct from the time of publication."}
+{"text": "Nature Communications8: Article number:14385 ; DOI: 10.1038/ncomms14385 (2017); Published: 02092017; Updated: 06012017In the original version of Supplementary Data 1 associated with this Article, the list of predicted enhancer-associated insertions was inadvertently truncated. The HTML has now been updated to include the correct version of the Supplementary Data 1."}
+{"text": "Scientific Reports7: Article number: 41279; 10.1038/srep41279 published online: 02012017; updated: 08042017.In the original version of this Article, Supplementary Dataset 1 was omitted. This has been corrected in the HTML version of the Article; the PDF version was correct at the time of publication."}
+{"text": "Scientific Reports7: Article number: 4517010.1038/srep45170; published online: 03242017; updated: 05222018This Article contains an error in Figure 7, where the arrows indicating the helical directions are inconsistent with Figure 2. The correct Figure 7 appears below as"}
+{"text": "Nature Communications8: Article number: 14356; DOI: 10.1038/ncomms14356 (2017); Published: 02162017; Updated: 04182017The original version of this Article contained an error in the spelling of the author Carlos S. Moreno, which was incorrectly given as Carlos Moreno. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports6: Article number: 3670210.1038/srep36702; published online: 11102016; updated: 01042017The original version of this Article contained errors. The publication date of the Article, 10th November 2016, was incorrectly listed as 10th October 2016.In addition, an incorrect version of There were typographical errors in formulas (1) and (2):now read:These errors have now been fixed in the HTML and PDF versions of this Article."}
+{"text": "Scientific Reports7: Article number: 3989010.1038/srep39890; published online: 01042017; updated: 03302017This Article contains a typographical error in the Results and Discussion section. In should read:"}
+{"text": "Nature Communications8: Article number: 15451 ; DOI: 10.1038/ncomms15451 (2017); Published 05162017; Updated 08232017The original version of this Article contained an error in the spelling of the author Leon Di Stefano, which was incorrectly given as Leon di Stephano. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Nature Communications8: Article number: 15519; DOI: 10.1038/ncomms15519 (2017); Published: 05302017; Updated: 02212018In the originally published version of this Article, reference 23 did not refer to the correct paper. This error has now been corrected in both the HTML and PDF versions of the Article."}
+{"text": "Giant condyloma acuminata are associated with malignant transformation in up to 50% of cases, high recurrence rate, and poor prognosis. Treatment strategies have included wide local excision, abdominopelvic resection, and addition of radiotherapy and adjuvant and/or neoadjuvant systemic chemotherapy. Question\u2010Quiz: What is this condition and how should it be treated?Answer: A 53\u2010year\u2010old woman visited our gynecology emergency room complaining about a perianal mass, bleeding, and odor. Clinical examination revealed a giant mass originating from anorectum. Biopsy samples of the tumor were retrieved and sent for pathological examination. Results indicated a well\u2010differentiated squamous cell carcinoma on the ground of a giant  condyloma acuminata (Fig.\u00a0IKP: Obstetrician and Gynaecologist, Author: involved in primary handling of the patient in the emergency room; KM: Obstetrician and Gynaecologist, Co\u2010author: involved in primary handling of the patient in the emergency room. GI: Oncology Radiologist, Member of the multidisciplinary oncological team: was responsible for radiation therapy received by the patient; DX: Oncology Radiologist: was responsible for radiation therapy received by the patient; VK: Surgeon, Member of the multidisciplinary oncological team: reviewed the manuscript; TMS: Surgeon, Director of the Surgical Department. ET: Obstetrician and Gynaecologist, Director of the Gynaecology Oncological Department. TMS and ET: were members of the multidisciplinary oncological team.None declared."}
+{"text": "Scientific Reports5: Article number: 1338610.1038/srep13386; published online: 08252015; updated: 08112018In the original version of this Article, the Supplementary Information file containing the derivation for individual payoffs was omitted. This error has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports7: Article number: 42845; 10.1038/srep42845 published online: 02202017; updated: 12222017.The original version of this Article contained an error in the spelling of the author Yuuki Imai, which was incorrectly given as Yu-ki Imai.This error has now been corrected in the PDF and HTML versions of the Article, and in the accompanying Supplementary Information."}
+{"text": "Scientific Reports5: Article number: 992110.1038/srep09921; published online: 04212015; updated: 03192018Correction to: The original version of this Article contained a typographical error in the volume number \u20185\u2019 was incorrectly given as \u20184\u2019. This error has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports5: Article number: 16922; 10.1038/srep16922 published online: 11202015; updated: 02212017.www.qzbiotech.com.The export of human derived tissues and related materials from China is currently subject to regulatory restrictions. Consequently, we are unable to share the human cell line described in this paper with researchers outside of China at the present time. However, scientists within China who wish to use this cell line for research only may obtain them from the following company: Cellular Biotech. Inc."}
+{"text": "The database includes the results from a geochemical and behavioral analysis of obsidian artifacts and debitage in the article entitled \u201cObsidian Procurement and Distribution in the Northwestern Maya Lowlands during the Maya Classic, a Regional Perspective\u201d   Specifications TableValue of the data\u2022The data summarizes the statistical results from the behavioral analysis of all the artifacts analyzed.\u2022The data illustrates the raw results from the EDXRF study of each artifact, which can be compared and used for similar studies.\u2022The data complements similar comparative studies with analogous methodologies and techniques.1The 2Every artifact was analyzed using a behavioral analysis of the formal attributes and physical characteristics Ti: TitaniumMn: ManganeseFe: IronZn: ZincRb: RubidiumSr: StrontiumY: YttriumZr: ZirconiumNb: NiobiumPb: LeadTh: ThoriumB1S1: nomenclature given to each artifact: B (Bag number) and S (Sample number).RGM1: Rhyolite, Glass Mountain Sample 1."}
+{"text": "Scientific Reports5: Article number: 1247010.1038/srep12470; published online: 07272015; updated: 01082018In this Article, figure 1 contains errors. Errors were made during the preparation of figure 1: the same HylD blot was accidentally used in figures 1 and 2. The correct"}
+{"text": "Scientific Reports7: Article number: 4384610.1038/srep43846; published online: 03072017; updated: 04272017In the Supplementary Information file originally published with this Article, Supplementary Tables 1 and 2 were omitted. This error has been corrected in the Supplementary Information that now accompanies the Article."}
+{"text": "Scientific Reports6: Article number: 28680; 10.1038/srep28680 published online: 07062017; updated: 09062017.In the original version of this Article, the Supplementary Software files were omitted. This has been corrected in the HTML version of the Article; the PDF version was correct at the time of publication."}
+{"text": "Scientific Reports6: Article number: 34879; 10.1038/srep34879 published online: 10172016; updated: 01192017.The original version of this Article contained an error in the spelling of the author Peter Guttmann, which was incorrectly given as Peter Guttermann.This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports6: Article number: 19007; 10.1038/srep19007 published online: 01082016; updated: 02212017.The original version of this Article contained an incorrect version of Supplementary Table S7. This error has now been corrected in the HTML version of this Article; the PDF version was correct at the time of publication."}
+{"text": "The new and evolving technologies of laser spectroscopy, laser cooling and trapping of atoms as well as squeezed states will have a dramatic impact on this area of metrology. While these topics have received a great deal of attention in their own right, there has not been a forum in which their impact on the field of fundamental measurements has been specifically addressed. For this reason, the National Bureau of Standards hosted a workshop on \u201cFundamental Measurements on Optically Prepared Atoms\u201d on September 29\u201330, 1986.Measurements of our fundamental scaling parameters . The second session dealt mainly with the kinetic state or velocity of atoms. Demonstration of highly efficient new laser-cooling techniques based on stimulated processes as well as spontaneous emission and speculation on what may be possible with ultra-cold atoms made for a very lively and exciting session. The idea that an atom placed in a box and cooled to a temperature so low that the deBroglie wavelength is long compared to atomic dimensions might lead to confinement with almost no perturbation from encounters with the walls. If verified experimentally, this idea could have profound consequences for precision measurements.The third session dealt with the limits to measurement accuracy as we understand them today and how those limits come into play with the new spectroscopic and cooling techniques. The last session dealt with an important applied field: the use of optically prepared atoms in frequency standards. Since frequency standards have many orders of magnitude more precision and accuracy than any other standard, they represent a great testing ground for the concepts discussed during the workshop.The workshop was attended by 45 people. Seven countries were represented with 40% of the attendees from outside the United States. Twenty-seven papers were presented in the four half-day sessions, which had to be augmented with an evening session to accommodate the lively discussion that followed most of the papers. The format of informal talks with no subsequent publication of papers was designed to encourage speculation and judging from the discussion during and following many of the talks, we were quite successful.A list of the workshops and talks follow:H. J. Kimble:Non-Classical Dynamics With Intra-Cavity AtomsP. Toschek:Absorption by the Numbers: Recent Spectroscopy of Trapped IonsD. McIntyre:Two-Photon Optical Ramsey Spectroscopy of Freely Falling AtomsL. Hunter:Search for an Electric Dipole Moment of the ElectronT. Bergeman:Proposed Application of Decelerated Atomic Beams to Observe Long-Lived (Interference Stabilized) Stark ResonancesS. A. Lee:Fast Beam Laser Spectroscopy: Present and FutureW. Fairbank:2 Reference Lines Near Hydrogen and Positronium Transitions at 4880\u00c5Precision Wavelength Measurement of TeS. Chu:Laser Cooling and Trapping of Atoms: Where are the Limits?C. Salomon:Cooling Atoms With Stimulated EmissionJ. Hall:Some Ideas About Experiments With Freely Falling AtomsW. Ertmer:Preparation of Cold Atoms for Precision MeasurementsW. Phillips:New and Future Experiments on Cooling and Trapping of Neutral AtomsF. Plumelle:+ IonsExperiments on Laser Cooled MgB. Jaduszliwer:Electron-Cesium Collisions With Optical State Preparation and AnalysisJ. Bahns:On Containerless Condensation of \u201cMirror\u201d MatterD. Wineland:Fundamental Limits to Spectroscopic AccuracyJ. S. Boulanger:Requirements for Evaluatable EnvironmentsJ. Shirley:Majorana Effects in Atomic BeamsA. DeMarchi:Does Spin Exchange Limit the Density of Neutral Vapors for Accurate Measurements?G. Hanes:Candidate Ions for Extended Observation PeriodsR. Douglas:Multiphoton Ionization for Atom-State Detection or State PreparationG. Theobald:Detailed Studies of Cesium Beam Optical Pumping; Applications to an Atomic ClockJ.-L. Picqu\u00e9:Laser Cooling and Optically Pumped Cesium Beam Frequency StandardsA. Clairon:The LPTF Optically Pumped Cesium Frequency StandardR. Drullinger:Design of the NBS Optically Pumped Frequency StandardM. Ohtsu:87Rb Atomic ClocksUltrahigh Sensitive Frequency Discrimination in Diode Laser Pumped H. Robinson:The Temperature Dependence of the Wall Shift in Some Evacuated Rb Cells"}
+{"text": "Nature Communications8: Article number: 14864; DOI: 10.1038/ncomms14864 (2017)); Published: 03282017; Updated: 04252017The original version of this Article contained a typographical error in the spelling of the author Beifang Niu, which was incorrectly given as Beifung Niu. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports6: Article number: 27452; 10.1038/srep27452 published online: 06102016; updated: 09012016.The original version of this Article contained a typographical error in the spelling of the author Muhammad Sahimi, which was incorrectly given as Muhammad Sahim. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Nature Communications7: Article number: 13176; DOI: 10.1038/ncomms13176 (2017); Published 10192016; Updated 02222017y axis in In this article, there are errors in the labelling of the"}
+{"text": "There is an error in the first sentence of the fourth paragraph of the results section. The correct sentence is as follows: The relationships between experiential avoidance, coping functions and demographic/ contextual factors were explored (see Table 3).The last paragraph of the Limitations section is incorrect. The correct paragraph is as follows: Notwithstanding these limitations, the study offers novel insight into the relationship between self-harm, experiential avoidance and coping function, expanding on the existing literature to consider the recency and frequency of self-harm engagement.There are errors in the Author Contributions. The correct contributions are: Conceived and designed the experiments: EN KS ET. Performed the experiments: EN. Analyzed the data: EN KS ET. Wrote the paper: EN KS ET."}
+{"text": "Scientific Reports6: Article number: 20029; 10.1038/srep20029 published online: 01292016; updated: 06302017.The original HTML version of this Article listed an incorrect volume number. This has now been corrected in the HTML version; the PDF version was correct at the time of publication."}
+{"text": "Nature Communications7: Article number: 12185; DOI: 10.1038/ncomms12185 (2016); Published: 07152015; Updated: 11222016The GEO accession number provided in this article is incorrect; the correct number is GSE74893."}
+{"text": "Scientific Reports6: Article number: 3949310.1038/srep39493; published online: 12222016; updated: 04052017This Article contains an error in the order of the Figures, where Figures 2 and 3 were inverted. The correct"}
+{"text": "Nature Communications7: Article number: 1253710.1038/ncomms12537 (2016); Published: 07272016; Updated: 09022016In Fig. 6 of this article, the division between the zincblende and wurtzite phases is misplaced in the low temperature range. The correct version of Fig. 6 appears below as"}
+{"text": "Nature Communications8: Article number: 15933; DOI: 10.1038/ncomms15933 (2017); Published 06212017; Updated 07172017The original version of this Article contained an error in the spelling of the author Denis Gebauer, which was incorrectly given as Denis Gebaue. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports7: Article number: 42262; 10.1038/srep42262 published online: 02102017; updated: 08292017.This article was published twice in error during a change in production systems. The publisher apologizes to the authors and readers for the error. When citing this work, please refer to the original version.1"}
+{"text": "Scientific Reports6: Article number: 39104; 10.1038/srep39104 published online: 12202016; updated: 03072017.The original version of this Article contained an error in the spelling of the author Karina Dolgilevica, which was incorrectly given as Karina Dolgevica.This error has now been corrected in the HTML and PDF versions of this Article."}
+{"text": "Scientific Reports6: Article number: 3223310.1038/srep32233; published online: 08302016; updated: 06042018A Supplementary Information file containing Appendices A and B was omitted from the original version of this Article. This has been corrected in the HTML version of the Article; the PDF version was correct at time of publication."}
+{"text": "Nature Communications8: Article number: 15875 ; DOI: 10.1038/ncomms15875 (2017); Published 06202017; Updated 12222017In Fig. 2 of the original Article, information indicating the extent of the lagged correlations between low-passed and detrended time series was inadvertently omitted during the production process. The correct version of this figure appears below as"}
+{"text": "Scientific Reports7: Article number: 3870610.1038/srep38706; published online: 01312017; updated: 03142017The Acknowledgements section in this Article was omitted. The Acknowledgements should read: \u201cThis work was supported by the National 863 Hi-tech Project (2015AA033703), National Natural Science Foundation of China  and Specialized Research Fund for the Doctoral Program of Higher Education (NO. 20120071110067)\u201d."}
+{"text": "Nature Communications7: Article number: 13542; DOI: 10.1038/ncomms13542 (2016); Published: 12062016; Updated: 01052017The original version of this Article contained an error in the spelling of the author Tommaso Poggioli, which was incorrectly given as Tommaso Pogglioli. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports7: Article number: 46314; 10.1038/srep46314 published online: 04102017; updated: 08242017.The original version of this Article contained an error in the spelling of the author Minseop Byun, which was incorrectly given as Minsueop Byun.This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports6: Article number: 2899510.1038/srep28995; published online: 07142016; updated: 09022016The original version of this Article contained a typographical error in the spelling of the author Sophie Petropoulos, which was incorrectly given as Sophie Petropoulous. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports6: Article number: 3632310.1038/srep36323; published online: 11032016; updated: 04052017The original version of this Article contained errors in the spelling of the author Sharon Baumel-Alterzon, which was incorrectly given as Sharon Alterzon-Baumel. These errors have now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports6: Article number: 2393410.1038/srep23934; published online: 03312016; updated: 12072016; updated: 11102017; updated: 03202018et al. PLoS Comp. Biol. [2014]) of this Article introduced a feature set called gapped k-mer for regulatory sequence prediction; this Article applied these gapped k-mer features to recombination spot identification, and a computational predictor was constructed for recombination spot identification.This Article reports an application of methodology originally reported in Reference 33 to recombination spot identification. Reference 33 (Ghandi, M. The original and corrected versions of the Article include ambiguous sentences and textual overlap without adequate attribution, which failed to give due credit to the authors of Reference 33. The original and corrected versions of the Article are therefore being retracted by the Editors. The authors do not agree with the retraction."}
+{"text": "Scientific Reports6: Article number: 31703; 10.1038/srep31703 published online: 08172016; updated: 11082016.The original version of this Article contained a typographical error in the spelling of the author Xiaochun Wan, which was incorrectly given as Xiachun Wan. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports6: Article number: 3786910.1038/srep37869; published online: 11292016; updated: 03162017This Article contains an error in the x-axis labelling of Figure 5. The correct Figure 5 appears below as"}
+{"text": "Scientific Reports6: Article number: 2899410.1038/srep28994; published online: 07262016; updated: 09142016The original version of this Article contained a typographical error in the spelling of the author Liang Zhao, which was incorrectly given as Liang Zhaog. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports6: Article number: 20010; 10.1038/srep20010 published online: 01292016; updated: 06302017.The original HTML version of this Article listed an incorrect volume number. This has now been corrected in the HTML version; the PDF version was correct at the time of publication."}
+{"text": "Nature Communications7: Article number: 12752 ; DOI: 10.1038/ncomms12752 (2016); Published 09152016; Updated 11142016The financial support for this Article was not fully acknowledged. The acknowledgements should have included the following:Yorgo Modis, PhD was supported by a senior research fellowship from the Wellcome Trust, grant no. 101908/Z/13/Z."}
+{"text": "Scientific Reports6: Article number: 30410; 10.1038/srep30410 published online: 07262016; updated: 12222014.In the Supplementary Information file originally published with this Article, Figures S8 and S12 were omitted.These errors have been corrected in the Supplementary Information file that now accompanies the Article."}
+{"text": "Scientific Reports6: Article number: 20136; 10.1038/srep20136 published online: 01292016; updated: 06302017.The original HTML version of this Article listed an incorrect volume number. This has now been corrected in the HTML version; the PDF version was correct at the time of publication."}
+{"text": "Nature Communications8: Article number: 15039; DOI: 10.1038/ncomms15039 (2017); Published: 04062017; Updated: 07062017The original version of the Supplementary Information attached to this Article did not contain Supplementary Figures 11\u201316 and Supplementary References. The HTML has now been updated to include a corrected version of the Supplementary Information file.Supplementary Figures and Supplementary References"}
+{"text": "Nature Communications7: Article number: 13637 ; DOI: 10.1038/ncomms13637 (2016): Published 11242016; Updated 10092017.The original version of this Article contained an error in the email address of the corresponding author George Church. The correct email is gchurch@genetics.med.harvard.edu. The error has been corrected in the HTML and PDF versions of the Article."}
+{"text": "Scientific Reports6: Article number: 2848310.1038/srep28483; published online: 06242016; updated: 09022016The original version of this Article contained an error in the spelling of the author Shuangchun Wen, which was incorrectly given as Shangchun Wen. This error has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports6: Article number: 2345810.1038/srep23458; published online: 03212016; updated: 01082018The original version of this Article contained a typographical error in the spelling of the author Ghaith Aljayyoussi, which was incorrectly given as Ghaith Al Jayoussi. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports7: Article number: 4634010.1038/srep46340; published online: 04192017; updated: 05262017The original version of this Article contained a typographical error in the spelling of the author Yeong Man Yu, which was incorrectly given as Yu Yeong Man. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports6: Article number: 3530810.1038/srep35308; published online: 10182016; updated: 04102017This Article contains an error in Figure 4F of this Article. The immunoblot for GAPDH is incorrect. The correct Figure 4F appears below as"}
+{"text": "Scientific Reports6: Article number: 26756; 10.1038/srep26756 published online: 06072016; updated: 12222017.Due to a technical error during the publication of the original version of this Article, the Supplementary Tables S2 and S3 were published in incomplete forms. These errors have been corrected in the Supplementary Information that now accompanies the Article."}
+{"text": "Scientific Reports6: Article number: 3214810.1038/srep32148; published online: 08252016; updated: 03302017The original version of this Article contained a typographical error in the spelling of the author Shuijin Hu, which was incorrectly given as Shuijing Hu. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports7: Article number: 45235; 10.1038/srep45235 published online: 03222017; updated: 12222017.The original version of this Article contained an incorrect link to the Breast Cancer Integrative Platform in the Abstract.http://omics.bmi.ac.cn/bcancer/).\u201d\u201cTo facilitate the identification of potential regulatory or driver genes, we present the Breast Cancer Integrative Platform .\u201d\u201cTo facilitate the identification of potential regulatory or driver genes, we present the Breast Cancer Integrative Platform (BCIP, This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "The following funding information is missing from the Funding section: Emerson Franchini was supported by FAPESP grant number: 2015/22315-9."}
+{"text": "Scientific Reports7: Article number: 44248; 10.1038/srep44248 published online: 03162017; updated: 04062018.The original version of this Article contained an error in the indexing of the author Shaymaa Mohamed Mohamed Badawy. This error has now been corrected."}
+{"text": "Scientific Reports6: Article number: 3475210.1038/srep34752; published online: 10132016; updated: 12232016In the PDF version of this Article, affiliations 2 and 3 are reversed; the HTML version of the Article was correct at the time of publication."}
+{"text": "Scientific Reports6: Article number: 2565510.1038/srep25655; published online: 05192016; updated: 11022016This Article contains an error in Figure 3(B), where the Fermi distributions of the pumping path are incorrectly shaded black. The correct Figure 3 appears below as"}
+{"text": "Scientific Data 4:170194 doi: 10.1038/sdata.2017.194 (2017); Published: 19 December 2017; Updated: 6 March 2018In the original version of the Data Descriptor the tables were presented in the incorrect order. This has now been corrected in the HTML and PDF versions."}
+{"text": "AbstractInsecta, Lepidoptera), some of them under severe long term threats due to small sized habitats or climatic changes. In this contribution, we present the IUCN Red List profiles of 34 endemic moths to the Azorean archipelago, including species belonging to two diverse families: Noctuidae (11 species) and Crambidae (eight species). The objective of this paper is to assess all endemic Azorean moth species and advise on possible future research and conservation actions critical for the long-trem survival of the most endangered species.The few remnants of Azorean native forests harbour a unique set of endemic moths (Eupitheciaogilviata). Therefore, we suggest as future conservation actions: (1) a long-term species monitoring plan and (2) control of invasive species.Most species have a large distribution (i.e. 58% occur in at least four islands), very large extent of occurrence (EOO) and a relatively large area of occupancy (AOO). Only nine species are single-island endemics, three of them from Flores, three from S\u00e3o Miguel and one from Pico, S\u00e3o Jorge and Faial. Most of the species also experience continuing decline in habitat quality, number of locations and subpopulations caused by the ongoing threat from pasture intensification, forestry, invasive plant species and future climatic changes. The lack of new records may indicate that one of the species previously named is extinct ( Lepidoptera from the Azorean archipelago is still scarce and skewed towards the diurnal species of Rhopalocera , eight grass moths (Crambidae), three geometer moths (Geometridae), three Stathmopodidae, three ermine moths (Yponomeutidae), two snout moths or pyralid moths , one twirler moth or gelechiid moth (Gelechiidae), one leaf-miner moth (Gracillaridae), one plume moth (Pterophoridae) and one fungus moth or tineid moth (Tineidae), which represent the majority of families present in the Azores  provide updated information on the distribution, abundance and ecology for the 34 Azorean endemic moths; 2) identification of the major threats involving these species; 3) the evaluation of the species conservation profiles for all known Azorean endemic moth species.Azorean Biodiversity Portal and downloaded CSV files with the distribution of each species; iv) species images were obtained from specimens deposited in Coll. ZMUC (Credit: Anders Illum) and also from the repository available at the Azorean Biodiversity Portal, the most important source of information on Azorean biodiversity. Species distributions in the Azores were obtained from the list of Azorean biota  and using an approximation to the standard IUCN 2 km \u00d7 2 km cells (4 km2). Final maps with species distributions were produced using the IUCN standards with Google Earth (.kmz files).Prior to the calculation of area of occupancy (AOO) and extent of occurrence (EOO), the 500 m \u00d7 500 m cells obtained from Critical information on species threats and conservation were mostly obtained from Crambidae, which are important pollinators of the Azorean native forest  and Neomarianiaoecophorella  for presenting a low value of AOO. Five more species have an AOO and EOO decline, which present a low range between 1,950-8,900 km2 for EOO and 16-48 km2 for AOO. In addition to this, nine of these species have a very restricted distribution, occupying a unique island  and, therefore, they have a very small EOO and AOO. Amongst the analysed taxa, it should be noted that, for five species, only one individual is known , leaving one of the two sexes totally unknown. These species have low areas of occupation and are frequently restricted to a single patch of native forest. The lack of new records may indicate that one of the species previously named is extinct (Eupitheciaogilviata). In addition, many other species are in a critical conservation situation and actions should be taken with some urgency, namely the implementation of area-based management plans for those species distribution historical sites.We evaluated that 15 endemic species have an extent of occurrence (EOO) and area of occupancy (AOO) that is stable with a range of between 6,200-62,00 kmHadenaazorica Meyer & Fibiger, 2002; Phlogophorakruegeri Saldaitis & Ivinskis, 2006; Apameasphagnicola Wagner, 2014; Apamearamonae Wagner, 2015) challenges the notion that Lepidoptera are one of the most well studied taxonomic groups of insects in the Azores  and invasive species . Consequently, formal education and awareness is needed to allow future investments in habitat restoration of areas invaded by invasive plants or impacted by forestry and dairy-cow management, located mostly at mid elevations. The use of greatly magnified images (extreme macro photography) of Lepidoptera may be a successful strategy to inform the public about the ecological an aesthetical value of Azorean endemic moths (e.g. see Climate change is one of the prevailing threats across the world affecting numerous species and studies on some Azorean taxa show its negative effects, such as on Macaronesian bryophytes  and Azored areas  and theie.g. see  (Fig. 13Concerning the most threathened Azorean moth species, a community monitoring plan is also crucial to generate data for the development of species recovery plans. Monitoring every ten years using the BALA protocol will inform about habitat quality e.g. see .DiscussionSupplementary material 1Eudoniainterlinealis mapData type: Map Google EarthEudoniainterlinealis in the Azores islands.Brief description: Distribution of File: oo_174738.kmzAnja DanielczakSupplementary material 2Eudonialuteusalis mapData type: Map Google EarthEudonialuteosalis in the Azores islands.Brief description: Distribution of File: oo_174739.kmzAnja DanielczakSupplementary material 3Eudoniamelanographa mapData type: Map Google EarthEudoniamelanographa in the Azores islands.Brief description: Distribution of File: oo_174740.kmzAnja DanielczakSupplementary material 4Scopariaaequipennalis mapData type: Map Google EarthScopariaaequipennalis in Azores islands.Brief description: Distribution of File: oo_174741.kmzAnja DanielczakSupplementary material 5Scopariacarvalhoi mapData type: Map Google EarthScopariacarvalhoi in Azores islands.Brief description: Distribution of File: oo_174742.kmzAnja DanielczakSupplementary material 6Scopariacoecimaculalis mapData type: Map Google EarthScopariacoecimaculalis in Azores islands.Brief description: Distribution of File: oo_174743.kmzAnja DanielczakSupplementary material 7Scopariasemiamplalis mapData type: Map Google EarthScopariasemiamplalis in Azores islands.Brief description: Distribution of File: oo_174744.kmzAnja DanielczakSupplementary material 8Udeaazorensis mapData type: Map Google EarthUdeaazorensis in the Azores islands.Brief description: Distribution of File: oo_174745.kmzAnja DanielczakSupplementary material 9Brachmiainfuscatella mapData type: Map Google EarthBrachmiainfuscatella in Azores islands.Brief description: Distribution File: oo_174746.kmzAnja DanielczakSupplementary material 10Cyclophoraazorensis mapData type: Map Google EarthCyclophoraazorensis in the Azores islands.Brief description: Distribution of File: oo_174747.kmzAnja DanielczakSupplementary material 11Eupitheciaogilviata mapData type: Map Google EarthEupitheciaogilviata in Faial island.Brief description: Distribution of File: oo_174748.kmzAnja DanielczakSupplementary material 12Xanthorhoeinaequata mapData type: Map Google EarthXanthorhoeinaequata in the Azores islands.Brief description: Distribution of File: oo_174749.kmzAnja DanielczakSupplementary material 13Micrurapteryxbistrigella mapData type: Map Google EarthMicrurapteryxbistrigella in Azores islands.Brief description: Distribution of File: oo_174750.kmzAnja DanielczakSupplementary material 14Apamearamonae mapData type: Map Google EarthApamearamonae in Flores island.Brief description: Distribution of File: oo_174751.kmzAnja DanielczakSupplementary material 15Apameasphagnicola mapData type: Map Google EarthApameasphagnicola in Azores islands.Brief description: Distribution of File: oo_174752.kmzAnja DanielczakSupplementary material 16Hadenaazorica mapData type: Map Google EarthHadenaazorica in S\u00e3o Jorge island.Brief description: Distribution of File: oo_174754.kmzAnja DanielczakSupplementary material 17Melanchragranti mapData type: Map Google EarthMelanchragranti in Azores islands.Brief description: Distribution of File: oo_174773.kmzAnja DanielczakSupplementary material 18Mesapameastorai mapData type: Map Google EarthMesapameastorai in Azores islands.Brief description: Distribution of File: oo_174755.kmzAnja DanielczakSupplementary material 19Noctuaatlantica mapData type: Map Google EarthNoctuaatlantica in Azores islands.Brief description: Distribution of File: oo_174756.kmzAnja DanielczakSupplementary material 20Noctuacarvalhoi mapData type: Map Google EarthNoctuacarvalhoi in Azores islands.Brief description: Distribution of File: oo_174757.kmzAnja DanielczakSupplementary material 21Phlogophoracabrali mapData type: Map Google EarthPhlogophoracabrali in Azores islands.Brief description: Distribution of File: oo_174758.kmzAnja DanielczakSupplementary material 22Phlogophorafurnasi mapData type: Map Google EarthPhlogophorafurnasi in Azores islands.Brief description: Distribution of File: oo_174759.kmzAnja DanielczakSupplementary material 23Phlogophorainterrupta mapData type: Map Google EarthPhlogophorainterrupta in Azores islands.Brief description: Distribution of File: oo_174760.kmzAnja DanielczakSupplementary material 24Phlogophorakruegeri mapData type: Map Google EarthPhlogophorakruegeri in Flores island.Brief description: Distribution of File: oo_174761.kmzAnja DanielczakSupplementary material 25Stenoptiliameyeri mapData type: Map Google EarthStenoptiliameyeri in S\u00e3o Miguel island.Brief description: Distribution of File: oo_174762.kmzAnja DanielczakSupplementary material 26Homoeosomamiguelensis mapData type: Map Google EarthHomoeosomamiguelensis in S\u00e3o Miguel island.Brief description: Distribution of File: oo_174763.kmzAnja DanielczakSupplementary material 27Homoeosomapicoensis mapData type: Map Google EarthHomoeosomapicoensis in Pico island.Brief description: Distribution of File: oo_174764.kmzAnja DanielczakSupplementary material 28Neomarianiaincertella mapData type: Map Google EarthNeomarianiaincertella in Flores island.Brief description: Distribution of File: oo_174765.kmzAnja DanielczakSupplementary material 29Neomarianiaoecophorella mapData type: Map Google EarthNeomarianiaoecophorella in Azores islands.Brief description: Distribution of File: oo_174766.kmzAnja DanielczakSupplementary material 30Neomarianiascriptella mapData type: Map Google EarthNeomarianiascriptella in Azores islands.Brief description: Distribution of File: oo_174767.kmzAnja DanielczakSupplementary material 31Eudarciaatlantica mapData type: Map Google EarthEudarciaatlantica in Azores islands.Brief description: Distribution of File: oo_174768.kmzAnja DanielczakSupplementary material 32Argyresthiaatlanticella mapData type: Map Google EarthArgyresthiaatlanticella in Azores islands.Brief description: Distribution of File: oo_174771.kmzAnja DanielczakSupplementary material 33Argyresthiaminusculella mapData type: Map Google EarthArgyresthiaminusculella in Azores islands.Brief description: Distribution of File: oo_174772.kmzAnja DanielczakSupplementary material 34Argyresthiapoecilella mapData type: Map Google EarthArgyresthiapoecilella in S\u00e3o Miguel island.Brief description: Distribution of File: oo_174769.kmzAnja Danielczak"}
+{"text": "Nature Communications7: Article number: 12992; DOI: 10.1038/ncomms12992 (2016); Published: 10052016; Updated: 11082016The original version of this Article contained an error in the spelling of the author Tin-Lap Lee, which was incorrectly given as T.P. Lee. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Nature Communications7: Article number: 1219510.1038/ncomms12195 (2016); Published: 07202016; Updated: 08312016The original version of this Article contained an error in which the first affiliation was incorrectly given as \u2018CNRS, ICMCB, UPR 9048, Pessac 33600, France'. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports6: Article number: 3642210.1038/srep36422; published online: 11102016; updated: 12092016The original version of this Article contained a typographic error in the spelling of Pranati Nayak, which was incorrectly given as Pranati Nayuk.This error has now been fixed in the HTML and PDF versions of this Article."}
+{"text": "Scientific Reports7: Article number: 42627; 10.1038/srep42627 published online: 02152017; updated: 04062018.The original PDF version of this Article contained an error in the order of corresponding authors. This has now been corrected in the PDF version of this Article; the HTML version was correct from the time of publication."}
+{"text": "Nature Communications7: Article number: 13526; DOI: 10.1038/ncomms13526 (2016); Published: 11242016; Updated: 01182017In Fig. 4c of this Article, the colour bars were inadvertently changed from graded to solid during the production process. The correct version of Fig. 4c appears below as"}
+{"text": "Scientific Reports6: Article number: 2592910.1038/srep25929; published online: 05162016; updated: 12232016In Supplementary Information published with this Article, the authors omitted Table S10, which contains information pertaining to the primers used in qRT-PCR. The correct"}
+{"text": "Nature Communications8: Article number: 14095; DOI: 10.1038/ncomms14095 (2017); Published: 01242017; Updated: 08302017.The authors inadvertently omitted Eltyeb Abdelwahid, who contributed to the generation of animal models and their initial evaluation, from the author list. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Nature Communications8: Article number:15308; DOI: 10.1038/ncomms15308 (2017); Published: 05182017; Updated: 06162017The original version of this Article contained an error in the spelling of the author Zemin Zhang, which was incorrectly given as Zeming Zhang. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Nature Communications7: Article number: 13867; DOI: 10.1038/ncomms13867 (2016); Published 12222016; Updated 02072017The original version of this Article contained an error in the spelling of the author Yih-Leong Chang, which was incorrectly given as Yi-Liang Chang. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports6: Article number: 3156710.1038/srep31567; published online: 08162016; updated: 03162017In this Article, the Gene Expression Omnibus (GEO) accession number for the RNA sequencing data was incorrectly given as GSE77446. The correct accession number is GSE77466."}
+{"text": "Scientific Reports6: Article number: 3573210.1038/srep35732; published online: 10212016; updated: 11292016The original version of this Article contained typographical errors in the spelling of the author Yong Ryoul Yang which was incorrectly given as Yong Ryul Yang.These errors have now been corrected in the PDF and HTML versions of this Article."}
+{"text": "Scientific Reports6: Article number: 2092710.1038/srep20927; published online: 02182016; updated: 09232016The original version of this Article contained a typographical error in the spelling of the author E. Gazquez, which was incorrectly given as E. Gazguez. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports7: Article number: 3981010.1038/srep39810; published online: 01052017; updated: 06072017This Article contains an error in Figure 3B where the y-axis label of the scale bar is missing. The correct Figure 3 appears below as"}
+{"text": "Scientific Reports7: Article number: 44797; 10.1038/srep44797 published online: 03202017; updated: 06162017.In the HTML version of this Article, Figure 6 was incorrect. The correct Figure 6 appears below as This error has been corrected in the HTML version of the Article; the PDF version was correct at the time of publication."}
+{"text": "Nature Communications7: Article number: 12494; DOI: 10.1038/ncomms12494 (2016); Published 08122016; Updated 12062016In Fig. 7a of this article, the structure of the intermediate compound was inadvertently misdrawn during the production process. The correct version of Fig. 7 appears below as"}
+{"text": "Scientific Reports5: Article number: 1285910.1038/srep12859; published online: 08052015; updated: 03092017This Article contains an error in the order of the"}
+{"text": "Scientific Reports7: Article number: 3976410.1038/srep39764; published online: 01042017; updated: 02172017In the Supplementary Information file originally published with this Article, Supplementary Table 1 was omitted. This error has now been corrected in the Supplementary Information that now accompanies the Article."}
+{"text": "Nature Communications7: Article number: 1267210.1038/ncomms12672 (2016); Published: 08312016; Updated: 1005201621.'In the originally published version of the Article, an incorrect reference number was cited. The final sentence of the first paragraph of the Introduction section should read: \u2018The likely reasons are technical difficulties in generating atomic size electron vortex beams, together with fine control of their resulting orbital angular momentum in the case of electron vortex beams, and a low EMCD signal fraction in the case of astigmatic beams"}
+{"text": "Scientific Reports6: Article number: 2298510.1038/srep22985; published online: 03092016; updated: 01122017This Article contains a typographical error in the name of fluorescence dye for the mutant LNA probe in"}
+{"text": "Nature Communications8 Article number: 16017 ; DOI: 10.1038/ncomms16017 (2017); Published: 07062017; Updated: 08072017.The financial support for this Article was not fully acknowledged. The Acknowledgements should have included the following:This work was supported by a Nanken-Kyoten grant from Tokyo Medical and Dental University (TMDU)."}
+{"text": "Nature Communications7: Article number: 10144; DOI: 10.1038/ncomms10144 (2016); Published: 01112016; Updated: 11162017This Article contains an error in Fig. 4. Figure 4b shows the structure of the rhodamine dye Alexa488, not the Alexa555 used in this work. The structure of Alexa555 is not known."}
+{"text": "Scientific Reports7: Article number: 4657810.1038/srep46578; published online: 04132017; updated: 05262017The original version of this Article incorrectly included the following text in the Methods section:\u201cStatistical analyses on volunteers and ELISAs, BAM files and reference genomes for genome assemblies, genome fragments too short for inclusion in GenBank, BEAST inputs and outputs, TempEst inputs and outputs and pipeline Perl scripts, are available from: doi://10.17635/lancaster/researchdata/111\u201d.This now appears in a Data Availability section in the PDF and HTML versions of the Article."}
+{"text": "Nature Communications8: Article number: 14482; DOI: 10.1038/ncomms14482; published: 02172017; Updated: 03222017The original version of this Article contained a typographical error in the spelling of the author Omid Kavehei, which was incorrectly given as Omid Kevehei. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports7: Article number: 4266610.1038/srep42666; published online: 02202017; updated: 03232017The original version of this Article contained a typographical error in the spelling of the author H. B. Zhuo, which was incorrectly given as H. B. Zhou. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports6: Article number: 20069; 10.1038/srep20069 published online: 01292016; updated: 06302017.The original HTML version of this Article listed an incorrect volume number. This has now been corrected in the HTML version; the PDF version was correct at the time of publication."}
+{"text": "Scientific Reports5: Article number: 994210.1038/srep09942; published online: 04232015; updated: 03012018The Acknowledgements section in this Article was omitted. The Acknowledgements section should read:\u201cKhashayar Khoshmanesh acknowledges the Australian Research Council for funding under the Discovery Early Career Researcher Award (DECRA) scheme (Project No. DE120101402).\u201d"}
+{"text": "Nature Communications8: Article number: 14778; DOI: 10.1038/ncomms14778 (2017); Published: 03162017; Updated: 05242017In Fig. 5 of this Article, the image in the centre column for [111] incorrectly replicates the image above. The correct version of Fig. 5 appears below as"}
+{"text": "Scientific Reports6: Article number: 2982510.1038/srep29825; published online: 07192016; updated: 09302016The original version of this Article contained a typographical error in the spelling of the author Masayasu Nagoshi, which was incorrectly given as Masayasu Yagoshi. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports6: Article number: 33784; 10.1038/srep33784 published online: 09282016; updated: 11212016.The original version of this Article contained errors in the spelling of the author Joydeep Das, which was incorrectly given as Das Joydeep.These errors have now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports7: Article number: 4507910.1038/srep45079; published online: 03242017; updated: 05042017The original version of this Article contained a typographical error in the spelling of the author Jin-Beom Kwon, which was incorrectly given as Jin-Beon Kwon. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports5: Article number: 1669710.1038/srep16697; published online: 11162015; updated: 09142016The original Supplementary Information file published with this Article was incorrect. This version included errors in the \u2018Calculation of Phonon Coherent Length (CL) in Si/Ge SNW and H-SNW\u2019 section and a number of typographical errors. The correct Supplementary Information file now accompanies the Article."}
+{"text": "Scientific Reports7: Article number: 3964710.1038/srep39647; published online: 01032017; updated: 03162017The SBML models provided in the original Supplementary Information files published with this Article contained formatting errors. These errors have been corrected in the Supplementary Information files that now accompany the Article."}
+{"text": "Nature Communications7: Article number: 10525; DOI: 10.1038/ncomms10525 (2016); Published: 01222016; Updated: 11172016The authors wish to add \u2018Mads H. Ribergaard' and \u2018John Mortensen' to the author list of this Article for the provision of oceanographic data. This has now been updated in both the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports7: Article number: 4127510.1038/srep41275; published online: 01302017; updated: 04052017In the original version of this Article, Affiliation 1 was incomplete. The correct affiliation is listed below.Institute of Geographic Sciences and Natural Resources Research, Chinese Academy of Sciences, Beijing 100101, China.These errors have been corrected in both the HTML and PDF versions of the Article."}
+{"text": "Scientific Reports6: Article number: 2650810.1038/srep26508; published online: 05242016; updated: 09212016This Article contains discrepancies between the HTML and PDF versions of Figures 14 and 15. The correct Figures 14 and 15, with their accompanying legends appear below as"}
+{"text": "Scientific Reports6: Article number: 3277710.1038/srep32777; published online: 09082016; updated: 11102016.The original version of this Article contained a typographical error in the spelling of the author Sebastien Magnifico, which was incorrectly given as Sebastien Magifico. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports6: Article number: 3684110.1038/srep36841; published online: 11142016; updated: 01032017The original version of this Article contained an error in the name of the first author Mark Zeller which was incorrectly given as Jelle Matthijnssens. This error has now been corrected in the PDF and HTML versions of this Article."}
+{"text": "In the Funding section, the grant number from the funder Medical Research Council (MRC) is listed incorrectly. The correct grant number is: MC_UU_12014/5."}
+{"text": "Nature Communications8: Article number:15533 ; DOI: 10.1038/ncomms15533 (2017); Published 06052017; Updated 07042017The original version of this Article contained an error in the formatting of the author name Yang Shu, which was incorrectly given as Shu Yang. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports6: Article number: 3186610.1038/srep31866; published online: 08182016; updated: 09212016The original version of this Article contained a typographical error in the spelling of the author Gholamreza Asadikaram, which was incorrectly given as Golamreza Asadikaram. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Nature Communications7: Article number: 11928 10.1038/ncomms11928 (2016); Published: 060162016; Updated: 09022016An incorrect version of the Supplementary Information was inadvertently published with this Article that contained errors in Supplementary Equations 18 and 19. The HTML has now been updated to include the correct version of the Supplementary Information."}
+{"text": "Scientific Reports7: Article number: 4287410.1038/srep42874; published online: 02232017; updated: 04052017The original version of this Article contained a typographical error in the spelling of the author Tony D. James, which was incorrectly given as Tony James. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports6: Article number: 37686; 10.1038/srep37686 published online: 11252016; updated: 05032017.In the Supplementary Information file originally published with this Article, Figure S3 was elongated and of poor quality. This error has been corrected in the Supplementary Information that now accompanies the Article."}
+{"text": "Nature Communications7: Article number: 13660; DOI: 10.1038/ncomms13660 (2016); Published: 12162016; Updated: 02092017This Article was originally published with an incorrect publication date. The paper was due to be published on 3 Jan 2017, but due to an error was published earlier on the 16 Dec 2016. The publication date in both the PDF and HTML versions of the paper has been updated to reflect this."}
+{"text": "Grants: R01AR045992 (MSM), R01AR062189 (MSM), R01AR052771 (MSM).The following information is missing from the Funding section: This study was funded through grants obtained from: National Institutes of Arthritis, Musculoskeletal and Skin Diseases (The publisher apologizes for the error."}
+{"text": "The grand challenge currently facing metabolomics is the expansion of the coverage of the metabolome from a minor percentage of the metabolic complement of the cell toward the level of coverage afforded by other post-genomic technologies such as transcriptomics and proteomics. In plants, this problem is exacerbated by the sheer diversity of chemicals that constitute the metabolome, with the number of metabolites in the plant kingdom generally considered to be in excess of 200 000. In this review, we focus on web resources that can be exploited in order to improve analyte and ultimately metabolite identification and quantification. There is a wide range of available software that not only aids in this but also in the related area of peak alignment; however, for the uninitiated, choosing which program to use is a daunting task. For this reason, we provide an overview of the pros and cons of the software as well as comments regarding the level of programing skills required to effectively exploit their basic functions. In addition, the torrent of available genome and transcriptome sequences that followed the advent of next-generation sequencing has opened up further valuable resources for metabolite identification. All things considered, we posit that only via a continued communal sharing of information such as that deposited in the databases described within the article are we likely to be able to make significant headway toward improving our coverage of the plant metabolome. Arabidopsis thaliana  forVisualization tools provide a simple means of representing and mapping metabolic changes in tools like PATHOS , PathWhiFew tools try to actually use mass spectra features to build the networks, which can also improve annotation of unknown compounds. MetaNetter  uses rawIt must be clear from previous sections that mass spectrometry\u2013based metabolomics, particularly metabolite annotation and data interpretation, relies heavily upon data from characterized mass spectra, molecular properties of analytes, and metabolic pathways. While all the different techniques offer a lot of flexibility, metabolomics struggles with standardization, and a great volume of metadata when compared with other omics techniques and still lags behind most of them in terms of public repositories of published data. Nonetheless, there is a wealth of databases with useful information for mass spectrometry\u2013based plant metabolomics, and we try to summarize some of the most relevant and the structure and functionalities of the resources available.Chemspider , PubChemThere are a few plant-specific databases with curated information on chemical composition and distribution across different plant species as well, namely KNApSAcK , with inDatabases that provide mass spectra of pure compounds under controlled conditions developed to allow searching for common spectra features for the identification of unknown compounds are an essential resource for MS-based identification of metabolites. As previously mentioned, the great stability and reproducibility of GC-MS generates reliable fragmentation patterns and relative retention indexes that are very efficient for metabolite annotation by spectra matching. NIST is a very popular commercial library for GC-MS annotation that also provide free access to some data through NIST Chem WebBook , contain++. Metabolite Link (METLIN) [in silico MS/MS data. Additionally, over 14 000 metabolites were analyzed, and mass spectra at multiple collision energies in positive and negative ionization mode obtained. METLIN also integrates isoMETLIN [in silico libraries from different sources. The search is limited to name, compound class, molecular formula, or exact mass of the metabolite. It can be filtered by type of spectra, and the results are presented as a single list of individual interactive spectra next to the metadata, making it easy to navigate through different spectra. The great diversity of phytochemicals observed in plants represents an important portion of all these numbers, and a few plant-specific databases are available, such as Spektraris [One of the greatest efforts in the field of metabolomics has been directed to the development of databases of mass spectra obtained from LC-MS analysis. The higher flexibility of this technique compared to GC-MS in terms of the chemical space that it can analyze comes with the drawback of a high sensitivity to multiple factors that can influence mass spectra quality and reproducibility. LC-MS databases are usually characterized by the greatest volume of metadata that accompany the analytical data and a more complex structure for search based on spectra features when compared to GC-MS databases. Some large general LC-MS databases include MassBank , a publi(METLIN)  currentlsoMETLIN , which asoMETLIN  is a datsoMETLIN . FinallysoMETLIN  is intenektraris , an LC-Mektraris  is a verektraris  is a colektraris , a metabA very common issue encountered in data from mass spectrometry is the presence of a variety of contaminants from sample preparation and analysis that can be challenging for data interpretation. Mass Spectrometry Contaminant Database (MaConDa)  providesSolanum lycopersicum with information on annotated metabolites where the user can search for specific masses or a range of masses. The database is based on accurate mass, and the user therefore does not have access to raw data and chromatograms. Nicotiana attenuata Data Hub (NaDH) [Nicotiana attenuata including LC-MS data on 14 different tissues, allows searching for spectra based on name and m/z and provides some interesting tools for data interpretation that are easily accessible directly from the metabolite entry, including metabolite-metabolite and metabolite-gene coexpression analysis and visualization of metabolite expression across different tissues in a bar chart or eFP browser interface. Optimas-DW software [Compound spectra databases are essential for identification of metabolites by mass spectrometry, but a significant effort has also been directed toward the development of repositories of experimental data on specific samples to facilitate dereplication studies and data analysis. These databases are often restricted to specific species, as is the case for AtMetExpress , an LC-Mb (NaDH) , a platfsoftware  is a datsoftware , a metabsoftware , currentsoftware  is an MSsoftware  is a datsoftware  and currsoftware , a repossoftware  is a larsoftware  is a repsoftware  is a crosoftware  is a datsoftware , a plantReactome.org and 44 metabolic models in a standardized description of metabolites and reactions where all metabolites have matched synonyms, resolved protonation states, and are linked to unique structures, and all reactions are balanced.As previously mentioned, many resources that are particularly useful for data interpretation organize the data in pathways based on literature data, and often also provide tools for data visualization and interpretation. Many of these databases contain either generic pathways or combine different organisms. One example is KEGG , which iin silico databases that are extremely useful for de novo metabolite identification, such as Metabolic In Silico Network Expansion Databases (MINE) [In Silico MS/MS Database (ISDB) [in silico database of natural products generated using CFM-ID [Together with the development of many prediction tools previously mentioned, we watched in the last years the development of some interesting s (MINE) , a databs (MINE) , a databe (ISDB) , an in sg CFM-ID  with inpThe complexity of metabolomics data experiments, particularly in terms of sample number and metadata, pushed the development of many tools for experiment and metadata management, and while many of these functions are integrated in some of the databases previously discussed, there are a few specialized tools such as QTREDS  and MASTThe enormous amount of data available for metabolomics raises many questions regarding how to easily access and unify all this data, taking into account the vast chemical space explored in these experiments. Many tools have been developed with the purpose of facilitating access to chemical data spread in the literature, from the development of identifiers to reduce duplication of information such as Spectral Hash , designeDifferent vendors usually export their data in proprietary formats, which complicates data transfer across different platforms. Most proprietary software packages are able to convert files to .cdf format, but some tools, the most popular being msConverter from Proteowizard , can han++ [All equipment for mass spectrometry comes with its own software for data visualization and some basic analysis, but those are usually not designed to deal with the complexities of metabolomics datasets. There are some interesting open source alternatives such as BatMass  and Mass++  for data++ , which p++ , capableMass spectrometry imaging is a relatively young technique that has being growing fast in importance, providing high-resolution special distribution of small molecules in molecular histology . Few tooin silico generated lipids databases LipidHome [Lipidomics data require a very specialized pipeline, and therefore many tools were developed exclusively for this kind of analysis; however, we will only briefly summarize these here. Analysis of Lipid Experiments (ALEX) , MultiplipidHome , SwissLiipidHome  ,and ARAipidHome .Many of the resources presented here were fruit of the efforts of setting the theoretical background for each step in the data processing and analysis workflow. However, more recent efforts are moving toward the development of integrated tools, which are often developed by the integration of already well-established tools into a single pipeline in an attempt to accelerate the process and in a few cases providing an easier interface. XCMS online, for example, is a web platform providing most of the function from XCMS with additional capabilities for interactive exploratory data visualization and analysis in a much easier interface than the original software . HayStacIt is clear from this review the infinity of choices for performing a variety of functions and the fast pace by which they change and get outdated; hence it is an arduous task to keep updated on all of them. Some research groups, engaged in the development of metabolomics tools, have their own repositories like KOMICS , MetaOpeAdditional file 1.xls: summary of resources for mass spectrometry\u2013based metabolomics.In Silico MS/MS Database; KaPPA\u2013view: Kazusa Plant Pathway Viewer; KEGG: Kyoto Encyclopedia of Genes and Genomes; KMMDA: Kernel Machine Approach for Differential Expression Analysis of Mass Spectrometry\u2013Based Metabolomics Data; Komic Market: Kazusa Omics Data Market; kpath: Khaos Metabolic Pathways; LC: liquid chromatography; LDA: latent Dirichlet\u00a0allocation; LDA: lipid data analyzer; LIMS: Laboratory Information Management System; LIMSA: Lipid Mass Spectrum Analysis; LOBSTAHS: Lipid and Oxylipin Biomarker Screening Through Adduct Hierarchy Sequences; m/z: mass-to-charge ratio; MaConDa: Mass Spectrometry Contaminant Database; MAGMa: MS Annotation Based on In Silico Generated Metabolites; MAIT: Metabolite Automatic Identification Toolkit; MarVis-Suite: Marker Visualization Suite; MathDAMP: Mathematica Package for Differential Analysis of Metabolite Profiles; MAVEN: Metabolomic Analysis and Visualization Engine; MeKO: Metabolite Profiling Database for Knock-Out Mutants in Arabidopsis; MetCCS: Metabolite Collision Cross-Section Predictor; MET-COFEA: Metabolite Compound Feature Extraction and Annotation; MET-COFEI: Metabolite Compound Feature Extraction and Identification; MET-IDEA: Metabolomics Ion-Based Data Extraction Algorithm; METLIN: Metabolite Link; MetNetDB: Metabolic Network Exchange Database; MFSearcher: Molecular Formula Searcher; MIA: Mass Isotopolome Analyzer; MID: mass isotopomer distributions; MINE: Metabolic In Silico Network Expansion Databases; MI-Pack: Metabolite Identification Package; MMCD: Madison Metabolomics Consortium Database; MMSAT: Metabolite Mass Spectrometry Analysis Tool; MoNA: MassBank of North America; MPA-RF: Model Population Analysis\u2013Random Forests; MPEA: Metabolite Pathway Enrichment Analysis; MPMR: Medicinal Plant Metabolomic Resources; MRM: multiple reaction monitoring; MRM-DIFF: Multiple Reaction Monitoring\u2013Based Differential Analysis; MRMPROBS: Multiple Reaction Monitoring\u2013Based Probabilistic System; MS: mass spectrometry; MS/MS: tandem mass spectrometry; MS2T: MS/MS spectral tag; MS-DIAL: Mass Spectrometry\u2013Data Independent Analysis; MSFACT: Metabolomics Spectral Formatting, Alignment, and Conversion Tool; MUSCLE: Multi-Platform Unbiased Optimization of Spectrometry via Closed-Loop Experimentation; NaDH: Nicotiana attenuata Data Hub; NIST: National Institute of Standards and Technology; OpenMSI: Open Mass Spectrometry Imaging; PCA: principal component analysis; PlantMAT: Plant Metabolite Annotation Toolbox; PLS-DA: partial least squares discriminant analysis; PMR: Plant/Eukaryotic and Microbial Systems Resource; PRIMe: Platform for RIKEN Metabolomics; RAMSY: Ratio Analysis of Mass Spectrometry; ReSpect: RIKEN MSn Spectral Database for Phytochemicals; SDBS: Spectral Database for Organic Compounds; SIRIUS: Sum Formula Identification by Ranking Isotope Patterns Using Mass Spectrometry; SMART: Statistical Metabolomics Analysis\u2013An R Tool; SoyMetDB: Soybean Metabolome Database; SPICA: Selective Paired Ion Contrast; SPLASH: Spectral Hash; T3DB: Toxin and Toxin Target Database; UNPD: Universal Natural Product Database; VaLID: Visualization and Phospholipid Identification; VANTED: Visualization and Analysis of Networks Containing Experimental Data; yamss: Yet Another Mass Spectrometry Software.ADAP: Automated Data Analysis Pipeline for Untargeted Metabolomics; AIST: National Institute of Advanced Industrial Science and Technology; ALEX: Analysis of Lipid Experiments; AMDIS: Automated Mass Spectral Deconvolution And Identification System; ANOVA: analysis of variance; apLCMS: Adaptive Processing of High-Resolution LC-MS data; ARALIP: Arabidopsis acyl-lipid metabolism; ASCII: American Standard Code for Information Interchange; BKM-react: BRENDA-KEGG-MetaCyc reactions; BNICE: Biochemical Network Integrated Computational Explorer; CAMERA: Collection of Algorithms for Metabolite Profile Annotation; CDF: common data format; CFM-ID: Competitive Fragmentation Modeling for Metabolite Identification; ChEBI: Chemical Entities of Biological Interest; CID: collision-induced dissociation; cosmiq: combining single masses into quantities; COVAIN: Covariance Inverse; CRAN: Comprehensive R Archive Network; CSI: FingerID: compound structure identification: FingerID; CTS: Chemical Translation Service; DIA: data-independent acquisition; EIC: extracted ion chromatogram; EssOilDB: Essential Oil Database; EXIMS: Exploring Imaging Mass Spectrometry Data; FT: Fourier transform; FunRich: Functional Enrichment Analysis Tool; GC: gas chromatography; GNPS: Global Natural Products Social Molecular Networking; GUI: graphical user interface; HCS: hierarchical cluster analysis; HMDB: Human Metabolome Database; HRMS: high-resolution mass spectrometry; ICT: Isotope Correction Toolbox; IIS: Integrated Interactome System; iMet-Q: Intelligent Metabolomic Quantitation; IMPaLA: Integrated Molecular Pathway Level Analysis; InCroMAP: Integrated Analysis of Cross-Platform Microarray and Pathway Data; IOKR: Input Output Kernel Regression; iPATH: Interactive Pathways Explorer; IPO: Isotopologue Parameter Optimization; ISDB: GIGA-D-17-00039_Original_Submission.pdfClick here for additional data file.GIGA-D-17-00039_Revision-1.pdfClick here for additional data file.GIGA-D-17-00039_Revision-2.pdfClick here for additional data file.Response_to_Reviewer_Comments_Original-Submission.pdfClick here for additional data file.Reviewer_1_Report_.pdfClick here for additional data file.Reviewer_1_Report_(Revision-1).pdfClick here for additional data file.Reviewer_2_Report_.pdfClick here for additional data file.Additional FileClick here for additional data file."}
+{"text": "Scientific Reports6: Article number: 20054; 10.1038/srep20054 published online: 01292016; updated: 06302017.The original HTML version of this Article listed an incorrect volume number. This has now been corrected in the HTML version; the PDF version was correct at the time of publication."}
+{"text": "Nature Communications8: Article number: 14290; DOI: 10.1038/ncomms14290 (2017); Published: 01302017; Updated: 02202017The original version of this Article contained an error in the spelling of the author Rossella Marullo, which was incorrectly given as Rosella Marullo. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Nature Communications8: Article number: 14350; DOI: 10.1038/ncomms14350 (2017); Published: 02082017; Updated: 05252017The original version of this Article contained a typographical error in the first sentence of the abstract in which \u2018Shockley-Queisser' was incorrectly given as \u2018Schottky-Queisser'. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports7: Article number: 44277; 10.1038/srep44277 published online: 03102017; updated: 04062017.The Acknowledgements section in this Article is incomplete.The investigation of novel molecular mechanisms of antidepressants at cellular level\u201d.\u201cNeuroNova gGmbH, Munich provided financial support between 2011 and 2016 aiming at should read:The investigation of novel molecular mechanisms of antidepressants at cellular level. C.B. and L.M. thank the excellence clusters Nanosystems Initiative Munich (NIM) and the Center for Integrated Protein Science Munich (CIPSM) as well as the Center for Nanoscience Munich (CeNS)\u201d.\u201cNeuroNova gGmbH, Munich provided financial support between 2011 and 2016 aiming at"}
+{"text": "Scientific Reports5: Article number: 1701410.1038/srep17014; published online: 11232015; updated: 12192016Supplementary Dataset S1 was omitted from the original version of this Article. This error has now been corrected."}
+{"text": "Scientific Reports6: Article number: 20067; 10.1038/srep20067 published online: 01292016; updated: 06302017.The original HTML version of this Article listed an incorrect volume number. This has now been corrected in the HTML version; the PDF version was correct at the time of publication."}
+{"text": "Scientific Reports6: Article number: 3247310.1038/srep32473; published online: 08312016; updated: 09262016.The original version of this Article contained a typographical error in the spelling of the author Mafalda Lopes da Silva which was incorrectly given as Silva Mafalda Lopes da. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports6: Article number: 33706; 10.1038/srep33706 published online 09202016; updated: 10102016.The original version of this Article contained a typographical error in the spelling of the author Huafang Wan, which was incorrectly given as Huafan Wan. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "The following information is missing from the funding section: This study was supported by CNPq, Brazil, grant # 308216/2014-8 to CLVL."}
+{"text": "There are errors in the Funding section. The correct funding information is as follows: This study was partially supported by a Grant-in-Aid from the Ministry of Education, Science, Sports, Culture and Technology, Japan, and partially supported by the National Natural Science Foundation of China (81460118-Dr. Shuohua Zhang). Dr. Al Shaimaa Hasan is supported by the joint supervision mission scholarship from the Ministry of Higher Education, Egypt. The funders played no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.There is a sentence missing after the fourth sentence of the third paragraph of the Introduction. The sentence should read: Furthermore, it has been recently demonstrated that CDCs limit acute injury by polarizing an effector macrophage population within the heart.A reference is omitted from the fourth sentence of the third paragraph of the Introduction, the second sentence of the fourth paragraph of the Introduction, and the second sentence of the third paragraph of the Discussion.10.1172/JCI81321.The reference is: de Couto G, Liu W, Tseliou E, Sun B, Makkar N, Kanazawa H, Arditi M, Marb\u00e1n E. Macrophages mediate cardioprotective cellular postconditioning in acute myocardial infarction. J Clin Invest. 2015;125:3147\u201362. doi: The fourth sentence of the third paragraph of the Introduction should read: Furthermore, it has been recently demonstrated that CDCs limit acute injury by polarizing an effector macrophage population within the heart .The second sentence of the fourth paragraph of the Introduction should read: Similar to previous study , results showed that CDCs-conditioned medium significantly promotes the macrophages to shift into a regulatory (M2) phenotype.The second sentence of the third paragraph of the Discussion should read: The immunomodulation property of MSCs has been demonstrated by previous studies, and a recent study has already demonstrated the potential role of CDCs for polarizing macrophages [18\u201321] .There are errors in the Author Contributions. The correct contributions are: Conceptualization: AH MAR SZ TL. Data curation: AH TL. Formal analysis: AH LL CY TZ YU SG MAR SMSZ TL. Funding acquisition: SZ TL. Investigation: AH LL CY TZ YU SG MAR SMSZ TL. Methodology: AH MAR SZ TL. Project administration: TL. Resources: AH LL CY TZ YU SG SZ TL. Software: LL CY YU SG. Supervision: TL. Validation: MAR SZ TL. Visualization: AH LL CY TZ YU SG MAR SMSZ TL. Writing\u2013original draft: AH TL. Writing\u2013review& editing: AH TL."}
+{"text": "Scientific Reports6: Article number: 1790810.1038/srep17908; published online: 01192016; updated: 11112016The Supplementary Information file originally published with this Article omitted the PDB codes in Table S1. This error has now been corrected in the Supplementary Information file that accompanies the Article."}
+{"text": "Nature Communications7: Article number: 13330 ; DOI: 10.1038/ncomms13330 (2016); Published 11022016; Updated 10092017.The original version of this Article contained an error in the email address of thecorresponding author George Church. The correct email isgchurch@genetics.med.harvard.edu. The error has been corrected in the HTML andPDF versions of the Article."}
+{"text": "Scientific Reports6: Article number: 3249810.1038/srep32498; published online: 09012016; updated: 10242015The original version of this Article contained a typographical error in the spelling of the author Maryam Alaayedi, which was incorrectly given as Maryam Alayedi. This error has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports6: Article number: 3082810.1038/srep30828; published online: 08262016; updated: 05022017In the original version of this Article, the author list for the \u201cTEDDY Study Group\u201d was incomplete.This has now been corrected in the PDF and HTML versions of this Article."}
+{"text": "Scientific Reports6: Article number: 24105; 10.1038/srep24105 published online: 04072016; updated: 04052018.This article contains an error in Figure 2, where the same image was inadvertently shown in both panel (a) and (b). The correct"}
+{"text": "Nature Communications8: Article number: 14024; DOI: 10.1038/ncomms14024 (2017); Published: 01192017; Updated: 03012017The present address for U. Sassi is incorrect in this Article. This author does not have a present address. The correct full affiliation details for this author are given below:Cambridge Graphene Centre, University of Cambridge, Cambridge CB3 0FA, UK."}
+{"text": "Scientific Reports6: Article number: 35990; 10.1038/srep35990 published online: 10262016; updated: 12062016.The original version of this Article contained errors in the spelling of the author Md Sainur Samad, which was incorrectly given as M.d. Sainur Samad.These errors have now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Poorly understood but highly diverse microbial communities exist within anoxic and oxygen-depleted marine sediments. These communities often harbour single-celled eukaryotes that form symbiotic associations with different prokaryotes. During low tides in South-western British Columbia, Canada, vast areas of marine sand become exposed, forming tidal pools. Oxygen-depleted sediments within these pools are distinctively black at only 2-3 cm depth; these layers contain a rich variety of microorganisms, many of which are undescribed. We discovered and characterized a novel (uncultivated) lineage of heterotrophic euglenozoan within these environments using light microscopy, scanning and transmission electron microscopy, serial sectioning and ultrastructural reconstruction, and molecular phylogenetic analyses of small subunit rDNA sequences.Bihospites bacati n. gen. et sp. is a biflagellated microbial eukaryote that lives within low-oxygen intertidal sands and dies within a few hours of exposure to atmospheric oxygen. The cells are enveloped by two different prokaryotic episymbionts: (1) rod-shaped bacteria and (2) longitudinal strings of spherical bacteria, capable of ejecting an internal, tightly wound thread. Ultrastructural data showed that B. bacati possesses all of the euglenozoan synapomorphies. Moreover, phylogenetic analyses of SSU rDNA sequences demonstrated that B. bacati groups strongly with the Symbiontida: a newly established subclade within the Euglenozoa that includes Calkinsia aureus and other unidentified organisms living in low-oxygen sediments. B. bacati also possessed novel features, such as a compact C-shaped rod apparatus encircling the nucleus, a cytostomal funnel and a distinctive cell surface organization reminiscent of the pellicle strips in phagotrophic euglenids.B. bacati n. gen. et sp. Molecular phylogenetic analyses demonstrated that this species belongs to the Euglenozoa and currently branches as the earliest diverging member of the Symbiontida. This is concordant with ultrastructural features of B. bacati that are intermediate between C. aureus and phagotrophic euglenids, indicating that the most recent ancestor of the Symbiontida descended from phagotrophic euglenids. Additionally, the extrusive episymbionts in B. bacati are strikingly similar to so-called \"epixenosomes\", prokaryotes previously described in a ciliate species and identified as members of the Verrucomicrobia. These parallel symbioses increase the comparative context for understanding the origin(s) of extrusive organelles in eukaryotes and underscores how little we know about the symbiotic communities of marine benthic environments.We characterized the ultrastructure and molecular phylogenetic position of  Euglena and Phacus), but the majority of the species are heterotrophic (osmotrophs or phagotrophs). Photosynthetic euglenids evolved from phagotrophic ancestors with a complex feeding apparatus and a large number of pellicle strips that facilitate a characteristic peristaltic cell movement called \"euglenoid movement\". This combination of characters allows phagotrophic euglenids to engulf large prey cells, such as eukaryotic algae, which eventually led to the acquisition of chloroplasts via secondary endosymbiosis .Both resin-embedded cells used for TEM and cells on gold sputter-coated SEM stubs have been deposited in the Beaty Biodiversity Research Centre (Marine Invertebrate Collection) at the University of British Columbia, Vancouver, Canada.Figs Tidal sand-flat at Centennial Beach, Vancouver, British Columbia, Canada .Marine sand, black layer 2-3 cm deep.bacati, ornamented with pearls. The etymology for the specific epithet reflects the presence of distinct longitudinal rows of spherical-shaped episymbionts, reminiscent of pearl necklaces.Specific epithet, Latin LSID for article: urn:lsid:zoobank.org:pub:40211D82-B95C-494A-B8D0-7E061E80DD18Bihospites: urn:lsid:zoobank.org:act:794D6C7B-BFB1-45C7-8DDA-32D44F3B0E50LSID for the genus B. bacati: urn:lsid:zoobank.org:act:E1549565-5434-4F85-B936-7D0C485596B8LSID for the species ar: accessory rod; CGS: congregated globule structure; Cyt: cytostome; Db: dorsal basal body; Db': dorsal pro-basal body; Df: dorsal flagellum; DL: dorsal lamina; DMt: dorsal microtubules; DR: dorsal root; E: extrusome; epi: epixenosome; ER: endoplasmic reticulum; FP: flagellar pocket; IR: intermediate root; LM: light microscope; MtD: mitochondrion-derived organelle; N: nucleus; Nu: nucleolus; PR: paraxial rod; r: rod; S: strips; SF: striated fibre; SEM: scanning electron microscope; TEM: transmission electron microscope; tz: transition zone; Vb: ventral basal body; Vb': ventral pro-basal-body; Vf: ventral flagellum; VL: ventral lamina; VR: ventral root; vt: vestibulum.SAB collected the sediment samples from Boundary Bay; generated the LM, SEM, and SSU rDNA sequence data; and wrote the first draft of the paper. NY generated the TEM data and helped with the phylogenetic analyses and interpretation of the TEM data. MH carried out the sampling, identification and LM work of the German material and helped with the identification of the Canadian material. BSL funded and supervised the collection and interpretation of the ultrastructural and molecular phylogenetic data and contributed to writing the paper. All authors have read, edited and approved the final manuscript."}
+{"text": "Dr. Luis D. Giavedoni was not included in the author byline. He should be listed as the sixth author and affiliated with Department of Virology and Immunology and Southwest National Primate Research Center, Southwest Foundation for Biomedical Research, San Antonio, Texas, United States of America.The author contributions should also be amended to the following: Conceived and designed the experiments: TRK JBB RDH JP PD. Performed the Experiments: RDH JC JP AC CT AC TRK LDG. Analyzed the data: RDH JC TRK AC LDG CT AC JBB PD. Contributed reagents/materials/ analysis tools: AC TRK JBB. Wrote the paper: JC JBB PD."}
+{"text": "Escherichia coli (E. coli). To gain an insight into the genes and pathways involved in hepatic APR of dairy cows we performed a global gene expression analysis of liver tissue sampled at different time points before and after intra-mammary (IM) exposure to E. coli lipopolysaccharide (LPS) treatment.Liver plays a profound role in the acute phase response (APR) observed in the early phase of acute bovine mastitis caused by Approximately 20% target transcripts were differentially expressed and eight co-expression clusters were identified. Each cluster had a unique time-dependent expression profile and consisted of genes involved in different biological processes. Our findings suggest that APR in the liver is triggered by the activation of signaling pathways that are involved with common and hepatic-specific transcription factors and pro-inflammatory cytokines. These mediators in turn stimulated or repressed the expression of genes encoding acute phase proteins (APP), collectins, complement components, chemokines, cell adhesion molecules and key metabolic enzymes during the APR. Hormones, anti-inflammatory and other hypothalamus-pituitary-adrenal axis (HPAA) linked mediators also seemed to participate in APR.E. coli mastitis, and that the bovine hepatic APR follows the same pattern as other mammals when they are challenged with LPS. Our work presents the first insight into the dynamic changes in gene expression in the liver that influences the induction, kinetics and clinical outcome of the APR in dairy cows.Performing global gene expression analysis on liver tissue from IM LPS treated cows verified that the liver plays a major role in the APR of  Escherichia coli (E. coli) is a common disease in lactating dairy cows. During infection, lipopolysaccharide (LPS) released from the cell wall of E. coli rapidly induces a sophisticated inflammatory response. Locally it is characterized by recruiting leukocytes especially neutrophils to the injured mammary tissue, as well as activation of macrophages in the mammary gland to produce pro-inflammatory cytokines  (the probe set is Bt.21216.1.S1_at), were significant.Differential expression of individual genes was assessed using linear modeling and empirical Bayes methods  as impleTo identify co-expression clusters, the 4610 DE transcripts were ordered by the hierarchical clustering. Centered Pearson correlation method was used as the distance measure. The optimum cluster number was determined using the ratio of the sums of squares between and within cluster  see Fig.There are 1789 UniGenes possessing Gene Ontology (GO) among all DE transcripts in contrast to 6843 UniGenes from the whole array. Within each co-expression cluster, overrepresentation of gene sets defined by the Biological Process (BP) of GO was tested using Fisher's exact test.E. coli: Escherichia coli; EGF: epidermal growth factor; GCRMA: GeneChip robust multi-array analysis; GH: growth factor; GO: gene ontology; HPAA: hypothalamus-pituitary-adrenal axis; IM: intra-mammary; i.p.: intraperitoneal; IU: international units; i.v.: intravenous; LIMMA: linear models for microarray analysis; LPS: lipopolysaccharide; MAS: microarray suite; MCP: monocyte chemotactic protein; MIP: macrophage inflammatory protein; NAP: neutrophil-activating protein; PG: prostaglandin; PRL: prolactin; PRLR: prolactin receptor; Q-PCR: quantitative polymerase chain reaction; RMA: robust multi-array analysis; SCC: somatic cell countAMPK: adenosine monophosphate-activated protein kinase; APP: acute phase proteins; APR: acute phase response; ATP: adenosine 5'-triphosphate; BP: biological process; CAM: cell-adhesion molecules; CC: complement components; cRNA: complementary ribonucleic acid; DE: differentially expressed; LJ and PS analyzed the microarray data and drafted the manuscript. CR carried out the animal challenge, KLI performed the liver biopsy and LV performed the Q-PCR. PS, CR and KLI designed the experimental plan. LJ, PS, CR and KLI contributed to the interpretation of results and iterative refinement of the manuscript. LJ is responsible for depositing microarray data in NCBI GEO.  LJ and PS contributed equally to this work."}
+{"text": "The Author Contributions are incorrect. They should read as follows: Conceived and designed the experiments: GA. Performed the experiments: AAM GA. Analyzed the data: AAM GA. Wrote the paper: GA GB."}
+{"text": "The Author Corrections are incomplete. The full Author Contributions are: Conceived of the study: CL BD. Performed the numerics: CL. Wrote the paper: CL BD."}
+{"text": "However, in order to fully utilize the scale-independent properties of CGR, it should be accessible through scale-independent user interface instead of static images. Here we describe a web server and Perl library for generating zoomable CGR images utilizing Google Maps API, which is also easily searchable for specific motifs. The web server is freely accessible at  Moreover, other web-pages or web-database sites can utilize our service to add CGR and  website .CGR: Chaos Game Representation; FCGR: Frequency matrices extracted from CGR; G-language GAE: G-language Genome Analysis Environment; IFS: Iterated Function System; REST: Representational State Transfer; ZUI: Zoomable User Interface.The authors declare that they have no competing interests.KA designed and developed the software, and drafted the manuscript. KO participated in the implementation of the software. MT supervised the project. All authors have read and approved the final manuscript."}
+{"text": "There were errors in the Author Contributions. The correct contributions are: Conceived and designed the experiments: GH DRS. Performed the experiments: GH SY NS KJD TS. Analyzed the data: GH DRS. Wrote the paper: GH DRS. Made the figures: GH KJD."}
+{"text": "Correction to: British Journal of Cancer (2006) 94, 1351. doi:10.1038/sj.bjc.6603068Owing to an author error, the title of the above letter was incorrect. The title should be:\u2018Mobile phone use and risk of acoustic neuroma: results of the Interphone case\u2013control study in five North European countries\u2019."}
+{"text": "Daphnia magna (Crustacea:Cladocera) to isolate variable number of tandem repeat (VNTR) markers for linkage mapping, Quantitative Trait Loci (QTL), and functional studies.Expressed sequence tag (EST) databases provide a valuable source of genetic data in organisms whose genome sequence information is not yet compiled. We used a published EST database for the waterflea Seventy-four polymorphic markers were isolated and characterised. Analyses of repeat structure, putative gene function and polymorphism indicated that intragenic tandem repeats are not distributed randomly in the mRNA sequences; instead, dinucleotides are more frequent in non-coding regions, whereas trinucleotides (and longer motifs involving multiple-of-three nucleotide repeats) are preferentially situated in coding regions. We also observed differential distribution of repeat motifs across putative genetic functions. This indicates differential selective constraints and possible functional significance of VNTR polymorphism in at least some genes.Databases of VNTR markers situated in genes whose putative function can be inferred from homology searches will be a valuable resource for the genetic study of functional variation and selection. Daphnia (Crustacea:Cladocera) are small planktonic crustaceans found in standing freshwater bodies around the world. They have a long history as model organisms for evolutionary, ecological and ecotoxicological research. Recently, the genus has been the focus of a major sequencing effort, and the full genome sequence of Daphnia pulex is now available : Concentration of MgCl2 used in the PCR buffer. An asterisk following MgCl2 concentration indicates hot start PCR.Click here for fileDescription of the 74 polymorphic VNTR loci. EST locus: locus containing the VNTR; Size: size of the repeated motif; Sequence: repeat consensus sequence. N: number of repeats, ; A: number of alleles. *: total number of alleles in loci with more than one repeated motif. He: Gene diversity.Click here for fileResults of homology searches and putative functions of EST loci. TM: transmembrane regions. Function categories: DEF: defense; MET: metabolism; OTH: other; SIG: signaling and gene expression regulation; SUR: surface and integumental proteins; UNK: unknown function. No hit: no significant homolog found .Click here for fileDistribution of allele sizes of polymorphic loci in each sampled location.Click here for file"}
+{"text": "The author contributions are incorrect. The correct contributions are: Performed the experiments: ZA RC LC ADB EAAF ON CT CU HK HPS"}
+{"text": "Hemophagocytic syndrome is a rare clinicopathological condition characterized by the activation of the mononuclear phagocyte system, resulting in hemophagocytosis in the reticuloendothelial systems. The pathogenesis of HPS remains unclear.We report the case of a 20-year-old soldier suffering from HPS. Because of long history fever and no reasons being found, his left groin lymph node and left neck lymph node biopsy were done with two weeks interval. We found a marked increase in plasma cells in left neck lymph node during the course of the disease.Our result provides a new thought for the researchers to understand the mechanisms responsible for the phagocytosis in HPS. Hemophagocytic syndrome (HPS) is a rare entity characterized by the dysfunction of cytotoxic T cells (CTL) and natural killer (NK) cells, and the activation of the mononuclear phagocyte system ,2. Its c9/L, red blood cell 3.42 \u00d7 1012/L, hemoglobin 107 g/L, platelet count 156 \u00d7 109/L, fibrinogen 0.67 g/L, triglyceride 13.9 mmol/L (Table A 20-year-old enlisted man presented with a 1-month history of discontinuous fever, panic, and hypodynamia, and was admitted to People's Liberation Army 152 hospital in May 2008. He had no other complaints. The patient had previously been healthy, with no history of infectious diseases or allergies to food or drugs. Physical examination showed a temperature of 37.3\u00b0C and no other remarkable signs. Laboratory measurements and examinations revealed no abnormalities. On admission, the patient was administered broad spectrum antibiotics and antiviral drugs. However, his fever failed to resolve and his temperature rose to between 38.5\u00b0C and 40.9\u00b0C. More than 2 weeks later, lymphadenopathy of the left neck, armpit, and left groin was detected by ultrasound. Left groin lymph node and bone marrow puncture biopsies were performed. Histopathological examination of the groin lymph node showed reactive hyperplasia and revealed one histiocyte engulfing few blood cells Figure. . The bonLeft neck lymph node biopsy and bone marrow puncture smear were performed. The results were characteristic of HPS Figure. . The gerHPS is a life-threatening condition characterized by the activation of the MPS. It can be divided into genetic HPS and secondary HPS . GeneticAlthough progress has been made in understanding the pathophysiology of HPS, the exact mechanisms responsible for the phagocytosis are unknown in HPS. Researchers found out that there have the RBC antibodies in the EBV-HPS and anti-RBC antibodies were involved in the phagocytosis of RBCs by macrophages . Also seThis case report showed plasma cells increased markedly in the left neck node during the progression of HPS. The result maybe provide one way to study the pathophysiology of the HPS.HPS: hemophagocytic syndrome; CTL: cytotoxic T cells; MPS: mononuclear phagocyte system; HAV: hepatitis A virus; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; CP: chlamydia pneumoniae; MP: mycoplasma; RSV: respiratory syncytial virus; Adv: adenovirus; WBC: white blood cell count; RBC: red blood cell; HGB: hemoglobin; PLT: platelet count; PT: prothrombin time; NR: international normalized ratio; TT: thrombin time; APTT: activated partial thromboplastin time; FIG: fibrinogen; TP: total protein; ALB: albumin; GLOB: globulin; DB: direct bilirubin; IB: indirect bilirubin; \u03b3-GT: \u03b3-glutamyl transpeptidase; CK: creatine kinase; CK-MB: creatine kinase-MB; HBDH: hydroxybutyrate dehydrogenase; LDH: lactate dehydrogenase; TG: triglyceride; \u03b22-MG: \u03b22-microglolulin; CRP: C-reactive protein; ALP: alkaline phosphatase.Written informed consent was obtained from the patient' older brother for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this Journal.The authors declare that they have no competing interests.L CY and M YY interpreted the data, operated on the patient and wrote the manuscript. L CG performed the histological examination. H XX reviewed the paper. All authors read and approved the final manuscript."}
+{"text": "Axiothella rubrocincta. Employing immunocytochemistry in combination with confocal laserscanning microscopy, we broaden the database on capitellid organogenesis, thereby incorporating classical histological data in our analysis. Besides assessing possible shared features with the echiurans, we also discuss the variability of neural and muscular characters within the Capitellida.Numerous phylogenetic analyses on polychaete annelids suggest a taxon Capitellida that comprises the three families Maldanidae, Arenicolidae and Capitellidae. Recent molecular studies support the position of the Echiura, traditionally ranked as a separate phylum, within the capitellids. In order to test the robustness of this molecular-based hypothesis we take a different approach using comparative analyses of nervous and muscle system development in the maldanid Axiothella, consists of cerebral commissures that give rise to simple circumesophageal connectives with fused ventral and dorsal roots and a single ventral neurite bundle. From the latter arise segmental neurites that innervate the peripheral bodywall. Since there is no observable regular pattern, and individual neurites are lost during ontogeny, their exact arrangement remains elusive. The pharynx is encircled by a prominent stomatogastric nerve ring, with a pair of anterior and lateral proboscis neurites directly connecting it to the central nervous system. One pair of ventral and one pair of dorsal longitudinal muscles form the earliest rudiments of the bodywall musculature in late larval stages, while a continuous layer of circular muscles is lacking throughout ontogeny.The scaffold of the adult central nervous system, which is already established in early developmental stages of Comparative neurodevelopmental analysis of capitellid and echiuran species reveals several common characters, including simple circumesophageal connectives, a single fused ventral nerve strand, and a stomatogastric ring nerve, that support a close relationship of both taxa, thus corroborating recent molecular phylogenetic analyses. The data on myogenesis show that four longitudinal muscle bands most likely represent an ancestral character not only for the Capitellida, but for the Annelida in general. Whether or not circular muscles are part of the annelid groundpattern remains uncertain. Axiothella rubrocincta not only offers an opportunity to assess the ingroup variability of neural characters within the Capitellida but also allows to compare neurogenesis and nervous system organization with those data that recently have become available for echiurans. This serves as an independent test of the molecular data which propose the placement of the echiurans within the Capitellida.The Maldanidae, also referred to as 'bamboo worms', comprise a group of deposit-feeding polychaete annelids that live in tubes composed of bottom material. They are usually considered related to the Arenicolidae and Capitellidae, and these three families are grouped together in the taxon Capitellida . Recent Axiothella may also aid in casting light on the ancestral state of muscular systems in annelids and lophotrochozoans as a whole. The musculature of the Capitellida comprises a closed outer layer of circular fibers similar to that of clitellate oligochaetes . The primary antibodies, polyclonal rabbit anti-serotonin , polyclonal rabbit anti-FMRFamide , and monoclonal mouse anti-acetylated \u03b1-tubulin , all in block-PTA, were either applied separately or in a mixed cocktail for 24 h. Subsequently, the specimens were rinsed in block-PTA with three changes over 6 h and incubated in a mixture of 4'6-diamidino-2-phenyl-indole [DAPI ], secondary fluorochrome-conjugated antibodies  and, for F-actin visualization, Alexa Fluor 488 phalloidin  in block-PTA overnight. Finally, the specimens were washed three times in PB without NaN3 and were directly mounted in Fluoromount G  on glass slides. A minimum of 10 immunolabeled specimens per developmental stage was analyzed for each antibody. Approximately 65 image stacks of optical sections were recorded as Z-wide-projections with 0.1-0.5 \u03bcm step size using a Leica DM IRE2 fluorescence microscope equipped with a Leica TCS SP 2 confocal laserscanning unit . Setae are visible in the tubulin scans due to autofluorescence. Images were processed with Adobe Photoshop CS3 to adjust contrast and brightness and were arranged into figure plates using Adobe Illustrator CS3 . The three-dimensional computer reconstructions were generated with the imaging software Imaris v. 5.5.3  using surface rendering algorhithms.The following steps were all performed at 4\u00b0C. Antibody staining was preceded by tissue permeabilization for 1 h in 0.1 M PB with 0.1% NaN1s-7s: setigers; a: anus; ac: apical cilia; apn: anterior proboscis neurite; as: anal sphincter; a-str: accessory stomatogastric nerve ring; bun: nerves of the buccal epithelium; cc: circumesophageal connective; cg: cerebral ganglion; cm-rs: circular muscle of the retractor sheath; dl-cg: dorsal lobe of the cerebral ganglion; dlm: dorsal longitudinal muscle bundle; d-sp: dorsal serotonergic perikarya; d-vlm: diagonal ventral longitudinal muscle; e: esophagus; ge: glandular epidermis; h: head; i: intestine; lm: longitudinal muscle fiber; lm-rs: longitudinal muscle of the retractor sheath; lpn: lateral proboscis neurite; ma: main strand; me: median strand; nn: nuchal neurite; nt: neurotroch; pc: posterior cilia; per: peristomium; ph: pharynx; pn: protonephridium; pnn: peripheral network of neurites; prn: prostomial nerves; pro: prostomium; pt: prototroch; py: pygidium; s: setae; sm: setal muscles; stp: neuronal stomatogastric projection; str: stomatogastric nerve ring; s-vlm: straight ventral longitudinal muscle; tt: telotroch; vl-cg: ventral lobe of the cerebral ganglion; vlm: ventral longitudinal muscle bundle; vnb: ventral neurite bundle; v-sp: ventral serotonergic perikarya.NB performed research, analyzed data and drafted the manuscript. AW designed and coordinated research and contributed to writing of the manuscript. Both authors conceived the study, read, and approved the final version of the manuscript."}
+{"text": "Due to the addition of author Dao-Fu Dai, the author contributions should now read: Conceived and designed the experiments: WL. Performed the experiments: LCE JFM PRT. Analyzed the data: LCE PRT MJE DFD WL. Contributed reagents/materials/analysis tools: NSW GSM PSR WL. Wrote the paper: LCE."}
+{"text": "Because the author Aruna Panda was added to the author byline after publication, the Author Contributions section does not correctly reflect the new authorship. The new Author Contributions should read:Conceived and designed the experiments: GN WK ZY DP SR CW DS. Performed the experiments: WK ZY DP LD SR CW ES HS HW GR AP. Analyzed the data: GN WK ZY DP MN SR CW DS. Wrote the paper: GN WK ZY DP SR CW DS AP."}
+{"text": "Objective: To investigate clinical experience with the apparent malignant transformation of benign liver cell adenomas.Design: Retrospective review of personal experience and literature.Setting: University hospital and affiliated community hospitals.Patients: All patients diagnosed with liver cell adenomas over a 30-year period.Interventions: Liver resection and/or tumor biopsy.Main Outcome Measures: Gender, age, drug associations, alpha-fetoprotein levels, response to treatment, and survival.Results: Thirteen patients from personal experience and 26 patients from the reports of others had liver cell adenomas that were not resected. Five of these patients subsequently developed hepatocellular carcinoma.Conclusions: Malignant transformation of a liver cell adenoma is a rare phenomenon, but it does occur. Alphafetoprotein levels may be more helpful in diagnosis than expected from previous reports. Solitary benign adenomas should be resected whenever possible. Patients with diffuse multiple tumors should be observed closely over a long period."}
+{"text": "There were errors in the Author Contributions. The correct contributions are: Conceived and designed the experiments: TK KH ZPF PR. Performed the experiments: TK KH WK NR GS. Analyzed the data: TK KH ZPF PR. Wrote the paper: TK KH ZPF PR."}
+{"text": "With the advent of functional magnetic resonance imaging (fMRI) in awake animals it is possible to resolve patterns of neuronal activity across the entire brain with high spatial and temporal resolution. Synchronized changes in neuronal activity across multiple brain areas can be viewed as functional neuroanatomical circuits coordinating the thoughts, memories and emotions for particular behaviors. To this end, fMRI in conscious rats combined with 3D computational analysis was used to identifying the putative distributed neural circuit involved in aggressive motivation and how this circuit is affected by drugs that block aggressive behavior.1a receptor antagonist SRX251 or the selective serotonin reuptake inhibitor fluoxetine, drugs that block aggressive behavior, both caused a general suppression of the distributed neural circuit involved in aggressive motivation. However, the effect of SRX251, but not fluoxetine, was specific to aggression as brain activation in response to a novel sexually receptive female was unaffected.To trigger aggressive motivation, male rats were presented with their female cage mate plus a novel male intruder in the bore of the magnet during image acquisition. As expected, brain areas previously identified as critical in the organization and expression of aggressive behavior were activated, e.g., lateral hypothalamus, medial basal amygdala. Unexpected was the intense activation of the forebrain cortex and anterior thalamic nuclei. Oral administration of a selective vasopressin VThe putative neural circuit of aggressive motivation identified with fMRI includes neural substrates contributing to emotional expression , emotional experience  and the anterior thalamic nuclei that bridge the motor and cognitive components of aggressive responding. Drugs that block vasopressin neurotransmission or enhance serotonin activity suppress activity in this putative neural circuit of aggressive motivation, particularly the anterior thalamic nuclei. Aggression is a normal component of mammalian behavior . For ani1a and 5HT1b receptor agonists  arginine vasopressin, blocks aggressive behavior -1for each subject (i) was also calculated.Anatomy images for each subject were obtained at a resolution of 2562 with a depth of 1200 \u03bcm, many small brain areas  cannot be resolved; or, if they could be resolved they would be represented by one or two voxels only . Consequently, small detailed regions are not included in the analysis or are grouped into larger \"minor volumes\" of similar anatomical classification. For example, in these studies we have the basal nucleus of the amygdala listed as a minor volume. This area is a composition of the basomedial anterior part, basomedial posterior part, basolateral anterior part and basolateral posterior part with a composite voxel size of 54. In this study, 12 brain slices were collected extending from the tip of the forebrain to the end of the cerebrum stopping at the midbrain just rostral to the cerebellum. Within these rostral/caudal boundaries we delineated 83 minor volumes. In addition, we grouped brain areas into \"major volumes\" . The volume of activation (number of significant voxels) can be visualized in these 3D major and minor anatomical groupings  is 486 \u03bcmt tests were performed on each voxel  of each subject within their original coordinate system. The baseline threshold was set at 2%. The t test statistics used a 95% confidence level, two-tailed distributions, and heteroscedastic variance assumptions. As a result of the multiple t test analyses performed, a false-positive detection controlling mechanism was introduced -1, mapped it within a voxel of subject (i). A tri-linear interpolation of the subject's voxel values (percentage change) determined the statistical contribution of subject (i) to the composite  location. The use of [Ti]-1 ensured that the full volume set of the composite was populated with subject contributions. The average value from all subjects within the group determined the composite value. The BOLD response maps of the composite were somewhat broader in their spatial coverage than in an individual subject; so only average number of activated pixels that has highest composite percent change values in particular ROI was displayed in composite map. Activated composite pixels are calculated as follows:A statistical composite was created for each group of subjects. The individual analyses were summed within groups. The composite statistics were built using the inverse transformation matrices. Each composite pixel location , premultiplied by [The composite percent change for the time history graphs for each region was based on the weighted average of each subject, as follows:N is number of subjects.where The percent change in BOLD signal for time history graphs see Figs , 7, 8 weACA: anterior cingulated; ACB: accumbens; AH: anterior hypothalamus; AL: agranular insular cortex; ALP: anterior lobe pituitary; AM: anteromedial nucleus thalamus; AON: anterior olfactory nucleus; AUD: auditory cortex; AV: anteroventral nucleus thalamus; BNST: bed nucleus stria terminalis; CA1: hippocampus; CA3: hippocampus; COA: cortical nucleus amygdale; DG: dentate gyrus; DS: dorsal striatum; ENT: entorhinal cortex; IC: inferior colliculi; ILA: infralimbic cortex; IPN: interpeduncular nucleus; LHA: lateral hypothalamus; LP: lateral posterior nucleus thalamus; LS: lateral septum; MEA: medial amygdale; MM: mammillary nuclei; MO: motor cortex; MRN: mesencephalic reticular nucleus; ORB: orbital cortex; OT: olfactory tubercle; PAG: periaqueductal gray; PIR: piriform cortex; PL: prelimbic cortex; PTL: parietal cortex; PVN: paraventricular nucleus hypothalamus; PVT: paraventricular nucleus thalamus; RE nucleus reunions thalamus; RSP: retrosplenial cortex; RPH: raphe; SC: superior colliculi; SN: substantia nigra; SSP: primary somatosensory cortex; VMH: ventromedial hypothalamus; VP: ventral posterior nucleus thalamus; VTA: ventral tegmental areaCraig Ferris and Mathew Brevard have a financial interest in Insight MRI the bioengineering company that manufactures the animal imaging equipment used in these studies. Craig Ferris and Neal Simon have a financial interest in Azevan Pharmaceuticals the company developing SRX251 an orally active V1a receptor antagonist used in these studies.Each author has made a significant contribution to these studies either in the acquisition of data , software development, data analysis , or study design and manuscript preparation . All authors read and approved the final manuscript."}
+{"text": "Escherichia coli, allowing for the estimation of energy generation and cell synthesis, based on intracellular fluxes and that may be used to characterize phenotypic growth.It is quite important to simulate the metabolic changes of a cell in response to the change in culture environment and/or specific gene knockouts particularly for the purpose of application in industry. If this could be done, the cell design can be made without conducting exhaustive experiments, and one can screen out the promising candidates, proceeded by experimental verification of a select few of particular interest. Although several models have so far been proposed, most of them focus on the specific metabolic pathways. It is preferred to model the whole of the main metabolic pathways in E. coli. Once intracellular fluxes were computed by this model, the specific ATP production rate, the specific CO2 production rate, and the specific NADPH production rate could be estimated. The specific ATP production rate thus computed was used for the estimation of the specific growth rate. The CO2 production rate could be used to estimate cell yield, and the specific NADPH production rate could be used to determine the flux of the oxidative PP pathway. The batch and continuous cultivations were simulated where the changing patterns of extracellular and intra-cellular metabolite concentrations were compared with experimental data. Moreover, the effects of the knockout of such pathways as Ppc, Pck and Pyk on the metabolism were simulated. It was shown to be difficult for the cell to grow in Ppc mutant due to low concentration of OAA, while Pck mutant does not necessarily show this phenomenon. The slower growth rate of the Ppc mutant was properly estimated by taking into account the lower specific ATP production rate. In the case of Pyk mutant, the enzyme level regulation was made clear such that Pyk knockout caused PEP concentration to be up-regulated and activated Ppc, which caused the increase in MAL concentration and backed up reduced PYR through Mez, resulting in the phenotypic growth characteristics similar to the wild type.In the present study, we considered the simulation of the main metabolic pathways such as glycolysis, TCA cycle, pentose phosphate (PP) pathway, and the anapleorotic pathways using enzymatic reaction models of E. coli for understanding metabolic changes inside the cell in response to specific pathway gene knockouts, considering the whole main metabolic pathways. The comparison of the simulation result with the experimental data indicates that the present model could simulate the effect of the specific gene knockouts to the changes in the metabolisms to some extent.It was shown to be useful to simulate the main metabolism of  One of the most challenging goals of metabolic engineering is to design the cell metabolism based on the analysis of metabolic regulation. For this, it is strongly desired to develop a mathematical model which can describe the dynamic behaviour of the cell in response to the changes in the culture environment and/or specific genetic modifications. Although an attempt has been made to develop a platform for the whole cell model , the totSaccharomyces cerevisiae  glucose, 0.4 g of [1-13C] glucose, and 3.2 g of naturally labeled glucose per liter. Biomass samples for GC-MS analysis were taken after one residence time. Sample preparation, analytical procedures for GC-MS analysis, and flux computation are given elsewhere  denotes the concentration, and the abbreviations for the metabolites are explained in Nomenclature. ll grows . As showThe estimation for the cell growth rate is by far important. In particular, it is critical for the prediction of the specific gene knockout mutant. The most typical equation for the cell growth rate is the Monod equation:S is the substrate concentration and S \u2261 [ex Glc] in the present case. The drawback of this equation is that the cell will keep growing at \u03bcm as far as S \u226b Ks where Ks is usually quite small in the case of the utilization of glucose as the substrate. This does not reflect the fermentation characteristics in practice. Therefore, we introduced another term such aswhere X is the cell concentration and Xm is the final value of X in the batch culture, and n is the model parameter. Xm may be set as S(0)YS/X where S (0) is the initial substrate concentration, and YS/X is the yield coefficient. Although this equation can be used to simulate the dynamic behavior in batch culture, Eq. (2b) may not be able express the cell growth rate for the mutants. We, therefore, introduce another idea by taking into account the effect of ATP generation on the cell growth rate based on experimental observation.where 2 can contribute in generating ATP via oxidative phosphorylation. The pathways involved in electron transfer and oxidative phosphorylation have variable stoichiometry due to the use of different dehydrogenases and cytochromes. Namely, the NADH dehydrogenase NDH-I encoded by nuo gene transports 2 H+/e-, while NDH-II encoded by ndh gene transports 0 H+/e- /[NAD] ratio increases as given by Eq.10) of Table 0 of Tablm = 8 mM) and Icl  compete for ICIT. This branch point is under both gene level regulation by aceBAK operon and the enzyme level regulation by the phosphorylation/dephosphorylation of ICDH. Here, we considered the rate equation for ICDH as given by Eq.(15) of Table For citrate synthase reaction, Eq.14) in Table 4 in TablAs for the glyoxylate pathway, Eq. 16) of Table 6 of TablFor G6PDH and 6PGDH reactions in the PP pathway, Eqs.(23) and (24) of Table 2 production rate Once the fluxes were determined, the specific CO2 production rate was computed by the product of net production of CO2 and biomass concentration, i.e. and the total COvNADPH may also be estimated byMoreover, the specific NADPH production rate \u03bc and vNADPH computed based on the flux estimates obtained from 13C-labeling experiments [It should be noted that the flux determination in the PP pathway is not easy for the enzyme-based kinetic equations. In particular, it is not easy to accurately predict the flux of G6PDH at the branch point of G6P. Figure eriments ,15, indikNADPH value from Figure kNADPH after \u03bc was computed. Then, the flux of G6PDH may be estimated.Once we identified As stated in introduction, it is not easy, even if it is not impossible, to express gene-level regulation by mathematical equations. Here, we alternatively introduced several rules for the simulation based on the experimental observations and the roles of global regulators such as given in Additional file Metabolites2KG: 2-Keto-D-gluconate; 6PG: 6-Phosphogluconolactone; ACE: Acetate; AcP: Acetyl phosphate; AcCoA: Acetyl-CoA; ASP: Aspartate; ADP: Adenosine diphosphate; ATP: Adenosine-5'-triphosphate; AMP: Adenosine monophosphate; DHAP: Dihydroxyacetone phosphate; E4P: Erythrose 4-phosphate; F6P: Fructose 6-phosphate; FDP: Fructose 1,6-bisphosphate; FUM: Fumarate; G6P: Glucose-6-phosphate; GAP: Glyceraldehyde 3-phosphate; ICIT: Isocitrate; NAD/NADH: Nicotinamide adenine dinucleotide; NADP/NADPH: Nicotinamide adenine dinucleotide phosphate; MAL: Malate; OAA: Oxaloacetate; P: Phosphate; PEP: Phosphoenolpyruvate; PYR: Pyruvate; R5P: Ribulose 5-phosphate; Ru5P: Ribose 5-phosphate; S7P: Sedoheptulose 7-phosphate; SUC: Succinate; X5P: Xylulose 5-phosphateProtien (enzyme)Glc,/EIICBGlc: Enzyme for glucose; Eno: Enolase; Fum: Fumarase; G6PDH: Glucose-6-phosphate dehydrogenase; GAPDH: Glyceraldehyde 3-phosphate dehydrogenase; ICDH: Isocitrate dehydrogenase; HPr: Histidine containing protien; Icl: Isocitrate lyase; MDH: Malate dehydrogenase; Mez: Malic enzyme; Ms: Malate synthase; Pck: Phosphoenolpyruvate carboxykinase; PDH: Pyruvate dehydrogenase; Pfk/Pfk-1: Phosphofructokinase-1; Pgi: Phosphoglucose isomerase/Glucosephosphate isomerase; Pgk: Phosphoglycerate kinase; Pgm: Phosphoglycerate mutase; Ppc: PEP carboxylase; Pps: Phosphoenolpyruvate synthase; Pta: Phosphotransacetylase; PTS: Phosphotransferase system; Pyk: Pyruvate kinase; Rpe: Ribulose phosphate 3-epimerase; Rpi: Ribulose 5-phosphate 3-isomerase; SDH: Succinate dehydrogenase; Tal: Transaldolase; TktA: TransketolaseI; TktB: TransketolaseII2KGDH: 2-Keto-D-gluconate Dehydrogenase; Ack: Acetate kinase; Acs: Acetyl coenzyme A synthetase; AcP: Acetyl phosphate; Aldo: Aldolase; CS: Citrate synthase; EI: Cytoplasmatic protein (enzyme1); EII, EIIB, EIIC,: Carbohydrate specific (enzyme II); EIIAGeneaceBAK: operon which encodes the metabolic and regulatory enzymes of the glyoxylate bypass; cra: Catabolite repressor/activator; crr: Catabolite repressor; fadR: Fatty acid metabolism regulator; icdA: Isocitrate dehydrogenase A; iclR: Transcriptional repressor IclR; pckA: Phosphoenolpyruvate carboxykinase gene; pfkA, pfkB: Phosphofructokinase gene; ppsA: Phosphoenolpyruvate synthase gene; ptsG, ptsHI: Pts gene; pykA, pykF: Pyruvate kinase geneThe authors declare that they have no competing interests.TAAK made modeling, experiment and computer simulation, AAM made some TCA cycle modeling and simulation, AMK supervised computer simulation, JM made formulation, KS made modeling and manuscripts preparation. All authors read and approved the final manuscripts.Effects of initial metabolite concentrations on the fermentation characteristics.Click here for fileSimulation result of wild type and Ppc mutant in batch culture.Click here for fileTable S1 - Ruled used for the simulation.Click here for fileSimulation result of wild type and Ppc mutant in continuous culture.Click here for fileSimulation result of wild type and Pck mutant in continuous culture.Click here for fileSimulation result of wild type and Pyk mutant in batch culture.Click here for fileSimulation result of wild type and Pyk mutant in continuous culture.Click here for fileComputational procedure for the simulation of fitting experimental data.Click here for file"}
+{"text": "There were errors in the Author Contributions. The correct contributions are: Conceived and designed the experiments: ACC KHAC LHW. Performed the experiments: ACC ELN LHW. Analyzed the data: ACC ELN KHBM KHAC LHW. Contributed reagents/materials/analysis tools: KHAC LHW. Wrote the paper: ACC KHAC LHW. Technical advice and discussion: ACC ELN KHBM KHAC LHW."}
+{"text": "The EQ-5D has been extensively used to assess patient utility in trials of new treatments within the cardiovascular field. The aims of this study were to review evidence of the validity and reliability of the EQ-5D, and to summarise utility scores based on the use of the EQ-5D in clinical trials and in studies of patients with cardiovascular disease.A structured literature search was conducted using keywords related to cardiovascular disease and EQ-5D. Original research studies of patients with cardiovascular disease that reported EQ-5D results and its measurement properties were included.Of 147 identified papers, 66 met the selection criteria, with 10 studies reporting evidence on validity or reliability and 60 reporting EQ-5D responses (VAS or self-classification). Mean EQ-5D index-based scores ranged from 0.24 (SD 0.39) to 0.90 (SD 0.16), while VAS scores ranged from 37 (SD 21) to 89 (no SD reported). Stratification of EQ-5D index scores by disease severity revealed that scores decreased from a mean of 0.78 (SD 0.18) to 0.51 (SD 0.21) for mild to severe disease in heart failure patients and from 0.80 (SD 0.05) to 0.45 (SD 0.22) for mild to severe disease in angina patients.The published evidence generally supports the validity and reliability of the EQ-5D as an outcome measure within the cardiovascular area. This review provides utility estimates across a range of cardiovascular subgroups and treatments that may be useful for future modelling of utilities and QALYs in economic evaluations within the cardiovascular area. Cardiovascular disease (CVD) imposes a great burden on societies around the world, with an estimated 16.7 million - or 29.2% of total global deaths - resulting from various forms of CVD.Increasingly over time, clinical trials within the cardiovascular field have included HRQoL measures. Such measures, alongside clinical measures of functionality, can help evaluate the physical, mental and emotional implications of CVD as well as the effects of surgical and medical treatments. Commonly used functional classification systems within the cardiovascular field are the New York Heart Association (NYHA) functional classification system for heart failure patients and the Canadian Cardiovascular Society (CCS) grading scale for angina pectoris,5. HRQoLAmong the available generic measures, the EQ-5D has gained widespread use due to its simplicity to administer, score and interpret. It also imposes minimal burden on the respondent as it is a brief, simple measure for patients to understand and to complete. The index-based score is generated by applying societal preference weights to the health state classification completed by the patient that consists of five dimensions , each with three levels of response or severity . The ability to convert self classification responses into a single index score makes the EQ-5D practical for clinical and economic evaluation. The indThe principle aims of this paper were: to synthesise the evidence on the validity and reliability of the EQ-5D in studies within the cardiovascular field; to summarise the EQ-5D based scores reported in studies within the CVD field; and to attempt to stratify mean utility scores according to level of disease severity.http://www.euroqol.org was also used to identify unique references, including working papers and conference proceedings that may not have been captured in the initial literature search. Only full-text published papers were included for analysis.A computerised search of the current published literature was performed using MEDLINE and EMBASE for the period January 1988 to October 2008. The search strategy combined exploded or medical subject headings relating to the CVD field and the EQ-5D as follows: ('cardiovascular'/exp OR 'cardiovascular') OR ('cardiac'/exp OR 'cardiac') OR ('cardiology'/exp OR 'cardiology') AND 'euroqol' OR 'EQ 5D' OR 'EQ5D'. The EuroQol website The inclusion criteria required that the paper was original research, and that it reported EQ-5D scores specific to cardiovascular disease or reported psychometric properties of the EQ-5D in a population with cardiovascular disease. Studies that only reported EQ-5D index or VAS scores graphically in terms of change over time were excluded from the analysis. When multiple studies used the same dataset, EQ-5D scores were only reported from one article to avoid double counting. No language restrictions were imposed. Study abstracts that potentially met the inclusion criteria were identified, and full-text articles were retrieved for further review. A standard data abstraction form was developed to facilitate the structured review, which included study design, patient characteristics, intervention information, published source of index-based preference weights and EQ-5D scores as well as details of any other clinical measures; disease-specific quality of life and generic HRQoL instruments. A summary of the results of the literature search is provided in figure I2 statistic [I2 statistic uses the sum of the squared differences of each study from the pooled estimate and the degrees of freedom of the test to provide a measure of the percent of total variation across studies due to heterogeneity between studies. A meta-analysis yielding a value of I2 above 75% suggests a high level of heterogeneity between the studies. Psychometric properties were summarised according to the type of property assessed , the comparison performed, and the statistical test result.Initially, studies that reported EQ-5D index-based scores and/or VAS scores were sorted into cardiovascular subgroups  that were informed by the latest WHO International Classification of Diseases (ICD-10: I00-I99 - diseases of the circulatory system)  explored construct validity (convergent and discriminative), typically in terms of correlations with other disease-specific HRQoL measures as well as reliability and responsiveness . Both the CCS and NYHA scales range from class I (mild symptoms) to class IV (severe symptoms) and CCS can also be graded as 0 for no symptoms  rely on generic measures such as the EQ-5D for the calculation of QALYs. Increased use of the EQ-5D may also support the view that patient reported outcomes and quality of life are becoming more widely accepted as routine measures in clinical studies, with the EQ-5D being an internationally recognised generic measure of HRQoL. This summary of EQ-5D index and VAS scores in the cardiovascular field complements other published reports describing the use of the EQ-5D in the cancer and asthma/COPD literature and of utility scores associated with various conditions -50.The review found that the majority of studies that included the EQ-5D were within IHD I20 - I25) and cerebrovascular disease (I60 - I69), subgroups, reflecting the relative prevalence of these diseases worldwide. Stratification by disease severity  was possible for IHD patients and heart failure patients and illustrated a positive relationship with the EQ-5D when moving from severe to mild disease severity  as well as non-disease-related factors such as other co-morbidities and demographic characteristics. Furthermore, no Overall, this study illustrated the difficulty in attempting to adequately deal with statistical heterogeneity based on aggregated data from published studies . This woHRQoL measures such as the EQ-5D can be useful tools to clinicians in terms of evaluating the impact of cardiovascular disease on patients and can help to inform decision making and resource allocation. The use of the EQ-5D in CVD studies has increased in recent years and published studies provide evidence of its validity and reliability. The variation in EQ-5D index and VAS scores reported here largely reflect systematic differences in terms of disease stage, treatment and patient characteristics. In the future, as more studies of CVD present EQ-5D scores according to disease severity, it may be possible to calculate pooled mean estimates that can be useful in modelling of CVD-related health outcomes in economic evaluations.AAA: Abdominal aortic aneurysm; ACS: Acute coronary syndromes; ACT: Anticoagulation therapy; AF: Atrial fibrillation; AH-Drug: Anti-hypertensive drug therapy; AHF: Advanced heart failure; AMI: Acute myocardial infarction; Amp.: Amputation; Angio: Coronary Angiography; ASA: American Society of Anaesthesiologists; ASCOT-AHD: Anglo-Scandinavian cardiac outcomes trial - anti-hypertensive drug treatment; Asym./Sym.: Asymptomatic/Symptomatic; AUT: Austria; AVR: Aortic valve replacement; BI: Barthel Index; BOTH-CABG/PCI/MM: Patients who are suitable for both CABG and PCI and receive CABG/PCI/MM; CABG: Coronary artery bypass graft; CABG-80: Coronary artery bypass surgery in octogenarians; CABG-CABG/PCI/MM: Patients who are suitable for CABG and receive CABG/PCI/MM; CABG-CPB: CABG using heart lung machine; CAD: Coronary artery disease; C-Arrest: Cardiac arrest; CCR: Comprehensive cardiac rehabilitation; CCS: Canadian Cardiovascular Society; CCU: Coronary care unit; CES-D: Centre for Epidemiological Studies - Depression Scale; CHD: Coronary heart disease; CHD-PHARM/Control: Community pharmacy-led medicines management programme/control treatment for patients with CHD; CML: Case method learning supported lipid-lowering strategy; COMM - CVD/NOCVD: Community dwelling-based elderly patients with/without CVD; CR: Cardiac resynchronisation; CR-Home/Hosp: Home/Hospital-based cardiac rehabilitation; C-REHAB: Cardiac rehabilitation; CS: Conservative strategy; CVA: Cerebrovascular Accident; CVD: Cardiovascular disease; Duplex US: Duplex ultrasonography; Echo: Echocardiography; EHS-CR: Euro Heart Survey on coronary revascularisation; Endo: Endovascular AAA surgery; ES: Effect size; Exercise-Qol: Long-term effects of exercise training on quality of life; F-u: Follow-up; GRS: Guyatt's responsiveness statistic; HeartMed: Lifestyle advice intervention by community pharmacists for heart failure patients; HF: Heart failure; HOSP - CVD: Hospital-based elderly patients with CVD; HRQoL: Health-related quality of life; HUI2/3: Health Utilities Index mark 2/3; IC: Intermittent claudication; ICC: Intra-class correlation; ICD: Implantable cardioverter defibrillator; ICP: Integrated care pathway; IHD: Ischaemic heart disease; IQR: Inter-quartile range; IS: Interventional strategy; IV: Intravenous; KCCQ: Kansas City Cardiomyopathy Questionnaire; LV: Left ventricular; MacNew: MacNew Heart Disease Quality of Life Questionnaire; MCS: Mental component summary; MDT: Multi-disciplinary team; MEDMAN: Community pharmacy-led medicines management services; MEPS: Medical expenditure panel survey; MI: Myocardial infarction; MI - Self-help: Home-based self-help rehabilitation package for MI patients; MIDCAB: Minimally invasive direct CABG; MM: Medical management; MR Angio: Magnetic resonance angiography; MRI: Magnetic resonance imaging; MT: Medical therapy; MVPS: Mitral valve prolapse syndrome; NYHA: New York Heart Association; OP-CABG: Off-pump CABG; Open: Open AAA surgery; PAOD: Peripheral arterial occlusive disease; PCI: Percutaneous coronary intervention; PCI-BMS: PCI with bare-metal stents; PCI-CABG/MM/PCI: Patients who are suitable for PCI and receive CABG/PCI/MM; PCI-DES: PCI with drug-eluting stents; PCS: Physical component summary; PER: Peripheral endovascular revascularisation; Pre-op: Pre-operation; Proxy: HRQol questionnaire completed by spouse/family member; PSM: Patient self-management; P-PTCA: Primary PTCA; P-Stent: Primary stent placement; PTCA: Percutaneous transluminal coronary angioplasty; QLMI: Quality of Life after MI questionnaire; QoL: Quality of life; RCT: Randomised controlled trial; REV/NO REV: Eligible/Ineligible for Revascularisation; SAH: Subarachnoid haemorrhage; SCOPE-Drug/Control: Study on cognition and prognosis in the elderly - Drug/Control treatment; SD: Standard deviation; SES: Socioeconomic status; SF-36: Short-form 36-item health survey questionnaire; SF-6D: Short-form 6D; SF-12: Short-form 12-item health survey questionnaire; SPECT: Single photon emission computed tomography; SRM: Standardised response means; Stroke-4Y: Four years post-stroke; TIA: Trans-ischaemic attack; Trans.: Heart Transplantation; Tx: Treatment; UC: Usual care; VAD: Ventricular assist device; VAS: Visual analogue scale; VascuQol: Vascular Quality of Life Questionnaire; -ve/+ve: Deterioration/Improvement in condition; WHO-ICD: World Health Organisation - International Classification of Diseases; W-list: Waiting-list.The authors declare that they have no competing interests.MD participated in the design of the study, carried out the systematic literature review, conducted any data analysis and drafted the manuscript. KG provided support in the statistical analysis and helped to draft the manuscript. LS participated in the design of the study, provided support in the statistical analysis and helped to draft the manuscript. MB conceived of the study, participated in the design of the study and helped to draft the manuscript. All authors read and approved the final manuscript.Tables. Table 1: Description of studies that have used the EQ-5D as an outcome measure in clinical and observational studies of patients with cardiovascular disease. Table 2: Summary of studies examining validity and reliability of EQ-5D in cardiovascular disease (n = 10). Table 3: Summary of EQ-5D utility scores reported in cardiovascular studies. Table 4: Canadian Cardiovascular Society (CCS) and New York Heart Association (NYHA) classification systems [ systems -95.Click here for file"}
+{"text": "The initials for author A. David Redish appear incorrectly in the Author Contributions. The correct initials are ADR. The Author Contributions should read: \"Conceived and designed the experiments: ZKN DDR. Performed the experiments: ZKN ADR. Analyzed the data: ZKN ADR. Wrote the paper: ZKN ADR.\""}
+{"text": "Although homeobox genes have been the subject of many studies, little is known about the main amino acid changes that occurred early in the evolution of genes belonging to different classes.In this study, we report a method for the fast and efficient retrieval of sequences belonging to the ANTP (HOXL and NKL) and PRD classes. Furthermore, we look for diagnostic amino acid residues that can be used to distinguish HOXL, NKL and PRD genes.The reported protein features will facilitate the robust classification of homeobox genes from newly sequenced bilaterian genomes. Nevertheless, in non-bilaterian genomes our findings must be cautiously applied. In principle, as long as a good manually curated data set is available the approach here described can be applied to non-bilaterian organisms as well. Our results help focus experimental studies onto investigating the biochemical functions of key homeodomain residues in different gene classes. Genes that belong to the homeobox family are characterized by the ability to code for a protein that contains a recognizable, although very variable, 'homeodomain', usually 60 amino acids in length ,2. Many Here, we report amino acid patterns typical of bilaterian HOXL, NKL, and PRD genes that can be used to quickly and efficiently retrieve amino acid sequences belonging to these classes and subclasses, among hundreds of other homeodomain sequences. Retrieving a given class or subclass of sequences from many animal genomes may be thus an easier task than previously thought. However, we show that these typical amino acid patterns should be cautiously used when sequences come from non-bilaterian animals.Since phylogenetic analysis was one of the primary sources of evidence used to establish the different classes and sub-classes, it is likely that most of homeobox gene classes and subclasses represent monophyletic lineages. Hence, it is conceivable that amino acid changes important for protein function in a given lineage may be revealed as fixed differences between classes and subclasses. Previous attempts have been made to classify genes within HOX families -9 but noWe have used the hand-curated data set of Holland et al. , the PROIn order to find amino acid patterns that distinguish genes from the ANTP subclasses, as well as genes from the PRD class, from genes belonging to other classes, a fast word discovery program  encode this amino acid pattern. None of the human NKL genes encode this amino acid pattern.The pattern LE [AGKNR]E  was buiDrosophila melanogaster AbdB, Drosophila melanogaster btn, Strigamia maritima Hox3b, Gallus gallus HMD2 (PROSITE annotation), Danio rerio HXABA (PROSITE annotation), and Salmo salar HXB2 (PROSITE annotation). These sequences do not form a closely related subgroup of sequences. For instance, the Drosophila melanogaster Abd-B and btn genes belong to two different HOXL gene families. Moreover, other genes belonging to these families do show the HOXL 1 amino acid pattern. The Fugu rubripes HXDBB (PROSITE annotation) and the Gallus gallus HXB8 (PROSITE annotation) sequences are incomplete, and thus it is not possible to determine whether they show this amino acid pattern. In addition to the 194 known HOXL genes showing the HOXL 1 pattern, 178/288 'unclassified' sequences also had this pattern .The HOXL 2 pattern is not as specific as the HOXL 1 pattern, since it is observed in about 46% of the genes belonging to the POU class and in a few NKL (0.5%) and PRD (8%) genes. All 16 PRD genes showing the HOXL 2 pattern belong to the Pax4/6 gene family, thus it is likely that this is a case of convergent evolution. The human POU homeodomains showing HOXL 2 pattern are POU1F1, POU3F1, POU3F2, POU3F3, and POU3F4. The latter four genes are closely related, although the POU1F1 gene is distantly related to those genes  [^DGHMPTVWY] [^CDGKMNPQR] [FL] [^CFILPTWY] [AEFHKQRV] [ADEGKNSTW] [CHKMPQR] [FHY]P (positions 16\u201326) PRD pattern, use a negatively charged amino acid at position 27 (DE) and a less polar or non-polar amino acid (^RKDENQ) at position 30. About 80% of all animal bilaterian PRD genes follow this description.ANTP  genes show the [HQ] [IV] [AKLT] (positions 44\u201346) ANTP 1 pattern. In contrast to PRD genes, ANTP genes do not use a negatively charged amino acid at position 27 (DE). Furthermore, at position 30, 99.8% of all bilaterian ANTP genes use a polar amino acid (RKDENQ). 97% of all ANTP bilaterian genes follow this description (data not shown).HOXL genes are characterized by the presence of the HOXL 1 pattern. 96% of all bilaterian HOXL genes show the [KT] [IV]WFQNRR [AMV]K [DEHKLMQWY] [KR] [KR] (positions 46\u201358) HOXL 1 pattern.NKL genes show the NKL pattern (positions 41\u201345) or a NKL derived pattern. About 98% of the bilaterian NKL genes follow this pattern. If the NKL pattern is generalized to include the derived NKL patterns then many hits are observed in other homeodomain classes (data not shown). This is why several NKL-related patterns are reported.The above definitions suggest that the region in between amino acid positions 16\u201330 and 44\u201358 are the most important for function specificity of genes belonging to different classes and sub-classes. The former region corresponds to the end of Helix 1, the inter Helix 1\u20132 region and to the first positions of Helix 2 . The regThe situation observed for NKL genes suggest that specific amino acid patterns may exist for groups of genes within major classes, as previously suggested . It alsoIt is tempting to use these features to classify homeobox containing genes. Nevertheless, given the very old age of the gene families considered, the possibility of convergent evolution must be considered when analyzing a given amino acid sequence. Therefore, for the purpose of gene classification, the features here described should not be decisive but rather used as additional evidence. It should be noted, that the reconstruction of gene genealogies is a hard problem, namely when proteins belonging to the same family share some of the same protein interaction partners, thus facing a similar selective environment . Any additional piece of evidence that may shed light on the correct classification of genes should therefore be used.In this work we report a method for the fast retrieval of bilaterian ANTP and PRD sequences. Given the availability of a sufficiently large curated data set this method can be applied to any group of proteins. Furthermore, we report some of the main amino acid changes that occurred early in the HOXL, NKL and PRD lineages. These features can be used for the classification of gene sequences, although, as shown, convergent evolution must be considered as an explanation for the presence of a given pattern in a sequence. The possibility that the region of the protein that allows distinguishing the different classes, also allows the distinction of different families within classes, has important practical and evolutionary consequences and must be explored in more detail.NAF, JV and CPV conceived the design of the study. NAF developed the software needed for the large-scale analyses, while JV and CPV collected, aligned the sequence data, and performed the phylogenetic analyses. JV drafted the manuscript. All authors participated in the results discussion and helped writing the final version of the manuscript. All authors read and approved the final manuscript.Gi numbers of the 251 non-bilaterian non-redundant sequences used for the analysis presented in Table Nematostella vectensis: 32263856; 32263873; 74039490; 74039492; 82621559; 82621587; 82621611; 82621663; 83356315; 156363224; 156363226; 156387518; 156397205Ephydatia fluviatilis: 438584Acropora millepora: 117581722; 117581724; 117581726; 117581728; Anemonia erythraea: 158936936; Ephydatia fluviatilis: 438585; 510584; Halichondria bowerbanki: 33641771; Nematostella vectensis: 32816231; 78190373; 82621509; 82621525; 82621533; 82621555; 82621557; 82621585; 82621591; 82621609; 82621625; 82621657; 82621665; 82621667; 110339021; 110339029; 110339121; 156353243; 156363798; 156367335; 156372762; 156397943; 168693291;Suberites domuncula: 34786940; 49659003; Sycon raphanus: 11066243Anthopleura japonica: 144369330; 144369363; Hydra vulgaris: 2331219; 7635735; Nematostella vectensis: 82570553; 82621543; 82621677; 110339077; 110339133; 156376845; 156402818; 156406963; 156407174Nematostella vectensis: 82621563; 82621631; 82621655; 156366927; 156402173Nematostella vectensis: 82621579; 82621647; 82621651; 110339063; 156388033; 156400908; 156407394Nematostella vectensis: 110339027Baikalospongia interm\u00e9dia: 62238212; Ephydatia fluviatilis: 1438870; Ephydatia muelleri: 3184520; Hydra vulgaris: 7635740; Nematostella vectensis: 82621517; 82621615; 82621619; 82621623; 82621635; 82621653; 156375827; 156375891; 156376334; 156401296; 156402692; Podocoryne carnea: 28188799; Potamolepis sp.: 62238208; Suberites domuncula: 49659001Anthopleura jap\u00f3nica: 144369334; Cladonema californicum: 9652040; Hydra vulgaris: 3021450; 3021452; 6503072; Nematostella vectensis: 38569883; 78190377; 82395396; 82395402; 82395404; 82395406; 82395408; 82395412; 82395414; 82570541; 82570557; 82570559; 82570563; 110339183; 110339213; 110339215; 110339225; 113120207; 156377162; 156615306;Tripedalia cystophora: 33391193Acropora formosa: 228960; Acropora millepora: 7335704; 7595811; 7595813; 13506878; 117581730; 117581732;Anthopleura jap\u00f3nica: 144369323; 144369326; 144369366; Aurelia aurita: 50841484; Cassiopea xamachana: 4894653; 4894655; 4894659; Cladonema radiatum: 47155918; 47155920; 47155922; Eleutheria dichotoma: 1147626; 91982983; 91982989; Hydra littoralis: 2102728; Hydra magnipapillata: 630481; 630482; 89242120; 144369369; 144369375; Hydra viridis: 7120; 7124; 7130; 83763566; Hydra vulgaris: 4433647; 4838455; 7635731; 7635733; 7635737; 7635742; 9945022; Hydractinia symbiolongicarpus: 2980868; 83272159; Nematostella vectensis: 5081328; 32816237; 74039494; 78190375; 82395398; 82395410; 82570519; 82570521; 82570527; 82570529; 82570537; 82570539; 82570545; 82570549; 82570555; 82570561; 82621507; 82621511; 82621513; 82621515; 82621519; 82621523; 82621527; 82621531; 82621535; 82621539; 82621541; 82621547; 82621549; 82621551; 82621565; 82621567; 82621571; 82621573; 82621575; 82621589; 82621595; 82621601; 82621603; 82621605; 82621613; 82621621; 82621627; 82621629; 82621633; 82621637; 82621643; 82621645; 82621671; 82621675; 83356317; 99030986; 110338989; 110339023; 110339061; 110339099; 110339101; 110339115; 110339171; 110339191; 110339211; 110339247; 113120203; 156356964; 156358580; 156361301; 156361303; 156364678; 156368221; 156371265; 156371439; 156372678; 156374167; 156377158; 156377160; 156377164; 156389076; 156390886; 156393340; 156395806; 156396978; 156398319; 156407912; Podocoryne carnea: 976094; 6118056; 6465862; 7649930; 9964019; 47155914; 62002543; Sarsia sp.: 9988771; Scolionema suvaense: 158936914; Suberites domuncula: 49659005; Trichoplax adhaerens: 38565482"}
+{"text": "The Open Rheumatology Journal,\u00a02018, 12: 1-10The type of Article has been revised as follows:Review ArticleThe type of article originally provided was:Research ArticleThe revised headings of declarations are mentioned below:CONSENT FOR PUBLICATION:Not applicable.The original headings of declarations provided were:ETHICS APPROVAL AND CONSENT TO PARTICIPATENot applicable.HUMAN AND ANIMAL RIGHTSNo Animals/Humans were used for studies that are base of this research."}
+{"text": "Correction to: Trials (2017) 18:22https://doi.org/10.1186/s13063-017-1906-7In the original publication  Figures There were some minor typographical errors on pages 2 and 4 and in the backmatter.Page 2 should have read: \u2018There is a clear knowledge gap with regard to effective strategies aimed at recruiters\u2019 ([The backmatter: Trial status: The first recruitment review took place in September 2015, and the last review in August 2016. The first 6-month follow-up took place in March 2016, with the last one in February 2017.\u2019Incorrect name tagging:Last Name: SalmanFirst Name: Rustam Al-ShahiCorrect author name tagging:Last Name: Al-Shahi SalmanFirst Name: RustamFollowing publication of the first correction article , we have"}
+{"text": "Nature Communications8: Article number: 14475; DOI: 10.1038/ncomms14475 (2017); Published: 02152017, Updated: 06252018The original HTML version of this Article omitted the article number; it should have been \u201814475\u2019. This has now been corrected in the HTML version of the Article. The PDF version was correct from the time of publication."}
+{"text": "Retirement preparation program: evaluation of resultsPsychology: Research and ReviewIncorrect version:Retirement preparation program: evaluation of resultsIt should read:The original publication (Psicologia: Reflex\u00e3o e Cr\u00edticaPsychology: Research and Review,"}
+{"text": "This article has been corrected: The correct Grant Support information is given below:GRANT SUPPORTThis work was funded by National Natural Science Foundation of China grant 81472606, Chinese Ministry of Science and Technology grant (973 grant) 2011CB812401, and the Beijing Municipal Government.https://doi.org/10.18632/oncotarget.6461Original article: Oncotarget. 2016; 7:3884-3896."}
+{"text": "This article has been corrected: The correct Acknowledgments information is given below:ACKNOWLEDGMENTSThe authors thank Tamar Ziv and Arie Admon  for the proteomic analysis. The authors also thank Antonella Di Pizio and Masha Y. Niv  for performing the structural analysis on predicted NF1 cleavage sites. The authors also thank The De Botton Protein Profiling institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science for identifying the proteolytic product of NF1. The work was supported by Minerva Foundation Grant.https://doi.org/10.18632/oncotarget.25805Original article: Oncotarget. 2018; 9:31264-31277."}
+{"text": "Nature Communications8: Article number: 14907; DOI: 10.1038/ncomms14907 (2017); Published: 04072017; Updated: 05252018The original version of this Article contained an error in the spelling of the author Aysegul Gezer, which was incorrectly given as Aysegul Geyser. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "AbstractHierodulapatellifera  occurs several Mediterranean countries, such as Italy. These arrivals could come from many factors: new pets or commercial human transport.Originally from Asia, Hierodulapatellifera  is here reported for the first time in France. A well settled and probably widespread population of this species is here discussed as its adaptability to the Mediterranean climate. Some considerations on the potential impacts on the local ecosystems and its future spreading in Europe as an invasive species are given.The presence of  Hierodulatenuidentata Saussure, 1869 in Italy, in the Po valley . Amongst these groups, insects are widely represented. In parallel, entomologists use, since 1999, the forum hosted on insecte.org to discuss their sigthings and upload them into a gallery of photographs where they are validated by the community. A third widely-used website for Citizen-Science is inaturalist.org. This website, which is also available as a mobile application, has been used to collect collateral information and monitor the presence of o valley .Mantodea male, located in Marseille, was put online with the app INPN Esp\u00e8ces and its identity discussed within the community. Sightings of alien Mantodea were then also highlighted on the forum insecte.org. The results of this research are presented here, highlighting the presence of a new Asian mantid species for France since at least 2013: Hierodulapatellifera .On 1 September 2019, a photo of a In addition, several species of mantids seem to invade Europe from Caucasus  and AsiaRecently, Citizen Science in France relies heavily on the application INPN Esp\u00e8ces. The sightings of insects are based on the website insecte.org and the World\u2019s fauna and flora observations are organised on the online database inaturalist.org.These three methods of publishing sightings in France are presented here:INPN Esp\u00e8cesA genuine tool for raising awareness and knowledge, building on the French biodiversity, INPN Esp\u00e8ces allows everyone to discover, from their mobile phone, the diversity of the species around us and to participate in the biodiversity inventory in France. It is the only app in France that allows us to investigate all the French Fauna and Flora species (mainland and overseas) through their characteristics, distribution or conservation status. Thanks to a data entry eased by images and geolocalisation from one\u2019s mobile, anyone can, with one click, improve the knowledge on the surrounding wildlife.To take part in the country\u2019s species surveying by transmitting our records to experts, only a few clicks are needed to share the sightings. The first identification by the observer is then checked by experts of each group involved in the project.insecte.org (\u2018Le Monde des insectes\u2019)This website is a gathering places for all insect lovers, whatever their level of knowledge, their approaches and their objectives. A discussion forum is organised according to the different orders of insects. When images in a post are validated collectively, the photos are placed in a gallery that serves as a reference library. Once a year, data are sent to the French national species inventory (INPN).inaturalist.orgOne of the world\u2019s most popular online wildlife databases, iNaturalist helps everyone identify the plants and animals around us. It allows connection to a community of over 750,000 scientists and naturalists who can help us learn more about nature. Moreover, by recording and sharing our sightings, people will create research quality data for scientists who are working to better understand and protect nature. iNaturalist is a joint initiative by the California Academy of Sciences and the National Geographic Society.Mantodea used here follow the latest update  was published, from the 9th district of Marseille  , one with a juvenile at Arles  and, finally, one with a female travelling on a boat in the Black Sea.In parallel, research was initiated on the forum of the website insecte.org, as well as on inaturalist.org. Alien Specimens from Mouri\u00e8s:Mantodea was observed in an olive grove. It was compared with a female Irisoratoria  on a photo published on insecte.org. During the many exchanges between naturalists, its identity was discussed between Sphodromantisviridis  and Hierodulatranscaucasica Brunner von Wattenwyl, 1878. On 28 September 2015, a new Mantodea female was discovered in the same locality. It seemed to be the same species. It was kept and put in breeding to observe an ootheca and to photograph it. It had been stated that the specimens observed were Hierodulatranscaucasica. The different people involved in the discussion were contacted. Detailed photographs were taken of the second captured female. The exact location of the captures was also noted. Oothecae and an old female were observed on olive trees in early November 2019 . It turns out that it was a female. Its identity was not fixed at the end of the discussions.On 27 July 2019, a nymph Specimen on the Black Sea:M.religiosa. Discussions then orientated for the identification towards H.transcaucasica. A synonymy with Hierodulatenuidentata Saussure, 1869, is suggested on the basis of recent references.On 22 September 2011, an adult female was photographed on a boat on the Black Sea. It was first mistakenly identified as Specimen from Marseille:H.patellifera. It was compared with a male of H.tenuidentata from the Greek island of Skopelos. Some morphological criteria, such as yellowish callous spots of the anterior coxae, are characteristic and can be observed on the photographed specimens. After examining the photographs of females from Mouri\u00e8s and the nymph (then adult) from Arles, it is possible to identify them as H.patellifera.The male from Marseille was studied morphologically. It is H.tenuidentata.On the other hand, the morphological criteria of the female on the boat on the Black Sea and its geographical location indicate that it is Serville, 18394A66F50F-FA2C-5B96-BDB4-D5106A1E3CF2Type status:Other material. Occurrence: recordedBy: Mattias Perez; individualCount: 1; sex: female; lifeStage: adult; Location: continent: Europe; country: France; stateProvince: Bouches-du-Rhone; county: Mouries; verbatimElevation: 30 m; verbatimLatitude: 43.69858; verbatimLongitude: 4.85217; verbatimCoordinateSystem: decimal degrees; Identification: identifiedBy: Nicolas Moulin; Event: samplingProtocol: hand catching; eventDate: 2013-11-03; eventRemarks: on oliveType status:Other material. Occurrence: recordedBy: Mattias Perez; individualCount: 1; sex: female; lifeStage: adult; Location: continent: Europe; country: France; stateProvince: Bouches-du-Rhone; county: Mouries; verbatimElevation: 30 m; verbatimLatitude: 43.69858; verbatimLongitude: 4.85217; verbatimCoordinateSystem: decimal degrees; Identification: identifiedBy: Nicolas Moulin; Event: samplingProtocol: hand catching; eventDate: 2015-09-28; eventRemarks: on oliveType status:Other material. Occurrence: recordedBy: Gauillaume Paulus; individualCount: 1; sex: female; lifeStage: nymph; Location: continent: Europe; country: France; stateProvince: Bouches-du-Rhone; county: Arles; verbatimElevation: 5 m; verbatimLatitude: 43.673112; verbatimLongitude: 4.633544; verbatimCoordinateSystem: decimal degrees; Identification: identifiedBy: Nicolas Moulin; Event: samplingProtocol: hand catching; eventDate: 2019-07-26; eventRemarks: in a gardenType status:Other material. Occurrence: recordedBy: Didier Aurelle; individualCount: 1; sex: male; lifeStage: adult; Location: continent: Europe; country: France; stateProvince: Bouches-du-Rhone; county: Marseille; verbatimElevation: 45 m; verbatimLatitude: 43.2565769; verbatimLongitude: 5.4097269; verbatimCoordinateSystem: decimal degrees; Identification: identifiedBy: Nicolas Moulin; Event: samplingProtocol: hand catching; eventDate: 2019-09-01; eventRemarks: on a balcony, 6th floorHierodulapatellifera, described from Java  will be updated with all these observations.Hierodulapatellifera occurs in a French department, Bouches-du-Rh\u00f4ne, on the basis of these records. The arrival would be prior to 2013. Several generations and a nymph have been observed. The first individuals could have arrived by Cargo from Asia or could have been voluntarily released, because it is a commonly reared pet. This would not be a continuation of colonisation with the known populations of H.tenuidentata in Northern Italy, in the Po Valley . The hypothesis of displacement by boat is valid because, a few years ago, a female specimen of H.tenuidentata was observed aboard a ship on the Black Sea. Its place of arrival in the boat could not really be located between Ukraine, Turkey, Romania, Bulgaria, Albania and the Danube Estuary. It is, however, well known that this species occurs in these countries  and is represented by one species: Sphodromantisviridis (Finally, the species of viridis .Mantodea must be in charge to identify them.Today, thanks to citizen science, it is important and possible to monitor such invasive alien species. However, the problem of the specific attribution of these specimens through photos is important. Then, some specialists of Vespavelutina (These invasive species could destabilise existing ecological niches by creating competition and ecological pressure, like the Asian Hornet, velutina . At the"}
+{"text": "Correction to: BMC Genomics (2019) 20:389DOI: 10.1186/s12864-019-5782-2Following the publication of this article , the autIn this Correction article the incorrect and correct author name are shown. The original publication of this article has been corrected.Rona DoyleOriginally the author name was published as:Ronan DoyleThe correct author name is:The publisher apologizes to the authors and readers for any inconvenience caused by this error."}
+{"text": "Objectives: To analyze how older adults conceptualize these intergenerational relationships. Methods: In this qualitative study, in-depth interviews were carried out with 316 older adults, aged 65-102, from three different nationalities who lived at home. Verbatim transcripts were examined. Results: Data analysis generated six themes representing intergenerational relationships: affection and reward; interest and integration; grandparent-grandchild interaction quality; privacy and boundaries definition; provision of support; and obligation of providing childcare, on two dimensions of ambivalence concerning their intergenerational relationships . Conclusions: The empirical findings from this research indicate how ambivalence in intergenerational relationships is experienced by older adults and stress the contradictory expectations of older adults with grandchildren. Keywords: Ambivalence; conflict; intergenerational relationships; older adults; support."}
+{"text": "AbstractClavicornaltica is a genus of very small flea beetles living in the leaf litter layer of Asian forests, easily sampled with Winkler extraction. The genus is presumably very rich in species, but their taxonomy is hampered by their small size and morphological uniformity.Clavicornalticabelalongensis n. sp., was discovered and taxonomically treated by the course participants. We also present the first DNA barcodes for the genus.On a \u2018taxon expedition\u2019-style field course at Kuala Belalong Field Studies Centre in Brunei Darussalam (Borneo), a new species,  We expect this concept may (i) improve the public appreciation for taxonomy and (ii) yield valid taxonomic output , discovered during the same field course, will appear elsewhere .In this paper, we provide partial results from a taxon expedition to the Ulu Temburong rainforest in Brunei, namely the taxonomic treatment of a new species of the leaf litter chrysomelid Callophylum sp., Dacroydes sp., and Horsfieldia sp., 70-80% canopy coverage, few vines, several decaying logs, and a distinct Dicuspiditermes termite presence.We worked in the vicinity of the Kuala Belalong Field Studies Centre (KBFSC) in the Ulu Temburong National Park in the Temburong district of Brunei. We collected specimens at the start of the \u2018Ashton Trail\u2019 just west of KBFSC, adjacent to the \u2018Earthwatch Plot\u2019 . The areClavicornaltica specimens removed. Our Winkler sampling yielded 12 specimens of Clavicornaltica which we provisionally assigned to four morphospecies, of which one was represented by sufficient individuals to warrant taxonomic description.On 27.09.2018 and 1.10.2018, we carried out the following field workshop. Field course participants collected leaf litter from two microhabitats, sampled separately (~75 l each): (i) open forest floor and (ii) the area between buttress roots. Leaf litter was then passed through a 1-cm mesh-width beetle sieve and subsequently extracted in a Winkler apparatus, the yield of which was preserved in 96% ethanol. This was then sorted under a dissection microscope and all Morphological examinations were carried out in the field lab with a Nikon SMZ445 dissection microscope with 10\u00d7 eye pieces (magnification up to 35\u00d7), a Leica ICC50 HD compound microscope and basic dissection materials. Photographs were made either with a smartphone through the eyepiece of a microscope or on a translucent white acrylic sheet with a Nikon D800e fitted with a Laowa 25 mm ultra-macro lens . Images were processed in Adobe Lightroom and subsequently stacked in Adobe Photoshop CS6. Genitalia and other dissected parts were embedded in polyvinylpyrrolidone . Lengthswww.boldsystems.com).One individual (TxExBr0004w-1) was analysed genetically as follows. DNA was isolated from a sample of abdominal soft tissue using the DNeasy Blood & Tissue Kit (Qiagen) and the extracted DNA was then purified with AMPureXP beads (Beckman Coulter). Around 10 ng of DNA were used in a PCR to generate amplicons for the COI barcoding region, using general primers ; institutionID: UBD; institutionCode: IBER-UBD; collectionCode: Zoology; basisOfRecord: PreservedSpecimenType status:Paratype. Occurrence: recordedBy: Taxon Expeditions field course participants; individualID: TxExBr0004w-2; individualCount: 1; sex: female; lifeStage: adult; preparations: card-mounted; disposition: in collection; Taxon: scientificName: Clavicornalticabelalongensis; kingdom: Animalia; phylum: Arthropoda; class: Hexapoda; order: Coleoptera; family: Chrysomelidae; genus: Clavicornaltica; specificEpithet: belalongensis; taxonRank: species; scientificNameAuthorship: Schilthuizen et al., 2019; nomenclaturalCode: ICZN; Location: locationID: TxExBr0004w; continent: Asia; island: Borneo; country: Brunei Darussalam; stateProvince: Temburong; locality: Kuala Belalong Field Studies Centre; verbatimLocality: Kuala Belalong Field Studies Centre, along Ashton trail; verbatimElevation: 120 m; verbatimLatitude: 4.5472; verbatimLongitude: 115.1571; Event: samplingProtocol: Winkler sampling; samplingEffort: 150 l of forest leaf litter; eventDate: 2018-09-27; habitat: Lowland dipterocarp forest; Record Level: type: PhysicalObject; bibliographicCitation: Clavicornalticabelalongensis (UBDM.3.01172); institutionID: UBD; institutionCode: IBER-UBD; collectionCode: Zoology; basisOfRecord: PreservedSpecimenType status:Paratype. Occurrence: recordedBy: Taxon Expeditions field course participants; individualID: TxExBr0014w-3; individualCount: 1; sex: female; lifeStage: adult; preparations: card-mounted; disposition: in collection; Taxon: scientificName: Clavicornalticabelalongensis; kingdom: Animalia; phylum: Arthropoda; class: Hexapoda; order: Coleoptera; family: Chrysomelidae; genus: Clavicornaltica; specificEpithet: belalongensis; taxonRank: species; scientificNameAuthorship: Schilthuizen et al., 2019; nomenclaturalCode: ICZN; Location: locationID: TxExBr0014w-3; continent: Asia; island: Borneo; country: Brunei Darussalam; stateProvince: Temburong; locality: Kuala Belalong Field Studies Centre; verbatimLocality: Kuala Belalong Field Studies Centre, along Ashton trail; verbatimElevation: 120 m; decimalLatitude: 4.5472; decimalLongitude: 115.1571; Event: samplingProtocol: Winkler sampling; samplingEffort: 150 l of forest leaf litter; eventDate: 2018-09-27; habitat: Lowland dipterocarp forest; Record Level: type: PhysicalObject; bibliographicCitation: Clavicornalticabelalongensis (UBDM.3.01173); institutionID: UBD; institutionCode: IBER-UBD; collectionCode: Zoology; basisOfRecord: PreservedSpecimenType status:Paratype. Occurrence: recordedBy: Taxon Expeditions field course participants; individualID: TxExBr0004w-4; individualCount: 1; sex: female; lifeStage: adult; preparations: card-mounted; disposition: in collection; Taxon: scientificName: Clavicornalticabelalongensis; kingdom: Animalia; phylum: Arthropoda; class: Hexapoda; order: Coleoptera; family: Chrysomelidae; genus: Clavicornaltica; specificEpithet: belalongensis; taxonRank: species; scientificNameAuthorship: Schilthuizen et al., 2019; nomenclaturalCode: ICZN; Location: locationID: TxExBr0004w; continent: Asia; island: Borneo; country: Brunei Darussalam; stateProvince: Temburong; locality: Kuala Belalong Field Studies Centre; verbatimLocality: Kuala Belalong Field Studies Centre, along Ashton trail; verbatimElevation: 120 m; decimalLatitude: 4.5472; decimalLongitude: 115.1571; Event: samplingProtocol: Winkler sampling; samplingEffort: 150 l of forest leaf litter; eventDate: 2018-09-27; habitat: Lowland dipterocarp forest; Record Level: type: PhysicalObject; bibliographicCitation: Clavicornalticabelalongensis (UBDM.3.01174); institutionID: UBD; institutionCode: IBER-UBD; collectionCode: Zoology; basisOfRecord: PreservedSpecimenType status:Paratype. Occurrence: recordedBy: Taxon Expeditions field course participants; individualID: TxExBr0004w-5; individualCount: 1; sex: female; lifeStage: adult; preparations: card-mounted; disposition: in collection; Taxon: scientificName: Clavicornalticabelalongensis; kingdom: Animalia; phylum: Arthropoda; class: Hexapoda; order: Coleoptera; family: Chrysomelidae; genus: Clavicornaltica; specificEpithet: belalongensis; taxonRank: species; scientificNameAuthorship: Schilthuizen et al., 2019; nomenclaturalCode: ICZN; Location: locationID: TxExBr0004w; continent: Asia; island: Borneo; country: Brunei Darussalam; stateProvince: Temburong; locality: Kuala Belalong Field Studies Centre; verbatimLocality: Kuala Belalong Field Studies Centre, along Ashton trail; verbatimElevation: 120 m; decimalLatitude: 4.5472; decimalLongitude: 115.157; Event: samplingProtocol: Winkler sampling; samplingEffort: 150 l of forest leaf litter; eventDate: 2018-09-27; habitat: Lowland dipterocarp forest; Record Level: type: PhysicalObject; bibliographicCitation: Clavicornalticabelalongensis (UBDM.3.01176); institutionID: UBD; institutionCode: IBER-UBD; collectionCode: Zoology; basisOfRecord: PreservedSpecimenType status:Paratype. Occurrence: recordedBy: Taxon Expeditions field course participants; individualID: TxExBr0004w-8; individualCount: 1; sex: female; lifeStage: adult; preparations: card-mounted; disposition: in collection; Taxon: scientificName: Clavicornalticabelalongensis; kingdom: Animalia; phylum: Arthropoda; class: Hexapoda; order: Coleoptera; family: Chrysomelidae; genus: Clavicornaltica; specificEpithet: belalongensis; taxonRank: species; scientificNameAuthorship: Schilthuizen et al., 2019; nomenclaturalCode: ICZN; Location: locationID: TxExBr0004w; continent: Asia; island: Borneo; country: Brunei Darussalam; stateProvince: Temburong; locality: Kuala Belalong Field Studies Centre; verbatimLocality: Kuala Belalong Field Studies Centre, along Ashton trail; verbatimElevation: 120 m; decimalLatitude: 4.5472; decimalLongitude: 115.1571; Event: samplingProtocol: Winkler sampling; samplingEffort: 150 l of forest leaf litter; eventDate: 2018-10-01; habitat: Lowland dipterocarp forest; Record Level: type: PhysicalObject; bibliographicCitation: Clavicornalticabelalongensis (UBDM.3.01175); institutionID: UBD; institutionCode: IBER-UBD; collectionCode: Zoology; basisOfRecord: PreservedSpecimenBody orange-red, small, nearly hemispherical, 1.15-1.30 mm long and 0.9-1.1 mm wide (i.e. ca. 1.25 times as long as wide) , densely beset with confluent double punctuation; tubercles and midfrontal sulcus poorly developed and inconspicuous. Eyes convex, each eye consisting of 26-30 ommatidia, ca. 1/5 the width of the head measured across the eyes in dorsal view. Antennae: clava long and moderately robust.Pronotum: Very weakly shagreened and punctuated; punctures sparse and minute, of similar strength to the subordinate punctuation on the elytra; pronotal surface therefore shiny. Lateral margin with a callosity that stretches from the anterior to the posterior corner. Lateral setiferous pore at 2/3 of the length of the margin, seta as long as the clava of the antenna, pore removed from the margin by a distance similar to the width of antennomere II. Posterior setiferous pore placed directly at the margin, the seta length similar to antennomeres IX+X.Hind wings: Absent.Elytra: Shiny, punctate in 9 longitudinal rows, scutellar row \u00bc the length of the other rows, consisting of ca. 6 punctures. Punctures in all rows deeply impressed along their entire length (puncture width is similar to their interspaces). In between, the major punctures are irregularly scattered and there are much smaller subordinate punctures. A rudiment of a 10th row exists in the final 1/3 flanking the elytral margin. A fine groove runs along the entire margin continuing to the apex; apex itself slightly drawn out. The internal edge of epipleura carries a short row of punctures, alongside the 4th and 5th visible sternite.Legs: Tibia and tarsus orange, femur dark orange and robust. Metafemur robust, oval, covered in reticulate microsculpture. External edge of metatibia bearing two parallel rows of 8-10 minute stiff setae placed along the terminal one-fifth and flanking the basis of metatarsomere I. Internal side of metatibia bearing ca. 10 thin setae that are placed along the terminal half of the tibia and increase to about 2.5\u00d7 the length of the external setae, then decrease in length towards the apex. The metatibia carries a long terminal spine of about the same length as metatarsomere I. No serrations or microteeth are visible on the spine.Mesosternum: Processus rounded, with a distinct margin, central area somewhat convex.Abdomen: Carina on the first visible abdominal sternite sharp and narrow, not broadened anteriorly or posteriorly, running along the length of the sternite. In reduced form, this carina is carried on to the four posterior sternites, which therefore, in lateral view, offer a slightly serrated aspect. The surface of the sternites carries a rough microsculpture of confluent punctures. Tergum IX (last visible tergite) with three longitudinal median ridges, the central one of which is much weaker than the two outermost. Subapically, tergum IX has a horizontal row of 8 serrations.Female genitalia: Spermatheca consisting of a pear-shaped receptacle, ca. 90 \u00b5m in length, with crosswise annulations Clavicornalticabelalongensis sp. n. differs from all other known Clavicornaltica are (i) the pear-shaped spermathecal receptacle that is distinctly separated from the pump and (ii) the medially keeled abdominal sternites. Furthermore, the new species can be separated from other oriental Clavicornaltica in the following respects: C.fortepunctata Scherer, 1974 (Vietnam) is more elongate  is black, the pronotum is impunctate and it is also much larger (1.9 mm)  have impunctate elytra  is larger (>1.5 mm)  is reddish-black and the elytral punctuation is reduced  has a widened first protarsomere and an anteriorly widened carina on the 1st abdominal segment  has a wide plate on the underside of the 1st abdominal sternite; Clavicornalticatrautneri Medvedev, 1993 is much larger (2.1 mm)  has a posteriorly narrowed pronotum  has an anteriorly widened carina on the 1st abdominal segment  has the spermathecal pump fused with the receptacle and a widened carina on the first abdominal segment  has the spermathecal pump fused with the receptacle  has the mesosternal processus flat, not convex  has the spermathecal pump wider than the receptacle  has vaginal palpi very short and the spermathecal pump wider than the receptacle  is 1.6 times as long as wide and has the carina on the 1st abdominal sternite widened posteriorly  is larger and more elongate; its head is not shagreened  has a spherical spermathecal receptacle, the carina on the 1st abdominal sternite is widened anteriorly and is flanked by rows of strong punctures, the metafemur is more elongated and the vaginal palpi are diverging, not parallel  has a much more elongate habitus  has impunctate elytra and a black body  ; Clavicoe elytra ; Clavico>1.5 mm) ; Clavico reduced ; Clavico segment ; Clavico(2.1 mm) ; Clavicopronotum ; Clavico segment ; Clavico segment ; Clavicoceptacle ; Clavicot convex ; Clavicoceptacle ; Clavicoceptacle ; Clavicoteriorly ; Clavicoagreened ; Clavicoparallel ; Clavico habitus ; finallyack body .Clavicornalticabelalongensis Schilthuizen et al., 2019, provided the full citation of this publication appears in the bibliography or elsewhere in the referring work.The species is named after the Belalong river; the new species was recorded in the close vicinity of the river\u2019s left bank. Following Article 51C of the Code , the speKnown only from a location near the confluence of the Belalong and Temburong rivers, at 120 m elevation . However, as pointed out by Clavicornaltica, which currently stands at 26 species, has barely scratched the surface of the true diversity. Given the morphological inaccessibility of this diversity, we expect DNA barcoding to be of some use. We hope the sequence we present here for C.belalongensis will be a starting point for further building up a database of DNA barcodes for this genus.These and previous results (ors e.g. , the speors e.g.  suggesteDespite the present single-species description based on limited material from a single locality, we believe that taxonomic work is best carried out in the context of larger revisions. However, we think that concise treatments of single species such as we present here, have value . As reso"}
+{"text": "Nature Communications8:15223 doi: ; DOI: 10.1038/ncomms15223 (2017); Published 05122017; Updated 05252018The originally published version of this Article contained an error in Fig. 1. In panel d, the uppermost western blot was inadvertently inverted during typesetting of the figure. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Reproducibility, or a lack thereof, is an increasingly important topic across many research fields. A key aspect of reproducibility is accurate reporting of both experiments and the resulting data. Herein, we propose a reporting guideline for mass spectrometry imaging (MSI). Previous standards have laid out guidelines sufficient to guarantee a certain quality of reporting; however, they set a high bar and as a consequence can be exhaustive and broad, thus limiting uptake.To help address this lack of uptake, we propose a reporting supplement\u2014Minimum Information About a Mass Spectrometry Imaging Experiment (MIAMSIE)\u2014and its abbreviated reporting standard version, MSIcheck. MIAMSIE is intended to improve author-driven reporting. It is intentionally not exhaustive, but is rather designed for extensibility and could therefore eventually become analogous to existing standards that aim to guarantee reporting quality. Conversely, its abbreviated form MSIcheck is intended as a diagnostic tool focused on key aspects in MSI reporting.We discuss how existing standards influenced MIAMSIE/MSIcheck and how these new approaches could positively impact reporting quality, followed by test implementation of both standards to demonstrate their use. For MIAMSIE, we report on author reviews of four articles and a dataset. For MSIcheck, we show a snapshot review of a one-month subset of the MSI literature that indicated issues with data provision and the reporting of both data analysis steps and calibration settings for MS systems. Although our contribution is MSI specific, we believe the underlying approach could be considered as a general strategy for improving scientific reporting. N-glycans  : \u201c2017/6/1\u201d[Date\u2014Publication])) AND maldi AND imaging\u201d on the 3rd of July 2017Additional File S8. R script required for plotting of MSIcheck review resultsDCI: data citation index; DOI: digital object identifier; EMBL: European Molecular Biology Laboratory; FTMS: Fourier Transform Mass Spectrometry; GUI: graphical user interface; LDI: laser desorption/ionization; MALDI: matrix-assisted laser desorption/ionization; MIAMSIE: Minimum Information About a Mass Spectrometry Imaging Experiment; MIAPE: Minimum Information About a Proteomics Experiment; MIRAGE: Minimum Information Required for a Glycomics Experiment; MS: mass spectrometry; MSI: mass spectrometry imaging; MSIS: Mass Spectrometry Imaging Society; SIMS: secondary ion mass spectrometry.The authors declare that they have no competing interests.O.J.R.G.'s position was funded by the Australian Research Council (ARC) Centre of Excellence for Convergent Bio-Nano Science & Technology . L.J.W.'s position was funded through Bioplatforms Australia . E.A.B.U. was funded by the ARC (DE160101142).Supplemental FileClick here for additional data file."}
+{"text": "Nature Communications8: Article number: 14479; DOI: 10.1038/ncomms14479 (2017); Published: 02152017; Updated: 06252018The original HTML version of this Article omitted the article number; it should have been \u201814479\u2019. This has now been corrected in the HTML version of the Article. The PDF version was correct from the time of publication."}
+{"text": "This article has been corrected: The correct Acknowledgment information is given below:ACKNOWLEDGMENTThis work was funded by National Natural Science Foundation of China grant 81472606, Chinese Ministry of Science and Technology grant (973 grant) 2011CB812401, and the Beijing Municipal Government.https://doi.org/10.18632/oncotarget.6491Original article: Oncotarget. 2016; 7:3367-3378."}
+{"text": "AbstractPolycentropusierapetraslovenica has been considered a narrow range endemic of Slovenia and surrounding areas. Rhyacophilaaurata, a species known from many parts of Europe, according to the current knowledge, is absent from a large part of the Balkan Peninsula.The knowledge about distribution, ecology and species composition of caddisflies of the Balkan Peninsula is still not complete. The ongoing investigations of the last years highlight this area as an important hotspot of caddisfly diversity. Trichoptera from the Republic of Kosovo with exact distribution data, based on sampling carried out randomly during 2014 and 2017. Polycentropusierapetraslovenica was found in several streams in Bjeshk\u00ebt e Nemuna Mountains and Karadak Mountains. Rhyacophilaaurata was found during this investigation at a single locality in Bjeshk\u00ebt e Nemuna Mountains.In this paper, we present records of these two rare taxa of The unexpected finding of these two taxa in Kosovo greatly enlarges their known distribution area and makes a contribution towards the better knowledge of distributional patterns of these rare taxa of caddisflies in this part of Europe. The knowledge about distribution, ecology and species composition of caddisflies in the Balkan Peninsula is still not complete. The recent and ongoing investigations in this area e.g.  make posUntil recently, there were only few registered records of caddisfly species in Kosovo, but the list has significantly increased during the past decade, with several new species being described e.g. . HoweverThe main goal of this study was to contribute to the list of caddisfly taxa in the Republic of Kosovo and improve the knowledge about geographic distribution of rare taxa of caddisflies in the Balkan Peninsula, to assist in proper conservation of freshwater ecosystems.Sampling was carried out occasionally during 2014 and 2017 at six sampling stations, three of them being located in Bjeshk\u00ebt e Nemuna and the other three in Karadak Mountains in the Republic of Kosovo Table  were plaMalicky, 1998F78BD300-7078-52F6-A6D0-77ECB1B42750https://www.gbif.org/species/6262227Type status:Other material. Occurrence: recordedBy: Halil Ibrahimi, Ruzhdi Ku\u00e7i, Astrit Bilalli, Milaim Musliu; individualCount: 5; sex: males; Location: higherGeography: Europe; waterBody: tributary of Lepenc River, Aegean Sea Basi; country: Kosovo; municipality: Hani i Elezit; locality: D\u00ebrmjak; verbatimLocality: streamlet above the village, towards the border with the Republic of North Macedonia; decimalLatitude: 42.17264; decimalLongitude: 21.31582; Event: samplingProtocol: UV light trap; samplingEffort: overnight; year: 2017; month: 6; day: 12; fieldNotes: collected with ultraviolet light over the white pan operating from dusk until the next morning; Record Level: institutionCode: University of Prishtina \"Hasan Prishtina\", Faculty of Mathematics and Natural Sciences, Department of Biology; collectionCode: caddisflies of KaradakType status:Other material. Occurrence: recordedBy: Halil Ibrahimi, Ruzhdi Ku\u00e7i, Astrit Bilalli, Milaim Musliu; individualCount: 5; sex: males; Location: higherGeography: Europe; waterBody: tributary of Morava e Bin\u00e7\u00ebs River, Black Sea basin; country: Kosovo; municipality: Gjilan; locality: Zheg\u00ebr village; verbatimLocality: streamlet above the village; decimalLatitude: 42.31572; decimalLongitude: 21.53148; Event: samplingProtocol: UV light trap; samplingEffort: overnight; year: 2017; month: 7; day: 14; fieldNotes: collected with ultraviolet light over the white pan operating from dusk until the next morning; Record Level: institutionCode: University of Prishtina \"Hasan Prishtina\", Faculty of Mathematics and Natural Sciences, Department of Biology; collectionCode: caddisflies of KaradakType status:Other material. Occurrence: recordedBy: Halil Ibrahimi, Ruzhdi Ku\u00e7i, Astrit Bilalli, Milaim Musliu; individualCount: 5; sex: males; Location: higherGeography: Europe; waterBody: tributary of Morava e Bin\u00e7\u00ebs River, Black Sea Basin; country: Kosovo; municipality: Viti; locality: Letinic\u00eb; verbatimLocality: stream above the village; decimalLatitude: 42.28727; decimalLongitude: 21.45736; Event: samplingProtocol: UV light trap; samplingEffort: overnight; year: 2017; month: 7; day: 20; fieldNotes: collected with ultraviolet light over the white pan operating from dusk until the next morning; Record Level: institutionCode: University of Prishtina \"Hasan Prishtina\", Faculty of Mathematics and Natural Sciences, Department of Biology; collectionCode: caddisflies of KaradakType status:Other material. Occurrence: recordedBy: Halil Ibrahimi, Arben Gashi, Besnik Em\u00ebrllahu, Naman Sinani; individualCount: 4; sex: males; lifeStage: adult; Location: higherGeography: Europe; waterBody: tributary of Lumbardhi i Pej\u00ebs River, Adriatic Sea basin; country: Kosovo; municipality: Pej\u00eb; locality: Drelaj; verbatimLocality: stream above the village; decimalLatitude: 42.706667; decimalLongitude: 21.18056; Event: samplingProtocol: UV light trap; samplingEffort: overnight; year: 2014; month: 7; day: 14; fieldNotes: collected with ultraviolet light over the white pan operating from dusk until the next morning; Record Level: institutionCode: University of Prishtina \"Hasan Prishtina\", Faculty of Mathematics and Natural Sciences, Department of Biology; collectionCode: caddisflies of Bjeshk\u00ebt e NemunaType status:Other material. Occurrence: recordedBy: Halil Ibrahimi, Arben Gashi, Besnik Em\u00ebrllahu, Naman Sinani; individualCount: 3; sex: males; lifeStage: adult; Location: higherGeography: Europe; waterBody: tributary of Lumbardhi i Pej\u00ebs River, Adriatic Sea basin; country: Kosovo; municipality: Pej\u00eb; locality: Pepaj; verbatimLocality: stream above the village; decimalLatitude: 42.700278; decimalLongitude: 20.143889; Event: samplingProtocol: UV light trap; samplingEffort: overnight; year: 2014; month: 9; day: 17; fieldNotes: collected with ultraviolet light over the white pan operating from dusk until the next morning; Record Level: institutionCode: University of Prishtina \"Hasan Prishtina\", Faculty of Mathematics and Natural Sciences, Department of Biology; collectionCode: caddisflies of Bjeshk\u00ebt e NemunaSlovenia, Italy, Bosnia and Herzegovina and Kosovo .We found that the flight period of this subspecies is from May to September. The subspecies is present at different altitudes, from 620 m up to 1307 m.slovenica subspecies  clearly point to the bspecies .Polycentropusierapetraslovenica in D\u00ebrmjak on 12.06.2017 are: Rhyacophilafasciata Hagen, 1859 , Rhyacophilaloxias Schmid, 1970 , Rhyacophilapolonica McLachlan, 1879 , , Rhyacophilatristis Pictet, 1834 , , Glossosomaconformis Neboiss, 1963 , Synagapetusiridipennis McLachlan, 1879 ; Philopotamusmontanus  , Plectrocnemiaconspersa  , Polycentropusexcicus Klap\u00e1lek 1894 , Polycentropusflavomaculatus  , Psychomyiaklapaleki Malicky, 1995 , Psychomyiapusilla  , Lypereducta  , Tinodesrostocki McLachlan, 1878 , Tinodesunicolor  , Potamophylaxluctuosus  , Silograellsii Pictet, 1865  and Oecismusmonedula  .Other species associated with Polycentropusierapetraslovenica in Zheg\u00ebr on 14.07.2017 are: Rhyacophilafasciata Hagen, 1859 , Rhyacophilatristis Pictet, 1834 , Philopotamusmontanus  , Hydropsychefulvipes Curtis, 1834 ; Hydropsychesaxonica McLachlan, 1884  and Oecismusmonedula  .Other species associated with Polycentropusierapetraslovenica in Letnic\u00eb on 20.07.2017 are: Rhyacophilafasciata Hagen, 1859 , Philopotamusmontanus   and Hydropsycheinstabilis   .Other species associated with Polycentropusierapetraslovenica in Drelaj on 14.07.2014 are: Plectrocnemiamojkovacensis Malicky, 1982 , Limnephilussparsus Curtis, 1834  and Micropternasequax McLachlan, 1875 .Other species associated with Polycentropusierapetraslovenica in Pepa on 17.09.2014 are: Rhyacophilaarmeniaca Guerin-Meneville, 1843 , Rhyacophilapalmeni McLachlan 1879  and Ecclisopteryxkeroveci Previ\u0161i\u0107, Graf & Vitecek .Other species associated with Brauer, 18573377AAF6-494F-57FA-B5C3-6E2762B7B25Fhttps://www.gbif.org/species/1433826Type status:Other material. Occurrence: recordedBy: Halil Ibrahimi, Naman Sinani, Arben Gashi; individualID: 1; sex: male; lifeStage: adult; Location: continent: Europe; waterBody: tributary of Lumbardhi i Pej\u00ebs River, Adriatic Sea basin; country: Kosovo; municipality: Pej\u00eb; locality: Stankaj; verbatimLocality: streamlet below the village; decimalLatitude: 42.700278; decimalLongitude: 20.143889; Event: samplingProtocol: UV light trap; year: 2014; month: 07; day: 20; fieldNotes: collected with entomological net; Record Level: institutionCode: University of Prishtina \"Hasan Prishtina\", Faculty of Mathematics and Natural Sciences, Department of Biology; collectionCode: caddisflies Bjeshk\u00ebt e NemunaAustria, Bosnia and Herzegovina, Czech Republic, Croatia, France, Germany, Italy, Liechtenstein, Poland, Slovakia, Slovenia, Switzerland .Rhyacophilaaurata in Stankaj on 20.07.2014 are: Rhyacophilaloxias Schmid, 970 , Rhyacophilapolonica McLachlan, 1879 , Rhyacophilapalmeni McLachlan, 1879 , Rhyacophilatristis Pictet, 1834 , Rhyacophilamocsaryi Klapalek, 1898 , Philopotamusmontanus   and Micrasemasericeum Klapalek, 1902 .Other species associated with Rhyacophilidae family is reported for the first time and one subspecies of Polycentropodidae is documented for the first time with the exact data from the Republic of Kosovo: Rhyacophilaaurata and Polycentropusierapetraslovenica.One species of the Polycentropusierapetra is endemic to South-eastern Europe and Turkey, with several known subspecies which are narrow endemics of certain areas  and Greece . In Bulgaria, only one subspecies  is known. The only subspecies with wider distribution is Polycentropusierapetraslovenica, which was described from Slovenia but was later found in Italy and Bosnia and Herzegovina as well  greatly enlarges their known distribution area. Previously, they have been reported from only few localities in the Balkans. It is only the second time that Psychomyiaklapaleki and the third time that Plectrocnemiamojkovacensis have been reported from Kosovo. This investigation shows that both mountainous areas where this investigation was conducted harbour a collection of rare caddisfly taxa, many of which are known only from a limited number of localities in the area, based on current knowledge. Further investigations of this area will most certainly increase the number of known species in Kosovo and improve the knowledge about this order of insects in the Balkans.Finding of several other rare species during this investigation (such as:"}
+{"text": "The Funding section is incorrect. The correct Funding section is: The authors would like to acknowledge the financial support of: FINEP (Financiadora de Estudos e Projetos\u2014Project 01.12.0476.01), CNPq  and PRPq-UFMG (Pro-Reitoria de Pesquisa da UFMG). The publisher apologizes for the error."}
+{"text": "This article has been corrected: The correct Due to erroneous figure processing and oversight, unintended mistakes occurred during the assembly of The authors apologize for the oversight. The authors declare that this correction does not affect the description, interpretation, or the original conclusions of the manuscript.https://doi.org/10.18632/oncotarget.4754Original article: Oncotarget. 2015; 6:26841-26860."}
+{"text": "AbstractAvrainvillea was recently discovered off the island of O\u2018ahu in the Main Hawaiian Islands. Specimens were collected from Honolulu Harbor, including its entrance channel, and near Ke\u2018ehi Harbor. These locations are both in M\u0101lama Bay on O\u2018ahu\u2019s south shore in or adjacent to urbanized estuaries, respectively. In situ observations, morphological and molecular assessments were conducted to examine the alga\u2019s habit and distribution, as well as to assess its putative species identification.A second species in the siphonous green algal genus Halophiladecipiens) and algal meadows composed of the green alga Halimedakanaloana and an unidentified Udotea species at the Ke\u2018ehi Harbor site. All analyses supported both populations as representative of the same taxa, reported until further investigation in the broad Pacific as Avrainvilleacf.erecta based on morphological and molecular analyses. This record of a second Avrainvillea species in Hawai'i is of particular concern considering that an alga recognized as A.amadelpha, first observed in 1981 from two locales on O\u2018ahu\u2019s south shore, has become invasive in Hawai\u2018i\u2019s intertidal to mesophotic environments.The alga occurred in sand as single individuals or in clusters of several individuals at both sites, and near or within seagrass beds ( Bryopsidales includes over 500 extant species  C. Agardh in the Mediterranean (Codiumfragilessp.tomentosoides(van Goor) P. C. Silva (=ssp.fragile (Suringar) Hariot) across the globe  A. Gepp & E. S. Gepp. However, A.amadelpha is most likely incorrect  were used to compare the newly recorded Avrainvillea sp. and the previously recorded \u201cA.amadelpha\u201d.Two specimens collected in 2014 BISH768338-9) and six collected in 2017 (BISH768278-83) that included what appeared to be mature and juvenile forms or possibly ecotypes were selected for morphological and molecular characterization  were borrowed from the Natural History Museum of London and included in our molecular assessment . DNA extraction was completed using the OMEGA E.Z.N.A\u00ae Plant DNA Kit . For the two type specimens, the protocol developed by rbcL  and tufA . These gene regions were selected as informative and reliably sequenced regions for siphonous green algae  and reverse (rbcLR) primers developed by 6 generations with chain sampling every 1,000 generations and a burnin value of 25% until congruence was met (standard deviation of split frequencies <0.05). Both RAxML and MrBayes were accessed on the CIPRES Science Gateway  A. Gepp & E.S. Gepp; Location: country: USA; municipality: Honolulu; locality: M\u0101lama Bay, seaward of Ke\u2018ehi Lagoon; minimumDepthInMeters: 25; maximumDepthInMeters: 40; decimalLatitude: 21.29; decimalLongitude: 157.9205; georeferenceProtocol: GPS; Identification: identifiedBy: Rachael M. Wade; dateIdentified: May-2017; identificationReferences: Olsen-Stojkovich 1985; Event: eventDate: Apr-22-2017; Record Level: language: en; basisOfRecord: PreservedSpecimenType status:Other material. Occurrence: catalogNumber: BISH768338-9; recordedBy: Kimberly Peyton, Kevin Foster, Paul Murakawa; individualCount: 2; otherCatalogNumbers: ARS09436-7; associatedSequences: MF969093-6; Taxon: scientificName: Avrainvillea cf. erecta; kingdom: Plantae; phylum: Chlorophyta; class: Ulvophyceae; order: Bryopsidales; family: Dichotomosiphonaceae; genus: Avrainvillea; specificEpithet: erecta; scientificNameAuthorship: (Berkeley) A. Gepp & E.S. Gepp; Location: country: USA; municipality: Honolulu; locality: M\u0101lama Bay, Honolulu Harbor; minimumDepthInMeters: 12; maximumDepthInMeters: 15; decimalLatitude: 21.30; decimalLongitude: 157.8689; georeferenceProtocol: GPS; Identification: identifiedBy: Rachael M. Wade; dateIdentified: Aug-2017; identificationReferences: Olsen-Stojkovich 1985; Event: eventDate: Oct-15-2015; Record Level: language: en; basisOfRecord: PreservedSpecimenType status:Other material. Occurrence: associatedSequences: MH938452; Taxon: scientificName: Avrainvilleaerecta; acceptedNameUsage: Avrainvilleaerecta Gepp & Gepp 1911; originalNameUsage: ChloroplegmapapuanumZanaradini 1878; kingdom: Plantae; phylum: Chlorophyta; class: Ulvophyceae; order: Bryopsidales; family: Dichotomosiphonaceae; genus: Avrainvillea; specificEpithet: erecta; taxonomicStatus: heterotypic synonym; Location: waterBody: Pacific Ocean; country: Indonesia; stateProvince: Papua; Identification: identifiedBy: Zanardini; dateIdentified: 1878; Event: year: 1872; month: May; fieldNotes: Collected by Odoardo Beccari; Record Level: institutionID: BM000561613; basisOfRecord: PreservedSpecimenAvrainvillea sp. was observed at six of 16 survey sites in the Honolulu Harbor entrance channel from 12-15m depths  in areas with deep sand , giving some thalli a U-shaped appearance. The holdfasts of larger, more mature individuals protruded from the sediment by approximately 1-5 cm, creating a conical mound at the base of the alga. Individuals were generally clean and not heavily epiphytized. The two morphologies at this location experienced very little water motion due to attenuation of wave motion with depth, and therefore were most likely the result of differences in age. The individuals with spherical assemblages of loose siphons were consistently much smaller in thallus size than the well-formed blade morphology.In 2017, the newly recorded Avrainvilleaerecta (Berkeley) A. Gepp & E.S. Gepp and their further morphological characterization by The specimens were olive-green upon collection and dried to a darker green with fulvous, or tawny, coloration Fig. c, d. Spe2rbcL and tufA, however, molecular characterization of historical material was only successful for rbcL for one of the heterotypic synonym type specimens - Chloroplegmapapuanum BM000561613. The concatenated alignment of the two gene regions yielded a dataset of 1,360 bp. Both the Maximum Likelihood and Bayesian inference phylogenetic reconstructions strongly supported that the newly recorded Avrainvillea species, A.cf.erecta, was clearly distinct from Hawai\u2018i specimens identified as \u201cA.amadelpha\u201d (obscura\u201d group while \u201cA.amadelpha\u201d clusters within the \u201clongicaulis\u201d group (A.cf.erecta (Berkeley) A. Gepp & E. S. Gepp from Japan and Micronesia. Although they exhibited two different morphs (loose siphons or blade), all specimens from the two Hawai\u2018i populations had identical DNA sequences.The majority of examined specimens were sequenced for both adelpha\u201d ; these ns\u201d group  Fig. 3)rbcL and Avrainvillea species showed most affinities to the description of A.erecta based on stipe length, blade habit, siphon width and morphology (constriction at dichotomy); however considering that we could not obtain material from type locality or the basionym type specimen (Dichonemaerectum Berkeley 1842), we temporarily consider the newly recorded species as A.cf.erecta until further research can be conducted  J.Agardh, in part due to the description of the species\u2019 ecomorphs that resemble both morphologies described here . However, during the past two years, H.kanaloana has begun to appear, and in many places, is now one of the dominant species. Similarly, Udotea sp. was only observed for the first time in the area earlier in 2017. Based on these observations, this habitat may be undergoing significant shifts in species composition, in which A.cf.erecta is playing a part .The site examined near Ke\u2018ehi Lagoon has historically been dominated by A.erecta  encompasses the East coast of Africa and the Red Sea to as far as the western Pacific in the waters of New Zealand and several Pacific Islands . Bolded character text represent character congruence with the newly discovered species from Hawai\u2018i.File: oo_233632.xlsxWade R"}
+{"text": "This article has been corrected: The correct Acknowledgment information is given below:ACKNOWLEDGMENTSThis work was funded by National Natural Science Foundation of China grant 81472606, Chinese Ministry of Science and Technology grant (973 grant) 2011CB812401, and the Beijing Municipal Government.https://doi.org/10.18632/oncotarget.5221Original article: Oncotarget. 2015; 6:31628-31639."}
+{"text": "Following publication of the original article , the autIncorrect tagging:Bart Staal JCorrect tagging:Staal JB"}
+{"text": "Nature Communications8: Article number: 15405; DOI: 10.1038/ncomms15405 (2017); Published online 05222017; Updated 05252018The originally published version of this Article contained errors in Figure 4. In panels c and d, the labeling of the light and dark blue lines was inverted. These errors have now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "OBJECTIVES/SPECIFIC AIMS: Objectives: To determine genes that are shared between human and obese Zucker rat hypertrophic hearts, in order to identify potential early biomarkers and drug target for heart failure. METHODS/STUDY POPULATION: Four age-paired lean and obese Zucker rats were used. The human data are derived from doi:10.1152/physiolgenomics.00122.2016. RESULTS/ANTICIPATED RESULTS: We expect to find genes that are upregulated and downregulated in Zucker rats and humans that present cardiac hypertrophy. DISCUSSION/SIGNIFICANCE OF IMPACT: The genes and proteins determined from this study will provide future directions in order to determine whether obese Zucker rats are a valid model organism for the development of cardiac hypertrophy."}
+{"text": "Nature Communications8: Article number: 14389; DOI: 10.1038/ncomms14389; Published: 02242017; Updated: 07132018The original HTML version of this Article had an incorrect article number of \u20180\u2019; it should have been \u201814389\u2019. This has now been corrected in the HTML version of the Article. The PDF version was correct from the time of publication."}
+{"text": "Nature Communications7: Article number: 11414; DOI: 10.1038/ncomms11414 (2016), Published 04252016; Updated 11232018In the original version of this Article, the accession codes section within the Methods was inadvertently omitted. This section has now been added in both the PDF and HTML versions of the Article."}
+{"text": "Correction to: BMC Public Healthhttp://dx.doi.org/10.1186/s12889-019-7144-zIt was highlighted that the original article  containeThe Publisher apologizes to the authors and readers for the inconvenience caused by the typesetting mistake.Incorrect title:Formative research for the design of a scalable mobile health program water, sanitation, and hygiene: CHoBI7 mobile health program.Correct title:Formative research for the design of a scalable water, sanitation, and hygiene mobile health program: CHoBI7 mobile health program.Incorrect Table Correct Table"}
+{"text": "Nature Communications8: Article number: 16081; DOI: 10.1038/ncomms16081 (2017); Published: 07172017, Updated: 07132018The original version of this Article omitted the following from the Acknowledgements:A. baumannii targets, based on whole genome sequencing and annotation of BM4454 strain; and Stephanie Van Horn, Allan Kwan, Elizabeth Valoret for A. baumannii genome sequencing and annotation.\u2019\u2018We thank Robert Kirkpatrick for implementing the high throughput protein design strategy that enabled screening and triage of essential Also, the original version omitted an acknowledgement to Prof. Lydia Tabernero as one of our collaborators for supplying the purified proteins used in the Tuberculosis screen.This has been corrected in both the PDF and HTML versions of the Article."}
+{"text": "J Clin Exp Dent2018;3:252-263 1 Mar), there is an error in the authors of the manuscript. The correct author list is: Ioannis Kioleoglou, Argirios Pissiotis, Konstantinos Michalakis.In this article by Kioleoglou and colleagues ("}
+{"text": "Nature Communications8: Article number: 15544; DOI: 10.1038/ncomms15544 (2017); Published: 05182017, Updated: 07132018In the originally published version of this Article, financial support was not fully acknowledged. The PDF and HTML versions of the Article have now been corrected to include support from the National Natural Science Foundation of China grant number 81573325."}
+{"text": "The first sentence of the second paragraph of the Introduction should read: Australia has had seven highly pathogenic avian influenza (HPAI) outbreaks on chicken farms during the last 42 years (1976\u20132018), two of which have occurred in the last 10 years.Reference 20 should read: Office of Chief Veterinary Officer (AU). National Avian Influenza Surveillance Dossier. Canberra: Australian Government Department of Agriculture, Fisheries and Forestry; 2010. 165 p. [The last sentence of the fifth paragraph of the Introduction should read: Six of the seven outbreaks occurred in poultry low density regions (as outlined in farm density maps [26]) and the potential for spread of HPAI between farms in higher density regions is also not known [26].A reference is omitted from the last sentence of the second paragraph of the Discussion section, included to account for the 2012 and 2013 outbreaks.The sentence should read: In the seven HPAI out-breaks reported in poultry in Australia, introduction of LPAI viruses from wild birds and subsequent mutation has been hypothesized as the most likely origin of these outbreaks .The reference is: Brown I, Abolnik C, Garcia-Garcia J, McCullough S, Swayne DE, Cattoli G. High\u2010pathogenicity avian influenza outbreaks since 2008, excluding multi\u2010continental panzootic of H5 Goose/Guangdong\u2010lineage viruses. In: Swayne DE, editor. Animal Influenza 2nd ed. New York City: USA: Wiley; 2016. pp. 248\u2013270."}
+{"text": "Nature Communications8: Article number: 14278; DOI: 10.1038/ncomms14278 (2017); Published 02152017, Updated 07182018The original HTML version of this Article omitted the article number; it should have been \u201814278\u2019. This has now been corrected in the HTML version of the Article. The PDF version was correct from the time of publication."}
+{"text": "Nature Communications8: Article number: 14485; DOI: 10.1038/ncomms14485 (2017); Published: 02152017; Updated: 06252018The original HTML version of this Article omitted the article number; it should have been \u201814485\u2019. This has now been corrected in the HTML version of the Article. The PDF version was correct from the time of publication."}
+{"text": "AbstractVanhorniaeucnemidarum Crawford is the only species of Vanhorniidae that occurs in North America. This species is rarely collected and thus the distribution is not well documented. Intending to uncover a more accurate range of this species, we assembled collection records from museums, personal collections and citizen science projects. Many of these records were non-digitised and had to be personally requested.V.eucnemidarum to include nine new provinces and states: Manitoba, Connecticut, Oregon, Mississippi, Missouri, New Hampshire, New Jersey, Texas and Wisconsin. Although Quebec has been listed as a previous locality, the recorded province was mislabelled, so Quebec is now also officially a provincial record.Here we expand the known distribution of  In spite of the fact that many species on our planet remain undescribed , our in-Vanhorniidae . They can be distinguished from other proctotrupoids using a combination of characters: exodont mandibles  and V.leileri Hedquist, 1976  found in dead maple  between the dates of 7-14 August 2015 in a stand of trees that included maple. Additional collection records were gathered from personal communications with museums (Table Two specimens of ms Table . The majAll locality records have been entered in Darwin Core archive format (Suppl. material All photos in this study were taken using a Canon 7D Mark II with either a Canon MP-E 65 mm F/2.8 Macro photo lens or a Mitutoyo M Plan Apo 10\u00d7 objective mounted on to the Canon EF Telephoto 70-200 mm zoom lens. Multiple images were taken across numerous focal planes and combined using Zerene Stacker 1.04. Images were edited using Adobe Photoshop CC and plates were prepared using Adobe Illustrator CC.Crawford 1909c0ba557b-ca86-5da2-b771-3b049a0609a0http://www.catalogueoflife.org/col/details/species/id/84c6010b1c8cef32c9a7ee8e730446b8Type status:Other material. Occurrence: catalogNumber: JBWM0378038; recordedBy: Amber Bass; sex: female; lifeStage: adult; occurrenceID: UCFC:Veuc:00000265; Taxon: scientificName: Vanhorniaeucnemidarum Crawford 1909; kingdom: Animalia; phylum: Arthropoda; class: Insecta; order: Hymenoptera; family: Vanhorniidae; genus: Vanhornia; taxonRank: species; scientificNameAuthorship: Crawford 1909; Location: continent: North America; country: Canada; countryCode: CA; stateProvince: Manitoba; verbatimLocality: Howden; geodeticDatum: WGS84; Event: samplingProtocol: Malaise Trap; eventDate: 2015-07-14; year: 2015; month: 07; day: 14; Record Level: institutionCode: WRME; basisOfRecord: PreservedSpecimenType status:Other material. Occurrence: catalogNumber: UCFC0528248; recordedBy: Amber Bass; sex: female; lifeStage: adult; occurrenceID: UCFC:Veuc:00000196; Taxon: scientificName: Vanhorniaeucnemidarum Crawford 1909; kingdom: Animalia; phylum: Arthropoda; class: Insecta; order: Hymenoptera; family: Vanhorniidae; genus: Vanhornia; taxonRank: species; scientificNameAuthorship: Crawford 1909; Location: continent: North America; country: Canada; countryCode: CA; stateProvince: Manitoba; verbatimLocality: Howden; geodeticDatum: WGS84; Event: samplingProtocol: Malaise Trap; eventDate: 2015-07-14; year: 2015; month: 07; day: 14; Record Level: institutionCode: UCFC; basisOfRecord: PreservedSpecimenVanhorniaeucnemidarum can be distinguished from other species of Vanhornia by the following combination of characters: Antennal sockets inserted immediately above dorsal margin of clypeus; tegulae black to dark brown but never yellow; and rugulose metasomal striations restricted to the basal third.V.eucnemidarum in the states of Connecticut, Mississippi, Missouri, New Hampshire, New Jersey, Oregon, Texas and Wisconsin in USA and the Canadian province of Manitoba (Fig. V.eucnemidarum (Fig. V.eucnemidarum north to Manitoba, west to Oregon and south to Texas. This vast increase in the known range of V.eucnemidarum may be due to rarity of collection (Our search discovered 278 specimen records and three BugGuide photos. These data represent new records for rum Fig. , illustrrum Fig. D. The nellection , lack ofV.eucnemidarum, presented here, do not include host associations, they do allow for some speculation regarding the only known host, I.ruficornis. Several records of V.eucnemidarum were found to be in a state or province in which the known host I.ruficornis has not yet been recorded (I.ruficornis may be present in these areas but has not yet been collected or V.eucnemidarum may have a wider host breadth than previously thought. If the latter is true, we suspect the host range may include other Isorhipis species.Though the new records of recorded . These iV.eucnemidarum are with maple and beech (Isorhipisruficornis is a generalist on dead and rotting wood and, in addition to maple and beech, this species has been known to associate with eastern hemlock (V.eucnemidarum across a range of possible hosts will provide more information about the host breadth of V.eucnemidarum and may help predict its full range and possible biological control potential.The only known host plant associations of nd beech . Isorhip hemlock  and elm  hemlock . TargeteBiodiversity studies, such as this one, assist in building more complete ranges for species, which are vital for ecological, evolutionary and applied biological research. Researchers often have limited access to these data, with an estimated 10% of specimen data stored in a digital form and even less made available online . Only 22Citizen science records provided another important source of locality data used in this study. Photos, uploaded through citizen science projects and social media websites such as BugGuide, Flickr and iNaturalist, are becoming frequent sources of legitimate taxonomic records . This fuV.eucnemidarum, using a combination of museum, citizen science and digitised records. Given the large increase in range discovered through this study, it is possible that this species is present throughout North America. We hope this paper will aid in recognition of V.eucnemidarum by curators and naturalists, which will further our understanding of this enigmatic family of parasitoid wasps.This study has updated the distribution records of 681c9921-66bc-5f3f-9b21-a6f5ab2021b110.3897/BDJ.7.e37569.suppl1Supplementary material 1Vanhorniaeucnemidarum NA RecordsData type: OccurrencesBrief description: This datasheet provides an accessible way to search collection records gathered during this study.File: oo_312013.xlsxhttps://binary.pensoft.net/file/312013Joshua Hogan"}
+{"text": "Previous computational modeling suggests it is much easier to segment words from child-directed speech (CDS) than adult-directed speech (ADS). However, this conclusion is based on data collected in the laboratory, with CDS from play sessions and ADS between a parent and an experimenter, which may not be representative of ecologically collected CDS and ADS. Fully naturalistic ADS and CDS collected with a nonintrusive recording device as the child went about her day were analyzed with a diverse set of algorithms. The difference between registers was small compared to differences between algorithms; it reduced when corpora were matched, and it even reversed under some conditions. These results highlight the interest of studying learnability using naturalistic corpora and diverse algorithmic definitions. Although children are exposed to both child-directed speech (CDS) and adult-directed speech (ADS), children appear to extract more information from the former than the latter , were independently transcribed by two undergraduate assistants, who resolved any disagreements by discussion. Transcription was done at the lexical level adapting the CHILDES minCHAT guidelines for transcription .We derived several versions of the ADS and CDS subcorpora crossing two factors see , we had Scripts used for corpus preprocessing, phonologization, and segmentation are available Cristia, . During Each algorithm  was run using the WordSeg package ), which is multiplied by 100 and reported as percentages here. Results for all other possible alternative metrics, and further discussion on these methods, are provided in the Supplemental Materials  and recall is .3 (one out of three gold words is correct). The overall F-score ranges from 0 to 1, as it is the harmonic mean of precision Cristia, .phonotactic-gold) sets the diphone probability threshold based on gold word boundaries. The unsupervised version (phonotactic-unsupervised) sets the threshold using utterance boundaries only. The phonotactics were computed on the concatenation of CDS and ADS versions of the corpus. The second algorithm, labeled TP, posits boundaries using transition probabilities between syllables, as proposed in Saffran, Aslin, and Newport (TP-relative). That is, given the syllable sequence WXYZ, a boundary is posited between X and Y if the transition probability between the X-Y is lower than between W-X and Y-Z. The second version uses average transitions over all pairs of syllables in the corpus as the threshold . The other variant, which we call lexical-multigram, is based on a more complicated rule set with hierarchically defined levels that are both smaller and larger than words . The other posits word boundaries at syllable edges (henceforth base-syll). The latter is likely to be effective for English CDS, which has a very high proportion of monosyllabic words  and whether CDS and ADS were matched in length . Positive difference scores, indicative of better CDS than ADS performance, were found in most matching conditions, regardless of whether automatic or human-utterance boundaries were used . HoweverIn short, we observe smaller CDS advantages than those found in previous work. To check whether this was due to algorithms or corpora, we applied our extensive suite of algorithms onto the Bernstein Ratner corpus ; ED from European Research Council (ERC-2011-AdG-295810 BOOTPHON), the Fondation de France, the Ecole de Neurosciences de Paris, the Region Ile de France (DIM cerveau et pens\u00e9e); MS from SSHRC . AC and ED acknowledge the institutional support of Agence Nationale de la Recherche (ANR-17-EURE-0017).AC: Conceptualization: Lead; Data curation: Lead; Formal analysis: Lead; Funding acquisition: Lead; Methodology: Lead; Project administration: Lead; Resources: Lead; Software: Lead; Validation: Lead; Visualization: Lead; Writing \u2013 original draft: Lead; Writing \u2013 review & editing: Lead. ED: Conceptualization: Supporting; Formal analysis: Supporting; Methodology: Supporting; Software: Supporting; Visualization: Supporting; Writing \u2013 review & editing: Supporting. NBR: Conceptualization: Supporting; Resources: Supporting; Writing \u2013 review & editing: Supporting. MS: Conceptualization: Supporting; Methodology: Supporting; Resources: Lead; Validation: Supporting; Visualization: Supporting; Writing \u2013 review & editing: Supporting.1\u2003The LENA Foundation built a hardware and software system to record and automatically analyze day-long child-centered recordings. For more information, see Soderstrom and Wittebolle .2\u2003https://osf.io/rvdbq/.The transcription manual is available from"}
+{"text": "Following publication of the original article , the autIncorrect Title:Associations between post-operative rehabilitation of hip fracture and outcomes: national database analysis (90 characters)Correct Title:Associations between post-operative rehabilitation of hip fracture and outcomes: national database analysis"}
+{"text": "Following publication of the original article , the autOriginally the author name was published as:Naima M. MoustaidThe correct author name is:Naima Moustaid-Moussa"}
+{"text": "Nature Communications8: Article number: 14375; DOI: 10.1038/ncomms14375 (2017); Published online: 02152017, Updated: 06252018The original HTML version of this Article omitted the article number; it should have been \u201814375\u2019. This has now been corrected in the HTML version of the Article. The PDF version was correct from the time of publication."}
+{"text": "Following publication of the original article , the autOn page 10:Equation but should read as:On page 12:The equation reads as:but should read as:The original article has been updated."}
+{"text": "Personality Traits in Fibromyalgia (FM): Does FM Personality Exists? A Systematic Review2018, 14: 223-232Clinical Practice & Epidemiology in Mental Health, CorrectionThe corrections are provided and replaced online which is mentioned as under:Original: The name of coauthor was Ciacchini RebeccaCorrected:The name of coauthor has been revised as Rebecca Ciacchini"}
+{"text": "This article has been corrected: An institutional investigation was conducted at the request of the Oncotarget editorial staff by the Academia Sinica Ethics Committee . The Committee concluded the following: \u201cThe partial duplication of Figure https://doi.org/10.18632/oncotarget.9660Original article: Oncotarget. 2016; 7:43629-43653."}
+{"text": "Scientific Reports6: Article number: 2876710.1038/srep28767; published online: 06302016; updated: 07182018The Corrigendum published 25 April 2017 did not explain that the issue of entanglement swapping had been raised previously by Pathak and Thapliyal"}
+{"text": "Nature Communications8: Article number: 14602; DOI: 10.1038/ncomms14602 (2017); Published: 02272017, Updated: 06252018The original HTML version of this Article had an incorrect article number of \u20180\u2019; it should have been \u201814602\u2019. This has now been corrected in the HTML version of the Article. The PDF version was correct from the time of publication."}
+{"text": "Nature Communications8: Article number: 15587; DOI: 10.1038/ncomms15587 (2017); Published: 05262017, Updated: 07132018In the originally published version of this Article, financial support was not fully acknowledged. The PDF and HTML versions of the Article have now been corrected to include support from the European Union\u2019s Horizon 2020 Framework Programme for Research and Innovation\u2014Grant Agreement No. 720824."}
+{"text": "AbstractPselaphodes Westwood, P.fansipanensis Bekchiev & Yin sp. n., is described from northern Vietnam. The unique modification of the antennomeres 9\u201310 of the male readily separates the new species from all known congeners.A new species of the genus Pselaphodes species from VietnamNew  Pselaphinae (Coleoptera: Staphylinidae) fauna of Vietnam is poorly studied. Until now, 112 species (Pselaphodes (Tyrini) have been described, all from the Oriental region - China, Nepal, India, Sri Lanka, Thailand, the Philippines and East Malaysia  and the National Museum of Natural History (Sofia), giving the opportunity to collect rich zoological material. One of the visited localities was Fansipan Mountain and, especially, the Fansipan Summit. It is the highest  mountain in the Indochinese Peninsula , hence its nickname \"the Roof of Indochina\u201d.Pselaphodes species, which is described below.Included in the material was a new The material was collected in an open habitat with shrubs and grasses Fig.  by soil Specimens were examined by Zeiss Stemi 2000C stereo-microscopes. Male genitalia and other dissected parts were studied using a Zeiss transmitted-light microscope at magnifications up to 500x. Genital segments were dissected and treated with potassium hydroxide (KOH). The dissected parts were mounted in Euparal and pinned with the relevant specimen.The following acronyms are used in the text: BL\u2014length of the body (= HL + PL + EL + AL); HL\u2014length of the head from the anterior clypeal margin to the occipital constriction; HW\u2014width of the head across eyes; PL\u2014 length of the pronotum along the midline; PW\u2014maximum width of the pronotum; EL\u2014length of the elytra along the suture; EW\u2014maximum width of the elytra; AL\u2014length of dorsally visible part of the abdomen along the midline; AW\u2014maximum width of the abdomen; NMNHS \u2013 National Museum of Natural History, Sofia, BulgariaPselaphodesfansipanensis sp. n.\u201d, \u201cR. Bekchiev & Zi-Wei Yin, 2019 \u201c .The type specimen is provided with a red printed label: \u201dHOLOTYPUS\u201d, \u201cBekchiev & Yinsp. n.D09F6ED4-1593-5404-953B-D5FB98029570urn:lsid:zoobank.org:act:EB4A1A24-6782-4926-97E6-08CCFF8B1B79Type status:Holotype. Occurrence: recordedBy: R. Bekchiev, N. Simov, I. Dedov, P. Beron; individualCount: 1; sex: male; lifeStage: adult; Taxon: scientificNameID: Pselaphodesfansipanensis; higherClassification: Coleoptera; Staphylinidae; Pselaphinae; class: Insecta; order: Coleoptera; family: Staphylinidae; genus: Pselaphodes; specificEpithet: fansipanensis; taxonRank: species; Location: locationID: Fansipan peak; higherGeographyID: Lao Cai Province; higherGeography: Vietnam; continent: Asia; verbatimElevation: 2992 m; verbatimLatitude: 22.30560; verbatimLongitude: 103.77625; decimalLatitude: 22.30560; decimalLongitude: 103.77625; Identification: identifiedBy: Rostislav Bekchiev, Zi-Wei Yin; dateIdentified: 2019; Record Level: institutionID: National Museum of Natural History-Sofia; institutionCode: NMNHSMale Fig. . Body reAntennomeres Fig. a 9\u201311 foLength of aedeagus 0.77 mm, median lobe broad and asymmetrical, parameres elongate, endophallus with one elongate sclerite Fig. d, e; theFemale. Unknown.The new species is named after Fansipan Summit, the type locality of the new species.North Vietnam: Lao Cai Province.The new species can be readily separated from all other members of the genus by the unique modification of the antennomeres 9\u201310 and the short, triangular metaventral processes of the male, as well as the shape of the aedeagus."}
+{"text": "Nature Communications6: Article number: 6262; DOI: 10.1038/ncomms7262 (2015); Published: 02092015, Updated: 06252018John S. Church, who provided access to the FLIR E60 infrared camera and provided guidance in its use, was inadvertently omitted from the author list in the originally published version of this Article. This has now been corrected in both the PDF and HTML versions of the Article."}
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+{"text": "Scientific Reports 10.1038/s41598-020-60928-0, published online 04 March 2020Correction to: This Article contains a typographical error in the Acknowledgements section.\u201cThis work was supported under the Science for Clear Energy (S4CE) project\u201dshould read:\u201cThis work was supported under the Science for Clean Energy (S4CE) project\u201d"}
+{"text": "Scientific Reports 10.1038/s41598-019-47814-0, published online 06 August 2019Correction to: This Article contains an error in Figure 2A, where there was an image processing error.https://www.rndsystems.com/products/human-ldlr-antibody_af2148#product-details). Therefore, the text in the Results, under the subheading \u201cHuman LDLR is proteolytically cleaved in its extracellular ligand binding domain\u201d,The product datasheet for antibody AF2148 has been updated, and the target region of this antibody has been specified as Asp193-Arg788  raised against the entire ectodomain of LDLR\u2026\u201dshould read:\u201c\u2026 antibody AF2148 (R&D Systems) raised against amino acids 193-788 of LDLR\u2026\u201dThe correct Figure 2A appears below as Figure"}
+{"text": "In the article titled \u201cThe Effectiveness, Tolerability, and Safety of Different 1-Day Bowel Preparation Regimens for Pediatric Colonoscopy\u201d ["}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-020-72409-5, published online 21 September 2020Correction to: This Article contains an error in Figure\u00a03, where the last image in panel (a) is incorrectly labelled \u2018Uninfected ECD\u2019. The correct Figure\u00a03 appears below as Figure"}
+{"text": "ScientificReports10.1038/s41598-017-09785-y, published online 30 August 2017Correction to: This Article contains typographical errors in Table6.The reference sequences of ACTA2 and MYH11, \u2018NM_001141945\u2019and \u2018NM_001040114\u2019 were incorrectly given as \u2018NM_001613\u2019 and\u2018NM_002474\u2019, respectively."}
+{"text": "A metabolic hallmark of many cancers is the increase in glucose consumption coupled to excessive lactate production. Mindful that L-lactate originates only from pyruvate, the question arises as to how can this be sustained in those tissues where pyruvate kinase activity is reduced due to dimerization of PKM2 isoform or inhibited by oxidative/nitrosative stress, posttranslational modifications or mutations, all widely reported findings in the very same cells. Hereby 17 pathways connecting glucose to lactate bypassing pyruvate kinase are reviewed, some of which transit through the mitochondrial matrix. An additional 69 converging pathways leading to pyruvate and lactate, but not commencing from glucose, are also examined. The minor production of pyruvate and lactate by glutaminolysis is scrutinized separately. The present review aims to highlight the ways through which L-lactate can still be produced from pyruvate using carbon atoms originating from glucose or other substrates in cells with kinetically impaired pyruvate kinase and underscore the importance of mitochondria in cancer metabolism irrespective of oxidative phosphorylation. In huma(2) Glc \u2192\u2192\u2192 methylglyoxal \u2192\u2192\u2192 pyruvate: This may occur through four different routes involving aldehyde dehydrogenase 9, zinc binding alcohol dehydrogenase domain containing two [more recently renamed to prostaglandin reductase 3 ] and at (3) Glc \u2192\u2192\u2192 PEP \u2192 pyruvate: the terminal reaction is catalyzed by tartrate-resistant acid phosphatases (TRAP), the molecular identity of which remained unknown well after their biochemical characterization ; they ar(4) Glc \u2192\u2192\u2192 PEP; PEP + GalNAc \u2192 GalNAc-1P + pyruvate: Terminal reaction catalyzed by N-acetylgalactosamine kinase isoforms 1 or 2 . These e(5) Glc \u2192\u2192\u2192 3-PG \u2192 2-PG (by phosphoglucomutase 1 or 2) \u2192 glycerate [probably through 2-phosphoglyceric acid phosphatase ] \u2192 3-OH-(6) Glc \u2192\u2192\u2192 3-PG \u2192 phosphohydroxypyruvate (Php), catalyzed by phosphoglycerate dehydrogenase; Php + Ala \u2192 phosphoserine (Pser) + pyruvate, catalyzed by phosphoserine aminotransferase (PSAT) : PSAT ov(7) Glc \u2192\u2192\u2192 3-PG \u2192Php ; Php + Ala (or Glu) \u2192 Pser + pyruvate (or \u2192Kg); the latter reaction is catalyzed by phosphoserine aminotransferase; Pser \u2192 Ser \u2192 pyruvate, catalyzed by serine dehydratase  or serin(8) Glc \u2192\u2192\u2192 Glyoxal \u2192\u2192\u2192 glyoxylate ; glyoxyl(9) Glc \u2192\u2192\u2192 3-PG \u2192Php ; Php + Glu \u2192 Pser + \u2192Kg; latter reaction catalyzed by phosphoserine aminotransferase; \u2192Kg + Ala \u2192 Glu + pyruvate, catalyzed by alanine aminotransferase .in vivo  glyoxylate entry into the mitochondria, (2) reversibility of the matrix phosphoenolpyruvate carboxykinase (PCK2), and (3) reversibility of the mitochondrial pyruvate carrier (MPC). Regarding glyoxylate, I was unable to find information on its transport across the inner mitochondrial membrane; however, it is known that it can be processed by the matrix-localized AGXT2 . PCK2 exin vivo . Regardiin vivo , pigeon in vivo , guinea in vivo , rabbit in vivo , chickenin vivo , and bulin vivo . Howeverin vivo , demonst in vivo ; relevan in vivo ; further in vivo ; indeed  in vivo ; however in vivo . Mindful(10) Glc \u2192\u2192\u2192 glyoxal \u2192\u2192\u2192 glyoxylate: Glyoxylate enters the mitochondria; glyoxylate + Ala \u2192 Gly + pyruvate through AGXT2. Pyruvate may exit the mitochondria through the MPC .via mitochondrial PEPCK evoking PEP transport across the inner mitochondrial membrane has also been demonstrated by the group of Kibbey ((11) Glc \u2192\u2192\u2192 PEP which enters the mitochondria; PEP transport across the inner membrane of mammalian mitochondria has been demonstrated to occur by the tricarboxylate carrier by f Kibbey ; PEP \u2192 O(12) Glc \u2192\u2192\u2192 PEP; PEP enters the mitochondria through the means outlined in pathway 11. PEP \u2192 OAA by PCK2; OAA \u2192 pyruvate by FAHD1 , 2015. FME2 knockdown suppresses tumor growth in lung cancer  Glc \u2192\u2192\u2192 PEP; PEP enters the mitochondria through the means outlined in pathway 11; PEP \u2192 OAA by PCK2; OAA \u2192 Mal by MDH2; Mal \u2192 pyruvate by ME2,3 . Pyruvatg cancer , while Mc cancer .ME1 knockdown inhibits the growth of colon cancer cells ((14) Glc \u2192\u2192\u2192 PEP; PEP enters the mitochondria through the means outlined in pathway 11; PEP \u2192 OAA by PCK2; OAA \u2192 Mal by MDH2; Mal exits the mitochondria; Mal \u2192 pyruvate by ME1 . ME1 knoer cells , and itser cells . In the er cells .(15) Glc \u2192\u2192\u2192 PEP; PEP enters the mitochondria through the means outlined in pathway 11; PEP \u2192 OAA by PCK2; OAA + acetyl-CoA \u2192 citrate by CS; citrate exits the mitochondria through the dicarboxylate carrier; citrate + ATP + CoASH \u2192 acetyl-coA + ADP + Pi + OAA by ACLY ; OAA \u2192 M(16) Glc \u2192\u2192\u2192 PEP; PEP enters the mitochondria through the means outlined in pathway 11; PEP \u2192 OAA by PCK2; OAA + Glu \u2192\u2192Kg + Asp by GOT2; Asp exits the mitochondria; Asp + \u2192Kg \u2192 Glu + OAA by GOT1; OAA \u2192 Mal by MDH1; Mal \u2192 pyruvate by ME1 .CLYBL was reported to be overexpressed in 465 out of 38,258 tumor samples in the COSMIC database8.(17) Glc \u2192\u2192\u2192 PEP; PEP enters the mitochondria through the means outlined in pathway 11; PEP \u2192 OAA by PCK2; OAA + acetyl-CoA \u2192 citrate by CS; citrate \u2192 cis-aconitate, intermediate of ACO2 reaction; cis-aconitate \u2192 itaconate by cADC; itaconate + CoASH + ATP (or GTP) \u2192 itaconyl-CoA + Pi + ADP (or GDP) by SUCL ; itaconyThese pathways are shown in (18) Ser \u2192 pyruvate, catalyzed by SDS or SDSL .(19) Ser \u2192\u2192\u2192 PEP; PEP \u2192 pyruvate; terminal reaction catalyzed by tartrate-resistant acid phosphatase .(20) Ser \u2192\u2192\u2192 PEP; PEP + GalNAc \u2192 GalNAc-1P + pyruvate. The terminal reaction is catalyzed by N-acetylgalactosamine kinase isoforms 1 or 2 .(21) Ala \u2192 pyruvate, catalyzed by L-amino-acid oxidases (LAAO) : SeveralMYC-dependent manner ((22) Ala + 2-oxoglrm \u2192 Gln + pyruvate, catalyzed by glutamine-pyruvate transaminase (GPAT) . GPAT ist manner .(23) Ala + 2-Oml \u2192 Aml + pyruvate, catalyzed by alanine-ketomalonate transaminase (ALXT) . I was uMYC-dependent manner ((24) Ala + \u03b1Kg \u2192 Glu + pyruvate, catalyzed by GPT: GPT\u2014similar to GPAT\u2014is upregulated in many cancers in a t manner .(25) Ala + OAA \u2192 Asp + pyruvate; enzyme unknown .(26) Ala + Glyoxylate \u2192 Gly + pyruvate, catalyzed by alanine-glyoxylate aminotransferase .(27) Ala + 3-OH-pyr \u2192 Ser + pyruvate, catalyzed by alanine-glyoxylate aminotransferase .(28) Thr \u2192 Gly + acetaldehyde, catalyzed by SHMT1 ; Gly + 5(29) Asp + \u03b1Kg \u2192 Glu + OAA, catalyzed by GOT1; OAA \u2192 Mal by MDH1; Mal \u2192 pyruvate by ME1 .(30) 4-OH-proline \u2192\u2192\u2192 pyruvate, through glyoxylate formation (see pathway no. 26).(31) Cys \u2192\u2192\u2192 pyruvate through the sulfinate pathway , 2020. N(32) Cys \u2192 3-sulfino-L-alanine catalyzed by aspartate 4-decarboxylase ; 3-sulfi2S + pyruvate through the 3-mercaptopyruvate pathway ((33) Cys \u2192\u2192\u2192 H pathway . Cys can2S by 3-mercaptopyruvate sulfurtransferase (3MST) ((34) L-cysteine is isomerized to D-cysteine by cysteine racemase (2-amino-3-mercaptopropionic acid racemase) ; D-Cys ie (3MST)  or thiose (3MST) . The pose (3MST)  in mamma3 and pyruvate through SDS, SDSL, or SRR  Ser \u2192 dehydroalanine (2-aminoacrylate) by serine dehydratase (SDS), serine dehydratase-like protein (SDSL), or serine racemase (SRR): Dehydroalanine can further hydrolyze to NH, or SRR ; sometimeaminase . Dehydroeaminase . The cru3, and pyruvate by selenocysteine lyase ((36) Se-methyl-L-selenocysteine  can be deaminated to methaneselenol, NHne lyase . SeMSC cne lyase . SeMSC wne lyase  and evenne lyase .(37) Val \u2192\u2192\u2192 2-methyl-3-oxopropanoate; 2-methyl-3-oxopropanoate can get transaminated with alanine by AGXT2 to D-3-amino-isobutanoate + pyruvate . The ove(38) Leu \u2192\u2192\u2192 3-methylbutanoyl-CoA; the latter compound is converted to isobutyryl-CoA through branched-chain fatty acid metabolism (many steps); isobutyryl-CoA \u2192\u2192\u2192 2-methyl-3-oxopropanoate; 2-methyl-3-oxopropanoate can get transaminated with alanine by AGXT2 to D-3-amino-isobutanoate + pyruvate . Because(39) Ile \u2192\u2192\u2192 2-methylbutanoyl-CoA; the latter compound is converted to isobutyryl-CoA through branched-chain fatty acid metabolism (many steps); isobutyryl-CoA \u2192\u2192\u2192 2-methyl-3-oxopropanoate; 2-methyl-3-oxopropanoate can get transaminated with alanine by AGXT2 to D-3-amino-isobutanoate + pyruvate . Because2 \u2192 CO2 + succinate + trans-4-hydroxy-L-proline, catalyzed by prolyl 4-hydroxylase subunit alpha ; trans-4-hydroxy-L-proline is then converted to L-1-pyrroline-3-hydroxy-5-carboxylate, also yielding NAD(P)H, by either pyrroline-5-carboxylate reductase  or left\u2013right determination factor 1 (LEFTY1), a member of the TGF-\u2192 family of proteins; L-1-pyrroline-3-hydroxy-5-carboxylate can be converted to L-erythro-4-hydroxyglutamate, also yielding NAD(P)H, by aldehyde dehydrogenase 4 family member A1; in turn, L-erythro-4-hydroxyglutamate is transaminated with either OAA by GOT2, yielding 4-hydroxy-2-oxoglutarate + aspartate, or \u2192Kg by GOT1 or GOT2, yielding 4-hydroxy-2-oxoglutarate + glutamate; finally, 4-hydroxy-2-oxoglutarate is converted to glyoxylate and pyruvate by 4-hydroxy-2-oxoglutarate glyoxylate-lyase. It is relevant that increased proline catabolism has been recently reported to support metastasis ((40) Pro + \u03b1Kg + Otastasis . Arg, thThese pathways are shown in (41) Thr \u2192\u2192\u2192 acetyl-CoA; acetyl-CoA + OAA \u2192 citrate, catalyzed by CS; citrate exits the mitochondria through the dicarboxylate carrier; citrate + ATP + CoASH \u2192 Acetyl-coA + ADP + Pi + OAA by ACLY ; OAA \u2192 M(42) Thr \u2192\u2192\u2192 acetyl-CoA; acetyl-CoA + OAA \u2192 citrate, catalyzed by CS; citrate \u2192 cis-aconitate, intermediate of ACO2 reaction; cis-aconitate \u2192 itaconate by cADC; itaconate + CoASH + ATP (or GTP) \u2192 itaconyl-CoA + Pi + ADP (or GDP) by SUCL; itaconyl-CoA \u2192 citramalyl-CoA by MGTK; citramalyl-coA \u2192 acetyl-CoA + pyruvate by CLYBL. Pyruvate may exit the mitochondria through the MPC .(43) Asn \u2192\u2192\u2192 Asp; Asp + \u03b1Kg \u2192 Glu + OAA by GOT2; OAA by PCK2; OAA \u2192 pyruvate by reverse operation of PC. However, this is expected to be a path of a very minor flux. Pyruvate may exit the mitochondria through the MPC. The crucial role of asparagine availability in cancer is explored in (44) Asn \u2192\u2192\u2192 Asp; Asp + \u03b1Kg \u2192 Glu + OAA by GOT2; OAA \u2192 pyruvate by acylpyruvase (FAHD1). Pyruvate may exit the mitochondria through the MPC .(45) Asn \u2192\u2192\u2192 Asp; Asp + \u03b1Kg \u2192 Glu + OAA by GOT2; OAA \u2192 Mal by MDH2; Mal \u2192 pyruvate by ME2,3. Pyruvate may exit the mitochondria through the MPC .(46) Asn \u2192\u2192\u2192 Asp; Asp + \u03b1Kg \u2192 Glu + OAA by GOT2; OAA \u2192 Mal by MDH2; Mal exits the mitochondria; Mal \u2192 pyruvate by ME1 .(47) Tyr, Phe \u2192\u2192\u2192 Fum; Fum \u2192 Mal by FH; Mal \u2192 pyruvate by ME2,3 .(48) Tyr, Phe \u2192\u2192\u2192 Fum; Fum \u2192 Mal by FH; Mal exits the mitochondria; Mal \u2192 pyruvate by ME1 .(49) Tyr, Phe \u2192\u2192\u2192 Fum; Fum \u2192 Mal by FH; Mal \u2192 OAA by MDH2; OAA \u2192 pyruvate by acylpyruvase (FAHD1). Pyruvate may exit the mitochondria through the MPC .(50) Thr \u2192\u2192\u2192 acetyl-CoA; acetyl-CoA + OAA \u2192 citrate, catalyzed by CS; citrate exits the mitochondria through the dicarboxylate carrier; citrate + ATP + CoASH \u2192 acetyl-coA + ADP + Pi + OAA by ACLY; OAA \u2192 PEP by PCK1; PEP enters the mitochondria; PEP \u2192 OAA by PCK2; OAA \u2192 pyruvate by acylpyruvase (FAHD1). Pyruvate may exit the mitochondria through the MPC .(51) Thr \u2192\u2192\u2192 acetyl-CoA; acetyl-CoA + OAA \u2192 citrate, catalyzed by CS; citrate exits the mitochondria through the dicarboxylate carrier; citrate + ATP + CoASH \u2192 acetyl-coA + ADP + Pi + OAA by ACLY; OAA \u2192 PEP by PCK1; PEP enters mitochondria; PEP \u2192 OAA by PCK2; OAA \u2192 Mal by MDH2; Mal \u2192 pyruvate by ME2,3. Pyruvate may exit the mitochondria through the MPC .(52) Thr \u2192\u2192\u2192 acetyl-CoA; acetyl-CoA + OAA \u2192 citrate, catalyzed by CS; citrate exits the mitochondria through the dicarboxylate carrier; citrate + ATP + CoASH \u2192 acetyl-CoA + ADP + Pi + OAA by ACLY; OAA \u2192 PEP by PCK1; PEP enters the mitochondria; PEP \u2192 OAA by PCK2; OAA \u2192 Mal by MDH2; Mal exits the mitochondria; Mal \u2192 pyruvate by ME1 .(53) Thr \u2192\u2192\u2192 acetyl-CoA; acetyl-CoA + OAA \u2192 citrate, catalyzed by CS; citrate exits the mitochondria through the dicarboxylate carrier; citrate + ATP + CoASH \u2192 Acetyl-coA + ADP + Pi + OAA by ACLY; OAA \u2192 PEP by PCK1; PEP + GalNAc \u2192 GalNAc-1P + pyruvate. Terminal reaction catalyzed by N-acetylgalactosamine kinase isoforms 1 or 2 .(54) Thr \u2192\u2192\u2192 acetyl-CoA; acetyl-CoA + OAA \u2192 citrate, catalyzed by CS; citrate exits the mitochondria through the dicarboxylate carrier; citrate + ATP + CoASH \u2192 acetyl-coA + ADP + Pi + OAA by ACLY; OAA \u2192 PEP by PCK1; PEP \u2192 pyruvate; the terminal reaction is catalyzed by tartrate-resistant acid phosphatases .In the literature, some reactions have been described to produce pyruvate but are incompletely characterized. These are collectively listed below:2O \u2192 pyruvate + 2 NH3, catalyzed by carbamoyl-serine ammonia lyase ((55) O-carbamoyl-L-serine + Hia lyase . O-Carbaia lyase ; mindful2O \u2192 a thiol + NH3 + pyruvate, catalyzed by cysteine S-conjugate \u2192-lyases ((56) L-Cysteine-S-conjugate + H\u2192-lyases . The pos2O \u2192 L-homocysteine + pyruvate + NH3 or cysteine + H2O \u2192 sulfide + NH3 + pyruvate or cystine \u2192 thiocysteine + pyruvate + NH3, all catalyzed by cystathionine gamma-lyase ((57) cystathionine + Hma-lyase . Cystathma-lyase . In the ma-lyase .2O \u2192 pyruvate + NH3 + sulfate catalyzed by serine-sulfate ammonia-lyase ((58) L-Serine O-sulfate + Hia-lyase . I was u(59) N-Acetylneuraminate \u2192 N-acetyl-D-mannosamine + pyruvate catalyzed by N-acetylneuraminate lyase ; relevan2O + O2 \u2192 pyruvate + NH3 + H2O2 catalyzed by DAAO ((60) D-Alanine + H by DAAO . The int3 catalyzed by glutamate dehydrogenase; this reaction exhibits a weak activity ((61) L-Alanine \u2192 pyruvate + NHactivity . The rol(62) 2-Oxosuccinamic acid + Ala \u2192 Asn + pyruvate, catalyzed by asparagine aminotransferase . The ori(63) Pyruvate oxime + acetone \u2192 pyruvate + acetone oxime, catalyzed by oximinotransferase . Due to (64) Methylmalonyl-CoA + pyruvate \u2192 propionyl-CoA + oxaloacetate catalyzed by methylmalonyl-CoA carboxytransferase . This re(65) L-Alanine + 3-oxopropanoate \u2192 pyruvate + \u2192-alanine, catalyzed by either \u2192-alanine-pyruvate transaminase  or alani(66) Phenylpyruvate + L-alanine \u2192 L-phenylalanine + pyruvate catalyzed by phenylalanine (histidine) transaminase . Phenylp(67) 2-Oxoisohexanoate + L-alanine \u2192 L-leucine + pyruvate, catalyzed by the mitochondrial branched-chain L-amino acid aminotransferase . The rol2 and pyruvate ((68) PCK1, ME1, and ME2,3 may also convert OAA to COpyruvate  (for con(69) Salsolinol can be converted to salsolinol-1-carboxylate by salsolinol synthetase which can then be catabolized to dopamine and pyruvate (by an unknown enzyme); salsolinol is an endogenous catechol isoquinoline detected in humans derived from dopamine metabolism . SalsoliThese pathways are shown in Lactate\u2014unlike pyruvate\u2014exhibits chirality; thus, it exists in L- or D- configuration. In humans, a putative D-lactate dehydrogenase is known to exist . In meta(70) D-lactate formation by methylglyoxal and intestinal flora   Pyruvate + QHl matrix , 1970. Ml matrix ; thus, i+ + pyruvate, catalyzed by D-lactate dehydrogenase; this reaction is mentioned in several databases, but no reference is given.(72) D- (or L-) Lactate + 2 ferricytochrome \u2192 2 ferrocytochrome C + 2 H+ + pyruvate, catalyzed by cytochrome B5 domain-containing protein 1; this reaction is mentioned in several databases, but no reference is given.(73) D- (or L-) Lactate + 2 ferricytochrome \u2192 2 ferrocytochrome C + 2 H+ + L-lactate, catalyzed by ADH ((74) Pyruvate + NADPH \u2192 NADPd by ADH . The man2O2 \u2192 L-lactate + O2, catalyzed by hydroxyacid oxidases  ((75) Pyruvate + HAO1,2,3) . HoweverAO1,2,3) . HAO2 wa(76) Protein deglycase (E.C. 3.5.1.124) may form D-lactate from proteins . Relevan(77) Methylglyoxal spontaneously forms a hemithioacetal adduct with GSH; subsequently, glyoxalase I  produces S-D-lactoylglutathione from this adduct , and gly+ to oxalate + NADH or \u03b1-ketobutyrate to \u2192-hydroxybutyrate or L-glycerate to hydroxypyruvate  \u2192 pyruvate , several other routes may also contribute   Gln \u2192 Glu \u2192 aKg \u2192 isocitrate \u2192 cis-aconitate \u2192 itaconate by cADC; itaconate + CoASH + ATP (or GTP) \u2192 itaconyl-CoA + Pi + ADP (or GDP) by SUCL ; itacony(80) Gln \u2192 Glu \u2192 aKg \u2192 isocitrate \u2192 cis-aconitate \u2192 citrate, exiting the mitochondria \u2192 citrate + ATP + CoASH \u2192 acetyl-coA + ADP + Pi + OAA by ACLY ; OAA \u2192 M(81) Gln \u2192 Glu \u2192 aKg \u2192 isocitrate \u2192 cis-aconitate \u2192 citrate, exiting the mitochondria \u2192 citrate + ATP + CoASH \u2192 acetyl-coA + ADP + Pi + OAA by ACLY; OAA \u2192 PEP by PCK1; PEP + GalNAc \u2192 GalNAc-1P + pyruvate. The terminal reaction is catalyzed by N-acetylgalactosamine kinase isoforms 1 or 2.(82) Gln \u2192 Glu \u2192 aKg \u2192 isocitrate \u2192 cis-aconitate \u2192 citrate, exiting the mitochondria \u2192 citrate + ATP + CoASH \u2192 acetyl-coA + ADP + Pi + OAA by ACLY; OAA \u2192 PEP by PCK1; PEP \u2192 pyruvate; the terminal reaction is catalyzed by tartrate-resistant acid phosphatases.(83) Gln \u2192 Glu \u2192 aKg \u2192 succinyl-CoA \u2192 succinate \u2192 fumarate \u2192 malate \u2192 pyruvate by ME2,3; pyruvate may exit the mitochondria through the MPC.(84) Gln \u2192 Glu \u2192 aKg; aKg transaminates with Asp forming Glu and OAA, by GOT2; OAA \u2192 pyruvate by FAHD1 , 2015; p(85) Gln \u2192 Glu \u2192 aKg; aKg transaminates with Asp forming Glu and OAA, by GOT2; OAA \u2192 Mal by MDH2; Mal exits the mitochondria; Mal \u2192 pyruvate by ME1 .(86) Gln \u2192 Glu \u2192 aKg; aKg transaminates with Asp forming Glu and OAA, by GOT2; OAA \u2192 Mal by MDH2; malate \u2192 pyruvate by ME2,3; pyruvate may exit the mitochondria through the MPC.+/K+ ATPase), 125 of them occur in the cytosol. Clearly, while it is imperative to prevent phosphofructokinase and hexokinase from ATP-dependent feedback inhibition and allow a high flux of glycolysis for the sake of generating intermediates shuttled toward other pathways, ATP is still needed for many other reactions. Crunching the numbers regarding cytosolic energetics is a daunting task, but what is definite is that a cell with nearly zero ATP production from glycolysis may not harbor ATP-consuming mitochondria, for whatever reason . This can be solved by maintaining the adenine nucleotide translocase in \u201cforward\u201d mode, i.e., providing ATP to the cytosol which is made by SUCL supported by glutaminolysis  highlight that L-lactate can still be produced from pyruvate using carbon atoms originating from glucose or other substrates in cells with kinetically impaired pyruvate kinase and (ii) show that the mitochondria may contribute to cancer metabolism irrespective of oxidative phosphorylation by providing means of contributing to pyruvate production. Having said that, it is important to emphasize that none of the aforementioned reactions take into account the potential regulatory effects of metabolites on other reactions such as those occurring on PK by amino acids . In addiCC wrote and edited the manuscript.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Nature Communications 10.1038/s41467-020-17123-6, published online 3 July 2020.Correction to: W\u201d should be corrected as \u201cl2 regularization of W\u201d; \u201cThe original version of this Article contained a typo in Eq. (1), in which the subscript of"}
+{"text": "Scientific Reports 10.1038/s41598-017-06835-3, published online 25 July 2017Correction to: This Article contains an error in Figure 4a and Figure 4b, where the units for \u2018Evans Blue exudation\u2019 were incorrectly given as \u2018mg/ml\u2019. The correct Figure 4 appears below as Figure"}
+{"text": "In the article titled \u201cMicrowave Tunneling and Robust Information Transfer Based on Parity-Time-Symmetric Absorber-Emitter Pairs\u201d , there w"}
+{"text": "Correction to: CVIR Endovasc (2019) 2:9https://doi.org/10.1186/s42155-019-0052-6\u2018In the published article (Salaskar et al. \u201cIRB approval not needed for this type of submission at our institution.\u201dshould read:\u201cInformed consent for publication of this case report and its accompanying images has been obtained from the patient\u201d"}
+{"text": "Scientific Reports 10.1038/s41598-020-74227-1, published online 14 October 2020Correction to: This Article contains errors.In Table 3, the Manufacturer for \u2018Elutax 3\u2019,\u201cAachen Resonance GmbH\u201dshould read:\u201cAR Baltic Medical UAB\u201d"}
+{"text": "Nature Communications 10.1038/s41467-020-18086-4, published online 26 August 2020.Correction to: The original version of this Article contained an error in Fig. 1j, where the correct Y-axis unit is \u201c\u03bcC\u201d instead of \u201cmC\u201d.This has been corrected in both the PDF and HTML versions of the Article."}
+{"text": "In the article titled \u201cEel's Head Powder Reduces Mild-Moderate Depression in Geriatric Individual: Result from Randomized Controlled Trial Study\u201d , there w"}
+{"text": "Cell Death & DiseaseCorrection to: 10.1038/s41419-019-2196-7 published online 06 January 2020This Article was originally published with the incorrect copyright line \u201cThe Authors\u201d. The correct copyright is \u201cUS Govt\u201d.The PDF and HTML versions of the Article have been modified accordingly."}
+{"text": "Scientific Reports 10.1038/s41598-020-78102-x, published online 03 December 2020Correction to: This Article contains an error. A Data Availability section was originally not included\u2014it should appear as below:"}
+{"text": "Scientific Reports 10.1038/s41598-019-40996-7, published online 14 March 2019Correction to: This Article contains a typographical error in the Methods section under subheading \u2018Nauplii production\u2019 where,\u201cThe content was then filtered (mesh size = 25 m) and fixed in Lugol (4%).\u201dshould read:\u201cThe content was then filtered (mesh size = 25 \u00b5m) and fixed in Lugol (4%).\u201d"}
+{"text": "Nature 10.1038/s41586-020-2561-9 Published online 05 August 2020Correction to: Ne between 500 thousand million years ago and 1 million years ago.\u201d, should have read: \u201ca rapid increase in Ne between 500 thousand years ago and 1\u00a0million years ago.\u201d. The original Article has been corrected online.In this Article, owing to an error during the production process, the text: \u201ca rapid increase in"}
+{"text": "Due to a production error, the funder \u201cPortuguese Foundation for Science and Technology (FCT),\u201d \u201cFCT-NSFC/0002/2016, PTDC/BIAANM/3484/2014, and CCMAR/Multi/04326/2019,\u201d and a PhD fellowship \u201cSFRH/BD/120040/2016\u201d to \u201cCarmen Sousa\u201d was erroneously omitted.The publisher apologizes for this mistake. The original article has been updated."}
+{"text": "The following sentence should read: \u201cUstekinumab exhibits a generally favourable treatment persistency profile in both biologic-na\u00efve and experienced patients, while SEC exhibits favourable persistency in biologic-naive but not in biologic-experienced patients compared with ADA\u201d instead of \u201cUstekinumab exhibits a generally favourable treatment persistency profile in both biologic-na\u00efve and experienced patients, while SEC exhibits favourable persistency in biologic-experienced but not in biologic-na\u00efve patients compared with ADA\u201d.This error has now been corrected online."}
+{"text": "Correction to: Antimicrob Resist Infect Control 9, 128 (2020)https://doi.org/10.1186/s13756-020-00782-xAfter publication of this article , it is r\u2018Torsten Feld\u2019 should be corrected to \u2018Torsten Feldt\u2019. The author name has thus been updated in this Correction.The original article has also been updated."}
+{"text": "In the article titled \u201cCorrigendum to \u201cAssociation between Serum Matrix Metalloproteinase- (MMP-) 3 Levels and Systemic Lupus Erythematosus: A Meta-analysis\u201d\u201d , an acknThe experiments for MMP-3 were supported by a grant from the Korean Society of Pediatric Nephrology."}
+{"text": "Correction to: J Exp Clin Cancer Res (2020) 39:8.https://doi.org/10.1186/s13046-019-1517-02-dependent mechanisms.\u201d, and the caption should refer to 25\u2009years and not 15\u2009years. Figure\u00a0In the original publication of this manuscript , Fig. 1 In addition, the following sentences have been adjusted to remove ambiguity and correct the record:\u2018Background\u2019 section, \u201cHypoxia Inducible Factor-1 (HIF-1), is an \u03b1/\u03b2 heterodimeric transcription factor that controls multiple oxygen-sensitive genes. In 1995 Semenza identified HIF-1\u03b1 as a basic-helix-loop-helix-PAS heterodimer regulated by cellular oxygen tension\u201d has been corrected to \u201cIn 1995, Semenza identified the Hypoxia Inducible Factor-1 (HIF-1) as a basic-helix-loop-helix-PAS \u03b1/\u03b2 heterodimeric transcription factor regulated by cellular oxygen tension.\u201d\u2018Background\u2019 section, \u201c\u2026 as evidenced by the increased number of papers published on this topic in the last 15\u2009years\u201d has been corrected to \u201c\u2026 as evidenced by the increased number of papers published on this topic in the last 25\u2009years.\u201dThe authors sincerely apologize for the inconvenience caused to the readers. The original article has been updated."}
+{"text": "December 2019 Issue, vol.113 (6), page 1138In Short Editrorial \u201cAdmission NT-ProBNP in Myocardial Infarction: an Alert Sign?\u201d, consider Lu\u00eds Beck-da-Silva as the correct form for the name of the author Lu\u00eds Beck da Silva."}
+{"text": "Correction to: BMC Anesthesiol 21, 60 (2021)https://doi.org/10.1186/s12871-021-01280-2non-emergent\u201d was changed to \u201cnon-emergency\u201d and the word \u201cthat\u201d found in 1st sentence of the 5th paragraph under Discussion section was deleted.Following publication of the original article , the autThe correct figures are as follows:The original article has been corrected."}
+{"text": "Scientific Reports 10.1038/s41598-020-68984-2, published online 22 July 2020Correction to: This Article contains an error in Table 1 in the Locus Tag column where,tonB1)\u201d.\u201cSLG_14330 (should read:tonB1)\u201d.\u201cSLG_14430 ("}
+{"text": "Scientific Reports 10.1038/s41598-020-59942-z, published online 20 February 2020Correction to: The Acknowledgements section in this Article was omitted. The Acknowledgements section should read:\u201cWe acknowledge support from the German Research Foundation (DFG) and the Open Access Publication Funds of Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin.\u201d"}
+{"text": "Xrcc4 or Lig4, leads to massive neuronal apoptosis in the central nervous system (CNS) that correlates with embryonic lethality in mice. Inactivation of either Paxx, Mri or Dna-pkcs NHEJ gene results in normal CNS development due to compensatory effects of Xlf. Combined inactivation of Xlf/Paxx, Xlf/Mri and Xlf/Dna-pkcs, however, results in late embryonic lethality and high levels of apoptosis in CNS. To determine the impact of NHEJ factors on the early stages of neurodevelopment, we isolated neural stem and progenitor cells from mouse embryos and investigated proliferation, self-renewal and differentiation capacity of these cells lacking either Xlf, Paxx, Dna-pkcs, Xlf/Paxx or Xlf/Dna-pkcs. We found that XRCC4-like factor (XLF), DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and paralogue of XRCC4 and XLF (PAXX) maintain the neural stem and progenitor cell populations and neurodevelopment in mammals, which is particularly evident in the double knockout models.Non-homologous end-joining (NHEJ) is a major DNA repair pathway in mammalian cells that recognizes, processes and fixes DNA damage throughout the cell cycle and is specifically important for homeostasis of post-mitotic neurons and developing lymphocytes. Neuronal apoptosis increases in the mice lacking NHEJ factors Ku70 and Ku80. Inactivation of other NHEJ genes, either  Double-strand DNA breaks (DSBs) are common DNA damage events that threaten the stability of our genome. DSBs can be repaired by homologous recombination (HR), classical non-homologous end-joining  and alternative end-joining  ,2,3,4. HC-NHEJ involves recognition of the DSBs by Ku70/Ku80 heterodimer (Ku), which in turn recruits DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to form a DNA-PK holoenzyme complex that protects free DNA ends. Assembly of DNA-PK triggers the autophosphorylation of DNA-PKcs, as well as DNA-PKcs-dependent phosphorylation of multiple other DNA repair factors . Ku faciXrcc4 [Lig4 [Ku70\u2212/\u2212 and Ku80\u2212/\u2212 knockout mice are viable, they present high levels of apoptosis in CNS and remarkable growth retardation [Genetic inactivation of Xrcc4  or Lig4 c4 [Lig4  in mice c4 [Lig4 ,10. Althardation ,12.Dna-pkcs\u2212/\u2212 [Xlf\u2212/\u2212 [Paxx\u2212/\u2212 [Mri\u2212/\u2212 [Dna-pkcsKD/KD) leads to Ku- and p53-dependent embryonic lethality, which correlates with high levels of apoptosis in the CNS [Dna-pkcs gene affects post-mitotic neurons. The apoptotic neurons were relatively rare in the proliferating ventricular zone [Dna-pkcs resulted in a neurological phenotype similar to observed earlier for mice lacking XRCC4 or LIG4 [Mice lacking NHEJ factors possess various phenotypes ,2,3,4. I-pkcs\u2212/\u2212 , Xlf\u2212/\u2212  [Xlf\u2212/\u2212 ,15, Paxx[Paxx\u2212/\u2212 ,18,19,20 [Mri\u2212/\u2212  knockout the CNS . Jiang elar zone ,23. Thus or LIG4 ,24, sugg or LIG4 . An impa or LIG4 . While pXlf and Dna-pkcs [Xlf and Paxx [Xlf and Mri [More recently, genetic interaction studies uncovered the importance of the NHEJ factors XLF, DNA-PKcs, PAXX and MRI in the development of immune and nervous systems and mouse development in general. Synthetic lethality was reported between Dna-pkcs ,27,28, tand Paxx ,17,19,20 and Mri . These s and Mri , no simiHere, using single and double knockout mouse models, we found that XLF, DNA-PKcs and PAXX are required to maintain pluripotency of neural stem cells, including aspects of self-renewal, proliferation, and differentiation to neurons and astrocytes.Dna-pkcs+/\u2212 [Xlf+/\u2212 [Paxx+/\u2212 [Dna-pkcs+/\u2212 and Xlf+/\u2212 mice were imported from Professor Frederick Alt lab . Paxx+/\u2212 mice were generated by Oksenych group .All experimental procedures involving mice were performed according to the protocols approved by the Comparative Medicine Core Facility at Norwegian University of Science and Technology . -pkcs+/\u2212 , Xlf+/\u2212  [Xlf+/\u2212 , and Pax[Paxx+/\u2212  mouse mo\u00aeG2 Green Master Mix  or Taq 2x Master Mix Kit  according to the manufacturer\u2019s instructions. Each reaction contained 50 ng of DNA and 0.8 \u00b5M of indicated primers  was used to determine the mouse genotypes. DNA was isolated from ear punches by incubating overnight at 56 \u00b0C with 2% proteinase K in DNA lysis solution, containing 10 mM pH = 9.0 Tris, 1 M KCl, 0.4% NP-40 and 0.1% Tween 20. Next, the samples were heat-treated for 30 min at 95 \u00b0C. The PCR reactions were performed using GoTaq primers  in a fin2 and 95% humidity. The neurospheres were dissociated every seventh day using 0.25% of trypsin in ethylenediaminetetraacetic acid (EDTA), as previously described in Castaneda-Zegarra et al. (2019) and Wang et al. (2010) [NSPCs were cultured as free-floating aggregates, also known as neurospheres ,30. Brie. (2010) ,30. For 2 and 95% humidity. At day 3, PrestoBlue\u2122 was added to final concentration of 10% in proliferation medium in each well, and the cells were incubated for 2 h at 37 \u00b0C, 5% CO2 and 95% humidity before measuring the fluorescence intensity using FLUOstar Omega system , 570 nm. The fluorescence intensity indicates the proportion of live cells. The NSPC proliferation assay was carried out on 6 replicates per clone, in 3 independent experiments.NSPCs\u2019 proliferation rates were analyzed using PrestoBlue\u2122 Cell Viability Assay  following the manufacturer\u2019s protocol and as described in Xing and Oksenych (2019) . BrieflyFor self-renewal assay, we followed the protocol described earlier . BrieflyDifferentiation was induced in dissociated NSPCs, as described previously ,30. BrieWestern blots were performed using antibodies against XLF, PAXX, DNA-PKcs, and \u03b2-actin  ,30.Xlf, Dna-pkcs or Paxx results in viable fertile mice without detectable phenotypes in the CNS [Xlf and Dna-pkcs [Xlf and Paxx [Xlf\u2212/\u2212, Paxx\u2212/\u2212, Dna-pkcs\u2212/\u2212, Xlf\u2212/\u2212Paxx\u2212/\u2212, and Xlf\u2212/\u2212Dna-pkcs\u2212/\u2212 mouse embryos (E15.5). NSPCs aggregated themselves form neurospheres within 7 days in culture. We used these neurospheres to characterize proliferation, self-renewal, and neural differentiation capacity of the NSPCs , while we recorded Xlf\u2212/\u2212Paxx+/+ (16) and Xlf\u2212/\u2212Paxx+/\u2212 (27) live-born mice (Xlf\u2212/\u2212Paxx\u2212/\u2212 (3), Xlf\u2212/\u2212Paxx+/+ (8) and Xlf\u2212/\u2212Paxx+/\u2212 (31) mice , while there were Xlf\u2212/\u2212Dna-pkcs+/+ (35) and Xlf\u2212/\u2212Dna-pkcs+/\u2212 (54) mice at day P30. However, live-born Xlf\u2212/\u2212Dna-pkcs\u2212/\u2212 mice were detected at days P1\u20132, in line with our previous observations [To obtain eviously , no liveorn mice A. By ana31) mice B, which  earlier . Brieflyrvations ,27,28. WXlf\u2212/\u2212 ; WT vs. Paxx\u2212/\u2212 ; WT vs. Dna-pkcs\u2212/\u2212 ; WT vs. Xlf\u2212/\u2212Paxx\u2212/\u2212 ; WT vs. Xlf\u2212/\u2212Dna-pkcs\u2212/\u2212 ; Xlf\u2212/\u2212 vs. Paxx\u2212/\u2212 ; Xlf\u2212/\u2212 vs. Dna-pkcs\u2212/\u2212 ; Xlf\u2212/\u2212 vs. Xlf\u2212/\u2212Paxx\u2212/\u2212 ; Xlf\u2212/\u2212 vs. Xlf\u2212/\u2212Dna-pkcs\u2212/\u2212 ; Paxx\u2212/\u2212 vs. Dna-pkcs\u2212/\u2212 ; Paxx\u2212/\u2212 vs. Xlf\u2212/\u2212Paxx\u2212/\u2212 ; Paxx\u2212/\u2212 vs. Xlf\u2212/\u2212Dna-pkcs\u2212/\u2212 ; Dna-pkcs\u2212/\u2212 vs. Xlf\u2212/\u2212Paxx\u2212/\u2212 ; Dna-pkcs\u2212/\u2212 vs. Xlf\u2212/\u2212Dna-pkcs\u2212/\u2212 ; Xlf\u2212/\u2212Paxx\u2212/\u2212 vs. Xlf\u2212/\u2212Dna-pkcs\u2212/\u2212 .Detailed statistical analysis for NSPC proliferation, Xlf\u2212/\u2212 ; WT vs. Paxx\u2212/\u2212 ; WT vs. Dna-pkcs\u2212/\u2212 ; WT vs. Xlf\u2212/\u2212Paxx\u2212/\u2212 ; WT vs. Xlf\u2212/\u2212Dna-pkcs\u2212/\u2212 ; Xlf\u2212/\u2212 vs. Paxx\u2212/\u2212 ; Xlf\u2212/\u2212 vs. Dna-pkcs\u2212/\u2212 ; Xlf\u2212/\u2212 vs. Xlf\u2212/\u2212Paxx\u2212/\u2212 ; Xlf\u2212/\u2212 vs. Xlf\u2212/\u2212Dna-pkcs\u2212/\u2212 ; Paxx\u2212/\u2212 vs. Dna-pkcs\u2212/\u2212 ; Paxx\u2212/\u2212 vs. Xlf\u2212/\u2212Paxx\u2212/\u2212 ; Paxx\u2212/\u2212 vs. Xlf\u2212/\u2212Dna-pkcs\u2212/\u2212 ; Dna-pkcs\u2212/\u2212 vs. Xlf\u2212/\u2212Paxx\u2212/\u2212 ; Dna-pkcs\u2212/\u2212 vs. Xlf\u2212/\u2212Dna-pkcs\u2212/\u2212 ; Xlf\u2212/\u2212Paxx\u2212/\u2212 vs. Xlf\u2212/\u2212Dna-pkcs\u2212/\u2212 .Detailed statistical analysis for the relative neurosphere count per well , Xlf\u2212/\u2212 ; WT vs. Paxx\u2212/\u2212 ; WT vs. Dna-pkcs\u2212/\u2212 ; WT vs. Xlf\u2212/\u2212Paxx\u2212/\u2212 ; WT vs. Xlf\u2212/\u2212Dna-pkcs\u2212/\u2212 ; Xlf\u2212/\u2212 vs. Paxx\u2212/\u2212 ; Xlf\u2212/\u2212 vs. Dna-pkcs\u2212/\u2212 ; Xlf\u2212/\u2212 vs. Xlf\u2212/\u2212Paxx\u2212/\u2212 ; Xlf\u2212/\u2212 vs. Xlf\u2212/\u2212Dna-pkcs\u2212/\u2212 ; Paxx\u2212/\u2212 vs. Dna-pkcs\u2212/\u2212 ; Paxx\u2212/\u2212 vs. Xlf\u2212/\u2212Paxx\u2212/\u2212 ; Paxx\u2212/\u2212 vs. Xlf\u2212/\u2212Dna-pkcs\u2212/\u2212 ; Dna-pkcs\u2212/\u2212 vs. Xlf\u2212/\u2212Paxx\u2212/\u2212 ; Dna-pkcs\u2212/\u2212 vs. Xlf\u2212/\u2212Dna-pkcs\u2212/\u2212 ; Xlf\u2212/\u2212Paxx\u2212/\u2212 vs. Xlf\u2212/\u2212Dna-pkcs\u2212/\u2212 .Detailed statistical analysis for the relative size of neurospheres , Xlf\u2212/\u2212Paxx\u2212/\u2212 and Xlf\u2212/\u2212Dna-pkcs\u2212/\u2212 double knockout neurospheres were reduced when compared to WT and single-deficient Xlf\u2212/\u2212, Dna-pkcs\u2212/\u2212 or Paxx\u2212/\u2212 neurospheres  D. Inactikgrounds D. We conXlf, Paxx or Dna-pkcs, and combined inactivation of Xlf/Paxx did not affect early neuronal differentiation based on average proportions of Tuj1-positive cells  were plated on pre-coated 48-well plates and cultured with differentiation medium for 5 days. Neuronal and glial lineages were identified by immunolabeling using markers for early neurons (Tuj1), and astrocytes (GFAP). Inactivation of ve cells A. Combinof NSPCs A,C. The of NSPCs B,D.Xlf\u2212/\u2212 ; WT vs. Paxx\u2212/\u2212 ; WT vs. Dna-pkcs\u2212/\u2212 ; WT vs. Xlf\u2212/\u2212Paxx\u2212/\u2212 ; WT vs. Xlf\u2212/\u2212Dna-pkcs\u2212/\u2212 ; Xlf\u2212/\u2212 vs. Paxx\u2212/\u2212 ; Xlf\u2212/\u2212 vs. Dna-pkcs\u2212/\u2212 ; Xlf\u2212/\u2212 vs. Xlf\u2212/\u2212Paxx\u2212/\u2212 ; Xlf\u2212/\u2212 vs. Xlf\u2212/\u2212Dna-pkcs\u2212/\u2212 ; Paxx\u2212/\u2212 vs. Dna-pkcs\u2212/\u2212 ; Paxx\u2212/\u2212 vs. Xlf\u2212/\u2212Paxx\u2212/\u2212 ; Paxx\u2212/\u2212 vs. Xlf\u2212/\u2212Dna-pkcs\u2212/\u2212 ; Dna-pkcs\u2212/\u2212 vs. Xlf\u2212/\u2212Paxx\u2212/\u2212 ; Dna-pkcs\u2212/\u2212 vs. Xlf\u2212/\u2212Dna-pkcs\u2212/\u2212 ; Xlf\u2212/\u2212Paxx\u2212/\u2212 vs. Xlf\u2212/\u2212Dna-pkcs\u2212/\u2212 .Detailed statistical analysis for the neuron differentiation, Xlf\u2212/\u2212 ; WT vs. Paxx\u2212/\u2212 ; WT vs. Dna-pkcs\u2212/\u2212 ; WT vs. Xlf\u2212/\u2212Paxx\u2212/\u2212 ; WT vs. Xlf\u2212/\u2212Dna-pkcs\u2212/\u2212 ; Xlf\u2212/\u2212 vs. Paxx\u2212/\u2212 ; Xlf\u2212/\u2212 vs. Dna-pkcs\u2212/\u2212 ; Xlf\u2212/\u2212 vs. Xlf\u2212/\u2212Paxx\u2212/\u2212 ; Xlf\u2212/\u2212 vs. Xlf\u2212/\u2212Dna-pkcs\u2212/\u2212 ; Paxx\u2212/\u2212 vs. Dna-pkcs\u2212/\u2212 ; Paxx\u2212/\u2212 vs. Xlf\u2212/\u2212Paxx\u2212/\u2212 ; Paxx\u2212/\u2212 vs. Xlf\u2212/\u2212Dna-pkcs\u2212/\u2212 ; Dna-pkcs\u2212/\u2212 vs. Xlf\u2212/\u2212Paxx\u2212/\u2212 ; Dna-pkcs\u2212/\u2212 vs. Xlf\u2212/\u2212Dna-pkcs\u2212/\u2212 ; Xlf\u2212/\u2212Paxx\u2212/\u2212 vs. Xlf\u2212/\u2212Dna-pkcs\u2212/\u2212 .Detailed statistical analysis for the astrocyte differentiation, Overall, XLF possesses functional redundancy with PAXX during the NSPC self-renewal, and with DNA-PKcs during cell growth and neuronal differentiation .Xrcc4\u2212/\u2212, Lig4\u2212/\u2212, Xlf\u2212/\u2212Paxx\u2212/\u2212 and Xlf\u2212/\u2212Dna-pkcs\u2212/\u2212 mice NHEJ is ablated. Therefore, to avoid increased genomic instability during proliferation, developing neurons undergo programmed cell death via the p53-dependent pathway [Here, we demonstrated that NHEJ factors XLF, PAXX and DNA-PKcs support proliferation of NSPCs during early mammalian neurogenesis, when the proliferation rate is high and the likelihood of DNA damages arising from DNA replication machinery is increased. In  pathway ,20,27,28Xlf\u2212/\u2212, Xlf\u2212/\u2212Paxx\u2212/\u2212 and Xlf\u2212/\u2212Dna-pkcs\u2212/\u2212 NSPCs is significantly lower than that in WT cells; proliferation of Xlf\u2212/\u2212Dna-pkcs\u2212/\u2212 NSPCs is lower than that in Paxx\u2212/\u2212 cells  factors in cells? As one option, it was suggested that XLF can be complementary to the second factor having an alternative function . Alternatively, the proteins can be completely redundant key structural components of NHEJ machinery  [An important question challenging current research is: what is the mechanism underlying genetic interaction between mutants) . Severalmutants) . More spmutants) . More remutants) .Another model suggests that there are two major structural complexes formed during the NHEJ. Ku70-Ku80-XRCC4-LIG4 form the flexible synaptic complex (FS). Next, DSBs are brought together through interaction of XRCC4, giving rise to two Ku-XRCC4-Lig4-DNA complexes. Both XLF and PAXX are required for transition from the flexible synaptic to the second synaptic complex, or close synapsis (CS). Here, XLF stabilizes the close synapsis to a greater extent. In this model, it was suggested that DNA-PKcs is not involved in the FS and CS formation ,50. MoreXLF is functionally redundant with PAXX during the neuronal stem and progenitor cells self-renewal and proliferation, and with DNA-PKcs during cell growth and neuronal differentiation. The NHEJ factors DNA-PKcs, PAXX and XLF are required for efficient early-stage development of neuronal stem and progenitor cells in mice. Additional NHEJ factors, such as MRI/Cyren, Ku70, Ku80, XRCC4 and LIG4, as well as multiple ATM-dependent DDR factors might have similar functions in neurodevelopment. Future studies will directly address the roles of NHEJ factors, including XLF, DNA-PKcs, PAXX and MRI, in learning, memory and mood regulations."}
+{"text": "In the article titled \u201cPreconditioning of Rat Bone Marrow-Derived Mesenchymal Stromal Cells with Toll-Like Receptor Agonists\u201d , there w"}
+{"text": "In the article titled \u201cPartial and Transient Clinical Response to Omalizumab in IL-21-Induced Low STAT3-Phosphorylation on Hyper-IgE Syndrome\u201d [The correct affiliation of Mario Alberto Ynga-Durand is \u201cLaboratorio de Inmunidad de Mucosas, Secci\u00f3n de Investigaci\u00f3n y Posgrado, Escuela Superior de Medicina, Instituto Polit\u00e9cnico Nacional, Mexico City, Mexico.\u201d The correct affiliation for Julio C\u00e9sar Alc\u00e1ntara-Montiel is \u201cDepartment of Molecular Biomedicine, CINVESTAV-IPN, Mexico City, Mexico.\u201dThe error was introduced during the production process of the article, and Hindawi apologises for causing this error in the article.The corrected list of affiliations is shown in the authors' information above."}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-020-63658-5, published online 24 April 2020Correction to: The original version of this Article contained an error in the title of the paper, where the expression \u201c2\u2032,3\u2032-cAMP\u201d was incorrectly given as \u201c2\u20323\u2032-cAMP\u201d.The original version of this Article also contained errors in the Abstract.\u201cIn cells lacking 2\u2032,3\u2032-cyclic nucleotide 3\u2032-phosphodiesterase , effects of IAA/DNP on exosome secretion were enhanced.\u201dnow reads:\u201cIn cells lacking 2\u2032,3\u2032-cyclic nucleotide 3\u2032-phosphodiesterase , effects of IAA/DNP on exosome secretion were enhanced.\u201dThese errors have now been corrected in the PDF and HTML versions of the Article and in the accompanying Supplementary Information file."}
+{"text": "In the article titled \u201cSelf-Compassion Demonstrating a Dual Relationship with Pain Dependent on High-Frequency Heart Rate Variability\u201d , the aut\u201cFigure 1: Analysis procedure of HF-HRV. For detailed information, please refer to the Methods section (derived from [37] which has been reproduced with permission from Elsevier).\u201d"}
+{"text": "Correction to: BMC Musculoskelet Disord 21, 303 (2020)https://doi.org/10.1186/s12891-020-03251-zFollowing publication of the original article , the autHealth- and work-related questions\u201cTo assess their self-rated general health, the following questions were used: How do you experience your [1] \u201cphysical health\u201d [2] \u201cmental health\u201d [3] \u201csocial environment\u201d [4] \u201cphysical environment\u201d and [5] \u201cwork ability\u201d? A seven-point scale with answers ranging from \u201cvery poor\u201d to \u201cexcellent, cannot be better\u201d was used. In the analyses, the answers were collapsed and coded into: poor (\u22643), good , or excellent (\u22656) according to Larsson et al. [16].\u201dThe original article  has been"}
+{"text": "In the article titled \u201cInterleukin-9 Deletion Relieves Vascular Dysfunction and Decreases Blood Pressure via the STAT3 Pathway in Angiotensin II-Treated Mice\u201d , the aut"}
+{"text": "Scientific Reports 10.1038/s41598-017-08774-5, published online 16 August 2017Correction to: murG/MurG. The correct names are ypfP/YpfP.Due to an annotation error, the gene and protein name for the processive diacylglycerol beta-glucosyltransferase in this Article is listed as murG\u201d and \u201cMurG\u201d in the Article should read \u201cypfP\u201d and \u201cYpfP\u201d, respectively.Therefore, all instances of \u201c"}
+{"text": "Scientific Reports 10.1038/srep45314, published online 28 March 2017Correction to: This Article contains an error in Table 5.In the first row heading, the number of male patients,\u201cMale (n\u2009=\u200970)\u201d.should read:\u201cMale (n\u2009=\u200960)\u201d."}
+{"text": "In the article titled \u201cN-Acetyl Cysteine as a Novel Polymethyl Methacrylate Resin Component: Protection against Cell Apoptosis and Genotoxicity\u201d , there w"}
+{"text": "Scientific Reports 10.1038/s41598-019-54461-y, published online 09 December 2019Correction to: The Article contains an error in Table 3, entitled \u201cSemi-quantitative comparisons of CNS proteins by IHC staining.\u201dIn the \u201cTyrosine Hydroxylase\u201d row under the \u201cDM-resistant, with PFB\u201d column, the value of 7+ was erroneously omitted."}
+{"text": "Scientific Reports 10.1038/s41598-019-57269-y, published online 15 January 2020Correction to: The original version of this Article contained missing bar chart outlines and missing error bars in all figures.Additionally, in Figure 1 the figure key was incorrect. The individual groups for \u201cCrysophyceae\u201d, \u201cBacillariophyceae\u201d and \u201cDinophyceae\u201d are now in one group \u201cOthers\u201d.As a result, the legend of Figure 1 was incorrect.a (Chl a) concentration under full sunlight (UVR\u2009+\u2009PAR) and photosynthetically active radiation (PAR) and under ambient phosphorus (P) concentration and P-added conditions. Bars represent the mean values and error bars represent the standard deviation (SD) (n = 3).\u201d\u201cSestonic N:P ratio (on a molar basis), phytoplankton abundance (PA) and chlorophyll now reads:\u201cSestonic N:P ratio (on a molar basis), phytoplankton abundance (PA) and chlorophyll a (Chl a) concentration under full sunlight (UVR + PAR) and photosynthetically active radiation (PAR) and under ambient phosphorus (P) concentration and P-added conditions. In Fig. 1b, Others group includes Cryptophyceae, Bacillariophyceae and Dinophyceae, and represents a small proportion of the total phytoplankton abundance. Bars represent the mean values and error bars represent the standard deviation (SD) (n = 3).\u201dThis has now been corrected in the PDF and HTML versions of the original article."}
+{"text": "In the article titled \u201cFrom ACTH-Dependent to ACTH-Independent Cushing's Syndrome from a Malignant Mixed Corticomedullary Adrenal Tumor: Potential Role of Embryonic Stem Cells\u201d , there w"}
+{"text": "Scientific Reports 10.1038/s41598-019-41642-y, published online 05 April 2019Correction to: The Acknowledgements section in this Article is incomplete.\u201cWe acknowledge Franck Fortuna and Laurent Delbecq for access and support to the nano-focused ion beam at the CSNSM laboratory . We acknowledge support from the PETACom FET Open H2020, support from the French ministry of research through the ANR grants 2014\u201dIPEX\u201d, 2016 \u201cHELLIX\u201d, 2016 \u201cBISCOT\u201d, 2017 \u201cPACHA\u201d, the DGA RAPID grant \u201cSWIM\u201d and from the C\u2019NANO research program through the NanoscopiX grant, and the LABEX \u201cPALM\u201d (ANR-10-LABX-0039-PALM) through he grants\u201dPlasmon-X\u201d, \u201cSTAMPS\u201d and \u201cHILAC\u201d. We acknowledge the financial support from the French ASTRE program through the \u201cNanoLight\u201d grant. We aknowledge support from Conseil R\u00e9gional de Nouvelle-Aquitaine grant 2017 \u201cFLOWA\u201d. Financial support by the Deutsche Forschungsgemeinschaft, grant KO 3798/4-11 and from Lower Saxony through \u201cQuanten- und Nanometrologie\u201d (QUANOMET), project NanoPhotonik are acknowledged. J.B. acknowledges financial support from the Spanish Ministry of Economy and Competitiveness (MINECO), through the \u201cSevero Ochoa\u201d Programme for Centres of Excellence in R&D (SEV-2015- 0522) and the Fundaci\u00f3 Cellex Barcelona.\u201dshould read:\u201cWe acknowledge Franck Fortuna and Laurent Delbecq for access and support to the nano-focused ion beam at the CSNSM laboratory . We acknowledge support from the PETACom FET Open H2020, support from the French ministry of research through the ANR grants 2014\u201dIPEX\u201d, 2016 \u201cHELLIX\u201d, 2016 \u201cBISCOT\u201d, 2017 \u201cPACHA\u201d, the DGA RAPID grant \u201cSWIM\u201d and from the C\u2019NANO research program through the NanoscopiX grant, and the LABEX \u201cPALM\u201d (ANR-10-LABX-0039-PALM) through the grants\u201dPlasmon-X\u201d, \u201cSTAMPS\u201d and \u201cHILAC\u201d. We acknowledge the financial support from the French ASTRE program through the \u201cNanoLight\u201d grant. We acknowledge support from Conseil R\u00e9gional de Nouvelle-Aquitaine grant 2017 \u201cFLOWA\u201d. Financial support by the Deutsche Forschungsgemeinschaft, grant KO 3798/4-11 and from Lower Saxony through \u201cQuanten- und Nanometrologie\u201d (QUANOMET), project NanoPhotonik are acknowledged. J.B. acknowledges financial support from the Spanish Ministry of Economy and Competitiveness (MINECO), through the \u201cSevero Ochoa\u201d Programme for Centres of Excellence in R&D (SEV-2015- 0522), the Fundaci\u00f3 Cellex Barcelona, ERC Advanced Grant \u201cTRANSFORMER\u201d, Agreement No. 788218 and Laserlab-Europe (EU-H2020 654148).\u201d"}
+{"text": "Scientific Reports 10.1038/s41598-018-29959-6, published online 07 August 2018Correction to: This Article contains errors in Table 2 where the two columns headings have been reversed. \u2018CAD/CAM NAM\u2019 and \u2018RapidNAM\u2019 should read \u2018RapidNAM\u2019 and \u2018CAD/CAM NAM\u2019 respectively."}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-020-63949-x, published online 24 April 2020Correction to: This Article contains errors in the Methods section under subheading \u2018Surgical procedures\u2019.\u201c\u201dshould read:\u201c\u201dAdditionally, in the Methods section, the subheading \u201cPlasma Measurements\u201d should read \u201cPlasma and Spleen Measurements\u201d."}
+{"text": "Correction to: Orphanet J Rare Dis 15, 171 (2020)https://doi.org/10.1186/s13023-020-01391-ySport and Nutrition section of the manuscript whereby it was stated that:\u2018Approximately 20\u201330 g of protein equivalent from protein substitute should be ingested post exercise.\u2019The original article  containe\u2026 20g of protein equivalent from protein substitute \u2026 \u2019 which has since been implemented in the original article.This sentence should instead have stated \u2018"}
+{"text": "Scientific Reports 10.1038/s41598-019-45909-2, published online 02 July 2019Correction to: This Article contains typographical errors in the \u2018Results and Discussion\u2019 section under subheading \u2018Refractive index as a function of salinity\u2019, where equation (8)\u201cshould read:\u201cand equation (10)\u201cshould read:\u201c"}
+{"text": "July 19, 2019,an equation appeared incorrectly because of an author error. In the \u201cInactivatingexponential integrate and fire model (iEIF)\u201d section of the Materials andMethods, Equation 1 should have stated \u201cfor V <\u03b8\u201d instead of \u201cfor V <TV.\u201d The online version has been updated.In the article \u201cCellular and Network Mechanisms May Generate Sparse Coding ofSequential Object Encounters in Hippocampal-Like Circuits,\u201d by Anh-Tuan Trinh,Stephen E. Clarke, Erik Harvey-Girard, and Leonard Maler, which published online on"}
+{"text": "Scientific Reports 10.1038/s41598-018-26623-x, published online 31 May 2018Correction to: This Article contains typographical errors.In the Discussion section,i.e. the average probability of a wrong base call is less than one in 16,000).\u201d\u201cThe sequencing data were considered of high quality .\u201d\u201cThe sequencing data were considered of high quality (In the Acknowledgements section,\u201cVicent Wen, PhD\u201dshould read:\u201cVicent Wen, MSc\u201d"}
+{"text": "His full name should have appeared as \u201cOlivier Drouin, MDCM, MSc, MPH.\u201d This article has been corrected.1In the Research Letter titled \u201cClinical Characteristics and Disease Severity Among Infants With SARS-CoV-2 Infection in Montreal, Quebec, Canada,\u201d"}
+{"text": "Correction to: BMC Plant Biology 20, 360 (2020)https://doi.org/10.1186/s12870-020-02562-6\u201cCK: Tobacco plants transformed with empty pROKII; 35::Th2Cys: Tobacco overexpressing Th2CysPrx;\u201d in the legend of Fig.\u00a03 should be removed.In the sentence \u201cFifteen lines were generated in the T0 generation.\u201d, \u201cFifteen\u201d should be \u201cFourteen\u201d.In the original publication of this article , the aut"}
+{"text": "Mycobacterium tuberculosis by Modulating the PI3K/Akt/mTOR Signaling Pathway\u201d [\u03ba6, mTOR, and pmTOR\u201d is identical to the band of \u201cTLR4\u201d shown in the \u201cwithout inhibitor.\u201d The corrected figure is shown below as In the article titled \u201cEpithelial Cells Attenuate Toll-Like Receptor-Mediated Inflammatory Responses in Monocyte-Derived Macrophage-Like Cells to Pathway\u201d , there w"}
+{"text": "Scientific Reports 10.1038/s41598-019-42365-w, published online 15 April 2019Correction to: This Article contains errors in Table 3.The subheading of the row for Body-mass index is incorrectly written as \u2018Body-mass index (BMI) (kg/m)\u2019.2)\u2019.The correct row subheading should read \u2018Body-mass index (BMI) (kg/m2)\u2019 section is incorrectly given as \u2018\u2265\u200930\u2019.Additionally, the third subheading of the \u2018Body-mass index (BMI) (kg/mThe correct row subheading should read \u2018\u2265\u200927\u2019."}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-020-64806-7, published online 13 May 2020Correction to: This Article contains errors in Equation\u00a01.\u201cAll time invariant unobserved heterogeneity is controlled for in the orchard-level fixed effects should read:\u201cAll time invariant unobserved heterogeneity is controlled for in the orchard-level fixed effects and,ct to capture all systemic price and yield movements that occur across all orchards jointly in each year.\u201d\u201cWe include y and should read:\u201cWe include"}
+{"text": "In the article titled \u201cClaudin-1 Is a Valuable Prognostic Biomarker in Colorectal Cancer: A Meta-Analysis\u201d ["}
+{"text": "Scientific Reports, 10.1038/s41598-020-71066-y, published online 02 September 2020Correction to: This Article contains errors.In the Results section under subheading \u2018Roma lineages show hidden phylogenetic complexity\u2019,\u201cInside the J2a-M92 clade, we detected 5 private SNPs markers common to all 18 samples (Supplementary Table S9).\u201dshould read:\u201cInside the J2a-M67 clade, we detected 5 private SNPs markers common to all 18 samples (Supplementary Table S9).\u201dIn addition, the Supplementary Information published with this Article contains an error in Supplementary Table S9, where,\u201cJ2a-M92\u201dshould read:\u201cJ2a-M67\u201dFinally, in the Acknowledgements section,\u201cThis work was supported by the Spanish Ministry of Economy and Competitiveness , PID2019-106485GB-I00 (MINEICO), and \u201cUnidad Mar\u00eda de Maeztu\u201d (MDM-2014-0370) to DC and FC; and Ag\u00e8ncia de Gesti\u00f3 d\u2019Ajuts Universitaris i de la Recerca .\u201dshould read:\u201cThis work was supported by the Spanish Ministry of Economy and Competitiveness , PID2019-106485GB-I00/AEI/10.13039/501100011033 (MINEICO), and \u201cUnidad Mar\u00eda de Maeztu\u201d (MDM-2014-0370) to DC and FC; and Ag\u00e8ncia de Gesti\u00f3 d\u2019Ajuts Universitaris i de la Recerca .\u201d"}
+{"text": "JCYJ20160425103911638).In the article, \u201cDiagnostic accuracy of serum dickkopf-1 protein in diagnosis hepatocellular carcinoma: An updated meta-analysis\u201d,"}
+{"text": "Correction to: CVIR Endovaschttps://doi.org/10.1186/s42155-018-0048-7\u2018In the published article (Fenwick et al., \u201cWaived by Institutional Review Board for case reports.\u201dshould read:\u201cInformed consent for publication of this case report and its accompanying images has been obtained from the patient\u201d."}
+{"text": "Scientific Reports 10.1038/s41598-018-23063-5, published online 03 April 2018Correction to: This Article contains a typographical error in the Results section, under the sub-heading \u2018Nasal airway X-chromosome DNA methylation of immune genes\u2019.http://www.pantherdb.org/)23 and IRIS (Immunogenetic Related Information Source)24.\u201d\u201cTo accomplish this we constructed a list of X-linked immune genes (Supplementary Table 4) compiling information from two large Gene Ontology databases: PANTHER 23 and IRIS (Immunogenetic Related Information Source)24.\u201d\u201cTo accomplish this we constructed a list of X-linked immune genes compiling information from two large Gene Ontology databases: PANTHER (Protein ANalysis THrough Evolutionary Relationships;"}
+{"text": "Scientific Reports 10.1038/s41598-020-72473-x, published online 23 September 2020Correction to: This Article contains an error in Figure\u00a02, where each graph is incorrect in the panel \u2018Spectacle dependence_near_post\u2019.The correct Figure\u00a02 appears below as Figure"}
+{"text": "Correction to: BMC Geriatricshttps://doi.org/10.1186/s12877-019-1249-1Following publication of the original article , we haveThe given name and last name of the author should be reflected as follows:Genevi\u00e8ve Painchaud Gu\u00e9rard"}
+{"text": "Scientific Reports10.1038/s41598-020-61002-5, published online 03 March 2020Correction to:This Article contains multiple typographical errors.In the Results section under subheading \u2018Sampling feedlot and downstream environment, a beef processing plant, retail meat and urban wastewater\u2019.\u201cUrban wastewater contributed 31 samples in total including composite influent  and effluent , which were collected over the same two year period as the fecal samples.\u201dshould read:\u201cUrban wastewater contributed 43 samples in total including composite influent  and effluent , which were collected over the same two year period as the fecal samples.\u201dIn the Results section under subheading \u2018Enterococcus recovery\u2019,Enterococcus spp. isolates were recovered from all sites/sources tested including bovine feces , feedlot catch basins (n\u2009=\u2009510), surface water/natural water sources (n\u2009=\u2009521), urban wastewater influent and effluent (n\u2009=\u2009222), beef processing (abattoir and retail beef) (n\u2009=\u2009774), and human clinical cases  .\u201d\u201cA total of 8,307 presumptive should read:Enterococcus spp. isolates were recovered from all sites/sources tested including bovine feces , feedlot catch basins (n\u2009=\u2009510), surface water/natural water sources (n\u2009=\u2009521), urban wastewater influent and effluent (n\u2009=\u2009222), beef processing (abattoir and retail beef) (n\u2009=\u2009774), and human clinical cases  .\u201d\u201cA total of 8,375 presumptive \u201cIsolate recovery rates from surface water, wastewater effluent and meat processing samples was lower for antibiotic-free as compared to non-selective media .\u201dshould read:\u201cIsolate recovery rates from surface water, wastewater effluent and meat processing samples was lower for antibiotic-selective as compared to non-selective media .\u201d"}
+{"text": "Scientific Reports 10.1038/s41598-020-73335-2, published online 01 October 2020Correction to: The Supplementary file that accompanies this Article contains a typographical error in the spelling of the author.\u201cIlaria De Ambrosis\u201dshould read:\u201cIlaria Deambrosis\u201d"}
+{"text": "Scientific Reports 10.1038/s41598-020-64905-5, published online 18 May 2020Correction to: This Article contains an error in the Results and Discussion section under the subheading \u2018Macroscopic quantities and Henry\u2019s law for NC gas\u2019 where,pxxk)\u03c9\u03c9\u03c9( is the mean-field part.\u2019\u2018where should read:\u2018where"}
+{"text": "Scientific Reports 10.1038/s41598-018-26300-z, published online 07 June 2018Correction to: This Article contains an error. The text in Figure 2\u2019s legend,\u201cBone mineral density (BMD) of the femoral bone was determined by using \u00b5CT\u2026\u201dshould read:\u201cBone mineral density (BMD) of the femoral bone was determined by using pQCT\u2026\u201d"}
+{"text": "Scientific Reports 10.1038/s41598-020-79203-3, published online 17 December 2020Correction to: This Article contains an error in the Figure legends of Figure\u00a01, 2, 3 and 4. The legends of these Figures were inadvertently switched.The legend of Figure\u00a01:206Pb/207Pb ratios for soils in Southeast China.\u201d\u201cPb content and should read:\u201cThe location of sampling sites.\u201dThe legend of Figure\u00a02:208Pb/206Pb vs. 206Pb/207Pb ratios. The ZSJ, ZCR and ZAJ soil profiles were represented for Sanjie, Chongren and Anjishan of Zhejiang province, respectively.\u201d\u201cshould read:206Pb/207Pb ratios for soils in Southeast China.\u201d\u201cPb content and The legend of Figure\u00a03:\u201cMass fraction of anthropogenic Pb for soils in Southeast China.\u201dshould read:208Pb/206Pb vs. 206Pb/207Pb ratios. The ZSJ, ZCR and ZAJ soil profiles were represented for Sanjie, Chongren and Anjishan of Zhejiang province, respectively.\u201d\u201cThe legend of Figure\u00a04:\u201cThe location of sampling sites.\u201dshould read:\u201cMass fraction of anthropogenic Pb for soils in Southeast China.\u201d"}
+{"text": "Nature 10.1038/s41586-020-2008-3Published online 03 February 2020Correction to: In the Acknowledgements section of this Article, the grant number \u2018SQ2019FY010009\u2019 should have been \u20182019FY101500\u2019; this has been corrected online."}
+{"text": "Scientific Reports 10.1038/s41598-020-67347-1, published online 25 June 2020.Correction to: This Article contains errors in Table 1.Acaulium peruvianum,In the LSU column, the GenBank accession number for \u201cMN991966\u201dshould read:\u201cMN991967\u201dKernia hippocrepida was omitted, and should read \u201cMN991966\u201dIn the same column, the GenBank accession number for"}
+{"text": "Scientific Reports 10.1038/s41598-020-69987-9, published online 06 August 2020.Correction to: This Article contains a repeated error in Figure 1 where \u2018WHZ\u2019 should read \u2018WLZ\u2019.The correct Figure"}
+{"text": "Scientific Reports 10.1038/s41598-019-57037-y, published online 15 January 2020Correction to: The original version of this Article contained several typographical errors. In the Abstract,\u201cIn our study we examined patterns of PCS, pl compared with planned TOLAC anned PCS (PPCS), vaginal birth after 1 previous CS (VBAC-1) and associated factors in Friuli Venezia Giulia (FVG), a region of North-Eastern Italy, collecting data from its 11 maternity centres (coded from A to K) during 2005\u20132015.\u201dnow reads:\u201cIn our study we examined patterns of PCS, planned PCS (PPCS), vaginal birth after 1 previous CS (VBAC-1) and associated factors in Friuli Venezia Giulia (FVG), a region of North-Eastern Italy, collecting data from its 11 maternity centres (coded from A to K) during 2005\u20132015.\u201dIn the Methods section under the subheading \u2018Ethics Statement\u2019,\u201cAccording to the Italian privacy law  regional NHS data can be used for scientific purposes within the frame of approved studies/protocols.\u201dnow reads:\u201cAccording to the Italian privacy law  regional data from the Italian National Health Service (NHS) can be used for scientific purposes within the frame of approved studies/protocols.\u201dPolyhydramnios: 657.0;Oligohydramnios: 658.0;Antepartum hemorrhage, abruptio placentae and placenta previa: 641.(0-1-2-3-8-9);Obstructed labour (except shoulder girdle dystocia): 660.(0-1-2-3-5-6-7-8-9);Non-reassuring fetal status: 656.3;Fetal anomalies: 655.9;Cord prolapse: 663.0;Premature rupture of membranes (PROM): 658.1;Eclampsia/pre-eclampsia: 624.(4-5-6-7);Rh iso-immunization: 656.1;In the Methods section under the subheading \u2018The database\u2019,Polyhydramnios: 657.0;Oligohydramnios: 658.0;Antepartum hemorrhage, abruptio placentae and placenta previa: 641.(0-1-2-3-8-9);Obstructed labour (except shoulder girdle dystocia): 660.(0-1-2-3-5-6-7-8-9);Non-reassuring fetal status: 656.3;Cord prolapse: 663.0;Premature rupture of membranes (PROM): 658.1;Eclampsia/pre-eclampsia: 642.(4-5-6-7);Rh iso-immunization: 656.1;now reads:\u201cThe 11 regional maternal facility centres were anonymized and coded by alphabetic letter from A to L.\u201dnow reads:\u201cThe 11 regional maternal facility centres were anonymized and coded by alphabetic letter from A to K.\u201dIn the Methods section under the subheading \u2018Conceptual framework\u2019,\u201c5. Obstetric conditions, shown in Table 5: oligohydriamnios, polyhydramnios, eclampsia/pre-eclampsia, placenta previa/abruptio placenta/ante-partum hemorrhage, non-reassuring fetal status, fetal anomalies, cord prolapse, PROM, RH iso-immunization, obstructed labour (except shoulder girdle dystocia), labour analgesia, labour induction, fetal presentation.\u201dnow reads:\u201c5. Obstetric conditions, shown in Table 5: oligohydriamnios, polyhydramnios, eclampsia/pre-eclampsia, placenta previa/abruptio placenta/ante-partum hemorrhage, non-reassuring fetal status, congenital malformations at birth, cord prolapse, PROM, RH iso-immunization, obstructed labour (except shoulder girdle dystocia), labour analgesia, labour induction, fetal presentation.\u201dIn the Discussion section under the subheading \u2018Key findings\u2019,43.\u201d\u201cBy including also VBAC-2 on women with 2 previous CS (N\u2009=\u200938) the overall VBAC rate in the region would slightly reduce to 25.3%, almost three times the corresponding national rate (9%) reported in 2017 for the entire Italian countrynow reads:43.\u201d\u201cBy including also VBAC-2 on women with 2+\u2009previous CS (N\u2009=\u200938) the overall VBAC rate in the region would slightly reduce to 25.3%, almost three times the corresponding national rate (9%) reported in 2017 for the entire Italian countryIn the Discussion section under the subheading \u2018Strengths and limitations\u2019,\u201cWe consider the VBAC rates on women with history of only one previous CS in the analysis, since the number of VBAC on women with 2 previous CS was negligible (N\u2009=\u200938).\u201dnow reads:\u201cWe consider the VBAC rates on women with history of only one previous CS in the analysis, since the number of VBAC on women with 2+\u2009previous CS was negligible (N\u2009=\u200938).\u201dIn the Discussion section under the subheading \u2018PCS and PPCS\u2019,28.\u201d\u201cAlthough suspected macrosomia is an increasing indication for PCS, fetal anomalies were not associated with PCS or PPCS in our study and the level of significance of birthweight\u2009\u2265\u20094,000\u00a0g and hypertension/diabetes on the PCS risk was relatively lowernow reads:28.\u201d\u201cAlthough suspected macrosomia is an increasing indication for PCS, congenital malformations at birth were not associated with PCS or PPCS in our study and the level of significance of birthweight\u2009\u2265\u20094,000\u00a0g and hypertension/diabetes on the PCS risk was relatively lowerAdditionally, the original version of this Article contained errors in Table 5. The \u2018Missing\u2019 value for the Factor \u2018Placenta previa/abruptio placenta/ante-partum hemorrage\u2019 was given incorrectly as \u201c909\u201d, and now reads \u201c751\u201d. For the same Factor, the value for \u2018All Births (N)\u2019 in the \u2018Yes\u2019 Stratum row was given incorrectly as \u201c1,182\u201d, and now reads \u201c1,282\u201d. The \u2018VBAC-1\u2032 value for the Factor \u2018Premature rupture of membranes (Missing: 751)\u2019 in the \u2018Yes\u2019 Stratum row was given incorrectly as \u201c30.4\u201d, and now reads \u201c30.8\u201d.Furthermore, there were errors in the Supplementary File. In Supplementary Table 1, the factor, \u2018Placenta previa/abruptio placenta/ante-partum hemorrage\u2019 now reads \u2018Placenta previa/abruptio placenta/ante-partum hemorrhage: Yes\u2019; the factor \u2018Obstructed labour (but shoulder dystocia)\u2019 now reads \u2018Obstructed labour (but shoulder dystocia): Yes\u2019; and the factor \u2018Eclampsia/pre-eclampsia\u2019 now reads \u2018Eclampsia/pre-eclampsia: Yes\u2019.In the same table, for the factor, \u2018Polyhydramnios: Yes\u2019, the value for \u2018PCS\u2019 under the \u2018Delivery Mode\u2019 was given incorrectly as \u201c3.39 \u201d, and now reads \u201c3.56 \u201d. For the factor \u2018Mother\u2019s nationality: Non-EU\u2019, the value for \u2018PCS\u2019 under the \u2018Delivery Mode\u2019 was given as \u201c1.22 \u201d, and now reads \u201c1.22 \u201d. For the factor \u2018Mother\u2019s education: secondary\u2019, the value for \u2018PCS\u2019 under the \u2018Delivery Mode\u2019 was given incorrectly as \u201c1.10 \u201d, and now reads \u201c1.24 \u201d. For the factor \u2018PROM: Yes\u2019, the value for \u2018PPCS\u2019 under the \u2018Delivery Mode\u2019 was given incorrectly as \u201c0.43 \u201d, and now reads \u201c0.43 \u201d.In the same table, the rows for the factors \u2018Mother\u2019s occupation: Blue collar\u2019 and \u2018Father\u2019s age: (40\u201344) years\u2019 were omitted from the table.In Supplementary Table 2, the upper bound confidence interval for the \u2018PCS\u2019 estimate of Hospital \u2018E\u2019 was given incorrectly as \u201c2.33 \u201d, and now reads \u201c2.33 \u201d. For the same Hospital, the upper bound confidence interval for the \u2018PPCS\u2019 estimate was given incorrectly as \u201c4.75 \u201d, and now reads \u201c4.75 \u201d. The upper bound confidence interval for the \u2018PCS\u2019 estimate of Hospital \u2018G\u2019 was given incorrectly as \u201c0.70 \u201d, and now reads \u201c0.70 \u201d. The upper bound confidence interval for the \u2018VBAC-1\u2019 estimate of Hospital \u2018I\u2019 was given incorrectly as \u201c0.36 \u201d, and now reads \u201c0.36 \u201d. The upper bound confidence interval for the \u2018VBAC-1\u2032 estimate of Hospital \u2018J\u2019 was given incorrectly as \u201c0.41 \u201d, and now reads \u201c0.41 \u201d.Lastly, in the Supplementary File, under the section \u2018Results of Supplementary Tables 1 and 2 belong to the same multivariable logistic regression models, adjusted for the same following factors\u2019, the factors \u2018maternal age\u2019 and \u2018eclampsia/pre-eclampsia\u2019 were omitted from the list under \u2018VBAC-1\u2019.These errors have now been corrected in the HTML and PDF versions of the Article, and in the accompanying Supplementary File."}
+{"text": "Scientific Data 10.1038/s41597-020-00687-9, published online 13 October 2020Correction to: The Figure 5 has been updated to include the missing part of the \u201cPlateau subtropical zone\u201d, and the subfigure labels, \u201c(a)\u201d and \u201c(b)\u201d."}
+{"text": "Substance use disorder (SUD) is associated with a high risk of physical and mental illness such as anxiety, depression, personality disorders, eating disorders, and abnormal mood changes. During the pandemic, SUD, a significant problem related to Coronavirus disease 2019 (COVID-19), is affecting adolescents. The recent available literature also emphasizes understanding the relationship between mental illness and SUD. Hence, it is essential to evaluate the scientific approach and examine the presented findings of articles published on SUD during the COVID-19 pandemic. A systematic review will be conducted using PubMed, PubMed Central, and Scopus bibliographic databases. The grey literature on the impact of SUD on mental health during the COVID-19 pandemic among adolescents will be identified using scholar google. The dependability and credibility of the findings will be examined using the ConQual approach. The methodologies of the included studies will be compared using ROBIS (risk of bias in systematic reviews tool), a measurement tool to assess systematic reviews (AMSTAR), and the JBI critical appraisal tool. The systematic review will be carried out on published articles, so it is exempt from ethics approval. The Center for Open Science (OSF) will be used as a data repository during the preparation of the protocol and completion of the systematic review. The research findings will be published in a related peer-reviewed journal. A recent national-wide cross-sectional study identified the prevalence of substance-induced anxiety  in China. Several systematic reviews have also confirmed the prevalence of comorbid mental health disorders in people having substance abuse.The risk of morbidity and mortality of mental disorders increases with substance misuse. According to the worldometer, there have been 599,438 deaths  caused by Coronavirus disease 2019 (COVID-19) and 14,194,726 infected  as of the 18th July 2020. The World Health Organization has recommended reducing watching, reading, or listening to news that makes anyone anxious and distressed.The advent and spread of the 2019 novel coronavirus (2019-nCoV) caused by severe acute respiratory syndrome 2 (SARS-CoV-2) pose major public health issues and a global pandemic. There will be an increase in the desire for substance abuse, such as smoking, because of social isolation and psychic distress. The rise in stress could lead to other substance abuse, such as alcohol misuse caused because of the improper functioning of the cortisol response and emotional regulation.,13 In addition to smoking and alcohol, the patients suffering from addiction and dependence, such as opioid use disorder, may face a challenge for treatment.\u201316 A national-wide case-control study in Korea has also depicted several comorbidities associated with COVID-19, including substance use . The list of physical and mental issues related to COVID-19 consists of anxiety, stigma, and stress, which could lead to domestic violence, boredom, physical inactivity, and time management issues.,21Several commentaries, correspondence, communications, editorials, and letters published in high impact journals have made prominent the effect of COVID-19 on mental health.1.1The objectives of this study are as follows:1.To identify the substance use among adolescents during the COVID-19 pandemic.2.To examine the quality assessment of original articles.3.To compare the different quality assessment methods of the included studies.4.To give future direction on how to improve the credibility of the findings on the mental issues among adolescents during a global pandemic.1.2Original research articles published in the English language in which substance use disorder and COVID-19 were considered as the primary measured variables. Review articles, commentary, correspondence, communication, editorials, opinions, and letters will be excluded.1.3This systematic review will target studies in which groups or subgroups of the participants are all 3 kinds of adolescents, such as early adolescence, middle adolescence, and late adolescence.1.4No time limit for setting the study or timeframe will be set for this systematic review. The psychological assessment questionnaires , mental and behavioral disorders and their methods to evaluate their characteristics will be included in the context of our systematic review.1.5Articles that have been published as open access and written in English will be selected under this systematic review, and there will be no limitation on the date of acceptance or publication. The researchers will consider only articles that have been published or are in the press.1.6 PubMed Central, and Scopus database, whereas gray literature will be identified using Scholar Google. ProQuest will be searched for dissertations.An electronic search will be performed through PubMed,1.7Our initial search syntax for PubMed will be:1.((((\u201csubstance-related disorders\u201d[MeSH Terms] OR (\u201csubstance related\u201d[All Fields] AND \u201cdisorders\u201d[All Fields])) OR \u201csubstance related disorders\u201d[All Fields]) OR (\u201csubstance\u201d[All Fields] AND \u201cdisorder\u201d[All Fields])) OR \u201csubstance use disorder\u201d[All Fields]) AND (((((((\u201ccovid 19\u201d[All Fields] OR \u201ccovid 2019\u201d[All Fields]) OR \u201csevere acute respiratory syndrome coronavirus 2\u201d[Supplementary Concept]) OR \u201csevere acute respiratory syndrome coronavirus 2\u201d[All Fields]) OR \u201c2019 ncov\u201d[All Fields]) OR \u201csars cov 2\u201d[All Fields]) OR \u201c2019ncov\u201d[All Fields]) OR ((\u201cwuhan\u201d[All Fields] AND (\u201ccoronavirus\u201d[MeSH Terms] OR \u201ccoronavirus\u201d[All Fields])) AND (2019/12/1:2019/12/31[Date - Publication] OR 2020/1/1:2020/12/31[Date - Publication])))2.((((\u201csubstance-related disorders\u201d[MeSH Terms] OR (\u201csubstance related\u201d[All Fields] AND \u201cdisorders\u201d[All Fields])) OR \u201csubstance related disorders\u201d[All Fields]) OR (\u201cdrug\u201d[All Fields] AND \u201caddiction\u201d[All Fields])) OR \u201cdrug addiction\u201d[All Fields]) AND (((((((\u201ccovid 19\u201d[All Fields] OR \u201ccovid 2019\u201d[All Fields]) OR \u201csevere acute respiratory syndrome coronavirus 2\u201d[Supplementary Concept]) OR \u201csevere acute respiratory syndrome coronavirus 2\u201d[All Fields]) OR \u201c2019 ncov\u201d[All Fields]) OR \u201csars cov 2\u201d[All Fields]) OR \u201c2019ncov\u201d[All Fields]) OR ((\u201cwuhan\u201d[All Fields] AND (\u201ccoronavirus\u201d[MeSH Terms] OR \u201ccoronavirus\u201d[All Fields])) AND (2019/12/1:2019/12/31[Date - Publication] OR 2020/1/1:2020/12/31[Date - Publication])))3.((((\u201cillicit drugs\u201d[MeSH Terms] OR (\u201cillicit\u201d[All Fields] AND \u201cdrugs\u201d[All Fields])) OR \u201cillicit drugs\u201d[All Fields]) OR (\u201cillicit\u201d[All Fields] AND \u201cdrug\u201d[All Fields])) OR \u201cillicit drug\u201d[All Fields]) AND (((((((\u201ccovid 19\u201d[All Fields] OR \u201ccovid 2019\u201d[All Fields]) OR \u201csevere acute respiratory syndrome coronavirus 2\u201d[Supplementary Concept]) OR \u201csevere acute respiratory syndrome coronavirus 2\u201d[All Fields]) OR \u201c2019 ncov\u201d[All Fields]) OR \u201csars cov 2\u201d[All Fields]) OR \u201c2019ncov\u201d[All Fields]) OR ((\u201cwuhan\u201d[All Fields] AND (\u201ccoronavirus\u201d[MeSH Terms] OR \u201ccoronavirus\u201d[All Fields])) AND (2019/12/1:2019/12/31[Date - Publication] OR 2020/1/1:2020/12/31[Date - Publication])))4.((((\u201csubstance-related disorders\u201d[MeSH Terms] OR (\u201csubstance related\u201d[All Fields] AND \u201cdisorders\u201d[All Fields])) OR \u201csubstance related disorders\u201d[All Fields]) OR (\u201csubstance\u201d[All Fields] AND \u201cabuse\u201d[All Fields])) OR \u201csubstance abuse\u201d[All Fields]) AND (((((((\u201ccovid 19\u201d[All Fields] OR \u201ccovid 2019\u201d[All Fields]) OR \u201csevere acute respiratory syndrome coronavirus 2\u201d[Supplementary Concept]) OR \u201csevere acute respiratory syndrome coronavirus 2\u201d[All Fields]) OR \u201c2019 ncov\u201d[All Fields]) OR \u201csars cov 2\u201d[All Fields]) OR \u201c2019ncov\u201d[All Fields]) OR ((\u201cwuhan\u201d[All Fields] AND (\u201ccoronavirus\u201d[MeSH Terms] OR \u201ccoronavirus\u201d[All Fields])) AND (2019/12/1:2019/12/31[Date - Publication] OR 2020/1/1:2020/12/31[Date - Publication])))5.((\u201cdrug misuse\u201d[MeSH Terms] OR (\u201cdrug\u201d[All Fields] AND \u201cmisuse\u201d[All Fields])) OR \u201cdrug misuse\u201d[All Fields]) AND (((((((\u201ccovid 19\u201d[All Fields] OR \u201ccovid 2019\u201d[All Fields]) OR \u201csevere acute respiratory syndrome coronavirus 2\u201d[Supplementary Concept]) OR \u201csevere acute respiratory syndrome coronavirus 2\u201d[All Fields]) OR \u201c2019 ncov\u201d[All Fields]) OR \u201csars cov 2\u201d[All Fields]) OR \u201c2019ncov\u201d[All Fields]) OR ((\u201cwuhan\u201d[All Fields] AND (\u201ccoronavirus\u201d[MeSH Terms] OR \u201ccoronavirus\u201d[All Fields])) AND (2019/12/1:2019/12/31[Date - Publication] OR 2020/1/1:2020/12/31[Date - Publication])))6.(\u201cdeviant\u201d[All Fields] OR \u201cdeviants\u201d[All Fields] drug use) AND (\u201cCOVID-19\u201d[All Fields] OR \u201cCOVID-2019\u201d[All Fields] OR \u201csevere acute respiratory syndrome coronavirus 2\u201d[Supplementary Concept] OR \u201csevere acute respiratory syndrome coronavirus 2\u201d[All Fields] OR \u201c2019-nCoV\u201d[All Fields] OR \u201cSARS-CoV-2\u201d[All Fields] OR \u201c2019nCoV\u201d[All Fields] OR ((\u201cWuhan\u201d[All Fields] AND (\u201ccoronavirus\u201d[MeSH Terms] OR \u201ccoronavirus\u201d[All Fields])) AND (2019/12[PDAT] OR 2020[PDAT])))7.((((\u201csubstance-related disorders\u201d[MeSH Terms] OR (\u201csubstance related\u201d[All Fields] AND \u201cdisorders\u201d[All Fields])) OR \u201csubstance related disorders\u201d[All Fields]) OR (\u201cdrug\u201d[All Fields] AND \u201cdependence\u201d[All Fields])) OR \u201cdrug dependence\u201d[All Fields]) AND (((((((\u201ccovid 19\u201d[All Fields] OR \u201ccovid 2019\u201d[All Fields]) OR \u201csevere acute respiratory syndrome coronavirus 2\u201d[Supplementary Concept]) OR \u201csevere acute respiratory syndrome coronavirus 2\u201d[All Fields]) OR \u201c2019 ncov\u201d[All Fields]) OR \u201csars cov 2\u201d[All Fields]) OR \u201c2019ncov\u201d[All Fields]) OR ((\u201cwuhan\u201d[All Fields] AND (\u201ccoronavirus\u201d[MeSH Terms] OR \u201ccoronavirus\u201d[All Fields])) AND (2019/12/1:2019/12/31[Date - Publication] OR 2020/1/1:2020/12/31[Date - Publication])))1.81.8.1The systematic review tool (ROBIS) is one of the newly developed tools to assess the risk of bias in the systematic review which consists of three main parameters .1.8.2A measurement tool for the \u201cassessment of multiple systematic reviews,\u201d AMSTAR is used to assess the quality of the manuscript using an improved quality assessment questionnaire that consists of 11 items.1.9The Joanna Briggs Insititute has constructed 10-item critical appraisal tools to evaluate the philosophical perspective, research questions or objectives, methods used to collect data, data analysis, and interpretation of the findings.1.10 Qualitative Data Analysis Software (QDA Miner) will be used to aid the data extraction Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines will be used to prepare the final manuscript.1.11 Moreover, the initial screening will be performed with the help of 2 independent reviewers.The final synthesized findings will be marked according to the ConQual approach for establishing confidence in the output of the qualitative research synthesis and presented in a summary of findings.1.12The reviewer will able to identify the impact of anxiety, depression, and attitude among adolescents against the COVID-19 pandemic from the baseline to the last available follow-up. Measures of the effects relative to the risks, odds ratios, and the risk difference of anxiety, depression, and attitude before and after COVID-19 will be observed.The authors gratefully acknowledge Xiamen University Malaysia for their support and guidance. Special thanks to Aishah Rose Marie, for her perseverance in proofreading the manuscript.Conceptualization: Yun Jin Kim, Linchao Qian, Muhammad Shahzad Aslam.Data curation: Linchao Qian.Funding acquisition: Yun Jin Kim.Methodology: Linchao Qian.Supervision: Linchao Qian, Muhammad Shahzad Aslam.Writing \u2013 original draft: Yun Jin Kim, Muhammad Shahzad Aslam.Writing \u2013 review & editing: Yun Jin Kim, Muhammad Shahzad Aslam."}
+{"text": "Scientific Reports 10.1038/s41598-019-48788-9, published online 22 August 2019Correction to: The Acknowledgements section in this Article was omitted. The Acknowledgements section should read:\u201cWe acknowledge the EU\u2019s Horizon 2020 research and innovation programme under the Marie Sk\u0142odowska-Curie grant agreement No 674901 (\u2018switchBoard) for funding this project.\u201d"}
+{"text": "Scientific Reports 10.1038/s41598-018-27461-7, published online 15 June 2018Correction to: This Article contains errors.In Table 1, the fourth column \u201cGene bank No.\u201dshould read:\u201cAccession No.\u201dAdditionally, row Gapdh is incorrect,\u201c5\u2032-TGACGACTTCAACAGCAACTC-3\u201dshould read:\u201c5\u2032-TGCGACTTCAACAGCAACTC-3\u201d\u201c5\u2032-ATGTAGGCCAATGAGGTCCAC-3\u2032\u201dshould read:\u201c5\u2032-ATGTAGGCCATGAGGTCCAC-3\u2032\u201d\u201cBC096590\u201dshould read:\u201cNM_008084\u201dCaSR,The Accession No. for \u201cNM_013803.3\u201dshould read:\u201cNM_013803\u201dFurthermore, in the Discussion section,32,37,51,52; in vivo studies using rat models reported that systemic use of SrRn (625\u2009g/kg) is well tolerated and safe with no adverse side effects53,54.\u201d\u201cHowever, it is reasonable to suppose that topical application during vital pulp therapy may pose a much lower risk of side effects compared to systemic applicationshould read:32,37,51,52; in vivo studies using rat models reported that systemic use of SrRn (625\u2009mg/kg) is well tolerated and safe with no adverse side effects53,54.\u201d\u201cHowever, it is reasonable to suppose that topical application during vital pulp therapy may pose a much lower risk of side effects compared to systemic application"}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-020-80147-x, published online 11 January 2021Correction to: This Article contains an error in Figue\u00a04, where one of the labels is misspelled in panels (b) and (d).\u2018Neun\u2019should read:\u2018NeuN\u2019The correct Figure\u00a04 appears below as Figure"}
+{"text": "In the article titled \u201cSolid Pseudopapillary Neoplasm of the Pancreas with High-Grade Malignant Transformation Involving p16-RB Pathway Alterations\u201d ["}
+{"text": "Correction to: Stem Cell Res Ther (2020) 11:493https://doi.org/10.1186/s13287-020-02019-5The original article  containsIn each caption, the word \u2018confocal\u2019 should be replaced by \u2018two-photon\u2019."}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-020-72215-z, published online 28 September 2020Correction to: This Article contains a typographical error in the Methods section under subheading \u2018Coupling parameters and uncertainties\u2019, where\u201cAfter fixing the exchange couplings should read:50 by fitting the results of full-spectrum exact-diagonalization calculations to the low-field magnetization data from Ref.\u00a070.\u201d\u201cAfter fixing the exchange couplings"}
+{"text": "Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved by the US Food and Drug Administration for adult patients with relapsed/refractory large B-cell lymphoma after \u22652 lines of systemic therapy . Grade \u22652 and fludarabine 30\u2009mg/m2 intravenously, days \u22125 to \u22123) and a single intravenous axi-cel infusion . Response was assessed using International Working Group response criteria for malignant lymphoma  and 1754 vs 1567\u2009mg/L\u2009\u00d7\u2009days [936\u20132545]).To understand the pharmacodynamic profile of CAR T-cell activity before and after nivolumab, serum cytokine levels were analyzed. Cytokines associated with proliferation (interleukin-15 [IL-15]), immune modulation (interferon-\u03b3 [IFN\u03b3]), inflammation (C-reactive protein [CRP]), and immune effector function , is prospectively evaluating checkpoint blockade after axi-cel.Supplemental Material"}
+{"text": "The terms should have instead been propensity-weighted and propensity score\u2013weighting, respectively. This article has been corrected.1In the Invited Commentary titled \u201cAre Observational, Real-World Studies Suitable to Make Cancer Treatment Recommendations?\u201d"}
+{"text": "We present here the recent advance in exploring new detection mechanisms, materials, processes, and applications of fiber optic sensors. In this Special Issue, we aim to focus on all aspects of the recent research and development related to fiber optic sensors. Recent advances in fiber-based sensing technologies have enabled both fundamental studies and a wide spectrum of applications ,2,3. ThiBelow is a brief summary of all the articles covered in this Issue. In \u201cHigh-Sensitivity, Large Dynamic Range Refractive Index Measurement Using an Optical Microfiber Coupler\u201d , a sensiIn \u201cAn Intra-Oral Optical Sensor for the Real-Time Identification and Assessment of Wine Intake\u201d , an intrIn \u201cLaser-Induced Deposition of Carbon Nanotubes in Fiber Optic Tips of MMI Devices\u201d , a laserIn \u201cFiber Link Health Detection and Self-Healing Algorithm for Two-Ring-Based RoF Transport Systems\u201d , a two-rIn \u201cDesign and Implementation of a Novel Measuring Scheme for Fiber Interferometer Based Sensors\u201d , a measuIn \u201cNonlinearity Correction in OFDR System Using a Zero-Crossing Detection-Based Clock and Self-Reference\u201d , a methoIn \u201cDynamic Deformation Reconstruction of Variable Section WING with Fiber Bragg Grating Sensors\u201d , a dynamIn \u201cMetal Forming Tool Monitoring Based on a 3D Measuring Endoscope Using CAD Assisted Registration\u201d , a setupIn \u201cA High Sensitivity Temperature Sensing Probe Based on Microfiber Fabry\u2013Perot Interference\u201d , a miniaIn \u201cHybrid Plasmonic Fiber-Optic Sensors\u201d , the devIn \u201cCarbon Allotrope-Based Optical Fibers for Environmental and Biological Sensing: A Review\u201d , the devIn \u201cRelative Humidity Sensors Based on Microfiber Knot Resonators-A Review\u201d , the recIn \u201cDual-Polarized Fiber Laser Sensor for Photoacoustic Microscopy\u201d , the rec"}
+{"text": "Vavilovskii Zhurnal Genetiki i Selektsii = Vavilov Journal of Genetics and Breeding. 2019;23(8):1076-1081 (in Russian)Page 1081, in Acknowledgements instead ofThis work was supported by State Budgeted Project \u0410\u0410\u0410\u0410-\u041017-117092070032-4.should readThis work was supported by State Budgeted Project 0259-2019-0011.The original article can be found under DOI 10.18699/VJ19.583"}
+{"text": "In the article titled \u201cBeta-Thalassemia Intermedia: A Single Thalassemia Center Experience from Northeastern Iraq\u201d , there w"}
+{"text": "In the article titled \u201cSevere Life-Threatening Pregnancy Complications, \u201cNear Miss\u201d and Maternal Mortality in a Tertiary Hospital in Southern Nigeria: A Retrospective Study\u201d , there w4Saving Mothers Giving Life Initiative, Pathfinder International, Calabar, Nigeria"}
+{"text": "In the article titled \u201cHypoxia Impairs NK Cell Cytotoxicity through SHP-1-Mediated Attenuation of STAT3 and ERK Signaling Pathways\u201d ["}
+{"text": "Correction to: J Ethnobiology Ethnomedicine 16, 43 (2020)https://doi.org/10.1186/s13002-020-00393-1Following publication of the original article , the autThe errors were the following:In the legend on \u2018Phytogeographical zones\u2019, it said \u2018Southern Sudanian\u2019 and \u2018Norther Sudanian\u2019 in place of \u2018South-Sudanian\u2019 and \u2018North-Sudanian\u2019.In panels j, k and l, it said \u2018Peulh\u2019 on the x-axis in place of \u2018Fulani\u2019.In panel h, it said \u2018Peulh\u2019 on the x-axis in place of \u2018Fulani\u2019.The original article  has beenThe authors apologize for any inconvenience caused."}
+{"text": "A low-resolution version of"}
+{"text": "In the article titled \u201cLow-Grade Endometrial Stromal Sarcoma with a Nodule-in-Nodule Appearance in Preoperative Magnetic Resonance Images\u201d , there w"}
+{"text": "In the article titled \u201cCathepsin B pH-dependent activity is involved in lysosomal dysregulation in atrophic age-related macular degeneration\u201d , an affi"}
+{"text": "Scientific Reports 10.1038/s41598-018-30152-y, published online 13 August 2018Correction to: The Article contains an error in Table 1 where the \u2018Host\u2019 column for the strain \u2018DE4576/Huestis\u2019 is incorrectly listed.Danio rerio), outbreak of the ZIRC National zebrafish facility\u201d\u201cZebrafish (should read:Danio rerio), outbreak of a laboratory facility, University of Oregon\u201d\u201cZebrafish (Additionally, in the \u2018Isolated from\u2019 column for the strain \u2018DE4576/Huestis\u2019, the city \u2018Eugene\u2019 is missing.\u201cOregon, USA\u201dshould read:\u201cEugene, Oregon, USA\u201d"}
+{"text": "Scientific Reports 10.1038/s41598-020-70970-7, published online 17 August 2020Correction to: In this Article, the legend of Figure 4 is incorrect:c) mandible of the rainforest rodent Pogonomys from the Riversleigh World Heritage site with molars colour coded and jaw bone rendered semi-transparent,\u201d\u201c(should read:c) mandible of the rainforest rodent Pogonomys from the Mount Etna Caves National Park\u00a0with molars colour coded and jaw bone rendered semi-transparent,\u201d\u201c("}
+{"text": "Scientific Reports 10.1038/s41598-019-57090-7, published online 09 January 2020Correction to: The Article contains a typographical error in the Methods section under subheading \u2018Sperm freezing\u2019.\u201cA male rat was euthanised via cervical dislocation, and then its two cauda epididymides were removed aseptically and transferred into a 300 \u03bcL drop of CPA in a 35 mm culture dish at room temperature .\u201dshould read:\u201cA male rat was euthanised via cervical dislocation, and then its two cauda epididymides were removed aseptically and transferred into a 3000\u2009\u03bcL drop of CPA in a 35\u2009mm culture dish at room temperature .\u201d"}
+{"text": "They should have read, \u201cNondefinitive therapy: systemic therapy\u201d and \u201cNondefinitive therapy: no treatment.\u201d This article has been corrected.1In the Original Investigation titled \u201cAssociation of Sociodemographic and Health-Related Factors With Receipt of Nondefinitive Therapy Among Younger Men With High-Risk Prostate Cancer,\u201d"}
+{"text": "Scientific Reports 10.1038/s41598-019-47755-8, published online 2 August 2019Correction to: This Article contains errors in the Method section under subheading \u2018Clinical samples\u2019.\u201cA written informed consent of the patients was obtained, samples and clinical information were anonymized.\u201dshould read:\u201cA written informed consent of the patients was waived, samples and clinical information were anonymized.\u201d"}
+{"text": "Translational PsychiatryCorrection to: 10.1038/s41398-020-01029-4 published online 13 October 2020The original version of this article unfortunately contained several typos in the unit of ethanol concentration. The unit of ethanol concentration should be \u201cmg/dL\u201d but not \u201cmg/mL\u201d. The original article has been corrected."}
+{"text": "Correction to: J Orthop Surg Res (2020) 15:231https://doi.org/10.1186/s13018-020-01747-xFollowing publication of the original article , we haveCorrected version:Outcomes-Fracture section, \u201cand the results obtained can prove that PLA has a higher fracture rate in patients than DAA\u201d should be corrected to \u201cand the results obtained can prove that DAA has a higher fracture rate in patients than PLA\u201d.In the Outcomes-Dislocation section, \u201cshowing PLA has a lower hip dislocation rate than DAA\u201d should be corrected to \u201cshowing DAA has a lower hip dislocation rate than PLA\u201d. Other contents need not be corrected after inspection.In the"}
+{"text": "Scientific Reports 10.1038/s41598-019-57274-1, published online 15 January 2020Correction to: This Article contains typographical errors in the Acknowledgements section.\u201c(Research grant T37413)\u201dshould read:\u201c(Research grant T39710)\u201d"}
+{"text": "Yongquan Chen are co-first authors.In the article, \u201cThe synonymous 903C>G mutation in the alpha 1,4-galactosyltransferase gene in a Chinese woman with habitual abortion: A case report\u201d,"}
+{"text": "Scientific Reports 10.1038/s41598-019-49102-3, published online 29 August 2019Correction to: The Acknowledgements section in this Article was omitted. The Acknowledgements section should read:\u201cThe author thanks \u0130lhami \u00dcnal and Aysun Say\u0131nt\u0131 for providing the measurement data made at Marmara Research Center of TUBITAK.\u201d"}
+{"text": "Translational PsychiatryCorrection to: 10.1038/s41398-020-00988-y published online 1 September 2020In the original article, Dr. Angela Ruban\u2019s name was misspelled as \u201cAangela Ruban\u201d. This has been corrected in the PDF, HTML and XML versions of this article."}
+{"text": "In the article titled \u201cSingle-Nucleotide Polymorphisms in XPO5 are Associated with Noise-Induced Hearing Loss in a Chinese Population\u201d , the inf"}
+{"text": "Scientific Reports 10.1038/s41598-020-59730-9, published online 20 February 2020Correction to: This Article contains a typographical error in the Introduction section where,\u201cIn addition, a canine IFN-\u03b1 formulation  has been commercially available as a pharmaceutical agent for periodontal treatment in animals since 2014.\u201dshould read:\u201cIn addition, a canine IFN-\u03b1 formulation  has been commercially available as a pharmaceutical agent for periodontal treatment in animals since 2014.\u201d"}
+{"text": "Scientific Data 10.1038/sdata.2017.165, published online 24 October 2017Correction to: In the Data Records section of this Data Descriptor, the data quality layer is incorrectly described as \u201craw data (0) or gap-filled (1)\u201d. This should instead read \u201craw data (1) or gap-filled (0)\u201d."}
+{"text": "In the article titled \u201cMucinous Histology, BRCA1/2 Mutations, and Elevated Tumor Mutational Burden in Colorectal Cancer\u201d ["}
+{"text": "Dr Zhang received award number 81800149. This article has been corrected.1In the Original Investigation titled \u201cPossible Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in a Public Bath Center in Huai\u2019an, Jiangsu Province, China,\u201d"}
+{"text": "The Funding statement is incorrect. The correction Funding statement is as follows: This work was funded by Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo (FAPESP) research grants 2015/22308-2 (to CAM-F) and 2014/50489-9 (to MMC-S) and Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico (CNPq) grant306893/2018-5 (to CAM-F). The funders had no role in study design, data collectionand analysis, decision to publish, or preparation of the manuscript.The publisher apologizes for the error."}
+{"text": "Correction to: BMC Medical Genetics (2019) 20:171https://doi.org/10.1186/s12881-019-0911-yFollowing publication of the original article , the autNamely, in the affiliations list (under the \u2018Author details\u2019) affiliations \u20181\u2019 and \u20182\u2019 are interchanged; affiliation \u20181\u2019 should be \u20182\u2019, and vice-versa.Please find the corrected order of affiliations in this correction."}
+{"text": "As of release 47 (April 2020) it features 79 species and includes genome sequence, gene models, and functional annotation. Comparative analyses help reconstruct the evolutionary history of gene families, genomes, and components of polyploid genomes. Some species have gene expression baseline reports or variation across genotypes. While the data can be accessed through the Ensembl genome browser, here we review specifically how our plant genomes can be interrogated programmatically and the data downloaded in bulk. These access routes are generally consistent across Ensembl for other non-plant species, including plant pathogens, pests, and pollinators.Ensembl Plants ( As the world population increased by 145% in the last 60 years, the yields of cereals increased even more, while not needing much more land  include http://plants.ensembl.org) is the Ensembl portal for plants and red algae [0][\u2018seq_region_name\u2019]:                                           mapping = map_cds[\u2018mappings\u2019][0]                                           # fetch VEP consequences for this region                                           SNPgenome_coord = ( mapping[\u2018seq_region_name\u2019] + \u2018:\u2019 +                                           str(mapping[\u2018start\u2019]) + \u2018-\u2019 + str(mapping[\u2018end\u2019]) )                                           ext = (\u201c/vep/\u201d+ species + \u201c/region/\u201d + SNPgenome_coord + \u201c/\u201d +                                           SNPbase + \u201c?content-type=application/json\u201d)                                           conseq = get_json(ext)                                           # Print all the relevant info for the given variant                                           if conseq[0][\u2018allele_string\u2019]:                                           for tcons in conseq[0][\u2018transcript_consequences\u2019]:                                           #... some lines omitted, check exampleREST.py                                           values =                                            for val in values:                                           print                                            print                                           species = \u2018triticum_aestivum\u2019                                           transcript_id = \u2018TraesCS4B02G042700.1\u2019                                           SNPCDScoord = \u2018812\u2019                                           SNPbase = \u2018T\u2019                                           check_snp_consequencesRecipe R8 queries two endpoints (map/cds/ and info/vep/:species/region). The first one translates CDS to genomic coordinates, the second one retrieves the predicted consequences of the SNP in the coding sequence. This recipe can be used to annotate genomic variants in a given gene across germplasm panels, as done in :def che3.7seeseeThe Ensembl VEP tool can be used to predict the effect of variants on genes, transcripts, and protein sequences see. As menthttps://github.com/Ensembl/ensembl-vep.git.Clone the repository: git clone Navigate to the Ensembl VEP directory: cd ensembl-vep.Install Ensembl VEP: perl INSTALL.pl.SPECIES=arabidopsis_thaliana                                          VEPCACHE=\u201c${SPECIES,,}*.tar.gz*\u201d                                          URL=\u201c${SERVER}/${DIV}/release-${EGRELEASE}/variation/vep/                                          ${VEPCACHE}\u201d                                          wget -c \u201c$URL\u201dDownload cache file with recipe F8tar xfz $VEPCACHE                                          grep sift \u201c${SPECIES}/${EGRELEASE}_*/info.txt\u201dUnpack downloaded cache file and check SIFT support:seeEGRELEASE=47                                          VCFILE=ensembl-vep/examples/arabidopsis_thaliana.TAIR10.vcf                                          VEPOPTIONS=                                          ensembl-vep/vep \u201c${VEPOPTIONS[@]\u201dPredict effect of variants, 3.8http://plants.ensembl.org/Triticum_aestivum/Info/Strains?db=core  and \u201cEnsembl REST API\u201d courses (https://www.ebi.ac.uk/training-beta/online/courses/ensembl-rest-api). Any data problems are reported on our blog http://www.ensembl.info/known-bugs. If the available documentation cannot answer your question, a helpdesk is provided (mail helpdesk@ensemblgenomes.org with your query).Documentation for Ensembl Plants, including FAQs, tutorials, and detailed information about the project, datasets, and pipelines that we run can be found under the \u201cDocumentation\u201d and \u201cWebsite help\u201d links at the top of every page. Detailed information for each species can be found on the species homepage. The EMBL-EBI train online website has several free courses on Ensembl, including the recently updated \u201cEnsembl Genomes (non-chordates): Quick tour\u201d ("}
+{"text": "Correction to: Bone Marrow Transplantation10.1038/s41409-019-0766-zy-axis title in this figure should read \u201c% CD34\u201d instead of \u201c% CD45\u201d.Following the publication of this article incorrect labelling of the axis in Fig."}
+{"text": "Correction to: BMC Anesthesiol 20, 248 (2020)https://doi.org/10.1186/s12871-020-01172-xFollowing publication of the original article , the autP\u2009<\u20090.001)\u201d It should be corrected to \u201cThe median number of attempts was lower in ultrasound-assisted group  than landmark-guided group , P\u2009<\u20090.001).\u201dIn the Abstract section, the sentence \u201cThe median number of attempts was lower in ultrasound-assisted group (1 [1]) than landmark-guided group , In the Result section, paragraph\u00a07, the sentence \u201c(Table 5) A subgroup analysis was conducted for 12 patients with scoliosis (Table 6).\u201d should be corrected to \u201cA subgroup analysis was conducted for 12 patients with scoliosis (Table 6).\u201dThe original article has been updated."}
+{"text": "Scientific Reports 10.1038/s41598-019-42523-0, published online 15 April 2019Correction to: The original version of this Article contained errors.The author Tamer R Kosbar was incorrectly affiliated with \u201cPerron Institute for Neurological and Translational Science, Perth, 6150, Australia\u201d. The correct affiliation is listed below.Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, 6150, Australia.OMe/2\u2019-F mixmer 1\u201d and \u201c2-\u2018OMe/2\u2019-F mixmer 2\u201d respectively.There was also an error in Figure 3C, where the x-axis labels \u201cLNA/2\u2019-F mixmer 1\u201d and \u201cLNA/2\u2019-F mixmer 2\u201d were incorrectly given as \u201c2-\u2018The Acknowledgements section contained a typographical error where,\u201cThe authors thank Prof. Steve Wilton and Prof. Sue Fletcher for kindly providing H2K cells, Prithi Raguraman for assistance towards experiments, Yanying An and Jessica Cale for help towards figure preparation and Kristin West for informative discussion.\u201dwas incorrectly given as:\u201cThe authors thank Prithi Raguraman for assistance towards experiments, Yanying An and Jessica Cale for help towards figure preparation and Kristin West for informative discussion.\u201dIn addition, the Supplementary Information file contained an error in Supplementary Figure S3, where the labels of gel C2 were shifted slightly to the right.These errors have now been corrected in the PDF and HTML versions of the Article, as well as in the accompanying Supplementary Information file."}
+{"text": "Page 9: the following sentence should be added to the \u201cData availability\u201d paragraph: \u201cRaw next-generation sequencing data have been deposited in the NCBI SRA database under accession no. SRR11085733 to SRR11085741.\u201dVolume 5, no. 1, e00807-19, 2020,"}
+{"text": "These should have appeared as usual care: \u22120.3 ; intervention: \u22121.8 . This article has been corrected.1In the Original Investigation titled \u201cEffectiveness of Internet-Based Exercises Aimed at Treating Knee Osteoarthritis: the iBEAT-OA Randomized Clinical Trial,\u201d"}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-020-71511-y, published online 03 September 2020Correction to: This Article contains an error in Figure\u00a02: the y axis labels for panels (b) and (c) mistakenly use the unit \u201cpg/ml\u201d, when the correct unit is \u201cng/ml\u201d. As a result, the Figure legend,\u201cEffects of prenatal hormone manipulation  and postnatal temperature manipulation (non-heated vs. heated nests) on offspring phenotype and physiology. (a) Nestling body mass growth pattern ; (b) plasma triiodothyronine (T3) concentration , (c) plasma thyroxine (T4) concentration , (d) mitochondrial density in blood cells , (e) blood total glutathione concentration  and (f) lipid peroxidation . Heated nests were on average 2.75\u00a0\u00b0C warmer than non-heated ones. See text and ESM for details on statistics and sample sizes.\u201dshould read:\u201cEffects of prenatal hormone manipulation  and postnatal temperature manipulation (non-heated vs. heated nests) on offspring phenotype and physiology. (a) Nestling body mass growth pattern ; (b) plasma triiodothyronine (T3) concentration , (c) plasma thyroxine (T4) concentration , (d) mitochondrial density in blood cells , (e) blood total glutathione concentration  and (f) lipid peroxidation . Heated nests were on average 2.75\u00a0\u00b0C warmer than non-heated ones. See text and ESM for details on statistics and sample sizes.\u201dThe correct Figure\u00a02b-c and the correct Figure legend appear below as Figure"}
+{"text": "Correction to: BMC Pregnancy Childbirth 20, 724 (2020)https://doi.org/10.1186/s12884-020-03257-4Following publication of the original article , the autStatement \u201cYLZ and JCC contributed equally to this work.\u201d in the Authors\u2019 contributions section deleted. \u201cYulong Zhang and Jiacheng Chen contributed equally to this work.\u201d was inserted as article note.The original article  has been"}
+{"text": "Correction to: Ital J Pediatr 46, 118 (2020)https://doi.org/10.1186/s13052-020-00881-wAfter publication of this article , it is n\u2018Melaku Desita\u2019 should be corrected to \u2018Melaku Desta\u2019. The author name has been thus updated in this Correction.The original article has also been updated."}
+{"text": "Correction to: BMC Biotechnol 19, 9 (2019)https://doi.org/10.1186/s12896-019-0501-2bold typeface.Following publication of the original article , the autThe correct figure and legends for Figs. In addition, the following textual errors were noted and corrected text is indicated below:\u2018Hind111\u2019 in \u2018Southern blot detection of transgenic plants\u2019 is HindIIIThe enzyme name \u2018microsomal-6 desaturase\u2019 is \u2018microsomal omega-6 desaturase\u2019.The word \u2018transgene\u2019 in the key of Fig. soybean\u2019 is \u2018Go Taq Flexi DNA polymerase\u2019.\u2018G\u00b0Taq Flexi DNA polymerase\u2019 within the results \u2018CRISPR-Cas9 construction for target mutagenesis in \u2018Tengo\u2019 buffer stated in Fig.\u00a03 legend is corrected to \u2018Tango\u2019 buffer."}
+{"text": "Here, we aimed to explore the genome-wide effects of PPAR\u03b3 on EVCTs and VCTs via treatment with the PPAR\u03b3-agonist rosiglitazone. EVCTs and VCTs were purified from human chorionic villi, cultured in vitro, and treated with rosiglitazone. The transcriptomes of both types of cells were then quantified using microarray profiling. Differentially expressed genes (DEGs) were filtered and submitted for gene ontology (GO) annotation and pathway analysis with ClueGO. The online tool STRING was used to predict PPAR\u03b3 and DEG protein interactions, while iRegulon was used to predict the binding sites for PPAR\u03b3 and DEG promoters. GO and pathway terms were compared between EVCTs and VCTs with clusterProfiler. Visualizations were prepared in Cytoscape. From our microarray data, 139 DEGs were detected in rosiglitazone-treated EVCTs (RT-EVCTs) and 197 DEGs in rosiglitazone-treated VCTs (RT-VCTs). Downstream annotation analysis revealed the similarities and differences between RT-EVCTs and RT-VCTs with respect to the biological processes, molecular functions, cellular components, and KEGG pathways affected by the treatment, as well as predicted binding sites for both protein-protein interactions and transcription factor-target gene interactions. These results provide a broad perspective of PPAR\u03b3-activated processes in trophoblasts; further analysis of the transcriptomic signatures of RT-EVCTs and RT-VCTs should open new avenues for future research and contribute to the discovery of possible drug-targeted genes or pathways in the human placenta.Trophoblasts, as the cells that make up the main part of the placenta, undergo cell differentiation processes such as invasion, migration, and fusion. Abnormalities in these processes can lead to a series of gestational diseases whose underlying mechanisms are still unclear. One protein that has proven to be essential in placentation is the peroxisome proliferator-activated receptor  The human placenta serves as a critical bridge between mother and fetus and thus plays a crucial role in maternal and fetal physiology. The placenta is composed mainly of trophoblast cells, which derive from the outer layer of the blastocyst. Certain trophoblasts can be further distinguished as villous cytotrophoblasts (VCTs), whose development progresses along with that of the placenta. In the process of embryo implantation and placenta formation, VCTs that invade the maternal uterus are known as extravillous cytotrophoblasts (EVCTs); these anchor the chorionic villi. Other VCTs differentiate and fuse to form the syncytiotrophoblast layer, which has critical functions in gas and nutrient exchange between the fetus and the mother. Defects in EVCT invasion and VCT differentiation and fusion contribute to a series of gestational diseases, such as fetus-related miscarriage , preterm\u03b3 regulates many downstream target genes involved in lipid metabolism, cell differentiation, and tumorigenesis. PPAR\u03b3 functions by forming a heterodimer with the nuclear receptor retinoid X receptor \u03b1 (RXR\u03b1) and then binding to the PPAR response element (PPRE) of target genes [\u03b3 leads to defects in trophoblast differentiation and abnormal vasculogenesis in mice [\u03b3\u2212/\u2212 embryonic lethality can be rescued via PPAR\u03b3 transfection in the trophoblast [\u03b3 inhibited the invasion of first-trimester EVCTs, which implicates PPAR\u03b3 in the regulation of invasion of the decidua [\u03b3 can also induce the differentiation of VCTs isolated from term placenta [\u03b3 on the regulation of EVCTs and VCTs suggests that it plays a critical role in trophoblast invasion and differentiation but also that these effects differ dramatically among different subtypes of trophoblast. PPAR\u03b3 thus appears to play a crucial but poorly understood role in placental development.As a member of the ligand-dependent nuclear receptor superfamily, PPARet genes . It has  in mice , 6, and phoblast . To be m decidua , 9. Furtplacenta . Taken t\u03b3 in biological processes, the PPAR\u03b3-agonist rosiglitazone has been widely applied to various tissues. In human placenta, rosiglitazone has been used for the study of placental metabolism [In vitro treatment with rosiglitazone has been shown to reverse inflammation of the placenta that is mediated by the PPAR\u03b3-NF-\u03baB pathway [\u03b3 pathway [\u03b3 [\u03b3 in both first-trimester EVCTs and term VCTs, as described in the research cited above on the influence of PPAR\u03b3 in trophoblast invasion and differentiation, was also accomplished by this PPAR\u03b3-agonist. Taken together, these studies show the enormous potential and benefit of rosiglitazone use in studies of the placenta.To explore the role of PPARtabolism , 12, inftabolism , 14, anttabolism , 16, andtabolism . In vitr pathway . Similar pathway . Other ithway [\u03b3 , 18. Fur\u03b3 is exclusively located in the nuclei of EVCTs during the first trimester and of VCTs throughout pregnancy [\u03b3 in these tissues and during these developmental periods. Therefore, our purpose here was to investigate the performance of PPAR\u03b3-activated trophoblasts by analyzing the transcriptomic signatures of rosiglitazone-treated EVCTs (RT-EVCTs) and VCTs (RT-VCTs). In this study, we isolated EVCTs and VCTs from first trimester and term human chorionic villi, respectively; cultured these cells with rosiglitazone; and quantified the transcriptome of each type of cell using microarray analysis, as shown in \u03b3, as well as on the specific genes and pathways targeted, and constitute an invaluable knowledge base for future research.In the human placenta, PPARregnancy \u201321. To dth gestational weeks and at term . Our ethics committee (CCPRB Paris Cochin no. 18-05) approved the collection of placentas from legal and voluntary terminations of pregnancy in the first trimester as well as of the normal term placentas.Placenta samples in this study were collected with patients' written informed consent, in compliance with the Declaration of Helsinki. Placenta tissues were collected from women with normal pregnancies during the 8-92+-, Mg2+-free Hanks' balanced salt solution for membrane removal. Mononucleated VCTs were isolated using digestion with trypsin-DNase and fractionation on a discontinuous Percoll gradient according to the protocol of Kliman et al. [4, 0.25% (wt/vol) trypsin powder (Difco), 100\u2009IU/mL penicillin, 25\u2009mM HEPES, and 100\u2009\u03bcg/mL streptomycin , and monitored under invert microscopy. The initial digested solution (consisting mostly of red blood cells) was discarded while the subsequent digested solution (clearly consisting of EVCTs) was retained. A discontinuous Percoll gradient (5\u201370% in 5% steps) was used to stratify the digested solutions; the middle layer (which included EVCTs) was retained for further analysis. The purified EVCTs were diluted with Dulbecco's modified Eagle's medium (DMEM), with 2\u2009mM glutamine, 100\u2009IU/mL penicillin, 100\u2009mg/mL streptomycin, and 10% decomplemented fetal calf serum (FCS), to a final density of 0.9 \u00d7 106 cells/mL in 60\u2009mm diameter plastic tissue culture dishes . In preparation for culturing, culture plates  were coated with Matrigel\u2122 , then seeded with EVCTs at a density of 5 \u00d7 104 cells/cm2. To maintain continuous culture conditions, DMEM-F12 medium was used that contained 10% heat-inactivated fetal calf serum (FCS), Glutamax, 100\u2009\u03bcg/mL streptomycin, and 100\u2009IU/mL penicillin (Invitrogen). Plates were incubated for 2\u2009h at 37\u00b0C and 5% CO2; then, nonadherent EVCTs were rinsed off. At this point, fresh medium with or without 1\u2009\u03bcM rosiglitazone (Cayman) dissolved at 1\u2009mM in ethanol (treatment) or 0.1% ethanol (vehicle) was added for another 24\u2009h of incubation.As previously described , five efn et al.  and Alsan et al. . In brie6 cells/mL were placed in a humidified incubator at 37\u00b0C under 5% CO2 for 3\u2009h. Nonadherent VCTs were rinsed off, fresh medium with or without 1\u2009\u03bcM rosiglitazone (Cayman) dissolved at 1\u2009mM in ethanol (treatment) or 0.1% ethanol (vehicle) was added, and dishes were incubated for another 24\u2009h.VCTs were isolated from five term placentas using the following procedures. Placentas were oriented with the maternal side facing upwards, and tissues were sampled at a depth of 1.5\u2009cm, half the distance from the edge to the centre. Villous tissues were rinsed, minced, digested, and purified using the steps described above. Culture dishes containing 0.9 \u00d7 10After 24\u2009h of incubation, RT-EVCTs and control EVCTs were harvested for microarray experiments. Cell RNA was extracted using TRIzol\u00ae reagents (Invitrogen) and purified using RNeasy\u00ae Mini Kits (Qiagen). RNA integrity and purity were examined with a 2100 Bioanalyzer with the RNA 6000 LabChip kit (Agilent Technologies). The U133A 2.0 GeneChip  was used for gene expression detection according to the manufacturer's manual. From the 22,000 probe sets on the gene chip, 14,500 genes were detected.\u03bcg total RNA, for RNA amplification, and 3\u2009\u03bcg amplified RNA were then labeled with Cy-dye using the 26 CyScribe first-strand cDNA labeling kit (Amersham Biosciences). Amplified RNA from rosiglitazone-treated VCTs was labeled with Cy5, and amplified RNA from control VCTs was labeled with Cy3. A Microcon YM 30 column (Millipore) was used to purify and concentrate the labeled mixture (Cy5 and Cy3) after additional modifications with human cot-1, yeast tRNA, and poly A. The probes were denatured and the mixture was hybridized at 65\u00b0C overnight in a sealed humidified hybridization chamber, then rinsed with 1XSSC, 2XSSC, 0.03% SDS, and 0.2% SDS solutions for 2\u2009min each. Arrays were scanned with a GenePrix 4000A microarray scanner (Axon Instruments).RT-VCTs and control VCTs were likewise harvested after 24\u2009h of incubation for microarray experiments; RNA extraction, purification, and quality control were performed as described. The SHDZ gene chip (Stanford University) was used for gene detection as described in : for eacSince gene expression in EVCTs and VCTs was detected using different microarray platforms, different procedures were followed for data processing. For EVCT gene expression, which was quantified using the GeneChip  application, data processing used the following filter thresholds: (i) percentage of missing data was no more than 50%, (ii) threshold to identify up- and downregulated genes for statistical comparison was set to a fold change of 1.5, (iii) maximum false discovery rate (FDR) was set to 5%, and (iv) fold change of one gene was equal to mean of treated groups minus mean of control groups and then divided by the minimum value from all (fold\u2009change = (mean\u2009(treated)\u2013mean\u2009(control))/minimum\u2009) . For VCTP values lower than 0.05 identified significant enrichment.ClueGO is a Cytoscape plug-in application for the functional classification of genes . Our anahttps://string-db.org) was used to analyze the interactions of DEG-encoded proteins and construct a PPI network. For this, the significant confidence score was set to greater than 0.4. Cytoscape was used to visualize and organize the PPI network. Proteins interacting with PPAR\u03b3 or RXR\u03b1 were indicated by different colors, and shapes were used to represent different groups. Binding site interactions between transcription factors and target genes were predicted by the Cytoscape plug-in iRegulon . Putative regulatory regions were defined as 10\u2009kb around transcription starting sites. The FDR was set to 0.1% to verify the interaction. The resulting chart was modified in Cytoscape using red to indicate upregulated genes and blue to indicate downregulated genes.The STRING database . Gene expression profiles of the rosiglitazone-treated (TRT) samples of EVCTs and VCTs were normalized (P < 0.05), of which 114 genes were upregulated (red) and 25 genes were downregulated (blue). In RT-VCTs, a total of 197 genes were identified as DEGs (P < 0.05), of which 181 genes were upregulated (red) and 16 genes were downregulated (blue)  .The entire set of DEGs from RT-EVCTs and RT-VCTs was separated by cell type of origin and submitted independently to ClueGO with the default parameters. GO and pathway enrichment were set up for analysis. DEGs were classified by three ways: by GO biological process, GO molecular function, and GO cellular component. Enriched pathways were identified through a search of the KEGG and Reactome databases. The results are visualized in Among the DEGs identified in RT-EVCTs, the main GO biological processes represented were \u201cnegative regulation of epithelial cell apoptotic process,\u201d \u201clong-chain fatty-acyl-CoA biosynthetic process,\u201d and \u201cphosphatidylcholine biosynthetic process.\u201d For the same group of DEGs, the GO molecular functions were mainly classified as \u201calpha-tubulin binding,\u201d \u201cwide pore channel activity,\u201d \u201cpositive regulation of cold-induced thermogenesis,\u201d \u201cglutathione transferase activity,\u201d \u201clong-chain fatty acid binding,\u201d \u201cregulation of cell adhesion mediated by integrin,\u201d and \u201cpositive regulation of non-motile cilium assembly.\u201d Finally, the GO cellular component that was most associated with these DEGs was \u201cdesmosome.\u201d In the pathway enrichment analysis of RT-EVCTs, DEGs were mainly associated with the terms \u201cHIF-1 signaling pathway,\u201d \u201cp53 signaling pathway,\u201d \u201cglutathione metabolism,\u201d \u201cNRAGE signals death through JNK,\u201d \u201cPPAR signaling pathway,\u201d \u201cplasma lipoprotein assembly,\u201d and \u201cremodeling and clearance\u201d.In the analysis of GO terms associated with the RT-VCT dataset, DEGs were mainly involved in the following biological processes: \u201cregulation of receptor biosynthetic process,\u201d \u201cnegative regulation of nucleotide metabolic process,\u201d \u201ccyclic nucleotide biosynthetic process,\u201d and \u201cnegative regulation of B cell apoptotic process.\u201d The molecular functions of this same group of DEGs were mainly linked to \u201cnegative regulation of DNA replication,\u201d \u201cregulation of protein deacetylation,\u201d \u201cubiquitin-like protein conjugating enzyme activity,\u201d \u201cHsp90 protein binding,\u201d \u201cnegative regulation of intracellular protein transport,\u201d and \u201cpositive regulation of phosphoprotein.\u201d With respect to GO cellular components, DEGs were mainly associated with the terms \u201cNuRD complex,\u201d \u201ccellular metabolic compound salvage,\u201d and \u201cimmunological synapse.\u201d Finally, the pathway enrichment analysis of RT-VCTs revealed that DEGs were mainly involved in \u201ctight junction,\u201d \u201cregulation of HIF by oxygen,\u201d \u201cunfolded protein response,\u201d \u201cHIF-1 signaling pathway,\u201d \u201cnuclear receptor transcription pathway,\u201d and \u201cplasma lipoprotein remodeling\u201d.DEGs that were upregulated in RT-EVCTs and RT-VCTs were submitted separately to ClueGO following the same procedure as described above. The results are visualized in Instead, from the DEGs that were upregulated in RT-VCTs, no significant GO biological process was identified. In the classification of GO molecular functions, these DEGs were mainly linked with \u201cpositive regulation of cell cycle\u201d and \u201cmitotic DNA damage checkpoint,\u201d and the most significant GO cellular component was \u201ctranscription factor complex.\u201d In the pathway enrichment analysis, upregulated DEGs in RT-VCTs were mainly associated with the terms \u201cmTOR signaling pathway,\u201d \u201ccell cycle checkpoints,\u201d \u201cDNA repair,\u201d \u201cdevelopmental biology,\u201d \u201cmetabolism,\u201d and \u201cvesicle-mediated transport\u201d.DEGs that were downregulated in RT-EVCTs and RT-VCTs with respect to controls were submitted to ClueGO using the same procedure as described above. Results are visualized in Instead, DEGs that were downregulated in RT-VCTs were mainly involved in the GO biological processes \u201ccyclic nucleotide biosynthetic process,\u201d \u201cnegative regulation of nucleotide metabolic process,\u201d \u201cncRNA 3'-end processing,\u201d and \u201cO-glycan processing;\u201d the GO molecular functions \u201cnuclear receptor activity,\u201d \u201chistone deacetylation,\u201d \u201cregulation of TOR signaling,\u201d \u201cHsp90 protein binding,\u201d \u201cion channel regulator activity,\u201d \u201cnuclear envelope organization,\u201d and \u201cpeptidyl-threonine modification;\u201d and the GO cellular component \u201corganellar ribosome.\u201d In the pathway enrichment analysis of RT-VCTs, downregulated DEGs were mainly associated with the \u201cHIF-1 signaling pathway,\u201d \u201ctransfer of ubiquitin from E1 to E3,\u201d \u201ccell-cell communication,\u201d \u201ctranscription regulation of RUNX3,\u201d and \u201cformation of NR-MED1 coactivator complex\u201d.P values less than 0.05.Next, we wanted to determine the extent to which the cellular processes affected by rosiglitazone treatment were specific to either EVCTs or VCTs, and which instead were present in both tissue types. To do this, we characterized the up- and downregulated DEGs of RT-EVCTs and RT-VCTs separately using clusterProfiler, using information from the GO and KEGG databases, as well as the Disease Ontology (DO) and Disease Gene Network (DisGeNET) databases. Terms appearing in at least three columns were thought important in both, while terms appearing only in the RT-EVCT or RT-VCT dataset were labelled tissue-specific; significance was determined by In both RT-EVCTs and RT-VCTs, the GO biological processes \u201cregulation of endothelial cell migration,\u201d \u201cnon-canonical Wnt signaling pathway,\u201d \u201creceptor metabolic process,\u201d \u201cnegative regulation of protein phosphorylation,\u201d and \u201cmetabolism process\u201d appeared to play important roles. Instead, processes specific to RT-EVCTs included \u201cglycogen catabolic process,\u201d \u201ccellular carbohydrate catabolic process,\u201d \u201cembryo implantation,\u201d \u201cfatty acid derivative biosynthetic process,\u201d and \u201clong-chain fatty-acyl-CoA biosynthetic process,\u201d while those specific to RT-VCTs were \u201ccytoplasmic mRNA processing body assembly,\u201d \u201cribonucleoprotein complex biogenesis,\u201d \u201cpositive regulation of phosphoprotein phosphatase activity,\u201d and \u201cnegative regulation of nucleotide metabolic process\u201d .The GO molecular functions \u201cnuclear hormone receptor binding,\u201d \u201clong-chain fatty acid binding,\u201d \u201cfatty acid binding,\u201d \u201cnuclear activity,\u201d and \u201ctranscription factor activity\u201d seemed to be important in both RT-EVCTs and RT-VCTs. Functions specific to RT-EVCTs included \u201csteroid hormone receptor binding,\u201d \u201ceicosanoid receptor activity,\u201d \u201cphosphatidylinositol phosphate kinase activity,\u201d and \u201cfatty acid ligase activity,\u201d while those specific to RT-VCTs were \u201cWnt-activated receptor activity,\u201d \u201ccyclin-dependent protein kinase activity,\u201d \u201ctransferase activity,\u201d and \u201cubiquitin-specific protease activity\u201d .Both tissue types shared the significant GO cellular components \u201csmooth endoplasmic reticulum,\u201d \u201cruffle,\u201d \u201ctranscription factor complex,\u201d \u201capical plasma membrane,\u201d \u201clumen,\u201d and \u201ccell-cell junction.\u201d Instead, the component terms \u201cbeta-catenin destruction complex,\u201d \u201cM band,\u201d \u201cintegral component of lumenal side of endoplasmic reticulum membrane,\u201d and \u201cA band\u201d were found only in RT-EVCTs, while \u201cspliceosomal complex,\u201d \u201cWnt signalosome,\u201d \u201cpronucleus,\u201d \u201cmicrotubule end,\u201d and \u201cautophagosome membrane\u201d appeared to be specific to RT-VCTs .Through a search of the KEGG database, the following pathways appeared to be important in both tissue types: \u201cprotein processing in endoplasmic reticulum,\u201d \u201cglucagon signaling pathway,\u201d \u201cEpstein-Barr virus infection,\u201d \u201cPPAR signaling pathway,\u201d \u201cHIF-1 signaling pathway,\u201d \u201cprogesterone-mediated oocyte maturation,\u201d and \u201cmTOR signaling pathway.\u201d Pathway terms specific to RT-EVCTs included \u201cprimary immunodeficiency\u201d and \u201cfatty acid metabolism,\u201d while those specific to RT-VCTs were linked with \u201cbacterial invasion of epithelial cells\u201d and \u201cparathyroid hormone synthesis, secretion, and action\u201d .From the Disease Ontology database, the terms \u201cpreeclampsia,\u201d \u201cHELLP syndrome,\u201d \u201cspinocerebellar ataxia,\u201d \u201cfamilial hyperlipidemia,\u201d \u201clipid metabolism disorder,\u201d and \u201cmusculoskeletal system cancer\u201d were important in both EVCTs and VCTs. Terms specific to RT-EVCTs included \u201cbreast benign neoplasm,\u201d \u201cthoracic benign neoplasm,\u201d \u201clipomatous cancer,\u201d \u201camyloidosis,\u201d and \u201cvein disease,\u201d while those specific to RT-VCTs were \u201calveolar rhabdomyosarcoma,\u201d \u201costeopetrosis,\u201d \u201cgiant cell tumor,\u201d and \u201cgerm cell and embryonal cancer\u201d .From a search of the DisGeNET database, the terms \u201cpreeclampsia,\u201d \u201chypertrophic cardiomyopathy,\u201d \u201cimmunologic deficiency syndromes,\u201d \u201cdiabetes mellitus,\u201d \u201cvascular inflammations,\u201d \u201chematopoietic neoplasms,\u201d \u201cnon-alcoholic fatty liver disease,\u201d \u201cvascular disease,\u201d \u201cischemic cardiomyopathy,\u201d and \u201ctriploidy syndrome\u201d were significant for both tissue types. Instead, \u201cchronic neutrophilic leukemia,\u201d \u201cglycogen storage disease,\u201d and \u201cmyeloid, chronic, atypical, and BCR-ABL negative leukemia\u201d were specific to RT-EVCTs, and \u201calport syndrome\u201d and \u201caggressive non-Hodgkin lymphoma\u201d were specific to RT-VCTs .\u03b3 by rosiglitazone, we next attempted to predict (i) the protein-protein interactions (PPI) of PPAR\u03b3 with DEG-encoded proteins and (ii) the transcription factor-target gene (TF-TG) interactions of PPAR\u03b3 with DEG promoters. In RT-EVCTs ; concentrations of up to 100\u2009\u03bcM of this compound have been reported to activate only PPAR\u03b3 . Moreovinvasion . In this\u03b3 in trophoblasts, in this study, we also analyzed gene expression changes in VCTs using microarray profiling, and, through various approaches, identified the enriched processes that were linked with these DEGs in RT-EVCTs and RT-VCTs. We were thus able to compare the similarities and differences between EVCTs and VCTs affected by activated PPAR\u03b3. In total, there were 139 DEGs in RT-EVCTs and 197 DEGs in RT-VCTs, and these were associated with enrichment in more than 200 GO and pathway terms  and NCoR (nuclear receptor corepressor), which block transactivation or the transcriptional coactivators CREB-binding protein (CBP), histone acetyltransferase p300 (p300), and PPAR-binding protein (PBP), which have the opposite effect [\u03b3 might affect the transcription complex formed by PPAR\u03b3 and RXR\u03b1, their cofactors or transcription partners, which could then lead to alterations in the regulation of different transcription circuits. Our results provided evidence for direct protein-protein and protein-promoter interaction with the PPAR\u03b3 complex. Among the proteins that appear to interact directly with PPAR\u03b3, several have been experimentally verified, including ANGPTL4 [\u03b3-MAPK-MMP signaling pathway. Commonly, phosphorylated PPAR\u03b3 stimulates the MAPK-activated pathway, leading to the activation of extracellular signal-regulated kinases (ERKs) that then induce the upregulation of matrix metalloproteinase (MMP) [\u03b3 activation. In addition to the direct target genes predicted here, the genes in secondary relationships should be paid equal attention in terms of potential regulation by other target genes. For example, our previous research has shown the key role of LOX1, through secondary interactions, in cytotrophoblast invasion [Finally, in order to facilitate study of the mechanisms behind the molecular interactions, we attempted to predict the protein-protein interactions between the DEGs recovered here and PPARe effect . We prop ANGPTL4 \u201361, ABCG ANGPTL4 , APOB [6 ANGPTL4 , CCNE1 [ ANGPTL4 , CPT1B [ ANGPTL4 , FABP4 [ ANGPTL4 \u201369, HMOX ANGPTL4 , and SER ANGPTL4 , 72. Manse (MMP) \u201375. Herese (MMP) , which iinvasion .\u03b3 activation in EVCTs and VCTs, highlighting extensive changes in gene expression and the biological processes and pathways affected. This study provides a broad perspective of PPAR\u03b3-influenced biological processes in trophoblasts and facilitates further study, particularly into potential drug-targeted genes or pathways in the human placenta.To our knowledge, our results reveal for the first time the widespread effects of PPAR"}
+{"text": "Couto, MD (Video).Please watch a video commentary on \u201cThe Combined Effect of Intravenous and Topical Tranexamic Acid in Liposuction: A Randomized Double-Blinded Controlled Trial\u201d"}
+{"text": "Scientific Reports 10.1038/s41598-019-47135-2, published online 23 July 2019Correction to: This Article contains errors in the Methods section under subheading \u2018Final molecular docking procedure\u2019.\u201cAutoDock Vina generates different ligands conformers using a Lamarkian genetic algorithm (LGA). The GA is implemented with an adaptive local method search\u201dshould read:\u201cAutoDock Vina generates different ligands conformers using a Broyden-Fletcher-Goldfarb-Shanno (BFGS) algorithm. The BFGS is implemented with an iterated local method search\u201d"}
+{"text": "Scientific Reports 10.1038/s41598-020-71435-7, published online 07 September 2020Correction to: This Article contains an error in Figure\u00a02, where a corruption has affected panels (d) and (e). The correct Figure\u00a02d, e appears below as Figure"}
+{"text": "In early-stage (cT1-2N0) oral cancer, occult lymph node metastases are present in 20\u201330% of patients. Accordingly, accurate staging of the clinically negative cervical nodal basin is warranted in these patients. Sentinel lymph node biopsy has proven to reliably stage the clinically negative cervical nodal basin in early-stage oral cancer. However, due to the limited resolution of conventional sentinel lymph node imaging, occult lymph node metastasis may be missed in particular circumstances. Therefore, technical developments are necessary to bring the diagnostic accuracy of sentinel lymph node biopsy, in early-stage oral cancer, to a higher level. This review evaluates novel sentinel lymph node imaging techniques for early-stage oral cancer, such as MR lymphography, CT lymphography, PET lymphoscintigraphy and contrast-enhanced lymphosonography. Their reported diagnostic accuracy is described and their relative merits, disadvantages and potential applications are outlined.99mTc]-labelled radiotracer followed by lymphoscintigraphy and SPECT-CT imaging. Based on these imaging results, the identified SLNs are marked for surgical extirpation and are subjected to histopathological assessment. The routine SLNB procedure has proven to reliably stage the clinically negative neck in early-stage oral squamous cell carcinoma (OSCC). However, an infamous limitation arises in situations where SLNs are located in close vicinity of the tracer injection site. In these cases, the hotspot of the injection site can hide adjacent SLNs and hamper the discrimination between tracer injection site and SLNs (shine-through phenomenon). Therefore, technical developments are needed to bring the diagnostic accuracy of SLNB for early-stage OSCC to a higher level. This review evaluates novel SLNB imaging techniques for early-stage OSCC: MR lymphography, CT lymphography, PET lymphoscintigraphy and contrast-enhanced lymphosonography. Furthermore, their reported diagnostic accuracy is described and their relative merits, disadvantages and potential applications are outlined.Sentinel lymph node biopsy (SLNB) is a diagnostic staging procedure that aims to identify the first draining lymph node(s) from the primary tumor, the sentinel lymph nodes (SLN), as their histopathological status reflects the histopathological status of the rest of the nodal basin. The routine SLNB procedure consists of peritumoral injections with a technetium-99m [ In early-stage cT1-2N0) oral squamous cell carcinoma (OSCC), occult lymph node metastases are present in 20\u201330% of patients, even when the status of the regional lymph nodes has been evaluated using combinations of advanced clinical diagnostic imaging modalities , magnetic resonance imaging (MRI) and/or computed tomography (CT)) -2N0 oral,5,6. AltThe concept of SLNB is based on the premise that lymph flow from the primary tumor travels sequentially to the sentinel lymph node (SLN) and then on to the other regional lymph nodes. Hence, the SLN is the lymph node that has the highest risk of harboring metastasis .The SLNB procedure aims to identify these first draining lymph node(s), as their histopathological status reflects the histopathological status of the rest of the nodal basin. Complementary nodal treatment  should be performed in case of metastatic involvement of SLN(s). A negative SLNB, however, would justify a wait-and-scan policy .99mTc; \u03b3-emitter]-labelled radiotracer followed by planar dynamic and static lymphoscintigraphy including SPECT-CT (single photon emission computed tomography-computed tomography) imaging. Based on preoperative lymphoscintigraphy, the position of the SLN(s) is marked on the skin. The marked SLNs are surgically removed, using a portable \u03b3-probe for intraoperative localization of SLNs. Subsequently, the harvested SLNs are subjected to meticulous histopathological assessment using step-serial-sectioning and immunohistochemistry -phytate was administered peritumorally, followed by planar lymphoscintigraphy. Intraoperatively, SLNs were localized using a conventional \u03b3-probe and were submitted for individual histopathological assessment. All SLNs depicted on 10 min MR lymphography were in accordance with planar lymphoscintigraphy and \u03b3-probe findings. MR lymphography at 30 min and 24 h post-injection showed more uptake of SPIO in SLNs. However, MR lymphography 24 h post-injection also visualized higher echelon nodes (HEN). Besides, on MR lymphography SPIO-induced streak artifacts were seen around the injection site, but did not prevent identification of SLNs in vicinity of the tracer injection site. Histopathological assessment confirmed presence of iron in all harvested SLNs. In one patient nodal metastases were found in a harvested SLN; no additional metastases were seen in the neck dissection specimen. No follow-up results were reported in this study. In two patients, tissue swelling was observed at the injection site after administration of SPIO, which was attributed to the volume of SPIO injected.Mizokami et al. performed MR lymphography using SPIO in three tongue cancer patients (cT2N0), planned for tumor resection and ipsilateral elective neck dissection . Seven d99mTc]-nanocolloid and SPIO (Resovist), in total 0.5 mL, was peritumorally injected on the day before surgery. MR lymphography was acquired 2 h post-injection. Lymph nodes were assessed as SLN if they corresponded with SPECT images and exhibited signal loss on T2*-weighted sequences. SPECT-MRI fusion was successful in both OSCC patients and showed corresponding SLNs. Intraoperatively, SLNs were localized using a \u03b3-probe and were sent for individual histopathological assessment. SLN metastases were found in the contralateral neck of one OSCC patient, leading to a complementary contralateral neck dissection. No  lymph node metastases were found in the neck dissection specimens of both patients. No follow-up results were reported.Maza et al. evaluated fusion of lymphoscintigraphic SPECT, SPIO MR lymphography and CT, for identification of SLNs in rather complex anatomical regions . FourteeAnother approach for high-resolution lymphography regards computed tomography (CT) lymphography using peritumoral administered iodine-based contrast agents. The use of CT lymphography has been investigated in several tumor types including breast, lung, esophageal, gastric and skin cancer ,61,62,63For reviewing the application of CT lymphography in early-stage OSCC, the systematic literature search led to retrieval of 112 PubMed indexed articles for CT lymphography, of which 17 were considered relevant ,70,71,72The case report of Saito et al.  was the n = 31; oral tongue) was reported by Honda et al. , [60Co])-labelled radiotracer, generally used for conventional lymphoscintigraphy, PET lymphoscintigraphy requires a positron emitting isotope -labelled radiotracer -labelled nanocolloid [99mTc]-labelled nanocolloid was performed. The results of PET and SPECT lymphoscintigraphy were compared. PET lymphoscintigraphy was able to visualize all foci (n = 22) that were identified on SPECT-CT and even visualized 5 additional foci that were considered to be SLNs; all of which were located near the injection site of the primary tumor  gas surrounded by a thin biocompatible shell generally made of phospholipids or proteins -labelled nanocolloid for SLN detection in OSCC patients, by visualizing all foci identified on SPECT-CT and even detecting 5 additional SLNs in vicinity of the tracer injection site. Additionally, in 80% of patients, lymphatic vessels were visualized and 2 lingual lymph nodes (7%) were identified as SLNs  and a \u03b3-emitter  could allow high-resolution preoperative PET lymphoscintigraphy and intraoperative localization of SLNs using the conventional portable \u03b3-probe. However, due to its half-life of 78.4 h, [89Zr] will interfere with the [99mTc]-signal [99mTc]-signal for intraoperative localization of SLNs using the conventional portable \u03b3-probe.To overcome the problems with the use of a PET-probe, a radiotracer labelled with both -signal . Therefo18F] is considered the ideal radioisotope for PET imaging owing to the low positron energy (0.64 MeV), providing high-resolution images. Furthermore, [18F] has a half-life of only 110 min [18F] relies on C\u2212F bond formation and is therefore difficult to label to currently used radiotracers for SLNB  [18F]-FDG has been investigated in patients with cervical or endometrial cancer and in healthy subjects [18F]-FDG was not considered feasible due to significant tracer washout to systemic capillaries  is a good candidate due to its half-life of only 68 min and its production with a [68Ga]-generator, which provides an opportunity to prepare PET-radiopharmaceuticals on site when needed  is complicated, mainly due to instability of the bond between [68Ga] and nanocolloids [68Ga] has been successfully labelled to tilmanocept [68Ga] and [99mTc]. The resulting tri-modal agent provides high-resolution preoperative PET-images for SLN mapping and intraoperative localization of SLNs with both a conventional portable \u03b3-probe and fluorescence imaging  manocept . Moreove imaging . This tr imaging ,110. AltCompared to conventional lymphoscintigraphy, lymphosonography has many advantages . ImportaHowever, lymphosonography has some disadvantages . Foremos6 phospholipid microbubbles with a mean bubble diameter of ~2.5 \u03bcm ) or  or (\u201cHead and Neck\u201d) and (\u201cSentinel lymph node\u201d[MeSH]) or (\u201cLymph\u201d) and (\u201cNode\u201d) or (\u201cSentinel\u201d) and (\u201cNode\u201d) or (\u201cSentinel node\u201d) and (\u201cLymphography\u201d[MeSH]) or (\u201cLymphography\u201d) or (\u201cLymphangiography\u201d) and (\u201cMagnetic resonance imaging\u201d[MeSH] or (\u201cMagnetic\u201d) and (\u201cResonance\u201d) and (\u201cImaging\u201d) or (\u201cMagnetic resonance imaging\u201d) or (\u201cMRI\u201d) or (\u201cMR\u201d).For magnetic detection of SLNs using superparamagnetic iron oxide, the following keywords and MeSH terms were included: (\u201cMouth\u201d[MeSH]) or  or (\u201cHead and Neck\u201d) and (\u201cSentinel lymph node\u201d[MeSH]) or (\u201cLymph\u201d) and (\u201cNode\u201d) or (\u201cSentinel\u201d) and (\u201cNode\u201d) or (\u201cSentinel node\u201d) and (\u201cIron\u201d[MeSH]) or (\u201cIron oxide\u201d) or (\u201cSPIO\u201d) or (\u201cSPION\u201d) and (\u201cMagnetics\u201d[MeSH] or (\u201cMagnetic\u201d) or (\u201cSuperparamagnetic\u201d) or (\u201csuperparamagnetic iron oxide\u201d).The following keywords and MeSH terms were included for CT lymphography: (\u201cMouth\u201d[MeSH]) or  or (\u201cHead and Neck\u201d) and (\u201cSentinel lymph node\u201d[MeSH]) or (\u201cLymph\u201d) and (\u201cNode\u201d) or (\u201cSentinel\u201d) and (\u201cNode\u201d) or (\u201cSentinel node\u201d) and (\u201cLymphography\u201d[MeSH]) or (\u201cLymphography\u201d) and (\u201cCT\u201d) or (\u201cComputed Tomography\u201d) or (\u201cComputed\u201d) or (\u201cTomographic\u201d).The following keywords and MeSH terms were included for PET lymphoscintigraphy: (\u201cMouth\u201d[MeSH]) or  or (\u201cHead and Neck\u201d) and (\u201cSentinel lymph node\u201d[MeSH]) or (\u201cSentinel lymph node\u201d) or (\u201cSentinel\u201d) and (\u201cNode\u201d) or (\u201cSentinel node\u201d) and (\u201cPositron Emission Tomography Computed Tomography\u201d[MeSH]) or (\u201cPositron-Emission Tomography\u201d[MeSH]) or (\u201cPET\u201d) or (\u201cPositron\u201d) or (\u201cPET/CT\u201d) or (\u201cPET-CT\u201d).The following keywords and MeSH terms were included for contrast-enhanced ultrasound lymphography: (\u201cMouth\u201d[MeSH]) or  or (\u201cHead and Neck\u201d) and (\u201cSentinel lymph node\u201d[MeSH]) or (\u201cSentinel lymph node\u201d) or (\u201cSentinel\u201d) and (\u201cNode\u201d) or (\u201cSentinel node\u201d) and (\u201cContrast-enhanced\u201d) or (\u201cContrast-assisted\u201d) or (\u201cCEUS\u201d) or (\u201cMicrobubbles\u201d) or (\u201cSonovue\u201d) or (\u201cSonazoid\u201d) or (\u201cOptison\u201d) or (\u201cLevovist\u201d) or (\u201cImagent\u201d) or (\u201cImavist\u201d) or (\u201cDefinity\u201d) and (\u201cDiagnostic Imaging\u201d) or (\u201cDiagnostic\u201d) and (\u201cImaging\u201d) or (\u201cUltrasound\u201d) or (\u201cUltrasonography\u201d[MeSH]) or (\u201cUltrasonography\u201d) or (\u201cUltrasonics\u201d[MeSH]) or (\u201cUltrasonics\u201d).99mTc]-labelled radiotracers. Nevertheless, several of these novel techniques may already become valuable by facilitating more targeted radiotherapy; adjusting the radiation dose based on the tumor\u2019s individual lymphatic drainage pattern.Novel diagnostic imaging techniques for detection of SLNs have the potential to bring the diagnostic accuracy of SLNB to a higher level for all early-stage OSCC subsites. However, technical improvements and further research of these novel techniques are required, if they are to replace the conventional SLNB procedure with ["}
+{"text": "Evidence-Based Complementary and Alternative Medicine has retracted the article titled \u201cGinseng on Hyperglycemia: Effects and Mechanisms\u201d [hanisms\u201d , this arWu Z, Luo JZ, Luo L. \u201cAmerican ginseng modulates pancreatic beta cell activities.\u201d Chin Med. 2007 Oct 25; 2:11."}
+{"text": "Scientific Reports 10.1038/s41598-018-37925-5, published online 04 February 2019Correction to: The Article contains an error in the Acknowledgements section.\u201cDr. Garc\u00eda-Porta is supported by the European Union through the Marie-Sklodowska Curie IF program 2016\u201dshould read:\u201cThis project has received funding from the European Union\u2019s Horizon 2020 research and innovation programme under the Marie Sk\u0142odowska-Curie grant agreement No 747441\u201d"}
+{"text": "Following the publication of this article , the autTherefore, the fourth paragraph under Recommendation #24 should be amended to read:\u201cLanadelumab (Takeda), a fully human monoclonal antibody against kallikrein, takes approximately 70\u00a0days to reach a steady state concentration [110], and is therefore not recommended for STP\u2026\u201dSimilarly, the first paragraph under Recommendation #27 should be amended to read:\u201cLanadelumab is a subcutaneously injectable, fully human, anti-active plasma kallikrein monoclonal antibody (IgG1/\u03ba-light chain)\u2026\u201d"}
+{"text": "Scientific Reports 10.1038/s41598-020-63910-y, published online 22 April 2020Correction to: This Article contains an error in the p-value reported for scores in the Patient Health Questionnaire-4 (PHQ-4).As a result, in the Results section, under the subheading \u2018Comparison between self-defined vegetarians/vegans and omnivores\u2019,\u201cSimilarly, vegetarians/vegans had significantly higher eating disorder psychopathology in the EDE-Q8 \u2009=\u20092.619, p\u2009=\u20090.009), as well as slightly, but not significantly, higher depression scores in the PHQ-4 \u2009=\u20092.327, p\u2009=\u20090.21) scores compared to omnivores\u201dshould read:\u201cSimilarly, vegetarians/vegans had significantly higher eating disorder psychopathology in the EDE-Q8 \u2009=\u20092.619, p\u2009=\u20090.009), as well as significantly higher scores in the PHQ-4 \u2009=\u20092.327, p\u2009=\u20090.021) compared to omnivores\u201dFurthermore, the incorrect p-value is also reported in Table 4. In the \u2018Statistics\u2019 column for row \u2018PHQ-4, mean (SD)\u2019,\u201cp\u2009=\u20090.21\u201dshould read:\u201cp\u2009=\u20090.021\u201d"}
+{"text": "Scientific Reports 10.1038/s41598-019-48060-0, published online 08 August 2019Correction to: In Figure 1, the plots of \u2018Asendorf 2015\u2019, \u2018Asendorf 2016\u2019 and \u2018Triesdorf 2016\u2019 have incorrect Y-axis scale measurements. The correct Figure"}
+{"text": "Correction to: CVIR Endovasc (2018) 1:30https://doi.org/10.1186/s42155-018-0039-8\u2018In the published article (Venturini et al. \u201cNot applicable\u201dshould read:\u201cInformed consent for publication of this case report and its accompanying images has been obtained from the patient\u201d"}
+{"text": "CorrectionThe Open Respiratory Medicine JournalBCG Vaccine does not Protect Against COVID-191,* and Ghada E. Amin1Mohamed F. Allam45-46The Open Respiratory Medicine Journal, 2020, 14: The following changes have been made in the article:1- Second author\u2019s name has been changed as follows:\u2003\u2003\u2003\u2003\u2003\u2003Ghada E. Amin"}
+{"text": "Nature Communications 10.1038/s41467-020-20836-3, published online 23 February 2021.Correction to: The original version of this Article contained an error in Equation (1). The equation incorrectly included a \u201c+\u201d sign within the \u201cgrowth-climate interactions\u201d term. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-020-65158-y, published online 21 May 2020Correction to: In Figure\u00a0In addition, a typesetting error led to the following sentence being incorrectly displayed as a sub-heading in the Introduction. It should be read as plain text.\u201cDifferent outcomes would support different theories\u201d"}
+{"text": "Nephrol Dial Transplant 2018; gfy351. doi: 10.1093/ndt/gfy351In Table 3 of the above article \u201cCompletion of RR\u201d has been corrected to \u201cNon-completion of RR\u201d."}
+{"text": "Scientific Reports 10.1038/s41598-019-50418-3, published online 25 September 2019Correction to: This Article contains\u00a0an error in the Methods section under subheading \u2018Embryo preparation\u2019.\u201cAll experiments were approved by the Animal Research Committee of SNFRI\u201dshould read:\u201cAll experiments were approved by the Animal Experiment Committee of SNFRI\u201d."}
+{"text": "A\u00a044-year-old man was admitted for an inferior ST-elevation myocardial infarction (STEMI), for which he underwent successful primary percutaneous coronary intervention of the occluded right coronary artery (RCA). Several hours later, ST-segment monitoring revealed a\u00a0strikingly regular pattern of intermittent inferior ST-elevation, confirmed by 12-lead electrocardiography (Fig.\u00a0Cyclic ST-elevation after acute coronary syndromes has been described previously . I\u00a0found"}
+{"text": "Trichosanthes tricuspidata Lour. Methanol Extract Exhibits Anti-Inflammatory Activity by Targeting Syk, Src, and IRAK1 Kinase Activity\u201d [In the article titled \u201cctivity\u201d . The aut"}
+{"text": "Correction to: Journal of Orthopaedic Surgery and Research 15, 390 (2020)https://doi.org/10.1186/s13018-020-01896-zData sources, part of Methods section as follows:Following publication of the original article , the aut\u201cThe main searching keywords included the following:  AND .\u201dShould be changed to:\u201cThe main searching keywords included the following:  AND  AND (\u201costeoporosis\u201d).\u201d"}
+{"text": "The authors of \u201cTowards a cancer mission in Horizon Europe: recommendations\u201d : 1589\u20101615. PMID: 32749074) ["}
+{"text": "Scientific Reports 10.1038/s41598-020-60502-8, published online 27 February 2020Correction to: This Article contains an error in Figure 1 where,\u2018Serovar Typimurium\u2019should read:\u2018Serovar Typhimurium\u2019In addition, the bars corresponding to Serovar Typhimurium are missing.The correct Figure"}
+{"text": "Scientific Reports 10.1038/s41598-019-42019-x, published online 08 April 2019Correction to: This Article contains an error in the order of the Figures. Figures\u00a0In addition, there is an error in Figure 6B, where \u201cCor>WL\u201d should read \u201cCor<WL\u201d.The correct Figures appear below."}
+{"text": "Childhood-onset asthma is highly affected by genetic components. In recent years, many genome-wide association studies (GWAS) have reported a large group of genetic variants and susceptible genes associated with asthma-related phenotypes including childhood-onset asthma. However, the regulatory mechanisms of these genetic variants for childhood-onset asthma susceptibility remain largely unknown.N\u2009=\u2009314,633) and two independent expression quantitative trait loci (eQTL) datasets (N\u2009=\u20091890). Furthermore, we applied various bioinformatics analyses, including MAGMA gene-based analysis, pathway enrichment analysis, drug/disease-based enrichment analysis, computer-based permutation analysis, PPI network analysis, gene co-expression analysis and differential gene expression analysis, to prioritize susceptible genes associated with childhood-onset asthma.In the current investigation, we conducted a two-stage designed Sherlock-based integrative genomics analysis to explore the cis- and/or trans-regulatory effects of genome-wide SNPs on gene expression as well as childhood-onset asthma risk through incorporating a large-scale GWAS data (PSMB9 (cis-rs4148882 and cis-rs2071534) and TAP2 . These 31 genes were functionally interacted with each other in our PPI network analysis. Our pathway enrichment analysis showed that numerous KEGG pathways including antigen processing and presentation, type I diabetes mellitus, and asthma were significantly enriched to involve in childhood-onset asthma risk. The co-expression patterns among 31 genes were remarkably altered according to asthma status, and 25 of 31 genes (25/31\u2009=\u200980.65%) showed significantly or suggestively differential expression between asthma group and control group.Based on comprehensive genomics analyses, we found 31 genes with multiple eSNPs to be convincing candidates for childhood-onset asthma risk; such as, We provide strong evidence to highlight 31 candidate genes for childhood-onset asthma risk, and offer a new insight into the genetic pathogenesis of childhood-onset asthma. Asthma is a complex and chronic respiratory disease that is diagnosed by evaluating the presence of reversible airflow obstruction and clinical symptoms, including cough, wheeze, and episodic shortness of breath . Around In the past decade, a plenty of genetic studies including candidate gene-based association studies, positional cloning studies, and genome-wide association studies (GWAS) have been performed to investigate the genetic architecture of both childhood-onset and adult-onset asthma . Especiacis- and/or trans-regulatory roles in modulating the expression level of a specific gene [cis with transcript levels of ORMDL3 are determinants of susceptibility to childhood asthma. Accumulating genomics studies have reported to explore whether GWAS-nominated genes whose differential changes of transcription levels are correlated with complex diseases due to pleiotropy [To complement the typical GWAS analysis for individual SNPs, more integrative genomics studies by integrating GWAS data with other layers of omics data are warranted to identify sets of functional genes for childhood-onset asthma risk. Previous studies , 24 havefic gene . For exafic gene  have demeiotropy \u201330. Receeiotropy  introduceiotropy , major deiotropy , 33, andeiotropy .In current study, the primary goal is designed to identify whether GWAS-nominated SNPs are correlated with both gene expression and childhood-onset asthma risk, and highlight novel susceptible genes. In the discovery stage, we conducted a Sherlock-based integrative genomics analysis by integrating a large-scale GWAS summary dataset with an eQTL dataset to identify expression-associated SNPs and risk genes for childhood-onset asthma. To validate the findings of the discovery stage, we re-performed the Sherlock analysis in an independent eQTL dataset. Furthermore, we employed systematical bioinformatics-based analyses based on multi-layers of evidence to highlight the underlie roles of novel identified genes in the pathogenesis of childhood-onset asthma.In the present study, we employed a large-scale GWAS summary dataset on childhood-onset asthma  for idenhttp://www.affymetrix.com) containing a total of 900,392 SNPs was employed to do the genome-wide genotyping. After utilizing a strict quality control of HWE, GCR, and MAF, a number of 675,350 SNPs remain for subsequent analysis. In addition, the Illumina HT-12 v3 BeadChip (http://www.Illumina.com) was used to conduct a genome-wide expression analysis for assessing the RNA expression levels of 37,804 genes. Among these genes, there were 22,305 genes obtaining prominent expression. Then, after omitting not well-characterized genes, a number of 12,808 well-characterized genes were chosen in the eQTL analysis.We first employed the monocyte eQTL dataset reported by Zeller et al.  as the dWe further used the eQTL dataset published by Dixon et al.  to carryP value is computed by the Sherlock analysis for each gene through simulation. The significance of each gene is adjusted by the Benjamini-Hochberg correction for multiple testing.Here, we used the Sherlock analysis  by poolihttps://ctg.cncr.nl/software/magma) [P values were extracted from childhood-onset asthma GWAS summary data as input for MAGMA gene-level analysis. For the MAGMA software, the multiple regression model was used to incorporate the linkage disequilibrium (LD) information among SNPs within a specific defined gene region and identify multi-variant combined effects. The SNP set of each gene was defined according to the location of the SNP whether located into the gene region or within extended +/\u2212\u200920\u2009kb downstream or upstream of the gene [P values.As an independent technique for providing supportive evidence of risk genes identified by Sherlock integrative analysis, we employed a gene-based analysis with the use of Multi-marker Analysis of GenoMic Annotation  . The SNPthe gene . We usedhttp://www.david.niaid.nih.gov) [P value of each enrichment analysis. We used the Benjamini-Hochberg procedure to compute the false discovery rate (FDR) for multiple testing.To annotate biological pathways and molecular functions of these identified genes by Sherlock Bayesian integrative analysis, we employed a pathway-based enrichment analysis with the use of the Database for Annotation, Visualization, and Integrated Discovery  . Based onih.gov) , we attehttp://www.webgestalt.org) [Based on the identified gene list, we used the online database of WEB-based Gene SeT AnaLysis Toolkit   to perfoalt.org)  and GLADalt.org) , and enralt.org)  and GLADalt.org)  databasetotal\u2009=\u2009100,000 times) to determine whether genes identified in the discovery stage were significantly overlapped with that identified from the replication stage and MAGMA analysis  by comparison with genes selected from background. By randomly choosing the same number as the significant genes from whole genes as background of each dataset  for 105 times, we counted the number of genes from random selection overlapped with genes identified in the discovery stage . Subsequently, we computed how many times of the number of genes for random selections were larger than the number of genes for real observation. Empirical P value = P value less than or equal to 0.05 considers to be significant.As a previous study , we herehttp://www.genemania.org) [With the use of GeneMANIA software (nia.org) , we perfN\u2009=\u200937) and severe asthma (N\u2009=\u200975) from the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) consortium. Blood samples of this cross-sectional study were collected at baseline. Significance was examined by using Student\u2019s T-test. P\u2009\u2264\u20090.05 was considered to be significant. The second used dataset of GSE103166 [N\u2009=\u200956) and age-matched controls (N\u2009=\u200931). For this dataset, a group of convalescent samples were also collected from children with follow-up at least 6\u2009weeks after an acute exacerbation of asthma or wheeze (N\u2009=\u200919). One-way ANOVA analysis was used to calculate the significance among control, convalescent, and asthma groups. In addition, we performed a co-expression patterns analysis of these identified risk genes among different groups. We made the R script for this co-expression pattern analysis available in the public github website (https://github.com/mayunlong89/CoA/blob/master/co_expression_pattern.R).We further downloaded two RNA expression datasets from NCBI GEO database (Accession Nos. GSE123750 and GSE103166) to replicate the functionality of these 31 identified genes. The first analyzed dataset of GSE123750 was based on blood RNA expression profiles that were collected samples from school-aged children who presented to mild-to-moderate asthma  with eQTL data (N\u2009=\u20091490) to identify whether abnormal gene expression convey susceptibility to childhood-onset asthma by using the Sherlock Bayesian analysis. Figure\u00a0HLA-DRD3 (FDR\u2009=\u20092.05\u2009\u00d7\u200910\u2212\u20094), HLA-DQA1 (FDR\u2009=\u20092.05\u2009\u00d7\u200910\u2212\u20094), HLA-DRB4 (FDR\u2009=\u20092.05\u2009\u00d7\u200910\u2212\u20094), NOTCH4 (FDR\u2009=\u20092.05\u2009\u00d7\u200910\u2212\u20094), PSMB9 (FDR\u2009=\u20092.05\u2009\u00d7\u200910\u2212\u20094), PALZ (FDR\u2009=\u20092.05\u2009\u00d7\u200910\u2212\u20094), HLA-DRB5 (FDR\u2009=\u20092.05\u2009\u00d7\u200910\u2212\u20094), HLA-DPB1 (FDR\u2009=\u20092.05\u2009\u00d7\u200910\u2212\u20094), and HLA-DRB1 (FDR\u2009=\u20092.05\u2009\u00d7\u200910\u2212\u20094). Of note, 37 of 560 genes have been well-documented in the database of GWAS catalog . The top-ranked significant genes of MAGMA-based analysis were yielded by HLA-DQA1 (MAGMA-based P\u2009=\u20093.38\u2009\u00d7\u200910\u2212\u200964), LOC101928947 (MAGMA-based P\u2009=\u20098.07\u2009\u00d7\u200910\u2212\u200961), ORMDL3 (MAGMA-based P\u2009=\u20094.55\u2009\u00d7\u200910\u2212\u200958), HLA-DQB1 (MAGMA-based P\u2009=\u20095.70\u2009\u00d7\u200910\u2212\u200957), GSDMA (MAGMA-based P\u2009=\u20091.61\u2009\u00d7\u200910\u2212\u200953), LRRC3C (MAGMA-based P\u2009=\u20091.39\u2009\u00d7\u200910\u2212\u200949), GSDMB (MAGMA-based P\u2009=\u20097.60\u2009\u00d7\u200910\u2212\u200948), ERBB2 (MAGMA-based P\u2009=\u20098.28\u2009\u00d7\u200910\u2212\u200945), and IL18R1 (MAGMA-based P\u2009=\u20092.61\u2009\u00d7\u200910\u2212\u200944). The genes of HLA-DQA1, NOTCH4, HLA-DRB5, HLA-DPB1, HLA-DRB1, ADORA1, TLR6, and IL18R1 have been previously reported to be associated with asthma risk , Graft-versus-host disease (FDR\u2009=\u20092.34\u2009\u00d7\u200910\u2212\u200910), and Allograft rejection (FDR\u2009=\u20097.41\u2009\u00d7\u200910\u2212\u200910). Interestingly, the pathway of asthma (FDR\u2009=\u20094.63\u2009\u00d7\u200910\u2212\u20097) showed a significant enrichment by these identified 83 genes  and peptide antigen binding (FDR\u2009=\u20092.51\u2009\u00d7\u200910\u2212\u20096) were significantly enriched  and integral component of luminal side of endoplasmic reticulum membrane (FDR\u2009=\u20093.81\u2009\u00d7\u200910\u2212\u20098). As for the term of BP, there were seven GO-terms significantly overrepresented by these 83 genes  and antigen processing and presentation of exogenous peptide antigen via MHC class II (FDR\u2009=\u20094.67\u2009\u00d7\u200910\u2212\u20097).Furthermore, we performed a pathway-based enrichment analysis by using these identified 83 genes based on the KEGG pathway resource. We found a number of 20 KEGG biological pathways were significantly enriched by these genes , Immune system diseases (FDR\u2009=\u20096.0\u2009\u00d7\u200910\u2212\u200916), Asthma (FDR\u2009=\u20091.61\u2009\u00d7\u200910\u2212\u20096), and Drug allergy (FDR\u2009=\u20099.02\u2009\u00d7\u200910\u2212\u20093). Subsequently, we also conducted a functional enrichment analysis of drug-related gene sets based on two databases of GeneBank and GLAD4U. A number of 29 significant gene sets relevant to different drugs were significantly overrepresented by these 83 genes . We found a number of 1164 significant or suggestive asthma-associated genes from the dataset #3  and rs2071534 (PeQTL\u2009=\u20091.30\u2009\u00d7\u200910\u2212\u20098 and PGWAS\u2009=\u20098.49\u2009\u00d7\u200910\u2212\u20096) have regulatory effects on PSMB9 gene. With regard to TAP2 gene, one trans-regulatory eSNPs of rs10447456 (PeQTL\u2009=\u20091.23\u2009\u00d7\u200910\u2212\u20096 and PGWAS\u2009=\u20095.79\u2009\u00d7\u200910\u2212\u20093) and three cis-regulatory eSNPs of rs9267798 (PeQTL\u2009=\u20096.68\u2009\u00d7\u200910\u2212\u20096 and PGWAS\u2009=\u20098.72\u2009\u00d7\u200910\u2212\u20094), rs4148882 (PeQTL\u2009=\u20093.71\u2009\u00d7\u200910\u2212\u200911 and PGWAS\u2009=\u20095.80\u2009\u00d7\u200910\u2212\u20099), and rs241456 (PeQTL\u2009=\u20091.40\u2009\u00d7\u200910\u2212\u200916 and PGWAS\u2009=\u20092.16\u2009\u00d7\u200910\u2212\u200927) were detected.Based on independent biological and technical replications, we prioritized a number of 31 childhood-onset asthma-risk genes with multiple significant eSNPs across all analyses , SMARCE1 (P\u2009=\u20090.025), CD52 (P\u2009=\u20090.02), TLR6 (P\u2009=\u20090.0086), and AHI1 (P\u2009=\u20090.0019).To test the co-expression patterns and differential gene expression of these 31 identified genes, we performed both co-expression analysis and differential gene expression (DGE) analysis in two RNA expression datasets  on childhood-onset asthma. For the dataset of GSE123750, by using the Pearson correlation analysis, we observed that the co-expression patterns of 31 genes were obviously changed in severe asthma group compared with mild-to-moderate asthma group (HSPA1A (Anova P\u2009=\u20090.018), HLA-DPB1 (Anova P\u2009=\u20090.00063), HLA-DRB5 (Anova P\u2009=\u20090.0018), ARL3 (Anova P\u2009=\u20090.0057), HLA-DRB1 (Anova P\u2009=\u20090.018), HLA-DQA1 (Anova P\u2009=\u20090.0014), LST1 (Anova P\u2009=\u20090.011), and RAD50 (Anova P\u2009=\u20090.05) were significantly differentially expressed across three groups , its protein of proteasome is a multicatalytic proteinase complex with a highly ordered ring-shaped 20S core structure. Gamma interferon induced the expression of PSMB9 gene, of which product replaces catalytic subunit 1 in the immunoproteasome. A recent genome-wide methylation study [PSMB9 gene might implicate in nitrogen dioxide (NO2)-exposure-related lung function damage or respiratory disease. Abnormal expressed of PSMB9 and TAP2 gene are prominently associated with POCD, and both PSMB9 and TAP2 gene accompanied with other COPD-expressed genes such as PSMB8 and TAP1 involved in the antigen processing and presentation pathway, which might change phenotypes of alveolar epithelial type II cells in COPD lungs [TAP2, it encodes a membrane-associated protein, which is a member of the superfamily of ATP-binding cassette (ABC) transporters. Many genetic variants in TAP2 gene have been reported to contribute susceptibility to pulmonary tuberculosis [TAP2 and TAP1 may partially deficient HLA Class I expression and then deficient antigen processing in small cell lung cancer lines (SCLC) [For the hub gene of on study  indicatePD lungs . Consistrculosis , 83, difrculosis , aspirinrculosis , and idirculosis . Down-res (SCLC) . TogethePSMB9 and TAP2 with multiple eSNPs as childhood-onset asthma-associated causative candidates. More molecular experiments are warranted to be conducted for uncovering the detailed biological mechanisms of these prioritized genes for childhood-onset asthma risk.In sum, current integrative genomics analysis provides an effective approach to connect genetic variants across the whole genome with genes through their cis- and/or trans-regulatory effects on expression, which is more biologically relevant and interpretable than a pure GWAS analysis for individual association signals. Based on multiple lines of evidence, we highlighted 31 genes including Additional file 1: Table S1. Sherlock Bayesian analysis identifies 560 genes as childhood-onset asthma-risk genes in discovery samples . Table S2. 83 Sherlock-identified genes from discovery Dataset #2 overlapped with MAGMA-identified genes. Table S3. Significant KEGG pathways enriched by childhood-onset asthma-relevant genes (N\u2009=\u200983). Table S4. Significant GO-terms of molecular function enriched by childhood-onset asthma-relevant genes (N\u2009=\u200983). Table S5. Significant GO-terms of cellular component enriched by childhood-onset asthma-relevant genes (N\u2009=\u200983). Table S6. Significant GO-terms of biological process enriched by childhood-onset asthma-relevant genes (N\u2009=\u200983). Table S7. Disease-related gene sets in GLAD4U database significantly enriched by childhood-onset asthma-relevant genes (N\u2009=\u200983). Table S8. Disease-related gene sets in DisGeNET database significantly enriched by childhood-onset asthma-relevant genes (N\u2009=\u200983). Table S9. Drug-related gene sets in GeneBank database significantly enriched by childhood-onset asthma-relevant genes (N\u2009=\u200983). Table S10. Drug-related gene sets in GLAD4U database significantly enriched by childhood-onset asthma-relevant genes (N\u2009=\u200983). Table S11. Multiple top-ranked eSNPs identified in 31 candidate genes implicated in childhood-onset asthma risk. Table S12. Sherlock-identified genes in the discovery stage reported in previous studies. Table S13. Genetic correlations between childhood onset asthma and other six autoimmune diseases. Table S14. Colocalization analysis for childhood onset asthma with other six autoimmune diseases.Additional file 2: Figure S1. Disease-based enrichment analysis of 83 childhood-onset asthma-related genes based on the DisGeNET database. Figure S2. Drug-based enrichment analysis of 83 childhood-onset asthma-related genes based on the Drugbank database. Figure S3. Drug-based enrichment analysis of 83 childhood-onset asthma-related genes based on the GLAD4U database. Figure S4. Consistent evidence of childhood-onset asthma-relevant genes based on independent datasets and techniques. a) Venn diagram of three identified childhood-onset asthma-relevant gene sets. b) Computer-based permutation analysis of 105 times for the comparison of genes from dataset #3 with that from MAGMA analysis . c) Computer-based permutation analysis of 105 times for the comparison of genes from dataset #3 with that from dataset #4 . Figure S5. Density plot show the differences of co-expression patterns between childhood-onset asthma (CoA) and matched controls. Figure S6. Boxplots show the differential expression profiles of 4 genes between mild-to-moderate asthma and severe asthma group. Figure S7. Boxplots show the differential expression profiles of 6 genes among control, convalescence, and severe asthma group."}
+{"text": "Scientific Reports 10.1038/s41598-019-40176-7, published online 05 March 2019Correction to: This Article contains an error in the Methods section, under the subheading \u2018Establishing the simulated explosion field\u2019.\u201cP was the shock wave pressure in kPa.\u201dshould read:\u201cP was the shock wave pressure in MPa.\u201d"}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-020-65156-0, published online 09 June 2020Correction to: This Article contains errors in Table 1 where columns \u2018Orbit A\u2019 and \u2018Orbit D\u2019 should be named \u2018Orbit Area\u2019 and \u2018Orbit Diameter\u2019 respectively.Furthermore, there are errors in column Orbit A where all data points given are incorrect.Finally, a column entitled \u2018Orbit Depth\u2019 is omitted. The correct Table"}
+{"text": "Correction to: Cell Death and Disease10.1038/s41419-018-0865-6, published online 24 July 2018On Pubmed, the name of co-author Roger Olofsson Bagge appeared incorrectly as \u201cBagge RO\u201d instead of \u201cOlofsson Bagge, Roger\u201d.This has been corrected in the PDF and HTML versions."}
+{"text": "In the article titled \u201cClinical Presentation, Natural History, and Therapeutic Approach in Patients with Solitary Fibrous Tumor: A Retrospective Analysis\u201d , a co-au"}
+{"text": "Scientific Reports 10.1038/s41598-018-34372-0, published online 01 November 2018Correction to: The Acknowledgements section in this Article was omitted. The Acknowledgements section should read:\u201cThis work has been funded by the EU\u2019s Horizon 2020 research and innovation programme under the Marie Sk\u0142odowska-Curie Grant Agreement No. 642563.\u201d"}
+{"text": "Scientific Reports 10.1038/s41598-019-49899-z, published online 16 September 2019Correction to: The Data Availability section in this Article is incorrect.\u201cAll relevant data will be made publicly available from mediaTUM (in preparation).\u201dshould read:\u201cAll relevant data is publicly available from mediaTUM (http://doi.org/10.14459/2019mp1515285).\u201d"}
+{"text": "Scientific Reports 10.1038/s41598-020-65569-x, published online 26 May 2020Correction to:This Article contains an error in Figure\u00a03, where the label for \u2018Air Temperature\u2019 is missing. The correct Figure\u00a03 appears below as Figure"}
+{"text": "Correction to: J Exp Clin Cancer Reshttps://doi.org/10.1186/s13046-020-1535-yIn the original publication of this manuscript , Fig. 2 In the first paragraph of the \u2018Negative feedback loop between HIF-1\u03b1 and ncRNA\u2019 section, there are two instances of \u2018miR-439\u2019; these should instead read \u2018miR-429\u2019."}
+{"text": "Both axes are labeled \u201cBCS rate, %.\u201d The y-axis label for Figure 1 should have read \u201cSurgery rate, %.\u201d The y-axis for Figure 2 should have read \"BM rate, %.\" This article has been corrected.1In the Research Letter titled \u201cRates of Bilateral Mastectomy in Patients With Early-Stage Breast Cancer,\u201d"}
+{"text": "Correction to: Journal of Anesthesia (2023) 37:749\u2013754 10.1007/s00540-023-03229-wIn the original publication of the article, under the section \u201cStatistical analysis\u201d, the following sentence was published incorrectly as \u201cThe chi-square test and multivariate logistic regression analysis were used to calculate the correlations between categorical variables\u201d. The correct sentence should read as follows, \u201cThe chi-square test was used to calculate the correlations between categorical variables\u201d."}
+{"text": "DNMT1) and miR-155-5p/miR-29b-5p-mediated suppression of activation-induced cytidine deaminase (AICDA) and suppression of BLIMP1 (via MDE let-7-5p/miR-125b-5p-targeting of PRDM1). After weaning with the physiological termination of MDE miR signaling, the infant\u2019s BCL6 expression and B cell proliferation declines, whereas BLIMP1-mediated B cell maturation for adequate own antibody production rises. Because human and bovine MDE miRs share identical nucleotide sequences, the consumption of pasteurized cow\u2019s milk in adults with the continued transfer of bioactive bovine MDE miRs may de-differentiate B cells back to the neonatal \u201cproliferation-dominated\u201d B cell phenotype maintaining an increased BLC6/BLIMP1 ratio. Persistent milk-induced epigenetic dysregulation of BCL6 and BLIMP1 expression may thus represent a novel driving mechanism in B cell lymphomagenesis. Bovine MDEs and their miR cargo have to be considered potential pathogens that should be removed from the human food chain.Epidemiological evidence supports an association between cow\u2019s milk consumption and the risk of diffuse large B-cell lymphoma (DLBCL), the most common non-Hodgkin lymphoma worldwide. This narrative review intends to elucidate the potential impact of milk-related agents, predominantly milk-derived exosomes (MDEs) and their microRNAs (miRs) in lymphomagenesis. Upregulation of PI3K-AKT-mTORC1 signaling is a common feature of DLBCL. Increased expression of B cell lymphoma 6 (BCL6) and suppression of B lymphocyte-induced maturation protein 1 (BLIMP1)/PR domain-containing protein 1 (PRDM1) are crucial pathological deviations in DLBCL. Translational evidence indicates that during the breastfeeding period, human MDE miRs support B cell proliferation via epigenetic upregulation of BCL6 (via miR-148a-3p-mediated suppression of DNA methyltransferase 1 ( Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous lymphoid neoplasm with variations in gene expression profiles, caused by genetic and epigenetic alterations. DLBCL is the most common type of non-Hodgkin lymphoma (NHL) worldwide, representing approximately 30\u201340% of all cases in different geographic regions ,2. PatieAICDA)-mediated chromosomal translocations and mutations  between 1995\u20132022 using various keywords such as \u201cB cell\u201d, \u201cB lymphocyte\u201d, \u201dB cell proliferation\u201c, B cell differentiation\u201d, \u201cmalignant B cell\u201d, \u201cmalignant B lymphocyte\u201d, \u201cdiffuse large B cell lymphoma\u201d, \u201cDLBCL\u201d, \u201cnon-Hodgkin lymphoma\u201d, \u201clymphomagenesis\u201d, lymphocyte-induced maturation protein 1\u201d, \u201cBLIMP1\u201d, \u201cPR domain-containing protein 1\u201d, \u201cPRDM1\u201d, \u201cB cell lymphoma 6\u201d, \u201cBCL6\u201d, \u201cmilk\u201d, \u201ccow\u2019s milk\u201d, \u201cdairy\u201d, \u201cmilk exosome\u201d, \u201cextracellular vesicle\u201d, \u201cEV\u201d, \u201cmicroRNA\u201d, \u201cmiRNA\u201d, \u201cmiR\u201d, \u201cexosomal miR\u201d, \u201cepigenetic\u201d, and \u201cepigenetic regulation\u201d. We also analyzed papers based on the bibliographic references cited by the studies found on PubMed during our search. Whenever possible, we selected the most recent and comprehensive reviews on the topic in question. All selected articles were written in English.We conducted our bibliographic research exclusively via PubMed ["}
+{"text": "Correction to: International Journal of Clinical Pharmacy https://doi.org/10.1007/s11096-022-01489-2th reference.In the original publication of the article, the author name \u201cJames DH\u201d is incorrectly abbreviated as \u201cHigman JD\u201d in the 37The correct reference is \u201cAbdel-Tawab R, James DH, Fichtinher A, et al. Development of the medication-related consultation framework (MRCF). Patient Educ Couns. 2011;2011(83):451\u20137.\u201dThe original article has been corrected."}
+{"text": "Nature Communications 10.1038/s41467-023-42100-0, published online 16 October 2023Correction to: In this article the author name Leila I\u00f1igo de la Cruz was incorrectly written as Leila M. I\u00f1igo de la Cruz. The original article has been corrected."}
+{"text": "British Journal of Cancer 10.1038/s41416-023-02453-1, published online 03 October 2023.Correction to: In this article, the original\u00a0title \u2018Targeting oncogenic microRNAs from the miR-371\u2009~\u2009373 and miR-302/267 clusters in malignant germ cell tumours causes growth inhibition through cell cycle disruption\u2019 contains a typographical error.It should read:Targeting oncogenic microRNAs from the miR-371\u2009~\u2009373 and miR-302/367 clusters in malignant germ cell tumours causes growth inhibition through cell cycle disruptionThe original article has been corrected."}
+{"text": "Scientific Reports 10.1038/s41598-023-46384-6, published online 06 November 2023Correction to: The original version of this Article contained errors, where in some instances the \u2018Bacillus amyloliquefaciens\u2019 was incorrectly misspelt as \u2018Bacillus amyloliquificiens\u2019.The original Article has been corrected."}
+{"text": "Correction to: Archives of Sexual Behavior 10.1007/s10508-022-02470-wTable 2 was missing from this article as originally published, while the table labeled \u201cTable 2\u201d was in fact Table 3.The original article has been corrected."}
+{"text": "The authors regret that the original version of above paper, unfortunately, contained three typos consisting of the incorrect spelling of \u201cToll-like receptor\u201d acronym, TRL4 instead of TLR4. The correct spelling is shown below:Title: \u201cInflammatory extracellular vesicles prompt heart dysfunction via TLR4-dependent NF-\u03baB activation\u201dIntroduction: \u201cThe systemic release of different subsets of cytokines and proteins by polarized M1/M2 macrophages implies the activation of toll-like receptor (TLR) and subsequent NF-\u03baB signalling cascades [8].\u201dMethods: \u201ctransmission electron microscopy; TLR: activation of toll-like receptor\u201dThe correction made in this erratum does not concern any published data. The authors apologize for any inconvenience that the errors may have caused."}
+{"text": "Scientific reports 10.1038/s41598-023-43619-4, published online\u00a028 September 2023Correction to: The original version of this Article contained errors.In the Abstract,\u201cInterestingly, high PFKFB4 expression was associated with both improved overall survival (OS) and worse progression-free survival (PPS) in COAD patients.\u201dnow reads:\u201cInterestingly, high PFKFB4 expression was associated with both improved overall survival (OS) and post-progression survival (PPS) in COAD patients.\u201dIn addition, Figure\u00a0The original Figure\u00a0The original Article has been corrected."}
+{"text": "Correction: Molecular Biology Reports10.1007/s11033-023-08823-5In this article, the author \u201cAhmed M. El-khawag\u201d was missed to be denoted as a corresponding author. The corresponding authors of this article should have been both \u201cDoaa S. R. Khafaga\u201d and \u201cAhmed M. El-khawag\u201d. The ORCID of the author \u201cAhmed M. El-Khawaga\u201d was incorrectly provided for \u201cDoaa S. R. Khafaga\u201d. The correct ORCID is updated for these authors.The original article has been corrected."}
+{"text": "Blood Cancer Journal 10.1038/s41408-023-00804-y, published online 22 March 2023Correction to: In the sentence beginning \u2018Patients in the MM-014 trial who received...\u2019 in this article, the text \u2018lower\u2019 should have read \u2018higher\u2019.Moreover, the sentence beginning \u2018However, these considerations should be balanced\u2019 should have been replaced with the following sentence.\u201cThe benefits of increased durations of lenalidomide maintenance therapy in prolonging PFS have been seen previously.\u201dThe original article has been corrected."}
+{"text": "Correction: BMC Vet Res 19, 52 (2023).10.1186/s12917-023-03593-5Following publication of the original article , the aut\u201cMoreover, despite their diferent H\u201d should be \u201cMoreover, despite their different H S release half-lives, there were no remarkable differences in the Gly- and Leu-NTA\u2019s effects on sperm function.\u201dThe original article has been corrected."}
+{"text": "In recent years, more evidence is emerging in favor of a new form of depression, aka \u201cModern-Type Depression\u201d (MTD). It has also been theorized that MTD may have multiple relationships with other psychiatric disorders, including techno-addictions.Our study aims at clinically characterizing subjects with MTD in a sample of individuals affected with Internet Gaming Disorder (IGD).1,157 subjects were recruited from a sample of Italian young people (aged 18-35), and selected only if they declared to be video game players . Video game players filled out the 22-item Tarumi\u2019s Modern-Type Depression Trait Scale (TACS-22), Motives for Online Gaming Questionnaire (MOGQ), Internet Gaming Disorder Scale-Short-Form (IGDS9-SF), Problematic Online Gaming Questionnaire (POGQ), Multidimensional State Boredom Scale (MSBS), Symptom Checklist-90 (SCL-90). Subjects were classified as IGD+/IGD- and MTD+/MTD-. Descriptive analysis, Mann-Whitney\u2019s U-test for independent data and Chi-square tests were carried out.60.5% (n=328) of the sample were male. 21.7% (n=118) were positive to MTD. MTD subjects reported significantly higher scores at IGDS9-SF (p<0.001), POGQ (p<0.001), MOGQ (p=0.003), MSBS (p<0.001). Significant higher scores were found at the MOGQ subscales \u201creality avoidance\u201d (p<0.001), \u201ccoping\u201d (p=0.001), and \u201cfantasy\u201d (p<0.001) and at the SCL-90 subscales \u201cinterpersonal sensitivity\u201d (p<0.001), \u201cphobic anxiety\u201d (p<0.001), and \u201cpsychoticism\u201d (p<0.001).MTD displayed a strong association with technopathies, particularly IGD. Therefore, further studies should evaluate whether MTD could represent a predictor to IGD onset and/or maintenance and adequately address this aspect from a preventive and treatment perspective.None Declared"}
+{"text": "Scientific Reports 10.1038/s41598-022-14787-6, published online 12 July 2022Correction to: The original version of this Article contained errors in Table 1, where the \u201cAll participants\u201d values for \u201cHigh Flow Oxygen Therapy\u201d and \u201cMechanical ventilation \u201d under \u201cType of respiratory support\u201d were incorrect. The correct and incorrect values appear below.Incorrect:Correct:The original Article has been corrected."}
+{"text": "Correction to: Microbial Cell Factories (2022) 21:4710.1186/s12934-022-01745-0Unfortunately, the original publication of the article  containeIn Fig.\u00a0In \u201cAbstract\u201d under the Results section, the IPTG concentration that reads as \u201cconcentration, 0.5 mM\u201d should read as \u201cconcentration, 0.05 mM\u201d.E.coli BL21 (DE3) \u25b3 tnaA/BH4/HaDDC-SmTPH whole cell factory\u201d, the sentence that reads as \u201cThe investment was carried out at varying concentration trajectories of L-Trp , IPTG \u2026\u2026\u201d, should read as \u201cThe investment was carried out at varying concentration trajectories of L-Trp , IPTG \u2026\u2026.\u201d.In \u201cMethods, under the sub heading \u201cOptimization of the production of 5-HT from L-Trp using The authors apologize for the mistakes."}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-023-37480-8, published online 28 June 2023Correction to: The original PDF version of this Article contained a repeated error where the oxide \u201cCo\u201d was incorrectly given as \u201cMg\u201d in the Abstract and Conclusions.The original Article has been corrected."}
+{"text": "Nature Communications 10.1038/s41467-023-40810-z, published online 22 August 2023Correction to: In this article the affiliation \u2018Instituto de Hortofruticultura Subtropical y Mediterr\u00e1nea La Mayora (IHSM) UMA-CSIC, 29010 M\u00e1laga, Spain\u2019 for Victor Carri\u00f3n was missing. The original article has been corrected."}
+{"text": "Blood Cancer Journal 10.1038/s41408-023-00902-x, published online 11 September 2023Correction to: In the sentence beginning \u2018Zanubrutinib achieved 100% peripheral blood...\u2019 in this article, the text \u2018160\u2009mg twice daily (BID) or 320\u2009mg once daily (QD), respectively\u2019 should have read \u2018320\u2009mg once daily (QD) or 160\u2009mg twice daily (BID), respectively.\u2019.The original article has been corrected."}
+{"text": "Dear Editor,,,ex\u00a0vivo.,Bernard-Soulier syndrome (BSS) is a bleeding disorder associated with abnormal platelets, due to mutations in one of three genes: GpIb\u03b1 (BSS-type A), GpIb\u03b2 (BSS-type B), or GpIX (BSS-type C) that are assembled in a glycoprotein complex on the surface of platelet membrane."}
+{"text": "Correction: European Archives of Oto-Rhino-Laryngology (2023) 280:3861\u20133866 10.1007/s00405-023-07976-0In the original publication of the article, the following author\u2019s \u201cJordan Idiare\u201d last name was published incorrectly as \u201cIdaire\u201d. The name is corrected in this correction article."}
+{"text": "Correction to: BMC Cardiovascular Disorders (2023) 23:45710.1186/s12872-023-03489-0In this article , The FunThen the author name \u201cWen-Yi Yang\u201d was incorrectly written as \u201cWenyi Yang\u201dThe original article has been corrected."}
+{"text": "Correction: Mol Cancer 22, 53 (2023).10.1186/s12943-023-01757-3Following publication of the original article [1], the authors reported that the third authors name should be \u201cLiu Jiachen\u201d instead of \u201cLiu Jiacheng\u201d.This has been updated above and the original article has been corrected."}
+{"text": "Correction to: Applied Microbiology and Biotechnologyhttps://doi.org/10.1007/s00253-023-12699-7In the published version of the original paper, the name of the third author has been misspelled.Jaiver Rosas-P\u00e9rez\u201d.It should be corrected from \u201cJavier Rosas-P\u00e9rez\u201d to \u201cThe original article has been corrected."}
+{"text": "Ukraine is at the forefront of one of the largest outbreaks of tuberculosis (TB) in Europe, including multidrug-resistant tuberculosis. Due to the ongoing armed conflict in this area, there is a significant number of refugees from Ukraine to other European countries. The aim of the study is to emphasize the essence of the problem of the increased incidence of tuberculosis, taking into account the impact of the armed conflict in Ukraine, resulting in the intensification of migration movements. A descriptive epidemiological method was used as the research method. The material was collected by analyzing source statistical data from WHO and statistical yearbooks of selected European countries. Particularly, Ukrainian refugees in Poland, Germany, the Czech Republic, and Slovakia are at higher risk of contracting tuberculosis due to factors like migration stress, poor nutrition, and comorbidities. Epidemiological data from these countries show a rise in tuberculosis cases among foreigners, emphasizing the need for European specialists to be more vigilant in this unique situation, focusing on refugees and other vulnerable populations. More research and collaborative efforts are essential to closely monitor and prevent the severe outcomes of tuberculosis transmission. The Russian invasion of Ukraine, which began on 24 February 2022, has contributed to a massive humanitarian crisis and disruption of health care . As a reA descriptive epidemiological method was used as the research method, which was carried out thanks to a collection of epidemiological data on the incidence of tuberculosis in selected European countries from the period before the war in Ukraine, covering the years 2018\u20132021 and 2022, when the Russian-Ukrainian conflict broke out on February 24. The aim of the study is to show changes taking place in the incidence of tuberculosis in Europe in the face of the ongoing war in Ukraine and to increase the vigilance of medical professionals towards people at risk of developing tuberculosis. In particular, we want to highlight the situation of a significant number of refugees from Ukraine who moved to Europe and epidemiological changes that were observed in the context of tuberculosis in some European countries that accepted large numbers of war refugees from Ukraine.The material was collected by analyzing source statistical data from WHO and statistical yearbooks of some European countries, such as Ukraine, Poland, Germany, the Czech Republic, and Slovakia. Nationally representative data on the incidence of tuberculosis is derived from a range of sources broadly defined as national administrative data. National administrative data are those coming from national systems, including registration of infectious diseases and statistics systems and national health management information systems. The presentation of data in charts was prepared using Microsoft Excel (2016). It is worth pointing out that the latest epidemiological data from Ukraine are statistical data without occupied territory and without territory where hostilities are taking place. Detailed sources of the analyzed data are provided below for a given country.(1)PolandGru\u017alica i Choroby Uk\u0142adu Oddechowego w Polsce w 2018 r. red. Maria Korzeniewska-Kose\u0142a. Instytut Gru\u017alicy i Choro P\u0142uc, Warszawa 2019Gru\u017alica i Choroby Uk\u0142adu Oddechowego w Polsce w 2019 r. red. Maria Korzeniewska-Kose\u0142a. Instytut Gru\u017alicy i Chor\u00f3b P\u0142uc, Warszawa 2020https://www.gov.pl/web/wsse-opole/stan-sanitarny-kraju-w-2022-roku (accessed on 9 August 2023)Stan Sanitarny Kraju w 2022 Roku\u2014Wojew\u00f3dzka Stacja Sanitarno-Epidemiologiczna w Opolu. Gru\u017alica i Choroby Uk\u0142adu Oddechowego w Polsce w 2022 r. red. Maria Korzeniewska-Kose\u0142a. Instytut Gru\u017alicy i Chor\u00f3b P\u0142uc, Warszawa 2023https://www.gov.pl/web/gis/swiatowy-dzien-gruzlicy-2023 (accessed on 9 August 2023)\u015awiatowy Dzie\u0144 Gru\u017alicy 2023\u2014G\u0142\u00f3wny Inspektorat Sanitarny. https://szczepienia.pzh.gov.pl/swiatowy-dzien-gruzlicy-w-tym-roku-pod-haslem-tak-mozemy-zwalczyc-gruzlice/ (accessed on 24 March 2023)\u015awiatowy Dzie\u0144 Gru\u017alicy w Tym Roku pod Has\u0142em Tak! Mo\u017cemy Wyleczy\u0107 Gru\u017alic\u0119. (2)Ukrainehttps://phc.org.ua/kontrol-zakhvoryuvan/tuberkuloz/statistika-z-tb (accessed on 11 August 2023)C\u0442a\u0442\u0438c\u0442\u0438\u043aa \u0437 T\u0411. \u0426e\u043d\u0442p \u0413po\u043ca\u0434c\u044c\u043ao\u0433o \u0417\u0434opo\u0432\u2019\u044f. https://www.who.int/publications/i/item/9789240050747 (accessed on 22 May 2022)WHO: \u201cWHO Information Note on Ensuring Continuity of Essential Tuberculosis Services for People with or at Risk of the Disease within Ukraine and in Refugee-Hosting Countries\u201d 2022. https://www.prostir.ua/?jobs=spetsialistka-z-upravlinnya-projektamy-tb-and-infectious-disease (accessed on 1 August 2023)C\u043fe\u0446ia\u043bic\u0442/\u043aa \u0437 Y\u043fpa\u0432\u043bi\u043d\u043d\u044f \u041fpo\u0454\u043a\u0442a\u043c\u0438 (TB and Infectious Disease). \u0413po\u043ca\u0434c\u044c\u043a\u0438\u0439 \u041fpoc\u0442ip. https://www.prostir.ua/?news=problema-tuberkulozu-pid-chas-vijny-scho-potribno-znaty-ta-kudy-zvertatysya-za-dopomohoyu (accessed 7 August 2023).\u041fpo\u0431\u043be\u043ca \u0422y\u0431ep\u043ay\u043b\u044co\u0437y \u043fi\u0434 \u0447ac \u0412i\u0439\u043d\u0438: \u0429o \u041fo\u0442pi\u0431\u043do \u0417\u043da\u0442\u0438 \u0442a \u041ay\u0434\u0438 \u0417\u0432ep\u0442a\u0442\u0438c\u044f \u0437a \u0414o\u043fo\u043co\u0433o\u044e. \u0413po\u043ca\u0434c\u044c\u043a\u0438\u0439 \u041fpoc\u0442ip. https://www.dw.com/uk/tuberkuloz-vil-ta-kholera-yaki-ryzyky-nese-viina-dlia-zdorovia-ukraintsiv/a-62092825 (accessed on 7 August 2023).\u042f\u043a \u0412i\u0439\u043da \u041fo\u0433ip\u0448y\u0454 E\u043fi\u0434e\u043ci\u0447\u043dy C\u0438\u0442ya\u0446i\u044e \u0432 \u0423\u043apa\u0457\u043di. Deutsche Welle (DW) 2022. https://www.nytimes.com/2022/02/25/world/europe/ukrainian-refugees-poland.html (accessed on 25 February 2023)At the Polish Border, Tens of Thousands of Ukrainian Refugees https://phc.org.ua/sites/default/files/users/user90/ZvitTB_Full.pdf (accessed on 9 September 2023)\u0417bit \u0437a Pe\u0437\u0443\u043b\u044ctatam\u0438 \u0414oc\u043bi\u0434\u0436ehh\u044f \u201c\u0411ap\u2019\u0454p\u0438 Bctahob\u043behh\u044f \u0414ia\u0433ho\u0437\u0443 ta \u041bik\u0443bahh\u044f T\u0443\u0431epk\u0443\u043b\u044co\u0437\u0443 \u0443 C\u043bi\u0434\u0447\u0438x I\u0437o\u043b\u044ftopax, \u0423ctahobax B\u0438kohahh\u044f \u041fokapah\u044c ta C\u043fe\u0446ia\u043bi\u0437obah\u0438x T\u0443\u0431epk\u0443\u043b\u044co\u0437h\u0438x \u041bikaph\u044fx \u0426O\u0417 \u0414KBC \u0423kpa\u00efh\u0438\u201d http://medstat.gov.ua/ukr/MMXXI.html?fbclid=IwAR2lEKBio9iGyLM2WKkxUpkXcjnI2aoGo7r32aZU_2-izhCkSA72NWfqOCw (accessed on 9 September 2023).\u0426e\u043d\u0442p \u041ce\u0434c\u0442a\u0442\u0438c\u0442\u0438\u043a\u0438\u2014\u0437a 2021. https://phc.org.ua/kontrol-zakhvoryuvan/tuberkuloz/statistika-z-tb (accessed on 11 August 2023)C\u0442a\u0442\u0438c\u0442\u0438\u043aa \u0437 T\u0411. \u0426e\u043d\u0442p \u0413po\u043ca\u0434c\u044c\u043ao\u0433o \u0417\u0434opo\u0432\u2019\u044f. https://www.statista.com/statistics/1312602/ukrainian-refugee-cost-by-country/ (assessed on 18 July 2023)Ukrainian Refugee Cost by Country 2022. Statista. (3)Germanyhttps://mediendienst-integration.de/artikel/gefluechtete-aus-der-ukraine-in-deutschland.html (accessed on 5 January 2023)Gefl\u00fcchtete aus der Ukraine in Deutschland. Mediendienst Integration. https://www.rki.de/DE/Content/Infekt/EpidBull/Archiv/2023/Ausgaben/11_23.pdf?__blob=publicationFile (accessed on 16 March 2023)Epidemiologisches Bulletin. 2023. (4)Czech Republichttps://szu.cz/aktuality/situace-s-vyskytem-tbc-zustava-v-cr-prizniva-ukazuji-data/ (accessed on 22 february 2023)\u010cechov\u00e1, \u0160. Situace s V\u00fdskytem TBC Z\u016fst\u00e1v\u00e1 v \u010cR P\u0159\u00edzniv\u00e1, Ukazuj\u00ed Data. SZ\u00da. Ofici\u00e1ln\u00ed Web St\u00e1tn\u00edho Zdravotn\u00edho \u00dastavu v Praze. (5)Slovakiahttps://www.ecdc.europa.eu/en/publications-data/tuberculosis-surveillance-and-monitoring-europe-2022-2020-data (accessed on 24 March 2022)Tuberculosis Surveillance and Monitoring in Europe 2020\u2014Data 2022 https://www.ecdc.europa.eu/en/publications-data/tuberculosis-surveillance-and-monitoring-europe-2020-2018-data (accessed on 24 March 2020)Tuberculosis Surveillance and Monitoring in Europe 2018\u2014Data 2020 https://www.hagy.sk/narodny-register-tbc/analyza-situacie-tbc-na-slovensku/?fbclid=IwAR3u07K3SL9JGypv44W1Y9mnDRvY5VJDYalCQsS2CWwvz2jL2h3vdfmfbGY (accessed on 24 August 2023)Problematika Tuberkul\u00f3zy na Slovensku Aktu\u00e1lne\u2014NUTPCHaHCH Vy\u0161n\u00e9 H\u00e1gy, N\u00e1rodn\u00fd Register Tuberkul\u00f3zy NCZI https://www.epis.sk/InformacnaCast/Publikacie/VyrocneSpravy/Files/VS_SR_2021.aspx?fbclid=IwAR0UvNIEI2gmxLQ-2S1WdpUC0vZcMuXo82l3R-QJwX-hZMA8WwoE-UlU69s (accessed on 24 August 2023)Anal\u00fdza Epidemiologickej Situ\u00e1cie a \u010cinnosti Odborov Epidemiol\u00f3gie v Slovenskej Republike za Rok 2021 https://www.ecdc.europa.eu/sites/default/files/documents/tuberculosis-surveillance-monitoring-2023.pdf?fbclid=IwAR1DaxBsZ6nuYXwQBg2ilXVyn_o1ZdFs2_pa__Vlais7Ico39K6MKOS_AHwTuberculosis Surveillance and Monitoring in Europe 2021\u2014Data 2023 From 2015 to 2018, a decrease in the total number of tuberculosis cases could be observed in Ukraine. In 2018, 25% fewer cases were recorded compared to 2015. This decrease was mainly due to greater efforts made by the state authorities to fight tuberculosis. 2020 turned out to be the year with the lowest number of cases in years. This was most likely the result of the outbreak of the COVID-19 pandemic and limited access to health services, so the number of cases is underestimated. The next two years were associated with an increase in reported cases of tuberculosis. The Public Health Center in Ukraine reported that in 2022, 18,510 cases of tuberculosis were registered in the country, which is a significant increase of over 2.5% compared to 2021 .p < 0.001). During the period from February 2022 to August 2022, the number of hospitalized adult tuberculosis patients remained relatively constant. Another problem is that the treatment of multidrug-resistant tuberculosis (MDR-TB) in Ukraine is unsatisfactory. The treatment success rate remains low at around 50% in 2021.Ukraine is also a country where multidrug-resistant tuberculosis (MDR) is very common, which is characterized by resistance to treatment with commonly used and strongest anti-tuberculosis drugs, i.e., isoniazid and rifampicin. Drug resistance in tuberculosis can have various causes. Improper use of drugs, especially irregular use and taking breaks between doses, contributes to the rapid development of drug resistance. In the international arena, it is Ukraine that is at the forefront of one of the largest outbreaks of this disease. Every year, an estimated 32,000 people become infected with active tuberculosis. The drug-resistant form occurs in about 33% of people with tuberculosis, which is 30 times more frequent than in Poland. In 2020, 4257 cases of drug-resistant tuberculosis (MDR-TB) were registered in Ukraine. In comparison, only 566 cases have been reported in the European Union/European Economic Area. Over the three years from 23 February 2019 to 23 February 2022, there was a gradual decrease in the average number of hospitalized adult tuberculosis patients  and 50.5% lower than in 2012, when the incidence rate was 19.6 per 100,000 population. In Poland, over the last five years, the situation of tuberculosis cases has been changing dynamically, and the growing share of foreigners in the statistics of cases attracts attention, which we would like to present on the diagram below . In 2018Despite the overall decrease in tuberculosis (TB) incidence between 2018 and 2022 in Germany, a concerning trend is the rising proportion of foreign nationals among TB patients. In 2022 alone, Germany saw an influx of nearly one million individuals of Ukrainian origin. In light of the ongoing war and intensified migratory movements, an increase in tuberculosis (TB) cases among foreigners has been observed within the territory of Germany. This trend is particularly pronounced among individuals immigrating from Ukraine. In 2022, there were 2847 reported cases of TB among foreigners, with 262 of these cases among the Ukrainian population\u2014an increase of 236 cases compared to the previous year. The reported TB case numbers for the years 2020\u20132022 may be slightly underestimated due to the ongoing COVID-19 pandemic and limited access to healthcare. Therefore, the actual number of cases is likely higher .Similar to Poland and Germany, in the Czech Republic, there has been an observed increase in tuberculosis (TB) cases among foreigners during the period of 2018\u20132022. In 2022, the highest number of cases among individuals from outside the country was recorded in the past 5 years\u2014156 cases, including a significant 87 cases among the Ukrainian population, which is over twice as many as the previous year . DespiteIn 2022, the number of tuberculosis cases among foreigners was the highest in the period 2018\u20132022 . People The aim of this analysis was to draw attention to the increasing incidence of tuberculosis, which is an important alarm signal to raise awareness of this disease. Especially nowadays, when the world is facing serious challenges regarding energy and food security, which the armed conflict in Ukraine has contributed to. The ongoing war has a multidimensional impact on the issue of public health in the world, which has already been weakened in recent years by the COVID-19 pandemic and ongoing climate change ,11,12,13This article included sources of statistical data from selected European countries that hosted the largest number of Ukrainians after the war outbreak to quantify and study the prevalence of tuberculosis in their populations in countries in 2018\u20132022. The article raises a very important and contemporary problem, emphasizing the possibility of mutual influence between socio-political upheavals and health crises. However, the present analysis was not without limitations. Descriptive studies are useful for estimating the burden of disease, e.g., prevalence or incidence in a population. This information is useful only for initial problem identification resource planning. This helps generate hypotheses regarding the cause of the problem, which should then be verified using another, more complex design, e.g., analytical methods such as cohort or case-control study.In 2022, when the war broke out, a noticeable increase was observed in the share of people born in Ukraine among tuberculosis cases in Poland, Germany, the Czech Republic, and Slovakia compared to previous years. Increased migration movements to European countries as a result of the armed conflict in Ukraine may potentially contribute to the increasing percentage of tuberculosis cases in these countries. There is a need to take further actions requiring multi-sectoral cooperation to monitor the spread of tuberculosis, as well as to continue educational and preventive programs to increase awareness of this disease in society. Doctors in Europe must also be more vigilant towards risk groups, especially refugees, given the background of this situation."}
+{"text": "Scientific Reports 10.1038/s41598-023-28640-x, Published online 30 January 2023Correction to: The Funding section in the original version of this Article was incomplete.\u201cThis work was supported by the Ministerio de Ciencia e Innovaci\u00f3n of Spain through research grant PID2019-111436RB-C21.\u201dnow reads:\u201cThis work was supported by the Ministerio de Ciencia e Innovaci\u00f3n of Spain through research grant PID2019-111436RB-C21 and by the Generalitat Valenciana through grant CIPROM/2021/003.\u201dThe original Article has been corrected."}
+{"text": "Correction: European Archives of Oto-Rhino-Laryngology 10.1007/s00405-023-07944-8In the original publication of the article, second author\u2019s name was published incorrectly as \u201cVerro Barbara\u201d. The correct name should read as follows \u201cBarbara Verro\u201d."}
+{"text": "Cell Death & Disease 10.1038/s41419-023-06217-w, published online 20 October 2023Correction to: In this article, the funding note has been corrected:This work was funded by Portuguese funds through FCT\u2014Funda\u00e7\u00e3o para a Ciencia e a Tecnologia under the projects PTDC/MED-NEU/1677/2021 and EXPL/MED-NEU/0588/2021.The original article has been corrected."}
+{"text": "Prostate Cancer and Prostatic Diseases 10.1038/s41391-022-00555-0, published online 3 June 2022Correction to: In this article, author names Yu-Hsuan Joni Shao, Jian-Hua Hong, Chun-Kai Chen, and Chao-Yuan Huang were incorrectly written as Shao Yu-Hsuan Joni, Hong Jian-Hua, Chen Chun-Kai, and Huang Chao-Yuan.Tables\u00a0In the sentence beginning with \u201cRisk groups defined by National Comprehensive Cancer Network...\u201d value \u201c20\u2009ng/ml\u201d has been changed to \u201c>20\u2009ng/mL\u201d.In this article and insertion to the caption to Fig 1 has been made. In the sentence beginning with \u201cSurvival curves...\u201d it now reads as \u201cSurvival curves showing MACE-free survival probability (significance of difference tested by log rank test)...\u201d.The original article has been corrected."}
+{"text": "Rio de Janeiro, March 20, 2019Dear readers,Association between Dietary Glycemic Index and Excess Weight in Pregnant Women in the First Trimester of Pregnancy : 04\u201310 DOI:10.1055/s-0038-1676096.), published online in Rev Bras Ginecol Obstet in December 2018, where it reads:In the Article https://orcid.org/0000-0001-7510-0485.ORCID ID is It should read:https://orcid.org/0000-0002-6145-2532.Edward Araujo J\u00fanior\u2019s ORCID is Rio de Janeiro, 20 de Mar\u00e7o de 2019Prezados leitores,Associa\u00e7\u00e3o entre o \u00edndice glic\u00eamico diet\u00e9tico e o excesso de peso em gestantes no primeiro trimestre de gesta\u00e7\u00e3o : 04\u201310 DOI: 10.1055/s-0038-1676096.), publicado online em Rev Bras Ginecol Obstet em Dezembro de 2018, onde se l\u00ea:No artigo https://orcid.org/0000-0001-7510-0485.ORCID ID is L\u00ea-se:https://orcid.org/0000-0002-6145-2532Edward Araujo J\u00fanior's ORCID is"}
+{"text": "Nature 10.1038/s41586-022-05084-3 Published online 17 August 2022Correction to: \u20133)\u201d. The errors have been corrected in the HTML and PDF versions of the article.In the version of this article initially published, in the legend for Fig. 3c, WSP-1 was erroneously denoted as magenta and F-actin as green. The corrected text now reads \u201cThick lines indicate the measured WSP-1 (green) and F-actin (magenta) nullclines\u201d. In addition, in the x-axis label of Fig. 4d, \u201cLifeact\u201d erroneously appeared as \u201cLifetime\u201d. The corrected label now reads \u201cLifeact concentration (IU \u03bcm"}
+{"text": "The correct study type is a cohort study. This article has been corrected.In the Original Investigation titled \u201cOne-Year Adverse Outcomes Among US Adults With Post\u2013COVID-19 Condition vs Those Without COVID-19 in a Large Commercial Insurance Database,\u201d"}
+{"text": "Correction to: International Microbiologyhttps://doi.org/10.1007/s10123-023-00332-6The authors regret that an unnecessary sentence* was embedded at the beginning of the \u201cResults and discussion\u201d section.* \u201cWe refer to 3 different parameters:(i) microbial ecology of the environment.(ii) nutritional habits.(iii) social habits\u201dThe original article has been corrected.\u00a0The authors apologize for any inconvenience caused."}
+{"text": "Scientific Reports 10.1038/s41598-023-42447-w, published online 14 September 2023Correction to: 2/CsSnI3/CuS\u201d was incorrectly given as \u201c28.76\u201d. Moreover, the device structure \u201cITO/PCBM/CsSnI3/CFTS/Se\u201d was incorrectly given as \u201cITO/PCBM/CsSnI3/CuSCN/Se\u201d.The original version of this Article contained errors in Table 7. The PCE (%) for \u201cITO/TiOThe incorrect and correct device structures and PCEs appear below.Incorrect:Correct:The original Article has been corrected."}
+{"text": "Mingrui Xia & Tao Wu are not co-first authors, but co-correspondents. The original article is now corrected\u201d."}
+{"text": "Correction to: Child's Nervous System (2022) 38:2181\u20132187 https://doi.org/10.1007/s00381-022-05632-2In this article, authors \u201cSaniya Mediratta\u201d and \u201cAswin Chari \u201c should be remove in author group field but included in \u201cDOLPHIN-UK Collaborators \u201c then listed at the bottom as corresponding authors.The original article has been corrected."}
+{"text": "Nature Communications 10.1038/s41467-023-40681-4, published online 19 August 2023Correction to: x axis incorrectly read \u2018Time (hrs)\u2019 rather than the correct \u2018Time (day)\u2019. The HTML has been updated to include a corrected version of the\u00a0The original version of this Article contained errors in Supplementary Fig.\u00a0Updated Supplementary Information"}
+{"text": "Scientific Reports 10.1038/s41598-020-74588-7, published online 15 October 2020Correction to: The original version of this Article contained errors in Table 1, where the value of \u2018iBAT ratio (%)\u2019\u00a0was erroneously stated as \u2018Liver ratio (%)\u2019 and \u2018Spleen ratio (%)\u2019 in the column \u2018WT\u2019.The correct and incorrect values appear below.Incorrect:Correct:The original Article has been corrected."}
+{"text": "Error in figure x-axis ("}
+{"text": "Correction to: BMC Infect Dis23, 237 (2023).10.1186/s12879-023-08181-4The original publication of this article contained 1 error:Mahsa Doomanlu\u201d should have been \u201cMahsa Doomanlou\u201d.The author name \u201cThe original article has been updated to correct this error."}
+{"text": "European Journal of Clinical Nutrition 10.1038/s41430-023-01311-w, published online 24 July 2023Correction to: In the original article, the funding grant number \u2018LGF21H020006\u2019 was given incorrectly as \u2018LGF21H090017\u2019. The original article has been corrected."}
+{"text": "Biomaterials Research (2023) 27:6410.1186/s40824-023-00402-wThe authors regret to report the grant number \u201c21871180\u201d in the original article [1] should instead state \u201c81872121\u201d."}
+{"text": "Medders, PharmD, PhD. This article has been corrected.1In the Original Investigation titled \u201cSecond-Line Pharmaceutical Treatments for Patients with Type 2 Diabetes,\u201d"}
+{"text": "Antimicrobial Resistance & Infection Control (2023) 12:8510.1186/s13756-023-01293-1The original article [1] contains a typo in the following sentence in the Methods section:\u201c[\u2026] hands using the hand scanner \u201dThe correct sentence should instead be as follows:\u201c[\u2026] hands using the hand scanner \u201d"}
+{"text": "Endoscopic submucosal dissection (ESD) is a minimally invasive surgery for laryngeal cancersA 72-year-old man presented with a 25\u200amm type 0-IIa lesion of the right piriform sinus , which Video\u20061\u2002Double-scope endoscopic submucosal dissection for superficial laryngeal cancer to preserve the superior laryngeal nerve.Proper traction with ds-ESD allowed visualization of the ibSLN and enabled nerve-sparing ESD . No dysEndoscopy_UCTN_Code_CCL_1AB_2AB"}
+{"text": "A 56-year-old man with a walled-off necrosis (WON) underwent endoscopic necrosectomy using a lumen-apposing metal stent (LAMS)  , which Video\u20061\u2002Steps to close the fistula associated with the placement of a lumen-apposing metal stent using an endoscopic hand-suturing device.Usually, LAMS-associated fistulas are closed in their natural courseEndoscopy_UCTN_Code_CPL_1AH_2AG"}
+{"text": "Eye 10.1038/s41433-023-02560-6, published online 03 May 2023Correction to: The name \u2018William Paley\u2019 was incorrectly given as \u2018William Paisley\u2019 within the original text. The correct sentence should read, \u201cIts stunning intricacies became a fundamental argument for creationism, characterised by William Paley\u2019s infamous watchmaker analogy and even Charles Darwin conceded it \u201cabsurd\u201d to consider the eye a product of evolution .\u201dThe original article has been corrected."}
+{"text": "Discussion section, the phrase \u201cstrain MSA35\u201d appeared as \u201cstrain stocktickerMSA35.\u201dDue to a production error, in the third paragraph of the The corrected sentence appears below.F. oxysporum strain MSA35 represses the expression of pathogenicity genes in F. oxysporum .\u201d\u201cFor example, the sesquiterpene volatile \u03b1-humulenone emitted by non-pathogenic The publisher apologizes for this mistake. The original article has been updated."}
+{"text": "Funding statement. The statement \u201cThis work was funded by the project ACTINODEEPSEA POCI-01-0145-FEDER-031045 (PTDC/BIA-MIC/31045/2017) financed by FEDER\u2014Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020\u2014Operacional Programme for Competitiveness and Internationalization (POCI), Portugal 2020, and by Portuguese funds through FCT\u2014Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia/Minist\u00e9rio da Ci\u00eancia, Tecnologia e Ensino Superior\u201d was included, but is incorrect. The correct Funding statement appears below.In the published article, there was an error in the"}
+{"text": "Correction: Breast Cancer 10.1007/s12282-023-01476-zIn the original publication of the article, the last author\u2019s name \u201cShinji Ohno\u201d was deleted and the first author name \u201cSumito Saeki\u201d was repeated instead during correction stage.\u00a0The original article has been updated.The publisher sincerely apologizes for any inconvenience this error may have caused."}
+{"text": "Title, the genus name \u201cClostridioides\u201d was misspelled as \u201cClostridiodes.\u201dIn the published article, there was an error. In the This sentence previously stated:Clostridiodes difficile toxin A inhibitor\u201d\u201cStructure-guided design of a potent The corrected sentence appears below:Clostridioides difficile toxin A inhibitor\u201d\u201cStructure-guided design of a potent Abstract section, first sentence. This sentence previously stated:A correction has been made to the HHs) bound to fragments of the combined repetitive oligopeptides domain of Clostridiodes difficile toxin A (TcdA) reveal that the C-terminus of VHH A20 was located 30 \u00c5 away from the N-terminus of VHH A26.\u201d\u201cCrystal structures of camelid heavy-chain antibody variable domains (VThe corrected sentence appears below:HHs) bound to fragments of the combined repetitive oligopeptides domain of Clostridioides difficile toxin A (TcdA) reveal that the C-terminus of VHH A20 was located 30 \u00c5 away from the N-terminus of VHH A26.\u201d\u201cCrystal structures of camelid heavy-chain antibody variable domains (VKeywords section. This keyword previously stated:A correction has been made to the Clostridiodes difficile\u201d\u201cThe corrected keyword appears below:Clostridioides difficile\u201d\u201cIntroduction section, first paragraph. This sentence previously stated:A correction has been made to the Clostridiodes difficile is a spore-forming Gram-positive bacterium capable of infecting humans and causing symptoms ranging from mild diarrhea to pseudomembranous colitis\u201d\u201cThe corrected sentence appears below:Clostridioides difficile is a spore-forming Gram-positive bacterium capable of infecting humans and causing symptoms ranging from mild diarrhea to pseudomembranous colitis\u201d\u201cAbbreviations section, page 2 Footnote. This abbreviation previously stated:A correction has been made to the Clostridiodes difficile toxin A\u201d\u201cTcdA, The corrected abbreviation appears below:Clostridioides difficile toxin A\u201d\u201cTcdA, Abbreviations section, page 2 Footnote. This Abbreviation previously stated:A correction has been made to the Clostridiodes difficile toxin B\u201d\u201cTcdB, The corrected abbreviation appears below:Clostridioides difficile toxin B\u201d\u201cTcdB, Figure 1 legend, first sentence. This sentence previously stated:A correction has been made to the Clostridiodes difficile TcdA.\u201d\u201cModel of the A20-A26 fusion protein bound to the CROPs domain of The corrected sentence appears below:Clostridioides difficile TcdA.\u201d\u201cModel of the A20-A26 fusion protein bound to the CROPs domain of The authors apologize for these errors and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "Dear Editor, we would like to share ideas on the publication \u201cStroke seven hours after SARS-CoV-2 vaccination\u201d.The authors declare no conflicts of interest."}
+{"text": "Nature Communications 10.1038/s41467-022-35309-y, published online 20 December 2022Correction to: Tjp1], and occludin [Ocln]), were reduced in AR-DSS compared to their DSS counterparts .\u201d in the Results section. The corrected sentence reads \u201cIn addition, colonic interleukin (IL)\u22121\u03b2, IL-6, and tumor necrosis factor (TNF)-\u03b1, were higher in AR-DSS  than their DSS counterparts, while the genes that regulate intestinal epithelial barrier function , were not reduced in AR-DSS compared to their DSS counterparts .\u201dIn this article the word \u2018not\u2019 was inadvertently omitted from the sentence \u201cIn addition, colonic interleukin (IL)\u22121\u03b2, IL-6, and tumor necrosis factor (TNF)-\u03b1, were higher in AR-DSS  than their DSS counterparts, while the genes that regulate intestinal epithelial barrier function (zonula occludin-1 [ZO-1; 59\u201c in the Discussion section should instead cite reference 60. The corrected sentence reads \u201cThis finding is consistent with previous study that found CS did not induce colitis in mice60\u201d.In addition, the citation to reference 59 in the sentence \u201dThis finding is consistent with previous study that found CS did not induce colitis in miceThese errors have been corrected in the HTML and PDF versions of the Article."}
+{"text": "International Journal of Impotence ResearchCorrection to: 10.1038/s41443-022-00560-w, published online 28 March 2022In this article the heading for table 4 should have read \u201cUnivariate and multivariate logistic regression models for predicting the erection hardness score\u2009\u2265\u20093 at 6 months post-operation.\u201d The original article has been corrected."}
+{"text": "Nature Ecology & Evolution 10.1038/s41559-023-02151-4, published online 14 August 2023.Correction to: P. macinnesi (Amebelodontidae)\u201d previously read \u201cP. macinnesi (Gomphotheriidae)\u201d. The sentence \u201cLocality mean ordinated hypsodonty values were obtained from the NOW-database (data (https://nowdatabase.org/now/database/) by the NOW Community / CC BY 4.0), and from additional literature sources (see Supplementary Data 2)\u201d has been moved from the fourth paragraph of \u201cThe ratchet effect of stepwise evolution under varying climate\u201d to the second paragraph of \u201cStratigraphy and palaeonenvironments\u201d. In addition, in the legend for Extended Data Fig. 9, \u201cM3 (dext.)\u201d has been corrected from \u201cM3 (sin.)\u201d. These changes have been made to the HTML and PDF versions of the article.In the version of the article originally published, in the legend for Fig. 3i, \u201c"}
+{"text": "Neuropsychopharmacology 10.1038/s41386-023-01635-y, published online 30 June 2023Correction to: The original online version of this article was revised: In the sentence \u201cWhereas some treatments are already available through off-label prescriptions (i.e R-ketamine [2]), most novel and rapid treatments are legally or practicably restricted to the realm of clinical studies  \u201d, \u2018R-ketamine\u2019 was corrected to \u2018ketamine\u2019. The original article has been corrected."}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-022-25022-7, published online 01 December 2022Correction to: The original version of this Article contained an error, where \u201c(CD\u2009\u2265\u2009IIIb)\u201d was incorrectly given as \u201c(CD\u2009>\u2009IIIb)\u201d in the Results section.As a result, in the Result, under the subheading \u2018Surgical outcomes\u2019,\u201cSerious adverse events (CD\u2009>\u2009IIIb) occurred in two patients (4.9%) in the CHASE cohort requiring reoperation;\u201dnow reads:\u201cSerious adverse events (CD\u2009\u2265\u2009IIIb) occurred in two patients (4.9%) in the CHASE cohort requiring reoperation;\u201dand,p  value = 0.565), but severe complications (CD\u2009>\u2009IIIb) were observed more frequently in the retrospective cohort.\u201d\u201cIn comparison to the retrospective cohort, no difference was observed in complication rate , but severe complications (CD\u2009\u2265\u2009IIIb) were observed more frequently in the retrospective cohort.\u201d\u201cIn comparison to the retrospective cohort, no difference was observed in complication rate (The original Article has been corrected."}
+{"text": "Scientific Reports 10.1038/s41598-021-01878-z, published online 06 December 2021Correction to: The original version of this Article contained errors in Figure\u00a01 (d) label, where SI units were incorrect.\u201cCalcium (in mg/ml)\u201dnow reads:\u201cCalcium (in mg/dl)\u201d\u201cPhosphorus (in mg/ml)\u201dnow reads:\u201cPhosphorus (in mg/dl)\u201d\u201cIron in (mg/ml)\u201dnow reads:\u201cIron in (ug/dl)\u201dAnd in Figure\u00a01 (e) x-axis label,\u201c(Glucose in mg/ml)\u201dnow reads:\u201c(Glucose in mg/dl)\u201dAdditionally, the Article contained an error in Figure\u00a02 (g) y-axis label, where\u201cRelative cell viability\u201dnow reads:\u201cPercent of cells\u201dThe original Figure\u00a0The original Article has been corrected."}
+{"text": "Nature 10.1038/s41586-023-05813-2 Published online 22 March 2023Correction to: In the version of this article initially published, there was a typographical error in the seventh sentence of the Methods \u201cSurgeries\u201d subsection, where in the text now reading \u201cOne week after injection, a 0.5-mm-diameter gradient refractive index (GRIN) relay lens (Go!Foton) was implanted above the ADN ,\u201d the AP coordinate \u201c\u20131.05\u201d originally read \u201c1.8.\u201d The error has been corrected in the HTML and PDF versions of the article."}
+{"text": "Nature Communications 10.1038/s41467-019-11756-y, published online 02 September 2019Correction to: WT\u2019 instead of the original, incorrect \u2018OmpK35ST258\u2019, and \u2018OmpK36ST258\u2019 instead of the original, incorrect \u2018OmpK36WT\u2019. The correct version of the 3rd row (\u2018ICC8003\u2019) states \u2018OmpK35ST258\u2019 instead of the original, incorrect \u2018OmpK35WT\u2019, and \u2018OmpK36WT\u2019 instead of the original, incorrect \u2018OmpK36ST258\u2019. This has been corrected in both the PDF and HTML versions of the Article.The original version of this Article contained errors in Table 1. The correct version of the 2nd row (\u2018ICC8002\u2019) states \u2018OmpK35"}
+{"text": "Biomaterials Research (2023) 27:6410.1186/s40824-023-00402-wThe original article [1] contains an incorrect grant number in the Funding section. The grant number \u201821871180\u2019 should instead be \u201881872121\u2019."}
+{"text": "Correction: Translational Neurodegeneration (2023) 12:17 (2023) 10.1186/s40035-023-00348-yFollowing publication of the original article , the aut\u201cLose\u201d was mistakenly typed as \u201cloose\u201d in the original title.The correct title should read: Starburst amacrine cells, involved in visual motion perception, lose their synaptic input from dopaminergic amacrine cells and degenerate in Parkinson\u2019s disease patients.The original article  has been"}
+{"text": "Journal of Plant Research10.1007/s10265-023-01446-8In the original publication of the article, titles of Tables 1, 4 were published incorrectly.In the title of Table 1, \u201cdifferentially expressed genes (DEGs)\u201d should read as \u201cdifferentially accumulated metabolites (DAMs)\u201d. Likewise, in the title of Table 4, \u201cdifferentially accumulated metabolites (DAMs)\u201d should read as \u201cdifferentially expressed genes (DEGs)\u201d."}
+{"text": "Correction: Biomark Res 7, 16 (2019)https://doi.org/10.1186/s40364-019-0168-9The ordinate scale is displayed incorrectly in Fig.\u00a0Fig.\u00a0P-value\u2019 columns of the \u2018Adjuvant chemotherapy\u2019 and \u2018Non-chemotherapy\u2019 rows that should have been deleted.Table The original article  containsThe corrected Fig."}
+{"text": "Correction: Trials 23, 818 (2022)https://doi.org/10.1186/s13063-022-06725-8The original publication of this article  containe1. The author name \u201cFoe\u201d should be \u201cDe Foe\u201d2. The affiliation of \u201cAlexander De Foe\u201d should be \u201cSchool of Educational Psychology and Counselling, Faculty of Education, Monash University, Clayton, Australia\u201dThe original publication has been updated."}
+{"text": "Correction: BMC Genomics 24, 201 (2023)10.1186/s12864-023-09287-4Following publication of the original article , it was Fig.\u00a03 Overlapping dinucleosome formation is stimulated by the nucleosome remodeler BRG1.\u201dThe caption of Fig.\u00a03 originally read: \u201cFig.\u00a03 Overlapping dinucleosome occupancy is dependent on the nucleosome remodeler BRG1.\u201dThe correct Fig.\u00a03 caption is: \u201cThe text describing the individual figure panels a-d was correct and remains unchanged. The original article has been updated."}
+{"text": "Publisher Correction: European Radiology10.1007/s00330-022-09239-8The original version of this article, published on 12 November 2022, unfortunately contained a mistake. The author\u2019s name Erik Thimansson was incorrectly given as \u2018Erick Thimansson\u2019. The original article has been corrected."}
+{"text": "Correction: World J Surg Onc 21, 133 (2023)https://doi.org/10.1186/s12957-023-03010-zFollowing publication of the original article , the autResults section, Literature search, 4th sentence \u201cpublished from 2012 to 2020,\u201d should be \u201cpublished from 2012 to 2021,\u201dIn tables 2 to 4, \u201cJeon HJ 2020\u201d should be \u201cJeon HJ 2021.\u201dThe original article has been updated."}
+{"text": "Correction to: Global Health Research and Policy (2023) 8:11 10.1186/s41256-023-00293-3Following publication of the original article [1], the authors reported that the fifth sentence in the last paragraph of the Background section needed to be updated.The original sentence was:hospital databases\u2019 or \u2018national health surveys\u2019, which possess evident restraints regarding reliability [10\u201312].\u201d\u201cAdditionally, most prior articles assessing cost-of-diabetes (COD) used secondary data acquired from \u2018The updated sentence is:hospital databases\u2019 or \u2018national health surveys\u2019, which possess evident restraints regarding reliability [10\u201311].\u201d\u201cAdditionally, most prior articles assessing cost-of-diabetes (COD) used secondary data acquired from \u2018The original article  has been"}
+{"text": "Correction: Odontology 10.1007/s10266-022-00741-5In the original publication of the article, the author \u201cDaniel Pop\u201d was published as co-corresponding author and co-corresponding authorship is removed from \u201cDaniel Pop\u201d in this article.The original article has been updated."}
+{"text": "Correction to: Journal of Natural Medicines 10.1007/s11418-023-01730-wO-monodesmoside, are incorrect. The incorrect \u201coleanolic acid 3-O-glucuronide (18)\u201d has now been replaced with the correct \u201coleanolic acid 3-O-glucuronide (16)\u201d, and the incorrect \u201cmomordin lc (16)\u201d has now been replaced with the correct \u201cmomordin lc (14)\u201d.In the original version of this article published on 12 July 2023, Fig.\u00a0The original article has been corrected. The publisher regrets the error."}
+{"text": "Four right-handed, healthy subjects participated in a visual stimulation experiment. Subjects were viewing a dartboard-shaped flickering checkerboard stimulus, divided into 4 rings and 12 segments, defining 48 sectors in the visual field. Local contrast in each sector was continuously varying across four levels and updated every 3 s. To maintain fixation, subjects had to respond to a stimulus at the center of the visual field.During the entire experiment, in which subjects performed 8 runs, each consisting of 100 trials, brain activity was measured with functional magnetic resonance imaging (MRI). Using a 3-T Siemens Trio MRI scanner, 220 echo-planar images were acquired in each run, with a repetition time of 1.5 s and voxel size of 3 x 3 x 3 mm.The dataset is publicly available from OpenNeuro and additionally includes region of interest maps for visual areas V1 to V4, left and right, obtained from another retinotopic mapping experiment. As such, the dataset allows for accurate mapping of receptive fields and their properties across several stages of human visual cortex.  Specifications Table\u2022Neuronal cells in visual cortex are characterized by receptive fields (RF) which means that individual neurons respond to stimulation in specific parts of the visual field. This concept has been extended to neuronal populations (pRFs) and voxels (vRFs) sampled with functional magnetic resonance imaging (fMRI). The present dataset allows to comprehensively map visual space to visual cortex by offering a tightly controlled visual stimulus and many data points in each individual subject.\u2022The dataset can be useful for three groups of people: Visual neuroscientists can investigate the data to learn more about the organization of early and later visual cortices \u2022The human visual system is one of the best-studied sensory systems in all of neuroscience. The concept of pRFs generalizes the idea of receptive fields to large groups of neurons which can be efficiently investigated with fMRI. Beyond the already established knowledge about the human visual system, the present dataset allows to research (i) higher-order interactions of receptive fields, i.e. integration of early visual representations in later stages of visual cortex; and (ii) sequence effects in visual perception, i.e. the influence of previous stimulation on the cortical response to current stimulation.1Human visual cortex is organized in a retinotopic fashion ,4. This 2\u2022\u201cdataset_description.json\u201d: a JSON file with basic information about the dataset\u2022\u201cparticipants.json\u201d: a JSON file containing subject-wise information \u2022\u201cparticipants.tsv\u201d: a TSV file specifying participant IDs and other participant information\u2022\u201ctask-CircRun_bold.json\u201d: a JSON file detailing functional MRI acquisition parameters\u2022\u201ctask-CircRun_events.json\u201d: a JSON file explaining trial-wise covariates\u2022\u201cREADME\u201d: a plain text file describing files contained in the datasetThe dataset is organized in the brain imaging data structure (BIDS) file format \u2022\u201cdata2BIDS_*_X.mat\u201d: MAT-files specifying batch editor jobs for Statistical Parametric Mapping, Version 12 (SPM12) used for converting the data to the BIDS format\u2022\u201cpreproc_X.mat\u201d a MAT-file specifying a batch editor job for preprocessing the data in SPM12 equivalent to the preprocessing procedure used in related work [2]Moreover, there is one sub-folder per subject in the main directory (e.g. \u201csub-AAA02\u201d) which contains the following files :\u2022\u201csub-X_T1w.json\u201d: a JSON file detailing structural MRI acquisition parameters\u2022\u201csub-X_T1w.nii\u201d: a skull-stripped, but otherwise unprocessed T1-weighted MPRAGE image of the subject in NIfTI format\u2022\u201csub-X_roi-Y-Z.nii\u201d: a NIfTI file specifying a binary mask for region of interest (ROI) analysis in preprocessed image space, when using the preprocessing routines mentioned above; X is the subject ID, Y gives the brain region  and Z gives the brain hemisphere (left or right); an exemplary filename would thus be \u201csub-AAA02_roi-V4-left.nii\u201dIn each subject folder, there is also a sub-directory called \u201canat\u201d containing the following files:\u2022\u201csub-X_task-CircRun_run-YY_bold.nii\u201d: a 4D NIfTI file storing the unprocessed functional MRI scans from a single run obtained during the experiment of interest; X is the subject ID and Y corresponds to the run number (1 \u2264 Y \u2264 8); an exemplary filename would thus be \u201csub-AAA02_task-CircRun_run-01_bold.nii\u201d\u2022\u201csub-X_task-CircRun_run-YY_events.tsv\u201d: a TSV file storing onsets, durations and trial-wise modulator values for all trials from a single run\u2022\u201csub-X_task-CircRun_run-YY_events.xls\u201d: the same information, stored in tabular format as a Microsoft Office Excel spreadsheet\u2022\u201csub-X_task-CircRun_run-YY_events.mat\u201d: the same information, stored in SPM12\u2019s \u201cnames, onsets, durations\u201d format [7]In each subject folder, there is also a sub-directory called \u201cfunc\u201d containing the following files:\u2022\u201csub-X/data2BIDS_*_X.mat\u201d\u2022\u201csub-X/preproc_X.mat\u201d\u2022\u201csub-X/anat/sub-X_roi-Y-Z.nii\u201d\u2022\u201csub-X/func/sub-X_task-CircRun_run-YY_events.xls\u201d\u2022\u201csub-X/func/sub-X_task-CircRun_run-YY_events.mat\u201dNote that the following files are not required per BIDS standard and merely exist for convenience of the dataset consumers:33.1Eight right-handed, healthy subjects participated in the visual stimulation experiment. All subjects had normal or corrected-to-normal vision and gave written informed consent to participate in the fMRI experiment. From these eight subjects, we provide the data of four subjects  who also took part in a retinotopic mapping experiment that was used for generating region of interest (ROI) images which are included in the dataset.3.2In both experiments , subjects were presented with a high-contrast, flickering circular checkerboard that was subdivided into 48 sectors see , Fig. 6 Intensity levels were logarithmically spaced between 0.1 and 1Intensity levels changed every 3 seconds and there was no inter-trial interval, yielding a continuous visual stimulation experiment. There were 8 runs of continuous stimulation and each run consisted of 100 trials, i.e. changes of local contrast in all sectors.Visual stimuli were projected onto a translucent screen at the rear of the scanner . The visual stimulus comprised a border along the vertical meridian resulting in completely independent visual stimulation in the two hemifields.During stimulation, subjects performed a fixation task at the center of the visual display. Landolt's C 3.3Magnetic resonance imaging (MRI) data were collected on a 3-T Siemens Trio  with a 12-channel head coil. In each run of the visual stimulation experiment, 220 T2*-weighted, gradient-echo echo-planar images (EPI) were acquired at a repetition time TR\u00a0=\u00a01.5 s, echo time TE\u00a0=\u00a030 ms, flip angle \u03b1\u00a0=\u00a090\u00b0 and in 25 slices , yielding a voxel size of 3 x 3 x 3 mm. In each run of the retinotopic mapping experiment, 160 EPIs were acquired at TR\u00a0=\u00a02 s with 33 slices . Finally, for each subject, a T1-weighted magnetization-prepared rapid acquisition gradient-echo (MPRAGE) image was acquired with TR\u00a0=\u00a01.9 s, TE\u00a0=\u00a02.52 ms, flip-\u03b1\u00a0=\u00a09\u00b0 and 192 slices (matrix size: 256 x 256) with a voxel size of 1 x 1 x 1 mm.3.4Retinotopic mapping was implemented via a traveling wave method with a double wedge and an expanding ring stimulus ,11. Angu3.5We used FreeSurfer for gray matter segmentation of the anatomical images Written informed consent was obtained from all subjects before participating in the experiments. The study was approved by the ethics committee of the University of Leipzig, Germany (protocol number 953) and conducted according to the Declaration of Helsinki Joram Soch: Formal analysis, Writing \u2013 Original Draft; Kai G\u00f6rgen: Software, Formal analysis, Data curation; Jakob Heinzle: Conceptualization, Methodology, Software, Validation, Formal analysis, Investigation, Data curation, Project administration, Writing \u2013 review & Editing; John-Dylan Haynes: Conceptualization, Methodology, Resources, Supervision, Funding acquisition.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."}
+{"text": "Nature Communications 10.1038/s41467-022-34477-1, published online 09 November 2022Correction to: 2\u201d.The original version of this article contained an error in the Methods section which incorrectly omitted \u201cCord blood units were obtained from Anthony Nolan Cell Therapy Centre (ANCTC).\u201d From page 9, Method section, subsection \u201cGeneration of humanised mice and their treatment with Abatacept and IgG-(IL-2)This now reads \u201c\u2026.CD34 Microbead Kit UltraPure (Miltenyi Biotec). Cord blood units were obtained from Anthony Nolan Cell Therapy Centre (ANCTC). On some occasions\u2026\u201dThis has been corrected in both the PDF and HTML versions of the article."}
+{"text": "Correction: BMC Medical Research Methodology 23, 81 (2023)10.1186/s12874-023-01882-z39 to 37 covariates. In section \u201cMatching specification\u201d, 39 has been changed to 37 (fourth paragraph), and \u201ccount of CDC high-risk conditions, count of mental health conditions,\u201c has been removed (fifth paragraph).Following the publication of the original article , the autThe original article  has been"}
+{"text": "Correction: European Archives of Oto-Rhino-Laryngology 10.1007/s00405-023-08025-6In the original publication of the article, the following author\u2019s name \u201cRadish Kumar Balasubramanium\u201d was published incorrectly as \u201cRadish Balasubramanium\u201d. The name is corrected in this article.The original article was updated."}
+{"text": "In fact, we wrote that \u201cpoly(PHL) was synthesized by a combination of ring-opening polymerizationof \u03b7-heptalactone (Scheme 1) and reversible addition\u2013fragmentationchain transfer (RAFT) polymerization, using diphenyl phosphate (DPP)as catalyst and 4-cyano-4-(((ethylthio)carbonothioyl)thio)pentanoic acid as initiator and chain transfer agent\u201d. Thesample has been, instead, synthesized, as described in our previouspaper,2 by ring-opening polymerizationof \u03b7-heptalactone using diphenyl phosphate as catalyst and 4-cyano-4-(((ethylthio)carbonothioyl)thio)pentanoicacid as initiator.We have realized thatin several parts of the paper and in the 1 and the corresponding Supporting Information should be corrected as follows:The following sentences in our paperAbstract,lines 2\u20134. The sentence \u201cPHL has been synthesizedby a combination of ring-opening polymerization of \u03b7-heptalactoneand reversible addition\u2013fragmentation chain transfer polymerizationusing diphenyl phosphate as catalyst.\u201d should be replaced with\u201cPHL has been synthesized by ring-opening polymerization of\u03b7-heptalactone using diphenyl phosphate as catalyst.\u201d40 PHL of low polydispersityof the molecular mass has been synthesized by ring-opening polymerizationof \u03b7-heptalactone combined with reversible addition\u2013fragmentationchain transfer (RAFT) polymerization using diphenyl phosphate as catalyst.\u201dshould be replaced with \u201cIn our recent previous report,40 PHL of low polydispersity of the molecular mass has beensynthesized by ring-opening polymerization of \u03b7-heptalactoneusing diphenyl phosphate as catalyst.\u201dIntroduction, page 4154, left column, lines 23\u201327. The sentence\u201cIn our recent previous report,40 by a combination of ROP of \u03b7-heptalactone(Scheme 1) and reversible addition\u2013fragmentation chain transfer(RAFT) polymerization, using diphenyl phosphate (DPP) as catalystand 4-cyano-4-(((ethylthio)carbonothioyl)thio) pentanoicacid as initiator and chain transfer agent...\u201d should be replacedwith \u201cPHL was synthesized as described in our previous report,40 by ROP of \u03b7-heptalactone (Scheme 1) using diphenylphosphate (DPP) as catalyst and 4-cyano-4-(((ethylthio)carbonothioyl)thio)pentanoic acid as initiator\u201d.Experimental section,page 4154, left column, lines 1\u20135.The sentence \u201cPHL was synthesized as described in our previousreport,S2 by a combination of ring-opening polymerization (ROP) of \u03b7-heptalactone and reversible addition\u2013fragmentationchain transfer (RAFT) polymerization, using diphenyl phosphate (DPP)as catalyst and 4-cyano-4-(((ethylthio)carbonothioyl)thio)pentanoic acid as initiator and chain transfer agent...\u201d shouldbe replaced with \u201cPoly (PHL) was synthesizedas described in our previous report,S2 by ring-openingpolymerization (ROP) of \u03b7-heptalactone  using diphenylphosphate (DPP) as catalyst and 4-cyano-4-(((ethylthio)carbonothioyl)thio)pentanoic acid as initiator\u201d.Supporting Information,page S2. The sentence \u201cPoly(PHL) was synthesized as described in our previous report,Supporting Information is attached.A corrected version ofthe"}
+{"text": "Nature Communications 10.1038/s41467-023-38841-7, published online 31 May 2023Correction to: The original version of this Article contained an inaccuracy in the Methods section \u201cCyTOF analysis\u201d.g, 5\u2032) prior to re-suspending in PBS with 4-element EQ normalization beads (Standard BioTools: 201078)\u201d should have read \u201cCells were then washed twice by centrifuging through PBS at 800\u2009\u00d7\u2009g, 5\u2019 prior to re-suspending in Maxpar Cell Acquisition Solution (Standard BioTools: 201241) with 4-element EQ normalization beads (Standard BioTools: 201078)\u201d.The original sentence \u201cCells were then washed twice by centrifuging through PBS (800\u2009\u00d7\u2009This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Correction to: Graefe\u2019s Archive for Clinical and Experimental Ophthalmology10.1007/s00417-022-05952-8 In the published version of this article, two author names contained some errors.Anne R\u00fcbsam\u201d and Josefine Urban should be named \u201cJosefine Lehmann\u201d.Anne Lehmann should be named \u201cThis is being corrected in this publication."}
+{"text": "Scientific Reports 10.1038/s41598-023-37795-6, published online 04 July 2023Correction to: The original PDF version of this Article contained a repeated error where, \u201cDensity Functional Theory (DFT)\u201d was incorrectly given as \u201cdistribution function theory (DFT)\u201d in the Abstract and Introduction sections.The original Article has been corrected."}
+{"text": "Eye 10.1038/s41433-021-01614-x, published online 11 June 2021Correction to: Figure 1 illustration had an error\u2014in the second panel (the PhNR waveform), the \u2018a\u2019 and \u2018b\u2019 labels were the wrong way around.The original article has been corrected"}
+{"text": "Nature Communications 10.1038/s41467-023-42092-x, published online 28 November 2023Correction to: t\u2009=\u20094.77, p\u2009<\u20090.001)\u2019 instead of \u2018At the group level, the mean regression coefficient (across subjects) was significantly different from 0 .\u2019\u00a0The original article has been corrected.The original version of this article contained an error in the \u201cResults\u201d section. A sentence incorrectly read \u2018At the group level, the mean regression coefficient (across subjects) was significantly different from 0 (two sample t test,"}
+{"text": "Scientific Reports 10.1038/s41598-023-29701-x, published online 14 February 2023Correction to: The Supplementary Information published with this Article contained an error.In \u201cAppendix C\u201d, Figures C1 and C2, the label of the Y-axis \u201cConcentration (ng/L)\u201d was incorrectly given as \u201cConcentration mg/l\u201d.This error has now been corrected in the Supplementary Information file that accompanies the original Article.Supplementary Information."}
+{"text": "We hereby declare that three errors were detected after publication of the article titled \u201cThe Eysenck Personality Questionnaire Revised \u2013 Abbreviated (EPQR-A): psychometric properties of the Brazilian Portuguese version\u201d (doi: https://doi.org/10.47626/2237-6089-2021-0342), in Trends in Psychiatry and Psychotherapy volume 45 (e20210342).First, affiliation no. 6 should read \u201cCentro de Investiga\u00e7\u00e3o em Psicologia\u201d (rather than \u201cCentro de Pesquisa em Psicologia\u201d).Second, the legend of Figure 1 should read \u201cPath diagram for the EPQR-A CFA model\u201d .Finally, the second subtitle of the Results section, \u201cInternal consistency\u201d, had been erroneously omitted and presented as figure legend."}
+{"text": "Correction: BMC Vet Res 19, 52 (2023).10.1186/s12917-023-03593-5.Following publication of the original article , the aut2S release half-lives, there were no remarkable differences in the Gly- and Leu-NTA\u2019s effects on sperm function.\u201d\u201cMoreover, despite their different H\u201d should be \u201cMoreover, despite their different HThe original article has been corrected."}
+{"text": "Scientific Reports 10.1038/s41598-022-18085-z, published online 19 August 2022Correction to: The Funding section in the original version of this Article was omitted. The Funding section now reads:\u201cThis work received \u2018Ricerca\u00a0Corrente\u00a02023\u2019 funding from the Italian Ministry of Health to cover publication costs.\u201dThe original Article has been corrected."}
+{"text": "Scientific Reports 10.1038/s41598-023-31772-9, published online 23 March 2023Correction to: The original version of this Article contained errors in Table 6, where the \u201cFP\u201d and \u201cFN\u201d values were interchanged. The correct and incorrect values appear below.Incorrect:Correct:The original Article has been corrected."}
+{"text": "Correction: European Journal of Ageing (2023) 20:4 10.1007/s10433-023-00753-2In the original publication of the article, the word \u201cUrinary incontinence\u201d should be replaced with \u201cincontinence\u201d throughout the article.The original article has been corrected."}
+{"text": "Correction: Journal of Gastroenterology (2022) 58:44\u201352 10.1007/s00535-022-01931-2In the original publication of the article, the first author\u2019s name should be \u201cTsukasa Yamakawa\u201d and not \u201cTsukasa Yamawaka\u201d."}
+{"text": "In the published article, there was an error in the Funding statement. The funding statement was displayed as \u201cThis work was funded by the Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia (PTDC/BIA-EVF/3247/2012 and PTDC/BIA-EVL/30212/2017) and iBiMED .\u201d. The correct Funding statement appears below."}
+{"text": "Correction: Human Cell (2022) 35:1650\u20131670 10.1007/s13577-022-00756-8In the original publication of the article, \u201cLi Xiao\u201d is the corresponding author and not \u201cChenyu Lin\u201d."}
+{"text": "Nature Communications 10.1038/s41467-023-40567-5, published online 10 August 2023Correction to: The original version of this Article contained errors in the legends of Figures 1\u20134, 6, and 7.P-value was determined by two-tailed Student\u2019s t-test.\u2019 The correct version replaces this sentence with \u2018P-values were determined by two-way ANOVA (Dunnett\u2019s test) (f) or two-way ANOVA (\u0160\u00edd\u00e1k\u2019s test) .\u2019The legend of Figure 1 originally incorrectly read \u2018P-value was determined by two-tailed Student\u2019s t-test.\u2019 The correct version replaces this sentence with \u2018P-values were determined by two-way ANOVA (\u0160\u00edd\u00e1k\u2019s test) , ordinary one-way ANOVA (Tukey\u2019s test) (h) or two-way ANOVA (Tukey\u2019s test) (l).\u2019The legend of Figure 2 originally incorrectly read \u2018d, VSV: *p\u2009=\u20090.0123, ****p\u2009<\u20090.0001 in sequence).\u2019 The correct version states \u2018For h\u2019 instead of \u2018For d\u2019.The legend of Figure 2h originally incorrectly read \u2018GFP-VSV titers were quantitated in plaque assay .\u2019 The correct version states \u2018***p\u2009=\u20090.0004\u2019 instead of \u2018***p\u2009=\u20090.0001\u2019.The legend of Figure 2l originally incorrectly read \u2018P-value was determined by two-tailed Student\u2019s t-test.\u2019 The correct version replaces this sentence with \u2018P-values were determined by two-way ANOVA (\u0160\u00edd\u00e1k\u2019s test)  or unpaired two-sided t-test (e).\u2019The legend of Figure 3 originally incorrectly read \u2018IFNB1 induction was measured by qPCR .\u2019 The correct version states \u2018IFNB1\u2019 instead of \u2018ISRE\u2019.The legend of Figure 3h originally incorrectly read \u2018P-value was determined by two-tailed Student\u2019s t-test.\u2019 The correct version replaces this sentence with \u2018P-values were determined by two-way ANOVA (\u0160\u00edd\u00e1k\u2019s test) (i).\u2019The legend of Figure 4 originally incorrectly read \u2018IFNB1 induction was measured by qPCR .\u2019 The correct version states \u2018****p\u2009<\u20090.0001\u2019 instead of \u2018***p\u2009<\u20090.0001\u2019.The legend of Figure 4i originally incorrectly read \u2018Cells were harvested at specified time points post infection and P-value was determined by two-tailed Student\u2019s t-test.\u2019 The correct version replaces this sentence with \u2018P-values were determined by two-way ANOVA (Tukey\u2019s test) , two-way ANOVA (\u0160\u00edd\u00e1k\u2019s test) (c) or two-way ANOVA (Dunnett\u2019s test) (d\u2013f).\u2019The legend of Figure 6 originally incorrectly read \u2018P-value was determined by two-tailed Student\u2019s t-test.\u2019 The correct version replaces this sentence with \u2018P-values were determined by two-way ANOVA (Tukey\u2019s test) , two-way ANOVA (\u0160\u00edd\u00e1k\u2019s test)  or Gehan-Breslow-Wilcoxon test .\u2019The legend of Figure 7 originally incorrectly read \u2018Wdr77CKO and Mavs-/- mice (n\u2009=\u200910 each) were injected intravenously with HSV at 1.5\u2009\u00d7\u2009108 PFU per mouse, and the survival rates were monitored for 15\u2009days (*p\u2009=\u20090.445).\u2019 The correct version states \u2018nsp\u2009=\u20090.445\u2019 instead of \u2018*p\u2009=\u20090.445\u2019.The legend of Figure 7i originally incorrectly read \u2018WT, This has been corrected in both the PDF and HTML versions of the Article.The original version of this Article contained errors in the legends of supplementary Figures\u00a0P value was determined by two-tailed Student\u2019s t-test.\u2019 The correct version replaces this sentence with \u2018P values were determined by two-way ANOVA (Dunnett\u2019s test) .\u2019The legend of supplementary Figure\u00a0P value was determined by two-tailed Student\u2019s t-test.\u2019 The correct version replaces this sentence with \u2018P values were determined by unpaired two-sided t-test (b), ordinary one-way ANOVA (Dunnett\u2019s test) (e) or two-way ANOVA (\u0160\u00edd\u00e1k\u2019s test) .\u2019The legend of supplementary Figure\u00a0P value was determined by two-tailed Student\u2019s t-test.\u2019 The correct version replaces this sentence with \u2018P values were determined by two-way ANOVA (\u0160\u00edd\u00e1k\u2019s test) .\u2019The legend of supplementary Figure\u00a0P value was determined by two-tailed Student\u2019s t-test.\u2019 The correct version replaces this sentence with \u2018P values were determined by two-way ANOVA (\u0160\u00edd\u00e1k\u2019s test) .\u2019The legend of supplementary Figure\u00a0P value was determined by two-tailed Student\u2019s t-test.\u2019 The correct version replaces this sentence with \u2018P values were determined by two-way ANOVA (\u0160\u00edd\u00e1k\u2019s test) (g).\u2019The legend of supplementary Figure\u00a0P value was determined by two-tailed Student\u2019s t-test.\u2019 The correct version replaces this sentence with \u2018P values were determined by ordinary one-way ANOVA (Dunnett\u2019s test) , two-way ANOVA (Dunnett\u2019s test)  or two-way ANOVA (\u0160\u00edd\u00e1k\u2019s test) (h).\u2019The legend of supplementary Figure\u00a0P value was determined by two-tailed Student\u2019s t-test.\u2019 The correct version replaces this sentence with \u2018P values were determined by two-way ANOVA (Dunnett\u2019s test) , e (lung), f ), two-way ANOVA (Tukey\u2019s test) , e (spleen), f (liver)), or two-way ANOVA (\u0160\u00edd\u00e1k\u2019s test) (e (liver)).\u2019The legend of supplementary Figure\u00a0The HTML has been updated to include a corrected version of the\u00a0The original version of this Article contained errors in the Statistical Analysis in the Methods.t-test was used to analyze the significance of mean values between groups. Kaplan\u2013Meier survival analysis was used to analyze mouse survival data by two-sided log-rank (Mantel\u2013Cox) test.\u2019The Statistical Analysis in the Methods originally incorrectly read \u2018Unpaired two-sided Student\u2019s t-test, ordinary one-way ANOVA and two-way ANOVA were used to analyze the significance of the differences between groups. Survival data of mice were analyzed using Gehan-Breslow-Wilcoxon test.\u2019The correct version replaces these sentences with \u2018Unpaired two-sided Student\u2019s This has been corrected in both the PDF and HTML versions of the Article.The original version of this Article contained an error in the Source Data for Figure 2h.WDR77-/- and omitted measurements for MAVS-/-. The correct version replaces these values with \u2018410000000, 310000000 and 370000000\u2019 for VSV titer in WT, and \u201844000000, 38000000 and 34000000\u2019 for VSV titer in WDR77-/-, and adds \u20181200000000, 1500000000 and 1300000000\u2019 for VSV titer in MAVS-/-.The Source Data for Figure 2h originally incorrectly read \u201935.6, 27.2 and 24.8\u2019 for VSV titer in WT, and \u20187.4, 6 and 8\u2019 for VSV titer in The HTML has been updated to include a corrected version of the Source Data.Updated Supplementary InformationUpdated Source Data"}
+{"text": "Scientific Reports 10.1038/s41598-023-39759-2, published online 04 August 2023Correction to: The original version of this Article contained an error in the Results section, under the subheading \u2018Systematic palaeontology\u2019, where the expanded form of the specimen number \u201cRWR-241(A\u2013K)\u201d was missing. Consequently,Holotype.\u00a0RWR-241 A\u2013K;\u201d\u201cnow reads:Holotype.\u00a0RWR-241 A\u2013K ;\u201d\u201cThe original Article has been corrected."}
+{"text": "Correction to: BMC Public Health 23, 1235 (2023)10.1186/s12889-023-16127-3The original publication of this article contained 3 errors:Fatimah Ali Alessa\u201d should have been \u201cFatimah Ali Aleisa\u201d.The author name \u201cHawra Wasel Alabdulmohsen\u201d should have been \u201cHawra Wasel Abdulmohsen\u201d.The author name \u201cProject No.545\u201d should be \u201cProject No.3694 \u201c.The funding number \u201cThe original article has been updated to correct these errors."}
+{"text": "Correction: J Gastroenterol (2023) 58:1\u201313  10.1007/s00535-022-01934-zIn the original publication of the article, the \u201cTable 1 continued\u201d column head was wrong.The original article has been corrected."}
+{"text": "Scientific Reports 10.1038/s41598-023-29642-5, published online 27 February 2023Correction to: The original version of this Article contained an error in the Acknowledgments section.\u201cThis work was supported in part by funding from the Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia (FCT) [grant number: PTDC/CED-EDG/31615/2017].\u201dnow reads:\u201cThis work was supported by national funds, from the Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia (FCT), in the scope of the project UIDB/04375/2020.\u201dThe original Article has been corrected."}
+{"text": "Correction: Discover Nano (2021) 16:120 10.1186/s11671-021-03580-52O4\u2011QDs\u201d part of the \u201cMaterial and Methods\u201d section:The original article  unfortunDue to a typographical error \u201cDiethanol amine\u201d was incorrently presented as \u201cDithranol amine\u201d.The original article has been corrected."}
+{"text": "An 88-year-old woman undergoing transcatheter aortic valve replacement (TAVR) using a 29-mm Evolut PRO+  Fig.\u00a0A complaiOchiai et al. suggested that selective engagement was impossible in all unfavorable coronary access cases with Evolut THVs . We have"}
+{"text": "Onde se l\u00ea:Leia-se:"}
+{"text": "Correction: BMC Women\u2019s Health (2023) 23:1 10.1186/s12905-023-02523-9.Following publication of the original article, in this article the author name \u2018Tegenu Balcha\u2019 was incorrectly written as \u2018Taganu Balcha\u2019The original article has been corrected."}
+{"text": "Blood Cancer Journal 10.1038/s41408-023-00813-x, published online 24 March 2023Correction to: In the fifth line of the second paragraph, the word of \u201cnegative\u201d in \u201cMRD-negative complete remission\u201d should be \u201cpositive\u201d.The original article has been corrected."}
+{"text": "Health and Quality of Life Outcomes (2020) 18:25010.1186/s12955-020-01494-xThe original article  mistakenThis study has been funded by Instituto de Salud Carlos III through the project \u201cPI16/00358\u201d ."}
+{"text": "Scientific Reports 10.1038/s41598-018-35220-x, published online 20 November 2018Correction to: This Article contains an error in the Abstract, where the volume of the Sansha Yongle Blue Hole is incorrect.3.\u201d\u201cThe SYBH resembles a ballet dancer\u2019s shoe and has a volume of ~499609\u2009mshould read:3.\u201d\u201cThe SYBH resembles a ballet dancer\u2019s shoe and has a volume of 1417149\u2009m"}
+{"text": "Correction to: BMC Health Services Research (2023) 23:31. 10.1186/s12913-022-09011-0.Following publication of the original article , the autbold):Corrections (marked in 2020\u20132021) (n\u2009=\u2009591) or usual care (n\u2009=\u2009469). (Abstract under \u201cInterventions\u201d)Participants were individually randomized (1\u20131 ratio) to either be exempted from the standard $5 charge per prescription item for one year ((1 Feb 2020 to 31 Jan 2021) (Methods).The primary outcome was length of stay  within the year of the study The original article  has been"}
+{"text": "Environ Health Perspect 121:A182\u2013A189 (2013)] referred to farms that companies \u201cco-own with farmers.\u201d These farms should have been referred to as \u201ccompany-owned.\u201d EHP regrets the error.The June 2013 News article \u201cCAFOs and Environmental Justice: The Case of North Carolina\u201d ["}
+{"text": "Adri\u00e1n Fern\u00e1ndez-Lodeiro, Javier Fern\u00e1ndez-Lodeiro, Cristina N\u00fa\u00f1ez*, Rufina Bastida, Jos\u00e9 Luis Capelo, and Carlos Lodeiro*The cover picture shows the formation of one-dimensional nanochains of silver nanoparticles (AgNPs) upon addition of a polyamine molecular linker. In the present work, the binding ability of this linker was exploited, bearing different functional groups, which favors the self-assembly of silver and gold nanoparticles (AuNPs) into one-dimensional nanochains in aqueous solution. These nanochains visually resemble the artistic work of \u201ccalceteiros\u201d (pavers) to build the \u201ccal\u00e7ada Portuguesa\u201d (Portuguese pavements) in Portugal . Polyamine ligands are very versatile materials due to their water solubility and flexibility. The study of AgNPs and AuNPs in one-dimensional nanostructured formations are finally used as new sophisticated heavy metal (Hg2+) ion chemosensors. For more details, see the Full Paper by Carlos Lodeiro, Christina N\u00fa\u00f1ez and co-workers, on p. 200 ff."}
+{"text": "Information concerning the the first author's funding was incorrectly omitted from the first sentence of the funding statement. The correct sentence is: MJS-B was funded by a FEBS postdoctoral fellowship during her stay in Cambridge (UK) and by a \u201cRam\u00f3n y Cajal\u201d contract (RYC-2008-03449) and the \u201cMinisterio de Econom\u00eda y Competitividad\u201d (grant number BIO2011-28184-C02-02) in Spain."}
+{"text": "There are multiple in-text citation errors in the Methods section and Figure Legends. The second sentence in the Methods section under the subheading \u201cImmunoblotting\u201d should end with: \u201c...and Bar209 anti-mono197 and unglycosylated PrP mAb [14] , recognizing a conformational epitope [14] likely involving human PrP168-181, like anti-mono197 PrP mAb V61 [12].\u201dThe last sentence of the Figure S1 Legend should be: \u201cBar209 has a conformational epitope (14), which likely involves PrP168\u2013181 as it recognizes PrPC depending on N181 occupancy, like V61 mAb (12).\u201dThe first sentence of the Figure S2 Legend should begin: \u201cThe following brain homogenates containing different PrP glycoforms were used [21]...\u201d"}
+{"text": "Muscle spindles, whose activity is determined by muscle length changes and by fusimotor drive (i.e. \u03b3-drive), provide critical information about movement position and velocity . HoweverOur conceptually simple computational model (an adaptation of ) allows Our simulations suggest that (i) empirically observed muscle spindle activity profiles can to a large part be explained by a strongly task-dependent \u03b3-drive Figure , (ii) obOur simulation predicts that \u03b3-drive is strongly modulated and task-dependent and that appropriate \u03b3-drive can explain many empirically observed aspects of group Ia and II muscle spindle responses during active movements."}
+{"text": "Journal of Pharmacology & Pharmacotherapeutics, 2010; 1: 122-3; Column 1, Paragraph 5, line 4.Title: Agomelatine: A novel melatonergic antidepressantThe drug name \u2018fluoxamine\u2019Should read as\u2018fluvoxamine\u2019The error is regretted- Chief Editor, JPP"}
+{"text": "OGX-011 is a second generation 21-mer oligonucleotide with a 20-O-(2-methoxy)-ethyl modification, generously provided by OncoGenex Technologies \u201d [The original version of the paper reports that \u201c"}
+{"text": "It should read BIC = k log n - 2 log L(theta_hat |Y). Please view the complete, correct equation here:"}
+{"text": "In the second sentence of the \u201cNext Generation Sequencing (NGS) Library Construction\u201d section, the sequence for primer F515 appears incorrectly in the text. The sentence should read: \u201cBriefly, the V4 domain of bacterial 16S rDNA was amplified using primers F515 (5\u2032-GTGCCAGCMGCCGCGGTAA-3\u2032).\u201d"}
+{"text": "Escherichia coli (ETEC) outbreaks, United States, 1996\u20132003,\u201d the serotype of the strain associated with outbreak number 16 was O169:H41 not O169:H49.On p. 519, in the table entitled \u201cCharacteristics of enterotoxigenic"}
+{"text": "Pyrus bretschneideri Rehd. 21S34S), the latter displaying a typical S-RNase-based gametophytic self-incompatibility (GSI). The pollen-part mutation (PPM) of \u2018Jin Zhui\u2019 might be due to a natural mutation in the pollen-S gene (34S haplotype). However, the molecular mechanisms behind these phenotypic changes are still unclear. In this study, we identified five SLF (S-Locus F-box) genes in \u2018Ya Li\u2019, while no nucleotide differences were found in the SLF genes of \u2018Jin Zhui\u2019. Further genetic analysis by S-RNase PCR-typing of selfed progeny of \u2018Jin Zhui\u2019 and \u2018Ya Li\u2019 \u00d7 \u2018Jin Zhui\u2019 progeny showed three progeny classes  as opposed to the two classes reported previously (21S34S and 34S34S), indicating that the pollen gametes of \u2018Jin Zhui\u2019, bearing either the 21S- or 34S-haplotype, were able to overcome self-incompatibility (SI) barriers. Moreover, no evidence of pollen-S duplication was found. These findings support the hypothesis that loss of function of S-locus unlinked PPM expressed in pollen leads to SI breakdown in \u2018Jin Zhui\u2019, rather than natural mutation in the pollen-S gene (34S haplotype). Furthermore, abnormal meiosis was observed in a number of pollen mother cells (PMCs) in \u2018Jin Zhui\u2019, but not in \u2018Ya Li\u2019. These and other interesting findings are discussed.\u2018Jin Zhui\u2019 is a spontaneous self-compatible mutant of \u2018Ya Li\u2019 ( S locus, which is comprised of the pistil-S and pollen-S genes S gene encodes a polymorphic ribonuclease (S-RNase) essential for rejection of self-pollen, and operates through inhibiting the growth of pollen tubes that possess the same S allele S locus itself is a cluster of pollen-expressed S-locus F-box genes named SLF/SFBBPetunia, Antirrhinum and Pyrus support a model in which the SLF functions as a component of the SCF E3 ubiquitin ligase complex that interacts with non-self S-RNases, leading to their degradation through the ubiquitin 26S proteasome proteolytic pathway Nicotiana suggests the resistance to non-self S-RNase by its sequestration from vacuolar compartments in compatible pollen tubes Gametophytic self-incompatibility (GSI) is a genetic mechanism in many flowering plants that prevents self-fertilization and promotes cross-fertilization. In Solanaceae, Plantaginaceae and Rosaceae, GSI is controlled by a single multi-allelic S-RNase and S-locus F-box genes as the S-determinants in Rosaceae, although functional approaches based on transgenic experiments have been proven problematic in this family. For instance, Okada et al. 2S4S). The cultivar had a 236 kb region deleted which included the 4-RNaseS of sm-S4haplotype. Whereas Li et al. Pyrus bretschneideri Rehd.) was caused by a single amino acid mutation in 21S-RNase. The European pears (Pyrus communis) \u2018Abugo\u2019 and \u2018Ceremeno\u2019 were found to be self-compatible where 21S\u00b0-RNase protein was absent in the style Prunus cerasus), a Mu-like element insertion upstream of 6m-RNaseS reduced the level of expression of S-RNase, correlating with reduced accumulation of S-RNase in the pistil and reversal of the rejection mechanism S determinants in Rosaceae. Meanwhile, self-compatible pollen-part mutants with non-functional SFB proteins have been widely reported in Prunus. In self-compatible sweet cherry (Prunus avium), the 4SFB 4 bp deletion caused a frame-shift resulting in defective SFB4 transcripts lacking two hypervariable regions. Similarly, a self-compatible Japanese apricot (Prunus mume) mutant was likely caused by insertion in the fSFB coding region, leading to a defective SFBf transcript that lacked the HVa and HVb containing C-terminus S determinants in prunus. Noteworthily, self-compatible pollen-part mutants with non-functional SLF/SFBB are little known in Solanaceae and the tribe Pyreae . Pollen-part self-compatibility (SC) in these species is due to the S-heteroallelic pollen effect S alleles induces breakdown of pollen SI function SLFs/SFBBs in Solanaceae and Pyrus (Rosaceae) support a \u2018non-self recognition by multiple factor SI system\u2019 Pyrus are mostly related to S-allele duplications.In recent studies, the use of induced or spontaneous self-compatible mutants have supported S-locus unlinked factors  that are required for GSI had also been associated with SC in Solanaceae and some genera of Rosaceae. In apricot cultivar \u2018Canino\u2019 (2SCS), a mutation was found in a modifier gene unlinked to the S-locus which independently caused the loss of pollen-S function S-locus. Zuriaga et al. S-locus unlinked PPM was located at the distal end of chr.3. Pollen modifier factors have also been identified in Petunia, Pyrus and Prunus, such as the pollen-expressed Skp1-like1 proteins. As a modifier, Skp1-like1 proteins were proposed to be involved in a SCF complex Pyrus, the loss of function of S-locus unlinked PPM that leads to self-compatibility has never been reported. Therefore, the identification of S-locus unlinked PPM in Pyrus will be necessary to give a more complete picture of the self-incompatible mechanism.However, mutations in 34S mutation S-locus unlinked PPM was probably involved in pollen-S function breakdown. Further mapping will be necessary to identify the underlying mutant S-locus unlinked PPM.\u2018Jin Zhui\u2019 is a spontaneous self-compatible mutant of SI pear cultivar \u2018Ya Li\u2019. Li et al. No specific permits were required for the described observation or field studies. For locations and activities partaken, a. no specific permissions were required; b. locations were not privately-owned or protected in any way and c. no endangered or protected species were involved.Pyrus bretschneideri Rehd.), \u2018Ya Li\u2019 , \u2018Jin Zhui\u2019 , \u2018Jin Feng\u2019 , \u2018Han Hong\u2019 , \u2018Han Xiang\u2019 , \u2018Jin Zhui\u2019 selfed progeny, and crossed progeny derived from \u2018Ya Li\u2019 \u00d7 \u2018Jin Zhui\u2019, \u2018Ya Li\u2019 \u00d7 \u2018Jin Feng\u2019, \u2018Jin Zhui\u2019 \u00d7 \u2018Jin Feng\u2019, \u2018Jin Zhui\u2019 \u00d7 \u2018Han Hong\u2019, \u2018Ya Li\u2019 \u00d7 \u2018Han Hong\u2019, \u2018Han Xiang\u2019 \u00d7 \u2018Jin Zhui\u2019 were used in this study. The pistils and pollen were collected and stored at \u221280\u00b0C for DNA and RNA extraction. Flower buds from \u2018Jin Zhui\u2019 and \u2018Ya Li\u2019 were collected in spring at the stage ideal for meiotic studies, and root-tips for the observation of chromosomal numbers of \u2018Jin Zhui\u2019 selfed progeny were obtained from the germinated seeds.Five cultivars of Chinese pear , and seeds from self-pollination and cross-pollination were used for segregation analysis of Genomic DNA from leaves and seedlings was isolated by the method described previously SLF alleles in pollen cDNAs from \u2018Ya Li\u2019 and \u2018Jin Zhui\u2019. PCR conditions were as follows: 20 \u00b5L reaction system, 50 ng genomic DNA, 2 \u00b5L 10 \u00d7 Ex Taq buffer (including 2 mM MgCl2), 0.2 mM dNTPs, 10 pM of each primer and 0.2 unit Ex Taq DNA polymerase (TaKaRa). PCR products were examined by 1% agarose gel, and purified using the Gel Extraction Kit  and then cloned into the pMD18-T vector (TaKaRa). Four independent clones of each PCR product were chosen for DNA sequencing. Sequence alignment was performed with MEGA version 5.0 SLF/SFBB were carried out using the neighbor-joining method implemented in MEGA, with 1000 bootstrap replicates. Homologs were identified by BLASTN searches of the National Center for Biotechnology Information database  \u00d7 \u2018Jin Feng\u2019 (19S34S) was used.Primers were screened from the PpSFBB primers reported by KaKui et al. se NCBI; . Specifi alleles . A segreSix cross-pollinations, \u2018Ya Li\u2019 \u00d7 \u2018Han Hong\u2019, \u2018Jin Zhui\u2019 \u00d7 \u2018Han Hong\u2019, \u2018Han Xiang\u2019 \u00d7 \u2018Jin Zhui\u2019, \u2018Ya Li\u2019 \u00d7 \u2018Jin Zhui\u2019, \u2018Jin Zhui\u2019 \u00d7 \u2018Jin Feng\u2019, \u2018Ya Li\u2019 \u00d7 \u2018Jin Feng\u2019 and two self-pollinations from \u2018Ya Li\u2019 and \u2018Jin Zhui\u2019, were performed in the field. Pollination was conducted as follows: all flowers were removed before anthesis except three per inflorescence, with the anthers in these three removed and insect-proof bags used to prevent accidental contamination by foreign pollen. Fruit set was recorded about 1 month later and fruits were collected up until harvest time, with the number of seeds and weight per fruit recorded.Pollen viability was estimated as the percentage of pollen grains stained with 0.5% fluorescein diacetate (FDA). Fresh pollen grains were germinated on a solid medium  in petri dish for 40 min at 28\u00b0C, and then the solid medium with germinated pollen grains was cut into small patches and placed on a glass slide. The germinated pollen grains were observed directly under a microscope  for germination tests. For tests of pollen viability, FDA (2.5 mg/ml) was added to solid medium for 10 min, and then the pollen grains were observed under a microscope . A total of 500 pollen grains were observed.Upon reaching the optimal stage for meiotic studies, flower buds of \u2018Jin Zhui\u2019 and \u2018Ya Li\u2019 were fixed in carnoy's fluid  for 24 hours and then stored in 70% ethanol at 4\u00b0C until used. Pollen mother cells were stained with 4\u2032, 6-diamino-2-phenylindole (DAPI) before observation. The chromosome numbers of \u2018Jin Zhui\u2019 selfed progeny were observed from root-tip cells with at least 30 cells observed per sample, fresh root-tips were harvested when 1\u223c2 cm long from germinated seeds and pretreated in 0.002 M 8-Hydroxyquinoline for 2 hours at room temperature, and then fixed with cannoy solution for 24 hours. After washing twice with distilled water, the root-tips were cut and kept in a solution of 2% cellulose and 1% pectinase at 37\u00b0C for 2 hours. Materials were washed twice with distilled water before being fixed again with cannoy solution and then stained on a pre-cooled slide with 4\u2032, 6-diamino-2-phenylindole pyrrolindone (DAPI). All chromosomal images were captured under the Olympus BX53 fluorescence microscope used with a microCCD camera.SLF alleles was performed using four different primer pairs as used for SFBB allele identification by Kakui et al. SLF alleles from the genomic DNA of \u2018Ya Li\u2019 (21S34S) using each primer pair , 34PbSLF1-S (GenBank accession number KC569799), 34PbSLF3\u03b1-S (GenBank accession number KC569800), 34PbSLF3\u03b2-S (GenBank accession number KC569801) and 21PbSLF4-S (GenBank accession number KC569802).To confirm whether the five S-RNases  C. TheseSLFs from \u2018Jin Zhui\u2019, seven SLFs including the five obtained in this study and two identified by Xu et al. SLFs showed no difference between \u2018Ya Li\u2019 and \u2018Jin Zhui\u2019 (data not shown).To determine whether mutations or indels existed in the S of the 34-Shaplotype. To further analyze the nature of the self-compatible mutant, pollination tests were performed. \u2018Ya Li\u2019 and \u2018Jin Zhui\u2019 were self-pollinated and reciprocally pollinated. The results from pollination tests showed that \u2018Jin Zhui\u2019, which had functional style and nonfunctional pollen, was self-compatible, while \u2018Ya Li\u2019, which had functional style and pollen, was self-incompatible  and two classes (19S34: S19S21S) by S-RNase genotyping, respectively. The observed ratios for S-genotype segregations fit with the expected ratios . These results supported self-compatibility (SC) in \u2018Jin Zhui\u2019 was associated with S-locus unlinked PPM rather than S-allele duplications.To further validate these observations, additional crosses were performed and analyzed . The cro21S21S:21S34S:34S34S) from selfed progeny of \u2018Jin Zhui\u2019 and crossed progeny between \u2018Ya Li\u2019 and \u2018Jin Zhui\u2019 were 9\u223674\u223611 and 6\u223645\u22369, respectively. These segregation ratios did not fit the expected ratios of 1\u22362\u22361, with \u03c72 values of 31.11, P<0.01 and 14.56, P<0.01 . As a self-incompatible cultivar, \u2018Ya Li\u2019 had normal meiotic behavior  A\u2013J. \u2018YaF-box genes within the S-locus region have been reported S genes had been determined experimentally Petunia and Pyrus, multiple SLFs/SFBBs as pollen S factors were proven to collaborate in recognizing non-self S-RNases and mediate their degradation S genes were always considered a reasonable explanation for self-compatible PPM, where Li et al. 34S genes. Our study on pollen-part mutation of \u2018Jin Zhui\u2019 should help us to understand the function of the pollen-S gene. We cloned five F-box genes from pollen cDNA of \u2018Ya Li\u2019, with linkage analysis showing them to be S-Locus F-box (SLF) genes. However, comparative analysis of seven SLFs, including the two SLFs identified by Xu et al. SLFs were probably not directly responsible for the SI breakdown of \u2018Jin Zhui\u2019. Subsequent genetic analysis further supported this hypothesis.In gametophytic self-incompatible (GSI) species of Solanaceae, Rosaceae and Plantaginaceae, multiple 21S34S) is a traditional Chinese pear (Pyrus bretschneideri) cultivar exhibiting self-incompatibility, and \u2018Jin Zhui\u2019 (21S34S) is a pollen-part mutant of \u2018Ya Li\u2019. Genetic analysis of 29 selfed progeny in \u2018Jin Zhui\u2019 showed that the pollen 34S allele might be mutated in \u2018Jin Zhui\u2019 \u2018Ya Li\u2019 (21S34S) was self-pollinated and reciprocally crossed with \u2018Ya Li\u2019 (21S34S). It is noteworthy that \u2018Jin Zhui\u2019 pollen tubes bearing either the 21S- or the 34S-haplotype were able to grow through \u2018Jin Zhui\u2019 and \u2018Ya Li\u2019 pistils and complete fertilization, producing three S-genotype classes  instead of the two classes observed previously (21S21S and 21S34S). However, no progeny were obtained in the reciprocal cross when using \u2018Jin Zhui\u2019 as the female parent. These results should support the PPM in \u2018Jin Zhui\u2019 was unlinked to the S-locus. The crosses between \u2018Han Xiang\u2019 (12S31S) and \u2018Jin Zhui\u2019 (21S34S), \u2018Jin Zhui\u2019 (21S34S) and \u2018Jin Feng\u2019 (19S34S) reinforced this conclusion.To investigate the genetics of SC in \u2018Jin Zhui\u2019, genetic populations were constructed. \u2018Jin Zhui\u2019   , Table 3 progeny . These rArabidopsis male sterile mutant, abnormal meiosis caused by a Ds insertion in the SKP1-LIKE1 gene was reported SLF complex, and proposed to degrade non-self S-RNase in the degradation model of Pyrus, prunus and AntirrhinumS-locus unlinked PPM might influence the pollen development of \u2018Jin Zhui\u2019. Two SSKs, which had been identified in \u2018Ya Li\u2019 S-locus unlinked PPM should help us to gain deeper insights into self-incompatibility in Pyrus.Abnormal meiotic behaviors in PPM \u2018Jin Zhui\u2019 were observed in many PMCs . Univale"}
+{"text": "The paper titled \u201cA Prospective Study of Early Loaded Single Implant-Retained Mandibular Overdentures: Preliminary One-Year Results\u201d , publish"}
+{"text": "There were errors in Figures 2, 4, and 7. -The correct Figure 2 can be seen here: [^]-In Figure 4 B-D, the y-axis was incorrectly labeled \u201cGAPDH.\u201d The correct labels are \u201c* tubulin.\u201d-The correct Figure 7 can be seen here: [^]"}
+{"text": "Peroxisome-proliferator\u2013activated-receptor-\u03b3 (PPAR\u03b3) acts as a transcriptional regulator of multiple genes involved in glucose and lipid metabolism. In vitro studies showed that activated PPAR\u03b3 suppresses AT1R-gene expression and vice versa. However, it has not yet been determined in vivo, whether AT1R-PPAR\u03b3-interactions play a relevant role in the pathogenesis of diabetic complications and specifically in accelerated atherosclerosis.\u2212/\u2212 and ApoE\u2212/\u2212/AT1R\u2212/\u2212-mice were rendered diabetic by intraperitoneal injections of streptozotocin. Diabetic and non-diabetic ApoE\u2212/\u2212-mice were further randomized to receive the AT1R antagonist telmisartan, the selective PPAR\u03b3 antagonist GW9662, telmisartan and GW9662 or vehicle for 18 weeks. Diabetic and non-diabetic ApoE\u2212/\u2212/AT1R\u2212/\u2212-mice were randomized to receive either GW9662 or vehicle. GW9662 treatment in diabetic ApoE\u2212/\u2212 and diabetic ApoE\u2212/\u2212/AT1\u2212/\u2212-mice resulted in the highest elevation of fasting blood glucose levels, whereas telmisartan treatment and AT1 deficiency in ApoE\u2212/\u2212-mice showed the lowest fasting blood glucose levels. Diabetic ApoE\u2212/\u2212-mice displayed severe impairment of endothelial function, enhanced oxidative stress and increased atherosclerotic lesion formation. ApoE\u2212/\u2212/AT1R\u2212/\u2212 and telmisartan-treated ApoE\u2212/\u2212-mice showed a significantly better endothelial function, decreased oxidative stress and reduced atherosclerotic lesion formation. Treatment of diabetic ApoE\u2212/\u2212 and ApoE\u2212/\u2212/AT1R\u2212/\u2212-mice with the selective PPAR\u03b3 antagonist GW9662 omitted the atheroprotective effects of AT1R deficiency or AT1 antagonism.ApoE\u2212/\u2212-mice via the PPAR\u03b3 pathway.Genetic disruption or pharmacological inhibition of the AT1R attenuates atherosclerosis and improves endothelial function in diabetic ApoE In vitro studies investigating the interaction of PPAR\u03b3 and the AT1R in vascular smooth muscle cells (VSMC) showed that activated PPAR\u03b3 suppresses AT1R gene expression and vice versa, suggesting that pharmacological blockade or genetic disruption of the AT1R leads to enhanced PPAR\u03b3 activity thereby mediating anti-atherosclerotic effects in the vascular compartment [in vivo model of diabetes. Whether interactions of AT1R and PPAR\u03b3 play a key role in the pathogenesis of diabetes-induced atherosclerosis remains undetermined.Diabetes mellitus is a leading cause of morbidity and mortality in western countries due to cardiovascular complications . It has partment ,15. HoweIn the present study we analysed the influence of AT1R-PPAR\u03b3 interactions on diabetic-induced atherosclerotic lesion formation and endothelial function in an experimental long-term diabetic mouse model. In this well characterized model, injection of the cytotoxin streptozotocin (STZ) results in a reduction in \u00df-cells and an increase in plasma glucose to diabetic levels . The val\u2212/\u2212) mice  and AT1A receptor knockout mice (AT1R\u2212/\u2212) with identical genetic background  were used for this study. Thirty-two ApoE\u2212/\u2212-mice and 12 ApoE\u2212/\u2212/AT1R\u2212/\u2212-mice were rendered diabetic by 5 daily intraperitoneal injections of streptozotocin  at a dose of 55mg/kg in citrate buffer or received citrate buffer  alone  at a dose of 40 mg/kg body weight per day orally via chow or the selective PPAR\u03b3 antagonist GW9662 (Sigma-Aldrich) i.p. at a dose of 1mg/kg body weight every second day or telmisartan and GW9962 or vehicle for 18 weeks  in conscious animals. Blood glucose levels were measured using Accu-Chek\u00ae-Sensor, Roche, Mannheim, Germany). Blood samples were collected by tail vein puncture. Body weights were measured weekly and changes in body weight at baseline compared to body weight after 18 weeks of treatment were calculated.After excision of the descending aorta, the vessel was immersed in chilled, modified Tyrode buffer containing, in mmol/L, NaCl 118.0, CaCl2 2.5, KCl 4.73, MgCl2 1.2, KH2PO4 1.2, NaHCO3 25.0, Na EDTA 0.026, D(+) glucose 5.5, pH 7.4. Three-millimeter rings were mounted in organ baths filled with the above-described buffer  and were attached to a force transducer, and isometric tension was recorded. The vessel segments were gradually stretched over 60 minutes to a resting tension of 10 mN. The drug concentration was increased when vasoconstriction or vasorelaxation was completed. Drugs were washed out before the next substance was added.Hearts with ascending aortas were embedded in Tissue Tek OCT embedding medium and sectioned on a Leica cryostat (9 \u03bcm), starting at the apex and progressing through the aortic valve area into the ascending aorta and the aortic arch and placed on poly-L-lysine (Sigma) coated slides. At least 15 consecutive sections per animal were used for analysis. For detection of atherosclerotic lesions, aortic cryosections were fixed with 3.7% formaldehyde and stained with oil red O working solution. For morphometric analysis, hematoxylin staining was performed according to standard protocols. Stained samples were examined with a Zeiss Axiovert 200 microscope  and an AxioCam MRc5. Images were acquired with Zeiss AxioVision software Rel. 4.5.0 and processed with Corel Graphic Suite X4. For quantification of atherosclerotic plaque formation in the aortic root, lipid staining area and total area of serial histological sections were measured. Atherosclerosis data are expressed as lipid-staining area in percent of total surface area. The investigator who performed the histological analyses was unaware of the hypothesis of this study and the treatment of the respective animal group.ROS release in intact aortic segments was determined by L-012 chemiluminescence, as previously described . ChemiluP\u2009<\u20090.05 indicates statistical significance.Data are presented as mean\u2009\u00b1\u2009SEM. Statistical analysis was performed using the ANOVA test followed by the Neuman\u2013Keuls post hoc analysis. \u2212/\u2212/AT1\u2212/\u2212-mice compared to ApoE\u2212/\u2212-mice. Heart rates were significant higher in diabetic animals. Measurements of fasting blood glucose levels showed pathological glucose levels in diabetic animals compared to non-diabetic animals. GW9662 treatment in diabetic ApoE\u2212/\u2212 and diabetic ApoE\u2212/\u2212/AT1\u2212/\u2212-mice resulted in the highest elevation of fasting blood glucose levels. Cotreatment with telmisartan and GW9662 markedly attenuated this effect in diabetic ApoE\u2212/\u2212-mice. Diabetic ApoE\u2212/\u2212-mice treated with telmisartan and diabetic ApoE\u2212/\u2212/AT1\u2212/\u2212-mice showed the lowest fasting blood glucose levels compared to the other diabetic animals. At baseline (d0) body weight was identical in all groups (data not shown). After 18 weeks of standard chow diet, all groups of diabetic ApoE\u2212/\u2212-mice had significant more loss of body weight than the corresponding groups of diabetic ApoE\u2212/\u2212/AT1R\u2212/\u2212-mice. Administration of GW9662 led to a significant decrease in body weight in diabetic ApoE\u2212/\u2212 and diabetic ApoE\u2212/\u2212/AT1R\u2212/\u2212-mice compared to vehicle treated diabetic ApoE\u2212/\u2212 and diabetic ApoE\u2212/\u2212/AT1R\u2212/\u2212-mice. Interestingly, GW9662 treated diabetic ApoE\u2212/\u2212-mice lost significant more body weight then GW9662 treated diabetic ApoE\u2212/\u2212/AT1R\u2212/\u2212-mice. In contrast, all groups of non-diabetic ApoE\u2212/\u2212-mice and non-diabetic ApoE\u2212/\u2212/AT1R\u2212/\u2212-mice had a uniform increment in body weight after 18 weeks. Total cholesterol levels were higher in diabetic ApoE\u2212/\u2212-mice and diabetic ApoE\u2212/\u2212/AT1\u2212/\u2212-mice compared to non-diabetic groups. Highest total cholesterol levels were detected in GW9662 treated diabetic ApoE\u2212/\u2212-mice, indicating poor glucose metabolism and increased lipolysis in GW9662 treated diabetic ApoE\u2212/\u2212-mice. Co-treatment with telmisartan reduced this effect significantly. GW9662 had no effect in diabetic ApoE\u2212/\u2212/AT1\u2212/\u2212-mice. All parameters are shown in Table\u00a0Total cholesterol levels, fasting blood glucose, change in body weight, blood pressure and heart rate were measured in all groups Table\u00a0. Mice we\u2212/\u2212/AT1R\u2212/\u2212-mice, endothelium dependent vasodilatation was significantly impaired in diabetic ApoE\u2212/\u2212-mice indicating that AT1R-deficiency attenuates endothelial dysfunction in diabetic animals. Endothelium-dependent vasodilatation was significantly impaired in GW9662 treated diabetic ApoE\u2212/\u2212-mice, whereas treatment with telmisartan led to a significant improvement of endothelium-dependent vasodilatation. Cotreatment with GW9662 abolished the beneficial effect of telmisartan on endothelial function (Figure \u2212/\u2212-mice treated with vehicle or telmisartan or telmisartan and GW9662 endothelial function was not significantly affected (Figure Vascular function was assessed in isolated aortic ring preparations. In contrast to diabetic ApoE\u2212/\u2212 -mice had significantly higher ROS levels than diabetic ApoE\u2212/\u2212/AT1R\u2212/\u2212-mice. AT1R-deficiency in diabetic ApoE\u2212/\u2212-mice and telmisartan treatment in diabetic ApoE\u2212/\u2212-mice significantly decreased vascular ROS release. Co-administration of GW9662 abolished this effect, whereas treatment with GW9662 alone induced the highest ROS release in diabetic ApoE\u2212/\u2212-mice (Figure Vascular release of ROS radicals was measured by L012-chemiluminescence assays in intact aortic segments. Figure e Figure A. In none Figure B.\u2212/\u2212-mice (Figure \u2212/\u2212-mice (Figure \u2212/\u2212/AT1R\u2212/\u2212-mice, atherosclerotic lesions were significantly diminished (Figure \u2212/\u2212-mice (Figure \u2212/\u2212-mice showed pronounced atherosclerotic lesion formation (Figure \u2212/\u2212/AT1R\u2212/\u2212-mice (Figure \u2212/\u2212/AT1R\u2212/\u2212-mice (Figure \u2212/\u2212-mice in the highest extent of atherosclerotic lesion formation (Figure \u2212/\u2212/AT1R\u2212/\u2212-mice compared to non-diabetic ApoE\u2212/\u2212-mice, indicating that AT1R-deficiency results in decreased atherogenesis not only in diabetic but also in non-diabetic conditions. Subgroup analysis in non-diabetic mice indicated that treatment with telmisartan led to reduced atherosclerotic lesion formation in ApoE\u2212/\u2212-mice (Figure \u2212/\u2212/AT1R\u2212/\u2212-mice (Figure \u2212/\u2212 controls (Figure \u2212/\u2212/AT1R\u2212/\u2212-mice (Figure \u2212/\u2212-mice treated with GW9662 (Figure Development of atherosclerotic lesions was quantified in diabetic and non-diabetic animals using oil red O-staining and macroscopic analysis of the aortic root after 18 weeks. Figure e Figure H, vehicle Figure A displayd Figure B and 4I.\u2212/\u2212-mice. In addition, we show for the first time that the antiatherosclerotic effects of AT1R-inhibition are in part mediated via PPAR\u03b3 in vivo. PPAR\u03b3-inhibition by GW9662 treatment resulted in enhanced ROS generation and atherosclerotic lesion formation in comparison to untreated diabetic ApoE\u2212/\u2212/AT1R\u2212/\u2212-mice.The present study demonstrates the major role of the AT1R in diabetes-induced atherogenesis. Here we show that AT1R blockade using a pharmacological approach and AT1R deficiency by gene deletion attenuates atherosclerosis and improves endothelial function in diabetic and non-diabetic ApoEPPAR\u03b3 belongs to the family of peroxisome proliferator-activated receptors, which control the expression of various genes attributed with potentially vasoprotective effects such as improved glucose metabolism, lipid homeostasis and reduction of oxidative stress ,18. IntekB pathway. In contrast to Sugawara et al. PPAR\u03b3 activation did not affect AT1 receptor expression but significantly reduced AT1 receptor dependent ERK1/2 regulation [One characteristic of the PPARs is that their activation can occur through a broad spectrum of ligands even with rather low affinity . This imgulation . Studiesgulation .\u2212/\u2212/AT1R\u2212/\u2212-mice resulted in enhanced ROS generation and atherogenesis in comparison to untreated diabetic ApoE\u2212/\u2212/AT1R\u2212/\u2212-mice. However, the here demonstrated ability of GW9662 to inhibit PPAR\u03b3 does not rule out occurrence of a mechanism independent of PPAR\u03b3-inhibition or counteracting AT1R-action by altering its signaling cascade olbeit in the literature, GW9662 has not been associated with pleiotropic pharmacological effects independent of PPAR\u03b3-inhibition or associated with AT1R-interference.Our results emphasize that AT1R-PPAR\u03b3-interactions are in part responsible for atheroprotective effects of AT1R-deficiency. Application of the specific PPAR\u03b3-antagonist GW9662 in diabetic ApoEDiabetes mellitus is associated with a profound risk of developing atherosclerosis and its complications such as myocardial infarction , stroke In conclusion, AT1R-deficiency or pharmacological inhibition of the AT1R and activation of PPAR\u03b3 with telmisartan in diabetic individuals have beneficial effects on oxidative stress, endothelial function and atherosclerotic plaque development especially in metabolic and RAAS abnormalities associated with diabetes indicating to a relevant interaction of PPAR\u03b3 and the RAAS in vivo. These findings suggest a potential utility of AT1R inhibitors with partial PPAR\u03b3 agonistic activity in the prevention and treatment of diabetic macrovascular complications.The authors declare that they have no competing interests.VT, GN, and SW conception and design of research; VT, AA and DL performed experiments; VT, UMB and CFHM analyzed data; VT, UMB and CFHM interpreted results of experiments; VT and UMB prepared figures; VT, UMB and CFHM drafted manuscript; VT, UMB and CFHM edited and revised manuscript; All authors have read and approved the final version of manuscript.Absolute values of endothelial funktion, oxidative stress and atherosclerostic plaque development.Click here for file"}
+{"text": "In the first sentence of the \u201cLibrary Construction\u201d section the sequence for primer F515 appears incorrectly in the text. The sentence should read: \u201cFor amplification of the V4 domain of bacterial 16S rDNA, we used primers F515 (5\u2032-GTGCCAGCMGCCGCGGTAA-3\u2032)\u201d"}
+{"text": "Previous studies have linked CD8+ T cell subset IFN-gamma production to HAM/TSP disease evolution ,2, as we"}
+{"text": "Asthma is a heterogeneous disease with various clinical, inflammatory and molecular phenotypes. Uncontrolled asthma is associated with an increased risk of asthma exacerbation. We evaluated sputum cytokine mRNA expression patterns in an unselected group of adults with stable asthma in comparison to healthy subjects in order to characterize patients\u2019 specific airway cytokine profiles.Differential cell counts and cytokine mRNA  were analyzed on sputum from 40 healthy and 66 asthmatic adults. A \u201ccytokine-high\u201d profile was defined if mRNA levels for that particular cytokine exceeded the 90th percentile value in the healthy population. Asthma control was assessed by Asthma Control Test (ACT) questionnaires.The \u201cIL-5-high\u201d asthma profile (n=13) merged with the \u201cIL-25-high\u201d (10/13) and surprisingly also with the \u201cIL-17A-high\u201d (11/13) profile. A sputum \u201cIL-25-high\u201d profile was even restricted to patients with an \u201cIL-5-high\u201d profile. Only a minority of \u201cIL-5-high\u201d patients were found to be \u201cIL-4-high\u201d (n=6), whereas 17 other patients had an \u201cIL-4-high\u201d profile without being \u201cIL-5-high\u201d. Patients with an \u201cIL-5-high\u201d, Il-17A-high\u201d and/or \u201cIL-25 high\u201d cytokine pattern had worse lung function parameters . Uncontrolled asthmatics had significantly higher sputum IL-5, IL-17A and IL-25 mRNA levels.Airway cytokine expression is highly heterogeneous amongst patients and their exact contribution to asthma pathogenesis is debated. Uncontrolled asthma was associated with higher levels of IL-5, IL-17A and IL-25 in the airways of asthmatics. Identifying patients\u2019 aberrant cytokine expression in the airways by non-invasive techniques might help to define responders to current and future therapies."}
+{"text": "J Ophthalmic Vis Res 2010; 5(1)], two errors were found regarding author names:In the January issue of this journal [J Ophthalmic Vis Res 2010; 5(1): 65\u201367), the author Reza Erfanian-Salim was misspelled as Mohammad-Reza Erfanian. The correct authors should read:In the Photo Essay, \u201cBilateral Orbital Cavernous Hemangiomas\u201d on page 65 : 3\u20139), the author Azade Doozande was omitted. The correct authors should read:In the Original Article, \u201cHigher-Order Aberrations in Myopic Eyes\u201d on page 3 (Farid Karimian, MD; Sepehr Feizi, MD; Azade Doozande, MD"}
+{"text": "Trigonella foenum-graecum) is a medicinal plant which is widely used for its pharmacological properties. In this study the phenolic composition of fenugreek crude seeds originating from Morocco has been investigated. Extraction was performed from defatted seeds by a hydromethanolic solution using an Accelerated Solvent Extractor. HPLC technique coupled to negative ion electrospray ionization mass spectrometry and diode array detection was employed to identify the polyphenol in the obtained extract. The obtained results allowed the detection of 32 phenolic compounds among which various flavonoid glycosides and phenolic acids have been tentatively identified on the basis of their UV and MS spectra, and comparisons with standards when available, as well as with literature data. A systematic study of the obtained MS spectra and the observed fragmentation showed that most of the identified compounds were acylated and non-acylated flavonoids with apigenin, luteolin and kaempferol as aglycons. Hydroxycinnamic acids mostly dominated by caffeic acid derivatives were also detected. The quantitative analysis of the identified compounds showed that the phenolic composition of the studied crude fenugreek seeds was predominantly acylated and non-acylated flavone derivatives with apigenin as the main aglycon.Fenugreek ( Trigonella foenum-graecum) is an annual plant of the Fabaceae family. The seeds of this plant are used by people in Asia, Africa and Mediterranean countries as one of the ingredients in daily diets \u2212 which was observed as base peak (m/z: 383 (Ag + 113) and m/z: 353 (Ag + 83) which are characteristics of di C-glycosylflavone fragmentations [m/z: 473 [(M \u2212 H) \u2212 120]\u2212 and corresponding to the 0,2''X0. This signal was observed with a low relative intensity, indicating to the loss of another glycosyl residue \u2212 (base peak). Additional fragment signals were observed at m/z: 473 [(M \u2013 H) \u2212 90]\u2212 , m/z: 443 [(M \u2013 H) \u2212 120]\u2212(\u22120.2''X0), m/z: 383 [(M \u2013 H) \u2212 120 \u2212 60]\u2212  and m/z: 353 [(M \u2013 H) \u2212 120 \u2212 90 ]\u2212 . These neutral losses are characteristics of a glucosyl and pentosyl residues as previously reported \u2212. The observed fragmentation pattern was typical of a di C-glycosylflavone [m/z: 503 [(M \u2212 H) \u2212 74]\u2212  and m/z: 473 [(M \u2212 H) \u2212 104]\u2212 , which are characteristics of a C-linked rhamonsyl [m/z: 383 [(M \u2212 H) \u2212 90]\u2212  and m/z: 353 [(M \u2212 H) \u2212 120]\u2212  were also observed and corresponded to the loss of a C-glucosyl moiety \u2212. The obtained MS data also showed fragment ion signals at m/z: 447 [(M \u2212 H) \u2212146]\u2212 (\u2212Y1'''7), m/z: 327 [(M \u2212 H) \u2212 146 \u2212 120]\u2212  and m/z: 285 [(M \u2212 H) \u2212 146 \u2212 162]\u2212 (\u2212Y07). The latter signal corresponding to the aglycon moiety indicated a loss of the O-rhamanosyglucosyl in agreement with previously reported data \u2212 (m/z: 383 (Ag + 113)  and m/z: 353 (Ag + 83)  in agreement with a di C-glycosylflavone [m/z: 593 [M \u2212 H \u2212 178]\u2212(Y2'') (acyl \u2212 18) and m/z: 473 [(M \u2212 H) \u2212 178 \u2212 120]\u2212 (\u22120.2''X0) suggesting an O-(Acyl)-glycosylflavone. The observed loss of 178 amu is in agreement with the molecular mass of a dehydrated dihydroferulic acid moiety connected through an interglycosidic 1\u21922 linkage to the C-glucosyl unit. This is due to the high relative intensity of the signal observed at m/z: 593 which was observed as base peak [10 was tentatively concluded to be apigenin 6-C-glucosyl 8-C-(2''-O-dihydroferuloyl)-glucoside.Compound [M \u2212 H]\u2212 . The MS lflavone . Additioase peak ,45. From12 showed a mass molecular ion at m/z: 749 [M \u2212 H]\u2212. The MS data also showed a fragment signal at m/z: 593 [M \u2212 H \u2212 156]\u2212 corresponding to the loss of a rhamnosyl moiety. Further ion signals were observed at m/z: 503 [(M \u2212 H) \u2212 156 \u2212 90]\u2212 , 473 [(M \u2212 H) \u2212 156 \u2212 120]\u2212 , with a low relative intensity, indicating the loss of a glucose residue. In the same spectrum a fragment ions signals were observed at m/z: 383 [(M \u2212 H) \u2212 156 \u2212 120 \u2212 90]\u2212 and 353 [(M \u2212 H) \u2212 156 \u2212 120 \u2212 120]\u2212, with high relative intensities, indicating to the loss of another glucose residue. Moreover, the ion fragment signals observed at m/z: 383 (aglycone + 113) and m/z: 353 (aglycone + 83), are characteristic of a di C-glycosylflavone fragmentation [12 was concluded to be an acylated vicenin derivative.The compound entation  with api21 presents a molecular ion at m/z: 725 [M \u2212 H]\u2212. The characteristic fragment signals at m/z: 383 (Ag + 113) and m/z: 353 (Ag + 83) , indicating a di C-glycosylflavone linkage were observed [m/z: 533 [(M \u2212 H) \u2212 192]\u2212 (acyl \u2212 18), m/z: 443 [(M \u2212 H) \u2212 192 \u2212 90]\u2212 (\u22120.2''X0) and m/z: 413 [(M \u2212 H) \u2212 192 \u2212 120]\u2212 , corresponding to the loss of the an O-(acyl)-C-pentosyl with a 1\u21922 interglycosidic linkage due to the high relative intensity (70%) of the signal observed at m/z: 533 \u2212. The MS data showed fragments signals at m/z: 593 [(M \u2212 H) \u2212 166]\u2212 (acyl \u2212 18) indicating a loss of an O-acyl moiety. The latter was concluded to be linked through a C-glycosylation, due to the presence of the fragments ions m/z: 383 (Ag + 113) and m/z: 353 (Ag + 83) which is indicative of di C-glycosylflavone [m/z: 473 [(M \u2212 H) \u2212 120]\u2212 , m/z: 383 [(M \u2212 H) \u2212 120 \u2212 90]  and m/z: 353 [(M \u2212 H) \u2013 120 \u2212 120]\u2212  (base peak), corresponding to the loss of the diglucosyl residue [m/z: 593 [(M \u2212 H) \u2212 166]\u2212 (acyl \u2212 18), showed a very low relative intensity (10%), compound 22 was concluded to be apigenin 6-C-glucosyl 8-C--glucoside.Compound lflavone . Other f15 and 16 present a molecular ion at m/z: 895 [M \u2212 H]\u2212. The MS data showed fragment signals at m/z: 563 [(M \u2212 H) \u2212 (acyl \u2212 2H) \u2212 162]\u2212, indicating an O-acylglycosylation on a phenolic hydroxyl through 1\u21926 interglycosidic linkage, due to their low relative intensity. Other fragment signals were observed at m/z: 447 [(M \u2212 H) \u2212 (acyl + 2H) \u2212 162 \u2212 (132 \u2212 16)]\u2212, m/z: 357 [(M \u2212 H) \u2212 (acyl + 2H) \u2212 162 \u2212 (132 \u2212 16) \u2212 90]\u2212  (Ag + 71) and m/z: 327 [(M \u2212 H) \u2212 (acyl + 2H) + 162 \u2212 (132 \u2212 16) \u2212 120]\u2212 (Ag + 41), corresponding to the loss of a pentosylglucoside with an interglycosidic 1\u21926 linkage in compound 15, and 1\u21922 for compound 16, due to a high relative intensity of the fragment ion m/z: 447 (compound 16) than in compound 15. The last fragment signals observed at m/z: 357 (Ag + 71) and m/z: 327 (Ag + 41) are typical of mono-glycosylflavones [C substitution [O-[6''-dihydrogalloyl]-glucosyl-8-C-pentosyl-(1\u21926)-glucoside was attributed to compound 15 and luteolin 7-O-[6''-dihydrogalloyl]-glucosyl-8-C-pentosyl-(1\u21922)-glucoside was attributed to compound 16.Compounds flavones ,48. The titution . Therefo18, 20 and 23 present a molecular ion at m/z: 863 [M \u2212 H]\u2212. The MS data showed a fragment signal at m/z: 563 [(M \u2212 H) \u2212 (acyl \u2212 18) \u2212 146]\u2212 (Y07\u2212), corresponding to the loss of an O-acylated rhamnosyl moiety. Other fragment signals were observed at m/z: 437 [(M \u2212 H) \u2212 300 \u2212 90]\u2212 , m/z: 443 [(M \u2212 H) \u2212 300 \u2212 120]\u2212 , m/z: 353 [(M \u2212 H) \u2212 210]\u2212 , m/z: 323 [(M \u2212 H) \u2212 300 \u2212 240]\u2212  and m/z: 311 [(M \u2212 H) \u2212 300 \u2212 240 \u2212 41]\u2212 (Ag + 41). These fragmentations are in agreement with the presence of a disaccharide moiety consisting of a pentosyl and a glucosyl residues. These were concluded to be linked through an interglycosidic linkage, due to the presence of the signal at m/z: 311 (Ag + 41), which is typical of the mono C-glycosylflavones \u2212. The MS data showed fragment ions at m/z: 563 [(M \u2212 H) \u2212 (acyl \u2212 18) \u2212 162]\u2212 (Y07\u2212), with a very low relative intensity (7%), indicating an O-(acyl)-glycosylation on the phenolic hydroxyl by interglycosidic 1\u21926 (24) and 1\u21922 linkage (25). Other fragment signals were observed at m/z: 473 [(M \u2212 H) \u2013 162 \u2212 (acyl \u2212 18) \u2212 90]\u2212 , m/z: 447 [(M \u2212 H) \u2212 314 \u2212 (132 \u2212 16)]\u2212 and m/z: 327 [(M \u2212 H) \u2212 314 \u2212 (132 \u2212 16) \u2212 120]\u2212 (\u22121.5'''X0). The latter\u2019s  and  corresponding to the loss of the pentosyl-rhamnoside residue by interglycosidic linkage at 2''' and 6''' position \u2212. The MS data also showed fragment signals at m/z: 577 [(M \u2212 H) \u2212 (acyl \u2212 18) \u2212 162]\u2212 (\u2212Y07) in agreement with the loss of an O-(acyl)-glucosyl (154 + 162 amu) moiety. This residue was concluded to be linked to the phenolic hydroxyl by interglycosidic 1\u21922 linkage (27), due to the high relative intensity of the signal located at m/z: 577 [m/z: 473 [(M \u2212 H) \u2212 316 \u2212 104]\u2212 , m/z: 383 [(M \u2212 H) \u2212 316 \u2212 104 \u2212 90]\u2212  and m/z: 353 [(M \u2212 H) \u2212 316 \u2212 104 \u2212 120]\u2212  corresponding to the loss of the rhamonsyl  and glucosyl  residues. The fragment signals at m/z: 383 (Ag + 113) and m/z: 353 (Ag + 83) which are characteristics of di C-glycosilflavone were also observed. The signal located at m/z: 353 was observed with a higher intensity in agreement with a 6-C-glucosyl-8-C-rhamnosyl-substitution. On the basis of the obtained results, these compounds were concluded to be apigenin 7-O--glucosyl-8-C-rhamnosyl-6-C-glucoside (26) and apigenin 7-O--glucosyl-8-C-rhamnosyl-6-C-glucoside (27).Compounds m/z: 577 . Other f28 presents a molecular ion at m/z: 925 [M \u2212 H]\u2212. The MS showed fragment signals at m/z: 605 [(M \u2212 H) \u2212 (acyl \u2212 18) \u2212 146]\u2212 (\u2013Y07), with a low relative intensity (6%), corresponding to the loss an O-(acyl)-rhamonsyl (174 + 146 amu) with a 1\u21926 interglycosidic linkage [m/z: 563 [(M \u2212 H) \u2212 320 \u2212 (acyl \u2212 18)]\u2212, m/z: 443 [(M \u2212 H) \u2212 320 \u2212 (acyl \u2212 18) \u2212 120]\u2212 , indicating to the Zj\u2212 (acyl \u2212 18) loss connected by interglycosidic linkage on the sugar moiety with a C-glycosylation. The ion m/z: 383 [(M \u2212 H) \u2212 320 \u2212 (acyl \u2212 18) \u2212 120 \u2212 60]\u2212  and m/z: 353 [(M \u2212 H) \u2212 320 \u2212 acyl \u2212 120 \u2212 90]\u2212 , corresponding to the loss of the glucosyl and pentosyl residue [m/z: 383 (Ag + 113) and m/z: 353 (Ag + 83) typical of the di C-glycosylflavone were also observed. The relative intensity of the [(M \u2212 H) \u2212 320 \u2212 (acyl \u2212 18) \u2212 120 \u2212 90]\u2212 signal was higher than that of [(M \u2212 H) \u2212 320 \u2212 (acyl \u2212 18) \u2212 120]\u2212 in agreement with a 6-C-pentosyl-8-C-glucosyl- substitution. These results suggested that compound 28 was luteolin 7-O-(6''-quinoyl)-rhamnosyl-6-C-pentosyl-8-C,O-(6'''-acetyl)-glucoside.Compound  linkage . Other f residue  were als29 presents a molecular ion at m/z: 547 [M \u2212 H]\u2212. The MS data showed fragment ion signals at m/z: 457 [(M \u2212 H) \u2212 90]\u2212 , m/z: 353 [(M \u2212 H) \u2212 90 \u2212 104]\u2212 and m/z: 327 [(M \u2212 H) \u2212 116 \u2212 104]\u2212 (Ag + 41), m/z: 297 [(M \u2212 H) \u2212 146 \u2212 104]\u2212 and m/z: 283 [(M \u2212 H) \u2212 164 \u2212 86 \u2212 14]\u2212. The neutral loss  and 104 amu was concluded to correspond to the loss of the O--C-glucosyl by interglycosidic 1\u21922 linkage, due to a high relative intensity of the ion m/z: 353. Moreover, the fragment ion signal observed at m/z: 327 (Ag + 41), is typical of mono C-glycosylflavones and confirmed the substitution in the C-8 position due to the low relative intensity of the fragment ion m/z: 327 [29 could be luteolin 8-C--glucoside.Compound m/z: 327 . These r30 presents a molecular ion at m/z: 935 [M \u2212 H]\u2212. The MS data also showed a fragment signal at m/z: 651 [(M \u2212 H) \u2212 (acyl \u2212 18 \u2212 2H) \u2212 132]\u2212 (Y07) corresponding to the loss of the an O-(acyl)-pentosyl with a 1\u21922 interglycosidic linkage due to its very high relative intensity (81%). Other fragment signals were observed at m/z: 547 [(M \u2212 H) \u2212 284 \u2212 104]\u2212 , m/z: 461 [(M \u2212 H) \u2212 284 \u2212 104 \u2212 86]\u2212, m/z: 327 [(M \u2212 H) \u2212 284 \u2212 190]\u2212  (Ag + 41) and m/z: 285 [Ag \u2212 H]\u2212 corresponding to the loss of the O--pentosyl-rhamnosyl- unit with 1\u21922 and 1\u21926 interglycosidic linkages due to the presence the fragment signal m/z: 285 (aglycone) [30 was concluded to be luteolin 7-O--pentosyl-4'-O--rhamnoside.Compound glycone) . On the 32 presents a molecular ion at m/z: 1133 [M \u2212 H]\u2212. Other fragment signals were observed at m/z: 1063 [(M \u2212 H) \u2212 70]\u2212 (base peak), m/z: 917 [(M \u2212 H) \u2013 70 \u2212 146]\u2212 (Y76'''), m/z: 577 [(M \u2212 H) \u2212 86 \u2212 146 \u2212 324]\u2212 (\u2212Y72'''Y70) corresponding to the loss an O--rhamnosyl-diglucosyl with 1\u21922 and 1\u21926 interglycosidic linkages according to relative intensity of the fragments ions. Additional fragment signals were observed at m/z: 413 [(M \u2212 H) \u2013 556 \u2212 164]\u2212 (\u2212Z36''''') and m/z: 293 [(M \u2212 H) \u2212 556 \u2212 164 \u2212 120]\u2212 , suggesting another loss of the O-dirhamnosyl moiety. The relative intensity of the ion signal at m/z: 293 was higher than that of m/z: 413 indicating a 3-O-dirhamnosyl-aglycone. These results suggested this compound could be kaempferol 7-O--rhamonsyl-diglucosyl-3-O-(6'''''-rhamnosyl)-rhamnoside.Compound Eight hydroxycinnamic acid derivatives with low concentrations were detected in the studied fenugreek seeds sample. The tentative characterization of these compounds was based on UV spectra, mass spectral data and comparision with the literature data ,53. Diff1 presents a molecular ion at m/z: 827 [M \u2212 H]\u2212 (m/z: 665 [(M \u2212 H) \u2212 162]\u2212, m/z: 503 [(M \u2212 H) \u2212 324], m/z: 383 [(M \u2212 H) \u2212 324 \u2212 120]\u2212, m/z: 341 [(M \u2212 H) \u2212 324 \u2212 162]\u2212 , m/z: 281 [(M \u2212 H) \u2212 324 \u2212 162 \u2212 60]\u2212, m/z: 221 [(M \u2212 H) \u2212 324 \u2212 162 \u2212 120]\u2212, and m/z: 179 [(M \u2212 H) \u2212 324 \u2212 162 \u2212 162]\u2212. The loss of 324 amu is in agreement with the presence of a diglucoside moiety [Compound [M \u2212 H]\u2212 . The MS e moiety . The las2 presents a molecular ion at m/z: 695 [M \u2212 H]\u2212. The MS data showed fragment signals at m/z: 619 [(M \u2212 H) \u2212 76]\u2212, with a high relative intensity (90%), m/z: 407 [(M \u2212 H) \u2212 76 \u2212 212], with a low relative intensity (6%), m/z: 309 [(M \u2212 H) \u2212 386]\u2212 (base peak) and m/z: 180 [(M \u2212 H) \u2212 515]\u2212 with a relative intensity of 66%. The last fragment signal indicated the loss of the caffeic acid molecule while the 515 amu indicated the loss of the deshydrated dicaffeoyl-hydroxyferulic acid. Therefore, this compound was tentatively identified as tricaffeoyl-hydroxyferulic acid.Compound 4 presents a molecular ion at m/z: 947 [M \u2212 H]\u2212. The MS data showed fragment signals at m/z: 765 [(M \u2212 H) \u2212 182]\u2212 (loss of hydrocaffeic acid), m/z: 382 [(M \u2212 H) \u2212 182 \u2212 383]\u2212 (loss of dehydrated hydro feruloyl-sinapic acid), m/z: 205 [(M \u2212 H) \u2212 182 \u2212 383 \u2212 177]\u2212 (loss of sinapic acid). These results, suggested that this compound could be disynapoyl-hydro feruloyl-feruloyl-hydrocaffeic acid.Compound 5 presents a molecular ion at m/z: 447 [M \u2212 H]. Other signals were observed at m/z: 224 [(M \u2212 H) \u2212 223]\u2212, m/z: 152 [(M \u2212 H) \u2212 295]\u2212. The loss of the 295 amu is in agreement with a coumaroyl-pentosyl-unit. The last fragment ions corresponded to the loss of the dehydrated gallic acid unit, suggesting that this compound could be galloyl-coumaric acid pentoside.Compound 6 presents a molecular ion at m/z 499 [M \u2212 H]\u2212. The MS data showed fragment signals at m/z: 377 [(M \u2212 H) \u2212 122]\u2212, m/z: 273 (M \u2212 H) \u2212 226]\u2212, m/z: 163 [(M \u2212 H) \u2212 336]\u2212 and m/z: 119 [(M \u2212 H) \u2212 336 \u2212 44]\u2212. The loss of the 336 amu, indicated to the loss of a dehydrated caffeoyl-quinic acid unit and the last fragment ion observed at m/z: 163, corresponded to the loss of a coumaroyl radical, suggesting that this compound could be a caffeoyl-coumaroyl-quinic acid.Compound 7 presents a molecular ion at m/z: 801 [M \u2212 H]\u2212. The MS data also showed fragment signals at m/z: 671 [(M \u2212 H) \u2212 130]\u2212, m/z: 477 [(M \u2212 H) \u2212 324]\u2212 corresponding to the loss of diglucosyl. Other signals were observed at m/z: 323 [(M \u2212 H) \u2212 324 \u2212 154]\u2212 (loss of protocatechuic acid), m/z: 144 [(M \u2212 H) \u2212 324 \u2212 154 \u2212 179]\u2212 . These results suggested that this compound could be dicaffeoyl-protocatechuic acid diglucoside.Compound After having studied the qualitative phytochemical composition of the crude fenugreek seeds extract, the quantitative analysis of the individual identified phenolic compounds was explored and the obtained results are gathered in 16, an acylated triglycoside derivative of luteolin, as a major compound (15.80%). This was followed by compounds 14 (14.41%) and 20 (12.02%), which are glycosides of apigenin. The non-acylated apigenin (17 and 11) and kaempferol (31) derivatives were present with similar percentages . The acylated apigenin glycosides (18) and luteolin (13) compounds were present with 6.59% and 5.60% respectively. Finally compounds 15 and 32, which are acylated derivatives of luteolin and kaempferol were present at 3.76% and 2.52% respectively. These flavonoids represent the major compounds with 87.80% of the total identified compounds. The other compounds were present at lower relative percentages.The obtained results showed that the identified compounds are present at different percentages, with compound The quantitative composition of the studied crude seeds was dominated by non-acylated flavonoid glycosides (48.60%), followed by acylated flavonoid glycosides (45.86%) and finally phenolic acids (5.55%). Apigenin was the major constitutive aglycon (61.30%), followed by luteolin (21.15%) and kaempferol (11.22%). This showed that the studied sample was dominated by flavone derivatives (83.20%).The data obtained thus demonstrates that acylated and non-acylated flavone derivatives, with apigenin as the main aglycon, dominate the phenolic composition of crude fenugreek seeds.C-neohesperidoside, luteolin 7-O-glucoside, kaempferol 7-O-neohesperidoside and apigenin 7-O-neohesperidoside were obtained from Extrasynthese .All the chemicals used were of analytical grade and were obtained from Sharlab S.L. . Apigenin, luteolin, kaempferol, apigenin 8-Trigonella foenum-graecum seeds were collected in June 2009 from the north Morocco area. Dried seed samples were ground to a powder using a commercial coffee grinder  and stored in plastic bags and kept in the dark at room temperature until extraction.Crude v/v) for polyphenols extraction. The temperature was 80 \u00b0C and the pressure was 1500 psi (10.3 Mpa) with 5 min for heating, 8 min as static time and 3 cycles for extraction. In the end, the extraction cell was flushed with solvent (60% cell volume) and purged with nitrogen (120 s). Three replicate extractions for each experimental condition were performed (n = 3). The extraction procedure was as follows: (1) Sample is loaded in the cell, (2) Cell is filled with solvent up to a pressure of 10.34 MPa, (3) Initial heat-up time is applied, (4) A static extraction with all system valves closed is performed, (5) The cell is rinsed (with 60% cell volume using extraction solvent), (6) Solvent is purged from the cell with N2 gas and (7) Depressurization takes place.Extraction was carried out using a Dionex ASE 200 Accelerated Solvent Extractor. This technique is also known as pressurized liquid extraction or pressurized fluid extraction. The system, automated and capable of sequential extractions, was made up of stainless steel extraction cells and its programmed parameters (temperature and pressure) were kept at their specified values by electronically controlled heaters and pumps. In this work, the extraction conditions were based on US EPA method . The usev/v) mixture and filtered through a 0.45 \u00b5m PVDF syringe filter, and analyzed by HPLC.At the end, the extracts were dried under a nitrogen flow at 40 \u00b0C, using Turbovap LV Concentration Evaporator . The residue was redissolved in 2 mL of methanol/water  column  at room temperature. The mobile phase consisted of water/AcOH (98/2) (solvent A) and acetronitrile/AcOH (98/2) (solvent B). Separation was performed using the following elution gradient: 0 to 80% B linear during 55 min, from 80% to 90% B during 2 min, 90% B isocratic during 13 min, from 90% to 95% B during 10 min and from 95% to 100% B during 10 min. This was followed by a washing with methanol and reequilibration of the column from 90 to 120 min. The flow rate was 1 mL/min, and the injection volume was 10 \u00b5L. The analysis was performed at 280, 310, 330 and 360 nm. Mass spectra were acquired using electrospray ionization in the negative ion mode scanning from m/z: 100 to 3000 using the following fragmentation program: from m/z: 0 to 200 (100 V) and from m/z: 200 to 3000 (200 V). Ionization parameters were as follows: drying gas (N2) at a flow of 10 L/min and a temperature of 350 \u00b0C. The nebulizer pressure was 55 psi and the capillary voltage was 4000 V.The HPLC\u2013DAD\u2013ESI/MS apparatus used consisted of a Waters 717 plus autosampler HPLC coupled to a Diode array detector and mass spectrometer . The separation was performed on a reversed-phase Waters Nova-Pak CIn this study, HPLC coupled to both ESI/MS and DAD was used to separate and identify 24 flavonoid glycosides in the extract of fenugreek crude seeds. Some minor phenolic acids were also detected and characterized. Both acylated and non-acylated flavonoid derivatives were detected. Most of the identified flavones were apigenin adducts followed by luteolin derivatives, while only two kaempferol glycosides were detected as flavonols. This work presents thus a more complete description of the phenolic compounds present in the crude fenugreek seeds. The obtained results indicate that crude fenugreek seeds could be considered as a rich source of bioactive phenolic compounds. Due to the widely reported antioxidant activity of flavonoids, crude fenugreek seeds could be exploited as an important supplement in food manufacturing such as functional foods or other herbal preparations."}
+{"text": "In the paper titled \u201cParticle Radiation-Induced Nontargeted Effects in Bone-Marrow-Derived Endothelial Progenitor Cells\u201d , there w"}
+{"text": "Scientific Reports6: Article number: 19051; 10.1038/srep19051 published online: 01112016; updated: 05202016.This Article contains errors.3 \u03bcm)\u2019 was incorrectly given as \u2018CPL(\u03bcm/mm2). The corresponding Figure legend,In Figure 1j, the x-axis \u2018CPL(\u00d710j) Graph showing a linear correlation between the ADC values and the cell perimeter length per pellet area  of HeLa S3, HL-60, and CV-1 cells.\u201d\u201c(should read:j) Graph showing a linear correlation between the ADC values and the cell perimeter length per pellet area  of HeLa S3, HL-60, and CV-1 cells.\u201d\u201c,should read:"}
+{"text": "Scientific Reports4: Article number: 709110.1038/srep07091; published online: 11182014; updated: 11122015This Article contains errors in Figure 2d and Figure 2e.In the last two histograms of Figure 2d, the y-axis should read \u2018MK-801\u2019 and \u2018MK-801+MH\u2019.In the last two histograms of Figure 2e, the y-axis should read \u2018Ngb\u2019 and \u2018Ngb+MH\u2019.The correct Figure 2d and Figure 2e appear below as"}
+{"text": "There are errors in the first sentence of the \u201cTargeted deep sequencing\u201d section of the Materials and Methods. The correct sentence is: A 169-bp fragment containing the human MPL sequence (43349278 to 43349446 of NC_000001.11) was PCR-amplified from genomic or standard plasmid DNA using forward (5\u2032- TGACCGCTCTGCATCTAGTGC -3\u2032) and reverse (5\u2032-GGTCACAGAGCGAACCAAGA-3\u2032) primers (see above).There is an error in"}
+{"text": "Unfortunately, the original version of this article  containeLykourgos Christos Alexakis was incorrectly assigned affiliation \u201cMahidol-Oxford Tropical Medicine Research Unit (MORU), Mahidol University, Bangkok 10400, Thailand\u201d (affiliation number 2), instead of \u201cAide M\u00e9dicale Internationale (AMI), Mae Sot, Tak, Thailand\u201d (affiliation number 4 in this erratum).All affiliations are correctly included in full in this erratum."}
+{"text": "The paper titled \u201cSystem Accuracy Evaluation of the GlucoRx Nexus Voice TD-4280 Blood Glucose Monitoring System\u201d , publish"}
+{"text": "Also, in Figure 1 the term \u201cNormal Dementia\u201d should have read\u201cNon-Alzheimer Group\u201d. The article has since been corrected online.In the article \u201cAn Increased Risk of Reversible Dementia May Occur After ZolpidemDerivative Use in the Elderly Population: A Population-Based Case-ControlStudy\u201d,"}
+{"text": "Scientific Reports5: Article number: 982110.1038/srep09821; published online: 04282015; updated: 10092015This Article contains typographical errors.In the Results section under subheading \u2018Simultaneous silence and HOIs of hippocampal neurons\u2019{\u03b8i,\u03b8ij} were adjusted to fit these statistics.\u201d\u201cThe parameters should read:{\u03b8i,\u03b8ij} were adjusted to fit these statistics.\u201d\u201cThe parameters In the Results section under subheading \u2018Simultaneous silence is a ubiquitous feature of HOIs\u2019\u201cBy expanding the SS term into the standard HOI-coordinates, we obtainshould read:\u201cBy expanding the SS term into the standard HOI-coordinates, we obtainIn the Result section under subheading \u2018Alternating signs of HOIs predicted by SS\u2019, equation (2)should read:In the Methods section under subheading \u2018A dichotomized gaussian (DG) model\u2019,i-th neuron (\u201cThe binary output of the should read:i-th neuron (\u201cThe binary output of the In addition,\u201cThe correlation coefficient between 2 output neurons is given by should read:\u201cThe correlation coefficient between 2 output neurons is given by In addition,m neurons are active and N-m neurons are inactive is given\u201d\u201cThe probability that exactly should read:m neurons are active and N-m neurons are inactive is given by\u201d\u201cThe probability that exactly In addition,\u201cThe signal for detecting the input correlation is given by should read:\u201cThe signal for detecting the input correlation is given by"}
+{"text": "After publication of this study , the aut\u201cThis work was partly funded by Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia (FCT), in the framework of the project PTDC/SAU-ENB/117631/2010, which is cofinanced by FEDER, through Programa Operacional Fatores de Competitividade - COMPETE of QREN (reference FCOMP-01-0124-FEDER-021141).\u201d"}
+{"text": "Scientific Reports6: Article number: 22610; 10.1038/srep22610 published online: 03072016; updated: 04292016.This Article contains typographical errors.In Equation 12,should read:In the Acknowledgements section,\u201cThis work is funded by the AIRC MFAG grant 17412, partially supported by partially supported by the \u201cStart-up Packages and PhD Program\u201d project\u201d.should read:\u201cThis work is funded by the AIRC MFAG grant 17412, partially supported by the \u201cStart-up Packages and PhD Program\u201d project\u201d."}
+{"text": "Zingiber zerumbet (L.) Smith: A Review of Its Ethnomedicinal, Chemical, and Pharmacological Uses\u201d [ Z. zerumbet.\u201d The correct caption text should have read \u201cFigure 1: The leaves and inflorescences of Z. zerumbet. .\u201d The new caption has been corrected in place.The article titled \u201cal Uses\u201d  has been"}
+{"text": "A 77-year-old man with a history of bypass surgery following an anterior myocardial infarction was admitted with a VT storm Fig.\u00a0. Coronar"}
+{"text": "Therefore, the correct results read as follows: \u201cF  \u200a=\u200a 7.43, All simple contrasts are described incorrectly as F-values, though they should be t-values."}
+{"text": "Since publication of our article , we have\u201cThe direction of association of BL1 with pCR or minimal residual cancer burden (RCB) in the 2188-gene model was similar (OR\u2009=\u20091.91) but did not reach significance (OR\u2009=\u20090.14).\u201dThis has been corrected to:\u201cThe direction of association of BL1 with pCR or minimal residual cancer burden (RCB) in the 2188-gene model was similar (OR\u2009=\u20091.91) but did not reach significance (p\u2009=\u20090.14).\u201dWe regret the error."}
+{"text": "There were 12 autonomic phenomena in this category[unspecific, analgesic effect, on various headaches. Our mean indomethacin continuation dosage was: 83 mg (range: 50-150), while in Goadsby's series it was 176 mg (25-500). HC is the unilateral headache with the least \u201clocal\u201d autonomic features, \u201cmigrainous\u201d and \u201cvascular\u201d components. It is a rather \u201cpure\u201d headache. The present classification brings HC nearer to other unilateral headaches with local autonomic symptoms, a misunderstood policy. CPH is exceptional with clinical similarities; the absolute indomethacin effect suggests a shared, core pathogenesis.Sjaastad & Spierings described \u201cHemicrania continua\u201d (HC) in 1984: permane category, with a"}
+{"text": "There is an error in the third sentence of the second paragraph under the \u201cDNA extraction, amplification and next generation sequencing\u201d subheading of the Materials and Methods section. The correct sentence is: The primer pair was labelled 18S_allshorts (Forward 5\u2019-TTTGTCTGSTTAATTSCG-3\u2019 and Reverse 5\u2019-TCACAGACCTGTTATTGC -3\u2019)."}
+{"text": "The\u00a0Results section in the Abstract erroneously reads \"57-year-old-male\u201d but should instead read \"59-year-old-male\u201d as it is correctly written later in the article."}
+{"text": "After publication of the original article  we were This work was supported by ARIA Project PTDC/DTP-SAP/1522/2012 from Foundation for Science and Technology (Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia - FCT) co-financed by European Regional Development Fundthrough Operational Competitiveness Programme (COMPETE) FCOMP \u221201-0124-FEDER-028797; and by the Portuguese CCDR-N for funding the research project \u201cE2BE\u201d (NORTE-07-0124- FEDER-000036), through the European Union FEDER programme."}
+{"text": "Scientific Reports5: Article number: 1576010.1038/srep15760; published online 10262015; updated on 01122016In the Methods section of this Article, all instances of \u2018g/u\u2019 should have been removed. The Methods section should read:E of the S+12\u039e term of an Aln cluster in Born-Oppenheimer approximation is given by O(S+12\u039e), are calculated using the GAMESS package.40 We use both Hartree-Fock (HF) method and complete active space self-consistent field (CAS-SCF) method. Our CAC-SCF many-evectron wavefunctions contain configuration interactions among the 3s and 3p valence shell and empty 3d-derived orbitals: CAS and CAS for Al2 and Al3, respectively. CAS stands for a CAS-SCF calculation with n active spaces and m active electrons. Atomic orbitals are expanded within the aur-cc-pVTZ basis set, and all nuclear positions are relaxed. This gives a virial ratio of \u2013V/T\u2009=\u20092.00000\u2009\u00b1\u20090.00003 for each molecular term S+12\u039e.The total energy"}
+{"text": "In the paper titled \u201cEnoxaparin Prevents Steroid-Related Avascular Necrosis of the Femoral Head\u201d , Rainer"}
+{"text": "Terminalia catappa Exerts Antimetastatic Effects on Hepatocellular Carcinoma through Transcriptional Inhibition of Matrix Metalloproteinase-9 by Modulating NF-\u03baB and AP-1 Activity\u201d [In the paper \u201c"}
+{"text": "Scientific Reports6: Article number: 2033110.1038/srep20331; published online: 02032016; updated: 03042016The original version of this Article contained errors in the spelling of the authors Encarnaci\u00f3n Medina-Carmona, Esperanza Pad\u00edn-Gonzalez and Noel Mesa-Torres which were incorrectly given as Medina-Carmona Encarnaci\u00f3n, Pad\u00edn-Gonzalez Esperanza and Mesa-Torres Noel.In addition, the \u2018How to cite this article\u2019 section quoted an incorrect abbreviation for Encarnaci\u00f3n Medina-Carmona. These errors have now been corrected in the PDF and HTML versions of the Article."}
+{"text": "The sentence should read: \u201cIn addition, Pmec-7 anoh-1b::mCherry also leads to the recovery of PS exposure on necrotic neuron surfaces .\u201dIn the Results section, under the subheading \u201cANOH-1 acts in touch neurons to promote the removal of necrotic touch neurons\u201d, the sentence \u201cIn addition, P"}
+{"text": "The article has since been corrected online.In the article \u201cEpstein\u2013Barr Virus-Positive T/NK-Cell Lymphoproliferative Disorders Manifested as Gastrointestinal Perforations and Skin Lesions: A Case Report\u201d,"}
+{"text": "Also, in Figure 3, the y-axis incorrectly read \u201cOverall survival (%)\u201d. It should have read \u201cDisease-free survival (%)\u201d. The article has since been corrected online.In the article \u201cHepatic Resection as a Safe and Effective Treatment for Hepatocellular Carcinoma Involving a Single Large Tumor, Multiple Tumors, or Macrovascular Invasion,"}
+{"text": "The unit for concentrations of IFN-\u03b2 was pg/dL. Here, we provide the right form of In \u201cHypothermia Reduces Toll-Like Receptor 3-Activated Microglial Interferon-"}
+{"text": "Scientific Reports6: Article number: 2550610.1038/srep25506; published online: 05032016; updated: 06272016.rs714598\u201d should read \u201crs713598\u201d.In this Article, all instances of \u201c"}
+{"text": "The grant number 3130441 is missing from the funding section. The correct funding statement is.http://www.conicyt.cl/fondecyt/) , and the Programa de Financiamiento Basal de la Comisi\u00f3n Nacional de Investigaci\u00f3n Cient\u00edfica y Tecnol\u00f3gica (http://www.conicyt.cl/pia/category/linea?s-del-programa/creacion-consolidacion-ce?ntros/ [grant number PFB16]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.This work was supported by the Fondo Nacional de Desarrollo Cient\u00edfico y Tecnol\u00f3gico Fondecyt ("}
+{"text": "Abu Hanna's name was originally presented incorrectly. The article has since been corrected online.In the article \u201cPerioperative Blood Glucose Levels <150\u200amg/dL are Associated With Improved 5-Year Survival in Patients Undergoing On-Pump Cardiac Surgery: A Prospective, Observational Cohort Study\u201d,"}
+{"text": "Aedes aegypti, (b)Aedes albopictus and (c) Culex quinquefasciatus, across detritus ratios ,\u201d incorrectly displays as a duplicate of Fig 1. Please see the correct"}
+{"text": "After the publication of this work , a few pPlasma miRNA analysis was performed on 18 HNSCC patients treated with local X-ray-irradiation using a linear accelerator [\u2026].The clinical data of patient 2 are incorrect. A revised version of Table\u00a017 out of 18 patients received concurrent chemotherapy (13 patients received 5-fluorouracil (5-FU) plus mitomycin C (MMC) [21], 3 patients MMC and 1 patient cisplatin weekly)\u201d.miR-425-5p. The correct sentence is:There is a typing error in the Results section  concerni\u201cThe qRTPCR assays confirmed an up-regulation of miR-425-5p with a p value close to the significance level (p\u2009=\u20090.052) [\u2026]\u201d.The corrections do not affect any results or conclusions of the published work."}
+{"text": "Scientific Reports5: Article number: 1545810.1038/srep15458; published online 10212015; updated: 01272016There is an error in the Materials and Methods section of this Article.31\u201d\u201cA rainbow trout double haploid clone, named B57should read:31\u201d\u201cRainbow trout from the INRA \u2018synthetic\u2019 strain"}
+{"text": "All three authors have PhDs. The article has since been corrected online.In the article \u201c(1\u21923)- \u03b2-D-Glucan Levels Correlate With Neurocognitive Functioning in HIV-Infected Persons on Suppressive Antiretroviral Therapy: A Cohort Study\u201d,"}
+{"text": "In the Results, under \u201cProduct-rule Mutations Lead to Sparse Structures, Sum-rule Mutations do not\u201d, the Symmetric product-rule should read as follows:"}
+{"text": "Following publication of the original article in BMC Genetics , it was Gossypium arboretum L.Furthermore, the keywords \u201cRehalose-6-phosphase synthase (TPS) and Gossypium arboretum\u201d are incorrect and should read: Trehalose-6-phosphase (TPS) and Also, in the \u201cMethods-Expression patterns analysis of cotton TPSs under stresses\u201d section, two extra blanks were introduced in \u201c2- \u0394 \u0394CT\u201d in the last sentence. The sentence should read: Relative quantitative analysis of target genes was calculated with the 2-\u0394\u0394CT method.The original article has been updated with the changes listed above."}
+{"text": "In Rana et al. , the folThe authors used the terms \u201cmicroRNA-21 mRNA\u201d and \u201cmicroRNA-29b mRNA,\u201d which are scientifically incorrect. The correct terms are \u201cmicroRNA-21\u201d and \u201cmicroRNA-29b.\u201dThe authors apologise for the errors."}
+{"text": "Why Fish Oil Fails: A Comprehensive 21st Century Lipids-Based Physiologic Analysis\u201d [The article titled \u201c"}
+{"text": "Scientific Reports5: Article number: 10778; 10.1038/srep10778 published online: 06022015; updated: 10202015.In this Article, the legend of Fig. 6 contains typographical errors.a) Gel and (b) HA/Gel scaffolds. Data are expressed as fold-regulation which represents fold-change results in a biologically expressive manner. Fold-regulation is equal to the fold-change (2\u2212\u0394\u0394Ct) for fold-change values greater than one, which indicate an up-regulation. Fold-change values less than one indicate a down-regulation: in this case the fold-regulation is the negative inverse of the fold-change (\u22121/2\u2212\u0394\u0394Ct). a\u2009=\u2009p\u2009<\u20090.05 vs CTRL; b\u2009=\u2009p\u2009<\u20090.05 vs 25/75 scaffolds; c\u2009=\u2009p\u2009<\u20090.05 vs 60/40 scaffolds.\u201d\u201cChanges in bmp2, runx2 and osteocalcin (bglap) mRNA expression in PDPCs seeded on (should read:a) HA/Gel and (b) Gel scaffolds. Data are expressed as fold-regulation which represents fold-change results in a biologically expressive manner. Fold-regulation is equal to the fold-change (2\u2212\u0394\u0394Ct) for fold-change values greater than one, which indicate an up-regulation. Fold-change values less than one indicate a down-regulation: in this case the fold-regulation is the negative inverse of the fold-change (\u22121/2\u2212\u0394\u0394Ct). *\u2009=\u2009p\u2009<\u20090.05 vs CTRL; #\u2009=\u2009p\u2009<\u20090.05 vs 25/75 scaffolds; \u00a7\u2009=\u2009p\u2009<\u20090.05 vs 60/40 scaffolds.\u201d\u201cChanges in bmp2, runx2 and osteocalcin (bglap) mRNA expression in PDPCs seeded on ("}
+{"text": "Scientific Reports5: Article number: 13908; 10.1038/srep13908published online: 09112015; updated: 10292015In this Article, all instances of \u201cArabidoPS Is\u201d should read \u201cArabidopsis\u201d"}
+{"text": "Regulation of retinal axon growth by secreted Vax1 homeodomain protein. Published 8 September 2014In the published article there was a typographical error in Figure 9B. The fourth and fifth labels on the x-axis were wrongly given as \u20186X-His + Robo-Fc\u2019 and \u2018Vax1 + Robo3-Fc\u2019. These labels should be \u20186X-His + Robo1-Fc\u2019 and \u2018Vax1 + Robo1-Fc\u2019 respectively.This article has been corrected accordingly."}
+{"text": "N-Glycan Branching, and Expression of O-Glycans in Seminal Plasma of Infertile Men\u201d [In the paper titled \u201cThe Analysis of Sialylation,ile Men\u201d , there w"}
+{"text": "F.pedrosoi\u201d sub-section of the \u201cMaterials and Methods\u201d section. The correct catalog number is \u201cMAB17561, R&D systems.\"The catalog number for the anti-mouse Dectin-1 blocking mAb is listed incorrectly as \u201cFAB17561, R&D systems\u201d in the \u201cCell culture, Dectin-1 blockage, and stimulation with"}
+{"text": "Scientific Reports 10.1038/s41598-022-21440-9, published online 07 October 2022Correction to: The original version of this Article contained an error in the Funding section.\u201cThis study was partially funded by the Italian Ministry of Health\u2019s \u201c5 Per Mille\u201d program.\u201dnow reads:\u201cThis study was partially funded by the Italian Ministry of Health under the \u201c5 per mille\u201d program.\u201dThe original Article has been corrected."}
+{"text": "This article has been corrected.1In the Original Investigation titled \u201cIncubation Period of COVID-19 Caused by Unique SARS-CoV-2 Strains: A Systematic Review and Meta-analysis,\u201d"}
+{"text": "Scientific Data 10.1038/s41597-022-01312-7, published online 10 May 2022Correction to: In this article the funding information relating to support from Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior - Brasil (CAPES) - Finance Code 001 was omitted. The original article has been corrected."}
+{"text": "Global Qualitative NursingResearch. https://doi.org/10.1177/23333936221128241Karlsson, M., Karlsson, C., and Kas\u00e9n, A. (2022). The Caring Mission \u2013 HealthcarePersonnel\u2019s Inner Driving Force in End-of-Life Care. The authors would like to notify that since the original online publication, the articletitle has been changed from \u201cThe Caring Mission\u2014Healthcare Personnel\u2019s Inner DrivingForce in End-of-Life Care\u201d to \u201cThe Caring Mission \u2013 Nursing Personnel\u2019s Inner DrivingForce in End-of-Life Care\u201d."}
+{"text": "The diagnosis and management of myocardial infarction with nonobstructive coronary arteries (MINOCA) are difficult due to its variable presentations, different causes, and challenging diagnostic approaches. Cardiac imaging modalities including cardiac magnetic resonance (CMR) are very useful tools for diagnosing and managing MINOCA. Myocardial infarction (MI) can be caused by coronary emboli that can\u00a0be contributed\u00a0to atrial fibrillation (AF). Rarely, coronary embolism with resultant MINOCA can occur after direct\u202fcurrent\u202fcardioversion (DCCV) even in fully anticoagulated\u202fpatients.\u202fWe present a\u202frare case of a coronary\u202fembolism following DCCV as well as a CMR finding of\u202fmicrovascular obstruction\u202f(MVO),\u202fwhich has\u202fnot previously been reported\u202fafter DCCV. This case also emphasizes the\u202fvalue\u202fof obtaining a CMR for patients with MINOCA. Determining the precise etiology\u202fof\u202fmyocardial\u202finfarction with nonobstructive coronary arteries (MINOCA) can be challenging. Cardiac magnetic resonance (CMR) imaging is very helpful in diagnosing, treating, and risk-stratifying patients with\u202fMINOCA. Cardiac emboli are one of the causes of myocardial infarction (MI), and atrial fibrillation (AF) accounts for\u202fapproximately\u202f15% of cardiac\u202femboli .A 51-year-old man with a past medical history of paroxysmal AF, hypertension, and morbid obesity presented to the emergency department with worsening dyspnea and lower extremity edema and was hospitalized for\u202fde novo\u202facute decompensated heart failure (ADHF). He was noted to be in AF with a rapid ventricular response. Transthoracic echocardiography revealed\u202fsevere systolic dysfunction\u202fwith a left ventricular ejection fraction (LVEF) of 20-25%. Coronary angiography demonstrated only minimal luminal coronary artery disease\u202f,\u00a0CMR was performed using a 1.5 T scanner . Retrospective ECG-gated breath-hold steady-state free precession cine images were obtained in short-axis slices at 10 mm intervals  and two-chamber, three-chamber, and four-chamber views. This revealed normal left ventricular size and ejection fraction and a hypokinetic basal anterolateral segment. Gadolinium-based contrast agent  was injected in a 15-mmol bolus and late gadolinium\u202fenhancement\u202f(LGE)\u202fimages were acquired 10 minutes later by using an inversion recovery gradient echo sequence. This revealed dense transmural hyperenhancement in the basal anterolateral myocardium with central\u202fhypoenhancement\u202fconsistent with microvascular\u202fobstruction , and absence of obvious causes of acute MI. Differential diagnoses of MINOCA include plaque erosion or rupture\u202fwith spontaneous recanalization, coronary embolism, spontaneous coronary artery dissection, microvascular disease, stress\u202fcardiomyopathy, and myocarditis. Due to the\u202fbroad differential diagnosis of MINOCA, treatment and prognosis vary remarkably\u202f,4. CMR iMVO\u202fis seen following coronary reperfusion therapy, especially after prolonged\u202fmyocardial ischemia.\u202fIt\u202fis caused by\u202fmicrovascular damage impairing blood flow\u202fthrough\u202fdamaged capillaries\u202fand is the CMR\u202fvisual\u202frepresentation of\u202fthe no-reflow phenomenon\u202f,8. On eaAF, infective endocarditis, and prosthetic valve thrombosis are the most common causes of coronary emboli; AF accounts for about 15% of coronary emboli .This case illustrates\u202fthe importance of obtaining CMR in patients with MINOCA.\u202fAlthough our\u202fpatient did not present with\u202fsymptoms of an\u202fMI, CMR was able to identify\u202fa\u202fsilent embolic\u202finfarct\u202fafter DCCV for AF.\u202fDespite its paucity, DCCV in AF patients can cause coronary\u202fembolism even in fully anticoagulated patients."}
+{"text": "Correction: Surgical Case Reports (2022) 8(1):148 https://doi.org/10.1186/s40792-022-01498-3Following publication of the original article , the autAuthor name \u201cSyunsuke Doi\u201d was mistakenly spelled, the correct author name should read \u201cShunsuke Doi\u201d.Author name \u201cSyouhei Kishida\u201d was mistakenly spelled, the correct author name should read \u201cShouhei Kishida\u201d.The original article  has been"}
+{"text": "An. balabacensis balaba Rev was written as 5\u2032-GC ACC GCT CTT GGC GGG ATA T-3\u2032 224\u2013228 bp. The correct In the original publication , there i"}
+{"text": "Scientific Reports 10.1038/srep01393, published online 6 March 2013Correction to: This Article contains errors in Figures\u00a01 and 2.In Figure 1C, the two top panels and the two bottom panels are reversed. Additionally, the panel labels contain errors, where the left top panel label should read \u201cTLR-deficient Control\u201d, the right top panel label should read \u201cTLR-deficient MPTP\u201d and the left bottom panel label should read \u201cWT Control\u201d.In Figure 2C, the panel labels contain errors, where the left top panel label should read \u201cWT Control\u201d, the left bottom panel label should read \u201cTLR-deficient Control\u201d and the right bottom panel label should read \u201cTLR-deficient MPTP\u201d.The correct Figures"}
+{"text": "In the corresponding author section, the address should have been \u201c1220 19th St NW, Washington, DC 20036.\u201d This article was corrected online.In the JAMA Forum titled \u201cHealth Insurance Coverage After the COVID-19 Public Health Emergency Ends,\u201d"}
+{"text": "Successful adolescence depends on ability to correctly understand emotionally expressive gestures, especially symbolic (same meaning for everyone) and expressive . Presence of an internal mismatch in adolescent\u2019s self-esteem between what he shows in society and what he really feels can lead to difficulties in forming an adequate adult self-esteem.Adolescents with affective disorders (F31) -12, normal adolescents - 32. Ages 12-17.Recognition of emotionally expressive movements: postures&gestures (gestures-test), direct self-esteem by Dembo-Rubinstein test and indirect self-esteem by color attitude test by Etkind.The Mann-Whitney test showed significant differences between samples in terms of self-esteem gap - \u201cmind\u201d , \u201ccharacter\u201d , \u201chappiness\u201d , gestures-test \u201csymbolic\u201d , \u201cexpressive\u201d , \u201cemotions\u201d . Cluster analysis divided each of groups into two distinct clusters. Normal: Cluster1 small self-esteem gap, good gesture recognition, negative pole of emotions prevails. Cluster2 small self-esteem gap, worse gesture recognition, pole of emotions is closer to positive. Affective: Cluster1 large self-esteem gap in \u201cmind\u201d, good gesture recognition. Cluster2 large self-esteem gap in \u201ccharacter\u201d, good gesture recognition and bright negative pole of emotions.Gestures recognition in normal group is significantly higher than in affective disorder group. Normal adolescents clusters are distinguished by change in gaps throughout self-esteem and pole of emotional recognition. Affective disorder clusters differ by significant gap in one of self-esteem parameters, as well as in the degree of emotional recognition. Those with the largest \u201ccharacter\u201d gap are more likely to attribute negative emotions to gestures than those with larger \u201cmind\u201d gap.No significant relationships."}
+{"text": "To estimate the incidence of, and trends in, catastrophic health expenditure in sub-Saharan Africa.We systematically reviewed the scientific and grey literature to identify population-based studies on catastrophic health expenditure in sub-Saharan Africa published between 2000 and 2021. We performed a meta-analysis using two definitions of catastrophic health expenditure: 10% of total household expenditure and 40% of household non-food expenditure. The results of individual studies were pooled by pairwise meta-analysis using the random-effects model.I2\u2009=\u200999.9%) for a threshold of 10% of total household expenditure and 8.7%  for a threshold of 40% of household non-food expenditure. Countries in central and southern sub-Saharan Africa had the highest and lowest incidence, respectively. A trend analysis found that, after initially declining in the 2000s, the incidence of catastrophic health expenditure in sub-Saharan Africa increased between 2010 and 2020. The incidence among people affected by specific diseases, such as noncommunicable diseases, HIV/AIDS and tuberculosis, was generally higher.We identified 111 publications covering a total of 1\u2009040\u2009620 households across 31 sub-Saharan African countries. Overall, the pooled annual incidence of catastrophic health expenditure was 16.5% (95% confidence interval, CI: 12.9\u201320.4; 50 datapoints; 462\u2009151 households; Although data on catastrophic health expenditure for some countries were sparse, the data available suggest that a non-negligible share of households in sub-Saharan Africa experienced catastrophic expenditure when accessing health-care services. Stronger financial protection measures are needed. In particular, we aimed to estimate the magnitude of, and between-country variation in, the annual incidence of catastrophic health expenditure between 2000 and 2021 and to investigate trends over time.https://www.who.int/publications/journals/bulletin/) for studies published between 1\u00a0January 2000 and 30\u00a0September 2021 in the 48 countries of sub-Saharan Africa  AND  OR \u201chealth expenditures\u201d[All Fields] OR  OR \u201chealth expenditure\u201d[All Fields])) OR  AND  AND (\u201cexpense\u201d[All Fields] OR \u201cexpenses\u201d[All Fields] OR \u201cexpensive\u201d[All Fields] OR \u201cexpensively\u201d[All Fields])) OR  AND  AND \u201cexpen*\u201d[All Fields]) OR  AND (\u201cimpoverish\u201d[All Fields] OR \u201cimpoverished\u201d[All Fields] OR \u201cimpoverishes\u201d[All Fields] OR \u201cimpoverishing\u201d[All Fields] OR \u201cimpoverishment\u201d[All Fields])) OR  AND (\u201cimpoverish\u201d[All Fields] OR \u201cimpoverished\u201d[All Fields] OR \u201cimpoverishes\u201d[All Fields] OR \u201cimpoverishing\u201d[All Fields] OR \u201cimpoverishment\u201d[All Fields])) AND (\u201cangola\u201d[MeSH Terms] OR \u201cangola\u201d[All Fields] OR \u201cangola s\u201d[All Fields] OR (\u201cbenin\u201d[MeSH Terms] OR \u201cbenin\u201d[All Fields] OR \u201cbenin s\u201d[All Fields]) OR (\u201cbotswana\u201d[MeSH Terms] OR \u201cbotswana\u201d[All Fields] OR \u201cbotswana s\u201d[All Fields]) OR (\u201cburkina faso\u201d[MeSH Terms] OR (\u201cburkina\u201d[All Fields] AND \u201cfaso\u201d[All Fields]) OR \u201cburkina faso\u201d[All Fields]) OR (\u201cburundi\u201d[MeSH Terms] OR \u201cburundi\u201d[All Fields]) OR (\u201ccabo verde\u201d[MeSH Terms] OR (\u201ccabo\u201d[All Fields] AND \u201cverde\u201d[All Fields]) OR \u201ccabo verde\u201d[All Fields]) OR (\u201ccameroon\u201d[MeSH Terms] OR \u201ccameroon\u201d[All Fields] OR \u201ccameroons\u201d[All Fields] OR \u201ccameroon s\u201d[All Fields]) OR  OR \u201ccentral african republic\u201d[All Fields]) OR (\u201cchad\u201d[MeSH Terms] OR \u201cchad\u201d[All Fields]) OR (\u201ccomoros\u201d[MeSH Terms] OR \u201ccomoros\u201d[All Fields] OR \u201ccomoro\u201d[All Fields]) OR \u201cdemocratic republic congo\u201d[All Fields] OR \u201crepublic congo\u201d[All Fields] OR \u201cCote d'Ivoire\u201d[All Fields] OR  OR \u201cequatorial guinea\u201d[All Fields]) OR (\u201ceritrea\u201d[MeSH Terms] OR \u201ceritrea\u201d[All Fields]) OR (\u201ceswatini\u201d[MeSH Terms] OR \u201ceswatini\u201d[All Fields]) OR (\u201cethiopia\u201d[MeSH Terms] OR \u201cethiopia\u201d[All Fields] OR \u201cethiopia s\u201d[All Fields]) OR (\u201cgabon\u201d[MeSH Terms] OR \u201cgabon\u201d[All Fields]) OR (\u201cgambia\u201d[MeSH Terms] OR \u201cgambia\u201d[All Fields] OR \u201cthe gambia\u201d[All Fields]) OR (\u201cghana\u201d[MeSH Terms] OR \u201cghana\u201d[All Fields] OR \u201cghana s\u201d[All Fields]) OR (\u201cguinea\u201d[MeSH Terms] OR \u201cguinea\u201d[All Fields] OR \u201cguinea s\u201d[All Fields] OR \u201cguineas\u201d[All Fields]) OR (\u201cguinea bissau\u201d[MeSH Terms] OR \u201cguinea bissau\u201d[All Fields] OR (\u201cguinea\u201d[All Fields] AND \u201cbissau\u201d[All Fields]) OR \u201cguinea bissau\u201d[All Fields]) OR (\u201ckenya\u201d[MeSH Terms] OR \u201ckenya\u201d[All Fields] OR \u201ckenya s\u201d[All Fields]) OR (\u201clesotho\u201d[MeSH Terms] OR \u201clesotho\u201d[All Fields]) OR (\u201cliberia\u201d[MeSH Terms] OR \u201cliberia\u201d[All Fields] OR \u201cliberia s\u201d[All Fields]) OR (\u201cmadagascar\u201d[MeSH Terms] OR \u201cmadagascar\u201d[All Fields] OR \u201cmadagascar s\u201d[All Fields]) OR  OR  OR (\u201cmauritania\u201d[MeSH Terms] OR \u201cmauritania\u201d[All Fields]) OR (\u201cmauritius\u201d[MeSH Terms] OR \u201cmauritius\u201d[All Fields]) OR (\u201cmozambique\u201d[MeSH Terms] OR \u201cmozambique\u201d[All Fields] OR \u201cmozambique s\u201d[All Fields]) OR (\u201cnamibia\u201d[MeSH Terms] OR \u201cnamibia\u201d[All Fields]) OR (\u201cniger\u201d[MeSH Terms] OR \u201cniger\u201d[All Fields]) OR (\u201cnigeria\u201d[MeSH Terms] OR \u201cnigeria\u201d[All Fields] OR \u201cnigeria s\u201d[All Fields]) OR (\u201crwanda\u201d[MeSH Terms] OR \u201crwanda\u201d[All Fields] OR \u201crwanda s\u201d[All Fields]) OR \u201cSao Tome and Principe\u201d[All Fields] OR  OR (\u201cseychelles\u201d[MeSH Terms] OR \u201cseychelles\u201d[All Fields]) OR \u201cSierra Leone\u201d[All Fields] OR  OR \u201cSouth Africa\u201d[All Fields] OR \u201cSouth Sudan\u201d[All Fields] OR (\u201csudan\u201d[MeSH Terms] OR \u201csudan\u201d[All Fields] OR \u201csudans\u201d[All Fields] OR \u201csudan s\u201d[All Fields]) OR (\u201ctanzania\u201d[MeSH Terms] OR \u201ctanzania\u201d[All Fields] OR \u201ctanzania s\u201d[All Fields]) OR (\u201ctogo\u201d[MeSH Terms] OR \u201ctogo\u201d[All Fields]) OR (\u201cuganda\u201d[MeSH Terms] OR \u201cuganda\u201d[All Fields] OR \u201cuganda s\u201d[All Fields]) OR (\u201czambia\u201d[MeSH Terms] OR \u201czambia\u201d[All Fields] OR \u201czambia s\u201d[All Fields]) OR (\u201czimbabwe\u201d[MeSH Terms] OR \u201czimbabwe\u201d[All Fields] OR \u201czimbabwe s\u201d[All Fields])))Note: Databases were searched for articles published between 2000 and 2021.Box\u00a02Central Africa: Burundi, Cameroon, Central African Republic, Chad, Congo, Democratic Republic of the Congo, Equatorial Guinea, Gabon and Sao Tome and Principe.Eastern Africa: Comoros, Djibouti, Eritrea, Ethiopia, Kenya, Madagascar, Mauritius, Rwanda, Seychelles, Somalia, South Sudan, Sudan, Uganda and United Republic of Tanzania.Southern Africa: Angola, Botswana, Eswatini, Lesotho, Malawi, Mozambique, Namibia, South Africa, Zambia and Zimbabwe.Western Africa: Benin, Burkina Faso, Cabo Verde, C\u00f4te d\u2019Ivoire, Gambia, Ghana, Guinea, Guinea-Bissau, Liberia, Mali, Niger, Nigeria, Senegal, Sierra Leone and Togo.Notes: The list includes the 48 countries of the sub-Saharan African region, as defined by the World Bank.Box\u00a03Observational or interventional studies (which included data on the pre-intervention period) published between 2000 and 2021 that reported population-level data for any of the 48 sub-Saharan African countries defined by the World Bank .9Studies reported in the published or unpublished (i.e. grey) literature.Publications that reported the incidence of catastrophic health expenditure for all individuals of all ages in the community as identified through household surveys or through studies based in health facilities that were representative of the entire community.Peer-reviewed publications in Arabic, English, French, Portuguese, Spanish or Kiswahili.Publications that estimated catastrophic health expenditure using either total household expenditure or income or non-subsistence expenditure.Publications that reported data on catastrophic health expenditure that could be extracted as an independent outcome along with the study population (i.e. the denominator).Publications that reported the incidence or proportion of catastrophic health expenditure based on a retrospective analysis of patients\u2019 charts, an analysis of hospital or pharmacy revenues, or a national or subnational budget analysis.Publications that reported the incidence of catastrophic health expenditure for all individuals of all ages based on studies carried out in one or several health facilities  that were not representative of the entire community.Interventional studies that reported the incidence of catastrophic health expenditure only after the intervention.Studies that used methods for estimating catastrophic health expenditure that were not clearly reported or defined or that reported catastrophic expenditure using terms such as \u201cexcessive out-of-pocket health care\u201d or the multidimensional poverty index.Articles that reported data for a population already included in the systematic review.Case reports, case series, systematic reviews, narrative reviews, letters to editors, commentary pieces and study protocols.,,Three authors independently extracted data from the included studies on: (i)\u00a0study countries; (ii)\u00a0year of publication; (iii)\u00a0study design; (iv)\u00a0data sources; (v)\u00a0year of data collection; (vi)\u00a0study population; (vii)\u00a0sample size; and (viii)\u00a0the incidence of catastrophic health expenditure as determined using a threshold of 10% of total household expenditure or 40% of household non-food expenditure or both. For surveys spanning several years, we regarded the survey\u2019s first year as the date of the survey. We grouped countries into four regions  using the African Union classification  and into,,Although studies have used different thresholds to define catastrophic health expenditure,Three authors independently assessed study quality using the appraisal tool for cross-sectional studies (AXIS) \u2013 a 20-question checklist designed to assess a study\u2019s risk of bias across five domains: introduction, methods, results, discussion and other information.2\u03c7 test with Cochran\u2019s Q statistic and quantified using the I2 statistic. We used Stata v. 17.0  for all statistical analyses and an \u03b1 of 0.05 was the cut-off for statistical significance.We used descriptive statistics to summarize the studies\u2019 characteristics. Individual results were pooled by pairwise meta-analysis using the random-effects model (DerSimonian-Laird approach) and the MetaProp Stata command with the Freeman-Tukey double arcsine transformation.We assessed the sensitivity of the pooled estimates to sample size by excluding the 10% of studies with the smallest sample size and the 10% with the largest sample size. The robustness of the estimates was assessed by excluding: (i)\u00a0studies with the largest and smallest sample sizes; (ii)\u00a0studies using pre-intervention data; (iii)\u00a0low-quality studies; and (iv)\u00a0studies that were not peer reviewed. We performed subgroup analyses along multiple dimensions, including: (i)\u00a0the data collection period ; (ii)\u00a0region ; (iii)\u00a0the country\u2019s income status ; (iv)\u00a0data type (i.e. primary or secondary); (v)\u00a0publication status (i.e. peer-reviewed or not); (vi)\u00a0UHC service coverage index ;,,,Finally, we performed a meta-regression analysis to explore factors associated with between-study heterogeneity for all catastrophic health expenditure incidence estimates pooled from 10 or more datapoints.We assessed overall evidence quality using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.https://www.who.int/publications/journals/bulletin/):\u2013Our initial search identified 1623 studies, including 36 from Google Scholar and citation tracking . After rThe quality of 95 of the 111 included studies (85.6%) was rated as high (AXIS score: 11\u201320), whereas the quality of the remaining 16 (14.4%) was rated as low (AXIS score: 0\u201310). When the risk of bias was weighted according to each study\u2019s sample size, studies covering 88.6% (921\u2009704/1\u2009040\u2009620) of households included were rated as having a low risk of bias, whereas those covering 11.4% (118\u2009916/1\u2009040\u2009620) were judged to have some quality concerns or were rated as having a high risk of bias. Of note, all studies included used sample frames and sampling techniques that closely represented the underlying population (as assessed using AXIS tool items 5 and 6).When the threshold for catastrophic health expenditure was defined as 10% of total household expenditure, the pooled annual incidence across 50 datapoints, which covered 462\u2009151 households, was 16.5% ; (ii)\u00a0the country\u2019s income status ; and (iii)\u00a0the country\u2019s UHC service coverage index . Full details are available in the data repository.At the country level, Cameroon and Sudan had the highest and second highest incidence, at 65.0% (95% CI: 64.1\u201365.9) and 52.8% (95% CI: 52.1\u201353.5), respectively (details available in the data repository).When the threshold for catastrophic health expenditure was defined as 40% of household non-food expenditure, the pooled annual incidence across 84 datapoints, which covered\u2009795\u2009355 households, was 8.7% ; (ii)\u00a0study quality as assessed using the AXIS score ; (iii)\u00a0the country\u2019s income status ; and (iv)\u00a0the country\u2019s UHC service coverage index . Full details are available in the data repository.P-value\u20090.024) and study quality  were independently associated with between-study differences in estimated pooled incidence. On average, studies that used secondary data reported a lower incidence of catastrophic health expenditure than those using primary data.At the country level, the Democratic Republic of the Congo and Mali had the highest and second highest incidence, at 21.9% (95% CI: 20.5\u201323.4) and 19.1% (95% CI: 18.1\u201320.2), respectively (details in the data repository).Estimates of the pooled incidence of catastrophic health expenditure for different disease groups  were genP-value\u20090.003 when the threshold was 10% of total household expenditure and P-value\u2009<\u20090.001 when it was 40% of household non-food expenditure). We were unable to determine whether the small-study effect was driven by publication bias because there was substantial heterogeneity in the data. For both thresholds, trim-and-fill analysis suggested that publication bias was absent (details available in the data repository).For the population-level meta-analyses, visual inspection of funnel plots suggested there was no publication bias. However, Egger\u2019s test for small-study effects gave a significant result , a substantially higher figure than for the general population. This result is consistent with growing evidence that noncommunicable disease is a major driver of health-care costs for households.,Most sub-Saharan African countries are also burdened by epidemics of infectious diseases, including human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), tuberculosis, malaria and pneumonia.,Our study also showed that the incidence of catastrophic health expenditure was high among people using maternal, neonatal and child health care services. Vulnerable families in most sub-Saharan African countries who require health care for severe obstetric complications, neonatal admission, or paediatric hospitalization or surgery are particularly at risk.,,,Our study has several strengths. The study is a methodological improvement on previous studies as we used several measures of catastrophic health expenditure.,There are also some limitations. First, survey-based evaluations of catastrophic health expenditure understate the risk faced by poorer households that are unable to seek care because of costs and thus report zero health expenditure. Consequently, our estimates should be taken as lower bounds of the true incidence of catastrophic health expenditure in sub-Saharan Africa. Second, in the absence of a universal definition, we defined catastrophic health expenditure using the thresholds of 10% of total household expenditure and 40% of non-food expenditure, as did 96% of eligible studies. A different definition could have given different pooled incidences. Finally, information on the UHC service coverage index was available only for 2015 and 2017 and data on social insurance coverage were sparse,Despite these limitations, our study provides important evidence for discussions on policy and health financing reform. By demonstrating that a substantial portion of the sub-Saharan African population experience catastrophic costs when accessing health care, our study underscores the urgency of designing effective and inclusive social protection mechanisms. Although identifying interventions was not a study objective, our findings highlight the need for measures such as insurance premium exceptions, co-payment exceptions, free medications and free diagnostic tests for households at most risk. Developing a social insurance system is the preferred long-term solution to catastrophic health expenditure and impoverishment in the region. In the short-term, increased donor funding for both public health care services and country-specific social safety nets are needed to ensure access for poor people. In addition, country-specific, targeted programmes can help reduce health inequity. Regular, nationally representative surveys remain critical tools for tracking health expenditure and for identifying the individuals, households and disease populations most at risk.The catastrophic health expenses experienced by many people in sub-Saharan Africa threaten poverty alleviation efforts. Stronger financial protection is critically needed in the region if continued progress is to be made towards achieving UHC and meeting the attendant SDGs."}
+{"text": "Correction to: Mol Neurobiol (2022) 59(3):1954-196910.1007/s12035-022-02738-1The original version of this article unfortunately contained a writing mistake in the first paragraph of Material and Methods. The \u201cC57BL/6 rats\u201d should be \u201cSprague Dawley rats\u201d."}
+{"text": "Correction: BMC Public Health 22, 2266 (2022)https://doi.org/10.1186/s12889-022-14632-5The headings of table 1 were incorrect as it listed \u201cMSM\u201d three times.The last 2 lines of table 3 were missing \u201cIC95\u201dThe original publication of this article  containeThe original article has been updated to correct these errors."}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-022-22343-5, published online 17 October 2022Correction to: The original version of this Article contained an error in Figure\u00a07, where the label of the Y-axis \u2018Relative TfR1 (OM/PM) protein expression\u2019 in panel (a) was incorrectly given as \u2018Relative TfR1 (PM/OM) protein expression\u2019. The original Figure\u00a0The original Article has been corrected."}
+{"text": "Int J Epidemiol 2022;51:537\u201346, https://doi.org/10.1093/ije/dyab140First published online: 14 October 2021, In the originally published version of this manuscript, an author\u2019s name was incorrect.The author\u2019s name should read \u201cMaria Feychting\u201d instead of \u201cMaria Feyching\u201d.This error has been corrected."}
+{"text": "Correction to: Naunyn-Schmiedeberg's Archives of Pharmacology (2022) 395:867\u201388510.1007/s00210-022-02250-2We regret to inform readers that our paper  had mistakenly stated that tralokinumab \u201cis administered via weekly subcutaneous injection\u201d (p. 873). This should have read that tralokinumab \u201cis administered as a loading dose, followed by subcutaneous injection every other week\u201d. We apologize for any inconvenience this mistake may have caused."}
+{"text": "Questions on the timing and the center of the Indo-European language dispersal are central to debates on the formation of the European and Asian linguistic landscapes and are deeply intertwined with questions on the archaeology and population history of these continents. Recent palaeogenomic studies support scenarios in which the core Indo-European languages spread with the expansion of Early Bronze Age Yamnaya herders that originally inhabited the East European steppes. Questions on the Yamnaya and Pre-Yamnaya locations of the language community that ultimately gave rise to the Indo-European language family are heavily dependent on linguistic reconstruction of the subsistence of Proto-Indo-European speakers. A central question, therefore, is how important the role of agriculture was among the speakers of this protolanguage. In this study, we perform a qualitative etymological analysis of all previously postulated Proto-Indo-European terminology related to cereal cultivation and cereal processing. On the basis of the evolution of the subsistence strategies of consecutive stages of the protolanguage, we find that one or perhaps two cereal terms can be reconstructed for the basal Indo-European stage, also known as Indo-Anatolian, but that core Indo-European, here also including Tocharian, acquired a more elaborate set of terms. Thus, we linguistically document an important economic shift from a mostly non-agricultural to a mixed agro-pastoral economy between the basal and core Indo-European speech communities. It follows that the early, eastern Yamnaya of the Don-Volga steppe, with its lack of evidence for agricultural practices, does not offer a perfect archaeological proxy for the core Indo-European language community and that this stage of the language family more likely reflects a mixed subsistence as proposed for western Yamnaya groups around or to the west of the Dnieper River. The puzzle of Indo-European origins is both an age-old and an ever topical problem. With the recent emergence of palaeogenetic methods the current mood is that the debate on the Indo-European homeland, which for several decades was dominated by a rivalry between the Steppe Hypothesis \u20133 and thFirst of all, many of the details of the linguistic fragmentation of the Indo-European speech community, i.e. the exact phylogenetic model, are still unclear. While there is relative consensus on the basal status of the Anatolian branch, leading to the formulation of the Indo-Anatolian Hypothesis :30, the The second, here central problem concerns the linguistic reconstruction of Proto-Indo-European economy. The pastoralist elements in the lexicon, including terminology related to the herding of sheep and cattle, are universally acknowledged. The field of Indo-European studies has traditionally been more divided, however, over how much Proto-Indo-European vocabulary can be reconstructed for the cultivation of plant domesticates, particularly cereals. According to Schrader , Proto-IThe controversy around Proto-Indo-European agriculture for a large part derives from differences in the methods used for linguistic reconstruction and ties back into the first problem of Indo-European phylogeny. In the traditional, perfect starburst model, where all branches are equally distantly related, any term that occurs in as few as two branches must be dated back to the protolanguage. Hirt thus arrived at a multitude of agricultural terms, many based on cognate sets only found in the European languages, and assumed that these terms were lost in Indo-Iranian. In a more stratified model, in which the split between the European and Asian branches (i.e. Indo-Iranian and Tocharian) is primary, only terms with continuants in both can be accepted for Proto-Indo-European. According to the latter criterion, Schrader accepted a more limited number, assuming that many of the terms exclusive to the European languages were acquired in Europe after the Indo-Iranian split. These different approaches, one maximalist, the other minimalist, produce highly divergent results.either are found in a European and an Asian branch, or in Anatolian and at least one other branch  like coarse grain by a sieve\u2019 [p\u00e1vana- \u2018sieve, winnowing basket\u2019. Although less certain, we may further adduce Alb. pah m. \u2018flour, chaff, dust\u2019 < *pouH-sk-o-  formation, i.e. OHG fewen, fouwen \u2018sift \u2019 < *pouH-eie-, but the meaning is rather generic and not clearly linked to the processing of cereals.It is possible that *winnowed :38\u201342. Ma sieve\u2019 :1491 and*pou-io- :47), pos(t)p(e)uH-o-, the initial cluster is not a regular development of PIE *p.No further comparanda are at hand. While it seems tempting to compare Gk. \u03c0\u03c4\u03cd\u03bf\u03bd, Att. \u03c0\u03c4\u03ad\u03bf\u03bd n. \u2018winnowing-shovel, fan\u2019, as if from **rugh-i- ; ON rugr m. \u2018rye\u2019, OE ryge m. \u2018rye\u2019 < PGm. *rugi-; OFri. rogga, OS roggo, OHG rocko m. \u2018rye\u2019 < *ruggan-; MW ryc, W rhyg m. \u2018rye\u2019 <? PC *ruk\u012b/i\u032fo-\u2018Roggen\u2019 :874; *ru*rughyos :110\u20131; *o- \u2018rye\u2019 :164): Lirugh-i- with the meaning \u2018rye\u2019. The British word may derive from divergent *rik\u012b/i\u032fo- or *ruk\u012b/i\u032fo-, if not borrowed from Old English [Wanderwort represented by Gk. \u1f44\u03c1\u03c5\u03b6\u03b1, Psht. wr\u00ed\u017ee, Skt. vr\u012bh\u00ed- \u2018rice\u2019 [The Germanic and Balto-Slavic languages secure a North European formation * English :517. The English :II, 265 - \u2018rice\u2019 :283.ru\u0292\u0301e\u032eg, Udm. \u0292\u0301eg, dial. \u0292\u0301i\u017aek, which appear to continue Proto-Permic *ru\u0292\u0301\u00e4g. In view of the suffix *-\u00e4g, these have been adduced to substantiate a Proto-Iranian form *ru\u01f0aka- or *ru\u01f0ika- [ide\u032eg \u2018angel\u2019 ~ Oss. (i)daw\u00e6g, Ko. \u0144ebe\u032eg \u2018book\u2019 ~ MP nib\u0113g. No such form is attested anywhere in Iranian, however. Shu. (Bajui) r\u014d\u0263\u030c\u0292 and Rosh. r\u016fz \u2018ear (of grain)\u2019 [ru\u0237\u030cika-, rather continue *r\u0101rza- [Wanderwort [Importantly, forms resembling the European word appear in the Permic languages, cf. Ko. *ru\u01f0ika- , cf. Ko. grain)\u2019 :876\u20137, a *r\u0101rza- :67. In v *r\u0101rza- :3\u20134. Giv *r\u0101rza- , it is pnderwort :595.The wild progenitors of rye spread from the Near East during the Neolithic, possibly as a weed infesting other grains. The transition of rye from a weed to a cultivated cereal is thought to have occurred in the Carpathian region from the second millennium BCE .\u2020*su(e)h2-ro/eh2- : sueh2-reh2- ~ *suh2-reh2- for Baltic, but we are most probably dealing with a Wanderwort [suro ~ sura \u2018millet\u2019 and perhaps Komi ze\u032er \u2018oats\u2019 and Udmurt ze\u032er \u2018bromegrass\u2019. The Ossetic word is rather derived from the Iranian root *hvar-, cf. YAv. xvar- \u2018consume, eat\u2019 < PIIr. *suar-, which is not consistent with a laryngeal.Witczak reconstructs  *nderwort :29 also ?*t\u1e31op-ero- (*k\u0302(\u00f3)pr\u0325 \u2018oats\u2019 [kappar- \u2018greens(?)\u2019 <? PAn. *\u1e31op-r-;? Jassic zabar \u2018avena\u2019 <? PIIr. *\u0107(\u0161)\u0101\u0306para-; ON hafri, OS ha\u0180oro, OHG habaro, haparo m. \u2018oats\u2019 < PGm. *hab(e/a)ran-\u0325 \u2018oats\u2019 :58; 193)\u1e31op-ro- meaning \u2018oats\u2019 has been reconstructed on the basis of Hittite, Germanic, Balto-Slavic and Iranian evidence [kappar- is unclear, which means that the proposed connection to PGm. *hab(a)ran- and Jassic zabar, both meaning \u2018oats\u2019, cannot be substantiated. Second, the Jassic form is only attested in a single word list and conspicuously close to Hung. zab \u2018oats\u2019, itself a borrowing from Sl. *zob\u044a [\u0107apara-, and a hypothetical Ossetic *s\u00e6v\u00e6r [\u0161ebar \u2018Alpine sedge \u2019 is related, we must instead reconstruct PIIr. *\u0107i\u0101\u0306par\u0101\u0306- [\u0107\u0161\u0101para- in view of Khot. \u1e63avara- \u2018a green plant\u2019, whose \u1e63 cannot reflect PIIr. *\u0107 [t\u1e31op-ero-. If the Asian East Iranian comparanda are accepted, however, they would at the same time demonstrate that the meaning \u2018(domesticated) oats\u2019 is not necessarily old.A protoform *evidence :133\u201343. l. *zob\u044a :159. It c *s\u00e6v\u00e6r :III, 306\u0101\u0306par\u0101\u0306- :301, or PIIr. *\u0107 :283. Nei\u2020*t\u1e31or-iano- :k\u0302\u00feoryanos has been proposed by Witczak [-ean cannot be equated with the Irish suffix -enn < PC *-inn\u0101 ~ *-ind\u0101 [A form * Witczak :99\u2013100. ~ *-ind\u0101 :199.?*gw(e)u-s-o- : Lat. b\u016bris, b\u016bra f. \u2018plow pole\u2019 \u226a? Sab. < PIt. *gweuso-; Gk. \u03b3\u03cd\u03b7\u03c2 m. \u2018curved piece of wood in a plow\u2019 < PGk. *guh\u0101-\u0259u-, g\u016b- :393\u20138): b\u016bris and b\u016bra are possible loans from Sabellic forms continuing PIt. *gweuso- [gwu-, Latin and Greek would attest to two different ablaut grades of an original neuter s-stem *gw\u00e9u-os, gen. *gu-s-\u00e9s \u2018curve\u2019 to the root *g(w)eu- \u2018curve\u2019. To further substantiate the Indo-European age of the s-stem, MP g\u014d\u0161ag \u2018corner, angle; detail\u2019 [gwou-s-o- [g\u014d\u0161\u0101 \u2018angle, corner; handle of a vessel; loop, noose\u2019 rather suggests an inner-Persian derivation from g\u014d\u0161 \u2018ear\u2019 . In conclusion, even if the s-stem existed in Proto-Indo-European, its agricultural meaning may have arisen late in the Mediterranean branches.Lat. *gweuso- :321. Ass detail\u2019 :186 has wou-s-o- :321. How*h2e\u1e31-on-eh2- : n-stem *h2e\u1e31-on-, cf. the formally close Gk. \u1f00\u03ba\u03cc\u03bd\u03b7 f. \u2018whetstone\u2019 as well as the potentially derived \u1f04\u03ba\u03b1\u03b9\u03bd\u03b1 f. \u2018spike, prick, goad\u2019 < *h2e\u1e31-n-ih2-. It appears that this formation went through a semantic shift from \u2018sharp object\u2019 to \u2018awn\u2019 in Germanic and Italic. The term additionally has a probable continuant in OPru. EV ackons \u2018awn\u2019, but the lack of palatalization of the velar is unexpected: if not due to depalatalization before n in one of the oblique cases [ahana.This is an Germano-Italic agricultural term. The formation resembles a neuter collective noun created to an ue cases :283, it *h2loh1-uo/eh2- [*al\u014du\u032f(-\u0101)-; OSw. l\u014d m. \u2018threshing floor\u2019 < PGm. *l\u014d(w)a--uo/eh2- :8: Gk. \u1f05h2elh1- or *h2leh1- as found in Gk. \u1f00\u03bb\u03ad\u03c9 \u2018grind, bruise, mill\u2019, Arm. a\u0142am \u2018grind\u2019 and Av. a\u0161a- ptc. \u2018ground\u2019 [h2l(e)h1-ur/n- continued by Gk. \u1f00\u03bb\u03ad\u03b1\u03c4\u03b1 \u2018wheat-groats\u2019, thematicized \u1f04\u03bb\u03b5\u03c5\u03c1\u03bf\u03bd, and possibly Arm. alewr, aliwr \u2018flour\u2019, if this is not a Greek loan [Two similar formations meaning \u2018threshing floor\u2019 are found in Germanic and Greek :78. It i\u2018ground\u2019 :277, whieek loan :90\u20135.\u1e2ball-anna-i \u2018trample down, flatten (fields and plants)\u2019. This verb apparently constitutes an imperfective formation in -anna/i- to the etymologically obscure root *\u1e2ball- < *h2(e)lH- or *h3(e)lH- [h2elh1- or *h2leh1- \u2018flatten\u2019 can be postulated, which in core Indo-European became associated with an activity related to the processing of cereals, possibly the technique of threshing cereals by having animals tramp them. It is more difficult to explain the emergence of the meaning \u2018grind\u2019 from the same semantic specialization, however.An additional  cognate may be found in Hitt. h3(e)lH- :271. If *(H)lois-eh2- : OCeh2-stem derived from an obscure root *(H)leis- [l\u00fds\u0117 f. \u2018bed (garden)\u2019 (and by extension OPru. EV lyso \u2018bed (field)\u2019) seems likely, but the acute intonation is problematic in that it at face value points to *(H)liH-s-.This is an (H)leis- :209, pro?*kweh2t-i- \u0101ti-(?*kwet- :104):? Gi-stem *kweh2t-i-. This i-stem may be derived from a verbal root *kweh2t-, as found in Gk. \u03c0\u03ac\u03c3\u03c3\u03c9 \u2018strew, sprinkle\u2019 and Lat. quati\u014d \u2018shake\u2019 < *kwh2t-ie- [qu\u0101lus m. \u2018wicker (*winnowing?) basket\u2019, if from PIt. *kwh2t-slo- [*\u0101 ought to have been preserved. The reconstruction *kweh2t-i- is thus rendered uncertain [(s)ku\u032feh1t- [c\u00e1ith by starting from an isolated o-grade form *ku\u032foh1t-i-.The Celtic and Greek forms are suggestive of an wh2t-ie- :1155, anh2t-slo- :504. Howncertain :632. Theku\u032feh1t- :563 can \u2020*mel(H)-i- : Lati/n stem [m\u00e1lnos f.pl. \u2018floating sweetgrass (Glyceria fluitans)\u2019 is doubtful: Lith. m\u00e1lna must rather be a loan from Polish manna \u2018floating sweetgrass\u2019  [milium \u2018millet\u2019 is often derived from PIt. *meli-, with quasi-regular raising of e to i before *i in the following syllable [i-stem has been argued to be behind Gk. \u03bc\u03b5\u03bb\u03af\u03bd\u03b7. The reconstruction of a shared i-stem is uncertain, however, since Lat. milium is synchronically a io-stem  and Gk. \u03bc\u03b5\u03bb\u03af\u03bd\u03b7 a substantivization of an adjective in -ino-.It is unclear if all the forms belong together due to the difference in vocalism and suffixation. They have been explained as a heteroclitic i/n stem :379, whichwaden) :167\u20138, wsyllable :81. The melh2- \u2018grind\u2019 [\u015by\u0101m\u0101\u0301ka- \u2018a type of millet\u2019 and Fr. millet/bl\u00e9 noir \u2018buckwheat\u2019 [milium and Gk. \u03bc\u03b5\u03bb\u03af\u03bd\u03b7 look like independent formations, meaning that no shared Indo-European protoform can be given.As to a root etymology for the Latin and Greek forms, the most popular suggestion is a connection with * \u2018grind\u2019 :I, 88. Ackwheat\u2019 :113. Regblan \u2018species of barley\u2019 < PIIr. *ml\u0101na- and ON melr m. \u2018sand ryegrass (Elymus arenarius)\u2019 [melr is short for the compound continued as Icel. mel-gresi, whose first element can be identified as ON melr m. \u2018sandbank\u2019 < PGm. *melha- [blan has alternatively been derived from an isolated Indo-Iranian root, cf. Skt. ml\u0101- \u2018to be limp, wither\u2019 [marH- \u2018to crush\u2019 [Other comparanda, such as Khow. narius)\u2019 :77, are  *melha- :615. Kho wither\u2019 :599, pos?*ne(h1)i-uo-  field\u2019 < *nj\u00ecvanei-u\u032fo- :8): Gk. ni \u2018low, below\u2019, through an adjective *nei-uo- \u2018low-lying\u2019, or from *neu-io- \u2018new ground\u2019. The Slavic form *njiva can regularly continue *nj\u016bva, which has been considered a contamination of the PSl. outcomes of *neu-h2 and a zero-grade form *nu-h2 [u-stem *n\u00e9(h1)i-u, gen. *n(h1)i-\u00e9u-s, pl. *n\u00e9(h1)i-u-h2, the many formal ambiguities cast doubt on the validity of the comparison.This old comparison involves several phonological problems. The Greek word may be derived from PIE *m *nu-h2 :303\u20134. W*neik- : Lineik- is reconstructed on the basis of Celtic, Greek and Baltic. Arm. nk\u2018oyr \u2018sieve\u2019 is also sometimes compared [oyr as a nominal suffix is hard to explain. It does seem possible to adduce PGm. *naik\u014d-, which through Pre-Proto-Germanic *naikk\u0101- can regularly continue *noik-n\u00e9h2- (with Kluge\u2019s law). Together, these formations secure a shared agricultural meaning \u2018winnow\u2019 for most of the European branches. Given the regular sound correspondences across the branches, there is no reason to doubt the inherited character of the word [paceA root *compared :III,477,neik- \u2018raise, stir up\u2019, cf. Hitt. nini(n)k-zi \u2018set in motion, raise, stir up\u2019, Gk. \u03bd\u03b5\u1fd6\u03ba\u03bf\u03c2 \u2018quarrel, strife\u2019, RuCS niknuti, SCr. n\u0209knuti \u2018appear, arise\u2019. Suitable semantic parallels are at hand, cf. Skt. \u00fad-bharati \u02bbraise\u02bc vs. Marathi ubhar\u1e47\u1ebd \u02bbwinnow\u2019 [ut-phalati \u02bbspring open, jump out\u02bc vs. Marathi uph\u0101\u1e37\u1e47\u1ebd \u02bbwinnow\u02bc < *ut-ph\u0101layati [On a deeper level, it seems likely that the root in question originated as a (core Indo-European?) semantic specialization of an Indo-Anatolian root *\u02bbwinnow\u2019 :75 and Sh\u0101layati :84.*pol\u1e31-eh2- :? OpolH-o- \u2018field\u2019 [A marginally attested formation found in at least Germanic and Celtic, although the latter is only indirectly recorded through Romance. The Slavic form has alternatively been derived from * \u2018field\u2019 :288.*pr\u1e31(-eh2)- : ONfere m. \u2018strip or plot of land; ridge between furrows\u2019 < *ferhan- [pr\u00f3-per\u0161a \u2018thawed patch in the ice, gap (in the clouds)\u2019, Skt. p\u00e1r\u015b\u0101na- m. \u2018chasm(?), valley(?)\u2019, which may ultimately derive from a verbal base \u2018dig, tear\u2019 [eh2-stem found in Italic and Celtic.A West European term for \u2018furrow\u2019. Within Germanic, it is in ablaut relation with Nw. dial. *ferhan- :244. Furg, tear\u2019 :475. Thi*se\u01f5h-e-tleh2- : se\u01f5h- \u2018hold firmly\u2019  [sa\u01f5h- while the Greek requires *se\u01f5h-. Pokorny offers a now-obsolete PIE reconstruction whereby a reduced vowel *se\u01f5h- was vocalized into *a in Celtic [s\u01f5h-e- that received a \u2018prop vowel\u2019 and independent vocalization with *e in Greek [se\u01f5h- to be original and proposes a Brittonic sound law PC *e > (*\u00e6 >) PBr. *a before *ge, *gi [Both the Greek and Brittonic words have been derived from (a thematic stem of) the root *, hold\u2019) :495. Then Celtic :889. Hamin Greek \u2013206. Sch*ge, *gi :134\u201341.ddel for PIE *-tleh2 is unexpected: the regular outcome of *-tleh2 is W -dl, cf. anadl \u2018breath\u2019 < *h2enh1-tleh2. This leads Pokorny and Hamp to reconstruct its allomorph *-dhleh2> *-\u03b8\u03bb\u03b7 that was dissimilated to -\u03c4\u03bb\u03b7 following a voiced aspirate in the stem. However, it is likely that both *-dhlo/eh2 and *-tlo/eh2 merged into *-\u00f0l in a Common Brittonic stage [tleh2.The W ending -ic stage :363. ThuAs a result, an exact Greco-Celtic isogloss for \u2018plow handle\u2019 may tentatively be reconstructed.*seh1-men- : Limn-stem derived from the root *seh1- \u2018sow\u2019. It has been argued that the meaning \u2018sow\u2019 developed from \u2018put in (the ground)\u2019, cf. Hitt. \u0161ai-i \u2018impress, prick\u2019 < *sh1-oi- [terminus post quem for the creation of this mn-stem. However, if Hitt \u0161\u0113li- \u2018granary\u2019 is to be compared to OIr. s\u00edl \u2018seed\u2019 through a protoform *seh1-li- [This is an *sh1-oi- :504, in seh1-li- :541, theseh1-li- :167, eve*solk-o- : Gkselk- \u2018draw\u2019, cf. ToB s\u00e4lk- \u2018pull, draw\u2019, Gk. \u1f15\u03bb\u03ba\u03c9 \u2018draw, drag\u2019 and probably also Arm. he\u0142g \u2018lazy, slow\u2019, exhibit a semantic shift to \u2018draw furrows, plow\u2019: 1) an o-stem shared between Latin and Greek, and 2) an isolated root noun in Germanic, viz. OE sulh f. \u2018furrow; plow\u2019 < PGm. *sulh-. The semantic shift appears complete in Germanic and Italic, whereas a more original range of meanings remains in Greek.Two formations in the European centum languages derived from the root **spor-eh2- : Gksper-, appears shared between Greek and Albanian [sper- was \u2018scatter\u2019, cf. Hitt. i\u0161p\u0101r-i \u2018spread (out), strew\u2019, which developed into \u2018sow\u2019 in some of the European branches, cf. Gk. \u03c3\u03c0\u03b5\u03af\u03c1\u03c9 \u2018scatter, spread; sow\u2019, whence also Gk. \u03c3\u03c0\u03ad\u03c1\u03bc\u03b1 \u2018seed, sowing\u2019 and \u03c3\u03c0\u03cc\u03c1\u03bf\u03c2 \u2018seed\u2019. In Celtic, the isolated Bret. (Pelletier) fer \u2018lentils\u2019 could theoretically continue another formation derived from the root *sper-, but because of the absence of cognates in British or Goidelic, this cannot be verified.This formation, clearly derived from the PIE root *Albanian :56. The *uogwh-(m)nis- ni(s)-; OPru. wagnis or wagins \u2018coulter\u2019 < PB *wagnV-; ON vangsni, OHG waganso, wagi(n)so m. \u2018plowshare\u2019 < PGm. *wagnisan-; Lat. v\u014dmer m. \u2018coulter, plowshare\u2019 < PIt. *wo\u03c7w-(s)mis-(?)ugschar\u2019 :1179\u201380)uegwh- [vag\u00e0 f. \u2018groove, furrow; patch of arable land\u2019 < *uogwh-eh2- and ON veggr, OE wecg, OHG wecki \u2018wedge\u2019, Lith. v\u00e3gis, Latv. vadzis \u2018peg; wedge\u2019 < *uogwh-io- [A well-known European word, possibly derived from a root *uegwh- :1179\u201380 ogwh-io- :1581\u20133.nis-, as this might be the common denominator for at least Greek and Germanic. In latter branch, at least ON vangsni looks like it could continue *wagnisan-. OHG waganso, on the other hand, was probably influenced by alansa f. \u2018awl\u2019 and segansa f. \u2018scythe\u2019, whose suffixes appear to have metathesized from *-es-neh2- [The original suffixation appears to have been *-es-neh2- :29.m of the suffix is unexpected and requires a phonetically conceivable but ad hoc assumption that it was rounded by the preceding labiovelar. Alternatively, it is possible to assume that all forms originally contained *-mn- and were reduced differently [wagense) [vannas and Est. dial. vadnas \u2018plowshare\u2019 (< *vatnas) would be most easily explained as a loan from Baltic [The interpretation of the Italic and Baltic forms is more difficult. In Italic, the ferently :491. Conwagense) :132\u20133. Wm Baltic .An early plowshare made of deer-antler has been found in phase B of the Gumelni\u0163a culture ; 213 datFrom the evaluation of the data presented here, which consists of cereal (cultivation and processing) terms with cognates in at least two independent Indo-European branches, several conclusions can be drawn.\u01f5hersdh- to *\u01f5hersd-. This is the least problematic category, however, as minor formal corrections are typically inconsequential to whether a term was inherited or not in the branches in which it occurs. In other cases, cognates had to be removed from the cognate set, leading to a more limited distribution in the Indo-European language family and potentially a more shallow time depth. Here we may mention removed cognates such as Hitt. \u0161\u0113\u0161a-, which cannot regularly be derived from *se-sh1-o-. It is particularly striking that in many cases, material from the Iranian languages has been liable to misinterpretation, probably due to their relatively late attestation and opaque evolution. Notable here is NP zurd \u2018millet\u2019 as a false continuant of *\u01f5hersd-. Where formal problems were insurmountable, comparisons had to be given up entirely, leading to a more radical reduction of the corpus of potentially inherited lexical items. Examples of such rejected comparisons are *keres- and *pano-, both assumed to have referred to millet. Strikingly, not a single word for millet can be reconstructed for Proto-Indo-European.First of all, strict application of the known sound laws has revealed that many of the previously proposed comparisons, including some listed by Mallory , are forWanderwort or of a term borrowed from a lost, non-Indo-European language (group). Accordingly, at least two terms have been reclassified from the inherited, potentially Indo-European category into a category of prehistoric loans from one or more unknown sources: *bhars- \u2018a cereal\u2019 and *au\u032fi\u011d- \u2018oats\u2019. Neither of these traditional reconstructions can be maintained for any level within the Indo-European pedigree.Special attention is required for terms showing resemblances that appear undeniable, but nevertheless exhibit irregular sound correspondences, and in addition have a localized or areal distribution, e.g. limited to (parts of) Europe. When the protoforms of the branches involved cannot be unified into a single reconstruction, the comparanda may indicative of prehistoric borrowing processes, i.e. reflect different manifestations either of an old d(e)rH-ueh2-, for instance, refers to a kind of grass in Indic and Celtic, and to wheat only in Middle Dutch. As a limited distribution of an agricultural meaning is most easily understood as resulting from an equally limited, post-Indo-European innovation, those meanings should not uncritically be projected back into the protolanguage. In many cases, it can be demonstrated that a meaning associated with the cultivation and processing of cereals does not date back to the oldest strata of the family, but developed at more shallow stages in a subset of the Indo-European branches. For instance, counter to previous views , flatten\u2019. It is further attractive to assume that the root *neik-, meaning \u2018winnow\u2019 in a large subset of the European branches, is etymologically identical to the root *neik- \u2018raise, stir\u2019, already found in Hittite. Even younger are the meanings that are of post-Tocharian date. Here we can mention the well-known example of *gwr(e)h2-uon-, meaning \u2018stone\u2019 in Tocharian, but \u2018grindstone\u2019 in the other branches in which it is attested. In addition, there is the s-stem *h2e\u1e31-os- meaning \u2018tip (of grass)\u2019 in Tocharian, and \u2018ear (of grain)\u2019 in Germanic and Italic only.Intriguingly, it is evident that many agricultural meanings that have habitually been reconstructed for Proto-Indo-European are effectively post-Anatolian. This has previously been demonstrated for the root *selk- \u2018draw\u2019, as continued by ToB s\u00e4lk- and Gk. \u1f15\u03bb\u03ba\u03c9, served as the basis for a root noun *slk- \u2018furrow; plow\u2019 in Germanic and an o-stem *solk-o- \u2018furrow\u2019 in Italic and Greek. The s-stem *h2e\u1e31-os- meaning \u2018tip (of grass)\u2019 in Tocharian, acquired the meaning \u2018ear (of grain)\u2019 in Germanic and Italic only. The related collective formation *h2e\u1e31-on-eh2- similarly acquired an agricultural meaning in the same branches. These semantic shifts, often absent or marginal in Greek, appear to cluster in the West European centum languages, and\u2014if not independent\u2014must have appeared late, in an already fragmenting, core Indo-European dialect continuum. A complete overview of the semantic intricacies of the various terms is given in It is, moreover, especially striking that several instances of semantic specialization are found exclusively in the European centum languages. The root *h2(e)lbh-it- \u2018barley\u2019 and *spor-eh2- \u2018seed\u2019, may be as recent as the last common ancestor, and should not be projected back into Proto-Indo-European, let alone Proto-Indo-Anatolian, at least not without the strongest of reservations. Furthermore, the demonstrable presence in our findings of formal and semantic archaisms in Anatolian and to a lesser extent in Tocharian unquestionably supports the modern consensus that these branches diverged from the other, core Indo-European branches relatively early. It appears that the split between basal and core Indo-European is more fundamental than the split between the European and Asian branches, at least in this subsection of the lexicon.Evidently, many of the formal and semantic issues tie back into the problem of the phylogeny of the Indo-European languages. In the starburst model, in which all core Indo-European branches are treated as equally distantly related, a term shared by as few as two branches must be admitted to the protolanguage, whereas a more structured model allows for more strata. Our findings underline that the latter is a priori more realistic than the starburst model. The creation of terms shared only by a limited subsection of Greek and Albanian, e.g. *In conclusion, while many cereal terms have been proposed in the literature, their number must be substantially reduced, especially for the most basal stage of Indo-European, Indo-Anatolian. The resulting picture is one that is far less problematic to the Steppe Hypothesis than has been previously suggested . The ove(H)ieu(H)- and perhaps *\u01f5h(e)rsd-. For the core Indo-European level, an even more extensive set of terms can be identified. In a model in which the split between the European and Asian branches is assumed to be primary, we must admit at least *h2erh3- \u2018plow\u2019, *h2erh3-ur/n- \u2018(arable) field\u2019, *peis- \u2018grind (grain)\u2019, *se-sh1-io- \u2018a cereal\u2019, *h2ed-o(s)- \u2018a (parched?) cereal\u2019, *dhoH-neh2- \u2018 seed\u2019 and *pelH-u- \u2018chaff\u2019. By applying the alternative, Indo-Slavic model, it is possible to relegate the latter two terms to the most recent subnode of the family, so as to deprive them of their core Indo-European status. However, even in this model, the remaining terms still stand. It is furthermore worth noting that at the second-most basal stage, prior to the Tocharian split, the root *h2erh3- had already undergone the semantic shift to \u2018plow\u2019, implying that this practice was known to the deepest layers of core Indo-European. In other words, unless cereal cultivation was a much more important aspect of the Yamnaya culture than recent archaeological interpretations suggest, this culture does not offer a perfect archaeolinguistic match for the original language community of the core Indo-European branches, including Tocharian. As a consequence, we may conclude that it is not possible to on the one hand support the Steppe Hypothesis (or the revised Anatolia Hypothesis for that matter) while at the same time assuming that steppe migrants had an exclusively pastoralist way of life, as has been proposed for the early Yamnaya culture [Nevertheless, our results also raise questions for the Steppe Hypothesis. For the oldest stratum, Indo-Anatolian, the lexical evidence for cereal use is relatively modest, but not zero: we must at least admit the cereal term * culture ; 215:17.We shall now return to the age-old question of to what extent Indo-Iranian participated in the general shift of the core Indo-European subgroups from a largely pastoralist economy to a more agricultural way of life. The question revolves around the two rival hypotheses by Hirt on the one hand and Schrader on the other: did Indo-Iranian lose many of the agricultural terms present in the European branches or did the European branches rather acquire them after the Indo-Iranian split?\u01f5rH-no- \u2018granule\u2019, plausibly derived from a root *\u01f5erH- \u2018scatter\u2019, with domesticated plant seeds is visible in Germanic, Ital(o-Celt)ic and Balto-Slavic, but if Pashto z\u0259\u0301\u1e47ai is to be relied on, (Indo-)Iranian may have preserved a more general meaning, i.e. a seed of any (domesticated or non-domesticated) plant. The root *peuH- retained its original meaning \u2018purify\u2019 in Germanic, Celtic and Italic. It might have developed into \u2018winnow\u2019 in Balto-Slavic, Greek and possibly Albanian, in view of the derivation *puH-ro- \u2018a kind of cereal\u2019, but Indo-Iranian takes up an intermediate position, in that it preserves the polysemy. Grinding is an activity that is not restricted to agricultural societies. Nevertheless, it is striking that the formation *gwr(e)h2-uon- has the generic meaning \u2018stone\u2019 in Tocharian, the more agricultural meaning \u2018quern\u2019 or \u2018millstone\u2019 in Germanic, Celtic, Armenian and Balto-Slavic, but the semantically intermediate \u2018(pressing) stone\u2019 in Sanskrit. A final showcase exemplifying the comparatively archaic semantics of Indo-Iranian is that of PIE *h2e\u01f5-ro-, whose original meaning \u2018plain (for driving cattle?)\u2019 was preserved in Indo-Iranian, while the European branches Germanic, Italic and Greek share a  semantic shift to \u2018cultivated field\u2019 [As described above, multiple semantic innovations can be observed in the European languages. Many of these innovations appear late and dialectally limited, i.e. post-Tocharian at the earliest and pan-European at best. They demonstrate how the European Indo-European dialects, in the period when they had started diverging from each other, were in the process of repurposing the vocabulary they had inherited from basal and core Indo-European to reference an increasingly agricultural way of life. However, Indo-Iranian typically does not participate or only marginally participates in the semantic shifts that characterize the European branches. This is evinced by a number of very subtle archaisms in this branch. An association of *d field\u2019 :9. Althoh2erh3- is also attested with the meaning \u2018plow\u2019 in Tocharian, which is widely held to have split off second, Indo-Iranian probably once possessed this verb, something that also follows from the preservation of the formation *h2rh3-ur/n- \u2018(arable) field\u2019 in this branch. It thus appears that both Schrader and Hirt were partially right. On the one hand, Indo-Iranian participated in the initial core Indo-European shift from a pastoralist to an agro-pastoralist economy, of which some elements later were lost. On the other hand, Indo-Iranian was peripheral to the more recent and more radical shift towards a farming economy, as reflected in the vocabularies of the European branches , whose similarities to the Epi-Corded Ware of the Carpathian region suggest an East-Central European origin [In conclusion, unlike the archaeological Yamnaya homeland, the linguistic homeland of the core Indo-European language community cannot be located in the eastern steppe, but must be situated around, and extending to the west of, the Dnieper River. After the formation of the core Indo-European dialect continuum in this area after ca. 3300 BCE, it gradually developed into a network of increasingly evolved and disconnected varieties of Indo-European speech, thus foreshadowing the final fragmentation of the language and the movements of the various branches into Europe and Asia. Intriguingly, Indo-Iranian and especially Tocharian were impacted less heavily by the later, more radical shift towards agriculture that manifests itself in the European branches, indicating that they were culturally but also geographically more peripheral. However, since these branches share the Indo-European words for \u2018plow\u2019 and \u2018pound grain\u2019, they must, too, somehow have been involved in or at least connected to the establishment of the core Indo-European continuum in the West Pontic region. Scenarios in which the European branches moved west and the Asian branch stayed east of the Dnieper  thereforn origin .A central question concerns the mechanism by which mobile pastoralism was adopted in the Lower Dnieper region during the westward expansion of the Yamnaya culture. Did incoming herders displace local groups, including their language, before the final expansion into Europe and Asia? Or did local groups adopt this lifestyle purely culturally, subsequently to become the source population that ultimately proliferated its genetic and linguistic features to much of Eurasia? From the linguistic perspective, it is worth noting that the Sredni Stog culture, with its limited evidence for agriculture, potentially offers a better archaeological fit for the basal, Indo-Anatolian language community than the eastern Yamnaya culture, which shows no traces of agriculture. This may support a scenario of linguistic continuity of local non-mobile herders in the Lower Dnieper region and their genetic persistence after their integration into the successive and expansive Yamnaya horizon.These archaeolinguistic considerations may furthermore help shed light on the genetic origins of the Yamnaya dispersal. The Corded Ware and Bell Beaker cultures, both promising vectors of Indo-European speech varieties, have high levels of steppe ancestry \u20138, but d"}
+{"text": "Correction: Eating and Weight Disorders - Studies on Anorexia, Bulimia and Obesity (2022) 27:1603\u20131619 10.1007/s40519-021-01287-1In this article, Figure\u00a01 contains an error. The correct rule-in cut-off of NAFLD Fibrosis Score indicating patients at intermediate-high risk of advanced fibrosis should read\u2009\u2265\u2009\u2009\u2212\u20091.455. The correct figure is reported below. The authors apologise for the mistake."}
+{"text": "Correction to: BMC Public Health 22, 1635 (2022)https://doi.org/10.1186/s12889-022-14034-7In the author contribution section \u201cCS\u201d should be \u201cCK\u201dTwo sentences (in Methods & Results) were unintentionally anonymizedThe significance bar was missing in figure 1The original publication  of this The article has been updated to amend these errors."}
+{"text": "Scientific Reports 10.1038/s41598-022-20327-z, published online 10 October 2022Correction to: The original version of this Article contained errors in Table 3, where the values for \u201cMode of step-time variability\u201d and \u201c8-step HR (arm-swing)\u201d under \u201cGait Quality\u201d were incorrect. The correct and incorrect values appear below.Incorrect:Correct:The original Article has been corrected."}
+{"text": "Correction: BMC Ophthalmol 22, 459 (2022)https://doi.org/10.1186/s12886-022-02650-1Following publication of the original article , the\u00a0autThe incorrect author name is: Juan Queiruga-Pi\u00f1eroThe correct author name is: Juan Queiruga-Pi\u00f1eiroThe author group has been updated above and the original article  has been"}
+{"text": "Burden of Severe Illness Associated With Laboratory-Confirmed Influenza in Adults Aged 50\u201364 Years, 2010\u20132011 to 2016\u20132017. Open Forum Infectious Diseases, Volume 10 Issue 1, January 2023."}
+{"text": "Scientific Reports 10.1038/s41598-022-15957-2, published online 07 July 2022Correction to: The original version of this Article contained an error in TGF-\u03b2 units in Figure\u00a04 (d)-(g) labels, where\u201c\u03bcg/ml\u201dnow reads:\u201cng/ml\u201dThe original Figure\u00a0Additionally, the same error occurred in Supplementary Information Figure\u00a02.Lastly, the article omitted to mention that BMDMs were cultured under serum-free media. Consequently, in Materials and methods, under the subheading \u2018Preparation of cells\u2019,now reads:\"For RNA analysis, cells were cultured under serum-free media  \u00a0during stimulation.\u201dThe original Article and Supplementary Information file have been corrected."}
+{"text": "By implementing a meta-analysis  based onWe conducted this updated meta-analysis in accordance with the statement of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) .2, micro- or macro-albuminuria, renal failure, dialysis, renal transplantation, or renal death; and MACE was defined as a composite of CVDH, MI, or stroke. We searched PubMed, Embase, and Web of science from inception date to May 2022. The whole search expression is (using PubMed as an example):  AND [Sodium-Glucose Transporter 2 Inhibitors (MH) OR \u201cSodium glucose transporter 2 inhibitor*\u201d (TIAB) OR \u201cSodium glucose cotransporter 2 inhibitor*\u201d (TIAB) OR \u201cSodium glucose co-transporter 2 inhibitor*\u201d (TIAB) OR SGLT*(TIAB) OR Gliflozin*(tiab) OR \u201cEmpagliflozin\u201d (tiab) OR \u201cDapagliflozin\u201d (tiab) OR \u201cCanagliflozin\u201d (tiab) OR \u201certugliflozin\u201d (tiab) OR \u201csotagliflozin\u201d (tiab)] AND [\u201cglucagon-like peptide 1 receptor agonist*\u201d (TIAB) OR \u201cGLP1*\u201d (TIAB) OR lixisenatide (TIAB) OR liraglutide (TIAB) OR semaglutide (TIAB) OR exenatide (TIAB) OR albiglutide (TIAB) OR dulaglutide (TIAB) OR Efpeglenatide (TIAB)] AND [\u201ccardiovascular\u201d (tiab) OR \u201ccardiac\u201d (tiab) OR \u201cheart failure\u201d (tiab) OR \u201cmyocardial infarction\u201d (TIAB) OR stroke (tiab) OR \u201cMACE\u201d (tiab) OR \u201cKidney\u201d (tiab) OR \u201crenal\u201d (tiab) OR \u201cCKD\u201d (tiab) OR \u201cESRD\u201d (tiab) OR \u201cESKD\u201d (tiab) OR \u201ccardiorenal\u201d (tiab) OR \u201cdeath\u201d (tiab) OR \u201cmortality\u201d (tiab)] AND [\u201ccohort study\u201d (tiab) OR \u201cobservational study\u201d (tiab) OR \u201creal world\u201d (tiab) OR \u201creal-world\u201d (tiab)].The studies eligible for inclusion were cohort studies directly comparing SGLT2is and GLP1RAs in cardio-renal endpoints in T2D patients. Seven endpoints of interest are the same as those in Qius et al. .The outcome data were extracted from included studies independently by two authors, and any discrepancies between them were solved by discussing with a third author. Just like Qiu et al. , we perfP for effect size = 0.04; P for effect size <0.01; P for effect size = 0.04; P for effect size = 0.82; P for effect size = 0.16; P for effect size = 0.11; P for effect size = 0.06; In this updated meta-analysis, we included a total of eighteen large cohort studies \u201319. We iThis updated meta-analysis revealed that SGLT2is vs. GLP1RAs were associated with significantly decreased risks of HHF and CKO and significantly increased risk of stroke in T2D patients, whereas these two drug classes had similar risks of MACE, MI, CVDH, and ACM. Substantially different with these findings, the main findings in the previous meta-analysis , General Programe for Fundamental Research (Grant No. JCYJ20210324142404012).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Apium graveolens L. Seeds via GC-TOF-MS and UHPLC-MS/MS\u201d [In the article titled \u201cAntiliver Fibrosis Screening of Active Ingredients from C-MS/MS\u201d , concernC-MS/MS\u201d . Specifi"}
+{"text": "Analytical Cellular Pathology would like to express concern with the article titled \u201cThe Long Noncoding RNA LOXL1-AS1 Promotes the Proliferation, Migration, and Invasion in Hepatocellular Carcinoma\u201d ["}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-023-27951-3, published online 17 January 2023Correction to: The original version of this Article contained a spelling error in the name of the author Nina Re\u0161\u010di\u010d, which was incorrectly given as Nina re\u0161\u010di\u010d.The original Article has been corrected."}
+{"text": "Correction: BMC Medical Imaging (2022) 22:187 10.1186/s12880-022-00918-yFollowing the publication of the original article , it was The incorrect word \u201cscrenned\u201d was inadvertently inserted under \u201c1598 duplicates removed\u201d in Fig.\u00a0The incorrect word has now been deleted and the correct Fig.\u00a0The original article has been updated."}
+{"text": "In the article titled \u201cA Collaborative Brain-Computer Interface Framework for Enhancing Group Detection Performance of Dynamic Visual Targets\u201d , Figure The corrected figure legend for Figure 8 has been given as follows where the adaptation is acknowledged.https://creativecommons.org/licenses/by/4.0/)).\u201d\u201cSummary of different BCI frameworks: (a) sBCI framework; (b) SC-cBCI framework; (c) MC-cBCI framework; (d) MLDANet-cBCI framework (adapted from [33] under a CC-BY 4 license ("}
+{"text": "The correct name is: Asl\u0131 Elif Tanu\u011fur-Samanc\u0131. The correct citation is: Tanu\u011fur-Samanc\u0131 AE, Keke\u00e7o\u011flu M (2021) An evaluation of the chemical content and microbiological contamination of Anatolian bee venom. PLOS ONE 16(7): e0255161. The publisher apologizes for the error."}
+{"text": "Evidence-Based Complementary and Alternative Medicine has retracted the article titled \u201cEffects of Tenofovir Combined with Recombinant Human Interferon \u03b1-2b on Negative Conversion Rate, Liver Function, Immune Status, and Drug Safety in Patients with Chronic Hepatitis B: A Systematic Review and Meta-Analysis\u201d [nalysis\u201d  due to cFollowing an investigation conducted by the Hindawi Research Integrity team , signifi"}
+{"text": "Nature Reviews Clinical Oncology 10.1038/s41571-020-00447-z, published online 8 December 2020.Correction to: In the original version of this Evidence-Based Guidelines, Fig. 3 contained errors regarding unfavourable factors for IDH-wild-type glioblastomas, WHO grade 4. The box label originally mentioning \u201cKPS <70 years\u201d has been corrected to \u201cage <70 years; KPS <70 years\u201d. In addition, greater clarity has been provided by changing \u201cage >70 years\u201d in other boxes to \u201cage \u226570 years\u201d. Fig. 3 has been corrected in the HTML and PDF versions of the article."}
+{"text": "Correction to: Journal of Assisted Reproduction and Geneticshttps://doi.org/10.1007/s10815-022-02547-4The \u201cFunding\u201d information section was missing from this article and should have read \u201cThis work was supported by the 2018 FORWARD grant (FORWARD2018_3) from GEDEON RICHTER.\u201dThe original article has been corrected."}
+{"text": "Correction to: Langenbeck's Archives of Surgery.https://doi.org/10.1007/s00423-022-02486-9The original version of this article unfortunately contained a small mistake in the body text which is \u201c4416 44,160\u201d.The corrected number should be: \u201c44160\u201d.The original article has been corrected."}
+{"text": "Scientific Reports 10.1038/s41598-022-10057-7, published online 09 April 2022Correction to: The original version of this Article contained a repeated error in\u00a0the Title, in the Results section under the subheading \u2018Antigenic reactivity of synthetic peptides with COMIRNATY vaccine recipient sera\u2019 and in the Methods section under the subheading \u2018Serum samples from COMIRNATY vaccine recipients\u2019 where\u201cCOMINARTY\u201dnow reads:\u201cCOMIRNATY\u201dThe original Article has been corrected."}
+{"text": "Biosensors such as toll-like receptors (TLR) induce the expression of interferons (IFNs) after viral infection that are critical to the first step in cell-intrinsic host defense mechanisms. Their differential influence on epithelial integrity genes, however, remains elusive. A genome-wide gene expression biosensor chip for gene expression sensing was used to examine the effects of type-I, -II, and -III IFN stimulation on the epithelial expression profiles of primary organotypic 3D air-liquid interface airway cultures. All types of IFNs induced similar interferon-stimulated genes (ISGs): OAS1, OAS2, and IFIT2. However, they differentially induced transcription factors, epithelial modulators, and pro-inflammatory genes. Type-I IFN-induced genes were associated with cell\u2013cell adhesion and tight junctions, while type-III IFNs promoted genes important for transepithelial transport. In contrast, type-II IFN stimulated proliferation-triggering genes associated and enhanced pro-inflammatory mediator secretion. In conclusion, with our microarray system, we provide evidence that the three IFN types exceed their antiviral ISG-response by inducing distinct remodeling processes, thereby likely strengthening the epithelial airway barrier by enhancing cross-cell-integrity (I), transepithelial transport (III) and finally reconstruction through proliferation (II). Important immune factors of the first line of cell-intrinsic host defense are the interferons (IFNs), which comprise type-I IFN , type-II IFN (IFN\u03b3), and type-III IFN . Biosensors such as toll-like receptors (TLRs) belong to the pathogen-recognition receptor family. TLRs sense so called pathogen-associated molecular patterns (PAMP) including viral nucleic acids and RNA and lead to IFN expression [+ T helper type-1 and by CD8+ cytotoxic T lymphocytes in an antigen-dependent [Type-I IFNs are expressed across different cell types like plasmacytoid dendritic cells and mononuclear phagocytes, whereas dendritic cells are the major source for IFN\u03bbs ,6. Due tependent  and -independent , therebyEach part of the respiratory tract shows a diverse and specific epithelial subtype that fulfills a different function; however, the impact of IFNs on these specializations is largely unclear. The lower airways mainly contain ciliated cells, which transport the mucus produced by goblet cells out of the airways, and columnar cells, which are important for the barrier function  Figure . PreviouAdditionally, the composition of the inflammatory environment determines the differentiation of the epithelium. Type-I and type-II immune responses can lead to type-I-primed (E1) or type-II-primed (E2) polarization of the airway epithelium, thereby enhancing, for example, asthmatic remodeling processes . The sevUsing a genome-wide gene expression biosensor chip sensing the gene expression in organotypic 3D air-liquid interface cultures, we were able to investigate the influence of IFNs on the airway epithelial barrier. We investigate the similarities of the IFNs in relation to expressed ISGs in this airway epithelial model. In this study, we also highlight the differentially induced transcription factors, epithelial mediators and inflammatory genes unique to each IFN family member and highlight the importance of IFN release for epithelial integrity. Type-I and type-III IFNs stimulation positively correlate with the expression of cell\u2013cell adhesion, tight junctions and intercellular signaling, whereas IFN\u03b3 promotes a pro-inflammatory environment and cell proliferation.n = 6) were grown in PneumaCult-Ex Plus expansion medium (Stemcell) on Corning transwell polyester membrane cell culture inserts  according to the manufacturer\u2019s instruction. Medium was applied to the basal and apical chamber until cells were grown 100% confluence. An airlift was performed by removing the apical medium and the basal medium was exchanged to Pneumacult-ALI maintenance medium (Stemcell). When the transepithelial electrical resistance (TEER), measured using EVOM2 instrument (World Precision Instruments), reached the threshold of 700 \u03a9, cells each donor were stimulated with IFN\u03b1 , IFN\u03b2 , IFN\u03b3 , IFN\u03bb1 , IFN\u03bb3  or medium as control for 24 h. Each negative control was genetically matched. TEER measurement was used to identify epithelial integrity prior stimulation and samples showing a TEER >700 \u03a9 were classified as integer. Cells were harvested and RNA was extracted using AllPrep DNA/RNA Micro Kit . BioRender.com (accessed on 26 August 2022).Low\u2013passage primary human bronchial epithelial cells  from six genet-ically independent donors  terms \u201c0008009\u201d, \u201c0005125\u201d, \u201c0005615\u201d and \u201c0007267\u201d were used for segregation of secreted genes, \u201c0070254\u201d, \u201c0097072\u201d, \u201c0001730\u201d, \u201c0035394\u201d and the gene symbols IFITM and IFIT for interferon stimulated genes, \u201c0009615\u201d, \u201c0039528\u201d, \u201c0039530\u201d, \u201c0039639\u201d, \u201c0051607\u201d and \u201c0009597\u201d for antiviral pathways. For identification of transcription factors GO terms \u201c0003676\u201d, \u201c0044212\u201d, \u201c0000976\u201d, \u201c0070491\u201d and the gene name forkhead was applied, GO terms for identification for pro- and anti-inflammatory genes \u201c0033209\u201d, \u201c0032640\u201d, \u201c0034612\u201d, \u201c0006954\u201d, \u201c0050727\u201d, \u201c0002526\u201d, \u201c0032611\u201d, \u201c0070555\u201d, \u201c2000661\u201d, \u201c0032635\u201d, \u201c0004915\u201d, \u201c0070741\u201d, \u201c0070103\u201d and \u201c0036363\u201d, \u201c0071604\u201d, \u201c0004920\u201d, \u201c0032613\u201d, \u201c0050728\u201d, \u201c0140105\u201d, \u201c0032733\u201d was used, GO terms \u201c0060429\u201d, \u201c0060428\u201d, \u201c0030054\u201d, \u201c0016049\u201d, \u201c0098609\u201d, \u201c0090136\u201d, \u201c0034103\u201d, \u201c0070160\u201d, \u201c0030057\u201d, \u201c0070160\u201d, \u201c0120193\u201d, \u201c0005923\u201d, \u201c0005915\u201d and \u201c0005921\u201d were applied to identify epithelial factors. A 1.5-fold change above the \u201cNormalized intensity values\u201d in relation to the medium control were classified as high (red) abundance.Cyanine-3 (Cy3) labeled cRNA was prepared from 25 ng RNA using the One-Color Agilent Low Input Quick Amp Labeling Kit (Agilent Technologies) accord-ing to the manufacturer\u2019s protocol, followed by RNAeasy column purification (QIAGEN) . Dye incstring-db.org (accessed on 12 September 2022), [In order to extract enriched cellular processes and pathways associated with epithelial mediators  and inflr 2022), ,24). Ther 2022), . The STRp < 0.05). IFN\u03b1 had the strongest and IFN\u03b2 stimulation the least influence on the differential gene expression (IFN-stimulated organotypic 3D air\u2013liquid interface (ALI) cultures were used to identify IFN-induced specific differentially expressed genes (DEGs). The IFNs were titrated prior to transcriptome analysis for biological activity based on a comparable expression (data not shown). All IFNs induced the upregulation of DEGs rather than their suppression . Type-I and type-II IFNs showed matching effects only in upregulating CBLL1, while type-I and type-III IFNs similarly induced PECAM1 A. FurtheTo identify enriched cellular gene networks induced by type-I, -II, and \u2013III IFNs, we performed a network analysis using the \u201cSTRING\u201d database , In partIn summary, all IFNs induced different gene expression patterns in the airway epithelium and enhanced several important factors related to inflammatory pathways and epithelial remodeling. Factors associated with beneficial effects on epithelial barrier integrity by enhancing cell\u2013cell adhesion, tight junctions and intercellular signaling were induced by type-I and -III IFNs, while type-II IFN stimulation resulted in cell growth and a pro-inflammatory environment.Although the mechanisms of the biosensors upstream of the interferon induction and the role of interferons in antiviral signaling pathways are well understood, their effect on airway epithelial processes is widely unknown. In this study, we provide evidence for the unique effect of each member of the IFN family on epithelial homeostasis, remodeling, and the inflammatory response of the human airway using genome-wide gene expression analysis of IFN-stimulated primary organotypic air-liquid interface cultures. In these cultures, all IFNs induced ISGs, as expected, but notably, the number of ISGs induced between individual IFN family members widely overlapped. The induced ISGs interfere with the viral entry (IFITM), viral mRNA synthesis (APOBECs), protein synthesis (IFIT1) and viral replication  , In thisIL18R1, whose expression was associated with asthma severity in human bronchial epithelial biopsy and in bronchial alveolar lavage [GATA4, which has been shown to play a role in early development of the lung mesenchyme [ICAM2, PECAM1, JAM2, TJP2). Previous studies have shown that IFN-enhanced epithelial resistance to influenza infection [CLDN9, CLDN25, JAML, PATJ). In addition, various studies have highlighted that JAM2 and PECAM1 are downregulated by the SARS-CoV-2 virus, which resulted in disruption of the alveolar\u2013capillary barrier [In particular, type-I IFN stimulation, specifically IFN\u03b1, induced the upregulation of the pro-inflammatory gene r lavage . In addir lavage . It is isenchyme . In addinfection , establinfection , and supnfection . Patientnfection . Our stu barrier . This stIL10 in differentiated airway epithelium. Previous studies have shown that IL-10 activation in dendritic cells and macrophages is dependent on type-I IFN signaling [FoxP2 and ZBTB20. Previous studies showed that processes during lung development and cell cycle progression regulated by Cyclin D1, Cyclin E and P21 are associated with FoxP2 and ZBTB20 [GABRR1, GABRA2, GLRA3, SYT9, GABRG3 and CTNNA1-3), that may differentially regulate both intracellular signaling processes and transepithelial and cross-epithelial ion transport along the barrier [TNFRSF1B [Despite the postulated similar mode of action of type-I and -III IFNs in antiviral host defense mechanisms, type-III IFNs stimulated a unique epithelial gene expression and resulted in a secondary process: the induction of anti-inflammatory gene expression and intercellular signaling. IFN\u03bb3 induced anti-inflammatory factors such as ignaling . It is id ZBTB20 . In addi barrier . In addiTNFRSF1B . These dCXCL9, CXCL11, GBP5, CD38, JAK2 and APOL3. This finding is in line with previously published mechanisms of type-I and type-II interferons shown for acute influenza A virus infection [Our data showed that IFN\u03b1 and IFN\u03b3 in particular shared the overlapping induction of pro-inflammatory genes such as nfection , where tnfection  and is anfection .IL1B, CCL7, KDR and ARHGEF5 indicative of a pro-inflammatory environment and cell proliferation. IL-1\u03b2, activated by the inflammasome, may dysregulate the epithelial barrier function in neutrophilic asthma and lead to increased mucin production and neutrophilic infiltration [VEGFA), have been associated with shorter survival times in lung cancer patients due to their effects on cell proliferation [ARHGEF5, which leads to cell invasion and tumor growth via Akt pathway [It is important to note that our data also provide evidence for a unique expression pattern in type-II IFN-stimulated cultures that result in a third epithelial process. IFN\u03b3 alone differentially induced genes such as ltration . High leferation , as has  pathway . TherefoOur data suggest that type-I IFNs improve cross-cell integrity by enhancing cell\u2013cell and gap junctions, thereby directly counteracting viral infection-induced airway barrier leakage. Type-III IFNs strengthen the epithelial barrier by enhancing transepithelial transport. Type-II IFNs, on the other hand, promote a pro-inflammatory microenvironment and stimulate epithelial cell proliferation, likely contributing to restoration of the airway barrier integrity after viral infection.This study not only demonstrates the relevance of genome-wide gene expression analysis using differentiated organotypic 3D air-liquid interface cultures but also showed that the different members of the IFN family have unique effects on airway epithelial barrier integrity in addition to their direct antiviral ISG-mediated functions. Future personalized inhalant therapies may profit from this study and target IFN-type-specific disfunction of epithelial integrity and support specific intrinsic anti-viral immunity. In particular, immunocompromised and elderly patients may profit from this personalized therapeutic strategy. Future studies need to examine long-term effects of these important antiviral mediators on the airway epithelium also post-infection, since an altered restoration process of the airway epithelium could contribute to adverse events as observed in patients with long COVID."}
+{"text": "Correction: J Exp Clin Cancer Res41, 284 (2022) https://doi.org/10.1186/s13046-022-02493-0Following publication of the original article , an erroFigure\u00a06E: The flow cytometry image of group HT29 sh2\u2009+\u2009erastinFigure\u00a06F: The group label \u201csh3\u201d should be corrected into \u201csh2\u201dThe correct figure is now been provided. The correction does not have any effect on the results or conclusions of the paper. The original article has been corrected."}
+{"text": "Correction to: Neurological Sciences (2022) 43:979\u2013984https://doi.org/10.1007/s10072-021-05392-yThe original article contains an error. The affiliation 5 \u201cMilan Center for Neuroscience (NeuroMI), Milan, Italy\u201d should be remove from the author Nadia Bolognini\u2019s address."}
+{"text": "European Heart Journal - Cardiovascular Imaging, jeab266, https://doi.org/10.1093/ehjci/jeab266In the originally published version of this manuscript, there was an error in the third author\u2019s name. The third author\u2019s name should read \u201cDorina-Gabriela Condurache\u201d instead of \u201cDorina Condurache\u201d. This error has been corrected."}
+{"text": "Scientific Reports 10.1038/s41598-021-03681-2, published online 07 January 2022Correction to: The original version of this Article contained errors in Table 1, where the data stated for \u2018Fiber internal diameter\u2019, \u2018Internal volume dialyzer fibers\u2019, \u2018Total internal volume dialyzer\u2019 and \u2018Effective membrane exchange area\u2019 was incorrect.The original Table The original Article has been corrected."}
+{"text": "Scientific Reports 10.1038/s41598-021-90848-6, published online 31 May 2021Correction to: The original version of this Article contained an error in Figure\u00a03, where the red line representing solvent-based (sb)-paclitaxel was incorrectly captioned as \u201cnanoparticle albumin-bound (nab)-paclitaxel\u201d, and the blue line representing nanoparticle albumin-bound (nab)-paclitaxel was incorrectly captioned as \u201csolvent-based (sb)-paclitaxel\u201d.The original Figure\u00a0The original Article has been corrected."}
+{"text": "Scientific Reports 10.1038/s41598-022-16761-8, published online 21 July 2022Correction to: In the original version of this article Katarzyna G\u0119ca and Magdalena Sk\u00f3rzewska were omitted as equally contributing authors.The original Article has been corrected."}
+{"text": "Correction: BMC Palliat Care 21, 188 (2022)https://doi.org/10.1186/s12904-022-01089-xFollowing publication of the original article , the autThe data \u201c\u2026 to ensure a total of 98 evaluable pairs of care giving parents, \u2026\u201d should read\u201c \u201c\u2026 to ensure a total of 88 evaluable pairs of care giving parents, \u2026\u201d\u201cThe original article has been updated."}
+{"text": "Correction: BMC Infectious Diseases (2021) 21:730 10.1186/s12879-021-06399-8The sentence currently reads:\u201cOn average 45,225 RSV-associated hospitalizations\u2026\u201dThe sentence should read:\u201cOn average 50,878 RSV-associated hospitalizations\u2026\u201dFollowing publication of the original article , the autThe original article  has been"}
+{"text": "Erratum zu:Bundesgesundheitsbl 202210.1007/s00103-022-03583-2In der urspr\u00fcnglichen Originalversion des Artikels wurden die Legenden zu den inkludierten Fu\u00dfnoten in der Abbildung Abb.\u00a0 nicht in"}
+{"text": "Correction to: Journal of Clinical Immunology10.1007/s10875-022-01298-2The article note is incorrect. It should have been stated as \u201cAlfonso Jos\u00e9 Tapiz i Reula, Alexis-Virgil Cochino, Andreia L. Martins and Diego Angosto-Bazarra contributed equally to this work.\u201dThe original version has been corrected."}
+{"text": "Scientific Reports 10.1038/s41598-022-15135-4, published online 30 June 2022.Correction to: The original version of this Article contained errors.In the Materials and methods section, under the subheading \u2018Sensor electrodes\u2019,\u201cAll experiments used the Palmsens screen-printed electrodes .\u201dnow reads:\u201cAll experiments used BVT screen printed electrodes .\u201dAs a result, the legend of Figure\u00a01 was incorrect.\u201cPalmsens screen printed electrodes.\u201dnow reads:\u201cBVT screen printed electrodes.\u201dThe original Article has been corrected."}
+{"text": "Scientific Reports 10.1038/s41598-022-09674-z, Published online 06 April 2022Correction to: The original version of this Article contained a typographical error in Table 2, where the unit of the computation time for the \u201cCollection volume without ground\u201d was incorrect.\u201cminh)\u201dnow reads:\u201c(min)\u201dThe original article has been corrected."}
+{"text": "Nature Communications 10.1038/s41467-022-33476-6, published online 02 October 2022Correction to: The original version of this Article contained an error in the Acknowledgments, which incorrectly read \u2018SNSF grant SMALL (20CH21_18699)\u2019. The correct version states \u2018SNSF grant SMALL (20CH21_186999)\u2019 in place of \u2018SNSF grant SMALL (20CH21_18699)\u2019. This has been corrected in both the PDF and HTML."}
+{"text": "Latino-Am. Enfermagem. 2021;29:e3436, page 3:Regarding the article \u201cPsychometric properties of the adapted instrument European Health Literacy Survey Questionnaire short-short form\u201d, with DOI number: Where was written:.\u201d\u201cAccording to the authors of the instrument, the final score values classify individuals according to three levels of HL: inadequate (\u22642); problematic (>2 and \u22643); and sufficient (>3)Now read:.\u201d\u201cAccording to the authors of the instrument, the final score values classify individuals according to three levels of HL: inadequate (\u22642); problematic (>2 and <3); and sufficient (\u22653)10.1590/1518-8345.5181.3494, published in the Rev. Latino-Am. Enfermagem. 2021;29:e3494, page 1:Regarding the article \u201cUse of the prone position in pregnant women with COVID-19 or other health conditions\u201d, with DOI number: Where was written:\u201cOriginal Article\u201dNow read:\u201cReview Article\u201d10.1590/1518-8345.5768.3518, published in the Rev. Latino-Am. Enfermagem. 2022;30:e3518, page 1:Regarding the article \u201cPsychopathological symptoms and work status of Southeastern Brazilian nursing in the context of COVID-19\u201d, with DOI number: Where was written:7 https://orcid.org/0000-0001-5180-1594\u201d\u201cDarcio Tadeu MendesNow read:7https://orcid.org/0000-0001-6059-9308\u201d\u201cDarcio Tadeu Mendes"}
+{"text": "In 4 places where it previously read \u201cdistance category\u201d it now correctly reads \u201cdiagnosis category.\u201d This article was corrected online.In the article titled \u201cReceipt of Out-of-State Telemedicine Visits Among Medicare Beneficiaries During the COVID-19 Pandemic\u201d"}
+{"text": "Morenas-Rodr\u00edguez E, Li Y, Nuscher B, et al. Soluble TREM2 in CSF and its association with other biomarkers and cognition in autosomal-dominant Alzheimer's disease: a longitudinal observational study. Lancet Neurol 21: 329\u2013412022; \u2014In this Article, the Copyright should read \u201c\u00a9 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license\u201d. In Figure 5, the y-axis of panel 5E should be \u201cRate of cognitive change (z-score per year)\u201d and the x-axis under panel 5F should be \u201cEstimated years to symptom onset\u201d. These corrections have been made to the online version as of April 13, 2022."}
+{"text": "Correction: BMC Cancer 22, 714 (2022)https://doi.org/10.1186/s12885-022-09722-xFollowing publication of the original article , the autThe description in the results of abstract section in this article currently reads \u201c\u2026 while the DDR_high/TM_low samples were enriched in Th17 cell diferentiation, ...\u201d. This is incorrect and should read as follows \u201c\u2026 while the DDR_high/TM_high samples were enriched in Th17 cell diferentiation, ....\u201d."}
+{"text": "Figure 5B: overlapping features can be seen within and between the \u201cONFH\u201d, \u201cagomir-NC\u201d, \u201cagomir-miR-410\u201d and \u201cWnt-11-siRNA\u201d panels.Figure 5G: blots can be seen to have highly uniform contrast against a uniform grey background.Figure 6C: overlapping features can be seen within and between the \u201cagomir-NC\u201d, \u201csiRNA-NC\u201d, \u201cWnt-11-siRNA\u201d, \u201cagomir-miR-410+OE-NC\u201d and \u201cagomir-miR-410+OE-Wnt-11\u201d panels.Figure 7D: blots can be seen to have uniform contrast against a uniform grey background.Figure 8E: blots can be seen to have uniform contrast against a uniform grey background.Figure 8F: overlapping features can be seen within and between the \u201cNormal\u201d, \u201cONFH\u201d, \u201cagomir-NC\u201d, \u201cagomir-miR-410\u201d, \u201csiRNA-NC\u201d, and \u201cagomir-miR-410+OE-NC\u201d panels.The Editors-in-Chief have retracted this article. Concerns have been raised regarding a number of figures, specifically:The Editors-in-Chief therefore no longer have confidence in the reliability of the data reported in the article. The authors have not responded to any correspondence from the editor/publisher about this retraction."}
+{"text": "Erratum to:Herzschr Elektrophys 202210.1007/s00399-022-00887-3Please note that the correct English title should read \u201cAtypical atrial flutter: Diagnostics and therapy\u201d. The original article has been corrected."}
+{"text": "Nature Communications 10.1038/s41467-022-31521-y, published online 02 July 2022Correction to: The original version of this Article contained an error in the figure legend of Figure 2L where \u201cTPA-TQT\u201d was mistakenly written as \u201cTPA-BBT\u201d. This has been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Accessed August 31, 2020.\u201dIn the report \u201cTrends in County-Level COVID-19 Incidence in Counties With and Without a Mask Mandate \u2014 Kansas, June 1\u2013August 23, 2020,\u201d on p. 1777, the sixth footnote should have read \u201c"}
+{"text": "Nuclei were counterstained with DAPI (blue). Scale bar = 20\u2009\u03bcm. (b) Three-dimensional reconstruction of microglia surrounding A\u03b2 plaque in the six-month-old female hippocampus. Scale bar = 20\u2009\u03bcm.Figure 8: MUTYH deficiency suppressed the morphological alteration of microglia in the"}
+{"text": "A\u00a064-year-old male with previous primary percutaneous coronary intervention (pPCI) of the left anterior descending artery (LAD) presented with cardiogenic shock and inferior wall ST-segment elevation myocardial infarction (STEMI) Fig.\u00a0a. Corona"}
+{"text": "Biosci Rep (2021) 41(3):BSR20202993. doi: 10.1042/BSR20202993). would like to correct The authors of the original article \u201cThe effects of myeloablative or non-myeloablative total body irradiations on intestinal tract in mice\u201d ("}
+{"text": "Ananas comosus \u2018Phulae\u2019, Ananas comosus \u2018Pattavia\u2019, Carica papaya \u2018Khaekdum\u2019, Carica papaya \u2018Khaeknuan\u2019, Durio zibethinus \u2018Monthong\u2019, Durio zibethinus \u2018Chanee\u2019, Psidium guajava \u2018Kimju\u2019, Psidium guajava \u2018Keenok\u2019, Mangifera indica \u2018Kaew\u2019 and Mangifera indica \u2018Namdokmai\u2019 were screened for their inhibitory activities against the key enzymes, cholinesterases and \u03b2-secretase (BACE-1), involved in AD pathogenesis. The top three fruit extracts with promising in vitro anti-AD activities were further investigated using rat pheochromocytoma PC-12 neuronal cell line and Drosophila AD model. Data showed that M. indica \u2018Kaew\u2019, M. indica \u2018Namdokmai\u2019 and P. guajava \u2018Kimju\u2019 reduced A\u03b21\u201342-mediated neurotoxicity by promoting glutathione-dependent enzymes, while M. indica \u2018Namdokmai\u2019 limited A\u03b21\u201342 peptide formation via BACE-1 inhibition and amended locomotory behavior of the Drosophila AD model. Results indicated the potential anti-AD properties of tropical fruits, particularly M. indica \u2018Namdokmai\u2019 in the prevention of A\u03b21\u201342-mediated neurotoxicity and as a BACE-1 blocker.Alzheimer\u2019s disease (AD) is a progressive neurological illness with few effective treatments. Thus, ameliorating the effects of AD using natural products has attracted global attention with promising efficacy and safety. In this study, ten tropical fruits including  Apparently, the difference in two amino acids of A\u03b2 cause significantly different structures, bioactivities, and clinical behaviors. A\u03b21\u201342 peptide is aggregated faster than A\u03b21\u201340 peptide and becomes more neurotoxic. The cerebrospinal fluid A\u03b21\u201342/1\u201340 ratio is currently used as an effective biomarker in AD pathology - Amyloid \u03b2/A4 Precursor Protein 770 Fragment 667-676- Lys-Arg-Arg amide substrate per minute at pH 4.5 at 37 \u00b0C.Quantification of A\u03b2 peptide and BACE-1 activity in fly brain were conducted as formerly detailed without modification . In brien = 3) or as indicated otherwise. The results are presented as mean \u00b1 standard deviation (SD). One\u2013way or two-way analysis of variance (ANOVA) with Duncan\u2019s multiple comparison test or Tukey\u2019s multiple comparisons test (more than two data) were used to state significant difference among values. For the comparison of two data sets, significant differences between values using Student\u2019s unpaired t-test were employed. Statistically analyses were performed using the statistical package for the social sciences .All experiments were performed in triplicate (M. indica \u2018Namdokmai\u2019 and M. indica \u2018Keaw\u2019) and guava (P. guajava \u2018Kimju\u2019) extracts, suggesting their potential roles in anti-AD properties. These three extracts were thus further investigated using cell culture and Drosophila model of AD. Additionally, we hypothesized that phenolics might be responsible for the in vitro activities. However, it is difficult to relate phenolics to their bioactivities due to limited information on LC-ESI-MS/MS analysis, which only presents the phenolic profiles of the selected fruit extracts  and only in vitro experiments may not be sufficient to define inactive extracts. Thus, excluding seven extracts could be considered a limitation of the present study. Nevertheless, M. indica \u2018Namdokmai\u2019 extract showed promising anti-AD potential by preventing A\u03b2-induced oxidative stress in neuronal cells and inhibiting BACE-1 in AD flies. Elucidation of the bioactive agents or effective doses in higher animal models, however, requires comprehensive further investigation.The in vitro results indicated the overall strong AChE, BChE, and BACE-1 inhibitory activities of mango ("}
+{"text": "Cell Death and Disease 10.1038/s41419-022-04834-5, published online 18 April 2022Correction to: The original version of this article unfortunately contained an error in an author name. instead of \u201cBravo-SanPedro\u201d, the name should be \u201cBravo-San Pedro\u201d with a space between \u201cSan\u201d and \u201cPedro\u201d. We apologize for this error. The original article has been corrected."}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-022-19570-1, published online 15 September 2022Correction to: The original version of this\u00a0Article contained an error in Figure 1 labels, where the material names were incorrect.\u201cmt-mAmCs\u201d.now reads:\u201cMMT-mAmCs\u201d.And \u201cmt\u201d.now reads:\u201cMMT\u201dThe original Figure\u00a0The original Article has been corrected."}
+{"text": "Neuropsychopharmacology 10.1038/s41386-022-01312-6, published online 27 April 2022Correction to: In the sentence beginning \u201cBehavior on Go and No-Go...\u201d and onward, the value] \u201cp\u201d should have read \u201cF\u201d. The original article has been corrected."}
+{"text": "It was possible to distinguished 27 Homogenousvs 30 Heterogenous IQ-profile.Reacting very little emotionally\u201d, \u201cTendency to isolation\u201d. Visual-Spatial-Index (VSI) with \u201cAbility to adapt to new people\u201d , \u201cfew interests\u201d . Verbal-Comprehension-Index (VCI) with \u201cReacting strongly to frustration\u201d, \u201cDifficulties to understand limits\u201d, \u201cSeparation anxiety\u201d. A significant difference between homogenous/heterogonous groups was shown regarding \u201cfew interests\u201d with high rate in the heterogonous group .No significant difference between homogenous/heterogonous groups, FIQ was positively significantly correlated with \u201cHIP seems to cover specific psycho-socio-emotional characteristics linked to IQ index distribution. Thus, it appears interesting to assess more the emotional and socio-cognitive field to understand these characteristics in HIP children.No significant relationships."}
+{"text": "Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been extensively shown to cause many neurological sequelae, and cognitive deficits (known as \u201cbrain fog\u201d) may particularly and widely occur even in individuals with mild symptoms . PeripheNature by Hosang et al. [\u201cLong COVID\u201d has become another major public health crisis. The \u201clung-brain axis\u201d has recently received increasing attention, and research published in g et al.  suggesteg et al. . The infg et al.  revealedThe peripheral cytokine storm initiated by SARS-CoV-2 infection may subsequently impact and trigger an inflammatory response in the nervous system . UnderstTaken as a whole, Fern\u00e1ndez-Casta\u00f1eda et al.  demonstrAn analysis of 2-years retrospective cohort study indicated that the increased cognitive deficit after COVID-19 persisted throughout the follow-up . Importa"}
+{"text": "Correction: Sports Medicine - Open (2021) 7:61 10.1186/s40798-021-00351-5After publication of \u2018Reply to: Comment on: \u201cUsing Field Based Data to Model Sprint Track Cycling Performance\u201d\u2019 , the pubAs a result, Fig.\u00a01a has been removed from the original article."}
+{"text": "Scientific Reports 10.1038/s41598-021-03016-1, published online 28 January 2022Correction to: The original version of this Article contained errors in the HPRT Reverse Primer and Probe primer sequences, which should read as: Antisense (HPRT-R) GGTCCTTTTCACCAGCAAGCT and Probe (HPRT-P) CTTTCCTTGGTCAGGCAGTATAATC. As a result, in the Materials and methods section, under the subheading \u2018Semi-nested RTqPCR for sample enrichment\u2019,\u201cThe qPCRBIO 1-Step Go Lo-Rox Kit reagents (PCR Biosystems) and manufacturer recommended cycling parameters were used with 900 nM TGACACTGGCAAAACAATGCA HPRT Forward Primer, 900 nM AGCTTGCTGGTGAAAAGGACC HPRT Reverse Primer and 250 nM TTTCCTTGGTCAGGCAGTATAATC VIC/TAMRA Probe (ThermoFisher Scientific).\u201dnow reads:\u201cThe qPCRBIO 1-Step Go Lo-Rox Kit reagents (PCR Biosystems) and manufacturer recommended cycling parameters were used with 900\u00a0nM TGACACTGGCAAAACAATGCA HPRT Forward Primer, 900\u00a0nM GGTCCTTTTCACCAGCAAGCT HPRT Reverse Primer and 250\u00a0nM CTTCCTTGGTCAGGCAGTATAATC VIC/TAMRA Probe (ThermoFisher Scientific).\u201dAdditionally, there was an error in 574P and 599R sequences in Table 2, where \u201cI\u201d should read \u201cN\u201d. Thermofisher does not provide the oigonucletides with an Inosine base. They provide equimolar amounts of each possible base in this position.should read:The original Article has been corrected."}
+{"text": "The secondary structures of ribosomal RNAs (rRNAs) were predicted. Six domains (III is absent in arthropods) and 44 helices were included in the 16S rRNA, and three domains and 24 helices were included in the 12S rRNA. We found three conserved fragments in all syrphid mitogenomes. Phylogenetic analyses were performed based on the nucleotide data of 13 PCGs and two rRNAs from 76 Muscomorpha and three outgroup species. In results the paraphyly of Aschiza and Schizophora were supported, the Acalyptratae was also paraphyletic but the relationships of its superfamilies were difficult to determine, the monophyly of Calyptratea was supported with the relationships of Oestroidea and Muscoidea need to be further reconsidered. Within Syrphidae the monophyly of family level was supported, the Syrphinae were clustered into one branch, while the paraphyly of Eristalinae was still well supported.In this study, 18 mitochondrial genomes (mitogenomes) of Syrphidae were sequenced. These mitogenomes ranged from 15,648 to 16,405 bp and contained 37 genes that were similar to those from other Syrphidae species. Most protein-coding genes (PCGs) started with a standard ATN codon and ended with TAA/G. All transfer RNAs (tRNAs) could be folded into the cloverleaf secondary structure except  The Platypezoidea diverged first, sister to the other species of Muscomorpha . The parThe Acalyptratae was paraphyletic in our results. The superfamilies Ephydroidea, Tephritoidea, Lauxanioidea, and Opomyzoidea were monophyletic . The supet al. [et al. [et al. [et al. [The monophyly of Calyptratea was supported. Its cluster formed almost as (Hippoboscoidea + (Oestroidea + (Muscoidea + Oestroidea))), and the family-level topology was always (Hippoboscidae + (Tachinidae + Oestridae) + )))) . Muscoidet al. , Wiegman [et al. , and Kut [et al.  conclude [et al.  found Oe [et al. ,35. Thiset al. [et al. [Asarkina ericetorum was most closely related to Dideoides latus, while in other trees it was more closely related to Ocyptamus sativus and Platycheirus albimanus. Also, while the topology of  was well supported, the position of this clade was less stable Click here for additional data file.S2 FigThe \u201c-\u201d indicates Watson-Crick base pairing and \u201c\u2022\u201d indicates non-Watson-Crick base pairing.(DOCX)Click here for additional data file.S3 FigThe \u201c-\u201d indicates Watson-Crick base pairing and \u201c\u2022\u201d indicates non-Watson-Crick base pairing.(DOCX)Click here for additional data file.S4 FigThe \u201c-\u201d indicates Watson-Crick base pairing and \u201c\u2022\u201d indicates non-Watson-Crick base pairing.(DOCX)Click here for additional data file.S5 FigThe \u201c-\u201d indicates Watson-Crick base pairing and \u201c\u2022\u201d indicates non-Watson-Crick base pairing.(DOCX)Click here for additional data file.S6 FigThe \u201c-\u201d indicates Watson-Crick base pairing and \u201c\u2022\u201d indicates non-Watson-Crick base pairing.(DOCX)Click here for additional data file.S7 FigThe \u201c-\u201d indicates Watson-Crick base pairing and \u201c\u2022\u201d indicates non-Watson-Crick base pairing.(DOCX)Click here for additional data file.S8 FigThe \u201c-\u201d indicates Watson-Crick base pairing and \u201c\u2022\u201d indicates non-Watson-Crick base pairing.(DOCX)Click here for additional data file.S9 FigThe \u201c-\u201d indicates Watson-Crick base pairing and \u201c\u2022\u201d indicates non-Watson-Crick base pairing.(DOCX)Click here for additional data file.S10 FigThe \u201c-\u201d indicates Watson-Crick base pairing and \u201c\u2022\u201d indicates non-Watson-Crick base pairing.(DOCX)Click here for additional data file.S11 FigThe \u201c-\u201d indicates Watson-Crick base pairing and \u201c\u2022\u201d indicates non-Watson-Crick base pairing.(DOCX)Click here for additional data file.S12 FigThe \u201c-\u201d indicates Watson-Crick base pairing and \u201c\u2022\u201d indicates non-Watson-Crick base pairing.(DOCX)Click here for additional data file.S13 FigThe \u201c-\u201d indicates Watson-Crick base pairing and \u201c\u2022\u201d indicates non-Watson-Crick base pairing.(DOCX)Click here for additional data file.S14 FigThe \u201c-\u201d indicates Watson-Crick base pairing and \u201c\u2022\u201d indicates non-Watson-Crick base pairing.(DOCX)Click here for additional data file.S15 FigThe \u201c-\u201d indicates Watson-Crick base pairing and \u201c\u2022\u201d indicates non-Watson-Crick base pairing.(DOCX)Click here for additional data file.S16 FigThe \u201c-\u201d indicates Watson-Crick base pairing and \u201c\u2022\u201d indicates non-Watson-Crick base pairing.(DOCX)Click here for additional data file.S17 FigThe \u201c-\u201d indicates Watson-Crick base pairing and \u201c\u2022\u201d indicates non-Watson-Crick base pairing.(DOCX)Click here for additional data file.S18 FigThe \u201c-\u201d indicates Watson-Crick base pairing and \u201c\u2022\u201d indicates non-Watson-Crick base pairing.(DOCX)Click here for additional data file.S19 Fig(DOCX)Click here for additional data file.S20 Fig(DOCX)Click here for additional data file.S21 Fig(DOCX)Click here for additional data file.S22 Fig(DOCX)Click here for additional data file.S23 Fig(DOCX)Click here for additional data file.S24 Fig(DOCX)Click here for additional data file.S25 Fig(DOCX)Click here for additional data file.S26 Fig(DOCX)Click here for additional data file.S27 Fig(DOCX)Click here for additional data file.S28 Fig(DOCX)Click here for additional data file.S29 Fig(DOCX)Click here for additional data file.S30 Fig(DOCX)Click here for additional data file.S31 Fig(DOCX)Click here for additional data file.S32 Fig(DOCX)Click here for additional data file.S33 Fig(DOCX)Click here for additional data file.S34 Fig(DOCX)Click here for additional data file.S35 Fig(DOCX)Click here for additional data file.S36 Fig(DOCX)Click here for additional data file.S37 Fig(DOCX)Click here for additional data file.S38 Fig(DOCX)Click here for additional data file.S39 Fig(DOCX)Click here for additional data file.S40 Fig(DOCX)Click here for additional data file.S41 Fig(DOCX)Click here for additional data file.S42 Fig(DOCX)Click here for additional data file.S43 Fig(DOCX)Click here for additional data file.S44 Fig(DOCX)Click here for additional data file.S45 Fig(DOCX)Click here for additional data file.S46 Fig(DOCX)Click here for additional data file.S47 Fig(DOCX)Click here for additional data file.S48 Fig(DOCX)Click here for additional data file.S49 Fig(DOCX)Click here for additional data file.S50 Fig(DOCX)Click here for additional data file.S51 Fig(DOCX)Click here for additional data file.S52 Fig(DOCX)Click here for additional data file.S53 Fig(DOCX)Click here for additional data file.S54 Fig(DOCX)Click here for additional data file.S55 FigInferred based on the 13 PCGs using ML.(DOCX)Click here for additional data file.S56 FigInferred based on the 13 PCGs using BI.(DOCX)Click here for additional data file.S57 FigInferred based on the first and second codons of the PCG12 using BI.(DOCX)Click here for additional data file.S58 FigInferred based on the first and second codons of the 13 PCGs and 2 rRNAs using ML.(DOCX)Click here for additional data file.S59 FigInferred based on the first and second codons of the 13 PCGs and 2 rRNAs using BI.(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S5 Table(DOCX)Click here for additional data file.S6 Table(DOCX)Click here for additional data file.S7 Table(DOCX)Click here for additional data file.S8 Table(DOCX)Click here for additional data file.S9 Table(DOCX)Click here for additional data file.S10 Table(DOCX)Click here for additional data file.S11 Table(DOCX)Click here for additional data file.S12 Table(DOCX)Click here for additional data file.S13 Table(DOCX)Click here for additional data file.S14 Table(DOCX)Click here for additional data file.S15 Table(DOCX)Click here for additional data file.S16 Table(DOCX)Click here for additional data file.S17 Table(DOCX)Click here for additional data file.S18 Table(DOCX)Click here for additional data file."}
+{"text": "Blood Cancer Journal 10.1038/s41408-022-00726-1, published online 06 September 2022Correction to: In this article the affiliation details for Shilpi Chaudhary and Reema Bisht were incorrectly assigned as \u20183\u2019 but should have been \u20182\u2019."}
+{"text": "This article has been corrected.1In the Research Letter titled \u201cAssociation of Symptoms After COVID-19 Vaccination With Anti\u2013SARS-CoV-2 Antibody Response in the Framingham Heart Study,\u201d"}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-022-20791-7, published online 12 October 2022Correction to: The original version of this Article contained errors in Table 1, where there was a missing value in a row under \u201cSmoking exposure at home\u2014Yes\u201d in column \u201cGirls\u2014No\u2014N\u201d. The correct and incorrect values appear below.Incorrect:Correct:The original Article has been corrected."}
+{"text": "In the article titled \u201cmiR-195-5p Suppresses the Proliferation, Migration, and Invasion of Oral Squamous Cell Carcinoma by Targeting TRIM14\u201d . With th"}
+{"text": "Retraction Note: BMC Complement Med Ther 20, 88 (2020)https://doi.org/10.1186/s12906-020-2873-1The Editor has retracted this article because of overlap within figures, specifically:Figure 6A (panel \u201cHedgehog\u201d) overlaps with Figure 6A (panel \u201cGli\u201d)Figure 11A (panel \u201cModel SSB group\u201d) overlaps with Figure 11A (panel \u201cModel Silymarin group\u201d)The Editor therefore no longer has confidence in the integrity of the data.Xu Wang does not agree with this retraction. None of the other authors has responded to any correspondence from the Editor about this retraction."}
+{"text": "European Journal of Human Genetics 10.1038/s41431-022-01163-1, published online 18 August 2022Correction to: In the sentence beginning \u2018Similarly...\u2019 in the third paragraph in Discussion, \u201cp.Arg559*\u201d should have been \u201cp.Arg550*\u201d.The original article has been corrected."}
+{"text": "Scientific reports 10.1038/s41598-023-28716-8, published online 27 January 2023Correction to: bind, \u0394GCoulomb, \u0394GCovalent, \u0394GHbondd, \u0394GLipo, \u0394GSolvGB and \u0394GvdW appeared under an incorrect column heading. Additionally, the column heading \u201c\u0394GCoulomb\u201d was incorrectly stated as \u201c\u0394GCoulom\u201d. The original Table The original version of this Article contained errors in Table The original Article has been corrected."}
+{"text": "Scientific Reports 10.1038/s41598-018-23897-z, published online 04 April 2018Correction to: th September 2021 contains an error in one of the accession numbers for the type strain H15-1957-10CT.The Author Correction published on 8\u201cCSUR Q5983\u201dshould read:\u201cCSUR Q5984\u201d"}
+{"text": "This article has an addendum: The skin squamous-cell carcinoma (sSCC) samples were collected and used in compliance with the study protocol n\u00b02016-01851, approved by Commission cantonale d\u2019\u00e9thique de la recherche sur l\u2019\u00eatre humain du canton de Vaud (CER-VD), in line with the legal requirements. Patients signed a general consent for use of health-related data.638-648. https://doi.org/10.18632/oncotarget.27915Original article: Oncotarget. 2021; 12:638\u2013648."}
+{"text": "Fig.\u00a01A.Following publication of the original article , it was Fig.\u00a01A\u00a0US image showing patchy mild changes in echogenicity with hypoechoic areas and corresponding subcutaneous echogenicity in the vastus lateralis (cross-section) in a 26-year-old with Anti-NXP2.\u201dThe caption previously read: \u201cFig.\u00a01A Mild increased echogenicity in the vastus lateralis (cross section) and subcutaneous tissue with patches of hypoechogenicity in a 26-year-old with Anti-NXP2 DM.\u201dThe correct caption is: \u201cThe article also contained several typographical errors, which have been corrected.The original article  has been"}
+{"text": "Correction: Trials 19, 103 (2018)https://doi.org/10.1186/s13063-018-2470-5qd four times daily\u201d. This should be \u201cqd once daily\u201d.Following publication of the original article  it was r"}
+{"text": "Nature Communications 10.1038/s41467-022-29908-y, published online 25 April 2022.Correction to: DDS loss\u201d in Fig. 8a was shifted under the label \u201cAraliaceae-common WGD\u201d. In addition, in the same figure panel, the labels of \u201cDc WGD-\u03b1\u201d and \u201cDc WGD-\u03b2\u201d were shifted toward the label \u201cApiales ancestor\u201d (see incorrect figure below).In the original version of this Article, the label of \u201cThese have been corrected in both the PDF and HTML versions of the Article (see corrected figure below)."}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-023-27770-6, published online 18 January 2023Correction to: In the original version of this Article Toshiyuki Itai and Atsushi Sugie were omitted as equally contributing authors.In addition, in Table 1, a \u201c\u2013\u201d sign was omitted for \u201cCraniofacial/Neck features\u201d of \u201cIndividual 3\u201d.Incorrect:Correct:The original article has been corrected."}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-021-95928-1, published online 19 August 2021Correction to: The original version of this Article contained an error in Table 1 where row 2 was incorrect for \u201cCharacteristic\u201d,\u201cSex, female/male, no\u201dnow reads:\u201cSex, male/female, no\u201dThe original Article has been corrected."}
+{"text": "Dear Editor,We would like to share ideas on \u201cAcute kidney injury (AKI) after COVID-19 vaccines: a real-world study . Vaccina"}
+{"text": "Scientific reportshttps://doi.org/10.1038/s41598-020-79930-7, published online 12 January 2021Correction to: 2\u201d was incorrectly given as \u201cS\u201d.The original version of this Article contained an error in Equation\u00a01, where \u201cSThe original Article has been corrected."}
+{"text": "Correction: BMC Oral Health (2022) 22:620 10.1186/s12903-022-02631-2In this article, there is a typo in the result section of the Abstract.Original Abstract text: \u201cThe overall mean DMFT score was 5.93 (n\u2009=\u200914 studies) and\u2026\u2026\u201dRevised Abstract text: \u201cThe overall mean DMFS score was 5.93 (n\u2009=\u200914 studies) and\u2026\u2026\u201dThe original article has been corrected."}
+{"text": "Figure 7 has been corrected to:In the article, \u201cOutcome of bone-patellar tendon-bone vs hamstring tendon autograft for anterior cruciate ligament reconstruction: A meta-analysis of randomized controlled trials with a 5-year minimum follow-up\u201d"}
+{"text": "Communications Biology 10.1038/s42003-022-03912-w, published online 16 September 2022.Correction to: In the original version of the Article, the Acknowledgements incorrectly referenced \u201cgrant 31003B_6005\u201d. The text should read \u201cgrant 310030B_182830\u201d. This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Correction to: EPMA Journal (2022)https://doi.org/10.1007/s13167-022-00295-0In this article the author name \u2018Tiancheng Xu\u2019 was incorrectly written as \u2018Tianchen Xu\u2019.The original article has been corrected."}
+{"text": "In the sentence beginning \u201cA C-shaped \u2026.\u201d in this article, the text \u201cin 3R tau and G304-E380 in 4R tau\u201d is mistakenly added. The correct sentence should read as \u201cA C-shaped core structure consisting of V306-F378 was identified in the brain of one individual with AD.\u201d"}
+{"text": "Correction to: Nature Communications 10.1038/s41467-022-31182-x, published online 20 June 2022\u22121 of air)\u201d instead of \u201cINPs x 10\u22123 (L\u22121 of air)\u201d. This has been corrected in both the PDF and HTML versions of the Article.The original version of this Article contained an error in Fig. 4, in which the y-axis should read \u201cINPs (L"}
+{"text": "Scientific Reports 10.1038/s41598-021-97880-6, published online 14 September 2021Correction to: + T-cell epitopes\u2019, where an incorrect Vaxijen score was stated for the epitope \u2018FKISVFGFA\u2019.The original version of this Article contained an error in the Results section under the subheading \u2018Prediction of cytotoxic T-cell/CD8\u201cA total of 77 CTL epitopes were detected to be antigenic in nature, with epitope \u2018FKISVFGFA\u2019 having the highest Vaxijen score of 2 0.2931.\u201dnow reads:\u201cA total of 77 CTL epitopes were detected to be antigenic in nature, with epitope \u2018FKISVFGFA\u2019 having the highest Vaxijen score of 2.2931.\u201dThe original Article has been corrected."}
+{"text": "In the article titled \u201cComprehensive Humoral and Cellular Immune Responses to SARS-CoV-2 Variants in Diverse Chinese Population\u201d , the loc"}
+{"text": "Nature Communications 10.1038/s41467-021-24792-4, published online 10 August 2021Correction to: In this article the grant number LS 139433-2016 relating to le comit\u00e9 Languedoc-Roussillon de la Ligue Contre le Cancer for B\u00e9reng\u00e8re Pradet-Balade was omitted. The original article has been corrected."}
+{"text": "Signal Transduction and Targeted Therapy 10.1038/s41392-022-00885-4, published online 02 March 2022Correction to: 1, the authors noticed the inadvertent mistakes occurred in Fig. After online publication of the articleThe authors mistakenly switched \u201c4h\u201d and \u201c1d\u201d UMAP plots. The correct version of Fig. The authos mistakenly spelled \u201cLeukocyte\u201d as \u201cLeukecyte\u201d. The correct version of Fig."}
+{"text": "The publisher apologizes for the error.The second author\u2019s name is spelled incorrectly. The correct name is: \u0141ukasz Wyro\u017cemski. The correct citation is: Yao Y, Wyro\u017cemski \u0141, Lundin KEA, Sandve GK, Qiao S-W (2021) Differential expression profile of gluten-specific T cells identified by single-cell RNA-seq. PLoS ONE 16(10): e0258029."}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-022-14416-2, published online 16 June 2022Correction to: The original version of this Article contained an error in the Materials and methods section, under the subheading \u2018Characteristics of the samples\u2019.IR: concrete characteristic equal to PC01REF but without inclined shear reinforcement, as shown in Fig.\u00a03d.\u201d\u201cPC04now reads:IR: concrete characteristic equal to PC01REF but with inclined shear reinforcement, as shown in Fig.\u00a03d.\u201d\u201cPC04The original Article has been corrected."}
+{"text": "Scientific Reports 10.1038/s41598-021-01411-2, published online 23 November 2021Correction to: The original version of this Article contained an error in the title of the paper, where the word \u201ctrials\u201d was incorrectly given as \u201ctrails\u201d. The original Article has been corrected."}
+{"text": "Correction: BMC Medical Research Methodology 22, 217 (2022).10.1186/s12874-022-01692-9Following publication of the original article , the autThe equation in \u201cData-generating mechanisms\u201d should be:The text \u201cCorrect specification of theS\u2009=\u20092 covariate distribution\u201d should be \u201cCorrect specification of the S\u2009=\u20092 covariate distribution\u201d.The original article has been updated."}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-022-15770-x, published online 18 July 2022Correction to: The original version of this Article contained errors in the Funding section.\u201cThis research has received funding from the Ministry of Science and Innovation PI20/01532 project, and the Centro de Investigaci\u00f3n Biom\u00e9dica en Red-Epidemiolog\u00eda y Salud P\u00fablica (CIBERESP/CB06/02/1014).\u201dnow reads:\u201cThis research has received funding from the Ministry of Science and Innovation, Instituto de Salud Carlos III, FEDER co-funding from European Union (PI20/01532 project), and the Centro de Investigaci\u00f3n Biom\u00e9dica en Red-Epidemiolog\u00eda y Salud P\u00fablica (CIBERESP/CB06/02/1014).\u201dThe original Article has been corrected."}
+{"text": "Scientific Reports 10.1038/s41598-022-05242-7, published online 26 January 2022Correction to: The original version of this Article contained an error in the copyright line.\u201c\u00a9 The Author(s) 2022\u201dnow reads:\u201c\u00a9 National Technology & Engineering Solutions of Sandia, LLC 2022\u201dThe original Article has been corrected."}
+{"text": "Correction to: J Behav Health Serv Res10.1007/s11414-022-09826-zThe first name of a co-author is misspelled. \u201cManual\u201d should be \u201cManuel\u201d.The original article has been corrected."}
+{"text": "Correction to: BMC Geriatrics 22, 176 (2022)https://doi.org/10.1186/s12877-022-02820-2After publication of this article , the autIn Table 1, there is a superfluous c behind \u201cN Vascular problems\u201d; this can be removed twice.In Table 1, \u201cExposure to famine\u201d is aligned incorrectly; should be moved to the right, above \u201cIn late gestation; In mid gestation; In early gestation\u201d (as in Table 2).In Table 2, a note is missing: \u201cd Model 4: Sex-specific logistic regression model, adjusted for birth weight, education and SES\u201dThe original article  has been"}
+{"text": "In the Invited Article, \u201cInvesting in Late-Life Brain Capital,\u201d DOI: 10.1093/geroni/igac-16, co-author Patrick Brannelly\u2019 name and was misspelled as \u201cBrannally\u201d. It has since been corrected."}
+{"text": "Nature 10.1038/s41586-021-04066-1 Published online 10 November 2021Correction to: In Extended Data Fig. 1 of this Article, the labels \u2018Market class\u2019 and \u2018Biological status\u2019 were inadvertently swapped. In the corresponding figure legend, \u201cTrack 1: Biological status; Track 2: Market class;\u201d should have been \u201cTrack 1: Market class; Track 2: Biological status;\u201d. The original Article has been corrected online"}
+{"text": "Correction: Pilot Feasibility Stud 8, 76 (2022)https://doi.org/10.1186/s40814-022-01030-2The safety analysis\u201d further down and \u201cThe recruitment\u201d and \u201cRetention\u201d on the page before under the heading Outcomes.Following publication of the original article , the autThe original article  has been"}
+{"text": "Scientific Data 10.1038/s41597-022-01899-x, published online 3 January 2023.Correction to: Two column headings, \u201cHospital admissions\u201d and \u201cICU admissions\u201d, were missing from Table 1 in the original version of the paper. These have been corrected in the HTML and pdf versions."}
+{"text": "Scientific Reports 10.1038/s41598-021-03913-5, published online 07 January 2022Correction to: The Funding section in the original version of this Article was incorrect.\u201cThis work was supported by the Italian Ministry of Health (\u201c5\u2009\u00d7\u20091000\u201d).\u201dnow reads:\u201cThis research was funded by the Italian Ministry of Health (RC 2022).\u201dThe original Article has been corrected."}
+{"text": "Correction to: Nature Communications 10.1038/s41467-022-30653-5, published online 19 July 2022In this article the funding from \u2018Alzheimer\u2019s Drug Discovery Foundation (ADDF)\u2019 was omitted. The original article has been corrected."}
+{"text": "Nature Communications 10.1038/s41467-019-13657-6, published online 20 December 2019.Correction to: In this article the author name \u2018Jennifer Karin Ocasio\u2019 was incorrectly written as \u2018Jennifer Ocasio\u2019. The original article has been corrected."}
+{"text": "Journal of Healthcare Engineering has retracted the article titled \u201cInhibiting Autophagy Pathway of PI3K/AKT/mTOR Promotes Apoptosis in SK-N-SH Cell Model of Alzheimer's Disease\u201d [Disease\u201d  due to cFollowing an investigation conducted by the Hindawi Research Integrity team , signifi"}
+{"text": "The purpose of this study was to determine and compare the percentage of completely healed meniscal tears after arthroscopic repair combined with anterior cruciate ligament reconstruction (ACLR) for the different vascular zones of the meniscus.PubMed, Embase, Web of Science, Cochrane library and Emcare were searched on 19 May 2020 for articles reporting healing rates after arthroscopic meniscal repair with concomitant ACLR for the different meniscal vascular zones as assessed by second-look arthroscopy. Data on meniscal tears were extracted as located in zones 1, 2 or 3, according to the Cooper classification. Studies were graded in quality using a modified Newcastle\u2013Ottawa Scale. Pooled analyses were performed utilizing a random-effects model. Meta-analyses were performed using R version 3.6.2 and SPSS statistical software version 25.0. The study was registered with PROSPERO (ID:CRD42020176175).n\u2009=\u200910) reporting zone 1 tears and 69% (95% CI 59\u201379%) for studies (n\u2009=\u20099) reporting zone 2 tears. No study reported healing rates for zone 3 tears. The pooled overall odds ratio was 2.5 (95% CI 1.00\u22126.02), indicating zone 1 tears as 2.5 times more likely to heal than zone 2 tears.Ten observational cohort studies met the inclusion criteria, accounting for 758 meniscal tear repairs in total. The pooled overall proportion of healing was 78% (95% CI 72\u201384%). The mean weighted proportion of healing was 83% (95% CI 76\u201390%) for studies (This study demonstrates that meniscal tears localized in vascular zone 1 were more likely to heal than those in zone 2.IV.The online version contains supplementary material available at 10.1007/s00167-022-06862-2. Meniscal lesions are one of the most common injuries in orthopaedic surgery and can be surgically treated by repair or by either partial, subtotal or total meniscectomy . When poIn 1982, Arnoczky et al. reported that the extent of vascular penetration in adults ranged from 10 to 30% for the medial meniscus and 10\u201325% for the lateral meniscus . LongituPre-clinical studies have shown that healing of meniscal tears is inherently bound to vascularity of the surrounding tissue , 8, 34. Completely healed meniscal tears after repair might result in functionally superior menisci and consequently better long-term outcomes than incomplete or non-healed tears. To assess healing, most studies look at clinical outcomes after meniscal repair, such as Patient Reported Outcome Measures (PROMs) or clinical tests, or imaging modalities such as MR imaging. The sensitivity, specificity and accuracy of clinical outcomes and different imaging modalities to determine biologically complete healing remains limited , 19, 27.This systematic review and meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and was registered with PROSPERO prior to the screening of studies .A search strategy was constructed by an experienced librarian (JS). PubMed, Embase, Web of Science, Cochrane library and Emcare were searched for publications up to 19 May 2020, without restriction of publication date. The search included two components: \u2018\u2018Meniscal tear\u2019\u2019 OR \u2018\u2019Meniscal repair\u2019\u2019 and \u2018\u2018Healing\u2019\u2019 OR \u2018\u2018Success\u2019\u2019 OR \u2018\u2018Failure\u2019\u2019 . Subsequently, full-text articles were reviewed by the same reviewers (MG&TvL). Discrepancies were resolved through discussion. Two additional reviewers (PvS&PvD) were available when consensus could not be reached. A PRISMA (statement 2020) flowchart is provided in Fig.\u00a0Data were extracted by both reviewers (MG&TvL) independently using a prespecified data extraction sheet in Microsoft Excel 2016 . Data on healing rates after meniscal repair for different vascular zones were extracted. Meniscal healing assessed with second-look arthroscopy is generally classified as \u2018\u2018complete\u2019\u2019, \u2018\u2018incomplete/partial\u2019\u2019 or \u2018\u2018no healing\u2019\u2019, according to the criteria of Morgan et al.  OR \u201ctear\u201d[tw] OR tear*[tw] OR ruptur*[tw])) OR \u201cTibial Meniscus Injuries\u201d[majr] OR \u201cMeniscus/injuries\u201d[majr] OR (\u201cKnee Injuries\u201d[majr] AND \u201cMeniscus\u201d[majr]) OR \u201cmeniscal repair\u201d[tw] OR \u201cmeniscal repairs\u201d[tw] OR \u201cmeniscus repair\u201d[tw] OR \u201cmeniscus repairs\u201d[tw]) AND ) NOT  NOT ((\u201cCase Reports\u201d[ptyp] OR \u201ccase report\u201d[ti]) NOT ) AND english[la]). ADJ5 ) OR ) OR \u201cmeniscal repair\u201d.ti,ab OR \u201cmeniscal repairs\u201d.ti,ab OR \u201cmeniscus repair\u201d.ti,ab OR \u201cmeniscus repairs\u201d.ti,ab) AND )) NOT  NOT (\u201cCase Report\u201d/ OR \u201ccase report\u201d.ti) AND english.la). OR  NEAR/5 (\u201ctears\u201d OR \u201ctear\u201d OR tear*)) OR \u201cmeniscal repair\u201d OR \u201cmeniscal repairs\u201d OR \u201cmeniscus repair\u201d OR \u201cmeniscus repairs\u201d) AND ti\u2009=\u2009) OR  NEAR/5 (\u201ctears\u201d OR \u201ctear\u201d OR tear*)) OR \u201cmeniscal repair\u201d OR \u201cmeniscal repairs\u201d OR \u201cmeniscus repair\u201d OR \u201cmeniscus repairs\u201d) AND ts\u2009=\u2009)) NOT ti\u2009=\u2009\u201dCase Report\u201d AND la\u2009=\u2009english NOT ti\u2009=\u2009. NEAR/5 (\u201ctears\u201d OR \u201ctear\u201d OR tear*)) OR \u201cmeniscal repair\u201d OR \u201cmeniscal repairs\u201d OR \u201cmeniscus repair\u201d OR \u201cmeniscus repairs\u201d) AND )):ti,ab,kw.Note: a study can be awarded a maximum of one star for each numbered item within the Selection and Outcome categories. A maximum of two stars can be given for Comparability.Truly representative of the average patient with a meniscal tear in the communitySomewhat representative of the average patient with a meniscal tear in the communitySelected group of patients, e.g. nurses, volunteers, military personnelNo description of the derivation of the cohortDrawn from the same community as the exposed cohortDrawn from a different sourceNo description of the derivation of the non-exposed cohortOnly one vascular zone describedRim width for classification of vascular region specified (in mm)No rim width for classification of vascular region specified (in mm)YesNoStudy only includes patients with the same type of tear Study controls for any other additional factor of possible influence Definition of healing based on 2nd-look specifiedDefinition of healing based on 2nd-look not specifiedYes, 2nd-look arthroscopy was at\u2009\u2265\u20096\u00a0monthsNoComplete follow-up\u2014all patients received 2nd-look arthroscopySubjects lost to follow-up unlikely to introduce bias, small number lost:\u2009>\u200980% follow-up rate or description provided of those who did not receive arthroscopy\u2009<\u200980% of meniscal repair patients received 2nd-look arthroscopy and no description of those lostNo statementQuality assesment of included studies, using the modified NOS.Ahn JH, Lee YS, Yoo JC, Chang MJ, Koh KH, Kim MH (2010) Clinical and second-look arthroscopic evaluation of repaired medial meniscus in anterior cruciate ligament-reconstructed knees. Am J Sports Med 38(3):472\u2013477Asahina S, Muneta T, Yamamoto H. (1996) Arthroscopic meniscal repair in conjunction with anterior cruciate ligament reconstruction: factors affecting the healing rate. Arthroscopy 12(5):541\u2013545Buseck MS, Noyes FR (1991) Arthroscopic evaluation of meniscal repairs after anterior cruciate ligament reconstruction and immediate motion. Am J Sports Med 19(5):489\u2013494Feng H, Hong L, Geng XS, Zhang H, Wang XS, Jiang XY (2008) Second-look arthroscopic evaluation of bucket-handle meniscus tear repairs with anterior cruciate ligament reconstruction: 67 consecutive cases. Arthroscopy 24(12):1358\u20131366Kang HJ, Chun CH, Kim KM, Cho HH, Espinosa JC (2015) The Results of All-Inside Meniscus Repair Using the Viper Repair System Simultaneously with Anterior Cruciate Ligament Reconstruction. Clin Orthop Surg 7(2):177\u2013184Kanto R, Yamaguchi M, Sasaki K, Matsumoto A, Nakayama H, Yoshiya S (2019) Second-Look Arthroscopic Evaluations of Meniscal Repairs Associated With Anterior Cruciate Ligament Reconstruction. Arthroscopy 35(10):2868\u20132877Matsushita T, Nagai K, Araki D, Tanaka T, Matsumoto T, Nishida K, et al. (2017) Factors associated with the status of meniscal tears following meniscal repair concomitant with anterior cruciate ligament reconstruction. Connect Tissue Res 58(3\u20134):386\u2013392Miao Y, Yu JK, Ao YF, Zheng ZZ, Gong X, Leung KK (2011) Diagnostic values of 3 methods for evaluating meniscal healing status after meniscal repair: comparison among second-look arthroscopy, clinical assessment, and magnetic resonance imaging. Am J Sports Med 39(4):735\u2013742Seo SS, Kim CW, Lee CR, Park DH, Kwon YU, Kim OG, et al. (2020) Second-look arthroscopic findings and clinical outcomes of meniscal repair with concomitant anterior cruciate ligament reconstruction: comparison of suture and meniscus fixation device. Arch Orthop Trauma Surg 140(3):365\u2013372Tachibana Y, Sakaguchi K, Goto T, Oda H, Yamazaki K, Iida S (2010) Repair integrity evaluated by second-look arthroscopy after arthroscopic meniscal repair with the FasT-Fix during anterior cruciate ligament reconstruction. Am J Sports Med 38(5):965\u2013971Supplementary file1 (SAV 10 KB)Below is the link to the electronic supplementary material."}
+{"text": "Funding statement. This work was funded by two different grants from FAPEMIG (CDS-APQ 00908-08 and APQ-00581-11), although just one was mentioned (CDS-APQ 00908-08). The correct Funding statement appears below.In the published article, there was an error in the \u201cThis work was supported by Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior (CAPES) (PNPD-2455/2011 and Finance code 001), Funda\u00e7\u00e3o de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG) (CDS-APQ 00908-08 and APQ-00581-11), and Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico (CNPq) (445096/2014-4) funding agencies\u201d.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "Scientific Reports 10.1038/s41598-022-13562-x, published online 03 June 2022Correction to: P-value\u2019 was incomplete for \u2018Females\u2019. Furthermore, data in the row \u2018CES-D\u2019 contained errors, where the p-value for \u2018Males\u2019 and the data \u2018Non-depressive symptoms\u2019 for \u2018Females\u2019 was displaced, and data for \u2018Depressive symptoms\u2019 for \u2018Females\u2019 was omitted.The original version of this Article contained errors in Table 1, where the column \u2018The original Table The original Article has been corrected."}
+{"text": "Nature Communications 10.1038/s41467-022-35076-w, published online 03 December 2022Correction to: In this article the patent application mentioned in the \u2018Competing interests\u2019 statement was incorrectly given as \u2018PCT/US2002/024082\u2019 but should have been \u2018PCT/US2022/024082\u2019. The original article has been corrected."}
+{"text": "We present images from a 71-year-old prostate cancer patient who underwent a robot-assisted radical prostatectomy and extended pelvic lymph node dissection (ePLND) complemented with experimental sentinel node (SN) resection .99mTc-nanoscan (218\u00a0MBq in 2\u00a0ml) was used, which has replaced the well-known ICG-99mTc-nanocolloid [99mTc-nanoscan . With that, the former can act as \u201cred-flag\u201d to highlight tissues that should be spared, while the latter provides\u00a0a \u201dgreen-flag\u201d for tissues that should be resected. As such, the presented three-way multiplexing approach may help preserve the oncological benefit of ePLND\u2009+\u2009SN [For SN identification, the bimodal/hybrid tracer ICG-ocolloid . Preoperocolloid . It is aocolloid , 6. WithLND\u2009+\u2009SN , while p"}
+{"text": "Following the publication of the original article , the autIncorrect line: L-OHP(\u2009+) group (n\u2009=\u200926), L-OHP(\u2009\u2212) group (n\u2009=\u200926).Corrected line: L-OHP(\u2009+) group (n\u2009=\u200921), L-OHP(\u2009\u2212) group (n\u2009=\u200921).The original article has been corrected."}
+{"text": "Scientific Reports 10.1038/s41598-021-98807-x, published online 28 September 2021Correction to: The original version of this Article contained a repeated error in Figure\u00a01 where the code name of the rubber \u201cLNR\" was incorrectly given as \u201cLPN\u201d.The original Figure\u00a0The original Article has been corrected."}
+{"text": "Nature Communications 10.1038/ncomms13344, published online 24 November 2016.Correction to: In the original version of this article the \u201cMethod\u201d section stated an incorrect provenance for the cardiomyocytes Cor.4U. These were not derived from human iPS cells, as stated in the original article, but were derived from the human embryonic stem (hES) cell line RUES2, as has recently been determined following short tandem repeat testing carried out by Ncardia AG (formerly Axiogenesis). This does not alter the findings and interpretation of the data, as the cells are bone fide human pluripotent cell derived cardiomyocytes.The original sentence in the \u201cMethods\u201d section read: \u201cMEA measurements in cardiomyocytes derived from induced pluripotent stem cells (iPS)  were performed\u201d. The sentence now reads: \u201cMEA measurements in cardiomyocytes derived from the hES cell line RUES2 ) were performed\u201d.The legend of Fig. 2k originally read: \u2018Representative traces of field potential in human iPS-derived cardiomyocytes highlighting effect of IL-1\u03b2 on the field potential duration (FPD)\u2019. This now reads: \u2018Representative traces of field potential in hES cell-derived cardiomyocytes highlighting effect of IL-1\u03b2 on the field potential duration (FPD)\u2019.The legend of Fig. 3e originally read: \u2018Representative traces of field potential in human iPS-derived cardiomyocytes highlighting inhibitory influence of CamKII with AIP of the IL-1\u03b2 effect on the field potential duration (FPD)\u2019. It now reads: \u2018Representative traces of field potential in hES cell-derived cardiomyocytes highlighting inhibitory influence of CamKII with AIP of the IL-1\u03b2 effect on the field potential duration (FPD)\u2019.In the \u201cResults\u201d section the sentence that read \u201cWe, therefore, tested IL-1\u03b2 effects in human induced pluripotent stem-cell derived cardiomyocytes (hIPS-CM) using field potential duration (FPD) measurement. Our experiments revealed longer FPD on IL-1\u03b2 treated hIPS cell-CM, when compared with untreated hIPS-CM\u201d now reads \u201cWe, therefore, tested IL-1\u03b2 effects in human embryonic stem-cell derived cardiomyocytes (hES-CM) using field potential duration (FPD) measurement. Our experiments revealed longer FPD on IL-1\u03b2 treated hES-CM, when compared with untreated hES-CM\u201d.In the \u201cResults\u201d section the sentence that read \u201cAdditionally, in order to elucidate whether the CaMKII inhibition also could have a key role in human cells, hIPS-CM were exposed to IL-1\u03b2 in the absence or in the presence of a selective CaMKII inhibitor (autocamtide\u20142\u2014related inhibitory peptide (AIP)). In this setting, it was observed that the CaMKII inhibition was able to prevent the IL-1\u03b2-induced longer FPD in hIPS-CM \u201d. now reads: \u201cAdditionally, in order to elucidate whether the CaMKII inhibition also could have a key role in human cells, hES-CM were exposed to IL-1\u03b2 in the absence or in the presence of a selective CaMKII inhibitor (autocamtide-2-related inhibitory peptide (AIP)). In this setting, it was observed that the CaMKII inhibition was able to prevent the IL-1\u03b2-induced longer FPD in hES-CM \u201d.In the Acknowledgements, the sentence that read: \u201cWe thank Axiogenesis AG for providing hiPS-derived cardiomyocytes and Genentech, which authorized the use Nlrp3\u2212/\u2212 mice\u201d now reads: \u201cWe thank Axiogenesis AG (now Ncardia AG) for providing hES cell-derived cardiomyocytes and Genentech, which authorized the use Nlrp3\u2212/\u2212 mice\u201d. These errors have now been corrected in the HTML and PDF version of the article."}
+{"text": "Cell Death Discovery 10.1038/s41420-021-00799-0, published online 10 January 2022Correction to: The original version of this article unfortunately contained an error in an author name. Hridindu Roychowdhury was incorrectly spelled as \u201cRoychowdury\u201d. The correct spelling is \u201cRoychowdhury\u201d. The original article has been corrected."}
+{"text": "Gene, namely\u2329x\u232aq=elnqquation \u2211n=1Equation .m of Equation(32)n=eq-mapping and its inverse The q-natural numbers satisfy q-natural numbers satisfy q-prime numbers for For q-primes, we should keep the factorization concept in q-mapping from q-generalized product of q-numbers) between any pair of q-integers q-transform of In order to introduce the concept of Equation , let \u2329m\u232a in Ref.  (its Equ in Ref.  follows zability:\u2329m\u232aq\u2297q\u2329n\u232aIn order that the above operations are meaningful in q-integer by construction.The following definitions satisfy properties  and 34)34):35)\u2329\u2329(35)\u2329m\u232aqq-product q-transform Closedness of the operation:CommutativityAssociativityDistributivity of the product q-additionNeutral element of the q-productNeutral element of the By construction, it is clear that this definition of the q-transformed integers, corresponding to Equation . We canEquation  as(56)\u2211Equation .q-algebra introduced here is sufficient to write down the q-version of the Euler sum and the Euler product in q-representation formally asThe definitions of the q. q. of , 0\u2329x\u2297EquatEquation  of 8]))q-produA19) of [x\u2295qy\u2261eqlnA19) of [x\u2295qy\u2261eqlnquations 4 and (A1The properties \u201345) als als45) aons (see ).(64)\u03b6qIn the next Section we present details on a specific generalization.q-generalizations of the Riemann q-number defined in Equation \u232918q-integer numbers into q-prime numbers  achieveequality ), or somq-primes remains the same as that for z, all nontrivial zeros belong to specific single continuous curves, q-generalizing the Since the inequality relation between q-number, Equation  and and\u03b6(s) quations , are idesee Ref. ), the otpositive maximal Lyapunov exponent) [q-generalized, in [q-generalizations of prime numbers and of the q-random matrices and to weak chaos  ,18,19,20ized, in ,22,23,24"}
+{"text": "The footnote \u201ca\u201d should have only appeared once. This article has been corrected.1In the Original Investigation titled \u201cModel-Estimated Association Between Simulated US Elementary School\u2013Related SARS-CoV-2 Transmission, Mitigation Interventions, and Vaccine Coverage Across Local Incidence Levels,\u201d"}
+{"text": "Correction to: Scientific Reports 10.1038/s41598-022-05353-1, published online 07 February 2022The original version of this Article contained an error in Figure 6 where \u201cNo Forecast\u201d was incorrectly given as \u201cNo Rorecast\u201d.The original Figure The original Article has been corrected."}
+{"text": "Scientific Reports 10.1038/s41598-021-03582-4, published online 04 February 2022Correction to: The Supplementary Information file published with this Article contained a repeated error, where the term \u201cinactive\u201d was incorrectly given as \u201ccontrol.\u201d The original This error has now been corrected in the Supplementary Information file that accompanies the original Article.Supplementary Information."}
+{"text": "Correction to: Mol Neurodegeneration 16, 2 (2021)https://doi.org/10.1186/s13024-021-00424-9The original article  containsAll instances of \u2018Masuperdine\u2019 should thus be considered as \u2018Masupirdine\u2019."}
+{"text": "Scientific Reports 10.1038/s41598-020-79866-y, published online 12 January 2021Correction to: p (cm/s2)\u201d\u00a0and \u201cv\u2019m (cm/s2)\u201d. The correct and incorrect values appear below.The original version of this Article contained errors in Table 2, where the values for echocardiography category were incorrect for \u201cv\u2019Incorrect:Correct:"}
+{"text": "Scientific Reports 10.1038/s41598-017-13180-y, published online 16 October 2017Correction to: The original version of this Article contains errors in Equation\u00a05 where a negative sign is omitted.Equation\u00a05:should read:"}
+{"text": "This article has been corrected: The \u2018Antibodies and Compounds\u2019 section has been updated to read, \u201cThe following antibodies were purchased from Cell Signaling Technology : anti-Smad2 and loading control antibodies (antiGAPDH or anti-beta actin).\u201d In addition, the \u2018Quantitative reverse transcription-PCR (qRT-PCR)\u2019 section has been updated to read, \u201cPrimers for SERPINE, SMAD7, SNAI1, PLAUR, and MUC5AC were purchased\u2026.\u201d The authors declare that these corrections do not change the results or conclusions of this paper.810-824. https://doi.org/10.18632/oncotarget.26574Original article: Oncotarget. 2019; 10:810\u2013824."}
+{"text": "Correction to: Arthritis Res Ther 23, 72 (2021)https://doi.org/10.1186/s13075-021-02453-7Following publication of the original article , a typo The word \u201ctrail\u201d should be corrected to \u201ctrial\u201d.The original article has been corrected."}
+{"text": "Microsystems & NanoengineeringCorrection to: 10.1038/s41378-020-00190-6 published online 5 October 20201.The authors would like to add the below \u2018Conflict of interest\u2019 statement to this article\u201cArka Majumdar and Karl F. B\u00f6hringer are co-founders of Tunoptix Inc., which is commercializing technology discussed in this article.\u201dThe original article has been updated."}
+{"text": "Correction to: BMC Public Health 21, 565 (2021)https://doi.org/10.1186/s12889-021-10565-7It was highlighted that the original article  containeIncorrectMore regularly, \u201cday-to-day discrimination [ \u2026] comes in the form of \u201cmicro-aggressions\u201d such as [\u2026] misguided comments\u201d ( p.n.p.),CorrectMore regularly, \u201cday-to-day discrimination [\u2026] comes in the form of \u201cmicro-aggressions\u201d such as [\u2026] misguided comments\u201d ( p.n.p.),IncorrectThey regularly encounter \u201cnegative weight-related attitudes and beliefs demonstrated by stereotypes, rejection and prejudice\u201d ( p.347).CorrectThey regularly encounter \u201cnegative weight-related attitudes and beliefs that are manifested by stereotypes, rejection and prejudice\u201d ( p.347).https://www.apa.org/topics/racism-bias-discrimination/types-stress. The reference has been updated.Finally, with regard to reference , the lin"}
+{"text": "Bromelia karatas on STZ-NA-Induced Diabetic Rats\u201d [In the article titled \u201cPhytochemical Composition and Chronic Hypoglycemic Effect of ic Rats\u201d , the aut"}
+{"text": "Scientific Reports 10.1038/s41598-021-91657-7, published online 08 June 2021Correction to: a\u201d value for \u201cECOG PS\u201d was incorrectly assigned. The correct and incorrect values appear below.The original version of this Article contained errors in Table 4, where the P value was omitted and the \u201cAdjusted HR (95% CI)Incorrect:"}
+{"text": "Scientific Reports 10.1038/s41598-019-49470-w, published online 10 September 2019Correction to: The original version of this Article contained errors in Figure 3C, where the graph showing \u201cPI\u201d was a duplication of \u201cLPE\u201d.The original Figure The original Article has been corrected."}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-021-86232-z, published online 23 March 2021Correction to: Massilia antibiotica\u00a0sp. nov.\u2019, where,The original version of this Article contained an error in the Result and discussions section, under the subheading \u2018Description of\u00a0T 1T (=\u2009KACC 21627T\u2009=\u2009NBRC 114363T), was isolated from oil-contaminated experimental soil in Kyonggi University, Republic of Korea.\u201d\u201cThe type strain, TW-1now reads:T (=\u2009KACC 21627T\u2009=\u2009NBRC 114363T), was isolated from oil-contaminated experimental soil in Kyonggi University, Republic of Korea.\u201d\u201cThe type strain, TW-1The original Article has been corrected."}
+{"text": "Mycoplasma capricolum subsp. Capripneumoniae (Mccp) Protein in Contagious Caprine Pleuropneumonia (CCPP) Vaccine\u201d [In the article titled \u201cDevelopment and Evaluation of an Immuno-Capture Enzyme-Linked Immunosorbent Assay to Quantify the Vaccine\u201d , informa"}
+{"text": "Nature Communications 10.1038/s41467-021-21785-1, published online 12 March 2021.Correction to: The copyright holder for this article was incorrectly given as \u2018The Author(s)\u2019 but should have been \u2018Battelle Memorial Institute\u2019."}
+{"text": "Curcuma longa, Chaenomeles sinensis, and Zingiber officinale Contains Anti-AChE Compounds and Improves \u03b2-Amyloid-Induced Memory Impairment in Mice\u201d [In the article titled \u201cWS-5 Extract of in Mice\u201d , there wIn addition, the authors wish to replace The corrected Figures"}
+{"text": "Scientific Reports 10.1038/s41598-021-89681-8, published online 13 May 2021Correction to: The original version of this Article contained errors in the Abstract.\u201cAdults (\u2265\u200918 years) who suffered a non-traumatic OHCA between January 2013 and December 2018, without return of spontaneous circulation or extracorporeal cardiopulmonary resuscitation therapy were eligible.\u201dnow reads:\u201cAdults (\u2265 18 years) who suffered a non-traumatic OHCA between January 2013 and December 2018\u00a0with return of spontaneous circulation, but without extracorporeal cardiopulmonary resuscitation\u00a0therapy were eligible.\u201dThe original Article has been corrected."}
+{"text": "Scientific Reports 10.1038/s41598-021-86827-6, published online 20 April 2021Correction to: The original version of this Article contained an error in the copyright line.\u201c\u00a9 The Author(s) 2021\u201dnow reads:\u201c\u00a9 NATO 2021\u201dThe original Article has been corrected."}
+{"text": "Correction to:Neth Heart J 201910.1007/s12471-019-01331-xThe original version of this article unfortunately contained a\u00a0mistake. The authors of \u201cFirst report of a\u00a0comparative patient-oriented perspective on the use of non-vitamin\u2011K oral anticoagulants or vitamin\u2011K antagonists in atrial fibrillation: patients\u2019 experiences, side-effects and practical problems leading to non-adherence brillation: patients\u2019 experiences, side-effects and practical problems leading to non-adherence\u201d (Neth Heart\u00a0J (2019) 27:596\u2013604) advise that in order to address concerns raised by the purported holders of intellectual property interests in the Morisky Medication Adherence Scale (\u201cMMAS\u201d), Appendices\u00a01\u20133 that include the Morisky Medication Adherence Scale\u20118 Item questionnaire should be removed from the article. As a\u00a0result, these appendices were removed and the remaining appendices were renumbered. The original article has been corrected.Appendix 1 \u2013 Questionnaire | questions on practical issues (in Dutch); Appendix 2 \u2013 Table S1 | Adverse events reported in VKA-users and NOAC-users"}
+{"text": "In the article titled \u201cmiR-183-5p Is a Potential Molecular Marker of Systemic Lupus Erythematosus\u201d ["}
+{"text": "Scientific Reports 10.1038/s41598-021-89166-8, published online 07 May 2021Correction to: The original version of this\u00a0Article contained an error in the caption of vertical coordinate in Figure 4(b). As a result,\u201cAlpha diversity index (v)\u201dnow reads:\u201cRelative abundance of Roseburia (v)\u201d.The original Figure\u00a0The original Article has been corrected."}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-021-99151-w, published online 01 October 2021.Correction to: The original version of this Article contained errors in Figure 6, panel (a). Under the EO and EC conditions, \u201cSim-AB\u201d and \u201cSim-iSCI\u201d were incorrectly given as \u201cSi AB\u201d and \u201cSi SCI\u201d. The original Figure The original Article has been corrected."}
+{"text": "Scientific Reports 10.1038/s41598-020-79525-2, published online 11 January 2021Correction to: The original version of this Article contained errors in Tables 3 and 4.\u201cLow-density lipoprotein cholesterol\u201d was incorrectly given as \u201cLow-sensitivity C-reactive protein\u201d.\u201cHigh-density lipoprotein cholesterol\u201d was incorrectly given as \u201cHigh-sensitivity C-reactive protein\u201d.The incorrect and correct values appear below:Table 3Incorrect:Correct:Table 4Incorrect:Correct:The original Article has been corrected."}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-020-78978-9, published online 10 February 2021Correction to: The original version of this Article contained errors.In Table 1, the cohort 2 \u201cHatchery\u201d Exit and \u201cFarm\u201d Entry months were inadvertently switched with the \u201cFarm\u201d Exit month. The correct and incorrect values appear below.Incorrect:Correct:Additionally, the Data Availability section was incorrect.\u201cData will be made available in UBC\u2019s Strait of Georgia Data Centre (sogdatacentre.ca) prior to publication.\u201dnow reads:https://doi.org/10.5061/dryad.x95x69pjz.\u201d\u201cData are available on the Dryad data repository at The original Article has been corrected."}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-021-02245-8, published online 22 November 2021Correction to: Eutypa cf. lata\u201d was incorrectly given as \u201cEutypalata\u201d in the key. The original Figure The original version of this Article contained an error in Figure 11 where \u201cThe original Article has been corrected."}
+{"text": "Correction to: Glycoconjugate Journal.10.1007/s10719-021-09988-6The original article has been corrected. The correct article title should be \u201cGlyconanoparticles as tools to prevent antimicrobial resistance\u201d instead of \u201cGlyconanano particles as tools to prevent antimicrobial resistance."}
+{"text": "Lim-Soh\u2019s author listing. Jeremy W. Lim-Soh\u2019s full name with degree should read: \u201cJeremy W. Lim-Soh, MA\u201d instead of \u201cWeizhong J Lim, MIS\u201d. The ORCID ID was inadvertently omitted and has been instated.In the article \u201cAgeism Linked to Culture, not Demographics: Evidence From an 8-Billion-Word Corpus Across 20 Countries\u201d [The Journals of Gerontology: Series B, gbaa181,"}
+{"text": "Correction to: BMC Medical Education 21, 410 (2021)https://doi.org/10.1186/s12909-021-02829-yFollowing publication of the original article , the aut\u201eFig.\u00a02 Person ability (top) and item parameter (bottom) distribution for the HygiKo-SJT \u201cinstead of \u201eFig.\u00a01 Sample item \u201cand vice versa.The explaining text below the sample vignette incorrectly reads \u201eFigure\u00a01 Sample item \u201c(page 4 of 8)\u201cFigure\u00a02 Person ability (top) and item parameter (bottom) distribution for the HygiKo-SJT \u201c(page 6 of 8)The correct descriptions to Figs.\u00a01 and 2 are:The original article has been corrected."}
+{"text": "We previously showed that superoxide dismutase 1 (SOD1) loss induced various aging-like pathologies via oxidative damage due to the accumulation of O2\u2022\u2212 in mice. However, the pathological contribution of XO-derived O2\u2022\u2212 production to aging-like tissue damage induced by SOD1 loss remains unclear. To investigate the pathological significance of O2\u2022\u2212 derived from XOR in Sod1\u2212/\u2212 mice, we generated Sod1-null and XO-type- or XDH-type-knock-in (KI) double-mutant mice. Neither XO-type- nor XDH-type KI mutants altered aging-like phenotypes, such as anemia, fatty liver, muscle atrophy, and bone loss, in Sod1\u2212/\u2212 mice. Furthermore, allopurinol, an XO inhibitor, or apocynin, a nicotinamide adenine dinucleotide phosphate oxidase (NOX) inhibitor, failed to improve aging-like tissue degeneration and ROS accumulation in \u2212/\u2212Sod1 mice. These results showed that XOR-mediated O2\u2022\u2212 production is relatively uninvolved in the age-related pathologies in Sod1\u2212/\u2212 mice.Reactive oxygen species (ROS) metabolism is regulated by the oxygen-mediated enzyme reaction and antioxidant mechanism within cells under physiological conditions. Xanthine oxidoreductase (XOR) exhibits two inter-convertible forms (xanthine oxidase (XO) and xanthine dehydrogenase (XDH)), depending on the substrates. XO uses oxygen as a substrate and generates superoxide (O These include mitochondrial respiration, xanthine oxidoreductase (XOR), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) [In mammalian cells, several mechanisms or pathways are associated with the production of reactive oxygen species (ROS), including superoxide (Ose (NOX) ,2. RedoxSod1-deficient (Sod1\u2212/\u2212) mice show complete SOD1 protein loss and increased intracellular O2\u2022\u2212 as well as various aging-associated organ pathologies, such as hepatic carcinoma [2\u2022\u2212 metabolism in intracellular redox regulation.To better understand the intracellular redox regulation, gene modification studies have been performed. Accumulating evidence has demonstrated that arcinoma , fatty larcinoma , accelerarcinoma ,6, macularcinoma ,8, dry earcinoma ,10, hemoarcinoma , osteopearcinoma ,13, skinarcinoma ,15, skelarcinoma , luteal arcinoma , and altarcinoma . SOD1 loarcinoma . Therefo2\u2022\u2212-mediated type that uses oxygen and generates O2\u2022\u2212, while (2) xanthine dehydrogenase (XDH) is an NAD+-mediated type that uses NAD+ as a cofactor and leads to reduced nicotinamide adenine dinucleotide production but not the generation of O2\u2022\u2212 [2\u2022\u2212 production impairs organ integrity under pathological conditions. Since XOR-knockout mice die within six weeks after birth due to renal failure [2\u2022\u2212, but not the XDH-stable-type mice that do not generate O2\u2022\u2212, showed markedly increased tumor growth associated with the activation of macrophages [Mammalian XOR is ubiquitously expressed and catalyzes the conversion of hypoxanthine to xanthine and xanthine to uric acid. XOR can be found in two inter-convertible forms: (1) xanthine oxidase (XO) is an O of O2\u2022\u2212 . These t of O2\u2022\u2212 . Pharmac of O2\u2022\u2212 ,23, hype of O2\u2022\u2212 , and neu of O2\u2022\u2212 . These r failure , it is d failure . The XO-rophages . However2\u2022\u2212 in Sod1\u2212/\u2212 mice, we generated SOD1 and XO-locked type- or XDH-stable-type KI double-mutant mice and investigated the pathological association between XO-produced O2\u2022\u2212 and age-related pathologies caused by SOD1 deficiency. Furthermore, we administered XOR or NOX inhibitors to Sod1-deficient mice and investigated the protective effect of suppression of XO- and NOX-derived O2\u2022\u2212 on the aging-like phenotypes induced by oxidative stress.In the present study, to investigate the pathological significance of XOR-mediated O2\u2022\u2212 in vivo [\u2212/\u2212Sod1 mice, we generated \u2212/\u2212Sod1 XO-locked-type double-mutant mice . As with Sod1\u2212/\u2212 mice, the \u2212/\u2212Sod1 XO-locked-type double-mutant mice also showed reduced red blood cells and splenomegaly  to elucidate the pathological role in XO-derived O in vivo ,27. To cant mice . Sod1\u2212/\u2212nomegaly A,B. The \u2212/\u2212 mice C\u2013F.2\u2022\u2212. We, therefore, expected XDH-stable-type mutations to rescue the aging-like phenotypes via reduction of the O2\u2022\u2212-induced oxidative damage in Sod1\u2212/\u2212 mice. To further clarify the protective effect of XDH against aging-like pathologies, we also analyzed the tissue changes in Sod1\u2212/\u2212 XDH-stable-type (C995R) KI double-mutant mice . Unexpectedly, XDH-stable type did not improve the hemolytic anemia associated with the splenomegaly induced by SOD1 deficiency  mice, the administration of allopurinol did not change the body weight, suggesting no noticeable adverse effects , an XO inhibitor, via drinking water reduces serum uric acid by 50\u201390% for 2\u201314 weeks ,29,30. A effects A. Sod1\u2212/ WT mice A. Unexpe WT mice B\u2013F.Sod1\u2212/\u2212 male mice. As in female mice, allopurinol did not improve any of these pathologies in Sod1\u2212/\u2212 male mice , an NOX inhibitor, to Sod1\u2212/\u2212 mice. Apocynin treatment also failed to improve the systemic aging pathologies in Sod1\u2212/\u2212 male mice . These data strongly suggest that SOD1 does not physiologically catalyze O2\u2022\u2212 derived from XO, NOX, or NOS. Mitochondria produce ROS, including O2\u2022\u2212, through the electron transport chains of complexes I and III and release O2\u2022\u2212 to both sides of the inner mitochondrial membrane [2\u2022\u2212 in the intermembrane space and cytoplasm. In contrast, mitochondrial SOD2 mainly degrades O2\u2022\u2212 in the mitochondrial matrix. Paraquat generates mitochondrial O2\u2022\u2212 via complex I inhibition, resulting in mitochondrial dysfunction [Sod1\u2212/\u2212 mice [2\u2022\u2212 derived from mitochondria plays a major role in SOD1-mediated metabolism in cytoplasm. Other mechanisms of ROS production have also been reported, such as via cyclooxygenase, Fenton, and Haber\u2013Weiss reactions mainly generating peroxy and hydroxy radicals [The two types of KI mice for XO-locked- or XDH-stable TKI mutations are powerful tools for clarifying the pathological effects of XOR in various tissues. In contrast to the therapeutic effects of allopurinol on the tissue pathologies induced by acute injuries ,23,24,25\u2212/\u2212 mice . We also\u2212/\u2212 mice . In an imembrane . SOD1 ismembrane ,33,34, sfunction . Paraqua\u2212/\u2212 mice , suggestradicals . These rSod1\u2212/\u2212 XOR double-mutant mice should be clarified in future studies. Furthermore, Sod1\u2212/\u2212 mice exhibited various tissue pathologies, including anemia, fatty liver, muscle atrophy, bone loss, and skin atrophy , suggesting alteration of the tumorigenesis profiles by redox imbalance. Neither Sod1\u2212/\u2212 XO-locked-type nor Sod1\u2212/\u2212 XDH-stable-type double-mutant mice exhibited tumor formation in the liver or other tissues at 7\u201312 months of age (data not shown). At older ages, XO-locked- and XDH-stable-type mutations may alter tumorigenesis in Sod1\u2212/\u2212 mice. To clarify the contribution of XOR to tumorigenesis in Sod1\u2212/\u2212 mice, further analyses are needed to characterize the pathogenic macrophages and tumorigenesis in Sod1\u2212/\u2212 XO-locked-type and Sod1\u2212/\u2212 XDH-stable-type double-mutant mice.A high level of ROS leads to the activation of various oncogenic pathways . We preve stages . To clarSod1\u2212/\u2212 mice, suggesting that XOR-mediated O2\u2022\u2212 production contributes relatively little to the aging-like pathologies in Sod1\u2212/\u2212 mice. SOD1 may use O2\u2022\u2212 produced by physiological and biological systems, such as mitochondrial energy production. The production source of O2\u2022\u2212 may affect tissue homeostasis and the optimal therapeutic strategy in ROS-related diseases in humans. Our results provide new insight into the pathophysiological role of O2\u2022\u2212 in oxygen metabolism by SOD and XOR.In conclusion, KI mutations of XOR and inhibitors of XO or NOX did not alter the aging-like pathologies in Sod1\u2212/\u2212 mice were purchased from the Jackson Laboratory . Genotyping of the Sod1\u2212/\u2212 allele was performed via genomic polymerase chain reaction using genomic DNA isolated from the tail tip, as reported previously [eviously . Two Xdheviously , were kiSod1\u2212/\u2212 mice were given 1 mM allopurinol  and 2 mg/mL of apocynin  in drinking water daily for 8 weeks from 7 weeks of age  and 12 weeks of age .The WT and Red blood cells were measured using Celltac a . Bone mineral density of the whole body was measured using a PIXImus instrument . The thickness of the isolated back skin was measured using a PEACOCK dial thickness gauge .p-values were less than 0.05. All data are expressed as the mean \u00b1 standard deviation (SD).Statistical analyses were performed using one-way analysis of variance/Tukey\u2019s test for comparisons of three or more groups. Differences between data were considered significant when"}
+{"text": "Nature Communications 10.1038/s41467-022-28635-8, published online 24 February 2022.Correction to: The original version of this Article contained an error in Fig. 5. The titles for Fig. 5a and Fig. 5g were incorrectly given as \u201cSST ChrimsonR (gain \")\u201d and \u201cSST ChrimsonR (gain !)\u201d instead of \u201cSST ChrimsonR (gain \u2193)\u201d and \u201cSST ChrimsonR (gain \u2191)\u201d, respectively. This has been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports 10.1038/s41598-021-90566-z, published online 26 May 2021Correction to: The original version of this Article contained an error in Table 5.The value given for the category \u201cMale\u201d for the \u201cHADS-A\u201d variable, \u201c0.30\u201d, was incorrectly given as \u201c0.00.\u201dThe incorrect and correct values are given below.Incorrect:Correct:The original Article has been corrected."}
+{"text": "Andrenabarbareae , A.clarkella , A.fulvicornis , A.intermedia , A.lapponica , A.pandellei , A.paucisquama , A.simillima , Panurginusherzi , Epeoloidescoecutiens , Nomadaleucophthalma , Chelostomanasutum , Hoplitisclaviventris , and Dasypodapyrotrichia . Almost all the species recorded so far in Serbia belong to the West-Palaearctic biogeographical region, except Megachilesculpturalis , which is an alien invasive species native to East Asia. According to the European Red List of bees, 221 species listed in this paper were assessed as Data Deficient; threatened species mostly belong to the families Apidae with 13 species, Colletidae with eight species, and Halictidae with five species. This study contributes to the knowledge of the distribution of bee species in Europe. The present work provides a baseline for future research of wild bee diversity in Serbia and neighbouring regions at the local and regional levels, and a basis for their conservation.The current work represents summarised data on the bee fauna in Serbia from previous publications, collections, and field data in the period from 1890 to 2020. A total of 706 species from all six of the globally widespread bee families is recorded; of the total number of recorded species, 314 have been confirmed by determination, while 392 species are from published data. Fourteen species, collected in the last three years, are the first published records of these taxa from Serbia:  Hymenoptera: Apoidea: Anthophila in the Balkan countries derives from the late 19th century, from the period of the Austro-Hungarian Empire. At that time, scientists were collecting data on the wild bee fauna while travelling through the area of today\u2019s Balkan countries, or they researched parts of the countries where they lived. The borders and names of the Balkan countries have changed several times since then. Therefore, in the present paper, the localities are shown within the current borders of the Republic of Serbia.The first available data on the faunistic research of Apoidea. The most reliable and comprehensive publication on the bee fauna of Serbia was published by Hymenoptera: Apoidea: Anthophila of Yugoslavia, including new data on bee fauna and sites for 114 bee species, which were recorded in Serbia. The earliest publication, which provided the data on the bee fauna of Serbia is by Lasioglossummarginatum  , L.interruptum  ), L.malachurum  ), H.sajoi , H.maculatus , H.asperulus , Seladoniakessleri  , Osmiabicornis Linnaeus, 1758, O.bicolor , O.rufohirta , O.bidentata , Xylocopaviolacea , X.valga , X.iris Christ, 1791 , Bombuspascuorum Scopoli, 1763 ), Apismellifera , Anthophoraplumipes Pallas, 1772 ), A.plagiata Illiger, 1806 ), A.salviae  , A.pubescens , Eucera  lyncea ), Eucera  nana ), Systrophaplanidens , S.curvicornis , Euceraexcisa , Megachileericetorum , and Ceratina spp. , H.quadricinctus , H.scabiosae , Megachilealbisecta Klug, 1817  , Anthophoraplagiata (as A.parietina), and A.salviae (as A.crinipes) . Grozdani\u0107 and Mu\u010dalica researched the fauna of Hymenoptera across former Yugoslavia; Mu\u010dalica collected insects for 33 years (1965\u20131997) in the area of Serbia and Grozdani\u0107 collected insects in the period from 1963 to 1972. Both collections are preserved in the Natural History Museum in Belgrade. The present paper lists 181 bee species recorded in Serbia by the above authors. Kruni\u0107 studied two important wild bee pollinators of Serbian orchards, namely Osmiacornuta  and O.bicornis ) in all aspects of their life history such as diapause, overwintering, distribution, population management, etc.  (Osmiacornuta and O.bicornis (as O.rufa), from the environmental, conservation, morphology, and management aspects (Megachilidae family of Fru\u0161ka Gora. Stanisavljevi\u0107 and Tomovi\u0107 (2006) presented the results of alfalfa seed production with the use of Megachilerotundata in Serbian agricultural farms. Mudri-Stojni\u0107 studied bee fauna in agro-ecosystems of Vojvodina province from 2011. Markov studied bee fauna in protected areas of Vojvodina province  , b. Mu\u010darinipes) , 1997. Mnt, etc. \u2013d. The os, 1793) , 1997. K aspects , b, 2013province  and theiprovince . \u0110uki\u0107 sThe importance of bees in terrestrial ecosystems, as well as their ecosystem role in the process of pollination of agricultural crops and wild plants, is widely known. In many European countries, Red Data Books or Red Lists of bees have been produced at the national level. Some European countries have developed specific national actions in order to enhance bee populations and to arrest decline, introduced legislation with the aim of legally protecting all or some species of bees, and/or produced checklists of bees. For some Balkan countries, such as Serbia, data on the diversity of bees are scarce. Among the reasons for such a situation are an insufficient number of wild bee experts and the absence of proper collections. Up-to-date entomological research programmes of wild bees have not been spatially systematic, so certain areas of Serbia have been studied more, while others less. Although there is clear evidence of a decline in pollinators diversity and abundance across Europe , there aThe present study summarises for the first time all the available records of species of wild bees in Serbia. This paper is not intended as a national checklist of bees, since there are undoubtedly more species yet to be found. The aims of this study are: 1) to review the records on the bee fauna, according to bibliographic sources known to the authors, 2) to present some more recent observations, and finally 3) to provide an updated preliminary list of the species of bees occurring in Serbia. The major purpose of this article is to broaden the knowledge of bee diversity in Serbia and pave the way for future research of wild bee fauna at local and regional levels. Another important aim is to improve an understanding of the status and trends of European pollinators.Serbia is situated in central and southeast Europe, mostly in the central Balkan peninsula, while its northern part spreads over the southern belt of the Pannonian Plain. The country\u2019s total area is 88,361 km\u00b2 . The main geographic units in Serbia are the Pannonian Region in the north, which covers a third of the country, the Peripannonian Region in the central part of the country, which chiefly consists of hills traversed by rivers, and the mountain and basin region which are dominant in the south. The Carpathian Mountains and the Balkan Mountains stretch in the north-south direction through east Serbia. The Dinaric Arc stretches in the west and southwest. The climate of Serbia is under the influences of the landmass of Eurasia, the Atlantic Ocean, and the Mediterranean Sea. It classifies as a warm-humid continental or humid subtropical climate. In the north of the country, the climate is more continental, whereas south and southeast Serbia are influenced by the Mediterranean climate . In the ASCI; 42 Important Bird Areas \u2013 IBA; 61 Important Plant Areas \u2013 IPA; 40 Prime Butterfly Areas \u2013 PBA; ten Ramsar sites. The ecological network also includes other spaces and places that have yet to be spatially identified . Agricultural production on annual crops is mostly present in the Pannonian Plain. Serbia produces various agricultural products, mostly grains, fruits, and vegetables. According to the FAOSTAT, Serbia is among the top five world producers of raspberries and plums, which are mainly produced in the southwest. Agricultural landscapes occupy 63.7% of the territory .Serbia is a country with a number of rich ecosystems, and species diversity of many groups of organisms is high and contributes to a significant part of Europe\u2019s biodiversity. According to previous research, in the territory of the Republic of Serbia there are: 39% of the European vascular flora, 74% of the European bird fauna, 67% of the European mammal fauna, 51% of the European fish fauna, and 49% of the European reptile and amphibian fauna . ConservHymenoptera: Apoidea: Anthophila) by This paper represents a list of bee species in Serbia based on the compiled data known to the authors, gathered from available entomological collections and literature sources between 1890 and 2020, and our own faunistic studies in the decade 2010\u20132020. Therefore, it includes previously published and unpublished data, supplied by different specialists, as well as some recent records from the authors of this paper. In total, more than 100 publications were examined for relevant records. Additionally, the present list was based on reviewing a database from the online Checklist of Western Palaearctic Bees ;AZ coll. Aleksandra Zatezalo collection of the Institute for Nature Conservation of Serbia, Belgrade, Serbia (determined by Zsolt J\u00f3zan);FSUNSDepartment of Biology and Ecology, Faculty of Sciences, University of Novi Sad, Novi Sad, Serbia;SG coll. Simeun Grozdani\u0107 collection of the NHMB , Serbia;ZM coll. Zoran Mu\u010dalica collection of the NHMB, Serbia.FSUNS. The material from the FSUNS entomological collection were determined by Zsolt J\u00f3zan. The cited Andrena  and Bombus  were not published in the paper by Halictus sensu lato species), and V. Popov (Bombus species). This collection was destroyed during World War II. The publication by The cited PhD thesis of A map of Serbia Fig.  shows thth century are marked with an asterisk (*). Among the species confirmed by determination of studied material, examined specimens are marked with the double oblique hyphen (\u2e17) and non-marked species represent records based only on literature data. The black small squares (\u25aa) mark species for which the only source of occurrence in Serbia is the Checklist of the Western Palaearctic Bees . Data about the new material examined are given for the specimens that represent the first published records of species for Serbia.tic Bees . At the Apidae 226 species (91/135), Megachilidae 148 species (62/86), Halictidae 138 species (73/65), Andrenidae 112 species (68/44), Colletidae 69 species (14/55), and Mellitidae 13 species (6/7). The present list includes 14 species with no previously published records for Serbia: Andrenabarbareae , A.clarkella , A.fulvicornis , A.intermedia , A.lapponica , A.pandellei , A.paucisquama , A.simillima , Panurginusherzi , Epeoloidescoecutiens , Nomadaleucophthalma , Chelostomanasutum , Hoplitisclaviventris , and Dasypodapyrotrichia .The list of bees in Serbia presented consists of six families, 58 genera, and 706 species, recorded during the past 130 years. Of the total number of the recorded species, 314 have been confirmed by determination, while 392 species are from literature data. The reported families with the numbers of species (confirmed by determination/based only on literature data) are: The diversity and proportional representation of bee families are given in Table Andrena Fabricius, 1775 (104 species)\u25aa Andrena aberrans Eversmann, 1852 in Kuhlmann et al. (2020). [NT]\u2e17 Andrena aeneiventris Morawitz, 1872 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); Vorgin (1955); Mocs\u00e1ry (1897). [LC]* Andrena albopunctata  in Mocs\u00e1ry (1897); as Andrena funebris  in Korlevi\u0107 (1890). [LC]\u2e17 Andrena alfkenella Perkins, 1914 in Mudri-Stojni\u0107 (2018); Lebedev (1931). [DD]Andrena argentata Smith, 1844 in Vorgin (1955); Mocs\u00e1ry (1897). [DD]Andrena atrata Friese, 1887 in Vorgin (1918); Mocs\u00e1ry (1897); as Andrena bicarinata  in Vorgin (1955); Lebedev (1931). [DD]\u2e17 Andrena barbareae Panzer, 1805 New material examined: 1 \u2640; Vlasina, Veliki \u010cemernik; 42.7368\u00b0N, 22.2723\u00b0E; 25 May 2019; M. Vuji\u0107 leg.; Andrej Gogala det.; A\u0110 coll. 1 \u2640; Vlasina, Vrtop; 42.7904\u00b0N, 22.372\u00b0E; 20 Jul. 2019; A. \u0110uki\u0107 leg.; Andrej Gogala det.; A\u0110 coll. [DD]Andrena barbilabris  as Andrena sericea Smith, 1791 in Vorgin (1955); as Andrena albicrus  in Mocs\u00e1ry (1897). [DD]\u2e17 Andrena bicolor Fabricius, 1775 in Kuhlmann et al. (2020); as Andrena gwynana  in \u017divojinovi\u0107 (1950); Lebedev (1931); A\u0110 coll [LC]Andrena bimaculata  in Kuhlmann et al. (2020); \u017divojinovi\u0107 (1950); Lebedev (1931). [DD]Andrena brumanensis Friese, 1899 in Kuhlmann et al. (2020); as Andrena clypeata Brull\u00e9, 1832 in \u017divojinovi\u0107 (1950). [LC]Andrena bucephala Stephens, 1846 in Kuhlmann et al. (2020); \u017divojinovi\u0107 (1950); Lebedev (1931). [DD]\u2e17 Andrena carantonica P\u00e9rez, 1902 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016); ZM coll.; as Andrena jacobi Perkins, 1921 in Lebedev (1931). [DD]\u2e17 Andrena chrysopyga Schenck, 1853 in Kuhlmann et al. (2020); Vorgin ; Lebedev (1931); ZM coll. [DD]\u25aa Andrena cineraria  in Kuhlmann et al. (2020). [LC]\u2e17 Andrena clarkella  New material examined: 1 \u2640; Vlasina Rid; 42.7253\u00b0N, 22.3284\u00b0E; 21 Jul. 2019; A. \u0110uki\u0107 leg.; Andrej Gogala det.; A\u0110 coll. [DD]* Andrena coitana  as Andrena shawella  in Mocs\u00e1ry (1897). [DD]Andrena colletiformis Morawitz, 1874 in Kuhlmann et al. (2020); Apfelbeck (1896). [DD]\u2e17 Andrena combaella Warncke, 1966 in Mudri-Stojni\u0107 (2018). [DD]\u2e17 Andrena combinata  in Kuhlmann et al. (2020); Lebedev (1931); Mocs\u00e1ry (1897); Apfelbeck (1896); ZM coll. [DD]\u25aa Andrena comta Eversmann, 1852 in Kuhlmann et al. (2020). [EN]\u2e17 Andrena confinis St\u00f6ckhert, 1930 in Markov (2017); Markov et al. (2016); \u017divojinovi\u0107 (1950).\u2e17 Andrena congruens Schmiedeknecht, 1884 in Kuhlmann et al. (2020); A\u0110 coll. [LC]\u2e17 Andrena cordialis Morawitz, 1877 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016). [DD]\u2e17 Andrena curvana Warncke, 1965 in Markov (2017); Markov et al. (2016). [DD]\u25aa Andrena decipiens Schenck, 1861 in Kuhlmann et al. (2020). [DD]Andrena denticulata  in Lebedev (1931). [DD]\u2e17 Andrena dorsalis Brull\u00e9, 1832 in Kuhlmann et al. (2020); ZM coll. [DD]Andrena dorsata  in Kuhlmann et al. (2020); \u017divojinovi\u0107 (1950); Lebedev (1931); as Andrena dubitata Schenck, 1870 in Vorgin (1955); Apfelbeck (1896). [DD]Andrena erythrocnemis Morawitz, 1870 in Lebedev (1931); Mocs\u00e1ry (1897). [DD]* Andrena fimbriata Brull\u00e9, 1832 in Mocs\u00e1ry (1897). [DD]\u2e17 Andrena flavipes Panzer, 1799 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); Mudri-Stojni\u0107 et al. (2012); Grozdani\u0107 (1971b); Vorgin (1955); \u017divojinovi\u0107 (1950); Lebedev (1931); AZ coll.; ZM coll.; also as Andrena extricata Smith, 1849 in Apfelbeck (1896); as Andrena extricata in Mocs\u00e1ry (1897); Korlevi\u0107 (1890); as Andrena fulvicrus Dufour, 1841 in Petrik (1958). [LC]\u2e17 Andrena florea Fabricius, 1793 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016); Apfelbeck (1896); as Andrena rosae var. austriaca Schmied. in \u017divojinovi\u0107 (1950); as Andrena austriaca Panzer, 1798 in Mocs\u00e1ry (1897). [DD]\u2e17 Andrena fulvago  in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); Mudri-Stojni\u0107 et al. (2012); Vorgin (1955); Lebedev (1931). [DD]\u2e17 Andrena fulvicornis Schenck, 1853 New material examined: 1 \u2640; Beo\u010din, Fru\u0161ka gora, \u010casorske livade; 45.1894\u00b0N, 19.7451\u00b0E; 15 Jun. 2018; S. Mudri-Stojni\u0107 leg.; Zsolt J\u00f3zan det.; FSUNS. [DD]* Andrena fuscosa Erichson, 1835 as Andrena ephippium Spinola, 1838 in Mocs\u00e1ry (1897). [DD]\u2e17 Andrena gelriae van der Vecht, 1927 in Markov (2017); Markov et al. (2016); AZ coll. [DD]\u2e17 Andrena gravida Imhoff, 1832 in Kuhlmann et al. (2020); Lebedev (1931); A\u0110 coll.; AZ coll.; ZM coll. [DD]Andrena grozdanici Osytshnjuk, 1975 in Kuhlmann et al. (2020); Mu\u010dalica (1984). [DD]\u2e17 Andrena haemorrhoa  in Kuhlmann et al. (2020); A\u0110 coll.; AZ coll.; as Andrena albicans auct. nec M\u00fcller in \u017divojinovi\u0107 (1950); Lebedev (1931). [LC]\u2e17 Andrena hattorfiana  in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); Mudri-Stojni\u0107 et al. (2012); Lebedev (1931); Vorgin (1918); Mocs\u00e1ry (1897); Apfelbeck (1896); A\u0110 coll. [NT]Andrena hedikae Jaeger, 1934 in Kuhlmann et al. (2020); Vorgin (1955). [DD]\u2e17 Andrena humilis Imhoff, 1832 in Kuhlmann et al. (2020); Lebedev (1931); in Apfelbeck (1896); A\u0110 coll.; as Andrena fulvescens Smith, 1847 in Vorgin . [DD]\u25aa Andrena hungarica Friese, 1887 in Kuhlmann et al. (2020). [DD]Andrena hypopolia Schmiedeknecht, 1884 in Kuhlmann et al. (2020); Vorgin ; Mocs\u00e1ry (1897); Korlevi\u0107 (1890). [DD]\u2e17 Andrena impunctata P\u00e9rez, 1895 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016). [LC]\u2e17 Andrena intermedia Thomson, 1870 New material examined: 1 \u2640; Vlasina, Veliki \u010cemernik; 42.7368\u00b0N, 22.2723\u00b0E; 21 Jul. 2019; M. Vuji\u0107 leg.; Andrej Gogala det.; A\u0110 coll. [LC]\u2e17 Andrena labialis  in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); Grozdani\u0107 (1970); Vorgin ; \u017divojinovi\u0107 (1950); Lebedev (1931); Mocs\u00e1ry (1897); Apfelbeck (1896); AZ coll.; ZM coll. [DD]\u2e17 Andrena labiata Fabricius, 1781 in Lebedev (1931); ZM coll. [DD]\u25aa Andrena lagopus Latreille, 1809 in Kuhlmann et al. (2020). [LC]\u2e17 Andrena lapponica Zetterstedt, 1838 New material examined: 1 \u2640; Vlasina, Gad\u017eini; 42.7378\u00b0N, 22.3042\u00b0E; 25 May 2019; A. \u0110uki\u0107 leg.; Andrej Gogala det.; A\u0110 coll. [LC]\u2e17 Andrena lathyri Alfken, 1899 in Kuhlmann et al. (2020); Grozdani\u0107 (1970); ZM coll. [DD]\u2e17 Andrena limata Smith, 1853 in Mudri-Stojni\u0107 (2018); as Andrena pectoralis Schmiedeknecht, 1883 in Vorgin (1955); Mocs\u00e1ry (1897); Korlevi\u0107 (1890). [DD]Andrena limbata Eversmann, 1852 in Lebedev (1931). [DD]Andrena marginata Fabricius, 1776 in Kuhlmann et al. (2020); Lebedev (1931); Mocs\u00e1ry (1897). [DD]\u25aa Andrena mehelyi Alfken, 1936 in Kuhlmann et al. (2020). [DD]\u2e17 Andrena minutula  in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016); Lebedev (1931); A\u0110 coll.; as Andrena parvula  in Apfelbeck (1896). [DD]\u2e17 Andrena minutuloides Perkins, 1914 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); Lebedev (1931). [DD]\u2e17 Andrena mocsaryi Schmiedeknecht, 1884 in Markov (2017); Markov et al. (2016). [LC]Andrena morio Brull\u00e9, 1832 in Kuhlmann et al. (2020); Petrik (1958); Vorgin (1955); Lebedev (1931); Mocs\u00e1ry (1897); Apfelbeck (1896). [DD]\u2e17 Andrena nasuta Giraud, 1863 in Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); Mudri-Stojni\u0107 et al. (2012); Vorgin (1918); Mocs\u00e1ry (1897). [DD]Andrena nigroaenea  in Kuhlmann et al. (2020); Vorgin (1955). [LC]\u2e17 Andrena nitida  in Kuhlmann et al. (2020); Vorgin (1955); Mocs\u00e1ry (1897); A\u0110 coll. [LC]\u2e17 Andrena nitidiuscula Schenck, 1853 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov et al. (2016); Mudri-Stojni\u0107 et al. (2012); Mocs\u00e1ry (1897); as Andrena lucens Imhoff, 1868 in Vorgin ; Korlevi\u0107 (1890). [LC]\u25aa Andrena niveata Friese, 1887 in Kuhlmann et al. (2020). [DD]Andrena nobilis Morawitz, 1874 in Kuhlmann et al. (2020); Vorgin (1955). [DD]\u2e17 Andrena oralis Morawitz, 1876 in Markov (2017); Markov et al. (2016); Vorgin (1955). [DD]\u2e17 Andrena ovatula  in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); Mudri-Stojni\u0107 et al. (2012); \u017divojinovi\u0107 (1950); AZ coll.; also as Andrena albofasciata Thomson, 1871 in Lebedev (1931); as Andrena afzeliella  in Petrik (1958). [NT]\u2e17 Andrena pandellei P\u00e9rez, 1895 New material examined: 1 \u2642; Novi Sad, Kameni\u010dki park; 45.2299\u00b0N, 19.8518\u00b0E; 20 Jun. 2018; A. \u0110uki\u0107 leg.; Zsolt J\u00f3zan det.; A\u0110 coll. [LC]\u2e17 Andrena paucisquama Noskiewicz, 1924 New material examined: 1 \u2640; Fru\u0161ka gora, Manastir Grgeteg; 45.1383\u00b0N, 19.9044\u00b0E; 20 May 2018; S. Mudri-Stojni\u0107 leg.; Zsolt J\u00f3zan det.; FSUNS. [DD]\u2e17 Andrena pilipes Fabricius, 1781 in Kuhlmann et al. (2020); Petrik (1958); Vorgin (1918); Korlevi\u0107 (1890); ZM coll.; as Andrena carbonaria  in Vorgin (1955); Lebedev (1931); Mocs\u00e1ry (1897); Apfelbeck (1896). [LC]\u2e17 Andrena polita Smith, 1847 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); Mudri-Stojni\u0107 et al. (2012); Lebedev (1931). [LC]\u2e17 Andrena potentillae Panzer, 1809 in ZM coll. [DD]\u2e17 Andrena propinqua Schenck, 1853 in Kuhlmann et al. (2020); Lebedev (1931); Mocs\u00e1ry (1897); ZM coll. [DD]\u2e17 Andrena proxima  in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016); Vorgin (1955); \u017divojinovi\u0107 (1950); Lebedev (1931); Apfelbeck (1896). [DD]* Andrena pyropygia Kriechbaumer, 1873 in Mocs\u00e1ry (1897). [LC]\u2e17 Andrena rhenana Stoeckhert, 1930 in ZM coll. [DD]\u2e17 Andrena rosae Panzer, 1801 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); Mudri-Stojni\u0107 et al. (2012); Lebedev (1931). [DD]\u25aa Andrena rufula Schmiedeknecht, 1883 in Kuhlmann et al. (2020). [LC]\u25aa Andrena schencki Morawitz, 1866 in Kuhlmann et al. (2020). [DD]\u25aa Andrena schlettereri Friese, 1896 in Kuhlmann et al. (2020). [DD]Andrena scita Eversmann, 1852 in Kuhlmann et al. (2020); Vorgin ; Mocs\u00e1ry (1897); Apfelbeck (1896). [DD]\u2e17 Andrena seminuda Friese, 1896 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016); as Andrena setigera Alfken, 1911 in Vorgin (1955). [DD]Andrena sericata Imhoff, 1868 in Kuhlmann et al. (2020); Apfelbeck (1896). [DD]\u2e17 Andrena simillima Smith, 1851 New material examined: 1 \u2640; Vlasina, Delnice-Ljote; 42.6933\u00b0N, 22.3176\u00b0E; 22 Jul. 2019; A. \u0110uki\u0107 leg.; Andrej Gogala det.; A\u0110 coll. [LC]\u2e17 Andrena simontornyella Noskiewicz, 1939 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016). [LC]\u2e17 Andrena subopaca Nylander, 1848 in Lebedev (1931); A\u0110 coll. [LC]\u2e17 Andrena suerinensis Perkins 1914 in ZM coll. [DD]\u2e17 Andrena symphyti Schmiedeknecht, 1883 in Markov (2017); Markov et al. (2016); AZ coll.; ZM coll. [DD]\u2e17 Andrena taraxaci Giraud, 1861 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Schwenninger (2015); Grozdani\u0107 (1971b); Grozdani\u0107 and Vasi\u0107 (1965c); Vorgin (1955); Lebedev (1931); ZM coll. [DD]\u2e17 Andrena tarsata Nylander, 1848 in Vorgin (1918); ZM coll. [DD]\u2e17 Andrena thoracica  in Mudri-Stojni\u0107 (2018); Vorgin (1955); Lebedev (1931); Mocs\u00e1ry (1897); Apfelbeck (1896). [DD]\u2e17 Andrena tibialis  in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Vorgin (1955); Apfelbeck (1896). [LC]\u2e17 Andrena trimmerana  in Lebedev (1931); ZM coll. [DD]Andrena truncatilabris Morawitz, 1877 in Kuhlmann et al. (2020); Vorgin ; Lebedev (1931); Mocs\u00e1ry (1897); Apfelbeck (1896). [DD]\u2e17 Andrena ungeri Mavromoustakis, 1952 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); Mudri-Stojni\u0107 et al. (2012). [LC]\u2e17 Andrena vaga Panzer, 1799 in Lebedev (1931); ZM coll. [LC]\u2e17 Andrena variabilis Smith, 1853 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016); Vorgin (1955); Lebedev (1931); AZ coll. [DD]Andrena varians  in Lebedev (1931); Vorgin (1955). [LC]Andrena ventralis Imhoff, 1832 in Kuhlmann et al. (2020); Lebedev (1931). [DD]\u2e17 Andrena ventricosa Dours, 1873 in Markov (2017); Markov et al. (2016); Vorgin (1918). [DD]\u2e17 Andrena viridescens Viereck, 1916 in Lebedev (1931); ZM coll. [DD]Andrena wilkella  in Vorgin (1955); as Andrena convexiuscula Kirby, 1802 in Petrik (1958); Mocs\u00e1ry (1897); Apfelbeck (1896). [DD]Camptopoeum Spinola, 1843 (2 species)\u2e17 Camptopoeum frontale Fabricius 1804 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Mudri-Stojni\u0107 et al. (2012); Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1918); Mocs\u00e1ry (1897). [DD]Camptopoeum friesei Mocs\u00e1ry 1894 in Grozdani\u0107 (1971b); Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); Mocs\u00e1ry (1897). [LC]Clavipanurgus Warncke, 1972 (1 species)\u25aa Clavipanurgus sculpturatus Morawitz 1872 in Kuhlmann et al. (2020). [DD]Melitturga Latreille, 1809 (1 species)\u2e17 Melitturga clavicornis Latreille 1808 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); Mudri-Stojni\u0107 et al. (2012); Petrik (1958); Mocs\u00e1ry (1897). [NT]Panurginus Nylander, 1848 (2 species)Panurginus labiatus Eversmann 1852 in Kuhlmann et al. (2020); Lebedev (1931). [DD]\u2e17 Panurginus herzi Morawitz, 1892 New material examined: 1 \u2640; Vlasina, Vrtop; 42.7904\u00b0N, 22.372\u00b0E; 20 Jul. 2019; A. \u0110uki\u0107 leg.; Andrej Gogala det.; A\u0110 coll. 1 \u2640; Vlasina Rid; 42.7253\u00b0N, 22.3284\u00b0E; 22\u201323 Jul. 2019; A. \u0110uki\u0107 leg.; Andrej Gogala det.; A\u0110 coll. [DD]Panurgus Panzer, 1806 (2 species)\u2e17 Panurgus banksianus Kirby 1802 in Kuhlmann et al. (2020); A\u0110 coll.; ZM coll. [LC]\u2e17 Panurgus calcaratus Scopoli, 1763 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); Lebedev (1931); Mocs\u00e1ry (1897); Apfelbeck (1896); A\u0110 coll.; as Panurgus lobatus  in Petrik (1958). [LC]Amegilla Friese, 1897 (5 species)\u2e17 Amegilla albigena Lepeletier, 1841 in Kuhlmann et al. (2020); ZM coll.; as Anthophora albigena Lepeletier, 1841 in Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin ; Mocs\u00e1ry (1897). [LC]\u2e17 Amegilla garrula Rossi, 1790 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016); as Anthophora garrula Rossi, 1790 in Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); as Anthophora garrulus in Mocs\u00e1ry (1897). [LC]Amegilla magnilabris (Fedtschenko 1875) as Anthophora magnilabris Fedtschenko, 1875 in Rafajlovi\u0107 and Sele\u0161i (1958); Mocs\u00e1ry (1897). [DD]\u2e17 Amegilla quadrifasciata de Villers, 1789 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Mudri-Stojni\u0107 et al. (2012); Stanisavljevi\u0107 (2000); ZM coll.; as Anthophora quadrifasciata  in Petrik (1958); Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931); as Anthophora quadrifasciatus in Mocs\u00e1ry (1897). [DD]\u2e17 Amegilla salviae Morawitz, 1876 in Kuhlmann et al. (2020); ZM coll. [DD]Ammobatoides Radoszkowski, 1867 (1 species)\u2e17 Ammobatoides abdominalis  in ZM coll. [EN]Ammobates Latreille, 1809 (2 species)* Ammobates punctatus  in Mocs\u00e1ry (1897). [LC]* Ammobates vinctus Gerst\u00e4cker, 1869 in Mocs\u00e1ry (1897). [LC]Anthophora Latreille, 1803 (18 species)Anthophora aestivalis Panzer 1801 in Kuhlmann et al. (2020); Lebedev (1931). [LC]\u25aa Anthophora atroalba Lepeletier 1841 in Kuhlmann et al. (2020). [DD]\u2e17 Anthophora bimaculata Panzer, 1798 in Kuhlmann et al. (2020); Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931); Vorgin (1918); ZM coll.; as Saropoda bimaculata in Petrik (1958); as Anthophora bimaculatus in Mocs\u00e1ry (1897). [LC]\u25aa Anthophora canescens Brull\u00e9 1832 in Kuhlmann et al. (2020). [DD]Anthophora crassipes Lepeletier, 1841 in Lebedev (1931). [DD]\u25aa Anthophora dalmatica P\u00e9rez 1902 in Kuhlmann et al. (2020). [DD]\u25aa Anthophora dufourii Lepeletier 1841 in Kuhlmann et al. (2020). [DD]\u2e17 Anthophora fulvitarsis Brull\u00e9 1832 in ZM coll. [DD]\u2e17 Anthophora furcata Panzer, 1798 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016); Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931); A\u0110 coll.; ZM coll.; as Anthophora furcatus in Mocs\u00e1ry (1897). [LC]\u25aa Anthophora orientalis Morawitz 1877 in Kuhlmann et al. (2020). [DD]\u2e17 Anthophora plagiata Illiger, 1806 in Kuhlmann et al. (2020); as Anthophora parietina  in Mu\u010dalica ; Grozdani\u0107 (1971b); Grozdani\u0107 and Stevanovi\u0107 (1965); Grozdani\u0107 and Vasi\u0107 (1965b); Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1918); ZM coll.; Anthophora parietinus in Mocs\u00e1ry (1897). [LC]\u2e17 Anthophora plumipes Pallas, 1772 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016); A\u0110 coll.; ZM coll.; as Anthophora acervorum  in Grozdani\u0107 (1971b); Grozdani\u0107 and Vasi\u0107 ; Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); Lebedev (1931). [LC]Anthophora podagra Lepeletier, 1841 in Kuhlmann et al. (2020); as Anthophora podagrus in Mocs\u00e1ry (1897). [DD]\u2e17 Anthophora pubescens Fabricius 1781 in Kuhlmann et al. (2020); Grozdani\u0107 and Radivojevi\u0107 (1972); Grozdani\u0107 (1971b); Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931); Mocs\u00e1ry (1897); SG coll. [DD]Anthophora quadrimaculata Panzer, 1798 in Kuhlmann et al. (2020); as Anthophora vulpina  in Rafajlovi\u0107 and Sele\u0161i (1958); as Anthophora vulpinusMocs\u00e1ry (1897). [DD]\u2e17 Anthophora retusa Linnaeus, 1758 in Kuhlmann et al. (2020); Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931); ZM coll.; as Anthophora retusus in Mocs\u00e1ry (1897). [LC]\u25aa Anthophora robusta Klug 1845 in Kuhlmann et al. (2020). [DD]\u2e17 Anthophora salviae  in Kuhlmann et al. (2020); Vorgin ; Lebedev (1931); Mocs\u00e1ry (1897); Korlevi\u0107 (1890); also as Anthophora crinipes Smith, 1854 in Rafajlovi\u0107 and Sele\u0161i (1958); as Anthophora crin ipes in Markov (2017); Markov et al. (2016); Mu\u010dalica ; Grozdani\u0107 (1971b); Grozdani\u0107 and Mu\u010dalica (1969); Grozdani\u0107 and Vasi\u0107 ; A\u0110 coll.; ZM coll. [DD]Apis Linnaeus, 1768 (1 species)\u2e17 Apis mellifera Linnaeus 1758 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); Mudri-Stojni\u0107 et al. (2012); Kulin\u010devi\u0107 et al. (1997); Kruni\u0107 ; Grozdani\u0107 ; Grozdani\u0107 and Vasi\u0107 (1966a); Petrik (1958); Vlatkovi\u0107 (1957); \u017divojinovi\u0107 (1950); Mocs\u00e1ry (1897); Apfelbeck (1896); A\u0110 coll.; ZM coll. [DD]Biastes Panzer, 1806 (3 species)\u2e17 Biastes brevicornis  in Petrik (1958); Rafajlovi\u0107 and Sele\u0161i (1958); Mocs\u00e1ry (1897); Apfelbeck (1896); SG coll. [LC]Biastes emarginatus  in Vorgin (1918). [LC]\u25aa Biastes truncatus  in Kuhlmann et al. (2020). [VU]Bombus Latreille, 1802 (47 species)\u2e17 Bombus argillaceus  in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); Rasmont et al. (2015); Grozdani\u0107 ; Grozdani\u0107 and Vasi\u0107 (1965c); Grozdani\u0107 and \u010colovi\u0107 (1955b); Lebedev (1931); ZM coll. [LC]\u25aa Bombus armeniacus Radoszkowski, 1877 in Kuhlmann et al. (2020). [EN]\u2e17 Bombus barbutellus Kirby, 1802 in Kuhlmann et al. (2020); Rasmont et al. (2015); SG coll.; as Psithyrus barbutellus  in Grozdani\u0107 and Vasi\u0107 (1966a); Vorgin (1955); Mocs\u00e1ry (1897). [LC]Bombus bohemicus Seidl, 1838 in Kuhlmann et al. (2020); Rasmont et al. (2015). [LC]\u2e17 Bombus campestris Panzer, 1801 in Kuhlmann et al. (2020); Rasmont et al. (2015); A\u0110 coll; as Psithyrus campestris f. francisanus K. and also as Psithyrus campestris f. rosiellus K. in Vorgin (1955). [LC]Bombus confusus Schenck, 1861 in Kuhlmann et al. (2020); Rasmont et al. (2015); Mocs\u00e1ry (1897). [VU]\u25aa Bombus cryptarum Fabricius, 1775 in Kuhlmann et al. (2020). [LC]Bombus cullumanus Kirby, 1802 in Kuhlmann et al. (2020); as Bombus serrisquama Morawitz, 1888 in Lebedev (1931). [CR]Bombus deuteronymus Schulz, 1879 in Kuhlmann et al. (2020); Rasmont et al. (2015); as Bombus bureschi Pittioni, 1939 in \u017divojinovi\u0107 (1950). [DD]\u25aa Bombus distinguendus Morawitz, 1869 in Kuhlmann et al. (2020). [VU]\u25aa Bombus flavidus Eversmann, 1852 in Kuhlmann et al. (2020). [LC]Bombus fragrans  in Kuhlmann et al. (2020); Mocs\u00e1ry (1897). [EN]\u25aa Bombus gerstaeckeri Morawitz, 1881 in Kuhlmann et al. (2020). [VU]\u2e17 Bombus haematurus Kriechbaumer, 1870 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016); Rasmont et al. (2015); Grozdani\u0107 (1971b); Grozdani\u0107 and Vasi\u0107 (1965c); \u017divojinovi\u0107 (1950); Lebedev (1931); ZM coll. [LC]\u2e17 Bombus hortorum Linnaeus, 1761 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016); Rasmont et al. (2015); Grozdani\u0107 ; Grozdani\u0107 and Vasi\u0107 (1966a); Grozdani\u0107 and Vasi\u0107 (1965c); Grozdani\u0107 and Baranov (1963); Vorgin (1955); \u017divojinovi\u0107 (1950); Lebedev (1931); Apfelbeck (1896); A\u0110 coll.; ZM coll. [LC]\u2e17 Bombus humilis Illiger, 1806 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); Rasmont et al. (2015); Mudri-Stojni\u0107 et al. (2012); Grozdani\u0107 and Vasi\u0107 ; \u017divojinovi\u0107 (1950); A\u0110 coll.; ZM coll.; as Bombus helferanus Seidl, 1838 in Vorgin (1955); Lebedev (1931); as Bombus variabilis Schmiedeknecht, 1878 in Mocs\u00e1ry (1897); Apfelbeck (1896). [LC]\u2e17 Bombus hypnorum Linnaeus, 1758 in Kuhlmann et al. (2020); Markov (2017); Rasmont et al. (2015); Mudri-Stojni\u0107 et al. (2012); \u017divojinovi\u0107 (1950); Lebedev (1931); A\u0110 coll. [LC]\u25aa Bombus jonellus Kirby, 1802 in Kuhlmann et al. (2020). [LC]Bombus laesus Morawitz, 1875 in Kuhlmann et al. (2020); Vorgin (1918); Mocs\u00e1ry (1897). [NT]\u2e17 Bombus lapidarius Linnaeus, 1758 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); Rasmont et al. (2015); Mudri-Stojni\u0107 et al. (2012); Grozdani\u0107 ; Grozdani\u0107 and Vasi\u0107 ; Vorgin (1955); \u017divojinovi\u0107 (1950); Lebedev (1931); Mocs\u00e1ry (1897); Apfelbeck (1896); A\u0110 coll.; ZM coll. [LC]\u2e17 Bombus lucorum Linnaeus, 1761 in Kuhlmann et al. (2020); Vorgin (1955); \u017divojinovi\u0107 (1950); Lebedev (1931); A\u0110 coll.; ZM coll. [LC]\u25aa Bombus mendax Gerst\u00e4cker, 1869 in Kuhlmann et al. (2020). [NT]\u25aa Bombus mesomelas Gerst\u00e4cker, 1869 in Kuhlmann et al. (2020). [LC]\u25aa Bombus mlokosievitzii Radoszkowski, 1877 in Kuhlmann et al. (2020). [DD]\u25aa Bombus mocsaryi Kriechbaumer, 1877 in Kuhlmann et al. (2020). [EN]\u25aa Bombus monticola Smith, 1849 in Kuhlmann et al. (2020). [LC]\u25aa Bombus mucidus Gerst\u00e4cker, 1869 in Kuhlmann et al. (2020). [NT]Bombus muscorum Linnaeus, 1758 in Kuhlmann et al. (2020); Stevanovi\u0107 and Lazarov (1977); Vorgin (1955). [VU]Bombus niveatus Kriechbaumer, 1870 in Kuhlmann et al. (2020); Rasmont et al. (2015); as Bombus vorticosus Gerst\u00e4cker, 1872 in Vorgin (1955). [LC]\u25aa Bombus norvegicus Sparre-Schneider, 1918 in Kuhlmann et al. (2020). [LC]\u2e17 Bombus pascuorum Scopoli, 1763 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); Rasmont et al. (2015); Mudri-Stojni\u0107 et al. (2012); A\u0110 coll.; ZM coll.; as Bombus cognatus Stephens, 1846 in Grozdani\u0107 (1971b); Grozdani\u0107 and Vasi\u0107 (1965c); Lebedev (1931); Vorgin (1918); as Bombus agrorum  in Grozdani\u0107 and Vasi\u0107 ; Grozdani\u0107 (1960); Grozdani\u0107 and Stevanovi\u0107 (1959); Petrik (1958); Grozdani\u0107 and \u010colovi\u0107 ; Vorgin (1955); \u017divojinovi\u0107 (1950); Lebedev (1931); Mocs\u00e1ry (1897); Apfelbeck (1896); Korlevi\u0107 (1890). [LC]\u2e17 Bombus pomorum Panzer, 1805 in Kuhlmann et al. (2020); Rasmont et al. (2015); Vorgin (1918); Mocs\u00e1ry (1897); A\u0110 coll. [VU]\u2e17 Bombus pratorum Linnaeus, 1761 in Kuhlmann et al. (2020); Markov (2017); Rasmont et al. (2015); Grozdani\u0107 and \u010colovi\u0107 ; \u017divojinovi\u0107 (1950); Lebedev (1931); Mocs\u00e1ry (1897); A\u0110 coll. [LC]Bombus pyrenaeus P\u00e9rez, 1879 in Kuhlmann et al. (2020); Rasmont et al. (2015). [LC]\u2e17 Bombus quadricolor Lepeletier, 1832 in Kuhlmann et al. (2020); Rasmont et al. (2015); A\u0110 coll. [LC]\u2e17 Bombus ruderarius M\u00fcller, 1776 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); Rasmont et al. (2015); Mudri-Stojni\u0107 et al. (2012); A\u0110 coll.; as Bombus derhamellus  in Lebedev (1931); Apfelbeck (1896). [LC]Bombus ruderatus Fabricius, 1775 in Petrik (1958); Vorgin (1955). [LC]\u2e17 Bombus rupestris Fabricius, 1793 in Kuhlmann et al. (2020); Rasmont et al. (2015); A\u0110 coll.; ZM coll. [LC]\u25aa Bombus sichelii Radoszkowski, 1859 in Kuhlmann et al. (2020). [LC]\u2e17 Bombus soroeensis Fabricius, 1776 in Kuhlmann et al. (2020); Rasmont et al. (2015); Vorgin (1955); ZM coll.; as Bombus proteus Gerst\u00e4cker, 1869 in Lebedev (1931). [LC]Bombus subterraneus  in Kuhlmann et al. (2020); Rasmont et al. (2015). [LC]\u2e17 Bombus sylvarum Linnaeus, 1761 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); Rasmont et al. (2015); Mudri-Stojni\u0107 et al. (2012); Grozdani\u0107 (1971b); Grozdani\u0107 and Vasi\u0107 ; Vorgin (1955); \u017divojinovi\u0107 (1950); Lebedev (1931); Mocs\u00e1ry (1897); Apfelbeck (1896); Korlevi\u0107 (1890); SG coll. [LC]\u2e17 Bombus sylvestris Lepeletier, 1832 in Kuhlmann et al. (2020); Rasmont et al. (2015); A\u0110 coll. [LC]\u2e17 Bombus terrestris Linnaeus, 1758 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); Rasmont et al. (2015); Mudri-Stojni\u0107 et al. (2012); Grozdani\u0107 ; Grozdani\u0107 and Vasi\u0107 ; Grozdani\u0107 and Baranov (1963); Petrik (1958); Grozdani\u0107 and \u010colovi\u0107 (1955b); Vorgin (1955); \u017divojinovi\u0107 (1950); Lebedev (1931); Apfelbeck (1896); A\u0110 coll.; ZM coll. [LC]\u2e17 Bombus vestalis Geoffroy, 1785 in Kuhlmann et al. (2020); Rasmont et al. (2015); A\u0110 coll.; SG coll.; as Psithyrus vestalis Geoffroy, 1785 in Grozdani\u0107 and Vasi\u0107 (1966a); Vorgin (1955); Lebedev (1931); Apfelbeck (1896). [LC]\u2e17 Bombus wurflenii Radoszkowski, 1859 in Kuhlmann et al. (2020); Rasmont et al. (2015); A\u0110 coll.; as Bombus mastrucatus Gerst\u00e4cker, 1869 in Apfelbeck (1896). [LC]Bombus zonatus Smith, 1854 in Kuhlmann et al. (2020); \u017divojinovi\u0107 (1950); Lebedev (1931); Mocs\u00e1ry (1897). [EN]Ceratina Latreille, 1802 (11 species)\u2e17 Ceratina acuta Friese, 1896 in Grozdani\u0107 (1971b); Rafajlovi\u0107 and Sele\u0161i (1958); ZM coll. [LC]\u2e17 Ceratina callosa Fabricius, 1794 in Grozdani\u0107 (1971b); Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); Lebedev (1931); Mocs\u00e1ry (1897); ZM coll. [LC]\u2e17 Ceratina chalcites Germar, 1839 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016); Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931); Vorgin (1918); Mocs\u00e1ry (1897). [LC]\u2e17 Ceratina chalybea Chevrier, 1872 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016). [LC]\u2e17 Ceratina cucurbitina Rossi, 1792 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016); Grozdani\u0107 (1971b); Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931); Mocs\u00e1ry (1897); Apfelbeck (1896); ZM coll. [LC]\u2e17 Ceratina cyanea Kirby, 1802 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016); Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931); Mocs\u00e1ry (1897); Apfelbeck (1896); A\u0110 coll.; ZM coll. [LC]\u25aa Ceratina dallatorreana Friese, 1896 in Kuhlmann et al. (2020). [LC]\u25aa Ceratina dentiventris Gerst\u00e4cker, 1869 in Kuhlmann et al. (2020). [LC]\u2e17 Ceratina loewi Gerst\u00e4cker, 1869 in ZM coll. [DD]Ceratina nigroaenea Gerst\u00e4cker, 1869 in Rafajlovi\u0107 and Sele\u0161i (1958). [LC]\u2e17 Ceratina nigrolabiata Friese, 1896 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); Mudri-Stojni\u0107 et al. (2012); Grozdani\u0107 (1971b); Rafajlovi\u0107 and Sele\u0161i (1958); A\u0110 coll.; ZM coll. [LC]Epeoloides Giraud, 1863 (1 species)\u2e17 Epeoloides coecutiens  New material examined: 1 \u2642, 1 \u2640; Vlasina, Blato, Bo\u017ei\u010dki kanal; 42.6786\u00b0N, 22.3543\u00b0E; 23 Jul. 2019; T. Tot, N. Veljkovi\u0107 leg.; Andrej Gogala det.; A\u0110 coll. [LC]Epeolus Latreille, 1802 (5 species)Epeolus cruciger Panzer, 1799 in Kuhlmann et al. (2020); Bogusch and Hadrava (2018); Rafajlovi\u0107 and Sele\u0161i (1958). [NT]Epeolus fasciatus Friese, 1895 in Bogusch and Hadrava (2018); Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931); Mocs\u00e1ry (1897). [DD]\u2e17 Epeolus schummeli Schilling, 1849 in SG coll. [NT]Epeolus transitorius Eversmann, 1852 in Bogusch and Hadrava (2018); Petrik (1958); as Epeolus julliani P\u00e9rez, 1884 in Kuhlmann et al. (2020). Note: According to Bogusch and Hadrava (2018)E. julliani is syn. nov. under E. transitorius. [DD]\u2e17 Epeolus variegatus Linnaeus, 1758 in Kuhlmann et al. (2020); Bogusch and Hadrava (2018); Markov (2017); Markov et al. (2016); Petrik (1958); Apfelbeck (1896); also as Epeolus productus Thomson, 1870 in Mocs\u00e1ry (1897). [LC]Eucera Scopoli, 1770 (33 species)Eucera alternans Brull\u00e9, 1832 in Kuhlmann et al. (2020); as Tetralonia ruficollis  in Petrik (1958); as Eucera ruficollis  in Vorgin (1918). [DD]Eucera caspica Morawitz, 1873 in Vorgin (1918). [LC]\u2e17 Eucera chrysopyga P\u00e9rez, 1854 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016); Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931); Vorgin (1918); Mocs\u00e1ry (1897); Apfelbeck (1896). [LC]\u2e17 Eucera cineraria Eversmann, 1852 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016). [LC]\u2e17 Eucera clypeata Erichson, 1835 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016); Mudri-Stojni\u0107 (2018); Mudri-Stojni\u0107 et al. (2012); Lebedev (1931); Vorgin (1918); Mocs\u00e1ry (1897); also as Eucera similis Lepeletier, 1841 in Rafajlovi\u0107 and Sele\u0161i (1958); Apfelbeck (1896). [LC]Eucera dalmatica Lepeletier, 1841 in Kuhlmann et al. (2020); Lebedev (1931); Mocs\u00e1ry (1897). [LC]\u2e17 Eucera excisa Mocs\u00e1ry, 1879 in Grozdani\u0107 ; Grozdani\u0107 and Vasi\u0107 (1967b); Vorgin (1918); Lebedev (1931); Mocs\u00e1ry (1897); ZM coll. [DD]\u2e17 Eucera hungarica Friese, 1896 in Mocs\u00e1ry (1897); SG coll.; also as Tetralonia hungarica  in Rafajlovi\u0107 and Sele\u0161i (1958). [LC]\u2e17 Eucera interrupta B\u00e4r, 1850 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931); Mocs\u00e1ry (1897). [LC]\u2e17 Eucera longicornis Linnaeus, 1758 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Petrik (1958); Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1955); \u017divojinovi\u0107 (1950); Lebedev (1931); A\u0110 coll.; SG coll.; ZM coll.; also as Eucera difficilis P\u00e9rez, 1879 in Mocs\u00e1ry (1897); Apfelbeck (1896). [LC]\u2e17 Eucera nigrescens P\u00e9rez, 1879 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016); ZM coll.; as Eucera tuberculata  in Grozdani\u0107 and Vasi\u0107 ; Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931). [LC]\u2e17 Eucera nigrifacies Lepeletier, 1841 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016); Mocs\u00e1ry (1897). [LC]\u2e17 Eucera pollinaris Kirby, 1802 in Markov (2017); Markov et al. (2016); as Eucera armeniaca  in Rafajlovi\u0107 and Sele\u0161i (1958). [DD]Eucera proxima Morawitz, 1875 as Eucera nitidiventris Mocs\u00e1ry, 1879 in Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1918); Apfelbeck (1896). [DD]\u25aa Eucera punctulata Alfken, 1942 in Kuhlmann et al. (2020). [DD]\u2e17 Eucera seminuda Brull\u00e9, 1832 in Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); Lebedev (1931); Vorgin (1918); ZM coll. [LC]\u2e17 Eucera taurica Morawitz, 1871 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016). [DD]Eucera tricincta Erichson, 1835 in Vorgin (1918); also as Tetralonia tricincta  in Rafajlovi\u0107 and Sele\u0161i (1958). [LC]\u25aa Eucera vittulata Noskiewicz, 1934 in Kuhlmann et al. (2020). [DD]Eucera vulpes Brull\u00e9, 1832 in Kuhlmann et al. (2020); as Eucera parvula Friese, 1896 in Rafajlovi\u0107 and Sele\u0161i (1958). [DD]Cubitalia Friese, 1911, Tetralonia Spinola, 1838 and Tetraloniella Ashmead, 1899 are placed as subgenera within Eucera Scopoli, 1770 :Note: According to \u2e17 Eucera  parvicornis Mocs\u00e1ry, 1878 as Cubitalia parvicornis in ZM coll.; as Eucera parvicornis Mocs\u00e1ry, 1878 in Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1918); Mocs\u00e1ry (1897). [DD]\u2e17 Eucera  malvae Rossi, 1790 as Tetralonia malvae in Kuhlmann et al. (2020); Grozdani\u0107 (1971b); Vorgin (1955); \u017divojinovi\u0107 (1950); Lebedev (1931); ZM coll.; also as Eucera malvae  in Rafajlovi\u0107 and Sele\u0161i (1958); as Eucera malvae in Mocs\u00e1ry (1897); Apfelbeck (1896). [LC]\u2e17 Eucera  alticincta Lepeletier, 1841 as Tetraloniella alticincta in Kuhlmann et al. (2020); Markov (2017); as Tetralonia alticincta  in Mudri-Stojni\u0107 (2018); Mudri-Stojni\u0107 et al. (2012). [LC]\u2e17 Eucera  dentata Germar, 1839 as Tetraloniella dentata in Kuhlmann et al. (2020); as Tetralonia dentata  in Mudri-Stojni\u0107 (2018); Lebedev (1931); as Eucera dentata Germar, 1839 in Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1918); Mocs\u00e1ry (1897). [LC]Eucera  fulvescens Giraud, 1863 as Tetraloniella fulvescens in Kuhlmann et al. (2020); as Tetralonia dufouri  in Vorgin (1955). [DD]\u25aa Eucera  glauca Fabricius 1775 as Tetraloniella glauca in Kuhlmann et al. (2020). [DD]\u2e17 Eucera  graja  as Tetraloniella graja in Grozdani\u0107 (1971b); ZM coll. [DD]\u2e17 Eucera  lyncea Mocs\u00e1ry, 1879 as Tetraloniella lyncea in Markov (2017); as Tetralonia lyncea Mocs\u00e1ry, 1879 in Mudri-Stojni\u0107 (2018); Mudri-Stojni\u0107 et al. (2012); Grozdani\u0107 (1971b); Grozdani\u0107 and Vasi\u0107 (1966b); Lebedev (1931); SG coll.; ZM coll; as Eucera lyncea  in Rafajlovi\u0107 and Sele\u0161i (1958); Mocs\u00e1ry (1897). [DD]\u2e17 Eucera  nana Morawitz, 1874 as Tetraloniella nana in Markov (2017); ZM coll.; as Tetralonia nana Morawitz, 1874 in Mudri-Stojni\u0107 (2018); Mudri-Stojni\u0107 et al. (2012); Grozdani\u0107 (1971b); Grozdani\u0107 and Vasi\u0107 (1967a); Lebedev (1931); SG coll.; as Eucera nana  in Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1918); Mocs\u00e1ry (1897). [DD]\u2e17 Eucera  ruficornis Fabricius, 1804 as Eucera ruficornis Fabricius, 1804 in Rafajlovi\u0107 and Sele\u0161i (1958); Mocs\u00e1ry (1897); as Tetralonia ruficornis  in Vorgin (1955); Lebedev (1931); SG coll. [DD]\u2e17 Eucera  pollinosa Lepeletier, 1841 as Tetralonia pollinosa  and also as Eucera pollinosa Lepeletier, 1841 in Mudri-Stojni\u0107 (2018); as Eucera pollinosa in Rafajlovi\u0107 and Sele\u0161i (1958); Mocs\u00e1ry (1897); as Macrocera fossulata in Korlevi\u0107 (1890). [DD]\u2e17 Eucera  salicariae Lepeletier, 1841 as Eucera salicariae  in Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1918); Mocs\u00e1ry (1897); Apfelbeck (1896); as Tetralonia salicariae  in Vorgin (1955); \u017divojinovi\u0107 (1950); SG coll.; ZM coll. [DD]\u2e17 Eucera  scabiosae Mocs\u00e1ry, 1881 as Tetraloniella scabiosae in Kuhlmann et al. (2020); Markov (2017); as Tetralonia scabiosae  in Mudri-Stojni\u0107 (2018); Mudri-Stojni\u0107 et al. (2012); Grozdani\u0107 (1971b); Rafajlovi\u0107 and Sele\u0161i (1958); SG coll. ZM coll.; as Eucera scabiosae Mocs\u00e1ry, 1881 in Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin ; Mocs\u00e1ry (1897). [DD]Habropoda Smith, 1854 (2 species)\u25aa Habropoda tarsata Spinola, 1838 in Kuhlmann et al. (2020). [LC]\u25aa Habropoda zonatula Smith, 1854 in Kuhlmann et al. (2020). [DD]Melecta Latreille, 1802 (7 species)\u2e17 Melecta albifrons F\u00f6rster, 1771 in Kuhlmann et al. (2020); as Melecta armata  in Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1918); ZM coll. [LC]\u25aa Melecta duodecimmaculata Rossi 1790 in Kuhlmann et al. (2020). [DD]\u25aa Melecta fulgida Lieftinck, 1980 in Kuhlmann et al. (2020). [DD]\u25aa Melecta funeraria Smith, 1854 in Kuhlmann et al. (2020). [DD]\u25aa Melecta italica Radoszkowski, 1876 in Kuhlmann et al. (2020). [DD]\u2e17 Melecta luctuosa Scopoli, 1770 in Kuhlmann et al. (2020); Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931); Vorgin (1918); ZM coll. [LC]\u25aa Melecta obscura Friese, 1895 in Kuhlmann et al. (2020). [DD]Nomada Scopoli, 1770 (77 species)Nomada alboguttata Herrich-Sch\u00e4ffer, 1839 in Kuhlmann et al. (2020); Smit (2018); Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931); Mocs\u00e1ry (1897). [LC]Nomada alpigena Schwarz, Gusenleitner, & Mazzucco, 1999 in Kuhlmann et al. (2020). Note: There are no type specimens listed from Serbia in Schwarz, Gusenleitner and Mazzucco (1999). [DD]Nomada argentata Herrich-Sch\u00e4ffer, 1839 in Kuhlmann et al. (2020); Smit (2018). [NT]\u2e17 Nomada armata Herrich-Sch\u00e4ffer, 1839 in Kuhlmann et al. (2020); Smit (2018); Rafajlovi\u0107 and Sele\u0161i (1958); Mocs\u00e1ry (1897); Apfelbeck (1896); A\u0110 coll. [NT]Nomada atroscutellaris Strand, 1921 in Kuhlmann et al. (2020); Smit (2018). [LC]Nomada basalis Herrich-Sch\u00e4ffer, 1839 in Kuhlmann et al. (2020); Smit (2018); Petrik (1958); Rafajlovi\u0107 and Sele\u0161i (1958); as Nomada tripunctata Morawitz, 1872 in Vorgin ; as Nomada flavomaculata Lucas, 1849 in Mocs\u00e1ry (1897); Apfelbeck (1896). [LC]\u2e17 Nomada bifasciata Olivier, 1811 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016); as Nomada pusilla in Rafajlovi\u0107 and Sele\u0161i (1958). [LC]Nomada bispinosa Mocs\u00e1ry, 1883 in Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931). [LC]\u2e17 Nomada bluethgeni Stoeckhert, 1943 in Kuhlmann et al. (2020); Smit (2018); Markov (2017); Markov et al. (2016). [LC]Nomada braunsiana Schmiedeknecht, 1882 in Kuhlmann et al. (2020); Lebedev (1931). [NT]* Nomada calimorpha Schmiedeknecht, 1882 in Mocs\u00e1ry (1897). [DD]\u25aa Nomada castellana Dusmety Alonso, 1913 in Kuhlmann et al. (2020). [LC]\u25aa Nomada confinis Schmiedeknecht, 1882 in Kuhlmann et al. (2020). [DD]Nomada conjungens Herrich-Sch\u00e4ffer, 1839 in Kuhlmann et al. (2020); Lebedev (1931). [LC]Nomada cruenta Schmiedeknecht, 1882 in Kuhlmann et al. (2020); Smit (2018); Vorgin (1918). [LC]\u2e17 Nomada distinguenda Morawitz, 1874 in Smit (2018); Markov (2017); Markov et al. (2016); Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1918); Apfelbeck (1896). [LC]\u25aa Nomada emarginata Morawitz, 1877 in Kuhlmann et al. (2020). [LC]Nomada errans Lepeletier, 1841 in Kuhlmann et al. (2020); Smit (2018); Lebedev (1931). [NT]Nomada erythrocephala Morawitz, 1870 in Rafajlovi\u0107 and Sele\u0161i (1958). [DD]\u2e17 Nomada fabriciana Linnaeus, 1767 in Kuhlmann et al. (2020); Lebedev (1931); A\u0110 coll. [LC]\u25aa Nomada facilis Schwarz, 1967 in Kuhlmann et al. (2020). [LC]Nomada femoralis Morawitz, 1869 in Kuhlmann et al. (2020); Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1918); Mocs\u00e1ry (1897). [LC]Nomada ferruginata Linn\u00e9 1767 in Kuhlmann et al. (2020); Smit (2018); Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin ; Lebedev (1931). [LC]\u2e17 Nomada flava Panzer, 1798 in Kuhlmann et al. (2020); Smit (2018); Lebedev (1931); A\u0110 coll. [LC]\u2e17 Nomada flavoguttata Kirby, 1802 in Kuhlmann et al. (2020); Smit (2018); Markov (2017); Markov et al. (2016); Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931); Apfelbeck (1896); A\u0110 coll. [LC]\u25aa Nomada flavopicta Kirby, 1802 in Kuhlmann et al. (2020). [LC]\u2e17 Nomada fucata Panzer, 1798 in Kuhlmann et al. (2020); Smit (2018); Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931); Vorgin (1918); Mocs\u00e1ry (1897); Apfelbeck (1896); A\u0110 coll.; as Nomada varia Panzer, 1798 in Petrik (1958). [LC]Nomada fulvicornis Fabricius, 1793 in Kuhlmann et al. (2020); Smit (2018); also as Nomada lineola Panzer, 1798 in Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931); as Nomada lineola in Vorgin (1955); Mocs\u00e1ry (1897); as Nomada robusta Morawitz, 1870 in Apfelbeck (1896). [LC]Nomada furva Panzer, 1798 in Kuhlmann et al. (2020); Rafajlovi\u0107 and Sele\u0161i (1958). [DD]\u25aa Nomada furvoides Stoeckhert, 1944 in Kuhlmann et al. (2020). [DD]Nomada fuscicornis Nylander, 1848 in Kuhlmann et al. (2020); Smit (2018); Vorgin (1918). [LC]\u25aa Nomada goodeniana Kirby, 1802 in Kuhlmann et al. (2020). [LC]* Nomada gribodoi Schmiedeknecht, 1882 as Nomada elegans Mocs\u00e1ry, 1897 in Mocs\u00e1ry (1897). [DD]Nomada guttulata Schenck, 1861 in Kuhlmann et al. (2020); Smit (2018); Vorgin (1918). [LC]\u25aa Nomada hirtipes P\u00e9rez, 1884 in Kuhlmann et al. (2020). [LC]Nomada hungarica Dalla Torre & Friese, 1894 in Rafajlovi\u0107 and Sele\u0161i (1958). [DD]Nomada immaculata Morawitz, 1874 in Vorgin (1918). [DD]Nomada incisa Schmiedeknecht, 1882 in Kuhlmann et al. (2020); Smit (2018); Lebedev (1931). [DD]\u2e17 Nomada integra Brull\u00e9, 1832 in Kuhlmann et al. (2020); A\u0110 coll. [LC]Nomada kohli Schmiedeknecht, 1882 in Kuhlmann et al. (2020); Smit (2018); Apfelbeck (1896). [LC]\u2e17 Nomada lathburiana Kirby, 1802 in Kuhlmann et al. (2020); SG coll. [LC]\u2e17 Nomada leucophthalma  New material examined: 1 \u2640; Vlasina, Veliki \u010demernik; 42.7368\u00b0N, 22.2723\u00b0E; 25 May 2019; M. Vuji\u0107 leg.; Andrej Gogala det.; A\u0110 coll. [LC]Nomada marshamella Kirby, 1802 in Kuhlmann et al. (2020); Smit (2018). [LC]Nomada mauritanica Lepeletier, 1841 in Smit (2018); as Nomada chrysopyga Morawitz, 1871 in Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1918); Mocs\u00e1ry (1897); Apfelbeck (1896). [LC]Nomada mocsaryi Schmiedeknecht, 1882 in Kuhlmann et al. (2020); Smit (2018); Mocs\u00e1ry (1897). [DD]\u25aa Nomada moeschleri Alfken, 1913 in Kuhlmann et al. (2020). [LC]Nomada mutabilis Morawitz, 1870 in Kuhlmann et al. (2020); Smit (2018); Vorgin (1918); Apfelbeck (1896). [LC]Nomada mutica Morawitz, 1872 in Kuhlmann et al. (2020); Lebedev (1931). [NT]Nomada nobilis Herrich-Sch\u00e4ffer, 1839 in Kuhlmann et al. (2020); Smit (2018); Mocs\u00e1ry (1897); Apfelbeck (1896). [LC]Nomada numida Lepeletier, 1841 in Kuhlmann et al. (2020); Smit (2018). [LC]\u25aa Nomada obtusifrons Nylander, 1848 in Kuhlmann et al. (2020). [NT]\u25aa Nomada opaca Alfken, 1913 in Kuhlmann et al. (2020). [NT]\u25aa Nomada pallispinosa Schwarz, 1967 in Kuhlmann et al. (2020). [DD]Nomada panzeri Lepeletier, 1841 in Kuhlmann et al. (2020); Smit (2018). [LC]Nomada pectoralis Morawitz, 1877 in Vorgin (1918). [DD]Nomada piccioliana Magretti, 1883 in Kuhlmann et al. (2020); Smit (2018). [LC]Nomada pleurosticta Herrich-Sch\u00e4ffer, 1839 as Nomada major Morawitz, 1872 in Lebedev (1931). [NT]\u25aa Nomada propinqua Schmiedeknecht, 1882 in Kuhlmann et al. (2020). [LC]Nomada pulchra Arnold, 1888 in Smit (2018). [EN]Nomada rhenana Morawitz, 1872 in Kuhlmann et al. (2020); Smit (2018); Rafajlovi\u0107 and Sele\u0161i (1958); Mocs\u00e1ry (1897). [NT]\u2e17 Nomada ruficornis Linnaeus, 1758 in Kuhlmann et al. (2020); Smit (2018); Apfelbeck (1896); Mocs\u00e1ry (1897); A\u0110 coll; also as Nomada bifida Thomson, 1872 in Rafajlovi\u0107 and Sele\u0161i (1958); as Nomada bifida in Lebedev (1931). [LC]Nomada rufipes Fabricius, 1793 in Kuhlmann et al. (2020); Petrik (1958); Rafajlovi\u0107 and Sele\u0161i (1958). [LC]Nomada sexfasciata Panzer, 1799 in Kuhlmann et al. (2020); Smit (2018); Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931). [LC]\u25aa Nomada sheppardana Kirby, 1802 in Kuhlmann et al. (2020). [LC]Nomada signata Jurine, 1807 in Kuhlmann et al. (2020); Rafajlovi\u0107 and Sele\u0161i (1958). [LC]Nomada similis Morawitz, 1872 in Vorgin (1918). [LC]Nomada stigma Fabricius, 1804 in Kuhlmann et al. (2020); as Nomada austriaca Schmiedeknecht, 1882 in Vorgin (1918). [LC]Nomada striata Fabricius, 1793 in Kuhlmann et al. (2020); as Nomada ochrostoma  in Apfelbeck (1896). [LC]\u25aa Nomada succincta Panzer, 1798 in Kuhlmann et al. (2020). [LC]\u25aa Nomada symphyti Stoeckhert, 1930 in Kuhlmann et al. (2020). [NT]Nomada tenella Mocs\u00e1ry, 1883 in Kuhlmann et al. (2020); Smit (2018). [NT]Nomada transitoria Schmiedeknecht, 1882 in Smit (2018). [LC]\u25aa Nomada tridentirostris Dours, 1873 in Kuhlmann et al. (2020). [LC]Nomada trispinosa Schmiedeknecht, 1882 in Kuhlmann et al. (2020); Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931). [LC]\u25aa Nomada verna Schmiedeknecht, 1882 in Kuhlmann et al. (2020). [DD]Nomada villosa Thomson, 1870 in Kuhlmann et al. (2020); Lebedev (1931). [NT]Nomada zonata Panzer, 1798 in Kuhlmann et al. (2020); Smit (2018); Lebedev (1931); Vorgin (1918). [LC]Pasites Jurine, 1807 (1 species)Pasites maculatus Jurine, 1807 in Petrik (1958); Rafajlovi\u0107 and Sele\u0161i (1958); Mocs\u00e1ry (1897). [LC]Thyreus Panzer, 1806 (7 species)Thyreus affinis Morawitz, 1874 in Kuhlmann et al. (2020); as Crocisa affinis Morawitz, 1874 in Rafajlovi\u0107 and Sele\u0161i (1958). [DD]\u2e17 Thyreus histrionicus Illiger, 1806 in Kuhlmann et al. (2020); ZM coll.; as Crocisa major Morawitz, 1875 in Rafajlovi\u0107 and Sele\u0161i (1958); Mocs\u00e1ry (1897). [LC]\u2e17 Thyreus orbatus Lepeletier, 1841 in Kuhlmann et al. (2020); ZM coll. [LC]\u25aa Thyreus picaron Lieftinck, 1968 in Kuhlmann et al. (2020). [DD]\u2e17 Thyreus ramosus Lepeletier, 1841 in Kuhlmann et al. (2020); ZM coll.; as Crocisa ramosa Lepeletier, 1841 in Rafajlovi\u0107 and Sele\u0161i (1958); Mocs\u00e1ry (1897). [LC]\u2e17 Thyreus scutellaris Fabricius, 1781 in Kuhlmann et al. (2020); ZM coll.; as Crocisa scutellaris  in Petrik (1958); Vorgin (1918); Mocs\u00e1ry (1897). [DD]Thyreus truncatus P\u00e9rez, 1883 in Kuhlmann et al. (2020); as Crocisa truncata P\u00e9rez, 1883 in Mocs\u00e1ry (1897). [DD]Triepeolus Robertson, 1901 (1 species)* Triepeolus tristis  as Epeolus tristis Smith, 1854 in Mocs\u00e1ry (1897). [NT]Xylocopa Latreille, 1802 (4 species)\u2e17 Xylocopa iris Christ, 1791 in Kuhlmann et al. (2020); ZM coll.; as Xylocopa cyanescens Brull\u00e9, 1832 in Grozdani\u0107 and Mu\u010dalica (1973); Grozdani\u0107 (1971b); Grozdani\u0107 and Vasi\u0107 (1966a); Lebedev (1931). [LC]\u25aa Xylocopa olivieri Lepeletier, 1841 in Kuhlmann et al. (2020). [LC]\u2e17 Xylocopa valga Gerst\u00e4cker, 1872 in Kuhlmann et al. (2020); Grozdani\u0107 and Mu\u010dalica (1973); Grozdani\u0107 ; Grozdani\u0107 and Vasi\u0107 (1965c); Grozdani\u0107 and Baranov (1963); Rafajlovi\u0107 and Sele\u0161i (1958); Grozdani\u0107 and \u010colovi\u0107 (1955b); Mocs\u00e1ry (1897); Apfelbeck (1896); A\u0110 coll.; ZM coll. [LC]\u2e17 Xylocopa violacea Linnaeus, 1758 in Kuhlmann et al. (2020); Grozdani\u0107 and Mu\u010dalica (1973); Grozdani\u0107 ; Grozdani\u0107 and Vasi\u0107 (1966a); Petrik (1958); Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); Lebedev (1931); Apfelbeck (1896); A\u0110 coll.; ZM coll. [LC]Colletes Latreille, 1802 (27 species)\u25aa Colletes albomaculatus  in Kuhlmann et al. (2020). [NT]\u2e17 Colletes anchusae Noskiewicz, 1924 Kuhlmann et al. (2020); Grozdani\u0107 and Vasi\u0107 (1966a); ZM coll. [EN]Colletes brevigena Noskiewicz, 1936 in Kuhlmann et al. (2020); Burger (2010). [LC]\u25aa Colletes carinatus Radoszkowski, 1891 in Kuhlmann et al. (2020). [LC]\u25aa Colletes caskanus  in Kuhlmann et al. (2020). [DD]\u25aa Colletes chengtehensis Yasumatsu, 1935 in Kuhlmann et al. (2020). [VU]\u2e17 Colletes cunicularius  in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016); Grozdani\u0107 ; Rafajlovi\u0107 and Sele\u0161i (1958); Mocs\u00e1ry (1897); A\u0110 coll.; ZM coll.; as Colletes cunicularia in Apfelbeck (1896). [LC]\u2e17 Colletes daviesanus Smith, 1846 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016); Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931); Mocs\u00e1ry (1897); A\u0110 coll.; as Colletes daviesana in Apfelbeck (1896). [LC]Colletes eous Morice, 1904 in Kuhlmann et al. (2020); Lebedev (1931). [LC]\u25aa Colletes floralis Eversmann, 1852 in Kuhlmann et al. (2020). [VU]\u2e17 Colletes fodiens  in Kuhlmann et al. (2020); Markov (2017); Petrik (1958); Rafajlovi\u0107 and Sele\u0161i (1958). [VU]\u25aa Colletes foveolaris P\u00e9rez, 1903 in Kuhlmann et al. (2020). [LC]Colletes gallicus Radoszkowski, 1891 in Rafajlovi\u0107 and Sele\u0161i (1958). [LC]\u25aa Colletes graeffei Alfken, 1900 in Kuhlmann et al. (2020). [EN]Colletes hederae Schmidt & Westrich, 1993 in Kuhlmann et al. (2020); Burger (2010). [LC]Colletes hylaeiformis Eversmann, 1852 in Kuhlmann et al. (2020); Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1918); Mocs\u00e1ry (1897). [LC]\u25aa Colletes inexpectatus Noskiewicz, 1936 in Kuhlmann et al. (2020). [LC]\u2e17 Colletes maidli Noskiewicz, 1936 in Kuhlmann et al. (2020); Markov (2017). [LC]Colletes marginatus Smith, 1846 in Kuhlmann et al. (2020); Petrik (1958); Rafajlovi\u0107 and Sele\u0161i (1958); as Colletes marginata in Apfelbeck (1896). [LC]\u25aa Colletes meyeri Noskiewicz, 1936 in Kuhlmann et al. (2020). [EN]\u25aa Colletes mlokossewiczi Radoszkowski, 1891 in Kuhlmann et al. (2020). [LC]\u2e17 Colletes nasutus Smith, 1853 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); Lebedev (1931); Mocs\u00e1ry (1897). [EN]\u25aa Colletes nigricans Gistel, 1857 in Kuhlmann et al. (2020). [LC]Colletes punctatus Mocs\u00e1ry, 1877 in Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1918); Mocs\u00e1ry (1897). [EN]\u25aa Colletes senilis  in Kuhlmann et al. (2020). [DD]Colletes succinctus  in Kuhlmann et al. (2020); Petrik (1958); Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); Lebedev (1931); Vorgin (1918). [NT]\u2e17 Colletes similis Schenck, 1853 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Petrik (1958); Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); Lebedev (1931); as Colletes picistigma Thomson, 1872 in Vorgin (1918); Mocs\u00e1ry (1897). [LC]Hylaeus Fabricius, 1793 (42 species)\u25aa Hylaeus adriaticus  in Kuhlmann et al. (2020). [DD]\u25aa Hylaeus alpinus  in Kuhlmann et al. (2020). [DD]Hylaeus angustatus  in Kuhlmann et al. (2020); as Prosopis angustata Schenck, 1861 in Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950). [LC]\u2e17 Hylaeus annularis  in Markov (2017); Markov et al. (2016); A\u0110 coll.; as Prosopis annularis  in Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950). Note: It is difficult to be certain about the correct status of specimens in the literature before Notton and Dathe (2008) who pointed out the confusion regarding previously understood interpretation of the name. [DD]Hylaeus annulatus  in Kuhlmann et al. (2020); as Prosopis annulata  in Vorgin (1955); Lebedev (1931). [DD]\u2e17 Hylaeus brevicornis Nylander, 1852 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); as Prosopis brevicornis  in Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931); Apfelbeck (1896). [LC]\u25aa Hylaeus clypearis  in Kuhlmann et al. (2020). [LC]\u2e17 Hylaeus communis Nylander, 1852 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); A\u0110 coll.; as Prosopis communis  in Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931); Apfelbeck (1896). [LC]\u2e17 Hylaeus confusus Nylander, 1852 in Kuhlmann et al. (2020); A\u0110 coll.; as Prosopis confusa  in Rafajlovi\u0107 and Sele\u0161i (1958); Apfelbeck (1896). [LC]\u25aa Hylaeus coriaceus  in Kuhlmann et al. (2020). [DD]\u2e17 Hylaeus cornutus Curtis, 1831 in Mudri-Stojni\u0107 (2018); as Prosopis cornuta  in Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin ; Mocs\u00e1ry (1897). [LC]\u25aa Hylaeus crassanus  in Kuhlmann et al. (2020). [NT]Hylaeus difformis  in Kuhlmann et al. (2020); as Prosopis difformis Eversmann, 1852 in Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); Vorgin (1918); Mocs\u00e1ry (1897). [LC]Hylaeus dilatatus  in Kuhlmann et al. (2020); as Prosopis dilatata  in Apfelbeck (1896). Note: It is difficult to be certain about the correct status of specimens in the literature before Notton and Dathe (2008) who pointed out the confusion regarding previously understood interpretation of the name. [LC]Hylaeus duckei  in Kuhlmann et al. (2020); as Prosopis duckei Alfken, 1904 in Rafajlovi\u0107 and Sele\u0161i (1958). [DD]Hylaeus euryscapus F\u00f6rster, 1871 in Kuhlmann et al. (2020); as Prosopis euryscapus  in Rafajlovi\u0107 and Sele\u0161i (1958); Prosopis euryscapa in Vorgin ; Mocs\u00e1ry (1897). Note: It is difficult to be certain about the correct status of specimens in the literature before Notton and Dathe (2008) who pointed out the confusion regarding previously understood interpretation of the name H. annularis. [DD]Hylaeus gibbus Saunders, 1850 in Kuhlmann et al. (2020); as Prosopis gibba  in Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931). [LC]\u25aa Hylaeus gredleri F\u00f6rster, 1871 in Kuhlmann et al. (2020). [LC]Hylaeus hyalinatus Smith, 1842 in Kuhlmann et al. (2020); as Prosopis hyalinata Smith, 1842 in Rafajlovi\u0107 and Sele\u0161i (1958); Mocs\u00e1ry (1897); Apfelbeck (1896). [LC]\u25aa Hylaeus hyperpunctatus  in Kuhlmann et al. (2020). [DD]\u25aa Hylaeus imparilis F\u00f6rster, 1871 in Kuhlmann et al. (2020). [LC]Hylaeus incongruus F\u00f6rster, 1871 as Prosopis genalis Thoms. in Vorgin (1918). [DD]\u25aa Hylaeus kahri F\u00f6rster, 1871 in Kuhlmann et al. (2020). [DD]Hylaeus leptocephalus  in Kuhlmann et al. (2020); as Prosopis bisinuata F\u00f6rster, 1871 in Rafajlovi\u0107 and Sele\u0161i (1958). [LC]\u2e17 Hylaeus lineolatus  in Kuhlmann et al. (2020); A\u0110 coll.; ZM coll.; as Prosopis lineolata Schenck, 1861 in Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931). [LC]Hylaeus meridionalis F\u00f6rster, 1871 in Kuhlmann et al. (2020); as Prosopis meridionalis F\u00f6rster, 1871 in Rafajlovi\u0107 and Sele\u0161i (1958); Mocs\u00e1ry (1897). [DD]\u2e17 Hylaeus nigritus  in Kuhlmann et al. (2020); A\u0110 coll.; as Prosopis nigrita  in Lebedev (1931). [LC]\u25aa Hylaeus nivaliformis Dathe, 1977 in Kuhlmann et al. (2020). [DD]\u25aa Hylaeus pfankuchi  in Kuhlmann et al. (2020). [LC]Hylaeus pictipes Nylander, 1852 in Kuhlmann et al. (2020); as Prosopis pictipes  in Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1918). [LC]Hylaeus punctatus  in Kuhlmann et al. (2020); as Prosopis punctata Brull\u00e9, 1832 in Rafajlovi\u0107 and Sele\u0161i (1958). [LC]\u25aa Hylaeus punctulatissimus Smith, 1842 in Kuhlmann et al. (2020). [DD]\u25aa Hylaeus punctus F\u00f6rster, 1871 in Kuhlmann et al. (2020). [DD]\u25aa Hylaeus rugicollis Morawitz, 1873 in Kuhlmann et al. (2020). [DD]\u25aa Hylaeus scutellatus  in Kuhlmann et al. (2020). [DD]Hylaeus signatus  in Kuhlmann et al. (2020); as Prosopis pratensis  in Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1955); as Prosopis bipunctata  in Mocs\u00e1ry (1897); Apfelbeck (1896). [LC]Hylaeus sinuatus  in Kuhlmann et al. (2020); Petrik (1958); as Prosopis minuta  in Rafajlovi\u0107 and Sele\u0161i (1958); as Prosopis sinuata  in Mocs\u00e1ry (1897). [LC]\u25aa Hylaeus soror  in Kuhlmann et al. (2020). [DD]Hylaeus styriacus F\u00f6rster, 1871 in Kuhlmann et al. (2020); as Prosopis styriaca  in Rafajlovi\u0107 and Sele\u0161i (1958). [DD]\u25aa Hylaeus taeniolatus F\u00f6rster, 1871 in Kuhlmann et al. (2020). [LC]\u25aa Hylaeus tyrolensis F\u00f6rster, 1871 in Kuhlmann et al. (2020). [DD]Hylaeus variegatus  in Kuhlmann et al. (2020); as Prosopis variegata  in Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931); Mocs\u00e1ry (1897); Apfelbeck (1896). [LC]Ceylalictus Strand, 1913 (1 species)Ceylalictus variegatus  in Kuhlmann et al. (2020); as Nomioides jucunda Morawitz, 1874 in Petrik (1958); as Nomioides variegatus  in Rafajlovi\u0107 and Sele\u0161i (1958); Mocs\u00e1ry (1897). [LC]Dufourea Lepeletier, 1841 (4 species)* Dufourea alpina Morawitz, 1865 in Apfelbeck (1896). [LC]Dufourea dentiventris  in Kuhlmann et al. (2020); as Halictoides dentiventris Nylander, 1848 in Lebedev (1931). [NT]\u2e17 Dufourea inermis  in Kuhlmann et al. (2020); A\u0110 coll. [NT]\u25aa Dufourea minuta Lepeletier, 1841 in Kuhlmann et al. (2020). [NT]Halictus Latreille, 1804 (18 species)\u2e17 Halictus asperulus P\u00e9rez, 1895 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016); Grozdani\u0107 (1972a); Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931). [DD]\u2e17 Halictus brunnescens  in Markov (2017); Markov et al. (2016). [DD]\u25aa Halictus carinthiacus Bl\u00fcthgen, 1936 in Kuhlmann et al. (2020). [EN]Halictus cochlearitarsis Dours, 1872 in Grozdani\u0107 (1966); Rafajlovi\u0107 and Sele\u0161i (1958). [LC]\u2e17 Halictus compressus  as Halictus eurygnathus Bl\u00fcthgen, 1930 in Markov (2017); Markov et al. (2016); \u017divojinovi\u0107 (1950). [LC]\u2e17 Halictus fulvipes  in Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); Mu\u010dalica (1968); Lebedev (1931). [LC]\u2e17 Halictus langobardicus Bl\u00fcthgen, 1944 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Rafajlovi\u0107 and Sele\u0161i (1958). [LC]\u2e17 Halictus maculatus Smith, 1848 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); Mudri-Stojni\u0107 et al. (2012); Grozdani\u0107 (1972a); Petrik (1958); Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1955); \u017divojinovi\u0107 (1950); Lebedev (1931); Mocs\u00e1ry (1897); Apfelbeck (1896); Korlevi\u0107 (1890); A\u0110 coll.; ZM coll. [LC]Halictus mucoreus Eversmann, 1852 in Vorgin ; Mocs\u00e1ry (1897). [DD]\u2e17 Halictus patellatus Morawitz, 1873 in Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); Mudri-Stojni\u0107 et al. (2012); Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1955); Mocs\u00e1ry (1897); Apfelbeck (1896); AZ coll.; ZM coll. [LC]\u2e17 Halictus quadricinctus  in Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); Mudri-Stojni\u0107 et al. (2012); Grozdani\u0107 ; Vasi\u0107 (1967); Grozdani\u0107 and Vasi\u0107 ; Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1955); An\u0111elkovi\u0107 (1949); Lebedev (1931); Mocs\u00e1ry (1897); Apfelbeck (1896); as Halictus quadristrigatus Latreille, 1805 in Petrik (1958); Vorgin (1955); Korlevi\u0107 (1890). [NT]Halictus resurgens Nurse, 1903 as Halictus holtzi Schulz, 1906 in Lebedev (1931). [LC]\u2e17 Halictus rubicundus  in Markov (2017); Markov et al. (2016); Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1955); \u017divojinovi\u0107 (1950); Lebedev (1931); A\u0110 coll.; as Halictus quadrifasciatus Smith, 1870 in Mudri-Stojni\u0107 (2018). [LC]\u2e17 Halictus sajoi Bl\u00fcthgen, 1923 in Grozdani\u0107 (1971a); ZM coll.; as Halictus veneticus M\u00f3cz\u00e1r, 1967 in Rafajlovi\u0107 and Sele\u0161i (1958). [DD]\u2e17 Halictus scabiosae  in Vasi\u0107 (1979a); Grozdani\u0107 ; Grozdani\u0107 and Vasi\u0107 ; Kruni\u0107 (1959); Vorgin (1955); Petrik (1958); Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931); Mocs\u00e1ry (1897); Apfelbeck (1896); ZM coll.; FSUNS. [LC]\u2e17 Halictus sexcinctus  in Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); Grozdani\u0107 ; Petrik (1958); Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); Lebedev (1931); Apfelbeck (1896); Mocs\u00e1ry (1897); Korlevi\u0107 (1890); AZ coll.; ZM coll. [LC]\u2e17 Halictus simplex Bl\u00fcthgen, 1923 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Mudri-Stojni\u0107 et al. (2012); Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); A\u0110 coll.; AZ coll.; ZM coll. [LC]\u2e17 Halictus tetrazonius  in Petrik (1958); Vorgin (1955); Mocs\u00e1ry (1897); Apfelbeck (1896); SG coll.; ZM coll. [DD]Lasioglossum Curtis, 1833 (72 species)Lasioglossum aeratum  as Halictus viridiaeneus Bl\u00fcthgen, 1918 in Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1955); as Halictus aeratus  in Mocs\u00e1ry (1897). [LC]\u2e17 Lasioglossum albipes  in Mudri-Stojni\u0107 (2018); Mudri-Stojni\u0107 et al. (2012); as Halictus albipes  in Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); Lebedev (1931); Mocs\u00e1ry (1897); as Halictus obovatus Kirby in Petrik (1958). [LC]\u25aa Lasioglossum alpigenum  in Kuhlmann et al. (2020). [LC]\u25aa Lasioglossum angusticeps  in Kuhlmann et al. (2020). [NT]\u25aa Lasioglossum apostoli Ebmer, 1970 in Kuhlmann et al. (2020). [DD]Lasioglossum bischoffi  in Kuhlmann et al. (2020); as Halictus bischoffi Bl\u00fcthgen, 1931 in Rafajlovi\u0107 and Sele\u0161i (1958). [DD]\u2e17 Lasioglossum brevicorne  in Markov (2017); Markov et al. (2016); A\u0110 coll.; ZM coll.; as Halictus brevicornis Schenck, 1870 [\u201c1869\u201d] in Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1955). [NT]\u2e17 Lasioglossum calceatum  in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); A\u0110 coll.; as Halictus calceatus  in Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); Lebedev (1931); Mocs\u00e1ry (1897); Apfelbeck (1896); as Halictus cylindricus  in Petrik (1958); Korlevi\u0107 (1890). [LC]\u2e17 Lasioglossum clypeare  in Markov (2017); Markov et al. (2016); as Halictus clypearis  in Vorgin (1955); \u017divojinovi\u0107 (1950); Lebedev (1931). [NT]Lasioglossum convexiusculum  as Halictus convexiusculus  in Rafajlovi\u0107 and Sele\u0161i (1958). [NT]Lasioglossum corvinum  in Kuhlmann et al. (2020); as Halictus corvinus Morawitz, 1877 in Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931). [LC]Lasioglossum costulatum  as Halictus costulatus Kriechbaumer, 1873 in Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); Lebedev (1931); Mocs\u00e1ry (1897). [NT]\u2e17 Lasioglossum crassepunctatum  in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); as Halictus crassepunctatus Bl\u00fcthgen, 1923 in Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1955). [DD]\u2e17 Lasioglossum discum  in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); Mudri-Stojni\u0107 et al. (2012); ZM coll.; as Halictus morbillosus Kriechbaumer, 1873 in Grozdani\u0107 (1971b); Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1955); \u017divojinovi\u0107 (1950); Lebedev (1931); Mocs\u00e1ry (1897); Apfelbeck (1896). [LC]Lasioglossum elegans  in Kuhlmann et al. (2020); as Halictus elegans Lepeletier, 1841 in Rafajlovi\u0107 and Sele\u0161i (1958); Mocs\u00e1ry (1897). [DD]\u2e17 Lasioglossum euboeense  as Halictus euboeensis Strand, 1909 in Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1955); SG coll. [DD]\u2e17 Lasioglossum fratellum  in Kuhlmann et al. (2020); A\u0110 coll.; ZM coll. [LC]\u2e17 Lasioglossum fulvicorne  in A\u0110 coll.; as Halictus fulvicornis  in Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950). [LC]\u2e17 Lasioglossum glabriusculum  in Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); Mudri-Stojni\u0107 et al. (2012); as Halictus glabriusculus Morawitz, 1872 in Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1955); \u017divojinovi\u0107 (1950); Lebedev (1931). [LC]Lasioglossum griseolum  as Halictus griseolus Morawitz, 1872 in Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1955). [LC]\u25aa Lasioglossum intermedium  in Kuhlmann et al. (2020). [NT]\u2e17 Lasioglossum interruptum  in Markov (2017); SG coll.; as Halictus interruptus  in Grozdani\u0107 and Mu\u010dalica (1968b); Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1955); Mocs\u00e1ry (1897); Apfelbeck (1896). [LC]\u25aa Lasioglossum kussariense  in Kuhlmann et al. (2020). [DD]Lasioglossum laeve  in Kuhlmann et al. (2020); as Halictus laevis  in Vorgin (1918). [EN]Lasioglossum laevigatum  in Kuhlmann et al. (2020); as Halictus laevigatus  in Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950). [NT]\u2e17 Lasioglossum laticeps  in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); as Halictus laticeps Schenck, 1868 in Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); Lebedev (1931). [LC]\u2e17 Lasioglossum lativentre  in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Mudri-Stojni\u0107 et al. (2012); ZM coll.; as Halictus lativentris Schenck, 1853 in Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); Lebedev (1931). [LC]Lasioglossum leucopus  in Kuhlmann et al. (2020); as Halictus leucopus  in Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950). [LC]\u2e17 Lasioglossum leucozonium  in Mudri-Stojni\u0107 (2018); Markov (2017); Mudri-Stojni\u0107 et al. (2012); A\u0110 coll.; ZM coll.; as Halictus leucozonius  in Grozdani\u0107 (1971b); Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin ; \u017divojinovi\u0107 (1950); Lebedev (1931); Mocs\u00e1ry (1897); Apfelbeck (1896). [LC]Lasioglossum limbellum  in Kuhlmann et al. (2020); as Halictus limbellus Morawitz, 1876 in Rafajlovi\u0107 and Sele\u0161i (1958). [DD]\u2e17 Lasioglossum lineare  in Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); SG coll.; as Halictus linearis Schenck, 1868 in Grozdani\u0107 (1971b); Grozdani\u0107 and Vasi\u0107 (1966a); Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1955); \u017divojinovi\u0107 (1950); Lebedev (1931). [DD]\u25aa Lasioglossum lissonotum  in Kuhlmann et al. (2020). [DD]Lasioglossum lucidulum  in Kuhlmann et al. (2020); as Halictus lucidulus  in Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1955). [LC]\u2e17 Lasioglossum majus  in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016); A\u0110 coll.; as Halictus major Nylander, 1852 in Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); Lebedev (1931); Vorgin (1918). [NT]Lasioglossum mandibulare  in Kuhlmann et al. (2020); as Halictus mandibularis Morawitz, 1866 in Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1955). [NT]\u2e17 Lasioglossum malachurum  in Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); Mudri-Stojni\u0107 et al. (2012); SG coll.; as Halictus malachurus  in Grozdani\u0107 ; Grozdani\u0107 and Vasi\u0107 ; Kruni\u0107 (1959); Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1955); \u017divojinovi\u0107 (1950); Lebedev (1931). [LC]\u2e17 Lasioglossum marginatum  in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); ZM coll.; as Halictus marginatus Brull\u00e9, 1832 in Vasi\u0107 ; Grozdani\u0107 ; Grozdani\u0107 and Vasi\u0107 (1965c); Kruni\u0107 (1959); Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1955); Lebedev (1931); as Halictus fasciatellus Schenck, 1868 in Vorgin (1955); Mocs\u00e1ry (1897); Apfelbeck (1896). [LC]\u25aa Lasioglossum marginellum  in Kuhlmann et al. (2020). [NT]Lasioglossum mesosclerum  in Kuhlmann et al. (2020); as Halictus mesosclerus P\u00e9rez, 1903 in Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1955). [DD]Lasioglossum minutissimum  in Kuhlmann et al. (2020); as Halictus minutissimus  in Rafajlovi\u0107 and Sele\u0161i (1958). [LC]Lasioglossum minutulum  as Halictus minutulus  in Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950). [NT]\u2e17 Lasioglossum morio  in Kuhlmann et al. (2020); A\u0110 coll.; as Halictus morio  in Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1955); \u017divojinovi\u0107 (1950); Lebedev (1931); Mocs\u00e1ry (1897); Apfelbeck (1896). [LC]\u2e17 Lasioglossum nigripes  in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); ZM coll.; as Halictus nigripes Lepeletier, 1841 in Vasi\u0107 (1979b); Grozdani\u0107 and Vasi\u0107 (1966a); Vorgin (1955); \u017divojinovi\u0107 (1950); Lebedev (1931); as Halictus vulpinus Nylander, 1853  in Rafajlovi\u0107 and Sele\u0161i (1958); Mocs\u00e1ry (1897). [LC]\u2e17 Lasioglossum nitidiusculum  in Kuhlmann et al. (2020); A\u0110 coll.; as Halictus nitidiusculus  in Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931). [LC]Lasioglossum nitidulum  as Halictus aeneidorsum Alfken, 1921 in Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1955). [LC]\u2e17 Lasioglossum obscuratum  in Kuhlmann et al. (2020); ZM coll.; as Halictus obscuratus Morawitz, 1876 in Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); Mocs\u00e1ry (1897). [DD]\u2e17 Lasioglossum pallens  in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016); as Halictus lineolatus Lepeletier, 1841 in Mocs\u00e1ry (1897). [LC]Lasioglossum parvulum  in Kuhlmann et al. (2020); as Halictus minutus  in Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950). [LC]\u2e17 Lasioglossum pauxillum  in Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); Mudri-Stojni\u0107 et al. (2012); A\u0110 coll.; as Halictus pauxillus  in Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); Lebedev (1931). [LC]\u2e17 Lasioglossum politum  in Markov (2017); Markov et al. (2016); as Halictus politus  in Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin ; \u017divojinovi\u0107 (1950); Lebedev (1931). [LC]\u25aa Lasioglossum pseudocaspicum  in Kuhlmann et al. (2020). [DD]Lasioglossum punctatissimum  in Kuhlmann et al. (2020); as Halictus punctatissimus  in Lebedev (1931). [LC]\u2e17 Lasioglossum puncticolle  in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); as Halictus puncticollis Morawitz, 1872 in Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931). [LC]\u2e17 Lasioglossum pygmaeum  in Markov (2017); Markov et al. (2016); ZM coll.; as Halictus pygmaeus  in Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1955). [NT]Lasioglossum quadrinotatulum  in Kuhlmann et al. (2020); as Halictus quadrinotatulus  in Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1955). [NT]Lasioglossum quadrinotatum  in Kuhlmann et al. (2020); as Halictus quadrinotatus  in Vorgin (1955); Apfelbeck (1896). [NT]\u25aa Lasioglossum rufitarse  in Kuhlmann et al. (2020). [LC]Lasioglossum semilucens  in Kuhlmann et al. (2020); as Halictus semilucens Alfken, 1914 in Rafajlovi\u0107 and Sele\u0161i (1958). [LC]Lasioglossum setulellum  as Halictus setulellus Strand, 1909 in Vorgin (1955). [NT]\u25aa Lasioglossum setulosum  in Kuhlmann et al. (2020). [NT]\u2e17 Lasioglossum sexnotatum  in Kuhlmann et al. (2020); A\u0110 coll.; as Halictus sexnotatus  in Vorgin (1918); Mocs\u00e1ry (1897). [NT]\u2e17 Lasioglossum sexstrigatum  in ZM coll.; as Halictus sexstrigatus Schenck, 1870[\u201c1869\u201d] in Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1955). [LC]Lasioglossum smeathmanellum  as Halictus smeathmanellus K. in Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin ; \u017divojinovi\u0107 (1950); Apfelbeck (1896). [LC]Lasioglossum subfasciatum  as Halictus subfasciatus  in Lebedev (1931). [EN]\u25aa Lasioglossum subfulvicorne  in Kuhlmann et al. (2020). [LC]Lasioglossum tarsatum  as Halictus tarsatus Schenck, 1868 in Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1955). [NT]\u2e17 Lasioglossum trichopygum  in ZM coll.; as Halictus trichopygus Bl\u00fcthgen, 1923 in Rafajlovi\u0107 and Sele\u0161i (1958); Grozdani\u0107 (1966); Grozdani\u0107 and Vasi\u0107 (1966a). [DD]Lasioglossum tricinctum  in Kuhlmann et al. (2020); as Halictus tricinctus Schenck, 1874 in \u017divojinovi\u0107 (1950). [DD]\u2e17 Lasioglossum truncaticolle  in Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); as Halictus truncaticollis Morawitz, 1877[\u201c1878\u201d] in Vorgin (1955); Lebedev (1931). [DD]\u2e17 Lasioglossum villosulum  in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); SG coll.; as Halictus villosulus Kirby, 1802 in Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1955); Lebedev (1931); Apfelbeck (1896). [LC]\u2e17 Lasioglossum xanthopus  in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); as Halictus xanthopus  in Petrik (1958); Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin ; Lebedev (1931); Mocs\u00e1ry (1897); as Lasioglossum xanthopum  in ZM coll. [NT]Lasioglossum zonulum  as Halictus zonulus Smith, 1848 in Petrik (1958); Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin ; Lebedev (1931); Mocs\u00e1ry (1897); Apfelbeck (1896). [LC]Nomiapis Cockerell, 1919 (3 species)\u2e17 Nomiapis bispinosa  as Nomia ruficornis Spinola, 1839 in Grozdani\u0107 (1971b); Petrik (1958); Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931); Mocs\u00e1ry (1897); as Nomia unidentata Oliver, 1812 in Mudri-Stojni\u0107 (2018). [LC]\u2e17 Nomiapis diversipes  in Mudri-Stojni\u0107 (2018); ZM coll.; as Nomia diversipes Latreille, 1806 in Markov (2017); Mudri-Stojni\u0107 et al. (2012); Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931); Mocs\u00e1ry (1897); Apfelbeck (1896); AZ coll.; as Pseudapis diversipes  in Markov et al. (2016). [LC]\u2e17 Nomiapis femoralis  in Kuhlmann et al. (2020); ZM coll.; as Nomia femoralis  in Petrik (1958); Rafajlovi\u0107 and Sele\u0161i (1958); Mocs\u00e1ry (1897). [DD]Nomioides Schenck, 1867 (1 species)Nomioides minutissimus  in Kuhlmann et al. (2020); Rafajlovi\u0107 and Sele\u0161i (1958); as Nomioides pulchellus Schenck, 1859 in Mocs\u00e1ry (1897). [LC]Rhophitoides Schenck, 1861 (1 species)\u2e17 Rhophitoides canus  in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Mudri-Stojni\u0107 et al. (2012); as Rophites canus Eversmann, 1852 in Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1918); Mocs\u00e1ry (1897); Apfelbeck (1896); ZM coll. [LC]Rophites Spinola, 1808 (2 species)\u2e17 Rophites hartmanni Friese, 1902 in Markov (2017); Markov et al. (2016); Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1918); AZ coll. [DD]\u2e17 Rophites quinquespinosus Spinola, 1808 in Mudri-Stojni\u0107 (2018); Mudri-Stojni\u0107 et al. (2012); Grozdani\u0107 (1971b); Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931); Apfelbeck (1896); Mocs\u00e1ry (1897); ZM coll. [NT]Seladonia Robertson, 1918 (8 species)Seladonia confusa  as Halictus perkinsi Bl\u00fcthgen, 1926 in Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1955); \u017divojinovi\u0107 (1950). [LC]\u25aa Seladonia gavarnica  as Halictus gavarnicus P\u00e9rez, 1903 in Kuhlmann et al. (2020). [LC]\u2e17 Seladonia kessleri  as Halictus kessleri Bramson, 1879 in Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); Mudri-Stojni\u0107 et al. (2012); Vasi\u0107 (1979b); Grozdani\u0107 ; Grozdani\u0107 and Vasi\u0107 (1966a); Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931); ZM coll. [LC]\u2e17 Seladonia seladonia  as Halictus seladonius  in Markov (2017); Markov et al. (2016); as Halictus geminatus P\u00e9rez, 1903 in Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1955); \u017divojinovi\u0107 (1950). [LC]\u2e17 Seladonia semitecta  as Halictus semitectus Morawitz, 1874 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Mudri-Stojni\u0107 et al. (2012); Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1955); Mocs\u00e1ry (1897). [EN]\u2e17 Seladonia smaragdula  as Halictus smaragdulus Vachal, 1895 in Markov (2017); Markov et al. (2016); Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1955); AZ coll. [LC]\u2e17 Seladonia subaurata  as Halictus subauratus  in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); Mudri-Stojni\u0107 et al. (2012); Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); Lebedev (1931); AZ coll.; as Halictus gramineus Smith, 1849 in Petrik (1958); as Halictus virescens Lepeletier, 1841 in Vorgin (1955); Mocs\u00e1ry (1897); Apfelbeck (1896). [LC]\u2e17 Seladonia tumulorum  as Halictus tumulorum  in Lebedev (1931); Apfelbeck (1896); A\u0110 coll.; as Halictus fasciatus Nylander, 1848 in Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1955); Lebedev (1931). [LC]Sphecodes Latreille, 1802 (25 species)\u2e17 Sphecodes albilabris Fabricius, 1793 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016); ZM coll.; as Sphecodes fuscipennis  in Petrik (1958); Rafajlovi\u0107 and Sele\u0161i (1958); Mocs\u00e1ry (1897); Apfelbeck (1896). [LC]\u2e17 Sphecodes alternatus Smith, 1853 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Mudri-Stojni\u0107 et al. (2012). [LC]Sphecodes crassus Thomson, 1870 in Kuhlmann et al. (2020); as Sphecodes divisus Hagens, 1882 in \u017divojinovi\u0107 (1950); Rafajlovi\u0107 and Sele\u0161i (1958). [LC]Sphecodes cristatus Hagens, 1882 in Kuhlmann et al. (2020); Rafajlovi\u0107 and Sele\u0161i (1958). Note: Bogusch and Straka (2012) reported this species as absent on Balkan Peninsula. [NT]\u25aa Sphecodes croaticus Meyer, 1922 in Kuhlmann et al. (2020). [NT]\u2e17 Sphecodes ephippius Linnaeus, 1767 in Kuhlmann et al. (2020); Vorgin (1918); A\u0110 coll.; ZM coll.; as Sphecodes similis Wesmael, 1836 in Apfelbeck (1896). [LC]Sphecodes ferruginatus Hagens, 1882 in Kuhlmann et al. (2020); Lebedev (1931); as Sphecodes rufescens Hagens, 1874 in Apfelbeck (1896). [LC]Sphecodes geoffrellus Kirby, 1802 in Kuhlmann et al. (2020); as Sphecodes fasciatus Hagens, 1882 in \u017divojinovi\u0107 (1950). [LC]\u2e17 Sphecodes gibbus Linnaeus, 1758 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); Lebedev (1931); Vorgin (1918); Mocs\u00e1ry (1897); Apfelbeck (1896). [LC]\u25aa Sphecodes hyalinatus Hagens, 1882 in Kuhlmann et al. (2020). [NT]\u2e17 Sphecodes longulus Hagens, 1882 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016); Rafajlovi\u0107 and Sele\u0161i (1958). [LC]\u25aa Sphecodes majalis P\u00e9rez, 1903 in Kuhlmann et al. (2020). [NT]\u2e17 Sphecodes miniatus Hagens, 1882 in Kuhlmann et al. (2020); A\u0110 coll. [LC]\u2e17 Sphecodes monilicornis Kirby, 1802 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); Grozdani\u0107 (1971b); Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); Lebedev (1931); as Sphecodes subquadratus Smith, 1845 in Vorgin (1918); Mocs\u00e1ry (1897); Apfelbeck (1896). [LC]Sphecodes niger Hagens, 1874 in Kuhlmann et al. (2020); Rafajlovi\u0107 and Sele\u0161i (1958). [LC]\u2e17 Sphecodes pellucidus Smith, 1845 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016); Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); A\u0110 coll. [LC]\u25aa Sphecodes pseudofasciatus Bl\u00fcthgen, 1925 in Kuhlmann et al. (2020). [DD]Sphecodes puncticeps Thomson, 1870 in Kuhlmann et al. (2020); Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950). [LC]Sphecodes reticulatus Thomson, 1870 in Kuhlmann et al. (2020); Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931); Mocs\u00e1ry (1897). [LC]Sphecodes rubicundus Hagens, 1875 in Lebedev (1931). [NT]Sphecodes rufiventris Panzer, 1798 in Kuhlmann et al. (2020); Mocs\u00e1ry (1897); as Sphecodes subovalis Schenck, 1853 in Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931). [LC]Sphecodes scabricollis Wesmael, 1835 in Kuhlmann et al. (2020); Rafajlovi\u0107 and Sele\u0161i (1958). [DD]\u2e17 Sphecodes schenckii Hagens, 1882 in Grozdani\u0107 (1971b); Rafajlovi\u0107 and Sele\u0161i (1958); ZM coll. [NT]\u25aa Sphecodes spinulosus Hagens, 1875 in Kuhlmann et al. (2020). [NT]\u25aa Sphecodes zangherii Noskiewicz, 1931 in Kuhlmann et al. (2020). Note: Bogusch and Straka (2012) stated that the distribution of this species is poorly known due the taxonomical problems in the past, as many specimens of this species  were missidentified S. croaticus. [DD]Systropha Illiger, 1805 (2 species)\u2e17 Systropha curvicornis  in Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); Grozdani\u0107 (1971b); Grozdani\u0107 and Mu\u010dalica (1966); Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); Lebedev (1931); Vorgin (1918), Mocs\u00e1ry (1897); ZM coll. [NT]\u2e17 Systropha planidens Giraud, 1861 in Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); Grozdani\u0107 (1971b); Grozdani\u0107 and Vasi\u0107 (1968); Grozdani\u0107 and Mu\u010dalica (1966); Vorgin (1918); Mocs\u00e1ry (1897); Apfelbeck (1896); SG coll. [VU]Vestitohalictus Bl\u00fcthgen, 1961 (2 species)\u2e17 Vestitohalictus pollinosus  as Halictus pollinosus Sichel, 1860 in Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); Mudri-Stojni\u0107 et al. (2012); Petrik (1958); Rafajlovi\u0107 and Sele\u0161i (1958); as Halictus carinaeventris Fahringer & Friese, 1921 in Mocs\u00e1ry (1897). [LC]\u2e17 Vestitohalictus vestitus  as Halictus vestitus Lepeletier, 1841 in Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1955); ZM coll. [LC]Aglaoapis Cameron, 1901 (1 species)Aglaoapis tridentata  as Dioxoides tridentata  in Stanisavljevi\u0107 (2000). [LC]Anthidiellum Cockerell, 1904 (1 species)Anthidiellum strigatum Panzer, 1805 in Kuhlmann et al. (2020); Stanisavljevi\u0107 (2000); as Anthidium strigatum  in Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1955); Mocs\u00e1ry (1897). [LC]Anthidium Fabricius, 1804 (12 species)Anthidium cingulatum Latreille, 1809 in Kuhlmann et al. (2020); Stanisavljevi\u0107 (2000); Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1955); Lebedev (1931); Mocs\u00e1ry (1897). [LC]\u25aa Anthidium diadema Latreille, 1809 in Kuhlmann et al. (2020). [DD]\u2e17 Anthidium florentinum Fabricius, 1775 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Stanisavljevi\u0107 (2000); Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1918); Mocs\u00e1ry (1897). [LC]Anthidium loti Perris, 1852 in Kuhlmann et al. (2020); Stanisavljevi\u0107 (2000); as Anthidium variegatum  in Rafajlovi\u0107 and Sele\u0161i (1958). [DD]\u2e17 Anthidium manicatum Linnaeus, 1758 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); Mudri-Stojni\u0107 et al. (2012); Stanisavljevi\u0107 (2000); Grozdani\u0107 and Vasi\u0107 (1966a); Petrik (1958); Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); Lebedev (1931); Apfelbeck (1896). [LC]\u25aa Anthidium montanum Morawitz, 1864 in Kuhlmann et al. (2020). [NT]\u2e17 Anthidium oblongatum Illiger, 1806 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016); Kruni\u0107 et al. (1988); Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1918); Mocs\u00e1ry (1897); A\u0110 coll.; as Proanthidium oblongatum  in Stanisavljevi\u0107 (2000) [LC]\u2e17 Anthidium punctatum Latreille, 1809 in Kuhlmann et al. (2020); Markov (2017); Stanisavljevi\u0107 (2000); Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); Mocs\u00e1ry (1897). [LC]Anthidium septemspinosum Lepeletier, 1841 in Kuhlmann et al. (2020); Stanisavljevi\u0107 (2000); Vorgin (1918). [DD]\u25aa Anthidium taeniatum Latreille, 1809 in Kuhlmann et al. (2020). [DD]\u25aa Anthidium undulatiforme Friese, 1917 in Kuhlmann et al. (2020). [NT]\u25aa Anthidium undulatum Dours, 1873 in Kuhlmann et al. (2020). [LC]Chelostoma Latreille, 1809 (12 species)\u2e17 Chelostoma campanularum Kirby, 1802 in Stanisavljevi\u0107 (2000); A\u0110 coll. [LC]Chelostoma distinctum Stoeckhert, 1929 in Kuhlmann et al. (2020); Stanisavljevi\u0107 (2000); as Eriades distinctus Stoeckhert, 1929 in \u017divojinovi\u0107 (1950). [LC]\u2e17 Chelostoma emarginatum Nylander, 1856 in Kuhlmann et al. (2020); A\u0110 coll.; also as Chelostoma appendiculatum  in Stanisavljevi\u0107 (2000); as Eriades emarginatus Nylander, 1856 and also as Eriades appendiculatus in Vorgin (1918). [LC]\u2e17 Chelostoma florisomne Linnaeus, 1758 in Kuhlmann et al. (2020); Stanisavljevi\u0107 (2000); A\u0110 coll.; SG coll.; as Chelostoma florisomnis in Mocs\u00e1ry (1897); as Eriades maxillosus  in Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); as Eriades florisomnis Spinola in Vorgin (1918); Apfelbeck (1896). [LC]\u25aa Chelostoma foveolatum Morawitz, 1868 in Kuhlmann et al. (2020). [LC]\u25aa Chelostoma grande Nylander, 1852 in Kuhlmann et al. (2020). [DD]Chelostoma handlirschi Schletterer, 1889 as Eriades handlirschi  in Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931). Note: According to M\u00fcller (2015) there are possible errors in older literature records regarding identification and distribution (\u201cReliable records exist only for Romania and Bulgaria\u201d) of this species. [DD]\u25aa Chelostoma mocsaryi Schletterer, 1889 in Kuhlmann et al. (2020). [LC]\u2e17 Chelostoma nasutum P\u00e9rez, 1895 New material examined: 1 \u2640; Vlasina Rid; 42.7253\u00b0N, 22.3284\u00b0E; 22\u201323 Jul. 2019; A. \u0110uki\u0107 leg.; Jelle Devalez det.; A\u0110 coll. [LC]\u2e17 Chelostoma rapunculi Lepeletier, 1841 in Kuhlmann et al. (2020); Stanisavljevi\u0107 (2000); A\u0110 coll.; as Eriades nigricornis Nylander, 1848 in Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931). [LC]\u25aa Chelostoma styriacum Schwarz & Gusenleitner, 1999 in Kuhlmann et al. (2020). [LC]\u25aa Chelostoma ventrale Schletterer, 1889 in Kuhlmann et al. (2020). [LC]Coelioxys Latreille, 1809 (17 species)\u25aa Coelioxys acanthura Illiger, 1806 in Kuhlmann et al. (2020). [DD]\u2e17 Coelioxys afer Lepeletier, 1841 as Coelioxys afra Lepeletier, 1841 in Kuhlmann et al. (2020); Stanisavljevi\u0107 (2000); Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931); Vorgin (1918); Mocs\u00e1ry (1897); A\u0110 coll.; SG coll.; as Coelioxys coronata F\u00f6rster, 1853 in Petrik (1958). [LC]Coelioxys alatus F\u00f6rster, 1853 as Coelioxys alata F\u00f6rster, 1853 in Kuhlmann et al. (2020); Stanisavljevi\u0107 (2000); \u017divojinovi\u0107 (1950). [LC]\u2e17 Coelioxys argenteus Lepeletier, 1841 as Coelioxys argentea Lepeletier, 1841 in Kuhlmann et al. (2020); Stanisavljevi\u0107 (2000); ZM coll. [LC]\u2e17 Coelioxys aurolimbatus F\u00f6rster, 1853 as Coelioxys aurolimbata F\u00f6rster, 1853 in Kuhlmann et al. (2020); Stanisavljevi\u0107 (2000); Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931); Vorgin (1918); FSUNS. [LC]Coelioxys brevis Eversmann, 1852 in Stanisavljevi\u0107 (2000); Rafajlovi\u0107 and Sele\u0161i (1958); as Coelioxys erythropyga F\u00f6rster, 1853 in Petrik (1958); Mocs\u00e1ry (1897). [LC]Coelioxys conoideus  as Coelioxys conoidea Illiger, 1806 in Kuhlmann et al. (2020); Stanisavljevi\u0107 (2000); Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950). [LC]Coelioxys echinatus F\u00f6rster, 1853 as Coelioxys echinata F\u00f6rster, 1853 in Kuhlmann et al. (2020); Stanisavljevi\u0107 (2000); as Coelioxys rufocaudata Smith, 1854 in Rafajlovi\u0107 and Sele\u0161i (1958); Mocs\u00e1ry (1897). [LC]\u2e17 Coelioxys elongatus Lepeletier, 1841 as Coelioxys elongata Lepeletier, 1841 in Kuhlmann et al. (2020); ZM coll. [LC]Coelioxys emarginatus F\u00f6rster, 1853 as Coelioxys emarginata F\u00f6rster, 1853 in Stanisavljevi\u0107 (2000); Petrik (1958); Rafajlovi\u0107 and Sele\u0161i (1958); Mocs\u00e1ry (1897). [LC]Coelioxys haemorrhoa F\u00f6rster, 1853 in Stanisavljevi\u0107 (2000); \u017divojinovi\u0107 (1950). [LC]Coelioxys inermis Kirby, 1802 in Kuhlmann et al. (2020); Stanisavljevi\u0107 (2000); as Coelioxys acuminata Nylander, 1852 in Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); Lebedev (1931). [LC]Coelioxys mandibularis Nylander, 1848 in Kuhlmann et al. (2020); Stanisavljevi\u0107 (2000). [LC]\u2e17 Coelioxys obtusus P\u00e9rez, 1884 as Coelioxys obtusa P\u00e9rez, 1884 in Kuhlmann et al. (2020); Stanisavljevi\u0107 (2000); SG coll. [LC]\u2e17 Coelioxys polycentris F\u00f6rster, 1853 in Kuhlmann et al. (2020); Stanisavljevi\u0107 (2000); Petrik (1958); Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1918); Mocs\u00e1ry (1897); SG coll. [LC]\u2e17 Coelioxys quadridentatus  in Kruni\u0107 et al. (1988); ZM coll.; as Coelioxys quadridentata  in Kuhlmann et al. (2020); Stanisavljevi\u0107 (2000). [LC]\u2e17 Coelioxys rufescens Lepeletier and Audinet-Serville, 1825 in Kuhlmann et al. (2020); Stanisavljevi\u0107 (2000); Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); Lebedev (1931); Vorgin (1918); Mocs\u00e1ry (1897); ZM coll. [LC]Heriades Spinola, 1808 (2 species)\u2e17 Heriades crenulata Nylander, 1856 in Kuhlmann et al. (2020); as Heriades crenulatus Nylander, 1856 in Mudri-Stojni\u0107 (2018); Mudri-Stojni\u0107 et al. (2012); Stanisavljevi\u0107 (2000); Kruni\u0107 et al. (1988); as Eriades crenulatus in Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1955); Mocs\u00e1ry (1897). [LC]\u2e17 Heriades truncorum Linnaeus, 1758 in Stanisavljevi\u0107 (2000); \u017divojinovi\u0107 (1950); Lebedev (1931); A\u0110 coll.; FSUNS; as Eriades truncorum (Linnaeus) in Rafajlovi\u0107 and Sele\u0161i (1958); Mocs\u00e1ry (1897). [LC]Hofferia Tkalc\u016f, 1984 (1 species)Hofferia schmiedeknechti Schletterer, 1889 in Stanisavljevi\u0107 (2000). [LC]Hoplitis Klug, 1807 (17 species)Hoplitis acuticornis Dufour & Perris, 1840 in Stanisavljevi\u0107 (2000); as Osmia acuticornis Dufour & Perris, 1840 in Rafajlovi\u0107 and Sele\u0161i (1958). [LC]\u2e17 Hoplitis adunca Panzer, 1798 in Kuhlmann et al. (2020); Markov (2017); Stanisavljevi\u0107 (2000); A\u0110 coll.; as Hoplites in Kruni\u0107 et al. (1988); as Osmia adunca  in Petrik (1958); Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); as Osmia spinolae Lepeletier, 1841 in Mocs\u00e1ry (1897). [LC]Hoplitis anthocopoides Schenck, 1853 in Stanisavljevi\u0107 (2000); as Osmia caementaria Gerst\u00e4cker, 1869 in Rafajlovi\u0107 and Sele\u0161i (1958). [LC]* Hoplitis bisulca Gerst\u00e4cker, 1869 as Osmia bisulca Gerst\u00e4cker, 1869 in Mocs\u00e1ry (1897). [LC]\u25aa Hoplitis campanularis Morawitz, 1877 in Kuhlmann et al. (2020). [LC]\u2e17 Hoplitis claviventris  New material examined: 1 \u2640; Vlasina Rid; 42.7253\u00b0N, 22.3284\u00b0E; 21 Jul. 2019; A. \u0110uki\u0107 leg.; Andrej Gogala det.; A\u0110 coll. [LC]\u2e17 Hoplitis dalmatica Morawitz, 1871 in SG coll.; as Anthocopa dalmatica  in Stanisavljevi\u0107 (2000); as Osmia dalmatica Morawitz, 1871 in \u017divojinovi\u0107 (1950). [LC]\u25aa Hoplitis illyrica Noskiewicz, 1926 in Kuhlmann et al. (2020). [LC]\u2e17 Hoplitis laevifrons Morawitz, 1872 in Kuhlmann et al. (2020); ZM coll. [LC]\u2e17 Hoplitis lepeletieri P\u00e9rez, 1879 in Stanisavljevi\u0107 (2000); SG coll. [LC]\u2e17 Hoplitis leucomelana Kirby, 1802 in Stanisavljevi\u0107 (2000); A\u0110 coll.; SG coll.; as Osmia parvula Dufour & Perris, 1840 in Rafajlovi\u0107 and Sele\u0161i (1958). [LC]\u2e17 Hoplitis loti Morawitz, 1867 in Stanisavljevi\u0107 (2000); SG coll. [LC]Hoplitis manicata Morice, 1901 in Kuhlmann et al. (2020); Stanisavljevi\u0107 (2000); as Hoplites in Kruni\u0107 et al. (1988). [LC]\u25aa Hoplitis perezi Ferton, 1895 in Kuhlmann et al. (2020). [LC]\u25aa Hoplitis praestans Morawitz, 1893 in Kuhlmann et al. (2020). [LC]\u2e17 Hoplitis tridentata Dufour & Perris, 1840 in Stanisavljevi\u0107 (2000); SG coll. [LC]\u2e17 Hoplitis tuberculata Nylander, 1848 in Stanisavljevi\u0107 (2000); SG coll. [LC]Icteranthidium Michener, 1948 (2 species)\u25aa Icteranthidium grohmanni Spinola, 1838 in Kuhlmann et al. (2020). [LC]Icteranthidium laterale Latreille, 1809 in Stanisavljevi\u0107 (2000); as Anthidium laterale Latreille, 1809 in Petrik (1958); Rafajlovi\u0107 and Sele\u0161i (1958); Mocs\u00e1ry (1897). [LC]Lithurgus Latreille, 1825 (2 species)Lithurgus chrysurus Fonscolombe, 1834 in Kuhlmann et al. (2020); Stanisavljevi\u0107 (2000); Kruni\u0107 et al. (1988); Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); Lebedev (1931); Mocs\u00e1ry (1897); Korlevi\u0107 (1890). [LC]\u2e17 Lithurgus cornutus Fabricius, 1787 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Mudri-Stojni\u0107 et al. (2012); ZM coll.; also as Lithurgus cornutus fuscipennis Lepeletier, 1841 in Stanisavljevi\u0107 (2000); as Lithurgus cornuta ssp. fuscipennis Lep. in Kruni\u0107 et al. (1988); as Lithurgus fuscipennis Lepeletier, 1841 Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); Mocs\u00e1ry (1897). [LC]Megachile Latreille, 1802 (34 species)\u2e17 Megachile albisecta Klug, 1817 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); Mudri-Stojni\u0107 et al. (2012); as Megachile sericans Fonscolombe, 1832 in Grozdani\u0107 (1971b); Vasi\u0107 (1968); Mocs\u00e1ry (1897); as Creightonella albisecta  in Stanisavljevi\u0107 (2000); SG coll. [LC]\u25aa Megachile albocristata Smith, 1853 in Kuhlmann et al. (2020). [LC]\u25aa Megachile alpicola Alfken, 1924 in Kuhlmann et al. (2020). [DD]\u2e17 Megachile apicalis Spinola, 1808 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); Mudri-Stojni\u0107 et al. (2012); Stanisavljevi\u0107 (2000); Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931); Vorgin (1918); Mocs\u00e1ry (1897). [LC]Megachile bombycina Radoszkowski, 1874 in Stanisavljevi\u0107 (2000); Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1955); \u017divojinovi\u0107 (1950); Mocs\u00e1ry (1897). [DD]\u25aa Megachile burdigalensis Benoist, 1940 in Kuhlmann et al. (2020). [DD]\u2e17 Megachile centuncularis Linnaeus, 1758 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016); Stanisavljevi\u0107 (2000); Kruni\u0107 et al. (1988); Grozdani\u0107 and Vasi\u0107 (1966a); Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); Lebedev (1931); Mocs\u00e1ry (1897); A\u0110 coll.; ZM coll. [LC]Megachile circumcincta Kirby, 1802 in Kuhlmann et al. (2020); Stanisavljevi\u0107 (2000); Rafajlovi\u0107 and Sele\u0161i (1958). [LC]\u2e17 Megachile concinna Smith, 1879 in Kuhlmann et al. (2020); as Megachile argentata  in Stanisavljevi\u0107 (2000); Petrik (1958); Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); Lebedev (1931); Mocs\u00e1ry (1897); ZM Coll. [DD]\u2e17 Megachile deceptoria P\u00e9rez 1890 in Kuhlmann et al. (2020); FSUNS. [DD]\u2e17 Megachile ericetorum Lepeletier, 1841 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); Grozdani\u0107 (1971b); Grozdani\u0107 and Mu\u010dalica (1968a); Grozdani\u0107 and Vasi\u0107 (1966a); Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1918); as Chalicodoma ericetorum  in Stanisavljevi\u0107 (2000); Kruni\u0107 et al. (1988); ZM coll. [LC]Megachile flabellipes P\u00e9rez, 1895 in Kuhlmann et al. (2020); Stanisavljevi\u0107 (2000). [DD]Megachile fulvimana Eversman, 1852 in Stanisavljevi\u0107 (2000). [DD]\u2e17 Megachile genalis Morawitz, 1880 in Kuhlmann et al. (2020); Stanisavljevi\u0107 (2000); ZM coll. [DD]\u25aa Megachile giraudi Gerst\u00e4cker, 1869 in Kuhlmann et al. (2020). [DD]Megachile hungarica Mocs\u00e1ry, 1877 as Chalicodoma hungarica Mocs\u00e1ry, 1877 in Stanisavljevi\u0107 (2000). [DD]Megachile lagopoda Linnaeus, 1761 in Kuhlmann et al. (2020); Stanisavljevi\u0107 (2000); Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); Lebedev (1931); Mocs\u00e1ry (1897). [LC]\u2e17 Megachile leachella Curtis, 1828 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016); ZM coll. [LC]Megachile leucomalla Gerst\u00e4cker, 1869 in Stanisavljevi\u0107 (2000); Petrik (1958); Mocs\u00e1ry (1897). [DD]Megachile ligniseca Kirby, 1802 in Kuhlmann et al. (2020); Stanisavljevi\u0107 (2000); Kruni\u0107 et al. (1988); Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); Lebedev (1931); Vorgin (1918). [DD]\u25aa Megachile manicata Giraud, 1861 in Kuhlmann et al. (2020). [DD]\u2e17 Megachile maritima Kirby, 1802 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016); Stanisavljevi\u0107 (2000); Kruni\u0107 et al. (1988); Petrik (1958); Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931); Mocs\u00e1ry (1897). [DD]\u2e17 Megachile melanopyga Costa, 1863 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Stanisavljevi\u0107 (2000); Rafajlovi\u0107 and Sele\u0161i (1958). [LC]\u25aa Megachile nigriventris Schenck, 1870 in Kuhlmann et al. (2020). [DD]Megachile octosignata Nylander, 1852 in Kuhlmann et al. (2020); Lebedev (1931). [DD]Megachile parietina Geoffroy, 1785 in Kuhlmann et al. (2020); also as Chalicodoma muraria auct. in Apfelbeck (1896); as Chalicodoma parietina  in Stanisavljevi\u0107 (2000); Kruni\u0107 et al. (1988). [LC]\u2e17 Megachile pilicrus Morawitz, 1877 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016); Stanisavljevi\u0107 (2000); Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); AZ coll. [DD]\u2e17 Megachile pilidens Alfken, 1924 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); Stanisavljevi\u0107 (2000); Grozdani\u0107 (1971b); Lebedev (1931); ZM coll. [LC]\u25aa Megachile pyrenaea P\u00e9rez, 1890 in Kuhlmann et al. (2020). [DD]\u2e17 Megachile pyrenaica Lepeletier, 1841 in Kuhlmann et al. (2020); as Chalicodoma pyrenaica  in Stanisavljevi\u0107 (2000); ZM coll. [DD]\u2e17 Megachile rotundata Fabricius, 1793 in Kuhlmann et al. (2020); Stanisavljevi\u0107 and Tomanovi\u0107 (2006); Stanisavljevi\u0107 (2000); Kruni\u0107 et al. ; Mihajlovi\u0107 et al. (1989); Rafajlovi\u0107 and Sele\u0161i (1958); ZM coll.; as Megachile pacifica  in Vorgin (1918); Mocs\u00e1ry (1897). [DD]\u2e17 Megachile sculpturalis Smith, 1853 in \u0106etkovi\u0107 and Ple\u0107a\u0161 (2017). New material examined: 1 \u2642, 1 \u2640; Ba\u010dki Magli\u0107; 45.3686\u00b0N, 19.5381\u00b0E; 20 Jul. 2019; B. \u0160ikoparija leg.; Sonja Mudri-Stojni\u0107 det.; FSUNS.\u2e17 Megachile versicolor Smith, 1844 in Kuhlmann et al. (2020); Stanisavljevi\u0107 (2000); Rafajlovi\u0107 and Sele\u0161i (1958); A\u0110 coll. [DD]\u2e17 Megachile willughbiella Kirby, 1802 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016); Mu\u010dalica and Stanisavljevi\u0107 (2005); Stanisavljevi\u0107 (2000); Petrik (1958); Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); Lebedev (1931); Mocs\u00e1ry (1897); A\u0110 coll.; ZM coll. [LC]Osmia Panzer, 1806 (26 species)\u2e17 Osmia andrenoides Spinola, 1808 in Kuhlmann et al. (2020); Rafajlovi\u0107 and Sele\u0161i (1958); Mocs\u00e1ry (1897); Apfelbeck (1896); as Anthocopa andrenoides Spinola, 1808 in Stanisavljevi\u0107 (2000); Kruni\u0107 et al. (1988); SG coll. [LC]\u25aa Osmia apicata Smith, 1853 in Kuhlmann et al. (2020). [LC]\u2e17 Osmia aurulenta Panzer, 1799 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); Mudri-Stojni\u0107 et al. (2012); Stanisavljevi\u0107 (2000); Kruni\u0107 et al. (1988); Grozdani\u0107 (1971b); Grozdani\u0107 and Vasi\u0107 (1965c); Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1955); Lebedev (1931); SG coll. [LC]\u2e17 Osmia bicolor Schrank, 1781 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016); Stanisavljevi\u0107 (2000); Grozdani\u0107 ; Grozdani\u0107 and Vasi\u0107 ; Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931); SG coll. [LC]\u2e17 Osmia bicornis Linnaeus, 1758 in Markov (2017); Markov et al. (2016); Grozdani\u0107 and Vasi\u0107 (1966a); Vorgin (1955); Grozdani\u0107 (1928); A\u0110 coll.; as Osmia rufa  in Kruni\u0107 and Stanisavljevi\u0107 ; Kruni\u0107 et al. ; Stanisavljevi\u0107 et al. ; Kulin\u010devi\u0107 et al. (1997); Grozdani\u0107 ; Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); Lebedev (1931); ZM coll.; SG coll. [LC]\u2e17 Osmia bidentata Morawitz, 1876 in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); M\u00fcller (2018); Markov (2017); Markov et al. (2016); Grozdani\u0107 and Radivojevi\u0107 (1972); Grozdani\u0107 (1971b); Lebedev (1931); Mocs\u00e1ry (1897); as Anthocopa bidentata  in Stanisavljevi\u0107 (2000); Kruni\u0107 et al. (1988); as Osmia affinis Frivaldszky, 1877 in Petrik (1958); as Hoplosmia bidentata  in SG coll. [LC]\u2e17 Osmia brevicornis Fabricius, 1798 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016); Stanisavljevi\u0107 (2000); as Osmia atrocaerulea Schilling, 1849 in Rafajlovi\u0107 and Sele\u0161i (1958); as Osmia panzeri Morawitz, 1869 in Mocs\u00e1ry (1897). [LC]\u2e17 Osmia caerulescens Linnaeus, 1758 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016); Stanisavljevi\u0107 (2000); Kruni\u0107 et al. (1988); Grozdani\u0107 and Vasi\u0107 (1966a); Rafajlovi\u0107 and Sele\u0161i (1958); A\u0110 coll.; SG coll.; as Osmia aenea Linnaeus, 1761 in \u017divojinovi\u0107 (1950); Lebedev (1931). [LC]Osmia cephalotes Morawitz, 1870 as Osmia cephalotes longiceps Morawitz, 1876 in Stanisavljevi\u0107 (2000). [LC]\u2e17 Osmia cornuta Latreille, 1805 in Markov (2017); Markov et al. (2016); Stanisavljevi\u0107 et al. ; Stanisavljevi\u0107 ; Kruni\u0107 and Stanisavljevi\u0107 ; Maccagnani et al. (2007); Kruni\u0107 et al. ; Kulin\u010devi\u0107 et al. (1997); Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931); A\u0110 coll.; AZ coll.; ZM coll. [LC]\u25aa Osmia croatica Friese, 1893 in Kuhlmann et al. (2020). [LC]\u2e17 Osmia emarginata Lepeletier, 1841 in Stanisavljevi\u0107 (2000); ZM coll. [LC]\u25aa Osmia erythrogastra Ferton, 1905 in Kuhlmann et al. (2020). [LC]Osmia gallarum Spinola, 1808 in Stanisavljevi\u0107 (2000); Lebedev (1931). [LC]\u25aa Osmia jason Benoist, 1929 in Kuhlmann et al. (2020). [LC]\u2e17 Osmia leaiana Kirby, 1802 in Stanisavljevi\u0107 (2000); Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); Lebedev (1931); A\u0110 coll.; as Osmia solskyi Morawitz, 1870 in Mocs\u00e1ry (1897). [LC]\u2e17 Osmia melanogaster Spinola, 1808 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016); Stanisavljevi\u0107 (2000); as Osmia melanogastra in Rafajlovi\u0107 and Sele\u0161i (1958); Mocs\u00e1ry (1897); as Osmia aterrima Morawitz, 1872 in Lebedev (1931). [LC]\u2e17 Osmia niveata Fabricius, 1804 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016); as Osmia fulviventris  in Stanisavljevi\u0107 (2000); Kruni\u0107 et al. (1988); Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1955); \u017divojinovi\u0107 (1950); Lebedev (1931); Apfelbeck (1896). [LC]\u25aa Osmia padri Tkalcu, 1974 in Kuhlmann et al. (2020). [DD]\u25aa Osmia pilicornis Smith, 1846 in Kuhlmann et al. (2020). [LC]\u2e17 Osmia rufohirta Latreille, 1811 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016); Grozdani\u0107 ; Grozdani\u0107 and Vasi\u0107 (1965c); Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); Mocs\u00e1ry (1897); SG coll; as Hoplitis rufohirta  in Stanisavljevi\u0107 (2000); as Hoplites rufohirta (Latr.) in Kruni\u0107 et al. (1988). [LC]\u25aa Osmia saxicola Ducke, 1899 in Kuhlmann et al. (2020). [LC]\u25aa Osmia signata Erichson, 1835 in Kuhlmann et al. (2020). [LC]\u2e17 Osmia spinulosa Kirby, 1802 in Mudri-Stojni\u0107 (2018); Mudri-Stojni\u0107 et al. (2012); Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1955); as Anhocopa spinulosa  in Stanisavljevi\u0107 (2000). [LC]Osmia submicans Morawitz, 1870 in Stanisavljevi\u0107 (2000); Rafajlovi\u0107 and Sele\u0161i (1958). [LC]Osmia versicolor Latreille, 1811 in Stanisavljevi\u0107 (2000); Apfelbeck (1896). [LC]Protosmia Ducke, 1900 (1 species)Protosmia longiceps Friese, 1899 as Eriades longiceps Friese, 1899 in Vorgin (1918). [DD]Pseudoanthidium Friese, 1898 (3 species)Pseudoanthidium scapulare  as Paranthidiellum lituratum  in Stanisavljevi\u0107 (2000); Kruni\u0107 et al. (1988); as Anthidium lituratum  in Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin (1918). [DD]* Pseudoanthidium reticulatum Mocs\u00e1ry, 1884 as Anthidium mocsaryi Friese, 1897 in Mocs\u00e1ry (1897). [DD]* Pseudoanthidium tenellum Mocs\u00e1ry, 1881 as Anthidium tenellum Mocs\u00e1ry, 1881 in Mocs\u00e1ry (1897). [DD]Rhodanthidium Isensee, 1927 (2 species)Rhodanthidium septemdentatum Latreile, 1809 in Kuhlmann et al. (2020); Stanisavljevi\u0107 (2000); as Anthidium septemdentatum Latreille, 1809 in Grozdani\u0107 and Vasi\u0107 (1965c); Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); Lebedev (1931). [DD]\u25aa Rhodanthidium sticticum Fabricius, 1787 in Kuhlmann et al. (2020). [DD]Stelis Panzer, 1806 (10 species)Stelis annulata Lepeletier, 1841 in Stanisavljevi\u0107 (2000); as Stelis frey-gessneri Friese, 1885 in Rafajlovi\u0107 and Sele\u0161i (1958). [DD]Stelis breviuscula Nylander, 1848 in Kuhlmann et al. (2020); Stanisavljevi\u0107 (2000); Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931); Vorgin (1918). [LC]Stelis minuta Lepeletier and Audinet-Serville, 1825 in Kuhlmann et al. (2020); Stanisavljevi\u0107 (2000); Rafajlovi\u0107 and Sele\u0161i (1958). [LC]\u25aa Stelis nasuta Latreille, 1809 in Kuhlmann et al. (2020). [LC]\u25aa Stelis odontopyga Noskiewicz, 1926 in Kuhlmann et al. (2020). [LC]Stelis ornatula Klug, 1807 in Kuhlmann et al. (2020); Apfelbeck (1896). [LC]Stelis phaeoptera Kirby, 1802 in Kuhlmann et al. (2020); Stanisavljevi\u0107 (2000); Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); Lebedev (1931). [DD]Stelis punctulatissima Kirby, 1802 in Kuhlmann et al. (2020); Stanisavljevi\u0107 (2000); as Stelis aterrima  in Rafajlovi\u0107 and Sele\u0161i (1958); Lebedev (1931); Mocs\u00e1ry (1897). [LC]\u2e17 Stelis signata Latreille, 1809 in Kuhlmann et al. (2020); Markov (2017); Markov et al. (2016); Stanisavljevi\u0107 (2000); Rafajlovi\u0107 and Sele\u0161i (1958). [LC]Stelis simillima Morawitz, 1876 in Kuhlmann et al. (2020); Kasparek (2015). [LC]Trachusa Panzer, 1804 (5 species)\u2e17 Trachusa byssina Panzer, 1798 in Kuhlmann et al. (2020); Stanisavljevi\u0107 (2000); Lebedev (1931); ZM coll. [LC]\u25aa Trachusa dumerlei Warncke, 1980 in Kuhlmann et al. (2020). [LC]Trachusa interrupta Fabricius, 1781 in Kuhlmann et al. (2020); Kasparek (2017); as Paraanthidium interruptum  in Stanisavljevi\u0107 (2000); as Anthidium interruptum  in Rafajlovi\u0107 and Sele\u0161i (1958); Mocs\u00e1ry (1897). [EN]\u25aa Trachusa laticeps Morawitz, 1873 in Kuhlmann et al. (2020). [NT]Trachusa pubescens Morawitz, 1872 in Kasparek (2017); as Archianthidium pubescens Morawitz, 1872 in Stanisavljevi\u0107 (2000); as Anthidium pubescens Morawitz, 1872 in Petrik (1958); Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); Mocs\u00e1ry (1897). [DD] Note: According to Kasparek (2018), Trachusa pubescens sensu lato is a complex of five species, and specimens from Serbia belong to the newly described Trachusa balcanica Kasparek, 2018.Dasypoda Latreille, 1802 (4 species)Dasypoda argentata Panzer, 1809 in Rafajlovi\u0107 and Sele\u0161i (1958); Mocs\u00e1ry (1897). [NT]\u25aa Dasypoda braccata Eversmann, 1852 in Kuhlmann et al. (2020). [EN]\u2e17 Dasypoda hirtipes  in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Markov (2017); Markov et al. (2016); A\u0110 coll.; also as Dasypoda plumipes Panzer, 1797 in Petrik (1958); as Dasypoda plumipes in Grozdani\u0107 (1971b); Rafajlovi\u0107 and Sele\u0161i (1958); Vorgin ; \u017divojinovi\u0107 (1950); Lebedev (1931); Mocs\u00e1ry (1897); ZM coll. [LC]\u2e17 Dasypoda pyrotrichia F\u00f6rster, 1855 New material examined: 2 \u2640\u2640; Vlasina, Dejanova reka; 42.6888\u00b0N, 22.3954\u00b0E; 24 Jul. 2019; A. \u0110uki\u0107 leg.; Denis Michez det.; A\u0110 coll. [LC]Macropis Panzer, 1809 (3 species)\u2e17 Macropis europaea Warncke, 1973 in Kuhlmann et al. (2020); A\u0110 coll.; as Macropis labiata  in Apfelbeck (1896). [LC]Macropis frivaldszkyi Mocs\u00e1ry, 1878 in Kuhlmann et al. (2020); Vorgin (1918); Mocs\u00e1ry (1897). [NT]Macropis fulvipes  in Kuhlmann et al. (2020); Lebedev (1931). [LC]Melitta Kirby, 1802 (6 species)Melitta budensis  in Grozdani\u0107 (1971b); Rafajlovi\u0107 and Sele\u0161i (1958). [LC]* Melitta dimidiata Morawitz, 1876 in Apfelbeck (1896). [NT]\u2e17 Melitta haemorrhoidalis  in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950). [LC]\u2e17 Melitta leporina  in Kuhlmann et al. (2020); Mudri-Stojni\u0107 (2018); Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); Morawitz (1876); Apfelbeck (1896). [LC]\u2e17 Melitta nigricans Alfken, 1905 in Kuhlmann et al. (2020); Rafajlovi\u0107 and Sele\u0161i (1958); \u017divojinovi\u0107 (1950); A\u0110 coll.; AZ coll. [LC]Melitta tricincta Kirby, 1802 in Kuhlmann et al. (2020); Rafajlovi\u0107 and Sele\u0161i (1958). [NT]Apidae (32%) and Megachilidae (21%). Apidae is also the family represented with most genera, 31% of the total number of 58. The genus most rich in species is Andrena (fam. Andrenidae) with 104 reported species, followed by Nomada (fam. Apidae) \u2013 77 and Lasioglossum  \u2013 72 species. Among all genera, 26 (44.8%) are represented with only one or two species. Regarding families, the lowest number of species is recorded within Mellitidae, only 13 (1.8%).Of the 706 species from six families of bees presented here for Serbia, more than half (53%) belong to only two families of the group of long-tongued bees, i.e. Apidae (28.1% / 27.2% of species), while the least diverse is Mellitidae (with only 1.9% / 1.7%). Considering there are approximately 20,000 bee species worldwide, Serbia hosts 3.5% of the total, 20.7% of Western-Palaearctic, and 34.4% of the European bee diversity, according to the list we present in this study. Regarding bee genera, more than half of Western-Palaearctic, and the majority of the European ones are represented in our list, 58 out of 105 and 77, respectively, the latter number updated form 75  are included in our list according to only one literature source each, and for almost a quarter (153) of all the species, the only source for their occurrence in Serbia is the \u201cChecklist of the Western Palaearctic Bees\u201d  have been found in various bibliographic sources and collections. However, for 97 species there are no publicly available records from the 21ic Bees\u201d . Of the Bombuscullumanus (fam. Apidae), is listed as Critically endangered at the European level. Three of the species categorised as Endangered according to the European Red List have not been recorded in Serbia in the 21st century. Therefore, Serbia hosts species of conservation concern in Europe; however, the current presence of some species requires re-confirmation and possible re-evaluation of their conservation status. Threatened species mostly belong to families Apidae , Colletidae  and Halictidae ; there is one EN species in each of the remaining three families. The pattern is similar to that at the European level, with most threatened species in Apidae, followed by Colletidae and Halictidae. The overall proportion of threatened  bee species is the same (4%), but the proportional representation of Data Deficient species is higher at 56.7% ; species assessed as Vulnerable in Europe. Comparing global and regional Red Lists has shown that species common within their overall geographical range can be threatened on a local scale, which also highlights the importance to implement conservation measures at various geographical scales (According to the European Red List , most spat 56.7% . Among sat 56.7% . Therefol scales .Andrenaconfinis, previously considered a synonym of Andrenacongruens but now regarded as a distinct species (Megachilesculpturalis, native to Eastern Asia. Until recently, European bee fauna has been without allochthonous species; however, this solitary bee has been imported, established, and is expanding rapidly, and the first record for south-east Europe was reported in Serbia in 2017 (Two of the species presented in our list are without the category of threat, since they are not in the European Red List  but they species . The sec in 2017 .An up-to-date species list is the foundation of biodiversity and conservation work, and knowing which species make up the diverse ecosystems will be critically important in order to protect and restore them. Bees represent one of the key components of global biodiversity, providing vital ecosystem services, being the primary pollinators of most agricultural crops and wild plants. Climate change, land-use change and other anthropogenic pressures have been affecting the diversity of bees throughout the world . During"}
+{"text": "In the article titled \u201cThree-Dimensional Cobalt Hydroxide Hollow Cube/Vertical Nanosheets with High Desalination Capacity and Long-Term Performance Stability in Capacitive Deionization\u201d , there w"}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-021-88390-6, published online 26 April 2021Correction to: The original version of this Article contained an error in the legend of Figure\u00a01.3, SD 223) than those with retained expression .\u201d\u201cF) Tumor cells with loss of BAP1 expression had significantly larger mean volume (801 \u03bcmnow reads:(F) tumor cells with loss of BAP1 expression had significantly larger mean volume  than those with retained expression .\u201d\u201cThe original Article has been corrected."}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-021-00041-y, published online 14 October 2021Correction to: The original version of this Article contained errors in Table 3b, where the heading showing data for \u201cRdRp\u201d and \u201cN gene\u201d was incorrectly given as \u201cMean Ct \u201d. The correct heading is \u201cMean Tt (RT LAMP)\u201d.The incorrect and correct values are given below.Incorrect:Correct:The original Article has been corrected."}
+{"text": "Scientific Reports 10.1038/s41598-021-81710-w, published online 26 January 2021Correction to: This Article contains an error in Figure\u00a03, where the color labels are reversed. The correct Figure\u00a03 appears below as Figure"}
+{"text": "Scientific Reports 10.1038/s41598-021-98183-6, published online 21 September 2021Correction to: The original version of this Article contained errors in the spelling of the authors Anna Le\u015bk\u00f3w, Ma\u0142gorzata Tarnowska, Izabela Szczuka & Dorota Diakowska which were incorrectly given as Le\u015bk\u00f3w Anna, Tarnowska Ma\u0142gorzata, Szczuka Izabela & Diakowska Dorota respectively.The original Article has been corrected."}
+{"text": "Scientific Reports 10.1038/s41598-020-78585-8, published online 10 December 2020Correction to: This Article contains errors in the Materials and methods section under subheading \u2018Statistical analyses\u2019.\u201cPrior plotting showed that the response variables changed non-linearly over time, and w in R-package itsadug54 version 2.4e therefore entered year as smooth function.\u201dshould read:\u201cPrior plotting showed that the response variables changed non-linearly over time, and we therefore entered year as smooth function.\u201d"}
+{"text": "Scientific Reports 10.1038/s41598-020-77775-8, published online 25 January 2021Correction to: The original version of this Article contained errors in Figure 3E, where the image used for \u201c3 mM Neomycin\u201d was inadvertently swapped with the image used for the \u201cControl.\u201dThe original Figure The original Article has been corrected."}
+{"text": "The authors regret that Fig.2F has been incorrectly titled. The correct title is \u201cFailure-free survival high burden M1\u201d."}
+{"text": "Correction to: Genome Biol 21, 215 (2020)https://doi.org/10.1186/s13059-020-02141-wFollowing publication of the original article , the autThe correct statement should read: \u201cWe used small RNA libraries generated from somatic tissues  as well as germline tissues (ovaries) to annotate 1441 piRNA clusters with an average size of 10.911\u2009kb  \u2026 \u201d"}
+{"text": "Case Rep. 11, 2021, was published with an error.Due to a desktop publishing error, the partial retraction notice \u201cPartial retraction of \u201cDyskeratosis congenita\u201d [Autops Case Rep 10(3) (2020) e2020203]\u201d :e2020203. The publisher apologizes for the errors."}
+{"text": "Scientific Reports 10.1038/s41598-018-38430-5, published online 14 February 2019Correction to: The Acknowledgements section in the original version of this Article was incomplete.\u201cThis work was supported by the French State programme \u201cInvestissements d\u2019Avenir\u201d managed by the Agence Nationale de la Recherche [LaBex LIFESENSES: ANR-10-LABX-65] and Groupe Optic 2000.\u201dnow reads:\u201cThis work was supported by the French State programme \u201cInvestissements d\u2019Avenir\u201d managed by the Agence Nationale de la Recherche [LaBex LIFESENSES: ANR-10-LABX-65] and Groupe Optic 2000, the ERC Consolidator Grant (773121), a James S. McDonnell Foundation, United States, scholar award (no. 652 220020284), and a Joy ventures grant to A.A.\u201dThe original Article has been corrected."}
+{"text": "Due to production errors, several corrections were omitted.In \u201cKey Components of The Polysomnographic,\u201d \u201cK-Complexes,\u201d the sub-title should be \u201cK-complexes.\u201dIn \u201cKey Components of The Polysomnographic,\u201d \u201cSleep Spindles,\u201d a sentence appears as follows: \u201cIn a clinical population of 47 patients with Obstructive sleep apnea (OSA) Headers are correct Confirmed, greater sleep spindle activity was associated with better implicit learning (Stevens et al., In \u201cCircadian Rhythms,\u201d \u201cThe Need to Assess Circadian Rhythms' to Define Sleep Disruption,\u201d a sentence appears as follows: \u201cChronobiological interventions, such as bright light therapy, have been administered as a stand-alone treatment and combined with CBT-I combined with CBT-I to moderate effect (Jank\u00f9 et al., The publisher apologizes for this mistake. The original version of this article has been updated."}
+{"text": "Nature Biomedical Engineering 10.1038/s41551-020-00675-9, published online 8 February 2021.Correction to: This Article was originally published online incorrectly without open access, whereas it is actually covered by an Open Access licence (CC BY 4.0). The copyright line in the PDF mistakenly read \u201c\u00a9 The Author(s), under an exclusive licence to Springer Nature Limited 2021\u201d but should have been \u2018\u00a9 The Author(s) 2021\u2019."}
+{"text": "Scientific Reports 10.1038/s41598-021-85394-0, published online 12 March 2021Correction to: The original version of this Article contained a repeated error, where the unit of measurement \u201cMeV\u201d was incorrectly given as \u201cmeV.\u201dThe original Article has been corrected."}
+{"text": "Scientific Reports 10.1038/srep41747, published online 02 February 2017Correction to: In this Article, the legend of Figure\u00a02 is incorrect:\u201cMEG power data for dominant (blue-patched eye) and non-dominant (red- unpatched eye) eyes before and after 150\u00a0min of monocular occlusion with either a black patch (top row) or a translucent patch (bottom row).\u201dshould read:\u201cMEG power data for non-dominant\u00a0(blue- unpatched eye) and dominant (red- patched eye) eyes before and after 150\u00a0min of monocular occlusion with either a black patch (top row) or a translucent patch (bottom row).\u201dIn the Results section,\u201cFigure\u00a02\u00a0displays the power data obtained for left (blue- patched eye) and right (red- unpatched eye) eyes using the frequency-tagging method normalized to the baseline power before monocular deprivation.\u201dshould read:\u201cFigure\u00a02\u00a0displays the power data obtained for non-dominant (blue- unpatched eye) and dominant (red- patched eye) eyes using the frequency-tagging method normalized to the baseline power before monocular deprivation.\u201d"}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-021-94121-8, published online 27 July 2021Correction to: The original version of this Article omitted the Funding section. The Funding section now reads:\u201cThis study has been funded by Instituto de Salud Carlos III through the projects \u201cPI15/00259\u201d and \"PI18/01025\", and co-funded by a European Regional Development Fund, \u201cA way of shaping Europe\u201dThe original Article has been corrected."}
+{"text": "Horticulture Researchhttps://doi.org/10.1038/s41438-021-00658-0 published online 01 November 2021Correction to: In the originally published version of this manuscript, there was an error in the CACMSInnovation Fund grant number. The grant number should read \u201cCI2021A04117\u201d instead of\u201cC12021A04117\u201d. This error has been corrected."}
+{"text": "Scientific Reports 10.1038/s41598-021-91011-x, published online 31 May 2021.Correction to: The original version of this Article contained an error in the Acknowledgments section.\u201cAB is supported by a Medical Research Council doctoral studentship [D79/543369/D-OTH/170890].\u201dnow reads:\u201cAB is supported by a Medical Research Council doctoral studentship [MR/N013867/1].\u201dThe original Article has been corrected."}
+{"text": "In the article titled \u201cUmbilical Cord Tissue-Derived Mesenchymal Stem Cells Induce T Lymphocyte Apoptosis and Cell Cycle Arrest by Expression of Indoleamine 2, 3-Dioxygenase\u201d , the aut"}
+{"text": "Communications Biology 10.1038/s42003-018-0227-z, published online 6 December 2018.Correction to: In the original version of the Article, errors were introduced in the labels in Fig.\u00a0Panels a\u2013c were incorrectly labelled \u201cLaser-Sham-2wk\u201d. The correct label for panels a and b is \u201cNormal CTRL-2wk\u201d. The correct label for panel c is \u201cNormal CTRL-4wk\u201d.Panels d\u2013f were incorrectly labelled \u201cLaser-TMSC-2wk\u201d. The correct label for panels d and e is \u201cLaser-Sham-2wk\u201d. The correct label for panel f is \u201cLaser-Sham-4wk\u201d.Panels g\u2013 i were incorrectly labelled \u201cLaser-Fibro-2wk\u201d. The correct label for panels g and h is \u201cLaser-TMSC-2wk\u201d. The correct label for panel i is \u201cLaser-TMSC-4wk\u201d.Panels j\u2013l were incorrectly labelled \u201cNormal CTRL-2wk\u201d. The correct label for panels j and k is \u201cLaser-Fibro-2wk\u201d. The correct label for panel l is \u201cLaser-Fibro-4wk\u201d.The originally published (incorrect) Fig.\u00a0The errors have been corrected in the HTML and PDF versions of the Article."}
+{"text": "Scientific Reports 10.1038/s41598-020-77818-0, published online 03 December 2020Correction to: This Article contains errors in Table 5, where the entries in the rows \u201cMinimum value\u201d and \u201cMaximum value\u201d are not aligned correctly with their corresponding columns. The correct Table 5 appears below as Table"}
+{"text": "Scientific Reports 10.1038/s41598-021-97977-y, published online 23 September 2021Correction to: The original version of this Article contained errors in Table 1, where the measurement precision values for \u201cThe common method\u201d and \u201cThe current method\u201d were inadvertently switched. The incorrect and correct values appear below.Incorrect:Correct:The original Article has been corrected."}
+{"text": "Scientific Reports 10.1038/s41598-021-99867-9, published online 14 October 2021Correction to: The original version of this Article contained an error.In the Materials and methods section, under subheading \u201cParticipants and samples\u201d,\u201cPatient demographics are provided in Table\u00a04.\u201dnow reads:\u201cPatient demographics are provided in Table\u00a01.\u201dThe original Article has been corrected."}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-020-76318-5, published online 11 November 2020Correction to: \u201cCraspedostauros sp.\u201d was incorrectly referred to as \u201cPinnularia sp.\u201d Furthermore, all references to \u201cC.sp.\u201d were incorrectly given as \u201cP.sp.\u201dThe original version of this Article contained a repeated error, where the algae species These errors have now been corrected in the original version of the Article and ts accompanying Supplementary Information file.\u00a0The original Supplementary Information 1 file is provided below.Supplementary Information."}
+{"text": "In the article titled \u201cHydroxychloroquine Effects on TLR Signalling: Underexposed but Unneglectable in COVID-19\u201d ["}
+{"text": "Scientific Reports 10.1038/s41598-021-95176-3, published online 13 August 2021Correction to: The original version of this Article contained errors in Figure\u00a05, where the x-axis label \u201cSoft drink\u201d was incorrectly given as \u201cCoca cola\u201d.The original Figure\u00a0The original Article has been corrected."}
+{"text": "Scientific Reports 10.1038/s41598-020-69271-w, published online 23 July 2020Correction to: This Article contains errors in the Methods section under subheading \u2018Patient recruitment\u2019.\u201cThe study was approved by the Joint Institutional Review Board of Taipei Medical University (TMU-JIRB No.: N201702062).\u201dshould read:\u201cThe study was approved by the Joint Institutional Review Board of Taipei Medical University (TMU-JIRB No.: N201701062 & N201812078).\u201d"}
+{"text": "In the article titled \u201cCritical Incident Disclosing Behaviors and Associated Factors among Nurses Working in Amhara Region Referral Hospitals, Northwest Ethiopia: A Cross-Sectional Study\u201d , there w"}
+{"text": "Due to a production error, the title was incorrectly written as \u201cMetformin Downregulates PD-L1 Expression in Esophageal Squamous Cell Catrcinoma by Inhibiting IL-6 Signaling Pathway\u201d. The correct title is \u201cMetformin Downregulates PD-L1 Expression in Esophageal Squamous Cell Carcinoma by Inhibiting IL-6 Signaling Pathway\u201d.The publisher apologizes for this mistake.The original version of this article has been updated."}
+{"text": "Nature Communications 10.1038/s41467-021-27668-9, published online 26 January 2022.Correction to: In this article the author name \u2018Agustin Ibanez\u2019 was incorrectly written as \u2018Augustin Ibanez\u2019. The original article has been corrected."}
+{"text": "Scientific Reports 10.1038/s41598-021-81462-7, published online 21 January 2021Correction to: This Article contains a typographical error in the Introduction section where,Coronaviridae is a matter of global concern.\u201d\u201cSARC-CoV2, an enveloped single stranded positive sense RNA virus belonging to family Should read:Coronaviridae is a matter of global concern.\u201d\u201cSARS-CoV2, an enveloped single stranded positive sense RNA virus belonging to family"}
+{"text": "Scientific Reports 10.1038/s41598-021-02863-2, published online 06 December 2021Correction to: The original version of this Article contained an error in the key for Figure\u00a03, where the light green colour indicating \u201cSevere\u201d was incorrectly labelled as \u201cD2Dx test score.\u201dThe original Figure\u00a0The original Article has been corrected."}
+{"text": "Correction to: Clinical Rheumatology10.1007/s10067-020-05546-xThe original version of this article contained error.\u201c(=33:52 h:mm)\u201d, it should have been \u201c (= 3:52 h : mm)\u201d. The original article has been corrected.In the last part of the formula under section \u201cNorm group data for timing sleep-wake behaviour in general population (study aim 1)\u201d was described"}
+{"text": "Scientific Reports 10.1038/s41598-021-99163-6, published online 12 October 2021Correction to: The original version of this Article contained errors in Equations\u00a024\u201326.In Equation\u00a024, \u201cIn Equation\u00a025, \u201cIn Equation\u00a026, \u201cnow reads:The original Article has been corrected."}
+{"text": "In the manuscript \u201cEducational program for the promotion of knowledge, attitudes and preventive practices for children in relation to traffic accidents: Experimental study\u201d, DOI: 10.1590/1984-0462/;2019;37;4;00012, published in the Rev Paul Pediatr. 2019;37(4):458-64, on page 463.Where it reads:FundingThis study did not receive funding.It should read:FundingThis study was \ufb01nanced in part by the Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior - Brasil (CAPES) - Finance Code 001."}
+{"text": "Nature Communications 10.1038/s41467-021-25998-2, published online 28 September 2021.Correction to: +\u2012anctional anal3\u203eanctional analysist assays>\u2019. The correct version states \u2018<Na+\u2012driven Cl\u203e/HCO3\u203e exchange transport assays>\u2019 in place of \u2018<Na+\u2012anctional anal3\u203eanctional analysist assays >\u2019. This has been corrected in both the PDF and HTML versions of the Article.The original version of this Article contained an error in the \u2018Methods\u2019 section, which incorrectly read \u2018<Na"}
+{"text": "Correction to: Alzheimers Res Ther 13, 164 (2021)https://doi.org/10.1186/s13195-021-00906-4Following the publication of the original article  the authBMI1 is associated with CSF amyloid-\u03b2 and rates of cognitive decline in Alzheimer\u2019s disease\u201d\u201cThe original article  has been"}
+{"text": "In the article titled \u201cLiproxstatin-1 Protects Hair Cell-Like HEI-OC1 Cells and Cochlear Hair Cells against Neomycin Ototoxicity\u201d ["}
+{"text": "In the article titled \u201cAn Efficient CNN for Hand X-Ray Classification of Rheumatoid Arthritis\u201d , referen"}
+{"text": "Scientific Reports 10.1038/srep31803, published online 18 August 2016Correction to: The Acknowledgments section in the original version of this Article is incomplete. \u201cThe authors gratefully acknowledge J.L. Noguera  for the animal material contribution. This work was funded by the Ministerio de Econom\u00eda y Competitividad (MINECO AGL2011-29821-C02 and AGL2014-56369-C2). A. Puig-Oliveras was funded by a \u201cPersonal Investigador en Formaci\u00f3\u201d (PIF) grant from Universitat Aut\u00f2noma de Barcelona (458-01-1/2011). M. Revilla was funded by a Formaci\u00f3 i Contractaci\u00f3 de Personal Investigador Novell (FI-DGR) Ph.D Grant from the Generalitat de Catalunya (ECO/1639/2013). M. Ballester is financially supported by a Ramon y Cajal contract (RYC-2013-12573) from the Spanish Ministry of Economy and Competitiveness.\u201dshould read:\u201cThe authors gratefully acknowledge J.L. Noguera  for the animal material contribution. This work was funded by the Ministerio de Econom\u00eda y Competitividad (MINECO AGL2011-29821-C02 and AGL2014-56369-C2) and the Fondo Europeo de Desarrollo Regional (FEDER). A. Puig-Oliveras was funded by a \u201cPersonal Investigador en Formaci\u00f3\u201d (PIF) grant from Universitat Aut\u00f2noma de Barcelona (458-01-1/2011). M. Revilla was funded by a Formaci\u00f3 i Contractaci\u00f3 de Personal Investigador Novell (FI-DGR) Ph.D Grant from the Generalitat de Catalunya (ECO/1639/2013). M. Ballester is financially supported by a Ramon y Cajal contract (RYC-2013-12573) from the Spanish Ministry of Economy and Competitiveness.\u201d"}
+{"text": "In the article titled \u201cSix-Year Outcomes of 25-Gauge Chandelier Illumination-Assisted Scleral Buckling\u201d , there wAdditionally, the acknowledgement section should be added as follows:"}
+{"text": "Correction to: Neurogeneticshttps://doi.org/10.1007/s10048-021-00666-1In the original published article, the name of the seventh author has been misspelled.\u201cJia-Hun Sun\u201d should be \u201cJia-Hui Sun\u201d.This is being corrected in this publication."}
+{"text": "Scientific Reports 10.1038/s41598-021-83872-z, published online 01 March 2021Correction to: The original version of this Article contained an error in Table 1, where primer sequences in the gene for \u201cSomatostatin\u201d was incorrect. As a result,\u201cForward 5\u2032-ACCCCAGACTCCGTAGTTT-3\u2032\u201d.now reads:\u201cForward 5\u2032-ACCCCAGACTCCGTCAGTTT-3\u2032\u201d.The original Article has been corrected."}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-019-56669-4, published online 27 December 2019Correction to: In the original version of this Article the Funding section was omitted.The Funding section now reads:\u201cFunda\u00e7\u00e3o de Amparo a Pesquisa do Estado do Rio de Janeiro FAPERJ , CNPq (grant 309577/2013-6), and European Union's Horizon 2020 Research and Innovation Programme under ZIKAlliance (grant Agreement no. 734548).\u201dThe original Article has been corrected."}
+{"text": "Scientific Reports 10.1038/s41598-021-92704-z, published online 24 June 2021 Correction to: The original version of this Article contained an error in the copyright line.\u201c\u00a9 The Author(s) 2021\u201dnow reads:\u201c\u00a9 UChicago Argonne, LLC, Operator of Argonne National Laboratory, Niowave Inc, and the Author 2021\u201dThe original Article has been corrected."}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-021-95660-w, published online 05 August 2021Correction to: The original version of this Article contained an error, where the model number \u201cLUX 3.0\u201d for the fluorescence imaging system was omitted.As a result, in the Materials and Methods section, subsection name:\u201cFluorescence imaging system design\u201d,now reads:\u201cFluorescence imaging system design (LUX 3.0)\u201d.\u201cAll of the fluorescence images in this study were obtained from the indigenously developed NIR fluorescence imaging system\u201d.now reads:\u201cAll of the fluorescence images in this study were obtained from the indigenously developed NIR fluorescence imaging system (LUX 3.0)\u201d.The original Article has been corrected."}
+{"text": "Scientific Reports 10.1038/s41598-021-02117-1, published online 23 November 2021Correction to: The original version of this Article contained errors.In Table 2, subheadings \u201cAlpha. Formula\u201d, \u201cSigma. Formula\u201d and \u201cBeta. Formula\u201d were incorrectly given as \u201cTheta. Formula\u201d.Incorrect:Correct:Additionally, in the section \u201cFuture directions and limitations\u201d,72 and white matter developing into the late 1920s73, despite the commonly accepted 18-year cutoff of adulthood72,73.\u201d\u201cThis is similar to humans, where neuromaturation continues well into \u201cyoung adulthood\u201d, with gray/white matter changes continuing beyond the age of 18now reads:72 and white matter developing into the late 20s73, despite the commonly accepted 18-year cutoff of adulthood72,73.\u201d\u201cThis is similar to humans, where neuromaturation continues well into \u201cyoung adulthood\u201d, with gray/white matter changes continuing beyond the age of 18The original Article has been corrected."}
+{"text": "Nature 10.1038/s41586-022-04460-3 Published online 31 January 2022Correction to: In this Article, the name of\u00a0author Jinal N. Bhiman was incorrectly shown as \u2018Jinal Bihman\u2019. The original Article has been corrected online"}
+{"text": "Following publication of the original article , the autThe correct statement is, \u201cElena M. Yubero-Serrano, Juan F. Alcal\u00e1-Diaz, Diego G\u00f3mez-Coronado and Jose Lopez-Miranda contributed equally to this work\u201d instead of \u201cElena M. Yubero-Serrano and Jose Lopez-Miranda contributed equally to this work\u201d.The original article has been corrected."}
+{"text": "Polygonatum sibiricum Polysaccharides in D-Galactose-Induced Heart Aging Mice\u201d [In the article titled \u201cAntioxidant Effect of ng Mice\u201d , there i"}
+{"text": "Scientific Reports 10.1038/s41598-022-07739-7, published online 07 March 2022Correction to: The original version of this Article contained an error in Figure 5 where the labels \u201cPTFE\u201d and \u201cGelatin\u201d were interchanged. The original Figure The original Article has been corrected."}
+{"text": "Scientific Reports 10.1038/s41598-021-90562-3, published online 26 May 2021Correction to: The original version of this Article contained a repeated error, where the reference number of the CECT strain \u201c30295\u201d was incorrectly given as \u201c30,295\u201d.The original Article has been corrected."}
+{"text": "Scientific Reports 10.1038/s41598-021-93944-9, published online 13 July 2021Correction to: The original version of this Article contained errors.In the legend of Figure\u00a02,C) Scatter plots for intra-session features with their best fit line.\u201d\u201cA larger distribution amplitude  in a regular \u201csaw-tooth\u201d pattern (indicating a lower approximate entropy) characterizes mice with lower rotarod scores in B compared to mice in A.  Scatter plots for intra-session features with their best fit line.\u201d\u201cA regular \u201csaw-tooth\u201d pattern (indicating a lower approximate entropy) characterizes mice with lower rotarod scores in B compared to mice in A.  Representative horizontal paw position changes over time for mice with greater (A) and smaller (B) rotarod scores. A broader distribution of amplitudes (indicating greater variance) is characteristic of mice with greater rotarod scores in A as compared to mice in (B). (C) Scatter plots for intra-session features with their best fit line.\u201d\u201c Representative horizontal paw position changes over time for mice with greater (A) and smaller (B) rotarod scores.  Scatter plots for intra-session features with their best fit line.\u201d\u201c(The original Article has been corrected."}
+{"text": "Although aging in the community promotes well-being in older adults, contextual factors  may impact this relationship. Identifying such risk factors represents a first step toward improving older adult well-being. NHATS data (Rounds 5\u20138) were used to answer two research questions (RQs). RQ1: \u201cIs housing cost burden significantly associated with well-being?\u201d RQ2: \u201cIs this association further moderated by neighborhood cohesion and neighborhood disorder?\u201d Participants were 18,311 adults \u2265 65 years old. Well-being was assessed by summing 11 commonly identified indicators. Two items were merged to assess housing cost burden . Neighborhood cohesion and disorder were combined . Both RQs were assessed through a random coefficient model controlling for established covariates. RQ1 results revealed that, compared to \u201cno burden,\u201d \u201cno money for utilities or rent\u201d  and \u201cno money for rent\u201d  were significantly associated with well-being. RQ2 results revealed that \u201cno cohesion, no disorder\u201d significantly moderated the association between \u201cno money for utilities or rent\u201d and well-being . These results indicate that increased housing cost burden is associated with decreased well-being, especially for those reporting no neighborhood cohesion. Future research should examine neighborhood-level protective factors promoting cohesion for older adults to support well-being."}
+{"text": "Christina Feller\u2019s degrees should have appeared as BA, BS. This article has been corrected.1In the Original Investigation \u201cClassification of Comprehensive Neuro-Ophthalmologic Measures of Postacute Concussion,\u201d"}
+{"text": "OncogeneCorrection to: 10.1038/s41388-020-01568-6In the original published version the \u201cFunding statement\u201d was incorrect. Please find the correct \u201cFunding statement\u201d below.The original article has been corrected."}
+{"text": "Paenibacillus larvae C3larvinA modulates catalytic efficiency\u201d (Biosci Rep (2021) 41(1), DOI: 10.1042/BSR20203727) would like to correct The authors of the original article \u201cThe N-terminus of"}
+{"text": "Correction to: Microbiome 9, 163 (2021)https://doi.org/10.1186/s40168-021-01096-9Following the publication of the original article , the autermichael\u201d should read \u201cMusie S. Ghebremichael\u201d\u201cMusie S. GhebThe original article has been updated."}
+{"text": "Conserv Physiol 10(1): coab099; doi: 10.1093/conphys/coab099In the originally published version of this manuscript, the spelling of the co-author\u2019sname was incorrect. The name should be \u201cLoan Thi Le\u201d instead of \u201cLoan Thi Li\u201d. This error hasnow been corrected online."}
+{"text": "Correction to: Reprod Biol Endocrinol 19, 28 (2021)https://doi.org/10.1186/s12958-021-00721-4Following publication of the original article , the autAbstract, MethodsHIPAA\u2026\u201d\u201cCross sectional cohort patient survey using an anonymous, self-reported, single time, web-based, HIPPA\u2026.\u201d Should read \u201cCross sectional cohort patient survey using an anonymous, self-reported, single time, web-based, COVID-19\u2026\u201dIntroduction, 2nd paragraph, 2nd line \u201cdue to the Covid-19\u2026\u201d should read \u201cdue to the Materials and Methods, 8th and 11th lines \u201cCovid-19\u201d should read \u201cCOVID-19\u201dHeading Covid-19 experience and attitudes, should read COVID-19Last sentence of that section \u201cPlease see Table 3 for summary of Covid-19 experience and attitudes\u201d should read \u201cPlease see Table 3 for summary of COVID-19 experience and attitudes.\u201dDiscussion section, 1st paragraph 2nd sentence: \u201cof the Covid-19 pandemic\u201d should read \u201cof the COVID-19 pandemic\u201dConclusions section, 1st paragraph, 2nd sentence \u201cpsychological experience and coping strategies of patients pausing their care due to Covid-19.\u201d Should read \u201cpsychological experience and coping strategies of patients pausing their care due to COVID-19. \u201c"}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-021-81643-4, published online 21 January 2021Correction to: The original version of this Article contained errors in Table 2, where the Unadjusted HR values were incorrect for \u201cBCG scar\u201d, \u201cRevaccination (BCG scar\u2009+\u2009new dose)\u201d and \u201cBCG applied at examination\u201d. The correct and incorrect values appear below.Incorrect:Correct:The original Article has been corrected."}
+{"text": "Scientific Reports 10.1038/s41598-021-87664-3, published online 16 April 2021Correction to: The original version of this Article contained an error in Table 1, where the emitting dipole strength of \u201cFast-method\u201d agg. was incorrectly given as \u201c78\u201d. The correct value is \u201c33.2\u201d.The original Article has been corrected."}
+{"text": "Scientific Reports 10.1038/s41598-020-76364-z, published online 06 November 2020Correction to: The original version of this Article and accompanying Supplementary Information file contained a repeated error, where the co-ordinates given for the Redcliffe Vale, Queensland study site \u201c\u201d was incorrectly given as \u201c.\u201dThe original Article and accompanying Supplementary Information file have been corrected."}
+{"text": "Scientific Reports 10.1038/s41598-021-85381-5, published online 26 March 2021Correction to: The original version of this Article contained an error in the Materials and methods section, under the subheading \u2018Data\u2019, where28.\u201d\u201cEstimates of county-level prevalence were age-adjusted using the 2000 United States standard population using the following age groups: 20\u201344, 45\u201364, and 65 and oldernow reads:28. Since T2D accounts for 90\u201395% of all types of diabetes, we have used T2M to represent USDSS county-level diabetes prevalence.\u201d\u201cEstimates of county-level prevalence were age-adjusted using the 2000 United States standard population using the following age groups: 20\u201344, 45\u201364, and 65 and olderIn addition, in the Discussion section,8\u201310.\u201d\u201cSeveral spatial modeling approaches have demonstrated an association between county-level T2D prevalence and obesitynow reads:8\u201310.\u201d\u201cSeveral spatial modeling approaches have demonstrated an association between county-level diabetes prevalence and obesityThe original Article has been corrected."}
+{"text": "Correction to:Wien Klin Wochenschr 202110.1007/s00508-021-01881-4The original version of this article unfortunately contained a\u00a0mistake in Fig."}
+{"text": "In Figures 1B and 2B, the x-axis label was incorrectly published as \u201cOR (95% CI)\u201d; that label should have appeared as \u201cOR.\u201d This article has been corrected.1In the Original Investigation titled \u201cMortality Rates Among Hospitalized Patients With COVID-19 Infection Treated With Tocilizumab and Corticosteroids: A Bayesian Reanalysis of a Previous Meta-analysis,\u201d"}
+{"text": "In the article titled, \u201cA Versatile Surface Bioengineering Strategy Based on Mussel-Inspired and Bioclickable Peptide Mimic\u201d , there w"}
+{"text": "Correction to: BMC Genomics 22, 531 (2021)https://doi.org/10.1186/s12864-021-07808-7Following publication of the original article , the autEndashaw TerefeGurja BelayAbdulfatai TijjaniJian-Lin HanOlivier HanotteThe corrected authorship list and the updated \u2018Authors\u2019 contributions\u2019 and \u2018Acknowledgements\u2019 declarations are provided in this Correction article. The original article  has been"}
+{"text": "In the article titled \u201cApplication of 3D Printing-Assisted Articulating Spacer in Two-Stage Revision Surgery for Periprosthetic Infection after Total Knee Arthroplasty: A Retrospective Observational Study\u201d , some of"}
+{"text": "Scientific Reports 10.1038/s41598-021-98414-w, published online 27 September 2021Correction to: The original version of this Article contained an error.In the Results section, under subheading \u2018High level of VISTA is frequent in epithelioid mesothelioma and its expression level correlates with Hedgehog and immune pathway components\u2019,P\u2009=\u20090.03, r\u2009=\u20090.42) and with MTAP score , consistent with disordered cellular division accompanying CDKN2A deletion.\u201d\u201cKi67 correlated with copy number burden  and with MTAP score , consistent with disordered cellular division accompanying CDKN2A deletion.\u201d\u201cKi67 correlated with copy number burden (The original Article has been corrected."}
+{"text": "Scientific Reports 10.1038/s41598-021-97443-9, published online 13 September 2021Correction to: The original version of this Article contained errors in the Figure legends of Figure\u00a03 and Figure\u00a04. The legends of these Figures were inadvertently switched.The legend of Figure\u00a03:Tc-\u03b22t cis-regulatory regions drive EGFP expression in testes. (A) Testes were dissected from Tc-\u03b22t-EGFP#2 (top right) and white eye mutant (lower left) beetles and viewed under bright field, EGFP or DsRED filters.\u201d\u201cnow reads:T. castaneum. (A) Transgenic adult male and female beetles viewed under bright field (B) DsRED filter and (C) GFP filter. Arrows indicate the abdomen where EGFP expression respectively was expected for transgenic male beetles in Tc-\u03b22t-EGFP lines in gfp field.\u201d\u201cFluorescent microphotographs showing sex-specific \u03b22t drive EGFP expression in The legend of Figure\u00a04:T. castaneum. (A) Transgenic adult male and female beetles viewed under bright field (B) DsRED filter and (C) GFP filter. Arrows indicate the abdomen where EGFP expression respectively was expected for transgenic male beetles in Tc-\u03b22t-EGFP lines in gfp field.\u201d\u201cFluorescent microphotographs showing sex-specific \u03b22t drive EGFP expression in now reads:Tc-\u03b22t cis-regulatory regions drive EGFP expression in testes. (A) Testes were dissected from Tc-\u03b22t-EGFP#2 (top right) and white eye mutant (lower left) beetles and viewed under bright field, EGFP or DsRED filters.\u201d\u201cThe original Article has been corrected."}
+{"text": "Scientific Reports 10.1038/s41598-020-79866-y, published online 12 January 2021Correction to: In the original version of this Article, the author Jorge Enrique Tovar Perez was incorrectly indexed.p\u00a0(cm/s2)\u2019 in \u2018Doppler No angle correction\u2019. The original Table In addition, Table 2 contained an error in the value for \u2018v\u2032The original Article has been corrected."}
+{"text": "Bioinformatics (2020) doi: 10.1093/bioinformatics/btaa758\u201cThe title of this paper was originally, erroneously displayed as \u201cDecombinator V4: an improved AIRR compliant-software package for T-cell receptor sequence annotation?\u201d. This should have appeared as \u201cDecombinator V4: an improved AIRR-C compliant software package for T-cell receptor sequence annotation. This has now been corrected online\u201d."}
+{"text": "Correction to: J Neurodev Disord 13, 41 (2021) 10.1186/s11689-021-09382-1Mir et al., 2020 \u2013 Quality weightings of \u2018Autism - 2\u2019 \u2018Sample Identification - 1\u2019 \u2018Design - 2\u2019.Vermeirsch et al., 2020 - Quality weightings of \u2018Autism - 2\u2019 \u2018Sample Identification - 1\u2019 \u2018Design.In the original publication of this article  the follThe correct Table"}
+{"text": "Scientific Reports 10.1038/s41598-021-88926-w, published online 30 April 2021Correction to: 3+\u201d was incorrectly given as \u201cC3+\u201dThe original PDF version of this Article contained a typographical error in the title of the paper, where \u201cCThe original Article has been corrected."}
+{"text": "Nature Communications 10.1038/s41467-022-28926-0; Article published online 10 March 2022Correction to: The HTML version of this Article included a redundant file \u2018Reporting Summary\u2019. This file and related description is now removed."}
+{"text": "Scientific Reports 10.1038/s41598-022-06009-w, published online 10 February 2022.Correction to: The original version of this Article contained a repeated error in the BioProject ID number where \u201cPRJNA805549\u201d was incorrectly given as \u201cPRJNA 828053\u201d.The original Article has been corrected."}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-021-83530-4, published online 15 February 2021Correction to: The original version of this Article contained a repeated error where the unit \u201cMeV\u201d was incorrectly given as \u201cmeV\u201d in the Introduction section.The original Article has been corrected."}
+{"text": "Scientific Reports 10.1038/s41598-021-92515-2, published online 23 June 2021Correction to: The original version of this Article contained an error in Figure\u00a04 where panel (c), (d) and (f) were incorrectly displayed. The original Figure\u00a0The original Article has been corrected."}
+{"text": "In the original article, there was an error. The patient selection criteria from the SEER database were incompletely entered, returning an incorrect number of patients, according to the criteria described in the study.Material and Methods, Inclusion and Exclusion Criteria, paragraph 5:A correction has been made to {Race, Sex, Year Dx.Sex} = \u2018 Female\u2019AND {Site and Morphology.ICD-O-3 Hist/behav} = \u20188500/3: Infiltrating duct carcinoma, NOS\u2019AND {Race and Age (case data only).Race recode }!= \u2018 Unknown\u2019AND {Stage - 7th edition.Derived AJCC M, 7th ed (2010-2015)} = \u2018M0\u2019,\u2019M0(i+)\u2019AND {Stage - 7th edition.Derived AJCC Stage Group, 7th ed (2010-2015)}!= \u20180\u2019,\u20190a\u2019,\u20190is\u2019,\u2019IV\u2019,\u2019IVNOS\u2019,\u2019IVA\u2019,\u2019IVA1\u2019,\u2019IVA2\u2019,\u2019IVB\u2019,\u2019IVC\u2019,\u2019NA\u2019,\u2019OCCULT\u2019,\u2019UNK Stage\u2019,\u2019Blank(s)\u2019AND {Extent of Disease.Breast Subtype (2010+)} = \u2018HR+/HER2+ \u2019,\u2019HR-/HER2+ (HER2 enriched)\u2019,\u2019HR+/HER2- \u2019,\u2019HR-/HER2- (Triple Negative)\u2019AND {Site and Morphology.Grade} = \u2018Well differentiated; Grade I\u2019,\u2019Moderately differentiated; Grade II\u2019,\u2019Poorly differentiated; Grade III\u2019,\u2019Undifferentiated; anaplastic; Grade IV\u2019AND {Therapy.Reason no cancer-directed surgery} = \u2018Surgery performed\u2019AND {Site and Morphology.Primary Site - labeled} = \u2018C50.0-Nipple\u2019,\u2019C50.1-Central portion of breast\u2019,\u2019C50.2-Upper-inner quadrant of breast\u2019,\u2019C50.3-Lower-inner quadrant of breast\u2019,\u2019C50.4-Upper-outer quadrant of breast\u2019,\u2019C50.5-Lower-outer quadrant of breast\u2019,\u2019C50.6-Axillary tail of breast\u2019,\u2019C50.8-Overlapping lesion of breast\u2019,\u2019C50.9-Breast, NOS\u2019AND {Site and Morphology.Laterality}!= \u2018Only one side - side unspecified\u2019,\u2019Bilateral, single primary\u2019,\u2019Paired site: midline tumor\u2019,\u2019Paired site, but no information concerning laterality\u2019AND {Multiple Primary Fields.Sequence number} = \u2018One primary only\u2019AND {Cause of Death (COD) and Follow-up.Survival months flag} = \u2018Complete dates are available and there are more than 0 days of survival\u2019AND {Cause of Death (COD) and Follow-up.SEER other cause of death classification}!= \u2018N/A not seq 0-59\u2019AND {Cause of Death (COD) and Follow-up.Survival months}!= 0-5AND {Stage - 7th edition.Derived AJCC T, 7th ed (2010-2015)}!= \u2018T0\u2019,\u2019Ta\u2019,\u2019Tis\u2019,\u2019Tispu\u2019,\u2019Tispd\u2019,\u2019T1mic\u2019,\u2019NA\u2019,\u2019TX\u2019,\u2019Blank(s)\u2019AND {Stage - 7th edition.Derived AJCC N, 7th ed (2010-2015)}!= \u2018N1mi\u2019,\u2019N1NOS\u2019,\u2019NA\u2019,\u2019NX\u2019,\u2019Blank(s)\u2019AND {Extent of Disease.ER Status Recode Breast Cancer (1990+)}!= \u2018Unknown\u2019AND {Extent of Disease.PR Status Recode Breast Cancer (1990+)}!= \u2018Unknown\u2019AND {Extent of Disease.Regional nodes examined (1988+)}!= 99AND {Extent of Disease.Regional nodes positive (1988+)}!= 95-99AND {Extent of Disease.CS tumor size (2004-2015)} = 1-995AND {Extent of Disease.CS extension (2004-2015)}!= 950-999AND {Extent of Disease.CS lymph nodes (2004-2015)}!= 130,150,155,255,257,290,510,610,735,740,745,810AND {Extent of Disease.CS Reg Node Eval (2004-2015)}!= 0-2,5-6,8-9AND {Extent of Disease.CS Tumor Size/Ext Eval (2004-2015)}!= 0-2,5-6,8-9AND {Extent of Disease.CS Mets Eval (2004-2015)}!= 9AND {Extent of Disease.CS mets at dx (2004-2015)} = 0-7AND {Extent of Disease.CS site-specific factor 6 (2004+ varying by schema)}!= 888-988AND {Therapy.RX Summ\u2013Surg Prim Site (1998+)}!= 19,90-99AND {Extent of Disease.CS site-specific factor 7 (2004+ varying by schema)}!= 998-999AND {Extent of Disease.CS site-specific factor 15 (2004+ varying by schema)}!= 988-999The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "In the manuscript \u201cRisk and preventive factors for traffic accidents: Analysis of children\u2019s perception using the edutherapeutic method\u201d, DOI: 10.1590/1984-0462/2020/38/2018281, published in the Rev Paul Pediatr. 2020;38:e2018281, on page 7:Where it reads:FundingThis study did not receive funding.It should read:FundingThis study was \ufb01nanced in part by the Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior - Brasil (CAPES) - Finance Code 001."}
+{"text": "BMC Medicine 20, 1\u201311 (2022)https://doi.org/10.1186/s12916-022-02234-2The original article contained an error whereby the \u2018HF\u2019 sub-heading within Table\u00a02 was mistakenly duplicated over the adjacent sub-headings. This has since been corrected."}
+{"text": "Background: Viruses cause various human diseases, some of which become pandemic outbreaks. This study synthesized evidence on antiviral medicinal plants in Africa which could potentially be further studied for viral infections including Coronavirus disease 2019 (COVID-19) treatment.Methods: PUBMED, CINAHIL, Scopus, Google Scholar, and Google databases were searched through keywords; antiviral, plant, herb, and Africa were combined using \u201cAND\u201d and \u201cOR\u201d. In-vitro studies, in-vivo studies, or clinical trials on botanical medicine used for the treatment of viruses in Africa were included.Results: Thirty-six studies were included in the evidence synthesis. Three hundred and twenty-eight plants were screened for antiviral activities of which 127 showed noteworthy activities against 25 viral species. These, were Poliovirus (42 plants), HSV (34 plants), Coxsackievirus (16 plants), Rhinovirus (14plants), Influenza (12 plants), Astrovirus (11 plants), SARS-CoV-2 (10 plants), HIV (10 plants), Echovirus (8 plants), Parvovirus (6 plants), Semiliki forest virus (5 plants), Measles virus (5 plants), Hepatitis virus (3 plants), Canine distemper virus (3 plants), Zika virus (2 plants), Vesicular stomatitis virus T2 (2 plants). Feline herpesvirus (FHV-1), Enterovirus, Dengue virus, Ebola virus, Chikungunya virus, Yellow fever virus, Respiratory syncytial virus, Rift Valley fever virus, Human cytomegalovirus each showed sensitivities to one plant.Conclusion: The current study provided a list of African medicinal plants which demonstrated antiviral activities and could potentially be candidates for COVID-19 treatment. However, all studies were preliminary and in vitro screening. Further in vivo studies are required for plant-based management of viral diseases. Viruses cause various human diseases of which several such as Ebola, HIV/AIDS, and Hepatitis B are hard to treat. Many pandemic outbreaks in world history were caused by a viral infection. The Spanish flu pandemic of 1918, the deadliest in history, infected an estimated 500 million people worldwide; which is about one-third of the planet\u2019s population, and killed an estimated 20 million to 50 million people (1). In recent years, pandemics have arisen and have also been contained using various approaches. For example, Ebola virus outbreak between 2013 and 2016 with 11323 deaths , CoronavThe use of natural medicinal agents dates back to human prehistory where plants formed the basis of traditional medicine (TM) systems. Traditional medicine refers to health practices, approaches, knowledge, and beliefs incorporating plant, animal, and mineral-based medicines, spiritual therapies, manual techniques, and exercises which are applied singularly or in combination to treat or to diagnose and prevent illnesses or maintain well-being . TraditiSeveral herbal medicines have been used to treat viral infections traditionally for a long time. Some studies have reported the inhibitory effect of medicinal plant extracts against several viruses. Some of these studies were conducted on HIV, herpes simplex virus, hepatitis B virus, and poliovirus. For example, ethnobotanical studies in Africa described the treatment of viral hepatitis with traditional medicine in Africa . FurtherThis review was conducted using database searches and followed statements for Reporting Systematic Reviews and Meta-Analyses .Data were collected from MEDLINE/PUBMED, CINAHIL, Google Scholar, and Scopus databases. No language limitations were applied to reduce selection bias and Google was used to translate articles published in other languages than English. The search strategy used the following terms with appropriate Boolean operators; (\u201cvirus diseases\u201d OR (\u201cvirus\u201d AND \u201cdiseases\u201d) OR \u201cvirus diseases\u201d OR  OR \u201cviral infection\u201d) OR (\u201cpoliovirus\u201d OR \u201cpoliovirus\u201d OR HSV OR (\u201csimplexvirus\u201d OR \u201csimplexvirus\u201d OR (\u201cherpes\u201d AND \u201csimplex\u201d AND \u201cvirus\u201d) OR \u201cherpes simplex virus\u201d) OR  OR \u201chuman influenza\u201d OR \u201cinfluenza\u201d) OR (astro AND (\u201cviruses\u201d OR \u201cviruses\u201d OR \u201cvirus\u201d)) OR (\u201cparvovirus\u201d OR \u201cparvovirus\u201d) OR (\u201crhinovirus\u201d OR \u201crhinovirus\u201d) OR  OR (\u201chiv\"OR \u201chiv\u201d) OR (\u201chiv\u201dOR \u201chiv\u201d OR (\u201chuman\u201d AND \u201cimmunodeficiency\u201d AND \u201cvirus\u201d) OR \u201chuman immunodeficiency virus\u201d) OR (semiliki AND (\u201cforests\u201dOR \u201cforests\u201d OR \u201cforest\u201d) AND (\u201cviruses\u201dOR \u201cviruses\u201d OR \u201cvirus\u201d)) OR (\u201cmeasles virus\u201dOR (\u201cmeasles\u201d AND \u201cvirus\u201d) OR \u201cmeasles virus\u201d) OR (\u201chepatitis viruses\u201dOR (\u201chepatitis\u201d AND \u201cviruses\u201d) OR \u201chepatitis viruses\u201d OR (\u201chepatitis\u201d AND \u201cvirus\u201d) OR \u201chepatitis virus\u201d) OR (\u201czika virus\u201dOR (\u201czika\u201d AND \u201cvirus\u201d) OR \u201czika virus\u201d) OR ((\u201cvesicular stomatitis indiana virus\u201dOR (\u201cvesicular\u201d AND \u201cstomatitis\u201d AND \u201cindiana\u201d AND \u201cvirus\u201d) OR \u201cvesicular stomatitis indiana virus\u201d OR (\u201cvesicular\u201d AND \u201cstomatitis\u201d AND \u201cvirus\u201d) OR \u201cvesicular stomatitis virus\u201d) AND T2) OR (\u201ccoronavirus disease 2019\u201d OR \u201cCOVID-2019\u2033) AND \u201cherbal medicine\u201d OR \u201ctraditional medicine\u201d OR \u201coriental medicine\u201d OR \u201cChinese medicine\u201d OR \u201cAfrican medicine\u201d OR \u201cherbal formula\u201d OR herb AND\u201d) AND (\u201c AND (\u201cafrica\"OR \u201cafrica\u201d) AND \u201cOR\u201d AND  OR \u201cafrican continental ancestry group\u201d OR \u201cafrican\u201d) AND countries).http://etd.aau.edu.et, http://erepository.uonbi.ac.ke). EndNote reference manager was used to remove the duplications of references before screening. Either in vitro studies or in vivo studies or clinical trials of herbal medicine on African medicinal plants were included. Studies were eligible for inclusion if they were conducted to determine antiviral activities using available scientific methods and conducted on medicinal plants in Africa. Studies conducted on medicinal plants outside of Africa were excluded from the study. Review articles and ethnobotanical studies were also excluded. Eligibility assessment was conducted by TB and SD independently and disagreement between authors was resolved by discussion.We included original research articles and unpublished dissertations from their inception to 2020. The unpublished dissertations were obtained from university website , HSV (34 plants), Coxsackievirus (16 plants), Rhinovirus (14plants), Influenza (12 plants), Astrovirus (11 plants), SARS-CoV-2 (10 plants), HIV (10 plants), Echovirus (8 plants), Parvovirus , Measles virus (5 plants), Hepatitis virus (3 plants), Canine distemper virus (3 plants), Zika virus (2 plants), Vesicular stomatitis virus T2 (2 plants). Feline herpes virus (FHV-1), Enterovirus, Dengue virus, Ebola virus, Chikungunya virus, Yellow fever virus, Respiratory syncytial virus, Rift Valley fever virus, Human cytomegalovirus each showed sensitivities to one plant \u20134. Isola2 plants,oe ferox , a polysLinearis , Asiaticasiatica , Catechiutescens .This study summarized the antiviral activities of African medicinal plants. Forty two African medicinal plants showed noteworthy activities against poliovirus and twenty four against HSV.Recently, 10 African medicinal plants from Morocco showed noteworthy activities against SARS-CoV-2 (58). However, there is no currently available published study on Africa medicinal plants demonstrating clinical effectiveness. In contrast, China has developed several Chinese herbal medicines (CHM) and produced numerous clinical studies and publications. There is a daring absence of published studies on herbal medicine use in Africa in comparison to the actual magnitude of its practice. Many Africans are using one or another type of African traditional medicine either for prevention or treatment of COVID-19.Artemisia annua called COVID Organics which was even exported abroad , a highly defined hit-list of seven compounds. Furthermore, four nontoxic, druggable plant-derived alkaloids and terpenoids that bind to the receptor-binding site and catalytic dyad of SARS-CoV-2 3CLpro were identified. More than half of the selected top 20 alkaloids and terpenoids had a binding affinity for the 3CLpro of the SARS-coronaviruses that surpassed reference inhibitors. The 6-oxoisoiguesterin from Bisnorterpenes had the highest binding affinity to the 3CLpro of SARS-CoV-2 while 20-epi-isoiguesterinol from Bisnorterpenes, isoiguesterin from Bisnorterpenes, 20-epibryonolic acid from Cogniauxia podolaena was the top docked compounds to 3CLpro of SARS-CoV and MERS-CoV. The study revealed that natural agents from the alkaloids and terpenoids class of compounds are capable of inhibiting the 3CLpro with a high inhibitory pattern to both SARS-CoV-2 and SARS-CoV , a natural product from the plant, acts on chemokine receptors and inhibits the entry of HIV  were identified. The previous study also showed that multiple phorbol esters had anti-HIV-1 activities  and funcin vitro with a CC50 value of more than 100\u00a0\u03bcg/ml. These were aqueous extracts from Carissa edulis (Apocynaceae), Prunus africana Kalkman (Rosaceae) and the methanol extract from Acacia mellifera Benth (Fabaceae). Extracts of C. edulis exhibited the highest activity; an over 12.15% inhibition rate relative to the negative control. P. africana and A. mellifera extract demonstrated 5% inhibition and 2.15% inhibition respectively, relative to controls. Further confirmation of the activity of these plants using the quantitative real-time PCR technique showed the aqueous extract of C. edulis and the methanol extract of A. mellifera exhibited sustained activity over a range of plant extract concentrations from 31.25\u00a0\u03bcg/ml to 125\u00a0\u03bcg/ml. The evaluation of the EC50 the two plant extracts exhibiting notable anti\u2013HBV activity using this technique yielded; C. edulis\u2019 EC50 was 331.6\u00a0\u03bcg/ml while that of A. mellifera was 295.0\u00a0\u03bcg/ml  against influenza A virus exhibited antiviral effect. Most effective result were obtained from Rapanea melanophloeos methanol leaf extract (EC50 = 113.3\u00a0\u03bcg/ml) and Pittosporum viridiflorum methanol, 100 and 30% ethanol and acetone leaf extracts   . Ethiopi A virus  (Table 2Carissa edulis (Apocynaceae) has shown significant anti-HSV activity in vitro and in vivo (in vitro with minimal cell cytotoxicity (Lannea schweinfurthii, Combretum adenogonium, Ficus sycomorus, and Terminalia mollis showed strong antiviral activity against Herpes Simplex Virus type 1. Out of 42 Egyptian medicinal plants, Ephedra alata and Moringa peregrina are found to have antiviral activity against HSV. Also, the results revealed that Capparis sinaica, Tamarix nilotica, and Cyperus rotundus are found to have a virucidal effect against HSV(In sub-Saharan Africa, high prevalence rates between 60 and 80% in young adults have been recorded in population-based studies. It is usually managed by antiviral drugs such as a nucleoside analog acyclovir. However, resistance to ACV has been reported mainly among immunocompromised patients . Medicin in vivo . The exttoxicity . The extainst HSV.in vitro possible dose range, duration of action and in vivo pharmacodynamics properties cannot be established.The current study is only a preliminary study where some studies reported naively. As all studies In conclusion, African medicinal plants pose significant antiviral activities and could potentially be candidates for viral disease treatment and/or management. It is imperative therefore that research on currently available African medicinal plants be highly recommended. Outcomes from such studies would potentially lead to breakthrough discoveries for the management and/or treatment of COVID-19 and various other viral infections upon appropriate optimization."}
+{"text": "Walking-based performance fatigability measures  may not adequately capture performance deterioration as self-pacing is a common compensatory strategy in those with low activity tolerance. To overcome this limitation, we developed a new approach with accelerometry  during fast-paced 400m-walk . Cadence (steps/second) was estimated using raw accelerometer data (R \u201cADEPT\u201d). Penalized regression splines (R \u201cmgcv\u201d) were used to estimate the individual-level smoothed cadence trajectories. \u201cTime-to-slow-down\u201d was defined as first time-point where the full confidence interval of change in cadence<0. Five participants were censored at stopping time . Median \u201ctime-to-slow-down\u201d was 1.86 minutes . Participants with longer \u201ctime-to-slow-down\u201d had slower starting cadence, longer 400m-walk time, and greater perceived fatigability , p\u2019s<0.05 (linear regression). Our preliminary findings revealed that detecting accelerometry-based performance fatigability/deterioration in older adults is feasible and needs to account for initial pace."}
+{"text": "Dekker,\u201d not \u201cJan-Willem T. Dekker.\u201d This article has been corrected.In the Original Investigation titled \u201cPredictors of 30-Day Mortality Among Dutch Patients Undergoing Colorectal Cancer Surgery, 2011-2016,\u201d"}
+{"text": "The figure labels indicating posterior probabilities of an odds ratio less than .08 should have used \u201c0.8\u201d instead. This article has been corrected.1In the Original Investigation titled \u201cAssociation of Convalescent Plasma Treatment With Clinical Status in Patients Hospitalized With COVID-19: A Meta-analysis,\u201d"}
+{"text": "Scientific reports 10.1038/s41598-021-92964-9, published online 09 July 2021Correction to: The Article contained an error in Table 2, where the \u201cEquation\u201d value was incorrect for \u201cn4\u201d. The incorrect and correct value appears below.Incorrect:Correct:The original Article has been corrected."}
+{"text": "Strock, MD (Video).Please watch a video commentary on \u201cSubpectoral Implant Repositioning With Partial Capsule Preservation: Treating the Long-Term Complications of Subglandular Breast Augmentation\u201d"}
+{"text": "Correction to:Environ Health Prev Med26, 76 (2021).https://doi.org/10.1186/s12199-021-00996-4Following the publication of the original article  the auth\u201cHousehold monthly income (\u20ae); n (%)\u201d.The original article  has been"}
+{"text": "Translational PsychiatryCorrection to: 10.1038/s41398-021-01358-y published online 24 April 2021The original version of this article unfortunately contained a mistake in the following sentence \u201cThese analyses indicate that the Ztbt16-regulated transcriptome is related to both ASD and SCZ\u201d. \u201cZtbt16\u201d should be changed to \u201cZbtb16\u201d. We apologize for the error. The original article has been corrected."}
+{"text": "Introduction: COVID-19 infections resulting in pathological kidney manifestations have frequently been reported in adults since the onset of the global COVID-19 pandemic in December 2019. Gradually, there have been an increased number of COVID-19-associated intrinsic kidney pathologies in children and adolescents reported as well. The pathophysiological mechanisms between COVID-19 and the onset of kidney pathology are not fully known in children; it remains a challenge to distinguish between intrinsic kidney pathologies that were caused directly by COVID-19 viral invasion, and cases which occurred as a result of multisystem inflammatory syndrome due to the infection. This challenge is made more difficult in children, due to the ethical limitations of performing kidney biopsies to reach a biopsy-proven diagnosis. Although previous systematic reviews have summarized the various pathological kidney manifestations that have occurred in adults following acute COVID-19 infection, such reviews have not yet been published for children and adolescents. We describe the results of a systematic review for intrinsic kidney pathology following COVID-19 infection in children and adolescents. Methods: A systematic literature search of published data up until 31 October was completed through the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines. Research articles reporting new-onset or relapsed intrinsic kidney pathology in children or adolescents (\u226418 years) following acute COVID-19 infection were included for qualitative review. COVID-19 infection status was defined by a positive result from a RT-PCR, or nuclear antibody testing. Only full-text articles published in the English language were selected for review. Results: Twenty-nine cases from fifteen articles were included in the qualitative synthesis of this systematic review. Nephrotic syndrome, as an umbrella condition, appeared as the most frequently observed presentation (20 cases) with disease remission noted in all cases with steroid treatment. Other cases included numerous glomerulonephritides, such as acute necrotizing glomerulonephritis, MPO vasculitis and collapsing glomerulopathy, and thrombotic microangiopathies, such as aHUS. For patients with transplanted kidneys, T-cell-mediated rejection and mild tubular interstitial infiltration were noted following testing positive for COVID-19. There were no mortalities reported in any of the included cases, although two patients remained dialysis dependent at hospital discharge. Conclusion: This systematic review highlights the various intrinsic pathological kidney manifestations in children and adolescents as a result of acute COVID-19 infection. The clinical timeline and presentation of these cases support the mechanistic hypothesis between COVID-19 infection and the onset of intrinsic kidney pathologies within this context. The progressive introduction of vaccination programs for children and adolescents may hopefully reduce the severity of COVID-19-associated illnesses, and pathological kidney manifestations in this population. The coronavirus disease COVID-19) that began in 2019 has spiraled into a global pandemic, continuing up to this day, since the identification of the first severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) case in Wuhan, China, in December 2019 9 that be. This isA novel syndrome, currently termed multisystem inflammatory syndrome in children (MIS-C), has been recognized by clinicians in the United Kingdom since April 2020. It describes previously healthy children presenting with severe systemic inflammatory syndrome following testing positive for a concurrent or recent COVID-19 infection . MIS-C hIsolated case reports and case series have been published since the onset of the COVID-19 pandemic, describing newfound or relapsed cases of podocytopathy, glomerular disease and other intrarenal pathologies in children following acute COVID-19 infection. Some of these reported cases are kidney-biopsy-proven, whereas others are empirical diagnoses determined through past medical history relating to kidney disease, non-invasive investigations, and responses to treatment.As of 31 October 2021, there have been no systematic reviews published to summarize the findings of kidney histopathology following acute COVID-19 infection in children. Here, we provide a systematic clinical review of the current literature to delineate the range of intrinsic kidney pathologies that have manifested following acute COVID-19 infection in children.All research articles reporting new-onset or relapsed intrinsic kidney pathology in children or adolescents (\u226418 years) following acute COVID-19 infection were included. COVID-19 infection status was defined by a positive result from a real-time reverse transcription polymerase chain reaction (RT-PCR), or nuclear antibody testing. Articles for inclusion described intrinsic kidney pathology in both native and transplanted kidneys. Only full-text articles published in the English language were selected for review. Only studies published before 31 October 2021 were included in this review.A systematic literature search was conducted by two independent authors (H.H.L.W. and R.C.) in the following databases: \u201cPubMed\u201d, \u201cWeb of Science\u201d, \u201cEMBASE\u201d and \u201cMedline-ProQuest\u201d. The search terms incorporated the following: \u201cCOVID-19\u201d AND \u201cKidney Histopathology\u201d AND \u201cChildren\u201d; \u201cSARS CoV-2\u201d AND \u201cKidney Histopathology\u201d AND \u201cChildren\u201d; \u201cCOVID-19\u201d AND \u201cRenal Histopathology\u201d AND \u201cChildren\u201d; \u201cSARS-CoV-2\u201d AND \u201cRenal Histopathology\u201d AND \u201cChildren\u201d; \u201cCOVID-19\u201d AND \u201cKidney Manifestations\u201d AND \u201cChildren\u201d; \u201cCOVID-19\u201d AND \u201cRenal Manifestations\u201d AND \u201cChildren\u201d; \u201cSARS-CoV-2\u201d AND \u201cKidney Manifestations\u201d AND \u201cChildren\u201d; \u201cSARS-CoV-2\u201d AND \u201cRenal Manifestations\u201d AND \u201cChildren\u201d; \u201cCOVID-19\u201d AND \u201cNephrotic Syndrome\u201d AND \u201cChildren\u201d; \u201cSARS-CoV-2\u201d AND \u201cNephrotic Syndrome\u201d AND \u201cChildren\u201d; \u201cCOVID-19\u201d AND \u201cGlomerulonephritis\u201d AND \u201cChildren\u201d; \u201cSARS-CoV-2\u201d AND \u201cGlomerulonephritis\u201d AND \u201cChildren\u201d; \u201cCOVID-19\u201d AND \u201cKidney Histopathology\u201d AND \u201cAdolescents\u201d; \u201cSARS CoV-2\u201d AND \u201cKidney Histopathology\u201d AND \u201cAdolescents\u201d; \u201cCOVID-19\u201d AND \u201cRenal Histopathology\u201d AND \u201cAdolescents\u201d; \u201cSARS-CoV-2\u201d AND \u201cRenal Histopathology\u201d AND \u201cAdolescents\u201d; \u201cCOVID-19\u201d AND \u201cKidney Manifestations\u201d AND \u201cAdolescents\u201d; \u201cCOVID-19\u201d AND \u201cRenal Manifestations\u201d AND \u201cAdolescents\u201d; \u201cSARS-CoV-2\u201d AND \u201cKidney Manifestations\u201d AND \u201cAdolescents\u201d; \u201cSARS-CoV-2\u201d AND \u201cRenal Manifestations\u201d AND \u201cAdolescents\u201d; \u201cCOVID-19\u201d AND \u201cNephrotic Syndrome\u201d AND \u201cAdolescents\u201d; \u201cSARS-CoV-2\u201d AND \u201cNephrotic Syndrome\u201d AND \u201cAdolescents\u201d; \u201cCOVID-19\u201d AND \u201cGlomerulonephritis\u201d AND \u201cAdolescents\u201d; \u201cSARS-CoV-2\u201d AND \u201cGlomerulonephritis\u201d AND \u201cAdolescents\u201d. The articles were screened by H.H.L.W. and R.C. for relevance and duplicate publications were removed. Duplicate screening and the eligibility check was performed by both H.H.L.W. and R.C. The study selection process was carried out using the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines . AmongstIf available, data including patient demographics , co-morbidities, clinical presentation, kidney parameters at the time of presentation , information on whether kidney biopsy was performed, treatment received following diagnosis and clinical outcome following treatment, were extracted from the included articles. These data are described in the results section of this article, and also presented in tabular form.A pre-defined review protocol was registered at the PROSPERO international prospective registry of systematic reviews, under registration number CRD42021289662.A total of 20 cases involving children or adolescents presenting with either new-onset or relapsed nephrotic syndrome following acute COVID-19 infection were included in our systematic review  10,11,1,16,17,18Glomerulonephritis and hemolytic-uremic syndrome in children and adolescents associated with acute COVID-19 infection included in our systematic review are presented in Basiratnia et al.  reportedA 17-year-old boy with recent hospital admission in relation to COVID-19 pneumonia  was re-admitted one month following his initial hospitalization . He re-pRelapse of recurrent anti-factor H antibody-associated atypical hemolytic uremic syndrome (aHUS) with an underlying complement factor H-related protein mutation was found in a 10-year-old boy with a positive COVID-19 infection diagnosis through nuclear antibody testing . The patRegarding children and adolescents with transplanted kidneys , a case Numerous intrinsic kidney pathologies were described following acute COVID-19 infection in children and adolescents within this systematic review, from which a total of 28 cases from 15 published articles were included in qualitative analysis. Nephrotic syndrome appeared as the most frequently reported clinical presentation. Nephrotic syndrome is a common kidney pathology observed in children and adolescents, characterized by minimal change disease in the majority (more than 80%) ,26. It iVarious glomerulonephritides have been reported in children and adolescents following COVID-19 infection. CG is a variant of Focal Segmental Glomerulosclerosis (FSGS), characterized by glomerular tuft collapse, segmentally or globally ,41,42. CAKI secondary to acute necrotizing glomerulonephritis and vasculitis in acute COVID-19 infection is hypothesized to be caused by glomerular hypoperfusion and tubular necrosis, leading to fibrinoid necrosis within the glomerulus and arterial walls of the intrarenal vessels ,48. NeutIn addition, aHUS following COVID-19 infection is thought to be caused by a prothrombotic state, as a result of complement-mediated inflammation and thrombotic microangiopathy-associated processes ,51. ModePoorer outcomes following COVID-19 infection in children and adolescents with prior kidney transplantation are expected due to chronic immunosuppression and other co-existing co-morbidities, such as diabetes, mellitus and hypertension, now recognized as significant risk factors for mortality following acute COVID-19 infection ,55,56. DThere remain knowledge gaps in our understanding of the mechanisms associating intrinsic kidney pathologies and COVID-19 infection. Incomplete data regarding kidney histopathology due to limitations in performing kidney biopsy and other invasive investigations for many cases involving children and adolescents has contributed to this. There was a published case series of AKI presentations with proteinuria and hematuria in children and adolescents, following positive COVID-19 PCR results . HoweverOur systematic review has been able to pool the currently reported cases of new-onset and relapsed intrinsic kidney pathology in children and adolescents following COVID-19 infection, and summarises the purported mechanisms behind the links between COVID-19 and the onset of intrinsic kidney disease. Although the adverse renal complications of COVID-19 vaccination are recognized in adults, these are very rare . The pro"}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-021-99160-9, published online 19 November 2021Correction to: The original version of this Article contained a typographical error in Equation\u00a010, where the '\u03b3' variable was omitted and \u2018FeO\u2019 was incorrectly given as \u2018Feo\u2019.The original Article has been corrected."}
+{"text": "Scientific Reportshttps://doi.org/10.1038/srep37459, published online 18 November 2016Correction to: The original version of this Article contains errors.In Figure\u00a04D, the representative images for the cell invasion assay experiments \u201cpre-miR-control+control vector\u201d and \u201cpre-miR-16+KRAS vector\u201d are partially duplicated from the image showing \u201cpre-miR-control\u201d.The correct Figure"}
+{"text": "Scientific Reports  10.1038/s41598-019-45392-9, published online 19 June 2019Correction to: The original version of this Article contained an error in Figure 3b, where the y-axis\u201c/(nA)\u201dnow reads:\u201c/(\u03bcA)\u201dThe original Figure"}
+{"text": "Scientific Reports 10.1038/s41598-021-83876-9, published online 24 February 2021Correction to: The original version of this Article contained an error in the title of the paper, where the term \u201crespiratory infection\u201d was incorrectly given as \u201cinfluenza infection\u201d.In addition, in the Discussion section,\u201cHere, we analyzed gene expression changes in PWH after influenza infections.\u201dnow reads:\u201cHere, we analyzed gene expression changes in PWH after respiratory infections.\u201dThe original Article and accompanying Supplementary Information file have been corrected."}
+{"text": "In the Abstract Results, the second use of the phrase \u201cin convalescent serum from COVID-19 survivors\u201d should have been omitted. In the Figure 1 color key, the colors given for \u201cPCR-positive\u201d and \u201cPCR-negative\u201d should have been reversed. This article has been corrected.1In the Original Investigation titled \u201cEvaluation of the SARS-CoV-2 Antibody Response to the BNT162b2 Vaccine in Patients Undergoing Hemodialysis,\u201d"}
+{"text": "In the original article, we neglected to include the \u201cFunder FAPESP, 2018/07707-6\u201d. The new Funding statement reads as follows:This study was financed in part by the Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior\u2014Brasil (CAPES)\u2014Finance Code 001 (GP), S\u00e3o Paulo Research Foundation (FAPESP) grant 2016/22335-2,2018/00070-2 (ACF), FAPESP grant 2018/07707-6 (PGM) and Brazilian National Research Council (CNPq) grant 301436/2017-7.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "CLINICS (Sao Paulo). 2021;76:e1512errhttps://doi.org/10.6061/clinics/2020/e1512, published in 2020.Erratum for: doi: Randomized trial of physiotherapy and hypertonic saline techniques for sputum induction in asthmatic children and adolescentsIn the article \u201cKarina Pierantozzi Verganid\u201d for: \u201cKarina Pierantozzi Vergani\u201dReplace and Page 6 \u2013 AUTHOR CONTRIBUTIONS\u201cVerganid KP\u201d replace for \u201cVergani KP\u201dwhere it reads"}
+{"text": "In the article titled \u201cMultifarious Beneficial Effect of Nonessential Amino Acid, Glycine: A Review\u201d , there w"}
+{"text": "In the article titled \u201cThe Inhibition of P-Selectin Reduced Severe Acute Lung Injury in Immunocompromised Mice\u201d , the inc"}
+{"text": "The authors regret to acknowledge financial support from Ministerio de Ciencia e Innovaci\u00f3n (MCI), Agencia Estatal de Investigaci\u00f3n (AEI) and Fondo Europeo de Desarrollo Regional (FEDER) through MOCCA Project (RTI2018-093941-B-C31).The authors would like to apologise for any inconvenience caused."}
+{"text": "Scientifica has retracted the article titled \u201cA Simple HPLC-UV Method for the Determination of Glutathione in PC-12 Cells\u201d ["}
+{"text": "PLoS Medicine, volume 2, issue 4: DOI:10.1371/journal.pmed.0030185Inp-Value Function Based on Data in [28].\u201d The correct title for Figure S1 should be \u201cEpisheet Showing Author's Relative Risk Calculation, Based on Data in [28].\u201dThe correct title for Figure 2 should be \u201cAuthor's Graph of"}
+{"text": "PLoS Medicine, volume 2, issue 9, DOI: 10.1371/journal.pmed.0020302In In the third paragraph of the section \u201cNeglected-Disease R&D Activity,\u201d the sentence \u201cNearly one-third of these projects are at the clinical trial stage, including seven drugs now in Phase III trials\u2026\u201d should read instead \u201cNearly one-third of these projects are at the clinical trial stage, including six drugs now in Phase III trials\u2026.\u201d"}
+{"text": "NDP gene c.313G>C. Accordingly, \u201cp.(Ala105Phe)\u201d should be corrected to \u201cp.(Ala105Pro)\u201d in the Results and Discussion. Also, In the article titled \u201cGenotype-Phenotype Characterization of Novel Variants in Six Italian Patients with Familial Exudative Vitreoretinopathy\u201d , there w"}
+{"text": "Scientific Reports6: Article number: 3342110.1038/srep33421; published online: 09152016; updated: 11112016This Article contains typographical errors. In the Materials and Methods section, under the subheading \u201cProtein adsorption assay\u201d\u201cThe protein solution  was pipetted onto and spread over each sample surface immediately and 28 days after treatment using UV or NTAPPJ treatment\u201d.should read:\u201cThe protein solution  was pipetted onto and spread over each sample surface immediately and 28 days after treatment using UV or NTAPPJ treatment\u201d.In the Results section, under the subheading \u201cChanges in surface chemical compositions in the UV- and NTAPPJ-treated groups\u201d\u201cHowever, the peaks of both UV- and NTAPJJ-treated groups were markedly decreased over time.\u201dShould read:\u201cHowever, the peaks of both UV- and NTAPPJ-treated groups were markedly decreased over time.\u201d"}
+{"text": "Sofia Toniolo's name appeared incorrectly.In the article, \u201cIs cerebral glucose metabolism related to blood\u2013brain barrier dysfunction and intrathecal IgG synthesis in Alzheimer disease? A 18F-FDG PET/CT study\u201d,"}
+{"text": "Caroline Grangeaon's name should have appeared as Caroline Grangeon-Chapon.In the article, \u201cFalse positive"}
+{"text": "In the article titled \u201cVisual Acuity Changes during Pregnancy and Postpartum: A Cross-Sectional Study in Iran\u201d , there w"}
+{"text": "In the article titled \u201cPercutaneous Transforaminal Endoscopic Lumbar Interbody Fusion: Clinical and Radiological Results of Mean 46-Month Follow-Up\u201d , the ima"}
+{"text": "Nature Communications 10.1038/s41467-017-02127-6, published online 12 December 2017Correction to: y-axis \u2018Strain energy (kbT)\u2019 was labelled \u2018Probability\u2019 and the left y-axis \u2018Probability\u2019 was labelled \u2018Strain energy (kbT)\u2019. This error has now been corrected in both the PDF and HTML versions of the Article.The originally published version of this Article contained an error in Figure 5. In panel f, the right"}
+{"text": "Scientific Reports6: Article number: 28506; 10.1038/srep28506 published online: 06242016; updated: 12082016.In this Article the Authors incorrectly stated that they had developed a novel method termed bisulfite amplicon sequencing (BSAS). The method was reported by Masser et al. (reference 18 in the Article). Thus the following sentence (which appears verbatim in ref 18):18\u201d.\u201cBy combining the benefits of bisulfite conversion, targeted amplification, tagmentation-based library construction, and NGS, we have developed a novel method termed bisulfite amplicon sequencing (BSAS) for targeted digital high accuracy quantitation of DNA methylationshould read:18\u201d.\u201cIn a previous study, Masser et al. developed a method termed bisulfite amplicon sequencing (BSAS) for targeted digital high accuracy quantitation of DNA methylation by combining the benefits of bisulfite conversion, targeted amplification, tagmentation-based library construction, and NGSThe following sections in \u201cMaterials and Methods\u201d failed to appropriately cite the protocols followed:\u201cDNA bisulfite conversion and bisulfite specific PCR\u201d.should read:13\u201d.\u201cDNA bisulfite conversion and bisulfite specific PCR\u201cNGS library preparation and sequencing\u201d.should read:18\u201d.\u201cNGS library preparation and sequencing\u201cReal-time PCR analysis\u201d.should read:13\u201d.\u201cReal-time PCR analysisAn additional reference is listed below as reference \u201cNGS data analysis and digital methylation quantitation\u201d.should read:\u201cNGS data analysis and digital methylation quantitationThe Authors apologize for these errors."}
+{"text": "Copernicia prunifera (Miller) H. E. Moore in Mice Diet-Induced Hypercholesterolemia\u201d [In the article titled \u201cAntihypercholesterolemic Effects of Fruit Aqueous Extract ofrolemia\u201d , Dr. Pau"}
+{"text": "The genus Streptococcus (Streptococcus pyogenes (Lancefield group A \u03b2-hemolytic streptococcus), S. pneumoniae, and other species.From the Greek tococcus  was name"}
+{"text": "Scientific Reports6: Article number: 2657010.1038/srep26570; published online: 05272016; updated: 08302016This Article contains an error in Figure 4a: the upper right \u201chTPC2 rescue\u201d trace is a duplication of the upper left \u201ccontrol\u201d trace. The correct Figure 4 appears below as"}
+{"text": "Scientific Reports 10.1038/s41598-017-11542-0, published online 12 September 2017Correction to: meas\u201d is incorrectly listed as \u201cR sym\u201d.This Article contains a typographical error in Table 1. In the \u2018Data Collection\u2019 column, \u201cR"}
+{"text": "The corresponding author should have appeared as \u201cLanjuan Li, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University, Hangzhou, China. email: li_doctor@yeah.net.\u201dIn the article \u201cExtracorporeal membrane oxygenation treatment of a H7N9-caused respiratory failure patient with mechanical valves replacement history: A case report\u201d,"}
+{"text": "Nevertheless, no information was available about the structural details of these of \u03b12\u20136-sialylated glycans. Here we used high performance liquid chromatography (HPLC) analysis combined with mass spectrometry (MS) to perform a structural and quantitative glycome analysis targeting both N- and O-glycans derived from early (with differentiation ability) and late (without differentiation ability) passages of adipose tissue-derived hMSCs. Findings in these cells were compared with those from human induced pluripotent stem cells (hiPSCs), human dermal fibroblasts (hFibs) and cartilage tissue-derived chondrocytes. A higher percentage of \u03b12\u20136-sialylated N-glycans was detected in early passage cells  compared with late passage cells (13\u201315\u00a0%). A major \u03b12\u20136-sialylated N-glycan structure detected in adipose-derived hMSCs was that of mono-sialylated biantennary N-glycan. Similar results were obtained for the cartilage tissue-derived chondrocytes, Yub621c (28\u00a0% for passage 7 and 5\u00a0% for passage 28). In contrast, no significant differences were observed between early and late passage hMSCs with respect to \u03b12\u20136-sialylated O-glycan percentages. These results demonstrate that levels of \u03b12\u20136-sialylated N-glycans, but not O-glycans, could be used as markers of the differential potential of hMSCs.Human somatic stem cells such as mesenchymal stem cells (hMSCs) have the capacity to differentiate into mesenchymal tissue lineages and to alter immune regulatory functions. As such, they hold promise for use in stem cell-based therapies. However, no method is currently available to evaluate the actual differentiation capacity of hMSCs prior to cell transplantation. Previously, we performed a comprehensive glycan profiling of adipose-derived hMSCs using high-density lectin microarray and demonstrated that  The percentage of sialyl Tn  was observed to be higher in late passage cells (lot#: 2117 P26 and lot#: 2118 P28) compared with early passage cells (lot#: 2117 P5 and lot#: 2118 P3).Asialo complex type No.13\u201316) and sialylated 3\u201316 and s No. 17\u20137 were als No. 17\u20137 were alN- and O-glycans of adipose-derived hMSCs were compared to hiPSCs (cell line 201B7) as a representative of human pluripotent stem cells, and to hFibs as a representative of somatic cells, in addition to another type of somatic stem cell, cartilage tissue-derived chondrocytes   Fig. . All of O-glycan signatures were different depending on the cell types under consideration. Interestingly, adipose-derived hMSCs gave a high percentage of sialylated O-glycans (average 84\u00a0%) relative to hiPSCs (39\u00a0%), hFibs (59\u00a0%), and cartilage-derived chondrocytes (31\u00a0%).In contrast, the overall N- and O-glycans, where \u201c\u03b12\u20133Sia\u201d and \u201c\u03b12\u20136Sia\u201d indicate N- or O-glycans containing \u03b12\u20133Sia and \u03b12\u20136Sia, respectively, and \u201c\u03b12\u20133Sia\u00a0+\u00a0\u03b12\u20136Sia\u201d indicate N- or O-glycans containing both \u03b12\u20133Sia and \u03b12\u20136Sia.We subsequently focused our attention on sialylation, since \u03b12\u20136Sia-binding lectins showed stronger binding to early passage hMSCs derived from adipocytes and bone marrow than their corresponding late passage cells, as previously reported . Figure N-glycans, 201B7 hiPSCs expressed exclusively \u03b12\u20136Sia (100\u00a0%), whereas, in contrast, hFibs expressed mostly \u03b12\u20133Sia (1\u00a0% for \u03b12\u20136Sia) [N-glycans  was indeed higher in early passage adipose-derived hMSCs  than for corresponding late passage cells . Similarly, early passage cartilage tissue-derived chondrocytes (29\u00a0% for P7) expressed a higher percentage of \u03b12\u20136-sialylated N-glycans than corresponding late passage cells (5\u00a0% for P28). A major \u03b12\u20136-sialylated N-glycan structure detected in adipose-derived hMSCs and cartilage tissue-derived chondrocytes was \u201cmono-sialylated biantennary N-glycan\u201d  and disialyl T GalNAc) were also detected in O-glycans  . In agre\u03b12\u20136Sia) , the perN- and O-glycans derived from 201B7 hiPSCs and hFibs representing undifferentiated and differentiated cells, respectively, using the same strategy described in the present report [N-glycans of 201B7 hiPSCs was found to consist exclusively of \u03b12\u20136Sia, whereas that of hFibs was mostly of the \u03b12\u20133Sia type [N-glycans, but not O-glycans, was found to be higher in early passage cells than late passage cells. Therefore, \u03b12\u20136-sialylaed N-glycans could serve as markers of the differentiation potential of stem cells.Previously, we performed a quantitative glycome analysis targeting both t report . A dramaSia type . RecentlSia type . SimilarSNA and SSA, but not TJA1 and rPSL1a, bound to bovine submaxillary mucins expressing sTn as described in the previous report . TherefoN-glycans, but not O-glycans. This might be the reason why \u03b12\u20136\u2013sialylation on N-glycans, but not O-glycans, changes depending on the differentiation potential of hMSCs. Combined with our findings showing that \u03b12\u20136Sia is dominant on N-glycans of hiPSCs and correlates with the differentiation capacity of cells, it seems that the expression of \u03b12\u20136-sialylated N-glycans is associated with \u201cstemness\u201d.The expression of \u03b12\u20136-sialyltransferase  has been shown to play an important role in the regulation of cellular pluripotency in human pluripotent stem cells \u201320. TherN-glycosylation sites is one of the carrier proteins of \u03b12\u20136Sia in cartilage tissue-derived chondrocytes [What are the roles of \u03b12\u20136Sia in stem cell functions? Previously we showed that \u03b15integrin with 14\u00a0drocytes . \u03b15\u03b21intdrocytes . TherefoN-glycans varies depending on the differentiation potential of stem cells. Rapid, sensitive, and nondestructive process analytical testing (PAT) is essential for the stable supply of hMSCs, which could be used for monitoring during the cell production process. The quality control system to assess hMSCs for use as CTPs will become increasingly more important and stringent from the viewpoint of regulatory science.The development of novel markers to evaluate the properties of hMSCs is keenly required for the realization of safe stem cell-based therapy, with such cells being used as hCTPs in regenerative medicine to treat various diseases. Here we have provided structural evidence showing that the expression of \u03b12\u20136-sialylated"}
+{"text": "The phrase \u201cT2-Imaging\u201d should be \u201cT2\u2019-Imaging.\u201d The publisher apologizes for the error. Please download this article again to view the correct version. The originally published, uncorrected article and the republished, corrected article are provided here for referenceS1 File(PDF)Click here for additional data file.S2 File(PDF)Click here for additional data file."}
+{"text": "Scientific Reports4: Article number: 5539; 10.1038/srep05539 published online: 07022014; updated: 04072017.Ribonucleotide Reductase Assay\u2019.This Article contains a typographical error in the Methods section under subheading \u2018+]-form columns prepared by replacing the Sephadex in NAP-10 columns (Amersham Bioscience) with 2\u2009mL of Dowex from Bio-Rad pre-packed columns\u201d.\u201cSupernatants were loaded onto pre-washed 2\u2009mL Dowex AG 1X8, 200\u2013400 in [Hshould read:+]-form columns prepared by replacing the Sephadex in NAP-10 columns (Amersham Bioscience) with 2\u2009mL of Dowex from Bio-Rad pre-packed columns\u201d.\u201cSupernatants were loaded onto pre-washed 2\u2009mL Dowex AG 50W-X8, 200\u2013400 in [H"}
+{"text": "PGJ2\u201d [In the article titled \u201cA Model for Spheroid versus Monolayer Response of SK-N-SH Neuroblastoma Cells to Treatment with 15-Deoxy-"}
+{"text": "B10203013.In the article, \u201cLong-term effectiveness of the Diabetes Conversation Map Program: A prepost education intervention study among type 2 diabetic patients in Taiwan\u201d,"}
+{"text": "In the article titled \u201cHyperglycemia Induces Toll-Like Receptor-2 and -4 Expression and Activity in Human Microvascular Retinal Endothelial Cells: Implications for Diabetic Retinopathy\u201d  an error"}
+{"text": "In the article titled \u201cExtraction of HCV-RNA from Plasma Samples: Development towards Semiautomation\u201d , the nam"}
+{"text": "Am J Trop Med Hyg 98(1):57\u201366 by Lui et al(https://doi.org/10.4269/ajtmh.17-0437) there is an error in the text. In thefirst sentence of the \u201cExperimental design and statistical rationale\u201d headingon page 58 it reads \u201cA total of 515 experimental plasma samples  were probed by protein microarray.\u201d It shouldinstead read \u201cA total of 508 experimental plasma samples  were probed by protein microarray.\u201dIn"}
+{"text": "In the article titled \u201cSugammadex-Enhanced Neuronal Apoptosis following Neonatal Sevoflurane Exposure in Mice\u201d , the con"}
+{"text": "A\u00a021-year-old female patient presented with unexplained weight gain and dyspnoea on exertion. The ECG showed third-degree atrioventricular (AV) block with a\u00a0junctional escape rhythm of 45\u2009bpm (Fig."}
+{"text": "In the original publication [was one of the author names spelled wrong.lication  was one Wrong: F\u00e9lix Alejandro Ayala-ParadesShould have read: F\u00e9lix Alejandro Ayala-ParedesThe original article was updated to rectify this error."}
+{"text": "Scientific Reports 10.1038/s41598-017-08401-3, published online 15 August 2017Correction to: This Article contains an error in Figure 5, where the \u2018undisturbed\u2019 and \u2018disturbed\u2019 bars for the control sample are reversed. The correct Figure 5 appears below as Figure"}
+{"text": "Candidatus Carsonella ruddii\u201d strain BT from Bactericera trigonica in Israel was sequenced. The full-length genome is 173,904\u00a0bp long and has a G+C content of 14.6%, with 224 predicted open reading frames (ORFs) and 30 RNAs.The genome of \u201c Candidatus Carsonella ruddii\u201d is an obligate symbiont of psyllids , which are plant phloem-feeding insects  (Ca. Carsonella ruddii\u201d associated with the carrot psyllid B.\u00a0trigonica from Israel.Certain psyllid species are vectors of the plant-pathogenic \u201cectively \u20135. Anothdisease) . We repoB.\u00a0trigonica, adult psyllids were harvested and flash frozen. Genomic DNA was prepared from three samples, one containing 4 adult psyllids (Ca. Carsonella ruddii.\u201d A BLAST search of assembled contigs found the complete \u201cCa. Carsonella ruddii\u201d genome on one contig. The genome was submitted to the Joint Genome Institute (JGI) IMG/M system  reported here with the ANIs of the following nine \u201cCa. Carsonella ruddii\u201d genome assemblies listed in NCBI: Pachypsylla venusta (strain PV) (GenBank assembly accession number GCA_000010365)  (GCA_000287235) (Ctenarytaina\u00a0spatulata (strain CS) (GCA_000287255) (Heteropsylla cubana (strain HC) (GCA_000287275) (Heteropsylla\u00a0texana (strain HT) (GCA_000287295) (Pachypsylla sp. \u201cceltidis\u201d (strain PC) (GCA_000287315) (Diaphorina\u00a0citri (strain DC) (GCA_000441575) (D.\u00a0citri (strain YCCR) (GCA_001274515) (B.\u00a0cockerelli (strain BC) (GCA_002009355) (Ca. Carsonella ruddii\u201d strain BT has the strongest relationship by ANI to \u201cCa. Carsonella ruddii\u201d strain BC (89.9%), which is the primary endosymbiont of the same psyllid genus (Bactericera). The lowest ANI score is with \u201cCa. Carsonella ruddii\u201d strain PC (73.89%). Between \u201cCa. Carsonella ruddii\u201d strains BT and DC, the ANI was 79.38%. The low ANI values shared between \u201cCa. Carsonella ruddii\u201d strains may be the result of limiting replicative environments, as well as the effect that the loss of DNA repair enzymes has on genome evolution  and 30 RNAs . We compared the average nucleotide identity (ANI) of \u201c0010365) , Ctenary0287235) , Ctenary0287255) , Heterop0287275) , Heterop0287295) , Pachyps0287315) , DiaphorCa. Carsonella ruddii\u201d strain BT is deposited at GenBank, NCBI, under the accession number CP024798.The complete genome sequence of \u201c"}
+{"text": "In the article titled \u201cNutritional Risk Factors for Age-Related Macular Degeneration\u201d , \u201cApolip"}
+{"text": "Scientific Reports 10.1038/s41598-017-01480-2, published online 28 April 2017Correction to: This Article contains typographical errors. In the Results section under subheading \u2018KLT inhibits NF-\u03ba\u0392 to sensitize colorectal cancer cell lines to Taxol\u2019,\u201cIn the cytosolic protein component , NF-\u03ba\u0392 was slightly down-regulated by Taxol and slightly upregulated by KLT.\u201dshould read:\u201cIn the cytoplasmic protein component , NF-\u03ba\u0392 was slightly down-regulated by Taxol and slightly upregulated by KLT.\u201dIn the Methods section under subheading \u2018\u201cParachute\u201d dye-coupling assay\u2019,et al.28\u201d\u201cFunctional GJIC was examined by the \u201cParachute\u201d dye-coupling assay, which was described by Wang should read:et al.30\u201d\u201cFunctional GJIC was examined by the \u201cParachute\u201d dye-coupling assay, which was described by Yu"}
+{"text": "Scientific Reports 10.1038/s41598-017-07827-z, published online 07 August 2017Correction to: This Article contains typographical errors in Table 1.For the Human v1, Brunello, Whitehead and Toronto KnockOut v3 libraries, the references should read \u201837\u2019, \u201827\u2019, \u201820\u2019 and \u201831\u2019 respectively."}
+{"text": "Scientific Reports7:628; doi:10.1038/s41598-017-00744-1; Article published online 04 April 2017In the original version of this Article, some instances of \u201cCSN\u201d were incorrectly given as \u201cCNS\u201d. This error has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Am J Trop Med Hyg 97(2): 403\u2013406 by Kim et al (https://doi.org/10.4269/ajtmh.16-0570) there is a note that reads\u201cFinancial support: This study was supported by research funds from ChosunUniversity Hospital 2016.\u201d This note should be deleted.In"}
+{"text": "Scientific Reports 10.1038/s41598-017-00805-5, published online 12 April 2017Correction to: This Article contains a typographical error in the Materials and Methods section under subheading \u2018Data Analysis\u2019.should read:"}
+{"text": "The article has since been corrected online.In the article \u201cComparative Treatment Failure Rates of Respiratory Fluoroquinolones or \u03b2-Lactam\u200a+\u200aMacrolide Versus \u03b2-Lactam Alone in the Treatment for Community-Acquired Pneumonia in Adult Outpatients: An Analysis of a Nationally Representative Claims Database\u201d,"}
+{"text": "In the article titled \u201cContent Patterns in Topic-Based Overlapping Communities\u201d,  the \u201cAck"}
+{"text": "Scientific Reports6: Article number: 3734010.1038/srep37340; published online: 11232016; updated: 03232017The Acknowledgements section in this Article is incomplete.\u201cKarla Itzel Vazquez Santillan was supported by a fellowship from CONACYT (165306), and this study is part of her doctoral thesis from the Biomedical Sciences Doctorate Program, Faculty of Medicine, Universidad Nacional Autonoma de Mexico. This project was partially supported by CONACYT grant CB-2009-01-132931\u201d.should read:\u201cKarla Itzel Vazquez Santillan is a doctoral student from Programa de Doctorado en Ciencias Biom\u00e9dicas, Universidad Nacional Aut\u00f3noma de M\u00e9xico (UNAM) and received fellowship 165306 from CONACYT. This project was partially supported by CONACYT grant CB-2009-01-132931\u201d."}
+{"text": "In the article titled \u201cSelf-Reported Adverse Drug Reactions, Medication Adherence, and Clinical Outcomes among Major Depressive Disorder Patients in Ethiopia: A Prospective Hospital Based Study\u201d , the nam"}
+{"text": "Suter, Battegay, and Schmid were incorrectly reported as having PhDs. In fact, all three authors are MDs.In the article \u201cEffect of vitamin D3 on self-perceived fatigue: A double-blind randomized placebo-controlled trial\u201d,"}
+{"text": "Salmonella Oslo Infections Linked to Persian Cucumbers \u2014 United States, 2016,\u201d the footnote on page 1430 should have read \u201c\u2020https://www.cdc.gov/foodnet/surveys/population.html.\u201dIn the report \u201cOutbreak of"}
+{"text": "Linum usitatissimum L.)\u201d [here.In the article titled \u201cmiR319, miR390, and miR393 Are Involved in Aluminum Response in Flax ("}
+{"text": "Scientific Reports 10.1038/s41598-017-05870-4, published online 18 July 2017Correction to: The Acknowledgements section in this Article is incomplete.\u201cAT is supported by the ESRC grant ES/K001477/1 (\u201cThe hearing body\u201d) and by a Spanish \u201cMinisterio de Econom\u00eda y Competitividad\u201d Ram\u00f3n y Cajal research contract (RYC-2014-15421). OD, MF and AM are supported by the AHRC RTS (\u201cRethinking the senses\u201d) grant AH/L007053/1. We thank Nick Wilkinson for helping with data collection, Temitayo Olugbade for helping with EMG recordings, and Alejandro Galvao Carmona, Vincent Hayward, Milagrosa S\u00e1nchez Mart\u00edn and Matthew Longo for their helpful suggestions.\u201dshould read:\u201cAT was supported by the ESRC grant ES/K001477/1 (\u201cThe hearing body\u201d) and by RYC-2014\u201315421 and PSI2016-79004-R , Ministerio de Econom\u00eda, Industria y Competitividad of Spain. OD, MF and AM were supported by the AHRC RTS (\u201cRethinking the senses\u201d) grant AH/L007053/1. We thank Nick Wilkinson for helping with data collection, Temitayo Olugbade for helping with EMG recordings, and Alejandro Galvao Carmona, Vincent Hayward, Milagrosa S\u00e1nchez Mart\u00edn and Matthew Longo for their helpful suggestions.\u201d"}
+{"text": "Scientific Reports 10.1038/s41598-018-22825-5, published online 15 March 2018Correction to: This Article contains typographical errors. In the Discussion section, all instances of\u201cEttenhoffer and Bardy\u201dshould read:\u201cEttenhofer and Barry\u201d."}
+{"text": "In the article titled \u201cGlutathione Peroxidase Level in Patients with Vitiligo: A Meta-Analysis\u201d , the ord"}
+{"text": "In the article titled \u201cLocal and Systemic Cardiovascular Effects from Monochromatic Infrared Therapy in Patients with Knee Osteoarthritis: A Double-Blind, Randomized, Placebo-Controlled Study\u201d , affilia"}
+{"text": "Scientific Reports 10.1038/s41598-017-06948-9, published online 02 August 2017Correction to: This Article contains an error in the legend of Figure 1.\u201c(b) Proportion of primary (in dark grey) compared to secondary (in light grey) drivers associated with different numbers of climate drivers\u201dshould read:\u201c(b) Proportion of primary (in light grey) compared to secondary (in dark grey) drivers associated with different numbers of climate drivers\u201dAdditionally, in the Results section,\u201cBy contrast, the distributions for protozoa (N\u2009=\u20097) and helminths (N\u2009=\u20096) were left-skewed or bell-shaped .\u201dshould read:\u201cBy contrast, the distributions for protozoa (N\u2009=\u20097) and helminths (N\u2009=\u20096) were left-skewed or bell-shaped .\u201d"}
+{"text": "Scientific Reports7: Article number: 4235610.1038/srep42356; published online: 02142017; updated: 03232017This Article contains an error in the Acknowledgements section.\u201cThis work has been supported by the Russian Scientific Foundation grant No. 15-13-20021\u201d.should read:\u201cThis work has been supported by the Russian Science Foundation grant No. 15-13-20021\u201d."}
+{"text": "In Figure 2(a) of the published article entitled \u201cmiR-1-Mediated Induction of Cardiogenesis in Mesenchymal Stem Cells via Downregulation of Hes-1,\u201d ["}
+{"text": "In the article titled \u201cPlant-Derived Antioxidants in Disease Prevention\u201d , affilia"}
+{"text": "Scientific Reports6: Article number: 31797; 10.1038/srep31797 published online: 08182016; updated: 04212017.In this Article, the compounds in the titles of Table 1 and Figure 9 have been mislabelled.The title of Table 1:\u201cZero-order kinetic parameters of X-3B degradation\u201d.should read:\u201cZero-order kinetic parameters of Scarlet 3R degradation\u201d.The title of Figure 9:\u201cUV\u2013vis absorption spectra changes of an AO7 aqueous solution during Al-Cu alloys treatment\u201d.should read:\u201cUV\u2013vis absorption spectra changes of a Scarlet 3R aqueous solution during Al-Cu alloys treatment\u201d."}
+{"text": "After publication, the authors were made aware of incorrect primer sequences listed for PPAR\u03b1 in the Mice section of Materials and methods.The correct primer sequences used to amplify PPAR\u03b1 cDNAs are as follows:\u2032-GAGAAGTTGCAGGAGGGGATTGTG-3\u2032Sense: 5\u2032-CCCATTTCGGTAGCAGGTAGTCTT-3\u2032Antisense: 5"}
+{"text": "Scientific Data 5:180016 doi: 10.1038/sdata.2018.16 (2018); Published 20 February 2018; Updated 27 March 2018.In Fig. 5 of this Data Descriptor the bottom-most y-axis label was inadvertently changed from \u2018\u0394PPT (mm)\u2019 to \u2018\u0394PPT (min)\u2019 during the production process. The correct version of Fig. 5 appears below as"}
+{"text": "The article has since been corrected online.In the article \u201cImmunologic Monitoring of T-Lymphocyte Subsets and HLA-DR-Positive Monocytes in Kidney Transplant Recipients: A Prospective, Observational Cohort Study\u201d,"}
+{"text": "In the Funding section, the grant number from the funder Austrian Science Foundation \u201cFonds zur F\u00f6rderung der wissenschaftlichen Forschung\u201d is listed incorrectly. The correct grant number is: P29032-N32."}
+{"text": "Leishmania Infection: Adding Layers of Complexity to a Complex Disease\u201d [Frontiers in Cellular and Infection Microbiology, 2:83, 2012:In the paragraph beginning with \u201cSeveral reports show\u2026\u201dL. major infection,\u201d \u201cBaldwin et al. found\u2026infected C57BL/6 mice,\u201d and \u201cIt is not clear whether\u2026protective or pathogenic T cell responses.\u201dIn the paragraphs beginning with \u201cEarly studies demonstrated\u2026where they present parasite-derived antigen to T cells,\u201d \u201cThe production of IL-12 by APCs \u2026 downregulate IL-12p40 production in response to leishmaniasis.\u201dIn the paragraph beginning with \u201cDCs express a wide variety\u2026immunity against In the paragraphs beginning with \u201cGiven the fact that\u2026multi-species/strain comparison\u201d and \u201cA more comprehensive\u2026activation of the adaptive immune system.\u201dDong Liu and Jude E. Uzonna, \u201cMacrophages and dendritic cells and its influence on the host immune response,\u201d Microbes and Infection, vol. 6, Issue 15, pp. 1402\u20131409, December 2004, http://www.sciencedirect.com/science/article/pii/S1286457904003053:In the paragraph beginning with \u201cDendritic cells (DCs) are a family of professional antigen-presenting cells (APCs)\u2026a wide range of microbial stimuli.\u201dOlga Brandonisio, Rosa Spinelli, and Maria Pepe: \u201cDendritic cells in Leishmania infection,\u201d Leishmania infection: progress in pathogenesis research and experimental therapy,\u201d Experimental Dermatology, 16: 340\u2013346, 2007, http://onlinelibrary.wiley.com/doi/10.1111/j.1600-0625.2007.00554.x/abstract:Leishmania parasites\u2026after the infection is healed\u201d and in the paragraph beginning with \u201cCurrent paradigms\u2026activation and killing of parasites.\u201dIn the sentence beginning with \u201cInfection with Von Stebut, \u201cCutaneous Leishmania spp.,\u201d Frontiers in Immunology, 26 November 2014, https://doi.org/10.3389/fimmu.2014.00604:Leishmania species that cause CL.\u201dIn the paragraph beginning with \u201cNowadays, different in silico approaches\u2026one or all Rafael de Freitas e Silva, Maria Carolina Accioly Brelaz de Castro, Ant\u00f4nio Mauro Rezende, and Val\u00e9ria R\u00eago Alves Pereira, \u201cTargeting dendritic cells as a good alternative to combat The article titled \u201cDendritic Cells and Disease\u201d  was founThe first author Daniel Feij\u00f3 apologizes for these errors."}
+{"text": "In the article titled \u201cT Helper 17/Regulatory T Cell Balance and Experimental Models of Peritoneal Dialysis-Induced Damage\u201d [This work was supported in part by grants from Ministerio de Economia y Competitividad SAF2010-21249 to Manuel L\u00f3pez-Cabrera, Comunidad Aut\u00f3noma de Madrid 2010-BMD2321 (FIBROTEAM) to Manuel L\u00f3pez-Cabrera, and Fondo de Investigaciones Sanitarias RETICS 06/0016 and PI 09/0064 to Rafael Selgas and from Fondo de Investigaciones Sanitarias (FIS)-FEDER funds, PI 12/01175 Instituto Carlos-III to Abelardo Aguilera Peralta. Georgios Liappas is fully supported from European Union, Seventh Framework Program \u201cEuTRiPD,\u201d under Grant Agreement PITN-GA-2011-287813. The authors would like to thank Juliette Siegfried and her team at ServingMed.com for editing the language of the paper."}
+{"text": "Scientific Reports6: Article number: 3851910.1038/srep38519; published online: 12082016; updated: 05032017This Article contains an error in the Acknowledgments section, where:\u201cThis work is supported by Austrian Science Fund (FWF Der Wissenschaftsfonds) through project I- 1778-N20\u201d.should read:\u201cThis work is supported by Austrian Science Fund (FWF Der Wissenschaftsfonds) through project I1788-N20\u201d."}
+{"text": "On page 6, in In the Surveillance Summary \u201cHealth-Related Behaviors by Urban-Rural County Classification \u2014 United States, 2013,\u201d errors occurred in Table 1 and"}
+{"text": "Saeed's name was misspelled. The correct name is Ummair Saeed.In the article \u201cDiagnostic accuracy of tumor necrosis factor-alpha assay for tuberculous pleurisy: A PRISMA-compliant meta-analysis\u201d,"}
+{"text": "In Vitro, and Increases Bone Density In Vivo\u201d [In the article titled \u201cMetformin Decreases Reactive Oxygen Species, Enhances Osteogenic Properties of Adipose-Derived Multipotent Mesenchymal Stem Cells In Vivo\u201d , an ackn"}
+{"text": "In the article titled \u201cAll-Atom Four-Body Knowledge-Based Statistical Potentials to Distinguish Native Protein Structures from Nonnative Folds\u201d , there w"}
+{"text": "Scientific Reports6: Article number: 30784; 10.1038/srep30784 published online: 08082016; updated: 10102016.In the Supplementary Information file originally published with this Article there was an error in Supplementary Figure 1b, where the y-axis \u201cGFP\u201d and x-axis \u201cCD4\u201d were inverted. These errors have been corrected in the Supplementary Information that now accompanies the Article."}
+{"text": "The genesis of the AIDS policy and AIDS Space in Brazil (1981-1989)\u201d published in the \u201cRevista de Sa\u00fade P\u00fablica\u201d, 2016;50:43, DOI: http://dx.doi.org/10.1590/s1518-8787.2016050005801; on page 8, 7th paragraph.In the article: \u201cWhere it reads:\u201cazithromycin (AZT)\u201dIt should read:\u201czidovudine (AZT)\u201d."}
+{"text": "Scientific Reports 10.1038/s41598-017-03516-z, published online 13 June 2017Correction to: The original Supplementary data file published with this Article contained a typographical error where \u2018toxi\u2019 now reads \u2018chem\u2019. The correct Supplementary data file now accompanies the Article."}
+{"text": "Scientific Reports 10.1038/s41598-017-01014-w, published online 19 April 2017Correction to: Euwallacea fornicatus\u201d was incorrectly given as \u201cEuwallacea fornicates\u201d.The original version of this Article contained a typographical error in the Title, where \u201cThis has now been corrected in the HTML and PDF versions of this Article."}
+{"text": "In the article titled \u201cSodium Fluorescein-Guided Resection under the YELLOW 560\u2009nm Surgical Microscope Filter in Malignant Gliomas: Our First 38 Cases Experience\u201d , there w"}
+{"text": "Lancet Diabetes Endocrinol 3: 243\u2013532015; \u2014The open access licence was listed as \u201cCC-BY-NC-ND\u201d whereas it should have been \u201cCC-BY\u201d. This correction has been made as of May 21, 2015.T"}
+{"text": "Escherichia coli O157 Outbreaks in the United States, 2003\u20132012  inadvertently changed the meaning. The sentence should have read, \u201cThe median annual number of outbreaks reported during 2008\u20132012 was higher than during 2003\u20132007  .\u201d The article has been corrected online (https://wwwnc.cdc.gov/eid/article/21/8/14-1364_article).An incorrect word in a sentence in"}
+{"text": "Scientific Reports 10.1038/s41598-018-21402-0, published online 14 February 2018Correction to: The Acknowledgements section in this Article is incomplete.\u201cThis work was funded by the CNRS, The University of Grenoble Alpes. This work is a contribution to the Labex Serenade (n\u00b0 ANR-11-LABX-0064) funded by the \u00ab Investissements d\u2019Avenir\u00bb French Government program of the French National Research Agency (ANR) through the A*MIDEX project (n\u00b0 ANR-11-IDEX-0001\u201302).\u201dshould read:\u201cThis work was funded by the CNRS, The University of Grenoble Alpes. This work is a contribution to the Labex Serenade (n\u00b0 ANR-11-LABX-0064) funded by the \u00ab Investissements d\u2019Avenir\u00bb French Government program of the French National Research Agency (ANR) through the A*MIDEX project (n\u00b0 ANR-11-IDEX-0001\u201302). Finally, Dr. Mireille Chevallet is acknowledged for their assistance in performing the ICP experiments.\u201d"}
+{"text": "In the article titled \u201cBiomechanical Evaluation of a Tooth Restored with High Performance Polymer PEKK Post-Core System: A 3D Finite Element Analysis\u201d , there w"}
+{"text": "Vagotomy in wild-type mice also significantly increased the serum osteoprotegerin/RANKL ratio, and elevated bone mass seen in nAchR7\u2212/\u2212 mice was reversed in \u03b17nAchR/osteoprotegerin-doubly-deficient mice. \u03b17nAchR loss significantly increased TNF\u03b1 expression in Mac1-positive macrophages, and TNF\u03b1 increased the osteoprotegerin/RANKL ratio in osteoblasts. Targeting TNF\u03b1 in nAchR7\u2212/\u2212 mice normalized both serum osteoprotegerin/RANKL ratios and bone mass. Administration of nicotine, an \u03b17nAchR ligand, to wild-type mice increased serum RANKL levels. Thus, vagal nerve stimulation of macrophages via \u03b17nAchR regulates bone mass by modulating osteoclast formation.The nicotinic receptor \u03b17nAchR reportedly regulates vagal nerve targets in brain and cardiac tissue. Here we show that  In terms of the former, activation of the sympathetic nervous system reportedly inhibits bone formation in response to leptin signals2022Here, we show that \u03b17nAchR is required to stimulate osteoclast formation and reduce bone mass by inhibiting circulating levels of OPG and elevating levels of RANKL. \u03b17nAchR-deficient mice exhibited increased bone mass due to an elevated OPG/RANKL ratio in serum, and increased bone mass seen in \u03b17nAchR-deficient mice was rescued in \u03b17nAchR/OPG double-knockout mice. TNF\u03b1 expression was aberrantly high in Mac1-positive macrophages among bone marrow cells in \u03b17nAchR-deficient mice, and increases in bone mass and the OPG/RANKL ratio seen in \u03b17nAchR-deficient mice were rescued in \u03b17nAchR/TNF\u03b1 double-knockout mice. Our results indicate overall that vagus nerve activity is required to maintain bone homeostasis by controlling systemic levels of OPG and RANKL via regulation of macrophage TNF\u03b1 expression.\u03b17nAchR\u2212/\u2212 relative to WT mice , number of osteoclasts per bone perimeter (N. Oc/B. Pm) and osteoclast surface per bone surface (Oc. S/BS) were significantly reduced in mutants, while osteoblastic parameters such as matrix apposition rate (MAR), bone formation rate (BFR) and osteoblast surface per bone surface (Ob. S/BS), were normal  mice to yield \u03b17/OPG DKO mice. In \u03b17/OPG DKO mice, elevated bone mass and inhibited osteoclastogenesis seen in \u03b17nAchR\u2212/\u2212 mice were significantly rescued  expression by realtime PCR in each; however, Tnfrsf11b expression was not detected in any of the three populations (data not shown). Serum RANKL levels were downregulated by transfer of \u03b17nAchR\u2212/\u2212 BM cell into either WT or \u03b17nAchR\u2212/\u2212 mice  expression was significantly elevated by TNF\u03b1 but not IL-1\u03b2 in MC3T3-E1 osteoblastic cells in vitro (Tnfsf11 (RANKL) expression was significantly downregulated by TNF\u03b1 in MC3T3-E1 cells  mice. Resulting double-knockout mice showed significantly reduced serum OPG and elevated RANKL, a reversal of what is seen in \u03b17nAchR\u2212/\u2212 single knockout mice The natural ligand of nAchRs is acetylcholine, an activity mimicked by nicotine. Smoking is a known risk factor for development of osteoporosis/osteopeniaTaken together, our data present new insight into regulation of bone homeostasis by the vagus nerve and how this interaction is mediated by inflammatory cytokine signaling.\u03b17nAchR+/\u2212, \u03b17nAchR\u2212/\u2212, Tnfrsf11b\u2212/\u2212 and Tnf\u03b1\u2212/\u2212 mice were maintained as described3537\u03b17nAchR\u2212/\u2212 and Tnfrsf11b\u2212/\u2212 mice or \u03b17nAchR\u2212/\u2212 and Tnf\u03b1\u2212/\u2212 mice were crossed to generate\u03b17nAchR\u2212/\u2212Tnfrsf11b\u2212/\u2212 or \u03b17nAchR\u2212/\u2212Tnf\u03b1\u2212/\u2212 mice, respectively.6 of bone marrow cells from 8-week-old donor (WT or \u03b17nAchR\u2212/\u2212) mice were transplanted intravenously into 10-week-old recipients (WT or \u03b17nAchR\u2212/\u2212), which were irradiated at a lethal dose immediately before transplant.Bone marrow transplantation was performed as previously described\u03b17nAchR\u2212/\u2212, Tnfrsf11b\u2212/\u2212, \u03b17nAchR\u2212/\u2212Tnfrsf11b\u2212/\u2212 or \u03b17nAchR\u2212/\u2212Tnf\u03b1\u2212/\u2212 mice, fixed with 70% ethanol and subjected to dual energy x-ray absorptiometric (DEXA) scanning to measure BMD (mg/cm2) at 20 proximal to distal points using a DCS-600R system . To evaluate bone architecture, micro-computed tomography (\u03bcCT) analysis was performed. Bone morphometric analysis and tartrate-resistant acid phosphatase (TRAP) staining were performed in tibiae from WT or \u03b17nAchR\u2212/\u2212 mice as describedFor bone mineral density (BMD) analysis, femurs were removed from WT, Animals were maintained under specific pathogen-free conditions in animal facilities certified by the Keio University animal care committee. Animal protocols were approved by that committee and carried our in accordance with the committee\u2019s guidelines.Bilateral subdiaphragmatic vagotomy or sham surgery was performed in 8-week-old WT mice as described\u03b17nAchR\u2212/\u2212, Tnfrsf11b\u2212/\u2212, \u03b17nAchR\u2212/\u2212Tnfrsf11b\u2212/\u2212 or \u03b17nAchR\u2212/\u2212Tnf\u03b1\u2212/\u2212 mice, and recipients transplanted with bone marrow cells twelve-week-after transplantation. Sera were also collected from vagotomized or nicotine administrated wild-type mice, or from mice administered 25\u2009mg/kg of Etanercept (Embrel\u00ae. Pfizer. Tokyo. Japan) twice a week for three weeks. OPG or RANKL levels in sera were examined by ELISA according to the manufacture\u2019s protocol (R&D).Sera were collected from 8-week-old WT, \u03b17nAchR\u2212/\u2212 mice were stained with FITC-conjugated anti-CD3, B220 or Mac1. Then, CD3-positive T cells, B220-positive B-cells and Mac1-positive monocyte/macrophage fractions were sorted separately using the B & D FACS AriaTM 2 system.Bone marrow mono-nuclear cells isolated from WT or Paraffin sections of tibia were deparaffinized and subjected to antigen retrieval as describedMacrophage colony-stimulating factor (M-CSF) and recombinant soluble receptor activator of nuclear factor \u03ba\u2013B ligand (RANKL) were purchased from Kyowa Hakko Kirin Co.  and Pepro-Tech Ltd. , respectively. Nicotine and acetylcholine were obtained from Sigma-Aldrich .in vitro, bone marrow cells were isolated from femurs and tibiae of WT and \u03b17nAchR\u2212/\u2212 mice and cultured 3 days in \u03b1-modified Eagle\u2019s minimum essential medium (Sigma-Aldrich Co.) containing 10% heat-inactivated FBS  and GlutaMax (Invitrogen Corp.) with M-CSF (50\u2009ng/ml). M-CSF-dependent adherent cells were then collected as osteoclast progenitors, and 5\u2009\u00d7\u2009104 cells were plated per well of 96-well culture plates and cultured with M-CSF (50\u2009ng/ml) and RANKL (25\u2009ng/ml) in the presence or absence of nicotine (1\u2009\u03bcM) or acetylcholine (1\u2009\u03bcM) for five days. Osteoclastogenesis was assessed by evaluation of TRAP and May-Giemsa staining under a microscope , and TRAP-positive cells containing more than three nuclei were scored as osteoclastsTo assess osteoclast formation Primary osteoblasts were isolated from newborn mouse calvariae as described\u03b2-actin expression was analyzed as an internal control. Primers for \u03b2-actin, Ctsk, Nfatc1, Tnf\u03b1, Tnfrsf11b (OPG) and Tnfsf11 (RANKL) are as follows.Total RNAs were isolated from cultured or sorted cells using the RNeasy mini kit (Qiagen), and cDNA was synthesized with oligo (dT) primers and reverse transcriptase (Takara Bio Inc). Quantitative PCR was conducted using the SYBR Premix ExTaq II  with a DICE Thermal cycler (Takara Bio Inc.) according to the manufacturer\u2019s instructions. \u03b2-actin-forward: 5\u2032-TGAGAGGGAAATCGTGCGTGAC-3\u2032\u03b2-actin-reverse: 5\u2032-AAGAAGGAAGGCTGGAAAAGAG-3\u2032Ctsk-forward: 5\u2032-ACGGAGGCATTGACTCTGAAGATG-3\u2032Ctsk-reverse: 5\u2032-GGAAGCACCAACGAGAGGAGAAAT-3\u2032Nfatc1-forward: 5\u2032-CAAGTCTCACCACAGGGCTCACTA-3\u2032Nfatc1-reverse: 5\u2032-GCGTGAGAGGTTCATTCTCCAAGT-3\u2032Tnf\u03b1-forward: 5\u2032-CTTCTGTCTACTGAACTTCGGG-3\u2032Tnf\u03b1-reverse: 5\u2032-CAGGCTTGTCACTCGAATTTTG-3\u2032Tnfrsf11b (OPG)-forward: 5\u2032-GACCACAATGAACAAGTGGCTGT-3\u2032Tnfrsf11b (OPG)-reverse: 5\u2032-CCAGTTTCTGGGTCATAATGCAA-3\u2032Tnfsf11 (RANKL)-forward: 5\u2032-GCATCGCTCTGTTCCTGTACTTT-3\u2032Tnfsf11 (RANKL)-reverse: 5\u2032-CGTTTTCATGGAGTCTCAGGATT-3\u2032t-test . All data are expressed as means\u2009\u00b1\u2009SD.Statistical analysis was performed using the unpaired two-tailed Student\u2019s How to cite this article: Mito, K. et al. The nicotinic acetylcholine receptor \u03b17 subunit is an essential negative regulator of bone mass. Sci. Rep.7, 45597; doi: 10.1038/srep45597 (2017).Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations."}
+{"text": "The correct name is: Iv\u00e1n Mej\u00eda-Guevara. The correct citation is: Gausman J, Mej\u00eda-Guevara I, Subramanian SV, Razak F (2018) Distributional change of women\u2019s adult height in low- and middle-income countries over the past half century: An observational study using cross-sectional survey data. PLoS Med 15(5): e1002568."}
+{"text": "Scientific Reports 7:7457; doi:10.1038/s41598-017-07568-z; Article published online 07 August 2017The original version of this Article contained errors in References 1\u201314, 16\u201328, 31\u201332 and 35\u201338. These errors have now been corrected in the HTML and PDF versions of this paper."}
+{"text": "The article has since been corrected online.In the article \u201cAssociation Between Leptin (-2548G/A) Genes Polymorphism and Breast Cancer Susceptibility: A Meta-Analysis\u201d,"}
+{"text": "The article has since been corrected online.In the article \u201cKeyhole Approach Combined With External Ventricular Drainage for Ruptured, Poor-Grade, Anterior Circulation Cerebral Aneurysms\u201d,"}
+{"text": "In the article titled \u201cCollagen Sponge Functionalized with Chimeric Anti-BMP-2 Monoclonal Antibody Mediates Repair of Critical-Size Mandibular Continuity Defects in a Nonhuman Primate Model\u201d , Dr. Son"}
+{"text": "Scientific Reports 10.1038/s41598-017-09676-2, published online 12 September 2017Correction to: This Article contains errors in Figure 1.\u201cPatient demand Roux-en-Y (n\u2009=\u20096)\u201dshould read:\u201cPatient converted to Roux-en-Y (n\u2009=\u20096)\u201d.In addition,\u201cPatient demand Billroth-I (n\u2009=\u20096)\u201dshould read:\u201cPatient converted to Billroth-I (n\u2009=\u20096)\u201d.The correct Figure"}
+{"text": "Following publication of the original article (Takahashi et al.  Following publication of the original article (Takahashi et al. 2 and O2 concentrations in normal and specialised shake-flask culture of E. coli IFO3301. a In the headspace; b in the culture medium. Symbols: circles oxygen; triangles carbon dioxide; closed normal shake-flask culture; open specialised shake-flask culture (with removal of\u2026\u2026\u2026\u2026\u2026..Figure\u00a02 Real-time COHowever, the sentence should read:2 and O2 concentrations in normal and specialised shake-flask culture of E. coli IFO3301. a In the headspace; b in the culture medium. Symbols: triangles oxygen; circles carbon dioxide; closed normal shake-flask culture; open specialised shake-flask culture (with removal of\u2026\u2026\u2026\u2026\u2026..Figure\u00a02 Real-time CO"}
+{"text": "Scientific Reports7:12638; doi:10.1038/s41598-017-12988-y; Article published online 03 October 2017The original HTML version of this Article contained errors in the Results section under subheading \u2018Domain architecture analysis of grape HB proteins\u2019.\u201cWe found that the comment\u2009=\u2009\u201cStyle change has been done. Please check.\u201cVvHB proteins represented 11 of these families\u201d.now reads:\u201cWe found that the VvHB proteins represented 11 of these families\u201d.\u201cThere are two comment\u2009=\u2009\u201cStyle change has been done. Please check.\u201cHB genes encoding HB-PHD proteins in both grape and Arabidopsis\u201d.now reads:\u201cThere are two HB genes encoding HB-PHD proteins in both grape and Arabidopsis\u201d.These errors have now been corrected in the HTML version of the Article; the PDF version was correct from the time of publication."}
+{"text": "The phrase \u201cMhc14 class-2 myosins \u201d appears incorrectly throughout the article. The correct phrase should be, \u201cMhc14 class-2 myosins .\u201d Please see the corrected"}
+{"text": "Scientific Reports7:4510; doi:10.1038/s41598-017-04601-z; Article published online 03 July 2017In the original version of this Article, size-based CTC-isolation is erroneously referred to as \u2018ISET\u2019. \u2018ISET\u2019 is a Trademark of Rarecells. The two incidences of \u2018ISET\u2019 (in the abstract and the \u2018CTC isolation method\u2019 section) have been removed."}
+{"text": "Scientific Reports7: Article number: 4263210.1038/srep42632; published online: 02152017; updated: 03282017in vivo\u201d, where:This Article contains a typographical error in the Results section, under the subheading \u201cTherapeutic efficacy \u201cFor the DOX-platelet treated group, a continuous tumor suppression was observed during the whole experiment \u201d.should read:\u201cFor the DOX-platelet treated group, a continuous tumor suppression was observed during the whole experiment \u201d."}
+{"text": "Scientific Reports6: Article number: 3079210.1038/srep30792; published online: 08032016; updated: 03082018This Article contains typographical errors. In the Results section,UBE3A gene (accession NM_130838)11, and from a normal healthy control person.\u201d\u201cWe reprogrammed primary dermal fibroblasts isolated from a female patient with AS harboring a three-base pair deletion in exon 4 of the should read:UBE3A gene (accession NM_130838)11, and from a normal healthy control person.\u201d\u201cWe reprogrammed primary dermal fibroblasts isolated from a female patient with AS harboring a three-base pair deletion in exon 5 of the In Table S8 of the Supplementary Information file, the sequence of the forward primer \u2018SNHG14_RT17_F\u2019 for \u2018qRT-PCR neuronal differentiation\u2019,\u201ccttgagtattccggaagtaaaagc\u201dshould read:\u201cctcttcttgcagtttacaacgg\u201d"}
+{"text": "Scientific Reports 10.1038/s41598-017-03717-6, published online 14 June 2017Correction to: Ne) FP/HG\u2019. The correct Figure 3 appears below as Figure\u00a0In Figure 3, the title \u2018Effective individuals per unit of productivity (Ne/NPP) FP/HG\u2019 is incorrectly given as \u2018Effective population size (This Article also contains errors in the Results section under subheading \u2018Migration\u2019.Ne in SE Asia Dataset 1\u201d\u201cTo take into account the mentioned hypotheses, we calculated the ratio of should read:Ne /NPP for food producers over foragers in SE Asia Dataset 1\u201d\u201cTo take into account the mentioned hypotheses, we calculated the ratio of"}
+{"text": "In the article titled \u201cThe Efficacy and Safety of Chinese Herbal Decoction in Type 2 Diabetes: A 5-Year Retrospective Study\u201d , there w"}
+{"text": "Lathyrus sativus L.): Genetic Control, Linkage Relationships, and Mapping with Aconitase and S-Nitrosoglutathione Reductase Isozyme Loci\u201d [The Scientific World Journal has retracted the article titled \u201cFlavonoid-Deficient Mutants in Grass Pea (me Loci\u201d . The art"}
+{"text": "Please see the corrected table below.In the article, \u201cRetrospective study of intravascular large B-cell lymphoma cases diagnosed in Quebec: A retrospective study of 29 case reports\u201d,"}
+{"text": "Scientific Reports7:2180; doi:10.1038/s41598-017-02310-1; Article published online 19 May 2017This Article contains typographical errors in the Acknowledgements section.\u201cThis research was supported by the Russian Scientific Foundation under contract \u2116 14-50-00124\u201d.should read:\u201cThis research was supported by the Russian Scien\u0441e Foundation (Project Number 14- 50-00124)\u201d."}
+{"text": "Eucharia A. Onu's name appeared incorrectly as Eucharia U. Onu.In the article, \u201cA rational-emotive stress management intervention for reducing job burnout and dysfunctional distress among special education teachers: An effect study\u201d"}
+{"text": "Scientific Reports7: Article number: 4166210.1038/srep41662; published online: 02062017; updated: 04282017This Article contains typographical errors.\u2018The C-terminal domain adopts an immunoglobulin fold in solution\u2019,In the results section under subheading \u201cA search for structurally similar proteins possessing using the Dali server identified many proteins containing an Ig-like fold, including immunoglobulin receptors, fibroblast growth factor receptors and the T-cell surface glycoprotein CD4.\u201dshould read:\u201cA search for structurally similar proteins using the Dali server identified many proteins containing an Ig-like fold, including immunoglobulin receptors, fibroblast growth factor receptors and the T-cell surface glycoprotein CD4.\u201dl2 column, the second T5\u2206dec value \u20181mM\u2019 should read \u20180.1mM\u2019.In Table 2 in the MgC"}
+{"text": "Hongqi Zhang appeared incorrectly as Qi Hong Zhang.In the article, \u201cA medium-term follow-up of adult lumbar tuberculosis treating with 3 surgical approaches\u201d,"}
+{"text": "Scientific Reports7: Article number: 42460; 10.1038/srep42460 published online: 03092017; updated: 02122018.The Acknowledgements section in this Article is incomplete:\u201cThis work was supported by the European Union FP7 projects MODERN , MARINA , and SUN , by FEDER funding through COMPETE  and Portugal funding through FCT (Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia) within the project bio-CHIP , and by a post-doctoral grant \u201dshould read:\u201cThis work was supported by the European Union FP7 projects MODERN , MARINA , and SUN , by FEDER funding through COMPETE  and Portugal funding through FCT (Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia) within the project bio-CHIP , and by a post-doctoral grant . Financial support was also received from CESAM (UID/AMB/50017 - POCI-01-0145-FEDER-007638), FCT/MCTES through national funds (PIDDAC), and the co-funding by the FEDER, within the PT2020 Partnership Agreement and Compete 2020.\u201d"}
+{"text": "Page 6 of the PDF, third full paragraph, line 4: \u201csmallpox\u201d should be \u201chorsepox.\u201d The corrected sentence should read \u201cGiven much of this information already exists in the literature, the publication of the horsepox experiments may only provide additional instructive capability to experienced actors.\u201dVolume 3, no. 2, e00074-18, 2018,"}
+{"text": "In the Discussion section, the phrase \u201cGram-negative\u201d appears incorrectly. For all instances within the Discussion section, the correct phrase is \u201cGram-positive.\u201d"}
+{"text": "Scientific Reports 10.1038/s41598-017-09064-w, published online 21 August 2017Correction to: This Article contains a typographical error.In the Methods section under subheading \u2018TGIRT-seq of E. coli genomic DNA\u2019,\u201c\u201dshould read:\u201c\u201d"}
+{"text": "In the report \u201cUpdate: Dura Mater Graft\u2013Associated Creutzfeldt-Jakob Disease \u2014 Japan, 1975\u20132017,\u201d on page 276, an error occurred in"}
+{"text": "Scientific Reports 10.1038/s41598-017-15257-0, published online 13 November 2017Correction to: This Article contains typographical errors in the Acknowledgements section.\u201cand the Spanish Society for the Research of Individual Differences (SEIDI), grant FIS2016-76163-R (FJA & JMB)\u201dshould read:\u201cand the Secretar\u00eda de Estado de Investigaci\u00f3n, Desarrollo e Innovaci\u00f3n (SEIDI), Spain, grant FIS2016-76163-R (JMB & FJA)\u201d"}
+{"text": "Scientific Reports 10.1038/s41598-017-00825-1, published online 19 April 2017Correction to: This Article contains a typographical error. In the Results section under subheading \u2018Analytical Model, Piecewise Linear System Dynamics and connection to Spectral Algorithms\u2019,v is normalized to vdd then p(s)\u2009=\u2009s.\u201d\u201cIf the voltage should read:v is normalized to vdd then p(s)\u2009=\u2009gms.\u201d\u201cIf the voltage gis should be gms.In addition, all instances of"}
+{"text": "Scientific Reports6: Article number: 3942610.1038/srep39426; published online: 11202016; updated: 03162017This Article contains errors in Table 3. In the \u201cB-lines \u226515\u201d column, the Timing of B-line quantification values using univariable analysis for \u201cEarly during hospital stay\u201d and \u201cAt discharge\u201d are inverted. The correct"}
+{"text": "In the article titled \u201cResveratrol-Enriched Rice Attenuates UVB-ROS-Induced Skin Aging via Downregulation of Inflammatory Cascades\u201d , the aff"}
+{"text": "Scientific Reports 10.1038/s41598-017-14260-9, published online 24 October 2017Correction to: This Article contains errors in Table 1, where incorrect values for \u2018Fasting plasma glucose (mg/dL)\u2019 and \u2018L/S ratio\u2019 are given. The correct Table\u00a0In addition, this Article contains a typographical error in the Methods section, under the subheading \u2018Statistical analysis\u2019 where,\u201cBonferroni connection\u201dshould read:\u201cBonferroni correction\u201d"}
+{"text": "Bruno Fantin's name appeared incorrectly as Fantin Bruno.In the article, \u201cCandida vertebral osteomyelitis (CVO) 28 cases from a 10-year retrospective study in France\u201d,"}
+{"text": "Scientific Reports7:2465; doi:10.1038/s41598-017-02496-4; Article published online 26 May 2017+/K+-ATPase inhibition-independent proarrhythmic ionic mechanisms of cardiac glycosides\u201d.The original version of this Article contained errors in the title.\u00a0\u201cElectronic supplementary materialIdentification of a Nanow reads:+/K+-ATPase inhibition-independent proarrhythmic ionic mechanisms of cardiac glycosides\u201d. These errors have now been corrected in the PDF and HTML versions of the Article.\u201cIdentification of Na"}
+{"text": "Klebsiella pneumoniae Compared to Nonproducing Isolates\u201d [In the Results section, \u201ca total of twenty-four different virulence profiles were observed among the tested isolates,\u201d should be \u201ca total of twenty-three different virulence profiles were observed among the tested isolates.\u201dIn the Discussion section, \u201canalysis of virulence factors combination has brought out 23 different virulence profiles including 2 to 8 virulence factors (Table 4),\u201d should be \u201canalysis of virulence factors combination has brought out 23 different virulence profiles including 2 to 9 virulence factors (Table 4).\u201d\u03b1-hemolysis-BssS-fimH-iss\u201d should be corrected to \u201cBiofilm-serum resistant-haemagglutination-hypermucoviscosity-lipase-\u03b1-hemolysis-BssS-fimH-iss.\u201d The correct table is shown as follows:In the eighteenth row of Table 4, \u201cBiofilm-serum resistant-haemagglutination-lipase-In the article titled \u201cAssociation between Virulence Factors and Extended Spectrum Beta-Lactamase Producingsolates\u201d , there w"}
+{"text": "In the article titled \u201cTopical Colchicine Gel versus Diclofenac Sodium Gel for the Treatment of Actinic Keratoses: A Randomized, Double-Blind Study\u201d , Dr. Fat"}
+{"text": "Nature Communications8:575 doi:10.1038/s41467-017-00474-y; Article published online: 18 September 2017n-hexane as the infused liquid.In Table 1 of this Article, the third row in the furthest right column contains a typographical error and should read \u2018NH\u2019, rather than \u2018NM\u2019, corresponding to"}
+{"text": "Scientific Reports 10.1038/s41598-017-02052-0, published online 12 May 2017Correction to: The Acknowledgements section in this Article is incomplete.http://www.3srbreeding.eu/). The authors thank all the partners involved. The authors also thank C\u00e9cile Albenne for her precious help in enzymology, St\u00e9phane Fabre, Marc Teisser and Julie Demars for their involvement and help with softwares and molecular part, and Aur\u00e9lie Tircazes for her help with genotype calling. Lipidomic analyses were performed on the Toulouse MetaToul-Lipidomique Core Facility , MetaboHUB-ANR-11-INBS-0010.\u201d.\u201cThe authors thank Pierre Martin and all the Capgenes breeding organizations for providing the data and their helpful contributions. This work was supported by grants from French organizations through \u201cPh\u00e9noFinlait\u201d , CAPGENES and FCEL) and EC (FP7/2007\u20132013), grant no. 245140, \u201c3SR\u201d, Sustainable Solutions for Small Ruminants (should read:http://www.3srbreeding.eu/). The authors thank all the partners involved. The authors also thank C\u00e9cile Albenne for her precious help in enzymology, St\u00e9phane Fabre, Marc Teisser and Julie Demars for their involvement and help with softwares and molecular part, and Aur\u00e9lie Tircazes for her help with genotype calling. Lipidomic analyses were performed on the Toulouse MetaToul-Lipidomique Core Facility , MetaboHUB-ANR-11-INBS-0010. Pauline Martin received a doctoral research grant from \u201cR\u00e9gion Midi-Pyr\u00e9n\u00e9es\u201d, Animal Genetics Department from INRA and GENOMCAP research programm including INRA, APIS-GENE, ALLICE (formerly UNCEIA), CAPGENES and FCEL). Cyrielle Maroteau received a CIFRE grant from ALLICE\u201d.\u201cThe authors thank Pierre Martin and all the Capgenes breeding organizations for providing the data and their helpful contributions. This work was supported by grants from French organizations through \u201cPh\u00e9noFinlait\u201d , CAPGENES and FCEL) and EC (FP7/2007\u20132013), grant no. 245140, \u201c3SR\u201d, Sustainable Solutions for Small Ruminants ("}
+{"text": "Scientific Reports 10.1038/s41598-018-20914-z, published online 09 February 2018Correction to: The original version of this Article contained typographical errors.In the Results section, the subheading,\u201cTropism of CD42b, CD41a and CD41a in dengue virus by two-dimensional analysis\u201dnow reads:\u201cTropism of CD42b, CD41 and CD41a in dengue virus by two-dimensional analysis\u201dIn the Results section, under the subheading \u2018Tropism of CD42b, CD41 and CD41a in dengue virus by two-dimensional analysis\u2019,\u201cThe stained cells were demonstrated under the fluorescence microscope herein to confirm that our immunostaining method detected platelet receptors superficially and DENV intracellularly .\u201dnow reads:22 .\u201d\u201cThe stained cells were demonstrated under the fluorescence microscope herein to confirm that our immunostaining method detected platelet receptors superficially and DENV intracellularlyIn the Results section, under the subheading \u2018Requirement of CD42b in dengue virus infection by three-dimensional analysis\u2019,\u201cWe further hypothesized that CD42b alone was a key requirement for DENV infection because we could not associate intracellular DENV+\u2009cells with CD42b\u2212 cells .\u201dnow reads:\u201cWe further hypothesized that CD42b alone was a key requirement for DENV infection because we could not associate intracellular DENV+\u2009cells with CD42b\u2212 cells .\u201dIn the Results section, under the subheading \u2018Dependence of dengue virus infection on CD42b by single-cell virus-protein analysis\u2019,p\u2009=\u200910\u22123, n\u2009=\u20092118).\u201d\u201c.\u201d\u201c(Fig. 4E; Additionally, this Article contained a typographical error in the Acknowledgements section.\u201cPatchanat Klaihmon\u201dnow reads:\u201cPhatchanat Klaihmon\u201dThese errors have now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Scientific Reports 10.1038/s41598-017-02278-y, published online 19 May 2017Correction to: -1 soil)\u2019 is incorrectly labelled as \u2018DOC (mg g\u22121 soil)\u2019. The correct Figure 3 appears below as Figure\u00a0This Article contains an error in Figure 3, where the y-axis \u2018DOC \u03bcg g- soil\u2019 is"}
+{"text": "Page\u00a02: Lines\u00a011\u201314 should read as follows: \u201c\u2026Unlike the genomes of other gammaproteobacterial methanotrophs, the USC\u03b3 draft genome contains nearly all essential genes for a complete serine biosynthesis pathway for formaldehyde assimilation. However, the enzymes unique to the typical RUMP pathway, hexulose-6-phosphate synthase and hexulose phosphate isomerase, were not detected\u2026.\u201dVolume 5, no. 17, e00047-17, 2017,"}
+{"text": "Scientific Reports6: Article number: 2816610.1038/srep28166; published online: 06212016; updated: 05172018This Article contains errors in the Results section under the subheading \u2018Development of a pH-stable GFP variant for use as biomarker\u2019,\u201cTo create a monomeric GFP variant, we created a construct comprised of two sfGFP-N149Y/Q204H separated by a flexible 25 amino acid linker, termed pH-stable tandem dimer GFP (pH-tdGFP).\u201dshould read:\u201cTo create a monomeric GFP variant, we created a construct comprised of two sfGFP-N149Y/Q204H separated by a flexible 22 amino acid linker, termed pH-stable tandem dimer GFP (pH-tdGFP).\u201dAdditionally, in the Materials and Methods section under the subheading \u2018Purification of GFP variants\u2019,\u201cpH-tdGFP is a tandem fusion of two yeast codon optimized sfGFP-N149Y/Q204H separated by the amino acid linker ITLGGTGSGSGDEVDGMVSKGEEVIK.\u201dshould read:\u201cpH-tdGFP is a tandem fusion of two yeast codon optimized sfGFP-N149Y/Q204H separated by the amino acid linker HGTGSTGSGSSGTASSEDNNMA.\u201d"}
+{"text": "Scientific Reports6: Article number: 3049110.1038/srep30491; published online: 07262016; updated: 09022016This Article contains errors in Figure 3a and 3d where the y axes \u2018y (\u03bcm)\u2019 is incorrectly given as \u2018y (mm)\u2019. The correct Figure 3 appears below as"}
+{"text": "Cordyceps militaris in High-Fat Diet-Induced Type 2 Diabetes Mellitus Mice\u201d [In the article titled \u201cHypoglycemic Activity through a Novel Combination of Fruiting Body and Mycelia of us Mice\u201d , there w"}
+{"text": "Scientific Reports6: Article number: 3168610.1038/srep31686; published online: 08232016; updated: 11102016.This Article contains typographical errors. In the legend of Figure 6, the descriptions corresponding to Figures 6c and 6d have been mislabelled \u2018(D)\u2019 and \u2018(E)\u2019 respectively. In the Results section,\u201cIn total, 1,998 genes were differentially expressed by more than eight-fold (<\u22128 or >8) under salinity stress,\u201dshould read:\u201cIn total, 1,198 genes were differentially expressed by more than eight-fold (<\u22128 or >8) under salinity stress,\u201d"}
+{"text": "The original publication  containsThe sentence should be: \u201cThese specific characteristics may significantly contribute to the psychosocial impairment and altered quality of life of these subjects.\u201dThe correct table legend can be found below: \u201cDASS Depression Anxiety Stress Scale, N/A not applicable, NRS numeric rating scale, SD standard deviation. + Mann\u2013Whitney-U-test; * chi square test\u201d."}
+{"text": "Scientific Reports7: Article number: 46025; 10.1038/srep46025 published online: 04062017; updated: 07272017.The original version of this Article contained errors. In the Abstract,\u201cThe patients in the community-acquired SBP (n\u2009=\u2009311) and the nosocomial SBP (n\u2009=\u2009264) groups exhibited significant differences in clinical symptoms (P\u2009<\u20090.01)\u201d.now reads:\u201cThe patients in the community-acquired SBP (n\u2009=\u2009264) and the nosocomial SBP (n\u2009=\u2009311) groups exhibited significant differences in clinical symptoms (P\u2009<\u20090.01)\u201d.In the Results section, under subheading \u2018Basic patient information\u2019,\u201cPatients were divided into either nosocomial (n\u2009=\u2009264) or community-acquired groups (n\u2009=\u2009311) according to the type of infection\u201d.now reads:\u201cPatients were divided into either nosocomial (n\u2009=\u2009311) or community-acquired groups (n\u2009=\u2009264) according to the type of infection\u201d.As a result, the values of the columns \u2018Community-acquired \u2019 and \u2018Nosocomial \u2019 in These errors have now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Erratum to:npj Schizophrenia (2017); doi:10.1038/s41537-017-0023-7; Published 11 May 2017The Competing interests section states, \u201cThe authors declare competing financial interests.\u201d However, it should be, \u201cThe authors declare no competing financial interests.\u201d These errors have now been corrected in the HTML and PDF versions of this article."}
+{"text": "To compare the incidence of toxicity of 8 different chemotherapy regimens, including doxorubicin + paclitaxel, doxorubicin, capecitabine, CMF (cyclophosphamide + methotrexate + 5-fluorouracil), FAC (fluorouracil + doxorubicin + cyclophosphamide), doxorubicin + docetaxel, doxorubicin + cyclophosphamide and paclitaxel in the treatment of metastatic/advanced breast cancer.This network meta-analysis included 8 randomized controlled trials (RCTs). The findings revealed that, with regard to capecitabine alone regimen exhibited higher incidence of nausea/vomiting than doxorubicin + paclitaxel regimen, doxorubicin alone regimen and paclitaxel alone regimen in the treatment of patients with metastatic/advanced breast cancer . Furthermore, doxorubicin + cyclophosphamide regimen had lower incidence of febrile neutropenia than doxorubicin + docetaxel . No significant difference in the incidence of stomatitis was observed among eight chemotherapy regimens.We initially searched PubMed, Cochrane Library and Embase databases from the founding of these databases to January 2016. Eligible studies investigating the 8 different chemotherapy regimens for treatment of metastatic/advanced breast cancer were included for direct and indirect comparison. The odds ratio (OR) and surface under the cumulative ranking curves (SUCRA) value of the incidence of toxicity among eight chemotherapy regimens were analyzed.Capecitabine alone regimen and doxorubicin + docetaxel regimen may have a more frequent toxicity in the treatment of metastatic/advanced breast cancer. Breast cancer, one of the most common malignancies worldwide, comprises 3% of all cancers in women worldwide . Approxiin vivo screens in laboratory mice implanted tumors and also found to possess cytotoxic activity in clinical application  OR breast cancer[tiab] OR Neoplasm, Breast[tiab] OR Tumors, Breast OR Mammary Neoplasms, Human[tiab] OR Human Mammary Neoplasm[tiab] OR Mammary Carcinoma, Human[tiab] OR Carcinomas, Human Mammary[tiab] OR Mammary Carcinomas, Human[tiab] OR Mammary Cancer[tiab] OR Cancer of Breast[tiab]#2: chemotherapy[tiab] OR \u201cCyclophosphamide\u201d [mh] OR \u201cDoxorubicin\u201d[mh] OR Farmiblastina[tiab] OR \u201cPaclitaxel\u201d[mh] OR \u201cDocetaxel\u201d[mh] OR \u201cCapecitabine\u201d [mh] OR \u201cgemcitabine\u201d [mh] OR \u201cEpothilone\u201d[mh] OR \u201cvinorelbine\u201d[Supplementary Concept] OR \u201cDDP\u201d [Supplementary Concept] OR \u201cCarboplatin\u201d [Supplementary Concept] OR \u201coxaliplatin\u201d[Supplementary Concept] OR \u201cPirarubicin\u201d[Supplementary Concept] OR \u201cEpirubicin\u201d[mh]#3: \u201crandomized controlled trial\u201d[pt] OR \u201ccontrolled clinical trial\u201d[pt] OR \u201crandomized controlled trials as topic\u201d[Mesh] OR \u201cclinical trials as topic\u201d[mh] OR \u201ccontrolled clinical trials as topic\u201d[mh] OR placebos[mh] OR \u201crandom allocation\u201d[mh] OR \u201cdouble-blind method\u201d[mh] OR randomized[tiab] OR placebo[tiab] OR randomization[tiab] OR randomly allocated[tiab] OR ((double[tw] OR treble[tw] OR triple[tw]) AND (mask* [tw] OR blind* [tw]))#4: #1 and #2 and #3The inclusion criteria: (1) study type: RCT; (2) interventions: doxorubicin + paclitaxel, doxorubicin, capecitabine, CMF (cyclophosphamide + methotrexate + fluorouraci), FAC (fluorouracil + doxorubicin + cyclophosphamide), doxorubicin + docetaxel, doxorubicin + cyclophosphamide, and paclitaxel; (3) chemotherapy: first-line therapy; (4) disease stage: stage III or IV; (5) patient population: hospital-based patient; (6) subjects: at least one measurable lesion in patients with metastatic/advanced breast cancer according to the Response Evaluation Criteria in Solid Tumors (RECIST) ; (7) outTwo reviewers abstracted the data independently with the unified data collection form, and disagreements were resolved by discussion with a number of investigators. The trial size, trial design, details of intervention including treatment duration, patient characteristics such as sex, age, mean duration of follow-up time as well as outcome data were extracted. For crossover trials, the data was extracted from the first period only in order to avoid possible carryover effects. The means and measures of dispersion were approximated from figures in the reports as previously described whenever necessary. Whenever possible, we extracted results from the intention-to-treat analyses. More than 2 reviewers evaluated the quality of RCT with a modified Cochrane risk of bias assessment tool , which iP value was higher than 0.05, the consistency model was used to analyze the results [Firstly, pairwise meta-analyses of direct evidence were conducted by the fixed-effects model, with R version 3.2.1 and the meta-package. We also calculated the pooled results of odd ratios (OR) with 95% credible intervals (CrIs) of three end point outcomes. Chi-square test and I-square test were carried out for testing heterogeneity among the studies . Then, R results . In orde results , 56. R 3"}
+{"text": "Atherosclerosis is an inflammatory process that develops in individuals with known risk factors that include hypertension and hyperlipidaemia, influenced by diet. However, the interplay between diet, inflammatory mechanisms and vascular risk factors requires further research. We hypothesised that interleukin-1 (IL-1) signaling in the vessel wall would raise arterial blood pressure and promote atheroma.\u2212/\u2212Apoe and \u2212/\u2212/IL-1R1\u2212/\u2212Apoe mice were fed high fat diets for 8 weeks, and their blood pressure and atherosclerosis development measured. \u2212/\u2212/IL-R1\u2212/\u2212Apoe mice had a reduced blood pressure and significantly less atheroma than \u2212/\u2212Apoe mice. Selective loss of IL-1 signaling in the vessel wall by bone marrow transplantation also reduced plaque burden (p<0.05). This was associated with an IL-1 mediated loss of endothelium-dependent relaxation and an increase in vessel wall Nox 4. Inhibition of IL-1 restored endothelium-dependent vasodilatation and reduced levels of arterial oxidative stress.The IL-1 cytokine system links atherogenic environmental stimuli with arterial inflammation, oxidative stress, increased blood pressure and atherosclerosis. This is the first demonstration that inhibition of a single cytokine can block the rise in blood pressure in response to an environmental stimulus. IL-1 inhibition may have profound beneficial effects on atherogenesis in man. Drugs to decrease plasma lipid levels and blood pressure are the basis of the medical treatment strategy for cardiovascular disease. Dietary modification of macronutrient and salt intakes has also been studied with some large effects upon systolic blood pressure in particular In the arterial wall, IL-1 is secreted primarily by monocytes and macrophages but also by endothelial and smooth muscle cells IL-1 is a powerful inflammatory stimulus to endothelial and vascular smooth muscle cells with effects that are plausibly linked with known mechanisms of atherogenesis \u2212/\u2212Apoe mice fed atherogenic diets. We also show a link between fat feeding and blood pressure that is mediated via IL-1 through modulation of the NADPH-oxidase subunit 4 (Nox 4).We report here the cardiovascular effects of abolishing IL-1 signaling either by genetic deletion of IL-1R1 or by administration of IL-1ra in proatherogenic More detailed methods can be found in the online supplemental material .\u2212/\u2212/IL-R1\u2212/\u2212Apoe mice were generated at JAX labs by cross breeding of \u2212/\u2212Apoe (JAX 2052) with \u2212/\u2212IL-R1 (JAX 3245) mice. All mice were on a C57BL/6 background. Male mice, 8 weeks of age, (12 per group) were fed normal chow , Western diet  or Western High Cholate (WHC or Paigen) diet  for 8 weeks. No differences in body weights between the strains were observed either with or without fat feeding. Diets were supplied by Special Diet Services, UK. All animal experiments were approved by the University of Sheffield Project Review Committee and conformed to UK Home Office ethical guidelines.Histologically stained paraffin wax embedded sections were analysed as previously described Systolic and diastolic blood pressures of mice were measured using a Visitech tail-cuff system  and mean blood pressure calculated  was used to determine arteriolar myogenic reactivity and responsiveness to nitric oxide, as previously described Irradiation and bone marrow transplantation of mice was performed as previously described in-situSuperoxide production in mouse aortic tissue sections was detected 2, annealing at 60\u00b0C and extension at 72\u00b0C. Primer sequences were as described in Quantification of Nox 2 and Nox 4 was performed by amplification of artery cDNA using a MX3000P instrument (Stratagene) with SYBR green dye, and normalization to 18S rRNA. For cultured cells, normalization was to \u03b2-actin. Optimized amplification conditions were 150 mmol/L primers, 2.5 mmol/L MgCl2, Emax, L-NAME effects and wall: lumen ratios were compared by t-tests. Data are presented as mean\u00b1SEM. p<0.05 was regarded as a significant difference.Data groups were analyzed by t-test or one-way ANOVA followed by a Bonferroni multiple comparison post-test, as appropriate. Blood pressure measurements were analyzed by global non-linear regression, followed by an F-test. Vessel diameters were analyzed by two-way repeated-measures ANOVA. pDFurther results can be found in the online supplementary text .\u2212/\u2212Apoe mice fed high fat diets displayed significant increases in atherosclerotic lesion area compared to mice fed chow, with the Western diet with high cholate (WHC) causing the a greatest increase , or Western diet (p\u200a=\u200a0.4). However, when fed the WHC diet, \u2212/\u2212/IL-R1\u2212/\u2212Apoe mice developed a 36% smaller atherosclerotic lesion in the aortic sinus compared to \u2212/\u2212Apoe mice (p<0.001)  . Represep<0.001) . Body we\u2212/\u2212Apoe and \u2212/\u2212/IL-R1\u2212/\u2212Apoe chimeric mice were used to determine the relative contribution of IL-1 signaling in cells derived from the bone marrow and non-bone marrow (tissue cells) upon the development of atherosclerosis following fat feeding. Irradiated \u2212/\u2212Apoe mice receiving \u2212/\u2212Apoe bone marrow had large, and \u2212/\u2212/IL-R1\u2212/\u2212Apoe mice receiving \u2212/\u2212/IL-R1\u2212/\u2212Apoe marrow relatively little, atherosclerosis in their aortic sinus following 8 weeks on a WHC diet, as expected and analogous to \u2212/\u2212Apoe and \u2212/\u2212/IL-R1\u2212/\u2212Apoe non-chimeric animals.\u2212/\u2212Apoe animals receiving \u2212/\u2212/IL-R1\u2212/\u2212Apoe bone marrow  did not develop a lesion that was significantly different from \u2212/Apoe mice receiving \u2212/\u2212Apoe marrow  developed a 1.9-fold smaller lesion than the \u2212/\u2212Apoe to \u2212/\u2212Apoe controls (p<0.05). The lesion size between \u2212/\u2212/IL-R1\u2212/\u2212Apoe into \u2212/\u2212Apoe and \u2212/\u2212Apoe into \u2212/\u2212/IL-R1\u2212/\u2212Apoe mice also differed significantly (p<0.05)  .Pathological analysis, by chromosome painting, of these animals showed all had engrafted donor marrow .\u2212/\u2212/IL-R1\u2212/\u2212Apoe mice fed the Western, WHC or chow diet (There was no difference in mean blood pressure in how diet . However or chow).\u2212/\u2212/IL-R1\u2212/\u2212Apoe or \u2212/\u2212Apoe fed a normal chow diet over an 8-week period (p\u200a=\u200ans)(\u2212/\u2212/IL-R1\u2212/\u2212Apoe mice fed either the Western or WHC diet had a significantly lower blood pressure (a level comparable to \u2212/\u2212Apoe mice on chow diet) than the \u2212/\u2212Apoe mice fed the equivalent diet . However\u2212/\u2212Apoe mice on WHC diets infused with IL-1ra using an osmotic pump also had a significantly lower blood pressure than \u2212/\u2212Apoe mice given placebo ( placebo . Elevati\u2212/\u2212Apoe and \u2212/\u2212/IL-R1\u2212/\u2212Apoe mice fed Western and WHC diets did not differ in their sensitivity to phenylephrine (PE) (\u2212/\u2212/IL-R1\u2212/\u2212Apoe mice fed these diets displayed significantly greater vasodilator sensitivity to acetyl choline (ACh) . In \u2212/\u2212/IL-R1\u2212/\u2212Apoe mice fed WHC diet there was greater constriction (19.1+/\u22121.3%) compared to \u2212/\u2212Apoe (8.6+/\u22122.7%) following incubation with N(G)-nitro-L-arginine methyl ester (L-NAME) (p\u200a=\u200a0.003), without a significant difference between pD2  (Mesenteric arteries from ine (PE) . However p<0.05;  comparedesponse) .\u2212/\u2212Apoe and \u2212/\u2212/IL-R1\u2212/\u2212Apoe mice demonstrated similar internal luminal diameters of small mesenteric arteries increased in response to increasing intraluminal pressure (active response), with \u2212/\u2212Apoe mice fed either diet showing a trend towards a reduced myogenic response (\u2212/\u2212/IL-R1\u2212/\u2212Apoe mice fed WHC diet demonstrated a greater active pressure-diameter response compared to chow fed \u2212/\u2212Apoe mice (Both response . However\u2212/\u2212 mice .h/R) \u2212/\u2212/IL-R1\u2212/\u2212Apoe vs 0.111+/\u22120.011 \u2212/\u2212Apoe, n\u200a=\u200a6). Endothelium-independent relaxation responses, assessed by superfusion of sodium nitroprusside (SNP), also did not differ  (\u2212/\u2212/IL-R1\u2212/\u2212Apoe mice fed a WHC diet compared with \u2212/\u2212Apoe mice (p\u200a=\u200ans) .NO bioactivity was increased in  p<0.05) . Activit(p\u200a=\u200ans) . QualitaWHC diet . Quantit, p<0.05). ROS pro, p<0.05). Generat, p<0.05). Apoe\u2212/\u2212\u2212/\u2212/IL-R1\u2212/\u2212Apoe mice fed the WHC diet compared to \u2212/\u2212Apoe mice , \u2212/\u2212Apoe mice develop aortic atheroma \u2212/\u2212Apoe mice fed high fat diets.The Apoe and IL-1 receptor 1 (IL-1R1) genes. As expected, aortic atheroma was significantly reduced in \u2212/\u2212/IL-R1\u2212/\u2212Apoe mice fed WHC compared with \u2212/\u2212Apoe controls. This is in agreement with previous studies that showed decreased atherosclerosis in IL-1\u03b2\u2212/\u2212 and IL-1\u03b1\u2212/\u2212 mice fed a high cholate diet \u2212/\u2212Apoe model \u2212/\u2212/IL-1R1\u2212/\u2212Apoe mice  showed no difference in blood pressure if given IL-1ra (data not shown), suggesting that IL-1ra does not act as a non-specific vasodilator.\u2212/\u2212/IL-R1\u2212/\u2212Apoe mice we investigated active arteriolar pressure-diameter responses and basal and agonist-induced NO production in \u2212/\u2212Apoe and \u2212/\u2212/IL-R1\u2212/\u2212Apoe fat-fed mice. The greater vessel diameter in response to increasing pressure in vessels from \u2212/\u2212/ILR1\u2212/\u2212Apoe, together with no observed difference in sensitivity to PE between groups or in vascular smooth muscle constriction for the given degree of muscle shortening , as well as the preserved response to SNP, all suggest a specific endothelial response.To study the mechanism of the attenuation of the blood pressure rise in the \u2212/\u2212/IL-1R1\u2212/\u2212Apoe mice compared to \u2212/\u2212Apoe in both diet groups as well as the greater contraction in response to L-NAME in the fat-fed \u2212/\u2212/IL-1R1\u2212/\u2212Apoe mice indicate a fundamental increase in bioavailable vessel wall nitric oxide as a result of selective loss of IL-1 signaling. This is emphasised by the observed increase in basal cGMP production seen in these mice. The activity of eNOS, in the presence or absence of eNOS co-factors, did not differ between the two mouse strains suggesting that the difference in bioavailable NO attributable to selective IL-1 inhibition is mediated by increased consumption of NO via increased arterial oxidative stress.The strikingly preserved agonist-induced NO dependent vasodilatation of resistance vessels from Apoe\u2212/\u2212 mouse attenuated by abolition of IL-1 signaling. Taken together, these results suggest a central role for IL-1 in modulating the blood pressure response to high lipids and that this is via a selective reduction in bioavailable nitric oxide.In support of these data, there was consistent reduction of arterial ROS levels in mice unable to signal via IL-1. Investigation of Nox isoforms, known to regulate NADPH activity et al. who showed reduced atherosclerosis in wild type, WHC-fed mice reconstituted with either IL-1\u03b2\u2212/\u2212 or IL-1\u03b1\u2212/\u2212 bone marrow The chimeric mouse experiments were conducted to examine the compartment in which IL-1 signaling was important. Only in chimeras where tissue cells were unable to signal via IL-1 was a there a decrease in atherosclerotic lesion size. These data complement a recent study by Kamari \u2212/\u2212Apoe and \u2212/\u2212/IL-1R1\u2212/\u2212Apoe strains on high fat diets. The myography experiments also suggest a selective endothelial loss of function. Thus, the data presented here add to the hypothesis that IL-1 signaling within the blood vessel wall cells is the mechanism involved in the blood pressure and atherogenic responses to fat feeding in \u2212/\u2212Apoe mice.We also demonstrate that vessel wall ROS production and Nox 4 levels are altered between the non-chimeric Our studies examined the effects of two different pro-atherogenic diets, administered for 8 weeks. Of these diets, the WHC diet is known to be the most aggressive, giving a chronic inflammatory response compared to the acute response of a standard Western (high cholesterol/low cholate) diet The WHC diet can cause intense metabolic disruption, hepatic dysfunction and inflammatory activation. We did not see these effects. Additionally, we saw similar index data (e.g. blood pressure and atheroma formation) for mice fed on the Western and the WHC diet, though the magnitude of the blood pressure effects was reduced with the Western diet. We feel, therefore, that where we have used the WHC diet for further detailed experimentation that this is justified and that the results derived are the result of elevation in cholesterol: the Western diet giving intermediate cholesterol levels and intermediate phenotype, and the WHC diet giving rise to high cholesterol and an advanced phenotype.There is considerable interest in harnessing knowledge of basic inflammatory mechanisms of atherogenesis for therapeutic benefit. We show that dietary manipulation in a murine model of atherosclerosis is associated with a rise in blood pressure, an effect attenuated by selective inhibition of a single cytokine. High fat diets may be particularly linked with elevation in blood pressure \u2212/\u2212Apoe mice, development of atheroma is not driven directly by the rise in blood pressure In our experiments, there was a concomitant reduction in blood pressure and atheroma development. In fat-fed These data raise the possibility of an entirely novel strategy for prevention of atherosclerosis. An anti-IL-1 based approach would be expected to have a beneficial effect upon atherogenic mechanisms at multiple levels. Indeed, very recent data have indicated a beneficial effect of IL-1ra upon patients with type II diabetes Text S1Expanded methods.(0.04 MB DOC)Click here for additional data file.Results S1Additional data(0.04 MB DOC)Click here for additional data file.Figure S1\u2212/\u2212 mice fed chow, Western, and WHC compared with ApoE\u2212/\u2212/IL-1R1\u2212/\u2212 mice. Original magnification\u00d72.Microscopic appearances around the aortic sinus of ApoE(1.18 MB TIF)Click here for additional data file.Figure S2\u2212/\u2212 mice on both high fat diets, an increase that was significantly reduced in the Apoe\u2212/\u2212/IL-R1\u2212/\u2212 mice on equivalent diets. (n\u200a=\u200a9\u201320)Modulation of IL-1 signaling decreases acute phase reactant serum amyloid A (SAA) levels. SAA was elevated in Apoe(4.80 MB TIF)Click here for additional data file.Figure S3Chromosome painting of bone-marrow transplanted mice. No Y-chromosomes were seen in male mice transplanted with female bone marrow, confirming engraftment was successful. Male recipients of male bone marrow all have Y-chromosomes, as expected, as a positive control for this method.(2.45 MB TIF)Click here for additional data file.Figure S4\u2212/\u2212 and Apoe\u2212/\u2212/IL-R1\u2212/\u2212 mice. Intraluminal arteriolar diameter in response to increasing pressure (0\u2013120 mmHg). *P<0.05 Apoe\u2212/\u2212/IL-R1\u2212/\u2212 (n\u200a=\u200a6) and **P<0.05 Apoe\u2212/\u2212 WHC (n\u200a=\u200a6) versus Apoe\u2212/\u2212 chow (n\u200a=\u200a4).Vascular reactivity of arterioles from Apoe(0.61 MB TIF)Click here for additional data file.Figure S5\u2212/\u2212 mice (n\u200a=\u200a6) (a) and human coronary endothelial cells (hCAEC) (n\u200a=\u200a6) (b). However, no increase in ROS are seen in ECs isolated from Apoe\u2212/\u2212/IL-1R1\u2212/\u2212 mice (n\u200a=\u200a6) (a). Nox 4 mRNA expression is increased in hCAEC stimulated with IL-1\u03b2 (n\u200a=\u200a5) (c).ROS and Nox 4 expression in endothelial cells in culture. Increased ROS are seen following IL-1\u03b2 stimulation of endothelial cells isolated from Apoe(9.90 MB TIF)Click here for additional data file.Figure S6ROS and Nox 4 expression in vascular smooth muscle cells in culture. No significant difference in ROS are seen following IL-1\u03b2 stimulation of VSMCs (n\u200a=\u200a6) (a). Nox 4 mRNA expression is decreased in VSMC stimulated with IL-1\u03b2 (n\u200a=\u200a1) (b).(0.30 MB TIF)Click here for additional data file.Figure S7\u2212/\u2212 mice following feeding of a high fat diet. Mice fed WHC had significantly more ROS than those fed chow alone, with Western diet giving intermediate levels of ROS. (n\u200a=\u200a9).ROS generation in Apoe(2.79 MB TIF)Click here for additional data file.Table S1\u2212/\u2212/IL-1R1\u2212/\u2212 and ApoE\u2212/\u2212 mice fed chow, Western High Cholate (WHC), and Western diets. Data represents mean+/\u2212SEM.Lipid, glucose and ALT levels in ApoE(0.05 MB DOC)Click here for additional data file.Table S2\u2212/\u2212/IL-1R1\u2212/\u2212 and ApoE\u2212/\u2212 mice fed chow, Western high cholate (WHC), and Western diets, determined by ELISA. Data represents mean+/\u2212SEM.Plasma levels of IL-1ra, IL-1\u03b2, IL-1\u03b1 and IL-6 in ApoE(0.04 MB DOC)Click here for additional data file.Table S3\u2212/\u2212/IL1R1\u2212/\u2212 and Apoe\u2212/\u2212 mice fed a Western high cholate (WHC), Western, or Apoe\u2212/\u2212 mice fed chow diet, assessed by pD2  and Emax (percentage maximum constriction). All data are means+SEM. p\u200a=\u200ans.Potency and efficacy of vasoconstrictor response to phenylephrine in pressurised mesenteric arterioles from Apoe(0.04 MB DOC)Click here for additional data file."}
+{"text": "One of the synthetic analogues, deacetyl-thymosin \u03b11, showed no restorative effect under the same conditions.Two deacetyl-thymosin \u03b1"}
+{"text": "Sir,We thank Luis I. Gonzalez-Granado for his comments regardin5"}
+{"text": "In the Results section, Neu5Ac stands for N-Acetylneuraminic acid ."}
+{"text": "There was an error in affiliation number 3. The correct affiliation is: Aide aux L\u00e9preux Emmaus-Suisse, Berne, Switzerland."}
+{"text": "Background: A case of pneumococcal septicemia associated with             laparoscopically documented acute salpingitis is reported.\t\t\t\t\tCase: Gram-stained cul-de-sac pus revealed gram-positive             encapsulated diplococci.\t\t\t\t\tConclusion: This case coupled with reanalysis of prior genital tract             involvement in nonpregnant individuals argues that Streptococcus pneumoniae can             mimic gonococcal diseases."}
+{"text": "The central Cd atom is chelated by the 4\u2032-p-tolyl-2,2\u2032:6\u2032,2\u2032\u2032-terpyridine ligand and is coordinated by the N atoms of three thio\u00adcyanate ions in an octa\u00adhedral geometry whereas the Ag atom is coordinated by the four S atoms of four thio\u00adcyanate ions in a distorted tetra\u00adhedral geometry. Of the three thio\u00adcyanate ions, one functions in a \u03bc               2-bridging mode and two in a \u03bc               3-bridging mode. The ribbon coordination polymer propagates along the a-axis.The title compound, [AgCd(NCS) DOI: 10.1107/S160053681003744X/nk2062Isup2.hkl            Structure factors: contains datablocks I. DOI:  crystallographic information; 3D view; checkCIF report            Additional supplementary materials:"}
+{"text": "Correction for:10.1371/journal.pmed.0050196Cheung AM, Tile L, Lee Y, Tomlinson G, Hawker G, et al. (2008) Vitamin K supplementation in postmenopausal women with osteopenia : A randomized controlled trial. PLoS Med 5(10): e196. doi:Three errors were made in the Funding and Acknowledgments sections of this article. In the Funding section, the \u201cWyeth Foundation\u201d should be replaced by the \u201cCentrum Foundation\u201d and \u201cWhitehall Robbins\u201d should be spelled \u201cWhitehall Robins.\u201d In the Acknowledgments section, \u201cDr. Faten Al-Doori\u201d should be spelled \u201cDr. Faten Al-Douri.\u201d"}
+{"text": "Nature Communications; 10.1038/s41467-018-08264-w, published online 22 Jan 2019.Correction to: x-axis labels inadvertently read \u2018Tmc1\u2019 instead of \u2018Tmc2\u2019. These errors have been corrected in both the PDF and HTML versions of the Article.The original version of this Article contained errors in Fig.\u00a05. In panels i and j the three rightmost"}
+{"text": "Gmelina arborea Roxb. (Family: Verbenaceae) Extract Upregulates the \u03b2-Cell Regeneration in STZ Induced Diabetic Rats\u201d [In the article titled \u201cic Rats\u201d , the fol\u03b2 Cell Regenerative Effects of Spondias pinnata (Linn. f.) Kurz. Bark Extract on Streptozotocin Induced Diabetic Rats\u201d [Animals in the healthy control, diabetic control, and glibenclamide-treated groups overlap with another article titled \u201cAntihyperglycaemic, Antihyperlipidaemic and ic Rats\u201d , as the ic Rats\u201d . Furtheric Rats\u201d , 2."}
+{"text": "Scientific Reports 10.1038/s41598-019-38509-7, published online 12 February 2019Correction to: This Article contains a typographical error in the \u2018Overall Amplifier Schematic\u2019 section where,http://www.fuw.edu.pl/mwinkowski/.\u201d\u201cFull schematic and printed circuit board (PCB) fabrication data is available at should read:http://www.fuw.edu.pl/~mwinkowski/.\u201d\u201cFull schematic and printed circuit board (PCB) fabrication data is available at"}
+{"text": "Scientific Reports 10.1038/s41598-018-32210-x, published online 26 September 2018Correction to: The original version of this Article contained typographical errors, where the unit \u2018ng/ml\u2019 was incorrectly given as \u2018pg/ml\u2019. As a result, in the Abstract,\u201cThe cut-off value of H-FABP, 4.143\u2009pg/mL, was determined using receiver operating characteristic curves.\u201dnow reads:\u201cThe cut-off value of H-FABP, 4.143\u2009ng/mL, was determined using receiver operating characteristic curves.\u201dIn the Results section under subheading \u2018Patients\u2019,\u201cThe cut-off value of H-FABP (4.143\u2009pg/mL) was determined by receiver operating characteristic curves (ROC) curve analysis  between the patients with and without CV events from the blood sample obtained at enrollment.\u201dnow reads:\u201cThe cut-off value of H-FABP (4.143\u2009ng/mL) was determined by receiver operating characteristic curves (ROC) curve analysis  between the patients with and without CV events from the blood sample obtained at enrollment.\u201dIn the Discussion section,\u201cThis study is the first prospective cohort study to demonstrate that a higher serum H-FABP level (\u22674.143 pg/mL) is an independent predictor for CV events, particularly for cardio- and cerebrovascular death and acute heart failure-related hospitalizations in patients with SCHD.\u201dnow reads:\u201cThis study is the first prospective cohort study to demonstrate that a higher serum H-FABP level (\u22674.143 ng/mL) is an independent predictor for CV events, particularly for cardio- and cerebrovascular death and acute heart failure-related hospitalizations in patients with SCHD.\u201dIn Table 2, the column headings \u2018H-FABP < 4.143\u2009pg/mL\u2019 and \u2018H-FABP \u2267 4.143\u2009pg/mL\u2019 have been corrected to \u2018H-FABP\u2009<\u20094.143\u2009ng/mL\u2019 and \u2018H-FABP \u2267 4.143\u2009ng/mL\u2019, respectively.In Table 3, the column headings \u2018H-FABP <4.143pg/mL, (n=843)\u2019 and \u2018H-FABP \u22674.143pg/mL, (n=228)\u2019 have been corrected to \u2018H-FABP <4.143ng/mL, (n=843)\u2019 and \u2018H-FABP \u22674.143ng/mL, (n=228)\u2019, respectively.In the legend of Figure 2,a), CV or cerebrovascular death-free rate (b), acute heart failure hospitalization-free rate (c), and total CV event-free rate except for angina-related hospitalization (d) in patients with serum H-FABP \u22674.143 pg/mL and H-FABP <4.143 pg/mL .\u201d\u201cKaplan\u2013Meier survival curves analysis showing total cardiovascular (CV) event-free rate (now reads:a), CV or cerebrovascular death-free rate (b), acute heart failure hospitalization-free rate (c), and total CV event-free rate except for angina-related hospitalization (d) in patients with serum H-FABP \u22674.143 ng/mL and H-FABP <4.143 ng/mL .\u201d\u201cKaplan\u2013Meier survival curves analysis showing total cardiovascular (CV) event-free rate (In addition, the original version of this Article contained typographical errors, where the unit \u2018g/dL\u2019 was incorrectly given as \u2018mg/dL\u2019. As a result, in Table 2, the row heading \u2018Hemoglobin, mg/dL\u2019 has been corrected to \u2018Hemoglobin, g/dL\u2019.These errors have now been corrected in the HTML and PDF versions of the Article."}
+{"text": "Scientific Reports 10.1038/s41598-018-26898-0, published online 31 May 2018Correction to: This Article contains an error in Table 1.In the \u2018Reproduction mode\u2019 column, Nassau grouper (Epinephelus striatus) should be listed as \u2018Gonochoristic\u2019, not \u2018Protogynous\u2019."}
+{"text": "Scientific Reports 10.1038/s41598-017-06706-x, published online 16 August 2017Correction to: C. glaucum\u2019,This Article contains errors in the Results section, under the subheading \u2018Analysis of interaction between CDPK and bHLH in \u201cThe three top ranking models of the CgCDPK-CgbHLH001 interaction complex were presented in Fig. 5c\u201dshould read:\u201cThe three top ranking models of the CgCDPK-CgbHLH001 interaction complex were presented in Fig. 6c\u201dIn addition,61-GKRLKS-66 was a putative action site for CgCDPK.\u201d\u201cPrediction of phosphorylation sites of CgbHLH001 revealed 39 potential amino acid residues , in which the motif of should read:91-GKRLKS-96 was a putative action site for CgCDPK.\u201d\u201cPrediction of phosphorylation sites of CgbHLH001 revealed 39 potential amino acid residues , in which the motif of"}
+{"text": "Scientific Reports 10.1038/s41598-019-45855-z, published online 01 July 2019Correction to: This Article contains errors in Tables 1 and 2, where the columns entitled \u201cF vale\u201d should read \u201cF value\u201d."}
+{"text": "The comment should have appeared as \u201cMinimal exposure, short follow-up period of 8.6 y.\u201d This article has been corrected.1In the Original Investigation titled \u201cAssociation Between Marijuana Use and Risk of Cancer: A Systematic Review and Meta-analysis,\u201d"}
+{"text": "Correction to: BMC Bioinf (2019) 20:312https://doi.org/10.1186/s12859-019-2843-0Following publication of the original article , the autIn the \u2018Results\u2019 section under heading \u2018Case study I: Measles\u2019, the following lines are missing in the published article:1. line \u2018KendrickModel SEIR\u2019 should be inserted before the following:2. line \u2018Simulation MeaslesRKSim rungeKutta\u2019 should be inserted before the following:3. line \u2018KendrickModel SIR\u2019 should be inserted before the following:4. line \u2018Experiment PopRateAnalysis\u2019 should be inserted before the following:"}
+{"text": "Scientific Reports 10.1038/s41598-017-15650-9, published online 15 November 2017Correction to: This Article contains an error in the Methods section under the subheading \u2018Statistics\u2019.\u201cThe sequencing data are available from the European Nucleotide Archive (accession number PRJEB21167).\u201dshould read:\u201cThe sequencing data are available from the NCBI Sequence Read Archive (accession number PRJNA390475).\u201d"}
+{"text": "Scientific Reports 10.1038/s41598-018-28365-2, published online 02 July 2018Correction to: This Article contains a typographical error in the Results and Discussion section in the second subheading where,\u201cVertical Eddy Flux (VEF)ss\u201dshould read:\u201cVertical Eddy Flux (VEF)\u201d"}
+{"text": "Correction to: CVIR Endovasc (2018) 1:19https://doi.org/10.1186/s42155-018-0027-zIn the published article (Duvnjak et al. \u201cNot applicable\u201dshould read:\u201cInformed consent for publication of this case report and its accompanying images has been obtained from the patient\u201d"}
+{"text": "The first corresponding author's, Guizhen Chen, email should be cgzhen2000@163.com.In the article, \u201cAcupuncture for primary osteoporosis: A network meta-analysis of randomized controlled trials protocol\u201d,"}
+{"text": "Scientific Reports 10.1038/s41598-017-06980-9, published online 07 August 2017Correction to: The Supporting Information file that accompanies this Article contains errors in SI-7, \u2018The average mass of single SPION and number of SPION in Magnetoliposomes\u2019,\u201cshould read:\u201c"}
+{"text": "LY15H200001.In the article, \u201cAn epidemiological survey of HBV infection and low-level HBsAg in military camps in eastern China\u201d,"}
+{"text": "In the article titled \u201cWingless-Type MMTV Integration Site Family Member 5a Is a Key Secreted Islet Stellate Cell-Derived Product that Regulates Islet Function\u201d , the key"}
+{"text": "Correction to: Translational Psychiatry;10.1038/s41398-018-0201-z;Published online 14 August 2018.The author\u2019s name was spelled incorrectly as \u201cMasahir Okamoto\u201d. This has been updated to \u201cMasahiro Okamoto\u201d in the HTML and PDF of the article."}
+{"text": "Sci., 2014, 5, 1533\u20131537.Correction for \u2018Utilizing the bioorthogonal base-pairing system of"}
+{"text": "Scientific Reports 10.1038/s41598-018-26947-8, published online 05 June 2018Correction to: In the \u201cSupplementary Table S2\u201d file originally published with this Article, columns E and G contained incorrect accession numbers. These errors have been corrected in the \u201cSupplementary Table S2\u201d file that now accompanies the Article."}
+{"text": "Detarium microcarpum, Guiera senegalensis, and Cassia siamea Induce Apoptosis and Cell Cycle Arrest and Inhibit Metastasis on MCF7 Breast Cancer Cells\u201d [In the article titled \u201cr Cells\u201d , an acknThe article is partially funded by USM-Bridging Grant: (304.CIPPT.6316239)."}
+{"text": "Scientific Reports 10.1038/s41598-018-31985-3, published online 12 September 2018Correction to: In Figure 5b the p-value is incorrect. The correct Figure 5 appears below as Figure\u00a0As such, this Article contains an error in the Results section under subheading \u2018Belief State Model predicts pupil responses quantitatively better than Stimulus State Model\u2019,\u201cFor the post-feedback interval, there was a trend towards a stronger correlation for the Belief State Model than the Stimulus State Model (p\u2009=\u20090.074).\u201dshould read\u201cFor the post-feedback interval, there was no difference between the models (p\u2009=\u20090.326)\u201d."}
+{"text": "Scientific Reports 10.1038/s41598-017-08253-x, published online 11 August 2017Correction to: This Article contains a typographical error in the Methods section under subheading \u2018Operation of the DT neutron generator\u2019 where,\u201cThe generator was set to a pulse length of 3.33 \u03bcs with a repetition rate of 300\u2009Hz.\u201dshould read:\u201cThe generator was set to a pulse length of 333.33 \u03bcs with a repetition rate of 300\u2009Hz.\u201dAdditionally, in the Results section under the subheading \u2018Localization of weapons-grade HEU\u2019,\u201cThe tungsten-moderated HEU configuration did not produced an increased correlated count rate (Table 1).\u201dshould read:\u201cThe tungsten-moderated HEU configuration did not produce an increased correlated count rate (Table 1).\u201d"}
+{"text": "Open Forum Infect Dis 2019; 6(3):ofz144]. The author listing of \u201cXuefang Zhang\u201d should state \u201cXuefeng Zhang.\u201d This has now been corrected online.An error appeared in an article published in the April 2019 issue of the journal [Kmush BL, Yu H, Huang S, et al. Long-term Antibody Persistence After Hepatitis E Virus Infection and Vaccination in Dongtai, China."}
+{"text": "Abdominal fat mass is associated with metabolic risk whilst gluteal femoral fat is paradoxically protective. MicroRNAs are known to be necessary for adipose tissue formation and function but their role in regulating human fat distribution remains largely unexplored.An initial microarray screen of abdominal subcutaneous and gluteal adipose tissue, with validatory qPCR, identified microRNA-196a as being strongly differentially expressed between gluteal and abdominal subcutaneous adipose tissue.HOXC locus, is an eQTL for miR-196a expression in abdominal subcutaneous adipose tissue (ASAT). Observations in large cohorts showed that rs11614913 increased waist-to-hip ratio, which was driven specifically by an expansion in ASAT. In further experiments, rs11614913 was associated with adipocyte size. Functional studies and transcriptomic profiling of miR-196a knock-down pre-adipocytes revealed a role for miR-196a in regulating pre-adipocyte proliferation and extracellular matrix pathways.We found that rs11614913, a SNP within pre-miR-196a-2 at the These data identify a role for miR-196a in regulating human body fat distribution.Medical Research Council and Novo Nordisk UK Research Foundation (G1001959) and Swedish Research Council. We acknowledge the OBB-NIHR Oxford Biomedical Research Centre and the British Heart Foundation (BHF) (RG/17/1/32663). Work performed at the MRC Epidemiology Unit was funded by the United Kingdom's Medical Research Council through grants MC_UU_12015/1, MC_PC_13046, MC_PC_13048 and MR/L00002/1.This work was supported by the  Body fat distribution is a strong predictor of metabolic health, independent of total adiposity. The role of microRNAs is regulating body fat distribution has not been well defined.We demonstrate that miR-196a shows strong adipose depot-specific expression patterns. A single nucleotide polymorphism in pre-miR-196a-2 influences the expression of miR-196a in abdominal subcutaneous adipose tissue and is associated with waist-hip ratio. Furthermore, functional studies demonstrate that miR-196a regulates pre-adipocyte proliferation and extracellular matrix composition.Our study identifies a role for miR-196a in regulating human body fat distribution. MicroRNAs hold potential as therapeutic targets and biomarkers.Alt-text: Unlabelled Box1The metabolic consequences of adiposity are dictated not only by absolute adipose tissue (AT) mass but also by its distribution , to the 22.12.1.1The OBB is a cohort of apparently healthy 30\u201350-year old men and women from Oxfordshire . All vol2.1.22, age 44\u22195 (42\u22198\u201348\u22195) years) who were undergoing bariatric surgery as previously described [Paired whole VAT and ASAT surgical biopsies were obtained from sixteen Caucasian women (BMI 43\u22191 (36\u22199\u201347\u22196) kg/mescribed .2.1.3et al [p-values were corrected using genomic control at the individual study level and again after meta-analysis. Manhattan plots for the meta-analysis are available here [The GIANT consortium has access to anthropometric and genotyping data for nearly 250,000 individuals. Shungin et al  conducteble here .2.1.4The UK Biobank includes anthropometric, biochemical and genetic data from >500,000 men and women recruited between 2006 and 2010 (REC 11/NW/0382). Further details are available elsewhere .2.1.5The EPIC-Norfolk cohort includes 25,000 men and women who were aged between 40 and 79 at recruitment and who underwent DXA imaging for body composition at the 20\u202fyear follow up assessment.2.1.6The Fenland Study is a population-based cohort study of the interaction between genetics and environment in the development of diabetes and obesity. The cohort contains a Cambridgeshire-based population of men and women without diabetes born between 1950 and 1975. Participants undergo detailed anthropometric and metabolic characterisation along with genotyping and DXA determination (GE Lunar iDXA) of body composition as recently described [2.1.7Genotyping and phenotypic data on fat cell size in ASAT was obtained as described previously .2.2n\u202f=\u202f1). The imAPAD and imGPAD cell lines have been described previously [v/v, 1:1), 10% foetal calf serum (FCS) , 0.25\u202fng/ml fibroblast growth factor (FGF), 100\u202fU/ ml penicillin and 0.1\u202fmg/ ml streptomycin). All cell cultures were incubated at 37\u202f\u00b0C with 5% CO2. To differentiate pre-adipocytes, confluent cells were cultured for 14\u202fdays with differentiation media (DMEM/F12 HAM (1:1) containing 2\u202fmM glutamine, 17\u202f\u03bcM pantothenate, 100\u202fnM human insulin, 1\u202fnM triiodo-L-thyronine (T3), 33\u202f\u03bcM biotin, 10\u202f\u03bcg/ ml transferrin and 1\u202f\u03bcM dexamethasone, with the addition of 3-Isobutyl-1-methylxanthine (IBMX) (250\u202f\u03bcM) and troglitazone (4\u202f\u03bcM) for the first 4\u202fdays).Primary pre-adipocytes were obtained by collagenase digestion of minced whole AT biopsies. Volunteers for AT biopsy were recruited from the OBB and were not included in other datasets involving OBB subjects. For determination of miR-196a in fractionated AT the floating adipocyte layer and stromal-vascular pellet were isolated after collagenase digestion and fractionation (eviously . For celHuman Embryonic Kidney 293 (HEK293) cell lines were cultured in growth media consisting of DMEM with 4500\u202fmg/l glucose, 10% FCS, 2\u202fmM glutamine, 100\u202fU/ ml penicillin and 0.1\u202fmg/ ml streptomycin.2.3E. coli . Amplified plasmids were isolated using the Midiprep plasmid kit .MISSION custom hsa-miR-196a-5p inhibitor  and ath-imAPAD and imGPAD cell line pre-adipocytes at passage 8 were plated in T25 flasks at a density of 1\u22192x105cells/flask in complete growth media. Cells were transduced by culturing in complete growth media with the addition of lentiviral particles and hexadimethrine bromide at a final concentration of 8\u202f\u03bcg/ml. Pre-adipocyte cell lines were cultured in the presence of 2\u202f\u03bcg/ml puromycin during the proliferative phase but not after the addition of differentiation media. The stable cell lines generated are referred to as imAPAD mir-196aKD, imAPAD-Con, imGPAD mir-196aKD and imGPAD-Con. Intracellular lipid levels were quantified using the AdipoRed assay reagent (Lonza) and a CytoFluor Multi-Well Plate Reader series 4000 (PerSeptive Biosystems). To calculate doubling time, pre-adipocytes were seeded at equal density in T75 flasks and were trypsinised and triple counted every 72\u202fh. Doubling time was calculated using the formula:Lentiviral particles were produced by co-transfection of HEK293 cells with the MISSION hsa-mir-196a-5p inhibitor or ath-miR-416 negative control vector along with packaging vectors  using Fugene 6 . To generate stable pre-adipocyte cell lines, Doubling time\u202f=\u202ft2-t1 ((log [where t\u202f=\u202ftime (days) and q\u202f=\u202fcell number.33.1PPIA) and phosphoglycerate kinase 1 (PGK1); miRNA and pre-miRNA abundance was quantified relative to the average of miR-103, miR-24 and miR-331 [RNA was isolated from Tri-reagent. For microarray experiments RNA was purified using MirVana Columns (Life Technologies). For other experiments RNA was purified using a standard Tri-reagent protocol. cDNA was synthesised using the miScript kit (Qiagen). For mRNA quantification qPCR was performed using Taqman Assays-on-Demand (Applied Biosystems) and Kapa Probe Fast Mastermix (Kapa Biosystems) in a 6\u202f\u03bcl final volume. For microRNA quantification Qiagen miScript primer assays were used with the QuantiTect SYBR Green PCR Kit  in an 8\u202f\u03bcl reaction. Gene expression was quantified using the \u0394\u0394CT method : mRNA wa miR-331 . Reading3.2Genomic DNA was extracted from whole blood by LGC Genomics . Genotyping in the OBB cohort was performed on 10\u202fng of DNA using KASP On Demand custom designed and validated primers for rs11614913 . Allelic discrimination performed was on the ABI Prism 7900 HT Real-Time PCR System  using SDSv2.3 software .3.3AB_1925078) at a 1:1000 and 1:1000 goat anti-rabbit IgG horseradish peroxidase (HRP)-conjugated secondary antibodies (DAKO). An enhanced chemiluminescence (ECL) reaction was performed using Clarity ECL substrate  and was visualised using both the ChemiDoc MP and imaging film. HOXC8 was quantified and normalised to total protein using Image Lab software .HEK293 cell lines transduced with miR-196a KD or control vector were cultured in 6-well plates and then lysed by the addition of 150\u202f\u03bcl of lysis buffer . Normalised protein samples were resolved on a Criterion Stain-Free precast gel . Protein transfer onto a polyvinylidene fluoride (PVDF) membrane was performed using the Trans-Blot Turbo system . The membrane was visualised with the ChemiDoc MP system  to quantify total protein in each lane. The membrane was probed with HOXC8 rabbit polyclonal antibody  and 7 overweight (BMI\u202f>\u202f25)) and paired GSAT biopsies from 8 of the men (5 lean and 3 overweight) were hybridized to individual Agilent Human microRNA Microarrays v2.0 . The DNA microarray scanner (Agilent G2565BA) was used to scan hybridized microarrays and features were extracted using the Agilent Feature Extraction image analysis tool (version 9.5.1) with default protocols and settings. Data were background corrected and quantile normalised in R  using th and 7 ov3.5imAPAD mir-196aKD, imAPAD-Con, imGPAD mir-196aKD and imGPAD-Con pre-adipocytes were harvested in Tri-reagent. Cells were harvested on day 3 after plating and were sub-confluent. RNA was isolated using the mirVana miRNA Isolation Kit (Life Technologies). RNA concentration was assessed using the Nanodrop ND-1000 spectrophotometer and by RiboGreen\u00ae assay and samples were normalised to give 100\u202fng RNA in a total volume of 11\u202f\u03bcl. RNA quality was verified using the Agilent TapeStation . RNA samples were reverse transcribed using the Illumina TotalPrep-96 RNA Amplification Kit and then converted into labelled cDNA using the Illumina Whole-Genome Gene Expression Direct Hybridisation Assay. The labelled ss-cDNA was then hybridized to two HumanGene2.1 ST-16 Array Plates. The array was washed, stained and scanned using the Affymetrix GeneTitan platform. Raw data were Robust multi-array (RMA) normalised and checked for quality. Differential expression analysis was performed in R [Six replicates of passage 10 med in R .http://www.david.niaid.nih.gov/ [p-values for the cluster. Transcripts were excluded from analysis if expression was below background intensity in both conditions being compared.Gene ontology (GO) enrichment analysis was performed in Database for Annotation, Visualization, and Integrated Discovery (DAVID)  with3.6HOXC locus, we first identified all of the independent signals in the locus using approximate conditional testing in Genome-wide Complex Trait Analysis (GCTA) [N\u202f=\u202f949), included in the GIANT analysis, was used as the reference dataset in the GCTA analysis. Once we had identified the independent signals contained in the locus, we performed conditional testing  to generate summary-level data for each signal. For example, to generate summary-level data for independent signal A (index SNP rs10783615), we conditioned on independent signals B (index SNP rs1443512) and C (index SNP rs2071449) and then stored the resulting summary-level statistics. We repeated this process for signals B and C. We used the index SNPs as reported in the initial genome-wide association study of WHR performed in GIANT [To generate credible sets of likely-causal variants at the s (GCTA)  using thWe performed an identical analysis using the UK Biobank data. We used the individual level genotypes from the UK Biobank as a reference for the GCTA analyses, and used the same three SNPs as index SNPs for conditional testing.3.7p-values are two-tailed.Statistical analyses were performed in SPSS 20.0 or 22.0. All 3.810.17632/krgbnvxc5v.1) and for miR-196a KD in immortalised abdominal and gluteal pre-adipocytes (DOI: 10.17632/m4xtmzmx39.1) are available at Mendeley (https://data.mendeley.com).Supplementary data for the microarray analysis of microRNAs in ASAT tissue from 15 men, with paired gluteal adipose tissue from 8 of the men (DOI: 44.12) and 7 overweight (BMI\u202f>\u202f25\u202fkg/m2)) together with paired gluteal subcutaneous adipose tissue (GSAT) from 4 lean and 4 overweight men. Of the 161 miRNAs included in the array and expressed in AT, 32 reached the significance threshold (p\u202f=\u202f0\u221905) for differential expression with a fold change of at least 20% (Table S1). Validation qPCR was performed on paired ASAT and GSAT biopsies from an expanded panel of 20 men and 20 women from the OBB and including both lean and overweight BMI categories (Table S2). Twelve of the original miRNAs remained significant after validation . MiR-196a is of particular interest because it is found within the HOXC13 locus, which has been linked to WHR adjusted for BMI in large-scale genome-wide association studies [HOXC8, which in turn regulates the adipogenic signal CEBP\u03b2 [p\u202f=\u202f0\u221918; GSAT: p\u202f=\u202f0\u221982, independent samples t-test). We therefore hypothesised that miR-196a could have a functional role in determining body fat distribution.To assess the extent to which miRNAs may contribute to body fat distribution, we performed microarray miRNA profiling of abdominal subcutaneous adipose tissue (ASAT) from 15 men recruited from the Oxford Biobank (OBB) . The depot-specific expression pattern of miR-196a was seen in both men and women (Table S3).Further dissection of miR-196a expression in AT using the expanded follow-up panel of 40 individuals (Table S2) demonstrated it was not influenced by sex  and markers of terminal adipocyte differentiation  was similar for both primary and immortalised differentiated pre-adipocytes derived from both depots, although cells of GSAT origin accumulated significantly more intracellular lipid  compared with ASAT, confirming the depot-specific expression pattern. Additionally, miR-196a is highly expressed in human AT compared to other tissues: a previous analysis of high-throughput sequencing data from 131 individuals from the MuTHER cohort [We next performed ectively ). Expresshown in ). The mill lines b-c, suggntiation b-c. ConsR cohort  revealedHOXA5 [, HOXB8 [HOXC8 [HOXA5: 5-fold lower in GSAT vs ASAT, p\u202f<\u202f0\u2219001; HOXB8: 3-fold lower in GSAT, p\u202f=\u202f0\u221916; HOXC8: 2-fold lower in GSAT, p\u202f<\u202f0\u2219001). These patterns were maintained during in vitro differentiation of primary pre-adipocytes and the immortalised pre-adipocyte cell lines .The homeobox miR-196a target mRNAs HOXA5 , HOXB8 [[, HOXB8 ,39 and H8 [HOXC8 ,39,40 din\u202f=\u202f40, 2.4-fold higher in GSAT than ASAT, p\u202f=\u202f.006, Wilcoxon signed rank test), which shows that miR-196a-2 is the predominant paralogue in human AT.There are three paralogues of the mir-196 gene located on different chromosomes: mir-196a-1 and 2 transcribe the same mature miRNA which cannot be distinguished by qPCR, but are derived from unique precursor sequences; miR-196b differs from mir-196a-1 and 2 by one nucleotide. Pre-miR-196a-1 was not detected by qPCR in either AT depot in the expanded panel (Table S2), whilst pre-miR-196a-2 showed depot-specific expression mirroring mature miR-196a \u202f=\u202f0.59 with rs2071449 indicating moderate linkage disequilibrium). To investigate whether rs11614913 has any functional consequences and is linked to the associations observed for this region we first confirmed an association between rs11614913 and body fat distribution. Meta-analysis data from the GIANT consortium [n\u202f=\u202f141,414, beta (se)\u202f=\u202f0\u221903 (0\u2219004), p\u202f=\u202f6\u22199\u202f\u00d7\u202f10\u221211) in both men \u202f=\u202f0\u221903 (0\u2219007), p\u202f=\u202f2\u22197\u202f\u00d7\u202f10\u22125) and women \u202f=\u202f0\u221902 (0\u2219006), p\u202f=\u202f1\u22191\u202f\u00d7\u202f10\u22127). This was mediated by an expansion in waist circumference \u202f=\u202f0\u221903 (0\u2219004), p\u202f=\u202f1\u22197\u202f\u00d7\u202f10\u221211; men: n\u202f=\u202f60,340, beta (se)\u202f=\u202f0\u221903 (0\u2219007), p\u202f=\u202f1\u22192\u202f\u00d7\u202f10\u22126; women: n\u202f=\u202f90,592, beta (se)\u202f=\u202f0\u221903 (0\u2219005), p\u202f=\u202f6\u22198\u202f\u00d7\u202f10\u22128) rather than an association with hip circumference \u202f=\u202f0\u22190003 (0\u2219005), p\u202f=\u202f0\u221995; men: n\u202f=\u202f56,413, beta (se)\u202f=\u202f0\u2219004 (0\u2219007), p\u202f=\u202f0\u221953; women: n\u202f=\u202f86,241, beta (se)\u202f=\u202f\u22120\u22190016 (0\u2219006), p\u202f=\u202f0\u221978). The association between the rs11614913 TT genotype and WHR adjusted for BMI replicates in the UK Biobank sample [n\u202f=\u202f120,126, beta (se)\u202f=\u202f0\u221903 (0\u2219004), p\u202f=\u202f1\u22194\u202f\u00d7\u202f10\u221210; men: n\u202f=\u202f56,863, beta (se)\u202f=\u202f0\u221902 (0\u2219004), p\u202f=\u202f3\u22198\u202f\u00d7\u202f10\u22123; women: n\u202f=\u202f63,308, beta (se)\u202f=\u202f0\u221903 (0\u2219004), p\u202f=\u202f1\u221904\u202f\u00d7\u202f10\u22129). Furthermore, within the OBB population rs11614913 was associated with lean mass of the arms \u202f=\u202f\u22120\u2219019 (0\u2219007), p\u202f=\u202f0\u2219008) following adjustment for age, gender, height squared and first four principal components. We did not observe a significant association between rs11614913 genotype and total lean mass \u202f=\u202f\u22120\u2219010 (0\u2219007), p\u202f=\u202f0\u221916) or lean mass of the legs \u202f=\u202f\u22120\u22190089 (0\u2219008), p\u202f=\u202f0\u221928), in keeping with the upper body regionality of the miR-196a AT phenotype.Previous genome-wide efforts have used conditional association testing to identify three independent signals for WHR adjusted for BMI harboured within the  B and C ). The sek sample   and UK Biobank data  to perform conditional testing on each of the three independent HOXC loci signals in each respective dataset. Using a Bayesian-refinement approach [n\u202f=\u202f24,010) showed that rs11614913 was specifically associated with ASAT expansion \u202f=\u202f(0\u22190093), p\u202f=\u202f1\u221905\u202f\u00d7\u202f10\u22128, Table S4). We therefore investigated whether there was a functional mechanism by which rs11614913 might be causal for AT expansion.To further characterise the contribution of this complex region to the observed WHR association, we used GIANT European-ancestry data , and determined miR-196a expression by qPCR in paired ASAT and GSAT biopsies. Expression of miR-196a was lower in ASAT for TT carriers  TT\u202f=\u202f0\u221970 (0\u2219053) CC/CT\u202f=\u202f1\u221902 (0\u2219098), p\u202f=\u202f0\u2219005, t-test; p\u202f=\u202f0\u2219011; women: \u221234%, p\u202f=\u202f0\u221918), consistent with a recessive effect, but not quite statistically significant in GSAT  TT\u202f=\u202f1\u221988 (0\u221916), CC/CT\u202f=\u202f2\u221905 (0\u221919), p\u202f=\u202f0\u2219061, t-test, men: \u22129%, p\u202f=\u202f0\u221938; women: \u221210%, p\u202f=\u202f0\u2219089) which has the higher overall expression. We saw no difference in levels of HOXA5, HOXB8 or HOXC8 between genotype groups in the panel of 90 individuals . However, within the larger MuTHER dataset [HOXC8 expression in ASAT . Within the panel of 90 individuals there was no effect of the genotype on pre-miR-196a-2 expression , suggesting that the effect of the T allele is occurring post-transcriptionally at the level of pre-miRNA processing. The rs11614913 is within the pre-miR-196a-2; in silico modelling of pre-miR-196a-2 in M-fold [A separate earlier study including 70 individuals did not identify rs11614913 as an eQTL for miR-196a , so to i dataset  rs116149n M-fold  predicte4.4imAPAD and imGPAD), which are derived from ASAT and GSAT respectively [HOXC8 [imAPAD-mir-196aKD vsimAPAD-Con\u202f=\u202f9\u22195%, p\u202f=\u202f0\u2219002; imGPAD-mir196aKD vsimGPAD-Con\u202f=\u202f12\u22193%, p\u202f=\u202f0\u2219002). There was no difference in adipogenesis of control vs. miR-196aKD pre-adipocytes, as determined by microscopy . These data suggest that lower miR-196a expression reduces the tissue adipocyte cellularity via adipocyte hypertrophy rather than hyperplasia. Histological examination of whole ASAT biopsies was consistent with this: in ASAT needle biopsies from an independent cohort [n\u202f=\u202f81, beta\u202f=\u202f0\u221915, p\u202f=\u202f0\u2219019), but not in women .To investigate if miR-196a influences adipogenesis we generated stable miR-196a knock down (KD) cell lines by lentiviral transduction from immortalised pre-adipocyte cell lines  enrichment analysis of 441 annotated transcripts significantly regulated between imGPAD miR-196aKD and imGPAD-Con demonstrated a significant enrichment for GO terms related to extracellular matrix (ECM) and vascular development (Benjamini-Hochberg adjusted data)  indicating that reduced abundance of miR196a may affect matrix expression in vivo (in vivo adipogenesis [To identify AT features that would sustain the observed adipocyte hypertrophy we performed microarray profiling of ed data) , suggest in vivo f. MiR-19ogenesis .Table 1G5MIR196A gene lies within the LD block defined by rs2071449, which is an intronic SNP within HOXC4 and C5, and the sentinel SNP for the WHR adjusted for BMI phenotype association in the region [HOXC locus. It should be noted that the populations used in these studies were almost exclusively of European ancestry, and further studies will be required to validate these findings in other populations. Men and women have markedly different body fat distribution. Whilst rs11614913 is associated with increased WHR in both sexes, the association between rs11614913 and adipocyte size was significant in men only. Therefore, in vitro miR-196aKD experiments were conducted using immortalised pre-adipocytes from a male donor. Further work is indicated to determine whether there is sexual dimorphism in the actions of miR-196a.The In conclusion, miR-196a, which shows strong AT depot-specific expression, is under genetic influence and exerts a regulatory effect on AT structure and human body fat distribution by affecting the transcriptome for ECM.imGPAD -196aKD and imGPAD-Con cell lines and between imAPAD -196aKD and imAPAD-Con cell lines, after Benjamini-Hochberg correction for multiple testing (p <\u202f0\u221905). Column 3 refers to annotated transcripts differentially expressed between imAPAD -196aKD and imAPAD-Control cell lines with a fold change >50% and an unadjusted significance of p\u202f<\u202f0\u221901. The enrichment score for each cluster is the geometric mean of the Bonferroni-corrected p-values for the cluster."}
+{"text": "Scientific Reports 10.1038/s41598-019-44499-3, published online 05 June 2019Correction to: The Supplementary File 1 originally published with this Article contained typographical errors where \u2018rnaSPAdes\u2019 was incorrectly given as \u2018rnaSPades\u2019. Additionally, in Table S7 the column subheadings \u2018Salmon\u2019 and \u2018RSEM\u2019 were inverted. These errors have been corrected in the Supplementary File 1 that now accompanies the Article."}
+{"text": "Scientific Reports 10.1038/s41598-019-51884-5, published online 25 October 2019Correction to: This Article contains errors in the Results section under subheading \u2018Total annual movement distances\u2019.Camelus bactrianus; Table 2; Fig. 2), which are among their prey species.\u201d\u201cIn southwest Mongolia, gray wolves moved more than khulan or wild Bactrian camels , which are among their prey species.\u201d\u201cIn southwest Mongolia, gray wolves moved more than khulan or wild Bactrian camels (Additionally, in Table 2, \u201cBactrian camel\u201d should read \u201cWild camel\u201d."}
+{"text": "The article does not support the hypothesis.The journal is retracting the article, \u201cHemolytic jaundice induced by pharmacological dose ascorbic acid in glucose-6-phosphate dehydrogenase deficiency: A case report\u201d,"}
+{"text": "Nature Communications 10.1038/s41467-019-10855-0, published online 27 June 2019.Correction to: n\u2019 were incorrectly referred to as \u2018FKBP-NFAST\u2019 and \u2018FRB-CFASTn\u2019, respectively, in a number of places. As a result of this, the following changes have been made to the originally published version of this Article:The authors became aware of a mistake in the original version of this Article. Specifically, the fusion proteins \u2018FRB-NFAST\u2019 and \u2018FKBP-CFASTIn Fig.\u00a01b and Fig.\u00a01c, the vertical labels on the right-hand side originally incorrectly read \u2018FKBP-N + FRB-C\u2019 instead of the correct \u2018FRB-N + FKBP-C\u2019.b\u2013e HEK293T cells co-expressing FK506-binding protein (FKBP)-NFAST and FKBP-rapamycin-binding domain of mammalian target of rapamycin (FRB)-CFASTn (n = 10 or 11) were labeled with 5 \u03bcM HMBR (4-hydroxy-3-methylbenzylidene rhodanine) (b) or 10 \u03bcM HBR-3,5DOM  (c) and imaged before and after the addition of 100 nM rapamycin\u2019. The correct version reads \u2018(FKBP)-CFASTn (n = 10 or 11)\u2019 in place of \u2018(FKBP)-NFAST\u2019 and \u2018(FRB)-NFAST\u2019 instead of \u2018(FRB)-CFASTn (n = 10 or 11)\u2019.The third sentence of the caption to Fig.\u00a01 originally incorrectly read \u2018e Temporal evolution of the fluorescence intensity after rapamycin addition in HMBR-treated cells co-expressing FKBP-NFAST and FRB-CFAST11 \u2019. The correct version reads \u2018FRB-NFAST\u2019 in place of \u2018FKBP-NFAST\u2019 and \u2018FKBP-CFAST11\u2019 instead of \u2018FRB-CFAST11\u2019.The sixth sentence of the caption to Fig.\u00a01 originally incorrectly read \u2018This has been corrected in both the PDF and HTML versions of the Article.In Supplementary Figs. 4a and 5a, the labels \u2018FKBP\u2019 and \u2018FRB\u2019 in the schematic at the top were incorrectly switched, both before and after the reaction.(a) Selected frames of representative HEK293 cells co-expressing FKBP-NFAST and FRB-CFASTn (n = 10 or 11) (labeled with 5 \u00b5M HMBR) upon addition of 100 nM rapamycin\u2019. The correct version reads \u2018FRB-NFAST\u2019 in place of \u2018FKBP-NFAST\u2019 and \u2018FKBP-CFASTn (n = 10 or 11)\u2019 instead of \u2018FRB-CFASTn (n = 10 or 11)\u2019.The second sentence of the caption to Supplementary Fig. 4 originally incorrectly read \u2018(a) Selected frames of representative HEK293 cells co-expressing FKBP-NFAST and FRB-CFAST11  upon addition of 100 nM rapamycin\u2019. The correct version reads \u2018FRB-NFAST\u2019 in place of \u2018FKBP-NFAST\u2019 and \u2018FKBP-CFAST11\u2019 instead of \u2018FRB-CFAST11\u2019.The second sentence of the caption to Supplementary Fig. 5 originally incorrectly read \u2018The HTML has been updated to include a corrected version of the Supplementary Information."}
+{"text": "Correction to: BMC Med Genomics10.1186/s12920-018-0412-4After publication of this supplement article , it was Please be advised that the correct title is \u201cHuman ancestry identification under resource constraints -- what can one chromosome tell us about human biogeographical ancestry?\u201dThat is, \u201cindentification\u201d should read \u201cidentification\u201d."}
+{"text": "In the article titled \u201cFibroblast Growth Factor-9 Activates c-Kit Progenitor Cells and Enhances Angiogenesis in the Infarcted Diabetic Heart\u201d , the nam"}
+{"text": "Scientific Reports 10.1038/s41598-017-17672-9, published online 18 December 2017Correction to: This Article contains errors.The reference to the PDB entry was missing. It is included below as Reference 1.\u201d\u201cVirtual screening was carried out on the IMP\u03b1:VEEV NLS crystal structure"}
+{"text": "In the original publication of the article the keywords are incorrectly online published. The correct keywords should read as \u201c\u03b1-conotoxin, nicotinc acetylcholine receptor, acetylcholine binding protein, X-ray crystallography\u201d."}
+{"text": "In the article titled \u201cIs IVF/ICSI an Independent Risk Factor for Spontaneous Preterm Birth in Singletons? A Population-Based Cohort Study\u201d , the acr"}
+{"text": "Correction to: Genome Biologyhttps://doi.org/10.1186/s13059-018-1586-yPage 5, paragraph\u00a03, line 4: \u201cPolyphenol oxidase (PPO) is an enzyme that causes browning in many fruits and vegetables. By knocking out this gene, Waltz and coworkers developed a non-browning mushroom\u201d. \u201cWaltz and coworkers\u201d should be \u201cYinong Yang and coworkers\u201d.Page 6, paragraph\u00a02, line 3: \u201cAdenine-deaminase-mediated base editing (ABE) is more complicated than CBE because no known naturally occurring cytidine deaminases catalyze adenine deamination in DNA rather than RNA\u201d. \u201cnaturally occurring cytidine\u00a0deaminases\u201d should be \u201cnaturally occurring adenine deaminases\u201d.Following publication of the original article , the aut"}
+{"text": "Sci., 2019, DOI: ; 10.1039/c8sc04561e.Correction for \u2018Palladium-scavenging self-assembled hybrid hydrogels \u2013 reusable highly-active green catalysts for Suzuki\u2013Miyaura cross-coupling reactions\u2019 by Petr Slav\u00edk"}
+{"text": "In the article titled \u201cToxic Effects of Trazodone on Male Reproductive System via Disrupting Hypothalamic-Pituitary-Testicular Axis and Inducing Testicular Oxidative Stress\u201d , there w\u201cThis study was supported by Anadolu University Scientific Research Projects Commission, (Grant Number: 1401S018)\u201d."}
+{"text": "Scientific Reports 10.1038/s41598-018-20024-w, published online 31 January 2018Correction to: In this Article, reference 23 is incorrectly cited in its third instance. The correct reference appears below as reference 1, and should appear in the Introduction as below:23\u201d\u201cMeanwhile, several modelling groups have used SIF data to optimise fluorescence model parametersshould read:1\u201d\u201cMeanwhile, several modelling groups have used SIF data to optimise fluorescence model parameters"}
+{"text": "Correction to: Translational Psychiatry10.1038/s41398-018-0311-7 Published online 14 December 2018Michael F. Grunebaum\u2019s name was misspelled/misstated as \u201cGruenbaum M.F.\u201d in the original Article. This has now been updated in the HTML and PDF versions of this Article."}
+{"text": "Regarding the article \u201cCross-cultural validation of the \u2018DISABKIDS\u2019 questionnaire forquality of life among Colombian children with chronic diseases\u201d, with DOI number:1518-8345.2378.3020, published in Rev. Latino-Am. Enfermagem, 2018;26:e3020, page 1:Where was written:2\u201cNadia Carolina Reina Gamba3Miguel Richart Martinez3\u201dJulio Cabrero Garc\u00edaNow Read:2\u201cNadia Carolina Reina-Gamba3Miguel Richart-Martinez3\u201dJulio Cabrero-Garc\u00eda"}
+{"text": "The article was submitted tomultiple journals and also published as \u201cPsychological Results of 438 Patients withpersisting Gastroesophageal Reflux Disease Symptoms by Symptom Checklist 90-RevisedQuestionnaire\u201d in Volume 7,Issue 2 of Euroasian Journal of Hepato-Gastroenterlogy.The article, \u201cThe psychological results of 438 patients with persisting GERD symptomsby Symptom Checklist 90-Revised (SCL-90-R) questionnaire\u201d,"}
+{"text": "Correction to: J Hematol Oncol (2016) 9:87https://doi.org/10.1186/s13045-016-0319-5The description, \u201c\u2026by four-color flow cytometry (FCM)\u201d was incorrect. The correct description should be \u201c\u2026by eight-color flow cytometry (FCM)\u201d.The description, \u201cLAIPs were detected by four-color FCM\u201d was incorrect. The correct description should be \u201cLAIPs were detected by eight-color FCM\u201d.The original article  contains"}
+{"text": "Correction to: International Journal for Equity in Health (2019) 18:36https://doi.org/10.1186/s12939-019-0935-0Following publication of the original article , the autThe published caption \u201cThe blue line between \u201cSocial Location\u201d and \u201cMaterial Circumstances\u201d should be double headed, having an arrow head at both ends\u201d needs to be replaced with \u201cHealth Equity Measurement Framework\u201d.Also, in Fig.\u00a0The original article has been corrected as well.The publisher apologizes for any inconvenience caused by this error."}
+{"text": "The author wishes to make the following corrections to this paper . Due to The corrections include: (1) replacing the title \u201cDesign, Synthesis, and Evaluation of Novel 2-Hydroxypyrrolobenzodiazepine-5,11-dione Analogues as Potent Angiotensin Converting Enzyme (ACE) Inhibitors\u201d with \u201cDesign, Synthesis, and Evaluation of Novel Phenolic acid/Dipeptide/Borneol Hybrids as Potent Angiotensin Converting Enzyme (ACE) Inhibitors with Anti-hypertension Activity\u201d; and (2) replacing \u201c2-hydroxypyrrolobenzodiazepine-5,11-dione analogues\u201d with \u201cphenolic acid/dipeptide/borneol hybrids\u201d in the abstract.The authors would like to apologize for any inconvenience caused to the readers by these changes."}
+{"text": "In the article titled \u201cOxidative Stress-Related Parthanatos of Circulating Mononuclear Leukocytes in Heart Failure\u201d , incorre"}
+{"text": "Correction to: Samad et al. BMC Genomics (2019) 20:586https://doi.org/10.1186/s12864-019-5954-0Following publication of the original article , the aut27 miRNAs were upregulated, whereas 31 miRNAs were downregulated\u201d.1) In the Results section of the Abstract the sentence \u201cAmong these 58 differentially expressed genes (DEGs), 33 miRNAs were upregulated, whereas 25 miRNAs were downregulated\u201d should read \u201cAmong these 58 differentially expressed genes (DEGs), with their isomiRNAs. Among these significantly regulated miRNAs, 27 were upregulated and 31 were downregulated\u201d.2) In the sub-section \u2018Differential expression of miRNAs in C and F libraries\u2019 the following sentences should read \u201cThe plot showed significant changes in the regulation of 58 miRNAs synthase 1 (FDS1), targeted by pmi-miR6173\u201d.3) In the sub-section \u2018Analysis of target transcripts involved in terpenoid pathway\u2019, \u201csesquiterpene synthase and farnesyl diphosphate synthase (FDS), targeted by pmi-miR6173\u201d should instead read \u201csesquiterpene synthase and farnesyl diphosphate FDS1 and sesquiterpene synthase, which are involved in the MVA pathway, were targeted by pmi-miR6173\u201d.4) In the sub-section \u2018Expression profiles of miRNAs and their targets by RT-qPCR\u2019 the sentence \u201cTwo target transcripts, FDP and sesquiterpene synthase, which are involved in the MVA pathway, were targeted by pmi-miR6173\u201d should instead read \u201cTwo target transcripts, Populus tremula\u201d.5) In the sub-section \u2018Expression profiles of miRNAs and their targets by RT-qPCR\u2019 the following citation  should hsix terpenoid related miRNAs could be utilized to regulate terpenoid biosynthesis by manipulating the MVA and MEP pathways through the RNAi mechanism.\u201d6) The final sentence of the \u2018Conclusions\u2019 section should read: \u201cThe above 7) The authors have provided corrected versions of Figs."}
+{"text": "Scientific Reports 10.1038/s41598-018-27740-3, published online 04 July 2018Correction to: In this Article, the ArrayExpress database accession number is incorrect. As a result, in the Results section under the \u2018miRNA microarray analysis\u2019 subheading and in the Methods section under the \u2018Accession codes\u2019 subheading,\u201cE-MTAB-3979\u201dshould read:\u201cE-MTAB-5589\u201d."}
+{"text": "Nature Communications 10.1038/s41467-019-12983-z, published online 01 November 2019.Correction to: The original version of this Article omitted the following from the last sentence of the Acknowledgements:UID/BIM/50005/2019, project funded by Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia (FCT)/ Minist\u00e9rio da Ci\u00eancia, Tecnologia e Ensino Superior (MCTES) through Fundos do Or\u00e7amento de Estado. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Sci., 2016, 7, 2563\u20132571.Correction for \u2018Designed multi-stranded heme binding \u03b2-sheet peptides in membrane\u2019 by Areetha D'Souza  The sentence \u201cDesigned peptides The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "There is information missing from the Funding section. The phrase \u201cNational Science Centre grants 2016/23/P/NZ3/03730 (BUR)\u201d should be \u201cPOLONEZ Fellowship of National Science Centre, Poland, 2016/23/P/NZ3/03730. This project has received funding from the European Union\u2019s Horizon 2020 research and innovation programme under the Marie Sk\u0142odowska-Curie grant agreement No 665778 (BUR).\u201d."}
+{"text": "In the article titled \u201cCombination Therapy with EpCAM-CAR-NK-92 Cells and Regorafenib against Human Colorectal Cancer Models\u201d , there w"}
+{"text": "Scientific Reports 10.1038/s41598-018-28422-w, published online 03 July 2018Correction to: This Article contains an error in the Acknowledgements section.\u201cThe standard analysis file (JRDR-09004) was used for this study.\u201dshould read:\u201cThe standard analysis file (SAF-2016-010) was used for this study.\u201d"}
+{"text": "Yi Fan Chen's name appears incorrectly as Yi Fang Chen.In the article, \u201cCemented versus uncemented hemiarthroplasty for displaced femoral neck fractures: A meta-analysis of randomized controlled trails\u201d,"}
+{"text": "Correction to: BMC Genomicshttps://doi.org/10.1186/s12864-018-4943-zreads \u2013 ChIP-seq recovery yields diminishing returns with read depths greater than 60 million reads\u201d.The sub-heading \u201cFootprints increase linearly with reads \u2013 ChIP-seq recovery yields diminishing returns with read depths greater than 60 million readz\u201d should be \u201cFootprints increase linearly with area under the receiver operating characteristic curve), a measure of a predictor\u2019s ability to predict true positives, increased non-linearly as read depths increased .\u201dThe sentence \u201cROC AUC (area under the repeater operating characteristic curve), a measure of a predictor\u2019s ability to predict true positives, increased non-linearly as read depths increased \u201d should read \u201cROC AUC (Following the publication of this article , the aut"}
+{"text": "Smilax glabra Roxb. Attenuates Inflammatory Responses in Complete Freund's Adjuvant-Induced Arthritis Rats\u201d [In the article titled \u201cAstilbin fromis Rats\u201d , the aff"}
+{"text": "The article appeared previously in Volume 5 of Scientific Reports as \u201cHybrid surgery versus anterior cervical discectomy and fusion for multilevel cervical degenerative disc diseases: a meta-analysis.\u201dThe article, \u201cHybrid Surgery Versus Anterior Cervical Discectomy and Fusion in Multilevel Cervical Disc Diseases: A Meta-Analysis\u201d,"}
+{"text": "Scientific Reports 10.1038/s41598-019-39707-z, published online 27 February 2019Correction to: In Figure 4, the \u2018RCA-1 cleaned\u2019 and \u2018Solvent cleaned\u2019 plots are labelled incorrectly. The correct Figure\u00a04 appears below as Figure"}
+{"text": "Correction to: Parasites & Vectors (2016) 9:535DOI: 10.1186/s13071-016-1821-xDiscussion section, in the sentence \u201cFor example a microfilaricide, either ivermectin (50\u2013200 mg/kg) or milbemycin oxime \u201d.Since publication of the original version of this article , it has that the mg units in the sentence should instead be \u03bcg; that is, \u201cFor example a microfilaricide, either ivermectin (50\u2013200 \u03bcg/kg) or milbemycin oxime \u201d.Please be advised The authors apologize for any inconvenience caused."}
+{"text": "Scientific Reports 10.1038/s41598-018-30571-x, published online 17 August 2018Correction to: This Article contains typographical errors in the Acknowledgements section.\u201c\u201dshould read:\u201c\u201d"}
+{"text": "Scientific Reports 10.1038/s41598-017-03613-z, published online 16 June 2017Correction to: This Article contains typographical errors in the Results section under the subheading \u201cTheorem 3\u201d, whereshould read:andshould read:"}
+{"text": "Correction to:Journal of Experimental & Clinical Cancer Research(2018) 37:283.Doi 10.1186/s13046-018-0953-6In the caption of Fig.\u00a01c the sentence \u201cThe 20 most highly upregulated EBV BART miRNAs identified between NPC specimens and normal nasopharyngeal mucosal specimens\u201d should instead read \u201cThe highly upregulated EBV BART miRNAs identified between NPC specimens and normal nasopharyngeal mucosal specimens\u201d.In Fig.\u00a0Following publication of the original article , the aut"}
+{"text": "In the article titled \u201cA Lucky Accident: Brugada Syndrome Associated with Out-of-Hospital Cardiac Arrest\u201d , there w\u201cIn 1992, Pedro and Josep Brugada first described this autosomal dominant arrhythmia in a series of eight patients who suffered from VF arrest.\u201d"}
+{"text": "Trusted Server as an alternative approach that provides a sealed and inaccessible computational environment in a cryptographically strict sense. During operation or by direct physical access to storage media, data stored and processed inside the Trusted Server can by no means be read, manipulated or leaked, other than by brute-force. Thus, secure and privacy-compliant data processing or evaluation of plain person-related data becomes possible even from multiple sources, which want their data kept mutually secret.A growing framework of legal and ethical requirements limit scientific and commercial evaluation of personal data. Typically, pseudonymization, encryption, or methods of distributed computing try to protect individual privacy. However, computational infrastructures still depend on human system administrators. This introduces severe security risks and has strong impact on privacy: system administrators have unlimited access to the computers that they manage including encryption keys and pseudonymization-tables. Distributed computing and data obfuscation technologies reduce but do not eliminate the risk of privacy leakage by administrators. They produce higher implementation effort and possible data quality degradation. This paper proposes the  This comprises person-identifying data , which privacy protection rules do address, as well as person-relatable information, which allow identifying a person by using re-identification techniques \u2003iptables -D INPUT 4\u2003## LIST IPTABLES\u2003iptables-save\u2003iptables -L \u2013n\u2003ip6tables-save\u2003ip6tables -L \u2013n\u2003cat /etc/hosts.allow\u2003cat /etc/hosts.deny\u2003## REMOVE SSH SERVER\u2003apt-get -y purge openssh-server\u2003apt-get -y autoremove\u2003systemctl status sshd\u2003## REMOVE ONLY LOGON USER - CREATES ERROR IF ALREADY CORRECTLY REMOVED\u2003userdel -f trust\u2003cat /etc/passwd\u2003cat /etc/shadow\u2003## REMOVE DISK ENCRYPTION KEY --\u2003cryptsetup luksErase /dev/sda2\u2003cryptsetup luksDump /dev/sda2\u2003## PRINT OLD VM KEY INFORMATION\u2003cryptsetup luksDump /dev/sdb2\u2003## AND REENCRYPT TS-VM DISK\u2003cryptsetup-reencrypt -v -d /mnt/keyfile -l 512 /dev/sdb2\u2003## PRINT NEW VM DISK KEY INFORMATION\u2003cryptsetup luksDump /dev/sdb2\u2003## CREATE ARCHIVES OF ETC AND ROOT FOR PUBLISHING\u2003zip -r /mnt/etc-host.zip\u2003 /etc\u2003zip -r /mnt/root-host.zip\u2003/root\u2003## LIST FILES AND SHA3 CHECKSUMS\u2003ls -RlA /\u2003rhash -r--sha3-512 /boot\u2003rhash -r--sha3-512 /etc\u2003rhash -r--sha3-512 /home\u2003rhash -r--sha3-512 /lib\u2003rhash -r--sha3-512 /lib64\u2003rhash -r--sha3-512 /lost+found\u2003rhash -r--sha3-512 /media\u2003rhash -r--sha3-512 /mnt\u2003rhash -r--sha3-512 /opt\u2003rhash -r--sha3-512 /root\u2003rhash -r--sha3-512 /sbin\u2003rhash -r--sha3-512 /srv\u2003rhash -r--sha3-512 /tmp\u2003## since /usr/bin has X11 -> . recursive link:\u2003rhash\u2003--sha3-512 /usr/bin/*\u2003rhash -r--sha3-512 /usr/games\u2003rhash -r--sha3-512 /usr/include\u2003rhash -r--sha3-512 /usr/lib\u2003rhash -r--sha3-512 /usr/local\u2003rhash -r--sha3-512 /usr/sbin\u2003rhash -r--sha3-512 /usr/share\u2003rhash -r--sha3-512 /usr/src\u2003rhash -r--sha3-512 /var\u2003## COPY LOG TO TS-VM BOOT PARTITION\u2003cp /root/0_init_trusted_mode_host.log /mnt\u2003## UNMOUNT TS-VM BOOT PARTITION\u2003umount /mnt\u2003## START TS-VM\u2003virsh start debian9cron-reboot.sh \u2003#!/bin/bash\u2003# cron-reboot TS-VM\u2003iptables-restore /home/trust/iptables.v4\u2003ip6tables-restore /home/trust/iptables.v6\u2003## INIT TRUSTED MODE AND CREATE VM SEALING LOG\u2003/home/trust/init_trusted_mode.sh > /var/www/log/1_init_trusted_mode.log 2>&1init_trusted_mode.sh \u2003set \u2013x\u2003## REMOVE HOST ACCESS PERMISSION AND VERIFY\u2003rm /etc/hosts.allow\u2003## SWITCH IPTABLES OUTGOING POLICY TO DROP AND DELETE SSH PERMISSION\u2003iptables -P OUTPUT DROP\u2003## [set line number accordingly:]\u2003iptables -D INPUT 5\u2003## LIST IPTABLES AND HOST ACCESS\u2003iptables-save\u2003iptables -L \u2013n\u2003ip6tables-save\u2003ip6tables -L \u2013n\u2003cat /etc/hosts.allow\u2003cat /etc/hosts.deny\u2003## REMOVE SSH SERVER\u2003apt-get -y purge openssh-server\u2003apt-get -y autoremove\u2003systemctl status sshd\u2003## REMOVE ONLY LOGON USER\u2003userdel -f trust\u2003cat /etc/passwd\u2003cat /etc/group\u2003cat /etc/shadow\u2003## REMOVE DISK ENCRYPTION KEY\u2003cryptsetup luksErase /dev/vda2\u2003cryptsetup luksDump /dev/vda2\u2003## MOVE HOST LOG AND ZIP TO WEBROOT\u2003mv /boot/0_init_trusted_mode_host.log /var/www/log\u2003mv /boot/etc-host.zip /var/www/log\u2003mv /boot/root-host.zip /var/www/log\u2003chown www-data:www-data /var/www\u2003## CREATE ARCHIVES OF /ETC AND /HOME/TRUST FOR PUBLISHING\u2003zip -r /var/www/log/etc-vm.zip\u2003/etc\u2003zip -r /var/www/log/trust-vm.zip /home/trust\u2003## CREATE LDAP LOG\u2003date >> /var/www/log/ldap.txt && slapcat -n 0 >> /var/www/log/ldap.txt && slapcat -n 1 >> /var/www/log/ldap.txt\u2003## SET PERMISSIONS TO APACHE2\u2003chown -R www-data:www-data /var/www\u2003## LIST FILES AND SHA3 CHECKSUMS\u2003ls -RlA /\u2003rhash -r--sha3-512 /boot\u2003rhash -r--sha3-512 /etc\u2003rhash -r--sha3-512 /home\u2003rhash -r--sha3-512 /lib\u2003rhash -r--sha3-512 /lib64\u2003rhash -r--sha3-512 /lost+found\u2003rhash -r--sha3-512 /media\u2003rhash -r--sha3-512 /mnt\u2003rhash -r--sha3-512 /opt\u2003rhash -r--sha3-512 /root\u2003rhash -r--sha3-512 /sbin\u2003rhash -r--sha3-512 /srv\u2003rhash -r--sha3-512 /tmp\u2003## since /usr/bin has X11 -> . recursive link:\u2003rhash\u2003--sha3-512 /usr/bin/*\u2003rhash -r--sha3-512 /usr/games\u2003rhash -r--sha3-512 /usr/include\u2003rhash -r--sha3-512 /usr/lib\u2003rhash -r--sha3-512 /usr/local\u2003rhash -r--sha3-512 /usr/sbin\u2003rhash -r--sha3-512 /usr/share\u2003rhash -r--sha3-512 /usr/src\u2003rhash -r--sha3-512 /var\u2003## ENABLE APACHE WEBSERVER\u2003systemctl start apache2\u2003## SEND MAIL\u2003echo $(date) >> /home/trust/date.txtbomhard@ibe.med.uni-muenchen.de <\u2003mail -s \"trusted server running@138.245.80.17\" \u2003home/trust/date.txtThe Trusted Server provides a new state-of-the-art regarding security and protection. Basic user authentication can be implemented using apache2's file based user- and password database. After TS sealing, no change to those files is possible except by permitting security-weakening file upload.Lightweight Directory Access Protocol (LDAP) .The standard CBH is a step function with jumps at each event time.Publishing the CBH in this form may allow to reidentify individual patients by observed event times. Therefore we use a smoothed form of the CBH which blurs observed event times. This deidentifying step is given in the code line www<-lowess. This is a very practical approach that needs more thinking in a real scenario.In the following we two R-scripts. The first R-script (plumber.R) starts the plumber server, which is remotely accessed over the apache2 proxy.plumber.R\u2003library(plumber)\u2003r <- plumb(\"<\u2026\u2025demo.R>\")\u2003r$run(port = 8000)The second script (demo.R) contains the analysis which mainly rely on three functions. The function getPacman attaches the library which manages the specific library attachments needed for the analysis. The function readDat concatenates the individual csv data files in the working directory to a common data object in R. The line with the hash mark before the evalrfc function is a decorator which can be interpreted by plumber defining the call the server should respond to. The function evalrfc provides the specific analysis data steps, returning the data that are responded, when the interface is called. After defining the functions, the script performs the following steps: attaching pacman, attaching the specific libraries over pacman and reading the data.The evaluation is started and results are provided by calling the URL: \"https://<ipAddressOrDomainName>:<port>/evalrfc\"demo.R\u2003\u2003getPacman <- function\u2003\u2003\u2003{\u2003\u2003\u2003\u2003if \u2003\u2003\u2003\u2003install.packages(\"pacman\")\u2003\u2003\u2003\u2003library(pacman)\u2003\u2003\u2003}\u2003readDat <- function(dir)\u2003\u2003\u2003{\u2003\u2003\u2003\u2003setwd(dir)\u2003\u2003\u2003\u2003all_files <- list.files\u2003\u2003\u2003\u2003dats <- lapply\u2003\u2003\u2003\u2003dat <- do.call\u2003\u2003\u2003\u2003return(dat)\u2003\u2003\u2003}\u2003#* @get /evalrfc\u2003evalrfc <- function\u2003\u2003\u2003{\u2003\u2003\u2003\u2003result <- mfp ~ fp + fp, family = cox, data = dat)\u2003\u2003\u2003\u2003coef <- summary(result)$coefficient\u2003\u2003\u2003\u2003haz <- basehaz(result)\u2003\u2003\u2003\u2003www<-lowess\u2003\u2003\u2003\u2003res <- list\u2003\u2003\u2003\u2003return(res)\u2003\u2003\u2003}\u2003getPacman\u2003p_load(mfp)dat <- readDat(\"path to data\")Any grade of privacy protection and security is relative. This of course is also valid for the TS. Its grade of protection depends on the quality and irrevocability of the Virtual Machine disk2 encryption. LUKS is cryptographically strong  and withServer BIOS and the CPU-Microcode are closed source and potentially contain undocumented functions and backdoors. This implies that today\u2019s real-world computing hardware cannot achieve absolute trust-to-the-last.The cryptographic strength of encryption techniques for Solid-State-Disks (SSD) is currently under discussion . ExploitAfter testing and approval, the system administrators activate the initialization scripts. At that point the administrators could change binaries or add scripts in the physical host or Virtual Machine. This intervention could break security, for example by sending out the secret key and LUKS-header created during Virtual Machine disk reencryption.Thorough review of the published logs and comparison of the TS\u2019 state after installation and its state after sealing are crucial. The SHA-3 hashes and log files published on the TS\u2019s website allow to detect changes and to reveal most manipulations.For maximum trust, transparency and control, disk images should be crated immediately before the sealing is initialized and securely provided to the concerned parties. Ideally representatives of all parties personally attend the sealing and receive their disk images. Video self-surveillance of the TS and sealing process may be disclosed over the TS website, too.Remove Gnome Virtual File System and any other auto-mounters for external storage to prevent code injection from scripts running automatically when an external USB storage or CD/DVD is inserted and external ports are needed for some reason.Specific scenarios recommend to use means like hardening, creating custom kernels, to use SELinux or AppArmour. Applications installed on the Trusted Server need a careful internal security check, too.Disclosing a full disk image for review allows corrupting the SSL transport encryption by a man-in-the-middle attack , since tA Cold-Boot , DMA 2323 or remAdditional protection and security is achieved by using a server-vault or strongroom with strict access management.A physical self-destruction mechanism triggered by any human access to the server-vault may protect the TS even against the strongest attackers.Aside from added security by sealing, a Trusted Server shares all vulnerabilities and contact surfaces with a conventional server having an identical setup. Therefore, we recommend additional security measures:The TS overcomes human-centric paradigms in privacy protection concepts. All current approaches base on either trust or mistrust in single or multiple real persons. Accordingly, they establish either a network of trust, which spreads information over multiple semi-trusted instances of human-driven institutions or use complex computation schemes of fully encrypted data so nobody needs to trust anyone but himself or herself. Compared to standard non-privacy-protected solutions both approaches require highly customized workflows.The TS may request moderately prolonged downtimes for maintenance and changes. Compared to multi stage approaches this compensates by quick and easy setup as well as minimized workflow customization.The TS provides a conventional computational environment that grants Privacy by Design independently from any individual. Since the TS behaves\u2014despite self-sealing and irrevocable encryption\u2014like any standard GNU/Linux based system, it is possible to run well-established computational solutions with the highest degree of privacy."}
+{"text": "Erratum to: Indian J Pediatr 81(11):1237\u20131239DOI 10.1007/s12098\u2013014\u20131487-3The original published online version's copyright line has to be corrected as Open Access (see updated copyright line shown above). Open access statement is also included below."}
+{"text": "The following information is missing from the Funding statement: Dr. Zsuzsanna Izsv\u00e1k was funded by European Research Council-2011-ADG-TRANSPOSOstress\u2013 294742."}
+{"text": "Scientific Reports 10.1038/srep45525, published online 31 March 2017Correction to: This Article contains a typographical error in the Materials and Methods section under the subheading \u2018Experimental animals\u2019 where,\u201cThe doses of AT-RvD1 and EDX used in this study\u2026\u201dshould read:\u201cThe doses of AT-RvD1 and DEX used in this study\u2026\u201d"}
+{"text": "Scientific Reports 10.1038/s41598-019-44290-4, published online 28 May 2019Correction to: This Article contains errors in Table 1. In column 17 \u2018Ref.\u2019, all instances of \u20181\u2019 should read \u201810\u2019. In addition, all instances of \u20182\u2019 should read \u20186\u2019.As a result, in the legend for Table 1,et al. 2002 (1) and Dartnall et al. 2017 (2)\u2019\u2018Presence/absence matrix of crustacean taxa in lakes of each study region based on Pugh should read:et al. 2002 (10) and Dartnall et al. 2017 (6).\u2019\u2018Presence/absence matrix of crustacean taxa in lakes of each study region based on Pugh The correct Table"}
+{"text": "The authors\u2019 names should appear as Ofer Kobo, Ronit Leiba, Ophir Avizohar and Amir Karban.In the article, \u201cNormal body mass index (BMI) can rule out metabolic syndrome: An Israeli cohort study\u201d,"}
+{"text": "Scientific Reports 10.1038/s41598-018-20422-0, published online 31 January 2018Correction to: The Acknowledgements section in this Article was omitted. The Acknowledgements section should read:\u201cThis research is supported by funding agency FAPDF.\u201d"}
+{"text": "In the article titled \u201cEffects of Electroacupuncture on Methamphetamine-Induced Behavioral Changes in Mice\u201d , there w"}
+{"text": "Scientific Reports 10.1038/s41598-019-47857-3, published online 07 August 2019Correction to: The Article contains an error on the second line of Table 2 where \u201cIn-Threshold Reads/pore/min\u201dshould read:\u201cIn-Threshold Reads/min\u201d"}
+{"text": "Correction to: Mobile DNAhttps://doi.org/10.1186/s13100-019-0186-zt-test pvalue in penultimate row\u2009=\u2009\u201c0.61\u201d should not be boldthe asterisks with significance levels should be as follows: \u201c\u201dFollowing publication of the original article , the autThe original article has been corrected. The correct presentation of Table"}
+{"text": "Scientific Reports 10.1038/s41598-018-32520-0, published online 24 September 2018Correction to: This Article contains an error in the Y axis of Figure 5, where \u2018LIPSS height (\u03bcm)\u2019 should read \u2018LIPSS height (nm)\u2019. The correct Figure 5 appears below as Figure"}
+{"text": "Scientific Reports 10.1038/s41598-017-13621-8, published online 12 October 2017Correction to: This Article contains typographical errors in the Acknowledgements section.\u201cThis study was supported by the UNAM grant IN201814 (ST),\u201dshould read:\u201cThis study was supported by the UNAM grant IN209317 (ST),\u201d"}
+{"text": "Due to a production error, an author name was misspelled. \u201cArbereska Bexheti-Ferati\u201d should be \u201cArb\u00ebresha Bexheti-Ferati.\u201dThe publisher apologizes for this mistake. The original article has been updated."}
+{"text": "Correction to: BMC Public Healthhttps://doi.org/10.1186/s12889-019-7322-zn\u2009=\u20099949 but the correct number is n\u2009=\u20099936. This Correction article shows the correct Fig.\u00a0It was highlighted that the original article  containe"}
+{"text": "Scientific Reports 10.1038/s41598-019-40092-w, published online 01 March 2019Correction to: The original version of this Article and the accompanying Supplementary Information file contained a repeated error where,\u201cLifeact-GFP\u201dnow reads:\u201cLifeact-TagGFP2\u201d"}
+{"text": "January issue of 2019, vol. 112(1), pages 67-75In \u201cSex-Related Effects of Prenatal Stress on Region-Specific Expression of MonoamineOxidase A and B Adrenergic Receptors in Rat Hearts\u201d, consider Tanja Jevdjovic as thecorrect form for the name of the author Tanja Jevjdovic.January issue of 2019, vol. 112(1), pages 91-103In \u201cArrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia (ARVC/D) - What We HaveLearned after 40 Years of the Diagnosis of This Clinical Entity\u201d, table 1 of thePortuguese version, item \u201c5. Arritmias\u201d, consider correct for the phrase \u201cTV n\u00e3osustentada ou sustentada com morfologia tipo BRD e eixo superior\u201d BRE in place ofBRD."}
+{"text": "MMWR Morb Mortal Wkly Rep 2018;67:465\u20139.\u201dThe second reference should have read \u201cCase SL, Lincoln JM, Lucas DL. Fatal falls overboard in commercial fishing\u2014United States,"}
+{"text": "Coronary angiography excluded stenotic lesions. A\u00a0wrap-around left anterior descending (LAD) with myocardial bridging in the mid-segment was observed Video\u00a02: IVUS demonstrating systolic compression of the mid-LAD with a minimum lumen area oscillating from 3.06\u202fmmVideo\u00a03: Left ventricular (LV) angiography revealing typical mid-apical ballooning with hypercontractility of the basal segmentsVideo\u00a04: Follow-up Echocardiography illustrating restoration of left ventricular function"}
+{"text": "In addition, clinical studies described that Parkinson's symptoms were notably worse after the onset of T2DM, and seven deregulated genes were identified in the DNA of T2DM and PD patients. Regarding treatment, the action of antidiabetic drugs, especially incretin mimetic agents, seems to confer certain degree of neuroprotection to PD patients. In conclusion, the available evidence on the interaction between T2DM and PD justifies more robust clinical trials exploring this interaction especially the clinical management of patients with both conditions.In the early sixties, a discussion started regarding the association between Parkinson's disease (PD) and type II diabetes mellitus (T2DM). Today, this potential relationship is still a matter of debate. This review aims to analyze both diseases concerning causal relationships and treatments. A total of 104 articles were found, and studies on animal and \u201cin vitro\u201d models showed that T2DM causes neurological alterations that may be associated with PD, such as deregulation of the dopaminergic system, a decrease in the expression of peroxisome proliferator-activated receptor-gamma coactivator-1 These factors impair insulin release and consequently cause hyperglycemia ) AND \u201cDiabetes Mellitus\u201d[Mesh],\u201d \u201c(\u201cParkinson Disease\u201d[Mesh]) AND \u201cInsulin Resistance\u201d[Mesh],\u201d \u201c AND \u201cDiabetes Mellitus\u201d[Mesh],\u201d \u201c AND \u201cInsulin Resistance\u201d[Mesh],\u201d \u201c(\u201cIslet Amyloid Polypeptide\u201d[Mesh]) AND \u201cParkinson Disease\u201d[Mesh],\u201d \u201c(\u201cMetformin\u201d[Mesh]) AND \u201cParkinson Disease\u201d[Mesh],\u201d \u201c(\u201cSulfonylurea Compounds\u201d[Mesh]) AND \u201cParkinson Disease\u201d[Mesh],\u201d \u201c(\u201cThiazolidinediones\u201d[Mesh:NoExp]) AND \u201cParkinson Disease\u201d[Mesh],\u201d \u201c(\u201cGlucagon-Like Peptide 1\u201d[Mesh]) AND \u201cParkinson Disease\u201d[Mesh],\u201d \u201c(\u201cBromocriptine\u201d[Mesh:NoExp]) AND \u201cDiabetes Mellitus\u201d[Mesh],\u201d \u201c(\u201cExenatide\u201d[Mesh:NoExp]) AND \u201cParkinsonian Disorders\u201d[Mesh],\u201d \u201c(\u201cLevodopa\u201d[Mesh]) AND \u201cDiabetes Mellitus\u201d[Mesh],\u201d \u201c(\u201cDipeptidyl-Peptidase IV Inhibitors\u201d[Mesh]) AND \u201cParkinson Disease\u201d[Mesh]\u201d, \u201c(\u201cSodium-Glucose Transporter 2 Inhibitors\u201d[Mesh]) AND \u201cParkinson Disease\u201d[Mesh].\u201d Letters, reviews, and articles in languages other than English were excluded.The review was based on the analysis of studies retrieved via PubMed up to September, 2019. Articles were screened according to the following eligibility criteria: original articles describing the relationship between PD and T2DM, unrelated to any other disease, using A total of 627 articles were found . Among tPGC-1\u03b1 (peroxisome proliferator-activated receptor-gamma coactivator-1\u03b1) , decrease in the expression of PGC-1\u03b1 (peroxisome proliferator-activated receptor-gamma coactivator-1\u03b1) [On the other hand, we also found pathophysiological components of T2DM that could lead to PD such as metabolic inflammation , downregator-1\u03b1) \u201339, incrator-1\u03b1) , increasator-1\u03b1) , 42, andator-1\u03b1) .Many studies evaluated the use of MPTP in diabetic rats to analyze the pathophysiological interaction between both diseases. The use of MPTP in diabetic rats resulted not only an accelerated loss of dopaminergic neurons and the activation of glial cells in the substantia nigra but also an increase in the activation of inflammatory molecules, including NLRP3 and alpha-synuclein aggregates in the pancreas and in the brain. In addition, the endoplasmic reticulum stress markers CHOP and GRP78 were positively regulated in the pancreas, liver, and brain of mice with T2DM . TherefoFuthermore, it was observed that insulin regulates dopamine synthesis and uptake within the substantia nigra . Some stPGC-1\u03b1, a regulator of enzymes involved in mitochondrial respiration, shows reduced expression [PGC-1\u03b1 is repressed by PARIS (ZNF746), a protein that causes neurodegeneration in PD due to parkin inactivation [PGC-1\u03b1 protects against the destruction of dopaminergic neurons [In insulin resistance, the gene pression , 39. Addtivation . Many re neurons , 38. As Another pathophysiological mechanism in T2DM is the protein PED/PEA-15. This protein is increased in many cells  in T2DM patients. A recent study showed that rats overexpressing this protein had a reduction in dopaminergic activity, a fact that may induce the development of PD .One recent association between PD and T2DM is the ADTIQ  and its precursor methylglyoxal (a subproduct of glucose metabolism that is increased in diabetic patients) . ADTIQ wFinally, the formation of alpha-synuclein aggregates can be observed in PD, whereas pancreatic amyloid plaques formed by the pancreatic islet amyloid polypeptide (IAPP) are present in T2DM. In one study, it was noted that the speed of alpha-synuclein aggregation is higher when it interacts with IAPP , thus shBiguanides (metformin) activate the AMP-activated kinase protein (AMPK)  responsiSulphonylureas  stimulate insulin release by inhibiting the ATP-sensitive K+ (K ATP) channel of pancreatic beta-cells resulting in the closure of the potassium channels and opening of calcium channels . HoweverPGC-1\u03b1, plasma interleukin 6, and urine 8-hydroxydeoxyguanosine [Several studies investigated the effect of thiazolidinediones (pioglitazone and rosiglitazone) in the treatment of PD , 109\u2013122uanosine . However\u03b2-cell lymphoma 2), which prevented apoptosis and reduced chronic brain inflammation [Incretin mimetics drugs (GLP-1/GIP agonists and DPP-4 inhibitors) activate glucagon-like peptide-1 (GLP-1) or glucose-dependent insulinotropic polypeptide (GIP) receptors on pancreatic beta-cells stimulating insulin secretion and synthesis , 166. Thammation , 103. Fiammation . This drammation \u2013106 explammation , and theammation . Moreoveammation . Hence, A relationship between T2DM and L-dopa therapy , 73 and \u03b1 (PGC-1\u03b1), an increase in the expression of phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes 15 (PED/PEA-15), and neuroinflammation, as well as acceleration of the formation of alpha-synuclein amyloid fibrils. Epidemiological studies suggested that T2DM increases the risks of PD. In addition, clinical studies described that Parkinson's symptoms were notably worse after the onset of T2DM. Regarding treatment, the action of antidiabetic drugs, especially incretin mimetic agents, seems to confer a certain degree of neuroprotection to PD patients. In conclusion, the available evidence on the interaction between T2DM and PD justifies more robust clinical trials exploring this interaction especially the clinical management of patients with both conditions.\u201cIn vitro\u201d and animal studies suggest that T2DM causes neurological alterations that may be associated with PD, such as deregulation of the dopaminergic system, a decrease in the expression of peroxisome proliferator-activated receptor-gamma coactivator-1"}
+{"text": "In the article titled \u201cHypophyseal Involvement in Immunoglobulin G4-Related Disease: A Retrospective Study from a Single Tertiary Center\u201d , the fir"}
+{"text": "Correction to: Trials (2018) 19:487https://doi.org/10.1186/s13063-018-2860-8Peripheral and neural biomarkers and genotype section was incorrectly phrased during editing. \u201c4 weeks of treatment (four active ABCR sessions twice a week or control group sessions twice a week)\u201d should have actually been described as \u201ctwo weeks of treatment \u201d.Following publication of the original article , the aut"}
+{"text": "Scientific Reports 10.1038/s41598-017-13892-1, published online 19 October 2017Correction to: The Supplementary material \u2018Risk calculators\u2019 that accompanies this Article contains an error in the \u20188-factor model\u2019 tab, where \u201cWake up several times per night\u201d should read \u201cDifficulty falling asleep\u201d."}
+{"text": "Scientific Reports 10.1038/srep43478, published online 03 March 2017Correction to: This Article contains an error in Figure 3b, where the y-axis label \u2018Hb (mg/ml)\u2019 is incorrectly given as \u2018Hb (mg/dl)\u2019. The correct Figure 3 appears below as Figure"}
+{"text": "Acinetobacter baumannii Bacteremia in Southwest China: A Five-Year Case-Control Study\u201d [In the article titled \u201cDeterminants of Mortality in Patients with Nosocomial l Study\u201d , there w"}
+{"text": "Scientific Reports 10.1038/s41598-019-49723-8, published online 18 September 2019Correction to: This Article contains typographical errors in the methods section, where:should read:In addition,should read:Additionally, in Figures 4 and 5 the following annotation \u201cSpearman\u2019s rho\u2009=\u2009\u2026 \u201d was incorrectly included.The correct Figures 4 and 5 appear below as Figures"}
+{"text": "In the article titled \u201cVitamin D-Binding Protein Clearance Ratio Is Significantly Associated with Glycemic Status and Diabetes Complications in a Predominantly Vitamin D-Deficient Population\u201d , the men"}
+{"text": "China (e-mail"}
+{"text": "Scientific Reports 10.1038/s41598-017-05029-1, published online 06 July 2017Correction to: The Acknowledgements section in this Article is incomplete.Advokat Bent Thorbergs Fond.\u201d\u201cThe authors thank Camilla Sk\u00e5nstr\u00f8m Dall and Tina Maria Estrup Axen for technical assistance. This project was supported by should read:Advokat Bent Thorbergs Fond. This project has received funding from the European Union\u2019s Horizon 2020 research and innovation programme under the Marie Sk\u0142odowska-Curie grant agreement No 642720.\u201d\u201cThe authors thank Camilla Sk\u00e5nstr\u00f8m Dall and Tina Maria Estrup Axen for technical assistance. This project was supported by"}
+{"text": "Scientific Report 10.1038/s41598-019-46095-x, published online 05 July 2019Correction to: In Figure 3(a) and (b), the x-axes are labelled wrong, where \u2018Frequency (THz)\u2019 should read \u2018Time (ps)\u2019. The correct Figure 3 appears below as Figure"}
+{"text": "Scientific Reports 10.1038/s41598-019-40399-8, published online 07 March 2019Correction to: This Article contains errors in the Methods section, under subsection \u2018Samples collection and genotyping\u2019.\u201cAll genotyped data will be made publicly available on the ebc.ee/free_data website and NCBI-GEO public repository (accession number XXXX)\u201d.should read:\u201cAll genotyped data will be made publicly available on the ebc.ee/free_data website and NCBI-GEO public repository (accession number GSE126882)\u201d."}
+{"text": "I have read the article \u201cBladder Cancer Specific Nuclear Matrix Proteins-4 May Be a Potential Biomarker for Non-Muscle-Invasive Bladder Cancer Detection\u201d with great interest . The art"}
+{"text": "Nature Communications 10.1038/s41467-019-09215-9, published online 19 March 2019.Correction to: +\u2019 and \u2018NADPH + H+\u2019 were incorrectly given as \u2018NADPH\u2019 and \u2018NADPH+ + H+\u2019, respectively. This has been corrected in both the PDF and HTML versions of the Article.The original version of this Article contained an error in Fig.\u00a01, in which the labels \u2018NADP"}
+{"text": "Scientific Reports 10.1038/s41598-019-49413-5, published online 12 September 2019Correction to: This Article contains errors.The Competing Interests section in this Article is incorrect and should read:\u201cThe authors are employed by The Ocean Cleanup, a non-for-profit organization that develops technology to rid the oceans of plastic.\u201dIn addition, the text for several equations is incorrect; Equation 6,\u201cshould read:\u201cThe text for Equation 7,\u201cshould read:\u201cThe text for Equation 8,\u201cshould read:\u201c"}
+{"text": "Nature Communications; 10.1038/s41467-018-07025-z; published online 7 November 2018Correction to: The original version of this Article contained an error in Fig.\u00a07. In panel c, the lanes of the western blots were incorrectly labelled \u2018+/+ +/+ \u2212/\u2212 \u2212/\u2212 +/+ +/+ \u2212/\u2212 \u2212/\u2212\u2019. This has been corrected in both the PDF and HTML versions of the Article."}
+{"text": "In the article titled \u201cInducible Conditional Vascular-Specific Overexpression of Peroxisome Proliferator-Activated Receptor Beta/Delta Leads to Rapid Cardiac Hypertrophy\u201d , there a"}
+{"text": "Scientific Reports 10.1038/s41598-018-35083-2, published online 16 November 2018Correction to: This Article contains a typographical error in the Results and Discussion section under subheading \u2018Identification and suggested fragmentation of verbascoside\u2019 where,29H35O15)\u2212 for VER [M-H]\u2212 structure whereas characteristic ion peak of the phenyl propanoid moiety recognized at m/z 161 [caffeic acid-H-H2O]\u2212 was due to loss of H2O from caffeic acid at m/z 179 [C9H7O4]\u2212 and the ion peak at m/z 461 represents [M-H-hexose sugar]\u2212 due to loss of a hexose sugar (\u2212162\u2009amu)25\u201327\u201d\u201cThe presence of molecular ion at m/z 623 (Cshould read:29H35O15)\u2212 for VER [M-H]\u2212 structure whereas characteristic ion peak of the phenyl propanoid moiety recognized at m/z 161 [caffeic acid-H-H2O]\u2212 was due to loss of H2O from caffeic acid at m/z 179 [C9H7O4]\u2212 and the ion peak at m/z 461 represents [M-H-Caffeoyl moiety]\u2212 due to loss of a Caffeoyl moiety (\u2212162\u2009amu)25\u201327\u201d\u201cThe presence of molecular ion at m/z 623 (CAdditionally, in Figure 3, the label on the peak is incorrectly labelled as \u201c[M-H-caffaeoyl-rhamnose]\u201d. The correct Figure 3 appears below as Figure"}
+{"text": "Scientific Reports 10.1038/s41598-017-11885-8, published online 14 September 2017Correction to: In the original version of this Article, all instances of \u201cTGF-\u03b21\u201d were incorrectly written as \u201cTGF-\u00e21\u201d.These errors have now been corrected in the HTML and PDF versions of the Article."}
+{"text": "Scientific Reports 10.1038/s41598-017-16730-6, published online 12 December 2017Correction to: The Article contains an error in Table 2. The heading:#\u201d\u201cGrade of allergic reaction at DBPCFCshould read:\u201cGrade of allergic reaction at OFC\u201d.Additionally, in Table 3, there are errors present in the \u201cCharacteristics\u201d column, where \u201c(IQR)\u201d is incorrectly labelled as \u201c(IRQ)\u201d"}
+{"text": "Figure In the article, \u201cParecoxib prevents early postoperative cognitive dysfunction in elderly patients undergoing total knee arthroplasty: A double-blind, randomized clinical consort study\u201d,"}
+{"text": "Wen-Yuan Ding should not appear as a corresponding author. The only corresponding author is Dr. Chun-Ming Zhao.In the article, \u201cAnterior cervical discectomy and fusion versus hybrid surgery in multilevel cervical spondylotic myelopathy: A meta-analysis\u201d,"}
+{"text": "Scientific Reports 10.1038/s41598-019-50686-z, published online 09 October 2019Correction to: This Article contains errors in Table 2 where the reported table heading was incorrect. The correct heading should read \u201cPredicted\\Actual\u201d."}
+{"text": "C. Roberto Simons-Linares appears incorrectly as Simons-Linares C. Roberto.In the article, \u201cAssociation between cannabis use and complications related to ulcerative colitis in hospitalized patients: A propensity matched retrospective cohort study\u201d,"}
+{"text": "Scientific Reports 10.1038/s41598-019-39748-4, published online 07 March 2019Correction to: The original version of this Article contained a repeated typographical error in the Abstract and Introduction where,Aedes aegpyti\u201d\u201cnow reads:Aedes aegypti\u201d\u201cThis error has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Syzygium cumini (L.) Skeels Leaf on Oxidative Stress-Induced Diabetic Rats\u201d [In the article titled \u201cProtective Effects of a Polyphenol-Rich Extract from ic Rats\u201d , the sec"}
+{"text": "Correction to:Translational Psychiatry10.1038/s41398-019-0538-y published online 20 August 2019In the original article, author Shouguo Gao\u2019s name was incorrectly stated as \u201cShuoguo Gao.\u201d This has been updated in the XML, HTML, and PDF versions of this article."}
+{"text": "In the article titled \u201cA Novel Curcumin-Galactomannoside Complex Delivery System Improves Hepatic Function Markers in Chronic Alcoholics: A Double-Blinded, randomized, Placebo-Controlled Study\u201d , the dos"}
+{"text": "In the article titled \u201cErbium-Based Perfusion Contrast Agent for Small-Animal Microvessel Imaging\u201d, there w"}
+{"text": "Correction to: CVIR Endovaschttps://doi.org/10.1186/s42155-018-0007-3In the published article (Zvavanjanja \u201cRetrospective anonymized and no patient photos therefore no institutional requirement.\u201dshould read:\u201cInformed consent for publication of this case report and its accompanying images has been obtained from the patient\u201d"}
+{"text": "In the article titled \u201cInhibitory Effects of Momordicine I on High-Glucose-Induced Cell Proliferation and Collagen Synthesis in Rat Cardiac Fibroblasts\u201d , there w"}
+{"text": "Correction to: British Journal of Cancer (2018) 119, 282\u2013290; 10.1038/s41416-018-0169-8; published online 11 July 2018.P-value columns which should have appeared below the heading \u2018Late sequelae independent of recurrent timepoint\u2018 have erroneously been listed under the \u2018Late sequelae before recurrence\u2018 heading. The correct format of Table\u00a0The authors have noticed in Table"}
+{"text": "In the article titled \u201cCombinatorial Cytotoxic Effects of Gelam Honey and 5-Fluorouracil against Human Adenocarcinoma Colon Cancer HT-29 Cells In Vitro\u201d , the nam"}
+{"text": "The corrected figure is shown below.In the article \u201cAnti-Interleukin-22-Neutralizing Antibody Attenuates Angiotensin II-Induced Cardiac Hypertrophy in Mice\u201d , there w"}
+{"text": "Results in the original paper  cannot bWeb of Science (WoS) includesWeb of Science Core CollectionData Citation IndexCurrent Contents Connect\u00ae Citation IndexBIOSIS\u00aeBiological AbstractsCABIChinese Science Citation DatabaseFSTA\u00aeInspec\u00aeMEDLINESciELO Citation Index\u00aeZoological RecordDerwent Innovations IndexJournal Citation ReportsEssential Science IndicatorsWeb of Science Core Collection includesScience Citation Index Expanded (SCI-EXPANDED)Social Sciences Citation Index (SSCI)Arts and Humanities Citation Index (A&HCI)Conference Proceedings Citation Index\u2014Science (CPCI-S)Conference Proceedings Citation Index\u2014Social Science & Humanities (CPCI-SSH)Book Citation Index\u2014Science (BKCI-S)Book Citation Index\u2014Social Sciences & Humanities (BKCI-SSH)Emerging Sources Citation Index (ESCI)Web of Science Core Collection: Chemical Indexes include:Current Chemical Reactions (CCR-EXPANDED)Index Chemicus (IC)http://wokinfo.com/products_tools/multidisciplinary/esci/). Web of Science Core Collection: chemical indexes as well as SSCI, A&HCI, ESCI, CPCI-S CPCI-SSH, BKCI-S, and BKCI-SSH are inappropriate for \u201cTrends and development in enteral nutrition application for ventilator associated pneumonia: a scientometric research study (1996\u20132018)\u201d  complements the highly selective indexes by providing earlier visibility for sources under evaluation as part of SCIE, SSCI, and A&HCI\u2019s rigorous journal selection process (6\u20132018)\u201d .One appropriate method is to use SCI-EXPANDED with searching keywords (\u201cventilator-associated pneumonia\u201d or \u201cventilator-acquired pneumonia\u201d) and  from 1996 to 2018. Language of \u201cEnglish\u201d and document type of \u201carticle\u201d were considered. This method resulted in 109 articles in SCI-EXPANDED. The SCI-EXPANDED is designed for researchers to find published literatures, not used for bibliometric studies .KeyWords Plus, were irrelevant to \u201centeral nutrition application for ventilator associated pneumonia\u201d   had search keywords in their \u201cfront page\u201d while 35 articles (32%) and 24 articles (22%) did not include (\u201cventilator-associated pneumonia\u201d or \u201cventilator-acquired pneumonia\u201d) and \u201centeral nutrition\u201d in their \u201cfront page,\u201d respectively. For example, highly cited review with 100 or more total citations from Web of Science Core Collection since publication to the end of 2017 (TC7 \u2265 100) , \u201cIncide7 \u2265 100) , did not7 \u2265 100)  did not 7 \u2265 100)  did not 7 \u2265 100) . Similar7 \u2265 100) , Renewab7 \u2265 100) , and Jou7 \u2265 100)  in previY-SH confirms being the sole contributor of this manuscript.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In the article titled \u201cYokukansan Alleviates Cancer Pain by Suppressing Matrix Metalloproteinase-9 in a Mouse Bone Metastasis Model\u201d , there w"}
+{"text": "Scientific Reports 10.1038/s41598-018-32907-z, published online 01 October 2018Correction to: The Acknowledgements section in this Article is incomplete.\u201cL. Freire acknowledges the financial support of S\u00e3o Paulo Research Foundation: Grant # 2016/21041-5, S\u00e3o Paulo Research Foundation (FAPESP). The authors acknowledge the Culture Collection of the Department of Food Science/CCDCA-UFLA for the donation of fungi strains used in this study. The authors are also thankful to Conselho Nacional de Desenvolvimento Cientifico e Tecnol\u00f3gico (CNPq) (Grant # 302763/2014-7). This study was financed in part by the Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior - Brasil (CAPES) - Finance Code 001\u201d.should read:\u201cL. Freire acknowledges the financial support of S\u00e3o Paulo Research Foundation: Grant # 2016/21041-5, S\u00e3o Paulo Research Foundation (FAPESP). The authors acknowledge the Culture Collection of the Department of Food Science/CCDCA-UFLA for the donation of fungi strains used in this study. The authors are also thankful to Conselho Nacional de Desenvolvimento Cientifico e Tecnol\u00f3gico (CNPq) (Grant # 302763/2014-7). This study was financed in part by the Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior - Brasil (CAPES) - Finance Code 001. ASS acknowledges the support of FAPESP (grant #2018/19341-6)\u201d."}
+{"text": "Scientific Reports 10.1038/s41598-019-41109-0, published online 18 March 2019Correction to: p-values recorded for the \u2018Daily average temperature column\u2019 are incorrectly placed under the \u2018Daily maximum temperature\u2019 column. The correct Table 4 appears below as Table\u00a0This Article contains an error in Table 4. The"}
+{"text": "There are typographical errors in the fourth and fifth sentences of the Abstract. \u201cIFN-\u03bc\u201d should appear as \u201cIFN-\u03b3.\u201d The correct sentences are: However, to confirm whether a multivalent vaccine can induce an individual epitope-specific CTL, the only viable screening strategies currently available are interferon-gamma (IFN-\u03b3 enzyme-linked immunospot (ELISPOT) assays using human peripheral blood mononuclear cells, or expensive human leukocyte antigen (HLA)-expressing mice. In this report, we evaluated the use of our developed murine-20S immunoproteasome (i20S) digestion assay and found that it could predict the results of IFN-\u03b3 ELISPOT assays.There is a typographical error in the Abbreviations. \u201cIFN-\u03bc\u039b, interferon-gamma\u201d should appear as \u201cIFN-\u03b3, interferon-gamma.\u201d"}
+{"text": "The following information is missing from the Funding statement: Dr. Zsuzsanna Izsv\u00e1k was funded by European Research Council-2011-ADG-TRANSPOSOstress\u2013 294742."}
+{"text": "Correction to: BMC Cardiovasc Disordhttps://doi.org/10.1186/s12872-019-1076-5\u2022 Originally published name:Ma\u0142gorzta Kabat\u2022 Corrected name:Ma\u0142gorzata KabatAfter publication of the original article , the aut"}
+{"text": "Nature Communications 10.1038/s41467-019-12499-6, published online 15 October 2019.Correction to: The original version of the published article had an error in the abstract, which originally stated \u201cyield a fourfold higher likelihood of epidemics\u201d. This has been corrected to \u201cyield a 1.63-fold higher likelihood of epidemics\u201d."}
+{"text": "Correction: BMC Med Res Methodol (2019) 19:129https://doi.org/10.1186/s12874-019-0754-4p-values pj are multiplied by the number of primary outcome\u201d in the Methods section, and should be deleted.In the original publication of this article , \u201c=1\u2009\u2212\u2009\u2009The original article has been corrected."}
+{"text": "Requests should be sent to pmimages@fas.harvard.edu.\u201d This article has been corrected.1In the Research Letter titled \u201cAtherosclerosis in 16th-Century Greenlandic Inuit Mummies,\u201d"}
+{"text": "In the article titled \u201cTotal Intravenous Anaesthesia with High-Dose Remifentanil Does Not Aggravate Postoperative Nausea and Vomiting and Pain, Compared with Low-Dose Remifentanil: A Double-Blind and Randomized Trial\u201d , there w"}
+{"text": "Correction to: Journal of Applied Genetics (2018) 59:281\u201328910.1007/s13353-018-0447-4This article was originally published electronically on 29 May 2018 with incorrect copyright line in the Publisher\u2019s internet portal (currently SpringerLink). The copyright line of the article should be \u201c\u00a9 The Author (s) 2018\u201d."}
+{"text": "Scientific Reports 10.1038/s41598-018-23978-z, published online 04 April 2018Correction to: This Article contains an error in the Results section under the subheading \u2018Performance comparison among call methods using simulation data\u2019.de novo assembly (Inchworm) did not work well (Table S3).\u201d\u201cWe found that when the insertions were \u22652\u2009bp length and contained repetitive sequence from the flanking region, should read:de novo assembly (Inchworm) did not work well (Table S3).\u201d\u201cWe found that when the insertions were \u226525\u2009bp length and contained repetitive sequence from the flanking region,"}
+{"text": "B, Correlation between rBAT-ASL and rTTP-DSC in all the 132 ROIs of lateral MCA territories and BG. rCBF-ASL\u200a=\u200arelative cerebral blood flow-arterial spin labeling, DSC\u200a=\u200adynamic susceptibility contrast, ROI\u200a=\u200aregion of interest, MCA\u200a=\u200amiddle cerebral artery, BG\u200a=\u200abasal ganglia.\u201dIn the article, \u201cComparative study of MR mTI-ASL and DSC-PWI in evaluating cerebral hemodynamics of patients with Moyamoya disease\u201d,"}
+{"text": "Correction to: BMC Pediatr (2019) 19:346https://doi.org/10.1186/s12887-019-1724-zAfter publication of the original article , it was Reference \u2018\u2019 (see reWhile reference \u2018\u2019 (see reThe authors apologize for any inconvenience caused."}
+{"text": "Nature Communications 10.1038/s41467-018-03942-1; published online 16 April 2018Correction to: In the originally published version of this article, the affiliation details for Hugo Mu\u00f1oz-Hern\u00e1ndez, Carlos F. Rodr\u00edguez and Oscar Llorca incorrectly omitted \u2018Centro de Investigaciones Biol\u00f3gicas (CIB), Spanish National Research Council (CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain\u2019. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Nature Communications 10.1038/s41467-018-03696-w; published online 10 April 2018Correction to: The original version of this Article contained an error in Equation (1), which incorrectly read \u201cThe correct version reads \u201c"}
+{"text": "Scientific Reports 10.1038/s41598-018-35347-x, published online 21 November 2018Correction to: The original version of this Article contained errors.Due to a typesetting error, Table\u00a0In addition, in Table 2 the headings \u201cWestern Mediterranean\u201d and \u201cEastern Mediterranean\u201d were reversed.These errors have now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Correction to: International Journal of Behavioral Nutrition and Physical Activity (2018) 15:126https://doi.org/10.1186/s12966-018-0756-3Following publication of the original article , the autreduced BMI over a 5-year period.\u201dIncorrect statement in published article: \u201cOn the other hand, a shorter time spent in MVPA predicted a increased BMI over a 5-year period.\u201dCorrected statement: \u201cOn the other hand, a shorter time spent in MVPA predicted an"}
+{"text": "Scientific Reports 10.1038/s41598-018-19671-w, published online 22 January 2018Correction to: This Article contains an error in Figure 3b where the blue bars for \u2018Th\u2019 are incorrectly marked as \u2018Tr\u2019. The correct Figure 3 appears below as Figure"}
+{"text": "In the article titled \u201cAre All Oral COX-2 Selective Inhibitors the Same? A Consideration of Celecoxib, Etoricoxib, and Diclofenac\u201d , there w"}
+{"text": "In the article titled \u201cSevere Drug-Induced Agranulocytosis Successfully Treated with Recombinant Human Granulocyte Colony-Stimulating Factor\u201d , the sec"}
+{"text": "Communications Biology 10.1038/s42003-019-0509-0, published online 11 July 2019.Correction to: \u201cAll reporter plasmids have a low-copy SC101 origin of replication with a kanamycin resistance cassette and a promoter transcriptionally controlling the gene for CFP.\u201d This has been corrected to: \u201cAll reporter plasmids have a kanamycin resistance cassette and a promoter transcriptionally controlling the gene for CFP.\u201dpurA, inaA, hdeA, \u03c370, acrAB, and sodA reporters use pBbS5k; all others use pBbE5k).\u201cthe vector was originally derived from the low-copy (SC101) vector pBbS5k.\u201d This has been corrected to: \u201cthe vector was either SC101 origin pBbS5k or ColE1 origin pBbE5k (In the original version of the article, the \u201cMethods\u201d section contained the following two incorrect statements:The errors have been corrected in the HTML and PDF versions."}
+{"text": "Correction to:Cell Death and Disease 9: 945;10.1038/s41419-018-1007-x;published online 20 September 2018The original version of this Article contained an error in the Abstract. \u201cPSA-NCAM positive neuroblastoma cells\u201d should have read \u201cPSA-NCAM positive neuroblasts\u201d. Similarly, in the first paragraph of the Discussion, \u201cthe number of neuroblastoma cells\u201d should have read \u201cthe number of neuroblasts\u201d.This has been corrected in both the PDF and HTML versions of the Article."}
+{"text": "The correct sentence is: For exogenous prostaglandin experiments, 10\u03bcM 16,16-dimethylprostaglandin EThere is an error in the"}
+{"text": "In the article titled \u201c6-Gingerol Protects Heart by Suppressing Myocardial Ischemia/Reperfusion Induced Inflammation via the PI3K/Akt-Dependent Mechanism in Rats\u201d , there w"}
+{"text": "In the article titled \u201cKnockdown of Sestrin2 Increases Lipopolysaccharide-Induced Oxidative Stress, Apoptosis, and Fibrotic Reactions in H9c2 Cells and Heart Tissues of Mice via an AMPK-Dependent Mechanism\u201d , the wes"}
+{"text": "Correction to: BMC Genomicshttps://doi.org/10.1186/s12864-018-5307-415 randomly chosen genes from those significantly enriched in the KEGG pathway.\u201dIn the Results section the sentence \u201cFurthermore, qRT-PCR analysis verified 18 randomly chosen genes from those significantly enriched in the KEGG pathway\u201d should be \u201cFurthermore, qRT-PCR analysis verified Fifteen DEGs from significant KEGG Pathway Classification Enrichment were randomly selected for qRT-PCR validation.\u201dIn Fig.\u00a04, caption (b) \u201cEighteen DEGs from significant KEGG Pathway Classification Enrichment were randomly selected for qRT-PCR validation\u201d should be \u201cb Fig.\u00a04b was duplicated as Fig.\u00a0Following the publication of this article , the aut"}
+{"text": "That link should be ht\u2217tp://links.lww.com/MD/C281.In the article, \u201cPrevalence of Depression in Patients With Hypertension: A Systematic Review and Meta-Analysis\u201d,"}
+{"text": "Scientific Reports 10.1038/s41598-018-30860-5, published online 17 August 2018Correction to: This Article contains errors in the Acknowledgements section.\u201cThis work was supported by Vietnam National Foundation for Science and Technology Development (NAFOSTED) [grant number \u201c104.06\u20132016.03\u201d (3/2017/104/H\u0110TN)].\u201dshould read:\u201cThis research is funded by Vietnam National Foundation for Science and Technology Development (NAFOSTED) under grant number 104.06\u20132016.03.\u201d"}
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+{"text": "Dear Editor,A 98-year-old male was referred complaining of a mass on his left cheek. He had never received immunosuppressive therapy. Physical examination showed a solid, dome-shaped, reddish tumor, 35\u202fmm in diameter, on his left cheek. Microscopic examination of a biopsy specimen revealed an infiltrative tumor in the dermis. The tumor was composed of sheets and trabeculae of atypical cells with scant cytoplasm, and round nuclei with stippled chromatin . Immunohvia the induction of regulatory T-cells, systemic immunosuppression may be an essential factor in the development of both conditions in a patient.Merkel cell carcinoma (MCC) is a rare cutaneous neuroendocrine cancer that is known to be a highly aggressive malignancy with frequent metastasis and a high mortality rate. A previous review article revealed increased risk of a second primary cancer after the diagnosis of MCC, and cutaneous malignant melanoma (MM) is one of the most common cancers after MCC.None declared.Masato Ishikawa: Drafting and editing of the manuscript; collection, analysis, and interpretation of data; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature.Toshiyuki Yamamoto: Approval of the final version of the manuscript; conception and planning of the study; critical review of the manuscript.None declared."}
+{"text": "Bioengineering on \u201cStem Cell Bioprocessing and Manufacturing\u201d addresses the central role in defining the engineering sciences of cell-based therapies by bringing together contributions from worldwide experts on stem cell science and engineering, bioreactor design and bioprocess development, scale-up, and the manufacturing of stem cell-based therapies.The next healthcare revolution will apply regenerative medicines using human cells and tissues. Regenerative medicine aims to create biological therapies or in vitro substitutes for the replacement or restoration of tissue function in vivo lost due to failure or disease. However, whilst science has revealed the biomedical potential of this approach, and early products have demonstrated the power of such therapies, there is a need for the development of bioprocess technology for the successful transfer of the laboratory-based practice of stem cell and tissue culture to the clinic as therapeutics through the application of engineering principles and practices. This Special Issue of In the last few years, human pluripotent stem cell (hPSC) derivatives have emerged as promising allogeneic cell therapy products, with amazing potential to treat a wide variety of diseases and a vast number of patients globally. Brian Lee and co-authors  addresseAmong the most promising hPSC derivatives, hepatic cell lineages represent a potential cell source, holding great potential for biomedical applications, such as in liver cell therapy, disease modelling, and drug discovery. Jo\u00e3o Cotovio and Tiago Fernandes  assessedAlongside the development of novel bioreactor configurations for cell therapy manufacturing, efforts have also been undertaken to optimize bioreactor operating conditions. In their study focused on the manufacturing of mesenchymal stem/stromal cell (MSC) therapies, Josephine Lembong and colleagues  developeAn additional key aspect towards the successful translation of cell therapy products is the need to use animal origin-free products -free) for the derivation, expansion, and differentiation of stem cells in order to minimize the risks of animal-transmitted diseases and immune reactions to foreign proteins. In this context, Valentin Jossen and colleagues  developeIn addition to the increasing demand for large-scale cell manufacturing protocols, there is a critical need to establish potency assays for stem cell therapy products and their derivatives. Katharina M. Prautsch and colleagues  developeExperimental culture conditions are critical for the ex vivo expansion and differentiation of stem cells. In fact, variables such as culture supplements, the purity of the initial cell population, the initial cell concentration, and the duration of culture affect the outcome of stem cell cultures and, consequently, the regenerative potential of ex vivo cultured stem cell-derived products. Sam L. Francis and co-authors  focused Finally, cell-delivery methods are a key part of regenerative medicine. The delivery of stem cells and their derivatives can be performed as scaffold-free products  or combined with polymer scaffolds. Traditionally, cells and biological agents are implanted into the matrix of the scaffold following electrospinning. The study performed by Nasim Nosoudi and colleagues  focused"}
+{"text": "In September 2017, Namibia\u2019s Ministry of Health and Social Services (MoHSS) identified an increase in cases of acute jaundice in Khomas region, which includes the capital city of Windhoek. Hepatitis E is a liver disease caused by hepatitis E virus, which is transmitted by the fecal-oral route, causing symptoms consistent with acute jaundice syndrome , development of effective communication strategies through a reformatted situation report, and supporting implementation of effective outbreak control and prevention measures.This is the third hepatitis E outbreak described in Namibia since 1983, the largest to date, and the first of nationwide scope ("}
+{"text": "Defining the role of nutrients in disease prevention and control has entered a renaissance because of both breakthroughs in studying the gut associated microbiome ,2 and deFrom the earliest pen strokes in their review, Gombart, Pierre, and Maggini appropriately remind the reader of the evidence that clinical deficiencies of specific micronutrients impair immune responsiveness . A classThe role of specific micronutrients and of various combinations are painstakingly documented in , althougFood-gut microbiome-immune system interactions are an unquestionable focus of the recently released National Institutes of Health (USA) Nutrition Research Strategy ,14. The A principal focus of the Gombart, Pierre, and Maggini review is directed to infectious diseases. While this is very appropriate, it must also be considered that 60% of deaths globally are due to chronic diseases in which the immune system, as well as the gut associated microbiome, play a significant role . Whether"}
+{"text": "The Role of the Lymphatic System in Lipid and Energy Metabolism, and Immune Homeostasis During Obesity and Diabetes\u201d summarizes the rapid development of the field of lymphatic vessel biology over the last two decades emphasizing its relevance to metabolism and metabolic dysregulated diseases. The Research Topic, available in Frontiers in Physiology\u2014Lipid and Fatty Acid Research, comprises 11 Reviews of the current literature, one Original Research Article, one Perspective, and one Hypothesis and Theory by experts in the field.The Research Topic \u201cXiao et al. discuss the emerging evidence that oral glucose and intestinal hormone glucagon-like peptide-2 (GLP-2) mobilize retained enteral lipid into the lymphatic system by two different mechanisms; (i) via glucose, by mobilizing cytoplasmic lipid droplets and (ii) via GLP-2, by targeting post-enterocyte secretory mechanisms. A second contribution by Zhou et al., discusses the importance of composition and properties  of the matrix in the lamina propria in regulating chylomicron diffusion and their entry in the lacteals. Zhou et al. provide insights into the activation of mucosal mast cells by fat absorption and the associated metabolic consequences highlighting the link between chylomicron transport, mucosal mast cell activation, leaky gut, and the microbiome. In the Hypothesis and Theory Article, Nauli and Matin discuss a potential mechanism related to higher accumulation of abdominal visceral fat in males as compared to pre-menopausal women. The authors propose that the accumulation of abdominal visceral fat in men, a strong independent predictor of mortality, is due to the higher dietary fat uptake by abdominal visceral fat. During the post-prandial state, the larger chylomicrons observed in males congest the lamina propria and the low-pressure lymphatics, predisposing the chylomicron triglycerides to hydrolysis by lipoprotein lipase. The liberated fatty acids are then stored by the nearby abdominal visceral adipocytes, leading to the accumulation of abdominal visceral fat. These mechanisms perhaps explain the reason of bigger and higher production of chylomicrons in males.The involvement of the lymphatic system in the transport and distribution of lipids has been known for centuries . Mouse models of obesity with defective lymphatic function are summarized in Norden and Kume.The link between the lymphatic system, metabolic dysfunction, inflammation, and the metabolic syndrome is not completely understood and likely to involve multiple mechanisms and different organs. A growing body of evidence suggest that dysfunctional lymphatic vasculature might promote obesity by impairing adipogenesis and promoting inflammation. This is somehow not surprising given the adipogenic properties of lymph  within the lymphatic function and progression of atherosclerosis. Another critical metabolic organ where lymphatic vessels are currently understudied is the liver. Burchill et al. review the inherent difficulties of using lymphatic markers to identify lymphatic vessels in the liver, where hepatic cells express many of the same proteins. The focus of the review, however, is summarizing newly identified roles for lymphatic endothelium in non-alcoholic steatohepatitis and hepatitis C infection.The Research Topic reviews the contribution of lymphatic biology in metabolically dysregulated diseases, including type 2 diabetes, atherosclerosis, myocardial infarction, and chronic liver disease. Zhang et al. provide a comprehensive review of the molecular regulation of LEC junctions during development, and diseases namely obesity and inflammation-associated conditions. The authors provide a comprehensive summary of lymphatic vascular phenotypes following genetic deletion of junctional proteins.Lymphatic endothelial cell (LEC) junctions are crucial for the maintenance of vessel integrity and proper lymphatic vascular function. Pawlak and Caron. The authors review five highly specialized hybrid vessel beds that adopt partial lymphatic programing for their specialized vascular functions namely (i) the high endothelial venules of secondary lymphoid organs, (ii) the liver sinusoid, (iii) the Schlemm's canal of the eye, (iv) the renal ascending vasa recta, and (v) the remodeled placental spiral artery. The authors summarize the morphology and endothelial expression pattern of these vessels and interrogate their specialized functions within the broader blood and lymphatic vascular systems (Pawlak and Caron). Finally, Azhar et al. discuss the current knowledge on the pathophysiology of lymphedema, a chronic and progressive disease arising from impaired lymphatic drainage, which causes accumulation of interstitial fluid and results in tissue swelling (Rockson, Vascular diversity and endothelial plasticity are reviewed by Rockson, . AuthorsIn conclusion, our understanding of the regulation of the lymphatic system in contributing to tissue remodeling, inflammation, and metabolic outcome during disease has greatly improved in the last two decades. However, more translational studies are needed to pave the way for novel therapeutic approaches to treat metabolically dysregulated diseases, including type 2 diabetes, atherosclerosis, myocardial infarction, and chronic liver disease, as well as lymphedema and lipedema.All authors wrote and revised the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The deformation and cracking of concrete will lead to various deterioration processes, which will greatly reduce the durability and service life of the concrete pavement. The relating previous studies and analysis revealed that the coupling action of environmental temperature, moisture, and wheel load will cause cracking and seriously affect the normal service and durability of pavement concrete. This paper presents theoretical and numerical state-of-the-art information in the field of deformation and failure of pavement concrete under coupling action of moisture, temperature, and wheel load and draws some conclusions. (a) Concrete is a typical porous material, moisture and heat transfer theory has obtained enough data to simulate the hygro-thermo properties of concrete, and the relationship between moisture and heat is very clear. (b) There are few studies on concrete pavement or airport pavement considering the coupling action of moisture, temperature, and wheel load. (c) Concrete pavement is subjected to hygro-thermal-mechanical coupling action in service, which has the characteristics of a similar period and its possible fatigue effect. (d) COMSOL software has certain advantages for solving the coupled hygro-thermal-mechanical of concrete. Cement concrete pavement is widely used in the construction of the airport runway and high-grade highway in China. More than 80% of the airport pavement in China adopts cement concrete . For pavThis paper will start from the coupling action of moisture, temperature, and wheel load that affects the deformation and failure of concrete pavement in the service life. The basic model of the multi-physical fields of concrete, research on the fatigue effect of concrete pavement, research on the deformation and failure of concrete pavement or airport pavement (except for concrete pavement or airport pavement), and the numerical simulation method of hygro-thermal-mechanical coupling deformation of concrete are discussed. This paper will provide new research ideas for the study of concrete deformation and failure of the pavement.Concrete is a typical porous medium material ,6, and iGenerally, it is assumed that the moisture transfer in porous cement-based materials is in the form of diffusion, and the humidity gradient is the driving force of humidity (liquid water and steam). According to Fick\u2019s law and mass conservation equation, the one-dimensional transmission formula is as follows :(1)\u2202\u2202x is as follows :(2). The rheological model is shown in In the formula, the For the pavement in the area with significant temperature and humidity changes, frequent takeoff and landing of aircraft or airport runway of large military multi-wheel aircraft, heavy load and frequent traffic, the pavement is more prone to deformation and damage. The problem of deformation and cracking of airport runway, highway, and urban road pavement has not been well solved because the influence factors of pavement concrete deformation and failure are not fully considered in the design stage. The above factors include temperature change, dry and wet change, and dynamic and static action of wheel load and its coupling effect. The research on the fatigue effect of airport concrete is mainly as follows: large scale airfield concrete slabs were tested by Jeffery R. Roesler  in the lIn the related research on deformation and failure of airport pavement or cement concrete pavement, many researchers mainly focus on the influence of temperature, fatigue load and freeze-thaw, temperature and humidity changes on the shrinkage, and cracking of pavement concrete ,30,31,32Seongcheol. Choi  et al. sMany Chinese researchers have carried out research on warpage stress. In recent years, there have been studies considering the joint effect of temperature effect and wheel load stress. Tan Zhiming et al.  earlier A 3D finite element model was established for analyzing the mechanical responses of cement concrete airport pavement to multiple-gear military aircraft loadings. The test results showed that the maximum tensile stress in the pavement occurred at the bottom of the slab, the tensile stress and the deformation of the pavement under two 8-wheeled gears were smaller than that under one 8-wheeled gear. The elasticity modulus of the slab, the resilience modulus of the base and the reaction modulus of the subgrade all had significant effects on the mechanical responses of the pavement.Zheng Fei and Weng Xingzhong  analyzedThe research on the hygro-thermal-mechanical coupling action analysis was previously in the field of rock engineering and had always been a research hotspot ,54. The In the research of the numerical simulation method of hygro-thermal-mechanical coupling deformation of concrete, there are four main numerical simulation methods:This method does not involve the internal heat and mass transfer mechanism and specific processes of the porous media, but only considers the relationship and cross effect between various flows and forces of heat and mass transfer. A phenomenological equation can be obtained to describe various flows. Phenomenological methods are difficult to apply in practice due to the influence of test conditions and many material parameters. Due to the lack of effective means and methods for testing moisture distribution, the moisture migration rate is slower than the thermal migration rate. In the process of solving various models, the values of some coefficients are basically based on experimental or empirical data, which affects the versatility of this method.This method considers the heat absorption or exotherm in the process of heat and mass transfer, and establishes a partial differential equation system based on the principles of mass conservation and energy conservation in the process of moisture migration. The method of numerical analysis is used to solve the equations to obtain the analytical solutions of the heat, humidity fields, and their dynamic changes ,73,74,75The finite element method is the most widely used numerical calculation method in scientific research and has become the main tool for solving scientific and technological problems. At present, many commercial finite element softwares have been developed, such as ANSYS, MSC, ADINA, ABAQUS, etc. In the finite element analysis method, the model should be established first, and then solved by self-programming ,58,63,81The analysis method of COMSOL multi-physical field coupling calculation software ,70,86 waThe studies of the coupled hygro-thermo-mechanical behavior of concrete pavement have been reviewed in this paper. The various aspects on the deformation and failure of concrete pavement under coupling action of moisture, temperature and wheel load presented in this paper could be summarized and concluded as:1. Concrete is a typical porous material, moisture and heat transfer theory had been obtained enough data to simulate the hygro-thermo-mechanical properties of concrete, and the relationship between moisture and heat is very clear.2. There has been some research on the moisture-heat-mechanical coupling of concrete materials, but most of the research focused on the performance of concrete in fire or high temperature. There are few studies on the moisture-heat-mechanical coupling deformation of concrete under normal service conditions.3. In the related research on deformation and failure of airport pavement or cement concrete pavement, many researchers mainly focused on the influence of temperature, fatigue load and freeze-thaw, and temperature and humidity changes, which lead to the shrinkage and cracking of pavement concrete. There are few kinds of literature considering the coupling action of moisture, temperature, and wheel load at the same time.4. Concrete pavement is subjected to hygro-thermal-mechanical coupled action in service, which has the characteristics of a similar period and its possible fatigue effect. In the existing moisture-heat-mechanical coupling research, the research on \u201cforce\u201d is mostly the load of a certain stress level continuously applied, but not enough attention is paid to the periodicity of wheel load and the change of temperature and humidity.5. COMSOL software has certain advantages for solving the coupled hygro-thermal-mechanical of concrete.In the later research, the deformation and failure mechanism of pavement concrete under the coupling action of moisture, temperature, and wheel load need to be studied."}
+{"text": "Since its discovery in 1997, the default mode network (DMN) and its components have been extensively studied in both healthy individuals and psychiatric patients. Several studies have investigated possible DMN alterations in specific mental conditions such as bipolar disorder (BD). In this review, we describe current evidence from resting-state functional magnetic resonance imaging studies with the aim to understand possible changes in the functioning of the DMN in BD. Overall, several types of analyses including seed-based and independent component have been conducted on heterogeneous groups of patients highlighting different results. Despite the differences, findings seem to indicate that BD is associated with alterations in both frontal and posterior DMN structures, mainly in the prefrontal, posterior cingulate and inferior parietal cortices. We conclude this review by suggesting possible future research directions. To date, however, neurobiological underpinnings of the disorder are still discussed, hindering the development of new pharmacological therapies and targeted rehabilitative interventions. Findings on brain structure in BD suggest ventricular, prefrontal and temporal abnormalities but remain largely inconsistent . Particularly, rs-fMRI is used to evaluate the functional interactions among remote neural systems that occur in a resting or task-negative condition, i.e. when an explicit task is not being performed. This technique provides information about intrinsic brain activity, not dependent on specific tasks or experimental settings. Most commonly, the brain functional connectivity (FC) at rest is studied by analysing the statistical dependencies among the blood oxygenation level-dependent (BOLD) signals from multiple brain regions, which reflect the spontaneous fluctuations in the oxygenation state of blood  within them  seed-based analyses (SBA), which require a-priori definition of the brain network nodes, (2) blind-source separation techniques, which adopt an unbiased approach by grouping brain voxels/regions based on their latent time series   the Salience Network (SN), composed of the ACC and the insula; (ii) the central-executive network (CEN) consisting of fronto-parietal regions and the posterior parietal cortex; (iii) the fronto-parietal network (FPN) that includes the cortex surrounding the intraparietal sulcus, the inferior parietal lobe, the dorsal motor cortex and the inferior frontal cortex; and (iv) the default-mode network (DMN) extending from the prefrontal medial cortex (mPFC) to the precuneus, posterior cingulate cortex (PCC) and inferior parietal cortex. The DMN is recognised as a key component of the brain functional architecture. The vmPFC composes the anterior part of the DMN and has been shown to modulate social behaviour, mood regulation, executive functioning and control processes  original publication in a peer-reviewed journal between 2010 and 2020, (ii) English language, (iii) a diagnosis of BD for the patient groups and (iv) the analysis of the DMN activity patterns through rs-fMRI. After an initial screening 71 studies were identified of which 23 studies were included in the review.et al., et al., et al., et al., et al., et al., et al., et al., Overall, findings from the reviewed studies suggest that BD patients compared to Healthy Controls (HC) are characterised by marked functional alterations of both anterior and posterior hubs of the DMN, including the PFC, PCC, precuneus and inferior parietal cortex. These alterations are mostly mixed across studies, consisting of both hypo and hyper-connectivity of the anterior DMN at rest .et al., et al., et al., et al., et al., et al., et al., et al., et al., v. HC, possibly indicating specificity of the PCC alterations for the psychotic conditions  showed aberrant functional activity in the posterior hubs of the DMN, of which five in the precuneus (21%) and 12 in the PCC (52%). These alterations are mostly hypo-activations of BD patients when compared with HC. Specifically, most of the studies showed FC reductions in BD compared to HC within these regions  suggesting a possible relationship between the two regions  without any history of medication. The authors suggest that the absence of alterations within the DMN may be due to specificity of the recruited group  or on the absence of medication.Only two studies found no alterations in the DMN of BD patients , different BD populations  or the lack of control for confounders  that may have influenced the results  compared to HC in both frontal and posterior hubs of the DMN. In particular, the evidence to date suggests that BD patients compared to HC have altered FC of the DMN in a number of regions including the PFC, the ACC and PCC and the precuneus. However, only a paucity of studies has been conducted and evidence is still sparse. The inconsistency of findings may be due (in part) to methodological issues such as heterogeneous analysis pipelines  can account for the complex dynamics in the interactions between brain regions as suggested by some studies  investigate the complex link between structure and function in the DMN and other networks involved in BD pathophysiology, (2) identify neurodevelopmental and maturation trajectories of FC patterns in relation to the natural course of the disease and in response to different therapeutic strategies, (3) disentangle the contributions of genetics, environment and their interaction to the large-scale functional brain network abnormalities underlying BD symptomatology.The data that support the findings of this study (search query) are available on request from the corresponding author."}
+{"text": "The Industrial Internet of Things  is the emerging core backbone construct for the various cyber-physical systems constituting one of the principal dimensions of the 4th Industrial Revolution. While initially born as a concept inside specific industrial applications of the generic IoT technologies, for the optimization of the operational efficiency in automation and control, it quickly became the vehicle for the achievement of the total convergence of Operational Technologies (OT) with Information Technologies (IT). Today, it is already breaking the traditional borders of automation and control functions in the process and manufacturing industry, towards a wider domain of functions and industries, embraced under the dominant, global initiatives and architectural frameworks of Industry 4.0 (or Industrie 4.0) in Germany, Industrial Internet in the US, Society 5.0 in Japan, and Made-in-China 2025 in China. As real-time embedded systems are quickly achieving ubiquity in people\u2019s everyday life and in industrial environments, and many processes already depend on real-time cyber-physical systems and embedded sensors, IoT integration with cognitive computing and real-time data exchanges is essential for real-time analytics and realization of digital twins in smart environments and services under the various frameworks\u2019 provisions ,2. In thThe ten articles in this Special Issue provide advances of real-time sensor networks and systems that are significant enablers of the Industrial IoT paradigm. In the relevant landscape, the wireless networking technologies domain is centrally positioned, as expected. Seferagi\u0107 et al. comparatively discuss various alternatives for the engineering and deployment of industrial wireless sensor and actuator networks (IWSAN) in . In thisSeveral articles in this Special Issue address important industrial IoT security and infrastructure protection issues. Tedeschi et al. analyze the integration of modern IoT and legacy industrial equipment for real-time machine condition monitoring applications, and the resulting security challenges in . The autThe real-time performance of the evolving IIoT networks and systems is increasingly considered among the major IIoT challenges, together with energy efficiency, security, and interoperability . Coming For all these reasons, we expect that the pressure for solutions will be increased with the upcoming penetration of 5G  and the"}
+{"text": "The importance of teamwork to improve the quality of care and overcome the complexity of health system is clear to everyone. Therefore the current study aimed to review the studies in the field of team-work assessment in hospital and pre-hospital emergency.In this review study, scientific texts with the key-words of teamwork, paramedic, emergency medical technician, emergency department and inter-professional practice were searched in Google scholar, PubMed, scientific information database(SID), and Magiran.Several studies have been found on the training and evaluation of teamwork in different parts, particularly in the treatment section. The results show that training and promotion of teamwork in health care lead to better performance and results, reducing clinical errors and reducing patient long length of stay In wards especially in the emergency department. Studies indicate that organizational support and teamwork training has the greatest impact in teamwork facilitate. In the pre-hospital emergency, there was a wide variety of teammates and less familiarity with teammates in EMS is associated with more occupational injuries. According to the aid team of pre-hospital emergency and their interaction with the hospital emergency department and other relief teams, training and evaluation of teamwork is important in EMS. However, there are few studies on teamwork in pre-hospital emergency especially in Iran. According to the importance of pre-hospital emergency mission, it is necessary to pay attention to teamwork in the emergency training curriculum and evaluation of teamwork in pre-hospital EMT. Teamwork, Pre-hospital, Emergency, Medical technician"}
+{"text": "This paper presents a comparative analysis of the gross regional products (GRPs) of 85 Russian regions. Statistical methods were used to analyze datasets on regional GRP, its sectoral composition and growth rates. Many datasets have been computed for the first time, including those of gross value added per capita and per employee. The work reviews a range of evidence on the contribution of the production of goods and market and non-market services to regional GRPs. The production of goods was further analyzed by economic sectors for each region. The data used in computations were provided by the Russian Federal State Statistics Service (ROSSTAT). The authors built a typology of Russian regions based on GRP figures, GRP sectoral composition and growth rates. The data obtained make it possible to determine a set of indicators of the geographical distribution of Russia's economy and its growth rates. The findings are presented in the form of tables, maps and graphic materials , displaying quantitative measures of the economic performance of Russian regions . In this work, we performed a comparative analysis of GRP output, GRP sectoral composition and growth rates of 85 Russian regions. These indicators have been extensively analyzed in economic literature. Many authors have built their typologies of regions based on GRP per capita This work presents a comprehensive large-scale assessment of the gross regional products of 85 Russian regions. The computations characterize the level of economic development of different parts of the country: GRP measures the value of goods and services produced in a region; GRP per capita reflects the economic output of a region and the standard of living; the ratio of different economic sectors defines the sectoral composition of regional economies. Special attention was paid to the analysis of datasets for the production of goods, market and non-market services.The sectoral composition of GRP was analyzed using two datasets \u2013 on GRP per capita and GRP growth rates. This makes it possible to evaluate the economic performance of individual sectors of the regional economy and to measure labor productivity and economic growth rates.Cartographic representation of GRP helps reveal similarities and disparities in regional economic development.1)GRP per capita and employee \u2013 gross value added per sector (per type of economic activity);2)GRP sectoral composition of consolidated groups of economic activity  \u2013 the production of goods per economic sector3)GRP growth rates - GRP per capita.Types and subtypes of regions were identified based on the following coupled indicators:The initial and computed statistical data are presented in three tables, two diagrams and 10 cartographic maps for all 85 regions of the Russian Federation. They illustrate GRP figures and sectoral composition in 2018 and the growth rates of GRP per capita during two periods \u2013 2004\u20132018 and 2013\u20132018.The economic differentiation of Russian regions is analyzed according to 30 indicators.The aggregated GRP and social indicators datasets on Russian regions are available in spreadsheets (Annex 1).The aggregated GRP per economic sectors in 2018 datasets on Russian regions are available in separate spreadsheets (Annex 2).Annex 3 contains tables presenting groups of Russian regions formed according to the chosen indicators see , Fig. 14Regions of the Russian Federation differ greatly in size, natural resources, the number and replacement rate of the population, GRP figures and other socio-economic indicators. For instance, Sevastopol, a city of federal importance, (territory \u2013 0.9 thousand sq. km) is 3.4 thousand times smaller than the Republic of Sakha (Yakutia) (3083.5 thousand sq. km). The population of the Nenets autonomous region  is 288 times smaller than that of Moscow . In 2018, the GRP of the Republic of Altai amounted to 51 billion rubles, whereas that of Moscow to 17 882 billion rubles, which is 351 times as much. In 2018, the highest average annual growth rate of GRP per capita as compared to 2013 was 6.5% , and the largest decrease was -2.0% in the Republic of North Ossetia-Alania.The GRP of Moscow is four times that of the Khanty-Mansi autonomous region, which is the second-largest oil-producing region in Russia. The Moscow region (forming a single agglomeration with the city of Moscow) and St. Petersburg, which is often referred to as the second or cultural capital of the Russian Federation , have almost reached the GRP of Moscow.The data in We established correlations between GRP per capita of Russian regions and some other socio-economic indicators. The coefficient of linear correlation of GRP per capita with urban population figures and population density is extremely small \u2013 0.25 and 0.08 respectively.Although many highly urbanized regions of Central Russia and the Volga region have rather low GRP per capita, the Moscow agglomeration boasting a very high level of urbanization is the social and economic nucleus of the country. The St. Petersburg agglomeration also plays an important role.The correlation between these two indicators is rather low: the linear correlation coefficient is 0.14. As Of all federal districts of Russia, only the regions of the Far East saw an increase in GRP per capita.In the Siberian Federal District, GRP per capita decreased in the analyzed period. The decrease was particularly dramatic in the Republic of Buryatia (7%), which had already had very low per capita figures. In the Ural Federal District, there are two territories, the Tyumen Oblast and the Khanty-Mansi autonomous region, which belong to regions with high GRP per capita.Two regions in the Southern Federal District and three in the North Caucasus  also have declining GRP figures. At least one region saw a decline in GRP per capita in the Central, Northwestern and Volga Federal Districts.Further research requires analysis of the GRP sectoral composition. The main Russian oil and gas regions have the largest share of the production of goods in their GRP structure: the Nenets (88.4%), Khanty-Mansi (83.4%) and Yamal-Nenets autonomous regions (82.7%) and Sakhalin (80.4%) , St. Petersburg (54%) and the Moscow (53%), Primorye (52%) and Novosibirsk (51%) regions. The highest percentage of non-market services (33%\u201350%) is typical of Russia's national republics \u2013 Ingushetia (50%), Chechnya, North Ossetia-Alania, the Karachay-Cherkess Republic in the North Caucasus, Altai, Tyva, Buryatia in southern Siberia, as well as of cities of national importance (Sevastopol). This can be explained by a weaker development of the other two sectors \u2013 the production of goods and market services.The Belgorod region, located in the Chernozem zone of Russia, has fertile soils and is well developed industrially. The region has the highest value added both per capita and per employee. Other regions of the Chernozem zone \u2013 Orlov, Kursk, Lipetsk, Voronezh, Tambov and Bryansk (the latter belongs to the Non-Chernozem zone and has intensive farming) are catching up.Regions of the North Caucasus , Volga regions  and the Novgorod region are characterized by a relatively high GRP per capita. High per capita figures of some coastal regions  can be attributed to the development of fishing and fish farming. The Primorye region also has highly developed forestry and logging. Many northern and eastern regions having relatively high gross value added figures  employ more people in forestry and logging than in agriculture. Territories with the least favorable natural conditions have poorly developed agriculture. These are the Arctic coastal regions of Siberia and the Far East, regions bordering Mongolia and the regions of the Northern Urals. Crimea and some regions of the Middle Volga region, Central and North-West of the European part of Russia have low value added figures.The highest value added per capita (over 1 million rubles) and per employee (over 10 million rubles) was registered in the main oil and gas regions \u2013 Sakhalin region and the Khanty-Mansi and Yamal-Nenets autonomous regions. The Republic of Sakha (Yakutia) and the Chukotka autonomous region have high value added per capita ranging from 500 thousand to 1 million rubles, and per employee \u2013 from 5 million to 20 million rubles. All these regions, except the Nenets autonomous region, are located in Siberia and the Far East. In the Krasnoyarsk (Eastern Siberia) and Magadan regions (Far East), the Orenburg region , the Komi Republic (North-West) and the Astrakhan region , value added per capita and per employee exceeds 200,000 rubles and 5 million rubles respectively. Central Russia (except the Belgorod region), the southern part of Russia's north-west, the east of the Volga region, North Caucasus and some southern regions of Western Siberia have the lowest per capita and employee figures.The manufacturing industry of Russia employs 14% of the working population. A higher percentage is observed only in trade and the repair and maintenance of motor vehicles and motorcycles (19%). The most developed manufacturing regions having high gross value added per capita and per employee are located in Central Russia and in the south of Russia's north-west, the Middle Volga region, in the Urals, as well as in the eastern regions of the country \u2013 primarily in the Krasnoyarsk region and the Tyumen region see . Most eaNorthern and eastern regions take the lead in the production of electric energy, gas, steam and air conditioning. This can be attributed to severe climatic conditions, which require considerable investment in the production of electric energy and heat for industrial and household needs . There aWater supply, wastewater treatment, waste collection and disposal and pollution elimination are most developed in the northern regions of Russia having cold climate \u2013 in the Republic of Sakha (Yakutia), the Murmansk region, the Yamal-Nenets and Chukotka autonomous regions) and in the most economically developed and highly urbanized regions . These industries are the least developed in the republics of North Caucasus, southern Siberia and the Far East .In construction and the production of goods, value added per capita differs from region to region . There iMoscow, the Republic of Tatarstan, and the Leningrad region have the highest indicators among industrially developed regions.Among market services, the share of trade and repair of motor vehicles and motorcycles in the GRP sectoral composition is 44%; that of transportation and storage, 17%. The development of these sectors largely determines the value added per capita and per employee, which is the highest (as is the case for the production of goods) in the two capital cities, Moscow and St. Petersburg, and in the main oil and gas regions, the Nenets, Khanty-Mansi and Yamal-Nenets autonomous regions  was used to form 13 groups within the 85 regions. Subdivision into subgroups was done by means of expert evaluation.The proposed classification of regions can be used for comparative analysis of the geographical distribution of economic centers in Russia and the assessment of Russia's economy.2Regions of Russia reference book. These data were used for computing average values of GRP per capita and per employee as well as chain indices of GRP growth rates. Coefficients of linear correlation between GRP and its growth rates, on the one hand, and other socio-economic characteristics of regions, on the other, were also calculated.Statistical data were obtained from the EMISS database of the Federal State Statistics Service of Russia and the The data obtained are presented in three tables, three charts and 11 cartographic maps displaying quantitative indicators.http://dx.doi.org/10.17632/n36vrd8zrp.1Transparency data associated with this article can be found in the online version at The authors declare no competing interests."}
+{"text": "This review focuses on different inflammation models established in zebrafish, and how they are being used for the development of novel anti-inflammatory drugs. The most commonly used model is the tail fin amputation model, in which part of the tail fin of a zebrafish larva is clipped. This model has been used to study fundamental aspects of the inflammatory response, like the role of specific signaling pathways, the migration of leukocytes, and the interaction between different immune cells, and has also been used to screen libraries of natural compounds, approved drugs, and well-characterized pathway inhibitors. In other models the inflammation is induced by chemical treatment, such as lipopolysaccharide (LPS), leukotriene B4 (LTB4), and copper, and some chemical-induced models, such as treatment with trinitrobenzene sulfonic acid (TNBS), specifically model inflammation in the gastro-intestinal tract. Two mutant zebrafish lines, carrying a mutation in the hepatocyte growth factor activator inhibitor 1a gene (hai1a) and the cdp-diacylglycerolinositol 3-phosphatidyltransferase (cdipt) gene, show an inflammatory phenotype, and they provide interesting model systems for studying inflammation. These zebrafish inflammation models are often used to study the anti-inflammatory effects of glucocorticoids, to increase our understanding of the mechanism of action of this class of drugs and to develop novel glucocorticoid drugs. In this review, an overview is provided of the available inflammation models in zebrafish, and how they are used to unravel molecular mechanisms underlying the inflammatory response and to screen for novel anti-inflammatory drugs.Dysregulation of the inflammatory response in humans can lead to various inflammatory diseases, like asthma and rheumatoid arthritis. The innate branch of the immune system, including macrophage and neutrophil functions, plays a critical role in all inflammatory diseases. This part of the immune system is well-conserved between humans and the zebrafish, which has emerged as a powerful animal model for inflammation, because it offers the possibility to image and study inflammatory responses  When the body encounters harmful stimuli, such as invading pathogens, wounding or damaged cells, the immune system will be activated and an inflammatory response is triggered ] and non-steroidal anti-inflammatory drugs  as a research model started in the 1950s and it was initially applied for studying embryonic development , for which guidelines have been published by the Organization for Economic Co-operation and Development . In addiFigure 2 for a schematic overview of these different methods), and we discuss how they are used for studies on the molecular mechanisms underlying the inflammatory response as well as for research aiming at the development of novel anti-inflammatory drugs, in particular novel GC drugs.The immune system of zebrafish is highly similar to that of humans. The innate branch of the immune system matures first during zebrafish development, and macrophages can be observed from 15 h post-fertilization (hpf)   promoter  ] gradient from the wounded site, through local activation of the epithelial NADPH oxidase Duox  was found to mediate migration by inducing actin polymerization and generating membrane protrusions at the leading edge through Rac activation and polarization of F-actin dynamics (in a Rac-independent way), which is required for actomyosin-mediated tail contraction  reporter line, similar to the differentiation processes that are observed in mammalian macrophages , and results in an increased expression of pro-inflammatory molecules like tnfa, il1b, il6, and il8   is known to be a potent chemoattractant for neutrophils in mammalian systems  resulted in impairment of the fin regeneration, and the presence of large vacuoles in the regenerated tissue  resulted in suppression of neutrophil apoptosis and reduced the level of inflammation in zebrafish larvae.In order to find new anti-inflammatory drugs from collections of existing or clinically approved drugs       and cytokines  -38, known to be an anti-apoptotic and anti-inflammatory factor, was reported to inhibit neutrophil migration toward the neuromasts and expression of pro-inflammatory genes (Leukotriene B4 (LTB4) is an eicosanoid released by leukocytes, acting as a pro-inflammatory mediator and enhancing leukocyte accumulation at sites of inflammation   represents a group of intestinal disorders that are characterized by inflammation of the digestive tract Hanauer, . IBD is il1b, tnfa, mmp9, ccl20, and il8 was observed upon TNBS treatment  has also been utilized to induce intestinal inflammation. This treatment recapitulates several aspects of TNBS-induced enterocolitis, inducing symptoms such as elevated expression of pro-inflammatory genes and neutrophil recruitment around the intestine , and was shown to result from soy saponin and not soy protein   and decreased the relative number of Firmicutes (Lactobacillus group) in the composition of the larval microbiota, and these changes correlated with the severity of the enterocolitis  anti-inflammatory and antibiotic drug treatments which ameliorated the response to TNBS   played a critical role. Morpholino knockdown of mmp9 partially rescued the abnormal epithelial phenotype as well as the neutrophilic infiltration of the epithelium, and restored the organization of collagen fibers.To identify genes with essential functions during zebrafish skin development, a screen of mutants generated by insertional mutagenesis was performed  gene was identified  axis, the fish equivalent of the HPA axis (Wendelaar Bonga, irg1l, thereby inhibiting the ROS production which is important for leukocyte migration (Hall et al., il8, tnfa, and il1b and reduced the recruitment of leukocytes toward the wounded area (Kyritsis et al., Upon tail amputation in embryos, treatment with several synthetic GCs has been shown to inhibit the migration of neutrophils toward the wounded site in a Gr-dependent manner. However, GCs leave the migration of macrophages unaffected in most studies (Mathew et al., 4 immersion of larvae, GCs also caused inhibition of neutrophil accumulation (d'Alen\u00e7on et al., In the LPS-induced inflammation model, GC administration was reported to inhibit the production of ROS and NO, the expression of pro-inflammatory genes, the recruitment of leukocytes, and the mortality (Wijesinghe et al., The clinical use of GCs is severely limited by the severity of their side effects, which include diabetes and obesity, osteoporosis, and impaired wound healing. Interestingly, these effects have been modeled in zebrafish as well, opening up the possibility to evaluate both the therapeutic anti-inflammatory effect and the adverse effects. GC effects on metabolism, including increased glucose concentrations, were observed in zebrafish embryos and the global transcriptional changes underlying these effects have been characterized (Chatzopoulou et al., in vivo, mainly due to the small size and transparency of zebrafish larvae. The similarities of the immune system and inflammatory responses between zebrafish and mammals guarantee good translational value.The use of animal models is a critical part of biomedical research and crucial for the development of novel drugs. A wide range of human disease models have been established in mammalian models such as rats and mice, which have largely contributed to the remarkable progress in our understanding of the mechanisms underlying these diseases and the development of novel therapies. However, the rodent systems have limitations such as the high cost of housing and breeding and they are not suited for large-scale automated screening. The development of the zebrafish animal model in the past decades has added a complementary system, which allows the performance of automated high through-put screening 2O2 gradient is created during the onset of an inflammatory response which signals to leukocytes in the tissues (Niethammer et al., in vitro assays and rodent experiments with great potential to accelerate the preclinical phase of anti-inflammatory drug development.In order to model inflammatory diseases, three types of inflammation models have been developed in zebrafish: wounding-, chemical-, and mutation-induced inflammation. These models have enabled a detailed investigation of the cellular and molecular mechanisms underlying the inflammatory response, adding to our knowledge of the mechanisms of leukocyte behavior and the identification of potential drug targets. For example, using the zebrafish model, it was observed for the first time that a tissue-scale HAM and MS: conceptualization, resources, and supervisions. YX, AM, and MS: methodology and writing\u2013review & editing. YX: investigation and funding acquisition. YX and MS: data curation and writing\u2013original draft. MS: project administration. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Internet of Things (IoT), or Industry 4.0, represents a smart shift to more interconnected manufacturing processes where individual entities within the supply chain communicate with each other to achieve greater flexibility and responsiveness in general manufacturing and leaner manufacturing to reduce the cost of production. IoT has become instrumental in driving leaner manufacturing and more efficient systems in other industries such as transportation and logistics. Cell-based therapeutic products could potentially transform various diseases; however, the delivery of these products is complex and challenging.This study aims to understand the applicability of IoT in cell-based product supply chains and delivery.We will search Medline, EMBASE (OvidSP), Web of Science, Cochrane Library &amp; HEED, Scopus, ACM digital library, INSPEC, ScienceDirect, and the IEEE Xplore Digital Library for studies published after 2008 using a combination of keywords and subject headings related to IoT used in cell therapies. Additionally, a Google search to identify gray literature will be conducted. Two authors will independently screen the titles and abstracts identified from the search and accept or reject the studies according to the study inclusion criteria. Any discrepancies will then be discussed and resolved. The quality of the selected literature will be assessed using the Critical Appraisal Skills Programme systematic review checklist.Data from eligible publications will be abstracted into a predesigned form to map the current and future directions of the technologies, applications, benefits, and challenges in the implementation of IoT in regenerative medicine. This study will be published in a peer-reviewed journal in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. This systematic review will be executed by June 2020, and the completed review will be published in a peer-reviewed journal to inform future developments in IoT application for the delivery of cell-based therapies.This review paper will provide an overview of all technologies available in the area and inspect the current IoT applications in cell-based therapies to identify the benefits, challenges, and future directions of using IoT to allow safe and cost-effective delivery of cell-based therapies.PRR1-10.2196/16935 Internet of Things (IoT) is a concept first proposed by Ashton  at a preOver the last two decades, IoT has been successfully implemented in various industries including aerospace, aviation, automotive, telecommunications, medicine and health care, independent living, pharmaceutical, retail, logistics and supply chains, manufacturing, process, environmental, transportation, agricultural and breeding, media and entertainment, recycling, and insurance ,3. VarioA survey of the trends and topics in IoT research conducted by Whitmore et al  in 2015 Technology platforms for facilitating information flow and exchange have been made available by industry and academic partnerships. Vitruvian Networks, for instance, is a partnership set up by GE Ventures  and Mayo Clinic  to make use of biomarkers, cell therapy processes, and clinical outcome data to guide therapy development . IoT allThis paper aims to systematically review all technologies available in the area, and inspect the current IoT application in cell-based therapies to identify the benefits, challenges, and future directions of using IoT to allow safe and cost-effective delivery of cell-based therapies.The aim of this review is to understand the current available technologies for IoT, the extent of implementation in cell-based therapy delivery, and the drivers and challenges for implementation of IoT. This will allow the gaps for IoT implementation to be identified and will inform future directions in cell therapy supply chain optimization.Our research questions are as follows:What is the current state of IoT implementation in cell-based therapy delivery? What companies and partnerships are engaged in IoT ?What are the technologies available for IoT specific to cell-based therapy delivery?What are the benefits of IoT in cell-based therapy delivery?What are the challenges of implementing IoT on cell-based therapy delivery?This systematic review will be conducted following the PRISMA  guidelines  20]..20].In accordance with the PRISMA-P (Protocols) checklist recommendation, the inclusion criteria of this protocol are in accordance with the PICO  standards. Details of the PICO to be included in the review are described in ParticipantPatients receiving cell-based therapyInterventionAny supply chain step using or interacting with the Internet of Things (IoT) technologies/networks in a cell-based therapy delivery process, from patient cell collection (if autologous) or cell sourcing  to postadministration monitoring and follow-upComparatorNo intervention, standard practice, or any other type of intervention that is not IoT such as paper-based batch recordsOutcomesBenefits and challenges of IoT implementation in tissue or cell-based therapy deliveryStudy typeAny study type (study type will not be subjected to any restrictions)Publications between 2008-2018English publicationsThe fields of both IoT and cell therapy are rapidly advancing; therefore, to ensure that studies found are up to date, only publications from 2008-2018 will be considered. Studies not published in the English language are excluded due to a language barrier. Studies relevant only to the discovery, research, and development phases of cell-based therapies are not in the scope of this review.The following databases will be searched: Medline, EMBASE (OvidSP), Web of Science, Cochrane Library & HEED, Scopus, ACM digital library, INSPEC, ScienceDirect, and the IEEE Xplore Digital Library. In addition, a search on Google to identify gray literature will be conducted. EndNote X8 software will be used for the removal of duplicates. Two reviewers will independently check each article to minimize bias using the collaboration\u2019s risk of bias tool as described in the Cochrane Handbook for Systematic Review of Interventions . All selThe eligible literature will then be described for its three-layer architecture of IoT proposed in various literature ,23. Any Current practice/company and future directions for the items belowSensing layer:Sensing devices and technologies such as radio frequency identification tagsNetwork layer:Service entities arrangement, virtual entity and information, resource modulesApplication layer:Functionalities of Internet of ThingsObserved benefits (if any)Observed challenges (if any)The study aims to provide a landscape of the application of IoT technologies in the cell therapy field and identify the gaps and challenges for IoT application. A sample search was conducted on the PubMed database, and the search strings used are described in This review paper will provide an overview of all technologies available in the area and inspect the current IoT application in cell-based therapies to identify the benefits, challenges, and future directions of using IoT to allow safe and cost-effective delivery of cell-based therapies."}
+{"text": "This Special Issue is focused on measuring and characterizing the mechanical and adhesive properties of cells and membranes.Cell mechanics has an important impact on cellular functions and cell fate. The field has developed very rapidly in the last two decades, incorporating elements of cell biology, biophysics and nanotechnology. In particular, the study of lipid membranes, erythrocytes, and endothelial cells have been performed with several techniques, such as scanning force microscopy, laser pinzette, optical tweezers, and many others. Although a great advance has been achieved in recent years, the characterization of the cells properties and the understanding of the results at cellular and molecular level are still a major challenge for researchers in this area.In this issue, the principles and techniques used in studies of cell and membrane biomechanics and adhesion have been addressed. The reader will find five comprehensive experimental research articles in the oncological field, and another article dealing with cell membrane adhesion modelling, which reports the last developments in the area of adhesion and biomechanics of cancer cells. Experimentally, three of them are closely connected, since the authors used a combination of atomic force microscopy and confocal and/or fluorescence microscopy to investigate morpho-structural/cytomechanical modifications induced by anti-neoplastic drugs or proteins in cancer cells and/or the cell membrane.In one of these contributions, Mariafrancesca Cascione and co-workers , in an aOn the same line, Jagoba Iturri et al.  employedIn another paper with a similar approach, Xiaoli Zhang and co-authors  have invADAM17 gene found in the tissue of colon cancer patients. In order to shed light on the role of ADAM17 in cancer development, as well as into the mechanisms that regulate maturation and cellular trafficking of ADAM17, they perform overexpression investigations of four ADAM17 variants located in the pro-, membrane-proximal- and cytoplasmic-domain of the ADAM17 protein in ADAM10/17-deficient HEK cells. They found a cancer-associated point mutation within the pro-domain of ADAM17 (R177C), to be most impaired in its proteolytic activity and trafficking to the cell membrane, and discovered similar functional limitations [In an interesting study, Egor Pavlenko and co-workers  characteitations . FinallyYAP1 target genes and cell proliferation [Another contribution authored by Jutamas Uttagomol et al.  investigferation . The curIn the only theoretical contribution, Long Li et al.  proposedFinally, we are confident that these articles will readily contribute to the progress in the area of nano/biomechanics, and will further stimulate future studies dedicated to understanding the link between the mechanical properties of cells and membranes, as well as the physico-biological mechanisms and pathways involved."}
+{"text": "Besides general information including Q&As, daily case counts, and maps with disease distribution, examples of latest updates comprise: Poster: Effective hand-washing, COVID-19 - How to minimise the spread? and Considerations relating to social distancing measures in response to the COVID-19 epidemic. ECDC also publishes regular risk assessments and the The European Centre for Disease Prevention and Control (ECDC) provides regularly updated information on coronavirus disease-2019 (COVID-19) relevant to Europe on a dedicated BoxOn 31 December 2019, a cluster of pneumonia cases of unknown aetiology was reported in Wuhan, Hubei Province, China. On 9 January 2020, China CDC reported a novel coronavirus as the causative agent of this outbreak, which is phylogenetically in the SARS-CoV clade. The disease associated with the virus is referred to as novel coronavirus disease 2019 (COVID-19).As of 11 March 2020, 118,598 cases of COVID-19 were reported worldwide by more than 100 countries. Since late February, the majority of cases reported are from outside China, with an increasing majority of these reported from EU/EEA countries and the UK.The Director General of the World Health Organization declared COVID-19 a global pandemic on 11 March 2020.All EU/EEA countries and the UK are affected, reporting a total of 17,413 cases as of 11 March. Seven hundred and eleven cases reported by EU/EEA countries and the UK have died. Italy represents 58% of the cases  and 88% of the fatalities (n=631). The current pace of the increase in cases in the EU/EEA and the UK mirrors trends seen in China in January-early February and trends seen in Italy in mid-February.In the current situation where COVID-19 is rapidly spreading worldwide and the number of cases in Europe is rising with increasing pace in several affected areas, there is a need for immediate targeted action. The speed with which COVID-19 can cause nationally incapacitating epidemics once transmission within the community is established, indicates that in a few weeks or even days, it is likely that similar situations to those seen in China and Italy may be seen in other EU/EEA countries or the UK.There are no vaccines available and there is little evidence on the effectiveness of potential therapeutic agents.In addition, there is presumably no pre-existing immunity in the population against the new coronavirus and everyone in the population is assumed to be susceptible. Clinical presentations of COVID-19 range from no symptoms (asymptomatic) to severe pneumonia; severe disease can lead to death. While the majority of cases (80%) are milder respiratory infections and pneumonias, severe illness and death is more common among the elderly with other chronic underlying conditions, with these risk groups accounting for the majority of severe disease and fatalities to date.The risk of severe disease associated with COVID-19 infection for people in the EU/EEA and UK is currently considered moderate for the general population and high for older adults and individuals with chronic underlying conditions, based on the probability of community transmission and the impact of the disease. The risk of healthcare system capacity being exceeded in the EU/EEA and the UK in the coming weeks is considered high. The impact and risk assessment on health system capacity can be mediated by the application of effective infection prevention and control and surge capacity measures.The risk of transmission of COVID-19 in health and social institutions with large vulnerable populations is considered high. The impact of transmission in health and social institutions can be mediated by the application of effective infection prevention and control and surge capacity.The EU/EEA and the UK are quickly moving toward a scenario of sustained community transmission of COVID19. The situation is evolving very quickly and a rapid, proactive and comprehensive approach is essential in order to delay transmission, as containing transmission to local epidemics is no longer considered feasible. A rapid shift from a containment to a mitigation approach is required, as the rapid increase in cases, that is anticipated in the coming days to few weeks may not provide decision makers and hospitals enough time to realise, accept and adapt their response accordingly if not implemented ahead of time. Measures taken at this stage should ultimately aim at protecting the most vulnerable population groups from severe illness and fatal outcome by reducing transmission and reinforcing healthcare systems.Given the current epidemiology and risk assessment, and the expected developments in the next days to few weeks, the following public health measures to mitigate the impact of the pandemic are necessary in EU/EEA countries:Social distancing measures should be implemented early in order to mitigate the impact of the epidemic and to delay the epidemic peak. This can interrupt human-to-human transmission chains, prevent further spread, reduce the intensity of the epidemic and slow down the increase in cases, while allowing healthcare systems to prepare and cope with an increased influx of patients.Such measures include:the immediate isolation of symptomatic persons suspected or confirmed to be infected with COVID-19;the suspension of mass gatherings, taking into consideration the size of the event, the density of participants and if the event is in a confined indoor environment;social distancing measures at workplaces ;measures in and closure of schools, taking into consideration the uncertainty in the evidence of children in transmitting the disease, need for day care for children, impact on nursing staff, potential to increase transmission to vulnerable grandparents;cordon sanitaire of residential areas with high levels of community transmission.Ensuring the public is aware of the seriousness of COVID-19. A high degree of population understanding, solidarity and discipline is required to apply strict personal hygiene, coughing etiquette, self-monitoring and social distancing measures. Community engagement and acceptance of stringent social distancing measures put in place are key in delaying and reducing further spread.Prevention and control of COVID-19 in hospitals and long-term care facilities is an immediate priority in order to: (1) slow the demand for specialised healthcare, such as ICU beds; (2) safeguard populations vulnerable to severe outcomes of infection (3); protect healthcare workers that provide care; (4) minimise the export of cases to other healthcare facilities and the community.Every healthcare facility should initiate training for all staff and those who may be required for healthcare provision during surge capacity. Countries should identify healthcare units that can be designated to care for COVID-19 cases, to minimise transmission to non-cases and to conserve PPE. Countries and healthcare institutions should identify additional facilities that can be used for the cohorting of cases with mild symptoms, in the event that surge capacity is exceeded by healthcare facilities. The highest priority for use of respirators (FFP2/3) are healthcare workers, in particular those performing aerosol-generating procedures, including swabbing.If resources or capacity are limited, rational approaches should be implemented to prioritise high-yield actions, which include: rational use of confirmatory testing, reducing contact tracing to focus only on high-yield contacts, rational use of PPE and hospitalisation and implementing rational criteria for deisolation. Testing approaches should prioritise vulnerable populations, protection of social and healthcare institutions, including staff.National surveillance systems should initially aim at rapidly detecting cases and assessing community transmission. As the epidemic progresses, surveillance should monitor the intensity, geographical spread and the impact of the epidemic on the population and healthcare systems and assess the effectiveness of measures in place. In circumstances with capacity shortages and strict implementation of social distancing measures, surveillance should focus on severe acute respiratory infections, sentinel surveillance in outpatient clinics or collection of data through telephone helplines.A strategic approach based on early and rigorous application of these measures will help reduce the burden and pressure on the healthcare system, and in particular on hospitals, and will allow more time for the testing of therapeutics and vaccine development.What is new in this update?Updated data on the epidemiological situation in the EU/EEA and the UKRecent findings on disease and transmissibility, including during the asymptomatic periodRisk associated with COVID-19 for people from the EU/EEA and the UKRisk of local and widespread national community transmission in the EU/EEA and UK in the coming weeksRisk to healthcare systems capacity being exceeded in the EU/EEA and the UK in the coming weeksRisk of transmission of COVID-19 in health and social institutions with large vulnerable populationsOptions for preparedness and response focused on the mitigation phase, including rational measures in case of resource constraints or shortagesUpdated surveillance objectives and methods for the mitigation phase.https://www.ecdc.europa.eu/sites/default/files/documents/RRA-sixth-update-Outbreak-of-novel-coronavirus-disease-2019-COVID-19.pdfSource: European Centre for Disease Prevention and Control (ECDC). Rapid risk assessment: Novel coronavirus disease 2019 (COVID-19) pandemic: increased transmission in the EU/EEA and the UK \u2013 sixth update. ECDC: Stockholm; 12 March 2020. Available from: COVID: coronavirus disease; ECDC: European Centre for Disease Prevention and Control; EU/EEA: European Union/European Economic Area; ILI: influenza-like-illness; SARS-CoV: severe acute respiratory syndrome coronavirus; UK: United Kingdom."}
+{"text": "With its roots firmly planted in the fields of CNS autoimmunity and infection, the rapidly growing field of neuroimmunology is branching out to include almost every area of neurophysiology and neurological disease to encompass brain development and function, psychiatric illnesses, inflammatory demyelinating diseases, cancer, infections, and neurodegeneration of the central and peripheral nervous systems. The nervous system is also functionally intimately interconnected, via immune mechanisms, to multiple other processes and organ systems including systemic inflammation, gut microbiome, and chronic pain, to name a few. The scope of neuroimmunology and its implications for the understanding of human health and disease, from diagnosis through therapeutics, was highlighted during the 14th Congress of the International Society for Neuroimmunology (ISNI) 2018, and the associated 2nd Global Schools of Neuroimmunology (GSNI), held together in August 2018 in Brisbane, Australia. The richness of topics covered is further illustrated through the series of related articles presented in this special issue of Frontiers in Neurology entitled \u201cUpdate on Translational Neuroimmunology Research of ISNI 2018.\u201dThe Congress highlighted the importance taking the knowledge gained from translational research and clinical experience back into the research environment to gain further understanding of immune-mediated diseases affecting the human CNS and how to overcome them. During the meeting, dedicated symposia covered diverse topics of CNS and PNS autoimmunity, immune dysfunction, and immunotherapy, covering a wide range of neuroimmune interactions in health and disease. For example, disease topics ranged from immune-mediated conditions, such as multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), myasthenia gravis, and autoimmune encephalopathies and neuropathies, to inflammation in conditions usually thought of as neurodegenerative, such as Alzheimer's disease (AD), Parkinson's disease (PD), motor neuron diseases, neuropsychiatric diseases, as well as traumatic injuries and infections by parasites and neurotropic RNA viruses including West Nile and Zika.McCombe et al. review the emerging evidence that the peripheral immune system contributes to motor neurodegeneration in amytrophic lateral sclerosis (ALS), and implications for therapeutic targeting to manage the disease. This parallels current thinking in AD that peripheral inflammation influences inflammation in the brain. In a similar vein, Yates et al. review the current evidence suggesting that extracellular vesicles (EVs) shed from CNS cells, cross the blood brain barrier (BBB), and play a critical role in activating peripheral immune responses to traumatic CNS injury. Vilquin et al. describe the consequences of autoimmune attack against components of the neuromuscular junction in myasthenia gravis, focusing on the response of the ultimate target in this disease, the muscle. Fujii et al. turn their attention to investigating the link between allergic inflammation and neuropathic pain, describing a possible role for spinal cord glial inflammation and autoantibodies that target sensory neurons in the dorsal root ganglia.The involvement of immune mechanisms in psychiatric diseases was introduced at GSNI on the first day of the meeting and during the main meeting in talks by Lennox and Brown. In this issue, van Langelaar et al. further discuss the types of T cell-B cell interactions that might be important for MS pathogenesis, Greer et al. report that autoantibodies to the major myelin protein, proteolipid 181\u2013230 peptides, are increased in a subgroup of MS patients and that their levels positively correlate with disease severity, while Young reviews the differential effects of antibodies to the GluN1 subunit of the glutamate NMDA receptor in pathogenesis of neurological diseases.The dramatic clinical success of B cell depleting immunotherapies in patients with MS, as well as CNS diseases that involve autoantibodies such as NMOSD, has focused research on understanding the critical roles of B cells, and their interactions with T cells, in the pathogenesis of MS and other neuroimmune diseases. B cells produce antibodies, present antigens to T cells, and produce pro-inflammatory and anti-inflammatory cytokines, and all these functions can contribute to CNS autoimmunity. At the Congress, The Immunology Lecture delivered by Vinuesa was dedicated to rare mutations that contribute to systemic autoimmunity. Focus was placed on genes that control mechanisms involved in the production, selection and elimination of memory B cells and antibody production, and specifically on the role of roquin, an E3 ubiquitin ligase, in the control of B cell-T cell interactions by T follicular helper cells (TFH) . In the Neutrophils are amongst the first immune cells to reach the CNS in the MS model experimental autoimmune encephalomyelitis (EAE) and are present in the CNS during NMOSD and severe MS, but little is known of their role in disease pathogenesis. Vallieres showed that neutrophils adopt macrophage-like properties once entering the CNS in a B cell-dependent EAE model and to promote inflammation via the neutrophil-specific protease ASPRV1 . MoreoveMS research is increasingly focused on myeloid cells and CNS-resident cells such as astrocytes, microglia, and oligodendrocytes, which contribute to disease pathology through additional mechanisms likely relevant for other neurologic diseases. One topic that remains hotly debated in the MS field is the identity of the antigen-presenting cell that is responsible for reactivating T cells in the CNS, and thereby licensing them to induce demyelinating lesions, since this is a potential target for more selective therapy. Various cell types, including dendritic cells, B cells, barrier-associated macrophages (BAM), and microglia are able to present antigen to T cells in the context of MHC class II, although which one is involved in the pathogenesis of EAE and MS still remains to be identified. Important targets are also the effector molecules communicating these interactions, as discussed by Becher for (GM-CSF) .Benmamar-Badel et al. review data regarding a unique subset of microglia that is found in development, during normal aging and in diverse diseases and discuss the possible functional significance of these cells. It is clear that much more needs to be learnt regarding the differential functions of myeloid cell subtypes before these cells can be both effectively and safely targeted for therapy.The functions of CNS-resident myeloid cell (microglia) in neuroinflammation continue to intrigue researchers. Unlike their peripheral counterparts (monocytes and macrophages), microglia perform essential functions in the CNS not only in pathologic states such as in repair of tissue damage, as discussed by Popovich, but also under normal physiologic conditions, such as shaping neuronal networks and clearing debris by phagocytosis. Loss of these functions during development has been implicated in schizophrenia and potentially in autism spectrum disorders, while loss of the same functions in the context of chronic inflammation may contribute to pathology in diseases such as MS and AD. For example, Waisman reported that selective depletion of A20 (an inhibitor of the transcription factor NF-\u03baB) in microglia, was sufficient to induce spontaneous neuroinflammation and CNS infiltration by CD8+ T cells, pointing to a homeostatic function for microglia in the brain . The TAMEvidence for inflammatory functions of CNS-resident oligodendrocyte precursor cells (OPC) was presented by Ransohoff wherein IL-17-induced Act1-NOTCH1 interactions in OPC promoted the inflammatory responses, cell proliferation and inhibited OPC differentiation into mature oligodendrocytes thereby inhibiting remyelination. Genetic depletion of NOTCH1 in OPC in mice, or administration of a decoy peptide based on IL-17RA, were sufficient to inhibit Th17-induced EAE . IncreasOur current understanding of CNS immune privilege and CNS barriers, including the blood brain barrier (BBB), blood CSF barrier (B-CSF), and brain surface barrier, was reviewed by Engelhardt at GSNI and elaborated during the congress itself, where the perivascular space at the BBB was implicated as a main entry point for immune cell infiltration in MS . Brain bJogia and Ruitenberg on the significance of gut microbiota in traumatic spinal cord injury, and from Cady et al., on the importance of dietary phytoestrogens in protection in EAE and possibly MS.Well-deserved attention was given to the gut-CNS axis and, in particular, the role of gut microbiota in immune homeostasis of the brain and in triggering CNS autoimmunity. This field developed following a landmark discovery made in the field of neuroimmunology just one decade ago. Since then the functional relationships between the gut microbiome and its effects on CNS pathology driven by peripheral and resident cells have been subject to intense investigation, as introduced at GSNI by Barazini, and updated in the Congress by Wekerle, Miyake, Weiner, Quintana and Yamamura, and by recent reviews \u201318. ThisSeveral talks highlighted the neuroimmunology of infectious diseases of both the peripheral and central nervous systems, including cerebral malaria by Idro and viral infections by Klein, Pender, Basu and Yamano.Prain et al. describe a clinically-based survey of NMOSD in Australia and New Zealand, and critically evaluate different assays for anti-AQP4 and anti-MOG antibodies used in the diagnosis of NMOSD and anti-MOG associated disease, respectively. In the case of anti-AQP4 antibody seronegative NMOSD, differential diagnosis from MS might be difficult. The current status of medical imaging research in MS and NMOSD, and its role in the diagnosis and management of these two diseases was discussed at the meeting by Stankoff and Paul, and is reviewed in this issue by Kuchling and Paul. Tea et al. together with the Australasian and New Zealand MOG Study Group, discuss data analysis tools for maximizing the diagnostic power of FACs cell-based assays that detect MOG autoantibodies. Gastaldi et al. critically report the results and main shortcomings of the 2018 Italian Neuroimmunology Association external quality assessment program (EQAP), which evaluated assays using a wide range of markers including oligoclonal bands, antibodies to intracellular and surface neuronal antigens, AQP4, MOG, and myelin-associated glycoprotein (MAG) antibodies, in different assay types used by 34 different laboratories. Jiang et al., describe improved novel biomarkers in the CSF of patients with autoimmune encephalitis for differential diagnosis between viral infections and autoimmune encephalitis. Masvekar et al. investigated whether apoptotic bodies/ apoptosomes, which are vesicles released from apoptotic cells, could represent a biomarker for MS, by measuring total and cell-specific apoptotic bodies in the CSF of MS patients by FACS using annexin V and antibodies to cell-specific markers.The search for improved diagnostic biomarkers continues, and is a particular focus of articles published in this special issue. While MS is the most common inflammatory demyelinating disease of the CNS, other rare disorders include NMOSD and anti-MOG associated disease, and the need for accurate diagnosis is stressed since prognosis and treatment of these three diseases are different. In this issue, Ottoboni et al.) and The Rita Levi-Montalcini Neurobiology Lecture delivered by Bartlett  2018, and the associated 2nd Global Schools of Neuroimmunology (GSNI), highlighting new developments in this rapidly moving field, as well as unanswered research questions and unmet clinical needs. This growing body of research sets up the stage for the upcoming ISNI/GSNI 2021 meeting in Nice, France.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "As organisms age, many changes occur to their physiology, which in turn impact the function of multiple tissues. It is therefore critical to investigate the fundamental mechanisms of how endocrine organs shape our physiology, and how changes in our physiology affect stem cell lineages, which generate new cells for maintenance and repair of tissues/organs throughout life. This symposium will highlight the research in the laboratories of Dr. Gerard Karsenty (Columbia University) on the multiple endocrine functions of bone, of Dr. Nicholas Buchon (Cornell University) on the role of host-microbe interactions in intestinal homeostasis, of Dr. Jane Hubbard  on the physiological control of the germline, and of Dr. Daniela Drummond-Barbosa (Johns Hopkins University) on how diet and adipocyte factors regulate oogenesis. As research by these and other groups illustrate, the complex physiological regulation of tissue/organ maintenance and function is not only a fascinating biological problem, but it also has implications for many diseases and other conditions that are tightly linked to our endocrine state, including aging."}
+{"text": "The psychosocial stress process model  remains a dominant theoretical framework characterizing the transactions between factors affecting outcomes of informal caregivers of people with dementia (PWD). Despite widespread agreement that the model provides an important framework for understanding caregiver experiences and predicting caregiver outcomes, it is not sufficient to clarify the needs of caregivers. Needs are conceptualized as the skills and resources that could be used to ameliorate the negative impacts of caregiving and promote quality of life . Determining caregiver needs requires appreciation of the complex background, contextual, and stress-related variables described in the stress process model and requires empirically- and theoretically-driven understanding of the diverse resources, materials, and skills that individuals require for global health and functioning. In this study, we conducted a content analysis of existing measures of dementia caregiver needs (N = 54), content analysis of materials related to evidence-based dementia caregiver interventions and government reports and documents (N = 28), and semi-structured in-depth interviews with current caregivers of PWD (N = 12) to identify the personal and care-related needs of family caregivers of PWD. We propose a framework of five inter-related need categories  that transact with the factors described in the stress process model, ultimately influencing functioning. In the future, we plan to test this model empirically with a nationally representative sample of caregivers."}
+{"text": "Due to their large number of applications, the pesticides pose potential toxicity risks to the non-target organisms. In recent years, the studies on the toxic effects of pesticides on non-target organisms, based on their gut microbiome and metabolome, have been continuously reported. As a dense and diverse microbial community, the gut microbiota in the mammalian gut plays a key role in the maintenance of host metabolic homeostasis. The imbalance in the gut microbiota of host is closely associated with the disturbance in the host's metabolic profile. A comprehensive analysis of the changes in the gut microbiota and metabolic profile of host will help in understanding the internal mechanism of pesticide-induced toxic effects. This study reviewed the composition and function of the gut microbiota of host, as well as the analysis methods and applications of metabolomics. Importantly, the latest research on the toxic effects of the exposure of pesticide to host was reviewed on the basis of changes in their gut microbiota and metabolic profile. Pesticides are widely used as an important mean for agricultural production. However, the pesticide residues its excessive and unreasonable use, which seriously threatens the quality of agricultural products and the safety of ecological environment . At presIn recent years, the studies on host gut microbiome and metabolomics have attracted more attention . The hosIn this study, the composition and function of gut microbiota, and the analysis methods and applications of metabolomics have been reviewed. Importantly, the effects of pesticides on the gut microbiota and metabolic profile of host were reviewed, which further emphasized on their key role in the pesticide-induced host toxicity.Firmicutes and Bacteriodetes. In addition, Proteobacteria, Verrumicrobia, Actinomycetes, Fusobacteria and Cyanobacteria are also relative abundant in the human intestines , carbon nuclear magnetic resonance spectroscopy (13C-NMR), nitrogen nuclear magnetic resonance spectroscopy (15N-NMR), and phosphorus nuclear magnetic resonance spectroscopy (31P-NMR), of which the 1H-NMR and 13C NMR are the most widely used NMR spectroscopies in metabolomics. The NMR can detect most of the endogenous metabolites in organisms, and can obtain a wealth of information about the tested samples. It provides stable results with good repeatability. In addition, the NMR has relatively simple requirements for the pretreatment of samples, and can perform unbiased and non-destructive analysis and detection of samples  and gas chromatography-mass spectrometry (GC-MS) are commonly used . These tDue to the limitations in existing analysis platforms, they are not suitable for the analysis of all metabolites in a biological sample. By combining various single analysis techniques to form a joint technique, its application range becomes wider, and provides accurate information about a specific metabolome. Therefore, in the field of metabolomics research, several analytical techniques are often used to study the metabolites. There is a continuous developmental trend in the modern analytical techniques, which will promote the metabolomics research. At present, the most common example of the combination of multiple analysis techniques is the combination of NMR and MS. This method can make the full use of the advantages of various techniques for the identification of metabolites in organisms to the greatest extent. This combined method is not only used in the pesticide environmental toxicology research, but also provides an opportunity for the integration of multiple omics in system biology .https://www.metaboanalyst.ca/), HMDB (the human metabolome database) and KEGG (Kyoto encyclopedia of genes and genomes), etc. are used to interpret the biological information of metabolites. Subsequently, the p value and pathway influence value (PIV) are used to find the significantly affected metabolic pathways, and the mechanism of toxicity can be explored in-depth through the changes in metabolic pathways.After obtaining the original data by measuring the samples through the above-mentioned analysis techniques, the data needs to be preprocessed to make it suitable for the multivariate analysis. Depending on the technique used, the processing steps are slightly different . The datMetabolomics has been playing an increasingly important role in the basic research and clinical applications, and has been widely for studying the different functional states and diseases of various organisms. Li et al. collected the blood samples of 150 patients with severe obstructive coronary heart disease (CHD) and 150 healthy controls for the metabolomics analysis using ultra-high performance liquid chromatography-quadruple time-of-flight mass spectrometry (UHPLC-QTOF/MS). The study found significant changes in the metabolites of 105 CHD patients. In addition, six metabolites, including palmitic acid, linoleic acid, 4-pyridoxic acid, phosphatidylglycerol, carnitine and lithocholic acid, had a strong correlation with the CHD . Zhao et. In addition, the metabolomics technology is also widely used in the identification of food quality. As early as 2002, Brescia et al. analyzed the metabolic profile of 41 red wines from southern, central and northern Apulia, Italy, using NMR. With the help of the PCA, the wines of these three regions could be clearly distinguished. The main substances that caused differences in the wine regions were amino acids , taurocholic acid (TCA), glyco-cholic acid (GCA) deoxy-cholic acid (DCA), taurodeoxycholic acid (TDCA), glycodeoxycholicacid (GDCA), lithocholic acid (LCA), taurolithocholic acid (TLCA), and glycolithocholic acid (GLCA) and decreased that of the \u03b2-MCA (Akkermansia, and a decrease in the abundance of Desulfovibrionaceae and Lactobacillus. In addition, the metabolites, mainly related to the metabolism of purine and BCAAs and TCA cycle in feces were changed, which ultimately led to an increase in the consumption of host energy (1H-NMR analysis showed that a total of 20 fecal metabolites, mainly including succinate, SCFAs, bile acids and trimethylamine, were affected (The increasing use of pesticides year by year has attracted more attention toward their toxic effects on non-target organisms in the environment. Interestingly, many recent studies have shown that the gut microbiota plays a key role in the toxic effects of pesticides . In addihe \u03b2-MCA . In addihe \u03b2-MCA . Studieshe \u03b2-MCA . In addihe \u03b2-MCA . The pert energy . In addit energy . Similart energy . Wu et aaffected . Moreoveaffected . CurrentIn recent years, the gut microbiota of host has received more attention. Generally, the dysbiosis of gut microbiota often occurs simultaneously with the metabolic disorder of host. The studies on the health effects of host based on the changes in gut microbiota and metabolic profile have been continuously reported. In the past few decades, the pesticides have been widely used, and their toxic effects on the non-target organisms have received increasing attention. In particular, some studies have confirmed the destructive role of pesticides on the gut microbiota and metabolic profile of host. Unfortunately, most of these studies have only established a simple correlation between the pesticides and host gut microbiota and metabolic profile, while the key roles of the gut microbiota and metabolic profile host in the pesticide-induced toxic effects are still not focused. In particular, some studies have shown that some specific bacteria in gut microbiota can regulate specific metabolites or specific metabolic pathways, further affecting the host health. However, the current studies on the toxic effects of pesticides have not established a clear relationship between the specific pesticides and specific gut microbiota or metabolites. On the other hand, the key role of the gut microbiota and metabolic profile of host in the pesticide-induced toxic effect is needed to be further confirmed either by the transplantation of microbiota or the dietary supplementation of specific metabolites. In summary, this study reviewed the studies on the toxic effects of pesticides based on the gut microbiome and metabolomics of host. This review further emphasized on the role of changes in the gut microbiome and metabolomics of host in the pesticide-induced host toxic effects."}
+{"text": "Brain computer interfaces (BCI) provide a direct communication link between the brain and a computer or other external devices. They offer an extended degree of freedom either by strengthening or by substituting human peripheral working capacity and have potential applications in various fields such as rehabilitation, affective computing, robotics, gaming, and neuroscience. Significant research efforts on a global scale have delivered common platforms for technology standardization and help tackle highly complex and non-linear brain dynamics and related feature extraction and classification challenges. Time-variant psycho-neurophysiological fluctuations and their impact on brain signals impose another challenge for BCI researchers to transform the technology from laboratory experiments to plug-and-play daily life. This review summarizes state-of-the-art progress in the BCI field over the last decades and highlights critical challenges. The brain computer interface (BCI) is a direct and sometimes bidirectional communication tie-up between the brain and a computer or an external device, which involves no muscular stimulation. It has shown promise for rehabilitating subjects with motor impairments as well as for augmenting human working capacity either physically or cognitively , replace , enhance , supplement , improve , and research tool  have been outlined as feasible and promising fields  a comfortable and convenient signal acquisition device, (2) system validation and dissemination, and (3) reliability and potentiality of BCI    the selection of the signal acquisition modality, which plays an important role in diagnosing neural states, (2) the design of feedback modality that has explicit association with the neural signal classification performance, (3) the consideration of application-specific feedback delays, and (4) the utilization of a suitable feedback modality  technologies together with BCI could offer immersive experiences and have many potential applications including arts and neurofeedback  experiments that involve decoding sender's cognitive intentions, translate them into commands for stimulating receiver's brain, have been explored (Pais-Vieira et al., Irrespective of the scientific breakthroughs in BCI field, there are key factors pertaining to safety, ethics, privacy protection and data confidentiality, community acceptance and socioeconomic aspects that should be considered with adequate precautions to maximize users' benefits and social impacts (Illes and Bird, Physical and mental safety of BCI users is important. Invasive procedures such as deep brain stimulation and intracortical microelectrode array may cause postoperative psychological and neurological side effects (Jotterand and Giordano, A user's expectations of achieving extended or auxiliary degree of freedom may not be fulfilled, and even the unfamiliar risk factors can diminish the accomplished advantage of using BCI Clausen, . CreatinIt is critical to introduce a suitable act for lawful utilization of BCI and preservation of privacy and confidentiality of stored data. Recent studies have demonstrated decoding of password or recognizing faces utilizing consumer-grade BCI successfully, prompting a potential concern of any illegitimate access to users' raw data and their further exploitation (Martin et al., Human Brain Project. In addition, the Brain Initiative has been announced by the White House. In our opinion, advanced understanding of basic neuroscientific phenomena will determine the structure, efficacy and applications of futuristic BCI.By creating a common networking platform for BCI researchers worldwide, the immediate proposition of a comprehensive list of universal guidelines is key to sustainable advancements of the field (Vaadia and Birbaumer, Numerous groundbreaking advances in neurosensors and computational tools herald great promise for more sophisticated and user friendly BCI systems requiring no or little maintenance. In addition to hi-fidelity signal acquisition, significant progress in signal processing and machine learning tools, their complementary roles, and high computation power and increased mobility of computers have significantly contributed in the emergence of BCI technologies. The future of BCI technology will rely greatly on addressing the following key aspects:Elucidating the underlying psychophysiological and neurological factors that potentially influence BCI performance.Designing less invasive sensors with reliable signal acquisition and resolution, while considering portability, easy maintenance, and affordability.Modeling session-to-session and subject-to-subject information transfer for the proposition of more generalized BCI models with insignificant or no calibration requirement.Establishing broad consensus on ethical issues and beneficial socioeconomic application of this technology.SS conceived the initial idea, wrote the first draft, and generated all figures and tables. KM, KA, RM, GN, and SD participated in the discussion and commented on the draft. AHK and MB provided further insight and helped SS to finalize the structure and materials. All authors read and approved the final paper.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Chinese animal industries face challenges in finding graduates with the appropriate training for the needs of a dynamic industry.The agricultural universities of China are working on methods to strengthen the specialized abilities of students to meet industry needs.The Chinese government has increased funding to encourage faculty and students to devote energy to animal science research not only in tradition field, but also in some new cross\u2013disciplinary areas, for example, artificial intelligence applications.These challenges have accelerated the formation of mutually beneficial relationships between the industries and universities but there is a long way to go.Following more than 20 years of rapid development, China is the largest producer of meat and eggs and the third-largest producer of milk in the world. Since 2016, the animal industry in China has reached a plateau in which the yields of meat, eggs, and milk increased by no more than 3% per year . MeanwhiChinese (mainland) imports of livestock and poultry products reached 36.2 billion U.S. dollars in 2019 . The SinMore importantly, animal disease epidemics heavily depress the development of a sustainable animal industry in China. For example, the spread of African swine fever (ASF) in China since 2018 caused producers to lose tens of billions (U.S. dollar) losses during 2019. In addition, hundreds of pig farms, especially mid- and small-sized farms, went out of business.To strengthen the ability of agricultural industries to withstand risk, more companies are beginning to integrate the feed industry, animal husbandry, and processing. Only powerful and integrated companies, along with some unique mid- and small- size enterprises, can survive and attain profit in China. A huge and integrated animal industry needs hundreds of thousands of employees involved in the primary and supporting industries. However, many young people prefer to move to urban areas to enjoy a convenient lifestyle rather than work on remote and isolated farms, causing a deficiency in farm labor throughout China. Considering the huge demands for qualified employees with well-trained professional knowledge, skills and interdisciplinary background, employers are willing to offer high salaries to qualified employees. Unfortunately, the candidates with a traditional background in animal science regardless of degree are at a relative disadvantage when applying for these high-salary positions due to the absence of cross-disciplinary training.To strengthen the graduates\u2019 abilities to deal with challenges and cooperate with colleagues from across branches in integrated enterprises, designing the animal science curriculum and supporting courses for the future has become a primary issue. Establishment of new courses reflecting the transformation of the industry to develop students with the following abilities would be welcomed.Application of artificial intelligence in the animal industries;Understanding experimental design, statistical analyses, interpretation of data, and scientific communication skills ;Training in biotechnology, including cell and molecular biology, genetic engineering, and fermentation engineering;Expertise and skill in nutritional strategies to keep animals healthy, minimize agricultural environmental impact and emissions, and promote production efficiency;Skills in control and prevention of infectious diseases;Animal product quality control and monitoring;Design of animal husbandry buildings and auxiliary infrastructure, including design of facilities, feed processing and conveyor systems, environmental control systems, and other engineering skills;Excellent interdisciplinary background covering animal husbandry, veterinary science, feed processing, environmental monitoring, financial accounting and analysis, and so forth.The Chinese government also annually identifies scientific issues on the frontier, including the common problems impacting the development of animal industries. They also create funding for projects addressing these priority issues through the National Natural Science Fund or other projects of national scientific programs.Issues concerning the development of animal genetic resources and breeding, control and prevention of epidemics, feed production/processing/efficient utilization, animal immunity, environmental stress and animal health, animal nutrition, application of artificial intelligent in the animal industry, animal waste processing and environmental protection, and animal behavior and animal welfare attract more financial support than has previously been available from the government and from the industries.According to the Statistical Bulletin on National Investment in Science and Technology for 2018 , the totThe government understands that investment in high-level scientific research activities of animal science and development of the full-fledged potential and ability/skills of students who will have careers in animal husbandry and related works is money well spent. Additionally, university administrators must do their best to provide facilities that encourage faculty and students to upgrade student skill sets for professional careers of the future because employment opportunities exist for well-trained graduates . To faciIn summary, it is of great importance for the university education system in China to cultivate students with professional knowledge and know-how to serve the rapidly transforming animal industry. This must be done by increasing the needed funds to promote multidisciplinary training and high-quality scientific research activities."}
+{"text": "On March 11, 2020, the World Health Organization declared the coronavirus disease 2019 (COVID-19) outbreak as a pandemic, with over 720,000 cases reported in more than 203 countries as of 31 March. The response strategy included early diagnosis, patient isolation, symptomatic monitoring of contacts as well as suspected and confirmed cases, and public health quarantine. In this context, telemedicine, particularly video consultations, has been promoted and scaled up to reduce the risk of transmission, especially in the United Kingdom and the United States of America. Based on a literature review, the first conceptual framework for telemedicine implementation during outbreaks was published in 2015.An updated framework for telemedicine in the COVID-19 pandemic has been defined. This framework could be applied at a large scale to improve the national public health response. Most countries, however, lack a regulatory framework to authorize, integrate, and reimburse telemedicine services, including in emergency and outbreak situations. In this context, Italy does not include telemedicine in the essential levels of care granted to all citizens within the National Health Service, while France authorized, reimbursed, and actively promoted the use of telemedicine. Several challenges remain for the global use and integration of telemedicine into the public health response to COVID-19 and future outbreaks. All stakeholders are encouraged to address the challenges and collaborate to promote the safe and evidence-based use oftelemedicine during the current pandemic and future outbreaks. For countries without integrated telemedicine in their national health care system, the COVID-19 pandemic is a call to adopt the necessary regulatory frameworks for supporting wide adoption of telemedicine. On March 11, 2020, the World Health Organization declared the coronavirus disease 2019 (COVID-19) outbreak as a pandemic, with over 720,000 cases reported in more than 203 countries as of 31 March. This announcement followed the declaration of a Public Health Emergency of International Concern (PHEIC) on January 30. The response strategy included early diagnosis, patient isolation, symptomatic monitoring of contacts, as well as suspected and confirmed cases, and a public health quarantine. The confinement of population and the outbreak impact on health care systems is disrupting routine care for non COVID-19 patients. In this context, telemedicine, particularly video consultations, has been promoted and scaled up to reduce the risk of transmission, especially in the United Kingdom  and AustTelemedicine was shown to be helpful in previous outbreaks, including former coronavirus outbreaks such as SARS-CoV (severe acute respiratory syndrome\u2013associated coronavirus) and MERS-CoV (Middle East respiratory syndrome coronavirus), or PHEICs related to Ebola and Zika viruses ,7. BasedAn updated framework for telemedicine during the COVID-19 pandemic has been defined in Technological improvements and cost reduction of telemedicine solutions combined with both the high-speed internet and mass spread of smartphones makes it possible to apply this framework and quickly deploy video teleconsultations from a patient\u2019s home.Most countries, however, lack a regulatory framework to authorize, integrate, and reimburse telemedicine in their care delivery for all patients, particularly in emergency and outbreak situations . Two posWith the second largest burden of COVID-19 in the world, Italy does not include telemedicine in the essential levels of care granted to all citizens within the National Health Service. No formal input was given on telemedicine by health authorities, despite high pressure on health services during the first phase of the epidemic ; not untIn France, the Ministry of Health signed a decree on March 9, 2020, allowing the reimbursement of video teleconsultations and tele-expertise by the National Health Insurance (NHI), for patients with COVID-19 symptoms and those confirmed with COVID-19 throughout the country, without the need to know the patient beforehand . The decThe pre-existing telemedicine regulations also enabled primary care and hospital doctors to switch scheduled face-to-face consultations with known patients to reimbursed teleconsultations, when suitable. This model was activated in the largest national public academic hospital (AP-HP) in Paris, to encourage mass use of outpatient teleconsultations to reduce patient visits to the hospital March 13, 2020). This has been reinforced by the High Council of Public Health, which recommended prioritization of teleconsultations for people with risk factors for severe disease in primary care March 14, 2020) [, 2020. T, 2020 ,. Among gIn this context, several challenges remain for telemedicine to be globally used and integrated into the public health response to COVID-19 and future outbreaks:The integration of telemedicine into international and national guidelines for public health preparedness  and response The definition of national regulations and funding frameworks for telemedicine in the context of public health emergenciesA strategy to quickly define telemedicine frameworks; use case scenarios; develop clinical guidelines; and standardize triage auto questionnaire and remote patient-monitoring algorithms for any outbreaks at local, national, or global scalesA strategy and operational plan guiding health care providers to switch to outpatient teleconsultations and increase tele-expertise and remote patient monitoringA communication toolkit to inform and educate the population on the recommended use of telemedicineA data-sharing mechanism to integrate telemedicine providers\u2019 data with epidemiological surveillanceA scientific evaluation framework and dedicated research funds to describe and assess the impact of telemedicine during outbreaksAll stakeholders are encouraged to address the challenges and collaborate to promote the safe and evidence-based use of telemedicine during the current pandemic and future outbreaks. For countries without integrated telemedicine within their national health care system, the COVID-19 pandemic is a call to adopt the necessary regulatory changes supporting wide adoption of telemedicine."}
+{"text": "The coronavirus disease (COVID-19) outbreak is rapidly progressing globally, and Italy, as one of the main pandemic hotspots, may provide some hard lessons for other countries. In this paper, we summarize the current organizational capacity and provide a pragmatic and narrative account of strategies and activities implemented by the Department of Prevention (Dipartimento di Prevenzione)\u2014the regional entity of the Local Health Authority of the Italian National Health Service in charge of public health\u2014since the beginning of the outbreak. We conduct a preliminary analysis of general strengths, weaknesses, opportunities, and threats (SWOT) of the response strategies from a local perspective. Furthermore, we provide firsthand insights on future directions and priorities to manage this unprecedented pandemic. Our case report gives a qualitative view of the healthcare response, based on the experience of frontline professionals, with the aim to generate hypotheses about factors which may promote or hinder the prevention and management of a pandemic locally. We highlight the importance of a public health approach for responding to COVID-19 and reshaping healthcare systems. The 2019\u20132020 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak, which was first identified in Wuhan, Hubei, China, in December 2019, has resulted in an ongoing coronavirus disease (COVID-19) pandemic. Exponential increases in the number of confirmed COVID-19 cases and deaths continue to be reported globally, and necessitate awareness and proactive action .On 30 January 2020, the World Health Organization (WHO) declared the COVID-19 outbreak a public health emergency of international concern, and on the same day, the Italian government banned air traffic from China ,5. The fIn Italy, only three cases were identified at the end of January, and all involved individuals who had recently traveled to China. The first case of pneumonia due to SARS-CoV-2, without history of possible exposure abroad, was diagnosed in northern Italy\u2019s Lombardy on 20 February . Within On February 21, the Ministry of Health ordered a mandatory supervised quarantine for 14 days for all individuals who had come into close contact with confirmed cases of disease. In addition, it required a mandatory communication to the Department of Prevention\u2014the entity of the Local Health Authority of the Italian National Health Service in charge of public health\u2014in identified areas from anyone who had entered Italy from areas with a high risk of COVID-19, followed by quarantine and active surveillance . The ItaThereafter, additional social distancing measures were initially enforced in Lombardy and within areas of other affected regions. Subsequently, draconian lockdown measures were extended nationwide, through several decrees enacted by the President of the Council of Ministers, closing schools (5 March), banning public events 9 March), limiting movement of people except if motivated by proven work needs or situation of necessity , and suspending all retailing and business activities, with the exception of essential goods and production activities that were strategic or relevant to the management of the crisis (22 March)  March, l,13,14. TIn March, the number of cases identified in Italy had rapidly increased, predominantly in northern Italy, although all regions of the country reported ever-increasing numbers of COVID-19 cases ,17. The Nevertheless, despite the de-escalation measures that are underway, the situation is far from normal and the Italian National Health Service  has faced the worst threat since its establishment more than 40 years ago. From the beginning of the crisis, professionals of the Italian healthcare system employed in all its different settings  have been fully and strenuously engaged in battling the SARS-CoV-2 outbreak. In this context, the Italian public health community has been at the forefront, fire-fighting this sweeping pandemic.With this case report, we aim to provide a general and qualitative perspective on the pandemic response implemented by the Department of Prevention , which is the operative branch of the local health authorities of the INHS in charge of public health. Drawing from the hard lessons of COVID-19 in Italy, the Western country most affected by the pandemic to date, we share a preliminary epicrisis and reflections on the current situation, as well as insights and priorities for the future. Firstly, the institutional role and activities of DPs during the initial phase of the pandemic are set out. Secondly, strengths and weaknesses, threats, and opportunities are described. Thirdly, we generate hypotheses about factors which may promote or hinder the prevention and management of a pandemic locally.Italy\u2019s healthcare system comprises a regionally organized NHS. The fundamental principles of the INHS include universal coverage, social financing from general tax revenues, and non-discriminatory access to healthcare services. The system provides largely free healthcare at point of delivery, and is regionally administered, with the central government sharing responsibility with the respective regions for healthcare services planning and delivery . At presThe Ministry of Health is the main institution responsible for public health at the national level. The functioning of the Ministry of Health is supported by several established governmental agencies. At present, the most important such agency for public health, including emergency responses, is the National Institute of Health (Istituto Superiore di Sanit\u00e0), which undertakes scientific research, surveillance, and promotion of public health practices. Within each region, the responsibility for the organization and delivery of services rests on specific geographically and population-defined institutions\u2014the Local Health Authorities . The Department of Prevention, which is one of the three \u2018pillars\u2019 of the INHS (legislative decrees no. 502 of 1992 and no. 229 of 1999), is the operative branch of every local health authority in charge of preventive medicine and public health, including pandemic response.The main functions of Departments of Prevention include prophylaxis of infectious and parasitic diseases; protection from the health risks of living environments and workplaces ; veterinary safety and health ; veterinary pharmacovigilance; hygiene of livestock production, and protection of health and hygiene of food of animal origin); food hygiene and safety; nutritional surveillance and prevention; and health promotion on noncommunicable diseases . DepartmThe epidemic scenario changed rapidly, as did the response strategy and measures. From 22 January  to mid-April 2020, the Italian government enacted over 160 decrees, orders, circular letters, notices, advices, or protocols related to the COVID-19 emergency  . AdditioWe summarize below the practical measures, grouped into three categories that were instituted for the containment and mitigation of the epidemic and were managed directly by the DPs.(1)Membership of local crisis task force.Epidemic risk assessment and analysis of scenarios and health system capacity .Development and updating of local emergency plans.Coordination with institutions  and non-healthcare bodies .Provision of information and education to healthcare workforce .Advice for vulnerable groups , schools, and businesses.Designating dedicated facilities for isolation.Support to the local health authority for coordination and management of the crisis:(2)Contingency plan: rescheduling non-urgent activities and maintaining only essential programs , telemedicine , assignment of staff to COVID-19 tasks, and protection of the workforce.Joint integrated response with primary care teams for detection, assessment, rapid reporting, and active surveillance of suspected or confirmed COVID-19 cases.Establishment of an alert system and dedicated helpline.Information system for the management and traceability of testing.Sharing practices and data with other DPs.Internal reorganization and infrastructure:(3)Active investigation of cases  and clusters and contact tracing (concentric circles approach).Deciding on the necessity for quarantine and home isolation.Swabbing and testing, especially through proximity diagnostics .Active surveillance for people under quarantine and home isolation.Implementation of orders and advice on physical distancing, environmental hygiene, mortuary police, veterinary medicine, and food safety.Guidance and controls on physical distancing and other preventive measures in different community settings .Advice and support for risk assessment and health surveillance in workplaces and other community settings .Risk communication and community engagement practices .Travel advice and screenings of travelers.Collection, analysis, and dissemination of surveillance data .Blocking and tackling:We undertook a strengths, weaknesses, opportunities, and threats (SWOT) analysis to provide a quick, pragmatic, and preliminary overview of the perceived state of response strategies and operations from the DP perspective. Such a tool has been applied elsewhere for reviewing healthcare response to COVID-19 .We drew from published literature, practical experience, and consensus brought together at short notice by a group of senior members of Italian Society of Hygiene, Preventive Medicine, and Public Health. In March and April 2020, we performed two rounds of discussion linked to two online meetings of members of the extended college of operators of Prevention, Public Health. and Medical Directorates  and one additional meeting of preparation of an online webinar on the state of pandemic response in Italian regions. Themes were collected and reviewed by the authors. To generate the SWOT factors, we set a limit of seven items for each factor, and we selected only items with a full consensus among professionals on priority, generalizability, and relevance.For analyzing and discussing results, we relied on available data from: the Italian Observatory on Prevention (pre-pandemic state of DPs) , a socieWe summarize below the results of the analyses of strengths, weaknesses, threats and opportunities.National event-based surveillance and analysis for public health emergencies and laboratory capacity for detecting prioritized diseases and providing real-time data .Well-functioning national influenza surveillance network that is supported by regional reference laboratories .Consolidated experience in first-line response to infectious emergencies, including the severe acute respiratory syndrome (SARS), the influenza pandemic, and Chikungunya, as well as the measles outbreaks and epidemic meningitis.National coordination and progressive strengthening of the response, consistent with risk assessments and recommendations of the World Health Organization and the European Center for Disease Prevention and Control.Key role of DP in the governance of the emergency within the Local Health Authority.Comprehensive and integrated community-based response supported by all the units of the DP .Awareness and early activation of the public health community.Inadequacy of national and regional public health emergency preparedness as well as response planning and operations, including laboratory capacity and medical countermeasures , which lRapid change, perceived inconsistency, and bureaucratic rigmarole  in technical orders and clinical protocols , sometimes due to international guidance .Non-homogenous and limited operational capacity of DP and integration with primary care.Patchwork responsiveness and communication at DP level, given the time needed to implement an unprecedented organized response.Reactive and \u201clocal mindset\u201d in critical thinking and \u201chomemade\u201d solutions to support operations of DPs .Sparse availability of tools for data integration and smart technologies deployable to support contact tracing, surveillance, and other public health interventions.Greater mandate and expanded capacity for preparedness planning, surveillance, and scientific advisory support from European and Italian national authorities.Rapid upgrade of national and regional infrastructure for emergency response, including increased human resources capacity and \u201cprotected\u201d supply chains.Allocation of resources and reengineering integration models and tools for robust collaboration, particularly \u201cintra-territorial care\u201d, between public health and primary care agencies.Pragmatic and action-oriented reframing of duties and powers between healthcare and other institutional authorities and politics.Accountable response supported by exponential technologies  and effective policies for real-life implementation of telemedicine.Insufficient resilience of supply chains for protective equipment and other medical countermeasures.Health consequences of prolonged interruption or delay of population-based prevention programs  and clinical care.Inconsistencies between regional strategies that alter the ability to set up uniform, robust planning for future responses to support overextended health and social care.Substantial countrywide social, political, and economic disruption that impacts health and social services.A proactive and targeted public health response is fundamental for interrupting human-to-human transmission chains and preventing further spread, thereby reducing the intensity of the epidemic. Therefore, in response planning, even at the local level, it is crucial that decision makers primarily understand the pandemic as a public health problem and not as a hospital (or intensive care) issue, especially after the emergency phase is over and the necessity for the containment role of hospitals is greatly diminished. The strengths and weaknesses of the local public health response during the first pandemic phase in Italy were several and varied. Support to the local health authority for coordination and management of the crisis, internal reorganization, and infrastructure guaranteed governance and stewardship for public health action. The cooperation with primary care was fundamental for managing \u201cblocking and tackling\u201d activities.Core fieldwork and labor-intensive practices for contact tracing and quarantining might have been affected by initial delays in tailoring the emergency response, multiple systemwide organizational and technological constraints, and excessive focus on symptomatic people during the epidemic\u2019s peak. In a rapidly changing epidemiologic scenario, it was essential to adapt strategies to locally available capacity and resources  and pressure on healthcare services.Until we have effective vaccines and treatments, public health work will continue to be crucial for protecting people and communities.In the 14th century, starting in 1348 during a bubonic plague outbreak in medieval Italy, physicians and public health officials started to implement some of the world\u2019s first effective practices of anti-contagion measures related to social distancing and disinfection of surfaces . CurrentEvidence to date from China, South Korea, and other Asian countries , as well as data emerging from some European countries, indicates that early decisive actions may reduce community transmission . FurtherThe comparatively high rate of critical cases and deaths observed in Italy versus some other high-income countries could be attributable to: demography and epidemiological factors ,22,43, lAt the time of writing (20 April), in Italy there were almost 81,000 people in home isolation  and around 1,400,000 tests performed  ,19. In IItalian regional and local responses were remarkably different. The regional structure of the Italian national health service caused diverse regional responses to the emergency .A thorough scientific comparative analysis of facts and outcomes is needed. Certainly, the COVID-19 crisis exacerbated existing fault lines and vulnerabilities that everyone in the public health community has recognized and warned about for years. What we can argue is that the response was more effective and proactive where organization, qualifications and competencies, operational capacity, and territorial capillary presence of Departments of Prevention were consistent with the current national legislation and guidance for organization, practice, and allocation of resources within the Italian National Health Service. A high level of integration of public health with primary care and hospital services is another factor hindering an effective response.An interesting Italian case study on the value of a territorial response may be provided by the Veneto Region, which probably benefited from an early but circumscribed outbreak . In thisPublic health approaches, smart social distancing policies, aggressive tactics for supporting preventive measures in the community , active surveillance, contact tracing and testing, and home care as an elective setting for early clinical treatment of mild COVID-19 patients during containment and mitigation of epidemics may reduce the growth of the contagion curve, prevent the saturation in hospital services and nosocomial viral spread, decrease the number of deaths, and enable de-escalation of control measures.To act swiftly in protecting medical personnel, to avoid loss of personnel capacity and limit nosocomial virus spread.For early and smart swabbing primarily linked to epidemiological investigations, and tracing of high-yield contacts (including home testing) and risk categories .For acute respiratory infection/influenza-like illness sentinel surveillance through sentinel general practice and telephone/app helplines.For policies and rationale for rapid point-of-care diagnostic testing and seroepidemiologic population surveys.For optimizing the use and benefits of public health interventions through real-time accessibility of data and systematic evaluation.Other lessons relevant to other countries, from the difficult but nonetheless educational episode that Italy has experienced, indicate the need:We grounded our assumptions and hypotheses about the factors which promote or hinder the prevention and management of a pandemic locally on perception and data available in an emergency and rapidly changing context. In addition, Italy has a slightly different health system compared to other developed systems, and we are aware that our analysis and suggestions may not be applicable in other settings. SWOT results and discussion relied on a pragmatic exchange and consensus process and were not based on any systematic literature review or quantitative analysis. Therefore, information gathered may be oversimplified, some data overlooked, and authors\u2019 biases introduced. Despite such limitations, we believe this case report can provide a preliminary, contextualized, and comprehensive insight into the local response of the Italian Department of Prevention and the value of certain public health measures during the COVID-19 crisis. Raising awareness of the complexity of activities to perform during an epidemic crisis may help countries and public health officials in their strategic planning and on-the-ground decision making.In moving from a strict physical distancing period (Phase 1) to a staged reopening phase (Phase 2), until an effective vaccine or treatment is available (Phase 3), public health is essential in managing risks of increased transmission of COVID-19 to the health and wellbeing of the public, society, and the economy, via measures taken to reduce the spread of the disease .Therefore, after the end of lockdown, in going back to a \u201cnew normal\u201d, public health will be the key driver for informing decision-making with the engagement of all stakeholders. Measures to phase out confinement need policies and actions at local, regional, national, and international levels . During Driving and organizing boot-on-the-ground prevention and surveillance to protect vulnerable groups and the general population.Continuing to reshape the public health risk assessment and management system to ensure optimal epidemic response capacity.Continuing education and capacity building of public health workers.Standardizing terminology, communication tools, guidelines, and actionable protocols for practice.Replacing structurally bureaucratic management and low-value interventions with pragmatic local, community-based practice and scientifically sound practice.While scientific research and biomedical innovators are tackling the virus at unprecedented speed, additional systemwide priorities are:Hopefully, we will be able to ride the wave of this dramatic health crisis, transforming it into a relevant scientific and professional opportunity for hygiene and public health, building in the post-COVID-19 period a cutting-edge, attractive, and modern discipline .The community of public health physicians, health assistants, and other prevention professionals working in DPs and in other positions within the Italian NHS are fully committed to a continued timely, professional, non-fungible, and resilient action and practice exchange. Sharing experiences in the field, in addition to research, is crucial for the better management of healthcare services during the pandemic crisis for saving lives and protecting communities.The Department of Prevention is the entity of the Local Health Authority of the Italian National Health Service in charge of hygiene and public health, including the management of epidemiologic emergencies.Since the beginning of the outbreak, the work of the Departments of Prevention was crucial in supporting coordination and management of response operations at the local level, as well as supporting and managing activities of case finding, tracing and testing, and quarantining and home isolation, as well as other public health community measures .Analysis and reporting of the local response may inform understanding of complexity of actions and challenges for controlling the COVID-19 pandemic faced by public health professionals.A community-based response to COVID-19 needs public health and primary care; regional and local differences in organization and strategies may explain different outcomes.Public health work is a key driver for a safe lifting of social distancing restrictions after the end of the lockdown."}
+{"text": "Global usage of electronic nicotine delivery systems (ENDS) has been increasing in the last decade. ENDS are non-combustible tobacco products that heat and aerosolize a liquid containing humectants, with added flavorings and often nicotine. Though ENDS are promoted as a less harmful alternative to smoking, current evidence links their use to a wide range of deleterious health effects including acute and chronic lung damage. ENDS can elicit an inflammatory response and impair the innate immune response in the lungs. Exposure to ENDS flavorings results in abnormal activation of the lung epithelial cells and \u03b2-defensins, dysfunction of the macrophage phagocytic activity, increased levels of mucin (MUC5AC) and abnormal activation of the neutrophilic response (NETosis). ENDS menthol flavorings disrupt innate immunity and might be associated with allergies and asthma through activation of transient receptor potential ankyrin 1 (TRAP1). Recent studies have expanded our understanding of the relationship between the homeostasis of lung innate immunity and the immunomodulatory effect of the host-microbiota interaction. Alterations of the normal respiratory microbiota have been associated with chronic obstructive pulmonary disease (COPD), asthma, atopy and cystic fibrosis complications which are strongly associated with smoking and potentially with ENDS use. Little is known about the short-and long-term effects of ENDS on the respiratory microbiota, their impact on the innate immune response and their link to pulmonary health and disease. Here we review the interaction between the innate immune system and the respiratory microbiota in the pathogenesis of ENDS-induced pulmonary dysfunction and identify future areas of research. Global usage of electronic nicotine delivery systems (ENDS) has increased in the last decade, especially among youth and young adults . The preThe recent outbreak of electronic cigarettes, or vaping, product use-associated lung injury (EVALI) raised national concern about the harmful effects of ENDS products and constituents . SimilarThe respiratory microbiota has also shown to play a crucial role in the lung innate immunity and inflammatory response in health and disease . Recent Prevotella spp.), Firmicutes (including Streptococcus spp. and Veillonella spp.), Proteobacteria, and Actinobacteria  and viral communities (Anelloviridae family)  .Tropheryma whipplei in the LRT  microbial immigration from the oropharynx  ; (b) mic the LRT  and the  the LRT . A unifi the LRT .The airways epithelium provides a biophysical protective barrier  and a siHaemophilus species in patients diagnosed with COPD. Thus, the respiratory microbiota interacts with the airway epithelium and phagocytic cells in a positive feedback loop to develop immunological tolerance and prevent exaggerated inflammatory responses. Further research is needed to elucidate specific mechanisms explaining immunological tolerance in the respiratory tract and to identify potential intervention targets in respiratory pathologies.According to The production of mucus and antimicrobial peptides and proteins is a key element of the innate immune system of the lung. The airway surface liquid facilitates the mucociliary transport of toxicants, microorganisms, or particulates; lubricates and hydrates the airways; and, contributes to the epithelial barrier . The muc2, immunoglobulin A, lung, and nasal epithelium clone protein, collectins (surfactant protein A and surfactant protein D), mannan-binding lectin, cathelicidins, and \u03b2-defensins  in the airways (Nicotine has been shown to increase mucin production and mucus viscosity through activation of the \u03b1 airways . Nicotin airways . However airways . Inhaled airways . Further airways . Thus, nin vitro model. Moreover, ENDS flavoring chemicals play a major role on the cytotoxic effects of e-liquids and e-liquid aerosols . ExposurStaphylococcus aureus, Streptococcus epidermidis, and Micrococcus luteus (Additionally, Clapp et al. showed that exposure to cinnamaldehyde-containing ENDS might decrease the mucociliary escalator motility by reducing bioenergetic activity  and may s luteus  and membs luteus . ENDS mes luteus , arthrits luteus , and asts luteus . Though in vitro, animal, and human studies are increasingly showing a link between the pathophysiology of respiratory disease and the exposure to ENDS aerosols (Little is known about the short- and long-term effects of ENDS on the respiratory microbiota, their impact on the innate immune response and their link to pulmonary health and disease. Preliminary studies have expanded our understanding of the relationship between the homeostasis of lung innate immunity and the immunomodulatory effect of the host-microbiota interaction. Existing and emerging evidence from aerosols . Relatedaerosols , asthma aerosols , and cysaerosols , which aFew studies have focused on the relationship between the respiratory microbiota and the immune response to air pollutants and toxicants in the respiratory tract. in vitro and in vivo models for the realistic evaluation of the respiratory microbiota-lung innate immune response in the context of immunotoxicity studies. Further research on the pathogenesis of flavor-vaping induced lung injury must consider the respiratory microbiota as a potential mediator of the immune and the inflammatory response after exposure to toxicants.The recent EVALI outbreak in the US, coinciding with a surge in youth vaping, generated a movement in the research community to establish research priorities and address challenges to support the Food and Drug Administration and World Health Organization efforts to regulate and control ENDS . ElucidaZQT, DJO, and IR initiated the idea for writing the manuscript, reviewed the literature, and edited the manuscript. ZQT drafted the manuscript. ZQT, DJO, IR, DC, DL, and SG revised, edited, and approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The therapeutic armamentarium in Systemic Lupus Erythematosus (SLE) is expanding with the introduction of novel biologic and small-molecule agents. Complementary to randomized controlled trials, registry-based studies are advantageous due to the inclusion of a wider range of patients from daily practice and the potential for long-term monitoring of the efficacy and safety of therapies. Moreover, data from registries can be used to identify disease phenotypes that best respond to biologic agents, and to correlate clinical response with parameters such as co-administered therapies and comorbidities. In this project, we will use the configuration of the Hellenic Registry of Biologic Therapies for inflammatory arthritides in order to design a dedicated SLE module with variables pertaining to global and organ-specific disease activity, severity, flares, organ damage/outcome, comorbidities and adverse events. The second stage will involve the pilot implementation of this platform for the multicentric registration of SLE patients who are treated with belimumab. The significance lies in the development of a structured registry that enables the assessment of the disease burden and the long-term efficacy and safety of existing and future biological agents in SLE. Piloting the registry can serve as a basis for establishing nationwide collaborative efforts. Although these agents are generally efficacious in controlling the disease, still, a considerable proportion of patients fails to achieve long-standing remission.2 Importantly, conventional drugs, particularly corticosteroids, are associated with excessive toxicity risks, accrual of comorbidities and irreversible end-organ damage.3Systemic lupus erythematosus (SLE) encompasses a wide range of clinical and immunological manifestations, which makes monitoring of patients and assessment of their response to therapy a challenging task.4 have led to the expansion of the therapeutic armamentarium due to repositioning of drugs administered in other medical conditions  and the increasing use of approved (e.g. belimumab6) and non-approved  biologic agents. Based on the findings of recently performed controlled trials,14 a number of innovative therapies in SLE, including monoclonal antibodies  and small molecules , are expected to be introduced in the near future.Scientific advancements in our understanding of the immunopathogenesis of SLE, coupled with better-designed clinical studies,16Post-marketing analysis of the efficacy and safety of new drugs is important in defining their application in routine clinical practice. In addition to the results from randomized clinical trials (RCTs), a significant amount of information can be derived from patient registries that systematically assess the effects of treatments under \u201creal-life\u201d conditions. Registries are also advantageous because they allow the inclusion of a wide spectrum of patients without the stringent exclusion criteria of RCTs , and monitoring for long-term drug efficacy and safety (including rare adverse events).In the case of SLE, which is a multifaceted, systemic auto-immune disease, data from organized patient registries may be particularly useful to approach clinically-relevant issues that cannot be easily addressed through clinical trials. These may include, for instance, the definition of disease endo-phenotypes that respond better to individual treatments, and the association between drug efficacy/safety with various disease parameters . Furthermore, collected data may help to obtain unique insights into the mechanisms of action of novel therapies.20 Likewise, large SLE registries, such as the Johns Hopkins Lupus Cohort, have provided significant knowledge with regards to the dose-dependent corticosteroid toxicity and the role of hydroxychloroquine in prevention of disease flare-ups.3 Another example is the British Isles Lupus Assessment Group (BILAG) Biologics Register of SLE patients, which has described the main features of patients who are candidates for biological treatment and has investigated the short-term efficacy and safety associated with the use of rituximab.7The value of establishing registries of patients receiving biological agents has been illustrated in inflammatory arthritides . Thus, analysis of registry-derived data has shed light on topics such as the identification of clinical factors that are predictive of treatment response, the safety of biologics in terms of the risk for latent infections and malignancies, the use of sequential therapies (\u2018switches\u2019), the main causes of drug discontinuations and other.To date, there is no structured platform for registering SLE patients in Greece under biologic therapies, and, accordingly, there is paucity of data on the indications, long-term efficacy and safety of these agents in real-life clinical settings. In this study, we seek to establish and implement a pilot system for the electronic registration and monitoring of patients with SLE who are treated with existing biologic but also, future novel therapeutics agents.The aim of the present study is to establish and run a pilot study of an electronic registry for monitoring SLE patients who are treated with novel/biologic therapies. The study has multicentric, prospective design with two implementation stages.This is a prospective study that will be performed at the Rheumatology Clinic, University of Crete Medical School and University Hospital of Heraklion (involved at stages I and II of the protocol) in collaboration with the Rheumatology Units/Clinics of the \u201cAttikon\u201d University Hospital, \u201cLaiko\u201d General Hospital, General Hospital of Asklepieion Voula, Hippokration University Hospital of Thessaloniki, and \u201cSismanogleio\u201d General Hospital (involved at stage II of the protocol). The study has been approved by the Ethics Committees of the participating centers.17 following amendments to capture at each visit: the dosage of main and secondary treatments, general and organ-specific indices of SLE disease activity, flares, organ damage, health-related quality of life and functional status, comorbidities, adverse events and causes of drug discontinuation (outlined below).The first stage (0\u20136 months) of the protocol includes the design of a specialized electronic platform (registry) for patients with SLE. The development of the registry will be based on the configuration and software of the existing registry of patients with chronic inflammatory arthritides who are treated with biologic agents ,21 SLICC 2012,22 EULAR/ACR 201923) for SLE, and b) already receive or are started on belimumab, which represents the single approved biologic agent in SLE.24The second stage (7\u201330 months) of the protocol will include the pilot use of the electronic registry for the multicentric enrolment and longitudinal monitoring of patients who meet the following inclusion criteria: a) fulfil at least one of the three classification criteria , attainment of low disease activity and remission states, the co-administration of glucocorticoids and other treatments, major events (comorbidities) and adverse events (outlined below).We also plan to update the long-term efficacy and safety data of a previously published cohort of patients.http://web-new.ics.forth.gr/ceha/). This is a web-based platform with secure connection, anonymised entry of patient data, encrypted data storage in line with the General Data Protection Regulation (GDPR) and ability to export selected data for further analysis. The SLE registry module will be based on the structure and configuration of the Hellenic Registry of Biologic Therapies for patients with inflammatory arthritides.17An online software is under development at the Rheumatology Clinic, University of Crete Medical School, in collaboration with the Centre for eHealth Applications and Services (CeHA) at the Institute of Computer Science, Foundation for Research and Technology \u2013 Hellas (ICS-FORTH) Date of diagnosis21 SLICC 2012,22 EULAR/ACR 201923)SLE classification criteria  based on BILAG-defined organ activity,Disease activity pattern 27 Physician Global Assessment [PhGA]28)Global activity indices Organ-specific activity indices Disease flares (SELENA-SLEDAI Index30 and remission31Definitions of Lupus Low Disease Activity State (LLDAS)32)Irreversible organ damage (SLICC/ACR Damage Index33)Functional status Comorbidities : detailed record of medications  and administered forms/dosagehttps://www.meddra.org/faq/meddra-general), treatment discontinuationsAdverse reactions and events  and/or at regular (6-month) follow-up intervals:Each participating centre will be granted access to the electronic platform (registry) with unique credentials in order to enter their own patient data. As this is a pilot implementation of the registry, we aim to enrol a total of 60 SLE patients under treatment with belimumab, which will allow to obtain statistically robust results.A single export of merged patient data from all centres will be obtained for statistical analysis (months 31\u201336). Descriptive results on demographics, proportion of patients with partial or complete clinical response, attainment of LLDAS and remission/flares will be calculated. Efficacy will be correlated with baseline clinical and demographic characteristics. Safety will be assessed according to occurrence of major events. Treatment survival and reasons for discontinuation will also be evaluated.Registries of patients with chronic rheumatic diseases receiving biological therapies have provided significant insights regarding their long-term efficacy and safety in \u201creal-life\u201d clinical practice. In recent years, biological agents such as belimumab and rituximab have been introduced in the treatment of SLE, and based on the results from ongoing clinical trials, it is likely that additional innovative therapies may be added in the near future. The importance of this project lies in the development and pilot use of a dedicated electronic registry of patients with SLE who are treated with novel/biologic therapies, which will enable the detailed monitoring of drug efficacy and safety by the use of validated clinical instruments . Moreover, the registry will help to assess the burden of the disease  among contemporary SLE patients who are seen at large Rheumatology Centres in Greece, as well as the long-term retention rates of the biological agents used in SLE such as belimumab. Importantly, the successful pilot implementation of the registry could pave the way for establishing broader collaborative projects at a national level."}
+{"text": "Sporotrix sp. He also had pulmonary involvement and therefore the disease was classified as systemic sporotrichosis, a rare form that usually affect patients infected with HIV. Chronic alcohol abuse was considered the factor of immunosuppression for the patient.A 44-year-old male patient presented with nodules that evolved with inflammation, following drainage of seropurulent secretion and ulceration. The patient had a 6 year-history of alcohol addiction and reported contact with cats. At the physical examination, the patient had skin-colored and erythematous nodules, and ulcers covered with thick, blackened crusts on the face, trunk and limbs. A culture of a nodule fluid revealed growth of  Sporothrix. Approximately 80% of the affected patients present the lymphocutaneous form. However, in patients with immunosuppression, disseminated forms can occur.2Sporotrichosis is a subacute or chronic subcutaneous mycosis caused by dimorphic fungi of the genus A 44-year-old male patient, presented with subcutaneous nodules that developed inflammation, following drainage of seropurulent secretion and ulceration. The patient had a 6 year-history of alcohol addiction. He denied comorbidities, although he reported prolonged contact with cats of unknown origin.At the physical examination, the patient had skin-colored and erythematous subcutaneous nodules, and ulcers covered with thick, blackened crusts on the face, trunk and limbs .Figure 1Due to compatible epidemiological history and the evolution pattern of the lesions, the main diagnostic hypothesis was sporotrichosis.Sporotrix sp. after 5 days  did not show any abnormal results, and the serology test results  were negative.High-resolution chest CT revealed atelectasis, ground-glass infiltrate, hilar lymphadenopathy and pleural effusion in both lungs.The disease was classified as systemic sporotrichosis, according to the classification recommended by Orofino-Costa et al,Patient was treated with amphotericin B lipid complex for 28 days, followed by itraconazole, during 11 months and had a good response, with healing of ulcers and without relapses in a 6-month follow-up.S. brasiliensis is the main (88%) etiological agent of human and animal sporotrichosis.The feline zoonotic transmission of sporotrichosis was observed in the 1990s in the State of Rio de Janeiro, Brazil, which is currently considered to be a hyperendemic area. In the South and Southeast Brazilian regions, Systemic forms are rare and usually affect immunocompromised individuals, mostly those with HIV .Chronic alcohol abuse results in lymphopenia and chronic activation of the T-cell pool, which may alter the T-cell ability to expand and respond to pathogenic agents, inducing to an anergy state and, changing Th1 and Th2 response.S. brasiliensis is the most virulent species of this genus, due to its ability to invade tissues and lead one to death.5Th1 response is considered as the main control factor of fungal infection. In addition to patient immunosuppression, we should emphasize that The high prevalence of alcohol abuse in the Brazilian population, estimated at 13.7%, and the increasing zoonotic transmission of sporotrichosis may lead to an increase in the prevalence of disseminated forms of the disease.Our report corroborates the association previously reported by others between alcoholism and the spread of sporotrichosis.10None declared.Norami de Moura Barros: Approval of the final version of the manuscript; conception and planning of the study; elaboration and writing of the manuscript; obtaining, analysis, and interpretation of the data; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.Allen de Souza Pessoa: Approval of the final version of the manuscript; conception and planning of the study; elaboration and writing of the manuscript; obtaining, analysis, and interpretation of the data; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.Arles Martins Brotas: Conception and planning of the study; obtaining, analysis, and interpretation of the data; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the literature.None declared."}
+{"text": "Since the first COVID-19 case importation on January 23, Vietnam is now the only country in the world contain the epidemic with 268 confirmed cases (52 active and 216 recovered) with no deaths over the past three months. Being proactive in contact tracing and restrict quarantine of multiple clusters early are common policies that helped Vietnam efficiently control the spread of COVID-19. However, they are resource-intensive while the country has a limited capacity for massive testing. How to ensure surveillance and detection at the grassroots level, especially in rural and remote areas, is a critical question that is challenging not only Vietnam but also other low- and middle- income countries. In this viewpoint, we first summarize the roles and responsibilities of the network of village health workers over its long history of development in Vietnam. Thereafter, we discuss the functionalities of this informal taskforce in monitoring COVID-19 epidemic and delivering packages of interventions, especially in disadvantaged settings.Sharing a borderline of nearly 1400 km with China, it has been speculated that the northern mountainous region of Vietnam is at substantial risk of COVID-19 transmission . The regIn Vietnam, village health care is part of the grassroots health system and playing an important role in primary health care (Understanding the important role of village health care in primary health care in the community, Vietnamese government and Ministry of Health issued a number of decisions on strengthening and empowering the grassroots health care network, including village health services. The Health Minister's Decision No. 3653 on November 15, 1999 of the Health\u2019s Minister defined the functions and tasks of village health workers, which provided village health workers with clear guides on their functions and duties in the care and protection of people's health. The decision introduced five major responsibilities of village health workers, namely health education and communication, instruction of performing hygiene for disease prevention, maternal and child health care and family planning, first aid and basic medical care, and implementation of health programs . AccordiCOVID-19, which is caused by the new strain of coronavirus SARS-CoV-2, is an infectious respiratory disease that can result in pneumonia in humans . InfecteIn the fight against COVID-19, it is essential to mobilize existing resources and provide materials and skills as well as lean management for at-risk communities to efficiently detect early signs of localized transmissions, identify infected areas and effectively quarantine them. In order to do so, Village Health Collaborators should be quickly equipped with knowledge and skills in COVID-19 control and prevention through multilingual training materials delivered by both local and national trainers. Governors should set up mechanisms and protocols for information exchange, data synthesis, sample collection, and surveillance. It is also important to notice that some important skills are missing, including the identification of mental health symptoms, mapping most vulnerable groups, such as the elderly, the poor, etc. and community-based rapid risk assessment. Counselling and social support should also be incorporated as parts of comprehensive approaches for those living in disadvantaged areas."}
+{"text": "This mini-review focuses on the emergence of locomotor-related movements in early infancy. In particular, we consider multiples precursor behaviors of locomotion as a manifestation of the development of the neuronal networks and their link in the establishment of precocious locomotor skills. Despite the large variability of motor behavior observed in human babies, as in animals, afferent information is already processed to shape the behavior to specific situations and environments. Specifically, we argue that the closed-loop interaction between the neural output and the physical dynamics of the mechanical system should be considered to explore the complexity and flexibility of pattern generation in human and animal neonates. Locomotor function bridges the entire life span but its development during fetal age and the first post-natal years of life is crucial for the acquisition of mature behavior. Where does locomotor behavior start? This question, suggesting a developmental continuity, is a central and long-standing issue , sensory signals originating in the limbs, and supraspinal signals (Grillner, During the early postnatal period, the locomotor-related movements also exhibit remarkable plasticity (Altman and Sudarshan, Based on the striking similarities in the early development of locomotion across mammalian species (Garwicz et al., More recently, Sylos-Labini et al.  suggestein vitro, called fictive locomotion (e.g., Matsushima and Grillner, To date, numerous experimental paradigms examine the development and early plasticity of locomotion Even if the afferent information is used to a limited extent to adapt motor behavior to specific environmental contexts in neonates (Hadders-Algra, The first years of life represent an important phase of maturation of the central nervous system, processing of sensory information, and posture control. Also, many constraints evolve during the first year, such as the muscle-to-fat ratio in lower-limbs (Thelen et al., In particular, studies showed considerable changes in muscle activity with age. For example, agonist-antagonist muscle co-activation during stepping decreases as age increased from 1 to 12 months (Teulier et al., Such spatiotemporal reorganization of the locomotor output has already been investigated during infancy, highlighting how the rudimentary locomotor-related movements of neonates evolve into mature sophisticated ones (Lacquaniti et al., The elements observed in infancy are not discarded but instead become adapted, in parallel with changes in locomotion biomechanics (Dominici et al., The fine-tuning and reshaping of activation patterns of the multiple precursors in the first year of life stems in part from a functional reorganization of interneuronal connectivity, growing integration of supraspinal, intraspinal, and sensory control (Forssberg, Human infants also appear to be sensitive to transient changes in sensory input and respond to it appropriately (Yang et al., Less insight is available on the role of experience in the developmental process in human neonates during the postnatal period. In animals, motor experience during the prenatal and postnatal period has consequent developmental implications Provine, . Also inIn this mini-review article, we highlight the need to increase our understanding of the fine-tuning and reshaping of multiple precursors during the development of mature locomotor movements. Since motor coordination in the neonate is already punctuated by developmental plasticity, early responsiveness to environmental context could potentially be used to diagnose developmental disabilities, but also to design and test early therapies. By calling attention to experience-dependent development of the motor system, we hope this will inspire future studies on the control of movement during early development.All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Trypanosoma cruzi infection, is considered nonendemic in the United States of America , assuming that this chronic affection\u2019s epidemiology is different from that of Latin American countries. The attention is mostly focused on blood bank screening, organ donation, and vertical (mother to child) transmission [T. cruzi, particularly in the light of a recent acknowledgment about the role that vectorial transmission may have on the CD in the USA. A low awareness among physicians about CD risk besides its migratory origin can contribute to an existing underreporting rate, thus masking the accurate estimation of CD burden in the USA [Human Chagas disease (CD), caused by the smission . This apT. cruzi infections in immunocompetent individuals can pass undiagnosed and undetected among residents [Cases of autochthonous infection in the USA are not accurately tracked since it is only mandatory to report it in seven states, i.e., Arizona, Arkansas, Louisiana, Mississippi, Tennessee, Texas, and Massachusetts . Howeveresidents . In the esidents . This anAlthough imported CD cases are undoubtedly a matter of concern, there are also environmental conditions leading to autochthonous infections . New encT. cruzi infection risk components because there are parasite reservoirs among wildlife species and vectors living in contact with humans [T. cruzi transmission might resemble those of other endemic areas. Surveillance of infection prevalence among local populations of Triatominae is critical for accurate assessment of the public health risk. We attempt to contribute to this with an extensive historical literature review of records of autochthonous T. cruzi and human-related data for CD in California. This method of review provides a contemporary account of this topic\u2019s breadth of knowledge. There has been no recent review of this theme at the state level to the best of our knowledge, as has already been conducted in some other states, such as Texas [It is essential to improve our knowledge of h humans . This isas Texas .T. cruzi in triatomines, mammals and humans (CD), and human-triatomine interaction for California counties. We found 62 articles published between 1916 and 2018 encompassing 35 countries , followed by Triatoma rubida and Paratriatoma hirsuta.Between 1916 and 1930, counties , rangingThe first report of domestic incidence was recorded in the 1940s. In 38.8% of the publications reporting collection site for triatomines (19/49), at least one was collected inside human habitation. Domestic triatomine incidence was associated with dispersion from the vicinity of residences in semirural, canyon, or mountain-foothill areas ; during the monsoon, houselights are attractive to triatomines, especially while mating and/or seeking blood-meals.Twenty-two publications reported 164 triatomine bites and ensuing anaphylactic reactions among residents of 11 California counties , 80% of In publications around the 1950s, the bulk of domestic triatomines reports and human exposure came from residents\u2019 testimonies, from Kern, Riverside, Fresno, and San Diego counties, and from descriptions of clinical cases . AlthougT. protracta saliva. Along with this, human blood-meals have been found in free-roaming triatomines [Research on human-triatomine interaction in California involved two surveys conducted 50 years apart. The State Department of Health conducted a study in 1962 in Mariposa and Tuolumne counties that recorded more than 101 bite cases. In 2012, Los Angeles\u2019 residents reported bites resembling the swelling  produced by triatomines, and rural residents in Santa Barbara were found with immunoglobulin G (IgG) against the atomines .In 1982, the first autochthonous human case of CD was reported for California in Tuolumne county: a 50-year-old woman from Lake Don Pedro . ThereafT. cruzi in California is the first one in more than 50 years. A temporal analysis of the publications shows an early scientific effort to compare some endemic areas; 80% of the articles were published before the early 1980s  have led to an increasing encroachment upon the natural habitat of triatomines and their mammal hosts. This might raise the chances of triatomine domestic incidence due to their flexibility in habitat and host requirements, including dogs and other mammals . Examples of Triatoma sanguisuga in Louisiana came after the disruption of hurricane Katrina; there was a change of infestations in human dwellings [Socioenvironmental changes of the last five decades in California have not been followed by research on their effects on human-triatomine interaction and wellings .T. cruzi distribution in California. This is due to the scarcity/absence of records in some areas and early discovery of the association triatomine-woodrat that might be biased to the field research. An ecological niche modeling approach of the geographic distribution of vector species indicates favorable host habitat in many unsurveyed regions of California [County-level maps of reports only partially reflect the lifornia .T. cruzi and CD needs research/intervention on the:Our review in California highlights that a critical and accurate assessment of the public health risk for T. cruzi infection for further robust analysis on habitat suitability and risk due to socioenvironmental changes;Spatial modeling of pattern occurrences of triatomine and Dynamics and mechanisms of transmission: spatial variation of triatomine activity, infection levels and their reliance on humans-blood, dynamics of dispersal flights and free-roaming triatomines feeding habits;Identification of sylvatic, synanthropic, and domestic  animal blood-sources and determination of infection variability;T. cruzi circulating strains and an analysis of the parasite\u2019s genetic variation;Identification of the Large-scale systematic programs of active surveillance, rigorous population-based data collection, and comprehensive assessment to determine infection prevalence and morbidity to identify factors that might inform policy and program-driven actions, especially among the vulnerable (impoverished residents living in substandard housing);Improvement of local knowledge local about epidemiology and ecology and the criteria for public health promotion to raise awareness among residents, physicians, and clinicians;Active screening of heart failure patients, hunters/campers, and pregnant women; andContinuing medical education programs on diagnosis and treatment among physicians.S1 Text(DOCX)Click here for additional data file."}
+{"text": "The beneficial effects of oxytocin on infarct size and functional recovery of the ischemic reperfused heart are well documented. The mechanisms for this cardioprotection are not well defined. Evidence indicates that oxytocin treatment improves cardiac work, reduces apoptosis and inflammation, and increases scar vascularization. Oxytocin-mediated cytoprotection involves the production of cGMP stimulated by local release of atrial natriuretic peptide and synthesis of nitric oxide. Treatment with oxytocin reduces the expression of proinflammatory cytokines and reduces immune cell infiltration. Oxytocin also stimulates differentiation stem cells to cardiomyocyte lineages as well as generation of endothelial and smooth muscle cells, promoting angiogenesis. The beneficial actions of oxytocin may include the increase in glucose uptake by cardiomyocytes, reduction in cardiomyocyte hypertrophy, decrease in oxidative stress, and mitochondrial protection of several cell types. In cardiac and cellular models of ischemia and reperfusion, acute administration of oxytocin at the onset of reperfusion enhances cardiomyocyte viability and function by activating Pi3K and Akt phosphorylation and downstream cellular signaling. Reperfusion injury salvage kinase and signal transducer and activator of transcription proteins cardioprotective pathways are involved. Oxytocin is cardioprotective by reducing the inflammatory response and improving cardiovascular and metabolic function. Because of its pleiotropic nature, this peptide demonstrates a clear potential for the treatment of cardiovascular pathologies. In this review, we discuss the possible cellular mechanisms of action of oxytocin involved in cardioprotection. Our important findings highlighted the discovery of a specific OT system, including the presence of OT and the OT receptor (OTR) in the rodent and human heart . The prea neural  and renaa neural . Conversa neural . Howevera neural . In facta neural .The role of OT in the regulation of blood pressure is well documented . OT reguin vitro and contain numerous cardiac progenitor cells (CPCs), which can contribute to cardiac reparative processes . Epidemiological studies have shown that death rates from cardiovascular diseases are increased in the patients with T2DM. This higher mortality rate is explained, in part, the downregulation of the pro-survival kinase pathways, disturbances in the mitochondrial permeability transition pore (mPTP), dysfunctional mitochondrial adenosine triphosphate (ATP)-sensitive potassium channel (mKATP) channels, and increased calcineurin activity, all of which are linked to loss of conditioning . The rolvia multiple mechanisms and pathways, affecting platelets, fibroblasts, endothelial cell, smooth muscle cells, and immune cells. In this regard, optimal cardioprotection likely requires the application of several combinations of additive or synergistic multitarget therapies (Coronary heart disease (CHD) in the form of acute myocardial infarction (MI) and acute coronary syndromes accounts for nearly one-third of heart disease-related deaths and disability in developed countries. Timely reperfusion of the coronary arteries after acute MI is critical for the restoration of blood flow. A reduction in infarct size can also be accomplished by subjecting the heart to repeated short periods of ischemia followed by IR . Rapid rherapies . In thisherapies . There iherapies . In rat herapies  and infaherapies . Downregherapies . In addiherapies . These eherapies .1/V2 receptors) and its potential involvement on cardiac function  of the G-protein coupled receptors is regulated by changes in receptor expression and resistance and local OT concentrations exposed to the OTR , which mediate the acute phase of an inflammatory response as seen in fever. The involvement of the NLRP3 inflammasome in conditions such as impaired glucose tolerance and peripheral inflammation from obesity has been reported, and evidence suggests that the inflammasome may contribute to the development of vascular and ventricular dysfunction . The mosIn addition, OT maintains the viability and morphology of CMC in the injured heart. To explain this effect, several mechanisms of action of OT in cardiac cells have been proposed. These mechanisms include decreased apoptosis, hypertrophy, and fibrosis in CMC as well as an increase in glucose uptake and oxidation. Benefits of OT also occur as a result of increased cell proliferation and differentiation of cardiac stem cells . We havein vitro model for the study of CMC in cardiac pathologies, including cardiac hypertrophy (via specific OTRs (unpublished data). This observation is consistent with the findings reported by via phosphoinositide-3-kinase (PI3K) and independent of insulin receptor signaling. This effect of OT was further increased in CMC with an uncoupler  of mitochondrial oxidative phosphorylation  and cGMP by NP production is a well-known mechanism that inhibits pathological hypertrophy  pathway. We have reported that OT regulates this pathway in CMC hypertrophy induced by ET-1 and Ang-II. In physiological concentrations (\u223c10 nM), OT prevented hypertrophy in newborn and adult rat CMC by several mediators, including PI3K/ERK1/2/ANP-cGMP/NFAT signaling . In thisertrophy . Our worertrophy . This meIn summary, OT is produced in the cardiovascular system and is critical in the regulation of cardiac and vascular function during early development and adulthood. The major actions of OT include regulation of chronotropy and inotropy of the heart as well as vascular tone of cardiac resistance vessels. OT is also involved in blood pressure and body volume regulation via the cardiac\u2013renal axis and the release of ANP and NO. In addition to cardiovascular regulation and protection, OT exerts robust anti-oxidative and anti-inflammatory effects in CMC. In cells, OT targets mitochondria, promoting glucose uptake and reducing the effects of ROS upon reperfusion.Animal studies indicate that OT is not only a cardiovascular protective peptide but also critical for cardiovascular homeostasis and in the reduction in the severity of cardiovascular pathologies. The significance of OT in cardioprotective signaling warrants further study.MJ, TB, and JG equally contributed to the organization and writing the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Dear Editor,Epidermolysis bullosa (EB) composes a group of hereditary bullous disorders in which the blisters arise spontaneously or are triggered by minimal trauma. Koebner suggested this denomination in 1886. EB is divided into four major types  and several distinct clinical phenotypes, according to the level of skin cleavage, as well as clinical and molecular characteristics.2Epidermolysis bullosa simplex with mottled pigmentation (EBS-MP) is an uncommon subtype of epidermolysis bullosa simplex . It is characterized by non-cicatricial blisters, mainly at the distal extremities, and progressive mottled hyperpigmentation. Until 2013, only 15 families and eight sporadic cases had been reported, according to the data from the Hospital Infantil Universit\u00e1rio Ni\u00f1o Jesus, in Madrid, which motivated this report.The patient was a 2-year-old girl, phototype III, with a history of blistering skin since birth. On dermatological examination she had desiccated blisters on the feet, as well as hyper- and hypochromic macules scattered over the tegument with mottled appearance . NormochFirst described in 1979 by Fischer and Gedd-Dahl, EBS-MP begins in childhood and has a genetic origin. It is a basal EBS caused by a mutation in the KRT5 gene that encodes cytokeratin 5. It occurs most commonly due to a punctual heterozygous p24L mutation in the non-helical V1 domain of cytokeratin 5.2The diagnosis of this dermatosis is based on typical clinical findings, family history, immunomapping, and/or transmission electron microscopy, as well as molecular/mutation analysis when possible.Clinically, it is characterized by non-cicatricial blisters, mainly at the distal extremities, as well as progressive mottled hyperpigmentation, which does not occur at the site of the blisters and often disappears in adulthood. Some cases may be accompanied by hypopigmented macules, as could be seen in this patient. There are also reports of palmar and plantar focal hyperkeratosis. Small acral verrucous papules, onychodystrophy, and mild involvement of the oral mucosa can be observed during childhood. Uncommon findings include photosensitivity and dental disorders (caries).The differential diagnosis of EBS-MP includes other types of EBS (mainly the herpetiformis type of Dowling-Meara), Kindler syndrome, Naegeli-Franceschetti-Jadassohn (NFJ) ectodermal dysplasia, other forms of dyschromia, Dowling-Degos disease, and even atypical cases of Darier's disease with mutations in ATP2A2.4Due to the clinical hypothesis of EB and to determine the level of skin cleavage, immunomapping or transmission electron microscopy should be performed. The immunomapping has diagnostic accuracy similar to transmission electron microscopy, with the advantage of simple and fast execution and reading. It is associated with the use of monoclonal antibodies and may be considered an indirect immunofluorescence technique. In the EBS, the skin cleavage occurs in the basal layer , and fluorescence deposition on the blister floor  is seen with all antigenic markers , as observed in this case.Ultrastructural analysis of the pigmented areas in this form of EBS demonstrates abundant mature melanosomes within the basal cells.Thus, this report details a rare case of a possibly sporadic EBS-MP. The authors emphasize the rarity of this subtype of EBS and its remarkable clinical characteristics favoring future diagnoses, and highlight its benign character, with no scarring or deforming lesions and regression of hyperpigmentation in adulthood.None declared.Fl\u00e1via Regina Ferreira: Approval of final version of the manuscript; conception and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.Carolina Fernandes Pereira: Approval of final version of the manuscript; conception and planning of the study; drafting and editing of the manuscript; critical review of the literature.Juliana Carvalho Moretto: Approval of final version of the manuscript; conception and planning of the study; drafting and editing of the manuscript; critical review of the literature.Mariana Patriota Naville: Approval of final version of the manuscript; conception and planning of the study; drafting and editing of the manuscript; critical review of the literature.None declared."}
+{"text": "Professor Daniel Noni Lantum , an AfriHe introduced several generations of doctors and public health professionals in his native Cameroon and in Africa to public health practice and directed over 500 theses. Prof Lantum is also well known for his invaluable contribution to the fight against iodine deficiency and associated disorders. His work with the World Health Organization, UNICEF, governments, non-governmental organizations (NGOs) and communities contributed enormously towards universal salt iodization, a key strategy to achieve elimination of iodine-deficiency related disorders for which he was awarded to Algepa Prize in 1996 in Paris and made him well-known in the nutrition and micro-nutrient circles. He is also known to have laid the groundwork for the creation of various faculties of medicine in Africa.Prof Lantum is also recognized for his passion for African cultural heritage. He worked tirelessly to promote African traditional medicine - that he practiced and taught unapologetically - as an important component of primary health care. Intellectual infatigable, Prof Lantum, wrote intensively in areas as diverse as education reforms, poetry, history, politics, African traditions, and religion.Prof Lantum studied Medicine at the University of Ibadan (Nigeria), graduating in 1962 with a Bachelor of Medicine and Bachelor of Surgery. He obtained a diploma in tropical medicine and hygiene at the Liverpool School of Tropical Medicine in 1965 and completed a Master (MPH) and Doctorate (DrPH) in Public Health at Tulane University (USA) in 1969 and 1970, respectively. His long and rich professional career encompasses the public sector, NGOs, and development organizations in various African countries. He was a member of numerous professional, traditional and cultural societies.In his academic career, Prof Lantum was Professor of Public Health at the Yaound\u00e9 University Centre for Health Sciences  since 1970 and was appointed in 1998 as Vice Chancellor of the Bamenda University of Science and Technology (Cameroon). He received countless distinctions from various governments, organizations, and universities across Africa.Prof Lantum will be remembered for his passion to transmit knowledge and educate the younger generation, his love for people, and his enthusiasm to address protracted public health issues in Africa. His extraordinary story telling abilities - rooted in his deep knowledge of the traditions and history of his people - translated his passion for African ancestral knowledge. May his soul rest in peace.He is survived by four children and seven grandchildren.Contributions from: Dr Raoul Kamadjeu  and Prof Charles Shey Wiysonge"}
+{"text": "The Special Issue \u201cNon-Destructive Testing of Structures\u201d has been proposed to present recent developments in the field of diagnostics of structural materials and components in civil and mechanical engineering. The papers highlighted in this editorial concern various aspects of non-invasive diagnostics, including such topics as condition assessments of civil and mechanical structures and connections of structural elements, the inspection of cultural heritage monuments, the testing of structural materials, structural health monitoring systems, the integration of non-destructive testing methods, advanced signal processing for the non-destructive testing of structures (NDT), damage detection and damage imaging, as well as modeling and numerical analyses for supporting structural health monitoring (SHM) systems. Engineering structures are gradually destroyed over time due to the influence of atmospheric conditions, excessive loads, and processes of natural aging. Since damage in a structural element may lead to improper operation of the whole object, various damage detection and structural health monitoring (SHM) methods have thus been investigated and developed to improve reliability and safety and to solve the maintenance problems of infrastructural and mechanical structures.The term non-destructive testing (NDT) covers a wide group of measurement and analysis techniques used in the process of assessing the current state of structural materials or elements. It is a quick and effective approach, the main advantage of which is the ability to examine the material in a non-invasive manner, without damaging or changing the composition or shape of the inspected object. In recent years, there has been growing interest in the development of non-invasive methods, including in the field of civil and mechanical engineering.The Special Issue \u201cNon-Destructive Testing of Structures\u201d has been proposed to gather the experience of civil and mechanical research communities in relation to the latest advances and trends in the field of diagnostics of structures and their components. A total of 22 papers were published in the Special Issue to touch different aspects connected with novel NDT approaches, with particular emphasis on the development of single and integrated measurement techniques, damage imaging procedures, advanced signal processing as well as modeling and numerical analyses for supporting SHM systems. A brief description of the Special Issue papers is presented below.pH(y) signal of the sample under different stresses. The fracture morphology was observed by using scanning electron microscopy (SEM). The results showed how different types of grooves influenced the magnetic intensity gradient changes [A wide range of experimental and numerical studies is reported in the papers in this Special Issue ,5,6,7,8.The second group of papers has been devoted to the condition assessment of concrete and cement-based materials and structures ,15,16,17Another group of articles concerned non-destructive testing of bridge structures ,19,20. KThe diagnostics of cultural heritage structures were the subjects of interest in the last two papers from this Special Issue ,22. TomaIn summary, the papers presented in this Special Issue concern various aspects of non-invasive diagnostics and present recent developments in the field of the diagnostics of structural materials and components in civil and mechanical engineering. Both interesting practical solutions and a significant contribution to the new approaches to NDT were achieved."}
+{"text": "Dear Editor,Cryptococcus neoformans is the etiological agent of cryptococcosis, an infectious disease that affects humans, domestic and wild animals. This pathogen is often found in pigeon excreta, possessing innumerable environmental sources.The diagnosis can be performed by analysis of cerebrospinal fluid (CSF), urine sediment, bronchoalveolar lavage fluid, wound exudates, floating node aspirate and suspected lesions biopsies.Treatment of cryptococcosis in immunocompetent and immunocompromised humans, consists of amphotericin B in combination with 5-flucitosin in disseminated infections; or with fluconazole or itraconazole, as an alternative for the treatment of cutaneous infections.Cryptococcus spp. The species identification and antifungal susceptibility were performed in the Vitek 2-Compact. The isolate was also identified by sequencing the D1/D2 domain of the rDNA using the primers NL1 and NL4 being identified as Cryptococcus neoformans (San Felice) Vuill (1901). Histopathology revealed numerous yeast fungal structures, best visualized by PAS staining (periodic acid-Schiff), with mucopolysaccharides capsules that stand out for Alcian Blue staining, with scarce inflammatory infiltrate in between  disease.C. neoformans meningitis.Drug resistance, when using fluconazole, is likely to occur during prolonged suppressive treatments as in cases of This report presents the medical history of a patient with cutaneous and pulmonary alterations, which allowed the diagnosis of cryptococcosis and the appropriate treatment for it. Through this report we could highlight the importance of the differential diagnosis of infectious conditions in renal transplant patients.None declared.Deborah Lucena Markman: approval of the final version of the manuscript; elaboration and writing of the manuscript; effective participation in research orientation; critical review of the literature.Pamella Paola Bezerra de Oliveira: elaboration and writing of the manuscript; critical review of the literature.Daniela Mayumi Takano: approval of the final version of the manuscript; effective participation in research orientation; critical review of the manuscript.Idalina In\u00eas Fonseca Nogueira Cambuim: approval of the final version of the manuscript; effective participation in research orientation; critical review of the manuscript.None declared."}
+{"text": "P \u2264 0.05. Three hundred and twenty-nine responded to the questionnaire. More than half of the respondents agreed that dental X-ray is hazardous to health (60.79%), and 68.1% were familiar with ALARA (as low as reasonably achievable) principle. However, only 34% are familiar with the recommendations of the National Council on Radiation Protection (NCRP) and International Commission on Radiological Protection (ICRP). The use of lead apron and thyroid collar for patients' protection from X-ray radiation was practiced among endodontic postgraduate students more frequently as well as those who are proactive in the academic field. Undergraduate students, endodontic postgraduate students, and endodontists in the academic field were the most aware towards radiation reduction measures. The use of the preventive measures needs to be emphasized more among general practitioners, endodontic postgraduate students, and endodontists especially in governmental hospitals and private sectors.The aim of this study is to evaluate the knowledge, attitude, and perception of radiation hazard and preventive measures among dental undergraduate students, general practitioners, endodontic postgraduate students, and endodontists in Saudi Arabia. Multiple choice questions questionnaires were distributed among undergraduate and endodontic postgraduate dental students, general practitioners, and endodontists in the colleges of dentistry in Saudi Arabia, government hospitals, and private clinics. The questionnaire included sociodemographic data, assessment of the knowledge of radiation physics and biology, assessment of the practice of dental radiography, and assessment of knowledge of radiation protection. Chi-square test was used for individual and multiresponse analysis. Level of statistical significance was set at  It may rnations . It has The effects of the X-ray on the living tissue are deterministic and stochastic. Both are harmful and could lead to serious complications ; therefoWe hypothesize that the knowledge and the perception of dental undergraduate students, general practitioners, endodontic postgraduate students, and endodontists on radiographic protection is high, but the attitude towards taking precautions might be low.The aim of this study is to evaluate the knowledge, attitude, and perception of radiation hazard and preventive measures of the ionizing radiation among dental undergraduate students, general practitioners, endodontic postgraduate students, and endodontists in Saudi Arabia.The present study was approved by the Institutional Review Board of Princess Noura Bint Abdulrahman University (H-01-R-059). Dental students and clinical practitioners that deal with radiography during their clinical practice were sent questionnaires related to knowledge, attitude, and perception of radiation hazard and preventive measures of ionizing radiation. The questionnaire was distributed among undergraduate and postgraduate endodontic dental students, staff, and faculty  in the colleges of dentistry at King Saud University (KSU), Princess Noura Bint Abdulrahman University (PNU), King Saud Bin Abdulaziz University for Health Sciences (KSAUHS), King Abdulaziz University (KAU), King Faisal University (KFU), Imam Abdulrahman Bin Faisal University (IAU), Umm Alqura University (UQU), King Khalid University (KKU), Taiba University (TU), Qassim University (QU), Prince Sattam University (PSAU), Hail University (UOH), Almajmaa University (MU), Riyadh Elm University (REU), and Alfarabi Colleges. Moreover, it was sent to clinicians  in government hospitals including Ministry of Health Dental Clinics (MOH), Security Forces Hospital (SFH), King Abdulaziz Medical City (KAMC), Prince Sultan Medical Military City (PSMMC), and private practice.The form was electronic based and distributed online through Google Forms by Twitter and WhatsApp social media platforms.The questionnaire was in the form of multiple choice questions related to the harmful ionizing radiation and protective measures. It was developed in English and a pilot test of 25 questionnaires was performed against a checklist to determine content clarity, language development, and validity. The questionnaire was divided into three sections: sociodemographic data that consisted of gender, age range, working place, years of clinical experience, and socioeconomic status. Assessment of the knowledge of radiation physics and biology, assessment of the practice of dental radiography, and assessment of knowledge of radiation protection were asked in the questionnaire.P \u2264 0.05.Data were entered into an electronic database and analyzed using SPSS  version 20 . Descriptive statistics were used. For differential statistics, the chi-square test was used for individual and multiresponse analysis. Level of statistical significance was set at P < 0.05), as undergraduate students showed most of the correct answers. On the other hand, most of the respondents (81.5%) agreed that radiation from dental X-ray accumulates over time, while 64.4% agreed that damage to living tissues by radiation is due to direct and indirect effect, and 61.1% agreed that short-term effects of radiation are due to large amount of radiation absorbed over a short period of time. Only 42.6% agreed that the cause of long-term effects of radiation is the small amount of radiation absorbed repeatedly over a long period of time. Almost half the respondents (53.2%) agreed that X-rays can be reflected from the walls of the room. In these responses, there was no statistically significant difference between the different educational levels (P > 0.05).Demographic data results are summarized in Most of the respondents use radiographs frequently in different stages of their endodontic treatment, either preoperatively for case evaluation (83%), or during treatment for verification of the procedure (78.1%), or postoperatively to evaluate treatment outcome (76%).Tables P < 0.05), where the endodontic postgraduate students and endodontists were mostly taking three and more radiographs compared to less number of radiographs taken by undergraduate students and general practitioners. These results were in accordance with previous studies, where they found that the number of radiographs taken during root canal treatment varies between three to four radiographs [Successful endodontic treatment requires adjunctive tools, such as intraoral radiographs, to be used preoperatively during endodontic examination and case evaluation, or during treatment for verification of the procedure, or postoperatively to evaluate treatment outcome. In this study, the frequency of taking radiographs during dental procedure differentiate statistically between the different educational groups  away from the patient at an angle of 90\u00b0\u2013135\u00b0 from the tube head (Position Distance Rule) . In 2014This study had some limitations where the number of respondents could not be controlled. Moreover, the number of respondents varied among specialities and working sectors and not equally distributed.Within the limitations of the study, it can be concluded that the knowledge of radiation hazard and preventive measures of the ionizing radiation among dental undergraduate students, endodontic postgraduate students, and endodontists in Saudi Arabia was quite fair especially in academic field. However, the radiation protection measures need to be emphasized more among general practitioners, endodontic postgraduate students, and endodontists especially in governmental hospitals and private sectors."}
+{"text": "Although oral diseases are largely preventable, they are among the most non-communicable diseases globally, and they disproportionately burden disadvantaged communities, specially within low- and middle-income nations. The COVID-19 pandemic has highlighted the social, economic, and health inequalities in our society, including the existing global oral health inequalities. There is a shortage of dentist-scientist all around the world, especially in developing countries, such as Thailand. The National Institute of Dental and Craniofacial Research (NIDCR) and Fogarty International Center (FIC), joined efforts on creating research capacity in oral health in South East Asia through the Fogarty International Center Training Program in Clinical, Public Health and Behavioral Oral Health Research for Thailand (2006\u20132016). The University of Washington (USA), Thammasat University (Thailand) and Khon Kaen University (Thailand) partnered to conduct short-, medium- and long-term training programs to build regional oral health research capabilities. Investing in research has not only impacted trainees\u2019 career development but enhanced advancement of oral health research of South East Asia. The success of partnership calls for expanding oral health research training in other low-income countries. Oral diseases are among the most common non-communicable diseases worldwide . AccordiThe number of dentists-scientists worldwide is decreasing as the new generation of dental students favor clinical paths . MotivatThe National Institutes of Health (NIH) has recognized the need to build the research training and capacity outside of the United States (U.S.) through the creation of the Fogarty International Center (FIC). FIC is dedicated to advancing the NIH mission by supporting and facilitating global health research conducted by the U.S. and international investigators, building partnerships between health research institutions in the U.S. and abroad, and training the next generation of scientists to address global health needs . By faciFIC efforts on increasing research training and capacity around the world include expanding training in policy development, implementation, and evaluation at the institutional, local, and national levels 789. Whil78The public health burden of oral diseases has influenced the development of Thai dental education. With almost 70 million inhabitants, the developing country of Thailand is an active member of the Association of South East Asian Nations interested in creating oral health research capacity and training. Since the first dental school opened in 1940, currently, there are now 12 public and 4 private dental schools offering the degree of Doctor of Dental Surgery (DDS) through 6 years of education with an additional 3 years of mandatory public service after graduating from public dental school . While gFor over 20 years, the University of Washington, School of Dentistry, has partnered with Thammasat University and Khon Kaen University to train a new generation of oral health researchers who have impacted the dental public health arena in South East Asia. As a result of this partnership, these institutions created the Fogarty International Center Training Program in Clinical, Public Health and Behavioral Oral Health Research for Thailand . By training over 200 trainees from 18 countries, this training site has brought Thailand to the international forefront of oral health research. As a result, Thai universities have become the regional resource for oral health research in South East Asia.Topics discussed in these 5-day workshops included general scientific principles in planning and carrying out clinical research projects, levels of evidence in evidence-based clinical research, study designs, principles in the design and conduct of randomized clinical trials, statistical concepts and principles in testing hypotheses, basic behavioral models and ethical issues in the conduct of research on human subjects, and research protocol writing.Junior faculty and graduate students from the two collaborating Thai institutions, as well as short-term trainees who attended previous workshops were eligible to participate in the Summer Institute in Clinical Dental Research Methods held at the University of Washington in Seattle, U.S. In addition to clinical/public health/behavioral pathways, program participants included those pursuing advanced basic sciences research and degrees. This six-week program was designed to provide a short but intensive research training program for dental school faculty and professionals interested in clinical research. Specifically, core courses included biostatistics, clinical epidemiology and study design, behavioral research in dentistry, a data analysis workshop, a short course in randomized clinical trials, and a seminar on grantsmanship.The third level of training was designed to augment and strengthen oral health research pathways in existing Ph.D. programs in Oral Science at Thammasat and Khon Kaen Universities. Trainees with English language skills spent one year in Seattle at the University of Washington to accomplish following three things: a) undertake the coursework in biostatistics, epidemiology or health services at the UW School of Public Health, that they might not have been able to access in Thailand. The kinds of coursework trainees would undertake depended on their interests, but were likely to be biostatistics courses involving design of medical studies, survival analysis, logistic regression, and analysis of correlated data; epidemiology courses on genetic epidemiology, exposure measurement, nutritional epidemiology, clinical epidemiology; and health services courses on applied community research, health program evaluation, health promotion and disease prevention, and evaluation of health program costs and outcomes; b) during the one-year stay in Seattle, trainees worked with one or more of the UW mentors on research projects they were developing to enhance their learning experiences; and c) trainees were required to plan and finalize a dissertation research project that they would work on over the period of the next year in Thailand.With the purpose to provide a perspective on the impact of the FIC and NIDCR support on creating training and research capacity in South East Asia, we conducted a survey of former trainees to inform us on their perception on how the Fogarty International Center Training Program in Clinical, Public Health and Behavioral Oral Health Research for Thailand impacted their professional paths. All the training types were rated high on a scale of 0\u20135 by the trainees Figure . Out of In Peru, the past three decades have witnessed impressive growth in biomedical research catalyzed from efforts made among local educational institutions and NIH securing international partnerships and funding through research training programs . As a reKenya is a lower middle-income Sub-Saharan country in Africa with a population of more than 48 million people. People living in poverty (36.1% of the population) have impaired overall health and are at high risk for HIV infection 13. With We aimed to provide opportunities for decreasing global oral health inequalities by investing in creating research training and capacity building in low- and middle-income countries. To this date, only one such training site has been funded by FIC targeting oral health. We need to increase our advocacy efforts to expand oral health within FIC and global health within NIDCR. With this article, we hope to provide insights on the effects of long-term investments and efforts made in building research capacity in Thailand, and to advocate to FIC and NIDCR to expand such opportunities to other low-middle-income countries."}
+{"text": "The coronavirus disease COVID-19) outbreak began in Wuhan, China, in December 2019; by March 11, 2020, it was declared a pandemic by the World Health Organization (WHO)  . These gSome national specialty societies have also set forth their recommendations on the management of benign and suspicious breast lesions during the COVID-19 pandemic. The Brazilian Society of Surgical Oncology  considerFor symptomatic patients with palpable breast lesions, suspicious nipple discharge, breast pain, or an abscess without a prior oncologic diagnosis, the Brazilian Society of Mastology, the Brazilian College of Radiology, and the Brazilian Federation of Gynecology and Obstetrics Associations highlight the importance of estimating how clinically suspicious lesions are defined and how imaging information impacts decision-making, particularly in patients older than 60 years . These cThese recommendations provide a detailed guide for caregivers regarding decision-making and are intended to provide the best balance between morbidity and mortality from breast disease, risk of self and healthcare team exposure to COVID-19, and consumption of health resources. With a goal of guiding service flow, triage, and treatment of benign and suspicious breast lesions in low-complexity and specialty care settings, we proposed recommendations as outlined in the flowchart in These recommendations regarding the users of the public health system are predicated on the free access and availability of safe health care facilities to mitigate risks for patients and professionals . ClinicaHealth routines and surgical algorithms are currently being reviewed and updated worldwide owing to the COVID-19 pandemic. Meanwhile, early breast disease diagnosis remains a priority in the Brazilian public health system . Here, wPurcino FAC, Ruiz CA and Costa AMM were responsible for the manuscript drafting, writing, editing and review. Baracat EC and Filassi JR were responsible for study supervision and manuscript drafting, writing, editing and review. Sorpreso ICE and Soares-J\u00fanior JM were responsible for the study conceptualization and supervision, as well as manuscript drafting, writing, editing and review."}
+{"text": "The Geriatrics and Aging Processes Research Branch of the National Institute of Mental Health (NIMH) supports research on the etiology, pathophysiology, and trajectory of late life mental disorders. The branch encourages research using neuroscience, cognitive and affective science, and social and behavioral science to translate basic and preclinical research to clinical research. The branch prioritizes research that investigates neuropsychiatric disorders of aging, how they interact with neurodevelopment/neurodegeneration, and how to assess, treat, and prevent them. Of particular interest is research on social isolation and suicide. Suicide prevention research is an urgent priority: NIMH\u2019s portfolio includes projects aimed at identifying those at risk for suicide, understanding causes of suicide risk, developing suicide prevention interventions, and testing the effectiveness of these interventions and services in real-world settings. In this talk, a NIMH program official will discuss the NIMH research agenda in the domain of late-life mental illness, social isolation, and suicide."}
+{"text": "Papillary intralymphatic angioendothelioma (Dabska tumor) is a rarely metastasizing lymphatic vascular neoplasm that usually affects children and young adults. The majority of these cases occur in soft tissues of extremities, and to date less than 40 cases have been described. Despite the generally indolent evolution, can be locally invasive with the potential to metastasize. We describe a case of a young woman presenting with a plantar lesion, for 9 months and histological diagnosis of Dabska tumor. This neoplasm should be considered in the differential diagnosis of vascular dermatoses, allowing early diagnosis and treatment. Long-term follow-up should be performed. A 35-year-old female patient sought a dermatologist, complaining of an injury to the sole of the right foot 9 months prior. She reported feeling only a slight size increase. Upon clinical examination, there was an area of violaceous staining, with poorly defined limits, on the sole of the right foot . DermoscPapillary intralymphatic angioendothelioma (PILA or Dabska tumor) is a rare vascular neoplasm, defined as low grade malignancy tumor, with high tendency of local recurrence.10None declared.Thadeu Santos Silva: Approval of the final version of the manuscript; conception and planning of the study; obtaining, analysis, and interpretation of the data; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature.Luciana Rebou\u00e7as de Araujo: Approval of the final version of the manuscript; elaboration and writing of the manuscript; obtaining, analysis, and interpretation of the data; critical review of the literature; critical review of the manuscript.Geise Rezende Paiva: Approval of the final version of the manuscript; conception and planning of the study; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature.Rodrigo Guimar\u00e3es Andrade: Approval of the final version of the manuscript; conception and planning of the study; obtaining, analysis, and interpretation of the data.None declared."}
+{"text": "The COVID-19 pandemic, a singular disruptive event in recent human history, has required rapid, innovative, coordinated and collaborative approaches to manage and ameliorate its worst impacts. However, the threat remains, and learning from initial efforts may benefit the response management in the future. One Health approaches to managing health challenges through multi-stakeholder engagement are underscored by an enabling environment. Here we describe three case studies from state , national (Ireland), and international (sub-Saharan Africa) scales which illustrate different aspects of One Health in action in response to the COVID-19 pandemic. In Ireland, a One Health team was assembled to help parameterise complex mathematical and resource models. In New South Wales, state authorities engaged collaboratively with animal health veterinarians and epidemiologists to leverage disease outbreak knowledge, expertise and technical and support structures for application to the COVID-19 emergency. The African One Health University Network linked members from health institutions and universities from eight countries to provide a virtual platform knowledge exchange on COVID-19 to support the response. Themes common to successful experiences included a shared resource base, interdisciplinary engagement, communication network strategies, and looking global to address local need. The One Health approaches used, particularly shared responsibility and knowledge integration, are benefiting the management of this pandemic and future One Health global challenges. The scope and impact of the COVID-19 pandemic is unprecedented in modern times. At the time of writing, over 10 million confirmed human cases and 0.5 million deaths from SARS-CoV-2 infection have been reported  projects. The approach also integrates a systems approach to project management, communication, and data integration as well as novel application of principles of social psychology to engage stakeholders and create a culture of high emotional energy vital to collaboration and creative problem solving . TherebyIn this article, we use three case studies from different world regions to discuss elements of One Health approaches in the COVID-19 response. The three case studies are based on the authors' experiences and illustrate which of the essential One Health dimensions listed above applied in practice during the crisis. They provide examples of collaboration, shared responsibility and knowledge integration and illustrate opportunities and weaknesses.In Ireland, the National Public Health Emergency Team (NPHET) was established on 27 January 2020, to provide national direction, support and expert advice on the development and implementation of a strategy to contain COVID-19 . The firNPHET was supported by a number of expert groups, including the Epidemiological Modeling Advisory Group (IEMAG), which was established on 7 March ; see Sup. IEMAG wThe requirement for a rapid response led to a broad call to action from stakeholders with various expertise to contribute, in some cases beyond the traditional human medical disciplines. The team was chaired by a veterinary epidemiologist, with interdisciplinary membership from human public health, agriculture, veterinary medicine, food safety, disease ecology, and One Health backgrounds. Initial team selection was guided by disciplinary expertise, full-time availability (at short notice) and prior working relationships. The group's diverse interests and skills were well-suited to rapidly gathering evidence, and undertaking quantitative secondary and meta-analyses, in response to the emerging threat \u201322. In tIn terms of lessons learned, the rapid community-based aggregation of skills applied to a single acute problem should be held as an exemplar of how a distributed network of expertise can contribute in an efficient and effective way toward a goal. Interdisciplinary synergies were central to progress, both between mathematics and the life sciences and, importantly, between medical and allied disciplines. One Health perspectives predominated and there was cross-pollination of ideas and skills across disciplines to achieve efficiencies and better, more dynamic, systems. Challenges included remote working while maintaining communication and ensuring there was no duplication of effort across various NPHET subgroup teams. Furthermore, given the finite resources available, the COVID-19 response led to a temporary diversion of expertise and resource from other aspects of national animal health management. This case study is an important example of new thinking, diversity of thought, and new networks of expertise within Ireland.On 21 January 2020, the Australian Chief Medical Officer (CMO) issued a determination adding \u201chuman coronavirus with pandemic potential\u201d to the Biosecurity (Listed Human Diseases) Determination 2016. As a result, the Australian Health Protection Principal Committee, the key decision-making committee for health emergencies formed by the CMO and state and territory Chief Health Officers, was convened and daily meetings activated. In addition, national coordination was also activated for responding to the health emergency through the National Incident Room, the strategic reserve of personal protective equipment through the National Medical Stockpile and the provision of clinical and academic leadership through the National Trauma Center. Meetings of state, territory and Commonwealth health ministers to discuss pandemic readiness also started. On 25 January, Australia reported its first case of COVID-19, and the Australian Health Sector Emergency Response Plan for Novel Coronavirus (COVID-19 Plan) was implemented on 7 February . The COVEarly in the response, a One Health approach was implemented through the collaborative engagement of animal health experts, including veterinarians and epidemiologists, from NSW Department of Primary Industries (DPI) and other institutions , sharing expert knowledge. This approach is pre-defined by EMPLAN, under which a Combat Agency is nominated to lead operations  and able to request support from other government areas, such as the NSW DPI. Animal health specialists worked for the Public Health Emergency Operations Center, responsible for activities such as tracing, research and providing expert advice, in the epidemiology and tracing units. In addition, the Ministry of Health liaised with other government agencies to establish remote tracing capabilities, including sharing of databases, online training and debriefs (due to the travel limitations) and the need to increase contact tracing capacity. As the responsible agency for providing agriculture and animal support during emergencies (under EMPLAN), NSW DPI as the Agriculture and Animal Services Functional Area was present within the State Emergency Operations Center throughout the response, liaising with health services with respect to animal care. Furthermore, the NSW state animal laboratory provided diagnostic services to NSW Health. NSW DPI worked with Australia's Animal Health Committee (AHC) to develop science-based, nationally consistent policy on animal health issues related to COVID-19, and supported the agriculture and animal sectors in achieving continuity of their businesses to safeguard animal health and welfare and help ensure a secure food supply . AHC devAs key learning of this response, COVID-19 highlighted the importance of a well-resourced response using a One Health approach, involving a broad range of human and animal health stakeholders and shared resources, which could then be scaled back as needed. The COVID-19 situation also highlighted the need for appropriate communication and management of animal health and welfare during human pandemics.The Africa One Health University Network (AFROHUN), formerly One Health Central and Eastern Africa (OHCEA) is a University led network of 24 public health, veterinary medicine, pathobiology and environmental health institutions and 16 universities in eight countries in East, Central and West African regions . Since its inception in 2010, AFROHUN supports institutional changes in teaching and learning environments in higher institutions that promote One Health approaches.In the absence of a global workforce, most African national COVID-19 response actions relied on national health professionals to provide the much-needed workforce in the management of the pandemic. Universities were among the key institutions that supported different national response task forces. University members served on scientific task forces with evidence-based and science-based data shaping response strategy options as the mainstream health workforce within ministries were at the forefront of the response.Between 23 March 2020 and 18 June 2020, AFROHUN through its wide continental network in collaboration with the USAID-funded One Health Workforce \u2013 Next Generation (OHW-NG) consortium led by University of California, Davis, provided a platform where network members (faculty and students), practitioners in One Health, and stakeholders virtually via ECHO  and we have been active in COVID-19. The club, a multidisciplinary team of students from Makerere University and Mbarara University of Science and Technology in Uganda have been raising awareness about COVID-19 to communities and providing mental health support.\u201d Muganzi David Jolly, President, Students One Health Innovation Club, Mbarara University of Science and Technology, Uganda.\u201cI was asked to lead a team that was responsible for advising the government on the design and necessity for wearing cloth face masks in crowded places such as bus stands, markets, hospitals and places of warship. Now mask use is widespread as one of the preventive actions against COVID 19. In my leadership role, I have used some of the ideas from the AFROHUN ECHO sessions.\u201d Prof. Japhet Killewo, Professor of Epidemiology at Muhimbili University of Health and Allied Sciences (MUHAS), Tanzania.\u201cAn AFROHUN internal review identified several lessons learnt from the three months of COVID-19 sessions. The power of existing platforms, strong leadership, the combination of global and in-country perspectives and the ability of leveraging networks was highlighted, with around 200 participants and experts being part of the sessions, providing valuable multi-disciplinary, global and local in-country perspectives. The tight schedules of the task force members at the frontline of the pandemic prevented engagement of mainstream ministries in the design of the sessions. Participation of representatives from government and members from different COVID-19 task forces helped bridge this gap. Their perspectives on the issues and dynamics of the pandemic helped to shape subsequent sessions. A more efficient information flow in the national response system to reach diverse users could have enhanced the design and delivery of the sessions. Official engagement of specific task forces such as the scientific committees on the ECHO sessions could have added value.The three case studies each demonstrate important benefits from the use of One Health approaches in the management of the COVID-19 pandemic. The sharing of resources, multidisciplinary engagement and communication network strategies were common across the three case studies, in support of knowledge integration and more effective response management. Each can be placed within a One Health framework , providiWith regards to the six One Health dimensions that are described at the beginning of the paper, the three case studies all had clear sharing and learning structures in place that facilitated an exchange of data, information, and knowledge, as well as accessing and generating new knowledge through collaborative processes. All case studies described working across disciplines, but remained within the boundaries of the natural sciences and did not engage either the social sciences or the humanities. Also, wider society engagement was lacking, which meant that collaborative working remained within the multi- and interdisciplinary spheres and did not reach transdisciplinary working. Holistic planning was a key feature of case study 2, which provided a strong basis for the actions implemented. Systemic organization was dominant for AFROHUN, with the existence of a large, formal network of universities that allowed prompt recruitment of scientific experts into the response. None of the case studies explicitly described systemic thinking even though it is advocated by the WHO  and the The case studies have demonstrated how expertise can be mobilized and shared quickly, given appropriate support infrastructure and in the light of the pressing needs of the pandemic. It is hoped that lessons learned can be extended to \u201cpeacetime,\u201d outside the crisis. Interdisciplinary synergies, underpinned by One Health concepts, will also be needed to manage critical global challenges, including those relating to climate change and antimicrobial resistance . To harnThe original contributions presented in the study are included in the article/BH, AB, and MH-J conceived the study. AB and SM wrote the case study 1 (Ireland). MH-J and OS wrote the case study 2 . WB and AY wrote the case study 3 (AFROHUN). All authors contributed to developing, writing, editing of the paper, and approved the manuscript for publication.JW was employed by the company Novometrix Research Inc, a social enterprise which facilitates alignment of diverse stakeholders for solutions in economic, social and environmental sustainability. JW and Novometrix Research have no financial interest in any aspect of this manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The national infrastructure FoodOmicsGR_RI coordinates research efforts from eight Greek Universities and Research Centers in a network aiming to support research and development (R&D) in the agri-food sector. The goals of FoodOmicsGR_RI are the comprehensive in-depth characterization of foods using cutting-edge omics technologies and the support of dietary/nutrition studies. The network combines strong omics expertise with expert field/application scientists . Human resources involve more than 60 staff scientists and more than 30 recruits. State-of-the-art technologies and instrumentation is available for the comprehensive mapping of the food composition and available genetic resources, the assessment of the distinct value of foods, and the effect of nutritional intervention on the metabolic profile of biological samples of consumers and animal models. The consortium has the know-how and expertise that covers the breadth of the Greek agri-food sector. Metabolomics teams have developed and implemented a variety of methods for profiling and quantitative analysis. The implementation plan includes the following research axes: development of a detailed database of Greek food constituents; exploitation of \u201comics\u201d technologies to assess domestic agricultural biodiversity aiding authenticity-traceability control/certification of geographical/genetic origin; highlighting unique characteristics of Greek products with an emphasis on quality, sustainability and food safety; assessment of diet\u2019s effect on health and well-being; creating added value from agri-food waste. FoodOmicsGR_RI develops new tools to evaluate the nutritional value of Greek foods, study the role of traditional foods and Greek functional foods in the prevention of chronic diseases and support health claims of Greek traditional products. FoodOmicsGR_RI provides access to state-of-the-art facilities, unique, well-characterised sample sets, obtained from precision/experimental farming/breeding  along with more than 20 complementary scientific disciplines. FoodOmicsGR_RI is open for collaboration with national and international stakeholders. In recent years, there has been an increased awareness towards the evaluation of food quality and safety in relation to human health and life. Existing legislation refers to technological processes of food, safety assessment by monitoring food contaminants, characterization of food composition and the determination of characteristic food nutrients. The \u201cclassical\u201d targeted analytical procedures are still dominant; however, the holistic characterization of food products through \u201comics\u201d technologies is gaining interest and applicability. Such novel approaches can provide new indicators of food quality, i.e., geographic and/or genetic origin, processing methods, adulteration, organoleptic characteristics, freshness, and so forth. Omic technologies are increasingly employed in nutrition studies aiming to increase the marketability of food products and to demonstrate and/or monitor their beneficial effects on human health. Nutrigenomics, Nutrigenetics and Nutritional metabolomics are topics and terms that are increasingly found in the literature and the wider public media.Foodomics  combinesFoodomics is applied in various R&D aspects. In the study of the origin and quality of foods, foodomics can reveal discriminatory markers and, most importantly, patterns that characterize foods according to their geographical origin or subtle pedoclimatic effects , the different legitimate or non-legitimate regimens/interventions applied by food producers . Such data are important to support marketability and branding, especially for Protected Designation of Origin (PDO) and Protected Geographical Indication (PGI) products.In food safety, foodomics research can assist in the discovery of (bio)markers and mechanisms of toxicity and facilitate the identification of potential hazards. Untargeted-holistic approaches may reveal underlying and unlooked-for mechanisms of toxicity, such as polymorphisms or sub-toxic (but increased and unwanted) concentrations of biomolecules. It can be a potential tool for the investigation of food allergies and the analysis of transgenic foods, providing further insight on the effect of unintended transformations ,3.In nutrition studies, foodomics can provide new knowledge on the effect of nutrition and the fate of nutrients in the human body; Foodomics can identify (among others) perturbations caused by certain dietary regimens and characteristic patterns that can allow the development of a personalized dietary intervention for certain groups , or patients with food-related disorders .Considering the needs for R&D in these topics, the Greek Secretariat for Research and Technology announced a call for new Research Infrastructures. To address the call, a consortium was formed and submitted a successful proposal that provided the means for the establishment of FoodOmicsGR_RI. FoodOmicsGR_RI is a distributed multidisciplinary national research infrastructure aiming to perform, assist and promote omics research in agri-food R&D fields in the Greek and international research environment. This research may have a strong impact on the Greek agri-food sector. Greece has a unique landscape at the crossroads of Europe with Asia and Africa. The land expands to distances of up to 1200 km in a mostly mountainous mainland. The country has a very lengthy coastline  and close to 3000 islands. Varying types of soil , water supply and pedoclimatic conditions result in a wide array of ecosystems and landscapes that give rise to one of the highest biodiversities in Europe, especially taking into account the area of the country. Flora includes 5752 species (452 endemic subspecies); the fauna includes 23,130 animal species, of which 3956 are characterised as Greek endemics. Furthermore, 3500 marine animal species and a high number of fungi species have been recorded in the Greek marine environment. Besides, a high proportion of these species are unique worldwide and this biodiversity results in the unique composition of Greek agricultural products.Greece has been an agricultural country, where until the 1960s the majority of the population lived in rural areas as farmers, maintaining traditional habits in life, farming and cuisine. All these factors converge to create a very large collection and a very strong portfolio of unique and characteristic food products. Highlighting these characteristics through advanced technology offers a way to support quality, nutritional or health claims, increase their attractiveness and marketability, and provide added value to local products. The central scope of FoodOmicsGR_RI is to serve the needs of the agri-food producers, providing concrete, solid and comprehensive data on the composition and nutritional value of their produce.http://biomic.web.auth.gr/) with specialist groups from the same University, and groups of researchers from the Universities of Athens, Crete, the Aegean, Ioannina, the Agricultural University of Athens, the International Hellenic University and the Biomedical Research Center of the Academy of Athens. This consortium is highly complementary, comprising scientists from 17 Departments of the participating Institutes (a full list is given in the http://foodomics.gr/).FoodOmicsGR_RI is a multidisciplinary consortium that joins forces from eight Greek Universities and Research Centers. FoodOmicsGR_RI brings together BIOMIC, a new interdisciplinary analytical laboratory of the Aristotle University of Thessaloniki (FoodOmicsGR_RI core (bio)chemical analysis groups provide expertise in bioanalysis, food analysis, metabolomics, elemental metabolomics, genomics and proteomics. Central technologies include analytical separations, Mass Spectrometry , Nuclear Magnetic Resonance (NMR) spectroscopy and Inductively Coupled Plasma Spectrometry. Analytical groups collaborate with (bio)informatics groups, food (bio)chemistry groups and application-oriented researchers with expertise in fields relevant to food and nutritional sciences: animal husbandry, veterinary pathology, fishery, apiculture, plant physiology, pomology, horticulture, vine and viticulture, environmental control, natural products, nutrition biochemistry and human exercise biochemistry. The core analytical groups have the critical mass to realise cutting-edge research in their specific field. Investment in infrastructure  and the As a major initiative, the governance of FoodOmicsGR_RI is a demanding task that expands at various levels. It includes the General Assembly (GA) that is composed of delegates from all involved institutions and a Steering Committee of five members from the participating institutions that manage the operation of the RI. An International Expert Advisory Board (IEAB) has been appointed with the scope to further enrich the knowledge, the experience and the network of the RI participants. The 11 IEAB members include scientists from consumer organisations, industry or other businesses, potential stakeholders, and representatives of the activities of the RI.-Consultancy services and uptake of experimental intervention for foodomics studies (food product -oriented studies) or nutritional studies.-Big Data Handling and statistical analysis by various modes and special software including bespoke scripts and algorithms.-Genomic, proteomic and metabolomic analysis of foods, food products and biological samples from nutritional studies.-Quantitative Determination of key target molecules  in foods and biological samples.The facility is open for collaboration subject to the conditions detailed at the central FoodOmicsGR_RI web page with templates for access-use of infrastructure, usage policy, protocols for sampling, sample delivery, and information about the different FoodOmicsGR_RI SOPs. The services offered by FoodOmicsGR_RI can be tailor-made including all or combinations of the following:FoodOmicsGR_RI can provide support for the realization of studies on small molecules (metabolomics), and cover genetics/genomics/epigenetics and proteomic fields, offering a \u201cone stop-shop\u201d model to stakeholders and users.A detailed list of validated protocols is given in The ideas and scope of FoodOmicsGR_RI are aligned with several of Research and Innovation Strategies for Smart Specialisation (RIS3) priorities for the agri-food sector. A list of relevant priorities is given in Omic approaches can become a tool to broaden the knowledge and understanding of how biodiversity (genotypic variation) can improve food and nutrition, influencing national policies and markets. This can be achieved via the examination of other nutrient-rich crops and plant species, not yet fully utilized, or unexplored traditional cultivars , benefiting both producers and consumers.Implementation: The strategy to approach such multidisciplinary and multifaceted work is to overcome the fragmentation of research by organising paths for effective samples\u2019 analyses and, similarly, paths for data curation that combine omics approaches to provide holistic analytical results and highlight characteristic features. The outline of specific sub-projects is described in the following sections.Foodomics research requires state of the art technologies and methods but also the existence of specialists\u2019 knowledge and high-quality sample banks, which, after comprehensive analysis, can provide data for the establishment of compositional databases. Compositional databases are the best means to provide the basis for the control of real samples (food products). Our consortium started this work with an exhaustive literature review. This resulted in the publication of topical reviews on metabolomics of different foods, such as the olive drupe and olive oil ,6,7, graAdditionally, Special Issues organised by FoodOmicsGR_RI members in 2020 include the following:\u201cMetabolomics in Food Authentication: Strategies and Applications\u201d in the MDPI Molecules Journal by Prof. Thomaidis and Dr. Dasenaki (guest editors), including important foodomics-based authenticity studies.\u201cNutritional Metabolomics\u201d in the MDPI Metabolites Journal, guest-edited by Prof. Georgios Theodoridis, Dr. Christina Virgiliou and Dr. Olga Deda.\u201cMetabolomics Methodologies and Applications II\u201d, guest-edited by professor Helen Gika, in the MDPI Metabolites Journal.Following this fundamental work, the consortium works further to generate databases of the molecular and elemental composition of foods to facilitate control, stir further technological developments and discover relationships between food constituents and/or elemental signatures with properties sought by consumers and producers. The generation of such databases started by thorough data-mining and text-mining of the literature and collaboration with expert groups from the control sector. As a starting step, nine foods/food products have been studied as priority commodities: olive oil, olives, wine, milk, cheese, yogurt, honey, royal jelly and pollen. Since the scope is to generate a database of the contents of Greek foods, a filter is set to study only publications that report Greek products, and exclude publications that map products and varieties that are not found or those that do not originate from Greece. Emphasis was given to map specific varieties/types of Greek produce. To generate data for a certain food, a set of keywords was selected; i.e., for wine, this includes characteristic Greek variety names: Asyrtiko, Nemea, Xinomauro and so forth.Text mining algorithms developed in our group are used to mine the international literature for publications containing carefully selected keywords of interest. The codes seek to gather quantitative information reporting the concentration of food constituents such as elements and small molecules. This information is subsequently curated by PhD level scientists to verify its validity and relevance, with extra caution given at concentration numbers and units.The generated database is now formatted as a web-based database to be soon open to the research community. During the realization of the works of FoodOmicsGR_RI, new data will be generated from FoodOmicsGR_RI sub-projects. Sample sets are analysed by various information-rich analytical platforms. The data are fused to generate an atlas of the content of these unique samples. New analytical data will populate, control, corroborate the data in the database. This strategy improves confidence in findings, while it can also reduce the impact of confounding factors  in large-scale analysis and help researchers to reach useful, statistically meaningful findings. The overall aim of this activity is to establish a curated, internet-based database hosted in FoodOmics portal, that would serve as a reference point for the search of the content  of Greek food products.Regarding milk, cheese and animal tissue samples, our expert research teams have also built a reference database through the implementation of various research projects ,22,23,24The central aim of FoodOmicsGR_RI is to strengthen the existing infrastructure of its partners and facilitate basic and applied translational research. With this upgrade, the aggregate capability for capital instrumentation of the laboratories reaches five hybrid time of flight mass spectrometers Q-TOF-MS hyphenated to UPLC systems (two with ion mobility capability(TIMS-TOF-MS)), a UPLC-QTRAP 6500+ MS/MS, more than 10 triple quadrupole MS/MS instruments hyphenated to UPLC, four UPLC-Orbitrap HRMS (one with nano-LC), three HPLC-MS (High-performance liquid chromatography mass spectrometry) single quadrupole instruments, an SFC-UV/MS system, more than 8 GC-MS , and three GC-MS/MS (Gas chromatography\u2013mass spectrometry systems with triple quadrupole MS). Mass Spectrometry capabilities of FoodOmicsGR_RI include Matrix-assisted laser desorption/ionization- time of flight- mass spectrometry (MALDI-TOF MS) exploiting the potential for high molecular weight analysis, enhancing the development of rapid and reliable high-throughput methodologies for food authenticity studies. NMR spectroscopy capabilities include two 600 MHz, two 500 MHz and four 400 MHz NMR spectrometers. Elemental analysis is performed in two ICP-MS Inductively coupled plasma- mass spectrometry) and two  ICP-OES instruments. In addition, virtually all necessary instrumentation is available in the laboratories of the partners including FT-IR (Fourier-transform infrared spectroscopy), NIR (near infrared spectroscopy), capillary electrophoresis (CE)-, and several HPLC and GC instruments linked with various detectors: UV, PDA (Photodiode Array Detector), fluorescence, ELSD (Evaporative light scattering detector) for LC; FID (flame ionization detector), ECD (Electron capture detector) for GC). FoodOmicsGR_RI involves strong informatics expertise and access to high computing power. Staff scientists and newly recruited researchers are working on data treatment and the implementation of fusion of data collected from the different analyses and omics platforms.Advancing and harmonising the available analytical methods is a central task. The RI partners have very strong track records in research, as evidenced by their publications/presentations and patents awarded. Partner selection provides high complementarity in methods, expertise, infrastructure and application orientation. The latter practically covers the whole Greek agri-food sector. An array of protocols for genetic/metabolomics/proteomics analysis in targeted and untargeted mode exists among the FoodOmicsGR_RI partners and a list of current protocols and methods is given in FoodOmicsGR_RI has established a multitude of methods for metabolic profiling as well as elemental, genetic and proteomic profiling. In addition, protocols exist for the analysis of nutrients and pollutants in foods and the characterization of foods by state-of-the-art technologies. These cutting-edge analytical tools are applied in the quest to reach a thorough characterization of food products with a focus on Greek products of high value and market potential, which includes but is not limited to olive oil, wine, honey, dairy products and seafood. A major concentration of analytical force is directed to the small molecule domain. Metabolic profiling or metabolomics is the largest and strongest sector of the FoodOmicsGR_RI, bringing together researchers from the mass spectrometry and the NMR spectroscopy fields. FoodOmicsGR_RI researchers have developed methods for metabolic profiling of wine, cheese, honey, royal jelly, olive oil, olives and several other foods, natural products and biological samples.Untargeted methods, combined with fit-for-purpose chemometric approaches, strengthen the breadth of traditional targeted analysis ,26 and rThe validation of findings and the development of Quality Control (QC) measures have been a major element of our research. FoodOmicsGR_RI laboratories have been central in the development of QC approaches and measures for LC-MS based metabolomics ,40,41,42As the metabolomics field is maturing, there is increased interest in the development of targeted methods . UltimatNMR spectroscopy is a method of choice for the analysis of complex mixtures as it permits simultaneous monitoring of all constituents within the inherent sensitivity limits. Numerous applications have been proposed in food classification and origin determination in combination with multivariate statistical analysis techniques.1H and 31P NMR spectroscopy, metabolomics approaches that deal with the authentication of extra-virgin olive oil against adulteration with seed oils, olive oils of low quality were developed and validated [We have used multinuclear and multidimensional NMR spectroscopy as a tool for food profiling, quality control and analysis of a variety of food products. In olive oil, the initial focus was the profiling of low molecular weight compounds that can be used as molecular markers of olive oil quality and provided information on olive oil age, degradation and storage history ,59. Basealidated ,61. Curralidated . SuccessWine analysis is another field of great interest, and we have developed and applied analysis protocols for metabolite profiling of red and white wines. For wines produced from grapes of different Cretan vine varieties on consecutive wine production seasons, we were able to classify commercial wines based on variety . We haveNMR employing 1D and 2D experiments remains the most powerful tool in unambiguous structures elucidation of small molecules . CombineThrough the acquisition of new NMR instrumentation by FoodomicsGR, the consortium has now access to a novel solid-state NMR spectrometer that offers the capability of NMR analysis of solid foods in their native state without the need for long and arduous extraction procedures. We are already working on developing suitable solid-state NMR analytical protocols, with our initial targets being foods such as cheese, seeds, olive fruits and meat, where the potential for a strong analytical impact in quality control and novel metabolomics method development is very promising.FoodOmicsGR_RI provides Genomic services through a Genetic traceability system that is based on the identification of animals and their products through the study of DNA. DNA is detectable in every cell, resistant to heat treatments, and allows for individual or species identification. The DNA molecule has the feature of being enormously variable among individuals, making it possible to distinguish among them ,71. OnceAt the species level, our research team has developed a \u201cDNA barcoding\u201d method for the genetic identification of fish species in order to detect phenomena of involuntary or deliberate mislabeling of fish products. Specifically, DNA sequencing and universal primers are used for the species determination in different fish products  of various fish species . Reliable species identification is accomplished through comparison with big databases such as the BOLD Database, providing 100% accuracy in most cases . For thehttps://fishreg.jrc.ec.europa.eu/web/aquatrace). For the sea bass, the panel of the 20 most informative SNPs demonstrates assignment accuracy over 90% for natural and over 60% for farmed individuals [Furthermore, geographic traceability genetic tools are developed within the Foodomics consortium, accomplished by a large genomic reference database that our research team has built through various research projects for a number of fish species, birds, and large mammals. In particular, for the two most common commercial fishes in Southern Europe, the sea bream and the sea bass, we have developed, in the framework of FP7 project \u201cAquaTrace: the development of tools for tracing and evaluating the genetic impact of fish from aquaculture\u201d, efficient, high fidelity and cost-effective genomic traceability tools, i.e., SNP panels, for the identification of the origin stock  of random individuals , we have analyzed the genome of the Chios Greek sheep breed, which is well known for its high milk yield characteristics as well as its fertility. Specifically, genome-wide association analyses (GWAS) are performed to identify specific genomic regions on the sheep genome associated with novel derived phenotypes regarding the future selection of animal producers unaffected by weather fluctuations due to climate change. In particular, genetic and genomic characterization of performance resilience to climate volatility under heat stress conditions will be presented regarding Chios dairy sheep. Indicatively, genetic correlations between performance resilience and lifetime milk production and also identification of additive SNPs spanning a region of fifth chromosome and associated with Chios resilience will be reported [https://www.smarterproject.eu/).Genomic analyses are additionally applied to livestock species , which constitute an important economic sector for our country, for their genetically assisted breeding. The genomic improvement of the species of interest regarding their products, such as milk yield and quality, meat, wool, etc., is widely performed through single nucleotide polymorphisms (SNPs), which scan the whole genome to identify regions associated with the desirable phenotypic characters. In the framework of iSAGE Horizon 2020 project: \u201cInnovation for Sustainable Sheep and Goat Production in Europe\u201d  for the improvement of food quality, the prevention of food spoilage and the extension of shelf-life by limiting microbial interactions ,79. FurtElemental Metabolomics have been developed in collaboration with the University of Boston and Griffiths University . ElementFoodOmicsGR_RI includes expert application groups and end-users with deep knowledge of specific food products and large, well-controlled historic sample banks of food products produced in a controlled environment with full historic records . All manipulations were performed by specialised research scientists working under strictly controlled conditions; samples were collected from specific restricted geographical areas, and were treated and stored in the same way.Sample banks containing honey and royal jelly samples were produced by specialised Apiculture Laboratories in experimental breeds. Olive oil collection has been built through participation in research projects and national initiatives and covers specific geographical areas, e.g., the islands of Crete and Lesvos, and mainland regions. Monocultivar olive oils have been collected after thorough control that ensured universal oil production technology. In a similar way, monocultivar wines have been collected from collaborating wine makers. Regarding animal tissue/DNA samples, our research team has built through various research projects a thorough reference database for several fish species as well as other species like birds and mammals. Partner laboratories maintain various sample banks of non-genetically modified soybeans cereals, nuts, almonds and other foods. Sample collections extend to several years, to enable the generation of representative profiles. Samples are accompanied by metadata: breed, species, exact geographic location of the farm, farming/feeding modes, and so forth.As an example, the process for the collection of milk and dairy products will be described in brief: Specialist groups (veterinary scientists) organised sample collection from well-known collaborating animal farms from certain geographical regions; detailed reporting of animal feed, animal breed, age was applied along with the application of strict sample collection, transportation and storage protocols. The collection of milk was organised from specific farms in various areas of Greece. For cheese samples, all production steps, from milk sampling until the cheese making, were monitored by trained scientists and veterinarians. Specifically, the hygienic condition of the farms was examined, taking into consideration the animal breeds, the territory of origin , the quality of the milk and the seasonal variation. Milk was selected from different flocks, with different grazing and production systems, whereas all zootechnical parameters were recorded. Cheeses were manufactured according to specific recipes, in absolutely strict conditions of safety and quality, with a fixed percentage of ovine and goat milk in the feta and graviera cheeses, the single breeds used, as well as the cheese-making technology, which was also recorded before the experimental analysis. One sample bank consists of 180 different milk samples from 180 different flocks of small ruminants corresponding to six restricted geographical areas and 140 produced cheeses in total, whereas 48 single breed cheeses were produced in certain regions, generating specific profiles to understand the actual differences among breeds, production methodologies and territory influences. Eighty commercial cheese products from four different regions were also compared, based on our strategic plan to differentiate the authentic and traditional way of cheese making from the industrial methods ,93,94. IThis research line aims to study the potential of omics technologies in the control of authenticity (authentication) of agricultural products, the identification of characteristic patterns of biomarkers and/or the certification of the geographic origin of foods. An impressive array of analytical techniques has been used in the literature for this quest. Omic technologies  and bioinformatics are currently being put to use, aiming to achieve unparalleled detailed food analysis, whilst providing useful information regarding the molecular content of foods. In the following section, selected examples of the work of the consortium are provided according to the analytical technology.Our consortium has extensively applied MS-based metabolic profiling to categorise foods such as wine, olive oil, olives, milk, apples grapes, Chios mastic and other foods. Authenticity studies regarding adulteration and geographical and varietal origin have been efficiently addressed by applying different MS-based screening strategies  ,30,95,96One of the most challenging tasks in food research is labeling verification, mainly regarding products characterized by PDO/PGI indication. An indicative example is the discrimination of PDO Kalamon olive drupes from drupes of different geographical origin, based on their full metabolome . MoreoveThe proteome domain can also be studied and used for the assessment of geographical origin. In a preliminary study on feta cheese samples from different areas of Greece, the full protein content of feta cheese was reported for the first time. A total of 489 proteins of diverse functions were detected and were linked to the identity of the product 1H and 13C NMR spectroscopy for metabolite profiling of a series of different food products [31P NMR spectroscopy after chemical derivatization was developed and was used to profile minor glyceride components in olive oil [Consortium members have developed several analytical protocols based on products ,103,104.live oil ,59, and live oil . Using tlive oil  or olivelive oil .For wine variety and region classification, FoodOmicsGR_RI members developed protocols for the analysis of the phenolic content after extraction using XAD technology resins Cheese samples  were investigated by the FoodOmcsGR_RI staff for the presence of a specific type of bacteria, which can determine the quality and sensory characteristics, and they were also authenticated in four different geographical areas of Greece. Conventional approaches used to identify different types of bacteria include microbiological techniques based on the morphological, biochemical, physiological (phenotype) and genetic characteristics (genotype) of the microorganisms ,108. IdeApplications of Elemental Metabolomics within our consortium include: determination of geographical and botanical type of honey , authentThe work of the consortium aims to combine metabolomics data from different platforms NMR, LC-MS, GC-MS to comprehensively map the metabolome of the foods under study. A further plan is to combine data across omics: for example, metabolomics with elemental analysis (ICP-MS) data, genetics and proteomics analysis data, and so on. Fusion of the data will be used to provide an integrated perspective of the studied specimen. FoodOmicsGR_RI staff have coined a novel term for such holistic approaches for food analysis: \u201cTrophometry\u201d, that is, the sum of omics techniques encompassing analysis of foods. The \u201cTrophometric Fingerprint\u201d is expected to be unique for any given food sample, and can provide information regarding traceability of raw materials as well as the origin and quality of each food itself .In addition, given the ability for sensory evaluation of food products in available premises, omics disciplines will assist in the elucidation of sensory-active compounds, considering all possible stimuli of multimodal perception  and including the biological perception of food as an additional analytical dimension to comprehensively assess the quality of a given product.In nutrition Research and Development (R&D), our strategy is to exploit the power of Omics technologies to assess domestic agri-food biodiversity for the consolidation of the value of Greek produce . Based oThis research line will analyse biological samples from animal models or humans after nutritional intervention. Within the facility, long expertise exists in profiling biological fluids and excreta such as urine, blood, feces, saliva ,114,115 Increased interest in foodomics is central in life/medical science towards the prevention of disease, the development of a personalised diet and the development of nutraceuticals and functional foods. In this line of research, FoodOmicsGR_RI partners realise collaborative projects with various partners from the private sector to improve the manifestation of quality claims of existing products or support R&D efforts toward the development of novel products containing bioactive ingredients from the Greek flora/marine organisms . In a recent example, functional foods containing phenolic-rich water extracts of olives generated during olive oil production, or plant extracts, were prepared, and their effect on animal and human metabolic models was evaluated . For fooMembers of the FoodOmicsGR_RI consortium have investigated the health benefits of different constituents of emblematic Greek traditional foods like olive tree polyphenols for their cardioprotective, anti-ischemic and hypolipidemic effects ,126,127 The agro-industry produces important amounts of solid and liquid by-products that are characterized, on the one hand, by high organic loading, while, on the other, by the presence of bioactive compounds. The future sustainable management of these by-products should focus on the application of management practices that achieve protection of the environment and simultaneous increases in revenues. Under this frame, the amounts of the agro-industrial wastewater that are produced in Greece will be estimated, while different physicochemical  and biolFoodOmicsGR_RI members have developed value chains in the food-agricultural industry that promote recycling economy by taking into account regional needs. These value chains are based on the integration of innovative technologies for recycling and extracting fine chemicals of high added value from constituents of agricultural wastes. The recovery of natural products with valuable health benefits like anti-oxidants, etc., can be achieved from agricultural wastes at an industrial scale using state-of-the-art green technologies like XAD adsorption resins or supercritical fluid extraction and used in numerous applications in food supplements, cosmeceuticals, etc. These applications can create not only new products from the food and agricultural industry but also lead to significant reductions in environmental footprint, enabling sustainable agriculture practices. Several applications have been developed for olive-oil mills, wineries and wood treatment. Additionally, FoodOmicsGR_RI partners are highly equipped for the treatment of agriculture wastes and bioproducts in three ,136,137 FoodOmicsGR_RI focuses also on the assessment of food safety from chemical contaminants which can be present in foodstuffs due to environmental contamination, cultivation practices or production, packaging and storage processes. One major task deals with the development, application and validation of sensitive, accurate and robust analytical methods based on various extraction techniques  and hyphenated quantitative techniques (such as LC(GC)-MS/MS and LC(GC)-HR-MS/MS) using state-of-the-art instrumentation for facing current and future needs of food surveillance and for identifying new aspects to be controlled. Different classes of traditional and emerging contaminants such as pesticides, biocides, pharmaceuticals, PAHs, phthalates, organohalogenated compounds, etc., as well as their metabolites and transformation products, are studied in terms of their fate, dissipation, levels in food commodities, compliance with current maximum residue limits (MRLs) and possible associated dietary risks. A greater interest is provided for the most significant food matrices of the Greek production market such as olive oil, wine, honey, milk, vegetables, aquaculture products, etc. ,144,145.In food safety assessment, strong interest also exists in the study of the effect of molecules  migrating from food contact materials (FCM) to food or food simulants. As such extensive work has focused on the determination of endocrine disruptors, different approaches have been studied including migration of the potential endocrine disruptor, bisphenol A (BPA), from polycarbonate baby bottles into aqueous food simulants , as wellRegulated substances and non-intentionally added substances (NIAS) migrating into food or official food simulants have been studied by different analytical approaches covering BPA, phthalates  and otheIt should be mentioned that in the framework of national and industrial food safety control, a wide range of the developed methodologies has been accredited by the Hellenic Accreditation System (E.SY.D) according to ISO 17025 and has been established for the in-depth monitoring of contaminants in different food matrices ,155,156 The establishment of the RI offers benefits for the Greek research system in conducting cutting edge research in Foodomics research topics. FoodOmicsGR_RI can provide a reference center, a center of excellence for the analysis of the molecular/elemental content of food products, with its spearhead on small molecule analysis (metabolomics). The consortium can assist and strengthen research proposals and R&D efforts of the RI partners, external researchers, private enterprises and stakeholders.Very important issues in food quality, namely fraud and authenticity, are recognised as major activities in different types of food, while the health benefits of specific nutrients attract the interest of a wide research community, as well as producers, retailers, and consumers. In this aspect, FoodomicsGR_RI can assist in the integration of major areas that are important for the development of new research in different areas: botanical-agricultural, veterinary, analytical, nutritional biological effects and food engineering and related technologies. The variety of methodologies covered within the RI permits the establishment of testing cascades for high-throughput information-rich screening methods suited for juridical proof of fraud, authenticity and quality control. This direction can offer an efficient, cost-effective strategy for surveillance and consumer protection, making it possible to harmonize future standards and guidelines for their implementation. This can attract collaboration from scientists from the regulatory bodies in the region, thus increasing the impact on the Greek society and national economy.The recent establishment of FoodOmicsGR_RI promotes agri-food and nutrition R&D in Greece, bringing the national research system in line with large European and global initiatives. The activities of FoodOmicsGR_RI promote effective networking and collaboration among the consortium partners, but also between the research and the private sector. The unique combination of facilities, controlled sample banks, databases and expertise is available to support researchers and entrepreneurs in the realisation of R&D efforts.Omics research necessitates collaborative work from different disciplines and standpoints. Apart from the infrastructure, and the portfolio of analytical methods, this activity required specialists\u2019 knowledge and high-quality sample banks, and FoodOmicsGR_RI combines these characteristics.FoodOmicsGR_RI addresses a priority for Greece because the country possesses unique biodiversity, as described above in detail. The characterization of unique traditional products, highlighting their value and the potential benefit of the Greek/Mediterranean diet, is best achieved by an evidence-based analytical description of their compositional characteristics with the application of advanced technology. This can increase the attractiveness and market value/demand for these products, thus supporting brand naming and generating higher revenue for the producers and national economy."}
+{"text": "Yunnan Province was considered the most difficult place in China for malaria elimination because of its complex malaria epidemiology, heterogeneous ecological features, relatively modest economic development, and long, porous border with three malaria endemic countries: Lao People\u2019s Democratic Republic, Myanmar, and Viet Nam.Academic publications and grey literature relevant to malaria elimination in Yunnan covering the period from 1950 until 2020 inclusive were considered. The following academic indexes were searched: China Science Periodical Database, China National Knowledge Infrastructure Database, and MEDLINE. Grey literature sources were mainly available from the National Institute of Parasitic Diseases (NIPD), the Chinese Center for Diseases Control and Prevention, and the Yunnan Institute of Parasitic Diseases (YIPD).A malaria elimination campaign in the 1950\u20131960s, based mainly on mass administration of antimalarial drugs and large-scale vector control, reduced morbidity and mortality from malaria and interrupted transmission in some areas, although elimination was not achieved. Similar strategies were used to contain outbreaks and a resurgence of disease during the 1970s, when malaria services were discontinued. From the 1980s, malaria incidence declined, despite the challenges of large numbers of mobile and migrant populations and an unstable primary health care system in rural areas following economic transformation. Launch of the national malaria elimination programme in 2010 led to adoption of the \u20181\u20133-7\u2032 surveillance and response strategy specifying timely detection of and response for every case, supported by the establishment of a real-time web-based disease surveillance system and a new primary health care system in rural areas. Border malaria was addressed in Yunnan by strengthening the surveillance system down to the lowest level, cross-border collaboration with neighbouring countries and non-governmental organizations, and the involvement of other sectors.Seven decades of work to eliminate malaria in Yunnan have shown the importance of political commitment, technically sound strategies with high quality implementation, a robust surveillance and response system at all levels, community participation and effective management of border malaria. The experiences and lessons learned from elimination remain important for prevention re-establishment of malaria transmission in the Province.The online version contains supplementary material available at 10.1186/s12936-021-03672-8. Plasmodium falciparum and Plasmodium vivax in Yunnan, registered in 2015 and 2016, respectively, were also the last indigenous cases of either species in China ."}
+{"text": "With cancer incidence increasing over time worldwide, attention to the burden of psychiatric and psychosocial consequences of the disease is now mandatory for both cancer and mental health care professionals. Psychiatric disorders have been shown to affect at least 30\u201335% of cancer patients during all phases of the disease trajectory, and differ in nature according to stage and type of cancer. Other clinically relevant distressing psychosocial and existential conditions  not included as \u2018disorders\u2019 in the usual diagnostic and nosological systems (i.e. meta-diagnostic conditions) have also been shown to be present in another 15\u201320% of cancer patients. In this editorial, we will present a summary of the extensive literature regarding the epidemiology of the several psychosocial disorders affecting cancer patients as a cause of distress and burden to be taken into consideration and addressed in cancer care through evidence-based intervention. For example, in palliative care, a marked reduction in performance, pain and fatigue, as well as loss of a vision of the future, make it difficult to differentiate major depression from other depressive spectrum disorders , the stage of cancer  and the type of assessment methods and tools used to determine caseness  are common in cancer care, particularly after chemotherapy.et al., et al., v. endogenous stressors) and temporal criteria (acute stressor in PTSD v. continuing and multiple stressful events in cancer).Trauma/stress-related disorders include post-traumatic stress disorder (PTSD) and sub-syndromic forms of PTSD hat has also shown to affect 15% of cancer patients  represent a frequent diagnosis at all stages of cancer, and describe the emotional reactions related to the multiple stressors linked to cancer, involving 20\u201325% of patients. Anxiety as well as depression can be also components of AD depression with intertwining effects in the manifestation of both conditions. However, several different problems emerge, not only with regards to oncology but all medical conditions, because of the low specificity of DSM criteria for the diagnosis of AD, the vagueness of the symptoms, the weakness of the concept of distress n Casey, .et al., et al., Somatisation and somatic-symptom disorders and their role in influencing patients' well-being are also important, not only because of its prevalence especially in long-survivors of cancer, but also in general for the multiple relationships between the perception of somatic symptoms and the patient's interpretation. Pain intensity, hypochondriacal concerns, disease labelling and dysfunctional interpretation of somatic symptoms, are part of a complex picture related to illness and abnormal illness behaviour; ways in which individuals adaptively or maladaptively monitor their body, experience, evaluate and respond to their state of health. All these issues have a significant role in cancer care, since somatic symptoms may magnify disability resulting from cancer, interfere with treatment adherence, decision making, cause delay in recovery, result in poor outcomes and recurrence, and reduce overall well-being and quality of life, and complicate the diagnosis of major depression   cognitive impairment or acute confusional states (delirium) secondary to the disease and its treatment. Mild neurocognitive disorders can be secondary to chemotherapy or chemotherapy associated with radiation therapy which can cause impairment of neuropsychological domains, such as memory, attention, concentration, learning functions, calculation and visual-spatial perception Wigmore, . Other cet al., et al., et al., A special area of interest is represented by delirium, one of the most common cognitive disorders in cancer, particularly in the advanced stages of disease. Delirium prevalence, depending on stage of disease, ranges from 10 to 80%, including both the hyperactive-agitated and mixed forms, although hypoactive delirium is most common in advanced cancer  and demoralisation (28.8%) are for example the most frequent clinically relevant psychosocial conditions diagnosable in cancer patients in different phases of illness  and in improving quality of life, well-being and return to work and illness behaviour (Li psychopharm-oncology) (Grassi and Riba, et al., et al., et al., Integrated psychopharmacological intervention (et al., et al., et al.,et al., Cancer has significant psychosocial consequences for both patients and their families. Today there is scientific evidence of the benefits of providing psychosocial cancer care as part of standard care in reducing distress and psychosocial morbidity associated with cancer and in fostering a better quality of life during and after treatment, and eventually in increasing survival. The significant advances in research in the area of psycho-oncology have favoured the development, implementation and dissemination of psychosocial guidelines and evidence-based treatments for several co-morbid psychiatric disorders in cancer, such as depression (Li"}
+{"text": "The COVID-19 pandemic, which began with reports of atypical pneumonia cases in the city of Wuhan in Hubei province of China, was declared a public health emergency of international significance by the WHO on January, 30 2020. The virus SARS COV2 has, to date, infected more than 16 million people around the world and over 0.6 million people have succumbed to it. The pandemic has affected more than 220 countries .The response in India, a LMIC, has focused on interrupting the transmission of infection through contact tracing, finding and isolating cases when they occur. The guidelines of the Ministry of Health recommends COVID care centers (CCC) be used for mild or very mild cases, separate dedicated COVID health centers (DCHC) for moderate cases (pneumonia without any signs of severe disease), and dedicated COVID hospitals with ICU facility (DCH) for critical cases .Though the steps taken in terms of prevention, interruption of transmission, and management of COVID-19 cases in India have been proactive, there is an urgent need to strengthen and integrate COVID care into the primary health care of the country. There exists a huge disparity between healthcare capacities among different states in India and states do not have similar capacities to and the ability to provide enough stand-alone centers like CCCs, DCHCs, or DCHs . Even inWe propose a three-tier system of community-based management of COVID-19 with a primary health care approach:Tier I : Local Self Government Tier II : CHC Tier III : District.The current practice in India focuses on the identification of suspects and confirmation of cases through RT-PCR testing. The ministry of health recommends the early segregation of cases into mild, moderate, and severe categories. The imperfect execution of segregation in many places has resulted in 77% of all patients admitted to hospitals having only mild symptoms of COVID-19 . MoreoveWe suggest that cases should be segregated based on the probability of future complications. Older patients with co-morbidities, pregnant mothers, children under 5 years of age, and patients exposed to high viral load in large closed door congregations should be admitted to dedicated COVID-19 hospitals with ICU facilities \u201312. PatiThe current practice of taking diagnosed COVID-19 patients to standalone healthcare centers promotes over-reliance on the health system, as a suspect is isolated from the community from the time of its contact tracing and quarantine through to testing, diagnosis, management, and finally, discharge (average 30 days) from the hospital. This increases the fear of disease among the population, which in turn increases the stigma not only against patients but also their family members, the recovered patients, and the health care workers who continue to stay in the community . This maThe Involvement of Community Health Centers (CHCs) the management of COVID19 will help diversify and decentralize the health care system in rural and semi-urban areas . It coulOne of the most important bottlenecks in the pandemic has been the lack of standardized, community-oriented, inclusive information, and a cohesive education and communication (IEC) strategy. A specialized IEC cell, with a community feedback mechanism under the district administration  will helThe current practice of laboratory diagnosis starts with the collection of nasopharyngeal and/or oro-pharyngeal swab by laboratory personnel or healthcare workers in individual hospitals or quarantine facilities or isolation centers. The samples are then sent to the designated laboratories for rt-PCR by maintaining the reverse cold chain . This inThe pandemic provides an opportune moment to expand primary healthcare infrastructure along with a once redundant network of telemedicine at community levels in India by resurrecting village-level resource centers .The community-based management of COVID-19 cases will not only help in reducing the fear and stigma prevailing during this pandemic but also enhance community engagement through participation and an increase in healthcare capacity. This will also improve community preparedness for future re-emergence of infectious diseases and will reduce the need for drastic measures like lockdowns in the future.SP: concept, intellectual content, and manuscript editing. SM: intellectual content and manuscript preparation. AJ: literature search and manuscript preparation. SK: literature search and manuscript preparation. AG: intellectual content and literature search. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "This paper reviews the evidence base for the health impacts of SIL on older adults, the risk factors, and the potential moderators and mediators of those relationships. Substantial evidence indicates that SIL are associated with physical, cognitive, and psychological morbidity; health-related behaviors; and health-related quality of life. Social isolation in particular is associated with a significantly increased risk of premature mortality from all causes. The evidence base for interventions in the clinical setting is also reviewed. Finally, the report\u2019s specific recommendations are discussed, including the need for basic science research, increased funding, key elements in the design and evaluation of interventions, and gap areas (including trends among current younger adults and approaches for specific understudied groups of at-risk older adults). Part of a symposium sponsored by Loneliness and Social Isolation Interest Group."}
+{"text": "Polypharmacy remains a significant healthcare issue in the United States, resulting in drug interactions, adverse drug reactions, and potentially dangerous complications. Polypharmacy, often defined as the simultaneous use of five or more medications, may lead to adherence problems and an increased risk of hospitalizations and death, particularly in the older population. Medication management was incorporated into undergraduate nursing clinical experience in an affordable housing urban community as part of the New Jersey Geriatric Workforce Enhancement Program (NJGWEP), a 5-year grant supported by DHHS-HRSA. This paper will describe the first phase of this project, which involved the determination of the prevalence of polypharmacy and high-risk medications in this setting. The charts of sixty residents were reviewed and along with demographic information, the following data was collected: total number of medications , high-risk medications using Beers criteria and identification of common themes or issues. The average age of the residents was 72 years, with cardiovascular diseases and diabetes mellitus being the most common comorbidities. Fifty-two of the sixty residents (86%) received five or more medications daily, meeting the definition of polypharmacy. The average number of medications taken on a daily basis was 8.9. Among the residents, centrally-active agents such as gabapentin, tramadol and lorazepam were the most commonly prescribed medications. The second phase of this project will include implementation of a medication reconciliation process to identify potential issues using the Beers criteria and implement appropriate interventions to ensure safe medication practices in this high-risk population."}
+{"text": "The novel coronavirus disease 2019, COVID-19, which is caused by severe acute respiratory syndrome virus 2 (SARS-CoV-2) . SARS-CoThe World Health Organisation (WHO) declared the novel coronavirus outbreak a Public Health Emergency of International Concern (PHEIC) on January 30, 2020 . As COVIOn February 27, 2020, the Federal Ministry of Health confirmed the first COVID-19 case in Ogun State, Nigeria, making the country the third country in Africa to recognise an imported COVID-19 case after Egypt and Algeria. The index case occurred in an Italian citizen who flew from Milan, Italy to Lagos, Nigeria on February 24, 2020, and travelled on to his company site in Ogun State the same day in a private vehicle. On February 26, 2020, he presented at the company clinic with symptoms consistent with COVID-19 and was referred to the Infectious Disease Hospital (IDH) in Lagos where a COVID-19 diagnosis was confirmed by real-time reverse transcription polymerase chain reaction (RT-PCR) on February 27, 2020.A total of 216 contacts in Lagos and Ogun States, including the passengers on the February 24 air flight, were identified for 14-day follow-up, with 40 of these contacts identified as high-risk. Eleven days later, an asymptomatic contact of the index case in Ogun State was confirmed as the nation\u2019s second case of COVID-19.The epidemiology of COVID-19 in Nigeria has since evolved, with cases identified in 35 of 36 states in the country, plus the Federal Capital Territory (FCT)  in order to ensure a cohesive and effective coordination of the country\u2019s preparedness efforts (Measures instituted by the NCPG included strengthening in-country diagnostic capacity for the testing of COVID-19 by leveraging and optimising three existing laboratories within the NCDC molecular laboratory network and assessing existing infectious disease treatment centres with a focus on identifying gaps and developing plans for case management. Interim protocols and guidelines for case management of COVID-19 were developed while the Nigeria Pandemic Influenza Preparedness and Response plan was reviewed for relevance to COVID-19 response. Infection prevention and control (IPC) and case management trainings were conducted for frontline health care workers in designated treatment centres.Findings from a WHO risk assessment identified 13 countries, including Nigeria, as high-risk priority zones for proactive surveillance, detection and containment of the spread of COVID-19 . ConsequFollowing the confirmation of the first COVID-19 case in Nigeria on February 27, 2020, the NCPG transitioned to a national multisectoral Emergency Operations Centre (EOC) at the NCDC. The EOC was activated at level three, the highest level of response in the country intended for public health emergencies requiring national coordination and use of all available resources for the response. The EOC comprises multiple pillars, including: coordination, surveillance and epidemiology, case management, laboratory, points of entry (PoE), IPC, risk communication, logistics, and research. POE and case management pillars are led by the Departments of Port Health Services and Hospital Services of the Federal Ministry of Health respectively. Sub-national EOCs were activated in both Lagos and Ogun states to coordinate the response in the first two affected states. National multidisciplinary rapid response teams (RRTs) were strategically deployed to the initial two states (Lagos and Ogun), plus FCT, and then to all states to strengthen coordination and response activities at the state and local government area (LGA) levels. The national RRTs, comprising NCDC staff and graduates/residents of the Nigeria Field Epidemiology and Laboratory Training Program (NFELTP), provided technical and logistical support at the state and sub-state levels.At the national level, the Presidential Task Force (PTF) on COVID-19 was established by the President of Nigeria on March 9, 2020, with an overarching mandate to coordinate and oversee the country\u2019s multi-sectoral and inter-governmental efforts both to contain the outbreak and to mitigate the impact of the COVID-19 pandemic in Nigeria. The National COVID-19 Multi-Sectoral Pandemic Response Plan was adopted by the PTF in March and serves as a blueprint for a whole-of-Government response.The PTF provided high-level strategic leadership to the national response guided by scientific evidence. Daily PTF media briefings were held to enlighten Nigerians on evolving evidence, address trending issues and provide update on the government\u2019s response. Technical evidence-based recommendations from the PTF informed the President of Nigeria\u2019s policy decisions for the various phases of the outbreak. Overall, Nigeria\u2019s response strategies were aimed at suppressing the transmission of COVID-19 by testing all suspect cases, isolating all confirmed cases, and tracing all contacts of confirmed cases, with the implementation of country-wide or regional non-pharmaceutical interventions as appropriate. The Nigerian response was characterised by robust collaborations with partners. Development and implementation of response strategies were facilitated by technical and material support from several local and international partners including the WHO, Africa CDC and philanthropic organisations. The need to generate relevant research evidence led to the formation of the Nigeria COVID-19 Research Consortium (NCRC) whose aim is to develop and implement a research agenda on COVID-19 with identified national priorities, in line with WHO\u2019s global research roadmap. NCRC also serves as the coordinating body for COVID-19 research in Nigeria.Given the novelty of the virus, the evolving nature of transmission in Nigeria from imported cases to clusters of cases to community transmission and level of response implemented, the NCDC EOC convened a mid-action review meeting on May 9, 2020, to strategically review the existing response approach, share lessons learnt, and identify key opportunities for improvement and further collaboration. The outcome and key recommendations of the meeting in line with the emerging data and global best practices have been used to improve response strategies, drive control and prevention measures against the disease, as well as focused interventions to strengthen the health system. The gaps identified include poor utilization of state level public health EOCs for coordinated responses, sub-optimal utilization of data to guide decision making, delayed turn-around-times of laboratory results, non-standardization of case management across treatment centers and poor adherence to IPC practices in health care facilities. Several intervention measures were instituted which include training and mentorship of State EOC teams on the incident management system as a tool for outbreak response coordination, development and operationalization of data management, analysis and use plans, deployment of the electronic surveillance system to laboratories to speed up the release of results, the establishment of a community of practice for COVID-19 case managers and deployment of online IPC training programme for health care workers.As of March 22, 2020, the initial 30 confirmed cases COVID-19 in Nigeria were travellers from abroad or their immediate contacts. This informed the initial international travel ban for passengers coming from countries with ongoing high transmission  to minimize rising imported cases. Ultimately, land borders were closed, all international flights were banned, and mandatory institutional quarantine and testing for international returnees to Nigeria was instituted on March 23, 2020 to reduce further importation of the disease from high-risk countries  in Lagos and Ogun States and FCT for an initial period of 14 days, extended for an additional 21 days in the same three states and adding Kano State. The states were selected based on a combination of the burden of disease and their risk: Lagos State was the initial epicentre of disease and had the highest number of cases; Ogun State borders Lagos State, was the source of the index case, and has a highly urban population with a high rate of travel into Lagos State; the FCT had the second-highest number of cases at that time. After the initial two-week lockdown period, incidence in Kano increased rapidly, prompting inclusion in the lockdown. The lockdown included closure of schools and workplaces, bans on religious and social gatherings, cancellation of public events, curfews, restrictions on movement, and cessation of interstate and international travel. Alongside the federal lockdown in Lagos, and Ogun States and the FCT, many states adopted measures as well, including school closure, movement restrictions, and curfews.The lockdown strategy was a drastic and temporary measure implemented with two objectives: first, to slow the spread of the virus across the country, and second, to buy time for the health system to increase its preparedness. During the lockdown period, the NCDC worked with all states to enhance contact tracing activities and increase capacity for case detection and treatment. Treatment centres were expanded from an initial single centre in Lagos with 35 beds, as of February 29, 2020, to 38 centres with 1055 beds by April 14; by May 30, 2020 Nigeria had 121 treatment centres with 6550 beds. In the four-week period, the number of laboratories able to carry out COVID-19 testing increased from the initial three to 13 laboratories in 10 states as of April 15, to 28 in 18 states by the end of May. More than 13\u2009000 health care workers were trained on IPC as well as on COVID-19 case management and personal protective equipment (PPE) and response commodities were deployed across the country to reinforce and better prepare the multi-sectoral response.Despite bans on interstate travel, the virus had already spread geographically. Ten states reported their first COVID-19 cases during the first 14-day phase of the Federal lockdown, while an additional 13 states reported index cases in the second phase of the lockdown. Index cases in several states were traced to domestically exported cases from Lagos State and FCT. Nearly three-quarters  of current cases have no known epidemiological link, suggesting substantial community transmission. Cumulatively, as of May 31, 2020, 337 of Nigeria\u2019s 774 LGA have reported a confirmed case.Although laboratory capacity was scaled up rapidly, testing numbers did not increase as planned. Testing capacity in terms of PCR machines as of mid-April was approximately 2500 tests per day and increased to more than 5000 per day as three Mega PCR Laboratories were activated for COVID-19 testing in Lagos and FCT by late May. However, inadequate testing reagents, due to delayed orders, and airport closures, hindered testing scale-up. Limited numbers of sample collection teams and testing centres, as well as hesitancy among some of the population to test, have also constrained increased testing. In the first two weeks of April, on average fewer than 300 tests per day were conducted; this increased to approximately 640 per day in the last two weeks of April, 1145 per day during the first two weeks of May, and 1410 per day during the last two weeks of May.The drastic lockdown measures came with a significant economic and social cost. Crime and domestic violence reportedly increased during the period  and manyGlobally, countries continue to employ diverse strategies to control the COVID-19 pandemic. These strategies are aimed at preventing, detecting, controlling, and mitigating the impact of the pandemic while taking into account the economic, social, cultural and religious factors unique to each country. Ultimately, the effectiveness of these strategies will be determined and sustained by country-level and community ownership .Nigeria has, to date, the second-highest number of confirmed COVID-19 cases in Africa, and accounts for 7% of all confirmed cases on the continent. This may be an underestimate of the actual case load given the relatively low testing rate in Nigeria. As of May 31, Nigeria had conducted 63\u2009882 COVID-19 tests, equivalent to 293 tests per million population; in comparison, Ghana had conducted 184\u2009343 (5948 per million population) and South Africa had conducted 488\u2009609 tests (8251 per million population) . The relBy the end of May 2020, all but one state, Cross River State, reported COVID-19 cases. Cases were concentrated in the two most densely populated states, Lagos and Kano, as well as the FCT. Many of the initial cases reported outside of these three states have been imported from Lagos State, the FCT, or Kano State. Meanwhile, the rising case numbers in conflict-affected areas such as Borno State pose additional concerns and require context-specific interventions to avert a looming health crisis, especially in camps for internally displaced persons ,17.Undetected imported cases may have played a key role in the beginning and accelerated the transition from clustered to community transmission in the Nigeria outbreak. This is because, as the outbreak began, prior to closure of international borders, arriving international passengers were allowed to self-quarantine (without testing) but encouraged to seek testing if symptoms developed. This may have led to multiple undetected imported cases. The rapid emergence of cases among individuals with no travel history or recognized epidemiological links to other cases despite contact tracing suggests multiple undetected cases may have been imported into the country or that potential contacts of the identified cases were missed. This guided subsequent approach such that following border closure, arriving passengers  had mandatory supervised quarantine for 14 days.Nigeria\u2019s states were facing critical challenges as the number of cases continues to increase across the country. Foremost among these is the limited number of COVID-19 treatment centres. Though greatly expanded since the outbreak\u2019s start, the limited number of beds, health workers, and critical care equipment such as oxygen and ventilators may quickly lead to an overwhelmed health system unable to minimize COVID-19 mortality and contain the spread of the disease. The NCDC continues to work closely with all state governments and partners to ensure adequate infrastructure is in place for timely case detection, management of cases, and to build capacity of the public health and clinical workforce.Although national testing capacity has significantly increased with private sector engagement, testing coverage and pace is still relatively low. By the end of May 2020, 293 tests had been conducted per million population, about 5% of what Ghana had done, with an average positivity rate of 15.9% overall. Nigeria needs to rapidly scale up testing to be able to quickly identify existing cases, isolate them, and control the pandemic. Securing sufficient testing supplies and personal protective equipment for health care personnel are immediate challenges of the response.Lock down containment measures were aimed at slowing the spread of the outbreak to new states, delaying the progression to community transmission, and increasing health system capacity at the initial phase of the outbreak. Though the lockdown slowed down COVID-19 transmission, it had undesired collateral effects on social protection, security, and daily subsistence for many. It is safe to assume that these negative consequences of the pandemic disproportionately affected women, people living in poverty, petty traders and those dependent on income from small and medium enterprises. The adverse effects of the lockdown exacerbated already difficult situations for many, rendering prolonged enforcement of preventive interventions such as lockdown and physical distancing unsustainable.A systematic approach was adopted to balance economic reopening with public health concerns, demonstrated in the phased easing of lockdown alongside a whole-of-society outbreak control strategy. This approach mobilises all sectors and communities to take ownership of and responsibility for response efforts towards control of the war against COVID-19 in Nigeria. The easing of lockdown measures came at a time when confirmed cases were on the uptick; however, the immense socioeconomic impact witnessed during the lockdown period necessitated a more balanced approach to public health interventions . FurtherNigeria mounted a swift and aggressive response to COVID-19, leveraging on its existing epidemic preparedness and learning from other parts of the globe where transmission began earlier. The country\u2019s initial response included early activation of the national EOC at the NCDC, establishment of the multi-sectoral COVID-19 PTF, and decisive actions to stop international travel and impose a time-limited lockdown in highly affected areas. By rapidly implementing this set of interventions, Nigeria likely slowed down the rate of virus transmission and bought extra time to implement a robust case detection, testing, and treatment centre capacity. However, these efforts, especially testing, needs more private sector involvement to significantly ramp up COVID-19 diagnostic centres across the country. Sensitising and mobilising citizens to take responsibility by strict implementation of preventive non-pharmaceutical measures is key to flattening the curve. A rapid, holistic, cohesive, whole-of-government approach that encompasses civil society and local-communities in the response will be absolutely critical to combating the COVID-19 pandemic in Nigeria  and rebu"}
+{"text": "Persons with dementia (PWD) are two-three times more likely to be hospitalized as persons without dementia and comprise one fourth of hospitalized older adults. Hospitalization often has a dramatic impact upon the health and disposition of the older PWD. They are at increased risk for hospital acquired complications (HAC) such as functional decline, behavioral symptoms of distress, and delirium, all of which contribute to increased disability, mortality, and long-term nursing home stays. Despite the unprecedented number of PWD admitted to acute care, little attention has focused on their specialized needs and HAC, and how they impact functional recovery. The purpose of this symposium is to describe the incidence of common HACs, and factors that influence their occurrence and presentation in PWD. Utilizing baseline findings from the Family-centered Function-focused Care (Fam-FFC) trial, the presentations will address this objective and discuss the ramifications for functional and cognitive post-acute recovery in PWD. The first presentation will describe the incidence and pharmacologic management of pain in PWD, and its association with common HACs. The second presentation will describe physical activity in PWD on medical units and the validity of the Motionwatch8 actigraphy. The third session will describe differences in common HACs between white and black PWD. The final presentation will examine function-focused goals developed in collaboration with family caregivers and patients, and the functional outcomes associated with goal attainment. Our discussant, Dr. Lorraine Mion, will synthesize the research findings and lead a discussion of future directions for policy and practice in dementia-capable acute care."}
+{"text": "Food, by nature, is a biological substrate and is therefore capable of supporting the growth of microbials that are potential producers of toxic compounds. Natural toxins include mycotoxins, marine biotoxins, plant toxins, cyanogenic glycosides, and toxins occurring in poisonous mushrooms. Natural toxins pose not only a risk to both human and animal health, but also impact food security and nutrition by reducing people\u2019s access to healthy food. The tracking and detection of natural toxins in foods back to their source is a primary responsibility of food producers, distributors, handlers, and vendors. National authorities should conduct monitoring and ensure that levels of the most relevant natural toxins in food commodities comply with both national and international maximum levels or relevant toxicological thresholds.Toxins includes some recent advances in analytical methodologies for the detection of natural toxins in food commodities and biological fluids. The collected contributions are relevant to two main analytical approaches, namely advanced liquid chromatography\u2013tandem mass spectrometry (LC-MS/MS) applications for the high sensitive and selective detection of emerging contaminants, and approaches for rapid and cost effective toxin detection based on immunoassays and cell-based assays.This Special Issue of The phytotherapeutic and nutritional use of plants and herbal-based products have increased in popularity over the last few years, however the improper usage of plants or unawareness of plant toxicity may lead to intoxication cases. Nowadays, highly sensitive and selective LC-MS/MS techniques represent a relatively easy to access and powerful tool to target plant toxins at low levels, and as a consequence, contaminants such as pyrrolizidine alkaloids and cardiac glycosides have surfaced as an issue of relevance in food safety. A method for the determination of pyrrolizidine alkaloids in honey has been set up by Hungerford et al. . The stuAmong the readily available in vitro methods, the functional assay known as the cell-based assay, which uses a neuroblastoma (N2a) cell line, is widely applied for routine surveillance of marine toxins. In their study, Viallon et al. optimized several key parameters of the cell-based assay, improving assay implementation and reliable toxin detection, making the final protocol suitable for future standardization and interlaborarory comparisons . The overall performances of immunoassays strongly depend on the quality of selected immunoreagents, first of all, of the antibody. For this reason, the development and testing of new antibodies continues to warrant considerable efforts in current research. Maragos et al. proposed a new competitive enzyme-linked immunosorbent assay (ELISA) to screen for citreoviridin and its geometric isomer, iso-citreoviridin, in white rice based upon the isolation of two novel monoclonal antibodies . The devWhen applying rapid screening tests for compliance testing, their fitness for purpose needs to be demonstrated through a validation study. The manuscript by Pecorelli et al. provides insights about the process of evaluating and comparing the performance profile of rapid methods currently applied for AFM1 screening in milk . AddressAntibodies as well as alternative receptors, such as aptamers, can be used in several biosensing platforms. The review by Zhuheng Li et al. updates the construction strategies of electrochemical biosensors such as immunosensors and aptasensors for the cost-effective determination of microbial toxins including bacterial toxins, fungal toxins and algal toxins . The papOverall, the papers included in this Special Issue have contributed to advance the state-of-art of analytical methods for the detection of natural toxins. Furthermore, a part of the published studies focused on emerging or less investigated toxins, thus providing the scientific community with new tools and/or data supporting a better understanding of related food safety issues."}
+{"text": "Social approaches such as distancing measures are essential components of the public health response to respiratory-related infectious disease outbreaks. Due to socio-economic and broader peculiarities of SSA countries, social approaches that were effective elsewhere may have limited practicality in these contexts, and if practical; may yield different or even adverse results. We highlighted the effectiveness of these social approaches and their practicality in SSA.we conducted a comprehensive literature search through multiple databases, to identify articles relevant to social distancing. Findings were thematically summarized.our review found emerging and varying empirical evidence on the effectiveness of social approaches in the control and mitigation of the COVID-19 pandemic; thus, limiting its applicability in SSA contexts. Nonetheless, our review demonstrates that the effectiveness and practicality of social approaches in SSA contexts will depend on available resources; timing, duration, and intensity of the intervention; and compliance. Weak political coordination, anti-science sentiments, distrust of political leaders and limited implementation of legal frameworks can also affect practicality.to overcome these challenges, tailoring and adaptation of these measures to different but unique contexts for maximum effectiveness, and investment in social insurance mechanisms, are vital. The pandemic has since spread to more than 192 countries and territories around the world. Evidence shows that COVID-19 is readily transmissible from person to person through air droplets and aerosols [The World Health Organization (WHO) declared the coronavirus disease 2019 (COVID-19) outbreak a pandemic on the 11aerosols . The goaaerosols  As of 21aerosols . Due to et al. [et al. is comprehensive, specific to respiratory disease pandemics and is widely cited across literature sources and publications addressing NPIs, hence highly relevant to our review. Further, the rationale for using this framework was due to its clear definition of each social approach. Based on that, we categorized the social approaches into five distinct but interrelated themes: 1) Isolation and quarantine; 2) Closure of schools; 3) Closure of workplaces; 4) Avoiding/cancellation of mass gathering; 5) Restriction of movement. We highlight in each category the evidence on the rationale and effectiveness of the interventions as well as their contextual implications within SSA.In the first prong, we reviewed the evidence on the effectiveness of social approaches to COVID-19 and respiratory disease outbreak response. To do this, we conducted a literature search of the following electronic databases: MEDLINE (via LitCOVID in PubMed), Google scholar, Cochrane Library, African Index Medicus, and EBSCOhost. To be eligible for inclusion, publications had to assess the effectiveness of social measures used in the response to COVID-19 or other respiratory disease outbreaks in SSA or other settings. Reference lists of relevant articles and documents on databases of the World Health Organization (WHO) and Africa Centres for Disease Control and Prevention (Africa CDC) were also scanned for potentially relevant articles. See et al. , to themIsolation and quarantine: the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spreads primarily by human to human transmission through infected droplets [droplets ,8 .Hencedroplets . Empiricdroplets . Commonldroplets -12. HowePracticality of isolation and quarantine in sub-Saharan Africa: the potential health, social, and economic impacts of the spread of COVID-19 in Africa are important considerations for governments and public health authorities in SSA to take pragmatic steps towards stemming the tide of transmission. While isolating cases and quarantining those exposed are reasonable interventions that are potentially effective for controlling infectious disease outbreaks, they are resource-intensive [ntensive . Given tntensive . As COVIntensive ,14.Isolation/quarantine facilities may also be crucial for contacts residing in overcrowded housing conditions and those who are homeless. Due to overcrowded homes, particularly in urban slums and informal settlements, implementing self-isolation/quarantine may expose other persons in the household and may lead to further community transmission. In addition, these living conditions may make staying indoors and complying with isolation/quarantine for the appropriate duration unbearably uncomfortable, particularly on hot days. Furthermore, the lack of improved water supply and sanitation facilities in communities may also complicate self-isolation of cases and voluntary quarantine of contacts of cases. As such, designated isolation/quarantine facilities could be an avenue for dealing with these practical and contextual constraints. Moreover, seven out of ten Africans work in the informal sector with implications for the practicality of self-isolation/quarantine. There is a high likelihood of non-compliance with these self-isolations /quarantine if people are faced with the risks of income or job losses while absent from work . InformaWhile the limitation of rights and freedom of movement during the enforcement of isolation and quarantine may be justifiable in the interest of public health in pandemic settings, it carries the inherent risk of being abused and implemented in draconian ways; particularly in the contexts of authoritarian leadership. This would be the case if there is fear, intimidation, abuse, or victimization. Such adverse outcomes have been highlighted by numerous reports of police and military brutality, intimidation and harassment across a number of African countries during the enforcement of movement restrictions. Hence, it is important for isolation and quarantine to be enforced with fairness and within human rights standards . Lastly,Workplace closure: evidence suggests that there is a substantial risk of respiratory disease transmission in occupational settings [settings . Implemesettings ,19. A 23settings . In addisettings . Comparasettings .Practicality of workplace closures in SSA: the majority of the population in SSA lives in poverty and in rural households without social insurance policy. As discussed earlier, the informal sector makes up about 70% of the workforce, and there are many people who rely on a daily income to eke a livelihood [velihood . Withoutvelihood  which isvelihood . Formal velihood .School dismissal and closure: school dismissal refers to schools remaining open to only administrative and teaching staff, vulnerable children, children of healthcare and essential workers [ workers . On the  workers . These t workers . School  workers . In Sing workers . Further workers -31. Howe workers . School  workers . Disenta workers .Practicality of school closures in SSA: school closure results in reduced parental productivity including loss of health-care staff to childcare duties [e duties -30,32. Te duties . Most lie duties . While se duties . It has e duties . These ce duties . Though e duties -38.Avoiding/cancellation of mass gatherings: mass gathering is a planned or spontaneous event where the number of people attending could strain the planning and response resources of the community or country hosting the event [he event . Examplehe event . Avoidinhe event . It invohe event ,41. Evidhe event ,43. Evidhe event . During he event .The timihe event .Practicality of avoidance /cancellation of mass gathering in sub-Saharan Africa: in many SSA countries, avoiding/restricting mass gathering has been used as a social distancing measure in limiting the spread of the SARS-CoV-2 .There have been reports of compliance in the shutting down of sporting events, in contrast to large pockets of partial to non-compliance with regards to some cultural and religious practices/events like burials, coronation events, weddings, church/mosque services  etc. In West Africa, there have been negative reactions, including riots, to the closure of places of worship  and incidences of 'super spreading' events at evangelical church sessions (in Burkina Faso and South Africa) [ Africa) -49. Thes Africa) . However Africa) . Again,  Africa) .Restriction of movement: lockdowns and curfews are categorized as restriction/halting of movement with the rationale of ensuring social distancing measures to delay the peak of the infection. While there is currently no consistent definition for lockdowns, we assume a rather more contextual definition to accommodate the variability in implementation. It ranges from hard or full lockdowns (active coercion with the agency of the police/army (state) in maintaining sit- at- home orders and enforcing no entry/exits into territories), to partial lockdowns . The lockdown seen in Wuhan, China is the prototype of hard lockdowns, while the one instituted in London is an example of partial lockdowns [ockdowns ,53. The ockdowns -58.et al. carried out a hierarchical cluster analysis to assess the impact of complete lockdown on total infection and death rates across 12 countries that declared lockdown [et al. reported that had a strict lockdown not been instituted in Wuhan-China, COVID-19 cases would have been 65% higher in the 347 Chinese cities outside Hubei province, and 53% higher in the 16 non-Wuhan cities inside Hubei [et al. modelling estimates by placing restrictions reduced COVID-19 transmission by a median 45% (42 to 49%) in Italy with over 200 000 hospitalizations averted as of March 25, 2020 [Ghosal lockdown . Data frlockdown . There wde Hubei ,. Simila25, 2020 . Institu25, 2020 .Practicality of restriction of movement: while effective in combating COVID-19, the WHO recognizes restricting movement as a blunt tool with social and economic costs [ic costs . The praOverall, our review suggests emerging and varying empirical evidence on the effectiveness of social approaches such as isolation, quarantine, school and workplace closures, movement restrictions and prohibition of mass gatherings, in the control and mitigation of the COVID-19 pandemic. We highlighted in each category of the social approaches the rationale for implementing the interventions and their contextual implications. To illustrate, while measures such as work, and school closures may be important for reducing the spread of COVID-19. In many SSA social contexts, these may have little practicality due to low internet penetrations to support online learning and teleworking. Similarly, contextual realities such as overcrowded living conditions and water supply deficits may constrain the practicality of the social distancing rule of staying or living at least 2 meters apart and the NPI of regular handwashing. Other challenges in the region include infrastructural deficits, limited technical capacity to undertake contact tracing and surveillance activities, inadequate or lack of social safety nets, weak legal and legislative frameworks, and mixed messages from some political leaders resulting in anti-science sentiments, and a general mistrust and low confidence in political leaders.Our review is not without its limitations. Given the very broad nature of the topic and time constraints, we were unable to conduct a systematic search of the literature. However, we minimized the risks of literature selection bias by an internal peer-review process that allowed each team member to critically appraise the literature identified by team mates. Because ours was a non-systematic review, it did not require a systematic quality assessment of included literature. As such, our quality assessment is narrative. The sources of the evidence we included in the review were mostly observational and simulation studies, thereby limiting the certainty of the evidence. Further, the certainty of this review\u00b4s evidence is limited by the ongoing and rapidly evolving nature of the pandemic, particularly with the lingering uncertainties around transmission dynamics. In addition, the integrated implementation of these social measures makes it difficult to distinguish the specific impact of each intervention from the cumulative effects of combined efforts. Nonetheless, our review demonstrates that social approaches have varying effectiveness and practicality, depending on available resources, the timing of the intervention, duration, intensity, combination with other measures, implementation monitoring, and compliance. For instance, there is substantial evidence that isolation, used together with contact tracing, quarantine and optimal testing, is beneficial in mitigating the spread of the virus .Finally, at the heart of the limited practicality of these social approaches in SSA countries are (1) fundamental challenges in equity: are the measures equitably implemented?, (2) sustainability: can the measures be implemented sustainably?; (3) financial and technical investments: do SSA countries have the economic and technical resources to implement some of these measures; are these economic resources judiciously and efficiently managed and used as planned? and (4) trust: do the citizens trust the messages from their leaders?In sum, there is emerging and varying empirical evidence on the effectiveness of the use of selected social approaches in the control of the COVID-19 pandemic in SSA contexts. There is limited practicality in implementing these social approaches due to infrastructural and economic deficits, limited technical capacity, anti-science sentiments, weak political coordination, distrust of political leaders and limited implementation of legal frameworks. To overcome these practical challenges, tailoring and adaptation of these measures to similar but unique contexts for maximum effectiveness, and investment in social insurance mechanisms, are vital.The coronavirus disease 2019 (COVID-19) pandemic has spread rapidly across most countries of the world;Social approaches such as distancing measures are essential components of the public health response to respiratory-related infectious disease outbreaks;Controlling the pandemic is challenging as there is limited evidence on the safety and effectiveness of appropriate medicines, with vaccines currently available for prevention.This review demonstrates varying effectiveness of social approaches such as isolation, quarantine, school and workplace closures, movement restrictions and prohibition of mass gatherings, in the control and mitigation of the COVID-19 pandemic;This review contextualizes the implications of these social approaches in sub-Saharan African contexts, summarizing the evidence in one paper, thus making it easy for readers to access the information;This review establishes that the effectiveness and practicality of social approaches in SSA contexts will depend on several important factors. Including the availability of resources; timing of the intervention, effective leadership and community trust."}
+{"text": "First WHO model list of essential in vitro diagnostics in 2018; the Indian Council of Medical Research  followed in its footsteps and released its first National essential diagnostics list in 2019.Accurate and affordable diagnostics are central to effective health care. Quality diagnostics, when made available as part of health-care services, influence disease diagnosis and treatment outcomes in patients and improve disease surveillance. Poor investment in diagnostics, especially in low- and middle-income countries, has translated into high out-of-pocket expenses on diagnostics. Furthermore, lack of diagnostics can result in serious public health challenges, such as antimicrobial resistance due to overuse of antibiotics.India has had a long history of vertical, disease-specific programmes, which contributed immensely to the control of infectious diseases such as human immunodeficiency virus (HIV), tuberculosis and malaria.India\u2019s essential diagnostics list is comprehensive and ambitious; through this list, the Indian Council of Medical Research seeks to cement diagnostics as an important component in health care. The list should translate into improved patient outcomes and reduction in out-of-pocket expenses on diagnostics. The list was drafted through a consultative process spearheaded by the Indian Council of Medical Research. The process of reaching a consensus on which diagnostics to include in the list consisted of five consultative meetings with clinicians, microbiologists, pathologists, radiologists, representatives of civil society, managers of national programmes, representatives of the diagnostics industry and other technical experts over a period of 15 months. The consultations focused on the latest available evidence of disease burden,In 2015, the Indian government, under the guidance of the National Health Mission, launched the Free Drugs Service and Free Diagnostics Service Initiative, as part of its nationwide effort towards the government-led Health for All objective.Having a national essential diagnostics list endorsed by all major stakeholders would have several advantages, mainly homogenizing diagnostics availability at every level. States can use the list as a reference document to forecast needs and guide their procurement; the list can also help them determine the volumes of tests and mechanisms required to meet demand and negotiate diagnostics\u2019 prices. Special pricing initiatives driven by aggregated volumes have been practiced by some disease control programmes in low- and middle-income countries to improve diagnostics availability.During the consensus-building process to develop the list, the committee of experts identified several important gaps where diagnostic solutions for priority health-care conditions specific to India are needed. In the last decade, the development of point-of-care diagnostics has advanced significantly, with scientists and entrepreneurs making strides in the development of next-generation point-of-care diagnostic devices that are based on modern technologies such as smartphones and cloud-based devices. While some point-of-care diagnostics such as rapid blood glucose, digital haemoglobinometer and cardiac biomarkers have already been included in the diagnostics list, point-of-care rapid tests for the detection of infectious diseases, such as typhoid, are needed.Through the national essential diagnostics list, the Indian government seeks to make the availability of quality diagnostics an essential component of the health-care system; the list can also become a guidance document for other countries to develop a similar tool. Strengthening of diagnostics infrastructure and improving the availability of diagnostics will be key to achieving diagnostics availability across all levels of health care. Even the point-of-care diagnostics, despite their promise of simplicity, affordability and shorter turnaround time, require a functional delivery system that is supported by laboratory and clinical expertise. We hope that implementing the national essential diagnostics list, which is underway through the Free Drugs Service and Free Diagnostics Service Initiative, will increase the availability of good quality diagnostics and therefore reduce out-of-pocket expenses on diagnostics and improve patient outcomes."}
+{"text": "The University of Nebraska Medical Center\u2019s Rural Patient and Stakeholder Engagement in Research project used a novel approach to patient engagement in research: just-in-time engagement. In this approach, patients were identified and matched with researchers with shared research interests without preemptive patient and stakeholder education and training. Ten research teams initiated engaged research design between August and October of 2019. In this presentation, we will share process and outcomes measures of the just-in-time approach: measures of ongoing engagement at 6 and 9 months; evidence of research productivity, and patient and stakeholder satisfaction with their research involvement. We will also address ethical challenges, including challenges to engaging a diverse population. Part of a symposium sponsored by the Patient/Person Engagement in Research Interest Group."}
+{"text": "Muir-Torre syndrome is a rare, autosomal dominant genodermatosis, characterized by sebaceous neoplasms and visceral carcinomas. The authors describe the case of a patient who, 16 years after the diagnosis of colon carcinoma, presented a verrucous plaque on the pubic region, histopathologically compatible with sebaceous adenoma. The need to investigate this syndrome is emphasized, especially in cases of sebaceous neoplasms located outside the head, face, and neck. Screening for neoplasms in these patients and their families is mandatory. The authors describe the case of a 79-year-old woman, presenting a warty, erythematous, and painless plaque for two years on the pubic region . There wa)Amelanotic melanomab)Condyloma acuminatumc)Squamous cell carcinomad)Sebaceous adenomaBased on clinical and histopathological findings, the authors reached the diagnosis of sebaceous adenoma in a patient with Muir-Torre syndrome (MTS). Sebaceous tumors are rare, most commonly located on the face and neck of the elderly.The diagnosis of sebaceous neoplasia makes MTS screening imperative. This is a rare variant of Lynch syndrome, autosomal dominant, characterized by the occurrence of sebaceous gland tumors  associated with visceral neoplasia. Among the sebaceous tumors related to MTS, adenoma is the most common, histologically characterized by lobular proliferation with predominance of mature sebocytes in the center and a minority of basaloid germ cells at the periphery. Colon adenocarcinoma is the most common associated visceral neoplasia, especially when proximal to the splenic flexure (unlike sporadic cases), followed by tumors of the genitourinary tract.The diagnosis of MTS is clinical, by finding sebaceous neoplasia and at least one visceral tumor without other contributing factors, such as radiotherapy or immunosuppression. Immunohistochemistry and molecular analysis are indicated in cases where there is no family or personal history of visceral neoplasms.The authors report a case of sebaceous adenoma with unusual location in the pubic region in a patient with colon and bladder cancer. The importance of investigating systemic neoplasms associated with SMT and the monitoring of these patients and their families is emphasized.None declared.Diego Henrique Morais Silva: Approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; intellectual participation in propaedeutic and/or therapeutic conduct of studied cases; critical review of the literature; critical review of the manuscript.Anna Karoline Gouveia de Oliveira: Design and planning of the study; collection, analysis, and interpretation of data.Neusa Yuriko Sakai Valente: Approval of the final version of the manuscript, effective participation in research orientation, intellectual participation in propaedeutic and/or therapeutic conduct of studied cases, critical review of the manuscript.Thais do Amaral Carneiro Cunha: Approval of the final version of the manuscript, intellectual participation in propaedeutic and/or therapeutic conduct of studied cases.None declared."}
+{"text": "Dear Editor,Purpura annularis telangiectodes of Majocchi is a rare subtype of pigmented purpuric dermatosis. It is more common in children and young females and predominantly affects the lower limbs, with symmetrical annular reddish-brown macules.4A 6-year-old female patient, daughter of consanguineous parents, presented lesions since 2 years old. The patient had no history of systemic symptoms, allergies, or continued use of medications, except sporadic use of paracetamol. In the beginning, the lesions were erythematous, and subsequently evolved to annular and/or irregular hyperchromic macules, symmetrical in the legs, as well as in the right upper limb, and with an isolated lesion in the anterior cervical region . A skin Purpura annularis telangiectodes of Majocchi is part of the pigmented purpuric dermatoses, which manifests as annular macules that are symmetrical, reddish-brown, and generally asymptomatic. It preferably affects children and young women, and there is no predominant ethnicity.None declared.Aline Soares Garcez:; elaboration and writing of the manuscript; critical review of the literature.Vit\u00f3ria Regina Pedreira de Almeida Rego: Approval of the final version of the manuscript; critical review of the literature.Thadeu Santos Silva: Approval of the final version of the manuscript; elaboration and writing of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of studied cases; critical review of the literature, critical review of the manuscript.None declared."}
+{"text": "Cardiovascular disease (CVD) has always been an important field of application for diagnostic imaging in small animal practices and, vice-versa, diagnostic imaging has greatly expanded the diagnostic capabilities of veterinary clinicians dealing with CVD. In addition to physical examination and electrocardiography, cardiac imaging offers unique opportunities to understand and investigate cardiovascular function and dysfunction. Among the different imaging modalities, each with specific advantages and disadvantages, some focus primarily on cardiac structure and anatomy and others are mainly concerned with cardiac physiology and function.For several decades in the last century, thoracic radiography and fluoroscopy, with or without the use of contrast medium , were the imaging techniques of choice to investigate dogs and cats affected by congenital or acquired CVD ,2. RadioStarting in the 1970s, the progressively increasing number of available ultrasound technologies, from M-mode via two-dimensional sector and then three-dimensional volume scanning techniques, in combination with various Doppler methods  and other advanced techniques , has considerably increased understanding of normal and abnormal cardiovascular anatomy and function . With thIn the last decade, the increasing accessibility of computed tomography (CT) and magnetic resonance imaging (MRI) units in small animal veterinary practices has offered additional powerful tools for the in-depth exploration of cardiac anatomy and the assessment of cardiac function. The high temporal and spatial resolution achievable with the modern multidetector-row CT scanners, which can acquire a three-dimensional dataset of the heart and thoracic vessels in a few seconds, allows the depiction of very small or difficult to access normal or abnormal cardiovascular structures  . FurtherThe heart and great vessels are very well visualized with MRI because the contrast between cardiovascular tissue and blood is more pronounced than in echocardiography and cardiac CT. Therefore, cardiac MRI is the reference imaging technique for the assessment of cardiac morphology and function and is often used for the evaluation of complex cardiovascular anomalies and specific myocardial disease processes in humans. In companion animals, the early application of MRI includes the precise assessment of cardiac morphology, volume and function, as well as the identification of subtle and challenging changes in poorly accessible cardiovascular structures such as the right ventricle, the pericardium and the heart base in animals with arrhythmogenic cardiomyopathy, mesothelioma, heart base masses and vascular abnormalities, respectively . Finally, veterinary cardiologists and radiologists have very recently started the early application of deep learning, an artificial intelligence application that uses computer-aided detection methods with the aim of helping clinicians recognize cardiac or left atrial enlargement on canine thoracic radiographs ,20.Cardiovascular imaging has witnessed an explosive expansion of available tools providing detailed information of cardiovascular structures and physiology with noticeable improvement in the diagnosis of CVD. The future directions of cardiac imaging include the increased interconnection among the different imaging techniques and their extended use, not only for diagnostic but also for prognostic purposes in animals with CVD."}
+{"text": "Dear Editor,Epithelioid sarcoma (ES) is a rare histopathological subtype of soft tissue sarcoma, accounting for less than 1% of all adult soft tissue sarcomas.None declared.Maraya de Jesus Semblano Bittencourt: Approval of the final version of the manuscript; collection, analysis, and interpretation of data; critical review of the literature; critical review of the manuscript.Caren dos Santos Lima: Drafting and editing of the manuscript; collection, analysis, and interpretation of data; critical review of the literature; critical review of the manuscript.Aline de Lima Days: Approval of the final version of the manuscript; Drafting and editing of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of studied cases; critical review of the literature; critical review of the manuscript.Camilla C\u00f4rrea Neri: Drafting and editing of the manuscript; collection, analysis, and interpretation of data; critical review of the literature; critical review of the manuscript.None declared."}
+{"text": "An age-dependent decreased number of AVT-positive neurons was seen in the medial preoptic area, medial preoptic nucleus, paraventricular nucleus, rostral part , and lateral preoptic area. Trends to effects of brooder rearing were found in both anteromedial preoptic nucleus and supraoptic nucleus, with dark brooder reared animals showing higher mean counts of AVT-positive neurons in both areas. No interactions between brooder raising and age were observed in AVT-positive neuron count. CORT levels were higher in primary wing feathers from 28 week old hens than in those from 16 week hens. No main effects of rearing with dark brooders or interactions between age and treatment were found on CORT levels. The age-dependent effects seen in the hypothalamus and CORT aids in further understanding of the development of chickens around puberty. The use of brooders tended to increase AVT expression in the anteromedial preoptic nucleus and supraoptic nucleus, an indication that dark brooder rearing may affect physiological responses regulated by these areas. The lack of effect of dark brooders on CORT in feathers is at the least an indication that the use of dark brooders is not stressful; in combination with the benefits of dark brooders on injurious pecking, fearfulness and early mortality, this pleads for the use of dark brooders in on-farm situations.Chickens cannot independently thermoregulate at hatch and lack opportunity to behaviorally thermoregulate with a hen in the egg layer industry, thus barns are heated to thermoneutral temperatures. Dark brooders are low-energy-consuming hot plates, which may be environmentally advantageous while providing welfare-enhancing aspects of maternal care . Dark brooder use has been demonstrated to decrease injurious pecking and mortality well into the production period of layers. To further understand hen development around lay onset and effects of dark brooders on the brain and HPA-axis, we examined effects of rearing with dark brooders on expression of vasotocin (AVT) in the hypothalamus and corticosterone (CORT) in the feathers of in total 48 layer Isa Warren hens at 16 w and 28 w of age ( Gallus gallus domesticus) hatch with limited ability to produce warmth by thermogenesis . Brooders may also have positive effects on welfare problems in the egg layer industry. Chicks bred with broody hens are less fearful than chicks bred without mother hens . LikewisAphelocoma coerulescens; . Maternal deprivation has been reported to affect the neuro-endocrine response to stress in mammals \u201316. Morelescens; ]. In youlescens; , and strlescens; . Maternalescens; . Both felescens;  and knowlescens; , 24, sugMaternal care, or lack thereof, can also lead to long-term changes in neuroanatomy visible even in adulthood in humans and rodents . PreviouGiven the impracticality of housing broody hens with chicks in industrial situations on the one hand, and the desirability of introducing aspects of maternal care to improve welfare and reduce energy use on the other hand, investigation of the effects of the use of dark brooders during rearing on physiological parameters related to stress and welfare is of strong interest. Previously published results from the present group of animals demonstrated strong positive effects of dark brooders on plumage condition, wound reduction and reduction in mortality rates . To furtAll procedures involving animals were in accordance with the Danish Ministry of Justice Law No. 382 (10 June 1987) and Acts 333 (19 May 1990), 726 (9 September 1993) and 1016 (12 December 2001). This study is part of a larger project that also evaluated the effects of brooders on welfare, including behavior, fear, injurious pecking damage, mortality and production parameters .The chickens used in this study were non-beak trimmed Isa Warren layers, obtained when 1 day old from Top\u00c6g Aps, Viborg, Denmark.2) and in whether the brooder was raised at regular intervals . DirectAge was found to affect the expression of AVT in the hypothalamus of chickens, and an age-dependent increase in CORT was seen in feathers of the hens. This information aids in further understanding of the development of chickens around puberty. The use of brooders tended to affect AVT expression in some areas of the hypothalamus. The lack of effect of dark brooders on CORT in feathers is at the least an indication that the use of dark brooders is not stressful; given previously shown positive benefits of dark brooders, e.g., prevention of injurious pecking, reduced fearfulness and lower mortality, this pleads for the use of dark brooders in on-farm situations.The datasets generated for this study are available on request to the corresponding author.All procedures involving animals were in accordance with the Danish Ministry of Justice Law No. 382 (10 June 1987) and Acts 333 (19 May 1990), 726 (9 September 1993) and 1016 (12 December 2001). This study is part of a larger project that also evaluated the effects of brooders on welfare, including behavior, fear, injurious pecking damage, mortality and production parameters .AR conceived and designed the study with RN. RN and AR drafted the manuscript with help from EZ. EZ and AD performed laboratory work, analysis of stained slides, and statistical analysis.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Nearly 59,000 human deaths worldwide are attributable to rabies annually, of which more than a third occur in Africa. In recent years, progress has been made in both action and collaboration including implementation of surveillance and prevention measures. In this review we assess the scale of surveillance, preventive, and control efforts of canine-transmitted human rabies in African countries. We reviewed literature published from 2014 to 2018, retrieved from electronic databases including MEDLINE, Global Index Medicus, BIOSIS, Science Citation Index, and EMBASE. WHO reports, national disease control program reports, and conference proceedings were also reviewed. The database search was conducted using keywords including rabies, control, and prevention. In forty countries (40/54), some level of rabies control and prevention strategy was available while in fourteen (14/54) countries, no specific national control and prevention strategy for human rabies could be retrieved. Thirty-four (34/54) countries utilized the Stepwise Approach towards Rabies Elimination (SARE) tool to monitor the national rabies control efforts\u2014five of these countries were at the lowest tier (0/5) of the SARE scoring system while no country had achieved the highest score (5/5). High burden countries need to step up the implementation of context specific national rabies control, prevention, and monitoring strategies. As a zoonosis, rabies control and elimination require coordination between human and veterinarian health sectors under the \u201cOne Health\u201d umbrella and with national master plans on the prevention and control of neglected tropical diseases ending in 2020, the time to act is now. Rabies, which is caused by viruses of the rhabdovirus family, genus lyssaviruses, has a worldwide distribution. Rabies is vaccine preventable; however, there is no cure, and it is usually fatal once symptoms appear . The neuThe Sustainable Development Goals (SDGs) of the 2030 agenda for sustainable development called for actions targeting improvements in health and education and ending epidemics of neglected tropical diseases (NTDs) in the next decade . As a deInvestigations from the past five years estimated the epidemiological and economic impact of intervention strategies strongly supporting the effectiveness of canine vaccination and equitable access to PEP in populations residing in endemic regions ,9,10,11.In this review, we assess the current control strategies, policies, programs, and actions directed at reducing canine-transmitted rabies in Africa. This summarized evidence will inform regional stakeholders, governments, and local officials to coordinate control, prevention, and elimination strategies across relevant governmental and non-governmental sectors to ensure enhanced collaboration in achieving the SDG targets. Further, the review will provide critical insight into the challenges and deficiencies related to current national policies and strategies. This will support development of informed and coordinated national and continental strategies for rabies elimination.https://www.un.org/en/member-states/index.html) (accessed on 21 January 2021). Searches were run combining the disease with each of the control and prevention related key words using Boolean words (AND/OR). Reference lists were scanned for relevant review articles and conference proceedings. English and French articles were included in the review. A scoping review of the control and prevention of canine-transmitted rabies in Africa was conducted by searching peer-reviewed articles from MEDLINE, Global Index Medicus, BIOSIS, Science Citation Index, and EMBASE published between 1 January 2014 and 31 December 2018. Search terms related to the disease , control and prevention efforts , and the region  were utilized. The selection of African countries was done in reference to the 54 sovereign states which are listed as member states of the United Nations  and national disease control program reports as well conference proceedings were also reviewed. Country specific data on SARE stages were retrieved through the Pan-Africa Rabies Control Network (PARACON) and Middle East and Eastern Europe Rabies Expert Bureau (MEEREB) interfaces of the Global Alliance for Rabies Control (GARC) .We also searched, retrieved, and reviewed specific rabies and generally neglected tropical diseases (NTD) national prevention and control strategies and plans through websites of Ministries of Health of each of the countries. Requests to key stakeholders for unpublished strategies, plans, and reports were also made for countries with no publicly available records. For countries with official languages other than English and French, we included literature, policy documents, and national guidelines translated into English or French.Quantitative and qualitative data were extracted from all available records in a structured data extraction tool in Microsoft Excel file. Key variables included the availability of a NTD and/or rabies national plan, whether rabies prevention and control is addressed in national plans/strategies, availability of a Stepwise Approach towards Rabies Elimination (SARE) score and human and/or animal vaccination programs. Furthermore, comprehensiveness of national strategic plans and challenges to rabies control and prevention were qualitatively evaluated against specific parameters including specific action items and monitoring plans in the extraction tool .https://rabiesalliance.org/tools/planning-tools/sare) (accessed on 21 January 2021). The SARE tool guides countries in the formal evaluation of their current status of rabies control [Blueprint for Rabies Prevention and Control\u201d [Under the umbrella of \u201cOne Health\u201d, a collaborative, multisectoral, and transdisciplinary approach including human and animal health and environmental scientists, countries are working towards elimination of canine rabies with the support of the WHO, the World Organization for Animal Health (OIE), the Food and Agriculture Organization of the United Nations (FAO), and GARC . This ef control . OperatiControl\u201d . Togethehttps://rabiesalliance.org/networks/paracon) (accessed on 21 January 2021). Another notable effort under the GARC is the Middle East, Eastern Europe, Central Asia, and North Africa Rabies Control Network (MERACON), that arose out of the Middle East and Eastern Europe Rabies Expert Bureau (MEEREB) in 2015, which unites scientific expertise and national stakeholders to inform prevention programs and complements the coverage of the African continent. PARACON, an advisory and networking initiative, was formed under the secretariat of GARC to unify all sub-Saharan African countries towards a One Health approach for rabies control and elimination . This reThe level of rabies awareness and adapted strategies for surveillance and prevention varied widely across countries. Thirty-nine  African countries have implemented an official vaccination program for animal vaccination against rabies. Vaccination programs in 15 of these countries focus on dog vaccination while in 10 countries, both dog and cat vaccinations are practiced. National efforts for rabies control and prevention need to be coordinated through strategic plans, which outline specific, attainable, and measurable actions; monitoring strategies; and the financial provisions for all the planned activities. Five countries including Algeria, Angola, Ivory Coast, Kenya, and Namibia have an accessible and specific national strategic plan for the elimination of rabies . In AlgeFourteen countries 14/54, 25.9%) included rabies prevention and control measures in their NTD Masterplan . Eritrea.9% incluThe Central African Republic , DR CongThe national program against rabies of the Kingdom of Morocco targets reduction of rabies incidence by 50% in 2021 and elimination of canine-transmitted rabies by 2025 . In TuniTanzania initiated a multi-faceted project in 2010, which was supported by the WHO in 28 districts on the Tanzanian mainland and the island of Pemba and in 2017 gave impetus to the development of a National Rabies Control and Elimination Strategy aiming at control of dog rabies incidence and elimination of human rabies by 2030 ,39. SimiBotswana and Ethiopia have no national rabies plan nor integrated measures in their respective NTD master plan and for five countries including Benin, Burkina Faso, Burundi, Cabo Verde, and Cameroon, no data was publicly available .In four countries, namely, Angola, Ivory Coast, Namibia, and Sierra Leone, national plans are mentioned in peer-reviewed publications or from sources linked to national policies or by the scientific community ,44,45,46Identification of the key challenges to implementation of rabies prevention and control strategies is an essential first step to successfully achieving regional, national, and global targets. Although most of the African countries are members of one of the rabies networks such as MEEREB or PARACON, national rabies plan, stand-alone or as part of the NTD master plan are not yet implemented. Qualitative assessment of existing plans is complicated by the diversity of country-specific definitions of prevention or control measures such as monitoring and surveillance or limited simply due to lack of data . FurtherThe lack of epidemiologic data is a significant challenge in streamlining rabies control and prevention. In Mali and Nigeria, despite having more elaborate strategies within the NTD Master Plan, the scarcity of prevalence and incidence data on rabies poses significant challenges to the control and prevention efforts ,26. In cIn Ethiopia, despite not publishing a national rabies elimination plan, a surveillance network exists including the Public Health Emergency Management of the Ethiopian Public Health Institute, the Ministry of Livestock and Fisheries, and Ethiopian Wildlife Conservation Authority .Monitoring progress of national programs is at the heart of the elimination efforts. Thirty-five African countries, as well as the semi-autonomous region Zanzibar, went through the self-assessment process with SARE and shared their score with PARACON including open access of data see . GeneralThe current level of implemented programs and activities shows that rabies is still a neglected disease and surveillance, prevention and control measures are still inadequate on the African continent. It is important for national and international stakeholders to understand that rabies has the highest case fatality ratio of all infectious human diseases and, more importantly, that human death related to canine-mediated rabies could be 100% prevented by enhanced vaccine coverage in the canine population. For example, in South Africa, current surveillance for rabies was described as meagre with inadequate dog rabies vaccine coverage in many areas . The decOur findings agree with those of other reviews that identified shortages in capacity to prevent and control canine-mediated rabies in Africa . The relCanine-mediated rabies should not be recognized as a neglected tropical disease for which endemicity is regionally limited to the African continent but instead be understood as a global infectious disease problem calling for more action and coordination worldwide. As with many infectious diseases, rabies does not respect national borders and can impact any country in the world given the unprecedent air travel. A recent review investigated cases of rabies in international travelers, expatriates, and migrants and found two-thirds of identified cases in migrants from rabies-endemic low-and middle-income countries . As longThe data included in this review was retrieved from peer-reviewed journals and publicly accessible literature. We do not claim full coverage of all available information on every African country since the search was limited to data available in English and French even though most governmental portals provide English versions. Country specific regulations, practices, national strategies, or plans might not have been shared publicly or might not have been accessible and hence were not included in this review."}
+{"text": "SARS-COVID-19 pandemic changed the World and urological practice. The SARS-COVID-19 pandemic has a great impact in all medical fields and because the important changes in Urology in last 3 months and due to the large volume of information and articles received, we chose to carry out this supplement. Despite these extremely difficult times, we are very happy because this supplement marks the beginning of the partnership between the Brazilian Society of Urology (BSU) and the American Confederation of Urology (CAU). Soon the International Brazilian Journal of Urology has everything to become the official information Journal of CAU reinforcing the impact of the International Brazilian Journal of Urology on the American continent.This Supplement presents original contributions with a lot of interesting papers about SARS-COVID-19 pandemic. The papers came from many different countries such as Brazil, USA, United Kingdom, Belgium, Colombia, Peru, Argentina, Germany, Netherlands, Italy, Spain, Canada, and China. As usual, the editor highlights some of them.Dr. Lauxman and colleagues from Germany performed in page 6  a nice Dr. Chen and colleagues from China performed in page 19  a nice Dr. Esperto and colleagues from Italy performed in page 26  an inteDr. Sanchez and colleagues from Spain performed in page 50  an impoDrs. Zequi and Abreu from Brazil and Uruguay performed in page 69  a nice Dr. Casco and colleagues from Spain performed in page 86 (Dr. Ibarra and colleagues from Spain Italy and Iran performed in page 104  a nice Dr. Gonzalez and Ciancio from USA and Spain performed in page 145  an impoDrs. Zampolli and Rodriguez from Brazil and USA performed in page 215  a nice The Editor-in-chief expects everyone to enjoy reading of this supplement and for sure better times will come soon around the World."}
+{"text": "Tissue Engineering and Regenerative Medicine International Society (TERMIS) is the most prominent organization in the field of tissue engineering and regenerative medicine globally. TERMIS promotes education, research, innovation, clinical translation, and social responsibility within the field of tissue engineering and regenerative medicine through regular meetings, training courses, scientific and lay publications, outreach activities, and other forms of communication. TERMIS provides an international forum for informed discussion on the challenges and achievements of tissue engineering therapies.Tissue Engineering Therapies: From concept to clinical translation and commercialisation.\u201d This special issue covers all aspects of tissue engineering and regenerative medicine, including computational models for the cost efficient production of cell-based tissue engineered products ; development of media  and tools  for more accurate cell culture and for effectively monitoring the fate of implantable devices ; the potential of large animal models in regenerative medicine ; and clinical indication specific discussion .This special issue is associated with the TERMIS EU Chapter 2019 meeting at Rhodes, Greece, 27-31 May. The theme of the meeting was \u201cCampos et al.), gellan gum hydrogels , elastin-like recombinamer hydrogels , poly electrospun scaffolds decorated with poly(lactic acid-co-glycolic acid) (PLGA) or poly(glycolic acid) (PGA) electrosprayed nanoparticles , tripolyphosphate crosslinked chitosan/gelatin biocomposite inks , inorganic calcium phosphate, chitosan, and hyaluronic acid scaffolds , polycaprolactone-polypyrrole printed conductive biomaterials ] for a diverse range of clinical targets, as well as advances in stimuli responsive materials as controlled delivery vehicles .Advancements in chemistry and engineering have made numerous new materials available and nano/micro fabrication technologies have potential in modern tissue engineering and regenerative medicine. With this in mind, this special issue discusses a range of natural and synthetic systems  and of in vitro pathophysiology models for drug screening purposes .Considering that cells are the basic building blocks of tissues , contemporary tissue engineering and regenerative medicine exploits the power of cells for the development of implantable devices that will revolutionize healthcare due to their therapeutic and reparative capabilities (e.g., hybrid bioprinting of chondrogenically induced human mesenchymal stem cell spheroids with a photocrosslinkable methacrylamide-modified gelatin printed medium (in vitro models for the study of disease progression and to assess the potential of novel therapies. This collection of manuscripts captures the state-of-play in this field, indicating that the development of effective therapies is underway.Tissue engineering and regenerative medicine have the potential to provide effective treatments for uncurable injuries and diseases, potentially enabling the development of All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The COVID-19 pandemic, caused by the emergence of a new strain of coronavirus (SARS-CoV-2) around the end of December 2019, has caused a worldwide public health emergency and a socioeconomic crisis during 2020. The lockdown imposed to cope with the health issues caused by the outbreak of the disease has dramatically challenged and negatively affected all the economic sectors of the modern global economy. Specifically, the livestock sector and its related industries are among the most impacted sectors. This is mainly ascribed to the limitations of animal movement and the decrease of production inputs' availability. Other factors negatively affecting the sustainability of the livestock sector have been the shortage of workers due to the lockdown/curfew, the strong decrease in the purchasing power of the consumer, and the intensification of health care tasks. Such an impact is not only highly relevant because of their economic consequences, but also because of the effects of the lockdown and sanitary rules on animal care and welfare. The current review aims to offer: (a) a comprehensive overview of the impact of COVID-19 on the welfare of farm animals and on the performance of livestock farming systems, on food chain sustainability, and finally, on the global economy and food security; and (b) a prospective outline of alleviation actions. By the end of December 2019, the world awoke to a public health crisis due to the emergence of a new strain of coronavirus, which was later named Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2 or COVID-19) .Globally, the COVID-19 pandemic has had a direct impact on food systems through changing the food supply-demand system, and an indirect impact through decreasing purchasing power and the capacity of food distribution and marketing, and increasing healthcare tasks . EconomiSuch a fact will cause severe effects worldwide, with larger effects seen on both the economies and sociodemographics of developing areas. The livestock sector is estimated to account for about 40% of global agricultural output value and two-thirds of the 600 million livestock keepers worldwide are women, so the current situation compromises their economic empowerment , 8. FarmThe closure of meat and milk processing plants has also contributed to the sharp disruption in the livestock supply chain, leading to substantial losses in production capacity and animal products. For instance, in the USA, the loss of production capacity due to the closure of plants have reached up to 25 and 43% for beef slaughterhouses, respectively . The porThis review discusses how the COVID-19 outbreak may affect animal welfare and livestock, the dairy and meat industry, and supply chains by using available scientific/organizational reports, and cited observations and complaints of farmers. Such data may help in taking suitable measures to improve the current status and to pose lessons for the future, avoiding the emergence of food insecurity.Homo sapiens) and other animals, including birds and mammals  and laboratory  animals  and camels (genus Camelus), inducing diarrhea, fever, and respiratory diseases, and thus causes negative impacts on animal welfare/productivity and farm profitability (Sixty percent of emerging contagious diseases have a zoonotic origin. Coronaviruses (CoVs) were first identified in the mid-1960s and are known to infect humans , rodents (order Rodentia), civets (Civettictis civetta), cats, pangolins (Family Manidea), minks (Neovisonvison), and tigers (Panther atigris), were found to test positive for COVID-19 (Canis lupus familiaris) and cats (Sus scrofa), cattle and sheep (Family Bovidae), horses, and poultry for antibodies of COVID-19 revealed negative results  or Suidae (pigs) as well as poultry are not COVID-19 reservoirs (Rhinolophus species) coronavirus HKU2, suggesting both a bat origin of the pig virus and a jumping across species  the main reservoir of COVID-19 are bats; (2) some wild , farmed (mink), and domestic (cats and dogs) animals can be a reservoir; (3) there is a possibility for the transmission of COVID-19 from humans to animals, animals to humans, and human to human; and (4) livestock belonging to the family  the mainservoirs . Despite species , 32. Ano species . Accordi species , 31. HenRegarding the handling and consumption of animal products, there is no direct evidence on food-borne infection, including meat and milk. Precautions and hygienic measures are advisable since there is a possibility that contamination of food materials can occur through the handling of food by infected individuals. These precautions and sanitary measures include hand washing or sanitizing following the processing of fresh and packaged animal products, avoiding contact between fresh and cooked food materials, consuming well-done cooked meat, and extending meat and meat-processed materials' freezing time by more than 2 days before consumption .It is expected that the sudden restriction on human activities and the economic crisis will affect farming and veterinary services, and therefore, affect animal health . The COVFurthermore, some associations, such as the Canadian Cattlemen's Association, has called farmers to put cattle on maintenance rations rather than finishing rations to limit feedlot placements, coping with the closure of processing plants, and limited market capacities . Also, tLivestock production farming systems and their supply chains are challenged by many logistical supply interruptions, like most other agricultural enterprises. The COVID-19 outbreak interrupted livestock chain sustainability in different areas, from the production process to marketing and consumption of animal products . The priRestrictions on import/export activities and local movements have prevented farmers from accessing livestock production inputs and given them limited marketing opportunities. The limitation of movements and the disruption of national and international trade routes drive to a substantial decrease in vital livestock farming materials and facilities, such as feed materials, replacement stocks , drugs and vaccines, feed additives, and other livestock farming inputs . For insSeveral companies working on vaccines, animal health products, feed additives, milk testing kits, and spare parts of pasteurization equipment to small-scale meat and dairy producers have indicated that the reductions in fluidity and foreign exchange were other significant factors affecting the sustainability of the livestock supply chain, specifically in developing countries . There iIt is widely believed that agricultural sectors, including meat and dairy production sectors, are heavily labor-dependent sectors. The COVID-19 outbreak has caused a severe shortage of labor numbers and workforce in both developed and developing countries, which is more problematic for countries that depend on an imported workforce, such as European countries . This shXinfadi market in Beijing's largest wholesale market  facilitating the direct distribution of food/animal products to consumers  and offering electronic marketing platforms (China and Morocco); (2) providing livestock production inputs, such as animal feeds, drugs, and machines ; (3) supporting the resumption of meat/milk processing enterprises (China); (4) creating agricultural, healthcare, and animal diseases control extension programs; and (5) providing direct funding support to seasonal and informal labors  , 49, 55.in vitro as an eco-friendly production technique, as methane emission by farm animals will be reduced , to the food supply chain as alternatives to animal protein sources is one of the suggested strategies , 56. Ano reduced , 58. How reduced . This al reduced , 61. Fur reduced . Recentl reduced . In this reduced .The availability of animals', feed ingredients, either through foraging or concentrate ingredients, was an additional challenge confronting the sustainability of the livestock supply chain. Data presented in our overview illustrated that one of the livestock supply chain's major disruptors was the inability of farmers to access animal feed. The restriction on import/export activity has negatively impacted the availability of essential feed ingredients . AcThe experience acquired through the COVID-19 crisis may also contribute to optimizing the part of the livestock supply chain that includes processing, retail, and marketing through strengthening the connection between producers, retailers, targeted markets, and consumers . The ineUnfortunately, to date there is no particular vaccine or therapeutic protocol to control the spread of COVID-19, and forecasts predict the continuation of this pandemic for a long time. In this scenario, livestock farmers have to be aware of different measures that they can apply themselves to maintain safe and efficient livestock farming. Successful farmers should maintain farm biosafety , 15, worIn this overview, we illustrated the significant disruptions that occurred in livestock, milk, and meat supply chains due to the outbreak of COVID-19. The COVID-19 pandemic revealed that, despite the vast advancements in knowledge and informatics technologies, we still need to create innovative applications and measures that can support the world against any future pandemic disasters. It is now clear that pandemic disasters are not only a matter of human health insecurity but can also encompass food insecurity and economic recession, increasing poverty and famines worldwide.NH: creating the main idea and writing the first draft. AG-B and AR-M: reviewing and final preparation of the manuscript. All authors approved the content for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Rheumatology as a research-intensive discipline may particularly benefit from the emerging digital evaluation tools, systematic search engines, distribution platforms, and repositories. Currently, processing journal submissions through advanced online systems allows detecting major inconsistencies and mistakes in research reporting and formatting manuscripts. Such systems, linked to regularly updated reviewer instructions of global editorial associations and supported by external bibliographic searches, enable fast evaluation of the novelty, originality, methodological rigour, and implications of the manuscripts by peer reviewers.In times of information deluge, editing and publishing a scholarly journal is increasingly dependent on digital tools and artificial intelligence.Open Researcher and Contributor IDs , are now employed by most publishers to validate individual profiles at the peer review and increase visibility of their contributions post-publication. The Mediterranean Journal of Rheumatology has also encouraged its contributors to register with and submit informative ORCID iDs with biographical notes, publication lists, and other academic accomplishments. The ORCID iDs are now integrated with the the Publons platform (https://publons.com), yet another indispensable digital tool for crediting reviewers and selecting active and skilled experts for further evaluations.3 Notably, the number of academic contributors with ORCID iDs is fast approaching the level of 6 million, and more publishers and standalone journals are partnering with Publons to streamline the peer review activities and global recognition of their reviewers. With the integration of Publons with Web of Science  in 2017 and further upgrades of the platform, the registered scholars are now offered automatic updates of their profiles by listing their WoS-indexed articles and tracking related citations. Publons profiles are particularly valued by emerging scholarly journals, aiming to attract scarcely available reviewers and increase the quality of peer review.5 The total number of registered reviewers on Publons is 541,093, including 571 in rheumatology . The Mediterranean Journal of Rheumatology acquired its profile on Publons this year to increase transparency of the peer review activities and give deserved academic credits to its best contributors .The author and reviewer identifiers, and particularly the Crossref, a powerful system for cross-linking references and updating individual digital profiles (http://crossref.org/). Launched in 2000, Crossref is currently run by the Publishers International Linking Association. The reference validation and formatting tools supported by Crossref permanent identifiers guarantee the accuracy of technical editing, formatting, and detecting plagiarism, to name just a few advantages of the system. With the expansion of Crossref services and integration with journal platforms , ensuring the efficiency of online publishing, navigating through myriads of scientific articles, and indexing with bibliographic databases are becoming closely interconnected. Once and for all, the concept of discoverability of scholarly items and systematic searches through online databases has shifted towards permanent article identifiers.7 Given the growing importance of the Crossref services, a decision was made to acquire DOIs for the Mediterranean Journal of Rheumatology this year to benefit from vast opportunities of improved visibility and integration with digital platforms and databases.The speed of processing and visibility of scholarly contributions are also increasingly dependent on Digital Object Identifiers (DOIs) issued by 8 The absolute majority of open-access medical journals have benefited from archiving by PubMed Central, the largest digital repository of medical articles. The editors\u2019 relentless efforts aimed to archive the Mediterranean Journal of Rheumatology by PubMed Central will widen prospects of indexing for this rapidly developing periodical.Over the past two decades, open-access publishing has increased global visibility and international recognition of journals across numerous subject categories. Various open access models have increased article views, downloads, and citations, transforming all these benefits into the scientific prestige of emerging and research-intensive fields of science.Mediterranean Journal of Rheumatology, and related links are embedded in the journal instructions: the Budapest Open Access Initiative (2002) and the Berlin Declaration on Open Access (2003).10 In line with the statements of these documents, the Open Access initiative is primarily aimed to increase the use of published items for research and education.11 Additionally, the improved visibility, one of the main achievements of the initiative, has enabled detecting and \u2018cleaning\u2019 erroneous and fraudulent literature.12 Although the main attribute of Open Access is free access to published works for readers, there are other, not less important, components related to digitization, preservation, and archiving. To meet the requirements of Open Access and satisfy indexing criteria of most bibliographic services, medical journal editors should familiarize themselves with the Journal Article Tag Suite (JATS) format of Extensible Markup Language (XML), which is employed by the National Library of Medicine of the US for encoding PubMed Central-archived items.13 The XML format enables machine-readability and makes it possible to index quality journals by most prestigious bibliographic databases and digital repositories.The basic principles of Open Access are outlined in two seminal documents, which are consulted by the editors of the Mediterranean Journal of Rheumatology to the area of medicine of the registry is an exemplary achievement for the whole field of rheumatology .While Open Access is gaining momentum and numerous journals opt for different models of open-access publishing , several global initiatives have been launched to distinguish periodicals with reliable peer-reviewed contents from spurious online platforms of wasteful publishing. The Directory of Open Access Journals (DOAJ) is one such initiative with strict scientific and technical criteria, listing 12,397 open access journals from 129 countries and offering records of 3,600,965 for systematic searches . The number of the listed medical journals is 699, with 472,913 linked items available for searches. The latest incorporation of the 14 The declared by the Mediterranean Journal of Rheumatology adherence to these principles is essential for its development and ethical promotion.Launched in 2003, the DOAJ project has passed a long way and become a \u2018whitelist\u2019 of reliable periodicals. The DOAJ collaborated with several global editorial associations to set principles of transparency in publishing.16 For medical journals, the DOAJ listing is proposed as one of the requirements for indexing by PubMed and archiving by PubMed Central.17 In 2015, the Scopus database introduced the open access indicator for separate marking DOAJ-listed journals, making it easier to navigate and search through the growing number of open-access periodicals which passed stringent quality checks.18 Notably, the SCImago Journal & Country Rank platform currently ranks 34,171 Scopus-indexed periodicals across all subject categories, including 4,504 for open access. In the field of rheumatology there are 60 Scopus-indexed periodicals, with 20 registered with DOAJ . These numbers will definitely continue to grow in the future.Acquiring the seal of DOAJ is a milestone in the journal digitization and recognition by the scientific community.International Committee of Medical Journal Editors  is perhaps the most important association; offering frequently updated editorial guidance for authors, reviewers, and editors. Editors claiming adherence to the ICMJE recommendations and enforcing its points in their daily practice offer good service to their community of authors and readers. Exemplary, the editors of the Mediterranean Journal of Rheumatology registered their interest in the recommendations at the ICMJE website in 2017.19While the recent digital innovations enormously influence the speed of publishing, editorial credentials still remain precious assets for the quality of publishing and impacting science. The journal editors with connections to global and regional editorial associations are capable of establishing networks of skilled peers, share experience, and add to the scientific prestige of respective periodicals. In the field of medicine, the 20 The editorial credentials and reviewer responsibilities are currently highlighted in the documents published by the Committee on Publication Ethics, the largest association of editors with more than 12,000 members. Member-editors of the COPE are now offered a set of updated recommendations about authorship problems, conflict of interest disclosures, ethics approval, copyright issues, journal management, and retractions.21 The latest incorporation of the updated publication ethics points into the instructions of the Mediterranean Journal of Rheumatology is an exemplary move towards better quality control for disseminating reliable information for the respective regional community.Several other global associations also allow advancing scientific and publishing editors\u2019 skills."}
+{"text": "This dataset presents data collected from household surveys from Upper Madi Watershed of Nepal describing the benefits of non-timber forest products (NTFPs) to people of mountain ecosystems, their perceptions of climate change, and perceived impacts of climate change on NTFPs ecosystem services. The data were collected from 278 households that were randomly selected from the four villages in the watershed during the period September to December 2019. The survey assessed socio-demographic information; collected and utilized NTFPs; perceptions of climate change, and; perceived impacts of climate change on NTFPs ecosystem services. These data are important in understanding the benefits of non-timber forest products in mountain ecosystems and the impacts of climate change as the benefits and impacts are currently not well understood. The data will be helpful in formulation and implementation of adaptation strategies to sustain the supply, protection, and management of NTFPs in mountain ecosystems. The survey data include the following sections: a) socio-demographic information of respondents including age, gender, ethnicity, educational background and occupation b) utilization of non-timber forest products by mountain communities c) perceptions of climate change d) Perceived impacts of climate change on non-timber forest products ecosystem services. The questionnaire is provided as a supplementary file. Social-demographic characteristics are presented in The details of non-timber forest product use in the Upper Madi Watershed of Nepal, number of non-timber forest plant species, purpose of NTFPs collection, respondent perceptions of climate change, perceived impacts of climate change on non-timber forest products ecosystem services are described in 2This research was based on primary data collection through a household survey Ethical approval was obtained from the faculty of Science Engineering and Built Environment Human Ethics Advisory Group, Deakin University (reference number STEC-31\u20132019-GURUNG). Respondents\u2019 participation was completely agreed, voluntary, and anonymous.Lila Jung Gurung: Conceptualization, methodology, data collection, and writing of the manuscript.Kelly Miller, Susanna Venn, and Brett A Bryan: Conceptualization, methodology, review and editing the manuscript.The authors declare that they have no known competing financial interests or personal relationships which have, or could be perceived to have, influenced the work reported in this article."}
+{"text": "The steppe zone is the huge area in temperate Eurasia where different grasslands form the main type of vegetation. The main part of this life zone has been transformed by human activity and used for crop cultivation (mainly wheat) and livestock. Regional and local transformations and/or climate changes can result in some shifts in species and population distribution of Orthoptera. Over this area, the climatic conditions and the dominated grasslands are suitable for numerous grasshoppers and their relatives, especially the graminivorous ones. The general level of their diversity is usually high. Many species are very abundant and may become important pests. However, there are also many rare species. The main aims of this paper are to reveal general patterns of Orthoptera distribution in the Eurasian steppes, to evaluate long-term trends of changes in distribution of taxa and populations, and to estimate the potential for population changes relative to human activity and global warming trends.Locusta migratoria, Calliptamus italicus, Dociostaurus maroccanus) is also discussed. Some notable changes of their populations\u2019 distribution and dynamics are characterized. The situation with rare Orthoptera is estimated. Retrospective and prospective of the steppe fauna of Orthoptera are discussed.The main aims of this paper are to reveal general patterns of Orthoptera distribution in the Eurasian steppes, to evaluate long-term trends of changes in distribution of taxa and populations, and to estimate the potential for population changes relative to human activity and global warming trends. The main publications concerning diversity and distribution of these insects over the steppes are analyzed. The fauna of the Eurasian steppes includes more than 440 species of Orthoptera. The general distribution of grasshoppers and their kin in the Eurasian steppes reflects their common associations with different grasslands. The species richness increases from the relatively cold forest-steppes to the semi-deserts with their warm summer. There are some endemic or subendemic taxa, including the tribe Onconotini (Tettigoniidae). The populations\u2019 distribution of Orthoptera is also analyzed. The populations of native Orthoptera extend through all the herbaceous landscapes. Under these conditions, the interrelating of colonies of each species may result in great abundance. The population distribution of three species locusts ( The steppe zone is the huge area in temperate Eurasia where different grasslands form the main type of vegetation ,2,3,4 F. The adjFrom the zoogeographic point of view, the steppe zone almost coincides with the Scythian (or Euro-Siberian Steppe) subregion of Palaearctic erected mainly on the basis of the species distribution analysis ,9,10,11.The main aims of this paper are to reveal general patterns of Orthoptera distribution in the Eurasian steppes, to evaluate long-term trends of changes in distribution of taxa and populations, and to estimate prospective of their population changes relative to human activity and global warming trends.Both qualitative and quantitative data were used. The analysis of geographic distribution was based on published and unpublished species range maps. Species data points for Eurasian Orthoptera were plotted onto base maps, usually on a scale of 1:25,000,000. My own collections, the collections of different museums, and published data were used ,9.2 (sometimes 0.5 \u00d7 0.5 m2 or 1 \u00d7 1 m2). After that, the average density was estimated for every habitat investigated. The samples were collected in the Eurasian steppe by the expeditions of Department of General Biology and Ecology (Novosibirsk State University) and the Laboratory of Insect Ecology  from 1972 to 2020. Numerous published papers and books (see the next parts of the publication) describing orthopteran distribution in different parts of the steppe life zone were also analyzed. In almost all cases, I use modern names of taxa ); (3) mesophilous ), and (4) hydrophilous . Distribution patterns of two species, namely Calliptamus abbreviatus Ikonnikov and Omocestus haemorrhoidalis, were unique. The three most abundant species  were also separated in time of their active life.Spatial and temporal heterogeneity and niche overlapping were also described for grasshoppers in the steppes of Inner Mongolia ,80. The In the steppes, acoustic and visual communication can serve as the very important mechanism for sharing ecological niches ,82. As aLocusta migratoria Linnaeus), the Italian locust , and the Moroccan locust (Dociostaurus maroccanus (Thunberg)), occur in the Eurasian steppe. These species have spatially structured populations with rather complicated dynamics. In some parts of their ranges, they are able to change their behavior from solitarious to gregarious and vice versa and irregularly produce devastating upsurges [Three species of locusts, namely the Migratory locust . However, these specimens mainly originated from South-East Kazakhstan , where sAchnatherum splendens (Trin.) Nevski on the lake terraces, some meadows with short mesophilous grasses along a small stream, and halophytic meadows in wide depressions near the lake. The Migratory locust was very abundant on the lake terraces; its density was up 1 ind. per m2. The locust aggregations were not observed both for adults and hoppers. The main traits were typical for the solitarious form, however, some traits of adults indicated that the population could be characterized by some level of gregarization [In 2017, a moderate population of the Migratory locust was found in Tuva (the Republic of Tyva) in the Altay-Sayan Mountains, near hypersaline Shara Lake. The discovered population inhabited several adjacent habitats: the local dry meadows with dominance of rization . The ratrization . The popThe Italian locust is a common species and the most important pest in the Eurasian steppes from their western limits up to the south-eastern parts of West Siberian Plain and East Kazakhstan. Numerous outbreaks of this species were described for these territories ,83,95,96Recently, the main data on the Italian locust distribution and ecology were summarized for the territory of the former USSR. The main part of the species range is connected with the semi-desert zone ,100,101.In the forest-steppes of West Siberia, the Italian locust is widely distributed. However, its populations are very localized and are at a low level of abundance across the overgrazed plain pastures. In the steppes, its populations occupy not only local watershed plains but the dry parts of upper flood plains and lower terraces and the stony southern slopes of hills. In this area, the specific additional optimum of this species is observed in the dry steppes of Kulunda . This opSpatial population distribution of the Italian Locust at periods between outbreaks both within the whole area and on better examining territory of the eastern parts of it range corresponds as a whole with the known rule of habitat change . In the It is important to recognize that the population dynamics within additionally infested areas differs significantly from those in the main area  because Poa bulbosa Linnaeus and on undisturbed clay soils [The Moroccan locust occurs only in the European steppes and, furthermore, it is distributed over the steppes of the Crimean Peninsula and the North Caucasus . Howeveray soils . Intensiay soils . In the ay soils  noted thay soils ,112. In ay soils ,111,112.Calliptamus italicus or Dociostaurus maroccanus) may be also almost extinct, but others are abundant [The fauna of the Eurasian steppes includes a few rare species. There are several implicit areas of Orthoptera diversity ,114. Theabundant ,111.Isophya boldyrevi Miram, I. doneciana, Bradyporus multituberculatus montadoni (Burr) (as a separate species\u2014M.S.). Listed as endangered (EN) are Isophya stepposa, I. zubovskii Bey-Bienko, Bradyporus macrogaster (Lefebvre), and Asiotmethis tauricus. Some forms (including widely distributed Saga pedo and Stenobothrus eurasius) are vulnerable (VU). This list does not include one of the rarest taxa of the European steppes\u2014Bradyporus multituberculatus multituberculatus. The species is on the Red Books of Russia and Ukraine [About 1500 orthopteran species are now on the International Union for Conservation of Nature (IUCN) Red List of Threatened Species , and man Ukraine . It was  Ukraine ,119. ForSaga pedo, Gampsocleis glabra (Herbst), Onconotus servillei ). However, some endemic and subendemic genera, species, and subspecies occur in the central and the eastern parts of the Eurasian steppes. Some of them are known from one or several localities. Besides, populations of many orthopteran insects can decline in regions with intensive agriculture.Unfortunately, the actual version of the IUCN Red List of Threatened Species does not include the steppe species associated with the steppes of South Siberia, Kazakhstan, Mongolia, and North China or with the steppe mountain landscapes of mountains of Central Asia. There are only some widely distributed species . The distribution patterns of several species, e.g., Asiotmethis muricatus , Notostaurus albicornis (Eversmann), and Mesasippus arenosus, did not change significantly during the last decades. Two species, namely Megaulacobothrus aethalinus and Aeropedellus variegatus, were recently found near the boundaries of the region. Four species , Stenobothrus carbonarius (Eversmann), Sphingonotus coerulipes) are extremely rare now. The local populations of almost all rare species are usually associated with a few types of habitats. This means that intensification and changes of human activity may result in their extinction.Recently, distribution patterns of rare acridid species in the south-eastern part of West Siberian Plain were analyzed . The ranReconstruction of the past of many taxa and faunas is problematic. The most important problem is the shortage of appropriate fossils. This results in development of different hypotheses explaining geographic and ecological history of different taxa and faunas. In the absence of adequate fossil data, some possible approaches can be based on a complex analysis of the ecological factors, adaptations to particular living conditions, and the optimum conditions, which can be estimated by some comparative studies of species range shapes and the population distribution within the range ,60,70.Chorthippus and its relatives), the genera Podisma Berthold, Stethophyma, Podismopsis Zubovsky, etc. He also mentioned some relationships between the Angarian fauna and the faunas of the southern parts of East Asia. Bey-Bienko [The history of Orthoptera of the Eurasian steppes was discussed in a number of papers. A century ago, Uvarov ,123 and y-Bienko ,65,124 hy-Bienko ).One of the principal results of retrospective views on faunas and populations is the opportunity to forecast their possible changes in the future. If the trend of global warming continues, the steppe zone will shift northwards , and theThe steppe species will shift the northern boundaries of their ranges northwards, and some of them will be able to use numerous transformed habitats, such as clearings, roadsides, agricultural fields, and pastures . BesidesIsophya costata and also Saga pedo, Arcyptera fusca, A. microptera , and Stauroderus scalaris, due to human activityIn Hungary, B. Nagy  noted siArcyptera fusca, A. microptera, Stenobothrus fischeri, Bryodemella tuberculata, Psophus stridulus Linnaeus, and Sphingonotus caerulans Linnaeus. He explained this declining by intensification and some changes of human activity. Besides, the isolated colony of Sphingonotus coerulipes was unexpectedly found on stockpiles of mining plants.In the northern steppes of Central Russian upland, A. V. Prisny  showed pPodisma pedestris, Euthystira brachyptera (Osckay), Gomphocerus sibiricus, Psophus stridulus, Bryodemella tuberculata, etc., were found here in the middle of the 19th century [Dericorys tibialis , Heteracris adspersa (Redtenbacher), Sphingonotus halophilus Bey-Bienko, Ramburiella turcomana , etc.) [Glyphonotus thoracicus  mainly associated with river valleys of deserts and semi-deserts was recently found in the southern parts of the steppes of Central and North-East Kazakhstan [Significant changes of orthopteran diversity were revealed for the vicinities of Lake Baskunchak in the semi-deserts of South-East Europe . Several century  but disa century  supposed), etc.) . The buszakhstan .Gomphocerus sibiricus significantly declined in the plain steppe habitats during the last decades [Podisma pedestris, Sphingonotus coerulipes) became very rare [Arcyptera microptera), some others crossed more than 100 km , Conocephalus fuscus (Fabricius), Dociostaurus brevicollis, Oedipoda caerulescens (Linnaeus), Oedaleus decorus, Epacromius pulverulentus) [Our published and unpublished data show conspicuous changes in distribution of several species in the south-eastern part of West Siberian Plain during the last decades. Populations in the first half of the 20th century of the widely distributed and abundant  decades . Severalery rare ,114. Howulentus) ,114. Almulentus) ,131 and ulentus) . On the I can conclude that, during last decades, biological diversity, geographic, and ecological distribution of Orthoptera over the Eurasian steppes have been characterized by rapid changes due to climatic variations and changes of local human activity. In many cases, we can observe declining and elimination of local populations but, on the contrary, other species can colonize new areas and habitats. This is true for both possible pests and rare species. This means we should constantly monitor orthopteran populations and assemblages over all huge territory occupied by the steppe biome."}
+{"text": "The peer review system is the soul of the Scientific journals. This process became an institutionalized part of the scholarly process in the latter half of the twentieth century . The serIn 2020 the International Brazilian Journal of Urology received more than 900 papers and the reviewers were very important to the entire process of our Journal. As a Editor-in-Chief I would like to thanks all the reviewers and specially the Doctors: Alexandre Danilovic, MD ; Ralf Anding, MD ; John Denstedt, MD, PhD (Western University Canada); Trushar Patel, MD (University of South Florida) and Gustavo Ruschi Bechara, MD  who reviewed more than 5 articles during the year and strictly within the deadline.Thanks a lot!!!!!Luciano A. FavoritoEditor-in-ChiefInternational Brazilian Journal of Urology"}
+{"text": "Molten salts play multiple important roles in the electrolysis of solid metal compounds, particularly oxides and sulfides, for the extraction of metals or alloys. Some of these roles are positive in assisting the extraction of metals, such as dissolving the oxide or sulfide anions, and transporting them to the anode for discharging, and offering the high temperature to lower the kinetic barrier to break the metal-oxygen or metal-sulfur bond. However, molten salts also have unfavorable effects, including electronic conductivity and significant capability of dissolving oxygen and carbon dioxide gases. In addition, although molten salts are relatively simple in terms of composition, physical properties, and decomposition reactions at inert electrodes, in comparison with aqueous electrolytes, the high temperatures of molten salts may promote unwanted electrode-electrolyte interactions. This article reviews briefly and selectively the research and development of the Fray-Farthing-Chen (FFC) Cambridge Process in the past two decades, focusing on observations, understanding, and solutions of various interactions between molten salts and cathodes at different reduction states, including perovskitization, non-wetting of molten salts on pure metals, carbon contamination of products, formation of oxychlorides and calcium intermetallic compounds, and oxygen transfer from the air to the cathode product mediated by oxide anions in the molten salt."}
+{"text": "In 2018, the government of the Republic of Korea (ROK), South Korean life science companies, and a group of international funders led by the Bill & Melinda Gates Foundation launched a new and innovative funding agency to support neglected-disease research and development (R&D). The new venture is known as the Research Investment for Global Health Technology (RIGHT) Fund. At the end of the Korean War in 1953, ROK was a devastated nation and ranked among the poorest in the world. A decade later, in response to its high prevalence rates of poverty-related neglected diseases, including soil-transmitted helminth infections, malaria, and tuberculosis, the ROK government in collaboration with a Korean Association for Parasite Eradication (KAPE) began programs of infectious and parasitic disease control . In someToday, the ROK boasts the 11th largest economy globally and one of the most advanced economies in Asia, with a gross domestic product (GDP) of 1.7 trillion USD . RecogniA key element of the ROK\u2019s economic success is its vigorous and productive life sciences and pharmaceutical industry, with advanced capabilities for drug, diagnostics, and vaccine development. The ROK has also well positioned to lead the convergence and integration of biotechnology, information and digital health, and communication technologies (ICT) for disease prevention, diagnosis, and treatment. These features afford a unique opportunity for the ROK to leverage and incorporate R&D into its programs of ODA.Recognizing the ROK\u2019s dual capacity to both contribute ODA at a high level and pursue a vigorous R&D agenda, the Bill & Melinda Gates Foundation pursued a partnership with both the ROK government and South Korea\u2019s life sciences industry for developing an innovative fund for neglected-disease technologies. Such activities built on a previous success in Japan where the Global Health Innovative Technology (GHIT) Fund was established in 2013 . HoweverIn July of 2018, a new Research Investment for Global Health Technology (RIGHT) Fund was created as a three-way nonprofit partnership between the Ministry of Health and Welfare (MOHW) of the ROK government, South Korean life science companies, and the Gates Foundation, in addition to other international funders  6]..6].Central to the RIGHT Fund is an innovative platform for the Korean partners to expand their contributions to global health and neglected-disease R&D projects, with a long-term objective to develop and deliver new neglected-disease drugs, diagnostics, and vaccines .An overall project goal of the RIGHT Fund is \u201cto advance the discovery and development of new health technologies to meet the needs of Low and Middle Income Countries (LMICs) by leveraging the intellectual, technological, and financial resources of the ROK\u201d . The FunThe RIGHT Fund operates through a management team that includes an Executive Director, together with individuals who lead operations in three areas\u2014strategy, investment planning and management, and government relations. The RIGHT Fund management works with an independent selection committee and reports to a Board of Directors composed of representation from the Korean MOHW and Korean Centers for Disease Control & Prevention (CDC), in addition to an ex officio observer from the Gates Foundation, and members at large. Also overseeing the entire RIGHT Fund is a Council with representation from the Korean MOHW, National Institute of Health, IVI, Gates Foundation, and the leadership of the five major South Korean life sciences industries.The technologies advanced by the RIGHT Fund are driven by the needs of the low-resource countries, typically measured through years of life lost or years lived with disability; their potential for impact; and whether they leverage the current strengths of life sciences R&D within ROK. An applicant should involve at least one Korean research organization or company. Another criterion is the potential of the technologies selected to expand the invovlement of Korean life sciencies organizations in the global health space and ecosystem. Fairness and transparency are also paramount. The three major technological areas include vaccines, therapeutic drugs, and diagnostics, with each area considering new approaches and constructs, product improvements, or patient access  6]. Req. Req6]. Haemophilus influenzae type b (Hib) vaccine. The therapeutic is a low-cost manufacturing process for a new antimalaria drug from the product development partnership (PDP) Medicines for Malaria Ventures (MMV), together with the Korean life sciences company SK Biotek. The two diagnostics are (1) a second-generation test for glucose-6-phosphate dehydrogenase (G6PD) from the Seattle-based PDP, PATH, and the Korean life sciences company SD Biosensor and (2) a point-of-care diagnostic for detection of Mycobacterium tuberculosis and multidrug-resistance mutations from a PDP with diagnostics expertise, Foundation for Innovative New Diagnostics (FIND), and Bioneer, another Korean company [In its first year of operations, investments have been made in five technologies: two vaccines, one therapeutic agent, and two diagnostics. The two vaccines include (1) a novel conjugate cholera vaccine under joint development by Harvard Medical School, Massachusetts General Hospital, IVI, and EuBiologics (a Korean life sciences company) and (2) a hexavalent vaccine produced by LG Chem, another Korean life sciences company, which combines diphtheria whole-cell pertussis-tetanus toxoid vaccine, inactivated polio vaccine, recombinant hepatitis B vaccine, and The concept of \u201cblue marble health\u201d finds an unexpected level of neglected-disease burden among the poor living in the Group of 20 (G20) nations ["}
+{"text": "To strengthen the fight against malaria, it is imperative to identify weaknesses and possible solutions in order to improve programmes implementation. This study reports experiences gained from collaboration between decision-makers and researchers from a World Bank project . The objectives of this paper were to identify bottlenecks in malaria programme implementation as well as related research questions they bring up.Questionnaire addressed to National Malaria Control Programme managers and prioritization workshops were used as a medium to identify research questions. The bottlenecks in malaria programme implementation were identified in seven thematic areas namely governance, human resources, drugs, service provision, use of prevention methods, monitoring and evaluation (M and E), and public support or buy-in. The first five priority questions were: (1) compliance with drug doses on the second and third days during the seasonal chemoprevention (SMC) campaigns, (2) the contribution of community-based distributors to the management of severe cases of malaria in children under 5\u00a0years, (3) the SMC efficacy, (4) artemisinin-based combination therapy (ACT) tolerance and efficacy according to existing guidelines, and (5) the quality of malaria control at all levels of the health system.This work showed the effectiveness of collaboration between implementers, programmes managers, and researchers in identifying research questions. The responses to these identified research questions of this study may contribute to improving the implementation of malaria control programmes across African countries. More often than not, local social determinants of health are hidden or overlooked by funding agencies, institutional researchers, and health systems, yet they may be slowing down or reducing programme implementation and impact. In addition, many of the physical constraints that impede the regular and effective delivery of health interventions to those who need them are much more pronounced in Low-to-Middle-Income Countries (LMIC) than in high income countries . Hence bIndeed, despite recent trends showing a reduction in malaria mortality rates in Africa generally, and in the region in particular , mortaliThis study reports experiences gained from collaborations between decision-makers and researchers, a part of a project undertaken in the framework of the regional World Bank funded project titled: Malaria and Neglected Tropical Diseases in the Sahel (SM/NTD). The objLocal and primary providers along with malaria programme managers were approached in the 15 countries of the Economic Community of West African States (ECOWAS), including eight French-speaking, five English-speaking and two Portuguese-speaking countries using two approaches, namely: a questionnaire survey and regional validation workshops were held as part of the activities of the SM/NTD project. This study only focuses on malaria.The questionnaire translated into the three official languages of ECOWAS, namely English, French and Portuguese, were sent to the malaria control programmes managers in the last semester of trimester of 2016. The questionnaires were divided into two (2) parts: (i) Bottlenecks in malaria programme implementation (ii) Priority research questions on malaria programme. Each part covered seven thematic areas: governance, human resources, drugs, service provision, use of prevention methods, monitoring and evaluation (M and E), and public support or buy-in. Questionnaires were thereafter sent through electronic messages (Email) to National Malaria Control Programme (NMCP) managers/coordinators of the 15 ECOWAS countries, with instructions on how to fill the questionnaires.Follow up actions were undertaken for two months to obtain a satisfactory response rate. Even though the countries have similarities as well as differences regarding their governance structure, epidemiological trends, and public health research, the authors conducted an initial in-depth analysis country by country. They then split bottlenecks recorded and questions into the seven \u201cECOWAS regional topics of interest\u201d according to the thematic areas mentioned above. This analysis was then presented at the ECOWAS malaria regional workshop.A two-day regional workshop was organized in Bamako by the West African Health Organization (WAHO), the ECOWAS specialized institution dealing with health concerns, such as malaria as well as NTDs programmes in West Africa. Participants included malaria programme managers, NTDs programme managers, Directors of Public Health of the various Ministries, monitoring/evaluation officers, countries project management unit coordinators, technical and financial partners . The results of the questionnaire survey were analysed, presented, and discussed in two plenary and two breakout sessions.The first breakout session on malaria was organized with two groups of 12 people each. The breakout sessions brought together malaria programme coordinators, researchers, partners, and the regional project team. These teams worked to validate the research problems and questions. The two breakout teams were tasked to review, complete the problems, prioritize, and justify the research questions. The two breakout teams reviewed the survey results using individual and average ratings. For the first plenary session, each group was instructed to choose the top 20 research questions. On the second plenary session, the representative of each group shared the top 20 research questions they have selected. The questions selected by the participants clarified some research questions and allowed to finalize list related to malaria management.The second breakout session focused on individual countries\u2019 participants. The participants worked together to select three priority research questions from the list of questions established during the plenary session. Representatives of each country were asked to prioritize the three questions they selected and to address them over a three-year  period. Finally, a third plenary session allowed each country\u2019s team to share their key questions to address and prepare a plan for the subsequent years, 2017, 2018 and 2020.The workshop was moderated by a expert in parasitology and malaria research from West Africa and at the end, the moderator reformulated some of the questions and justifications in accordance with the adopted guidelines.Out of the 15 ECOWAS countries, 11  responded to questions related to malaria and Table In all seven thematic areas, there were challenges that limited the effectiveness of programme implementation. In the area of governance, issues of coordination and collaboration with partners in the field came up as well as weaknesses in the managerial capacity at the regional and district levels. The human resources problems identified were mainly related to capacity, competence, motivation of community health workers, weaknesses in research skills and capacity of programme actors. There were also difficulties in the area of management of medicine logistics, from ordering commodities to the distribution to patients, and also difficulties in pharmacovigilance. In service provision thematic area, difficulties of direct observed treatment were pointed out, especially for the second and third day doses of SMC, while for prevention, low uptake of vector control measures, the absence of insecticides for the impregnation of protective materials, and the low use of protective means were the major problems mentioned. In terms of monitoring and evaluation, challenges of access to quality data, especially from the community level, and inadequacy in the dissemination of research results were reported.Finally, in terms of public support, refusal or reluctance to participate in mass drug distribution during SMC campaigns, failure in adopting preventive measures and behaviour were reported by programme managers.Table The first five priority questions were related to (1) compliance with drug doses for the second and third days of SMC campaigns, (2) contribution of community-based distributors to severe malaria cases management in children under 5\u00a0year, (3) SMC efficacy, (4) ACT efficacy and tolerance of ACT under current guidelines, and (5) quality of malaria cases management at all health system levels.The prevention theme was ranked first with five questions, followed by the governance and medicines with four questions, and the monitoring and evaluation (M and E) with three questions. The five prevention questions were related to the effectiveness and non-use of long-lasting insecticidal nets LLIN), the level of use and effectiveness of indoor residual spray (IRS), conducting a study on the effectiveness of mosquito soap, and the possibility of using two insecticides to impregnate nets. Governance issues were related to the best strategy for the implementation of SMC campaigns, quality of malaria case management at all health system levels, the place of information and communication technology in data quality management and the type of collaboration framework between the Ministry of Health and partners. For the medicines theme, the four priority questions focused on the efficacy and tolerance of ACT under current guidelines, the side effects of ACT, the efficacy of traditional medicines and the comparative advantage of the dihydroartemisinin (DHA)-piperazine combination over sulfadoxine\u2013pyrimethamine (SP)\u2009+\u2009amodiaquine (SP-AQ). Regarding M and E, questions related to adherence for the second and third dose during seasonal chemoprevention campaigns, the performance and use of rapid diagnostic tests. In terms of human resources, the two priority issues were related to the contribution of community health workers in severe malaria case management and the supervision of the second and third doses during SMC campaigns. At the service delivery level, both issues were related to the quality and performance of the drug supply and management chains. Finally, in terms of public support, the questions were related to communication channels, media and strategies to ensure behavior change. Table It was noted that the research questions related to factors influencing adherence to second day (day 2) and third day (day 3) doses of SMC were highlighted as first priority by Mali and Niger participants. The same questions were flagged as second priority by Burkina Faso participants. It was followed by questions related to the contribution of community health workers in the supervision of the second and third doses of drug during the SMC campaigns in Burkina and Niger. The final ones were in order of importance, the questions on the most efficient strategy in the implementation of SMC in Burkina Faso, the toxicological effects of administering multiple doses of SP-AQ in children, the impact of communication interventions in 2nd and 3rd days in Mali, and the therapeutic effectiveness of SP-AQ in Niger.This work allowed the identification of key challenges limiting the implementation of NMCP in West Africa. Priority research themes in malaria has helped to highlight similarities between countries regarding malaria control programmes. Most of the bottlenecks highlighted by this work are related to the poor coordination and collaboration with partners, the skills and motivation of community health workers responsible for drug distribution during mass treatment. In addition, the bottlenecks were also due to weaknesses in the supply and distribution chain, poor use of prevention measures, difficulties in accessing quality data, especially at community level, and the population buy-in and acceptance of strategies. The problems that have emerged in malaria control programmes in this work have already been reported by some authors in Africa \u201311. The This work was designed to assess the implementation, operational bottlenecks, and success of public health practice in West Africa. Furthermore, this study evaluated the relationship between programme implementing actors, African researchers, and the constraints they face in their respective countries. Local researchers should work in coordination with programme actors to address local problems. The New Partnership for Africa\u2019s Development (NEPAD)\u2019s Consolidated Plan of Action 2005\u20132014 (CPA) and the Science Technology Innovation Strategy 2024  attempteThe landscape of global health keeps changing because new innovations and new discoveries are being implemented in interventions against emerging diseases (infectious and non-communicable). New discoveries either technically or \u201cprocess, are not easy to incorporate in public health interventions since they require drawing new strategic plans and other logistics. Hassan  has repoPlasmodium falciparum carriage rate in the SMC implementing areas; on adverse toxicological effects of multiple administration of SP-AQ, and on potential factors affecting adherence to mass drug administration (MDA) in nomadic population.After the identification of research priority questions, the project funded some research activities taking into account these priorities. For instance, a regional research was commissioned in the three countries related to the factors that influence adherence to day 2 and day 3 doses during SMC. The research started in 2018 and the primary result will be obtained in 2020. The overall results will be validated in the countries and published in 2021. Still at the regional level, a second research was conducted to analyse all communication interventions and impact on malaria programmes. Currently the preliminary results on the mapping of communication interventions are being finalized and the impact study is ongoing. Between 2018 and 2020, a lot quality assurance sampling survey (LQAS) was conducted in Burkina Faso and Mali in order to analyse the performance of the SMC campaign. Further research work is needed to on research questions not addressed in this study. In Mali, three studies were conducted including the prevalence of This study showed the effectiveness of collaboration between policy makers and researchers in identifying and funding research needed to improve malaria control programmes. The research questions identified can be adapted to other ongoing research to improve malaria control in different countries."}
+{"text": "The endocannabinoid system (ECS) is a complex signaling system that includes cannabinoid receptors, their endogenous ligands (endocannabinoids), and biosynthetic and hydrolytic enzymes . ECS conThis Special Issue of the International Journal of Molecular Sciences is a collection of eight review articles and five original research articles, and offers an updated overview of current knowledge on ECS in both physiological and pathological conditions. An update on the epigenetics of the ECS has been reported in the review article by the group of Pierantoni, with focus on its emerging role in reproduction and fertility. ECS undergoes epigenetic modulation by life style and environmental factors, with consequences on health and disease. Nevertheless, the modulation of ECS induces epigenetic changes, to different extents, of target genes, with possible trans-generational effects in the off spring through the transmission of deregulated epigenetic marks in the gametes .Cnr1-/- knockout mice, the authors demonstrate the requirement of CB1 activity, in driving the formation of inter-/intra-protamine disulphide bridges, and in histone removal in a mechanism involving the hyper-acetylation of histone H4, once again confirming the need of CB1 activity for the production of high-quality spermatozoa [The activity of cannabinoid receptors, CB1 and CB2, in male germ cell development\u2014from gonocyte up to mature spermatozoa\u2014has been reviewed by Barchi et al.; interestingly, new roles in paternal epigenetic trans-generational inheritance and testis cancer are also discussed . Furtherrmatozoa .Moving toward female reproduction, Cecconi and coworkers report the expression of major endocannabinoid-binding receptors  at different stages of mouse oocyte maturation, and investigate the effects of specific receptor antagonists, revealing a new possible role for GPR55 and potentially offering new targets for the therapy of female reproductive alterations . The involvement of CB1 in the hypothalamic control of food intake and reproduction has been investigated by Zuccarini et al., through the pharmacological and genetic manipulation of CB1 in zebrafish. The CB1-dependent effect on the guidance, fasciculation and routing of GnRH3 (Gonadotropin Releasing Hormone 3) and AgRP1 (Agouti-related peptide 1) axons has been demonstrated, suggesting the need of CB1 signaling in the correct development of neuroendocrine function related to food intake and reproduction . In this respect, the gut\u2013brainaxis represents a key regulator of the hypothalamic neuronal networks related to food-sensing and appetite. Therefore, the review article by Forte et al. summarizes the emerging role of an \"expanded ECS\", or endocannabinoidome (eCBome), encompassing endocannabinoid-like mediators in the modulation of the communication between microbiota and gut\u2013brainaxis, with consequences on host metabolism and a critical role in obesity onset .ECS may be a therapeutic target for the treatment of disease, and the modulation of endocannabinoid tone by the fatty acid hydrolyzing enzyme (FAAH) is a key step in ECS signaling. In this respect, the research article by Giacovazzo et al. compares different administration routes  to in vivo inhibit FAAH activity in mouse brains. Interestingly, the authors demonstrate the efficacy of intranasal FAAH inhibition, and suggest this delivery model as a suitable alternative to enhance the tone of endocannabinoids within the brain, for the treatment of neurodegenerative disorders and the improvement patients\u2019 compliance .The functional participation of the ECS in neurodegenerative disorders has been analyzed by Bhatia-Dey and Heinbockel, who focused a review article on the endocannabinoid-mediated neuromodulation in the olphactory bulb, a brain region in which neurogenesis continues throughout the life span, suggesting possible therapeutic interventions in decelerating neurodegenerative pathology . -/-Cnr2 mice, suggesting different signaling mechanisms for basal and damage-induced neurogenesis [In spite of the known involvement of CB2 in the neuorogenesis in both neuroinflammatory conditions and in response to pathophysiological stimuli, Mensching et al. demonstrate that stable adult neurogenesis occurs in the hyppocampus of ogenesis .The Interplay between the ECS, epilepsy and cannabinoids has been reviewed by the group of Mitchell. The deep involvement of ECS in neuroinflammation points out the possible use of cannabinoids-based treatments to modulate ECS, as alternatives to more conventional pharmacological therapies, but also underlines the need for further research in the field to sustain the use of therapeutic cannabis .The review article by Argenziano et al. analyzes the role of ECS in the pathogenesis and onset of pediatric inflammatory and immune diseases, like immune thrombocytopenia, juvenile idiopathic arthritis, inflammatory bowel and celiac disease, obesity and fatty liver disease, neuroinflammatory diseases, and type 1 diabetes mellitus .Cannabis sativa, of particular interest for clinical application. In this respect, the review article by Kis et al. summarizes the anticancer effects of CBD in vitro and in vivo, and its main pharmacological and toxicological aspects [As reviewed by Laezza et al., ECS can exert anticancer activity, modulating several signaling pathways involved in cell proliferation, differentiation, migration and angiogenesis , but the aspects . Taken together, this Special Issue provides a very updated overview on ECS activity and modulation in physiological and pathological conditions, through the presentation and integration of data from experimental animal models and clinical observation. The deep involvement of ECS in the control of biological functions is far from fully clarified, but all the submitted manuscripts expand the knowledge in the field of ECS involvement in both health and disease, with a particular attention to the possible therapeutic exploitation. Lastly, the Editor hopes this Special Issue of the International Journal of Molecular Sciences may be useful for basic and clinical scientists working in the field, and deeply thanks all the authors who contributed with excellent works, and the reviewers engaged for the peer-review process."}
+{"text": "Military service and exposure to war may influence the development of depression, leading to disparities in the condition among veterans and non-veterans. This study included 10,512 older men from the 1996 to 2014 waves of the Health and Retirement Study (HRS). We estimated Center for Epidemiology Depression (CESD) score trajectories among veterans and non-veterans and veterans of different war cohorts in growth curve models, controlling for early, mid, and late life characteristics. CESD score trajectories were lower among veterans and war veterans than non-veterans and non-war veterans, respectively. The highest levels of depression were among war veterans who served in more than one war. Veterans demonstrated lower levels of depression than non-veterans, calling into question the health advantage of veterans and selection mechanisms into the military and out of HRS. Multiple war veterans showed the highest levels of depression, representing the greatest mental health threat to veterans in the study. Part of a symposium sponsored by the Aging Veterans: Effects of Military Service across the Life Course Interest Group."}
+{"text": "The issue of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has created enormous threat to global health. In an effort to contain the spread of COVID-19, a huge amount of disinfectants and antibiotics have been utilized on public health. Accordingly, the concentration of disinfectants and antibiotics is increasing rapidly in various environments, including wastewater, surface waters, soils and sediments. The aims of this study were to analyze the potential ecological environment impacts of disinfectants and antibiotics by summarizing their utilization, environmental occurrence, distribution and toxicity. The paper highlights the promoting effects of disinfectants and antibiotics on antibiotic resistance genes (ARGs) and even antibiotic resistant bacteria (ARB). The scientific evidences indicate that the high concentration and high dose of disinfectants and antibiotics promote the evolution toward antimicrobial resistance through horizontal gene transformation and vertical gene transformation, which threaten human health. Further concerns should be focused more on the enrichment, bioaccumulation and biomagnification of disinfectants, antibiotics, antibiotic resistance genes (ARGs) and even antibiotic resistant bacteria (ARB) in human bodies. As the coronavirus disease 2019 (COVID-19) epidemic worsens, various disinfectants and pharmaceuticals have been actively used to control the spread of the virus. Disinfectants, such as alcohols, chlorine, formaldehyde, glutaraldehyde, ortho-phthalaldehyde, hydrogen peroxide, iodophors, peracetic acid, phenolics, and quaternary ammonium compounds were recommended to use alone or in combinations on public health by authorities. The Chinese Center for Disease Control and Prevention (China CDC), United States Environmental Protection Agency (US EPA) and World Health Organization (WHO) successively released the guidance for disinfectant utilization to against the virus, while the lack of necessary training program for public could raise the adverse effects of disinfectant on human health . TherefoIn the times of COVID-19 panic, disinfectants and antibiotics were overused for the coronavirus disease control and treatment, since the effective treatment measures and medications are not yet determined. Until 2020 March, China has dispensed at least 2000 tons of disinfectants in the city of Wuhan alone . Bacteria, only carrying antibiotic resistance genes (ARGs), can survive and persist in these contaminated environments. A disinfection by-products study reported that disinfection by-products can select strain with high-level resistance via broadly conserved cellular functions and pathways at the minimal inhibitory concentrations .In fact, ARGs and antibiotic resistant bacteria (ARB) can be target selected in disinfectants and antibiotics contaminated environments.. The ARGBesides HGT, ARGs and ARB can also be transferred from environments or microorganisms to higher trophic levels through drinking water, food and respiration . Human hCOVID-19 has threatened the global health remarkably. High concentration and high dose of disinfectants and antibiotics used during the COVID-19 pandemic, which entered into environments, are definitely accelerating the target selection of AMR in environments . HGT amo"}
+{"text": "Jiangsu was one of the first four pilot provinces to engage in comprehensive health care reform in China, which has been on-going for the past 5\u2009years. This study aims to evaluate the equity, efficiency and productivity of health care resource allocation in Jiangsu Province using the most recent data, analyse the causes of deficiencies, and discuss measures to solve these problems.Data were extracted from the Jiangsu Health/Family Planning Statistical Yearbook (2015\u20132019) and Jiangsu Statistical Yearbook (2015\u20132019). The Gini coefficient (G), Theil index (T) and health resource density index (HRDI) were chosen to study the fairness of health resource allocation in Jiangsu Province. Data envelopment analysis (DEA) and the Malmquist productivity index (MPI) were used to analyse the efficiency and productivity of this allocation.From 2014 to 2018, the total amount of health resources in Jiangsu Province increased. The G of primary resource allocation by population remained below 0.15, and that by geographical area was between 0.14 and 0.28; additionally, the G of health financial resources was below 0.26, and that by geographical area was above 0.39. T was consistent with the results for G and Lorenz curves. The HRDI shows that the allocated amounts of health care resources were the highest in southern Jiangsu, except for the number of health institutions. The average value of TE was above 0.93, and the DEA results were invalid for only two cities. From 2014 to 2018, the mean TFPC in Jiangsu was less than 1, and the values exceeded 1 for only five cities.The equity of basic medical resources was better than that of financial resources, and the equity of geographical allocation was better than that of population allocation. The overall efficiency of health care resource allocation was high; however, the total factor productivity of the whole province has declined due to technological regression. Jiangsu Province needs to further optimize the allocation and increase the utilization efficiency of health care resources.The online version contains supplementary material available at 10.1186/s12939-020-01320-2. Health care resources are the basis for the development of health services, and the rationality of their allocation not only affects residents\u2019 health level but also plays an important role in the sustainable development of medical and health services , 2. TherIn recent years, due to economic development, an ageing population, the prevalence of chronic diseases and the improvement in health concepts, higher standards have been established for the allocation of health resources. The equity and efficiency of health resource allocation and health service utilization are attracting increasing attention in China , 7. To eJiangsu was one of the first four pilot provinces to engage in comprehensive health care reform in China. Jiangsu is located in the eastern coastal area of China and has 13 prefecture-level cities, such as Nanjing, Zhenjiang, Suzhou and Huaian . JiangsuJiangsu Province has implemented comprehensive health care reform for the past 5\u2009years, and the year 2020 is also the last year of the Healthy China 2020 strategy . This stData were extracted from the Jiangsu Health/Family Planning Statistical Yearbook (2015\u20132019) and Jiangsu Statistical Yearbook (2015\u20132019), which cover 13 cities in Jiangsu Province. The series of longitudinal data were used to analyse the equity and efficiency trends in Jiangsu from 2014 to 2018.On the basis of the economic development level, geographical position and the Jiangsu Statistical Yearbook, the 13 cities in Jiangsu Province were divided into three groups: the most economically developed southern zone , the moderately developed middle zone  and the less economically active northern zone . Health care institutions included hospitals, primary health institutions, professional public health institutions and other health institutions.Considering representation, stability, availability and independence, capital, labour and financial investment are deemed to be important input variables in the delivery of health services. The number of institutions and beds represents the capital, the number of health workers represents labour, and the government financial subsidy and total expenditure represent financial investment. Health workers include physicians, registered nurses, assistant physicians, medical personnel, other technical personnel and health administrative staff. They were chosen as input indicators to measure equity. The annual numbers of outpatient visits, the hospitalization rate and general income represent output indicators.The Gini coefficient is the optimal tool to assess the equity of health resource allocation in terms of demographic and geographical aspects . The GinXi: cumulative percentage of health resources in the ith city of Jiangsu Province after ranking according to the per capita or regional average share of health resources.Yi: cumulative percentage of population or geography in the ith city of Jiangsu Province after ranking according to the per capita or regional average share of health resources.k: total number of cities.G: value of the Gini coefficient.The Theil index is used to analyse the inequity of resource allocation. The advantage of the Theil index is that it can measure the contributions of intra- and inter-regional differences to total inequity . FormulaPi: percentage of population or geography of each city in Jiangsu Province.Ei: percentage of health resources of each city in Jiangsu Province.T: value of the total Theil index.The total Theil index can be decomposed into the intra-Theil index and inter-Theil index . FormulaTintra: value of the intra-Theil index. In this study, it represents the intra-different distribution of health resources in southern, central and northern areas of Jiangsu Province.Tinter: value of the inter-Theil index. In this study, it represents the inter-different allocation of health resources among southern, central and northern areas of Jiangsu Province.Pg: proportion of population or geography of three regions  for the overall number of Jiangsu Province.Eg: proportion of health resources of three regions  for the overall number of Jiangsu Province.Tg: value of the Theil index of three regions .Tintra and Tinter can be calculated by dividing the total Theil index [The contribution rates of il index .The HRDI displays the influence of population and geographical factors on the agglomeration of health resources while avoiding bias caused by a single population or geographical aspect. Formula  is used HRi: health resource quantity of the ith region.Ai: geography of the ith region.Pi: population of the ith region.HRDI: value of the Health Resource Density Index.DEA is a nonparametric method that evaluates the performance of mathematical planning models, including the relative efficiency of decision-making units (DMUs), using multiple input and output indicators , 19. TheIn the BCC model, technical efficiency (TE) can be disassembled into pure technical efficiency (PTE) and scale efficiency (SE). Formula  is used TE expresses the production efficiency of DMU, which is based on input resource. PTE reflects the advance in productivity resulting from the efforts of managers and workers and the effective combination of production factors. SE indicates different levels of changes in DMU\u2019s economies of scale . Values Whereas DEA measures relative efficiency for a period of time, TFPC measures dynamic changes in productivity from time t to time t\u2009+\u20091 . TFPC caValues of TFPC, TEC, TC, PTEC and SEC above 1 indicate improvement. The DEA and TFPC were calculated using DEAP V.2.1.From 2014 to 2018, the total amount of primary health resources increased in Jiangsu Province. In a general sense, the primary resources include capital and labour . In termFor financial resources, we counted government financial subsidies and total expenditures. From 2014 to 2018, government financial subsidies continued to grow to 37.3 billion yuan  , South K , South Although we use a variety of methods to evaluate the equity and efficiency of health care resource allocation in Jiangsu Province, there are still some limitations to this study. First, although the selection of indicators is commonly used in similar research and indicators for health workers are included, we did not further subdivide these workers into doctors, nurses and other personnel. Second, this study mainly analyses the fairness of health care resource allocation from the perspective of population and geography, without considering the actual health status and health service needs of different regions. Third, due to the limitations of the basic DEA method, there are no bias adjustments for efficiency and productivity scores.In the past 5 years, the total amount of health resources in Jiangsu Province has increased steadily, and the overall equity of health care resource allocation has been good. The equity of basic medical resources was better than that of financial resources, and the equity of geographical allocation was better than that of population allocation. However, there were great differences among regions: health care resources in southern Jiangsu were plentiful, while those in central and northern Jiangsu were relatively lacking. The overall efficiency of health care resource allocation was high, but some cities faced low efficiency. In addition, the total factor productivity of the whole province has declined. Therefore, to ensure the sustainable development of medical services, the government should further optimize the allocation of health resources, comprehensively consider geographical and demographic factors, and strive to narrow the gap in medical resources in different regions. In addition, to increase the utilization efficiency of limited medical resources, technical efficiency needs to be improved by developing the service ability of basic medical institutions, strengthening cooperation among medical institutions at all levels, and improving training and incentive mechanisms for doctors.Additional file 1:Fig. S1.The Lorenz curves of health care resources in Jiangsu Province from 2015 to 2017. A-F show the Lorenz curves of primary resources allocated by geographical area (A-C) and population (D-F). G-L show the Lorenz curves of financial resources allocated by geographical area (G-I) and population (J-L). A, D, G, J are in 2015; B, E, H, K are in 2016; C, F, I, L are in 2017."}
+{"text": "Pearl River Declaration, emanated from the symposium, called for establishing a One Health Cooperation Network in the Southeast Asia\u2013Pacific region with a vision to strengthen regional health security through sharing each other\u2019s knowledge and experience, and making investments in workforce development, scientific innovations such as vaccine research and development, sharing epidemic intelligence, risk identification, risk communication and appropriate response measures against emerging health threats.The Second International Symposium on One Health Research (ISOHR) was held in Guangzhou city, China on 23\u201324 November 2019. A transdisciplinary collaborative approach, One Health (OH), was the central theme of the symposium which brought together more than 260 experts, scholars and emerging researchers from human health, veterinary health, food safety, environmental health and related disciplines and sectors. More than 50 organizations including World Health Organization, Centers for Disease Control (USA), and Queensland Government  participated in the symposium. Scholars, experts and emerging researchers, policy-makers and practitioners in their respective fields delivered over 50 presentations at the symposium, highlighting the collective vulnerability to some of the emerging health challenges the region was combating. These included emerging infectious diseases, antimicrobial resistance, climate change, food safety and the growing burden of non-communicable diseases. The  Emerging infectious diseases, antimicrobial resistance, climate change, food safety and security, and the growing burden of non-communicable diseases were identified as some of the most pressing challenges to global health security at the Second International Symposium on One Health Research (ISOHR) held in Guangzhou, China on 23\u201324 November 2019. The symposium was jointly organized by Sun Yat-sen University (China), Griffith University , South China Agricultural University (China) and Guangzhou Medical University (China). A transdisciplinary collaborative approach, known as One Health, was identified as a key opportunity to promote human, animal and environmental health within and between countries around the world [The ISOHR brought together more than 260 experts, scholars and emerging researchers from China and around the world in as diverse areas as public health, clinical medicine, veterinary medicine, laboratory science, food safety, environmental health, agricultural science, military medicine, health systems and policies. More than 50 organizations including multiple Chinese Government departments and research institutions, and representatives from World Health Organization, Centers for Disease Control (USA), and Queensland Government  participated in the symposium.Over the past two centuries the world has witnessed spectacular innovations and successes in public health and medical science. The most notable among those were the invention of vaccines (1796\u2009AD) and antibiotics 1928), the eradication of small pox (1979) and the introduction of a simple, low-cost oral rehydration therapy  for treatment of dehydration caused by diarrhea. Collectively, these innovations have saved tens of millions of lives 8, the er. These aInternational Health Regulations 2005 [The novelty of the virus, the nature and speed of the interspecies and cross-border transmission of COVID-19 prompted World Health Organization to declare it a \u2018Public health emergency of international concern\u2019 , whereasons 2005 .The ISOHR observed with a great concern that over the past five decades, the world has witnessed the emergence of about 40 new diseases including Legionnaires\u2019 disease, HIV/AIDS, hepatitis C, mad-cow disease, SARS, Middle East Respiratory Syndrome (MERS), Nipah and Ebola virus diseases. Twenty of these diseases were found in China alone . Many ofThe ISOHR acknowledged the role of economic globalization in the twenty-first century and the associated growth in tourism and trade. These and other developments have significantly increased the mobility of populations and trade in goods worldwide and increased the risk of infectious disease spread across regions and countries. In some areas this has resulted in a continuing epidemic and pandemic threat. The impact of global climate change, agricultural intensification, rapid economic growth combined with population growth and urbanization, further complicate public health challenges globally and more specifically in LMICs . Today, In the recent past, the region has experienced some of the deadliest epidemics resulting in formidable losses not only to health but also impacting heavily on their economies with substantial sociological and political repercussions . For exaCountries increasingly recognize the value of working collaboratively and sharing knowledge, expertise and resources for the protection of their own country and to address the collective vulnerability in today\u2019s globalized world. This recognition is evidenced by the Australian Government\u2019s regional health security initiative known as \u2018Indo-Pacific Centre for Health Security\u2019 established in 2017 . The iniThe ISOHR noted with concern that the growing antimicrobial resistance (AMR) was a significant threat to the core of modern medicine as it seriously hampers the efficacy and sustainability of an effective public health response to infectious diseases. The complex root of the problem and the process of widespread, systematic misuse of antibiotics in human and animal medicine, and in food production, demands systematic and coordinated action involving multiple sectors, and disciplines beyond health . The unrInfectious diseases and AMR are not the only causes of concern for the global health security. Similarly, the scope of OH is not limited to infectious disease only. The growing burden of chronic disease, the double burden of malnutrition which is defined as the coexistence of overnutrition (overweight and obesity) and undernutrition (stunting and wasting) , climateInfectious disease transmission occurs at the human-animal-environment interface. The magnitude of the impact of disease and its transmission is influenced by many factors including human behavior, and society, the environment, and the culture of the community. Thus, a broad-based, holistic approach, known as One Health (OH), has received prominence in recent years. Countries increasingly recognize the collective vulnerability to emerging health security threats such as epidemics and pandemics and seek to forge joint effort for mutual benefit. One example of such collaboration effort is the Australian Government\u2019s regional health security initiative, the \u2018Indo-Pacific Centre for Health Security\u2019.  EstablisLooking through the lens of etiology, infectious diseases are not only caused by bacteria, viruses and parasites. They are also influenced or shaped by social, economic, political, legal and cultural conditions. Thus, the breadth of emerging health issues and the application of OH to address those will go much farther than the traditional health outlook.In line with its fast-paced economic development, China remains focused on combating emerging health threats including emerging infectious diseases such as SARS and the coronavirus disease (COVID-19), and controlling the spread of antimicrobial resistance , 29. HavIn line with this acknowledgement, the Pearl River Declaration  Table 11 called The process of initiating such a regional collaboration by Griffith University, a co-convener of the ISOHR, began as early as 2016 with the establishment of the Global Research Consortium on Risk Communication, Emergency Management and Adaptation to Climate Change for Health (REACCH). This was undertaken in partnership with 15 institutions including government departments across the region. REACCH members have contributed to joint research, policy advocacy and capacity-building to improve health systems and address collective vulnerability to emerging health threats.(i.)The One Health Research Network, established in 2016\u2013\u2013a collaboration with One Health networks in China and Indonesia, focusing on diseases that occurs at human-animal-environment interface.(ii.)The country programs network for Bangladesh, China, Indonesia, Mongolia, the Philippines and Vietnam, consisting of many institutional members from these countries guided by a Memorandum of Understanding of each with Griffith University, having been gradually expanded since 2006. These collaborations focus on health system policies and operational capacity building in the region, as well as emerging health challenges including climate change adaptation, disaster risk reduction, zoonotic and vector-borne disease control.The establishment of a cross-disciplinary Research and Policy Advocacy Hub for Global Health Security at Griffith University, Australia in 2019 further supports this overall regional objective. The Hub hosts two broad networks:Among many tangible outcomes achieved through the establishment and function of these networks has been the delivery of over 10 public health leadership programs that have successfully nurtured more than 120 Fellows across the region. Many of these Fellows have gone on to leadership of the COVID-19 pandemic response in their respective countries over recent months .Addressing emerging health challenges is the collective responsibility of nations as they are collectively vulnerable in the globalized world. If health is for all, as it is often heard being said, then all should be working for health. The resounding message of the Pearl River Declaration was the need for greater commitment and collaboration among nations across the mountains and seas under the umbrella of OH for a future healthy global community. As important regional development partners in health in the Indo-Pacific region, countries such as Australia, China, Thailand, Singapore and international bodies such as Asian Development Bank and WHO can play a pivotal role in country-capacity building through sharing knowledge and experience, as well as making investments in workforce development, scientific innovations such as vaccine research and development. These can be better achieved through establishing a regional One Health Cooperation Network."}
+{"text": "Annular epidermolytic ichthyosis is a rare subtype of epidermolytic ichthyosis that is characterized by erythematous, polycyclic, and migratory scaly plaques accompanied by palmoplantar keratoderma. This report presents the case of an 8-year-old girl who developed migratory, erythematous, scaly plaques associated with palmoplantar keratoderma. The initial hypothesis was erythrokeratodermia variabilis et progressiva; however, the finding of epidermolytic hyperkeratosis in histopathological examination led to the diagnosis of annular epidermolytic ichthyosis. Annular epidermolytic ichthyosis (AEI) is a rare phenotypic variant of epidermolytic ichthyosis (EI), also known as congenital bullous ichthyosiform erythroderma, an autosomal dominant disorder characterized by extensive erythroderma and formation of blisters in early life.4An 8-year-old female patient was attended at the pediatric dermatology outpatient clinic of the Hospital Santa Casa of Porto Alegre with a report of diffuse dermatosis that began in the first months of life. Upon examination, the patient presented erythematous, scaly, hyperkeratotic plaques with prominent borders, affecting the mesogastrium, cubital fossae, popliteal fossae, and inguinal and cervical regions, as well as palmoplantar hyperkeratosis and yellowish hyperkeratotic plaques on the scalp and nasal introitus . No assoThe patient denied any symptoms and there was no background of family history of similar cases and consanguinity. After one month, she was reassessed and the appearance of the plaques changed, increasing the extension of the affected areas; however, the polycyclic aspect disappeared B.Skin biopsy in the extensor portion of the forearm showed acanthosis, papillomatosis, and hyperkeratosis with marked epidermolysis in the granular layer .Figure 4AEI was first described in 1992 by Sahn et al.10In the histopathology, the hyperkeratotic lesions of the AEI revealed hyperkeratosis, acanthosis, and a thickened granular layer. Keratinocytes in the spinous layers and superior granulosa of the epidermis demonstrated cytoplasmic vacuolization and prominent keratohyaline granules.5The main differential diagnosis of annular epidermolytic ichthyosis is with erythrokeratodermia variabilis et progressiva (EKVP),Treatment options in the small number of patients reported included topical medications such as retinoids, topical corticosteroids, propylene glycol, calcipotriene, and keratolytic agents, and little response was observed.None declared.Emanuella Stella Mikilita: Approval of final version of the manuscript; conception and planning of the study; drafting and editing of the manuscript.Irina Paipilla Hernandez: Approval of final version of the manuscript; conception and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; critical review of the literature.Ana Let\u00edcia Boff: Drafting and editing of the manuscript; collection, analysis, and interpretation of data.Ana Elisa Kiszewski: Approval of final version of the manuscript; conception and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.None declared."}
+{"text": "This article describes priority areas for research on the impact of the Covid-19 pandemic on older adults that have been identified by the CIHR Institute of Aging (CIHR-IA). The process used by CIHR-IA consists of several iterative phases and thus far has resulted in identification of three key areas for Covid-19 research needs and four cross-cutting thematic areas. The key research priority areas are as follows: response of older adults to disease, vaccination, and therapeutics; mental health and isolation; and supportive care environments. The four cross-cutting themes are equity, diversity, and inclusion (EDI); ethical/moral considerations; evidence-informed practices; and digital health technologies. The priorities outlined in this article will inform CIHR-IA\u2019s responses to Covid-19 research needs. On March 11, 2020, the World Health Organization announced that Covid-19 had reached pandemic status.The mission of the Canadian Institutes of Health Research Institute of Aging (CIHR-IA) is to support research, to promote healthy aging, and to address the causes, prevention, screening, diagnosis, treatment, support systems, and palliation for the complex health challenges that can be present in older individuals.CIHR-IA focuses on the entire trajectory of life while specifically addressing the health challenges of older individuals and is a national leader in addressing health research priorities related to aging. Initiatives led by CIHR-IA not only link and support researchers across the country, but also bring together a broad group of stakeholders, including different levels of government, practitioners, health charities, voluntary health organizations, and older adults themselves. At the start of the Covid-19 crisis, CIHR-IA mobilized quickly to identify research priority areas related to this pandemic and its dramatic effects on older adults. The goal of this article is to describe the approach implemented by CIHR-IA to rapidly understand Covid-19 research needs for older adults in Canada. These priorities will be used to shape future actions of CIHR-IA within the context of Covid-19.The process initiated by CIHR-IA consists of a number of actions and consultations as illustrated in In early February 2020, CIHR launched the Canadian 2019 Novel Coronavirus (Covid-19) Rapid Research Funding Opportunity. A total of 100 grants were funded in this competition for a Government of Canada investment of $55.3 million, with the primary focus on medical countermeasures research and social and policy countermeasures research. At this early stage in the identification and investigation of the health impacts of Covid-19, older adults had not yet been recognized as an especially vulnerable population. Thus, no funded projects focused on Covid-19 consequences on the health, wellness, and welfare of older adults. Given this outcome and the rapidly evolving situation related to Covid-19 and older adults, CIHR-IA mobilized to identify research priorities to respond to the needs of the aging population in preparation for the Institute\u2019s participation in funding opportunities coming forward from CIHR and partners.With review of the available published literature and emerging data, CIHR-IA identified initial areas of research need related to Covid-19\u2019s impact on older adults. This was followed by the initiation of a fast-track process to engage stakeholders and gain insight into the impact and implications of Covid-19 on research in aging in Canada. In April 2020, CIHR-IA sent a survey to the more than 4,000 mailing list subscribers; over 600 responses were received from researchers, trainees, decision-makers, health care administrators, public servants, health care providers, older adults, and caregivers. The survey comprised eight questions designed to obtain both quantitative and qualitative responses. Qualitative responses were analysed using a thematic approach and classified by emerging themes. In early June, CIHR-IA engaged in targeted consultations with key stakeholders, including the Institute of Aging Advisory Board members and the directors of the 35 Canadian Research Centres on Aging. Information from these consultations was collated with data obtained from the survey, resulting in the identification of several key research priorities.The CIHR-IA priority identification process resulted in three key areas and four cross-cutting themes for research on the impact of Covid-19 on older adults and aging, as illustrated in Aging is a multifaceted process involving numerous cellular and molecular mechanisms in different organ systems. This can include functional and structural alterations in the immune system that can manifest as a decreased ability to fight infection and constitutive low-grade inflammation (inflammaging)  homes.Equity, diversity, and inclusion (EDI)CIHR has implemented a range of strategies and solutions to foster equity, diversity, and inclusion in the research ecosystem.Ethical/moral dilemmas around end-of-life care in pandemic situations or emergenciesEthical and moral considerations in research on older adults are critical within the Covid-19 crisis. Research related to illness, resource rationing, palliative care, and isolation are of critical importance.Trials informing best practices for care of older adults with covid-19 and translation and implementation of knowledge for best practices in emergency preparednessCIHR-IA supports the inclusion of older adults in trials that inform best practices that involve Covid-19 care. Historically, older adults have been omitted from trials that will impact their own care.Digital health technologies supporting health services and care delivery, including drug discovery and vaccine production, and monitoring and social interventionsCIHR-IA is a co-lead of the CIHR eHealth Innovations initiative. This initiative supports exceptional national and international digital health research to develop solutions to maintain and improve the lives of older adults. Research that brings together a diversity of stakeholders will enable enhanced collaboration through the entire health research continuum from basic research to public health.Four important cross-cutting themes are also identified that intersect with the aforementioned three key research areas.Soon after the start of the Covid-19 pandemic, it became apparent that older adults were the most at-risk group to develop complex symptoms and had the greatest risk of mortality. To advance our mandate to improve the health and lives of older adults, CIHR-IA reacted rapidly, including by consulting stakeholders and experts, to identify priority research needs related to older adults and Covid-19. The key research areas laid out in this article, ranging from the response of older adults to disease, vaccination, therapeutics, and clinical trials, to mental health and supportive care environments, will continue to inform the responses made by CIHR-IA over the longer term.In parallel with the consultation process and identification of priority research needs, CIHR-IA rapidly mobilized to partner on two important CIHR funding opportunities; Covid-19 May 2020 Rapid Research Funding Opportunity and the Covid-19 and Mental Health (CMH) Initiative, as well as a funding opportunity initiated by the Canadian Frailty Network (CFN) to fund research projects focused on the interaction between frailty and Covid-19 in older adults. Research carried out in these three programs has the potential to begin to address the priority needs in each of the key areas identified. CIHR-IA will continue to seek opportunities to develop and partner on research programs that will address the needs of older adults in this area.The four cross-cutting themes identified through the consultation process pinpoint crucial elements to be included in research on the impact of Covid-19 on older adults. As with all health research, considerations related to equity, diversity, and inclusion of under-represented populations must be integrated into the research plan and, in particular, older adults must be engaged meaningfully in all aspects of the research. With regard to the specific situation of older adults during the Covid-19 pandemic, considerations related to mental health issues and ethical/moral dilemmas around end-of-life care in a pandemic or emergency situation should be carefully integrated into the research. This is an opportunity to rethink the status and role of older adults in our society and to specifically address the impact and influence of ageism in decision-making and the delivery of care. Research leading to public policies that reduce social exclusion of seniors and fight ageism and stigma associated with end of life, frailty, and vulnerability, is needed now more than ever. The inclusion of older adults in trials to inform best practices for Covid-19 care is of the utmost importance. At this time of evolving tools and techniques, digital health research should be harnessed to bring solutions to maintain and improve the lives of older adults.CIHR-IA seeks to ensure that research needs on aging in Canada are met and so is committed to fostering research programs to find approaches to support the health and wellness of older adults during the Covid-19 pandemic and in the post-pandemic recovery period."}
+{"text": "The burden of sickle cell disease (SCD) is greatest among African nations. Effective scalability of evidence-based interventions  screening) is urgently needed particularly in these settings for disease management. However, Africa is constrained by limited resources and the lack of capacity to conduct implementation science research for proper understanding of context, and assessment of barriers and facilitators to the uptake and scalability of evidence-based interventions (EBI) for SCD management.We outline implementation science approaches to embed EBI for SCD within the African context and highlight key implementation research programs for SCD management. Building implementation research capacity will meet the major need of developing effective life-long and accessible locally-tailored interventions for patients with SCD in Africa.This commentary communicates the importance of the application of implementation science methodology to scale-up evidence-based interventions for the management of SCD in order to reduce pain, prevent other morbidities and premature death experienced by people with SCD in Africa, and improve their overall quality of life. These studies were conducted exclusively among pediatric and adults populations in clinical settings in Nigeria (n=2), and Jamaica (n=1). Findings suggest that adoption is low, as observed through reported provider practices and patient adherence, in part shaped by misinformation and fear of side effects among patients, provider beliefs regarding affordability and organizational challenges with procuring the medicine [Effective scalability of health interventions is urgently needed particularly in low-and middle- income countries (LMICs), considering the constraints these countries bear, and the lack of capacity to conduct implementation science research. For Africa, sickle cell disease (SCD), the inherited blood disease characterized by anemia, severe pain and other vasoocclusive complications, and early mortality, has significant financial, social, and psychosocial impacts and burdens individuals, families, and health systems. Currently it is projected that over 300,000 individuals are born annually with SCD in Africa , 2. Compmedicine . This coacceptability, adoption, appropriateness, costs, feasibility, fidelity, penetration, and sustainability [PARIHS , etc.) [Implementation science, defined as the scientific study of methods to promote the systematic uptake of research findings and other evidence-based practice into routine practice  guided bnability  are not ), etc.) , 14 and ), etc.) , 16, to ), etc.) , 18, andWhat is currently lacking within Africa is a comprehensive multicomponent implementation strategy that explores for example, the reach, uptake, and long-term sustainability of EBIs for SCD. This strategy, would ideally incorporate patient /provider/ community/ policy engagement  for the EBIs needed to manage SCD exist. The American Society of Hematology Sickle Cell Disease Guidelines provide SCD management recommendations including broad pain management approaches, pharmacological and nonpharmacological interventions and analgesic delivery  blood trThis commentary highlights the need for EBIs for SCD management across Africa. It also outlines key implementation research programs that should employ implementation science strategies and capacity building activities for SCD management. We note the success of EBIs in high-income countries that have reduced childhood SCD-related deaths but yet resource-constrained settings, including Africa lack access to EBIs. We acknowledge the critical importance of investigators implementing clinical trials in Africa for SCD management to plan for sustainability at the onset and throughout the implementation process, considering the tremendous amount of resources required to implement these trials. We, therefore advocate for a comprehensive multicomponent implementation strategy with strong patient and community stakeholder engagement, and the need to build capacity at the provider and health systems level to conduct implementation science research for proper understanding of context, and assessment of barriers and facilitators to the uptake, sustainability, and scalability of EBIs for SCD management within the African context."}
+{"text": "Although significant progress has been made in understanding mental health issues, racial/ethnic minorities are disadvantaged in terms of knowledge, attitude/stigma toward mental illness, and access to treatment. Older Koreans and Korean Americans are high-risk groups with great prevalence of stigma and limited access to mental services. The two groups share similarities as well as differences. For example, Older Korean Americans, a first-generation immigrant group, tend to share traditional values and beliefs with older Koreans. However, differences in social and cultural contexts, availability of social networks and resources, and access to health care systems present unique challenges and strategies. The purpose of this symposium is to enhance the understanding of critical issues in mental health among older Koreans and Korean Americans and identify challenges and strategies to promote mental health and well-being. Five studies conducted in Korea and the US will explore a variety of personal, social, and cultural factors related with mental health, based on quantitative and qualitative approaches. The diverse topics cover the mediating role of self-esteem in the relationship of stigma to emotional well-being, the effect of stress and coping on well-being, loneliness and negative family interactions, the relationship of life stressors and social capital on mental distress among older Korean Americans compared with other older Asian Americans, and community leaders\u2019 attitude toward depression. The issues of vulnerabilities and resources will be discussed from the cultural perspectives as well as implications for future research and practice."}
+{"text": "P. purpureum because of higher adherence between the particles and mucous covering of the algae. Silica NPs caused significant inhibition of microalgae growth-rate predominantly produced by mechanical influence.Nanoparticles (NPs) have various applications in medicine, cosmetics, optics, catalysis, environmental purification, and other areas nowadays. With an increasing annual production of NPs, the risks of their harmful influence to the environment and human health is rising. Currently, our knowledge about the mechanisms of interaction between NPs and living organisms is limited. Additionally, poor understanding of how physical and chemical characteristic and different conditions influence the toxicity of NPs restrict our attempts to develop the standards and regulations which might allow us to maintain safe living conditions. The marine species and their habitat environment are under continuous stress due to anthropogenic activities which result in the appearance of NPs in the aquatic environment. Our study aimed to evaluate and compare biochemical effects caused by the influence of different types of carbon nanotubes, carbon nanofibers, and silica nanotubes on four marine microalgae species. We evaluated the changes in growth-rate, esterase activity, membrane polarization, and size changes of microalgae cells using flow cytometry method. Our results demonstrated that toxic effects caused by the carbon nanotubes strongly correlated with the content of heavy metal impurities in the NPs. More hydrophobic carbon NPs with less ordered structure had a higher impact on the red microalgae  The growing industry of nanotechnology inevitably results in an increase of risks associated with the nanomaterials (NMs) and nanoparticles (NPs) to affect living organisms including humans. Carbon- and silica-based NPs could be highlighted among the variety of engineered NPs ,2. Due tThe consumer products, large-scale manufacturers producing NMs, synthesizing, and research laboratories could be highlighted among the main sources leading to the release of NPs in the environment ,27. DespThe difficulty of risk assessment in nanotoxicology is complicated by the variety of factors that could significantly change the properties and, therefore, the toxicity of NPs. Moreover, much uncertainty still exists about the relation between different parameters such as size, form, surface area, zeta potential of NPs, protein corona formation, and transformation of NPs inside of organisms and in the environment or combinations of these parameters and toxic properties of NPs ,33,34,35Attheya ussuriensis (Bacillariophyceae), Chaetoceros muelleri (Bacillariophyceae), Heterosigma akashiwo (Raphidophyceae), and Porphyridium purpureum (Rhodophyceae).The aim of this study was to evaluate and compare the toxic level and biochemical effects caused by the influence of different types of carbon nanotubes, carbon nanofibers, and silica nanotubes on four marine microalgae species, namely In this research, we used two types of multiwalled carbon nanotubes  , two typHeterosigma akashiwo [Carbon nanotubes and nanofibers were synthesized and characterized in the Boreskov Institute of Catalysis  . The strakashiwo .Silicon nanotubes were kindly provided by the Department of Chemistry, Inha University Republic of Korea . The samCharacteristics of NPs used in this research are represented in Marine biobank of the National Scientific Center of Marine Biology, Far Eastern Branch of the Russian Academy of Sciences (NSCMB FEB RAS). The toxicity bioassay of NPs was carried out on four marine microalgae: two types of diatom species Attheya ussuriensis [Chaetoceros muelleri [Heterosigma akashiwo [Porphyridium purpureum [Microalgal cultures were provided by The Resource Collection uriensis  and Chaemuelleri , a raphiakashiwo , and a rurpureum . Culturiurpureum  with minurpureum ,59.The microalgae species were selected based on its abundance among the microalgae of the Sea of Japan , and itsThe samples of NPs were added to filtered seawater to obtain the working suspensions with a concentration of 1000 mg/L. Before each series of bioassays, the working suspensions of NPs were sonicated with ultrasound homogenizer Bandelin Sonopuls GM 3100  using maximal intensity for 30 min.The exposition of microalgae cells to the suspensions of NPs was carried out in 24-well plates. Each well was filled with 2 mL of microalgae cell aliquot and the corresponding volume of the working suspension to obtain the final concentrations 1, 10, and 100 mg/L. The filtered seawater without NPs was added to the control group. The exposure of each used concentration and control group was performed in four biological replicates.6) [Microalgae cell counting and registration of morphological and biochemical changes during the experiment were carried out with flow cytometer CytoFLEX  with the software package CytExpert v.2.0. The changes of microalgae cells after exposure to NPs were evaluated using specific fluorescent dyes. Microalgae growth-rate inhibition was determined by staining with propidium iodide (PI) according to the standard bioassay protocol . Esteras6) ,68. To dPrior to the assessment of growth-inhibition, esterase activity, and membrane potential of each microalgae species, we made a series of preliminary measurements to determine the optimal concentration of fluorescent dyes and the optimal duration of staining as described in our previous report . The reg50) are one of the most common values used for evaluation cytotoxic effects in macroalgae bioassay [Growth-rate inhibition and changes in the size of microalgae cells should be estimated as a benchmark of direct cytotoxic effects or as an indicator of mortality. The 96\u2009h and 7 days half maximal effective concentration .p \u2264 0.05 was considered statistically significant.Statistical analyses were performed using the software package GraphPad Prism 7.04 . The one-way ANOVA test was used for analysis. A value of 50 concentrations of microalgae growth-rate, FDA fluorescence intensity (esterase activity), and DiOC6  fluorescence intensity compared to control. The calculated mean EC50 concentrations and 95% confidence limits are given in For all the samples of NPs, we calculated ECFor visualization of calculated data  and analC. muelleri and P. purpureum.Silica nanotubes SNT-1 and SNT-2 demonstrated the most pronounced influence on the microalgae growth rate. The level of toxicity increased for all microalgae species after seven days of exposure except for the samples SNT-1 and SNT-2 after 96 h of the treatment affected growth-rate only for A. ussuriensis, C. muelleri, and H. akashiwo both after 96 h (acute toxicity) and seven days (chronic toxicity) of the treatment. Carbon nanofibers CNF-1 and CNF-2 also did not reveal any significant influence on the growth rate of these three species in acute toxicity assessment but chronic toxicity and growth-rate inhibition was detected for A. ussuriensis and H. akashiwo. Moreover, all the carbon NPs caused significant inhibition of esterase activity and depolarization of membranes for A. ussuriensis, H. akashiwo, and C. muelleri. However, the nanofiber sample CNF-2 did not affect the esterase activity of diatomic algae A. ussuriensis and stimulated esterase activity of diatomic algae C. muelleri.Carbon nanotubes CNT-1 and CNT-2 had almost no influence on the growth rate of P. purpureum significantly differed from three other microalgae species. P. purpureum was the only species responded by growth-rate inhibition to the influence of carbon NPs. At the same time, the red algae had the lowest changes in esterase activity and membrane potential.The toxicological profile of the red algae The data of flow cytometry analysis indicated the changes in the size of microalgae cells after the treatment of NPs as demonstrated in A. ussuriensis after the treatment with the samples CNT-1 and CNT-2 at the concentration of 100 mg/L and after the treatment with silica nanotubes at the concentrations of 10 and 100 mg/L  on esterase activity and membrane potential, we can conclude that the main mechanism of toxic action of these samples on the red microalgae was a physical damage caused by adhesion of clusters of NPs with extracellular mucopolysaccharides of P. purpureum [The current statement correlated with the results of the structural and surface analysis of the samples of carbon NPs . It was urpureum .A. ussuriensis, H. akashiwo, and C. muelleri was probably caused by the lower mechanical interaction between microalgae cells and the NPs. However, observed esterase activity inhibition, membrane depolarization, and size changes of microalgae cells might be produced by the influence of metal impurities containing in carbon NPs  silica NPs did not affect the esterase activity and membrane potential of the cells of all four microalgae species even at higher concentrations but caused significant inhibition of growth-rate, which indicated predominance of mechanical damage as a mechanism of toxicity for used samples of silica nanotubes.In this study, the aim was to assess the level of toxicity and the mechanisms of toxic action of carbon nanotubes, carbon nanofibers, and silica nanotubes using four microalgae species as the objects of aquatic toxicity bioassay. The results of this investigation show that (1) carbon nanotubes samples CNT-1 and CNT-2 had non-significant toxic effect on the growth rate of all four microalgae species but caused a high inhibition of esterase activity and depolarization of cell membranes, which was most probably caused by heavy metal impurities in NPs; (2) more hydrophobic carbon NPs with less ordered structure had a higher impact on the red microalgae The findings of this research provide insights for the formation of the principles of safe design, production, and utilization of NPs . We beli"}
+{"text": "Post-workshop self-assessment (completed by 21 participants) noted significant median gains in knowledge domains related to NGS targeted sequencing, bioinformatics for genome assembly, and sequence quality assessment. The participants also reported that the information on study design, sample preparation, sequencing quality control, data quality assessment, reporting, and basic and advanced bioinformatics analysis were the most useful information presented in the training. While longer-term evaluations are planned, the training resulted in significant short-term improvement of a laboratory\u2019s self-reported wet lab and bioinformatics capabilities. This framework can be used for future DoD laboratory development in the area of NGS and BI for infectious disease surveillance, ultimately enhancing this global DoD capability.Epidemics of emerging and re-emerging infectious diseases are a danger to civilian and military populations worldwide. Health security and mitigation of infectious disease threats is a priority of the United States Government and the Department of Defense (DoD). Next generation sequencing (NGS) and Bioinformatics (BI) enhances traditional biosurveillance by providing additional data to understand transmission, identify resistance and virulence factors, make predictions, and update risk assessments. As more and more laboratories adopt NGS and BI technologies they encounter challenges in building local capacity. In addition to choosing the right sequencing platform and approach, considerations must also be made for the complexity of bioinformatics analyses, data storage, as well as personnel and computational requirements. To address these needs, a comprehensive training program was developed covering wet lab and bioinformatics approaches to NGS. The program is meant to be modular and adaptive to meet both common and individualized needs of medical research and public health laboratories across the DoD. The training program was first deployed internationally to the Basic Science Laboratory of the US Army Medical Research Directorate-Africa in Kisumu, Kenya, which is an overseas Lab of the Walter Reed Army Institute of Research (WRAIR). A week-long workshop with intensive focus on targeted sequencing and the bioinformatics of genome assembly ( Development of Next-Generation Sequencing (NGS), or High-Throughput Sequencing (HTS), has revolutionized life sciences, dramatically increasing the variety of questions that can be answered using genomic sequence data. With this continuously evolving and growing field, the need for adequate computational hardware resources, software, and expertise to analyze large and complex data is also increasing. The field of bioinformatics has thus experienced substantial growth and advancement in recent years, and the requirement for highly skilled and specialized personnel has surged.Staphylococcus aureus (MRSA); pathogens that have the ability to negatively impact United States force readiness and mission goals (Within the Department of Defense (DoD), NGS and bioinformatics are routinely used to answer many scientific and research questions that ultimately aid in protection of the armed forces, as well as the general population . Infection goals , 2019. Ion goals . The DoDon goals . Unsurpron goals . Howeveron goals . TherefoIn 2017, GEIS created a Consortium to address the increasing needs and challenges associated with NGS and bioinformatics at DoD medical research and public health laboratories. The vision of the Consortium is to rapidly detect and characterize known, emerging, and novel infectious disease agents through establishment of a harmonized DoD laboratory NGS and bioinformatics capability to inform force health protection decision making. The Consortium today represents a network of DoD laboratories that use NGS and bioinformatics for infectious disease surveillance. A baseline assessment and initial training effort was led by GEIS and three DoD core sequencing and bioinformatics laboratories: WRAIR-VDB , NMRC-BDRD , and USAMRIID-CGS . The Consortium performed an assessment of the GEIS DoD laboratory partners with access to Illumina MiSeq or other NGS instrument(s), in order to evaluate existing laboratory capabilities in NGS and bioinformatics, and to map gaps and needs in laboratory utilization of these tools to meet their mission goals of infectious disease surveillance. Limited access to experienced and knowledgeable NGS and bioinformatics personnel was one of the main gaps, making basic and advanced bioinformatics analyses a common challenge across the network. Another challenge was the restrictive and limited informatics infrastructure, especially in some of the participating laboratories located in low-and-middle income countries (LMICs). However, the challenge of finding personnel with sufficient training in NGS and bioinformatics was not only observed in laboratories located in LMICs, it was also apparent in domestic laboratories, thus highlighting the need to develop a structured NGS and bioinformatics training for the specific needs of DoD biosurveillance programs. Such training would have to be standardized across the Consortium network, as well as made agile enough to meet different levels of needs and computational resources of the participating DoD laboratories. Using the baseline information from the assessment, desired sequencing capabilities for DoD research and public health laboratories were divided into three tiers . Here weSamples used for the NGS hands-on training included dengue virus 2 (DENV-2) and chikungunya (CHIKV) and were provided on-site. Controls for library preparation, MiSeq sequencing and TapeStation for both DENV-2 and CHIKV were validated and prepared at VDB-WRAIR in the months prior to the planned NGS&BI training in Kenya. Prior to shipment of controls to Kenya, the control concentrations were measured and documented and the information was sent to MRD-A. Coordination of the reagent and control shipment from VDB-WRAIR to Kisumu, Kenya started a month prior to the training. Four Linux laptops and two Linux servers were prepared for hands-on bioinformatics training. A list of software was prepared by the Consortium and sent out to MRD-A Lab for installation onto the training computers. The software list included ngs_mapper, IGV, Geneious, MEGA7, EDGE (servers only) . Three wLectures and theory included: History of sequencing, overview of NGS, library preparation, quantification, validation and pooling. In detail: (i) List of library preparation kits used by core DoD for different projects and specimens were highlighted; (ii) Several topics on types of kits for viruses, bacteria and parasite work were heavily discussed throughout the lecture; (iii) Specific library preparation kits were highlighted including TruSeq, QIASeq Fx, Kappa, NexteraXT, RNA Access and DNAFlex; (iv) AmpureXP Beads clean up after PCR reactions and library preparation was emphasized as preferred method; (v) Different library validations, including qPCR, Qubit and TapeStation were highlighted as essentials for quality control (QC); (vi) Library pooling based on TapeStation and Qubit were introduced; (vii) Two exercises of how to calculate amount of each library for pooling were conducted. Preparations were made for the upcoming bioinformatics training.Hands-on training for NGS wet lab was performed with 24 participants. The participants were separated into two groups based on their NGS background and interests for hands-on performance. Group 1 prepared the NexteraXT library from the amplicons and assessed amplicons using both Qubit and TapeStation prior to NexteraXT library preparation. The NexteraXT libraries were validated using both Qubit and TapeStation. Group 2 validated the pooling based on the controls from the shipment and prepared sample sheets, the MiSeq instrument and PhiX controls. The libraries were loaded onto the Miseq. Bioinformatics training dataset was prepared on each computer. Server performance was tested for running the pipelines and tools needed for the training, and the training dataset analyses were executed to test functionality prior to the hands-on bioinformatics training.Hands-on wet lab activities from Day 2 were summarized and any questions and concerns were addressed. Lectures on laboratory project experimental design (to include bioinformatics), bioinformatics data cleaning and pre-processing, and genome assembly through reference mapping were performed, as well as exercises in experimental design and genome consensus calling. For hands-on bioinformatics training, the 24 participants were divided into six different groups, each group utilizing one training computer or server. Ngs_mapper was used as the example of a reference mapping pipeline. The first training was performed on the DENV fastq dataset, including training on usage of different stages of the pipeline, setting a desired reference genome and running the pipeline. After ngs-mapper jobs were completed, interpretation of the output, how to utilize data quality scores and depth of coverage, how to assess the performance of the sequencing and the genome assembly were performed. Manual QC and genome curation were performed. The second training dataset consisted of CHIKV fastqs and was used for training on multiple reference usage and reference selection, in addition to repeating the above steps for dataset one.de novo genome assembly, assembly of bacterial genomes, and troubleshooting and maintenance of the MiSeq platform.Bioinformatics hands-on training was continued by evaluation of the CHIKV runs for reference genome selection. Based on the best reference choice, the reference mapping run was repeated. The repetition was incorporated on purpose to ensure better knowledge retention. Following reference mapping, the output of CHIKV assembly was evaluated and its genome curated. The data that were used for this training were purposefully chosen to be of lower quality, so that different challenges of genome assembly curation were highlighted, as well as the importance of QC and what consequences a lack of QC might result in. The last reference mapping analysis was performed on CHIKV data but now the participants learned how to change different pipeline thresholds, picking their own requirements for minimum base quality, consensus type output and the like. In addition, lectures were conducted covering theory of A summary of wet lab activities and library pooling to obtain optimal cluster density was presented. An exercise aimed at the evaluation of several MiSeq runs was performed. Management of sequencing libraries and data, and prevention of chimeric sequence data generation and mislabeling were discussed. Bioinformatics training on the influenza dataset was performed separately since influenza virus has a segmented genome and bioinformatically, full genome assembly is slightly more complicated. How to recognize presence of influenza reassortment was covered. A workshop survey was distributed  and the A comprehensive training curriculum was constructed that consisted of standardized wet lab and bioinformatics theory modules  as well Based on the results of the initial laboratory assessment, training was recommended for the GEIS partner US Army Medical Research Directorate \u2013 Africa (MRD-A) laboratories in Kenya. For MRD-A\u2019s initial needs, which mainly cover sequencing and analyses of known pathogen outbreaks and epidemics in the region, a 1 week on-site workshop was constructed where the wet lab targeted sequencing was covered in both lectures (specific assembled modules) and hands-on practice, followed by bioinformatics theory (specific assembled modules) and hands-on practice of pathogen genome assembly and curation . This apWe undertook a rapid evaluation of participants\u2019 self-reported baseline and post-workshop knowledge across ten skill domains related to genomic sequencing . We alsoThere were substantial gains in self-reported knowledge across all skill domains , with thThe participants were also asked in which topics they felt they would like more training and experience  and how The rapid growth and utility of NGS and bioinformatics for research and biosurveillance has resulted in the emergence of DoD requirements for implementation of sequencing and computational technologies, as well as access to highly trained and knowledgeable personnel in the fields of NGS and bioinformatics. Specifically the latter point remains one of the major challenges across the DoD, and even though bioinformatics programs have more recently gained larger momentum in academia, lack of workforce with early-on and/or specialized bioinformatics training is still palpable in the government settings, particularly in government labs outside the continental United States. Therefore, NGS and bioinformatics training programs for infectious disease surveillance have recently been developed by many government agencies or non-governmental organizations. Within the United States Government, Canada, and the European Union, there is movement towards training and coordinated promotion of standardized quality assurance and quality control practices for pathogen genome sequencing using NGS technologies  . Some reOur experience in deploying a comprehensive yet customizable classroom and hands-on training in NGS and bioinformatics in Kenya was overall successful (see caveats of assessment below) and is a potential model for future training programs in similar environments. This training program consisted of foundational material in sequencing theory and experimental design which formed a basis for more applied modules in targeted sequencing and metagenomics. Additionally, hands-on NGS wet lab and bioinformatics modules were further tailored to meet the needs of the laboratory participants using information obtained from a baseline landscape assessment. This training shows that a highly modular and deployable set of NGS and bioinformatics workshop components can be used within the DoD network of medical research and public health laboratories to improve sequencing wet lab capability, and analysis and interpretation of pathogen genomic data gathered using NGS and bioinformatics.Embedded within this training workshop was a post-self-assessment questionnaire to gauge immediate improvements in knowledge gained from the workshop materials. It is important to note that this questionnaire has several limitations including a small sample size, the immediate nature of the assessment tool which does not allow one to measure long-term benefits, and the fact that the assessment was only delivered through written evaluation and self-report. Further, more objective measurements of knowledge and skill gains after workshops may not directly translate into effective implementation and retention of these skills. The latter requires medium and longer term evaluations in an implementation science framework . HoweverFollowing this workshop a mechanism to facilitate reach back support with embedded long-term training and mentorship has been instituted to overcome challenges associated with long-term sustainability of a sequencing capability at MRD-A. Included in this 5-year NGS and bioinformatics implementation plan for MRD-A are: (i) continuous contact and support by the core DoD sequencing laboratories, (ii) repetition of training with focus on real data and troubleshooting, (iii) additional hands-on training in other wet lab and bioinformatics approaches to achieve capability diversification, (iv) development of local computational infrastructure for bioinformatics, and (v) regular assessments of wet lab and bioinformatics knowledge retention. Laboratory-level assessments of proficiency and skill retention 1\u20132 years post-training have included external review of raw sequence data and consensus genomes generated from GEIS funded surveillance projects. We also anticipate deploying periodic blinded panel of samples or data files for follow-up assessments of knowledge retention and capability development. At the end of this period, the goal is to achieve a high quality diversified portfolio of NGS and bioinformatics capabilities at the site, which then may serve as a central DoD hub for sequencing and advanced characterization of Force Health Protection (FHP) relevant pathogens in Africa.The current COVID-19 pandemic has further highlighted the importance of access to the NGS and bioinformatics in laboratories throughout the world. This makes the need of workshops such as ours even greater. However, the pandemic has also made travel and in-person learning a challenge, and therefore, GEIS is planning on development of virtual versions of the workshops to continue development of this important DoD-wide capability. In addition, Oxford Nanopore\u2019s MinION platform has increasingly been used in pathogen outbreak studies for real-time in-field analyses throughout the world, including analyses of SARS-CoV-2 . AlthougMore broadly, the Consortium goal is the establishment of basic proficiencies and adopted norms in quality assurance and quality control in targeted (hybridization- or amplicon-based) and metagenomic sequencing for viral and bacterial pathogens leading to more reliable results which will ultimately improve DoD public health surveillance and response. An additional objective is the development and maintenance of advanced genomics and bioinformatics capabilities in the United States and priority overseas locations, in order to enhance global health surveillance and facilitate faster response to infectious disease outbreaks. Development of these capabilities with GEIS DoD laboratory partners will require sustained commitment and global coordination. The end results will be the ability to reliably and rapidly sequence, identify, and characterize pathogens of public health importance in order to improve biosurveillance efforts and inform FHP measures throughout the world.All datasets presented in this study are included in the article/IM, WR, KB-L, LM, and RJ designed the training modules and the workshop modules. IM, WR, LV, LM, KP, RJ, JW, SP, and RC prepared and instructed the workshop. IM, WR, LV, KP, SP, RC, JK, KB-L, LM, JW, and RJ performed workshop post-assessment and wrote the manuscript. All authors contributed to the article and approved the submitted version.The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Army, Department of the Navy, Department of Defense, or United States Government. Several of the authors are United States Government employees. This work was prepared as part of their official duties. Title 17 U.S.C. \u00a7105 provides that \u201cCopyright protection under this title is not available for any work of the United States Government.\u201d Title 17 U.S.C. \u00a7101 defines a U.S. Government work as a work prepared by a military service member or employee of the U.S. Government as part of that person\u2019s official duties.LV and RC were employed by company Leidos, United States. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Mycobacterium leprae, an acid-fast bacillus that mainly affects the skin and peripheral nervous tissue. Many of the clinical manifestations of leprosy can mimic connective tissue diseases. The authors present the case of a 49-year-old woman who had been treated for four years for systemic lupus erythematosus in a rheumatological service. Skin biopsy of a plaque on the inguinal region was compatible with borderline lepromatous leprosy associated with a type 1 lepra reaction. The patient is undergoing treatment with multibacillary multidrug therapy, showing clinical improvement.Leprosy is an infectious disease with chronic evolution, caused by  A 49-year-old woman reported pain in the interphalangeal joints and lower limbs, a skin rash, and alopecia; all symptoms persisted for four years. She was being treated for systemic lupus erythematosus with hydroxychloroquine, azathioprine, methotrexate, and prednisone. On physical examination, she presented generalized erythematous plaques, and infiltrated areas on the trunk, on the ears, and fingers, as well as diffuse non-healing alopecia .Figure 1She presented 24-hour proteinuria within normal limits, positive ANA , positive anti-cardiolipin IgM antibodies, and anti-SM and anti-double helix DNA, both negative.a)Subacute lupusb)Dermatomyositisc)Lepromatous leprosyd)Diffuse eosinophilic fasciitisShe also presented paresthesia of the lower limbs, and thickening and pain on palpation of the left ulnar and left external sciatic popliteal nerves.The bacilloscopy of the ear and two trunk lesions was positive (smear index: 3.33). Histopathology of the plaque in the inguinal region showed an epidermis with hyperkeratosis; in the dermis, edema and a perivascular, periadnexal, and interstitial mild inflammatory infiltrate composed of lymphocytes, histiocytes, plasmocytes, epithelioid cells, and sparse giant Langhans cells, involving the subcutaneous tissue, adipocytes and septa. Wade staining showed a large number of intracellular acid-fast bacilli, grouped in globi, fragmented and granular A and 3 BMycobacterium leprae, an acid-fast bacillus, with tropism for Schwann cells and the reticuloendothelial system. The bacillus mainly affects the skin and peripheral nervous tissue.M. leprae to regulate cytokine production and induce Th1 or Th2 responses contributes to the variety of clinical presentations of the disease.Leprosy is a chronic contagious infectious disease, caused by Rheumatological manifestations are observed in 64% to 77% of patients with multibacillary leprosy, especially when presenting lepra reactions.Positive ANA can be observed in 3% to 34% of leprosy patients. Titers are generally low, and the speckled and homogeneous patterns are the most common.The different clinical manifestations of leprosy pose a diagnostic challenge, since they can mimic other diseases, including autoimmune disorders. The difficulty of diagnosing leprosy early can increase the chance of transmission and cause deformities secondary to peripheral nerve involvement.None declared.Larissa Daniele Machado G\u00f3es: Elaboration and writing of the manuscript; critical review of the literature; critical review of the manuscript.Juliana Alves Scrignoli: Approval of the final version of the manuscript; conception and planning of the study; elaboration and writing of the manuscript; obtaining, analyzing, and interpreting the data; effective participation in research orientation; intellectual participation in propaedeutic and/or therapeutic conduct of studied cases; critical review of the literature; critical review of the manuscript.Patr\u00edcia Morais: Statistical analysis; approval of the final version of the manuscript; conception and planning of the study; elaboration and writing of the manuscript; obtaining, analyzing, and interpreting the data; effective participation in research orientation; intellectual participation in propaedeutic and/or therapeutic conduct of studied cases; critical review of the literature; critical review of the manuscript.Patr\u00edcia Morais: Statistical analysis; approval of the final version of the manuscript; conception and planning of the study; elaboration and writing of the manuscript; obtaining, analyzing, and interpreting the data; effective participation in research orientation; intellectual participation in propaedeutic and/or therapeutic conduct of studied cases; critical review of the literature; critical review of the manuscript.None declared."}
+{"text": "Indomethacin (IND) is a drug which after successful clinical trials became available for general prescription in 1965 and from that time is one of the most widely used anti-inflammatory drug with the highest potencies in the in vitro and in vivo models. However, despite its high therapeutic efficacy in relieving the symptoms of certain arthritis and in treating gout or collagen diseases, administration of IND causes a number of adverse effects, such as gastrointestinal ulceration, frequent central nervous system disorders and renal toxicity. These obstacles significantly limit the practical applications of IND and make that 10\u201320% of patients discontinue its use. Therefore, during the last three decades many attempts have been made to design novel formulations of IND aimed to increase its therapeutic benefits minimizing its adverse effects. In this review we summarize pharmacological information about IND and analyze its new lipid formulations and lipid bioconjugates as well as discuss their efficacy and potential application. This compound is one of the most useful antirheumatic drugs and prime drug recommended for the treatment of gout, collagen diseases, ankylosing spondylitis, osteoarthritis, and acute shoulder pains. Indomethacin was discovered in 1963 and two years later has been approved by the Food and Drug Administration (FDA) as a drug with anti-inflammatory, analgesic, and antipyretic properties for use in the United States . The. The2]. ammation . In 2002ammation . In termammation .Indomethacin belongs to the group of non-selective non-steroidal anti-inflammatory drugs. Similarly, to acetylsalicylic acid, diclofenac or ketoprofen, indomethacin also acts on the way of additional mechanisms of formation of pain and inflammation demonstrating the ability to inhibit the passage of leukocytes through the vascular walls to the site of inflammation in the tissues . AccordiThe relative potency of NSAIDs increases in the following order: aspirin < phenylbutazone < ibuprofen < naproxen < indomethacin both in the in vitro and in vivo models. This indicates the potent anti-inflammatory effect of indomethacin compared to other NSAIDs and partially is responsible for the popularity of the first three drugs . IndometO-demethylation, N-deacylation, or both reactions (O-desmethyl-indomethacin (DMI), O-deschlorobenzoyl-indomethacin (DBI), O-desmethyl-N-deschlorobenzoyl-indomethacin (DMBI), and their conjugates with glucuronides . Du. Du64]. In the next years the effect of lipid composition and size on the targeting potential of liposomes encapsulated IND in arthritic rats as well as methods for increasing their circulation time have been extensively studied by Srinath and coworkers ,70,71. MThe enhancement of absorption of IND by increasing the retention time at the absorption site and reducing the distance to the blood was reported for liposomes modified with chitosan . In fastThe safety of liposomal formulation of IND was evaluated in a pregnant mouse model ,74. RefuBioconjugation of therapeutics is an effective method for targeted drug delivery and reduction of their undesired side effects. Linkage of drug with other biomolecule via covalent bond offers many clinical benefits like enhanced disease-specific targeting, reduced toxicity, optimized pharmacokinetics, and improved efficacy, safety, and tolerability. Especially bioconjugates are attractive which include lipids as the building blocks. As hydrophobic compounds, lipids after passing through the intestinal walls, penetrate into the lymphatic system through which they connect with the circulatory system at the level of the thoracic vein. This way of transporting lipids in the circulatory system distinguishes them from hydrophilic compounds, which, after penetration into the intestinal walls, reach the blood vessels, and then are transported through the portal vein to the liver, and then to the general circulation. Giving a lipid character to drugs after their conjugation with lipid molecule increase their concentration in the body, prolong release and blood circulation . Active sn-2 position of triacylglycerol (TAG) skeleton, which ensured the appropriate level of salicylates in the blood excluding the occurrence of gastric irritation ..2 enzymeThis work presents an overview of the literature data about indomethacin developed during the past few decades, methods of reduction of its gastrotoxicity, and targeted delivery by formation of lipid formulations and bioconjugates. The study summarized in this review established lipid bioconjugates of indomethacin as promising candidate for future clinical studies and proved that lipids protect against acute intestinal epithelial injury caused by indomethacin and effectively increased the therapeutic efficiency of this drug.Application of phospholipids and nanotechnology is a promising approach for further development of innovative formulation for indomethacin and other drugs from the group of NSAIDs and is expected to grow in the near future."}
+{"text": "Amphiphilic Polymer Co-networks: Synthesis, Properties, Modelling and Applications is a new and very interesting book published by the Royal Society of Chemistry and edited by Prof. Costas S. Patrickios (University of Cyprus). Herein, a brief review of the most important features of the book and its contents is provided from a personal perspective. The presence in these materials of the hydrophobic segments, in addition to the hydrophilic ones, allows only limited water absorption , rendering them less fluid-like and mechanically stronger than classical hydrogels. Provided that the hydrophobic components come in segments of several consecutive hydrophobic units, these hydrophobic segments aggregate and the APCNs undergo self-organization in water, a process analogous to surfactant aqueous micellization. Upon APCN deformation, these hydrophobic pockets dissipate mechanical energy, rendering these materials stronger. The hydrophobic pockets can also solubilize hydrophobic solutes, such as drugs to be subsequently delivered, or sequester oils or other hydrophobic pollutants for environmental remediation. Polymeric hydrogels are crosslinked hydrophilic polymers which are capable of absorbing water, having the characteristics of both a solid and a fluid. Their higher water content makes hydrogels more fluid and transparent but also more fragile. Polymeric materials consisting of crosslinked hydrophilic and This book  Figure  is aboutN-vinylimidazole), poly(ethylene glycol), poly[(2-dimethylamino)ethyl methacrylate], polysaccharides or poly(ethylene glycol)s, among others, and hydrophobic domains derived, for instance, from poly(tetrahydrofuran), polyisobutylene, poly(\u03b5-caprolactone), four-armed star poly(ethyl glycidyl ether)s and poly(dimethylsiloxane)-based crosslinkers. Important properties discussed throughout different chapters include aqueous swelling, thermophysical and mechanical properties, self-assembly mechanism, morphological features, external stimuli responsiveness, , degradation and protein adsorption. In addition, useful comparisons between the properties of these materials and those of common polymeric hydrogels are provided for important examples. Applications described in the book chapters include, for instance, the use of APCNs in soft contact lenses, drug delivery, tissue engineering, heterogeneous biocatalysis , and for the fabrication of membranes of controllable permeability and antibacterial hybrid materials. Furthermore, an important theory chapter on the simulation of the self-assembly of APCNs, focusing on microphase separation and order\u2013disorder transitions, is also included.The book\u2019s 15 chapters are written by experts in the field, coming from four continents and 12 countries, and are organized into four sections that include synthesis, properties, modeling and applications. The chapters describe and discuss new developments in the field, while the history of APCNs since their origin in 1988 is summarized in the Foreword by Prof. J. P. Kennedy of the University of Akron and in Chapter 1 by the editor of the book. A brief outlook for the field is provided at the end of Chapter 1. The co-network architectures discussed in this book are mainly derived from hydrophobic macromolecular crosslinkers which represent the classical approach; however, more modern designs as well as the use of more efficient coupling chemistries are also presented. Among different APCNs, the book emphasizes those based on the combination of hydrophilic components such as poly(Professor Costas S. Patrickios obtained his PhD in 1993 at the Massachusetts Institute of Technology (MIT) in Cambridge, Massachusetts in the USA. Between 1994 and 1996, Dr. Patrickios worked as a post-doctoral researcher at the University of Sussex in the UK. Then, he served as a Lecturer at the University of Manchester Institute of Science and Technology (UMIST) (1996\u20131997), also in the UK. In 1998, he joined the Department of Natural Sciences (now Department of Chemistry) at the University of Cyprus (Republic of Cyprus), where he has remained since then. His main research has been focused on the synthesis and characterization of amphiphilic polymer co-networks based on interconnected amphiphilic block copolymers prepared using the living/controlled polymerization techniques group transfer polymerization (GTP), atom transfer radical polymerization (ATRP) and reversible addition-fragmentation chain transfer (RAFT) polymerization. He is currently the Chair of the Polymer Networks Group (PNG), an international organization promoting research on polymer networks and gels.In conclusion, this is a timely and decisively important book with well-articulated content, which invites the hydrogel research community to consider adding a hydrophobic block/segment to their materials in order to convert them into amphiphilic gels and examine whether the resulting properties are improved for the particular application compared to those of the original hydrogels. The book\u2019s style and its content diversity make it appropriate for graduate students and researchers interested in hydrogels, polymer chemistry, polymer networks, self-assembly and nanomaterials. Certainly, this is a must-read book for all those who are passionate about engineering new functional hydrogels that can contribute to solving real-world challenges."}
+{"text": "Improving food and nutritional diversity based on the diversity of traditional plant-based foods is an important dietary strategy to address the challenges of rapidly emerging diet- and lifestyle-linked noncommunicable chronic diseases (NCDs) of indigenous communities worldwide. Restoration of native ecosystems, revival of traditional food crop cultivation, and revival of traditional knowledge of food preparation, processing, and preservation are important steps to build dietary support strategies against an NCD epidemic of contemporary indigenous communities. Recent studies have indicated that many traditional plant-based foods of Native Americans provide a rich source of human health\u2013relevant bioactive compounds with diverse health benefits. Based on this rationale of health benefits of traditional plant-based foods, the objective of this review is to present a state-of-the-art comprehensive framework for ecologically and culturally relevant sustainable strategies to restore and integrate the traditional plant food diversity of Native Americans to address the NCD challenges of indigenous and wider nonindigenous communities worldwide. Loss of plant-based food diversity and subsequent changes in dietary patterns closely associated with higher daily intake of more hyperprocessed and calorie-dense foods have partly contributed to the rapid rise of diet- and lifestyle-linked noncommunicable chronic diseases (NCDs) across different communities worldwide , 2. The Most public health reports from last 2 decades have suggested that Native American communities and Alaska Natives of the United States are facing increasing health challenges due to the NCD-linked epidemic of type 2 diabetes (T2D) and cardiovascular diseases (CVDs) , 8. A naThe framework and strategies suggested in this review are to revive and revitalize the traditional plant-based food diversity of Native Americans and to integrate such foods into contemporary healthy dietary patterns as part of overall public health solutions for NCD epidemics. Kuhnlein and Receveur  defined The foundations of life, such as food resources, medicines, cultures, rituals, and spiritual integrity, of indigenous Native American communities have long been rooted and associated with their respective native and localized ecosystems . DiverseTherefore, a resilient native ecosystem with high species biodiversity, including plant-based food diversity, is essential for the sustainability and well-being of dislocated Native American communities . The negPrior to developing sound food diversity and nutritional intervention strategies to advance public health policies addressing NCD-linked health disparities of Native American communities, it is important to understand and recognize significant dietary and lifestyle changes and what has happened in the socioeconomic and ecological domains in these communities. Until the early 20th century, most Native American tribes farmed, hunted, or fished on their own lands and wetlands or gathered foods and medicinal plants from the woods and forests . The traHowever, in the last century the growth of industry and technology triggered a general shift from home cooking to higher consumption of commercially produced food products from a few calorie-dense food plants and rise in commercial animal farming that led to the development of multiple popular food chains across the United States . To suppNCDs such as obesity-linked T2D and CVDs are rapidly increasing in prevalence and becoming the leading cause of death in different communities, including indigenous and wider nonindigenous populations worldwide . HoweverThe latest report of the National Center for Chronic Disease Prevention and Health Promotion indicates the highest prevalence of diagnosed diabetes in Native American and Alaska Natives, with 14.9% in men and 15.3% in women . HoweverTraditional wisdom, invention, and continuous observation guided early humans to adopt and incorporate plant-based foods in their diet and for medicinal uses depending on their availability and nutritional properties relevant to human well-being , 12. MesIn this context, many plant-based foods from very specific and localized ecosystems such as wild rice of the Great Lakes region or cranberry from North-Eastern America were widely used in traditional Native American diets , 37. FurSeveral traditional food plants and wild edibles of Mesoamerican origin are rich sources of phytochemicals relevant to human health, such as phenolic bioactives, with diverse health benefits . These tTherefore, traditional plant-based foods of Native Americans, with their rich source of natural phenolic antioxidants, can be incorporated in dietary intervention strategies to counter chronic oxidative stress and other metabolic dysfunctions commonly associated with T2D, CVDs, and GDM , 38, 40.Squash is also a rich source of phenolic antioxidants and has natural angiotensin-converting enzyme (ACE) inhibitors, which are important for T2D-linked hypertension management . High phOverall, the average consumption of traditional and ethnic plant-based foods by Native American communities is <10%, and many living in the reservations do not even have access to traditional foods . TherefoEarly human migration and settlement, such as the migration of Native American tribes across North America, was partly guided by the quest for food and based on the availability of diverse plant and animal food resources in their respective ecosystems . HoweverTherefore, it is important to revive the knowledge of traditional food systems of Native Americans and restore information about traditional food plants, wild edibles, and other relevant natural food resources . To achiScreening and comparing human health\u2013relevant nutritional profiles and diverse health benefits of traditional plant-based foods is essential for building more resilient and robust dietary intervention strategies, especially to counter the diet-linked NCD epidemic of indigenous communities , 47. OveRevival of traditional knowledge of indigenous culture-specific cultivation practices is as important as understanding the nutritional qualities and associated health benefits of the native food plants. Appreciation of natural food and nonfood resources and their spiritual connection with native ecosystems is a significant part of the ethos of indigenous Native American tribes . The traSimilar to different traditional cultivation practices, food preparation, processing, and preservation practices of traditional food plants and wild edibles also have significant relevance in determining optimum nutritional qualities and associated health benefits of traditional Native American foods . AnotherTo address the NCD-linked health disparities of Native American communities, it is also important to integrate nonindigenous food plants and plant-based foods rich in human health\u2013relevant bioactives into traditional Native American diet models . Such inActive participation and continuous engagement of Native American communities in decision processes around food and health policy are extremely important for successful outcomes of any intervention strategies , 37. SucRestoring indigenous food sovereignty is essential to address the severe public health challenges linked to food and nutritional security of contemporary Native American communities. However, challenges related to indigenous food sovereignty are extremely complex due to interlinkage of different cultural, ecological, social, political, and economic factors. Therefore, to address such complex indigenous food sovereignty issues, it is important to develop more sustainable and community-oriented strategies based on a systems approach by understanding the ecological, cultural, social, and economic contexts of traditional foods of Native Americans. Additionally, such resilient and robust strategies to improve food and nutritional diversity based on traditional food plants and native medicinal plants of Native Americans should also have enough flexibility to adjust and evolve based on the needs of Native American communities and their contemporary cultural and ecological relevance. Therefore, restoration of traditional food systems of Native Americans and integration of nonindigenous healthy foods from contemporary American diets into traditional food systems to enhance nutritional diversity can have a profound impact on advancing nutritionally linked health outcomes of Native American communities, especially to combat the rapidly increasing NCD epidemic. However, most importantly we have to recognize that access to nutritionally balanced traditional foods is not a privilege but a right of indigenous people of North America and worldwide. Overall, acknowledging and accepting this simple fact can help to develop and advance more effective and sustainable policy measures to enhance traditional food and nutritional diversity in contemporary diets for improving the health, livelihood, and well-being of Native American communities and wider nonindigenous communities."}
+{"text": "Abrupt industrialization, urbanization, and the emergence of the nuclear family have contributed to the increase of single-person households, placing an emphasis on individualization in society. Because of such changes, more people are living alone and feeling lonely, alienated from society and family. This research examined the association between loneliness and age-friendly environment, a community equipped with policies, settings, services, and structures that promote active ageing and aging-in-place, with the mediating roles of social support and sense of community. The study analyzed a total of 590 respondents aged 45 and above using data from the age integration survey conducted by the OO Research Institute of South Korea. Structural equation modelling and the bootstrapping method were applied. Age-friendly environment was positively associated with social support  and sense of community . Social support was negatively associated with loneliness . The full mediation effect of social support was observed in the pathway from age-friendly environment to loneliness . Social support was fundamental in lowering loneliness, and age-friendly environment could only reduce loneliness by following a pathway that enhances social support. In other words, despite how well an age-friendly environment is established, it would not decrease an individual\u2019s loneliness unless it also enhances social support level. This finding sheds importance in maintaining satisfactory relationships that enable sharing of feelings, and fulfilling emotional and social needs in lowering loneliness. Measures to increase social support level within community are suggested."}
+{"text": "Functional polymers show unique physical and chemical properties, which can manifest as dynamic responses to external stimuli such as radiation, temperature, chemical reaction, external force, and magnetic and electric fields. Recent advances in the fabrication techniques have enabled different types of polymer systems to be utilized in a wide range of potential applications in smart structures and systems, including structural health monitoring, anti-vibration, and actuators. The progress in these integrated smart structures requires the implementation of finite element modelling using a multiphysics approach in various computational platforms. This special issue presents six scientific report articles.The Special Issue opens with work from Eindhoven University of Technology in a joint study with Bernal Institute, University of Limerick, Ireland, in which the researchers developed a finite element method (FEM) for representing the microstructural behaviour, particularly the swelling of hydrogel beads . As the In the second article, Zhang and colleagues from Northeast Agricultural University, China, designed a novel hierarchical metamaterial with a tuneable negative Poisson\u2019s ratio by re-entrant representative star-shaped unit cells . In thisZolfagharian and Kaynak from the School of Engineering in Deakin University, Australia, worked on the fracture resistance analysis of three-dimensional 3D) printed polymers in collaboration with Khoshravani from the University of Siegen in Germany [D printedIn the fourth article, , Carleo The Special Issue closes with the work of international researchers from the UK, USA, and Egypt in which Atif and colleagues developed a computational fluid dynamics (CFD) model to investigate characteristics of high-speed submicron polyvinylidene fluoride (PVDF) fibres as they are expelled from a blow spinning (SBS) nozzle . The aut"}
+{"text": "This commentary describes the creation of the Zika Virus Individual Participant Data Consortium, a global collaboration to address outstanding questions in Zika virus (ZIKV) epidemiology through conducting an individual participant data meta-analysis (IPD-MA). The aims of the IPD-MA are to (1) estimate the absolute and relative risks of miscarriage, fetal loss, and short- and long-term sequelae of fetal exposure; (2) identify and quantify the relative importance of different sources of heterogeneity  for the risk of adverse fetal, infant, and child outcomes among infants exposed to ZIKV in utero; and (3) develop and validate a prognostic model for the early identification of high-risk pregnancies and inform communication between health care providers and their patients and public health interventions . By leveraging data from a diversity of populations across the world, the IPD-MA will provide a more precise estimate of the risk of adverse ZIKV-related outcomes within clinically relevant subgroups and a quantitative assessment of the generalizability of these estimates across populations and settings. The ZIKV IPD Consortium effort is indicative of the growing recognition that data sharing is a central component of global health security and outbreak response. Aedes-aegypti endemic areas in Asia and Africa [While the world has turned to face COVID-19, recent epidemics are re-emerging . Even asd Africa . Despited Africa ,6. IdentBMJ Open (https://bmjopen.bmj.com/content/9/6/e026092).In February 2017, a group of researchers formed the ZIKV Individual Participant Data (IPD) Consortium to conduct an individual participant data meta-analysis (IPD-MA) of ZIKV-related longitudinal studies of pregnant women and their children. The ZIKV IPD Consortium initiative arose from a meeting of international organizations and Ministries of Health in June 2016 to coordinate and harmonize ZIKV-related research efforts . The resAs of August 2020, 52 cohort studies and country-level active surveillance system sites from 28 countries and territories have agreed to contribute de-identified data to the ZIKV IPD Consortium IPD-MA. The use of participant-level data from diverse geographies and populations will allow the team to better identify the clinical, virological, environmental, and individual-level factors that predict severe ZIKV-related fetal effects or adverse neurocognitive or neurodevelopmental outcomes in the child, several of which can only be measured after two years of age . For exaThe global response to ZIKV has been characterized by unprecedented levels of collaboration between countries, research organizations, universities, and surveillance systems . The ZIKWomen living in and travelling to countries with ongoing or recent ZIKV transmission face a tremendous burden from the fear and uncertainty around the risks associated with ZIKV infections during pregnancy, guidance from public health authorities to avoid or delay pregnancy, and the lack of economic and social support for the challenges of raising infants with congenital Zika syndrome (CZS) and other ZIKV-related disabilities and developmental delays ,18. ReseDespite the persistent threat of ZIKV infection to pregnant women and women of reproductive age worldwide, investment in critical areas of ZIKV research is waning. Leveraging existing investments through collaboration will accelerate the development of effective prevention, harm reduction, and control strategies. Best practices and lessons learned from the research response to ZIKV can be used to improve the coordination and speed of the global research response to emerging pathogens.Global travel, trade, urbanization, and climate change have all facilitated the development of novel hosts  and exte"}
+{"text": "Caregiving is often considered stressful, even more so if the care recipient has been diagnosed with dementia. The current study examines the rate of cognitive decline of spousal caregivers of persons with dementia (CG-D) when compared to spousal caregivers of persons without dementia (CG) before and after the death of the care recipient. Health and Retirement Study (HRS) data from 1998-2016 were used to examine cognitive trajectories of CG-D (n=364) and CG  before and after the care recipient death. Cognition was measured through the HRS\u2019s shortened Telephone Interview of Cognitive Status and separated into measures of total cognition and memory. Covariates included age, education, sex, race, ethnicity, care hours, frailty, socioeconomic status, nursing home placement of the recipient, and whether the death was expected. Piecewise mixed models were constructed to examine two two-year periods of decline leading up to the death of the care recipient, and two two-year periods of decline after the death of the care recipient. CG-D and CG declined at equivalent rates on measures of total cognition and memory (ps > .05). In all caregivers, total cognition and memory declined at a stable rate before the death of the care recipient. However, an accelerated decline was evident after the death of the care recipient (ps < .001). Our results suggest that cognitive decline is not differentially affected by care recipient dementia diagnosis. We find evidence that the death of a spousal care recipient is accompanied by hastened cognitive decline in our population-based sample."}
+{"text": "The author has undertaken multiple echocardiographic studies during his academic career; most of these were published in peer-reviewed journals. These studies include an evaluation of the role of echocardiography in the estimation of left-to-right shunt in isolated ventricular septal defects, an examination of the utility of contrast echocardiography in the diagnosis of anomalous connection of the right superior vena cava to the left atrium, a description of pitfalls in M-mode echocardiographic assessment of the aortic root in left ventricular hypoplasia syndromes, reviews of echocardiographic evaluation of left ventricular function, study of the role of contrast echocardiography in the evaluation of hypoxemia following open heart surgery, a quantification of left ventricular muscle mass by m-mode echocardiography in children, an examination of race and sex related differences in echocardiographic measurements in children, study of cardiac size and function in patients with sickle cell disease, an examination of afterload reduction in the management of primary myocardial disease, study of the utility of echo-Doppler studies in the evaluation of the results of balloon pulmonary valvuloplasty, study of the usefulness of Doppler in the prediction of pressure gradients in valvar pulmonary stenosis, a review of Doppler echocardiography in noninvasive diagnoses of heart disease, echo-Doppler studies of the evaluation of the results of balloon angioplasty of aortic coarctation, study of the value of Doppler in the prediction of pressure gradients across coarctation of the aorta, and a characterization of foramen ovale and transatrial Doppler velocity patterns in the normal fetus. When the author was named as Interim Director of Pediatric Echocardiography Laboratory at Children\u2019s Memorial Hermann Hospital/University of Texas-Houston Medical School, Houston, Texas in 2006, some of the staff critiqued this appointment, as the author was considered to be an interventionist pediatric cardiologist. The author responded to this critique by sending them a list of the his echo publications ,31,32,33At the time of the author\u2019s fellowship training in 1969/1970 at Stanford University Medical Center, Palo Alto, California, there were only two echocardiography recording machines in the United States: one was at University of Indiana, Indianapolis, Indiana and the other at Stanford University. The author was exposed to echocardiography to evaluate mitral valve motion and pericardial effusion on M-mode tracings. During subsequent fellowship training at Case-Western Reserve University and the University of California at Los Angeles, the echo machines had not yet arrived at the respective institutions. By 1972, when the author joined the Faculty at the Medical College of Georgia, Augusta, Georgia, there were indeed echocardiography facilities at that institution. Shortly thereafter, Dr. Wesley Covitz  joined our faculty at Georgia and provided the author with additional understanding of the principles and practice of M-mode echocardiography, thereby adding to the author\u2019s knowledge base. This resulted in the author\u2019s active participation in echocardiography research at that time ,4,5. Twop < 0.01) than those of control subjects , we compared the cardiac catheterization data with echocardiographic values (echo performed within 24 h of cardiac catheterization) in 35 babies; 35 children with normal hearts by physical examination and ECG were used as controls ) in the modified Bernoulli equation. Duration-related measures of Doppler flow signal distal to the coarctation site, namely, acceleration time (AT) and antegrade flow time (AFT)  , were al2) peak instantaneous and catheterization-measured peak-to-peak gradients resulted in a correlation coefficient of 0.757. (22 \u2212 V12]) in the modified Bernoulli equation (r = 0.763). A comparison of the catheterization data with antegrade flow time (r = 0.82) and antegrade flow time fraction (r = 0.737) showed marginal, if any, improvement in the correlation coefficients  following balloon angioplasty of native aortic coarctation; this was similar to reduction in peak-to-peak pressure gradients by catheterization. A discussion of possible reasons for the lack of correlation between Doppler and catheter gradients included peak-to-peak vs. peak instantaneous gradients and possible collateral vessel flow in aortic coarctation. It was concluded that (i) the magnitude and duration related Doppler velocity recordings are helpful in estimating coarctation gradients, and (ii) Doppler is useful in demonstrating the relief of obstruction by balloon angioplasty [It was further noted that the Doppler flow velocity magnitude and calculated gradients improved  in fetal circulation, the size of and shunt velocity patterns across the FO in the fetus had not been thoroughly investigated as of the mid-/late-1980s. Therefore, we endeavored to define the normal size of FO and the Doppler velocity patterns across the atrial septum in the normal fetus. Normal human fetal ultrasound studies in 48 consecutive fetuses were examined and the size of FO, foramen flap angle , its motThe maximal FO diameter was similar to the diameter of the Ao at all gestational ages ; there wOur study showed that the size of normal foramen ovale is similar to aortic root diameter, and that the foramen flap angle reaches 30 degrees or greater. Right-to-left flow is as anticipated for fetal circulatory physiology; the left-to-right flow documented in this study was unexpected and may be related instantaneous pressure difference between atria, as previously shown in patients with tricuspid atresia . These fThe author\u2019s contributions to the echocardiography literature from 1991 to the current date will be detailed in Part II of this review."}
+{"text": "Genital lesions are an unusual presentation of American cutaneous leishmaniasis. Conditions such as disseminated cutaneous leishmaniasis and HIV infection may be associated with genital involvement. The authors present five cases of American cutaneous leishmaniasis with genital lesions and discuss the clinical and epidemiological aspects observed in this case series. Leishmania transmitted by the bite of infected female sandflies, insects of the genus Lutzomyia.3American cutaneous leishmaniasis (ACL) is an infectious disease caused by protozoa of the genus DL constitutes up to 2% of ACL cases and probably occurs due to the lymphatic or hematic spread of the parasite from the bite site.4Genital lesions are an unusual presentation of ACL and suggest hematic dissemination in patients with DL or direct inoculation of the parasite in patients with isolated genital lesions who sleep naked outdoors or perform bodily functions in endemic areas of ACL without sanitary facilities.Leishmania (Viannia) braziliensiss, as all patients were inhabitants of the state of Rio de Janeiro with no recent history of travel.Although Sexually Transmitted Infections (STIs) are the main causes of penile ulcers, other conditions such as fixed drug eruption erythema, autoimmune bullous dermatoses, psoriasis, Beh\u00e7et's disease, Reiter's syndrome, pyoderma gangrenosum, lichen planus, and squamous cell carcinoma can also cause genital ulcers.ACL should be considered in the differential diagnosis of chronic genital lesions in patients who reside in or travel from endemic areas, especially when associated with mucosal lesions in UADT and multiple, polymorphic skin lesions. Furthermore, the presence of genital lesions can aid in the differential diagnosis of granulomatous diseases with similar clinical presentation, such as paracoccidioidomycosis, histoplasmosis, and disseminated sporotrichosis.Genital involvement in ACL probably occurs due to hematic dissemination in patients with DL. Therefore, ACL should be included in the differential diagnosis for patients from endemic areas with genital ulcers, especially in the presence of mucosal lesions in UADT and multiple skin lesions.Instituto Nacional de Infectologia Evandro Chagas (INI).Marcelo Rosandiski Lyra: Approval of the final version of the manuscript; conception and planning of the study; elaboration and writing of the manuscript; obtaining, analyzing, and interpreting the data; intellectual participation in propaedeutic and/or therapeutic conduct of studied cases; critical review of the literature; critical review of the manuscript.Alan Bittencourt da Silva: Elaboration and writing of the manuscript; obtaining, analyzing, and interpreting the data; critical review of the literature; critical review of the manuscriptCl\u00e1udia Maria Valete-Rosalino: Approval of the final version of the manuscript; elaboration and writing of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of studied cases; critical review of the literature; critical review of the manuscript.Maria In\u00eas Fernandes Pimentel: Approval of the final version of the manuscript; elaboration and writing of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of studied cases; critical review of the literature; critical review of the manuscript.None declared."}
+{"text": "Statistical models are increasingly being used to estimate and project the prevalence and burden of asthma. Given substantial variations in these estimates, there is a need to critically assess the properties of these models and assess their transparency and reproducibility. We aimed to critically appraise the strengths, limitations and reproducibility of existing models for estimating and projecting the global, regional and national prevalence and burden of asthma.We undertook a systematic review, which involved searching Medline, Embase, World Health Organization Library and Information Services (WHOLIS) and Web of Science from 1980 to 2017 for modelling studies. Two reviewers independently assessed the eligibility of studies for inclusion and then assessed their strengths, limitations and reproducibility using pre-defined quality criteria. Data were descriptively and narratively synthesised.We identified 108 eligible studies, which employed a total of 51 models: 42 models were used to derive national level estimates, two models for regional estimates, four models for global and regional estimates and three models for global, regional and national estimates. Ten models were used to estimate the prevalence of asthma, 27 models estimated the burden of asthma \u2013 including, health care service utilisation, disability-adjusted life years, mortality and direct and indirect costs of asthma \u2013 and 14 models estimated both the prevalence and burden of asthma. Logistic and linear regression models were most widely used for national estimates. Different versions of the DisMod-MR- Bayesian meta-regression models and Cause Of Death Ensemble model (CODEm) were predominantly used for global, regional and national estimates. Most models suffered from a number of methodological limitations \u2013 in particular, poor reporting, insufficient quality and lack of reproducibility.Whilst global, regional and national estimates of asthma prevalence and burden continue to inform health policy and investment decisions on asthma, most models used to derive these estimates lack the required reproducibility. There is a need for better-constructed models for estimating and projecting the prevalence and disease burden of asthma and a related need for better reporting of models, and making data and code available to facilitate replication. Resources are limited and health system planners need to make investment decisions based on available evidence of disease prevalence, associated morbidity and health care utilisation, mortality and costs, how these are likely to have the potential to change over time and their amenability to interventions -8. ModelFocusing specifically on estimates of asthma prevalence and burden, we observe that varying estimates have been reported in the published literature at national, regional and global levels, which are not consistent over the years  and published in any language. Our outcomes of interest were the prevalence of asthma and different components of the disease burden of asthma. The components of disease burden were direct and indirect costs of asthma , disability-adjusted life years (DALYs), years lived with disability (YLDs), years of life lost (YLLs), potential years of life lost, healthy years of life lost, active life expectancy, disability-free life expectancy, disability-adjusted life expectancy, and healthy life expectancy (HALE).We identified relevant published and unpublished studies through searching electronic databases, hand-searching of pertinent journals and checking reference lists of all the eligible papers for studies published between January 1980 and September 2017. The following electronic databases were searched: Medline, Embase, World Health Organization Library and Information Services  and Web of Science Core Collection. Journals that were hand-searched included The Lancet, BMJ (1980-2017), European Respiratory Journal (1988-2017), Lancet Respiratory Medicine (2013-2017), Lancet Global Health (2013-2017) and Journal of Global Health (2011-2017). We ran the last searches on 16 September 2017. We included papers published in any language and translated the papers that were not in English with the help of fluent or native speakers.Comprehensive search strategies were developed for all the aforementioned databases in consultation with a senior medical librarian at The University of Edinburgh to identify both published and unpublished (grey literature) primary studies as well as reviews. The search terms used included but were not limited to asthma, wheeze, epidemiology, prevalence, burden, morbidity, mortality, DALY, QALY, HALE, primary health care, emergency service, hospitalisation, absenteeism, cost of illness, model, estimate, projection. The detailed search strategies used to search each database are given in Appendix S1 in the Two reviewers independently checked and screened the titles and abstracts of identified articles against the inclusion criteria. Full-text copies of potentially eligible studies were obtained and assessed by two independent reviewers (MRB and MAI) on the basis of the inclusion criteria. Discussion between the two reviewers resolved the majority of discrepancies; a third reviewer (BIN) arbitrated in the case of any disagreements.We developed a data extraction form and used it to extract relevant data from included studies. The data extraction form was piloted on 10 included studies and was then refined accordingly prior to full use in the review. Data extraction was performed independently by two reviewers (MRB and MAI). Any discrepancies in data extraction were resolved through discussion between the reviewers, with arbitration by a third reviewer (BIN) if a decision could not be reached.The following data items were extracted from each paper: 1) study identification ; 2) aims and methods of the study ; 3) model information .As this review mainly focused on the properties of models rather than quantitative measures, we did not perform any quantitative synthesis of the data.We produced a tabular summary of the data to summarise the overall evidence. Descriptive statistics and graphical presentation were used to summarise the results. A detailed critical narrative synthesis of the models was undertaken regarding their strengths, limitations and reproducibility.To our knowledge, there is no existing quality appraisal tool to assess the quality of the components of models for estimating the prevalence and burden of diseases. We therefore developed our own model evaluation checklist by adapting relevant sections from pertinent critical appraisal checklists ,23, repoOur checklist consists of 13 quality criteria that a model should possess. We present the checklist by a pyramid in This systematic review is reported following the guidelines of the Preferred Reporting Items for Systematic review and Meta Analysis (PRISMA) checklist .Our electronic search of the databases yielded a total of 23\u2009571 references. After removing duplicates, 18\u2009502 study titles and abstracts were screened against our inclusion criteria. Among these, 287 full-text articles were assessed in detail. Finally, 92 papers met the inclusion criteria. An additional 16 papers identified from hand-searching of journals and scrutinising reference lists of included studies met the inclusion criteria. Therefore, a total of 108 studies were included in the systematic review. The PRISMA flow diagram of the selected papers is presented in We identified 94 studies that estimated the prevalence and burden of asthma at a national level; two at a regional level; seven at both global and regional levels; and five at global, regional and national levels ; two models were used to derive regional level estimates; four were used for global and regional estimates; and three models were used to derive global, regional and national estimates  studies ,35-127 pMost studies failed to fulfil two internal model quality criteria and all the external criteria. Sixty-two 57.4%) studies ,127-129 .4% studiWe found only 20 (18.5%) studies ,117,122 Further analysis, assessing whether the included studies adhered the new Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER)  showed tThis systematic review of the international literature has found that a variety of models are used to estimate disease prevalence and burden; most models, however, suffer from methodological limitations, in particular, lack of reproducibility and sub-optimal reporting.Almost all the studies provided a clear statement about the questions that the models aimed to answer. The majority of the studies described the structure of the models explicitly; mentioned the methods used to fit the models or used to estimate model parameters; and applied appropriate modelling tools to deal with the nature, distribution and type of input data. These were the strengths of the models. However, these models had substantial limitations. We observed a lack of clarity in reporting the models. The majority of the studies did not provide any information on the model assumptions, methods of model building, methods of model diagnosis, methods of handling missing data, model validation and sensitivity analysis. In addition, many studies did not adequately present the final model parameter estimates, standard errors and confidence intervals. Moreover, most of the models could not be reproduced as the studies did not provide input data , computer coding, a model fitting manual or complete information about the process of model formulation.The main strengths of this review include the comprehensive search strategy employed, the use of established methodology  and the inclusion of studies from all over the world including studies published in any language. Critical appraisal of identified models and expert involvement in developing model assessment tools further strengthened the credibility of this review. However, this review has a number of potential limitations. As with any systematic review, we may have missed some studies. Although risk factor based models or association models are particularly essential to assess determinants of a disease, we did not include studies that used models to estimate risk factors or to assess association rather than estimating prevalence and disease burden using model. The use of a self-developed customised model evaluation tools, due to the lack of appropriate critical appraisal checklist, may be considered to be a further limitation of this review. There is a need for the development of an internationally standard tool that will be used for the purpose.This systematic review is the first to synthesise models for prevalence and burden of asthma in the context of national, regional and global estimates and projections. Previous systematic reviews on disease modelling studies were mainly undertaken on other domains, such as prediction models -139, ecoExisting estimates are heavily reliant on modelling studies due to lack of data on direct measurements of asthma cases in many countries and regions. Whilst these modelling studies have advanced better understanding and appreciation of the burden of different diseases, the lack of reproducibility of the models, as highlighted in this review, requires concerted effort from researchers and decision makers to set in place platforms that will ensure that estimates of disease burden produced can be reproduced. Policymakers should thus be aware of the transparency of modelling processes and the reliability of the input data when making decisions on the basis of these model-based estimates.The findings of this review suggest that models should be carefully designed to incorporate all the necessary methodological components required to develop a robust model, including an explicit statement about the purpose and structure of the model; statement of necessary model assumptions; variable selection applying appropriate techniques; model diagnostic accuracy checking; assessing goodness-of-fit; addressing missing data by applying suitable techniques; applying optimum methods of parameter estimation; carrying out sensitivity analysis; and performing both internal and external model validation. Besides, a highly complex model usually lacks understanding, usability, reproducibility and, hence, credibility. While publishing models, sufficient information about the complete modelling process, therefore, should be reported to facilitate its understanding and usability for non-technical audiences. For example, a model development manual should be made publicly available, including input data and necessary computer code, to describe the step-by-step process of model development with illustrative examples. Although the perspectives of this review are prevalence and disease burden of asthma, these recommendations also apply to the modelling prevalence and burden of other chronic diseases.Future research could potentially be undertaken to develop consensus guidelines for developing or fitting and reporting models for prevalence and burden of diseases. Moreover, developing a critical appraisal checklist for assessing the quality of models for prevalence and burden of diseases is another key area for future research.Of the available approaches, we found the Bayesian meta-regression method- DisMod-MR, DisMod-MR 2.0, DisMod-MR 2.1 and CODEm ,9,14,17 Amidst data types and their sources, modelling remains indispensable for estimating the prevalence and burden of disease. This evidence synthesis has shown that existing models that have been applied to estimate the prevalence and burden of asthma suffer from methodological limitations, in particular, suboptimal reporting and lack of reproducibility. There is a need to enhance the reportage of models used for estimating and projecting the prevalence and disease burden of asthma and making data and code available to facilitate replication. Moreover, there is also a need for developing better-constructed asthma-specific models in an attempt to produce more accurate and consistent estimates. In the interim, we suggest using Bayesian meta-regression models and cause of death ensemble models for estimating national, regional and global prevalence and burden of asthma, and Box-Jenkins regression- autoregressive integrated moving average (ARIMA) model to make projections in relation to these estimates. We also suggest to validate the Bayesian meta-regression models against their alternative frequentist or classical models to check which modelling approaches generate better estimates of prevalence and burden of asthma than the others."}
+{"text": "Aedes aegypti. Especially in the tropics, inefficacy of mosquito control causes arboviruses outbreaks every year, affecting the general population with debilitating effects in infected individuals. Several strategies have been tried to control the proliferation of A. aegypti using physical, biological, and chemical control measures. Other methods are currently under research and development, amongst which the use of nanotechnology has attracted a lot of attention of the researchers in relation to the production of more effective repellents and larvicides with less toxicity, and development of rapid sensors for the detection of virus infections. In this review, the utilization of nano-based formulations on control and diagnosis of mosquito-borne diseases were discussed. We also emphasizes the need for future research for broad commercialization of nano-based formulations in world market aiming a positive impact on public health.Arboviruses such as yellow fever, dengue, chikungunya and zika are transmitted mainly by the mosquito vector  Aedes aegypti and Aedes albopictus are the most important global vectors of arboviruses, such as dengue, yellow fever, chikungunya, and zika viruses  is often late, ineffective, and dependent on the clinical symptoms. The final decision on the infection generally requires a long waiting time, collection of samples from suspected patients , transportation and preservation, and laboratory procedures by trained health staff.Rapid diagnosis of important arboviruses-borne diseases such as dengue, chikungunya, zika, and yellow fever is essential in order to reduce and avoid further dissemination of the infections within the general population  Sethi, . These rSeveral recent studies have used mainly LFAs as the basis for the construction of ASSURED biosensing devices. These assays can be performed using microfluidic technologies such as paper-based miniaturized devices that combine several recognition steps in a small area for naked-eye detection and quantification of compounds in complex mixtures, with the sample being collected on a test device and the results being displayed in real time  bound covalently to the surface of one or more carbon nanotubes and/or metal nanoparticles present on part of a microelectrode surface, together with an electrically conducting part where a transduction system (sensor) converts the biochemical response into an electric signal . Encapsulation also protects the active agent against premature degradation caused by the effects of light, temperature, oxidation, and humidity, among others , average size around 100\u2013200 nm, zeta potential around\u221240 mV. Both encapsulated EOs reached lethal dosages within 24 h of exposure and total mortality of the tested pests , with the chitosan-based formulations having the best effects. These findings demonstrated the potential of polymeric nanoparticles containing essential oils for use as eco-friendly larvicidal products  for the encapsulation of essential oils (geranium and bergamot). Evaluation was also made of the acute and residual larvicidal activities of the formulations against Piper aduncum L. and Piper hispidinervum C. in gelatin nanoparticles, with evaluation of the biological effects against Aedes aegypti. The encapsulation efficiencies exceeded 80%, and the particles were spherical, monodispersed, and smaller than 100 nm in size. Both of the encapsulated essential oils provided lethal effects within 24 h of exposure, with Aedes aegypti mortality greater than 80%  and nanoemulsions containing citronella and neem oil, for the control of insects such as Aedes aegypti. The results showed that both the nanoemulsions and the NLCs loaded with the essential oils caused 100% mortality of A. aegypti larvae during the first day of exposure, while the NLCs without essential oil induced 100% mortality after 10 days of exposure. Both carriers showed satisfactory efficacy in the control of A. aegypti larvae  synthesized using an aqueous extract of Euphorbia hirta leaves against the larvae of Aedes aegypti (LC50 = 13.2 mg/L) and Culex quinquefasciatus (LC50 = 6.89 mg/L) (Udayabhanu et al., Recent studies have reported the synthesis of various nanoparticles using different natural extracts, with demonstration of the larvicidal, ovicidal, and mosquiticidal activities of these nanoparticles. Udayabhanu et al. observed the larvicidal effect of titanium dioxide nanoparticles (TiOQuisqualis indica plant showed high toxicity against the vectors of filariasis, zika virus, and malaria. In addition, toxicity tests employing three non-target organisms indicated low toxicity of these systems (Govindarajan et al., Another study proposed the green synthesis of Ag NPs for use as an environmentally-friendly alternative to pyrethroid and carbamate larvicides. Silver nanoparticles synthesized from extracts of the The patent databases include inventions that describe methods of green synthesis of metal nanoparticles and metal oxides, with broad applications in consumer products, medicines, pharmaceuticals, and other biomedical products (Hoag et al., The potential application of nano-based formulations in the field of arboviruses management was investigated by analyzing the number of publications in the last ten years. The results revealed that around 1000 articles were published worldwide, which an exponential trend in publication numbers after 2016, mainly for researches related to zika and chikungunya. Overall, many publications have shown that nanotechnology has led to rapid advancements in the development of pesticides, repellents, drug delivery system and diagnostic devices for arboviruses management. However, the clinical translational of nano-based formulations has some bottlenecks that hinders the broad acceptance and commercialization of these products (Hua et al., Much debate still exists regarding the legislation of nanomaterials, which is in an early stage of development. In addition, there is a lack of a clear definition of nanomaterials, lack of standard methods for assessment of pharmacology, toxicology and efficacy evaluation of nano-based formulations and lack of worldwide network for gathering and sharing pertinent information. According to Schnell-Inderst et al.  12% of tAlso, economic issues can limiting the broad commercialization of nano-based formulations Ventola, . In compAedes aegypti-borne diseases.As conclusion, as indicated in this review, it is important to learn and appreciate the great potential offered by nanotechnology in relation to the development of new and more efficient tools and products. In this regard, it is extremely important that ongoing research involves all sectors: academia, industries, research centers, and government agencies, in order to turning this technology into a sustainable commercial reality and to create alternatives for detection and control of EC, JO, and LF proposed the structure of the manuscript. EC, JO, DA, CR, CB, VM, and RM wrote the manuscript. EC and LF revised the manuscript. All authors read and approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Addressing the psychological mechanisms and structural inequalities that underpin mental health issues is critical to recovery following disasters and pandemics. The Asia Pacific Disaster Mental Health Network was established in June 2020 in response to the current disaster climate and to foster advancements in disaster-oriented mental health research, practice and policy across the region. Supported by the World Health Organization (WHO) Thematic Platform for Health Emergency and Disaster Risk Management , the network brings together leading disaster psychiatry, psychology and public health experts. Our aim is to advance policy, research and targeted translation of the evidence so that communities are better informed in preparation and response to disasters, pandemics and mass trauma. The first meetings of the network resulted in the development of a regional disaster mental health agenda focused on the current context, with five priority areas: (1) Strengthening community engagement and the integration of diverse perspectives in planning, implementing and evaluating mental health and psychosocial response in disasters; (2) Supporting and assessing the capacity of mental health systems to respond to disasters; (3) Optimising emerging technologies in mental healthcare; (4) Understanding and responding appropriately to addressing the mental health impacts of climate change; (5) Prioritising mental health and psychosocial support for high-risk groups. Consideration of these priority areas in future research, practice and policy will support nuanced and effective psychosocial initiatives for disaster-affected populations within the Asia Pacific region. Disasters create an environment of disruption, trauma and grief, with potential for sustained mental health impacts. Heightened stress during pandemics and disasters can impair individual wellbeing , cognitive function , high-risk behaviours  and behavioural outcomes  ,2. The mThe Asia Pacific region records the highest frequency of hazards and greatest number of people affected by disasters annually ,10. The In response, the Asia Pacific Disaster Mental Health Network was established in June 2020 to create a collaborative platform for rigorous research, evidence-based practice and tailored policy designed to support improvements in mental health among disaster-affected communities. The network is supported by the World Health Organization (WHO) Thematic Platform for Health Emergency and Disaster Risk Management  and its research network . At its The Asia Pacific Disaster Mental Health Network comprises fifteen representatives , selected for their expertise in responding to health emergencies and natural disasters, and work with trauma-affected communities within the region. The network is open to all Asia Pacific nations and currently includes representatives from Australia, Japan, China, Nepal, Sri Lanka, India and the USA. The purpose of the network\u2019s early meetings was to establish a collaborative platform for future research and policy development and set overarching priorities in line with the goals of the WHO Thematic Platform for Health EDRM and its research network. Monthly meetings are conducted via videoconference. The selection of research priorities was conducted through open consultation within the network. An iterative-generative reflective method was adopted, whereby experiential knowledge of network members gleaned through their immersion with affected communities allowed for iterative debate . As reflLarge-scale climate disasters, severe wildfires and the COVID-19 pandemic have drawn renewed global attention to disaster response this year. The COVID-19 pandemic has amplified the structural injustices of race, faith, gender, age, migration and economic inequality within and across societies, with significant implications for mental health (e.g., ,16,17,18Reinforcing local social networks, social solidarity and engagement with community groups in responding to disasters and other mass trauma events will enhance psychosocial outcomes ,25,26. CDisasters create multiple waves of healthcare need. Early response requires a focus on physical injuries, bereavement and re-establishing critical infrastructure for survival . EstabliThe COVID-19 pandemic has fast-tracked the development and widespread adoption of technology in mental healthcare in many settings. Digital mental health services include treatment sessions conducted via video call, telephone helplines, clinical text messaging services, digital health applications and platforms, online streaming and therapy services and mass dissemination of mental health resources on social media ,46. EnabClimate change has increased the frequency and severity of natural disasters in the Asia Pacific region, with resulting risks for mental health problems ,56,57. THigh-risk groups, including those disadvantaged or discriminated against due to the characteristics and intersection of age, gender, sexuality, ethnicity, faith, ability, migration and economic status, may be at greater risk of mental health difficulties during and after disasters ,64. In aThe Asia Pacific Disaster Mental Health Network was established to foster advancements and coordination of psychosocial supports and mental health service delivery, policy development and collaborative research in the region. In line with the priorities of the WHO Thematic Platform for Health EDRM and its research network ,72, the"}
+{"text": "Despite the recent advances in treatment, antineutrophil cytoplasmic antibody (ANCA) associated vasculitides (AAV) are among the rheumatic diseases with the highest morbidity and mortality. These outcomes are affected by a variety of factors apart from the disease itself, and are driven by infections, cardiovascular disease and drug toxicity. Even after the induction of remission, patients and their treating physicians are challenged by frequent relapses, accrual of chronic damage and impaired quality of life. Given their rarity along with their heterogeneous disease spectrum, patient registries are of utmost need for the study of all aspects of AAV. Already established AAV registries have a significant contribution in the apprehension of these diseases outside the strict context of clinical trials, and are becoming increasingly important as new drugs and treatment strategies are about to be introduced in daily practice. We here describe the design of a contemporary, web-based and easy-to-use patient registry specifically for patients with AAV, including all the necessary domains suggested by international working groups. This project is anticipated to contribute in better understanding of AAV in our country, with a future prospect of contributing to and sharing data with other international registries. B-cell depletion (rituximab) is considered a first line therapy for induction and maintenance of remission in patients with GPA and MPA today.5 However, new issues have emerged, given the similar rates of serious infections with cyclophosphamide-based regimens,4 optimal (regular versus biomarker-tailored) dosing, and the management of patients who relapse while on treatment. Significant research projects on AAV are ongoing or recently completed and published, investigating the role of the novel oral, selective C5a receptor inhibitor avacopan as a steroid-sparing agent6 or clarifying the exact role of plasma exchange and lower dose corticosteroids during induction of remission.7Antineutrophil cytoplasmic antibody (ANCA) associated vasculitides (AAV) include granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA) and carry the highest mortality and morbidity among systemic vasculitides. Even when aggressively treated with glucocorticoids (GCs) and traditional immunosuppressives, mortality is still high (~25% at five years).2 especially in patients with lung involvement, positive PR3 autoantibodies, and high damage index, while it has been shown that the number of relapses correlates with the development of chronic lesions. Prevention, early diagnosis and management of vasculitis-associated damage have been recognised as of paramount importance. Damage in ANCA vasculitis occurs early in the course of the disease, varies according to the type of vasculitis, is correlated with both the disease itself and the treatment the disease itself and the treatment, and significantly affect prognosis.8Nevertheless, the impact and uptake of these promising strategies will need to be studied in real-life settings outside the strict boundaries of clinical trials. Although current therapeutic regimens induce remission in the great majority of patients (70\u201390%), disease relapses are quite common (~40% in 5 years),There are limited data in the literature regarding the long-term prognosis, comorbidities and mortality of patients with AAV in daily clinical practice, outside randomised trials and their extensions. Moreover, the complexity of these diseases in terms of differential diagnosis, the need for interdisciplinary collaboration, the treatment and assessment of outcomes and the long-term vigilance for relapses makes the management of AAV patients quite cumbersome. Due to the rarity of the disease, establishment of patient registries are crucial for the better understanding of the natural course of AAV and, interestingly, registries are one of fields of interest of the EUVAS Research Council along with disease assessment, biomarker studies, epidemiology and aetiology, clinical trials, genetics, toxicity and infection, database, and histology.9 Furthermore, the working group proceeded in the development of AAV-specific patient-reported outcome (PRO) after taking into account and incorporating patients\u2019 perceptive of the impact of the disease on quality of life (AAV-PRO)10 and the implementation of these tools in registries of real-life patients is imperative. Recently, patient registries across Europe and the United States have provided useful information in that direction. Most of these registries are web-based, and this design enables easy access and data entry of participating centers.11The OMERACT (Outcome Measures in Rheumatology) Vasculitis Working Group has recently proposed a core set of outcome measures in AAV research in order to align data collection and assure homogeneity of different datasets. This set includes at least assessment of disease activity, damage, patient-reported outcomes and mortality.To design and establish a Greek Registry, where patients with AAV  will be registered and prospectively followed. Candidate participating centres will be rheumatology, nephrology and pulmonary clinics or departments with an expertise in the clinical care of patients with AAV.The registry will include patients with GPA, MPA and EGPA that fulfil 2012 Chapel Hill Consensus Conference Disease Classification Criteria. Patients will be registered irrespective of their age, in order for rare cases of paediatric patients with ANCA vasculitis to be included. Informed consent will be obtained from all study subjects. Patients will be retrospectively and prospectively registered and evaluated at baseline, then every 6 months or at relapse (confirmed or suspected), and data will be entered into an electronic web-based platform. For any new registration, the user will be asked to enter epidemiologic data, a clinical assessment of disease activity  and severity/chronicity (VDI), patient-reported outcomes (AAVPRO), comorbidities, hospitalisations (except from those caused by infections), infections (irrespective of severity), laboratory measurements, biopsy and imaging reports and medications. Especially for hospitalisations, infections and medications, universal coding is used to assure optimal data entry. In addition, biologic samples storage (Biobank) is designed, including information on storage of peripheral blood, serum, PBMCs, mRNA in order to enable future biomarker- or basic research projects.AAV are a diverse group of diseases that, although rare, carry high mortality and morbidity and several unmet needs. This study is anticipated to reflect the current clinical and laboratory spectrum of patients with AAV in Greece, to describe treatment regimens currently used and compliance of treating physicians with guidelines, to document rates of chronic lesions and complications related to disease itself or immunosuppressive therapy, to assess efficacy, tolerance and complications of novel biologic agents, and create a biobank of biologic samples from different phases of the disease. Finally, a significant prospect of this study includes the future incorporation of this registry with similar international ones and its participation in multicentre studies held by the vasculitis community."}
+{"text": "Generalized Structural Equation Modeling (GSEM) in prediction of injury leading to motorcyclist hospitalization: a case-control study Abstract Background and Objectives: Given that the SEM model includes both structural and measurement models, It is also a method for the exact test of theoretical models and is very useful for causal modeling. The purpose of the present study is to investigate the predictors of injuries caused the hospitalization of motorcyclists using a Generalized Structural Equation Modeling (GSEM) with mediator in a case-control study.In this case-control study, 300 cases and 156 controls were selected from 150 clusters using a cluster random sampling in Tabriz, Iran. Using of motorcycle-riding behavior questionnaire (MRBQ), Attention-deficit/hyperactivity disorder (ADHD). The GSEM model was used to examine the linear direct and indirect linear relationships of variables in the conceptual model and considering the binary response variable of the model. Also, MRBQ were considered as a mediator variable for the underlying and ADHD and Data analysis was performed by STATA14 software.The predictors of injury were: MRBQ, ADHD and Demographic, The results indicated significant linear and direct relationships between odds of injury and cell phone answering , hyper active child , dark hour riding  and MRBQ , while significant inverse relation between injury and being married, academic education .Based on the results GSEM model, Due to the significance of the variables, having intervention programs, on the ADHD, and those who answer their cell phones while driving, and dark hour riding is highly recommended.SEM, GSEM, Traffic, Injury, MRBQ, ADHD"}
+{"text": "Staphylococcus aureus (MRSA) across the human, animal and environmental compartments in East Africa.The emergence and spread of antimicrobial resistance (AMR) present a challenge to disease control in East Africa. Resistance to beta-lactams, which are by far the most used antibiotics worldwide and include the penicillins, cephalosporins, monobactams and carbapenems, is reducing options for effective control of both Gram-positive and Gram-negative bacteria. The World Health Organization, Food and Agricultural Organization and the World Organization for Animal Health have all advocated surveillance of AMR using an integrated One Health approach. Regional consortia also have strengthened collaboration to address the AMR problem through surveillance, training and research in a holistic and multisectoral approach. This review paper contains collective information on risk factors for transmission, clinical relevance and diversity of resistance genes relating to extended-spectrum beta-lactamase-producing (ESBL) and carbapenemase-producing Enterobacteriaceae, and Methicillin-resistant blaCTX-Ms (45.7%), SCCmec type III (27.3%) and IMP types (23.8%), respectively.The review of the AMR literature (years 2001 to 2019) was performed using search engines such as PubMed, Scopus, Science Direct, Google and Web of Science. The search terms included \u2018antimicrobial resistance and human-animal-environment\u2019, \u2018antimicrobial resistance, risk factors, genetic diversity, and human-animal-environment\u2019 combined with respective countries of East Africa. In general, the risk factors identified were associated with the transmission of AMR. The marked genetic diversity due to multiple sequence types among drug-resistant bacteria and their replicon plasmid types sourced from the animal, human and environment were reported. The main ESBL, MRSA and carbapenem related genes/plasmids were the The high diversity of the AMR genes suggests there may be multiple sources of resistance bacteria, or the possible exchange of strains or a flow of genes amongst different strains due to transfer by mobile genetic elements. Therefore, there should be harmonized One Health guidelines for the use of antibiotics, as well as regulations governing their importation and sale. Moreover, the trend of ESBLs, MRSA and carbapenem resistant (CAR) carriage rates is dynamic and are on rise over time period, posing a public health concern in East Africa. Collaborative surveillance of AMR in partnership with regional and external institutions using an integrated One Health approach is required for expert knowledge and technology transfer to facilitate information sharing for informed decision-making. Staphylococcus aureus (MRSA) and extended spectrum beta-lactamase (ESBL)-producers. For instance, MDR invasive non-typhoidal Salmonella (iNTS) disease poses a major challenge to the clinical management of infections in resource-limited settings especially as alternative more effective antibiotics remain either unaffordable or simply unavailable for majority of patients , ESBL and MRSA , ESBL (13.1%), and MRSA (24.25%) were reported in studies conducted from 2013 to 2016, 2009\u20132012, and 2013\u20132016 respectively. The rise of ESBL, CAR, and MRSA carriage rates in East Africa pose a threat to public health particularly in the geographical areas where the rates are very high. A limitation of this analysis is the fact that these data were collected from unlinked cross-sectional studies conducted in different geographical areas in East Africa; consequently, some important information may have been missed.Figure\u00a0The genetic diversity at antibiotic resistance loci could determine a population\u2019s capacity to cope with future challenges of the antimicrobial drugs used for infection control . The genThe high MRSA carriage rates among patients and health workers in the East Africa is a concern given poor infection prevention and control measures in our settings . In KenyE. coli in humans, animals and their environments are conducted by postgraduate students of the SACIDS Foundation for One Health at the Sokoine University of Agriculture and Muhimbili University of Health and Allied Sciences in Tanzania. This work is attempting to understand the transmission dynamics of AMR genes and their virulence [The World Health Organization, the Food and Agriculture Organization of the United Nations and the World Organization for Animal Health has advocated for a holistic and multisectoral approach to address the AMR problem. This has been strengthened by the collaboration of regional consortia involving local and regional academic and research institutions in Africa, and a joint dedication of efforts to fight against infectious diseases in animals, humans and their environments. Regional consortia such as the SACIDS Foundation for One Health in collaboration with the London School of Hygiene and Tropical Medicine, London International Development Centre, Royal Veterinary College, Chatham House of the Royal Institute of International Affairs in the United Kingdom and the American Society of Microbiology of the United States, have partnered to address AMR problem through research and training. Strategically, surveillance is being supported by phenotypic and genomic data, to understand the flow of resistomes across human, animal and environmental compartments. For instance, research programs focused on genomic epidemiology of ESBLs producing irulence , and wilThe implementation of effective and sustainable AMR surveillance programmes in Africa is hampered by a lack of infrastructure and other resources required to perform optimal surveillance . Most laThe high genotypic diversity of the AMR genes among the bacterial isolates might suggest possible exchange of strains or a flow of genes among different strains due to transfer by mobile genetic elements or multiple sources of resistance bacteria. Such levels of diversity prompt the calling for immediate interventions, including guidelines concerning antibiotics use and regulations governing their importation and sale. However, antibiotic use and regulation is likely to be a very complex system because other factors such as cultural and ecological conditions favour transmission of bacteria. There is a high likelihood that people will have AMR bacteria irrespective of how antibiotics are used. Therefore, control strategies against AMR need to be tailored, beyond antibiotic use and availability, to local practices that affect bacterial transmission. Moreover, the trend of ESBL, MRSA and CAR carriage rates is dynamic and are on rise over time period, posing a public health concern in East Africa. In addition to that, phenotypic and genotypic drivers of AMR should be investigated within an integrated One Health framework. Such investigations will inform transmission dynamics of resistomes across compartments, and facilitate information sharing for informed decision making; ultimately, reducing the spread of AMR genes in bacteria. Further, the application of advanced techniques such as whole genome sequencing for detection of AMR could cut a bridge between clinical research and care, so that case management and treatment decisions can be informed and personalised."}
+{"text": "Cells show an impressive range on the pathophysiological relevance of ROS and RNS, including the relevance of second messengers of free radicals like 4-hydroxynonenal, allowing us to assume that the future will reveal even more detailed mechanisms of their positive and negative effects that might improve the monitoring of major modern diseases, and aid the development of advanced integrative biomedical treatments. Our common knowledge on oxidative stress has evolved substantially over the years, being focused mostly on the fundamental chemical reactions and the most relevant chemical species involved in human pathophysiology of oxidative stress-associated diseases. Thus, reactive oxygen species and reactive nitrogen species (ROS and RNS) were identified as key players in initiating, mediating, and regulating the cellular and biochemical complexity of oxidative stress either as physiological (acting pro-hormetic) or as pathogenic (causing destructive vicious circles) processes. The papers published in this particular Special Issue of  Cells is to cover broad aspects of these important scientific areas, still focusing on the cellular level. However, since many disorders are based on altered cellular functions involving interactions of reactive oxygen species (ROS) and reactive nitrogen species (RNS) with macromolecules, in this Special Issue we also try to tackle physiological and pathological aspects of cellular ROS and RNS related to specific cellular processes affecting the entire organism.For decades, free radicals were mostly considered as harmful molecules that contribute to the toxic, mutagenic, and carcinogenic bioactivities of different chemical and physical stressors. However, after hydrogen peroxide and nitric oxide were found to have multiple, often cell-type and dose-dependent effects, the new era of interdisciplinary molecular biosciences and translation medicine made significant progress in studies on the pathophysiology of oxidative stress and associated disorders. Therefore, the major goal of this Special Issue of .), known for its ability to damage almost any biomolecule, induce lipid peroxidation, and cause DNA strand breaks i) and the secretion of vonWillebrand factor (vWF) in human umbilical vein endothelial cells (HUVECs), and on the relaxation of rat aorta in response to histamine. They found that VAS2870 attenuated histamine-induced secretion of vWF, although it did not inhibit its basal secretion. However, VAS2870 did not change the degree of histamine-induced relaxation of rat aortic rings constricted by norepinephrine. In accordance, the authors suggest that NOX inhibitors might be useful as a tool for preventing deep vein thrombosis induced by histamine release from mast cells without affecting vasorelaxation, which, of course, requires intense additional studies, both in vitro and in vivo.The association of inflammatory factors, such as histamine, and the onset of oxidative stress affecting the blood vessels was studied by P. Avdonin et al. . In partThe association between oxidative stress and the functional activities of blood vessels is usually addressed in terms of tackling the onset and progression of atherosclerosis. Therefore, S. Fiorelli et al. analyzed the oxidative stress from the aspects of the Nrf2/HO-1 axis in monocyte-derived macrophages (MDMs) obtained from healthy subjects and from patients with coronary artery disease (CAD), in relation to coronary plaque features evaluated in vivo by optical coherence tomography (OCT) . They fo2+ imbalance and mitochondrial membrane depolarization was attenuated by IH, which also reduced the I/R-induced Ca2+ overload. Moreover, IH increased the expression of superoxide dismutase (SOD), notably of Cu/Zn SOD and Mn SOD, the total antioxidant capacity, and the activity of catalase, suggesting that IH may indeed protect the cardiomyocytes against H2O2- and I/R-induced oxidative stress, maintaining Ca2+ homeostasis as well as the mitochondrial membrane potential and upregulation of antioxidant enzymes.The frequent consequences of atherosclerotic changes affecting coronary blood vessels are ischemia and reperfusion of the heart, i.e., induced oxidative stress of the cardiac muscle cells. However, there are indices suggesting that short-term intermittent hypoxia (IH), similar to ischemia preconditioning, could be beneficiary, and even cardioprotective. This phenomenon was focused on in the research produced by K.T. Young\u2019s group . Aiming Cells deals with novel and challenging topic of oxidative stress modulation as an option to regulate the healing of soft-tissue wounds or even bone fractures [The last paper of this Special Issue of ractures . Thus, Eractures . The autractures . Thus, tractures . In the ractures . Cells show an impressive range on the pathophysiological relevance of ROS and RNS, including the relevance of second messengers of free radicals like 4-HNE, allowing us to assume that the future will reveal even more detailed mechanisms of their positive and negative effects that might improve the monitoring of major modern diseases and the development of advanced integrative biomedicine treatments. Observed together, the papers published in this particular Special Issue of"}
+{"text": "Sodium hyaluronate eye drops are frequently prescribed for dry eye disease in South Korea.This study analyzed the trends in the utilization of sodium hyaluronate eye drops and evaluate the impact of the introduction of high-priced disposable forms in the South Korean market.The yearly claims data for sodium hyaluronate eye drops from 2002 to 2015 were retrieved from the National Health Insurance Service-National Sample Cohort. Prescriptions of sodium hyaluronate eye drops were sorted by the characteristics of patients and health care institutions.The number of prescriptions has continuously increased and the share of disposable forms in total prescriptions reached 37% in 2015. Particularly, the prevalence of prescriptions  has increased during the study period from 2,562/100,000 persons in 2002 to 14,732/100,000 persons in 2015, while the incidence of prescriptions (new users) has remained steady during the study period, approximately 3,500/100,000 persons. More female patients were noted in terms of general users and new users, and the proportion of male patients was higher in new users than in general users. The average age of general users increased during the study period, while that of new users slightly decreased. Finally, the distribution of prescription category was significantly different between sex and age groups in frequently prescribed users.Eye drops in disposable forms, which are safe and more convenient to use, have expanded the market in South Korea and caused equity issues in utilization. Thus, the utilization of eye drops should be closely monitored from the perspectives health equity. Dry eye disease (DED) is the most common ocular disease causing patients to visit ophthalmology clinics . DED is The management of DED is complicated due to the multifactorial characteristics of DED, and the aim of DED management is to restore the homeostasis of the ocular surface and tear film . Thus, aIn South Korea, sodium hyaluronate eye drops are prescribed for patients with corneal epithelial disorders caused by endogenous and exogenous diseases and are reimbursed under the National Health Insurance Services (NHIS). Endogenous diseases include Sj\u00f6gren's syndrome, cutaneous mucosal syndrome (Steven-Jones syndrome), and dry eye syndrome, while exogenous diseases are caused by surgery, chemicals (including drugs), or the wearing of contact lenses. The majority of these patients are prescribed eye drops for dry eye syndrome . CurrentOphthalmic preservatives have been recognized as a risk factor for corneal and conjunctival inflammation, indicating that preservative-free eye drops reduce iatrogenic dry eye . Thus, cThis study has two aims. First, we will analyze the trends in the utilization of sodium hyaluronate eye drops in South Korea from a large-scale population-based dataset. With this analysis, we could approximate the prevalence of DED in South Korea. Second, we will evaluate the impact of the introduction of high-priced disposable forms in the South Korean market from the perspective of health financing and equity in utilization. To this end, we will analyze prescriptions including sodium hyaluronate eye drops, patients who were prescribed medicines, and health-care institutions prescribing medicines to understand for whom, under what conditions, and how eye drops in disposable forms are prescribed.The National Health Insurance Service-National Sample Cohort (NHIS-NSC), a population-based cohort established by the NHIS, was used for this study . The NHIThe NHIS-NSC consists of four databases, including information on participants and their medical treatments and health examination, and information on health-care institutions, for the period from January 2002 to December 2015. The database on participants includes demographic and socioeconomic characteristics of participants, such as the age, sex, level of income, and types of health insurance. The database on medical treatments covers prescriptions, such as the date and duration of the prescription, the prescribed drug's international nonproprietary name, the dosage, and the prescribing health-care institution. The database on health-care institutions includes types and locations of health-care institutions.Currently, two types of eye drops are available on the market: disposable and multiuse forms. Disposable eye drops were defined as medicines with packing specifications less than 1 ml without the presence of ophthalmic preservatives, while multiuse forms were defined as medicines with packing specifications greater than 1 ml with the presence of ophthalmic preservatives. With these definitions, separated information on prescriptions, patients, and health-care institutions was obtained. Additionally, frequently prescribed users were categorized into two groups: the disposable user group and the multiuse form user group.Descriptive statistics were used to examine the characteristics of prescriptions, patients , and health-care institutions. At the patient level, information on the sociodemographic characteristics of the patients, including sex, age, and types of health insurance, were collected. Types of health insurance included the NHIS for the population and the Medical Aid Program for low-income household. Members of the NHIS were categorized into two types: self-employee and the employee. In South Korea, the premium that the member of NHIS pay are calculated based on their income and assets. Thus, the premium was used to proxy their income level, and separated into quintiles. The first quintile indicates the lowest income, while the fifth quintile indicates the highest income.At the health-care institution level, information on the location and type of institution were obtained. First, the location was divided into several regions based on the administrative district. In the end, four regions were created, including Seoul, metropolitan excluding Seoul, city excluding metropolitan, and rural. Second, the health-care institutions were categorized as primary-, secondary-, tertiary-, and quaternary-care institutions : primaryA deidentified secondary dataset was used for this study, indicating that the study was exempted from review by the Institutional Review Board (IRB) of Ewha Woman's University (IRB No ewha-201903-0005-01).No patients were involved in developing or conducting the research. Thus, the dissemination of the results of the research directly to the eligible participants is not required.The proportion of category IV users (or disposable users) has increased, while that of category I users (or multiuse form users) has decreased during the study period. The proportion of disposable user and multiuse form users in 2013 was 27% and 57%, respectively, indicating that the number of multiuse form users was still higher than that of disposable users among frequently prescribed users. Then, frequently prescribed users in 2005 and 2010 were selected to examine the odds ratio between demographic variables  and prescription categories. In this study, we evaluated the trends in the utilization of sodium hyaluronate eye drops in South Korea from a large-scale population-based dataset and analyzed prescriptions, patients, and health-care institutions, which were separated by disposable and multiuse forms, to discuss the impact of the introduction of expensive disposable forms from the perspective of health financing and equity in utilization.et al. (2014) reported that the overall prevalence of DED diagnosis and the prevalence of dry eye symptoms in South Korea were 8 and 14.4%, respectively, in 2010\u201311  USD and 1.7 million (65%) USD for multiuse and disposable forms, respectively. Furthermore, the proportion of disposable users among frequently prescribed users is increasing, indicating that the utilization of disposable forms might be an additional burden for the insurer from the perspective of health financing. For instance, the proportion of expenditure for sodium hyaluronate eye drops in total benefits, including medical service and prescription drugs, increased from 0.06% in 2002 to 0.34% in 2015. Thus, understanding for whom, under what conditions, and how eye drops in disposable forms are prescribed is essential to address their impacts on health financing.Furthermore, introducing disposable forms of eye drops caused equity issue in utilization. In this study, we demonstrated that sex and age of users were associated with utilizing eye drops in disposable forms. Particularly, female users  and users under 30 years old (reference more than 60 years old) are more likely to be prescribed eye drops in disposable forms. DED is closely related to wearing contact lenses and eye makeup , which aSodium hyaluronate eye drops are prescription drugs that should be prescribed at health-care institutions. In this study, we found that the majority of eye drops (approximately 90%) were prescribed by primary-care institutions, indicating that DED was the most common disease causing patients to visit ophthalmology clinics. Furthermore, we found that the proportion of the prescription of disposable forms and their speed of adoption were different among various types of institutions. For instance, the proportion of the prescription of disposable forms was in the order of quaternary- tertiary-, secondary-, and primary-care institutions, which might imply that physicians at quaternary-care institutions were more likely to prescribe eye drops in the disposable form to their patients, including patients with glaucoma and patients who need multiple eye drops. However, note that the number of total prescriptions involving disposable and multiuse forms from quaternary-care institutions is much less than that of prescriptions from primary-care institutions, where the majority of eye drops are prescribed. Thus, the total impact of the introduction of disposable forms on health financing is greater in primary-care institutions.We also found an interesting result in variance among four regions, including Seoul, metropolitan excluding Seoul, city, and rural area, for the prescription of disposable forms. The proportion of the four regions in prescriptions involving the disposable form was in the order of Seoul (38%), rural (26%), city (20%), and metropolitan excluding Seoul (15%) in 2004. However, the proportion of the Seoul area slightly decreased, while that of the rural area slightly increased during the study period. Finally, the proportion of the four regions in prescriptions involving the disposable form were converged to 25% in 2015. Similarly, we presented the proportion of disposable forms in the total prescriptions  for the publication of any potentially identifiable images or data included in this article.K-BS developed the concept of the paper, undertook the analysis, and wrote the manuscript.The author disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Taejoon Pharmaceutical Co., LTD. However, the funding source was not involved in the study design, collection, analysis and interpretation of data, writing of the report, and the decision to submit the article for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Dirofilaria (Nochtiella) repens and Candidatus Dirofilaria (Nochtiella) Honkongensis Provide Evidence for Presence of Cryptic Species. The title contains spelling errors and should be corrected to: The Mitochondrial Genomes of the Zoonotic Canine Filarial Parasites Dirofilaria (Nochtiella) repens and Candidatus Dirofilaria (Nochtiella) hongkongensis Provide Evidence for Presence of Cryptic Species.The title currently is The Mitochondrial Genomes of the Zoonotic Canine Filarial Parasites th author, Tran Anh Le, is currently Department of Parasitology, Viet Nam Veterinary Medical University, Ha Noi, Viet Nam. The correct affiliation of the 10th author, Tran Anh Le, is Department of Parasitology, Vietnam Military Medical University, Hanoi, Vietnam.The affiliation of the 10In the manuscript, there is reference to canine blood samples used to amplify partial mitochondrial DNA sequences of the putative species Dirofilaria sp. \"Thailand II\". This is incorrect. It should be noted that the samples came from cats and not dogs."}
+{"text": "Most of these applications are still at an early stage of development and have technological challenges and a lack of fundamental comprehension. Furthermore, the functional memristive properties of TiO2 thin films are heavily dependent on their processing methods, including the synthesis, fabrication, and post-fabrication treatment. Here, we outline and summarize the key milestone achievements, recent advances, and challenges related to the synthesis, technology, and applications of memristive TiO2. Following a brief introduction, we provide an overview of the major areas of application of TiO2-based memristive devices and discuss their synthesis, fabrication, and post-fabrication processing, as well as their functional properties.Titanium dioxide (TiO Owing to an appropriate combination of physical and chemical properties, environmental compatibility, and low production cost, polycrystalline TiO2 has found a large variety of applications and is considered to be a promising material for future technologies. One of the most distinctive physical properties of this material is its high photocatalytic activity , biohybrid systems, and sensors, as schematically shown in 2-based memristors. A special focus is placed on the relationships between the synthesis and deposition methods, the effects of post-synthesis treatment, and the resistive switching properties.Currently, the development of TiO2 . Alternatively, TiO2 thin films may serve as an interface material in various biohybrid devices. The bio- and neurocompatibility of a TiO2 film has been demonstrated in terms of its excellent adsorption of polylysine and primary neuronal cultures, high vitality, and electrophysiological activity  capacitors  the synthesis of a nanostructured material, (ii) deposition of the functional layer, (iii) arrangement of the electrodes, and (iv) post-processing annealing at an elevated temperature under a suitable atmosphere. The first stage is required for traditional chemical synthesis routes, while the first two stages take place at the same time for physical deposition methods.The fabrication of a TiOVT), retention time, switching time, and the resistive switching ratio (ROFF/RON). The main technological, topological, and exploitative characteristics of typical memristive devices are summarized in The choice of fabrication route is thus a trade-off in complexity, cost, scalability, desirable topology , threshold electroforming voltage , the solvent type, and the temperature  or TiCl4 have been used as precursors  have also been reported  have been demonstrated . In these methods, Ti-based precursors  are decomposed in the presence of an oxidizer   gas mixtures  under vacuum (Schmidt et al., 2 thin films that have often been addressed as prototype oxide memristors for many research applications. Numerous recent achievements highlighted in this mini-review demonstrate the rapid development of TiO2-based memristors in various application fields, while the growing interest in these devices is seemingly far from saturation.The current renaissance of the resistive switching phenomenon over the last 12 years has been intimately associated with studies on TiO2 memristors have been outlined in several previous reviews and remain essentially unsolved. Technologically, the emerging properties of memristive systems concern the operational stochasticity, number of distinguishable states, switching energy, switching speed, endurance, retention, and feature size. Their relationship in various types of modern memristive systems has been comprehensively addressed in a recent topical review (Zhang et al., 2 polymorphs (Scanlon et al., 2 memristors by choosing appropriate electrodes and an appropriate operating voltage regime or by affecting the phase ratio, defect structure, and microstructure of the synthesized materials using post-processing annealing under ambient or inert atmospheres (Goren et al., 2. Meanwhile, only a few studies have systematically addressed the effect of thermal annealing at reduced oxygen partial pressures on the resistive and resistive switching properties of TiO2 thin films (Lai et al., The major challenges of TiO2-based memristors, we can expect an increasingly large role of chemical approaches to device fabrication, lowering of the production costs, rapid development of neuromorphic computing systems, and further convergence of artificial electronic neurons with biological cells based on TiO2 thin films.In view of the current trends and challenges of TiOAll authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In recent years the popularity and application of both research- and consumer-grade wearable physical (PA) activity monitors have witnessed substantial growth in large observational studies and clinical trials. For example, the NHANES and UKBiobank, have collected accelerometry data on thousands of participants contributing to the reputation of wearable technology overall as well as in aging-oriented research. As a result, more aging-focused studies including the Baltimore Longitudinal Study of Aging, Maastricht Study, Finnish Retirement and Aging study, and the National Health and Aging Trends Study, along with clinical trials have introduced accelerometry protocols into their design. The symposium focuses on challenges in the implementation of the objective measurements of PA into large studies on older adults. We will discuss the design of successful projects held and/or completed in the United States and Europe including: (1) types of devices, (2) size of datasets, (3) steps necessary for the successful device implementation, (4) data management and (5) statistical analyses. We will also present primary, PA-related findings in each study, together with funded or planned follow-up work. Collectively, these presentations will improve understanding of the technology and effort necessary for the successful application of objective PA monitoring and the resulting data analysis, providing a better context for investigators in the field of aging who want to introduce wearable devices into existing and upcoming research. The discussion will focus on the future of these technologies in the context of geriatric medicine and gerontology and the consequent steps essential for their best utilization and further expansion."}
+{"text": "Incorporating geographic information science and technology (GIS&T) into COVID-19 pandemic surveillance, modeling, and response enhances understanding and control of the disease. Applications of GIS&T include 1) developing spatial data infrastructures for surveillance and data sharing, 2) incorporating mobility data in infectious disease forecasting, 3) using geospatial technologies for digital contact tracing, 4) integrating geographic data in COVID-19 modeling, 5) investigating geographic social vulnerabilities and health disparities, and 6) communicating the status of the disease or status of facilities for return-to-normal operations. Locations and availability of personal protective equipment, ventilators, hospital beds, and other items can be optimized with the use of GIS&T. Challenges include protection of individual privacy and civil liberties and closer collaboration among the fields of geography, medicine, public health, and public policy. Incorporating geographic information science and technology (GIS&T) into COVID-19 pandemic surveillance, modeling, and response enhances understanding and control of the disease.Applications of GIS&T include developing spatial data infrastructures for surveillance and data sharing, incorporating mobility data in infectious disease forecasting, using geospatial technologies for digital contact tracing, integrating geographic data in COVID-19 modeling, investigating geographic social vulnerabilities and health disparities, and communicating the status of the disease or status of facilities for return-to-normal operations.Protections for individual privacy and close collaboration among the fields of geography, medicine, public health, and public policy to use GIS&T are imperative.The spread of infectious disease is inherently a spatial process; therefore, geospatial data, technologies, and analytical methods play a critical role in understanding and responding to the coronavirus disease 2019 (COVID-19) pandemic. Geographic information science and technology (GIS&T) is the academic field centered on geospatial data and analysis. The field encompasses geographic information systems (GIS), spatial statistics and visualization, and location-based data derived from global navigation satellite systems  and remotely sensed imagery. Opportunities for incorporating GIS&T into COVID-19 pandemic surveillance, modeling, and response include 1) developing spatial data infrastructures (SDI) for surveillance and data sharing, 2) incorporating mobility data in infectious disease forecasting, 3) using geospatial technologies for digital contact tracing, 4) integrating geographic data in COVID-19 modeling, 5) investigating geographic health disparities and social vulnerabilities, and 6) communicating the status of the disease or status of facilities for return-to-normal operations. Locations and availability of personal protective equipment, ventilators, hospital beds, and other items can be optimized with the use of GIS&T.Current surveillance of COVID-19 at the national and global levels is built on lessons learned from maintaining previously developed databases of contamination and disease, such as FluNet . The assAn important aspect of monitoring the spread of infectious disease is spatial data infrastructure (SDI), composed of the human resources and institutions that create and maintain the foundation to which additional spatial data can be attached and used. Key components of an SDI include geospatial culture and awareness, resources for information and communications technology, common standards for data integration and interoperability, a legal framework for data security and privacy, a common lexicon, the use of robust statistical and epidemiological methods, and interdisciplinary collaboration and partnerships . Along wMaps play a key role in communicating the risks and spread of COVID-19 . InteracThe GIS&T community has long worked toward development of the National Spatial Data Infrastructure (NSDI) for the United States , an effoAlong with handwashing and social distancing, perhaps the foremost mitigation strategy for reducing person-to-person contact and transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the absence of pharmaceutical intervention is regulation restricting mobility . Consequently, one key role for geospatial technologies in responding to the COVID-19 pandemic is monitoring population distribution and mobility through the use of social media and location-tracking applications embedded in mobile telephones that employ GNSS, cell phone tower connections, and/or wireless connections .Modeling population distribution and mobility has a long history in GIS&T and focuses on fine-scale estimations of population distribution and mobility ,12, mostMonitoring mobility at the individual level, in addition to the population level, has also emerged as an important use of geospatial technologies, particularly in its application to digital contact tracing. Conventional contact tracing, involving identifying, contacting, and encouraging quarantine for the people with whom an infected person has had close contact to mitigate disease transmission, is labor intensive. The process can be made more efficient and scaled up to large populations by exploiting individual digital mobility data, as well as data indicating proximity among mobile telephones using Bluetooth or related technologies, to computationally show close proximity among individuals . Such loAdvances in GIS&T have been made in modeling the geographic trajectories of individuals throughout their daily lives, their interactions with other people, and their immediate environment using geographic and computational constructs such as activity space and space\u2013time prisms \u201320. HoweA strength of GIS is the ability to integrate diverse spatial data sets based on georeferencing, facilitating the integration of health data with contextual characteristics. Descriptive modeling research that leverages this capability has examined the spatial associations of COVID-19 with socioeconomic and environmental characteristics. This research found, for example, that lower income and income inequality , higher Computational infectious disease models are widely used to predict or forecast the spread of COVID-19 disease and the effects of intervention strategies. Predictive modeling approaches can be generally categorized as SEIR/SIR  , agent-bSpatial transportation and mobility data can play an important role in forecasting disease prevalence, where, for example, the effect of nonpharmaceutical interventions  on city-level transmission of COVID-19 in China was analyzed using mobility data harvested from mobile telephone location-based services. This method allows one to parameterize the local contact rate and forecast the geographic distribution of disease prevalence under different intervention timing scenarios . RelatedIndices of social vulnerability are place-based variables that incorporate factors such as race/ethnicity and socioeconomic status to encode the vulnerability to adverse health outcomes and other types of hazards . CommuniResources for investigating COVID-19-related social disparities include publicly available data on COVID-19 cases by small areas, such as zip codes , althougThe multidimensional social, economic, and health consequences of the COVID-19 pandemic are geographically inequitable: some places and populations have greater social, economic, health and other effects than other places and populations. Beyond the need to identify such factors as lack of access to resources or the prevalence of pre-existing health conditions is the need to recognize and understand the mechanisms of vulnerability that have been in place and led to the exacerbation of the COVID-19 crisis in some communities. Community recovery from the COVID-19 pandemic requires incorporation of social, economic, and health components and an emphasis on investigating how place shapes the uneven effect of COVID-19.www.ucgis.org/covid-19-resources), the OGC (www.ogc.org/resources-for-COVID-19-from-ogc), and the National Alliance for Public Safety GIS Foundation (www.napsgfoundation.org/resources/covid-19).We have outlined how GIS&T can be used for understanding and responding to the COVID-19 pandemic and future infectious disease epidemics and pandemics. Central to this understanding and response is a commitment for the use of GIS and geospatial technologies as the platform for collecting, integrating, and analyzing georeferenced data on the locations and characteristics of individuals and the spatial distribution of socioeconomic, health, and built and natural environmental characteristics. Geospatial resources for COVID-19 response are available through several organizations, including the University Consortium for Geographic Information Science (Leveraging GIS&T for responding to the COVID-19 pandemic requires a close and extensive collaboration between researchers in the fields of geography, medicine, public health, and public policy. The field of GIS&T has a long history of research in data synthesis, statistical modeling, and computational simulation for spatial data and applications. Recognizing that GIS&T is a theoretical and scientific approach rather than simply a set of analytical tools will facilitate transdisciplinary collaboration. Advances in preserving individual privacy and civil liberties in the age of big spatial data, where geospatial technologies generate massive repositories of individual-level data on movement, health, and behavior widely available, are also necessary. These advances will likely require enhanced government regulations, corporate policies, and technological innovations in data sharing and privacy protection.The COVID-19 pandemic is still in the beginning phase, and the research community is continuing to learn and revise the best way to respond to this global public health crisis. Geospatial data, methods, and technologies have a crucial role to play in understanding and responding to the pandemic, and the lessons learned on the use of GIS&T for pandemic response at this time should enhance preparedness and response for future public health crises."}
+{"text": "The burden of substance use disorders in sub-Saharan Africa has been projected to increase by an estimated 130% by 2050. Despite this, little is known about the substance use disorder treatment and prevention systems in the region.The objective of this review is to describe the public sector substance use disorder treatment and prevention systems in Kenya guided by the World Health Organization health systems framework model, with the aim of informing decision-making.We reviewed official government documents obtained from hand-searching the websites of relevant governmental organizations including: Ministry of Health, National Authority for the Campaign Against Alcohol and Drug Abuse, Parliament of Kenya, Ministry of Treasury & National Planning, National Law Reporting Council, Kenya National Bureau of Statistics, the National Non-Governmental Organization (NGO) Coordination Board and the 47 County Governments. We augmented those searches with official documents that the authors were aware of by virtue of being practitioners in the field. Draft and retired documents were excluded. The findings of the search are presented as a narrative review.Mental Health Act 1989, the main legislative framework governing substance use disorder treatment and prevention, focuses on institutional care only. While there are only three public health facilities offering substance use disorder treatment in Kenya, several non-public sector actors are involved in SUD treatment and prevention activities. Unfortunately, there is limited cross-sector collaboration. The Ministry of Health has no specific budget for substance use disorder treatment and prevention, while the National Authority for the Campaign Against Alcohol and Drug Abuse has an annual resource gap of about US$ 5,000,000. The substance use disorder workforce in Kenya has not been characterized.The Mental Health (Amendment) bill 2018. (2) Integration of substance use disorder treatment and prevention into primary health care to increase access to care. (3) Utilization of money from taxation of alcohol, tobacco and betting to increase funding for substance use disorder treatment and prevention. (4) Characterization of the substance use disorder workforce to inform planning. (5) Enhanced collaboration between the government and non-state actors in order to increase access to SUD treatment and prevention.We propose five key strategies for strengthening substance use disorder treatment and prevention systems in Kenya including: (1) Enactment of the  The burden of substance use disorders (SUDs) in sub-Saharan Africa has been projected to increase by an estimated 130% by 2050 . In AfriThe World Health Organization (WHO) defines health systems strengthening as the process of improving the six health system building blocks namely service delivery, workforce, health information, medical products, financing and governance in order to achieve optimal health outcomes . A well-Mental Health Act 1989 [Unfortunately, the existing SUD treatment and prevention systems in Kenya are inadequate. The main legislative framework governing SUD treatment and prevention, the Act 1989  is outdaAct 1989 . MoreoveAct 1989 , 16 (ii)Act 1989 , and tarAct 1989 .Since our aim was to describe the public sector SUD treatment and prevention systems, we reviewed official government documents. We hand-searched the websites of relevant governmental organizations for documents and web pages that had content on SUD treatment and prevention. The organizations whose websites were searched include: MOH, National Authority for the Campaign against Alcohol and Drug Abuse (NACADA), Parliament of Kenya, National Council for Law Reporting, Kenya National Bureau of Statistics (KNBS), National Non-Governmental Organization (NGO) Coordination Board, each of the 47 County Governments.The Vision 2030 , Kenya\u2019sMental Health Act, 1989 [Constitution of Kenya, 2010 which devolves health functions to the county governments [Mental Health Act, 1989 [Unfortunately, the ct, 1989  which prct, 1989 . Moreovect, 1989  however ct, 1989 .Mental Health (Amendment) Bill, 2018 [Mental Health Act, 1989 [Constitution of Kenya, 2010 [The proposed ll, 2018 , currentct, 1989 . In addrMental Health (Amendment) Bill, 2018 [Importantly, this bill is aligned with Vision 2030 , and guill, 2018  will theMental Health Act 1989, several other laws contain provisions that seek to address SUD treatment and prevention in Kenya. The Health Act, 2017 [,The Tobacco Control Act, 2007 [, The Alcoholic Drinks control Act, 2010 [and The Narcotic Drugs & Psychotropic Substances (Control) Act, 1994 [Other than the ct, 2017 ,The Tobact, 2007 , The Alcct, 1994  all mandThe Alcoholic Drinks Control Act, 2010 [and the Narcotic Drugs & Psychotropic Substances, Act 1994 [Narcotic Drugs & Psychotropic Substances Act, 1994 [Alcoholic Drinks Control Act 2010 [Act 1994  specificct, 1994  providesAct 2010 , 60.Alcoholic Drinks Control Act 2010 [and the Narcotic Drugs & Psychotropic Substances Act 1994 [Unfortunately, The Act 1994  mandate Act 1994 . In a joAct 1994 . This haWorkplace policies on SUD treatment and prevention are an integral part of SUD management at the institutional level and are an International Labor Organization (ILO) requirement . Such poSUD treatment and prevention services are delivered within the health sector by the MOH, and the County Government Departments of Health; and outside the health sector by the NACADA and various County Government Departments.The key responsibilities of the MOH include developing health policies, managing five national referral health facilities as well as oversight of service delivery at the County level. The County Departments of Health are in turn tasked with the delivery of facility and community based health care at the county level, and report to the MOH . In realThe health sector SUD services however remain scarce and inaccessible. Out of 5800 health facilities run by the MOH and County Departments of Health in Kenya, only three offer SUD rehabilitation services and all are located in urban centers . FurtherThe NACADA is a State Corporation in the Ministry of Interior and Coordination of National Government. Its role centers on SUD prevention . The NACIn the 2019/2020 financial year, 70% of the Counties had their SUD programs under various departments including Public administration, Education, Social services and Youth empowerment  Capacity building of faith based organizations, community based organizations and mutual self-help groups by the government in order to make them potential means for SUD treatment and prevention at the grassroots level. (ii) Accreditation of private SUD treatment facilities by the National Hospital Insurance Fund (NHIF) to increase access to specialized SUD treatment. Currently, only three private rehabilitation facilities are accredited .The MOH had no specific budgetary allocation for SUD treatment and prevention . At the The cost of interventions for alcohol use disorders has been estimated and could serve as a guide during planning. For example, public awareness campaigns to prevent harmful alcohol use have been approximated to cost US$ 0.2\u20130.8 per person in the population per annum, and that of brief interventions offered within the health sector US$ 0.4\u20131.8 per person in the population per annum . StrategGlobally, the SUD treatment and prevention workforce is diverse comprising of peers, teachers, counselors, social workers and nurses , 70. CerKenya has a number of sources of information on substance use that could inform interventions. The KNBS in collaboration with various stakeholders conducts several national household surveys. The Kenya Demographic Health Survey collects data on the patterns of alcohol consumption among other health indicators and has been conducted twice so far (in 2003 and 2014) . The GloThe MOH through its health sector indicator manual  providesThe WHO recommends that at the minimum, health systems must have nicotine replacement therapy and methadone for the management of SUDs . The KenA limitation of this review is that it describes the SUD treatment and prevention systems in Kenya based on documents and information that was available online. Information unavailable on the internet such as some County government budgets and implementation levels of planned programs was therefore missed out. A future study obtaining data from key informant interviews and review of hard copies of government documents, and guided by a structured tool such as the World Health Organization-Assessment Instrument for Mental health Systems (WHO-AIMS)  could prMental Health (Amendment) bill 2018. (2) Integration of substance use disorder treatment and prevention into primary health care to increase access to care. (3) Utilization of money from taxation of alcohol, tobacco and betting to increase funding for substance use disorder treatment and prevention. (4) Characterization of the substance use disorder workforce to inform planning. (5) Enhanced collaboration between the government and non-state actors in order to increase access to SUD treatment and prevention.The SUD treatment and prevention systems in Kenya are under-resourced. We propose five key strategies for strengthening SUD treatment and prevention systems in Kenya: (1) Enactment of the"}
+{"text": "The Support at Home pilot program provided financial support for the purchase of home care services by middle-income adults with disabilities in San Francisco to support aging in place. Enrollees had income below the area median and made copayments based on household income. The mixed-methods evaluation of the program incorporated administrative records, surveys of clients and comparison group members, surveys of unpaid caregivers, surveys of paid care providers, and focus groups with clients and unpaid caregivers. Outcome measures included the Older People\u2019s Quality of Life Questionnaire, Patient Health Questionnaire-2, an adapted Burden Scale for Family Caregivers, and self-reported falls, emergency department visits, and hospitalizations. Analyses included pre-post chi-squared and t-test comparisons between client and comparison groups and multivariate regressions. An economic analysis was conducted to learn whether changes in costs associated with reduced health care utilization were greater than the costs of the program. Results indicated statistically significant positive changes in client ratings of personal and financial stress, but not in the composite quality of life score. There were statistically significant reductions in attendance at medical appointments, falls, emergency department visits, and hospitalizations. Similar changes were not found in the comparison group. The focus group data supported the findings regarding personal and financial stress and indicated that clients and their caregivers perceived quality of life benefits. The economic analysis indicated substantial cost savings from the program due to reduced use of medical services. Due to its positive impacts, San Francisco has made Support at Home a permanent program."}
+{"text": "Current pathology practice is being shaped by the increasing complexity of modern medicine, in particular of precision oncology, and major technological advances. In the \u201cnext-generation technologies era\u201d, the pathologist has become the person responsible for the integration and interpretation of morphologic and molecular information and for the delivery of critical answers to diagnostic, prognostic and predictive queries, acquiring a prominent position in the molecular tumor boards. In 1953, Crick and Watson\u2019s discovery of the DNA double-helix , Giovanni Battista Morgagni placed anatomo-clinical correlations at the heart of modern medicine [The performance of autopsy has been widely recognized for several decades as a fundamental part of routine pathology practice. In 1761, with the publication of medicine . The lesmedicine .However, since the last decades of the twentieth century, the rate of autopsies has decreased significantly, due to increasing confidence in ante-mortem diagnosis, more complex legislations regarding human tissues procedures and also insufficient priority given to autopsies by pathologists themselves, burdened with increasing workloads of surgical resections, biopsies, and cytology .The declining autopsy rate should be a source of concern among the scientific community, given its great potential for the advancement of medical knowledge and improvement of clinical practice. As demonstrated by the COVID-19 experience, the post-mortem examination, together with state-of-the-art molecular diagnostics, plays a central role in the diagnosis and clinical management of newly emerging diseases .Current pathology practice is being shaped by the increasing complexity of modern medicine and major technological advances . In the However, traditional organ, tissue and cellular pathology lays the foundation for the development of molecular pathology and, as demonstrated by the on-going COVID-19 pandemic, still provides essential tools to greatly enhance clinical practice.Current practicing and future pathologists are called on to actively incorporate molecular knowledge into their diagnostic armamentarium and deeply transform laboratory frameworks and pathology educational training programs.We are facing an epochal evolution of the figure of the pathologist who must necessarily find fertile ground both in laboratories, thanks to economic availability and mental openness towards innovation, and also in the training programs of young pathologists. Studies aimed at new technologies will be a fundamental background for the pathologist\u2013in-training.Collaboration between different professional figures must acquire more and more importance in the context of the MTB. The first experiences of multidisciplinary teams in the molecular field are demonstrating how an integration between different knowledge in specialized fields such as clinical, molecular and surgical pathology and engineering can lead to an increasingly targeted therapy, to an increasingly personalized follow-up and a more precise cancer risk stratification."}
+{"text": "Many countries within the European Union report significant difficulties in retaining and recruiting healthcare workers and are facing increasing levels of predicted staff shortages over the long term  summarize the accepted papers in this special issue and discuss how they relate to the concept of Healthy Healthcare; and (iii) to present a new research agenda, drawing on occupational health psychology research to further advance our understanding of the concept of Healthy Healthcare.This editorial, therefore, aims to: (i) introduce the concept of Healthy Healthcare\u201d refers to a new interdisciplinary system-based perspective of healthcare practices encompassing three main pillars: (1) quality of patient care; (2) worker health and well-being; and (3) the organization and practices of healthcare organizations. It recognizes that healthcare systems must be organized, managed, and financed in balance with the health and performance of available workers in mind  can potentially disadvantage another pillar. Ultimately a system-based perspective considering the dynamics between the patient(s), the worker(s), and the complex healthcare system will lead to a more resource-efficient delivery of high-quality healthcare services.\u201cHealthy Healthcare. The inter-disciplinary nature of Healthy Healthcare aligns well with the discipline of occupational health psychology given that the latter is also inherently multidisciplinary and draws on occupational health and psychology as well as being inclusive of public health, human factors, organizational studies, economics, industrial engineering, and more  the organization of healthcare; (ii) workers' health and well-being; and (iii) the quality of care provided.The complexity of a system-based perspective of Broetje et al.). It also includes two different two-wave longitudinal panel studies examining age-related factors among aging healthcare workers . There is a cross-sectional study investigating the relationship between job autonomy, self-leadership, work engagement, and health among healthcare workers , and a process-evaluation qualitative study among hospital executives about the key process factors in implementing health-related work design interventions . The issue also includes a qualitative study exploring the emerging psychosocial risks of healthcare accreditation in workplaces .In total, six papers were accepted. The special issue includes a systematic review examining the influence of psychosocial work characteristics in explaining the mental health of nursing staff  for different types of healthcare practices and contexts among a variety of healthcare workers, but also includes insights about the interrelation of the main pillars from the perspective of current systems. This includes healthcare assistants, nursing workers, upper and middle managers within a hospital, different levels of seniority as well as different levels of organizational practices. Moreover, the research questions of these papers address diverse issues related to Healthy Healthcare through different theoretical frameworks such as the JD-R Model and theory , the full concept of Healthy Healthcare remains theoretically as well as empirically untested, and further research is needed to develop and examine the core concepts postulated by it. Emphasis needs to be placed on linking different antecedents of its three core pillars, including the mechanisms that explain these relationships to possible outcomes among patients, healthcare workers, and organizations. These will contribute to developing and refining the overarching theoretical model presented in Multilevel study designs. Occupational health researchers typically neglect the fact that relationships are situated within a wider context, with important factors at the organizational, sectoral, societal, and national level all influencing the three pillars of Healthy Healthcare .Van der Heijden et al.; de Lange et al.), gender, ethnicity, and immigrant workers . These potential interventions aim to ensure employee health and well-being  can also give voice and provide insights on how individuals make sense of the healthcare system  developing an overarching theory and concepts of Healthy Healthcare  expanding our focus of well-being to include more positive manifestations; (vi) focusing on primary and organizational-level interventions; and (vii) embrac different research methodologies and paradigms.A system-based perspective is needed to address the challenges faced in healthcare and to increase the uptake of knowledge from occupational health psychology into healthcare. The All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The widely-cited failure within the Millennium Development Goals to adequately reduce infant deaths and reverse maternal health inequalities prompted incorporation of new goals in the 2016 UN Sustainable Development Goal (SDG) three to \u2018ensure healthy lives and promote well-being for all at all ages\u2019 . With amAnnually, the placental disorders of pregnancy  are associated with 46,000 maternal and 2.5 million perinatal deaths [While placental disorders of pregnancy are well investigated in HICs, this is not so in LMICs. LMIC-based placental disorder research is under-represented in the global portfolio. Moreover, the pathways to disease within a resource-constrained setting in sub-Saharan Africa are likely to differ from pathways in HICs where much of the research has been conducted. For example, synergistic challenges of malnutrition, rural settings underserved by transport infrastructure and health facilities, high burdens of infectious diseases, and other adverse social determinants of health may contribute to pathways of disease in ways that are currently not captured by HIC research. Understanding the interactions between placental complications and contextual factors may provide a critical step towards the development of precision healthcare to optimise maternal, fetal and infant outcomes.The PRECISE  Network is a new and interdisciplinary group of research scientists and health advocates from sub-Saharan Africa, Europe, Canada and the USA, that is investigating the origins and outcomes of the placental disorders in sub-Saharan Africa. Funded by the UK Research and Innovation Global Challenges Research Fund (GCRF), PRECISE aims to develop a robust clinic-based research infrastructure, database and biobank that will catalyse formative research describe the pathways to placental disorders and their complications in sub-Saharan Africa, and inform the design of effective interventions. Importantly, this programme will provide essential information about the impact of placental disorders on women\u2019s lives and their communities.The five papers in this supplement introduce the scientific scope and vision of this ambitious programme of work and describe the development of key components of PRECISE: the study protocol, clinical database, biorepository, qualitative work plans, and partnership and capacity-building elements. The first three papers describe the design of the prospective pregnancy cohort study and the research platform to collect epidemiological data and biological samples from approximately 10,000 pregnant Gambian, Kenyan and Mozambican women, 1500 of whom we anticipate will have a pregnancy complicated by at least one placental disorder. In addition, we will recruit 1800 non-pregnant women of reproductive age as a control group to provide representative regional data and biological samples. The unified data collection platform of the PRECISE database and the biorepository links together sociological, clinical and discovery bioscience research. The second and third papers in this series describe the issues and challenges around their creation, development, management and scientific uses. PRECISE takes a 360\u00b0 approach to understanding both individual-level co-exposures and contextual factors associated with the placental disorders. The fourth paper in the series describes the value of qualitative research in helping to understand quantitative and biological data. The fifth paper in the series brings the picture of the PRECISE Network together with capacity-building in research infrastructure, strengthening emerging leaders in reproductive science and supporting advocacy for research. Together, the papers in this supplement describe a vision and the developmental journey of research platform that seeks to fill current knowledge gaps related to placental conditions in sub-Saharan Africa, and strengthens capacity for research and health improvement related to placental disorders."}
+{"text": "Percutaneous Transforaminal Endoscopic Discectomy (PTED) offers an exceptional visualization of foraminal anatomy. Dorsal root ganglion and adjacent foraminal structures are satisfactorily visualized, thereby minimizing the risk of their intraoperative injury. Percutaneous Transforaminal Endoscopic Discectomy (PTED) offers an exceptional visualization of foraminal anatomy. Dorsal root ganglion and adjacent foraminal structures are satisfactorily visualized, thereby minimizing the risk of their intraoperative injury Percutaneous Transforaminal Endoscopic Discectomy (PTED) represents a novel minimally invasive method for surgical treatment of lumbar disc herniation (LDH). PTED provides access to the underlying pathology through Kambin's triangle, a right angle triangle located at the lower portion of lumbar intervertebral foramen (LIF). This triangle defined by the exiting nerve root as the hypotenuse, the posterolateral edge of superior endplate of underlying vertebra horizontally and the superior articular facet vertically.Authors have no conflict of interest to declare.KS: involved in conception and design, acquisition of data, analysis and interpretation of data, critical revision of manuscript, general supervision, and final approval. GN: involved in acquisition of data, drafting of manuscript, and critical revision of manuscript. TT and GM: involved in acquisition of data, analysis and interpretation of data, and critical revision of manuscript.Conduction and publication of this specific article was approved by Institutional Review Board and Ethics Committee of Interbalkan European Medical Center, Thessaloniki, Greece."}
+{"text": "The AFU global initiative begin with a collaborative agreement by Arizona State University (ASU), Dublin City University (DCU), and the University of Strathclyde in 2012. The vision was to spur other universities to be fully inclusive of all generations. In 2013, ASU and DCU created a Trans-Atlantic Catalyst Fund to spur AFU initiatives at each institution, with an early focus on research in on dementia, technologies for \u201caging in place,\u201d challenges of caregiving, healthy and active aging, and retirement community design. Since then, ASU has embedded Age Friendly practices throughout the institution via creation of a new foundational charter , creation of ASU-wide Center for Innovation in Healthy and Resilient Aging, a re-purposed Osher Lifelong Institute, construction of the Mirabella community (twenty-story gateway for older adults into ASU), new inter-generational learning platforms, and implementation of universal learning systems."}
+{"text": "Diseases related to Coronavirus-19 and their consequences APS , b are fThese conditions may also provide us with a unique opportunity to engage in studies that may be able to provide important and crucial information to understand the various ways and the extent to which the COVID-19 and its consequences may be impacting on language function and cognition, development of linguistic categories, cross-language learning, language-specific concept formation, memory and retrieval of specific events, the role of emotions on language production, etc.Semantic analysis of medical misinformation on social media during the Covid-19 pandemicUsing public figures as case studies for how language has changed during the course of the pandemic. Using their social media posts over time to provide linguistic data.Analysis of pandemic narratives. Asking people to speak about their experience of being isolated, how their memory (for what category) may be affected, what gives them comfort, changes in perceptions and language expression, etc.Linguistic content analysis of individuals with or without a previous history of traumaIssues related to differential effect of increased emotional concern  on language learning and language performance in children, young adults, and the elder populationsImpact of change in attentional preoccupation on language functioningImpact of COVID-19 on specific mechanism involved in reading, writing, concept formation, abstract thinking, etc.Difference and quality of metaphor and changes in dimension of metaphor in general population, children, elderly in relation to the Coronavirus experienceMetaphor interpretation and reading abilityOrganization in speech eventsSpeech perception in its multilevel processing systemCoding and sentence retrievalChanging in propositional reasoning with or without propositionDevelopment of young children\u2019s awareness of words, syntax, grammatical structures, etc.Children\u2019s conversational repairsParsing strategies and discourse contextChanges in comprehension of complex sentences: A Developmental analysisFunction of stages in the acquisition of syntaxImpact of emotional conflicts in voluntary and involuntary component of speechProcessing of idioms with multiple meaningsEffect of gender and topic on speech processing, production, stylesSemantic and syntactic processing in monolingual and bilingualsConditional reasoning and semantic contextUnderstanding and processing linguistic time sequenceChildren\u2019s Knowledge of propositional phrase structureChildren\u2019s concept of wordIdentifying deception in language communicationChanges in electrophysiological correlates of semantic featuresImpact of increased emotionality and ambiguity in Dyslexic individuals\u2019 reading and language processing/productionImpact of ambiguity on language perception and judgment of intentionality in normal and paranoid subjectsChanges in linguistic markers: Concepts of health, illness, and diseaseSemantic and pragmatic factors in the representation of near and far or spatial dimensionsLanguage acquisition and children\u2019s representation of knowledgePerception of stress contrasts in semantic and nonsemantic contexts by children and adultChanging in mentalism and language productionBilingual frequency encodingInput/output switch in bilingual code-switching of ordinary and emotionally-laden contentEffect of stress on linguistic generalization in bilingualsLanguage processing and language organization in bilingual populationSpeed perception: Word recognition in foreign languageProcessing of COVID-19 experience among the deaf and mute populationsSemantic and phonemic verbal fluency in blindsEtc.In response to this challenge, we are launching a call for specialized contributions meant to help address some of these challenges. We are accepting contributions in a form of special issues or individual manuscripts focusing on research and theoretical constructs geared at advancing and guiding research methodology for a variety of topics related to psycholinguistics. Below are some of the themes to consider:For any questions about the special issue or suitability of a manuscript, please feel free to contact the Editor-in-Chief at javierr@stjohns.edu or initiatives@stjohns.eduWe are requesting a brief abstract of no more than 500 words clearly stating the specific relevance of the manuscript in addressing the contribution of psycholinguistic science in advancing our understanding of the impact of COVID-19 on language processing and production, neurolinguistic issues likely to be affected, impact on psycholinguistic research, etc. We welcome innovative linguistic models likely to encourage new ways of fulfilling our scientific responsibility in virtual contexts while protecting the scientific integrity of the academy. Those submitting a special issue topic should include a brief abstract for each of the contributions to be included in that special issue with the information listed below.Please, include a cover letter providing names, email addresses and other relevant contact information for three independent reviewers . Reviewers from different career stages, institutions, and countries are encouraged. It should also include the following to be submitted to the Editor-in-Chief, Rafael Art. Javier (javierr@stjohns.edu and initiatives@stjohns.edu).Abstract submission: June 1, 2020.Submission of complete manuscript: October 1, 2020.Title of the manuscript (s)List of author (s) and affiliation (s)Abstract (s)Estimated time of completionWhen submitting your proposal (s), include the following for each manuscript, in addition to the cover letter:Accepted manuscripts will be electronically published on an ongoing basis. The first special issue is expected to be published by June 2021. Subsequent special issue publications will follow, if appropriate."}
+{"text": "Francisella tularensis, isolated from diverse sources, have been reported in recent years. In this announcement, we present the complete sequence of the circular chromosome of one of the closest neighboring genera of Francisella, the type strains of Allofrancisella inopinata and Allofrancisella frigidaquae.Near neighbors to the causative agent of tularemia,  Francisella tularensis, isolated from diverse sources, have been reported in recent years. In this announcement, we present the complete sequences of circular chromosomes of one of the closest neighboring genera of Francisella .Near neighbors to the causative agent of tularemia,  Francisellaceae, named Allofrancisella, was published, with three different species  and of the type strain of Allofrancisella frigidaquae SYSU 10HL1970 , in addition to the already published complete genome sequence of the type strain of Allofrancisella guangzhouensis . Short-read sequencing libraries were prepared using a Nextera XT 600-cycle kit  and sequenced on an Illumina MiSeq sequencer, followed by trimming using Trimmomatic  under the accession no. CP038017, SRR11853073, and SRR11853074.These complete genome sequences are the first versions and have been deposited in GenBank/SRA. Genome and read sequences for SYSU YG23 (FSC1302) are available under the accession no."}
+{"text": "Multiple sclerosis (MS) is a chronic inflammatory/demyelinating disease of the central nervous system (CNS)  animal models of MS etiopathology, (ii) cellular processes in MS pathophysiology, and (iii) tools and biomarkers enabling investigation of Titus et al. and Sen et al. summarized the most updated models supporting either the outside-in or the inside-out theory of MS. In particular, the first study concluded that, due to the heterogeneous manifestation of MS pathology, a combination of both paradigms, rather than one of the two, may better explain the origin of MS. Conversely, the second article supported the value of more recently developed models, like the cuprizone (CPZ) mouse, to investigate primitive changes occurring in MS brains. Interestingly, CPZ models seem ideal to reveal the mechanisms involved in MS origin before the immune attack intervenes, and to study MS progression in conditions of immune reaction and protection.Ferr\u00e8 et al. provided an update of genetic factors associated with MS onset, progression and treatment response. At present, the majority of genes and biological processes associated with a higher MS risk are implicated in immune functions  enables identification of focal demyelination in white matter and cortical lesions already from the earliest phases of MS. Lesion burden was associated with serum neurofilament light chain (sNfL) levels, a biomarker of axonal injury. Moreover, the 2-year longitudinal changes of cortical and white matter lesion burden correlated with the cognitive performances of MS patients. This underlined the relevance of MRI biomarkers and sNfL to identify from the earliest disease phases reliable markers of neurodegeneration, disease severity and progression.Pathological studies and experimental models are the gold standard approaches to investigate MS pathophysiology. However, recently, several laboratory, neuroradiological and neurophysiological tools have been applied to define reliable biomarkers for understanding MS development and progression Frontiers in Cellular Neuroscience, -Immunology, and -Neurology provides an integrated overview of the \u201chot topics\u201d in the field of MS cause. Emerging from the article collection is a complex picture where a dichotomy between outside-in/inside-out theories is replaced by a more integrated vision where both theories might equally apply according to the specific condition. The studies published in this issue emphasize the need for a re-evaluation of cellular processes, previously regarded as pure indicators of immune attack , in combination with the individual (genetic) variability of MS patients, and the development of highly predictive experimental models/accurate biomarkers to unravel the unknown cause of the MS in the coming years.In conclusion, this issue of AL, PP, and B'tH wrote the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Neglected tropical diseases (NTDs) are a group of infections that are prevalent in many of the tropical and sub-tropical developing countries where poverty is rampant. NTDs have remained largely unnoticed in the global health agenda. There is a substantial gap between the burden of disease for NTDs in cardiovascular diseases (CVD) and research devoted to the affected populations. We created a Latin-American initiative with emerging leaders (EL) from the Interamerican Society of Cardiology (IASC) with the objective to perform multiple systematic reviews of NTDs and other infectious diseases affecting the heart: The NET-Heart Project.To describe the rationale and design considerations of the NET-Heart project.The NET-Heart Project is a collaborative work of the IASC EL program. The main objective of the NET-Heart project is to systematically evaluate the available evidence of NTDs and other infectious diseases and their cardiovascular involvement. As a secondary objective, this initiative aims to offer recommendations and potential diagnostic and therapeutic algorithms that can aid the management of cardiovascular complications of these infectious diseases. After an expert discussion 17 initial infectious diseases were selected, for each disease we created one working group. The project was structured in different phases: Systematic review, brainstorming workshops, analysis and results, manuscript writing and recommendations and evaluation of clinical implications.The NET-Heart project is an innovative collaborative initiative created to assess burden and impact of NTDs and other infectious diseases in CVD. NTDs can no longer be ignored and must be prioritised on the health and research agenda. This project aims to review in depth the evidence regarding cardiac compromise of these serious conditions and to propose strategies to overcome barriers for efficient diagnosis and treatment of cardiovascular complications. NTDs are a group of bacterial, parasitic, viral and fungal infections that are prevalent in many of the tropical and sub-tropical developing countries where poverty is rampant affecting more than one billion people . By contAccording to the last meeting of the Strategic and Technical Advisory Group for NTDs, the World Health Organization (WHO) has in its portfolio a diverse group of heterogeneous diseases, such as: Chagas disease, Buruli ulcer, Rabies, Soil-transmitted helminthiases, Trachoma, Schistosomiasis, Snakebite envenoming, Scabies and other ectoparasites, Taeniasis/Cysticercosis, Dengue and Chikungunya, Dracunculiasis (guinea-worm disease), Leishmaniasis, Leprosy (Hansen\u2019s disease), Echinococcosis, Foodborne trematodiases, Human African trypanosomiasis (sleeping sickness), Onchocerciasis (river blindness), Lymphatic filariasis, Mycetoma, Yaws (Endemic treponematoses), chromoblastomycosis and other deep mycoses . NTDs haNTDs cause a significant portion of disease. In the 2010 Global Burden of Disease Study, NTDs accounted for 26.06 million disability-adjusted life years (DALYs) . MoreoveCVD is the leading cause of mortality worldwide . More th9There is a substantial gap between the burden of disease for NTDs in CVDs and research devoted to the affected populations. Furthermore, considering the difficulties to access healthcare services that exist in many regions affected by NTDs, the usual recommendations may not be easy to implement so alternative strategies might be necessary. We created a Latin American initiative with the EL program from the IASC with the objective to perform multiple systematic reviews of NTDs and other infectious diseases affecting the heart: The NET-Heart Project.The purpose of this paper is to describe the rationale and design considerations of the NET-Heart project.The NET-Heart project is a collaborative work of the IASC EL program.The EL program is comprised of a group of enthusiastic, talented and creative young cardiologists, residents, pre-grad students and fellows from different countries of north and south America Figure .The main objective of the NET-Heart project is to systematically evaluate the available evidence of NTDs and other infectious diseases and their cardiovascular involvement. As a secondary objective, this initiative aims to offer recommendations and potential diagnostic and therapeutic algorithms that can aid the management of cardiovascular complications of these infectious diseases.After consulting experts in tropical diseases and cardiologists, we chose the infectious diseases that presented major impact on the cardiovascular system. We selected 17 infectious diseases: human immunodeficiency virus, dengue, zika, chikungunya, tuberculosis, African trypanosomiasis, malaria, Chagas, schistosomiasis, Lyme, cysticercosis, echinococcosis, fascioliasis, leishmaniasis, coronavirus disease 2019, rabies and toxoplasmosis.For each disease we created one working group led by a principal investigator with a co-investigator, an expert on the infectious disease to be investigated, and a supervisor. Globally they had a director (AB) and coordinator (CS) Table .The project was structured in four main phases.Systematic review: It includes studies evaluating the infectious disease and its cardiovascular involvement. We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement in conducting and reporting the systematic reviews .\u201cBrainstorming\u201d Workshops: Based on the systematic review research results, workshops were held with the experts to determine the focus and design of the study .Analysis and results.Manuscript writing and recommendations and evaluation of clinical implications.All initial meetings and workshops were conducted through video conferences. Currently, the vast majority of the project\u2019s working groups are starting phase 3.The NET-Heart project is an innovative collaborative initiative to assess burden and impact of NTDs and other infectious diseases in CVDs. Considering that the burden of traditional risk factors cannot fully explain the increase in CVDs in LMICs, and that there is lack of information about the contribution of NTDs to CVD, we aim to review in depth the evidence regarding cardiac compromise of these serious conditions. We also intend to propose strategies to overcome barriers for early diagnosis and efficient treatment of cardiovascular complications."}
+{"text": "This study examined the effect of registered nurse (RN) staffing level, work environment, and education on adverse events experienced by residents in nursing homes. A cross-sectional study was conducted with 216 RNs working in nursing homes who were selected using random stratified sampling by location and bed size. Self-reported questionnaires regarding staffing level, work environment, education level, adverse events, and nurse characteristics were administered. Data from the National Health Insurance Service were used to describe nursing home characteristics. Both multiple and multinomial logistic regressions were used to control for the characteristics of nurses and nursing homes, and investigate the effects of nursing staffing level (number of older adults assigned to a nurse), work environment , and level of nursing education on the adverse events experienced by residents. An increase of one resident per RN was significantly associated with a higher incidence of pressure ulcers . Poor work environment increased the incidence of adverse events such as pressure ulcers  and sepsis . Compared to RNs with a baccalaureate or higher, RNs with diplomas reported increased incidence rates of pressure ulcers . RN staffing, work environment, and education level affect the incidence of pressure ulcers, and the work environment affects the incidence of sepsis among residents in nursing homes. Policy-wise, improving the level of nurse staffing, nursing work environment, and nursing education will improve health outcomes of residents."}
+{"text": "The use of ultrasound (US) in emergency departments (ED) has become widespread. This includes both traditional US scans performed by radiology departments as well as point-of-care US (POCUS) performed by bedside clinicians. There has been significant interest in better understanding the appropriate use of imaging and where opportunities to enhance cost-effectiveness may exist. The purpose of this systematic review is to identify published evidence surrounding the cost-effectiveness of US in the ED and to grade the quality of that evidence.We performed a systematic review of the literature following Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. Studies were considered for inclusion if they were: (1) economic evaluations, (2) studied the clinical use of ultrasound, and (3) took place in an emergency care setting. Included studies were critically appraised using the Consolidated Health Economic Evaluation Reporting Standards checklist.We identified 631 potentially relevant articles. Of these, 35 studies met all inclusion criteria and were eligible for data abstraction. In general, studies were supportive of the use of US. In particular, 11 studies formed a strong consensus that US enhanced cost-effectiveness in the investigation of pediatric appendicitis and 6 studies supported enhancements in the evaluation of abdominal trauma. Across the studies, weaknesses in methodology and reporting were common, such as lack of sensitivity analyses and inconsistent reporting of incremental cost-effectiveness ratios.The body of existing evidence, though limited, generally demonstrates that the inclusion of US in emergency care settings allows for more cost-effective care. The most definitive evidence for improvements in cost-effectiveness surround the evaluation of pediatric appendicitis, followed by the evaluation of abdominal trauma. POCUS outside of trauma has had mixed results. Ultrasound (US) is well established as a safe and effective imaging modality for the rapid diagnosis and management of emergency conditions. At the bedside, it also improves success and patient safety during invasive procedures \u20135. In thThere is a common assumption that US is cost-effective in emergency care settings as it is diagnostically valuable, rapid, and less expensive than other imaging modalities like computed tomography (CT) and magnetic resonance imaging (MRI) . HoweverCost-effectiveness analysis is a tool that combines economic and health outcome data to produce standardized ratios of costs and benefits. The outputs of CEAs allow for comparison of diagnostics that vary by both price and clinical utility, and generate important data to support decisions related to health policy and investment. The validity and reliability of CEAs are highly dependent on the rigor with which they are conducted. In 2013, health economists developed consensus-based guidelines on the conduct and reporting of health economic evaluations, called the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist .We present a systematic review of the published evidence surrounding the cost-effectiveness of US in emergency care settings. Our aim is to characterize the existing knowledge regarding the costs and benefits of emergency US, to examine the quality of cost-effectiveness studies using the CHEERS checklist, and to provide guidance for future research efforts.A systematic review of the literature was performed using the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines . The revwww.covidence.org), an online platform for systematic review. Studies were considered for inclusion if they were: (1) economic evaluations that assessed costs and outcomes of comparative strategies; (2) studied the clinical use of US; and (3) took place in an emergency care setting. Two reviewers  with experience in reading, writing and reviewing economic evaluations independently assessed titles and abstracts for inclusion in a blinded fashion. Studies progressed to a full-text review if both reviewers agreed on the relevance based on the research question. Studies then underwent full text reviews for eligibility by each reviewer. Disagreements were resolved by consensus. The following information was extracted from each of the studies in the review: country, year of publication, intervention, comparator, time horizon (the time over which the costs and effect are measured), discount rate (the rate at which future costs and benefits are discounted), perspective (which costs are included or excluded), health outcome, sensitivity analyses (an assessment of the level of uncertainty in the modeling), and findings.All studies were collated and screened for eligibility through Covidence , biliary, venous, and renal applications. A small group of studies also evaluate general US processes and impact in the emergency department (ED). Tables We identified 11 studies that assessed the cost-effectiveness of US in the evaluation of acute appendicitis \u201328. The Six studies examined US in the setting of acute trauma \u201334. TheySix studies examined US in the setting of renal, biliary, or venous pathology \u201340. The Three studies assessed US in the evaluation of emergency OB/GYN complaints \u201343. One Four studies assessed echocardiography in the emergency care setting \u201347. ThreFinally, we identified a collection of studies evaluating the downstream impact of emergency US on resource utilization \u201352. One While we tailored our search criteria to identify formal attempts at CEA, considerable variability remained in the quality of the economic evaluations conducted in the studies we identified. Most studies received about half the possible points on the CHEERS checklist. Inadequacy in the performance or the reporting of study perspectives, preference-based health outcomes , modeling assumptions, transparency of costs, characterization of uncertainty, and incremental cost-effectiveness ratios contributed to the majority of downgrading. For example, only nine of the 35 studies presented any characterization of the uncertainty surrounding their cost-effectiveness results, only seven presented an incremental cost-effectiveness ratio, and only 11 explicitly stated the economic perspective from which they were calculating costs.To our knowledge, this is the first systematic review to broadly evaluate the cost-effectiveness of US in the emergency care setting across all applications, including both radiology-performed and POCUS exams. The body of literature identified through this systematic review is fairly consistent in supporting the increased cost-effectiveness of integrating US in emergency care settings across a variety of applications. Healthcare systems have begun to focus on value-based approaches throughout the hospital including the ED , and theOf the studies identified in this systematic review, those pertaining to the cost-effectiveness of US in the ED evaluation for pediatric appendicitis were the most plentiful and consistent in demonstration of cost-effectiveness gains, particularly when used in conjunction with clinical decision rules \u201328. ThreUse of POCUS evaluation of trauma is ubiquitous and recommended by the American College of Surgeons . The sixCost-effectiveness of consultative ED US was demonstrated across a variety of applications, including echocardiography, appendicitis, venous thromboembolism, renal, and obstetric. This is consistent with a prior narrative review that demonstrated increased cost-efficiency of US across the spectrum of clinical medicine .The studies identified in this review generally support the cost-effectiveness of POCUS, although some reach the alternative conclusion. The aforementioned studies evaluating POCUS in trauma consistently demonstrated cost savings. Additionally, multiple studies demonstrated potential cost savings in POCUS for biliary and OB/GYN applications , 37, 42.None of the studies included in this systematic review specifically address the widely-inferred cost-effectiveness of POCUS due to increased efficiency  and patient throughput, or the decreased adverse iatrogenic events due to US guidance of procedures \u201359. ThisThis systematic review sought to identify all relevant articles by searching five databases without language or date restrictions; however, it remains possible that pertinent articles were missed. Multiple independent reviewers were utilized at each step of the study selection and data abstraction process to minimize the likelihood of excluding relevant studies. Additionally, the mixed quality of methodology and reporting surrounding the economic evaluations conducted in these studies is notable. Most authors did not frame their analysis as a formal cost-effectiveness study, which may have led to the lack of robust methodology. Both past and recent reviews of cost-effectiveness studies in radiology have highlighted the need for standardized approaches , 61. ThiIn summary, the body of existing evidence, though limited, is generally supportive of the cost-effectiveness of US in the emergency care setting. The strongest evidence of cost-effectiveness of ultrasound in the ED exists in the evaluation of pediatric appendicitis and of abdominal trauma. Further study, using established best-practice standards in the methodology of cost-effectiveness analysis, is needed to definitively establish the cost-effectiveness of consultative and POCUS across a variety of applications in emergency care settings."}
+{"text": "To develop a clinical technique for objective estimation of exact location and degree of participation of face and neck soft tissues in age-related deformations for determine effective mini-invasive treatment techniques.Ultrasound examination was performed in 2017-2019 at 63 patients with age-related face changes. Examination was done in the vertical position for determine the role, exact location and participation degree of different soft tissues of the face and neck in age-related changes.Great diagnostic value of ultrasound examination of involutional changes in soft tissues of lower third of face and neck was noted to determine all causes of contour age-related deformities. These results were used to choose effective minimally invasive methods for correction.Ultrasound examination is a non-invasive, harmless, clinically available, inexpensive examination that allows to determine exact localization and degree of participation of different soft tissues of face and neck in age-related changes. That is very important for planning and use different minimally invasive techniques for facial and neck rejuvenation. As the people\u2019s life in the world has increased, they want to stay longer healthy, active, young and look good.Historically, in plastic surgery, methods for objective assessment of deformities in the lower third of the face and neck are not so important for open surgical techniques, when a surgeon can correct his actions based on intraoperative situation. Good visualization of tissues is impossible during minimally invasive correction, but it is very important for objective evaluation of tissues causing the deformation and for correct planning the actions of plastic surgeon. The first report on facial muscle imaging using ultrasonography was published in 1988.The aim of our research was to develop a clinical technique for objective estimation of exact location and degree of participation of face and neck soft tissues in age-related deformations for determine effective mini-invasive treatment tactics.The prospective analysis of examination and treatment of 137 patients with aged-related involutional changes in soft tissues of lower third of face and neck was performed in Federal Research Clinical Center of the FMBA in the period from 2017 to 2019. The stages of the study were approved by the Ethics Committee of the N.I. Pirogov Russian National Research Medical University . We have obtained the patent \u2018Method for choosing treatment techniques for age-related involutive changes in the face and neck soft tissues\u2019 RU 2710671 30.12.2019. Written consent of all patients to use the results of research and photos was obtained.The age of patients was from 38 to 62 years. Among them, women were 121 (88.3%), men \u2013 16 (11.7%). The average age was 49 \u00b1 0.5 years (\u00b1 standard deviation average). Presurgery ultrasound examination was done to 63 patients. The examination was performed using an ultrasound device Voluson E8Voluson E8 (Austria), a linear sensor 9 L, with a radiation frequency of 3-8 MHz. Ultrasound examination was done in the vertical position of patient to determine the maximal point of soft tissues ptosis of lower third of the face and submandibular area. Then tissue composition was determined using ultrasound without compression in this position. Parameters were measured: surplus subcutaneous and subplatysmal adipose tissue and its thickness, the thickness of platysma and the level of divergence of the edges of platysma from the mandible edges, ptosis platysma strands. Composition of tissue disturbing the contour of lower jaw from both sides was defined in the same position of patient. The thickness of the skin, subcutaneous fat and ptosis of muscles were assessed, i.e. the degree of participation of each tissue in age-related deformities.During our work we noted great diagnostic value of ultrasound examination of involutional changes of soft tissues of the lower third of the face and neck to determine all the causes of contour deformities and to define minimally invasive methods for their correction. Some clinical cases are present for illustration.Patient H, 45 years old, complained of ptosis of soft tissue face and neck, violation of aesthetic. Clinical diagnosis: Age-related soft tissue atrophy of lower third of the face and neck. During examination we found slight sagging of soft tissues in the lower third of the face and submandibular area. There were slight excess skin and wrinkles with possibility of correction without excision and formation of deforming relief .On ultrasound examination accumulations of adipose tissue was found in the lower third of the face, neck and chin (73% of the thickness of soft tissue that violated contours of the lower jaw and the neck-submandibular angle). There were no atrophic age-related changes in platysma .Result of ultrasound examination showed that the local removal of excess subcutaneous fat in areas of disturbed contours of lower jaw and submandibular area was enough to correct the aesthetic lines of these areas, it was confirmed by the results of treatment of the patient .Patient G., 54 years old, complained of soft tissue ptosis of the face and neck. Clinical diagnosis: Age-related soft tissue atrophy of lower third of the face and neck. During examination we found slight sagging of soft tissues in the submandibular area and platysma strands, painless and moderately displaced by palpation. There were excess skin and wrinkles with possibility of correction without excision and formation of deforming relief .On ultrasound examination in the vertical position of the patient we found ptosis of platysma strands from both sides, causing deformation of the contours of neck-submandibular angle, accumulation of fat tissue over platysma was inconsiderable and did not exceed the thickness of subcutaneous fat in adjacent regions. It was found that 68% of the thickness was determined by excessive deposition of subcutaneous fat.Result of ultrasound examination showed that violation of contours of the neck-submandibular area was caused by age-related involution of tissues of subcutaneous neck muscle (platysma) and was not caused by local excessive accumulations of subcutaneous fat or skin ptosis. Violation of contours of lower jaw was mainly by local excessive accumulation of subcutaneous fat, with secondary unexpressed ptosis and excess skin . Thus, cPatient K., 58 years old, complained of ptosis of soft tissue face and neck, problems of aesthetic. Clinical diagnosis: Age-related soft tissue atrophy of lower third of the face and neck. Visually, there was a sagging of soft tissues in the submandibular and cervical area, excessive accumulation of adipose tissue, violation of the contour of the lower jaw, and a smoothed neck- submandibular angle .On ultrasound examination in the vertical position of the patient we found excessive accumulation of adipose tissue above the platysma in the chin and neck area problems of lower jaw contour due to accumulation of fat, ptosis of medial platysma was diagnosed. There were not determined either visually on palpation during physical examination .Based on the results of ultrasound, it was concluded that age-related problems were caused by local excess deposition of subcutaneous fat and ptosis of platysma cords. Thus, liposuction and platysmotomy was performed with intraoperative ultrasound control which were sufficient to correct age-related changes in this area for our patient .Success of aesthetic surgery considerably depends on understanding of mechanisms of each specific deformity formation, skills to evaluate them in planning and making surgical correction as well as rehabilitation measures in postoperative period.8Aging process affects all parts of the face and neck. Deformation in neck area can be determined by several factors: weakness of skin and platysma, appearance of platysma bands, ptosis of submandibular glands, lipodystrophy and even jaw resorption. Changing of face and neck proportions, quality and structure of skin, volume and location of fat make some interventions more difficult and may limit to obtain positive results.11Analysis reveals that only few studies have been performed for objective diagnosis of involutional changes caused in lower third of face and neck. Unfortunately, practically all authors rely on subjective assessment of clinical situation. At the same time, based on anatomical studies, it is evident, that it is necessary to differentiate specific anatomical structures of soft tissue deformations. It is also difficult in many cases on general physical examination, especially in patients with thick skin and expressed subcutaneous fat cellular.For example, it is not rare situation in such patients, when liposuction eliminate excess fat, but contours of neck-submental angle were deformed by platysma bands that became visual after surgery, on ptosis of all platysma.Many authors in their works note the importance of accurate assessment of causes of neck contour disorders. Nevertheless, they often neglect to use diagnostic methods. Only lately publications in the world literature appeared about role of instrumental examinations in planning surgical correction of facial and neck tissue atrophy.Japanese authors tried to use computed tomography for objective visualization and evaluation of age-related soft tissue changes of face and neck. Okuda I. et al. in their study (57 women aged 21-57 years), in which they used multi-detector row computed tomography (MDCT) for diagnostic.Alfen N. V. was one of the first to use ultrasound to examine facial muscles in patients with myotonic dystrophy, and proved that this is perspective non-invasive method of diagnostics and monitoring in neuromuscular disorders. Ultrasound can be used for detecting early or subclinical face muscles lesion in Duchenne muscular dystrophy and Moebius syndrome to determine certain facial muscles are absent or atrophic.13Volk G. F. et al. in their research described diagnostic value of ultrasound in lesions of facial nerve after injuries and tumors, that lead to atrophy of face muscles. Ultrasound was used to control regeneration and sizes of face muscles after reconstructive surgery, thickness and intensity of echo in patients with chronic peripheral facial paralysis at different stages of denervation and reinnervation. This method simultaneously presented functional and structural information about muscle state.15Safran T et al. noted the importance of using ultrasound in cosmetology. They measured muscle thickness after botulism toxin injection, skin thickness after implantation of polylactic acid filaments and before eyelid and face surgeries. Their research indicated the importance of patients\u2019 anatomy visualizing in real time for low complication rate  without radiation exposure.16X. Wortsman, and colleagues have described in detail the ultrasound anatomy of face for non-invasive cosmetic and plastic surgery, pointed to the importance of ultrasound examination of facial structures in various deformities, paresis muscles and bruxism.G. Mashkevich et al. used ultrasound examination of the submandibular area in 10 patients. It helped to identify, which of this area components mainly caused deformation, especially in patients with so-called \u201cheavy\u201d necks.18Analysis of works reveals that ultrasound is a non-invasive, not inexpensive method in clinical practice that can visualize in detail the anatomy of soft tissues of face. However, it was not previously used in clinical practice for diagnostic involute changes of face lower third and neck to determine treatment tactics.New idea and finding of our work are the use of ultrasound examination for age-related changes of soft tissues of the lower third of face and neck in the vertical position of the patient. Different ptosis tissues and the degree of their participation in age-related changes are visible in different anatomical areas. It significantly help in determination of effective minimally invasive treatment methods in a number of clinical situations.Ultrasound examination is non-invasive, harmless, clinically available, inexpensive examination that allows to determine exact localization and degree of participation of different soft tissues of face and neck in age-related changes. It is very important for planning of use different minimally invasive techniques for facial and neck rejuvenation.VS: Conceived, designed the study, data collection, editing of manuscript, review and final approval of manuscript.SA, AT, LS: Did statistical analysis, data collection and manuscript writing."}
+{"text": "Dysfunction of the autonomic nervous system has been implicated in the pathogenesis of cardiovascular disease, including congestive heart failure and cardiac arrhythmias. Despite advances in the medical and surgical management of these entities, progression of disease persists as does the risk for sudden cardiac death. With improved knowledge of the dynamic relationships between the nervous system and heart, neuromodulatory techniques such as cardiac sympathetic denervation and vagal nerve stimulation (VNS) have emerged as possible therapeutic approaches for the management of these disorders. In this review, we present the structure and function of the cardiac nervous system and the remodeling that occurs in disease states, emphasizing the concept of increased sympathoexcitation and reduced parasympathetic tone. We review preclinical evidence for vagal nerve stimulation, and early results of clinical trials in the setting of congestive heart failure. Vagal nerve stimulation, and other neuromodulatory techniques, may improve the management of cardiovascular disorders, and warrant further study. The autonomic nervous system regulates all aspects of cardiac function, including chronotropy, inoptroy, dromotropy, and lusitropy . In the via C7 to T6 rami to the superior cervical, middle cervical, stellate, or cervicothoracic ganglia, and acts though norepinephrine and neuropeptide Y (The anatomy of the cardiac nervous system is complex and has been categorized into: (1) central components, (2) intrathoracic extracardiac components, and (3) intrinsic cardiac components . The inteptide Y . Affereneptide Y . These aeptide Y  initiatieptide Y . The ICNeptide Y . These geptide Y . Contrareptide Y . Moreoveeptide Y . For exaeptide Y . Similareptide Y . Given tIn this review, we provide a brief foundation for understanding the structure of, and organization of the cardiac autonomic nervous system and highlight neural control of cardiovascular function, emphasizing the roles of the sympathetic, parasympathetic, and ICNSs. Based on this scientific foundation, an overview of current neuromodulatory therapies is presented, focusing on cardiac sympathetic denervation and VNS . We highAutonomic control of the cardiovascular system is mediated through afferent and efferent pathways and neural networks involving the brain stem, spinal cord, peripheral ganglia, and ICNS . FeedbacCanonical organization of the sympathetic nervous system traditionally considers two sets of neuronal projections, defined by location of cell bodies and neurotransmitters mediating cell to cell communication. Preganglionic neurons with cell bodies in the intermediolateral cell column of the cervical and thoracic spinal cord (C7-T6) project to the superior, middle, cervicothoracic or stellate ganglia, and the remainder of paravertebral chain, with fibers running through ventral horns . Postganin vivo surrogate for action potential duration  evaluated the adjunct use of the Demipulse  VNS system for left or right cervical vagal nerve stimulation in a cohort of patients with heart failure with reduced ejection fraction and New York Heart Association functional class II-III symptoms . ImproveTwo other major studies have explored the impact of VNS on cardiovascular outcomes in the setting of heart failure, with mixed results . The NEuThe INcrease Of VAgal TonE in Heart Failure (INOVATE-HF) trial randomized 707 patients with HFrEF (LVEF \u2264 40%) with NYHA class III symptoms to medical therapy or medical therapy and VNS using an R-wave triggered pulse . Of noteOur prior work has described the concept of the neural fulcrum \u2013 an equilibrium point between activation of afferent and efferent vagus nerve pathways, resulting in a null heart response to stimulation with intact neural circuits . TitratiMultiple cardiovascular disorders including myocardial infarction and congestive heart failure result in excessive sympatoexcitation and a withdrawal of central parasympathetic tone . The majJH and JLA contributed to writing, reviewing, and editing of the manuscript. Both the authors approved the submitted version.University of California, Los Angeles has patents developed by JLA relating to cardiac neural diagnostics and therapeutics. JLA is a co-founder of NeuCures, Inc.The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Dear Editor,Mastocytosis is a heterogeneous group of disorders whose signs and symptoms are characterized by mast cells infiltrate in tissues.peau d\u2019orange appearance , abdominal symptoms, respiratory symptoms, hypotension and even anaphylaxis.DCM is a rare condition that usually manifests with erythema, dermal thickening, skin folds accentuation, and edema with a typical leather or peau d\u2019orange appearance.4A review of DCM cases concluded that the majority were congenital and that even in cases of high tryptase the prognosis was good.Reliable prognostic criteria are still lacking to predict the risk of systemic involvement in DCM and maculo-papular mastocytosis. Most cases of DCM resolve spontaneously in childhood or adolescence, however these patients are at a greater risk of complications such as hypotension, anaphylaxis and diarrhea and they should be monitored regularly.None declared.Julia Marcon Cardoso: Approval of the final version of the manuscript; conception and planning of the study; elaboration and writing of the manuscript; critical review of the literature; critical review of the manuscript.Camila Angelico S. Cabral: Conception and planning of the study; critical review of the literature;Rute Facchini Lellis: Approval of the final version of the manuscript; obtaining, analysis, and interpretation of the data.None declared."}
+{"text": "The development of medicines designed for children can be challenging since this distinct patient population requires specific needs. A formulation designed for paediatric patients must consider the following aspects: patient population variability; dose flexibility; route of administration; patient compliance; drug and excipient tolerability. The purpose of this Special Issue entitled \u201cPaediatric Formulation: Design and Development\u201d is to provide an update on both state-of-the-art methodology and operational challenges in the design and development of paediatric formulations. It aims at re-evaluating what is needed for more progress in the design and development of age-appropriate treatments for paediatric diseases, focusing on: formulation development; drug delivery design; efficacy, safety, and tolerability of drugs and excipients. This editorial, briefly, summarizes the objects of nine original research and review papers published in this Special Issue. When designing and developing paediatric medicines, the route of administration, dosage form, and dose of the active ingredient (API) are decided on the basis of the expected duration of the therapy, the disease affecting a patient and his/her age, size, physio-pathological condition, API organoleptic and physicochemical properties , its pharmacokinetic and pharmacodynamic properties, and stability during manufacture, storage, and use of the chosen formulation ,2,3,4.The paediatric population is a heterogeneous group ranging from preterm newborn infants to adolescents with wide physiological and developmental differences regarding organ and skin maturation, metabolism, and other factors that impact on the pharmacokinetics and pharmacodynamics of a drug .It is a challenge to formulate one dosage form appropriate for this heterogeneous group of the human population. The goal should be to safely cover as wide an age range as possible with one specific dosage form. The guiding principle for choosing paediatric formulations should be the equilibrium of risks and benefits, taking into account the specific needs of these vulnerable patients. Key aspects in paediatric formulations involve the design and development of novel dosage forms, which should be adjustable for age and size, acceptable and palatable, easy to administer, and, at the same time, safer and effective ,3,4.Current use of medicines for paediatric patients reflects the full range of dosage forms and routes of administration used for adult medicines. There is, however, limited information on the acceptability of different paediatric dosage forms in relation to age and therapeutic needs and on the safety of excipients in relation to the development of the child ,3,4,6,7.Since its establishment, the biopharmaceutical classification system (BCS) has facilitated the development of oral drug formulations designed for adult patients. Theoretically, the BCS tenets could be applied also to paediatrics. Children\u2019s peculiarities and physiological differences from adults justify the need for a specific paediatric biopharmaceutics classification system (PBCS). Several scientific works attempted to provisionally classify oral drugs listed on the latest World Health Organization\u2019s Essential Medicines List for Children into age appropriate BCS. Validating a PBCS would provide a valuable tool to apply in specific paediatric formulation design by reducing time and costs and avoiding unnecessary paediatric experiments restricted by ethical reasons. Additionally, PBCS could minimize the associated risks to the use of adult medicines on pharmaceutical compound formulations for children. Moreover, developing a PBCS classification might be helpful in the process of harmonizing extemporaneous oral formulations in the hospital setting ,9.As a result of the great interest in developing age-appropriate dosage forms for children, this Special Issue, entitled \u201cPaediatric Formulation: Design and Development\u201d, was programmed to highlight the need of formulating safer and effective medicines for paediatric patients. A total of nine papers were accepted for publication in this issue: four reviews and five primary data manuscripts, focusing on (1) the design, characterization, and safety evaluation of orodispersable formulations for paediatric tuberculosis pharmacotherapy; (2) development and palatability assessment of ritonavir powder for the paediatric population; (3) development of new praziquantel paediatric formulations in schistosomiasis treatment; (4) tridimensional retinoblastoma cultures as a vitreous seeds model for live-cell imaging of chemotherapy penetration; (5) preparation and characterization of dasatinib/cyclodextrin complex for the potential treatment of paediatric neuromuscular disorders; (6) efficacy, safety, and tolerability of tyrosine kinase inhibitors in the treatment of paediatric chronic myeloid leukaemia; (7) technologies and modern approaches to modify drug release in paediatric dosage forms; (8) challenges in formulating neonatal medicines; (9) efficacy, safety, and tolerability of anti-interleukin-1 (anti-IL-1) treatment in paediatric autoinflammatory diseases.Palatable orodispersible film formulations are ideal for patients with swallowing difficulties such as babies and children because they are stable and dissolve rapidly within the oral cavity in the presence of saliva, without the need to chew or drink water. In this Special Issue, Matawo and co-workers  investig\u00ae oral powder (NOP) was developed to replace the oral solution, which provided reasonable bioavailability but exhibited taste-masking challenges and required the use of solvents with potential paediatric toxicity. In this study, the authors provided an overview of the development of NOP and palatability assessment strategy. In summary, NOP provided dose flexibility, enhanced stability, eliminated solvents, and maintained consistent bioavailability, with reduced bitterness and improved palatability via administration with common food products.In this Special Issue, Morris and colleagues  presenteHere, Albertini and co-workers  evaluateRetinoblastoma is the most common intraocular tumour of childhood ,14. ThisFor the first time, in this issue, a new inclusion complex of dasatinib, the first-choice oral drug in the treatment of chronic myeloid leukaemia and the excipient hydroxypropyl-beta-cyclodextrin (HP-\u03b2-CD), was described and fully characterized by Cutrignelli and co-workers  for the Recently, tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib have been approved for the treatment of chronic myeloid leukaemia in children, even though the studies that were concerned with efficacy and safety toward this population are still awaiting defined and more accurate data ,18,19. IIn pharmaceutical technology, the paediatric population still represents the greatest challenge in terms of developing flexible and appropriate drug dosage forms. In their review article published in this issue, Trofimiuk and colleagues  elucidatIn this Special Issue, O\u2019Brien at al.  publisheThe safety profile of treatment is of paramount importance when children with autoinflammatory disorders are managed, since it may affect adherence to treatment and overall clinical efficacy ,24,25. IThe high number of articles published in this Special Issue entitled \u201cPaediatric Formulation: Design and Development\u201d highlights the significant amount of research being conducted on the development of medicines designed for paediatric patients.Formulating an appropriate dosage form is a challenge when considering chronic diseases that affect children and minimizing the dose frequency. Key aspects in paediatric formulations involve the design and development of novel dosage forms, which should be adjustable for age, palatable, easy to administer, and, at the same time, safer and effective."}
+{"text": "Due to the exceptionally high transmissibility and robust infectiousness of the underlying virus [severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)]  was first identified in Wuhan, China, in December 2019. It was then declared a public health emergency of international concern on 30Since no vaccine is far available for containment of this virus, thus unprecedented large-scale quarantine measures are one of the best ways to prevent the chain of events leading to transmission of SARS-CoV-2. In many countries, mandatory requirements for social isolation, including stay-at-home orders, banning social contacts, canceling public events, and closing mass transit systems have been ordered by governments , 5. AlthIn social animals, positive social interactions are fundamental for increasing cognitive ability, promoting brain development, and maintaining mental and physical health, ultimately contributing to survival and reproduction , 10. LonStress due to social isolation accounts for one of the most common sources of chronic stress in humans. Previous studies have shown that chronic social isolation correlates with a higher risk of morbidity and mortality . ChronicThe brain is a vital organ that is vulnerable to influence by the external environment. Regulation of social behavior and emotion depends on complex neural circuits within the brain . PreviouExposure to social isolation stress induces a variety of endocrine changes, and dysregulation of the neuroimmune-endocrine system has been shown to be one vital mechanism for the development of psychological disorders . StudiesFurthermore, social isolation stress has also been shown to alter levels of neurotransmitters and receptor sensitivities in many regions of the central nervous system (CNS) , 39. IntSocial isolation stress can also alter neurotrophin levels. Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors, which are key regulators of synaptogenesis, neuronal plasticity, and adult neurogenesis , 44, creFor many countries, the COVID-19 pandemic may necessitate long-term and wide-ranging social isolation. This social isolation will not only change the reaction norms of daily activities, but may also create dramatic adverse psychological effects, including loss of freedom, isolation from friends and family, and feelings of loneliness and uncertainty. Unfortunately, chronic stress-induced neurochemical and neuroendocrine disorders are often neglected until they become psychological illness. Given that a mandatory quarantine of confirmed and suspected cases is the best way to avoid spread of COVID-19, a series of measures are needed to avoid the negative physiological and psychological effects induced by chronic social isolation, including potential neurochemical and neuroendocrine system disorders. First, national public health emergency systems should provide fundamental and explicit guidelines for prevention of mental illness induced by mandatory social distancing and thereby mitigate physiological and psychological stressors. These guidelines should include recommendations for positive social interactions and maintenance/development of social supports, including online communication with relatives and friends . Second,In conclusion, both governments and citizens must recognize the important neurochemical and neuroendocrine changes induced by the chronic social isolation stress of the COVID-19 pandemic to help prevent potential psychological and mental illnesses that are often invisible and easy to neglect.LW: literature searched and wrote the original draft. GN: literature searched and wrote the original draft. TZ: manuscript revised. DL and YW: study designed. DL: wrote the final manuscript. All authors contributed to the article and approved the submitted version.This work was supported by the National Natural Science Foundation of China  to DL and the Natural Science Foundation of China of Hebei Province (C2020205005) and China Postdoctoral Science Foundation (2020M670685) to LW.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Preterm birth is associated with a significantly increased risk for childhood and adolescent psychopathology relative to full-term birth, with an inverse relationship between gestational age at birth and later risk for psychopathology. The manifestation of symptomatology and comorbidity profiles of emotional and behavioral adjustment problems in this high-risk group have been shown to be distinct from the broader pediatric population. Acknowledging these differences, a preterm behavioral phenotype has been proposed and increasingly recognized, highlighting the unique, frequent co-occurrence of symptomatology associated with attention-deficit/hyperactivity disorder, autism spectrum disorder, and anxiety disorders. The current state-of-the-art review provides a comprehensive characterization of this phenotype to date and further highlights key knowledge gaps primarily regarding the evolution of symptoms, co-occurrence of disorders and/or symptomatology within the phenotype, and associations of the phenotype with chronological age and degree of prematurity. Preterm birth (<37 weeks gestation) affects approximately 15 million infants and their families around the world, annually, with vast improvements in survival reported in recent times , 3. PretDiagnostic and Statistical Manual of Mental Disorders (DSM) Third Edition Revised (DSM-III-R), Fourth Edition (DSM-IV), or the International Classification of Diseases 10th Revision (ICD-10) in children, adolescents, and young adults aged 10 to 25 years and born preterm or with low birth weight (LBW) compared to full-term peers , and if they made explicit reference to the preterm behavioral phenotype in the background or discussion of the study when interpreting findings. Studies were excluded if they investigated only one of the three phenotype clusters or if they exclusively recruited a medically high-risk preterm sample , due to these groups being less representative of the larger preterm population. In line with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines , a systeLoe et al.  investigDSM-IV disorder, there were significantly more ELBW adolescents meeting criteria for three or more disorders (n=10 vs. 1). In contrast, ELBW adolescents self-reported lower scores on all measures compared to normal birth weight adolescents, with significant differences for item ratings of oppositional defiant disorder and rates of inattentive ADHD and conduct disorder. From ELBW self-reports, there were also no significant differences in the rates of one or more, or three or more, co-occurring disorders. While a strength of this study is the comparison between parent and adolescent reports, a limitation in the current context is the failure of the study to focus specifically on the co-occurrence of disorders within the phenotype. This information would have provided support for the proposed unique pattern of behavioral and emotional difficulties. Methodologically, findings may be further limited by reliance on clinical cutoff thresholds as applied to ratings rather than on clinical psychiatric diagnoses.Taylor et al.  is the fKorzeniewski et al.  describeFollowing on from this, Samuelsson et al.  investigUnlike the previous studies reviewed above, Johnson et al. investigated the comorbidity of cognitive and behavioral outcomes in late to moderate preterm (LMPT) born toddlers in the United Kingdom . This isAnother investigation of the comorbidity of symptoms comprising a potential preterm behavioral phenotype was conducted by Burnett et al. . This stMaintaining the theme of cluster-based approaches, Lean et al.  identifiSince the conceptualization of the preterm behavioral phenotype, seven studies have investigated two or three symptom clusters characteristic of ADHD, ASD, or anxiety, with explicit reference to the phenotype in the study rationale or interpretation of findings. Research has increased knowledge of the variable pattern of behavioral and emotional difficulties in the preterm population and of the co-occurrence of symptom clusters within the phenotype. Despite these advances, there are several methodological challenges that continue to hamper our knowledge in this area. The first challenge is the substantial heterogeneity of outcome measures administered in follow-up assessments of preterm samples. As shown in A prevailing limitation of the existing literature is that the manifestation of the preterm behavioral phenotype is very rarely described in relation to underlying etiological mechanisms. Therefore, it remains unclear if the unique comorbid nature of the phenotype has a distinct neurological or psychosocial basis precipitating its development.The impetus to conduct more research on neurological alterations associated with the preterm behavioral phenotype is growing with the increase in magnetic resonance imaging studies of preterm samples. In the preterm population, ADHD has been associated with reduced volumes in total cerebral and frontal areas , 41, venMaternal mental health is another factor that may underlie the unique development of comorbid psychopathology in preterm children . MothersThe primary mechanisms of the preterm birth experience and the resultant maternal mental health can both negatively impact parenting behavior and mother\u2013child relationships , 61, whiEight systematic reviews and meta-analyses have been published since the preterm behavioral phenotype was proposed in 2011 \u201368, eachDSM-IV/V\u2013based conceptualization of the preterm behavioral phenotype is needed in view of the vast variability in the preterm population in etiology, symptom presentation, and comorbidity.Enhancing understanding of the preterm behavioral phenotype will require further investigation of the neonatal, neural, and psychosocial antecedents of the types and comorbidity of behavioral and emotional problems in preterm children. Longitudinal studies are needed to address questions regarding influences on developmental precursors of psychiatric disorders and identification of risk and resilience factors. Finally, critical review of the current The objective of this state-of-the-art review was to comprehensively synthesize and describe the studies characterizing the preterm behavioral phenotype since conceptualization in 2011. Findings confirm the suggestion that children born preterm are at significantly increased risk for symptoms of ADHD, ASD, and anxiety disorders. Although there is some additional support for comorbidity of these three symptom clusters, few studies have investigated the extent to which these clusters occur conjointly as a unitary phenotype, in isolation, or in combination with other behavioral, cognitive, or learning impairments. The pattern of comorbidities associated with preterm birth has implications for neurodevelopmental assessment of children born preterm and for addressing their clinical needs. As profiles of impairment may vary with age, knowledge of comorbidities may be useful in improving early identification of children at the highest risk for ongoing psychiatric disorders. Identification of profiles of comorbidity may also be useful in guiding more individualized approaches to intervention.The corresponding author, SB, had full access to all of the study data and is primarily accountable for all aspects of the work, including the decision to submit for publication. GF conceptualized and designed the review protocol, acquired data, interpreted the results, drafted and revised the initial manuscript, and approved the final manuscript as submitted. GT substantially contributed to the oversight of the conceptualization of the review, interpreted the results, critically reviewed and revised the initial manuscript, and approved the final manuscript as submitted. SB acquired funds and resources, conceptualized the review, supervised the designing of the review protocol and data acquisition, interpreted the results, critically reviewed and revised the initial manuscript, and approved the final manuscript as submitted.This work was supported by a Mater Foundation Principal Research Fellowship to SB and the University of Queensland Research Training Program and Frank Clair scholarships to GF. The funding sources had no role in the writing of the manuscript or in the decision to submit it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The functional consequences of the aging brain include several aspects of physical and cognitive decline that ultimately cause loss of mobility and dementia. Although in certain individuals, the cognitive and physical correlates of the aging brain occur in parallel, others show decline in one of these functional parameters. Underlying mechanism of this complex process that lead to different manifestations is not well understood. Proposed mechanisms include brain structural changes, tau pathology, specific white matter degeneration, metabolic derangement mostly including lipids metabolism and others. This symposium aims to address the complexity of the aging brain by showcasing studies that span the continuum from normal aging to dementia using data from the Baltimore Longitudinal Study of Aging (BLSA). The wealth of neuroimaging and phenotype data from the BLSA provides the unique opportunity to investigate neural substrates and predictors of aging phenotype, and mechanisms of age-related neurodegeneration and pathology, such as dementia, and loss of mobility. First, we identify multimodal neuroimaging predictors of important aging phenotypes of gait decline (Sargent/Tian) and memory decline (Bilgel). Second, using advanced quantitative MRI technology, we investigate underlying mechanisms of age-related white matter degeneration through potential oligodendrocyte metabolism (Bouhrara). Third, we demonstrate unique cognitive and neuroimaging profiles of dual memory and gait decline (Tian) and neural substrates for bile acids, the primary cholesterol breakdown products (Varma) in relation to dementia. We seek to generate discussions of mechanisms of the aging brain that connect the age-related phenotypes, such as decline of mobility and cognition, to the development of dementia."}
+{"text": "Thyroid hormone has effects on the skin. Patients with hypothyroidism have changes such as dry, scaly and rough skin. Increase carotene in the dermis becomes a yellowish tone to the skin of the patient with hypothyroidism. There is an increase in capillary cycle (anagen phase) and nail growth and a reduction in eccrine gland secretion. It is a case of primary hypothyroidism with nail manifestations associated with dermatologic disorders and successful treatment with levothyroxine. Receptors for thyroid hormone have already been found in keratinocytes, fibroblasts, hair follicles and sebaceous glands. Genes responsive to thyroid hormones and elements of the hypothalamic\u2013pituitary\u2013thyroid axis were identified on the skin. This report highlights the importance of cutaneous manifestations as markers of thyroid disease. Thyroid hormone effects on the skin.4Male, 58-year-old, seller, referring nail dystrophy in all the quirodactyls  and firsCutaneous manifestations are important as external markers of thyroid disease. Thyroid hormone receptors have been found in keratinocytes, fibroblasts, hair follicles and sebaceous glands. Genes responsive to thyroid hormones and elements of the hypothalamic\u2013pituitary\u2013thyroid axis were identified on the skin. Hypothyroidism reduces the activity of enzymes in the cholesterol sulfate cycle, causes changes in the skin barrier, affects the development of lamellar granules (Odland bodies),None declared.Thadeu Santos Silva: Conception and planning of the study; elaboration and writing of the manuscript; obtaining, analysis, and interpretation of the data; critical review of the manuscript.Gustavo Baptista de Almeida Faro: Elaboration and writing of the manuscript; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature.M\u00e1rcia Gabrielle Bonfim Cortes: and planning of the study; obtaining, analysis, and interpretation of the data; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the manuscript.Vit\u00f3ria Regina Pedreira de Almeida Rego: of the final version of the manuscript; elaboration and writing of the manuscript; effective participation in research orientation; critical review of the literature.None declared."}
+{"text": "In Europe, discussions are currently ongoing to harmonize front-of-pack nutritional labelling, while some countries have adopted or are considering implementing the Nutri-Score. However, its adaptability to multiple nutritional contexts in Europe requires further investigation. This study aimed to evaluate the applicability of the Nutri-Score in various European countries, regarding its ability to discriminate the nutritional quality of foods and its consistency with national dietary recommendations. The European Food Information Resource (EUROFIR) nutritional composition databases from eight European countries  were used. The distribution of foods across the Nutri-Score classes within food groups was assessed, as well as the discriminating performance of the label, and the adequacy of nutritional recommendations. The Nutri-Score demonstrated high discriminating ability for all food groups, with similar trends in the eight countries, and consistency with nutritional recommendations. For instance, fruit and vegetable products were mainly classified in the two healthiest Nutri-Score categories, while sugar and animal fat products were mainly classified in the two less healthy categories of the Nutri-Score. Our results support the fact that the Nutri-Score would be a relevant tool to discriminate the nutritional quality of products within and across relevant food groups in different European countries, with consistency with nutritional recommendations. In 2017, the European region was the most affected World Health Organization (WHO) region by non-communicable diseases , accounting for approximately 77% of the burden of disease and 88% of deaths . In thisHowever, in view of the plurality of FoPLs on the European market, potentially leading to confusion for consumers, the European Commission has launched discussions among member states on the potential reopening of the INCO regulation , includiMore specifically, the Nutri-Score is a color-coded graded scale of five letters based on the United Kingdom\u2019s Food Standards Agency (FSA) nutrient profiling system (NPS), adapted to the French context by the French High Council for Public Health (HCSP), namely the FSAm-NPS ,19. The Data were retrieved from the European Food Information Resource (EUROFIR), an international non-profit association created to promote international cooperation in the nutrition field, in particular through the collection of validated national nutritional databases . FollowiFood products were categorized according to the EUROFIR classification, grouping foods with similar use and nutritional characteristics . Herbs aThe following elements in the nutritional composition table of each country were required for the calculation of the FSAm-NPS score and thus the Nutri-Score of each food: energy, sugars, fats, Saturated Fatty Acids (SFA), proteins, fiber, and sodium. In order to limit the number of missing data, the content of some nutrients was recalculated using usual equations with other data available in the tables  = total protein (g) * 17 + total carbohydrates (g) * 17 + total fat (g) * 38 + alcohol (g) * 29 + total dietary fiber (g) * 8). Moreover, in order to verify the quality of the nutritional composition data, control procedures were performed on variables of interest for the FSAm-NPS calculation, including verification on the total energy content. The analyses were finally carried out on the eight following countries, for which all necessary data were available: Finland, France, Norway, Poland, Portugal, Slovakia, Sweden, and Switzerland. Finally, 11,347 foods and beverages from the eight countries contained data on food composition and classification and were thus used for the analyses. The number of food products available in each group or subgroup varied across countries. In total, 2075 food products were included in the database for Finland, 2309 for France, 1101 for Norway, 919 for Poland, 921 for Portugal, 1183 for Slovakia, 1990 for Sweden and 849 for Switzerland. The flowchart of the food databases used in the present study is described in Based on the nutritional composition for 100 g of food (or 100 mL of beverage), the FSAm-NPS assigns positive points for the amounts in elements that should be limited, including energy (kJ), total sugars (g), SFA (g), and sodium (mg) (0 to 10 positive points for each). Negative points are then attributed to the amount in elements that should be promoted, including fruits, vegetables, legumes and nuts , fibers (g) and protein (g) (0 to 5 negative points for each). The FVLN component was not available per se in the composition tables. Thus, values were estimated for each product, using French generic food composition databases for which FVLN amounts had been estimated ,35,38,39For each main food group and subgroup, the distribution of foods and beverages in the different classes of the Nutri-Score was computed . This distribution was assessed across and within the eight countries. Further, within each main food group and subgroup, the modal class and the percentage corresponding to the predominant Nutri-Score class were calculated. The ability of the Nutri-Score to discriminate the nutritional quality of products within main food groups and subgroups was assessed using the number of available colors in each group. Discriminating performance was considered satisfying when at least three classes of Nutri-Score were available in the food group. In addition, the overall distribution of foods in the different classes of the Nutri-Score was compared with the food-based dietary guidelines from the different countries included in the study and the general guidelines from the WHO . Thus, fOverall, a final sample of 11,347 foods and beverages was used, including 1800 fresh or processed fruits, vegetables and nuts, seeds or kernels; 1898 breads and cereal products; 2506 meat, fish and egg products; 906 milk and dairy products; 336 fats or oils; 2655 composite products; 614 sugar or sugar products; and 632 beverages.Overall, for the eight countries combined, the distribution of the different Nutri-Score classes for each main food group and subgroup is displayed in Overall, in the eight countries combined, at least three classes of the Nutri-Score were observed for all main groups and subgroups, except in the \u201cpulse and pulse product\u201d subgroup, where only two classes of the Nutri-Score (\u201cA\u201d and \u201cB\u201d) were represented. The results on the overall discriminating performance of the Nutri-Score in each country are displayed in In this study, the distribution of foods within the Nutri-Score classes showed a good performance of the FoPL to discriminate the nutritional quality of products within main food groups and subgroups, and across relevant food groups in terms of purchase, use or consumption, with high consistency with official dietary guidelines in the eight countries tested\u2014Finland, France, Norway, Poland, Portugal, Slovakia, Sweden and Switzerland. These results are consistent with other studies using food composition databases of manufactured foods from the French and German markets, therefore validating the ability of the Nutri-Score to discriminate the nutritional quality of products in various sociocultural contexts ,35. A scThe validation of the ability of the Nutri-Score to discriminate the nutritional quality of products in different markets using the FSAm-NPS profile is particularly important to assess its transferability given the current European context. Beyond the country-specific food database, the concordance of our results confirms the performance of the Nutri-Score system in achieving product discrimination in various European countries ,21. OnlyDietary guidelines and FoPLs such as the Nutri-Score are complementary and synergic measures, based on different approaches and principles. Dietary guidelines aim to provide consumers practical guidelines to adopt a healthy diet, by helping them identifying the food groups that should be encouraged  and those that should be limited  . NeverthThe use of the EUROFIR database, including both generic and specific food and beverages of multiple European countries, is the main strength of the present study. Indeed, it allowed us to perform cross-cultural comparisons of the discriminating performance of the Nutri-Score, particularly important in the current European context of front-of-pack nutritional labelling harmonization. This comparative study across eight European countries remains the first study in terms of the validation of the NPS underlying the Nutri-Score in different sociocultural contexts on a large variety of generic foods. These findings are complementary to studies conducted in other food databases such as Open Food Facts providing data on multiple industrial foods of different brands. However, some limitations should be acknowledged. First, data from EUROFIR were retrieved from different sources  and did not allow us to analyze the representativeness of the sample of foods collected in our database. Nevertheless, our objective was to assess the discrimination capacity of the Nutri-Score; we did not need to be exhaustive and the EUROFIR database provided a large number of food products for each country. In addition, some disparities were observed between countries regarding the number of foods available, or even the composition of foods or both. Given these heterogeneities of the database structures, we elected not to perform statistical tests to determine the significance of the intercountry differences. However, only a few countries  were concerned, and their results remain consistent with the literature mentioned above. Moreover, several procedures were applied to verify the validity of the data and optimize the number of products in each database. In addition, results on the distribution of foods in the different Nutri-Score classes depended on the EUROFIR classification that was used in the present study. Another limitation of the present study remains the somewhat arbitrary aspect of the measurements of the discriminating performance of the FoPL and the consistency with dietary guidelines. Nevertheless, in the absence of a consensual indicator to which to compare the performance of nutrient profiling, we used a similar methodology to previous studies ,35. FinaOur results provide additional evidence of the relevant application of the Nutri-Score and its adaptability to the European context, particularly in Finland, France, Norway, Poland, Portugal, Slovakia, Sweden, and Switzerland, with regard to discrimination within main food groups and subgroups. This FoPL is notably strongly supported by European consumer associations who launched a petition (\u201cPRO-NUTRISCORE\u201d) in order to encourage the European Commission to change the regulation and make the label mandatory. This study supports the Nutri-Score as an interesting alternative for European countries wishing to implement complementary nutrition labelling on the front of food packaging, and ultimately avoid confusion among consumers through the coexistence of several systems on the European market."}
+{"text": "Canine Morbillivirus  is the causative agent of one of the most important diseases in domestic dogs and wild fauna. It belongs to the Paramyxoviridae family, order Mononegavirales, which has a non-segmented, single-stranded linear negative polarity RNA genome , CDV infects multiple species within the Order Carnivora, including several wild species as Canidae, Felidae, Procyonidae, Mustelidae, Hyaenidae, Ursidae, and Viverridae families. CDV infection has also been reported in other Orders such as Rodentia (rodents), Primates, Artiodactyla, and Proboscidea  with neurological signs . Both of these belong to the Myrmecophagidae Family , family Choloepodidae, order Pilosa, was reported with clinical signs that included hyporexia, lethargy, mucopurulent nasal discharge, and oral and facial ulcers confirmed as CDV South America/North America-4 lineage  and wild and domestic dogs in the United States (North America) , white-lipped peccary (Tayassu pecari), collared peccary (Pecari tajacu), white-tailed deer (Odocoileus virginianus) and the Central American red brocket deer (Mazama temama), carnivores such as the jaguar (Panthera onca), puma (Puma concolor), and ocelot , and insectivores like the giant anteater (Myrmecophaga tridactyla); all of them are mostly forest specialists  ranging from ungulates to carnivores and even insectivorous species, and CDV has been reported to infect most of those species   , margay (Leopardus wiedii), jaguarundi (Herpailurus yagouaroundi), Jaguars (Panther onca), ocelots , jaguarundis (Puma yaguaroundi), pampas cat (Leopardus colocolo), and other wild canids such as the maned wolf (Chrysocyon brachyurus), crab-eating fox (Cerdocyon thous), hoary fox , striped hog-nosed skunk (Conepatus semistriatus), and coati (Nasua nasua), among others  contribute more than 75 % of biomass to the observed diet of the jaguar (Panthera onca) in the Cerrado, central Brazil , another species that has been commonly been reported as being at risk of infection with CDV (Noon et al., In the Mesoamerican and South American areas, CDV has been described as infecting the cougar (Our understanding of the circulation of CDV in the Americas allows us to speculate on the number of critical factors. These factors include the presence of specific viral lineages in large geographical areas, and the susceptibility of circulating species in interconnected regions which favors viral exchange across the continent and represents a risk for wild endangered populations. For this reason, it is imperative to establish not only the dynamics but also diverse aspects of the circulation of CDV among wildlife in the Americas, such as prevalent linages and their associations that would enable us to elucidate the main circulating stains.There is a great possibility that there is an underreporting of CDV infection and that the published cases only represent the tip of the iceberg in the epidemiology of CDV in wild populations in the Americas.We recommend enhancing the monitoring of CDV among wildlife corridors and to evaluate the CDV dynamics among different target populations regardless of whether clinical signs are observed. Moreover, we encourage the implementation of an interdisciplinary approach that would enable us to understand the critical role of high impact/mortality diseases such as CDV on the wildlife conservation. Also we encourage the assessment of the impact of CDV circulation and vaccine coverage of domestic dogs on wildlife epidemics, as this topic has not been evaluated in the America corridor areas.JR-S conceived the study. SR-M, MM-G, JS, and JR-S were involved in all other aspects of the study, including data collection, data analysis, drafting and editing the paper. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Coronavirus disease 2019 (COVID-19) has accelerated the adoption of telemedicine globally. The current consortium critically examines the telemedicine frameworks, identifies gaps in its implementation and investigates the changes in telemedicine framework/s during COVID-19 across the globe. Streamlining of global public health preparedness framework that is interoperable and allow for collaboration and sharing of resources, in which telemedicine is an integral part of the public health response during outbreaks such as COVID-19, should be pursued. With adequate reinforcement, telemedicine has the potential to act as the \u201csafety-net\u201d of our public health response to an outbreak. Our focus on telemedicine must shift to the developing and under-developing nations, which carry a disproportionate burden of vulnerable communities who are at risk due to COVID-19. The novel coronavirus disease COVID-19) emerged at the end of 2019 in Wuhan (People's Republic of China) and the viral outbreak was declared as a pandemic by World Health Organization (WHO) on March 11, 2020 9 emerged\u20136. The gPandemics challenge the preparedness of health systems-exposing the structural barriers . Amidst Existing telemedicine frameworks and policies of various countries/regions and their implementation stage are analyzed using Gladhart  and Pan The existing telemedicine framework/s across various regions/countries, status or maturity of telemedicine implementation, and various developments or changes that have been adopted during the COVID-19 are summarized. A comparative analysis of existing telemedicine frameworks using Gladhart and WHO/PAHO hat models, their stage, and recommendations from this consortium on improving telemedicine uptake during and beyond COVID-19 have been provided in A 2016 multi-country study by Suzuki et al. assessed the possibility of introducing telemedicine services in several developing Asian countries . IndicatAsian telehealth platforms are reporting drastically increased usages, such as Indonesian telehealth platforms Alodokter, Halodoc, and GrabHealth, driven by government support and recommendation . The DocSingapore is a front-runner in Asia in terms of telemedicine adoption and healthcare system efficiency. In 2018, the Singapore Ministry of Health launched a regulatory sandbox to facilitate innovation and form relationships between the government and telehealth partners . There aFederated National Health Information System.\u201d It proposes to link systems within private- and public-health provider organizations across primary-, secondary-, and tertiary-care value chains , Department of Information Technology, Ministry of External Affairs and MoHFW . HoweverSome of the national projects undertaken by the Ministry of Health and Family welfare are Integrated Disease Surveillance Project (IDSP), National Cancer Network (ONCONET), National Rural Telemedicine Network, National Medical College Network, and the Digital Medical Library Network . The fraCurrently, no national telemedicine framework in Bangladesh exists; and current systems suffer from lack of technological infrastructure, healthcare inequities, and poor treatment quality . The curChina has a sizeable urban-rural health gap, which major telehealth networks such as the International MedioNet of China network, Golden Health Network, and the People's Liberation Army Telemedicine Network have not been able to rectify . In SeptDevelopment of telemedicine in rural health care,\u201d was launched in 2005 within the framework of the state program  in 2004 . Its pur program . During ormation . As a paormation . At presormation . This ex country . KazakhsSub-Saharan Africa is a region of swift telehealth development, as program implementation increases, and smartphone penetrance is expected to reach 66% by 2025 . This reTelemedicine is still in its infancy in Africa due to ongoing conflicts and war, inadequate information communication technology (ICT), and lack of funding and political support for technology diffusion and policy . In lighLatin America has one of the fastest-growing elderly populations worldwide and has a big divide in access to healthcare providers between rural and urban regions . A 2019 Targeted government support of telemedicine is needed in this region, as telemedicine in countries such as Mexico falls under the standard practice of medicine regulations, instead of being governed by a focused telehealth department . In 2018Telehealth in the Caribbean is in a relatively early stage, with a lack of cohesive telehealth strategies and policies. The National Health Authority in the Bahamas announced a new Electronic Health Record (EHR) system at the end of 2019 , which rAustralia is in the process of making telehealth implementation more accessible for providers since the COVID-19 outbreak . New MedThe Ministry of Health in New Zealand has released an advisory on available teleconsultation technologies for health care practitioners and best practices around patient privacy . The MedFrench Doctolib and Qare, Swedish LIVI, UK's Push Doctor, and Germany's Compugroup Medical SE have all seen considerable increases in European uptake numbers , telecommunication companies such as BT, Virgin Media, and Sky in the United Kingdom have agreed to support the National Health Services (NHS) in rolling out telehealth for healthcare practitioners . PrimaryIt has been reported that many Italian hospitals lack the infrastructure for effective telehealth platforms, due to supply-chain breakdown and insufficient internet capabilities . Italy avia video or phone consultations by nurses were provided. This was expanded to include teleconsultations by speech therapists on March 25, 2020.The telemedicine regulations in France developed before COVID-19 allowed tertiary and primary care physicians to switch scheduled in-person consultations to teleconsultations, as and when appropriate . All vidDenia Marina Salud Hospital have reported a rapid switch to telemedicine for outpatients and staff conferences to good effect  consortium is formed to champion the safety of healthcare workers, policy development, and advocacy for global pandemic preparedness and action.SBh devised the project, the main conceptual ideas, including the proposal for a new telemedicine workflow, the proof outline, and coordinated the writing and editing of the manuscript. SBh and SBr wrote the first draft of the manuscript. SBh encouraged SBr to investigate and supervised the findings of this work. All authors discussed the results and recommendations and contributed to the final manuscript.SP is the Vice President of Immersive Medicine at Luxsonic technologies, a medical technology company specializing in virtual/augmented reality for medical education, collaboration, and training. AAt is the Scientific Founder and Board Member of Rx.Health, and founding chair of NODE.Health . The opinions expressed in this article are those of the authors and do not necessarily represent the decisions, official policy, or opinions of the affiliated institutions. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Cellular senescence, the decline of cellular function due to aging, causes gradual loss of physiological functions and induces some chronic diseases, which negatively affect the quality of human life. Intervention in the cellular senescence process may reduce these incidences and delay the progression of age-related diseases, thereby contributing to the longevity of human lifespan. The budding yeast, Saccharomyces cerevisiae, is a model system that can provide significant insights into the genetics and molecular biology of senescence and is a suitable cellular model for research on mammalian cells. In the 2019 GSA meeting, we had revealed that the prolongation of yeast cell lifespan was induced by the addition of immature pear fruits extracts (iPE). In this study, we have focused on investigating the anti-senescence effects of hydrophilic (WiPE) and hydrophobic (OiPE) components of iPE on yeast cells and their genes and their possible application in extending human lifespan. The anti-aging effects of iPE were investigated using a chronological lifespan assay on S. cerevisiae cells. The chronological lifespan of the yeast was significantly extended in those treated with both WiPE and OiPE at 1% (v/v). The expression of sirtuin-related genes, which regulate cellular senescence, was examined by RT-PCR. Interestingly, gene expression was found to be significantly increased only in WiPE treated cells. The results suggested that the different polarity components from iPE exhibited anti-aging effects on the cells via different mechanisms. Research on the identification of useful components in iPE and the possibility of application to mammalian cells is ongoing."}
+{"text": "Each year, billions of ornamental young plants are produced worldwide from cuttings that are harvested from stock plants and planted to form adventitious roots. Depending on the plant genotype, the maturation of the cutting, and the particular environment, which is complex and often involves intermediate storage of cuttings under dark conditions and shipping between different climate regions, induced senescence or abscission of leaves and insufficient root development can impair the success of propagation and the quality of generated young plants. Recent findings on the molecular and physiological control of leaf vitality and adventitious root formation are integrated into a systemic perspective on improved physiologically-based control of cutting propagation. The homeostasis and signal transduction of the wound responsive plant hormones ethylene and jasmonic acid, of auxin, cytokinins and strigolactones, and the carbon-nitrogen source-sink balance in cuttings are considered as important processes that are both, highly responsive to environmental inputs and decisive for the development of cuttings. Important modules and bottlenecks of cutting function are identified. Critical environmental inputs at stock plant and cutting level are highlighted and physiological outputs that can be used as quality attributes to monitor the functional capacity of cuttings and as response parameters to optimize the cutting environment are discussed. Facing the great genetic diversity of ornamental crops, a physiologically targeted approach is proposed to define bottleneck-specific plant groups. Components from the field of machine learning may help to mathematically describe the complex environmental response of specific plant species. Plant propagation is the initial process of producing ornamental crops that already sets the first benchmark for the whole cultivation process by determining the quality of the young plant. Many ornamental plant species are propagated vegetatively by rooting of shoot tip cuttings. Depending on the plant genotype, the developmental stage of the cutting, and specific constellation of environmental factors, impaired vitality of cuttings or insufficient adventitious root (AR) formation in the stem base can cause leaf losses and dying of cuttings or failures in rooting and delayed or uneven root formation among individuals that impairs synchronous subsequent growth. Furthermore, the increasing demand on sustainability of young plant production requires improved propagation protocols that should provide maximum utilization of the genetically determined endogenous potential of the crop.Propagation of ornamental plants by cuttings can be characterized as follows:(1)It involves control of plant development in highly equipped ecosystems, that are mainly determined by technically controlled environmental inputs, for example in greenhouses, growth and storage rooms etc. I propose the term \u201ctechnoecosystems\u201d for such systems.(2)Environmental inputs are highly dynamic, because propagation involves a complex chain of subsequent processes that occur in different environments. Stock plant cultivation and harvest of cuttings occurs in diverse climatic regions far remote from the market of young plants and is followed by packaging, storage, transport, sticking and cultivation of cuttings close to the market.(3)The chain is continuously changing, because new priorities in the society and developing technologies provide new demands and options. Examples are the increasing demand for saving energy and reducing pollution, the changing lighting technology and the up-coming rooting systems that are compatible with transport logistics and sticking robots.(4)Chrysanthemum varieties were submitted to the Community Plant Variety Office , which determines the specific developmental stage as well as the source-sink and hormonal status of the cutting tissues at time of harvest.Important functional modules are the stem base (SB) as zone of root regeneration and of C and N utilization, the upper stem (US) as transport unit for all compounds and as intermediate storage unit of C and N, the fully developed leaves (FL) as source organs for providing C, N and possibly auxin, and the developing leaves (DL) and shoot apex (SA) as competitive utilization sinks for C and N and as potential source (DL) or sink (SA) of auxin.hormone homeostasis, signaling and function control the dedifferentiation (Dediff), induction, initiation and expression of adventitious roots, with Aux/IAA proteins, auxin responsive factor (ARF) transcription factors, GH3 proteins, and cell fate regulating transcription factors (CTF) such as GRAS, AP2/ERF and WOX as important components. Sink establishment and C and N utilization provide building blocks, energy and metabolic signals. Wound-induced accumulation of ethylene (ET) and jasmonic acid (JA), a decrease in levels of root-sourced cytokinins (CK) and strigolactones (SL) due to isolation from the stock plant, and accumulation of IAA contribute to dedifferentiation and induction of ARs. IAA accumulation in the stem base is dependent on auxin re-mobilization from the upper shoot, with DL and FL as potential auxin sources and polar auxin transport (PAT) as important process of translocation.In the SB, leaf retention and greenness by affecting leaf senescence and abscission, with ethylene (ET) and cytokinins (CK) as classical trigger and inhibitors of leaf senescence or abscission, respectively. Whether the principally known agonistic effects of jasmonic acid (JA) and strigolactones (SL) on leaf senescence have relevance to cuttings, requires further investigation. High sugar levels, particularly of glucose can counteract leaf senescence/abscission, possibly via depressed ET signalling.Depending on the sensitivity of the leaves, systemic effects of the changed plant hormone homeostasis may control establishment and the strength of the new utilization sink in the stem base as compared to the competing sink in the upper shoot limits the influx of C and N resources into the stem base. Activity of cell wall invertase (INVcw) as crucial driver of initial sink activity may be under positive control by IAA and JA.The earliness of C and N re-mobilization from the upper shoot, particularly from fully developed leaves is an important process for the delivery of sugars and amino acids (AA) to the utilization sink in the stem base, with sucrose (Suc), asparagine (Asn) and glutamine (Gin) as important components of phloem transport (PT).gross)of gross photosynthesis (P and respiration in the light and in the dark (RLD) determines the carbon gain or loss of the leaf and thus its carbohydrate pool, with starch (Sta) and Suc as intermediate storage and main export fraction, respectively, while glucose (Glu) and Fructose (Fru) are locally utilized.The balance assimilation of nitrate and ammonium, that have been initially delivered from the root system of the stock plant, determines one influx of N into the AA and protein (Prt) pools, while competing with the sugar pool for C skeletons. Under prolonged dark conditions of whole cuttings that deplete the carbohydrate pool of leaves, leaf metabolism is readjusted towards a survival strategy, resulting in accumulation of AA, while proteolysis contributes to this process. If the released AAs are further catabolized to free ammonium, this may trigger leaf senescence.Light-dependent Depending on the plant genotype and configuration of environmental inputs at stock plant and cutting level, different processes may constitute the bottleneck (B) of cutting function .Rosa or Hydrangea macrophylla, can exhibit low rooting capacity in dependence on the specific genotype , no or few ARs will be formed. Cuttings, particularly of woody ornamentals such as genotype  or when genotype . The undgenotype . In somegenotype , 2019. Ipulation . However factors  requiresIf AR source cells require dedifferentiation before AR induction, early wound induced accumulation of ET and JA, together with CKs may contribute to this process by enhancing auxin responsiveness  (see B1)If AR source cells are root competent , AR induction is dependent on local accumulation of IAA and further supported by a decrease in levels of the antagonistic CKs and SLs. Cutting off from (a) the root-ward auxin-drain and (b) the root-sourced delivery of CKs and SLs initiates these changes which may be supported by local IAA biosynthesis or release from auxin conjugates .In intact plants, IAA is synthesized in young expanding leaves and is in the stem either transported root-ward by polar auxin transport (PAT) in xylem parenchyma and cambium cells or co-transported in the phloem associated with assimilate transport (AT) , while iInitiation and expression of ARs requires a decrease of IAA and probably also of the physiologically active conjugate of JA after the induction phase. Obviously, upregulation of specific GH3 proteins that function as acyl acid amido synthetases conjugating IAA or JA to specific AAs has an important role for this dynamic . IAA levTemporal courses of carbohydrates and amino acids (AA) in the stem base of cuttings during rooting  and the B7a) or N source (B7b) may limit rooting (If the sink in the SB is sufficiently high to attract resources (B6), their influx can be limited by the source capacity of the upper shoot, with the fully developed leaves (FL) as main source organs . Dependi rooting . The ava rooting , while c rooting . The lev rooting .Senescence or abscission of leaves can impair the visual quality and vitality of cuttings and may finally cause decay and loss of whole cuttings. Changed concentrations in cuttings particularly of ET, JA, and CK in response to their excision have consequences for leaf senescence and/or abscission when the changed hormone homeostasis meets the respective responsiveness of the leaf . Both, t2 on the C gain of cuttings, distinct effects of light spectrum may involve changes of auxin homeostasis and signaling (Serendipita indica (former Piriformospora indica) at stock plant or cutting level on leaf vitality and AR formation may involve changed C source and hormone signaling in cuttings. However, effects of such inoculations are highly variable and even include negative effects on AR formation, when comparing different environmental conditions, modes of inoculation and plant genotype  on rooting of cuttings are unclear , monitorcuttings . In addicuttings . Howevergross. One of the most frequently used non-invasive tools for chlorophyll analysis in plant leaves is the Soil Plant Analysis Development (SPAD)   chloropht (SPAD) . This tot (SPAD) . Very hit (SPAD) . Howevert (SPAD) . Digitalt (SPAD)  is one at (SPAD)  and are t (SPAD) .Infrared gas analyzers can be used to determine the current carbon gain of cuttings or cutting leaves under the condition of measurement, which may, however, differ from the real conditions of rooting depending on the used measuring system . Use of Considering that sugars and of AA in source tissues of cuttings reveal important fractions for the crucial C and N re-mobilization, analysis of their levels provides important information about the C and N source limitation of rooting . The N sARF and GH3 genes (Since hormone levels in the cutting tissues have decisive functions in leaf senescence and AR formation, their analysis can discover important bottlenecks of cutting function. Whereas commercial systems are available to measure ET emission by plants in closed environments such as storage packages or boxes , analysiH3 genes , RNA-basThe high complexity of highly dynamic environmental inputs in young plant production by cuttings and responding metabolic and hormonal pathways  is a chaAll datasets generated for this study are included in the article/UD wrote the article.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The discovery of COVID-19 was linkedto the Huanan seafood market in Wuhan, China. As of February 27, 2020, there have been 82\u2009294confirmed cases globally with the first case in New Zealand.Because Samoa is an international tourism destination and, coupled with her conservativenature, is highly susceptible to an outbreak of COVID-19 if strict public health regulationsare not enforced. This is imperative considering the extent of spread and rapidity of virustransmission, especially among vulnerable populations. The rise of COVID-19 brought back thehorror of the last measles epidemic in Samoa and some Pacific Island countries. The gradualdecline in the measles epidemic trend was met with a sedulous approach toward case diagnoses,detection, and confirmation. It further stresses the importance of having well-equippedstate-of-the-art diagnostic health facilities, public health disease control centers, andhighly trained infectious disease personnel. This is a necessity for early disease detectionand diagnosis to prevent the occurrence of an epidemic of COVID-19 in Samoa.2 The successful implementation of this action plan is determined by many factors inindividual countries, and it mostly involves a cohesive teamwork between the local Ministry ofHealth and the Joint IMT composed of representatives from WHO and regional donor partners suchas Australian Department of Foreign Affairs and Trade (DFAT), New Zealand Ministry of ForeignAffairs and Trade (MFAT), Pacific Community (SPC), and the United Nations Children\u2019s Fund (UNICEF).2 The establishment and activation of Samoa\u2019s Health Emergency Operations Centre (HEOC)through the Ministry of Health (MOH) is a step forward for Samoa in preparation for COVID-19to enhance health sector surveillance, coordination, and provision of situational analysisupdates.It suffices to reason that the small Pacific Island countries could defeat an outbreak ofCOVID-19 by benchmarking and collaborating with both regional and internationalmultigovernment institutions for technical and financial support. The COVID-19 Joint IncidentManagement Team (IMT), coordinated by the WHO office in the Pacific, has developed and isimplementing a 6-month Pacific Action Plan for COVID-19 Preparedness and Response.2 The MOH has also put in place some public health measures against COVID-19 on theministry\u2019s website to ensure the general public is updated about the ongoing pandemic and, most important, to beaware of prevention and management strategies against COVID-19.Similarly, ongoing are campaigns on epidemic preparedness via leveraging on availableresources, capacity building; procurement of laboratory packaging and personal protectiveequipment (PPE); appropriate identification of isolation and quarantine facilities; anddeveloping case management protocols and strengthening communications to raise publicawareness and counter rumors and misinformation."}
+{"text": "The Research Centers in Minority Institutions (RCMI) Program was congressionally mandated in 1985 to build research capacity at institutions that currently and historically recruit, train, and award doctorate degrees in the health professions and health-related sciences, primarily to individuals from underrepresented and minority populations. RCMI grantees share similar infrastructure needs and institutional goals. Of particular importance is the professional development of multidisciplinary teams of academic and community scholars (the \u201cworkforce\u201d) and the harnessing of the heterogeneity of thought (the \u201cthinkforce\u201d) to reduce health disparities. The purpose of this report is to summarize the presentations and discussion at the RCMI Investigator Development Core (IDC) Workshop, held in conjunction with the RCMI Program National Conference in Bethesda, Maryland, in December 2019. The RCMI IDC Directors provided information about their professional development activities and Pilot Projects Programs and discussed barriers identified by new and early-stage investigators that limit effective career development, as well as potential solutions to overcome such obstacles. This report also proposes potential alignments of professional development activities, targeted goals and common metrics to track productivity and success. Achieving long-term health and wellness in communities that suffer disproportionately from racial, ethnic, environmental, and social and/or economic inequalities and inequities demands building institutional capacity and enhancing infrastructure on many levels. Particularly at institutions of higher education and health-professions schools, a major component of this infrastructure is the professional development of diverse teams of academic and community scholars (the \u201cworkforce\u201d), who understand the challenges faced by underserved and vulnerable populations because of shared life experiences (the \u201cthinkforce\u201d), to collaboratively explore and identify the causes of health disparities, to design and test the best measures and methods for studying health disparities, and to develop and implement the most effective and culturally appropriate interventions for reducing and eliminating health disparities ,2,3. FunHouse Report 98-911, attached to H.R. 6028 , provided the original language to establish research centers in predominantly minority institutions, which offered doctoral degrees in the health professions and/or the health-related sciences to individuals from underrepresented, underserved, and minority populations [Originally administered by the National Center for Research Resources (NCRR), of the National Institutes of Health (NIH), the RCMI Program provided support to two inaugural institutions: Florida Agricultural and Mechanical University (FAMU) and Ponce School of Medicine (PHSU). The next cohort, in 1986, included Clark Atlanta University, Meharry Medical College (MMC), University of Hawaii at Manoa (UHM), and University of Puerto Rico Medical Sciences Campus (UPR-MSC), followed in 1987 by Howard University (HU) and Morehouse School of Medicine (MSM). The annual operating budget of the fledgling RCMI Program, initially less than $1 million, has grown to more than $74 million in FY2020. Such growth has been justified by the successful leveraging of RCMI funds by RCMI grantee institutions and supported through strong congressional advocacy.As part of the NIH reorganization to create the National Center for Advancing Translational Sciences (NCATS), NCRR was dismantled in 2011 , and theA principal goal of the RCMI Specialized Centers is to create environments conducive to career enhancement for all investigators, and particularly women, persons with disabilities, and those from racial and ethnic groups which are underrepresented in biomedical research, as defined by the National Science Foundation . These environments are designed to assist investigators in becoming more successful in obtaining competitive extramural funding for basic biomedical, behavioral, clinical and/or population health research on diseases and conditions that disproportionately affect the health and well-being of ethnic minority and other underserved and marginalized communities, including the poor, homeless, rural persons, sexual and gender minorities, and recent immigrants. Another goal of the RCMI Centers is to strengthen and sustain partnerships with community-based and other non-academic organizations that reach the intended underserved populations to collaborate on the dissemination and implementation of culturally appropriate and contextually relevant interventions for health promotion and disease prevention. In short, the RCMI Centers are meant to diversify the workforce, enhance the quality of scientific inquiry, and promote collaborative research that improves minority health and reduces long-standing health disparities.As instructed in the funding opportunity announcements RFA-MD-17-003, RFA-MD-17-006, RFA-MD-18-018, issued by NIMHD, each RCMI Specialized Center had to be structured with four distinct cores: Administrative Core (AC), Community Engagement Core (CEC), Investigator Development Core (IDC), and Research Infrastructure Core (RIC). The primary goal of the IDC is to create a supportive career development milieu for post-doctoral fellows, junior faculty, and other early-stage investigators to conduct hypothesis-driven basic biomedical, behavioral, and/or clinical research that results in significant return on investment, as measured by peer-reviewed publications in high-impact journals and successful NIH grant applications, among other metrics. The IDC is also expected to develop and implement a Pilot Projects Program to provide funding on a competitive basis to new and junior investigators.The shared goals and expected functions of the RCMI IDC provide an unparalleled opportunity to improve coordination, increase efficiency and leverage resources for professional development across all RCMI Centers. Accordingly, the primary objective of the RCMI IDC Workshop, held in conjunction with the RCMI Program National Conference in Bethesda, Maryland, in December 2019, was for IDC Directors to meet each other and to learn first-hand about the professional development activities and Pilot Projects Program at each RCMI Center with the goal of stimulating problem-solving discussions around common challenges to strengthen each RCMI Center and the collective RCMI Program. The near-term desired outcome was relationship building to facilitate the development of an IDC Consortium, comprising RCMI IDC Directors, which would meet regularly to enhance resource sharing to build a diverse workforce and thinkforce to reduce health disparities.The logistics and organization of the IDC Workshop were handled by the Research Coordinating Center, of the former RCMI Translational Research Network ,5, and tThe workshop started with an Information-Sharing Session to allow each Center to present a brief summary of their IDC activities, focusing primarily on professional development activities and on the Pilot Projects Program. Because the RCMI Centers have different project start dates, and because some RCMI Centers were transitioning from funding through the prior G12 funding mechanism while other RCMI Centers had no previous RCMI funding history, some Centers had data about the number of Pilot Projects Program project proposals received and reviewed, whereas other Centers were limited to presenting their plans. Nevertheless, the final slide of each presentation was devoted to articulating challenges and barriers to effective execution of IDC activities.Next, during the Problem-Solving Session, the IDC Directors and other workshop participants discussed the challenges and barriers encountered in implementing mentoring efforts and the Pilot Projects Program. Participants also shared potential solutions, and discussed milestones and common metrics to better track progress and to arrive at best practices and harmonization.Both the Information-Sharing Session and the Problem-Solving Session were informed by data collected from RCMI Investigator Needs Assessment Surveys, previously performed by the RTRN Research Coordinating Core. That is, the barriers and obstacles to optimal mentoring and professional development, as well as potential solutions, were those articulated by basic biomedical, behavioral, and clinical researchers at all academic levels, including junior investigators, who played a significant role in providing input through their real-life experiences.Finally, during the Networking and Evaluation Session, participants completed an evaluation survey about the workshop and were allowed time for unstructured interactions and relationship building to form the basis for the establishment of the envisioned IDC Consortium and sustained engagement of IDC Directors to achieve shared goals.The IDC Workshop was well attended, with active participation from 14 RCMI Centers: FAMU, FIU, HU, MMC, MSM, MSU, PHSU, SDSU, Tuskegee University (TU), UCR, UHM, UPR-MSC, University of Texas at El Paso (UTEP), and Xavier University of Louisiana (XULA). Each Center provided an overview of their mentoring and investigator development activities, as well as Pilot Projects Program.Common features were evident in the IDC of each RCMI Center. Specifically, the IDC provided personalized mentoring in scientific and career development to junior and early-stage investigators, as well as senior postdoctoral fellows. The IDC Directors acknowledged that effective mentoring was a key factor to successful career development. However, the process of identifying promising junior investigators and matching them with mentors who are compatible in terms of their personality, temperament, scientific knowledge, history of NIH funding, and mentoring skills is not fool proof and requires thoughtful, personalized attention. Research networking tools, such as the open-source Profiles Research Networking Software originally developed by Harvard Medical School and enhanced by the University of California San Francisco , can proInvestigator development activities at nearly all RCMI Centers consisted of developing mentoring teams, providing grant writing workshops, and arranging seminars, featuring internal and external researchers speaking about their research and topics related to health disparities and professional development. Importantly, junior investigators were provided opportunities to meet with speakers to foster mentorship and collaboration.The HU IDC presented a systematic and methodological program to fast track the development of junior faculty and early-stage investigators, using a tri-faceted approach that involved providing pilot seed-grant support, coordinating comprehensive career mentoring that included both discipline-specific research and professional advancement mentoring, and offering professional development trainings relevant to early-stage investigators .At FIU, mentoring activities were largely outcomes-driven and closely linked with the Pilot Projects Program. Recipients of pilot funding met regularly with RCMI faculty and other awardees for advice and support, with linkages to RCMI research training, RCMI research opportunities, RCMI community connections, and career development activities through the RCMI and other university-wide programs.Similarly, the FAMU IDC and MMC IDC focused mentoring efforts and other professional development activities and resources on recipients of pilot funding. MMC investigators were able to request a Studio ,9, whereThe SDSU IDC provides two avenues for career enhancement: a year-long program to awardees of pilot project funding, and open-forum career enhancement activities for all interested parties. For pilot project awardees, the SDSU IDC offers highly structured monthly mentoring sessions that cover wide-ranging topics, including individual development plans, project management, data management and safety, and optimizing success. The open-forum career enhancement activities generally focus on a specific topic or skill, such as how to select an appropriate electronic data capture system, how to effectively partner with external organizations on minority health and health disparities research, among others.The MSM IDC was built on the foundation of their well-developed Mentoring Academy  that worThe MSU IDC provided a summer mini-sabbatical for its RCMI investigators to build collaborations at partnering institutions in Baltimore, such as the University of Maryland and Johns Hopkins University School of Medicine.The PHSU IDC provided a two-year program, known as Strategic Academic Research Training (START), to approximately six scholars per year. Emphasis was placed on enhancing the diversity that their scholars brought to the scientific workforce.At TU, mentoring and professional development activities were focused on early-stage investigators. In addition, the IDC was intent on supporting senior or established investigators, who were transitioning into research on the science of health disparities from non-biomedical fields or biomedical fields not directly related to minority health and health disparities.The UCR IDC\u2019s Big Feasible and Fundable Seminar Series was linked with the AC\u2019s Interdisciplinary Research Workgroups to create pipelines for identifying and recruiting junior investigators and to facilitate their acquisition of essential skills in communicating and collaborating across disparate disciplines. That is, Individual Multidisciplinary Mentorship Teams comprised mentors from within the trainee\u2019s discipline and from complementary disciplines.At UPR-MSC, IDC mentoring activities included informal meetings, rehearsal of scientific presentations, discussion of topics relevant to successful transition to running a lab (using the best-seller book: \u201cAt the Helm: Leading your Laboratory\u201d), and mock study sections. Trainees regularly review their five-year plans for grants, publications, and promotion.At UTEP, the IDC uses a \u201csynergy = success\u201d model, which incorporated the commitments of multiple stakeholders at the university, programmatic, and external levels to ensure sustained support of RCMI investigators. Apart from intensive training on grant writing, course release was offered to investigators in exchange for preparing and submitting grant applications, and senior postdoctoral fellows and senior investigators were provided opportunities to secure short-term starter funds and bridge funds, respectively.At XULA, the matching of junior investigators with collaborators and mentors occurred even before new faculty were officially recruited and multiple activities linked early-stage investigators, mid-career faculty and research scientists to RCMI and non-RCMI resources.Professional development activities for new and early-stage investigators at RCMI Centers can be generally grouped into three categories: Professional Conduct, Research Resources, and Career Skills and Knowledge. As an illustration, Through input from junior faculty at their institutions, the IDC Directors reported multiple barriers and obstacles to professional development . Among tIn addition to needing compatible mentors, junior faculty frequently mentioned other barriers to professional development, including their lack of knowledge about finding funding and training opportunities; the lack of pre-award grant application preparation; the lack of internal grants review system; the lack of bridging funds to continue while awaiting funding decisions.Apart from individual barriers to professional development, there were institutional obstacles that limited the growth of a diversified workforce for research on the science of minority health and health disparities at RCMI Centers. For example, institutional hiring freezes, limited institutional start-up funds for newly recruited faculty, insufficient grants development support, high administrative leadership turnover, and lack of positions for postdoctoral fellows in the absence of training grants, both individually and collectively, stifle the growth of a critical mass of investigators in specific research areas. In addition, broken promises and unfulfilled commitments by institutional leadership have occurred because of changes in organizational structure and/or changes in administration, as well as downturn in financial wellbeing.For each barrier and obstacle, potential solutions and enablers were identified to optimize mentoring and professional development of new and early-stage RCMI investigators . A possiCoordinating and leveraging the IDC infrastructure of the RCMI Centers, as well as engaging non-RCMI programs, including the Clinical and Translational Science Awards (CTSA), Institutional Development Award (IDeA), Centers for AIDS Research (CFAR), and Transdisciplinary Collaborative Centers (TCC), to serve on mentoring teams will accelerate attainment of research independence of early-stage RCMI investigators. Intensified engagement with the RCMI IDC Directors and the formation of an IDC Consortium would facilitate better alignment of professional development activities across the RCMI Centers . For exaThe IDC of each RCMI Center is expected to develop and manage a Pilot Projects Program to provide funding through a competitive process to RCMI investigators. Inherent in this approach are the expected outcomes of accelerating the pace of scientific discovery, heightening research productivity, increasing competitiveness for mainstream extramural funding, and ultimately improving the health of the nation. Currently, the awards for such pilot projects have ranged between $30,000 and $50,000 per year. For most RCMI Centers, the funding period for pilot projects was one year, but in the case of UPR-MSC, XULA, and SDSU, two or more years of support were granted. More than one year of funding was deemed especially necessary for community-engaged research projects. Thus far, the number of awards has varied from two to five pilot projects per year. However, insufficient data were available from many of the Pilot Projects Programs to assess success or return on investment.The FIU Pilot Projects Program planned to fund up to five pilot projects per year, with a goal of up to 20 projects during the five-year funding cycle. To date, eight FIU junior faculty have been funded, and each is preparing an NIH grant application .The UCR Pilot Projects Program provides support through four mechanisms: (1) Fostering Interdisciplinary Research-early STage Awards (FIRST Awards) serve as transition awards aimed at increasing competitiveness at obtaining external funding; (2) Pilot Interdisciplinary Collaborative grants (PIC Grants) seek to support goals of interdisciplinary research working groups; (3) Interdisciplinary Research Work Group Awards (IRWG Award) funds problem-focused interdisciplinary health disparities research; and (4) Continuity Collaborative Fellowships are awarded twice a year to fill gaps in research and database management in ongoing community-based research projects, conducted by graduate students or postdoctoral fellows.The XULA Pilot Projects Program, which focuses on early-stage investigators engaged in clinical and population research involving cancer health disparities, solicits applications jointly with the Louisiana Cancer Research Center (LCRC) and Project Pathways, of the Building Infrastructure Leading to Diversity (BUILD) program. Of 16 pilot applications submitted in 2019, three were funded through RCMI, three with LCRC, and six by BUILD.The MSM Pilot Projects Program involves a letter-of-intent. In 2019, full applications were invited from five of 11 investigators who originally submitted a letter-of-intent, and two awards were made. Applicants who were not funded were encouraged by the IDC to revise and resubmit their applications to the next round or to submit to other funding agencies.The UHM Pilot Projects Program also has a two-phase process. In the first phase, one-page abstracts and NIH Biosketches of the applicant(s), mentors and collaborators are reviewed by the principal investigators and core directors. In the second phase, invited full applications are evaluated by outside reviewers. Over three funding cycles, 83 abstracts were received and 37 full applications were invited, from which 15 pilot awards were made, resulting in 71 publications and 34 new grants .The HU Pilot Projects Program has had similar outcomes from seven pilot awardees, who have been responsible for 31 publications and 11 new grants, with a return on investment of 6.4 over two funding cycles.The RCMI Centers identified multiple barriers to the effective implementation of the Pilot Projects Program . Among tPotential solutions were identified to optimize the implementation of the Pilot Projects Program at RCMI Centers . As in mHeavy teaching loads for junior faculty and insufficient protected time for clinicians served as major deterrents to preparing proposals for Pilot Projects Programs. Finding solutions to these barriers is not a simple matter. Institutional investments are required at the department and college or school level. Particularly for newly hired basic scientists, a one- or two-year postponement of teaching obligations, coupled with intensive mentoring, would heighten the probability of grant success. Similarly, providing several months-long periods of protected time for clinical faculty would likely boost the number of grant proposals submitted and the likelihood of success, and once such faculty garner grant support, their mentors and IDC Directors should serve as strong advocates to negotiate reductions in teaching loads and clinical assignments.Alignment or harmonization of the processes and procedures of the Pilot Projects Programs at RCMI Centers would result in the achievement of specific goals each year . For exaContinued assistance to RCMI investigators whose applications were not selected for funding would constitute another way to align Pilot Projects Programs. That is, the professional development function of the IDC Consortium should be inextricably linked with the Pilot Projects Program function. The annual outcomes and goals in The opportunity for IDC Directors to meet face-to-face, nearly all for the first time, and to share their experiences, as well as to discuss their challenges at the IDC Workshop, has laid the foundation for the creation of an IDC Consortium, comprising the IDC Directors from RCMI Centers, to work collaboratively to overcome obstacles in professional development activities and to promote greater efficiency in the review process of pilot project proposals. The newly funded RCMI Coordinating Center will serve as a communications hub to facilitate the scheduling of regular meetings of the IDC Consortium and to coordinate continued interactions, resource sharing and problem solving to achieve the collective goals of advancing the careers of underrepresented minority investigators and those conducting minority health and health disparities research.By leveraging the leadership, expertise and talent of the RCMI IDC Consortium, there is every expectation that performance outcomes will improve and productivity measures will increase at individual RCMI Centers and in the overall RCMI Program. Although there are institution-specific barriers to building research capacity , there aJunior RCMI faculty do not typically encounter institutional racism, discrimination and/or bias, in large part because all RCMI grantee institutions serve predominantly racial and ethnic minorities and individuals from disadvantaged socio-economic backgrounds, and because many senior RCMI faculty and IDC Directors have themselves experienced hardships and barriers and understand the challenges faced by junior faculty. The lack of generational pipelines and access to academia is a well-known barrier to success. While not mentioned or discussed during the workshop, persistent barriers to professional development in the Science, Technology, Engineering, Mathematics, and Medicine (STEMM) pipeline perpetuate racial disparities in academia. Solutions lie in earlier exposure and access to resources, supportive mentoring networks, and comprehensive training programs for racial and ethnic minority students and trainees at each career stage . MultiplIn addition to monthly IDC Consortium-wide meetings, periodic regional meetings based on geography and time zones might further strengthen relationship building, enhance resource sharing, and facilitate and expedite the review of pilot project proposals. Currently, there are 21 RCMI Centers, distributed in 12 states, the District of Columbia, and Puerto Rico. Each regional sub-consortium could comprise four or more RCMI IDC , and theProfessional development activities are also enhanced through resources within the RIC and CEC of each RCMI Center, as well as leveraged through considerable resources available in collaborations and partnerships with other NIH-funded infrastructure programs, such as CTSA, IDeA, CFAR, and TCC, at non-RCMI grantee institutions ,23. MoreCommunity-driven and culturally relevant solutions to eliminating health disparities necessitate the creation of a supportive mentoring milieu to accelerate the career development of diverse and multidisciplinary teams of scholars (the \u201cworkforce\u201d) and to harness the heterogeneity of their thought and thinking (the \u201cthinkforce\u201d). That is, only by embracing and celebrating the power of different perspectives, tempered by unique lived experiences and influenced by cultural and indigenous beliefs, as well as age-old community practices and norms, can one expect to pose previously unasked research questions and to design distinctly alternative approaches that lead to innovative interpretations of data and sustainable strategies for disease prevention and health promotion for underserved populations and marginalized communities. The IDC Consortium provides an exciting platform for productive interactions that foster the sharing of research resources and human capital across the RCMI Centers to hasten the acquisition of new knowledge to improve minority health and to reduce health disparities. Such interactions are also likely to strengthen and sustain inter-institutional collaborations and partnerships with non-RCMI grantee institutions ,23."}
+{"text": "The 9th Conference of the International Society for Integrated Disaster Risk Management (IDRiM) was held in Sydney on 2\u20134 October 2018. The event was hosted by Data61, the data innovation hub of Australia\u2019s National Science Agency CSIRO. The IDRiM annual conference series traditionally brings together researchers and practitioners across all disciplines of disaster risk management (DRM) and the Australian instalment was no exception. More than 120 participants from 20 countries attended the congress, representing all sectors of DRM including academia, industry, and governmental agencies, to exchange on ideas and best practices through a mix of plenaries, presentations, panel discussions, and poster sessions.Data-Driven Approaches to Integrated Disaster Risk Management, mirrors the overarching theme of the 2018 IDRiM conference, which set out to explore the ever-increasing role of data in all areas of disaster risk and emergency management. The articles included in this special issue have been selected to represent the diversity of data-driven approaches under active development for DRM. They are also illustrative of the multidisciplinary nature of DRM, its applications ranging from natural hazards  to man-made disasters or even a combination of the two. All four phases of DRM, namely prevention (or mitigation), preparedness, response, and recovery are covered in this volume, and many of the themes that were extensively discussed during the conference are further explored here.This special issue, entitled In the prevention phase, data science and analytics can inform us on the potential impact of both natural hazards and man-made disasters to help protect the ecological diversity of our environment and make better long-term choices and investments, which in turn will improve the safety and welfare of our communities, as discussed in Liu et al. In this context, the ability to access extensive databases is a critical element of building evidence-based strategies for prevention and preparedness purposes . Important challenges remain, however, when dealing with heterogeneous sources of data and several of the technologies presented in the special issue aim to address the issues of data collection, data curation, and data sharing to dramatically improve such cross-disciplinary collaboration .Digital technologies such as smartphones have become ubiquitous in modern life, but their application to DRM has yet to be fully realized. An example of such application is discussed in Yamori and Sugiyama, where a smartphone app was developed to increase the preparedness of the local community by simulating tsunami evacuation drills. Another example of the potential application of digital technologies is the development of evidence-based decision support systems both for planning  and operational (response) purposes. As the volume and accuracy of available data increase, a number of initiatives around the world have been focussing on developing such systems in recent years to help emergency coordinators make informed decisions. Two of the articles in this special issue discuss these concepts as applied to storms, floods, and landslides in Japan (Takenouchi and Yamori) and debris flows in Indonesia .Improved resilience is achieved through risk assessment and risk reduction, which in turn implies understanding and reducing various sources of uncertainty in the data and in the processes at play. Two articles propose methodologies to address these important issues in the context of hurricane vulnerability  and post-earthquake lifeline systems recovery (Deelstra and Bristow). This last article in the volume also exemplifies that perhaps one area where the unrealized potential of data-driven approaches is the most evident is in fact in the post-disaster recovery phase. The premise here is to help communities regain a sense of stability and rebuild faster after being struck by a disaster.Each of the articles in this special issue may be briefly summarized as follows:Variability in Regional Ecological Vulnerability: A Case Study of Sichuan Province, China by Yimeng Liu, Saini Yang, Chuanliang Han, Wei Ni, Yuyao Zhu. The authors developed a data-driven method to assess the vulnerability of ecological systems to external stress factors such as natural hazards and human activities. They found that for the case study of Sichuan Province, anthropogenic construction activities increased ecological vulnerability more than any other factors considered, including natural hazards.Seismic Policy, Operations, and Research Uses for a Building Inventory in an Earthquake-Prone City by Ken Elwood, Olga Filippova, Ilan Noy, Jacob Pastor Paz. A building inventory database integrating datasets from multiple sources was created for the city of Wellington, New Zealand to manage the risks associated with earthquake events. The multiple uses of such a database discussed in this article, ranging from planning to response, highlight the importance of easily accessible data in the decision-making process.Disaster Risk Management through the DesignSafe Cyberinfrastructure by Jean-Paul Pinelli, Maria Esteva, Ellen M. Rathje, David Roueche, Scott J. Brandenberg, Gilberto Mosqueda, Jamie Padgett, Frederick Haan. This article presents a cloud-based cyber-infrastructure platform designed to address the challenges associated with collecting, curating, sharing, and analyzing heterogeneous datasets for disaster risk management purposes. The article discusses the application of this multi-disciplinary tool to several cases including soil liquefaction, seismic risk analysis, and hurricane recovery.Extracting Natech Reports from Large Databases: Development of a Semi-Intelligent Natech Identification Framework by Xiaolong Luo, Ana Maria Cruz, Dimitrios Tzioutzios. This contribution explores the use of machine learning algorithms to extract information about natural hazard-triggered technological accidents from large databases for risk management purposes. It provides an example of using state-of-the-art computing technologies to realize the potential of available data for disaster risk management.Development and Social Implementation of Smartphone App Nige-Tore for Improving Tsunami Evacuation Drills: Synergistic Effects between Commitment and Contingency by Katsuya Yamori and Takashi Sugiyama. Nige-Tore is a smartphone app that allows the user to participate in a tsunami evacuation drill. Participants take actions and choose escape routes based on real-time updates of a simulated tsunami displayed on a map. The authors discuss at length the benefits and challenges of the human-digital technology interactions brought about by this app, and explore how these new technologies may be useful resources to improve our preparedness for natural hazards and disasters.Synergistic Integration of Detailed Meteorological and Community Information for Evacuation from Weather-Related Disasters: Proposal of a \u201cDisaster Response Switch\u201d by Kensuke Takenouchi and Katsuya Yamori. The importance of high-resolution meteorological data and weather forecasting models is discussed in the context of several common hazards in Japan, namely storms, floods, and landslides. From the results of this study it is apparent that the development of data-driven decision support systems is critically needed to assist local authorities develop appropriate and evidence-based emergency response, and to determine the timing of an evacuation.Na\u00efve Bayes Classifier for Debris Flow Disaster Mitigation in Mount Merapi Volcanic Rivers, Indonesia, Using X-Band Polarimetric Radar by Ratih Indri Hapsari, Bima Ahida Indaka Sugna, Dandung Novianto, Rosa Andrie Asmara, Satoru Oishi. A debris flow disaster warning system for a volcanic region in Indonesia is presented. The method estimates debris flow susceptibility through a simple data mining approach. The study also highlights the need for higher-resolution data to improve the robustness of the model.Uncertainty Reduction through Data Management in the Development, Validation, Calibration, and Operation of a Hurricane Vulnerability Model by Jean-Paul Pinelli, Josemar Da Cruz, Kurtis Gurley, Andres Santiago Paleo-Torres, Mohammad Baradaranshoraka, Steven Cocke, Dongwook Shin. This contribution discusses the issue of epistemic uncertainty and approaches for uncertainty reduction with hurricane vulnerability as a case study, in the context of insurance claims. By integrating various sources of data augmented claims may be constructed, which then facilitate the development of a vulnerability model.Characterizing Uncertainty in City-Wide Disaster Recovery through Geospatial Multi-Lifeline Restoration Modeling of Earthquake Impact in the District of North Vancouver by Andrew Deelstra and David Bristow. The authors studied, through a data-driven modeling approach, the recovery of lifeline systems in the earthquake-prone area of the district of North Vancouver. One of the uses of their model is to determine which systems are more likely to be restored first following a disaster and to allocate resources accordingly to accelerate the overall recovery process.Following the 2018 IDRiM conference in Australia, the next congress was held in Nice, France, in October 2019 and focused on \u201cknowledge-based disaster risk management\u201d thus expanding on the notions of information and data science applied to risk reduction, resilience, and sustainable development. Two major events in 2019-2020 dramatically illustrated the relevance of these two themes of data- and knowledge-based approaches for disaster risk management.The first was the catastrophic bushfire season that occurred across six states in Australia between the second part of 2019 and ended in May 2020. This event caused 34 direct fatalities and in excess of 400 indirect fatalities  and affected almost three billion animals, not to mention the economic and broader ecological costs that are both yet to be fully estimated. Following this major disaster, it became clear that in order to become more resilient to such large-scale events as a society, better data analytics, artificial intelligence (AI) solutions, and new digital innovations were needed. The Australian government thus invested a further AUD 88.1 million over the next 10\u00a0years in the Bushfire and Natural Hazards Cooperative Research Centre, with space monitoring and predictions of natural hazards, development of new digital technologies, and AI solutions all at the heart of the center\u2019s mission.As catastrophic as the Australian bushfires had been, they were almost eclipsed in the media by the global COVID-19 pandemic that developed worldwide in 2020. Again, the role of data-driven science in the fight against the spread of the virus was abundantly clear. Many governments based their decisions to implement lockdown measures on predictive scientific models that utilized the latest available data to help assess the effectiveness of potential mitigation strategies in slowing down the spread of the virus. Moreover, geospatial monitoring has been used worldwide to manage this crisis, firstly through the development of smartphone apps to improve the enormous task of contact tracing, and secondly to understand the effect of restrictions on the mobility of individuals put in place by authorities.Now more than ever, the world has therefore become acutely aware of the key role that data-driven approaches play in disaster risk management, and we hope that this special issue will provide the reader with an overview of some of the important initiatives currently pursued in this area.Vincent Lemiale, Mahesh Prakash, and Ana Maria CruzGuest Editors"}
+{"text": "Epidemiological evidence has demonstrated the association between dietary factors and non-communicable diseases. Great attention has been payed to the Mediterranean dietary pattern, given its richness in anti-oxidant and anti-inflammatory molecules. Numerous reports from the SUN (Seguimiento Universidad De Navarra) cohort have shown that higher adherence to the Mediterranean dietary pattern may be inversely associated with mortality, type 2 diabetes and cardiovascular diseases. Likewise, a link with mental health outcomes, such as depressive symptoms, cognitive status and quality of life was also found, suggesting its beneficial effects toward brain health. Non-communicable diseases are the leading causes of premature mortality and disability in developed countries ,2. ObesiThe SUN (Seguimiento Universidad De Navarra) study represents one of the main cohorts in the European Mediterranean area aiming to explore the association between dietary factors and non-communicable diseases. It involves individuals aged 20 years and over who have previously graduated from the University of Navarra, as well as from other different Spanish universities; the cohort has adopted an open continuous recruitment of highly educated participants, which is supposed to reduce the potential risk of bias. The project has contributed for over 20 years to evidence on the importance of traditional dietary patterns, such as the Mediterranean diet, as an ideal dietary choice for the prevention of chronic diseases . The artAnother line of research investigated within the context of the SUN cohort has been the role of the Mediterranean diet on mental health, including depressive symptoms, cognitive status and quality of life. Higher adherence to the Mediterranean and other healthy dietary patterns has been associated with a lower risk of depression . SimilarA traditional Mediterranean diet characterized by (i) high intake of plant-derived foods ; (ii) use of olive oil, nuts and fish as the main sources of fats; (iii) low consumption of meat and processed foods; and (iv) moderate alcohol intake (mostly wine) during meals, and is a dietary pattern that provides an ideal content of healthy nutrients (such as poly- and monounsaturated fatty acids) and bioactive components exerting anti-inflammatory and antioxidant properties (such as vitamins and polyphenols) , many ofThe contribution of the SUN cohort to nutritional science was crucial in making modern knowledge on the role of certain dietary factors, among which the Mediterranean diet is the core research question of this cohort, in human health. The results obtained are in line with those reviewed in two umbrella reviews of meta-analyses of the role of the Mediterranean diet in preventing non-communicable diseases ,37. The"}
+{"text": "Investigators from the Soroka University Medical Centre, The Hebrew University of Jerusalem, and Tikun Olam Ltd. in Israel studied the safety and efficacy of medical cannabis treatment on 188 patients with autism spectrum disorder (ASD) for six months. Investigators from the Soroka University Medical Centre, The Hebrew University of Jerusalem, and Tikun Olam Ltd. in Israel studied the safety and efficacy of medical cannabis treatment on 188 patients with autism spectrum disorder (ASD) for six months. The study examined the efficacy of cannabidiol (CBD) through a quality-of-life assessment, global assessment rating, and an ASD symptom severity assessment looking at restlessness, rage attacks, agitation, speech impairment, cognitive impairment, anxiety, incontinence, depression, and more. The safety of CBD was examined by assessing physiological and cognitive side effects. The largest national provider of medical cannabis in Israel employed several of the authors and sponsored this study. [COMMENTARY. ASD is a developmental disorder with two clusters of symptoms: 1. persistent deficits in social communication and social interaction, and 2. restricted, repetitive patterns of behavior, interests, or activities  and effeSafety was assessed by analyzing the frequency of side effects, while efficacy was analyzed using the ASD symptom severity assessment. Many of the same symptoms were reported as both side effects of the treatment and comorbid symptoms of prior diagnoses, making it difficult to interpret the results. The safety of medical cannabis was assessed within a one-month, and six-month follow up. Progress of patients who received extra THC doses was not differentiated from the remainder of patients.Long-term safety from prolonged usage could not be determined from this study. Patient outcomes and side effects were only recorded at months one and six; the selection of this specific follow-up period is not clearly explained. Observational studies, such as this one, are essential in identifying the short-term safety and efficacy of medications; CBD's long-term safety for ASD spectrum patients is unclear.Subjective self-reporting by parents of patients was used as the basis of this study. Parents' expectations likely influenced their reporting. Assessment of parental perceptions and expectations of safety and efficacy at baseline could have elucidated these potentially confounding factors. Furthermore, this study was sponsored by a large local CBD manufacturer and the study population was using the product, which could have added an extra layer of parental reporting bias. Prospective, independent, placebo-controlled clinical trials are required to determine more accurate long-term efficacy and dosing guidelines for CBD in ASD.The authors have declared that no competing interests exist."}
+{"text": "In this data collation study, we aimed to provide a comprehensive database describing the epidemic trends and responses during the first wave of coronavirus disease 2019 (COVID-19) throughout the main provinces in China.From mid-January to March 2020, we extracted publicly available data regarding the spread and control of COVID-19 from 31 provincial health authorities and major media outlets in mainland China. Based on these data, we conducted descriptive analyses of the epidemic in the six most-affected provinces.School closures, travel restrictions, community-level lockdown, and contact tracing were introduced concurrently around late January but subsequent epidemic trends differed among provinces. Compared with Hubei, the other five most-affected provinces reported a lower crude case fatality ratio and proportion of critical and severe hospitalised cases. From March 2020, as the local transmission of COVID-19 declined, switching the focus of measures to the testing and quarantine of inbound travellers may have helped to sustain the control of the epidemic.Aggregated indicators of case notifications and severity distributions are essential for monitoring an epidemic. A publicly available database containing these indicators and information regarding control measures is a useful resource for further research and policy planning in response to the COVID-19 epidemic. The coronavirus disease 2019 (COVID-19) outbreak was first reported in Wuhan City, Hubei Province, China in late December 2019 . From laThe Imperial College London COVID-19 Response Team initiated data collection activities in mid-January 2020 to understand the epidemic in China. Together with volunteers, the Imperial Team made considerable efforts to collate aggregated data and individual patient information from publicly available, national, and local situation reports published by health authorities in China. Individual case or death reports are considered crucial for informing the determinants of disease severity and fatality during the emergence of the epidemic , but theThe data we extracted from Chinese official reports may also be useful for the wider research community by building on other existing data collection activities . In the https://github.com/mrc-ide/covid19_mainland_China_report.Daily situation reports of the COVID-19 epidemic were extracted from mid-January to 31 March 2020 in 31 provinces/municipalities  of mainland China. We downloaded these reports from the websites of local health commissions and used Google translate to obtain English versions for each province/municipality. In addition, reports from the National Health Commission website and Wuhan City Health Commission website were included. We extracted aggregated numbers of cases, deaths, recoveries, contacts, and details on disease severity and case importation from the official reports released each day . The quaWe reviewed the timing of implementation and subsequent lifting of the following control measures: i) cancellation of cross-province public transportation; ii) temperature checks for inbound travellers at provincial borders; and iii) community-level lockdown  that reported the highest numbers of confirmed cases up to the end of March 2020. These provinces accounted for 90% of the total COVID-19 cases in mainland China. Hubei alone accounted for 80% of the total number of reported cases .Figure 1We first calculated the proportion of recoveries from 15 January to 31 March as:  results .To investigate the disease severity across provinces, we obtained the crude case-fatality ratio (cCFR) as: eporting , but it According to the guidelines for contact investigation published by the On 26 January 2020, In addition to school closures, In addition to the key dates for initiating and lifting the three most common control measures, We explored the association between the epidemic trend and health care burden based on the time-varying proportions of the total confirmed cases who recovered . Most prA wide variation in cCFRs was reported in each province by 31 March 2020 . Most ofProvincial differences in disease severity were also demonstrated by the analysis of hospitalised cases , where HFinally, we investigated the scale of contact tracing for infection control at the national and provincial levels by using the ratio of total contacts relative to total cases by the end of March . On averIn this study, we conducted data collation and descriptive analyses of the COVID-19 epidemic trends and control measures in mainland China between mid-January and March 2020. In most provinces, the local epidemics peaked in early February and declined in early March, but they were not completely eliminated because the number of imported cases increased. School closures, travel restrictions, contact tracing, and other control measures were enforced at a similar time from late January across provinces. However, in Hubei where the origin of the COVID-19 pandemic was reported, increased levels of case fatality and severity were reported compared with the other five most badly affected provinces analysed. Based on the descriptions of the epidemic trends and timings of interventions, we observed the potential effects of early implementation and timely adjustment of the control strategies on containing the COVID-19 epidemic in mainland China. The collated data have been made available and they may provide a useful resource for further research into epidemic control and policy planning.Domestic travel restrictions were implemented at similar times across provinces in China , althougThe timing of school reopening in China depended on the local epidemic situation , but theA particularly high cCFR was reported in Hubei compared with the other provinces according to our analysis. This difference in disease severity was also consistently demonstrated by the proportion of critical and severe cases over the last few months. Another study that accounted for right-censoring when estimating the true case fatality demonstrated a similar discrepancy across provinces to that we determined based on the cCFRs . This siThe indicators comprising cCFR and proportions of currently critical and severe cases exhibited different relationships across the provinces in China . Henan pContact tracing was implemented nationally at the beginning of the epidemic in China as a key strategy coupled with case management . We founA major limitation of our descriptive analysis is the use of aggregate cases, deaths, recoveries, and contacts data. These indicators are convenient for monitoring and comparing the epidemic trends by province, but further inferring the effects of risk factors on the transmission dynamics is not possible. Patient characteristics such as age and comorbidities are essential for understanding the heterogeneity of disease severity. Estimations of the setting-specific incubation period, reporting delay, and disease progress also rely on the date of symptom onset and care-seeking pathways for individual cases . AnotherMany containment measures have been implemented in the different provinces of China since the beginning of the COVID-19 outbreak in Wuhan City, Hubei Province. Similar control measures were also introduced in other countries, such as Singapore and South Korea, although the practical implementations varied . Social HF, HW, XX, NI, and SB conceptualised and conducted the analysis. HF, HW, XX, AB, YW, SLvE, and NI set up the data collation framework and maintained the quality of the data sets. HF, HW, XX, AB, YW, WH, KJF, RM, DOM, JS, AL, TD, AD, KECA, LC, GC, ODE, NS, HAT, HJTU, and LKW extracted the data. HF wrote the first draft of the manuscript. All authors contributed to the revised version of the manuscript and agreed with its submission.UK Medical Research Council and Department for International Development [grant number MR/R015600/1]. This study was also supported by the National Institute for Health Research Health Protection Research Unit in Modelling Methodology, the Abdul Latif Jameel Foundation, and the EDCTP2 programme supported by the 10.13039/501100000780European Union.We acknowledge Joint Centre Funding from the The authors declare that they have no conflicts of interest.This study did not require ethical approval because aggregated publicly available data were used."}
+{"text": "Zea mays genes were expressed with various expression levels in the tested development stages, including dough stage, fruit formation, anthesis, inflorescence formation, stem elongation, seedling stage and germination (In the The Expression Profile During Different Development Stage and Different Tissues of the RNA Helicase Genes in Four Species Under Normal Growth Conditions subsection of the Results, there is an error in the first sentence of the third paragraph. The correct sentence is: Approximately 108 mination .There are errors in the number of RNA expression profiles in the captions of The image for"}
+{"text": "The time trend of prevalence and mortality of major cancers is the result of three competing processes: changes in the incidence rate, stage-specific survival, and ascertainment at early stages. Partitioning approach allows for evaluating the relative contribution of each of these competing processes to the overall trend. In this report we applied the partitioning methodology developed for the SEER registry data for prostate, colorectal, lung, female breast, bladder, ovarian, stomach, pancreas, kidney, liver cancers and melanoma. The analysis involves the design and estimation of four models for each cancer site: i) incidence rate using the Armitage-Doll model with individual predisposition modeled by the gamma distribution, ii) probability of relative survival after cancer diagnosis using the Weibull model for time after disease onset, iii) frequencies of stage at onset, and iv) mortality in the general population using the Gompertz model. B-splines are used to fit the time patterns of model parameters obtained for each year Relative contributions of the partitioning components were evaluated for individual cancers , improved survival (29%), and improve stage ascertainment (12%)) and compared among all considered cancers. The results were discussed in the light of the effect of the accumulation of survivors occurring in early years  and their higher mortality  in later years ."}
+{"text": "This presentation will share examples of arts-based and creative interventions serving people and their families living with dementia representing evidence-based and promising practices in the United States. Such interventions offer effective non-pharmacological approaches to dementia care including use of the visual arts  and performing arts ; literature and writing including reminiscence, biographical approaches, and life story work; photography and Photovoice; and dance and movement as intervention modalities. Current evidence will be presented that demonstrates the effectiveness of arts-based interventions as a form of psycho-social and self-care to alleviate the effects of dementia and enhance the quality of life. Recommendations for future research will be discussed. Strategies will be proposed to develop interprofessional health humanities networks between universities, healthcare systems, libraries, museums, and the arts community to collaborate on the creation of arts-based programs in communities currently without the benefit of such programs."}
+{"text": "The COVID-19 epidemic is still spreading globally. Contact tracing is a vital strategy in epidemic emergency management; however, traditional contact tracing faces many limitations in practice. The application of digital technology provides an opportunity for local governments to trace the contacts of individuals with COVID-19 more comprehensively, efficiently, and precisely.Our research aimed to provide new solutions to overcome the limitations of traditional contact tracing by introducing the organizational process, technical process, and main achievements of digital contact tracing in Hainan Province.A graph database algorithm, which can efficiently process complex relational networks, was applied in Hainan Province; this algorithm relies on a governmental big data platform to analyze multisource COVID-19 epidemic data and build networks of relationships among high-risk infected individuals, the general population, vehicles, and public places to identify and trace contacts. We summarized the organizational and technical process of digital contact tracing in Hainan Province based on interviews and data analyses.An integrated emergency management command system and a multi-agency coordination mechanism were formed during the emergency management of the COVID-19 epidemic in Hainan Province. The collection, storage, analysis, and application of multisource epidemic data were realized based on the government\u2019s big data platform using a centralized model. The graph database algorithm is compatible with this platform and can analyze multisource and heterogeneous big data related to the epidemic. These practices were used to quickly and accurately identify and trace 10,871 contacts among hundreds of thousands of epidemic data records; 378 closest contacts and a number of public places with high risk of infection were identified. A confirmed patient was found after quarantine measures were implemented by all contacts.During the emergency management of the COVID-19 epidemic, Hainan Province used a graph database algorithm to trace contacts in a centralized model, which can identify infected individuals and high-risk public places more quickly and accurately. This practice can provide support to government agencies to implement precise, agile, and evidence-based emergency management measures and improve the responsiveness of the public health emergency response system. Strengthening data security, improving tracing accuracy, enabling intelligent data collection, and improving data-sharing mechanisms and technologies are directions for optimizing digital contact tracing. The COVID-19 epidemic is still spreading rapidly worldwide. Tens of millions of people have been infected, and the number of infections is still growing rapidly. Most countries or regions are still in states of public health emergency. Although China, the United States, and other countries have successfully developed COVID-19 vaccines, the production and application of the vaccines still have large gaps. Moreover, effective drugs for treatment of COVID-19 have not been successfully developed. Therefore, quickly identifying and tracing individuals infected with COVID-19 and their contacts and adopting active emergency management measures, such as travel restrictions, health monitoring, and home-based quarantine, are necessary for all countries and regions to overcome the COVID-19 epidemic [Contact investigation has always been an important public health strategy and a key process in epidemic emergency management. The scale of COVID-19 infection poses a major challenge to contact investigation . TraditiDigital contact tracing uses electronic information to identify exposures to infection; it has the potential to address the limitations of traditional contact tracing, such as scalability, notification delays, recall errors, and contact identification in public spaces ,11. CurrThe data storage and processing models of digital contact tracing adopted by some countries and regions are generally divided into centralized and decentralized models . In the applet to collect residents\u2019 self-reported health characteristics and travel history and to combine the location information generated by the users\u2019 specific quick response (QR) codes to trace infected persons and contacts for individual risk assessment. A health code is generated for the identification of personal infection risk; this code serves as a voucher for passage, work resumption, and school resumption [South Korea and China have adopted the centralized model for digital contact tracing . Korea\u2019ssumption ,16. The The decentralized model was adopted by countries and regions such as Europe, North America, and Singapore . Google,App-based digital contact tracing in a decentralized mode can only be effective when used by 40%-70% of smartphone users . The earAn empirical study  showed tTherefore, this study aimed to overcome the insufficient use and objectivity of existing digital contact tracing\u2013related practices and provide new solutions to further improve the effectiveness and reliability of digital contact tracing. Hainan Province, China, was selected as the case in this study. Hainan Province adopted a centralized model to conduct contact tracing during the COVID-19 epidemic. Moreover, the model gathered multisource epidemic data that relied on the government\u2019s big data public service platform, which enabled government agencies to apply graph database algorithms, data visualization, and other digital technologies to determine and trace contacts from hundreds of thousands of epidemic records. This study describes the organizational process, technical process, application prospects and possible obstacles of digital contact tracing in Hainan Province, which may provide a more effective solution and technical support for other countries and regions.Hainan Province is one of the most popular tourist destinations among Chinese and even global tourists because of its tropical island scenery. Due to the massive influx of tourists, the flow rate of the population of Hainan Province is very large. Additionally, due to the geographical location of the island, the influx of infected individuals is the main challenge in the emergency management of the COVID-19 epidemic. As of August 7, 2020, Hainan Province reported a total of 171 confirmed individuals infected with COVID-19 [Hainan Province issued the \u201cRegulations on the Development and Application of Big Data in Hainan Province\u201d in October 2019 , which cWe conducted semistructured interviews in collaboration with the project manager and technical staff of the Big Data Administration who were in charge of Hainan\u2019s COVID-19 epidemic digital contact tracing project to understand the details of the whole process. We explained the purpose and content of the interview to the interviewees before the interview, recorded the outlines during the interview, and transcribed the voice recording to text format after the interview.Under the leadership and coordination of the Command of Hainan Provincial Epidemic Prevention and Control, the Hainan Provincial Big Data Administration collected epidemic data from different agencies, including epidemic investigation records, confirmed infected individuals\u2019 information and their spatiotemporal trajectory, high-risk population information, information on close contacts and patients with fever, and the mobile phone signaling data of imported residents or travelers with a history of residence in Hubei Province . The information in the specific databases is shown in A graph database is a new type of database system based on graph theory and algorithms that efficiently processes complex relational networks. A graph database can efficiently process large-scale, complex, interconnected, and changeable data, and its computational efficiency is far higher than that of a traditional relational database . A graphMost graph databases provide a query language that is suitable for representing graph structures and graph query. Neo4j  is a Java-based open-source graph database with high performance, high reliability, and strong scalability . The graOur research used the Cypher algorithm of Neo4j version 3.4.15 to construct an association graph among the high-risk population, the general population, vehicles, public places, and other key information; reveal the hidden network of relationships; and identify the risks in the relationships to identify and trace the contacts of COVID-19 cases.ECharts (Apache Software Foundation) is an open-source visualization tool based on JavaScript that can run smoothly on personal computers and mobile devices and is compatible with most current web browsers. The bottom layer relies on a vector graphics tool, ZRender, to provide intuitive, interactive, and highly personalized data visualization . EChartsOur research used ECharts to visualize basic data and the results of the graph database algorithms as well as to develop web portals and interactive operating systems to intuitively and dynamically query and analyze epidemic data.Based on the data planning, data collection, data storage, data analysis, and data application processes involved in the data life cycle, we used interview data to summarize the activities performed by various participants in the digital contact tracing process of the COVID-19 epidemic in Hainan Province. The specific organizational process is as follows.Data planning includes organization, assessment of the situation and demand, and the formulation of strategic goals. This project was initiated by the Hainan Provincial Command of COVID-19 Epidemic Prevention and Control on January 29, 2020. The governor of Hainan Province, as the person in charge, instructed various government departments to cooperate with the Big Data Administration to apply big data technology to COVID-19 epidemic emergency management\u2013related work. That is, the Hainan Provincial Command of COVID-19 Epidemic Prevention and Control played a leading and coordinating role, the Hainan Big Data Administration played a leading role in implementation, and other government departments played cooperative roles. Thus, an integrated and flat organizational structure and coordination mechanism were formed.The Hainan Big Data Administration immediately assessed the COVID-19 epidemic situation and emergency management measures, coordinated communication with the Command of COVID-19 Epidemic Prevention and Control and other relevant government departments, and organized epidemiologists and big data technicians to formulate an implementation plan. The plan determined the specific implementation details of using multisource epidemic big data for digital technology tracing and submitted achievable data requirements to the Command of COVID-19 Epidemic Prevention and Control. Then, the COVID-19 Epidemic Prevention and Control headquarters coordinated the cooperation of work by relevant departments and provided the specified data.Hainan Provincial Big Data Management collected the first batch of data in Excel format (Microsoft Corporation) from the Command of COVID-19 Epidemic Prevention and Control, Public Security Department, Health Commission, communication operators, and other departments on February 10, 2020.The technicians of the Hainan Provincial Big Data Administration cleaned and merged the data under the guidance of officials and epidemiologists, uploaded all databases to Hainan\u2019s big data public service platform, and used the hive data warehouse tool to manage, extract, query, and analyze the data.The data technicians of the Hainan Provincial Big Data Administration retrieved data from Hainan\u2019s big data public service platform; used the graph database Neo4j algorithm to perform association analysis on key populations, vehicles, and public places; and then used ECharts to visualize the data analysis results and determine contacts and high-risk public places.The Hainan Provincial Big Data Administration regularly writes COVID-19 epidemic contact tracing reports based on the results of data analysis and reports them to the Command of COVID-19 Epidemic Prevention and Control. The Command of COVID-19 Epidemic Prevention and Control promptly releases early warning information to the public; strengthens cross-departmental sharing of information; and guides the Health Commission, CDC, medical and health institutions, and grassroots residents\u2019 committees in the implementation of measures, such as isolation, health monitoring, and nucleic acid testing of contacts. Measures are also implemented to limit the flow of people and close high-risk infected public places.The technicians of the Hainan Provincial Big Data Administration took confirmed, suspected, and asymptomatic infected individuals, as well as individuals with a history of residence in Hubei Province, as the nodes of population; private cars, trains, and flights as the nodes of transportation; and communities and shopping malls as the nodes of public places. The technicians defined a relationship as appearance in the same public place or vehicle at the same time. Based on these nodes and relationships, the Neo4j Cypher algorithm graph database was applied to build an association graph to analyze and display the associations among key populations, vehicles, public places, and other key pieces of information. The core algorithm of the graph database used in our research is shown in The representative analysis results of the graph database algorithm are shown in The Hainan Provincial Big Data Administration applied ECharts data visualization tools to compute and visualize the distribution of the population with a residence history in Hubei Province in all cities of Hainan Province. As shown in The Hainan Provincial Big Data Administration applied the graph database algorithm to rank the frequency of confirmed, suspected, and asymptomatic infected individuals and their contacts appearing in shopping malls and communities. The results were used to infer and predict public places with high risk of infection.The Hainan Provincial Big Data Administration used ECharts to visualize the basic data and analysis results and also designed an interactive operating system that can be accessed through a web page on a browser. The system interface is shown in The Hainan Provincial Big Data Administration identified 61,439 analysis objects from hundreds of thousands of records and identified 10,871 contacts. The authorities took measures to isolate, transport, and monitor these contacts. Hainan provincial digital contact tracing identified 378 individuals with the highest infection risk , including 106 close contacts and 154 second-degree contacts who traveled on the same vehicles, 110 contacts within the same communities, and 8 contacts within the same malls. The Hainan Provincial Big Data Administration identified 6 high-risk communities and a number of high-risk shopping malls. According to the list of the highest-risk infected individuals and high-risk shopping malls and communities, the Command of Hainan Provincial COVID-19 Epidemic Prevention and Control directed health committees, the CDC, medical and health institutions, grassroot governments, and community residents\u2019 committees to take mandatory measures  for the highest-risk infected individuals and to implement emergency shutdown measures for high-risk public places. As a result, a patient who was not detected by traditional contact tracing was discovered through digital contact tracing, which provided vital information support to comprehensively curb the spread of the COVID-19 epidemic from the source.We summarized the organizational process, technical process, and main achievements of the graph database algorithm in tracing the contacts of COVID-19 cases in Hainan Province, China. This approach has practical importance in overcoming the limitations of traditional emergency management measures and existing digital contact tracing methods. From the perspective of the organizational process, our research found that Hainan Province formed a scientific and effective organizational structure and operating mechanism for digital contact tracing during the COVID-19 epidemic. The success of the organizational process is attributed to (1) the establishment of a special high-level administrative leadership agency to coordinate the entire process, namely, the Hainan Provincial Command of COVID-19 Epidemic Prevention and Control; (2) the clarification of the rights and obligations of relevant emergency management agencies in the digital contact tracing of the COVID-19 epidemic; (3) the formation of a flat and integrated organizational structure and operating mechanism for multiple agencies to communicate effectively in a timely manner and achieve collaborative governance; (4) the establishment of a dedicated big data management department to provide technical support required for data lifecycle management; and (5) the establishment of a government big data public service platform that supports the storage, recall, and analysis of multisource data according to the centralized model, and the application of the platform in digital contact tracing during the COVID-19 epidemic.From the perspective of the technical process, our research is based on the use of the Neo4j graph database algorithm and ECharts data visualization tool to mine and analyze multisource COVID-19 epidemic big data. Hidden contacts and public places associated with confirmed patients, suspected patients, and asymptomatic infections were discovered and traced so that contacts and high-risk public places could be accurately identified. The results show that the digital contact tracing in Hainan Province is compatible with multisource heterogeneous epidemic big data; it can quickly and accurately find close, second-degree, or third-degree contacts, and it can identify public places with high risk of infection. Visualization technology is of great importance in optimizing public decision-making . In our Our research is expected to overcome the main difficulties faced in emergency management of the COVID-19 epidemic in different countries and regions due to their unique political, cultural, and civic concepts ,19,28-31The main limitation of our research is the small coverage and insufficient information of COVID-19 epidemic data. Thus, tracing high-risk infected populations among the entire population of Hainan Province and their contacts is impossible. The participants in digital contact tracing in Hainan Province are limited to people with a history of residence in Hubei Province. This selection greatly reduces the scope of digital contact tracing. In addition, WeChat positioning\u2013based GPS data, UnionPay consumption data, and railway and flight passenger information, which can accurately reflect the trajectory of residents, are owned by enterprises. These enterprises did not agree to provide users\u2019 spatiotemporal trajectory data to the Hainan Provincial Big Data Administration to protect the privacy of their users.Hainan Province needs to further improve the accuracy of data contact tracing using a graph database algorithm. Authorities need to adopt more comprehensive, accurate, and dynamic population spatiotemporal trajectory data to combat the epidemic. These data are the key to improve the accuracy of digital-based tracing. In addition, when confirmed, suspected, and asymptomatic infected individuals come into contact with the general population, the distance and duration of exposure are the main indicators for assessing the risk of cross-infection . Hainan Furthermore, security issues in the process of digital contact tracing of epidemics based on a digital government platform under the centralized model need to be properly resolved in two aspects: governance and technology. In terms of governance, the law, system, and data management structure must be improved for the government to obtain citizens\u2019 personal information in public health emergencies. Data sharing standards, authority management, and data security management in the process of epidemic data analysis and application, as the bases for the government to adopt useful data to respond to epidemics under the premise of ensuring the privacy of citizens, should be clarified. In addition, the government\u2019s use of data from enterprises, social organizations, and other nongovernmental organizations to respond to the epidemic needs to be further clarified and improved. In terms of technology, data security technologies, such as cryptography methods, data encryption technologies, system vulnerability monitoring and repair technologies, virus-killing technologies, and automatic data deletion technologies, must be comprehensively used in the digital platform for epidemic emergency management.Finally, the methods of collecting epidemic data were not sufficiently intelligent. For example, epidemiological investigation data were mainly collected by health personnel through face-to-face interviews with the cooperation of community resident committees. These data were manually entered into the information system by the staff of the CDC or medical institutions. This data collection method was relatively inefficient and requires substantial staffing. Furthermore, onsite investigation by staff increases the risk of cross-infection. Therefore, for digital contact tracing, it is necessary to develop more intelligent means of completion. Therefore, authorities should follow the development trend of governance in the digital age; develop an epidemic emergency management big data platform with the aid of governmental big data platforms; and fully use cloud transmission, cloud storage, and cloud computing technology to realize the real-time and dynamic collection of epidemic data from the transaction information systems of public and private agencies through a network interface to replace the traditional methods of collecting multisource epidemic data.Hainan Province, China, was selected as the case for this study. The use of a graph database algorithm and ECharts visualization tools in Hainan Province to trace contacts and identify high-risk public places was summarized in a centralized model during the process of emergency management of the COVID-19 epidemic. Moreover, the organizational and technical processes of the case we studied can help government agencies to implement precise emergency management measures and provide agile, evidence-based decision support to improve the responsiveness of the public health emergency response system. The organizational arrangements and technology involved in our research can be applied in different countries and regions to respond to the COVID-19 epidemic and can be applied at different stages of the COVID-19 epidemic. Future research should focus on solving the problems of insufficient data coverage information, insufficient contact tracing accuracy, insufficient intelligence of data collection methods, security concerns, and insufficient real-time performance of data sharing caused by the tradeoff between citizen privacy and public health security to optimize digital contact tracing."}
+{"text": "To the Editor:1 The reasons for the decision were multifactorial, including the opportunity for medicalschools to develop and implement educational programs to fully educate all their students, toensure medical student and patient safety, and to conserve personal protective equipment.Due to the COVID-19 outbreak, the Association of American Medical Colleges (AAMC) recommendedthe suspension of all direct patient contact for clinical rotations by medical studentseffective immediately on March 17, 2020.2 Endorsed by the AAMC, Abraham Flexner later influenced medical education throughrecommendations of science-based programs in university departments linked to teaching hospitals.2 With COVID-19 being the first pandemic to affect the United States in the modern era,the outbreak resulted in the first immediate cessation of clinical education for medicalstudents in the United States.Apprenticeship on clinical rotations remains as relevant today in the education of medicalstudents as it did when Sir William Osler, FRS, FRCP, established clerkships a century ago,giving students a role on clinical services.3 The HMS organizational framework was shared with multiple medical schools across theUnited States.With no precedent, medical students with and without faculty oversight across the countryacted through the development of both social connectedness and wellness, but more importantlycommunity service, to assist patients in the general population. Locally, medical students atthe University of Cincinnati College of Medicine developed a free service program throughwhich student volunteers provided free delivery of groceries, medications, and meals topatients at risk for COVID-19-associated complications if they acquire the viral infection.Moreover, a group of medical students at Harvard Medical School (HMS) implemented a team of500 volunteers to develop a student-led organization to optimize mobilization of interestedstudents in the COVID-19 response, both clinically and in the community, and to serve as aliaison between administration for the needs and efforts of these engaged students.4 During this unprecedented time when medical students are removed from clinical servicesat US teaching hospitals, they do not have to feel powerless as noted by the HMS students.Medical students can empower themselves through sustaining the quality of health of the mostvulnerable in the broader community.Our job as physicians is to heal the sick, especially when patients are at their mostvulnerable. The innate characteristics of physicians to heal patients is developed beforegraduation from medical school. Many students develop optimistic and altruistic behavior and asense of morality patients during their medical education.University of Cincinnati, Cincinnati,OHCincinnati Children\u2019s Hospital Medical Center, Cincinnati,OHDon Hayes Jr, MD, MS, MEd"}
+{"text": "Cofilin is an actin-binding protein that regulates filament dynamics and depolymerization. The over-expression of cofilin is observed in various cancers, cofilin promotes cancer metastasis by regulating cytoskeletal reorganization, lamellipodium formation and epithelial-to-mesenchymal transition. Clinical treatment of cancer regarding cofilin has been explored in aspects of tumor cells apoptosis and cofilin related miRNAs. This review addresses the structure and phosphorylation of cofilin and describes recent findings regarding the function of cofilin in regulating cancer metastasis and apoptosis in tumor cells. Once cofilin is activated by dephosphorylation, it servers actin by translocating into the nucleus with binding to actin  and slingshot phosphatases (SSH). Phosphorylation on Ser3 deactivate cofilin, while dephosphorylation works in the opposite way. In addition, the phosphorylation status of Ser3 also affects the ability of cofilin to translocate to the mitochondria  and Thr505 (LIMK2) threonine residue, whereas upstream effectors are Rho GTPases, including RhoA, Rac1, and Cdc42 . EMT can dissolve cell\u2013cell adhesion and alter the cell morphology to fibroblast-like forms as a consequence of actin reorganization, which collectively translate into metastasis properties , such as miR-342, miR-429, miR-182-5p, act as inhibitors of cofilin activity and upstream effectors of proliferation and migration in cancer cells  and phosphatases (SSH1) can change the activation of cofilin, and LIMK1 and SSH1 have been extensively studied as regulators in cofilin-mediated pathways in cell motility and cancer metastasis. However, there are contradictory results and data regarding the expression of cofilin in tumor cells, effects of dephosphorylation of cofilin and the expression level of LIMK1 on cell migration and invasion. Further studies are needed to explore the potential mechanisms behind these contradictory results. The effect of cofilin on apoptosis is a new focus of studies on tumor development, and a growing body of research has found that cofilin is involved in apoptosis under the regulation of AITC, UA, etoposide and arnidiol in various leukemia cells and breast cancer cells. Active (dephosphorylated) cofilin induces apoptosis by translocating to the outer membrane of mitochondria and promoting the release of cytochrome C. Therefore, cofilin can be developed as a new anti-tumor target. The regulation of apoptosis by cofilin in cancer cells can be a very promising research direction. With further study of the pathway linking cofilin and apoptosis, cofilin may be not only a biomarker and prognostic indicator of cancers but also a therapeutic target for various cancers.JX, YH, and JZ: wrote-original draft preparation. LW, QQ, YL, GL, and JL: wrote-review and editing. HL and HW supervised and approved the final submitted version. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Dear Editor,Although onychomadesis secondary to hand-foot-and mouth disease (HFM) is an an uncommon clinical manifestation; it threatens parents and child caregivers. In a case series of 145 Thai patients, it occurred in 5\u201337% of cases, depending on the virus.None declared.Juliana Polizel Ocanha Xavier: Approval of the final version of the manuscript; conception and planning of the study; elaboration and writing of the manuscript; obtaining, analysis, and interpretation of the data; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.Jos\u00e9 C\u00e2ndido Caldeira Xavier Junior: Approval of the final version of the manuscript; critical review of the literature; critical review of the manuscript.None declared."}
+{"text": "Scientific Reports 10.1038/s41598-017-15839-y, published online 13 November 2017Correction to: Bram Van den Bergh was omitted from the author list in the original version of this Article. This has been corrected in the PDF and HTML versions of the Article, and in the accompanying Supplementary Information file.The Author Contributions section now reads:CC designed the experiments with CWM, executed the experiments, analyzed the data, and wrote the manuscript. CL and VvN conducted the in silico analysis of Ger receptor genes in 152 gIICb strains. BVdB performed the bioinformatic analysis of the genome sequence of the gerBAC deletion mutant. CWM conceived the study and finalized the manuscript. All authors discussed and interpreted the data."}
+{"text": "Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide. Sorafenib remained the main stay treatment for patients with advanced HCC for over a decade ,2. In thA minority of patients have locoregional disease at the time of presentation and are candidates for potentially curative options. Surgical resection remains one of the cornerstone curative strategies but, given the underlying liver disease, is not an option for many. Ju et al. review the advantages and disadvantages of anatomical resection (AR) over non-anatomical resection (NAR) in HCC patients and outline outcome measures of both the techniques . AR can Limited models exist for studies of prevention and rationally done studies with tolerable therapies, when given long term, are much needed to design chemoprevention trials. In the woodchuck model of hepatitis B related hepatocellular cancer, Iyer et al. demonstrate the chemo prevention potential, tolerability and immunomodulatory role of low dose sorafenib. High doses of sorafenib upregulated nuclear factor of activated T cells 1 (NFAT1) signaling, and were associated with an immunosuppressive phenotype, with reduced T cell proliferation and enhanced PD-1 expression . Dose reThis issue contains four original research reports examining novel therapies in preclinical models (n = 3) and patients (n = 1). Chen et al. show that magnolol, a compound extracted from the bark of Magnolia officinalis, enhances the therapeutic efficacy of sorafenib via protein kinase B (AKT) inactivation . Co-admiSeveral papers in the issue comprehensively review different therapies under development. Jiang et al. review the role of AMP-activated protein kinase (AMPK) in HCC . DownregThe lack of or limited available tumor tissue in hepatocellular cancer patients poses a challenge in biomarker development. To this end, various groups have suggested using readily available non-invasive laboratory values, to aid patient selection and prognostication. Ueshima et al., demonstrate the effect of baseline liver function in terms of the Child-Pugh score and ALBI  grade on efficacy and adverse event outcomes of patients treated with lenvatinib . AntkowiThe plethora of treatment modalities available to manage HCC patients, many showing efficacy compared to placebo but not compared head to head, present unique challenges in patient selection and sequencing. Standardized approaches are lacking, due to the differences in biological characteristics, patient comorbidities and the paucity of data regarding the appropriate sequencing of novel therapies. In a review by Gholam et al., the authors highlight the importance of multidisciplinary teams to maximize the outcomes of HCC patients, especially in the setting of unresectable disease, and the important roles various subspecialists will play to ensure optimal patient outcomes . In rapidly fatal cancers like HCC, the goal of therapy is an improvement in the quality of life (QoL), in addition to prolonging survival. This has been challenging in the HCC space, due to multiple factors, including absent or lack of standardized quality of life reporting in clinical trials, as well as worse liver function and performance status of real-world patients. Zhou et al. summarize the efficacy and safety outcomes of systemic treatment options, along with QoL data, and provide a reference for management of treatment toxicities . Li et aIn conclusion, despite the recent additions to our armamentarium of drugs, HCC remains an area with unmet need. Although more therapy options exist than before, determination of optimal sequencing of therapies, combinations and the impact of these decisions on patient-reported QoL, and on cost of overall care delivery are new challenges that we face. This Special Issue illuminates further understanding into the biology of this aggressive disease and provides innovative solutions for development of new therapies and biomarkers, as our collective efforts towards improving the survival and quality of life outcomes of HCC patients continue."}
+{"text": "We recently adapted the published National Institute for Health and Care Excellence (NICE) Attention deficit hyperactivity disorder (ADHD) diagnosis and management guideline to the Saudi Arabian context. It has been postulated that adaptation of evidence-based clinical practice guidelines to the local healthcare context rather than de-novo development will improve their adoption and implementation without imposing a significant burden on resources. The objective of this paper is to describe the adaptation process methodology utilized for the generation of the first national guideline for management of people with ADHD in Saudi Arabia.We used the KSU-Modified-ADAPTE methodology for the guideline adaptation process. We describe the full process in detail including the three phases of set-up, adaptation, and finalization. The process was conducted by a multidisciplinary guideline adaptation group in addition to an external review for the clinical content and methodology.The group adapted ten main categories of recommendations from one source CPG (NICE). The recommendations include: (i) service organisation and training, (ii) recognition, identification and referral, (iii)\u00a0diagnosis, (iv) support, (v) managing ADHD, (vi) dietary advice, (vii) medication, (viii) maintenance and monitoring, (ix) adherence to treatment, and (x) review of medication and discontinuation. Several implementation tools were compiled and developed to enhance implementability including a clinical algorithm, quality measures, coding system, medication tables, translations, patient information, and online resources.The finalized clinical practice guideline provides healthcare providers with applicable evidence-based guidance for the management of people with ADHD in Saudi Arabia. The project also demonstrated the effectiveness of KSU-Modified-ADAPTE, and emphasized the value of a collaborative clinical and methodological expert group for adaptation of national guidelines. Adaptation of guidelines is a valid alternative to de novo development for generation of evidence-based guidelines.The \u2018King Saud University (KSU)-Modified-ADAPTE\u2019, as a formal methodology for guideline adaptation, is less resource-intensive than de-novo development without losing the methodological rigor.Balanced clinical and methodological expertise in the guideline group is essential for the success of similar projects.We describe the process and outputs of a comprehensive national guideline adaptation initiative with multidisciplinary contributions for management of people with ADHD.These findings contribute to the work to enhance adaptation or customization of clinical practice guidelines and highlight implementability issues for ADHD.Attention deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders that affects cognitive, emotional, social, academic, and occupational functioning . It is cThere were\u00a0no standardized clinical guidelines for ADHD management in Saudi Arabia. There is, however, a large volume of internationally published CPGs for ADHD that may create a dilemma for relevant healthcare providers and clinicians who care for people with ADHD in Saudi Arabia during the processes of sharing healthcare decisions and care provision. Furthermore, although some initiatives have targeted the management of ADHD in primary care, they are in their infancy; ADHD is mainly diagnosed and treated in tertiary care and the private sector and managed in a variety of settings, sometimes inappropriately or ineffectively. This results in significant variability in clinical practice, and suboptimal quality of care \u201310.As part of its strategy to improve access to care for people affected by ADHD in Saudi Arabia, the Saudi ADHD Society formed a multidisciplinary team to remedy this situation. The resulting clinical practice guideline (CPG) was adapted from the National institute for Health and Care Excellence (NICE) guideline entitled, Attention deficit hyperactivity disorder: diagnosis and management (NG87) , to imprClinical Practice Guidelines (CPGs) are defined as \u2018statements that include recommendations intended to optimize patient care, which are informed by a systematic review of evidence and an assessment of the benefit and harm of alternative care options . CPGs haAdaptation of CPGs is a valid and efficient alternative to de novo development of CPGs especially in resource-limited healthcare settings. It was proposed to avoid duplication of efforts, to use the available resources in a cost-effective manner, and to encourage trans-contextual customization of the CPG prepared for different economic and healthcare settings reflecting the local context and system \u201316.Given that there were\u00a0no published CPGs for ADHD management in Saudi Arabia, the presented evidence-based CPG is proposed as a National CPG using an evidence-based and formal CPG adaptation methodology. The aim of this study was to adapt the international clinical practice guidelines\u2019 recommendations for people with ADHD to fit the healthcare setting in the Saudi Arabian context including primary, secondary, and tertiary care settings.We utilised the \u2018King Saud University (KSU)-Modified-ADAPTE\u2019  adaptatiThe two main reporting standards for CPGs recommended by the EQUATOR  Network are the Appraisal of Guidelines for Research and Evaluation (AGREE) II reporting checklist and the Reporting Items for practice Guidelines in HealThcare (RIGHT) statement \u201320. DespIn phase one, Attention deficit hyperactivity disorder (ADHD) was identified by the Saudi ADHD Society as the health topic for this CPG adaptation project. An initial exploratory search regarding ADHD CPGs was conducted to identify whether there were existing CPGs related to this topic. The guideline adaptation working group (GAG) was formulated at the outset to include a child psychiatrist, two pediatric neurologists, a developmental pediatrician, a clinical neuropsychologist, a clinical pharmacist, a general pediatrician and CPG expert methodologist, a project manager, and a patient advocate. Participation of the patient advocate in the GAG and all of its meetings was intended to capture the patients\u2019 or public\u2019s views and preferences in addition to the support and insight from the networks and resources of the Saudi ADHD Society. The results of the preliminary search for ADHD Source CPGs encouraged us to proceed and officially launch this CPG adaptation project with a national scope. Capacity building sessions were conducted by the CPG methodologist for the rest of the GAG on concepts of evidence-based healthcare including the CPG adaptation process methodology and its associated toolkit , 14, 17.The target patient population for the adapted CPG is children and adults suspected of having or diagnosed with ADHD. The identified target intended users include physicians, clinical psychologists, other behavioral health clinicians, nurses, occupational therapists, pharmacists, social workers, dieticians, medical students, and health sciences students.The healthcare settings include primary, secondary and tertiary care dealing with assessment, treatment and management of ADHD in Saudi Arabia.In phase two, we identified specific health questions using the PIPOH model, relevant inclusion and exclusion criteria, and a full search strategy including a list of keywords. The elements of the PIPOH model include the target patient population (P), intervention(s) (I), professionals and clinical specialties (P), outcomes (O), and healthcare setting or context (H) that were reported earlier , 12. We Based on the results of the AGREE II appraisal  and in-dWe decided not to conduct further assessment of the certainty of the body of evidence and the strength of recommendations and relied on the high standardized domain score of domain 3 (rigour of development) of the AGREE II appraisal and the evidence-base of the NICE source CPG based on its provided Grading of Recommendations: Assessment, Development, and Evaluation (GRADE) evidence profiles .Moreover, the GAG identified, revised, and discussed all the recommendation statements through successive focus group discussions against the local and national healthcare system in Saudi Arabia. Drafting the first version of the adapted CPG was the last step of this phase.In phase three, the first draft of the adapted CPG full document was finalized including assessing the recommendations for acceptability and applicability in the local Saudi Arabian healthcare settings. This adapted CPG draft was then disseminated to a selected national panel of external reviewers of specialized healthcare providers, topic experts, and methodologists from relevant healthcare sectors. The feedback of reviewers was revised and discussed within the GAG and was reflected in the final version of the adapted CPG. A set of CPG implementation (CPGI) tools was included in the final CPG full document.th of January 2017 till 30th of May 2019. Seven meetings were conducted for planning, reviewing, and focus group discussions including two training sessions with ongoing hands-on advisory on the CPG appraisal and adaptation tools.The overall duration of this CPG adaptation project was two years and five months from 4This work marks the first national CPG adaptation project for the management of people with ADHD using the \u2018KSU-Modified-ADAPTE\u2019.The aforementioned GAG was formulated in January 2017 as a multidisciplinary group with expertise in ADHD  and evidence-based CPGs (YA). ADHD was selected as a high priority health topic with clear practice variation and lack of national CPGs for its management. The necessary resources and skills were identified and allocated. All of the GAG members signed declaration of conflicts of interest statements.The feasibility of the CPG adaptation process was confirmed by conducting a preliminary search for published CPGs. The working plan was drafted and discussed at the outset using the relevant CPG adaptation working plan template from the KSU-Modified-ADAPTE , Table 3For the first and second phases, a systematic review for the recently published ADHD Source CPGs was conducted and published in a separate report, which included the PIPOH model, eligibility criteria, results of the search and screen for Source CPGs, in addition to the results of the ratings and commentary of the AGREE II appraisal .Six source ADHD CPGs were reviewed and critically appraised including those developed by the American Academy of Pediatrics, Canadian ADHD Resource Alliance, National Health and Medical Research Council, National Institute for Health and Care Excellence (NICE), Singapore Ministry of Health, and University of Michigan Health System .The NICE CPG was superior in all of the six standardized domain scores of the AGREE II Instrument and it addressed all care options for ADHD across the lifespan. The AGREE II ratings of the NICE CPG were 100% (domain 1: scope and purpose), 96% (domain 2: stakeholder involvement), 93% (domain 3: rigour of development), 89% (domain 4: clarity and presentation), 92% (domain 5: applicability), 92% , and 100%  [Afterwards, we assessed the currency of the NICE Source CPG to ensure the validity and currency of its recommendations and their evidence-base using the related assessment of the CPG currency from the KSU-Modified-ADAPTE , Table 4The GAG reviewed and discussed the AGREE II assessment standardized domain scores and decided to adopt all of the recommendations of the NICE CPG. Relevant customization of the recommendations was conducted after several focus group discussions of facilitators and barriers to CPGI especially regarding variable health systems, medications, or healthcare provider positions.https://www.nice.org.uk/about/what-we-do/our-programmes/nice-guidance/nice-guidelines/making-decisions-using-nice-guidelines in addition to further explanation in, Chapter 9: writing the guideline of, \u2018Developing NICE guidelines: the manual\u2019: https://www.nice.org.uk/process/pmg20/chapter/writing-the-guidelineWe have followed the same format or presentation of recommendation statements developed by NICE that relied on the \u2018wording\u2019 of each recommendation rather than highlighting a quality of evidence and grade of recommendation like other CPG developers may opt for. The rationale for this format has been clearly stated in the NICE website: The GAG decided to adopt the CPGI tools provided by the NICE Source CPG, i.e. baseline assessment tool and quality standards. Additional CPGI tools were included by the GAG based on and relevant to the adapted ADHD recommendations including: (i) two medication tables; one for treatment of children and young people and the other for treatment of adults with ADHD (a summary medication table has been provided in this article), (ii) a clinical algorithm for management of ADHD Fig.\u00a0, (iii) tThirteen members participated as the external review panel from the target audience of the CPG based on their expertise in caring for people with ADHD  and in methodologies of evidence-based CPGs (HAA and SA) in addition to their representation of multiple relevant healthcare sectors in Saudi Arabia. Two international experts with local experience were invited to contribute to the external review of the clinical content as well (MG and MJN).The external review comments were compiled using a template , revisedThe customization or adaptation of recommendations was conducted with regards to the differences in the health systems and delivery of healthcare services especially for people with ADHD between the United Kingdom (UK) and the Kingdom of Saudi Arabia. The similarities in the health systems in both countries being nationalized healthcare systems where the government provides the majority of healthcare services, in addition to the similarity of income levels, facilitated the process of adaptation of recommendations to the local context . FurtherHealth benefits, side effects, and risks were evaluated in the Source CPG (NICE) as part of the AGREE II assessment  and wereThe values and preferences of the target patient population was considered and discussed throughout the CPG adaptation process through the input of the patient advocate. Moreover, reports from the patient and public encounters during related services were provided by the society.As a part of quality assurance, the finalized adapted CPG from the Saudi ADHD Society was then critically reviewed and endorsed by the Saudi Health Council as well as five national professional societies: the Saudi Pediatric Neurology Society, the Saudi Pediatric Association, the Saudi Pharmaceutical Society, the Saudi Psychiatric Association, and the Saudi Society of Professional Psychology. The adapted CPG included recommendation statements organized into ten sections including: (i) Service organisation and training, (ii) Recognition, identification and referral, (iii)\u00a0Diagnosis, (iv) Support, (v) Managing ADHD, (vi) Dietary advice, (vii) Medication, (viii) Maintenance and monitoring, (ix) Adherence to treatment, and (x) Review of medication and discontinuation.The Saudi ADHD Society contacted NICE, the Source CPG developer, and finalized an official end user license agreement in line with the original NICE terms and conditions and the NICE UK Open Content license.https://cpg.adhd.org.sa/.A summary of the key recommendations is provided in Table The GAG recommended for the next review of this adapted CPG to be after four years from its publication (2020) which should be on (2024) after checking for updates in the Source CPG, consultation of expert opinion on any suggested updates needed according to the newest evidence and recommendations published in this area in addition to the implementation and evaluation results at relevant healthcare organizations in the Kingdom of Saudi Arabia. The Checklist for the Reporting of Updated Guidelines (CheckUp) is recommended by the EQUATOR network to report the updating of CPGs .A full set of CPGI tools was an integral component of the adapted CPG full document Fig.\u00a0, 2. SeveThe GAG recommends using this adapted CPG as a core tool within regular Plan-Do-Study-Act (PDSA) healthcare quality improvement cycles to support and promote quality and safety of healthcare services and best practice for people with ADHD.Several potential facilitators and barriers to implementation were identified during the CPG adaptation process.Facilitators include the relevant national strategies, committees, initiatives, and new healthcare services that are expected as a part of the new model of care, to support implementation. Contribution of representatives of multiple local healthcare sectors are designed to facilitate early dissemination and implementation. Furthermore, leadership engagement and support from the organizing society and from the contributing and endorsing national organizations played a major role in the success of this CPG project.Identified barriers and challenges that require a pro-active intervention to address them as a part of planning for implementation include, but are not limited to, the following: (i) medication availability, access, and sustainability; (ii) dissemination of the adapted CPG; (iii) lack of awareness of the primary care regarding the updated evidence-based recommendations of ADHD; (iv) lack of seamless integration between different national healthcare sectors; and (v) poor transition from pediatric to adult healthcare services.https://cpg.adhd.org.sa/development/).An overall decision support record for the ADHD CPG adaptation group (GAG) using the KSU-Modified-ADAPTE methodology is provided in The aim of this study was to adapt the international CPGs and their recommendations to the Saudi healthcare context for the comprehensive management of people with ADHD across all local healthcare sectors.The iterative process of the ADHD CPG adaptation reveals the nature of intensive work and capacity building that was an integral component of this project, and the specialized expertise required for such a process irrespective of the clinical or methodological expertise. The long timeline observed was not unique to this CPG adaptation project and was reported in other local CPG adaptation projects as well .The GAG did not experience a shorter timeline for this CPG adaptation project compared to the 2\u20133-year period often suggested for de-novo development of CPGs . This coNevertheless, the adaptation of CPG recommendations is a good and valid alternative to de-novo developing a CPG for people with ADHD, especially given the lack of relevant local high-quality systematic reviews and randomized controlled trials.A strength of this study is the use of the \u2018KSU-Modified-ADAPTE\u2019 method because it is clearly structured and easy to follow with a set of tools to support the process.Another noted strength was the inclusion of a patient advocate in the GAG with major contributions and input to the finalized adapted CPG.There are increasing initiatives and projects related to knowledge translation in general and CPGs in particular nationally and regionally , 30, 31.For the medication recommendations and monitoring for both children and adults, we have minimal concerns about stimulant abuse in the local population since medication prescription has strict regulations in the country and has a clear system for controlled drugs regulations.Conducting the needs assessment, that had a significant impact, is by default part of the set-up phase of adaptation and this is consistent with the experience of the GAG, which coincides with published evidence. This is an essential prerequisite of such a CPG adaptation project to practically determine the expected workload, resources, expertise, and the need for dedicated leadership and project management.The \u2018KSU-Modified-ADAPTE\u2019 methodology for CPG adaptation is a rigorous, practical, and intensive tool that\u2014along with the AGREE II instrument as a major component of the adaptation process\u2014has been demonstrated to be particularly feasible for national CPG projects.Our experience with this adaptation methodology provides useful insight into its utilization on a national level in Saudi Arabia, and further demonstrates its potential suitability for the Eastern Mediterranean region. Additional modifications to the adaptation process and tools as per the context are recommended and accepted , 17.Participation of a large number of healthcare sectors through multi-disciplinary groups in the CPG adaptation process aims at increasing the future uptake of the recommendations of this CPG. We anticipate an increase in the level of collaboration and integration of ADHD-related healthcare services as a result of the adoption of this adapted CPG.Availability of a national CPG is essential but not sufficient to guarantee ultimate standardization of patient healthcare. The degree of positive impact on people with ADHD will highly depend on the effectiveness of dissemination and implementation strategies in addition to other quality improvement and safety interventions.A formal cost-analysis is suggested to decide whether the process of CPG adaptation is cost-effective. Research evidence is required as well to determine the effectiveness of CPGI tools and strategies for ADHD, as well as effectiveness of the adapted CPG in the following areas: (i) early identification and referral of children and adults with ADHD, (ii) appropriate transition of care from child to adult healthcare services for ADHD, (iii) parent training programs, (iv) initiation of drug treatment with dose adjustment as indicated, (v) regular assessment of the response to medication, and (vi) annual review of drug treatment.Additional file 1. AGREE Reporting Checklist"}
+{"text": "Metabolomics which deals with the biological metabolite profile produced in the body and its relation to disease state is a relatively recent research area for drug discovery and biological sciences including toxicology and pharmacology. Metabolomics, based on analytical method and multivariate analysis, has been considered a promising technology because of its advantage over other toxicogenomic and toxicoproteomic approaches. The application of metabolomics includes the development of biomarkers associated with the pathogenesis of various diseases, alternative toxicity tests, high-throughput screening (HTS), and risk assessment, allowing the simultaneous acquisition of multiple biochemical parameters in biological samples. The metabolic profile of urine, in particular, often shows changes in response to exposure to xenobiotics or disease-induced stress, because of the biological system\u2019s attempt to maintain homeostasis. In this review, we focus on the most recent advances and applications of metabolomics in toxicological research."}
+{"text": "Management of CHF involved multifaceted programs that included the participation of multiple health care professionals, patient and physician education, promotion of intensive drug therapy and lifestyle modifications, and close patient monitoring. The most common CHF management strategies were case management and physician education, with an emphasis on close patient monitoring. Hypertension and hyperlipidemia-CAD intervention programs focused on chronic outpatient management and regular follow-up, with an emphasis on self management skills. These programs were managed through regular and periodic interventions, including pharmacist-managed clinics and automated provider notices. Many of the studies employed \"before-after\" comparisons in the absence of a truly experimental design and posed significant limitations due to variations in the outcomes measured, lack of transparent disease severity stratification, and variation across types of managed care organizations.A number of cardiovascular disease management strategies in the literature reported promising results. Many of the multidisciplinary CHF disease management programs were more complex than were programs for hypertension and hyperlipidemia-CAD, due, at least in part, to the nature and severity of the disease. A lack of agreement on appropriate economic and clinical outcomes for evaluating the effectiveness of cardiovascular disease management strategies is readily apparent."}
+{"text": "Early in 2021, India embarked on the uphill journey of the COVID-19 vaccination of the largest population group in the world in a prioritized manner and in the shortest possible time. Considering the endless variety of geography and diverse socio-economic demographic, religious, and community contexts, there was a high likelihood of certain population subgroups with known vulnerabilities facing inequities, which were anticipated to be further accentuated by a digital divide. This necessitated devising solutions for such communities in a localized manner to aid the local government in breaking the service access and uptake barriers with an inclusive approach. To bridge this vital gap, the Momentum Routine Immunization Transformation and Equity project implemented a three-tiered collaboration, viz., government, non-governmental organizations (NGOs), and a wide range of vulnerable and at-risk communities, utilizing knowledge exchange and use of data. The project implemented localization strategies through the NGOs for community engagement in conjunction with government vaccination teams to universalize COVID-19 vaccination uptake up to the last mile. The collaboration resulted in reaching close to 50 million beneficiaries through messaging and facilitated the administration of more than 14 million vaccine doses, including 6.1 million doses for vulnerable and marginalized communities in 18 States and Union territories in India, along with suggesting implications for public health practice and research. The Indian Government launched its COVID-19 vaccination drive in January 2021, with the objective of vaccinating the world\u2019s largest national population group of 1.06 billion people . Within According to the \u2018UN Women,\u2019 adolescents, teenagers, children, women, the elderly, people with disabilities, indigenous people, refugees, migrants, and minorities face the highest social and economic marginalization . MarginaCollaboration is integral to the success of any public health program. The fundamental assumption underlying collaborative participation is that addressing complex problems involves a combination of diverse resources owned or managed by different organizations . CollaboIn August 2021, the MOMENTUM Routine Immunization Transformation and Equity (M-RITE) project, supported by the U.S. Agency for International Development (USAID) and led by John Snow India Pvt. Ltd. under the guidance of the Ministry of Health and Family Welfare (MoHFW) of the Government of India, pioneered multiple pathways for scaling solutions for reaching the most vulnerable with COVID-19 vaccination\u2014particularly through successful collaboration with the community-oriented non-governmental organizations (NGOs), community influencers, religious leaders, and associations of people. The model presented in this paper introduces a novel case of innovation in collaborative management with a strategic focus on vulnerable and at-risk communities through collaborations with local NGOs. The learning and experiences shared in this paper provide considerations for public health managers to work beyond the boundaries of specialization and management style in forming and convening collaborations and providing a framework applicable to emergency and routine health scenarios.World Health Organization (WHO), in its operational planning guidelines to support country-preparedness and response to COVID-19, has prioritized risk communication and community engagement by recommending collaborating with civil society as an important approach to dealing with the impact of the pandemic . SimilarAn extensive literature search for possible collaboration approaches did not yield results for a comprehensive collaborative approach suitable for vaccine delivery in emergency situations like COVID-19, but did provide insights for developing a collaborative model. For example, Solana EF\u2019s public\u2013private not-for-profit partnerships (PPNP) model (2014) suggests equitable allocation of tasks among partners to maximize value generation . G\u00f3mez JThe project team assisted the MoHFW of India at the national, state, and district levels to develop a collaboration mechanism that utilized the strengths of NGOs specializing in working with vulnerable and marginalized populations in 18 states and union territories (UTs) and 298 districts, as shown in The collaboration followed a four-step consultative process between the government, donors, and project implementation team:Step 1: Need-assessment for identification of areas of collaborative support and geographies for intervention.Technical assistance (TA) for vaccine planning and prioritization for equitable delivery, including supply chain and vaccine safety;TA for catalyzing service delivery and use, including innovative delivery modalities, health workforce expansion, capacity building, community engagement, demand generation, and risk communication;Identification of intervention geographies for addressing gaps in last-mile delivery based on the COVID-19 vaccination coverage up to August 2021. Eighteen states, including seven in the northeastern part of India, known for its hard-to-reach terrain, were identified for technical support and on-the-ground interventions;Concluding that the high-priority vulnerable populations, as the key target group, included, but were not limited to, the elderly age group, differently-abled people, remote and/or tribal communities, truckers, and migrants. Priority groups also included pregnant and lactating women, transgender people, people with disabilities, adolescents in childcare institutions, etc.The project team underwent multiple rounds of discussions with the MoHFW of India, as well as the project funders, to finalize the areas of intervention as indicated below:A detailed account of activities under each intervention area has been discussed at length in the forthcoming sections.Step 2: Identification, onboarding, and capacity building of NGOs to address last-mile delivery gaps.The project collaborated with NGOs, which had a significant role in implementation, particularly at the district level and below, to support last-mile service delivery and social mobilization and community engagement activities for equitable vaccine coverage. The selection criteria included: local NGOs ; active presence in the low-vaccine-coverage districts; valid Foreign Contribution Regulation Act (FCRA) certification; prior experience of working in USAID projects; understanding of local issues; the organization\u2019s vision being aimed towards marginalized and vulnerable populations in the area; and strong history of financial management, administration, and compliance with laws.Step 3: Devising risk-communication strategies for effective community-based collaboration with the flexibility to customize demand-generation activities.The on-the-ground communication strategy was designed in accordance with the national government\u2019s COVID-19 Vaccine Communication Strategy, and focused on managing vaccine eagerness, hesitancy, and crises with respect to fear of adverse events following immunization. The project team supported state and district governments with demand-generation activities for cohorts for social mobilization and increasing awareness across project states and districts.The team emphasized collaboration with the local governments, as well as in workplaces, community-based organizations (CBOs), and faith-based organizations (FBOs) to customize interventions to meet the objectives of demand generation and target and reach specific population groups . Activities included mapping and reaching out to vulnerable populations, raising awareness, mobilizing communities, and connecting beneficiaries to the health system. Aligning with the national and state government needs, the NGOs customized the delivery of messages during the \u2018Har Ghar Dastak\u2019 (knock every door) campaign of the national government.Step 4: Devising a monitoring, evaluation, and learning (MEL) framework for reporting collaborative efforts.The project identified requirements for project monitoring, evaluation, and learning for the data collection and management system, and developed a system, in collaboration with the USAID Strategic Information Team, to ensure maximum efficiency in data reporting.The team also developed standardized data-capturing and reporting formats for NGOs. To ensure the quality of data reported by the NGOs, the project state teams and supervisory-level staff of the NGOs collated details of beneficiaries from the reported line lists and checked the status of vaccination of the beneficiaries . Around 5% of reported vaccinations were subject to back-checks on a monthly basis.The collaboration model was designed and implemented with a three-tiered approach, viz., collaboration with the government, NGOs, and the community, as depicted in The project\u2019s efforts were complementary to the efforts of the national and state governments in multiple ways, such as the provision of technical assistance, catalyzing program implementation, monitoring, and evaluation, and knowledge exchange.Technical assistance: The project team collaborated with the national government on capacity-building, vaccine supply-chain management, data analysis of vaccination coverage, communication strategies, adverse events following immunization (AEFI), and most importantly, designing various vaccine delivery approaches. Support was also seconded to the Government Medical Store Departments (GMSD) to facilitate a regular and uninterrupted supply of vaccines and syringes, and the tracking of vaccines from manufacturers to regional and state stores in coordination with supply-chain personnel. On many occasions, the collaboration allowed the generation of crucial evidence, such as shortages of vaccines, hesitancy issues, expiring vaccines, etc., which led to the re-alignment of efforts that enhanced the vaccination program. This was especially important when the vaccination staff and healthcare workers were overwhelmed in mitigating the effects of the second COVID-19 wave. Notably, the project team advocated for and facilitated the redistribution of near-expiry vials to districts with low coverage.Catalyzing project implementation: The project teams at the sub-national level identified barriers to vaccination service uptake and demand, and concurrently provided information to district administrations to advocate for organizing special camps tailored to their community\u2019s needs. One such example of facilitating vaccination among daily wage workers is shared in Box 1state of Jammu & Kashmir is home to manymigrant laborers. Health staff observed that it was difficult to vaccinatethem during the working hours of the day. The project team, along with thesub-awardee, organized a rapid coverage survey, followed by an awarenessdrive and vaccination camp lasting three days, and running into the lateevenings. Night camps were organized at three different sites, which resultedin the successful facilitation of vaccine doses at times convenient to thecommunity. The state of Maharashtra, the tribal populationof Nandurbar (district) is occupied in daily wage work. Due to the workers\u2019busy daytime schedules, they were unable to make time for vaccination.Successful advocacy by the project team with the district administration ledto the organizing of night awareness-and-vaccination camps in the tribalsettlements, resulting in outreach to 15,000 people with messages and nearly1450 people with vaccination. In the Punjab,Rajasthan, and Chhattisgarhx.Similar initiatives were taken in other states such as Monitoring & evaluation: The state project teams supported government officials with their data management systems to ensure consistent data collection, systematic data cleaning, and sufficient analytics. Using the CO-WIN data portal which has been developed by the Government of India, the project team supported state governments with management information system (MIS) based factsheets for better decision-making, informing strategies to address low vaccine coverage and assessing the effectiveness of NGO-led interventions.The state dashboards were automated for all 18 project states; the one presented in Knowledge sharing is imperative to collaboration. For uninterrupted functioning of the project collaboration, all partners under the project met with donors at the national level each month to discuss synergy in all critical areas of work. The project also conducted reviews/knowledge-sharing meetings with the NGOs and government at the sub-national level to share best practices and key learnings on the engagement of marginalized and vulnerable groups at the field level and share the support received from the local administration in all project regions, especially hard-to-reach areas, for vaccine supply.To increase the demand for, distribution of, and uptake of COVID-19 vaccination, particularly among vulnerable and marginalized populations, it was important to build public trust in vaccines and seek public participation. The project team, therefore, identified NGOs for partnership in districts that had low COVID-19 vaccination coverage in discussion with the state governments and were highly ranked in the priority list of state governments. The main objective of the collaboration was to identify low coverage and/or inaccessible areas; engage in the prioritization of these areas; and support vaccine delivery planning and supply-side interventions, demand generation through community engagement, and social mobilization. The project team and collaborating NGOs joined hands to support the physical mobilization of the elderly and persons with disabilities to vaccination centers; establish referrals, link-up beneficiaries for enhancing vaccine access and conducting follow-ups, and conduct need-based assessments to understand misconceptions regarding COVID-19 vaccination and combat vaccine hesitancy. The state project teams facilitated training for the onboarded NGOs\u2019 human resources on project implementation activities. For effective counseling and outreach efforts, a detailed set of reference materials, including interpersonal communication (IPC) for rapport-building and frequently asked questions (FAQs) were used to allay fears and mitigate negative messaging in the community. The NGOs brought different forms of expertise and helped reach various marginalized and neglected groups, as depicted in Box 2The project team collaborated with ground-based NGOs withdiverse areas of specialization to mitigate the varied set of projectchallenges:Church\u2019s Auxiliary for Social Action (CASA), an organization specialized in working with hard-to-reachcommunities in the northeastern region of India, has a strong presence amongthe faith-based community, and works closely with them to address commonmisconceptions and/or misinformation which cause vaccine hesitancy.HelpAge India, withits expertise in providing elderly care, aided the project in overcomingresistance, mobility restrictions, and the digital divide  among the elderly.Samarthan-Centre for Development Support, with its deep-rooted presence in tribal populations inChhattisgarh, helped build trust in COVID-19 vaccination among hard-to-reachpopulations.Shanta Memorial Rehabilitation Centre (SMRC) worked strongly to implement the \u201cNear to homevaccination\u201d advisory by MoHFW for all individuals who were unable to leavetheir homes for a variety of reasons, including illness and disabilities.Transport Corporation of India Foundation (TCIF) supported the vaccination of the truckercommunity and allied populations.Gilmore et al. in 2020  identifiBox 3North India: Theproject team worked closely with the Sikh Gurudwara Prabandhak Samiti (SGPC)in the state of Punjab. It conducted awareness generation activities andbeneficiary counseling, shared a written appeal in favor of COVID-19vaccination, and facilitated regular announcements from gurudwaras, whichhelped build vaccine confidence and enhance community engagement among thepopulation of the state. The team also facilitated vaccination near theplaces of worship.Central India: Theproject team worked closely with religious and community leaders of TajjulMasjid (one of the biggest mosques in Asia), which is located in Bhopal, thecapital city of Madhya Pradesh. The project team, under the leadership of thestate government, sensitized and facilitated vaccination for around 400religious leaders from various parts of the state, who in turn pledged tosupport COVID-19 vaccination from various mosques in the state. As a resultof sensitization, the Masjid undertook intensive community-engagementactivities to spread awareness, such as sharing messages through amplifiedannouncements and local television.North East India: In northeastern states,the project team collaborated with churches to create awareness among andmobilize people for vaccination by organizing vaccination camps on churchpremises, which helped to build vaccine confidence among the masses. Thereligious leaders were facilitated with vaccination on a priority basis sothey could motivate community members to become vaccinated. The strategy adopted by the project team was guided by inclusivity\u2019, and \u2018equity\u2019, and was well-aligned with the government\u2019s strategy for COVID-19 vaccination. However, achieving this strategy necessitated improved access, awareness, and demand generation among the most vulnerable and marginalized groups. Since the project NGOs are deeply entrenched in the project geographies and trusted by the target communities for their health-related needs, they were instrumental in identifying \u2018influencers\u2019 from the community, making for an impactful initiative.Among the transgender community in Chhattisgarh, the team identified and engaged two influencers who were members of the Third Gender Welfare Board constituted by the State Government of Chhattisgarh. Similarly, the team collaborated with a local community in Manipur to create and disseminate socially-inclusive messages and social media posts on vaccine uptake among the targeted marginalized communities of lesbian, gay, bisexual, transgender, intersex, queer/queer-questioning, asexual people (LGBTQI+); people living with HIV/AIDS (PLHIV); individuals who were homeless; orphans; and older adults. The case has been depicted in Box 4The project team identified the \u2018transgender community\u2019as a sub-group that was vulnerable to COVID-19, but that remainedmarginalized and could not access vaccination campaigns. The transgendercommunity in the state of Chhattisgarh was hesitant to take the vaccine becausemany of them were receiving hormone replacement therapy (HRT), and believedthat the vaccine would be unsuitable for them. Moreover, with the highprevalence of STDs and the widespread use of HRT, the community believed themyths that vaccination would adversely affect their health due to druginteraction. To increase vaccine uptake among this community, the projectteam identified a key influencer/ leader from the group who was receptive tovaccination messaging. The team conducted interpersonal counseling sessionswith the leader, and developed and showed videos of positive behaviourregarding the safety of vaccines to the community leader. The receptiveleader in Chhattisgarh received the first vaccine dose, which motivated theremaining transgender community to take their own vaccinations.Community engagement was made possible by unconventional partnerships that contributed to improving COVID-19 vaccine uptake. Some of these are detailed below.The project team engaged \u2018Persons with disabilities\u2019 using collaborative efforts and connected them to benefits provided by the social welfare departments. The team also collaborated with NGOs, which organized awareness generation activities by using sign language among teenagers with visual and hearing impairments and cerebral palsy. \u2018Drug users\u2019, often situated away from the mainstream, were apprehensive about vaccination due to misconceptions related to the safety of vaccines and fear of side effects. With the support of the Medical Officers at rehabilitation centers, NGOs organized special awareness sessions for drug users and discussed the benefits of the COVID-19 vaccine. The team engaged \u2018older adults\u2019; and \u2018pregnant and lactating women\u2019 with the help of government systems, including frontline health women workers, Community Health Officers (CHO), Gram Pradhans (village heads), and Panchayat Development Officers (PDO) (who monitor and supervise the work of Gram Pradhans), through counseling and building trust in vaccine safety. The project team mapped \u2018tribal villages\u2019 with low COVID-19 vaccination rates in states like Jharkhand, Odisha, Chhattisgarh, and Maharashtra. The project team and NGO staff covered long distances to interact with the communities through folklore activities, in which storytelling was done through acting.The project, with its prompt and proactive on-ground implementation, reached approximately 50 million beneficiaries (January\u2013December 2022) through IPC, mid-media , hard-copy prints , and telephonic reminders (on the due date of vaccination and publicizing upcoming camps). The administration of more than 14 million vaccine doses was facilitated between January and December 2022 through ground-based activities by local NGOs and project teams, including mobilizing, facilitating hard-to-reach populations to ongoing camps, and organizing special vaccination camps. Since, the modalities  were culturally acceptable to the target communities, they had a significant contribution in bringing the marginalized communities to the public health mainstream. A significant proportion of doses were facilitated for vulnerable populations (6.1 million). The results are listed activity-wise below.Apart from mobilization and camp facilitation, this success can also be attributed to the IPC efforts of the project. Since the funding mandate prevented the project\u2019s communication activities from using mass media such as social media, TV, radio, etc., the outreach workers utilized innovative communication methods such as folklore, engagement of FBOs, street shows, engagement through community champions etc. Considering the rapid nature of the COVID-19 vaccination initiative and the inaccessibility of the target group, the 14.1 million doses made a significant contribution to reaching the unreached.To ensure the fulfillment of one of the key objectives of reaching marginalized and vulnerable population groups, the project team organized special camps to ensure adequate participation of target beneficiaries. During the 18 months of project planning and execution, the team gained several learnings regarding the effectiveness of the activities and interventions. State and demographic-wise data can be obtained upon request. The detailed results of MEL activities are outside the purview of this document. The current focus is on highlighting the structured collaborative approach for replication and adaptation in research and practice. The results have been shared briefly to indicate the contribution of the project to COVID-19 vaccination of individuals at an overall and demographic level.Engagement of government stakeholders: Involving government staff at all levels  facilitates the timely implementation of interventions  in hard-to-reach areas and catalyzes feedback and action.Involvement of local NGOs: Engaging with local NGOs is an effective mechanism for accelerating social and community mobilization. Local NGOs with a strong ground presence and footprint help to quickly map and reach out to target audiences and seek the support of local stakeholders such as village heads, FBOs, self-help groups, elected representatives, etc.Contextualization of information, education, and communication (IEC) materials: The development and adaptation of available IEC materials in local languages and local formats ensures quick vaccine acceptance and community action.Customized demand generation approaches: Tailored approaches\u2014such as night camps, and collaborations with community and religious leaders to suit local needs and raise awareness of COVID-19 vaccination\u2014help in targeting specific subpopulations that might be more likely to miss vaccinations due to the fear of wage loss and other competing work and family commitments.All the approaches to vaccination were instrumental in achieving the project\u2019s objectives. Some activities that were of particular importance were:The project\u2019s collaborative approach clearly met the necessary conditions of \u2018collaborative rationality\u2019 set forth by Innes and Booher : (1) TheSeveral considerations were critical to the success of this collaborative approach, including understanding the needs and limitations of the NGOs; working directly with communities to identify appropriate outreach and engagement strategies; prioritizing strategies that supported a multi-directional exchange of information; and adapting strategies based on grounded realities and internal lessons learned. Strategies evolved over time, and the level and quality of community participation increased during planning and implementation. Real-time data analysis facilitated quick and timely decisions; constant effort helped establish collaborations between corporates, funding organizations, and senior team members, which developed mutual confidence because of timely and planned knowledge-sharing sessions. The team overcame many barriers; however, in the process, new obstacles emerged, ones which were then addressed by preemptive approaches. Experiences gained from the project can be used to encourage the consideration of collaborative participation in routine immunization, new vaccine introductions, and other public health programs and decision-making processes.The limitations faced during the project span bring forth certain considerations for community health practices. The challenges, limitations, and lessons from the project\u2019s implementation suggest the following considerations:\u2212A strategic orientation with a clearly determined target group and implementation approach is important to keep the activities of collaborators aligned and prevent confusion among the partners.\u2212Collaboration partners must be chosen wisely through a rigorous vetting process. In the current project, we ensured the recruitment of local Indian NGOs that specialize in dealing with specific vulnerable populations.\u2212The current project deployed the M&E indicators to keep policy partners informed and aligned with the ground realities on vaccine uptake. However, in the future, the monitoring and evaluation efforts must also be designed according to research priorities.\u2212Specific requests must be shared with collaborative partners and discussed during follow-up meetings. Achievable plans must be prepared for the next period in tandem with the capacities and potential of collaborative partners.\u2212Managerial capacities of the collaborating partners  must be upgraded periodically.\u2212The management of collaborations must aim towards convening rather than commanding and constraining partners. Mutual and respectful cooperation must be fostered by sharing management responsibilities with ground-level partners.\u2212Community participation by involving religious and community leaders, CBOs, and FBOs, and facilitating a sense of ownership among them must be contemplated in the initiatives targeting marginalized, vulnerable, and hard-to-reach people. The global strategy to ensure maximum inclusion in immunization programs advocates the usage of community-based organizations in strengthening accountability and ownership for immunization at the ground level. The same could be leveraged for reaching out to \u2018zero-dose\u2019 vulnerable communities.Public health initiatives targeted at sizable populations are complex due to a combination of behavioral, psychosocial, political, and cultural factors. The conditions at the ground level (particularly in pandemics) require decision-making and the rollout of activities on a war footing. Therefore, it is important to identify and enroll people and agencies who can bring ground-level insights to the initiative and act swiftly to implement changes. Eventually, most program implementation partners enter a collaborative mode, but such collaborations are often unplanned and need-based, therefore, there is a lack of strategic orientation and trustworthiness among partners. Such arrangements often result in overlapping work, non-clarity as to objectives, and fragmentation. The authors propose that a collaborative approach must be at the heart of any vaccination or public health program of this scale. The project activities align with the Immunization Agenda 2030 (IA2030) , which eThe need to disseminate research results of public health programs beyond academic and clinical audiences has been expressed repeatedly , but limOverall, the project has devised ways to strengthen the existing healthcare system by identifying and filling existing gaps in equiBox vaccination programming. Efforts to curb vaccine-preventable diseases have, in both the past and the present, recognized the importance of collaborative partnerships which can be utilized to extend routine immunization services to regularly reach \u201czero dose\u201d and under-immunized children and communities. Engaging community-level partners and ground-based institutions broadens the horizon of public health practice. The local NGOs have a deep understanding of underlying problems in their respective communities. They hold positions of high trustworthiness and receptivity among the communities. The learnings of the project have applicability in the routine immunization program management for the equitable distribution of vaccines by prioritizing efficient storage and redistribution. The coordination between district officials and NGOs was remarkable in this project.The geographical reach and experiential attributes of these NGOs are well-positioned to be leveraged for reaching the unreached in national primary healthcare programs, with a special focus on routine immunization, strengthening of data systems, appropriate messaging, and emergency response."}
+{"text": "Worldwide efforts to standardize instruments measuring quality in psychiatric care are rare. The international project \u201cQuality in Psychiatric Care\u201d (QPC) is a large research programme aiming at adapting the versions of the QPC instrument for patients and staff to different international settings.The aims were to test the psychometric properties and equivalence of dimensionality of the different language versions of QPC and also to describe and compare the quality of psychiatric out-patient, in-patient, forensic in-patient and psychiatric care across different countries.The QPC is a family of instruments based on a definition of quality of psychiatric care from the patients perspective with adapted versions for staff. In this project, we used different language versions in three areas for patient and staff: psychiatric out-patient (QPC-OP/OPS), in-patient (QPC-IP/IPS), and forensic in-patient (QPC-FIP/FIPS).Patients in out-patient psychiatric care in Brazil rated the quality of care higher than Swedish patients. Comparisons of forensic in-patient care (QPC-FIP/FIPS) patients were more critical of the care they received while staff were generally more positive on the quality of care provided in both Denmark and Sweden. Quality of in-patient care (QPC-IP/IPS) in Spain show staff rating lower quality of care than patients and lowest in the secure environment, which the Swedish staff rated low as well. In Indonesia the patients rated lower quality than staff and lowest in the discharge dimension, followed by the participation dimension. Generally, staff and patients were similar in their perceptions of the low quality of participation. Several studies in Turkey, Indonesia, Spain, Faroe Islands and Norway is ongoing.The psychometric test and validations of the instrument QPC in different language and country versions will assist countries to compare quality of care, quality improvement and permits benchmarking. Since there are few standardized instruments for measuring quality of care in the psychiatric care, the QPC is expected to make an important contribution to the development in the field.None Declared"}
+{"text": "Editorial on the Research TopicSport as a tool for social inclusion, employment, and improved healthCurrently, sports are well-known as a prominent means to address a wide spectrum of social goals. This acknowledgement of sports' social impact has been achieved through international acts and advocacy actions involving the United Nations (UN), the International Olympic Committee (IOC), sport federations, national governments and civic society over time . A recenAs a consequence of the identification of sports as catalysts for diverse social outcomes on the global and national agenda, the sport for development and peace (SDP) movement has emerged. SDP encompasses a wide range of actions, programs and studies wherein sports are utilised and investigated as means to promote non-sporting and peace building goals . SDP stuDespite the richness of studies in the field, some open questions remain concerning the efficient use of sports as a tool for social and developmental purposes. First, the literature lacks frameworks and models guiding efficient sport-based program planning, structuring and management to maximize social outcomes \u201324. SecoMost of the researches of the Research Topic draw upon data from diverse sport-based interventions aimed at various social goals  and implemented in different geographical areas, ranging from southern Africa to China, and from northern and southern Europe to Latin America. Despite the variety of social goals promoted by the programs analyzed in these studies and their geographical diversity, the articles provide similar evidence-based insights guiding: (i) the development of theoretically grounded sport initiatives; (ii) effective action planning; and (iii) efficient monitoring and evaluation of these initiatives.Burnett demonstrates that engaging in such an initiative provided the participants with a high level of soft skills transferable to the working environment. The study advocates for a robust monitoring, evaluation, and learning (MEL) framework capable of capturing the nuances of the different contexts of program implementation.Analyzing the results of a 6-month government-funded sport-for-development program implemented in Africa, with a focus on youth employability, Gozzoli et al. describe the participatory development of a training framework aimed at promoting sport coaches' awareness of their role in enhancing employability skills. The authors highlight the lack of clarity regarding the theoretical and methodological assumptions that guide the design of training courses and propose a constructivist approach to structure effective training programs for coaches.In their contribution, Commers et al. analyze a program in Flanders aimed at transferring job skills to young people through sports. The research underscores the absence of clear definitions and theoretical operationalization of program outcomes, leading to gaps in efficiently monitoring and evaluating the participants\u2019 progress within the intervention. The authors advocate for theory-based program planning, which could help outline the desired outcomes and impacts of the sport-based interventions more effectively.Gadais et al. describe the experiences of Colombian youth from disadvantaged backgrounds and program managers who participated in an SDP intervention that took them from a local community sports club to the Olympic Games. The authors recommend the intensification of evaluation research on SDP programs, including close collaboration between academics, community-based organizations, donors, and the international community.Kunlun et al. study the spatio-temporal distribution and evolution pattern of Chinese Go League Clubs and emphasize their cultural and economic impact at the local level.Finally, Commers et al. advocate for grounding and planning sport-based programs based on the principles of the theory of change. Employing the theory of change offers the advantage of anticipating desired outcomes and impacts, providing a logical sequence of actions and inputs to achieve specific social changes. On the other hand, Gozzoli et al. suggest adopting less top-down approaches and promoting participatory methods for program development, involving local stakeholders and beneficiaries at all stages of the planning process. Future research should analyze and compare the opportunities and challenges of both approaches to advance the understanding of this field.The comprehension of programme components, structure, planning and effective management remains a fundamental area for analysis to advance research and implementation in SDP . The artBurnett and Gadais et al. underscore the need to enhance M&E research in SDP. Future M&E investigations should encompass the nuanced impact of these interventions from various stakeholders' perspectives and should consider not only the individual effects of sport-based programs but also their broader economic and cultural implications .Effective program planning in sport-based initiatives is not only crucial for action delivery and impact but also has significant implications for monitoring and evaluation (M&E). There exists a circular relationship between planning, program implementation, and M&E."}
+{"text": "Natural products derived from herbal medicine are a fruitful source of lead compounds because of their structural diversity and potent bioactivities. However, despite the success of active compounds derived from herbal medicine in drug discovery, some approaches cannot effectively elucidate the overall effect and action mechanism due to their multi-component complexity. Fortunately, mass spectrometry-based metabolomics has been recognized as an effective strategy for revealing the effect and discovering active components, detailed molecular mechanisms, and multiple targets of natural products. Rapid identification of lead compounds and isolation of active components from natural products would facilitate new drug development. In this context, mass spectrometry-based metabolomics has established an integrated pharmacology framework for the discovery of bioactivity-correlated constituents, target identification, and the action mechanism of herbal medicine and natural products. High-throughput functional metabolomics techniques could be used to identify natural product structure, biological activity, efficacy mechanisms, and their mode of action on biological processes, assisting bioactive lead discovery, quality control, and accelerating discovery of novel drugs. These techniques are increasingly being developed in the era of big data and use scientific language to clarify the detailed action mechanism of herbal medicine. In this paper, the analytical characteristics and application fields of several commonly used mass spectrometers are introduced, and the application of mass spectrometry in the metabolomics of traditional Chinese medicines in recent years and its active components as well as mechanism of action are also discussed. Exploring the safety and effectiveness of herbal medicine, such as traditional Chinese medicine (TCM), is the key to its modernization and internationalization . It is oTerminal downstream products of the genome are known as the metabolome , which iAt present, there are four main analytical instruments to analyze and identify the structure of compounds, which are nuclear magnetic resonance (NMR) spectroscopy, infrared (IR) spectroscopy, ultraviolet-visible (UV) spectroscopy and mass spectrometry (MS). NMR spectroscopy has the characteristics of the same sensitivity to all detected substances, simple sample processing and non-invasiveness, so it can be applied in isotope labeling to trace metabolic pathways . HoweverHigh-resolution mass spectrometers such as Orbitrap, time of flight (TOF) and Fourier transform ion cyclotron resonance (FT-ICR) can attain a mass resolution of nearly 10 million and are suited for correctly determining the precise molecular mass and molecular structure of substances. Although high-resolution mass spectrometry is better at quantifying chemicals, the costs of both its purchase and maintenance are substantial . The mosThe quadrupole mass spectrometer (QMS) is the most classical mass spectrometer  with outThe most common multistage tandem MS system is a three-stage tandem mass spectrometer--QQQ. In three-level tandem quadrupole mass spectrometry, three quadrupole analyzers are connected in series to form a QQQ sequence, which can also be called TQMS . This alin vivo metabolites of TCM can also be identified and characterized by UPLC-QTOF/MS  that adds auxiliary radiofrequency to the QQQ can do selective excitation and provide the functional advantage of multistage serial for the QQQ  and contemporary digital technology were combined to create Fourier transform mass spectrometry (FT-MS), also known as Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS). FTICR-MS has the highest resolving power and is often used as equipment for high-end scientific research, and its unique analytical characteristics make it an essential tool for studies on proteomics, metabolomics and complex mixtures. A common method for micromolecule and proteomic analysis uses FTICR-MS in conjunction with ion preselection and fragmentation equipment and its bonding with reversed-phase LC. The high fidelity of detection linearity and frequency determination are inherent properties of FTICR-MS, which can realize the resolution, mass accuracy and dynamic range . Since iIn the traditional MS, the new separation and measurement factor of ion mobility is added, thus constituting the IM-MS system. IM-MS has multidimensional separation, which increases peak capacity, shortens analysis time, separates structural analogues or isomers, and has multiple fragmentation modes and acquisition modes. Experimental data that cannot be provided from MS alone when IM is coupled with MS. Ion-size isomers can be measured by adding an ion migration cell to the MS. Isobaric lines and conformational isomers are separated, and chemical noise is decreased, which are characteristics of IMS. Additionally, ions with a similar charge state and those with structural similarities can be grouped into categories according to the lines where their mass-mobility relationships appear . At presin vivo and in vitro studies, the effectiveness of TCM was scientifically expressed, and the overall pharmacodynamic action process of TCM was efficiently analyzed under the premise of effectiveness. Effectiveness is a fundamental property of a drug. Despite the fact that TCM is frequently used in clinical settings, it is still challenging to demonstrate its usefulness through science . FurtherIn the clinical setting, the effectiveness of TCM is crucial. Contrary to modern medicine, TCM\u2019s multiple active ingredients are affected by a variety of parameters, including the source, provenance, and processing methods of medicinal ingredients . The nonThe quality marker of TCM is the basis of a modern TCM research system that combines macroscopical and microscopic aspects and includes the study of compatibility law of TCM compounds, the basic study of chemicals and the modern pharmacological study from the molecular point of view. The determination of TCM quality markers is based on the overall view of \u201cpharmacodynamic components,\u201d, that is, those that have clear chemical structure and biological activity. It is conducive to carrying out layer-by-layer analysis of the pharmacodynamic components that play an important role in TCM, and gradually elucidating its pharmacological effects and mechanism of action, which is the premise for traditional Chinese medicine to carry out subsequent research.TCM formula has always been the most common type of medication in clinical research, and it is a group of drugs that are properly compatible according to the composition principle after selecting the appropriate dosage of drugs after determining the treatment method based on syndrome differentiation examination. TCM formulas containing two or more medicinal herbs tend to obtain better efficacy and fewer side effects than the single herbs . Jun-Chein vivo, that is, the effects of TCM compatibility on in vivo processes such as absorption, distribution, metabolism, and excretion, and finally reflect the synergistic or resistant biological effects in TCM compounds through effect indicators, bioavailability, and target recognition.The research on the chemical constituents of Chinese herbal compounds alone is not enough to clarify the compatibility law of Chinese herbal compounds and their basic efficacy and mechanism of action. As a result, using mass spectrometry, it is necessary to analyze the qualitative or quantitative changes in active ingredients of drugs before and after compatibility, study the pharmacokinetic interactions Although there is only one drug, single herbs contain a variety of active ingredients. While TCM formulas are composed of several herbs and dozens of components, these components are decomposed into countless chemical molecules, so elucidating the mechanism of action of TCM is a very difficult thing . Metabolvia integrating UPLC-QTRAP-MS, GC-MS, Western blotting and molecular docking techniques. Ultimately, it was discovered that the main targets of the QRKSG for the therapy of NS were AKT1, MTOR, CASP3, and BCL2L1. Hydroxysaffloryellow A in the treatment of traumatic brain injury, as PTGS2, XDH, NOS1 and ACHE. Many studies showed that the main active components of TCM can target one or more specific molecules and thus perform a variety of clinic treatment functions . ExploriA large number of research studies have shown the utility of metabolomics in discovering the pharmacodynamic material basis of TCM and TCM formulations . The phaMetabolomics, as a science that can comprehensively analyze the metabolome, can elucidate the mechanism of action and the change rule of action of TCM by specifically comparing the changes in metabolic profile. It provides a powerful grasp of \u201cmulti-component-multi-target\u201d for TCM, and provides a more scientific and reasonable comprehensive explanation for elucidating TCM. As the most important instrument for the analysis and identification of compound structure, MS lays the foundation for the scientific elaboration of the metabolome change contour, pharmacodynamic material basis, mechanism of action, safety, and compatibility principles of TCM. Metabolomics also emerged as a result of the development of MS. With the addition of high-tech and more MS databases, the characterization and identification of metabolites are also more accurate.With the advancement of science and technology and the passage of time, the types of MS and MS-based analysis technology have been continuously updated, reformed and broken through, and the sensitivity, scope of application, throughput and identification technology of instruments have been greatly improved. The development of MS has contributed to the promotion of metabolomics applications, giving researchers a more comprehensive understanding of small molecule metabolites. Although mass spectrometry has the traits of high resolution, good precision, and maximum throughput, the research progress of metabolomics is still slow due to the complexity of organisms, the huge number of metabolites, and unrepeatable experimental protocols in different laboratories. Different types of MS have their own advantages, and appropriate mass analyzers are selected according to different sample characteristics and requirements. Compared with the acquisition of data, the subsequent processing and mining of data are the bottleneck problems facing metabolomics. Although the existing metabolome database has shortcomings in terms of scale, the open MS database and shared metabolome dataset provide convenience for the qualitative identification of metabolomics. Introducing the quick algorithms of computers into the field of metabolomics is of great help to the annotation as well as the accuracy of the data. The research direction of multi-omics conforms to the root of the overall regulation of organisms, and multidisciplinary cross-fusion can promote the development of metabolomics."}
+{"text": "According to current diagnostic systems, affective symptoms do not represent a fundamental criterion for the diagnosis of DD. However, numerous studies have highlighted frequent comorbidity between DD and Mood Disorders and have elucidated the importance of the affective state in the development and persistence of delusions. Thus, some factor analysis studies have identified the existence of a depressive dimension in DD, suggesting a substantial psychopathological heterogeneity in DD. However, these important affective features have not evaluated from a phenomenological point of view and in their relationship with delusions.The aim of the present study is to investigate the relationship between personality, trait affectivity and severity of delusions in patients with Delusional Disorder (DD).Thirty-two outpatients affected by DD were administered the Structured Interview for DSM-IV-TR Personality Disorders (SIDP-IV), the Pathological Narcissism Inventory (NPI), the Positive and Negative Affect Schedule (PANAS) and the Psychotic Symptom Rating Scale (PSYRATS). Next, we analysed the prevalence of personality disorder in our sample of patients with DD and studied the correlations between the severity of delusions and the different affective variables. Finally, we obtained a multivariate explanatory model of the severity of the delusions.The severity of delusions was directly associated with \u201cGrandiose Fantasy\u201d item of narcissistic personality and inversely related with the feelings of shame, fear and guilt. In the multivariate model, the feeling of shame was the only independent variable capable of accounting for the severity of the delusions, that, in in DD patients, would lie on an affective core of shame.The severity of delusional beliefs in DD patients would lie on an affective core of shame upon predisposing personality traits. These findings could help to develop a psychotherapeutic approach for delusional patients focused in the feeling of shame.None Declared"}
+{"text": "Dear Editor,Bruton's tyrosine kinase (BTK) is essential for the development and maturation of B-lymphocytes. These cells do not mature in individuals with mutations in this enzyme, and they have X-linked agammaglobulinemia, the most common type of congenital agammaglobulinemia.BTK is also expressed in tumor cells, and its inhibition is gaining increasing importance in the treatment of B-lineage neoplasms.Ibrutinib is a potent irreversible BTK inhibitor and was the first inhibitor of this enzyme approved by the FDA for the treatment of the following diseases in adults: 1) Chronic graft-versus-host disease, after the failure of one or more systemic therapy lines; 2) Chronic lymphocytic leukemia/small cell lymphocytic lymphoma (CLL/SCLL); 3) CLL/SCLL in adults with 17p deletion; 4) Mantle-cell lymphoma in adults who have received at least one prior therapy; 5) Relapsed/refractory marginal zone lymphoma, in adults who require systemic therapy and have received at least one prior anti-CD20-based therapy; and 6) In Waldenstr\u00f6m's macroglobulinemia.The described side effects are fatigue, diarrhea, peripheral edema, cardiac arrhythmia , bleeding, and infections (respiratory tract).6Ibrutinib can have cutaneous adverse effects, with a peak incidence in the first year of treatment. The most common manifestations are skin rash, petechiae and ecchymosis. Also, urticaria, herpes simplex and herpes zoster reactivation, panniculitis, and Stevens-Johnson syndrome may occur.7Despite the specificity for BTK, some skin effects are similar to those produced by EGF  inhibitors,in natura with scanning electron microscopy. At medium magnification, discreet longitudinal channels were observed in the hair shafts (A 72-year-old patient who had received ibrutinib for six months to treat mantle lymphoma unresponsive to conventional therapy was assessed. The patient reported a slight alteration in his hair, with a change in its curling . Some har shafts A and B, r shafts C. At higr shafts .Figure 1The authors did not find any reports in the literature of an examination of hairs shafts with scanning electron microscopy showing alterations caused by ibrutinib. There are some reports with EGF inhibitors, in which channels were also described in the hair shafts,The findings of this patient demonstrate, on ultrastructural examination, a similarity between the alterations of EGF and BTK inhibitors.BTK inhibition is an expanding concept in the treatment of hematologic malignancies, with 22 drugs under development, and the emergence of drugs with less systemic and cutaneous toxicity is possible in the near future.12None declared.Hiram Larangeira de Almeida Jr: Approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.Debora Sarzi Sartori: Approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.Douglas Malkoun: Approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.Carlos Eduardo Pouey Cunha: Approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.None declared."}
+{"text": "Neural plasticity promotes the reorganization of language networks and is an essential recovery mechanism for poststroke aphasia (PSA). Neuroplasticity may be a pivotal bridge to elucidate the potential recovery mechanisms of acupuncture for aphasia. Therefore, understanding the neuroplasticity mechanism of acupuncture in PSA is crucial. However, the underlying therapeutic mechanism of neuroplasticity in PSA after acupuncture needs to be explored. Excitotoxicity after brain injury affects the activity of neurotransmitters and disrupts the transmission of normal neuron information. Thus, a helpful strategy of acupuncture might be to improve PSA by affecting the availability of these neurotransmitters and glutamate receptors at synapses. In addition, the regulation of neuroplasticity by acupuncture may also be related to the regulation of astrocytes. Considering the guiding significance of acupuncture for clinical treatment, it is necessary to carry out further study about the influence of acupuncture on the recovery of aphasia after stroke. This study summarizes the current research on the neural mechanism of acupuncture in treating PSA. It seeks to elucidate the potential effect of acupuncture on the recovery of PSA from the perspective of synaptic plasticity and integrity of gray and white matter. Poststroke aphasia (PSA), a language-acquired disorder, is one of the most devastating symptoms after stroke. PSA affects approximately one-third of stroke patients, and 30\u201343% of them suffer from long-term effects of aphasia , 2. PeopAcupuncture promotes the process of repairation of the nervous system by regulating neuroplasticity. As one of the ordinary means for PSA treatment, acupuncture has unique advantages in alleviating PSA. Acupuncture has the characteristics of evident efficacy, low price, flexible use, and few adverse reactions. According to traditional Chinese medicine theory, acupuncture applied to specific acupoints can dredge meridians, reconcile Yin and Yang, strengthen the body resistance, and dispel blocked energy by acupuncture on specific acupoints. Thus, acupuncture is one of the alternative methods that has been a favorable choice for PSA patients who need long-term treatment .In this study, we summarize the effects of acupuncture that promoting the recovery of PSA patients and review the language processing of PSA and its regulation at the cellular and molecular levels to provide a complementary perspective, and promote neuroplasticity.PSA is mainly related to infarction in language function-related areas, especially in the middle cerebral artery (MCA). Lesions, such as hypertension and ischemia, cause arterial stenosis or occlusion in these related areas, reducing blood perfusion and blood flow in the penumbral area, and thus affecting the corresponding language function \u201314. The 2+-ATP pump) on the cell membrane. Then, excessive neuronal depolarization, excitatory neurotransmitter release, and reduced neurotransmitter reuptake occur in the extracellular space, resulting in an increased intracellular calcium ion (Ca2+) concentration. Accumulation of calcium ions causes a downstream neurotoxic cascade, including calcium-dependent enzymes and hyperactivation of signaling, causing impaired neuronal function and irreversible damage . NM. NM51]. Evidence has demonstrated the exact efficacy of acupuncture therapy on CNS plasticity. Acupuncture-induced neuroplasticity is associated with neurotransmitters and NTFs, which may be the potential molecular basis for promoting aphasia recovery. Neuroplasticity is an important bridge to promote the recovery of neurodegenerative lesions . Almost Although the increasing number of neuroimaging studies on PSA have significantly advanced the knowledge on the mechanisms of PSA recovery, many issues remain unresolved regarding the mechanism of acupuncture on PSA. We analyze the literature and propose that the language recovery mechanism under acupuncture may involve two points: (1) glutamate receptors and neurotransmission of neurotransmitters may play a key role in the normal physiological process of language and the transmission of language information; (2) astrocytes exert an effect on neural plasticity through cellular homeostasis, and therefore intervene in the recovery of language function. This cellular homeostasis improves the outcome of PSA by promoting synaptic reconstruction and remodeling nerve conduction pathway. This study emphasizes the effect of acupuncture, and how can glutamate receptors, neurotransmitters, and astrocytes shed light on the biological mechanisms of acupuncture and neuroplasticity, and increase our understanding how acupuncture affects specific language disorders by regulating dysregulation of neurotransmitters/astrocytes."}
+{"text": "Editorial on the Research TopicSex differences in adiposity and cardiovascular diseaseSex Differences in Adiposity and Cardiovascular Disease was proposed a few months before the COVID pandemic by AJ from the University of Mississippi Medical Center (USA) and ROM from the Universidad Nacional de Tucuman (Argentina) with the goal to aid the understanding of the role of the body fat constitution as a cardiovascular risk factor, and whether this risk is similar for men and women. In addition to this, to determine if sex steroids play a specific role either in the health of females and males.The Research Topic Today, although there is progress in the study of the effect of sex hormones on the adipocyte\u2019s metabolism and distribution, its role is still unclear in cardiovascular and metabolic diseases. Controversial evidence suggests that different fat types contribute to the high risk of cardiovascular events . Thus, vZhao et al. examines the association between hypertension and its control with atrial fibrillation and how the biological sex affects this association. The original research study by Khatami et al. explored whether iron biomarkers mediate sex differences in NT-proBNP levels. Authors investigated, using linear regression analyses, the association of sex and iron biomarkers with NT-proBNP levels, independent of adjustment for potential confounders. Another original research study by Li et al. examined the effects of age and sex on outcomes of coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) in non-ST-segment elevation acute coronary syndrome (NSTE-ACS) patients with the three-vessel disease (TVD) and the interaction between treatment and age or sex in NSTE-ACS and TVD. Finally, the cohort study by Huang et al. showed the sex difference temporal trends of short-term and long-term mortality after CAD admission in China. It was based on 11 years of data from a sample of 24,432 people in the largest cardiovascular disease center in South China.In our proposal, we received six original research manuscripts that indirectly fill the aim of our topic and contribute to the leading journal Frontiers in Global Women\u2019s Health. Of 100% of the manuscript submitted to our topic, 67% were accepted, and 33% were rejected. The case-control study by In this experience, we learned to manage different situations involved during the publication process, where, in the present day, the offer to publish and review manuscripts is increasing. The limitation was finding reviewers for the specific field."}
+{"text": "Over the last decade, there has been an increase in research surrounding the specific pathologies related to gene mutations in ALS and FTLD. It has long been recognized that familial forms of these diseases can show hallmark pathologies related to mutations, e.g., ALS-FUS or FTLD-MAPT. This has been expanded recently by the identification of the C9orf72 expansion and its characteristic pathology . HoweverHenderson et al. discuss the evolution of the frontal lobes, metabolic adaptations during human evolution, and the consequences of aging on neuronal processes, linking them to known ALS/FTD pathomechanisms, mainly those related to RNA/protein turnover. The authors propose that neurodegenerative processes affecting the frontal lobes, specifically ALS and FTD, may result from a mismatch between cellular and metabolic pathways and increasing lifespan within an evolutionary framework.We have therefore collected, in this Research Topic, a number of papers that cover various aspects of neuropathology, pathophysiology, biomarkers, and genetics related to ALS and FTD. Butchbach and Scott. They offer their perspective on novel conceptual frameworks which could help find common therapies for MNDs. They point out how research has so far mainly focused on investigating the pathomechanisms linking mutations in a gene to a certain MND and propose an alternative system biology approach to understand early-onset MNDs, paving the way for new therapeutic possibilities for these diseases.A general overview of biological networks and complexity in early-onset Motor Neuron Diseases (MNDs) is given by Scarian et al. report recent findings on the role of the valosin-containing protein (VCP) gene, an ATPase involved in many different biological functions including protein degradation, autophagy, and lysosomal and mitochondrial homeostasis. The authors report evidence of possible therapeutic approaches targeting the VCP pathway, describing the use of many different drugs already developed for the treatment of other diseases, such as VCP inhibitors able to: (i) prevent muscle cell death and restore muscle integrity and mitochondrial size in VCP mutants; (ii) increase the oxygen consumption rate of patient's fibroblasts; and (iii) reverse the mislocalization of TDP-43 and FUS in mutant motor neurons.This Research Topic also concentrates on the role of causative genes shared in ALS and FTD, highlighting possible therapeutic approaches for these gene mutation-linked diseases. Zhang et al. investigate the correlation between serum NfL levels and the severity of lower motor neuron (LMN) axonal degeneration in patients with ALS, particularly in the early stages of the disease. The authors show that the use of NfL blood levels reflects the extent of limb LMN axonal damage but not upper motor neuron involvement among ALS patients, indicating that the use of this biomarker may have a profound effect on patient selection and efficacy monitoring of treatment in disease-modifying clinical trials.Additionally, the field shows interest in studying the role of neurofilament light chain (NfL) as a biomarker in ALS that can provide a deeper understanding of the pathophysiological mechanisms and potentially effective therapies for this disease. In their prospective cross-sectional study, The four articles included in this Research Topic provide an overview of the current state-of-the-art research on the role of gene mutations in the neuropathology of ALS and FTD, ranging from characterizing the pathomechanisms related to a specific genetic variation to re-evaluating biomarkers useful for the stratification of patients and directing the search for disease-modifying therapies. Much has been done and much needs to be done to better describe the gene-linked pathology in ALS and FTD. Traditional and new technologies still show many limitations, for example, in detecting the correct size of large expansions of C9ORF72, and better biomarkers are needed. The next decade promises to shed light on new aspects of the relationship between gene mutations, disease pathology, and clinical manifestation in ALS and FTD, enabling improvements in treatment and the finding of effective cures for these devastating diseases.Both authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
+{"text": "In the age of neural networks and the Internet of Things (IoT), the search for new neural network architectures capable of operating on devices with limited computing power and small memory size is becoming an urgent agenda. Trends in the development of artificial intelligence (AI) applications in the field of the Internet of Things include smart healthcare services ,2,3,4,5,AI technologies for IoT devices and edge computing are demanded in mobile healthcare , as well as in close application domains. Ambient intelligence (AmI) environments are constructed in IoT domains to provide smart services based on real-time analysis of human cognitive and motion functions. This Special Issue focuses on recent developments in the constantly growing application field of computing technologies and artificial intelligence algorithms. It includes new approaches to the organization of artificial intelligence on edge devices, as well as the organization of modular, feed forward, distributed, reservoir, recurrent, convolutional, and deep neural networks for various IoT-enabled smart applications. The guest editors are Andrei Velichko (Institute of Physics and Technology), Dmitry Korzun (Institute of Mathematics and Information Technology), and \u0438 Alexander Meigal ; they are all from Petrozavodsk State University, Russia.The Special Issue collects eleven papers to provide a multi-domain overview of the trends and developments in the edge computing and starts with the illustration of achievements in smart healthcare services. The digitalization of healthcare driven by the IoT and AmI leads to the effective use of sensors, when various parameters of the human body are instantly tracked and processed in daily life ,2. The cAn IoT-enabled system to monitor gait in subjects with Parkinson\u2019s disease is presented in study . ParkinsSmart healthcare applications, the Internet of Things (IoT), and artificial intelligence are arguably the most appropriate customized solutions for such shortcomings of traditional healthcare systems, such as long waiting times, unnecessary long trips to health centers, high costs, and mandatory periodic doctor visits. The comprehensive literature review  determinAnother illustration of the effective application of neural networks in healthcare is presented in study . Speech The realm of smart object-recognition applications of AI systems is presented in the subsequent articles ,7,8. DriFor the IoT-enabled smart applications, point clouds are one of the most widely used data formats created by depth sensors. Research on feature extraction from disordered and irregular point cloud data has advanced recently. The overview  of the dThe research direction of smart environment monitoring is presented by the study , in whicSmart disaster rescue is presented by an interesting development of a wearable device for search dogs that recognizes the behavior of a dog when a victim is found, using deep learning models . With thIn conclusion, this Special Issue illustrates advanced cases of using the AI technology for IoT-enabled smart applications. Each case demonstrates a promising trend for applying AI in IoT environments, making a step towards the effective use of modern technologies in our everyday life."}
+{"text": "On 19 April 2022, in order to overcome a succession of recent global food health and agriculture safety (FHAS) incidents, the Taiwanese government instituted and announced 20 comprehensive Articles under the Taiwanese Food and Agricultural Education Law (TFAEL) for regulating the Taiwanese FHAS in order to completely construct the international strategies under the current global food security challenges of the FAHS. As a result, this research study firstly employs the learning community model (LCM) of the learning theory to measure the implementing depth of the international sustainability practice of the 20 Articles of the Taiwanese FHASE from a learning performance analytical perspective. Then, the social learning theory (SLT) of the educational theory is applied to consolidate the individual behaviors of the relative stakeholders, the organizational management of the relative industries and the socialized consent of the multilateral organization performance assessment network (MOPAN) of the Food and Agriculture Organization (FAO) of the United Nations (UN). After completing quantitative and qualitative analyses, the two most valuable conclusions and findings were as follows: (1) Not only Article 12, but also Articles 3, 4 and 5 of the new law can empirically facilitate strategic management for supporting and promoting the Taiwanese FHAS educational policy dialogue at a global, regional and country scale in order to effectively advance the international sustainable compatibility of the TFAEL. (2) Articles 6, 11 and 16 of the new law can completely construct operational management for building normative and standard-setting Taiwanese FHAS educational works in order to efficiently advance the international sustainable compatibility of the TFAEL. Therefore, beyond the analytical results of this research, the international sustainable compatibility of the TFAEL provides a direction for the development of sustainable food systems, food policies, agricultural food markets and food chains in order to overcome the various contemporary global food security challenges. For a long time, governments have paid attention to stabilizing the supply and volatility of food prices and crops, and to technical guidance and marketing promotion on the agricultural production side. Further, most people have deemed that the food health and agriculture safety (\u201cFHAS\u201d) issue is the government\u2019s responsibility , which rRecent incidents of the Taiwanese food health and agriculture safety (\u201cTFHAS\u201d) include the contaminated soy sauce and starch food safety incident in 2013, the rancid cooking and feed oil that was used as edible oil in 2014, the \u201cMin Dou\u201d pesticide residue food safety incident of schools\u2019 nutritious lunches in 2014, the pesticide residues in tea beverages in hand-shaken beverage shops in 2012 and 2015, the presence of antibiotics in honey in 2015, the high fipronil content in eggs in 2017, the pudding powder and other products made with expired additives in 2018, and in 2019, a high fipronil content was once again detected in eggs. Therefore, the Taiwanese public has started to break their silence by expressing their own opinions on FHAS. They strongly request more TFHAS regulations and rules in nutrition, housekeeping, health, food health, agriculture safety and ecological education. In order to effectively reflect these public requirements, the Taiwanese government has specially integrated not only the TFHAS standards, but also educational concepts and behaviors into the legislation source design of the 20 Articles of the Taiwanese Food and Agricultural Education Law (\u201cTFAEL\u201d) on 19 April 2022 to overcome the current global food security challenges. Firstly, the TFAEL has officially declared the Executive Yuan, at the Council of Agriculture, as the main authority responsible for the entire TFHAS. Secondly, new goals and principles were incorporated into the TFAEL in order to bring positive benefits to the expansion of domestic ingredient use for local production and public consumption ,7,8.However, it is difficult to make a comprehensive survey on the international sustainable compatibility of the TFAEL ,10,11 afIn order to extensively consider the educational sustainability of these 20 Articles of the TFAEL, the public, democracy and pursuing excellence philosophies of the learning community model (LCM)  from theIn In order to statistically measure the interplays, the factor analysis (FA)  approachSignificantly, the 20 Articles of the TFAEL can be refined based on .Articles 1 to 4 legislatively institute the power and responsibility of the TFHAS to the relative competent authorities to effectively facilitate the participation of the Taiwanese public in promoting the developed sustainability of the TFAHS.Article 3 firstly defines the empirical implemented terms of the educational activities of the TFAHS. Its content is described as follows: \u201cTFHAS is to refer to the use of educational methods to cultivate citizens\u2019 understanding of national basic agricultural production, agricultural product processing, friendly environment, friendly production and breeding and animal husbandry, animal welfare, food selection, knowledge and practice of catering preparation, leftover food disposal, and enhance the connection between food, the environment and agriculture\u201d .Articles 4, 5 and 6 legally point out that each level of the central, municipal and local Taiwanese government must set the TFHAS-related competent authorities, responsible agencies or departments to facilitate the planning, supervision, awards and professional labor training of the TFHAS. Furthermore, these TFHAS-related competent authorities have the direct duty to organize professional committees to advance the implementation, performance, development and gathering resources for the administrative guidance of the TFHAS.Article 5 directs each TFHAS-related competent authority, responsible agency or department to take the legal rights and responsibilities to dominate the direction of international development and social needs, formulate promotion policies and set up specific implementation indicators for comprehensively developing sustainability.Article 8 states that each TFHAS-related competent authority, responsible agency or department has to regularly hold two meetings per year to update the amendment-related policies by inviting various experts, scholars and non-governmental representatives.Article 11 directly empowers each TFHAS-related competent authority, responsible agency or department to have the legal priority to expropriate local agricultural products or foods to all national government agencies (departments), public institutions, administrative legal persons, schools, kindergartens and foundations in order to sustainably develop TFHAS-related industries.(1) First session of the TFAEL:In order to improve the labeling regarding the place of production or origin, Articles 12 and 16 currently regulate that primary food staples consumed by Taiwanese people such as egg, rice, chicken, soybean, etc., must be clearly labeled to identify the origins of these primary food and agricultural products.Article 12 regulates that each TFHAS-related competent authority, responsible agency or department has to guide cater and food businesses to use local ingredients; label the origin of the ingredients according to the municipality, county (city) or township  name; promote the consumption of local agricultural products; reduce food waste; reduce the amount of ingredients and reduce leftovers. Thus, Article 12 not only effectively encourages food and catering industrialists to use local ingredients while labeling the original production location and to reduce leftovers in the operation, but it also efficiently guides consumers to think about the sources of necessary ingredients by giving priority to domestic and local ingredients sourced in Taiwan.Article 16 regulates that each TFHAS-related competent authority, responsible agency or department has to set up not only a network platform to integrate relevant information, but to also construct a food and agriculture education information integration platform to strengthen consumption channel information, promote local agricultural products and labels, and integrate food and agriculture education teaching materials, teaching plans, professionals, teachers, volunteers and publicity materials.Articles 12 and 16 manifestly rule that each TFHAS-related competent authority, responsible agency or department has to design and offer the appropriate rewards to the TFHAS-related industrialists and institutions that provide outstanding contributions.(2) Second session of the TFAEL:As Taiwan is a part of the global economy, these 20 Articles of the TFAEL must not only be considered, but they must also be measurable in order to comprehensively develop the internationalization and sustainability of the TFHAS, because the international sustainable compatibility can effectively advance the legitimacy, effectiveness, implemented performance and international sustainability of the TFAEL through the international sustainable compatibility.In order to achieve the research goal, the institutional theory (IT) was applied to emphasize the impact of institutions on the international convergence of the TFHAS. It can be argued that the TFHAS system and the TFAEL rules shape the country\u2019s overall individual behaviors and organizational cooperation model and drive all Taiwanese people to adopt and abide by common legal standards through institutional norms and constraints. The institutional theory (IT) originally emerged in the late 19th and early 20th centuries to be formed as a prominent sociological perspective used to examine the role of institutions and society in shaping individual and collective behavior. The core concepts were (1) the significance and role of normative, regulative and cognitive institutions in regulating individual behaviors and organizational policies, and (2) the role of rational\u2013legal authority and formal organizations in society. Comprehensively, the institutional theory (IT) continues to evolve, incorporating insights from other disciplines such as economics and political science. It has expanded to study fields beyond organizations, including international institutions, healthcare, education and sustainability. Continuously, a lot of researchers began to utilize the institutional theory (IT) to examine how multiple institutional logics or socially constructed systems of values, norms and beliefs coexist and influence organizations and society. This perspective emphasizes the tension and conflicts that arise when individuals and organizations are subjected to different institutional pressures. Overall, the institutional theory (IT) can not only evolve, incorporating insights from other disciplines such as economics and political science, but it can also be used to extensively study fields beyond organizations, including international institutions, healthcare, education and sustainability.In order to effectively advance the legitimacy, effectiveness, implemented performance and international sustainability of the TFAEL, the democracy philosophy (DP), pursuing excellence philosophy (PEP) and public philosophy (PP) of the learning community model (LCM) have further been employed to assess the legal educational performance and effectiveness of the TFHAS on the entire Taiwanese society, as shown in In detail, firstly, the democracy philosophy (DP) of the learning community model (LCM)  can demoSecondly, the pursuing excellence philosophy (PEP) of the learning community model (LCM)  can illuThirdly, the public philosophy (PP) of the learning community model (LCM)  can presIn order to comprehensively assay the interactions and dependences among the democracy philosophy (DP), pursuing excellence philosophy (PEP) and public philosophy (PP) of the learning community model (LCM), the social learning theory (SLT) was further applied, as shown in Significantly, the individualism characteristic of the social learning theory (SLT) can explore both the democracy philosophy (DP) of the learning community model (LCM) and the normative considered role of the institutional theory (IT) in the TFAEL. Each Taiwanese citizen has equal rights and duties to speak and attend the various TFHAS activities and political campaigns. Particularly, the individual concepts and behaviors of the TFHAS-related stakeholders  directly affect the organizational measures of the TFHAS-related industries  . ReciproAt the same time, the TFHAS public consent  regarding the multilateral organization performance assessment network (MOPAN) of the Food and Agriculture Organization (FAO) of the United Nations (UN) can also reversely disturb the organizational measures of the TFHAS-related industries . Critically, the TFHAS public consent of the TFHAS  regarding the multilateral organization performance assessment network (MOPAN) of the Food and Agriculture Organization (FAO) of the United Nations (UN) can also directly impact the individual concepts and behaviors of the TFHAS-related stakeholders  and the organizational measures of the TFHAS-related industries  . MeanwhiHence, the officers and staffs of the TFHAS-related competent authorities have to accomplish a series of relative classes of the FHASE and then must report the completed learning outcomes and performances in connection with the international sustainability practice. Measurably, the first session of Articles 3, 4, 5, 6 and 11 were defined as the pursuing excellence philosophy (PEP) of the learning community model (LCM) for assessing the organizational management of TFHASE-related industries and the second the Article 12 and 16 were classified as the democracy philosophy (DP) of the learning community model (LCM)  for apprIn terms of the achievement of research reliability, representativeness, validity and accuracy, this research cross-employs the factor analysis (FA) of quantitative analysis  to condiariables ,32,33.XStep 1: Standardize the intersection of variance to be 1 (maximum).If maximization occurs:, the interaction-compared measurements of the \u201cdiscrete probability connections\u201d in the interactive dependences were completely computed in the entropy triangular weight ((3) from .(3)H\u00a0YXSignificantly, the interplays and dependences among the individual behaviors of the TFHAS-related stakeholders, organizational management of the TFHAS-related industries and TFHAS socialized consent of the multilateral organization performance assessment network (MOPAN) of the Food and Agriculture Organization (FAO) of the United Nations (UN) were comprehensively assessed by systematically analyzing the structure of the evaluated mode of the international sustainable compatibility of the TFHAS through the effective assessments of the triangle entropy method (TEM) of qualitative analysis.As shown in (1)The first step: We concretely explored the most core determinants of the international sustainable compatibility of the TFAEL under the current global food security challenges to achieve the main goal of this research by cross-employing the institutional, learning community and social learning theories and statistical analyses of the factor analysis (FA) and triangle entropy method (TEM).(2)The second step: We not only extensively explored the literature about the main concept of the FAHS and TFAEL, but also systematically reviewed the literature about the institutional, learning community and social learning theories as well as comprehensively integrated the statistical analyses of the factor analysis (FA) and triangle entropy method (TEM).(3)The third step: We implemented the factor analysis (FA) of quantitative analysis in detail to empirically deal with the large-scale questionnaire data with a higher research validity and representativeness, as well as used the triangle entropy method (TEM) of qualitative analysis to practically execute the expert\u2019s weighted questionnaire results with a higher research reliability and exactness.(4)The fourth step: Based on the systematic measurements and assessments of the statistical analyses of the factor analysis (FA) and triangle entropy method (TEM), we induced the valuable conclusions and contributive findings in order to academically resupply the interdisciplinary research gap and empirically provide the most effective recommendations for the international sustainable practice of the Taiwanese Food and Agricultural Education Law under the current global food security challenges.In According to With reference to the methodological measures of the factor analysis (FA) of quantitative analysis , the conEssentially, the larger the number of samples selected, the higher the accuracy of the inference of the statistical analysis results to the actual situation, which can help to avoid the effective detection of differences caused by too few samples. Significantly, the authors of  addresseIn detail, there were 199 interviewees that had previously taken related courses regarding the international sustainable compatibility of the TFHAS. This induces that approximately 86.15% of the interviewees have experience with regard to the international sustainable compatibility of the TFHAS. Fifty-seven (57) out of the 231 interviewees (or 24.68%) were not willing to support the international sustainable compatibility of TFHAS, even if they were knowledgeable on the contents of Article 5 of the TFAEL. In addition, with respect to the expert\u2019s questionnaires,  clearly Furthermore, Particularly, the majority of the entire commonalities of the appraised, assessed and evaluated criteria were higher than 0.6 and close to 0.7, which means there was a higher associated interplay among each criterion through measuring the 231 valid large-scale questionnaires in the FA approach of quantitative analysis.After executing the FA of quantitative analysis, the entire communalities among these four appraised, five assessed and two evaluated criteria in the 231 valid interviewed questionnaires were integrated into the computation of Equations (2) and (3) of the TEM of qualitative analysis for achieving the higher research validity and representativeness. Furthermore, the 30 valid experts\u2019 weighted questionnaires were conducted into Equations (2) and (3) of the THM of qualitative analysis through the statistic entropy method with the communalities of the FA of quantitative research. Continuously, Finally, In view of Continuously, they also agreed that the OM-BNSW  of the Food and Agriculture Organization (FAO) of the United Nations (UN), the cognitive institutions role of the institutional theory (IT), public philosophy (PP) of the learning community model (LCM) and the socializationism of the social learning theory (SLT)) was affected by Article 16 , democracy philosophy (DP) of the learning community model (LCM) for the individualism of the social learning theory (SLT)) and Article 11 , pursuing excellence philosophy (PEP) of the learning community model (LCM) and the organizationism of the social learning theory (SLT)).(1)Not only Article 12 , democracy philosophy (DP) of the learning community model (LCM) for the individualism of the social learning theory (SLT)), but also Articles 3, 4 and 5 , pursuing excellence philosophy (PEP) of the learning community model (LCM) and the organizationism of the social learning theory (SLT)) can empirically facilitate the strategic management for supporting and promoting the TFHAS policy dialogue at the global, regional and country levels in order to effectively advance the international sustainable compatibility of the TFAEL. The TFHAS has instituted the source of law that the central, municipal and local levels of the Taiwanese government must set the TFHAS-related competent authorities, responsible agencies or departments to facilitate the planning, supervision, awards and professional labor training of the TFHAS. Particularly, the central, municipal and local governments also have the direct duty to organize the professional committees to facilitate the implementation, performance, development and gathering resources for the administrative guidance of the TFHAS.(2)Article 16 , democracy philosophy (DP) of the learning community model (LCM) for the individualism of the social learning theory (SLT)) as well as Articles 6 and 11 , pursuing excellence philosophy (PEP) of the learning community model (LCM) and the organizationism of the social learning theory (SLT)) can completely construct the operational management for building normative and standard-setting TFHAS works in order to efficiently advance the international sustainable compatibility of the TFAEL. Each TFHAS-related competent authority, responsible agency or department has to guide cater and food businesses and industries to use local ingredients, label the origin of the ingredients according to the municipality, county (city) or township  name, and promote the consumption of local agricultural products, reduce food waste, reduce the amount of ingredients, and reduce leftovers by giving priority to domestic and local ingredients sourced in Taiwan.Since the continuous appearances of a succession of the recent global FHAS incidents, a majority of people have commenced to realize that the FHAS is not only a governmental responsibility, but that they also have a public duty. Facing the development trend of the world\u2019s FHAS, the Taiwanese government instituted the comprehensive 20 Articles of the TFAEL on 19 April 2022 for overcoming various current global food security challenges of the FAHS. In order to cross-evaluate the legitimacy, effectiveness, implemented performance, international compatibility and educational sustainability of the 20 Articles of the TFAEL, the three role considerations  of the institutional theory (IT), the three essential philosophies of the learning community model (LCM) and the three basic characteristics  of the social learning theory (SLT) were cross-employed to measure the large-scale and experts\u2019 weighted questionnaires through the factor analysis (FA) of quantitative analysis. As a result, the most two valuable conclusions and findings are concluded as follows:Therefore, beyond the analytical results of this research, the international sustainable compatibility of the TFAEL is a direction towards sustainable food systems, food policies and agricultural food markets and food chains for overcoming the various contemporary global food security challenges. However, as for the limited research resources, there are more measured methodologies of the quantitative and qualitative analyses to be utilized to detect the key determinants of the evaluation and construct the assessed model in the future."}
+{"text": "Conductive anaesthesia of the nerves around the head is one of the methods of intraoperative pain relief (under deep anaesthesia but before proceeding with the procedure). Performing this procedure on primates is especially challenging for the veterinarian, due to their cranial anatomy and topography, which has more in common with the human skull than with the skulls of other animals. Knowledge of key bony structures, including cranial foramina, is essential for effective anaesthesia of the cranial nerves.Colobus angolensis), Celebes crested macaque (Macaca nigra), L\u2019Hoest\u2019s monkey (Allochrocebus lhoesti), baboon , buff-bellied capuchin (Sapajus xanthosternos), black-and-white ruffed lemur (Varecia variegata), crowned lemur (Eulemur coronatus), and a ring-tailed lemur (Lemur catta) coming from the Wroclaw Zoological Garden (Poland). The cranial nerves running through the foramina have also been described and their anaesthesia techniques against bone points have been tested to relieve post-operative pain in the area of the head supplied by these nerves.In this study, the differences in the topography of the cranial foramina in eight selected species of primates were examined: Angola colobus (The tests carried out show differences in the topography of the cranial foramina, and therefore also differences in the methods of injection, so the results obtained in this study may be useful in veterinary medicine, especially for practising veterinarians. Camelus dromedarius) [Sus scrofa) [Bos taurus) [Macaca mulatta) [Cranial nerves that originate in the brain pass through openings in the skull and they innervate various tissues and organs of the head and its surroundings. The foramina differ in their structure, topography and size depending on the animal species and individual characteristics and they are a reference point for the veterinarian to perform perineural injections, for example, to relieve pain while reducing the dose of systemic anaesthetic. This reduces the risk of complications and the patient\u2019s recovery time \u20133. Regioedarius) , Eurasia scrofa) , domesti taurus) , New Zea taurus) . In addimulatta) . This memulatta) . When itmulatta) , 11. It mulatta) . Anothermulatta) . Accordimulatta) . For themulatta) , 14\u201318.The basic problem with conduction anaesthesia (nerve blocks) is the fact that the anaesthetic should not be administered into the nerve trunk itself - this can lead to serious complications, including permanent nerve damage. In addition, perineural injections carry the risk of hematoma, peripheral neuritis, or abscess . DependiThe research aimed to learn the topography of the skull of primates, paying attention to the foramina from which the cranial nerves exit. Knowledge of bone structures is necessary for the effective use of anaesthesia because some injections used in other animal species are not applicable in primates precisely because of the characteristic structure of the skull. The skull publication is only the first in a series. Part II will concern the use of anaesthesia with attention to the anatomical structures of soft tissues, i.e. major salivary glands, lymph nodes, blood vessels and nerves. Knowledge about the anatomy of above mentioned structures and the described procedures will allow veterinarians to apply the appropriate method of anaesthesia block to the appropriate nerve. Such data on exotic primates, while not necessarily of use to a general practitioner, is especially important for veterinarians practising in zoos, primate sanctuaries and national parks, and with primate researchers. However because a limited number of individuals were available in some instances the proposed routes for and placement of needles should be interpreted as guidance and less as a directive.Collection of Specimen and Conservation status. The study material compared eight adult captive species of primates: yellow Angola colobus (Colobus angolensis), Celebes crested macaque (Macaca nigra), L\u2019Hoest\u2019s monkey (Allochrocebus lhoesti), baboon , buff-bellied capuchin (Sapajus xanthosternos), black-and-white ruffed lemur (Varecia variegata), crowned lemur (Eulemur coronatus), and a ring-tailed lemur (Lemur catta) coming from the Wroclaw Zoological Garden (Poland). These animals were collected in the years 2016\u20132022 in the Division of Animal Anatomy of the Department of Biostructure and Animal Physiology, Faculty of Veterinary Medicine, Wroclaw University of Environmental and Life Sciences . The thermal dissection was completed when the remains of soft tissues were imperceptible on the bones. The skulls were then cleaned in clean running water and left in a ventilated room to dry completely [mpletely . After ampletely . Values Topography of the cranial foramina.foramen jugulare) is located on the border of the basilar part of the occipital bone and the temporal bone on both sides of the foramen magnum. In the centre of the jugular opening is the intracervical process (processus intrajugularis), which divides it into two parts. The medial part - relatively smaller - contains the glossopharyngeal nerve (nervus glossopharyngeus), the lateral part \u2013 relatively larger \u2013 contains the vagus nerve (nervus vagus) and the accessory nerve (nervus accessorius) [The jugular foramen (ssorius) \u201327. In bforamen infraorbitale) is located on the anterior surface of the maxillary body below the infraorbital margin and there may be more than one foramen. From it comes the infraorbital nerve  - a branch of the maxillary nerve. The infraorbital nerve gives off the superior alveolar branches responsible for the innervation of the maxillary teeth and the terminal branches innervating the skin and mucosa of the nose, upper lip and lower eyelid [The infraorbital foramen  is present in the posterior part of the palatal surface of the horizontal plate of the palatine bone, and the greater palatine nerve  emerges from it [The greater palatine foramen  is located on the medial side of the mandibular branch and is the beginning of the mandibular canal. The inferior alveolar nerve  runs through it, originating from the mandibular nerve (nervus mandibularis), which passes into the mental nerve  and exits through the mental foramen . There may be more than one mental foramen and more than one mental nerve [The mandibular foramen  is located between the jawbone and the sphenoid bone. It connects with other cranial spaces through numerous openings and canals: sphenoid-palatine foramen, inferior orbital fissure, circular foramen, pterygoid canal, palato-vaginal canal, and greater palatal canal. The pterygopalatine fossa is bounded: superiorly by the body of the sphenoid bone, anteriorly by the body of the maxilla and the orbital process of the palatine bone, posteriorly by the pterygoid process of the sphenoid bone and the greater wing of the sphenoid bone, laterally by the pterygopalatine fissure , medially by the vertical plate of the pterygopalatine bone. It passes from below into the greater palatal canal. The most important nerve structures present in the pterygopalatine fossa are the pterygopalatine ganglion  and the maxillary nerve (nervus maxillaris) [The pterygopalatine fossa (illaris) , 25, 33.foramen ovale) is located on both sides of the skull in the greater wing of the sphenoid. The mandibular nerve (nervus mandibularis) emerges from the oval foramen and runs nasally-inferiorly giving branches to the masticatory nerve (nervus masticatorius), lingual nerve , auricle-temporal nerve , mandibular-hyoid nerve (nervus mylohyoideus), and inferior alveolar nerve  [The oval foramen (nferior) , 25, 34.Anaesthesia of the infraorbital nerve. The infraorbital nerve gives off the superior alveolar branches responsible for the innervation of the maxillary teeth and the terminal branches innervating the skin and mucous membrane of the nose, upper lip and lower eyelid.Intraoral method. The needle is inserted into the vestibule of the oral cavity, between the first and second incisor, and moved upwards and outwards, towards the pupil of the eye looking ahead [ng ahead . Baboon Anaesthesia of the greater palatine nerve. The greater palatine nerve is responsible for innervating the mucous membrane of the hard palate. The needle is inserted at the level of the last molar [st molar . It is dAnaesthesia of the mental nerve. The mental nerve is responsible for the sensory innervation of the skin of the chin and the mucous membrane of the lower lip. The needle is inserted through the skin after palpating the mental foramen with a finger. This method can be applied to all monkey species tested . Thus our proposed routes for and placement of needles should be interpreted as guidance and less as a directive."}
+{"text": "Artificial intelligence (AI) has made an indelible contribution to the progress and development of human society, which has major applications in the fields of national defense, transportation, finance, logistics, education, etc. As a branch of computer science, AI has made significant breakthroughs in machine translation, intelligent control, language and image processing, automatic programming, and storage computing. Artificial intelligence-driven healthcare technologies are rapidly evolving into solutions that are applicable to clinical practice. AI has greatly helped improve health outcomes by using patient-relevant clinical data for early diagnosis of symptoms and better prognosis. Therefore, there is reason to believe that AI can make greater contributions to the prevention and diagnosis of mental disorders.There have been relevant representative studies based on AI technology that have made breakthrough contributions in the prevention, diagnosis, and treatment of other diseases. In order to improve the applicability of AI technology in the mental disorder field, it is necessary to propose new theories, technologies, architectures, algorithms, and mechanisms. The goal of this Research Topic is to bring together relevant researchers from industry and academia to share their latest findings and developments in the application of AI in medicine, especially in the prevention and diagnosis of mental disorders. It was our unexpected pleasure to have 4 papers in this topic which reported new exciting findings and cutting edge methodologies.In this Research Topic, four articles focus on the performance of artificial intelligence in the field of mental disorders, such as symptom diagnosis, adjunctive treatment, and model optimization.Depression recognition model:Xie et al. explored the application of the depression recognition model (DR model) based on AI machine learning (ML) in the diagnosis of depression. They explored the rhythms of adrenocorticotropic hormone (ACTH) and cortisol in depressed and anxious patients and their effects on mental status, and extracted data features based on electroencephalo-graph (EEG) data from different patients to construct a DR model for diagnosis .AI-based chatbot micro-intervention for parents:Entenberg et al. investigated the effectiveness of intelligent chatbots to help parents with parenting. The authors recruited a sample of 170 parents with at least one child to participate in the chatbot intervention. Parents can learn skills for parenting such as effective praise techniques. This study analyzed the effectiveness of parenting chatbot micro-interventions, the learning gained by participants from pre to post-intervention, and the user characteristics of parents. According to the experimental results, mental health chatbots are a promising method for busy parents of children and adolescents to enhance parenting skills .Point of interest (POI) recommendation based on preference perception: Graph embeddings and graph neural networks are fail to capture deep graph structure information in point-of-interest recommendation tasks, resulting in unsatisfactory representation results. To address the above issues, Shu et al. proposed a general framework based on the diffusion of preference-aware graphs to capture the deep structural information neglected in most existing methods for POI recommendation.Understanding psychiatric illness through natural language processing: The diagnosis of mental disorders is mainly based on the level of experience of each psychiatrist and often lacks objectivity. To this end, Kishimoto et al. created a large Japanese speech dataset, used natural language processing to quantify the linguistic features of mental disorders and neurocognitive disorders. Finally, objective and easy-to-use biomarkers were developed. These biomarkers quantify the linguistic features of mental disorders, allow more detailed examination of their correlation with other clinical indicators, and improve the accuracy of disease prediction .These typical research efforts are artificial intelligence for the adjunctive treatment of psychiatric conditions, diagnosis and optimization of neural network models, which are important for the development of novel network models and intelligent diagnostic techniques. The development of artificial intelligence provides new ways of diagnosis and treatment in medicine. We look forward to closer interaction as well as breakthroughs between AI and the field of mental disorders. Finally, we thank all contributing authors for their novel research works and publishers, as well as the editorial team for their efforts in organizing this Research Topic.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
+{"text": "The hit-to-lead optimization, which represents a crucial step in the early drug discovery process, aims at improving the drug-likeness by modifying physicochemical properties, improving pharmacokinetic/pharmacodynamic (PD) profiles, and reducing off-target activities. Increasingly, lead optimization may benefit from the support of dictions  and the dictions  by adopthemistry . Howeverhemistry .Streptomyces aureofaciens, artemisinin from Artemisia afra, doxorubicin from Streptomyces peucetius, cyclosporine from Tolypocladium inflatum, and so on , Khandazhinskaya et al. describes the synthesis of a new series of 5\u2032-norcarbocyclic fleximers bearing an artificial sugar fragment with a pyrazole-containing heterocyclic base, and the inhibitory properties in respect to purine nucleoside phosphorylase (PNP). Today, fleximer analogues of nucleosides are in the crossroad of heterocyclic and nucleoside chemistry, and this class of compounds is very promising because of a wide spectrum of biological activities. Specifically, the design with the fleximer aza/deazapurine bases can ensure additional conformational freedom in order to maximize structural interactions in the active site of the target enzyme while maintaining the structural similarity with a normal nucleoside substrate. Thus, helping with better understanding of enzyme specificity. The new compounds interact with the active site of the PNP of E. coli like natural heterocyclic bases, showing weak, non-competitive inhibitory activity.The second article by VNN1 gene. The main effect of vanin-1/VNN1 is related to its pantetheinase sulfhydrylase activity, which can hydrolyze pantetheine into pantothenic acid and cysteamine. The enzymatic activity of vanin-1/VNN1 has been found to be essential in the development of many diseases. Wang et al. used fluorescent and bioluminescent probes to establish a series of visual screening methods and evaluate the inhibitory activity of a number of novel VNN1 inhibitors with different backbones. The authors demonstrated that VNN1 has a role of a pro-inflammatory agent during the onset of inflammatory bowel diseases (IBDs). Thus, the development of VNN1 inhibitors can provide a new avenue for effective IBD treatment to alleviate suffering.Pantetheinase is an enzyme that in humans is encoded by the Tamatam et al. describes methodologies and mechanistic insights for the synthesis of nitrogen-containing heterocyclic quinazolines via transition metal-catalysed reactions, paying attention to the advantages, limitations, and future perspectives of quinazoline synthesis via such reactions.Finally, the review article by In conclusion, this Research Topic of articles demonstrates the importance of the heterocycles of natural or synthetic origin in molecules with therapeutic properties and recent advances in the preparation of the quinazoline scaffold."}
+{"text": "Optimal resource allocation within national health systems represents the ultimate challenge in diverse countries worldwide. Major part of the literature points that health systems decentralization potentially address the challenge. The present commentary focuses on the debate referring to effects of health systems decentralization, based on the evidence of the study of Arianna Rotulo and colleagues. Studies on the subject emphasize the role of path dependence and the influence of choice of indicators for measurement of effects in the assessment of health systems decentralization. Acknowledging the complexity of the phenomena, the results of the study of Rotulo et al on health system decentralization in Italy are highlighted through the analysis of recent evidence from the literature. The present commentary shows that there are diverse indicators adopted in the literature on the subject, pointing to mixed results, depending on country characteristics and selection of indicators in the analysis. The synthesis of indicators gathered in recent studies also indicate that health system indicators are sensitive to path dependence, thus, requiring additional attention to assumptions of studies on health systems decentralization. Thus, studies should consider the influence of path dependence on organizational practices and institutional structures involved in decentralization processes, in addition to acknowledging that assessments on decentralization vary substantially according to indicators adopted in the analysis, and their links with previous decisions within health systems. The present commentary focuses on the debate regarding effects of health systems decentralization, based on evidence from the study of Arianna Rotulo and colleagues.4 Optimal resource allocation within national health systems represents the ultimate challenge in diverse countries worldwide. Major part of the literature points that health systems decentralization potentially address the challenge, particularly in countries with substantial intervention of the public sector, considering that the provision of merit goods may benefit from supply at local level due to in-depth knowledge of population needs and preferences.1 showed that fiscal decentralization may negatively impact health services due to intensification of existing inequalities in the distribution of resources within the country, through decrease of healthcare availability, accessibility, and utilisation. According to the authors,1 the allocation of pooling and expenditures to local governments aggravated disparities among Italian regions from 2001 until 2017, showing decrease in access and availability of resources in public hospitals, whilst increasing resources in private healthcare settings. Yet, evidence from studies assessing health systems decentralization during recent decades identifies mixed results, depending on country characteristics and selection of indicators. Rotulo et al1 Acknowledging the complexity of decentralization phenomena, Rotulo et al1 highlight negative effects of fiscal decentralization of the Italian health system through the analysis of selected indicators in the context of Italy, a high-income country. Considering elements in the literature of health systems decentralization, authors should ponder the influence of path dependence and choice of indicators for assessment of decentralization effects.Servizio Sanitario Nazionale) was intended towards promotion of universal healthcare access , funded through federal taxes and operationalized at local level. Fiscal decentralization occurred in 2001, including services restructuration and additional financing at local level with co-payment.1 First, concerning path dependence, authors emphasize historical inequalities among country regions, and underscore that the design of the Italian National Health Service  or increase in unplanned readmissions . Healthcare utilization was represented by hospitalizations in public and private hospitals, potentially including premature discharges, which may lead to negative health outcomes, including complications, unplanned readmissions, and higher mortality.1 should consider interactions with other variables, since it is important to acknowledge that prevention represents lower costs and higher quality of life for individuals and populations, whilst curative tertiary level interventions result in higher costs and potential detrimental impacts on individuals\u2019 health and wellbeing. Therefore, part of the indicators in the study of Rotulo et al1 may be linked to either lower costs or higher quality of private healthcare (in comparison to public sector), or to higher public sector expenditures in prevention strategies in high-income regions, leading to improvements in population health outcomes. Finally, the potential effects of decentralization referring to expansion of private sector in low-income regions1 Costa-Font and Turati6 showed that inequalities in outcomes and outputs in Italian and Spanish health systems were associated to differences in design and management of health services by local governments, instead of healthcare decentralization processes. However, the authors adopted different measures of regional inequality output and health system outcome with different empirical strategy, based on concentration indexes, for the analysis of pre- and post-decentralization inequalities within national health systems. Contradicting the results from Rotulo et al,7 indicated potential opportunistic behaviour of local governments to benefit from spillovers from public expenditures of neighbour regions in the process of decentralization in Italy from 1996 to 2010. In addition, authors point to economies of scale, shift of demand to the private sector, and movement of individuals to regions with higher income due to unsatisfaction with local health services. The authors focused on levels of public expenditures in three sectors  using spatial Durbin model to assess the impact of decentralization on spillover effects.7 De Siano and D\u2019Uva8 Evidence from studies on health system decentralization in other countries reinforce divergences according to country characteristics and type of indicator. Health system decentralization has been usually associated with beneficial results in primary healthcare in developed and developing countries,10 which are related to health promotion and disease prevention at lower costs, and associated with long term beneficial health outcomes for the population. Major part of studies on health systems decentralization focuses on indicators of responsiveness, efficiency, and effectiveness in healthcare delivery.11 showed that decentralization of governance, financing, and healthcare delivery generally present positive effects, whilst resource management decentralization may have negative effects. According to evidence from 30 European countries from 1996 to 2015, the effects of decentralization of healthcare expenditures were negative on populations\u2019 perceptions of healthcare quality.12 Cobos Mu\u00f1oz et al13 performed a systematic review of literature, showing mixed results regarding the effects of decentralization on health system indicators, although effects on indicators of system performance and health outcomes were generally positive. However, it is important to highlight that the authors assessed the quality of studies included in the systematic review, considering only 10 studies with low risk of bias. Dwicaksono and Fox14 synthesized quantitative and qualitative evidence on the effects of health systems decentralization in low-, medium- and high-income countries, indicating mechanisms and contextual factors at institutional, socioeconomic, and geographic levels influencing decentralization results on equity, efficiency, and resilience in healthcare. In addition, the decentralization process may present different effects in developing countries compared to developed countries, emphasizing the role of path dependence in the evolution of organizational practices and institutional arrangements within diverse structures of incentives. Abimbola et al14 The authors emphasize the complexity of the decentralization phenomena, showing that national and local government characteristics may influence the results of health systems decentralization. Therefore, decentralization may generate competition, cooperation, or coopetition (competition and cooperation) among organizations and governments through creation of multiple governance centres with vertical and horizontal relations amongst themselves.1 the decentralization process in the Italian health system follows the path of aggravating previous patterns of inequities through the mechanism of \u2018voting with feet,\u2019 phenomena based on the migration of individuals and resources from low- to high-income locations.13 In relation to the study of Rotulo et al,9 Recent evidence indicates that the process of decentralization may present important trade-offs between economies of scale, transaction costs and agency costs due to bureaucracy. In addition, lack of public sector accountability may support the capture of political power by local elites, jeopardizing efficiency, efficacy, and outcomes in local health systems. Thus, previous inequities in distribution of resources among local governments play important role in determining the capacity of provision of public services, contributing to divergences in results of health system decentralization.15 On the one hand, decentralization may generate disproportionate bureaucracy whilst pursuing improvements in quality, safety, and efficiency of healthcare delivery; on the other hand, health system centralization may lead to imposition of ineffective patterns for provision of health services at national level, depending on country characteristics.16 argue that health systems decentralization comprises diverse processes referring to various models of delegation or distribution of activities regarding organization, financing, management, and delivery of healthcare within different socioeconomic, cultural, and political backgrounds. Consequently, assorted degrees of responsiveness, efficiency, and effectiveness should be expected accordingly, especially considering the fundamental role of organizational practices and institutional structures in determining incentives and accountability to achieve optimal performance whilst minimizing risks of principal-agent problems.17 In fact, Costa-Font and Greer16 is supported by the synthesis of evidence on indicators gathered from studies previously discussed, reinforcing the requirement for careful consideration on the assumptions adopted in studies assessing health systems decentralization ."}
+{"text": "The grading of recommendations assessment, development and evaluation (GRADE) method was adopted for the development of evidence, evidence classification, and recommendations that can be systematically evaluated. For evidence lacking clinical research support, the quality of evidence was evaluated and recommended based on the evidence level standard of ancient books of traditional Chinese medicine, and The Appraisal of Guidelines for Research and Evaluation II (AGREE II) and The Reporting Items for Practice Guidelines in Healthcare (RIGHT) were referred to. This guideline plan mainly introduces the guideline formulation process of constructing clinical questions and selecting outcome indicators, evidence retrieval, generation of recommendations,  Acute primary headache causes pain in the organism, and long-term, persistent headache is a trigger and aura manifestation for many highly disabling diseases,3 The current treatment for acute primary headache is primarily analgesia. As no clinical practice guideline exists specifically for the treatment of acute primary headache using Traditional Chinese Medicine (TCM), this guideline was developed to recommend TCM treatments for acute primary headache aimed to relieve pain and standardize clinical behaviors of physicians, and allied health professionals who treat or care patients with acute primary headache in outpatient/emergency/in-patient care. It aims to recommend TCM for the treatment of acute primary headache, and improve the management, clinical efficacy, and quality of life in patients with headache.Headache is either a disease or a clinical symptom of multiple diseases.Syndrome differentiation and modification are critical in improving the efficacy of TCM in treating acute primary headache. However, such clinical evidence is difficult to obtain through randomized controlled trials (RCTs) or systematic reviews. Ancient literature is a treasure trove of TCM, an important basis for decision making in TCM clinical practice, and has a wide range of guidance for the treatment of acute primary headache using TCM. Therefore, the ancient TCM literature was also used as a major element of clinical evidence in the development of this guideline.This guideline focuses on acute primary headache and provides recommendations for their treatment using TCM, which can be used as a guide and reference for clinical practice by physicians in TCM internal medicine, neurology, and other related departments, and it will be revised according to clinical practice and advances in evidence-based medicine. The guidelinedoes not function as a medical code of conduct or a legal basis. Clinical practice based on this guideline may have different benefits for different patients and may produce different clinical outcomes.guidelines-registry.org/), with registration number IPGRP-2021CN156.The guideline proposals were registered on the practice guideline registration for transparency (PREPARE) , guideline secretary group, and guideline review group. The working group members are multidisciplinary experts, not only involving clinicians and methodologists but also due consideration on the values and wishes of potential conflicting parties and patients.The guideline steering committee comprises 10 to 15 experts. It has two chairpersons: professional and methodological chairpersons. All experts signed a conflict of interest statement, and at least one of the chairpersons did not have a conflict of interest related to this guideline. The main responsibilities of the guideline steering committee are as follows: (1) determine the topic and scope of the guideline; (2) approve the guideline proposals; (3) manage its conflict of interest statement; (4) oversee the guideline development process; (5) approve the guideline recommendation; and (6) approve the guideline publication.Guideline development groupThe GDG is composed of multidisciplinary clinical experts and methodologists. The main responsibilities of the GDG are as follows: (1) identify population, intervention, comparative measures, and outcome indicators and determine the scope of the guideline; (2) draft the guideline proposal; (3) collect and select clinical questions and outcome indicators, and construct clinical questions according to patient/population problem, intervention, comparison or control, and outcome (PICO) principles; (4) assess the importance of clinical questions and outcome indicators; (5) develop systematic reviews, evidence grading, and decision tables; (6) investigate patients\u2019 wishes; (7) determine quality grading of evidence and reach consensus on recommendations; (8) write the full text of the guideline, complete the coordination of the external review of the guideline, and handle the external review comments; (9) document the whole process of guideline development; and (10) manage matters related to guideline development.The external review group contains relevant experts and stakeholders, and its main task is to review the developed guideline recommendations.A conflict of interest statement form was made. All members of the guideline steering committee and guideline development group are required to fill in the form and agree to present the conflict of interest statement and the results of its handling as an annex to the guideline. For those who have a conflict of interest, the guideline steering committee decides whether or to what extent they would participate in the development of the guideline after discussion; those who do not have a conflict of interest could participate in the whole process.The purpose of this guideline is to recommend TCM treatment for acute primary headache, to guide clinicians and nursing staff to standardize the use of TCM for the treatment of acute primary headache with the main purpose of pain relief, and to improve the management of patients with headache, clinical efficacy, and the quality of life of patients. Users of the guideline include physicians and nursing staff of TCM internal medicine, neurology, and other related departments. The target population of the guideline is patients who were diagnosed with acute primary headache. which includes a class of diseases with headache as the main clinical feature caused by external factors and internal injury resulting in constriction or loss of nourishment of the veins and channels or by unfavorable clearing of the orifices. Western medicine diagnosis is based on the International Classification of Headache, Third Edition. Primary headache includes migraine, tension-type headache, trigeminal autonomic headache, and other primary headaches. This guideline does not cover secondary headaches, painful cranial neuropathy, other facial pain, or other types of headaches. This guideline applies to the pharmacological treatment of ongoing headaches and does not apply to the prevention of headaches during remission in patients with headache. Interventions include oral and topical TCM treatments.The clinical questions covered in this guideline relate to the TCM treatment of acute primary headache. The diagnosis of headache is based on the diagnostic criteria of headache disease in the Development of Internal Medicine of Traditional Chinese Medicine, The selection of clinical problems will be completed through multiple rounds of questionnaires.The working group investigates the importance of the collected and summarized PICO clinical questions and outcome indicators after reviewing relevant guidelines and surveying clinicians, multidisciplinary experts, and patients. The survey respondents are multidisciplinary experts and patients/guardians who rate the importance of clinical questions and outcome indicators. The importance of the outcome indicator is assessed through the method recommended by the GRADE working group. and a retrieval report will be produced. The National Library of Medicine (PubMed), the Cochrane Library, and the Cochrane CENTRAL database , Guideline International Network (GIN), National Guideline Clearinghouse (NGC), National Institute for Health and Clinical Excellence (NICE), Scottish Intercollegiate Guide Network , World Health Organization (WHO) database, Wanfang, China National Knowledge Infrastructure (CNKI), China Biomedical Literature Database (SinoMed), and Chinese Sci-tech Journal Database (VIP), Baidu Xueshu (https://xueshu.baidu.com/), Yimaitong (https://www.medlive.cn/), and Zhonghua Yidian (TCM Dictionary) version 5.0 will be searched. Specific retrieval strategies are developed based on the characteristics of different databases using a combination of subject terms and free words. The development of retrieval strategies and the literature retrieval are conducted under the guidance of a literature retrieval specialist. No language limitation is applied. In addition, references from included studies are traced to gain access to relevant literature. Information such as relevant retrieval strategies and results are reported in a formal guideline document.In this guideline, published relevant guidelines, systematic reviews, and related literature published domestically and internationally in the past 3 years are retrieved based on the questions covered. Evidence evaluation will be performed based on the results of systematic reviews if the evidence in existing guidelines is not sufficient to answer the clinical questions posed in this guideline; relevant literature will be retrieved by the guideline development group to produce systematic reviews if high-quality systematic reviews in the past 3 years are not retrieved. Evidence from ancient sources lacking clinical studies is retrieved by an antiquarian literature agency based on the Classification Standard of Evidence in Ancient Books of TCM, The evidence quality will be categorized as \u201chigh\u201d, \u201cmoderate\u201d, \u201clow\u201d, or \u201cvery low\u201d. The evaluation process is completed independently by at least three people, and the coefficient of internal consistency among the evaluation team members is calculated. The methodological quality of the included systematic reviews re-review, systematic reviews, meta-analyses, and network meta-analyses were evaluated using the AMSTAR scale. The evaluation of the ancient evidence is completed by the guideline development group according to the TCM ancient evidence standards. The evaluation process is completed independently by two members, and if there is disagreement, it is discussed together, or a third party is consulted to resolve it. If no systematic reviews related to the clinical questions is retrieved, GDG will make a new round of systematic reviews to answer the clinical questions.The methodological quality of the included guidelines is evaluated using the GRADE approach.The guideline development group develops a \u201cProblem-Recommendations-Evidence\u201d decision form, sets the expert opinions as \u201cAgree, Disagree, and Uncertain,\u201d and submits it to the expert steering committee. The expert steering committee will reach consensus on the recommendations by telephone, email, or face-to-face method.The guideline recommendations will be submitted to the external review team for feedback, and the feedback will be reviewed by the guideline steering committee to determine and publish the final version of the recommendations of the guideline.After the guideline is reviewed and revised by the expert steering committee based on the external review, the full text of the guideline will be published in relevant journals, popular science journals, and other relevant mass media. Dissemination will be performed by holding relevant conferences and training courses.The guideline is planned to be updated every 5 years.The development group of TCM Guidelines for Acute Primary Headache will raise clinical questions through the real needs of clinicians in the practice of TCM for acute primary headache. The group raises clinical questions, performs evidence retrieval, quality evaluation, and recommendations, and formulates high-quality and practical clinical practice guidelines, considering the opinions of relevant experts, the wishes of patients with headache, and economic factors, to guide the clinical TCM treatment of acute primary headache and improve clinical outcomes of patients."}
+{"text": "Dear Editor,3, but without treatment for hepatitis C. He complained of cutaneous lesions with two years of evolution, and significant worsening in the last months, with local pruritus. On examination, erythematous, infiltrated papules and plaques were observed in the gluteal region bilaterally, as well as in the left abdominal, cervical and upper dorsal regions , non-reactive rheumatoid factor, proteinogram with no monoclonal peaks. A skin biopsy was performed, which showed abundant mucin deposits in the upper and middle dermis  and hepatitis C virus (HCV) infection three years before. He was undergoing regular treatment with antiretroviral therapy , and had an undetectable viral load, with a CD4 cell count of 534 cells/mm regions . He undee dermis .Figure 1a)Lichen amyloidosus;b)Lichen myxedematosus;c)Eruptive collagenoma;d)Granuloma annulare.The diagnosis of lichen myxedematosus was confirmed through clinical-pathological correlation. The patient was instructed to maintain antiretroviral therapy and to start treatment for hepatitis C.Lichen myxedematous (LM) is a rare, chronic subtype of mucinosis that clinically manifests as papules, nodules, or plaques restricted to the skin. It is characterized by fibroblast proliferation, with varying degrees of fibrosis, and mucin deposition in the dermis, in the absence of thyroid disease.7The current classification of mucinoses was proposed by Rongioletti et al. and divides the papular mucinoses into scleromyxedema, a variant with systemic involvement and associated with paraproteinemia, and localized papular LM. Localized LM is divided into 5 subtypes: discrete papular mucinosis, persistent acral papular mucinosis, self-healing cutaneous mucinosis, juvenile papular mucinosis, and nodular papular mucinosis.Diagnostic criteria include papular rash, mucin deposition, and variable degree of fibroblast proliferation on histopathological examination, as well as the absence of gammopathy, thyroid disease, or systemic involvement.There are no well-defined treatments reported in the literature, and the recommended approach is clinical observation alone.None declared.Nathalia Hoffmann Guarda: Design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.Renan Rangel Bonamigo: Approval of the final version of the manuscript; design and planning of the study; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.Renata Heck: Approval of the final version of the manuscript; design and planning of the study; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.None declared."}
+{"text": "Activation of regeneration upon tissue damages requires the activation of many developmental genes responsible for cell proliferation, migration, differentiation, and tissue patterning. Ample evidence revealed that the regulation of chromatin organization functions as a crucial mechanism for establishing and maintaining cellular identity through precise control of gene transcription. The alteration of chromatin organization can lead to changes in chromatin accessibility and/or enhancer-promoter interactions. Like embryogenesis, each stage of tissue regeneration is accompanied by dynamic changes of chromatin organization in regeneration-responsive cells. In the past decade, many studies have been conducted to investigate the contribution of chromatin organization during regeneration in various tissues, organs, and organisms. A collection of chromatin regulators were demonstrated to play critical roles in regeneration. In this review, we will summarize the progress in the understanding of chromatin organization during regeneration in different research organisms and discuss potential common mechanisms responsible for the activation of regeneration response program. Particularly, the combination of single-cell chromatin profiling techniques ("}
+{"text": "The advent of machine learning and its subsequent integration into small interfering RNA (siRNA) research heralds a new epoch in the field of RNA interference (RNAi). This review emphasizes the urgency and relevance of assimilating the plethora of contributions and advancements in this domain, particularly focusing on the period of 2019\u20132023. Given the rapid progression of deep learning technologies, our synthesis of recent research is paramount to staying apprised of the state-of-the-art methods being utilized. It not only offers a comprehensive insight into the confluence of machine learning and siRNA but also serves as a beacon, guiding future explorations in this intersectional research field. Our rigorous examination of studies promises a discerning perspective on the contemporary landscape of machine learning applications in siRNA design and function. This review is an effort to foster further discourse and propel academic inquiry in this multifaceted domain. Enveloped within the expansive discipline of RNA interference (RNAi) , the intMachine learning employs algorithms that improve automatically through experience . It is eIt is this synthesis of machine learning and siRNA, an emergent and vital topic, that captures our academic interest. As the landscape of machine learning continues to diversify and mature, and siRNA\u2019s influence in genetic research and therapeutic innovation becomes more profound, our review serves as a catalyst for fostering academic dialogue and nurturing exploratory research. Herein, we have carefully investigated studies published between 2019 and 2023 through Web of Science (WoS) using keywords of machine learning and siRNAs. The utilization of the WoS platform stems from its comprehensive incorporation of solely peer-reviewed journal articles of high quality. The specific timeframe of 2019\u20132023 was chosen not solely based on the quantity of research produced, but also due to the significant advancements in machine learning techniques, particularly deep learning methodologies, during this period.This academic landscape is mirrored by a discernible gap in research studies focusing on machine learning applications for siRNAs, as shown in In the course of our comprehensive review of recent developments in the application of machine learning for siRNAs, it is observed that an intriguing distribution of machine learning models were implemented in the examined studies. The predominant model of choice was the Neural Network (NN), utilized in a total of 10 studies, illustrating a preference for its ability to model complex non-linear relationships and its inherent aptitude for handling high-dimensional data typical in siRNA research. The Support Vector Machine (SVM) model was adopted in five studies, reflecting its well-regarded robustness and efficacy in dealing with both linear and non-linear classification problems. Meanwhile, the Random Forest (RF) model was employed in three studies, underscoring its suitability for managing multi-dimensional datasets with its ensemble-based approach and inherent feature selection mechanism. Lastly, the Partial Least Squares (PLS) model was applied in two studies, illustrating its utilization in situations where predictors are highly correlated, a common occurrence in biological data. The majority of studies employed correlation and least squares as performance metrics in their analyses. Notably, some studies deployed multiple models, acknowledging the unique strengths of each model and adopting a more holistic, hybrid approach to tackle the multifaceted complexities inherent in siRNA design and analysis.Machine learning has emerged as a crucial tool in the field of siRNA research, facilitating nuanced investigations into the complex dynamics of siRNA. Two particularly salient areas of exploration are the prediction of siRNA efficacy and the elucidation of off-target effects. A comparative analysis of the studies by in silico prediction of siRNA ionizable-lipid nanoparticles\u2019 in vivo efficacy. The authors adopted an array of machine learning techniques, including Artificial Neural Networks (ANNs) and SVM, for Quantitative Structure-Activity Relationship (QSAR) modeling, signifying a broader perspective of machine learning implementation. Notably, their model successfully predicted the siRNA dose, with ANNs delivering the most robust performance.On the other hand, Exploring off-target effects and RNA production regulation, in vivo efficacy of siRNA nanoparticles. Further, machine learning proved to be instrumental in understanding off-target effects and RNA production regulation, demonstrating the versatility and potential of these techniques in decoding the complexities of siRNA.Both the methodological approaches, i.e., GNN and ANNs/SVM, show significant potential in siRNA research, albeit in different contexts. While GNN exhibited a superior ability in siRNA-mRNA interaction analysis, the versatility of ANNs/SVM was beneficial in predicting The integration of high-throughput screening in siRNA studies has ushered in a new era of comprehensive insights into cellular behavior and mechanisms under the influence of genetic modification. These following articles underscore this trend, showcasing how machine learning techniques are employed to delve deeper into proteome regulation, cellular delivery, and phenotype expression.On the other hand, Two recent studies provided insights into the usage of machine learning for precision delivery and phenotype assessment in siRNA studies, respectively. These studies underscore the significant potential of machine learning, from neural networks to principal component analysis, in advancing siRNA research. Whether it is the identification of new cellular pathways, the precise delivery of functional molecules, or the high-throughput screening of phenotypes, machine learning methodologies emerge as vital tools, showcasing the increasing intersection between computational and biological sciences.Biomedical research has witnessed the transformative potential of machine learning, catalyzing breakthroughs in disease diagnosis and prognosis. Two notable applications of these technologies involve the identification of prognostically significant genes in cancer and the discovery of diagnostic gene biomarkers. In these contexts, the incorporation of deep learning methods has yielded significant insights.The study by in vitro. This study is a compelling example of how machine learning can drive novel insights in diagnostic biomarker discovery and influence therapeutic strategies.On the other hand, Both studies demonstrate the profound potential of machine learning in the exploration of disease genetics, either in a prognostic or diagnostic capacity. However, the approaches vary in their specificity. The approach by 2, encapsulating both curcumin and Bcl2 siRNA. The promising results obtained underscore the potential of deep learning models in predicting siRNA delivery and release patterns, thus potentially revolutionizing the design of more effective siRNA delivery systems.The convergence of deep learning and machine learning techniques is propelling siRNA research, particularly in designing efficient delivery systems and accelerating the drug discovery process. As exemplified in the study by On the other hand, The rise of machine learning techniques has brought about a significant paradigm shift in siRNA research. Recent investigations have successfully harnessed both traditional machine learning and deep learning approaches to address challenges and answer pivotal questions in the field. This subsection provides the recent trend of emerging machine learning methodologies in siRNA studies, focusing on their unique applications, effectiveness, and particular roles in advancing siRNA research.In relation to nanopore technology, Penguin  and SequMeanwhile, In conclusion, the application of machine learning, from traditional algorithms to deep learning methods, is proving vital in various aspects of siRNA research, including structural profiling, prediction of vsiRNAs, cellular uptake prediction, and identification of mRNA cleavage sites. Although the methods and applications vary, the overall advancement in the field signifies the transformative potential of machine learning in this area. The comparison further highlights the benefits of non-linear and deep learning models over traditional linear models in terms of predictive accuracy and versatility, leading to valuable discoveries in the field of siRNA research.The confluence of machine learning and siRNA research has already brought to light numerous applications and technological advancements. From predicting siRNA efficacy and off-target effects, to uncovering cellular processes involving siRNA and elucidating the role of siRNA in diseases, the combination of these fields has opened up new avenues for scientific exploration and innovation. However, similar to all emerging fields, it comes with its own set of unique challenges and limitations.The application of machine learning techniques in siRNA research is hampered by the lack of expansive, high-fidelity datasets. This is a common problem in many machine learning applications, but it is particularly pronounced in the field of biological research, where experimental data can be costly and time-consuming to generate. However, as techniques such as high-throughput screening continue to advance, the availability of high-quality datasets for siRNA research is expected to increase. Moreover, strategies such as transfer learning and data augmentation could be leveraged to overcome the scarcity of data and enhance the learning capacity of machine learning models. As an alternative approach, the high-content screening techniques proposed by Another significant challenge is the inherent complexity of biological systems. The multitude of interacting factors and the non-linear nature of biological processes pose significant difficulties for the construction and optimization of machine learning models. However, novel machine learning methods, such as GNN and deep learning , have deFinally, the lack of interpretable machine learning models in this field is a crucial area that needs to be addressed . DespiteWhile challenges and obstacles lie ahead, the potential rewards of integrating machine learning and siRNA research are vast. It is our hope that this review will provide a useful roadmap for future researchers navigating this exciting and rapidly evolving field.In conclusion, the fusion of machine learning and siRNA marks a promising Frontier in the realm of RNA interference. Although faced with challenges, such as the need for large, high-quality datasets and the intricate nature of biological systems, the continued development of advanced machine learning models and feature engineering techniques offers an optimistic outlook on the field\u2019s future.The rapidly evolving landscape of machine learning necessitates frequent and thorough investigation of recent studies, particularly when coupled with the emergent field of siRNA. This review has thus aimed to provide a comprehensive, timely exploration of these two intertwined fields, bridging the gap between computational advancements and biological complexities. It is our fervent hope that this work will serve as a foundation for future explorations and will inspire novel, cross-disciplinary endeavors."}
+{"text": "Value in Healthcare, defined as the relationship between outcomes and costs , includiThe objective of this Research Topic was to contribute to the existing body of knowledge with a clear picture of the current scenario of the Value-Based approach in oncologic clinical practice to deliver sound experience on its impact, potential benefits, challenges to address, and future research needs.A total of 21 manuscripts were submitted, eleven of which were accepted.Most of the contributions aimed at evaluating the economic efficacy or the financial impact of single/combined treatments of cancer diseases with a particular public health burden.Bigi et al.); they analyzed a new tool to combine reported quality experiences and patient-reported outcomes .In other cases, authors shared the results of their research on the impacts of the application of effective models of value-based care ; a Value-Based approach to untangle the full benefit of HPV-related cancers elimination strategies and identify priority and best practices  have been reported, respectively.Also, organizational and financing implications from reshaping the delivery of healthcare services according to a Value-Based care approach have been published. For example, studies on the experience of involving patients and professionals in a co-constructed therapeutic pathway , thus various conceptual frameworks have been proposed , and we tried to orient publishing according to validity, rigor, and relevance .We also tried to challenge the public health research community to address future research needs, such as refinement of performance indicators to include patients' perspective (PROMS/PREMS); implementation of shared decision-making as routine in clinical practice; reshaping of logistics and operations to respect the values of \u201cgreen\u201d care delivery; digital support for the implementation of Value-Based approaches; reshaping of reimbursement systems to bundled payments based on clinical outcomes.Indeed, we received a few feedbacks on some of these items.Value-based healthcare in oncology to improve the quality of care on an individual level and consider patients' concerns and needs; reduce unwarranted duplications and wastes in care provision via more regular or systematic assessment of the effectiveness of care and monitoring of disease progression; increase patient information, communication, and shared medical decision-making, thus paving the way for precision and personalized medicine.Thus, from a public health perspective and by considering the great expansion of the research community, particularly from emerging countries and low-income countries, it will be crucial for healthcare organizations to use AB: Writing\u2014original draft, Writing\u2014review and editing."}
+{"text": "The biomedical application of optical spectroscopy and imaging is currently an active, developing area of research, supported by recent technical progress in the development of light sources and detectors. Furthermore, the development of portable and low-cost optical imaging systems shows strong potential for the implementation of these technologies in everyday life and the daily practice of clinicians. In recent years, many studies have demonstrated that the use of modern optical imaging methods in conjunction with a priori data, as well as advanced data mining approaches, can significantly improve the quality of the medical diagnostic services provided ,2.The probing radiation of optical diagnostic methods is scattered due to random spatial variations in tissue morphology. Detection of diffuse reflected or transmitted light can provide information on the scattering and absorbing components of biological tissue. Changes in tissue morphology, including hyperplasia, collagen degradation in the extracellular matrix, and an increase in the nuclear\u2013cytoplasmic ratio associated with the progression of various diseases, can affect the scattering signals. In addition, changes in hemoglobin-absorbing properties can assist with angiogenesis processes, the presence of tissue hypoxia and ischemia, etc. At the same time, incident radiation can excite biological tissue molecules, causing fluorescent radiation. Most endogenous fluorophores are associated with the morphology of the tissue or with various metabolic processes responsible for the functional state of the tissue. Mitochondrial function is an important parameter of tissue viability. According to indicators of respiratory chain activity, it is possible to predict cell death, diagnose tissue ischemia, or, on the contrary, talk about its malignant activity. Additionally, the dynamic change of scattering centers of biological tissues probed by laser radiation leads to the formation of speckle fields, the study of which makes it possible to obtain perfusion (blood flow) maps in various anatomical areas. Thus, biophotonic methods can provide unique opportunities for structural and functional analysis of biological tissues, as well as for early and non-invasive diagnosis and monitoring of the effectiveness of therapy in various diseases .Biophotonics has broad prospects for development, since relatively cheap optical technologies allow images to be obtained and human tissues and organs to be influenced in real time with micron resolution and without the use of ionizing radiation. These technologies have found numerous applications in scientific research and clinical practice: dynamic light scattering methods  . The speJ. Sachs et al. evaluated the possible impact of dual-energy computed tomography (DECT) on cataract formation . The aut2) as a reference standard. The high correlation coefficients were shown between the measurements of the perfusion parameters using IOFF and TcPO2. This study demonstrates that the IOFF method allows the identification of patients with a critical decrease in TcPO2 < 20 mmHg with sensitivity and specificity of 85.7% and 90.0%, respectively.P. Glazkova et al. studied the possibilities of incoherent optical fluctuation flowmetry (IOFF) to analyze the perfusion of foot tissues in patients with diabetes mellitus . PerfusiThe work of E. Zharkikh et al. focuses on studying microcirculation features in patients who underwent COVID-19 using novel wearable laser Doppler flowmetry (LDF) devices . In patiIn a study by E. Cinotti et al., the use of line-field confocal optical coherence tomography (LC-OCT) for the diagnosis of skin cancer was demonstrated . LC-OCT in vivo experiments in human skin. The new method showed high stability to instrumental disturbances introduced into the source and detection channels, while the traditional single-slope approach demonstrated stability only to perturbations in the source channels.Two studies were devoted to the use of diffuse reflectance spectroscopy (DRS). V. Perekatova et al. reported on the comparative study of self-calibrating and single-slope DRS in terms of stability against various measurement disturbances . The autIn another study  A. SelifFinally, I. Zlotnikov et al. demonstrated the use of confocal laser scanning microscopy (CLSM) and Fourier-transform infrared spectroscopy (FTIR) to study the interactions of antibacterial drugs with bacterial cells . More spThus, this Special Issue contains new developments and advanced ideas pertaining to optical spectroscopy and imaging for active translation to biological and clinical practice. The published manuscripts provide new insight into state-of-the-art modern methods of biomedical optics and expand readers\u2019 knowledge of the possible areas of their application.The peculiarity of biophotonics is that it combines physics, biology and medicine. The interdisciplinarity of biophotonics allows scientists from different fields to unite and collaborate to solve complex problems. Biophotonics and related fields are continuously developing and will undoubtedly become the main avenue for the development of biomedical engineering in the coming decades."}
+{"text": "Broadly speaking, forensic psychiatry is the scientific study of the relationship between mental disorders and criminal behavior in a forensic context, and the application of psychiatric knowledge to crime, criminal and civil law, and the impact of law on human behavior. Psycho-criminology (or simply as psycho-criminology) is generally concerned with the use of psychological knowledge and skills  in explaining, describing, and potentially preventing deviant, delinquent, and offending behavior \u20136. More The emphasis of this Research Topic (RT) focuses on the application of psycho-criminological approaches and constructs to criminal behavior and mental health in forensic settings. There are six articles included in this RT, which explored various features of crime and delinquent/criminal behavior through the application of psychological and criminological concepts and theories. Contributions to this RT are geographically diverse, with topics covering Africa (Nigeria), Asia (Hong Kong and mainland China), Europe (the UK), and the Middle East (Iran). More importantly, the collection of these articles addresses varied features of deviant and criminal behavior , delinquency and crime , and in the forensic settings .Shek et al.. This article examines the relationship between family functioning and adolescent delinquency, and the mediating role of positive youth development (PYD) attributes on this relationship. Analyzing a two-wave short-term longitudinal data (6 months apart) collected from 4,922 mainland Chinese adolescents, findings are that family functioning at the initial period (Wave 1) were negatively associated with the level of and change in delinquent behavior at the subsequent period (Wave 2), and PYD attributes (Wave 2) are found to mediate this relationship. Also, the general strain theory was tested by Wang et al. by surveying 687 mainland Chinese inmates recruited from 60 prisons, who were former public officials convicted of corrupt behaviors. They aim to explore the potential mediating effect of strain on the public officials' corrupt behaviors. Their findings indicate that clerks (a higher rank) and non-clerks (a lower rank) tended to have different experiences of status-related strain and personal financial strain, but it is the work-related strain that significantly distinguishes them. Compared to non-clerks, the work-related strain has more significant impact on clerks.The first article in this RT is an empirical study of family functioning and adolescent delinquency in a large sample of mainland Chinese adolescents by Chan recruited a nonclinical sample of 863 young people aged 17\u201320 years to examine the psychosocial risk factors of low self-control, risky sexual behavior (RSB), and paraphilic interests. Men are found to have significantly higher levels of threat of sexual assault and of general as well as of 12 subtypes of paraphilic interests than women, while women have a higher level of paraphilic interest on transvestic fetishism than men. Low self-control and more RSB and paraphilic interests are generally significant predictors of sexual assault threat issuance and perpetration of both penetrative and nonpenetrative sexual assault. Next, Ghazanfari et al. recruited a randomly selected sample of 259 male prisoners in Iran to examine their psychological wellbeing, family cohesion, and purposeful life. They found that the inmates' psychological wellbeing is significantly positively associated with their family cohesion, but both psychological wellbeing and family cohesion are not significantly correlated with their sense of a purposeful life.Examining the dynamics of sexual offending among youth in Hong Kong, Lilley et al. sampled a group of 108 jury-eligible university students to partake in one of nine identical 12-person mock trial simulations  depicting a videotaped stage-setting of an intimate partner rape trial. Investigating the role of jurors' traits of psychopathology, crime-specific attitudes, sexual victimization experience, and demographic characteristics, the authors found that rape myth beliefs and juror ethnicity are positively associated with verdict decisions both pre- and post-deliberation. Besides, a diminished affective responsiveness (empathy) and experience of sexual victimization significantly predicted guilty verdict selections by the participants in the post-trial deliberation. Similarly, from a legal perspective, Ogunwale et al. critically examined the insanity plea in the Nigerian legal system. Adopting reform-oriented and fundamental legal research and psycho-legal formulated illustrative cases, the authors contend that there is a misalignment between the subjective experience of the mentally ill defendant and the objective judicial unawareness of the defendant's psychiatric conditions in some cases in Nigeria. As a result, a potential miscarriage of justice can occur. Hence, the authors argue for a reform based on current multidisciplinary knowledge whereby mental health professionals should be involved in all insanity plea cases.In the UK, Based on studies conducted in different countries, this RT collectively demonstrate the significance of applying psycho-criminological knowledge to advance our understanding of the fundamental mechanisms  related to offending behavior in the intersections of mental health and the law, especially in the forensic setting. In this emerging subdiscipline of psycho-criminology, it is utterly imperative to continue moving forward with more international research to advance our knowledge and contribute to the repertoire of literature, which can have implications for research, practice, and policy development or refinement. Importantly, given the geographically diversified studies in this RT, it is noteworthy to acknowledge the importance of cultural influences wherein culturally adapted psychiatric and psychological interventions should not be neglected .The author confirms being the sole contributor of this work and has approved it for publication."}
+{"text": "Mouse models have improved our understanding of mammary gland growth and development under the control of endocrine signals.Micro RNAs (miRNAs) can influence the effects of hormone axes and protein families in the mammary gland.Due to the presence of miRNAs in exosomal vesicles, miRNAs can be exported from the mammary gland to peripheral and central tissues of the animal or to suckling offspring.It is necessary to identify the biological effects of milk miRNAs in the offspring but also in human consumers of dairy products, the latter can be considered a critical issue of food safety.The insulin-like growth factor (IGF) system represents an important effector of mammary gland growth and development. Notably, in the mouse mammary gland, the IGF system integrates signals from growth hormone (GH) and prolactin. Within the cell, the IGF system impacts the pathway activating protein kinase B (AKT) and mammalian/mechanistic target of rapamycin (mTOR), which also mediates metabolic signals . AccordiIn the absence of the GH/IGF system, virtually no postnatal growth is observed in vertebrates. Accordingly, this system represents the most important endocrine system for controlling somatic growth. Under the control of GH and IGF, both cell size and cell number can be increased, thus defining the central parameters of tissue size. GH is produced in the pituitary gland and has direct effects on its target cells or tissues. In addition, GH can induce gene expression of IGF1 and thus impact growth by IGF-dependent mechanisms. Furthermore, tissue specificity is due to differential expression of IGFBPs, IGFBP-proteases, inhibitors of IGFBP-proteases, and calcium, as we rule out further down. In mice, IGFs, IGFBPs, and IGF1R are expressed in the virgin and the developing mammary gland, and cell-specific expression patterns have been described for IGFBPs . The perThe origins of life can be attributed to the inherent feature of RNA molecules to form comparably stable RNA/RNA structures . AccordiRNAhybrid (https://bibiserv.cebitec.uni-bielefeld.de/rnahybrid/), interactions of miRNAs also with exonic mRNA can be postulated, which is provided as an example for different IGFBP4 RNA transcripts (https://www.ensembl.org/). Except for IGFBP1 and IGFBPL1, the members of the expanded IGF system are putative targets of several miRNAs, and several miRNAs regulate multiple members of the expanded IGF system. The greatest degree of interaction between miRNAs, published by Wang et al. (Intricate interactions of both systems during mammary gland development in mice can be deduced from the study of Wang et al. , demonstnscripts  extracteg et al. , and theg et al. . Notablyg et al. .In contrast to classical hormones, the specificity of miRNAs is expressed on a much lower level since miRNAs can have thousands of putative gene targets . The lacIn the signature of 11 miRNAs regulated during mammary development in mice , mmu-miRA direct link from miRNA to mTOR signaling has also been established for two additional members of the miRNA signature provided in Finally, the effects of regulated miRNAs on the IGF system might not only affect the development and function of the mammary gland in female mice but also have implications for distant tissues . Indeed,A crucially missing piece of the puzzle of IGF-dependent control of mammary growth and development was provided by the integration of the metzincin family members PAPPA1 and 2 into the current concept of an expanded IGF system. It is thus possible to describe the interactions of IGFs and IGFBPs and longitudinal control of IGF-related activity by PAPPAs and STCs during growth and involution of the mammary gland in mice. Since metzincins can bind zinc and calcium , we need"}
+{"text": "The Fort McMurray wildfire (2016) was one of the most expensive and devastating natural disasters that ever happened in the history of Canada. According to the Insurance Bureau of Canada (2016), the cost of this disaster was estimated at USD 3.6 billion in insured losses. Despite the fundamental role of resilience in the daily functioning of individuals in the form of a protective shield that ameliorates the devastating impact of disasters on their mental well-being, to date, the long-term impact of wildfires on resilience and its associated predictors of low resilience has not been well studied and evaluated.The study aimed to enhance the understanding of the psychological impact of wildfires through the evaluation of the prevalence and predictors of resilience among the affected residents of Fort McMurray five years after the devastating wildfires.This study applied a cross-sectional survey design which was used to gather quantitative data through an online-based self-administered questionnaire. The surveys included standardized rating scales for resilience (BRS), depression (PHQ-9), anxiety disorder (GAD-7), and post-traumatic stress disorder (PTSD) (PCL-C) was used to measure the prevalence of resilience and its demographic, clinical, as well as wildfire-related predictors. The data collection spanned between April and June of 2021. Data were analyzed using the Statistical Package for Social Sciences (SPSS) version 25 and univariate analysis with done using a chi-squared test and binary logistic regression analysis.A total of 249 residents accessed the online survey and 186 completed the survey. Therefore, there was a response rate of 74.7%. Most of the respondents were females , above 40 years of age , employed , and in a relationship . The study identified two variables, thus having PTSD symptoms , and the age of respondents significantly predicted low resilience in our sample. The prevalence of low resilience in our sample was found to be about 37.4%.The study finding demonstrated that age and the presence of PTSD were the independent significant risk factors associated with low resilience in the affected population of Fort McMurray five years after the devastating wildfire disaster. This result further provides new information about the association between resilience, demographic, and clinical characteristics while adding to the rising body of evidence on the benefits of resilience in individuals during and after disasters. However, further research is needed to enhance understanding of the pathways toNone Declared"}
+{"text": "Cardiac involvement results in an infiltrative cardiomyopathy that leads to progressive heart failure and carries a high rate of morbidity and mortality , 2. The The prevalence of ATTR-CA in the Middle East, and particularly in the largest country that is Saudi Arabia is significantly underrepresented in the literature. What is clear is that this condition remains underdiagnosed, and the vast majority of patients go undiagnosed. Recent studies conducted in the Middle East and the Gulf region demonstrate significant shortcomings regarding the diagnostic modalities and therapeutic approaches for cardiac amyloidosis, mainly due to a lack of awareness among health care professionals , 11. SucThe objectives of this manuscript are to highlight the magnitude of the under/misdiagnosis of ATTR-CA in Saudi Arabia and neighboring Gulf countries and to explore the barriers that impede the proper diagnosis and management of ATTR-CA in the region.2.2.1.In order to highlight the magnitude of the underdiagnosis of ATTR-CA in the Middle East and Gulf region, we extrapolated the projected prevalence of ATTR-CA in Saudi Arabia. Published epidemiological studies in Saudi Arabia indicate a case burden for chronic heart failure of approximately 455,222 cases, and thus a prevalence of 1%\u20132% in the general population , 13. WitThe estimation of ATTR-CA case burden in Saudi Arabia has several shortcomings. First, our approximation does not take into account the gender preponderance of ATTR-CA among males or the influence of age as the disease increases in incidence with age, since the HEART registry did not factor in either parameter. Second, the projected estimation does not include the prevalence of ATTR-CA amongst patients with severe aortic stenosis undergoing transcatheter aortic valve replacement (TAVR). Several studies have previously highlighted an association between ATTR-CA and severe aortic stenosis in elderly patients being relatively common with an estimated prevalence of 8%\u201315% , 17. HowTo our knowledge, there are no published studies that have evaluated the incidence or prevalence of cardiac amyloidosis in Saudi Arabia. Furthermore, our search results utilizing Pubmed and Medline databases have not yielded any current population or cohort-based studies relating to ATTR-CA within the region. We hypothesize that the discrepancy in the expected prevalence of ATTR-CA when compared to the literature emerging from the region is likely due to shortcomings in the diagnosis of cardiac amyloidosis rather than lower rates of prevalence.2.2.This section addresses the possible shortcomings and barriers regarding the diagnosis of ATTR-CA and highlights the practical applications to overcome these issues within the region. ATTR-CA is a disease with a high misdiagnosis rate up to 34%\u201357% of patients . MoreoveTwo recent physician surveys have investigated the barriers to the diagnosis of cardiac amyloidosis in the Middle East , 11. FinMultidisciplinary education campaigns and meetings are essential to familiarize physicians with the clinical, biological, and imaging clues that should prompt further investigations for the disease. Additionally, subgroups of patients such as those with left ventricular hypertrophy, HFpEF, and those with low flow low gradient aortic stenosis requiring TAVR should be identified and further screened for ATTR-CA. A recent scientific statement from the American Heart Association (AHA) has identified clinical and imaging clues that should prompt further investigation(s) for CA  can be uAnother significant barrier to the diagnosis of ATTR-CA lies in the utilization of appropriate investigative tools. According to guidelines published by the AHA and European Society of Cardiology (ESC), patients with suspected ATTR-CA and without monoclonal gammopathy should undergo screening by cardiac radionuclide scintigraphy imaging , 9. HoweTTR gene that requires proper investigation (TTR gene mutations causing ATTR-CA (TTR variants in the region (TTR mutations, three TTR variants known to be associated with ATTR-CA and three novel variants were identified. However, the data identified in the study requires further clinical correlation.Since the hereditary form of ATTR-CA arises from a mutation in the tigation , an addi ATTR-CA , 20. Mor ATTR-CA . The fine region . Using dTTR variants associated with hereditary ATTR-CA and to detect the individuals carrying these genetic variants who are at risk of developing the disease. Moreover, individuals with confirmed hereditary ATTR-CA should receive counseling and their family members should be offered genetic testing in line with AHA and ESC guidelines. Hence, a multidisciplinary effort is required to provide access to genetic testing sites that are equipped with appropriate resources and are adequately staffed. Additionally, this setup would allow for the conduction of further genomic studies to identify potentially pathogenic TTR variants and simultaneous clinical investigations to validate the findings from these genomic studies.Based on the above data, collaborative efforts within the region among specialists in cardiology and genetic medicine are required to identify A pertinent approach towards overcoming the underdiagnosis of ATTR-CA in the region is underpinned by the utilization of regional patient registries and the subsequent establishment of nationwide screening programs. The use of national/regional patient registries may facilitate improved awareness of disease prevalence and incidence, enhance collaborative efforts and communication amongst clinical specialists, improve knowledge and awareness of the disease, facilitate the generation of referral and screening pathways, and enhance the cost-effectiveness of managing patients with ATTR-CA . PatientThe underdiagnosis of ATTR-CA in the region has resulted in significant shortcomings in the management of the disease. Physician surveys emerging from the region highlighted deficiencies in the awareness of the management modalities for ATTR-CA . The recThe application of AHA and ESC guidelines regarding the diagnosis and management of cardiac amyloidosis in the Middle East and Gulf region is likely to lead to significant advances in understanding the epidemiology and clinical features of the disease in the region, while concomitantly improving patient outcomes. However, the application of the aforementioned guidelines may prove challenging due to potential barriers. 3.Limited data are available regarding the prevalence, incidence, and clinical features of ATTR-CA in the Middle East and Gulf region. Based on international epidemiological studies, the majority of cases of cardiac amyloidosis in this region remain undiagnosed. Physician surveys conducted in our region identified key areas for improvement, particularly relating to awareness regarding the diagnosis and treatment of ATTR-CA. Collaborative efforts are required to promote disease awareness and improve physician knowledge regarding the epidemiology, clinical features, and management of ATTR-CA. Moreover, appropriately staffed national and regional specialized referral centers equipped with the relevant diagnostic modalities ought to be established within the region. Multidisciplinary teams consisting of clinical experts from various backgrounds should collaborate to develop clinical pathways to identify and investigate patient groups with high suspicion for cardiac amyloidosis. Implementing these measures would improve the diagnosis and management of cardiac amyloidosis in the region, thereby allowing for disease detection at an earlier stage and the utilization of targeted disease-modifying therapies."}
+{"text": "Planetary health education focuses on the climate and ecological crises and their adverse health effects. Given the acceleration of these crises, nationwide integration of planetary health education into undergraduate and graduate education, postgraduate training and continuing education for all health professionals has repeatedly been called for. Since 2019, planetary health education has been promoted by several national initiatives in Germany that are summarized in this commentary:1. National Working Group Planetary Health Education,2. Manual for planetary health education,3. Catalog of National Planetary Health Learning Objectives in the National Competency-Based Catalog of Learning Objectives for Medical Education,4. Working Group Climate, Environment and Health Impact Assessment at the Institute for Medical and Pharmaceutical Examinations,5. Planetary Health Report Card, and6. PlanetMedEd study: planetary health education in medical schools in Germany.We hope these initiatives promote collaboration across institutions involved in educating and training health professionals, inter-professional cooperation as well as rapid implementation of planetary health education. Planetary health education focuses on the climate and ecological crises and their adverse health effects . Given tThe inter-professional working group, jointly hosted by the German Alliance on Climate Change and Health and Health for Future, was founded in February 2021 to provide a platform for knowledge exchange targeting all health professionals involved in planetary health education. The working group focuses on different aspects of planetary health education including presentations of innovative modular teaching materials and syllabi of elective courses as well as journal clubs covering seminal contributions to the field of planetary health education. The WeChange platform is used to network and to collect material pertinent to planetary health education.https://www.klimawandel-gesundheit.de/ag-lehre-mailingliste/]Sign up to the mailing list: [https://wechange.de/project/ag-planetary-health-lehre/]Sign up to the WeChange platform: . The latest version of the manual is available online . The catalog comprises learning objectives on clinical competencies for climate adaptation and climate-sensitive anticipatory guidance as well as skills supporting physicians in initiating and implementing change processes outside patient care that contribute to climate mitigation and sustainability. To promote the integration of planetary health education in all areas of medical education, the catalog contains cross references to the main chapters of the Competency-Based Catalog of Learning Objectives for Medical Education. The planetary health learning objectives can guide, inter alia, the development of longitudinal planetary health curricula or focus areas within medical curricula stipulated in the current version of the updated medical licensing regulations for Germany.The Catalog of National Planetary Health Learning Objectives  was deveThe Institute for Medical and Pharmaceutical Examinations, developing and administering centralized state examinations for medicine, dentistry, pharmacology, and psychotherapy in Germany, founded the working group in January 2021. The inter-professional working group comprises external experts and aims at adding aspects of planetary health education to the syllabi of the state examinations.In this international initiative, medical students evaluate their medical schools based on standardized planetary health indicators covering the following areas: planetary health curriculum, interdisciplinary research, institutional support for student-led initiatives, community outreach and advocacy, and campus sustainability. https://phreportcard.org/]. While previously restricted to the USA, Canada, UK and Ireland, several medical schools in Germany have been evaluated based on the report card since 2021. The extension of the report card to curricula of other health professionals is currently prepared by the international PHRC team. The results of the assessment are published online on Earth Day every year:  , , .The authors declare that they have no competing interests."}
+{"text": "Assuring the quality of medical products manufactured, imported or distributed in francophone sub-Saharan Africa remains a challenge, despite positive signals like the growing engagement in the benchmarking of regulatory authorities and -particularly- in the establishment of the African Medicines Agency. In this short report, we describe the existing activities to prevent, detect and respond to substandard and falsified products (SF) in this region, either through African multilateral organizations and initiatives led by the World Health Organization, or through the contribution of other stakeholders, such as local universities and procurement agencies. We underline that these emerging local stakeholders may play a pivotal role to guide and inform the national regulatory authorities about the prevalence and patterns of SF medical products, complementing the market surveillance and control, and building awareness of the importance of pharmaceutical quality assurance for public health. Substandard and falsified products (SF) , 2 causeAfrican Union (AU) and the World Health Organization (WHO) started in 2009 the African Medicine Regulatory Harmonization (AMRH) Initiative; and in 2021, following the Treaty ratification by 15 member states, they started the establishment of the African Medicines Agency (AMA). Second, the Economic Community of West African States (ECOWAS) endorsed the West African Health Organization (WAHO) Strategic Plan 2016\u20132020 [West African Economic and Monetary Union [Medicrime Convention[Pharmaceutical quality assurance (QA) is high on the agenda of continental organizations, with important aspirational objectives. First, the 016\u20132020 , a Techn016\u20132020  promptedry Union . Finallyonvention.Member State Mechanism was established to tackle SF medical products from a public health approach [Global Benchmarking Tool (GBT) [Global Surveillance and Monitoring System [The approach . It is gol (GBT) . Currentg System , throughg System . HoweverUniversity of Senegal Cheikh Anta Diop and the University of Douala in Cameroon are among the first implementers of a curriculum guide on SF medical products, developed by WHO, International Pharmaceutical Federation, and others, targeting undergraduate pharmacy students [(West) African academics can contribute to the fight against SF medical products by educating future specialists and policymakers. The students .University of Kinshasa (UniKin) in the Democratic Republic of Congo built this capability by investing in academic partnerships, particularly with the University of Li\u00e8ge, Belgium. The UniKin QC laboratory, LACOMEDA, is accredited by the Ministry of Public Health for QA and QC of Health Products. It conducts high-quality research, based on a four-phases analytical methodology: a rapid field screening; a second screening in the vicinity; full chemical analysis at central level; and standardized findings\u2019 compilation. For the screening, the program uses portable vibrational spectroscopy tools, chosen based on performance, costs and field feasibility, and suitable for post-marketing surveillance and border screening. This model, where academia builds local capacity through international networks and produces rigorous research to guide policy-makers [Universities can also play a pivotal role to understand the prevalence and patterns of SF medical products. For instance, the y-makers \u201319, coulProcurement agencies may engage in surveillance. The Ecumenical Pharmaceutical Network (EPN), an independent, non-profit, Christian organisation committed to provide quality-assured pharmaceutical services, started in 2010 the Minilab project , and thePreventing, detecting and responding to SF medical products remains a challenge in Francophone sub-Saharan Africa, despite positive signals like the growing engagement in the WHO GBT process and the construction of AMA. The NRAs already engaged in the AMA should prioritize participation in technical committees, e.g., the AMQF-TC for market surveillance and control. Academic institutions and procurement agencies can effectively support surveillance, and they should systematically share their findings with NRAs. All activities should be framed in universal health coverage, as access to essential medicines will eliminate the demand for illegal markets."}
+{"text": "Recent studies report a prevalence of comorbid anxiety disorder of 38% and 80% of sleep disorders in schizophrenia. Insomnia has been associated with worsening of psychopathological symptoms and increased hospitalization rates.The aim of our work was to review mechanisms of action and the use of benzodiazepines, GABAergic drugs and melatonin for the treatment of anxiety and insomnia in schizophrenia.We carried out a narrative review of studies focusing on the treatment of anxiety disorders and insomnia in schizophrenia through PubMed and Google Scholar (2002-September 2022). The use of benzodiazepines, GABAergic drugs and melatonin in schizophrenia are discussed, illustrating them with case reports.A total of 32 studies were included. (A)Benzodiazepines (BZD) work facilitating the inhibitory actions of gamma-aminobutyric acid (GABA) by binding GABA type A receptors. The beneficial effect of combined use of antipsychotics and BZD is controversial . (B)GABAergic drugs: gabapentin (GP) and pregabalin (PG) , have no direct GABAergic action and act inhibiting voltage-gated calcium channels. The efficacy of GP and PG in the treatment of anxiety symptoms in schizophrenia is understudied. Positive effects of GP in schizophrenia suffering from restless legs syndrome receiving clozapine. (C )Melatonin, an hormone produced in the pineal gland has been used to treat insomnia. Positive effects on metabolic syndrome and cardiovascular risk factors have been reported. Several works considered it an alternative in schizophrenia.Few evidence is available on the use of BZD, GP, and PG in schizophrenia. Melatonin is a promising compound to treat insomnia.None Declared"}
+{"text": "The process of initiating and completing clinical drug trials in hospital settings is highly complex, with numerous institutional, technical, and record-keeping barriers. In this study, we independently developed an integrated clinical trial management system (CTMS) designed to comprehensively optimize the process management of clinical trials. The CTMS includes system development methods, efficient integration with external business systems, terminology, and standardization protocols, as well as data security and privacy protection.The development process proceeded through four stages, including demand analysis and problem collection, system design, system development and testing, system trial operation, and training the whole hospital to operate the system. The integrated CTMS comprises three modules: project approval and review management, clinical trial operations management, and background management modules. These are divided into seven subsystems and 59 internal processes, realizing all the functions necessary to comprehensively perform the process management of clinical trials. Efficient data integration is realized through extract-transform-load, message queue, and remote procedure call services with external systems such as the hospital information system (HIS), laboratory information system (LIS), electronic medical record (EMR), and clinical data repository (CDR). Data security is ensured by adopting corresponding policies for data storage and data access. Privacy protection complies with laws and regulations and de-identifies sensitive patient information.The integrated CTMS was successfully developed in September 2015 and updated to version 4.2.5 in March 2021. During this period, 1388 study projects were accepted, 43,051 electronic data stored, and 12,144 subjects recruited in the First Affiliated Hospital, Zhejiang University School of Medicine.The developed integrated CTMS realizes the data management of the entire clinical trials process, providing basic conditions for the efficient, high-quality, and standardized operation of clinical trials. Clinical trials of drugs are an important stage in drug research and development and are means to improve the development of medical science and technology \u20135. StandIn recent years, owing to the increase in clinical trial projects in our hospital, professional and standardized information systems were urgently needed to assist in the management of clinical trials throughout the hospital. At present, the need for a centralized clinical trial project management platform reliant on the clinical data system of the hospital itself is intensifying. Based on the local area network (LAN) security architecture of our hospital, we have constructed a CTMS, which organically integrates the clinical trial organization management office, ethics committee, clinical trial center pharmacy, and clinical professional departments. The management system covers the entire process of clinical trials, including trial project establishment, ethical review, signing of agreements, trial implementation, trial conclusion, sponsor management, subject management, follow-up management, and centralized management of pharmacies supporting medication trials. The personnel involved include clinical departments, institutional management offices, central pharmacies, and ethics committees. With the help of the information system, a large number of personnel and complicated work processes are organically integrated to realize information sharing and collaborative work. With the help of this CTMS, the implementation of clinical trials can be standardized and the entire process can be traceable. As a site of clinical trials, hospital management involves multi-party collaboration, as well as study project management, subject management, investigational product management, quality control, financial management, and other complex business processes. Hospitals must develop dedicated systems to assist the entire process management of clinical trials to ensure their efficient and high-quality operation. The main objectives of this study are as follows. We aim (1) to develop an integrated CTMS as a dedicated database for clinical trials; (2) to achieve efficient data integration of CTMS with hospital business systems , laboratory information system (LIS), clinical data repository (CDR), picture archiving and communication systems (PACS), and electronic medical record (EMR), etc.); (3) to facilitate standardization and consistency of terminology in the development of database models and business processes; and (4) to ensure the safety and security of clinical data as well as protect patient privacy to comply with relevant regulations.The First Affiliated Hospital, Zhejiang University School of Medicine (FAHZU) has six campuses with approximately 5,000 beds. In 2020, the institution recorded over 4.2 million outpatient and emergency visits, and 236,100 discharges. As one of the pioneering and earliest-founded National Drug CTIs in China, the first batch of clinical pharmacology bases under the Ministry of Health was established in 1998. As a first-class integrated service platform for clinical research in China, it operates 24 specialized groups and depends on an internationally recognized and independent ethics examination system, and has undertaken more than 2000 items of foreign and domestic clinical trials since its establishment, including both Phase I\u2013IV drugs and medical devices.The development of an integrated CTMS began in March 2014, and after 18\u00a0months, the first version of the CTMS was launched in FAHZU in September 2015. The complete system development process was carried out in four stages, including two months of requirement analysis and problem collection, four months of system design, six months of system development and testing, and six months of system operation training and pilot runs. Based on the feedback from the use of the first version of CTMS and the continuous in-depth exploration of the business, the system\u2019s functionality and user experience continue to be iteratively updated. By March 2021, the updated version 4.2.5 was launched. Through the construction of an integrated CTMS, the entire process of clinical trial data management is realized, which provides the basic conditions for the efficient, high-quality, and standardized operation of clinical trials in the hospital.The collection and analysis of CTMS requirements defined the existing problem set to be solved. This stage is the most critical and determines the final goal direction of the system. The collection of requirements started in March 2014, and the participants included the CTI office director, CTI office secretary, ethics committee (EC) members, EC secretary, principal investigator (PI), sub-investigator, study nurse, clinical research associate (CRA), clinical research coordinator (CRC), investigational product custodians, financial officer, quality control expert, statisticians, data manager, pharmacovigilance associate, and information technology expert. After two months of formal and informal interviews, as well as an analysis of the collection requirements, the design goal of CTMS was determined. The overall goal of the CTMS is to realize the entire process of clinical trial management, including study project approval, ethical review, subject recruitment, subject management, investigational product management, financial management, and quality management. Table In the second stage, the CTMS design process included the definition of the system architecture and data interchange mechanisms, selection of storage media, database modeling and standardization, user interface (UI) and user experience (UX) design, and development of security and privacy policies based on analyzing and categorizing the requirements collected in the first phase, referring to Good Clinical Practice (GCP) and the guidance documents of the National Medical Products Administration (NMPA). The functions and data required by each participant in the clinical trial are determined. Figure\u00a0The third stage focused on the development and testing of the CTMS. This was divided into two steps according to the definition of the design stage. The first step realizes clinical trial approval and review management, and the developed subsystems include CTPMS, CTEMS, and PMMS, which focus on the process management of the study project application and review stage, and do not involve data integration with external systems. The second step realizes clinical trial operational management. The developed subsystems include CTSMS, CTIPMS, CTFMS, and CTQMS, which complete internal function development and data integration with external systems, and realize the entire process of data management. The CTMS was developed based on the distributed architecture of the Java programming language, and its database is Oracle Database 11\u00a0g Release 2 on a server running the Linux CentOS 7.6 operating system; data integration with external systems is managed through an interface services unified management platform. The system adopts browser/server architecture and supports current mainstream browsers, such as Google Chrome, Internet Explorer, and Firefox Browser for encrypted access via hypertext transfer protocol secure (HTTPS). System testing mainly includes verification of functional effectiveness, data security, system reliability, and the efficiency of data integration with external systems.This stage involved CTMS deployment and system operation training. In November 2014, CTPMS, CTEMS, and PMMS were officially launched, realizing clinical trial approval and review management in FAHZU. In March 2015, the development of CTSMS, CTMMS, CTFMS, and CTQMS was completed. Considering that the clinical trial operational management involves data integrity verification and data integration with external systems, a new pilot run phase was needed. By selecting a certain number of clinical trials in Phases I\u2013IV, the operating results were used to verify the compatibility of the system with different types of clinical trials. The CTMS pilot run system first selects Phase I clinical trials and runs a total of 20 projects. Through continuous updating of functions during operation, it can fully meet the needs of Phase I clinical trial operational management. Subsequently, it selects clinical trials in Phases II\u2013IV. A total of 10 projects have been run, and the functions have been stable and meet the requirements of various types of clinical trials. However, training hospital staff in the use of CTMS is critical. Through a variety of methods including face-to-face training and offline data learning, all staff related to clinical trials have been trained. The first version of CTMS was fully launched in FAHZU in September 2015.FAHZU is the first hospital in China to independently develop an integrated CTMS; the system has been successfully implemented in the hospital since September 2015. As of March 2021, the hospital now runs an updated version of CTMS known as V4.2.5. The data management of the entire process of clinical trials from project approval and review management to operational management has been fully realized. The FAHZU CTMS operates independently by design as a fully functional system at the application level (not as a component of the HIS), establishes a dedicated clinical trial database at the data level, and completes data integration with external systems through a unified interface system, to achieve process continuity and data integrity. Through the construction of an integrated CTMS, the flow of multi-party collaboration tasks is optimized, and non-research matters such as finance and data processing are simplified, to effectively improve the efficiency and quality of clinical trials. The results shown below are based on the latest stable version of FAHZU CTMS, V4.2.5.The first level involves clinical trial project approval and review management, and its functions cover the rationality review of clinical trial study projects and related affairs management by CTI and EC. Table The second level comprises clinical trial operational management, which is a complex and continuous management process. Table The third level is backstage management, which is indispensable for the stable operation of the CTMS. Table FAHZU CTMS realizes the entire process management of clinical trials through the organic combination of project approval and reviews management, clinical trial operational management, and backstage entire process management, which is further categorized into 59 internal processes by combining user and authority management Fig.\u00a0. ClinicaTo use the CTMS as a dedicated database for clinical trials, data integration with external systems is indispensable. Figure\u00a0Data security and privacy protection ensure that a mature process is developed and maintained throughout the design life cycle. Data security primarily involves data storage and data access security. Privacy protection focuses on ensuring data security while complying with laws and regulations to de-identify sensitive patient information.Data security mainly includes the two aspects of data storage security and data access security. Interms of data storage security, FAHZU CTMS adopts two strategies: (1) multi-node storage of data to achieve high availability of data services and a data backup strategy to ensure that data will not be lost in case of failure, and (2) encrypted storage of sensitive data . Policies for data access security are (1) security at the network level, through safety equipment , to implement access control and prevent illegal access, (2) security at the application level through multiple roles of authority management system access controls on data content, especially including rules to ensure no open access to prescriptions (such as CRC non-prescription issuance authority) as well as finding and repairing the vulnerabilities of the application through penetration testing and completing the information security technology-evaluation requirement for classified protection of cybersecurity\u2014Level 3, and (3) maintaining a detailed data change log can be useful in tracing the record of the process of data recovery.Subject privacy protection aims to protect sensitive patient information through a series of de-identification processes, which are explicitly required in the GCP. The FAHZU CTMS strictly implements the requirements of subject privacy protection in the GCP guidelines and refers to the Information Security Technology Personal Information Security Specification issued by the Standardization Administration of China and the HIPAA Regulations issued by the U.S. Department of Health. Final compliance with HIPAA\u2019s Protected Health Information Disidentifiability Requirements Implementation Specifications excludes 18 personal health identifiers (PHIs) from the CTMS  to comply with international and national laws. For CTMS users to identify subjects, we used the clinical trial protocol number, subject screening number, and subject name initials to uniquely identify them. At the level of data interaction, the patients\u2019 medical record numbers in the hospital are systematically encrypted and stored in the CTMS database, which is linked to the data of external business systems  for automatic data transmission.The evaluation of the CTMS is ongoing and mainly conducted at two levels: clinical trial project approval and review management, and clinical trial operational management. The former focuses on the convenience of multi-party collaboration and the efficiency of project approval, whereas the latter focuses on the evaluation of subject-centered data management throughout the process and the improvement of the quality of clinical trials.The improved clinical trial project approval and review management after applying the FAHZU CTMS, compared with that before the system was implemented, mainly embodies the following advantages: (1) It realizes process automation management based on task and combined with workflow technology, cooperates with user authority management systems, realizes automatic triggering of node events, and performs automatic assignment of processing personnel and message notifications such that personnel only need to process their personal to-do lists according to the message reminder, reducing the complexity of system use under multi-party collaboration. (2) Clinical trial project approval supports remote application, electronic document management enables online submission of project approval materials as well as online review and summary of revision opinions in the review process, which reduces the workload of project approval materials review and improves the efficiency of project review. Since CTMS began to operate in the hospital in December 2014, 1,388 study projects have been accepted and 43,051 documents have been submitted through CTMS as of March 31, 2021.The focus at the clinical trial operational management level is centered on patient outcomes to achieve full-cycle data management. Here, the advantages are more significant. The core advantages are summarized as follows: (1) The CTMS requires that the research plan must be entered before the recruitment of subjects, and the visit content of the current visit cycle can be automatically correlated during the subject visit. It is transformed into to-do tasks in the current research stage, with timely reminders, reducing deviations from the protocol. (2) An independent billing model is adopted for clinical trial-related inspection and treatment expenses so that subjects can be exempted from expense reimbursement and be marked in the hospital business system to meet non-clinical trial diagnosis and treatment reminders and clinical trial inspection green special requirements such as channels. (3) The CTMS contains the data on each subject, including newly generated data during operation and data collected in the hospital business system. Through strict authority classification, the scope of the data queries, such as those issued by the CRC and other data query authorities, are limited to subjects who are responsible for the project. (4) Clinical trial drugs are label-based full-cycle closed-loop managed, and transfers are completed through label scanning, and support some special properties of clinical trial drugs, such as open, single-blind, and double-blind studies, and situations with other prescriptions, where drugs need to be random, and when the serial numbers and medicine need to be recalled.The clinical trial operational management of CTMS began a pilot run at FAHZU in March 2015. Pilot runs are conducted to validate and improve the effectiveness of system functions and compatibility with different types of clinical trials. Since September 2015, all newly initiated clinical trials on the site have been managed through CTMS. According to statistics, as of March 31, 2021, a total of 12,144 subjects have been included in the management of CTMS, across 472 study projects. Figure\u00a0Informatization is an inevitable trend in clinical trial management . At presThe protection of private information is a more important consideration than the system construction \u201312. The Compared with the traditional paper CRF, e-CRF allows researchers to enter the CRF electronically based on the source data rather than fill it in manually . HoweverIn future, we also want to utilize the data in the clinical trial management platform to realize intelligent subject recruitment and improve the efficiency of subject recruitment. Recruiting subjects for some clinical trials is difficult, especially those involving rare diseases, stringent admission criteria, and special subgroups. Owing to information asymmetry, researchers only know the condition of the patients they are treating, and patients do not know that their disease may be under research at the hospital, which can seriously affect the progress of clinical trials \u201319. To fSince the outbreak of COVID-19, many jobs around the world have been stalled to a certain extent. In the event of a major public health emergency, carrying out clinical trials and ensuring the smooth implementation of monitoring work has become a problem for clinical trial practitioners, and remote monitoring has therefore been put on the agenda. The U.S. Food and Drug Administration has long encouraged more centralized monitoring, where inspectors perform inspections in the office using relevant information tools rather than at research institutions . The development trend of clinical trial monitoring is to replace on-site monitoring with centralized monitoring . Remote Compared with other information systems, CTMSs are more professional and personalized. The realization of the effectiveness of a CTMS requires a significant amount of time, and the more clinical trials undertaken, the more significant the effect. Compared with the system design, the comprehensive and efficient application of the system takes longer to achieve. With the digitization of clinical research, the sharing and integration of research data will bring many management advantages, such as an increase in available management resources, scientific and data support for major decisions, the convenience of remote management, pertinacity, and pre-operation. The CTMS developed by our hospital will be constantly updated and upgraded, and its functions will constantly improve. The system update will keep pace with developments in international drug clinical trial management, promote the development of clinical trials in a more standardized direction, and promote the disciplinary status of the hospital regarding high-level clinical trials.The FAHZU CTMS, as the first integrated CTMS independently developed by a hospital in China, can better adapt to the institutional needs for individualized, whole-process, and dynamically comprehensive evaluation and supervision of clinical trials. The integrated CTMS contains three levels and seven subsystems, which fully realizes the whole-process data management of clinical trials from project approval and review management to operational management. Through the unified interface system, the developed CTMS provides a variety of access methods to complete efficient data integration with the clinical business systems, and applies multiple security policies combined with privacy protection methods to effectively ensure the security of data and the privacy of subjects during clinical trial operation. The operation results based on the integrated CTMS show that it can effectively control the risks in the clinical trial process, so as to improve the science, safety, and timeliness of the new drug development process."}
+{"text": "Within FAR SEAS, a multi-component evidence-based community intervention was implemented and evaluated in Mazovia (Poland), with the aim of preventing alcohol-exposed pregnancies, and therefore preventing FASD.n = 441) to groups for low- (70%), moderate- (23%), or high-risk (7%) of alcohol exposed pregnancy, to provide interventions tailored to their needs. The non-parametric sign test, testing differences between pairs of observations before and after intervention was used to evaluate the outcomes.Multi-disciplinary professionals from different services , recruited women of child-bearing age (pregnant and not pregnant) in local communities, screened them for alcohol risk, and allocated participants (Follow-up data (collected from 93% of participants) indicated positive changes in the key outcome variables: risky alcohol consumption dropped by 81%, contraception use increased by 15% and visiting a gynecologist increased by 39%; as well as in associated psychosocial risk factors . No changes were noted in frequency of other service use . The most prominent changes were observed in the moderate-risk group.Changing risky behaviors  to prevent alcohol exposed pregnancies is feasible at the local level, even without engagement of medical professionals. Key challenges, related to engaging professionals and local authorities, must be addressed; and procedures should be adapted to local contexts and needs. Alcohol consumption during pregnancy may result in a series of adverse effects to the fetus including congenital anomalies and behavioral, cognitive and adaptive deficits, collectively known as Fetal Alcohol Spectrum Disorder (FASD). FASD is preventable by abstaining from drinking alcohol during pregnancy but effective prevention is complex and requires activities at various levels, targeting general population, women of childbearing age, women with alcohol problems and postpartum . For thiThe region chosen for the pilot was the Mazovian voivodeship in central Poland due to: relatively high prevalence of alcohol consumption reported by Polish pregnant women   .The small number of pregnant participants in the study does not allow conclusions to be drawn on the effectiveness of the FAR SEAS approach during pregnancy specifically . However, our findings do suggest positive influences of the interventions on the participants taken as a whole, especially those who drink alcohol at risky level and/or present other psycho-social risk factors of drinking alcohol during pregnancy, and therefore at higher risk of giving birth to a child with FASD .Given the importance of being able to target the intervention to the group most in need of support, i.e., women most at high risk of alcohol exposed pregnancy, the result indicating significant reductions in risky alcohol consumption among the high-risk subgroup is very promising. It is also important that the interventions offered to this group within the FAR SEAS project had positive effects on their domestic situation (reduced violence) and mood (depressive symptoms). However, more intensive or different interventions, or the engagement of other specialists  are needed to improve their reproductive health , and to reduce other psychoactive substance use in pregnancy.The improvement of some health behaviors  in the low-risk group, suggests a need for basic health education for the general Polish population, especially among women in childbearing age.The applicability of the study results to different populations and contexts may be limited by the uneven spread of participants across the different geographical and urban sites. An unstable social and medical situation at the time of the study made the recruitment of local stakeholders and individual specialists very difficult. Out of the six local teams that signed up for the project, only 4 teams were active, including 2 which were active only at a minimal level. In two other locations of the project (P\u0142ock and Radom), interdisciplinary teams of specialists  were established to implement all the planned activities. Both highly active teams were led by people evidently well predisposed to this role: engaged, well organized, oriented to problem-solving and communicative , 57. In One other limitation of the study, which is encountered in many alcohol prevention interventions, is the reliance on self-reported data for alcohol use, which may result in a social desirability bias . In addition, the freedom of local staff in selecting the project participants, although reflecting natural context of their work, may be considered a limitation of the study. It is possible that, consciously or subconsciously, they introduced a bias by inviting women they feel they can more easily work with, who may not be those most in need of the intervention. This indicates the need of more rigorous training and enforcement of research experiment standards in future studies.The positive results of the pilot project indicate the feasibility and validity of implementing multi-center regional FASD prevention through inter-disciplinary teams at the community level. The most prominent changes in the prevalence of risky alcohol consumption were observed in the moderate risk group indicating potentially high returns on investment of addressing FASD prevention and interventions to this group; which should not be overlooked, despite the priority of focusing on women at high risk of alcohol exposed pregnancies. The results suggest an opportunity to build on the receptivity of women in the moderate risk group to prevention and advice, and that delivering timely interventions may prevent women from developing more risky behaviors leading to alcohol exposed pregnancies. Dissemination of FASD prevention at the local level requires the involvement of local authorities and directors of key institutions and coordinated work in a multidisciplinary team, which is one of the key facilitators of good implementation and sustainability of FAS/FASD prevention.The main learning points and findings from the FAR SEAS pilot study have been fed forward into the FAR SEAS Guidance, which comprises 22 evidence-based recommendations, validated through international expert consensus, aimed at reducing alcohol consumption in women of childbearing age, particularly in pregnant women.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The study involving humans was approved by the Ethics Committee of State Agency for Prevention of Alcohol Related Problems (Poland). The study was conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants\u2019 legal guardians/next of kin.KO-K, LS-G, FB, CG, and ES contributed to conception and design of the study. KO-K and MZ-S organized the database. KO-K, SG, and MZ-S performed the statistical analysis. KO-K, FB, LS-G, and CB wrote the first draft of the manuscript and sections of the manuscript. FB, SM, KO-K, and LS-G supervised the project implementation. FB and SM administered the project. FB, SM, and KO-K acquired funding for the project. All authors contributed to manuscript revision, read, and approved the submitted version."}
+{"text": "The aim of this article review is to analyze some models and clinical issues related to the implementation of accelerated diagnostic protocols based on specific cardiac biomarkers in patients admitted to the emergency department (ED) with symptoms compatible with acute cardiac disorders. Four specific clinical issues will be discussed in detail: (a) pathophysiological and clinical interpretations of circulating hs-cTnI and hs-cTnT levels; (b) the clinical relevance and estimation of the biological variation of biomarkers in patients admitted to the ED with acute and severe diseases; (c) the role and advantages of the point-of-care testing (POCT) methods for cardiac-specific biomarkers in pre-hospital and hospital clinical practice; and (d) the clinical role of specific cardiac biomarkers in patients with acute heart failure (AHF). In order to balance the risk between a hasty discharge versus the potential harms caused by a cardiac assessment in patients admitted to the ED with suspected acute cardiovascular disease, the measurement of specific cardiac biomarkers is essential for the early identification of the presence of myocardial dysfunction and/or injury and to significantly reduce the length and costs of hospitalization. Moreover, specific cardiac biomarkers  are useful predictors of mortality and major adverse cardiovascular events (MACE) in patients admitted to the ED with suspected acute cardiovascular disease. To guide the implementation of the most rapid algorithms for the diagnosis of Non-ST-Elevation Myocardial Infarction (NSTEMI) into routine clinical practice, clinical scientific societies and laboratory medicine societies should promote collaborative studies specifically designed for the evaluation of the analytical performance and, especially, the cost/benefit ratio resulting from the use of these clinical protocols and POCT methods in the ED clinical practice. In September 2021, a systematic review by the Agency for Healthcare Research and Quality U.S. Department of Health and Human Services (AURQ Report) showed that (a) overall diagnostic accuracy in the emergency department (ED) is high, but some patients receive an incorrect diagnosis (~5.7%); (b) about 2.0% of these patients suffer an adverse event because of the incorrect diagnosis; and (c) about 3.0% of adverse events are serious (~0.3%) .,49.26,49Norman et al.  assessedDawson et al.  analyzedIn the last 5 years, three POCT hs-cTnI methods have become commercially available worldwide ,26,36,37\u00ae IM High-Sensitivity Troponin I (hs-cTnI) assay, Siemens Diagnostics, Marburg, Germany) for the rapid rule-out of AMI, using a single hs-cTnI measurement at presentation in patients presenting to an ED. Authors enrolled 1171 patients, including 97 (8.3%) with AMI, 78.3% of which were type 2 AMI   providedThe implementation of hs-cTnI POCT methods requires not only a careful education of the personnel responsible for biomarker measurement, but also an accurate evaluation of analytical, clinical, and organizational issues related to the routine use of the POCT methods in the ED ,36,37,74HF represents a relevant public health burden in European and North American countries, considering the high risk of morbidity and mortality, particularly among patients \u2265 65 years ,75,76. IThe 2015 consensus paper from the Heart Failure Association of the European Society of Cardiology, the European Society of Emergency Medicine, and the Society of Academic Emergency Medicine Acute Heart Failure has defined AHF as the new onset or worsening of symptoms and signs of HF with associated elevated circulating levels of natriuretic peptides . AHF is Several recent studies and two meta-analyses confirmed the relevance of the measurement of cardiac-specific biomarkers in patients presenting to the ED with acute dyspnea or AHF ,93,94,95The most important limitation of the clinical studies concerning the role of cardiac NPs  in patients admitted to the ED with AHF is that these studies have commonly enrolled relatively small, selected patient cohorts. Specific clinical characteristics  are prevalent in AHF patients ,78,79,80In 2022, a meta-analysis evaluated the NT-proBNP concentrations of 10,368 individual patients with AHF, with the purpose to develop and validate a decision support tool combining biomarker concentrations and clinical characteristics . In thisIn patients admitted to the ED with suspected ACS, including those with AHF, the measurement of hs-cTnI and hs-cTnT should be considered the first-line biomarkers, in order to identify the presence of myocardial injury and to quickly rule out ACS, leading to a significant reduction in the duration and costs of hospitalization ,101,102.According to the most recent clinical studies, high levels of both cardiac-specific biomarkers  in AHF patients are consistently associated with an increased risk of morbidity and mortality, due to the combined presence of a severe reduction in cardiac function and myocardial injury (or even ACS) ,102,104.In order to balance the risk between a hasty discharge versus the potential harms caused by a cardiac assessment in patients admitted to the ED with suspected acute cardiovascular disease, the recent expert documents and guidelines recommend the measurement of specific cardiac biomarkers (NPs and hs-cTn) for the early identification of the presence of myocardial dysfunction and/or injury and to significantly reduce the duration and costs of hospitalization ,100,101.The very recent development of some POCT methods capable of measuring hs-cTnI (as well as NPs) represents a fundamental advance because these methods can significantly reduce the TAT of biomarker measurement ,26,36,37To guide the implementation of the POCT methods, capable of measuring both the specific cardiac biomarkers, into routine clinical practice, clinical scientific societies and laboratory medicine societies should promote collaborative studies specifically designed for the evaluation of the analytical performance and, especially, the cost/benefit ratio resulting from the use of the rapid algorithms for the diagnosis of NSTEMI and the use of POCT methods in the ED clinical practice."}
+{"text": "Objective\u2003To compare the effects of expectant versus interventionist care in the management of pregnant women with severe preeclampsia remote from term.Data sources\u2003An electronic search was conducted in the Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica Database (EMBASE), Cochrane Central Register of Controlled Trials (CENTRAL), Latin American and Caribbean Health Sciences Literature , World Health Organization's International Clinical Trials Registry Platform (WHO-ICTRP), and OpenGrey databases. The International Federation of Gynecology and Obstetrics , Royal College of Obstetricians and Gynaecologists (RCOG), American College of Obstetricians and Gynecologists (ACOG), andColombian Journal of Obstetrics and Gynecology(CJOG) websites were searched for conference proceedings, without language restrictions, up to March 25, 2020.Selection of studies\u2003Randomized clinical trials (RCTs), and non-randomized controlled studies (NRSs) were included. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach was used to evaluate the quality of the evidence.Data collection\u2003Studies were independently assessed for inclusion criteria, data extraction, and risk of bias. Disagreements were resolved by consensus.Data synthesis\u2003Four RCTs and six NRS were included. Low-quality evidence from the RCTs showed that expectant care may result in a lower incidence of appearance, pulse, grimace, activity, and respiration (Apgar) scores\u2009<\u20097 at 5\u2009minutes  and a higher average birth weight . Very low quality evidence from the NRSs suggested that expectant care might decrease the rates of neonatal death , hyaline membrane disease , and admission to neonatal care . No maternal or fetal differences were found for other perinatal outcomes.Conclusion\u2003Compared with interventionist management, expectant care may improve neonatal outcomes without increasing maternal morbidity and mortality. Preeclampsia is one of the most important causes of maternal morbidity and mortality,Pregnant women with severe preeclampsia remote from term can receive expectant or interventionist care.Two recent systematic reviews with meta-analysesThe purpose of the present review was to compare the effects of expectant and interventionist care in the management of pregnant women with severe preeclampsia remote from term. We included RCTs and NRSs in which women with severe preeclampsia between 24 to 34 weeks of gestation were recruited. Expectant care was defined as a policy of delayed-interval delivery until a specific maternal or fetal indication or 34 weeks of gestation. The maternal primary outcomes included: death; eclampsia; HELLP syndrome; and placental abruption. The primary fetal outcomes were stillbirth; neonatal death; intraventricular hemorrhage (IVH); and small-for-gestational-age fetuses. For the women, the secondary outcomes were: an increase in the rate of Cesarean section; pulmonary edema; renal failure; and prologation of the pregnancy; for the newborns, they were low appearance, pulse, grimace, activity, and respiration (Apgar) score (at five minutes); respiratory distress syndrome; low birthweight; admission to neonatal intensive care unit (NICU); and bronchopulmonary-dysplasia.Colombian Journal of Obstetrics and Gynecology(CJOG) was hand-searched, and citation searches of included studies were screened for additional references. The experts in the field were contacted. No language or date restrictions were applied, and the search was conducted until 25 March 2020.An electronic search was conducted in the Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica Database (EMBASE), Cochrane Central Register of Controlled Trials (CENTRAL), and Latin American and Caribbean Health Sciences Literature  databases. Furthermore, searches were conducted in the OpenGrey, International Federation of Gynecology and Obstetrics , Royal College of Obstetricians and Gynaecologists (RCOG), American College of Obstetricians and Gynecologists (ACOG) websites for dissertations, theses, and conference proceedings, and in the World Health Organization's International Clinical Trials Registry Platform (WHO-ICTRP) for ongoing studies. TheThe authors of the present study independently screened all titles and abstracts for eligibility, extracted the data, and assessed the risk of bias. Disagreements were solved through consensus. Two authors (MAQ-O and CFG-A) entered the data into the Review Manager  software and checked them for accuracy. The risk of bias was evaluated in accordance with the criteria proposed by the Cochrane Bias Methods group for RCTs and NRS .2) test and the I-squared (I2) statistic, and it was considered substantial if thep-value was lower than 0.10 in the \u03c72test, or if the I2was greater than 40%.The statistical analysis was performed with the RevMan software, using the Mantel-Haenszel fixed-effect model for dichotomous data and the inverse of the variance for continuous data, in which the trials were judged sufficiently homogeneous.The publication bias was to be explored through an assessment of funnel plot asymmetry and formal tests. However, because the present review included fewer than 10 RCTs and NRSs in the meta-analysis, this analysis was not performed. \u201cSummary of findings\u201d tables were prepared using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to assess the certainty of the evidence.The searches yielded 2,098 references; after removing duplicates, 2,059 studies were screened. From these studies, 45 had their full texts reviewed. A total of 10 studies met the inclusion criteria: 4 were RCTs,The RCTs were conducted between 1990 and 2013, and they included studies from Egypt, South Africa, and the United States. One study recruited participants from different Latin American countries. The studies included 430 women with single or multiple pregnancies, regardless of parity, and with gestational ages at admission between 28 and 34 weeks. Three trialsExpectant management was characterized by bed rest and treatment with magnesium sulfate, antihypertensives, and glucocorticoids, followed by delivery only for specific maternal/fetal indications or completion of 34 weeks of gestation. The maternal indications for termination of pregnancy were uncontrollable hypertension, abruptio placenta, renal failure, HELLP syndrome, persistent severe headache or visual changes, or epigastric pain; the fetal indications for delivery were non-reassuring fetal status, and fetal growth restriction. Interventionist care consisted of induction of delivery from 24 to 48\u2009hours after complete fetal pulmonary maturation. For both groups, fetal wellbeing was assessed through the non-stress test, a doppler evaluation, and periodic ultrasound .The NRSs were retrospectiveExpectant care involved bed rest, daily recording of maternal weight, fluid balance, monitoring of the maternal blood pressure and of the urine output every four hours, the administration of magnesium sulfate or anticonvulsants ,For the generation of random sequences and allocation concealment, three trialsThe NRSs were judged to be at high risk for the confounding bias and selection bias domains. The cohorts were prone to exclusion of some eligible participants, and one or more prognostic variables could have predicted the intervention received. Regarding the classification of interventions, all NRSs were assessed as having a low risk of bias; it is unlikely that bias will be introduced by the differential or non-differential misclassification of the intervention status. The NRSs included were judged as high-risk for bias due to deviations from the intended interventions; there were some systematic differences between experimental interventions and comparator groups in terms of the care provided (such as corticosteroid administration). For the biases due to missing data and due to measurement of the outcome domains, all NRSs were appraised as low-risk. No individuals with missing data were included in the cohorts, and because the outcomes were objectively assessed, differential or non-differential errors in the measurement of the outcome data are unlikely. Finally, the protocols of the NRSs were not available, making the risk of bias for selective reporting unclear.2\u2009=\u2009not estimable), of HELLP syndrome , of pulmonary edema , or of stillbirth , because the quality of the evidence for these outcomes was low , of intraventricular hemorrhage , of hyaline membrane disease , and of admission to the NICU , and may not have any effect on maternal morbidity , but the quality of the evidence was low, and the results were imprecise.Expectant care may not decrease the rates of neonatal death  and higher average birthweight . On average, expectant care may extend pregnancy by 1 week , and increase the risk of small-for-gestational-age newborns , with little or no effect on the rates of cesarean section .The newborns in the expectant care group may have a lower incidence of appearance, pulse, grimace, activity, and respiration (Apgar) scores\u2009<\u20097 at 5\u2009minutes , HELLP syndrome , and pulmonary edema . Expectant care had no clear effect on the incidence of placental abruption , or renal failure .Very low quality evidence from the NRSs showed that it is uncertain whether expectant care may increase the rates of: maternal mortality , the incidence of Apgar scores\u2009<\u20097 at 5\u2009minutes , and may result in a small increase in small-for-gestational-age newborns . Interventionist care may not reduce the incidence of stillbirth , but, once again, the results were imprecise.Evidence from the NRSs suggested that, compared with interventionist care, expectant management may not decrease the frequency of intraventricular hemorrhage  and be effective in decreasing the rates of neonatal death , of hyaline membrane disease , and of admission to the NICU , with little or no effect on the rates of caesarean section .Very low quality evidence from the NRSs showed that expectant care may increase birthweight (MD: 144.2\u2009g; 95%CI: 20.7 to 267.8; 4 cohort studies; 285 newborns; IThe management of the women with severe preeclampsia remote from term is a challenge for the obstetrician, and requires weighing maternal and fetal risks and benefits.Some findings of the present review differ from those reported in other publications. One reviewAnother reviewThe present systematic review has some strengths,Despite its limitations, the present systematic review has some implications for the clinical practice. Low quality of evidence from the RCTs showed that expectant care may result in a lower incidence of Apgar scores\u2009<\u20097 at 5\u2009minutes and a higher average birthweight. Very low quality evidence from the NRSs suggested that expectant care may decrease the rates of neonatal death, hyaline membrane disease, and admission to the NICU. No maternal or fetal differences were found for other perinatal outcomes. More studies with higher methodological quality and with adequate sample sizes are required."}
+{"text": "The foundations of Artificial Intelligence (AI), a field whose applications are of great use and concern for society, can be traced back to the early years of the second half of the 20th century. Since then, the field has seen increased research output and funding cycles followed by setbacks. The new millennium has seen unprecedented interest in AI progress and expectations with significant financial investments from the public and private sectors. However, the continual acceleration of AI capabilities and real-world applications is not guaranteed. Mainly, accountability of AI systems in the context of the interplay between AI and the broader society is essential for adopting AI systems via the trust placed in them. Continual progress in AI research and development (R&D) can help tackle humanity's most significant challenges to improve social good. The authors of this paper suggest that the careful design of forward-looking research policies serves a crucial function in avoiding potential future setbacks in AI research, development, and use. The United States (US) has kept its leading role in R&D, mainly shaping the global trends in the field. Accordingly, this paper presents a critical assessment of the US National AI R&D Strategic Plan and prescribes six recommendations to improve future research strategies in the US and around the globe. The roots of Artificial Intelligence (AI) as a research field are usually traced back to a workshop held in 1956 on the campus of Dartmouth College  knowledge discovery from multi-modal, noisy, and big data; (ii) perceptual capabilities of AI systems via sensors and other means; (iii) understanding of theoretical limitations of AI concerning available hardware; (iv) general-purpose artificial intelligence that is capable of performing different kinds of tasks like humans do; (v) coordination of multi-AI systems; (vi) human-like AI that can learn from small sample sizes, and that can explain itself; (vii) robotic technologies; (viii) hardware specialized for AI; and (ix) AI for improving hardware design. This strategy mentions several vital concepts such as perception and attention, commonsense and probabilistic reasoning, combinatorial optimization, knowledge representation, natural language processing, and human-machine interaction as prioritized areas for fundamental AI research.The second strategy is concerned with developing effective methods for human-AI collaboration. The strategy suggests that many applications of AI will not be completely autonomous. Instead, a combination of AI and human systems will work together. An effective and efficient human-AI collaboration requires additional R&D. The strategy highlights some development challenges: (i) human-aware intelligent systems that are capable of intuitive interaction with humans; (ii) AI techniques that enhance human capabilities, for instance, through wearable devices; (iii) human-AI interfaces to present increasingly complex data in a human-understandable manner; and (iv) better language processing systems that overcome current challenges such as noisy surroundings, heavily accented speech, impaired speech, and real-time dialogue with humans. The strategy also argues that trust in AI is necessary for human-AI collaborations, which is related to fairness, explainability, and transparency.The third strategy is concerned with understanding and addressing AI's ethical, legal, and societal implications. This strategy focuses on fundamental concepts such as trustworthiness, fairness, transparency, accountability, explainability, and ethics. The strategy presents three subsections to explore critical challenges: (i) incorporating fairness, transparency, and accountability in the design of AI systems, (ii) building ethical AI; and (iii) designing system architectures incorporating ethical reasoning.The fourth strategy is concerned with ensuring the safety and security of AI systems. The strategy emphasizes the vital role of safety and security in achieving robust and trustworthy AI systems. The strategy presents several challenges: (i) developing AI systems that are capable of explaining the reasons behind the outputs they produce; (ii) building trust in AI; (iii) enhancing verification and validation of AI systems by meeting formal specifications and user's operational needs, respectively; (iv) robustness against cyber-attacks; and (v) developing self-monitoring architectures for the safety of self-modifying systems.The fifth strategy involves developing shared public datasets and environments for AI training and testing. The strategy presents three critical areas of importance: (i) developing a wide variety of accessible datasets for the needs of the whole spectrum of AI applications; (ii) ensuring responsiveness of training and testing resources to public and commercial needs; and (iii) open-source software for making AI technologies more accessible. The strategy further stresses the importance of findability, accessibility, interoperability, and reusability principles for datasets and potential privacy and bias issues in datasets. Moreover, the need for computational resources to process data is underlined.The sixth strategy is concerned with measuring and evaluating AI technologies based on well-established standards and benchmarks. The strategy highlights several areas as needing further progress: (i) developing AI standards for the broad spectrum of AI; (ii) establishing benchmarks for evaluating AI and its compliance to the standards; (iii) increasing the availability of testbeds in all areas of AI; and (iv) engaging users, industry, government, and academia in standards and benchmarks. Further, the strategy calls attention to measuring and evaluating AI systems to assess and assure safety, security, privacy, robustness, explainability, transparency, and fairness.The seventh strategy is to understand better the national AI R&D workforce needs. It highlights the increasing demand for AI expertise and calls for improving the existing efforts for advancing the AI R&D workforce. The strategy explicitly mentions enhancing instructional capacity from K-12 to graduate level, nurturing computer scientists and experts from other fields such as cognitive science, economics, linguistics, and others.The last strategy concerns expanding public-private partnerships to accelerate advances in AI. The strategy explicitly states government, universities, and industry entities for public-private partnerships. The benefits of such collaboration include leveraging resources to push innovation, supporting the practices based on these innovations, and enhancing the training for future researchers and practitioners.The increasingly decisive role of AI in people's lives necessitates a sociotechnical viewpoint  improving fairness, transparency, and accountability by design, (ii) building ethical AI, and (iii) designing architectures for ethical AI. However, as described in the Plan, these three challenges largely overlap without clear and intuitive distinctions. Also, explainability is discussed in the fourth strategy, which is concerned with the safety and security of AI systems. In contrast, this paper argues that it is more appropriate to discuss explainability concerning the other components of the third strategy and within its scope.Recommendation: The third strategy may be rewritten to present notions and challenges concerning social implications and accountability of AI systems, which include concepts such as responsibility, explainability, robustness, and fairness. It should also contain references to other related strategies, such as the second strategy on human-AI collaboration, the fourth strategy on privacy and security of AI systems, and the sixth strategy on developing methods, metrics, benchmarks, and standards to evaluate AI systems.VI. The trust to be placed in AI and its expanding role in society depends not only on the benefits of AI but also on its risks, potential harms, and remedies (Knowles and Richards, Recommendation: The Plan should support research initiatives that tackle questions related to understanding and operationalizing the risks and harms of AI systems so that risk ratings, certifications, and insurance become feasible for AI systems. This recommendation relates to Strategies 3, 4, and 6.V. The seventh strategy addresses the increasing demand for AI researchers and practitioners. While it acknowledges that the AI workforce is not composed only of computer and information scientists and engineers but also includes multidisciplinary teams, it appears to present the other fields and domains as areas \u201cin which AI may be applied.\u201d We suggest that multidisciplinary work where people from different disciplines work together is insufficient. Instead, an interdisciplinary and transdisciplinary approach (van den Besselaar, Recommendation: Considering the emerging intertwined nature of AI and human lives, the importance of cultivating an interdisciplinary and transdisciplinary AI workforce should be emphasized.VI. The eighth strategy supports expanding public-private partnerships focusing on government-university-industry research and development partnerships. Given the social implications of AI, civil society organizations play a relevant and valuable role in representing the expectations of the broader society.Recommendation: The eighth strategy should be expanded to include collaboration with civil society organizations, particularly concerning future developments regarding the societal implications of AI.The US is leading in shaping AI research and development trends globally. Such trends are highly relevant for the future of the field, especially to direct resources to prevent another AI Winter, improve social good, and ensure the safe progress of the society toward the new sociotechnical paradigm. Given this pressing issue, this paper investigates the official AI R&D strategies of the US government with a critical lens. It offers six recommendations to improve AI research strategies in the US and beyond.The first recommendation calls for more fundamental research on causality in AI. The second recommendation calls for a better understanding of and mechanism design for human oversight of AI. The third recommendation calls for a clear and comprehensive presentation of accountable AI to guide future research. The fourth recommendation calls for further efforts to facilitate risk ratings, certifications, and insurance for AI systems. The fifth recommendation calls for more interdisciplinary and transdisciplinary research. Finally, the sixth recommendation calls for the participation of civil society actors in AI research collaborations.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.FG and IK contributed to conception and design of the study, contributed to manuscript revision, read, and approved the submitted version. FG wrote the first draft of the manuscript. All authors contributed to the article and approved the submitted version."}
+{"text": "One Health approach is crucial to tackling complex global public health threats at the interface of humans, animals, and the environment. As outlined in the One Health Joint Plan of Action, the international One Health community includes stakeholders from different sectors. Supported by the Bill & Melinda Gates Foundation, an academic community for One Health action has been proposed with the aim of promoting the understanding and real-world implementation of One Health approach and contribution towards the Sustainable Development Goals for a healthy planet.The proposed academic community would contribute to generating high-quality scientific evidence, distilling local experiences as well as fostering an interconnected One Health culture and mindset, among various stakeholders on different levels and in all sectors. The major scope of the community covers One Health governance, zoonotic diseases, food security, antimicrobial resistance, and climate change along with the research agenda to be developed. The academic community will be supported by two committees, including a strategic consultancy committee and a scientific steering committee, composed of influential scientists selected from the One Health information database. A workplan containing activities under six objectives is proposed to provide research support, strengthen local capacity, and enhance global participation.The proposed academic community for One Health action is a crucial step towards enhancing communication, coordination, collaboration, and capacity building for the implementation of One Health. By bringing eminent global experts together, the academic community possesses the potential to generate scientific evidence and provide advice to local governments and international organizations, enabling the pursuit of common goals, collaborative policies, and solutions to misaligned interests.The online version contains supplementary material available at 10.1186/s40249-023-01124-w. The One Health approach, centered around holistic thinking at the interface of humans, animal, and the environment, aims to promote the health and sustainable development of these sectors through multi-sectoral, interdisciplinary, and cross-border collaboration . It is aIn October 2022, the Food and Agriculture Organization of the United Nations (FAO), the United Nations Environment Programme (UNEP), the World Health Organization (WHO), and the World Organization for Animal Health (WOAH) jointly released the One Health Joint Plan of Action (OHJPA) [Supported by Bill & Melinda Gates Foundation, an academic community for One Health action has been proposed by Shanghai Jiao Tong University in Shanghai China, with the aim of promoting the understanding, contribution and real-world implementation of the One Health approach towards the Sustainable Development Goals (SDGs). In order to strategize the construction of this academic community, a Scientific Steering Committee (SSC) was jointly formed up with a wide engagement of more than 26 experts and institutions over 18 countries and regions Providing high-quality scientific evidence through collaborative research, joint publications, and conferences on issues such as (re-)emerging infectious diseases, climate change, and antimicrobial resistance (AMR).(ii)Distilling local experiences and analyzing current One Health practices to prioritize national strategies and international collaborations.(iii)Fostering an interconnected One Health community, where partners have visibility of resources and policymakers have access to One Health solutions.The academic community can contribute to achieving the goal by:The academic community will develop a research agenda for global partners working in One Health and promote information sharing by providing a collaborative body for members. The academic community will also connect different disciplines and stakeholders at national, regional, and global levels to promote innovation in implementation and increase the impact of One Health work, including through cooperation with international organizations such as the WHO and the World Bank.The academic community also serves as an international exchange and cooperation platform for One Health solutions tailored for the diverse socio-ecological settings within the networks, which also provides an additional benefit to the inter-governmental collaborations that extend beyond the realm of One Health.Finally, the academic community will advocate for awareness of the links between human, animal, and environmental health and engage with policy makers at both national and international levels to promote the inclusion of One Health measures. The academic community will also collaborate with non-governmental organizations, academic institutions, and others in the public and private sectors to promote education and public awareness of One Health.The organizing structure of the academic committee has been proposed. A Strategic Consultancy Committee (SCC) and a Scientific Steering Committee (SSC) will be constructed to form the leadership of the academic community. The SCC, composed of high-level key opinion leaders, is responsible for developing strategic plans and action guides for the academic committee, supervising the work of SSC and secretariat and leveraging resources to catalyze the implementation of workplans. The SSC is composed of top-ranking academic experts, who have been selected from the One Health information database  based onUnder the three goals of the academic community, six objectives have been developed: conducting collaborative research project (objective 1), expanding interconnected research network (objective 2), identifying and disseminating local cases (objective 3), promoting knowledge- and data- sharing platform (objective 4), fostering One Health culture and mindset (objective 5), and engaging broader partnership (objective 6). The workplan to achieve these objectives and goals is shown in Fig.\u00a0Based on overarching goals of the academic community for One Health action, research priorities to support the community will focus following five areas, including One Health governance, control of zoonotic infections, food security and food safety, control of AMR, and impact evaluation of climate changes on health.One Health governance refers to the development, implementation, and oversight of policies that support the One Health approach. It encompasses eight dimensions, including public participation, rule of law, transparency, responsiveness, consensus orientation, fairness and inclusivity, effectiveness and efficiency, and policy support . An effeA major challenge is the lack of coordination between different sectors and stakeholders . Many coTo address this issue, the academic community should facilitate the development of effective One Health governance frameworks that span multiple sectors and disciplines, drawing from lessons learned towards best practices. The academic community will also advocate for the establishment of a global governance framework for One Health, providing an international reference point for countries aiming to improve their own One Health governance.Zoonotic diseases are a high-priority target for the One Health approach. Zoonotic diseases are challenging for global surveillance, prevention, and control measures. One of the main factors is the emergence of these diseases, which highlights the need for a better understanding of the dynamics of pathogen spillover and transmission between animals and humans so that intervention strategies could be developed to zoonoses more effectively . AdditioTo address these challenges, the academic community will facilitate research to identify the drivers of zoonotic disease emergence and enhance surveillance and prevention strategies. This will require interdisciplinary collaboration among public health, veterinary medicine, wildlife ecology, and the social and economic sciences. The academic community will also strengthen countries\u2019 capacities to detect, report, and respond to zoonotic disease outbreaks by three activities: (i) expanding laboratory capacity, including improving laboratory professional level, building reference laboratory networks, standardizing standard operating procedures, etc.; (ii) improving disease surveillance efficiency, including applying innovative surveillance tools, enhancing surveillance and response systems, improving the surveillance evaluation approaches, etc.; and (iii) strengthening animal health systems, including enlarging animal surveillance networks, developing animal disease alarming system, optimizing animal health management, etc.Food security and food safety is a complex issue that affects all aspects of human life. It involves ensuring that people have access to sufficient, safe, and nutritious food that is appropriate for their culture and lifestyle . One of Currently, over 820 million people worldwide suffer from chronic hunger, while an additional 2 billion people suffer from malnutrition due to a lack of essential micronutrients in their diets . ClimateTo improve food security, the academic community will promote sustainable agricultural practices, enhance the resilience of supply chains to climate change and other shocks, reduce food waste, improving food safety, and enhance food accessibility. The One Health approach will address these objectives by working with organizations and governments to incorporate the interdependence of human, animal, and environmental health in their initiatives.AMR is a major public health threat and another key focus of the academic community. AMR occurs when bacteria, viruses, fungi, or parasites develop resistance to antimicrobial drugs, making it more difficult to treat infections . The misOne of the main challenges in addressing AMR is the lack of awareness and understanding among the public who access drugs over the counter, and healthcare professionals who administer them in bulk, both behaviors that contribute to resistance. Additionally, developing new antimicrobials is slow and costly, and even newly developed drugs can quickly become ineffective if they are similarly misused .To combat AMR, the academic community targets at educating the public and healthcare professionals about the risks of AMR and the importance of appropriate antimicrobial use, as well as improving access to diagnostic tests to ensure that antimicrobials are only used when necessary.In addition to these efforts, the academic community should work to improve surveillance and monitoring of AMR in various One Health components including wild life and migratory birds along with development of better methods for tracking the spread of resistant pathogens between animals, humans and ecosystems. The academic community also supports the development of rapid and cost-effective point-of-care testing AMR diagnostic technologies, alternative treatments, and vaccines to mitigate the impact of AMR. Through these efforts, the academic community hopes to slow the spread of AMR and preserve the effectiveness of crucial drugs.Climate change is one of the most pressing global challenges of our time. Its impacts are vast and far-reaching, affecting not only the natural world but also human health and well-being. Disadvantaged and vulnerable populations are disproportionately affected. Climate change exacerbates existing health problems and poses new risks, such as increased frequency and severity of extreme weather events, changing patterns of infectious diseases, and food and water insecurity . AddressThe One Health approach provides an essential framework for addressing the health impacts of climate change . Key strTo build an academic community for One Health action, four approaches have been proposed as follows.The academic community connects resources to support interdisciplinary research in the field of One Health. This includes advocating funding agency to put One Health on their high profile and linking funding opportunities to research projects that investigate the links between human, animal, and environmental health. Meanwhile, the academic community supports joint research programs and collaborations across different sectors and countries and also cultivate the research competitiveness for professionals in One Health to improve their capabilities to obtain funding and resources.The academic community serves as a bridge to translate scientific knowledge from research to evidence-based solutions for policy makers. Through applying both bottom-up and top-down approaches, the academic community supports implementation science to identify local needs and real gaps, and builds up dialogues between local practitioners, scientists, funders and policy makers. Meanwhile, the academic community can also contribute to developing innovative mechanisms to connect the local with the regional, and to scale up regional experiences to global policy agenda.The academic community supports training programs and other capacity-building initiatives to strengthen the research capabilities of individuals and organizations working in One Health fields. This includes training in research paradigms, methods, experimental practices, and data analysis, as well as the development of One Health related disciplines and research networks, with an emphasis on early career researchers and researchers from low- and middle-income countries.The academic community develops communication and engagement strategies to promote public awareness of One Health, and encourages diversity of the participants in One Health initiatives. It also coordinates stakeholders from around the world, together with representatives from the governments, non-governmental organizations, academic institutions, and the private sector, to promote One Health policies and practices.This article proposes to foster an academic community for One Health action, which is expected to incorporate the experience of a diverse variety of experts and stakeholders, who will be organized under the structure of SCC and SSC. Overarching research agenda followed by specific workplans and activities has been elaborated in this article, based on the exchanges and consensus of SSC. Multifaceted approach, that involves systematic thinking, evidence-based activities, transparent mechanisms, education, and communication, should be adapted profoundly in building up the community.With the tasks of promoting wider and deeper collaboration in research and practice, the community will contribute to producing novel scientific evidence, facilitating dialogues among different stakeholders, and advising for national and international policy, in its efforts to tackle global public health security at the human-animal-environment interface.Additional file 1: Table S1. The list of geographic distributions and research areas of Scientific Steering Committee (SSC) members of the proposed academic community"}
+{"text": "The research area of adolescent health corresponds to the summary of a wide range of scientific interests and investigations, focusing on the first years of life of an individual . It has Health, and in particular adolescent health, are inexorably tied to the levels of physical activity and fitness; thus, a number of publications focused on this topic. Specifically, based on the 2018 Chinese National Student Physical Fitness Standard Test data, Tong et al., used a multi-scale approach to investigate the spatial heterogeneity and regional clustering of factors influencing Chinese adolescents\u2019 physical fitness, providing a national-level view . FurtherPhysical activities, such as the ones described above, are often identified as the visible expression of emotional adolescent health. Therefore, a few publications focused on emotions and emotional health. Using cross-sectional, survey-based data from Norway between 2017\u20132019, the association between physical activity organized in sports clubs, non-organized physical activity, other organized leisure-time activities, and depressive symptoms among adolescents were investigated . A diffeThe concepts affecting behaviors and perceptions were investigated further by four separate studies. In particular, the prevalence and predisposing factors related to self-medication among medical and pharmacy students in Serbia, as attitudes towards conventional and complementary medicine among future healthcare professionals can impact their future pharmacotherapy practice . A crossA third group of submitted manuscripts involved the perspectives of food and nutrition, in particular the teen-identified indicators of targeted food marketing, with a particular focus on the aggressive marketing of unhealthy foods . Two revThe fourth and final thematic group that emerged in the papers published as part of this Special Issue had a biological and molecular focus. This included two cross-sectional studies: one of ocular changes in adolescents with diabetes mellitus in health facilities in Ghana , and oneTaken together, the above provide a successful collection of research studies on adolescent health and highlight the necessary interdisciplinarity of the work required to address current scientific questions. The COVID-19 pandemic has acted as a catalyst , bringin"}
+{"text": "The last decade has seen a noticeable upsurge in the use of biologics, including platelet-rich plasma (PRP), for applications in musculoskeletal regenerative medicine. Clinical trials, case series, systematic reviews and meta-analyses have shown the safety and efficacy of PRP for the management of several musculoskeletal disorders . Additio2) to tissues and carbon dioxide (CO2) from tissues to the lungs [2 and CO2. The typical life cycle of an RBC is 120 days, and RBC senescence is responsible for their removal from circulation by macrophages. The shear forces involved in whole-blood phlebotomy procedures or imperfect PRP concentration practices can cause damage to RBCs in PRP formulations. This results in the disintegration of the RBC membrane and the secretion of noxious hemoglobin, appraised as plasma-free hemoglobin, iron and hemin [RBCs are anuclear, comprise protein-bound heme, and transport oxygen , a potent cytokine . MMIF caIn addition, the function of RBCs in tissue regeneration is yet to be determined. There are no pre-clinical or clinical investigations assessing the efficacy of RBC-rich PRP compared to RBC-poor PRP. Thus, until the role of RBCs is established and the pros of including RBCs in a PRP formulation outweighs its cons, it is essential to reduce or eliminate the content of RBCs in PRP formulations to avoid the damaging effects of hemolysis and eryptosis on musculoskeletal tissues."}
+{"text": "Disorders of sex development (DSD) are characterized by an atypical development of chromosomal, gonadal, and anatomic gender. DSD are divided to three classes with male normal, female normal and abnormal karyotypes and have an incidence at birth of approximately 1 in 5000. DSD patients are exposed during their long-term follow-up to severe psychological stress.The aim of our study was to determine the behavioral concerns of adults with DSD and to identify the major factors that may influence their emotional and psychological well-being.We explored, through our genetic counselling reports at the medical University of Sfax, the quality of life and the psychological concerns of all adults patients assessed for DSD with and without chromosomal and/or molecular genetic abnormalities. We also assessed their need of psychological support.During the last two decades of our genetic counselling experience, 46 adult patients (age superior to 18 years) were selected for this study. The analysis of data revealed that the major psychological concern in our DSD patients was related to their reproductive capacity. In contrast, they have poor subjective norms of communicating sexual and reproductive issues with their partners. Patients who presented non-corrected ambiguous genitalia were in the majority anxious and depressed with a constant feeling of social shame.Sex development plays a fundamental role in determining the physical attributes of the body, the structure of the brain, behavioral tendencies, and the self-concept. The clinical and social approaches of DSD conditions in our society need to be improved. Genetic and psychological counselling should thorough a deep medical education regarding reproductive and sexual health in each particular case of DSD. We emphasis, that early genetic diagnosis, involvement of patients and families in a patient-centered decision-making process, and consideration of long-term health-related quality-of-life outcomes should be considered in DSD.None Declared"}
+{"text": "Negative symptoms has been classically associated with cognition, psychosocial functioning and quality of life in patients with schizophrenia. But negative symptoms are not a unitary construct, encompassing two different factors: diminished expression, and motivation and pleasure. Few works have studied the relationship between these two different negative symptoms factors and cognition , psychosocial functioning and quality of life, jointly, in patients with a first psychotic episode of schizophrenia.The objective of the present work was to study, in a sample of patients with a first psychotic episode of schizophrenia, the relationship between the negative symptoms (diminished expression and motivation and pleasure) and neurocognition, social cognition, functioning and quality of life.The study was carried out with 82 outpatients with a first psychotic episode of schizophrenia from two Spanish hospitals . The patients were assessed with the Clinical Assessment Interview for Negative Symptoms (CAINS) for evaluating diminished expression (EXP) and motivation and pleasure (MAP) symptoms, the MATRICS Consensus Cognitive Battery (MCCB) for evaluating neurocognition and social cognition, the Social and Occupational Functioning Assessment Scale (SOFAS), and the Quality of Life Scale (QLS).A negative correlation was found between neurocognition and the two negative symptoms subscales: CAINS-EXP  and CAINS-MAP ; but with social cognition only CAINS-EXP was correlated . Also, it was found a high negative correlation between SOFAS scores and CAINS-MAP ; and a medium negative correlation with CAINS-EXP . Finally, QLS score was high correlated with both CAINS subscales: CAINS-EXP  and CAINS-MAP .This study found a relationship between negative symptoms and neurocognition, social cognition, functioning and quality of life in a sample of patients with a first psychotic episode of schizophrenia. But the two different negative symptom factors, diminished expression, and motivation and pleasure, are associated differently with psychosocial functioning, but especially with social cognition where the relationship was only found with diminished expression symptoms.None Declared"}
+{"text": "The situation that has been going on in Ukraine for the past six months has led to catastrophic consequences. This forces neuroscientists and, including psychiatrists, to turn to the study of the impact of all these events on the mental health of the population of Ukraine. In 90th of XX Russian psychiatrist Y. A. Alexandrovsky expressed opinion of presence the group of so-called social-stress disorders (SSD) that was determined like psychogenic-actual for most people in definite social, economic and political situation. Most of the people in Ukraine now experience both SSD and post-traumatic stress disorder (PTSD).Most of the people in Ukraine now experience both SSD and post-traumatic stress disorder (PTSD).The method of clinic-psychopathological interview with patients who applied out-patient consultation on the chair of psychiatry.The main changes in psychic state include following behaviors and clinical implications: loss of the value of human life, which is manifested in indifference to death in lowering caution when hazardous situations, willingness to sacrifice lives without any ideals. There is unrestrained lost for pleasure and moral promiscuity, exacerbation of personality typological traits, development of hyperstenic reactions (to self-destructive non-expedient behavior), hypostenic disorders, panic reactions, depression, dissociative and conversive irregularities, loss of communicational plasticity, loss of the ability to adapt to what happens with the preservation prospects of targeted actions, manifestations of cynicism, the tendency to antisocial actions. Patients had complaints on increase anxiety, pessimistic attitudes, existential vacuum, sense of uselessness and loss of perspectives, tendency to irrational perception of reality with including mechanisms of autistic and archaic thinking.Thus, psychological status of the population of Ukraine is a model of complicated combination of SSD plus PTSD can be considered like a basis which leads to the decreasing of the individual barrier of mental adaptation with the next manifestation of different forms of psychopathological syndromes and needs further in-depth and detailed research.None Declared"}
+{"text": "The contributions in this Research Topic collectively explore the nature of functional brain connectivity and its relation to cognition, emphasizing shared mechanisms and brain complexity. Results presented here reveal common themes in how the brain dynamically reorganizes and adapts to task- and disease-related perturbations.Stylianou et al.), a dimensionality reduction technique to facilitate comparisons of oscillatory patterns across task paradigms and modalities , a new adaptation of the dynamic causal modeling (DCM) approach to capture connectivity changes during more ecological tasks such as movie watching (Nag and Uludag), a new connectivity method based on the Kuramoto model of coupled oscillators applied to network-level fMRI data , and a framework to study the relationship between functional connectivity and complexity (Das and Puthankattil).Some of the contributions present a variety of theoretical and methodological approaches to studying the relationship between connectivity, dynamics, and complexity. The articles include a novel multi-fractal functional connectivity estimation to track changes during visual pattern recognition , changes in individual differences along the language network hierarchy and their potential as biomarkers , the adaptation of the dorsal attention network to demands of a spatial attention task , the relationship between memory, depression, and inter-network connectivity , and the recovery of cognitive functions and related task networks after anesthesia .From an application perspective, contributions focus on the study of the large-scale cortical networks supporting cognition, in health and disease, including navigation subnetworks representing different types of spatial relation representations (We consider that the integration of these studies has the potential to advance our understanding of common principles governing the dynamic and complex relationship between brain connectivity and cognition.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
+{"text": "A chronic illness exerts a profound impact on an individual's physical and mental wellbeing, while also influencing their identities, familial relationships, and social responsibilities. Managing a chronic condition is a lifelong endeavor that demands substantial lifestyle adjustments, strict adherence to medication and treatment regimens, and the implementation of preventive measures. Informal caregivers, typically partners, spouses, family members, and friends, play a pivotal role in this experience: they are tasked with a range of complex and demanding responsibilities, such as responding to emergencies, mediating disagreements between patients and physicians, participating in treatment decisions, and addressing patients' emotional and practical needs. Promoting and supporting both patient and caregiver engagement is therefore vital for effective management of the disease.This Research Topic (RT) delves into the complex interplay between individuals facing chronic health conditions and their caregivers. The contributions included emphasize the intricate dynamics of patient-caregiver relationships and the interdependence between their actions and outcomes, encompass diverse populations such as patients and caregivers facing cardiac diseases, multiple sclerosis, amyotrophic lateral sclerosis, hemodialysis, and multimorbidity. The studies presented shed light on the theme of engagement by delving into the topic of caregiver burden and by presenting psychological interventions health education programs, and self-care programs aimed at increasing engagement.Golan and Vilchinsky; Rapelli, Giusti, Tarquinio, et al.; Rapelli, Giusti, Donato, et al.) explored the relationship between patient and caregiver wellbeing and different aspects of cardiac disease management. The study by Rapelli, Giusti, Tarquinio, et al. offered a scoping review of the existing psychological couple-oriented interventions conducted for patients with heart disease and their partners. The review collected 11 studies with heterogeneous designs, theoretical backgrounds, types of intervention, personnel involved, intervention formats , number of sessions, and duration. Results indicated high variability among couple-based interventions, lack of adequate details regarding the training of professionals delivering them, the contents of the interventions, and the theoretical models informing these programs. Interventions for patients with cardiovascular disease and their partners were found to moderately improve psychosocial outcomes. Furthermore, in most studies, only the patients' psychological strategies and outcomes were considered. Current contributions also revealed the stress experienced when a transplant or the implantation of an external device such as the Left Ventricular Assist Device (LVAD) is needed. The qualitative study by Rapelli, Giusti, Donato, et al. utilizes a phenomenological hermeneutic approach to understand the experience of six patient-caregiver dyads undergoing cardiac rehabilitation Four were the main themes: Being between life and death, Being human with a heart of steel, Sharing is caring (and a burden), and Being small and passive. Finally, Golan and Vilchinsky reflect on the necessity of applying a dyadic approach in the context of Left Ventricular Assist Device transplantation to enriching the understanding of patients' coping with this disease.Three of the studies included in the present RT  considered the issue of care burden in informal caregivers of patients with multiple sclerosis (MS), given the risk of impaired quality of life, physical, and mental wellbeing of this population. The authors illustrate the Family-Centered Empowerment Model  and compared it with TAU , showing that the intervention proposed does not have a favorable effect in reducing the care burden among caregivers of patients with MS. Another article  contributed to the literature about caregiver-focused interventions. The authors aimed to evaluate the effectiveness of a health education program based on the \u201cTiming it Right\u201d framework (IG) on the caregivers' care ability, emotions, and health-related quality of life in the context of haemodialysis. However, the intervention had no significant effect in alleviating care burden. Similarly, the study protocol by Gomes de Souza e Silva et al. aims to investigate the effects of a self-care education program via telerehabilitation on the burden and quality of life of caregivers of individuals with Amyotrophic Lateral Sclerosis. This program has the potential to be widely disseminated among health professionals, increasing remote monitoring of individuals with difficulty performing practical care activities.One study  and overlapping cognitive assessments of the circumstance  emerged as higher-order factors from the quotations. Second, relationship-related tactics, such as striking a balance between autonomy and equity in the couple, were frequently highlighted. Third, some couples discussed the advantages of individual strategies that focus on developing partners' resources outside of their romantic partnerships (such as creating relationships with their grandchildren or spending time in nature).Care coordination and distress increase in case of multimorbidity , the physical, psychosocial, and relational changes and aspects of threats elicited by multimorbidity also provoke significant emotional responses. The qualitative study by This Research Topic underscores the significance of recognizing chronic illness management as a collaborative experience shared by patients and informal caregivers. The studies presented shed light on the complexities of patient-caregiver relationships, offering insights into the effectiveness of interventions and the evolving needs of those navigating chronic illnesses. By adopting a dyadic perspective, healthcare professionals can better support individuals facing chronic illnesses and their caregivers and tailor care approaches to their needs. Future research should continue to explore dynamics within these partnerships and develop tailored interventions that address the multifaceted challenges they encounter.GR: Writing \u2013 original draft. CA: Writing \u2013 original draft. EG: Writing \u2013 original draft. SD: Writing \u2013 original draft."}
+{"text": "The 1978 Italian reform of psychiatric services initiated the closure of psychiatric hospitals encouraging the development of community mental health. However, there is wide variability across regions in the amount of resources devoted to community-based psychiatric care, and the range of services provided still is cause of concern.To evaluate the quality of mental health care delivered to patients with schizophrenia and related disorders taken-in-care by mental health services in four Italian regions .Thirty-one clinical indicators concerning accessibility, appropriateness, continuity, and safety were defined and estimated using healthcare utilization (HCU) databases, containing data on mental health treatments, hospital admissions, outpatient interventions, lab tests and drug prescriptions.A total of 70,586 prevalent patients with schizophrenia treated in 2015 were identified, of whom 1,752 were newly taken-in-care. For most patients community care was accessible and moderately intensive. However, care pathways were not implemented based on a structured assessment and only half of the patients received psychosocial treatments. One patient out of ten had access to psychological interventions and psychoeducation. Activities specifically addressed to families involved a third of prevalent patients and less than half of new patients. One patient out of six was admitted to a community residential facility, and one out of ten to a general hospital psychiatric ward (GHPW); higher values were identified in new cases. In general hospitals, one-fifth of the admissions were followed by readmission within 30 days of discharge. For two- thirds of patients continuity of community care was met, and six times out of ten a discharge from a GHPW was followed by an outpatient contact within two weeks. For cases newly taken-in-care the continuity of community care was uncommon, while the readiness of outpatient contacts after discharge was slightly more frequent. Most of the patients received antipsychotic medication, but their adherence to long-term treatment was low. Antipsychotic polytherapy was frequent and the control of metabolic side effects was poor. The variability between regions was high and consistent.The Italian mental health system could be improved by increasing the accessibility to psychosocial interventions, improving the quality of care for newly taken-in-care patients, focusing on somatic health and mortality, and reducing regional variability. Clinical indicators demonstrate the strengths and weaknesses of the mental health system in these regions, and, as HCU databases, they could be useful tools in the routine assessment of mental healthcare quality at regional and national levels.None Declared"}
+{"text": "As of November 2022, over 417 397 confirmed cases and 2631 deaths related to coronavirus disease (COVID-19) were reported in Pacific island countries and areas (PICs). Most PICs have faced challenges accessing therapeutics recommended for the treatment of COVID-19 due to their high demand worldwide and supply chain constraints.The World Health Organization (WHO) coordinates and provides tailored technical and operational support to 21 PICs. Since the start of the pandemic, WHO has worked with partners to establish a mechanism to ensure equitable access to three novel COVID-19 therapeutics  for lower-income countries, including 11 eligible PICs.WHO coordinated the requests, procurement and distribution of the three novel therapeutics. In addition, WHO supported PICs by providing trainings in clinical management of COVID-19, developing critical supply needs estimates, and facilitating regulatory approval of clinical therapeutics, including emergency use authorization.The main barriers to procurement of novel COVID-19 therapeutics were identified as prolonged negotiations with licence holders, sourcing funding, the high cost of therapeutics and limited capacity to provide safety monitoring.Uninterrupted supply and availability of essential medicines in the Pacific region is dependent on external and local sourcing. To overcome procurement barriers and ensure access to novel COVID-19 therapeutics in PICs, WHO\u2018s pandemic support to Member States focused on strengthening regulatory requirements, safety monitoring and supply chain activities. The first case of coronavirus disease (COVID-19) in the Pacific was reported in March 2020 in French Polynesia. . , which collectively are home to 3.2 million people spread across an ocean that covers 30% of Earth\u2019s surface.  coordinates and provides tailored technical and operational support to 21 PICs  Food and Drug Administration (FDA), the European Medicines Agency (EMA), the Therapeutic Goods Administration of Australia, as well as the New Zealand Medicines and Medical Devices and Safety Authority (MEDSAFE). At the time of writing, only tocilizumab, molnupiravir and nirmatrelvir/ritonavir were available for WHO procurement under the emergency use listing. . The webinars covered topics such as indications for use, storage conditions, care pathways, therapeutic management of severe and non-severe cases, and safe and appropriate use, as well as country experiences. Trainers comprised experts and clinicians from WHO DPS, the WHO Regional Office for the Western Pacific, the Australian Therapeutic Goods Administration, the Central and Northern Adelaide Local Health Networks  the Royal Alfred Hospital , the University of South Australia , New Zealand MEDSAFE, the WHO Global Outbreak Alert and Response Network, Fiji, the Marshall Islands, FSM and Palau. More than 150 health-care professionals including nurses, medical doctors, pharmacists and health advisers attended the webinars. Attendees represented 12 PICs \u2013 Fiji, Kiribati, the Marshall Islands, FSM, Nauru, Niue, Papua New Guinea, Solomon Islands, Tokelau, Tonga, Tuvalu and Vanuatu. The webinars provided a platform not only for participants to learn lessons from countries such as Australia and New Zealand , but also for neighbouring countries to share information and their experiences of therapeutics and clinical management of COVID-19 cases.In the Pacific, the level of regulatory systems development for medicines is either non-existent or very limited. .  and corticosteroids, (Several PICs experienced difficulties in procuring an adequate supply of some essential medicines required for treatment of moderate-to-severe COVID-19, in particular dexamethasone, (In addition to supply chain issues, the COVID-19 pandemic highlighted the limited capacity of PICs to conduct safety monitoring activities for novel therapeutics. Although existing data suggest that newly introduced COVID-19 therapeutics were generally well tolerated, (Finally, the pandemic phase focused attention on the potential risk to public health posed by the general absence of robust quality control and assurance systems for medical products that exist across the Pacific. The identification of batches of falsified COVID-19 therapeutics in countries of neighbouring regions (This report has some inevitable limitations. As it describes the experience of PICs, due to the huge diversity in social systems, health-care provision, economic factors and geography, the findings might not be generalizable to all countries in the Pacific. Likewise, each PIC is unique in its culture and customs, and therefore even within the group of PICs, the responses and lessons learned may not apply universally. Nevertheless, in a field with a paucity of literature, this report not only contributes to new knowledge but also provides some important lessons for countries that share similar characteristics, namely geographical isolation and limited regulatory systems, in terms of the management of future infectious disease outbreaks in which novel therapeutic interventions are required.Throughout the COVID-19 pandemic, WHO DPS, in collaboration with partners, has delivered tailored support to PICs. This support has taken the form of assistance with procurement and emergency use authorization of novel therapeutics; provision of clinical management guidance and technical support; and regulatory system strengthening, in particular building capacity in safety monitoring and quality assurance programmes. Looking ahead, WHO DPS support should continue to be focused on strengthening regulatory requirements, safety monitoring and supply chain activities to ensure access to and implementation of novel COVID-19 therapeutics in all PICs. To ensure sustainable access to quality-assured therapeutics in the event of future pandemics, it will be important to continue to develop methodologies to estimate critical supply needs and demands."}
+{"text": "Studies have explored the correlates of insecticide-treated nets in Nigeria. The few studies that focused on Northern Nigeria mostly examined individual correlates, but largely ignored the community correlates. Also, the persistence of armed insurgencies in the region calls for more research attention. This study examines the utilization and the associated individual and community factors of insecticide-treated nets in Northern Nigeria.The study adopted a cross-sectional design. Data were extracted from the 2021 Nigeria Malaria Indicator Survey (NMIS). A weighted sample size of 6873 women was analysed. The outcome variable was the utilization of insecticide-treated nets. The explanatory variables selected at the individual/household level were maternal age, maternal education, parity, religion, sex of head of household, household wealth, and household size. The variables selected at the community level were the type of place of residence, geo-political zone of residence, the proportion of children under five who slept under a bed net, the proportion of women aged 15\u201349 who heard malaria media messages, and the community literacy level. Two variables, namely, the number of mosquito bed nets in the household, and the number of rooms used for sleeping were included for statistical control. Three multilevel mixed-effect regression models were fitted.The majority of childbearing women (71.8%) utilized insecticide-treated nets. Parity and household size were the significant individual/household characteristics associated with the utilization of insecticide-treated nets. The proportion of under-five children in the community who slept under mosquito bed nets, and the geopolitical zone of residence were significant community correlates of the use of insecticide-treated nets. In addition, the number of rooms for sleeping, and the number of mosquito bed nets in the households were significantly associated with the utilization of insecticide-treated nets.Parity, household size, number of sleeping rooms, number of treated bed nets, geo-political zone of residence, and proportion of under-five children sleeping under bed nets are important associated factors of the utilization of insecticide-treated nets in Northern Nigeria. Existing malaria preventive initiatives should be strengthened to target these characteristics. Anopheles gambiae, Anopheles arabiensis, and Anopheles funestus [The transmission of malaria is endemic in most low-and-middle-income countries \u20133. In Nifunestus \u20136. Globafunestus . In addifunestus , 9. Amidfunestus \u201313, whicThe malaria preventive interventions being implemented seek not only to achieve malaria control but also to ensure the elimination of malaria in the country. These preventive interventions rest largely on the scaling-up of existing preventive initiatives, such as Indoor Residual Spraying (IRS), the universal coverage of Insecticidal-Treated Nets (ITN), and the use of Intermittent Preventive Treatment in pregnancy (IPTp) . EvidencOne key factor that occasioned the lack of universal utilization of malaria preventive interventions in the country is a poor understanding of the associated factors of the preventive interventions. Though, numerous studies have explored the correlates of different malaria preventive interventions in Nigeria and other countries \u201325. HoweOne, armed insurgency, such as the Boko Haram insurgency, destroys existing health facilities by reducing the numbers of healthcare personnel, the availability of essential drugs for malaria treatment, hinders access to appropriate care and makes the practice of preventive measures difficult \u201333. Two,The objective of the study was, therefore, to examine the prevalence and the associated individual and community factors of insecticide-treated nets in Northern Nigeria. The focus is on insecticide-treated nets because among the dominant preventive interventions in Nigeria, it is more widely accessible to Nigerian households, and freely distributed to households during malaria sensitization campaigns , 40. Tho. [The findings in the study will provide additional inputs for developing appropriate strategies to boost the use of insecticide-treated nets in Northern Nigeria. The study was guided by the question: what are the associated factors of the utilization of insecticide-treated nets in Northern Nigeria? The socio-ecological model developed by McLeroy et al.  anchored. , 46.https://dhsprogram.com/pubs/pdf/MIS41.pdf. Overall, interviews were completed with 14,476 women aged 15\u201349 in 13,727 households. The individual and household datasets of the 2021 NMIS were merged in the study because some of the variables of interest were not available in the individual dataset. However, some women were excluded from the study. These are women from the southern region, women who do not have a mosquito bed net for sleeping, and women practicing traditional or other faiths, who were excluded due to their insignificant proportion in the population covered. The study thus analysed a weighted sample size of 6,873 women.The study adopted a cross-sectional design. The design entails analysing the 2021 Nigeria Malaria Indicator Survey (NMIS) data to describe the malaria-related characteristics of childbearing women in Northern Nigeria and to examine the possible associations between the characteristics and the use of insecticide-treated nets in the region. The survey was executed by the National Malaria Elimination Programme (NMEP) under the auspices of the Federal Ministry of Health (FMoH), and in collaboration with the National Population Commission (NPC) . The genThe outcome variable in the study is the utilization of insecticide-treated nets. The utilization was measured by asking women whether they slept under a mosquito bed net the night preceding the survey. This yielded a binary response, with \u2018yes\u2019 indicating that the respondent utilized the intervention, and \u2018no\u2019 indicating otherwise. Existing studies have applied this measure to operationalize the utilization of insecticide-treated nets , 48, 49.The explanatory variables were selected at the individual/household and community levels based on findings in existing studies that the utilization of preventive interventions is influenced by different factors operating at different levels of the social environment, particularly at the individual/household, and community levels \u201351. The The variables selected at the community level were the type of place of residence , geo-political zone of residence , the proportion of under-five children in the community who slept under mosquito bed nets , the proportion of women age 15\u201349 exposed to malaria media messages in the community , and community literacy level . These variables have also been identified as important correlates of the utilization of malaria preventive interventions , 50, 57.Statistical analyses were performed at different levels using Stata version 14 . At the Table Respondents from the north-west geo-political zone constitute more than half of the women (54.0%), while women from the north-central geo-political zone were the least sampled (18.8%). The majority of respondents reside in rural areas (72.9%). More than one-third of respondents live in communities with a high proportion of children under 5 sleeping under a mosquito net compared to those who reside in communities with either a low or moderate proportion of under 5 children who slept under a mosquito bed net. The proportions of low, medium, or high exposure to media messages about malaria were similar in the communities although the proportion residing in communities with moderate exposure was higher among the respondents (34.8%). The proportion of respondents who reside in communities with low literacy levels was higher among the sampled women (35.7%). Nearly half of the respondents live in households with two or fewer mosquito bed nets (47.3%). Likewise, more than two-fifths of the respondents live in households that possessed three to five mosquito bed nets. The households of the majority of respondents had three or fewer rooms for sleeping (67.6%).Table The association between the proportion of under-five children who slept under a bed net in the community and the use of insecticide-treated nets by childbearing women was positive, with a consistent rise in the level of use as the proportion of children who slept under a bed net in the community increased. In contrast, the proportion of reproductive-age women exposed to media messages about malaria reveals a mixed association with the use of insecticide-treated nets. Likewise, community literacy levels had a mixed association with the utilization of insecticide-treated nets. At the low and moderate literacy levels, a slight rise in the level of utilization was observed, but a dip occurred at the high literacy level. The geopolitical zone of residence had a positive association with the use of insecticide-treated nets, with a higher level of use observed in the northeast zone. A higher level of use of insecticide-treated nets was observed in the rural areas compared to the urban areas showing a significant positive association. A significant positive association was observed between the number of mosquito bed nets and their utilization, while the number of rooms used for sleeping was negatively associated with the use of insecticide-treated nets. All the variables showed a VIF value of less than ten and were selected for the multilevel modeling. However, religion, sex of the head of household, and proportion of women exposed to media messages about malaria were excluded having shown no statistical significance at the bivariate level.Table In Model 2, higher parity remained significantly associated with higher odds of the use of insecticide-treated nets, while a large household size remained significantly associated with lower odds of the use of insecticide-treated nets. Other individual/household characteristics revealed no statistical significance. Two community-level characteristics, namely, the proportion of under five children who slept under a mosquito bed net in the community and geopolitical zone of residence were significantly associated with the utilization of insecticide-treated nets. However, the proportion of variation in the use of insecticide-treated nets attributable to the community factors dropped compared to the proportion in Model 1 (ICC\u2009=\u20090.216).In the full model (Model 3), on one hand, two individual/household characteristics, namely, parity and household size, were significantly associated with the use of insecticide-treated nets. On the other hand, two community characteristics, namely, the proportion of under-five children who slept under a mosquito bed net in the community and the geopolitical zone of residence were significant correlates of the use of insecticide-treated nets. As parity was increasing, the odds of utilizing insecticide-treated nets also increased consistently. Childbearing women living in large-sized households were associated with lower odds of utilizing insecticide-treated nets . As the proportion of under-five children who slept under mosquito bed nets in the community increased, the odds of utilizing insecticide-treated nets by childbearing women consistently increased. The odds of utilizing insecticide-treated nets were higher in the northeast zone  and northwest zone  compared to the northcentral zone. Also, an increasing number of mosquito bed nets in households was associated with higher odds of their utilization. In contrast, increasing the number of rooms for sleeping in households was associated with lower odds of utilizing insecticide-treated nets.The study examined the prevalence and associated factors of the utilization of insecticide-treated nets in Northern Nigeria. The study found a utilization level lower than the observed average for the region in a recent Nigerian study . HoweverThe study further revealed that some individual/household and community characteristics are important correlates of the utilization of insecticide-treated nets. One, gender matters in the utilization of insecticide-treated nets. It is reasoned that since more females compared to males use malaria preventive interventions , women aThree, community contexts are source of variations in the level of use of insecticide-treated nets, though not in a substantial proportion. These community factors include the geo-political zone of residence and the proportion of under-five children in the community who slept under treated bed nets. The geopolitical zone of residence, particularly being residents in the states in the northeast and northwest zones was found to the drive utilization of insecticide-treated nets in line with findings in two recent studies , 51. ThiThe paper assessed the prevalence and correlates of the utilization of insecticide-treated nets in Northern Nigeria based on data extracted from a nationally representative survey. The study revealed that the utilization of insecticide-treated nets was not universal among childbearing women in the region and that some individual-level and community-level characteristics were associated with the utilization of insecticide-treated nets. Improving the level of utilization in the region requires targeting more individual characteristics of childbearing women, as well as embarking on more community engagements to amplify governments and non-government strategies to boost utilization of malaria preventive measures."}
+{"text": "In Egypt, academic organizations, professional societies, and research groups develop clinical practice guidelines (CPGs) in order to improve patient quality care and safety. Although important improvements have been made over the past years, many of these consensus-based guideline documents still lack the transparency and methodological rigor of international standards and methodologies recommended by reference evidence-based healthcare and guideline organizations like the Guidelines International Network.In the Egyptian Pediatric Clinical Practice Guidelines Committee (EPG), we have adopted one of the CPG formal adaptation methodological frameworks named the \u2018Adapted ADAPTE\u2019, relevant CPG resources , and involved key stakeholders including clinical and healthcare topic experts and guideline methodologists in producing 32 trustworthy national evidence-based CPGs and one protocol customized to the healthcare context and services provided for Egyptian children. An EPG online website was launched to make these CPGs available and accessible as CPG summaries for pediatricians and relevant healthcare providers.The lessons learned, enablers, challenges, and solutions relevant to Egyptian National Pediatric CPGs identified in this paper could be used to address and enrich the debate on pediatric high-quality CPGs, especially for countries of similar contexts and systems.The online version contains supplementary material available at 10.1186/s42269-023-01059-0. Clinical practice guidelines (CPGs) are statements that include recommendations for improving patient care. A systematic review of evidence and an assessment of the benefits and costs of alternative care options inform these statements (Institute of Medicine (US) Committee on Standards for Developing Trustworthy Clinical Practice Guidelines High-quality evidence-based CPGs are known to support the clinical decisions of relevant healthcare providers and to improve patient outcomes  and adaptation (when there are existing and published one or more eligible CPGs)  (and the former ADAPTE Collaboration) as \u201cthe systematic approach to the modification of a guideline(s) or recommendation(s) produced in one cultural and organizational setting for application in a different context. Adaptation may be used as an alternative to de novo guideline development  existing guideline/s to suit the local context)\u201d ], CPG tools , or CPG standards . Yao et al.  reportedWang et al.  coined tTo date, there have been several institutional and national CPG adaptation initiatives in the Eastern Mediterranean Region. One of the early CPG formal adaptation methodological frameworks that were applied in the Arab Republic of Egypt was the ADAPTE and one of its modified versions: The \u2018Adapted ADAPTE\u2019 , 9 modules, and 24 steps. The \u2018Adapted ADAPTE\u2019 was proposed by the founding members of the Alexandria Center for Evidence-Based Clinical Practice Guidelines at Alexandria University, Egypt and it included the same overall framework of the original ADAPTE in addition to 3 modified tools, 3 new tools, and 4 alternative steps  was established and conducted several strategic planning meetings and discussions and launched the first pediatric national CPG program with the Supreme Council of Egyptian University Hospitals  marks the first national and collaborative initiative for the generation of Pediatric CPGs using an evidence-based methodology in Egypt.After the foundation of the EPG under the auspices of the Supreme Council of Egyptian University Hospitals and the Armed Forces College of Medicine, it added 5 EPG subcommittees for (i) strategic planning, (ii) CPG advisory (methodology), (iii) implementation, (iv) publication and research, and (v) quality control.The strategic plan for national pediatric evidence-based CPGs included: (i) identifying the national healthcare priorities  in the field of pediatrics and child health; (ii) identifying a scientifically rigorous and evidence-based methodology for CPGs; and (iii) scope of function, roles, and responsibilities of the members of the EPG and the subspecialty CPG groups.The EPG decided to use the CPG adaptation methodology, specifically the \u2018Adapted ADAPTE\u2019 methodological framework. The Adapted ADAPTE CPG adaptation process is summarized in Fig.\u00a0The founding members reached out and recruited representative faculty staff from the Departments of Pediatrics of 14 Egyptian Universities and one National Research Centre, including, in alphabetical order, the faculties of medicine at the universities of Ain Shams, Al-Azhar, Alexandria, Assiut, Benha, Cairo, Helwan, Mansoura, Menoufia, Minia, October 6, Port Said, Suez Canal, and Zagazig, as well as the Ministry of Health  with a clinical lead and several contributors from multiple universities in the same subspecialty  (in contrast to the known term Guideline Development Group or GDG that is saved for groups that use the de-novo development methodology), and (2) The External Review Group (or ERG).The CPG adaptation project involved the collaboration of two main distinct and independent groups: (1) The Each GAG was divided into two subgroups: (i) The Clinical expert subgroup, which includes the Clinical lead of the GAG and its members nominated by the related EPG Pediatric subspecialty group with the EPG Chairman, and (ii) The CPG Methodology supervision subgroup that includes faculty staff and pediatricians with expertise as CPG Methodologists and working experience with the Adapted ADAPTE.Most members of the EPG CPGs\u2019 GAGs and ERGs are staff of Egyptian Universities, University Hospitals, National Research Centres, the Ministry of Health, or their clinical and methodological networks. They have contributed to the EPG CPG projects on a voluntary basis not related to or funded by any pharmaceutical company, industrial body, or research grants. Some members of the ERGs were international clinical or methodological experts. The declaration of the conflict of interests of all contributors was transparent.The recruitment process for EPG members was open to any interested child healthcare provider primarily pediatricians and others like clinical pharmacists, and nurses as relevant to the specific health topics representing university hospitals and different healthcare sectors and facilities in Egypt.The EPG has completed five waves of parallel CPG adaptation projects from 2018 to date that has produced 32 adapted national Evidence-Based CPGs for high-priority pediatric health topics in Egypt, in addition to a consensus-based national protocol for COVID-19 (including four versions so far)  and other social media networks.Furthermore, as faculty teaching staff, chairpersons of pediatrics or child healthcare departments, senior consultants, or directors in their institutions, EPG members represent clinical and quality champions supporting CPG implementation. Detailed post-implementation findings for each CPG health topic will be reported individually.The EPG has future plans to evaluate the success of uptaking and implementing its CPGs in real pediatric practice and evaluate their accessibility to the relevant healthcare providers and target users through interventions like (i) Knowledge, Attitude, and Practices (KAP) surveys, (ii) audit and feedback, and (iii) Plan-Do-Check-Act (PDCA) Quality Improvement Cycles.Despite the fact that the COVID-19 pandemic posed challenges to education, research, and other projects and services, the EPG different GAG clinical and methodology members expressed great enthusiasm and resilience by shifting all of the face-to-face meetings and activities to online Zoom meetings and a set of WhatsApp groups for each GAG in addition to the main EPG group  was recently established in 2018 as part of the Universal Health Insurance System in Egypt. GAHAR published seven handbooks of accreditation standards covering different healthcare services throughout which it recommended adherence to CPGs, protocols, and policies and procedures .Lack of financial support dedicated to developing, disseminating, and implementing National CPGs to cover costs like design and printing and article processing fees for CPGs and other potential implementation resources such as National CPGs\u2019 website or database maintenance and CPG mobile Apps.There is lack of a national agreement on the process of development, adaptation, official approval, Implementation, revision and update, and auditing of National Guidelines in Egypt.There is no national body or center assigned to develop, revise, evaluate, validate, and/or officially approve National Guidelines in Egypt similar to the examples of the National Evidence-Based Medicine Center of the Saudi Health Council in Saudi Arabia, the Ministry of Public Health in Qatar, the National Authority for Assessment and Accreditation in Healthcare in Tunisia, the National Institute for Health and Care Excellence (NICE) in the United Kingdom, and the National Health and Medical Research Council (NHMRC) in Australia , Curative Care Organization (CCO), Teaching hospitals and institutes organization (THIO), Health Insurance Organization (HIO), Ministry of Higher Education (MOHE) , and Ministry of Defense (MoD) and Ministry of Interior (MoI). The private sector has the Private medical insurance, Household out-of-pocket payments, and Non-Governmental Organizations. This pluralistic healthcare system poses great challenges to implementing National Guidelines in Egypt. Universal health insurance (UHI) is a new entity established to provide Universal Health Insurance services for all Egyptians and is expected to address some of these barriers Saleh .There is lack of integration and collaboration with relevant national initiatives like the Health Technology Assessment (HTA) Institutionalization by The Egyptian Authority for Unified Procurement, Medical Supply and the Management of Medical Technology (UPA) in collaboration with NICE International  and the National Egyptian Network Pediatric Stroke and Hemiplegia Registry (NENPSHR), there is a lack of relevant national registries for other high-priority pediatric health topics that in turn disable our estimates for diagnostic and management difficulties in these topics  with the CPG evidence-based recommendations as they fear that CPGs adherence may limit their clinical autonomy, flexibility and individualized approach  and the International Network of Agencies for Health Technology Assessment (INAHTA)].Collaborate with similar national guidelines centers in the Eastern Mediterranean Region to build capacity and exchange experiences with consideration of the similarities and differences between the health systems.Integrate the EPG CPGs into the GAHAR Accreditation Standards that are related to child healthcare services and facilities.Integrate formal training, modules, and courses of evidence-based healthcare and CPG tools and skills into the curricula of undergraduate and postgraduate students of Health Colleges and Faculties like Medicine, Pharmacy, Nursing, etc. [a good example is the recently launched International Guideline Development Credentialing & Certification Program (or INGUIDE)] INGUIDE .Integrate and align relevant national initiatives to achieve the balance between clinical evidence through CPGs and economic evidence through HTAs (Mason et al. We are, on behalf of the EPG, proposing the following recommendations and solutions to address the aforementioned barriers to National Pediatric CPGs in Egypt and to open them for discussion in countries of similar contexts and systems:The lessons learned enablers, challenges, and solutions relevant to Egyptian National Pediatric CPGs identified in this paper could be used to address and enrich the debate on pediatric high-quality CPGs, especially for countries of similar contexts and systems.Additional file 1. Recognition and Honor List."}
+{"text": "For many years, the central nervous system (CNS) was thought to be immune-privileged due to the presence of the blood-brain barrier (BBB) and the absence of lymphatic vasculature. However, recent studies have uncovered the intricate interactions between the CNS and the immune system. In particular, microglia\u2013resident immune cells in the brain\u2013share developmental origins and functions with monocytes in the immune system, playing crucial roles in monitoring and modulating neuronal activity  produced by the choroid plexus in the brain can enter the cervical lymph nodes and cranial bone marrow via the dura lymphatic system   inhibits inflammatory signaling pathways and promotes anti-inflammatory polarization of microglia in ischemic rats.To date, rehabilitation is a widely used and effective treatment for brain injury in the clinic. Rehabilitation programs include stimulation with electricity, magnetism, light, and heat on the CNS and peripheral nervous system (PNS), along with physical therapy, virtual reality, motion imagination, and so on. Although the neuroprotective mechanism of rehabilitation involves multiple targets and multiple factors, inflammatory regulation is its pivotal process. Transcranial-direct-current-stimulation (TDCS) can decrease microglial activation and reduce the release of pro-inflammatory cytokines in experimental stroke models , which can proliferate, migrate, and differentiate into neural cells, can take part in nerve repair and neural plasticity by replacing the injured neural cells (Liu et al., Overall, neuroimmune communication is correlated with the physiological functions of various tissues and organs and the internal environmental balance. Dysregulation of neuroimmune communication homeostasis is both the underlying pathological mechanism and the potential therapeutic target in brain injury. A thorough clarification of the cellular and molecular mechanisms of neuroimmune communication in brain injury is an essential and necessary endeavor in the search for new therapeutic targets for this type of disorder.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
+{"text": "Acute exacerbations of chronic bronchitis (AECB) are recurrent and potentially severe medical events for the 13 million people in the United States who have chronic bronchitis. Medical resource use associated with AECB can have a substantial economic impact on the patients, health care system, and society overall.To evaluate literature on the economic impact of AECB in terms of cost of illness, cost of treatments, and cost-effectiveness.A MEDLINE literature search was conducted for studies of chronic bronchitis and costs. Reference lists of identified articles were also retrieved for review.Eight published studies were identified: 2 cost-of-illness studies, 1 comparative cost study, and 5 cost-effectiveness studies. Important drivers of costs associated with AECB include hospitalization and choice of antibiotics. In mild to moderate AECB, patient adherence with therapy is essential to consider when selecting treatment. The antibiotic with the lowest acquisition cost has not been shown to be the most cost effective, as adherence and clinical outcomes, particularly re-hospitalization rates, differ.Further research in these areas is needed to guide clinical decision making and the conduct of disease management programs."}
+{"text": "Dear Editor,A Caucasian woman, 54 years old, Fitzpatrick phototype II, complained of a painful lesion on the right malar region, with rapid growth and aggressive behavior, which had appeared three months before. The patient lived in a rural area and worked in agriculture, referring chronic sun exposure due to her working conditions. When questioned, she denied history of trauma at the site of the lesion, previous skin cancer, immunosuppression, and exposure to artificial radiation. Dermatological examination showed an infiltrated and painful erythematous plaque with exudation, crusts, ulceration, and telangiectasias in the malar region extending to the right nasal ala . Skin daThe immunohistochemical analysis showed positivity for cytokeratin 5/6 and p63; and was focally positive for BerEp4, EMA, and factor XIIIa; with negativity for adipophilin, androgen receptor and CEA , confirmCutaneous squamous cell carcinoma (SCC) is classified into many subtypes, with a wide range of clinical manifestations ranging from indolent growth to aggressive tumors with significant metastatic potential.Cutaneous clear-cell SCC is a rare neoplasia the etiology of which is still incompletely understood. This variant was described in 1980 by Kuo.SCC usually manifests itself on photo exposed areas of elderly Caucasian men with a history of chronic sun exposure and multiple skin neoplasms.Clear-cell SCC can be classified into three variants: keratinizing (type I), non-keratinizing with no connection to the epidermis (type II), and pleomorphic (type III).On histopathology, the atypical clear cells showed evident nuclear pleomorphism, squamous differentiation foci, and areas of acantholysis, with some dyskeratotic cells amidst pseudo glandular spaces.It is difficult to define the prognosis of this rare variant, as few cases were published in the literature up to 2022. Cohen et al. (2008) suggested that human papillomavirus (HPV) infection may be associated with tumor oncogenesis, but only two reported cases were associated with this virus.In conclusion, the present study describes the atypical case of a 54-year-old woman with a facial neoplasm compatible with clear cell SCC, histopathologically mimicking sebaceous carcinoma. Both dermatologists and dermatopathologists must be aware of the peculiarities of this SCC variant, which grew fast and was quite aggressive in the present report.None declared.Emily Neves Souza: Design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; critical review of the literature; critical review of the manuscript.Lucia Martins Diniz: Design and planning of the study; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied case; critical review of the literature; critical review of the manuscript; approval of the final version of the manuscript.Luana Amaral de Moura: Design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; critical review of the literature.Alexandre Calegari Oliosi: Design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; critical review of the literature.Marcela Sc\u00e1rdua Sabbagh de Azevedo: Design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; critical review of the literature.M\u00e1rgya Neves Souza: Design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; critical review of the literature.None declared."}
+{"text": "Obsessive-compulsive and related disorders (OCRDs) constitute a group of psychiatric conditions characterized by obsessive thoughts and/or compulsive behaviors. In DSM-5, the section on OCRDs is narrowly defined, including obsessive-compulsive disorder (OCD), body dysmorphic disorder (BDD), hoarding disorder (HD), trichotillomania (TTM) or hair-pulling disorder, and skin-picking (excoriation) disorder (SPD) . The ICDWhile significant progress has been made in understanding these underrecognized disorders, there are still aspects not yet fully understood. This Research Topic in Frontiers in Psychiatry aimed to shed light on the current state of knowledge on OCRDs in general community and clinical samples of all ages. This Research Topic presents nine manuscripts, including a brief research report, a clinical trial, several original research papers, and a systematic review, from experts worldwide.Strappini et al. investigated the therapeutic alliance as a component of treatment in OCD. Their systematic review and meta-analysis provided evidence of an interactive effect between the therapeutic alliance and outcomes of cognitive behavior therapy (CBT) in patients with OCD. They recommended that future studies should focus on refinement of the temporal assessment of the alliance, in larger samples, and measurement of other interacting variables, to enrich the current understanding of therapeutic change factors that could benefit evidence-based treatment.Liao et al. provided evidence of satisfactory psychometric properties of the Family Accommodation Scale Self-rated version (FAS-SR) in a large group of patients with OCD and relatives, suggesting that this scale can assist in the evaluation and treatment of OCD.In addition to the therapeutic relationship, the relationship between OCD and family dynamics has also attracted increasing attention from researchers. The concept of family accommodation (FA) refers to family members' participation in patients' rituals and accommodating their compulsions to alleviate their anxiety. Addressing FA is an important part of the treatment plan. Hollmann et al. demonstrated the effectiveness of internet-based CBT in German children and adolescents with mild to moderate OCD.CBT including exposure exercises with response prevention (E/RP), is the established treatment of choice for OCD. However, there are many barriers to accessing CBT, including lack of availability, lack of experience of service providers, and financial and time constraints. Internet-based psychotherapy could help overcome some of these barriers and Wang et al. explored the moderating effect of executive functioning on the relationship between anxiety and compulsive checking in adults with OCD. The study suggested that anxiety symptoms play a negligible role in explaining compulsive checking in individuals with OCD with relatively strong visuospatial working memory ability, but a substantial role in explaining compulsive checking in individuals with relatively weak visuospatial working memory. These findings encourage further research regarding how cognitive vulnerability factors of OCD and emotional factors interact to induce or maintain different OCD symptoms, providing additional insights into the mechanisms underpinning OCD.Changing direction from investigations of treatment to the mechanisms underpinning OCD, Kang et al. used survey to investigate BDD and depression in male university students in Malaysia. The study found that a significant proportion exhibited symptoms of BDD and depression, with BDD concerns mainly related to dissatisfaction with their height, which significantly correlated with the severity of depressive symptoms. This study responds to the quest for more research on the epidemiology of mental disorders among male adolescents, and highlights the importance of better support services.Addressing the paucity of research on, and low treatment rates of, mental illnesses in men, Brennan et al. used a qualitative approach to explore the lived experiences of individuals with BDD (In press). Three themes were identified: being consumed by the disorder, the flawed self, and intolerance of uncertainty about appearance, and were discussed in relation to the cognitive-behavioral model.In another contribution to this Research Topic on OCRDs, Aquino and Lins investigated the association between problematic buying/shopping with the Big Five's personality factors, during the COVID-19 pandemic, using an online survey of Portuguese adults. Regression analysis revealed significant correlations between various instances of buying/shopping, such as impulsive buying, compulsive buying, and panic buying, and some of the Big Five traits, highlighting the potential for improved understanding of these traits to inform preventive measures and effective treatment approaches.Rocha et al. conducted a survey on the association between early maladaptive schemas (EMS) and compulsive and impulsive buying in young adults from Portugal. They found the overvigilance and inhibition schema was the main predictor of both impulsive and compulsive buying and that impaired limits was negatively associated with these tendencies. Coping mechanisms within this context were also explored.Both aforementioned studies contribute to the conceptualization and study of problematic buying/shopping tendencies in populations other than Western, Educated, Industrialized, Rich, and Democratic (WEIRD) samples.Di Ponzio et al. reported on the positive effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) over the left DLPFC in Italian individuals with OCRDs, including SPD, TTM and HD. This study suggests that this rTMS protocol is a promising treatment option for OCRDs and highlight common circuits involved in these disorders.In conclusion, the manuscripts included under this Research Topic cover a diverse range of themes, from the mechanisms underlying OCRDs, to the quest for personalized treatment approaches across the lifespan, while also addressing the misconception that these disorders are merely bad habits. The authors emphasized the need to further elucidate the etiologies and lifespan trajectories of OCRDs, as well as the development of eHealth treatment approaches. Nonetheless, this initiative demonstrates the progress made through global efforts, employing rigorous methodological standards, which can enhance clinical practice in addressing the unmet needs of patients throughout their lifetime.CL: Writing\u2014original draft, Writing\u2014review and editing. KP: Writing\u2014review and editing. EG: Writing\u2014review and editing."}
+{"text": "Axial spondyloarthritis (axSpA) is a subtype of SpA that mainly affects the sacroiliac joints and the spine. One of the hallmarks of axSpA is radiographic progression, which refers to the progressive structural damage seen on imaging tests. Radiographic progression is associated with increased disability, quality of life, and higher healthcare costs . The datKhmelinskii et al. reviewed the role of various imaging modalities in the diagnosis, classification, and monitoring of axSpA. They highlighted the advantages and limitations of X-rays, MRI scans, computed tomography (CT), and ultrasound, and discussed the use of various scoring systems, such as the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS), the Berlin MRI score. They concluded that a combination of imaging tests and clinical assessments is necessary for accurate and timely diagnosis and monitoring of axSpA, and that new imaging techniques and biomarkers are promising avenues for future research.The diagnosis of axSpA is based on a combination of clinical features, laboratory tests, and imaging findings. Imaging techniques play a crucial role in detecting and monitoring the spinal and sacroiliac joint inflammation and structural damage in axSpA. Kang et al. used group-based trajectory modelling and decision trees to identify the patterns and predictors of radiographic progression in patients with ankylosing spondylitis (AS). They classified the patients into four distinct trajectory groups based on the mSASSS scores over 10 years of follow-up: no progression, slow progression, moderate progression, and rapid progression. They found that male sex, older age, longer disease duration, elevated C-reactive protein (CRP), and higher baseline mSASSS scores were associated with a higher risk of radiographic progression. They also developed decision trees that showed the most important predictors of each trajectory group. This study provides valuable insights into the heterogeneity of radiographic progression in AS/r-axSpA and the potential for personalized risk prediction.Radiographic progression is a major concern in the management of axSpA, as it can lead to irreversible structural damage and functional impairment. Therefore, identifying the predictors of radiographic progression is an important research area. Lee et al. investigated the impact of pregnancy on radiographic progression in 36 women with r-axSpA using CT scans of the spine and sacroiliac joints before and after pregnancy. They found that pregnancy did not significantly affect radiographic progression, as measured by the mSASSS and New York criteria scores. They also observed a trend towards decreased inflammation scores during pregnancy, suggesting a potential beneficial effect of pregnancy on disease activity. However, this study has some limitations, such as the small sample size, the lack of a control group and the imaging technique (CT) adopted.AxSpA disease onset is frequently observed in childbearing age. Therefore, pregnancy can affect the course and outcome of axSpA. Nam et al. explored the impact of smoking status on radiographic progression in patients with AS/r-axSpA who received tumor necrosis factor inhibitors (TNFi) treatment. They found that current smokers had a higher risk of radiographic progression, as measured by the mSASSS scores, than former or never smokers. They also observed that current smokers had lower serum TNFi levels and higher CRP levels than non-smokers, indicating a possible mechanism for the detrimental effect of smoking on treatment response and radiographic progression. This study highlights the importance of smoking cessation in the management of axSpA.Smoking is a well-known risk factor for radiographic progression in axSpA . Unlike In conclusion, radiographic progression in axSpA is a complex and multifactorial process that affects the spine and sacroiliac joints and the articles in this topic show crucial role of imaging in the diagnosis and classification, the effect of smoking and pregnancy on radiographic progression and help to predict prognosis in patients with AS. Additionally, recent studies have identified several risk factors and predictors of radiographic progression, such as male sex, older age, longer disease duration, elevated CRP, and smoking. These findings have important implications for the personalized management of axSpA and the development of new therapeutic strategies. This topic also shows more research is required and future research may focus on the validation and implementation of imaging biomarkers and scoring systems, as well as the exploration of novel treatment targets and approaches.FP-S and NA drafted the manuscript. All authors reviewed and approved the editorial."}
+{"text": "AlGhamdi  The authors regret the omission of two of the authors, Sheta M. Sheta and Said M. El-Sheikh, from the original manuscript. The corrected author list is as shown above.The authors regret that the funding information was incorrectly shown in the acknowledgements section of the original manuscript. The corrected funding acknowledgement is as shown below:The authors extend their appreciation to the Deanship of Scientific Research at Northern Border University, Arar, KSA for funding this research work through the project number NBU-FFR-2023-0051.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "The World Health Organization has called on economic operators to \u201csubstitute, whenever possible, higher-alcohol products with no-alcohol and lower-alcohol products in their overall product portfolios, with the goal of decreasing the overall levels of alcohol consumption in populations and consumer groups, while avoiding the circumvention of existing regulations for alcoholic beverages and the targeting of new consumer groups with alcohol marketing, advertising and promotional activities\u201d (see ).As Anderson et al. discuss, lower-strength alcohol products can be split into two groups: (i) specifically produced no-alcohol products; (ii) existing products reformulated to contain less alcohol . Across When considering the public health impact of non-alcoholic products, one of the difficulties relating to monitoring and evaluation is the differing definitions across jurisdictions . To resoAs reviewed by Anderson et al. , and speFurther analyses of Spanish household data found that decreases in the ABV of existing beers and wines had a much greater impact in reducing purchases (in grams) of all alcohol than the relatively small increases in purchases of no-alcohol beers and wines . AnalyseWith respect to the health impact, it has been questioned whether people with severe alcohol problems  safely switch to consuming no-alcohol products. On the one hand, as noted in the review by Anderson et al. , survey Rehm et al. undertook a modeling study to estimate the population-level health impact achieved by the current introduction of no- or low-alcohol beverages in Great Britain and Spain, and the impact of reducing the ABV of all alcohol products by a relative 10% amongst France, Germany, Italy, Poland, Spain, and United Kingdom . They foThrough addressing the product, reducing the ABV is only one of several innovative policy approaches. An alternative approach is to reduce serving sizes. The narrative review of Mantzari & Marteau found that reducing the size of servings, glasses, and bottles of wine could reduce wine consumption across populations .Nutt and colleagues proposed an even more novel approach: developing functional drinks that do not use alcohol yet mimic the positive, pro-social effects of alcohol without the associated harm .In conclusion, the introduction of no-alcohol products has health benefits for individual consumers, but very limited benefit at the population level due to very low levels of consumption; reformulation of existing products to contain less alcohol could, if realized across all products with a 10% relative reduction in ABV, have a substantial population-level impact, reducing the harm caused by alcohol. Alcohol producers should respond to the World Health Organization\u2019s call for substitution by reducing the alcoholic strength of all their products forthwith. Governments can promote substitution by increasing taxes on alcohol products, with harmonization of taxes per gram of alcohol and taxes rising per ABV of the product; were the tax rises much steeper at very low levels of ABV, this would also promote increased demand for and consumption of no-alcohol products (see )."}
+{"text": "The globalization of the food market has created a pressing need for food producers to meet the ever-increasing demands of consumers while ensuring adherence to stringent food safety and quality standards . The comIn response to these challenges, the field of food analysis has witnessed remarkable advancements through the utilization of advanced spectroscopic techniques. These cutting-edge methods, including X-ray-based approaches, hyperspectral and multispectral imaging, NMR, Raman, IR, mass, UV, visible, and fluorescence spectroscopy, offer non-destructive, rapid, solvent-efficient, eco-friendly, and cost-effective alternatives to conventional methods . LeveragIt is with great pleasure that we present this Special Issue, which focuses on recent developments and applications of advanced spectroscopic techniques in food analysis, quality evaluation, safety assessment, and practical industrial implementations, with a specific emphasis on chemometric approaches. The collection of papers included in this Issue offers a valuable insight into the diverse range of research and applications in this field, shedding light on the potential of these techniques to revolutionize food analysis.The accepted papers cover a broad spectrum of topics within the scope of this Special Issue. The first paper presents a comprehensive review of the current applications of advancing spectroscopy techniques in food analysis, focusing on the data handling aspect with chemometric approaches . This reFritillaria thunbergia [Furthermore, one paper details an innovative application of laser-induced breakdown spectroscopy coupled with variable selection algorithms and chemometrics for the detection of heavy metals in unbergia . Anotherunbergia . Additiounbergia .In another study, the discrimination of Brazilian stingless bee honey based on its iron-based biogeographical origin is investigated, showcasing the applicability of discriminant analysis in ensuring the authenticity and traceability of food products . The quaAdditionally, the effect of moisture content on the analysis of quality attributes of red pepper powder is explored using a hyperspectral system, providing valuable insights into the impact of moisture on food analysis outcomes . MoreovePrunus genus by botanical origin and harvest year based on carbohydrates profiles is investigated, shedding light on the application of spectroscopic techniques for the authentication of botanical products [Salvia botanicals are explored using GC/Q-ToF and chemometrics, providing crucial insights into the identification and characterization of herbal products [Furthermore, the classification of products . The cheproducts .Lastly, the detection of pesticide residue levels in grapes is studied using hyperspectral imaging and machine learning, illustrating the potential of these techniques for ensuring food safety .In conclusion, this Special Issue brings together a collection of research papers that highlight the immense potential of advanced spectroscopic techniques in the field of food analysis and quality evaluation. By presenting a range of innovative applications, these studies demonstrate the power of these techniques to enhance food safety, authenticity, and overall quality. We hope that the papers in this Special Issue provide valuable insights, inspire further research, and encourage the adoption of advanced spectroscopic techniques in the food industry."}
+{"text": "Nanomaterials proudly presents a Special Issue titled \u201cState-of-the-Art 2D and Carbon Nanomaterials in France\u201d, showcasing the groundbreaking research from some of the most eminent researchers in the field. The various publications cover a wide range of topics, including the synthesis, characterization, and applications of various carbon-based nanomaterials. These contributions shed light on the significant progress made in this area and collectively offer valuable insights into the current state and prospects of nanomaterial research in France.Nanotechnology has revolutionized various industries by enabling the manipulation and fabrication of materials at the nanoscale. In the realm of nanomaterials, 2D materials and carbon nanomaterials have emerged as frontrunners, promising a plethora of applications ranging from electronics to energy storage. France, with its rich scientific heritage, has been at the forefront of nanomaterials research, and the journal One of the key areas of focus in this issue concerns the synthesis of vertically aligned carbon nanotubes (VACNTs), wherein researchers in France have made noteworthy contributions and their insights have the potential to revolutionize the applications and production of VACNTs. By exploring various factors such as carbon source content , Fe/C raFurthermore, within the realm of carbon nanomaterials, this issue presents cutting-edge research exploring the world of curved polyaromatic hydrocarbons, known as carbon nanobelts. Employing laser-induced vaporization and ionization techniques, scientists have investigated collision impacts between species, leading to mass loss and the formation of new circular strained dehydrobenzoannulene species . These fAnother exciting contribution to this issue is the exploration of germanane, a two-dimensional material with stacks of atomically thin germanium sheets. The study focused on improving germanane\u2019s electrical transport properties to develop atomic-scale devices . The res2/graphene hetero-bilayer by varying the twist angle [2 monolayers, including the tunable WS2 spin-orbit splitting, offering new avenues for controlling the band dispersion of van der Waals materials. The insights gained from this research offer exciting opportunities for designing novel electronic devices and uncovering previously unexplored physical phenomena, holding immense potential for the electronics industry and future technological advancements.The potential of hetero-bilayer structures, where strain and spin-orbit coupling can be engineered, is also explored in this Special Issue, revealing exciting possibilities for tuning electronic band structures in van der Waals materials. Scientists have investigated the band structure of the WSst angle . Their wAdditionally, this issue includes research on the transfer process of monocrystalline graphene and its influence on the quality, morphology, and electrical properties of the transferred graphene . The con2 and KOH-based approaches, to enhance CO2 adsorption capacity [2 adsorption performance, showcasing the potential for efficient CO2 capture using activated graphene. This research highlights the significance of activation techniques in enhancing the surface and porosity of carbon nanomaterials, opening up potential carbon dioxide capture applications. Such advancements are critical in addressing environmental challenges and exploring sustainable energy solutions.Moreover, this Special Issue delves into the activation of graphene oxide, using COcapacity . These aIn addition, the exploration of hydrogen storage in nanoporous carbons holds promise for unlocking the potential of hydrogen-based energy systems. A review in this Special Issue explores the possibilities of nanoporous carbons for effective hydrogen storage by physisorption, highlights the current limitations, and proposes strategies to improve storage performance, including chemical modifications of carbon pore walls . PrelimiFinally, the complex structure and extraordinary properties of glass-like carbon (GLC), a vitreous material with exceptional properties that remain relatively unexplored, are discussed. By reviewing different models and a physical route involving pulsed laser deposition, the author outlines our understanding of GLC structure, topology, and geometry . The anaTo summarize, the contributions in this issue cover a wide range of topics, including the design of novel materials, the development of new synthesis methods, and the characterization of the properties of nanomaterials. French researchers have been at the forefront of advancing the understanding of carbon-based nanomaterials, such as carbon nanotubes and fullerenes, exploring their unique electronic, optical, and mechanical properties.One of the most exciting aspects of the research highlighted in this issue is its potential for real-world impact. For example, the development of 2D materials with tailored properties could lead to breakthroughs in electronics and photonics, while the use of carbon-based nanomaterials in energy storage devices could help to address the growing demand for renewable energy. Additionally, the biocompatibility of these materials makes them promising candidates for use in biomedical applications such as drug delivery and biosensing.Nanomaterials provides a comprehensive and up-to-date overview of the latest research in 2D and carbon-based nanomaterials in France. The contributions of French researchers in this field are significant, and their work is helping to advance our understanding of the unique properties and potential applications of these materials. As nanotechnology continues to evolve, it is clear that France will remain a key player in this exciting field. As we move forward, the collaboration between various stakeholders will be vital in translating these discoveries into practical solutions that benefit society and contribute to a more sustainable future.Overall, this Special Issue of We hope that this collection will provide a comprehensive overview of the current state-of-the-art of 2D and carbon nanomaterials research in France. We would like to express our gratitude to the authors for their valuable contributions to this Special Issue. We also thank the reviewers for their insightful comments and suggestions, which have greatly improved the quality of the papers. Finally, we hope that this Special Issue will inspire further research and collaboration in the field of nanomaterials in France and beyond."}
+{"text": "Superconducting materials have been gradually applied in many areas including energy, transportation, medical imaging and communication. Among them, superconducting magnets that can generate a strong magnetic field above 10 Tesla with absolute advantages of higher quality, lower energy loss, and smaller volume, have become key to the performance improvement of cutting-edge science and large-scale engineering devices such as high-energy accelerators, thermonuclear fusion reactors, and magnetic resonance imaging devices  and all-This special topic includes a review, an interview and two research papers, whose main purpose is to introduce the concept and connotation of \u2018mechanical perturbations induced quench\u2019, and the latest research progress, including studies of alleviating the brittleness of superconducting materials, and the influences of cracks on the thermomagnetic instability, which is often considered a reason for quench.The authors of the review article are Prof. You-He Zhou and Prof. Y. Iwasa, who are from Lanzhou University and Massachusetts Institute of Technology, respectively. They reviewed the research progress and challenges of fundamental mechanical problems in high-field superconducting magnets . In thiset al. [2Cu3O7-x (YBCO) superconductors, without reducing its superconducting properties, based on the customized 3D printing combined with a freeze-drying process. The second research paper in this special issue comes from Prof. Ze Jing of Northwestern Polytechnical University. Prof. Jing has been selected into the Young Elite Scientists Sponsorship Program of the China Association for Science and Technology, and won the first prize of the Jan Evetts SUST Award by the international journal Superconductor Science and Technology in 2020. Prof. Jing focuses on the effects of edge cracks on the thermomagnetic instability (TMI) of Type-II superconducting films and finds that the threshold field, the avalanche patterns, and the multifractal spectrum of the TMI process transit with the extension of the edge crack [The first research paper in this special issue comes from Lanzhou University. Zhang et al.  have conIt can be seen from the above articles and interview that, on the one hand, SM is extremely important for the development of high-field superconducting magnets; on the other hand, the influence of mechanics to superconductivity, is not only part of the traditional understanding of superconductivity degradation, but also central to the new concept of \u2018mechanical perturbations induced quench\u2019. It is hoped that through the publication of this special issue of SM, electrical engineers can better understand the nature of \u2018mechanical perturbations induced quench\u2019, and continue making progress in developing high-field superconducting magnets."}
+{"text": "Vitamin D performs a differentiating, metabolic and anti-inflammatory function, through genomic, non-genomic and mitochondrial mechanisms of action. In fact, vitamin D not only controls the transcription of thousands of genes and is involved in the modulation of calcium fluxes, but it also influences cellular metabolism and the maintenance of specific nuclear programs. Due to its broad spectrum of action, and because of the large number of target tissues, the deficiency of vitamin D and the molecular defects of its signaling pathway, such as VDR polymorphism or epigenetic silencing, can be involved in many pathologies.In this Special Issue, many scientists have contributed to elucidating the role of vitamin D in health and disease. Eight research articles and a compendium of nine reviews are published, covering different aspects of the activity of vitamin D and its defective signaling or low levels associated with many pathological conditions. Among diseases, the impact of vitamin D deficiency and supplementation in COVID-19 remains a hot topic, as revealed in the previous Special Issue \u201cThe role of vitamin D in human health and diseases\u201d and confirmed in this collection. Here, in addition to a systematic review discussing the evidence of beneficial effects of vitamin D supplementation in COVID-19 patients . SimilarThe effect of vitamin D in pregnancy was considered in two other studies of this collection. A systematic review examined the associations between maternal vitamin D levels and offspring neuropsychiatric and psychiatric outcomes, finding a positive association for attention-deficit/hyperactivity disorder and schizophrenia . MoreoveAmong the signaling pathways analyzed in this collection, the antioxidant and anti-inflammatory properties of vitamin D were largely investigated, and several studies revealed the central role of vitamin D in inflammatory diseases, such as COVID-19, diabetes, AKI, liver and kidney disease. The anti-inflammatory effects of vitamin D were explored in the adipose tissue of obese mice fed a high-fat diet , in T ceAmong the causes of variability in vitamin D signaling, single nucleotide polymorphisms (SNPs) are to be mentioned. Indeed, SNPs can influence the expression and/or functions of the VDR and of other genes in the vitamin D metabolic pathways, and may justify interindividual differences in responsiveness to the hormone. One study of this Special Issue explored five SNPs in the VDR gene in order to unravel the role of genetic polymorphisms on VDR expression in periodontal fibroblasts during simulated orthodontic compressive force . GeneticFinally, the effects of vitamin D supplementation were investigated in inflammatory diseases ,10 and iAs a whole, this Special Issue contains an interesting combination of research articles and reviews that present novel data on the effects of vitamin D in many pathologies, such as COVID-19 and diabetes, and in kidney, liver and cardiometabolic disease. The anti-inflammatory properties of vitamin D are the \u201cfil rouge\u201d in the heterogeneous spectrum of beneficial effects of the hormone described in this collection, which discusses current knowledge of the impact of vitamin D deficiency and supplementation in a variety of diseases."}
+{"text": "Although nicotine and its pharmacological effects are central for sustaining tobacco product use, they may be insufficient to support product acceptance, as sensory stimuli attributable to flavors are particularly critical, reducing subjective measures of craving and withdrawal4. Therefore, in recent years, the tobacco industry has developed and introduced various cigarette technologies and design features, including new tobacco blends, additives, and, subsequently, new flavors. While the importance of flavors has been researched by the tobacco industry in the context of product development, the assessment of flavors for regulatory purposes with the use of sensory and chemical analyses is still under development \u2013 hence an emerging area for incoming tobacco control researchers5.The design and additives of tobacco products are significant factors that facilitate industry innovations that may undermine public health programs and contribute to tobacco use and addictionFurthermore, novel tobacco products that further perpetuate the complexity of understanding and effectively regulating products have emerged, and hence tobacco control research now covers a breadth of products. Like the breadth of COVID-19 variants encountered during the pandemic \u2013 each tobacco product has a different epidemiology and different \u2018high-risk groups\u2019, but all can be appropriately addressed with the application of specific surveillance and mitigation measures.6. The project proposes a series of integrated studies that were proposed to facilitate the training of researchers to examine tobacco product systems, their mechanisms and purpose, interactions between key design characteristics and their assessment, and monitoring in the population. The research training facilitated within EUREST-RISE will be coupled with training on communicating to key stakeholders, among others, policymakers, the media and the general public.In response to this new reality in tobacco control, the EUREST-RISE Project was launched with funding under the Marie Sk\u0142odowska-Curie Action for Staff ExchangesWith a consortium of academic and non-academic partner organizations, the EUREST-RISE project has three operational pillars, each of them directly linked to one of the vertical Work Packages (WPs).WP2 aims to facilitate the exchange of expertise on complex dataset analysis and interpretation at both the product and population level through the analysis of European Union Common Entry Gate (EU-CEG) product-level data and available European population-based secondary datasets.WP3 supports the exchange of expertise on the sensory and chemical analysis of tobacco, e-cigarettes and novel products, including training and research on chemical and toxicological assessment.WP4 supports training in advocacy, policy integration and communication on tobacco control with training in peer-to-peer, media, and stakeholder communication.The complex and multidisciplinary nature of tobacco product regulation involving public health, epidemiology, toxicology, chemistry, sensory science, and public policy, are constructs of training which have yet to be formulated into any formal academic training process in the EU. It is this gap that the EUREST-RISE project will cover through the creation of a cohort of researchers who will be trained as scholars on state-of-the-art aspects of European tobacco product regulatory science."}
+{"text": "Science and technology have allowed human beings to live longer, more comfortably, and in relative safe life from natural weathering. In this scenario, non-communicable diseases linked to aging, sedentarism, and excess of energy consumption have become the major disorders to be contended with. Unfortunately, occasional movements against science have denied the benefit of historical conquests such as vaccination. Meanwhile, nutrition has a special appeal to the unscientifically minded; cyclically, a micronutrient emerges as a panacea able to guarantee health and protect against several chronic disorders. This thinking, similarly to the unfounded concern over vaccinations, tends to find basis in only observational studies with little other scientific backing. The last decade marked the turn of vitamin D. Previously considered a specialized molecule involved in the regulation of mineral metabolism, vitamin D is currently considered a pleiotropic hormone, as virtually all tissues and cells express vitamin D receptor   - 3 . SuIn time of pandemic, researchers, physicians, and all chain of health employees are working hard to develop vaccine and drugs, as well as to assist patients harboring the SARS-CoV-2. Unexpectedly, they must also waste time alerting people to avoid false offers of therapy for prevention and treatment of COVID-19 that have no scientific basis and can have detrimental effects, including pharmacological dosage of vitamin D. In the present issue of the Archives of Endocrinology and Metabolism, Santos and cols. bring an appropriate view on the recommendation of vitamin D for those subjects showing vitamin D deficiency   . More iFinally, I would like to give to the reader the consensual opinion from The International Osteoporosis Foundation (IOF), American Society for Bone and Mineral Research (ASBMR), American Association of Clinical Endocrinologists (AACE), Endocrine Society, European Calcified Tissue Society (ECTS), and National Osteoporosis Foundation (NOF) on usage of vitamin D in response to the current global pandemic, the COVID-19   . They aIn summary, safe exposition for few minutes (15-30 min) to sunshine naturally enables human beings to acquire the necessary amount of vitamin D, via auto sustainable synthesis of cholecalciferol. Alternatively, exogenous Vitamin D may safely bypass the thermal control of cholecalciferol synthesis within the skin when used in appropriate amounts. This target can securely be attained in most adults following the recommendation of IOM   . The ra"}
+{"text": "Cognitive Social Learning theory Bandura,  tries toSelf-efficacy beliefs as a predictor of quality of life and burnout among university lecturers . The second analyzes How does teacher-perceived principal leadership affect teacher self-efficacy between different teaching experiences through collaboration in China .A total of 9 articles and 68 authors have contributed to the objective of showing recent models and evidence, derived from Albert Bandura's original theoretical model. Two papers, carried out by the participating researchers, analyze the effect of a key construct in Bandura: the Self-Efficacy. The first work is focused on the effect of Predictive model of the dropout intention of Chilean university students ; the second, entitled You and Me Versus the Rest of the World: The Effects of Affiliative Motivation and Ingroup Partner Status on Social Tuning .Other works have presented evidence regarding the effect of motivation in the teaching-learning process. The first refers to the The effect of individual and classroom moral disengagement on antisocial behaviors in Colombian adolescents  shows this phenomenon.An article has addressed another essential aspect of his theory, referred to the moral impact of disengagement, as an explanatory mechanism of aggression and antisocial behavior. The work entitled Self-Regulated Learning, an essential construction derived from A. Bandura's theory. Shows the Short and Long-Term Effects on Academic Performance of a School-Based Training in Self-Regulation Learning .An experimental work is focused on internal and external regulation, applicable to different psychological contexts, in the paper entitled Advances on Self-Regulation Models: A New Research Agenda Through the SR vs ER Behavior Theory in Different Psychology Contexts . Complementarily, an initial validation study of the Assessment Scales of the Regulation/non-regulation/dyregulation construct  is presented, in the work titled Self- vs. External-Regulation Behavior Scale TM in different psychological contexts: A validation study .Finally, two papers show a new, broader model of self-regulation, derived from the Theory of A. Bandura, presenting types of In conclusion, this Research Topic is also dedicated to the incredible person and psychologist Albert E. Bandura (1925-2021). Dr. Albert Bandura, was one of the most influential psychologists of all time. Bandura pioneered the field of social learning theory  with his landmark Bobo doll experiment. He defined the construct of self-efficacy and proposed an agentic theory of human behavior that challenged the central tenants of behaviorism. Born in Alberta, Canada, in 1925, Bandura earned his undergraduate degree from the University of British Columbia in Vancouver and his graduate degree from the University of Iowa. He joined the faculty at Stanford University in 1953, where he served as the David Staff Jordan Professor of Social Science in Psychology. Bandura was elected APA president in 1973 and encouraged our organization to pursue matters of public interest. Bandura's significant contributions to the field of psychology were recognized in 1980 with APA's Distinguished Scientific Contribution Award and in 2004 with our Award for Outstanding Lifetime Contribution to Psychology. He also received the Gold Medal Award for Distinguished Lifetime Contribution to Psychological Science from APF and the Lifetime Career Award from the International Union of Psychological Science. In 2016, he was awarded the National Medal of Science by President Barack Obama.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
+{"text": "Staphylococcus aureus is an extracellular bacterium that causes surface to severe hematogenous infections with high infection rate and mortality. Thus, novel antibiotics are urgently required to treat these bacteria. Essential oils (EOs) showed the antibacterial activity and has become the basis of many applications, including alternative medicine, natural therapies, food preservation, raw and processed, and pharmaceuticals. Natural products with EOs can be make use of as raw materials in antibacterial substances.Subjects and Methods: In this study, the \u0251-pinene is a major compound of Pinus densiflora Sieb. et Zucc. (PSZ) EOs. The antibacterial activity of the essential oil extracted from PSZ against MRSA was investigated. The inhibitory effect of \u0251-pinene on MRSA growth, acid production, biofilm formation and expression of virulence factors were examined.Results: PSZ EO was analyzed by gas chromatography (GC) and GC coupled for mass spectrometry, which identified 58 constituents, accounting to 90.98% of the total EO. The most components in all the EOs is \u03b1-pinene (20.56%). At concentrations of higher than 0.25\u2005mg/mL (p<0.05), the \u0251-pinene was examined to inhibit the growth of MRSA. After using the safranin staining method, \u0251-pinene showed an inhibitory effect against biofilm formation. As well as the experimental results were similar to the scanning electron microscopy. At high concentrations with \u0251-pinene in a concentration dependent manner (of 1\u20138\u2005mg/mL) also showed a bactericidal effect by the confocal microscopy. According to the real-time polymerase chain reaction, mRNA expression of virulence factor genes, sea, agrA, mecA, and sarA, was observed. All the expression was observed at a concentration of 0.25\u2005mg/mL by \u0251-pinene.Conclusions: These results suggest that \u0251-pinene, a major compound of PSZ EOs, has the antibacterial activity against MRSA, antibiotic resistant bacteria.This paper was supported by Wonkwang University in 2019.aCunbo Wua Chongqing Mental Health Center, Gele Mountain, Shapingba district, Chongqing, China.Objective: To investigate whether modified electronconvulsive therapy (MECT) causes fever and its causes and feature.Methods: In accordance with the inclusion and exclusion criteria, Data analysis was conducted on 12 patients with mental disorders who were treated with modified electronconvulsive fever after treatment from February to May 2022 at chongqing Mental Health Center.Results: Fever is more common in adolescents after MECT treatment, 4 persons under the age of 20, accounting for 33.3%; 5 persons aged 20-29, accounting for 41.7%; mainly with moderate fever, 7 cases (58.3%), usually occurs in the second time of MECT (50%) and in that afternoon of the day after operation, 11 cases (91.6%). One case was fever after the third time, accounting for 10%; Two cases (20%) developed fever after the eighth MECT. 4 cases  had normal blood routine after MECT. 8 cases (66.7%) had elevated WBC. 4 cases (33.3%) showed normal CRP during fever after MECT. CRP was elevated in 8 cases (66.7%). Among the patients with fever, there were 5 females (41.7%) and 7 males (58.3%). 9 cases (75%) of febrile patients were schizophrenic. 2 cases of affective disorder (16.7%); 1 case (8.3%).Conclusions: The fever caused by MECT should not be ignored and should be treated promptly. Relevant auxiliary examination should be improved to clarify the cause and further treatment. MECT treatment should be suspended if necessary.a, Bing Hua, Qinjing Lia, Linlin Liua, Zhenzhen Doua, Zhihui Zhaob, Liang Zhua, Tianming Chena, Lingyun Guoa, Gang LiuaXin Guoa Key Laboratory of Major Diseases in Children, Ministry of Education, Department of Infectious Diseases, Beijing Children\u2019s Hospital, Capital Medical University, National Center for Children\u2019s Health, Beijing, 100045, China, b Department of Heart Diseases, Beijing Children\u2019s Hospital, Capital Medical University, National Center for Children\u2019s Health, Beijing, 100045, China.Background: Infective endocarditis (IE) is a rare and fatal disease in children, with Staphylococcus aureus (SA) as the leading cause in many regions of the world. Staphylococcus aureus infective endocarditis (SAIE) often presents sudden onset of sepsis and embolism, with multiple organs damage. SAIE with persistent bacteremia is a challenge in clinical practice. Some specific antibiotics such as daptomycin are available as an alternative when conventional treatment fail.Subjects and Methods: The research team retrospectively analyzed the medical records of 7 pediatric patients with infective endocarditis caused by Staphylococcus aureus admitted to Beijing Children\u2019s Hospital from February 1, 2018 to February 28, 2021. The etiology, symptoms and signs, laboratory results, treatment and prognosis were collected, and compared with 13 other cases. Blood culture and echocardiography were used to diagnose the disease, and the efficacy of different antibiotics was analyzed.Results: SAIE accounted for 35% (7/20) of all IE patients, with 7 cases ranging in age from 1 year 5 months to 13 years 8 months. 3 cases (42.9%) had methicillin- resistant Staphylococcus aureus (MRSA) and 4 cases (57.1%) were methicillin-sensitive Staphylococcus aureus (MSSA). A total of 4 cases (57.1%) had congenital heart disease. All patients (100%) had fever and 3 cases (42.9%) had major vessel embolic events. 4 cases (57.1%) had central nervous system complications and 4 cases left heart endocarditis. All patients initially received vancomycin-based treatment regimens. 2 cases (28.6%) with persistent bacteremia were changed to a 9\u2005mg/kg/dose of daptomycin when the conventional treatment failed to vancomycin therapy. The outcomes were good and no significant side effects occurred. Daptomycin in our study was first applied successfully for SAIE with persistent bacteremia in Chinese children.Conclusions: SA was the common major pathogen detected in IE. Appropriate antibiotic therapy needs to be adopted, and evaluation of persistent bacteremia and vascular embolic events is needed. The study also showed that vancomycin and linezolid are still the first-line choices for treatment of the disease, but daptomycin can also be an effective treatment option.The authors would like to thank Huiyu Liu\u2019s writing support from MSD, Qinjing Li and Tianming Chen\u2019s support during the conduction of this study.a, Lin Niub, Haijun Shana, Caihong Caoa, Yingying Zhanga, Yujin HouaXiaosu Jiea Child Rehabilitation Department, Henan Province Hospital of Traditional Chinese Medicine, Zhengzhou, China, b Department of medical technology, Zhengzhou Railway Vocational and Technical College, Zhengzhou, China.Background: This study analyzed the effects of Jiao\u2019s scalp acupuncture combined with task-oriented training on gross motor function classification, gross motor function assessment and motor development of children with spastic cerebral palsy. Spastic cerebral palsy is the most common type of cerebral palsy with motor dysfunction among the main clinical manifestations. Even the severe patients can not walk for life. So exercise intervention is the focus of cerebral palsy treatment. This study aims to provide more effective treatment methods for pediatric spastic cerebral palsy.Subjects and Methods: Fifty children admitted to our hospital for spastic cerebral palsy from January 2020 to June 2021 were enrolled, and assigned to the control group (n=25) receiving task-oriented training, and the observation group (n=25) receiving Jiao\u2019s scalp acupuncture plus task-oriented training. Before and at 6 months after treatment, the gross motor function grade, gross motor function assessment score changes and the satisfaction of children\u2019s guardians with rehabilitation treatment were compared.Results: After the treatment, the total gross motor function score was higher in the observation group (P<0.05). The number of gross motor function in patients with decreased grade, the Peabody motor development score, the satisfaction and overall clinical efficacy of the children\u2019s guardians were higher in the observation group .Conclusions: Jiao\u2019s scalp needle was founded by Professor Jiao Shunfa in 1971. Based on the theory of cerebral scalp needle has been widely used in the clinical treatment of various encephalopathy in China due to its convenient acupoint selection and simple operation, and has achieved positive clinical effect in the treatment of spastic cerebral palsy in children. Jiao\u2019s scalp acupuncture combined with task-oriented training applied in spastic cerebral palsy children has obvious practical effect. They can reduce the disease of children and improve the level of gross motor function of children, improve the quality of life and self-reliance, self-care ability of children at the same time. It also can enhance parents\u2019 confidence in rehabilitation and improve parents\u2019 satisfaction with rehabilitation treatment. As a result, the effect is better than that of task-oriented training routine treatment.This work was supported by the Scientific research project of traditional Chinese medicine in Henan Province, Project: 2019ZY2056a, Yi FengaChenlin Wanga School of Art and Design, Beijing Forestry University, Beijing, China.Background: The incidence of Autism Spectrum Disorder (ASD) in children around the world is on the rise, and the development of mental health in autistic children due to physical defects can lead to cognitive, emotional, behavioral and other disorders. Since the etiology and biochemical abnormalities of ASD have not been fully elucidated, and there is no specific drug to treat ASD pathologically, ASD has increasingly become a worldwide problem facing human society. The importance of toys for the healthy development of children makes it possible to improve the above problems through toy training. The design of cognitive behavioral training toys for children with ASD has received a lot of attention. The INPD method is widely used in many fields, providing the possibility to solve the problem of designing cognitive behavioral training toys for children with ASD.Subjects and Methods: Based on the design method of INPD theory, the design strategy of ASD Children\u2019s cognitive behavioral health training toys is explored. This paper uses INPD, combined with AHP, to guide the toy design ideas for ASD children. Firstly, the design gaps is found from SET analysis method; then, a questionnaire survey is conducted on ASD children\u2019s families to clarify the needs of ASD children\u2019s families for cognitive behavioral health training toys and classify the needs to form a hierarchical diagram of user needs; finally, the nine-scale method of AHP hierarchical analysis is introduced to calculate the important priorities of different levels of needs. Finally, different requirements are sorted into design strategies in priority order.Results: The product concept is then translated into a design strategy. According to the priority order of needs, the design strategy of ASD children\u2019s cognitive behavior training toys should focus on logic and cooperation in content, establish toy IP and develop intelligent training toys. In addition to following the safety principle, the design principle should also pay attention to the simplicity and scalability of toys, so as to fully realize the purpose of training the physical functions of ASD children and letting them grow up healthily.Conclusions: The design method of combining INPD and AHP effectively solves the problem of prioritization of user needs in toy design, provides a new design idea for the design of cognitive behavioral health training toys for autistic children, and also provides a new method for other research on user needs.aJunwei Wanga Wuhan Sports University, Wuhan 430079, China.Background: With the rapid development of high quality in the education, the aim of this study was to Children sensory integration has become the focus of global education. It has important theoretical and practical significance to improve children\u2019s sensory integration through sports activities or training.Subjects and Methods: Take the development frontier and practice cases of children sports and sensory integration abroad as an opportunity, this paper uses comprehensive analysis methods, such as literature review and data statistics, to comb the meaning, application and design of children\u2019s sport and sensory integration. Meanwhile, this research will focus on the development history, current situation, function and role of sensory integration. Combining the special functions of sports and empirical cases, explain children\u2019s bad behaviors in the environment, life, and learning, and provide a scientific de mainly base sign path.Results: Sensory integration training is based on games to cultivate children\u2019s learning interest, self-consciousness, and teamwork capabilities. They Correct children\u2019s incorrect standing, sitting, walking, running, etc. through specific language environment, body movements and teaching aid guidance and behavior habits. Therefore, children sports is a brand-new training model tailored to the individual needs of children. Studies have found that the early childhood stage is a key stage for the development of the sensory nervous system. It is believed that the sensory system is a sub-component of the brain motor control system, which needs sports activities or training to stimulate the neural linkage, and the linkage is realized through the complementary relationship between static and dynamic components, On the child\u2019s brain growth and limbs and trunk have a healthy role in promoting.Conclusions: Sports activity or training can promote children\u2019s body, vestibular, tactile and other sensory systems to process, improve the flexibility and adaptability of children\u2019s body posture, joints, muscles, eyesight, hearing and other body parts during exercise, and have a positive impact on children\u2019s cognitive and mental health. The purpose is to solve children\u2019s behavioral cognition and mental strengthening training, so that the child\u2019s brain can smoothly integrate and process various sensory information and make correct decisions. Therefore, learning sports activities in childhood is an important functional attribute of promoting the healthy growth of children.Foundation Project: 2019 Scientific Research Program of Hubei Provincial Department of Education (Project number: B2019196); Wuhan Sports University Scientific Innovation team of young and middle-aged funding project.a,b, Haili Lib, Shi Guob, Guoping Wangb and Hairong LiubPenghui Xua Department of Management, Jiangsu University, Zhenjiang, Jiangsu 212013,China, b Anhui Key Laboratory of Philosophy and Social Sciences for Public Health Crisis Management in Colleges and Universities, Wannan Medical College, Wuhu 241002, China.Background: To investigate the impact mechanism of health input structure attributes on health development and its regional differences based on the perspective of human capital.Subjects and Methods: Using panel data from 31 Chinese provinces from 2011 to 2018 and using the systematic GMM estimation method, the public health output effects of the health expenditure structure and its regional differences were investigated.Results: Firstly, the empirical results showed that social health expenditure significantly increased public health output. There were regional differences: the eastern region showed the strongest effect in this regard, the central region had the second strongest, and the western region involved the weakest effect. However, government health and personal hygiene investment did not significantly increase public health output. Second, the number of doctors per thousand people had a significant impact on public health output, but there were significant regional differences: the eastern region had the strongest promotional effect, while the central and western regions were not significant. Third, there were significant regional differences in the impact of the number of beds per thousand people on health output, of which the western region was the most significant, followed by the central region, and the promotional effect in the eastern region is not significant. Fourth, the per capita GDP and environmental factors in the three major regions of eastern, middle, and western China had no significant impact on the health level, while there was a significant regional difference in the impact of per capita education level on the health level. The regional promotional effect was relatively high, while the central and western regions were not significant.Conclusions: The conclusions of this study have important policy implications. In order to further improve the health of residents and build a healthy China, we put forward the following policy recommendations: Strengthen the input of health resources in key areas is to ensure basic medical services, effectively ensure the equalization of basic medical services, and improve the accessibility and affordability of medical services; The government should increase support for social health in the central and western regions, implement a variety of tax incentives to promote the continuous growth of social health expenditure, and build a mechanism to maximize the efficiency of health resources.The authors thank all participants who made an effort in this study. This study was funded by the grants from the Ministry of Education of China (grant 20YJCZH193) and Anhui Provincial Department of Education (grant SK2017A0212).a, Xiaoyu Changa, Qinglan Liua, Kaiwen Zhaob, Songqiang Yic, Yingmei Yua, Sansan Shaoa, Zhenghua Huanga, Ruili Lid, Siming LiaHan Yana Key Laboratory for quality and safety control of poultry products, Ministry of Agriculture and Rural Affairs of the People\u2019s Republic of China, Institute for Quality & Safety and Standards of Agricultural Products Research, Jiangxi Academy of Agricultural Sciences, Nanlian Road 602, Nanchang 330200, China, b Nanchang Institute of Technology, Nanchang 330044, China, c Agricultural Technology Extension Center of Jiangxi Province, Nanchang 330046, China, d Yantai Academy of Agricultural Sciences, Yantai 265500, China.Background: Selenium is a necessary nutrient element in the human body. Because the human body cannot synthesize selenium, it needs to be supplemented from the outside. Moderate supplement of selenium can improve human immunity and resistance, and promote human health. At the same time, with the improvement of people\u2019s living standards, the development of healthy and safe functional selenium enriched eggs has attracted more and more attention. In this study, Dongxiang green-shell laying hens was taken as the experimental object, to investigate the effect of nine different kinds of selenium (Se) feeding methods to Dongxiang green-shell laying hens with different morphological characteristics (red and purple comb) on egg concentration, viscera antioxidant properties, and slaughter index. In order to provide a basis for the production of safe and healthy selenium enriched green shell eggs.Subjects and Methods: The experiment was carried out on two hundred and fifty two 30-week-old Dongxiang black feather laying hens and the red comb ones and purple crests ones equal share of the total number of the test. These hens were allocated to nine dietary treatments and each group was divided into four parallels with 7 hens per replicate and two of the replicates have red crests and the other have purple crests. respectively. The hens were free to eat and drink during the experiment. We controlled the winter feeding temperature between 16 and 18 \u00b0C and the lighting in hen house was 14h daily.Results: The result shows that the organic selenium group has higher portion of selenium in all indicators measured than inorganic selenium group significantly (P<0.1). Also the total selenium content is higher in high concentration group than in low ones under the stress of the same selenium source. Moreover, enrichment of selenium content in egg and breast was the most effective  via application of dietary selenomethionine (0.6\u2005mg/kg) in purple crown group. Statistically, there is a significant difference (P\uff1c0.1) in the concentration of selenium deposition in eggs between purple and red cockles in the same selenium source group . And the difference in the color of chicken\u2019s crown had a significant effect on the selenium content deposited in the plasma and visceral of the selenomethionine treatment group (P<0.1).Conclusions: the selenium supplemental concentration was positively correlated with the anti-oxidant capacity in viscera and the effect was significant. In conclusion, adding 0.6\u2005mg/kg selenomethionine in the diet of purple crown laying hens has the best effect on selenium enrichment in eggs and tissues, and the detection indexes are better than those of red crown ones. This study provides a theoretical basis for the development of selenium-rich products.Study on selenium deposition mechanism and key technologies of Product development and utilization in green shell eggs (Item number: 20202BBFL63029); Study on technology system of nutritional evaluation of agricultural products (JXXTCXNLTS202103); Study and application of key technologies for high value fermentation of Selenium-rich rice (Item number: 20202BBFL63011).a,b, Weixiong Liaoa, Zhongyan Wenb, Yue Zhaoc, Yonghui Liub, Jincan ChenbGanbin Qiua Imaging department of Zhaoqing Medical College, Zhaoqing 526020, China, b Department of Radiology, The First People\u2019s Hospital of Zhaoqing, Zhaoqing 506040, China, c Department of Radiology, The First Affiliated Hospital of Jinan University, Guangzhou 510000, China.Background: To compare the changes of brain low-frequency amplitude (ALFF) in patients with primary insomnia (PI) and healthy control group (HC) before and after the treatment of Shenmen combined with Neiguan point, and to explore the neural mechanism of brain function changes in patients with PI by electroacupuncture Shenmen combined with Neiguan point.Subjects and Methods: From November 2019 to May 2022, 23 PI patients  were recruited in Zhaoqing First People\u2019s Hospital as the study group, and 26 healthy volunteers  with age, sex and education level were recruited in society as the control group; All the subjects were scored with the clinical Pittsburgh Sleep Quality Index (PSQI), Hamilton Depression Scale (HAMD) and Hamilton Anxiety Scale (HAMA) before acupuncture, and all the subjects were scanned with resting MRI before acupuncture treatment; Then select Shenmen and Neiguan points of the two groups of subjects for electroacupuncture therapy. After \u201cDeqi\u201d, the electroacupuncture will continue to stimulate for 30 minutes. After another electroacupuncture treatment the next day, the resting MRI scan will be performed again. The low frequency amplitude (ALFF) analysis method was used to calculate the ALFF of brain regions between PI group and HC group before and after acupuncture, and the rest state in PI group before and after acupuncture.Results: There was no significant difference in gender and age between the two groups (p>0.05), but the PSQI score, HAMA score and HAMD score of patients in the study group were significantly higher than those in the control group (p<0.05). Before acupuncture treatment, the brain areas with increased ALFF values in PI group included the right cuneiform lobe, left inferior temporal gyrus, left amygdala, etc., while the brain areas with decreased ALFF values included the right parahippocampal gyrus, right anterior cuneiform lobe, left inferior parietal lobule, and left thalamus; After acupuncture treatment, the brain areas with increased ALFF values in PI group included the left posterior cingulate gyrus, bilateral anterior cuneiform lobe and right cuneiform lobe, and the brain areas with decreased ALFF values included the left amygdala, the right transverse temporal gyrus, and the right posterior central gyrus.Conclusions: The brain regions of default network, significant network and part of emotional cognitive network in patients with primary insomnia (PI) are damaged, which may be the microcosmic manifestation of daily behavior and cognitive abnormalities in PI population. The combination of electroacupuncture at Shenmen and Neiguan points can activate part of the damaged brain areas of PI population, so as to improve the mental state and sleep, which may provide a new auxiliary scheme for clinical treatment of PI population.This work was supported by the Science and Technology innovation of Zhaoqing City, Guangdong Province, China under Grant (No. 2019N008). This work was supported by Medical Scientific Research Foundation of Guangdong Province, China under Grant (No.B2020225).a, Tian Tiana, Shengzhi Tana, Tao Liua, Dong Wanga, Yuan Lia, Di Wua, Rong TanaKai Cuia Department of Spine Surgery, Strategic Support Force of Chinese PLA, Beijing, 100101, China.Background: To evaluate the safety and reliability of minimally invasive Dynesys implantation and discectomy (MIS-Dynesys) and minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) under Quadrant tube in single level lumbar degenerative diseases.Subjects and Methods: From January 2016 to December 2018, a retrospective analysis was carried out on 65 patients with single-segment lumbar degenerative diseases admitted to our hospital. Among them, 21 patients, 12 males and 9 females, with an average age of 64.57\u2009\u00b1\u20096.8 years, were treated in the MIS-Dynesys group, and 44 patients in the MIS-TLIF group, 19 cases in men and 25 cases in women, with an average age of 64.16\u2009\u00b1\u20095.71 years old. The general data, duration of surgery, bleeding volume, drainage, and oswestry disability index (ODI), JOA score (Japanese Orthopedic Association), and Visual Analogue Scale (VAS) for preoperative and postoperative and final follow-up were recorded to evaluate clinical efficacy. Before surgery, X-rays of lumbar orthovertebral lateral position and flexion and extension position, lumbar CT, lumbar spine MRI combined with clinical determination of the responsibility gap. 2 days after the operation, X-rays of the lumbar vertebrae in the lateral position and the flexile and extensive position were taken, and the LUM CT was re-determined to determine the internal fixation position and then moved to the ground. At the last follow-up, both patients were taken X-rays of the lumbar orthovertebral lateral position and flexion and extension motility position, the mobility of the surgical segment was measured, and the fusion group reviewed the CT to assess the fusion effect, and the data were collected for comparative study.Results: The follow-up time of the two groups of patients was 6-39 months. The results of the MIS-Dynesys group and the MIS-TLIF group were not statistically significant in terms of general data, and operation time, and bleeding volume (P>0.05), and the former had significantly lower drainage than the latter, and the difference was statistically significant (P<0.05). Preoperative ODI JOA lumbago and leg pain VAS scores in 2 groups were not statistically significant (P>0.05); ODI JOA and lumbago and leg pain VAS scores in 2 groups at the end of 3 months after surgery were significantly improved compared with those before surgery, and the differences were statistically significant (P<0.05); ODI JOA and lumbago and leg pain VAS scores were not statistically significant between the two groups at the end of 3 months after surgery(P>0.05).There was no statistical difference in the activity results of the preoperative target segment (P>0.05) between the two groups, and the postoperative follow-up, the former of which still maintained a certain degree of activity, and the latter was well fused, the mobility was 0, and the difference was statistically significant (P<0.05).Conclusions: For single level lumbar degenerative diseases, MIS-Dynesys can achieve similar result with the MIS-TLIF. The MIS-TLIF group had more drainage and fusion. The MIS-Dynesys group maintain a degree of motion.a, Fangliang Huanga, Tongping ShenaHuanqing Xua School of Medicine and Information Engineering, Anhui University of Chinese Medicine, Hefei, Anhui 230012, China.Background: To cultivate new medical talents with high information literacy and healthy mental qualities, the teaching of basic computer courses in medical schools should be made more practical, specialized and useful. The goal of this paper is to study how the characteristics and advantages of the subject matter of basic computer courses in medical schools can be combined with mental health education and permeated in classroom teaching, in order to cultivate good motivation and a healthy personality for students and to establish a positive and active mental quality for later entry into the workplace.Subjects and Methods: This paper is to highlight the professional characteristics of medicine in the teaching of basic computer courses at Anhui University of Chinese Medicine, and to create a computer course with a \u201cmedical flavor\u201d. The course integrates computational thinking into the curriculum and further enhances students\u2019 understanding and absorption of knowledge by \u201cdissecting\u201d complex problems at different levels. In addition, the online and offline integration of the SPOC teaching model can fully motivate students to learn on their own. In the teaching of basic computer courses, the overall objective of quality education should be taken as the basis for establishing corresponding mental quality objectives. Through training, counselling, implication and infection, students\u2019 mental quality will be improved, their mental barriers will be solved, their mental health will be promoted and their healthy mental qualities will be cultivated.Results: After one cycle of reform practice, the teaching results of four Applied Psychology classes of different grades taught by the author were remarkable. A comparison of the course formative assessment results shows that the SPOC combined with the computational thinking development teaching model and integrate into mental health education has greatly stimulated students\u2019 interest in learning, with a significant increase in both pass and merit rates.Conclusions: Classroom practice shows the importance of integrating computational thinking and health education into the SPOC teaching model as a \u2018new treatment\u2019 to facilitate the development of pedagogical reform in the course.This study was supported by the Key Project of Scientific Research in Anhui Higher Education Institutions of China under Grant NO. KJ2021A0587 and NO. SK2020A0244, the Provincial Quality Engineering Project in Anhui Higher Education Institutions of China under Grant No.2020jyxm1029 and 2022jyxm857.a, Feng Shana, Yimeng Wangb, Ya Liua, Yao Liua, Yunfang ZhenaJun Wena Department of Orthopaedics, Children\u2019s Hospital of Soochow University, Suzhou, Jiangsu 215000, China, b Department of Orthopaedics, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, China.WJ and SF contributed equally to this study.Background: To explore the efficacy of interlocking intramedullary nail in the treatment of femoral shaft fractures in adolescents.Subjects and Methods: The clinical data of 10 adolescent femoral shaft fractures treated with interlocking intramedullary nailing in our hospital from January 2020 to December 2021 were retrospectively analyzed. Among the patients, 8 were male and 2 were female. Their ages ranged from 11.5 to 15.3 years . Their weight ranged from 50.2kg to 70.2\u2005kg . The procedure was fixed with a static interlocking intramedullary nail. Periodic follow-up examinations were performed to monitor the occurrence of complications and to record the time of union of the fracture. At the last follow-up, neck shaft angle (NSA), medial proximal tibial angle (MPFA), femoral head diameter (FHD), femoral neck diameter (FND), and articulotrochanteric distance (ATD) were measured on the X-ray. Functional recovery of the affected limb was assessed using Thoresen\u2019s criteria.Result: The mean follow-up time was 14.4 months (10-17 months). All fractures healed, and all incisions healed at the first stage. No infection or incision dehiscence occurred. The average fracture union time was 5.1 weeks (4-8 weeks). The average radiological union time of the fracture was 9.6 weeks (6-12 weeks). There was no nonunion of the fracture,no delayed union, no malunion, no broken nails, no re-fracture. A leg length discrepancy of 1.4cm was observed in one case. One patient had ectopic ossification above the greater trochanter. Pressure ulcers occurred at the ankle in one patient. The NSA, MPFA, FHD, FND, and ATD at the final follow-up were, respectively,  for the affected side,which were insignificantly different from those for the healthy side  (P>0.05). According to the Thoresen criteria, there were 8 (80%) excellent, 1 (10%) good, and 1 (10%) satisfactory results with an excellent to good rate of 90%.Conclusion: Interlocking intramedullary nailing is clinically effective in the treatment of femoral shaft fractures in adolescents, with excellent fracture union, few complications and no significant effects on proximal femur development in the short term.This work was supported by funds from National Natural Science Foundation of China (no. 82172520).a, Guoshuai Mab, Gandan Sic, Xiaoqiang Liud, Lixin CheneFenglan Guoa School of Physical Education, Xinjiang Normal University, China, b Xinjiang Institute of Engineering, China, c School of Physical Education, Changji University, China, d Urumqi NO.8 middle school, China, e Xingjiang Vocational Institute of Energy Technology, China.Background: In the era of \u201cInternet +\u201d, the application of blended teaching method has become an important starting point for the construction of first-class physical education courses in China, which is the direction of the curriculum reform of higher physical education and highlights its unique advantages in the application and development of physical education classroom teaching, namely, blended teaching can not only be applied to the theory and health knowledge classroom, but also can be combined with physical education technology teaching. And then provide services to promote students\u2019 health, health education and its physical and mental health.Subjects and Methods: This study takes blended teaching method of general track and field courses as the research theme, adopts the methods of literature review, questionnaire survey and on-the-spot investigation to carry out the application implementation of the online and offline blended teaching method for the students in Grade 2021 of physical education major, and explores the application effect of online and offline blended teaching practice of general track and field courses.Results: (1) Blended teaching of track and field general courses should include independent learning, cooperative learning, question answering, practice consolidation, summary and evaluation. (2) The application of mixed teaching of track and field general courses has different degrees of influence on the innovation of teaching and learning, the working efficiency of teachers, the improvement of students\u2019 technical skills and abilities, and the evaluation of teaching performance. (3) Combining mixed teaching of track and field general course with ideological and political practice of the course has a certain promoting effect and value on the mining, design and practical application of ideological and political elements of the course. (4) Through the combination of online and offline teaching and practice platform of track and field courses, the concept of physical and medical integration can be integrated into the sports training and rehabilitation education and learning of college students majoring in physical education, so that the sports health education of college students majoring in physical education can develop in a scientific wayConclusion: (1) Use the Chaoxing Learning platform to carry out blended teaching design and practice, expand students\u2019 multiple ways of learning in track and field, meet students\u2019 professional learning needs, and improve students\u2019 self-learning ability (2) By teaching theories and health knowledge about track and field events online, and learning skills online and offline, students can better master the health knowledge about track and field, fitness means and skills, cultivate students\u2019 professional quality of teachers, and enhance students\u2019 comprehensive ability of sustainable development. (3) The referee practice of track and field general training events and the ability training of demonstration and explanation are carried out in the way of cooperative group rotation, so as to stimulate students to give full play to their potential, integrate and expand the application of what they have learned, and cultivate the core quality of physical education teachers in primary and secondary schools. (4) Integrate ideological and political education into the online and offline teaching process, improve students\u2019 comprehensive ability and the effect of ideological and political education in the course, so that the core quality of students\u2019 future teacher career can be improved accordingly, which is in line with the talent training program. (5) The combination of online and offline teaching methods can organically combine skill practice with theoretical learning of sports health education, so as to promote the effectiveness and scientific development of track and field courses.This work was supported by the First-Class Undergraduate Course of Xinjiang Normal University in 2021 ----Hybrid Online and Offline First-Class Courses (Track and Field), the Social Science Fund of Autonomous Region, Project No.: 22CTY031.aJian Xua China Export & Credit Insurance Corporation, Beijing 100033, China.Background: To illustrate how RCEP offers positive psychological incentives and emotional regulation for the traders and investors, thus promoting trade and investment in East Asia, and to give some suggestions on how China export credit insurance could play an important role in serving China\u2019s opening up and supporting enterprises to develop markets in the contracting parties.Methods: This paper, from the psychological perspective, compares RCEP with the General Agreement on Tariffs and Trade (GATT), the General Agreement on Trade in Services (GATS), the Agreement on Trade-Related Investment Measures (TRIMs), the Trade Facilitation Agreement (TFA), Agreement on Safeguards(AS), the US-Canada-Mexico Agreement (USMCA), the EU-Canada Comprehensive Economic and Trade Agreement (CETA), and the Comprehensive and Progressive Agreement for Trans-Pacific Partnership (CPTPP) to illustrate how RCEP offers psychological incentives and emotional regulation for the traders and investors, thus promoting trade and investment in east Asia. Besides, the paper preliminarily judges the opportunities and challenges of China export credit insurance to support China\u2019s enterprises in conducting trade and investment in the contracting parties, finally, it gives some suggestions on how China export credit insurance could play an important role in serving China\u2019s opening up and supporting enterprises to develop markets in the contracting parties.Results: The analysis of RCEP rules shows that RCEP will give positive psychological incentives and emotional regulation to traders and investors in East Asia, and then expand regional trade and investment in the region. At the same time, RCEP allows the parties to take relevant protective measures, which may reduce the psychological expectations of traders and investors, and thus may have negative effects on trade and investment in the region. Based on the above, from a practical point of view, China export credit insurance could strengthen the positive psychological incentive and emotional regulation of the agreement, stabilize the psychological expectation of China\u2019s traders and investors to develop market in East Asia.Conclusions: RCEP rules could give positive psychological incentives and emotional regulation to traders and investors in East Asia. At the same time, RCEP may have negative effects on trade and investment in the region. China export credit insurance, starting from the following 4 aspects, could strengthen the positive psychological incentive and emotional regulation of the agreement, stabilize the psychological expectation of China\u2019s traders and investors to develop market in east Asia: 1. A deep understanding that opportunities brought by RCEP are conducive to better integration of China export credit insurance into the China\u2019s development; 2. Take the bidding list of the contracting parties within RCEP as the starting point, and clarify the specific support direction from China export credit insurance for China\u2019s enterprises; 3. China export credit insurance shall provide timely support to promote China\u2019s enterprises to build a more mature supply chain layout of foreign trade industry among contracting countries within RCEP.a, Qiyan JiangbDawei Yanga Shandong Polytechnic, Jinan, Shandong, 250104, China, b Zaozhuang Transportation Service Center, Zaozhuang Shandong, 277800, China.Background: The purpose of this dissertation is to explore the impact of rural health human resource allocation on the mental health of rural residents. The increasingly prominent problem of health human resource allocation in rural areas affects the quality and coverage of medical services and has an important impact on the psychological health of rural residents.Subjects and Methods: Through collecting relevant literature and field research, this paper analyzes the main problems of rural health human resource allocation, including insufficient number of medical personnel, low level of medical technology, and uneven distribution of medical resources. These problems have led to difficulties in accessing medical services and mental health support for rural residents. This dissertation also explores the relationship between rural health human resource allocation and the mental health of rural residents.Results: An unreasonable allocation of health human resources can lead to rural residents\u2019 dissatisfaction and distrust of medical resources, which in turn affects their mental health status. The lack of professional mental health service personnel and psychological support mechanisms is also an important cause of mental health problems among rural residents. However, some positive practices and countermeasures have been proposed, including strengthening the training and introduction of health human resources, improving the mental health literacy of medical personnel, and establishing a sound mental health service network.Conclusions: Through an in-depth study of the impact of rural health human resource allocation on the mental health of rural residents, we can better understand the root causes of the problem and the mechanisms of influence, and make corresponding policy and practice recommendations. Improving rural health human resource allocation and providing better medical services and psychological support are important for promoting the mental health of rural residents. This study provides useful references for relevant departments and policy makers to better respond to the rural health human resource allocation problem and improve the mental health of rural residents.a, Jin Yana, Feiqin LibKaigang Yia School of Business Administration, Zhejiang Gongshang University, Zhejiang, 310018, China, b Zhejiang Gongshang University Hangzhou College of Commerce, Zhejiang, 311508, ChinaBackground: Credit is the key mental health factor to support the economic development of the platform, while demand-side users are the direct \u201cfact implementers\u201d of credit fraud on the network platform, but they are also easily overlooked subjects. Studying the formation mechanism of demand-side users\u2019 credit fraud from the perspective of consumer psychology can provide a new direction for the governance of credit fraud on the network platform. Based on the theory of planned behavior and fraud risk factors, this paper integrates and constructs a theoretical model of the mechanism of credit fraud of platform demand-side users through theoretical applicability analysis.Subjects and Methods: On the basis of theoretical deduction, seven hypotheses were constructed, and 312 valid questionnaires were collected by taking the demand-side users of online shopping platform as the empirical research object. On the basis of reliability and validity test, the structural equation model was used to statistically test the fitting degree and research hypotheses of the whole model, and then the nest model method was used for further verification.Results: (1) attitude of credit fraud, subjective norms of credit fraud, and control of perceived behavior of credit fraud have direct positive effects on the intention to commit credit fraud; (2) Perceived risk indirectly affects the intention to commit credit fraud through the control of perceived behavior of credit fraud; (3) Risk preference plays a moderating role in the influence of perceived risk on the control of perceived behavior of credit fraud.Conclusions: According to consumer psychology, credit fraud committed by platform demand-side users is influenced by personal morality and interests, government supervision and punishment, and important stakeholders in society, which provides a certain direction for innovative research on governance countermeasures. (1) At the regulatory level, the government and the platform main body should first pay more attention to the harmfulness of credit fraud of demand-side users of the platform, and speed up the formulation of special programs or special documents to deal with this problem; (2) At the technical level, we should, on the basis of the relatively mature technical discrimination against credit fraud of platform supplier users, draw lessons and innovate technical means to strengthen the transaction management of demand-side users, and use technology to empower supervision and warn fraud, so as to reduce the implementation space of fraud; (3) At the social level, it is necessary to carry out thematic series of publicity and reports in combination with the special actions of industry and commerce department, public security department and other departments aimed at the governance of online platform credit fraud.This paper was funded by the Youth Project of the National Philosophy and Social Sciences Foundation (19AGL009) and the Zhejiang Philosophy and Social Science Foundation (17NDJC218YB).a, Xiaoyu Changa, Qinglan Liua, Jiewei Liub, Ruili Lib, Kaiwen Zhaoc, Dawen Zhanga, Yingmei Yua, Huanhuan Wana, Biaojin Zhanga, Siming LiaHan Yana Key Laboratory for quality and safety control of poultry products, Ministry of Agriculture and Rural Affairs of the People\u2019s Republic of China, Institute for Quality & Safety and Standards of Agricultural Products Research, Jiangxi Academy of Agricultural Sciences, Nanlian Road 602, Nanchang 330200, China, b Institute of Animal Science, Yantai Academy of Agricultural Sciences, Yantai, Shandong 265500, China, c Nanchang Institute of Technology, Nanchang, Jiangxi 330044, China.H Yan and XY Chang contributed equally to this study.Background: The trace element selenium is not only one of the essential nutrients for the human body, but also an indispensable element for animal growth and development that is closely related to many important physiological functions of animals. At the same time, a lack of selenium lowers the body\u2019s immune function, which is a hallmark of depression. This experiment was designed to investigate the effects physiological functions of different selenium sources on slaughter performance, meat health and antioxidant activity of Dongxiang green-shell laying hens.Subjects and Methods: A total of 450 30-week-old healthy Dongxiang green-shelled laying hens with similar body weight were randomly divided into 9 groups. All the animals were fed the same basal diet. The control group was fed a non-supplemented diet. T1 and T2 were added sodium selenite (SS).T3 and T4 were enriched with selenium yeast (SY). T5 and T6 were fed with diet comprising Kappa-Selenocarrageenan (SK). And T7 and T8 were supplemented with selenomethionine (SM). And the concentrations of each type of selenium medium added above were 0.30\u2005mg/kg and 0.60\u2005mg/kg, respectively. The prefeeding period was 3 days, and the formal experiment lasted for 28 days.Results: 1) The carcass weight of T7 and T8 were increased significantly (P<0.05) compared with the control group. The rate of half breast meat was higher in T7 group higher than in other groups (P<0.05). The abdominal fat percentage in groups T1, T2 and T4 was higher than that in control group (P<0.05). 2) The ovarian index of Dongxiang green-shelled laying hens increased significantly (P<0.05) in T7 and T8 groups. The spleen index of T2 group was lower than that of control group (P<0.05). The liver index of Dongxiang green-shelled laying hens was not significantly affected by different levels of selenium sources in additive groups (P>0.05). 3) Chromaticity values of T1 and T3 were lower than those of the control group (P<0.05). PH value in T2 and T3 groups was higher than that in control group (P<0.05), while that in T6 group was lower than that in control group (P<0.05). A higher Se level was detected in all experimental groups (P<0.05). And selenium content increased with the increasing supplemental level, and T8 group had the highest selenium content, which was 0.191mg/kg. 4) The antioxidant values of liver and spleen in experimental groups were significantly higher than those in control group (P<0.05). Serum antioxidant values of experimental groups except T1 were significantly higher than those of control group (P<0.05).Conclusions: Different selenium source levels can regulate physiological and immune functions of Dongxiang green-shelled laying hens. Reasonable supplementation of organic selenium sources, especially selenium-rich yeast and selenium-methionine can improve slaughter performance, meat quality and antioxidant capacity of Dongxiang green-shelled laying hens.This work was supported by two key research and development projects of Jiangxi Province, their project numbers are 20202BBFL63029, JXXTCXNLTS202103 and 20202BBF63011.a, Yiwen CaoaYuan Wanga Institutes of Education, Dalian University, Dalian, Liaoning, China.Background: The big data era has changed society, including education, requiring teachers to possess data literacy skills. However, little research exists on primary school teachers\u2019 data literacy skills, particularly regarding gender psychological differences. This study aims to investigate potential gender psychological differences in data literacy to promote gender equity in developing these skills. Understanding gender psychological differences can enhance teachers\u2019 ability to use data to improve teaching decisions.Subjects and Methods: The study collects data on the completion process and results of assignments of pre-service elementary school teachers of different genders through an online teaching platform that assigns data analysis assignments in education and teaching fields. The study also uses a questionnaire to gain insight into the current gender psychological differences in data literacy of pre-service elementary and secondary school teachers in China. The questionnaire is divided into two parts, the first part is the basic information of the respondents, and the second part is a survey on the current situation of data literacy of pre-service elementary school teachers of different genders. The study conducts a big data analysis using descriptive statistics, t-tests, and regression analysis to analyze the data. Understanding gender psychological differences can enhance teachers\u2019 ability to use data to improve teaching decisions and promote gender equality.Results: This study analyzed the data literacy of pre-service elementary school teachers of different genders in terms of their completion of data analysis assignments, four dimensions of data literacy, and gender psychological differences. The results showed that male pre-service elementary school teachers have slightly higher data literacy than female pre-service elementary school teachers. The mean score of data literacy of male pre-service elementary school teachers was high, while the mean score of data literacy of female pre-service elementary school teachers was moderate. Male pre-service elementary school teachers had a significantly higher mean score than female pre-service elementary school teachers in the core skills dimension. The regression analysis showed that gender was a significant predictor of data literacy after controlling for age and educational level. The findings suggest the importance of addressing gender psychological differences in data literacy and providing targeted training programs to promote data literacy among female pre-service teachers.Conclusions: The study found significant gender psychological differences in specific aspects of data literacy among pre-service elementary school teachers in the context of big data. Despite similar overall levels of data literacy between male and female participants, targeted interventions are necessary to address these differences and improve the data literacy skills of all pre-service teachers. However, the study\u2019s limitations suggest the need for larger, more diverse samples and objective measures of data literacy in future research. Overall, the study contributes to our understanding of gender psychological differences in data literacy and highlights the importance of addressing these differences to effectively navigate the era of big data in education.aAihua Liua School of Preschool Education, Changsha Normal College, Changsha, Hunan, China.Background: To explore the influence of Chinese excellent traditional cultural knowledge and experience level on the development tendency of prosocial behavior of children aged 5-6 based on children\u2019s native mental health education.Subjects and Methods: 260 children from 8 classes of 3 kindergartens in XX Province of China were selected as subjects, including 2 in cities and 1 in township, aged 5-6 years, all of whom were native speakers of Chinese. After conducting the prosocial behavior development tendency evaluation on 260 people, 130 children  randomly selected from the main test participated in the interview on the knowledge and experience level of Chinese excellent traditional culture and scored. 7 modules of \u201csocial adaptation\u201d of 5-6 years old in the Chinese version of the Guidelines for the Development of Children Aged 3-6 years old were used as the evaluation tool of prosocial behavior development tendency; Compile the knowledge and experience of Chinese excellent traditional culture and the main test questionnaire. Statistical analysis was conducted for the two types of results.Results: There is a statistical correlation between the level of knowing and experiencing Chinese excellent traditional culture and prosocial behavior development tendency; The difference of prosocial behavior development tendency between high level group and low level group was statistically significant; There is a statistically negative correlation between the level of knowledge and experience excellent Chinese traditional culture and the modules of \u201clike and adapt to group life\u201d and \u201cabide by basic rules of behavior\u201d, which lead to the risk of mental health education.Conclusion: There is a statistical correlation between the level of knowledge and experience excellent Chinese traditional culture and the development tendency of prosocial behavior of 5-6 year old children, and there is a statistical correlation with some high-level prosocial behavior modules; The unsuitable education mode of Chinese excellent traditional culture has educational risks, which have a negative impact on the mental health of preschool children.a, Chen Yea, Xiaoyi Hub, Yan JiangcYun Luoa School of Education, Zhaoqing University, Duanzhou District Zhaoqing, 526061, China, b Faculty of English Language and Culture, Guangdong University of Foreign Studies, 2 North Baiyun Street, Guangzhou, 510420, China, c Psychological Counseling Center, Shanghai University, 99 Shangda Road, Baoshan District, Shanghai, 20444, China.Background: Since 2020, great social changes have occurred, and people\u2019s mental health have been affected due to the COVID-19 pandemic. The COVID-19 outbreak changed the lifestyle of college students significantly. One of the changes is in learning experience. The shift from traditional, offline, face-to-face teaching to online teaching often requires the use of smart devices. Studies have shown that incorrect or problematic smartphone use will lead to depressive symptoms. The model of recovery from depressive symptoms states that while facing malignant life events, individuals with depression will experience higher levels of hopelessness. Thus, people prefer to explain and attribute malignant life events in negatively and individual attribution will affect the level of academic burnout. This study explored the relationship between depressive symptoms and academic burnout among university students during the COVID-19 pandemic.Subjects and Methods: We conducted an online survey with 3,123 undergraduates from universities in Shanghai from March to April 2020. The study used the nine-item Patient Health Questionnaire, Maslach Burnout Inventory\u2013Student Survey, and Positive Psychological Capital Questionnaire. In this study, SPSS 26.0 was used to perform an independent sample t test for groups between students whose academic performance was affected by the pandemic and students whose academic performance was not affected, and the results demonstrated that it was statistically significant. Second, descriptive statistics and correlations for the two groups were analyzed for three dimensions. Third, AMOS 23.0 was used to construct the structural equation model and analyze it to test whether the mediation model was valid.Results: The results showed that depressive symptoms predicted academic burnout. Psychological capital played a mediating role between depressive symptoms and academic burnout. The higher the level of depressive symptoms, lower the level of psychological capital and higher the degree of academic burnout. Furthermore, the effects among students whose academic performance had been affected by the COVID-19 pandemic were significantly different from those whose academic performance had not been affected.Conclusions: These findings have potential implications for practical measures while facing a pandemic. Positive psychological capital is conducive for college students and for the establishment and maintenance of a stable mental health state during the COVID-19 pandemic. Furthermore, in this study, the effect of psychological capital on academic burnout manifests not only in its own characteristics but also from its opposite side: psychological inflexibility, and scholars have explained this mechanism. Thus, depressive symptoms are significant negatively predicted academic burnout through psychological capital and its four dimensions.aHanyang Lia School of Journalism and Communication, Minnan Normal University, Zhangzhou, 363000, ChinaBackground: Federico Fellini\u2019s film Amarcord, released in 1973, presents a vivid and surreal world that captures the essence of a small Italian provincial town in the 1930s. The film combines chaos, absurdity, and ordinary life to create a poetic and humorous narrative. Fellini\u2019s unique aesthetic style reconstructs the dreams, dignity, and poetry of ordinary people during that era. This article explores the carnival poetics theory proposed by Mikhail Bakhtin and its relevance to understanding the imagery in Amarcord.Subjects and Methods: The article applies Bakhtin\u2019s theory of carnival poetics to analyze the film\u2019s imagery. The theory describes carnival as a festival that breaks social norms, allowing for subversion and renewal. It emphasizes the universal, inclusive, festive, and dual nature of carnival laughter. The analysis focuses on the structure of Amarcord, the carnival-like atmosphere throughout the film, and its portrayal of universal laughter, festiveness, and duality.Results: The analysis reveals that Amarcord exhibits the key features of carnival poetics as defined by Bakhtin. The film\u2019s structure is a mosaic-like collection of stories that portray the town\u2019s life in a comical manner. Laughter permeates the film, representing a carnival-style banter that is universal and inclusive, embracing all aspects of life. The festive atmosphere in the film reflects a connection between the cycle of seasons and the cycle of human life, emphasizing rebirth and renewal. The duality in Amarcord is evident in its use of laughter to both reflect and criticize societal norms, ideologies, and institutions. This duality offers a thought-provoking perspective on the world, inviting viewers to challenge rigid and stagnant beliefs.Conclusions: Fellini\u2019s Amarcord effectively captures the spirit of carnival through its imagery and narrative. The film\u2019s carnival poetics, influenced by Bakhtin\u2019s theory, presents a world that is simultaneously ordinary and extraordinary. The universal laughter, festiveness, and duality depicted in the film challenge established hierarchies and ideologies, providing a profound reflection on human existence. Amarcord\u2019s exploration of the carnival spirit offers viewers an opportunity for introspection, renewal, and a deeper understanding of the complexities of life. By engaging with the film\u2019s carnival imagery, audiences can experience a psychotherapeutic effect that encourages critical thinking and reevaluation of societal norms. Ultimately, Amarcord stands as a timeless masterpiece that invites audiences to revisit its poetic images and contemplate the inherent truths of the human experience.a, Yi FengaHongsu Chena School of Art and Design, Beijing Forestry University, Beijing, China.Background: The increasing abundance of material goods and the rising health awareness of the whole population. Healthy living has become the new trend, and healthy eating is an important part of it. Healthy cooking not only reduces the loss of nutrients in food, but also prevents cancer and can effectively reduce the incidence of diseases such as high blood sugar and high blood cholesterol. Maintaining a healthy diet over time reduces the risk of obesity, cardiovascular disease, diabetes and other chronic diseases. Physical health has a positive effect on mental health. At the same time, healthy eating habits can improve the user\u2019s sense of pleasure and contribute to mental health. With the Chinese eating habit of three meals a day, rice cooker is an essential household appliance. Kansei engineering theory is widely used in many fields and provides new ideas for understanding the shape of the user\u2019s favourite smart rice cooker.Subjects and Methods: Based on the design method of Kansei engineering theory, the product appearance design strategy of intelligent rice cooker is studied. Establish a product sample space through market research, extract product design elements, collect perceptual image vocabulary, and then measure users\u2019 perceptual needs using semantic difference method. Key perceptual image words are obtained through factor analysis. Then perform partial correlation analysis on the results of the above methods to identify the corresponding relationship between factors and perceptual image space. Finally, obtain the corresponding relationship between the user\u2019s emotional needs and the design elements of the intelligent rice cooker.Results: Translate the mapping relationship between emotional needs and design elements into design strategies. The more exquisite the smart rice cooker looks outside, the easier it is to win the favor of users. Users choosing smart rice cookers can effectively improve their nutritional level and dietary health, ensure their physical and mental health can balance development, and achieve the goal of physical and mental health.Conclusions: This research mainly uses the research methods of Kansei engineering to guide the appearance design of smart rice cookers, effectively providing new design ideas for the design and development of smart rice cookers, which is conducive to improving consumers\u2019 satisfaction with the appearance of smart rice cookers.a, Lili Huanga, Xinmin Yanga, Di Wua, Yan LiaLixin Bua Chengde College of Applied Technology, Chengde, 067060, China.Background: The objective of the study is to establish an evaluation system that can mobilize teachers to devote themselves to education, thus cultivating a generation of the new era with overall development of moral qualities, intellectual ability, physical fitness, aesthetic appreciation, hard-working spirit, and healthy mentality. Guided by establishing scientific education objectives to ensure a correct development direction of education, the establishment of the new system starts from the perspective of guiding the psychological health of teachers and students, and shaping their positive qualities. Aimed at cultivating the positive power and qualities of teachers and students, developing their psychological potential, and promoting a full, vibrant, and happy life for them, the evaluation features \u201cimproving result, strengthening process, exploring added value, and improving comprehensiveness\u201d.Subjects and Methods: Firstly, based on modern information technology, the study aims to comprehensively showcase the positive psychological factors that lead teachers\u2019 professional growth and students to possess a scientific career, energetic emotions, optimistic personality, and other positive psychological factors. The experimental goals of the study are ensured by scientifically and accurately identifying the core elements that affect teachers\u2019 educational ability and students\u2019 physical and mental health, developing scientific and effective intervention strategies, increasing positive emotions among teachers and students, shaping optimistic personalities, and tapping into psychological potential, so as to maintain the best state of their lives and to achieve happiness in education. Secondly, strategies and design plans will be formulated in research and practice from the aspects of core goals, consensus on concepts, institutional construction, team building, practical promotion, expected results, and demonstration and promotion. A scientifically sound new evaluation model will be formed ultimately, which will guide the implementation of the fundamental task of cultivating morality and virtues, establish standards for improving students\u2019 physical and mental health education and guide the promotion of \u201c Educating Six Domains Simultaneously\u201d. This model will further lay a foundation for improving the quality control system, adding impetus to the modernization of governance in vocational colleges.Results: The \u201cFive Ones\u201d goals of the reform: to establish a system; to cultivate a new generation; to generate a batch of achievements; to foster virtue through education; to develop a new evaluation model that guides teachers and students to establish correct values and promote the development of physical and mental health.Conclusion: Guided by the overall development of moral qualities, intellectual ability, physical fitness, aesthetic appreciation, hard-working spirit and healthy mind, the new evaluation system targets at guiding teachers to establish the goal of \u201c cultivating morality and virtues \u201c and leading students to coordinated development of thought, body, mind, academic ability, and personality. The model will fully utilize information technology to extract core elements that affect teachers\u2019 professional development and students\u2019 physical and mental health. An internal evaluation system will be formulated through Directionality Principle in psychology, helping teachers and students better unleash their potential and creativity. The system highlights the distinct characteristics of vocational education as a type of education, which will promote the high-quality development of the college and play a leading and exemplary role in evaluation reform in corresponding regions.Research Project of Social Science Development in Hebei Province in 2022 (Project category: key project. Project number: 20220101003).a, Han YanbXiaoyan Chena School of Economics and Management, North China University of Technology, Beijing, China, b School of Management, Xiamen University, Fujian, China.Background: In the context of China\u2019s green development strategy system, corporate environmental governance and executives\u2019 management mode both face great challenges. How to achieve excellent business performance and environmental performance in the market competition raises many questions about executive psychological anxiety. Corporate executives show many unhealthy psychological problems and psychological anxiety, such as short-termism and utilitarianism, they are eager to pursue short-term corporate value and make decisions that harm the environment. It is urgent for enterprises and the whole society to find correct solutions to achieve personal development, sustainable economic and social development. For example, when corporate environmental violations occur, the government\u2019s environmental penalties and enforcement can timely ease such psychological anxiety problems of executives and improve their correct cognition of sustainable environmental governance, and enhance their positive attitude of other business management behaviors such as corporate tax payment.Subjects and Methods: This paper aims to explore the impact of government environmental penalties on corporate tax burden and executive psychological anxiety. This paper subdivides environmental penalties into two dimensions: environmental penalty frequency and environmental penalty intensity based on the breadth and depth of environmental penalties. Then I take Chinese listed firms in heavy pollution industries as research samples, and use OLS regression analysis to test the impact of environmental penalty frequency and environmental penalty intensity on corporate tax burden. Finally, I conducted field interviews with some executives to analyze the impact of environmental penalties and law enforcement on their psychological anxiety.Results: The study finds that both the frequency and intensity of government environmental penalties have a significant positive impact on corporate tax burden, indicating that the more environmental penalty frequency and the greater environmental penalty intensity, the higher level of corporate tax burden. Further analysis shows that the direct influence path of the above effect is the increase of corporate tax payment rate and corporate income tax burden, and the indirect influence path is the decrease of tax shield effect of corporate new bank loan. In addition, the interview study finds that executive psychological anxiety about short-termism and utilitarianism has been effectively alleviated after the government\u2019s environmental penalties.Conclusions: The results show that environmental law enforcement can help ease executive psychological anxiety problems in terms of corporate sustainable development, and enhance their positive attitude of business management behaviors such as environmental sustainability and tax payment. This study reminds executives to focus on long-termism rather than short-termism. In addition, this study has important practical significance and enlightenment for promoting the multi-party co-governance of environmental governance by the government, tax authorities and firms. I suggest that the government, tax authorities and firms should make joint efforts to create a good environmental governance system.This research was supported by Research Foundation Project of North China University of Technology (Grant No. 110051360002).a, Dandan Wangb, Yulan YubJun Luoa Guangdong University of Science and Technology, Dongguan, China, b Department of Psychology/ Research Center for Quality of Life and Applied Psychology, Guangdong Medical University, China.JL and DW contributed equally to this work.Background: Adverse childhood experiences (ACEs) are associated with pool mental health, whereas few studies paid attention to the potential buffers. This study aims to: (a) establish predictive relationships between ACEs and character strengths (CS); and (b) exam the joint contribution of ACEs and CS to predict depressive symptoms.Subjects and Methods: We used systematic sampling technic to get samples and performed a self-administered survey among students at a university in southern, China. We analyzed data through descriptive statistics, logistic regression model and mediating effect analysis.Results: Linear regression model in the present study showed that history of ACEs predicted lower relationship (p=0.049), enthusiasm (p=0.009), vitality (p=0.0002) domains of character strengths significantly, while vitality (p=1.23e-08) and justice (p=0.03) domains predicted lower depressive symptoms significantly. Vitality domain of character strengths was a full mediator in the relationship between ACEs and depressive symptoms among university students. Indirect effect was 0.25, 95%CI , and direct effect was 0.21, 95%CI , and total effect was 0.46, 95%CI . Proportion of mediation was 54%.Conclusions: Vitality domain of character strength mediated the effect of ACEs on depressive symptoms fully. The finding provided mechanism explanation and empirical evidence for future intervention direction among university students with ACEs. However, caveats regarding recall bias, social desirability bias, and lack of generalizability are also recommended in the interpretation of the study findings.This research was funded by Guangdong Provincial Philosophy and Social Science Planning Project (GD22XJY25) and Postgraduate Education Innovation Project of Guangdong Province (2022JGXM106).aZemei Shena School of Medicine, Chongqing Institute of Engineering, Chongqing, China.Background: The purpose of this paper is to explore the feasibility of cross-regional coordinated development and cooperation between private universities in the two cities under the drive of the Chengdu-Chongqing economic circle, and its influence on students\u2019 psychological health, and to sort out the problems of students\u2019 psychological health in this process.Subjects and Methods: Literature research method was used to study and analyze the present situation, theoretical basis, driving factors of cross-regional collaborative development of private universities in Chengdu-Chongqing Economic Circle, as well as the importance, convenience and substantive significance of factors influencing students\u2019 psychological health, main problems, and cross-regional development of professional education on the maintenance of students\u2019 psychological health, in the hope of helping private universities in Chengdu-Chongqing Economic Circle achieve cross-regional coordinated development, and also to alleviate students\u2019 psychological problems such as learning pressure and learning anxiety in the process of cross-regional development of professional education in private universities in both places, so as to maintain the psychological health of students in private universities in both places.Results: The study found that private universities are an important part of higher education in China. Under the drive of the Chengdu-Chongqing Economic Circle, a study on the development status of private universities in the Chengdu-Chongqing economic circle and the promotion of cross-regional coordinated development between private universities in the two cities can better promote the scale and cluster-based management of private universities in the Chengdu-Chongqing economic circle, improve the quality of education, and provide more comprehensive talent and intellectual support for the current construction of the Chengdu-Chongqing economic circle. Meanwhile, discussing the influence of the cross-regional development of professional education in private universities in the two places on the maintenance of students\u2019 psychological health can also provide some help for the training of talents in the two places and escort the smooth cross-regional coordinated development of private universities in Chengdu and Chongqing.Conclusions: Private universities in the Chengdu-Chongqing Economic Circle should strengthen cross-regional coordinated development, learn from each other\u2019s strengths, and progress together. Meanwhile, due to the challenges that students may face in the process of cross-regional coordinated development, such as poor resilience, fear of learning, high learning pressure, and anxiety, it is important to pay attention to and jointly maintain students\u2019 psychological health.Fund Project: \u201cResearch on Influencing Factors, Mode Construction and Realization Path of Cross-regional Coordinated Development of Private universities in Chengdu-Chongqing Economic Circle\u201d in Research and Planning Project of Humanities and Social Sciences of Chongqing Education Commission in 2022 (22SKGH502); The offline \u201cgolden course\u201d of Chongqing Institute of Technology\u2019s \u201cGolden Courses\u201d Construction Project in 2021\u2014Market Survey (KC20210323).aJie Baia Zi Jie Medical Beauty, Beijing 100006, China.Objective: This study aims to investigate the effect of lower eyelid blepharoplasty via transconjunctival route combined with nano fat transplantation in orbital rejuvenation.Methods: Retrospective analysis was conducted on 126 orbital rejuvenation surgery patients admitted in our hospital from August 2019 to August 2021, who were divided into combined surgery group and conventional surgery group according to the treatment approach. Patients in the combined surgery group received lower eyelid blepharoplasty via transconjunctival route combined with nano fat transplantation, including a total of 76 patients, and patients in the conventional surgery group received lower eyelid blepharoplasty via transconjunctival route, including a total of 50 patients. The recovery results of the two groups at 6 months after surgery were observed, and the tear trough deformity scale scores, patient satisfaction and postoperative complication rates of the two groups were compared.Results: The postoperative TTRS scores decreased in both groups, with more obvious decrease in the combined surgery group than in the conventional surgery group, showing significant difference between the two groups (P < 0.05). The surgical satisfaction rate was 96.05% in the combined surgery group and 80.00% in the conventional surgery group, showing statistically significant difference between the two groups (P < 0.05). The incidence of postoperative complications was 11.84% in the combined surgery group and 24.00% in the conventional surgery group, showing no statistically significant difference between the two groups (P > 0.05).Conclusion: Lower eyelid blepharoplasty via transconjunctival route combined with nano fat transplantation has good efficacy in orbital rejuvenation, with patients\u2019 symptoms significantly alleviated. The surgery has certain safety, and patients have high satisfaction with the postoperative results.a, Zhihui Yangb, Zhifei Songa, Xiaobo TaoaXihuang Laia Graduate School, North China University of Technology, Beijing, China, b Brunel London School, North China University of Technology, Beijing, China.Background: Improving postgraduates\u2019 mental health will be implemented as an important reference factor for the layout of degree authorization points. The integration between industry and education is an important way to guarantee postgraduates\u2019 mental health. Those joint training bases built on the mutual collaboration provide strong guarantees for graduates in shaping their mental health, cultivating the application ability of basic theory and expanding the field of vision of industry.Subjects and Methods: This paper proposes a strategy of multi-dimensional mutual encouragement and integration, multi-mode construction approaches, as well as multi-dimensional evaluation and guarantee system, which can better solve the problems of shortages of resources, lack of mutual trust in school enterprise cooperation, imperfect operation mechanism and system, which exist widely in local universities and have significant impact on postgraduates\u2019 mental health. In addition, combined with the operating experience of the joint training base for graduate students in relevant universities, an overall management scheme of the bases is given from the viewpoint of base creation, daily management and sustainable development of bases in order to provide practical implementation reference for the construction of bases among local universities.Results: The construction of the joint training base for graduate students of the school has achieved initial results. Up to now, the number of off-campus joint training bases for graduate students has grown from 8 at the beginning to 180 at present, and the production and education integration joint training base has truly achieved a win-win situation between school and enterprise, both of which improve postgraduates\u2019 mental health to a great extent.Conclusions: To improve postgraduates\u2019 mental health, universities should start from the three aspects of \u201cmulti-mode training base\u201d, \u201cmulti-faceted training guarantee\u201d and \u201cmulti-dimensional evaluation system\u201d to build a joint training base construction mode of \u201cmulti-dimensional mutual encouragement\u201d. With the overall goal of \u201cprofessional knowledge plus ability expansion\u201d, the school has established a graduate ability pool and provided ability reports for graduate students. \u201cMulti-mode training base\u201d, \u201cmulti-faceted training guarantee\u201d and \u201cmulti-dimensional evaluation system\u201d have formed a new model for the construction of joint training bases for graduate students in local universities, and the three influence and promote each other to achieve pluralism and unity, which can effectively mobilize the enthusiasm of enterprises and participate in the construction of practice bases, and improve postgraduates\u2019 mental health significantly.This article is a phased research result of the 2021 ideological and political work research topic of Beijing colleges and universities by the Education Work Committee of the Beijing Municipal Committee of the Communist Party of China and Beijing Higher Education Teaching Reform and innovation project, \u201cConstruction and Implementation of an Evaluation System for the Comprehensive Development of Postgraduates Oriented by Ability Cultivation\u201d (Project No.BJSZ2021ZC63).a, Yuan Songb, Tao Liub, Jiaxuan Shena, Xudong Lianga, Jing Qiaoa, Keyu Zhua, Shenghua LibTuanzhuang Zhanga Gansu University of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Lanzhou 730000, Gansu Province, China, b Gansu Hospital of Traditional Chinese Medicine, Hand Surgery, Lanzhou 730050, Gansu Province, China.Background: This study aims to investigate the effect of Xiaozhong Zhitong mixture on flap ischaemia-reperfusion (I/R) injury and its action mechanism.Methods: Sixty SPF SD rats were randomly divided into six groups (n=10 each): sham operation group, model control group, Xiaozhong Zhigang mixture group, p38MAPK inhibitor group, PPAR\u03b3 inhibitor group, and NF-\u03baB inhibitor group. Random flaps (8cm\u00d72cm) were constructed on the back of rats except those in sham operation group. After operation, the flaps were sutured in situ with 3-0 suture to establish the flap I/R injury model. At 7 days after surgery, the rats were observed morphologically and the levels of TNF\u03b1, IL-6 and intercellular adhesion molecule-1 (ICAM-1) were measured. Western blotting was used to detect the protein expression of p38 MAPK-PPAR\u03b3/NF-\u03baB pathway. The whole genome chip was used to screen the differentially expressed genes after treatment, and the expression patterns of the differentially expressed genes were analyzed by clustering, GO and KEGG. The differentially expressed genes and the biological processes and the most important signal transduction pathways in the process of Xiaozhongzhipain mixture in the treatment of flap ischemia reperfusion injury were screened. The highest and lowest temperatures of the flaps of rats were detected by infrared thermography, and the edema and leukocyte infiltration of the flaps were observed by hematoxylin-eosin staining.Results: On POD 7, the survival area of rats in the Xiaozhong Zhitong mixture group, p38 MAPK inhibitor group, and NF-\u03baB inhibitor group increased. The levels of TNF\u03b1, IL-6 and ICAM-1 were decreased by Xiaotumorzhidong mixture, p38 MAPK inhibitor and NF-\u03baB inhibitor. Xiaozhong Zhutong mixture can up-regulate the expression of PPAR\u03b3 and I\u03baB\u03b1, and down-regulate the expression of p38MAPK and NF-\u03baB. The whole genome microarray analysis showed that the attenuation of flap I/R injury by Xiaotumoranalgesic mixture was related to inflammatory response, immune system process regulation, cell proliferation, cell adhesion and neutrophil migration. Xiaotumorzhidong mixture can alleviate flap I/R injury in PPAR signaling pathway, MAPK signaling pathway and NF-\u03baB signaling pathway.Conclusions: The Xiaozhong Zhitong mixture may reduce I/R injury in rat flaps by modulating the p38 MAPK-PPAR\u03b3/NF-\u03baB pathway.This work was supported by a grant from the Regional Project of the National Natural Science Foundation of China (Grant No.81860863).a,b, Chunyan Daia,c,dChaoyan Denga Rattanakosin International College of Creative Entrepreneurship, Rajamangala University of Technology, Phuttamonthon, Nakhon Pathom 73170, Thailand, b School of Chemistry and Materials Engineering, Liupanshui Normal University, Liupanshui, Guizhou 553004, China, c School of Management Science and Engineering, Chongqing Technology and Business University, Chongqing 400067, China, d Development Information Management Engineering Technology Research Center in Chongqing, Chongqing 400067, China.Background: As the social progress and economic development have brought about an increasingly warming climate, countries have promised their carbon neutrality goals, and China has solemnly promised to the world that it will achieve carbon neutrality in 2060. For this reason, the relevant carbon emission accounting and scenario prediction are particularly important to provide the technical and theoretical basis for urging the low-carbon transformation of relevant industries. Under the current local policies of industrial revitalization and characteristic tourism development, it is of great significance to analyze and study the carbon emission intensity and residents\u2019 health under the vision of \u201ccarbon neutrality\u201d for Liupanshui as an old industrial city in the former third-line construction, the Coal Capital in the Regions South of the Yangtze River and the Cool Capital of China.Subjects and Methods: In this study, the energy consumption and production carbon emissions of four administrative regions including Zhongshan District, Shuicheng District, Liuzhi Special District, and Panzhou City, which constitute Liupanshui City, were calculated from 2011 to 2020. The carbon emissions increment model of Liupanshui City was constructed by the Logarithmic Mean Divisia Index (LMDI) method, and the impact of carbon emissions on residents\u2019 health in Liupanshui City was studied through qualitative analysis. On this basis, the spatial distribution model of carbon emissions in Liupanshui was constructed by using big data, energy consumption data and infrastructure spatial distribution data. The driving force and influencing factors of carbon emissions in Liupanshui were analyzed by using historical data of Liupanshui, and the internal mechanism of carbon emissions, socio-economic factors and spatial form indicators was explored.Results: The results show that in recent ten years, the overall trend of carbon emissions in Liupanshui is wavy, the trend of carbon emissions per capita is similar to the intensity of carbon emissions, and the intensity of carbon emissions shows a steady downward trend. The empirical analysis of carbon emission increment of energy consumption in Liupanshui shows that the carbon emission increment caused by economic scale effect first increases and then decreases, the carbon emission increment caused by regional structure effect changes little, the carbon emission increment caused by technological progress effect is sometimes positive and sometimes negative, and the carbon emission increment caused by energy consumption structure effect is similar to technological progress effect. Extreme weather caused by greenhouse gases indirectly harms people\u2019s physical and mental health, induces an increase in the incidence of cardiovascular and respiratory diseases, and accelerates the spread and spread of epidemic diseases. Based on people\u2019s recognition, local residents are actively making improvements towards a healthier lifestyle. In addition, the government is also strengthening the introduction of relevant low-carbon policies.Conclusions: The above research results will provide data support and decision-making suggestions for energy conservation and emission reduction, urban planning, and related scientific research, and policy suggestions on how to implement energy conservation and emission reduction planningas well as feasible solutions on how to achieve the goal of \u201ccarbon neutrality\u201d in Liupanshui in the future, a good environment for physical and mental health of Liupanshui residents.The authors gratefully acknowledge the financial support of Guizhou Social Sciences \u201cTheoretical Innovation Project\u201d special fund supported project (No. GZLCZB-2022-3-5-1); Philosophy and Social Science Project of Liupanshui City (No. lpsskllh-2022-76).a, Zhen RenaMingmin Hea Sichuan University Jinjiang College, Meishan 620860, China.Background: The purpose of this study was to investigate the effectiveness of two embodied learning approaches, finger-tracking, and observation-tracking, in Chinese character learning and to explore their relationship with learners\u2019 working memory and students\u2019 anxiety.Subjects and Methods: A total of 31 undergraduate students from non-native Chinese speaking universities, of whom 7 were male and 24 were female, participated in our study. The working memory capacity was measured using the Visual Patterns Test (VPT). The study materials included 36 kanji (12 kanji for each teaching style). We measured the effectiveness of learning through two rounds of tests: immediate post-test and delayed post-test. The effectiveness of finger tracking and observational finger tracking in Chinese language learning was investigated empirically by comparing the performance of the finger tracking group, the observational tracking group and the control group on the recognition and cue recall tasks in the post-test and the delayed post-test. As an indication of experienced anxiety during the learning phase and directly after each of the post-test phases participants were questioned on a 7-point anxiety scale.Results: We found that: 1) the observation tracking learning method could improve the performance on the delayed post-test during the learning of Chinese characters for beginners, resulting in better retention of learning effects and was effective only for learners with low working memory capacity; 2) the finger-tracking learning method had a negative impact on performance in Chinese character learning, especially for learners with low working memory capacity; 3) students in the observation tracking task report significant less anxiety compare to in the finger-tracking learning task and control learning task; students in the finger-tracking learning task report the higher anxiety than in other tasks.Conclusions: The results of this study suggest that when designing instruction for Chinese language learning, instructors should choose a reasonable teaching style. Observational tracking learning as a form of embodied learning helps Chinese language learning and reduces students\u2019 anxiety.The finger-tracking learning method had a negative impact on performance and increased students\u2019 learning anxiety, especially for learners with low working memory capacity.aShiyong Songa School of Political Science and Law, Qilu University of Technology (Shandong Academy of Sciences), Jinan, Shandong 250353, China.Background: The management and legal protection of trade secrets is the common goal of all countries. At the same time, however, the issue of trade secrets profoundly reflects the psychological game between obligees, obligors and infringers. In judicial practice, a large number of infringement cases are actually done maliciously by the infringer based on the unhealthy psychology of prying, which also causes psychological anxiety to the business secret manager that he may leak at any time. Metaverse, as a new concept, has produced great social influence in the economic field of various countries. Blockchain protection of trade secrets is considered to be the best mode in the meta-universe. The characteristics of decentralization and traceability of Blockchain technology can limit the infringer\u2019s unhealthy psychology of snooping, reduce the inner anxiety of trade secret managers, improve their psychological satisfaction and professional happiness, and promote the benign development of trade secret protection.Subjects and Methods: Taking Russia and India of the Shanghai Cooperation Organization for reference, through literature review and empirical analysis, this paper probes into various legal problems faced by countries with trade secret laws and countries without special trade secret protection laws in the two-way psychological game between trade secret owners (managers) and infringers who apply this law. Compared with China\u2019s anti-unfair competition law as the main mode of regulating trade secrets, Russia has a special trade secret protection law. India has not included trade secrets in its intellectual property protection system. India\u2019s trade secret protection mainly provides comprehensive protection through its criminal law, contract law and information technology law. In the face of different legal provisions, anyone will always choose his own behavior mode according to the higher and closer standards of his psychological happiness index. The purpose of this study is to explore the psychological obstacles faced by users at all nodes of Blockchain under the cosmic background , as well as various legal risks and coping strategies at this time.Results: Although the meta-universe has exerted great social influence in the economic fields of various countries, on the whole, the meta-universe is only a beautiful idea under the kidnapping of various kinds of capital, and it does not have the conditions for special legal regulation. Users of Metaverse can\u2019t completely move freely without Blockchain technology, which has caused their psychological limitations in behavior, which is reflected in the protection of trade secrets. They don\u2019t have a higher sense of happiness and satisfaction psychologically because of Blockchain technology, but they continue to need to guard against infringement at all times. At the same time, due to the transnational characteristics of users under the background of Blockchain technology and meta-universe, this psychological fear will be further amplified.Conclusions: Compared with the traditional environment, the meta-cosmic scene is more likely to cause more psychological obstacles to the trade secret owners, and generally has a distrust of new technologies, thus affecting their normal social communication ability. At present, the manipulation of the Metaverse by capital magnifies people\u2019s abnormal snooping psychology and unhealthy psychology of illegal possession of social public assets, which is extremely unfavorable to the protection of trade secrets.This work was supported by: Shandong Philosophy and Social Science Planning Project---Study on the Overall Risk of Blockchain Protecting Trade Secrets in Meta-Universe (Grant No.22CFXJ03); The major special project of regional and country studies  of Shanghai Cooperation Organization of Qilu University of Technology (Shandong Academy of Sciences) (Grant No.2022-122).a, Wenjuan Yana, Dixia Qia, Hui Yaoa, Shuxian Lia, Juan Zhaoa, Nan Kanga, Rongyan Zhanga, Aiqin Xua, Fang Liua, Fang Liua, Juan Zhaoa, Yinghui Pana, Yongfang Fenga, Ningli Suna, Jing Xua, Shunda Liua, Wenjuan Zhanga, Guilian MaaYuxia Zhua Ningxia Hui Autonomous Region People\u2019s Hospital, Yinchuan City, Ningxia, 750002, ChinaBackground: To explore the effect of knowledge-belief-practice model on influencing factors of quality of life in elderly patients with acute myocardial infarction (AMI).Subjects and Methods: 124 elderly patients with AMI were randomly divided into control group and observation group with 62 cases in each group. The control group was given routine nursing through clinical pathway, while the observation group was given questionnaires by patients\u2019 general questionnaire and quality of life rating scale (WHOQOL-BREF) on the basis of the control group, and the results were analyzed by single factor and multivariate analysis.Results: In the observation group, sex, marital status, educational level, heart function at admission, hospitalization times and payment methods of medical expenses were the main factors affecting the quality of life of elderly AMI patients. Logistic regression analysis showed that resilience (CD-RISC), health belief (CHBMS), depression (SDS) and anxiety (SAS) were the influencing factors of comprehensive scores of elderly AMI patients. Taking the above influencing factors as the main problems of intervention research, the KAP model was applied to intervene, and the effects of the two groups before intervention and one week after intervention were compared. After one week of intervention, the scores of CD-RISC and CHBMS in the observation group were 76.89\u2009\u00b1\u20096.82 and 141.12\u2009\u00b1\u200922.28 respectively, which were higher than those in the control group (P < 0.05); SDS and SAS scores of patients in observation group were lower than those in control group (P < 0.05). After the intervention, the scores of knowledge, belief and behavior in the observation group were higher than those in the control group (P < 0.01).Conclusions: KAP model can effectively improve the resilience level, health belief and negative emotion of elderly AMI patients.This work was supported by Ningxia Hui Autonomous Region Science and Technology Benefiting the People Project (2022KJHM0020).a, Qianyu Zhuangb, Junyi Duanc, Jin Xuc, Zhanbiao Zhaoa, Ping ZhangaJianlei Wanga AECC Beijing Institute of Aeronautical Materials, Beijing, China, b National Innovation (Qingdao) High speed Train Material Research Institute Co. LTD, Qingdao, China, c School of Environmental Science and Safety Engineering, Tianjin University of Technology, Tianjin, China.Background: With the rapid development of the construction industry, the number of safety accidents is increasing. Safety psychology is a science that studies people\u2019s psychological state and its changes in production activities. It can point out the direction for how to mobilize the enthusiasm of construction workers to reduce the occurrence of safety accidents. Therefore, how to analyze the psychological problems of construction workers from the perspective of safety psychology, find out the main conflicts causing psychological problems and put forward safety strategies has become a new research task.Subjects and Methods: Based on safety psychology, this paper analyzes and points out the unsafe psychology and occupational health problems of construction workers in the construction industry, as well as the conflict relationship between individuals, families and enterprises (industries) environment, etc., and puts forward safety strategy suggestions for the application of safety psychology in the construction industry. It can achieve the purpose that construction workers have correct occupational health and safety psychology and reduce safety accidents, thus promoting the healthy development of individuals and enterprises.Results: Before the accident, the construction workers generally had fluky psychology, burnout psychology, rebellious psychology, paralysis psychology and conformity psychology, and the prominent occupational health and safety psychological problem was burnout psychology. There are many factors that cause unhealthy psychological problems, such as individuals themselves, families, and enterprises (industries). All parties should pay more attention to the psychology of construction workers, be good at self-regulation, build a harmonious family relationship, and improve the mechanism of enterprises (industries), starting from the maintenance of mental health and the implementation of safety strategies.Conclusions: With regard to the safety strategy of construction workers in the construction industry, it is necessary to explore the psychological activity rules and contradictions of construction workers under the guidance of the theory of safety psychology, so as to accurately predict the unsafe behaviors of construction workers, adjust and deal with unsafe psychology with scientific methods, prescribe the right medicine, and avoid unsafe psychological problems and safety accidents. The safety strategy based on safety psychology has very important theoretical and practical significance for reducing the frequency of safety accidents in construction.a, Lei Wanga,bRong Huanga School of Physical Education, Shaanxi University of Technology, Hanzhong, 723001, Shaanxi, China, b School of Computer Science and Engineering, Xi\u2019an University of Technology, Xi\u2019an, 710048, Shaanxi, ChinaBackground: The World Health Organization has recently recommended the amount of aerobic exercise for teenagers. However, the guidelines are more instructive than practical, and cannot be directly used as the individualized aerobic fitness program for college students. Under the background of \u201ccombination of sports and medicine\u201d, the principle of \u201csuiting the remedy to the case\u201d followed by medical rehabilitation work is also applicable to the sports fitness programs. Meanwhile the manner in which to apply machine learning to individualized aerobic exercise programs has attracted more and more attention. In this research it assumed that the relationship between human body data indicators and aerobic fitness program could be expressed by an artificial neural network.Subjects and Methods: The research aimed to verify the feasibility and effectiveness of constructing the functional relationship between college students\u2019 static body data and aerobic fitness programs based on artificial neural network, and realize the individualized aerobic fitness activities for college students with the assistance of smart bracelets and mobile phones. 60 normal college students  were recruited from Shaanxi University of Science and Technology to measure their static body data, meanwhile the test for heart rate under the aerobic exercise with different intensity and duration was carried out by smart bracelet. Based on the target heart rate (THR), a 3-layer artificial neural network between the static body data of the experimental object and the aerobic fitness program was constructed.Results: We had 52 participants  to complete the experiment on schedule. The 3-layer artificial neural network was constructed by Back Propagation Algorithm which was iterated 5 times, and the relationship between human body indicators and running program was represented by the artificial neural network with 17 parameters in hidden layer and 10 parameters in output layer. However, because of the neglect of the lifestyle and chronic diseases for participant, 2 of 20 college students who engaged in the final test got unexpected result.Conclusions: The college students could achieve THR in exercise according to motion speed and duration of running provided by the artificial neural network without fitness professional. Considering the effectiveness, convenience and popularity, the running was selected as the aerobic fitness event, but there were many other aerobic exercises we could use. The 3-layer artificial neural network could be further optimized through multi-dimensional information obtained from different channels and multi-objective analysis method, by which it could promote the applicable scope of the 3-layer artificial neural network. At the same time, with the rapid development of cloud computing, big data and 5G technology, more complicated, efficient and convenient intelligent exercise prescription system will be constructed.This work was supported by a project grant from the Western China project of National Natural Science Foundation of China (Grant No.21XTY012).a, Junfan XiaoaRui Tana College of Humanities & Social Sciences, Huazhong Agricultural University, Wuhan, China.Background: Patients\u2019 trust deficit in doctor-patient relationships in China has caught research attention in recent times. The risk of trust between doctors and patients makes patients often suffer from anxiety, hesitation and other Negative emotions, which leads to the failure of diagnosis and treatment. Therefore, it is of great practical significance to explore the basis of trust between doctors and patients.Subjects and Methods: This study presents a framework for the effects of patients\u2019 risk resistance regarding patient trust, having applied multivariate regression models to analyse the causes of the patient trust deficit, based on data from the China Family Panel Studies .Results: It was shown that in terms of economic resilience, more comprehensive medical insurance and higher income among patients represented their capability to resist the economic risks induced by medical care, and that their willingness to establish good patient trust was stronger. In terms of social resources, higher social status levels and more stable work statuses improved patients\u2019 capability to handle the risk of medical resources and gave them the confidence to receive good medical services, which positively influenced the establishment of patient trust. With respect to health literacy, sound physical health conditions improved patients\u2019 capability to handle life safety risks.Conclusions: The results show that the lack of patient risk tolerance is the deep-seated reason it is difficult to build patient trust, which is reflected in the fact that the level of patient trust decreases when patients\u2019 economic resilience, social resources, and health literacy are insufficient. Therefore the government should embed the improvement of patients\u2019 risk resistance into all aspects of development of the medical field, pay attention to the assessment of risks faced by patients, and promote the sustainable development of patients\u2019 risk resistance.This study was supported by the Fundamental Research Funds for the Central Universities (Grant numbers: 2662021JC007).a, Tian LiaXueyan Jina College of Arts, Gansu University of Political Science and Law, Lanzhou 730070, China.Background: The construction of the Mogao Caves was influenced by Indian cave temples and embodies the characteristics of traditional Chinese wooden architecture, representing a process of localization of cave architecture. The architectural structure and spatial form exhibit distinct historical and regional features under the influence of geological environment, excavation technology, and subjective psychological perception of cave space by social groups. Forced by the expectation of survival, the lower class people can extricate themselves from the suffering of reality by worshiping Buddha piously, while the grottoes provide people with a space for spiritual practice, chanting and worshiping. The solemn and sacred atmosphere in the space promotes the frescoes of good and evil causality, and the dignified colored sculptures can heal people\u2019s psychological and physiological health, build their values and even promote the renewal of personality changes, help improve their psychological resilience, reduce stress and anxiety, improve their psychological emotions, and place beautiful expectations on life. It has positive significance in mental health and psychological rehabilitation.Subject and Methods: The shape of the main chamber roof in Mogao Caves is mainly divided into flat top, even Ceiling, herringbone drape and truncated pyramidal ceiling top. The number of caves Pyramidal Ceiling top is the largest, it was found that its spatial volume and top slope value showed an increasing trend. It provides a broad field of vision and enhances fluidity, making it possible to create large-scale three-dimensional sculptures and murals. In addition, the transparent and spacious top of truncated pyramid ceiling of cave forms a perspective effect with algae wells that progressively recede from outside to inside at different levels, extending users\u2019 psychological space while reducing feelings of psychological oppression. This is conducive to creating a solemn, peaceful, profound and sacred heavenly world. Devout believers will be integrated with the cave space and consciously immersed in the quiet and harmonious space atmosphere, so that their body and mind can be relieved and their spiritual and emotional sustenance can be relaxed; So as to alleviate the psychological pressure, anxiety, helplessness and other negative emotions brought by real life, maintain psychological balance and ensure mental health.Results: Although ancient people lacked systematic scientific exploration and analysis in constructing caves, they established relatively mature systems for cave structure shapes, proportional scales and environmental psychological mapping through persistent practical exploration and accumulated experience. The Mogao Caves\u2019 architecture not only reflects the progress of construction technology but also shows the development of users\u2019 psychological needs. As experiencers and users of cave architecture, people\u2019s ideology will penetrate every aspect of cave construction. Quantitative factors, such as cave structure, shape, spatial scale, color pattern, etc., will also guide and sort out people\u2019s negative emotions, which is beneficial to mental health.Conclusions: This paper discusses the construction technology of the caves from the space layout, scale, psychological atmosphere and other aspects, and discusses many influencing factors in the caves construction, which provides reliable information for studying the structural characteristics of the caves and the psychological mapping of users to the caves in vision and even subconscious. It is helpful for us to know the outstanding wisdom of the ancients in underground engineering technology and architectural psychology. Find out the positive influence of cave architecture on people\u2019s mental health.In addition to the influence of geographical environment and rock structure, the change and development of the structure and scale ratio of cave architecture are also related to the rule of the regime at that time, the life of the common group and the functional needs of the caves. From the perspective of scientific exploration and using computer simulating test, four models were established based on the same conditions, and the deformation and principal stress of Mogao Caves were compared, and it is found that the stability of pyramidal ceiling > even roof > herringbone > flat roof. Although the excavation was limited by cutting equipment and technique at that time, the top structure of caves cleverly utilized the structure and characteristics of rock mass, and the sequence of excavation from top to bottom reduced the influence on the surrounding rock of caves. Under the condition of no supporting lining, the stability and self-supporting ability of surrounding rock were guaranteed, and the demands of culture spreading and exhibition were taken into account in different times, showing the wisdom and engineering experience of ancient Chinese craftsmen, which had certain guiding significance for underground engineering construction. 2021 Young Doctor Fund Project of Gansu Province (Project No.: 2021QB101).aJia-qing Wanga School of Economics and Management, Wuhan University of Engineering Science, Wuhan 430200, Hubei, China.Background: The essence of psychological anxiety is a kind of psychological sub-health, which is externally manifested as negative and anxious emotions of employees\u2019 work attitude and behavior. In enterprise management, there is a basis for psychological anxiety in addition to personal characteristics, it is also related to the job position, job responsibilities and the management style of superior leaders, especially related to the company\u2019s principle of mutual benefit. The principle of mutual benefit is the basic factor for the harmonious coexistence of the organization, leaders and employees, and it is also the pillar of the maintenance of the organizational system, the implementation of leadership activities and the development of work behavior. If the principle of mutual benefit is not well guaranteed, then psychological anxiety will lose its space for existence, and correspondingly, organizational operation, leadership behavior and work behavior can be smoothly implemented. The principle of interest and emotion is the core of psychological anxiety, and it is also the legal principle of relationship performance and production performance. Charismatic leaders can have a positive effect on employee performance by alleviating psychological anxiety as an intermediate variable. Based on the internal logic of charismatic leadership traits and psychological anxiety, the relationship between psychological anxiety and employee performance and the mechanism of charismatic leadership and employee psychological anxiety alleviation were analyzed.Subjects and Methods: The research goal of this paper is to explore the positive leading role of alleviating psychological anxiety on employee performance from the perspective of organizational operation. The article argues that a leadership style that is highly consistent with the behavior of alleviating psychological anxiety is needed, that is, leadership ability and leadership art that is appealing and attractive. At the same time, based on the internal analysis and examination of the characteristics of charismatic leadership style, it is found that this leadership style feature is compatible with psychological anxiety behavior, and can stimulate employees\u2019 work initiative and enthusiasm in the form of alleviating psychological anxiety, thereby improving employee relationship performance and effectively interacting with organizational performance. By using a variety of statistical analysis techniques such as content analysis, literature analysis, exploratory factor analysis, confirmatory factor analysis, structural equation model and regression analysis, the influence of charismatic leadership on employee performance was studied with psychological anxiety as the mediating variable.Results: Through theoretical analysis and empirical research, it is found that the personal charisma traits of leaders constitute the main dimension of charismatic leadership. From the perspective of leadership behavior practice, the dimension of charismatic leadership is specifically manifested in the following aspects, namely: common vision, caring for employees, paying attention to the environment, daring to take risks and innovation, and extraordinary behavior. Charismatic leadership can play a role in alleviating psychological anxiety because of the application of these five elements. Based on a shared vision, charismatic leaders are usually exemplary and benchmarking to reinforce the alignment of employees with their own tasks, and guide employees to make efforts to improve organizational performance. The impact of charismatic leadership on employee performance is manifested as: the role model of charismatic leadership can strengthen employees\u2019 engagement in work; The vision of charismatic leaders can effectively awaken employees\u2019 work motivation; The personality factors of charismatic leaders can better enhance employees\u2019 loyalty to the organization; Charismatic leaders care for their jobs and improve employee satisfaction.Conclusions: This paper proposes a path for charismatic leaders to improve employees\u2019 performance from the perspective of alleviating psychological anxiety: focusing on the consistency between charisma traits and alleviating employees\u2019 psychological anxiety; Organizational commitments and rules for alleviating psychological anxiety construction should be followed; Caring about job satisfaction in the dimension of employee psychological anxiety; Lead and inspire employee loyalty to the organization.aJunjun Chena Student Affairs Office, Shandong Polytechnic, Jinan, Shandong 250104, China.Background: In recent years, more and more foreign students have entered higher vocational colleges in China. Mental health education of foreign students in higher vocational colleges is facing great challenges.Subjects and Methods: The purpose of this paper is to explore the application of painting psychological analysis in the mental health education of Bangladeshi students in higher vocational colleges, and to explore a new way to promote the harmonious development of physical and mental health of foreign students in higher vocational colleges. A total of 50 Bangladeshi students in Shandong Polytechnic were enrolled in the study. This paper evaluates the reliability and validity through qualitative research.Results: Painting psychoanalysis, which is characterized by its variety, easy operation and freedom from time and space constraints, is mainly used as a means of communication to bring more vitality and enlightenment to the mental health education of college students. The physical and mental health of Bangladeshi students in vocational colleges were fully developed and achieved psychological growth. The classroom atmosphere is more active. The students\u2019 psychological stress was significantly reduced, and their self-identity significantly increased.Conclusions: The psychological analysis of painting is integrated into the mental health education activities of the foreign students in Bangladesh, which is very popular among the foreign students. Through communication, teachers, counselors, students generally agree that painting activity has achieved good results. From the practice, it is found that the psychological analysis of painting is helpful to overcome the negative influence of culture and language, and is suitable for Bangladeshi students to carry out mental health education.aYadong Wanga School of Education, Nanchang Institute of Science and Technology, Nanchang, Jiangxi, China.Background: To explore effective ways of cultivating critical thinking quality of English majors from the perspective of educational psychology, especially the willpower. For willpower plays an important role in the entire process of cultivation of critical thinking quality. Students who possess strong willpower can consciously control and adjust their actions according to the purpose, and can overcome various difficulties to achieve the purpose. Also a strong willpower will usually lead to a strong determination, which is a key factor to success. A strong willpower is also helpful in cultivating students\u2019 healthy psychological mindset and character building.Subjects and Methods: 1. The willpower and motivation method: First, purpose education. To educate the students about the purpose and necessity of cultivating critical thinking quality. Then, turn them into a strong motivation. Third, educate the students about the importance of a strong willpower.When meeting difficulties, encourage them to get over difficulties by their strong willpower. 2. The willpower cultivation method: Besides educating students about the theoretical side of willpower, the teacher also educate them about the practical side, i.e. how to obtain a strong willpower. The teacher adopts various ways to cultivate students\u2019 physical and psychological willpower. To cultivate students\u2019 physical willpower, the teacher requires students to make a very specific plan for physical exercise. For example, running a certain distance every day and stick to it strictly. To cultivate students\u2019 psychological willpower, the teacher requires students to memorize a certain number of English vocabulary every day and stick to it strictly. The teacher controls the process by checking the students\u2019 progress periodically and establish a certain reward mechanism. In this way, help students cultivate a strong willpower as well as a healthy psychological mindset. 3. Integration method: The elements of critical thinking are integrated into classroom teaching activities such as text teaching, writing teaching, reading teaching. Through text analysis, main idea summary and question answering, students\u2019 logical thinking ability is exercised and developed. Through critical writing practice, students\u2019 critical ability is trained and developed.Results: 1. Through teacher\u2019s education of the purpose, the students know the importance and necessity of cultivating critical thinking quality. Through teacher\u2019s willpower and motivation education, the students know the important role the willpower plays in the cultivation process. The students\u2019 learning enthusiasm is greatly aroused with a strong motivation. 2. The logic theory required in the cultivation process is usually abstract, dull and hard to understand. However, through teacher\u2019s willpower education and cultivation, the students\u2019 strong willpower is gradually obtained and further enhanced. Thus, it enables the students to get over various difficulties occurred during the cultivation process. Meanwhile, it also helps the students develop a healthy psychological mindset and a good character.Conclusions: English teaching integrated with cultivation of critical thinking of English majors from the perspective of educational psychology is feasible. For willpower plays an important and irreplaceable role in the cultivation of critical thinking quality and a healthy psychological mindset. In colleges that do not offer a separate course on critical thinking, this method is both realistic and useful.a, Huayu GuanbMingchi Zhua Beijing-Dublin International College at BJUT, Beijing 100124, China, b Finance Office, School of Emergency Technology and Management, North China Institute of Science and Technology, Langfang 065201, China.Background: From the perspective of psychological satisfaction, fintech can reduce the management costs of commercial banks, improve operational efficiency, meet customer psychological needs, and achieve psychological satisfaction, thereby enhancing their core competitiveness. The Internet can break through the limitations of time and space blockade, increase the customer range of commercial banks, improve their psychological satisfaction level, greatly reduce the service costs of commercial banks, and thus increase the psychological satisfaction and loyalty of commercial bank customers.Subjects and Methods: This article studies the impact mechanism and empirical analysis of financial technology on customer psychological satisfaction from the perspective of customer psychological satisfaction, combined with the characteristics of commercial banks, from both theoretical and empirical perspectives. Based on this, this article uses the \u201ctext mining\u201d method to construct the impact index of financial technology, using state-owned large commercial banks, joint-stock banks, and urban commercial banks as samples, and measures the customer psychological satisfaction index, empirically analyzing the impact mechanism of financial technology on customer psychological satisfaction.Results: This article analyzes the impact mechanism of financial technology development on customer psychological satisfaction, and benchmark test results show that the development of financial technology significantly improves the level of customer psychological satisfaction. After a series of robustness tests, the main conclusions of this paper remain unchanged. Mechanism analysis found that the improvement of income level, the development of entrepreneurial activities, and the narrowing of urban-rural income gap are important reasons for the impact of financial technology development on customer psychological satisfaction.Conclusions: Financial technology can improve customers\u2019 psychological satisfaction, increase their happiness index, and achieve psychological satisfaction. According to empirical research results, due to historical and management system reasons, large state-owned commercial banks seem to have a slight lag in responding to external environmental changes, and their impact on customer psychological satisfaction is relatively low. However, equity banks and urban commercial banks are significantly weaker in responding to the impact of financial technology. Therefore, commercial banks should base themselves on their own strength, seize opportunities in the external environment, and enhance psychological satisfaction. At the same time, the government should support the development of fintech, promote the standardization of fintech in China, formulate policies and regulations related to fintech, promote the sustainable and healthy development of the financial industry, and thus improve customer psychological satisfaction and happiness index to a greater extent.a, Fujun Rena, Xiaoling Rua, Hui Guoa, Xiuyou WangaShigan Yua Fuyang Normal University Fuyang, 236041, Anhui, China.Background: The era of emerging engineering has endowed college teachers with a new mission, and training high-quality professionals to meet the needs of emerging engineering has become a new goal. As the core course of computer-related majors, the traditional teaching mode of the course lags behind the requirements of the emerging engineering era, which leads to the lack of learning initiative, low academic performance, backward practical ability, and weak ideological and political consciousness of the students majoring in computer science, thus causing their concerns about their employability after graduation. It makes students worried about their future and causes serious psychological problems. Therefore, the teaching mode of this course needs to be reformed.Subjects and Methods: This paper analyzes the problems in the traditional teaching process, studies the pain points in teaching, faces the strategic requirements of the new engineering era, takes training high-quality talents as the goal, takes students as the center, and makes students busy, teachers strong, management strict and the effect practical. This paper proposes PBL (Problem-based Learning) and \u201cPreview, Bridge in, Discussion, Evaluation, Exercise, Designing\u201d six-step teaching model, Online and offline hybrid teaching ideas, flipped classroom teaching methods, progressive curriculum ideological and political teaching process, experiential learning and Outcome-based Education (OBE) concept combined teaching system and curriculum innovation evaluation system.Results: Through the investigation and statistical analysis of the teaching reform results, it can be found that the innovative teaching reform aiming at the principle of computer composition has enhanced students\u2019 learning initiative, improved their academic performance, increased their practical ability, enhanced their ideological and political awareness, and cultivated a large number of patriotic and high-quality talents required by the new engineering era. It can reduce students\u2019 worries about their future employability and alleviates students\u2019 psychological problems. Conclusions: The new teaching method proposed in this paper has been proved to be efficient in practice, which can improve students\u2019 comprehensive ability, make students full of confidence in the future and relieve psychological anxiety, and preliminarily meet the requirements of the emerging engineering era. The course presenter will continue to promote the reform of teaching mode according to the connotation of the requirements of the emerging engineering, and cultivate a larger team of high-quality professionals.The work was supported in part by Quality project of Anhui Province with Grant number 2018mooc061, 2020xsjxms182, 2020mooc386, 2020zdxsjg260, 2020jyxm1423, 2021sx117, 2021jyxm1121 and 2021jxtd215, in part by Talent research launch start-up project of Fuyang Normal University under grant 2019kyqd0018, in part by Anhui Province university key research project under grant KJ2018A0669 and 2022AH052820, in part by List of first-class undergraduate programs in Anhui Province under Grant 209 and in part by Ministry of Education industry-school cooperative education project under grant 220601363062820.a, Tao Fana,b, Jian Wanga, Yan ShenaHuan Wanga College of Architectural and Civil Engineering, Xinjiang University, Urumqi 830047, China, b College of Architecture and Urban Planning, Tongji University, Shanghai 200092, China.Background: Due to the impact of the Internet on traditional business, bazaars in Xinjiang, China, have developed slowly in recent years. In order to activate this traditional commercial form, the government has carried out a series of construction practices of large bazaars. Although the actual operation effect of many bazaars is ideal, the problem of many bazaars is that the degree of public mental health and happiness is not enough, so it is necessary to study the strategy of commercial promotion based on the degree of public mental health and happiness.Subjects and Methods: The research object of this paper is the most famous commercial complex in Xinjiang -- Xinjiang International Grand Bazaar. Firstly, the objective analysis of customer behavior of Xinjiang International Grand Bazaar on the spot investigation of public mental health and happiness, including: walking traffic space status analysis, walking square space status analysis, function and landscape analysis. Secondly, 743 on-site and online questionnaires were used to conduct subjective analysis and evaluation on the status quo of public mental health and happiness in Xinjiang International Grand Bazaar.Results: Based on the objective analysis and subjective evaluation of public mental health and happiness, it is concluded that Xinjiang International Grand Bazaar puts emphasis on the renovation and upgrading of public square public space, gives full play to the synergistic effect produced by the combination of public space and commercial space, and improves the public mental health and happiness. The space has a strong degree of openness and inclusiveness. However, there is still some room for improvement in the degree of public mental health and happiness: (1) The utilization rate of the square is not enough, the lack of public space to meet different mental health needs. (2) Single functional area to increase functional space to meet more mental health needs. (3) Accessibility is not ideal and happiness is reduced.Conclusions: And finally put forward the promotion of mental health and happiness degree strategy: \u2474 rich square space to meet a variety of mental health needs, to create a comfortable and pleasant rest space, interactive space to promote mental health communication. (2) Expansion and reconstruction of functional zoning, reasonable distribution in each area of the International Bazaar; (3) establishment of body traffic, formation of \u201cmultiple first floor\u201d mode, and use of air corridor to increase building connectivity. This paper studies the degree of public mental health and happiness in Bazaar, the design strategy proposed in this paper can further activate the vitality of the Bazaar, attract consumers to higher floors or underground Spaces, and contribute to a more benign interaction between the International Grand Bazaar and the city, so as to improve its actual operation effect. It provides theoretical reference for the reconstruction of Xinjiang International Grand Bazaar and similar building design in the future.This work was supported by the project grant from 2020 Xinjiang Natural Science Foundation Youth Fund \u201cResearch on the Design Strategy of Public Cultural Service Function Based on Synergy Theory: A Case Study of Xinjiang Commercial Complex\u201d (Grand No. 2020D01C059).a, Mengjie Denga, Hao Tiana, Wenjing HuangbYihua Lia School of Transportation & Logistics, Central South University of Forestry & Technology, Changsha 410004, Hunan, China, b School of Materials Science and Engineering, Central South University of Forestry & Technology, Changsha 410004, Hunan, China.Background: In order to effectively cope with urban public health crisis, improve the toughness of the public health system, improve the level of medical health, and ensure the safety of consumers\u2019 medication. This study focuses on the most pressing difficulties and problems that are of great concern to the people in the field of medical and health. It aims to achieve low cost, high efficiency and high safety distribution of pharmaceutical products by conducting research on the joint distribution mode of pharmaceutical cold chain logistics.Subjects and Methods: In this paper, we first compose the development of pharmaceutical cold chain logistics and its infrastructure construction in China in recent years. Secondly, we compare and analyze three mainstream distribution modes in pharmaceutical cold chain logistics industry. Then we summarize the social benefits of carrying out joint distribution of pharmaceutical cold chain logistics. Finally, we enumerate the technical advantages of blockchain.Results: The results show that the development of pharmaceutical cold chain logistics has a bright prospect, and the implementation of joint distribution in pharmaceutical cold chain logistics can improve resource utilization, reduce business risks, help environmental friendliness and promote healthy development of the industry. The technical advantages of blockchain such as decentralization, distributed storage, tamper-evident, traceability and smart contract provide great convenience for the development of joint distribution business.Conclusions: The blockchain-based information service platform for joint distribution of pharmaceutical cold chain logistics can play a role in reducing costs and increasing efficiency, promoting cooperation and facilitating supervision. In addition, the real-time reaches of logistics data can greatly reduce the medical safety incident caused by the quality of medical products deteriorate in transportation process. The establishment of this information service platform has enlightening significance for the information construction of the entire pharmaceutical logistics industry.Support for this study was jointly provided by General Project of Chinese National Social Science Foundation \u201cResearch on the Balanced Path of the Cold Chain Logistics Structure System of Agricultural Products in the Digital Village Background\u201d (22BGL173), Major project of the Hunan Social Science Review Committee \u201cResearch on the Implementation Countermeasures for Promoting the Equalization of Basic Public Services in Hunan Province by Medical Cold Chain Logistics Driven by Data\u201d (XSP22ZDA006) and General Project of Hunan Natural Science Foundation (2022JJ31015). The authors would also thank all the institutions and units for providing statistical data, information, and documents used in this study.a, Ke Yinb, Yumeng YangcYi Xiaoa College of Public Administration; Chongqing Technology and Business University; Chongqing 400067, China, b College of Geographical and Travel, Chongqing Normal University, Chongqing 400047, China, c College of Business Administration, Chongqing Technology and Business University, Chongqing 400067, China.Background: Poverty alleviation in 2020, farmers still face various types of livelihood risks. In the livelihood risk analysis, livelihood capital is the core of the analysis. Therefore, it is necessary and practical to study the impact of livelihood capital on the livelihood risk and mental health of farmers in poor mountainous areas in Southwest China, so as to provide empirical basis for the government to better formulate relevant policies and consolidate the results of poverty alleviation.Subjects and Methods: Based on this, this study takes the questionnaire of 321 poverty-stricken farmers in the southwest poor mountainous areas as the sample data, analyze the impact of farmers\u2019 livelihood capital on their livelihood risk and mental health.Results: The results show: (1) Livelihood risks of poverty-stricken farmers include natural risks, economic risks, welfare risks and social risks. (2) Economic risk is affected by financial capital and human capital, natural risk is affected by natural capital and material capital, and welfare risk is affected by social capital, financial capital and material capital. Social risk is affected by natural capital and financial capital. It can be seen that human capital and financial capital are the key factors affecting the livelihood risk of farmers.Conclusions: On the one hand, the local government should increase the investment in the human capital of rural households to promote the systematization, diversification and specialization of farmers\u2019 employment training. Secondly, we should increase investment in education, improve the capital stock of farmers\u2019 livelihood and guide their mental health development as a whole; On the other hand, the government should improve the land utilization rate and promote the marketization process of rural land transfer. At the same time, the government should increase its support for farmers\u2019 cooperative organizations, accelerate the construction of a modern rural financial system, develop a diversified rural credit support model, and increase the financial capital stock of farmers, so as to effectively improve the livelihood level of farmers.This study was funded by National Social Science General Project: Study on Livelihood Risk and Sustainable Guarantee of Poverty Alleviation Farmers in Poor Mountainous Areas (20BJY166).a, Yi Yua, Zhiwei Tanga, Bo Hub, Dr. Ali AbidcXiaoke Yina Hunan Biological And Electromechanical Polytechnic, Changsha, 410127, China, b Beiya Middle School of Changsha, Changsha, 410005, China, c Allied Hospital, Faisalabad, Punjab 54590, Pakistan.Objective: According to the latest statistics of the World Health Organization, mental health problems are one of the main causes of extreme events (such as suicide). Therefore, the psychological health of college students is an extremely important research topic. The research on college students\u2019 mental health is traditionally based on small-scale questionnaires, scales or experimental data. This paper creatively proposes a diversified information based teaching method that combines online open courses, intelligent teaching platforms and virtual simulation teaching resources, and uses big data technology and concepts to analyze a large range of samples.Methods: The online open courses and virtual simulation teaching resources were organically integrated to solve the problem that students were difficult to understand the real learning situation; Integrate virtual simulation teaching resources and intelligent teaching platform organically to solve the problem that teachers cannot fully understand students\u2019 learning effects; The smart teaching platform and online open courses will be organically integrated to solve the problem that managers are difficult to understand the teaching situation. From the aspects of university economic life, academic performance, comprehensive performance, mental health and school satisfaction, the development of special enrollment plan students in rural and poor areas will be discussed.Results: The online open courses, intelligent teaching platform and virtual simulation teaching resources were integrated organically and promoted as a whole, and teaching methods were innovated, teaching resources were enriched and teaching effectiveness was improved. A machine learning model has been established to predict postpartum depression and depression through social media data, and the accuracy of the latter can reach 70%. Research based on microblog text and Instagram photos has also proved that machine learning methods can be used to identify patients with early depression with high accuracy. Literature systematically analyzed Sina Weibo users based on multi task regression and incremental regression algorithms and used them to predict the five personality traits.Conclusion: It can not only make up for the shortcomings of traditional classroom in colleges and universities, fully mobilize students\u2019 enthusiasm for learning, but also evaluate students\u2019 learning effects and timely adjust teaching strategies, so as to promote the comprehensive application of information and intelligence in education. Inspired by the recent education big data and computational social economics methodology, this paper intends to explore the relationship between students\u2019 mental health problems, especially depression symptoms and students\u2019 social behavior by analyzing students\u2019 behavior data under uncontrolled conditions.Obtained the \u201cFourteenth Five Year Plan\u201d of Hunan Education Planning Science in 2022, and \u201cResearch on the Path of Multi information Integration Teaching Means in Higher Vocational Colleges\u201d (Project No.: XJK22CGD076).aDeng Xina Department of Law, School of Political Science and Law, Xinjiang Normal University, Guanjing Road No. 100, Shuimogou District, Urumqi, Xinjiang, China.Background: With the fierce competition in modern society, various psychological problems have become important factors that seriously affect people\u2019s health and life satisfaction. The National Health Conference held in 2016 and the Outline of the Healthy China 2030 Plan issued after the conference raised the issue of universal health to a national strategic level. The Guidelines on Implementing the Healthy China Action, issued on July 15, 2019, clearly states that mental health promotion actions should be carried out. Thus, it can be seen that guaranteeing the mental health of the whole people plays an important role in the strategy of \u201cHealthy China\u201d. The formation of the national mental health system requires the construction of the top-level mental health coordination mechanism under the guidance of the idea of ecological civilization, and the system innovation of realizing the national mental health from the perspective of legal protection. To build an ecological mental health model for the whole people, this paper discusses the role of ecological civilization thought as an important ideological guidance as well as its application in realizing the legalization of promoting the national mental health.Subjects and Methods: To this end, this paper combs out the internal correlation between the thought of ecological civilization and the legal system of national mental health from the aspects of theoretical basis, logical consistency and historical experience, and analyzes the internal mechanism of realizing the legalization of the national mental health from the aspects of ecological jurisprudence foundation and ecological psychological system construction. From the perspective of legalization, this paper discusses the value, implication and practical path of how to raise the mental health problem of the whole people to the level of legal rights under the guidance of ecological civilization.Results: Based on the above analysis, this paper proposes to construct the legal environment through inheriting the excellent ecological mental health culture and creating the legal atmosphere of ecological mental health; unify the individual value orientation and common consciousness orientation by constructing a mental health ecological legal education system formed by theoretical cognition and practice; and leads the construction of the mental health awareness system of the whole people by optimizing the mental health rule of law under the guidance of ecological civilization.Conclusions: To realize the legal path of the right to mental health of the whole people, it is necessary to establish a right protection system on the basis of clarifying the subject of rights and the relative subject of obligations, and clarifying the content of rights and obligations between subjects. By integrating ecological civilization thought and practice into the process of exploring the legalization of promoting the national mental health, it is possible to promote all nationalities to actively construct the legal coordination mechanism and the relief assistance mechanism of mental health, providing a reference for the theoretical research and practice on promoting the national mental health.This work was supported by the project of \u201cResearch and Reform of Undergraduate Education and Teaching in Colleges and Universities\u201d by the Department of Education of Xinjiang Autonomous Region in 2022, \u201cIn-depth exploration and Organic integration of ideological and political Elements in the Course of Environmental and Resource Protection Law\u201d. (Grant No. XJGXPTJG-202227).a, Hua Zhoub, Yingli Lib, Mengqi WangbYuhang Wanga Institute of physical culture, Harbin University, Harbin, Heilongjiang 150076, China, b School of Marxism Northeast Agricultural University, Harbin, Heilongjiang 150030, China.Background: As we all know, physical exercise helps to enhance physical fitness and promote physical health. However, the effects of different physical exercise programs on psychological anxiety and depression have not attracted sufficient attention from scholars. This paper adopts the method of exercise intervention to study the impact of different physical exercise programs on anxiety and depression symptoms in college students, providing a theoretical reference for solving the mental health problems of college students, and providing a scientific basis for the formulation of exercise prescription.Subjects and Methods: Using the whole group sampling method, 60 undergraduates of Northeast Agricultural University with anxiety and depression symptom were selected as subjects. The subjects were divided into basketball group, badminton group and aerobics group according to their interest. The three groups of subjects were given 16 weeks of physical exercise intervention training. And Self-rating Anxiety Scale (SAS), Self-rating Depression Scale (SDS) were used for assessment before and after the intervention. SPSS 20.0 statistical software was used for statistical analysis of the obtained data. The data before and after the same exercise program was compared by independent sample t test, and the data before and after the experiment between different exercise programs was compared by single factor ANOVA.Results: The anxiety level of the basketball group, the anxiety and depression level of the badminton group and the depression level of the aerobics group were significantly different before and after the experiment . The anxiety level of the aerobics group was extremely significant, and the depression of the basketball group was extremely significant . After the intervention, it was also found that SAS scores between basketball group and aerobics group, basketball group and badminton group, badminton group and aerobics group were all statistically significant  and SDS scores between basketball group and aerobics group, basketball group and badminton group, badminton group and aerobics group are all statistically significant as well .Conclusions: The three kinds of physical exercise program can all significantly alleviate the anxiety and depression symptoms of college students, among them, aerobics program has the most significant effects on anxiety symptoms of college students followed by badminton program and basketball program. And badminton program has the most obvious effect on reducing the symptoms of depression followed by badminton program and aerobics program. This study only considered the effects of physical exercise programs on anxiety and depression of college students. It did not put the mediating variables such as gender factor, physical quality, personal characteristics into consideration, which should be considered in the follow-up study.Supported by a project grant from GJB1423410; GJE1422083.a, Yi WangaJiangxin Hea School of Marxism, Xi\u2019an University of Science and Technology, Xi\u2019an 710600, China.Background: The public recognition of low carbon psychology and anxiety about the environment are not only the objective requirement of people\u2019s response to climate change, but also the realistic need of the transformation and optimization of agricultural industry. Although low carbon life is a new concept, it does raise the world sustainable development of the old problem, it reflects the human because of climate change and the future environment concerns and anxiety. With agricultural modernizing, a great demand for carbon emission reduction and sequestration in agriculture and rural areas.Subjects and Methods: By identifying and confirming the basis and main types of carbon sources and sinks, as well as searching literature and conducting research, we found in-depth understanding of the existing problems of carbon emission in the Yangtze River Economic Belt, and ensure that the path of carbon emission reduction and sequestration is reasonable and effective. In this way, it can enhance people\u2019s recognition of low carbon psychology and relieve people\u2019s anxiety caused by environmental change.Results: Through studying the path of carbon emission reduction and sequestration in agriculture and rural areas under the condition of low carbon psychological identity and environmental anxiety, some problems existed in the Yangtze River Economic Belt region. For example, in the implementation of carbon reduction and sequestration goals, first of all, we should adhere to the green development of agriculture at the same time; Secondly, we should ensure the safety of agricultural products. While ensuring food production, we should also pay attention to the safety of agricultural products, which is related to people\u2019s health. Finally, we should optimize and innovate the system and mechanism.Conclusions: In order to promote the smooth implementation of carbon reduction and sequestration in agriculture and rural areas under the condition of low carbon psychological identity and environmental anxiety, technological innovation can be promoted and utilized. Developing conservation-oriented agriculture; Optimize agricultural management; Enhancing public awareness and changing lifestyles; Afforestation and other ways to solve the problem of carbon emissions polluting the environment, through these effective and reasonable paths, further improve the environmental state that people rely on for survival, can improve the public\u2019s psychological identification of low-carbon lifestyle, but also can alleviate people\u2019s anxiety about carbon emissions polluting the environment.a, Yuncai NingaSongtao Wanga School of Management, China University of Mining & Technology, Beijing, 100083, China.Background: Inclusive green growth is an important symbol of high-quality economic growth, and emotional regulation is a representative of social equity. The purpose of this article is to explore the impact of the digital economy on inclusive green growth, including emotional regulation, and analyze the important role of emotional regulation in inclusive green growth.Subjects and Methods: From the perspective of emotional regulation, a system dynamics model including emotional regulation was constructed to study the impact of the digital economy on emotional regulation. The system dynamics model includes stocks, variables, constants, etc.Results: The system dynamics model simulation results show that the digital economy can form positive feedback on emotion regulation, and emotion regulation plays a positive role in inclusive green growth. It can be seen from this that emotion regulation can reduce the income gap and promote inclusive green growth. The impact mechanism of the digital economy on inclusive green growth is that it can positively regulate emotions, thereby reducing the wealth gap and promoting inclusive green growth.Conclusions: This article studies the impact mechanism and system operation rules of the digital economy on inclusive green growth from the perspective of emotional regulation, which can provide theoretical support for relevant policy recommendations in the later stage. Therefore, the following policy recommendations are proposed: promoting the development of the digital economy is conducive to public emotional regulation, thereby reducing the wealth gap and improving mental health. Emphasizing the positive mechanism of the digital economy on emotional regulation is beneficial for inclusive green growth and strengthening the application of the digital economy. And utilize the strong vitality of the digital economy to promote inclusive green growth in cities, thereby promoting economic growth, alleviating national psychological pressure, and improving mental health. In the process of developing the digital economy, we should focus on increasing investment in the information industry, encouraging the development of new startups, and strengthening the application of the digital economy to strengthen it.a,b, Jianmei Xua, Xingying LibFusheng Lianga Huangshan University, Huangshan, 245041 China, b East China Normal University, Shanghai, 200241, China.Background: This paper discusses the developmental characteristics of fundamental motor skills of children aged 3-6 in Anhui Province, providing a basis for the creation and implementation of physical activities and games for young children, a reference for the improvement of children\u2019s physical fitness, as well as for the integration of sports, education, and medicine.Subjects and Methods: A total of 240 young children aged 3\u20136 in Anhui Province were selected as the survey subjects for statistical analysis by using the measurement tool of TGMD-3.Results: The average total scoring rate of fundamental motor skills for 3-6 year-old children in Anhui Province is 48.7%. Specifically, the average total scoring rate for fundamental motor skills is 30.1% for 3-4 year-olds, 47.85% for 4-5 year-olds, and 67.58% for 5-6 year-olds. There is a significant difference (P<0.05) in the Horizontal jump (S5) between boys and girls aged 3-4 years and 5-6 years, but there is no significant difference (P>0.05) in all other items for all age groups. The three items of Run (S1), Skip (S4), and Underhand throw (S13) all show significant differences (P<0.05), while the other items and total scores do not show significant differences (P>0.05). There is a significant difference (P<0.05) between the underweight and overweight groups for 3-4 year-olds and the overweight and normal groups for 4-5 year-olds. There is a highly significant difference (P<0.01) in the obese group for 4-5 year-olds. The multiple correlation coefficients of the comprehensive influencing factors for each age group are R=0.820, R=0.688, and R=0.866, and the significance is P<0.05 for all.Conclusions: Boys between the ages of 3-6 perform better in both locomotor skills and manipulative skills compared to girls of the same age group. There are significant differences in the development of fundamental motor skills between adjacent age groups of 3-6 year-olds, and the scoring rate increases are more pronounced in the 4-6-year-old group, with several individual items showing a greater increase. There are some urban-rural differences in the development of fundamental motor skills in 3-6 year-old children, and BMI has a certain impact on their fundamental motor skills. The family\u2019s exercise atmosphere, crawling experience in infancy, and participation in sports interest classes are positively correlated with children\u2019s fundamental motor skills, with the main effect of the family\u2019s exercise atmosphere being the most significant.This research was supported by the Young Backbone Teachers\u2019 Domestic Visiting Program of Anhui Province Provincial Education Department (gxgnfx2019036); the College Students\u2019 Innovation and Entrepreneurship Program in Anhui Province Province (S202010024); the Key Research Project in Humanities and Social Sciences in Higher Education Institutions in Anhui Province Province (SK2021A0632); and the Teaching and Research Project of Huangshan University (2021JXYJ12).a, Dan Wanga, Qiurong WangaZhaochu Qiana Chongqing Business Vocational College, Shapingba, Chongqing, China.Objective: Investors\u2019 confidence in the market largely affects the trend of foreign trade enterprises and even foreign trade markets. Based on the perspective of investors\u2019 psychological anxiety, this research analyzes the development status and practical constraints of Chongqing\u2019s foreign trade, and puts forward countermeasures to achieve high-quality development of Chongqing\u2019s foreign trade, so as to comprehensively promote the high-quality development of foreign trade in ChongqingMethods: Based on the change of investors\u2019 psychology, this research makes a multi-dimensional exploration of development in Chongqing from the perspective of investors\u2019 psychological anxiety by means of market subject analysis, quantitative analysis and field research.Results: The overall momentum of foreign trade development in Chongqing is good, but there are still some unfavorable factors. In terms of the external environment, the high inflationary pressures around the world is sustaining; the European economy is suffering a double blow; the impact of the mutation of the novel corona virus is continuing; the Sino-US economic and trade frictions is constant and presenting a long-lasting trend; the foreign trade enterprises are suffering survival pressure; and the investors\u2019 psychological anxiety is obvious. In terms of the internal constraints, the survival pressure of foreign trade enterprises is increasing; the structure of foreign trade is still unbalanced; the new drivers of foreign trade are not yet mature; and the ability of investors to withstand pressure is limited.Conclusion: After clarifying the causes of investors\u2019 anxiety, this research combines the law of foreign trade development with the law of investors\u2019 psychology change according to the actual development of foreign trade in Chongqing, and puts forward that the healthy development of foreign trade in Chongqing needs to work together from four aspects: strengthening the rescue of foreign trade enterprises, ensuring the stability and smooth of foreign trade industrial chain and supply chain, expanding foreign trade diversification and developing new business forms of foreign trade.This research has received the kind care, guidance and help from Chongqing Municipal Commission of Commerce and relevant enterprises in Chongqing. The systematic, forward-looking and practical content of this research has been significantly improved.aZhang Xiaa School of Foreign Language Mianyang Teachers\u2019 College Mianyang, Sichuan, China.Background: This study is to investigate internal and external factors that influence on the effectiveness of relieving students\u2019 psychological anxiety under the web-based college English teaching management.Subjects and Methods: The author mainly used quantitative study methodology. Data was collected from 445 students of eight colleges/universities in Mianyang city. Also introduced the phenomenological study by in-depth interview technique to support the quantitative study. The key informants are six college teachers, two leaders and twelve students from eight colleges/universities in Mianyang city. The study instruments were questionnaires and in-depth interviews. The statistics in analyzing the data were percentage, mean, standard deviation, one-way ANONA, T-test, correlation analysis, and multiple regression analysis.Results: The results showed that the internal factors have much more influence than external factors on the effectiveness of relieving students\u2019 psychological anxiety under the web-based college English teaching management.Conclusions: Finally, it concludeed the special management would be like this: \u201cweb-based teaching in class and web-based autonomous learning after class\u201d: that is to take full advantages of internet and build a good platform for students\u2019 self-learning, personalized learning and collaborative learning, so as to improve effectiveness on relieving students\u2019 psychological anxiety under web-based college English teaching management.aRenlin Guoa Beijing Enterprise Safety and Environment Information Science Research Institute, Beijing 100048, China.Background: Psychological anxiety is an important factor that causes safety risks for employees. In order to evaluate the impact of psychological anxiety on safety culture, this article constructs an SEM model to study the quantitative impact of psychological anxiety on safety culture in high-risk industries.Subjects and Methods: Psychological anxiety is influenced by multiple factors. As an important method to measure the impact of one group of multiple factors on another group of multiple factors, this article uses structural equation modeling to study the impact of psychological anxiety on safety culture in high-risk industries based on the obvious factors of psychological anxiety and safety culture.Results: The conclusion indicates that psychological anxiety is an important factor affecting the level of safety culture in high-risk industries, and there is a negative correlation between the two. That is, the higher the psychological anxiety of employees in high-risk industries, the lower the level of enterprise safety culture. Therefore, enterprises in high-risk industries should strengthen the level of enterprise safety investment, try their best to eliminate employee psychological anxiety, thereby improving the level of safety culture, and adopt various methods to alleviate employee anxiety, Enable employees to work in a warm atmosphere, thereby creating a good level of safety culture in the enterprise.Conclusions: The conclusion indicates that psychological anxiety is an important factor affecting the safety culture level of high-risk industry enterprises. Therefore, high-risk industry enterprises should eliminate employee psychological anxiety and improve safety culture level in the following aspects: firstly, strengthen safety investment, cultivate a good corporate safety culture, and minimize employee psychological anxiety; Secondly, carry out various safety activities to reduce employees\u2019 psychological anxiety and create a warm working atmosphere; The third is to correctly view psychological anxiety and safety management level, and organically link the two together.This research was supported by the Langfang science and technology research and development project (project number: 2021029083).a,b, Rui Sunc, Yuan YuancKun Zhaoa Tan Siu Lin Business School, Quanzhou Normal University, Quanzhou 362021, China b National Academy of Econnomic Strategy, Chinese Academy of Social Sciences, Beijing 100028, China c School of Business Administration of Huaqiao University, Quanzhou 362021, China.Background: The article analyzes the impact of online trust of Chinese investment company TMT on investment decision propensity of entrepreneurial projects and investors\u2019 psychological health.Subjects and Methods: Firstly, the article defines the \u201ctrust\u201d in the individual behavior attribute as \u201csituation trust\u201d and \u201cquality trust\u201d as the conceptual basis, and defines the trust relationship between the investment enterprise TMT and the entrepreneur. Second, by conducting an inductive longitudinal cross-case analysis on three Internet startup platforms in China, this study summarizes the relationships of the acquisition of situational and quality trust by investment company TMTs with the investment decision-making for entrepreneurial projects made by these TMTs. Thirdly, a research proposition is then proposed for further verification, from which the influence mechanism of investors\u2019 psychological health under the condition of interacting situational trust and quality trust of TMTs are identified.Results: The article finds that TMT online trust have a positive impact on TMT investment decision-making and investors\u2019 psychological health. Online situational trust influences investment decision propensity through the heterogeneity of situational perception, while when TMT shows higher quality trust, it helps investors to take joint action on market, information, and cooperation, as well as to conduct experimental learning to generate investment value, and to improve online investment decision propensity and reduce psychological anxiety. The existence of transactional or value-based trust transfer between online situational trust and quality trust determines different types of relationships between the two trusting subjects and induces TMT to choose the investment strategy corresponding to them.Conclusions: The article has important implications for further deepening the research on TMT online decision propensity of entrepreneurial projects and investors\u2019 psychological health. First, the article fills a gap in the literature regarding the \u201cinternal mechanisms\u201d and \u201ctrust transfer\u201d of online trust processes in explaining investment decision propensity and investor mental health. Second, by revealing the mechanism of online trust transfer between TMT situational trust and quality trust based on transactional and value-based, the article provides new ideas for in-depth interpretation of investors\u2019 online investment decisions and reduction of psychological anxiety. Thirdly, TMT should fully consider its own trust type and trust level, carefully design online trust investment mechanism, and choose the investment psychological strategy that fits with the trust type and trust level. Consistent with the problems of established inductive case studies, the findings of this study have limited external generalizability, and future research could expand the sample through other methods to improve external validity.Supported by a project grant from \u201cCognitive neural mechanism of personalized recommendation users\u2019 privacy response\u201d (Grand No.21FGLB041) and \u201cResearch on the formation mechanism and evolution path of intrepreneurial capability of manufacturing enterprises in Fujian driven by digital innovation\u201d (Grand No.FJ2022B055).a,b, Shuqin TianbDongqiang Wanga School of Management Science and Real Estate, Chongqing University, Chongqing, 400045, China, b Chongqing University of Arts and Sciences, Chongqing, 402160, China.Background: At present, the rural areas become the leading position, key area and weak link of epidemic prevention and control along with people\u2019s mental health in China.Subjects and Methods: This study trys to construct modern governance system for epidemic prevention and control in rural areas and analyse their impact on people\u2019s mental health from the perspective of all aspects, the whole process and all elements. A total of four cases were collected and analyzed according to the database involved epidemic prevention and control in rural areas in China and their impact on people\u2019s mental health built by the text analysis, grounded theory and multi-case analysis.Results: The results show that four typical models of epidemic prevention and control in rural areas in China and their impact on people\u2019s mental health, including legal leading model, local mobilization model, general grid model, and technical service model, are summarized and and a multi-case comparative study is conducted from the aspects of governance orientation, governance way, and governance mechanism. No matter which mode, COVID-19 had an impact on people\u2019s mental health, mainly manifested as depression, anxiety, stress, loneliness, helplessness.Conclusions: From the perspective of holistic management, this paper puts forward some policy suggestions to further strengthen the work of epidemic prevention and control in rural areas and reduce their impact on people\u2019s mental health: functional integration to establish a centralized and efficient leadership and command system; benign interaction to improve the communication and coordination mechanism of effective connection between different departments; demand orientation to take a holistic management and diversification model according to local conditions; crossing borders to build and share the work digital information platform of epidemic prevention and control in rural areas.This paper was supported by the National Social Science Foundation Project \u201cResearch on the Effect Measurement and Path Optimization of Social Forces Participating in Rural Revitalization in Key Assistance Counties\u201d (No. 22ASH014).a, Can Chenb, Yusheng LongcYajun Gua Tongji Zhejiang College, Jiaxing 314051, Zhejiang Province, China, b Jiaxing Nanhu University, Jiaxing 314001, Zhejiang Province, China, c Beijing University ShenZhen Hospital, ShenZhen 518000, Guangdong Province, China.Background: Investment decisions should not only consider the investment-return itself, but also analyze the psychological state of the decision-making subject, especially the psychological stability of the decision-making entity. This is a destabilizing factor that is independent of technological drivers. An individual\u2019s psychological stability is subject to biological factors such as disease, psychological factors such as personality traits, sociological factors such as the family environment of origin, and other factors. The result of the decision-making entity\u2019s processing of the above information ultimately becomes the key to the investment decision.Subjects and Methods: 1. The factor analysis method and the comprehensive analysis method are used to obtain the main contents affecting the psychological stability of the decision-making subject. 2. The investment decision-making model is constructed. Based on the assumption that the state of technological progress and the efficiency of new technology adoption are uncertain, the Bellman equation for optimal investment is obtained, and the optimal investment time of the project operator is calculated. 3. Parameter analysis of the investment decision-making model. 4. Using association analysis, relying on the psychological stability analysis of decision-making subjects, the decision-making results under different preferences are obtained according to the risk preferences of decision-making subjects.Results: 1. Psychological stability is subject to a variety of factors, and has strong instability and randomness. 2. The speed of technological progress is positively correlated with the uncertainty of positive benefits brought about by the adoption of new technologies, the positive rate of change in the adoption efficiency of new technologies, and the opportunity value F(V) and investment threshold V* adopted by telecommunications operators, while the negative rate of change in the adoption efficiency of new technologies is negatively correlated with the opportunity value F(V) and investment threshold V* adopted by new technologies adopted by telecommunications operators.Conclusions: In the field of telecommunications, operators make decisions on investment in new technologies, which is not only determined by technology itself, but also by the psychological stability of decision-making subjects is more decisive for the implementation of decision-making behavior. In fact, the psychological stability or broad sense of decision-making subjects is mental health the key to the success or failure of decision-making. In order to avoid the uncontrollability of individual decisions, team decisions can more rationally complete new telecommunications investment decisions. Broadly, similar methods can be used to make other types of decisions.aHao Penga School of Foreign Languages, Wuhan Polytechnic University, Wuhan 430024, China.Background: Language is a tool for human beings to convey their feelings and ideas. Human beings use language not only to convey information, but also to express their inner feelings. Therefore, language is also a window into people\u2019s mental health. Through verbal communication, psychiatrists can diagnose patients with mental disorders; Using big language data, scientists can quantify the special experience of doctors and develop intelligent products for early diagnosis of mental disorders. Linguistic researchers not only need to reveal the information of mental health through language, but also need to explore the neural mechanisms related to it.Subjects and Methods: AI studies how to use computer to simulate the ability of human brain to recognize, understand, participate, reason, learn, think and solve problems, and AI can perceive the external environment, further think, learn, and output corresponding behavior. AI has been described as the use of algorithms and software to approximate human cognition when resolving complex data. All AI involved in this paper belongs to the field of computer science and will adopt a series of technologies and methods: machine learning, natural language processing, speech processing, robotics, and similar automated decision making, etc., for developing and implementing human-specific language cognitive processes and mental health monitoring therapies.Results: Language production involves brain networks that process auditory, somatosensory, and visual input, as well as language perception and production. Mental illness often results in abnormalities in these brain networks, so analyzing language patterns can help diagnose mental disorders. Deficiencies in verbal communication are evident in many severe mental disorders, particularly those involving psychomotor retardation, affective retardation, and poverty of speech content. Language is an effective method to detect the mental state of patients. Existing research using artificial intelligence techniques to analyze voice and language patterns has been highly accurate in screening for mental health problems. Some researchers have developed algorithms into artificial intelligence systems that evaluate speech samples and compare them with previous samples of the same patient to score their mental status. Research has found that AI model scoring can be as accurate as human clinicians.Conclusions: Thanks to the rapid development of machine learning, the accuracy of predicting mental disorders by analysing linguistic data is also increasing. Language is a window through which experienced psychiatrists can assess a patient\u2019s mental state. If artificial intelligence can quantify the doctor\u2019s special experience, it will greatly improve the objectivity and popularity of diagnosis. In addition to the flexibility and universality of the collection, language features as a tool for early screening of mental disorders have unique advantages. In addition, social platform language big data can also be used for monitoring users\u2019 psychological status, and the analysis results can provide objective basis for government departments\u2019 decision-making in mental health. Similarly, rapid advances in neuroscience and biological science have provided scientific tools for exploring the relationship between explicit language and Behavior and internal psychology and spirit. Although artificial intelligence and neuroscience have made initial achievements in exploring brain mechanisms and identifying mental disorders using language information, they are still far from practical clinical application. On the way of monitoring and protecting people\u2019s mental health through the window of language data, multidisciplinary linguistic research still has a long way to go.a, Wen Shia, Hongbo FuaYuezi Weia School of Biomedical Engineering, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China.Background: For the higher mathematics curriculum, it is still a new subject to carry out curriculum ideological and political reform and integrate ideological and political elements into curriculum teaching. Higher emotional intelligence is conducive to the formation of sound personalities. Combining ideological and political education with curriculum reform and teaching practice has an important means and method to cultivate people\u2019s personality.Subjects and Methods: Starting from affairs around us and national events, we internalized ideological and political education into the classroom teaching of higher mathematics, and practiced and explored the actual links. Through the teaching of ideological and political cases with the characteristics of the epoch and infectious, it opens a channel for students to connect mathematics with the outside world, and establishes the sound mentality of students.Results: In this way, students\u2019 enthusiasm and initiative in learning mathematics are improved, knowledge updating and cross-integration are realized, and students get the ability to find and solve problems. Through ideological and political education, psychological education cultivates students\u2019 high-quality emotional intelligence and shapes sound personalities, so that college students can form a healthy psychology.Conclusions: Teaching with ideological and political materials can promote the establishment and perfection of students\u2019 mentality. By integrating ideological and political education with the study of mathematics, it not only educates students in ideology and morality, but also allows students to understand the method of mathematical modeling from the mathematical model, and understands the practicality of mathematics. We will train professionals who have a healthy personality, healthy psychology, ideal and faith, morality, correct value pursuit, ability and responsibility of The Times, and promote the construction of new engineering and new medical sciences.This work was supported by the Second Batch of Industry-University Collaborative Education Project of the Ministry of Education in 2019 (Project No. 201902120032); the Education Science Planning Project of Guangzhou in 2020 (Project No. 06-410-2113029); and the First-class Major Construction Project of Guangzhou Medical University (Project No.: 02-408-2304-11-010XM).aFengxiang Denga School of Marxism, Hunan City University, Yiyang, Hunan, 413000, China.Background: During the COVID-19, many universities used remote online teaching methods, and online examination became a research topic. College students have two distinct psychological attitudes towards courses during the pandemic. The first type is a relaxed mentality, believing that loose and remote exams will give them great opportunities, so there is no need to study hard. The second type is anxiety, where some students are worried that the exam format may not be suitable or that they may find it difficult to achieve good grades. Some students may believe that remote exams can lead to inconsistent exam situations for different students, thereby harming the fairness and justice of exams.Subjects and Methods: The first is the feasibility of online exams. The progress of technology and society has put forward new requirements for exams, and the popularization of computers and mobile phones has made online exams possible. The emergence of the epidemic and natural disasters has made online exams necessary. Online exams are not only an improvement in assessment methods, but also a beneficial practice of open and personalized assessment, which meets the basic requirements of course teaching. The second is how effective online exams can be in eliminating exam anxiety among college students. There are three research methods. The first is literature research. We have collected various international achievements on the psychological anxiety caused by online exams and solutions, and screened the correctness and universality of these views in order to obtain the best solution based on our research subjects. The second is to conduct empirical research through online exams, which includes three parts: pre exam preparation, exam implementation, and post exam summary and improvement. The third is a survey of candidate satisfaction.Results: In theory, our colleague Lin Xiaojin et al.\u2018s research has proven that online exams are feasible. Practitioner Yue Sun also believes that universities should give more consideration to the selection and construction of online platforms, and carefully arrange online teaching. In practice, we have conducted ten years of repeated practice and compared the results of the offline exam in 2018 with the online exam in 2020, demonstrating that the results of the online and offline exams are equivalent. Through public opinion surveys, it is believed that online exams are better than offline exams.Conclusions: Online and offline exams have equivalence, and are superior in terms of convenience and fairness compared to offline exams. College students are very satisfied with online exams, with 66.23% of students highly recognizing computer-based exams, 24.12% of students believing that computer-based exams can be used, and only 9.65% of students still cling to traditional offline exams. This indicates that online exams during the epidemic period based on student anxiety resolution are successful.This work has been supported by the Education Department of Hunan Province, China . Professor Tu Jianhua of the Principles Teaching and Research Section of the School of Marxism, Hunan City University, China, has made great contributions to this topic, and other colleagues of the teaching and research section have participated in the research of this topic.a,b, Yuan Yuana,b, Yuntao Liua,b, Shunjie Zhonga,b, Luotong Liua, Liang Liua,cZhiyong Taoa Department of Neurosurgery, Affiliated Hospital of Southwest Medical University, No.25, Taiping Street, Luzhou City, Luzhou, 646000, China, b Neurosurgery Clinical Medical Research Center of Sichuan Province, Luzhou, China, c Neurosurgery Clinical Medical Research Center of Sichuan Province, Neurological Diseases and Brain Function Laboratory, Luzhou, China.Background: VP shunts provide an important means of treating hydrocephalus, and infection is one of the main complications after a shunt placement operation. Infection can cause intellectual damage and ventricle separation and even lead to patient death. According to the affected site, infections associated with VP shunts can be classified as wound infections, meningitis, peritonitis, and shunt infections. Shunt infection caused by gastrointestinal perforation is a rare complication after VP shunt placement. After gastrointestinal perforation, intestinal bacteria can enter the intracranial system through the shunt, leading to ventriculitis, meningitis and even infection of intracranial nerves and brain parenchyma. At present, the cause of gastrointestinal perforation after VP shunt placement is not clear. We report a case of the intestinal penetration of a traumatic hydrocephalus-associated VP shunt in which intracranial infection resulted.Subjects and Methods: A patient of admitted to the neurosurgery department from October 2011 in Affiliated Hospital of Southwest Medical University was enrolled in the study. A case report.Results: The patient was a 10-year-old male with car accident-related injuries resulting in a consciousness disorder that required hospitalization. The diagnosis at admission was diffuse axonal injury. During hospitalization, the results of a head CT showed that the patient had hydrocephalus, and the patient received a ventricular abdominal shunt. Postoperatively, the patient could open his eyes on his own and had a GCS score of 7 points; 4 months after surgery, the patient developed a high fever. A head CT examination suggested bilateral lateral ventricle posterior angle abnormal density fluid level on imaging, which supported a suspicion of intracranial infection. The patient\u2019s abdominal CT examination showed a drainage tube that visibly ended in the ascending colon. The child underwent laparoscopic exploration, and the abdominal end of the tube was found to have entered the intestine. The patient\u2019s drainage device was removed, and the patient underwent external drainage surgery. Postoperatively, anti-infection and antiepilepsy treatments were given. Two months after surgery, the patient died due to circulatory failure.Conclusions: Infection is one of the main complications after shunt placement; a shunt infection due to gastrointestinal perforation is a rare complication after VP; and neurosurgeons should pay close attention to the development of intracranial infection after VP shunt placement.Experimental study on the effect of TPO on apoptosis and inhibition of brain edema, Luzhou Science and Technology Bureau, No.2021-JYJ-63.a,b, Zehua Panb, Minhan XieaPeng Hana Xiamen Huaxia University, Xiamen 361024, China, b Japan and South Korea Creative Entrepreneurship Research Center, Liaoning University, Shenyang 110036, China, c Jiangxi Industry Polytechnic College, Nanchang 330099, China.Background: This paper aims to analyze the influence of perceptual elements in agricultural product packaging on the purchase intention and psychological sentiment behavior of consumers from consumer psychological perception.Subjects and Methods: This paper applied a combination of internet content analysis and the IPA model analysis to capture comment information on consumer about agricultural products packaging on the Internet and used the ROST CM6 software to perform high-frequency vocabulary, semantic network, and emotional perception analysis on internet content. This research summarized and encoded the agricultural product packaging elements that affect the purchase intention and emotional behavior of consumers. At the same time, this paper used the IPA analysis to construct the analysis model. It analyzed the influence of the satisfaction and attention of each perceived factor in the packaging of agricultural products on the purchase intention and psychological needs of consumers.Results: The results showed that perceptual factors such as packaging appearance, capacity space, and material significantly impact the purchase intention and emotional behavior changes of consumers. Meanwhile, the aspects of low consumer satisfaction, such as packaging pattern, durability, and bearing capacity, needed to be further optimized.Conclusions: This paper analyzed the influence of perceptual elements on the purchase intention and changes of psychological emotional behavior of consumers from the perspective of consumer psychological perception. It summarized the theoretical ideas of agricultural product packaging design in line with the perceived value and psychological emotional behavior of consumers and enriched the research content of agricultural product packaging.This work was supported by a project grant from education and research project of young and middle-aged teachers in Fujian Province in 2022, Grant number (JAS22213).a, Zhiyong Taoa, Yuan Yuana, Shunjie Zhonga, Liang LiuaYuntao Liua Department of Neurosurgery, Affiliated Hospital of Southwest Medical University, Luzhou 646000, China.Background: Intracranial teratomas, which represent 0.5% of all intracranial tumors and 2\u20134% of pediatric intracranial tumors, can be classified into mature, immature and malignant types depending on histological variation. Most intracranial germinomas occur in the midline. Teratomas are commonly found in the pineal gland and suprasellar region but rarely in the third ventricle. Rupture of mature teratomas is a rare event. To date, only four cases of intracranial teratoma rupture have been reported: a spontaneous teratoma rupture in a 16-year-old female and a teratoma rupture in a 45-year-old male, while the other two patients died during the fetal period. Intracranial teratoma rupture with hemorrhage, on the other hand, has never been reported. We were the first to report a case of spontaneous rupture and hemorrhage of pediatric teratoma and achieved a good outcome through surgical treatment.Subjects and Methods: This study reports a 9-year-old boy who was hospitalized due to symptoms such as lethargy accompanied by headache, nausea and vomiting. Cranial computed tomography (CT) revealed a mass with hemorrhage in the third ventricle. MRI revealed a mass in the third ventricle with hemorrhage and an intraventricular hematocele.To solve the symptoms caused by hydrocephalus and tumor hemorrhage, bilateral ventriculocentesis and drainage were performed and then tumorectomy was performed through a transcallosal approach. Postoperative pathology showed mature teratoma rupture with hemorrhage.Results: After the operation, the serum AFP decreased to normal, and \u03b2HCG was significantly reduced (32.78 mIU/ml). The patient had clear consciousness and little speech when discharged from the hospital. His right upper and lower limb muscle strength was grade 4, his left limb muscle strength was normal. Enhanced MRI reexamination revealed no residual tumor or recurrence 3 months after surgery. Currently, the patient is in good condition and can walk independently without signs of tumor recurrence.Conclusion: To the best of our knowledge, this is the first report of mature teratoma rupture with hemorrhage in the third ventricle. We performed serum \u03b2HCG tests on the pediatric patient before and after surgery and found that the preoperative blood \u03b2HCG was >1,000 mI/ml, while the postoperative \u03b2HCG declined significantly to 32.78 mIU/ml, thus proving the possible diagnostic value of \u03b2HCG for teratomas. We proposed a treatment scheme in which the symptoms of tumor apoplexy and hydrocephalus are relieved by ventricular drainage prior to performing tumor resection. With these procedures, the patient had a good outcome, without the presence of residual tumor or recurrence during follow-up.a, Jiuwang Yub, Zhiheng Dongc, Dusubilige Wend, Lidao Baob, Lan WudSachula Baoyina Beijing University of Chinese Medicine, Beijing, 010030, P. R. China, b Hohhot Hospital of Traditional Chinese Medicine and Mongolian Medicine, Hohhot, Inner Mongolia, 010030, P. R. China, c Department of Pharmacy, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia, 010059, P. R. China, d Mongolia Medical School, Inner Mongolia Medical University, Hohhot, Inner Mongolia, 010110, P. R. China.S Baoyin and JW Yu contribute equally to this work.Background: In this study, the protective mechnism of traditional Mongolian medicine Nagab-9 on acute lung injury model rats and its material base were discussed.Method: Acute lung injury model were developed using SPF SD male rats by bleomycin thorugh trachea injection (3.5\u2005mg/kg). Then, model rats randomly devided into Nagab-9 middle dose (126\u2005mg/kg), Nagab-9 high dose (252\u2005mg/kg) and dexamethasone  groups, 12 rat each group. Rats of sham-operated  group were given same amount of physiological saline. Drug was given for once a day and continued for 21 days. Lung pathological changes were observed by HE staining method. The level of serum TNF-a and IL-6 were detected by ELISA and qPCR. The differentially expressed genes comparing different groups were examined by transcriptional screening technique and validated by qPCR. Also, related signaling pathways were analyzed through KEGG and GO analysis. The active metabolic compounds of Nagab-9 were tested by UPLC-QE-MS/MS untargeted metabolic assay and the active molecules from Nagab-9 were observed. Furthermore, AutoDock Tools (1.5.6) was used to analyze the detected active molecule of Nagab-9 and its target. Finally, the level of NF-kB in lung tissue was tested by immunohistochemistry and the level of proteins Raf, p-Raf, MEK1/2, p-MEK1/2, ERK1/2, p-ERK1/2, Nur77 was analyzed by western blot.Result: Nagab-9 effectively reduced the level of inflammatory factors TNF-a and IL-6 in serum of ALI rats. Transcriptomic analysis found the expression level of NR4A1, Raf, Mek, ERK and NF-kB genes were significantly regulated by Nagab-9. KEGG and GO analysis showed MAPK signaling pathway was significantly mediated, especially, NR4A1 was highly expressed in model. Serum pharmacology result showed 24 of Nagab-9 compounds. Among them, small molecule lidocaine showed coorelation with MEK/ERK and NF-kB pathway. Molecular docking result revealed that the the interacting score of lidocaine and Nur77 was -5.0. Lidocaine was also detected and quantified in blood sample. qPCR and western resluts indicated that Nagab-9 can significantly down-regulate NR4A1, Raf/Mek/ERK, NF-kB at protein level in the lung tissue of ALI rats.Conclusion: Nagab-9 can effectively relieve normal symptoms and lung pathalogical changes of ALI rats. The possible molecular mechanism is that the small molecule lidocaine from Nagab-9 inhibit the expression of NR41 and prevent Raf/Mek/ERK pathway, thereby prohibit Raf/Mek/ERK pathway and consequently decrease NF-kB inflammation and reaction.This research is funded by the following projects: Natural Science Foundation of China (No. 82160794 and 82160703); Natural Science Foundation of Inner Mongolia Autonomous Region (No. 2020MS08106); Project of Health Science and Technology in Inner Mongolia Autonomous Region (No. 202201238); Inner Mongolia Autonomous Region Chinese Medicine (Mongolian Medicine) Young and Middle-aged Leading Talents Cultivation Project; Grassland Yingcai in Inner Mongolia Autonomous Region; Qihuang Scholar.a, Fangfang Mab, Gongxing Wub, Huiyuan ZoubYanhong Lia School of Management, West Yunnan University of Applied Sciences, Dali, 671000, China, b School of Management Engineering and Electronic Commerce, Zhejiang Gongshang University, Hangzhou, 310018, China.Background: In recent years, the COVID-19 pandemic, the China-Us trade war and other events have caused an unprecedented impact on globalization. The profound adjustment and restructuring of the global industrial chain have had a profound impact on the supplier and customer relations and trade development of enterprises. At the present time of fluctuating global economic situation, how to build a solid trade relationship network and consolidate the psychological and emotion relationship network of both sides of the trade is worth in-depth discussion in a scientific and effective way. In the context of the digital economy, this study analyzes and discusses the mechanism of the supplier - customer relationship network affecting the high-quality trade development from the perspective of emotion regulation.Subjects and Methods: Using enterprise supplier - customer data to construct enterprise supplier - customer relationship network, calculate PageRank value to depict enterprise supplier - customer relationship strength, and use the data of China\u2019s A-share listed companies from 2010 to 2020 to carry out empirical research. The influence mechanism of supplier - customer relationship network on trade quality development under the adjustment of digitalization degree and marketization degree is analyzed. The methods proposed in this study can also be further developed theoretically from the perspective of emotional regulation. Through the construction of a network of psychological and emotional exchanges and win-win cooperation, it can provide strong support for a more solid and stable e-commerce trade, so as to promote the high-quality development of China\u2019s trade.Results: The results show that both the supplier and customer network relationship and its proportion have a positive and significant impact on the development of trade quality. Both the degree of digitalization and the degree of marketization have a positive interaction effect on the relationship between supplier - customer relationship network and trade quality development. Moreover, in the market environment with weak environmental uncertainty, the supplier - customer relationship network is more significant to the high-quality trade development, and the moderating effect of the degree of digitalization and the degree of marketization of enterprises is also stronger. Under a stable emotional regulation network, both sides of the trade can adjust their trade psychological health and maintain high-quality economic and trade development with positive behaviors and communication trends.Conclusions: Based on the calculation results and theoretical analysis of this study, we can deeply study the influence mechanism of supplier-customer relationship network to promoting high-quality trade development from the perspective of digital economy and emotion regulation, analyze the various characteristics of cross-border e-commerce in modern enterprise trade which are different from traditional trade, and analyze how to regulate supplier-customer emotional network relationship, maintain a positive attitude under the situation of good behavior, high-quality economic and trade development. At the end of the paper, some directional suggestions are given for further research.Supported by the Digital Trade and Silk Road E-commerce Engineering Research Center of Yunnan Provincial Education Department and Major scientific and technological support projects in Dali prefecture \u201cThe Application of Digital Trade and Cross-border E-commerce in Dali Prefecture\u201d.a, Ri Chena, Qihui MaaJiayi Wanga Cilin Hospital, Ningbo, Zhejiang Province, China.Objective: To explore the effect and safety of calcium polycarbophil combined with compound polyethylene glycol electrolyte powder on bowel preparation for colonoscopy.Methods: A total of 539 patients undergoing colonoscopy and treatment in Cixi Cilin Hospital, Ningbo, Zhejiang Province from January 2021 to July 2022 were randomly divided into three groups: A, B and C. Study group A (n=180) adopted calcium polycarbophil tablets within 48 hours before taking compound polyethylene glycol electrolyte powder in preparation for intestinal colonoscopy. Study group B (n=180) adopted calcium polycarbophil tablets within 72 hours before taking compound polyethylene glycol electrolyte powder in preparation for intestinal colonoscopy. Control group C (n=179) only took compound polyethylene glycol electrolyte powder for intestinal cleansing. The intestinal cleaning effect and antifoam effect of the three groups were evaluated by the Boston Bowel Preparation Scale (BBPS), and the adverse reactions during the bowel preparation of the three groups were observed.Results: The Boston scores were corrected by the Bonferroni method. The intestinal cleanliness and antifoam effect of the patients in study group A and study group B were significantly higher than those in control group C and there were significant differences (P<0.001). There were no significant differences in intestinal cleaning effect and antifoam effect of the patients between group A and group B  which points the effects in the two groups were equivalent. No serious adverse reactions occurred in all three groups, and the incidence of adverse reactions was low without statistical difference between groups (P>0.05).Conclusion: The effect of taking calcium polycarbophil tablets combined with compound polyethylene glycol electrolyte powder for intestinal preparation 48 hours and 72 hours before colonoscopy are better than that of using compound polyethylene glycol electrolyte powder alone which are safe and acceptable with low incidence of adverse reactions and no serious adverse reactions.This work was supported by the  under Grant [number CN2018010].a, Qian Lia, Yesong Chenga, Fei Pengb, Dingqiang HuangaWujun Zoua Department of otorhinolaryngology head and neck surgery, Chengdu Second People\u2019s Hospital, Chengdu 610000, China, b Department of Anesthesia, West China Hospital of Sichuan University, Chengdu 610000, China.Background: Tonsillectomy is one of the most frequent operations performed by otolaryngologists in children. Hence, it is essential to prevent postoperative complications in children undergoing tonsillectomy. A successful preoperative education might prevent postoperative complications. This study aimed to investigate the effect of preoperative education using a cartoon video for the prevention of postoperative complications in children scheduled for tonsillectomy.Subjects and Methods: A total of 154 patients scheduled for elective tonsillectomy met the inclusion and exclusion criteria and were randomly divided into the control (77 cases) and cartoon video (77 cases) groups. Patients\u2019 eline data were carefully recorded. The duration of operation, intraoperative blood loss, postoperative diet recovery time, VAS pain scores on the first, third and seventh day after surgery, tonsillar fossa infection, the incidence of postoperative bleeding, upper respiratory symptoms and digestive symptoms was evaluated.Results: Compared with the control group, the average visual assessment score (VAS) pain scores on days 1 and 3 after surgery were significantly decreased in the cartoon video group (P < 0.05). Moreover, the eating time was markedly reduced in the experimental group (P < 0.05). There was no significant difference in intraoperative blood loss, postoperative pain score (day 7), postoperative bleeding, tonsillar fossa infection, digestive symptoms and upper respiratory tract infections.Conclusions: For children scheduled for tonsillectomy, preoperative communication using the cartoon video can effectively improve postoperative recovery. The cartoon video can help children understand the contents of preoperative education more easily, deserving extensive promotion.aChen Chena School of Business Management, Hangzhou Polytechnic of Science and Technology, Hangzhou, China.Background: By investigating the employment quality of e-commerce employees and its impact on Subjective Happiness, this paper proposes countermeasures for improving employment quality that can improve the happiness of e-commerce employees, and provides opinions and suggestions for e-commerce employees, governments, universities and enterprises.Subjects and Methods: Taking e-commerce employees of small and medium-sized enterprises in Hangzhou, Ningbo, Wenzhou, Taizhou, Jinhua and Yiwu as the research objects, this paper adopts the subjective and objective evaluation indicators of employment quality and the data of 379 valid questionnaires collected from the survey to study the employment quality and its impact on Subjective Happiness. In the research process, questionnaire survey, field survey, interview and other methods are mainly adopted. The questionnaire designed was answered by Likert\u2019s 5-point scale. In the data processing process, SPSS software and Excel were mainly used to carry out statistical analysis. For example, univariate analysis , bivariate analysis , or multivariate correlation analysis is used.Results: (1) Among the four dimensions of employment quality, the average score of interpersonal relationship is the highest, followed by job adaptation and career development, and the score of work intensity is the lowest. (2) Most people think they can adapt to their current jobs, and as they grow older, they become more adaptable; (3) E-commerce employees work long hours and are under great pressure, but they are still looking forward to their work; (4) Most people pay more attention to whether their job has development prospects and whether doing this job has harm to their health. The happiness index of a job with prospects and good health is high; (5) They think their spare time is colorful, but they don\u2019t have enough time to spend with their families; (6) Career development, job adaptation and interpersonal relationship have a significant positive impact on job Subjective Happiness, and work intensity has a significant negative impact on job Subjective Happiness; Career development, job adaptation and interpersonal relationship have a significant positive impact on Life Subjective Happiness, while work intensity has a significant negative impact on Life Subjective Happiness.Conclusions: In order to improve the Subjective Happiness of e-commerce employees, it is suggested that the government level, enterprise level and individual level make joint efforts to create a fair and just competition environment for the e-commerce industry and promote the realization of higher quality employment of e-commerce employees, including the establishment of supervision mechanism and the improvement of social insurance mechanism. Pay attention to the career development of employees, improve the welfare and compensation system, give full play to the initiative of employees; Do a good job planning, according to interests and professional ability to choose positions and other countermeasures.a, Jun Denga, Zhihua Liaob, Si Chenc, Rongjun ZhaoaYuxiao Luoa Department of Foreign Languages, Zhongshan Institute, University of Electronic Science and Technology of China, Zhongshan, Guangdong, 528402, China, b Department of Humanities, Shanghai University of Finance and Economics, Shanghai, 200433, China, c Department of Nursing, Southwest Medical University, Luzhou, Sichuan, 646000, China.Background: Mobile learning has been regarded as an essential scheme to optimize the allocation of educational resources and to ensure the fairness of education. Scholars both domestically and internationally have conducted the extensive research on mobile learning by utilizing the UTAUT model and other related prior models, in order to glean insights and ideas for improving learners\u2019 emotional and behavioral experiences during the mobile learning process. However, compared with the general College English, the influencing factors of behavioral emotions in the mobile learning process of Medical English have rarely been included in the current massive amounts of studies.Methods: Based on the UTAUT model, a schematic model of the influencing factors was constructed, and a quantitative questionnaire was designed to profoundly explore the influencing factors of behavioral emotions in the mobile learning process among Medical English learners. The questionnaire scale includes participants\u2019 moderating factors, critical factors, and behavioral emotions, which involves 50 declarative sentences. The simple random sampling was applied to choose 180 participants from 360 learners in Medical English. The descriptive statistics, Pearson Chi-Square analysis, Pearson correlation analysis, and regression analysis have been employed to validate hypotheses.Results: There are no significant differences in participants\u2019 behavioral emotions including potential intentions and genuine attitudes to embark on the mobile learning behaviors with the aid of modern information technology when participants are grouped into male-science, male-liberal arts, female-science, and female-liberal arts. There is a positive significant correlation between participants\u2019 voluntary and four critical factors. There is also a positive significant correlation between participants\u2019 experience and four critical factors. Participants\u2019 moderating factors positively correlate with their behavioral emotions, including potential intentions and genuine attitudes. The univariate linear regression analysis shows that there is a linear regression relationship between participants\u2019 extent of facilitating condition and their behavioral emotions, between participants\u2019 extent of effort expectancy and their behavioral emotions, between participants\u2019 extent of social influence and their behavioral emotions, and between participants\u2019 extent of performance expectancy and their behavioral emotions.Conclusions: The results of this study imply that participants\u2019 psychological capital can not only help them identify the critical influencing factors, but also mobilize their own behavioral emotions including potential intentions and genuine attitudes, which may finally be transformed into the practical mobile learning behaviors. This research may not only provide some inspirations for administrators and teachers to improve behavioral emotions of learners in the mobile learning process, but also usher in some theoretical and practical implications for researchers who intend to conduct relative studies in the near future.Supported by projects\u2019 grant from Research on Influencing Factors of Learners\u2019 Stickiness in the First-Class Course from the Perspective of Social Cognition Theory (Grant No. GD22XJY18); Research on the Intervention Mechanism of College Students\u2019 Psychological Health Based on Self-Regulation (Grant No. 2021GXSZ117).a, Chuna Chena, Pan Chena, Xiaojun Jinb, Qingtian Menga, Xuchang ZhangcYanxia Qina Department of rehabilitation medicine, Second Affiliated Hospital of the Chinese University of Hong Kong, Shenzhen, 518172, China, b Imaging Department, Second Affiliated Hospital of the Chinese University of Hong Kong, Shenzhen, 518172, China, c Department of Geriatric Medicine, Second Affiliated Hospital of the Chinese University of Hong Kong, Shenzhen, 518172, China.Background: It is well known that swallowing is a more complex sensorimotor activity, which includes both the voluntary movement but also the non-voluntary movement. All of these movements require the brain stem, the cortex and the nerves around the brain stem to regulate. Stroke is an important cause of patients with swallowing disorders, in the process of clinical treatment of swallowing disorder patients after stroke, medical staff by taking transcranial direct current stimulation has achieved good experimental results, and transcranial direct current stimulation as a new type of non-invasive brain nerve stimulation technology, is increasingly applied to the clinical after stroke swallowing function rehabilitation. However, the injury mechanism after cerebral hemisphere stroke is yet clear. This article mainly analyzes by taking the stroke patients transcranial direct current stimulation can improve the specific function of swallowing, and contrast into the patients of side, side swallowing cortex transcranial direct current excitatory stimulation after specific curative effect difference, the application of blood oxygen level dependent functional magnetic resonance imaging (BOLD-fMRI) technology in before and after tDCS treatment brain structure and function of imaging data, analysis of tCS on the cortex, clear swallowing function rehabilitation and brain function activation mode, location is relationship.Subjects and Methods: By selecting 60 patients with swallowing disorders who came to our hospital from January 2021 to November 2022, and by using a random allocation of numbers. They were divided into three groups: affected side group, healthy side group and control group, for these three groups of patients are subjected to routine swallowing training, ice stimulation, and functional electrical stimulation therapy, for patients in the healthy group and patients in the affected group. On the basis of swallowing training, ice stimulation, and functional electrical stimulation therapy, give excitatory stimulation on the healthy side and excitatory stimulation on the affected side, respectively.Results: After treatment of the 60 patients, the SSA scores were significantly higher in all three groups than before treatment, Healthy side group> affected side group > control group; swallowing lithography (VFSS) examination: before treatment than after treatment, and healthy side group > affected side group > control group; cranial fMRI examination: blood oxygen level dependent method (BOLD-fMRI) examination showed bilateral anterior central gyrus, posterior central gyrus, cingulate gyrus, insula, prefrontal, cuneus swallowing activation area, respectively, more than and stronger than before treatment, and the healthy side group > affected side group > control group.Conclusions: In conclusion, after treatment, the patients in the healthy group were significantly higher than patients in the affected group and the control group, and the difference between the affected group and the control group was not statistically significant.This work was supported by the Shenzhen Longgang District Economic and Science and Technology Development Special Fund for Medical and Health Science and Technology Project (LGKCYLWS2020001764).a, Shuoyang ZhaobYanqiu Yanga Director of Hospital Infection-Control Department, Beijing Daxing District People\u2019s Hospital, Beijing 102600, China, b Beijing Jishuitan Hospital, Beijing 100096, China.Background: To evaluate the reliability of ultra-fast fluorescence bio-monitoring method in high pressure steam sterilization monitoring.Subjects and Methods: The software program SPSS 20.0  was used to conduct the statistical analysis. Continuous variables were expressed as mean \u00b1 standard deviation (SD). Discontinuous variables were expressed in percentage (%). P<0.05 was considered statistically significant. We compared two methods  under three conditions: 134\u00b0C/70 S, 134\u00b0C/160 S and 134\u00b0C/250 S. The sterilization effect of pressure steam was monitored by these two methods, and the reliability of the ultra-fast fluorescent biological method was evaluated by comparing this with the results obtained through the conventional bio-monitoring method.Results: The one-hour ultra-fast fluorescence test result obtained by the biological reader was highly consistent with the result of the 48-hour incubation with ultra-fast bio-indicators, as well as the incubation result after seven days using the traditional biological monitoring method. It was found that there was no significant difference between these. Using the traditional biological monitoring methods, the cultivation needs a long time, which is not good to the turnover and effective use of surgical instruments. The purchase of more surgical instruments for turnover will need more money, which is generally not approved by the hospital. A better solution is speeding up the cleaning, disinfection and sterilization of surgical instruments. Biological monitoring is the gold standard for surgical instruments, especially those with implants or lumens, and sterilization is mainly a process of killing pathogenic microorganisms. Therefore, the parameters of accelerated biological monitoring were selected for verification, to ensure the safety of surgery and medical treatment while ensuring the speed. When the ultra-fast bio-indicator was self-cultured, 36 of these turned yellow at 48 hours, and 36 of these turned yellow at 168 hour. There was no increase in positive results, and the results detected within one hour were consistent with the final biological culture results. The color change results were identical with those of the traditional bio-monitoring sterilization indicator at the seven-day culture.Conclusions: The one-hour ultra-fast fluorescence bio-monitoring method is extremely accurate and reliable. This method can be widely used to improve the time-efficacy of biological monitoring. In conclusion, the results obtained by this kind of ultra-fast fluorescence biological monitoring method are both accurate and reliable, and can be used in the biological monitoring of high-pressure steam sterilization. This can fundamentally solve the limitation of the long monitoring of traditional biological indicators, realizing a seamless workflow process of cleaning, packaging, sterilization and distribution, and thereby improving the turnover rate and work efficiency of equipment.a, Pengfei LibShaoyu Donga School of Business Administration, Northeastern University, Shenyang, China, b School of Computer Science and Engineering, Northeastern University, Shenyang, China.Background: Chinese family firms have entered a peak period of inheritance, development, transformation, and upgrading; intergenerational succession is bound to affect family firms substantially. The smooth inheritance of a family firm is not only related to the longevity of the firm itself but also to the healthy and sustainable development of the national private economy. Therefore, seeking global-scale development opportunities has become essential for sustainable development for family firms. However, current studies mainly focus on the influence of family firms\u2019 internationalization based on the intergenerational succession scale. Moreover, psychological anxiety is another important factor that can impact family firm internationalization. Starting or expanding a business in a foreign market can be a daunting task, and psychological anxiety can make this process even more challenging. Few studies focus on family firm successors\u2019 psychological anxiety at different stages of succession, and few focus on the intrinsic logic and action mechanism of second-generation successors\u2019 impact on family firm internationalization. In this paper, we innovatively combined the concept in cognitive psychology to understand better the influence of intergenerational succession and psychological anxiety on family firm internationalization.Subjects and Methods: In this paper, we explored the internal mechanism of intergenerational succession that affects the degree of internationalization of family firms and further proposed a series of theoretical hypotheses based on the characteristics of China\u2019s trade policy environment and the actual situation of the intergenerational succession of family firms. This paper takes 1219 listed family businesses in China from 2010 to 2018 as a sample to study intergenerational succession\u2019s impact on the degree of internationalization.Results: By providing comprehensive empirical tests, we found a positive correlation between family firm intergenerational transfer and the degree of internationalization. Further tests, such as instrumental variables, Tobit regression, and robustness tests, show that: (1) intergenerational succession has a significant positive impact on the degree of family firm internationalization, and the results still hold after considering potential endogeneity issues and conducting a series of robustness tests.; (2) through analyzing of mediating effect test results, we find that increases in long-term borrowing and corporate social responsibility is an important means for intergenerational succession to enhance internationalization; (3) the heterogeneity analysis results reveal that family firms belonging to the high-tech industry can promote the degree of internationalization in the stage of intergenerational succession, and compared with the period of parent-child co-governance, \u201csecond-generation autonomy\u201d can promote the degree of internationalization because it eliminates the psychological anxiety of managers.Conclusion: Our study enriches the research in intergenerational succession on the degree of internationalization of family firms, and we also provide a reference for exploring family firm inheritance and maintaining long-term competitiveness by providing four aspects of suggestions.This work was supported by National Natural Science Foundation of China (No. 71873027); Humanities and Social Science Foundation of Ministry of Education of China (18YJA790063).aRenlin Guoa Beijing Enterprise Safety and Environment Information Science Research Institute, Beijing, China.Background: Psychological health is the foundation of safety culture. This article uses the DEA-tobit model to evaluate the safety culture of enterprises, and proposes policy recommendations to improve the level of psychological health.Subjects and Methods: Mental health is the focus and important aspect of safety culture construction. Based on clarifying the concept of mental health, this article reviews the literature on mental health and evaluates the efficiency of safety culture from the perspectives of industry and enterprises using the DEA-Tobit model. The level of mental health is calculated, and policy recommendations are proposed based on the research conclusions.Results: Research based on the measurement of mental health and safety culture shows that there is a positive correlation between mental health and safety culture levels in coal mines. The higher the level of mental health, the higher the level of safety management in coal mining enterprises. Therefore, coal mining enterprises must clarify the importance and necessity of mental health, in order to build a strong level of safety culture, reveal the relationship between safety culture and mental health, and have significant implications for improving the level of coal mine safety management. This will enable coal mines to increase safety investment, establish long-term mental health concepts, and comply with various safety production and investment regulations.Conclusions: The research conclusions of this article include improving the mental health level of coal mines, increasing safety investment, establishing a soft culture of coal mine safety, enabling employees to establish correct mental health concepts, accelerating enterprise modernization, improving safety management level, raising the entry threshold for frontline employees from the perspective of mental health, strengthening investment in safety training and education, improving and improving labor union organizations, and increasing investment in safety funds and scientific research funds, Effectively improving the level of mental health and safety culture.This research was supported by Shandong Social Science Planning and Research Project: Research on the comprehensive allocation level measurement and optimization strategy of urban innovation factors in Shandong Province under the digital economy (22DGLJ23).a, Changgan FangbWei Qina Youth League Committee of Wuzhou University, Wuzhou, Guangxi 543002, China, b Department of Scientific Research, Wuzhou University, Wuzhou, Guangxi 5430002, China.Background: With the continuous deepening of global modernity, traditional dance must undergo new adaptation and reproduction under the influence of modernity. Dancers have psychological problems such as stage fright, excessive excitement, and ineffective emotional expression in the process of traditional dance reproduction.Subjects and Methods: From the perspective of dance psychology, this study takes dancers in the reproduction process of the Zhuang traditional board shoe dance \u201crun for the sun\u201d as the research object, and uses qualitative research methods to conduct the research. By using the researcher as the research instrument, the non-scale methods such as personal in-depth interviews, focus group interviews, state observation, and psychoanalysis were employed to investigate the dancers\u2019 psychological phenomena as a whole in a natural context. The author collected and recorded data in various aspects, analyzed the data using inductive methods to form theories, gained an interpretive understanding of the dancers\u2019 movement behaviors and meaning constructions through interaction with the research objects.Results: Based on the choreographer\u2019s requirements of neatness, upper-air technical difficulty, and character portrayal for the dancers in the traditional dance reproduction, the psychological problems that the dancers encounter or exhibit in the traditional dance reproduction and the adverse effects on the dancers\u2019 physical and psychological health are analyzed. On this basis, by observing the dancer\u2019s psychological quality and character traits, it was analyzed that the dancer\u2019s psychological problems are caused by unsound psychological quality, which trigger unstable behaviors such as nervousness and stiff limbs. Based on the analysis of psychological problem images and causes, effective methods are proposed to overcome the psychological problems in the traditional dance reproduction, and finally the reproduction of traditional dance and the construction of dancers\u2019 psychological health are completed.Conclusions: The results show that psychological intervention based on dance psychology can achieve the effects of stabilizing self-emotions, improving self-confidence and enhancing cultural quality, which plays an important role in the cultivation of dancers\u2019 physical and psychological health.This work was supported by the 2019 Annual Stage Art Creation Founding Project of National Arts Foundation under Grant 2019-A-02-(079)-0211.a, Tiantian Wanga, Li Zhua, YanQiong Goua, Hui Tana, JinZhi MaaYuan Wena Yellow River Sanmenxia Hospital, Henan Province, Sanmenxia 472000, China.Background: Objective Analysis found that the young urethral orifice mass as the main manifestation, and misdiagnosed as vagina, clinical diagnosis and treatment of vegetation, in order to improve the understanding of the disease.Subjects and Methods: Reviewing a case admitted to Sanmenxia Hospital in Henan Province, the clinical and laboratory examination data from January 27, 2023 to February 2, 2023, reviewed relevant documents, analyzed the causes of the misdiagnosis and summarized the literature.Results: In this case, the child was misdiagnosed as the vaginal burden because the child could not cooperate with the examination, and the final intraoperative exploration was hysteroscopy after anesthesia, and after detailed examination, it was confirmed as the uroid mass, and the pathology was confirmed as condyloma at the urethral mouth after resection. The main reasons for delayed diagnosis and misdiagnosis include: lack of awareness of the disease. Failed to grasp the exclusion features of diagnosis, the medical history was not detailed, and the children could not cooperate with the physical examination. The incidence of vaginal and urethral mass was low. Young period, vaginal and urethral anatomical position, when long vegetation larger, mass root through simple physical examination is not easy to find, children fear and fear for detailed physical caused difficult.Conclusions: the conclusion of seemingly young vaginal oral redundant cases for clinical characteristics, because of the young vaginal, urethral opening distance close, difficult to identify, need to find the urethral opening anatomical location if failed to find obvious urethral entrance or children completely cannot cooperate, need to consider the urethral opening mass, and urethral opening mucosal valgus may be, need further examination under anesthesia. In order to avoid misdiagnosis and mistreatment. Condyloma acuminata is less rare, condyloma acuminata growing around the urethral opening is rarer, friction tissue edema, easy to misdiagnosed vaginal tumor and urethral opening mucosa valgus. Therefore, young girls to prevent such diseases pay attention to improve their own immunity and resistance, but also to prevent other ways of infection.a, Dawei LiuaQian Lia College of Public Management, Guizhou University of Finance and Economics, Guiyang 550025, China.Background: Whether the regional disparities in the development of higher education in China have changed since the implementation of the connotative development has received widespread attention from the society. However, few studies have focused on this issue based on statistical data. The regional disparities in higher education development have a direct impact on the difficulty and quality of students\u2019 college admission, which in turn can affect the psychological needs of students from different regions for entering their ideal universities and their anxiety towards college admission.Subjects and Methods: Using a panel data approach covering the period of 2013-2020, this study comparatively analyzed the regional disparities in higher education development in the Eastern, Central, Western, and Northeastern regions of China as well as across provinces. Furthermore, the study explored the possible impact of these disparities on students\u2019 anxiety about college admission.Results: From 2013 to 2020, the number of regular institutions of higher education per million people in China increased from 1.82 to 1.94. Notably, the densities of institutions of higher education in Beijing and Tianjin were much higher than in other provinces, at 4.20 and 4.04 institutions per million people, respectively. With regard to high-level educational resources, in 2020, the number of doctoral students in Beijing exceeded that of undergraduate students by 20%, while the number of master\u2019s students exceeded that of undergraduate students by 55%. Meanwhile, in some western provinces, the number of doctoral students was still less than 1% of the undergraduate student population. The proportion of GDP allocated to higher education increased from 1.33% in 2013 to 1.41% in 2020 on a national level.Conclusions: Since the implementation of the connotative development, the disparity in the scale of higher education among different regions in China has gradually narrowed. The distribution of high-level educational resources in the central and western regions lags significantly behind that in the eastern regions. The regional differences in high-level education have a direct impact on students\u2019 psychological expectations for college entrance, which in turn leads to varying degrees of college-going anxiety.This paper was supported by the Humanities and Social Sciences Project of the Ministry of Education of China (22XJA790005) and Research Initiation Projects for Introduced Talents of Guizhou University of Finance and Economics (2018YJ44).a,b; Yunru Sic; Jian XiaodNali Shena Business School, Southwest University of Political Science and Law, Chongqing 401120, China, b China Region Public Brand Research Center at Southwest University of Political Science and Law, Chongqing 401120, China, c School of Public Management, Chongqing University, Chongqing 400044, China, d School of Mathematics and Statistics, Chongqing University, Chongqing 401331, China.Background: In this paper, we study the incentive mechanism of customer knowledge sharing and revenue sharing designed by the manufacturer as the core firm in the supply chain based on emotional behavior in big data environment. The value of customer knowledge sharing and potential barriers were analyzed, then by designing an effective incentive mechanism to create a positive emotional climate that fosters customer knowledge sharing and ultimately leads to better cooperation benefits for both retailers and the manufacturer.Subjects and Methods: Considering retailers\u2019 emotional behaviors, a principle-agent theory method was used to build mathematical models to analyze behaviors of manufacturers and retailers. The organization emotional behavior theory about incentive was also used to analyze the original organizational psychological states and changes after executing incentive mechanism. And a numerical method was applied to describe change trends of the main factors for knowledge sharing between electronic retailers and manufacturers.Results: there is a positive correlation between a single e-retailer\u2019s effort level of customer knowledge sharing to maximize its expected revenue based on its emotional behavior in big data environment, and the proportion of revenue sharing and the number of e-retailers owned by the manufacturer. The optimal revenue sharing ratio obtained by e-retailers is negatively correlated with the manufacturer\u2019s customer knowledge innovation ability and the number of e-retailers owned by the manufacturer, but positively correlated with the e-retailers\u2019 customer knowledge sharing ability.Conclusions: Revenue sharing incentive is an effective mechanism based on organization emotional behavior. The number of manufacturer-owned e-retailers have a positive effect on e-retailers\u2019 efforts to improve customer knowledge sharing. The optimal revenue-sharing ratio was related with the effort elasticity coefficient the manufacturer and retailers, and emotional behaviors would affect their efforts in the process of knowledge sharing. The incentive mechanism for customer knowledge sharing has changed the organizational emotional behavior of retailers, affected the emotional behavior of manufacturers, would promote knowledge sharing between both parties, and ultimately improved cooperation performance. Therefore, in the knowledge sharing cooperation between retailers and manufacturers in big data context, analyzing the organizational emotional behavior before cooperation, designing incentive mechanisms to affect their emotional behaviors, motivating both parties to make efforts to share customer knowledge, which can promote cooperation benefits for both parties.This work supported by a project grant from National Social Science Fund of China (18BGL102).a, Runzhao Qib, Xue Baic, Ke HuangaWenjing Donga School of Architecture and Urban Planning, Chongqing Jiaotong University, Chongqing, China, b School of Architecture and Environmental Art, Sichuan Fine Arts Institute, China, c Institute of Architecture & Planning Design Co., Ltd., Chongqing University, Chongqing, China.Background: Public health is a public service that is related to the public health of a country or region, and the prevention of major infectious diseases is the top priority. Driven by the public health affairs of the global COVID-19 outbreak, people pay more and more attention to the indoor air quality in public places. Indoor air quality in public places plays a decisive role in public health, and is an important factor affecting the physical health, work efficiency and mental health of users. As a crowded place, creating good indoor air quality is the necessary guarantee to ensure the physical and mental health of teachers and students and improve the efficiency of teaching activities.Subjects and Methods: Taking public health as the guide, this paper combines many technical measures for the reconstruction of existing classrooms to form different reconstruction schemes, and uses numerical simulation method to compare and analyze the indoor air environment quality of a university classroom in Chongqing under different schemes. The article puts forward built-in thermal insulation, closing the gaps of doors and windows, and setting fresh air as the transformation measures. At the same time, taking into account the use conditions of opening and closing doors and windows, the paper selects five factors that affect the indoor air quality: temperature, humidity, CO2 concentration, O2 concentration, and PM2.5 concentration for comparative analysis.Results: The results show that the increase of thermal insulation layer has the greatest impact on the temperature in the classroom when the doors and windows have gaps; Fresh air has the best effect on reducing CO2 concentration in the classroom, followed by fully open doors and windows; After strengthening the treatment of door and window gaps, closing the doors and windows and ventilating fresh air have the best effect on the control of PM2.5 concentration in the classroom.Conclusions: The effect of continuous fresh air in reducing the concentration of indoor pollutants is better than that of natural ventilation. The internal thermal insulation setting can effectively ensure the indoor temperature. The research results can provide a basis for putting forward a reasonable classroom reconstruction plan, controlling the quality of indoor air environment, and providing a certain reference for creating a comfortable and healthy indoor thermal environment in public places and ensuring public health.a, Shanshan ZhouaXiaocheng Gua Department of Accounting, Anhui Business & Technology College, Hefei, Anhui, China.Background: To verify that Power Business Intelligence (Power BI) tool is more efficient than traditional Excel tool in processing financial data through typical financial cases, and can improve the efficiency of financial personnel data processing. At the same time, using questionnaire survey method, this paper explores the impact of Power BI on the mental health of financial workers in Chinese enterprises from a micro perspective, which is helpful to understand the relationship between the development of financial digitalization and individual behavior at the micro level. To find out the psychological needs of financial workers, and make timely intervention and adjustment, effectively resolve the contradiction, to ensure the efficient and orderly progress of financial work.Subjects and Methods: Excel and Power BI were used to solve financial problems in typical financial cases, and the complexity of the two calculation processes was compared and analyzed to show the high efficiency of Power BI tools in financial number processing. Through a questionnaire survey, we compared and analyzed the work and psychological impact of using Excel and using Power BI to solve financial problems, and discussed the impact of digitalization on financial practitioners from the perspective of psychology.Results: Power BI tools also provide financial workers with more efficient choices in data processing. Our study answers the question of whether the development of financial digitization affects individual psychological health, which has important theoretical and practical significance. In addition, based on China, a typical developing country, the research results have important practical significance for the development of financial digitization in developing countries.Conclusions: Financial digital transformation is an inevitable trend in the digital era. Power BI tool can improve the efficiency of financial workers\u2019 data processing and is an important tool in digital transformation. However, the process of digital transformation will also bring certain psychological pressure to financial workers, including digital overload and cognitive load, which requires timely intervention and adjustment. At the same time, under the background of digitalization, financial personnel need to constantly learn and update their skills, adapt to the changes and challenges of the digital environment, and improve their competitiveness. In order to better participate in the financial business in the digital era.This work was supported by the provincial Quality Engineering Teaching and Research Project of Anhui Province [grant number 2021JYXM0161]; the provincial Quality Engineering Teaching and Research Project of Anhui Province [2022JYXM152]; Anhui Province Teaching and Research Project [2021XJJY19]; Anhui Province Teaching and Research Project [2019XJJXTD01].a, Tieliang Guob, Qing LicJunjie Zhanga Academic Affairs Office, Wuzhou University, Guangxi 543002, China, b College of Electronics and Information Engineering, Wuzhou University, Guangxi 543002, China, c Psychological Counseling Center, Wuzhou University, Guangxi 543002, China.Background: Since the outbreak of new coronavirus pneumonia, it has attracted extensive international attention. In order to understand the impact of this public health emergency on the mental health of young people, The subjects of this survey are all young people aged 18-22..Subjects and Methods: Through the network questionnaire survey, a total of 4305 students were surveyed, including 1222 boys and 3083 girls. This study adopts the self-made general situation questionnaire and the norm of symptom checklist (SCL-90) as well as interviews for factors.Results:In the early and later stages of the epidemic, students\u2019 emotions changed. Most of the students had a good psychological state, while a small number of students had bad emotions such as nervousness, fear and irritability. College students, SCL-90 the difference in the detection rate of symptoms of each factor was not statistically significant. The trend of the factors of different gender students was different before and after the epidemic, and the factors of different levels at different levels, and different data were obtained after the variance.Conclusions: Through mental health testing of 18-22 year olds, comparative analysis of the gap between negative and positive effects, the differences in young people\u2019s personal health adjustment in the face of public health emergencies are studied from the aspects of health philosophy, health knowledge and healthy lifestyle, Explore low-cost paths that can alleviate the lack of medical resources, release the pressure of the medical system, and promote the sustainable development of public health. According to research, since the outbreak of the epidemic, young people with a calm mind have mostly adopted art related adjustment methods. Through promotion, the test was conducted again among young people, and the influencing factors of some young people\u2019s mental health decreased significantly. Therefore, it is suggested that such methods can be used for reference in the adjustment of public health after public health emergencies.The work was supported by the 2022 Guangxi Higher Education Undergraduate Teaching Reform Project (Grant No. 2022JGZ167), and the 2020 Guangxi Higher Education Undergraduate Teaching Reform Project (Grant No. 2020JGB369).a, Caixia WuaXiaobei Huanga School of Economics and Management, North China University of Technology, Beijing, 100144, China.Purpose: The purpose of this paper is to investigate whether investors who develop psychological anxiety will rely more on the management earnings forecast of Chinese listed firms during the coronavirus pandemic.Methods: Based on the quarterly earnings forecasts of all A-share listed companies in China from 2018 to 2021, this paper examines the market reactions of investors to management earnings forecasts before and after the coronavirus pandemic using difference-in-difference methods.Results: The results show that uncertainty due to the coronavirus pandemic can affect investors\u2019 psychological expectations of the future economic situation and induce psychological anxiety, which will trigger investors\u2019 vague aversion, the irrational sentiments lead to pessimistic judgment of investors on the future operation of listed companies, resulting in a significant decline in the market reaction to management earnings forecast during the pandemic. The quality of the management earnings forecast is further controlled in the regression model and the research conclusion remains unchanged, excluding the impacts of information quality on the research conclusion.Conclusions: The coronavirus pandemic has caused unprecedented uncertainty, which also triggers psychological anxiety of investors and affects investment decisions. In the pandemic, investors have demonstrated ambiguity aversions, and less trust in earnings forecasts of corporate management. The results are not driven by the changes in the quality of management earnings forecasts. This research helps the market learn more about the behavioral logic of corporate management and the influence of investors\u2019 decision-making during the pandemic, which can also provide evidence for regulators to further standardize the information disclosure of listed companies and improve the information environment of the Chinese capital market.The paper was supported by National Natural Science Foundation of China (71602004), the Social Science Foundation of Beijing (19GLC059).aQun Wanga University of Jinan, Jinan, Shandong 250022, China.Background: The excellent traditional culture of China is the inexhaustible motive force for the Chinese nation\u2019s endless and sustainable development. Integrating the excellent traditional culture of China into the mental health education in colleges and universities, stimulating the vitality and vitality of the excellent traditional culture of China, and highlighting the value of the times are not only important measures to improve the effectiveness of mental health education for college students, but also important measures to inherit the national spirit blood, absorb rich historical and cultural nourishment, and enhance the national cultural soft power and international discourse power, It is a realistic need to build a socialist cultural power with Chinese characteristics and comprehensively improve the cultural literacy of the people. Given that there are still many problems with the excellent traditional Chinese culture in college students\u2019 mental health education, we must strengthen efforts to promote the creative transformation and innovative development of the excellent traditional Chinese culture.Subjects and Methods: Mental health education in colleges and universities is related to the major issue of cultivating qualified builders and successors of socialism with Chinese characteristics for the new era. We must take scientific and effective measures, adhere to the principle of making the past serve the present, bring forth the new, treat them differently, inherit the useful and discard the useless, draw essence from the excellent traditional Chinese culture, and strive to use all the spiritual wealth created by the Chinese nation to educate people with culture.Results: Do a good job in the creative transformation and innovative development of Chinese excellent traditional culture in college mental health education, and build a harmonious campus culture by exploring the harmonious view of Chinese excellent traditional culture; Pay attention to the space concept of the excellent traditional Chinese culture and do a good job in its \u201cthree entry\u201d work; Develop the dynamic view of Chinese excellent traditional culture, innovate teaching methods, and pay attention to educational effectiveness; Highlight the characteristics of Chinese excellent traditional culture and enrich the carrier of Chinese excellent traditional culture education; Strengthen the people-oriented view of Chinese excellent traditional culture and improve the teaching level of teachers; Adhere to the concept of knowledge and action of Chinese excellent traditional culture, and build a \u201ctrinity\u201d education model of Chinese excellent traditional culture of school, society and family.Conclusions: The excellent traditional Chinese culture is both historical and contemporary; It is both national and global. We should more consciously and actively promote the adaptation of the excellent traditional Chinese culture to the contemporary society and the coordination with the modernization process, better promote the creative transformation and innovative development, and promote the mental health education of college students.This paper was supported by a project from the foundation \u201c Research on the Integration of Excellent Traditional Chinese Culture into the Education and Teaching of Ideological and Political Theory Course\u201d\u20142015 Shandong Provincial Social Science Planning Project (15cszj04).a, Tao Xiaob, Meihong ZhengcYinchou Zhoua Department of Foreign Languages and Literatures, Tsinghua University, Beijing 100084, China, b Institute of Industrial Development and Governance Innovation, Zhejiang Guangsha Vocational and Technical University of Construction, Jinhua, 322103, Zhejiang, China, c School of Social Sciences, Tsinghua University, Beijing 100084, China.Background: Current treatments of transcortical motor aphasia are based on the attribution of typical symptoms and brain regions. However, the large individual differences between patients and the uncertainty of stroke injury areas make it difficult to adapt to the dynamic changes of post-stroke aphasia recovery. In order to make the symptom analysis of transcortical motor aphasia more dynamic and better fit for patients, this study attempts to reexamine the specific symptom representations with the perspective of a holistic process from verbal intent to speech behavior.Subjects and Methods: Based on the neural basis of language processing as well as the results of the PDC model and P-chain model, we have proposed a three-module model consisting of linguistic expression, coordinated connectivity, and motor output \u2014\u2014after generating the expressive intention in part 1 and then projects the expressive intention and content to the motor control system in part 3 through the coordination of part 2 and the motor output of the language after integrating the articulatory organs, thus completing the complete language expression.Results: Language expression can be understood as a process from intention to behavior, in which \u201clanguage production\u201d at the beginning and \u201cmotor output\u201d at the end of the process are linked in a loop, while the aSPPO area is specific for speech-motor connectivity and there is overlap with brain areas damaged in patients with transcortical motor aphasia. Thus transcortical motor aphasia can be at least partially explained by the fact that disruptions in the coordinated connectivity pathway involving the aSPPO area may lead to the inability of individuals to produce effective language output even when the speech production and vocalization sites are functional.Conclusions: Based on brain plasticity and the fact that the aSPPO area is between the hand action area and the oral-facial action area, there may be practical value in two behavioral intervention treatment options for transcortical motor aphasia: assistance in functional overlap areas, which means after training individuals to conceptualize verbal content in the brain (without expressing it) while performing non-verbal actions such as licking their lips and smiling, the originally damaged coordination connectivity pathways involved in aSPPO can be reactivated to some extent; and compensation in adjacent areas, referring to individuals who perform right-handed hand action or facial action training will have significantly improved verbal motor output.a, Shizheng LibXiaoxue Zhanga School of Management Science and Engineering, Anhui University of Finance and Economics, Bengbu 233030, China, b School of Finance, Anhui University of Finance and Economics, Bengbu 233030, China.Background: Despite the multitude of studies exploring the causes of mental health problems among college students in China, the impact of academic performance on mental health has not been adequately investigated. Purpose: Analyzing the relationship between student self-evaluation comprehensive academic performance score, as well as their scores on 7 different sub-dimensions of academic performance, and the mental health status of college students.Subjects and Methods: A 41-item scale was developed to evaluate participants\u2019 academic performance. 10 items from the PSS-14 were used to measure the mental health status of participants. Descriptive statistics were initially employed to analyze the distribution and numerical characteristics of academic performance and perceived stress among the participants. Seven logistic regression models were constructed to investigate the predictive effect of different dimensions of academic performance on the mental health.Results: Online teaching prompted by the COVID-19 pandemic did not yield a significant impact on the mental health of the respondents. Gender did not emerge as a predictive factor for mental health status. Stress related to academic performance is not limited to students who struggle with their studies, as academic achievers may face higher risks. Academic performance scores obtained through the self-evaluation scale demonstrated better predictive power for mental health status than traditional GPA scores.Conclusions: The threshold for safeguarding the mental health of college students must be shifted to an earlier stage of education. It is imperative for China to pursue a gradual and sequenced approach to the implementation of mental health education in primary, secondary, and tertiary schools, with a focus on enhancing the professionalism and expertise of mental health education practitioners.This work is supported by Anhui University of Finance and Economics\u2019 Teaching Research Project (acjyzd2020004).a, Weiqing Zhaoa, Ye Liub, Yaozhou Wanga, Caiyun Xionga, Hao ZhouaLinyin Luoa Department of Pediatrics, Guizhou Provincial People\u2019s Hospital, Guiyang, 550002, China, b Department of Otolaryngology, Guizhou Provincial People\u2019s Hospital, Guiyang, 550002, China.LL and WZ contributed equally to this research.Background: This study examined changes in \u03b3-aminobutyric acid type A (GABAA) \u03b11 (GABAA\u03b11) and \u03b12 (GABAA\u03b12) receptor expression in autism model rodents and children with autism spectrum disorders (ASD) with the aim of providing insights about causes and treatment of autism.Subjects and Methods: Neuronal expression of GABAA\u03b11 and GABAA\u03b12 in the frontal cortex of control rats  and gestational valproic acid (VPA)-induced ASD rats was measured by immunohistochemistry (IHC), western blot, and real-time quantitative PCR (RT-qPCR). Serum GABAA\u03b11 and GABAA\u03b12 expression in 37 autistic children and 32 healthy children were determined by enzyme-linked immunosorbent assay (ELISA).Results: Immunohistochemical staining showed that the VPA-induced ASD rats had significantly higher mean GABAA \u03b11  and GABAA\u03b12  expression than controls. Western blot detection showed that the relative grayscale values of GABAA\u03b11  and GABAA\u03b12  protein were slightly higher in the VPA group than in controls, although the differences were not statistically significant. The VPA group also had higher GABAA\u03b11 (P>0.05) and GABAA\u03b12 (P<0.05) mRNA expression in the frontal cortex compared to controls. Similar to the findings in rodent models, autistic children had higher serum GABAA\u03b11  and GABAA\u03b12  levels than controls.Conclusions: Abnormal expression of GABAA receptor subunits may contribute to autism pathogenesis.a,b, Xiaodan Bia,b, Xingqiang Huanga,b, Xu Tanga,b, Jinpeng Yanga,b, Tingting Zhaoa,bZhenrun Zhana Heping Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi 046000, China, b Changzhi Medical College, Changzhi, Shanxi 046000, ChinaBackground: Atherosclerosis, an immunoinflammatory disease caused by lipids, is a significant factor in coronary heart disease and stroke. Researchers worldwide are working to develop more effective ways of diagnosing and treating it. This article introduces a machine-learning algorithm that screens biomarkers and performs pan-cancer analysis as a reference.Subjects and Methods: We first downloaded the GEO dataset containing information on atherosclerotic patients for differential gene screening and analyzed differential mRNAs using KEGG and GO enrichment analysis. Then, we combined WGCNA, protein interaction network analysis, and mechanistic learning algorithms to screen for core genes, perform basic experimental validation, and immuno-infiltration analysis. Finally, we used TCGA and GTEx databases for pan-carcinogenic analysis of differentially expressed genes.Results: After screening differentially expressed genes from the GSE28829 dataset, we performed WGCNA and obtained 122 key genes by combining module genes and differential expression genes. We used four machine learning algorithms  to calculate the critical genes and obtain the junction of the results, which led us to identify four hub genes . Next, we built a diagnostic model and assessed its capabilities. The ROC curves of the four genes suggested their critical role in the development of atherosclerosis. We then performed gene correlation analysis, immune infiltration analysis, and RT-PCR verification of the four core genes and finally screened out TLR2 for pancarcinoma. Our analysis found that TLR2\u2019s expression in patients with various tumors differed from that in healthy individuals, and it was strongly associated with the prognosis of patients with diverse cancers.Conclusions: TLR2 may be a target for intervention in developing diseases such as atherosclerosis and tumors.This study was supported by the Shanxi Province Graduate Education Innovation Project (2022Y726/737), the Basic Research Program of Shanxi Province (202203021212010), and the Youth Start-up Fund of Heping Hospital affiliated to Changzhi Medical College (HPYJ202225).a, Zhong Lib, Weibai LiucYongcai Zhanga School of Law and Business, Shaoyang University, Shaoyang 422000, China, b School of Business Administration, Hunan University of Finance and Economics, Changsha 410205, China, c School of Economics and Management, Hunan University of Science and Technology, Yongzhou 425199, China.Background: Food satisfaction can solve the problem of hunger, alleviate social anxiety and improve people\u2019s mental health. Food is an important source of food, Food security is the most important ballast for economic development and social stability. Therefore, the social status of food is decisive and its yield and quality is particularly important. Food security lies not only in output growth, structural adjustment and optimization, but more importantly in further improvement of grain productivity and alleviate social anxiety.Methods: Fuzzy logic theory, super-efficiency DEA and Bootstrap DEA methods are used to measure the grain productivity of China from 1978 to 2018. Fuzzy logic adopts \u201cFuzzy ToolkitUoN\u201d to make a fuzzy logic control, with its implicit boundaries of the qualitative knowledge and experience, the aid of concept of subordinate degree function, fuzzy set and relation, the fuzzy logic can simulate the human brain implementation of rule-based reasoning, deal with the uncertainties created by logic deficiency of \u201claw of excluded middle. The super-efficiency DEA model includes several models such as CCR, BCC and SBM, which is to make the same type of unit  evaluation based on the decision making unit of \u201cinput\u201d and \u201coutput\u201d data. Bootstrap-DEA method is to introduce Bootstrap into DEA model. Bootstrap sample data are constructed repeatedly through the method.Results: The above data indicate that the traditional DEA method has defects, and more accurate super efficiency DEA and Bootstrap-DEA are needed to calculate the efficiency. Show that the grain yield efficiency is closely related to national policies and social development. China\u2019s grain productivity is relatively stable on the whole, but the return to scale fluctuates greatly, and the return to scale even decreased for 13 consecutive years. Therefore, how to improve the production of food and its productivity in scientific ways to alleviate social anxiety. Since 2013, the comprehensive efficiency has been on a steady rise, and the efficiency value gradually increased from 0.8370 to 1. In addition, its technical efficiency has been stable with an efficiency of 1 for four consecutive years since 2015, indicating that technological progress has promoted the improvement of comprehensive efficiency. At the same time, the scale efficiency value is also above 0.9, and the comprehensive effect of technological progress and scale efficiency got a higher comprehensive efficiency value, improve people\u2019s mental health.Conclusions: To ensure the sustainable development and food security of China\u2019s grain industry and alleviate social anxiety, it is necessary to strictly observe the minimized reserve of cultivated land, strengthen the efforts for the protection of cultivated land, establish and improve policies and incentive mechanisms for the introduction of agricultural scientific and technological personnel, strengthen efforts to make grain more market-oriented, and promote the integrated development of the grain industry with the secondary and tertiary industries. The efficiency of food production will be improved and when society is active, improve people\u2019s mental health, maintain family and social security.Research and Planning Fund for Humanities and Social Sciences of the Ministry of Education of China (22YJA790038);Projects of Natural Science Foundation of Hunan Province, China ; Project of Education Department of Hunan Province, China .aMingzhou Wanga Shanghai Urban Construction Vocational College, Shanghai, 200438, China.Background: Cultural festivals and events refer to a series of cultural activities or events held in cities, which have strong local, cultural, concentrated, and interesting characteristics. They can meet the psychological needs of citizens, enhance their sense of happiness, help alleviate social anxiety, and promote social stability and harmony. By analyzing and summarizing the key factors that can successfully host world-renowned cultural festivals, this paper proposes innovative measures to host the Yangtze River Cultural Festival.Subjects and Methods: Using literature review and data collection methods, we selected world-renowned cultural festivals such as the London Mayor\u2019s Thames Riverside Festival, Seoul\u2019s \u201cHan River Celebration\u201d, and Dalian International Beach Cultural Festival as research objects to analyze the positive effects of cultural festivals on citizens and tourists, such as joy of participation, stress relief, relaxation, and psychological pleasure, and discussed creativity, brand The role of participants and other factors in cultural festival activities.Results: Currently, with the rapid development of society, the pace of life has significantly accelerated, and with the rapid growth of the economy, there are also tremendous negative emotions such as stress, anxiety, and depression, which pose a great threat to people\u2019s psychological and physical health. By participating in cultural festivals and experiencing lively and interesting activities, citizens can gain more opportunities for interpersonal communication, increase individual social interaction, resist negative emotional influences, eliminate depression and anxiety, and promote mental health. A successful cultural festival event must rely on the city\u2019s existing resource endowment, use innovative thinking for top-level design, pay special attention to setting up distinctive and interesting activities, mobilize the participation of diverse subjects, especially young people, and actively meet their daily entertainment and mental health needs. In addition, it is necessary to create a market-oriented, government assisted operating mechanism.Conclusions: As one of the cultural supply products in cities, cultural festivals and events have a positive impact on enriching citizens\u2019 daily cultural life and promoting their mental health. Research has shown that participating in cultural events can help people maintain good interpersonal relationships and self understanding, maintain a positive mental state, and effectively reduce the incidence of mental illness. Cities along the Yangtze River have rich resources to carry out Yangtze River cultural festivals. By learning from the successful experience of world-renowned cultural festivals and holding colorful Yangtze River cultural festivals, it is possible to explore a new path for urban cultural supply.a,b, Xiaodong Zhenga,c, Miao Wanga, Fan ZhangaYongping Lia Faculty of Humanities and Arts, Macau University of Science and Technology, Macau 999078, China, b Ningbo University of Finance and Economics, Ningbo, Zhejiang 315175, China, c School of Computer and Information Engineering, Nantong Institute of Technology, Nantong, Jiangsu 226002, China.Background: Under the background of consumption era, more and more tourist areas begin to create unique cultural symbols as an important basis for their market attraction and brand effect. However, in the past few years, influenced by COVID-19, people are generally anxious and have no strong desire to travel, which leads to a sharp drop in tourist flow in scenic spots, a continuous downturn in tourism consumption, and a huge impact on tourism. With the gradual disappearance of the epidemic, the global tourism industry has regained its confidence and gained great opportunities. How to accurately grasp and construct cultural symbols, so as to alleviate tourists\u2019 anxiety and enhance tourists\u2019 willingness to travel, has become an important proposition to be solved urgently in every tourist area.Subjects and Methods: Taking Putuo Mountain Tourist Area in Zhoushan City, Zhejiang Province as the research object, this paper discusses the relationship between cultural symbol cognition, tourism psychology and tourism willingness, aiming at clarifying the difficulties faced by Putuo Mountain Tourist Area, helping to establish and strengthen its unique cultural symbols, thus effectively improving the popularity and passenger flow of the tourist area. Firstly, based on the theory of symbolic interaction and symbolic consumption, the corresponding question hypothesis and questionnaire are put forward. Secondly, the questionnaire survey was carried out through the network platform, and the questionnaire results were processed and analyzed by SPSS software. Finally, the corresponding results are obtained by regression analysis to verify the hypothesis.Results: A total of 1000 questionnaires were distributed and 833 questionnaires were collected. After eliminating 172 invalid questionnaires, 661 valid questionnaires were obtained. Using SPSS software to process and analyze the questionnaire data, the results show that tourists\u2019 cognition of Putuo Mountain cultural symbol is positively correlated with their willingness to travel, and the degree of tourists\u2019 psychological anxiety is also positively correlated with their willingness to travel. In addition, the analysis results show that personal education level, personal age, personal income level, image perception of tourist destination and hardware facilities are also important factors affecting tourism willingness.Conclusions: Zhoushan is the main maritime gateway for China to open to the outside world, and it is the only place for Chinese and foreign ships to sail from south to north. There are unique mountain and sea landscapes and island fishing customs here, and tourism has become one of the local pillar industries. As an important scenic spot in Zhoushan, Putuo Mountain attracts a large number of tourists every year with its beautiful scenery and unique cultural heritage. In the future, Putuo Mountain must vigorously publicize its unique cultural symbols, enhance its cultural heritage and speed up the construction of tourism infrastructure to maintain its sustainable attraction as a tourist destination.This paper is supported by 2021 Nantong Science and Technology Plan Project (JCZ21074), 2020 Jiangsu University Philosophy and Social Science Research Project (2020SJA1612), Young and Middle-Aged Key Teachers Training (Scientific Research) Project of Nantong Institute of Technology (ZQNGGJS202120), Key Scientific Research Project of Zhejiang Provincial Department of Culture and Tourism (2021KYZ006), Key Project of Ningbo Education Science Planning (2021YZD019).a,b, Yongtian Wub, Zhiheng Chenc, Xuekai WeibJianping Liua College of Civil and Environmental Engineering, Hunan University of Science and Engineering, Yongzhou, Hunan, 425199, China, b Bama Hetai Longevity Industry Co., Ltd., Bama, Guangxi, 547500, China, c Department of Health Management, Xiangya Third Hospital, Central South University, Changsha, Hunan 425099, China.Background: The high incidence of hyperuricemia has become a major medical and social problem affecting the health of Chinese residents. The existing medical system has not yet explored the formation mechanism of hyperuricemia, resulting in little effect on the prevention and treatment of hyperuricemia.Subjects and Methods: From the perspective of nutritional medicine, the development and changes of nutrient intake and dietary preferences of Chinese residents in the past three decades have been analyzed in depth by using the time series analysis method, and the formation process and mechanism of hyperuricemia have been systematically studied by using the whole-cycle theory.Results: The research shows that excessive uric acid production and too little uric acid excretion are the two causes of high incidence of hyperuricemia. The excessive production of uric acid is caused by the preference for high-purine food, the structural nutrient intake imbalance caused by the overall insufficient intake, the excess intake of some nutrients and the uneven intake of nutrients of long-term nutrients, and the metabolic abnormalities of human related enzymes. Too little uric acid excretion is caused by the structural imbalance of long-term nutrient intake, which is the main cause of hyperuricemia.Conclusions: The basic mechanism of hyperuricemia is the excessive re-absorption of kidney caused by the long-term imbalance of nutrients intake, especially the insufficient intake of water nutrients. We can effectively prevent and treat hyperuricemia by controlling the intake of high-purine exogenous foods, balanced intake of daily nutrients, taking disease-based strategies, strengthening daily independent health management and other measures. The research provides a new theoretical perspective and specific implementation methods for the prevention and treatment of hyperuricemia in China, which has great theoretical value and practical significance.This work was supported by a project grant from Natural Science Foundation of Hunan Province (Grant No.2019JJ50915) and Hunan University of Science and Technology Applied Characteristic Discipline Construction Project (Grant No.18TSXK-001).a, Youyou Zhanga, Yuehan QiaoaHuansong Yanga Hangzhou Normal University, Hangzhou City, Zhejiang Province 310000, China.Background: According to the 2019 Chinese Women\u2019s Confidence Report, 40 percent of Chinese women underestimate themselves. In other words, two out of every five Chinese women are not confident. A survey of 2,000 women by a UK institute found that 42 percent of women never give themselves a good compliment and criticize themselves at least eight times a day. This paper takes the method of psychological mining and performance of the hero of character documentary as the research content, explores the influence and contribution of streaming media anchor, a new profession, on the development of female mental health, and strives to find out a set of methods of psychological mining and performance of documentary characters.Methods: Based on psychological principles such as threshold effect, seesaw law, congruence effect, external behavior and manner of characters reflecting internal psychology, and research methods, this paper explores the psychological mining methods of film and television character documentaries, and explores the positive influence of the rise of \u201ca female anchor who sells goods through live streaming\u201d on women\u2019s mental health according to specific character interviews and surveys. The research on the psychology of the protagonist in the character documentary of \u201ca female anchor who sells goods through live streaming\u201d can provide experience and reference for the creation of character documentary in the future, so as to better shape the character image in the documentary creation.Results: The research shows that: 1. In professional documentaries, the use of audio-visual language can excavate the psychological changes of characters to a certain extent. For example, the use of long lens and depth of field lens can capture and amplify the psychological and emotional changes of characters.2.the color tone of the picture, simultaneous sound processing and music sound can play a key role in the portrayal of the character image and character psychology.3. The rise of \u201ca female anchor who sells goods through live streaming\u201d has greatly enhanced women\u2019s self-confidence and has a positive impact on women\u2019s mental health.4. As women have found broader career paths, their social status and recognition have also increased along with their economic level, which has a significant effect on their mental health.Conclusions: With the development of the e-commerce industry, a large number of women have found their own value in the work, thus blooming the charm and brilliance of different age groups. Influencing and inspiring others while maximizing their own worth is part of the magic that careers confer on women. Through the psychological mining and mental health research of the heroine of \u201ca female anchor who sells goods through live streaming\u201d, the author hopes that in the future career development and career planning, there will be more emerging industries to help women realize their self-worth.This research was supported by Fund program: Zhejiang Province digital cultural and creative Industry Production and education integration engineering base project (Zhejiang development reform society [2020] No.319)a, Li LibHongqi Zhoua Xianda College of Economics and Humanities, Shanghai International Studies University, Shanghai 200000, China, b Hunan University of Technology, Zhuzhou, Hunan 412000, China.Background: This study focuses on the behavioral and psychological needs of users and advocates the use of universal design concepts to improve the design of open space facilities in country parks, so as to better reflect the \u201cpeople-oriented\u201d purpose of design and meet the needs of users for respect, comfort, equality and care. The research provides reference for the design of public space facilities.Subjects and Methods: Firstly, through literature research method, the basic theories related to the study were summarized. Secondly, through on-site investigation, the current status of recreational facilities was understood, and the needs of users\u2019 physiological and psychological fairness, respect, safety and other characteristics were understood. Finally, through investigation and analysis, strategies for the universal design of recreational facilities in the countryside park were proposed.Results: According to the characteristics of country parks, the physical and psychological needs of users, the design of country park recreation facilities should follow the principles of fairness, systemization, safety, comfort and aesthetics, and embody the \u201cpeople-oriented\u201d design purpose, so that urban recreation facilities can better meet the needs of everyone.Conclusions: Recreational facilities are an important part of the recreational space in the countryside park, and their design should fully respect users\u2019 behaviors and psychological needs. The design should aim to provide equal, safe, and comfortable universal functions for as many users as possible, effectively reducing conflicts between environmental facilities and individual characteristics. This approach can better embody social care and equity.a, Yan LuaYabing Shana The Third Affiliated Hospital of Zhejiang Chinese Medicine University, Hangzhou, China.Background: We aim to develop a preoperative nomogram to evaluate the risk of death within a year of the operation in patients with resectable hepatocellular carcinoma.Subjects and Methods: Retrospective study of 490 hepatocellular carcinoma patients who were treated with hepatectomy. Multiple logistic regression analysis was performed to identify factors associated with early death in these patients. A nomogram was constructed based on the independent risk factors, and predictive accuracy of nomogram was valued.Results: Tumor size, portal vein tumor thrombus, fibrinogen to albumin ratio and geriatric nutritional risk index were found to be independent predictors of death at 1 year after surgery in resectable hepatocellular carcinoma patients and were finally entered into the nomogram. The calibration curves for the possibility of one year mortality showed optimal agreement between nomogram prediction and actual observation. The concordance index and the area under curve of receiver-operating characteristic showed that the nomogram in current study was superior to the Barcelona Clinic Liver Cancer classi\ufb01cation, Child-Pugh score, and Okuda stage in predicting early death of hepatocellular carcinoma patients with sugery.Conclusions: Our nomogram got a better accuracy in predicting mortality within a year after operation in patients with hepatocellular carcinoma.The authors disclose the receipt of financial support for the research, authorship, and/or publication of this article from the Planned project of Zhejiang Administration of Traditional Chinese Medicine approved by Zhejiang Provincial Health Commission (2011ZB059).a, Wenhui Zhanga, Jin Xua, Yiwen QiaZhenfeng Xiaoa Tianjin University, Tianjin 300350, China.Background: Flannery O\u2019Connor is a representative writer of postmodernism in the American Southern literary genre. She lived at a time when the American South was in the midst of intense turmoil, with the rise of the feminist movement, the rapid expansion of the capitalist economy, increasing social conflicts, and serious distortions in human relationships and the inner spirit of man. With her own unique life experience and keen insight into the darkness of human nature, O\u2019Connor was deeply influenced by Jung and consciously used the psychological perspective in her creation to penetrate the hidden inner world of the characters and present their true spiritual state, shaping a group of characters who abandoned their faith and had deformed personalities. The externalized expression of individual thoughts and mental activities is a direct mapping of character. In modern society, the reason why human beings live in an orderly and harmonious society lies in the regulation of law and ethics, while in the American South at the early stage of development and even in the period of seclusion, the root of the stability of social relations lies in the internal control of individuals, i.e., self-control, and psychological health and personality perfection are the basic conditions for the existence of self-control. This paper analyzes the O\u2019Connor series of novels from a psychological perspective. The purpose of this article is to study the results of the influence of psychological and external factors on the development of individuals and society.Subjects and Methods: Psychological analysis is not only a method of literary criticism, but also a way and perspective to see the world. Based on Jung\u2019s personality theory, this paper takes five short stories of O\u2019Connor: A Good Man is Hard to Find, Good Country Man, Greenleaf, and To Save a Man is to Save Himself as the objects of textual research, aiming to analyze the characters in O\u2019Connor\u2019s novels from a psychological perspective through a close reading of the text, with the intention of studying the influence of psychological factors and external factors on personal development and even social. O\u2019Connor draws a rich and diverse portrait of a monstrous group of characters in his short stories. In the development of the characters\u2019 personalities, the external personality masks play a key role. Through the external personality masks, the distorted life caused by the unbalanced mask and shadow of the main character is analyzed, thus revealing the indifference and alienation between people in a sick society.Results: Jung\u2019s theory of analytical psychology explains the madness hidden in the depths of the collective unconscious and reveals the complexity and universality of human psychological contradictions. The purpose of this study is to examine the influence of psychological factors and external factors on individual development and even on society. From the outside to the inside, the potential implications are explored to reveal the rich connotation and great tension of the characters in O\u2019Connor\u2019s novel under Jung\u2019s archetypal theory. O\u2019Connor\u2019s unique artistic style, her use of dynamic language, the expression of the grotesque and death, gives the novel a different kind of aesthetic interest. At the same time, the alienated society and the radical changes of the times make us see the goodness, evil, beauty and ugliness of human nature through the archetypal characters, and understand the fate of the characters, while more than anything else, it arouses our concern for life, our desire for the sublime, and our persistent pursuit of faith.Conclusions: In human history, society is often in a state of constant change, and with it, the transformation of human psychology, in other words, the course of human psychological development is closely related to the continuous development of society. In other words, the course of human psychological development is closely related to the continuous development and change of society, which is a huge collective of individuals with different personalities and psychological states. The society is a huge collective of individuals with different personalities and psychological states, and being in the collective, the universal or majority will is regarded as the unified goal and premise of development in the society. The intersection of psychology and literature is adapted to the needs of the times. Understanding a work is not only limited to knowing people, but also based on understanding the psychology of the writer, in order to better enter into the main character of the work. O\u2019Connor was deeply influenced by Jung, and looking at O\u2019Connor from the perspective of Jungian analytical psychology undoubtedly opens a new door for us to know O\u2019Connor and her novels.This work is supported in part by the Tianjin Philosophy and Social Sciences Research Program Funding Project under Grant TJWW21-006.a, Zhenzhao Wanga, Jing SuaWei Liua School of Mathematics and Computer Science, Guangdong Ocean University, Zhanjiang, Guangdong, China.Background: As of September 17, 2022, the World Health Organization has reported 59147 laboratory confirmed cases of monkeypox virus and 489 possible cases, including 22 deaths. The rampant spread of the monkeypox virus poses a grave threat to the lives and well-being of people worldwide. In order to reduce the large-scale spread of monkeypox in the world and reduce the impact of monkeypox on the public health system and international trade economy, it is essential to timely warn monkeypox through artificial intelligence.Subjects and Methods: We integrate 131 days of monkeypox infection data  into the Susceptible- Exposed-Infection-Removed (SEIR) model and the Long Short Term memory (LSTM) model to obtain the epidemic curve. We also propose a four-tier architecture system that can visualize data and predict epidemic situation. The system submits the predicted data to the module within the corresponding system to form a clear and concise visual page, which is displayed on the IOT device.Results: We compare the prediction performance of SEIR and LSTM models for monkeypox virus, and found that LSTM neural network performs well in the prediction of monkeypox epidemic. The LSTM model used by the ten countries most affected by the epidemic has good fitting results . We predict the United States, Spain, Brazil, France, the United Kingdom, Germany, Peru, Canada, Colombia and the Netherlands, the top 10 countries in the list of infections. The goodness of fit R2 of several countries exceeded 0.99 . According to the model, the threat of monkeypox virus will basically end in December 2022, while the United States will end early around November 19, 2022 (in the LSTM model).Conclusions: This paper proposes a monkeypox virus early warning and visualization system based on LSTM neural network. The results show that it is feasible to use LSTM neural network to predict monkeypox epidemic. The visualization system can assist decision makers to make decisions and minimize the harm of infectious diseases, which is worthy of our promotion.a, Jun RenbLiuliu Shenga Taizhou Vocational and Technical College, Zhejiang 318000, China, b Zhejiang Normal University, Zhejiang 321000, China.Background: With the development of the network society and the wide spread of negative cases, some regions have been labeled as \u201cstigmatized\u201d, and regional stigma has been constantly constructed, thus forming a negative stereotype of the region. Negative stereotypes not only affect people\u2019s mental health, but also lead to the formation of bad coping styles, thereby affecting their social functions. To explore whether regional stereotypes exist in North and South China and what characteristics they have at the explicit and implicit levels. Subjects were randomly selected from the southern population and the northern population, with the Qinling-Huaihe Line as the boundary.Methods: In the process of research, it is necessary to pay special attention to the mental health of the subjects. The existence of regional stereotype may induce the psychological stress and anxiety of the subjects, thus affecting their emotional and behavioral performance. Therefore, it is necessary to give full informed consent in advance, introduce the main content and purpose of the experiment to the subjects, and inform them that they have the right to refuse to participate in the experiment without any punishment, gain or loss. It is necessary to pay full attention to and protect the mental health of the subjects in the process of research to ensure the scientific and reliability of the experimental results. In the whole process of the study, free response method and trait corresponding behavior were used to collect questionnaires to verify the existence of regional stereotypes. Then explicit regional stereotypes were measured by behavior rating questionnaire and implicit regional stereotypes were measured by stereotype explanatory bias questionnaire.Results: The measurement, collection and analysis of regional stereotypes can help people understand their own psychological conditions, including emotions, thinking, behavior and other aspects, and identify the factors causing negative regional stereotypes, so as to take corresponding actions, measures and interventions to improve their mental health. Among the findings: (1) At the explicit level, the subjects had negative regional stereotypes. The main effect of gender on negative stereotypes was not significant, while the main effect of household registration was significant. The interaction between gender and household registration was not significant. Both Southern and Northern subjects showed in-group preference and out-group rejection. (2) At the implicit level, the subjects had negative regional stereotypes. The main effects of gender and household registration were not significant, and the interaction was also not significant. Both Southern and Northern subjects showed more attributions and external attributions for inconsistent situations, and fewer attributions and internal attributions for consistent situations. (3) Presenting a larger amount of counter-stereotype information can reduce negative stereotypes of the target group more effectively. The research results support the Thin Slice Model. Presenting moderately abnormal counter-stereotype information can reduce negative stereotypes of the target group more effectively than presenting extremely abnormal counter-stereotype information, which is inconsistent with the content of the Transformation Model. Presenting moderately abnormal and a larger amount of counter-stereotype information is most effective in reducing negative regional stereotypes.Conclusions: At the explicit and implicit levels, regional stereotypes exist in both the north and south groups in China, showing the characteristics of in-group preference and out-group rejection. Medium anomaly and large amount of counter-stereotype information can suppress negative regional stereotypes more effectively. In the future, while applying the research results to promote social harmony and stability, it is necessary to pay attention to and protect the mental health, and adopt reasonable means and methods to reduce the negative emotional experience of the subjects such as anxiety and pressure. For example, researchers can use psychological intervention methods to stimulate positive emotions, guide cognitive reconstruction, relieve stress and anxiety during the experiment to help subjects adjust their mental state and mental health, and promote their positive emotions and physical and mental health. In addition, the results show that the medium anomaly and large amount of counter-stereotype information can effectively suppress the negative regional stereotype. Therefore, in real life, relevant departments and individuals can adopt some scientific and rational means and measures to encourage diversification and promote exchanges and cooperation, present moderate abnormal and large amount of positive information, reduce the negative impact of regional stereotypes, and promote the harmonious and stable development of society. In conclusion, while promoting the application of research results, we need to pay full attention to and protect the mental health of the participants, promote social stability and people\u2019s happiness, and achieve the goal of healthy, harmonious and sustainable development.This work was supported by the [2022 Professional Development Project for Domestic Visiting Scholars and Teachers in Colleges and Universities] under Grant [number: FX2022130], and by the Taizhou Aien Kangze Health Management Co., Ltd under Grant [number: HX2022237].a, Lu Zhanga, Miaoyu WangaXingxiang Xinga Shaoxing Central Blood Station, Shaoxing City 312000, China.Background: To understand the blood safety situation in the Shaoxing area and propose effective measures to prevent and control transfusion-related infectious diseases.Subjects and Methods: A retrospective analysis was conducted on the results of 8 transfusion-related infectious disease markers from 214,474 voluntary blood donation samples collected between 2019 and 2022. Five of these markers were compared with results from 190,264 voluntary blood donation samples collected between 2006 and 2010. An empirical study was also conducted on the blood testing strategy for voluntary blood donation.Results: The overall rate of unqualified test results for the 8 markers was 1.25%, with the unqualified rates for ALT, HBsAg, Anti-HCV, Anti-HIV, Anti-TP, HBV-DNA, HCV-RNA, and HIV-RNA being 0.42%, 0.17%, 0.15%, 0.08%, 0.18%, 0.19%, 0.01%, and 0.01%, respectively. These rates were at a relatively good level and showed a significant decrease compared to the rates from 2006 to 2010. The analysis of population characteristics showed that the unqualified rates were relatively higher for males, young people, farmers and workers, those with low education levels, and first-time donors. A total of 83.38% of infection markers were detected as unqualified in all ELISA tests (including Anti-TP). The total detection rates of HBV, HCV, and HIV infection in ELISA testing after the first and second tests were completed were 39.24%, 59.61%, 85.94%, 100%, 39.89%, and 99.44%, respectively. The proportion of ELISA first test results that match the ELISA second test results was 21.32%. There were 16 cases of Anti-HIV positive, accounting for 94.12% of WB confirmed cases. All Anti-TP cases were screened by ELISA, and the detection rate of the first test was 41.42%. NAT could detect 65.85% of HBV-infected individuals (40.39% of which were supplemented by screening based on ELISA), 3.75% of HCV-infected individuals , and 100% of confirmed HIV-infected individuals . The proportion of NAT and ELISA results that are consistent was 16.53%Conclusions: ELISA is the basic means to ensure blood safety and can detect most transfusion-related infectious disease markers. NAT can detect hidden, \u201cwindow period\u201d infected individuals, etc., reducing missed diagnoses and is an important means of blood screening. Under the current context of mature and routine NAT, it is still necessary to continue with ELISA testing twice. Blood testing is an important step in preventing the transmission of transfusion-related infectious diseases, but the role of recruiting blood volunteers and pre-blood collection screening cannot be ignored.We would like to express our gratitude to Director Sang Liyong and Vice Director Fu Liqiang of the Shaoxing Central Blood Station, as well as Director Chen Jinkun of the Shaoxing Center for Disease Control and Prevention, for their significant assistance, guidance, and support in this study.a, Mingxiu Yanga, Xinbin Xiaa, Zhaojie Wanga, Jiale Lia, Zheming TianaYing Dua School of Humanities and Management, Hunan University of Chinese Medicine, 300 Xueshi Road, Yuelu District, Changsha, Hunan Province, 410208, China.Background: To calculate and analyze the treatment costs of malignant tumors in Hunan Province in 2021, to investigate the depression and anxiety of tumor patients, so as to clarify the influence of patients\u2019 disease economic burden on their psychological anxiety, and to provide data support for the formulation and improvement of policies by the health department.Subjects and Methods: Referring to the \u201c2021 Hunan Province Health Finance Annual Report\u201d and \u201c2021 Hunan Province Health Statistics Summary\u201d, based on the \u201cSystem of Health Account 2011\u201d, we calculated and analyzed the disease types, beneficiaries, institutional distribution and financing status of malignant tumors diseases. Then we investigated the status quo of depression and anxiety in patients with malignant tumor and analyzed its dynamic changes.Results: In 2021, the total cost of malignant tumor treatment in Hunan Province was 440,596,800 yuan. The top five were malignant tumors of digestive organs (40.10%), malignant tumors of respiratory and intrathoracic organs (17.62%), and malignant tumors of breast (12.24%), female genital organ malignant tumors (9.88%) and lip, oral cavity and pharynx malignant tumors (6.87%). The 35 to 79-year-old age group has higher treatment costs. The costs are concentrated in general hospitals. Funding sources mainly come from government financing and family health expenditure. Among them, family health expenditure accounts for a relatively high proportion. The main influencing factors of malignant tumor hospitalization expenses are gender, length of stay, age, drug proportion, institution level and medical institution type.Conclusions: The disease burden of malignant tumors is relatively serious, and it has a positive effect on patients\u2019 anxiety. The primary medical and health institutions lack health resources. Because the household health expenditure accounted for a relatively high proportion, the economic burden of patients with malignant tumor Further aggravated. As a result, the patients\u2019 psychological anxiety was promoted. This directly influenced the quality of life and life expectancy of patients. Therefore, hierarchical diagnosis and treatment should be promoted reasonably, key diseases and populations should be focused, medical security policies should be improved. These initiatives are expected to reduce the economic burden of disease in patients with malignant tumors and their families\u2019, reduce their psychological anxiety and improve their quality of life and life expectancy.a, Fu Jiangb, Yanyan LiuaKunxiu Lua Guangdong University of Science & Technology, Guangdong, 523083, China, b Guangdong Peizheng College, Guangdong, 510830, ChinaObjective: Under the background of the new era, the turnover rate of the new generation of employees is high, which brings some problems to the enterprise development. From the employee\u2019s point of view, the intention to leave must also have its own internal psychological factors based on the antecedent influences. In view of this, this study takes new employees who have worked for less than three years after 90 years as the investigation object, focuses on the inner evolution process of employees\u2019 psychological feelings based on emotion regulation theory, and examines the research on the influence path of new generation new employees\u2019 perceived overqualification on turnover intention.Methods: Based on the theory of emotion regulation, the structural equation model was used to analyze the questionnaire of 357 new employees.Results: Perceived overqualification had a positive effect on turnover intention, the adjustment effect of working years on perceived overqualification and turnover intention was not significant.Conclusion: This study explores the direct influence of perceived overqualification on turnover intention and the influence factors of boundary. From the results of the study, perceived overqualification is one of the sources of stress for new employees, which in turn leads to negative emotional attitudes such as intention to leave, so companies need to be concerned about the psychological perceptions  of new generation employees. In addition, enterprises should pay more attention to employees who have left their jobs and understand the reasons for leaving so as to alleviate the talent shortage caused by employees leaving.This research received partial financial support from Planning Office of Philosophy and Social Sciences of Guangdong Province, China (Grant Number: GD21CGL07); Guangdong Education Department, China (Grant Number: 2021ZDJS113); and Guangdong University of Science & Technology, China (Grant Number: GKY-2022 KYZDW-6).a,bDaogang Hea School of Leisure Sports and Tourism, Beijing Sport University, Beijing, China, b Chengdu Aeronautic Polytechnic, Chengdu, China.Background: Ultimate Frisbee is a popular recreational sport that combines physical exercise and recreation, and is emerging as a lifestyle choice for young people. Previous studies have shown that participating in leisure-time physical activity is linked to improved mental well-being, but few studies have investigated the relationship between motivation and mental health. This study aimed to segment and analyze the motivations for participating in Ultimate Frisbee and explore their association with mental health.Methods: A mixed research approach was used, based on self-determination theory, to investigate the drivers of participation in Frisbee sports. This included the Physical Activity and Leisure Participation Motivation Scale, observational data from interviews, and field surveys of disc participants (N=207), as well as focus group interviews with 18 participants. Data were analyzed to identify motivations for disc sports participation and their relationship with mental health, using the basic psychological needs theory.Results: The study identified six dimensions of motivations for disc sports participation, including entertainment, appearance, physical condition, others\u2019 expectations, competition/ego, and social interaction. These dimensions were related to the need for autonomy, competence, and relatedness, represented by health, recreation, and socialization. All motivations for participation were related to mental health, in addition to physical condition. Qualitative analysis identified three motivational factors, including gender equality, trend following, and additional skill level, which were related to the six dimensions. Psychological need satisfaction was primarily related to changes in autonomy and competence, as well as physical activity and mental health.Conclusions: The study identified six distinct motivations for participating in disc sports, including recreation, appearance, physical conditioning, expectations from others, competition/ego, and social interaction. These dimensions were further elaborated upon, and three additional motivational factors - gender equality, following trends, and skill level - were also identified. Motivators related to mental health, such as social interaction, recreational motivation, appearance, and expectations of others, were confirmed as significant factors for participating in Frisbee. Releasing psychological stress through participation in Frisbee, thus promoting mental health and enhancing well-being, is also an important motivation for people to participate in Frisbee. The following trends and gender equality as motivational factors of disc participants can firmly explain the widespread phenomenon of disc sports. It also provides a new perspective for assessing disc sports and their participation motivation from a sociological perspective. The resulting framework provides a comprehensive understanding of the various motivations that drive individuals to participate in disc sports.This study was supported by a grant of the Youth Project of National Social Science Foundation of China (to Xi CHEN) (21CTY007) and Sichuan Province Philosophy and Social Science Key Research Base Tianfu International Sports Events Research Center (YJY2020010).a,b, Shuyue Zhanga, Qiuju WangcWeiwei Huanga Faculty of Education, Guangxi Normal University, Guilin 541004, China, b School of Education, Zhaoqing University, Zhaoqing 526061, China, c Normal College, Eastern Liaoning University, Dandong 118003, China.Background: The healthy physical and mental growth of children is a major concern for parents, and childcare services for children under the age of 3 are an important form of early childhood education in China. High-quality childcare services are a basic guarantee for the healthy physical and mental growth of children and an important way to reduce parents\u2019 parenting anxiety. Therefore, in response to the current situation that child care services in China fail to meet parents\u2019 psychological needs, this study explores how to improve and optimize the quality of child care services for children under 3 years old from the perspective of enhancing parents\u2019 satisfaction and reducing parents\u2019 parenting anxietySubjects and Methods: In this study, on the basis of in-depth understanding of parents\u2019 psychological needs and the factors affecting the parenting anxiety of parents through interviews, the author compiled the Survey Scale of Parents\u2019 Satisfaction with Childcare Service Quality for Children Under the Age of 3.The Survey Scale of Parents\u2019 Satisfaction with Childcare Service Quality for Children Under the Age of 3 was used to survey parents in a province in East China, and 516 valid questionnaires were collected, and the data were analyzed using the Kano-IPA integrated model.Results: The analysis results showed that in order to reduce parents\u2019 anxiety and increase their willingness to send their children to childcare institutions, childcare institutions need to improve the five areas parents are most concerned about: \u201cChildcare service institution could provide safety inspection reports for their decoration materials, facilities, equipment, toys, etc.,\u201d, \u201cService personal of the childcare institution has first aid knowledge\u201d, \u201cSpecific sleeping area in the childcare institution\u201d, \u201cIndependent and safe outdoor space for activities in the childcare institution\u201d, and \u201cThe childcare institution has sufficiently large indoor activity space for children\u201d.Conclusions: Whether the materials used in the hardware facilities of childcare institutions for children under the age of 3 are safe or not is an issue that parents are very concerned with, and it is a basic attribute that affects the satisfaction of parents. The rationality and adequacy of the space setting of childcare institutions for children under 3 years old are factors parents attach importance to, and they are very easy to be perceived and evaluated by parents due to obvious comparability. The qualifications of the staff of the childcare institution constitute a factor that ensures the quality of the service. Only by paying close attention to the psychological needs of parents and improving the quality of childcare services, can childcare institutions institutions improve the satisfaction of parents, reduce the anxiety of parents in raising children, improve the willingness of parents of child-bearing age to have children, and alleviate the problem of population aging.This study was supported by a research grant from the National Natural Science Foundation of China (32060197).aJia Zhenga Xi\u2019an Polytechnic University, Xi\u2019an, Shaanxi 710048 China.Background: The psychological health of individuals is of paramount importance in the university context, where there is a constant demand for innovation and inheritance of both traditional culture and modern developments. This study proposes an innovative model of instruction for art majors, with a focus on the living transmission of intangible cultural heritage (ICH) as its defining characteristic. The study underscores the positive interaction between psychological health education and the inheritance of ICH in arts courses.Subjects and Methods: Four paired models for the \u201cliving transmission\u201d of ICH - namely, \u201ctheoretical teaching\u201d, \u201cpractical teaching\u201d, \u201ctalent cultivation base construction\u201d, and \u201cInternet teaching\u201d- that incorporate diverse cultural elements, enrich students\u2019 innovative thinking abilities and enhance their confidence, thereby providing potential avenues for independent entrepreneurship were proposed.Results: The study finds that learning ICH skills enriches the content of talent cultivation, improves an individual\u2019s manual skills, and has a positive effect on concerning issues such as stress relief and anxiety emotions discharge in modern society.Conclusions: This study highlights the necessity of integrating \u201cliving transmission\u201d elements of ICH into theoretical teaching, practical teaching, talent cultivation base construction, and internet teaching, and establishes the innovative teaching model of the \u201cliving transmission\u201d of ICH in art teaching.aYang Lia School of Public Finance and Taxation, Central University of Finance and Economics, Beijing, China.Background: Cross-border investment is a strategic choice for enterprises to test their comprehensive capabilities, which requires comprehensive measurement of their own financial capabilities, management levels, mental health of enterprises managers, market sensitivity and technology absorption capabilities. Based on the data of enterprises with overseas connections among China\u2019s A-share non-financial listed companies from 2009 to 2019, this paper attempts to construct a theoretical framework of technological innovation effect and transmission mechanism of cross-border investment of Chinese enterprises.Subjects and Methods: Based on the theory analysis, this research uses econometric methods, using enterprise-level microdata for data analysis and model regression. Meanwhile, in the process of analyzing the innovation spillover effect of cross-border investment of enterprises, this research adopts the two-stage least squares method and introduces instrumental variables for endogenous problem analysis.Results: The results show that cross-border investment by Chinese enterprises has a positive effect on technological innovation, and the leap in technological innovation capability is the most significant through the reverse technology spillover mechanism, followed by the optimization effect of resource allocation, and the transmission effect of financing constraint mitigation is not significant. In the process of cross-border investment, entrepreneurs show their desire and demand for technological innovation, market sensitivity and personality and psychological needs determine the effectiveness of cross-border investment innovation.Conclusions: Based on the research conclusions, this paper further puts forward policy suggestions to optimize government support to guide more enterprises to promote technological innovation through cross-border investment.a, Qiuchen ZhengaZhiyue Zoua Guangzhou Xinhua University, Guangzhou 510520, China.Background: To investigate whether the T3 sandhi of Mandarin in adults with cochlear implantation has the same computational mechanism as in hearing adults.Subjects and Methods: 6 cochlear-implanted adults and 6 hearing adults were tested for mandarin T3 sandhi. After collecting the corpus, the analysis is carried out in two ways: first, three teachers of speech correction for the hearing impairment score all the corpus subjectively, and compare the correct rate of pitch shift; second, extract the fundamental frequency through the Praat  and convert it into a semitone value, make a contrast curve and observe.Results: From the perspective of the correct rate of tone-shifting in the two groups, the correct rate of the three types of words in the experimental group was much lower than that in the control group, the correct rate of true words was higher than that of the other two types of words, and the correct rate of false words was the lowest. From the analysis of the comparison curve, it was found that the curve of some subjects in the experimental group was close to that of the control group, but the fluctuation was small, and it could still be regarded as a correct tone change. The curves of other subjects were flat or fluctuated greatly. When combined with non-T3, the tail tuning was up, which has the meaning of the original tuning. Therefore, it shows that adults with cochlear implants have mastered a certain T3 tuning mechanism.Conclusions: The T3 sandhi of adults with cochlear implantation is far behind that of hearing adults. If they want to master the T3 sandhi more proficiently, they should first change the phonetic environment, and control the low point of the fundamental frequency by listening to the correct pronunciation. Hearing equipment is upgraded to the best or adjusted to expand the range of hearing thresholds.This work was supported by a project grant from Guangzhou Xinhua University (Grant No. 2019KYQN17).a,bXing Hea China West Normal University, College of Management, Nanchong, Sichuan 637002, China, b Sichuan Research and Study Travel Development Research Center, Nanchong, Sichuan 637002, China.Background: Since the reform and opening up for 40 years, my country\u2019s tourism industry has experienced a development process from a rise, rapid to a comprehensive, and has gradually become the most dynamic industry in the national economic system.Subjects and Methods: According to the tourism research and residents\u2019 mental health level situation in the past 40 years of my country\u2019s reform and opening up, the development of my country\u2019s modern tourism industry is divided into four development stages: commercialization, marketization, industrialization and socialization, and summarizes eight major turning points in the development of my country\u2019s modern tourism industry. This study chooses worry, perceived control and desire to stimulate to represent emotion, cognition and motivation respectively, and constructs an impact model of psychological factors on tourism risk prevention behavior. Taking actual tourists as the research object, it uses questionnaire method to conduct empirical tests to verify the deep influence mechanism of emotional factors, cognitive factors, motivation factors and risk prevention behavior, as well as the condition boundary of this mechanism channel.Results: It also sorts out, compares and reviews related literatures with qualitative and quantitative research methods, which usefully supplements the theoretical and methodological results of modern tourism research in my country since the reform and opening up, and also conducts research on the shortcomings of modern tourism development in my country Reflection. The study found that the impact mechanism of psychological factors on tourists\u2019 risk perception and prevention behavior is very complex. Worry will not directly affect risk prevention behavior, but will significantly affect prevention behavior through perceived risk; Perceived control directly and indirectly affects risk prevention behavior through perceived risk; Stimulating desire will have a significant negative impact on risk prevention behavior. This mechanism path is regulated by tourism experience. Compared with the first tourists, the revisiters\u2019 concerns, perceived control and perceived risk have a greater impact on risk prevention behavior. Tourism experience also regulates the intermediary role of perceived risk, while the intermediary role of perceived risk of first-time tourists is not significant; The intermediary effect of perceived risk of revisiters is significant.Conclusions: Therefore, more attention should be paid to the impact of psychological factors such as emotion, cognition and motivation on tourists\u2019 tourism risk perception and prevention behavior, and more accurate risk management strategies should be adopted for newcomers and revisiters. At the same time, it is proposed that the combination of modern information technology and \u201ctourism+\u201d industrial research, in the face of unknown public safety incidents, strengthening international cooperation, and building a world tourism community with a shared future will be the development trend of modern tourism in my country.This paper is Supported by the 2022 project of Sichuan Social Science Planning (No.: SC22C026), the Sichuan Ethnic Mountain Economic Development Research Center Project (No.: SDJJ202224), the Sichuan Ethnic Mountain Economic Development Research Center Project (No.: YX22-38), the Sichuan Provincial Key Research Base for Humanities and Social Sciences of Colleges and Universities, the 2022 project of Sichuan Research Travel Development Research Center (No.: YX22-38) The 2022 Project of Sichuan Tourism Development Research Center, a key research base of social sciences in Sichuan Province (No. LY22-40), the Innovation Team for Studying Travel Theory and Practice of West China Normal University (No. SCXTD2022-6), the 2021 Doctoral Initiation Project of West China Normal University (No. 21E002).a,b, Panzhen Zhaoc,d, Long ShiaJun Chena Youjiang Medical University for Nationalities, Baise, China, b Philippine Christian University Center for International Education, Manila, Philippines,1004, c Faculty of Educational Studies, Universiti Putra Malaysia, Selangor, Malaysia, d College of Foreign Languages, Baise University, Baise, China.Background: The first consultation at the grass-roots level is the key link to promote the construction of hierarchical diagnosis and treatment system, which is conducive to promoting the sinking of public health resources and increasing the accessibility of residents\u2019 medical services. Research on residents\u2019 choice behavior and its influencing factors, which has important practical significance for establishing the first diagnosis system at the grass-roots level and guiding residents to form good medical habits.Subjects and Methods: Based on the data of household follow-up survey in China in 2018, based on Andersen\u2019s behavior model as the theoretical analysis framework, the article analyzed the influence of predisposition factors, energy-promoting factors and demand factors on the behavior of Chinese residents\u2019 choice of medical facilities by using the method of disorder and multi-classification Logistic regression.Results: The study found that the grass-roots medical institution is the place with the highest possibility for Chinese residents to go to hospital when they are ill. Meanwhile, due to the unbalanced distribution of medical resources in China, there is a certain degree of difference in the medical level of different levels of medical institutions. There are obvious differences in the behavior of Chinese residents in choosing medical institutions for medical treatment when they are ill. Still, more than one third of respondents prefer to go to general hospitals when they are ill. The study also found that (1) in terms of propensity factors, gender, job nature, education level, social frequency and satisfaction with medical conditions had a significant impact on residents\u2019 choice behavior of medical places; (2) in terms of energy promoting factors, personal income, medical insurance participation, etc. had a significant impact on residents\u2019 choice behaviors of medical places; (3) in terms of demand factors, Health self-assessment and chronic disease have significant influence on residents\u2019 choice behaviors of medical places.Conclusions: The improvement of the system of first diagnosis at the grass-roots level shall take into full consideration of the influencing factors of Chinese residents\u2019 choice of medical facilities, guide the residents to choose basic medical institutions for medical treatment through improving the incentive mechanism of basic medical insurance, and encourage residents to cultivate the reasonable habit of first-time diagnosis and two-way referral system. so as to promote the optimal allocation of medical resources.This study was supported by the Project of the Planning Project of Guangxi Province Philosophy and Social Science (2021CGL002), National Natural Science Foundation of China (72164036), National Natural Science Foundation of Guangxi Province (2019JJA180060).aHuizhen Xua Fair Friend Institute of Intelligent Manufacturing, Hangzhou Vocational& Technical College, Zhejiang, ChinaBackground: With the continuous development of the times and the deepening reform of university education, the engineering education model is also changing, which presents new challenges and opportunities for the cultivation of design talents. The transformation and upgrading of enterprises have intensified the challenges of design talent cultivation, and how to effectively carry out design education and cultivate innovative design talents with complex technical skills has put design teachers under increasing pressure. However, these pressures may lead to psychological problems such as anxiety and emotional disorders among teachers, which will affect students\u2019 learning outcomes and teachers\u2019 teaching reforms if not addressed effectively and timely. The purpose of this study is to explore the current situation of talent cultivation in design disciplines and the reform practice of design teaching from the perspective of psychological health.Methods: This study adopts a problem-oriented approach, introduces the concept of health psychology and TRIZ theory, and uses the cause-and-effect analysis method to conduct an in-depth analysis of the pain and difficulties in design teaching to find the deep-seated reasons for the difficulty in implementing teaching reform. Combining the deep-level reasons, the expectation model of physical-field is constructed, the design teaching reform strategy with psychological health as the starting point is proposed, and the design teaching reform scheme of creative ideas materialization is practically applied to solve the problems of difficult creative innovation, difficult implementation and difficult technical realization in design teaching, and the feasibility of its scheme is verified.Results: For design majors, a four-stage \u201cTRIZ+ Core Curriculum\u201d training system was designed, a \u201cTRIZ+ Design\u201d resource case platform of interest to students was created, a \u201cstudio-style\u201d teaching environment and an interdisciplinary teaching team were formed, and precise assessment and evaluation were designed. The five-step project-driven teaching method is implemented, including \u201cinitiation, teaching and learning, practice and enlightenment, evaluation, and expansion\u201d, which effectively solves the problems in design teaching, transforms virtual concepts into physical objects, enables students to understand design ideas more intuitively, and cultivates students\u2019 understanding of design. Students and teachers have achieved fruitful teaching results, and the satisfaction of enterprises has been improved, and the effect of teaching reform has been significantly improved.Conclusion: From the perspective of psychological health, the teaching reform strategy of creative ideas materialization can transform the pressure of teachers and students into motivation and relieve the psychological pressure of teachers and students in design disciplines. This teaching reform strategy can not only help teachers improve their teaching ability, but also help students enhance their innovation and engineering realization ability, and promote the rapid development of design education. Through the successful practice of this study, teachers and students will get a broader space to play and a more genuine sense of achievement.a, Fan Zhangb, Siti Rohaida Binti Mohamed ZainalcJiaqi Zhanga School of Management, Universiti Sains Malaysia (USM), GelugorPulau Penang, Malaysia, b School of Innovation and Entrepreneurship, Guangdong Polytechnic Normal University (GPNU), Guangzhou, China, c School of Management, Universiti Sains Malaysia (USM), GelugorPulau Penang, Malaysia.Background: Based on the perspective of competitive value architecture, this paper discusses the impact mechanism of strategy on organizational effectiveness of enterprises, and proposes corresponding application strategies.Subjects and Methods: In the increasingly competitive environment, enterprise employees are facing increasing psychological pressure. Enterprise employees are prone to problems such as low mood, physical and mental exhaustion, lack of work enthusiasm, decreased awareness of corporate culture, and lack of innovative spirit. Therefore, this puts forward higher requirements for enterprise human resource management. From the perspective of competitive value architecture, this article discusses strategic human resources, competitive value architecture theory, and strategic human resource management models. It analyzes the impact mechanisms of different strategic human resource management models, such as win-win cooperation, open innovation, control and coordination, and performance evaluation models, on enterprise organizational effectiveness, reveals the role of strategic human resource management in enterprise organizational effectiveness, and propose corresponding application strategies.Results: The impact carriers of strategic human resources on organizational effectiveness include organizational culture and organizational commitment. In order to protect and enhance the mental health of employees, it is very valuable to pay attention to the psychological empowerment of employees. Employee mental health is the key to improving organizational effectiveness. Among them, organizational commitment also affects employees\u2019 psychological empowerment, which in turn affects their level of loyalty to the organization. Employees feel empowered when they feel influential and meaningful within the organization. Therefore, psychological empowerment is of great significance to both employees and organizations, such as improving employee motivation and engagement, which in turn affects organizational performance. Building on the concept of psychological empowerment, this paper finds that, under the win-win cooperation model, a scientific, reasonable, fair and impartial performance contribution evaluation system is used to improve employee compensation satisfaction, enhance employee evaluation fairness, and generate a sense of belonging to the enterprise, thereby promoting the achievement of organizational efficiency goals. Under the open innovation model, both professional quality and innovative creativity affect organizational effectiveness through organizational culture and organizational commitment, stimulate enterprise innovation and creativity, promote enterprise development and innovation, promote the integration of internal and external resources, build resource synergy, and improve organizational efficiency. The control and coordination model enhances organizational effectiveness through a fair, just, and coordinated organizational culture and standardized and institutionalized organizational commitment. The performance evaluation model adopts a quantitative evaluation method to directly evaluate the contribution of strategic human resources to the organizational effectiveness of enterprises, providing a basis for optimizing the structure of strategic human resources and improving the quality of strategic human resources.Conclusions: This study found that, strategic human resource management mainly affects organizational effectiveness through organizational culture and organizational commitment. It is undeniable that there is often a positive correlation between employees\u2019 perceptions of psychological empowerment and mental health. The significant impact of organizational commitment on psychological empowerment of employees will further affect organizational effectiveness by affecting factors such as employee loyalty and enthusiasm.a, Landong Xub, Sixiang Taoa, Jingtang HeaHongzhao Wanga Department of Physical Education, Huainan Normal University, Huainan 232038, China, b School of Physical Education, Changchun Guanghua University, Changchun 130033, China.Background: Fitness and health (FH) testing in universities in China involved several health related components, such as BMI, vital capacity, flexibility, speed, aerobic endurance, power and muscle strength by National Fitness and Health Standards of Students (NFHSS). These components with specific reference values are considered markers of physical and mental health, and has been shown to be positively associated with cognition, weight status, and academic performance. Evaluation physical condition is a matter of concern of in public physical education (P.E) not only for conforming prevalence of FH conditions but also for implementing strategy of effective teaching. Monitoring physical fitness indicators is therefore considerable importance for social medicine, health education and health management, but it requires specialized equipment. Consequently, FH is rarely measured at the population level in public P.E teaching due to time, budget, complicated procedures and logistic limitations. A single-index of physical fitness components is a simple and cost-effective method to estimate FH status, which is an alternative to integrated testing system. Therefore, the purpose of the observational study was to examine the validity of pull-ups\u2019 cut-off score screening FH status among physically excellent male college students from Northeast, China.Subjects and Methods: The study was based on NFHSS, which was performed in 3 dimensional conducts consisting of morphology, function and fitness. A total of 5669 male college students aged 18-21 years were selected from Changchun Guanghua University. All participants\u2019 FH status were categorized into trichotomy groups as excellent, sound and no-pass by NFHSS. The difference of FH were analyzed by one-way ANOVA with components of the dependent variable and FH status as the factor. Regression analyses indicated whether the pull ups was able to predict the FH status of male college students among physically excellent and sound. Receiver operating characteristic (ROC) curve was applied to evaluate pull ups cut-off score indicating FT status and to discriminate the prediction ability of male college students among physically excellent and sound.Results: Mutually adjusted analysis showed a significant association between FH status and performance of pull ups in male college students who are physically excellent and sound. The cut- offs of pull-ups assessed by the ROC curve can discriminate the FH status between excellent and sound.Conclusions: Pull-ups was significantly associated with FH status and contributed to the excellent/sound model\u2019s prediction for FH status among physically excellent and sound students. Single index of pull-ups could be a useful prediction tool to identify and monitor variation in FH status of male college students between physically excellent and sound.This work was supported by a project grant from Scientific Research Foundation of Education Department of Anhui Province of China (Grant No.SK2021A0560).a, Lan DingaYuchang Houa School of Foreign Languages, Henan University, Kaifeng 475001, China.Background: Under the current situation of the \u201cdouble reduction\u201d policy in China, formative assessment in EFL (English as a foreign language) classroom is receiving increasing attention. According to Positive Psychology, emotions have direct influence during language learning process. For achieving satisfactory result of formative assessment, the present paper aims to investigate the EFL teacher\u2019s emotions in formative assessment and put forward practical strategies and skills to better use teacher\u2019s positive emotions and reduce their negative emotions, such as anxieties, gloominess and self-doubt.Subjects and Methods: To study the current level of emotions of EFL teachers towards formative assessment, questionnaires and interviews were administered randomly to 20 EFL teachers from 4 major junior high schools in China. To study the influence of EFL teacher\u2019s positive emotions on the effect of formative assessment, an 18-week positive psychology-based professional development program was conducted with a series of methods for result analysis including interviews, class observations, discussions and exams. To make the above-mentioned two studies reasonable, logical and scientific, all the experiments in the present paper were tightly grounded on the relevant theories and models to positive psychology.There are two limitations in the present study. First, the number of participants is not large. Second, the professional development program does not last long enough. Despite these limitations, this is a new study showing the emotion factor of EFL teachers during the formative assessment, a more emphasized kind of assessment under the \u201cdouble reduction\u201d policy newly and currently implemented in China.Results: Study 1 of the present paper found that the current level of classroom emotions of Chinese Junior School EFL teachers is not satisfactorily high. Data collected from Study 2 of the present paper showed that the professional development program was greatly beneficial. All the 20 participants have demonstrated an increased level of empathy toward students, which in turn brings motivation, enjoyment and confidence to themselves.Conclusions: Chinese teachers in junior high school have already noticed the importance of classroom emotions and teachers\u2019 positive emotions can make students ease in mind and actively engage in class tasks. Moreover, teachers\u2019 positive emotions can enhance their feedback that moves students forward. In general, teachers\u2019 positive emotions can act as instructional resources for building a closer and friendlier relationship with students and boost their teaching of English eventually.As we are trying to improve English teaching effectiveness and coming across more difficulties under the \u201cdouble reduction\u201d policy, it would probably be a reliable solution to shift from the summative assessment to the formative assessment, from the learner to the teacher, and from the teaching and learning of knowledge to the classroom emotions.This study was supported by the Teacher\u2019s Development Research Fund of Henan University (Grant No.: YB-JFZX-2022-19) and the Education Reform Project for Postgraduate Program of Henan University (Grant No.: SYLAL202201) and the Undergraduate-oriented Project of Henan University Research Laboratories (Grant No: 20221701024).aJialin Chenga Zhuhai College of Science and Technology, Zhuhai 519041, China.Background: In the post-pandemic era, life education for university students has become particularly necessary and important, as the COVID-19 pandemic has not only caused huge losses to people\u2019s lives and property, but also had a significant impact on the knowledge production mode and talent cultivation methods of higher education. In this context, life education for university students has acquired a richer connotation and significance.Subjects and Methods: It should cover three aspects: life consciousness education, survival ability education, and life value sublimation education. To achieve this, it is necessary to further broaden the concept of life education, enrich its content, innovate its methods, build its platforms, and ensure the effectiveness of the education process and its components.Results: The serious problems of narrow educational concepts, knowledge-based educational contents, fixed educational methods, limited educational levels, and closed educational platforms in life education for university students have seriously affected the formation of their life consciousness, the improvement of survival ability, and the sublimation of life values. Apparently, focusing on the physical and mental health and life development of university students, strengthening life education for university students in the post-epidemic era is not only a timely choice to adapt to the external environment of higher education but also an active choice to implement the fundamental task of moral education and talent cultivation.Conclusions: Strengthening life education for university students can help them establish a correct view of life and practice a positive outlook on life.a, Zehui JiangaMing Wanga Zhuhai College of Science and Technology, Zhuhai, Guangdong 519041, China.Background: With the change of times, the rapid development of economy and society, medical and health undertakings and sports industry is undergoing a period of rapid development; The decline of physical health has gradually become the main public health problem faced by human beings, and people\u2019s pursuit and need for health has become a rigid need. The Outline of the Healthy China 2030 Plan has been issued, and the combination of physical medicine has quickly become a new model of health intervention, emphasizing the need to add more means of physical fitness to modern medical treatment and rehabilitation.Subjects and Methods: By looking up literature related to the combination of physical medicine and its model, traditional national sports on CNKI platform, and looking up books about sports promoting health in the library, data were collected for the writing of this paper. At present, we advocate the organic combination of sports and medicine as well as the health intervention of non-medical means, and aim to establish the promoting mechanism of health education in schools with a focus on colleges and universities, and analyze the differences in the implementation of national traditional physical education courses under the concept of combination of physical medicine. From the school, physical education teachers, families and students four aspects try to analyze the relevant influencing factors, and put forward countermeasures.Results: The combination of physical medicine is a long-term method to enhance physical fitness and immunity. Based on the construction of \u201cfirst-class undergraduate courses\u201d, this paper starts from three aspects: general education courses, professional education courses and practical education courses, establishes the educational concept of \u201cintegration of physical and medical\u201d, optimizes the construction of the content system of \u201cintegration of physical and medical\u201d ethnic traditional sports courses, and cultivates ethnic traditional sports guidance talents to ensure public health. It can also build up cultural confidence in colleges and universities and promote the inheritance and development of traditional national sports.Conclusions: The \u201cGuangdong-Hong Kong-Macao Greater Bay Area\u201d strategy has been put forward and implemented, and the exchanges and coordination in the economy, science and technology, education, culture and quality life circle of the \u201c9\u2005+\u20052\u201d urban agglomeration are constantly expanding. Traditional ethnic sports, as an important way of cultural exchange, play an important role in promoting the coordinated development of sports and industries in the Guangdong-Hong Kong-Macao Greater Bay Area. By means of literature research, field research, SWOT analysis and other methods, this paper analyzes the strengths, weaknesses, opportunities and threats of the coordinated development of ethnic traditional sports in colleges and universities in the Guangdong-Hong Kong-Macao Greater Bay Area. It is suggested to promote the coordinated and integrated development of traditional ethnic sports in higher education institutions in the Greater Bay Area by implementing national strategies and policies, building exchange platforms for higher education institutions, cultivating academic exchange talents, building ethnic sports events, and combining sports and medicine.This work was supported by 2021 Annual Education Science Planning Project  \u201cResearch on the inheritance and development of traditional ethnic sports culture in universities in the Guangdong-Hong Kong-Macao Greater Bay Area\u201d (Project No.: 2021GXJK080) and \u201cThree Levels\u201d talent Construction Project of Zhuhai College of Science and Technology.aJingjing Caoa School of Culture and Media, Xi\u2019an Eurasia University, Xi\u2019an, Shaanxi, China.Background: With the continuous development of emerging digital media technology and the continuous expansion of the application scenarios of digital media technology in daily life, building a digital country has become a global consensus, and promoting the digital village strategy has become an inherent requirement and inevitable choice for building the network powerful nation,digital China and smart society. However, according to the survey Investigation and Analysis Report on Digital Literacy in Rural China under the Background of Rural Revitalization Strategy released by the Center for Informatization Study of the Chinese Academy of Social Sciences, the digital literacy gap between urban and rural residents is 37.5%. The digital literacy score of rural residents is significantly lower than that of other professional groups. Rural residents\u2019 digital identity anxiety began to emerge.Subjects and Methods: The psychological identity of digital identity and digital literacy of rural residents has a direct impact on the digital village, rural revitalization and digital China construction. How to improve the digital literacy of rural residents in the strategic perspective of comprehensively promoting rural revitalization has become an urgent problem to be solved. Therefore, based on the existing research, the author discusses the value connotation, current situation, existing problems and reasons of rural residents\u2019 digital literacy, and then puts forward a practical and feasible way to improve rural residents\u2019 digital literacy.Results: The author puts forward four feasible suggestions according to the problems and reasons of rural residents\u2019 digital literacy: solve the rural residents\u2019 digital gap based on the problem of using digital products, solve the idle problem of digital products based on the use demand of rural residents, provide training on digital literacy and cultivate digital village culture, introduce digital technology cultivation projects and enhance the participation of rural residents.Conclusions: Rural residents\u2019 psychological anxiety about digital identity comes from the application of digital identity in individual virtual practice in the digital era. Improving the digital literacy of rural residents has a direct impact on alleviating this problem. Improving the digital literacy of rural residents is a long-term and arduous task, which requires a large amount of human, material and financial resources.This research is under the scientific research project \u201cResearch on the promotion path of digital literacy of rural residents in Shaanxi Province from the perspective of Rural Revitalization\u201d, which is supported by the Shaanxi Provincial Education Department (Grant No. 22JK0133), and the project of the 14th Five-Year Plan \u201cResearch on the Practice of Mixed Teaching Mode for News and Communication Courses in the Digital Era\u201d, which is supported by Shaanxi Academy of Educational Sciences.aWenqu Xua School of business Minnan Normal University, Zhangzhou, Fujian 363000, China.Background: The healthy personality of college students is a kind of self-consciousness gradually built up by college students in their life experience with their lifestyle and life style. It is a comprehensive embodiment and important symbol of people\u2019s world outlook, psychological quality and moral cultivation, and it is the psychological basis for college students to accurately grasp themselves, find a social position suitable for their own development, and obtain respect and goodwill from others. College students are the mainstay of the country\u2019s future development and the most valuable human resources of the country. The research on the shaping of college students\u2019 healthy personality and guiding college students to establish healthy and optimistic psychological quality have important practical enlightenment for cultivating college students to become talents with all-round development of morality, intelligence and physique and realizing the prosperity of the country.Subjects and Methods: The subjects of this study are college students in a university in Fujian. The scale used in this study was the Big Five Personality Inventory simplified version (NEO-FFI). The Big Five personality trait model divides personality into five dimensions, including neuroticism, extraversion, openness, agreeableness and conscientiousness, which are measured by five sub-tests of 12 questions per dimension, with a total of 60 questions. The simplified Big Five Personality Inventory (NEO-FFI) is a personality measurement tool for Chinese college students. Its \u03b1 reliability coefficient is 0.77 for neuroticism, 0.78 for extraversion, 0.63 for openness, 0.72 for agreeableness, and 0.74 for conscientiousness, which has good reliability and validity. Stratified sampling was used in the questionnaire survey, and 309 valid questionnaires were collected. In terms of statistical processing, SPSS22.0 Chinese version was used for statisticalanalysis of the survey data, mainly using specific statistical analysis methods such as descriptive statistics, independent sample T test and variance test.Results: Through the analysis of the NEO-FFI questionnaire, the research found that: first, there is no significant difference in personality traits between different genders and different grades; Second, the personality traits of different majors, whether they are student leaders, future planning types and self-promotion types have significant differences in a certain dimension. Specifically, in terms of professional categories, the neuroticism of liberal arts is significantly higher than that of science; The conscientiousness and extraversion of student cadres are significantly higher than that of non-student cadres, while neuroticism is significantly lower than that of non-student cadres. In terms of future planning type, the extroversion and conscientiousness of students with clear goals were significantly higher than those with uncertain goals. In terms of self-improvement types, conscientiousness and extraversion were significantly higher in students with ideas and practices than in students with no ideas and practices, while neuroticism was significantly lower than in students with no ideas and practices.Conclusions: College students in the new era are the hope and future of the country. The healthy personality of college students is related to the prosperity and prosperity of the country. It is suggested that the theory and method of human resource management should be integrated into the whole process of cultivating healthy personality of college students. Recruitment and configuration, training and development, performance management, salary welfare management and labor relations management six modules as the research basis, on college students\u2019 healthy personality training targeted Suggestions, so as to cultivate good social adaptation ability and stable sense of self, and good quality, independent thinking, good ability to life positive and optimistic attitude, emotion regulation and interpersonal harmony friendly health, etc Excellent college students with personality characteristics will provide qualified builders and successors for realizing the prosperity of the country.This work was supported by a project grant from2020 Fujian Young and Middle aged Teacher Education Research Project (JAT200333) and 2019 General Project of Fujian Research Center for Socialism with Chinese Characteristics (2019ZTD19).a,c, Yun Lib, Shanxian LiaXuejun Wanga College of Sports Economics and Management, Guangxi University of Finance and Economics, Nanning, Guangxi 530001, China, b School of Big Data and Artificial Intelligence, Guangxi University of Finance and Economics, Nanning, Guangxi 530001, China, c College of Education, Jose Rizal University, Manila, Philippines.Background: To speed up high-quality economic development and further give play to the sports industry\u2019s role in promoting green development, expanding domestic demand and cultivating new economic driving force cannot be separated from the support of local policies. The introduction of local policies will promote economic development, expand employment, and alleviate pressure through internal emotional regulation to generate positive emotions such as joy and happiness.Subjects and Methods: Taking the sports industry development of Guangxi as an example, the sports industry-related policies issued by 14 cities since 2018 were studied, focusing on the correlation between the policy issuance of each city and the development of the sports industry. By constructing the PMC-E quantitative policy evaluation system, the quality index of Six Aspects of Emotional Regulation local policies promoting the development of sports industry is quantified from a multi-dimensional perspective, and the quality index of local sports industry policy development is measured according to the weight, and the effect of various local policies promoting the development of sports industry is tested.Results: Nanning, Liuzhou and Guilin had strong local policies. Good effect on emotional regulation, Urban sports industry policy is reasonable. Other cities are in the acceptable range, the city sports industry policy is generally applicable.Conclusions: The average structure level of sports industry policies in Guangxi is reasonable, which promotes the release of vitality of sports market, Good emotional regulation, generating positive emotions. The PMC-E value of sports industry promoted by urban policies is consistent with the overall objective data, and the optimization suggestions are put forward for improving the local policies to promote the development of sports industry in Guangxi.This work was supported by the 2022 Guangxi Philosophy and Social Science Planning Project: Research on Artificial Intelligence Empowering High-Quality Sports Development in Guangxi (22FTY019); funded by the 2022 Guangxi First-class Discipline Applied Economics (Sports Economics and Management) Project.a,b, Zhibing Zoua, Shiqi Liua, Ruhai Feia, Wang Zhanga, Licheng Qina, Jiaxiang Fana, Guosong Wua, Liwei Zhenga, Nianmao LicWenxing Tana School of Sports and Health Science, Xiangsihu College of Guangxi Minzu University, Nanning, 530008, China, b Graduate School, University of Baguio, Baguio City 2600, Philippines, c School of Sports and Health Science, Guangxi Minzu University, Nanning, 530006, China.Background: From the perspective of mental health, the identification of their own identity is also an important evaluation index. Students\u2019 recognition of their major affects their choice of future career and attitude towards future work, which is professional cognition from the level of consciousness. The employment of college students directly reflects the quality of talent training in colleges and universities, which is related to the selection and training of high-quality talents. Based on the perspective of psychological identity, Combined with the background of targeted employment, this paper analyzes various practical problems that affect the training of social sports guidance and management professionals.Subjects and Methods: Subjects and Methods: Based on a common perspective of mental health and professional identity. This paper takes the major of social sports guidance and management as the research object, and adopts the research methods of literature review, interview and logical analysis.Results: The research shows that there are some problems in the training process of applied talents in social sports guidance and management: the absence of courses and teachers, the lack of social sports industry experience of teachers; The professional boundary is not clear, and the characteristics of applied professional skills training are not significant; The separation of specialty and occupation makes it difficult to cultivate and design applied talents. The disconnection between the profession and the society and the failure to train professional talents according to the needs of the society. The fundamental goal of talent training in colleges and universities is to cultivate healthy professional talents for the society, and the health here should be a comprehensive health state including mental health and moral health. Psychological identity is the basis of students\u2019 identification of professional learning, recognition from the internal recognition of the professional, is also the basis of learning motivation, and has a close relationship with their academic achievement. Application-oriented talents should be cultivated in an educational environment conducive to students\u2019 psychological identity, which can help students have a deeper understanding of their major. This paper puts forward the construction of application-oriented courses based on professional requirements to realize the effective diversion of talents; puts forward practical skills training-oriented by professional characteristics to link vocational qualification certificates; puts forward social need-oriented service-oriented teaching practice to accurately meet employment needs; puts forward the cultivation of core competitiveness oriented by targeted employment to improve the reform and innovation ways of talent provision mechanism.Conclusions: The major of social sports guidance and management is an application-oriented talent trained for social sports service and a professional talent characterized by practical maintenance group. Considering the students\u2019 mental health and professional cognition, the formation of their own professional identity is a prerequisite for the establishment of long-term career development planning. Professional identity directly affects the learning attitude, motivation and performance of students majoring in physical education, as well as their career development direction. Based on students\u2019 psychological identification with the major of social sports guidance and management, a four-in-one application-oriented talent training system of \u201ctheoretical knowledge-sports skills-teaching ability-comprehensive literacy\u201d is constructed, and the exploration and practical experience of \u201chigh-grade, targeted and advanced\u201d talent reform are summarized in combination with the background of targeted employment.This work was supported by 2022 key project of Guangxi Higher Education Undergraduate Teaching Reform Project [number 2022JGZ187]; 2023 Guangxi Young and Middle-aged Teachers Basic Research Ability Improvement Project [number 2023KY1668]; 2023 Annual Project of the \u201c14th Five-Year Plan\u201d of Guangxi Education Science [number 2023A122].a, Jinsan Qib, Hui Wangc, Zhixiang GaodHui Lia School of Foreign Languages, Zhejiang University, Hangzhou 310058, China, b School of Foreign Languages, Anyang Normal University, Anyang 455000, China, c College of Humanities, Ningbo University of Finance & Economics, Ningbo, 315175, China, d School of Foreign Languages, Institute of Disaster Prevention, Sanhe 065201, China.Background: Non-literal language is a typical pragmatic expression, and the comprehension and production of non-literal language involve advanced cognitive activities. Children with autism spectrum disorder (ASD), however, are pervasively impaired in processing non-literal language. Therefore, non-literal language comprehension and production ability can be important means to investigate pragmatic competence in autistic children. Recently, with the shift of language pathology to pragmatics, non-literal language processing in autistic children has become a research hotspot in clinical pragmatics worldwide. This paper intends to systematically formulate the comprehension and production characteristics, and the developmental patterns of non-literal language in autistic children, and then to provide worthwhile insights for future clinical language research and intervention.Subjects and Methods: According to the Convention on the Rights of the Child, this paper concerns autistic children under the age of 18. This review paper first retrieves empirical studies in irony/metaphor/idiom/proverb/pun/metonymy in autistic children from the Web of Science in the past two decades. And literature is further selected by refining the titles and abstracts, examining the comprehension and production of non-literal language in autistic children, and then expanding the search via literature-tracking. Finally, 34 empirical research papers are chosen.Results: This paper summarizes that research in non-literal language comprehension and production in autistic children roughly follows three pathways, that is, the characteristics of acquisition and development, the cortical activation patterns, and the influencing factors. To be exact, compared with their typically developing counterparts, not only are autistic children developmentally delayed in comprehending and producing non-literal language, significant differences exist among autistic children, but also they exhibit unique neural activation patterns. Moreover, performances in autistic children are constrained by their structural language competence, general cognitive mechanisms and deficient capacity of online semantic integration, and the complexity or diversity of the experimental tasks. Even so, autistic children do possess some capabilities to comprehend and produce non-literal language and even exhibit creativity to some extent.Conclusions: Three research threads sorted out by this paper presents a comprehensive picture of research in comprehension and production of non-literal language in autistic children. Overall, typically impaired and delayed in comprehending and producing non-literal language, autistic children demonstrate their unique developmental patterns and characteristics. Moreover, due to the complex nature of non-literal language, the nature of experimental tasks, and autistic children\u2019 cognitive abilities, their social environments, structural language capacities as well as pragmatic skills need to be coordinated. However, there exists a debate over the specific role these factors play. Heterogeneous participants and lack of standardized methodologies make the experimental results lack comparability and inclusiveness. Accordingly, several implications for future research and intervention are advocated such as the standardization of experimental research, the implementation of qualitative analysis, the setting of a specific target for individuals, etc.This study is supported by the key project of Social Science Foundation of China \u201cA Comparative Study on Multimodal Reference Strategies of Chinese Children with Autistic and Typical children\u201d (Project No: 17AYY009).aXiaomeng Lyua School of Economics and Management, Shenyang Institute of Technology, Shenyang, Liaoning, 113122, China.Background: With the development of mobile internet technology and the popularity of smart phones in the world, mobile apps has rapidly entered the daily life of people, which has a profound impact on people\u2019s thoughts, emotions and consumer behavior. It is generally believed that the cost of acquiring new customers is much higher than retaining existing customers. However, app users still have varying degrees of concern during the using process. More specifically, the level of psychological anxiety can to some extent affect users\u2019 use behavior and intention to continue using. This study aims to investigate the relationship between the degree of psychological anxiety of college students and the intention to continue using mobile travel Apps.Subjects and Methods: In order to achieve the purpose of the study, literature analysis method, questionnaire survey method and statistical analysis method were used in this research. In order to ensure the diversity of sample sources, different major groups of college students were selected from different universities in China. An online questionnaire platform \u201cQuestionnaire star\u201d has been used to distribute and collect questionnaires. Finally, 489 questionnaires were collected. Before data analysis, strict data filtering is performed to check whether there is invalid data or abnormal values. Questionnaires with incomplete and missing items and the questionnaire with the same answer on 5 consecutive questions were considered invalid, and 445 valid samples were obtained. After data collection, SPSS 22.0 and AMOS 22.0 were adopted as tools for data analysis. The data analysis of this study was conducted using structural equation modeling (SEM) technique and followed the two-step approach of for assessing the measurement and structural models respectively.Results: By referencing the results of significance analysis of path coefficients, the eight hypotheses proposed in the study were supported. These findings in this study are also consistent with those in Bhattacherjee\u2019s study, the five original hypotheses of ECM model are supported. And this study further supports that ECM has the ability to interpret users\u2019 continuance intention of mobile travel apps. Besides, the variable of perceived interactivity was also verified in the study to have an impact on satisfaction and continuance intention. The revised model can be used to guide research on post-acceptance behavior. Increased perceived usefulness, confirmation and perceived interactivity can reduce the degree of psychological anxiety of college students and improve users\u2019 satisfaction and continuance intention. The results extend the findings of ECM model to the context of mobile travel apps and the hypothesis testing indicate that the ECM model is applicable to and can be stretched to the study of travel apps continuance intention.Conclusions: Improved perceived interactivity can reduce psychological anxiety of college students and enhance consumers\u2019 intention to continue using. E-commerce platforms should attach importance to enhancing perceived interactivity.This work was supported by my thesis advisor Professor Youngkyu Kim from Keimyung University.a,b, Qinghua LicRong Xiea School of Architecture and Engineering, Suqian University, Suqian City 223800, China, b School of Fine Arts, Qiongtai Normal University, Haikou City 571100, China, c School of Arts and Communications, Suqian University, Suqian City 223800, China.Background: With the increasingly prominent problems of modern diseases, urban diseases and sub-health, the wellness industry, as an important supplement to modern medical and old-age care institutions, has been booming, and the wellness homestay is one of the important forms of business.Subjects and Methods: The development of the healing function is inseparable from the elaborate design and construction of its landscape space and atmosphere. The article introduced Herman. Schmitz\u2019s new phenomenological concept of body economics to study the psychological mechanism of the healing function of landscape space in wellness homestays. In that case, the carefully created landscape space and atmosphere can effectively adjust and intervene in the structural and dynamic characteristics of the occupant\u2019s body economics, so that the occupant\u2019s body economic structure and dynamic characteristics can maintain a good state of tension, and can achieve a smooth transition between narrow atmosphere and wide atmosphere.Results: In an ideal state, not only the indoor and outdoor environment and landscape space of wellness homestay are carefully designed, organic agriculture, fishery, gardening and traditional handicraft practices are carefully organized and carried out, but also the rich regional culture, traditional festival folk custom, lifestyle, as well as the rich ethnic culture play a vital role in the atmosphere of wellness homestay space.It also has an important impact on the health function of homestays.Conclusions: All these colorful original and present elements, through the effective adjustment and intervention of the economic structure and dynamic characteristics of the body in the process of the restoration and liberation of the subject personality of the residents, can help them to restore a good balance and tension state, complete the smooth transition between the restoration and liberation of the subject personality, and finally realize the healing function of the landscape space of the residential health.This paper is an in-depth study of the complex psychological mechanisms in this process.This work was supported by Philosophy and Social Science Planning Project in Hainan Province (HNSK(ZC)21-163).a,b, Yanhua Zhangc, Chengfan Dua, Shijun Xia,d, Xiaochun Penga,eQiong Wanga Department of Pathophysiology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434023, China, b Department of Nursing, Health Science Center, Yangtze University, Jingzhou, Hubei 434023, China, c Department of Physiology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, China, d Shanghai Zhaxin traditional Chinese western medicine hospital, Jing\u2019an District Shanghai, 200435, China, e Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434023, China.QW and YZ contributed equally to this study.Background: The ideological and political education (IPE)as an integral part of higher education is faced with different challenges amid this modern era of globalization. Therefore, the integration of IPE into the whole subject teachings, the so-called curriculum ideological and political education (CIPE)is an effective way to solve this problem. This study is the first to properly introduce the concept and history of curriculum ideological and political education in China. Additionally, it also analyzes the evaluation of students\u2019 psychological state and the importance of mental health education for the implementation of the curriculum IPE.Subjects and Methods: For those purpose, a total of 211 research subjects from Yangtze university are investigated to report the students\u2019 motivation and behavior toward the ideological, political, and pathophysiology courses Furthermore, a questionnaire survey is used to explore the relationship between pathophysiology and ideological and political courses, and their satisfaction with the implementation of ideological, and political courses in pathophysiology and mental health education importance.Results: The results demonstrate that there are significant differences between educational background and the degree of interest in ideological and political courses, gender differences, and the feedback data on the learning of professional courses. Postgraduate students are more interested in the ideological and political courses, whereas the females report that it is difficult to study pathophysiology; In addition, the results of one-way ANOVA show that the implementation effect of IPE in the pathophysiology curriculum depends on the degree of interest in IPE and pathophysiology curriculum, the degree of considering the importance of professional courses, the professional harvest after learning pathophysiology, and the degree of understanding the relationship between IPE and CIPE. A total of 81.04% of the students believe that the teachers telling stories themselves is the most popular way to spread education in the process of CIPE. This reflects the importance of mental health education from the perspective of CIPE. Additionally, this study also implies that PBL and flipped classroom teaching modes are the popular modes of teaching for CIPE.Conclusions: This study is conducive to promoting the improvement and implementation of CIPE with mental health education in higher education courses; thereby, providing valuable insights for the educational decision-makers.This work was supported by a project grant from National innovation and entrepreneurship training program for College Students (grant no. 202010489017), Hubei Province Natural Science Foundation of China (grant no. 2017CFB786), the Scientific Research Project of Education Department of Yangtze university (grant no. JY2020134), the Curriculum Ideology and Politic Project of Graduate School of Yangtze University (grant no. YSZ202111), and Yangtze University 2022 Full-English Teaching Course Construction Project(grant no. 202215).aYongli Tana Department of English, Chengdu University of Technology, Chengdu, Sichuan 510059, China.Objective: To investigate the efficacy of aesthetic education in reading and writing through the spatial image description reading of a famous writer\u2019s novels, and to analyze the college students\u2019 aesthetic psychological needs when they are in face of anxiety.Methods: First, close-reading is used in the interpretation. Bai Xianyong\u2019s novels have their own narrative discourse aesthetic feeling. The artistic characteristics are mainly elegant, light and gentle, delicate and sensitive, and peeling off impurities. There is a sense of loneliness in the works, showing a unique aesthetic style. From his works to observe the presentation of aesthetic style, spatial image is an indispensable means of expression. Second, observation is used in the classroom teaching. During a semester, the author systematically observed, recorded and analyzed students\u2019 mood changes in reading Bai Xianyong\u2019s novels in order to obtain the relationship of aesthetic reading and relieving the students\u2019 reading and writing anxiety. The author tried to keep objective and maintain the natural exposure of the observed students, and the obtained results were relatively effective.Results: In the reading and writing, there were a comparatively focused time out of interference and the participation of the students was full. And through the close-reading and observation, the author found the students\u2019 anxiety was relieved when the teacher served them novels with beautiful descriptions, and their aesthetic psychological needs were largely satisfied. Since novels have integrated the author\u2019s observer perspective, creative expression and the aesthetic consciousness of the readers\u2019 imagination, aesthetic reading before writing is an effective way to overcome writing anxiety.Conclusions: I suggest that the aesthetic psychological needs are students\u2019 innate motive for reading and writing, so meeting the aesthetic psychological needs of students have potential to assist educators to become more reflective about their full development and to assist the students to relieve the anxiety and to articulate their own reading and writing schedule. In this paper\u2019s example, through the aesthetic interpretation of the three types of spatial images with the highest frequency in Bai Xianyong\u2019s novels, the residence living room, the midnight park and the ballroom and the bar, the students understand the space-time dislocation, identity pursuit and uncertain fate. The students were led to discuss the relationship of psychology and metaphor, and to explore the specific aesthetic space elements such as body perception, emotion and thought in the novels. After the aesthetic analysis of this novel, the students were more active about their own readings and writings.This research was supported by Chengdu University of Technology \u201cDouble First-Class\u201d Initiative Construction Philosophy and Social Sciences Key Construction Project (ZDJS202318).a, Zhifang HanbXiaobo Taoa Graduate School, North China University of Technology, Beijing, China, b School of Economics and Management, North China University of Technology, Beijing, China.Background: With the development of economy and society, the personal quality of employees has been generally improved. However, many employees feel more pressure on how to achieve the best results in the competition with rising tide. Some near-morbid competition phenomena have caused many unhealthy psychological problems, such as high psychological pressure and heavy depression tendency. It is urgent for enterprises and the whole society to find correct solutions to achieve personal development, sustainable economic and social development. Sustainable supply chain management seems to be a reasonable choice. It is a modern management mode that comprehensively considers and balances economic, social, and environmental benefits. As an important part of social benefits, mental health can be maintained in a reasonable range through sustainable supply chain management.Subjects and Methods: Through interviews with three companies, namely company A, company B and company C, which all belong to the manufacturing industry, this paper analyzes the interview results with View of Grounded Theory. The reason why the selected companies belong to the manufacturing industry is that the popularization of automation in the manufacturing industry has become the trend of the times, which makes employees face the major problem of how not to be eliminated in the performance appraisal. Generally speaking, it is difficult for employees to maintain a healthy psychological state under such circumstances, which makes the manufacturing industry a very suitable research object for this article. In the analysis of the interview results, this paper divided the experiment into three parts according to the grounded theory: open coding, spindle coding and selective coding.Results: Based on the grounded theory, this paper sorted out 108 open coding results, 24 spindle coding results and 6 selective coding results in the interview contents. This paper described and analyzed the spindle coding results and the selective coding results to ensure that the sources of the results are true and credible, and finally proposed possible research issues and research directions.Conclusions: Research and analysis based on grounded theory shows that sustainable supply chain management will effectively improve the psychological health of employees. This will require enterprises to consider and discuss multiple aspects when formulating sustainable supply chain management strategies, and develop more diversified sustainable supply chain management strategies, so as to achieve the improvement of multiple benign indicators and benefits, and ultimately help employees and society achieve healthy and sustainable development.aMingzhu Zhua Innovation and Entrepreneurship Development Center, Tianjin Sino-German University of Applied Sciences, Haihe Education Park, Tianjin 300350, China.Background: To realize the development of innovation and entrepreneurship education in Chinese application-oriented universities, the integration with professional education is an important way to cultivate the entrepreneurship of students and promote the higher quality employment of graduates. In recent years, outstanding achievements have been made in the theoretical research and practice of innovation and entrepreneurship education in Chinese universities. However, China\u2019s innovation and entrepreneurship education is still in the exploration stage, especially in the integration with professional education. The separation has a negative impact on students\u2019 innovation and entrepreneurship education. Moreover, it is unknown to what extent the impact on students\u2019 mental health. This paper tries to comprehensively analyze the current situation, problems and results of the integration of innovation and entrepreneurship education and professional education. The corresponding solutions are proposed to help students complete better innovation and entrepreneurship education and to play a positive role in students\u2019 mental health.Subjects and Methods: This paper adopts the case analysis method and the questionnaire survey method. Taking an application-oriented university as a case, this paper analyzes the status in the integration of this university to find the phenomena and problems in the practice of innovation and entrepreneurship education in universities. Students are the important subjects and direct beneficiaries of education. Students\u2019 subjective feelings and objective needs are both important factors influencing education. The actual impact on the mental health of the students is analyzed through the questionnaire survey of the students in this university.Results: The integration model of innovation and entrepreneurship education in application-oriented universities is proposed from the perspective of universities, government and enterprises based on the symbiosis theory. An application-oriented university is taken as a case to explore the mechanism of innovation and entrepreneurship education, and the successful experience in the integration of education and its impact on students\u2019 mental health. Finally, three suggestions are put forward for the effective integration of innovation and entrepreneurship education and professional education in Chinese application-oriented universities. This also can play a positive role in students\u2019 mental health.Conclusions: The development of innovation and entrepreneurship education in universities should be deeply integrated with professional education. The universities, government and enterprises, all three should participate in the whole development of innovation and entrepreneurship education. The integration of innovation and entrepreneurship education and professional education in application-oriented universities can cultivate students\u2019 entrepreneurship better, help students to complete employment better, and help students\u2019 to improve in mental health better.This work was funded by achievements of the key research project of Tianjin education (JYDY-20223006) and the scientific research project of Tianjin Sino-German University of Applied Sciences (zdkt2021-013).aXinyi Zhanga School of Marxism, China University of Political Science and Law, Beijing, China.Background: To investigate whether the psychopathic agents who have deficits in emotional processing and inhibitory control are really competent with moral concepts and can make genuine moral judgements as non-psychopathic agents do, and to defend a specific kind of ethical view based on the analysis of relevant results came from psychological and neuroscientific experiments.Subjects and Methods: A certain number of representative existing moral psychological experiments were discussed and analyzed with an eye to arguing for and against relevant competing views about moral concepts and judgements, i.e. the judgmentalist view and the motivationalist view. These experiments including roughly three types, among which the first type is the experiments that using the moral/conventional distinction to test whether psychopaths have the ability to distinguish between moral transgressions and conventional transgressions, the second type is the experiments that using moral dilemmas such as the trolley problem constructed by philosophers to test whether psychopaths can properly distinguish personal harms from impersonal harms. Two phenomena could be observed from these empirical tests, i.e. firstly, psychopaths and non-psychopaths make different judgements with regard to personal aggressions; secondly, both psychopaths and non-psychopaths show the capacity to distinguish personal aggressions from impersonal aggressions. Since the judgmentalist view and some sophisticated version of motivationalist view could accommodate the two phenomena equally well, a third type of psychological experiments was appealed to, i.e. the neuroscientific experiments that using brain imaging techniques such as functional magnetic resonance imaging (fMRI) to reveal patterns of activation in cognitively-relevant areas and emotionally-relevant areas when psychological and non- psychological subjects are presented with moral dilemmas and make moral judgements as well as judgements about how to act. The data from fMRI scans were then used to support the judgmentalist and emotionist hypothesis about moral judgements.Results: The brain imaging experiments showed that, with regard to judgements about the moral properties of relevant actions and judgements about degrees of severity of moral violations, there was some kind of symmetry in psychopaths\u2019 mental mechanisms as well as in non-psychopaths\u2019 when they make moral evaluations. Non-psychopaths\u2019 judgments about moral properties and judgments about severity are both associated with emotion-related brain regions, while both types of judgments of psychopaths are connected to cognition-related brain regions. These two types of judgements are not actually generated by different mental mechanisms and processes.Conclusions: Although there is no significant difference between psychopaths and non-psychopaths in various moral judgment results, psychopaths lack the ability to make genuine moral judgments. This gives us a good reason to support the judgmentalist and emotionist view.The work on this paper was supported by the Humanities and Social Science Foundation of Ministry of Education of China (Grant No. 22YJC720022).a,bHaixia Baia Tourism and Economic Management Department, Lijiang Teachers College, Lijiang 674199, China, b School of Business, Yunnan University of Finance & Economics, Kunming 650221, China.Background: Huge Crisis always brings unprecedented impact to the tourism industry, leading the theme of resilience which aims for recovery become a hot topic in tourism research. However, the tourists\u2019 psychological resilience has been largely ignored, the mechanism of how tourists give play to their psychological resilience when facing the destination crisis is still ambiguity, and the impact on tourism industry is also unclear, forming a huge research gap. By exploring tourists\u2019 psychological resilience, this paper aims to enrich the literature on tourism resilience theoretically, and in practice, explores the enlightenment of tourism recovery under the crisis context from the perspective of demand.Subjects and Methods: Based on SOR theory and Maslow\u2019s Needs theory, this paper adopts the longitudinal research method to collect data to track the diachronic changes of the COVID-19 pandemic situation from January 2020 to December 2022 in Lijiang, a small tourist city in southwest China that is popular with domestic and foreign tourists. The Focus group discussion (FGD) method is used to summarize the stages of tourists\u2019 psychological changes, analyze the important role played by technology forces in this process, and predict the trend of digital transformation in the tourism industry.Results: In the early stage of the pandemic, due to the risk perception of external policies and internal loss aversion, tourists show travel fear or travel avoidance behavior out of the motivation of seeking safety. In this stage, they think highly of digital based countermeasures to ensure health and safety. In the middle stage, the depressed tourism demand seeks to release. On the one hand, tourists flow to local tourism markets such as travel around, suburban tourism, rural tourism and micro vacation, increasing the stable closed-loop circulation capacity of the local market. On the other hand, they pursue new forms of digital tourism, which can relieve the suffering of \u201clovesickness\u201d for tourism to some extent. In the later stage, the pandemic situation tends to ease, some tourists show a tendency of compensatory tourism and start taking \u201can instant trip\u201d mode, while more tourists remain cautious and planning long distance travel. At this stage, tourism psychology shows a strong preference for social needs and shows dependence on digital technology.Conclusions: Amid the crisis, tourists follow the psychological mechanism model of \u201cEnvironment-perception- motivation -behavior\u201d, showing the evolution and change law of three stages, namely, early period-travel fear, middle period-demand depression, late period-differentiation and transformation. Besides, digital technology plays an important role in each stage. From the perspective of tourists\u2019 psychology, this paper reveals that after the crisis, the recovery of tourism industry needs a process of gradual adaptation and restart. This research also gives some advice on the research agenda of tourists\u2019 psychological resilience in the future.This work was supported by a project grant from The National Social Science Fund of China (Grant No.22BGL151).a, Shizhen BaiaShiying Wanga School of Management, Harbin University of Commerce, Harbin 150028, China.Background: In recent years, as COVID-19, Ebola, monkeypox and other infectious diseases continue to spread around the world, public health emergencies have become another important factor affecting people\u2019s work and life. Public health emergencies are unexpected, unpredictable and irresistible, and they will cause devastating consequences and damage people\u2019s body, mind, spirit and other aspects. When people face these stressful events, once they cannot solve or deal with them, serious psychological imbalance will occur, which is called crisis. Acute psychological disturbance  may occur during a crisis. The main reason for this is that people are afraid of the uncertainty and opacity of the event itself. Therefore, this paper uses the infectious disease model to establish the prediction model of public health emergencies. Through the model, the development trend of the events, mortality and other indicators are effectively predicted, so as to alleviate people\u2019s panic.Subjects and Methods: In this paper, a prediction model of public health emergencies based on SEIHD was established by improving the traditional infectious disease model and using three indicators, namely viral infection rate, virus incubation period and recovery rate. The SEIR model was improved and the parameters were modified to simulate the external intervention measures to predict the development trend of the epidemic.Results: In this paper, the law of epidemic transmission in Hubei Province was taken as an example to predict the number of confirmed cases and the number of deaths in two stages. The cumulative number of confirmed cases in Wuhan from January 11, 2020 to February 18, 2020, predicted by the prediction model, and the real data during this period was fitted. The two curves were compared, showing good fitting. The data of the COVID-19 epidemic in Hubei Province from January 11, 2020 to February 18, 2020 were input into the model as the basic data to predict the death toll during this period. The data were fitted to the real data respectively. At the same time, it was assumed that quarantine measures were taken ten days in advance to predict the death toll. The same method was used to predict the number of confirmed cases and deaths from February 18, 2020 to April 14, 2020, and the results were correct.Conclusions: The prediction results are basically consistent with the real data, which confirms the validity of this prediction method. The research proves that early detection, early prevention and control of public health emergencies can control their development trend, curb their widespread spread, and reduce the harmful impact on social life and economy. At the same time, it can alleviate people\u2019s panic about the epidemic to a certain extent. So as to avoid the acute psychological disturbance caused by insufficient cognition of public health emergencies.This work is supported by Humanities and Social Science Project of Ministry of Education (18YJCZH175); the National Grant Natural Science Foundation of Heilongjiang Province (YQ2019G004); University Nursing Program for Yong Scholars with Creative Talents in Heilongjiang Province (UNPYSCT-2020081).a, Yuanxin ZhangbXueqing Kanga School of Economics, Sichuan University, Chengdu 610065, China, b Chengdu Institution of New Economic Development, Chengdu 610042, China.Background: New-type urbanization is not only the urbanization of population, but also the citizenization of agricultural transfer population and realize social psychology integration in aspects of lifestyle, cultural types, psychological resources and corresponding social structure. The psychological health level of the agricultural transfer population is a key component of promoting social integration of agricultural transfer population into cities, which can improve new-type urbanization. Compared with the expanding capital demand of these related projects, it is far from enough to rely on fiscal revenue, therefore optimizing investment and financing mechanism for urbanization and strengthening financial support for new urbanization is urgent.Subject and Method: This study aims to analyze the agricultural transfer population\u2019s demand of social integration to improve their psychological health level and conduct to optimize the allocation of supporting financial resources in process of new-type urbanization. By analyzing the financial support mechanism of agricultural transfer populations\u2019 social integration from the perspective of environmental psychology, we establish a new financial support path design containing general path as well as specific path, tested by structural equation model based on panel data 31 provinces of mainland China from 2008 to 2017.Result: The results show that the effect of financial support for agricultural transfer population\u2019s social integration to China\u2019s new-type urbanization is more significant than fiscal revenue support, and the supporting function is realized through general path and specific path respectively to ensure migrant people\u2019s equal access to infrastructure and public services to help them to form place connection to gain social integration, which is beneficial for the agricultural transfer population to obtain a sense of happiness from urban life, thereby improving their psychological health status.Conclusion: This study recommends that the enterprises engaged in agricultural transfer population employment and governments need to pay attention to their psychological health status and enhance related infrastructure and equalization of social security to help them achieve social integration. Meanwhile, it is indispensable to build a diversified financial support system in paths of entity economy development, infrastructure construction, employment, education, housing, social security to form place connection from physical environment dimension and solve the recent financial support system\u2019s problem of unitary structure, insufficient innovation and scale, which will enhance agricultural transfer population\u2019s security sense of social security and local trust through place connection to raise their psychological health level to realize social integration.This paper is supported by the National Social Science Fund of China (grant number 14BJY055).a, Tae-Won KangbJing Chia Department of Global Entrepreneurship, Kunsan National University Gunsan 54150, Republic of Korea, b Department of Supply Chain and Logistics, College of Social Sciences, Kunsan National University, Gunsan 54150, Republic of Korea.Background: To explore the promotional strategies for university library reading and summarize the experience gained in the course of disseminating Chinese traditional culture in the context of national reading, based on user psychological needs and relying on college student volunteers.Subjects and Methods: In 2009, the Library of SDNU analyzed user needs, refined its collection advantages, and took the dissemination of traditional Chinese culture as a starting point to bring college student volunteers into the role of reading promoters, gained support from the university as well as the social forces, uniformly planed marketing development and focused on the impact assessment. In this article, the specific case of the SDNU Library Reading Promotion Project \u201cPromoting Volunteerism and Reading to the N-th Power\u201d was analyzed, and the origin, goals, products, evaluation and main processes of project were introduced.Results: The reading marketing project \u201cPromoting Volunteerism and Reading to the N-th Power\u201d was planned and organized by the Library of SDNU from 2009. The inspiration for the project derived from the classic book A Single Spark Can Start A Prairie Fire by Mao Zedong, the great leader of China. Since the launch of the project, the Library of SDNU has been awarded the national-level \u201cDemonstration Base for National Reading\u201d (at the team level); the university student volunteers in the library have won three gold awards in the three major categories of university student reading promotion nationwide ; the cooperation between the Library of SDNU and public welfare organizations and social enterprises has become increasingly close (at the marketing level); the satisfaction survey of readers among the faculty and students at SDNU Library has ranked first for consecutive years, and the number of social readers following their new media platform for marketing projects has been increasing year by year . The volunteer reading promotion project for college students in the Library of SDNU has been reported by many media outlets such as Renmin.com, Dazhong.com, Fenghuang.com, Qilu Evening News, and Life Daily, and has aroused strong social repercussions . The \u201cPromoting Volunteerism and Reading to the N-th Power\u201d reading marketing project of SDNU Library is gradually realizing the potential of starting a prairie fire with a single spark, taking university libraries as the front line.Conclusions: This project, based on users\u2019 psychological needs, leveraging college student volunteers to promote traditional Chinese culture in university libraries, is a positive manifestation of the views and attitudes of the International Federation of Library Associations and Institutions (IFLA) strategic plan. The project is conducive to the internationalization and branding development of Chinese library reading marketing projects and the establishment of a marketing system for the global dissemination of traditional Chinese culture through university library systems. The design and implementation of the project\u2019s working methods have a close social, school, and personal background. The Library of SDNU has actively responded to the National Reading initiative by cultivating excellent reading promotion projects that can be used for reference and easy to replicate, spreading the permanent charm of Chinese culture and the style of the times, which is conducive to enhancing the reading happiness of people at all levels of society, including entrepreneurs, students, farmers, and other groups; and by cultivating excellent reading promoters, giving full play to the advantages of peer partners, and achieving positive self-development through mutual assistance and cooperation, which is conducive to the unification of the \u201cself-value\u201d and \u201csocial value\u201d of the personality of the Chinese youth generation.aLancang Wanga Beijing University of Chemical Technology, Beijing 100029, China.Background: According to a survey of 126000 college students in China, it was found that 20.23% of college students have psychological disorders, 11.7% of college students have different degrees of psychological diseases, and 75% have experienced psychological crisis. Will quality is an important part of athletes\u2019 competitive ability, a necessary guarantee for their excellent performance, and also the embodiment of sports spirit and sports culture, especially for college athletes at the growing stage. At the same time, mental health is of great significance for college athletes to resist mental diseases, improve learning efficiency, complete training tasks, and improve interpersonal communication and quality of life.Subjects and Methods: This paper uses the methods of literature, experiment and mathematical statistics to study the CUBA players of several universities in Chaoyang District of Beijing. The experiment was divided into two groups. The experimental group added outward bound training to the training plan, while the control group carried out according to the original training plan. Before and after the experiment, the professional psychological scale was used to measure and record the various indicators of the subjects for analysis and research.Results: Through theoretical analysis and experimental research, outward bound training plays a positive role in the cultivation of CUBA athletes\u2019 mental health. The experimental research shows that the addition of outward bound training in the training has a positive effect on the cultivation and improvement of the will quality of college students\u2019 athletes. Although this improvement is unbalanced, there is no significant difference in the three aspects of hardiness, tenacity and goal clarity from the statistical point of view, but it is very obvious in the three aspects of decisiveness, self-control and self-confidence (P<0.05).Conclusions: It is suggested to pay more attention to and cultivate the mental health level of college athletes. It is suggested that university sports teams should selectively integrate part of outward-bound training into the training of sports teams according to their own conditions, so as to improve the mental health level and willpower quality of athletes. And gradually establish and improve the curriculum system in line with the training of various projects of the university based on their own needs.a, Ling Miaob, Yanjie WangcXiaoxi Suna The CPC Henan Provincial Party Committee Party School, Zhengzhou, Henan 451464, China, b The CPC Henan Provincial Party Committee Party School, Zhengzhou, Henan 451464, China, c College of Humanities and Development Studies, China Agricultural University, Beijing 100089, China.Background: This article analyzes the development of franchising in China, its growing role in the Chinese economy, and how its development differs from that of developed economies. And the article attempts to analyze from three dimensions: system, culture, and practitioners\u2019 mental health. The results show that these three dimensions will have a significant impact on franchising in China, and it is necessary to focus on these three aspects when formulating policies and implementing them in the future. In particular, the psychological health of practitioners is closely related to the future sustainable development of franchising operations to a certain extent. Therefore, it is necessary to conduct necessary intervention and guidance on the psychological health of practitioners to ensure that they can maintain a good psychological state to carry out their daily work. Franchising in China has shown great advantages and taken a crucial role in the rapid growth of the Chinese economy. While few scholars have explained the unique practices of franchising in the Chinese context. Franchising has become a significant business model in China after reform and opening up as in Western countries.Subjects and Methods: This article is organized as follows. First provide a brief review of the franchising around the world and then discuss the trends of franchising development in China. With a comparison of law and regulation, economy, and culture, the institutional and cultural differences in China are analysed. After that, this article summarize the unique characteristics of franchising in China and discuss how franchising works differently in China. Finally, the authors identify special issues and shed new light on the existing franchising literature in the emerging business environment.Results: Present the growth of franchising in China as a business model relative to the West. The cultural and institutional characteristics compared with the West make franchising in China different. Successful franchises in China have less reliance on contracts and more on trust and personal ties between franchisor and franchisee.Conclusions: In general, franchising will become increasingly accepted and encouraged because the arrival of franchises contributes to the growth of the economy in China. Since the first pilot franchise regulations were adopted in the late 1990s, domestic franchises have taken off with the growing purchasing power gained by Chinese consumers. In addition, universal cultural trends allow many international franchises to enter China. As in Western economies, both international and domestic franchise chains have become a significant business model in China and have grown substantially over the past twenty years. Although this competitive business model has received a surge of scholarly interests, research in this area has sought to provide a franchising model from the Western perspective. The public\u2019s understanding of franchising in China is low. This research focuses on the differences in franchising in China. Franchising in China has developed specific characteristics compared with the West, which is by driven institutional and cultural differences, as well as China\u2019s level of development. Built on trust, a franchisor-franchisee relationship has the requisite guanxi for business success in China. The implications can be applied to some Asia countries with similar cultural backgrounds. Future studies are encouraged to compare the development of franchising in emerging business landscapes, which accounts for most of the world\u2019s population and over half of the world\u2019s natural resources.Soft Science Project: Challenges and Countermeasures for the Digital Transformation of Traditional Industries in Henan Province under the \u201cDouble Carbon\u201d Goal (232400410201).a, Min ZhangaXiang Lia School of Education, Huaibei Normal University, Huaibei 235000, Anhui, China.Background: The emotion of gratitude reflects the level of individual mental health by affecting moral judgment. This study aims to investigate the impact of gratitude on college students\u2019 moral judgment ability.Subjects and Methods: In experiment 1, the psychological experimental programming software E-prime was used to compile moral word judgment task for pre-post test. Experiment 2 adopted a 2\u2009\u00d7\u20092\u00d72 experiment design between subjects, which revealed the influence mechanism of gratitude on college students\u2019 moral judgment by examining three variables: gender, gratitude degree  and whether one word is moral word or not.Results: It was found that: (1) the short film used in the study could effectively induce the subjects\u2019 gratitude ; (2) College students displayed significant gender difference in moral word judgment task ; (3) College students\u2019 gratitude degree exerted significantly different impact on moral word judgment task ; (4) College students\u2019 gender and gratitude degree exerted significant interaction effect on moral word judgment task . Conclusions: Gratitude  has a significant impact on college students\u2019 moral judgment. High gratitude  individuals have more active cognitive processing, resulting in greatly improved quality in thinking and decision-making. Also, such individuals have higher moral judgment level, showing greater positivity than low gratitude  individuals in moral judgment.The paper was supported by Study on Mental Health Promotion Model for Special Education Teachers Based on Mental Resilience (Project No.: 23500024).a, Lin Kuanga, Tingyu Xua, Wei Lua, Jialing ShiaYangfan Wua Hunan University of Chinese Medicine, Changsha, Hunan, ChinaBackground: Genital herpes (GH) is a common sexually transmitted disease mainly caused by herpes simplex virus type 2 (HSV-2), which lurks innerve roots and causes recurrent disease. Currently, there is no cure for GH, but nucleoside antiviral drug can inhibit viral replication,and acyclovir is one of the drugs commonly used in clinic to improve its symptoms.Subjects and Methods: The effect of acyclovir on HSV-2 infected human neuroblastoma cells (SH-SY5Y) was studied by label-free quantitative proteomics in order to explore the action mechanism of acyclovir on HSV-2 virus lurking in neurons. In this study, we treated SH-SY5Y cells infected with HSV-2 virus with acyclovir drug-containing serum. After modeling, extracted cell proteins, detected protein expression differences using label-free quantitative proteomics, and analyzed the GO functional enrichment, domain enrichment and transcription factor annotation of these differential proteins.Results: The results showed that 1011 proteins were involved in the intervention of acyclovir against HSV-2 virus lurking in neurons, of which 513 were up-regulated and 498 were down-regulated. These proteins were mainly concentrated in biological processes, cell composition and molecular function. The results of GO functional enrichment analysis, domain enrichment analysis and transcription factor analysis of differential proteins showed that, the potential targets of acyclovir are mainly concentrated in the nucleus and mitochondria, acyclovir mainly acted on mitochondrial carrier domain, ATPase conserved sites and annexin sites, and acyclovir mainly interfered with HMG-box, zf-C2H2, CSD, Homeobox and other transcription factors to inhibit the replication of HSV-2 virus.Conclusions: Acyclovir interferes with the replication of HSV-2 virus in cells by affecting the catabolic process of nuclear transcription mRNA, mitochondrial respiratory function and ATPase activity.This study was supported by grants from Project supported by the National Natural Science Foundation of China (Grant No.82174391); Chinese Medicine Scientific Research Foundation of Hunan (Grant No.2021058).aYulan Zhoua Academy of Fine Arts, Sichuan Minzu College, Kangding, Sichuan 626001, China.Background: Tibetan embroidery of Relieving anxiety and improving mental health is facing the inheritance crisis such as the fault of the inheritance population, the increase of Tibetan embroidery substitutes and the decrease of public acceptance. Promoting the industrialization development of Tibetan embroidery skills with the integration of culture and tourism; drive the personalized development of Tibetan embroidery skills with innovative ideas; drive the intensive development of Tibetan embroidery skills with capable craftsmen; promote the socialized development of Tibetan embroidery skills with targeted poverty alleviation.Subjects and Methods: Conduct empirical research in Tibet-related areas.Results: How Tibetan embroidery can help poverty alleviation and rural revitalization under the consciousness of building a Chinese national community.Conclusions: Carefully summarize and promote the experience of poverty alleviation, and continue to consolidate the stable employment of the helpers; fully implement the revitalization of Tibetan embroidery, focusing on strengthening the integrated development of Tibetan embroidery tourism; focus on building the development of the whole industry chain of Tibetan embroidery, and promote the revitalization of Tibetan embroidery industry to empower rural areas; adhere to innovation to lead the living inheritance of Tibetan embroidery and expand the market consumption space of Tibetan embroidery products; guide college students with relevant ambitions to tap the cultural and creative resources of Tibetan embroidery, highlight the advantages of manual creation, and finally realize that college students can promote employment through entrepreneurship and alleviate the pressure of social employment. Tibetan embroidery plays an increasingly important role and shoulders the mission and responsibility from poverty alleviation to rural revitalization. The internal logical mechanism between the two requires Tibetan embroidery to take the initiative to take advantage of the development of the rural revitalization strategy. It is necessary to strengthen the inheritance education of Tibetan embroidery, enhance the consciousness and self-confidence consciousness of the inheritance subjectivity, reshape the self-respect and self-confidence of its own historical and cultural characteristics, cultivate the endogenous motivation of rural revitalization, and awaken the road consciousness and road self-confidence of Tibetan compatriots to conspire with their own national characteristics. We should also adhere to innovative development, live inheritance, fully tap the profound cultural heritage and unique capitalization transformation advantages of Tibetan embroidery, enhance the potential industrial development ability of Tibetan embroidery in various forms, and promote the integration of Tibetan embroidery into modern life on the basis of maintaining the national style and local characteristics of the original process.This work was supported by 2021-2023 Sichuan Higher Education Talent Training Quality and Teaching Reform Project: Theoretical and Practical Research on Teaching Reform of Building the Chinese National Community Consciousness Education in Universities in Ethnic Areas (JG2021-1417); National Ethnic Affairs Commission\u2019s Teaching Reform Project \u201cResearch on Building Chinese National Community Consciousness into the Ideological and Political Curriculum Construction of Ganzi Universities\u201d (ZL21064);Sichuan Minzu College 2021-2023 Higher Education Talents Training Quality and Teaching Reform Project \u2018 Research and Practice of Diversified and Innovative Talents Training of Tibetan Folk Crafts\u2019 (JG202111).a, Feng Luob, Zhe WangbWei Shanga School of Management, Chengdu University of Information Technology, No.24 Block 1, Xuefu Road, Chengdu, China, b School of Economics and Management, Sichuan Tourism University, No.459, Hongling Road, Chengdu, ChinaBackground: As a new form of team joint, cross-platform service emerges at the moment and gets good feedback from the market. In recent years, performance appraisal as an environmental cue has been widely concerned by the academic community. However, the impact of performance appraisal on cross-platform services is unknown, especially given the psychological awareness and stress of employees, which is undoubtedly an urgent issue for enterprises to understand.Subjects and Methods: Based on the two-factor theory, this paper explores the influence of performance appraisal on cross-platform service preference and its internal mechanism, and explores the moderating effects of different types of performance appraisal  in this process. Through 4 experiments, experiment 1 is a field experiment between single factor groups, experiment 2 is a laboratory experiment between single factor groups, experiment 3 is an online questionnaire between single factor groups, experiment 4 is a 2\u2009\u00d7\u20092 field experiment, the research method of combining field experiment and laboratory experiment is adopted, and the research design supported by actual service evaluation and questionnaire measurement is adopted. The variance analysis and bootstrap method were used to examine the internal mechanism of performance appraisal\u2019s preference for cross-platform services through psychological stress and anxiety.Results: The results show that experiment 1 verifies that compared with non-performance appraisal state, employees in performance appraisal state show lower preference for cross-platform services. In experiment 2, other competitive explanation mechanisms were excluded and it was again verified that, compared with non-performance appraisal state, employees were less likely to prefer cross-platform services in appraisal. Experiment 3 verifies that the two-factor theory plays a psychological mediating role in the relationship between performance appraisal and cross-platform service preference, and clarifies the internal two-factor psychological cognition mechanism of this relationship. In experiment 4, the experimental situation was changed, that is, the performance appraisal level was divided into assessment and non-assessment, and the assessment type was divided into individual assessment group and class assessment group, which verified the rationality of the two-factor theory as the internal mechanism of performance appraisal for cross-platform service preference. At the same time, it is found that the performance appraisal type  has a moderating effect on the influence of performance appraisal on cross-platform service preference and the mediating effect of the two-factor theory.Conclusions: The research results theoretically expand the relevant theoretical research on job assessment, employee psychology, service support and manufacturer association. At the same time, in practice, it not only provides feasible suggestions for the work arrangement and psychological pressure relief of employees in manufacturing enterprises, but also provides valuable suggestions for service providers to carry out manufacturer association and cross-platform service recommendation. Therefore, this paper has important theoretical contribution and practical significance.a,b,c, Nan Kanga,b,c, Wenjuan Yana,b,cYuxia Zhua People\u2019s Hospital of Ningxia Hui Autonomous Region, Yinchuan, Ningxia 750001, China, b Ningxia Eye Hospital, Yinchuan, Ningxia 750001, China, c The First Affiliated Hospital of Northwest University for Nationalities, Yinchuan, Ningxia 750001, China.Background: To investigate the effect of Child-Pugh grading standard in the surgical treatment of liver cirrhosis with gallstones in elderly patients.Subjects and Methods: This retrospective analysis selected 68 elderly patients of liver cirrhosis with gallstones treated in Ningnan Hospital  from February 2021 to February 2022. According to Child-Pugh grading criteria and the individual liver reserve function, all patients were divided into three grades, grade A, B and C. Then, patients were classified into different groups according to varies surgical methods. 33 patients were in the first group which following laparoscopic cholecystectomy (named LC), 28 patients were in the second group which following traditional laparotomy for cholecystectomy (named OC), while 7 cases were in third group for mixed ways (named LC + OC). All the patients were confirmed by CT and MR. The effectiveness results of 68 elderly patients with cirrhosis complicated with gallstones after different surgical treatment were analyzed.Results: Child-Pugh grading on a scale of 5 to 7 is the safest range for the three types of surgery. When the score is higher than 10, it implicates a great risk, and surgical treatment should be carefully selected according to the patient\u2019s condition in these cases. The 33 patients in LC group recovered quickly and were discharged from hospital on the 5th day after surgery. Among the 28 patients in the OC group, the condition recovery was slower than that in the LC group, and 4 patients had mild complications and extended hospitalization for 3 days. Among the 7 patients in LC+OC group, due to their serious condition, 1 patient had complications during the recovery period and was hospitalized for 5 days longer. Another 1 patient\u2019s condition deteriorated and died 2 days after surgery in LC+OC group. The study also conducted a followed up process, 67 patients were discharged and followed up, 11 of which were re-hospitalized.Conclusions: Child-Pugh grading criteria can help doctors effectively evaluate the liver reserve function of patients, and has a guiding effect on the rehabilitation of elderly patients with liver cirrhosis complicated with gallstone after surgical treatment. Our research finds that Child-Pugh grading can reduce the risk of surgery, shorten the length of hospitalization, reduce the re-hospitalization rate, prevent complications and improve the quality of life of the patients.This work was supported by a project grant from Major R & D Plan Project of Ningxia Hui Autonomous Region (Grant No. 2017 BY 036)a, Yiru YangaDeyu Chena School of Accounting, Guangzhou College of Commerce, Guangzhou 511363, China.Background: With the rapid upgrading of the industrial structure in the Pearl River Delta (PRD), the competition in the manufacturing market is becoming more and more fierce? It not only causes the psychological anxiety of the managers and employees of the enterprises in the Pearl River Delta, but also directly affects the economic benefits of the enterprises and their sustainable development in the future. At present, an important obstacle to the construction of a harmonious socialist society is the pressure and psychological anxiety of employees. The manufacturing industry in the Pearl River Delta region is developed with a large number of employees. Due to the employees\u2019 educational background, skills and income being in a weak position, they bear more pressure and psychological anxiety than other organizations, reduce corporate profits, while bringing serious family and social problems to society.Subjects and Methods: This paper discusses the current situation and causes of cost management of manufacturing enterprises in the Pearl River Delta, taking kub pen company as an example, this paper analyzes the psychological anxiety of enterprise cost managers in the Pearl River Delta by means of activity-based costing (ABC), which includes the lack of cost awareness, the lack of cost management, the lack of material management and the lack of basic work.Results: The various problems in cost management of manufacturing industry in the Pearl River Delta (PRD) have resulted in the decline of the profits of manufacturing enterprises. The manufacturing enterprise has no core competitive power, and the low-cost comparative advantage is losing, the crisis is not only the production crisis, but the survival crisis, which also causes the enterprise manager\u2019s psychological pressure to be extremely big, even part of the enterprise management because can not stand the pressure to choose to jump off the building to end life. To solve these problems, we must make a reasonable response strategy to enhance the sustained competitiveness in the whole market economy.Conclusions: According to the psychological anxiety of enterprise cost managers in the Pearl River Delta, the author puts forward some countermeasures: strengthening the management of activity-based costing, establishing the management mechanism of responsibility cost, improving the quality of basic data; Develop preventive measures and strict cost accounting. By establishing a scientific and effective cost management system, the manufacturing enterprises in the Pearl River Delta can alleviate the psychological anxiety of the managers and employees, and improve the economic benefits of the manufacturing industry, thus enhance the competitiveness of enterprises in the Pearl River Delta in the regional market.a, Lili Zhoub, Xin XucKaige Zhoua New Economic Reseach Institute, Ningbo University of Finance&Economics, Ningbo, Zhejiang 315175, China, b Nanchang Institute of Technology, Nanchang 330511, China, c Library of Huaiyin Normal University, Huai\u2019an, Jiangsu, 223001, China.Background: Emergency medical supplies are a necessary material guarantee for dealing with public health emergencies. Good emergency medical supplies inventory management is an important part of emergency medical management mechanism, which will provide strong support for effective response to public health emergencies.Subjects and Methods: Supply chain management of emergency medical supplies has become an important factor to reduce sudden disasters and emergency medical accidents. The optimization of medical supplies inventory can improve the level of emergency medical treatment, control the spread of infectious diseases and reduce the losses caused by infectious diseases. Medical big data shows that the formulation of emergency medical supplies inventory strategy is affected by demand, price and other factors. This paper proposes and analyzes the dynamics of a supply chain system under inventory and price factors with the feature of piecewise linearity. This switched linear model composed of four subsystems extends the classic inventory models under inventory. Based on properties of switched model, some analytical stability results are derived, and the global dynamic behavior is theoretically examined. Simulation experiments are designed to show the stability results and observe other nonlinear phenomena. It is illustrated that the inventory-dependent demand function and the forecasting inventory rate combine to bring about the stability result or arise more complicated nonlinear dynamics, such as chaotic and periodic fluctuations of inventory and order.Results: These results are suitable for understand the dynamic complexities of supply chain system and present the direction for choosing the decision parameters to improve overall performance. Some illustrative examples demonstrate the effectiveness of the obtained scheme.Conclusions: Efficient inventory management based on medical big data can flexibly respond to the rapidly changing demand of medical supplies in an emergency epidemic, so as to improve the accuracy and timeliness of medical assistance, promote the early control of the emergency, shorten the spread time of the emergency, and reduce the harm caused by the emergency to the society. It has positive significance for the rapid elimination of major emergency after the outbreak, and is worthy of promotion.This work was supported by a project grant from the 2021 Annual Project of \u201cthe Chinese Society for Technical and Vocational Education\u201d & \u201cNew-Era TVET Institute of China\u201d, Historical Mission and responsibility of vocational education in the construction of Healthy China (Grant No.SZ21A003).a, Yuanhui CuiaGuangwei Zhanga School of Information Science and Engineering, Dalian Polytechnic University, Dalian, Liaoning 116034, China.Background: To explore methods of body fat measurement and improve the accuracy of body fat measurement. It is of great significance for body shape management, monitoring human health, and preventing diseases such as hypertension and hyperglycemia.Subjects and Methods: An impedance measurement system was designed based on a human body impedance measurement model. Sixty college students were randomly selected to measure their body fat ratio, body impedance, height, weight, age, and gender to form 60 sets of data sets. Use MATLAB software to build an extremum learning body fat prediction model based on tent mapping and particle swarm optimization (TPSO-ELM). The traditional extremum learning machine (ELM) model and standard particle swarm optimization extremum learning machine (PSO-ELM) model were set as control experimental groups. Then select 50 sets of data from 60 sets of data as the training dataset, and the remaining 10 sets of data as the test dataset.Results: Observe the extremum learning body fat prediction model based on tent mapping and particle swarm optimization and the broken line chart of the body fat prediction results of the control group. The predicted results of the extremum learning body fat prediction model based on tent mapping and particle swarm optimization have the best fit with the true value curve. Calculate the absolute error of the extremum learning body fat prediction model based on tent mapping and particle swarm optimization and the control group. Then calculate the average of the absolute errors of 10 sets of data. The average absolute error of the predicted value of the extremum learning body fat prediction model based on tent mapping and particle swarm optimization was 0.0085, compared to 0.22 and 0.023 in the control group. Therefore, the body fat prediction algorithm of extreme learning machine based on particle swarm algorithm of tent mapping proposed in this paper improves the accuracy of body fat measurement.Conclusions: This paper proposes an extremum learning body fat prediction model based on tent mapping and particle swarm optimization. Human impedance, height, age, weight, and gender were used as input parameters for the body fat prediction model. The simulation experiment proves that the new body fat prediction model proposed in this paper improves the accuracy and efficiency of body fat prediction. Body mass index (BMI) is currently the standard recommended by the World Health Organization (WHO) to evaluate body fat and lean. The experimental data were validated according to the obesity and obesity standards established by the World Health Organization, and the results showed good consistency. The fitness prediction algorithm proposed in this paper improves the accuracy of body fat prediction to a new level. The predicted body fat by this method is more useful in monitoring human health and effectively preventing diseases.aGuangli Longa School of Physics and Telecommunication Engineering, Shaanxi University of Tecnology, Hanzhong City 723001, China.Background: The purpose of health management is to prevent and control the occurrence and development of diseases, to reduce the medical cost and to improve the quality of life, and health risk factors associated with their lifestyle, through health information collection, health testing, health assessment, personalized monitoring management programs, health interventions and other means to continue to improve the process and methods. The problem of food safety is a key issue concerning human health, the most important part of which is the detection of food spoilage, spoilage and deterioration of food, regardless of sensory or physical and chemical properties, it is very important to detect the level of food spoilage quickly and accurately.Subjects and Methods: In view of the current problems is people\u2019s concern about the relationship between food and human health, as well as the harmful effects of rotten food on the human body, etc., a kind of food spoilage detection circuit based on health management is designed, The circuit is based on STC12C5A60S2 microcontroller using resistance detection network and moisture sensors to collect data,DHT11 temperature sensor is used to measure the temperature, test results are displayed by the LCD12864 and broadcast by the voice broadcast module SYN6288, and several kinds of normal food standard values are stored in the microprocessor, kinds of food is replaced by pressing button.Results: The experiment proved that the circuit can realized the normal measurement of food. Measurement time, food resistance and moisture as well as the current room temperature can be displayed on the display, the test results whether the food consumed can be broadcasted.Conclusions: Health management is the use of information and medical technology, a complete, thorough and personalized service procedures are built on health care, medical science, its aim is to help healthy people and sub-healthy people to establish an orderly and healthy life style, reduce risk state and keep away from disease by maintaining and promoting health, through the arrangement of medical services, as soon as possible to restore health. In this paper, the mechanism of food spoilage was studied. The resistance and moisture content of food were detected by using water detection circuit and resistance detection network, and compared with the standard value of fresh food, to judge the extent of spoilage of food spoilage, to make food edible or not. Spoilage and deterioration of food can cause poisoning or potential harm to the human body. People with mild poisoning often have symptoms of acute gastroenteritis, such as vomiting, diarrhea or abdominal pain, fever, etc., severe poisoning in the respiratory, nervous, circulatory and other system symptoms, a slight delay may appear life-threatening. Therefore, food spoilage and deterioration has a great impact on human health, detection of food spoilage and deterioration of human health management is of great significance.This work was supported by Ministry of Education industry-university Cooperation Project (project number: 220604307070644), and this paper is supported by the college-level first-class specialty Communication Engineering Construction Project of in Shaanxi University of Technology.a, Xinmeng KebSha Lia Department of Foreign Language, Zhengzhou University of Science and Technology, Zhengzhou, Henan 450064, China, b Office of Academic Affairs, Zhengzhou Railway Vocational and Technical College, Zhengzhou, Henan 450064, China.Objective: In recent years, in college oral English teaching, it has been found that more and more students are feeling anxious and afraid of opening their mouth to speak English, which hinders the improvement of their oral communicative ability. This is not in line with the policy of cultivating application-oriented talents. Therefore, this paper aims to analyze the reasons that lead to students\u2019 anxiety in oral English class and then proposes strategies that could help to adjust students\u2019 anxiety. It is hoped that teachers could get some suggestions to ease students\u2019 anxiety and help them maintain a healthy mentality in oral English learning, which is conducive to cultivate students\u2019 communicative ability to meet the standards of application-oriented talents cultivation.Method: This paper mainly adopts qualitative analysis based on the analysis of previous literature. In order to effectively solve the problem of students\u2019 anxiety in oral English learning, this paper first makes a brief summary of anxiety from psychological perspective, and then analyzes in depth the important impact of anxiety on college students\u2019 oral English learning. Then, the main subjective and objective factors influencing the degree of students\u2019 anxiety are analyzed. Based on the problems found in previous section, effective strategies to ease students\u2019 anxiety are put forward.Results: It is pointed out in this paper that anxiety has an negative influence on students\u2019 oral English learning. Then the subjective and objective factors contributing to anxiety are analyzed. The subjective factors are ideal level, learning motivation and learning ability while the objective factors are teachers\u2019 teaching ability and region differences. At last, strategies to help students reduce anxiety in oral English learning are proposed. The main strategies are building a good classroom atmosphere for oral English teaching, organizing group activities appropriately, timely guiding students to correct oral mistakes, scientifically designing classroom questioning, enriching language and culture input.Conclusions: Based on the analysis of the negative impact of anxiety on oral English learning and its major influencing factors from both the subjective and objective perspective, the strategies proposed in this paper are aimed to help students adjust their anxiety, overcome the psychological stress during the learning process so as to fundamentally promote students\u2019 oral English learning efficiency and effect, exercise and develop their oral expression and English application skills, which can ensure the effect and quality of oral English teaching to truly meet the needs for oral English professionals for the development of the society in the context of globalization.a, Weirong Wanga, Wen Qiaoa, Xinyi LiaTing Zhanga Department of Public Policy and Management, Northwestern Polytechnical University, Xi\u2019an, Shaanxi 710072, China.Background: The provincial comprehensive medical reform is an important pilot policy to improve the efficiency of China\u2019s basic medical and health services. It is of great theoretical and practical significance to systematically explore the impact of policy implementation on optimizing resource allocation and improving the service efficiency of primary medical and health institutions.Subjects and Methods: Based on this, we first adopted the super-efficient DEA model to evaluate the medical service efficiency in primary healthcare institutions in China from 2010 to 2019, then analyzed the effect and the influencing factors of policy implementation in the first pilot areas through the synthetic control method.Results: 1. the service efficiency of primary healthcare institutions in China ranges from 1.061 to 1.01, the average values of the efficiency in the eastern, central and western regions were 1.259, 0.835 and 0.962 in that order. The eastern region shows an inverted \u201cN\u201d shape, the central region shows a \u201cU\u201d-shaped cycle, and the western region has shown a fluctuating downward trend. 2. In the pilot area, the gap between Jiangsu and synthetic Jiangsu is widening after the implementation of the policy, it shows that the provincial healthcare reform pilot policy effect in Jiangsu is obvious. The probability of the ineffectiveness of that policy is less than 10%. The placebo test was not effective in the pilot areas other than Jiangsu.Conclusions: 1. The service efficiency of grass-roots medical and health institutions in China presents an Eastern > Western > Central trend. The service efficiency shows a decline in different degrees, with a large gap between provinces. 2. Only Jiangsu province has an apparent positive policy effect among the first batch of pilot regions. After the policy implementation, the changing trends of the Anhui, Fujian and Qinghai provinces cannot reflect the effect of the policy. To improve the efficiency of medical and health institutions in China, this paper puts forward some suggestions in terms of strengthening the structural investment of medical resources in the central and western regions and promoting the implementation of a graded diagnosis and treatment system.This work was supported by a project grant from General Project of National Social Science Fundation (Grant No.20BJY076).a,b, Yufei Qiua, Sitong Jia, Jianwu Chenb, Lu Yuc, Shengnan Oud, Xiaoya XiedMingwei Xua Department of Safety Engineering, School of Safety Engineering,Beijing Institute of Petrochemical Technology, Beijing 102617, China, b China Academy of Safety Science and Technology Beijing 100083, China, c Department of Safety Engineering, School of Traffic and Transportation Engineering, Dalian Jiaotong University Dalian 116021, China, d School of Civil and Resource Engineering, University of Science and Technology Beijing 100083, China.Background: In modern workplaces, noise pollution has been identified as a significant risk factor that poses a threat to the safety productivity and workers\u2019 occupational health. However, the impact of sound level and frequency on workers\u2019 attention and behavior in confined spaces is not fully understood. Therefore, this study aimed to investigate the effects of sound level and frequency on attention concentration ability, reaction time, and discrimination time in a confined space environment.Subjects and Methods: A human experiment was conducted with 13 participants. The experiment design included three sound levels  and three frequency levels . Participants were exposed to different sound levels and frequencies in a confined space to investigate the impact of sound level and frequency on their attention concentration ability, reaction time, and discrimination time.Results: The study results showed that sound level and frequency had different mechanisms of influence on attention. Sound level had a more significant impact on workers\u2019 attention concentrating ability, indicating that the greater the sound level, the less attention was paid to safety. On the other hand, frequency primarily affected attention concentration level, with intermediate frequency noise significantly reducing the attention concentration level. When the sound level was 70 dB or the frequency was 1000 Hz, the simple reaction time and discrimination time increased significantly, and the concentration ability was the weakest. When the sound level was 60 dB or the frequency was 100 Hz, the attention level of the subjects was the lowest.Conclusions: This study\u2019s findings demonstrate that noise pollution in confined spaces can have detrimental effects on workers\u2019 attention concentration, reaction time, and discrimination time. Sound level and frequency were found to have different impacts on attention, with sound level being more significant in reducing attention concentration ability. These findings highlight the need to control noise pollution in confined spaces and to consider both sound level and frequency when developing noise control strategies to enhance occupational safety and efficiency. Therefore, appropriate noise control measures must be implemented to minimize the risk of noise exposure and protect workers\u2019 health and well-being.This work was supported by a project grant from Beijing Municipal Commission of Education (Grant No. KM202310017002) and National Natural Science Foundation of China (Grant No. 5230041812).a, Farzaneh Haratyana, Fei JiangbQingzhao Lia School of Foreign Languages, Suzhou University, Suzhou, Anhui, 234000, China, b School of Information Engineering, Suzhou University, Suzhou, Anhui, 234000, China.Background: Emotional regulation refers to a psychological process in which individuals change the intensity, quality, and duration of emotions through self-regulation in an environment that stimulates emotions. Emotional regulation is closely related to nonverbal communication, as nonverbal communication is often the main way to express emotions. In nonverbal communication, individuals can convey their emotional state by adjusting their own facial expressions, gestures, and sounds, while also interpreting others\u2019 nonverbal signals to obtain information and infer others\u2019 emotional state. Both verbal and nonverbal communications are involved in the teaching and learning activities. Verbal behavior is the main channel through which teachers impart knowledge to students, while nonverbal behavior is the main channel through which teachers convey their emotions, simplify teaching instructions, activate the student\u2019s learning interest and enhance teaching effectiveness.Subjects and Methods: This paper reviewed the findings of twenty recently related research inside and outside Chinese contexts and discussed how they converged or diverged in their achieved results about this concept of nonverbal communication in pre covid and post covid era. This paper also included the way it has been defined, practiced, and evaluated considering various variables that interact and affect nonverbal communication.Results: The changes in emotional regulation and nonverbal communication pre covid and post covid are mainly reflected in the attitudes of positive expression, negative emotions and moderate expression. There are close links between the nonverbal signals and the emotional expressions, and the intention of the sender of the information can be revealed frequently from non-verbal cues. Both students and teachers can benefit from practicing nonverbal communication skills.Conclusions: The changes in emotional regulation in nonverbal communication before and after the epidemic reflect people\u2019s psychological state and coping strategies in the epidemic environment. In nonverbal communication, people can communicate and obtain information by adjusting their emotions, and they can also infer the emotional state of others by interpreting their nonverbal signals. This paper maintains how students\u2019 attention, initiative and participation beside other psychological mechanisms in education can be influenced and how to focus on emotional regulation and nonverbal communication strategies to promote both students and teachers\u2019 emotional health. Effective non-verbal communication skills have a positive effect on both teaching and learning. This paper is beneficial to teacher trainers to enhance the effectiveness of college English teaching.This work was supported by a project grant from Anhui Provincial Department of Education, (Grant No. 2020jyxm2196) and a project grant from Anhui University Humanities and Social Sciences Research Project (Grant No. SK2021A0714).a, Xiao Tanb, Siyang Yub, Xilong QubZhecong Wanga Software Academy, Changsha Commerce & Tourism College, Changsha, Hunan 410116, China, b School of Information Technology & Management, Hunan University of Finance and Economics, Changsha, Hunan 410205, China.Background: Environmental monitoring plays a crucial role in medical facilities, impacting patient outcomes and staff safety. Manual monitoring methods are time-consuming and prone to errors. However, with advancements in sensor technology, ZigBee communication protocols, and mobile devices, intelligent environmental monitoring systems offer efficient and accurate real-time monitoring. In hospitals, monitoring temperature, humidity, air quality, and other environmental factors is essential for maintaining a sterile and safe environment for both patients and healthcare providers. Traditional manual detection and recording methods are labor-intensive and error prone. Intelligent environmental monitoring systems, on the other hand, offer several benefits that can enhance the quality of care in medical facilities.Subjects and Methods: Wireless communication between sensing devices, using ZigBee technology, and a central monitoring system allows easy deployment and scalability. Sensing devices placed throughout the hospital monitor critical areas such as operating rooms, patient rooms, and laboratories. The data collected from these sensors transmits quickly to the central monitoring system, alerting healthcare providers if there are any deviations from the desired environmental conditions. The integration of mobile devices such as smartphones or tablets enables remote access to the monitoring system, facilitating real-time monitoring of different areas of the hospital. Healthcare providers can monitor environmental conditions, even when they are not physically present in the hospital, ensuring timely intervention if required.Results: Moreover, intelligent environmental monitoring systems have expanded beyond temperature and humidity control. They can also monitor gas levels, radiation, and dust particles to ensure a safe environment for patients and healthcare providers. Additionally, they can monitor power consumption, contributing to energy-efficient management in medical facilities. Considering the complex environment of hospital storage, we attach the monitoring system to a mobile tool (such as a mobile car), which can make the detection method of the entire system more flexible, with a wider detection radius, and enable the system to be used for temperature and humidity monitoring in these diverse environments.Conclusions: When ZigBee technology, sensing technology, and mobile devices are combined to form a temperature and humidity monitoring system, it has the advantages of low cost, rapid installation, and high availability compared to common solutions in the industry. As technology continues to advance, further research and development in environmental monitoring systems will lead to more effective applications in modern medical treatment.This research was supported by Scientific Research Key Project of Hunan Education Department[21A0592], Education Reform Project of Hunan Province[HNJG-2021-1378], Hunan Natural Science Foundation Project (2023)[Research on Resource Scheduling Strategy for Energy Efficiency Optimization in Mobile Cloud Computing].aQiang Zhoua School of Finance and Economics Management, Sichuan University of Arts and Sciences, Dazhou, 635002, China.Background: In the implementation process of the rural revitalization strategy in the Sichuan Shaanxi Revolutionary Old Area, due to the relative uncertainty of policy responses from multiple parties, this article takes the alleviation of psychological anxiety in the process of changing the livelihood of farmers in the revolutionary old area during the government governance process as one of the research subjects. In analyzing the effectiveness of the rural revitalization strategy with the participation of social capital, the strategic evolution game between the government, social capital, and farmers is taken as the research goal, Defining farmers in old areas as units that examine the effectiveness of social capital and government policies is in line with the implementation units and fields of the current rural revitalization strategy. Reflect the stability, continuity, and balance of interests of all parties in the long-term dynamic strategy process.Subjects and Methods: Evolutionary game theory was used to study the dynamic process of governance, select a mechanism with dynamic incentive factors, and combine the social capital participation in the process of rural revitalization with the measures taken by villagers to alleviate life anxiety and psychological counseling in the process of rural revitalization, reflecting the relative stability and long-term nature of the government decision-making process and the process of people\u2019s livelihood.Result: As the government actively promotes rural revitalization and the development of red tourism resources in revolutionary old areas, and improves the effectiveness of incentive subsidies, the probability of social capital and farmers choosing cooperation strategies in the short term increases. However, due to the long-term existence of subsidies, incentive subsidy policies can only stimulate cooperation between the two in a short period of time. In addition, with the increase in subsidy amounts, the convergence speed actively promoted by the government due to incentive subsidy expenditures has also slowed down. Similarly, numerical simulations can simulate the impact of punishment costs on the level of psychological anxiety during changes in social capital, farmer behavior, and livelihood status. Overall, in regulating non cooperative behavior between social capital and farmers, the increase in punishment costs is more effective than incentives, and all three are more sensitive to incentive returns. Thus, in the process of promoting rural revitalization policies, the anxiety state of farmers\u2019 livelihood changes caused by policy promotion has been effectively improved.Conclusion: The stability of the evolutionary game model established at the governance level of rural revitalization strategy will directly have a significant impact on the implementation of rural revitalization policies. And it plays a certain helping role in improving the livelihood status of regional farmers and alleviating psychological anxiety. Therefore, this article has certain theoretical innovation significance and practical value. The countermeasures derived from the tripartite evolutionary game model have certain guiding significance for policy and theoretical decision-making departments.a, Zitong Suna, Xiwen Xua, Ling Sub, Yuting Lia, Xiuran Wanga, Wei HuaMei Yanga College of Life Sciences, Jilin Agricultural University, Changchun, Jilin 130118, China, b Engineering Research Center of Edible and Medicinal Fungi Ministry of Education, Jilin Agricultural University, Changchun, Jilin 130118, ChinaObjective: enzymatic hydrolysis peptide of antler plate is an ossified substance formed in the spring of the second year after deer antler is cut off or sawed. Modern pharmacological research shows that anlter plate has many pharmacological activities. Protein and peptides account for about 40% of the total components of antler plate. They are rich in amino acids, including essential amino acids. According to the content and types of amino acids, it is speculated that the bioactive protein or polypeptide contained in the enzymatic hydrolysis peptide of antler plate of sika deer-red deer hybrid deer has immune activity. The active peptide is a protein peptide segment with biological function after protein is hydrolyzed by protease. The peptide segment not only has certain biological activity, but also retains its original biological activity.Patients and Methods: In this study, the enzymatic hydrolysis peptide of antler plate of sika deer-red deer hybrid was used as raw material. The enzymatic hydrolysis peptide of enzymatic hydrolysis peptide of antler plate was obtained by enzymatic hydrolysis technology, and the immune activity of the enzymatic hydrolysis peptide was evaluated by its influence on the immune function of mice. Firstly, the total protein was extracted from the enzymatic hydrolysis peptide of antler plate of sika deer-red deer hybrid deer by alkali extraction and acid precipitation, and the effects of several common proteases  on the total proteolytic efficiency and immune activity of enzymatic hydrolysis peptide of antler plate were investigated, so as to obtain the enzymatic hydrolysis peptides with the best immune activity. The gastric administration doses of enzymatic hydrolysis peptides of mice in each group were 100\u2005mg/kg in low dose, 200\u2005mg/kg in medium dose and 400\u2005mg/kg in high dose respectively for 14 days. Then cyclophosphamide was used to induce mice to establish immunosuppressed mouse model. Finally, the changes of body weight, immune organ index, proliferation ability of mouse spleen lymphocytes and phagocytic activity of peritoneal macrophages were detected, and the changes of cytokine and immunoglobulin expression levels in serum were detected by ELISA sandwich method.Results: The Results showed that the proliferation ability of RAW264.7 macrophages treated with trypsin was the best, so trypsin was selected to hydrolyze the total protein of anlter plate. The enzymatic hydrolysis conditions were as follows: temperature 40\u2103, time 3h, E/S 3%, pH 7 and enzyme dosage 3000\u2005U/g. The immune activity experiment showed that compared with the model group, the experimental group could significantly increase the weight of mice, improve the index of immune organs, enhance the proliferation of spleen lymphocytes and the phagocytosis of peritoneal macrophages, and also improve the expression levels of serum cytokines  and immunoglobulins .Conclusions: enzymatic hydrolysis peptide of antler plate has obvious immunoregulation effect on immunosuppressed mice, and effectively improves the suppressed humoral immune function of mice.This study was supported by Jilin Science and Technology Development Plan Project (Nos.20200404024YY), and Special Fund Project for Provincial Industrial Innovation in Jilin Province (Nos. 2018C048-4).a, Guoxia Hub, Shuling HecSuitai Suna College of Art of Guangxi Minzu Normal University, Chongzuo, Guangxi 532200, China, b College of Marxism of Guangxi Minzu Normal University, Chongzuo, Guangxi 532200, China, c Institute of Applied Technology of Honghe University, Honghe, Yunan 661199, China.Purpose: College students\u2019 mental health, aesthetic taste and aesthetic ability have been deeply concerned by all social strata in recent years. Therefore, the ultimate purpose of this study is to explore the necessity of carrying out aesthetic education in universities to alleviate college students\u2019 mental health problems and cultivate aesthetic values.Methods: By means of questionnaire survey and interview, the necessity of aesthetic education in alleviating the mental health problems and cultivating aesthetic values of college students of different majors, grades, genders and sources were investigated and analyzed.Results: The mental health index of male students and female students before and after aesthetic education from freshman to senior year were significantly different. The mental health indexes after aesthetic education were 97%, 94%, 90% and 86%, respectively, and the decline trend was slow. Science, engineering and sports students mostly considered beauty to be natural beauty, while music and art students, on the other hand, considered beauty to be exotic dresses or a fashion trend. The proportion of freshmen who considered beauty is natural beauty was the highest 85%, the proportion of junior college students who think beauty is fashion trend and exotic clothes is the same as that of sophomore college students, accounting for 56%. The proportion of male students and female students in the fourth grade of university who thought beauty as natural beauty was 32%, 31% respectively. The proportion of freshmen who considered beauty is natural beauty is the highest at 42%, the proportion of urban sophomores who prefer fashion trends is the highest at 44%, the proportion of urban juniors who think beauty is fashion trends is the highest at 48%, and the proportion of urban seniors who think beauty is physical beauty is the highest at 32%. Among parents of college students from different walks of life, 70.84% of the parents of farmers and 50.58% of the parents of workers think that college education is the main front and effective way to cultivate college students\u2019 aesthetic education. Teachers of different subjects in colleges and universities think that the average values of aesthetic education in colleges and universities are respectively 55.4%, 26.0%, 12.3% and 6.4%. Students of different grades participate in different activities in different numbers, types and ways. According to the average number of college students taking part in different practice channels, the number of students taking part in summer three trips to the countryside accounted for 18% at most, and the number of students visiting red bases accounted for 13.5% at least.Conclusion: It is necessary to carry out aesthetic education in colleges and universities to alleviate college students\u2019 psychological health and cultivate aesthetic values.This is the Class B Project of Undergraduate Teaching Reform Project of Guangxi Higher Education in 2021 \u201cThe Construction and Teaching Research of Red Resources in Left and right river area Region into the Courses of Art Major in Local Colleges and Universities\u201d (Project No.: 2021JGB378); 2022 School-level Curriculum Ideological and Political Teaching Team of Guangxi Normal University for Nationalities \u201cInheriting Classics: Ideological and Political Teaching Team of Chinese Painting Course\u201d (Project No.: KCSZJXTD202204); 2022 School-level Curriculum Ideological and Political Demonstration Course of Guangxi Normal University for Nationalities \u201cCreation of Chinese Landscape Painting\u201d (Project No.: KCSZSFKC202207) Phased results. The completion of this thesis is inseparable from the valuable suggestions and suggestions put forward by your colleagues. Thank you again for giving me a lot of encouragement and help. Recall the whole writing process of the thesis, although it is not easy, but let me get rid of impetuous, a lot of gains.a, Lili TangaAihui Jina Zhuhai College of Science and Technology, Zhuhai 519041, China.Background: Chinese culture, since ancient times, has been instrumental in nurturing the refinement, cognitive skills, and ethical virtues necessary for building and maintaining a healthy society, thus serving as the \u201cidentity card\u201d and spiritual glue of the nation. With the advancement and progress of society, propelled by modern science and technology, and the ongoing process of economic globalization, new cultural elements have emerged. These include network culture, information culture, competition culture, and leisure culture, which are increasingly diverse and prominent. In the current cultural milieu, university students not only engage in knowledge acquisition but are also exposed to a diverse range of cultures that affect their values, which may give rise to various psychological and cognitive issues. The psychological and value-oriented issues among university students caused by cultural problems have prompted widespread attention.Subjects and Methods: Private universities, as an essential constituent of universities, share a responsibility for imparting the core socialist values, promoting the excellent traditions of Chinese culture, guiding students\u2019 healthy psychological development and assume significant influence on education.Results: Exploring the convergence between ideological and political education and Liberal Arts Education in the context of contemporary healthy psychological culture can establish students\u2019 accurate worldview, life philosophy, and values, which can help in enhancing their overall psychological well-being.Conclusions: The significance of cultural psychology in achieving cultural inheritance, resisting the invasion of decadent culture, and establishing student beliefs is instrumental, especially in the context of cultural integration. Therefore, in the education and teaching of private universities, schools must prioritize a healthy psychological and cultural perspective and pay attention to the role of cultural psychology in the integration of Liberal Arts Education and ideological and political theory courses. This will enable schools to exploit their specific educational advantages, which will foster better development and progress of students in private universities.Supported by the 2020 research project of the \u201cThirteenth Five-Year Plan\u201d for Guangdong Province\u2019s Education Science / Office of the Leading Group for Guangdong Education Science Planning: \u201cIn-depth Research on the Integrated Development of Liberal Arts Education and Ideological and Political Education in Private Universities from the Perspective of Cultural Power\u201d. (Project No.: 2020JKDY056).aFuhong Guoa City Institute, Dalian University of Technology, Dalian 116600, China.Background: Consumer psychological anxiety is a negative emotion that occurs when there is a BTM cost in the P2P leasing market, resulting in a decrease in total consumer surplus. When perceived threats or risks of the elasticity suppliers and renters exceed their personal control, it leads to negative emotions such as unease, tension, and distress, resulting in psychological anxiety for both elasticity suppliers and renters. This is manifested as the concern for the new elasticity suppliers whether they should continue to rent out their unused products and the concern of renters whether they should rent products in the P2P leasing market. Although theoretically elastic suppliers can rent out their unused assets for free in the P2P rental market, in practice, there is at least some cost associated with providing a rentable product. The rise of the \u201csharing economy\u201d has been driven by a significant reduction in these costs, and the P2P rental market has brought an increase in consumer surplus and social welfare. However, in the long run, the cost of entering the market, or the BTM cost, has reduced the total consumer surplus in the P2P rental market. This paper analyzes the mechanism through which BTM costs affect consumer surplus in the P2P rental market and finds that they reduce the total consumer surplus, leading to a decrease in profits for elastic suppliers and renters, and causing them psychological anxiety about whether to exit the P2P rental market. Based on this, the paper proposes recommendations for reducing consumer anxiety and promoting the operation and development of the P2P rental market.Subjects and Methods: Firstly, this paper reviews the literature on P2P rental market, BTM costs and consumer psychological anxiety. Secondly, this paper compares short-term consumer surplus between the existence and absence of BTM costs in P2P rental market and draws conclusions. Thirdly, when BTM costs exist, this paper compares long-term and short-term consumer surplus in P2P rental market and draws relevant conclusions. The last part is the conclusion and inspiration of this paper.Results: This paper concludes through the comparative analysis of short-term and long-term consumer surplus in P2P rental market with and without BTM costs: BTM costs reduce total consumer surplus in P2P rental market and cause psychological anxiety for elastic suppliers and renters. Short-term consumer surplus is higher than long-term consumer surplus, and even when long-term consumer surplus reaches the lowest point, psychological anxiety for elastic suppliers and renters reaches its highest point, which leads to their unwillingness to participate in P2P rental market.Conclusions: Based on the analysis results, P2P rental platforms should reduce BTM costs, as much as possible in the long term. This can increase the income of elastic suppliers and renters, thereby reducing the psychological anxiety of both parties and lower psychological anxiety for elastic suppliers and attract more elastic suppliers who can offer more idle products in P2P rental market. There are two main ways to reduce BTM costs: one is for P2P rental platforms to find renters and achieve the best match between elastic suppliers and renters, while monitoring the entire process of product rental use, protecting the rights and interests of elastic suppliers, and reducing their psychological anxiety. The other is to achieve economies of scale and scope in P2P rental market, which can reduce unit cost for elastic suppliers and rental price for renters, and lower their psychological anxiety, thus increasing the willingness of elastic suppliers and renters to participate in P2P rental market.This work was supported by a project grant from the Funding Project for Teaching and Research of Liaoning Provincial Department of Education. (Grant No. LJKR0679) and Project funded by the Liaoning Provincial Social Science Fund (Grant No. L18BJY014).a, Jingyun Yub, Zhaoru Zhoub, Haotian Wangb, Shuo Hana, Hao Suna, Zhipeng Zhaoa, Pengda SunaSitong Zhoua Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun, Jilin, China, b The School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin, China.SZ and JY contributed equally to this work.Background: Increasing incidence of colon cancer, the role of Scutellaria barbata polysaccharides (SBP) in tumors has drawn widespread attention. In order to further investigate its mechanism of action in the treatment of colon cancer, this paper try to use network pharmacology approaches to predict its possible mechanism of action.Methods: The literature was reviewed to understand the active components of SBP; the Swisstarget database was used to obtain the potential targets of the active components of SBP; the GeneCards and DisGeNET databases were used to screen the disease-related targets of colon cancer, set the relevant parameters and summarize the disease targets, and finally the intersection of the potential targets of SBP and the disease targets was taken to plot the Venn. The STRING database was used to construct the target protein interaction (PPI) network to obtain the core target proteins; gene ontology (GO) analysis and Kyoto Encyclopedia of Genomes (KEGG) pathway enrichment analysis were performed on the potential genes, and the key signaling pathways of SBP in colon cancer were obtained by using the DAVID6. 8 online tool.Results: The results showed 12 monosaccharide components were obtained from some magazines and journals, such as Rhamnose, Fucose, Arabinose, Xylose and Mannose etal. The Swisstarget database records 23 potential targets of Scutellaria barbata polysaccharides (SBP), and there are 1391 colon cancer disease targets, which were summarized from two databases, GeneCards and DisGeNET. There were 8 intersecting targets of Scutellaria barbata polysaccharides and colon cancer, namely VEGFA, HSP90AA1, LGALS3, FGF2, CDK1, HPSE, LGALS4, and FOLH1. Enrichment analysis showed that MAPK signaling pathway, PI3K-Akt signaling pathway, and HIF-1 signaling pathway were the main affected pathways. We predict that the process of colon carcinogenesis may be regulated by acting on intersectional targets as well as signaling pathways to alleviate disease symptoms.Conclusions: Scutellaria barbata polysaccharides is a kind of polysaccharide formed by the compound of many monosaccharides. It can exert the mechanism of action for the treatment of colon cancer through multiple components with multiple targets and pathways.This work was supported by project grants from Natural Science Foundation of Jilin Province (Grant No.20200201014JC) and Finance Department Health Special Project of Jilin Province (Grant No. 3D5204921429).a, Zhiyao LiaXutao Zhenga China University of Mining and Technology (Beijing), Beijing 100083, China.Background: To investigate the dissemination effects and audience attitudes towards various types of epidemic prevention slogans, with the aim of better safeguarding the positive emotions of the public during public health emergencies.Subjects and Methods: In this study, the linguistic styles of epidemic prevention slogans were divided into serious, friendly, rude and other categories, and 831 epidemic prevention slogans were quantitatively analyzed. At the same time, 55 people were interviewed to study the influence of different linguistic styles of slogans on the attitudes of the audience. In particular, this paper focuses on the impact of rude slogans on the mood of the audience.Results: The study found that there were significant differences in linguistic styles among epidemic prevention slogans released in urban and rural areas, as well as those released by different regions or publishers. Even in the early stages of the pandemic, rude slogans were not the majority among epidemic prevention slogans. The center region has a larger percentage of crude slogans as compared to other areas. Villages have a larger percentage of crude slogans than towns do. The township (subdistrict office), public organizations, and village (neighborhood) committees are more likely to print rude and friendly slogans as compared to other levels of public management organizations. The severity of the pandemic, the publisher\u2019s understanding of the target audience, the publisher\u2019s role in epidemic prevention, and legal awareness were all factors that affected the content of the slogans. Different audience attitudes were observed towards various linguistic styles of the slogans. Slogans that can bring positive feelings to the audience are more likely to be observed by the audience. Serious and friendly slogans were more likely to receive positive evaluations and compliance. Although rude slogans could elicit some degree of compliance, they were not easily accepted by the audience and may even prompt negative emotions such as resistance, dissatisfaction, anger, fear, and other adverse responses. The reasons why rude style slogans are followed by some people may be related to the potential punishment of the publisher, the authority of public management organizations and the warning effect of such slogans.Conclusion: In terms of the dissemination effects of epidemic prevention slogans, public managers and researchers should not only focus on whether the public is complying with the epidemic prevention policies and following the requirements of the slogans, but also pay attention to the impact of epidemic prevention slogans on public emotions and psychology. During public health emergencies, public managers must pay close attention to emotional management, respect the emotions of audience, protect citizen privacy, and use more friendly slogans rather than crude ones.a, Wenjing DuanaXia Taoa Wuhan Institute of Technology, School of Marxism, Wuhan 430200, China.Background: The youth of today are the backbone of social development and the leaders of the progress of the times. In the context of the new era, the key to achieving comprehensive rural revitalization lies in education, and the key to education development lies in teachers, especially young teachers. Through research and studies, it is found that the phenomenon of rural young teachers\u2019 attrition is obvious, and teachers\u2019 mental health problems are prominent, especially young teachers in rural areas with lower economic development levels have relatively high psychological anxiety index. Therefore, it is urgent to provide high-quality education services in rural areas, strive to build an excellent teaching force, further narrow the gap between urban and rural education, alleviate teachers\u2019 psychological anxiety, and stabilize the development of rural basic education.Subjects and Methods: For rural schools in province H with different levels of economic development, 16 rural young teachers who joined in 2015 and had leaving experiences were selected through a targeted sampling method, and the texts of the interviewees were coded and analyzed using the rooted theory research method, and after open coding, spindle coding, and selective coding, a theoretical model was constructed for the influencing factors of rural young teachers\u2019 attrition and their psychological anxiety.Results: Through the analysis of the rooted theory research method, the four highest dimensional categories were finally summarized and concluded that the factors affecting rural young teachers\u2019 attrition and their psychological anxiety are mainly school factors, parental factors, social factors, and personal factors, and specific contents were collated in each factor, containing a total of 14 aspects.Conclusions: Based on the current situation of rural young teachers\u2019 attrition and their psychological anxiety, this study endeavors to improve teachers\u2019 psychological quality, enhance their sense of belonging and happiness at work, and devote themselves to education with full motivation from the perspective of paying attention to teachers\u2019 psychological health. Based on this, reducing rural young teachers\u2019 attrition rate and alleviating teachers\u2019 psychological anxiety are mainly based on improving school infrastructure, focusing on joint home-school education, accelerating rural economic development, and meeting career development needs, which have practical implications for the development of rural basic education.This research was supported by the open fund project of Hubei Teacher Education Research Center, a key research base of humanities and social sciences in Hubei universities in 2022, entitled \u201cResearch on the Influencing of Rural Teacher Loss and Psychological Anxiety: an Empirical Study based on Province H\u201d (Project No. jsjy202203).a, Naikao WangbLinwen Xiaoa School of Economics and Management, Nanning Normal University, Nanning, Guangxi 530001, China, b School of Journalism and Communication, Nanning Normal University, Nanning, Guangxi 530001, ChinaBackground: In traditional China, the gap between urban and rural areas is large, so is the psychological distance between urban and rural areas. There is a two-way stereotype between urban people and rural people. In the process of rapid urban-rural integration, they need to break the psychological barrier quickly. If this problem is not solved well, the social group will appear psychological sub-health state.Subjects and Methods: In recent years, China\u2019s urban-rural integration has accelerated. However, neither urban nor rural people showed any of these collective mental health problems. In order to find out how to adjust urban and rural psychological contradictions in the process of accelerated integration, the research group selected Gangwei Town, Longhai District, Zhangzhou City, Fujian Province, China, as the research object, and conducted research using the grounded theory research method.Results: The results show that: (1) In the process of urban-rural integration, the melting speed of urban-rural cultural and psychological boundary is greater than that of urban-rural material space boundary. (2) Short video plays an important role in psychological adjustment during the process of psychological boundary ablation. (3) In the creation, dissemination and consumption of short videos, urban people and rural people participate in the process of cultural production, forming a psychological adjustment mechanism of cultural communism and cultural sharing. (4) Under this psychological adjustment mechanism, the cultural boundary between urban and rural people is eliminated, and the psychological gap is crossed, and no mental health problems caused by the rapid integration of urban and rural areas appear.Conclusions: Short videos satisfy the psychological needs of mutual lookout between urban and rural areas, and content creators actively promote the cultural communization and sharing mechanism between urban and rural areas, avoiding the group mental health problems caused by the rapid integration of urban and rural areas. The Chinese government should pay full attention to the psychological adjustment role of short video and other new media in the process of urban-rural integration, guide people\u2019s new understanding, new attitude and new behavior of the new urban-rural relationship through new media, and then actively promote the rural revitalization and urban-rural development. This study is a case study, and this mechanism may be more complicated, which needs further discussion.This work was supported by a project grant from The 14th Five-Year Plan Education Project of Fujian Province, China \u201cResearch on the Training Mechanism of College Students\u2019 Short Video Content Entrepreneurial Talents\u201d(Grant No.FJKBK21-135).a,d, Yan Duana, Rubing Xiaa,d, Jinwei Lvc, Peng Zhanga, Zhizhong Shena,d, Yong Lua, Mingku Jue, Haoran Tenga, Yang HuangbHao Wua College of Humanities and Social Development, Nanjing Agricultural University, Jiangsu, Nanjing 210095, China, b School of Cultural Heritage and Information Management, Shanghai University, Shanghai 200444, China, c Institute of History, Jiangsu Academy of Social Sciences, Jiangsu, Nanjing 210004, China, d College of Agricultural Civilization, Grand Canal Cultural Belt Construction Research Institute, Jiangsu, Nanjing 210004 China, e School of History and Culture, Henan Normal University, Henan, Xinxiang, 453007, China.Background: The dietetic culture heritage of the Jiangsu section of the Grand Canal has a very important impact on people\u2019s physical and mental health. Diet is based on agriculture. In terms of traditional Chinese social form, China has always been an agricultural society. Agriculture is the main production sector of society, providing food services to the people, and the vast majority of social material wealth is provided by agriculture. Based on this natural ecological environment, the regional dietetic culture of the people in the Jiangsu section of the Grand Canal has been integrated into the cultural mechanisms of different cities in Jiangsu, with unique cultural symbolic significance and emotional memory. The resulting customs and habits show the local people\u2019s understanding of the nature of food. Along the Grand Canal, people\u2019s preferences for food taste, food material types and even cooking skills express the residents\u2019 preferences for food mental health, and the resulting ideological, emotional and economic factors, which are the living inheritors of the sustainable development of dietetic culture\u2019s dietetic culture heritage.Subjects and Methods: This paper takes the operation, service and management concepts of the inheritors of dietetic culture heritage as the research entry point, systematically combs the dietetic culture related heritage in the Intangible Cultural Heritage List of Jiangsu Province, combs the number of national level projects, interviews the inheritors of dietetic culture heritage, investigates their attitude towards the future development of dietetic culture heritage, and analyzes their psychological and external reasons for this attitude. At the same time, it combed the dietetic culture inheritance bases related to Grand Canal in Jiangsu Province, discussed the relationship between base construction and inheritance protection, and the resulting impact on the mental health of residents along the Grand Canal.Results: Through the above investigation and analysis, the development of dietetic culture heritage of Grand Canal in Jiangsu has a positive impact on the mental health of surrounding residents. We will find that a specific diet structure will produce a specific diet psychological structure, while the dietetic culture heritage of Grand Canal in Jiangsu has a long history, healthy diet, strong cultural genes, relatively perfect diet hygiene conditions and other characteristics. It is no longer just a simple satisfaction of appetite, but increasingly displays aesthetic psychological characteristics. At the same time, the dietetic culture heritage of Grand Canal in Jiangsu still has four problems: lack of strategic thinking and specific development goals, lack of talent training mechanism, imperfect support system, and unclear inheritance and protection standards. Although the existence of these problems does not have a great impact on the mental health of residents, in the long run, these problems will lead to negative effects on the dietetic culture heritage of Grand Canal in Jiangsu. In order to prevent these negative problems, this paper puts forward some suggestions, such as formulating comprehensive strategic goals, strengthening the psychological health intervention of inheritors, improving food hygiene policy support, highlighting the development of key dietetic culture heritage, strengthening academic support of universities, so that the dietetic culture heritage of Grand Canal in Jiangsu can develop healthily and orderly, and continue to adhere to the principle of the unity of truth and innovation in the process of inheritance, And incorporate the concepts of food tradition, food hygiene, and food innovation.Conclusions: The formation of dietetic culture heritage in the Jiangsu section of the Grand Canal is closely related to the mental health of residents along the Grand Canal. What to eat is not only a phenomenon, but also a psychological behavior of people, which is inseparable from the psychological factors behind it. Therefore, we adhere to the principle that the dietetic culture heritage of Grand Canal in Jiangsu should be global, national, scientific and historic. Only in this way can the dietetic culture heritage of Grand Canal in Jiangsu maintain its vitality in the new historical period, thus having a positive impact on the residents along the Grand Canal in its development process.This work was supported by a project grant from Grand Canal Cultural Belt Construction Research Institute (Jiangsu) think tank special research project \u201cResearch on Agricultural civilization resources and its Exploitation and utilization in Grand Canal\u201d (DYH19ZXA1). Nanjing Agricultural University Central University operating funds project \u201cInvestigation and research on the Diet Cultural Heritage in the Grand Canal coastal area of Jiangsu Province\u201d (SKYC2020008). Key project of Sichuan Cuisine Development Research Center, Philosophy and Social Science Key Research Base of Sichuan Education Department \u201dStudy on Conservation of Jiangsu Traditional Diet Cultural Heritage Resources\u201d(CC18W01)a, Ziyang ZhouaJianhua Zhua School of Economics and Finance, Zhanjiang University of Science and Technology, Zhanjiang, Guangdong 524094, China.Background: to summarize the effects of psychological anxiety under the intensity of environmental regulation on foreign direct investment FDI and the technological complexity of Chinese exports, and to analyze the regularity of such effects, in order to improve the technical complexity of China\u2019s export products, we can alleviate the psychological anxiety caused by environmental regulation, improve the psychological expectation of FDI, optimize the psychological account and investment portfolio.Subjects and Methods: Based on Chinese provincial panel data from 2010 to 2019, the GMM model was used to examine the relationship between export technology complexity, foreign direct investment anxiety and environmental regulation intensity, the degree of psychological anxiety was quantified by the size of the foreign direct investment, and the panel threshold model was used to examine the relationship between the export technological complexity and the foreign direct investment under different environmental regulatory intensities, and the foreign direct investment characteristics of export technological complexity and the variation of psychological anxiety under different environmental regulatory intensities.Results: (1)environmental regulation had a significant positive effect on the psychological anxiety of FDI. Different environmental control intensity will lead to \u201cPollution halo\u201d and \u201cPollution shelter\u201d, but it will not change the psychological goal and investment direction of FDI. (2) there is a U-shaped relationship between environmental regulation and the increasing complexity of export technology. The increased complexity of exporting technology depends on the sum of the \u201cCost-offsetting\u201d and \u201cInnovation-offsetting\u201d effects, as well as the degree of psychological anxiety of the foreign direct investment. (3)the psychological anxiety of the foreign direct investment has a significant effect on the increase of export technological complexity. With the increase of environmental regulation, the complexity of FDI and export technology shows the \u201cN\u201d-type double threshold characteristics affected by investment psychological anxiety. (4) while foreign direct investment are affected by the psychological anxieties arising from the strengthening of environmental regulations, and the complexity of exporting technologies is indirectly affected through the effective interaction of environmental regulations, the intensity of environmental regulations must be moderate, can only play a catalytic role in a certain range.Conclusions: under the background of strengthening environmental supervision, the psychological anxiety of FDI will increase, and it will affect the technological complexity of export products, moreover, there is a significant positive effect between the intensity of environmental regulation, the degree of psychological anxiety of FDI and the technological complexity of export products, it is necessary to stabilize investment expectations for FDI, to control foreign direct investment anxiety and to increase the technological complexity of Chinese exports.The authors acknowledge support from Major Program of National Social Science Foundation of China [19XMZ089].a,b, Yi Wangc, Youyang Youd, Yufei Hed, Yangyu Oud, Qiuyue ZoudDonghua Zhanga School of Economics, Yunnan University of Finance and Economics, Kunming 650221, China, b School of Economics and Management, Dali University, Dali, 671003, China, c School of Logistics and Management Engineering, Yunnan University of Finance and Economics, Kunming 650221, China, d International Business School, Yunnan University of Finance and Economics, Kunming 650221, China.Background: As an important part of our life, happiness has become an important indicator to measure a person\u2019s quality of life, which helps to enhance personal and physical health, increase social stability, and promote personal and social development. People with high levels of well-being tend to be more able to experience positive emotions, such as optimism, self-confidence, satisfaction, happiness, etc., and are also more likely to cope with negative emotions and stress in life. Mental health can improve the quality of life and happiness of individuals, promote physical health, and also contribute to social stability and development. Among the many factors that affect residents\u2019 sense of well-being and happiness index, the impact of urban innovation level cannot be ignored. As a key path to improve the city\u2019s happiness index and residents\u2019 sense of well-being, technological progress has become a hot spot in academic research.Subjects and Methods: This paper takes the Yangtze River Delta urban agglomeration as the research object, and explores the innovation efficiency of the Yangtze River Delta urban agglomeration and its influencing factors by constructing a three-stage DEA model and a K-means cluster analysis model. The advantages of using the three-stage DEA model to measure the innovation efficiency of the Yangtze River Delta urban agglomeration lie in the following aspects: First, the weights of input variables and output variables are generated by mathematical models through data, and do not need to be set in advance, which reduces the error of subjective weight setting; The second and third stages of DEA eliminate the influence of environmental variables and random noise in the second stage, making the results more accurate. K-means clustering further expands the research of this paper.Results: The research found that: (1) After excluding environmental factors and random factors, the innovation efficiency of cities in the Yangtze River Delta urban agglomeration has been significantly improved; (2) Urban innovation efficiency is affected by the level of economic development, the degree of advanced industrial structure, government support, and the intensity of innovative human capital. (3) The innovation efficiency level of the Yangtze River Delta urban agglomeration can be roughly divided into innovation lagging type, innovation development type and innovation leading type.Conclusions: This study has important guiding significance for improving the innovation efficiency of urban agglomerations and enhancing the mental health and happiness of residents.a, Songyan ZhangaYijie Tanga School of Economics and Management, Zhejiang University of Science and Technology, Hangzhou, Zhejiang 310000, China.Background: Healthy mental state needs to be based on good material conditions. The economic level and material conditions in rural areas are lower than those in urban areas, which may lead to adverse development of rural household mental health. As one of the important factors to promote regional economic development, financial model can affect the mental health of farmers by changing material conditions. Therefore, the innovation and development level of financial model deserve high attention. At present, there are some financial problems such as brain drain, low financing demand, few mortgage loans, poor infrastructure, imperfect credit investigation system and diversified demand in the process of rural revitalization in Zhejiang Province. In rural areas with low economic level, there are some mental health problems such as spiritual poverty, lack of confidence, lack of motivation for poverty alleviation and incorrect concept of development. This paper aims to study the operation mechanism of innovative financial model in rural areas of Zhejiang Province and its impact on farmers\u2019 mental health, and put forward relevant suggestions for promoting rural revitalization, sustainable development of agricultural health and cultivation of farmers\u2019 mental health in Zhejiang Province.Subjects and Methods: The innovative financial model in rural areas of Zhejiang Province is selected as the research object. First, look up and read a large number of case materials, and have an in-depth understanding of the rural revitalization strategy, the concept of financial model, the situation of rural revitalization in Zhejiang Province and the mental health status of rural households. Second, the paper investigates the innovative financial models generated in the process of rural revitalization in Zhejiang Province and makes a preliminary analysis. Third, select influential and representative innovation models such as \u201cinsurance + futures\u201d model, supply chain finance model, \u201cclean energy + green building\u201d model as the main research object. This paper analyzes how different financial models support rural revitalization and affect the mental health status of farmers, and obtains the operating mechanism, key content and main impact from actual cases.Results: The three innovative financial models have a good effect on the development of financial level in rural areas, effectively solve the financial problems and farmers\u2019 mental health problems in rural areas of Zhejiang Province, and significantly improve the economic level, material conditions and farmers\u2019 mental health degree in rural areas.Conclusions: \u201cInsurance + futures\u201d mode can affect the psychology of farmers and promote the development of their mental health by improving their material conditions. Supply chain finance model plays a significant role in solving the psychological poverty problem of farmers. The model of \u201cclean energy + green building\u201d can promote farmers to shape the concept of sustainable development and form healthy psychology.This research was supported by a project grant from National College Student Innovation and Entrepreneurship Training Program.a,b, Qing ZhangcWenjun Zhanga School of Marxism, Chongqing Technology and Business University, Chongqing, China, b People\u2019s Government of Oitak Town, Aketao County, Xinjiang, China, c Primary School of Xinli Town, Zhongxian County,Chongqing, China.Background: This paper aims to investigate the current situation and influencing factors of Chinese college students\u2019 psychological Sense of Gain in the process of Ideological and Theoretical Courses, so as to provide reference for the implementation of curriculum teaching reform for China and other countries.Subjects and Methods: This paper uses the \u201csurvey method\u201d to conduct the relevant research, and uses SPSS software to sort out the questionnaire data, and adopted descriptive statistics and correlation analysis to carry out empirical analysis of the status quo and influencing factors of the Sense of Gain of more than 800 Chinese college students.Results: From the investigation, the psychological Sense of Gain of Chinese college students from Ideological and Theoretical Courses is between \u201caverage\u201d and \u201crelatively strong\u201d, which is not strong enough. From the viewpoint of the factors influencing students\u2019 learning psychology in the Ideological and Theoretical Courses, the \u201cSense of Gain\u201d is mainly influenced by the learning psychological stress and learning participation, and the teaching objectives, contents and methods, teachers\u2019 emotional care and affinity also has a relatively influence. Moreover, the students\u2019 learning environment also has some influence on learning psychology in Ideological and Theoretical Courses.Conclusions: In view of the current situation of college students\u2019 psychological Sense of Gain in Ideological and Theoretical Courses and the existence of these influencing factors. First of all, Ideological and Theoretical Courses teachers and other course teachers need to increase the teaching affinity between teachers and students in the Ideological and Theoretical Courses, close the psychological distance between teaching and students, ease students\u2019 negative emotion. Second, teachers need consider the learning psychology needs of college students when formulating the objectives, content and methods, reduce students\u2019 psychological stress of learning. Third, teachers need give college students enough emotional care in the course to create a heart warming study environment, so that to inspire college students\u2019 produce positive learning motivation, so as to stabilize their will to learn. Those methods could promote the \u201cemotional resonance\u201d and \u201cpsychological integration\u201d between teachers and students, making college students feel the positive emotional and psychological impact in course. Moreover, it isn\u2019t only helps college student continuously increase the knowledge in the learning process,but also achieves the purpose of further enhancing college students\u2019 psychological Sense of Gain in Ideological and Theoretical Courses.a,b, Haijian HucChang Yua School of Music, Guangdong Polytechnic Normal University, Guangzhou 510665, Guangdong, China, b School of Education, City University of Macau, Macau 999078, China, c School of Marxism, Guangdong Polytechnic of Science and Technology, Zhuhai 510640, Guangdong, China.Background: Dance education in China has experienced new development since the turn of the century, and the evaluation of the effectiveness of dance teaching in colleges and universities has expanded after the \u201cOverall Plan for Deepening Educational Evaluation Reform in the New Era\u201d was issued by the State Council. During the process of teaching dance, it is essential to effectively understand students\u2019 psychological response to dance and the positive psychological effects of learning dance. It is important to cultivate self-awareness, self-control, self-efficacy, and adaptive thinking in students, which will help them handle challenges and stress in learning, achieve higher quality learning outcomes, and increase satisfaction with their dance education. Such psychological qualities are also integral to the development of a student\u2019s dance performance, and can greatly enhance the effectiveness of dance teaching.Subjects and Methods: Based on the theory of the 21st Century 5C Key Competencies Model and the maturity scale of domestic classroom teaching effectiveness, starting in2020 this study adapted and verified the 5C key competencies and dance teaching effectiveness scale specifically for college dance majors. Descriptive, correlation, and regression analyses were used to analyze 634 valid questionnaires from Guangdong universities and explore the correlation between 5C key competencies and the effectiveness of dance teaching in universities. Thus, this study explores the path from the 5C key competencies to dance psychology to ensure the teaching effectiveness of \u201cHeart-Dance in Harmony.\u201dResults: The results of data analysis showed a significant correlation between the 5C key competencies and the effectiveness of dance teaching in colleges; the 5C key competencies had predictive power for the effectiveness of college dance teaching.Conclusions: Dance education has a positive impact on reducing students\u2019 stress and negative emotions from multiple aspects. In dance teaching, students can cultivate their understanding and appreciation of culture, which helps them feel a sense of self-identity and belonging in dance while enhancing their cultural confidence. Improving critical thinking skills can reduce loneliness and self-doubt, enabling students to face challenges and stress more confidently. Developing innovative skills can enhance students\u2019 dance thinking ability and creative ability, increase self-efficacy and belief. In collective teaching and training, effective communication and cooperation can build stronger and healthier interpersonal relationships, fostering students\u2019 cooperation spirit, trust, sharing, and sense of responsibility. the 5C key competencies are bestowed upon educational and psychological research, enabling students to deal with stress, alleviate pressure, and promote their mental and physical health more effectively. This study aimed to explore the effectiveness of university dance education in light of the 5C key competencies. It adhered to the principles of combining scientificity and practicality in education, focusing on positive psychological effects. In this modern age, university educators must encourage the physical and mental development of their students in line with the 5C standards while also possessing the 5C key competencies themselves. Through focused efforts, they can enhance the reach, depth, and orientation of dance instruction within university classrooms. A key aspect of this endeavor is the exploration of individual potential and strengths. This involves honing the creativity, communication, cooperation, critical thinking, and cultural awareness of students to aid in their attainment of success and personal fulfillment.This work was supported by a project grant from 2022 Annual Project of the \u201c14th Five-Year Plan\u201d for the Development of Philosophy and Social Sciences in Guangzhou; \u201cResearch on developing Guangzhou as a model city for educational reform and development in the Guangdong-Hong Kong-Macao Greater Bay Area: from the perspective of aesthetic education empowering a humanistic Bay Area development\u201d (Project grant No.2022GZGJ289).a, Qiong WangaAizhong Wanga College of Tourism, Chongqing University of Arts and Sciences, Chongqing 402160, China.Background: Under the background of all-for-one tourism, the integration of fruit tourism is becoming an important driving force for the development of rural tourism. This paper studies the consumer psychological needs and consumption behavior of rural tourism consumers in Wulong District, Chongqing municipality, analyzes the problems existing in the integrated development model of fruit tourism in Wulong District and the integrated development of fruit tourism in the whole district, and puts forward targeted countermeasures to provide a basis for policy formulation and long-term planning of the government and rural tourism enterprises.Subjects and Methods: Based on the theory of consumer behavior, this paper takes consumer behavior and consumer psychology research as the breakthrough, adopts the methods of stratified sampling and random sampling, divides the tourist population into existing consumers and potential consumers, selects several typical rural tourism scenic spots, important fruit production areas, leisure picking intensive areas as the research area, and investigates the demographic characteristics of tourists, the characteristics of tourists\u2019 consumption behavior, the psychological characteristics of tourists, and the development status, mode and problems of fruit tourism. A total of 1,000 questionnaires were distributed, and 988 were recovered, with a recovery rate of 98.8%, of which 926 were valid. After the survey, the data were statistically analyzed using SPSS20.0 software.Results: Relaxation, leisure and entertainment, psychological anxiety, melancholy getting rid of, emotional regulation, nostalgia, perception and show-off, personality traits, etc. have become the main motivations for people to choose fruit tourism. Among them, relaxation, leisure and entertainment are the traditional influencing factors of rural tourism development, and the importance of nostalgia, personality traits and psychological anxiety in the integration of fruit tourism is becoming more and more prominent. The survey results of tourist satisfaction show that there is a serious phenomenon of psychological homogenization and inferiority among tourists caused by the lack of fruit tourism products and projects is serious, and the lag of public service facilities, the lack of human resources, and the lack of integration mechanism aggravate tourists\u2019 sense of disappointment and psychological identity. According to the psychological characteristics and behavioral habits of tourism consumers, the integrated development model of fruit tourism in Wulong District is divided into government intervention type, collective loose type and peasant household freedom type.Conclusions: Under the background of all-for-one tourism, the consumer factors of the integrated development of fruit tourism in Wulong District should not only consider the consumption needs of traditional tourists such as relaxation and leisure, but also pay attention to psychological motivations such as psychological anxiety, depression and desolation, emotional regulation, nostalgia, personality traits and perception of show-off. Relevant parties can regulate and control by studying the actual needs of tourism consumers, tapping regional advantages and characteristics, optimizing public infrastructure construction, and building an innovative mechanism for the linkage development of fruit tourism.This work was supported by the Humanities and Social Sciences Project of the Ministry of Education\u201c Research on the Global Development Mode and Realization Mechanism of Non-Optimal Tourism District in Wuling Mountain Area under the Strategy of Rural Revitalization\u201d (19YJC630161)a, Lu Zhanga, Qichao Maoa, Miaoyu WangaXingxiang Xinga Shaoxing Central Blood Station, Shaoxing City 312000, China.Background: To understand and evaluate the detection efficacy of different testing strategies for transfusion-transmissible infections markers in blood donations, to choose appropriate testing strategies, and to effectively prevent transfusion-transmitted infections.Subjects and Methods: The detection results of transfusion-transmissible infections markers in 214,474 blood donation samples collected between 2019 and 2022 were retrospectively analyzed and compared using three testing strategies  based on relevant specifications.Results: The total nonconformity rate of blood tests under testing strategy A was 1.25%, and the nonconformity rates of ALT, HBsAg, Anti-HCV, Anti-HIV, Anti-TP, HBV-DNA, HCV-RNA, and HIV-RNA were 0.42%, 0.17%, 0.15%, 0.08%, 0.18%, 0.19%, 0.01%, and 0.01%, respectively, indicating a relatively low level of nonconformity. Among 17 confirmed HIV-infected donors, NAT detected 1 case first. The consistency rates of positive results for HBV, HCV, and HIV infection-related markers were 16.53%, 27.09%, and 20.43% under testing strategies A, B, and C, respectively. The total nonconformity rates of HBV, HCV, and HIV infection-related markers were 0.52%, 0.40%, and 0.39%, respectively, with statistically significant differences in nonconformity rates between HBV and HIV infection-related markers. Compared with testing strategy A, the relative detection rates of HBV, HCV, and HIV infection-related markers were 77.69% and 76.06% under testing strategies B and C, respectively. Testing strategy B detected 247 fewer cases compared to strategy A, with 246 fewer cases of HBV infection, no difference in HCV infection, and 1 fewer case of HIV infection. On the other hand, testing strategy C detected 265 fewer cases compared to strategy A, with 113 fewer cases of HBV infection, 46 fewer cases of HCV infection, and 106 fewer cases of HIV infection.Conclusions: Testing strategies with more comprehensive detection items ensure a higher level of blood safety. Multiple testing methods with different types of markers are necessary in practice. Testing strategies with fewer detection items need to be cautiously applied. NAT is essential for blood screening, and the combination of multiple testing methods can improve detection rates.We would like to express our gratitude to Mr. Sang Liyong, Director of Shaoxing Central Blood Station, and Mr. Fu Liqiang, Deputy Director, for their valuable guidance, help, and support during this study.aZhiying Liua Jiang Su Urban and Construction Vocational College, Changzhou city, Jiangsu Province 213000, China.Background: According to the research report of China Academy of Fiscal Science on the labor cost of China labor market, in the first half of 2018-2021, the average monthly wage of sample enterprises increased from 4,182 yuan to 5,367 yuan, with an average increase of 9.44%, especially in the first half of 2021, the average monthly wage increased by 12.63%. Enterprises are facing the pressure of rising costs, and job seekers are facing a state of job anxiety, how to solve the adverse effects and provide a positive signal for job seekers is the focus of this paper. Under the difficulty of rising labor costs, enterprises have psychological anxiety; job seekers face the increasing problems of rising living and housing costs. If the psychological anxiety problem is not paid attention to, and cannot be alleviated, it will develop into anxiety disorders, which may lead to changes in people\u2019s body, and cause social problems.The accurate distribution and analysis of labor cost realize reasonable control and provides a feasible path for enterprises.Subjects and Methods: This paper studies the multi-level analysis of labor cost difference in standard cost method; In the paper the comparative analysis and case analysis are used. In the article a manufacturing company is chosen as a typical case.Results: The labor cost problem needs the joint efforts of internal and external parties, such as external policy support, but it is also very important for enterprises to adopt appropriate cost methods. At present, there are two systems for the treatment of labor costs, which are the actual cost allocation method based on working hours and the standard cost method based on standards. Both methods have their shortcomings.Conclusion: The key to the traditional standard based accounting and distribution method lies in the determination of standard working hours and wage rate standards. Besides the strong subjectivity in the formulation of standards, the reference factors are single and the labor level and the nature of jobs are not considered, which is also a major problem. The multi-level analysis of standard cost method proposed in this paper ensures the stability and systematic of cost indicators. This method can explain the causes of differences in detail and provide data support for later cost control and provide positive signal and relief the mental pressure relative to labor.a, Qinhai MaaYing Zhaoa School of Business Administration, Northeastern University, Shenyang 110819, China.Background: This research aims to investigate the impact of brand logo change on consumers\u2019 emotion regulation by exploring the effects of logo design characteristic changes. Enterprises often modify their logos to maintain their brand image, which requires continuous planning and adaptation to consumers\u2019 emotion regulation. Therefore, brands aim to keep up with the times and maintain a positive image by redesigning their logos in ways that satisfy consumers\u2019 emotional needs. Such needs include familiarity for loyal customers, meaning similarity with the old logo for the target audience, and the ability to evoke positive affect and good surprise. Consumers\u2019 emotional needs are critical for brand logo changes to be effective, as they influence how consumers respond to and engage with logos.Subjects and Methods: Our research involves conducting empirical experiments to investigate the relationship between logo design characteristics and consumer responses. Firstly, we identified eight distinct logo design characteristics. Secondly, we identified four different types of consumer responses to logo changes. Thirdly, we identified four underlying design dimensions of logo changes, which are natural, harmonious, elaborate, and integral, and four response dimensions. Finally, we conducted an empirical analysis of 100 logos to identify those that meet three different strategic objectives.Results: Our empirical research has led us to propose design guidelines for logo changes that take into account consumers\u2019 emotion regulation. Our analysis revealed that for minor logo changes in a mature market, the change should be medium in terms of naturalness and elaboration, low in terms of harmony, and high in terms of integrity. Conversely, major logo changes in a mature market should involve a high level of natural change transitioning to medium, a positive and substantial change in harmony, a low to medium level of elaboration, and a negative and low change in integrity. For logo changes in a young market, the guidelines suggest a low to medium level of natural change, a positive and substantial change in harmony, a low to medium level of elaboration, and a negative and low change in integrity.Conclusions: Our findings indicate that any change in brand logos can have a significant impact on consumers, highlighting the importance of catering to their emotion regulation. The design guidelines for logo changes provide marketing managers with a reliable theoretical basis for minimizing or avoiding potentially negative effects, such as reduced market competitiveness, increased costs, or the risk of losing brand assets. Our research contributes to the design guidelines of brand logo change in several ways. First, it offers a new perspective on the relationship between a series of design characteristics of brand logos and their impact on consumers\u2019 response, which is closely linked to their emotion regulation. Second, it proposes design guidelines for logo changes with respect to three different strategic objectives. Third, we provide purely illustrative recommendations for different types of logo changes, taking into account the impact on consumers\u2019 emotion regulation.a, Hongmei Lib, Lizhang DongbYifan Wanga School of Education, Baoshan University, Yunnan 678000, China, b School of Psychology and Cognitive Science, East China Normal University, Shanghai 200062, China.Background: Since the start of the epidemic, people across the country have experienced a \u201clockdown period\u201d in early 2020, when all places are closed down and travel restricted, and a \u201cplateau period\u201d when the epidemic is relatively stable after the epidemic is brought under control and the lockdown is lifted. The plateau period is a period of continuous response, reflection and adjustment to the epidemic situation. It is of great value and significance to explore the mental health status of college students during the plateau period, which can provide a new direction of thinking for the subsequent mental health education of college students. Depression is a condition to be concerned about; Psychological capital is an effective mediating variable of the psychological stress response of college students under the epidemic. For the mental health education of colleges and universities, it is helpful to reduce the impact of the major epidemic on the mental health of college students, promote the self-growth of college students, and promote the scientific psychological education model of colleges and universities. The impact of major epidemic on the psychological capital of Chinese college students has both advantages and disadvantages Positive environment and support resources such as effective prevention and control of the government, concerted efforts of the people and family companionship are conducive to the growth of optimism and hope factors of psychological capital. At the same time, the major epidemic has a negative impact on the self-efficacy and psychological resilience of college students with little stress experience, weak personality foundation, high psychological pressure and little social support. In order to explore the influence of college students\u2019 risk perception level on their depressive state and the protective role of psychological capital in the stable period of the epidemic, this study investigated freshmen and seniors of Baoshan University in Yunnan Province.Subjects and Methods: Totally 5138 college students were surveyed using the COVID-19 Risk Perception Scale (PRCPS), Depression Angst Stress Scale (DASS-21) and Compound PsyCap Scale (CPC-12)Results: (1) Risk perception positively predicts depression; (2) Hope, efficacy and optimism in psychological capital can negatively predict depression; (3) The efficacy dimension of psychological capital moderates the relationship between risk perception and depressive state, that is, the predictive power of risk perception on depressive state decreases with the increase of efficacy.Conclusion: High risk perception tends to lead to depression in college students, while psychological capital can reduce the occurrence of depression, and the efficacy dimension of psychological capital plays a protective role in the relationship between risk perception and depression.a, Aihong WangaDan Longa School of Design and Art, Jingdezhen Ceramic University, Jingdezhen 333000, China.Background: \u201cIt is one of the important varieties of glaze decoration of traditional Chinese ceramics, and is an artistic expression with ceramics as the carrier. The development of pastel has a certain transitional period. This paper studies the beauty of ceramic pastel decoration in the three Qing dynasties  from the perspective of \u201cpsychological needs\u201d and explores the role of its \u201cunique\u201d painting language in psychological healing. The purpose of this study is to examine the psychological development of the human psyche and the psychological role of aesthetics.Subjects and Methods: Using Maslow\u2019s Theory of Needs as a theoretical guide and a combination of qualitative and quantitative and comparative research methods, the study aims to analyze the role and healing of the \u201caesthetic expression\u201d of the painting language of pastel decoration in the Qing and Third Dynasties on mental health.Results: The analysis focuses on the meaning of the lines, composition and craftsmanship in relation to psychological needs and psychological health, and the interrelationship between the \u201cartistic characteristics\u201d and \u201cpsychological needs\u201d of Qing Dynasty pastels. The analysis shows that the Qing Dynasty pastel decorations were effective in relieving people\u2019s stress and anxiety at the level of \u201cpractical needs\u201d, in healing people\u2019s aesthetic psychology at the level of \u201caesthetic needs\u201d, and in relieving people\u2019s negative emotions at the level of \u201cvalue needs\u201d.Conclusions: From this, it is concluded that the pastel decoration of the Qing Dynasty has a unique aesthetic of art, both psychological regulation and compensatory dynamic function, but also can make the artistic literacy and artistic inculcation of people to facilitate the maintenance of psychological health, art from life and above life, so that art into real life, so that people maintain a positive and healthy psychological needs of the development of the situation is particularly necessary.This research was supported by the  project.a, Xiaoshu Lib, Ruhaizin Sulaimana, Khairul Manami Kamarudina, Rosalam Che MeaKang Jia Faculty of Design and Architecture, Universiti Putra Malaysia, Serdang, 43400, Malaysia, b School of art & design, Zhengzhou University of Aeronautics, Zhengzhou, 450046, China.Objective: Maintaining a healthy lifestyle plays a vital role in personal health and social development. However, in reality, many people have various problems maintaining healthy behaviors and are unable to maintain a healthy lifestyle. Most of the existing healthy lifestyle-related products on the market are designed based on the principle of persuasion, and intervene in behavior through various persuasive strategies, so as to achieve the purpose of changing behavior. In order to provide designers and researchers with more effective design solutions in product design in the future, this study systematically analyzes and gives an objective assessment of the persuasive principles and strategies used in product persuasive design.Methods: Through the method of systematic literature review, search the persuasion technology and application of persuasion strategies in healthy life and the Fogg behavior model (FBM) from the two search engines of Scopus and Connected Paper, then strictly follow the PRISMA flow chart to provide relevant screening and evaluation according to the requirements of eligibility, inclusion or exclusion of articles, 23 eligible articles were finally selected for systematic analysis.Results: This study found that the Fogg Behavior Model and persuasive strategy used in the existing products can effectively promote the formation of healthy behavior and improve people\u2019s healthy lifestyle. In addition, the effectiveness of persuasive technology will also be affected by a variety of other factors, such as the influencing factors of target behavior, social environment, intervention stage of persuasive strategy, intervention duration, etc. In order to improve the effectiveness of products, these factors should be considered by researchers and designers.Conclusions: The systematic literature review provides an important theoretical basis for designers and researchers in the process of product design related to healthy lifestyle through the study of persuasive principles, persuasive strategies and Fogg Behavior Model. This study emphasizes the importance of persuasive technology and design in the process of healthy lifestyle intervention and summarizes the advantages of persuasive design from four aspects: orientation, friendliness, interactivity and ethics.a, Haiju Liub, Chunsheng LiaXiaolei Rena Urology Department, Affiliated Hospital of Chifeng University, Institute of Urology, Chifeng University 024000 Chifeng, China, b Cancer Screening Department, Chifeng Cancer Hospital, 024000 Chifeng, China.XR and HL contributed equally to this study.Background: To evaluate the safety and efficacy of 980\u2005nm diode laser enucleation for treatment of non-Muscle-invasive bladder cancer.Subjects and Methods: The data of the patients with non\u2013muscle-invasive bladder cancer treated by either 980\u2005nm diode laser enucleation (n=56) or conventional transurethral resection of bladder tumor (n=52) were analyzed retrospectively. The preoperative characteristics and intraoperative complications were compared in the 2 groups.Results: No significant differences in the sex, age, mean tumor number, mean tumor max. size, tumor multiplicity, tumor location, tumor stage, and recurrence risk of the 2 groups were observed. All patients accepted the successful 980\u2005nm diode laser enucleation or TURBT, respectively. No obturator nerve reflex and bladder perforation occurred during surgery in the 980\u2005nm diode laser group. However, 11 patients in the conventional transurethral resection of bladder tumor group encountered obturator nerve reflex, and 2 of them encountered bladder perforation. There were no significant differences between the 2 groups in transfusion rate. Patients in the 980\u2005nm diode laser group had shorter the mean duration time of the operation, duration postoperative continuous bladder irrigation time, and catheterization time than that in the conventional transurethral resection of bladder tumor group. There was no significant difference in the overall 1-year recurrence rate between the 2 groups during the follow-up periods. Also, no statistical difference was found when the comparison was made among every risk subgroups between the two groups.Conclusions: 980\u2005nm diode laser enucleation for treatment of non\u2013muscle-invasive bladder cancer demonstrates an advantage over conventional transurethral resection of bladder tumor in reducing intraoperative complications, shortening the mean duration time of the operation, shorting the time of duration of postoperative continuous bladder irrigation, and shorting the time of catheterization.This research was supported by Inner Mongolia Autonomous Region Higher Education Science Research Project: NJZY21140.a,Tong ZhaobGuirong Hea Department of China International Language and Culture College, Krirk University, Bangkok10220, Thailand, b Department of Culture Industry, College of Humanities and Social Sciences, Kwangwoon University, Seoul, 01897, Republic of Korea.Background: With the acceleration of the process of globalization, more and more people have a strong interest in learning Chinese language and culture. In international Chinese education, Chinese calligraphy, as a unique cultural and artistic form, has profound historical origin and cultural connotation, and has become an effective way and means to attract foreigners to learn Chinese. However, in the actual teaching process, due to the different cultural background and learning style, different psychological pressure, psychological anxiety and other bad emotions that are not conducive to physical and mental health will be produced in the learning process. How to effectively teach Chinese calligraphy in the cross-cultural background has become an urgent problem to be solved. In order to improve the effect of Chinese calligraphy education, promote the common development of international Chinese education and mental health education. Based on the mental health perspective, this paper studies the development of the communication mode of Chinese calligraphy education for international Chinese education.Subjects and Methods: Based on this, in order to improve the effect of integrating mental health education into Chinese calligraphy education in international Chinese education, and promote the integrated development of international Chinese education and mental health education. This paper first discusses the basic situation of international Chinese education; then it analyzes the basic connotation of Chinese calligraphy education. Then, from the perspective of psychology, this paper discusses and analyzes the psychological health factors of the communication mode of Chinese calligraphy education. Finally, based on the investigation of the audience of international Chinese education, this paper analyzes the specific mode of the future development of Chinese calligraphy education in China.Results: This paper mainly adopts the form of questionnaire survey to study Chinese calligraphy education under international Chinese education. The results show that the highest proportion of male study time is less than one year, accounting for about 35%. While the highest proportion of female study time is 3-4 years, accounting for about 23%. With the growth of age, the study time of participants under the age of 20 was less than one year, accounting for about 77% of the total; the study duration of 20-30 year-old participants is less than one year, accounting for about 48%; the study duration of participants over 30 years old is the highest of 2-3 years, accounting for about 36%. At the same time, the most popular way of learning is an online course, which accounts for about 40% of women. The largest number of Chinese calligraphy communication carriers that participants are interested in is painting, which accounts for about 34% of participants aged 20-30.Conclusions: This research not only provides a reference for improving the effectiveness of Chinese calligraphy education, but also makes an objective contribution to the future sustainable development of international Chinese education.This work was supported by a project grant from the Connotations and Values of Local Calligraphy Heritage in Zhongshan City, which used Xiaolan Town in Zhongshan City as an example. (Grant No.202357).a, Qinhai MaaYing Zhaoa School of Business Administration, Northeastern University, Shenyang 110819, China.Background: In the digital age, online reviews have become a crucial factor in shaping consumer purchase decisions. As such, understanding the factors that influence the credibility of online reviews is essential for businesses that seek to attract and retain customers. Previous research has identified several factors that affect online review credibility, such as review valence, length, and source credibility. However, little is known about how the psychological needs of consumers may impact their perceptions of review credibility. This study aims to investigate the influence of psychological needs, such as the need for social validation and the need for self-enhancement, on consumers\u2019 perceptions of online review credibility.Subjects and Methods: A survey was conducted with 500 participants who had recently made an online purchase. Participants were asked to rate the credibility of a fictitious online review, which varied in terms of review valence, length, and source credibility. Participants also completed a questionnaire that measured their psychological needs, such as the need for social validation and the need for self-enhancement. Structural equation modeling was used to analyze the data and determine the extent to which psychological needs influenced consumers\u2019 perceptions of online review credibility.Results: The results of the study indicate that psychological needs play a significant role in consumers\u2019 perceptions of online review credibility. Specifically, the need for social validation was found to positively influence consumers\u2019 perceptions of review credibility, while the need for self-enhancement was found to negatively influence consumers\u2019 perceptions of review credibility. Furthermore, the results suggest that the influence of psychological needs on review credibility may vary depending on the source credibility of the review.Conclusions: This study provides important insights into the factors that influence consumers\u2019 perceptions of online review credibility. The findings suggest that businesses can enhance the credibility of their online reviews by appealing to consumers\u2019 psychological needs for social validation, while avoiding tactics that may trigger consumers\u2019 need for self-enhancement. By understanding the psychological needs that underlie consumers\u2019 perceptions of online review credibility, businesses can better tailor their review management strategies to attract and retain customers.a, Li LibXianli Gaoa School of Foreign Languages, Guangdong Pharmaceutical University, Guangzhou, Guangdong 510006, China, b School of Foreign Studies, Guangzhou University, Guangzhou, Guangdong 510006, ChinaBackground: With the development of positive psychology, well-being, as a healthy psychological mechanism, has become an important factor to explain employees\u2019 behavioral attitudes and improve their job performance, which gradually enriches the relevant researches on teachers\u2019 subjective well-being. Predicting job performance based on subjective well-being has always been a major concern in the field of organizational behavior. In view of this, based on the perspective of positive management, the purpose of this study was to explore the internal mechanism of the impact of tertiary teachers\u2019 subjective well-being on job performance in the context of innovation and entrepreneurship by introducing organizational identity as a moderating variable.Subjects and Methods: Two hundred and sixty-seven Chinese tertiary teachers of foreign languages in innovation and entrepreneurship education from 10 universities were chosen through random sampling. Questionnaires were employed to measure job performance, subjective well-being and organizational identity in this study, and the data was analyzed by the descriptive statistics, correlation and regression analyses to examine the internal mechanism of the impact of tertiary teachers\u2019 subjective well-being on job performance in the context of innovation and entrepreneurship by introducing organizational identity as a moderating variable.Results: The findings obtained from the study are as follows: (a) Subjective well-being and organizational identity were important factors affecting job performance of tertiary teachers of foreign languages, (b) Subjective well-being of tertiary teachers of foreign languages had a significant positive impact on job performance and organizational identity, (c) Organizational identity had a significant positive impact on job performance of tertiary teachers of foreign languages. Conclusions: The moderating mechanism between teachers\u2019 subjective well-being and job performance is also a problem worthy of in-depth study. The propulsive relationship of organizational identity on subjective well-being and job performance showed that Chinese tertiary teachers of foreign languages could improve subjective well-being and job performance through organizational identity. Therefore, urging Chinese tertiary teachers of foreign languages to identify with institutions of higher learning and motivating teachers\u2019 enthusiasm for innovation and entrepreneurship education was one of the effective ways to improve teachers\u2019 job performance.th Five Year Plan of National Education Sciences grants (No. 2020GXJK468); The 2st Batch of Industry-University Cooperative Education Projects in 2022 by the Ministry of Education of China grants (NO. 220802193315018); Higher Education Special Funds (2021) of Department of Education of Guangdong Province.This work was supported by Guangdong Provincial Undergraduate Teaching Reform and Quality Engineering Construction Project grants (No. GDJG2021295); Planning Subject for the 13a, Yanrui Jiab, Xiaoyan XinbYu Wanga School of Management, Guangdong University of Science & Technology, Dongguan, Guangdong 523083, China, b School of Business Administration, Jimei University, Xiamen, Fujian 361021, China.Background: With the rise and development of e-commerce, the speed and scope of IWOM have spread more rapidly and extensively than traditional word-of-mouth. IWOM affected consumers\u2019 shopping mood and decision-making behavior. The quality of IWOM is increasingly becoming a primary consideration in consumer shopping choices.Subjects and Methods: The influencing factors of IWOM quality were analyzed from four dimensions such as IWOM recipients, channels, merchants and IWOM itself. The influencing factors of consumers mainly included consumers\u2019 gender, personality, mood and the type of products they bought. The influencing factors analyzed from the communication channels were the type and authority of websites. From the merchants\u2019 perspective, their influencing factors were the merchants\u2019 reputation, after-sales service, payment methods and measures such as cashback to consumers in order to get good reviews, as well as the merchants\u2019 handling of poor reviews given by consumers. The influencing factors of IWOM itself were mainly the directionality and the level of detail of IWOM. The questionnaire was designed according to the above four dimensions, and the proposed hypotheses were argued one by one through the empirical analysis method of questionnaire survey.Results: The study found that the stronger the trust tendency in consumers\u2019 mood, the higher the credibility of IWOM. Consumers\u2019 gender has no effect on IWOM quality. Consumers are more influenced by IWOM quality for highly involved products. Website authority, merchants\u2019 credibility and guarantee measures positively affect IWOM quality. Merchants\u2019 means of misleading implementation negatively affect IWOM quality. The higher the level of detail of IWOM, the higher its IWOM quality. The type of online platform and the positive or negative nature of IWOM itself do not have significant effects on IWOM quality.Conclusions: Based on the research results, certain reference suggestions are made for enterprises or businesses, consumers, governments, and communication channels. Enterprises should encourage and guide consumers to publish more detailed IWOM as much as possible. They should focus on and influence consumer mood and try to target their marketing to consumers with lower expertise and higher trust tendency. Consumers, as publishers or disseminators of IWOM information, should adhere to the principle of truthfulness and truthfulness, and publish true and effective IWOM. The government can formulate relevant legal norms and take measures to punish merchants to reduce false IWOM and enhance the objective accuracy of IWOM. Websites, as the main communication channels, should avoid the spread of false IWOM on websites by strengthening supervision.a, Xinzhe Zhaib, Yi Wub, Jianli HanaRui Yanga General Surgery Department, Shanxi Bethune Hospital, Shanxi, Taiyuan 030032, China, b Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Shanxi, Taiyuan, 030032, China.Background: Metabolic diseases caused by obesity are diverse, and many large population studies have reported a direct correlation between obesity and the occurrence of various diseases, which can affect the function of multiple endocrine organs including thyroid function. The relationship and mechanism between Hashimoto\u2019s thyroiditis (HT) and type 2 diabetes mellitus (DM) as two common obesity-related complications remain yet unclear.Subjects and Methods: The National Center for Biotechnology Information (NCBI) database was searched for GEO datasets (https://www.ncbi.nlm.nih.gov/geo), and datasets GSE18470 and GSE138198 were selected for data analysis. After analyzing the differentially expressed genes between the groups, the results were submitted to the DIANA TOOLS website and the MirPath tool was used for pathway enrichment analysis. The KEGG pathway enrichment results were selected as the data for further analysis, and key genes were identified.Results: Compared with simple obesity, there are more associated genes in obese patients with type 2 diabetes (DM) and HT, suggesting that type 2 DM may increase the chance of obese patients developing HT. The TGF-beta signaling pathway and Proteoglycans in cancer pathways contained the most genes, with 10 genes each. The TGF-beta signaling pathway (p=1.776067e-06) ranked higher than the Proteoglycans in cancer pathway (p=8.47584e-05), suggesting that the TGF-beta signaling pathway may be the key pathway for obese patients with type 2 DM to develop HT.Conclusions: This study not only found that there are more associated genes in obese patients with type 2 DM and HT, but also suggested that the TGF-beta signaling pathway is the key bridge for the occurrence of these two conditions. The 10 associated genes in the TGF-beta signaling pathway identified in this study can be the focus of future research. Identifying the possible mechanisms leading to the occurrence of HT in obese patients with type 2 DM can provide feasible treatment options for subsequent HT treatment.This study was funded by Shanxi Province \u201c136 Revitalization Medical Project Construction Funds\u201d (2021YZ05).a, Weiwei Fana, Qingqing MaaYanrui Jiaa School of Business Administration, Jimei University, Xiamen, Fujian 361021, China.Background: With the rapid development of Internet technology, a wide variety of digital information technologies have gradually integrated into people\u2019s lives and effected consumers\u2019 usage willingness and mood. Consumers have begun to expect payment methods to become more secure, convenient, and intelligent. Then various payment methods based on human biometric for identity verification have gradually emerged.Subjects and Methods: This study combined initial trust theory and perceived risk theory to investigate the effects of a total of five factors such as structural assurance, trust propensity, company reputation, initial trust, and perceived risk on consumers\u2019 psychological willingness and mood to use face swipe payment. Structural assurance is the guarantee of consumers\u2019 environmental security when using face payment. Trust propensity is the degree of consumers\u2019 personal tendency to believe in something new. Company reputation refers to the reputation of the backend company of face payment. Initial trust is the degree of consumers\u2019 trust in face payment in the beginning. Perceived risk refers to consumers\u2019 psychological expectation of unknown negative effects brought by using face payment. With the above five factors as independent variables and consumers\u2019 willingness and mood as dependent variables, the research model was constructed and the hypotheses were verified by using questionnaires and SPSS data analysis.Results: Structural assurance, trust propensity, company reputation, and initial trust significantly and positively affect consumers\u2019 willingness and mood to use face payment. Perceived risk significantly and negatively influenced consumers\u2019 willingness and mood to use. The details are as follows specifically. Higher structural assurance enhances consumers\u2019 initial trust in face payment and thus consumers\u2019 willingness to use it. The characteristic of being more likely to believe in something new positively drives consumers\u2019 initial trust in face payment. The good reputation of the company makes consumers more willing to use the company\u2019s face payment technology. The higher the initial trust, the stronger consumers\u2019 willingness to use face payment. The higher the perceived risk level of face payment, the lower the willingness to use.Conclusions: Valuable reference suggestions were proposed for enterprises to influence consumers\u2019 willingness and mood to use face swipe payment. They need to develop consumer-related protection mechanisms and establish comprehensive information security to maximize the safety of consumers\u2019 personal information and property. Enterprises should pay attention to maintaining their good reputation. Providing consumers with high-quality products and good services is the basis for enterprises to establish good reputation. They should emphasize the advantages of payment technology to attract consumers. When promoting face payment, enterprises should emphasize its convenient and safe functional advantages. They need to strictly comply with the laws and regulations related to face payment and protect consumers\u2019 rights and interests, which is the way to long-term development of enterprises.aLingling Tonga School of Social Service and Development, Zhengzhou Normal University, Zhengzhou, Henan, 450000, China.Background: Chinese entrepreneurs are known as the world\u2019s most hardworking, indomitable and persistent qualities. They not only have the ability to withstand tremendous pressure and deal with complex practices, but also able to keep a balance between their career, family and self-growth. In fact, many Chinese entrepreneurs have serious psychological and health problems due to their work stress and psychological anxiety.Subjects and Methods: From January 2022 to February 2023, 100 entrepreneurs and executives from different fields and industries were selected in Beijing, Shenzhen, Hubei, Xi \u2018an, Zhengzhou and other places for case interviews, observation, visits and questionnaires.Results: In recent years, with the integration of the world economy, the embedding of the Internet economy and the vigorous development of the digital economy, the pace is getting faster and faster, which makes the work pressure and physical and mental health condition of Chinese entrepreneurs cannot be ignored. Many entrepreneurs have physical health problems due to the work pressure and psychological anxiety cannot be well alleviated, such as sleep disorder, fatty liver, chronic gastritis, migraine, alcohol paralysis, low performance, depression, Job burnout, etc.Conclusions: This paper analyzes the influencing factors of entrepreneur\u2019s stress on individual psychological anxiety and establishes a structural model of the influence of entrepreneur\u2019s stress on emotion. Based on the empirical research data, this paper proposes the adjustment strategies and means of entrepreneur\u2019s job stress.Key words: Chinese entrepreneur; psychological anxiety; work pressure; affective disorder; health indicators1.This paper is one of the key research results of the undergraduate Teaching Engineering and Teaching Reform Research project of Zhengzhou Normal University, Research on the Cultivation Model and Standard Evaluation of Undergraduate Excellent Teachers  \u201cResearch on the Impact of University Financial Assistance on the Development of Poor Students and Its Influencing Factors\u201d .aWenju Hana College of Foreign Languages and Literature, Northwest Normal University, Lanzhou, China.Background: This paper studies Martin Amis\u2019s masterpiece Money: a Suicide Note, aims to reveal the socioeconomic and psychological impact of mass media\u2019s consumption of body, such as the psychological anxiety.Subjects and Methods: This paper studies the novel from the perspective of media ecology, Baudrillard\u2019s social theories on the consumer society, body in the consumer culture, psychological anxiety and etc.Results: By focusing on the under-examined correlation between mass media, body consumption and anxiety in Amis\u2019s Money, this paper finds out that unlike orality and typography which produce abstract image of body in the mind of different people, the visual media such as TV produce concrete standards of body images, which highlight the importance of appearance, wiping out the uniqueness in people\u2019s appearance. By presenting a vast amount of visual images of the body through make-up, plastic surgery, lights, dressing and etc, the visual media construct ideal and standard images of male and female body, which foreground forever youth, beauty and health that are in fact impossible, and body image is associated with masculinity, femininity, self-discipline and social status, arousing people\u2019s consciousness of their body and anxiety, creating their desire of consumption to maintain their body, thus the mass media reach the goal of promoting consumerism and selling the goods. In order to meet or approximate the criteria of beauty set by visual media, people take various instrumental means to build their body. In this process, they accept the capital and power\u2019s discipline of their body willingly.Conclusions: In conclusion, this paper argues that the male and female body is commodified by mass media, causing great anxiety. In Amis\u2019s Money, under the discipline of media culture, John Self, the protagonist, is preoccupied with his appearance and full of anxiety. Self is so willing to do everything to preserve his body that he would rather quit reading because it hurts his body, which causes anti-intellectualism. And the male characters model after the film stars in their body image and even undergo plastic surgery. So in the age of visual media and high technology, body is oppressed and damaged to a deeper degree. The female characters in Money such as Selina, Caduta self-monitor their body to meet the standards of beauty set by the mass media. Therefore, mass media strengthen the commodification of male and female body, which reduces the value of female to sex and consumption. Instead of being liberated, the human body is still oppressed by aesthetic violence in the contemporary consumer society.This work was supported by the [Northwest Normal University] under Grant [number 2916]a, Chuanping Leib, Qingda Lia, Junling Mac, Li JiadHong Changa School of Marxism, Zhongkai University of Agriculture and Engineering, GuangZhou, Guangdong 510550, China, b School of Marxism, Sun Yat-sen University, GuangZhou, Guangdong 510275, China, c School of Humanities and Management, Guangdong Medical University, Dongguan, Guangdong 523808, China. dHC and CL contributed equally to this study.Background: Human enhancement technology can help people solve better social, economic, and medical problems and improve the social and medical environment. Human enhancement technology aim to improve human productivity through retinal implants, cochlear implants, and other audio-visual enhancement technologies, brain enhancement technologies such as drugs, brain implants, and brain-computer interfaces, and physical enhancement technologies such as exoskeletons and quality of life, thus promoting the progress of society.Subjects and Methods: This study aims to explore the research hotspots and cutting-edge trends of human enhancement technologies in the past 20 years. This study collected literature on human enhancement technologies from the Web of Science database. This study used bibliometric and visual analysis methods to conduct the study. The main paths of knowledge evolution of human enhancement technologies were mapped using CiteSpace visualization software. One of the main ways to perform word contribution analysis is to extract keywords, abstracts, and other relevant information from the dataset and draw a visual knowledge map to determine the relationships between topics in the disciplines represented in the dataset. The literature and the degree of deviation from the current knowledge structure are studied according to the structural transformation model in the citation network.Results: In the last 20 years of human enhancement research, this study identified 159 highly productive scholars and ten collaborative teams with large research sizes. Cluster analysis revealed that the Research was focused on \u201ccognitive enhancement,\u201d \u201cethical enhancement,\u201d \u201cemotional enhancement,\u201d and \u201cdisease and technology enhancement ethics\u201d. There are three shifts in the research themes and directions of human augmentation research, from disease treatment research to general human augmentation research; from medical examination of human cognitive augmentation to ethics of moral and emotional augmentation research; and from human drug augmentation research to biotechnological augmentation research under convergence technology. The frontier literature on human enhancement technology research involves multiple disciplines such as medicine, neuroscience, molecular biology, psychology, ethics, and sociology, and future Research is bound to focus on the convergence and innovation of multiple technologies, multiple topics, and multiple fields.Conclusions: The results of this paper can provide necessary references for researchers engaged in human genetic engineering, drugs, biomedical technology and other aspects of human enhancement technologies, and provide necessary guidance for future research directions.This work was supported by a project grant from \u201cHuman Enhancement Technology Risk Research: Causes, Models and Protocols\u201d, Ministry of Education, Humanities and Social Sciences Research Youth Project (Grant No. 22YJCZH012); \u201cA Philosophical Hermeneutic Study on Emerging Human Enhancement Technologies\u201d, Guangdong Philosophy and Social Sciences Planning Project (Grant No. GD20CZX01); Teaching reform Project of Guangdong Medical University \u201cResearch on Humanistic Quality Training Path of Medical Students in the Vision of Collaborative Education\u201d (Grant No.1JG21083); Guangdong Provincial University characteristic innovation project \u201cConstruction of Humanistic Medicine from the Perspective of Life Culture\u201d (Grant No.2021WTSCX034).a, Qin Zhoua, Wenchao GaobCui Shana College of Civil Engineering, Putian University, Putian, Fujian 351131, China, b CNNC Huachen Construction Engineering Co., Ltd, Putian, Fujian 351100, China.Background: With the rapid rise of China\u2019s social economy from 1998 to 2022, university teachers constantly face dual challenges from society and profession. Their mental health is constantly affected, especially female teachers in Chinese universities. This paper which analyzes the research results on the mental health of female teachers in universities from 1998 to 2022, reveals the development law of the research, summarizes and analyzes the research contents.Subjects and Methods: On the platform of China National Knowledge Network (CNKI), a total of 93 valid literatures were obtained, through the advanced search of the two subject words \u201cfemale teachers in universities\u201d and \u201cmental health\u201d. CiteSpace software is used to cluster analysis for the sample literature. It mainly contains the cluster analysis of literature authors, research institutions and keywords.Results: (1) From the annual trend of research results, the research development trend in the field of mental health of female teachers in universities can be roughly divided into three periods. First, the initial exploration period, paying attention to mental health investigation. Second, the rapid growth period, focusing on the psychological characteristics and influencing factors of female teachers in universities. Finally, the slow growth period, caring on the analysis of coping strategies in mental health problems and the improvement of career happiness. Moreover, the number of published papers peaked in 2008. (2) From the perspective of literature sources, key authors and research institutions, the research results in the field of mental health of female teachers in universities have been published in a wide range of journals, especially in mental health, education and teaching, higher education research field. (3) From the perspective of research contents, hotspots, frontiers and trends, the research contents in the field of mental health of female teachers in universities include the investigation of mental health status, influencing factors of mental health, and strategies for improving mental health. (4) Research hotspots focused on the female teachers in universities mental health status, and strategies to improve mental health problems. (5) Research frontiers can be roughly divided into three research periods.Conclusions: (1) From 2014 to now, the research popularity in the field of mental health of female teachers in universities has declined, and the quantity and quality of research results in this field have great room for improvement. (2) In the future, new technologies and methods, such as simulation prediction model and big data, can be introduced into the research methods in oder to improve the practicability and innovation of the research results in this field. (3) China\u2019s first-tier cities have more developed economies, and more students, higher school standards, and greater pressure on teachers\u2019 life and career. Therefore, the future research area can be further focused on China\u2019s first-tier cities. (4) At present, most researchers and research institutions have a lot of room for future cooperation. The further expansion of cooperative relations is conducive to the overall development of China\u2019s higher education.This work was supported by a project grant from Education and Research Project for Young and Middle-aged Teachers of Fujian Province  (Grant No.JAS21249); Education Science Planning Project of Fujian Province (Grant No.FJJKC2020-029); University-level Education Reform Project of Putian University (Grant No. JG2022068).a, Xiaofeng LuobLimin Zhanga Sichuan University Jinjiang College, Pengshan, Sichuan, 620860, China b Sichuan Police College, Luzhou, Sichuan, 646000, China.Background: At the beginning of 2020, the COVID-19 began to sweep across China from Hubei, and the public health safety of Huanggang in Hubei was the first to bear the brunt. Huanggang was known as Huangzhou in ancient China. In 1079 AD, Su Shi, who was selected by the French newspaper Le Monde as one of the \u201cheroes of the millennium\u201d who influenced the world, was demoted to Huangzhou due to the Wutai poetry case. When the plague broke out, he announced the anti epidemic prescription \u201cSheng San Zi Fang\u201d to the public, and countless people survived!Subjects and Methods: During his demotion, Su Shi encountered plagues many times. Due to his rich epidemic prevention experience and effective public health management measures, he repeatedly saved people from distress. In terms of Su Shi\u2019s anti epidemic practice, effective public health management measures are as follows: During the initial stage of the epidemic, go deep into the epidemic area, truthfully report to the superior, and bought time for the government\u2019s timely rescue; Pay attention to drinking water hygiene and prevent accidents before they occur; During the epidemic, he actively promoted the use of prescription drugs to treat the epidemic, while donating funds to establish the \u201cAnle Fang\u201d equivalent to the prototype of a modern square cabin hospital to carry out isolation and self rescue, And integrate civil forces to assist in combating the epidemic; After the epidemic, it is recommended that the government exempt taxes and provide relief to restore people\u2019s livelihood. He also requires that officials who fail to perform their duties in the prevention and control of the epidemic be held accountable, and rectify the official atmosphere to ensure the normal operation of state power in the future.Results: In the early stages of the epidemic, due to the implementation of timely and effective public health prevention measures, the source of infection of the epidemic was quickly cut off; During the epidemic, Public health management measures are timely and effective, fully mobilizing the forces of all sectors of society, saving countless people, and minimizing the harm of the epidemic; After the epidemic ended, economic remedial measures were taken to appease the people\u2019s livelihood, and the lives of the people and government functions gradually returned to normal operation.Conclusion: Su Shi\u2019s series of anti epidemic practices from prevention to treatment are also scientific and reasonable, and still have important reference significance for the prevention and treatment of contemporary epidemic situations; As a great scholar, he also had a profound understanding of traditional Chinese medicine; Whether selflessly donating anti epidemic prescriptions, compiling medical books, or generously donating money to build a shelter hospital to fight the epidemic, these fully reflect his people-oriented, benevolent and pragmatic medical feelings.aXinxia Fanga Department of Music, Yancheng Teachers University, Yancheng, 224007, China.Background: China\u2019s National Mental Health Development Report (2021-2022) shows that the primary factors affecting depression and anxiety levels are age and income, and among which young people are the high-risk groups. According to the report and some relevant statistics, young people are faced with many troubles and challenges such as academic pressure, employment pressure, economic pressure, emotional pressure and so on. Mastering the ability to adjust emotions or words and deeds such as self-regulating depression, dissatisfaction and irritability, and learning to maintain an optimistic and peaceful attitude is a necessary quality to relieve psychological anxiety. What\u2019s more, traditional Chinese culture contains rich and profound psychological values, among which the representative works, such as Jung\u2019s theory of analytical psychology, are greatly inspired by traditional Chinese culture. The Chinese government attaches great importance to the inheritance of traditional Chinese opera, and has issued relevant policies such as \u201cOpinions on the Implementation of traditional Chinese Opera on Entering the Campus\u201d, \u201cOpinions on Comprehensively Strengthening and Improving School aesthetic education in the New Era\u201d, \u201cCompulsory Education Curriculum Plan and Curriculum Standards (2022 Edition Curriculum Standard)\u201d and so on to further encourage the inheritance and development of traditional Chinese opera, which promotes the mental health development of students to a large extent. In the era of new media, it should be remembered that only through continuous innovation can the inheritance methods and means of traditional Chinese opera achieve more remarkable results.Subjects and Methods: Relying on its advantages of low cost, immediacy, fast interaction, etc., the new media has become an important communication platform for traditional Chinese opera. Taking TikTok and Bilibili as an example, the author uses a combination of quantitative analysis and qualitative research to carry out research, and then analyzes the characteristics and trends of people\u2019s cognition, aesthetics and other aspects of traditional Chinese opera, so as to put forward targeted plans for primary and secondary school students to improve their cultural spiritual literacy, enhance the sense of national cultural identity and strengthen their mental health.Results: According to some relevant surveys, there are still insufficiency in netizens\u2019 awareness of traditional Chinese opera inheritance and knowledge reserve. In order to promote the physical and mental health of the general public through the dissemination of traditional Chinese opera, it is really necessary to cultivate their appreciation ability of traditional Chinese opera from an early age, strengthen the promotion of aesthetic education infiltration practice activities on primary and medium-sized campuses, and realize the whole process of aesthetic education for the whole people.Conclusions: The peaceful, harmonious, tenacious and optimistic aesthetic characteristics embodied in the traditional Chinese opera will not only have a positive guidance to the audience\u2019s psychology, but also strengthen their sense of national cultural identity and enhance their national cohesion. Additionally, while inheriting traditional Chinese culture, we should realize that the personality development and mental health of students and always bear in mind that the cultivation of aesthetic consciousness should be cultivated from an early age. What counts most is that, rich and colorful traditional Chinese opera aesthetic education activities should be designed according to the psychological characteristics and learning ability of students of different ages.aShuhan Hua School of Visual Communication, Lu Xun Academy of Fine Arts, Liaoning Province, China.Background: Art therapy is a separate discipline born in Europe in the 1930s and 1940s from the fusion of art and psychology as a form of creative expression for therapeutic purposes. The art therapy process consists primarily of the creation of art as therapy itself, and the resulting interaction between the practitioner and the subject. Art therapy has been widely used in Europe and the United States and has been shown to have a positive effect on a person\u2019s mental health and to alleviate many mental illnesses through art therapy, while art therapy is still in its infancy in theory and practice in China.Subjects and Methods: This paper first discusses the relationship between art creation and mental health, and then goes through the applications of art therapy in life, medicine and society respectively, pointing out through case studies that art creation can release psychological stress, relieve pain, alleviate illness and make a prominent contribution to mental health, followed by a brief overview of the current state of development of art therapy in China.Results: Artistic creation in psychological healing is not only an expression of one\u2019s emotions, but also a clear contribution to physical and mental health.Conclusions: Art therapy is an art of communication methods that has made an outstanding contribution not only to the psychological meaning of visual symbolism, to the relationship between creativity and health, but also to alternative therapeutic approaches. In the future this discipline will play an even greater role in building the field of mental health and has even greater potential to be explored. It has a role to play in human understanding of the self, healing and healthy living that cannot be ignored.a, Luxia LinaYanrui Jiaa School of Business Administration, Jimei University, Xiamen, Fujian 361021, China.Background: With the rapid development of Internet and information technology, a number of \u201cnet celebrities\u201d with distinctive features and economic benefits have emerged on social media platforms. Through social media platforms, net celebrities conveyed information about corporate brands or products to consumers, which improved their visibility and profoundly affected people\u2019s online consumption intention and mood. It is an emerging trend for companies to rely on social media platforms to influence consumers\u2019 shopping behavior through the Netflix model.Subjects and Methods: This paper firstly explained the theoretical foundation of social media and the current situation of Netflix, and analyzed the influencing factors of consumers\u2019 online purchase intention and mood, then deduced the influencing factors of consumers\u2019 purchase behavior under the Netflix model. Secondly, through the empirical study of quantitative analysis, the model of the influence of Netflix communication on consumers\u2019 purchase intention was constructed, with consumers\u2019 purchase intention as the dependent variable and with the product factor, the Netflix factor and the perception factor as independent variables. Finally, relevant conclusions were drawn by using questionnaires, SPSS data correlation analysis and regression analysis.Results: The factors that positively influence consumers\u2019 purchase intention and mood under Netflix social communication include product quality, users\u2019 product evaluation, interactive attitude of Netflix, multi-channel publicity of Netflix, and consumers\u2019 perceived value of the product. The specific descriptions are as follows. The higher the product quality, the better the consumer\u2019s shopping experience. The better the user\u2019s product evaluation, the stronger the consumer\u2019s purchase intention. The good interactive attitude can meet the consumer\u2019s demand. The multi-channel publicity both reduces the cost and expands the effect of Netflix. The higher the consumer\u2019s perceived value of the product, the stronger the consumer\u2019s purchase intention. In contrast, product information and perceived risk have no positive influence on consumers\u2019 purchase intention, i.e., specific and accurate product information does not have a significant positive influence on consumers\u2019 purchase intention, and consumers\u2019 perceived risk of the product has no significant negative influence on purchase intention.Conclusions: Marketing suggestions for enterprises to effect consumers\u2019 purchase intention and mood are presented. Firstly, enterprises can use differentiated Netflix groups to improve consumers\u2019 perceived value of their products. Secondly, focus on interactive marketing. Net celebrities should publish content according to consumers\u2019 interests, share their own real feelings of using the products, and actively interact with consumers on platforms such as video, live streaming or social. Thirdly, improve product quality. Companies can enhance consumer participation, so that consumers can participate in the process of designing and improving products. Finally, establish channel advantages. Enterprises should choose the right social media platform for cooperation according to their own product and industry characteristics to establish their long-term channel advantages.aFeng Yanga College of Chinese Language and Culture, Zhejiang Yuexiu University, Shaoxing, Zhejiang 312000, China.Background: This paper combines respiratory and acoustic signals from a physiological and acoustic perspective to write a program that divides the prosodic hierarchy based on the magnitude of respiratory reset amplitude, explores the corresponding relationship between the respiratory reset amplitude and the prosodic hierarchy, also explores the respiratory physiological mechanisms of acoustic features such as pauses, pitch dips, and amplitude dips in speech flow. To provide methods for speech rehabilitation training, improve patients\u2019 speech naturalness and fluency, enhance the effect of speech rehabilitation training. It provides a new method and thought for speech rehabilitation.Subjects and Methods: In this paper, the acoustic analysis method is used to record the voice and respiratory signals of 80 short passages read by four announcers. Write a Matlab program to analyze the four signals. Firstly, automatically mark the various respiratory reset positions of the chest and abdomen respiratory signals, calculate parameters such as respiratory reset amplitude, inhalation and exhalation duration, and then divide the prosodic hierarchy based on the magnitude of respiratory reset amplitude, mark the boundaries of prosodic units, and finally output parameters such as the duration, fundamental frequency, and amplitude of each prosodic unit.Results: The results show that there is a corresponding relationship between the repositioning amplitude of respiration and the prosodic boundary in discourse reading. (1) In discourse reading, the amplitude of respiratory reset can be divided into three levels. The first level respiratory reset corresponds to paragraph or complex sentence boundaries, the second level respiratory reset corresponds to clause boundaries, and the third level respiratory reset corresponds to prosodic phrase boundaries. (2) The pause coincides with the inspiratory segment, and the reason for the pause is to inhale for pronunciation, while the phonetic segment coincides with the expiratory segment. (3) Along with the pitch dip, the amplitude dip occurs simultaneously within a breathing cycle. The dip is caused by the continuous exhalation of air flow from the lungs during the exhalation pronunciation stage, resulting in a decrease in air pressure. The focus stress is mainly manifested as an increase in pitch. Phonological fluency is related to respiratory reassignment, which can be used for phonological rehabilitation training.Conclusions: The physiological reason for the pause is the completion of inspiratory movement, and the downward pitch and amplitude decline are caused by the attenuation of the airflow pressure in the expiratory segment of the lungs. In the process of language rehabilitation training, patients should master the correct breath control method, and adopt different sizes of breath resets according to the pause position of the discourse, so as to improve the effect of language rehabilitation training and the naturalness of the pronunciation of reading training.This work was supported by Major Projects of National Social Science Foundation \u2018Research on the contact and integration of Chinese languages\u2019 (Grant No.22&ZD213).a, Huiqiong HubBin Liua Jingzhou Central Hospital, Jingzhou 434020, China, b Hubei College of Chinese Medicine, Jingzhou 434020, China.Background: To provide reference for the diagnosis and treatment of influenza A (H3N2) in clinic and to reduce the mortality in patients with influenza A (H3N2) through the study on the level change of serum amyloid A (SAA), interleukin-6 (IL-6) and hypersensitive-C-reactive protein (hs-CRP) in patients with influenza A (H3N2).Subjects and Methods: 177 patients who had the clinical manifestations of influenza and were positive for H3N2 subtype influenza virus in the nucleic acid testing of the nasopharyngeal swab or sputum samples in Jingzhou Central Hospital from January 1, 2022 to December 30, 2022 were selected as the influenza A (H3N2) group. Another 169 subjects who underwent health examinations during the same period were selected as the healthy control group. The venous blood samples were collected in the influenza A (H3N2) group and healthy control group to detect the levels of SAA, IL-6, and hs-CRP in peripheral blood. The levels of the SAA, IL-6, and hs-CRP in the influenza A (H3N2) group and healthy control group were analyzed, and area under the curve (AUC), cutoff value, sensitivity, specificity, and Yoden index of single detection of SAA, IL-6, and hs-CRP and joined detection (SAA + IL-6+ hs-CRP) were compared to analyze the diagnostic value of single detection and joint detection on the diagnosis and treatment of influenza A (H3N2).Results: The levels of SAA, IL-6 and hs-CRP in influenza A (H3N2) group were 46.49\u2009\u00b1\u200929.08\u2005mg/L, 22.03\u2009\u00b1\u200911.59 pg/mL and 14.88\u2009\u00b1\u20097.80\u2005mg/L, respectively, significantly higher than those in healthy control group. The differences of SAA, IL-6 and hs-CRP between the two groups were statistically significant in test . The area under the curve (AUC), cutoff value, sensitivity, specificity and Yoden index of single detection of SAA, IL-6 and hs-CRP in influenza A (H3N2) group showed that the cutoff value of the serum SAA was 12.40\u2005mg/L with AUC, sensitivity, specificity, and Yoden index of 0.952, 0.819 and 0.988, respectively, significantly higher than that of IL-6 and hs-CRP; the AUC, sensitivity, and Yoden index of the joint detection (SAA + IL-6+ hs-CRP) were 0.964, 0.938, and 0.820, respectively, higher than those in the single detections; however, the specificity of the joint detection (SAA + IL-6+ hs-CRP) in influenza A (H3N2) group was 0.882, lower than that in the single detection.Conclusions: Markedly increased level of serum SAA can be found in patients with influenza A (H3N2). The joint detection of of SAA, IL-6 and hs-CRP is helpful for the diagnosis and evaluation of conditions of patients with influenza A (H3N2), which can be used as the reference for the diagnosis and treatment of influenza A (H3N2) in clinic with significant clinic value.a, Longhui ZhoubLiqiu Lina College of Physical Education and Health, Guangdong Vocational College of Science and Technology, 519090, Zhuhai, Guangdong, China, b Physical Education, Guangdong Jiangmen China Medicine College, Jiangmen 529000, Guangdong, China.Background: To briefly discuss related strategies of integrating sports psychology into physical education teaching in colleges and universities, so as to provide experience reference and help for practitioners in related industries, and promote the development of sports literacy of students in colleges and universities. This paper discusses the significance of integrating physical education into sports psychology health education in colleges and universities, and puts forward relevant countermeasures accordingly, in order to provide reference for physical education teachers in colleges and universities.Subjects and Methods: Questionnaire survey, logical analysis, expert interview and empirical research were used to explore the significance of integrating physical education into sports psychology health education in colleges and universities, and corresponding countermeasures were put forward.Results: In the physical education teaching practice of colleges and universities, it is necessary to infiltrate and integrate the related content of sports psychology, so as to continuously enhance the mental health quality in the teaching process and achieve excellent results in sports training. Constantly improve the ability of thinking control and self-regulation control of college students, to improve the physical psychology of college students to lay the foundation. In order to realize the cultivation of mental health quality of young people in colleges and universities in sports, the organization and development of sports should be guided by the law of physical and mental development of young people and the law of physical education teaching, take positive emotion, experience success, democratic autonomy and individual guidance as the basic principles, and take the organic, moderate and flexible penetration in the process, content and method of sports as the main strategy, so as to be practical. Training design and effective classroom management as process control to construct the physical sports youth mental health quality training path.Conclusions: By analyzing the correlation between the discipline orientation of sports psychology and the connotation of sports core literacy, the promoting effect of sports psychology research content on sports core literacy, and how to cultivate sports core literacy in sports psychology teaching, this paper tries to clarify the role of sports psychology curriculum in promoting students\u2019 sports core literacy, so as to better cultivate students\u2019 knowledge of sports psychology. Ability to solve problems related to sports practice.a, Manyi Chenb, Junling Maa, Cheng Yuc, Chuanping LeidLi Jiaa School of Humanities and Management, Guangdong Medical University, Dongguan, Guangdong 523808, China, b Nanling Corridor Country Revitalization Research Institute, Xiangnan University, Chenzhou 423000, China, c School of Medicine, Sun Yat-sen University, Shenzhen 518107, China, d School of Marxism, Sun Yat-sen University, GuangZhou, Guangdong 510275, China.LJ and MC contributed equally to this study.Background: The frequent occurrence of doctor-patient conflicts and medical disputes in the process of healthcare system reform has made medical humanities research a critical issue in public and scientific research. Despite the increasing number of studies on medical humanities, there is a lack of comprehensive and systematic combing based on bibliometrics.Subjects and Methods: This study uses author collaboration, institutional collaboration, keyword co-occurrence, cluster analysis, Structural Variation Analysis, bipartite graph overlay, and country and keyword bimodal mapping construction based on medical humanities-related research literature data from 1974-2022 in the Web of Science database to comprehensively and systematically sort out medical humanities.Results: The study found that the authors in the field of medical humanities research have been working on the following topics: scientific cooperation, research hotspots, and frontiers, knowledge base evolution trends, and prediction of potential, influential literature. It was found that author co-location and institutional cooperation in medical humanities research are relatively close, forming a complex cooperative network. Institutional research is more active in countries such as the United States, Canada, and the United Kingdom. The knowledge base and significant fields in medical humanities research show diversified development, and the intersection of subject areas is becoming stronger. Hot research issues represented by medical humanities education, medical humanities care, doctor-patient communication, and medical ethics have been formed. Moreover, 11 pieces of potentially influential literature have been mined.Conclusions: This study uses bibliometrics to systematically sort out the development trend, research hotspot and potentially influential literature in the field of medical humanities research since 1974, so as to provides relevant theoretical references and references for research in medical humanities and even medical humanities education.This work was supported by a project grant from National Social Science Fundation: Research on China\u2019s Experience and Global Sharing in Building a Human Health Community (Grant No. 20&ZD122); Teaching reform Project of Guangdong Medical University \u201cResearch on Humanistic Quality Training Path of Medical Students in the Vision of Collaborative Education\u201d (Grant No.1JG21083); Guangdong Provincial University characteristic innovation project \u201cConstruction of Humanistic Medicine from the Perspective of Life Culture\u201d (Grant No.2021WTSCX034).a, Deling Yanga, Feng Fenga, Jianhua Yangb, Xijun Huanga, Shiqi ChenaXiao Zhanga Guangzhou Academy of Fine Arts, Guangzhou, China, b Qingdao University of Science and Technology, Qingdao, China.Background: To explore the main technical applications for increasing the effectiveness of smart museum exhibitions in providing psychologically therapeutic services for visitors in the aftermath of the COVID-19 pandemic, with the goal of investigating the development of museum services for psychological treatment of visitors.Subjects and Methods: From the perspectives of art therapy and cognitive psychology theory, this paper provides a literature review of relevant papers and monographs on social psychological therapy in smart museums. Focusing on museums\u2019 psychological therapeutic services, the analysis examines trends in the development of smart museum exhibition technologies for visitors\u2019 psychological therapeutic services.Results: The psychological problems caused by the pandemic are similar to those of post-traumatic stress disorder (PTSD), making museums an ideal platform for artistic experiences and psychological healing. First, museums provide visitors with an experience environment that reflects a beautiful society and life, helping them to recover from negative emotions and addressing issues related to intrusive memory affecting psychological health. Second, museums offer creative exhibition activities to enhance social communication, helping visitors overcome fear and anxiety, while cultivating confidence and hope for a better future, addressing psychological health problems related to excessive pessimism leading to a loss of willpower. Third, museums provide an enjoyable experience that helps to heal the soul, addressing psychological health problems related to social anxiety.Conclusions: Firstly, smart museums can provide more open and inclusive services to the public by integrating online and offline exhibitions through the use of virtual reality and mobile communication technologies. By breaking down social barriers and alleviating post-pandemic social anxiety, smart museums can attract visitors to return to the museum environment. Secondly, by closely integrating artificial intelligence, the Internet of Things and collection resources in the planning of museum exhibitions, smart museums can create distinctive features that provide more targeted healing solutions for diverse groups of people with various psychological disorders. Thirdly, smart museums can explore scientific methods for treating psychological problems through exhibitions by leveraging big data, cloud computing and collaborating with relevant institutions, thereby making the focus on visitors\u2019 psychological health an important service content of museums. This study aims to contribute new technological applications to the development and construction of enhancing visitors\u2019 psychological health in museum exhibitions.This research partially funded by Ministry of Education of China under the Humanities and Social Sciences with the project \u201cResearch on the normal form of personalized interpretation of smart museum exhibition\u201d (project number 21YJA760093). The research is partially supported under and the 2021 Guangdong province graduate education innovation plan with the project \u201cGuangdong joint postgraduate training demonstration base\u201d (project number: 6040121010). Thanks should go to Ministry of Culture and Tourism of China under the Art Research Key Project Support Plan of 2022 Social Science Fund with the project \u201cComparative Study of Chinese, Japanese and Hollywood Animation Film Aesthetic and Cross-Cultural Communication Strategy\u201d (project number 22AC003). Special thanks to Guangzhou Academy of Fine Arts for the support of project on Film and Television Special Effects (project number: 6040321054), Science and Technology Art Experimental Class (project number: 6040321002), Research on the Teaching Method of Cultivating Graduate Students\u2019 Cross Media Art Creation Practice (project number: 6040122012LHKY), Research on the Design Method of Digital Exhibition in Smart Museums Based on Technology and Art (project number: 23XSC32).a, JinQi SongaXuan Songa Central South University of Forestry and Technology of Business, Changsha 410000, Hunan, China.Background: Based on the sustainable livelihood analysis framework, this paper conducts in-depth research on the impact of livelihood capital and mental health on the differentiation of farmers in mountainous areas. This is important as industrial differentiation provides a reference for promoting multi-channel income generation for farmers and achieving rural revitalization in mountainous areas.Subjects and Methods: A comparative analysis and multivalue selection model were used to explore the occupational differentiation of 180 farmers in mountainous areas of Hunan Province under different influencing factors.Results: The research results indicate that social capital differentiates pure and non-agricultural farmers into part-time farmers. Rich natural capital can attract farmers to differentiate into pure farmers or part-time farmer enterprises. Moreover, increased financial capital will help part-time farmers focus on agricultural production and encourage non-agricultural operators to engage in agricultural operations. The impact of physical capital will transform farmers into pure or non-agricultural full-time farmers. However, farmers with work experience are likelier to choose part-time agricultural forms. Providing agricultural technology training to farmers can help them immerse themselves in agricultural production by improving their production and management abilities. Additionally, mental health positively impacts the differentiation of pure farmers into part-time farmers and the livelihood capital differentiating the farmers depending on the proximity to the central market.Conclusions: The following suggestions are proposed. Increase psychological health training, develop farmers\u2019 enthusiasm, implement \u201cendogenous\u201d and \u201cexogenous\u201d industrial assistance, and ensure employment. Additionally, attention should be paid to optimizing and combining various livelihood capital and increasing immigrant livelihoods\u2019 sustainable endogenous driving force. Moreover, increase opportunities for immigrants to engage in non-agricultural businesses and encourage the development of ethnic minority characteristic tourism industries and online operation of \u201ccharacteristic products\u201d. While increasing support for non-agricultural skill training, it is necessary to assist the psychological health construction of migrant workers\u2019 families mainly engaged in agricultural production. Land asset transfer and appreciation work for contracted land for relocation, mountainous forest land, and homestead land are also important. Finally, restoring social networks, cultural protection, and development for ethnic minority immigrants should be considered.a, Li Zhonga, Qinghong Houa, Yunning TanbChangping Yina School of Accounting, Chongqing University of Technology, Chongqing, China, b School of Accounting, Chongqing Technology and Business University, Chongqing, China.Background: \u201cMitigating and adapting to global warming and reducing carbon dioxide emissions\u201d has become the political consensus of all countries in the world, and is also a common challenge for the world. Greenhouse gas emissions, such as carbon dioxide, not only affect political, economic and cultural development, but also have a significant negative impact on the psychological health and happiness of the general public. In order to reduce carbon emissions, the countries of the world have signed and introduced the Kyoto Protocol, the Paris Agreement, the Glasgow Climate Convention and other international conventions. In September 2020, China proposed at the 75th session of the United Nations General Assembly that \u201cChina should strive to reach peak carbon dioxide emissions by 2030 and achieve carbon neutrality by 2060\u201d .Subjects and Methods: On February 28, 2022, the United Nations Intergovernmental Panel on Climate Change (IPCC) issued a bulletin stating that greenhouse gas emissions such as carbon dioxide can lead to a series of psychological health problems. In order to better reduce carbon emissions, this paper constructs a carbon audit index system under the carbon peaking and carbon neutrality target based on the hierarchical analysis method with the perspective of the audit and the carbon peaking and carbon neutrality target as the guide.Results: This paper constructs a carbon audit index system based on the main line of \u201ccarbon emission policy formulation and implementation \u2192 carbon emission reduction governance investment \u2192 carbon emission project management \u2192 carbon emission governance output \u2192 carbon emission management effect\u201d, in an attempt to comprehensively, systematically and scientifically evaluate and authenticate the carbon reduction and emission reduction behaviors of each region and unit, and suppress the negative impact of carbon emission on people\u2019s psychological health.Conclusions: Carbon emission is a global issue, closely related to human economic and social development and physical and psychological health. As the \u201cinspector\u201d of policy implementation and the main national governance system, we should give full play to the role of audit in promoting the \u201cdouble carbon\u201d work, strengthen the audit supervision of carbon emission policies, projects, funds and benefits, and help achieve the national carbon peaking and carbon neutrality goals.This work was supported by a project grant from China Postdoctoral Science Foundation (Grant No. 2020M683255), and the National Social Science Fund Item (No. 22BJY033), and the Humanities and Social Sciences Project of the Ministry of Education (No. 19YJC630205).a, Deling Yanga, Feng Fenga, Jianhua Yangb, Shiqi Chena, Xijun HuangaXiao Zhanga Guangzhou Academy of Fine Arts, Guangzhou, Guangdong Province, People\u2019s Republic of China, b Qingdao University of Science and Technology, Qingdao, Shandong Province, People\u2019s Republic of China.Background: Contemporary social work and life stress bring about psychological issues such as depression and anxiety. However, due to limited medical resources, it is necessary to explore the use of art healing as a means to provide psychological therapy services to the general public.Subjects and Methods: This study explores the application of traditional immersive garden exhibition art healing as a method of psychological therapy through natural scenery and humanistic art therapy for the general public. Specific research includes the ways in which exhibitions soothe the emotions of the general public, the use of immersive experiential innovative art healing in exhibitions, and the integration of individuals undergoing art healing into society through exhibitions. Through the analysis of psychological therapy cases and qualitative analysis, taking the \u201cThree Mountains and Five Gardens Exhibition\u201d as an example, the application of art healing in exhibitions for psychological therapy is analyzed and studied from the aspects of communicating audience emotions, allowing audiences to immerse themselves in the art field, and creating a panoramic discourse space for artistic symbols to project new emotions from the audience.Results: First, the \u201cThree Mountains and Five Gardens Exhibition\u201d constructs artistic discourse and achieves emotional resonance and psychological comfort for the audience. Second, virtual reality immersive exhibitions encourage audience participation and artistic experience, achieving emotional healing. Third, the exhibition integrates artistic symbols, recreates cultural symbol representations through various media, and forms a panoramic discourse space constituted by artistic symbols, projecting the audience\u2019s emotions into a new cultural imaginary space for psychological healing.Conclusions: First, art healing fulfills the social responsibility of exhibition updates, reflects the exhibition\u2019s deeper care for the public, and extends the psychological therapy services of traditional immersive garden exhibitions. Second, exhibitions innovate the psychological therapy methods of art healing. Through the panoramic discourse space created by the exhibition\u2019s artistic symbols, the audience can project new emotions and achieve physical and mental healing. Third, the healed audience can better express their thoughts and release emotions through exhibitions to enhance communication. Therefore, the exhibition of innovative art therapy can serve the mental health of the public in a new way.This research partially funded by Ministry of Education of China under the Humanities and Social Sciences with the project \u201cResearch on the normal form of personalized interpretation of smart museum exhibition\u201d (project number 21YJA760093). The research is partially supported under and the 2021 Guangdong province graduate education innovation plan with the project \u201cGuangdong joint postgraduate training demonstration base\u201d (project number: 6040121010). Thanks should go to Ministry of Culture and Tourism of China under the Art Research Key Project Support Plan of 2022 Social Science Fund with the project \u201cComparative Study of Chinese, Japanese and Hollywood Animation Film Aesthetic and Cross-Cultural Communication Strategy\u201d (project number 22AC003). Special thanks to Guangzhou Academy of Fine Arts for the support of project on Film and Television Special Effects (project number: 6040321054), Science and Technology Art Experimental Class (project number: 6040321002), Research on the Teaching Method of Cultivating Graduate Students\u2019 Cross Media Art Creation Practice (project number: 6040122012LHKY), Research on the Design Method of Digital Exhibition in Smart Museums Based on Technology and Art (project number: 23XSC32).a, Menghua Liub, Qian Dua, Xianglei ZhucLongchao Xua Department of Social policy & Social work, School of Humanities, Taiwan National Chi Nan University, Taiwan, China, b Graduate School, University of Perpetual Help System DALTA, Las Pi\u00f1as City, Philippines, c Department of Health Sociology, School of Humanities and Management, Guangdong Medical University, Dongguan, China.LX and ML contributed equally to this study.Background: In recent years, the widespread use of smart devices for the elderly has also triggered more and more attention to how the elderly use smart devices and the importance of smart devices for the health management of the elderly. To this end, this study will investigate the relationship between the use of smart devices and the health management of the elderly to provide a scientific reference basis for optimizing the use of smart devices and implementing health management in the elderly.Subjects and Methods: This paper mainly uses the ordered Probit model to study the effects of smart device use on physical health and mental health of older adults. This paper examines the effects of attitudes, subjective norms, and perceived behavioral control on the physical and mental health of older adults based on planned behavior theory using CGSS 2017 data on older adults aged 60 years and older as a research sample, and analyzes the effects of educational attainment on the relationship between them.Results: It was found that more positive attitudes towards smart device use were associated with higher levels of physical and mental health. However, the moderating effect of educational attainment on the relationship between smart device use and physical and mental health was not significant. In addition, this paper makes the following recommendations: (1) communities increase education and training on the application of smart device for older adults. (2) Family as the smallest unit of support system, with intergenerational interaction to promote digital feedback, can effectively drive the digital integration of older adults.Conclusions: This study found that in China, older adults have more positive attitudes toward smart device use. Moreover, the more positive the attitude toward smart device use, the higher the level of physical and mental health. However, the moderating effect of education level on the relationship between smart device use and physical and mental health was not significant, but the regression coefficient was negative. This paper to provide more practically meaningful guidance and suggestions for the use of smart devices in the elderly, and to provide better support and assistance for health management and smart device use in the elderly.This article is the research output of the introduced talent scientific research launch fund project of Guangdong Medical University--\u201cApplication and improvement research of innovative technology of social work service for the Elderly\u201d.a,b, Yongtian Wub, Peitao Yangc, Xuekai WeibJianping Liua College of Civil and Environmental Engineering, Hunan University of Science and Engineering, Yongzhou, Hunan 425199, China, b Bama Hetai Longevity Industry Co., Ltd., Bama, Guangxi 547500, China, c College of Economics, Central South University of Forestry and Technology, Changsha, Hunan 410004, China.Background: The psychological recognition level of rural residents is the basis and prerequisite for choosing and promoting innovative development of rural industries. However, for a long time, the relatively weak foundation of rural industrial development, insufficient competitive advantages in industries, and relatively low output return rates have led to deep doubts among rural residents about whether they can promote innovative development of rural industries. It is urgent to alleviate the psychological anxiety of rural residents in both theoretical and psychological aspects, this has important theoretical and practical significance in promoting innovation and sustainable development of rural industries, achieving coordinated development between urban and rural areas and regions. However, there has been no research exploring the correlation and impact of rural industrial development and residents\u2019 psychological interaction from the perspective of psychological health and symbiosis theory.Subjects and Methods: Using the research method of symbiosis theory, an in-depth analysis and summary of the common anxiety problems in villagers\u2019 psychology were conducted from the perspective of mental health management. A comprehensive and systematic study in Some aspects of the construction and improvement of villagers\u2019 psychological health, improvement of psychological cognition level, composition of rural industrial symbiosis system, symbiotic connection mechanism, symbiotic interface, symbiotic mode, symbiotic ecosystem and other aspects has been researched on the interactive mechanism between the psychological logic and motivation of villagers\u2019 psychological anxiety and the innovative development of rural industries.Results: The research results indicate that villagers\u2019 psychological anxiety is the fundamental obstacle that restricts the innovative development of rural industries. The level of villagers\u2019 psychological health is the fundamental prerequisite for determining and influencing the innovative development of rural industries. Insufficient or biased psychological cognition of villagers is the primary obstacle that hinders the development of rural industries, and the lag in development awareness and thinking is the internal reason that hinders the development of rural industries, The insufficient level and depth of integration are the main practical problems faced by the development of rural industries, and the weak linkage mechanism is the fundamental reason that restricts the development of rural industries.Conclusions: There is an urgent need to build a sustainable development path for rural industries in some aspects of alleviating villagers\u2019 psychological anxiety, improving their mental health level, improving their psychological cognition level, strengthening the concept of innovative symbiotic development, constructing a connecting carrier platform, constructing efficient symbiotic mode, smoothing symbiotic interfaces, creating a positive symbiotic environment, constructing symbiotic connection mechanism, and strengthening co-effectiveness, in order to create a symbiotic ecosystem for innovative development of rural industries, To provide theoretical and practical references for promoting the sustainable development of rural industries.This work was supported by a project grant from Natural Science Foundation of Hunan Province(Grant No.2019JJ40545) and Hunan University of Science and Technology Applied Characteristic Discipline Construction Project(Grant No.18TSXK-001).a, Shanshan Niua, Yijian WangaChunyi Caoa Zhejiang Institute of Economics and Trade, Zhejiang Province, Hangzhou, China.Background: To achieve rural revitalization more quickly and effectively, it is necessary to enhance the quality of the vast peasantry, as farmers are an important human resource for rural revitalization. However, there are still issues such as low mental health level of farmers and long-term neglect of farmers\u2019 psychological problems. Therefore, it is imperative to conduct research on improving the mental health level of farmers in the context of rural revitalization.Methods: Based on Maslow\u2019s Hierarchy of Needs theory, research and analyses of farmers\u2019 actual needs can be conducted. With the support of metaverse technologies, artificial intelligence and virtual reality technologies, an all-in-one agricultural assistance platform can be built to provide innovative digital content applications for farmers\u2019 production, sales, and livelihood.Results: Based on the agricultural assistance platform, 3D virtual sports interaction with fun elements can be utilized to address the issues of inadequate sports facilities and farmers\u2019 weak awareness of fitness, thereby improving farmers\u2019 physical fitness and meeting their physiological needs. Through online and offline e-commerce skills training and the agricultural assistance platform, the problem of farmers lacking e-commerce skills and sales channels can be solved, thus fulfilling farmers\u2019 safety needs. By leveraging metaverse technologies to allow users to understand the original production process of products, communication between farmers and consumers can be promoted, satisfying farmers\u2019 social needs. Through big data and AI technologies, brand planning and design for agricultural products can be carried out, thus meeting farmers\u2019 self-actualization needs and promoting the holistic development of rural residents\u2019 physical and mental health.Conclusions: As a research hotspot in the digital economy, the integration and development of metaverse with the agricultural field holds great potential. Particularly, the innovative approach of incorporating metaverse into farmers\u2019 mental health in this article is noteworthy. Improving the overall mental well-being of rural areas is crucial for ensuring sustainable development in rural areas, and there is still a long way to go.a, Weifeng Xieb, Guo Fengb, Pengpeng Yub, Xianhui DuanaYanhua Zhoua College of Urban Construction, Jiangxi University of Technology, Nanchang 330098, China, b Department of Material Science and Engineering, Jingdezhen Ceramic Institute, Jingdezhen 333000, China.YZ and WX contribute equally to this work.Background: The rapid development of phosphor application materials and technology provides a very important platform and means for the research and development of medical detection, and the key to effective control and treatment of diseases is that accurate detection can be carried out at an early stage, so the development of new, stable, simple preparation conditions, practical value of red phosphor is a very meaningful work. Near-infrared light has important applications in security monitoring, biomedicine, plant lighting, spectral detection and other fields. Traditional near infrared light source cannot meet people\u2019s demand for fast and convenient use of near infrared equipment. Near-infrared phosphor conversion LED can make up for the deficiency of the traditional near-infrared light source, and it is the most promising new near-infrared light source to replace the traditional near-infrared light source.Subjects and Methods: Red phosphor has excellent optical properties, can emit red fluorescence, has the advantages of high stability and high efficiency, and can be used for biomedical detection. NaLa4(SiO4)3F: Eu3+ red phosphor was prepared by solid-phase method, and the influence of preparative process parameters on performance was systematically studied.Results: The study found that: the minimum temperature for the synthesis of NaLa4(SiO4)3F phase by solid-phase method was 750\u2103, the minimum temperature for the preparation of NaLa4(SiO4)3F pure phase was 850\u2103, and the optimal heat treatment temperature is 950\u2103. The optimal dosage of sodium fluoride (multiple of relative stoichiometric ratio) x = 1.3. The use of heat treatment and heterogeneous methods to strengthen the conversion of fluorescent materials in disease and biomedical detection has great significance and considerable application prospects. It is believed that the thermal stability regulation and design of phosphor will become an important research hotspot of phosphor research, will be widely concerned by researchers, and will become a kind of very potential phosphor matrix materials.Conclusions: The phosphor particles prepared by the solid phase method are spherical-shaped, with clear edges and surfaces, narrow particle size distribution, and are suitable for LED packaging. NaLa4(SiO4)3F: Eu3+ red phosphor will become an important tool to assist related medical testing, and is also widely used in portable and real-time related testing, providing important support and guarantee for medical testing.This work was supported by the Higher Education Teaching Reform Project of Jiangxi Provinc China (JXJG-22-24-5), the National Natural Science Foundation of China , Jiangxi Provincial Natural Science Foundation , Open fund project of the Key Laboratory of Inorganic Coating Materials, Chinese Academy of Science (ICM-202001), the Projects of Jiangxi Provincial Department of Science and Technology (20202BABL214013), the Science Foundation of Jiangxi Provincial Department of Education .aShaoyun Yanga Business Administration School, Zhuhai Technology Colleg, Zhuhai City 516000, China.Background: In recent years, with the acceleration of urbanization and economic development, the sense of happiness and belonging brought by cities has not been satisfactory. Cities gather population and various resources, but at the same time, the oppression and decadence caused by living issues such as wages, childbirth, education, transportation, and prices are becoming increasingly severe. Citizens\u2019 impression of the city has changed from a warm home to ubiquitous work pressure. This phenomenon constantly reminds us that there have been social and psychological problems in China\u2019s urbanization process. A series of popular communication trends such as \u201cfleeing Beijing, Shanghai, and Guangzhou\u201d have shown us that the main body of urban image shaping should be understanding the happiness of life, reflecting more on the psychological health and spiritual satisfaction of citizens. Nowadays, people have created increasingly diverse forms of communication through the communication platforms provided by modern technology, and their recognition of regional culture is becoming increasingly strong. The increasing pressure and anxiety in urban life are psychological issues in the development of Chinese cities, but these issues also provide soil for the construction and development of urban culture and image.Subjects and Methods: Urban image refers to various perceptual factors presented by a city in the public\u2019s mind, which can be the influence of various aspects such as architecture, culture, history, environment, cultural activities, etc., as well as people\u2019s understanding and interpretation of the symbols and meanings generated by these factors.Audience psychology refers to the thinking, emotions, and behavioral reactions that occur during the process of receiving and processing information. In communication activities, understanding the characteristics and changing trends of audience psychology can effectively formulate communication strategies and creativity, thereby improving communication effectiveness.Literature research and data analysis methods are used in this article. In the current era of information explosion, all kinds of communication media are using different communication strategies to attract the attention of the audience. In fact, they are trying to break through the audience\u2019s psychological system: make appropriate information according to the criteria of the audience\u2019s psychological selection, so that the information transmitted can enter the audience\u2019s psychological system faster and better through the psychological selection of the audience. Therefore, the psychological selection process of the audience has become the \u201cinvisible axis\u201d of various media production content today.Understanding the psychological characteristics of the audience is the foundation for developing effective communication strategies. Communicators need to deeply understand the characteristics and needs of the audience, design and optimize communication content and methods based on the audience\u2019s psychology, in order to maximize the effectiveness of communication.Results: The attractiveness of a city\u2019s image to its audience is not only an external manifestation of its comprehensive strength, but also a symbol of its soft power. People come with \u201cdreams\u201d and strive for their dreams in the city. However, when the development of the city encounters bottlenecks or lags behind, people\u2019s dreams will also be shattered, leading to a series of social psychological effects such as weakened individual psychological feedback and increased social exclusion. When regional economic development lags behind, people tend to focus more on material interests rather than emotional needs, but at the same time, the motivation to participate in social or economic activities decreases, entering a vicious cycle. Due to the motivating effect of urban image internally and the attractive effect externally, the dissemination of urban image will expand the space for urban development: the combination of the creativity of foreign residents and new spaces provides vitality for urban development, while also providing a path to realize dreams and spiritual support for citizens. Urban popularity is an important indicator of urban development. Through urban image promotion, more people can understand the city, generate interest and favoritism towards the city, and attract more people to travel, study, work, and live in the city.Conclusion: In recent years, with the acceleration of urbanization and economic development, the sense of happiness and belonging brought by cities has not been satisfactory. Cities gather population and various resources, but at the same time, the oppression and decadence caused by living issues such as wages, childbirth, education, transportation, and prices are becoming increasingly severe. Citizens\u2019 impression of the city has changed from a warm home to ubiquitous work pressure. This phenomenon constantly reminds us that there have been social and psychological problems in China\u2019s urbanization process. A series of popular communication trends such as \u201cfleeing Beijing, Shanghai, and Guangzhou\u201d have shown us that the main body of urban image shaping should be understanding the happiness of life, reflecting more on the psychological health and spiritual satisfaction of citizens. Nowadays, people have created increasingly diverse forms of communication through the communication platforms provided by modern technology, and their recognition of regional culture is becoming increasingly strong. The increasing pressure and anxiety in urban life are psychological issues in the development of Chinese cities, but these issues also provide soil for the construction and development of urban culture and image.a, Yuxing Shanga, Qiaoyi Lva, Yangjing Zhaoa, Hui Wanga, Weili Caib, Hui Zhangc,Yanling Zhud, Xiuting Liangd, Qixiang Shaoa,bZhanghui Lia Reproductive Sciences Institute, Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang 212013, Jiangsu, P. R. China, b Institute of Medical Genetics and Reproductive Immunity, School of Medical Science and Laboratory Medicine, Jiangsu College of Nursing, Huai\u2019an 223002, Jiangsu, P. R. China, c Department of Clinical Laboratory, The Affiliated Hospital of Jiangsu University, Zhenjiang 212001, Jiangsu, P. R. China, d Department of Gynaecology and Obstetrics, The Xuzhou Hospital Affiliated to Jiangsu University, Xuzhou 221005, Jiangsu, P. R. China.Background: Ovarian cancer (OC) is one of the three malignant tumors with the highest mortality rate in the female reproductive system. Owing to the special anatomic location and the lack of typical clinical symptoms, the early onset is insidious. Due to drug resistance and easy recurrence, the 5-year survival rate of ovarian cancer remains has not improved significantly in the past thirty years, and mortality rate is also at a very high level, despite the great progress in chemotherapy, surgery and immune therapy. However, the mechanism of oncogenesis, progression, recurrence, and drug resistance of ovarian cancer have not been fully elucidated. Recently, it has been reported that N6-methyladenosine (m6A) and long non-coding RNAs (lncRNAs) play pivotal roles in ovarian cancer initiation, progression, drug resistance and recurrence. Whereas, the regulatory role and its mechanisms of m6A modification on lncRNAs in ovarian cancer are still unclear. Therefore, it is important to elucidate the regulatory role of m6A modification of lncRNAs and its effects on the development and prognosis of ovarian cancer.Subjects and Methods: We comprehensively evaluated the m6A modification patterns of 29 m6A modification-related genes in 374 samples from the TCGA ovarian cancer database, constructed an independent prognostic model based on m6A modification-related lncRNAs. ROC analysis was performed to verify the reliability of the prognostic model based on the age, stage and type of the patients. The data of the patients were divided into high-risk group and low risk group. TMB analysis, GO and KEGG pathway analysis of immune cells, immune infiltrate analysis and drug sensitivity analysis were performed in the prognostic model. QRT-PCR was used to detect the expression levels of 5 m6A modified lncRNAs in ovarian cancer tissues, and the changes of immune checkpoints in peripheral blood of ovarian cancer patients were analysed by flow cytometry.Results: The prognosis model that we constructed was reliable, through the prognosis model, we found that the prognostic characteristics of patients with ovarian cancer are related to the prognostic model, Naive B cell was necessary and played an important role in ovarian cancer, TIGIT had high value in immune checkpoint analysis in prognostic models, and Pazopanib might be a targeted medicine for ovarian cancer. In tumor tissues and peripheral blood of patients, we further verified that FOXP4-AS1 played a m6A dependent role in ovarian cancer and TIGIT was abnormally elevated in the tumor microenvironment of patients with ovarian cancer.Conclusions: The results demonstrated that m6A modification-related lncRNAs participated in malignant progression, recurrence, and drug resistance of ovarian cancer by regulating the tumor immune microenvironment. FOXP4-AS1 may will serve as a potential biomarker for ovarian cancer.This work was supported by the National Natural Science Foundation of China (82071738). Institutional Review Board Statement: The study was conducted in accordance with the guidelines of the Declaration of Helsinki, and was approved by the Ethics Committee of the Affiliated Hospital of Jiangsu University (KY2022K0913) and the Ethics Committee of Xuzhou Hospital Affiliated of Jiangsu University (2019-02-010-K01), respectively.a, Wei Cuia, Lisheng ChenaWenlong Zhoua Shandong Youth University of Political Science, Shandong, China.Background: With the development and progress of the economy and society, accounting work is playing an increasingly important role. Accounting psychological barriers can easily lead to unethical accounting behavior. How to provide psychological adjustment is currently the focus of accounting work. This article explores the relationship between accounting psychological barriers and unethical accounting behavior from the perspective of accounting psychology, focusing on the specific manifestations of accounting psychology and unethical accounting behavior, as well as feasible suggestions for psychological adjustment of the psychological barriers that may arise. This article provides theoretical support and practical guidance for the psychological adjustment of unethical accounting behavior, and summarizes its application experience.Subjects and Methods: This research will primarily use normative analysis, supplemented by qualitative analysis, logic, and other methods. The main focus of this paper is to explore the relationship and influence between accounting psychological barriers, accounting misconduct, and psychological adjustment from the perspective of accounting psychology. Due to the difficulty of obtaining relevant research samples and data from public sources in both behavioral accounting research and accounting psychology research, this paper conducts a review of relevant literature and develops a survey questionnaire. Through theoretical analysis of the generation and change of psychological barriers in accounting subjects, as well as the relationship with accounting misconduct, this paper provides explanations and rationalization suggestions for the psychological adjustment of accounting psychological barriers.Results: This paper expounds on the historical development and current situation of accounting, analyzes the content, composition, and influencing factors of accounting psychology, explains the reasons and influencing factors of accounting psychological barriers and accounting misconduct. The relationship between accounting misconduct and accounting psychological barriers is discussed, and the process of accounting misconduct is emphasized. By referencing literature, questionnaire surveys, and other materials, this paper reveals the internal relationship between the subjective and objective environment and personal characteristics of accounting practitioners and the factors that contribute to the occurrence of psychological barriers and accounting misconduct. Finally, from the perspective of how to adjust psychological barriers, suggestions are made to standardize accounting behavior.Conclusions: The psychological barriers of accounting subjects engaged in accounting work are the key factors that lead to accounting misconduct. The two are closely related and influence each other. The psychological barriers of accounting subjects are the main reasons that affect the occurrence of accounting misconduct, while accounting misconduct is the manifestation of accounting psychological barriers. By studying the relationship between accounting psychological barriers and accounting misconduct, exploring the reasons for the emergence of accounting psychological barriers, and implementing reasonable and effective psychological adjustment measures, can we fundamentally find methods and strategies to standardize accounting behavior.Shandong Province Education Science \u201cthe thirteenth Five-Year Plan\u201d project: research on the construction of \u201cbig accounting\u201d professional practice teaching system in the era of digital intelligence (project number: 2020YB005).a, Hongyu Lana, Xinyu Laoa, Guangning Luob, Xiaolan MaaLeyi Shaoa School of Education Science, Nanning Normal University, Nanning, China, b Nanning School for the Special Education, Nanning, China.Background: Early childhood experience has a profound impact on an individual\u2019s lifelong development, and the quality of development is influenced by many factors of biological and social environment, among which the traumatic experience of children in early childhood is closely related to their later psychological problems and anxiety disorders, traumatic experiences mainly include physical abuse, physical neglect, emotional abuse, emotional neglect, sexual abuse, etc. Social anxiety disorder will directly affect social skills, which is not conducive to the development of individuals\u2019 social functions and the construction of good interpersonal relationships. Compared with normal students, Hearing-impaired students tend to perceive certain prejudice and hostility, so they have a strong defensive psychology and often exaggerate such prejudice. This hostility and distrust towards others can have a negative impact on the establishment of their interpersonal relationships, thus making them prone to anxiety when communicating with others. So they are more prone to emotional problems such as social avoidance and social anxiety. Emotional regulation self-efficacy, as a kind of self-efficacy with emotional regulation characteristics, actually refers to a sense of confidence formed by individuals based on their subjective evaluation of their own emotional regulation ability, which is a key factor to reduce social anxiety in adolescents. Under the dynamic effect of emotional regulation self-efficacy, individuals can take effective emotional regulation strategies and properly deal with emotional events, especially negative emotional events. Therefore, it is of great significance to explore the mechanism of emotional regulation self-efficacy between childhood maltreatment and social anxiety.Subjects and Methods: To investigate the influence mechanism of childhood maltreatment on social anxiety of hearing-impaired students, 135 hearing-impaired students were investigated by the Childhood Maltreatment Questionnaire (CTQ-SF), the Emotional Regulation Self-efficacy Scale (SR-ESE), and the Social Interaction Anxiety Scale (SIAS).Results: The results indicated that: (1) childhood maltreatment significantly positively predicted social anxiety; (2) childhood maltreatment and emotional regulation self-efficacy showed a significant negative correlation, and there was a significant positive correlation between emotional regulation self-efficacy and social anxiety; (3) emotional regulation self-efficacy played a mediating role between childhood maltreatment and social anxiety.Conclusions: It suggested that childhood maltreatment may have a long-term negative influence on hearing-impaired students\u2019 social anxiety, which is partially mediated through emotional regulation self-efficacy.This study is the phased research achievement of 2023 Guangxi Education Science \u201c14th Five-Year Plan\u201d Topic: Mental Health Status and Service System Construction of Sound healthy siblings in Families with Special Children, Project No.: 2023B145.a, Yuanyuan Maa,b, Zhiqiang Baoc, Narenchaoketua, Huan Wangd, Hua Lia, Huhemurena, Shui Linga, Siqina, Naqina, Yingsong Chena,dGuizhia Inner Mongolia Medical University Inner Mongolia, Hohhot 010010, China, b Affiliated Hospital of Inner Mongolia Medical University, Inner Mongolia, Hohhot 010010, China, c Inner Mongolia Hospital of International Mongolian Medicine, Inner Mongolia, Hohhot 010065, China, d Inner Mongolia Minzu University, Tongliao 028000, China.Guizhi and YY Ma contributed equally to this study.Background: This research aims to examine the molecular mechanism of Mongolian medicine Nuan Gong Qi Wei Pill (NGQW) in treating diabetic kidney disease (DKD) based on network pharmacology and molecular docking and analyze the molecular regulatory mechanisms of its major active ingredients docking with the significant targets of DKD.Subjects and Methods: The active ingredients and their targets of NGQW were acquired from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), Encyclopedia of Traditional Chinese Medicine (ETCM), and a high-throughput experiment- and reference-guided database of traditional Chinese medicine (HERB). DKD-related targets were founded by searching four databases: DisGeNET, Gene Cards Human Gene Database (GeneCards), Online Mendelian Inheritance in Man (OMIM), and Therapeutic Target Database (TTD). The STRING database was used to construct a protein-protein interaction (PPI) network to search for major targets. Additionally, enrichment analysis involving main biological processes and pathways was carried out using the Database for Annotation, Visualization, and Discovery (DAVID) and Metascape databases. Cytoscape software was used to construct and analyze networks. AutoDock Vina and PyMOL were used to validate molecular docking between significant active ingredients and major key targets.Results: Collectively, 174 NGQW active ingredients, 492 potential targets, and 4227 DKD targets were screened. After the intersection procedure, 295 potential targets of NGQW for DKD were obtained. In addition, quercetin, beta-sitosterol, oleic acid, isoliquiritigenin, and apigenin were the possible key active ingredients of NGQW, Signal transducer and activator of transcription 3 (STAT3), Nuclear factor NF-kappa-B p65 subunit (RELA), Mitogen-activated protein kinase 1 (MAPK1), Heat shock protein 90 alpha family class A member 1 (HSP90AA1), and AKT Serine/Threonine Kinase 1 (AKT1) were important targets in the PPI network. The PI3K/AKT signaling pathway, the lipid and atherosclerosis signaling pathway, the AGE-RAGE signaling pathway in diabetic complications, and the MAPK signaling pathway were all involved in the enrichment analyses along with biological processes including the cellular response to oxidative stress, hormones, and nitrogen compounds. Furthermore, this study highlighted a good binding activity between key active ingredients and key targets.Conclusions: NGQW has the potential to treat DKD through multiple pathways, targets, and compounds. The main active ingredients in this medicine, such as quercetin, isoliquiritigenin, beta-sitosterol, oleic acid, and apigenin interfere with multiple signaling pathways including cellular response to nitrogen compounds, hormones, and oxidative stress by regulating crucial targets such as STAT3, RELA, HSP90AA1, MAPK1, and AKT1.This work was supported by a project grant from the word-class discipline\u201c construction project of Traditional Chinese Medicine (Mongolian medicine) of Inner Mongolia Medical University, (Grant No.myxylxk2022017).a, Chao FanbXiaobo Taoa School of Economics and Management, North China University of Technology, Beijing 100144, China, b School of Business, Central University of Finance and Economics, Beijing 100098, China.Background: With the continuous advancement of technology and the ongoing innovation of business models, companies are facing an increasingly competitive business environment. In this context, successful development of new products has become one of the key strategies for companies to cope with competition. In reality, practices led by companies and inviting customers to participate in new product development are becoming quite common, and as a result, many forms of customer involvement have emerged. However, the issue of how to effectively improve the satisfaction and mental health of customers, and encourage them more proactive and engaged in the company\u2019s new product development process, has received little attention. Mental health refers to a person\u2019s overall psychological well-being, including their emotional, cognitive, and social functioning. It encompasses how an individual thinks, feels, and behaves, as well as their ability to cope with life\u2019s challenges and adapt to changes. The promotion and preservation of mental health contributes to individuals\u2019 overall quality of life, productivity, and social integration, and it reduces the burden of mental illness on individuals, families, and society. Therefore, favorable levels of mental health among customers are conducive to enhancing their efficiency in participating in new product development.This requires companies to choose more appropriate forms of customer involvement in the new product development process, so as to not only improve customers satisfaction and mental health, but also further enhance company performance and put new product development on a healthier and more sustainable track. Based on this, the study will conduct a systematic exploration of how different forms of customer involvement affect new product development performance.Subjects and Methods: This study conducted a questionnaire survey on 287 high-tech companies with independent R&D departments in five provinces and cities including Beijing, Tianjin, Shandong, Shanghai, and Jiangsu. Finally, a set of 267 valid questionnaires was obtained. These questionnaires were mainly distributed across industries such as electronic information technology, biotechnology and new pharmaceutical technology, and aerospace technology.Results: Based on the regression analysis, the results suggested that customer involvement had a significant positive impact on new product development performance. Furthermore, the study revealed that the stronger the incremental innovation capability, the stronger the impact of customer involvement as an information source on new product development performance, while the impact of customer involvement as innovators was weaker. In comparison, the stronger the radical innovation capability, the stronger the impact of customer involvement as innovators on new product development performance, and the weaker the impact of customer involvement as an information source. However, the interaction effect of incremental or radical innovation capability and customer involvement as co-developers was not significant.Conclusions: When a company possess strong incremental innovation capability, customer involvement as an information source is more advantageous for enhancing new product development performance. Conversely, when companies possess strong radical innovation capability, customer involvement as innovators is more conducive to enhancing new product development performance. During this process, the mental health of customers plays a crucial role. The participants\u2019 good mental health level triggered by appropriate customer involvement strategies not only strengthens their ability to cope with stress, challenges, and maintain positive interpersonal relationships at work, but also further enhances their initiative and work efficiency in participating in new product development. Therefore, improving the mental health of participants is of significant importance in enhancing the performance of new product development. The study enriches the understanding of the mechanisms through which customer involvement influences new product development performance and offers empirical evidence for companies with diverse innovation capabilities to determine suitable customer involvement strategies for new product development.a, Lijun Wangb,c,d, Yuepeng Sune, Hyoung-Kil KangfJinggang Lia Sports Department, Jilin International Studies University, Changchun 130000, Jilin, China, b College of Physical Education and Health, Yulin Normal University, Yulin 537000, Guangxi, China, c International College, Krirk University, Bangkok 10220, Thailand, d Wuchang University of Technology, Wuhan 43000, Hubei, China, e Sports Department, Dalian Maritime University, Dalian, Liaoning 116026, China, f Graduate School of Education , Kyungnam University, Changwon, Republic of Korea.Background: This study aims to investigate the impact of Adversity Quotient Theory on the exercise persistence of Chinese college students and to develop an Exercise Adversity Coping Scale to explore the relationship between exercise adversity coping ability and student anxiety alleviation.Subjects and Methods: The present study aimed to develop an Exercise Adversity Coping Scale based on the Adversity Quotient Theory. The scale includes three dimensions and twelve items, and has been shown to have good reliability and validity. In addition, the study sought to validate the effect of the Adversity Quotient Theory on exercise persistence and the alleviation of student anxiety, through exercise behavior surveys and student interviews.Results: Based on data collected from interviews and questionnaires, typical exercise adversities were identified using NVivo12 software. Next, Exploratory Factor Analysis (EFA) was conducted on a sample of 345 Chinese college students to evaluate the psychometric properties of 54 items and develop a 15-item Exercise Adversity Coping Scale with three dimensions: Exercise Adversity Responsibility, Exercise Adversity Control, and Exercise Adversity Influence. This scale explained 63.54% of the cumulative variance, and its internal consistency reliability and split-half reliability were found to be 0.909 and 0.874, respectively. Additionally, Confirmatory Factor Analysis (CFA) was conducted on another sample of 300 college students, and the remaining 12 items were validated. According to the results of exercise behavior surveys, college students who consistently exercised had an average score of 3.63 on the exercise adversity coping ability scale. Moreover, interviews conducted with students who had high exercise adversity coping abilities revealed that they considered physical exercise to be an effective means of relieving stress, which is supported by related literature.Conclusions: The Exercise Adversity Coping Scale developed in this study has demonstrated acceptable reliability and validity. Moreover, the findings suggest that developing exercise adversity coping ability can enhance exercise persistence, which in turn may help alleviate student anxiety.a, Xiang WangbYan Jianga Psychological Counseling Center, Shanghai University, Shanghai, 20444, China, b Department of Nursing, Zhuhai Campus of Zunyi Medical University, Zhuhai 519041, China.Background: The lifestyles and mental health of numerous college students were affected by the outbreak of the novel coronavirus disease. However, no study has examined the impact of subjective evaluations of exposure to the pressure on mental health. The current study was conducted and examined the relationship between problematic mobile social media usage and depressive symptoms, and the moderating effect of perception of the novel coronavirus disease.Subjects and Methods: A cross-sectional online questionnaire study of 3123 Chinese college students in the Shanghai was conducted in March and April 2020. Problematic mobile social media usage was assessed by the Problematic Mobile Social Media Usage Assessment Questionnaire and depressive symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9). 2056 students reported that they were affected by COVID-19, and 1067 students formed the \u201cunaffected group.\u201d Structural equation modeling (SEM) in Mplus 8.0 was used to examine whether the hypothesized relationship between problematic social network usage and depressive symptoms was affected by whether the respondents reported being affected by COVID-19.Results: The effect of problematic mobile social media usage on depressive symptoms was significant. The level of problematic mobile social media usage and depressive symptoms in the affected group was significantly higher than that in the unaffected group. The interaction between problematic mobile social media usage and perceived influence of COVID-19 was statistically significant. The effect of problematic mobile social media usage on depressive symptoms was moderated by perceived COVID-19 influence. Specifically, compared with students who were unaffected by the novel coronavirus disease, those affected showed more severe depressive symptoms.Conclusions: The findings suggest independent and interactive effects of problematic mobile social media usage. The results highlighted the underlying mechanisms in the relationship between problematic social media usage and depression. These findings provide practical insights into the development and implementation of psychological interventions when facing pressure.a, Qiuxiang Bib, Zhouyin Zhangc, Luote DaidAnzhong Huanga School of Economics and Management, Nanchang Institute of Science and Technology, Nanchang, 330108, China, b School of Management, Guangzhou Xinhua University, Dongguan, 523133, China, c School of Accounting and Finance, Anhui Xinhua University, Hefei, 230088, China, d School of Digital Economy and Trade, Wenzhou polytechnic, Wenzhou City, 325035, China.Background: Based on the hypothesis of the positive relationship between poverty and its vulnerability and residents\u2019 mental health, this paper aims to test whether the digital divide affects the efficiency of poverty alleviation in inclusive finance, so as to affect people\u2019s mental health.Subjects and Methods: Poverty is the main acoustic factor of people\u2019s mental health. Whether inclusive finance can improve poverty and finance to alleviate people\u2019s mental health has been debated in academic circles. Based on econometric analysis, this paper holds that the digital divide has a downward effect on the poverty alleviation effect of general finance, which in turn affects people\u2019s mental health.With the development of digital technology, digital inclusive finance is becoming the mainstream. However, the digital divide significantly affects the inclusiveness of financial development.Based on the measurement of China\u2019s digital financial inclusion and digital divide, this paper studies the moderating effect of digital divide\u2019s financial inclusion.Results: The test results show that family health, labor, the dependency ratio, per capita income levels, and the influence of the level of cash deposits are significantly negative, family average age for the action of increasing poverty vulnerability, and the influence of family size is may be due to the large family, more than in the case of more than three generations would cohabit stroke young family in pension spending is higher, This burden increases the vulnerability of households to poverty. The development of digital inclusive finance weakens the poverty vulnerability of households on the whole. The existence of digital divide does negatively affect the poverty alleviation effect of digital inclusive finance.Conclusions: The development of digital financial inclusion has a significant negative effect on the vulnerability to poverty and the digital divide significantly weakens the mitigation effect of digital financial inclusion on poverty vulnerability. Through poverty and poverty fragility, the digital divide has a negative impact on residents\u2019 mental health. The digital divide has a huge impact on families\u2019 mental health by affecting financial inclusion. The digital divide has a huge impact on families\u2019 mental health by affecting financial inclusion. So addressing the digital divide can not only improve financial inclusion, but also address the mental health pressures that families face. There is a significant negative correlation between the digital divide and the mental health of the poor resident. Therefore, addressing the digital divide can improve mental health of the poor resident.This study was supported by the 13th Five-Year plan research project of philosophy and social sciences of Guangdong province (GD17YGL03); the Project of Philosophy and Social Sciences Research in Jiangsu Universities (2019SJA1932); the Youth Fund Project of Humanities and Social Sciences Research of Ministry of Education (21YJC790086); the key project of Humanities and Social Sciences (SK2021A0776) and the Anhui Philosophy and Social Science planning Project (AHSKY2020D53).aChunlu Gaoa Chongqing Aerospace Polytechnic College, Chongqing, China.Background: With the improvement of people\u2019s living standards, contemporary individuals are constantly pursuing higher levels of experiential satisfaction in their daily lives. Travel demand, to a large extent, is inspired by the diverse and colorful cultural heritage found throughout different destinations, providing opportunities to experience and explore the diversity and uniqueness of culture. Intangible cultural heritage embodies the civilization of human society and represents the diversity of global cultures. Introducing intangible cultural heritage-related courses to students majoring in tourism management at vocational colleges is beneficial for enhancing their sense of pride in traditional Chinese culture, cultivating their interest in further learning and researching intangible cultural heritage, and encouraging them to find their life goals and build self-confidence, thereby promoting their mental health development.Subjects and Methods: The paper analyzed the impact of integrating intangible cultural heritage into tourism management education on enhancing students\u2019 self-efficacy, promoting cultural identity, and fostering respect and dedication. Further, it explored specific intangible cultural heritage elements that can be integrated into the teaching process, and proposed targeted strategies for incorporating these elements into the curriculum.Results: The findings indicate that integrating intangible cultural heritage into tourism management education allows students to gain knowledge and insights about intangible cultural heritage and its inheritors. Incorporating intangible cultural heritage into the growth process of cultivating personal character, developing professional skills, and fostering ethical values can produce positive emotions and fulfill students\u2019 psychological needs, mitigating the negative impact of emotions such as depression, low self-esteem, and sensitivity. This integration produces a significant positive effect on students\u2019 mental health and contributes greatly to their growth and development in the future.Conclusions: Based on the findings, it is recommended that the teaching curriculum of tourism management should be developed based on real-world contexts, with a focus on the theme of \u201cprotection and inheritance of intangible cultural heritage\u201d. It is crucial to recognize the significant role that tourism plays in safeguarding intangible cultural heritage and to undertake education reform and practical exploration to promote the simultaneous development of intangible cultural heritage preservation and tourism management education towards a \u201cwin-win\u201d outcome.This work was supported by the General Project of Higher Education Science Research of Chongqing Higher Education Institute from 2019 to 2020 \u201cResearch on Teaching Reform of \u20181+X\u2019 Certification System in Vocational Tourism Management Program\u201d under Grant number CQCJ19B142.a, Xinyu Laoa, Yexiao Lianga, Xia Chena, Rongchao Gonga, Liting LiuaLeyi Shaoa School of Education Science, Nanning Normal University, Nanning 530299, ChinaBackground: As direct participants in the education and rehabilitation of children with special needs, the anxiety of parents of children with special needs affects the rehabilitation process of children with special needs to a certain extent. In this study, we investigated the anxiety of parents of children with special needs and assessed the relevant factors affecting parents\u2019 anxiety levels.Subjects and Methods: In this study, a questionnaire was administered to 176 parents of children with special needs using the Self-Assessment Scale for Anxiety (SAS) and the results were statistically analysed using SPSS 20.0 software to investigate the anxiety status of parents of children with special needs, including basic personal information of the parents, basic information of the children, educational status of the children, monthly household income and educational status. At the same time, in order to ensure the completeness and richness of the information required for the study, a foundation was laid for the subsequent data collation and analysis. The researcher also conducted interviews with the parents of special children.Results: This study investigates the anxiety of parents of children with special needs and analyses the relevant factors that influence the level of parental anxiety, which consists of basic information about the family and the basic situation of the child. The anxiety index of parents of special children was shown to be (56.16\u2009\u00b1\u200912.55) points, which are at a mild level of anxiety. Among these factors, parental gender, age, type of family of the special child, parental status of the special child, occupation, education, monthly household income, number of children, gender of the child, type of disability of the child, degree of disability of the child, pattern of rehabilitation expenditure, special school and family placement had no effect on the anxiety level of the parents of the special child. The total anxiety score of parents of exceptional children was positively correlated with parental status, occupation, degree of impairment and the institution attended, and negatively correlated with the placement of the child in a regular kindergarten.Conclusions: By establishing a sound education system for children with special needs and increasing employment opportunities for parents of children with special needs, as well as conducting regular parent training and parent group support activities, these measures can effectively reduce the psychological pressure on parents of children with special needs.This study is the phased research achievement of 2023 Guangxi Education Science \u201c14th Five-Year Plan\u201d Topic: Mental Health Status and Service System Construction of Sound healthy siblings in Families with Special Children, Project No.: 2023B145.a, Kai Lia, Haonan Zhenga, Zhihu DingaWangwang Zenga Information Center, The First People\u2019s Hospital of Yunnan Province, Kunming 650032, China.WZ and KL contributed equally to this study.Background: With the continuous development of information technology and the continuous improvement of people\u2019s living standards, more and more people have put forward higher requirements for physical and mental health. While information technology has promoted the rapid development of hospitals, it has also produced a large number of redundant data. Patients have put forward higher requirements for the construction of hospital informatization. This paper will improve the quality of hospital data through a series of data governance measures, Improve the clinical business processes of hospitals to ensure their efficient operation. Through various national assessments such as interconnectivity ratings, three-level public hospital performance evaluations, and electronic medical record ratings, we aim to meet patients\u2019 requirements for hospital informatization construction to the greatest extent possible, enhance people\u2019s sense of medical service happiness, and ultimately promote the high-quality development of modern hospitals.Subjects and Methods: A special team for data governance was set up, a series of data governance rules and regulations were formulated, and software tools of the multi-party data governance platform were introduced. The team members regularly investigated the psychological needs of patients during diagnosis and treatment, and obtained specific opinions of patients on the hospital\u2019s diagnosis and treatment process and information system. Then, the diagnosis and treatment process was optimized, and the information system was transformed to meet the psychological needs of patients to the greatest extent, and improve the happiness of patients during the medical treatment process.Result: The outpatient volume and operational data of discharged patients in the hospital have significantly improved. The outpatient volume of the hospital has increased significantly for five consecutive years, and the average waiting time of patients has decreased for five consecutive years. In the questionnaire survey, it was found that the satisfaction of patients who came to the hospital for medical treatment has been greatly improved, their psychological needs have been met, and their sense of happiness has significantly improved. The hospital has made two consecutive breakthroughs in the performance evaluation ranking of tertiary public hospitals, and ranks first in the province through the interconnection of Class IV and Class AConclusion: Through data governance, various data indicators of the hospital have been significantly improved, and the hospital has developed at a high speed. Every year, the hospital can provide more patients with better quality diagnosis and treatment services. When patients come to the hospital for treatment, they always have a relaxed and happy diagnosis and treatment experience. While diagnosing and treating patients\u2019 physiological diseases, the psychological needs of patients have also been more satisfied, and the happiness of patients in the area has been greatly improved.This work was supported by a project grant from Yunnan Provincial Basic Research Program (Grant No.202201AY070001-258).a, Hanteng Liaob, Shaohe ZhangcHui Liua Business School, Nanfang College GuangZhou, Guangzhou 510970, China, b Higher Education Impact Assessment Center, Nanfang College GuangZhou, Guangzhou 510970, China, c School of Economics, Guangzhou College of Commerce, Guangzhou 511363, China.Background: To realize the practical theoretical innovation of industrial Internet combining modern service industry and advanced manufacturing industry, it is necessary to integrate the existing mainstream theories of sustainable transformation and update the meaningful case studies. Satisfying consumers\u2019 psychological needs and emotional behavior is key to promoting consumer upgrading under the new development pattern of \u201cdual circulation\u201d. The innovative practice theory of industrial Internet can provide more personalized, convenient, and efficient products and services, enabling consumers to enjoy pleasure and satisfaction in the purchasing process. This further enhances consumer loyalty and reputation for brands, bringing greater commercial value to businesses.Subjects and Methods: This paper uses theoretical analysis and case study methods. Based on the practical achievements of Rookie Network, this study firstly analyzes the development process of Rookie Network, as a logistics link under the digital economy, from the earliest information platform to intelligent logistics system with the mainstream theory of Industry 4.0 \u201cCyber-Physical System\u201d (CPS). As the mainstream multi-perspective sustainable transformation \u201csocial-technical system\u201d theory of sustainable transition, CPS is used to demonstrate and analyze the transition process of rookie network from the earliest odd-job economic platform to the \u201clow-carbon\u201d social-technical system that provides consumers with high-level emotional value and upgrades consumer experience.Results: The construction of intelligent logistics based on consumer psychological needs of intelligent logistics construction from C-end consumers and consumption scenarios must include the overall theoretical view of Industry 4.0 CP Logistics and multi-perspective sustainable transformation \u201csocial-technological system\u201d. Only in this way can logistics companies meet consumers\u2019 increasingly high demands on logistics. Help them to get logistics information quickly and accurately. Enjoy convenient and efficient logistics services, and improve the sense of experience and service quality in the logistics process. Get a sense of pleasure and satisfaction over good logistics services.Conclusions: It can ensure that the digitalization and digital transformation capabilities at the consumer side can be extended to the working side of commerce and industry, and drive the industrial transformation and upgrading path of advanced manufacturing industry with the deep integration of digital capacity building. Thus, enterprises can better understand consumer needs and launch products and services that meet their psychological needs and emotional behavior more accurately, and sustain development.This work was supported by two projects grant one from Nanfang College, Guangzhou A study on the influence of hog futures on hogs and the industry chain price of hogs (Grant No. 2021XK25), the other from The reform of digital teaching mode of Internet finance based on project management, a general project funded by the 14th Five Year Plan of China Association of Higher Education - A case study of Theory and Practice of Internet Finance (Grant No.21SZYB29).aJie Lia MBA Center, Shanghai University, Shanghai, 200444 China.Background: To alleviate the problems of extensive production, insufficient investment in cold chain, high transportation loss, and asymmetric information in China\u2019s agricultural product supply chain, regulate the management of the agricultural product supply chain, meet consumers\u2019 psychological needs for high-quality agricultural products, and guide suppliers to optimize the agricultural product supply chain mode based on consumers\u2019 attitudes, emotions, and hobbies.Subjects and Methods: Based on consumers\u2019 psychological needs for tea product quality, this paper took the agricultural standardization policies issued by 16 provinces in China as the basis and applied the panel data from 31 provinces between 2000 and 2020. Multiple-period difference-in-difference (DID) method was used to study the growth effect of the agricultural standardization work plan on the tea industry in China.Results: The results showed that the promotion of agricultural standardization work and the support of relevant policies can promote the growth of local tea production and also have a promoting effect on the growth of local tea value. Furthermore, it can effectively meet the psychological needs of consumers for high-quality tea, and influence consumers\u2019 purchasing motivation and behavior.Conclusion: Agricultural standardization has a positive impact on the yield and output value of agricultural products, is an important guarantee for promoting the development of the agricultural industry, and is also an important prerequisite for the standardization construction of the agricultural supply chain. It is recommended that China accelerate the research on the standardization of agricultural product supply chain, and take specific measures such as \u201ccontinuously strengthening the standardization of agricultural product supply chain, developing universal agricultural product supply chain standards; strengthening the construction of organizational guarantee measures to ensure the implementation of agricultural product standardization plans; strengthening the construction of logistics infrastructure to enhance the responsiveness of agricultural product inventory and distribution\u201d. This provides new ideas, new methods, and new channels for China to carry out agricultural product standardization construction, meeting consumers\u2019 psychological needs for agricultural products\u2019 freshness. Additionally, this has important theoretical and practical implications for the quality upgrading of agricultural product circulation.a, Kexiang Chenga, Xiaolin TanaCunbo Wua Chongqing Mental Health Center, Gele Mountain, Shapingba District, Chongqing,400036, China.Background: Autism comorbidities of mental retardation and epilepsy with cisterna magnum occipitalis in children are rare, Early recognition by clinicians is difficult, which led it easy to be neglect and difficult to thrapy that affect the children\u2019s mental health and physical health and increased the burden on the familySubjects and Methods: A child with autism comorbidities of mental retarded development and epilepsy with cistercius macroccipitalis was promptly treated with oxazepine for antiepilepsy from Chonging mental health center, he was emotional unstable, irritable, impulsive wounding, accompanied by obvious mental symptoms and anxiety, repeated toilet visits, could not speak human language, could not take care of his own life. We used Risperidone oral liquid for antipsychosis, Quetiapine combined with Ziprasidone injection for mood stabilization, completed relevant auxiliary examination, supplemented by rehabilitation training such as psychotherapy, behavior modification, hypnotherapy, biofeedback therapy to promote the rehabilitation of the child.Results: The child became emotional stability, not irritable, impulsive, hurtful and anxious feelings any more, mental symptoms gradually disappeared, could cooperate with simple educational training, although discharged automatically.Conclusions: Autism comorbidities with severe mental retardation and epilepsy are rare and difficult for clinicians to treat due to communication difficulties. Autism and mental retardation mainly rely on education training and psychotherapy, while epilepsy and primary disease caused by mood disorders, clinical psychiatry mainly medicated to solve. The patient is accompanied by large cisterna, whether it is the cause of the disease or coincidence, and whether it is used as the auxiliary basis for diagnosis, needs a large number of clinical samples and data to study. For such patients, it is also necessary to be cautious in drug use. Due to the retarded neurological development, the drug sensitivity is reduced and the drug tolerance is easy, so the choice of drugs should be more careful. Early identification, timely antiepileptic treatment and appropriate drug sedation therapy are very necessary for clinicians to pay attention to Comorbidities of mental retardation and epilepsy in children.aWeiwei Liua Basic Teaching Department Shandong Huayu University of Technology, Dezhou, Shandong, 253000, China.Background: From the perspective of mental health, this paper uses cognitive psychology, personality psychology and Nida\u2019s functional equivalence theory to further explore the translation strategies of English film and television drama language, so that film and television art can better play the role of film and television art in people\u2019s mental health and personality. The positive role of shaping clarifies the linkage relationship between the translation of film and television texts in promoting people\u2019s mental health and all-round development, in order to provide reference for the development of film and television style translation.Subjects and Methods: In order to promote the healthy development of people\u2019s mental health, this paper discusses the principles, methods and strategies of film and television translation on the basis of analyzing and summarizing the characteristics of film and television stylistic language - colloquial, easy to understand, cross-cultural and immediacy. According to the different contexts, semantics, and discourse conditions of specific translation examples, the principles and effects of the application of translation, free translation, abbreviated translation, and compilation strategies are emphasized.Results: In the process of translating film and television scripts, the translator must face the audience and give more consideration to the audience\u2019s objective needs, aesthetic taste and acceptance level, so as to finally achieve harmony and unity between the audience\u2019s expectations and the original intention of the translation, and improve the expression and integration of individual emotions. Control ability, promote the formation of human personality and the overall development of mental health. At the same time, we must strive to:1. Make good use of cognitive psychology theories and laws of cognitive psychology to complete the understanding and expression of the original text, actively mobilize the translator\u2019s psychological activities in the translation process, and improve the quality of translation.2. Make good use of the positive influence of personality factors in the translation process of film and television style, determine the translation objects and expressions, maintain the original style, and improve the translation quality.Conclusions: The translation of film and television style should not only pay attention to the expression of artistic techniques and stylistic characteristics, but also be people-oriented. It is absolutely necessary to promote people\u2019s mental health. Carrying out the translation strategy research of film and television style from the perspective of mental health can not only make the translator\u2019s personality tendency and film and television text realize two-way adaptation, but also make the correlation between the translator\u2019s cognitive activity law. The people-oriented concept has been deeply integrated, and the translator\u2019s emotional activity rules have been fully reflected in the translation examples, which has opened up a new path worth trying for the translation of film and television genres.This article is the phased research result of the 2019 scientific research platform research project of Shandong Huayu University of Technology - Applied Translation Research Center (No. 09) and College English Curriculum Construction.aChin-niang Chana School of Art, Minnan Normal University, Zhangzhou, Fujian, China.Background: As a product of artistic development, traditional Chinese opera is associated with human emotions through the process of visual and spiritual experience, thereby having a profound impact on human mental health. Through in-depth analysis of how traditional Chinese opera art affects emotions through visual experience, this study explains the close relationship between traditional Chinese opera art and mental health from a micro perspective, using the way that traditional Chinese opera art affects mental health.Subjects and Methods: This study examines the relationship between art and mental health in art therapy, using art based techniques such as traditional Chinese opera music as evidence based interventions for mental health issues such as anxiety and depression. More and more evidence suggests that art can be used in non-therapeutic environments to promote mental health, such as performing arts to understand the core subject areas of a school or to maintain a sense of mental health. In other words, practicing art can be used to establish the ability to manage a person\u2019s mental and emotional health.Results: The research results show that art affects mental health, and the healing effect of art works needs to be carried out to the extent that the audience can understand. If opera has a psychological relief and healing effect on the audience, then the art works or performers of this opera are effective for these audiences. The direction of this study is to focus on the artistic works themselves, as well as the psychological world and healing function of opera performances, in terms of art and mental health.Conclusions: The impact of traditional Chinese opera art on mental health is mainly produced through aesthetic experience. In the process of creating traditional Chinese opera art, individuals tend to pay attention to the expression of their physical and emotional tendencies in the actual inner experience of the artistic work; In the process of appreciating traditional Chinese opera art, individuals experience emotional flow and emotional release through re-experiencing the emotions expressed in artistic and technical works. The integration of artistic experience and artistic techniques can enable an individual to gain respect for their own feelings, thereby achieving the release and sublimation of the surrounding environment within. Show the artistic style characteristics of Gezi Opera and its healthy body and mind.a,b, Jie Fuc, Chi ZhangaTuo Shia Beijing Police College Department of Public Security Management, Beijing 102202, China, b Institute of Scientific and Technical Information of China, Beijing 100038, China, c Beijing Miyun District Administration Bureau, Beijing 100050, China.Background: With the increasing application of artificial intelligence (AI) in the field of public security and law enforcement, its integration into the practice of law enforcement is no longer a one-dimensional technical innovation, but a multidimensional empowerment that includes promoting the formation of multi-subject collaborative governance models, forcing upgrades of supporting institutional frameworks for public security, and driving the technological transformation of law enforcement methods. While AI has effectively improved law enforcement efficiency, it has also brought risks such as discrimination, privacy infringement, and deprivation of rights, causing psychological anxiety about technology.Subjects and Methods: This study discusses the negative effects of law enforcement caused by technology defects. It is supported by the theoretical framework of comprehensive public security and law enforcement, and integrates methods such as situational analysis and systematic deconstruction. The study systematically analyzes the types of psychological anxiety risks caused by AI technology integration into law enforcement, and investigates the inducements and impacts of psychological anxiety from the multidimensional perspectives of structural imbalances of the law enforcement subject, ineffective governance systems, and technological alienation.Results: From the perspective of the relationship structure of governance subjects, the monopoly of AI technology resources undermines the original intention of promoting the participation of multiple subjects in governance, and can even cause risks such as social disorder and psychological imbalance caused by the feeling of injustice among subjects. It becomes a huge obstacle to the modernization of governance capacity, deviating from the governance goal of \u201cjoint construction, joint governance, and sharing\u201d. From the perspective of the role of governance subjects, it causes further polarization and even group isolation and confrontation among social subjects, and algorithm-driven social polarization and even group isolation and confrontation causes more serious psychological disorder. From the perspective of technological alienation, over-reliance on data algorithms and the risk of uncontrolled application bring insurmountable psychological anxiety to subjects.Conclusions: The study results show that the main ways to effectively alleviate the psychological anxiety of subjects at the technical level include: the government\u2019s comprehensive coordination of the structural relationship among multiple subjects under the embedding of AI, promoting the formation of a multi-subject collaborative governance pattern, following up and improving warning decision-making, information resource sharing, and public security and crime prevention and control systems, and accelerating the construction of an \u201cAI governance system\u201d.This work was supported by a project grant from National Social Science Foundation Youth Program (Grant No.21CSH05).a, Shi Zhengb, Feng HuaWeichao Chenga School of Economics and Management, West Anhui University, Luan 237012, China, b School of Business, Sichuan University Jinjiang College, Meishan 620860, China.Background: The collapse of stock price will quickly evaporate the wealth of shareholders, greatly increasing their anxiety. Anxiety can have a dual impact on people\u2019s physical and mental well-being, Anxiety can bring complex and unpleasant emotions such as tension, unease, worry, annoyance, Insomnia and dreaminess to people, thereby affecting family harmony and happy life. Due to the late development of China\u2019s capital market, there is room for improvement in China\u2019s market regulatory mechanism and legal system, and the stock price crash risk are higher risk.Subjects and Methods: This paper using the Shapley-Shubik power index, which is based on cooperative game theory, and investigates the impact of major shareholders\u2019 shareholding structure on the psychological anxiety of shareholders, based on the perspective of stock price crash risk. stock price crash risk by examining a sample of A-share listed companies in China from 2003 to 2018. This study uses regression methods such as least squares to empirically test the research hypotheses proposed in this paper.Results: The study finds that: (1) Cash flow rights significantly reduce stock price crash risk, alleviated the anxiety of shareholders. The separation of cash flow rights and control rights significantly increases such risk, increased the anxiety of shareholders. While the control rights have no significant effect on the stock price crash risk; (2) More supportive behaviors and fewer hollowing-out ones play a partially intermediary role in the suppression of stock price crash risk by the cash flow rights, whereas fewer supervisory and more hollowing-out behaviors play a partially intermediary role in the crash effect of separation degree of control and cash flow rights.(3) The more powerful a firm\u2019s management and the weaker its external supervision, the more significant the role of the cash flow rights in suppressing stock price crash risk, and the more conspicuous the crash effect of separation degree of control and cash flow rights.Conclusions: Cash flow rights significantly alleviate the anxiety of shareholders, while the separation of cash flow rights and control rights significantly increases the anxiety of shareholders. The findings of this paper could provide useful theoretical and practical guidance for optimizing firms\u2019 shareholding structure, suppressing the risk of share price collapse, improving the quality of listed companies, promoting the stability of capital markets, and alleviating the anxiety of shareholders.This research was funded by West Anhui University Talent Introduction School Research Start-up Fund Project (No. 00701092302) and Youth foundation of SCUJJ (No. QNJJ-2022-A07).a, Yun YangbLing Miaoa The CPC Henan Provincial Party Committee Party School, Zhengzhou 451464, China, b School of Economics and Management, Zhongyuan University of Technology, Zhengzhou 450007, China.Background: As one of the most important social relationships in market economy, the labor-capital relationship is \u201cthe axis of rotation around all modern social systems\u201d (Engels). Nowadays, this relationships under China\u2019s \u201cnational integration model\u201d has basically completed the market-oriented transformation, but the labor-capital dilemma has become increasingly severe. According to the Chinese Law Blue Book, labor-capital incidents have accounted for 36.5% of China\u2019s mass incidents, which become major threats to China\u2019s economic and social construction, possible solutions thereby are needed. And in the current era where emotional health is becoming increasingly important, using emotional behavior as a research entry point can more intuitively reflect internal mechanisms and problems.Subjects and Methods: Based on the statistical data from 2000 to 2015, this paper concludes that (i) the number of mass labor disputes is proportional negative correlated to the labor compensation, while (ii) the number of mass labor disputes is proportional positive correlated to the capital property income with the cointegration theory and the generalized impulse response function. This paper studies the endogenous relationship between the loss of labor property rights, the decline of labor compensation proportion and the \u201coutside institutional struggle\u201d under property rights theory. Combined with data validation, it verifies the relationship between emotional behavior and large-scale industrial events, and verifies that emotional behavior can have an impact on industrial events.Results: We propose to (i) increase the proportion of labor compensation at the initial distribution stage as the reform direction; (ii) improve the \u201cthree rights of labor and capital\u201d; (iii) establish a long-term mechanism for wage growth; and (iv) develop the redistribution and adjustment mechanism of compensation to solve the problems mentioned above. And attention should be paid to the prevention and guidance of negative emotions and unhealthy behaviors caused by negative emotions.Conclusions: The decline in the proportion of labor compensation does not necessarily lead to mass labor incidents, but in a long run, labor compensation and capital property income have a causal relationship with mass labor disputes. That is, the continuous decline in the proportion of labor compensation makes workers fall into a psychology of disadvantage and their \u201cdeprivation feeling\u201d become solidified. An accidental event may lead to the mass labor-capital incidents. Furthermore, the consequence of the generalized impulse response function indicates that the number of mass labor disputes is negative correlated to labor compensation, while positive correlated to capital property income, which presents a crowding effect on labor compensation. Obviously, the long-term crowding effect of the labor compensation and the continuous decline of the labor compensation ratio have become the inherent reasons for mass labor and capital incidents. The prevention and guidance of emotions and behaviors can effectively solve the current practical problems in enterprises or society. Therefore, the prevention of negative emotions and the guidance of unhealthy behaviors caused by negative emotions are urgent.The period research results of the National Social Science Fund General Project \u201cResearch on the Fire-retardant Mechanism and Governance of Massive Labor Incidents Network\u201d (No. 18BGL237).a,b, Boping TianaJinyang Liua School of Mathematics, Harbin Institute of Technology, Harbin 150006, China, b School of Statistics, Chengdu University of Information Technology, Chengdu 610103, China.Objective: It is common knowledge that in the history of the world\u2019s medical development, various infectious diseases have been the most dangerous and deadly diseases for human health. Considering that the virus has not been fully explored and the scale of contagion is becoming more and more widespread, there is an urgent need for timely prediction of the spread of infectious diseases. With the continuous development of artificial intelligence in recent years, deep learning techniques have been used to predict infectious diseases in addition to traditional prediction methods. Therefore, proposing prediction models with better performance based on depth techniques is the main objective of this study.Methods: Long short-term memory (LSTM) and convolutional neural networks (CNN) are deep learning models, both of which perform well in predicting time-series data. Based on summarizing previous studies, the LSTM based on scaled dot-product attention and the CNN combined with feature-wise linear modulation (FiLM) were proposed. These methods improve the ability to capture key information about infectious diseases, which in turn improves the predictive performance of the model. To evaluate the fitting performance of those models, LOSS, RMSE, Pearson coefficient, and R2 of models were calculated in this study.Results: The fitting results of Scaled Dot-product Attention-LSTM and CNN-FiLM on time series data of infectious diseases from four countries were obtained based on Python. In conjunction with the calculated results of the evaluation metrics for model fitting, it can be seen that the two methods proposed in this study, based on Scaled Dot-product Attention-LSTM and CNN-FiLM, are suitable for the effective prediction of infectious disease time series, and both methods have improved to some extent in terms of model fit. Compared with Japan and Armenia, the two improved methods were relatively better fits for the epidemic data from China and India.Conclusions: To ensure effective prediction of infectious diseases, it is necessary to actively explore the establishment of excellent methods and models, strengthen the ability of models to be applied to different data, and minimize the error rate in prediction. Scaled Dot-product Attention-LSTM and CNN-FiLM can be easily adapted to many different temporal data analysis tasks, which greatly increases the scalability of time series prediction models. This study makes some attempts at the prediction methods and models of infectious diseases, and the research results may play a certain role in the effective response to similar infectious diseases that may occur in the future.This work was supported by a project grant from the Natural Science Foundation of China(NSFC) (No.91646106).a, Zhihui Yangb, Jing Caoc, Zhi FangdXihuang Laia Graduate School, North China University of Technology, Beijing 100144, China, b Brunel London School, North China University of Technology, Beijing 100144, China, c School of Electrical and Control Engineering, North China University of Technology, Beijing 100144, China, d School of Humanity and Law, North China University of Technology, Beijing 100144, China.Background: As the fresh troops in national innovative talents cultivation, postgraduate education shoulders the important mission of building China into a world leader in science and technology. However, the increasingly complex international environment and fierce competition of employment prospects make postgraduates bear great pressure. Some students even have mental problems. In order to alleviate the anxiety of the postgraduates nowadays, we put forward the goal of all-round development of talent cultivation on the basis of mental health with the corresponding assessment indicator system, trying to cultivate the sound personality and comprehensive quality of graduate students from the macro level of management and the micro level of personal development.Subjects and Methods: Firstly, through the method of literature survey, this paper analyzes in detail the practical dilemma and implementation bottleneck of mental health education based on physical, aesthetic and labor development at the graduate level. Then it combined with the management characteristics of our school, as well as the mental education, to establish a cultivation framework for the all-round development of graduate students. Secondly, according to the requirements of the comprehensive development in moral, intellectual, physical, aesthetic and labor aspects, and the demand of innovative-applied talents, we designed a relatively systematic questionnaire about postgraduate learning experience and mental health status, and carried out long-term data survey of our graduate students. On this basis, we further optimized the process of talent cultivation by putting forward the implementation strategy of \u201cmoral and intellectual education as the foundation, mental health education as the connection, practice as the way, team as the body part and multiple educations working together\u201d.Results: Under the influence of the reform of the postgraduates\u2019 comprehensive development mechanism of our university, the self-assessment survey of postgraduates\u2019 learning experience and mental health in recent two years shows that their degree of satisfaction with the work of multi-education integration carried out by our university is on the rise. We have successfully diverted students\u2019 attention and relieved their psychological problems caused by employment pressure, academic pressure, classmate relationship and emotion factors through conducting physical, aesthetic and labor education. And we have gradually shaped students\u2019 healthy psychology and sound personality as well as guide their all-round development in the process of education.Conclusions: The mental health of graduate students has been paid more and more attention, and universities are focusing on solving students\u2019 mental problems. We promote the organic integration of five educations with mental education, continue to improve the assessment system of graduate talent cultivation and optimize the implementation approach, urge the graduate management department to enhance the working methods through the way of assessment, and guide the graduate students to form good research habits and healthy mental state, to further improve the quality and effectiveness of graduate education. It is believed that the implementation strategies will provide a strong support and guarantee for cultivating high-level talents with excellent professional quality, noble character and mental health.This work was supported by the ideological and political work research project of Beijing universities (support project): Construction and implementation of the comprehensive development of postgraduates oriented by ability cultivation (Grant No. BJSZ2021ZC63), the Beijing higher education association project : Exploration and research on the quality evaluation of graduate practice in the new era (Grant No. MS2022291).aXuemin Zhua School of Foreign Languages, Sichuan University Jinjiang College, Pengshan, Sichuan 620860, China.Background: L2 motivation research has already attracted much attention in L2 field and this paper mainly focuses on the explorations of possible causes of low motivation in English learning in colleges of China and L2 motivational strategies in English Teaching of Chinese Context. Under the condition of maintaining and improving students\u2019 mental health, the investigation of the demotivation in EFL classrooms also takes psychological factors into consideration, which would probably help Chinese students ease academic stress and relieve anxiety in EFL classrooms, with the purpose of building students\u2019 confidence in L2 learning. Motivational problem also could be part of the contributions to promoting more effective language learning and teaching.Subjects and Methods: On the basis of related literature review, a qualitative research method is adopted in this study and therefore observation is chosen to be employed as the major method in the research. Meanwhile a case study is conducted among the college students. The discussing objects are mainly confined to the non-English majors who are studying in some colleges of the southwest city of China, in order to make the topic more clearly defined and elaborated.Results: Motivation to learn a foreign language depends on how much the individuals would like to learn L2 and how much satisfaction they would gain during the process of learning. In observational studies, the target learners have low motivation in EFL classrooms and the demotivating factors involves a series of problems, among which negative attitudes towards language learning have detrimental influence on the success of acquiring L2. Negative attitudes towards EFL classrooms may be caused by some psychological factors, including classroom anxiety and academic stress. Teaching methods, classroom atmosphere, teacher-and-student relationship and facilities problem are also taken into account.Conclusion: Negative attitudes are common and unavoidable in the discussed context, however, there is a more general recognition that suitable strategies may offer good chances to convert negative attitudes towards L2 learning into positive ones and even promotes the enjoyable process of language learning in some interesting ways. Moreover, this paper examines the teachers\u2019 role of setting up rapport with students in the motivational perspective and how it works as a spur to make L2 learners more confident and engaging in English learning. It also illustrates how important it is to create a pleasant and supportive environment for L2 learners to ease the pressure and anxiety in the process of language learning.a, Chunting DiaobRuiyue Zhua Clinical College of Traditional Chinese Medicine, Hubei University of Chinese Medicine, Wuhan, Hubei 430061, China, b School of Medical Humanities, Hubei University of Chinese Medicine, Wuhan, Hubei 430070, China.Background: Alzheimer\u2019s disease has become one of the epidemic diseases in contemporary human society. In recent years, the number of elderly people in China has increased year by year, and the aging process has obviously accelerated. Among them, people with Alzheimer\u2019s disease in China have occupied a large proportion of the population. Alzheimer\u2019s disease, as an elderly disease that will lead to serious consequences and extensive effects, should attract people\u2019s extensive attention. Emotional therapy of Traditional Chinese Medicine is a kind of therapy based on the theory of Traditional Chinese Medicine, which is simple to operate and rarely has side effects. This paper discusses the effect of emotional therapy of Traditional Chinese Medicine on improving Alzheimer\u2019 s disease, and provide the application path.Subjects and Methods: Research subjects are elderly patients with Alzheimer\u2019s disease, generally considered to be 45 years old and above. Patients receive treatment from the emotional theory of Traditional Chinese Medicine, mainly including transforming emotions, meeting demand, dispelling doubts, diverting attention, hinting to switch ideas. This paper uses the method of literature review to sort out and analyze the literature related to emotional therapy of Traditional Chinese Medicine and Alzheimer\u2019s disease in recent 20 years.Results: The theory of emotion of Traditional Chinese Medicine emphasizes that the human body can help repulse the influence of negative emotions by mobilizing the positive emotions of the whole body, restore the body to a peaceful state, and balance the function of viscera thereby relieving or treating various diseases. Depending on the patient\u2019s condition, different Traditional Chinese Medicine emotional therapies can be selected. When the patient is emotional, transforming emotions therapy can be selected. When the patient has requirements, meeting demand therapy can be selected. In addition, the patient can also be enlightened by dispelling doubts therapy firstly. If the effect is unsatisfactory, hinting to switch ideas therapy can be continued. Based on the above, Traditional Chinese Medicine treatment mainly based on psychotherapy can effectively improve the symptoms of Alzheimer\u2019s disease.Conclusions: Traditional Chinese Medicine emotional therapy can effectively regulate the abnormal emotions of patients, help patients to release themselves, obey their wishes, and promote physical and mental health. It has a positive effect on improving the symptoms of patients, and is worthy of comprehensive promotion.This work was supported by a project grant from the Hubei Provincial Department of Education\u2019s Philosophy and Social Science Fund Project in 2020 (Grant No.20Q075).a, Nur Syuhada binti Mat Sina, Afeez Nawfal bin Mohd Isaa, DuoBao ChenbQi Chena Sultan Idris Education University, 35900, Tanjong Malim, Perak, Malaysia, b Anhui University of Science and Technology, 232001, Huainan, Anhui, China.Background: The development of new media has brought significant changes in the way people communicate and engage with the world. However, elderly people may struggle to keep up with the fast-paced technological advancements due to changes in their cognitive and physical capabilities. The prolonged exposure to new media may have adverse effects on senior mental health, such as depression, anxiety, and loneliness. Moreover, seniors\u2019 decreased ability to concentrate and process information may lead to difficulty in navigating complex digital interfaces, resulting in low adoption rates. It is crucial to consider the changing behavior and mental health of elderly individuals when designing digital technology to ensure inclusivity and accessibility for all age groups.Subjects and Methods: In this research, by analyzing the consumption demand and usage status of new media among elderly people, as well as the factors affecting their sense of happiness in life. we propose measures to optimize the new media platform, establish a comprehensive system for the elderly to enhance their living quality and mental health.Results: By analyzing a quantity of files, the elderly prefer simplicity and may become more conservative in their thinking. They still require social interaction, particularly spiritual support from loved ones. A user-friendly media application could help bridge the digital divide for them. In this research, conducting several points to elaborate key direction for improving the elderly\u2019s living experience and mental health.Conclusions: The proposed measures not only aim to improve the usability and accessibility of new media platforms for seniors but also promote their digital literacy, social engagement, and overall well-being. Through technology training classes and user-friendly interfaces, seniors can enhance their digital skills and feel more confident and connected while using new media. Additionally, optimizing new media platforms to meet the specific needs of the elderly, such as larger fonts, simpler navigation, and audio instructions, can significantly improve their user experience. Ultimately, promoting the adoption of new media among seniors can bring substantial benefits, including improved mental health, social connectedness, and quality of life.a, Yuewu Zhenga, Rumeng Tiana, Lei Pengb, Mushan LiaYing Zhanga School of Emergency Management, Henan Polytechnic University, Jiaozuo 454003, China, b School of Energy Science and Engineering, Henan Polytechnic University, Jiaozuo 454003, China.Background: In recent years, frequent occurrence of public health emergencies posed a serious threat to social public security. After the occurrence of public health emergencies, people concern about their own health and the unstable situation, along with media and public opinion out of control, emotion focused coping and irrational behavior happen frequently. As the important factor of responding to public health emergencies, public risk perception has important practical value. Therefore, studying the influencing factors of public risk perception under public health emergencies can help the government guide to respond to public health emergencies, so the public\u2019s risk perception ability will improve, and minimize the serious consequences of public health emergencies.Subjects and Methods: First of all, based on the PSR (Press-State-Response) model this article identifies and analyzes the influencing factors of public risk perception. It is concluded that the inherent risk of public health emergencies, the actual progress of the event, the government response, and the media communication as influencing factors and the degree of reaction of the public\u2019s own response behavior as dependent variable to interpret public risk perception level. Secondly, integrating previous research achievements, a theoretical model is constructed based on the research hypothesis of influencing factors of public risk perception under public health emergencies. Thirdly, data are obtained through questionnaire survey, and empirical analysis is conducted using structural equation models. Finally, this article proposes countermeasures and suggestions for scientifically optimizing the level of public risk perception.Results: The inherent risk of events and media communication have a positive impact on public risk perception; The actual progress of events and government response have a negative impact on public risk perception.Conclusions: Improving the public\u2019s risk perception ability, optimizing existing emergency management policies, strengthening the government\u2019s risk communication ability, and improving the media\u2019s risk information dissemination can improve the public\u2019s risk perception ability, and provide a decision-making basis for guiding the public to respond scientifically to public health emergencies.This study was supported by the General Project of Humanities and Social Sciences Research in Henan Universities (2021-ZDJH-0139), the Key Science Research Project in Universities of Henan (21A630015), Ph.D. Fund of Henan Polytechnic University (B2017-62), China Engineering Science and Technology Development Strategy Henan Research Institute Strategic Consulting Research Project (2023 HENZDB 05) and the Teaching Reform Research Project of Henan Polytechnic University \u201cExploration and Practice of Safety System Engineering Teaching Reform in the Perspective of New Engineering\u201d.aMingyue Suna Nanchang Institute of Technology, Nanchang, 330000,China.Background: In the film Wrath of Silence, due to illegal mining and urbanization, the dual contradiction between urban and rural areas becomes increasingly prominent, forming a completely different social landscape between rural and urban areas. Under the influence of psychological pressure, people living here adopt different ways of making a living, forming a distinct pyramid shaped social structure. In the psychological context, the \u201csilence\u201d of the lower class is a passive and ineffective struggle, while the \u201csilence\u201d of mining owners from the emerging upper class and lawyers from the middle elite class is an active choice. The film intuitively displays the negative psychology of anxiety, inferiority, depression, mania, cowardice, suspicion, greed, indifference, etc. among the pyramid class population. The dual dilemma of physical and psychological forces people belonging to different classes to implement a breakthrough in reality.Subjects and Methods: By talking about the film semiotics analysis, this paper deconstructs the structure of the story hidden in the text and the expression method of the text from the perspective of story, narrative time, narrative space and expression techniques. The details considered from a psychological perspective are as follows. First, through the dual tone of the film\u2019s realism and surrealism (magic) coexistence, we examine how the film establishes the style and tone of the entire film. Secondly, it deconstructs the pyramid shaped social structure through the gaze perspective in Freud\u2019s psychoanalysis. This tower shaped display image symbol is in line with the contemporary Chinese landscape of class opposition and interest conflicts. The collapsed and imbalanced hierarchical structure makes the tragedy presented in the film more profound and powerful. Third, by reconstructing the time sequence of the film, the deeper meaning of metaphors in each image symbol is deciphered. The film examines the different desires pursued by people of different classes.Results: Different from other crime suspense genre narrative films, to find the child is the starting point of the film, but not around the crime committed or crack crime to narrate. Instead, from the Gestalt film theory of mind, a large number of plots are left blank. Through a large number of symbols and plot blank, the audience can think and feel who is the real villain. The film seems to be looking for children, but in reality, it is the pursuit of different desires by people from different social classes.Conclusions: This study focuses on the imbalance of urban-rural development through the film Wrath of Silence, and explores the reality of the physical and mental plight of people in China\u2019s classes, especially in the rural areas, exploring the social symptoms of the upper class\u2019s loss of attitude, the middle class\u2019s loss of morality, the bottom class\u2019s loss of speech, and the earthly disorder. And the complexity and diversity of mental health issues will also lead to diverse discussions on the desires, difficulties, and psychology of different social classes in rural China. Furthermore, it brings positive psychological thinking to the audience, in order to alleviate negative psychology such as anxiety, stress, and suspicion.a; Zhongyan LinbKexin Jianga The Bartlett School of Environment, Energy and Resources, University College London, London, WC1H 0NN, UK, bSchool of International Digital Economy, Minjiang University, Fuzhou, China.Background: A person spends most of their time indoors. The quality of the indoor environment (IEQ) has a direct impact on people\u2019s comfort and health. In this circumstance, IEQ becomes the professional\u2019s main concern. For many years, offices have been one of the main topics of research. A variety of aspects that affect office occupants\u2019 health, wellbeing, and comfort have been researched and listed by many researchers, including indoor air quality, thermal comfort, and biophilic design.Subjects and Methods: This study focuses on the comfort, health, and wellbeing of office workers. Using Alker et al.\u2018s structure of office design to produce the literature review structure, the study first develops the overall picture of office design variables with health, welfare, and comfort. Then, a variety of studies are succinctly analyzed and organized to demonstrate the most recent findings in the area. Then, biophilic design as the main focal point in this study is analyzed. With the help of the biophilic design framework, a literature analysis is conducted to summarize the most recent research and offer recommendations for workplaces to improve the health, wellbeing and comfort status of employees.Results: There is information available on every aspect of workplace design, along with their recommendations. The table of research demonstrates the validity of the framework by Alker et al. and the relationships between various elements and the comfort, wellbeing, and health of occupants. The research on biophilic design then presents an ongoing process in the field and the significance of having the biophilic design in workplaces based on the framework for biophilic design. Some of the recommendations, meanwhile, have flimsy supporting data, necessitating more investigation. There is a need to do additional quantitative research on the relationships between biophilic components and health as a result of the limited research approaches in this study and existing research gaps.Conclusions: Based on the findings, stakeholders should take the office design structure into consideration to enhance the working environment. The compiled biophilic design recommendations can help design teams and building owners further optimize their workplaces for the comfort, health, and welfare of their employees. Additionally, a larger variety of constructed surroundings should emphasize the value of biophilic design in order to enhance the relationship between humans and nature.This work was supported by project grants from The National Key R&D program, the Intergovernmental International Science, Technology and Innovation Cooperation Project (EU Horizon Project-No.2017YFE0118800); Central Financial support for Local Science and Technology Development Special (No.2018L3007); Foreign cooperation project of Fujian Provincial Science and Technology Plan (NO.2020I0040).aHua Wanga School of Marxism, Xi\u2019an International Studies University, Xi\u2019an 710119, China.Background: Starting from the value of traditional Chinese health preservation and self-cultivation culture, analyze the main manifestations of current college students\u2019 psychological anxiety, and interpret the positive role and broad value of traditional Chinese health preservation and self-cultivation culture in alleviating college students\u2019 psychological anxiety.Subjects and Methods: The article mainly analyzes and summarizes the combined methods and practical significance of alleviating college students\u2019 psychological anxiety based on traditional Chinese health preservation and self-cultivation cultural concepts and practical practices. In the process of research, the methods of literature research and induction were mainly used. The article summarized and organized the content and characteristics of traditional Chinese self-cultivation culture, as well as the manifestations of college students\u2019 psychological anxiety, including relevant concepts and practices in traditional Chinese culture, as well as the methods to solve college students\u2019 psychological anxiety summarized through practical implementation and exploration.Results: Based on the analysis of the connotation of traditional Chinese health and self-cultivation culture and the main manifestations of college students\u2019 psychological anxiety, this article explores the role of traditional Chinese health and self-cultivation culture in positively alleviating college students\u2019 psychological anxiety, the specific implementation methods, and its broader practical and world significance in the future. This provides new ideas for the management of psychological anxiety among college students, and also provides a model for applying Chinese health preservation and self-cultivation culture to a wider range in the future.Conclusions: The concepts of calmness, harmony, and self consistency contained in traditional Chinese health and self-cultivation culture, as well as traditional practice methods such as traditional Chinese medicine and Tai Chi, have a very significant effect on positively relieving the psychological anxiety of college students. From a broader perspective, China\u2019s traditional health and self-cultivation culture has more practical and extensive value in relieving psychological anxiety for a wider population in the future.a, Lintao FubJingtong Zhaoa Department of Electronic Commerce and Law, Beijing University of Posts and Telecommunications, Beijing City 100000, China, b Department of Software engineering, Beijing University of Posts and Telecommunications, Beijing City 100000, China.Background: This paper aims to study the intellectual property protection platform for intangible cultural heritage digital works based on blockchain technology. With the development of digital technology, intangible cultural heritage (ICH) works face the challenge of intellectual property protection in digital dissemination. This study constructs a new type of intellectual property protection platform by utilizing the decentralized, transparent, and tamper resistant characteristics of blockchain. The platform adopts smart contract technology to ensure the confirmation, authorization, and supervision of intellectual property rights, and ensures the traceability and tamper resistance of works through the distributed storage and timestamp functions of blockchain. At the same time, the platform also provides a convenient authorization management and copyright trading mechanism, providing a fair, transparent, and efficient intellectual property protection solution for artists and rights holders. Through empirical research and case analysis, this paper verifies the feasibility and effectiveness of a blockchain based intellectual property protection platform for intangible cultural heritage digital works. This platform can not only promote the inheritance and protection of intangible cultural heritage works, but also promote the healthy development of digital art market. In order to protect the copyright of intangible cultural heritage works, assist in the standardized collection, digital protection and dissemination of intangible cultural heritage. In terms of mental health, intangible cultural heritage has a unique therapeutic and soothing effect. Participating in the inheritance and practical activities of intangible cultural heritage can help individuals reduce stress, alleviate anxiety, and promote emotional balance and self adjustment. The aesthetic experience and artistic creation of intangible cultural heritage can also stimulate people\u2019s creativity and imagination, enhance individual self-esteem and self-confidence. In addition, intangible cultural heritage activities can promote social interaction and group cohesion, provide social support and emotional security, and help prevent and respond to mental health issues.Subjects and Methods: This article proposes a blockchain based intellectual property protection platform for intangible cultural heritage digital works to address the copyright issues encountered in the current digitization process of intangible cultural heritage works. Provide a more humane and easy to understand operation process on the platform, better fit the psychological needs of non-genetic heirs.Results: By integrating blockchain technology into the intangible cultural heritage creation and exchange platform, blockchain stores the information of intangible cultural heritage creators and works. Blockchain, as a decentralized, reliable, and secure storage technology, can provide copyright protection for digital works, as well as new ideas and methods for digitizing intangible cultural heritage and IP construction. At the same time, at the level of mental health, the use of blockchain increases the security of data, so that creators can store data more securely, so as to form a platform with a credible degree that meets the psychological expectations of the authors.Conclusions: Taking the IP digitization process of the intangible cultural heritage of Buyi people \u201cMaple fragrans Dyeing\u201d in Daihua Town, Changshun County, Guizhou Province as an example. Non-genetic heirs have a good experience on the platform, which is in line with psychological expectations. This case verifies the effectiveness of using blockchain to confirm the rights of digital works of intangible cultural heritage and further implement the copyright transformation mode.a, Yunying Shib, Fangmei LiangaYingli Guoa School of Teacher Education, Hechi University, Hechi 546300, China, b School of Big Data and Computer, Hechi University, Hechi 546300, China.Background: In schools, issues related to mental health among students have been a significant concern for several years. Before the outbreak, statistical sources indicated a significant and increasing rate of depressive disorders, suicidal behavior, and various other issues in educational institutions among students. This includes issues such as the possibility of being depressed and worst committing suicide. Thus, this qualitative study aimed to explore the Hechi University students\u2019 lived experiences with online learning during the COVID-19 pandemic. Specifically, this analyzes college students\u2019 mental health and it is influencing factors during online learning. Based on the findings recommendations were proposed and the implications were presented.Subjects and Methods: This research utilized a qualitative method of research, particularly descriptive phenomenology. The participants of the study were ten (10) students studying using the online learning platforms, they were selected using convenient sampling. The criteria for the participants\u2019 selection were students from all levels, male or female, and those using the online learning modality. Thus, they are the most suitable participants of this study as they can best give their responses and testimonials based on what they have experienced while using the new learning platform. The data gathering for this study commenced from November to December 2022. The researcher conducted in-depth one-on-one interviews in gathering the data.Results: The overall results suggested that most students expressed a wide variety of unfavorable emotions they believed they had encountered throughout the course of the global outbreak. Throughout the lockdown, several pupils expressed feelings including \u201cfrustration,\u201d \u201cconstriction,\u201d \u201canxiety,\u201d and/or \u201cdepression.\u201d After then, a few of them discussed why these feelings affected their day-to-day performance, often in significant ways. Thus, it was revealed that distance learning can be strongly demanding for the mental health of the students. Thus, assistance for student\u2019s mental health is needed during online classes since virtual learning exacerbates pupils\u2019 anxiousness throughout a disease outbreak.Conclusions: Online education was deemed to have a severe effect on the student\u2019s mental health. It was recommended that the results of this study shall be presented to the Ministry of education to provide information, plan activities, and strategies, and create innovations to provide sufficient intrinsic and extrinsic motivation to excel and improve their academic achievement and attain quality and relevant education during the pandemic.This work is supported by Guangxi Natural Science Foundation Project  and Research Basic Ability Improvement Project for Young and Middle-aged Teachers of Guangxi Universities .a,b,c, Peiyun Guoa, Linbo ZhuaJing Zhaoa Institute of Human Geography, School of Tourism, Xi\u2019an International Studies University, Xi\u2019an 710128, China, bShaanxi Tourism Research Institute, Xi\u2019an International Studies University, Xi\u2019an 710128, China, c Research Center for Tourism Cooperation and People-to-people Exchange among SCO Nations, Xi\u2019an International Studies University, Xi\u2019an 710128, China.Background: Growing volume of research suggests mental health benefits of natural environments. Psychological needs and motivations of tourists of different age groups and how to promote mental health of tourists remain relatively unexplored. This research was aimed to examine association between rural tourism and mental health among tourists of different age groups.Subjects and Methods: Analyzing psychological needs and features of tourists of different ages, this study constructed a table to summarize. In addition, this research analyzed the existing resources of rural tourism in Shaanxi, China, and explored how to use these resources to meet the different psychological needs of tourists, relieve their psychological anxiety, and promote their mental health.Results: Rural tourism can promote the mental health of tourists of different ages. Adolescents face a variety of pressures, such as difficulties of interpersonal communication, heavy academic burden, excessive expectations of parents and so on, which can trigger psychological anxiety of varying degrees. Middle-aged people bear the pressure from emotion, home, work, and physical health, in the face of high-intensity work tasks in the workplace, at the same time, bear the responsibility to take care of the elderly and children in the family, is the most anxious stage of life. Unlike adolescents and middle-aged people, loneliness may cause anxiety for elderly people, especially empty-nesters who live alone. Different types of rural tourism can meet different psychological needs. Wildlife tourism can meet psychological needs of seeking novelty and knowledge of tourists. Living in the countryside with beautiful scenery, tourists can experience the natural, simple and sincere lifestyle and cultural expression of the countryside, and meet the nostalgia psychological needs. Forest tourism can enable tourists to appreciate natural scenery, enjoy quiet time, relax in fresh air, relieve the pressure of life, and promote mental health of tourists.Conclusions: People of different ages groups in modern society are under great pressure and prone to psychological anxiety. The natural environment, wild animals and homestays in rural areas can meet the psychological needs of tourists from different angles, so that tourists can obtain happiness and satisfaction, produce a positive tourism experiences, and promote the mental health of tourists.This research was supported by the Innovation Capability Support Program of Shaanxi (Program No.2022KRM038), Shaanxi Higher Education Teaching Reform Research Project (No.21BY092), Research and Practice Project on Comprehensive Reform of Postgraduate Education of Xi\u2019an International Studies University (No. 22XWYJGA08). The authors also wish to thank the editor and the reviewer for their valuable comments.aJuanmiao Shia Department of Social Work, Zhejiang University of Finance Economics Dongfang College, Jiaxing 314000, China.Background: With the development of the infant care service industry, all sectors of society gradually focus on how to create a friendly environment for infants and children. Especially the concept of \u201cchild-friendly community\u201d advocated in recent years, all sectors of society gradually focus on how to create a friendly environment for infants and children. The independent infant care service model cannot fundamentally solve the parenting pressure of young families and solve the problem of gradually decreasing child ratio. An appropriate service model is urgently needed to relieve the physical and mental pressure of infant families, promoting the healthy growth of infants and their family members. This study combined with the social organization in the process of service integration community resources to assist the practice of infant family nursery demand experience, put forward the appropriate infant nursery service intervention path-integrated service mode.Subjects and Methods: Selecting \u201cz\u201d social organization as research object, this paper expounds how \u201cz\u201d social organization integrates resources of community health service centers, voluntary service organizations and other community social organizations to provide physical, psychological and social services for infants in the community, so as to promote the healthy growth of infants and young children.Results: In this study, social organizations provide services for infants relying on child-friendly community platforms, and an integrated service model suitable for infant care needs is proposed. The integrated infants nursery care model mainly takes baby-friendly service projects as samples, integrates the resource advantages of women\u2019s federations, grass-roots civil affairs departments, medical and health organizations and medical volunteers, provides social support for infants in the community, and creates a child-friendly community atmosphere of \u201csystem-friendly, environment-friendly and service-friendly\u201d, responding to the needs of infants and families and promoting the healthy growth of infants.Conclusions: According to the practical experience of social organizations using the integrated service mode to provide services for infants in the community, it is concluded that the integrated service mode has realized the needs of infants in the community to a certain extent, and according to the practical experience of the integrated service mode, it clarifies the roles and tasks of each resource subject in the infant care and nursing. The integrated service model of infant service plays an important role in the healthy development of infant\u2019s physical, psychological and social ability.This work was supported by a project grant from the 2021 Philosophy and Social Science Planning project of Zhejiang Province \u201cResearch on the Improvement of Children\u2019s Psychosocial Ability from the Perspective of Community Governance- -Taking the Children\u2019s Friendly (Grant No.21NDQN301YB), 2023 Zhejiang Province Civil Policy Theory Research Project \u201cResearch on the Path of Social Organizations Participating in Children Friendly Services from the Perspective of Community Governance\u201d (Project No.: ZMKT202388) and the key topics of Zhejiang University of Finance Economics Dongfang College \u201cResearch on the Construction of Early Development Service System of 0-3 Year Old Children in Zhejiang Province\u201d(Grant No.2020dfy001).a, Faridah binti SahariaYarui Huoa Faculty of Applied and Creative Arts, Universiti Malaysia Sarawak, Sarawak, Malaysia.Background: The trouser production industry is in the transformation and upgrading of the attack period. Intelligent manufacturing is an important strategic direction for the transformation and upgrading of China\u2019s manufacturing industry, the emotional behavior of employees affects the organizational efficiency of the trouser production line, and the study of organizational efficiency is the core of automated production in the face of the new pattern of industry development, the trouser production line managers fully consider the emotional behavior of employees, the introduction of automated equipment to help improve the organizational efficiency of the production line It is imperative to do so.Subjects and Methods: This paper explores the factors influencing the introduction of an automated hanging system in trouser production lines in four dimensions: employee emotional behavior, i.e., intention to use, user satisfaction, and system quality and organizational efficiency, and constructs a theoretical model of organizational efficiency of an automated transfer hanging system. This study was conducted with 268 front-line employees in a Chinese trouser manufacturing company and analyzed by structural equation modeling (SEM).Results: The results showed that (i) system quality had a significant positive effect on employees\u2019 emotional behavior, i.e., intention to use and user satisfaction; (ii) user satisfaction had a significant positive effect on intention to use. (iii) Employee\u2019s emotional behavior, i.e., intention to use and user satisfaction, positively affects organizational efficiency.Conclusions: This study addresses the results of the study, fully considers the direct and positive impact of employees\u2019 emotional behavior on the organizational efficiency of the automatic hanging system, and puts forward practical and feasible guiding suggestions for trouser manufacturing enterprises to introduce automated equipment and enhance their automation and intelligent development capabilities based on meeting employees\u2019 emotional needs.a,b, Deying Lina, Zhaomin Sanga, Xin Zhanga, Jinhua Wua, Luxiang HouaXiaolan Huanga Department of Psychology, Third Affiliated Hospital of Guizhou Medical University, Duyun 558000, Guizhou China, b School of Nursing, Guizhou Medical University, Guiyang 550000, Guizhou, China.Background: To study the positive effect of cognitive therapy in rehabilitation treatment and nursing of depression in adolescents in the southern ethnic regions of Guizhou.Subjects and Methods: 1. The study subjects were adolescents with depression who were officially admitted to our hospital for rehabilitation treatment in the southern ethnic regions of Guizhou from July 2020 to May 2022. 2. They were randomly divided into a clinical pathology research experimental group  and a clinical pathology control group (referred to as the control group). The control group was given symptomatic conventional drug treatment and routine nursing measures for psychiatric and psychological departments; while the experimental group was given cognitive therapy intervention on the basis of the conventional rehabilitation treatment and nursing measures of the control group. The Hamilton Depression Scale (HAMD) scores of the two groups of depressed patients before and after the intervention were compared. 3. Firstly, analyze and study the gender, age, education level, ethnicity, living environment, and other factors of the control group and experimental group of adolescent depression. 4. Use SPSS 21.0 statistical software for statistical analysis and data processing. The basic data is presented as mean \u00b1 standard deviation. Single-factor ANOVA test and post-hoc multiple comparisons (LSD method) are used for statistical analysis of the experimental and control groups.Results: The research results show that: 1. Adolescent depression is mainly concentrated in female Bouyei ethnic middle school students in rural areas. This is mainly due to the lack of care from parents for their female children while working outside the home. This should be highly valued by the school, society, and family, and proper care and frustration education should be given to left-behind children to enhance the life confidence and ability to withstand pressure of female students.2. After rehabilitation treatment intervention, the HAMD scores of the experimental group were significantly reduced compared to those of the control group. The clinical comprehensive evaluation index was significantly better in the experimental group compared to the control group, and the difference had important clinical statistical guidance significance (P<0.05).Conclusion: In the rehabilitation treatment and nursing of depression in adolescents in the southern ethnic regions of Guizhou, cognitive therapy can be effectively applied to improve the degree of depression and enhance the ability of emotional self-control. It is worth promoting in the clinical rehabilitation treatment and nursing of depression in adolescents.This research was supported by:1. 2020 Special Scientific Research Project of Nursing Discipline of Guizhou Medical University (Project No. YJ20070);2. 2023 Science and Technology Fund Project of Guizhou Provincial Health Commission (Project No. gzwkj2023-146).a, Wenlu WeibZhichao Songa School of Economics and Management, North China University of Technology, Beijing 100000, China, b School of Communication, Weifang University, Weifang 261000, China.Background: With the development and maturity of social media power, the influence of social media on the communication effect of agricultural brands is becoming increasingly apparent. Relevant practitioners feel more pressure on how to meet the psychological needs in the competition of the new industry. Some pathological competition also affects the psychological health of practitioners, such as disorderly competition and industry anxiety. The industry and society need to find answers to the problems based on development to meet individual psychological needs, solve industry pathologies, and sustainable development of agricultural brands. Research on the mechanism of agricultural products\u2019 brand communication in the social media environment will be one of the solutions. It is a generalization and summary of communication methods and effects, and a universal and replicable communication mechanism is refined based on communication practice, which can also meet psychological needs, solve anxiety problems and protect psychological health.Subjects and Methods: This article uses grounded theory and coding analysis through theoretical studies, policies, news, activity reports, and in-depth interviews on the communication of agricultural brands on various social media platforms. Through the coding analysis, the research finds the causes of industry anxiety, the conditions to meet psychological needs, and the solution ideas of pathological competition, and the article constructs a model of the influence mechanism of social media on the communication of agricultural brands.Results: Based on grounded theory, this paper sorted out 58 open codes, 26 spindle codes, and six selective codes in interviews and data screening. This paper describes and analyzes the selective codes, and the extensive data ensures the rigor and credibility of the result sources. Finally, it proposes a mechanism for agricultural brand communication that satisfies psychological needs and alleviates industry anxiety.Conclusions: Research and analysis based on grounded theory show that the influence mechanism of social media on agricultural brand communication will effectively meet psychological needs, relieve industry anxiety and improve mental health. This requires government authorities, industry associations or enterprises, and brand users to think and discuss various aspects when formulating communication strategies and developing more three-dimensional communication strategies to realize the benefits of transformation of agricultural brand communication and ultimately help the industry and practitioners to grow healthily and sustainably.aZhitao Xiaoa Department of General Education, Guangzhou Huali College, Guangzhou 511325, China.Background: With the progress of society and the development of medical technology, people need to integrate a large amount of medical resources, allocate medical tasks reasonably, and achieve higher efficiency and less wastage in completing tasks. This article presents a principle submatrix algorithm for the assignment problem where the number of medical tasks exceeds the number of people.Subjects and Methods: Firstly, we present the theory of same solution transformation for n persons and kn tasks assignment problems, followed by a principle submatrix algorithm for this type of problem. Then, we transform the medical assignment problem with more tasks than the number of people into a n persons and kn tasks assignment problem with the same solution, and finally use the principle submatrix method to find the optimal assignment of the problem. The characteristic of this principle submatrix algorithm is that it does not need to consider the overall assignment matrix of the assignment problem, only needs to perform operations locally on the assignment matrix, starting from the first order principle submatrix, and finding the optimal assignment of the problem step by step in a regular manner.Results: For medical assignment problems with more tasks than the number of people, we do not need to transform it into a balanced assignment problem where the number of tasks equals the number of people, this assignment problem is first transformed into an n persons and kn tasks assignment problem with the same solution, and then the principle submatrix algorithm is used to obtain the optimal allocation of the original medical assignment problem. The principle submatrix algorithm for this medical assignment problems with more tasks than the number of people proposed in this article is more regular and operable compared to the commonly used Hungarian method for solving assignment problems.Conclusions: The principle submatrix method proposed in this article is a polynomial algorithm with a computational complexity of. The algorithm starts from a row minimum group of the principle submatrix of the first order of the assignment problem, finds the row minimum groups of the principle submatrix of each order step by step, and finally obtains an optimal assignment of the original medical assignment problem. Through this method, it is convenient to find the optimal assignment of medical tasks that exceed the number of people, and efficiently complete the reasonable assignment of medical resources.aHua Ouyanga Guangxi University of Finance and Economics, Nanning, Guangxi 530003, China.Background: The 21st century is the ocean century, the ocean is rich in resources, social and economic development is an important support. Guangxi is located in the Southwest China, with an area of about 40,000 square kilometers in the Gulf of Tonkin Sea, and has huge potential for marine economic development. But at present, the development of Guangxi\u2019s marine economy has encountered a bottleneck. Especially in the digital transformation of the marine economy, the development of digital economy and intelligentization has also brought about the problems of machine dependence, loss of skills, infatuation with the network, separation from reality and spiritual loss, so that people\u2019s mental health has been affected.Subjects and Methods: By analyzing the background and current situation of Guangxi Marine Economy Digital Transformation, this paper probes into the painful and difficult problems in the process of Guangxi Marine Economy Digital Transformation. In particular, the paper deeply analyzes the mental health problems brought by the digital transformation of marine economy, and puts forward feasible solutions.Results: Through the research, the paper finds that although the progress of Guangxi\u2019s marine economy digitization is steady and good, it still faces many problems and challenges, mainly as follows: the marine economy digitization process lags behind, the marine digital economy enterprises lack vitality, the marine digital talents are seriously lacking. The digital development of marine medicine is absent, and the digital transformation affects people\u2019s mental health.Conclusions: We should break the shackles of the traditional economic model on the development of marine industry, and promote the digital development of Guangxi Marine Economy, and finally realize the transformation from \u201cDigital ocean\u201d to \u201cSmart Ocean\u201d. First, to build a strong digital marine area and a modern digital marine economy; second, to accelerate digital innovation and promote a high degree of integration between the digital economy and the marine industry; and third, to formulate preferential policies, fourth, to construct the system of marine medicine to alleviate the mental illness brought by digitalization. We should actively carry out psychological intervention, find out problems as early as possible and try to adapt to the development process of digital economy, so as to fully enjoy the changing modern civilization.This work was supported by The 2018 National Social Science Foundation Project (Grant No.18BJL049), Guangxi First-class Discipline Applied Economics Construction Project Fund (Grant No.2022YBD06) and the 2022 Annual scientific research project of land-Sea Economic Integration Collaborative Innovation Center (Grant No.2022YB10).a, Bingquan Luoa, Huayu Zhaob, Jun Chua, Zihao Lia, Jiwen Zhanga, Wenrui ZhangaYue Rena Capital University of Physical Education and Sports, Beijing 100191, China, b Northeastern University at Qinhuangdao, Qinhuangdao 066004,China.Background: Multi-information sensing technology has gained prominence in various industries, including sports. Long jump, an ancient sport, requires a deep understanding of muscle contraction methods and characteristics during each stage. Previous studies have primarily focused on movement patterns and joint muscle activity, without exploring the anatomical function of muscles and joints or the role of individual joint muscle groups in exercise techniques. By incorporating multi-information fusion technology in long jump research, this study aims to investigate the muscle-specific capabilities of long jumpers and contribute to the medical and health aspects of sports performance.Subjects and Methods: Utilizing multi-source information fusion technology, this study examined the biomechanical attributes of muscle-specific capabilities during the take-off phase of long jumpers, aiming to effectively identify changes in muscle vitality of the take-off leg. The research employed the widely-accepted multi-source information fusion technology to explore the specific conditions of long-jumpers\u2019 leg muscles during the take-off action, which accurately reflects the athletes\u2019 physical condition and has potential implications for injury prevention, athlete health, and performance enhancement.Results: The findings demonstrate that the hip joint of the take-off leg generates greater hip extensor torque during the long jump take-off action, highlighting the importance of active contraction ability of the knee flexor group for successful take-off and avoidance of damage to the posterior femoral muscle group. The range of pressure center change lies between 51.26% and 74.35%, suggesting valuable applications in actual training for improving athletes\u2019 well-being, overall health, and performance in the long jump. Additionally, these results can contribute to the development of personalized training and rehabilitation programs that minimize the risk of overuse injuries and muscle imbalances, ultimately promoting better overall health and longevity in athletes\u2019 careers.Conclusions: This study provides valuable insights into the muscle-specific abilities of long jumpers during the take-off phase using multi-source information fusion technology, which has significant implications for medical and health-related aspects of sports performance. The results emphasize the importance of hip extensor torque and knee flexor group contraction in injury prevention and optimal performance, with potential applications for enhancing training regimens, promoting athlete health, and prolonging careers. Furthermore, the knowledge of these biomechanical characteristics can assist in the early detection and intervention in cases of suboptimal performance, thereby allowing timely adjustments to training or rehabilitation programs and ensuring the athletes\u2019 well-being.a, Yubiao Lib, Wenqi GongbYouxi Yana Department of International Applied Technology, Yibin University, Yibin, Sichuan 644000, China, b Department of Resources and Environment, Wuhan University of Technology, Wuhan, Hubei 430070, China.Background: Minqin settlement system located in the downstream of Shiyang River Basin is surrounded by Tengger Desert in the northeast and surrounded by Badain Jaran Desert in the northwest, with strong ecological sensitivity. At the end of the last century, with the increase of settlement population, excessive reclamation and wood-cutting activities resulted in lack of ecological barrier of settlement system and deterioration of human settlement environment, and the residents were in deep anxiety. In order to solve people\u2019s psychological anxiety and repair the residential environment of settlement system, the state and local governments have successively launched the key governance projects of Shiyang River Basin after 2000, and completed the treatment in 2015 and carried out the acceptance of the treatment results smoothly.Subjects and Methods: In order to objectively analyze the restoration effect of key governance on the ecological environment of the settlement system and regulate the anxiety of residents in Shiyang River Basin, the TM remote sensing images of Minqin County in 1980, 2000 and 2015 are taken as the main data sources, and the landscape pattern of Minqin County Settlement System is interpreted through image fusion, geometric correction, image enhancement, data registration and sampling verification by referring to the geospatial data cloud of Chinese Academy of Sciences.Results: In 1980, 2000 and 2015, the area of settlement patches continued to increase, the patch area of cultivated land first increased and then decreased, the patch area of grassland decreased first and then increased, the patch area of forest land was flattened first and then increased, the patch area of water area first decreased and then increased, and the area of desert patches decreased in turn, and the key governance effect did not appear, and the adjustment effect of residents\u2019 anxiety was unsatisfactory.Conclusions: The reason is that the key governance measures of Shiyang River Basin are improper, and the water conveyance mode in the settlement is still artificial lined channels, and the natural water transportation mode of Daxi River and Dadong River is abandoned. The east and west ecological barriers of settlement system cannot be restored naturally due to water shortage, and the residents are still anxious about ecological problems.This work was supported by Yibin University \u201cSailing\u201d plan project (2020QH02), General Project of Ministry of Education Foundation on Humanities and Social Sciences in 2021 (21XJA630008) and the fourth round key discipline of Yibin University \u201cResources and Environment\u201d.a,b, Boping Tiana, Guangqiang TengaJinyang Liua School of Mathematics, Harbin Institute of Technology, Harbin 150006, China, b School of Statistics, Chengdu University of Information Technology, Chengdu 610103, China.Objective: Infectious diseases are often fierce, dangerous, widely spread, and have a huge social impact. Countries have developed different prevention and control strategies according to the epidemiological status, disposal capacity, and social characteristics of their infectious diseases. Few quantitative studies have been conducted to compare and analyze the intervention effects of infectious disease epidemics in multiple countries. This study aims to use scientific models and methods to evaluate the effect of infectious disease intervention in different countries, sum up experience and lessons, and provide some suggestions for minimizing or effectively controlling infectious diseases that may occur in the future.Methods: This study used the classical epidemiological SIR model and calculates its basic regeneration number to compare the effectiveness of infectious disease epidemic control in four countries: China, America, Italy, and India. By solving the SIR model with a system of differential equations, the infectious disease epidemic curves can be fitted relatively accurately based on available data. It is only necessary to estimate the model parameters to predict the spread of infectious diseases, and then evaluate the intervention effect of infectious diseases.Results: In this study, the epidemic trends of infectious disease in four countries, China, America, Italy, and India, under natural conditions and government control, were obtained by simulation and the basic regeneration numbers were calculated. The study shows that the spread of the epidemic was effectively interrupted earlier in China under control, while the epidemic control was not more effective in America, Italy, and India.Conclusions: As transportation levels increase and the number of mobile populations grows, prevention of infectious diseases is no longer simply a matter of prevention in a particular region or country, but has expanded to a global level. In this study, the SIR model was used to compare and analyze the prevention and control effects of infectious disease outbreaks in four countries. The findings of the study deepen the understanding of infectious diseases and their intervention measures to a certain extent, which plays a role in the common and effective response to similar outbreaks of major infectious disease epidemics in the future. China\u2019s infectious disease intervention measures and related experiences are worthy of active reference by countries around the world.This work was supported by a project grant from the Natural Science Foundation of China(NSFC) (No.91646106).a, Ji GuoaTian Lia College of Arts, Gansu University of Political Science and Law, Lanzhou 730070, China.Background: Art therapy, also known as art psychotherapy, is an important intervention method for treating psychological issues. It spans multiple disciplines, including art, psychology, and medicine, and has gained increasing attention as society continues to develop. Painting therapy is one of the methods of expressive art therapy, which allows painters to use nonverbal tools through the creative process of painting to guide chaotic psychological states and feelings into a clear and orderly state. It can present the suppressed emotions and conflicts within the subconscious and obtain relief and satisfaction during the painting process, thus achieving diagnostic and therapeutic effects.Subjects and Methods: A certain number of college students with psychological issues were selected, and interviews, questionnaires, and analysis were conducted to summarize their psychological problems. Different treatment strategies were employed based on the specific psychological issues of the college students. There are various forms of painting therapy strategies, including free painting, theme painting , gestalt painting , and so on.Results: Painting therapy is a service-oriented profession that presents individual development, abilities, personality, interests, concerns, and conflicts through the use of painting media or materials, artistic imagery, creative artistic activities, and patient feedback on the work. Art therapy is generally suitable for individual psychotherapy. Through art therapy, various tense emotions and pressures can be released during the creative process, inherent experiences can be clarified, thoughts can be concretized, and certain psychological needs can be conveyed. Art creation opens a pathway to the subconscious, facilitating the expression, reflection, integration of individual development, abilities, interests, personality, thoughts, and inner emotional states, making it more accessible to the public.Conclusion: Through painting therapy, the suppressed emotions and conflicts in the patient\u2019s subconscious are presented. At the same time, during the process of painting therapy, the patient releases negative energy in their mind, emotions, and thoughts, decompresses, releases emotions, adjusts emotions and attitudes, repairs spiritual wounds, fills gaps in their inner world, and obtains a sense of satisfaction, achievement, and confidence, thereby achieving good diagnostic and therapeutic effects. Art therapy has vast prospects, but due to various objective factors and the low attention given to this therapy in China, there is limited research, insufficient studies, and a lack of prominent case studies, making it difficult to conduct specific and effective art therapy. This article mainly explains the implementation, directions, and unique significance of art therapy, aiming to provide a detailed introduction to the entire process of art therapy, its advantages, and development prospects.This study was supported by the 2021 Young Doctor Fund Project of Gansu Province (Project No.: 2021QB101).a, Borhannudin Bin Abdullahb, Hazizi Bin Abu SaadcChenxi Lua Faculty of Educational Studies, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia, b Faculty of Educational Studies, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia, c Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia.Background: Intelligent somatosensory interactive exercises are the primary focus of this study because of their potential to improve motor skills and effect and on the psychological status in autistic children.Subjects and Methods: The present issues of hand movement training for children with autism, as well as the impact of somatosensory games on psychological status as well as on rehabilitation training for autism, are explored via the use of case studies. Somatosensory activities for teaching kids with autism how to use their hands effectively were studied. The impact of various variables on users\u2019 immersion is investigated via data collecting, classification, and analysis. Functions, programme flow, main features, and implementation effects of the somatosensory game are displayed, and an introduction to the development platform and key technologies used in the design and development of the somatosensory game module are provided.Results: Modelling, character management, task flow management, collision detection, an interactive interface, and natural interaction techniques including gesture and voice interaction are all presented as part of the somatosensory interaction system\u2019s development process. This research paper defines autism and describes its symptoms and features in youngsters. It lays the groundwork for future study by discussing the viability of using somatosensory games in the hand movement training of autistic children and by providing an in-depth analysis of the development status and use of somatosensory games. It also clarifies the product\u2019s intended direction and design content for somatosensory interactive training products based on the defined study material.Conclusion: Somatosensory games have been demonstrated to be useful in the improving the psychological status and rehabilitation of autistic youngsters. Children with autism showed improvements in their visual responses, anxiety responses, verbal communication, and interpersonal relationships after participating in a healthcare intervention based on intelligent interactive gesture technology.a, Yuanyuan DaiaHeshuang Yea Physical Education Institute, University of the Chizhou, Chizhou, Anhui 247100, China.Background: With the rapid development of society, college students often face various pressures, such as study, employment, love and so on. These pressures will seriously affect the mental health of college students. Only strong mental toughness can help them overcome difficulties and promote the good development of mental health.The purpose of this study is to explore the characteristics of mental toughness of college students majoring in physical education and non-physical education, and to provide ideas for further enhancing the mental health level of students of different majors.Methods: The psychological toughness of 788 students of different majors in Chizhou University was investigated by using the Adolescent Mental Toughness Scale and questionnaire survey. Among them, 340 students (217 boys and 123 girls) majored in physical education and 448 students (177 boys and 271 girls) majored in non-physical education. The collected scales and questionnaires were classified, and the data were recorded into Excel for statistics and SPSS 25.0 for independent sample T-test.Results: (1) The total score of the respondents\u2019 mental toughness was 81.02\u2009\u00b1\u200915.16. Among the dimensions of mental toughness, family support was the highest, followed by interpersonal assistance, goal focus and emotional control, and goal focus was the lowest. (2) For physical education major and non-physical education major, there were significant differences in goal focus, emotional control, family support and interpersonal assistance (P<0.01), and there were significant differences in total score of mental toughness and positive cognition (P<0.05); (3) There were significant differences in total score of mental toughness, emotional control, family support and interpersonal assistance between male physical education major and non-physical education major (P<0.01), and there were significant differences in goal concentration (P<0.05). (4) There were significant differences in goal focus, emotion control, positive cognition and interpersonal assistance between females majoring in sports and females not majoring in sports (P<0.01). (5) Male and female physical education major: The total score of mental toughness and each dimension had no statistical significance (P>0.01).Conclusion: (1) Family support had a significant impact on the psychological resilience of the respondents; (2) The overall mental toughness of physical education major is significantly better than that of non-physical education major; (3) In terms of total score of mental toughness, emotional control, family support and interpersonal assistance, male physical education major are better than female physical education major. In terms of goal focus and positive cognition, male physical education major are weaker than female physical education major. Tips: (1) When improving the mental toughness of college students, it is necessary to unite with their families. Through the joint intervention of family and school, the mental toughness of college students can be effectively promoted; (2) Physical exercise can effectively promote the level of mental toughness. Schools should strengthen physical education and create a strong physical exercise atmosphere. (3) In the work of mental health education, we should pay attention to gender differences and pay attention to teaching students according to their aptitude.This work was supported by 3 project grant from Key Humanities Project of Chizhou University(Grant No.CZ2021RWZ18); Key Research Project of Philosophy and Social Sciences in Higher Education Institutions of Anhui Province(Grant No.2022AH051811); Key Teaching Research Project of Chizhou University (Grant No.2021XJYXM03).a,b,c,d, Hao Tiana,b,c,d, Qin Maa,b,c,d, Lunzhi Yanga,b,c,d, Xue Zhoua,b,c,d, Ting Xiaoa,b,c,d, Ling Taoa,b,c,d, Linjing Wua,b,c,dYing Chena School of Pharmacy, Key Laboratory of Optimal, Utilizaiton of Natural Medicine Resources, Guizhou Medical University, Guiyang 550025, Guizhou, China, b State Key Lab of Functions and Applications of Medicinal Plants, Guiyang 550025, Guizhou, China, c Key Laboratory of Natural Medicine Pharmacology and Drug Evaluation of General Colleges and Universities in Guizhou Province, Guiyang 550025, Guizhou, China, d Guizhou Provincial Efficient Utilization Engineering Center of Featured Natural Medicine Resource, Guiyang 550025, Guizhou, China.YC and HT contributed equally to this work.Background: Rheumatoid arthritis is a type of inflammatory arthritis characterized by joint inflammation, swelling, pain and potential damage. Western medicine primarily focuses on controlling inflammation and regulating immune function in the treatment of RA, with commonly used clinical drugs including non-steroidal anti-inflammatory drugs, glucocorticoids, antirheumatic drugs and biological agents. However, prolonged use of these medications may lead to liver and kidney dysfunction as well as gastrointestinal complications. Polygonatum exhibits characteristics of \u201cmulticomponent, multitarget, and multipathway\u201d which provide potential advantages in the treatment of rheumatoid arthritis (RA). Network pharmacology integrates network biology with various pharmacological approaches based on existing databases. By investigating multiple targets, a \u201ccomponent-target-disease\u201d network can be constructed, providing a novel approach to explore the mechanism and synergistic effects of Polygonatum in treating rheumatoid arthritis.Subjects and Methods: This study aims to investigate the mechanism of rheumatoid arthritis treatment using network pharmacology and molecular docking techniques. Through literature mining and database retrieval, the compound components of Polygonatum were obtained, the potential targets of the compounds were predicted using the TCMSP database, and the related targets of rheumatoid arthritis were obtained through GeneCards, OMIM and other databases, and the intersection targets of Polygonatum for the treatment of rheumatoid arthritis were obtained. Based on the STRING database, Cytoscape software was used to construct the interaction network of the common target protein of Polygonatum and Rheumatoid Arthritis, and the key targets were selected for molecular docking with the chemical components of Polygonatum to verify and analyze the interaction between them.Results: The final screening results revealed the identification of 12 active components, 65 potential targets, and 4797 potential targets for rheumatoid arthritis. Additionally, a total of 48 common targets were identified. GO and KEGG enrichment analysis led to the discovery of 343 signal pathways related to the main components found in Polygonum japonicum. The core components \u03b2-sitosterol and baicalein exhibited strong binding affinity with key targets VEGFA and RELA.Conclusions: Through the application of TCM network pharmacology, this study revealed that Polygonatum may play a multi-component, multi-target and multi-pathway therapeutic effect on rheumatoid arthritis by regulating cell apoptosis and cholesterol-like hormone receptors, participating in cancer pathways and other mechanisms, which may provide a reference for the screening of clinical efficacy evaluation indicators for the treatment of rheumatoid arthritis.The research was supported by Guizhou Provincial Basic Research Program  and Guizhou Provincial Key Technology R&D Program (No. [2020]4Y104).aChong Hea Department of Economics, Zhejiang University, Hangzhou 310030, China.Background: Study the incentives of the country for reporting emerging infectious disease outbreak, in order to reduce public panic and herd behavior during public health events.Subjects and Methods: This paper expands the existing single signal game on the motivation of national reporting epidemic to the infinite signal game. In the model, the main benefit of reporting infectious disease outbreak is to reduce casualties, while the main loss is the decrease in income caused by trade and travel disruptions. The model incorporates the loss of mental health of the population due to panic in an epidemic and the losses caused by disrupting social order due to herd behavior such as rushing to buy household goods. In addition, the model takes into account the accuracy of medical detection of infectious disease outbreak as a way to distinguish the behavior of the country under different parameters.Results: The country is more willing to truthfully report the diagnostic test of the disease outbreak in the infinite game than in a one-shot game in order to win the trust of the public and reduce social psychological panic. When trade and travel disruption intensifies, the country will tend to adopt an \u2018oscillating\u2019 strategy: conceals or adopts a mixed action when the volume of trade and travel is above the threshold, but truthfully reports the diagnostic test when the volume is below the threshold. The rapid growth of trade and travel may inhibit the willingness of the country to truthfully report the detection information and increases the risk of disease transmission.Conclusions: When making decisions, the government should not only consider economic losses, but also consider the psychological health issues among the public caused by the epidemic and lack of information, which helps the government truthfully report infectious disease outbreak. It is not better for the partner to impose trade and travel disruption as harshly as possible. The increase in assistance from international organizations such as WHO can help the country to report truthfully, but blindly improving the detection accuracy may only lead to the waste of funds. What\u2019s more, a financial mechanism led by the World Bank should be set up to compensate national and local governments for economic losses associated with outbreaks, especially in areas with the greatest lack of health resources.a, Dongyi Huangb, Wu LiucKaiwen Lia Wenshan University, Yunnan Wenshan 633099, China, b School of Sports Science, Guangzhou College of Applied Science and Technology, Guangzhou 511370, China, c Yunnan Vocational College of Mechanical and Electrical Technology, Yunnan Kunming 650203, China.Background: With the rapid development of China\u2019s economy, more and more college students are in the state of sub-health, among the types of exercise used in the clinical management of sub-health, some are related to the ancient Chinese traditions as Baduanjin. Despite the growing interest of the scientific community in Baduanjin, which has the theoretical basis of traditional Chinese medicine, its research is still in its infancy. It is noteworthy that, to the best of our knowledge, there are no studies that verified the influence of Baduanjin on sub-healthy college students. Therefore, the main objective of the present study was to investigate the effects of the Baduanjin, a traditional Chinese Qigong, on the physical and mental health of sub-healthy college students.Subjects and Methods: Explore the intervention effect of Baduanjin exercise on sub-health college students. The average age . Methods Comparative analysis method was used. Practicing baduanjin for 18 weeks, after the experiment, the improvement of physical, mental and fatigue sub-health was assessed by \u201cPersonal Health Status Questionnaire\u201d. HK6000, G100, JGW-B and FCS-10000 were used to evaluate the physical forward bend, grip strength, Reaction time, and vital capacity.Results: The 220 students were randomly allocated to the control or experimental group. Physical and mental health, fatigue status, and physical fitness were assessed in both groups before and after the experimental protocol. Compared with the control group, the physical subhealth and mental subhealth of the experimental group were significantly improved (P<0.05). The fatigue state of the experimental group was significantly relieved (P<0.05). Baduan jin intervention significantly improved sitting forward flexion ability and lung volume (P<0.05).Conclusion: It is proved that baduanjin has significant therapeutic effect on sub-health of college students. It provides a new way for researchers and coaches to conduct research and intervention from the perspective of traditional medicine.Thanks to Professor Gu Yongkun, Professor Liu Wu and coach Lu Tianxue for their support to the sub-health intervention students.aChin-niang Chana School of Art, Minnan Normal University, Zhangzhou, Fuijian, China.Background: Music therapy is different from conventional instrumental music, as it has the ability to evoke every possible emotion. A melodious voice can heal a person, and music therapy is a constantly evolving concept that can promote healing. Mainly, it is a therapeutic method that utilizes the natural emotional enhancement characteristics of music. In addition, it can also help people improve their mental health and overall happiness.Subjects and Methods: Music therapy includes developing music, writing songs, singing, dancing, listening to and discussing music. Especially, this form of treatment may be helpful for people with depression and anxiety. In addition, it may help improve the quality of life for people with physical health issues. The music of playing the yangqin can make us soar to unimaginable heights, comfort us in sadness or loneliness, help us release our anger or frustration in a way that does not harm anyone, make our bodies move, and bring peace and tranquility to our hearts.Results: Music therapy is an expressive art therapy that uses music to improve and maintain an individual\u2019s physical, psychological, and social well-being. In addition, it also involves a wide range of activities, such as listening to music, singing, and playing musical instruments. Music can also improve our health and happiness. Music heals, allowing wonderful music to improve our physical and mental well-being. After experiencing the baptism of hundreds of years of Chinese culture, the yangqin has achieved outstanding development in its performance form. In addition to solo performances, the yangqin is widely involved in various forms of performance such as traditional Chinese opera, Quyi accompaniment, ensemble, large, medium, and small ensemble, and has become an important component of Chinese ethnic instruments. A large number of literature references and field research are combined to obtain the original data, and the results can be obtained only after analysis and research.Conclusion: The increasing evidence of music therapy suggests that music therapy is not just a great way to boost energy, but can improve medical outcomes and quality of life in various ways. Surprised by the magic of music and its benefits in treating mental illnesses. Not only that, music therapy can also cure some symptoms of physical problems. Of course, there are some types of music to enhance emotions and relieve stress. The yangqin has been continuously absorbed, integrated, transformed, and developed in the process of historical transformation, and its development requires the improvement of the content of the work. In the creation and performance of traditional and modern works, it is necessary to strive for innovation through change and progress through development, making contributions to enriching and improving the art of yangqin.a,b, Bo Sua,bLingshan Lia School of Management, Hubei University of Chinese Traditional Medicine, Wuhan, Hubei 430070, China, b Research Center for the Development of Traditional Chinese Medicine, Key Research Institute of Humanities and Social Sciences of Hubei Province, Wuhan, Hubei 430070, China.Background: With the great contribution of the traditional Chinese medicine (TCM), China has made significant breakthroughs in combating the epidemic. Moreover, China has released many relevant policies to support the development of the traditional Chinese medicine industry. For the public, more and more people are paying attention to personal health management. The development of the traditional Chinese medicine industry will further promote the health of the entire population.Subjects and Methods: In order to further understand the degree of the development of Chinese medicine industry in China, this paper selects 62 listed companies in the traditional Chinese medicine (TCM) industry to research their growth in the future with their financial data in 2022. With reference to listed company performance evaluation index system, we constructed a index system of 12 indicators from 4 aspects using factor analysis for empirical analysis. These four indicators are profitability, debt paying ability, operational ability, and growth ability. These four abilities can comprehensively measure the overall situation of a company.Results: According to the empirical results, it can be found that among the 62 listed TCM companies, 32 companies got a growth score of more than 1, accounting for 51.61%, indicating that these companies had a good development prospect. However, only 3 listed TCM companies scored more than 1 in all indicators, which suggests that there is still a lot of development space for other companies to explore. The top ten companies all have well-known products and operate well.Conclusions: The TCM company needs to develop its own characteristics to enhance its growth potential. The TCM companies also need comprehensive development to be more competitive. The development of a company needs to meet the public\u2019s health needs in order to have greater development space. The development of the traditional Chinese medicine industry plays an important role in disease prevention and can better assist people in health management.a; Qiushuang DuanaXuecheng Wanga School of Economics and Management, North China University of Technology, Beijing, China.Background: Investor\u2019s mental health has a great impact on their investment behavior. Anxiety, autism and personality disorders may cause investors to loss their judgment, rely more on the herd effect, and make irrational investment behaviors. Frequent trading triggered by rumors and hot spots causes investors to ignore the value of stocks and lead to investment failure. The existing research shows that the digital transformation strategy has little impact on the profit of R&D-dependent industries as pharmaceutical and health industries. Will the hype about the concept of the digital economy lead to investors exhibiting irrational behaviour? Will listed companies in the pharmaceutical industry use the digital economy to push up their stock prices? This paper will examine the above issues.Subjects and Methods: This paper have tested whether there is an irrationality investment behavior caused by unhealthy psychology with individual fixed panel regression models of 299 A-share listed companies in China\u2019s pharmaceutical industry from 2010 to 2020.This paper uses abnormal trading volume to represent unassertive investment due to blindness, pressure and other negative psychology, uses the FGLS estimation method to estimate the parameters of the model, and use the two-step correction method for the coefficient correction of AR(1) and the PSCE method for the heteroskedasticity-robust covariance correction to produce more reliable regression results. We also performed robustness tests to avoid regression bias. All methods are based on theoretical deduction and empirical analysis of investment psychology.Results: The hypothesis that unhealthy investment psychology attracted by investment hot-spots encourages blind investment is well tested. There is a herd effect attracted by the digital transformation strategy of pharmaceutical companies. Investors trade frequently and drive up the stock price severely than normal. On average, an increase of 1 unit in the frequency of digital economy related vocabulary (per thousand words) in the annual reports will increase stock trading volume by 1000 million in a whole year. This result is significant at the 1% level. This result proves that overinvestment due to psychological problems exists. The robustness test also shows that the stock price will be raised by about 23.89%.The results can be used to explain the collective psychological problems in investment, such as excessive profit pressure, choice anxiety, and excessive comparison.Conclusions: Under the influence of herd mentality, investors will indeed make irrational investment behaviors. This unhealthy psychology is transmitted between groups, causing distortions in the value of the stock market. It can be seen that investors have high hopes for the digital transformation of pharmaceutical companies. But poor knowledge and overstress drive people to ignore risks. Before the digital economy strategy takes effect, investors should overcome anxiety and maintain a healthy mind. Pharmaceutical companies should increase corporate profits and promote the lasting development of the industry. The mechanism of individual psychological problems on market failure is the subject of further research.This research was supported by Beijing Social Science Foundation (Grant No.22JCC077) and Beijing Urban Governance Research Base of North China University of Technology.a, Dongmei Lia, Changqing FengaHongyan Shena Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang 110032, China.Background: In recent years, with the increasing incidence of tic disorder in children, the author observed children suffering from tic disorder accounted for nearly one fifth of the chronic disease patients in the pediatric outpatient department of our hospital. Ranking the second after spleen and stomach disease, tic disorder has witnessed a decreasing trend in its onset age. Due to the complex etiology of tic disorder, there is no specific treatment method at present.Subjects and Methods: To explore the etiology and pathogenesis and provide favorable methods about prevention and treatment of tic disorder in children according to the theory of \u201coccurrence due to adding causative factors\u201d.In the process of the clinical research on tic disorder, we consulted, collected and sorted out a lot of literatures, including classical TCM ancient books and medical journals, etc., combined with clinical data, and systematically analyzed the diagnosis and treatment of tic disorder. We collected and referred to huge amounts of information in TCM books and periodicals, in order to further clarify the pathogenesis of tic disorder, and to identity the focus of treatment and prevention for tic disorder. In this paper, the pathogenesis of tic disorders in traditional Chinese medicine is clarified from all aspects. This study is based on the theory of \u201coccurrence due to adding causative factors\u201d, which clarify the pathogenesis of tic disorder from the inside to the outside, from the point to the surface, from multiple perspectives, including the children\u2019s constitution, body endowment and traditional Chinese medicine Yin and Yang, the five elements, and the visceral state.Results: The etiology and pathogenesis of tic disorder in children are similar to the theory of \u201coccurrence due to adding causative factors\u201d in Canon, which is the most classical TCM ancient book. The pathogenesis of tic disorder in children can be explored from the theory of \u201coccurrence due to adding causative factors \u201c, so as to guide the treatment for children with tic disorders.Conclusions: The treatment based on the theory of \u201coccurrence due to adding causative factors\u201d for children with tic disorder can better guide clinical treatment and differentiation of syndromes, so as to achieve \u201ccuring the disease to seek the root\u201d, guide the clinical children to \u201cprevent diseases before occurrence\u201d, and thus has certain clinical practical value.This paper was supported by the basic research project of the education department of Liaoning province (2100221274).a, Huiling Lua, Xiaopan Dia, Yan Lia, Bo Chena, Danyang Lia, Long Zhanga, Yuping Zhanga, Hui YaoaWei Duana Department of Medical, People\u2019s Hospital of Ningxia Hui Autonomous Region, Yinchuan, Ningxia 750001, China.Background: To investigate the efficacy of 4S lying position lung rehabilitation exercise, in hospital-family integrated lung rehabilitation nursing of acute exacerbation of chronic obstructive pulmonary disease(AECOPD) patients,and to summarize the application experience.Subjects and Methods: A total of 99 AECOPD patients who were hospitalized from March 2019 to June 2020 in People\u2019s Hospital of Ningxia Hui Autonomous Region were enrolled in the study. According to the inclusion criteria, Patients were randomly divided into observation group (49 cases) and control group (50 cases). The observation group had 34 males and 15 females, ranging in age from 63 to 84 years, with an average of (72.19\u2009\u00b1\u20097.89) years; the control group had 33 males and 17 females, ranging in age from 66 to 83 years, with an average of (73.70\u2009\u00b1\u20095.32) years. There was no statistically significant difference in gender and constitutional indext (P>0.05).Both groups received the same drug treatment. The observation group received 4S lying position lung rehabilitation exercise, while the control group received routine lung rehabilitation program. mMRC scores, 6MWT, CAT scores and compliance of family lung rehabilitation were compared between the two groups before and after intervention for 12weeks.Results: Comparison of the compliance of family lung rehabilitation between the observation group and the control group after 12 weeks of intervention was improved, but the improvement degree in the observation group was significantly higher than that in the control group(P < 0.05), with statistical significance. 12 weeks after intervention, the scores of mMRC, 6MWT and CAT in both groups were improved. The improvement of the observation group was significantly higher than that of the control group (P<0.05), with statistical significance.Conclusions: 4S lying position rehabilitation exercise is safe, effective and simple.It can relieved patient\u2019s dyspnea symptoms,promote exercise ability and quality of life, which has positive significance for patients\u2019 self-care ability, maximum social function and is thus worthy to promote hospital-family integrated lung rehabilitation nursing mode for AECOPD patients.This work was supported by a project grant from Ningxia Hui Autonomous Region Health System Scientific Research Project (Grant No.2022-NWKY-006).a, Junfang Zhub, Huifang Chenc,d, Haichao Huangb, Bo Lib, Yan Lid, Jianhua Yie, Bing Liuf, Hua Caod, Li YaogYang Niea School of Pharmaceutical Engineering, Guangdong Food & Drug Vocational College, Guangzhou 510520, China, b Experimental Training Center, Guangdong Food & Drug Vocational College, Guangzhou 510520, China, c College of Chemistry & Pharmacy, Guangxi Normal University, Guilin, 541004, China, d Guangdong Lingnan Institute of Technology, Guangzhou 510663, China, e Department of Orthopedics, East Hospital of the First Affiliated Hospital of Sun Yat sen University, Guangzhou,510700, China, f School of Health, Guangzhou Huaxia Vocational College, Guangzhou 510935, China, g School of Food Science and Biology, Guangdong Polytechnic of Science and Trade, Guangzhou, 510430, China.Y Nie and HF Chen contribute equally to this work.Background: This project aims preferred clebopride bioadhesive sustained-release tablets of the prescription and preparation processes, and to study the effects of Clebopride (CBP) bioadhensive sustained-release tablets on experimental gastric ulcer and gastrointestinal motility disorder.Subjects and Methods: Release tablets release as an indicator, the use of orthogonal design to optimize select clebopride prescription bioadhesive sustained release tablets. Gastric ulcer rat model was induced by ethanol and aspirin, and then divided into model group , common tablet (CBP tablet 0.072\u2005mg/kg) and sustained-release tablet high-dose and low-dose groups ; normal rats were included in normal control group ; they were given relevant medicine intragastrically, twice a day for sustained-release tablet, three times a day for other. Ulcer area were observed 2 and 4 days after medication to calculate healing rate of ulcer (n=6). Gastrointestinal motility disorder mice model was induced by atropine, and then divided into model group , common tablet group (CBP tablet 0.1\u2005mg/kg) and sustained-release tablet high-dose, medium-dose and low-dose groups ; normal mice were included in normal control group ; they were given relevant medicine intragastrically, once a day, for consecutive 3 days. The rate of gastric emptying and small intestinal propulsion were detected (n=6).Results: The optimized formulation consisting of hydroxypropyl methyl cellulose (HPMC 5.5g/100 tablets) and carbomer (CP 2.2g/100 tablets) bioadhesive and skeletal material, lactose as diluent (1.2g/100 film), starch as a filler and a disintegrant (2.0g/100 tablets), optimized in line with a sustained-release tablets prescription kinetic process, release meet the design requirements. Simultaneously with clebopride ordinary tablets measured and compared to the rat gastrointestinal tract adhesion. Compared with normal control group, ulcer area of rats increased in model group; compared with model group, that of rats decreased in common tablet group and sustained-release tablet high-dose, low-dose groups, with statistical significance (P< 0.01); healing rates of gastric ulcer were 32.35%-48.24% 2 days after medication, and those were above 70% 4 days after medication. Compared with normal control group, the rate of gastric emptying and small intestinal propulsion in mice decreased in model group; compared with model group, those of mice increased in common tablet group and sustained-release tablet high-dose, medium-dose, low-dose groups. The effects of sustained-release tablet high-dose and medium-dose groups were better than that of common tablet group; those difference had statistical significance (P< 0.01 or P< 0.05).Conclusions: This study obtained clebopride bioadhesive sustained-release tablets have good slow-release effect, reasonable preparation process is simple, and significant adhesion performance to meet clinical needs, CBP bioadhensive sustained-release tablets have improvement effects against gastric ulcer of rats and gastrointestinal motility disorder of mice, CBP bioadhensive sustained-release tablet has good development prospects.This work was supported by the key project grant of Natural Science Foundation of Guangxi Province in 2022: mitochondrial autophagy inhibits aBelta deposition and tau phosphorylation to improve cognitive function of AD model animals (Grant No.2022GXNSFAA035447).This thesis is also supported by the following project funds: 1) 2019 Guangdong Medical and Health Education Steering Committee Project: Deep Research on the Teaching Reform of Biopharmaceutical Technology Course under the Background of \u201cSchool enterprise Cooperation\u201d (Project No. 2019LX025); 2)the project of Guangdong Provincial Health and Health Commission on the development, pharmacokinetics and pharmacodynamics of coagulation factor XIII microsphere long-acting injection (No. A2021203) In 2021; 3)Evaluation on the Introduction, Tissue Culture, Rapid Propagation and Planting Effect of Genuine Rhizoma Bletillariae of Guangdong Provincial Bureau of Traditional Chinese Medicine (No. 20191242) in 2020."}
+{"text": "ASD are heterogeneous pathological conditions characterized by difficulties in establishing social contacts and the manifestation of repetitive behavior. An atypical trajectory of brain maturation, impaired neurogenesis, synaptogenesis, and an imbalance in the excitatory and inhibitory systems of the CNS form the morphofunctional basis of the ASD.To understand the functioning of this complexly organized system in time and space, a three-dimensional model is needed. The closest in vitro model of the human brain from early embryonic stages to aging is brain organoids. Human brain organoids are self-organizing three-dimensional cell aggregates derived from pluripotent stem cells (hiPSCs)Organelles generalize neurogenesis, gliogenesis, synaptogenesis, cell migration and cell differentiation, gyrification of the cerebral cortex, and reflect the connections of brain regions.The use of telencephalon organelles in the RAS model revealed a deficit in neuronal migration, acceleration and disruption of cell cycle synchronization, aberrant cell proliferation, abundant synaptogenesis, temporary deviations in the development of the cortex, increased branching of neurons, unbalanced inhibitory differentiation of neurons, high activity of ion channels is a consequence of a violation of FOXG1 activity. Organelles generalize neurogenesis, gliogenesis, synaptogenesis, cell migration and cell differentiation, gyrification of the cerebral cortex, and reflect the connections of brain regions.The use of telencephalon organelles in the RAS model revealed a deficit in neuronal migration, acceleration and disruption of cell cycle synchronization, aberrant cell proliferation, abundant synaptogenesis, temporary deviations in the development of the cortex, increased branching of neurons, unbalanced inhibitory differentiation of neurons, high activity of ion channels is a consequence of a violation of FOXG1 activity .hiPSCs can provide insight into the cellular mechanisms underlying ASD as a neuropsychiatric disorder, providing access to the development of platforms for in vitro drug screening and individualized patient therapy.None Declared"}
+{"text": "In this Special Issue, six articles using the Japan National Health and Nutrition Survey (NHNS) were published. Among the six articles, two examined the time trends ,2, two uIn Japan, the prevalence of hypertension has decreased with the improvement of medical treatment and decreased dietary salt intake. In panel data analysis, the trends in hypertension prevalence, treatment, and control were investigated by life expectancy at the prefectural level . It was Using the Joinpoint Regression Program, trends in food group intake were evaluated by physical size in young Japanese women in NHNS 2001\u20132019 data [In the super-aged society of Japan, it is expected that reducing dietary salt intake prevents cardiovascular disease and hence curbs growing healthcare expenditures. The effect of achieving global and national targets of salt reduction on cardiovascular events and national healthcare expenditures was estimated . CompareJapan experienced a decrease in cardiovascular mortality concurrently with a reduction in salt intake of the population since the 1950s. The impact of salt intake reduction on the long-term trends in cardiovascular mortality was estimated . CompareThe association between sources of free sugars and weight status among children and adolescents was examined in a cross-sectional study using the 2016 NHNS . It was In the NHNS, efforts are made to raise participation rates to ensure representativeness. Local government personnel in charge of NHNS were invited to discuss the measures to improve participation rates. The following measures were identified: standardization of survey methods, skills of survey staff, survey organization, venue setting, accessing target households, time of the survey, responses during the survey, confirming meal contents reported in the dietary intake survey, rewards/incentives, possible rewards, feedback on survey results, and practices during the COVID-19 pandemic . These rThese findings will help readers understand the current situation of health and nutrition of the Japanese population."}
+{"text": "The World Health Organization\u2019s strategy toward healthy aging fosters person-centered integrated care sustained by eHealth systems. However, there is a need for standardized frameworks or platforms accommodating and interconnecting multiple of these systems while ensuring secure, relevant, fair, trust-based data sharing and use. The H2020 project GATEKEEPER aims to implement and test an open-source, European, standard-based, interoperable, and secure framework serving broad populations of aging citizens with heterogeneous health needs.We aim to describe the rationale for the selection of an optimal group of settings for the multinational large-scale piloting of the GATEKEEPER platform.The selection of implementation sites and reference use cases (RUCs) was based on the adoption of a double stratification pyramid reflecting the overall health of target populations and the intensity of proposed interventions; the identification of a principles guiding implementation site selection; and the elaboration of guidelines for RUC selection, ensuring clinical relevance and scientific excellence while covering the whole spectrum of citizen complexities and intervention intensities.Seven European countries were selected, covering Europe\u2019s geographical and socioeconomic heterogeneity: Cyprus, Germany, Greece, Italy, Poland, Spain, and the United Kingdom. These were complemented by the following 3 Asian pilots: Hong Kong, Singapore, and Taiwan. Implementation sites consisted of local ecosystems, including health care organizations and partners from industry, civil society, academia, and government, prioritizing the highly rated European Innovation Partnership on Active and Healthy Aging reference sites. RUCs covered the whole spectrum of chronic diseases, citizen complexities, and intervention intensities while privileging clinical relevance and scientific rigor. These included lifestyle-related early detection and interventions, using artificial intelligence\u2013based digital coaches to promote healthy lifestyle and delay the onset or worsening of chronic diseases in healthy citizens; chronic obstructive pulmonary disease and heart failure decompensations management, proposing integrated care management based on advanced wearable monitoring and machine learning (ML) to predict decompensations; management of glycemic status in diabetes mellitus, based on beat to beat monitoring and short-term ML-based prediction of glycemic dynamics; treatment decision support systems for Parkinson disease, continuously monitoring motor and nonmotor complications to trigger enhanced treatment strategies; primary and secondary stroke prevention, using a coaching app and educational simulations with virtual and augmented reality; management of multimorbid older patients or patients with cancer, exploring novel chronic care models based on digital coaching, and advanced monitoring and ML; high blood pressure management, with ML-based predictions based on different intensities of monitoring through self-managed apps; and COVID-19 management, with integrated management tools limiting physical contact among actors.This paper provides a methodology for selecting adequate settings for the large-scale piloting of eHealth frameworks and exemplifies with the decisions taken in GATEKEEPER the current views of the WHO and European Commission while moving forward toward a European Data Space. Worldwide socioeconomic improvements have prolonged and will further prolong life expectancy, progressively shifting the structure of population pyramids toward aging populations . TherefoeHealth  must be The European Horizon 2020 project GATEKEEPER  is a European multicentric large-scale pilot on smart living environments . In lineThe GATEKEEPER project differs from most eHealth-related projects because of its broader scope. GATEKEEPER aims toward implementing a platform serving broad populations of aging citizens with heterogeneous needs, rather than disease-specific eHealth systems or settings targeting well-defined subgroups of citizens with homogeneous characteristics. Therefore, the definition of the most appropriate group of settings where the platform should be tested represents a challenge on its own. This paper describes the rationale for the selection of the group of settings used to test the GATEKEEPER platform, and presents the different implementation sites and reference use cases (RUCs), to provide an overview of the clinical and scientific meaningfulness of this platform.Testing a platform capable of accommodating any number and type of eHealth solutions for broad study populations of older citizens with diverse needs requires being systematic. To do so, we adopted a double stratification pyramid reflecting at the same time the overall health of the target study population for a given intervention as well as the intensity of the proposed intervention . The firOnce the GATEKEEPER double stratification pyramid was established, the next step involved the selection of deployment sites and the identification of relevant RUCs to be implemented. Two considerations were taken into account for the selection of implementation sites. First, it was important to test the system in as many different countries as possible, especially given the differences in regulations, health care systems\u2019 characteristics, and study population needs. In this regard, we plotted candidate countries by latitude and nominal Gross Domestic Product per capita (US dollar) from the International Monetary Fund\u2019s 2021 World Economic Outlook Database , to ensuSeven European countries were selected by trying to cover the geographical (north-south and east-west) and socioeconomic (spectrum of gross domestic product) heterogeneity of Europe: Cyprus, Germany, Greece, Italy, Poland, Spain, and the United Kingdom . Within Foremost, RUCs should act as demonstrators of the clinical and scientific value of the GATEKEEPER platform. All of the Project\u2019s RUCs were built upon existing expertise and resources matured in previous projects, such as ACTIVAGE . The cenThe main purpose of RUC1 is the promotion of healthy lifestyles among healthy older people to prevent or delay the onset and worsening of controlled common chronic diseases, such as obesity or hypertension. RUC1 will be based on timely interventions provided by artificial intelligence\u2013based digital coaches through natural language processing techniques, patient-generated longitudinal multidimensional data analyses, structured conversations, consultation, and education. Big data analytics techniques will be exploited to address risk stratification and early detection, based on lifestyle analysis, including pattern recognition for the improvement of public health surveillance ,18 and fChronic obstructive pulmonary disease has a huge burden worldwide, accounting for 3.3 million deaths and 74.4 million disability-adjusted life-years (DALYs) in 2019 . RUC2 prDiabetes mellitus (DM) is the leading cause of blindness, end-stage renal failure, nontraumatic limb amputations, and cardiovascular morbidity and mortality and has an immense burden worldwide . RUC3 aiParkinson disease (PD) is a long-term degenerative disorder of the central nervous system that mainly affects the motor system . It is aHeart failure (HF) is a common disease, being the second leading cause of global DALYs loss in 2019 . RUC5 prStroke is a common disease, being the third leading cause of global DALYs loss in 2019 . RUC6 wiRUC7 targets chronic older patients with variable complexity according to GATEKEEPER\u2019s risk stratification pyramid. The EIP on AHA blueprint \u201cpersonas\u201d can provide good examples of potential participant profiles . RUC7 prHypertension or high blood pressure (HBP), is a serious medical condition with an estimated worldwide prevalence of 31% of adults (1.4 billion) that significantly increases the risk of heart, brain, kidney, and other diseases . RUC8 prAs of January 2023, more than 650 million COVID-19 cases and 6.7 million deaths have been confirmed globally . The onsThe establishment of the implementation sites and RUCs is the basis for the definition and execution of large-scale implementation studies. It is key to conceive the different studies individually, with their own target study population, interventions, and evaluation, but also collectively, as a federation of studies aiming to not only test the effectiveness of a given eHealth intervention but also assess the overall performance of a platform hosting the different interventions in a federated way. The promotion of common validated tools measuring activation, adherence, compliance, and outcomes is highly recommended, but it is even more important to consider a common evaluation framework. In this regard, the European Commission promotes the use of indicators for socioeconomic impact assessment by means of the Monitoring and Assessment Framework for the European Innovation Partnership on Active and Healthy Aging , which iThis paper describes how the GATEKEEPER consortium tackled the challenge of implementing and testing a platform  serving broad study populations of aging citizens with heterogeneous needs, rather than disease-specific eHealth systems or solutions focusing on well-defined subgroups of citizens with homogeneous characteristics. Accordingly, we presented the rationale for the identification and definition of the most appropriate group of settings for the platform to be tested, including (1) the adoption of a double stratification pyramid reflecting at the same time the overall health of the target study population for a given intervention as well as the intensity of the proposed interventions, (2) the identification of a set of principles guiding the selection of implementation countries and sites, and (3) the elaboration of some guidelines for the selection of RUCs so they can be scientifically sound and clinically relevant while covering the whole spectrum of citizen complexities and intervention intensities. Finally, this has been completed with a description of the chosen implementation sites and RUCs, specific aims, and clinical relevance and scientific interest in the GATEKEEPER project.In recent years, the European Commission has shifted its scope in relation to eHealth implementation. After years of encouraging eHealth projects tackling a given disease in closed-controlled settings, the focus is moving toward fostering integrated programs and, later on, whole structures capable of sustaining multiple such programs while promoting big data approaches with a secured data flow. Projects, such as CONNECARE ,38 and AThe creation of a European Data Space (EDS)  is one oIn conclusion, the approach presented in this paper is leading the current trends and the view of the European Commission, and it provides a methodology for setting up the required large-scale pilots, each with its specific features, that will eventually sustain the creation and development of the EDS. Moreover, this blueprint could be expanded to contexts and constraints outside Europe, as demonstrated by the inclusion of Asian implementation sites in GATEKEEPER."}
+{"text": "Dear Editor,A 14-year-old female patient with a history of Down syndrome referred the appearance of lesions disseminated throughout the body that started at the age of seven. On dermatological examination, she had phototype IV skin, with erythematous plaques arranged in an annular fashion, superimposed by pustules at the periphery, located mainly on the trunk, skinfold regions, limbs and scalp, sparing the face and mucous membranes, associated with pruritus . For dia2, the patient showed complete resolution of the skin condition, maintaining lesion remission after phototherapy discontinuation, while maintaining dapsone use. There were only residual hyperchromic macules throughout the body (She then underwent phototherapy with narrow band-UVB (NB-UVB), associated with dapsone 100\u202fmg/day, which was already being used. After 36 sessions of NB-UVB twice a week, at a total cumulative dose of 10.7\u202fmJ/cmthe body .Fig. 3 and the most resistant to conventional therapies when compared to the intraepidermal neutrophilic type. In a histopathological analysis of 116 patients diagnosed with IgA pemphigus, in addition to intercellular IgA deposition, all patients had an inflammatory infiltrate in the dermis, consisting predominantly of neutrophils.The patient in the present case underwent treatment with dapsone for five years, at an optimized dose, without improvement. Therapy with NB-UVB was based on reports in the literature of its use as a therapeutic option for other chronic and immune-mediated dermatoses, being effective and safe for the treatment of children. The use of phototherapy reduces systemic therapies such as corticosteroids, and the pediatric age group presents mild, localized, and tolerable side effects.Phototherapy with NB-UVB decreases T-cell activation, the production of pro-inflammatory cytokines, and the number of antigen-presenting cells in the skin. In addition, this therapy increases the number of Treg cells that secrete suppressor cytokines, which contributes to a reduction in the inflammatory response in the dermis, a probable mechanism of action in the treatment of IgA pemphigus.There is no consensus in the literature regarding the treatment of IgA pemphigus. This study shows the use of phototherapy as a therapeutic option in the reduction of systemic therapies in extensive cutaneous dermatoses in the pediatric age group. Further studies are required to determine the mechanism of action and duration of treatment with NR-UVB to allow long-term disease control.None declared.Lilian Lemos Costa: Approval of the final version of the manuscript; drafting and editing of the manuscript; design and planning of the study; collection, analysis and interpretation of data; critical review of the literature; critical review of the manuscript.Roberta Buense Bedrikow: Approval of the final version of the manuscript; design and planning of the study; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.Carolina Gon\u00e7alves Contin Proen\u00e7a: Approval of the final version of the manuscript; design and planning of the study; intellectual participation in the propaedeutic and/or therapeutic conduct of studied cases; critical review of the manuscript.Rute Facchini Lellis: Approval of the final version of the manuscript; design and planning of the study; effective participation in research orientation; critical review of the manuscript.None declared."}
+{"text": "RSC Advances article due to significant portions of text overlap with a number of sources throughout the article, in particular ref. 13 and 14 of the original article and ref. The Royal Society of Chemistry hereby wholly retracts this The authors were informed about the retraction of this article but did not respond.RSC AdvancesSigned: Laura Fisher, Executive Editor, Date: 22nd August 2023"}
+{"text": "Musical performance activities are the culmination of arduous work and dedication. Musical interpretation is, at its core, an act of openness and vulnerability, which makes stage anxiety a relevant issue in the musical community. Music Performance Anxiety (MPA) is a complex and multifaceted phenomenon, manifesting in different ways and affecting musicians to varying degrees, across all educational levels and musical genres  and energetic arousal . The authors concluded that their findings point to the usefulness of stage training to become accustomed to realistic public self-exposure.Chang-Arana et al. investigated the effects of pianists' trait MPA, situational stress , and familiarity with the piece on listeners' perception and understanding of musical expressiveness. Their preliminary analyses with a group of 30 listeners  showed that perceived expressiveness was significantly affected by pianists' trait MPA and familiarity with the piece, whereas interpersonal accuracy of musical expressiveness was significantly affected by situational stress. These findings were independent of listeners' musical background.Herman and Clark reviewed the literature to identify possible reasons for the limited efficacy of current approaches to managing MPA. They synthesize and discuss a broad array of key concepts. They note that MPA is predominantly seen as a negative construct with undesirable symptoms and, accordingly, most interventions aim at managing MPA by ameliorating symptoms. They conclude that depathologizing MPA could open new perspectives and have significant practical and theoretical implications.Starting from the observation that the prevalence of MPA has remained largely unchanged over the last 40 years, Irie et al. analyzed the content of reports by 38 student musicians and semi-structured interviews with eight musicians to find that the experience of mental MPA symptoms started as soon as musicians begin to prepare for public performance, the experience of physiological MPA symptoms peaked shortly before public performance, and the experience of behavioral MPA symptoms peaked during public performance. To deal with these different symptoms, musicians reported to use specific strategies such as positive self-talk, concentration, and deep breathing.Kenny, the creator of this instrument, examines the research that has used the K-MPAI and touches on a number of important related topics and constructs such as cross-cultural validation, theoretical and clinical conceptualizations of MPA, depression, low self-esteem, somatization, performance quality, and the idiosyncratic nature of MPA in each musician.The Kenny Music Performance Anxiety Inventory (K-MPAI) is one of the most widely used questionnaires to assess MPA. In her review article, Kirsner et al. take a lifespan perspective on MPA by investigating the potential impact of caregiver experiences and patterns of dysfunctional cognitive schemas during childhood and adolescence on the manifestation and severity of MPA in adulthood. Combining data from a survey with 100 musicians and from interviews with eight musicians, these authors show that high-anxious and low-anxious musicians differed in numerous childhood experiences with their parents and in the development of cognitive schemas related to the themes of failure, catastrophizing, and incompetence/dependence.Lubert et al. investigated the effects of a 10-week psychological chocking intervention comprising acclimatization training, goal setting, imagery, self-talk, and relaxation techniques in six musicians, two dancers and one actress. Their mixed-methods analysis revealed reduction in performance anxiety and fear of negative evaluation, and improved self-efficacy and performance quality.Choking under pressure refers to performing worse than expected despite high skills and motivation to perform well. In their study, Mazzarolo et al. explored the strategies that music educators use to help manage their students' MPA and teacher and student perceptions of teachers' role in MPA management. The nine articles included in the review indicate that the most common strategies are simulated performance, positive outlook, preparation, and breathing. Most of these strategies are not specifically employed by the educators to influence MPA; rather, they are part of their regular teaching practice. Most students would like to receive support both from their teachers and experts.In their PRISMA-based systematic review article, Moral-Bofill et al. investigated the effects of a 12-week electronic intervention program called Self-Regulation Skills for Performing Musicians on flow experience , MPA and social skills. Compared to a control group, the experimental group reported a significant improvement in flow experience (mainly in sense of control and loss of self-consciousness) and MPA from pre- to post-intervention.Passarotto et al. investigated the relationship between MPA, practice behaviors (practice time and number of repetitions), and performance quality by monitoring 30 healthy pianists practicing a short musical excerpt. State anxiety correlated positively with practice time and number of repetitions, which the authors interpreted as supporting the hypothesis that more anxious musicians are at higher risk of developing playing-related injuries as a result of overuse and repetitive strain. Pianists who improved their playing were also less anxious in the latter part of the experiment.Rosset et al. conducted a comprehensive health-related survey among 205 university first-year music students at the beginning of their first semester and 62 students at the end of their second semester. On average, mental health was good at the start of the first year but decreased at the end of the second semester. The article highlights differences between performance majors and music education majors in health-related knowledge and coping abilities and between instrument types in practice time and bodily pain. Moreover, students attending courses on musicians' health improved their knowledge about health risks.Sokoli et al. found that students' age, gender, and instrument were significant predictors of their pre-performance affective, cognitive, and somatic experience. The study further found that worsening in performance quality from practice to public performance was reported by almost half of the students and best predicted by pre-performance anxious feelings and breathing-related complaints. The authors suggested that the assessment of MPA could be refined by better taking into account instrument specific performance-related bodily complaints.In a sample of 186 university-level classical music students, Spahn et al. assessed dispositional MPA and state MPA during a concert among 67 young amateur musicians of a brass choir. In line with previous classifications, the authors identified three types of MPA with about 75% of the musicians being assigned to the positive type characterized by low levels of MPA symptoms and high levels of self-efficacy and positive functional coping. The article also provided an analysis of the degree of correlation between dispositional MPA and state MPA.Yao and Li investigated to what extent the Individual Zone of Optimal Functioning model can help predict performance quality using the three anxiety dimensions somatic anxiety, cognitive anxiety, and self-confidence among 30 college-level piano-major students. The study highlighted the strengths and limitations of this model, the idiosyncratic nature of the relationship between self-perceived anxiety and expert-rated performance quality, as well as important directions for future research in this area.In conclusion, the articles of this Research Topic greatly contribute to the advancement of our understanding of MPA and its role and implications for musicians' wellbeing, health, and career. They also show avenues and opportunities for further developments, demonstrating that MPA remains a highly relevant topic for research and practice in performance science.PG: Writing \u2013 original draft. OC: Writing \u2013 review & editing. KH: Writing \u2013 review & editing. MY: Writing \u2013 review & editing."}
+{"text": "Durability and sustainability are important objectives within the development of cement and concrete composites , and havThis Special Issue, \u201cDurability and Sustainability of Cement and Concrete Composites\u201d aims to collate a set of papers presenting recent advances in the field of durability and sustainability of cement and concrete composites, including design, processing, performance, curing and maintenance, and on-site applications of cement and concrete composites. In total, we received 19 submissions, and 12 of them were published. Researchers from China, the United Kingdom, Japan, and France chose to share their recent research findings via this particular issue.Solid wastes , as alternative cementitious binders, help to reduce carbon footprint and improve the sustainability of cement and concrete composites. Ground-granulated blast-furnace slag (GGBS) is a kind of high-activity waste slag formed via the quenching and granulation of silicate and alumino-silicate as the main components in blast-furnace smelting pig iron. Feng et al.  prepared2 and forming more compact hydration products. Furthermore, Yan et al. [In order to improve the negative effects of alternative cementitious binder on the early mechanical properties of cement-based materials, Wang et al.  used poln et al.  used natIn addition, low reactive or inert solid waste can also be used as an alternative aggregate. Recycled tyre shreds and crumbs were used by Maddalena  to repla2 curing, and investigated its influence on the corrosion resistance of cement concrete. It was found that the freeze/thaw resistance and corrosion resistance of inner steel bars were improved by the application of CO2-cured sludge ceramsite. It was also found by Xu et al. [The major characteristic and advantage of sustainable development is the more efficient use of energy and the greater recycling of materials, achieved by conserving and reducing waste. Therefore, improving the durability of concrete can contribute to the sustainable development of concrete. It was reported in  that theu et al.  that theu et al.  investigFurthermore, during its service life, the shrinkage and high-temperature resistance of concrete are also important factors affecting its durability. Yang et al.  comparedThe findings presented in this editorial contribute to recent progress in the durability and sustainability of cement and concrete composites. Durability and sustainability will always be the focus of cement concrete research. Therefore, low carbon emissions and long service life should be the key objectives of the future development of the concrete industry."}
+{"text": "Human trafficking is the third most lucrative form of trafficking in the world (following drugs and counterfeit goods). Multiple outbreaks of unrest between October 2016 and August 2017 in the Rakhine State of Myanmar triggered ~745,000 influxes of Rohingyas crossing into Bangladesh through the border boundaries at Teknaf and Ukhiya sub-districts of Cox's Bazar. In this regard, the media confirmed that over a thousand Rohingya people, particularly women and girls, were victims of human trafficking. This research aims to explore the underlying causes of human trafficking (HT) during emergency responses and seeks to understand how the knowledge and capacity of the refugee, local administration, and law enforcement agencies in Bangladesh can be improved in promoting counter-trafficking (CT) and safe migration processes. In order to achieve the objectives, this study reviews acts, rules, policies, and action plans of the Government of Bangladesh on the HT, CT, and safe migration processes. Then, a case study has been applied to present the ongoing CT and safe migration programs of an NGO called Young Power in Social Action (YPSA), which received funding and technical support from the International Organization of Migration (IOM) for this purpose. This study also evaluates the effectiveness of the program through conducting key informant interviews (KIIs) and focus group discussions (FGDs) with the beneficiary and non-beneficiary participants including refugees, law-enforcing agencies (LEAs), and NGOs in Teknaf and Ukhyia. Thus, this study identifies program-level strengths and weaknesses in relation to the CT and safe migration process and provides key directions on how they can be improved. It concludes that non-state actors have a significant role in preventing HT and promoting CT and safe migration for Rohingyas in Bangladesh. The Rohingya people have been experiencing massive state-driven discrimination, torture, and a sense of statelessness due to the deprivation of their basic needs and human rights in Rakhine State, Myanmar, since 1978 . Due to The forcibly displaced Rohingya Muslim population who crossed the borders of Myanmar to Bangladesh traveled a laborious path by foot or boat for safety and were forced to leave everything behind. In fact, many of their houses were burnt down to ashes in the Rakhine state. Due to geographical location and the scarcity of economic activities where they took refuge, there has been evidence of HT for years . A numbeTo place the literature review, research methods, results, and conclusions into context, we have considered definitions used by the United Nations. According to Article 3, paragraph (a) of the protocol to prevent, suppress, and punish trafficking in persons recognized by the United Nations, \u201chuman trafficking\u201d is defined asthe recruitment, transportation, transfer, harboring, or receipt of persons, by means of threat or the use of force or other forms of coercion; of abduction, of fraud, of deception, of the abuse of power or of a position of vulnerability, or of the giving or receiving of payments or benefits to achieve the consent of a person having control over another person, for the purpose of exploitation\u201d [ interventions including creating community awareness and mobilization; capacity-building within the community, its leaders, and law enforcement agencies (LEAs); and facilitating linkage and networking between VoTs and service providing entities were required , 9. OverSince the recent Rohingya influx in August 2017, donor agencies have been operating in the camps to provide protection, education, health, nutrition, food security, water, shelter, sanitation, and hygiene as well as to coordinate logistics for the sites. National and international NGOs have been working on HT in the Rohingya camp areas. Among them, YPSA, which is a leading, voluntary not-for-profit, and non-political organization, has been working on HT in Cox's Bazar since 1990. Donors contributed USD 2.59 billion between 25 August 2017 and 25 August 2021 to the Rohingya people . Notwithkey leader engagements' (KLEs) liaising with NGOs and LEA to combat human trafficking.If the planned activities are implemented, HT can be reduced to a great extent. YPSA in support of the IOM and other agencies is working to prevent HT and promote CT and safe migration processes for the Rohingya and host communities. Of these initiatives, a project entitled \u201cinitiatives to prevent human trafficking in emergency response\u201d has been launched, aiming to increase the knowledge of refugees and host communities on CT, and safe migration capacity-building with the community leaders through \u2018This research aims to evaluate the effectiveness of the program through conducting interviews and focus group discussions (FGDs) with the beneficiary and non-beneficiary participants from school teachers, journalists, the Rohingya community, local administration, and LEA to combat human trafficking in one of the world's largest refugee camps and its adjacent areas.Leda  MS, Leda A, Leda-B, Leda C, and Leda D  for this purpose. In addition, the evaluation team conducted dedicated meetings and conversations with project staff on different aspects of project management and interventions. Finally, an evaluation of the effectiveness of the program is provided which was a result of conducting KIIs and FGDs with both beneficiary and non-beneficiary participants from teachers, journalists, Rohingya refugees, local administration, and LEAs in Teknaf, and Ukhyia sub-districts.In the second phase, the study conducted a cross-sectional study interviewing both beneficiaries and non-beneficiaries with a pre-tested questionnaire that consists of both qualitative and quantitative questions. The questionnaire was pre-tested on 10 beneficiaries comprising five members from each group. The respondent's comments were considered while developing the main evaluation questionnaire. Targeted sampling was used to collect data from Rohingya and non-Rohingya communities between September and October 2019. Prior to conducting interviews, the participants were briefed on ethical protocols, the research purpose, and possible outcomes. Next, after being informed of the earlier, they could decide to either proceed and participate in the interviews or turn down the invitation. For this study, ethical clearance was sought and approved by the University of Chittagong's Ethics Committee for the Department of Geography (Protocol number: CUNI-13/0022). No personal identifiers were collected. The participants were coded by beneficiaries and non-beneficiaries with their professional identities remaining anonymous. Thus, the study maintained ethical standards, specifically in accordance with the Declaration of Helsinki\u2014ethical principles for research involving human subjects.Majhis (Majhis are community leaders of the Rohingyas).In this study, experimental research was designed in order to understand the knowledge gap between the beneficiary and non-beneficiary groups after project implementation. The data were collected using information from the questionnaire which assessed knowledge and awareness differences about HT, CT, rules and regulations, and the safe migration process. The participants included school teachers, journalists, Rohingya households, and Before conducting interviews, a checklist was prepared for the beneficiary participants who would be invited for interviews and FGDs. A total number of 48 interviews were conducted with the beneficiary and non-beneficiary groups to understand the difference in knowledge between the groups during the mid-term evaluation of the project. The interviews were conducted with school teachers and journalists.Majhis because of their strong influence on the Rohingya community. Of the four FGDs conducted, two each were conducted with beneficiary Majhi and non-beneficiary Majhi, respectively. The time and location of FGDs were pre-arranged in consultation with the participating Majhis. Eight Majhis who were cooperative and enthusiastic attended each FGD session. Majhis who participated in the FGDs are male subjects who represent muscular dominancy in the group. Finally, observation (overt and covert) has been used to document eyewitnesses and to understand the ongoing project interventions by project staff. This field visit also helps to understand the camp entry and exit gates, connectivity to adjacent roads and host communities, and overall environment . The weightage analysis method was used for exploring the quantitative finding of the study. Cronbach's alpha statistics were used to check the reliability of the weightage analysis performed. Cronbach's alpha reliability coefficient normally ranges between 0 and 1. The closer the coefficient is to 1.0, the greater the internal consistency of the items (variables) in the scale. Cronbach's alpha coefficient increases either as the number of items (variables) increases, or as the average inter-item correlations increase . After the completed Cronbach's alpha statistic to test reliability, the test found excellent condition (0.9) out of the five levels  very confident to (1) very low confident . The tese levels .The results of the study are presented in two sections. First, we present the results of a review of the evaluation of the humanitarian initiatives led by YPSA. Especifically, we reviewed project activities such as intervention reports, quarterly progress reports, and training manuals. Second, the paper presents the research findings from the evaluation with the beneficiary and non-beneficiary stakeholders.Leda (specific name of the camp), and two locations in two administrative areas, particularly the Ukhia and Teknaf sub-district. Over 463,515 individuals live across 21 areas. The project's staff have attempted to implement different trafficking prevention activities for targeted beneficiaries. These programs directly addressed four different activities, namely courtyard meetings, drama/cultural events on CT, meetings with Majhi, and CT messages on Radio Naf  such as early marriage and polygamy which are considered as the pull factors to HT. Finally, they explained how to deliver referral pathways and how services were made available for victims. The trainers who have expertise in HT have facilitated these programs at camp areas in the presence of YPSA's executive members.The project staff arranged the orientation program about CT issues and referral mechanisms with In the past, YPSA was partnered with the IOM on a project entitled \u201cInitiatives to Prevent Human Trafficking in Emergency Response (PHTER)\u201d to increase the knowledge of refugees and host communities on trafficking and safe migration, and capacity-building of community leaders, NGOs and LEA to combat HT. The participants in the capacity-building program receive training on the causes and consequences of HT, how to work together for the prevention of HT, the identification of the victims, and the referral mechanisms to learn about the key laws such as The Prevention and Suppression of Human Trafficking Act 2012 . In thisThe project team has prepared the module on developing awareness and capacity-building of Rohingya, Majhi, camp focal point person, and host community in selected camps areas. First, the module focused on the concept, causes and consequences, and prevention of HT. It also highlights the safe migration process. Then, it referred to a different awareness and prevention-related initiatives, particularly courtyard meetings, introducing District Manpower Office (DEMO), HT-related reference mechanisms, and provision of laws and policies. Finally, it developed and implemented referral modules to prevent HT and promote CT and safe migration.The quarterly reports are prepared to monitor and evaluate project activities and deliverables. Each activity was completed on time, except the activity on the orientation of the HT Act and referral services with law enforcement agencies. It was noted that a number of factors including prolonged rainy season and associated flash flooding, late approval from the office of the Refugee Relief and Repatriation Commissioner (RRRC), and staff dropouts interrupted the program's activities.Majhis and host communities on CT issues and referral mechanisms. They organized a \u201cWorkshop for Media Professionals/Journalists on Human Trafficking Act & Preventing TIP\u201d at the Mushroom Center, Bus Terminal, and Cox's Bazar Sadr. Moreover, the project staff observed \u201cWorld Day Against Trafficking-in-Persons\u201d and organized four street dramas to create awareness about anti-human trafficking in the Rohingya and host community. Furthermore, the project launched an awareness program on HT through community Radio Naf 99.2 FM which is a popular media in the project intervention area. Therefore, after the first quarter, project staff developed and maintained effective communication channels with targeted stakeholders.The quarterly progress report has evidenced that the project staff have successfully developed awareness of HT- and CT-related modules and arranged 216 courtyards meeting out of a total of 770 meetings with the Rohingya and host community. Some of the courtyard meetings were interrupted due to bad weather conditions. A session titled \u201cOrientation on Safe Migration Related issues for potential and out-going migrants\u201d was facilitated for the host community at DEMO, Cox's Bazar. The project organized five meetings with The findings suggest that school teachers and journalists who received orientation have higher levels of awareness and knowledge about the HT act and other acts, as well as referral services and safe migration, than non-beneficiary/non-beneficiaries. They have gained knowledge or ideas about the Prevention and Suppression of Human Trafficking Act 2012. In contrast, the non-beneficiary participants were very unaware of the act. All participants in KIIs have an understanding of the first chapter of the Prevention and Suppression of Human Trafficking Act 2012. The beneficiary group could mention ways to provide referral services for HT. The majority of participants were confident in explaining the HT act and referral services in both camp areas and host communities. On contrary, non-beneficiary participants were less confident in explaining about HT act and referral services in both camp areas and host communities. The beneficiary participants could identify nine types of acts and rules related to HT: (1) Bangladesh Constitution ; (2) Prevention and Suppression of Human Trafficking Act 2012; (3) Women and child prevention and suppression SAARC convention 2012; (4) Child Act 1974; (5) Bangladesh Labor Act 2006; (6) Women policy 2011; (7) Child right policy 2011; (8) Immigration rules 1982; and (9) Bangladesh Passport Act 1973.All beneficiary participants knew about the Bangladesh Constitution Articles, 34 and 38 on trafficking issues, Prevention and Suppression of Human Trafficking Act 2012, Child Act 1974, Women policy 2011, and Child right policy 2011. The majority of non-beneficiary participants personally knew about Bangladesh Constitution , Child Act 1974, and the Women policy 2011. Beneficiary participants suggested that they benefitted and received different training activities  organized by YPSA on the human trafficking act and referral services. By attending orientation sessions and training, the participants have a clear idea about trafficking processes and traffickers, knowledge about anti-human trafficking tribunals and the trial of offenses, the human trafficking Act and rules, and how and where victims get security and legal support. The findings from KIIs have identified two major weaknesses: (1) training session on HT and CT is short; (2) there were not adequate local district and sub-district levels civil administrators, LEA  and lawyers in the process.In response to causes of HT, most of the beneficiary participants identified nine reasons that include (1) financial insolvency; (2) expectation of a good job; (3) greed for money; (4) unemployment; (5) lack of awareness; (6) uncertain future; (7) violence; (8) lack of job; and (9) lack of appropriate housing. There are two types of factors, push and pull, which are responsible for human trafficking. During our opinion survey, beneficiary participants mentioned that 11 types of push factors responsible for the irregular migration include: (1) improved life expectation; (2) unemployment; (3) family feud; (4) a high number of forced marriages; (5) more earning offer; (6) border crossing opportunity; (7) early marriage; (8) physical, mental and sexual harassment; (9) helpless and dowry; (10) experiencing conflict situation; and (11) uncertain life and violence. Of these factors, unemployment, more earning offer, improved life expectation, and border crossing opportunity were the most prevalent push factors for HT among Rohingya communities.Beneficiary participants identified that six types of traffickers are involved in their regular migration processes. This includes relatives, neighbors, friends, influencing local leaders, employers/persons who help them to get employment, and unknown persons. The non-beneficiary participants said that five types of traffickers are responsible for illegal migration such as relatives, neighbors, friends, employer/person helping them to get employment, and unknown person, respectively. However, both beneficiary and non-beneficiary groups opined that most people are trafficked by strangers. In response to knowledge about victims of trafficking, both beneficiary and non-beneficiary Rohingya communities have clear ideas about who are the potential victims of HT. The potential victims include children, adolescents, males, females, widows, isolated persons, homeless persons, unemployed persons, and orphans.By attending CT and safe migration-related orientations such as courtyard meetings, day observation, Radio Naf, and street drama, beneficiary participants have a better understanding of counter-trafficking and safe migration than non-beneficiary participants do. The beneficiary Rohingya communities confirm that they are aware of six types of incidences involved with HT such as threat, force, kidnapping, exploitation, taking disadvantaged situations, and offering money. The participants heard about the incidence of threats, force, and kidnapping in the areas. They also reported that the victims were psychologically stigmatized and experienced different types of consequences such as personal , health , bad reputation, isolation or compel to leave overseas, social and economic losses.The beneficiary host community participants could identify a series of steps for safe migration that were introduced in training and courtyard meetings. These include having a passport, Bureau of Manpower Employment and Training (BMET) registration, registered recruitment agency, paying money with receipt, legal job agreement, visa, and its verification processes, BMET release letter and smartcard, and opening a bank account, respectively. In contrast, non-beneficiary participants opined that having a passport, visa, and its verification processes and BMET registration are the main steps for safe migration. Beneficiary participants suggested that courtyard meetings, street drama, day observation, and awareness of HT through Radio Naf are the most effective ways for reducing human trafficking and promoting CT in these areas. In response to queries relating to referral services for victims in the camp, the beneficiary participants mentioned three types of referral services: (1) referring to the relevant organization/entities for counseling and basic support; (2) referring to the relevant organization and entities for legal help and; (3) proper maintenance for the referral system.Chitttagonian  language, the Rohingya communities suggest to use their own Rohingya language in Radio Naf; and (6) excessive people in each meeting.This evaluation has attempted to identify the weakness of CT and safe migration-related project items and delivery mechanisms. The participants identified six major weaknesses that include: (1) the number of meetings is less; (2) the duration of meetings was short; (3) the presence of women is less; (4) long time gap between two meetings; (5) instead of using Majhis from both beneficiary and non-beneficiary suggested that eight types of victims are trafficked, due to irregular migration in these areas. These victims are children, adolescents, males, females, widows, isolated, homeless persons, unemployed persons, and orphans. More recently both children and women have been trafficked by strangers or unknown persons and friends in these areas. By attending CT and safe migration-related awareness training, meetings, street drama, and listening to Radio Naf programs, the beneficiary Majhis could more confidently explain the legal procedure on CT and referral services for victims of trafficking. They also could confidently explain more about the push and pull factors of trafficking, potential type of traffickers, the most vulnerable victims, and safe migration procedures.Beneficiaries from both Rohingya and host communities became aware of HT and CT because they enhanced their understanding from different types of awareness programs such as courtyard meetings, street drama, day observation, and programs on HT through Radio Naf. Quantitative analysis suggests that the beneficiary participants from school teachers and journalists had a better understanding of HT, CT, and safe migration than the remaining three groups . This maThe weighted analysis suggests that the mean score of Majhi is low (2.0) among the four non-beneficiary groups . The aveThe quantitative evaluation of the HT and CT intervention activities undertaken by the YPSA suggests four types of activities including orientations on safe migration with potential migrants, day observation, street dramas on CT, and awareness on CT through Radio Naf are found useful. The other four types of activities, courtyard meetings, orientation sessions with Majhis, orientations on the human trafficking act and referral services, and capacity-building workshops for journalists are useful. The participants show positive gestures to attend the activities in the future and also provide specific suggestions for each type of activity .By conducting a narrative review of the literature, Lugova et al.  reportedCounter-trafficking interventions gained phenomenal popularity since the adoption of the UN Trafficking Protocol 2000 which prompted the undertaking of a variety of efforts from the UN agencies, national governments, International Non-Governmental Organizations (INGOs), and NGOs . The actMajhi are to be empowered considering their influence and trust in the communities. It will require increasing the surveillance of LEA with modern equipment at each entry and exit gate. Sufficient food for the Rohingya people must be ensured because food insecurity is the main push factor to fall victim to traffickers. Partnership development with community, community-based organizations (CBOs), NGOs, and local administration, especially police for the CT process will be of great help.The key project intervention activities, courtyard meetings, orientations on safe migration with potential migrants, day observation, and street dramas on CT were attended by the beneficiary participants. This study identifies several key loopholes that need to be treated and improved. Interventions are required for future project deliveries. First, with regard to awareness generation activities, the beneficiary participants support ongoing courtyard meetings, orientation sessions, and street dramas that need to occur more frequently in a better place with appropriate facilities. Although women participated in each event, their equal participation should be ensured by the implementing organizations. Education and training activities launched by the other organizations at the camp may include HT awareness and the CT process. Awareness activities should be delivered in the local dialect especially when targeted participants are Rohingya communities. Because local administration and law enforcement authorities play a crucial role in the CT process, their inclusion should be one that will enhance the community's confidence in such types of interventions. Local community leaders and The Government of Bangladesh and Bangladeshi communities showed great humanity by hosting over 900,000 stateless Rohingyas which is appreciated by international communities. It was a significant challenge given the limited time to organize all the required food, clothing, shelter, and arrange for health opportunities for the large influx of Rohingyas. Due to limited basic needs and untight security options, there was evidence of HT of Rohingya refugees. Several international agencies, particularly the IOM, in partnerships with NGOs were active since August 2017 providing support to the local government and Rohingya community to promote CT activities. The activities implemented by the YPSA in the camp and adjacent host community demonstrated their effectiveness in creating awareness about HT, promoting CT, and safe migration in the area. The findings of this research and recommendations may be useful to enhance CT and safe migration in the refugee and non-refugee setting in Bangladesh and beyond. The study mainly evaluates HT-related activities implemented at the field level and the effectiveness of their deliveries. Thus, comments cannot be made on the actual outcome of the project activities. Therefore, more studies need to be conducted to evaluate the impact of the CT programs that were implemented following a rapid and large influx of Rohingya refugees in Bangladesh.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by the Institutional Review Board (or Ethics Committee) of the Department of Geography and Environmental Studies at the University of Chittagong, Bangladesh  for studies involving humans. Written informed consent was obtained from the individual participant for the publication of any potentially identifiable images or data included in this article. The patients/participants provided their written informed consent to participate in this study.Conceptualization and writing\u2014review and editing: EA, MAR, and JB. Methodology and formal analysis: EA and MHM. Validation: EA, MKI, and MAR. Investigation: EA, MHM, and JB. Resources and supervision: EA and MAR. Data curation and visualization: EA and MKI. Writing\u2014original draft preparation: EA and MHM. Project administration: EA."}
+{"text": "Musculoskeletal (MSK) disorders are among the top five contributors to disability-adjusted life years (DALYs) worldwide . These dSeveral articles in this Special Issue delve into the diagnostic accuracy of radiological measurements in different musculoskeletal conditions. Tagliafico et al. investigated the reliability of the Myeloma Spine and Bone Damage Score (MSBDS) in assessing myeloma-related spine and bone damage using whole-body computed tomography (WBCT) . This muThis Special Issue also explores the application of novel techniques to skeletal radiology. New sequences are expanding diagnostic capabilities, and AI-based techniques are revolutionizing the field via enhancing image interpretation and improving image acquisition protocols. Despite being introduced some time ago, the utilization of relatively new MRI sequences like DWI in skeletal radiology has been limited due to their susceptibility to artifacts and inhomogeneity . HoweverIn addition to diagnostic accuracy and advancements in skeletal radiology, this Special Issue features studies focusing on specific clinical applications. The diagnosis of systemic disorders, characterized by their wide-ranging impact on different organs, significantly relies on the field of skeletal radiology. Due to the non-specific nature of their clinical presentations and the presence of overlapping features, familiarity with the radiologic findings of these disorders is crucial. Radiologic and dermatologic presentations of systemic disorders, the visualization of dialysis-related amyloid arthropathy via 18F-FDG PET-CT scans, and radiographic findings of inflammatory arthritis and mimics in the hands are the topics of the studies focusing on systemic disorders in this issue ,14,15. TThis Special Issue on skeletal radiology encompasses a comprehensive array of articles that contribute to the advancement of this dynamic field. From studies on diagnostic accuracy to emerging applications and clinical reviews, the included articles show the progress and potential of skeletal radiology in improving patient care. The field of skeletal radiology offers promising prospects. Ongoing discussions focus on leveraging emerging technologies to enhance diagnostic capabilities and treatment planning. However, challenges persist, such as the need for standardized protocols, the addressal of data quality and privacy concerns, and the optimization of the integration of artificial intelligence. Further research is required to explore the potential of novel imaging techniques, including advanced MRI sequences and functional imaging modalities, in providing valuable insights into skeletal pathologies. The corresponding evolving technology and imaging techniques have the potential to revolutionize the practice of skeletal radiology, enabling more accurate diagnoses, personalized treatment approaches, and improved patient outcomes."}
+{"text": "This significant milestone provided an opportunity to reflect on two decades of scientific advancements in the field of neurotrauma. Renowned speakers and participants from around the world gathered in the captivating city of Krakow, Poland, from May 12th to May 13th, 2023 . The Congress employed a hybrid model to increase accessibility to information, extending its reach beyond geographical borders. This model enabled a large audience to explore the complexities of neurotraumatology with greater depth. The event was attended by over 250 participants from diverse nations, including Romania, Poland, Egypt, Azerbaijan, Uzbekistan, and Mexico.The th, 2023  and brouEuropean Federation of Neurorehabilitation Societies (EFNR), World Federation for Neurorehabilitation (WFNR), the Foundation of the Society for the Study of Neuroprotection and Neuroplasticity (SSNN), European Academy of Neurology (EAN), European Society of Clinical Neuropharmacology (ESCNP), and the Foundation for the Study of Nanoneurosciences and Neuroregeneration. These collaborations enable the AMN to stay at the forefront of neurotraumatology research, teaching, and practical applications.The AMN actively strives for the advancement of neurotraumatology through various engagements, bringing upfront international scientific congresses to facilitate, encourage, and enhance knowledge and expertise exchange through comprehensive collaboration activities among experts. The Academy for Multidisciplinary Neurotraumatology makes the best use of its communication pillar that, over the decades, has developed into an acknowledged network of national and international associations, societies, and organizations involved in neurotraumatology. Furthermore, it is worth mentioning that the AMN is committed to delivering excellence in education by fostering cooperation with scientific academies, associations, societies, research institutions, and companies dedicated to neurotraumatology. The Academy boasts a global membership of over 600 individuals and maintains partnerships with prominent organizations such as the A teaching course on cognitive assessment after neurotrauma marked the beginning of the congress. The course was conducted by Prof. Nicole von Steinb\u00fcchel (Germany), the past President of the Academy for Multidisciplinary Neurotraumatology (AMN), who discussed the most relevant scientific scales in the domain of post-neurotrauma cognitive assessment.The welcome address of the 20th AMN Congress was expressed by Prof. Dr. Dafin Muresanu , Prof. Volker H\u00f6mberg (AMN Chairman of the Scientific Committee & WFNR President) and the president of the AMN, Prof. Johannes Vester.The first day of Congress was built upon a four-session structure, each session focusing on different aspects of neurotrauma. The Presidential Session covered topics related to neurological rehabilitation, recent advancements in clinical research on traumatic brain injury (TBI), non-interventional comparative effectiveness in TBI, and the impact of sociodemographic, premorbid, and injury-related factors on post-traumatic stress, anxiety, and depression following TBI. Complementary to the first session, the AMN Presidential Panel entitled \u201cThe pitfalls of neurotrauma basic and clinical research\", chaired by Michael Chopp (USA) and Dafin Muresanu (Romania), explored both the challenges and advancements of neurotrauma dynamics, with an emphasis on the value of multidisciplinary perspectives as a tool for broadening the field of neurotraumatology. The second session was focused on blood-brain barrier monitoring during acute ischemic stroke, the role of neurotrophic factors, the influence of endothelial cell-derived exosomes, and the effect of concussive head injury on Alzheimer's disease pathology. The third session marked a shift from the effects of neurotrauma to prehospital care for severe TBI patients and the use of multimodal approaches in ICU-based TBI treatment.The closing fourth session of the day centered around diffuse axonal injury (DAI), endoscopic surgery for acute subdural hematoma, and surgical interventions for TBI. As such, expertise was illustrated on the duration of coma after DAI, the occurrence of persisting motor weakness, and time of recovery for patients with DAI as opposed to focal injuries; regarding research on acute subdural hematoma (ASDH), radiologic and clinical data were presented, converging to the conclusion that endoscopic subdural hematoma removal is, under certain conditions, an effective and safe surgical technique. Further on, going beyond the need for guidelines in neurotrauma, the time factor was highlighted as a central focus in neurosurgery, with \u201cTime is Brain\u201d surpassing all technological developments. Esteemed speakers present at the event included Johannes Vester (Germany), Dafin Muresanu (Romania), Volker H\u00f6mberg (Germany), Nicole von Steinb\u00fcchel (Germany), S\u0142awomir Michalak (Poland), Michael Chopp (USA), Hari Shanker Sharma (Sweden), Helmut Trimmel (Austria), Klaudyna Kojder (Poland), Wojciech Dabrowski (Poland), Pieter Vos (The Netherlands), Se-Hyuk Kim (Korea), and Christian Matula (Austria), Razvan Chereches (Romania), Karin Diserens (Switzerland), Peter Lackner (Austria), Jongmin Lee (South Korea), Johannes Leitgeb (Austria), Marcin Michalak (Poland), Polona Pozeg (Switzerland), Katrin Rauen (Switzerland), and Andreas Winkler (Austria).The Patient Registry - Short Essential Neurotrauma (PRESENT) is an innovative initiative designed to provide comprehensive and multidisciplinary data regarding traumatic brain injury management and facilitate healthcare delivery across different countries. The registry also encourages long-term follow-up of patients. Marcin Michalak (Poland) presented the experience with the first 50 Polish patients included in the PRESENT registry, emphasizing its practical application. Furthermore, Peter Lackner (Austria) underlined the importance of neurotrauma registries in obtaining accurate assessments to further enhance patient care, and Razvan Chereches (Romania) discussed the piloting of a TBI registry in Moldova, Armenia, and Georgia. Following the presentations, the speakers shared interactive discussions with the audience. Session 5 of the event delved into post-TBI neurological assessments, highlighted the global burden of post-TBI depression, and emphasized the role of interdisciplinary neurotrauma management.The second day of the congress commenced with a round table entitled \u201cReal-World Evidence in TBI \u2013 Why Registries Matter\u201d, a dynamic session that highlighted the significance of real-world data in TBI and the vital role of registries in neurotrauma management, pinpointing the latest developments and implementation stages at various country levels. A stimulating discussion was brought forward by \"The AMN Vision - Panel on How to Develop Multidisciplinary Teams in Clinical Routine. The NTSC Vienna concept\" that pinpointed to the innovative Neurotrauma Treatment Simulation Center (NTSC) Program. The NTSC Program had its second edition on April 16-21, 2023 in Vienna, Austria, showcasing a novel approach to neurotrauma education and training. An innovative method in the field of neurotrauma, the program brings together specialists from various backgrounds, such as neurology, neurosurgery, trauma care, and anesthesiology, for a five-day training program in different medical locations. The panel, chaired by participants from the first NTSC edition, respectively Agata Andrzejewska (Poland) and Bassem Boulos (Egypt), featured the Austrian faculty members of the NTSC program, namely Christian Matula, Peter Lackner, Andreas Winkler, Johannes Leitgeb, and Helmut Trimmel. The special panel explored the concept of experiential learning and multidisciplinary teamwork promoted by the NTSC while placing under the loop the objectives of the program and the real-world impact it has on diagnosis, treatment, patient care, and follow-up.The last session of the day focused on motor recovery after neurotrauma, psychiatric neurorehabilitation, and multimodal neuroimaging of covert consciousness. Once again, experience and knowledge were shared regarding specific challenges in neurorehabilitation, i.e., high incidence and prevalence of TBI, notable and permanent degree of disability, and multimorbidity in the elderly. With the concept of neuronal plasticity as the core scientific basis for neurorehabilitation, therapeutic interventions, such as Transcranial Magnetic Stimulation (TMS) and Transcranial Direct Current Stimulation (tDCS) are of top importance for restructuring neural networks.www.brain-amn.org and on YouTube.The AMN conducted an insightful interview with the AMN President Johannes Vester, addressing key messages for the Congress participants and AMN members and future developments and projects of the Academy for Multidisciplinary Neurotraumatology. Further on, the AMN Interview Series  that conth edition of the AMN Congress , between 7-8 June . The eve"}
+{"text": "Frontiers in Cell and Developmental Biology  and reverse transcription\u2013polymerase chain reaction and/or immunohistochemical (IHC) analysis; ii) availability of histopathology, imaging, and clinical information; iii) exclusion of the possibility of bone metastasis  and the triple sign and pseudo-cystic sign (via magnetic resonance imaging), those results had relatively low sensitivity  precise diagnosis, ii) adequate clinical information, and iii) exclusion of metastasis. Such reviews would enable clarification of the real clinicopathological characteristics of the disease and, in turn, lead to meaningful prospective studies for standardization of therapy."}
+{"text": "Dear Editor,Pseudoxanthoma elasticum (PXE) is an autosomal recessive genetic metabolic condition characterized by aberrant calcification with the fragmentation of elastic fibers in the dermis, retina and tunica intima of arteries.A 33-year-old woman with a history of systemic lupus erythematosus was referred because an ocular fundus examination revealed angioid streaks associated with decreased foveolar brightness and diffuse pigmentary changes called \u201cpeau d\u2019orange\u201d . PhysicaThe prevalence of PXE varies between 1/25,000 and 1/100,000, with female predominance. It is caused by a mutation in the ABCC6 gene, located on chromosome 16, which encodes a transmembrane transport protein MRP6.Although cutaneous findings usually represent the first clinical sign, they are typically subtle and not evident until the second or third decade.The first visible changes on funduscopy are pigment irregularities with a \u201cpeau d\u2019orange\u201d appearance that typically precedes angioid streaks by one to eight years. Angioid streaks originate from the optic disc and radiate outwards as brownish-grey irregular lines, histopathological findings show breaks of the calcified and thickened Bruch\u2019s membrane. The latter predisposes to secondary choroidal neovascularization with the consequent risk of hemorrhage and blindness in the later stages of the disease.Manifestations of vascular involvement include loss of peripheral pulses, claudication, hypertension, myocardial infarction and ischaemic or hemorrhagic strokes. These findings reflect the mineralization of the middle and intimal layers of small and medium-caliber arteries.3We present this case given the unusual clinical presentation and highlight the importance of cutaneous alterations in the diagnostic confirmation of this entity.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.Catalina Jahr: Approval of the final version of the manuscript; composition of the manuscript; collection, analysis, and interpretation of data; participation in the design of the study; critical review of the literature; critical review of the manuscript.Valentina Vera: Approval of the final version of the manuscript; collection, analysis, and interpretation of data; critical review of the manuscript.Roberto Bustos: Approval of the final version of the manuscript; collection, analysis, and interpretation of data; critical review of the manuscript.Jos\u00e9 Contreras: Approval of the final version of the manuscript; collection, analysis, and interpretation of data; critical review of the manuscript.None declared."}
+{"text": "However, simple assessment and reporting of rates of contact with mental healthcare potentially overestimate the full expected health benefits of services. Therefore, in addition to monitor the coverage rate achieved by the services, the evaluation of the effectiveness of the care provided (effective coverage)  is also of relevant importance.The evaluation of healthcare pathways must be considered of fundamental importance. The quality of care provided to patients with severe mental disorders (SMD) does not correspond to the standards set by the recommendations. Therefore, measures such as the real coverage rate of psychiatric patients\u2019 needs . 45,761 newly taken-in-care cases of depression, schizophrenia, bipolar, and personality disorder were included. A variant of the self-controlled case series method was used to estimate the incidence rate ratio (IRR) for the relationship between exposure  and relapse episodes .Figure) during periods covered by (i) psychotherapy for patients with depression  and bipolar disorder ; (ii) psychosocial interventions for those with depression , schizophrenia  and bipolar disorder , (iii) pharmacotherapy for those with schizophrenia , and bipolar disorder . Coverage with generic mental healthcare, in the absence of psychosocial/psychotherapeutic interventions, did not affect the risk of relapse.11,500 relapses occurred. Relapse risk was reduced (Image:effective coverage, showing that real-world data can represent a useful resource to monitor mental healthcare paths and to assess the effectiveness of a mental health system.Psychosocial interventions, psychotherapies and specific pharmacotherapies can be considered particularly effective in treating patients with bipolar, depressive, and schizophrenic disorders. This study ascertained the gap between utilization of mental healthcare and None Declared"}
+{"text": "Seafood is consumed all around the world. It is considered a high-quality food and an excellent source of vitamins, minerals, proteins, essential amino acids, and fatty acids \u20133. SeafoContamination of coastal areas and oceans, originating from human activities, disturbs marine ecosystems, thus causing seafood to be also a potential source of pollutants such as microplastics, pesticides, synthetic musks, persistent organic pollutants, metals, and pharmaceuticals \u20136. ThereLi et al. combined molecular biology and metabolomics techniques to thoroughly investigate the molecular mechanisms by which different plant proteins affect the proliferation and degradation of muscle proteins of yellow catfish. The authors found soybean meal, peanut meal, cottonseed meal, sesame meal and corn gluten meal regulated the biosynthesis and degradation of muscle protein by affecting the content of vitamin B6, proline, glutamic acid, and phenylalanine (tyrosine) in muscle. The plant proteins improved the flesh quality and texture, despite significantly reducing the growth performance. The authors observed that inhibition of myocyte proliferation-related genes in cottonseed, sesame and corn gluten groups might additionally be regulated by the increase of glutamic acid and the decrease of tyrosine contents . The work provides a needed theoretical basis for further understanding the mechanism of plant proteins regulating flesh quality.Fish is highly consumed around the world, representing 17% of the total animal protein consumed by humans  in the feeds of aquaculture crayfish. Crustaceans have long been considered a delicacy. The demand for crustaceans, on the one hand, has been increasing worldwide, which can lead to overexploitation of wild species. On the other hand, the aquaculture farming of these species is costly due to the substantial amount of fishmeal required in the feeds . Insects are high in protein and fat, and an alternative of low environmental footprint. The investigation of Alvanou et al. found that 98 days fishmeal replacements of 50 and 100% in juvenile diets increased crayfish survival but negatively affected its growth performance and feed utilization. The inclusion of the fly larvae in the diet also altered the fatty acid levels and profiles of crayfish. The study shed some light on contradictory results available in the literature for other species.Still related to alternative protein sources, Quaresma et al. studied the protein quality of dried salted cod fish, the 3rd highest consumed fish in the European Union. Due to high demand and capture, Atlantic cod is considered a vulnerable species by the International Union for the Conservation of Nature. In comparison, Pacific cod is captured in lower amounts. Considering this, Quaresma et al. evaluated and classified the nutritional quality in relation to the cod species  and harvesting areas (Norway and Iceland Exclusive Economic Zones) using an essential amino acid index. They found the amino acid profiles and the index produced full accurate discrimination of the cod species. Discrimination of the location was above 85%. Furthermore, Norwegian cod protein was classified as of high quality, while that of Iceland cod was of useful quality protein. The same five limiting amino acids were found in both species.On another relevant topic and with a different approach, Gao et al. approached seafood from the innovative perspective of marine bioactive peptides. They studied the potential of peptides from tilapia skin for the treatment of ulcerative colitis, which is a main type of Inflammatory Bowel Disease. Tilapia peptides display anti-inflammatory, antioxidant, antihypertensive, and immunomodulatory properties amongst others . The mechanistic investigation points out a role of such bioactive peptides in the protection against external stimuli, which passes through enhancing the barrier function of the colon epithelium, reducing the release of inflammatory cytokines, and suppressing apoptosis.By contrast, t others . The autIn sum, the contributing articles address either the benefits of seafood consumption, potential health usages, or alternatives to improve seafood safety and quality. These bring new information on relevant aspects of the topic, opening questions and challenges for future research related to alternative protein sources, the nutrient sensing signaling pathways, quality evaluation and species discrimination based on essential and non-essential amino acid profiles, and the role of fish bioactive peptides in health and disease.SS and MM wrote the original draft of the article. LG and VD reviewed and edited the article. All authors contributed to the article and approved the submitted version."}
+{"text": "With increasing health awareness, food safety and quality have been a growing demand globally. Food safety and quality depend upon many factors, including microbes in food production, processing, preservation, and storage. On the one hand, microbes such as bacteria, molds, and yeasts have a long history of application in food production, such as in the production of wine, beer, bread, and dairy products. On the other hand, the growth of microorganisms and contamination by microorganisms lead to food spoilage or even foodborne illness, threatening the development of the food industry.Microorganisms play a crucial role in the production, preservation, and improvement of food. By transforming the chemical constituents of raw materials of plant/animal sources, functional microorganisms, particularly bacteria and yeast, can improve the sensory quality of food, enhance the bioactivity of nutrients, produce antioxidant and antimicrobial compounds, and promote food safety.Liu, Cao et al. utilized a mixture of yeast and Lactobacillus rhamnosus YL-1 as a starter in the fermentation process of salami sausage, which could effectively decrease the degree of lipid oxidation and result in changes in flavor profiles. The combination of Lactobacillus fermentum YZU-06, Staphylococcus saprophyticus CGMCC 3475, and leucine has also been applied in the production of fermented sausage, which improves not only the diversity of flavor compounds but also the overall quality of sausages . Liao et al. compared the quality and the main metabolic changes of instant dark teas fermented by different fungi, such as Aspergillus cristatus, Aspergillus niger, and Aspergillus tubingensis, revealing that the chemical constituents of instant dark teas were affected by the fungi. Tao et al. reviewed the utilization of microbiome in the fermentation process, which could remove the unpleasant beany flavors and enhance the aroma profile of plant-based meat analogs. Probiotics make a great contribution to gut health by improving digestion and enhancing nutrient absorption. Zhu Y. et al. demonstrated that feeding patterns can affect gut microbiota and the metabolites of Tibetan pigs, which further led to changes in meat quality.The physicochemical properties and the volatile flavor compounds of food are closely related to the nature of microorganisms, especially in fermented food. Yu et al. found that the temperature of beef aging could affect the microbial community, physiochemical attributes, and flavor profiles of beef. Liu A. et al. observed significant differences between the bacterial community of vinegar from the same day with different fermentation depths, but no apparent difference appeared in the fungal community. In addition, the function of microbiota and volatile flavor compounds were affected by the microbial community at different depths. By comparing the physicochemical properties and microbial community compositions of Jinhua fat ham and lean ham, Zhang et al. explored the potential mechanism of characteristic microorganisms affecting the formation of flavor in lean dry-cured hams.The process of fermentation is influenced by several factors such as temperature, time, pH, oxygen levels, and microbial starter cultures. Food quality can be monitored through the regulation of fermentation conditions. Liu C. et al.; Guo et al.; Fulano et al.). Unscientific storage of food can cause an infestation of harmful microorganisms. For example, various fungal strains have been found in the production and preservation of dark tea, leading to the proliferation of fungi toxins. Xu et al. reviewed the contamination levels of common mycotoxin species, the main microbial sources of mycotoxin, and the possible ways to cause mycotoxin contamination in dark tea, providing a foundation for the prevention of harmful fungi.Spoilage and pathogenic microorganisms are considered one of the main factors threatening food quality and safety (Chen et al. found that the microbiota, mainly Lactobacillus, inhibited the formation of biogenic amines during the traditional fermentation of Scomber japonicus. To extend the shelf life of food, packaging materials have been explored to protect food from chemical and microbiological changes. Schmid et al. investigated the contaminating bacterial growth and survival in different fiber-based food packaging materials and evaluated the role of pH as an intrinsic antimicrobial factor. Furthermore, some active substances have been found to have inhibitory effects on the growth and toxicity production of microorganisms. Some Aspergillus niger produce ochratoxin A, which has harmful effects on human health, whereas tea polyphenols and epigallocatechin gallate were found to inhibit the growth of Aspergillus niger and ochratoxin synthesis, according to Zhao et al.'s study. Based on Propidium Monoazide combined with real-time PCR, Liu, Huang et al. developed a new method for fast detection of the antibacterial and bacteriostatic activity of disinfectants.To avoid illness and prevent food from spoiling, various technologies of food preservation have been developed to control the growth of microorganisms. Some microorganisms produce antimicrobial compounds and organic acids that inhibit the growth of spoilage-causing bacteria. In conclusion, this Research Topic explored the beneficial and harmful effects of microorganisms on food quality and safety, highlighting the correlation between microbial community and volatile compounds. The reasonable application of beneficial microorganisms and the regulation of harmful microbial infestation are essential to achieve the desired properties, leading to reliable food products and ensuring food quality, safety, and consistency.YW, CZ, and FG collected literatures, organized information, and wrote the first draft of the article. JC provided writing ideas and checked and revised the first draft. All authors contributed to the article and approved the submitted version."}
+{"text": "Dear Editor,Extramammary paget\u2019s disease (EMPD) has been associated with other several malignancies.in situ EMPD of the scrotal region .%.2, 6, 7It has been frequently reported that EMPD is associated with various malignant tumors.Kiltos et al.In our case, lymphadenopathies extending from the right external iliac artery were considered as manifestations of metastases of invasive EMPD. However, the subsequent distant metastases were likely malignant lymphoma. The rapidly enlarging abdominal subcutaneous tissue, maxillary sinus, and skull bone were suggestive of malignant lymphomas.In our case, immunostaining for MYC and BCL-2 showed positive findings. MYC/BCL-2 co-expression without underlying rearrangements is a new adverse prognostic indicator, termed double\u2010expressor lymphoma.Invasive EPMD also metastasizes to the lymphatics and may be difficult to be distinguished from malignant lymphoma, as observed in our case. The diagnosis of high-grade B-cell malignant lymphoma was established for the first time based on a resected metastatic skin lesion specimen. This pathological condition significantly affects the treatment, prognosis, and systemic condition of patients.We believe that patients with invasive EMPD require follow-up, considering the possibility of the development of malignant tumors that can influence the prognosis, in addition to genitourinary and colorectal cancers.None declared.Misato Ueda: Approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; effective participation in research orientation; intellectual participation in therapeutic conduct of studied cases; critical review of the literature; critical review of the manuscript.Makoto Omori: Approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; effective participation in research orientation; intellectual participation in therapeutic conduct of studied cases; critical review of the manuscript.Ayumi Sakai: Approval of the final version of the manuscript; design and planning of the study; intellectual participation in therapeutic conduct of studied cases; critical review of the manuscript.None declared."}
+{"text": "This paper highlights the mutual influences and the relationships between the variables of type II diabetes, the type of psychiatric conditions, the administered treatment schemes, the imaging examinations and the impact on the functioning and quality of life of the patients.Analysis of the influences between diabetes and psychiatric disorders, studying the relationships between the variables of type 2 diabetes, the type of psychiatric disorders, treatmentregimens, imaging examinations and the impact on the functioning and quality of life of patients.Psychiatric interview, Hamilton, Reisberg and Rosenberg scales, laboratory analysysPatients with pre-existing diabetes, psychiatric disorders led to deterioration of its evolution, documented by HbA1c values, treatment schedule, frequency of diabetic emergencies; the increased frequency of psychotic phenomena  is directly proportional to the number of diabetic emergencies; patients with uncontrolled, long-term diabetes have higher scores on HAM-D and Reisberg scales, while patients with controlled diabetes have higher scores on the self-esteem and quality of life scales; in patients with taste or odor disorders, cortical atrophy may be seen on CT examination, elevated HbA1c levels and the presence of polyneuropathy; alcohol consumption, smoking, high cholesterol levels, determine the advancement of diabetic complications, and these in turn correlate with higher scores on the HAM-D scales, Reisberg; patients who show large variations in blood glucose in the first days after hospitalization are those who exhibit irritability, irritability, nervousness and heteroaggression at the time of hospitalization;65% patients with depressive disorders, 10% - with organic personality disorder, 25% - with affective disorders and 30% associated with cognitive impairment. The duration of diabetes mellitus, glycosylated hemoglobin levels and the presence of diabetic complications is directly related to the HAM-D and Reisberg scores; and inversely proportional to quality of life scores and self-esteem.None Declared"}
+{"text": "Immediately after Russia commenced aggression against Ukraine, the Polish Psychiatric Association publicly called for humanitarian support for Ukraine and initiated meetings with representatives of Psychiatric Societies operating in Ukraine in order to identify current needs in the war-stricken areas and coordinateaid.The PPA allocated its financial resources to humanitarian aid and, through the EPA, appealed for condemnation of military operations as well as support for Ukraine by individual NPAs.According to the UHNR data over 4 million displaced people, refugees, came to Poland so far and some of them benefited from such help.The Polish Psychiatric Association supports the initiatives of non-governmental organizations supporting refugees and monitors and responds to the needs reported by the Ukrainian side on an ongoing basis. At present, the PPA activities focus on the following priorities:1. Need-adapted-help: Provision of customized aid - not only medications but also power generators, technical equipment. And so, the PPA shipped to Ukraine some basic equipment, sleeping mats, bedding, mattresses, backpacks, cleaning products, personal hygiene products, as well as tools for renovation and construction.2. Awareness - highlighting the consequences of Russia\u2019s aggression on people with mental disorders in Ukraine and its impact on the entire population . Inviting and lobbying for dissemination of personal reports of Ukrainian health care workers and patients at international conventions, forums, events3. Empowerment of personnel - strengthening competences required in provision of assistance in war-related disorders, training, projects of activities both across Poland and Ukraine4. Supporting and responding to the needs reported by local psychiatric assistance centers facilitating and strengthening the competence of personnel in helping refugeesNone Declared"}
+{"text": "The BRAIN Foundation  hosted Synchrony 2022, a translational medicine conference focused on research into treatments for individuals with neurodevelopmental disorders (NDD), including those with autism spectrum disorders (ASD). One of the four roundtables focusing on some of the most difficult and unsolved problems in ASD focused on advancing the understanding and treatment of epilepsy and seizures in individuals with ASD. This is because epilepsy and seizures in ASD are more severe and difficult to treat as compared to those in typically developing individuals.Dr. Richard E. Frye, MD, Ph.D., President of the Autism Discovery and Treatment Foundation, chaired a roundtable with experts in epilepsy and ASD treatments. The selected experts gave presentations focusing on important topics . HoweverDr. Samuel Pleasure, MD, Ph.D., Professor of Neurology at the University of California, San Francisco, provided an overview of the role of autoimmunity in epilepsy. This included the specific characteristics of autoimmune epilepsy, specific autoantibodies involved in it, its syndromes, scoring systems used to assist in its diagnosis, and high-throughput techniques used for the discovery of novel autoantibodies that might drive it.Manuel F. Casanova, MD, Professor of Biomedical Sciences at the University of South Carolina, reviewed studies on ASD that indicated a high prevalence of brain malformations. Differences in cortical thickness, surface area, and cortical folding in neuroimaging studies indicate a disruption of normal brain development. Higher resolution studies using postmortem techniques evidence disturbances of both cell division and migration. A prominent commonality between human and animal models of ASD is the reduction in the number of parvalbumin interneurons. In ASD, the loss of these fast-spiking interneurons offers a neuropathological mechanism common to both seizures and executive dysfunction.Richard G. Boles, MD, Director of the NeuroGenomics Program at NeurAbilities and Chief Medical and Scientific Officer of NeuroNeeds, provided an overview of both genetic causes and contributors of epilepsy with a specific focus on ASD. He reviewed the large studies that outlined the genetic causes of epilepsy, specific cases of ASD in which novel de novo presumably causal variants were identified after extensive re-analysis of raw whole genome sequencing data, and inherited non-causal disease variants that may have provided a significant contribution to the underlying pathophysiological disease processes. Most significantly, Dr. Boles discussed various treatment approaches that could be implemented and improve outcomes in patients based on their identified genetic variation. He presented specific cases in which dramatic improvements in function and outcome resulted from the implementation of genetically guided treatments.Jeffrey Lewine, CEO of the Center for Advanced Diagnostics, Evaluation, and Therapeutics, discussed both clinical seizures and subclinical epileptiform activity in his presentation. Dr. Lewine demonstrated the significant advantage of using magnetoencephalography (MEG) for detecting subclinical discharges because of its increased sensitivity over standard and extended encephalography. Dr. Lewine demonstrated how MEG reveals patterns that correspond with clinical characteristics, such as language impairment and neurodevelopmental regression, and are predictive of the response to steroid treatment.John Gaitanis, Chief of Child Neurology at Hasbro Children\u2019s Hospital, Brown University, discussed several topics. Dr. Gaitanis introduced the novel hypothesis that individuals with ASD, neurodevelopmental regression, epilepsy, and aggressive behavior are linked. Dr. Gaitanis then went on to discuss the history of cannabis use in the treatment of epilepsy, demonstrating that it had originally been utilized to control the disorder in ancient China in 2838 BC by Shen Nung, the \u201cred emperor\u201d. Dr. Gaitanis went on to describe the important active components in cannabis and their mechanism of action on the brain. Dr. Gaitanis reviewed the preclinical and clinical studies supporting the use of cannabis in the treatment of epilepsy, including its marked efficacy for treating Dravet\u2019s syndrome and Lennox\u2013Gastaut syndrome.1, B9, E, and D; biotin; magnesium; manganese; selenium; calcium; and carnitine, and posited that a targeted multivitamin/mineral/micronutrient could be a safe and effective adjunctive treatment to other more traditional anti-epileptic drugs in order to improve seizure control in individuals with ASD.James Adams, Director of the Autism Program at Arizona State University, discussed dietary and nutritional changes in children with ASD and epilepsy and the implications of these changes on treatment. Dr. Adams reviewed the evidence for the use of the ketogenic diet and the modified Atkins diet for the treatment of epilepsy. Dr. Adams discussed the importance of key nutrients in pathways important for controlling seizures, including vitamins BLastly, Dr. Richard E. Frye discussed the specific metabolic disorders that are commonly associated with ASD and epilepsy, particularly cerebral folate deficiency, mitochondrial disorders, and redox abnormalities, including potential treatment approaches that have the potential to improve the disorder.Better defining the characteristics, etiology, diagnosis, and treatment of epilepsy in ASD, particularly in how they differ from epilepsy in those without ASD;Considering whether one unprovoked seizure should indicate initiation of anti-epileptic treatment given the high risk of its recurrence in individuals with ASD;Defining the difference between individuals with ASD who have early-onset and late-onset epilepsy;Defining the association between epilepsy and behavioral exacerbations;Defining the influence of common comorbid conditions on epilepsy, especially with the possibility of leveraging treatment of these comorbid abnormalities to improve treatment of epilepsy in ASD;Defining medical care models for improving seizure control in those with ASD.The discussion throughout the roundtable session converged on several important points that parents, clinicians, and scientists agreed should gain more attention: In an effort to move forward, many of the panelists agreed to work together to develop several review papers outlining current knowledge, defining knowledge gaps, and providing recommendations based on the available data. The ultimate goal of the group will be to develop a guideline that will be useful for clinicians in improving the care of children with ASD and epilepsy."}
+{"text": "Depending on the specific neuronal subtype, human axons extend over distances that range from a few microns to over a meter in length. Accordingly, axons contain proportions of the neuronal cytoplasm that far surpass that of the somato-dendritic domain by thousands of orders of magnitude. Remarkably, nearly all cellular components contained in axons must be actively transported from their main site of synthesis at the neuronal soma. This daunting cellular process, collectively referred to as ) Black, , is furt) Black, . The larunique complements of membrane-bounded organelles (MBOs), cytoskeletal and soluble protein components. For example, the rapid propagation of action potentials in myelinated neurons depends on acute voltage-sensitive portions of the axonal plasma membrane at the AIS and nodes of Ranvier. This is achieved by the local insertion of vesicles containing specific subsets of voltage-gated sodium and potassium channels at the AIS axolemma, as well as the insertion of vesicles containing a different subset of channels to the nodes of Ranvier's axolemma , nodes of Ranvier, and presynaptic terminals are primary examples of discrete axonal subcompartments sustaining neuronal connectivity. Their specialized functions require a continuous, highly localized supply and turnover of phosphorylation represents the most widespread and better-documented mechanism. By extension, research addressing the roles of kinases and phosphatases in the axonal compartment is essential for a complete understanding of neuronal function.The correct functionality of specialized axonal subcompartments requires the coordination of diverse cellular processes including AT, assembled and localized remodeling of the cytoskeleton, spatial restriction of signaling pathways, and recycling of old materials and defective MBOs, among many others. From various mechanisms that regulate proteins involved in the execution of these cellular processes, Baculis et al. suggests a potential mechanism linking neuronal activity to ERK1/2 kinases and levels of potassium Kv7.3 channels inserted at the AIS  to collectively modulate neuron-wide responses, including transduction of signals to the distant neuronal nuclei and the control of protein synthesis (Berth et al. discusses published work on the roles played by several protein kinases on specific molecular events supporting macroautophagy, a cellular process involving sequestration, packaging, and delivery of old and defective cellular components to lysosomes for degradation (Two manuscripts discuss both hypothesized and established roles of specific protein kinases in the regulation of cellular processes sustaining axonal health. ynthesis . In addiradation .Consistent with a critical role of kinases and phosphatases on axonal function, a large body of genetic and experimental evidence has linked alterations in their activities to axonal pathology, an early pathological signature common to most neurodegenerative disorders. Specifically, work from various experimental systems revealed that specific neuropathogenic proteins promote abnormal activation of selected axonal kinases and phosphatases, alterations in AT, and axonopathy (Brady and Morfini, Waller and Collins focuses on SARM1, an enzyme that acts as a sensor of metabolic stress and a critical component of pathways leading to axonal degeneration. These authors discuss findings supporting bi-directional regulation of axonal SARM1 and JNK kinases, as well as SARM1's ability to inhibit regeneration of injured axons through activation of the MAPK kinase ASK1 and its downstream effector kinase p38 (Baltissen et al. reports that a soluble fragment derived from proteolytic cleavage of the Alzheimer's disease-related protein APP ameliorates neuropathological features in a mouse model of a human tauopathy. Interestingly, this beneficial effect was associated with the inhibition of the kinase GSK3, which is aberrantly activated in this model and has been shown to inhibit anterograde AT (Morfini et al., Richards and Jaesnich hypothesizes a potential mechanism underlying axonal pathology and neurological complications associated with SARS-CoV-2 infection. This hypothesis is based on independent lines of experimental evidence showing that SARS-CoV-2 promotes the secretion of glial cytokines known to activate the kinases p38 and CK2, and reports show that active forms of these kinases inhibit AT by directly phosphorylating motor proteins (Morfini et al., A mini-review by nase p38 . In addiThe focus of this Research Topic is unique because it specifically features research on kinases, phosphatases, and phosphorylation-dephosphorylation-based mechanisms relevant to axonal function and pathology. Considering the rapid advance of methodologies for the study of kinases and phosphatases (White and Wolf-Yadlin, GM wrote the original draft. Both authors made substantial, direct, and intellectual contributions to the work. Both authors approved the final version of this Editorial for publication."}
+{"text": "The accumulated experience, both with typical and atypical children, led to the desire for an easier integration into the collective.Detecting and encouraging the skills of the atypical child, with the help of combined arts techniques and environmental stimulation, supports their\u2019s integration into the comunity.Beneficiaries-Centered Art therapy, with the aim of identifying and developing outstanding skills, trough environmental manipulation and combined arts techniquesThe environmental manipulation method is used in the art therapy session trough artistic installations and colorful fabrics. Trough chromatics and textures are generated different contexts and atmospheres sense, through which the atypical child comes to accept and discover that environment. Through the manipulation of artistic installations, gross motor skills are also required, having to produce large movements with the whole body, in order to shape the elements in the environment.Costume making as a transitional phase in the adaptation of the beneficiary to the previously created environment independently or together with the art therapist, consists in harmonizing the beneficiary with the environment. These stages are achieved through mixed techniques of artistic work, painting, decorating, modeling, collage, weaving and binding techniques.By practicing these methods during the art therapy sessions, the beneficiaries increased their self-esteem through the achievements they had and discovered and improved their outstanding skills: fine and gross motor skills, color sense, visual thinking, hand-eye coordination; improved and developed both verbal and non-verbal communication between beneficiary - art therapist and beneficiary - beneficiary, in the case of group sessionsImage:Image 2:Image 3:The role of the artist/Art-therapist can be to identify and encourage the creative potential of the beneficiaries by making both individual and team artworks; to support social integration through art and to value the outstanding skills of the beneficiaries.None Declared"}
+{"text": "Dear Editor,A one-year-old boy had erythematous-violaceous macules on the left lower limb and trunk since birth , associaThe investigation showed a normocephalic child, cervicothoracic scoliosis, posteriorly rotated ears, straight palpebral fissures, enlarged nasal base, retrognathia, flattened nasal philtrum, high palate, downturned oral commissures, and a palpable mass in the right epigastric region. He also had hemihypertrophy of limbs, enlarged hands and toes , and increased feet volume (left foot larger than the right one) with syndactyly between the second and the third and between the fourth and the fifth toes on the right. Vascular malformations were observed in the left lower limb, dorsum, thorax and genital region, besides linear epidermal nevus on the thorax. He had adequate neuropsychomotor development, without ocular alterations. The genetic analysis disclosed a male karyotype , with no qualitative or structural alterations.aProteus syndromebMaffucci SyndromecKlippel-Trenaunay-Weber syndromedMilroy DiseaseNamed in 1983 by Wiedmann et al.,The clinical manifestations are variable, with cases ranging from focal changes (isolated macrodactyly),The diagnosis of Proteus syndrome is based on clinical criteria, making it necessary to differentiate from other hamartoses, such as Klippel-Trenaunay-Weber and Maffucci syndromes .2Table 1Treatment is individualized and multidisciplinary, requiring a psychological and psychomotor evaluation when orthopedic and vascular surgical approaches are indicated. Oral inhibitors of the mTOR pathway (sirolimus 0.1\u202fmg/kg/d) have been reported to be effective in preventing the growth of connective tissue hamartomas.This child was followed by the dermatology, pediatrics, psychology, vascular surgery and orthopedics teams for 12 years. At the age of ten, he experienced a worsening of the gigantism of the lower limbs, leading to difficulty in walking and weight loss. The multidisciplinary team decided for a transtibial amputation of the right lower limb and a transfemoral amputation of the left lower limb.None declared.B\u00e1rbara Elias do Carmo Barbosa: Drafting of the manuscript; effective participation in research orientation; effective participation in propaedeutics; critical review of the literature; critical review of the manuscript; approval of the final version of the manuscript.Melissa Almeida Corr\u00eaa Alfredo: Drafting of the manuscript; effective participation in research orientation; effective participation in propaedeutics; critical review of the literature; critical review of the manuscript; approval of the final version of the manuscript.Luciana Patr\u00edcia Fernandes Abbade: Drafting of the manuscript; effective participation in research orientation; effective participation in propaedeutics; critical review of the literature; critical review of the manuscript; approval of the final version of the manuscript.H\u00e9lio Amante Miot: Drafting of the manuscript; effective participation in research orientation; effective participation in propaedeutics; critical review of the literature; critical review of the manuscript; approval of the final version of the manuscript.None declared."}
+{"text": "Berry fruits  contain a wide range of nutrients such as fiber, vitamins, minerals, and bioactive compounds such as (poly)phenols. Emerging scientific evidence supports their health-promoting potential against oxidative stress, inflammation, vascular dysfunction, and numerous metabolic dysregulations. However, most of the evidence derives from in vitro and animal models, while observations from human studies deserve further investigation. The Special Issue \u201cBerries and Human Health: Mechanisms and Evidence\u201d was open for submission of original research manuscripts focused on (i) dietary intervention studies exploring the role of berries and their (poly)phenols in the protection and promotion of human health; (ii) cell culture and animal studies devoted to evaluating the molecular mechanisms underpinning the modulation of metabolic and functional activities; (iii) systematic reviews and/or meta-analyses investigating the impact of berries in the modulation of risk factors and health outcome.This Special Issue features six contributions: two original articles ,2 and foRubus chamaemorus L.) attenuated the development of metabolic inflammation in a high-fat diet mouse model of obesity. Results showed that 6- and 12-week supplementation with cloudberry prevented the rise in the systemic inflammation marker serum amyloid A and the hepatic inflammation/injury marker alanine aminotransferase, as well as the increase in the expression of many inflammation-related genes in the liver and adipose tissue.The two articles focused on the anti-inflammatory effect of two different berries in animal models ,2. In deKim and coworkers  evaluateThe four reviews collected in the Special Issue cover different topics. The review by De Amicis and colleagues  focuses The remaining three reviews focus on the effects of berries on markers of cardio-metabolic health. Vendrame et al.  providedFinally, the review by Venturi and coworkers  summarizTaken together, results from the papers included in this Special Issue provide further evidence about the potential beneficial effects of berries on markers of human health, mostly related to cardiometabolic health and cognitive function. However, due to the heterogeneity of results found within studies, further evidence is needed to better elucidate the valuable role of the inclusion of berry fruits in the diet and the mechanisms that underpin such potential health effects."}
+{"text": "The Inaugural Monash International Health Science and Technology Conference (MONASH INITIATE), with the theme \u201cInspiring Innovation via Multidisciplinary Collaboration,\u201d held in the School of Pharmacy of the Monash University Malaysia on 16th\u201317th June, 2021. The conference attracted over 100 local and international attendees with participation from Malaysian and foreign universities, research institutions and industry partners.The Research Topic aims to gather selected pharmacology-focused contributions to, The Research Topic compiles five high-quality review articles contributed by scientists in the field. The Research Topic of these publications revolve around cancer therapy, the traditional uses of medicinal plants, and the molecular mechanisms of phytochemicals in anticancer applications. These articles provide comprehensive overviews of the current research and knowledge in drug delivery and natural products-based drug discovery areas.Miatmoko et al., outlines the delivery of Ursolic acid by nano particles, namely, liposomes, nanospheres and polymeric micelles in cancer therapy. The authors highlighted that nanoparticles in particular are effective in improving relative survival rate; reducing tumor resistance, and improving tumor tissue histopathology. They are safe to be used preclinically and clinically, and it is worth noting that the use of liposome delivery of ursolic acid is in a phase 1 clinical trial.A scoping review article by Arbain et al., discussed the distribution, traditional uses, phytochemicals and biological activities of 96 species of Alocasia. The genus is distributed across Asia, Southeast Asia and Australia. Phytochemicals from the genus of the plants can be categorized into lignan, saponin, alkaloids, and phenolic compounds. Despite demonstrating numerous biological activities, including antidiabetic, antinoceptive, antiinflammation effects, the author highlighted the compound alocasgenoside B from A. cucullata tuber was potently cytotoxic to the cancer cells in-vitro.The systematic review article by Khuayjarernpanishk et al., outlined the anticancer activities of Polygonum odoratum Lour. The review highlighted eight anticancer studies from the phytochemicals of Polygonum odoratum including Flavanoids, tannins, and saponins. A range of cancer cell lines was screened and their anticancer activity reported against oral, lung, breast, colon, liver, T lymphoblast, lymphoma, and leukemia cells. The mechanistic study was reported, and included the inhibition of Akt expression, phosphorylated Akt, mTOR, and phosphorylated mTOR. The authors also identified the gaps and limitations in the current research that warrants future study, including the discovery and identification of different classes of phytochemicals as well as informed in-vivo studies.A systematic review by Yang et al., focuses on the mechanism of action of Scutellaria barbata on hepatocellular carcinoma. A rather systematic multi-step investigation biodiscovery approach was utilized in this study. Initially, the active components of Scutellaria barbata were identified using a database of traditional Chinese medicine compounds. Then, the potential targets of these active components were predicted using network pharmacology tools. Following that, the hepatocellular carcinoma related genes were collected from various databases, and the overlapping targets between Scutellaria barbata and hepatocellular carcinoma related genes were identified. Further analysis was conducted to explore the potential biological functions and pathways involved in the interactions between Scutellaria barbata and hepatocellular carcinoma. Eventually, the effect of Scutellaria barbata, a widely used medicinal herb in traditional Chinese medicine, was found to exert modulation of various signaling pathways, such as the PI3K/AKT, MAPK, and NF-\u03baB pathways in hepatocellular carcinoma.Meanwhile, Liang et al., reviews current literature on the anticancer applications of phytochemicals in gastric cancer. It summarizes the effects of different phytochemicals, such as flavonoids, phenolic compounds, alkaloids, and terpenoids, on gastric cancer cells in laboratory settings and animal models. Various mechanism of actions associated with the anticancer effect were detailed, including inhibiting cancer cell proliferation, inducing apoptosis (programmed cell death) in cancer cells, suppressing angiogenesis (formation of new blood vessels that supply tumors), inhibiting metastasis (spread of cancer to other parts of the body), and modulating signaling pathways involved in cancer development and progression. The article articulates the potential synergistic effects of combining different phytochemicals or combining phytochemicals with conventional chemotherapy or radiotherapy in the treatment of gastric cancer. It also emphasized a discussion on safety and bioavailability of phytochemicals, and their potential use as adjuvants to conventional therapies in gastric cancer patients.Finally, These publications provide valuable insights into the current research on cancer therapy which exploit the traditional uses of medicinal plants, nanoparticles, and the potential integration of network pharmacology methodology in identifying bioactive(s) and the elucidation of their molecular mechanism actions in cancer treatment. These publications contribute to the understanding of these fields and may serve as references for further research and development of novel cancer therapies. The editorial team would like to express gratitude to the review editors, reviewers, and authors for their contribution to this Research Topic. The editorial team is looking forward to having interested researchers participate in the forthcoming Monash INITIATE 2023 on 25th\u201326th October 2023 at Monash University Malaysia."}
+{"text": "Glioma is a rapidly growing and aggressive primary malignant tumor of the central nervous system that can diffusely invade the brain tissue around, and the prognosis of patients is not significantly improved by traditional treatments. One of the most general posttranslational modifications of proteins is glycosylation, and the abnormal distribution of this modification in gliomas may shed light on how it affects biological behaviors of glioma cells, including proliferation, migration, and invasion, which may be produced by regulating protein function, cell\u2014matrix and cell\u2012cell interactions, and affecting receptor downstream pathways. In this paper, from the perspective of regulating protein glycosylation changes and abnormal expression of glycosylation-related proteins (such as glycosyltransferases in gliomas), we summarize how glycosylation may play a crucial role in the discovery of novel biomarkers and new targeted treatment options for gliomas. Overall, the mechanistic basis of abnormal glycosylation affecting glioma progression remains to be more widely and deeply explored, which not only helps to inspire researchers to further explore related diagnostic and prognostic markers but also provides ideas for discovering effective treatment strategies and improving glioma patient survival and prognosis. Glioma is among the most frequently occurring primary brain tumors and accounts for \u223c80% of primary malignancies in the central nervous system (CNS) . NumerouAlthough studies regarding the impact of DNA mutations on tumor progression provide genetic insights into cancer biology, the crucial role of epigenetic alterations in the development and treatment response of gliomas has recently attracted much attention \u20136. ProteIn the following work, we first describe the current understanding of glycosylation modifications, including N-linked glycosylation and O-linked glycosylation, sialylation, and fucosylation, and their implications for the progression of neoplastic diseases. Apart from summarizing the emerging evidence for glycosylation in glioma, we talk about how aberrant glycosylation mechanism is correlated with the proliferation and migration of glioma. Considering glycosylation alterations and the aberrant expression of glycosylation-associated enzymes  in glioma, potential biomarkers and therapeutic targets are finally discussed. This review aims to yield a profound understanding of how abnormal glycosylation conduces to the proliferation, invasion and metastasis of glioma and to inspire novel strategies utilizing these changes in the advancement of biomarkers and targeted therapy.At present, many kinds of glycosylation process have been identified in mammalian species. In this paper, N-linked and O-linked glycosylation are mainly discussed according to the classification of linkage relationships between oligosaccharides. In addition, sialylation and fucosylation can be added to both and are also included. These glycosylation patterns are closely associated with glioma progression.N-linked glycosylation is one of the most general synergistic/posttranslational modification in eukaryotes; that is, oligosaccharides attach to nascent proteins by forming N-glycosyl bonds between monosaccharides and asparagine residues of the consensus sequence Asn-X-Ser/Thr/Cys, which has a profound impact on protein folding, oligomerization, quality control, and physiological function , 12.2. (ii) Under the replacement of Alg1, Alg2 and Alg11 mannosyltransferases (MTases), . I. I96]. Ima cells .Glycosylation is also the research direction of glioma treatment strategy because it can promote the drug delivery process, affect the interaction in targeted therapy and improve the stability of targeted drug delivery during the treatment. For example, human bone marrow mesenchymal stem cells (BM-hMSCs) have unique characteristics, including the ability to migrate or home and transplant into GBM, and have been investigated for therapeutic delivery in GBM, while their entry into tissues is largely dependent on glycosylation of glycan-glycans and glycan-protein adhesions between cells and the endothelium. It has been demonstrated that glycan composition differs between tissues causing homing of BM-hMSCs and tissues hindering BM-hMSCs in preclinical glioma stem cell xenograft (GSCX) models of GBM . In anotMultiomics analyses, such as TCGA and the Repository for Molecular Brain Tumor Data Repository (REMBRANDT), have revealed many cancer-related potential molecular targets, and the application of these successful personalized medicine approaching in other cancers is often unsatisfactory in gliomas . For exaThe application of glycosylation in glioma treatment strategies is discussed from the perspectives of glycosylation inhibitors, expression changes in glycosylation-related enzymes, promotion of drug delivery and targeted therapy, and potential molecular targets. In view of the link between abnormal glycosylation and the malignant behavior of glioma, the current research on glycosylation-related strategies is multifaceted and not limited to the four categories above. For example, Wen et al. tried to disrupt the interaction between neuron glial antigen 2 (NG2) chondroitin sulfate proteoglycan and galectin-3 to reduce glioma cell invasiveness, while N-linked glycosylation of NG2/D3 (D3 domain of NG2 core protein) was crucial in the interaction between the two . StudiesOverall, this article focuses on the evidence for aberrant glycosylation in glioma and its impact on tumor progression, related biomarkers and targeted therapeutic strategies. First, we summarized the research evidence that confirmed abnormal glycosylation in glioma cells and extracellular matrix based on the classification and specific process of glycosylation. Then, we investigated the specific mechanism of abnormal glycosylation affecting glioma progression from the perspectives of regulating protein function, affecting cell\u2012cell interactions, and triggering receptor downstream pathways. Its effects include promoting glioma cell proliferation, migration, and invasion, thereby enhancing the malignant characteristics of glioma. Finally, we discuss the utility of aberrant glycosylation in biomarkers and targeted therapies. In terms of markers, from the occurrence of altered protein glycosylation and abnormal expression of glycation-related proteins  in gliomas, some proteins are expected to give some enlightenment for the advancement of novel diagnostic or prognostic biomarkers. In terms of treatment, this article discusses glycosylation inhibitors, regulation of glycosylation-related enzyme expression, promotion of drug delivery and targeting, and other targeted strategies and related targets. Although the current research on glycosylation and gliomas has involved many aspects and multiple angles, this topic needs to be more deeply explored compared with similar studies on other malignancies. For example, it is also necessary to enhance our thinking and understanding of (i) specific pathways downstream of receptors triggered by abnormal glycosylation; (ii) the link between glycosylation and glioma immunosuppression and evasion; (iii) how to apply the conjecture of glycosylation-related treatment strategies mentioned above to clinical practice; and (iv) how to break through tumor heterogeneity, signaling pathway redundancy and the blood\u2012brain barrier and strengthen the thinking and understanding of glycosylation-related glioma treatment and prognosis. With the development of data science, the existing glycosylation databases such as OGT-PIN and NetNGlyc can help the prediction of O-linked glycosylation and N-linked glycosylation modification sites respectively , 165. So"}
+{"text": "The intention of this Special Issue is to highlight the peculiarities of low-intensity/low-concentration exposures for organisms and to examine the molecular mechanisms of the organismal responses.Low-intensity exposures are the most unexplored field of modern molecular toxicology. A lack of knowledge on the mechanisms of low-intensive factors causes problems in (1) the prediction of biological effects, (2) overcoming negative consequences, and (3) the application of positive results. Therefore, the analysis of low impacts is topical from both fundamental and applied standpoints, particularly important for ecology, biology, and medicine.Studies of the biological effects of low-dose exposures have been conducted since the 1960s ,3. ModerStudies of biological responses to various bioactive compounds and the radiation of different types under the conditions of low-intensity exposures were encouraged in this Special Issue. A chemical and biochemical basis for these responses was of interest. The results presented contribute to understanding the molecular mechanism of \u201chormetic\u201d responses to low concentrations of bioactive compounds and low-intensity radioactivity. One of the findings of this Special Issue is that the time of low-intensity exposure is a critical parameter in hormetic responses, along with the dose and type of active compounds . SimilarThe biomedical aspect of low-intensity exposure is the most evident in the papers published in the Special Issue. For example, antimicrobial, anti-inflammatory, and tissue-stimulating effects of cold argon atmospheric plasma (CAAP) accelerate its use in various fields of medicine. Ermakov and coworkers  investigThe work of Hanson and coworkers  focuses Kovel  and SushThe advantages of bacterial bioluminescent bioassays were applied while studying the bioactivity of iron oxide nanoparticles  and diffUnder the conditions of model oxidative stress, the bacterial bioassay revealed prooxidant activity, with a corresponding decay in the content of reactive oxygen species . The resThe review by Kolesnik and coauthors  focused As an outline, the current Special Issue combined successfully research works which elucidated the molecular mechanisms of organismal low-dose/low-intensity responses to different physico-chemical factors, such as cold argon atmospheric plasma, low-dose radiation, and nanomaterials of different structures."}
+{"text": "Neurometabolic imaging is the study and measurement of neurometabolic activity in the brain using various imaging methods. It is an important field of neuroimaging that has been widely employed in clinical research. Emission computed tomography and fMRI  are among the methods used. Because of the benefits of non-invasive, non-radiation, and reproducible scanning, fMRI remains the primary imaging tool for the investigation of neurometabolism. This Research Topic contains a collection of papers on the application of neurometabolism-related fMRI methods to clinical disorders, intending to summarize research accomplishments in the field of neurometabolic imaging and probable future paths of development.Wu et al. used 1H-MRS (proton magnetic resonance spectroscopy) technology in conjunction with the Mescher-Garwood point resolved spectroscopy sequence to detect metabolite levels in the brain of MRI-negative temporal lobe epilepsy (TLE) patients and discovered \u03b3-Aminobutyric acid to be a potential biomarker for lateralization and monitoring the frequency of epileptic seizures in TLE patients in this Research Topic. However, MRS has long had drawbacks such as low spatial resolution and signal-to-noise ratio, as well as limited resolution of overlapping peaks, whereas chemical exchange saturation transfer imaging, a newer noninvasive method for characterization and quantification of intracerebral metabolites, has high sensitivity and spatial resolution. Zheng H. et al. discovered that the GluCEST  technique was able to identify brain biochemical changes after acute carbon monoxide poisoning earlier than conventional MRI, and that the CEST technique might be able to compensate for the shortcomings of MRS to some extent. Lin et al. used 1H-MRS combined with the GluCEST technique to evaluate the condition and prognosis of patients with acute bilirubin encephalopathy, and discovered that the combination of the two could monitor metabolite levels in the patients' brains and assess the severity of the disease. In a multimodal magnetic resonance study of patients with bipolar disorder and depression, Kong et al. combined 1H-MRS, GluCEST, and diffusion kurtosis imaging techniques and discovered that the combination of multiple techniques helped to differentiate between these two disorders. Multimodal magnetic resonance methods will remain appealing and beneficial in the future as one of the avenues of advancement in neurometabolic imaging research.Magnetic resonance spectroscopy is a well-established method for quantifying metabolite concentrations in the brain. ex (proton exchange rate) MRI  technique. DTI-ALPS is a new technique capable of quantitatively measuring the function of the lymphoid system proposed by Taoka et al. (On the other hand, the invention and refining of novel neurometabolic imaging methods are equally important research avenues. By investigating whether CEST-based ka et al. , and whia et al. , for exaIn conclusion, this Research Topic article enumerates the use of various types of neurometabolic imaging technologies in clinical research, emphasizes that the cross-use of different technologies and the advancement of new technology development can help to broaden the research space and improve the credibility of experiments, and enumerates the prospects for the use of corresponding technologies in various types of diseases. It serves as a resource for understanding the advancement of neurometabolic imaging techniques and directing future research.WZ: Data curation, Project administration, Writing\u2014original draft, Writing\u2014review and editing. ZD: Project administration, Writing\u2014review and editing. RW: Conceptualization, Project administration, Supervision, Writing\u2014review and editing. HS: Project administration, Writing\u2014review and editing."}
+{"text": "Novel Therapeutic Approaches to Treat Neuroinflammation in the CNS as a Research Topic for Frontiers in Pharmacology. The topic is focused on neuroinflammation as a marker of multiple pathological conditions. Studies on the mechanisms associated with CNS-centered inflammation provide us with the knowledge to design safer and more effective therapeutics for treating various diseases.We are excited to present Hou et al. on the in vivo effect of Chinese Dodder seed, a medicinal plant, on the gut-neuroinflammation axis. The study uses a chronic unpredictable stress-induced depression model in mice to assess the effect of plant-derived compounds on multiple markers of inflammation, including proinflammatory cytokines, inflammatory proteins, and microglia activation. The observed anti-inflammatory effects were correlated with the changes in the gut microbiota of treated animals. Finally, Hou et al. stated the importance of the combination effects of chlorogenic acid and hypercin, the main constituents of this plant extract, on the in vivo outcomes.Our issue begins with an original research paper by Zhang et al. report the effect of levetiracetam, an antiepileptic drug, on the cognitive function of diabetic rats. Using the streptozotocin-induced diabetes model, the authors observed dose-dependent enhancement of cognitive function and hippocampus morphology of treated rats, as well as inhibition in microglia activation and CNS inflammation levels. This novel work is the first to report the ability of FDA-approved levetiracetam to prevent microglia polarization and induce mitochondrial M2 transformation as part of the cognitive impairment treatment strategy.The interplay between metabolic diseases and immune responses, immunometabolic responses, is a significant factor that defines clinical representation and treatment outcomes for multiple disorders, including diabetes and obesity. Further, microglia activation in animals has been linked with neuronal injury and cognitive impairment, possibly explaining higher risks of cognitive dysfunction in patients with diabetes. Lullau et al. have shown that multifaceted actions of this polypharmacological CNS agent result in a rapid and potent reduction of depression symptoms, increased stress resilience, and reversal of stress-induced dysfunctions.In the comprehensive review by a Norway team of scientists, the potential role of ketamine in the treatment of resistant cases of depression disorders has been assessed from multiple aspects, including neuroinflammation, neurotoxicity, and neurodegeneration. Archie et al. looking at the bases of postnatal neuroinflammation associated with prenatal e-sig exposure. The data conclusively show high levels of oxidative stress and mitochondrial dysfunction in pups of CD1 mice exposed to the e-cig vapor with 2.4% nicotine. In addition, higher levels of neuronal injury markers were observed in the postnatal brain, linking this publication to the previous work by this research team on the deterioration of motor, learning, and memory function in e-cig-exposed animals. These data warrant extensive studies on the effect of vaping in pregnant women on the levels and longitude of neuronal injury in neonates.Our issue is concluded with the original research article by Novel Therapeutic Approaches to Treat Neuroinflammation in the CNS\u201d provides recent advances in the deconvoluting mechanisms involved in this pathological process and identifying effective therapeutic strategies for the corresponding treatments. We acknowledge the contributions of all authors to make this research volume possible.Taken together, the issue of this Research Topic: \u201c"}
+{"text": "Editorial on the Research TopicEducation and learning for digital healthEducation and Learning for Digital Health sparks novel thinking and insights into how and why health professionals learn to use emerging technologies. The Research Topic builds on established educational practices and associated works of literature on e-learning, blended learning, immersive virtual reality, digital simulations, and virtual patients. See for example the Frontiers Research Topic, Advancing Teaching and Learning in Health Sciences Across Healthcare Professionals. Many robust educational resources and tools for digital health have been developed, including Health Education England's e-learning for health (https://www.e-lfh.org.uk/). The COVID-19 pandemic impelled further innovation in health professionals\u2019 online learning as education providers worked tirelessly to avoid disruption to learning, as captured in the Frontiers Research Topic, Impact of COVID-19 on Healthcare Professions Education.At a time of rapid digital innovation, the Research Topic, 17 world-leading clinicians, researchers, and educators from Australia, Canada, the United States, and the Republic of Ireland, together with the expertise of article editors and peer reviewers from Finland, Netherlands, Ireland, Australia, the United Kingdom, United States, and Canada, advance the scientific paradigm of the discipline in four specific areas:\u2022Health professionals learning to adapt and use virtual care (VC)\u2022Digital professionalism in the use of smartphone technologies\u2022Preparing medical students to use artificial intelligence (AI) and machine learning (ML)\u2022Safe use of virtual reality (VR) technologies in professional educationIt is significant that the international collaborations, studies, and articles on this Research Topic were all produced during the pandemic. In effect, this context ignited digital health by necessity in order to maintain clinical care during social distancing and infection control protocols, while safeguarding human rights and preserving the ethics of healthcare.The articles in this Research Topic, which have been produced by Virtual Care and COVID-19: A Survey Study of Adoption, Satisfaction, and Continuing Education Preferences of Healthcare Providers in Newfoundland and Labrador, Canada, provides insights into healthcare providers\u2019 experiences during the unfolding pandemic. It demonstrates that not all VC methods were perceived to deliver the same quality of care that would be expected in traditional face-to-face clinical encounters, but there can be other advantages for maintaining virtual proximity to patients whilst minimising the risk of infection transfer. As a result, the authors recommend healthcare provider organisations ensure VC is backed up with Continuing Professional Development (CPD), guidelines, and resources including patient educational support.For example, in the first article, authors Vernon Curran, Ann Hollett, and Emily Peddle explain how the use of virtual care, such as virtual examinations, clinical assessments, and remote patient monitoring, expanded during COVID-19 to enable continued access to healthcare. Their survey study, Smartphone Technology for Clinical Communication in the COVID-19 Era: A Commentary on the Concerning Trends in Data Compliance. They argue that smartphone technologies afforded clinicians and patients many observed advantages during COVID-19, yet the long-term use of such devices needs to be compliant with protecting patient data security and privacy. Solutions offered include healthcare institutional guidelines, supportive digital professionalism training, and education opportunities.The second article focuses on the legal and ethical dimensions of smartphone technology. From the Republic of Ireland, Bernadette John, Christine McCreary, and Anthony Roberts authored The Desire of Medical Students to Integrate Artificial Intelligence Into Medical Education: An Opinion Article. They draw on their wealth of experience in precision medicine, drug discovery, diagnostics, and hospital administration to argue that the advancement of AI and machine learning algorithms are reshaping the way physicians and healthcare providers approach the practice of medicine. They call for medical schools across the world to take up their essential educational role to ensure that changes to healthcare are for the better and that future physicians will be more competent, inventive, and compassionate in the medicine of tomorrow.The authors of the third article in this Research Topic suggest that changes to support future healthcare should begin in medical schools. From the United States, authors Timothy Frommeyer, Reid Fursmidt, Michael Gilbert, and Ean Bett elaborate on Innovation During a Pandemic: Developing a Guideline for Infection Prevention and Control to Support Education Through Virtual Reality. Their article focuses on virtual reality as an educational technology with the ability to deliver flexible and immersive education. Their attention to safe infection control practices of VR head-worn display systems is ensuring safer transfer between clinicians.The fourth article considers how, alongside changes in curricula content, advanced technologies are changing the modes of education delivery to provide digitally enhanced learning experiences. From Australia, authors Nathan Moore, Kathy Dempsey, Peter Hockey, Susan Jain, Philip Poronnik, Ramon Shaban, and Naseem Ahmadpour explain their work on The insights from these articles show that education and learning for digital health need to address a growing range of patient rights, professional practice, and governance issues. The issues extend from the level of individual practitioner's use of technologies protecting patient confidentiality; to institutional policies, data licencing, copyright agreements, and intellectual property rights; to whole health system design and regulation of digital health technologies; as well as raising public awareness and trust in such advances .The Good Side of Technology: How We Can Harness the Positive Potential of Digital Technology to Maximize Well-being. The design and use of advanced technologies in healthcare are increasingly looking beyond hybrid and \u201chuman in the loop\u201d models towards the symbiosis of human-AI intelligent caring in healthcare design, resourcing, evaluation, and improvement (Looking to the future, it is through the combination of education and learning in humans and machines that new knowledge will gain the greatest power to maximise well-being, as explored in the related Frontiers Research Topic, rovement . This nerovement  reinforcrovement . The iderovement  takes thThe present innovative digital health landscape creates an opportunity to rapidly advance human-AI intelligent caring through enhanced educational curricula and transformative learning experiences ("}
+{"text": "The worldwide spread of the COVID-19 pandemic affected all major sectors, including higher education. The measures to contain this deadly disease led to the closure of universities across the globe, introducing several changes in students\u2019 academic and social experience. During the last two years, self-isolation together with the difficulties linked to online teaching and learning, have amplified psychological burden and mental health vulnerability of students.We aimed to explore in depth students\u2019 feelings and perspectives regarding the impact of the COVID-19 on their mental health and to compare these data among students from Italy and the UK.Data were resulting from the qualitative arm of \u201cthe CAMPUS study\u201d, a large ongoing project to longitudinally assess the mental health of university students enrolled at the University of Milano-Bicocca  and the University of Surrey . We conducted in-depth interviews through the Microsoft Teams online platform between September 2021 and April 2022, and thematically analysed the transcripts.A total of 33 students (15 for Unimib and 18 for UoS), with a wide range of sociodemographic characteristics, were interviewed. Four themes were identified: i) impact of COVID-19 on students\u2019 mental health; ii) causes of poor mental health; iii) most vulnerable subgroups; vi) coping strategies.Anxiety symptoms, social anxiety, and stress were frequently reported as negative effects of the pandemic, while the main sources of poor mental health were identified in loneliness, exceeding time online, unhealthy management of space and time, bad organization/communication with university, low motivation and uncertainty about the future. Freshers, international or off-campus students, as well as both extremely extroverted and introverted subjects, represented the most vulnerable populations, because of their extensive exposure to loneliness. Among coping strategies, the opportunity to take time for yourself, family support, and mental health support were common in the sample.Some differences were found comparing students from Italy and the UK. While at Unimib the impact of COVID-19 on mental health was mainly described in relation to academic worries and the inadequate organization of the university system, UoS students, familiar to the conviviality of campus life, explained these effects as a result of the drastic loss of social connectedness.The current study highlights the key role of mental health support for university students, mainly during crisis times, and calls for measures to improve communication between students and the educational institution, as well as to encourage social connectedness.None Declared"}
+{"text": "Editorial on the Research TopicEfficacy, safety and biomarkers of novel therapeutics and regimens in the peri-operative setting of bone and soft tissue sarcomaRecent strides in the field of oncology have witnessed new advances and hope for patients with bone and soft tissue sarcomas. This research topic explores the evolving landscape of novel therapeutics and regimens in the peri-operative setting, highlighting their efficacy, safety, and the role of biomarkers in guiding treatment decisions for treating these rare diseases.The paradigm shift from amputation to limb salvage surgery seen 3 decades ago reflects the emergence of peri-operative chemotherapy and the understanding of tumor biology of sarcoma by sarcoma surgeons and tremendously impacts the treatment regimens of sarcoma . SimilarLi et al.), the early experience of implementing cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal malignancies , the safety and risk factors of chest wall malignant tumor as well as the clinicopathological features of giant cell hemangioblastoma . These results have greatly improved our therapeutic armamentarium against bone and soft tissue sarcoma in the peri-operative stage.In this research topic, four exciting studies are focusing on various aspects of biomarkers and multimodal therapies for bone and soft tissue sarcoma, including a machine learning algorithm to predict the metastasis of osteosarcoma (While these studies provide novel insights to the landscape of sarcoma management, further research encompassing genetic alterations, gene expression patterns, and immune signatures is needed to be incorporated into the treatment regimens and the selection of appropriate therapies at the molecular level. Advancements in genomic sequencing, transcriptomics, and proteomics have facilitated the identification of potential biomarkers, paving the way for the development of such personalized treatment approaches. For example, preoperative therapies, including neoadjuvant chemo-radiation  and otheWhile progress in sarcoma research fuels optimism, challenges remain on the path toward widespread implementation of these innovations. Combining targeted therapies into the peri-operative setting poses a threat of increasing post-surgery complications . AdditioIn conclusion, recent advancements in the efficacy, safety, and biomarkers of novel therapeutics and treatment regimens have infused the peri-operative management of bone and soft tissue sarcomas. The journey toward personalized medicine, guided by the intricate interplay of oncology practice and translational research, offers new avenues for improved patient outcomes. Continued collaboration among clinicians, researchers, and industry stakeholders is essential to surmount these challenges."}
+{"text": "In May 2022, an unprecedented global outbreak of mpox emerged,Therefore, the Director-General of WHO concurred that the outbreak remained a Public Health Emergency of International Concern. WHO advised Member States to strengthen key areas of readiness and response to stop the outbreak, and to strive towards mpox elimination or control based on specific epidemiological contexts.First, as countries monitor the outbreak and develop elimination and control plans, surveillance must be sustained and strengthened. As the number of reported mpox cases continues to decline globally, all Member States should sustain national surveillance for suspected cases and continue to report confirmed and probable cases and deaths.,Second, integrate mpox surveillance, detection, prevention and care into primary care and sexual health services. Among mpox cases with known human immunodeficiency virus (HIV) status, approximately half are living with HIV, and advanced infection is an important risk factor for severe complications and death related to mpox.Third, enhance global commitment and cooperation to facilitate equitable access to diagnostics, vaccines and therapeutics. The mpox outbreak has again highlighted global inequities as vulnerable populations, ethnic minorities and persons living in low-income countries continue to face barriers to care.Fourth, strengthen and support capacity in resource-constrained settings, including for One Health approaches and for research at the animal-human interface, where zoonotic spillover is known or suspected to occur. Understanding of animal reservoirs and transmission to humans remains limited. Identifying factors that contribute to amplification of outbreaks or extended chains of transmission is also critical. Improving multisectoral collaboration to address socioeconomic and behavioural risk factors will support research to characterize animal-to-human and human-to-human transmission in different contexts.Fifth, implement a strategic and coordinated research agenda to ensure ongoing evidence generation. Strategic areas of focus include: investigating the origins of monkeypox virus; characterizing epidemiology and dynamics of viral transmission including for the global outbreak of clade IIb.B.1, which has never been found in animals;To achieve these goals, WHO will propose a global strategy for mpox elimination and control and approaches to support countries in all regions to develop their own integrated plans. This dual approach will help countries set clear targets for stopping human-to-human transmission; maintain high-quality indicator-based surveillance and event-based monitoring; support broader efforts towards epidemic and pandemic preparedness; and ensure adaptation of public health and communication strategies for specific contexts and groups at risk, particularly where mixed modes of transmission are observed.We have the tools to end this outbreak and ensure elimination of human-to-human transmission and ongoing control of mpox. To do this, the global health community must come together and invest in the key areas highlighted."}
+{"text": "The COVID-19 pandemic has heavily influenced the teaching and practical training required for students enrolled in health sciences courses globally both at undergraduate, graduate and postgraduate levels. This public health threat has impacted not only the formation of physicians, dentists, pharmacists, nurses and midwives but of all healthcare professionals, mainly due to the cancellation of clinical clerkships and the transition of on-site to online education . HoweverEuropean Journal of Investigation in Health, Psychology and Education. Thus, it is beyond doubt that a Special Issue dedicated to the COVID-19 pandemic was warranted in the Health Sciences before, during and after the COVID-19 Pandemic, we explored relevant topics regarding the impact of the SARS-CoV-2 pandemic on  education, as well as highlighted the results of research endeavors that thrived during this period of isolation. Following a thorough external peer-review, five papers were accepted for publication in this Special Issue: two original articles, one brief report and two systematic reviews .Herein, in the Special Issue In their cross-sectional study, Rogowska and Meres assessed the crosstalk established between job and life satisfaction and emotional intelligence. Their investigation enrolled over 300 subjects, consisting mainly of primary and secondary school teachers and pinpointed that emotional intelligence predicts both life and job satisfaction. In addition, they demonstrated that job satisfaction predicts life satisfaction, concluding that job satisfaction emerges as a mediator in the crosstalk of emotional intelligence and life satisfaction .Nash evaluated the potential role of doodling in the evaluation of burnout in healthcare researchers who experienced anxiety and/or depression related to their workplace activities. The investigator compared in-person pre-pandemic versus online meetings during the COVID-19 pandemic and pointed out that individuals who partook in these mindfulness activities were more likely to feel relaxed when doodling during in-person meetings, possibly because there was more interaction between participants during physical meetings .Tanoubi et al. explored the benefits of simulation-based education in the training of dental surgeons in procedural sedation and the management of related complications by means of theoretical and practical applications. A total of 16 Canadian dentists with expertise in oral and maxillofacial surgery were trained in anesthesia techniques and crisis resource management using simulation-based clinical scenarios. The authors argue for a need for sedation training for dental surgeons engaging in oromaxillofacial interventions .As the COVID-19 pandemic has mostly impacted the production of original research, researchers worldwide have focused on the production of narrative or systematic reviews, as well as meta-analyses, two of which have been published in this Special Issue.In their systematic review, Tsagkaris et al. investigated the applications of infrared radiation techniques in the management of musculoskeletal conditions: knee osteoarthritis, fibromyalgia, chronic low back pain, chronic myofascial syndrome, sacroiliitis and Gulf War Illness. Based on their findings, infrared radiation has been successfully applied in the therapeutic approach of knee osteoarthritis, fibromyalgia and chronic myofascial syndrome .In addition, Moysidis et al. explored the interplay between polycystic ovary syndrome and atrial fibrillation based on the data derived from electrocardiographic and echocardiographic studies. Their findings reflect that polycystic ovary syndrome is characterized by abnormal atrial conduction, as the meta-analysis point out that there is a prolonged maximum P-wave duration, an increased P-wave dispersion, increased echocardiographic measurements of atrial electromechanical delay, as well as altered electromechanical coupling parameters in the aforementioned endocrine disorder .In conclusion, the present Special Issue provides an overview of several aspects of the impact of the COVID-19 pandemic on health sciences, and also allows for the publication of several high-quality papers."}
+{"text": "In many respects, the continent of Africa is undergoing multiple transitions of which the nutrition transition is the most prominent\u2014from a public health perspective. Popkin et al.  define nWhile the papers included in this Research Topic do not cover the current COVID-19 pandemic, the Russia-Ukraine war, and other global crises such as climate change, the impact of these crises on the food environments, food availability, food prices, food affordability, and food security is real , 5. The However, our current understanding of the dynamics of the rapidly transitioning African food environments is limited. While hunger and food insecurity still persist, other forms of malnutrition such as obesity and related NCDs have emerged. Toward addressing malnutrition in all its forms, improving food environments in Africa is an urgent priority. Data-driven approaches, fit-for-local policies and actions and responding to all forms of malnutrition are needed. Fit-for-local purpose data can give insights into which policies may be more effective in combating the multiple forms of malnutrition in Africa. This Research Topic on African Food Environments aimed to solicit practice-impacting and policy-influencing evidence from researchers and practitioners working on the African food environments. It comprises a collection of nine papers from six African countries\u2014eight empiric studies, and a review.Mahopo et al.) and examined the nexus between food security indicators and anthropometric health. The authors identified opportunities for improving the food environments of a rural South African setting through the implementation of government policies that target street vendors. The authors recommended that, government in partnership with non-state actors deliver such interventions as training and microfinance to improve the business skills of street food vendors while promoting food safety and nutritious foods. Harper et al. estimated the prevalence of double burden of malnutrition in select South African households, and showed that about 70.2% of all stunted children lived with an overweight or obese adult.Two studies from South Africa characterized the operations of the street food enterprises . Only about 10% of the School Meal Programs identified overweight/obesity prevention as an objective. As Africa becomes increasingly urbanized, with transitioning dietary practices that favor processed foods, high in salt, high in sugar, high in unhealthy fat foods with limited consumption of fruits and vegetables but  from the 2019 Global Survey of School Meal Programs, bles but , policy The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.ALaa: conceptualization and writing of first draft. KB, FZ, GA, and ALar: reviewing and editing of first and final drafts. All authors contributed to the article and approved the submitted version."}
+{"text": "From the first appearance of Red Bull (RB) on the market in 1987  for the developing brain of adolescents and the medical and socio-legal standpoints on this EDs association.Petribu et al. analyzed several studies reporting that the acute or chronic AMED consumption, enhanced the alcohol intake and his motivational value, dose-dependently stimulated locomotion, and deteriorated movements capability. AMED intake time-dependently reduced anxiety, and a wide variety of effects on memory have been reported. The acute administration of AMED did not modify alcohol metabolism, but after its chronic assumption, blood alcohol concentrations were higher or lower than those of the alcohol-only group depending on the paradigm used. A comparable range of effects has been described about metabolic dysfunction. AMED intake produced an increase of pro-inflammatory cytokines, created oxidative stress and lipid peroxidation, but also in this case the results obtained depend on the protocol used. Briefly, AMED produces different outcomes depending on the amount of alcohol and EDs and the age, sex, and line of animals used.Sefen et al. addressed this issue and reported that the stimulatory properties of caffeine reduce the sedative effects of alcohol, making individuals more inclined to consume higher amount of alcohol -as they do not perceive the feeling of drunkness- and promoting risk-taking behavior. The increase of AMED drinking can be explained through activation on adenosine A2A receptors, which reduces alcohol intake , adenosine modulates immature synapses (Jeong et al., final cortical maturation (Serdar et al., Purines are involved in the refinement of several processes during the development of the brain, in particular in its growing architecture (Rodrigues et al., Sefen et al. on the regulation of AMED around the world can help the scientific community and influence public opinion and regulatory agencies to reflect on the need to regulate the sale and the consumption of EDs and AMED. In this regard, we foresee that the articles presented in this Research Topic provide a view of current preclinical and clinical studies in the field and allow new insights into the effects of AMED consumption on human health.Finally, the original report by VB wrote the article. EA, LD, MC, and JS critically revised and approved the final version of the manuscript. All authors contributed to the article and approved the submitted version."}
+{"text": "Acute coronary syndrome (ACS) and venous thromboembolism (VTE) are costly conditions, largely due to the high initial cost of treatment, patient nonadherence to prescribed antiplatelet therapy, avoidable rehospitalization in patients with ACS, and high rate of recurrence and long-term complications in patients with VTE.To discuss the economic impact of ACS and VTE; factors that contribute to preventable morbidity, mortality, and costs associated with these conditions; and strategies that managed care pharmacists can use to improve clinician knowledge of evidence-based treatment guidelines and patient adherence to the treatment plan, thereby improving clinical and economic outcomes.Premature discontinuation of antiplatelet therapy increases the risk of death and rehospitalization in patients with ACS. Factors associated with premature discontinuation include advanced age, lack of education, unmarried status, pre-existing cardiovascular disease, high cost of health care, failure to receive discharge instructions, and lack of referral for cardiac rehabilitation. Managed care plan benefit design should provide for the effective treatment of ACS and VTE by identifying the optimal type and duration of anticoagulant and antiplatelet therapy. In patients with VTE, the use of low-molecular-weight heparin (LMWH) in outpatients is as safe and effective and less costly than standard intravenous unfractionated heparin on an inpatient basis. Long-term LMWH treatment for acute deep vein thrombosis is safe and effective, and it is preferred over warfarin for patients with cancer. Managed care pharmacists can improve the quality of care for patients with ACS and VTE by using a variety of strategies to improve clinician knowledge of evidence-based treatment guidelines and patient adherence to the treatment plan.Efforts by managed care pharmacists to improve the quality of care for patients with ACS and VTE can improve patient outcomes and reduce health care utilization and costs."}
+{"text": "Decades of research and scholarship2\u20134  have shown that race is fundamentally not biological. A substantial body of evidence clarifies that race is a sociopolitical, not biological construct.5 Nevertheless, the harmful, unscientific practices of racial biological essentialism persist, which helps explain why the misuse of race in clinical decision-making, research, and education remains pervasive.The practices of contemporary clinical decision-making and care rely heavily on racial biological essentialism, which is a set of ideas originating in modern science that describes populations as comprising distinct subpopulations with unique sets of essential, heritable characteristics and propensities  purportedly due to their biology.6 This work has taken many forms, including the de-implementation of race-based algorithms used as clinical decision-making tools. In 2020, the Ways and Means Committee in the U.S. House of Representatives asked professional societies across medical disciplines to rethink their use of race-based clinical algorithms. The Committee sent a \u201cRequest for Information\u201d (RFI) to medical professional societies endorsing the elimination of race-based clinical algorithms. The study findings and RFI responses were captured in a 2021 report and captured responses from the professional societies as well as recommendations to improve clinical decision-making.7 The Agency for Healthcare Research and Quality (AHRQ) is also taking on this issue. At the time of this publication, AHRQ is undertaking a systematic review to provide Congress and the public responses to key questions on the impact of race-based clinical algorithms on health outcomes, and what can be done to address and/or mitigate racial bias on the development, validation, etc., of clinical algorithms.8For many years, medical trainees, health equity scholars, and public health physicians have explained how race consciousness , which is the understanding of race as a sociopolitical construct, provides a more useful understanding for medicine and public health than racial biological essentialism does.9 The American College of Obstetrics and Gynecology no longer endorses a vaginal birth after caesarean calculator that uses race.10 Most recently, the American Thoracic Society issued updated recommendations in spirometry testing and the race-neutral reference equation for all patients, irrespective of race.11Since 2021, several professional societies have updated their positions on the inclusion of race in clinical algorithms within their respective specialties. The National Kidney Foundation and the American Society of Nephrology officially endorsed an estimated glomerular filtration rate (e-GFR) calculator without a race variable.12 Many social and clinical factors contribute to this stark inequity, including the misuse of race to modify the e-GFR score, which is used in the diagnosis and treatment of chronic kidney disease (CKD). Race and other social factors have been linked to the e-GFR and other statistics, which has been associated with disproportionate suffering due to (CKD) and its sequalae among Black populations .13As research continues to elucidate the harms and any benefits from including race in clinical algorithms, the urgency to address race-based algorithms is only intensifying. For instance, 35% of Americans suffering from renal failure are Black, while only representing 13% of the population.14 To meet the urgency of this moment, the NYC Department of Health and Mental Hygiene launched the Coalition to End Racism in Clinical Algorithms (CERCA). This coalition is a citywide initiative consisting of both safety-net hospitals and academic medical centers representing all five boroughs of NYC. Participation in CERCA requires that each coalition member commit to de-implement at least one race-based algorithm. Members are also required to furnish work, evaluation, and patient engagement plans regarding their de-implementation of race-based algorithms.16Health equity experts agree to the implementation of nonrace-based clinical algorithms that cannot be subjected to the over 10-year timeframe typical for medical research and its adoption into practice.16In the summer of 2023, the NYC Department of Health and Mental Hygiene hosted the first annual New York City Anti-racism in Medical Education Symposium in partnership with the Josiah Macy Jr. Foundation, the American Academy of Medical Colleges, and the Fund for Public Health NYC. This symposium aimed to identify key stakeholders involved in anti-racism and curriculum development at NYC medical schools and understand the depth and breadth of anti-racism praxis incorporated into their educational programming.Health Equity hopes to contribute to this growing body of knowledge regarding the de-implementation efforts needed to holistically address and eradicate race essentialism from practice and education. Specifically, this issue highlights scholarship in the following areas:Historical origins of race adjustment in medicine, clinical decision-making tools, and artificial intelligence tools in medicine;Current activities, successes, and challenges around removal of race from clinical decision-making tools at the institution- and system-level and its impact on patient outcomes;City, state, and federal policies and policy analysis supporting removal of race adjustment from clinical decision-making tools; andPrograms, interventions, and policies intended to interrupt or end algorithmic racial discrimination in medicine and health care.This special issue of We hope this publication captures the latest work in addressing race-based medicine and facilitate the adaptation and implementation of initiatives to correct and mitigate the harmful effects of racial discrimination in health care. As we chart the next steps of this movement\u2014which include equitable transplantation access, federal changes in Medicaid and Medicare policy on use of race-based algorithms, biases in artificial intelligence, application of public health critical race praxis (PHCRP) in research, to name a few emerging areas\u2014remaining abreast of current and needed work will be essential to realizing a more equitable, just, and healthy society.disciplinary self-critique, this special issue documents the continued misuse of race in clinical algorithms. It also offers constructive alternatives that can be implemented immediately.18According to PHCRP, which is a health equity offshoot of Critical Race Theory, the first step toward advancing health equity is to acknowledge how the conventions of our field help reinforce inequities however well-intentioned our efforts may be. The use of arbitrary race corrections in clinical algorithms relies on and reifies racial biological determinism. It undermines the ability of clinicians to uphold their commitment to beneficence, nonmaleficence, and justice in the provision of care. Failure to uphold them harms minoritized patients and communities through, for instance, delayed or missed diagnoses and the exacerbation of racialized stigmata. A substantial body of scholarship and research now exists to promote more equitable clinical decision-making and care. Consistent with the PHCRP principle of"}
+{"text": "Saccharomyces, thanks to careful dissection of metabolic properties  regulon after the ancestral whole genome duplication (WGD) in yeasts. This WGD results from an ancestral hybridization between two divergent non-WGD clades  mapping in the progeny of crosses between two wine starter strains, one of which had an admixed genome with flor strains, the authors identify genetic factors of adaptive divergence between the flor yeast and the wine yeast and show also that introgressions from flor strains promoted the metabolic variability observed. Finally, the article by Krogerus et al. use synthetic tetraploid hybrids between Saccharomyces cerevisiae and Saccharomyces eubayanus to generate genetic diversity in the F2 progeny through meiotic segregation. They show that some of these derived strains show fermentation capacities similar to commercial lager strains and found that higher ploidy was generally associated with faster fermentation. This study highlights the potential of synthetic hybrid formation, followed by selection on the progeny, to generate new strains of industrial relevance.Due to their unique ability to adapt to new niches, hybrids are common among human-altered environments, including industrial settings. The two remaining articles of this Research Topic focus on Altogether, the six contributions to this Research Topic provide important new insights on diverse aspects related to fungal hybrids and underscore the potential of genomic approaches to study them.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.TG acknowledges support from the Spanish Ministry of Science and Innovation for grant PID2021-126067NB-I00, cofounded by European Regional Development Fund (ERDF); from the Catalan Research Agency (AGAUR) SGR423; from the European Union\u2019s Horizon 2020 research and innovation programme (ERC-2016-724173); from the Gordon and Betty Moore Foundation (Grant GBMF9742); from the \u201cLa Caixa\u201d foundation (Grant LCF/PR/HR21/00737), and from the Instituto de Salud Carlos III (IMPACT Grant IMP/00019 and CIBERINFEC CB21/13/00061- ISCIII-SGEFI/ERDF). CTH acknowledges support by the Great Lakes Bioenergy Research Center, U.S. Department of Energy, Office of Science, Office of Biological and Environmental Research under Award Number DE-SC0018409; the National Science Foundation under Grant Nos. DEB-1442148 and DEB-2110403; and the USDA National Institute of Food and Agriculture (Hatch Project 1020204). CTH is an H. I. Romnes Faculty Fellow, supported by the Vice Chancellor for Research and Graduate Education with funding from the Wisconsin Alumni Research Foundation.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Precision health refers to personalized healthcare that combines genetic and genomic sequence, protein, metabolite, and microbiome information (collectively known as \u201comics\u201d information) with lifestyle, social, economic, cultural, and environmental influences to help individuals achieve optimal health and well-being ,2. The gThe need to provide precision healthcare to hereditary breast and ovarian cancer (HBOC) and Lynch Syndrome (LS) patients and their families has long been recognized and has been supported with efforts at national and international levels ,6,7. TheCancers, titled \u201cPrecision Healthcare and Interventions in Hereditary Breast and Ovarian Cancer and Lynch Syndrome\u201d, four reviews and three original research articles highlight recent trends, updates, and progress in caring for HBOC and LS individuals and families. The papers cover precision healthcare from prevention and early detection, treatment of disease, and psychosocial care of individuals carrying HBOC- and LS-associated variants and their biological relatives.In this Special Issue of BRCA1 and BRCA2 founder pathogenic variants within the Portuguese population. Their conclusions have implications for the development of genetic testing panels, the cost-effectiveness of cascade testing among biological relatives, and the accuracy of risk prediction models that are commonly used in clinical practice to aid medical decision making in prevention, early detection, and cancer surveillance.Vicente and colleagues review evidence supporting the prevalence of Two reviews by Gambini and colleagues and by Cassar and colleagues focus on the molecular mechanisms of carcinogenesis in LS and in ovarian cancer, respectively, and provide insights into opportunities for future therapeutic interventions. Gambini and colleagues present recent guidelines regarding early detection in LS patients. Regarding primary prevention, the authors focus on the comparative advantages of chemoprevention with aspirin, other non-steroidal anti-inflammatory drugs, and progestins over risk-reducing surgery, and highlight concerns over limited or conflicting evidence regarding some of the chemoprevention agents. Cassar and colleagues focus on the role of regulatory T cells in the development of ovarian cancer and review the role of these cells in pathophysiological mechanisms regulating the tumor microenvironment, angiogenesis, metastasis, drug resistance, and tumor immunity. Both reviews by Gambini and colleagues and by Cassar and colleagues emphasize the possibilities of immunotherapies that harness frameshift peptide effector T-cell responses, immunocheckpoint inhibitors, epigenetic drugs, and combinations of immunotherapies with regulatory T-cell-targeting drugs as promising new therapeutic pathways.Bernsetin-Molho and colleagues review recommendations for managing individuals with HBOC, focusing especially on those who have not developed cancer, and for whom primary cancer prevention and early detection are of pivotal importance. The authors reviewed 15 guidelines published by governmental and professional bodies in the US, Europe, and Australia, and other countries around the world. They point out inconsistencies, including conflicting or limited evidence in areas of modifiable risk factors, such as the age of first live birth, the use of oral contraception, and the use of tamoxifen for chemoprevention. For early detection, they point out the lack of consensus regarding the optimal surveillance and risk management of younger (<30 years old) and older (>60 years old) individuals with HBOC-associated pathogenic variants, and the conflicting or limited evidence regarding the value of biomarkers such as CA-125 and screening for pancreatic cancer. Finally, they review evidence regarding effects of in vitro fertilization and pre-implantation genetic testing diagnosis, and suggest that consistent evidence shows that there is no association between in vitro fertilization and the risk of breast and ovarian cancer.BRCA1 or/and BRCA2 variant. Their study included findings of a survey with n = 505 participants and in-depth interviews with a subsample of n = 40 participants. The study focused on childbearing practices before and after knowing one\u2019s BRCA status and on decision-making processes and self-conceptualization. The study found that most women of reproductive age who already had children opted not to have more children, while younger women who did not have children were likely to have children after risk-reducing surgery. Regardless of their childbearing practices, many participants felt significantly vulnerable and stigmatized, especially if they had already developed cancer. The sense of vulnerability did not diminish over time because the focus shifted from oneself to one\u2019s family. The study sheds light on a relatively unexplored topic and identifies unmet needs of these women for ongoing care and support.Hesse-Biber and colleagues focused on the psychosocial management of women with HBOC and conducted a mixed-methods study with women carrying a pathogenic n = 1933 participants from n = 518 family units harboring HBOC-associated variants. The study found that, although genetic literacy was higher among participants who had counselling, some risk factors were poorly understood, especially among those that had genetic counseling more than 5 years ago, had fewer years of formal education, and did not have a pronounced family history of cancer. Sarki and colleagues provided strong evidence for the potential impact of cascade testing as a precision public health intervention, as their study found that, from 304 individuals with HBOC- or LS-associated variants and 115 of their relatives, on average 10 biological relatives per participant were potentially eligible for cascade genetic testing. However, only two out of three individuals with a pathogenic variant wanted to invite their relatives to the cohort, and about 50% indicated a preference for family-mediated communication of testing results, possibly with the assistance of digital technology. Both studies emphasize the importance of the family environment as a means to facilitate better management of HBOC and LS and the implementation of cascade testing as a precision public health intervention.Finally, the studies of Pedrazzani and colleagues and Sarki and colleagues focus on family-mediated communication of genetic testing results and the impact on cascade testing of biological relatives. Pedrazzani and colleagues examined genetic literacy and the flow of information from carriers of pathogenic variants who had genetic counseling to their biological relatives who did not have counseling. The study combined data from three studies conducted in the U.S. and in Switzerland over 10 years with a pooled sample of In conclusion, technological advances and the growing application of precision healthcare and precision public health interventions have increased our knowledge of HBOC and LS and offer pathways for novel and personalized therapeutic opportunities. Personalized therapeutic opportunities will be most advantageous for individuals diagnosed with cancers associated with high morbidity and mortality, such as ovarian, pancreatic, and bile duct cancers. However, the translation of this knowledge into concrete and consistent prevention and early detection guidelines is lagging behind, due, to limited evidence from large epidemiological studies with comprehensive assessments of genetic and genomic, socioeconomic, cultural, and health behavioral data. There is even less evidence regarding the translation of this knowledge into the equitable psychosocial care of these individuals and families. This Special Issue helped identify areas where more evidence, from high-quality studies, is needed."}
+{"text": "Affective science is a broad and burgeoning field, and the National Institutes of Health (NIH) support research on a similarly broad range of topics. Across NIH, funding is available for basic, translational, and intervention research, including research in non-human animals, healthy populations, and those with or at risk for disease. Multiple NIH Institutes and Centers have specific programs devoted to topics within the affective science umbrella. Here, we introduce the funding priorities of these six: the National Cancer Institute (NCI), National Center for Complementary and Integrative Health (NCCIH), National Institute of Mental Health (NIMH), National Institute on Aging (NIA), National Institute on Drug Abuse (NIDA), and National Institute on Minority Health and Health Disparities (NIMHD). We then discuss overlapping themes and offer a perspective on promising research directions. The experience, expression, and regulation of emotions influence many facets of health and well-being. Affective states and affective regulation can mediate and moderate behavioral and physiological processes, thereby impacting health outcomes. Social disconnection and loneliness increase the odds of all-cause mortality by more than 25% and have been labeled an epidemic by the United States Surgeon General . NCCIH seeks to fund research incorporating transdisciplinary approaches in the basic social, behavioral, psychological, and biological sciences to understand the factors that influence EWB, as well as clinical research on the use of mind\u2013body interventions to enhance EWB and whole person health. NCCIH\u2019s EWB High-Priority Networks include efforts to (1) explore the relationship between economic burden of illness and EWB; (2) study the modifiable elements of EWB across biological, behavioral, and experiential levels; and (3) deepen our understanding of how best to measure EWB and mechanisms through which mind\u2013body interventions promote and maintain EWB. The EWB Networks recently published a provisional conceptualization of EWB, accompanied by commentaries from various well-being research stakeholders, including NIH  health services for youth and have the capacity to reach large and, importantly, diverse populations of children at different developmental time periods. NCCIH supports projects to test the efficacy or effectiveness of mind\u2013body interventions that can be delivered in a school-based setting or with students to promote MEB health and prevent MEB disorders among youth.NIMH\u2019s mission is to transform the understanding and treatment of mental illnesses, and research on the mechanisms underlying mood, affect, and their disruptions in mental illnesses is an integral part of NIMH\u2019s basic and translational research portfolios. Basic neuroscience priorities include investigations of neurobiological mechanisms underlying affect, resilience, and vulnerability to stress in humans and animals. NIMH supports research on mood and anxiety disorders in humans, including diagnostic and transdiagnostic studies of the developmental trajectories, etiology, progression, risk factors, assessment, treatment, and prevention of mental illness associated with dysregulated mood and affect. A transdiagnostic framework within NIMH\u2019s Research Domain Criteria (RDoC) initiative supports studies in affect-relevant domains of functioning, including arousal and regulatory systems, negative valence (threat and loss), positive valence (reward), and social processes. NIMH also aims to enhance support of research on affective processes and disorders that engages underrepresented study populations to understand mechanisms that contribute to mental health disparities.Examples of affective science research areas of interest to NIMH include (1) understanding how distributed brain circuits dynamically represent multi-dimensional social-emotional information. (2) Understanding the neurobiological mechanisms underlying stress mediated changes in social-affective and cognitive processes  research.normative developmental trajectories of aging. Topics of particular interest include (1) impacts of early-life adversity on later life outcomes; (2) individual- and context-based variations in affective processing in mid- and late-life; (3) neural mechanisms underlying emotional changes with age; (4) social isolation and loneliness; and (5) impacts of optimism, purpose in life, compassion, and generativity on health and well-being across the lifecourse. In the context of AD/ADRD, NIA seeks to identify predictive psychological, behavioral, and biological markers for changes in emotional expression and regulation that may presage cognitive decline. We also support the development of strategies to detect, prevent, and treat affective and behavioral dysregulation in people living with dementia, including effects on caregiver health and well-being.NIA seeks to elucidate the core biopsychosocial processes underlying changes in affective functions, the interactions between affective and cognitive processes, and the complex profiles of emotional adaptation and compensation across NIA encourages basic and translational affective science research in humans and/or appropriate animal models. NIA strongly encourages the application of psychometrically sound behavioral assessment approaches, and use of digital technology to measure affective, motivational, and social responses across time in \u201creal-world\u201d contexts. NIA provides expansive support for longitudinal studies and cross-cohort comparisons. All NIA research is expected to make use of the NIA Health Disparities Research Framework . NIDA\u2019s interest in supporting research on affective neuroscience relates particularly to factors that influence risk for and protection from development of SUD, as well as relapse and recovery. Priorities include 1) expanding from studies of specific circuits or unidimensional constructs to the full constellation of affective and behavioral dysfunction observed in SUD; (2) multi-level and multidimensional approaches to conceptualizing SUD \u2014 considering individual , social  that cannot be fully modeled in non-humans and challenges with aligning human neurobehavioral development with that of model species, we encourage investigators to consider modeling analogous social factors , and considering homologies (and limits thereof) across humans and model species with respect to the neuroaffective system of interest.Given the complexities surrounding SUD, we encourage longitudinal research designs, the use of large datasets Table , and NIDThe mission of the National Institute on Minority Health and Health Disparities (NIMHD) is to improve minority health and reduce health disparities through research including integrative biological and behavioral science, as well as community health, population sciences, clinical and health services research, and research on health systems and workforce development. Critically, research supported by NIMHD must include a focus on one or more of the following NIH-designated populations that experience health disparities in the United States: African Americans, Latinos/Hispanics, American Indians and Alaska Natives, Asian Americans, Native Hawaiians and other Pacific Islanders, less privileged socioeconomic groups, underserved rural populations, and sexual and gender minorities.The NIMHD Research Framework developmental sensitive periods, and on systemic capacities for change. For this reason, NIH institutes prioritize studies incorporating developmental trajectories and recommend the use of longitudinal designs and datasets. We also note that temporal scales vary enormously: molecular events unfold in nanoseconds; an individual\u2019s developmental trajectory can take days, months, or years; affective and social experiences can influence health trans-generationally. NIH institutes recognize the challenges associated with incorporating the temporal dimension, and we encourage investigators in the affective sciences to embrace these challenges.All the NIH Institutes in this commentary support basic, translational, intervention, and clinical affective science research. NIH recognizes that affect is embedded with many aspects of life and health, and an NIH-wide goal is to better understand the roles and mechanisms by which emotional experiences impact health and well-being. We especially encourage multi-level investigations of stress, emotion regulation and buffering, resilience, reward systems, positive emotions and emotional well-being, and social and interpersonal factors and their impact during development and across the lifespan."}
+{"text": "Chemical vapor deposition synthesis of graphene on polycrystalline copper substrates from methane is a promising technique for industrial production and application. However, the quality of grown graphene can be improved by using single-crystal copper (111). In this paper, we propose to synthesize graphene on epitaxial single-crystal Cu film deposited and recrystallized on a basal-plane sapphire substrate. The effect of film thickness, temperature, and time of annealing on the size of copper grains and their orientation is demonstrated. Under optimized conditions, the copper grains with the (111) orientation and a record size of several millimeters are obtained, and the single-crystal graphene is grown over their entire area. The high quality of synthesized graphene has been confirmed by Raman spectroscopy, scanning electron microscopy, and the sheet resistance measurements by the four point probe method. To obtain single-layer graphene of a large area and high quality by chemical vapor deposition (CVD), in addition to the synthesis process itself, the surface on which the nucleation of the carbon film begins is important. One of the most efficient ways to grow an ideal graphene monolayer is to use a smooth single-crystal bulk copper ,2,3. How2 and Ar gas atmosphere  direction, which is optimal for graphene synthesis, during the usual stage of substrate annealing in a hydrogen atmosphere to remove natural oxide from its surface before graphene growth. In this case, high-quality single-crystal graphene is synthesized over the entire surface of recrystallized copper film. The quality of graphene has been approved by Raman spectroscopy, scanning electron microscopy, and the sheet resistance measurements using the four point probe method. The obtained result demonstrates the high potential of graphene CVD synthesis on thin copper films for industrial production and application. Of particular interest, in our opinion, is the possibility of using such a sandwich (sapphire/copper film/graphene) for the BB-LIFT of graphene patterns on an arbitrary substrate."}
+{"text": "The ocean is a vast carbon sink and mediates global carbon cycling, essential for mitigating climate change. The deep-sea pelagic and sub-seafloor environments represent the largest microbial habitats on Earth and are key sites for organic matter remineralization and storage in the biosphere. Moreover, diverse unique and extreme habitats, e.g., seamounts, trenches, cold seeps, and hydrothermal vents exist in the deep sea, developing special and active microbial communities and metabolic processes that significantly impact global carbon cycling. It is therefore important to understand the diversity, activity and metabolism of deep-sea microorganisms, particularly their mechanisms for utilization and transformation of organic matter, and the environmental factors affecting these processes. The main aim of this Research Topic is to collect recent work focusing on the diversity and metabolic activities of microorganisms in different deep-sea habitats, in order to understand the microorganisms that drive carbon cycling in the deep ocean.Bradley et al. investigated patterns in the distribution of microbial cells, organic carbon, and the amounts of power used by microorganisms in global sediments. They found that trends in cell abundance, particulate organic carbon storage and degradation, and microbial power utilization are mainly structured by depositional settings and redox conditions, rather than sediment depth and age. Sediments deposited on continental shelves and margins are predominantly anoxic and contain active microbial cells that decline in power utilization in deeper and older settings. Conversely, microorganisms in abyssal sediments use consistently low amounts of power across large gradients in sediment depth and age. Overall, the study demonstrated broad global-scale connections between depositional settings and activity of deep biosphere microorganisms.Marine sediments harbor diverse physicochemical properties that regulate the assemblages of microorganisms. However, it is unclear how variations in sediment physicochemical properties impact microorganisms on a global scale. Zhang et al. compared the composition and functions of the microbial communities in sediments from deep-sea seamounts, trenches and cold seeps in the Pacific Ocean, via amplicon sequencing and metagenomic analysis. They demonstrated that the microbes in deep-sea sediments were diverse and were functionally different  from each other in the seamount, trench, and cold seep ecosystems. These results help improve the understanding of the composition, diversity and function of microbial communities in deep-sea environments.Webster et al. characterized the microbial diversity, geochemistry and methanogenic activities of prokaryotic communities in seven Gulf of C\u00e1diz mud volcanoes. They concluded marked differences between the microbial biogeochemistry of mud volcano sediments and deep-sea control sediments. They found that methanogenic activities from methyl compounds, especially methylamine, within the top two meters of sediment were much higher than with the substrates H2/CO2 or acetate. The potential archaea responsible for the methanogenic metabolisms were explored and sediment enrichments were dominated by Methanococcoides methanogens.Deep-sea seeps are extreme environments with high hydrostatic pressure, yet the seep systems have a great impact on global carbon cycling through discharge of methane and petroleum hydrocarbons. Lyu et al. investigated the potential and activities of deep-sea microorganisms for alkane degradation in the sediments of cold seep areas. They enriched five oil-degrading consortia from sediments collected from the Haima cold seep areas of the South China Sea, and further isolated seven efficient alkane-degrading bacteria belonging to Acinetobacter, Alcanivorax, Kangiella, Limimaricola, Marinobacter, Flavobacterium, and Paracoccus. The degradation rates of these bacteria were the highest in alkanes with medium chains. This study provides insights into the community structures, and oil-degrading activity of the bacterial inhabitants in the Haima cold seep areas, South China Sea, and offers bacterial resources for cultivation of candidates with oil bioremediation application potential.RL wrote the draft. YW and GW revised and provided essential comments on the article. All authors have proofread and approved it for publication."}
+{"text": "Long-term production practice proves that good liquor comes out of the old cellar, and the aged pit mud is very important to the quality of Luzhou-flavor liquor. X-ray diffraction, Fourier transform ion cyclotron resonance mass spectrometry, and infrared spectroscopy were used to investigate the composition characteristics of iron-bearing minerals and dissolved organic matter (DOM) in 2-year, 40-year, and 100-year pit mud and yellow soil  of Luzhou Laojiao distillery. The results showed that the contents of total iron and crystalline iron minerals decreased significantly, while the ratio of Fe(II)/Fe(III) and the content of amorphous iron (hydr)oxides increased significantly with increasing cellar age. DOM richness, unsaturation, and aromaticity, as well as lignin/phenolics, polyphenols, and polycyclic aromatics ratios, were enhanced in pit mud. The results of the principal component analysis indicate that changes in the morphology and content of iron-bearing minerals in pit mud were significantly correlated with the changes in DOM molecular components, which is mainly attributed to the different affinities of amorphous iron (hydr)oxides and crystalline iron minerals for the DOM components. The study is important for understanding the evolution pattern of iron-bearing minerals and DOM and their interactions during the aging of pit mud and provides a new way to further understand the influence of aged pit mud on Luzhou-flavor liquor production. Chinese liquor is one of the oldest distilled spirits in the world, of which strong-flavor baijiu (SFB), also known as Luzhou-flavor liquor, is the best-selling in China, accounting for over 70% of total consumption in the Chinese baijiu market ,2. SFB pclostridium . T. T26]. TDOM compounds can also be further divided into different molecular types based on their element composition B 26]. T. T26]. TDOM is widespread in terrestrial ecosystems and plays a critical role in the evolution of soil biogeochemical processes and structure . The larPCA was used to evaluate the correlation between iron (hydr)oxides and DOM compounds . The difo has a larger specific surface area and more binding sites compared to Fec, resulting in a stronger adsorption capacity to preferentially bind to CDPA, VPDP, and HULP [c and positively correlated with Feo  are more susceptible to bonding with iron (hydr)oxides to form Fe-OM complexes ,43. In aand HULP ,45. Thuswith Feo . In addio to Fec . Thus, t pit mud .Correlation analysis of NOSC values, O/C ratios, and Fe(II)/Fe(III) can also further explain the relationship between DOM and iron (hydr)oxides. The NOSC value and O/C ratios can represent the oxidation state of DOM molecules . The conc and CHONP molecules oxides are more dominant in aged pit mud. The richness, unsaturation, and aromaticity of DOM increased significantly during the aging of pit mud. DOM from aged pit mud contained more lignin/phenolics, polyphenols, and polycyclic aromatics. Furthermore, there is a significant correlation between the changes in the morphology and content of iron-bearing minerals in pit mud and the chemical characterization of the DOM molecules. Therefore, the use of microbial fermentation and other biotechnological methods to reduce the iron content of local yellow soil  may help to promote the aging of new pit mud.In summary, the contents of total iron and crystalline iron minerals decreased significantly with the increase in cellar age, and the ratio of Fe(II)/Fe(III) and the content of amorphous iron (hydr)oxides increased significantly. In connection with this, the richness, unsaturation, and aromaticity of DOM and the ratio of lignin/phenolics, polyphenols, and polycyclic aromatics in pit mud were increased. The research showed that molecular diversity and chemical properties of DOM compounds were closely correlated with the content and morphological changes of iron (hydr)oxides during the aging process of pit mud, and the interaction between DOM and iron (hydr)oxides changes the inorganic and organic components in pit mud, which further changes the physicochemical properties of pit mud and affects the aging of pit mud. The changes in the content and composition of iron-bearing minerals and DOM are important potential factors affecting the aging of pit mud, which not only provides a new idea to improve the aging of pit mud by using biotechnology but also helps to understand the process and mechanism of aging of pit mud from the perspective of mineral and DOM composition."}
+{"text": "Sustainable Stress Management: Aquatic plants vs. Terrestrial plants (IGW-SSMAT) which was jointly organized at the Friedrich Schiller University of Jena, Germany from 25 to 27 July 2022 by Prof. Dr. Ralf Oelm\u00fcller, Friedrich Schiller University of Jena, Germany as the German coordinator and Dr. K. Sowjanya Sree, Central University of Kerala, India as the Indian Coordinator. The workshop constituted researchers working in this field from both India and Germany and brought together these experts in the field of sustainable stress management for scientific discussions, brainstorming and networking.The Indo-German Science and Technology Centre (IGSTC) funded an Indo-German Workshop on  Climate change and the rapid growth of the human population are major global challenges. Evolving sustainable strategies to counter their effects will be the tasks for the future. We need to produce more food, which includes higher crop yields per area, with plants that are better adapted to the upcoming threats, while nature and climate need to be protected simultaneously . Besides crop production for food and feed, the growing human population and modern technology require plant biomass also for energy production, in the chemical and pharmaceutical industries, in housing and in the textile industry. Further to the promotion of our knowledge on resistance mechanisms in utilized crop species, higher crop yields and biomass production require novel approaches such as the use of new non-conventional crop species and the exploration of new agriculturally suitable areas. Finally, the scientific achievements obtained with conventional crop plants must be tested and eventually transferred to newly introduced crop species, if possible, or new strategies need to be developed for new crop species and new agricultural systems.Sustainable Stress Management: Aquatic plants vs. Terrestrial plants (IGW-SSMAT) was organized at the Friedrich Schiller University of Jena, Germany from 25 to 27 July 2022. This workshop was funded by the Indo-German Science and Technology Centre (IGSTC) with Prof. Dr. Ralf Oelm\u00fcller, Friedrich Schiller University of Jena, Germany, as the German coordinator and Chair of the workshop and Dr. K. Sowjanya Sree, Central University of Kerala, India, as the Indian Coordinator and Co-chair of the workshop. The scientific organization of the workshop was supported by Dr. Klaus J. Appenroth, Friedrich Schiller University of Jena, Germany. Interestingly, the workshop was held in a seminar room of the Department of Indo-German Studies, University of Jena, Germany, which was an apt location for the exchange of scientific ideas between the researchers of the two countries , whereas strategies that allow the faster propagation of the plant population under different environmental conditions might be more important for aquatic plants.Wolffia arrhiza and Wolffia globosa) for human nutrition under the law of novel food cyt changes and phytohormones like jasmonates. Moreover, volatile-mediated plant\u2013plant communication play an important role in the biotic stress response  improved the productivity of tomato crops both qualitatively and quantitatively. Prime-Verdant-applied plants performed well also under stress conditions . Furthermore, vegetable crop plants can become heavily infected by different plant viruses which results in damage to the crops. It is difficult to mitigate RNA and DNA viral diseases in vegetable crops. Piriformospora indica-colonized tomato plants developed increased resistance to Tomato yellow leaf curl virus, and the colonization of fruit plants like banana and papaya with P. indica effectively reduced the disease symptoms induced by RNA viruses like Banana bract mosaic virus and Papaya ring spot virus, respectively. Additionally, vegetable crops  in association with P. indica developed more resistance against RNA virus , and DNA virus (Tomato leaf curl virus and Bhindi yellow vein mosaic virus) infections. Thus, P. indica colonization protects plants also against viral diseases . To understand the molecular basis of this P. indica-induced resistance, colonized and uncolonized crops after viral infections should be analysed with the molecular and biochemical tools available in the consortium.Autotrophs are constantly challenged by abiotic as well as biotic stressors. Insect pests of plants are one of the major biotic stressors. Plants have evolved several strategies to protect themselves from insect infestation. However, the signal transduction pathways induced early on that connect the process of wounding as a result of insect herbivory to the plant defence responses are yet to be well comprehended. Perceived by specific chemicals (herbivore-associated molecular patterns or damage-associated molecular patterns), plants respond with local and systemic signalling processes including [CaGermany; ,25). PlaLemna root re-growth test -tolerance capacity. The application of such management approaches is important, especially in the scenario where the ability of these plants to produce high amounts of biomass at a fast pace and the increasing practical applicability of this biomass in a circular economy are transforming duckweeds into a sustainable cropping system. The anatomical and molecular basis for the fast growth rate of these tiny aquatic plants was also revealed , i.e., by increasing salinity, a lack of nutrients or their exposure to heavy metals . EvidentGermany; ). The ma, India; ,28,29). , India; ). Flower, India; ). In angGermany; ). In a sGermany; . This unKnowledge flow between the researchers from both India and Germany on sustainable stress management in terrestrial and aquatic plants has helped to widen the understanding of the mechanism of stress management in general and also allowed inputs and learning into each field in order to work towards developing sustainable aquatic and terrestrial cropping systems that can deal with stress in a more efficient manner. The development of well-organized sustainable agriculture systems, which will enable us to create innovative technologies that can be integrated into circular economy, is the future. Our efforts to understand the stress-management strategies in both terrestrial plants and aquatic plants facilitated a holistic understanding of the requirements and strategies for building sustainable cropping systems."}
+{"text": "In the past few decades, the rapid development and decreasing costs of sequencing technologies dramatically changed the landscape of epidemiological studies and surveillance of infectious diseases. Subsequently, pathogen genomic studies have become the forefront tool for investigating emerging infectious disease epidemics and supporting decision-making processes related to the mobilization of intervention resources. Since the introduction of next-generation sequencing (NGS), which expanded the capacity for whole genome sequencing (WGS), and the revolutionary growth of computational resources, viral or bacterial complete genomes can now be sequenced and characterized within a few days or even hours. Therefore, high-throughput sequencing technologies resulted in the exponential growth of genomic databases, unveiling novel insights into the biology, pathophysiology, and molecular epidemiology of infectious disease pathogens. Such significant developments in genome sequence technologies also resulted in important advances in the field of phylogenetic analysis. Modern analytical methods in phylogenetics improved the tracking and understanding of pathogen transmission and evolution of human and animal diseases. Thus, phylogenetic analysis of big genomic databases can be used to clarify key questions related to infectious disease epidemiology, such as the initial detection and characterization of outbreaks, accurate tracing of transmission chains between hosts, and dispersal among and within geographical regions. The threat of emerging and re-emerging infectious diseases continues to be a challenge to global public and animal health, in which sequencing is not just a critical tool in surveillance but also has a major role in a pandemic or outbreak response. The main objective of this Research Topic is to explore the current status and future perspectives of sequencing technologies in the control and prevention of infectious diseases, including the elucidation of diagnosis, molecular evolution, and epidemiology of infectious disease pathogens.Kariithi et al., Kim H.-J. et al., and Abbas et al. demonstrated multiple approaches in utilizing sequencing and phylogenetic analysis resources for improving genomic surveillance of avian infectious bronchitis virus in poultry by characterization of phylogenetic relationships, detection of critical recombination events, assessing vaccination effectiveness, and identifying evolutionary origins of endemic and emerging strains. Furthermore, Kim S.-W. et al. were able to confirm that avian reoviruses circulating in poultry flocks were originating from wild birds using straightforward traditional molecular characterization tools, similar to what Goraichuk et al., did with the Newcastle disease virus. However, Baek et al. went a step further by implementing Bayesian phylodynamic analysis to shed deeper insights into the evolutionary epidemiology of H5N8 avian influenza viruses. They demonstrated that wild birds were the ancestral host for multiple introductions of H5N8 viruses into poultry, but domesticated ducks more important in virus circulation and transmission among poultry flocks.NGS has become a primary diagnostic and characterization tool for genomic surveillance of pathogens that threaten biosecurity and food safety. Hyeon, Tseren-Ochir, et al., Gallardo et al., and Kim G. et al. Furthermore, the combination of WGS and phylodynamic analytical approaches was used by Pamornchainavakul et al. to unveil novel findings on how the rapid recombination events among porcine reproductive and respiratory syndrome virus 2 strains can accelerate their genetic mutations leading to the emergence of more virulent strains. Similarly, Wei et al. were able to identify evolutionary characteristics and geographical origins of the lumpy skin disease virus in cattle, using multiple gene segments of a strain isolated from an outbreak in China in 2009. Rossi et al. extended their genomic analytical pipeline by integrating ecological niche models to quantify the role of environmental and demographic risk factors in shaping the evolutionary epidemiology of Mycobacterium bovis in Cameroon, which is considered a novel and critical step in improving genomic surveillance of infectious diseases.African swine fever continues to be the most important devastating pathogen to swine populations, causing unprecedented annual economic loss on a global scale. NGS and WGS also continue to be the most essential tools for providing critical genetic, epidemiologic, therapeutic, and vaccine development resources for African swine fever intervention efforts, as illustrated by Chung et al. and Hyeon, Helal, et al. used NGS and WGS approaches to deeply characterize the genetic features of West Nile virus and lyssaviruses from wild animals in selected regions in the United States in order to shed important insights about their origins and transmission dynamics. Additionally, it is important to include genomic surveillance of pathogens in exotic pet animals, such as reptiles, to monitor evolutionary characteristics that may result in the emergence of novel pathogens, as demonstrated by Varga-Kugler et al..Genomic surveillance of infectious diseases in wildlife is the foundational pillar of implementing the One Health concept globally. Indeed, the rapid emergence and spread of West Nile and Rabies viruses from wild animal origins played an important role in building the foundation of the One Health concept, which necessitates integrating disease surveillance of humans, wildlife, and domestic animals. In this Research Topic, Lorente-Leal et al. revised the performance and agreement of four commonly used pipelines for WGS data analysis of M. bovis, the causative agent of bovine tuberculosis, Butt et al. highlighted the feasibility and utility of long-read random sequencing approaches to identify pathogens in clinical samples, and Cho et al. developed a novel tiling amplicon PCR method for feasible and rapid sequencing of complete genomes in clinical samples.Continuous development and revision of NGS and WGS pipelines are critical for ensuring the sustainable generation and accumulation of sound and reliable genetic data. In this Research Topic, Our Research Topic reinforces the importance of sequencing technologies in changing the landscape of infectious disease surveillance in animals and humans, with the aim of highlighting NGS and WGS approaches that continue to become more feasible and accessible globally. This Research Topic highlights the versatility of techniques for bench science and sequence analysis in its application to many problems in infectious diseases of veterinary importance. In this Research Topic alone, investigations on 13 infectious diseases of poultry, swine, bovine, and wildlife were presented. Furthermore, the authors of these investigations span 23 countries and five continents, highlighting the accessibility of NGS techniques and its continued lowering of costs. In this Research Topic, we aspire to further motivate physicians, veterinarians, epidemiologists, microbiologists, diagnosticians, and other scientists from related fields to make sequencing technologies the gold standard for the diagnosis and surveillance of infectious disease pathogens in order to improve their current and future intervention efforts.All authors were involved in the writing of this editorial and editing contributions to this Research Topic."}
+{"text": "The South African Noise Induced Hearing Loss (NIHL) Regulations, mandates employers to conduct a noise risk assessment, which records specific variables for determining the status of exposure and the need for implementation of control measures.The study evaluated company noise risk assessment practices for alignment with legal requirements and specific risk assessment guidelines.Convenience sampling was used to select the four manufacturing and utilities companies that participated in the study. The participating companies submitted latest noise risk assessment records for evaluation through the READ approach.The noise risk assessment records of three of the four companies omitted the recording of factors such as the reasonable deterioration in or failure of control measures, adequate control and formalisation of hearing conservation programmes (HCPs). When evaluated against the South African National Standard 31000 Risk Assessment guidelines, the risk assessment processes of the respective companies were lacking in addressing aspects related to establishing communication and consultation, evaluation, adapting, continually improving, leadership and commitment, and integration.The recorded information on the noise risk assessment reports from the four participating companies were incomplete, negatively affecting subsequent HCP management processes and decision-making. Future studies should investigate other aspects such as the implementation status of recommended noise controls as well as their effectiveness as recorded in the noise risk assessment records.This study provided firsthand insights of company noise risk assessment practices, specifically identifying functional and technical areas requiring improvement to enhance current efforts directed towards the minimisation of NIHL within HCPs. The study highlighted that the current practices on recording noise risk assessment information remain incomplete, adversely diminishing the impact of the assessment as an important decision-making tool. The identified technical issues specifically, when addressed, will increase trust on the decisions derived from noise risk assessments. Occupational health programmes, including hearing conservation programmes (HCPs), offer employers a risk management tool for managing and minimising the impacts of exposure Khattab,  and are A risk assessment is vital within the overall risk management process and includes aspects such as communication and consultation, context establishment, risk analysis, risk evaluation, risk treatment, monitoring and review  31000.The participating companies were conveniently selected, informed by a risk-based criteria of confirmed historic NIHL incidence, determined through the evaluation of sustainability reports. The final selected companies were identified and selected using a longitudinal study of 20 manufacturing and utilities companies, the method of which has been previously reported by Rikhotso et al. ; 2022a. The submitted noise risk assessment records were evaluated based on a criteria derived from the NIHL Regulations   approach  Faculty Committee on Research Ethics-Science: FCRE 2020/10/015 (FCPS 02) (SCI). The primary investigator (O.R.) signed disclosure agreements with the participating companies, as applicable.The confirmation and availability of the noise risk assessment records from the four companies were in response to employer obligations for securing legal compliance and to satisfy internal voluntary requirements. The reporting format of the submitted records diverged between full Microsoft Word, PDF, Microsoft Excel spreadsheets and checklists. The type and format of the noise risk assessment record affects the thoroughness and quality of information contained in such documents.Employers from Companies A, B and C delegated the duty of conducting noise risk assessments to occupational hygiene professionals who had varying Southern African Institute for Occupational Hygiene (SAIOH) certification levels ranging from occupational hygiene assistants, occupational hygiene technologist to occupational hygienists . These oThe NIHL Regulations prescribe that the assessment be conducted with involvement and participation of various stakeholders. Stakeholders with recorded involvement and participation in the respective company assessments  includedn = 2, 18%) facilities recorded the noise sources. None of the companies recorded the reasonable deterioration in or failure of control measures. Furthermore, only two of 11  at Company A, two of six  at Company C, and none for Companies B and C recorded the factors for determining the adequate control of exposure status. At Company D, none of the noise risk assessment variables outlined by the NIHL Regulations were recorded, a limitation of the use of a checklist as a risk assessment tool.The recorded information in the noise risk assessment records varied between the respective participating companies  for Company A, whereas none was recorded for Companies C and D. Noise zone demarcation, an administrative control, was recorded in 6 of 11  and 2 of 6  at Company A and Company B, respectively. Furthermore, only 3 of 11  facilities at Company A recorded historic noise reduction efforts undertaken by the respective facilities, whereas none of Companies B, C and D recorded the same information, as applicable. None of Company D noise risk assessment records recorded the variables specified in SANS 10083 code of practice.In addition to the NIHL Regulations-prescribed variables to be recorded in noise risk assessments, the SANS 10083 code of practice also recommends the recording of additional information in the assessment. The recording of the HCP implementation status was 3 of 11 (The noise risk assessment frameworks of all participating companies did not demonstrate tangible evidence of conformance to the SANS 31000 clauses regarding leadership and commitment, integration, establishing communication and consultation, evaluation, adaptation and continual improvement, in general. This is expected against a national gap without a prescribed and adopted standard for conducting risk assessments by regulated industry.Once completed, the risk assessment should be reviewed, and the effectiveness of implemented control measures be continuously monitored. Companies A, B and C  omitted At the time of writing, there remained limited publicly available scientific literature on the subject matter and studies of a similar study design to enable result comparisons.The reviewed records attest that participating companies were conducting noise risk assessments for regulatory compliance purposes HSE, , and forRisk assessors are expected to have thorough understanding and in-depth technical knowledge of a process being assessed to achieve meaningful results (Center for Chemical Process Safety, The multidisciplinary team required for conducting a noise risk assessment  should cThe noise risk assessment determines and records sources of hazards, exposure levels where available, routes of exposure, exposure duration and frequency, and identification of the most exposed job categories (South Africa, Fragmentation in the risk assessment process, which can be avoided by adopting guidelines such as the SANS 31000, has implications that impact the decision-making process of deciding on implementing required control measures. The risk assessment processes of the participating companies in this study were misaligned with certain selected clauses of SANS 31000 (South African National Standard, Following the completion of the entire risk assessment process, practical steps to manage identified health risks should be taken, followed by an evaluation to assess the effectiveness of the effected measures, instruction and training HSE, , a practNoise risk assessments were a confirmed practice at the participating companies and were conducted by employer-delegated professionals inclusive of occupational hygienists, occupational health nurse or practitioner as well as a risk officer. Stakeholder involvement and participation during noise risk assessments was recorded extensively at Companies B and C, an indicator of internal communication and consultation in the risk management processes. Legally, health and safety representative and health and safety committee involvement and participation in noise risk assessment is an enforceable legal requirement which was absent in some facilities. Factors such as mention of any reasonable deterioration in or failure of control measures, adequate control and formalisation of HCP, recorded as part of risk assessment variables in the records were generally omitted in the noise risk assessments, adjudging the process as incomplete. The recording of information relating to these factors affects the risk analysis phase. The enrolled risk assessment records were also adjudged as being improperly aligned, in general, to the risk assessment guidelines specified in the SANS 31000 relating to elements such as establishing communication and consultation, evaluation, adapting, continually improving, leadership and commitment, and integration. Additionally, the review and monitoring of the assessed noise risk assessment aspects remained non-existent across all participating companies. Conclusively, the noise risk assessment processes at the four participating companies had technical shortcomings, which influences subsequent HCP management process. In general, an improvement in the noise risk assessment processes among the participating companies is recommended, in order to minimise the pervasive NIHL.Future studies should investigate the implementation stages and status of recommended noise controls and their effectiveness as outlined in noise risk assessment records. Furthermore, future studies should also investigate the roles of both the health and safety representatives, and health and safety committees in following up on recommended or proposed corrective actions for noise control."}
+{"text": "With climate change becoming a global concern, a low-carbon economy has become an inevitable trend. Carbon neutrality is considered an important step in curbing global greenhouse gas emissions and reducing carbon footprints. However, a low-carbon economy is not only about environmental protection but also closely related to human health. Against this background, a special topic on low-carbon economy and health in the context of carbon neutrality is proposed, aiming to promote the emergence of a series of emerging research and the sustainable development of low-carbon economy and human health. The articles included under this topic have been researched from different perspectives, introducing new research perspectives, methods, and techniques for the further development of the topic, which will have a positive impact on promoting the in-depth research and development of the topic.Zhu et al. concluded that the NSGA-II algorithm performs well in the doctor-patient bilateral matching problem, but the matching accuracy needs to be further improved. In terms of the pharmaceutical supply chain, Fu and Zhao considered the risk of pharmaceutical supply chain disruption under two modes of centralized and decentralized decision-making and constructed a combined contract model to effectively coordinate the pharmaceutical supply chain under supply disruption crises, but further research is needed in the area of stable coordination of pharmaceutical supply chain with multi-levels and multi-objects. In terms of public health expenditures, Omri et al. concluded from their study that public and private health expenditure is effective in mitigating environmental degradation on health status in Saudi Arabia, especially public health expenditure. In terms of regional green development, Wang W et al. constructed a rating model for the high-quality development of China's Yangtze River Delta Green Integration Demonstration Zone, and proposed methods and approaches to measure the construction milestones of high-quality development, which provides a reference for the evaluation study of high-quality development in other city clusters. The model suitability can be further improved by combining the actual data of city clusters in future studies. In terms of government guidance, Xu et al. observed in their study that the characteristics of local government information sources  have a significant positive effect on consumers' willingness to purchase low-carbon agricultural products, which can effectively promote the development of low-carbon agriculture. However, the study lacks quantitative research on the degree of contribution of regional brand low-carbon agricultural products to the development of low-carbon agriculture. Hu et al. offer suggestions for establishing and managing a low-carbon technology innovation system, along with insights into theoretical research on public health and high-quality development in China. Wang Q et al. examine the impact mechanism of environmental education on environmental quality in the context of low-carbon economy. Wu et al. analyze the optimal use of urban resources based on public health. Bai et al. utilize unit root tests, co-integration tests, and regression analysis to empirically investigate the associations between carbon emissions and GDP in the industry, construction, and transportation sectors. Zheng et al. provide significant practical contributions to sustainable development and the promotion of responsible population growth.The topic of low-carbon economy and health in the context of carbon neutrality has been studied multidimensionally in the articles included in this topic. In terms of the doctor-patient relationship, To sum up, for the special topic of low-carbon economy and health in the context of carbon neutrality, researchers have carried out relevant research in the areas of healthcare resource allocation, public health resources, urban green and low-carbon development, and the process of low carbonization of sub-fields. The further deepening of this topic expands the research field, provides subdivided research directions, relevant theoretical foundations, research methodological references, data support, and case analyses, and plays a positive role in promoting subsequent in-depth research. In more in-depth research in the future, the following can be further explored: the evaluation system of healthcare resource allocation and the construction of a low-carbon supply chain, the supply and allocation of public health resources in less developed regions, the quantitative assessment method of the impact of low-carbon economic policies and measures on health, and the process of decarbonization in the fields of agriculture, industry, and urban construction, as well as synergistic effects among different fields.YZ: Writing\u2014original draft. ZL: Writing\u2014review and editing. CH: Writing\u2014review and editing."}
+{"text": "Editorial on the Research TopicHighlights in quality of life 2021/22www.pubmed.gov, the growth immediately becomes apparent, with 2,038 papers published in 1992, 7,391 in 2002, but a staggering 40,740 in 2022 alone.Quality of life (QoL) has long been a part of medical research, attracting a steadily increasing amount of attention from scholars around the world. However, recent years have seen an unprecedented rise in research about the topic. Once the terms [(patient-reported outcomes) or ] are entered into the search strategy at Patient-Reported Outcome Measures (PROs) are used to assess QoL. A PRO has been defined as any report about patient health status which comes directly from the patient, without being interpreted by a physician or anyone else . PROs arProtocol for the Cultural Translation and Adaptation of the World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project Endometriosis Participant Questionnaire (EPHect) presents the process in detail. Content and face validity of WERF EPHect EPQ-M were performed. The cross-cultural translation and adaptation of the questionnaire was carried out using the recommended guidelines and COnsensus-based Standards for the selection of health status Measurement Instruments (COSMIN standards) (The paper andards) . The proandards) .International databases are becoming increasingly important, especially in the context of collecting data to conduct analyses on large groups of subjects in many conditions, e.g., in endometriosis, as presented in the paper. Research data registries contain shared datasets and facilitate collaborative research between various international centers. Surgical databases which collect information about the outcomes of the procedure and complications are of great importance.Community-Engaged Approaches to Cervical Cancer Prevention and Control in Sub-Saharan Africa: A Scoping Review, deals with the issues of cervical cancer prevention. Organized screening has decreased cervical cancer incidence in the developed countries. However, at the same time, cervical cancer remains to be the leading cause of cancer-related mortality among African women. The paper is a narrative review describing community-engaged approaches to cervical cancer prevention and control methods in Sub-Saharan Africa (SSA). The Covidence systematic review software was used and nine articles were selected for the final analysis. The objectives of the review were as follows: to describe community engagement activities in cervical cancer prevention and control in SSA, to identify the aspects of cervical cancer research which used community engagement, and to describe the best practices for community engagement in achieving the goal of cervical cancer prevention and control. The study presented a Community-Based Participatory Research (CBPR) framework and analyzed the research, in accordance with its eight principles.The following article, Cervical cancer is a global public health problem, with a particularly high burden in many low- and middle-income countries. The proven effectiveness of interventions such as vaccination against the most oncogenic human papillomavirus (HPV) types, and screening, particularly with HPV-based methods, makes cervical cancer a largely preventable disease . SubstanMis et al., is released under the auspices of the World Endometriosis Research Foundation. The organization aims to be a global charity facilitating research into endometriosis to improve knowledge and treatment. In turn, the authors of the narrative review highlight the role of tribal leaders, religious leaders, and community health workers in increasing knowledge about cervical cancer and screening. They highlight strategies to identify and engage target populations and improve awareness.Both articles address the topic of research methodology. On the one hand, we have a paper on an international database covering a variety of patient medical data to improve our understanding of endometriosis. On the other hand, we have a paper evaluating the feasibility of community-based prevention of cervical cancer. The authors of these papers aim to reduce the morbidity of endometriosis and the incidence of cervical cancer. The WERF EPHect EPQ-M questionnaire, whose validation is presented by"}
+{"text": "Efficient and secure supply chains are vital for effective health services worldwide. In low- and middle-income countries, the accessibility, affordability and availability of essential medicines, including antimicrobials, remain challenging. Ineffective supply chains often cause antimicrobial shortages, leading to inappropriate use of alternative agents and increasing the risk of antimicrobial resistance. Shortages, coupled with insecure supply chains, also encourage the infiltration of substandard and falsified medicines, leading to suboptimal treatment and further promoting antimicrobial resistance. Addressing antimicrobial supply-chain issues should be considered a key component of antimicrobial stewardship programmes. We have explored the link between medicine supply chains and antimicrobial use in seven focus countries: Kenya, Malawi, Nigeria, Sierra Leone, Uganda, United Republic of Tanzania and Zambia. We explored country medicine supply-system structures, national medicine supply-chain policy documents and global study reports. Our aim was to develop evidence-based strategies to enhance the effectiveness and efficiency of the medicine supply chains in supporting antimicrobial stewardship efforts. Better management of medical supply chains involves rational selection, quantification, forecasting, procurement, storage, distribution, use and stock management of antimicrobials. Important supply-chain considerations include pooled procurement networks to ensure consistent pricing of quality-assured antimicrobials, and improved resource utilization and information exchange among relevant stakeholders. We propose adaptable recommendations for integrating medicine supply chains as an essential part of antimicrobial stewardship programmes, with a call for action at the local, regional and national levels in low- and middle-income countries. Antimicrobial resistance disproportionately affects low- and middle-income countries.Health supply chains are the processes and operations required to get products and medicines from manufacturers to health-care staff and patients at the right place, price, time, cost, quality, efficacy and quantity. Strong and secure supply chains save lives. They are the fundamental building blocks of national welfare systems and are necessary for the achievement of the sustainable development goals. The coronavirus disease 2019 (COVID-19) pandemic drew attention to the importance of resilient supply chains in national emergency response efforts.A continuing challenge in low- and middle-income countries is inadequate access to essential medicines and medical supplies, including antimicrobial medicines.There is limited published information specifically on the supply chains for antimicrobials and access to these medicines in low- and middle-income countries. In this article we explore the impact of medicine supply chains on antimicrobial use, focusing on seven countries of the Commonwealth Partnerships for Antimicrobial Stewardship programme. We issue a call to action on incorporating supply-chain considerations into antimicrobial stewardship policies and processes.\u00ae articles published between 2015 and 2021. \u2013All seven countries obtain, fund and distribute essential medicines through a combination of health ministries, nongovernment organizations and the private sector. The existing systems are classified as tier systems, single agencies or devolved. Except for Nigeria, every country has a centralized supply chain. All seven countries have existing national essential medicine lists. Kenya, United Republic of Tanzania and Zambia have WHO AWaRe  categories of antimicrobials recommended in their national essential medicine lists. All seven countries face challenges in the management of health products and technologies that are familiar to many high-income countries. Challenges reported in medicine supply chains include: inadequate quality assurance; weak regulation; poor enforcement of laws; unavailable and unaffordable medicines; transport and storage infrastructure; poor information and logistics management; inadequate human resources; and inadequate financing.Local supply chains for medicines and medical supplies in Kenya are dependent on three supply chains within the health sector: the health ministry; non-profit procurement agencies; and private distributors and wholesalers.\u2013Shortages of essential medicines in KenyaThe supply chain for essential medicines in Malawi follows a rigorous process that ensures compliance with the Public Procurement Act (2003) and the Public Procurement Guidelines (2004). The Central Medical Stores Trust sources medicines and other health commodities in accordance with the policies and guidelines of the Director of Public Procurement. Essential medicines are distributed from a central warehouse to three regional medical stores which supply public health facilities.Malawi has other parallel supply-chain systems for essential medicines, especially relating to disease programmes such as tuberculosis, malaria and reproductive health. Chronic stockouts of medicines at the central medical stores and in health facilities remain a challenge.There are two key agencies in Nigeria involved in medicine supplies: the National Agency for Food and Drug Administration and Control; and the Pharmacists Council of Nigeria. The pharmaceutical services division within the Nigerian food and drug authority is part of the health ministry and regulates and monitors the pharmaceutical supply chain, supporting access to quality medicines in Nigeria.Nigeria supplies agencies have faced difficulties with selection of medicines and vaccines, procurement and distribution of medicines, inventory management and storage infrastructure.,The National Medical Supplies Agency of Sierra Leone, formerly the Directorate of Drugs and Medical Supplies, undertakes the transparent and cost\u2013effective procurement, warehousing and distribution of drugs and medical supplies on behalf of all public institutions throughout the country.The impact of the COVID-19 pandemic on the local pharmaceutical industry resulted in severe drug shortages and medicine insecurity in the country due to the restrictions imposed on cross-border imports.The management of essential medicines and health supplies in Uganda is guided by the Essential Medicines and Health Supplies Management Manual of 2018. The National Medical Stores provide the public health-care facilities with the core antibiotics.As in many other low- and middle-income countries, Uganda faces challenges with enforcement of regulations, creating multiple nodes of entry for medicines into the market that may accelerate the proliferation of substandard and falsified products.The United Republic of Tanzania has a centralized procurement system for medicines. The Medical Stores Department, under the Public Procurement Act 2004 and Regulations 2005, is empowered to advertise, receive, evaluate and award successful bidders for government contracts. The price and quality of the product are given equal consideration when awarding the tender.The country has a higher use of antimicrobials compared with many other countries worldwide. Contributing factors include a relatively higher burden of infectious diseases; limited diagnostic services in health facilities; widespread availability of antibiotics without prescription; and the unexplained use of certain antibiotics in the animal health sector.Zambia has a three-tier public sector distribution system for essential drugs. The primary distribution of drugs and other health commodities is managed by the Zambia Medicines and Medical Supplies Agency, formerly Medical Stores Limited. The secondary distribution of commodities falls under the responsibility of district health management teams reporting to the health ministry. The national pharmacovigilance unit under Zambia\u2019s Medicines Regulatory Authority leads and coordinates the pharmacovigilance or drug safety monitoring programme in the country.According to Zambia\u2019s national health strategic plan, the key planning issues for the medicines, vaccines and medical supplies sector are weak coordination mechanisms and accountability in supply-chain management, and an inadequate quality management system for data in the supply chain.,Challenges within antimicrobial supply chains worldwide, including in low- and middle-income countries, make forecasting and mitigating antimicrobial shortages difficult.,Antimicrobials, especially antimalarials and antiretrovirals, are the most commonly falsified medicinal products worldwide.The main functions of countries\u2019 national medicines regulatory authorities include: (i)\u00a0control of pharmaceutical products through registration and post-marketing surveillance; (ii)\u00a0control of activities by licensing and inspection of manufacturers, importers, exporters, wholesalers, distributors, pharmacies and retail outlets; (iii)\u00a0control of clinical trials; and (iv)\u00a0control of promotion of pharmaceuticals. However, in 2010 the World Health Organization (WHO) estimated that 34 out of 38 national medicines regulatory authorities in sub-Saharan Africa were not enforcing basic regulatory functions.Drug shortages, combined with inappropriate prescribing and use of antimicrobials, accelerate the development of antimicrobial resistance and hence reductions in antimicrobial effectiveness.,Pharmacists have an important role to play.,Addressing supply-chain challenges requires consistent efforts at the global, national and regional levels, building on existing partnerships and legislation. We need to address ways to pool the procurement of medicines, improve the forecasting of supply needs and increase the commitment to improving processes and resources. Measures could include appropriate storage conditions, implementing efficient transportation and distribution systems, and maintaining reliable quality control measures throughout the supply chain. Sustainability of medicine supply chains remains an elusive goal that is yet to be integrated into discussions.We can improve antimicrobial stewardship and strengthen the knowledge and evidence base of factors contributing to antimicrobial resistance through ongoing surveillance and research.WHO AWaRe  antibiotic book offers clear and evidence-based recommendations on the appropriate antibiotic choice, dosage, administration route and treatment duration for over 30 prevalent clinical infections in both primary health care and hospital settings. The book\u2019s information aligns with the antibiotic recommendations outlined in the WHO Model list of essential medicines and WHO Model list of essential medicines for children, as well as the WHO AWaRe antibiotic classification.African antibiotic treatment guidelines for common bacterial infections and syndromes also provide care workers with expert recommendations for antimicrobial selection, dosage and duration of treatment for common bacterial infections and syndromes among paediatric and adult patient populations in Africa.It is important to ensure that, as far as possible, appropriate Access and Watch antibiotics are available for the most common infections within hospitals across Africa. The Post-marketing surveillance and pharmacovigilance is needed to detect substandard and falsified medicinal products. Efforts are also required to improve medicine quality by strengthening the medicine distribution chain; ensuring the use of quality-assured drugs through improved pharmaceutical governance; and strengthening the technical capacity of regulatory laboratories, particularly in poor and rural communities.We propose that the basic principles of medicine supply-chain systems should be included in capacity-building for antimicrobial stewardship teams and health-care personnel at local, national and global levels. The managers of procurement systems within a country are responsible for ensuring the continuous availability of essential quality-assured medicines at an affordable price. Implementing monitoring and evaluation systems for antimicrobial resistance and antimicrobial use as part of national action plans could contribute to the use of quality-assured medicines, and reduce the distribution of substandard and falsified medical products.In the absence of stringent national and international regulatory oversight, ensuring the quality of medicines becomes a choice rather than a duty. As a result, there is a risk that poor-quality medicines will enter the supply chain, causing harm to individuals and public health.Box\u00a01Optimize appropriate antimicrobial use through pre-service and in-service training for health-care workers on effective medicine procurement, inventory control and distribution management.Designate local resource mobilization as a priority area in health ministries to build and sustain the medicine supply-chain systems.Engage the right human workforce into the local supply chains to ensure reliability of the systems .Establish or empower medicine and drug and therapeutics committees to act as an oversight mechanism in health-care facilities.Establish antimicrobial stewardship programmes that include supply-chain management as an essential component, to ensure rational antimicrobial selection, quantification and forecasting, procurement, storage, distribution, use and stock management of antimicrobials.Streamline and strengthen national medicine supply-chain systems. Use pooled procurement networks, to ensure consistent pricing of quality-assured antimicrobials and to improve resource utilization and information exchange between organizations.Harmonize drug master files and specifications required for antimicrobial resistance surveillance.Standardize pre-qualified supply mechanisms, including those from manufacturers, to ensure constant availability of antimicrobials.Increase the number of well-designed studies into medicine supply-chain management to identify gaps and challenges in low- and middle-income countries.Increase quality assurance programmes that conduct routine inspections of manufacturers, suppliers and warehouses to ensure medicines meet international quality standards.Consider approaches such as the Lom\u00e9 Initiative to criminalize the trafficking of falsified medical products.Increase regulatory capacity and reporting mechanisms to detect and tackle substandard and falsified medical products.Strengthen national medicines regulatory agencies and harmonize legislation, taking a collaborative approach through the African Medicines Agency.Increase local production of antimicrobials to strengthen supply-chain resilience and reduce the risk of infiltration of substandard and falsified antimicrobials.Encourage more national policies and government regulatory frameworks for the essential infrastructure, such as national warehousing, distribution and transport of quality-assured health products.Incorporate analysis of bottlenecks into national supply chains to identify underlying causes and human behaviours that influence procurement agencies and practices.Integrate digital health systems interventions, with the implementation and scale-up of logistics management information system software, to improve the forecasting, monitoring, evaluation, tracking and planning of medicine supply chains. Model list of essential medicines.Ensure that appropriate Access and Watch antibiotics are available for key diseases relevant to the national context and the World Health OrganizationSet up consumption surveillance systems for antimicrobials to ensure rational antimicrobial selection and use, particularly lower down the supply chain.Develop and implement antimicrobial national action plans to include supply-chain management.Ensure antimicrobial stewardship initiatives address over-prescribing and inappropriate prescribing; improve patient adherence to treatment regimens; and address potential environmental contamination, for example through inappropriate disposal of antimicrobials.Update mechanisms for the review and reporting of substandard and falsified medicines, providing a user-friendly and safe environment to encourage reporting and facilitate feedback."}
+{"text": "A wide variety of traits is heritable and has genetic loading, including schizophrenia spectrum disorders (SSDs) and its associated neurocognitive features. The genetic architecture of SSDs is polygenic, with the contribution of thousands of single nucleotide polymorphisms of small effect with an estimated SNP-heritability of 24%. The same occurs with neurocognitive phenotypes such as intelligence or educational attainment. Therefore, the method of polygenic risk scores (PRS) is useful in estimating the genetic burden of such traits. Moreover, the use of PRS in a sample of genetically related individuals would allow analyzing the contribution of genetic and environmental factors involved in the development of the disorder and its candidate endophenotypes.To estimate PRS for schizophrenia, and polygenic scores for intelligence and educational attainment in patients with First Episode Psychosis (FEP), their first-degree relatives (siblings and parents), and a group of healthy controls.The sample is comprised of 579 participants of the PAFIP-FAMILIAS project in Santander, Spain . All provided sociodemographic information and completed the same neuropsychological battery. Participants\u2019 DNA was extracted from venous blood samples, and genotyping was performed at the Centro Nacional de Investigaciones Oncol\u00f3gicas (CeGen) by the Global Screening Array v.3.0 panel (Illumina). Data quality control, imputation, calculation of PRS, and genetic association analysis are being performed using PLINK, SHAPEIT, IMPUTE2, SPSS and R.Data analysis is currently in progress, at the quality analysis stage, in collaboration with the Institute of Psychiatric Phenomics and Genomics (IPPG) in Munich, Germany. We expect to find higher PRS for schizophrenia in FEP patients, while their first-degree relatives will potentially show intermediate risk scores between patients and healthy controls. A similar finding is expected regarding intelligence and educational attainment, as FEP patients may show more genetic burden for low intelligence and education.The estimation of PRS has demonstrated to be valuable in studying complex traits such as schizophrenia. We believe that by applying this method in a family design can provide interesting insights on the development of SSDs and its potential endophenotypes, and potentially useful in their prevention.None Declared"}
+{"text": "We are delighted to publish the second volume of the Research Topic: Antimycobacterial Drug Discovery\u2014Molecular Therapeutics and Target Identification. The Research Topic continues the discussion with an emphasis on the identification of novel antimycobacterial compounds and, more broadly, antibacterial compounds isolated from natural products or derived synthetically. Studies on the mechanisms of action of these bioactive molecules provide insights into the design of safer therapeutics and antimicrobials for the treatment of multidrug-resistant infections.Khare et al. The authors provide a comprehensive summary of the effects produced by alkaloids, phenolic compounds, terpenes, and coumarins against drug-resistant pathogens, with a focus on the major determinants of antibiotic resistance, such as efflux pumps, cell permeability, and modification of the antibiotic targets. Rubio et al. report on the mechanism of cellular uptake of mycolactone, a lipid toxin produced by Mycobacterium ulcerans, from the circulating plasma Using a combination of dynamic light scattering and fluorescence spectroscopy, the authors demonstrate how mycolactone behaves in solution and how it interacts with serum albumin and lipoproteins in plasma. Monitoring plasma levels of complexes formed by mycolactone and albumin/lipoproteins could be useful for the early diagnosis of patients with Buruli ulcer disease. Wang et al. investigate the effect of the labdane diterpenoid andrographolide on the hemolytic activity of S. aureus. Andrographolide dose-dependently inhibits hemolytic activity by significantly downregulating the transcript levels of the Hla gene, which in turn is responsible for the expression of the crucial virulence protein Hla. Molecular dynamics simulations of Hla-andrographolide interactions provide valuable insights into the structural requirements for the observed activity and have the potential to design more potent andrographolide analogs. Hoffmann et al. demonstrate the repurposing potential of nitroxoline for the treatment of multidrug-resistant tuberculosis (MDR-TB). Originally approved for the treatment of urinary tract infections, nitroxoline was tested in a panel of MDR-TB cells and found to have MIC values of 4\u20138\u00a0mg/L. Finally, Korycka-Machala et al. report the synthesis of thiosemicarbazide-based compounds and their structure-activity relationship against Mycobacterium tuberculosis. The authors demonstrate the efficacy of these compounds in inhibiting the growth of intracellular M. tb and reducing biofilm formation. The selection of resistant mutants and their whole genome sequencing identified the mmpR5 gene as a target for these analogs.The second volume begins with a review of the antimicrobial properties of phytochemicals by Taken together, the second volume of this Research Topic: \u201cAntimycobacterial Drug Discovery: Molecular Therapeutics and Target Identification\u201d, provides recent advances in the development of antibacterial and antimycobacterial agents. We acknowledge the contributions of all the authors that made this research volume possible."}
+{"text": "After the introduction of nanotechnology as a new science, there were tremendous changes in its application. Nanomaterials rapidly penetrate a diverse area of biomedicine and pharmaceutical research, including drug development, drug delivery, tissue engineering and medicinal chemistry. Its versatile use helps in alleviating complex difficulties faced with drug administration and absorption, controlled release, targeted delivery and cellular uptake. Due to their distinctive physico-chemical properties and ability to form various solid-state formulations, they find increased use in the preparation of new drug formulations, imaging techniques and particularly in medicinal chemistry as catalysts for the sensitive determination of drugs and other biologically active compounds. The role of nanomaterials as catalysts in the preparation of substances with pharmacological properties, the preparation of sensors, or the degradation and removal of medicinal compounds polluting the environment is undeniable.This special issue aims to cover recent advances in the preparation and application of nanomaterials in the above-mentioned fields. Its scope includes the role of nanomaterials in drug delivery and the development of new drug formulations, novel polymorphs and other solid-state forms, the influence of nanotechnology on the physico-chemical properties of importance to adsorption, distribution and metabolism of drugs, tissue and cellular uptake of nanomaterials and their treatment potential and application of nanomaterials as catalysts for the sensitive and selective determination of biologically active compounds.The special issue is guest-edited by Hassan Karimi-Maleh, Afsaneh L. Sanati, Rozhin Darabi. The whole issue will be split into two consecutive issues. This issue, the first of the series, consists of 5 review articles and 6 original papers. Two reviews address the synthesis of nanomaterials and their applications . A review by D. Pylypenko (\u201cLiposomes: from August Wassermann to vaccines against COVID-19\u201d) covers liposomal antigens as antigen-delivery systems for diagnosis and immunoprophylaxis. Two additional reviews tackled the use of nanomaterials as therapeutics (\u201cSupremacy of nanoparticles in the therapy of chronic myelogenous leukemia\u201d and \u201cInfections associated with SARS-CoV-2 exploited via nanoformulated photodynamic therapy\u201d). The original papers present the preparation and application of nanoparticles of different materials such as cyclodextrin, silica, selenium, silver, chitosan and polyvinyl alcohol."}
+{"text": "The number of patients reporting the use of cannabis for medical purposes, whether through state-regulated medical marijuana programs or through over-the-counter hemp extracts, continues to grow. The growth in medicinal use of cannabis has in many ways surpassed the scientific data on the benefits and hazards of cannabis, and the scientific community has largely been left playing catch-up. Since 1996, when California became the first jurisdiction to legalize medical cannabis, the number of states following suit has grown and is currently at 37, while nearly 50 countries have legalized medical cannabis  including Canada, Austria, Uruguay, Australia, South Korea, and Lesotho.Cannabis sp. produces a number of phytochemicals with potential medical benefits including terpenes, flavonoids, and a unique class of molecules called cannabinoids, of which \u03949-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the two most studied [ studied ,2. Amazi studied .Cannabis and Cannabinoid Research, in 2016, Medical Cannabis and Cannabinoids, in 2018, and The Journal of Cannabis, in 2019.The recent growth in cannabis and cannabinoid research is perhaps best highlighted by the establishment of three scholarly journals devoted solely to this topic in the past few years, namely, This Special Issue features fourteen original research articles across a wide range of topics and includes 10 reports on phytocannabinoids, 2 studies examining the endocannabinoid system, and 2 papers using synthetic cannabinoids. Three of these studies looked at the role of cannabinoids at mediating pain, two studies examined cannabinoids for treating mental illness, two studies addressed the potential safety of cannabinoids, two looked at cannabinoids as treatment options for gastrointestinal inflammation, and two studies examined the impact of cannabinoids on neurodevelopmental diseases. Other studies examined the impact of cannabinoids on cancer cell growth, anti-inflammatory activity in fibroblasts from patients with rheumatoid arthritis, regulation of matrix metalloproteases and cell proliferation, and regulation of neuroprotective genes in the brain. These various topics highlight the wide-ranging potential benefit of cannabis and cannabinoids to treat an array of human illness and disease.In a study by Moreno-Sanz and colleagues, the impact of inhaled cannabis to treat pain and anxiety was examined . The autIn addition to the Moreno-Sanz study described above, one other study examined cannabinoids in mental illness. A study by Zer-Aviv et al., found that inhibition of the endocannabinoid metabolizing enzyme fatty acid amide hydrolase (FAAH) produces a stress-protective effect through activation of \u03b2-catenin in the nucleus accumbens region of the brain . The stuHajjar and colleagues examined the use of prescription and non-prescription medications in patients using medical cannabis, as self-reported by patients . The stuBacalia et al. examined the impact of CBD on intestinal inflammation, and they found that in female mice, CBD suppresses inflammation in the absence of estradiol, but it enhances inflammation in animals with estradiol . YekhtinG\u00e1ll and collaborators found that CBD increases the latency to the first seizure and decreased the mortality associated with the pentylenetetrazol (PTZ)-kindling model of epilepsy in rats . HoweverIn another study that examined the anti-inflammatory activity of cannabinoids outside of the gastrointestinal tract, Lowin et al. found that the impact of THC on inflammation in synovial fibroblasts from rheumatoid arthritis (RA) patients is dose dependent . TherefoCannabis and the potential therapeutic utility of some of these molecules to treat a number of medical conditions [Four review articles in this Special Issue summarize information on a wide array of topics related to cannabinoids. Duranti and collaborators review the current literature on the endocannabinoid system with regard to neuroprotection and neuroregeneration . The focnditions . Tudorannditions . Finallynditions .In a brief report by Sestan-Pesa et al. the authors explore the mechanism by which THC may lead to increased risk of schizophrenia, depression, and anxiety by looking at ghrelin signaling . GhrelinLicitra and colleagues performed a systematic review of the literature on cannabinoids in zebrafish . The autCannabis is a complicated plant that produces over 100 cannabinoids in addition to terpenes and flavonoids. Adding to the complexity of trying to address the mechanism of action for cannabis is the fact that the cannabinoids that have been studied have been reported to exhibit activity at a number of different receptors. This makes cannabinoids (and cannabis) a promiscuous drug. While typically viewed as a negative, promiscuous drugs do offer some advantages, most notably the ability to target different pathways of a disease with one medication [dication . The fie"}
+{"text": "Editorial on the Research TopicAugmented-, virtual- and mixed reality in visceral surgeryTechniques such as Augmented Reality (AR), Virtual Reality (VR), and Mixed Reality (MR) are increasingly entering the medical workplace and, in conjunction with the field of visceral surgery, represent a potential paradigm shift that could reshape surgical strategies, training methods and patient education. For this reason, the present research topic serves to explore the interrelationship between these immersive technologies and the complex field of visceral surgery.The development of patient-specific, three-dimensional organ models using advanced imaging modalities such as computed tomography (CT) and magnetic resonance imaging (MRI) had enabled groundbreaking progress in this field, offering immense potential of immersive technologies in the field of visceral surgery.Enhanced by AR or embedded in a virtual environment by VR, these complex, patient-specific 3D models provide surgeons with unprecedented insight into the complexity of their patients\u2019 condition, potentially improving not only the precision of surgical planning but also providing an excellent opportunity for patient education. Furthermore, it provides surgeons, both experienced and trainee, with the unique ability to immerse themselves in immersive training scenarios that mimic real-world situations. These capabilities will allow these technologies to serve as cornerstones for the next generation of surgeons to train their skills in a risk-free environment.The collaborative nature of this research topic embodies the multi-faceted methodology essential for navigating the unexplored terrain of Extended Reality in the context of visceral surgery. This field brings together general surgeons, visceral surgeons, anatomists, biologists, and distinguished faculty members from renowned medical institutions. Their common effort is to advance the clinical, translational, and basic research that provides the foundation for these new technologies. Through the combined effect of our efforts, we aim to uncover the full spectrum of the potential of AR, VR, and MR, thereby finding solutions to both known and unforeseen challenges.Cetin et al. particularly address the utilization of a VR headset as a tool to assess the feasibility of an innovative illumination concept for the operating room. Meanwhile, Reinschl\u00fcessel et al. and Staubli et al. focus on the 3D visualization of patient-specific anatomical structures and the utilization of the generated models for preoperative planning. In addition, Pu et al. showed the possibilities of using SpyGlass in the treatment of complex pancreatic stones of the pancreatic duct.In this context, Cetin et al. describe a feasibility study regarding the utilization of automated lighting systems in the operating room. Both real-world and virtual tests were conducted to investigate the effectiveness of the automated lighting systems. The findings demonstrate that the application of automated lighting systems in the operating room presents a promising possibility for enhancing visibility during surgery and facilitating working conditions for medical personnel. In this paper, Virtual Reality assumes a central role, as a VR simulation was employed to assess the efficacy of an automated illumination system within the operating room. The VR simulation was executed on a computer, presenting an operating room-like scenario.Reinschl\u00fcessel et al. delineate in their work the utilization of VR technology for the planning of liver tumor resections. Two instances of liver tumor resections are expounded upon, wherein VR was employed for surgical planning and preparation. The authors deliberate upon the advantages and challenges relating to the application of VR technology within the domain of surgery.Staubli et al. outline a novel approach aimed at enhancing comprehension of biliary anatomy and facilitating surgical trainee education through the integration of Magnetic Resonance Cholangiopancreatography (MRCP) with VR. The authors have developed a VR application enabling users to visualize and manipulate biliary anatomy in a three-dimensional context. The application was subjected to case studies, demonstrating its capacity to augment the understanding of biliary anatomy and streamline the instructional process for surgical trainees.Pu et al. discuss the use of endoscopic retrograde cholangiopancreatography (ERCP) combined with SpyGlass technology for the treatment of pancreatic duct stones (PDS). The authors present a case study of a 54-year-old male with severe abdominal pain and pancreatic duct stones. The study emphasizes the advantages of SpyGlass-assisted ERCP, including improved visualization, accurate biopsy, and successful stone removal, particularly for complex cases.The integration of immersive technologies such as AR, VR and MR into the field of medicine, specifically within the complex field of visceral surgery, unveils a vast array of potential opportunities that have the capacity to revolutionize patient care and everyday clinical practices across almost all domains. The studies of this Research Topic serve as the initial step towards a series of upcoming research projects vividly demonstrate the range of potential applications of extended reality techniques."}
+{"text": "The globalization of food trade and the emergence of disease outbreaks involving several foodborne pathogens and foods has focused the attention of both the research community and consumers on food safety. Microbial contamination can involve different stages of food processing and distribution, with a potentially dramatic impact on human health and food business. Several methods, involving culture-dependent and -independent techniques, were developed to detect foodborne pathogens in the food supply chain. In this respect, gold-standard reference methods are currently available for most pathogens, but some of them are time-consuming and expensive. Moreover, routine controls carried out by manufacturers and food safety authorities are normally focused on bacteria and not on viruses and fungi, which can have a significant impact on food safety. In the European Union, the number of human cases caused by Noroviruses and other Caliciviruses increased sharply in 2021 .w), are now known to allow the persistence of pathogens [The conditions imposed by the physical and chemical characteristics of food products, as well as by the hurdles adopted in food manufacturing, act as selective factors for the survival and the growth of pathogens . Howeverathogens . Dominanathogens ,6. Interathogens ,8. On thThe control of food-borne pathogens in food systems has evolved over time to promote the safety of food products and extend their shelf-life. The main control methods aim to inhibit the growth of foodborne pathogens by chemical and physical approaches. However, many of these methods affect the characteristics of food products, show low effectiveness over time, have a significant environmental footprint, and are not appreciated by consumers. New biocontrol methods have been proposed to maintain food appearance and acceptability, to preserve nutrients and to extend shelf-life . Among tSalmonella enterica, Campylobacter jejuni, enterohaemorrhagic Escherichia coli and Listeria monocytogenes are the most common foodborne pathogens in human cases [Aliarcobacter spp., Cronobacter spp., Vibrio spp., Clostridioides difficile, Mycobacterium paratuberculosis, Streptococcus suis, Helicobacter pylori, and Yersinia enterocolitica [Surveillance is a long- or short-term control and management measure, aimed to monitor foodborne pathogens and their socio-economic impact, which includes the systematic collection of relevant incident data, disease frequency and additional factors regarding the incidence and the spread of outbreaks . Trackinan cases ,17. HoweThis Special Issue aims to publish quality articles on the detection and control of foodborne pathogens, also considering the impact of innovative technologies and the emergence of new foodborne pathogens."}
+{"text": "New England Journal of Medicine [The purpose of this perspective is to highlight potential unintended and adverse consequences of the increasing use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in children and adolescents. We propose a set of activities suited in particular to the NIH National Center for Advancing Translational Science (NCATS) network of Clinical and Translational Science Award (CTSA) hubs to mitigate these possible threats to pediatric health. Our apprehension is heightened, ironically, because recent studies have corroborated in children and adolescents the remarkable effectiveness of the GLP-1RAs in the management of type 2 diabetes and, as satiety-enhancing medications, in obesity that had been previously demonstrated in adults. Two studies were published in the impactful Medicine . CurrentMedicine , their iA major element of our concern is that unbalanced and inappropriate reductions in caloric (energy) intake could be induced by GLP-1RA in children and adolescents. Energy in children and adolescents is expended not only on physical activity but also, unlike in adults, on growth and development. The balance of energy intake and energy expenditure influences growth and health across the lifespan. For example, with appropriate levels of exercise and diet during adolescence, bone mineralization is increased and the risk of osteoporosis and pathologic fractures much later in life is lessened . Almost Rapid development of oral-administration formulations of GLP-1RA and the proclivity among adolescents for risk-taking  create aAnecdotal clinical experience of our group suggests that there is already widespread knowledge in the pediatric population about the GLP-1RA\u2019s effectiveness as satiety medication aiding weight loss, not helped by apparent widespread use documented in the popular media . Health et al. cited above in their publication on semaglutide effectiveness in pediatric obesity [Adding to our concerns about potential abuse and overuse of the new GLP-1RA medications is the increasing medicalization of pediatric conditions , many of obesity ,19. HoweWe recognize the challenges imposed by implementing truly effective lifestyle interventions in children and adolescents who are obese or suffer from frank type 2 diabetes. By the time such children or adolescents gain access to medical intervention (which is currently limited at best) or are eligible for clinical trials, the clinical trialist and primary care provider must overcome the years of poor diet, sedentary behavior, and lack of available, safe, and supportive venues for vigorous play and exercise that for the majority of these children paved the way for their conditions. In the classic 2002 NEJM study designed to prevent the transition of pre-diabetes to frank type 2 diabetes in adults [The pharmacokinetics and pharmacodynamics of certain GLP-1RAs like liraglutide have been studied in both adult and pediatric populations ; howeverBuild and support multidisciplinary teams of frontline clinicians, community partners, physiologists, and behavioral and pharmaceutical scientists to address the knowledge gap in GLP-1RA effects in children and adolescents , mandated in sixteen states covering \u223c 60% of American school children . SB-PFT Work with the FDA and other agencies to update guidelines for lifestyle interventions in pediatric clinical trials that incorporate state-of-the-art approaches to quantifying, monitoring, and evaluating physical activity, adherence to diet, and accurate measurement of body composition beyond the current reliance on the body mass index, a suboptimal metric of overweight and obesity in adolescents .Elevate and enhance training of the clinical trial workforce on state-of-the-art understanding of effective lifestyle interventions. Such training should also target primary care pediatricians whose exposure to exercise and nutritional science is currently quite limited .Develop, demonstrate, and disseminate learning modules for school personnel , parents, school-aged children, primary care pediatricians, and child mental health professionals about the GL1-RA medications, their appropriate uses, and possible abuse.The GLP-1RA class of medications will benefit children and adolescents with morbid obesity and type 2 diabetes. We also believe that their overuse and abuse are inevitable. The NCATS emphasis on the science of translation positions the network of CTSA hubs to mitigate these potential threats to child and adolescent health. Attention to real-world data, team science, community engagement, implementation and dissemination, and health disparities will be key in formulating research and policy planning. Accordingly, we propose the following elements as a call to action for CTSA hubs across the nation:"}
+{"text": "This Special Issue of the journal Materials aims to gather recent advancements and novel developments in the field of finite element modeling of microstructures in composite materials. The primary focus of this Special Issue is to explore the intricate relationship between composite microstructure and its macroscopic behavior through the utilization of finite element modeling techniques. By showcasing the latest research, this Special Issue aims to enhance our understanding of the fundamental principles governing the mechanical response of composites at the microscale and their implications at the macroscale. Researchers from various disciplines are encouraged to contribute their valuable insights, methodologies, and findings, thus fostering a collaborative environment for advancing the field of microstructural modeling in composite materials.The microstructure of composite materials is incredibly intricate, encompassing the arrangement, distribution, and interaction of constituent components, such as phase materials, voids, and defects. It plays a crucial role in determining the macroscopic behavior of composites, and the relationship between microstructure and macroscopic behavior is highly complex. To investigate this relationship, various tools have been employed, including analytical analysis, mechanical testing, and numerical modeling. Among these, numerical modeling, particularly finite element simulation, offers numerous advantages. The development and refinement of finite element models for microstructures in composite materials have revolutionized virtual testing and prototyping. This approach significantly reduces the reliance on expensive and time-consuming experimental trials, making it a cost-effective and efficient tool for exploring different design configurations and optimizing composite structures. Finite element modeling excels in predicting and analyzing the failure mechanisms of composite materials. By simulating crack initiation and propagation, delamination, and other damage mechanisms, researchers can pinpoint critical regions, evaluate the structural integrity of the material, and propose strategies to enhance its durability and reliability. Leveraging finite element modeling empowers researchers and engineers to gain valuable insights into the effects of microstructure on composite behavior, enabling informed decision-making in composite material design and optimization processes.In terms of future implications, the advancements in finite element modeling of microstructures in composite materials hold immense potential for further progress. Continued developments in computational techniques, algorithms, and multiscale modeling approaches will contribute to even more accurate and efficient simulations. The integration of experimental data with modeling results will synergistically enhance predictive capabilities, resulting in more reliable and optimized composite materials.Moreover, the integration of finite element modeling with artificial intelligence and machine learning techniques opens up exciting opportunities for data-driven material design and optimization. The ability to rapidly analyze vast amounts of data, extract meaningful patterns, and generate novel microstructures with desired properties will revolutionize the field, accelerating the development of advanced composite materials.In summary, the field of finite element modeling of microstructures in composite materials is of paramount importance with far-reaching implications. Its impact extends from fundamental research to industrial applications, enabling improved material design, enhanced performance, and cost-effective solutions. The ongoing advancements in this area will undoubtedly shape the future of composite materials, driving innovation, and pushing the boundaries of their capabilities."}
+{"text": "Tropical veterinary diseases remain a major global concern for the health and well-being of animals and humans. The hot-humid climate in many tropical and subtropical regions promotes the spread of diseases caused by pathogens such as viruses, bacteria, parasites, and fungi. Some of the tropical veterinary diseases include foot-and-mouth disease (FMD), hemorrhagic septicemia (HS), Newcastle disease, influenza, rabies, malaria, and dengue fever. The prevalence of tropical veterinary diseases is high in many parts of these regions, particularly in rural communities that rely on livestock for food and income.These diseases also pose risk to human health, either through direct contact with infected animals or through indirect contact with contaminated fomites, food, or water. Circumstantial factors, such as poverty, restricted access to veterinary facilities, and lack of preventative measures, have worsened the situation. The impact of these diseases can be significant, leading to economic losses for the livestock industry, and imposing severe threats to existing and future food security. To address this issue, effective control and prevention strategies, such as awareness of tropical veterinary diseases among the various stakeholders, improved biosecurity measures, strengthened veterinary services in affected areas, improved innovative technologies by incorporating surveillance AI in diagnostic tools, and sustainable vaccine programs, must be implemented. Nevertheless, there is still much work to be done to effectively address the situation, and ongoing research and strategic collaboration from affected countries are crucially needed.The advancement of modern biotechnology, including molecular biology techniques, has significantly contributed to the understanding of the pathogenesis of infectious diseases, specifically tropical veterinary diseases. Molecular pathogenesis research includes the study of the molecular mechanisms underlying the development and progression of a disease, and it has become a critical tool in the control and prevention of diseases. With this, it is possible to study host\u2013pathogen interactions and host immune responses, develop new vaccines and treatments, and improve monitoring and surveillance. For instance, molecular pathogenesis research has led to the discovery of new vaccine targets, the development of novel vaccine platforms, and the identification of new drug targets for the treatment of these diseases.Iurescia et al. conducted a multidisciplinary study to understand the cause of death of captive African penguins (Spheniscus demersus) infected by avian malaria. The approach includes pathological examinations of the penguins' tissues, molecular characterization of the Plasmodium species and lineages, and mosquito surveillance. The investigation reveals that P. matutinum was responsible for the deaths, and Culex pipiens mosquito, which is present in the region, was involved in the transmission of the disease. The study provides important information about the cause of death and highlights the importance of monitoring and preventing the spread of avian malaria in captive populations of African penguins.In captive bird populations, such as in zoos, the presence of mosquitoes and other vectors can facilitate the transmission of avian malaria, leading to outbreaks of the disease. In this collection, Wardhani et al. investigated the presence of viral neuropathogens in the brains of rabies-negative cats and dogs that were submitted to the Thai Red Cross Society (TRCS) with neurological signs before death. Based on the selective viral molecular screening, the study found that various viral neuropathogens were detected, including carnivore protoparvovirus-1 (CPPV-1) [canine parvovirus (CPV) and feline parvovirus (FPV)], feline calicivirus (FCV), feline bocavirus (FBoV), feline alphaherpesvirus-1 (FeHV-1), and canine distemper virus (CDV). Immunohistochemistry was also employed to further investigate the localization of each viral pathogen. The results revealed that CPPV-1 was present in most of the brain samples, which may have contributed to the neurological signs observed in the animals. The study highlights the importance of considering other viral pathogens in addition to rabies in the diagnosis of neurological diseases in animals.Moreover, Huang et al. elucidated the role of a specific amino acid in the non-structural protein 1 (NS1) on the virulence of the H5N6 influenza A virus (IAV). The study analyzed the pathogenicity of the H5N6 IAV strains isolate A/duck/Hubei/WH18/2015 (JX) and A/chicken/Hubei/XG18/2015 (XGD) in mice. Accordingly, the JX strain was more virulent than the XGD strain with substantial weight loss, severe damage to the lungs and heart, and increased lethality being observed in infected mice. Moreover, the pathogenicity of recombinant viruses demonstrated that 139D mutation in the NS1 could potentially have an impact on the virulence of the JX strain in mice. This study highlights that the amino acid 139D is significant for the virulence of the virus in mice and could serve as a marker for identifying different variants of the influenza virus.Liu et al., differentially expressed circular RNAs (circRNAs) were identified in various liver cells, including hepatic stellate cells (HSCs), hepatocytes (HCs), and Kupffer cells (KCs), after infection with the Echinococcus multilocularis parasite. The findings were validated using quantitative real-time polymerase chain reaction (qRT-PCR) on a selected set of circRNAs. The study also aimed to explore the circRNA\u2013microRNA\u2013mRNA network in these cells during the infection. The result found that the expression of certain circRNAs in the liver cells was changed after infection and that some of the circRNAs had a role in regulating the expression of microRNAs and mRNAs, which in turn play a role in the host response to the parasite. The study highlights the importance of understanding the role of circRNAs in the host response to parasitic infections, which may provide insights into the development of new therapeutic strategies.In recent years, the expression of circular RNAs (circRNAs) has been extensively studied especially for its biological functions in human cells. In the study reported by Macrobrachium rosenbergii, is highly exported and one of the most economically important seafood in Asia. Zhuo et al. analyzed the complete genome of highly pathogenic non-O1/O139 Vibrio cholerae strain GXFL1-4, isolated from freshwater prawn, Macrobrachium rosenbergii. The study identified the genes that contribute to the pathogenicity and antibiotic resistance of this strain. Based on the prediction, the genome contained multiple genes associated with pathogenicities, such as those involved in motility, adhesion, and toxin production. Multiple antibiotic-resistant genes, including kanamycin, ampicillin, tetracycline, aminoglycosides, and beta-lactams, were identified. The study provides valuable insights into the genetics of this strain of V. cholerae and highlights the presence of genes associated with pathogenicity and antibiotic resistance. The findings may aid in the development of more effective control and mitigation strategies for the disease.The giant river prawn, Wu et al. investigated integrated vector surveillance in Zhejiang Province, China, in 2020, to monitor the occurrence of tropical vector-borne diseases (VBDs). The aim was to identify potential vectors of VBDs, as well as investigate the pathogen infection rates among arthropod vectors and reservoir hosts, including mosquitoes, rodents, ticks, and chigger mites. A pathogen infection survey on mosquitoes and rodents and a drug resistance survey on Aedes albopictus were conducted. The survey demonstrated that the primary vectors of tropical VBDs in the region were mosquitoes and ticks and that the pathogens and reservoir hosts were present in certain areas of the province. The study highlights the importance of integrated vector surveillance programs in the early detection and control of tropical vector-borne diseases.In terms of surveillance in tropical veterinary diseases, Thus, the study of molecular pathogenesis plays a crucial role in enhancing the understanding of tropical veterinary diseases and developing new strategies for control and prevention. Studying the molecular basis of diseases helps in developing more accurate diagnostic methods, effective treatments, and strategies for disease prevention, leading to improved health and wellbeing of animals and humans in tropical regions. This collection will be beneficial in adding an in-depth insight into the molecular pathogenesis of tropical veterinary diseases.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
+{"text": "The neuro-developmental deficits of Attention-Deficit Hyperactivity Disorder (ADHD) including decreased attention span, hyperactivity, distractibility, and impulsivity are frequently observed in children, adolescents and adults with a range of conditions , Cochran et al. report (n = 734), contrary to previous studies, that maternal smoking during pregnancy and pregnancy associated hypertension are did not predict ADHD at 10 and/or 15 years.In the ELGAN Study sample of children born at extremely low gestational age , more than double the prevalence of ADHD in otherwise healthy pediatric populations, highlighting that the negative influence on neuropsychiatric functioning likely begins sooner in the disease course than previously anticipated. The authors propose these findings are of large practical importance as ADHD symptoms are likely to impact routine everyday decisions crucial for diabetes management .Several studies in this issue describe specific aspects of ADHD and ADHD \u201csymptoms\u201d in chronic pediatric conditions. Duquette et al. describe ADHD in children with Chronic Kidney Disease (CKD). Although the sample size was small, results from the current study provide some of the most comprehensive findings to date on the differential attention functioning of children with CKD. Taken together, these findings suggest the existence of specific types of attention dysfunction, particularly in the focus/execute, sustain, and encoding, components of attention .Uliel-Sibony et al. provide a comprehensive literature review of the common co-occurrence of ADHD and epilepsy, and describe the latest research regarding possible etiologies explaining the common co-occurrence. This review looks at the influence of medications on both disorders and the recommended treatment approaches in accordance with the latest literature .Sabag and Geva provide a neurobiological perspective on the very significant comorbidity of attention in autism spectrum disorder (ASD), describing the framework of attention network activation in ASD, and suggesting that this neurobiological perspective be considered for further investigation in naturalistic settings.Slobodin and Davidovitch highlight the associations and differences between children's self-reports, parents' and teachers' reports, and standardized continuous performance test (CPT) data, and discuss the clinical and ethical imperative of taking children's perspectives into account during ADHD diagnosis and treatment.Dakwar-Kawar et al. providing initial support for the efficacy of this combined method in improving processing speed in the presence of mental fatigue in pediatric ADHD.Novel treatment approach of trans-cranial electric stimulation combined with cognitive training is described by Dutta et al. complete the series with a bottom-up holistic approach to the psychopharmacology of ADHD in the context of recent models of attention and suggest that future studies are greatly needed to better appreciate the interactions among an ADHD diagnosis, stimulant treatment across the lifespan, and structure-function alterations in the aging brain.We hope this Research Topic will update our readers on both research and clinical aspects of ADHD.IB, AL, and YL conceptualized and conducted the project, collected the study data, drafted the manuscript, and reviewed the final manuscript. All authors have read and approved the final manuscript."}
+{"text": "Frontiers in Nutrition Research Topic aimed to address various issues related to the robustness of nutritional science, from methodological issues with field-specific research and counseling, to managing conflict of interest and problems with scientific decision making in public health nutrition. Our Research Topic gathered 30 authors from North America, Europe and Asia that provided a mix of original research, review and perspective papers that timely suit co-editors invitation, exploring topics in nutritional epidemiology, food policy and economics, and nutritional methodology. Addressing the aforementioned topics holds the potential to fortify evidence-based knowledge within the realm of human nutrition as a scientific field, and perhaps pave the way for the establishment of elevated scientific standards and a heightened sense of public responsibility, echoing the sentiments expressed by Ioannidis  delved into the international research landscape of the past decade concerning vitamin D and its implications on reproductive health. The researchers meticulously analyzed over 1,800 articles and reviews, revealing a significant diversity in terms of represented subdisciplines, authors' backgrounds, research frontiers, and the quality of peer-reviewed journals where these papers were disseminated. While the field of study has garnered substantial global attention, it has displayed an uneven progression, marked by multidisciplinary research hotspots primarily focusing on risk factors and detrimental consequences of vitamin D deficiency. Nevertheless, the report emphasizes the need for more robust investigations. Specifically, it suggests delving into the heterogeneity of vitamin D deficiency across populations, enhancing the utility of vitamin D-related biomarkers, and adopting a mechanistic approach to scrutinize the effects of vitamin D on health indicators. This significant report reiterates the call for the design of more comprehensive cause-and-effect studies within the realm of nutritional sciences. Furthermore, it underscores the importance of embracing personalized approaches, aligning with previous views of Bassaganya-Riera et al. . Through collaborative efforts involving federal and public stakeholders, as well as expert groups, and the meticulous execution of systematic reviews, NESR has emerged as a pivotal initiative in informing evidence-based decisions by the U.S. government concerning public health nutrition. This encompasses pivotal contributions to the development of the Dietary Guidelines for Americans. The article also underscores the imperative need for other organizations to contemplate adopting a similar approach, perhaps modeled after NESR, to ensure a collaborative process that adeptly addresses potential or perceived conflicts of interest among all stakeholders involved.Another review article within this Research Topic look into the systematic review process of the U.S. Department of Agriculture's Nutrition Evidence Systematic Review Branch (NESR), exemplifying the utilization of a diverse range of expertise and experiences while effectively managing potential conflicts of interest  and randomized-controlled trials may offer a more favorable strategy for generating pertinent insights into the intricate interplay between nutrition and health.A thought-provoking perspective article by Ko et al. investigated the reliability and validity of the Korean version of the Children's Eating Behavior Questionnaire (K-CEBQ) for children with anorexia. This parent-reported measure is designed to assess variations in eating style, and the researchers conducted two rounds of the study, surveying over 350 participants online. They demonstrated good internal consistency reliability and temporal stability of the K-CEBQ, indicating its reliability for assessing the eating behavior of children with this eating disorder. The paper also calculated the optimal cut-off values for the two category scores of the K-CEBQ, food approach and food avoidance. This provides a practical tool for healthcare professionals that could aid in diagnosing children with anorexia and assessing their treatment progress. The article emphasizes the need for future studies to consider other confounding factors (besides age and gender) that may influence anorexia features in children.Finally, a research paper by The current Research Topic offers a comprehensive overview of advancements in the realm of scientific integrity within nutritional research, advocating for a robust and practical approach from both clinical and public health standpoints. By adopting optimal strategies for research data generation and analysis, while also embracing a personalized approach such as precision nutrition, and considering diverse diet-specific neuro-psychological factors, the field can be revitalized. This rejuvenation holds the potential to bolster public policy, shed light on the broader population, and ultimately contribute to a more informed and healthier society.SO: Writing\u2014original draft. N\u00d8: Writing\u2014review & editing."}
+{"text": "The medical care costs for procedures, medications, and testing associated with atrial fibrillation (AF) in the United States are high and projected to increase markedly in the future as the number of Americans affected grows. The burden on patient quality of life, the health care system,and society are pharmacoeconomic considerations in managing AF.To identify key pharmacoeconomic considerations in managingAF and describe ways in which managed care pharmacists can improve the cost-effectiveness of and outcomes from drug therapy for AF.The high medical care costs of AF are largely the result of the high cost of hospitalization and inpatient procedures. Recurrence of AF dramatically increases costs, especially for hospital care.Managed care pharmacists have many opportunities to provide cost effective care to and improve outcomes in patients with AF. Policy and process review, population management, and case management are key strategies for improving outcomes in patients with AF. Pharmacist input into policy and process review, including pharmacy benefits design, formulary management, and the use of information technology, can help ensure that the use of drug therapy for AF is cost-effective. Population management strategies, such as development of clinical pathways and patient registries,seek to improve the quality, consistency, and cost-effectiveness of care and the likelihood that desired therapeutic outcomes are achieved through targeted interventions. Case management strategies focus on longitudinal care for individuals in order to improve quality. Pharmacist-managed anticoagulation services and antiarrhythmic drug monitoring are the 2 most widely known case management strategies for patients with AF. Managed care pharmacists can screen patients with AF for the use of anticoagulation,which is needed to prevent embolic stroke but is under-used, even though recommended by evidence-based guidelines. The clinical efficacy and cost-effectiveness of pharmacist-managed anticoagulation services forpatients with AF are well documented. Pharmacist-managed antiarrhythmic drug monitoring is a less well-known case management strategy that facilitates early detection and intervention to minimize toxicity.Managed care pharmacists can play an instrumental role in implementing strategies to improve the cost-effectiveness of and outcomes from drug therapy for AF."}
+{"text": "The purpose of this paper is to describe NASA\u2019s approach to establishing and maintaining a set of Agency-level Space Flight Human System Standards managed by the Office of the Chief Health and Medical Officer (OCHMO) at NASA that enables space flight missions by minimizing health risks to astronauts, providing vehicle design parameters, and supporting the performance of both flight and ground crews. NASA standards capture and provide knowledge, guidelines, thresholds and limits for the successful design and operation of spacecrafts and missions. The NASA Space Flight Human-System Standard (NASA-STD-3001) consists of two separate volumes of technical requirements: NASA-STD-3001 Volume 1: Crew Health addresses the requirements needed to support astronaut health and provide medical care; NASA-STD-3001 Volume 2: Human Factors, Habitability, and Environmental Health addresses human-integrated vehicle system design and operational requirements that will maintain astronaut safety and promote human performance. These standards are managed by an OCHMO team who continuously works with national and international subject matter experts and with each space flight program to provide the best technical requirements and implementation documentation to support the development of new programs. Through partnerships across the space flight industry, these technical requirements are constantly evolving to enable successful implementation of NASA programs and the commercialization of human space flight. These primary hazards include:4, the impact of radiation on pharmaceuticals and food should be minimal, but additional research is being conducted to fully assess the impact6. Sources of increased radiation exposure include galactic cosmic rays, solar particle events, and onboard radioactive technologies. Vehicle design and engineering can provide a certain level of protection to crewmembers from radiation exposure, however not all types of radiation can be shielded from, and crewmembers are invariably exposed to higher levels of radiation during spaceflight compared to on Earth. Reference Radiation Protection NASA OCHMO Technical Brief for additional information7.Radiation Exposure: Outside of Earth\u2019s natural protection, radiation exposure is abundant in space. Crew exposure to the space radiation environment may pose health risks including the risk of neoplasm, damage to the central nervous system, altered cognitive functioning, reduced motor functioning, and acute behavioral changes. In addition, based on analysis and limited data from the International Space StationAcceleration, Acoustics, Artemis Lighting, Cabin Architecture, Carbon Dioxide, Decompression Sickness (DCS), Environmental Control and Life Support System (ECLSS), Food and Nutrition, Electrical Shock, Lighting Design, Sleep Accommodations, Vehicle Hatches, Waste Management, and Water NASA OCHMO Technical Briefs for additional information21.Hostile/Closed Environment: Spacefaring humans must depend on an enclosed vehicle to survive, which involves inherent risks due to engineering . The habitability of the spacecraft is imperative for astronaut health and safety. The spacecraft must also provide astronauts the essential elements they require to live and work in space, including food, body waste management, sleep accommodations, and exercise. Reference Behavioral Health and Performance, Behavioral Health Mishaps, Cognitive Workload, Usability, Workload, Error, and Sleep Accommodations NASA OCHMO Technical Briefs for additional information25.Isolation and Confinement: Crewmembers live and work within a small, enclosed environment with other crewmembers for extended periods of time during space flight. Even with careful selection of crewmembers and extensive training, interpersonal and behavioral health issues within the crew are expected. Workload considerations, circadian desynchronization and sleep disturbances, and lack of communication with Earth all play a role in potential performance decrements, negative health outcomes, and potentially loss of mission objectives. NASA has developed several methods to monitor crewmembers\u2019 behavioral health status during space flight and developed tools and technology to identify potential issues earlier and provide the appropriate treatment or intervention. Reference Spaceflight Experience and Medical Care Technical Brief26.Distance from Earth: As the future of space travel moves toward longer-duration missions beyond lower-Earth Orbit to the Lunar surface and Mars, distance from Earth will become one of the biggest obstacles of safe and productive human space flight. Lack of resupply vehicles, communication delays, potential medical emergencies, and equipment failures are just some of the obstacles that astronauts will face during future space flight missions. Reference Principles of Clinical Medicine for Space Flight27 for a comprehensive review of the human systems affected by space flight and microgravity. Appropriate countermeasures and interventions are imperative to keep crewmembers healthy, safe, and performing at their highest potential. Reference Bone Loss, Spaceflight Experience and Medical Care, and Pharmaceuticals and Medications NASA OCHMO Technical Briefs for additional information29.Altered Gravity Environment: The experience of astronauts transitioning from one gravitational field to another introduces a host of considerations for crew health, safety, and performance. Future missions will involve several changes in the gravity environment, thus operational parameters must implement all strategies available to mitigate these decrements as much as possible. In addition, humans living and working in space for extended periods of time leads to many health complications that makes returning to Earth\u2019s gravitational environment difficult. Changes to bones, muscles, eyes , and the cardiovascular system are just some of the problems that astronauts deal with when returning from space flight. Reference There are five primary hazards of space flightWhen combined, these five hazards of space flight create a complicated landscape and impact the ability to support the health, safety, and optimal performance of space flight crews. In addition, as mission duration lengths increase with a greater focus on deep space exploration, these hazards become even more important to address in order to enable the future of space travel.30. The Human System Risk Board (HSRB) was created to implement this process by the NASA Health and Medical Technical Authority. Its responsibility includes implementing a consistent process of gathering and assessing evidence, providing a likelihood and consequence of the risks, and in turn providing recommendations to updating the NASA-STD-3001 documents so that the set of technical requirements remains up to date with the most current knowledge.Over the past 50+ years of human space flight, NASA has collected an evidence base of medical, environmental and research data on the effects of space flight on the human body. However, even with years of collected data, NASA has a relatively small population of flown astronauts, making it difficult to fully understand the effects of space flight hazards. In order to address this difficulty, NASA implemented a new cross-discipline process to understand the hazards of space flight and gather, assess, and correlate evidence to better predict the probability of an event occurring and the level of consequence the event would have on human health and productivity. This strategy provides the ability to weigh the risks relative to each other and leads to effective tradeoffs to ensure maximal mission success with the least risk to human health31. It was first adopted by the International Space Station Program (ISSP) and written primarily for the International Space Station (ISS) infrastructure. As time passed and the development of new programs with needs separate from the ISS emerged, an updated set of standards with broader applicability was needed to replace NASA-STD-3000. Driving reasons behind this update included the fact that the original standard was too comprehensive, was too focused on design solutions, and raised questions on the verifiability of some technical requirements. After a second variation of NASA-STD-3000 and an accompanying handbook were created32, NASA-STD-3001 was baselined and implemented in 2009 by the NASA OCHMO. These standards are applicable to all human space flight programs and projects, enabling the creation of human-centered program-specific technical requirements. Each technical requirement within these documents includes a \u2018shall\u2019 statement that must be considered in the development of a program-specific set of human-systems design requirements. Technical requirements include rationales which provide additional information and justification for the purpose of the technical requirement, as well as some potential guidance on how to verify the technical requirements being met. Figure The first set of space flight human system standards was baselined Agency-wide in late 1980s and was known as NASA-STD-3000: Man-System Integration Standards (MSIS)Volume 1 of NASA-STD-3001 focuses on human physiological functioning and views the human system as an important part of the overall vehicle design process and mission design. It sets the standards for fitness for duty, space permissible exposure limits, permissible outcome limits, medical care, medical diagnosis, intervention, treatment and care, and countermeasures. Aerospace medicine is deeply rooted in preventive care in addition to being prepared to respond to known physiological and psychological challenges of space flight, as well as unexpected injury and illnesses that could impact crewmembers during their career as an astronaut. Volume 1 seeks to address this comprehensive approach through screening, preventive healthcare strategies, medical care, launch and landing contingencies, and post-mission care, reconditioning, and long-term monitoring. NASA-STD-3001 Volume 1 contains 72 technical requirements as of Revision B published in 2022 that are levied against all human-integrated space flight programs. Table Volume 2 of NASA-STD-3001 focuses on human-systems integration, including human physical and cognitive capabilities and limitations, and defines requirements for spacecrafts , internal environments, ground processing, facilities, payloads, and related requirement, hardware, and software systems. These include requirements to the design of systems that directly interface with the flight crew such as environmental support systems, architecture, controls and displays, and operations, as well as requirements for the design of systems that both ground and/or flight crew access during assembly, test, checkout, or troubleshooting procedures supporting ground processing, launch, landing, and recovery operations. NASA-STD-3001 Volume 2 contains 471 technical requirements as of Revision C published in 2022 that are levied against all human space systems and must be tailored for each individual system to ensure that the end product meets all the requirements. Table Each individual NASA program that will include human-rated systems must implement NASA-STD-3001 in the development of their specific program requirements. The program is responsible for reviewing the set of standards, identifying the technical requirements that are applicable to their specific program/design reference mission, and tailoring the standards into detailed requirements to be implemented in the program. In addition, the programs must provide verification information which details the program\u2019s plan to verify that their requirements are meeting their intent. Examples of a tailored 3001 technical requirement to program requirement and its related verification language is provided in Fig. 33 was developed to provide a tool to determine how individual technical requirements impact future missions and programs. It provides the ability to look \u201cacross\u201d all of the technical requirements and assess their impact on a mission\u2019s success in relation to loss of crew, loss of mission, and loss of mission objectives. The pyramid is broken down into six levels, with the base representing the most fundamental system needs (both vehicle and human) and the top-level representing optimization of human and mission performance. This hierarchy is useful in determining the applicability of technical requirements for programs during the formulation stage of development. The pyramid also helps to categorize technical requirements that increase the probability of achieving mission objectives.During the early formulation stage of a program, it is helpful to assess the cross-relationship of standards and how they impact specific missions and programs. The Human Space Flight Standards Hierarchy Fig. 33 was de32 is a companion document designed to accompany NASA-STD-3001 Volume 2. It includes information specific to human space flight history and lessons learned, design information, reference data and background information, and application guidance for the wide variety of disciplines and topic areas covered by NASA-STD-3001. The main purpose of the HIDH is to help requirements writers prepare program-specific human requirements and to help designers develop designs and operations for human interfaces in spacecrafts. The scope of the handbook encompasses all crew operations both inside and outside spacecrafts in space and on Lunar or planetary surfaces. It includes design guidelines for crew interfaces with workstations, architecture, habitation facilities, extravehicular activity (EVA) systems; information describing crew human capabilities and limitations ; and environmental support parameters. The potential users of the HIDH include program managers, program/system requirements writers, human factors practitioners, engineers and designers, crews and mission/flight controllers, and training and operations developers.The Human Integration Design Handbook (HIDH)34 that cover a range of topics. Each technical brief includes information regarding technical data, background, reference information, and application notes to aid with the development of hardware, systems, and vehicles, as well as human needs and limitations. This information is used by vehicle developers, program requirement writers, and medical professionals. These technical briefs integrate content from multiple technical requirements and provide a quick, informative resource to reference when working with NASA-STD-3001. Currently, there are 31 published human space flight technical briefs with additional topics being added on a regular basis. Stakeholders, NASA SMEs, and other potential users are encouraged to submit their ideas for future technical brief topics that would be informative and useful for ongoing work.The OCHMO 3001 Standards Team has developed a repository of human space flight technical briefsNASA Subject Matter Experts (SMEs) are invaluable resources for ensuring that current technical requirements include relevant and important content for each individual area of interest, utilizing the expertize and experience of the SMEs to provide the best available information to form new and update existing technical requirements.Human System Risk Board (HSRB) as described previously, helps to inform the standards through regular reviews of identified space flight human health risks which includes an overview of the related technical requirements and potential recommendations to update those technical requirements to address any changes or concerns regarding each specific risk.35. The results from HRP\u2019s research and findings helps to inform the technical requirements and provide important updates using new and updated knowledge,NASA Human Research Program (HRP) is a program dedicated to conducting ongoing space flight research in many facets of human space travel and includes five elements: the International Space Station Medical Projects, Space Radiation, Human Health Countermeasures, Exploration Medical Capability, and Human Factors and Behavioral PerformanceThe NASA-STD-3001 documents are reviewed and updated in a continuous cycle in order to keep the technical requirements current and up-to-date with the latest knowledge and guidance. Potential updates and recommendations for the technical requirements are identified through several different avenues, which include but are not limited to:The process for updating the NASA-STD-3001 documents and related handbooks includes a specific set of steps to be followed to ensure consistent and accurately documented changes to the standards. Figure The future of NASA and human space flight is undergoing significant changes, with the landscape of space travel and exploration turning toward longer-duration missions on the Lunar surface and eventual deep space to Mars. In addition, commercial partners have become the primary contributors to supporting ongoing human space travel and thus it is imperative to consider their role in the future of space flight. The NASA-STD-3001 documents are invaluable resources for the evolving space flight environment, providing commercial partners with the necessary knowledge and guidance to enable safe and effective human space travel. In addition, lessons learned and feedback from previous programs development activities and operations helps to inform future programs on how to appropriately integrate the 3001 technical requirements to achieve their goals and objectives and overall mission success."}
+{"text": "There is a wide range of renewable materials with attractive prospects for the development of green technologies for the removal and recovery of metals from aqueous streams. A special category among them are natural fibers of biological origin, which combine remarkable biosorption properties with the adaptability of useful forms for cleanup and recycling purposes. To support the efficient exploitation of these advantages, this article reviews the current state of research on the potential and real applications of natural cellulosic and protein fibers as biosorbents for the sequestration of metals from aqueous solutions. The discussion on the scientific literature reports is made in sections that consider the classification and characterization of natural fibers and the analysis of performances of lignocellulosic biofibers and wool, silk, and human hair waste fibers to the metal uptake from diluted aqueous solutions. Finally, future research directions are recommended. Compared to other reviews, this work debates, systematizes, and correlates the available data on the metal biosorption on plant and protein biofibers, under non-competitive and competitive conditions, from synthetic, simulated, and real solutions, providing a deep insight into the biosorbents based on both types of eco-friendly fibers. Natural cellulosic (plant) and protein  fibers from biological sources (biofibers) are remarkable for their renewability, biodegradability, variety, variability, carbon dioxide neutrality, and recyclability. They fold very well on the coordinates of sustainability, which is one of the most challenging goals of today\u2019s society. With an anticipated annual production of around 40 million tons per year by the middle of the 21st century [Biofibers have historically been used to produce textiles, ropes, carpets, fabrics, and wires . Today, Among the common methods for the removal of toxic metal ions from aqueous media, adsorption occupies a prominent position ,18,19,20The published reviews are either specifically devoted to biofibers and their sources for the adsorption of pollutants in water purification, or cover multifaceted applications of some natural fibers, of which those related to pollution control and remediation are briefly addressed . DespiteThe originality and novelty of this work is that it connects, for the first time, the information on the biosorption capabilities of both cellulosic and protein natural fibers  for the removal and recovery of both toxic and valuable metals from diluted aqueous solutions. In addition to its integrative nature, this article is distinguished from the other reviews by the following elements: (i) focus on the ways in which the biosorption activity of natural fibers is affected by industrial competitive conditions; (ii) discussions and comparisons, from two different perspectives, namely natural plant and animal fibers as potential and practical biosorbents for metal uptake. After an overview on biofiber classification and properties, the major debated issues concern: (i) plant natural fibers for metal biosorption from mono- and multi-component aqueous synthetic solutions; (ii) protein natural fibers for metal sequestration from mono-metallic and poly-metallic synthetic solutions; and (iii) practical applications of metal biosorption on natural fibers to real solutions for decontamination and recycling goals.Given the wide range of green fibers, this article will be inevitably incomplete, but its aim is to provide a comparative analysis on practical coordinates, that will be helpful to guide and promote sustainable approaches based on natural fibers in the separation and recovery processes of metals.Biofibers, which are the predominant class of natural fibers can be described as polymeric materials of biological origin that are intact, thin, long, and easily bendable to form an elongated tissue . DependiNatural vegetable fibers originating from more than 2000 kinds of plants worldwide consist mainly of cellulose, hemicellulose, and lignin and are also known as lignocellulosic fibers . As can Bombyx mori.The second group of natural fibers includes animal fibers consisting of proteins (keratins). According to Natural plant and animal fibers possess a variety of properties of physical, chemical, mechanical, electrical, thermal, biological, optical, acoustic, or ecological nature, which make them very attractive biomaterials . The oveNatural fibers are characterized by their environmental friendliness, worldwide occurrence, low cost, air permeability, low abrasiveness, tunability, and low energy consumption, and have intermediate mechanical properties and higher moisture and temperature sensitivity than synthetic fibers . The maiThe presence of keratins, which are more sensitive to chemical attack and harsh environmental conditions than cellulose, weakens the properties of natural fibers of animal origin . Thus, cBiosorption is an environmentally friendly process of metal separation from a liquid phase as a result of its retention via physical and chemical bonds on a bio-based material (biosorbent) ,25. The As with all biosorbents, the most important property controlling the biosorption capability of natural fibers is their unique surface functionality with high reactivity. The uptake of metal ions on plant biofibers is due to the surface active functional groups, such as the carboxylic groups of hemicelluloses and lignin, the hydroxyl groups in cellulose, hemicelluloses, and lignin, the phenolic groups of lignin, and the carbonyl groups of hemicelluloses . The bioThe surface properties summarized in In addition, because of the remarkable ability of natural raw fibers to be subjected to various treatments, the improvement in the surface properties such as those listed in The successful use of fibers from renewable resources as biofilters for the biosorptive separation of metals depends on the extent to which they meet specific requirements expressed as high biosorption capacity, satisfactory selectivity at different concentrations, high efficiency in sequential or simultaneous removal of toxic metal ions, favorable kinetics, good stability, recyclability, and adaptability to different designs (batch and fixed bed column systems of biosorption) and environmental conditions ,30,32.From this point of view, batch equilibrium and kinetic studies provided most of the knowledge on the removal properties of natural fibers, such as the maximum capacity of metal biosorption and the biosorption rate. These involve immersing a suitable mass of biofibers in a known volume of a synthetic aqueous solution until equilibrium is reached, whereupon the phases are separated . Figure Hibiscus Canabicus kenaf fibers [Additionally, for practical purposes, the information provided by fixed bed column studies is much more relevant and useful. In fixed bed biosorption methods, which can be used to the treatment of large sample volumes, the aqueous metal solution flows continuously at a defined flow rate through a column filled with a given amount of biosorbent . Howeverf fibers , and woof fibers  can be mLike all lignocellulosic biomasses, natural plant fibers proposed as biosorbents for the metal removal from mono-component synthetic aqueous solutions often showed performances very close to those of ion exchange resins . Their bLuffa cylindrica fibers [a fibers , okra fia fibers ,166, or a fibers ,168 modia fibers . The moda fibers .2O3 was reported to occur by electrostatic attraction and ligand exchange [Data analysis showed that the mechanism of the biosorption process of metal ions from mono-contaminated model solutions on untreated and modified forms of lignocellulosic fibers is complicated due to the involvement of a variety of cellulosic and non-cellulosic functional groups. At the same time, it is obvious that much research is still needed for a comprehensive understanding. Most proposed mechanisms are based on single or combined chemical interactions, such as ion exchange, electrostatic interactions, complexation, coordination/chelation, acid-base interactions, and precipitation. The dominance of ion exchange was highlighted for the mechanism of biosorption of Cu(II), Pb(II), and Zn(II) on flax fibers , retentiexchange .The strength of the bonds between the metal ions and the natural lignocellulosic fibers was also confirmed by desorption studies ,176,177.Research on the effects of the coexisting ions on the removal performance of the natural plant fibers is not very productive. The most addressed issues relate to the influence of the type, number, and initial concentration of the foreign ions on competitive biosorption. In this context, the studies published so far have mainly investigated the effects of bi-valent heavy metal ions ,198,199,3 [Pejic and coworkers reported efficiencies of 93.01%, 43.9%, and 43.84% for the removal of Pb(II), Cd(II), and Zn(II) from a multi-ionic solution containing Pb(II) (0.2 mmol/L), Cd(II) (0.2 mmol/L), and Zn(II) (0.2 mmol/L) by biosorption on hemp fibers modified with sodium chlorite, which showed almost the same uptake capacity for Pb(II) under competitive and non-competitive conditions . It was 3 . The pap3 . The max3 . Despite3 .Ficus carica fibers was unaffected by the presence of Na+, Cl\u2212, and SO42\u2212, decreased under the condition of Ca(II) and Mg(II) coexisting cations, and increased in the presence of HCO3\u2212 anions [3\u2212 and ClO4\u2212 anions [The reported slight decreases in the maximum biosorption capacity of carboxyl modified jute fibers for Pb(II), Cd(II), and Cu(II) in the presence of Na(I), K(I), Ca(II), and Mg(II) ions were correlated with the increase in light metal ion concentration from 0 to 500 mg/L . Gupta a\u2212 anions . The neg\u2212 anions . The cha\u2212 anions .It is worth mentioning recent works confirming the selective and advanced biosorption of U(VI) on some new biosorbents based on hemp fibers under the conditions of simulated seawaters. Thus, by using polyethylenimine and guanidinyl functionalized hemp fibers, an efficiency of more than 85% was achieved in the removal of U(VI) from artificial seawater with multiple coexisting ions and low initial uranium concentration (3.05\u201399.03 \u00b5g/L) . The neaAs can be seen from the above considerations, the consonant conclusion of all the studies is that the biosorbents based on natural plant fibers have a low biosorption capacity for the coexisting ions under competitive conditions, while they retain a pronounced affinity and selectivity for the metal ions of interest for removal and recovery.In contrast to lignocellulosic biofibers, information on the use of natural fibers of animal origin as biosorbents for water detoxification are scarce and mainly refers to wool, silk, and human hair. This limitation has been justified by the inferior kinetic properties and lower capacity of biosorption of protein biofibers compared to biosorbents based on polysaccharides . However-wool powder and oxidized wool powder performed better than waste wool fibers in biosorption of Cu(II) and Zn(II) from mono-component synthetic aqueous solutions, the optimum pH being 6 ;-Bombyx mori silk > wool order was determined for Co(II) uptake on different untreated protein fibers [tussah silk > n fibers ;-the removal efficiencies of some powdered biosorbents have shown the trends: silk powder > wool powder > cashmere guard hair powder and cashmere guard hair powder > wool powder > silk powder versus Zn(II) and Cr(VI), respectively ;-the efficiency of biosorption of Pb(II) from aqueous solutions with pH = 5.8 on human hair, goat hair and sheep wool has reached the highest value (33 mg/g) on human hair .Most biosorption studies have been conducted on one of the aforementioned biofibers, in the form of loose fibers, powder, or non-woven fabrics. Although accurate comparative analyses are sporadic, given their practical relevance to the selection of the most suitable biosorbent, the following ascertainments should be introduced:Against this background and taking into account the specifics of the properties of the individual fiber types, the metal removal and desorption properties of wool fibers, silk fibers, and human hair waste are discussed separately below.The most targeted protein fibers are wool fibers, through studies mainly concerned with the behavior of low quality native wool, wool waste from industrial processes, and recycled woolen textiles in the biosorption of heavy metal ions , Cd(II), Zn(II), and Cr(III)) from mono-metal synthetic aqueous solutions with initial metal concentrations below 10 mmol/L. As in the case of plant biofibers, the Langmuir isotherm model and the pseudo-second order kinetic model are the optimal solutions for the description of the metal uptake on wool fibers. The significant results of these works are presented in S. aureus and E. coli), anaerobic and sulfate-reducing bacteria, and C. albicans fungus [2 particles have been described as a precursor of a new class of biosorbents for recycling U(VI) from seawater.The focus was to find the best treatment method to improve the biosorption properties of wool fibers. To achieve this goal, wool fibers recommended as potential materials for wastewater treatment were often modified by the irradiation with accelerated electron-beam and graft copolymerization. The significant increase in metal uptake on electron irradiated wool compared to non-irradiated wool  is strons fungus . With a s fungus , amidoxiTo obtain a complete picture, the promising desorption properties of some wool biosorbents are described in In addition to the high desorption efficiency, mostly with EDTA, the tested wool fibers have also shown no significant loss of biosorption activity over three to six cycles. For example, the wool graft polyacrylamidoxime exhibited a 5% decrease in Hg(II) desorption efficiency at the end of the fifth cycle . The levBombyx mori silk fabrics [Bombyx mori and Antherae pernyi silk fibers [Bombyx mori and Tussah silk on the fiber composition, the nature of metal ion, and the type of modifying agent [Unlike other natural fibers, the metal binding capacity of silk fibers is determined by the extent of degumming treatment that must be performed prior to use . For exa fabrics  and Bombk fibers , untreatng agent . All theThe valorization of these properties for metal ion removal and recycling applications has been hindered by the high cost of raw silk fibers, which are less economical than natural plant fibers ,234,235.Although very rarely investigated for potential applications in the treatment of metal-contaminated aquatic systems, discarded human hair offers some significant advantages over analogous biosorbents. Aside from its universal availability, human hair waste could be used directly as a water filter, without the need for additional pretreatments such as pelletization or immobilization. The data on the performance of human hair waste to the removal of pollutant metal cations from individual synthetic aqueous solutions are systematized in 3 by means of the absorbed energy dose control was proposed [The studies on the behavior of protein biofibers in the uptake of metal ions from poly-metal aqueous synthetic solutions are by no means numerous. Those that already exist followed two lines of investigation: (i) description of the competitive effects in multi-component systems of biosorption ,246,247;proposed . In anotproposed . On the proposed . Chlorinproposed .The available information on the compatibility of biofibers with the real systems of metal-laden wastewater treatment is summarized in -expanding the range of natural fibers tested for biofilter function and target metals;-complete clarification and quantification of the relationships between chemical composition, structure, and properties of the bio-based fibers;-replacement of pollutant chemical methods applied for the treatment of biofibers with cleaner procedures;-a substantial increase in the number of studies on: (i) competitive biosorption; (ii) fixed bed column biosorption; (iii) desorption\u2013regeneration; (iv) disposal of exhausted biosorbents;-thorough deciphering of the biosorption mechanism;-expanding the process scale;-economic analyses;-strong expansion of work on real samplesThe expected transition of natural fibers from suitable candidates to practical biosorbents implementable in greener technologies for the removal, recycling, and reuse of metals requires extensive research focusing in particular on the following:A comprehensive analysis of the scientific literature was carried out, addressing the function of natural lignocellulosic and protein fibers as biosorbents for the removal and recovery of metals from synthetic and real aqueous solutions. Most attention has been paid to natural plant fibers, batch biosorption systems, and studies on the Cu(II), Zn(II), Cd(II), and Pb(II) ions uptake from mono-component synthetic aqueous solutions. In contrast, natural protein fibers, continuous biosorption systems, and multi-metal synthetic aqueous solutions have been much less studied. The proposed mechanisms of metal biosorption on natural fibers are dominated by interactions of ion exchange, electrostatic type, complexation, and coordination/chelation. The promising results of the desorption studies are strong evidence of the good recyclability of the biosorbents based on natural fibers, even if their number is very limited. The preliminary results of the tests with real effluents are encouraging for future industrial applications of biofibers for the severe reduction of water contamination with metal ions and the recovery of valuable metals. Research on the metal uptake capabilities of natural fibers, especially those of animal origin, needs to be continued and deepened, especially in the context of real-world scenarios and a pilot- and large-scale applications."}
+{"text": "Africa faces both a disproportionate burden of infectious diseases coupled with unmet needs in bioinformatics and data science capabilities which impacts the ability of African biomedical researchers to vigorously pursue research and partner with institutions in other countries.The African Centers of Excellence in Bioinformatics and Data Intensive Science are collaborating with African academic institutions, industry partners, the Foundation for the National Institutes of Health (FNIH) and the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (NIH) in a public-private partnership to address these challenges through enhancing computational infrastructure, fostering the development of advanced bioinformatics and data science skills among local researchers and students and providing innovative emerging technologies for infectious diseases research. The emergence of innovative, genomic, and related-omics technologies has revolutionized how basic and clinical researchers are studying infectious diseases and vast amounts of diverse, large, and complex biomedical data are being generated at an unprecedented rate. Bioinformatics and data science-including powerful analytical tools-are providing tremendous opportunities for extracting knowledge from these data sets and accelerating research and discoveries in infectious diseases. Thus, increasing our understanding of pathogens and the diseases they cause impacts the development of new and improved therapeutic interventions and diagnostics. These incredible opportunities are aligned with challenges in storage, management, sharing, finding, visualizing, accessing, integrating, and analyzing data, and highlights the critical need for highly trained bioinformaticians, biostatisticians, and biomedical data scientists.Despite significant advances and recognition that bioinformatics and data-intensive science are essential research tools and critical skills for biomedical researchers in their efforts to pursue basic and clinical research in infectious diseases, Africa faces both a disproportionate burden of infectious diseases and unmet needs in the bioinformatics and data science capabilities ,2. ChallSome efforts to address these challenges in Africa are ongoing and have served to advance the understanding of the nature and etiology of infectious diseases and to inform efforts to develop and provide effective therapeutic interventions; and to improve treatment, healthcare, surveillance, and public health responses including COVID-19 pandemic in Africa . There hNIH career development and bioinformatics training programs supporting global health and data science include the Fogarty International Center\u2019s Nurturing Genomics and Bioinformatics Research Capacity in Africa (BRecA), the Eastern Africa Network for Bioinformatics Training (EANBiT), West African Center of Excellence for Global Health Bioinformatics Research Training program, and African Postdoctoral Training Initiative (APTI) in partnership with the Bill and Melinda Gates Foundation and the African Academy of Sciences. Industry programs such as IBM Research-Africa have worked across African countries to increase capabilities and training in data science and to promote data-driven strategies for healthcare in preventing, treating, and diagnosing infectious diseases. Investments by the World Bank such as the African Higher Education Centers of Excellence Project are also addressing national, regional, and local global health challenges and enhancing and building innovative capacities in training and research. The Developing Excellence in Leadership and Genetics Training for Malaria Elimination program in sub-Sahara Africa (DELGEME), sponsored by the Wellcome Trust in partnership with the Department of International Development, the Alliance for Accelerating Excellence in Science in Africa (AESA), and many other African partners, supports the development of analytical skills in bioinformatics, biostatistics, and emerging technologies for malaria control and elimination in sub-Saharan Africa. In addition, the establishment of the African Society for Bioinformatics and Computational Biology (ASBCB) has enabled the development of communities of bioinformaticians and data scientists across the continent.NIAID has significant experience and investment in supporting basic and clinical global research in infectious diseases and in building and sustaining partnerships, especially in low and low middle-income countries. These are key to fulfilling NIAID\u2019s mission and to improving the health of the global community. As part of this investment, NIAID has a long-standing commitment to supporting bioinformatics and data resources such as computational infrastructure, data platforms and repositories, hands-on-bioinformatics training, and computational tools development to provide the basic and clinical research community with access to state of the art and innovative research data resources. These resources stand ready to assist in the event of emerging diseases, global pandemics, and health emergencies. This community of scientists and trainees can work with tools at the highest level using these established data resources on which to learn and hone their skills.The achievements of NIAID\u2019s ICERs in Africa, as mentioned above, coupled with serious burden of infectious diseases and unmet bioinformatics infrastructure and training needs in Africa were the foundation for the establishment of the NIAID ACE consortium . AlthougThe first ACE Center was established in Mali in 2015 as a public-private partnership between the University of Sciences, Techniques and Technologies of Bamako (USTTB)-who was launching a master\u2019s graduate degree program-and with industry partners Intel Corporation, Hewlett Packard (through the Intel partnership), BioTeam, and EMC Corporation and the Foundation for the National Institutes of Health (FNIH). In 2019, a second ACE Center was opened in Uganda with Makerere University and the Infectious Diseases Institute (IDI), the Research and Educational Network of Uganda (RENU), the Texas Advanced Compute Center (TACC) and ENDUVO. Just as ACE-Mali serves as a regional bioinformatics resource center for research and academic institutions in West Africa, ACE-Uganda serves as a regional resource center for East Africa. ACE Centers offer high performance computing infrastructure for compute and storage capabilities; master\u2019s and Ph.D. degree-granting programs in bioinformatics in collaboration associated with academic partners; telelearning classrooms with over 20 workstations; and superior audio, visual, and networking environments for enhancing virtual, collaborative global research with ACE researchers and students. ACE-Uganda piloted a visualization laboratory featuring virtual reality-based technology with six virtual reality (VR) workstations for research and training. A similar VR laboratory was set up at ACE-Mali in 2020.The ACE Centers are built on a unique framework anchored in public-private partnerships that drive the support of computing infrastructure and bioinformatics training programs, both critical components for enhancing bioinformatics capabilities in Africa. This partnership allowed centers to be established, anchored by academic institutions with access to research space and environments, research and teaching faculty, degree-granting programs, and students interested in careers in bioinformatics. Industry partners provided in-kind contributions and donations for services, consulting, hardware, software configuration, internet connectivity, and software licenses. All the partners contribute to the Centers to support the objectives of ACE and to enhance research through education and infrastructure. For the universities in Mali and Uganda, their contributions included space in their institution\u2019s buildings, renovated classrooms, and the faculty and staff to support the activities. U.S. partners contributed infrastructure, support services, and licenses for software used in the ACE Centers.The ACE consortium is governed by the ACE Global Council, the Scientific Advisory Council, and the NIAID ACE Global Operations Team. The Global Council\u2019s members are outstanding and well-respected scientists with diverse expertise in bioinformatics and data science, infectious diseases, and biotechnology and include non-voting members from the NIAID and ACE centers. Additionally, individual ACE Centers have local management teams to oversee the day-to-day centers\u2019 operations. These are typically constituted by representatives from local collaborating institutions. As a partner, in addition to providing computational infrastructure, NIAID contributes scientific and technical staff to serve as members of the Scientific Advisory Council and Global Operations Team to assist the ACE Directors and faculty on Centers operations, teach courses and hands-on-workshops with faculty from African academic institutions, and provide scientific and technical support.The ACE centers provide a research and training environment with state-of-the-art computational and training facilities that foster networking and collaborations to strengthen research activities. Networking and collaborative activities include hosting workshops and symposia. For example, ACE-Mali and ACE-Uganda have co-hosted workshops with MRC-University of Glasgow on viral bioinformatics. ACE-Mali held the 1st Congress of African Associations for Research and Control of Antimicrobial Resistance on-site with attendees from across the continent and hold an annual Global Health in Bioinformatic Symposium with a training bioinformatics workshop on advanced topics in data science. ACE-Uganda hosted data science workshops in collaboration with the African Center of Excellence in Materials, Products, and Nanotechnology at Makerere University and most recently provided a Virtual Reality demonstration at ACE-Uganda for participants of a workshop organized by Health Education England on Immersive Technology in Emergency Medicine. The ACE consortium supports rapid and timely sharing and access to diverse data sets generated by ACE Centers collaborative research projects and activities that promote the sharing of data in open access data repositories, where data are easy to find, accessible, and can be used and reused. ACE is committed to adhering to the F.A.I.R. principles for data sharing and access  and policies and guidelines of the NIAID, the NIH, and other funding agencies, as appropriate ,9. TheseThe ACE Centers offer bioinformatics and data science training programs and activities to enhance, foster, and sustain a diverse workforce of well-trained basic and clinical scientists with bioinformatics and computational expertise who can apply these skills to address global health issues in Africa. Sustaining a diverse workforce of well-trained scientists with bioinformatics and computational expertise and experience with advanced analytics such as artificial intelligence/machine learning will be dependent on increasing a wide range of training opportunities and degree-granting programs, and strong and committed mentors, coupled with career opportunities in Africa.A multi-faceted training program supports master\u2019s and Ph.D. degree-granting programs with academic partners USTTB, IDI, and Makerere University. Support includes curriculum and short and long course development, hands-on-train-the-trainer workshops, seminars, and lectures; all facilitated by ACE Centers\u2019 state-of-the-art telelearning environments for in-person and remote and digital learning with dedicated access to high performance computing infrastructure and internet. A NIAID team of computational biologists, structural biologists, genomic scientists and others in collaboration with ACE faculty members and staff, develops and teaches courses in bioinformatics and emerging technologies as well as organizes workshops and seminars. Since 2017, almost 100 students from across the African continent have enrolled in ACE associated master\u2019s and Ph.D. programs, and in ACE Mali 27 have completed advanced graduate degrees. Over two thirds of these MS graduates are either pursuing a PhD or have started working as Research Assistants in Malian laboratories and pursuing careers in data science or seeking advanced degrees. ACE-Uganda is currently supporting 58 Masters\u2019 students and 9 Ph.D. students. It is anticipated that first cohort of students will be graduating in 2023 and some have already secured data science related positions. Most recently, ACE-Uganda has begun supporting postdoctoral fellows. The ACE consortium has developed and supported more than 200 on-site or remote bioinformatics lectures and hands-on-training on technical topics such as \u201cIntroduction to Linux\u201d to introductory courses in bioinformatics, genomics, systems biology, structural biology, metabolomics, and proteomics. The students in both ACE Centers have been working on research topics that will have a direct impact on health, specifically on infectious diseases well known to their communities such as Malaria, Leishmaniasis, Retrovirus infection, and Tuberculosis. In addition, students are developing data analysis and bioinformatic workflows for broader use which leverages the knowledge acquired through ACE and compute infrastructure .ACE-Uganda is providing the computational infrastructure and data resources to students, faculty, and researchers in support of the new bioinformatics training program, co-hosted by the Department of Immunology and Molecular Biology, College of Health Sciences and Department of Computer Science at the College of Computing and Information Science at Makerere University. The \u201cNurturing Genomics and Bioinformatics Research Capacity in Africa\u201d (BRecA) program leverages highly skilled local and international faculty to increase the number of bioinformaticians in Africa and builds on the programs of the H3Africa-supported consortia . The first cohort of the BReCA program enrolled 50 students and second cohort 24 additional students. In addition to access to the ACE infrastructure, the faculty of the BRecA program works closely with the ACE Global Operations Team to provide bioinformatics training for faculty through train-the-trainer workshops and developing and participating in remote hands-on courses and lectures for students. For example, ACE-Uganda is providing computational infrastructure and services to BRecA for data analysis to develop a software tool that provides HIV risk scores through a telehealth platform as part of funding from the Ugandan government.ACE-Uganda hosted bioinformatics and data science training workshops, one with Makerere University and one with CUNY for postgraduate students and provided bioinformatics training on advanced computational tools related to areas such as structural biology and genomic data analysis. Currently, it is also supporting the development of the national sickle cell disease registry in collaboration with the Department of Pediatrics at Makerere University\u2019s College of Health Sciences. ACE-Uganda has provided high performance computational infrastructure and access to develop and test a bioinformatics training/mentorship model that uses local computational infrastructure. It aims at supporting the faculty from Makerere University and enrich the curriculum with additional hands-on-skills training and mentorship and has successfully served to mentor students . Since iAs an example of ACE Centers providing computational infrastructure and analysis to enhance research projects at partner academic institutions, one of ACE-Mali\u2019s research collaborators used the data resources available at the ACE Center to support their clinical and genetic studies of hereditary neurological disorders (HND) in Mali. Facing several challenges in computational infrastructure as data storage and reliable internet and availability of bioinformaticians for data analysis, ACE-Mali provided infrastructure and technical bioinformatics support for data analysis.Although there has been significant growth in Africa for enhancing computational infrastructure to accelerate biomedical research, significant gaps still exist that limit the ability of researchers and students to manage, use and re-use, access, and analyze data. The continuing lack of strong and reliable high-speed internet impacts the use of cloud-based data resources such as data repositories and advanced computational tools and platforms for data management and analysis. Technical support and maintenance are critical components in building a sustainable model for bioinformatics research and training centers in low-resource settings. The NIAID Global Operations team has been able to manage the infrastructure and classroom learning environments remotely using tools such as Git, Python, Salt and OpenStack to provide configuration management, versioning, and maintenance. The goal is to build sustainable support systems in Africa for training and research\u2013working towards the goal of infrastructure-as-code (IAC) that can allow configuration management and system administration in cloud platforms. The infrastructure leverages cloud operating systems to provision not just to the ACE Centers, but also cloud platforms such as Amazon Web Services, Google, or Microsoft Azure Stack. With this new infrastructure, ACE collaborators, students, and scientists have the data resources to develop and run scientific computing tools for data analytics needed to keep local research current and competitive.Over the last six years, the ACE Centers have become regional bioinformatics centers to support biomedical researchers and students. Using in-kind donations from public-private partnerships, the Centers are equipped and managed with state-of-the-art computational infrastructure that includes strong compute cores, high speed internet access, and a telelearning center with more than 20 stations. ACE-Uganda\u2019s cutting edge biomedically-focused virtual reality technology is available for research and training with six Virtual Reality (VR) stations and used to enhance learning and training for students and faculty. During the COVID-19 pandemic, ACE-Uganda took advantage of the VR stations and equipment and developed a training course in Infection, Prevention, and Control (IPC) which included using personal protection equipment (PPE) for frontline healthcare workers . The locThe ACE consortium serves as a model using a public-private partnership with industry, academic institutions, African governments and other governments as U.S. and non-profit organizations work together to address unmet needs in bioinformatics capacity in Africa and is uniquely poised to impact the training the next African generation of scientists in bioinformatics that are highly skilled to address key research questions in infectious diseases. The partnership includes the use of research facilities and degree-granting programs in academic institutions in Africa, in-kind donations from industry for consulting and computational infrastructure, the Foundation for the National Institutes of Health (FNIH) to facilitate the public-private partnership model, and NIAID\u2019s contribution of scientific and technical staff to assist the ACE Directors and faculty on day-to-day centers operations, teaching courses with faculty from African academic institutions, and provide considerable technical support.Despite the accomplishments of the ACE consortium and other related programs in Africa in reducing barriers in bioinformatics and data science capabilities by improving access to high performance computing and reliable internet, enhancing bioinformatics and data science training and mentorship, increasing the number of trained bioinformaticians in Africa, and advancing biomedical research, much remains to be done. Academic and research centers with strong bioinformatics capacity and training programs exists, yet data research resources and training are not consistently available across the African continent. The sustainability of the ACE Consortium is of highest priority to ensure continuous operation and provide innovative and state-of-the-art facilities and computational capabilities. Key to sustainability will be to enhance local capabilities and funding at ACE Centers for infrastructure, training, and faculty research projects and for the ACE Centers to develop local and international partnerships and seek funding opportunities from local governments, associated academic institutions, local industry, funding agencies, and nonprofit organization to support ACE consortium.The availability and accessibility of data research resources and bioinformatics training for African biomedical researchers and students as they tackle data-intense research projects is essential to leveraging data-driven strategies and transforming data into knowledge, thus impacting the development of new and improved therapeutic interventions, prevention strategies, and diagnostics to reduce the threat of infectious diseases and improve health care in Africa. These efforts need to be expanded across the continent and the key is sustainability through continuous commitment and funding to maintain state-of-the-art computational infrastructure and other data research resources and bioinformatics training programs."}
+{"text": "Dear Editor,This case describes an 80-year-old female Caucasian patient, who sought dermatological evaluation for a lesion on the left foot after local trauma, with progressive growth over two years. Dermatological examination showed a nodular, vegetating, tumor-like lesion covered by hematic crusts on the left plantar region, overlapping an extensive area of deformities in the foot anatomy, caused by healing by secondary intention of burn lesions that occurred in childhood . HistopaThe lesion was completely excised, as well as the ipsilateral lymph nodes, after confirmation of a positive sentinel lymph node for metastatic melanoma. Imaging exams showed alterations suggestive of metastasis in face and skull bones. The patient died after eight months.Marjolin ulcer is a rare and aggressive tumor, occurs mainly in the fifth decade of life, and is prevalent in the male sex.In the epidemiology of melanomas, the nodular type represents the second most frequent one (approximately 15% of diagnosed melanomas), and 5% of nodular melanomas are amelanotic.Amelanotic acral melanoma has an incidence of 1.8% of melanoma cases,5The diagnoses of Marjolin ulcer and melanoma are defined by clinical history, physical examination, and histopathology. The therapeutic options depend on TNM staging, including excision surgery with wide margins or limb amputation, in addition to chemotherapy and radiotherapy.Scars are susceptible to trauma due to a lack of collagen organization and vascular supply compromised by fibrosis, which obstructs vessels. Virchow's theory attributes the development of malignancy in scars to repeated trauma in the area, which leads to chronic irritation, repeated re-epithelialization, and local damage to the skin immune system, with a reduction in Langerhans cells and production of toxins in the affected area, in addition to genetic predisposition.3A rare manifestation of Marjolin ulcer is presented in this case, which presented as a nodular acral amelanotic melanoma, reinforcing the need for advice to patients, care, and regular follow-up of burn scars, for early diagnosis and treatment, reducing morbidity and mortality.None declared.Valentina Louren\u00e7o Lacerda de Oliveira: Design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; critical review of the literature; critical review of the manuscript.Lucia Martins Diniz: Approval of the final version of the manuscript; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the manuscript.Karla Spelta: Intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the manuscript.Elton Almeida Lucas: Intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the manuscript.None declared."}
+{"text": "Background: COVID-19 caused devastating effects on global healthcare systems. The elderly and people with chronic comorbidities were at a particularly high risk of mortality and morbidity. However, the evidence on the association of COVID-19 severity with noncommunicable diseases (NCDs) in the African population is scarce. Objective: The aim is to estimate COVID-19 severity among African patients with hypertension, diabetes, and cardiovascular diseases (CVDs) and its implications for case management. Methods: We will adhere to the extension for Scoping Reviews of PRISMA (PRISMA-ScR). The following electronic databases will be searched: PubMed, Scopus, Web of Science, Embase, CINAHL, and Joanna Briggs Institute. The search will be conducted after the publication of this protocol. Two reviewers will extract data from articles published after March 2020 without language restrictions. A descriptive analysis of the important findings and a narrative synthesis of the results will serve as the basis for interpretation. Expected results and conclusions: This scoping review is expected to determine the odds of patients with chronic comorbidities to progress to severe stages of COVID-19. The review will generate an evidence-based and set foundation for recommendations toward the establishment of surveillance systems and referral guidelines for the management of NCDs in the face of COVID-19 and future pandemics. Coronavirus disease 2019 (COVID-19), is an illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) , there wThe effect of the COVID-19 pandemic on global healthcare systems has been profound. In particular, the impact of the pandemic on the elderly and people with non-communicable diseases (NCDs) has been devastating ,5,6,7,8.The increasing burden of NCDs along with the enduring burden of infectious diseases in Africa and other settings in low- and middle-income countries (LMICs) has been well noted . NeverthNonetheless, information on the effect of COVID-19 in Africa focused on health system challenges, and evidence on the effect of COVID-19 in African patients with hypertension, diabetes, and cardiovascular diseases (CVDs) was extrapolated from what was obtained in other parts of the globe. In order to properly allocate scarce resources and to support clinical decisions during the COVID-19 pandemic, it is important to have an evidence-based record, derived from available epidemiological and clinical data on the comorbidity between NCDs and COVID-19 among African patients. This is of particular importance as in many African countries, the demography is characterized by a large proportion of young people and a lower prevalence of lifestyle risks , which may prevent against severe SARS-CoV-2 ,19,20,21A preliminary search on International Prospective Register of Systematic Reviews (PROSPERO) , Open ScWhat type of severity outcomes were reported in the included studies?What relative impact did the selected NCDs have on the severity of COVID-19?Are there specific patient characteristics that increase the risk of COVID-19 severity among patients with the selected NCDs, namely hypertension, diabetes, and CVDs?What strategies and interventions have addressed the risk factors for COVID-19 severity in comorbid patients?Which of the three selected NCDs had a major impact on exacerbating COVID-19 severity in Africa?What impact did the COVID-19 response have on the services for NCDs in Africa?The overarching aim of this review is to focus on the potential factors related to the severity of COVID-19 for African patients with hypertension, diabetes, and CVDs and their implications for case management. The following research questions will guide to conduct this scoping review:http//:osf.io/e9r28 accessed on 12 May 2023) on 17 November 2022.The scoping review will be conducted in accordance with the guidance for pursuing systematic scoping reviews, put forth by Peters and colleagues from JBI in Australia . The metStudies focusing on COVID-19 patients meeting the following criteria will be included: (i) studies that estimated the quantitative relationship between COVID-19 and hypertension, diabetes, and CVDs; (ii) studies conducted on the African continent; (iii) and studies of both observational  and interventional  designs.Not considered will be studies that met at least one of the following exclusion criteria: (i) studies that evaluate COVID-19 patients without considering NCDs and vice versa; (ii) position papers, editorials, policy statements, case reports, case series studies, perspectives, commentaries, published abstracts, poster and oral presentations, and author reply articles; (iii) studies on the potential association between COVID-19 and other infectious diseases, malignancies, or autoimmune disorders, but not considering diabetes and hypertension; and (iv) articles that speculatively extrapolate findings from studies conducted outside Africa to explain the effects of COVID-19 in Africa.The literature search will include results from studies reporting on COVID-19 and NCD comorbidities among African patients. The review will include studies on adults aged \u226518 years, irrespective of their gender. Data on patients participating in clinical trials, cross-sectional epidemiological studies, or cohort studies (both retrospective and prospective) will be included in the review. Data on patients admitted to any healthcare facility, including outpatient departments, emergency rooms, and intensive care units (ICUs) and reporting to have comorbidities of COVID-19 and NCDs are eligible for the review. However, the review will not consider studies that report from African diaspora patients (living outside of Africa).The review will address the severity of COVID-19 symptoms among African patients due to either one or several of the selected NCDs. For pragmatism and homogeneousness, the review will consider the standard definitions of COVID-19 severities set forth by the World Health Organization (WHO). The common categories for the level of aggravation of COVID-19 among adult population are nonsevere (mild or early stage), moderate, severe, and critical . MoreoveThe systematic search strategy will mainly be aimed at published peer-reviewed articles. To identify potentially suitable articles, we will search documents from the following electronic databases: PubMed/MEDLINE, Embase/Elsevier, Scopus, Cumulative Index to Nursing & Allied Health Literature (CINAHL)/EBSCO, and Web of Science. Because the first COVID-19 case was confirmed in Africa on 14 February 2020, we will search the databases from March 2020 to 28 February 2023 (3-year period) without language restrictions.A three-step search strategy will be used in this review. First, an initial search of PubMed will be undertaken followed by an analysis of the text words contained in the title and abstract and of the index terms used to describe the article. Second, using all the identified keywords and index terms, we will search all the other databases. Third, we will undertake a hand search of the reference list of all the identified relevant documents for potential additional articles. An example of the terms and strings of words applied on PubMed is provided in Records retrieved through the aforementioned search strategy from all databases will be imported into the bibliometric software EndNote\u2122 X9  and screened for relevance and duplication. The criteria for relevance are based on the scope and objectives of the review. Using the inclusion criteria set above, two reviewers will conduct full assessment of the identified scientific publications, and any duplicates will be removed. Any disagreement will be resolved through discussion, and with a third reviewer, as the case might be.The reviewers will develop a data abstraction tool to capture relevant information from the selected documents. The tool will encompass detailed information that includes (i) participant characteristics, such as demographics of patients; (ii) study characteristics, such as study setting, study types, publication dates, authors, methodology, etc.; and (iii) outcomes and key findings related to the review objective. Two reviewers will independently chart information from each selected document to ensure charting consistency and inter-reviewer reliability. In case of disagreements, the two reviewers will resolve through discussion or in consultation with a third team member.\u00ae Excel 2016 . A draft data abstraction tool is provided in All extracted data will be exported to MicrosoftOutcome of the systematic search will be analyzed descriptively using frequencies and percentages. Moreover, graphical presentation including tables and charts will be used, whenever applicable. This will compare and/or reflect the effect of NCDs on the severity of COVID-19. Effect of comorbidities of selected NCDs  will be mapped accordingly and will be presented in comparison to those without any comorbidities.In this section, we will summarize the results of the search strategy and the process of document selection, inclusion, and exclusion in both text and chart formats. We will tabulate and describe detailed information about the selected studies. Emphasis will be placed on the following information: authors, year of publication, country, aim of the study, study design, study setting, participant characteristics, sample size, main findings, measures of outcomes, and effect size (if relevant).The abstracted information in relation to the objectives of the review will be summarized and presented in detail. For example, we will present the number of studies that examined associations between COVID-19 and hypertension. We will describe the relative frequencies of the studies by geographical location and number and characteristics of the participants included in terms of age, sex, and severity of COVID-19. Moreover, the types of study designs and outcome measurements will be described. Additionally, the types and strengths of the reported relationships between COVID-19 and hypertension will be given, and the consistency of the findings will be reported. We will also recount the effect of the COVID-19 response measures  on patients.After describing the reported relationship between COVID-19 and the three selected NCDs, we will report the relationship between COVID-19 and concurrent NCDs. The final synthesis will present the overall severity of COVID-19 in people with all the selected NCDs.This scoping review is expected to determine the odds of patients with chronic comorbidities to advance into severe stages of COVID-19 and to estimate the extent to which NCD services were affected during the COVID-19 response in Africa. In doing so, the review will provide new evidence and set foundations for recommendations toward the establishment of surveillance systems and referral guidelines for the management of NCDs during the COVID-19 pandemic and future pandemics. The outcome of the review will increase awareness of healthcare professionals, policy makers, and other key stakeholders. It will also enhance further collaboration among research, surveillance systems, and technological advancement to develop new advanced diagnostic tools and to set up policies that deal with the silent pandemic of the dual burden of NCDs and infectious diseases in Africa."}
+{"text": "Chronic stress has far-reaching consequences on brain circuits, behavior, and mental health, often leading to abnormal behavior and psychiatric disease. The repercussions of chronic stress affect society as a whole, placing undue strain on the economy and increasing the risk of catastrophic events in communities with easy access to firearms. Developing innovative treatments and preventative measures for stress-induced abnormal behavior requires a more comprehensive understanding of how chronic stress impacts the brain.Neuroplasticity, the process of brain modification at the cellular and circuit levels, has traditionally been associated with learning and memory. However, recent research reveals its role in altering innate and adaptive behavioral responses, especially those influenced by stress. By inducing plasticity within specific brain circuits, many chronic stress-related effects can be mitigated.This Research Topic delves into the complex relationship between chronic stress, neuroplasticity, and abnormal behavior. It features original research and review articles that employ novel tools, pharmacological approaches, and various animal models to investigate the potential of augmenting plasticity within brain circuits as a means of treating symptoms caused by chronic stress. Topics span early life stress, synaptic remodeling, and epigenetic factors that increase susceptibility to stress-induced abnormal behavior.This Research Topic adopts an interdisciplinary approach, combining research from various disciplines to provide a comprehensive and multifaceted understanding of the relationship between chronic stress, neuroplasticity, and abnormal behavior.Shi et al. investigates the effects of direct and indirect stress on synaptic plasticity in the anterior insular cortex (aIC) using an observational fear mouse model. The results provide insights into the changes in synaptic plasticity in the aIC after physiological and psychological stress and suggest that different types of stress may have different underlying mechanisms, which could aid in the treatment of stress-related disorders. This study highlights the importance of understanding how various forms of stress impact neural circuits and contribute to abnormal behavior, ultimately informing targeted interventions.Bartsch and Nordman focuses on understanding the early signs and deterioration of perceived fatigue in healthy middle-aged individuals to develop preventive strategies for chronic fatigue (CF) and chronic fatigue syndrome (CFS). By understanding fatigue development in middle-aged adults, the study aims to contribute to the establishment of countermeasures for CF and CFS. This research underscores the significance of early detection and prevention of fatigue-related disorders, which can have debilitating effects on individuals' quality of life and productivity.Putra et al. discussed how NMDA receptor antagonists, such as ketamine and memantine, have emerged as promising alternatives for treating aggressive behavior due to their quicker onset of action, fewer observed side effects, and potential to serve as long-lasting treatment options. However, their effects on aggression are highly dependent on dosage, context, and personal experience. A study in this Research Topic explores the complexities of these factors and their impact on the effectiveness of NMDA receptor antagonists in managing aggressive behavior. The findings emphasize the need for further research and careful consideration of individual factors to ensure the responsible use of these drugs and to maximize their benefits while minimizing potential risks.Ronan et al. investigated the impact of intracerebroventricular administration of corticotropin-releasing factor (CRF) and vasopressin (AVP) on extracellular serotonin release in the central nucleus of the amygdala (CeA), shedding light on potential mechanisms underlying stress-induced affective reactivity in humans. This knowledge may prove useful in understanding and treating stress-related psychiatric disorders, such as anxiety, depression, and posttraumatic stress disorder. By examining the neurochemical changes associated with stress-induced affective reactivity, this research advances our understanding of the complex relationship between chronic stress and mental health disorders.Lastly, This broad scope offers a more complete picture of the complex relationship between chronic stress and mental health, with promising implications for the development of novel therapeutic interventions and preventative measures for stress-related disorders.In vivo pharmacological manipulations enable targeted drug administration to the brain, while novel behavioral paradigms, such as the observational fear mouse model, allow for exploration of different stress types on brain circuitry. Assessments of individuals in highly social and stressful environments emphasize the importance of early detection and prevention. Direct manipulations of plasticity in live animal models offer targeted approaches to understanding stress-induced effects. Examining the consequences of pharmacological interventions for treating stress-related aggression provides insights into potential benefits and risks. These cutting-edge methods significantly contribute to ongoing efforts in developing innovative treatments and preventative measures for stress-induced abnormal behavior.The Research Topic features innovative methodologies to study the relationship between chronic stress, neuroplasticity, and abnormal behavior. This Research Topic's implications are significant, contributing to our understanding of chronic stress and its impact on mental health while pointing to novel therapeutic interventions for stress-related disorders. The featured studies explore various aspects of the complex relationship between chronic stress, neuroplasticity, and abnormal behavior. They examine the effects of stress on brain circuitry, neurochemical changes, and early signs of fatigue, as well as the potential of NMDA receptor antagonists to treat aggressive behavior. Collectively, these studies contribute to a holistic understanding of the impact of chronic stress on mental health and wellbeing.As our understanding of the relationship between chronic stress, neuroplasticity, and abnormal behavior deepens, we become better equipped to address the pressing challenges of mental health and support individuals and society as a whole in coping with the often devastating consequences of chronic stress.We hope this collection of articles serves as a catalyst for further research and collaboration among scientists, clinicians, and policymakers, driving the development of innovative and personalized interventions for those suffering from stress-related disorders. Together, we can work toward a future where the adverse effects of chronic stress are better understood, managed, and ultimately, mitigated. With continued research and collaboration, we can make strides in developing effective treatments and preventative measures for stress-induced abnormal behavior, improving mental health outcomes and the overall quality of life for individuals affected by chronic stress.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
+{"text": "The pituitary hormone, oxytocin (Oxt), is gaining more and more interest from researchers in neuroscience over the years. Such attention is due to the multitude of heterogeneous effects on neural circuits and pro-social behavioral responses that Oxt elicits through its receptor, the Oxt receptor (OxtR). Imbalances in the oxytocinergic system are implicated in neuropsychiatric diseases associated with altered socio-emotional competence , but also in some neurodegenerative diseases, such as Huntington's Disease and amyotrophic lateral sclerosis. Understanding the complex neurobiology of the oxytocinergic system in physiologic and pathologic conditions is a still open scientific challenge. The potentiality of Oxt to be used as a drug treatment further increases the need to extend, collect, and organize knowledge concerning this molecule.In this special issue, we feature an assortment of contributions  exploring through different approaches and from multiple angles the specific effects exerted by Oxt in the brain. This collection expands and collects current understanding in the neurobiology of Oxt and will provide direction and guidance for future studies in this field.Manjila et al. integrated brain wide connectivity of Oxt neurons with OxtR expression in mice. Accordingly, they provided insights for three functional circuit-based modules across the whole brain, modulated by the Oxt. These modules regulate respectively (i) the internal state , (ii) somatic/visceral responses , (iii) cognitive responses . The specific effects of Oxt on the neurons of one of these circuit\u2014the learning and memory circuit, involving the hippocampal formation\u2014have been finely investigated in multiple studies, as review in Talpo et al. Variations in the oxytocinergic functional modulation of the different neurons in each hippocampal subregion appear to account for distinct information processing tasks exerted by each subregion, comprehensively summarized in this review.Oxt is widely released in the brain, exerting specific neuromodulation of each cerebral region. Borroto-Escuela et al. reviewed the existence of D2R-OxtR, OxtR-GHS-R1a, 5-HT2AR-OxtR, and 5-HT2CR-OxtR heterocomplexes. In line with this evidence crosstalk between Oxt and other neurotransmitters should be seriously considered.An additional element of complexity in the neuromodulation operated by Oxt is due to the presence in many brain regions of higher order G-protein coupled heteroreceptor complexes of the OxtR. Triana-Del Rio et al., Coccia et al., Chen et al. and Muscatelli et al. described different aspects of these pro-social behavioral responses elicited by the Oxt. Triana-Del Rio et al. summarized how Oxt signaling in the limbic network modulates social and stress/threat-related behaviors, starting from the description of the underling cellular and molecular mechanisms. Authors describe how these responses are especially important in the interactions with conspecifics. Coccia et al. extended this concept by explaining the importance of empathy in social decision-making to survive in social environment. Indeed, Oxt modulates some of the major components of social decision-making  and is associated to empathy-like and pro-social behaviors in rodents. In the context of conspecific interactions, strong evidence of the role of Oxt is offered by the analysis of the parental caregiving behaviors of male mice, as discussed in the opinion paper by Chen et al. Referring to a recent paper by Kazunari Miyamichi's team  was significantly downregulated in periodontitis tissues compared to control tissues, suggesting a potential role for oxytocin-related pathways in the development and progression of periodontitis. However, further research is needed to understand the underlying mechanisms and the correlation between the expression of these genes and the pathological stage of periodontitis.Additionally, The papers in this Research Topic provide insights into the neurobiology of Oxt in health and disease, spanning from the delineation of the pro-social role of Oxt, to the description of the effect of Oxt on specific brain networks, the clarification of crosstalk phenomena between Oxt and other neurotransmitters, the identification of the intracellular pathways activated by Oxt. Then, they provide an overview of the current body of knowledge about Oxt in the brain and highlight the many potentialities of research in this field. In this view, we hope that this Special Topic can stimulate further studies unraveling the missing pieces of knowledge in the mechanisms of oxytocinergic brain modulation, possibly accelerating the development of therapeutic strategies and drugs that use this molecule.All authors contributed to this editorial and approved the submitted version."}
+{"text": "The term \u201cbiological data\u201d refers to information derived from living organisms and their products. The unique characteristics of biological data make biological data management particularly challenging. Diverse biological research generates vast amounts of different types of big data, such as sequence data and protein structures, in a variety of research fields, including transcriptomics, genomics, proteomics, and metabolomics. The scale of biological data is growing exponentially due to rapid technological advances and declining prices for new technologies used to produce biological data. Biological information now plays an essential role in scientific progress. As such, it is very complex compared to other forms of data. The integrated analysis of different data types is attracting research interest these days.This issue contains an important article regarding a biological data repository in Korea by Lee et al. . Lee and his colleagues introduced a new biological data repository, the Korea BioData Station (K-BDS) for sharing biological data , GenBank, Protein Data Bank (PDB), and DNA Data Bank of Japan (DDBJ). These databases were built to share vast biological datasets and have played an important role in scientific research by storing, managing, and providing access to increasingly large datasets. The future of biological research is highly dependent on the proper use and management of data. However, the complexity of biological data and the unprecedented exponential rate of production present significant challenges in archiving, integrating, and translating big data.Despite the government's large-scale R&D investments in the field of biology, Korea has not previously taken active steps toward the establishment of a biological database. Recently, however, the Korean government officially announced a national strategy for sharing biological data generated with national R&D funding. The Korean government has funded the Korea Bioinformation Center (KOBIC) to develop a new data repository, the Korea Biodata Station (K-BDS).The K-BDS is a data repository for all types of data for biological research. It provides free access to various database resources to archive raw biological data and support research activities. The data structure of K-BDS uses international data standards and formats. The K-BDS will evolve through the optimization and automation of data submission, curation and analysis procedures, infrastructure upgrades for storing big data, and the migration and development of new tools and pipelines to support biological research. I hope that the K-BDS will become a centralized archive in Korea and support research activities in academia and industry around the world."}
+{"text": "The COVID-19 pandemic has had an unprecedented detrimental impact on mental health in people around the world. It is therefore important to examine factors that may buffer or heighten the risk of mental health problems in this context.The current study explores the buffering effects of different flows of compassion  and the magnifying effects of fears of compassion on the impact of perceived threat of COVID-19 on indicators of mental health and psychosocial wellbeing.4057 adult participants collected from the general community population across 21 countries from Europe, Middle East, North America, South America, Asia and Oceania, completed self-report measures of perceived threat of COVID-19, compassion, fears of compassion, social safeness, loneliness, depression, anxiety, stress, posttraumatic stress and growth.Self-compassion moderated the impact of perceived threat of COVID-19 on depression, anxiety and stress, whereas compassion from others moderated the effects of fears of COVID-19 on social safeness. Fears of compassion moderated the impact of perceived threat of COVID-19 on psychological distress. Only fears of compassion from others moderated the effects of fears of COVID-19 on social safeness. Furthermore, social connection  predicted higher post-traumatic growth and traumatic stress, whereas social disconnection (fears of compassion and loneliness) predicted increased traumatic symptoms only. Social connection heightened the impact of perceived threat of COVID-19 on post-traumatic growth, while social disconnection weakened this impact. Social disconnection magnified the impact of the perceived threat of COVID-19 on traumatic stress. The effects were consistent across countries.Our findings highlight the universal protective role of compassion and social connection in promoting resilience and buffering against the harmful effects of the COVID-19 pandemic on mental health and psychosocial wellbeing. Furthermore, our results reveal that fears of compassion have a magnifying effect on the damaging impact of the COVID-19 pandemic on mental health.None Declared"}
+{"text": "Post-Traumatic Stress Disorder (PTSD), with prevalence of 14%, causes disability and burden to the person, his/her close environment and whole society due to, among other factors, interruption in a range of daily life activities. To date little research was done to delineate comprehensive patterns of daily life participation among people with PTSD. Despite extensive research, our understanding of factors affecting the participation in PTSD is limited, given that relief in the PTSD symptoms does not guarantee returning to satisfying daily life activities.Investigate objective and subjective participation dimensions among individuals with PTSD in comparison to healthy controls; and explore the impact of personal and illness-related factors, body functions and environment on the participation in PTSD.Sixty two individuals with PTSD  and matching by age and gender healthy controls participated in this cross-sectional study. They completed standard assessments for PTSD symptoms severity, general cognitive profile, executive functions (EF) based on self-report and performance, sensory processing, self-efficacy, capacity to perform everyday activities, environmental properties, and actual participation in daily life in objective  and subjective  dimensions.The participation was found to be inferior in PTSD in the following dimensions: number of activities, participation frequency, and enjoyment , and experienced low meaning within the participation. Number of participated activities was correlated with self-reported EF , and environment properties . Frequency of participation was associated with self-reported EF . In addition, number of activities, frequency and experience of meaning were inferior in those who reported on avoidance from sensory stimuli in daily life . PTSD symptoms severity was not correlated with the participation .The restriction in both objective and subjective dimensions of participation in PTSD raises major concern given the profound effect of participation on well-being, and individual and community burden. The study reveals unique patterns of association between the participation indices and personal and illness related factors in PTSD, suggesting that objective factors are of less impact in comparison to subjective ones; and aspects of cognitive and sensory regulation as well as environment are of particular importance for participation. This pilot study demonstrates a need for further research to expand our knowledge in the field with the ultimate goal of contributing to well-being and health of individuals with PTSD.None Declared"}
+{"text": "A meeting, sponsored by the Bill and Melinda Gates Foundation (BMGF) and organised by Clinglobal, was held at The International Livestock Research Institute (ILRI) in Nairobi, Kenya, from 19th\u00a0\u2013\u00a0to 21st\u00a0October 2022. The meeting assembled a unique group of experts on tick control in Africa. Academia, international agencies (FAO and ILRI), the private Animal Health sector and government veterinary services were represented. The significant outcomes included: (i) a shared commitment to standardisation and improvement of acaricide resistance bioassay protocols, particularly the widely used larval packet test (LPT); (ii) development of novel molecular assays for detecting acaricide resistance; (3) creation of platforms for disseminating acaricide resistance data to farmers, veterinary service providers and veterinary authorities to enable more rational evidence-based control of livestock ticks. Implementation of enhanced control will be facilitated by several recently established networks focused on control of parasites in Africa and globally, whose activities were presented at the meeting. These include a newly launched community of practice on management of livestock ticks, coordinated by FAO, an African module of the World Association for the Advancement of Veterinary Parasitology (WAAVP-AN) and the MAHABA  initiative of Elanco Animal Health.  Ticks and tick-borne diseases significantly constrain livestock production globally, especially in Africa . The ecoRhipicephalus microplus is the most important ixodid tick species causing mortality or morbidity in livestock, multiple tick species transmit additional major livestock pathogens through sub-Saharan Africa. These include East Coast fever (ECF), caused by the protozoan parasite Theileria parva, which is transmitted by the tick Rhipicephalus appendiculatus, and heartwater, caused by the rickettsial pathogen Ehrlichia ruminantium and transmitted by several species of ticks in the genus Amblyomma [In contrast with other regions where mblyomma .R. microplus, originating from Southeast Asia.Ticks and tick-borne diseases in Africa have become increasingly severe because of the introduction of the invasive one-host tick,\u00a0Rhipicephalus microplus is now well established in tropical and subtropical regions, including Latin America, Australia and, more recently, Africa. The economic importance of this tick species results from its capacity to transmit the highly pathogenic protozoans Babesia bovis and B. bigemina and the rickettsial pathogen Anaplasma marginale. After introduction of R. microplus to Madagascar in 1959, the tick spread to South Africa and Tanzania, frequently displacing the indigenous \u2018blue tick\u2019 Rhipicephalus decoloratus, notably in Tanzania [R. microplus was introduced twice to West Africa (Benin and Cote D\u2019Ivoire) from Brazil [R. decoloratus in that country, [Rhipicephalus annulatus and R. geigyi (unpublished data). Data from Kenya similarly suggest R. microplus has displaced R. decoloratus from the coastal region [Tanzania . More rem Brazil , 5 and hcountry,  and possl region .Given the absence of alternative control measures, the application of acaricides for tick and tick-borne disease control remains the main practical option. Several recent publications have reviewed the status of acaricide deployment and resistance in Africa together with the perceptions of livestock keepers regarding ticks, tick-transmitted diseases and control methods \u201311.However, as in other continents, resistance to the major classes of acaricides, synthetic pyrethroids, organophosphates, amidines and macrocyclic lactones , 13 has The goals of the meeting were to review the current knowledge relating to the prevalence of acaricide resistance in sub-Saharan Africa; learn from the progress of ongoing tick control initiatives; review updated protocols for standardisation of existing acaricide resistance diagnostics and assess the potential value of novel assays. There was also a discussion on enhancing the dissemination of accrued knowledge to farmers and national veterinary institute staff through digital and direct platforms for engagement with multiple clients .R. appendiculatus, which transmits T. parva (causing East Coast fever in cattle), and the recently introduced R. microplus, transmitting highly pathogenic B. bovis and A. marginale to livestock, particularly cattle. He reviewed the current techniques for acaricide resistance diagnosis, in particular the larval packet test (LPT) and adult immersion test (AIT). These are currently relatively expensive and require a network of laboratories with the expertise and resources to perform them. Doctor Vudriko further highlighted additional dimensions of the acaricide resistance problem, including lack of resources, appropriate infrastructure and government extension services, leading to the suboptimal application of acaricides, and even crop pesticides instead of acaricides. Maria Tumwebaze, also of the RTC unit, presented data generated using the LPT and adult immersion test (AIT), indicating that resistance occurs among all three major classes of acaricides that are currently widely marketed in Uganda: synthetic pyrethroids, organophosphates and amidines.The keynote presentation was given by Dr Patrick Vudriko, Director of the RTC at Makerere University in Kampala, Uganda. He emphasised issues constraining efficient tick control and detecting acaricide resistance in Uganda and other countries in the region. His major emphasis was on the mitigation of resistance to Thomas Bazarusanga of ACRE Africa confirmed that resistance, as indicated using LPT, is also present against multiple acaracide types in Rwanda, with Amitraz being the most frequently implicated product . As in Uganda, suboptimal application of acaricides was observed as well as the use of unsuitable crop pesticides. Doctor Bazarusanga\u2019s key recommendations for improvement of acaricide resistance surveillance (ARS) and the agencies with responsibility for this in Rwanda were summarised as enhanced extension services (RAB), enforcement of regulation at Rwanda Food and Drugs Authority (RFDA) and Licensing of Agrovet attendants from Rwanda Council of Veterinary Doctors (RCVD).Amblyomma variegatum and R. microplus, and the main techniques used for assessment are LPT, AIT and larval immersion test (LIT). Maps were presented showing the geographical distribution of resistance within the region. For R. microplus, resistance in the field has been confirmed using the LPT in Burkina, Faso, Cote-D\u2019Ivoire, Togo, Mali and Benin. As in Rwanda, Amitraz is the most frequently used product . Unlike East Africa, acaricide application in West Africa is primarily by brushing, rather than spraying, using backpacks, which may result in differences in the evolution of acaricide resistance between East and West Africa.Abel Biguezoton of CIRDES summarised the current situation regarding ARS for eight countries in West Africa. In this region, the major tick species of economic importance are R. microplus at the Kenyan coast. ILRI provides assay backstopping through quality control, training and, in future, the supply of reference susceptible tick strains. Trials of a similar collaboration between a dedicated centre of excellence, specifically the RTC at Makerere, and the District Veterinary Office of Kiboga, Uganda, were presented by Timbiira John Bosco, the regional DVO. Veterinarians were trained in tick collection, and subsequent analysis at RTC used the adult immersion technique (AIT).Doctor Naftaly Githaka of ILRI provided a preliminary example of how diagnostic assays for acaricides could be integrated into the programmes of departments of veterinary services (DVS) in Africa through his work on acaricide-resistant R. microplus but can be adapted for organophosphates and amidines. Although the most widely adopted assay, it is a lengthy undertaking involving field sampling followed by six weeks in a specialised laboratory, because of the requirement to generate larval ticks from engorged adults. Professor Frans Jongejan of FAO summarised the history of the test and its application in Africa. The LPT was originally described and adopted in 1960s [The LPT remains the gold standard assay for evaluating acaricide resistance phenotypes in ticks. It has primarily been applied to diagnosing acaricide resistance to synthetic pyrethroids in in 1960s  and the in 1960s  as an alThe two principal resistance mechanisms are metabolic resistance, associated with the enhancement of the detoxification enzyme system, or target-site resistance, associated with modification of the binding site of the acaricide. The tick proteins targeted by the most widely used acaricides are relatively well characterised. They are usually part of the nervous system and Single Nucleotide Polymorphism (SNP) at the target site have been correlated with resistance. The primary target sites for synthetic pyrethroids are the voltage-gated sodium channel; for organophosphates, the acetylcholinesterase receptor; and for macrocyclic lactones, the GABA-gated sodium channels. In the case of formamidines, which are Octopamine receptor agonists, the picture is the most complex, the octopamine/tyramine receptor contains SNPs implicated in resistance, but other genes, such as monoamine oxidases and ATP-binding cassette transporters, are also suspected targets. Professor Christine Maritz-Olivier presented the genetic complexity underpinning acaricide resistance phenotypes\u00a0as shown in\u00a0Table R. microplus isolates from Africa and North and South America, Clinomics has developed a preliminary PCR-based assay for field detection of synthetic pyrethroid resistance in R. microplus. Dr Francois Maree presented the assay details and coordinated a practical demonstration for workshop participants. The current objective of the project is to show proof of concept for a field-applicable assay capable of providing rapid diagnosis of the presence of markers for acaricide resistance. The approach has the potential for multiplexing, incorporating additional targets for other acaricide classes in a format that may be used to support conventional bioassays in the future\u00a0Fig. Based on sequence data derived from acaricide-resistant and susceptible The MAHABA programme , managed by Elanco Animal Health and GALVmed and supported by BMGF, was presented by Dr Chandra Bhushan. The MAHABA programme is intended to deliver a practical strategy for managing ticks and the impact of tick-borne disease and to equip small-scale producers in Uganda and Nigeria with the necessary tools (acaricides) and knowledge  to realise livestock productivity gains. This represents a significant advance relative to companies maximising acaricide sales without corresponding client engagement.https://virtual-learning-center.fao.org/mod/page/view.php?id=7392).Doctor Ayo Majekodunmi (WAAVP-AN co-chair) and Dr Weining Zhao (FAO) presented details on developing regional and global networks to support future research and guidelines for tick control. The WAAVP-AN is an African network of experts in veterinary parasitology. It is intended to improve knowledge on veterinary parasites as well as communication and networking on parasitology in Africa. Recently, FAO has established a global Community of Practice that will underpin the development of a new set of guidelines on acaricide resistance and the management of livestock ticks which can be accessed at  to central laboratories and validate the results with LPT and future molecular tests. LTT could be a transition bioassay until the molecular tests are fully developed and validated.Improved data collection and centralised management to improve mapping and the dissemination of information to farmers, veterinary services and policymakers.Continued refinement of field-based molecular assays to increase the number of markers, acaricide classes and tick species which the assay can support.Evaluation of integrated control, including evidence-based implementation of acaricide rotation and combination strategies.Organisation of follow-up meetings with inclusive African country coverage, involving veterinary authorities and research organisations, to review resistance data in more detail and develop country-specific or regional models for implementation of acaricide resistance surveillance.Additional priorities:R. microplus within the continent and the reliance on acaricides to control this tick. This initial meeting of multiple experts highlighted the potential to deploy technical and knowledge-based solutions to mitigate the acaricide resistance problem in African livestock ticks and the role of recently implemented networks in catalysing this process.Acaricide resistance is widespread in Africa, and the impact on the control of ticks and tick-borne diseases has severe implications for farmer\u2019s livelihoods. Multiple laboratories have confirmed the detection of resistance to all widely deployed classes of chemical acaricides. Furthermore, the problem is increasing because of the rapid spread of"}
+{"text": "Therefore, the indiscriminate administration of fluids to allpatients with hemodynamic instability, in addition to not obtaining the possiblebenefits induced by the increase in cardiac output, has the potential to aggravateorgan dysfunctions, since the excess of fluids, represented by the accumulatedhydric balance, is an independent factor for an increase ICU length of stay,duration of mechanical ventilation, probability of acute kidney injury andmortality.-4Despite the different methodologies and definitions in the literature, the mostaccepted concept of fluid responsiveness (FR) is an increase in cardiac outputgreater than 10-15% induced by an increased preload. Thus, volume expansion is theinitial measure most frequently used to optimize tissue perfusion in ahemodynamically unstable patient. However, the prevalence of FR in the intensivecare unit (ICU) is approximately 50%. , in turn, is the ability of the body to receive an infusion offluids without progressing to organ dysfunction . PossiblThus, the combined evaluation of FR and FT is of fundamental importance in themanagement of hemodynamically unstable patients because the absence of FT, even in afluid responsive patient, can mitigate any benefit induced by volume expansion andeven aggravate or cause new organ dysfunctions.Considering the presence or absence of FR and FT, there are four hemodynamicprofiles:- A: FR present and FT present.- B: FR absent and FT present.- C: FR absent and FT absent.- D: FR present and FT absent.Depending on the hemodynamic profile in question, it is possible toindividualize, the most appropriate approach for hemodynamic resuscitation for agiven hemodynamically unstable patient, with the objective of preventing and/orreversing organ dysfunction .The following are basic principles:- Volume administration should not be performed in the absence of FR (profiles Band C). In the absence of FR and FT (C profile), the need for de-resuscitationshould be assessed. Fluid administration in a fluid tolerant patient but withoutFR criteria (profile B) can lead to the loss of FT, with the risk of newhypervolemia-induced organ dysfunction, thus requiring conservative managementwith regard to the administration of fluids.- In the presence of FR, volume administration with the greatest potentialbenefit and lower risk of inducing or worsening organ dysfunction will be in theconcomitant presence of FT (profile A).- In the presence of FR and absence of FT (profile D), volume administrationshould take into account the potential for inducting and/or aggravating organdysfunction, and early initiation of vasoactive drugs should be considered.Fluid tolerance should be evaluated in two different compartments; left,considering the left heart chambers filling pressures and the degree ofpulmonary congestion; and right, assessing the right heart chambers fillingpressures and the degree of fluid overload in the systemic venouscompartment.Static measures of filling pressure in right and left cardiac chambers, such ascentral venous pressure (CVP) and pulmonary artery occlusion pressure (PAOP),depend on the interaction between venous return function and ventricularfunction, and are also influenced by increases in intrathoracic pressure insituations such as pneumothorax, cardiac tamponade and the use of positiveend-expiratory pressure (PEEP). Therefore, they have a limited role in theidentification of FR and volemic status; however, extremely low values (<6mmHg) increase the probability of FR. On the other hand, high values (CVP >12mmHg and PAOP > 18mmHg) may indicate a low FT capacity in certain clinicalcircumstances and are associated with an increased risk of peripheral edema,ascites, pulmonary edema, renal and hepatic dysfunction. In addition, themeasurement of these variables requires the use of invasive devices, such as acentral venous catheter for CVP and a pulmonary artery catheter for PAOP.Hemodynamic monitoring by transpulmonary thermodilution may assist in theevaluation of FT, especially on the left compartment, using variables such asglobal end-diastolic volume (GEDV), extravascular lung water (EVLW) and thepulmonary vascular permeability index (IPVP), and is useful in the differentialdiagnosis between inflammatory and hydrostatic alveolar-interstitial syndrome.Despite being a less invasive tool than a pulmonary artery catheter, theinsertion of central venous and arterial catheters is required and has high costlimiting its availability in most intensive care units. and the evaluation of left ventricular fillingpressures, as assessed by the relationship between the E wave and the A wave ofthe transmitral flow on pulsed Doppler and the E wave over the E\u2019 wave on tissueDoppler, help in the evaluation of left FT. Venous excess ultrasound score(VExUS) takes into account the diameter of the inferior vena cava and the venousflow pattern on Doppler ultrasound in the portal, suprahepatic and intrarenalveins ( and may be useful instrategies of resuscitation and management of ultrafiltration in patients onhemodialysis,(11.being an interesting tool for the evaluation of right FT (Point-of-care ultrasonography is becoming increasingly available in ICUs, withthe potential for wide application for evaluation of both left and right FT. Theestimation of EVLW using lung ultrasoundalveins , shows aright FT .The growing evidence in critically ill patients of aggravation of organ dysfunctionrelated to fluid overload implies that hemodynamic evaluations should advance beyondfluid responsiveness and begin to encompass fluid tolerance. The coordinatedevaluation of these two variables has the potential to prevent and reverse acuteorgan dysfunction and assigns a new obligation to intensivists: fluidresponsibility."}
+{"text": "Evidence-Based Quality Improvement (EBQI) involves researchers and local partners working collaboratively to support the uptake of an evidence-based intervention (EBI). To date, EBQI has not been consistently included in community-engaged dissemination and implementation literature. The purpose of this paper is to illustrate the steps, activities, and outputs of EBQI in the pre-implementation phase.The research team applied comparative case study methods to describe key steps, activities, and outputs of EBQI across seven projects. Our approach included: (1) specification of research questions, (2) selection of cases, (3) construction of a case codebook, (4) coding of cases using the codebook, and (5) comparison of cases.The cases selected included five distinct settings , seven EBIs  and five unique lead authors. Case examples include both community-embedded and clinically-oriented projects. Key steps in the EBQI process included: (1) forming a local team of partners and experts, (2) prioritizing implementation determinants based on existing literature/data, (3) selecting strategies and/or adaptations in the context of key determinants, (4) specifying selected strategies/adaptations, and (5) refining strategies/adaptations. Examples of activities are included to illustrate how each step was achieved. Outputs included prioritized determinants, EBI adaptations, and implementation strategies.A primary contribution of our comparative case study is the delineation of various steps and activities of EBQI, which may contribute to the replicability of the EBQI process across other implementation research projects. The conThe combination of community-engaged research and D&I, termed community-engaged dissemination and implementation (CEDI) research, reflects the intersection of community-partnered research in implementation research design, methods, and dissemination . The ovebest available research evidence at all stages of the process, from the \u201cdiagnosis\u201d of performance issues to the development and tailoring of implementation strategies . QI aims to improve local multi-level processes and outcomes by using data from the local context, local expert input and opinions, and local multi-disciplinary teams . A revierategies , and in rategies . Specifirategies  and selerategies .deliberative, partnered, and evidence-driven process to inform the selection and tailoring of implementation strategies and EBI adaptations. This definition of EBQI reflects a conceptualization that EBQI would fit under the umbrella of more global approaches to research  and could be operationalized with other methods . We acknowledge that EBQI can be applied across all stages of implementation  the formation of local teams to consider data on barriers and facilitators to implementation and (2) drafting, iterating, and planning a locally contextualized implementation strategy to increase uptake of an EBI . Additio(1)What steps do researchers accomplish using EBQI in practice?(2)How do researchers accomplish the steps of EBQI? That is, what activities are used to accomplish EBQI steps?The purpose of this paper is to illustrate the steps, activities, and outputs of EBQI in the pre-implementation phase as operationalized across seven projects to illustrate common elements and variations in application of EBQI . This go2.To identify key steps, activities, and outcomes of EBQI methods, we retrospectively examined a set of seven case examples of EBQI application in research projects. Specifically, our goal was to use case examples to create a holistic description of EBQI and capture how each case selected and tailored implementation strategies and/or made EBI adaptations that would be subsequently tested in a research study . We applNatural variation and overlap in the cases were a key interest. Specially, cases were purposively included to maximize variation  in the E2.1.The research team developed a case codebook to collect a standard set of information for each case and coded each case using this codebook. This codebook included basic features of the EBQI process , the progression of EBQI meetings, and activities that were used at each meeting. Using the codebook, the lead investigator for each case extracted details of their respective projects. When needed, the lead author solicited additional information or clarification from investigators. This directed template analysis approach  allowed 3.The team completed a cross-case analysis to identify similarities, differences, and the range of steps, activities, and outputs across cases. We used this comparison to generate a list of the key steps of EBQI and corresponding examples of activities to accomplish each step. Cases were examined and compared for key basic features including the number of EBQI meetings held, types of partners included, and modality of meetings. Included case studies ranged in the number of meetings from 2 to 5 , 27, 31.Commonalities and variations across case studies suggest basic steps that are core to EBQI in the pre-implementation phase; these are presented in https://www.liberatingstructures.com/), live editing of documents], illustrating the flexibility of activities to achieve multiple purposes.The activities taken to achieve these steps were diverse See . Each stWe have expanded on the Swindle  case to 4.This perspective examined 7 case studies of the application of EBQI in the pre-implementation phase. Comparison of cases suggested 5 common steps of EBQI to prepare for implementation. These steps cut across the variety of settings and EBIs included in our case examples, which illustrates the widespread applicability of these steps. For each step, we identified several activities. That is, various activities were used across the cases to achieve each step. The diversity of activities identified illustrates how each step may be achieved depending on the context and needs of the project. Commonly, the steps identified led to prioritized determinants of implementation, adaptations for EBIs, and fully specified implementation strategies ready for testing. As such, the primary contribution of our perspective is the delineation of steps and activities of EBQI, particularly when used as a deliberative, partnered, and evidence-driven process to inform the selection and tailoring of implementation strategies and EBI adaptations prior to implementation. Thus, our work answers a recent call to provide transparency and detailed descriptions for the process of tailoring in implementation science .Ultimately, the process of EBQI identified in included cases expands on steps of the EBQI model as laid out by early users . The 5 chow to move through EBQI in the pre-implementation phase. Key to many of our activities and an important recommendation for future application of EBQI is the inclusion of end users, which was present in 6 of our 7 cases. Other authors have made a compelling case for the importance of participatory approaches for optimizing fit of EBIs within context (Within each EBQI step, we identified several activities. This illustrates a non-exhaustive catalogue of options for  context , address context , and adv context . Our cas context .Notably, EBQI has historically been and continues to be used beyond the pre-implementation phase. Work by Hamilton and colleagues  illustraWe believe EBQI used at any phase of implementation is an example of quality CEDI work and fits with other recommended CEDI methods . However"}
+{"text": "Elite athletes are continually subjected to a range of constraints specific to high performance, and these can have a negative impact on their health. Although many studies have explored the individual factors related to risky behaviors and disorders in elite sport contexts, and have provided prevention programs, few have focused on health promotion. Consequently, the interpersonal, institutional, and policy factors of the health-related behaviors of elite athletes are still poorly explored. Based on the socioecological model of health, this study aimed to identify the factors involved in the health-related lifestyle of elite athletes.Semi-structured interviews were conducted with 45 participants: athletes , their coaches  and managers of elite sport centers . Interviews were audio recorded and transcribed verbatim. Both deductive and inductive thematic analyses were performed. This study was approved by the local Ethic Committee of the University.Our results highlight the different levels of factors related to the health-related lifestyle of elite athletes, using the socioecological model, as perceived by athletes themselves, coaches, and managers. Regarding intrapersonal factors, resilience qualities and health literacy appeared as key factors to influencing the health-related lifestyle of elite athletes. At the interpersonal level, parents and coaches were considered as the main sources of educational support. Regarding institutional factors, the health policies of the elite sport centers were key factors in supporting the athletes\u2019 healthy lifestyle. Similarities and specificities of the views of the different actors have been identified.These results show the interest of the application of the socioecological model in the elite sport domain. They encourage the development of health-promotion programs at different levels of intervention of the socioecological model, beyond traditional health prevention programs. In addition, this study suggests to consider the different perspectives of each actor to co-construct health promotion programs."}
+{"text": "The EuResist cohort was established in 2006 with the purpose of developing a clinical decision-support tool predicting the most effective antiretroviral therapy (ART) for persons living with HIV (PLWH), based on their clinical and virological data. Further to continuous extensive data collection from several European countries, the EuResist cohort later widened its activity to the more general area of antiretroviral treatment resistance with a focus on virus evolution. The EuResist cohort has retrospectively enrolled PLWH, both treatment-na\u00efve and treatment-experienced, under clinical follow-up from 1998, in nine national cohorts across Europe and beyond, and this article is an overview of its achievement. A clinically oriented treatment-response prediction system was released and made available online in 2008. Clinical and virological data have been collected from more than one hundred thousand PLWH, allowing for a number of studies on the response to treatment, selection and spread of resistance-associated mutations and the circulation of viral subtypes. Drawing from its interdisciplinary vocation, EuResist will continue to investigate clinical response to antiretroviral treatment against HIV and monitor the development and circulation of HIV drug resistance in clinical settings, along with the development of novel drugs and the introduction of new treatment strategies. The support of artificial intelligence in these activities is essential. Although a cure for HIV cannot be achieved with available antiretrovirals (ARVs), the last 25 years saw dramatic improvement in the prognosis and management of HIV infection, thanks to the use of multiple drugs from different antiretroviral classes ,2,3. IndAs longer periods of follow-up data have become available, the clinician\u2019s attention has shifted towards treatment tolerability and durability. Nevertheless, the impact of pre-existent drug-resistant mutations has remained a challenge in clinical practice, especially in PLWH exposed to suboptimal regimens in the first ART era . In addiIn 2006, a multidisciplinary group of scientists created the EuResist consortium to fight ARV resistance and obtained a grant by the European Commission under the 6th Framework Programme. The project integrated three existing national cohorts from Italy, Germany and Sweden to form a large dataset of clinical and virological information from around 17,000 PLWH, thus giving rise to the EuResist Integrated DataBase (EIDB). By modeling these data via statistical learning, the EuResist project delivered a clinical decision-support tool for predicting the best ART for specific PLWH by leveraging curated real-world data. The multicohort EuResist Network was established in 2008 as a follow-up of the EuResist project to manage the EIDB and the EuResist ART response prediction system. Currently, the EIDB is one of the world\u2019s largest datasets suitable for training genotype-centered treatment-response models. The EIDB collects information about pseudonymized demographic and clinical characteristics of PLWH, including antiretroviral therapies, reasons for treatment change, AIDS defining events, viral co-infections, CD4 + T cells counts, viral load measurements, and HIV sequences.Originally, the EIDB was developed by integrating biomedical information from the three founding nationwide databases: ARCA , AREVIR (Germany), and InfCareHIV at Karolinska Institute, Stockholm (Sweden). Following the initial setup, other centers became partners of the EuResist Network and provided biomedical data to the EIDB. Most of these remain active contributors, together with the three founders; at time of writing, this includes: the Instituto de Higiene e Medicina Tropical ; the IrsiCaixa Foundation (Spain); the Laboratoire de R\u00e9trovirologie of CRP-Sant\u00e9 (Luxembourg); the Gamaleya Institute of Virology (Russia); the Koacaeli University Medical Faculty (Turkey); and the CoRIS cohort (Spain). Additionally, data from the Rega Institute (Belgium); the National Referral Laboratory of Rwanda; the DUET study conducted by Tibotec; and the Resist study conducted by Boehringer Ingelheim, from the Infectious Diseases, AIDS and Clinical Immunology Research Centre of the State Institution Centre Public Health Ministry of Health of Ukraine and from the Infectious Diseases AIDS and Clinical Immunology Research Centre (IDACIRC) of Georgia were integrated in the past . https://www.euresist.org/eidb accessed on 31 March 2022). Data integrity and updating have been ensured for the last 15 years and onwards through an iterative process of data cleansing and periodical refresh from the contributing centers. The key uses of the EIDB have included the training of a machine-learning-based engine assisting treatment choices and providing curated datasets for specific studies, focusing on HIV variability, treatment, and drug resistance [The EIDB is updated twice a year with new data from the contributing centers by using import routines maintained centrally by the EuResist IT staff. Currently, it contains data from 105,903 PLWH, contributing 102,851 viral sequences, 248,249 treatment regimens, 1,451,753 viral load measurements and 1,486,295 CD4 cell counts A. The masistance .The objective of this manuscript is to offer an overview of the main contribution provided by the EuResist multicohort initiative in the fight against HIV drug resistance during the last 15 years, based on the efforts of many researchers from different European countries.The EuResist Network complies with the General Data Protection Regulation (GDPR) and all applicable laws, rules and regulations, with particular reference to ethical issues concerning the collection of data belonging to HIV patients and the relative manipulation and sharing procedures. All the data contributors to the EIDB certify that: the data collection was approved by the local ethics committees in agreement with local requirements and written informed consent was obtained from all patients before participation when necessary; the procedures are performed under the guidance and responsibility of the contributing centers; personal data are lawfully processed and may be contributed to the EIDB for scientific purposes on the basis of the data subject\u2019s consent or another legal basis valid under the GDPR (art. 6 and art. 9).This study is performed in accordance with the ethical principles of the Declaration of Helsinki and the Good Clinical Practice guidelines of the International Conference on Harmonization.Data are securely stored in Italy. They contain sensitive human subject information and cannot be shared publicly because of privacy issues. Data are available under request to the EuResist Scientific Board, comprising all the data controllers. The EuResist Network has received research grants from the European Commission and unrestricted research grants from the following pharmaceutical companies: Abbott, Janssen Tibotec, Gilead Sciences, Merck Sharp and Dohme, Pfizer, Theratechnologies, and ViiV Healthcare. Neither the companies nor the patients had any role in the design, recruitment, or conduct of the studies.The emergence of antiretroviral drug resistance has long been a leading cause of treatment failure in PLWH. Particularly, before the advent of compact, high-genetic-barrier cART, the development of drug resistance was almost inevitable at some point in time. Thus, strategies for delaying the onset of resistance, preserving treatment options and avoiding cross-resistance were typically aided by algorithms interpreting HIV genotype. While these systems were mostly based on expert reviews of the literature, the EuResist consortium proposed a novel approach for predicting the in-vivo efficacy of antiretroviral drug regimens against a given virus isolate, based on statistical learning from a large amount of data correlating virus genotype and patient data on treatment response in clinical practice. vs human Experts) study in which 25 complete patient histories were provided to a panel of 10 global top experts in HIV drug resistance, who had to indicate whether the next ART regimen used would be effective or not. The EuResist system outcompeted nine of the experts in accuracy and equaled the most proficient one, demonstrating the strength and feasibility of the approach in a real-world simulation [Based on the analysis of the EIDB data, different predictive models have been developed over the years. In 2008, the first machine-learning engine was reported, which combined three models as follows: (a) generative-discriminative method, (b) regression with derived evolutionary features and (c) regression with a mixture of effects. The engine demonstrated an increase in the accuracy of prediction when taking into account clinical information and demographic factors in addition to genotypic information [mulation . In 2010, Bogojeska et al.  developehttps://hivdb.stanford.edu/ accessed on 10 April 2023) provides an impressive number of options for querying a curated HIV sequence database derived from published HIV sequences, with novel features and services released on a regular basis.It must be noted that, despite considerable efforts to improve the algorithms for prediction of response to ART, the increase in accuracy with respect to standard systems based only on the interpretation of HIV genotype has been limited. Factors impeding higher benefits by applying advanced statistics have not been identified but likely include the sparse representation of data in the training datasets and the complete lack of data on one major determinant of response to treatment, namely adherence to therapy. Moreover, the gain in accuracy comes at the cost of additional data to be input into the system\u2014something that most doctors are reluctant to do. Additional bottlenecks for the transition from simple to improved yet more-complex methods include the lower degree of human interpretability of the latter and the globally decreased impact of drug resistance in modern ART . As a maThanks to the continuous and longitudinal accumulation of viral sequences and patient data, the EIDB has offered a tremendous opportunity to monitor the selection and spread of transmitted and acquired resistance-associated mutations (RAMs), the circulation of different viral subtypes, and their impact on treatment outcome, most often as measured by changes in viral load. In more recent years, non-B subtypes have become endemic in the European population, likely due to human migration from non-B areas. This may have had an impact on the global picture of drug resistance since most non-B areas have been characterized by a different coverage of ART regimens and consequently different patterns of emergent drug resistance. This effect has been later diluted and will continue to be diluted by the harmonization of ART regimens, particularly those based on high-genetic-barrier regimens, significantly limiting drug resistance and failure.A key issue in HIV drug resistance is the prevalence and incidence of multidrug resistance, resulting in an extensive loss of treatment options and the inability to control virus replication and halt disease progression. Two EuResist studies have shown a declining trend of resistance to the four main classes of ARVs, including protease inhibitors (PI), nucleoside (NRTI) and non-nucleoside (NNRTI) reverse transcriptase inhibitors, and integrase strand transfer inhibitors (INSTI). The first study analyzed viral sequences collected from 3414 individuals with at least 1 genotype test result available between 2008 and 2019 and found that high-level resistance to at least 1 drug in each of the 4 main ARV classes declined from 5.6% in 2008 to 2.4% in 2018, with only 2.5% of the patients accumulating four-class resistance over time . NotablyThe studies conducted by Lapokov et al.  and NeshA recent study conducted by van de Klundert et al.  showed, Over the years, the EIDB was used to explore the clinical impact of specific RAMs. For example, Theys et al.  observedInspired by the updates of the international HIV treatment guidelines, the EuResist Network explored the real-world effectiveness of different treatment strategies. Understanding and predicting treatment efficacy and duration of effectiveness, i.e., how long an antiretroviral therapy can be sustained without changes, even in the presence of pre-existing RAMs, has become an important challenge in the context of addressing HIV treatment optimization. For example, the analysis of the EIDB data suggested that the efficacy of the innovative dual-drug strategy combining the NNRTI etravirine with the ritonavir-boosted PI darunavir was comparable to that of alternative regimens where etravirine was coupled with an alternative boosted PI . In 2019More recently, two studies explored the effectiveness and discontinuation rate of INSTI, a key component of most current ART regimens. Among 2976 INSTI treatments started by na\u00efve PLWH, elvitegravir- or dolutegravir-based first-line antiretroviral treatment was highly effective in routine practice across Europe, even in the presence of transmitted drug resistance for the accompanying NRTIs. However, the rate of INSTI discontinuation was much higher than the rate of virological failure . InteresAnother study by Miranda et al.  investigThe EuResist Network has been collaborating with other non-European cohorts and global initiatives to investigate HIV-resistance-related issues, particularly in low-income countries. From 2010 to 2013 it participated in the ENEAA project (EDCTP JP.2009.10800.002), coordinated by Karolinska Institut and involving the Addis Ababa University, Ethiopia; the Muhumbili hospital, Dar-es-Salaam, Tanzania; and the World Friends Hospital, Nairobi, Kenya, integrating training activities and IT infrastructures to improve capacities in the eastern African area. The TenoRes collaboration included data from adult HIV treatment cohorts and clinical trials in Europe, Latin and North America, sub-Saharan Africa, and Asia. Among 1926 PLWH enrolled after virological failure with first-line tenofovir-containing ART, HIV drug resistance was detected in an alarmingly high fraction of cases, strengthening the need for the surveillance of transmitted drug resistance . AnotherThe EIDB can be accessed upon formal request by scientists aiming at investigating HIV treatment and drug-resistance-related topics. The EuResist Management Board processes requests in a reasonable time and asks the individual cohorts for permission to access the data for the specific study, which has to be well-defined and scientifically sound. EuResist encourages other clinicians and scientists, also from non-European countries, to collaborate for the advancement of knowledge on HIV drug resistance and treatment, and it is open for scientific studies. Karolinska Institutet  ;Max Planck Gesellschaft (Germany);University of Siena ;InformaPRO s.r.l. ;Cologne University (Germany).EuResist Network is a non-profit European Economic Interest Grouping (EEIG) composed by:th Framework Programme (FP)), the EuResist Network participated in and guided several research projects funded by the European Commission, among which we can mention: CHAIN-Collaborative HIV and Anti-HIV drug resistance Network, a large scale integrated project ; CARE-Common Action against HIV-TB HCV across the Regions of Europe, ; and EuCARE-European Cohorts of Patients and Schools to Advance Response to Epidemics , where the focus moves to SARS-CoV-2 ad its variants.In addition to the already mentioned EuResist project (Grant n. IST-2004-027173, 6EuResist also runs dissemination and training activities. Further to the cited ENEAA EDCTP project, it offers training tools on its website; it participates in the annual ARCA Mentor School event, and has organized a EuResist Mentor School in Cologne in 2018 with the objective to bridge the gap between data science and medical/biological sciences.Since 2007, EuResist has contributed to the annual Arevir Meeting organized by the University of Cologne and Genafor, holding a EuResist session.The main strength of the EuResist Network is the inclusion of all PLWH followed at each of the participating centers, ensuring the full representativeness of the real-life setting, including individuals typically not enrolled in randomized trials due to, e.g., the presence of baseline drug resistance or past virological failures. The sample size of the cohort is also notable, with a total of 105,903 PLWH as of March 2022. Likewise, the geographic distribution of the participating centers is Europe-wide, with additional cases from Turkey, Russia, Ukraine, Georgia, and Rwanda. The observational, retrospective, and prospective multicohort design provides an extraordinarily large time span, with data collection starting as early as the late 1980s, translating into a unique opportunity to follow virus evolution and investigate very different treatment strategies across all antiretroviral treatment eras.The main limitation of the EIDB is that most contributing cohorts collect only routine clinical and viro-immunological data. Some data can be missing in the individual databases, making the overall data collection not uniform across areas and resulting in the exclusion of large datasets when specific variables are required. The lack of information on tolerability issues, adherence to ART, clinical non-AIDS-related events and concomitant medications make the cohort not suitable for many kinds of investigations. Lastly, although a semiannual update is planned, delays between local data collection and the availability of an updated centralized database often occur, postponing the possibility to study the most recent treatments, which are typically of maximum interest.The EuResist cohort was established with the purpose of developing a clinical decision-support tool predicting the most effective antiretroviral therapy for PLWH based on their clinical and virological data. Later, the cohort widened its activity to the more general area of antiretroviral treatment with a focus on virus evolution and drug resistance. Following its interdisciplinary vocation, EuResist will continue to investigate clinical response to antiretroviral treatment against HIV and monitor the development and circulation of HIV drug resistance in the clinical setting along with the development of novel drugs and the introduction of new treatment strategies. The support of artificial intelligence in these activities is essential."}
+{"text": "Dear Editor,A 33-year-old male patient presented with multiple erythematous-brown papules measuring 1 to 5\u00a0mm, disseminated on the upper limbs, trunk and thighs . DermoscHistopathology showed proliferated capillary vessels with dilated lumen A and mulAfter he was instructed about the condition, the patient chose not to undergo treatment for aesthetic purposes and returned after one year with spontaneous significant improvement in the number, pigmentation, and size of the lesions .Figure 5Multinucleate cell angiohistiocytoma is a rare benign fibrous histiocytic proliferation, described in 1985.Treponema pallidum infection. Another theory proposes that MCA arises under the influence of female hormones due to the identification of estrogen receptor alpha expression in the interstitial and multinucleate cells of lesions in several patients.Since the first description of MCA, several hypotheses have been proposed for its etiology and pathogenesis. Most authors believe it to be a reactive process and reports of spontaneous remission further support this hypothesis.Dermoscopy can show some similarities with dermatofibromas, such as whitish areas and a fine peripheral reticulated pattern. Diffuse reddish areas with blurred edges, which likely represent the characteristic vascular dilation, may also be found.Histopathology shows proliferation of dilated capillaries, fibrous stroma with thickened collagen bundles, and the presence of multinucleate giant cells. The overlying epidermis may be normal or hyperplastic. The presence of at least three of the described in the adequate clinical context is highly specific for MCA and allows differentiation from fibrous papule and dermatofibroma. The criteria considered for the diagnosis were: a) Presence of atypical and multinucleate fibroblasts with at least two nuclei; b) Presence of superficial parallel dermal fibrosis; c) Presence of thickened superficial papillary dermal vessels; d) Absence of perifollicular fibrosis.Regarding immunohistochemistry, the multinucleate cells are typically negative for factor VIII and CD34 and positive for vimentin and factor XIIIa. There is a positive correlation between CD68-positive expression of endothelial cells and lesion size, and an inverse correlation between CD68-positive expression on multinucleate cells and the development of multiple lesions.2 laser.The biological behavior of MCA is progressive in most cases, albeit benign, with spontaneous improvement being rare. Treatment can be carried out for aesthetic purposes. The currently available therapeutic options include topical or intralesional corticosteroids, surgical excision, cryotherapy, argon laser, intense pulsed light, and COTreponema pallidum infection and suspected by dermoscopic findings. Because it is rare, it is important that dermatologists and pathologists are able to recognize it for a better approach and to provide recommendations to the patient. Multiple treatment options are available to improve the aesthetic appearance, most of which are supported by case reports.In conclusion, the authors describe a rare case of MCA possibly triggered by None declared.Patricia Mayumi Ogawa: Design and planning of the study; drafting and editing of the manuscript; collection, analysis and interpretation of data; critical review of the literature.Maria Cristina Arci Santos: Approval of the final version of the manuscript; drafting and editing of the manuscript; collection, analysis and interpretation of data; effective participation in research orientation; critical review of the manuscript.Nilceo Schwery Michalany: Approval of the final version of the manuscript; collection, analysis and interpretation of data; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; effective participation in research orientation; critical review of the manuscript.Renato Shintani Hikawa: Approval of the final version of the manuscript; collection, analysis and interpretation of data; design and planning of the study; intellectual participation in propaedeutic and/or therapeutic conduct of studied cases; effective participation in research orientation; critical review of the manuscript.None declared."}
+{"text": "Reviews in ophthalmology 2022.\u201d This issue is dedicated to providing a comprehensive overview of the latest advancements, challenges, and future directions in the field of ophthalmology. As we navigate through the third decade of the 21st century, it is clear that our understanding of ocular diseases and their management has significantly evolved, driven by groundbreaking research and technological innovations.Welcome to the Research Topic, \u201cIn this Research Topic, we have compiled a series of reviews that delve into various aspects of ophthalmology, from the surgical management of corneal disorders to the genetic underpinnings of complex ocular diseases. These reviews provide a snapshot of the current state of knowledge, highlighting the strides we have made and the challenges that lie ahead.Each review in this Research Topic offers a unique perspective, reflecting the breadth and depth of research in ophthalmology. From exploring the effectiveness of different surgical techniques and treatment modalities to unravelling the genetic complexities of ocular diseases, these reviews represent the cutting edge of ophthalmic research.Reviews in ophthalmology 2022,\u201d we hope to foster a deeper understanding of the current landscape of ophthalmology, stimulate further research, and ultimately contribute to improving patient care. We invite you to delve into these insightful reviews, gain new knowledge, and join us in the ongoing quest to unravel the complexities of the human eye.As we present \u201cThe field of ophthalmology has witnessed significant advancements in understanding and managing ocular surface diseases. This Research Topic summarises recent research on various ocular conditions, including ocular graft-vs.-host disease (oGVHD), Dry Eye Disease (DED), Keratoconus (KC), paediatric keratoconus, pterygium, and Fuchs' endothelial corneal dystrophy (FECD).Salari et al. highlighted the effectiveness of superficial keratectomy (SK), a surgical procedure involving the manual dissection of the superficial layers of the cornea. The review emphasised the versatility of SK in addressing various ocular conditions, including corneal degenerations, dystrophies, scarring, recurrent corneal erosions, and retained corneal foreign bodies.Tappeiner et al. focused on the challenges and concepts in diagnosing and managing oGVHD, a condition characterised by tissue inflammation following allogeneic hematopoietic cell transplantation. The review underscored the importance of interdisciplinary treatment approaches to improve patients' quality of life and prevent potentially irreversible visual loss.Ling et al. discussed the increasing incidence of DED and the role of immune regulation defects in its pathogenesis. The review emphasised the need for anti-inflammatory drugs in treating moderate-to-severe DED and highlighted the potential of Traditional Chinese Medicine in managing the condition.Hao et al. provided a comprehensive analysis of the pathogenesis of KC, an aetiologically heterogeneous corneal ectatic disorder. The study identified several genes and pathways involved in the disease's development, offering an integrated insight into the gene-based aetiology and pathogenesis of KC.Li et al. conducted a meta-analysis comparing the efficacy of different corneal collagen cross linking (CXL) methods for paediatric keratoconus. The study concluded that standard epithelium-off CXL and accelerated epithelium-off CXL appear to be comparable in efficacy, with standard CXL providing greater changes in visual and pachymetric outcomes.Taher, Alnabihi et al. performed a systematic review and meta-analysis on the management of primary pterygium, a common ocular surface disease. The study confirmed the effectiveness of a single intraoperative topical application of 0.02% mitomycin C during excision of pterygium followed by conjunctival autograft in reducing the rate of pterygium recurrence.Tsedilina et al. conducted a systematic review of the role of variants in the genes SLC4A11, ZEB1, LOXHD1, and AGBL1 in the development of FECD. The study confirmed the causal role of SLC4A11 variants in FECD, but further evidence is needed to confirm the roles of ZEB1, LOXHD1, and AGBL1 variants.Lastly, In this Research Topic, we, also, explore the latest technological advancements, delve into the complex pathophysiological mechanisms, and discuss innovative therapeutic strategies that are shaping the future of retinal treatments.Ladha et al.'s exploration of subretinal therapy, we are introduced to the potential of robotic technology in enhancing the precision and standardisation of ocular gene and cellular therapy delivery. The authors highlight the limitations of manual delivery, including the risk of iatrogenic damage and variability in delivery. They also underscore the importance of understanding the immune response elicited by the introduction of exogenous viral vectors or transplanted cells to the eye. The use of microprecision medical robotic technology is proposed as a solution to these challenges, offering reproducible and standardised delivery independent of injection speed.Starting with Tang et al. provide a comprehensive review of the development of risk factors and cytokines in Retinal Vein Occlusion (RVO), the second most prevalent retinal disease. The authors emphasise the complexity of RVO mechanisms due to the interrelated nature of risk factors. They also highlight the role of cytokines as powerful mediators of pathological conditions such as inflammation, neovascularisation, and macular oedema. This review underscores the need for continued research into the mechanisms and treatment targets of RVO.Next, Casciano et al. then delve into the role of the mammalian target of rapamycin (mTOR) pathway in diabetic retinopathy (DR). They outline how chronic hyperglycaemia can lead to retinal neurodegeneration through overactivation or inhibition of the mTOR pathway. The authors highlight the mTOR pathway's role in coordinating multiple anabolic and catabolic processes, such as autophagy, oxidative stress, cell death, and the release of pro-inflammatory cytokines. This review provides valuable insights into the potential of targeting the mTOR pathway in the management of DR.Haydinger et al. provide a clinical overview of macular oedema, a complication of many retinal diseases that can lead to severe and permanent visual impairment and blindness. The authors discuss the mechanisms of disease, highlighting the dysregulation of the blood-retinal barrier as a key factor driving fluid accumulation in the central retina. They also discuss current treatments, including vascular endothelial growth factor blockers, corticosteroids, and non-steroidal anti-inflammatory drugs, and identify areas of opportunity for future research.Finally, In the realm of paediatric ophthalmology, two papers have made significant strides in understanding and treating conditions that affect the eyes of children.Gan et al., conducted a meta-analysis to evaluate the efficacy and safety of varying doses of atropine in slowing myopia progression in children. Myopia, or short-sightedness, is a common condition that affects a significant number of children worldwide. The study found that the efficacy and adverse effects of atropine are dose-dependent. High-dose atropine was found to be effective in slowing myopia progression, but its efficacy reduced after the first year of treatment. On the other hand, low-dose atropine showed better efficacy over a longer follow-up period. However, the higher the dose of atropine, the higher the incidence of adverse effects, such as photophobia. This meta-analysis provides valuable insights for clinicians in determining the appropriate dosage of atropine for treating myopia in children.The first paper, led by Taher, Ghaddaf et al., conducted a systematic review and meta-analysis to assess the efficacy and safety of intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections for the treatment of retinopathy of prematurity (ROP). ROP is a potentially blinding eye disorder that primarily affects premature infants. The study found that anti-VEGF monotherapy was associated with fewer adverse events than laser therapy. However, there was no significant difference between the two treatments in terms of recurrence rate, treatment switching, retreatment, and mortality rate. This study provides a comprehensive review of the current standard treatment for ROP and offers valuable insights for future research and clinical practice.The second paper, by The recent studies on the ocular implications of COVID-19 and other viral infections, as well as the effects of their respective vaccines, have shed light on a critical aspect of these pandemics that often goes unnoticed.Zauli et al. highlighted the potential therapeutic role of the MDM2 inhibitor Nutlin-3 in protecting the eye from SARS-CoV-2 infection. The study suggests that the protein p53, present in high levels in the cornea, conjunctiva, and tear film, could play a protective role against the virus. The authors propose that the topical use of Nutlin-3 might protect the anterior surface of the eye from SARS-CoV-2 infection, thereby reducing the spread of the virus.Akbari and Dourandeesh provided an updated overview of the ocular manifestations of COVID-19. The study emphasises the importance of paying attention to ocular manifestations during COVID-19, as they can be a presentation of life-threatening events such as stroke. Conjunctivitis is the most common presentation, which can develop at any stage of COVID-19, and there are also reports of life-threatening complications, such as rhino-orbital cerebral mucormycosis.Taha et al. conducted a literature review highlighting the ocular complications of recent viral pandemics, including Monkeypox, SARS-CoV-2, MERS, Ebola, H1N1, and Zika viruses. The review also discusses the ocular complications of the vaccines and treatments used during these pandemics, and the role of the eye as a significant route of viral transmission.Scalabrin et al. provided an overview of the ocular effects caused by viral infections and their corresponding vaccines, focusing on varicella zoster virus, measles virus, influenza viruses, hepatitis B virus, and SARS-CoV-2. The study aimed to establish a risk-benefit relationship from an ophthalmological point of view, comparing the pathological effects on the eye due to these viral infections with the possible ocular adverse effects of their respective vaccines.Abu-Ismail et al. discussed the impact of the COVID-19 pandemic and the wearing of face masks on ophthalmology practice. The study found that wearing face masks for long periods increases the chances of dry eyes and other ocular issues. The pandemic has also affected ophthalmology practices in managing patients, with new factors to consider, such as the risk of endophthalmitis, tests and symptoms of patients with glaucoma, and the emerging symptoms associated with the COVID-19 vaccination.Lastly, In conclusion, the reviews presented in this Research Topic provide a comprehensive overview of the current state of ophthalmology, highlighting the significant strides made in understanding and treating various ocular conditions. The reviews underscore the importance of continued research and innovation in addressing the challenges that lie ahead. The impact of the COVID-19 pandemic on ophthalmology, particularly the effects of prolonged face mask use, has emerged as a critical area of study. As we continue to navigate through these unprecedented times, it is crucial to adapt our practices and explore new avenues to ensure the best possible care for our patients. We hope that the insights provided in these reviews will stimulate further research and contribute to the advancement of ophthalmology.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
+{"text": "The COVID-19 pandemic highlighted some potential limitations of transmission-based precautions. The distinction between transmission through large droplets vs aerosols, which have been fundamental concepts guiding infection control measures, has been questioned, leading to considerable variation in expert recommendations on transmission-based precautions for COVID-19. Furthermore, the application of elements of contact precautions, such as the use of gloves and gowns, is based on low-quality and inconclusive evidence and may have unintended consequences, such as increased incidence of healthcare-associated infections and spread of multidrug-resistant organisms. These observations indicate a need for high-quality studies to address the knowledge gaps and a need to revisit the theoretical background regarding various modes of transmission and the definitions of terms related to transmission. Further, we should examine the implications these definitions have on the following components of transmission-based precautions: (i) respiratory protection, (ii) use of gloves and gowns for the prevention of respiratory virus infections, (iii) aerosol-generating procedures and (iv) universal masking in healthcare settings as a control measure especially during seasonal epidemics. Such a review would ensure that transmission-based precautions are consistent and rationally based on available evidence, which would facilitate decision-making, guidance development and training, as well as their application in practice. Standard and transmission-based precautions are essential elements of infection prevention and control (IPC) practices ,2. TransEmerging scientific evidence and revisiting previously available studies support the argument that the distinction between droplets and aerosols is artificial, and dogmatic size thresholds for \u2018large droplets\u2019 and \u2018aerosols\u2019 are not fully consistent with the physical properties that are relevant for the transmission of respiratory viruses -7. WhileMycobacterium tuberculosis, and the measles and varicella-zoster viruses, have traditionally been considered as being transmitted obligatorily or preferentially through the airborne route, thus necessitating precautions against airborne transmission, including the use of respirators and hospitalisation in single rooms with negative pressure [Only a few microorganisms, such as pressure . These rpressure ,12.Altogether, the relevant role of various routes of transmission, which includes the physical transport of an infectious particle leading to infection, has been challenging to assess. Efforts to define criteria of proof for each transmission route have been useful but it is difficult to draw any conclusion with certainty ,14. The Furthermore, the quality and certainty of evidence on the effectiveness of various elements of PPE used for transmission-based precautions remains low, as the evidence is based mostly on observational studies and only a few randomised controlled trials. Several systematic reviews and meta-analyses have been published but the certainty of the conclusions is limited by the bias of the underlying studies . This meLater variants of SARS-CoV-2 are characterised by higher transmissibility than previous variants . On the These observations indicate a need to revisit transmission-based precautions and their effectiveness for preventing transmission of SARS-CoV-2 in particular and other respiratory viruses in general, as well as a need to fund, design and execute high-quality studies to fill the evidence gaps for transmission-based precautions .On 16 March 2022, the European Centre for Disease Prevention and Control (ECDC) convened a group of 11 IPC experts to explore whether modifications in transmission-based precautions would be needed to address what we learned during the COVID-19 pandemic and to identify knowledge gaps and research needs. Experts were selected as a convenience sample from the ECDC Expert Directory based on declared expertise in hygiene and infection control. The discussion was structured based on the following elements of the Evidence to Decision (EtD) framework : (i) HowBoxA review of the theoretical framework, and definitions of terms, for modes of transmission underpinning the IPC paradigm;Risk assessment parameters for IPC measures based on risk of infection transmission inclusive of: transmissibility of infection, impact of infection, patient factors, staff risk factors, practice/procedure factors and environmental factors, while taking into consideration: healthcare workers\u2019 preference, desirable and undesirable anticipated effects and the balance between them, overall certainty of the evidence of effects, acceptability and ease of implementation;Design and implementation of high-quality applied clinical research to inform:- The use of respirators and medical face masks in various risk scenarios,- The impact of gowns, aprons and eye protection as part of transmission-based precautions,- Optimal masking strategies to reduce risk of transmission inclusive of sessional vs risk-targeted, wider masking policy, including behavioural insights to adherence, any unintended consequences for staff and patient safety, and staff preferences,- A risk-based approach to the selection of personal protective equipment considering the time of exposure, the proximity to the patient and the procedure/task.IPC: infection prevention and control.Given that neither the current droplet nor the airborne precautions address the role of aerosols at short distances, various options could be considered for adapting current transmission-based precautions. Droplet precaution measures could be expanded to address the theoretical risks linked to inhalation of short-range aerosols. A two-tiered risk-based approach could be applied, based on proximity, length of exposure, type of symptoms and type of care: (i) contacts with prolonged, close proximity to the patient, including the performance of high-risk procedures, are associated with higher risk and justify the use of high-efficacy respiratory protection; (ii) for contacts without prolonged, close proximity to an infectious patient in adequately ventilated spaces, the effectiveness of medical face masks would be sufficient.Gloves are part of contact precautions that have been recommended for the prevention of the transmission of respiratory viruses such as influenza and SARS-CoV-2. However, hand hygiene, including alcohol-based hand rubs, is an effective measure against SARS-CoV-2 and other respiratory viruses ,30, as wWhile the desirable anticipated effects from the use of gloves and gowns/aprons are small, the undesirable anticipated effects are at least moderate. Therefore, the balance of desirable and undesirable effects does not favour the routine use of gloves or gowns/aprons for the prevention of COVID-19 and other respiratory virus infections. An exception may be prolonged, close exposure to a case, especially a patient who is coughing or sneezing heavily, when high-risk procedures are required, or in cases when there is a high risk of exposure to infectious body fluids - as stipulated by standard precautions.There is emerging evidence that the increased risk of infection from some aerosol-generating procedures may be more related to proximity with the patient than to increased generation of aerosols by the procedure itself . SeveralGiven that the risk of transmission is related not only to the microorganism, but also to the duration and proximity of contact, the applied transmission-based precautions should ideally be selected following a point-of-care risk assessment, taking into account proximity, duration of exposure, risk of aerosol production and the type of task performed.Various forms of continuous face mask use, such as universal masking, applying to healthcare workers, patients, visitors and persons accompanying the patient, and targeted continuous masking, applying to healthcare workers , especiaThe eyes have been identified as potential routes of entry for respiratory viruses either directly, by infection of the ocular mucosa, or by transfer to the nasopharynx through the nasolacrimal duct . AvailabA limitation of the above suggestions is the low level of available evidence in epidemiological studies or clinical trials for the effectiveness of specific elements of transmission-based precautions, including elements of PPE. Emerging evidence may increase our certainty in the magnitude of their effectiveness. A better understanding of the physical processes of exposure does not automatically translate into more effective prevention measures, as infection is a more complicated process than the transfer of infectious particles, involving immune processes and the suitability of various exposed host tissues for the entry of viruses. The applied preventive measures aim at mitigating the risk of infection to an acceptable level, taking into account the assessed risk but also other parameters such as preferences, ease of implementation and unintended consequences. Studies which use various forms of modelling and laboratory experiments to investigate the role of procedures and behaviours in generating and dispersing respiratory particles are limited and ultimately do not provide adequate evidence to address transmission in the complex healthcare environment. There is a need for applied clinical research on the effectiveness but also the unintended consequences of preventive measures to support the development of evidence-based recommendations for guidance. Furthermore, human challenge studies, taking carefully into consideration any ethical issues , may proTransmission-based precautions are important but are not the only measures to control SARS-CoV-2 transmission in healthcare. It should be noted that PPE is only one among several control measures in the hierarchy that includes elimination and substitution, engineering and administrative controls . TransmiMeasures to prevent and control an infection with high morbidity and case fatality and without treatment options are influenced by the assessed risk of adverse outcome  and ofteThe ECDC expert panel suggested that the IPC community should consider revisiting the current transmission-based precaution framework, including the theoretical background regarding various modes of transmission and the definitions of terms related to transmission, to account for available and emerging scientific evidence and the role that the consequence of infection plays on the choice of the precautions. Such a review would ensure that transmission-based precautions are consistent and rationally based on available evidence, which would facilitate decision-making, guidance development and training, as well as their application in practice to prevent transmission of SARS-CoV-2 and of other respiratory viruses. High-quality studies are imperative to address the current knowledge gaps and strengthen the evidence for any future revision of transmission-based precautions."}
+{"text": "The National Agrobiodiversity Center under the Rural Development Administration (RDA) in Jeonju, Republic of Korea stands as the foremost national genebank in the country. Over the years, the National Agrobiodiversity Center has remained committed to enriching its collection with foreign genetic resources, elevating its status to a world-class plant genetic resources (PGR)- holding genebank. Currently, several steps are being undertaken to improve the accessibility of the collection to national as well as international researchers, improve the data available on the resources, and amend the passport information for the accessions. With the implementation of the Nagoya Protocol, the origin of genetic resources is being highlighted as an important input in the passport information. The RDA-Genebank actively responds to the Nagoya Protocol by supplementing passport data for resources lacking information on their origin. In addition, a large number of conserved resources are continuously multiplied, and agronomic traits are investigated concurrently. With the traditional methods of characterization of the germplasm requiring a significant amount of time and effort, we have initiated high-throughput phenotyping using digital techniques to improve our germplasm data. Primarily, we have started adding seed phenotype information followed by measuring root phenotypes which are stored under agronomic traits. This may be the initial step toward using largescale high-throughput techniques for a germplasm. In this study, we aim to provide an introduction to the RDA-Genebank, to adopted international standards, and to the establishment of high-throughput phenotyping techniques for the improvement of passport information. The National Agrobiodiversity Center in Jeonju, Republic of Korea, under the administration of the Rural Development Administration (RDA), plays a pivotal role in the collection, evaluation, conservation, and distribution of diverse plant genetic resources, including both seeds and vegetative germplasms. With the establishment of a low-temperature seed storage facility in 1975 and a seed management office in 1976, around 3300 germplasms were managed at local agricultural institutions. Later, in 1980, official documentation of 12,865 rice germplasms conserved by local agricultural institutions and universities was carried out, followed by their addition to the low-temperature seed storage collection. While seed germplasms were conserved at the genebank, external management institutions managed vegetative germplasms. In 1993, the RDA-Genebank began international cooperation starting with the N.I. Vavilov All-Russian Institute of Plant Genetic Resources (VIR) (1993\u20132019). At the RDA-Genebank, researchers aim to secure germplasm diversity by continuously collaborating with international joint research institutes including the Uzbek Research Institute of Plant Industry (UzRIPI) in Uzbekistan (1996\u20132004), the Department of Agriculture (DOA) Genebank in Thailand (1998), the Leibniz Institute of Plant Genetics and Crop Plant Research (IPK) (1998\u20131999) in Germany, the International Rice Research Institute (IRRI) in the Philippines, the Plant Science and Agricultural Research Institute (PASRI) in Mongolia, the National Bureau of Plant Genetic Resources (NBPGR) in India, and the Georgian Academy of Agricultural Sciences (GAAS) in Georgia. Adoption of international policies such as the Convention on Biological Diversity (CBD) at the United Nations conference on environment and development (UNCED) in 1992 and the Nagoya Protocol on Access to Genetic Resources and the Fair and Equitable Sharing of Benefits Arising from Their Utilization in 2010 has further reinforced germplasm conservation efforts. Despite the limitations on data disclosure and international distribution of germplasms, Korea remains one of the significant countries conserving plant biodiversity. The Nagoya Protocol is an international agreement that aims to promote the fair and equitable sharing of benefits arising from the use of genetic resources, including those held in genebanks. The protocol was adopted in 2010 under the United Nations Convention on Biological Diversity (CBD) and entered into force in 2014 . The hisOverall, the Nagoya Protocol represents a significant milestone in the international effort to promote the conservation and sustainable use of genetic resources, including those held in genebanks, and to ensure that the benefits of these resources are shared fairly and equitably. In accordance with the Nagoya Protocol, RDA-Genebank continuously updates passport data on the origins of germplasms to actively respond to the utilization of genetic resources and the sharing of benefits accordingly. As a method of supplementing origin information, the passport data disclosed on the homepage of the relevant genebank was reflected on the basis of the original international genebank resource number.http://genebank.rda.go.kr/plantMain.do, accessed on 23 Mar 2023). Whereas the Korean version provides access to essential passport data, including conserved genetic resources of plants for distribution, the English version falls short in divulging the current status of resource conservation and the pertinent passport data. Consequently, this omission poses challenges for foreign researchers seeking to obtain and investigate our germplasms.The website of our institution presently offers visitors the option to select either the Korean or the English version  were domestically distributed in the Republic of Korea, while only a small proportion (0.73%) was circulated internationally . The treIn 2018, the RDA-Genebank initiated a collaboration research program, the Technology Development Project for Customized Agricultural, Forestry, and Fishery Products and Services, partnering with agricultural organizations such as seed companies and private research institutions. The objectives of this program were to broaden and improve the characterization and evaluation information of the conserved germplasms, augment their diversity, propagate them, and concurrently conduct characterization research. Through chemical composition profiling or disease resistance evaluation, commendable genetic resources have been shortlisted from the outcomes of these research endeavors, to be recommended for breeding and further scientific investigations. During 2010\u20132013, a total of 1343 accessions were distributed for local propagation of rice to the IRRI, the Philippines. For the purpose of germplasm exchange with international genebanks, the RDA-Genebank has introduced 568 accessions in the ARS (2012) in the US, 995 accessions in the UzRIPI in Uzbekistan (2011\u20132014), 10 in the VIR in Russia (2014), 235 in the AVRDC in Taiwan (2013\u20132016), and 232 in the GAAS in Georgia (2015\u20132016) as a part of its germplasm exchange policy. We have also supplied to private entities, including the distribution of 62 sesame accessions to the Tainan District Agricultural Research and Extension Station in Taiwan. The distribution overseas can be categorized into two types: those sent through Korea Project to the International Agriculture (KOPIA) center as part of Official Development Assistance (ODA) projects, which provide country-specific farming techniques, and those distributed through the 3-FACI. The 3-FACI initiative includes the Asian Food & Agriculture Cooperation initiative (AFACI), the Korea\u2013Africa Food & Agriculture Cooperation initiative (KAFACI), and the Korea\u2013Latin America Food & Agriculture Cooperation initiative (KoLFACI). These programs aim to facilitate multi-continental research and collaboration to address common farming problems. Despite RDA-Genebank\u2019s possession of world-class germplasms, limited overseas distribution has occurred due to the unavailability of individual resource information on online platforms such as Genesys, managed by the Global Crop Diversity Trust. Exceptions to this pattern have occurred only when researchers with Korean affiliations have utilized publicly available history information to apply for resource distribution. Our institution is diligently making preparations, including the dissemination of passport information, to ensure the continuous availability and accessibility of our plant genetic resources for international distribution.In order to improve the utilization of the conserved germplasms, systematic passport data management is indispensable . GermplaGlycine max), the morphological characteristics of 650 landraces were investigated, about 40 of them were selected as a core collection, and a molecular genetic profile was promoted [Capsicum spp.), the analysis of capsaicin content, the cultivation of anthracnose-resistant intermediate seedlings, the evaluation of Chinese cabbage (Brassica rapa ssp. penkinensis) landraces, the cultivation of superior groups, and the cultivation of intermediate seedlings resistant to wart disease of cabbage [In response to consumer preferences, there is a notable increase in the incorporation of evaluation data concerning chemical composition profiles, such as glucosinolate levels in Brassica ssp. and disease resistance. This highlights the importance of considering these factors in the evaluation process. Since the 1990s, the RDA-Genebank has systematically investigated its conserved genetic resources for their qualitative and quantitative traits to promote the use of germplasms by consumers of the end product. During the early stages, the characterization centered on seed viability and primary characteristics of germplasms such as seed coat color, width, and length. From 1995, the organization was subdivided into several divisions for cereal crops, horticultural crops, and special crops, respectively, and their evaluation data was augmented. In addition, chemical composition profiles such as the oil and fatty acid content of sesame seeds; the protein content, amylose and amylopectin content, and starch characteristics of rice landraces; and the DNA polymorphism analysis of rice and barley were initiated . In the promoted . Among t cabbage . The gerB. rapa subsp. pekinensis), our studies focused on analyzing the individual glucosinolates of the mustard leaf (B. juncea) and the Choy Sum (B. rapa subsp. chinensis var. parachinensis) [Starting in 2019 with Chinese cabbage (inensis) ,14. The With further work carried out on expanding the information available in the evaluation data for germplasms conserved at the RDA-Genebank, substantial consideration has been given to using high-throughput techniques to study the germplasms. One such aspect is using digital phenotyping for largescale analysis and screening of the germplasms.r2) between image-based and actual height and the width measurements of soybean seeds  [Glycine max), and diversity analysis was performed using origin  and status  [Glycine max) and adzyki bean (Vigina angularis) germplasms for the first time across international genebanks [Glycine max cv. Enrei Japanese varieties, which are known for their excellent nodulation characteristics. Additionally, these digital phenotyping techniques can be applied to various other crops conserved at the RDA-Genebank. For instance, in wheat, RGB images obtained from a digital camera can be utilized to measure agronomic traits such as tiller number per plant, canopy (including leaf number and length), phenotypic characteristics of wheat spike, and tomato internode length. In the future, RGB images captured using unmanned aerial vehicles can also be used to measure plant heights in crops such as rice, wheat, barley, and corn [The significance of seed traits is widely acknowledged, and seeds are selected on the basis of their phenotypic characteristics to improve crop yield and quality, making this one of the oldest phenotyping techniques . Phenotyctively) . Therefond wild) . Currentnd wild) . In geneenebanks ,23. Specenebanks . We confand corn .Hyperspectral sensors have been utilized to measure photosynthesis and respiration, which are directly related to crop growth and are currently being studied in tobacco, corn, and wheat . In addiThe augmentation of phenotype data with existing characterization information, as well as the integration of genomic, phenomic, and other molecular data, can significantly aid researchers in selecting optimal accessions for breeding and elucidating various evolutionary characteristics . In the Given the accelerating loss in biodiversity worldwide due to changing climatic conditions and anthropogenic activities, the importance of agricultural genetic resources is becoming more prominent. At plant genebanks throughout the world, continuous efforts are being taken towards improving the quality and quantity of germplasm collection along with ease of access. The germplasms we conserve at the National Agrobiodiversity Center are continuously investigated for agricultural traits and building an updated database. Recently, we have also concentrated on methods for investigating agricultural traits by applying digital techniques. We expect information on the germplasms conserved in the RDA-Genebank to be made accessible at an early juncture to researchers all over the world. Ensuring timely access to vital genetic resources will foster international collaboration and contribute to the advancement of research and agricultural development worldwide. By promoting transparency and facilitating the exchange of germplasms, plant biologists can collectively work towards enhancing global food security, biodiversity conservation, and sustainable agriculture. As custodians of invaluable genetic resources, the RDA is committed to promoting their widespread availability and fostering fruitful partnerships with researchers and institutions across the globe."}
+{"text": "To describe the current knowledge on safety and effectiveness of the tumor necrosis factor (TNF)-a antagonists and identify current knowledge/evidence gaps for study by the Agency for Healthcare Research and Quality (AHRQ) Effective Health Care Program.Evidence-based Practice Centers (EPCs) and the Developing Evidence to Inform Decisions about Effectiveness (DEcIDE) network of AHRQ's Effective Health Care Program will study the safety and effectiveness of biologic and nonbiologic disease-modifying antirheumatic drugs . The current knowledge of safety and effectiveness of TNF-a antagonists is reviewed.Treatment of adult rheumatoid arthritis (RA) involves determining which agents are safe, effective, and cost effective for an individual. Each individual patient's health system may also play a role in which agents are chosen. Many agents are available for the management of RA, some with high cost and unknown safety. Section 1013 of the Medicare ModernizationAct of 2003 authorizes AHRQ to study comparative effectiveness and safety ofRA treatments through both EPCs and DEcIDE centers to develop scientific knowledge for RA management as well as through epidemiologic studies.Results will be compiled through a Clinical Decisions and CommunicationsScience Center, then disseminated to all appropriate stakeholders, including patients, payers, and health care professionals. The current knowledge of safety and effectiveness of TNF-a antagonists in the treatment of RA is reviewed. Increased rates of serious infections, including Mycobacterium tuberculosis (MTB), or tuberculosis reactivation, may occur with the use ofTNF-a antagonists. It is still unclear if RA increases the risk of developing cancer, or if use of TNF-a antagonists increases cancer risk.TNF-a antagonists are costly, yet effective treatments for early and late RA. Use of these agents provides rapid relief of RA symptoms and provides positive outcomes, defined as improvements in AmericanCollege of Rheumatology 20, 50, 70 scores; Health Assessment Questionnaire ratings; activities of daily living; joint space narrowing; erosions; and acute phase reactants. Reactivation of latent MTB or onset of other infections or cancers may occur in RA patients with TNF-a antagonists."}
+{"text": "On any given day, almost 11 million people globally are deprived of their liberty. In 2020, the global female population was estimated to be 741,000, an increase of 105,000 since 2010. In order to investigate progress in the adoption of the Bangkok Rules since 2010, we conducted a legal realist assessment based on a global scoping exercise of empirical research and United Nations (UN) reporting, using detailed MESH terms across university and UN databases. We found evidences in 91 documents which directly relate to violations of the Bangkok Rules in 55 countries. By developing a realist account, we document the precarious situation of incarcerated women and continued evidence of systemic failures to protect them from custodial violence and other gender-sensitive human rights breaches worldwide. Despite prison violence constituting a complex and multifaceted phenomenon, very little research  has been conducted on custodial violence against women since 2010. Although standards of detention itself is a focus of UN universal periodic review, special procedures (violence against women) and concluding observations by the UN committees, very few explicitly mentioned women, and the implications of violence against them while incarcerated. We highlight three central aspects that hinder the full implementation of the Bangkok Rules; the past decade of a continued invisible nature of women as prisoners in the system; the continued legitimization, normalization, and trivialization of violence under the pretext of security within their daily lives; and the unawareness and disregard of international (Bangkok and others) rules. On any given day, almost 11 million people globally are detained in prisons or other closed settings . In 2020Bangkok Rules; Tokyo Rules;Nelson Mandela Rules; Mandela Rules do not specifically refer to women (with Rule 7 referring to self-perceived gender identity), the Bangkok Rules as soft law principles lay the foundation for intensified efforts to support women deprived of their liberty . The 2015 UN Subcommittee on Prevention of Torture and other Cruel, Inhuman or Degrading Treatment or Punishment  in the community, and the spotlight has been shone on torture and inhumane treatment in detention itself, very little has been dedicated to gender-specific aspects of countering interpersonal custodial violence against women deprived of their liberty , most particularly so when experienced as torture or cruel, inhuman or degrading treatment, or punishment within the power-imbalanced custodial setting. Under international law, rape constitutes torture when it is carried out by or at the instigation of or with the consent or acquiescence of public officials, with other forms of sexual abuse violating the prohibition on cruel, inhumane, or degrading treatment or punishment. Other identified forms of custodial GBVAW include strip searches conducted by men or in the presence of men, virginity testing, verbal sexual harassment, use of restraints (including during labor), psychotropic drugs and solitary confinement to control prisoners, inappropriate surveillance by guards during undressing or showers, and the denial of access to medical care by nonmedically trained officials  and CEDAW observations at the global level since 2010. 101 UN CAT reports and 158 CEDAW reports were scrutinized, with human rights violations pertinent to the identified Bangkok Rules found in 15 UN CAT, 32 UN CEDAW, and 21 other domestic and UN Human Rights Council reports. Third, the academic literature was examined, and we found 23 relevant records where breaches of the Bangkok Rules were evident. In total, 91 documents related directly to violations of the Bangkok Rules in 55 countries. Despite prison violence constituting a complex and multifaceted phenomenon, very little academic research  has been conducted on GBVAW in custodial settings since 2010, with the bulk of the evidence centering on Special Rapporteur and UN  country-level reporting. Although standards of detention itself is a focus of UN periodic reports, very few explicitly mentioned women, and the implications of violence against them while incarcerated. See Empirical studies from the United Kingdom (UK) and the United States reveal that the female prison environment continues to be as emotionally suppressive, conflict-laden, and violent as in male settings, particularly relating to fighting and physical assaults, with inmate-on-inmate violence comparable across male and female facilities, including sexual assaults, transactional sex in return for protection, privilege or basic necessities, and intimate partner violence between prisoners . At the . The 2016 CEDAW report on Canada criticizes the presence of male guards in female prisons in Canada   .With regard to the Middle East, the UN CAT documents allegations of gender-based violence, including torture, ill treatment and rape, against women in detention in Iraq in 2015 . There aBangkok Rules at the global level as they pertain to the conditions of women in detention since adoption, particularly the prevention of and protection from custodial violence when deprived of their liberty. Gender inequity and inequality is pervasive. Although custodial violence in essence violates the internationally recognized prohibition on cruel, inhuman or degrading treatment or punishment, it remains a largely hidden and sensitive topic for both genders when deprived of liberty, with insufficient surveillance of the issue, coercion threatening disclosure (particularly for women), very low rates of perpetrator accountability, and scant prevalence data available at the global level  rules; and the task to organize different modes of incarceration environment for  prisoners who committed nonviolent crimes. Human rights violations encountered by women in the criminal justice and penal systems continue worldwide. Many countries have not fully adopted the Bangkok and Tokyo Rules, leading to congestion and overcrowding in female prisons, lack of protection against violence, particularly when housed in nonsegregated prisons, either perpetrated by officials or by fellow inmates (of both genders), use of psychotropic and physical restraints, arbitrary detention and solitary confinement, and the lack of full access to gender specific medical care, trauma-informed and trauma-responsive mental health supports, and drug treatment . Inadvertently, our realist account highlights the continued lack of resourcing of female prisons, lack of implementation of noncustodial sentencing for minor and nonviolent offenses, lack of consideration of GBVAW, exploitation and trauma-related pathways into crime (largely poverty or drug-related), and overall lack of oversight in disclosure and penal complaint mechanisms where GBVAW is perpetrated in the closed setting.These insights give a well-founded basis for relevant UN agencies  and the World Health Organization to provide technical assistance and promote further improvements and penal reforms worldwide. Moreover, this gives a substantiated starting point for human rights organizations such as Amnesty International, the Howard League for Penal Reform, Penal Reform International, and Harm Reduction International to appoint targeted and fitting actions to reduce GBVAW in custodial settings. See Further, we wish to underscore how this neglect not only constitutes grave human rights abuses but also fuels self-harm, suicide, psychiatric disorders and deaths, and the spread of disease  bridging between prisons and communities. Addressing disease hinges on prison system approached and parameters to address physical and sexual violence in prisons, trauma-related mental health issues, and unsafe injecting of drugs. UN reporting continues to highlight such issues globally where women are discriminated and treated in an unequal manner, alongside the dearth of academic research and access of research teams into prisons . It is f"}
+{"text": "With aging, the frequency of stress-related diseases, including mental, metabolic, cognitive, cardiovascular, and neurodegenerative disorders, increases dramatically. Despite this generalized phenomenon, there are notable individual differences in both vulnerability and resilience to stress and stress-related pathologies. Despite the plethora of studies in stress research, the mechanisms underlying individual vulnerability to stress and age-related diseases remain unclear.The HPA axis is a key modulator of both the endocrine and behavioral adaptation to stress, and dysfunction of the HPA axis can contribute to the development of various stress-dependent diseases. Function of the HPA axis deteriorates during aging both in basal conditions and in response to stress. However, the type and magnitude of HPA axis deterioration are not similar in all individuals and appear to be associated with different behavioral characteristics. In particular, a higher activity of the HPA axis has been noted in elderly individuals with depression and in non-human primates that exhibit depression- and anxiety-like behavior (DAB) \u20133. ThereGoncharova et\u00a0al. presents original data on the responses of the HPA axis to acute psycho-emotional stress exposure (ASE) in young and old female rhesus monkeys with standard healthy and DAB behavior under conditions of continuous constant lighting (CL) using LED lamps that are commonly encountered in offices and apartments. The unique findings were that CL reduces the cortisol (CORT) response to ASE applied in the afternoon (15.00-17.00 h) and also disrupts the circadian rhythm of CORT secretion in all animals, regardless of age and behavior.Here, we provide a brief editors\u2019 overview of the articles published in this field. The article by The mechanisms underlying this phenomenon, however, are age-dependent. In young animals, the transhypophyseal pathway mediates the effect, whereas in older animals the effect is mediated primarily by an extra-hypophyseal neural pathway. The effects of CL on the stress reactivity of the HPA axis in young individuals were similar to its influence on the corticotropin and the CORT responses to administration of arginine vasopressin. A number of individual differences were also noted in DAB animals compared to normal behavioral controls. The findings suggested a potential risk of reduced adaptive capacity under CL resulting in stress-dependent pathology and accelerated aging, especially in the DAB-compromised organism. Such findings are relevant in connection with intensive night lighting and work and other activities at night.Konstandi and Johnson presents important data on the role of the HPA axis in the regulation of hepatic cytochrome P450 (CYP)-dependent drug metabolism, which is largely genetically determined and not the same in different individuals. Genetic polymorphisms and mutations of CYP genes are observed among several ethnic populations, such as Africans, White and African Americans, Asians, Caucasians, and Europeans. Activation of the HPA axis during stress and aging can lead to disruption of CYP gene regulation and CYP-dependent drug metabolism with pronounced inter-individual variations in the effectiveness and side effects of standard treatment protocols. The implications are particularly important in the treatment of age-related diseases, such as depression, cancer, hypertension, and diabetes. Individual differences in CYP-dependent drug metabolism may also contribute to age-related individual differences in the functioning of the HPA axis.The review by Degroote et\u00a0al. focuses on the study of the relationship between individual differences in the daily activity of the HPA axis in middle-aged and elderly people and coronary heart disease (CHD). This is also a main risk factor for arterial hypertension. Both are widespread in these age groups. The authors examined the concentration of CORT in saliva in hypertensive and normotensive men and men with CHD at different times of the day. Additionally, they prospectively tested the cortisol awakening response (CAR) for association with biological risk factors for CHD. They found that lower total daytime CORT secretion and CAR independently predicted increases in cardiovascular risk, as evidenced by increases in the circulating levels of biomarkers of atherothrombotic risk. The findings confirmed the pathogenetic role of age-related disturbances in the HPA axis function in the development of age-related cardiovascular pathology.The article by Dai et\u00a0al. was to investigate the role of the HPA axis in the effectiveness of modified electroconvulsive therapy (MECT) for the treatment of drug treatment-resistant depression (TRD). A considerable amount of literature suggests that dysregulation of the HPA axis plays a key role in the pathophysiology of TRD. However, contrary to reports by other authors who identified an association of efficacious electroconvulsive therapy with normalization of the HPA axis dysregulation, these authors found no statistically significant differences in serum CORT levels before and after MECT in elderly patients with TRD. Adequate assessment of the HPA axis function, in this case, may require not just the determination of total blood CORT concentration but also measurement of, for example, dehydroepiandrosterone sulphate and corticotrophin as well. Other confounding factors that may play a role include the time of day when MECT is performed, such as in the evening, a period of reduced circadian HPA axis activity.One of the main aims of the study presented in Collectively, the articles presented here strongly suggest that the disruption of the HPA axis activity observed across aging has notable deleterious effects on the function of other physiologic systems, namely, 1) altered adaptation to the inhibitory effect of continuous lighting on the cortisol response in acute psycho-emotional stress, 2) modification of the intensity of CYP-dependent drug metabolism, 3) increased vulnerability to cardiovascular pathology, and 4) the daily activity of the HPA axis in basal cortisol concentration and the cortisol awakening response. The general premise supported by most studies is that\u00a0age-related dysfunctions of the HPA axis form the pathophysiological conditions for the development of age-related pathology and that individual differences in the characteristics and intensity of age-related dysfunctions of the HPA axis may underlie differences in vulnerability to age-related pathology.NG wrote the first draft of the manuscript, and DB and EJ revised the manuscript. All authors read and approved the final version."}
+{"text": "Attention-deficit/hyperactivity disorder (ADHD) impairs the lives of both children and adults. Undiagnosed and untreated, ADHD may have serious lifelong consequences. Research has identified diagnostic clues, neurotransmitter pathways, and psychiatric comorbidities related to ADHD, as well as effective pharmacologic, behavioral, and psychosocial interventions. Stimulant agents have been the foundation of ADHD therapy for more than 50 years. Availability of new extended-release (XR or ER) and longer-acting (LA) formulations and novel agents allows for wider and more individualized treatment choices. Side effects of stimulants are generally mild, short lived, and responsive to adjustments in dosage or timing.Outcomes in ADHD treatment can be improved with the use of clear treatment guidelines and tools to aid clinicians in implementing them efficiently and effectively. The Texas Children's Medication Algorithm Project (CMAP)provides a system of algorithm-driven treatment decisions that is evidence based and easy to implement.To (1) review the psychological components of attention, the neurotransmitter pathways associated with ADHD, and the array of therapeutic options for ADHD, with an emphasis on the most recent introductions to the therapeutic armamentarium; (2) discuss the rare psychiatric and cardiovascular side effects associated with stimulants; (3) review abuse liability,comorbidities, and suggested approaches to these issues; and (4) review the development and use of CMAP and offer resources for its implementation in clinical practice.The pathophysiology of ADHD is linked to dysfunction of front osubcortical networks and dysregulation of dopaminergic, noradrenergic, and nicotinic neurotransmitter systems. An additive effect of multiple genes as well as environmental influences contributes to the clinical picture.Treatment with stimulants and nonstimulants has proven effective in different subgroups, with the effectiveness of specific agents most likely related to the primary neurotransmitter involved. Availability of XR, ER, LA, and transdermal stimulant formulations, as well as alternative nonstimulantagents, offers new options for the pharmacotherapy of ADHD. Major concerns associated with abuse liability of stimulants have been allayed by the availability of ER formulations, which have reduced reinforcing effects associated with short-acting preparations. Medication outcomes in ADHD can be enhanced by the use of evidence-based algorithms such as CMAP. Keys to success are adequate initial assessment and diagnosis, the use of sustained release products, sufficient dose titration, and the use of clinical rating scales with feedback from caregivers and teachers. Optimal treatment out comes can be achieved by appropriate pharmacotherapy combined with psychosocial interventions."}
+{"text": "The advent of robotic-assisted thoracic surgery (RATS) has revolutionized the field of thoracic surgery, offering a new paradigm for personalized, precision, and individualized medicine. The unique capabilities of RATS, including enhanced dexterity, precision, and visualization, allow for a more tailored approach to each patient\u2019s specific needs. This personalized approach is particularly relevant in managing thoracic malignancies, where the surgical approach can significantly impact patient outcomes . As we c<Innovative robotic approach for personalized lung resection>Sakakura et al. report a novel approach to robotic lung resection, namely segmentectomy . The aut<Tailoring RATS for diverse mediastinal tumor settings>Building on the concept of personalized surgical approaches, the second paper, from Okazaki et al., discusses the benefits of RATS for different types of mediastinal tumors, including anterior, superior, middle, and posterior mediastinal tumors . The aut<Enhancing lung segmentectomy outcomes with RATS>The third paper emphasizes the importance of personalized surgery in the era of precision medicine. Eguchi et al. discuss the use of RATS in lung segmentectomy, highlighting the role of RATS in improving operative performance due to its core technological features . The aut<Evolution of robotic port placement for personalized surgery>Sakakura and Eguchi discuss the four phases of port placement variations, from the initial phase of mimicking video-assisted thoracic surgery (VATS) to the fourth phase of maximizing the functional features of the da Vinci Xi robotic system . They hi<Superior noncancer outcomes with RATS in lung cancer treatment>The final paper, from Zhang et al., compares RATS and open thoracotomy in the context of non-small cell lung cancer treatment . The autThe future of RATS in thoracic surgery is promising, with ongoing advancements expected to further enhance the precision and personalization of surgical interventions. As technology continues to evolve, we anticipate further improvements in surgical outcomes, patient recovery, and overall quality of life. The integration of artificial intelligence and machine learning into RATS may also offer new opportunities for personalized medicine, potentially enabling more accurate preoperative planning, intraoperative navigation, and postoperative monitoring. As we continue to move forward in this exciting era of precision medicine, the role of RATS in providing personalized and optimal treatment for thoracic malignancies is expected to become increasingly prominent."}
+{"text": "British Journal of Cancer 10.1038/s41416-020-01153-4, published online 16 November 2020Correction to: The original version of this article contained an error in an affiliation. Upon careful review of the paper, the authors noticed that the affiliation for Goran Malenkovic was not written correctly. The authors only submitted the following affiliation Gynecologic Oncology Department Clinic for Operative Oncology, Institute of Oncology of Vojvodina, Serbia but they missed to notice that the Faculty of Medicine Novi Sad, University of Novi Sad, Serbia should also be in the affiliation."}
+{"text": "Incorrect AcknowledgmentsIn the published article, there was an error in the Acknowledgments statement.The authors gratefully acknowledge technical and financial support provided the Ministry of Education and King Abdulaziz University, DSR, Jeddah, Saudi Arabia for funding this research work to publish through the project number (IFPIP:1166-662-1443). The authors extend their appreciation to VEGA1/0664/22 Mitigation of the effects of environmental stresses in photosynthesis and plant production.The correct Acknowledgments statement appears as follows.AcknowledgmentsThe authors gratefully acknowledge the technical and financial support provided by the Ministry of Education and King Abdulaziz University, DSR, Jeddah, Saudi Arabia, to this research work through project number IFPIP: 1166-662-1443.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "Bone metastasis is a complex and challenging clinical problem, affecting patients with advanced stages of cancer . AccordiInternational Journal of Molecular Sciences includes a total of six contributions: five original articles and one review providing significant advances in the understanding and treatment of bone metastasis.In this scenario, the Special Issue entitled \u201cBone Metastasis Challenge: New Ideas and Future\u201d of the The study by Mbese and Aderibigbe reported the potential of bisphosphonate-based conjugates and derivatives as therapeutic agents for osteoporosis, bone cancer, and metastatic bone cancer . The autThe additive benefits of the combination of Radium-223 Dichloride and Bortezomib in a systemic multiple myeloma mouse model have been investigated by Suominen and colleagues . The resFurthermore, the osteoprotective effects of Loganic Acid on osteoblastic and osteoclastic cells and osteoporosis-induced mice were studied . ExperimIn addition, a research paper investigated the expression profile of new marker genes involved in the differentiation of canine adipose-derived stem cells into osteoblasts . This stCold atmospheric plasma (CAP) has also been investigated for its potential in promoting regeneration-associated cell functions of murine cementoblasts in vitro . The resFinally, the study of Panahipouret al.  investigIn conclusion, studies published in the Special Issue \u201cBone Metastasis Challenge: New Ideas and Future\u201d provide valuable insights into the molecular mechanisms underlying the development and progression of bone metastases and offer promising strategies for the prevention and treatment of this devastating disease. Moreover, the combination of molecular, pathological, and imaging data could open new and intriguing perspectives for developing therapies based on personalized medicine principles ."}
+{"text": "In recent years, the U.S. government has designated funding of several large-scale initiatives for comparative effectiveness research (CER) in health care. The American Recovery and Reinvestment Act (ARRA) of 2009 apportioned more than $1 billion to support CER programs administered by the Department of Health and Human Services (DHHS), the National Institutes of Health (NIH), and the Agency for Healthcare Research and Quality (AHRQ). CER is generally defined as the undertaking of original research or systematic reviews of published literature in order to compare the benefits and risks of different approaches to preventing, diagnosing, or treating diseases. These approaches may include diagnostic tests, medications, medical devices, and surgeries. The overall goals of CER are to support informed health care decisions by patients, clinicians, payers, and policy makers and to apply its evidence to ultimately improve the quality, effectiveness, and efficiency of health care.To (a) provide managed care professionals with general definitions of CER, specifically as it is administered by AHRQ; (b) discuss the importance of CER to clinical and managed care pharmacists; and (c) summarize key methods and findings from AHRQ\u2019s 2007 comparative effectiveness review on therapies for rheumatoid arthritis (RA).As supported by AHRQ, CER is conducted in order to synthesize comprehensive evidence on the comparative benefits and harms of treatment interventions. The findings from comparative effectiveness reviews can thus contribute to informing therapeutic strategies and treatment decisions. In 2007, a multitude of RA treatment options and studies motivated AHRQ to commission a systematic comparative effectiveness review. Conducted by investigators at the RTI-University of North Carolina Evidence-Based Practice Center, the review included comparisons of synthetic disease-modifying antirheumatic drugs (DMARDs), biologic agents, synthetic DMARDs versus biologic agents, and various combination therapies. Head-to-head comparisons of synthetic DMARDs generally revealed no significant differences in long-term clinical and radiographic outcomes, or in functional capacity or health-related quality of life. Two nonrandomized prospective cohort studies and 1 open-label effectiveness trial reported no differences in ACR20 and ACR50 response rates in patients treated with the tissue necrosis factor (TNF)-alpha inhibitors etanercept and infliximab. Comparisons of TNF-alpha inhibitors generally indicated no significant differences in rates of adverse events, including serious infections, and no increases in rates over time. In comparisons of a biologic agent combined with methotrexate versus a biologic agent alone, combination therapies were generally associated with better clinical response rates and better outcomes of functional capacity and quality of life. The most common adverse events observed in studies on biologic agents were diarrhea, headache, nausea, rhinitis, injection site reactions, and upper respiratory tract infections."}
+{"text": "The authenticity of probiotic products and fermented foods and beverages that have the status of protected designation of origin (PDO) or geographical indication (PGI) can be assessed via numerous methods. DNA-based technologies have emerged in recent decades as valuable tools to achieve food authentication, and advanced DNA-based methods and platforms are being developed. The present review focuses on the recent and advanced DNA-based techniques for the authentication of probiotic, PDO and PGI fermented foods and beverages. Moreover, the most promising DNA-based detection tools are presented. Strain- and species-specific DNA-based markers of microorganisms used as starter cultures or (probiotic) adjuncts for the production of probiotic and fermented food and beverages have been exploited for valuable authentication in several detection methods. Among the available technologies, propidium monoazide (PMA) real-time polymerase chain reaction (PCR)-based technologies allow for the on-time quantitative detection of viable microbes. DNA-based lab-on-a-chips are promising devices that can be used for the on-site and on-time quantitative detection of microorganisms. PCR-DGGE and metagenomics, even combined with the use of PMA, are valuable tools allowing for the fingerprinting of the microbial communities, which characterize PDO and PGI fermented foods and beverages, and they are necessary for authentication besides permitting the detection of extra or mislabeled species in probiotic products. These methods, in relation to the authentication of probiotic foods and beverages, need to be used in combination with PMA, culturomics or flow cytometry to allow for the enumeration of viable microorganisms. Aimed at achieving an economic gain, food labeling or food products may be tampered with, substituted or misrepresented, thus committing food fraud. To overcome this problem, which causes an estimated burden of USD 10\u201315 billion per year on consumers and industry [As stated in the consensus statement on fermented foods by the expert panel of the International Scientific Association for Probiotics and Prebiotics (ISAPP), \u201cfermented foods are foods made through desired microbial growth and enzymatic conversions of food components\u201d . The EurEach fermented food and beverage is characterized by a peculiar microbiota originating from the raw materials, equipment and processing environment, whose composition and evolution is affected by biotic and abiotic factors that intervene during each specific process of production. Such a microbial consortium ensures both the primary fermentation activities, which guarantee the technological results of the transformation, and the accessory ones, which contribute notably to the definition of the characteristics of typicality and quality, bases of their notoriety. Different microbial fingerprints have been found to be specific to the geographic area of origin . For thiBut while in the case of fermented foods and beverages, only the detection of either microorganisms used as starter cultures/adjuncts or the whole microbiota is satisfactory, in the specific case of probiotic foods and drinks, the quantification of each probiotic mentioned in the label is also mandatory ,13,14. ITo date, several methods are available to qualitatively and quantitatively detect microbial markers of authenticity in fermented and probiotic foods and beverages. Among these, DNA-based methods, mainly due to their speed, robustness, sensitivity and specificity, are gaining ground in recent decades.Herein, we provide a review of the advanced DNA-based techniques currently in use or that can be used in the near future to evaluate the authenticity of fermented and probiotic foods and beverages.Since 1983, when the scientists of the Cetus Corporation of Emerville   launchedThe authenticity of a technological or probiotic microorganism should be determined not only at the species level but also at the strain level, as stated in the guidelines proposed by the Council for Responsible Nutrition and International Probiotics Association , as wellRandom amplified polymorphic DNA (RAPD)-PCR, which employs an oligonucleotide primer to amplify anonymous DNA providing complex strain-specific banding patterns, and amplified fragment length polymorphism (AFLP)-PCR, which combines the restriction endonuclease of the genomic DNA with a PCR involving adaptor- and restriction site-specific primers, are genotyping techniques providing polymorphic banding patterns that allow for strain discrimination . HoweverRAPD-PCR, AFLP-PCR and REA-PFGE have been applied to ascertain the authenticity of probiotic foods ,36,37, tWhole genome sequencing (WGS) allows the identification of a target microorganism at both species and strain level. Furthermore, WGS data analysis provides a preliminary in silico assessment of microbial safety and probiotic potential ,42, evalAuthentic is any probiotic food or supplement whose content is consistent with that claimed on its label ,13,14.Assessing the authenticity of a probiotic food is crucial and requires verifying not only the presence and viability of the labeled probiotic but also the labeled amount of viable cells of the probiotic. The gold-standard method to quantify microorganisms is plating. However, plating is time- and labor-consuming and requires more days to achieve results. Moreover, the selective media used to enumerate microorganisms do not allow the enumeration of microbes in the viable but non-culturable (VBNC) state. To overcome this drawback, methods that combine the use of selective and non-selective media in one single system, such as the Lutri plate, the Overlay (OV), the membrane-transferring surface-plating and the thin agar layer (TAL) methods, firstly proposed to detect VBNC pathogenic bacteria, can be used ,71. UsinReal-time PCR, which is rapid, robust, sensitive and user-friendly, besides being high-throughput and multiplexing, is being widely applied to investigate the authenticity of probiotic and fermented foods. Using this technique, it is possible to monitor the emission of fluorescence by DNA-intercalating agents or labeled probes at each amplification cycle, which, being proportional to the DNA present in the reaction mixture, allows the real-time quantification of the target DNA and, thus, of the amount of the target microorganism. However, although more sensitive, intercalating dyes are not as specific as labeled probes. This drawback may be overcome by using the melting or the high-resolution melt (known as either hi-res melting or HRM) curve analysis of the obtained amplicons . To makeHowever, as stated above, DNA-based methods do not discriminate among viable or dead microorganisms, discrimination that can be achieved using culture-based approaches or flow cytometry methodologies ,72,93. PAmong the numerous diagnostic methods currently available to detect technological and probiotic microorganisms in food, biosensors are promising tools capable of providing high levels of faster and more automated surveillance. These analytical devices combine a sensitive biological element (the receptor) with a chemical or physical transducer to selectively and quantitatively detect the presence of a specific compound in a given environment . The selThe rapid evolution of micro- and nano-technologies has opened new horizons towards the integration and miniaturization of conventional sensing platforms, resulting in the so-called lab-on-a-chip devices that incorporate various laboratory processes in a miniaturized and semi-automated system. However, PCR requires a thermal cycler instrument, which significantly limits the potential miniaturization of the system . To overThe development and use of these integrated platforms for the detection and quantification of microorganisms are still limited to the detection of pathogenic microorganisms .The obvious advantages of these integrated and miniaturized technologies for the detection of technological and probiotic microorganisms lie in the reduction in the volume of reagents used and, therefore, the associated costs, as well as the reduction in time to results. Furthermore, the possibility of making the entire detection system portable and automated facilitates its use not only in the agri-food sector but also in other strategic sectors such as anti-fraud services, port and border control authorities, certification agencies/bodies of control of consortia for the protection of typical products, and public and private control laboratories.PCR amplification of variable regions of the 16S rRNA gene (for bacteria) or 18S or 26S rRNA gene (for yeasts and fungi) followed by denaturing gradient gel electrophoresis (PCR-DGGE) is another technique frequently used in recent decades to investigate the authenticity of probiotic and fermented foods and beverages. This PCR-based method is based on the separation, in a denaturing gradient gel, of amplicons of the same size but with different sequences, based on the differential denaturation (melting) profile . PCR-DGGBased on the same principle as PCR-DGGE, 16S metagenetic analysis and metagenomics may allow the characterization of fermented foods and the authentication of PDO and PGI products as well as that of probiotic foods. Metagenetics, also called amplicon sequencing, metabarcoding, metataxonomics, 16S metagenomics (targeting bacteria), 18S or 23S or ITS  metagenomics (targeting fungi), consists of the PCR amplification of target genes from metagenomic DNA combined with sequencing and alignment against a reference database to detect the microbial composition of a microbial community .Lactobacillus helveticus dominated both natural whey starter cultures and the corresponding Caprino and Vaccino cheeses, two traditional cheeses produced in the same dairy farm, whereas Staphylococcus equorum and Streptococcus thermophilus dominated Cacioricotta and Pecorino cheeses, respectively, also produced in the same dairy plant. The parallel assessment of the enzymatic activities, degree of proteolysis, and concentrations of the main compounds involved in the sensory traits of these 4 traditional cheeses produced in the same dairy plant allowed the authors to highlight the distinctive features of these cheeses and to find the relationships between their microbiological and biochemical characteristics [As an example of using this technology to describe the microbial community of foods, Celano et al. , via 16Seristics . Also, 1eristics . For exaeristics  combinederistics  used a pHowever, metagenetics has drawbacks linked to the low discriminatory power of ribosomal RNA to identify phylogenetically closely related bacteria and fungi, apart from the biases of PCR amplification . These pDNA-based technologies are valuable tools to assess the authenticity of probiotic, PDO and PGI (fermented) foods and beverages. Several DNA-based methods are presently available , but, dePMA real-time PCR-based assays, being a multiplexed and high-throughput method, allow for the simultaneous qualitative\u2013quantitative detection of numerous probiotics or starter cultures directly from different food and beverage matrices. However, the primers and probes should be strain-specific to allow for the qualitative\u2013quantitative detection of the labeled probiotic strain or starter culture. In this context, the pangenome-based design of primers and probes specific to each target strain is worthwhile.If the necessity is to investigate the presence of extra species or of mislabeled species in probiotic food and beverages or to assess the authenticity of PDO and PGI fermented foods and beverages, it is necessary to use the whole microbiota as an authenticity marker. In this case, depending on the budget and equipment available, metagenomics or PCR-DGGE can be used. But while the sole microbial pattern of PDO and PGI fermented foods and beverages allows for their authentication, in the case of probiotic food and beverages, a quantitative detection method for viable microbes such as the use of PMA in combination with the above-mentioned methods or the employment of culturomics or flow cytometry in combination with these community fingerprinting techniques is mandatory."}
+{"text": "The gut microbiota is the largest symbiotic ecosystem in the host and has been demonstrated to play an important role in maintaining intestinal homeostasis. The symbiotic relationship between the microbiota and the host is mutually beneficial. The host provides important habitat and nutrients for the microbiome. The gut microbiota supports the development of the metabolic system and the intestinal immune system's maturation. Intestinal microbes ingest dietary components such as carbohydrates, proteins, and lipids, and the metabolites are reported to directly or indirectly affect human health. Therefore, there is an inseparable relationship between the gut microbiota and the nutrition of the host.Gut microbiota not only participates in the digestion, absorption, and synthesis of some nutrients but also regulates host metabolism. A detailed understanding of this relationship between gut microbiota and animal nutrition physiology is necessary to rationalize dietary interventions targeted at the gut microbiota in the future. The emergence of omics methods and research on the animal microbiome has completely changed our understanding of gut microbiota and nutritional physiology. This Research Topic (RT) focuses on all aspects of the research on digestive tract microorganisms and nutritional physiology.Yang, Wang, et al. explored the impact of different dietary ratios of amylose and amylopectin on the gut health and microbiome of weaned pigs during feed transitions or after exposure to the lipopolysaccharide toxin of Escherichia coli. Wang M. et al. investigated the effects of an herbal extract mixture on the gut microbiota and intestinal antioxidant capacity of weaning piglets. Zhou H. et al. researched the effects of administering all-trans retinoic acid (ATRA) to pregnant sows on the gut bacterial community of neonatal piglets with different genetic backgrounds. Zheng et al. looked into the mechanisms underlying the effects of beta-hydroxy-beta-methylbutyrate (HMB) on lipid metabolism in Bama Xiang mini-pigs. Li et al. compared the effects of compound enzymes and antibiotics on growth performance, nutrient digestibility, blood biochemical index, and intestinal health in weaned pigs. All these studies demonstrated that the dietary interventions could lead to alterations in the gut microbiome of pigs and piglets, suggesting improved gut health and physiological functions like resistance to bacterial toxins, enhanced anti-oxidative capacity, growth performance, etc.Various research articles submitted on this RT focus on the impact of specific dietary interventions on the microbiome and the physiology of certain farming animals, including pigs and piglets, lambs and goats, ducks, chickens, bullfrogs, and shrimps. Wang Q. et al. assessed the impact of different dietary energy levels in male Hu lambs during the fattening period, and Yang, Zhang, et al. assessed the effects of dietary supplementation with mannan oligosaccharide (MOS) on the passive transfer of immunoglobulin G (IgG), anti-oxidative capacity, immunity, and intestinal microbiota in neonatal goats. The first study suggested that the medium rather than the high dietary energy levels could be more appropriate during the lamb fattening period based on the changes observed in rumen fermentation, gastrointestinal tract histology, and microbiome diversity. The second study concluded that MOS could improve all parameters tested and thus its addition as a feed supplement for neonatal goats is suggested.Furthermore, Liu et al. and Peng et al. explored the effects on gut microbiota, growth performance, and intestinal morphology among other physiological parameters of dietary ferulic acid or Bacillus and non-starch polysaccharase, respectively. He et al. studied the effects of incorporating black soldier fly larvae meal (BSFLM) into the diets of Xuefeng Black-Bone chickens on their gut microbiota and intestinal morphology. The studies mentioned above indicated that the dietary interventions tested had positive effects on the gut health and productivity of poultry.An additional three studies focused on dietary improvements in poultry. In ducks, Wang Z. et al. analyzed the effects of supplementing autochthonous gut bacteria in plant-based diets on the growth, nutrient digestibility, and gut health of bullfrogs (Lithobates catesbeianus). Wang W. et al. looked at the effects of dietary supplementation with Phaffia rhodozyma astaxanthin on growth performance, carotenoid analysis, biochemical and immune-physiological parameters, gut microbiota, and disease resistance in the giant tiger prawn Penaeus monodon. Again, a positive influence was recorded for each of the interventions in the two organisms which could be related to the gut microbiome, gut physiology, and growth performance.The final two studies on farming animals were on organisms related to aquaculture. Wen et al. investigated the effects of heat stress on the gut microbiota and metabolomic profiles in mice. Heat stress was found to have a negative effect on the gut microbiome composition and caused metabolic alterations which could be related to inflammation and oxidative stress. Zhuang et al. studied the effects of resveratrol on growth performance, intestinal morphology, gut microbiota composition, and metabolism in mice. Zhai et al. unraveled the mechanisms underlying the effects of Eucommia ulmoides leaf extract (EULE) on colonic epithelium integrity in rats. Zhou D. et al. tested the application of phytic acid-degrading bacteria on mineral element content in mice. Wan et al. checked the effects of caffeic acid supplementation on colonic inflammation, oxidative stress, and gut microbiota in mice. Resveratrol had a positive impact on all physiological and morphological parameters tested. EULE supplementation led to improvements in colonic epithelium integrity, accompanied by a reduction in inflammation and oxidative stress. EULE action was found to be mediated through the gut microbiota-bile acids-TGR5 axis. Degradation of the anti-nutrient phytic acid, which binds to minerals and inhibits their absorption in the gut, led to their increased absorption and utilization. This effect was accompanied by positive alterations in the composition of the gut microbiome. Moreover, caffeic acid supplementation led to reductions in colonic inflammation and oxidative stress along with positive changes in the gut microbiota composition. The antioxidant and anti-inflammatory effects of caffeic acid were associated with changes in the level of gene expression.The next five studies were performed in mice or rats as the model organisms. Lonicera japonica extracts (LJE) in animal production, with a focus on their effects on intestinal health. In this review, Tang et al. discussed the mechanisms underlying the positive effects of LJE on the gut microbiota, gut barrier function, and immune function. Overall, the review suggested that LJE has potential applications in animal production for promoting gut health, enhancing animal performance, and reducing the need for antibiotics. In the second review, Yang Y. et al. presented recent research on the relationship between cow's milk protein allergy (CMPA) and the gut microbiota in infants. The authors suggested a relation between CMPA and gut dysbiosis, as well as the potential use of probiotics, prebiotics, and synbiotics in the prevention and management of CMPA. In the third and final review, Hu et al. discussed the potential applications and functions of prophage activation in the intestine. The study highlighted that prophage activation could play a role in the modulation of gut microbiota composition and function, in the treatment of disease  and infection , as well as in engineering the microbiome .Finally, three review articles were published in the RT. The first concentrated on the potential use of The studies featured in this RT encompass significant contributions from diverse authors, highlighting the multifaceted aspects between nutritional physiology and the gut microbiome in animal and human health.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
+{"text": "Infection of the bone is a difficult problem in orthopedic diseases. The key and basis of the treatment of bone infection is the effective control of local infection, as well as the elimination of infection focus and dead cavities. The most commonly used approach utilized for the prevention and management of bone infection is the application of antibiotic bone cement. However, the incorporation of antibiotics into the cement matrix has been found to considerably compromise the mechanical characteristics of bone cement. Moreover, some investigations have indicated that the antibiotic release rate of antibiotic bone cement is relatively low. Polyetheretherketone (PEEK) and its composites have been considered to perfectly address the challenges above, according to its favorable biomechanical characteristics and diverse surface functionalizations. This article provides a comprehensive overview of the recent advancements in the antimicrobial modification of PEEK composites in the field of antibacterial therapy of bone infection. Furthermore, the potential application of PEEK-modified materials in clinical treatment was discussed and predicted. Staphylococcus aureus, Methicillin-resistant S. aureus (MRSA), Escherichia coli, Pseudomonas aeruginosa, Streptococcus, and others are prevalent pathogens , resembling that of bone tissue . FurtherIt was widely reported that poor osseointegration and bacterial infections had been identified as the primary factors contributing to the failure of PEEK and its composite implants . The bacThe initial stage in the pathophysiology of foreign body infection is thought to involve bacterial adhesion to the surface of biological material . Followicocci infections, owing to its ability to eliminate a vast majority of gram-positive bacteria and various drug-resistant bacteria , a glycopeptide antibiotic, can inhibit the synthesis of bacterial cell walls. This inhibits bacterial reproduction and proliferation. Van has emerged as an efficacious antibiotic for the treatment of drug-resistant bacteria . Van witubstrate . The Zn via PDA coating, followed by its combination with gelatin methacrylate (GelMA) and subsequent application onto the biologically inert sulfonated PEEK (SPEEK) (Gentamicin sulfate (GS) and tobramycin (TOB) are aminoglycoside antibiotics. TOB inhibits the synthesis of bacterial proteins. Polydopamine (PDA) possesses good adhesion and antioxidation , which c (SPEEK) . As show (SPEEK) . This in (SPEEK) .in vitro. The utilization of PEEK with co-administration of diverse antimicrobial agents had been shown to enhance the osseointegration and antibacterial efficacy of biomaterials, which exhibits considerable clinical potential.The simultaneous administration of multiple medications and the exploitation of the combined effects of antibiotics potentially enhanced the antibacterial and biocompatible properties of PEEK. S. aureus while maintaining outstanding mechanical properties  and plant polyphenols have received a great deal of attention and research in recent years because of their clinical application potential for antimicrobial resistance and biocompatibility.via electrostatic contact. By regulating the immune response of the host, AMPs assisted in the indirect elimination of the pathogen from the host  could proliferate osteogenically when the BMP/Smad signaling pathway was stimulated by KR-12 . The pos in vivo . To incr in vivo . It was  in vivo . MBD-14  in vivo .in vivo are insufficient. Research in this field is still primarily focused on better AMP stability, higher selectivity, and reduced toxicity. Developing an effective dosing schedule, combining AMPs with other compounds to increase their antibacterial efficacy, and other measures will be necessary for the clinical application of AMPs  was carefully prepared by cold pressing and sintering (E. coli and S. aureus in vitro because of the synergistic interaction between the -SO3H group and the continuous release of genistein. Plant polyphenol chlorogenic acid (CGA) was predominantly extracted from Fols Lonicerae. In order to solve the problem of large area defect and related infection in clinical bone grafting, CGA was loaded on the surface of SPEEK using a hydrogel system (E. coli and S. aureus and minimizing the probability of early implant infection. Curcumin (CR) is a polyphenol compound produced by turmeric extract that inhibits the replication of bacteria and fungi as well as inflammation and oxidation , a type of photothermal catalyst provided with unique single-layer carbon atomic nanosheet structure and excellent intrinsic antibacterial effect , has bee in vivo . Accordi in vivo . Ouyang,via electrostatic interaction, controlled cell adhesion, and stimulated specific gene expression. Consequently, the synergistic effect of GO/Dex-loaded liposomes increased cellular adhesion and migration, as well as improved cellular biocompatibility.Furthermore, the antibacterial activity and biocompatibility of PEEK were significantly improved by synergistic effect of photothermal catalysts and antimicrobial agents. Ouyang, et al.  modifiedin vitro and in vivo. Meanwhile, bio-persistence of GO in the human body might have an impact on pathology and immunology  Strategies including strong acid sulfonation, and 3D printing make sure the enhancement of the surface roughness of PEEK, augmentation of the hydrophilicity and promotion of the adhesion of osteocyte and bacteria. 2) Establishment of optimal dose and the appropriate controlled-released system to achieve the balance between therapeutic efficacy and cytotoxicity. 3) According to the characteristics of bone infection, such as dead cavity, local infection, bone defection, and so on, multifunctional formulation with antibacterial, osteointegration, and osteogenesis is also an important future direction of modified PEEK in bone infection."}
+{"text": "Dear Editor,A 34-year-old white female complained of vertex alopecia for six years, associated with pruritus and local burning sensation. She reported that, since the onset of the condition, she observed the development of pustules at the periphery of the lesion. She denied comorbidities or ongoing medication use. She reported having had cycles of trimethoprim-sulfamethoxazole for 60 to 90 days, with partial improvement. The examination disclosed cicatricial alopecia area on the vertex region of the scalp, with follicular pustules at the periphery, erythema and areas with polytrichia . Dermosca)Folliculitis decalvansb)Folliculitis decalvans and lichen planopilaris phenotypic spectrumc)Centrifugal cicatricial alopeciad)Lichen planopilarisFolliculitis decalvans and lichen planopilaris phenotypic spectrum (FDLPPPS) is a recently described cicatricial alopecia, more prevalent on the vertex of the scalp in adults, which combines clinical and histopathological features of two other alopecias: lichen planopilaris (LPP) and folliculitis decalvans (FD), presenting with lymphocytic and neutrophilic inflammatory infiltrates, respectively.Staphylococcus aureus induces a biofilm that stimulates the innate immune response, perpetuating the neutrophil-mediated inflammatory process.3The pathogenesis of LPP and FD is still poorly understood; however, whereas in LPP there is activation of TCD8+ lymphocytes and loss of follicular immune privilege, in DF the presence of The etiology of FDLPPPS is still under discussion, given the coexistence  of both inflammatory processes. It has been suggested that dysbiosis of the DF follicular microbiome may induce the exposure of follicular autoantigens, stimulating a Th1 response pattern.4As for the clinical picture, patients with FDLPPPS usually show a sequential biphasic process with the characteristics of FD preceding LPP, or even concomitant clinical characteristics: areas of cicatricial alopecia with follicular pustules, erythema and perifollicular desquamation, which may evolve with polytrichia, as in the present case.6Regarding histopathology, a mixed infiltrate is observed in the infundibulum region, with destruction and atrophy of the follicular epithelium and prevalence of plasma cells and histiocytes, in contrast to the predominance of neutrophils in the FD and lymphocytes in the LPP.8There is yet no standardized treatment for FDLPPPS, given its recent description. However, treatments used in FD and LPP are usually associated, such as corticosteroids, sulfonamides, doxycycline, retinoid antimalarials, and immunosuppressants, according to the predominance of clinical and trichoscopic characteristics. In this case, oral hydroxychloroquine 400\u202fmg/d and isotretinoin 30\u202fmg/d, and clobetasol 0.05% gel were introduced, with stabilization of the condition after six months. The rationale for choosing anti-inflammatory drugs and oral retinoids was based on the predominance of clinical and trichoscopic signs of the LPP spectrum, in this case, mainly after previous treatment with antibiotics, aiming to reduce the neutrophil activity intensity.The cases described in adults and children with FDLPPPS do not seem to reach a large area of the scalp, despite the delay in its diagnosis.8Dermatologists should be aware of the diagnosis of FDLPPPS in the presence of less characteristic cases of cicatricial alopecia on the vertex of the scalp, with pustules, erythema and follicular desquamation, in which the inflammatory infiltrate is mixed, or with alternating patterns in subsequent biopsies, and containing plasma cells.None declared.Miola AC: Design and planning of the study; collection, analysis and interpretation of data; critical review of the literature; critical review of the manuscript; writing and approval of the final version of the manuscript.Ramos PM: Critical review of the literature; critical review of the manuscript, writing and approval of the final version of the manuscript.Miot HA: Design and planning of the study; effective participation in research orientation; critical review of the literature; critical review of the manuscript, writing and approval of the final version of the manuscript.None declared."}
+{"text": "The development of vaccines against the SARS-CoV-2 virus has become a big challenge for many countries in 2020-2022. mRNA vaccines were shown to be effective and safe and have been widely used worldwide in the fight against the COVID-19 pandemic. The fundamental factor in creating mRNA vaccines, which ensures effective delivery of mRNA to the host cells, is the composition of lipid nanoparticles, namely the presence of ionized charged lipids, which ensures the binding of mRNA molecules. However, the significant role of liposomes in the development of liposomal vaccines and identification of immunochemical reactions involving lipids should be assessed in the context of the development of the pioneering idea of August Wassermann about the use of liposomal antigens in the diagnosis and immunoprophylaxis of serious human diseases.The review is devoted to the use of liposomal antigens as antigen-delivery systems for diagnosis and immunoprophylaxis.Studies of cardiolipin antigen in serodiagnosis of syphilis became the foundation of antibodies in diagnosing various infectious diseases and pathological conditions, such as tuberculosis, lupus erythematosus, COVID-19, borreliosis, etc. Identification of antiphospholipid antibodies (mainly anticardiolipin) and today is the most important diagnostic tool for antiphospholipid syndrome.The liposomal system first proposed in 1906 for the diagnosis of syphilis evolved more than a century later into mRNA vaccines, which are used today in the fight against the COVID-19 pandemic. Treponema pallidum (syphilis) in humans using the complement fixation reaction with lipid antigens (Ag), called \u201cWassermann reaction\u201d , differing in qualitative and quantitative composition . . 9-11]. e.g. DPG, phosphatidylglycerol (PG), phosphatidylserine (PS) or phosphatidic acid (PA)), neutral lipid  and Chol was offered ..55].Similarly to classical liposomes , the catThe algorithm for polylipid composition design of mRNA vaccine aims to form LNP and encapsulate the mRNA into its structure due to the interaction of the anionic phosphate backbone of the mRNA with the ionized lipid. In the design process, the mRNA contacts four lipids in a water-organic environment under the control of pH level and hydrophobic-hydrophilic balance to ensure the binding of the mRNA to the ionized lipid. Bound mRNA is identified in the inner cavity of multilayer LNPs formed by complementary lipid components. In this case, DSPC forms the main bilayer of the liposomal membrane, and the presence of PEG-lipid and Chol ensures optimal hydrophilicity, stability, and size of LNPs with encapsulated mRNA.A liposome-based vaccine candidate EG-COVID differs from the composition of Pfizer-BioNTech product, consists of DOTAP , DOPE  and Chol, induces stable humoral and cellular immunity to the SARS-CoV-2 virus, and suppresses the SARS-CoV-2 viral infection in Vero cells . The optIn conclusion, the significant role of liposomes in the development of liposomal vaccines against COVID-19 and the identification of immunochemical reactions involving lipids should be assessed in the context of the development of the pioneering idea of August Wassermann about the diagnostic use of liposomal antigens in the creation of innovative liposomal preparations for the diagnosis and immunoprophylaxis of serious human diseases. Thus, the liposomal system first proposed in 1906 for the diagnosis of syphilis  evolved Conflict of interest: The author declares no conflict of interest."}
+{"text": "The COVID-19 pandemic has had significant consequences, impacting not only physical health but also mental wellbeing, social interactions, and economic stability . These eMental Illness, Culture, and Society: Dealing with the COVID-19 Pandemic\u201d builds upon the previous five volumes  is a serious global issue that threatens healthcare workforce retention and health system resilience, especially during the fragile post-COVID \u201cnormalization\u201d period. The authors used a comparative approach, analyzing the epidemiological, political, and geographic contexts of Brazil, the United Kingdom, New Zealand, and Germany to identify similarities and differences in violence against HCWs. Overall, the results showed a general sensitivity of HCWs to violence, with women, nurses, and migrant/minority groups being particularly exposed. The authors emphasized the need for attention to this topic and to all forms of violence in the world.Huang et al. aimed to compare depressive symptoms among HCWs in high-risk areas (HRAs) and low-risk areas (LRAs) during the initial stage of the COVID-19 pandemic in China. The results showed that HCWs in LRAs had 1.96 times higher odds of having depressive symptoms than those in HRAs. There were also significant differences in workplace environment characteristics and the Health Belief Model between the two groups. The study highlighted the importance of considering the mental health of HCWs, especially in LRAs, and tailoring interventions to their specific needs.The study by Savu et al. aimed to determine the mediating role of HCWs' perception of their own health on pandemic stress, work-family conflict, work engagement, meaning and commitment to work, satisfaction of basic psychological needs, patient care, and burnout symptoms. The authors identified significant correlations between the investigated variables. In particular, HCWs with a positive perception of their own health were better at managing pandemic stress, burnout effects, and work-family imbalances.The study conducted by Ayub et al. reviewed the impact of the COVID-19 pandemic on religious activities and beliefs, and explored the potential role of religious leaders and communities in mitigating the pandemic's impact through public health measures and community engagement. The authors identified the following main themes: the relationship between religious practices, beliefs, and the spread of COVID-19, and the role of religious leaders and faith communities in coping with and mitigating the impact of COVID-19. The review highlighted the essential role of religious leaders, faith-based organizations, and faith communities in promoting education, preparedness, and response efforts during the pandemic. The importance of collaboration between religious leaders, institutions, and public health officials was also emphasized.Ryu et al. aimed to understand COVID-19 vaccine acceptance and related factors among 572 individuals with mental disorders residing in Korea. Clustering revealed three groups in relation to vaccine acceptance: totally accepting, somewhat accepting, and hesitant groups. Individuals in the high vaccine acceptance group were older, more likely to receive the influenza vaccine regularly, and more likely to trust formal information sources. The study highlighted the importance of understanding the behavioral and psychological characteristics associated with vaccine acceptance, to be able to effectively communicate its importance to individuals with mental disorders.Carbone and Knapp investigated the use of mandatory psychiatric treatments during the COVID-19 pandemic, with a focus on the first and subsequent phases. Interviews were conducted with mental health care professionals and scholars from four countries. The analysis identified four major themes: the culture of psychiatric care services, the effect of the pandemic on involuntary hospitalizations, exceptional management of hospitalization to reduce infection spread, and policies and suggestions for more inclusive mental health treatments. The study found that during the first wave, there was a decrease in the use of involuntary treatments, while a gradual increase was observed in the following months.Qiao et al. documented the unique challenges faced by rural black women during the COVID-19 pandemic and tried to highlight their needs for effective management of social, physical, and mental health challenges. The study aimed to inform evidence-based decision-making for policymakers and to contribute to the development of public health emergency preparedness plans. This would help promote the resilience of rural Black women and their families during future infectious disease outbreaks and other public health emergencies.With their study protocol, Park et al. examined the connections between pandemic-related factors and anxiety/depressive symptoms in young adults from South Korea and the U.S.. The findings from 1,123 participants collected during the COVID-19 lockdown period showed similar network structures in both countries, suggesting a consistent relationship between the pandemic and internalizing symptoms, irrespective of sociocultural differences. COVID-related stress and negative anticipation of the future were identified as key factors connecting pandemic-related elements to psychological distress.The study by Du discussed the impact of the COVID-19 pandemic on community-centered engagement and healthcare services. The author particularly described the experiences of migrant workers in Singapore and community volunteers in Shanghai and the effectiveness of coordinated community efforts in providing essential supplies and support during lockdowns Du. The article also emphasized the role of community health centers in testing and vaccination programs, especially among marginalized populations.Finally, In brief, the articles collected in the Sixth Volume of this Research Topic provide a novel perspective on the pandemic's impact on mental health, further emphasizing the role of sociocultural, economic, and individual factors in this interplay. The influence of COVID-19 on psychiatry and mental health is significant and enduring. Further clinical and epidemiological research is necessary to address the vulnerabilities of the most fragile segments of society.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
+{"text": "Nyatega et al.)  \u20139. The d et al.) , 11. An  et al.) , studies et al.) , 14, phy et al.) , 16 and  et al.) . These t et al.) . Recent  et al.) , 20 and Therefore, in this Research Topic, we present a collection of articles that showcase recent advances in neuroimaging and non-invasive brain stimulation techniques and their application to the study of the brain's structural and functional organization.Understanding the brain's structure and function is vital in the diagnosis and treatment of neuropsychiatric disorders. Advances in neuroimaging and NIBS techniques have enabled researchers to explore the underlying mechanisms of disorders such as depression, SCZ, anxiety and post-traumatic stress disorders , 21, 22.These articles demonstrate the applications of neuroimaging in studying drug abuse, bipolar disorder (BP), dysmenorrhea, white matter lesions (WML), functional dyspepsia (FD), and SCZ. The meta-analysis of cocaine addiction shows how drug abuse affects the brain. The study on BP reveals the relationship between cerebral WML and the incidence of BP. The investigation of primary dysmenorrhea offers insights into the relationship between pain and the brain, while the exploration of differential brain responses to meal ingestion in FD patients provides a better understanding of this meal-induced syndrome. Finally, structural magnetic resonance imaging studies provide insights into the pathophysiology of SCZ.Dang et al. These findings suggest that drug addiction is a complex neurobiological disorder and not solely a behavioral problem. Identifying the specific brain regions and circuits impacted by cocaine addiction can help develop new treatments targeting these neural mechanisms . These findings provide valuable insights into the structural and functional organization of the brain in individuals with BD . These findings provide insights into the structural and functional organization of the brain in FD patients and may have implications for the diagnosis and treatment of neuropsychiatric disorders involving visceral hypersensitivity and emotional dysregulation (gulation , 34. OveAdamu et al.'s structural MRI study sheds light on the pathophysiology of SCZ, showing that individuals with the disorder have structural brain abnormalities linked to specific symptom clusters and cognitive impairments. The study also highlights the use of machine learning to identify patterns of brain structure associated with symptoms and impairments. The findings contribute to our understanding of the structural and functional organization of the brain in neuropsychiatric disorders and could improve diagnosis and treatment (reatment , 36. By The articles in this Research Topic highlight the importance of continued research on the structural and functional organization of the brain and its potential impact on the diagnosis and treatment of neuropsychiatric disorders \u201341. The MT, MD, and SB contributed to conception and design and wrote sections of the manuscript. MT wrote the first draft of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version."}
+{"text": "Dear Editor,A 64-year-old female patient has complained of darkening and deformity of the nail of the third left finger for two years. On examination, onychodystrophy, slight subungual thickening, and irregularly pigmented longitudinal melanonychia (LM) measuring 3\u202fmm were observed A. Dermosin situ, has a variable record of its frequency, possibly due to failure in its recognition or underreporting. On the other hand, SCC is the most common neoplasm of the nail apparatus, often with late diagnosis. Typically, ungueal BD presents as subungual hyperkeratosis or a verrucous lesion of the nail plate or bed; with periungual erythema and paronychia associated with crusts, ulcerations, or fissures, onychocryptosis, and/or nail dystrophy, and rarely with LM.Ungueal BD, or squamous cell carcinoma (SCC) Exogenous pigment deposits , blood, and melanin are frequent causes nail plate and nail bed pigmentation, and melanocytic activation and benign melanocytic nevi are the most common causes of LM in adults and children, respectively. However, about 2/3 of ungueal melanomas present clinically as LM.Some clinical criteria should raise the index of suspicion of melanoma in acquired LM in adults: the presence of heterogeneous pigmentation in bands or lines of variable colors, fissures or clefts in the nail plate, especially in the distal region (triangular shape), the sudden appearance of nail plate pigmentation, and blurring of the nail fold edges.Digital pigmented BD mimics melanoma and may show a chaotic pattern on dermoscopy: atypical parallel pattern of grooves and ridges, and a chaotic pattern with segmental radial lines suggestive of melanoma, associated with other dermoscopic characteristics suggestive of BD, such as squamous surface and linear arrangement of dotted vessels.LM dermoscopy is limited to the observation of the distribution of pigment deposited in the nail plate, and the underlying lesions can be misinterpreted, which is why intraoperative dermoscopy becomes relevant. Hirata et al. defined four patterns of intraoperative dermoscopy of the nail matrix and nail bed in LM: regular gray, regular brown, regular brown with globules or spots, and irregular pattern.Among dermoscopy findings, hyperkeratosis located on the free edge of the nail plate was the criterion significantly associated with subungual SCC.Despite the clinical and dermoscopic findings of the nail plate, and intraoperative dermoscopic findings of the nail bed and matrix raising the suspicion of melanoma, histopathological evaluation did not show proliferation of atypical melanocytes, confirmed by negative immunohistochemistry for HMB45 and S100 protein. Positive immunohistochemistry for AE1/AE3, an antibody against human epidermal keratins, therefore, a marker of normal epithelial cells, carcinomas, and other tumors with epithelial differentiation such as BD, revealed the epithelial nature of the neoplasm in the present case.Pigmented BD of the nail apparatus is a rarely diagnosed neoplasia and should be considered in the differential diagnosis of LM, particularly in the differential diagnosis with nail melanoma.A careful evaluation and management of patients with nail pigmentation, taking into account clinical features, dermoscopy of the nail plate, and intraoperative examination of the nail matrix and nail bed can help rule out common causes of nail pigmentation; however, the histopathological examination still remains the reference to confirm the diagnosis of the lesion which is determining LM.None declared.Guilherme de Medeiros Holanda: Design and planning of the studied case; collection, analysis and interpretation of data; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied case; critical review of the literature; drafting and editing of the manuscript.Bruno de Carvalho Fantini: Design and planning of the studied case; collection, analysis and interpretation of data; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied case; approval of the final version of the manuscript.Guilherme Raya Ravelli: Approval of the final version of the manuscript; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied case.Cacilda da Silva Souza: Design and planning of the studied case; collection, analysis and interpretation of data; critical review of the literature; drafting and editing of the manuscript; approval of the final version of the manuscript.None declared."}
+{"text": "In this Research Topic, we explore health policy and systems research at the nexus between urbanization and health. The global trend of urbanization will not abate in the near future and the related challenges are many. Low- and middle-income countries (LMICs) are observing a continued expansion of informal settlements, residential segregation, a double burden of life-long conditions and (re-emerging) infectious diseases. Important socio-ecological challenges relate to urban sprawl, unregulated economic activities, pollution, and environmental degradation. A central concern in LMICs is the impact of urbanization on equity and social inclusion , 2.community, experiential, environmental, and structural policy level\u201d . Their study uses modeling in management of urban emergencies and illustrates how such techniques can improve decision-making in crisis situations when uncertainty is high.The occurrence of natural disasters and other large-scale emergencies represents another aspect of urban health that transcends sectors and dimensions. Almasi et al. and Banke-Thomas et al. report on the integration of geographical data in urban health policy and system analysis. Almasi et al. investigated the location of medical laboratories in Kermanshah (Iran) and its impact on access to laboratory services. The authors used a combination of GIS-based mapping of facilities and network analysis to map locations of laboratories and their accessibility for urban residents. They found coverage gaps in specific areas of the city, pointing to inequitable distribution of facilities and access problems. Banke-Thomas et al. investigated how, in big cities, the travel time of pregnant women requiring urgent care can be estimated using Google Maps data. The authors developed a method to estimate the travel time of women requiring Emergency Obstetric Care in Lagos (Nigeria). Next, they plan to co-create dashboards with urban health policymakers and data companies, which will combine data on travel time with data on the functionality of hospitals. Similar to Almasi et al., they highlight inequities related to the place of residence. Such approaches could contribute to a better understanding of how the urban advantage can become a disadvantage for those living in underserved areas  developed local initiatives for evidence building and information distribution during the COVID-19 wave of July 2020. Family practitioners considered that the contact tracing system set up by the Flemish government would be ineffective in their superdiverse neighborhoods. In < 2 weeks and in close collaboration with city and provincial authorities, they set up a successful alternative system of COVID coaches in support of contact tracing and self-isolation. This study illustrates how in situations of high uncertainty, national responses can and must be adapted to local contexts. Yet, this requires a strong learning culture, embedded in adaptive governance arrangements, and the importance of incorporating local innovations into broader policies and programs  identify systemic relations within the spatial context, (b) facilitate integration of quantitative and qualitative data, and (c) guide the formulation of policy recommendations, informing public and urban health planning.\u201d They illustrate this in a study on malaria in Jimma (Ethiopia) and on tuberculosis and COVID-19 in Lima (Peru). Fang et al. addressed another intersecting set of challenges: aging, rapid urbanization, and increasing digitisation of social spaces and resources. This requires cities and communities to develop age-friendly community ecosystems that put intergenerational relationships at the center. The authors adopted a community-based participatory research approach and co-creation methods to co-create recommendations for research, policy, and practice. The paper illustrates how Bronfenbrenner's ecological systems theory provides a multi-level framework to assess how wellbeing is shaped an interplay of micro- and macro-level factors.Unpacking the relationships between the social, political, economic, infrastructural, and ecological determinants of health in cities is key to understanding urban health. This requires multidisciplinary approaches and multi-actor knowledge production. Two papers address this methodological challenge. The papers included in this Research Topic present unique methodological, empirical, and practical contributions that speak to the complex nature of the urbanization-health nexus. Yet, they also show that research into urban inequities, residential segregation and social exclusion merits more attention. More research is also needed on the dynamic interplay between cities, the national and the global level regarding health. National development plans and urban policies shape cities. Cities have open boundaries through which people migrate continuously. Cities are also players in networked global markets and are hubs in global disease transmission patterns. Moreover, the interface between global warming and health calls for more research on intersectoral action for climate-resilient urban health systems.This Research Topic shows that interesting and innovative research is being done at the still little explored frontier of urbanization and health. In these turbulent times, the challenges confronting urban  planners, managers, and researchers, as well as people, providers and communities are only amplified. The Health Policy and Health System Research community will need to rise up to contribute to making cities healthier for its people through more innovative studies.All authors contributed to the conceptualization, drafting, and final revision of this editorial."}
+{"text": "Consumers are increasingly demanding higher quality meat products. However, meat products manufactured using traditional processing procedures are often perceived as unhealthy or hazardous foods, due to the significant amounts of sodium chloride added, the excessive accumulation of harmful substances, and the abnormal growth of spoilage microorganisms. Green processing is a new concept aiming to meet the challenges of the 21st century, and should be the result of a whole chain of values to protect both the environment and consumers. In the meantime, it will hopefully drive industries to be more ecologic, economic, and innovative. Green technologies show great potential in decreasing or preventing the formation of hazardous substances, increasing the shelf life, and maintaining the sensory attributes and nutritional qualities of meat products during the manufacturing of food. Thus, this topic will discuss the effect of green processing on the mechanism of quality development of meat and meat products from the perspective of chemical and biochemical composition and structure changes in molecules during the processing of meat products, as well as the chemistry related to the major components of meat products, and their nutritional, physiological, sensory, flavor, and microbiological properties.This Special Issue is made up of eighteen research articles aiming at providing up-to-date research on the abovementioned aspects related to raw meat, by-products, meat products, and advances made in meat quality assessment. The different works can be assigned to four distinct groups. One portion of these studies focused on the quality assessment of raw meat; another portion of these studies investigated the antioxidant, gelling, and emulsion properties of proteins; another portion characterized the spoilage of meat and meat products; and the remaining portion mainly evaluated the flavor and texture of processed meat products.Regarding the quality assessment of raw meat, Cao et al.  highlighClostridium and Pseudomonas are the key genera involved in this process. Pseudomonas lundensis exhibited the strongest spoilage potential during the storage of chilled chicken [Clostridium was mainly responsible for the spoilage in deeply spoiled ham [Clostridium perfringens [Pseudomonas was also inhibited by the chitosan/collagen peptides/cinnamon bark essential oil composite coating [Green processing has a significant effect on the functional properties of meat proteins, and on decreasing or preventing the spoilage of meat products. The improvements in the gelling, rheology, and emulsion properties of meat protein were highlighted using typical green technologies, including ultrasonication, high-pressure homogenization, and isoelectric solubilization/precipitation ,7,8. Sev chicken ; Clostriiled ham . The comfringens . Further coating .Texture and flavor are the key parameters of fermented and spiced meat products. The addition of halogen and spicy flavors showed a positive effect for the relative content of alkanes and ketones during the processing of a Midu pork roll . Zhang e"}
+{"text": "Energy management methods (EMMs) utilizing sensing, communication, and networking technologies appear to be one of the most promising directions for energy saving and environmental protection of fuel cell vehicles (FCVs). In real-world driving situations, EMMs based on driving cycle information are critical for FCVs and have been extensively studied. The collection and processing of driving cycle information is a fundamental and critical work that cannot be separated from sensors, global positioning system (GPS), vehicle-to-vehicle (V2V), vehicle-to-everything (V2X), intelligent transportation system (ITS) and some processing algorithms. However, no reviews have comprehensively summarized the EMMs for FCVs from the perspective of driving cycle information. Motivated by the literature gap, this paper provides a state-of-the-art understanding of EMMs for FCVs from the perspective of driving cycle information, including a detailed description for driving cycle information analysis, and a comprehensive summary of the latest EMMs for FCVs, with a focus on EMMs based on driving pattern recognition (DPR) and driving characteristic prediction (DCP). Based on the above analysis, an in-depth presentation of the highlights and prospects is provided for the realization of high-performance EMMs for FCVs in real-world driving situations. This paper aims at helping the relevant researchers develop suitable and efficient EMMs for FCVs using driving cycle information. Energy shortage and environmental pollution are urgent problems that all countries in the world need to face . AcademiPrevious studies have shown that driving cycle information can make a difference in vehicle energy management ,13,14. IDriving cycle information is very critical for the development of EMMs, mainly reflected in the current driving patterns and future driving characteristics. However, in real-world driving situations, the driving cycle changes in real time. Consequently, obtaining current and future driving cycle information is a difficult and inaccessible task. As a matter of fact, some papers have proposed some EMMs considering driving cycle information for FCVs, mainly based on driving pattern recognition and future driving characteristic prediction. It is noticed that recent reviews have stated the advances progress in energy management methods for fuel cell vehicles ,23,24,25Motivated by the literature gap, this review mainly focuses on the technologies and progress of EMMs for FCVs from the perspective of driving cycle information, and strives to be comprehensive and innovative. The main contributions of this review are as follows: (i) providing a state-of-the-art understanding of EMMs for FCVs from the perspective of driving cycle information; (ii) providing a detailed description for driving cycle information analysis, including driving cycle collection and processing; (iii) providing a comprehensive summary of the latest EMMs for FCVs, with a focus on EMMs based on driving pattern recognition and driving characteristic prediction; and (iv) providing an in-depth presentation of the important highlights and prospects regarding the innovation of EMMs for FCVs. This review hopefully accelerates the realization of high-performance EMMs for FCVs in real-world driving situations.The rest of this review is organized into several sections: As the driving cycle is discerned as the input of the EMMs for FCVs, its information would affect the control performance of EMM extremely ,26. In aWith the development of intelligent networking technology, information and communication technology and big data technology, it is no longer difficult to collect and analyze the driving cycle. In recent years, global positioning system (GPS) receivers , on boarDue to the influence of the driving environment, jamming signals, zero drift, and buildings, the driving information collected often exhibited bad data . Bad datThe preprocessed driving cycle can be divided into some kinematic segments to reduce the complexity of subsequent processing. This segmentation is performed for the driving cycle characteristics analysis . DrivingPrevious studies have shown that driving pattern can greatly influence the effectiveness of EMMs ,57,58. FIn other studies of this area, supervised algorithms are adopted to recognize the vehicle driving pattern , such asThe driving cycle of a vehicle can be predicted by driving characteristic prediction (DCP) techniques, and the results indicate the current or future driving characteristics of the vehicle, like velocity and acceleration ,71. The The other is DCP based on positioning, sensing, interaction-aware, and other traffic information service technologies, such as V2X, V2V, and ITS ,82,83. TAs mentioned above, FCVs are one of the most promising future vehicles , and suiPrevious studies have extensively studied the EMMs of FCVs to improve energy efficiency and durability. The EMMs of FCVs can be divided into three major categories: (i) rule based, (ii) optimization based, and (iii) other based, as shown in As a new research hotspot in the field of artificial intelligence (AI) and internet of vehicles (IOV), learning-based and cycle information-based EMMs have been applied to achieve the optimal fuel economy of FCVs in real time ,111. ProIn recent years, to improve the performance of the EMMs for FCVs, research on driving pattern recognition has been proposed ,119,120.Moreover, to further improve the comprehensive economy of FCVs and extend the life of the ESSs, optimization algorithms and learning algorithms were combined and adopted in the design of EMMs. In , a genetCompared to the related research on the EMMs for FCVs based on driving pattern recognition, research on the EMMs for FCVs based on driving characteristic prediction is more extensive and in-depth due to the promotion of the intelligent process of NEVs ,131,132.Accurate driving pattern recognition: The accuracy of driving pattern recognition is crucial for the development and implementation of EMMs. However, recognition accuracy and algorithm complexity are interrelated. Some advanced recognition algorithms in the existing literature have the problem of low recognition accuracy. In the future, the sampling time, the selection of characteristic parameters, and the recognition period can all be combined with advanced recognition algorithms to construct recognition methods with excellent recognition accuracy and efficiency.Short-term driving characteristic prediction: Affected by the impacts of real-world driving conditions, the driving characteristics of vehicles will change in real time. Therefore, short-term driving characteristic prediction remains a hot and challenging issue, as it depends on various factors like the prediction method and traffic conditions. In the future, with the help of V2V, V2X, ITS and predictive algorithms, driving characteristics like speed, mileage, slope, and traffic signal light states can be predicted in the short term.Real-time energy management optimization: Ideal energy management optimization methods can adaptively generate effective control decisions considering the DPR and DCP results. However, most current energy management optimization methods are difficult to apply to real vehicles. Advanced algorithms bring up more possibilities of real-time energy management optimization which are worth exploring. In the future, real-time/online/adaptive EMMs will be considered for supplying an excellent control effect.Integrated driving style recognition: Even the same driver can exhibit different driving styles under different road conditions, and different driving styles can directly affect the energy management of the FCVs. Therefore, introducing the influence of driving styles into the EMMs for FCVs will be valuable and crucial. However, driving style is often described qualitatively, and is not integrated into the EMMs. In the future, integrated driving style recognition of drivers in real social driving networks will improve the effectiveness of EMMs for FCVs.In order to improve the energy economy and prolong the powertrain system durability of FCVs, it is urgent and meaningful to develop suitable and efficient EMMs. As driving cycle information is extremely important in EMMs for FCVs, some studies have studied driving cycle information collection and processing, which lay the foundation for the development of EMMs based on driving cycle information. This paper provides a state-of-the-art understanding and a detailed overview of EMMs for FCVs from the perspective of driving cycle information. More specifically, this paper comprehensively reviews studies on driving cycle information analysis and the EMMs for FCVs, which mainly focuses on EMMs based on DPR and DCP. This paper can provide potential guidance for the design and development of EMMs for FCVs in real-world driving situations. Although great progress has been made in the EMMs based on driving cycle information for FCVs, there are still many challenges. The main prospects of this review are the following:Accurate driving pattern recognition algorithms, short-term driving characteristic prediction algorithms, real-time energy management optimization methods and integrated driving style recognition methods will improve the energy economy and prolong the powertrain system durability of FCVs. In the future, our work will focus on the development and application of EMMs for FCVs based on the ITS and DCP technologies."}
+{"text": "Colorectal cancer (CRC) is the third most common malignancy in terms of global tumor incidence, and the rates of morbidity and mortality due to CRC are rising. Experimental models of CRC play a vital role in CRC research. Clinical studies aimed at investigating the evolution and mechanism underlying the formation of CRC are based on cellular and animal models with broad applications. The present review classifies the different experimental models used in CRC research, and describes the characteristics and limitations of these models by comparing the research models with the clinical symptoms. The review also discusses the future prospects of developing new experimental models of CRC. Colorectal cancer (CRC) is the most common malignancy worldwide, in terms of both morbidity and mortality . The undIn vitro models of CRC established using intestinal cells and CRC cells are frequently employed for obtaining rapidly growing cellular models of CRC and for facilitating experimental control. In vitro models of CRC can simultaneously generate several populations of homogeneous cells. Specific cellular targets of macroscopic systems can be conveniently studied using these models by analyzing the experimental results , including the cells and acellular components constituting the structural complexity of the in vivo environment. Altogether, these indicate that CRC cell lines fail to accurately mimic the in vivo growth characteristics of tumor cells.Although the characteristics of CRC cell lines are highly consistent with those of human cancer models, they have certain limitations. CRC cell lines facilitate the investigation of the molecular and phenotypic characteristics of CRC. However, as only one side of the cells is in contact with the medium during culture, the majority of cells gradually flatten, undergo abnormal division, and lose their differentiation phenotype following isolation from tissues and plate culture. Additionally, CRC cells continue to proliferate In vitro 3D culture models, including spheroids and organoids, are therefore used for overcoming the limitations of 2D cellular models. Spheroids comprise a mixture of single-cell or multicellular systems, while organoids are generally formed of specific stem cells or ancestral cells from organs , tumorospheres, tissue-derived tumor spheres (TDTS), and organotypic multicellular spheroids OMS;  Weiswal.in vivo  was used in the early 2000s for evaluating the differentiation capacity of tumors. However, because there are no morphological phenotypes associated with the phenotypic instability of CSCs, the tumorosphere model is unable to faithfully simulate the f tumors .in vitro 3D cell culture models of CRC  culture models that are frequently used in CRC research. Organoids are self-organizing organotypic cultures that are produced from various stem cells, including tissue specific adult stem cells (ASCs), embryonic stem cells (ESCs), or induced pluripotent stem cells (iPSCs)  . The steructures  (Lancastructures .+) intestinal stem cells in a medium containing stem cell niche restatement factors and tissue-specific growth factors  mutations, poor differentiation, or mucinous phenotypes related to CRC. The application of organoids to CRC research can be improved by employing the co-culture model of organoids in which immune cells and mesenchymal cells are co-cultured for simulating the in vivo TME.Organoids are typically used for investigating the mechanism underlying the development of CRC, screening anti-CRC drugs, and determining the efficacy and mechanism of action of drugs. However, there are various limitations to the application of organoids in studies on CRC, which are described hereafter. First, the current methods for organoid culture lack the technological means for maintaining the blood vessels, immune system, and peripheral nervous system of tumor cells, and organoids lacking these characteristics cannot be used in CRC research . Second,he tumor . Third, The establishment of models using the corresponding tumor cells is crucial for investigating the mechanism underlying the development of CRC and discovery of anti-CRC drugs . The appThe occurrence of diseases such as cancer that occur spontaneously in animals is largely attributed to genetic diversity and immune functions. Therefore, studying the methods for generating animal models of CRC can aid in elucidating the mechanisms underlying the development of cancer . Animal Rodent models are conducive tools for conducting cancer research, and are extensively used for elucidating the etiopathogenesis and molecular mechanisms underlying the development of CRC. Previous studies have demonstrated that the protein-coding genes of mice and humans share high homogeneity . AdditioAPC (adenomatous polyposis coli) are commonly inherited in adenoma-carcinoma transitions observed during the development of CRC , Kirsten rats arcomaviral oncogene homolog (KRAS), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), F-box and WD repeat domain containing 7 (FBXW7), SMAD family member 4 (SMAD4), transcription factor 7-like 2 (TCF7L2), NRAS proto-oncogene (NRAS), AT-rich interaction domain 1\u00a0A (ARID1A), SRY-box transcription factor 9 (SOX9), and APC membrane recruitment protein 1 (FAM123B) can also increase the risk of CRC  and western medicine are two different medical theoretical systems. The research model based on the etiological mechanism theory of TCM is applied to animal studies with TCM syndrome, as shown in Understanding the inherent advantages and limitations of the different models of CRC, and the appropriate application of these models in drug development and studies on the mechanism of tumor occurrence and development are important in CRC research.in vitro physiological or pathological models that closely represent the in vivo condition, and can be used for studying the interactions between cells, and between cells and the culture environment. It has been reported that 3D models can mimic the physiological characteristics of parental tumors, including tumor heterogeneity (in vivo.Human cell lines and xenograft models have been extensively employed over the past few decades owing to their low cost and ease of application. However, these models are incapable of reproducing the heterogeneity of CRC tumors . The celogeneity . Howeverogeneity . It is tThe intestinal microarray platforms used in CRC research, which consist of intestinal organoids and organic chips, can summarize the important structural features and functions of the natural duodenum. This platform can be applied for studying drug conveyance, metabolism, and drug-drug interactions . Multi-lin situ models and the cell and tissue transplantation models of CRC. Owing to the relatively simple modeling approach of human tumor xenotransplantation, this model is presently widely used for studying the efficacy of anti-CRC drugs. The effects of CRC xenotransplantation can be closely related to clinical activity via the rational application of these models. For instance, genetically engineered murine models have been used for studying the progression of tissue-specific molecular changes in CRC by determining the effect of specific molecular targets. Chemical induced-CRC animal model is one of the most commonly CRC models, in which CAC model is usually induced by AOM/DSS to study the mechanism of inflammation related-tumorigenesis and development (Animal models of CRC have been widely used for studying the complexity of CRC. There are primarily two types of animal models, namely, elopment . The CRCelopment . Mouse ielopment .The application of molecular tools and genetic strategies has aided the advancement of cancer research, and the cellular and animal models of CRC are being continually improved. Further understanding of the genetic and epigenetic events in CRC, including the alterations in molecular networks associated with the initial stages of development, are facilitated by high-resolution approaches.in vivo and in vitro models in CRC research, combined with advanced scientific techniques for simulating a more realistic tumor environment in vivo and in vitro, can help replicate the complex scenarios of tumor occurrence and development, identify novel therapeutic approaches for inhibiting tumor growth, and elucidate the molecular mechanisms underlying tumor formation.Although CRC research has advanced immensely in recent years, several clinical issues remain to be resolved to date, which is partly attributed to the absence of suitable preclinical research models. The application of"}
+{"text": "The human exposome represents the totality of all environmental exposures over a lifetime, from conception to death, and the effect of these exposures on human health and disease , 2. In rIn this Research Topic, we invited original research, commentaries, and opinions to demonstrate the multidisciplinary nature of exposome research and the challenges in the use of metabolomics for this endeavor. Here, we highlight some of these aspects with emphasis on methodological and technological developments, data processing approaches, and the role of environmental, dietary, and occupational exposures.Price et al., aiming to address the lack of high-resolution electron ionization mass spectral libraries (HR-[EI+]-MS) for environmental chemicals, constructed a retention-indexed HR-[EI+]-MS library following analysis of authentic compounds via GC-Orbitrap MS. The library is freely provided alongside a compound database of predicted physicochemical properties and offers a significant resource to the research community as an open science and open-source tool. Currently, the library contains over 350 compounds from 56 compound classes and includes a range of legacy and emerging contaminants. The RECETOX Exposome HR-[EI+]-MS library expands the number of freely available resources for use in full-scan chemical exposure studies and is available as described in the manuscript.One of the greatest challenges of metabolomics and exposome research is metabolite identification and the lack of suitable metabolite libraries and databases for this purpose. In the field of GC-MS, EI mass spectra have been compiled in libraries for years, however, most of these spectra have been reported at low resolution. Nikou et al., the authors used state-of-the-art metabolomics methodologies to identify chemical biomarkers characteristic of geographical origin, cultivation practice, and production procedure of olive oil, a part of the Mediterranean diet that has been characterized as a healthy dietary pattern. Metabolomic profiling with Flow Injection Analysis - Magnetic Resonance Mass Spectrometry (FIA-MRMS) and LC-Orbitrap MS platform were used to analyze intact oil and the corresponding polyphenols of Extra Virgin Olive Oils. The methodology has the potential to offer a tool to tackle food fraud and adulteration and to also identify components of healthy dietary patterns.Metabolomics offers unique opportunities to identify food constituents and understand their role in the dietary exposome and food quality. In the manuscript by Borroni et al., the authors evaluated the effect of night shift work on the serum metabolome in a population of Italian female nurses working on night shifts and female colleagues not employed on night shifts, demonstrating differences in the levels of taurine, serotonin, aspartic acid, and some lipids, all of which offer clues on the biological alterations involved in shift work.An important part of the exposome is occupational exposures and patterns, including shift work, which in recent years has been associated with several physiological changes and potentially correlating with several diseases. In the manuscript by Barupal et al., the authors demonstrated that the re-processing of metabolomics datasets, already published and publicly available, can change the number of metabolite identifications made and potentially uncover new biomarkers that may have been missed during the initial processing. The authors used MS-Dial for data pre-processing, a publicly available software, and applied less stringent data processing thresholds compared with the original data pre-processing approach that used the mass spectrometer manufacturer's software. The manuscript demonstrated the opportunities and also the challenges that arise from the fact that different software and even slight changes in pre-processing parameters can impact the quality and volume of data reported. The manuscript initiated a lively debate with two further commentaries by Keski-Rahkonen et al. and Barupal, which contributed to the overall metabolomics community discussions about methodologies, software and parameters of data pre-processing, reporting standards and formats, and inter-comparability between data pre-processing methodologies.In the manuscript by The study of the exposome and metabolomics is remarkably multidisciplinary and fast-moving, and this Research Topic captured some of the recent exciting developments and concepts in the field. We believe that the reader will find this Research Topic to be a useful reference that can inspire future research and innovations.This manuscript was initially written by AS. Manuscript was revised and edited by HK, RK, BW, and LM. All authors contributed to the article and approved the final submitted version."}
+{"text": "Among the neurophysiological methods of investigating the brain, electroencephalography (EEG) and quantitative electroencephalography (QEEG) are known for showing constant increases in sensitivity and specificity, and exponential advancement in clinical utility. Detection and interpretation of the human brain waves using EEG allows a deeper understanding of brain functioning. Building on this, QEEG involves the use of various algorithms leading to the transformation of brain waves into numerical data, which can be analyzed to gain insight into signal complexity, neural networks, and connections within the human brain. The technique has been applied extensively in clinical settings, including the study of neuropsychiatric disorders, human behavior, epilepsy, stroke, or traumatic brain injury.Neurotechnology connects a wide variety of fields aiming to diminish the existing gaps in neurosciences, from medicine and psychology to assistive technologies, engineering, and artificial intelligence. Its objective is to investigate brain principles from bench to bedside, promoting a thorough understanding of cerebral processes, and the development of innovative technologies with experimental and clinical applications.EUNeurotech, the European University of Brain and Technology, brings together nine prominent universities and a large variety of stakeholders covering all European regions. The goal is to facilitate collaboration among all interested stakeholders  thus establishing a complex European network of neuroscientific excellence focusing on neurological research and technology. The project fosters a competitive, diverse, and multilevel approach to achieve its goals.EU and Erasmus+ Programme, the University of Medicine and Pharmacy Iuliu Ha\u021bieganu (UMFIH) organized the second edition of the QEEG Summer School (QEEGSS) between the 17th and 21st of July 2023 in Cluj-Napoca, Romania.After a successful first edition in 2022, developed as a Blended Intensive Program (BIP) in the framework of NeurotechEU Alliance, while one came on demand from Cologne University.The educational program, coordinated by Prof. Dr. Dafin Mure\u0219anu and Dr. Livia Popa, assembled 25 junior researchers from six countries: France \u2013 Lille University (7 delegates), Germany \u2013 Bonn University (3 delegates), Cologne University (1 delegate), the Netherlands \u2013 Radboud University (1 delegate), Iceland \u2013 Reykjavik University (4 delegates), Spain \u2013 Miguel Hern\u00e1ndez University (4 delegates), and Romania \u2013 UMFIH Cluj-Napoca (5 delegates). Most candidates had a bachelor\u2019s degree in medicine, psychology, bioengineering, biotechnology, industrial technology, or biological sciences. However, a few medical students were also admitted to the program. Among the participants, twenty-four were affiliated with universities from the NeurotechThe training adopted a basic-to-intricate approach, starting with the fundamentals of EEG and progressing to different types of QEEG analysis , and the association of QEEG with other technologies  and eye tracking).The educational event was strategically designed to maximize engagement and active learning. Each day included morning lectures followed by interactive hands-on sessions in the afternoon in two locations: the RoNeuro Institute for Neurological Research and Diagnostic and UMFIH. This format was maintained over a four-day period. On the fifth day, the participants presented their projects and were evaluated regarding their understanding of the course content, acquired skills, approach to the project, presentation skills, and originality. Subsequently, the winning team was established and awarded for their efforts.BrainVision Analyzer 2 and MATLAB toolboxes , and engaged in team-oriented activities that promoted multidisciplinary learning and exchange of skills.During the program, the participants became familiar with various QEEG analysis tools, such as The curriculum content was structured in:EEG Basics;Theoretical Foundations of QEEG;QEEG Analyses;QEEG and Other Technologies;Group Projects on QEEG.To ensure seamless implementation, the following technical resources were made available: complete equipment for EEG recording on 21-channels (Neurosoft \u2013 LIAMED), respectively 32 channels , and BrainVision Analyzer Educational Licenses offered with the courtesy of Brain Products GmbH, wherewith the preprocessing steps were accomplished. Brainstorm application for feature analysis along with the R programming language was preferred for further processes.EU Alliance.The opening of the event took place at the RoNeuro Institute for Neurological Research and Diagnostic, a prestigious institution affiliated with UMFIH and a scientific partner of the NeurotechThe QEEGSS was organized under the guidance of Professor Dr. Dafin Fior Mure\u0219anu, the Chairman of RoNeuro, Chairman of the Neuroscience Department at the UMFIH, President of the Society for the Study of Neuroprotection and Neuroplasticity (SSNN), and President of the European Federation of NeuroRehabilitation Societies (EFNR). Dr. Livia Popa, neurophysiologist and researcher, lead of the QEEG Lab at the RoNeuro Institute, emphasized in the opening remarks the enthusiasm and motivation of the local team  in organThenceforward Dr. Popa pinpointed the primary objective of the QEEGSS, which is to deliver a comprehensive introduction to the field of QEEG for a better understanding of brain activity and inform on its wide-ranging applications in clinical practice and research. The activities covered during the summer school were then presented, namely the exploration of data collection intricacies and analyzing techniques (preprocessing and processing) and acquisition of experience in QEEG interpretation, along with the possible integration of these findings into clinical practice and more advanced topics, such as source localization and connectivity analysis. The QEEGSS students were randomly assigned to teams and worked together for the following five days on common projects fostering a spirit of cross-disciplinary learning and multidisciplinary cooperation.The Paradigm of Brain Technology and Neuroscience focused on the importance of collaboration between neurodisciplines grouped around the technology-dominated core. As the main scope of the European University of Brain and Technology is bridging European communities of young neuroscientists, UMFIH Cluj-Napoca plays a key role in reinforcing this position by elaborating translational and clinical research projects in several centers of excellence, such as:The initial presentation, Centre for Translational Research in Neurosciences;Centre for Research on the Dissemination of Drug-Related Information;Centre of Research in Functional Genomics, Biomedicine and Translational Medicine;Centre for Experimental Medicine and Practical Skills;MedFUTURE \u2013 the Research Centre for Advanced Medicine.EU through its various research groups focusing on EEG, QEEG, TMS, Eye tracking, Cervical and Transcranial Sonography, besides the keen interest in Cerebrovascular Diseases, Cognitive Neurology, Neurotraumatology, Neurorehabilitation, and Neuroepidemiology.The RoNeuro Institute for Neurological Research and Diagnostic represents an additional fundamental pillar of support for neuroscientific research and education materialized by the close collaboration with UMFIH and NeurotechNeurobiology of EEG Signals. Dr. Livia Popa then offered a detailed presentation of the EEG Basic Concepts, where she illustrated the Montage selection \u2013 the arrangement of electrodes on the scalp to record EEG signals; the Acquisition of EEG signals \u2013 proper electrode placement, amplifying and filtering the signals to obtain accurate data; Patterns identification \u2013 recognizing different patterns, such as alpha, beta, theta, and delta brain oscillatory activity  and/or epileptic discharges; Types of activity \u2013 alertness, resting state, drowsiness, sleep or seizure; Artifacts \u2013 electrode pop, electrode bridge, physiological artifacts , as well as noise coming from electrical interference; and Clinical applications \u2013 epilepsy, sleep disorders, brain tumors, traumatic brain injury, stroke, encephalopathies of different etiologies.After the introductory lecture that placed QEEG in the contemporary neurotechnological context, Dr. Diana Chertic explained the The second part of the day focused on analyzing a live EEG recording . SubsequData Preprocessing, Artifact Rejection, and Reduction . Her introduction to QEEG was complemented by a brief presentation by Dr. Diana Chertic on artifact removal through the application of Independent Component Analysis (ICA) and Principal Component Analysis (PCA). The theoretical part of the day was concluded by Dr. Victor D\u0103bal\u0103 with a captivating lecture about Frequency Domain and Time-Frequency Domain Analysis, referring to the Fast Fourier Transform (FFT), the Dot Product, the Convolution Theorem, and the Construction of Wavelets. During the afternoon hands-on session, each student performed QEEG Signal Preprocessing in BrainVision Analyzer 2 and Brainstorm.Dr. Livia Popa marked the start of the second day by highlighting specific methods of The third day of the intensive course brought a deeper perspective into QEEG's clinical and research applicability.Frequency-Domain Connectivity. She also covered the topics of correlation, cross-correlation, transfer entropy, mutual information, and Granger causality, which are included in Time-Domain Connectivity, along with explaining what a connectivity matrix represents. The theoretical discussions were complemented by clinical cases that illustrated the applications of QEEG in daily neurological practice. These cases sparked lively debates on differential diagnoses, ranging from neurodevelopmental to neurodegenerative disorders.The first two presentations, delivered by Dr. Hanna-Maria Drago\u0219, referred to the possibilities of neuronal communication through synchronicity modulation (coherence), which is included in Electrophysiological Source Imaging detection, providing several EEG source localization tools for participants.Dr. Diana Chertic continued the day with a presentation on Data \u2013 from Brainstorm to R, Stud. Vlad Chelaru demonstrated a workflow for the integration of Brainstorm computations with frequentist statistical analysis software, exporting QEEG-based indexes  in a format compatible with other software packages such as R.Later on, through his presentation QEEG Feature Extraction, led by Dr. Victor D\u0103bal\u0103 and Dr. Diana Chertic concluded the day. Participants had the opportunity to transform the time series data  into topographical maps and numerical data using BrainVision Analyzer 2 and Brainstorm algorithms.A workshop on The fourth day focused on blending Quantitative means of EEG analysis with complementary investigative technologies. Therefore, the presentation of Dr. Irina Vlad covered a wide array of technologies that might be utilized alongside QEEG: Functional Magnetic Resonance Imaging (fMRI), Functional Near-Infrared Spectroscopy (fNIRS), Transcranial Direct Current Stimulation (tDCS), Transcranial Alternating Current Stimulation (tACS), and Magnetoencephalography (MEG). She provided a comprehensive introduction to these technologies offering additional means of exploration when paired with QEEG. Dr. Vlad`s overview encompassed their development, functionalities, and mechanisms, in addition to the research applications. Her display, followed by two other lectures \u2013 QEEG & Transcranial Magnetic Stimulation (TMS) delivered by Dr. Anca Demea and QEEG & Eye Tracking (ET) presented by Dr. Emanuel \u0218tef\u0103nescu \u2013 sparked considerable interest among the audience. The majority of the participants actively engaged by asking questions and sharing their own experiences.The second part of the day was dedicated to teamwork and project coordination. QEEGSS students had the opportunity to cooperate in 5-member groups, applying the knowledge and skills acquired during the first three days. While working on their project proposals, they utilized transversal competencies such as critical thinking, decision-making, problem-solving, and creativity.The fifth and final day of the QEEGSS testified to the power of collaboration, innovation, and relentless pursuit of knowledge. This day was dedicated to project presentation, as each team was randomly assembled at the beginning of the week to foster a spirit of cooperation and cross-disciplinary learning.Throughout the week, each team worked diligently on their assignments, their efforts extending into the evenings following the day\u2019s theoretical courses and hands-on sessions. The result was a rich tapestry of unique projects, reflecting the diverse skills and perspectives of the team members. The projects provided refreshing insights into EEG analysis, including innovative approaches to EEG signal cleaning through ICA, meticulous manual artifact-free epoch selection, and insightful comparisons of absolute and relative spectral densities.One team, demonstrating a commendable spirit of independence and technical acuity, chose to use the Python MNE package for their analysis in lieu of the BrainVision Analyzer and Brainstorm software. This decision allowed them to execute their analysis in a more controlled manner and across different operating systems, including macOS or Linux-based distributions. Another team engaged in a thoughtful critique of one literature study that focused on the same data set as the participants. They proposed several ways to mitigate the identified limitations, demonstrating a deep understanding of the subject matter and a critical approach to scientific research. This team's exceptional work earned them the winning position, and they were duly awarded for their achievement .A key takeaway from the day\u2019s presentations was the importance of standardizing analysis methods in QEEG research. Given the subjectivity of some steps, such as artifact interpretation, and the wide range of software available for analysis, one participant highlighted the need for clear and detailed descriptions of the steps used in QEEG analysis. This would ensure transparency and reproducibility, contributing to the robustness of the scientific literature in this field.At the end of the course, the students completed an online evaluation questionnaire that assessed learning outcomes and their level of satisfaction with the entire event.The closing ceremony  was offiThe 2023 QEEG Summer School was a journey of discovery, a celebration of collaboration, and evidence of the power of innovative thinking in advancing scientific understanding.EU is an educational event that confirms the strong interest of young scientists from the European consortium in exploring the intricacies of the human brain. Year after year, quantitative means of exploring neural data will gain more ground on the boundary of neuroscience and biotechnology, defining a new area in exploring brain functionality.The second edition of QEEGSS  in the fThrough the implementation of these intensive educational programs, the scientific alliance is empowered to foster an environment of academic excellence and intellectual growth as well as be a catalyst for significant achievements in the field of neurotechnology through multidisciplinary collaborative endeavors."}
+{"text": "The Inter European Union Reference Laboratories (EURLs) Working Group on Next Generation Sequencing (NGS) involves eight EURLs for microbiological food and feed hazards and has been working since 2017 to promote the adoption of NGS by the National Reference Laboratories (NRLs) in the European Union. This work illustrates the results of the first 5\u2009years of activity. By working together, the EURLs involved have released guidance documents for assisting NRLs in all the steps of NGS, helping the transition from classical molecular methods towards whole genome sequencing while ensuring harmonization, with the final aim of improving preparedness in the use of NGS to characterize microbial hazards and trace the sources of infection. The authors confirm all supporting data, code and protocols have been provided within the article.The Inter European Union Reference Laboratories (EURLs) Working Group on Next Generation Sequencing (NGS) involves eight EURLs for microbiological food and feed hazards and has been active since 2017 on a mandate of the European Commission for promoting the adoption of NGS across the respective National Reference Laboratory (NRL) networks in the European Union, by building capacity and ensuring harmonization of procedures. Here, we present the main achievements of the working group at the current stage and plans for the future, mainly consisting of offering continuously updated resources as guidance documents, reference genome sequences and training opportunities, contributing to the growing ability of the NRLs to apply NGS technology for diagnosing and/or tracing microbiological foodborne infectious diseases in Europe.The global surveillance and outbreak investigation of infectious disease agents, including viral, parasitic and bacterial pathogens, and associated antimicrobial resistance (AMR) in a One Health context is currently amid a paradigm shift from traditional microbiology to genomics. The transition started around 2010 with the introduction of affordable benchtop next-generation sequencing (NGS) platforms. A decade later, this technology represents a powerful all-in-one solution to obtain complete characterization of microbial pathogens at lower costs and often in shorter time than with traditional microbiology. However, as with all molecular methods, its adoption in routine monitoring of infectious disease agents in food and animals and in outbreak investigations aimed at source tracking requires optimization and harmonization.The European Union Reference Laboratories (EURLs) for food and feed hazards are designated according to Regulation (EU) 2017/625 of the European Parliament [Escherichia coli including Shiga-toxin-producing E. coli, Listeria monocytogenes, coagulase-positive staphylococci, Salmonella, Campylobacter, foodborne parasites, AMR and foodborne viruses. The location of the EURLs involved in the WG is detailed in In 2017, the \u2018Inter-EURLs Working Group (WG) on NGS\u2019 was established based on a mandate by the European Commission (EC), with the aim to promote the use of NGS across the EURLs\u2019 networks, by building capacity and ensuring harmonization of procedures within the EU. The WG consists of representatives of eight EURLs for the following microbiological hazards: The WG meets twice a year, with the aim of coordinating activities and providing guidance documents for the organization of NGS-based proficiency tests (PTs), for the application of NGS laboratory procedures and analytical bioinformatics tools and for benchmarking analytical methods, while following the activities for the development of ISO 23418\u200a:\u200a2022 \u2018Whole genome sequencing for typing and genomic characterization of bacteria\u2019 [in vitro amplification steps.The level of adoption of NGS across the NRLs was estimated by launching a survey in spring 2018 and subsequently by monitoring the participation in the PTs for NGS-based methods organized by the EURLs . About hIn detail, EURLs for coagulase-positive staphylococci, parasites and foodborne viruses reported ongoing progress throughout their networks since 2018, when fewer than ten NRLs per network had declared as having access to NGS. This improvement was mainly achieved due to participation in research projects, which are expected to provide tangible preparedness in the next couple of years.E. coli website [The use of established protocols in the production and the analysis of NGS data is essential to achieve comparability of results, which is particularly important for example in the framework of an outbreak investigation. With the aim of supporting the NRLs, since 2020 the Inter-EURLs WG on NGS has released and routinely updated a collection of guidance documents, as detailed below. All these documents are published on the web pages specifically dedicated to the activities of the WG, present on the websites of each of the involved EURLs. An example is represented by the page included in the EURL for  website , linkingThe availability of high-quality nucleic acids (DNA/RNA) is a prerequisite for the successful application of NGS methodologies. Due to the large biological differences among bacterial, viral and parasitic pathogens, different methods are required, in particular for uncultivable target organisms. A guidance document was prepared by gathering Standard Operating Procedures (SOPs) generated during previous EU projects, such as COMPARE , ENGAGE The bioinformatics tools most used for NGS data analyses, including quality checking, trimming, assembly, multi-locus sequence typing (MLST), virulotyping, serotyping and identification of AMR genes, were referenced in a guidance document . In addiA further guidance document that aimed to inform and support NRLs in the choice of methods to be used for cluster analysis was released . This doE. coli, L. monocytogenes, Salmonella, Campylobacter and AMR all performed PTs focusing on prediction of: (1) specific subtypes ; (2) determinants ; (3) phylogeny based on SNPs or gene-by-gene approaches; and (4) genome quality metrics.Standardization of WGS procedures from DNA preparation to the final genome is pivotal to provide reliable data for surveillance and outbreak detection. To ensure the production of reliable high-quality genomic data, laboratories routinely applying NGS technology should participate in inter-laboratory studies or external quality assurance schemes (EQAs)/PTs. A document describing the approach used in genomics PTs at each of the EURLs and the experiences collected during the organization was published and will be routinely updated . The EURIn the future, the organization of PTs focusing on metagenomics approaches could be useful for the networks dealing with difficult-to-grow hazards, such as viruses and parasites.Different approaches were used to collect the PT results, in some cases requiring the submission of sequence files, in addition to analysed results, which poses problems of heavy data exchange and of workload for the analysis needed at the EURLs for evaluation. In other cases, the analysed results are submitted without exchanging sequence files, which provides an easier solution, though not allowing control of the quality of the sequence file(s) produced.A reference genome collection, useful for the validation and benchmarking of bioinformatics tools, was compiled. Sequences of different pathogens produced by participants of PTs organized by the EURLs are listed in the guidance document .EURLs and NRLs need to document the performance of the laboratory procedures and bioinformatics tools with appropriate and comprehensive benchmarking. The document \u2018Guidance document for WGS-Benchmarking\u2019  was prepde novo assembly. The document also includes statistical analyses to perform the benchmarking.The wet bench component includes any of the following processes: handling of strains, extraction of nucleic acids, fragmentation, barcoding (molecular indexing) of isolates, enrichment of targets for exome or gene panels, adapter ligation, amplification, library preparation, flow cell loading and generation of sequence reads. Sequence generation is almost entirely automated, and the output consists of millions to billions of short sequence reads. The dry bench workflow is followed by intensive computational and bioinformatics analyses that use a variety of algorithms to align the short sequence reads to a linear reference bacterial genome sequence, and to perform As NGS practices are not yet routine for several NRLs and are also in constant update, there is a need for NGS training. Since 2018, EURLs regularly organize training courses for their respective NRL network and the first joint training session with all the EURLs that are part of the WG was organized in 2022 focusing on dry lab analysis, with the aim of bringing NRLs together to ensure exchange of opinions and establishing fruitful collaborations. Moreover, a document  aimed atThis initiative has brought the EURLs together, allowing common strategies to be found to stimulate the adoption of NGS for monitoring microbiological foodborne pathogens. In 5\u2009years of activity, the WG has released guidance documents for assisting NRLs in all the steps of NGS, helping the transition from classical molecular methods towards genomics while ensuring harmonization. These resources are routinely updated on EURL websites, making them available for any laboratory wishing to follow the same path, with the aim of contributing to improve preparedness in the use of NGS to characterize microbial hazards and trace the sources of infection."}
+{"text": "Salvia hispanica L.) and Lacticaseibacillus paracasei on intestinal functionality, morphology, and bacterial populations, in vivo  [Acrocomia aculeata) pulp oil to prevent adipogenesis, inflammation and oxidative stress in mice fed a high-fat diet [Malus domestica) juice, pomace, and pulp and the modulation of intestinal functionality, morphology, and bacterial populations in vivo  [Salvia hispanica L.) associated with high-fat diet on the intestinal health of wistar rats [Gallus gallus) [Zea mays L.) on cecal microbial populations in vivo  [Gallus gallus) of catechin and its derivatives [Vitis labrusca L.) puree, juice, and pomace on intestinal morphology and functionality, and on bacterial populations in vivo  [Gallus gallus) of genistein alters mineral transport, intestinal morphology, and gut microbiota [Gallus gallus) of nicotinamide riboside and its derivatives [This monograph, based on a Special Issue of Nutrients, contains 16 manuscripts\u20142 review manuscripts and 14 original research manuscripts\u2014that reflect the wide spectrum of currently conducted research in the field of Emerging Dietary Bioactives in Health and Disease. The manuscripts in this Special Issue collection include contributions from researchers from multiple countries, including the USA, Brazil, United Kingdom, Italy, Norway, China, and Israel. The presented manuscripts cover a wide variety and range of topics in the field of dietary bioactives in health and disease, with emphasis on the investigation of the effects hydrolyzed protein of chia  ; the efftar rats ; the int gallus) ; the inv gallus) ; the dem gallus) ; the altivatives ; the per gallus) ; the demcrobiota ; the occivatives ; and an Plant-based diets contain wide varieties of metabolites that may impact on health and disease prevention. Most are focused on the potential bioactivity and nutritional relevance of several classes of phytochemicals, such as polyphenols, flavonoids, carotenoids, phyto-oestrogens, and frucrooligo-saccharides . These cThis Special Issue and collection of manuscripts constitutes a useful summary of progress in various areas related to emerging dietary bioactives in health and disease."}
+{"text": "Ischemic heart disease is one of the leading causes of morbidity and mortality worldwide. Continuous advances in diagnostic, prognostic and therapeutic methods have led to an improvement in patient outcomesover the past few decades.In recent years, developments in molecular assessments, laboratory assays and imaging techniques have enabled a comprehensive characterisation of ischemic heart disease. Circulating biomarkers involved in the pathogenesis of CAD (coronary artery disease) have the potential to detect the disease in its early stages: inflammatory markers, biochemical markers (proteins), epigenetic markers , and transcriptional markers (gene expression) . CardiovThis Special Issue explores some of the latest research on the diagnosis of coronary artery disease.Calmac et al.  discuss An important section of this Special Issue is dedicated to the implications of myocardial bridge in patients with CAD . The myoFinally, the systematic review by Kampmann et al.  addresseAll papers presented in this Special Issue emphasise the importance of diagnostic techniques in CAD allowing for patient-tailored treatment, and thus reducing ischemic-heart-disease-related complications and improving patient outcomes. Advances in diagnostic techniques and the management of these patients may substantially reduce the burden of cardiovascular diseases in the future."}
+{"text": "Obsessive-compulsive disorder (OCD) is a disorder diagnosed on the basis of the presence of obsessions  and compulsions (compulsive and transiently satisfying actions performed in response to obsessions). A separate clinical phenomenon in the broadly understood anankastic spectrum is obsessive-compulsive disorder (OCPD). OCPD is characterized by scrupulousness, over-normative morality, perfectionism and an inability to make concessions in terms of cooperation. It is assumed that the incidence of OCPD in the course of OCD is 25-32% and it is a report with an unfavorable course and a more difficult therapeutic prognosis. It also means an early onset of OCD with a greater intensity of compulsions and a predominance of symptoms related to the sphere of purity, symmetry and gathering.The main aims of the study were as follows:1. To assess the prevalence of OCPD in OCD patients.2. To compare both groups of patients for the severity, level of insight, aggression, impulsiveness and affective symptoms.3. To verify whether the presence of OCPD depend on factors such as age, gender, treatment duration and delay in starting treatment.-Brown Obsessive Compulsive Scale (Y-BOCS), Hamilton Depression-Rating Scale (HDRS), Young Mania Rating Scale (YMRS), Buss-Perry Aggression Questionnaire (BPAQ), Barratt Impulsiveness Scale (BIS-11), Brown Assessment of Beliefs Scale (BABS) and DSM 5 criteria for OCPD.The study was conducted in a group of 78 patients diagnosed with and treated for OCD. The patients were divided into two groups: patients with OCD and OCPD  and patients with OCD without OCPD . The groups were subsequently compared for the severity of anankastic symptoms, the level of insight, aggression, impulsiveness and its components and affective symptoms . The following tools were used for the diagnosis: YaleOur results confirmed that OCPD is common in OCD and occurred in 55,12% of patients with OCD . The study shows that the presence of OCPD in the course of OCD negatively affects the severity of obsessive-compulsive symptoms, the level of insight, the level of aggression and impulsiveness, and affective disorders. Patients with OCPD obtained higher scores on the YBOCS, BABS, HDRS, and YMRS scales compared to patients with OCD without OCPD. The occurrence of OCPD in the study group did not depend on gender, duration of OCD treatment, or delay in starting it.The occurrence of OCPD is common in OCD and can cause delay of treatment, worse course, greater intensity of egosyntonic symptoms, and thus worse insight. The presence of OCPD can lead to more hostility and more affective disorders. Screening for OCPD in patients with OCD should be an integral part of an OCD diagnostic process.None Declared"}
+{"text": "The sudden and large-scale Russian invasion of Ukraine has caused significant stress not only in Ukrainians but also in citizens of countries which have received the largest numbers of refugees.The aim of the current study was to identify stress, resilience, and self-efficacy levels, as well as to examine the relationships between these variables, in a sample of women from Ukraine, Poland, Slovakia, and Romania during the third month of Russian aggression on Ukraine.Perception of Stress Questionnaire, the Brief Resilience Scale, and the Generalized Self-Efficacy Scale in May 2022.The study involved measuring a sample of Ukrainian (N = 82), Polish (N = 102), Slovak (N = 79), and Romanian (N = 42) women using the The results showed that during the third month of Russian aggression on Ukraine, stress levels and its components  were the highest among Ukrainian women and the lowest among Polish women. The sense of self-efficacy was the lowest among Ukrainian women and highest among Polish women, while resilience was the lowest among Ukrainian women and the highest among Slovak women.Women from Ukraine reported being in the worst mental state compared to the rest of the sample. Moreover, a path analysis of the measured variables points to a multifaceted relationship between stress, resilience, and self-efficacy among women from Ukraine, Poland, Slovakia, and Romania during the third month of the Russian invasion.None Declared"}
+{"text": "The Horn of Africa is a large area of arid and semi-arid land, holding about 10% of the global and 40% of the entire African livestock population. The region\u2019s livestock production system is mainly extensive and pastoralist. It faces countless problems, such as a shortage of pastures and watering points, poor access to veterinary services, and multiple endemic diseases like foot-and-mouth disease (FMD). Foot-and-mouth disease is one of the most economically important livestock diseases worldwide and is endemic in most developing countries. Within Africa, five of the seven serotypes of the FMD virus (FMDV) are described, but serotype C is not circulating anymore, a burden unseen anywhere in the world. The enormous genetic diversity of FMDV is favored by an error-prone RNA-dependent RNA polymerase, intra-typic and inter-typic recombination, as well as the quasi-species nature of the virus. This paper describes the epidemiological dynamics of foot-and-mouth disease in the Horn of Africa with regard to the serotypes and topotypes distribution of FMDV, the livestock production systems practiced, animal movement, the role of wildlife, and the epidemiological complexity of FMD. Within this review, outbreak investigation data and serological studies confirm the endemicity of the disease in the Horn of Africa. Multiple topotypes of FMDV are described in the literature as circulating in the region, with further evolution of virus diversity predicted. A large susceptible livestock population and the presence of wild ungulates are described as complicating the epidemiology of the disease. Further, the husbandry practices and legal and illegal trading of livestock and their products, coupled with poor biosecurity practices, are also reported to impact the spread of FMDV within and between countries in the region. The porosity of borders for pastoralist herders fuels the unregulated transboundary livestock trade. There are no systematic control strategies in the region except for sporadic vaccination with locally produced vaccines, while literature indicates that effective control measures should also consider virus diversity, livestock movements/biosecurity, transboundary trade, and the reduction of contact with wild, susceptible ungulates. The language in which the search was performed was specified as English. The search items were limited to fully accessible manuscripts or reports. The time period for the literature to be retrieved electronically was set between 1 January 1999, and 9 March 2023.The key words used per the sections were as follows: Introduction: Livestock production system in East Africa OR Horn of Africa OR animal Product supply and demand Horn of Africa OR Livestock provides milk, meat, draft power OR Livestock Sector Report Horn of Africa OR FMD host range and pathogenesis OR FMD prevalence in the Horn of Africa OR Ethiopia OR Kenya OR Uganda OR Eritrea OR Sudan OR South Sudan. Serotype or topotype diversity: Serotype/topotype O or A OR SAT 1, 2,3 Horn of Africa OR Ethiopia OR Kenya OR Sudan OR South Sudan OR Eritrea OR Djibouti OR Uganda OR East Africa. Acute and persistent infection: Acute infection in cattle FMDV epidemiology OR Between animal and farm transmission of FMD OR FMD in carrier and persistent state OR Acute and persistent infection. Livestock movement and trade: Foot-and-mouth disease livestock movement OR pastoralism and livestock disease in East Africa OR foot-and-mouth disease virus dispersal in East Africa OR Cross border livestock movement in Africa. Wild animals and FMDV: Wild animals and foot-and-mouth disease in East Africa OR Role of wild ungulates for foot-and-mouth disease epidemiology OR Viral disease and African ungulates. FMD vaccines: Foot-and-mouth disease vaccines in East Africa OR Foot-and-mouth disease vaccines in Ethiopia OR Foot-and-mouth disease vaccine strain selection in East Africa. For the remaining sections, global FMD distribution OR FMD distribution, was used. In total, 210 articles were retrieved, and after applying the inclusion  and exclusion (outside the horn area and not related to the mentioned factors) criteria, 102 citations were considered potentially eligible for inclusion in this review. In addition, for the most recent laboratory reports on the WRLFMD web site , some articles were searched manually using the Google Search engine .Articles published in peer-reviewed journals were obtained via the online search engines: Pub Med, Google Scholar, and the World Reference laboratory resource for foot-and-mouth Disease (WMRLFMD) website  is one of the most important contagious livestock diseases and has an important economic impact globally. FMD affects over 70 domestic  and wild  cloven-hoofed animals  and exisIn general, the genetic diversity of ribonucleic acid (RNA) viruses such as FMDV results from the error-prone replication process of the RNA-dependent RNA polymerase (RdRp), large population diversity, and high replication rate  as well In addition to the above, genetic recombination is another determinant in the generation of new variants. In FMDV 15, recombination events were more evident in the non-structural proteins than in the genes coding for the structural proteins (capsid) ,19. FurtExcept for Greenland, Iceland, New Zealand, and the smaller islands of Oceania, every region in the world has, at least once, experienced an FMD outbreak. The outbreak reports of 1929, 1952, 1954, and 1970 in the USA, Canada, Mexico, and Australia, respectively, marked the last outbreak of FMD in these countries. The last sporadic outbreak of FMD on the European continent dates from 2011, as the disease was eradicated in Europe in the 1980s ,28. GlobGlobally, FMD is distributed into seven virus pools, and within each pool, several serotypes of FMDV can be found ,30. AfriFMD is endemic in the Horn of Africa, with variable prevalence in different countries. In Ethiopia, seroprevalence studies using NSP ELISA range from 5.6% to 72.1% in cattle, from 4% to 11% in small ruminants, and 30% in ungulate wildlife ,39,40,41Syncerus caffer) was recorded to be 74% in Uganda .,62.59,62\u22123 nucleotide substitutions per site per year over 58 years was recorded (1958\u20132016) , inactivated with 0.3% of formaldehyde, and adjuvanted with saponin. The duration of protection of this vaccine is a maximum of six months  concentrate that is adjuvanted with saponin [The FOTIVAX of the KEVEVAPI FMDV vaccine is in the form of an aluminum hydroxide gel [Al(OH) saponin  and puri saponin . The FMD saponin . This va saponin . At leas saponin . For ser saponin ,51,71,89https://kevevapi.or.ke/fotivax/, accessed on 20 February 2023). However, in the Horn of Africa, vaccination does not always seem to be protective against FMD, not even in the peri-urban semi-intensive production system. Maintaining a sound biosecurity practice helps to prevent the introduction and spread of the FMDV into a particular farm or country [The KEVEVAPI duration of protection is 6 months, or every 4 months for better protection ( country .As reviewed by Ambaye Kenubih, the importance of both structural and non-structural proteins of the FMDV on both the cellular and humoral arms of the immune system should be studied for sterile and long-lasting immunity development . As reviFoot and mouth disease epidemiology in the Horn of Africa is complex as a result of serotype and topotype diversity. In addition to this, unrestricted animal movements and insignificant control approaches exacerbate the epidemiological dynamics of the disease. The Horn of Africa harbors five FMDV serotypes and more than twenty topotypes, with a continuous threat of the spread of new topotypes within the region. Countries such as Ethiopia, South Sudan, Sudan, and Kenya are known as hotbeds for the emergence of new FMDV strains in the region and in other regions as well. The livestock movement in the area within and between the regions is unrestricted due to diverse factors, of which the search for markets, watering points, and pastures is the most important. The presence of wild animals is the third major factor affecting the epidemiology of the disease. However, the presence of African buffalo in the Horn of Africa may have less of an effect on FMD infections in cattle in comparison to the southern part of Africa. The danger of FMD in the region is increasing because of high genetic diversity, poor husbandry, a poor control approach, no biosecurity practices coupled with unregulated trade, and pastoral herds movement in search of pasture and water as a result of recurring drought. To this end, early diagnosis and implementation of a suitable control approach need to focus on biosecurity."}
+{"text": "The global burden of disease (GBD) has shifted from communicable, maternal, perinatal, and nutritional causes to non-communicable diseases such as atherosclerosis or metabolic disease within the last 20\u201330 years , 2. In 2According to reports of the Lancet Commission on Pollution and Health , the WorThe present special issue provides an overview of the health effects of tobacco cigarette and shisha smoking, E-cigarette vaping, usage of other novel nicotine delivery systems, sedentary lifestyle or over-nutrition, and alcohol use with a focus on adverse effects on endothelial function and cardiovascular health. The negative effects of the toxic constituents of these tobacco (replacement) products, as well as the beneficial effects of exercise or fasting on different biological pathways, will also be discussed, especially regarding their impact on key vascular processes such as nitric oxide signaling, smooth muscle proliferation, remodeling, and atherosclerosis, in part driven by oxidative stress and inflammatory cascades. With the present Special Issue, we want to highlight the pathomechanisms underlying cardiovascular and metabolic disorders in response to environmental  risk factors and the existing research gaps. We will also emphasize emerging mechanisms based on dysregulation of epigenetic pathways by environmental lifestyle and behavioral risk factors.The overview provided by Daiber et al. highlights the threats and benefits of E-cigarette vaping in comparison with classical tobacco cigarette and shisha smoking . The toxFasipe et al. provide a review on the cardiometabolic health risks of sedentary lifestyle and the beneficial effects of physical exercise . The autLifestyle risk factors share common pathophysiological pathways centered on oxidative stress and inflammation. Oxidative stress and inflammation also represent hallmarks of all cardiovascular, neurodegenerative, and metabolic diseases. Due to this overlap of these central pathomechanisms, we may expect additive/synergistic adverse biochemical effects in response to environmental, lifestyle, and traditional health risk factors leading to aggravated pathogenesis of non-communicable diseases in a bonfire fashion , 33. Whe"}
+{"text": "Respiratory syncytial virus (RSV) is a leading cause of acute respiratory infections resulting in a significant burden worldwide, particularly in children and older adults. This collection calls for original research papers that advance our understanding of the epidemiology, evolution, diagnosis, clinical management, and prevention of RSV infections. Respiratory syncytial virus (RSV) is a leading cause of acute respiratory tract infection, including lower respiratory tract infection (LRTI). Before the coronavirus disease 2019 (COVID-19) pandemic RSV represented the fourth cause of overall disability-adjusted life-years at all ages .RSV annual epidemiology is also impacted by the alternation of the subtypes A and B and, within them, by genetic variations of strains or lineages . Indeed,Before the COVID-19 pandemic, the detection of RSV infections followed a predictable seasonal pattern each year. During the first year of the pandemic, respiratory viruses, including RSV, caused an unusually low number of infections and related hospitalizations in the first phase of the COVID-19 pandemic, due to the implementation of non-pharmaceutical interventions . The subCurrently, treatment of RSV infections relies on supportive care including supplemental oxygen, rehydration, and mechanical ventilation when critical. Antiviral treatment with aerosolized ribavirin is limited to severe infections in immunocompromised patients . Until rTM) for adults aged 60 and older and for pregnant women (AbrysvoTM) to protect infants from birth up to 6 months of age [On the vaccine front, after decades of troubled RSV vaccine development, four randomized clinical trials in older adults and pregnant women were recently published revealing a breakthrough in providing a high level of protection against RSV \u201315. The s of age .The recent advances and progress toward the prevention of RSV have re-energized the field and highlighted the need for continued research to better understand the disease as well as the epidemiology and evolution of RSV. Studies assessing the impact of the newly approved immunotherapeutic and vaccines on RSV burden and genetic diversity are critically needed. This collection calls for original research papers that aim to improve our understanding of RSV epidemiology, evolution, diagnosis, clinical management and prevention."}
+{"text": "The rapidly evolving field of Behavioral Neuroscience has made significant strides in understanding the complex mechanisms that govern human behavior, decision-making, and wellbeing. One area of particular interest is the study of Motivation and Reward, which has the potential to provide valuable insights into the underlying processes driving these behaviors. This Research Topic aims to highlight the latest advancements, challenges, and future perspectives in this area of study by showcasing a diverse range of original research and review articles submitted by esteemed researchers.Bessa et al. used Siamese Fighting Fish (Betta splendens) as a biological model to study hormonal fluctuations during foraging. They found that an optimal level of cortisol maximizes foraging performance, while extreme levels of basal cortisol, both low and high, are associated with reduced average reward . Importantly, to model foraging decisions, the authors applied the \u03b5-greedy algorithm  2013 data was used by Aslam et al. to conduct a Latent Class Analysis (LCA) for the entire sample of teenagers, as well as separately for each sex. In this original research article, the authors identified five subsets of youth engaging in risky behavior: those who do not engage in risky behavior , those with depressive symptoms and suicidal thoughts (Class 3), those with a high likelihood of using cigarettes and liquor (Class 4), and those who are polysubstance users (Class 5). Gender variations were also detected in the higher risk of mood disorders and depression among females.The manuscripts collected here encompass various aspects of Motivation and Reward, demonstrating the interdisciplinary nature of this field. Topics explored in the three original research articles include the application of machine learning techniques to understand the impact of stress hormones on animal behavior, the study of the differences between males and females in the long-term learning deficit induced by the co-exposure to the main consumed drugs during adolescence , and the role of race and ethnicity in shaping risk-taking behaviors in adolescents. Specifically, a first study by Weinstein, enriches the Research Topic of a comprehensive analysis of the literature on the fMRI studies conducted on healthy subjects, both on motivation and reward in tasks such as the Sequential choice task (Symmonds et al., Monetary incentive delay task (Mori et al., Monetary and verbal reward task (Albrecht et al., Reaction-time task with goal-irrelevant expectancy violations in states of high- or low-reward motivation (Murty and Adcock, Kibret et al., which illustrates an up-to-date scenario of this contribution. The role of motivation and reward in promoting healthy behaviors was timely addressed by Michaelsen and Esch, who provide an insightful critical reading on the throughput that goal-oriented, stimulus-driven, and approach motivation play in nudging (Hansen and Jespersen, The current state of neuroimaging research in the context of motivation and reward, reviewed by Collectively, the potpourri of original research and reviews included in this Research Topic provides a comprehensive overview of the current state of Motivation and Reward research. By highlighting the latest discoveries, developments, and future challenges, this Research Topic seeks to inspire further research, promote funding opportunities, and guide researchers in their pursuit of unraveling the complex mechanisms that drive motivation and reward. Furthermore, this Research Topic emphasizes the importance of interdisciplinary collaboration, incorporating perspectives from biosciences, life sciences, medicine, psychiatry, and the mind to facilitate a more comprehensive understanding of motivation and reward mechanisms. By fostering an environment of curiosity and open-mindedness, we hope to encourage the development of innovative approaches and solutions to the challenges faced in this rapidly advancing field.We believe that this Research Topic will serve as a valuable resource for researchers, academics, and professionals interested in the study of motivation and reward, providing direction and guidance for future investigations, and promoting the growth of knowledge in this essential area of Behavioral Neuroscience.MK: Writing\u2014original draft, Writing\u2014review and editing. EA: Writing\u2014original draft, Writing\u2014review and editing. LF: Writing\u2014original draft, Writing\u2014review and editing."}
+{"text": "The prevalence of oral squamous cell carcinoma (OSCC) has increased in recent decades, and its impact on the health system has become a new aspect. In addition to the well-known exogenous noxae like nicotine and alcohol consumption, as well as some distinct nutritional habits such as betel nut chewing and virus infection by the human papilloma virus (HPV), its transfer via sexual practices augmented the recent increase in the incidence of oropharyngeal cancer . FinallyIn parallel, our understanding of the initiation and development of oral cancer has also changed substantially. The molecular basis for the epithelial invasion mechanisms, including the epithelial\u2013mesenchymal transition (EMT) and remodeling of the extracellular matrix (ECM), not only intensified our knowledge concerning the underlying pathology but also brought more sophisticated diagnostic methods and prognostic tools, as well as promising therapeutic options for patients with OSSC ,3,4.The original research and review articles included in this Special Issue elucidate the diversity of molecular mechanisms involved in the onset, invasion, and progression of OSCC, with particular attention paid to the role of HPV infection and multimodal treatment. Finally, a state-of-the-art review of modern 3D-based microsurgical reconstruction following ablative oncologic surgery of the head and neck region enriches the scope of this Special Issue ,6. These"}
+{"text": "Since the first report in March 2020, Kenya experienced five waves of coronavirus 2019 (COVID-19), with cases and deaths reported in all 47 counties, amounting to 323\u2009000 and 5600, respectively, in late March 2022  function as an instrument of international law and provide a legal framework that binds member states . Its mon functionThe first COVID-19 IAR was conducted in Kenya from 31 May to 1 June 2021. Ninety-five from national and county levels participants attended the meeting with the Ministry of Health and multiple stakeholders ). The IAR in Kenya identified best practices and challenges, suggesting recommendations based on nine COVID-19 response pillars:Country-level coordination, planning, and monitoring;Risk communication, community engagement, and infodemic management;Surveillance, case investigation, and contact tracing;Points of entry;National laboratory system;Infection prevention and control;Case management and knowledge sharing about innovations and the latest research;Operational support and logistics in the management of supply chains and workforce resilience;Strengthening essential health services during the COVID-19 outbreak.Best practices were summarised in four points:Strong political will and support at national and county levels, enabling smooth COVID-19 operations and resource allocation;Strong coordination and partnership mechanisms;Early development and dissemination of guidelines, policies and Standard Operating Procedures (SOPs);Utilization of existing structures and resources, such as a legal framework for emergencies, coordination structures, infrastructure, previous capacities developed through training, and existing supply chain management.Conversely, the key challenges identified were as follows:Funding gaps and delayed disbursements, leading to inadequate resources;Lack of strong monitoring and evaluation systems;Inadequate supply chain management and lack of capacity for local manufacturing ;Inadequate data management systems including paper-based systems;Fast-evolving pandemic requiring prompt adaption of systems, infrastructure, guidelines, policies;Surge in cases and deaths by waves, with 5180 health worker infections and 40 deaths reported from all counties.While these findings were largely similar to outcomes in other WHO AFRO countries , some stThe IAR process was not an evaluation, but an open, honest reflection of key stakeholders on their contribution to the response. It helped with critically reviewing the prolonged COVID-19 response in Kenya and identifying areas for improvement without assigning blame, making honest reflection possible. The findings were successfully shared with multiple partners and senior management decision-makers, helping with the development of a COVID-19 resurgence plan, the review of response policies, guidelines, SOPs, and the application for funding.However, due to insufficient implementation of IAR recommendations to address the discovered gaps, several challenges identified from mid-2021 still have to be addressed. Since June 2021, the variant of concern (VoC) Delta became dominant in Kenya, and inadequate resources in surveillance, rapid response, and case investigation brought higher SARS-CoV-2 test positivity rate and hindered timely information sharing, adequate risk assessment and projections, effective public health actions, and data-driven decision-making. The high demand for intensive care units (ICUs) and medical oxygen highlighted issues in health service delivery and workforce, including manufacturing, procurement, and supply chain of medical oxygen. Regarding infection prevention and control (IPC), sub-optimal allocation of personal protective equipment (PPEs) contributed to a higher number of COVID-19 patients among health care workers.The emergence of the Omicron VoC from November 2021 also exposed critical challenges in laboratory pillar to detect new variants. The number of genomic sequencings did not reach the optimal level of over 100 sequences per month . Due to The IAR was able to identify cross-cutting issues across response pillars. Attendance of health sector partners added value to the overall pandemic preparedness and response. Strong leadership and governance to strengthen incident management structure and response capacity is a key area to achieving an effective coordination at national and sub-national levels. The use of home-based care during COVID-19 has brought positive opportunities and contributed significantly to reduce the burden on health facilities in the country and facilitated the engagement with the community. It is promising that findings from IAR were incorporated into the resurgence plan and were internally reviewed for launching the National Action Plan for Health Security. However, as the COVID-19 pandemic is expected to continue for years, regularly conducting IAR and reviewing the responses across pillars will be beneficial as a monitoring and evaluation tool to continuously improve on identified weak areas for health emergency response. Integrating the vaccine pillar into the next IAR at the national level will enrich the discussion.These challenges need to be addressed in view of building resilient and sustainable systems for health. Findings from the IAR should inform the review of existing health policies, strategies, and preparedness plans. Despite an initial huge impact, Kenya could gradually mitigate the impact of COVID-19 on essential health services (EHSs), setting a good example . SeveralThere have also been multiple health emergencies in Eastern Africa, such as outbreaks of yellow fever, cholera, dengue, rift valley fever, and drought in the Horn of Africa. To mitigate their impact on the lives and livelihoods of citizens, Kenya can reinforce and exert its leadership in public health at the regional level. Encouragingly, Kenya will host a second logistic hub which will equip emergency medical personnel, stockpile commodities, and equipment  and willIn conclusion, we recommend the following:The IARs, if conducted with participation of all responders and partners, enable countries to institute corrective measures during the emergency.Regular conduction of IAR and review of responses across pillars will help strengthen capacity in health emergency preparedness and response.Findings from the IAR must be fully utilised for health initiatives outside of health emergencies, as root causes of challenges are sometimes interlinked.The launch of new logistic hub and transfer of technology for vaccine production will elevate Kenya to exert its leadership in public health at the regional level."}
+{"text": "Social inclusion is a multidimensional concept, referring to ample participation in key social, cultural, economic and political activities. Since the turn of the century, social inclusion has become a guiding principle in policy recommendations of many international  and national bodies, aiming to improve the lives of people with mental ill-health. More recently, social inclusion has been increasingly used as an outcome measure, to test the effectiveness of complex interventions, especially in the field of global mental health.This presentation will focus on: (1) current definitions and controversies in research on social inclusion for and with people with mental ill-health; (2) measuring social inclusion; and (3) the evidence-base of interventions to improve social inclusion. Special attention will be given to recovery-oriented interventions in global mental health such as peer support.In summary, over the last years, impressive conceptual and methodological advances have been made to transform policy rhetoric into meaningful and effective interventions. However, challenges remain, including consensus on culturally appropriate measurement of social inclusion, and balancing the roles and responsibilities of all stakeholders  across the entire exclusion-inclusion continuum to promoting social inclusion and mental health.None Declared"}
+{"text": "Although mastectomy is a treatment for the cleaning of cancer cells in the breast, it can also cause psychological changes in women.This research was carried out to investigate the cognitive distortions, mental symptoms, and marital adjustment relationships in women with mastectomy.The descriptive and comparatice study was conducted in a public hospital with 90 mastectomies and 90 healthy female samples. The data were collected using The Cognitive Distortions Scale (CDS), The Brief Symptom Inventory (BSI), and Marriage Adjustment Scale (MAS) and were evaluated by descriptive statistical analyzes, t test, Mann-Whitney U test and Spearman Correlation Analysis.Women with mastectomy scored high in the healthy control group in all sub-dimensions of CDS and BSI and this difference is highly significant . Women with mastectomy scored higher in total agreement sub-dimensions than the healthy control group and the difference between them was statistically significant . There ara positive, very strong and statistically significant relationships between all sub-dimensions of the CDS and the total sub-dimension scores of the BSI . There are positive, strong and statistically significant relationships between the sub-dimensions of the CDS and the sub-dimension of the agreement and the total score of MAS (r=681 and 734). There are strong and statistically significant relationships between the total and sub-dimension scores of the BSI and the sub-dimension and total score of the MAS\u2019s agreement .Cognitive distortions and mental symptoms are significantly higher in women with mastectomy, and cognitive distortions are associated with mental symptoms. Cognitive distortions and psychological symptoms scores, marriage adjustment scores and agreement sub-dimension scores increase in women.None Declared"}
+{"text": "Professor RNDr. Petr Nachtigall, PhD passed away on 28 December 2022. He was an internationally recognized expert in computational materials science; working at Charles University in the Department of Physical and Macromolecular Chemistry. We honor his memory. Professor Petr Nachtigall was an internationally recognized expert in computational physical and materials science. He received his PhD at the University of Pittsburgh. After returning to Prague, he worked at the J. Heyrovsky Institute of Physical Chemistry, later at the Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, and since 2009 at the Faculty of Science of Charles University where he was a major leader in the Charles University Centre for Advanced Materials. Petr has regularly published in the most prestigious scientific journals: he is the author of 181 well-recognized publications.Petr was a computational chemist who liked to solve materials chemistry problems in close collaboration with experimentalists and he was very successful in that. Where necessary, he implemented techniques beyond routine methodology. In particular, he found ways to overcome the limitations of density functional theory. Petr had wide-ranging expertise in computational chemistry and he advanced the understanding of adsorption complexes and reaction mechanisms in zeolites and metal\u2013organic frameworks at the molecular scale. His studies of new types of two-dimensional materials lead to an improved understanding of their very interesting properties, for example the superior lithium-storage properties of silicene nanosheets or utilization of two-dimensional zeolites for fabrication of new materials.Petr\u2019s theoretical insight into the synthesis of new materials contributed significantly to the discovery and theoretical explanation of the new ADOR (assembly-disassembly-organisation-reassembly) method of zeolite synthesis, thanks to which more than 10 new types of zeolites have already been synthesized. Petr received several awards during his career, including the Bed\u0159ich Hrozn\u00fd Prize for Basic Research (2015), the Prize of the Czech Minister of Education, Youth and Sports for significant results of basic research in natural sciences (2019) and the Donatio Universitatis Carolinae (2021).In Petr Nachtigall we lose not only an outstanding scientist, teacher, and mentor, but also a great person, a dear colleague and friend."}
+{"text": "The emergence of the infectious diseases, such as the novel coronavirus, as a significant global health threat has emphasized the urgent need for effective treatments and vaccines. As infectious diseases become more common around the world, it is important to have strategies in place to prevent and monitor them. This study reviews hybrid models that incorporate emerging technologies for preventing and monitoring infectious diseases. It also presents a comprehensive review of the hybrid models employed for preventing and monitoring infectious diseases since the outbreak of COVID-19. The review encompasses models that integrate emerging and innovative technologies, such as blockchain, Internet of Things (IoT), big data, and artificial intelligence (AI). By harnessing these technologies, the hybrid system enables secure contact tracing and source isolation. Based on the review, a hybrid conceptual framework model proposes a hybrid model that incorporates emerging technologies. The proposed hybrid model enables effective contact tracing, secure source isolation using blockchain technology, IoT sensors, and big data collection. A hybrid model that incorporates emerging technologies is proposed as a comprehensive approach to preventing and monitoring infectious diseases. With continued research on and the development of the proposed model, the global efforts to effectively combat infectious diseases and safeguard public health will continue. The coronavirus pandemic has had a devastating impact on the world, spreading to 188 countries and causing more than 1 million deaths. Governments have reacted by executing arrangement bundles, such as closing schools and limiting individuals to their homes, which have been effective in abating the development of the infection. In the subsequent sections, a detailed review of the hybrid models utilized for disease prevention and monitoring, analyzing their effectiveness by incorporating blockchain, IoT, big data, and AI, is presented. Furthermore, the proposed hybrid conceptual framework model, highlighting its potential to tackle the current pandemic through proactive and preventative measures, is discussed.The advent of the novel COVID-19 virus has prompted a substantial amount of research into the creation of useful methodologies for the prevention and monitoring of diseases. The primary objective of this literature review is to provide a comprehensive overview of the hybrid models utilized to tackle the issues presented by infectious illnesses, with an explicit emphasis on the emerging technologies, such as blockchain, IoT, big data, and AI.By combining these technologies, this model seeks to revolutionize the way we respond to public health crises, opening new possibilities for the future. Most importantly, the hybrid conceptual framework model advocates for a preventive strategy to reduce the spread of the virus and its impact on society. This paper seeks to explore the potential of this innovative framework and its ability to revolutionize our response to the pandemic.Blockchain innovation can be utilized to guarantee the secure and tamper-resistant capacity and sharing of sensitive well-being information. It provides a decentralized and straightforward stage where information can be safely stored and controlled through cryptography. Within the setting of irresistible illnesses, records, tests, inoculation information, and other pertinent data can be stored in the blockchain, guaranteeing the security and authenticity of the information . IndividInternet of Things (IoT) devices, including wearable sensors, environmental sensors, and medical equipment, can gather information about infectious diseases in real time. IoT devices, for instance, can track vital signs, such as respiratory rate, heart rate, and body temperature, to identify early signs of infections. Environmental sensors can track the air quality and look for pathogens nearby. The collected data can be securely transmitted by these IoT devices to the blockchain for additional analysis. Big data analytic techniques can be used to process and analyze the enormous amount of data gathered from IoT devices as well as other pertinent data sources, such as social media, electronic health records, and public health databases. Infectious-disease-related patterns, correlations, and trends can be found using this analysis. Using cutting-edge analytic algorithms, machine learning and data mining make it possible to detect disease events, forecast the spread of infections, and evaluate the effectiveness of prevention measures . IoT colArtificial intelligence (AI) algorithms can be employed to provide decision support in various aspects of infectious disease prevention and monitoring. For instance, machine learning models can predict the likelihood of an individual contracting a specific disease based on their health records and environmental data. AI can also help in contact tracing by analyzing data from multiple sources and identifying potential infection hotspots. Natural language processing (NLP) techniques can be used to extract relevant information from the medical literature and assist in drug discovery or treatment recommendations . AI techBig data offers an effective way to map and combine various data sources to gain insight into the tracking of the COVID-19 outbreak. Furthermore, it enables us to comprehend virus structure and treatment, as big data platforms can be equipped with sophisticated modelling tools that enable the construction of complex simulation models using the COVID-19 data stream. Therefore, text mining algorithms are essential. Nevertheless, the sheer amount of data and the speed at which it must be processed necessitates the use of AI-based intervention .A comprehensive review and comparison of existing techniques is presented in this section regarding the prevention and monitoring of infectious diseases. The objective is to provide a thorough assessment of the strengths, weaknesses, and effectiveness of various approaches employed in detecting and monitoring infectious diseases, particularly in the context of the COVID-19 pandemic. The review encompasses a wide range of techniques, including big data analytics, artificial intelligence, nature-inspired computing, blockchain, Internet of Things, and other emerging technologies. By systematically analyzing and comparing these techniques, the article aims to identify the most promising and effective strategies for disease prevention, contact tracing, and data management. Through this review and comparison, valuable insights and recommendations can be derived to guide future research and development efforts in the field of infectious disease surveillance and control.Agbehadji et al.  discusseThe study in  reviewedA theoretical model called virus epidemic prediction system (VEPS) was proposed for predicting infectious diseases . The modTopol  highlighDeebak and Al-Turjman  proposedEach study in the table demonstrates the utilization of emerging technologies to tackle different aspects of the pandemic. By summarizing the tools used and the outcomes achieved, the table provides a comprehensive overview of the research landscape in the field of infectious disease management. It showcases the diversity of approaches and the potential of these emerging technologies in combating the spread of infectious diseases and improving public health outcomes.The purpose of this matrix is to assess and compare different techniques in terms of their capabilities for managing and monitoring the spread of a pandemic. This quick comparison of these techniques based on their specific features aids researchers and practitioners in understanding the strengths and limitations of each technique within the context of a hybrid system for pandemic management.The proposed hybrid system is called hybrid disease prevention, monitoring, and management system (HDPMMS). This hybrid system, which combines emerging technologies, including blockchain, IoT, big data, and AI, provides a comprehensive solution for disease prevention, monitoring, and management see . The HDPBlockchain-based secure contact tracing and source isolation: The HDPMMS utilizes blockchain technology to enable secure and transparent contact tracing. It ensures that the transmission of infections can be effectively tracked, and source isolation can be implemented securely. By leveraging the decentralized nature of blockchain, the system enhances data privacy and security, reducing the risk of unauthorized access and tampering.Integration of IoT sensors for real-time data collection: IoT sensors are integrated into the HDPMMS to collect real-time data on vital health parameters. These sensors can monitor various physiological indicators, such as body temperature, heart rate, and respiratory rate. The continuous data collection allows for the early detection of potential outbreaks and enables proactive interventions.Big data analytics for data-driven insights: The HDPMMS incorporates big data analytic techniques to analyze the collected data from IoT sensors and other sources. Through data preprocessing, cleaning, and analysis, the system can derive meaningful insights and identify patterns related to disease dynamics. This enables researchers and healthcare professionals to make informed decisions and develop data-driven strategies for disease prevention and control.AI for symptom identification and drug manufacturing support: The HDPMMS employs AI algorithms to support symptom identification and drug manufacturing. AI algorithms can analyze vast amounts of patient data and medical records, identifying patterns and symptoms associated with specific diseases. This aids in early detection, accurate diagnosis, and timely interventions. AI can also assist in drug-manufacturing processes, such as predicting the efficacy of potential therapeutics and optimizing drug development.The HDPMMS represents a proactive approach to disease prevention and monitoring by integrating the power of blockchain, IoT, big data, and AI technologies. By combining these technologies, the system aims to provide real-time insights, secure contact tracing, early detection of outbreaks, and support for effective drug development. The HDPMMS has the potential to revolutionize disease control strategies, enabling timely interventions and proactive measures to combat the ongoing pandemic and future global health threats.The hybrid disease prevention, monitoring, and management system incorporates various functions to effectively address disease prevention and monitoring. Secure contact tracing: The HDPMMS utilizes blockchain technology to enable secure contact tracing. It allows for the recording and tracking of individuals\u2019 interactions, ensuring that the transmission of infectious diseases can be effectively monitored and traced. The decentralized and tamper-resistant nature of the blockchain ensures data integrity and privacy.Source isolation: The HDPMMS facilitates source isolation by identifying and isolating the origin of the infection. By leveraging blockchain technology, the system can securely track the source of infection and prevent further spreading. This function is crucial in containing outbreaks and minimizing the impact of infectious diseases.Real-time data collection: The HDPMMS integrates IoT sensors to collect real-time data on vital health parameters. These sensors monitor individuals\u2019 physiological indicators, such as body temperature, heart rate, and respiratory rate. Continuous data collection enables the early detection of potential outbreaks and provides real-time insights into individuals\u2019 health conditions.Data analytics and insights: The HDPMMS incorporates big data analytic techniques to analyze the collected data. Through data preprocessing, cleaning, and analysis, the system derives meaningful insights and identifies patterns related to disease dynamics. This function enables healthcare professionals and researchers to make informed decisions, develop data-driven strategies, and allocate resources effectively for disease prevention and control.Symptom identification: The HDPMMS employs AI algorithms to identify symptoms associated with infectious diseases. By analyzing vast amounts of patient data and medical records, AI algorithms can detect patterns and identify specific symptoms indicative of diseases. This function aids in early detection, accurate diagnosis, and timely interventions.Drug-manufacturing support: The HDPMMS utilizes AI to support drug-manufacturing processes. AI algorithms can analyze molecular structures, predict the efficacy of potential therapeutics, and optimize drug development. This function enables researchers and pharmaceutical companies to expedite the drug discovery and development process, thus leading to more effective treatments for infectious diseases.Overall, the HDPMMS combines secure contact tracing, source isolation, real-time data collection, data analytics, symptom identification, and drug-manufacturing support to provide a comprehensive approach to disease prevention and monitoring. By leveraging the emerging technologies, the HDPMMS aims to enhance early detection, proactive interventions, and effective response strategies, ultimately mitigating the impact of infectious diseases on a global scale.Implementing the HDPMMS framework can enhance disease surveillance capabilities by enabling real-time data collection and analysis. The integration of IoT sensors and the utilization of big data analytics allow for the early detection of outbreaks, prompt response to emerging threats, and accurate monitoring of disease trends. This leads to more effective disease surveillance and better-informed decision-making.Improved contact tracing and source isolation: The HDPMMS\u2019s secure contact-tracing function through blockchain technology enables the efficient and transparent tracking of individuals\u2019 interactions. By accurately identifying and isolating the source of the infection, the system helps to contain the spread of infectious diseases more effectively. This capability minimizes the risk of further transmission and contributes to the overall control of outbreaks.Timely symptom identification and diagnosis: The integration of AI algorithms in the HDPMMS enables timely and accurate symptom identification. By analyzing patients\u2019 data and medical records, the system can detect specific symptoms associated with infectious diseases, allowing for early diagnosis and appropriate treatment. This leads to improved patient outcomes and facilitates the implementation of targeted interventions.Facilitated drug-manufacturing and development process: The HDPMMS\u2019s AI-driven drug-manufacturing support function streamlines the drug discovery and development process. By leveraging AI algorithms to analyze molecular structures and predict drug efficacy, researchers and pharmaceutical companies can expedite the development of effective therapeutics. This accelerates the availability of treatments and improves the overall management of infectious diseases.Proactive and data-driven decision-making process: The HDPMMS provides decision-makers with data-driven insights and actionable information. By utilizing big data analytics, the system generates meaningful insights and patterns related to disease dynamics. This empowers healthcare professionals, policymakers, and researchers to make proactive decisions, allocate resources efficiently, and implement targeted interventions to prevent and control the spread of infectious diseases.The implementation of the HDPMMS results in improved disease surveillance, efficient contact tracing and source isolation, timely symptom identification, facilitated drug manufacturing, and proactive decision-making. These outcomes contribute to the overall effectiveness of disease prevention and monitoring efforts, helping to mitigate the impact of infectious diseases and safeguard public health.In conclusion, the HDPMMS presents a comprehensive and innovative approach to address the challenges posed by infectious diseases. By integrating blockchain, IoT, big data analytics, and AI, the HDPMMS offers a holistic solution for disease prevention and monitoring. Through the implementation of the HDPMMS, several key benefits can be achieved. The system enables secure contact tracing and source isolation, ensuring the effective control of disease transmission. Real-time data collection from IoT sensors facilitates the early detection of outbreaks and provides valuable insights into individuals\u2019 health conditions. The application of big data analytics allows for data-driven decision-making, enhancing disease surveillance and response strategies. Additionally, AI supports symptom identification and drug manufacturing, improving diagnosis and facilitating the development of effective therapeutics.The HDPMMS emphasizes proactive measures and preventive solutions, rather than over-reliance on treatments and cures. By leveraging emerging technologies, the system empowers healthcare professionals, researchers, and policymakers to take prompt actions, allocate resources efficiently, and implement targeted interventions to mitigate the impact of infectious diseases.The HDPMMS has the potential to revolutionize disease prevention and monitoring strategies, leading to improved public health outcomes. However, it is important to acknowledge that the implementation of such a hybrid system requires the careful consideration of ethical, legal, and privacy implications. Collaboration among various stakeholders, including healthcare organizations, technology providers, and regulatory bodies, is crucial to ensure the responsible and effective deployment of the HDPMMS.Henceforth, further research and development are needed to refine the HDPMMS and optimize its performance. Continued advancements in technology, data management, and algorithmic capabilities will contribute to the ongoing evolution of this hybrid system. By harnessing the power of emerging technologies, the HDPMMS offers promising prospects for addressing the ongoing pandemic and future global health threats, ultimately improving the health and well-being of populations worldwide."}
+{"text": "To introduce Section 1013 of the Medicare Prescription Drug,Improvement, and Modernization Act (MMA) of 2003 and the Agency forHealthcare Research and Quality's (AHRQ) Effective Health Care Program.AHRQ, under Section 1013 of the MMA of 2003, has be encharged with conducting specific health care outcomes studies through the Effective Health Care Program. This research is aimed specifically at determining the safety and effectiveness of certain pharmaceuticals since comparative data is currently lacking. Highly utilized, high-cost (or both)treatments are the focus of the studies that will be conducted through AHRQ's Evidence-based Practice Centers (EPCs) and the Developing Evidence to Inform Decisions about Effectiveness (DEcIDE) Network. Current and completed projects are noted, including more detailed information on the reviews pertaining to treatment of rheumatoid arthritis with nonbiologic disease-modifying antirheumatic drugs (DMARDs) and biologics (anti-tumor necrosis factor[TNF]-a therapies).AHRQ's EPCs and the DEcIDE Network are studying safety and the comparative effectiveness of a number of different pharmaceutical-related topics, including the safety and effectiveness of biologic and nonbiologic DMARDS . The final reports, once complete, will be translated  and then disseminated to all stakeholders."}
+{"text": "This Special Issue is aimed to collect scientific papers that support holistic methodological approaches, both top-down and horizontal, for the correct application of various omics sciences because, when well-integrated, they can contribute to our understanding of the genotypic plasticity of plant species.The goal of molecular biology scientific research on agricultural crops is to use the developed technologies in order to recognize and manipulate the levels of metabolites for food applications such as nutraceutical, clinical therapeutic and pharmaceutical purposes and for the subsequent formulation of appropriate dosages, with positive effects on metabolic syndromes, including reduced risks of morbidity and mortality. In the field of bioinformatics and computational biology, high-throughput omics technologies, which can be used with tailored and even predictive approaches, such as genomics, transcriptomics, proteomics, lipidomics, metabolomics, interactomics and systems biology, are undertaking to develop and characterize specific molecular markers linked to loci of interest in order to decrease the time duration of specific breeding programs through the fast screening of thousands of genotypes for traits of interest, enabling researchers to produce intermediate and final metabolites in plants that are useful in translational biology ,2,3.In fact, the most readily transposable approach concerns the study of the aggregation of successive reactions in a model multienzymatic pathway within organelles , because it can be implemented without drawbacks. In fact, the instability of biological systems and low efficiency of non-compartmentalized metabolic pathways are often observed both when catalyzed by spatially separated enzymes and when crowding, the formation of nanodomains and altered local viscosities have effects on biochemical processes involving proteins ,5,6,7. TPhylogenetically, organellar enzymes show significant sequence similarity (homology) between plants and cyanobacteria and/or closely related lifeforms, which facilitates the isolation of species-specific genes. Therefore, the starting point is bioinformatics for a complete in silico study of both the known gene loci (which transcribe enzymes) and the metabolites (such as substrates or end products) involved in the highlighted pathway. In particular, comparative genomics studies of orthologous genes in pathways of interest, both between and within species, that are identifiable in public databases and already functionally characterized , should Today, the application of genomic, biochemical and physiological approaches for enhancing our knowledge of specific metabolic pathways and their related genes, include the systemized NGS, Illumina, Ion Torrent, PacBio and nanopore technology sequencing platforms; high-throughput genome annotation for genotyping purposes; phenomics platforms; high-resolution transcriptomics; and the bioinformatic analysis of DNA sequencing data , as well as RNA, micro-RNA and micro-transcriptomics via laser capture microdissection (LCM), chromatin immunoprecipitation (ChIP), in situ hybridization, proteomics, lipidomics and epigenomics. Several research consortia have pursued the aims of sequencing plant genomes and studying their structures, characterizing transcriptomes, identifying genes, regulatory elements and metabolomes, and developing new markers to enhance the potential of a species in order to re-evaluate and protect germplasms and to breed desirable genotypes required for productive, sustainable and resilient agriculture.It is my belief that well-designed and well-executed scientific experiments in the field of plant metabolism genetics can be used to answer questions and support hypotheses more promptly and effectively than the reductive but no less important conception and execution of in silico solutions, while supporting the validity of the predictive indication of the latter.By querying in databases, genomic sequences  are identified from cDNA libraries based on the sequence homology of the exons. On the other hand, the certainty of identifying the two possible alleles at the gene locus of interest (tissue- and moment-specific), in both homozygosity and heterozygosity, is based on the sequence homology of the introns .The cloning and sequencing of the gene loci for germplasm genotyping lead to the identification of the variable allelic composition structure and reveal the alleles carrying high or low expressions of the traits. These processes also lead to the development of SNPs (Single-Nucleotide Polymorphisms), insertion/deletion and SSR databases which can represent the precious molecular markers within a plant species for the functional genotyping of varieties which show differential gene expressions for the production of metabolites of interest, which can be defined as real QTLs ,11,12. IqRT-PCR is used to analyze different correctly collected plant and fruit tissues in different stages of development , allowing us to determine the relative expression levels in the plant and the loci that behave as endogenous genes (housekeeping) that could act as the best controls a\u2013c. ThisThis research combines EST-cDNA (Expressed Sequence Tag) libraries and subtractive libraries, transcriptomes and RNA-Seq data on organs/tissue that are available with the quantification of the gene expression levels (RPKM) ,16,17. TThe data available on the gene sequences and the genetic factors that control the agronomic behavior of plants are still scarce and fragmentary, partly because the comparative genomes have not yet been obtained as secure assembling of chromosomes, especially in highly heterozygous plants with highly repeated genomes . HoweverFor the sake of methodological thoroughness, functional genomics studies are an attractive means of making significant progress in translational research . Thus, aThe applications of multiple molecular biology, computational and bioinformatics technologies in the scientific contributions accepted for publication in this Special Issue offer peculiar/specific demonstrations of the implementation of various desired and correct macro-approaches."}
+{"text": "Brazilian National Survey on ChildNutrition (ENANI-2019) pointed out several advances but numerouschallenges. In this paper, we reflect on the implementation progress ofbreastfeeding, complementary feeding and young children malnutrition strategiesand programs in Brazil and how existing challenges can be overcome through thelens of implementation science. First, we present a brief history of suchprograms. Second, we selected two breastfeeding initiatives to illustrate andreflect on common implementation challenges. In these case studies, we used theRE-AIM  frameworkto analyze the implementation and scaling up barriers and facilitators. We foundcommon barriers related to unclear goals about the reach of programs, challengesin assessing effectiveness and fidelity/quality during the real-worldimplementation, discontinuation or lack of funding, and lack of monitoring andevaluation impacting the sustainability of programs. We also discuss the use ofimplementation science to achieve adequate nutrition by 2030 and presentcritical elements for successful scale implementation of nutrition programsbased on global evidence. Despite the investment to implement different actionsaimed at facing infant feeding and malnutrition, high-quality implementationresearch must become a priority to catalyze progress in Brazil. Malnutrition in all its forms has risen on global agendas due to the recognitionof its magnitude and consequences for a wide range of human, social, andeconomic outcomes. Implementing strategies and programs with the needed scaleand quality is a major challenge. The  Attention is drawn, for example, tothe increased consumption of ultra-processed foods in the first years of life The FederalConstitution of 1988 incorporated a concept of social security asan expression of the social rights inherent to citizenship through the guaranteeof a set of economic and social policies, including creating the BrazilianUnified National Health System (SUS) Law n. 8,080), which established the SUS, providedguidance for monitoring nutritional and dietary practices.In the 1980s, social movements focused on defending the return to democracygenerated the Brazilian Health Reform Movement. The At the end of the 1990s, the Brazilian National Food and Nutrition Policy (PNAN)was created and coordinated by the Brazilian Ministry of Health through theGeneral Coordination of Food and Nutrition Policy (CGPAN), currently theGeneral-Coordination of Food and Nutrition (CGAN) In this period, along with important achievements of the SUS, such as theexpansion of primary health care coverage, the reduction of infant mortalityrates, and the promotion of food and nutrition security, Brazil experiencedseveral changes in socioeconomic and demographic indicators that led to anepidemiological and nutritional transition Ordinance GM/MS n. 1,130 of August 5, 2015).Specifically, the second pillar explicitly promotes breastfeeding and healthycomplementary feeding. After the extinction of INAN in 1997, breastfeeding promotion, protection, andsupport were coordinated by the children\u2019s health area within the BrazilianMinistry of Health. In 2015, the Brazilian National Policy for IntegralAttention to Children\u2019s Health (PNAISC) posed a set of comprehensive actions andstrategies across seven pillars to promote child development and mitigatevulnerabilities , establishing principles and guidelinesfor formulating public policies to fulfill the rights of children, increase theeffectiveness of integrated policies, define strategies for intersectoralcoordination, and define food and nutrition as priority areas.Finally, the Legal Framework for Early Childhood was published (https://cadernos.ensp.fiocruz.br/static//arquivo/supl-e00053122_5122.pdf). We organized into three themes a brief historical overview of strategies andprograms on children\u2019s food and nutrition implemented in the health sector inBrazil: (1) child malnutrition and micronutrient deficiencies; (2) breastfeedingand complementary feeding; and (3) childhood obesity. A detailed description ofthese strategies and programs is presented in Supplementary Material  Child malnutrition. Substantial declines in the prevalence of childundernutrition in Brazil have been attributed to gains in family income,maternal schooling, and expanded coverage of public education, sanitation,and health care services Over time, these programs have incorporated new approaches and been replacedby more comprehensive actions. The II PRONAN, in the late 1970s, announced aset of activities with a broader approach to combat hunger and malnutrition.However, many of these actions never came to fruition. The \u201cMilk is HealthProgram\u201d (PLS), launched in 1993, is one example of a food supplementationprogram. The goal of PLS was to reduce the prevalence of malnutrition byproviding free milk supplementation for specific groups (including childrenunder five years of age) identified through the SISVAN In the late 1990s, the Program to Combat Nutritional Deficiencies (PCCN) wascreated to replace the PLS. The PCCN included actions beyond foodsupplementation, such as promoting breastfeeding, monitoring nutritionalstatus, and preventing and treating iron and vitamin A deficiencies. Theestimates of the target audience for PCCN were based on statistical modelsprepared by the Center for Nutrition and Health Research, University of S\u00e3oPaulo (NUPENS/USP), which significantly changed the transfer of federalresources to the fight malnutrition, reversing traditional practices ofequal treatment for unequal situations In the 2000s, food supplementation programs were replaced with cash transferprograms, which had more significant potential for addressing the socialdeterminants of malnutrition ,,,,,In 2003, the Food Schoolarship Program was replaced by the Brazilian IncomeTransfer Porgram, in which social vulnerability was prioritized, defining afamily poverty cutoff as the criterion for eligibility accompanied by healthand education conditionalities. The health conditionality included a minimumof health care visits for children of beneficiaries\u2019 families and monitoringthe nutritional status. Evidence of programs to prevent and controlmalnutrition shows that positive responses to child malnutrition are closelyrelated to confronting social determinants of health and equity-orientedpolicies, i.e., the redistribution of income and guarantee of universalaccess to health, education, and basic sanitation OrdinanceGM/MS n. 894/2021).Despite reducing the prevalence of malnutrition in Brazil, the problempersists in some population subgroups, demanding focused attention andsocial investments. In 2012, the Brazilian Ministry of Health instituted theAgenda to Intensify Nutritional Care for Child Malnutrition targetingBrazilian municipalities with the highest prevalence of malnutrition amongchildren under five based on data from SISVAN. However, this strategy wasonly implemented and financed from 2012 to 2015 (b) Micronutrients deficiencies. The actions to combat micronutrientdeficiencies in the health sector were initially included in programs tocombat malnutrition At the end of the 1970s, following the international movement led by the WHOand UNICEF to return to breastfeeding, the II PRONAN included a proposal tocreate a program to promote breastfeeding. However, this proposal was onlyput into effect in 1981, creating the PNIAM. The PNIAM gained internationalattention for its diversity of actions aimed at promoting , protecting , and supporting breastfeeding Federal Constitution and the formationof the SUS in 1988 impacted children\u2019s healthcare in Brazil, evolving fromvertical maternal-infant programs of the 1970s and 1980s to the perspectiveof comprehensive care, aimed at ensuring rights, overcoming vulnerabilities,reducing morbidity and mortality, and promoting health and quality of lifeFederal Constitution guaranteed to workingwomen, with a formal employment relationship, benefits including 120 days ofmaternity leave, the right to two half-hour breaks during the workday tobreastfeed the child up to six months of age, and the right to daycare inthe workplace. In 2008, Law n. 11,770 established theCorporate Citizen Program, aimed at extending maternity leave to six-monthby granting a tax incentive. In addition, the Supporting Working Women andBreastfeeding (MTA) was adopted in partnership with the Brazilian Society ofPediatrics. It consisted of three strategic axes: extension of maternityleave to 180 days, implementation of daycare in the workplace, and creationof lactation rooms in the workplace The enactment of the ,Another milestone for legal protection was created in 1988 with the BrazilianCode of Marketing of Food for Infants (NBCAL) In 1988, the Brazilian Ministry of Health also regulated the human milk banksas centers for collecting, processing, and storing human milk and provingskilled lactation support Law n. 13,435/2017 established August as the Monthof Breastfeeding - \u201cGolden August\u201d In the early 1990s, Brazil was one of the twelve countries to adopt the BFHI.To leverage its implementation, the Brazilian Ministry of Health intensifiedthe availability of four courses proposed by the WHO: an 18-hour course formaternity teams; an 80-hour course to train monitors; a 40-hourBreastfeeding Counseling Course; and Quick Course aimed at raising awarenessamong managers ,The 2000s marked important advances to protect, promote, and supportbreastfeeding. The Kangaroo method, is codified in the Standard forHumanized Attention of Low-Birth Weight Newborns Dietary Guidelines for BrazilianChildren Under Two Years of Age (published in 2002 and revisedin 2010). These \u201cdietary guidelines\u201d were revised again in 2019 to respondto recent changes in social transformations and dietary practices and alignits approach and recommendations with the dietary guidelines for theBrazilian adult population The promotion of healthy complementary feeding was intensified by developingand disseminating various educational materials targeting healthprofessionals. These include the Decree n.9,759 of April 11, 2019, and was reactivated underOrdinance GAB/SAPS n. 13, 2022 as a Technical AdvisoryCouncil.To strengthen the governance of breastfeeding actions in 2006, the BrazilianNational Breastfeeding Committee was created. In 2012, the composition ofthis national committee was revised to include a representation of amothers\u2019 group, civil society, international organizations, andrepresentatives of educational institutions The Brazilian Breastfeeding Network (RAB) was created in 2008 and theBrazilian National Strategy for Healthy Complementary Feeding (ENPACS) in2010, both based on the principles of critical-reflexive education and theSUS Continuing Health Education Policy, which aimed to review and supportinterdisciplinary work processes in primary health units to increase theprevalence of breastfeeding and healthy complementary feeding Bases for Discussion of the National Policy onBreastfeedingAn analysis of the implementation of actions to promote, protect, and supportbreastfeeding concluded that the process which led to the successful scalingup of breastfeeding promotion in Brazil included investments in thefollowing areas: (1) baseline needs assessment including data on infantfeeding practices; (2) advocacy ; (3) national and local mass media campaigns,social mobilization ; (4) implementation and spread of the BFHI;(5) lactation management and communications/counseling training (developmentof human resources); (6) legislation ; and (7) monitoring and evaluation (includingmonitoring of the WHO code) In 2011, the PNAN expanded the concept of healthy eating and comprehensivecare for diseases related to food and nutrition, such as childhood obesity.It defined a set of actions within the health sector and other sectors toensure environments that favor healthy eating and active lifestyles. In thesame year, the Federal Government launched the Strategic Action Plan toCombat Chronic Noncommunicable Diseases (2012-2022), recognizing obesity asa disease and a risk factor for noncommunicable diseases. In 2014, theInterministerial Committee on Food and Nutrition Security (CAISAN), anintersectoral committee to articulate the ministries for the food andnutrition security agenda, launched the document Intersectoral Strategy forthe Prevention and Control of Obesity. Two initiatives that stand out to combat childhood obesity specifically werethe Brazilian Healthy Growing Program (2017) obesity prevention andtreatment requires a whole-of-government approach in which policiesacross all sectors systematically take health into account, avoidharmful health impacts, and thus improve population health and healthequity\u201d Importantly, both Brazilian actions to fight against child obesity arealigned to the recommendations published by the WHO Commission on EndingChildhood Obesity in 2016, which states that \u201cBrazil\u2019s long trajectory builds a robust framework for infant and young children\u2019snutrition policies and initiatives; however, there are still challenges for theirimplementation. We selected breastfeeding protection, promotion, and supportinitiatives - the BFHI  and the EAAB  - to illustrate and reflect on common implementationchallenges. In these case studies, we used the RE-AIM  framework to analyze the implementation andscaling up barriers and facilitators Innocenti Declaration and the World Health Assemblyresolutions of 1994 and 1996, and in 2002 included in the Global Strategy forInfant and Young Child Feeding ,,,,The BFHI was conceived in the early 1990s by the WHO and UNICEF, ratified by theThe Brazilian BFHI accreditation follows the global criteria to comply with the\u201cTen Steps\u201d and three additional criteria: (1) compliance with the NBCAL, (2)the mother-friendly care practices, and (3) assurance that the mother or father remains with the newborn 24-hours. In 2022, the BrazilianBFHI will complete 30 years of implementation. However, despite considerableefforts made by the Brazilian Ministry of Health as well as State and MunicipalHealth Departments to mobilize managers and professionals from maternityhospitals to adopt the Ten Steps, its implementation at scale is still facingseveral challenges. ,,Law n. 11,265/2006 and do notdistribute breast milk \u201csubstitutes\u201d in the primary health clinics; (5)participation of at least 85% of the primary care professionals in thecontinuing education workshop; (6) comply with at least one activity toencourage breastfeeding, and one for healthy complementary feeding agreed in theaction plan The EAAB is the latest initiative of the Brazilian Ministry of Health focused oninfant feeding. Rooted in the critical-reflexive concept, the EAAB aims tostrengthen actions to promote, protect, and support breastfeeding and healthycomplementary feeding for children under two years of age, improving the skillsand abilities of health professionals within the scope of primary care Our implementation analysis identified essential elements across RE-AIM dimensionsthat could improve the implementation and sustainability of both programs andpractices. Documenting and paying attention to the RE-AIM elements have been provedto increase the likelihood of improving successful implementation and, ultimately,the health of the entire population ,,,Implementation science in nutrition is a body of systematized knowledge about how toimprove the implementation of nutrition-specific and sensitive interventions ,,In the last 30 years, Brazil has achieved nearly universal access to primary healthcare for the population, thanks to the expansion of the coverage of the FamilyHealth Strategy, which reaches 60% of the population However, fiscal policies implemented in 2016 ushered in austerity measures that,alongside the current Brazilian government\u2019s new environmental, educational, andhealth policy, could reverse the hard-earned achievements of the SUS, impacting theimplementation of infant feeding and nutrition policies ,,,,Although improving infant and young children\u2019s nutrition requires information aboutbiology and epidemiology, the increasing complexity and multisectorality ofnutrition initiatives highlight sociopolitical factors that determine which actionsare appropriate and acceptable The exercise of applying the RE-AIM, one of the most widespread frameworks inimplementation research, in the analysis of two brief case studies on breastfeedingpolicies in Brazil, allowed us to identify implementation barriers in differentdimensions. We found common barriers related to (1) unclear goals regarding thereach of programs; (2) challenges in assessing effectiveness and fidelity/qualityduring the real-world implementation; (3) discontinuation or lack of funding andlack of monitoring and evaluation, impacting the sustainability of programs.Therefore, implementation research can provide pragmatic programmatic lessons andguidance on how to scale up nutrition interventions by better understandingdifferent contexts, identifying barriers and facilitators, and allocating resourcesand funds for maximum impact ,Hence, high-quality implementation research within large-scale nutrition programsmust become a priority to catalyze progress. Implementation research for nutritionis not new but has not been prioritized"}
+{"text": "BMC Medicine and BMC Neurology is to synthesize current concepts and most recent findings concerning the evaluation, etiology, pathophysiology and clinical relevance of the potential involvement of the extracranial venous system in the pathology of multiple CNS disorders and in aging.The extracranial venous system is complex and variable between individuals. Until recently, these variations were acknowledged as developmental variants and were not considered pathological findings. However, in the last decade, the presence and severity of uni- or bi-lateral jugular venous reflux (JVR) was linked to several central nervous system (CNS) disorders such as transient global amnesia, transient monocular blindness, cough headache, primary exertional headache and, most recently, to Alzheimer's disease. The most recent introduction of a composite criteria-based vascular condition named chronic cerebrospinal venous insufficiency (CCSVI), which was originally linked to multiple sclerosis, increased the interest in better understanding the role of the extracranial venous system in the pathophysiology of CNS disorders. The ultimate cause-consequence relationship between these conditions and CNS disorders has not been firmly established and further research is needed. The purpose of this article collection in http://www.biomedcentral.com/1741-7015/11/260.Please see related debate:  The potential involvement of the extracranial venous system in the pathology of central nervous system (CNS) disorders and in aging is largely debated at this time ,2. This The extracranial venous system is complex with variability between individuals and is frequently asymmetric . Until ret al. examined 109 MS patients and found no evidence of an association between the presence and severity of CCSVI with cognitive impairment and depression in patients with MS [et al. evaluated 61 MS patients and found no association between CCSVI and cognitive impairment, fatigue, depression, bladder/sexual symptoms and self-reported quality of life [The debate article by Zivadinov and Chung  provides with MS , while L of life . These f of life ,20.The limited understanding of the pathophysiology of the extracranial venous system may consequently underestimate the impact of cerebral venous drainage abnormalities in a variety of CNS disorders . Becauseet al.[One of the most convincing indicators towards a \u201cvascular origin\u201d for MS comes from neuropathological observations showing that MS plaques are exclusively perivenular and dimensions of the veins determine the shape, course and dimension of the lesions . This iset al. presentset al.[per se is not sufficient to increase the hydraulic resistance of the cerebral vascular bed but that other mechanisms must be at work, including the potential role of various precipitating risk factors.The pathophysiology of extracranial venous abnormalities may be further elucidated by exploring the role of precipitating risk factors ,5,25,26.et al. tested tet al. provide a comprehensive review of non-invasive and invasive imaging methods for the detection of extracranial venous abnormalities, including CCSVI [et al. evaluated the non-invasive and invasive multimodal imaging correlates of 20 MS patients with relapsing MS who were enrolled in the Prospective Randomized Endovascular therapy in Multiple Sclerosis\u201d (PREMiSe) study [At this time, there is no established diagnostic imaging modality, non-invasive or invasive, that can serve as the \u201cgold standard\u201d for the detection of any extracranial venous abnormalities . Howeverng CCSVI . They dee) study . They coet al. present a novel model in a clinical setting that suggests the pivotal role of the collateral network in draining the blood into the superior vena cava under CCSVI conditions [When there is narrowing of the principal pathways of the extracranial venous system, collateral veins usually form as physiological secondary compensation for the compromised venous system outflow ,4. The pnditions . One of et al. showed in 23 transient monocular blindness (TMB) patients who had no carotid stenosis and in 23 age- and sex-matched healthy controls that there was a greater severity of IJV compression/stenosis in TMB patients [While a link between the presence and severity of extracranial venous abnormalities and several CNS disorders as well as aging is emerging, it is to be determined whether those may play a potential role, as precipitating factors, to increased susceptibility for a number of CNS disorders. Although the presence and severity of JVR and CCSVI have been linked to a number of CNS disorders, the ultimate cause-consequence relationship has not been firmly established. In an original article, Cheng patients . Therefo\u2018Venous Involvement in Neurological Disorders and Aging\u2019 article collection in BMC Medicine and BMC Neurology has attempted to present a fair and balanced discussion of the examined topics. It is hoped that the contents of this collection will encourage the readers to continue their research on this subject.The CBF: Cerebral blood flow; CCSVI: Chronic cerebrospinal venous insufficiency; CNS: Central nervous system; CSF: Cerebrospinal fluid; ET-1: Endothelin-1; IJV: Internal jugular vein; JVR: Jugular venous reflux; MS: Multiple sclerosis; NPH: Normal-pressure hydrocephalus; PREMiSe: Prospective Randomized Endovascular therapy in Multiple Sclerosis; TMB: Transient monocular blindness.Robert Zivadinov received personal compensation from Teva Neuroscience, Biogen Idec, EMD Serono, Bayer, Genzyme-Sanofi, Novartis, Claret and General Electric for speaking and consultant fees. He received financial support for research activities from Biogen Idec, Teva Neuroscience, Genzyme-Sanofi, Novartis and EMD Serono.Robert Zivadinov, M.D., Ph.D., is a professor of neurology with tenure at the Department of Neurology, School of Medicine and Biomedical Sciences, University of Buffalo, State University of New York (SUNY) and clinical professor of neurology at the Florida International University College of Medicine. He is director of the Buffalo Neuroimaging Analysis Center and of the MR Imaging Clinical Translational Research Center at the University of Buffalo.He has performed extensive research in multiple sclerosis and imaging, having published more than 250 articles and 400 abstracts in leading peer-reviewed journals. He is currently pursuing research studies on quantitative magnetic resonance, ultrasound, angiography and optic coherence tomography imaging findings in multiple sclerosis, Parkinson\u2019s and Alzheimer's disease and aging. His current interests also concentrate on therapeutic interventions, including strategies towards assessing neuroprotective efforts in neurodegenerative disorders, as well as venous function, genetic and neuroepidemiology fields of these diseases.BMC Medicine and BMC Neurology with the aim of synthesizing most recent concepts concerning the evaluation, etiology, pathophysiology and clinical relevance of the potential involvement of the extracranial venous system in the pathology of multiple CNS disorders and in aging. Dr. Zivadinov is one of the leading authorities in the field on this topic, having published more than 30 original and review articles in peer-reviewed journals.Dr. Zivadinov guest-edited this article collection in All articles in this article collection have been independently prepared by the authors and have been subject to the standard peer-review processes of the journals."}
+{"text": "Despite the need for a reduction in levels of childhood exposure to environmental tobacco smoke (ETS) being a recognised public health goal, the delivery of ETS preventive care in child health service settings remains a largely unstudied area. The purpose of this study was to determine the prevalence of ETS preventive care in child health services; differences in the provision of care by type of service; the prevalence of strategies to support such care; and the association between care support strategies and care provision.One-hundred and fifty-one (83%) child health service managers within New South Wales, Australia completed a questionnaire in 2002 regarding the: assessment of parental smoking and child ETS exposure; the provision of parental smoking cessation and ETS-exposure reduction advice; and strategies used to support the provision of such care. Child health services were categorised based on their size and case-mix, and a chi-square analysis was performed to compare the prevalence of ETS risk assessment and ETS prevention advice between service types. Logistic regression analysis was used to examine associations between the existence of care support strategies and the provision of ETS risk assessment and ETS exposure prevention advice.A significant proportion of services reported that they did not assess parental smoking status (26%), and reported that they did not assess the ETS exposure (78%) of any child. Forty four percent of services reported that they did not provide smoking cessation advice and 20% reported they did not provide ETS exposure prevention advice. Community based child and family health services reported a greater prevalence of ETS preventive care compared to other hospital based units. Less than half of the services reported having strategies to support the provision of ETS preventive care. The existence of such support strategies was associated with greater odds of care provision.The existence of major gaps in recommended ETS preventive care provision suggests a need for additional initiatives to increase such care delivery. The low prevalence of strategies that support such care delivery suggests a potential avenue to achieve this outcome. Children are particularly vulnerable to the harmful effects of environmental tobacco smoke (ETS) because of their relatively underdeveloped immune and pulmonary systems, their small body size, and their higher rates of ventilation ,2. ExposGiven that child exposure to ETS is most commonly associated with smoking by parents and other household member -8, interHealth facilities present an ideal opportunity to deliver ETS-prevention advice to parents . First, Limited international evidence provides an insight into the level of ETS prevention care routinely provided in child health care settings. Such evidence is primarily United States based and addresses care provided by physicians only ,21-23. ITo date, research describing the provision of ETS-prevention care by heath care professionals, and the prevalence of strategies to support such care is limited. Given this, a study was undertaken to determine the: prevalence of ETS preventive care in child health services; the differences in care provision by type of child health services; the prevalence of strategies to support such care; and the association between care support strategies and care provision.A cross-sectional survey of public child health care services in New South Wales, Australia was undertaken in 2002. Eligible services were firstly, those units within hospitals that primarily cared for children aged 0-15 years of age, including all paediatric, postnatal and neo-natal units, and secondly, all community-based child and family health services. The eligible respondent for each health service was the Senior Nurse Manager within hospital settings, or the Senior Manager of child and family health services.A self-report questionnaire was developed based on recommendations included in the United States' Clinical Guidelines for Treating Tobacco Use and Dependence , and on Pen and paper questionnaires were forwarded by the Chief Health Officer of New South Wales to all Health Services within the state. The Chief Executive of each service was asked to distribute the questionnaire to specified respondents within their organisation. Respondents were asked to complete the survey based on their knowledge of practices within their unit.Health Services that did not return the surveys within three weeks received a telephone reminder prompt by the Chief Health Officer's staff. Ethics approval for human research was obtained from the University of Newcastle's Human Research Ethics Committee.In the questionnaire respondents were asked to indicate if their unit assessed two forms of ETS risk: parental smoking status, and the ETS exposure of children . Those respondents, who indicated assessment was undertaken were asked to estimate the proportion of parents for whom each of form of assessment was routinely undertaken .Respondents were asked whether their unit provided two forms of ETS exposure prevention advice to parents of children at risk: quit smoking advice and ETS reduction advice ('yes' 'no' or 'unsure'). Those respondents who indicated that advice was provided were asked to estimate the proportion of parents for whom such advice would be routinely provided . Such respondents were also asked to indicate the type of advice offered  ('yes' or 'no').Respondents were asked if the provision ETS preventive care was supported by: documentation in the form of written policies; staff training; or organisational prompts such as computer based prompts and medical record stickers .Respondents were asked to indicate the type of child health service  that they were reporting on.Hospitals were categorised into one of two groups based upon their size and case-mix. Group 1 hospitals included principal referral and major metropolitan and non-metropolitan hospitals treating between 10,000 and 25,000 patients per year. Group 2 hospitals included district and community hospitals treating between 2,000 and 10,000 patients per year. As a consequence, all units were clasified as either a Group 1 or Group 2 hospital, or a child and family health service.Responses regarding the estimated proportion of parents that routinely received either form of ETS risk assessment, and the proportion of parents that routinely received either form of ETS exposure prevention advice were collapsed into four categories: 'none' (0%), 'less than 75%' (1-75%), 'almost all' (76-99%) and 'all patients' (100%). Based on these categories, the overall prevalence of both ETS risk assessment and ETS exposure prevention advice were examined. Differences in the prevalence of each form of care between the types of services  were examined by chi-square analysis.The prevalence of each type of care support strategy is reported as a proportion. Differences in the prevalence of such strategies between the types of services were examined by chi-square analysis.p < 0.05). Evidence of confounding and possible interactions were investigated.Chi-square and logistic regression analyses were used to examine associations between the existence of care support strategies (independent variable) and each of the four forms of care  (dependent variables). For these analyses, responses regarding the proportion of patients receiving each form of care were collapsed into two groups, 0-75% of patients (some) and 76-100% of patients (most) . ResponsAll analysis was undertaken using the statistical software package SAS 9.1.2 . A finitCompleted questionnaires were received from 153 of the 183 eligible units (83%). Response rates did not differ significantly between health service settings, or between hospital peer groups (range 81% to 84%). Seventy-two percent (n = 111) of respondents were from hospital units and 28% (n = 42) were from community-based child and family health services. Sixty one percent (n = 67) of hospital respondents were from Peer Group 1.p < 0.001).Twenty-six percent of all respondents indicated that their service did not assess the smoking status of any parents (see Table p < 0.001).Seventy-eight percent of all respondents, and 86%-87% of hospital units reported that their service did not assess the ETS exposure for any child. Fourteen percent indicated that their facility routinely assessed the ETS exposure for most children. A greater proportion of respondents from child and family health units reported assessing the ETS exposure of most children. Thirty-six percent of community-based child and family health respondents reported that they assessed the smoking status of most parents (>75%) compared to 4% of Peer Group 1 and 7% of Peer Group 2 respondents (p = 0.003).Nearly half of all respondents (44%) indicated that their service did not provide smoking cessation advice to any parents (see Table Of those units that reported providing smoking cessation advice to parents (56%), 86% provided brief verbal advice, 75% provided written materials, 30% offered referrals, 22% provided extended verbal advice, 19% provided advice regarding NRT, and 13% provided NRT. Eighty percent of such units reported providing more than one type of quit smoking advice to parents.p = 0.036).Twenty percent of respondents indicated that their service did not provide ETS-reduction advice to any parents of children at risk, whilst approximately one half (46%) reported that such advice was provided to most parents. A greater proportion of respondents from community-based child and family health services reported providing ETS-reduction advice to most parents. Sixty-three percent of child and family health respondents reported that they provided ETS-reduction advice to most parents of children at risk compared to 47% of Peer Group 1 and 25% of Peer Group 2 respondents (Of those units that reported providing ETS reduction advice to parents (80%), 88% provided brief verbal advice, 65% provided written materials, 27% provided extended verbal advice, and 19% offered referrals. Seventy six percent of such units reported providing more than one type of ETS reduction advice to parents.p = 0.356 and p = 0.839 respectively) or the existence of prompts for the provision of ETS-prevention care (p = 0.781). Community-based child and family health unit respondents (68%) reported a higher prevalence of staff training in the provision of ETS-prevention care compared to Peer Group 1 (41%) and Peer Group 2 respondents (36%) (p = 0.007).As shown in Table Independent of type of service, respondents who reported the existence of an ETS prevention policy had approximately twice the odds of assessing parental smoking status . Respondents who reported the existence of training regarding ETS prevention care had twice the odds of assessing parental smoking status  and over four times the odds of assessing child ETS exposure .Independent of type of service, respondents reporting the existence of a quit smoking policy had nearly three times the odds of providing parental smoking cessation advice  (see Table The existence of an ETS prevention care policy significantly increased the odds of providing ETS exposure advice (OR 3.0 CI 1.3-6.6). No other associations were evident between service support strategies and the provision of such advice.This study is the first that reports the prevalence of ETS preventive care routinely delivered by Australian public child health services. We found that a large proportion of such services failed to routinely assess ETS risks or provide ETS exposure prevention advice to parents of attending children. The results also suggest the limited existence of clinical practice strategies to support the provision of such care. The results indicate a considerable need and potential for additional clinical practice initiatives to realise the benefits of ETS prevention care for children.The results of this study, despite methodological differences, are consistent with those of research in other countries that suggest that approximately half of child health services fail to assess the smoking status of the majority of parents ,21,23,25The results of the current study suggest that most services fail to routinely provide smoking cessation and ETS reduction advice to parents, which is consistent with previous research ,21,23,25The results of this study extend previous research by examining and demonstrating differences in the prevalence of ETS prevention care between types of services and clinicians ,23. The Evidence suggests that intervention strategies that are most effective in increasing ETS prevention care are system level strategies such as policies , remindeThe findings of this study support such previous research, by suggesting that where clinical practice is supported by a written policy, training and care prompts, clinicians are more likely to assess children's ETS risk and provide ETS prevention care. Despite this positive finding, it is evident that the majority of child health services do not incorporate support strategies within their organisations. Training regarding ETS prevention care was the most often reported support mechanism (47%) followed by ETS care prompts (20%), the existence of a policy outlining the provision of smoking cessation care (22%), and policy outlining ETS reduction care (12%). Such outcomes are similar to those reported in the adult inpatient setting .The observed low levels of organisational support can be argued to have contributed to the finding that the majority of children attending child health services are not being assessed for ETS risk, or provided ETS prevention care. As these findings occur in the context of international and national guidelines that mandate the provision of ETS prevention interventions ,38, the The findings of this study should be considered in the context of a number of its methodological characteristics. First, the study relied on the use of an indirect estimate of care prevalence by utilising self-report data of senior unit managers. Results obtained from self-report studies can be confounded as respondents commonly over-report the routine provision of assessment and advice . If thisThere is a clear need to further enhance the provision of ETS prevention care in child health services. Considering the documented efficacy of care support strategies such as reminders, education and policy, the further dissemination of ETS preventive care guidelines should incorporate such strategies.The authors declare that they have no competing interests.TH contributed to: conception and design of the study, acquisition of data, analysis and interpretation of the data, drafting of the manuscript, provided statistical expertise, read and approved the final manuscript.JD contributed to: conception and design of the study, acquisition of data, analysis and interpretation of the data, drafting of the manuscript, provided supervision, read and approved the final manuscript.JB contributed to: conception and design of the study, analysis and interpretation of the data, drafting of the manuscript, revision of the manuscript for important intellectual content and provided supervision, read and approved the final manuscript.MF contributed to: conception and design of the study, analysis and interpretation of the data, drafting of the manuscript, revision of the manuscript for important intellectual content and provided supervision, read and approved the final manuscript.JW contributed to: conception and design of the study, acquisition of data, analysis and interpretation of the data, drafting of the manuscript, revision of the manuscript for important intellectual content, involved in obtaining funding, providing supervision, read and approved the final manuscript.This study was undertaken with the support of Hunter New England Population Health and infrastructure support from the Hunter Medical Research Institute.The sources of funding for the study, for each author, are as follows:TH: Hunter New England Population Health, New South Wales (NSW) Department of Health, Australia; Faculty of Psychology, The University of Newcastle, NSW, Australia; Hunter Medical Research Institute, NSW Australia.JD: Hunter New England Population Health, New South Wales (NSW) Department of Health, Australia; Faculty of Health, The University of Newcastle, NSW, Australia; Hunter Medical Research Institute, NSW Australia.JB: Faculty of Health, The University of Newcastle, NSW, Australia; Hunter Medical Research Institute, NSW Australia.MF: Hunter New England Population Health, New South Wales (NSW) Department of Health, Australia; the Faculty of Health, The University of Newcastle, NSW, Australia; Newcastle Institute of Public Health, NSW Australia; Hunter Medical Research Institute, NSW Australia.JW: Hunter New England Population Health, New South Wales (NSW) Department of Health, Australia; Faculty of Health, The University of Newcastle, NSW, Australia; Newcastle Institute of Public Health, NSW Australia; Hunter Medical Research Institute, NSW Australia.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/11/324/prepub"}
+{"text": "Workshop on Carbohydrate Moieties as Vaccine CandidatesBethesda, MD, USAOctober 6-7, 2004Haemophilus influenzae b and pneumococcal conjugate vaccines. However, our understanding of several aspects of polysaccharide vaccines is limited, and more knowledge is needed to allow greater development and deployment. The goals of this workshop were to examine the mechanisms involved in generating an appropriate immune response to selected carbohydrate antigens, highlight recent and novel advances, and discuss how this information could be used in the development of effective vaccines. The workshop participants included national and international research scientists and clinicians from the National Institutes of Health, the Food and Drug Administration, academia, and industry.Whole microbes, microbial subunits and extracts, and peptide and protein antigens have been the focus of much vaccine research and development. While studies of peptide and protein antigens have been facilitated by the rapid advances in genomics and proteomics, studies of sugar chains, which are abundantly expressed on the outer surfaces of viral, bacterial, protozoan, and fungal pathogens and on the membranes of mammalian cells, have not kept pace with technologic advances. Polysaccharide-based vaccines have demonstrated efficacy in disease-prevention strategies, e.g., Francisella tularensis, a potential weapon of bioterrorism) to T cells. The evidence that CD1-restricted T cells contribute to immunity against microbial infection includes the observation that CD1 is expressed at higher levels in lesions of tuberculoid leprosy in comparison to lepromatous leprosy. The design of optimal vaccines against such pathogens should include lipid and peptide antigens.The meeting was organized into 7 sessions on such topics as genetic and cellular mechanisms of carbohydrate immunity, carbohydrate antigens for vaccines, and new tools for studying carbohydrates. Understanding the mechanistic aspects of the genetic control and the cellular pathways of the immune response to bacterial carbohydrate antigens should provide insights into ways to enhance the immune response and thus facilitate vaccine development. Studies were also presented on novel molecules involved in the recognition of carbohydrate antigens such as specific intercellular adhesion molecule (ICAM)\u2013grabbing nonintegrins, which are C-type lectins that show substantial expression in many tissues, and toll-like receptors, which function as pattern recognition receptors for conserved pathogen structures and serve as key links between innate and adaptive immunity. Investigations are ongoing to determine how these molecules function in bacterial clearance and in signaling innate and adaptive responses. A number of presentations were focused on the role of CD1 proteins, which present lipid antigens  has been established at the Scripps Research Institute and has developed a novel glycan array format that uses covalent coupling of glycans to glass slides.New technologies such as carbohydrate microarrays, automated syntheses of oligosaccharides, and biophysical and computational methods for studying antigen-antibody interactions are now available for providing insight into the structure of and immune response to carbohydrate antigens. Additionally, peptide mimotopes may be used in carbohydrate technologies designed for proteins. An oligosaccharide synthesizer is now being used in the development of a number of vaccines, including those for malaria, leishmaniasis, HIV, tuberculosis, and leprosy. A Consortium for Functional Genomics  elucidating the mechanisms of immunity to and regulation of carbohydrate antigens in adults, children, and neonates and using opportunities  for modeling carbohydrate antigen-antibody interactions; 2) defining the molecular basis of enhanced immunogenicity with glycoconjugate vaccines and investigating the role of adjuvants; 3) examining the role of CD1-reactive T cells in the immune response to capsular polysaccharides; and 4) developing surrogates for in vivo immunity for the use of glycolipids as CD1-based vaccines in humans. Resource needs include the following: 1) enhanced availability of carbohydrate microarrays; 2) development of appropriate animal models and the availability of a transgenic mouse platform that allows generation of human antibodies; 3) development of tetramers and analytical chemistry to help in the identification of antigens, e.g., for the use of glycolipids as CD-1-based vaccines; and 4) enhanced good laboratory practice (GLP) resources to produce synthetic carbohydrate vaccines and GLP testing for vaccine candidate safety in animals and for production of good manufacturing practice vaccine candidates. As a result of the workshop, an open LISTSERV (GLYCOIMMUNOLOGY) has been established, and the Journal of Clinical Infectious Diseases will publish a review article. For additional information, contact ctaylor@niaid.nih.govThe workshop was sponsored by funds from the National Vaccine Program Office and the National Institute of Allergy and Infectious Diseases."}
+{"text": "Normal placental structure and function is essential for a healthy pregnancy; the placenta is responsible for nutrient and oxygen transport, removal of waste products, protection from infection, modulation of the maternal immune system and hormone production to maintain pregnancy. The human placenta is structurally adapted to fulfil this role as it is haemomonochorial, minimising the distance between maternal and fetal circulations to maximise exchange. Disorders of the placenta including: FGR, pre-eclampsia, placental abruption and abnormal (velamentous) cord insertion are associated with over 50% of stillbirths and are frequently cited as the primary cause of death -3.Abnormal placental structure and function significantly increases the risk of stillbirth. Levels of pregnancy associated plasma protein A (PAPP-A) in the lowest 5% and alpha fetoprotein (AFP) in the highest 5% increase the risk of stillbirth by 50-fold and 2.8-fold respectively ,5. In woDue to its central role in determining pregnancy outcome, detailed examination of the placenta can give useful information about the cause of stillbirth and is recommended by the Royal College of Obstetricians and Gynaecologists (RCOG), American College of Obstetricians and Gynecologists (ACOG) and Perinatal Society of Australia and New Zealand (PSANZ) ,13. ExamDespite the value of placental examination to identify conditions associated with stillbirth including: fetal thrombotic vasculopathy, chronic intervillositis, villitis, chorioamnionitis, funisitis, infarction, massive perivillous fibrin deposition, villous dysmaturity , villous immaturity and cord lesions further research is needed to increase the understanding of placental pathology in stillbirth. This is reflected in the research priorities for high-income countries synthesised by an international panel of experts which mention need for repositories of well-phenotyped samples from stillbirths and from well-matched controls and the need to understand the pathophysiological pathways in common conditions associated with stillbirth including: diabetes, cigarette smoking and maternal obesity .An important goal of translational medicine is to use the increased understanding of placental dysfunction to develop improved tests of pregnancy wellbeing. For example, factors derived from the placenta, such as human placental lactogen or placental growth factor may provide novel means to identify pregnancies at highest risk of stillbirth . Discove"}
+{"text": "Jundishapur University of Medical Sciences (AJUMS) officiated as host to the second nanodrugs congress on March 2012, which was held by nanotechnology research center of AJUMS in cooperation with Shahid Chamran University of Ahvaz, Iran. This scientific event was scheduled to be held in a bid to create an appropriate environment for idea exchange among the specialists and researchers active in the field of drug delivery. The objectives of the organization of this congress was introducing the latest achievements in the field of nanodrugs, considering targeted drug delivery aim for the treatment of incurable diseases, improving the life quality and social health, and converting science and technology into wealth.One of the major scopes of the congress was the application of nanotechnology in the field of natural pharmaceutical products. Recently there have been considerable researches on developing biocompatible and biodegradable nanocarriers/nanodevices as novel drug delivery systems. Natural polymers or biopolymers are generally biocompatible, biodegradable, non-toxic and non-immunogenic. They occur widely in nature and are classified into 2 groups; polysaccharides and proteins . ChitosaLipids also are a broad group of naturally occurring molecules that include fats, waxes, sterols, phospholipids, fat-soluble vitamins, mono-, di-, and tri-glycerides which are advantageous to formulation of a wide range of lipid-based nanocarriers; such as solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), and lipid drug conjugates (LDC) to minimize the drawbacks associated with polymeric nanoparticles specially low drug loading for hydrophobic drugs .Moreover some research are being focused on development of novel drug delivery systems for herbal extracts or plant actives, such as polymeric nanoparticles, nanocapsules, liposomes, phytosomes, nanoemulsions, microsphere, transferosomes, and ethosomes, to protect active herbal ingredients from physical and chemical degradation, enhance safety and pharmacological activity, and overcome solubility and bioavailability problems associated with plant medicine . Finally"}
+{"text": "The aim of the study was to evaluate the prognostic value of Killip classification in terms of health-related quality of life (HRQoL).The sample consisted of 112 patients treated for myocardial infarction (MI), as onset manifestation of coronary artery disease (CAD), during 2008/09 in a prefectural hospital in northern Greece. At 1-year follow-up visit, HRQoL was measured using a generic and a disease-specific instrument. The 15D consists of a visual analogue scale (VAS) and a total score. The scoring algorithm of the MacNew generates a global score, and three separate domains scores: emotional, physical and social.Patients were grouped into the four Killip classes according to the degree of pulmonary congestion at admission Table . Mean HRPatients with MI as an onset manifestation of CAD present with varied degrees of pulmonary congestion. The prognostic value of the Killip classification is highlighted in terms of the extent of CAD (number of affected vessels and revascularization technique), of NYHA class and, last but not least, of HRQoL."}
+{"text": "Long standing Hashimoto Thyroiditis (HT) causes shrinking and atrophy of the thyroid, but may also lead to diffuse enlargement of the gland and/or formation of nodules. These nodules should be differentiated from papillary thyroid carcinoma (PTC) and primary thyroidal non-Hodgkin lymphoma (PTL), which are possible complications of HT, and require pre-surgical diagnoses and different treatments.This study focuses on the role of fine-needle cytology (FNC) in the clinical surveillance and pre-surgical diagnosis of HT with diffuse and nodular enlargement of the gland in elderly patients.Thirty-four elderly patients (\u2265 65 yrs) with HT and diffuse or nodular enlargement of the thyroid underwent ultrasound (US)-guided FNC. Smears were routinely stained and evaluated; additional passes were used for flow cytometry (FC) assessment of lymphoid infiltrate in 6 cases.The cytological diagnosis was HT in 12 cases with prevalence of Hurtle cells in 2 cases, PTC in 1 case and PTL in 2 cases. FC assessed the reactive, non-lymphomatous nature of the lymphoid infiltrate in 5 cases and demonstrated light chain restriction, hence the lymphomatous nature of the lymphoid infiltrate in 2 cases of PTL.FNC plays a key role in the clinical surveillance and pre-surgical diagnosis of diffuse enlargement and nodular presentation of HT in elderly patients. FNC can correctly diagnose HT, PTC and PTL indicating the need for surgery and its extension in suspicious or neoplastic cases, leaving other cases to the medical treatment and clinical surveillance. Hashimoto Thyroiditis (HT) is the most common autoimmune disease; the typical clinical presentation is a painless diffuse enlargement of the thyroid, with high serum thyroid autoantibodies ,2. HT isBetween January 2010 and December 2012, 1.256 patients with thyroidal nodules or diffuse swelling underwent FNC in the outpatient clinics of the Azienda Ospedaliera Universitaria, University of Salerno. Before FNC, patients were informed of the diagnostic procedure and related risks; informed consent was obtained from all patients for the performance of FNC, diagnostic procedures and the scientific use of biological material. Sixty patients were diagnosed with HT or suspected HT because of the clinical, serologic, and/or ultrasound (US) presentation. Clinical signs and symptoms included swollen thyroid gland, with or without discrete nodules and, rarely, mild fever. US examination generally showed poorly defined hypoechoic areas, thin fibrous strands with diffuse hypervascular pattern or diffuse glandular enlargement with scattered nodules. Clinical, serological and US data were available for all patients and FNC produced a sufficient amount of cells to prepare adequate cytological smears and perform ancillary techniques, when needed. Whereas the definition of elderly is related to the pathophysiology of aging -33, the The diagnostic procedure and related risks were first discussed with the patients, who were also informed that 1 or 2 supplementary passes might have been needed, and their informed consent was obtained. FNC was performed under US control, as previously described ,36, and The cytological diagnosis was typical HT in 10 cases, HT with prevalence of Hurthle cells in 2 cases, PTC in 1 case and PTL in 1 case. Typical HT showed different cytological patterns due to the prevalence of lymphoid cells or follicular and Hurthle cells. Those with prevalence of lymphoid cells were characterized by small lymphocytes, either isolated or intermingled with histiocytes, occasional plasma cells, and stretched lymphocytes. This pattern was referred as ''lymphocytic'' (6 cases) (Figure HT clinical presentation reflects the pathological modifications of the gland over time. After an initial diffuse swelling, the gland undergoes progressive loss of thyroid follicular cells and replacement by lymphocytes, with the formation of germinal centres and fibrosis. Apoptosis is considered to be the main pathogenetic mechanism of follicular cell destruction; a predominantly Th1-mediated immune activity may promote apoptosis of thyroid follicular cells, leading to thyroid cell destruction and HT , althougFNC has a definite role in the clinical surveillance and pre-surgical diagnosis of thyroidal diffuse enlargement and nodular presentation of HT; it can be conveniently used in elderly patients. FNC can also indicate the need for surgery and its extension in selected cases, as well as the need for medical treatments and clinical surveillance in others.The authors declare that they have no competing interests.PZ, MV: conception and design, interpretation of data, AC, EV, VDS, MV, AG, VDC, MPC: acquisition of data, drafting the manuscript, PZ, MV: critical revision, given final approval of the version to be published.AC = Assistant of Pathology at University of SalernoEV = Assistant of Pathology at University of Naples \"Federico II\"MV = Associate Professor of Endocrinology at University of SalernoVDC = Aggregate Professor of Thoracic Surgery at University of SalernoMC = Aggregate Professor of Anatomy, University of Naples \"Federico II\"CC = Aggregate Professor of Oncology, University of Naples \"Federico II\"AG = Aggregate Professor of Pediatric Surgery at University of SalernoPZ = Associate Professor of Pathology at University of Salerno"}
+{"text": "Recent advancement in genomic and genetic sequencing technology has ushered in a new era in which unprecedented amount of genomic sequence and transcript sequence data with extraordinary detail can be generated at incredibly short time. As part of this advancement, the approaches that utilize the powerful next generation sequencing technology, such as RNA-Seq, may have dramatically changed the field of non-coding RNA (ncRNA) research. Since these new approaches do not require prior knowledge of annotated transcripts for probes, theoretically the entire transcriptome of a given sample can be sequenced. This enables the detection of novel transcripts, including both protein coding and ncRNA, as well as RNA with somatic mutations and alternative splicing forms  bases in the human genome are transcribed into genes that code for proteins , which is believed to be the transcripts of 1\u20133% of the human genome. miRNA is highly involved in brain development and plasticity at the neuronal level (Kapsimali et al., de novo gene mutations also provides valuable and necessary tools for the addiction research field.A much less tapped area in ncRNA research for the understanding of addiction of cocaine, or other substances of abuse, is the lncRNA; Wapinski and Chang, The complexity and abundance of ncRNA, especially lncRNA, mandate advanced non-traditional, large scale and high throughput transcript sequencing, and analysis. While microarray technology enjoys established base and proven utility, the next generation sequencing technology represented by RNA-Seq emerges as the future choice approach for the task because of its unbiased coverage of the entire transcriptome of the genome. In addition, RNA-Seq allows versatile experimental design for sequencing depth and adjustable detection sensitivity, using machines of different throughputs and multiplexing different numbers of samples on a sequencing lane. Furthermore, the inherited benefit of RNA-Seq (Mane et al.,"}
+{"text": "The ninth author's name was spelled incorrectly. The correct name is: Leonidas Stamatatos.Additionally, the correct spelling of the name of the individual who provided SIL, mentioned in the SIL section of Methods, is Ralf Torsten-Pohl."}
+{"text": "We report the development of an international registry for Neurodegeneration with Brain Iron Accumulation (NBIA), in the context of TIRCON (Treat Iron-Related Childhood-Onset Neurodegeneration), an EU-FP7 \u2013 funded project. This registry aims to combine scattered resources, integrate clinical and scientific knowledge, and generate a rich source for future research studies. This paper describes the content, architecture and future utility of the registry with the intent to capture as many NBIA patients as possible and to offer comprehensive information to the international scientific community. Rare mendelian disorders are being characterized with increasing success owing to the rapid development of tools for defining phenotypic and genetic determinants. The elucidation of disease pathogenesis may simultaneously trigger the identification of pathway-specific treatment targets, but the development of disease-modifying medications is often hampered by the fragmentation of efforts and the low number of available patients. The integration of scattered resources is, therefore, crucial for the success of future scientific accomplishments. Here we report the inception of a central data repository for a group of rare disorders collectively called Neurodegeneration with Brain Iron Accumulation (NBIA).6 and consists of several genetically-defined entities that clinically often overlap but also have unique features  manages links to the deferiprone trial database, the NBIA image archive and biobank. The collected information includes demographics, family and patient history, clinical signs, neurological exam, laboratory results, brain iron assessment and volumetry by imaging, treatments and trials. The disease course is captured by standardized scales measuring dystonia severity, quality of life and sleep, functional independence, cognition, motor functioning and activity of daily living. The annually entered information enables a longitudinal reconstruction of the disease course, while genomic, transcriptomic, proteomic and metabolomic data from research on the biobank specimens contribute additional dimensions to the registry.As a central data repository of TIRCON, the NBIA registry  will be entered into the registry database. Together with these patient pseudonyms, codes identifying biospecimens, images, and data in the deferiprone trial database are kept in the registry and safeguarded by a sophisticated security and privacy architecture.The registry\u2019s security and privacy concept builds upon the security architecture of the German mitoNET repository , which For the use of data and biosamples, agreements have been specified and approved by local ethics committees and data protection authorities. Future research proposals will be reviewed by the TIRCON\u2019s Scientific Steering Committee (SSC). If the proposal is approved, pseudonymous or anonymous data will be released to the future investigator, depending on the proposal and the vote of the SSC. As an additional safeguard, re-identification attempts are prohibited by the data use agreements.In summary, this registry longitudinally collects multi-dimensional information on NBIA disorders to provide a rich resource for future natural history studies, evaluations of clinical and paraclinical surrogates or potential predictors of the disease, and correlation analyses of clinical subentities with pathogenic mutations, alleles of disease modifying genes, results of \u201c-omics\u201d and environmental factors. It will support the design of placebo-controlled, randomized, double-blind clinical trials, and allow probing which clinical, imaging or laboratory features of the disease may be modified by a treatment modality. The NBIA registry represents a paradigm fostering integration of international resources for the enhancement of scientific synergism and future research activities in a group of rare diseases.Methods of Information in Medicine, the International Journal of Medical Informatics, it \u2013 Information Technology, and Informatics. He serves on the Scientific Advisory Board of OFFIS, Oldenburg, and he has served for the Austrian Accreditation Council. He receives funding from BMBF grants 01 GM 1113C, 01 KN 1104, 01 EX 1020 E, Z76010067200, 80005012, and EU grants 284209, 277984; Ronald Lautenschlaeger \u2013 Receives personal compensation from TMF e.V.: Umbrella Organization for Networked Medical Research in Germany; Dr. Thomas Klopstock - Has received research support from government entities  and from commercial entities ; Has been serving on scientific advisory boards for commercial entities  and for non-profit entities . He has received speaker honoraria and travel costs from commercial entities . He has been doing consultancies for the Gerson Lehrman Group, USA, and has been serving as a Section Editor for BMC Medical Genetics from 2011. Other co-authors  declare that they have no competing interests.Dr. Bernadette Kalman \u2013 Received travel support and honoraria for giving lectures on MS from Biogen-IDEC and Novartis; Serves as an Associate Editor for BMC Neurology; Received research grants from the NMSS and EMD Serono in the past; Dr. Klaus Kuhn - serves/has served on the Editorial Boards of Bernadette Kalman: Drafted main part and created the final version of the manuscript, designed the clinical and scientific content of the registry.Ronald Lautenschlaeger: Implemented the content and participated in the design of the IT \u2013 architecture and data security concepts of the registry, reviewed and revised the manuscript.Florian Kohlmayer: Participated in the design of the IT - architecture and the data security concept of the registry, reviewed and revised the manuscript.Boriana Buechner: Reviewed and revised the manuscript.Tomasz Kmiec: Contributed to the content of the registry, reviewed and revised the manuscript.Thomas Klopstock: Principal investigator for TIRCON. Contributed to the content design of the registry, reviewed and revised the manuscript.Klaus Kuhn: Designed the IT - architecture and data security concept of the registry, drafted part of the manuscript, reviewed and revised the final manuscript."}
+{"text": "Field trials are extremely important for all facets of research, breeding, and biotechnology. Tree physiology is distinctively different in greenhouses or growth chambers vs. field environments. Thus, results from non-field environments can be very misleading with respect to identification of promising biotechnologies and elite varieties. Large regulatory impediments to conduct of field tests of genetically modified (GM) trees will therefore tend to stifle scientific and technological development. This appears to be the case for genetically modified trees, where regulatory burdens to conducting field tests have grown in stringency in the USA and elsewhere in recent years ,2. Here,Information Systems for Biotechnology (ISB)  maintainPopulus, Pinus, Eucalyptus, and Malus, with the first two accounting for approximately 60% of all field trials , Pinus, Ulmus (American elm), Prunus, Musa, Citrus, and Juglans. Forty field trials are being conducted by private companies, with ArborGen alone accounting for 36 of the 40 active field trials. Cornell University, North Carolina State University, Oregon State University, Purdue University, the United States Department of Agriculture (ARS) and the University of California, Davis are among the public institutions currently conducting field trials. One of ArborGen\u2019s field trials with cold tolerant Eucalyptus covers 197.2 acres. This is the largest current field trial in terms of acres and is being conducted in six different states. In terms of research objectives of current trials, marker genes dominate in terms of frequency of trials, with modification of wood quality the next most common objective.Currently, there are more than sixty field trials covering eleven different genera, with In the USA, transgenic trees are regulated in the same manner as agricultural crops , using rTM apples because of the color of their skin. The company has petitioned the Animal and Plant Health Inspection Service (APHIS) for deregulation of the product in the USA [A company known as Okanagan Specialty Fruits has taken the lead in the production of transgenic tree varieties produced by the insertion of cisgenes and intragenes . Non-bro the USA .Cold tolerant eucalyptus varieties were developed by ArborGen . The comA new two year pilot project has recently been announced by APHIS . Under t"}
+{"text": "Despite increasing control measures, numerous parasitic and infectious diseases are emerging, re-emerging or causing recurrent outbreaks particularly in Asia and the Pacific region, a hot spot of both infectious disease emergence and biodiversity at risk. We investigate how biodiversity affects the distribution of infectious diseases and their outbreaks in this region, taking into account socio-economics , geography (latitude and nation size), climate  and biodiversity . We show, among countries, that the overall richness of infectious diseases is positively correlated with the richness of birds and mammals, but the number of zoonotic disease outbreaks is positively correlated with the number of threatened mammal and bird species and the number of vector-borne disease outbreaks is negatively correlated with forest cover. These results suggest that, among countries, biodiversity is a source of pathogens, but also that the loss of biodiversity or its regulation, as measured by forest cover or threatened species, seems to be associated with an increase in zoonotic and vector-borne disease outbreaks. The Asia-Pacific region, and particularly Southeast Asia, is recognized as a hotspot for biodiversity Infectious disease (ID) incidence has clearly increased during recent decades et al.The increased interactions between humans and wildlife resulting from habitat fragmentation are also affected by changes in wildlife species richness and community composition. At the local level, a reduction in biodiversity may lead to an increase in the prevalence and transmission rates of certain vector-borne diseases as reviewed by Keesing The original level of biological diversity is also important to explain the overall richness of infectious diseases Here, we explored the effects of biodiversity on patterns of infectious disease richness and outbreaks in Asia-Pacific. We considered two predictions related to the diversity of infectious diseases and the number of infectious disease outbreaks. First, the richness of ID should increase with increasing biodiversity , supporting regionally the pattern observed globally by Dunn et al. www.gideononline.com), which contains information on the presence of human infectious diseases and occurrence of epidemics in each country. This source has regularly been used in comparative studies of pathogen diversity http://worldbank.org/ddp/home.do) included country area and population, per capita gross domestic product (GDP), per capita health expenditure, forested surface area and forest as a proportion of each country\u2019s total area. Data on bird and mammal species richness are from Bird Life International (http://birdlife.org/datazone/home) and the International Union for Conservation of Nature . Per capita healthcare expenditure and the number of diseases for which a survey has been conducted in a country (GIDEON) were used as measures of investigation effort. The increase in health expenditure through time is likely associated with an increase in surveillance detection  and outbreak reporting. This information was obtained from the Total Economy Database (www.conference-board.org/data/economydatabase/). We restricted our analyses to 28 countries for which sufficient data were available  using the package ade4 (version 1.5\u20132) implemented in the R freeware programming environment . Correlation analyses and PCA allowed the identification of highly correlated variables such as latitude and temperature, or evapo-transpiration and mean annual precipitation . This fiWe used general linear models (GLMs) using package lme4 implemented R 2.10 to explain disease richness and number of outbreaks as a function of our explanatory variables. In order to explain to explain the richness in infectious diseases, an initial model included the following explanatory variables : mean annual temperature, mean annual precipitation, bird and mammal species richness (in log), population size (in log), nation size (in log), number of surveys, GDP and health expenditure. These explanatory variables included the ones selected in the study of Dunn et al. A second initial model, in order to explain the total number of outbreaks, included the following explanatory variables: mean annual temperature, mean annual precipitation, bird and mammal species richness (in log), population size (in log), nation size (in log), number of survey, GDP, health expenditure and richness of infectious diseases. We added also two other variables that represent the importance of impacts on biodiversity, the number of threatened bird and mammal species and the percent forest cover of the country. Additionally, we separated the disease outbreaks into three types: total, zoonotic, and vector-borne, and modelled each category. Selection of the best models was done using a step forward procedure based on AICc criterion. Initial and intermediate models are given in In order to illustrate graphically the effects of patterns of biodiversity and biodiversity loss on the richness and total number of outbreaks, we used the residuals of the selected regression models.The best model showed that the richness of infectious diseases is positivey linked to temperature (i.e. climate), population size and richness in bird and mammal species see . A countUsing the GIDEON data base, and over the period from 1950 to 2008, 124 different diseases with epidemics were identified in Asia-Pacific countries. An increase in both the number of outbreaks and the number of different diseases causing outbreaks through time was observed .Three models were created to explain the number of total infectious diseases, the total number of zoonotic infectious diseases and the total number of vector-borne diseases with outbreaks  and the occurrence of epidemics in order to investigate different scenarios for the effects of changes in biodiversity on infectious risks File S1(DOC)Click here for additional data file.File S2(DOC)Click here for additional data file."}
+{"text": "India has made appreciable progress and continues to demonstrate a strong commitment for establishing and operating a disease surveillance programme responsive to the requirements of the International Health Regulations (IHR[2005]). Within five years of its launch, India has effectively used modern information and communication technology for collection, storage, transmission and management of data related to disease surveillance and effective response. Terrestrial and/or satellite based linkages are being established within all states, districts, state-run medical colleges, infectious disease hospitals, and public health laboratories. This network enables speedy data transfer, video conferencing, training and e-learning for outbreaks and programme monitoring. A 24x7 call centre is in operation to receive disease alerts. To complement these efforts, a media scanning and verification cell functions to receive reports of early warning signals. During the 2009 H1N1 outbreak, the usefulness of the information and communication technology (ICT) network was well appreciated. India is using ICT as part of its Integrated Disease Surveillance Project (IDSP) to help overcome the challenges in further expansion in hard-to-reach populations, to increase the involvement of the private sector, and to increase the use of other modes of communication like e-mail and voicemail. With the adoption of the International Health Regulations [IHR(2005)] by the World Health Organization (WHO), it has become obligatory for the Member States to put in place requisite manpower, money and material to comply with the provisions of the regulation. Each signatory country is expected to achieve identified capabilities, including developing and maintaining core capacities to detect and respond to potential public health emergencies of international concern (PHEIC) within its national borders. Use of modern tools of communication and international technology has helped to scale-up the rapid sharing of data.For rapid detection and response to any outbreak, natural or deliberate, a sensitive surveillance system is essential. A good communication system is the \u2018brain\u2019 of the surveillance system. It is the speed of communication which is most critical to contain or stamp out an outbreak, save lives, and prevent misery. It is challenging, however, to set up an effective communication system, and even more so in a country as large, populous, and technologically and linguistically varied as India.India, with an estimated population of 1.15 billion in 2010, supports almost one fifth of world\u2019s population on only about 2.5 percent of its surface area . This evThe Union Ministry of Health & Family Welfare adopted an Integrated Disease Surveillance Project (IDSP) to connect all district hospitals and state-run medical colleges to facilitate tele-education, training of health professionals and monitoring of disease trends. The disparity between states\u2019 urban and rural regions is bridged using modern information and communication technology (ICT). The goal of this World Bank-assisted project (USD 102 million), is to establish a decentralized, state-based disease surveillance system. The project aims to detect early warning signals of impending disease outbreaks and initiate effective and rapid health actions with the help of ICT at the district, state and national levels. The project is implemented through the Central Surveillance Unit within the National Centre for Disease Control (NCDC) at New Delhi .The IDSP is being strengthened to make it compliant with IHR(2005) requirements by supporting a nationwide effort for the immediate reporting of outbreaks. The establishment and operation of decentralized surveillance system meeting performance standards, with technical support from the WHO and the U.S. Centers for Disease Control and Prevention (CDC) in the areas of disease surveillance and outbreak investigations, health informatics, and laboratory-based surveillance, has been vital in implementation of IHR(2005). Several specific steps have been taken to:1) enhance the quality and frequency of use of communication network;2) further training for district level epidemiologists and data managers on use of portal;3) streamline the urban surveillance component;4) enhance networking of infectious disease hospitals;5) improve quality and timeliness of reporting.Some of the key components of the IDSP in India include:\u2022 Integration and decentralization of surveillance activities through establishment of surveillance units at national, state and district levels;\u2022 Human Resource Development through training of State Surveillance Officers, District Surveillance Officers, multi-disciplinary Rapid Response Teams, and other medical and paramedical staff on all aspects of disease surveillance;\u2022 Use of ICT for the collection, collation, compilation, analysis and dissemination of data through a web portal;\u2022 Strengthening of public health laboratories.In addition to monitoring diseases like vector borne infections, diarrhoeal diseases, respiratory diseases, and vaccine preventable diseases, the IDSP also has a category called \u2018unusual clinical syndromes,\u2019 which would alert public health professionals to an intentional release of any biological-agent. The local governments in each state have the option to add any other health condition to the list as deemed appropriate. The ICT network is then used for the collection, analysis, and rapid communication of data.Eight hundred sites have been identified to be part of an ICT satellite network. Sites include District Headquarters (604), State Headquarters 35), academic institutions like Government Medical Colleges (133), premier medical institutions (15) and Infectious Disease Hospitals (7). At the national level these are connected to the National Informatics Centre, the Central Surveillance Unit (at the NCDC) and the Ministry of Health & Family Welfare. [, academiThe India Space Research Organization (ISRO), through its Education Satellite (EDUSAT), has connected 360 of the 400 ICT network sites. The network operation centre  is housed at the NCDC, and the Satellite Interactive Terminals (SITs) are located at State Headquarters, District Surveillance Units and Government Medical Colleges. ISRO connects all sites in northeastern states, hilly and island states, Tamil Nadu, Gujarat, and Maharashtra. The National Informatics Centre (NIC) has provided terrestrial (broadband) connectivity to 776 of the 800 sites. It has also provided high-end video conference equipments at all state and Union Territory headquarters. Upon completion, the network will enable 800 sites on a broadband network of which 400 sites will have dual connectivity with satellite and broadband ,6.http://www.idsp.nic.in) with options for data entry and analysis from the district level upwards related to disease surveillance. It is quicker, easier, and more powerful to update than print-based media. The portal can also convert data into charts and graphs. The data entry operators and data managers have been trained in data entry, analysis and transmission. The portal also has information on media and outbreak alerts.The NIC has created a single-stop web portal  .The telecommunication industry is one of the fastest growing industries in India. The total telephone subscription base is approaching 600 million . The oveData is collected and reported on a weekly basis under the IDSP. When health workers at sub-centres suspect a case, they fill out Form-S (suspect case). The doctors at Primary Health Centres, Community Health Centres and Hospitals fill form P (probable case/presumptive case). The cases that are confirmed by the laboratory fill up Form L (lab-confirmed case). Data managers receive these completed forms from various centres, and data compilation and analysis is done at the district, state and national levels. Cases representing and unusual or rising trends are investigated by a Rapid Response Team (RRT) to diagnose and control the outbreak. Major hospitals and Infectious Disease Hospitals are also required to report surveillance data. Eighty-five percent of all districts are now reporting weekly data to IDSP ,6.To ensure preparedness and enhance the quality of disease surveillance, regular video conferences are organized by central surveillance unit of IDSP to discuss outbreak investigations and verification and control measures with various State Surveillance Officers, District Surveillance Officers and the Rapid Response Teams. Additionally, project review and monitoring for different aspects of the IDSP is undertaken periodically. Video conferencing facilities are also used for training purposes ,6.For efficient functioning of the surveillance system training of various IDSP functionaries is an on-going process. Educational satellite (EDUSAT) classrooms are available at State Headquarters, District Headquarters, Medical Colleges, Premier Institutions and Infectious Disease Hospitals ,9. The cThe call centre received 35,000 calls related to H1N1. The video conferencing facilities were used for training of medical officers in clinical management, infection control practices and laboratory support. The network also facilitated prompt receipt of test results.Appreciable progress has been made in putting together the infrastructure and development of skills to make the ICT network functional in disease surveillance programme. As previously mentioned, 776 out of 800 sites have been networked, 738 sites have videoconferencing facilities, about 850,000 sub-centres send weekly report on syndromes, about 150,000 Primary Health Centres, Community Health Centres, and hospitals send list of probable cases. Facilities for distance education have also been established. There are other areas which still need to be addressed, including encouraging private sector reporting, strengthening skills for data use and analysis at all levels, enhancing the convergence of information and communication technology with other national health programmes, improving media scanning and verification, and making data transmission all-inclusive by incorporating, mobile, text, voice, email and fax.CDC: Centers for Disease Control and Prevention; EDUSAT: Education Satellite; ICT: Information and Communication Technology; IDSP: Integrated Disease Surveillance Project; ISRO: Indian Space Research Organization; NCDC: National Centre for Disease Control; NIC: National Informatics Centre; PHEIC: Public Health Emergencies of International Concern; SIT: Satellite Interactive Terminals; WHO: World Health Organization; IHR: International Health Regulations.The authors declare that they have no competing interests.LK: developed the concept, drafted and finalized the manuscript. SKK: provided information, revised the manuscript.Both authors read and approved the manuscript."}
+{"text": "There is a dearth of evidence regarding the impact of urban regeneration projects on public health, particularly the nature and degree to which urban regeneration impacts upon health-related behaviour change. Natural experiment methodology enables comprehensive large-scale evaluations of such interventions. The Connswater Community Greenway in Belfast is a major urban regeneration project involving the development of a 9 km linear park, including the provision of new cycle paths and walkways. In addition to the environmental improvements, this complex intervention involves a number of programmes to promote physical activity in the regenerated area. The project affords a unique opportunity to investigate the public health impact of urban regeneration.The evaluation framework was informed by the socio-ecological model and guided by the RE-AIM Framework. Key components include: (1) a quasi-experimental before-and-after survey of the Greenway population , in tandem with data from a parallel Northern Ireland-wide survey for comparison; (2) an assessment of changes in the local built environment and of walkability using geographic information systems; (3) semi-structured interviews with a purposive sample of survey respondents, and a range of community stakeholders, before and after the regeneration project; and (4) a cost-effectiveness analysis. The primary outcome is change in proportion of individuals identified as being regularly physically active, according to the current UK recommendations. The RE-AIM Framework will be used to make an overall assessment of the impact of the Greenway on the physical activity behaviour of local residents.The Connswater Community Greenway provides a significant opportunity to achieve long-term, population level behaviour change. We argue that urban regeneration may be conceptualised meaningfully as a complex intervention comprising multiple components with the potential, individually and interactively, to affect the behaviour of a diverse population. The development and implementation of our comprehensive evaluation framework reflects this complexity and illuminates an approach to the empirical, rigorous evaluation of urban regeneration. More specifically, this study will add to the much needed evidence-base about the impact of urban regeneration on public health as well as having important implications for the development of natural experiment methodology. Most people in high income countries lead inactive lives, fuelling the rise in non-communicable diseases . PhysicaA review of gaps in the evidence for physical activity promotion highlighted a need for socio-ecological studies of community interventions . A systea priori hypotheses, clear definitions of target populations, explicit sampling criteria and the use of valid and reliable measures of outcomes [Given the scale, it is impossible for researchers to implement built environment interventions and therefore the use of natural experiments has often been the only option to evaluate the impacts of such interventions on health and wellbeing. Natural experiments are interventions that are not under the control of researchers, but often employ observational methods to understand the effects, compared to a control or comparison group . The metoutcomes .The aim of this study is to determine the impact of a systems-wide community intervention to promote physical activity in the context of a major inner city urban regeneration project.Specific objectives include evaluating:(i) The impact of a suite of community-based interventions to promote physical activity;(ii) The role of the local built environment, and of individual, community and organisational networks in sustaining change; and,(iii) The cost-effectiveness of this socio-ecological and systems-based approach to effecting physical activity behaviour change.The Connswater Community Greenway (CCG)  is an exThe PARC Study is a before-and-after evaluation of the effects of the CCG on physical activity and health, and comprises of four main elements:1. A quasi-experimental before-and-after survey of the CCG population , utilising data from a parallel Northern Ireland-wide survey for comparison;2. Assessment of change in the local built environment and walkability using geographic information systems (GIS);3. Semi-structured interviews with 60 residents, and a range of community stakeholders before and after the regeneration project;4. A cost-effectiveness evaluation.The study has been approved by the Office for Research Ethics Committees, Northern Ireland (09/NIR02/66).A survey of a random selection of households will be conducted before-and-after the regeneration of the CCG. The target area was selected as 29 electoral wards identified during the development of the CCG project Figure\u00a0. The samThe survey content is informed by, and reflects the various levels of, the socio-ecological model comprising measures of individual, community and environmental factors Figure\u00a0. The priOutcomes which may moderate/mediate the relationship between changes in the built environment and physical activity will be assessed. These include (i) perceptions of the characteristics of the environment associated with active travel and physical activity, including aesthetics, safety and walkability  - a \u201cwalTo control for the possible influence of weather patterns on physical activity, data for the seven days preceding interview will be collated from the nearest weather station via the UK MET office. This will include daily rainfall, hours of sunshine, minimum and maximum temperature and wind speed.In addition to participating in the household survey, a randomly selected sub-sample of 100 residents will be invited to wear an Actigraph GT3X accelerometer  at both time points (before and after CCG construction) to provide an objective measure of physical activity for comparison with self-reported questionnaire data (GPAQ). Participants will be asked to wear the accelerometer from the time they wake-up to the time they go to bed, for seven consecutive days. Standard cut-off values for moderate and vigorous physical activity will be used to calculate total minutes of moderate and vigorous physical activity per week .Comparison data will be drawn from Northern Ireland-wide surveys of physical activity in approximately 4,000 randomly selected individuals from the general population at the same two time points . This wiThe sample size was estimated using the same method as Cochrane et al. , based o2 test. Multinomial logistic regression will be used to test a prediction model for categories of change in physical activity by area/age/income bracket, allowing a comparison of odds ratios for the various categories of physical activity by area [Area-by-category classifications of change in the proportion of the population meeting the physical activity guidelines will be compared by cross-tabulation and the difference in distributions assessed for statistical significance using the \u03c7 by area . A key sIn addition to the household survey, a comprehensive process evaluation, informed by the socio-ecological model, will be conducted before and after CCG construction Figure\u00a0.A purposive maximum variation sample of 60 households representing varying distance from the Greenway, and individuals of a range of age, gender and socio-economic position (SEP) will be selected and invited to participate in detailed semi-structured interviews. Participants will be identified from respondents to the household survey. The interviews will explore the effects of key determinants on physical activity behaviour. Specific topics will include (i) perceptions of own health, its determinants and lifestyle behaviours, (ii) perceptions of the barriers and facilitators to healthy lifestyles, (iii) effects of local environment on behaviours, motivation and personal health, (iv) knowledge of the Greenway and related local health promotion initiatives, and (v) perceptions of the quality of the local environment, including safety issues and expectations from the urban regeneration. The same participants will be interviewed at two time points, pre and post CCG construction. The qualitative data emerging from this series of interviews will add richly to the explanatory power of our quantitative data .Physical activity intervention design and implementation can benefit from meaningful participation of the community and relevant agencies. Focus groups (n=14) will be conducted with community stakeholders utilising the networks and knowledge of local community agencies. This collaborative approach will facilitate purposive sampling to recruit adults for the focus group discussions representing the diverse population of the study area . Topics explored will include engagement in physical activity, barriers and facilitators to physical activity in the local area, views on local facilities and opportunities for physical activity and the perceived usefulness of the proposed Greenway to encourage local residents to be more active. Focus groups will be audio-recorded and data will be analysed using a mixture of text-based content analysis and thematic analysis ,37.The sustainability of any efforts to support behaviour change at both individual and organisational levels will depend on the strength and empowerment of the community and inter-organisational networks. An assessment of the processes that facilitate or inhibit the effective implementation of the intervention strategy will form an integral part of the overall design . The evoIn order to examine the specific influence of changes to the built environment, GIS data of the environmental features in the area at the finest available spatial level  pre- and post-regeneration will be collected. This will include mapping of the footpath network  across the study area, topography, transport features, physical activity opportunities, for example, green space, local amenities, parks, using a mix of aerial photography, and checked using open source spatial data and aerial photography. The network will be tested and validated by peer checking of mapped elements and ground-truthing  to assure its quality. The development and validation of the Real Walkable Network will be the subject of a future publication. These data will be used to revise the \u201cwalkability index\u201d for a 500 m and 1000 m buffer zone around the household of each respondent to the household survey. Analysis will include an assessment of the changes in walkability of the neighbourhoods and the influence of distance decay (exposure to the regeneration project) on physical activity behaviour. We will also map and describe individual household level change in objectively measured accessibility to the regenerated, environmental physical activity opportunities and examine the association between change to the built environment and change in physical activity and other health-related outcomes.Direct observation of usage of the Greenway will be conducted in two ways: (i) conducting before-and-after Intercept Surveys of CCG use (at four locations on the Greenway), adapting SUSTRANS methodology; (ii) employing the SOPARC (System for Observing Play and Recreation in Communities) methodology, a validated technique to assess the use being made of green space and parks in the area before and after the construction of the CCG . We willFurther, effective mechanisms are in place to collect information to assess the reach, \u2018dose\u2019 and fidelity of intervention implementation and of the resources used. The Belfast Health and Social Care Trust and the East Belfast Community Development Agency will collect core data on the number of people enrolling and completing various physical activity promotion initiatives in the CCG area.During the construction of the Greenway, aspects of local or regional transport infrastructure and policy may change, with implications for the active travel behaviour of local residents. Changes will be monitored using routinely available information, including bus timetables and traffic survey data collated by the Department for Regional Development (DRD). The latter will yield comparative information on average annual distances travelled by all forms of transport and access to and use made of public transport. DRD also collects routine information on bicycle use via electronic monitors dispersed throughout the city. In addition, effects on road traffic accidents will be monitored using routinely available statistics, compiled by the Police Service of Northern Ireland (PSNI). The effect of the urban regeneration on tenancy turnover rates, the quality of local social housing stock, and crime statistics in the target area and in neighbouring areas will also be monitored using Northern Ireland Housing Executive and PSNI data respectively.Conducting an economic evaluation of environmental interventions that promote physical activity is fraught with methodological difficulties and multiple approaches have been recommended . FirstlyReach, Effectiveness, Adoption, Implementation and Maintenance of any changes wrought by the regeneration [The RE-AIM Framework will be used to make an overall assessment of the impact of the Greenway on the physical activity behaviour of local residents, so that we have a clearer understanding of the neration ,48. ThisA major urban regeneration project has afforded a unique opportunity to evaluate a \u2018real world\u2019 natural experiment. The CCG is a complex intervention with multiple interacting components affecting a diverse population. Many challenges must be overcome in the development and implementation of an evaluation of such an intervention, requiring both methodological innovation and development.In response to the Foresight report  and WanlThe RE-AIM Framework has been used to guide the evaluation of interventions that address the different levels of the socio-ecological model, including individual, community, organisational, and population level. King and colleagues  have refA comprehensive evaluation framework has been developed by a multi-disciplinary research team comprising of academics from public health, economics, sociology, psychology, statistics and spatial planning. The research team has actively engaged with the local community partnerships, city council, health practitioners and a variety of government departments in planning the evaluation framework. Previous research suggests that building meaningful partnerships of diverse communities can improve health outcomes . The PARCCG: Connswater Community Greenway; DRD: Department for Regional Development; EAPRS: Environmental Assessment of Public Recreation Spaces; EQ-5D: EuroQol-5D; GIS: Geographic Information Systems; GPAQ: Global Physical Activity Questionnaire; ICER: Incremental Cost-effectiveness Ratio; PAF: Postcode Address File; PARC: Physical Activity and the Rejuvenation of Connswater; PSNI: Police Service of Northern Ireland; RE-AIM: Reach, Effectiveness, Adoption, Implementation, Maintenance; SEP: Socio-economic Position; SF-8: Short Form 8 Health Survey; SOPARC: Systems for Observing Play and Recreation in Communities; SportNI: Sport Northern Ireland.The authors declare that they have no competing interests.All authors contributed to the development of the study protocol and to the critical revision of the paper and approved the final version. FK  had the original idea for the study and led the design of the study and the application for grant funding. MT, HMcA, GE, GH, LP, MD, MS, and MC (co-investigators) contributed to the design and writing of the original protocol and funding application. RH and MT wrote the first draft of the manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/13/774/prepub"}
+{"text": "In silico methods are used in genome studies to discover putative regulatory genomic elements . Although a number of methods have been developed for motif discovery, most of them lack the scalability needed to analyze large genomic data sets.An important focus of genomic science is the discovery and characterization of all functional elements within genomes. word space and (2) scores words with a distributed Markov chain model.This manuscript presents WordSeeker, an enumerative motif discovery toolkit that utilizes multi-core and distributed computational platforms to enable scalable analysis of genomic data. A controller task coordinates activities of worker nodes, each of which (1) enumerates a subset of the DNA Arabidopsis thaliana; the results of the analysis were integrated into The Arabidopsis Gene Regulatory Information Server (AGRIS). A public version of WordSeeker was deployed on the Glenn cluster at the Ohio Supercomputer Center.A comprehensive suite of performance tests was conducted to demonstrate the performance, speedup and efficiency of WordSeeker. The scalability of the toolkit enabled the analysis of the entire genome of WordSeeker effectively utilizes concurrent computing platforms to enable the identification of putative functional elements in genomic data sets. This capability facilitates the analysis of the large quantity of sequenced genomic data. The importance of discovering the patterns and features in genomic sequences is motivated by a number of scientific contexts. The Encyclopedia of DNA Elements project (ENCODE) seeks \u2018to identify all functional elements in the human genome sequence\u2019 . Anotherwords) or sets of related substrings  in DNA sequences. Most enumeration methods create a data representation of the input sequence(s) that provides fast retrieval of elementary word statistics. The representation serves as a central data structure for a number of other analyses, including statistical word scoring, word-clustering, and motif discovery. A number of algorithmic techniques for word space enumeration have been proposed. Each of the enumeration algorithms can be classified as either index-based range.Figure Figures Speedup and efficiency experiments were performed to assess in detail the scalability and the performance boundaries of the WordSeeker implementation. Figures The speedup and efficiency results show a drop in performance for very short words (5bp) and for very long words, (50bp and 75bp), but yield good results for word lengths of 10bp and 20bp. The performance drop for short word lengths occurs because the parallelization overhead outweighs the computational benefit; for longer word lengths, cache inefficiency and front-side bus contention cause performance to decrease (see  for a deWordSeeker is a general purpose, scalable, open source approach to word enumeration. It supports an important set of use cases, has been applied to interesting case studies, and effectively exploits parallel and distributed computing hardware to provide scalable performance.WordSeeker is being used currently to perform complete word space enumerations on a genomic scale; to construct word and motif encyclopedias for whole genomes; to perform word-based characterizations of pathways, tissues, and co-regulated genes; and to identify motifs in ChIP-Seq data. Ongoing work includes the construction of OpenMotif, a project that combines a number of motif discovery open source projects into a cohesive framework.ENCODE: Encyclopedia of DNA Elements; DNA: Deoxyribonucleic acid; AGRIS: The Arabidopsis Gene Regulatory Information Server; UTR: Untranslated Region; ChIP-chip: Chromatin Immunoprecipitation with microarray technology; ChIP-Seq: Chromatin Immunoprecipitation with massively parallel DNA sequencing; OWEF: Open Word Enumeration Framework; MPI: Message Passing Interface; A, C, G, T: Adenine, Cytosine, Guanine, Thymine; RAID: Redundant Array of Independent Disks.The authors declare that they have no competing interests.JL contributed to the design, implementation and validation of the algorithms and models, the generation of the results and the writing of this document. KK, LN, LJN contributed to the development and implementation of the models and algorithms and the generation of the results. XL, RA contributed to the generation of the results. JDW, EJ and TB contributed to the development and implementation of the models and algorithms. KE and SSL contributed to the development of the models and algorithms. LE contributed to the development of the biological models. In addition to conceptualizing the architecture employed in this research, FD and LRW contributed to the design and validation of models and algorithms, and to the writing of this manuscript."}
+{"text": "The health system in India suffers from low level of public spending and high out of pocket payment. Public health facilities are funded on a fixed and uniform basis irrespective of their needs and performance. The National Rural Health Mission has introduced an innovative approach of flexible financing to public health facilities under Untied Funds (UF), Annual Maintenance Grant (AMG) and Aarogya Raksha Samithi Corpus Funds (ARS). Funds are currently allocated @ of INR 10000 at village level, INR 20000 at subcentre level, INR 175000 at Primary Health Centre, INR 250000 at community health centre and INR 500000 at district hospital level. Though funds are allocated to health facilities with adequate guidelines and flexibility, utilization of these funds is poor. Given the limited resource available for healthcare in the country, there is a need to rationalize the distribution of funds and allocate them efficiently. We undertook a study to propose a differential financing model for public health facilities.We conducted a cross sectional study of 46 primary and secondary level facilities in two districts of Karnataka in the year 2011-12. Retrospective data on resources, finance and performance of 2008-09, 2009-10 and 2010-11 were collected. In addition, interviews were conducted with members of ARS committee responsible for taking decisions on utilization of funds.The study found that utilization of funds in health facilities are influenced by several factors. These included per-capita allocation, distance from district headquarter, availability of equipment and infrastructure.We observed that there was no definite trend of impact of availability of human resources, number of beds, staff residing at the facility compound, training, cooperation among members and availability of guidelines on utilisation of funds at health facilities.The study strongly advocates the need for a more rational and systematic planning for utilization of funds allocated to health facilities taking into consideration other health system constraints. The study proposes a formula for allocating funds on differential financing method: at the village level committee at INR 10 per-capita, at the sub-centre level at INR 4 per-capita, for primary health centre at INR 6 per-capita, at the level of community health centre at INR 1.04 per-capita and at INR 4167 per functional bed and the current norm of INR 500000 per district hospital. Such a model would result in efficient utilization of funds, leading to better of quality of delivery of services.None declaredThe study was funded by the Karnataka State Health System Resource Centre, Bangalore and the Centre for Budget and Policy Studies, Bangalore."}
+{"text": "AbstractPossibilities of the assessment of a landscape with the use of succession development stages, monitored with the value of the Mean Individual Biomass (MIB) of carabid beetles and the occurrence of bird species are discussed on the basis of an example from Poland. Higher variability of the MIB value in space signifies a greater biodiversity. Apart from the variability of MIB, it is suggested to adopt the occurrence of the following animals as indicators, (in the order of importance), representing underlying valuable landscapes: black stork, lesser spotted eagle, white-tailed eagle, wolf, crane and white stork. The higher number of these species and their greater density indicate a higher value of the landscape for biodiversity and ecosystem services, especially carbon sequestration. All these indicators may be useful to assess measures for sustainable land use. As part of the ongoing discussion on the sustainable use of landscapes and ecosystem services we give here an overview on the relationship between biodiversity and carbon sequestration in forests as revealed by a long-term study in north-western Poland with particular reference to carabid beetle diversity.From the very beginning of life, environmental resources on Earth have been shaped by natural succession processes, influenced by climate, and by various disturbances such as orogenic movements, windfall, floods and fires. Depending on latitude and the geological base, these disturbance factors vary among various places on the globe. The lack of catastrophes entails the buildup of organic substances, which can be measured simply with the content of carbon. The content of carbon in a single hectare of natural forest of the moderate climatic zone shaped by succession processes for thousands of years, exceeds 350 tons/ha with upper limits estimated between 500 and 700 tons/ha . Half ofCaprimulgus europaeus), skylark (Alauda arvensis), northern dune tiger beetle (Cicindela hybrida) and, with the appearing pine wilding, the sticky bun (Suillus luteus) can strive (PageBreakPageBreakIn such old forests (old ecosystems created by nature), ecosystems have a specific composition of plant, animal and fungal species. Species that are linked to old trees, old decaying wood, and well developed soil, occur here . In suchn strive . The cren strive . Such spn strive .Camprimulgus europaeus) and woodlark (Lullula arborea) would have had no place to nest and the majority of birds of prey nesting in old trees would not have been able to hunt. Carabid beetles like Carabus nitens, Bembidion nigricorne, Pterostichus lepidus, Calathus erratus, Masoreus wetterhallii and Harpalus rufitarsis  would not have occurred in this region (Suillus luteus), sulfur tufts (Hypholoma fasciculare) or, slightly later, chanterelles (Cantharellus cibarius) and porcinis (Boletus edulis) would not have been possible (PageBreakPageBreak(about 250 mg) is higher compared to a young pine plantation (Fringilla coelebes), great tit (Parus major) and coal tit (Parus ater). Carabids characteristic for this stage of succession include Carabus arcensis, Carabus nemoralis and Pterostichus niger and the most frequent and numerous fungi include the sickener (Russula emetica), brown roll-rim (Paxillus involutus), false morel (Gyromitra esculenta) and the cauliflower mushroom (Sparassis crispa). The planting of beech as undergrowth in ca. sixty year old pine stands followed by the removal of the pines ten years later results in the creation of beech stands, several of which in Poland are about eighty years old (Drycopus martius), stock pigeon (Columba oenas) and chaffinch (Fringilla coelebes). Characteristic carabids include Carabus coriaceus, Carabus hortensis and Carabus intricatus. Characteristic fungi are the dotted stem bolete (Boletus erythropus), fleecy milk-cap (Lactarius vellereus) and the death cap .Humans play a similar role in shaping ecosystems and landscapes. Ecological catastrophes can destroy the effects of our economic activities and constitute a danger our its safety. This is why humans manage the environment by trying to reduce floods, fires and windfalls. However, to preserve the full range of biodiversity, humans replace the forces of nature and mimic its destructive role by active management. This can clearly be illustrated for forests in Poland. If it was not for the interference with natural succession and the reduction of the carbon content of up to a few dozen tons per ha  due to cs region . Additiopossible . The despossible , carbon antation . The speears old , Fig. 4cCiconia nigra) and the lesser spotted eagle (Aquila pomarina)  and the wolf (Canis lupus) (Grus grus) and white stork (Ciconia ciconia)  . These bs lupus) . The exiciconia) . Cranes in space . In lighin space .Landscape quality includes biodiversity (highest in mosaic landscapes) and carbon storage (highest in peat bogs and old forests) and sequestration (highest in regenerating forests), as well as other ecosystem services. Sustainable land use is essential in maintaining or creating landscapes with high natural qualities. There is a need to assess measures of sustainable land use, and various animals mentioned in this paper, including carabid beetles and their MIB values, may serve as important indicators for this."}
+{"text": "Natural product medicine (NPM) has been used to prevent and treat various human diseases in China, India, Japan, and other countries for centuries. Due to its long historical clinical uses and excellent therapeutic efficacy, NPM more and more attracts global attention, and many research institutes and pharmaceutical companies have been actively exploring NPM as a source for new drug discovery and development . HoweverWith the development of globalization and modernization of NPM, an important issue is the consistency and control ability of quality of NPM. Traditionally, identification of NPM is performed according to its morphological character, one or a few markers' thin-layer chromatography identification, and/or content determination , 4. HoweThe characteristics of action of NPM are synergistic action of multicomponents and multitargets . By a coIn this special issue of quality control of NPM and nutrient supplements, 15 research papers have been published by the previously mentioned chromatographic or spectroscopic methods and contributed to quality control of NPM. These papers focused on the quantification analysis of multiple chemical components, bioactivity and their mechanism of actions of chemical components, and pharmacokinetics and tissue distribution studies.Evodia rutaecarpa has been completed by HPLC-DAD method. The results indicated that the quality control of Evodia rutaecarpa could be simplified to the measurement of four constituents and that limonin, 1-methyl-2-undecyl-4(1H)-quinolone, and dihydroevocarpine should also be served as the chemical markers together with evodiamine for the quality control of Evodia rutaecarpa.Firstly, multicomponents determinations play a critical role in evaluating the quality of NPM and understanding the synergistic action of multicomponents and multitargets. Multicomponents quantitative methods of NPM were reported in this special issue. Among the analytical methods for NPM, HPLC with easy operation, high accuracy, and wide suitability is still the most popular method for the qualitative and quantitative analyses of NPM. For example, simultaneous quantification of limonin and six alkaloids in in vitro or in vivo experiments in this special issue. Secondly, active components of NPM should be clarified by different methods in order to achieve better quality control of NPM and nutrient supplements. The bioactivities of pure compounds or crude extract form NPM have been evaluated by Last but not least, with the development of pharmacy, more and more researchers focus their attention on pharmacokinetics in drug discovery. Pharmacokinetics including absorption, distribution, metabolism, and excretion is regarded as the foundation of new drug discovery. Pharmacokinetics encompasses a broad spectrum of experiment and connotation. Five articles devoted to pharmacokinetics and identification of metabolites from pure compounds or crude extract of NPM. The complexity of single herbs or compound preparations causes diverse pharmacokinetics, and these articles provide key information for researchers in the future studies.All in all, the published research papers will contribute to the development, improvement, validation, and/or extension of application of analytical methodology in the natural medicine sciences and nutrition supplements. Quality control of NPM has to establish reasonable analytical methods for analyzing the active constituents in NPM in order to clarify their therapeutic basis and mechanism of action more clearly. Shuang-Qing ZhangShuang-Qing ZhangFeng WeiFeng WeiYu-Ming FanYu-Ming FanFeng SunFeng SunYing-Yong ZhaoYing-Yong ZhaoShuhua BaiShuhua Bai"}
+{"text": "Coronary heart disease (CHD) is the leading cause of death. As the main treatment of CHD, modern medicine has improved dramatically in recent years. Although researches of TCM and integrative medicine on CHD are witnessed encouraging progress in many respects, the role TCM playing in the prevention and treatment of CHD has been unprecedentedly challenged under such circumstance of the very fast development of modern medicine. In order to share mutual complementary advantages of TCM and western medicine, this review summarizes the relatively prominent researches of TCM and integrative medicine on CHD in recent years, and illuminates the issue of the orientation of the further research of integrative medicine on CHD, including (1) original innovation of TCM etiology and pathogenesis, (2) combination of disease and TCM syndrome, (3) biological basis of TCM syndrome of CHD, (4) clinical design and quality control of integrative medicine research, (5) herb-drug interaction, (6) difficulties and hot issues of modern medicine.  So far, there are so many researches of TCM and integrative medicine on CHD, however, with insufficient enhancement of clinical effectiveness. If the work on blood-stasis syndrome (BSS) is a milestone of TCM and integrative medical research on CHD, activating blood circulation by removing blood-stasis and its derived therapies have significantly improved the clinical effectiveness of TCM therapy on CHD , when co Combining disease with TCM syndrome is an important treatment model in TCM clinical practice. The theory of combining disease with syndrome reflects the principle of inheritance and innovation, which has been widely accepted by TCM and integrative medical practitioners for the advantages of scientificity and operability. Thus, it is the important breakthrough point of integrative medicine research on CHD. Previously, most of the TCM syndrome researches on CHD are cross-sectional studies focusing on syndrome distribution characteristics of CHD and different subgroups, which have made certain progress. Many results have shown that patients with CHD have the syndrome of asthenia in origin and asthenia in superficiality, and blood-stasis is the main syndrome element of CHD, followed by qi deficiency , 12. The It is worth mentioning that in the process of the occurrence, development, and prognosis of CHD, TCM syndrome is always in a dynamic change, so the research on the evolution law of CHD syndromes may help us understand the pathogenesis and prognosis of CHD in each stage or population and then improve clinical syndrome differentiation and treatment. But research in this field is still less and need to be strengthened. Mei et al.  conducte\u03b3 are the possible marker proteins that might play crucial roles in the occurrence and development of BSS patients with CHD. Zhao et al. [\u03b2-hydroxybutyric acid, oleic acid, glucose, and alanine. The results showed that CHD-BSS is related with lipid metabolism, glycometabolism, as well as the stress induced by hypoxia and agonia. Applying various omics technologies, we can conduct researches in the holistic level, and provide strong technical support for the research on biological basis of TCM syndrome. Treatment based on syndrome differentiation is one of the characteristics and advantages of TCM in preventing and treating disease, but how to conduct syndrome differentiation exactly is the key to improve the clinical efficacy. The rapid development of modern medicine has provided technical support and good opportunity for the expansion and extension of the four methods of diagnosis of TCM and the organic combination of traditional macroscopic and modern microcosmic syndrome differentiation. In recent years, Chinese scholars have studied relevant factors affecting TCM syndrome differentiation of CHD and the biological basis of syndrome in the aspects of coronary artery lesion, cardiac function, changes in ECG, blood lipid, insulin resistance, homocysteine and inflammation factors, related gene, and so on . They hao et al.  also appo et al.  proposedo et al.  found th In recent years, with the concept of evidence-based medicine (EBM) widely accepted, a number of multicenter, randomized controlled trials (RCT) with large sample focusing on the prevention and treatment of CHD have been carried out successively both in the fields of Chinese medicine and integrative medicine, for example, the randomized, double-blind, placebo-controlled trial on the effect of Xuezhikang (XZK) for regulating blood lipids and secondary prevention of CHD . The resStrengthen the top-level design of clinical trials and choose appropriate clinical research methods based on the clinical demands and research objectives. For most intervention studies, RCT including explanatory randomized controlled trial (ERCT) and pragmatic randomized controlled trial (PRCT) is usually the first choice. Recently, real-world study (RWS) , which iOutcome measures should be appropriate . Avoid mTrials are designed and conducted according to good clinical practice (GCP) principle. Strengthen the implementation of process management and quality control of clinical trials, such as the international registration of clinical trials, ethical approval, the third-party evaluation of end point, and data management, and reported trials in accordance with the consolidated standards of reporting trials (CONSORT) statement 2010 , in orde When conducting clinical trials of integrative medicine on CHD, we should pay attention to the following three points.If the combination of disease and syndrome is the integration of TCM and Western medicine in diagnostic level, then interaction of Chinese and Western medicine can be the practical problem we face in treating disease with integrative medicine. As the integrative medical model of patient-centered healthcare and combined application of botanical and chemical drugs evolving into a new trend of modern medicine in preventing and treating disease nowadays, the combined application of Chinese and Western medicine is increasing, and the potential interactions are drawing more and more attention .Herb-drug interaction has two meanings. One is the advantageous function of effect-enhancing and toxicity-reducing. CHD and other chronic noncommunicable diseases are often related to multiple risk factors, complex interventions, and multitarget treatment are more appropriate. Combination therapy with a TCM formula has been the feature and advantage of TCM. Some international scholars also proposed the concept of \u201cpolypill\u201d , which hhypericum perforatum, motherwort, ginseng, gingko biloba, salvia miltiorrhiza, garlic, and aconite, can possibly increase the risk of adverse events in patients with cardiovascular diseases by the interactions with other drugs, particularly in elderly patients who always consume multiple prescription medications in the same time for comorbidities [Another meaning of herb-drug interaction is the potential of increased risk of adverse reactions. International researches discovered that some botanical drug products including Chinese herbal medicine, such as bidities . In clinSo, herb-drug interaction is the issue that cannot be ignored in the research of integrative medicine on CHD. In clinical practice, doctors should notice the reference application of evidence-based medication , 49, pay Meanwhile, the firsthand material should be accumulated in routine clinical practice, as there is an important way to discover the meaningful clues of herb-drug interactions through the real-world data analysis. On this basis, design experiment scientifically, carry out the relevant studies involved in drug metabolism, pharmacokinetic, efficacy, toxicology, and the relevance of toxicity and efficacy, and conduct in-depth study of herb-drug interactions and their mechanism from drug absorption, distribution, transformation, metabolism, excretion, and so on.The development of modern medicine has brought new hope for the prevention and treatment of CHD. However, some new problems have unavoidably been presented, such as aspirin resistance (AR), restenosis after PCI, late thrombosis of drug-eluting stent (DES), the no-reflow phenomenon after revascularization, vulnerable plaque, contradiction of therapeutic angiogenesis, the viability and differentiation ability of transplanted cells when operating stem cell transplantation, and residual cardiovascular risk. These are still challenges which modern medicine has to face positively. Focusing on these key issues that influence the curative effect, we should give full play to the characteristics of TCM, complement each other's advantages of Chinese and Western medicine, and conduct researches scientifically.For instance, to the clinical problem of AR, we may screen potential Chinese herbals which have antiplatelet effect, then explore its material basis and active ingredients, illustrate the target point of drug action, find the lead compound, and optimize its structure. An effective Chinese herb with high-efficacy and low-toxicity will be of great significance in the prevention and treatment of cardiovascular disease. Some domestic scholars  have recSalvia miltiorrhiza combined with bone marrow mononuclear cells autotransplantation through cardiac catheter to the model of myocardial infarction in swine, it promoted transplanted cell to survive, differentiate, and amplify, and many new myocardial cell and myocardial small vessel emerged. These facilitated the repair of damaged myocardial cells by synergies and complementing each other's advantages [Stem cell transplantation is also a hot issue. It may be a new dawn for the treatment of myocardial infarction, and its preliminary clinical study outcome was inspiring. A study  indicatevantages  and predIn conclusion, integrative medical research on CHD has made great development. Present studies shed light on the orientation of integrative medicine. From the progress of integrative medicine on CHD, in order to further complement each other's advantages of Chinese and Western medicine, researches should keep focusing research on original innovation of TCM etiology and pathogenesis, combination of disease and TCM syndrome, biological basis of TCM syndrome of CHD, difficulties and hot issues of modern medicine such as stem cell transplantation and strengthen clinical design and quality control of integrative medicine research. In addition, herb-drug interaction should not be ignored."}
+{"text": "Background: Firefighters have a high probability of being exposed to a variety of traumatic events. Potentially traumatic events can occur during a single rescue such as: providing aid to seriously injured or helpless victims. Moreover, firefighters who are injured in the line of duty may have to retire as a consequence of their injury. The psychological cost of this exposure may increase the risk of long-term problems, such as post-traumatic stress disorder (PTSD) symptoms, depression, and anxiety. Objective: The purpose of this study was to investigate the prevalence of PTSD symptoms, depression, anxiety, and assess related variables such as coping strategies and social support among Saudi firefighters. Method: Two hundred firefighters completed the Fire-fighter Trauma History Screen (FTHS) to measure the number of traumatic events, Screen for Post-traumatic Stress Symptoms (SPTSS) scale to assess the prevalence of PTSD symptoms, Hospital Anxiety and Depression Scales (HADS) to assess depression and anxiety, Brief Cope (BC) scale to measure coping strategies used, and Social Support scale was used to evaluate the firefighter's support received. Results: The results showed that 84% (169/200) of firefighters were exposed to at least one traumatic event. The result presented that 57% (96/169) of exposure firefighters fully met the DSM-IV criteria for PTSD with high levels of depression and anxiety; 39% (66/169) partially met the PTSD criteria. However, only 4% participants have not met the PTSD criteria. The results also revealed that adaptive coping strategies and higher perceived social support was associated with lower levels of PTSD. Conclusion: The high prevalence rate of PTSD related to the type and severity of the traumatic events and years of experience in the job. Accordingly, many firefighters were severely affected by their experiences, and we should be developing methods to help them."}
+{"text": "Salmonella-contaminated animal feed and their impact on public health. The workshop followed an article published in Clinical Infectious Diseases, which provided three recommendations to reduce human foodborne disease caused by Salmonella-contaminated animal feed  on January 23, 2004, to discuss issues pertaining to Salmonella-contaminated feed, and data showing how contaminated animal feed contributes to human foodborne illness.A variety of organizations were represented at the workshop, including international government agencies, the United States Department of Agriculture (USDA), the United States Food and Drug Administration (FDA), and consumer groups. Speakers offered perspectives on bacterial contamination of animal feed, including examples of human illnesses traced to Salmonella in animal feed. Officials from the National Veterinary Institute of Sweden and the Norwegian Agriculture Inspection Service gave an overview of the control measures implemented in Sweden and Norway to ensure Salmonella-negative animal feed. Norway and Sweden have extensive surveillance programs for Salmonella control in animal feed. The measures implemented in Norway and Sweden are important contributing factors to the virtual absence of Salmonella in the food supply in their countries.The opening plenary session focused on international experiences in controlling Salmonella in food animals.Several U.S. government agencies, including CDC; USDA; and the National Institutes of Health, National Institute of Allergy and Infectious Diseases, presented research findings at the workshop. Presentations included results from animal feed commodity studies that look at the factors contributing to microbial pathogens, mycotoxins, and chemical residues in animal feed. Researchers from FDA and Washington State University also provided data indicating that contaminated animal feed continues to be a source of Salmonella-contaminated animal feed. Collaboration among all groups was stressed as a useful measure in controlling contaminated animal feed in the future.Further studies are necessary to document the precise contribution of contaminated animal feed to human illness. Nevertheless, some presentations suggest that practical interventions are available to reduce the prevalence of http://www.cdc.gov/narms/mce/animalfeeds.htm.A compact disk, including all of the presentations, agenda, and list of participants from the workshop, is available online at"}
+{"text": "Bifidobacterium and Bacteroides manifested the difference between SE and TE types. For anthropometry, body weight, body mass index, and waist circumference of the TE type were significantly higher than those of the other types. Overall, findings indicated a possible link between SC types and gut microbiota within a narrow age range. Further investigations are deemed necessary to elucidate the influences of age, gender, and other factors in the context of SC types and gut microbiota.The Sasang constitutional medicine has long been applied to diagnose and treat patients with various diseases. Studies have been conducted for establishment of scientific evidence supporting Sasang Constitutional (SC) diagnosis. Recent human microbiome studies have demonstrated individual variations of gut microbiota which can be dependent on lifestyle and health conditions. We hypothesized that gut microbial similarities and discrepancies may exist across SC types. We compared the difference of gut microbiota among three constitutions , along with the investigation of anthropometric and biochemical parameters. Firmicutes and Bacteroidetes were predominant phyla in all SC types. The median plot analysis suggested that Firmicutes and Bacteroidetes appeared more abundant in SE and TE, respectively, in the male subjects of 20\u201329 years old. At the genus level,  Individualized treatment according to the patients' \u201csyndrome\u201d pattern is one of the characteristics of traditional oriental medicine in the East Asian countries. The Sasang constitutional medicine, a holistic approach based on the unique constitutional typology, has long been applied to diagnose and treat patient with various diseases. Characteristics pertaining one's physical, psychosomatic, and emotional aspects are integrated in the determination of Sasang constitutional (SC) types. The SCM deals with biological and psychological traits in individuals and explains individual differences in behavioral tendencies, physical characteristics, and varying levels of vulnerability to disease and responsiveness to environmental stimuli. Diagnosis under the SC typology divides human beings into four categories  according to their inherited traits, including appearance, physiology, susceptibility to disease, and personality. Traditional Korean medical doctors classify patients using SC for diagnosis and treatment in clinics. However, like other forms of complementary and alternative medical systems worldwide, the identification of SC has been subjective and fallible because of lack of standardization and scientific evidence for a long time . Therefo12 cells per gram) in the intestine, and the diversity of microbes was higher in the intestine, compared with other sites .Supplementary Figure 3: The double pie chart of bacterial communities obtained from each sample of So-Yang. The inner circle indicates the composition of the phylum, and the outer circle indicates the composition of the genus.Supplementary Figure 4: The composition of bacterial communities obtained from each sample of So-Eum in the double pie chart. The inner circle indicates the composition of the phylum, and the outer circle indicates the composition of the genus.Click here for additional data file.Click here for additional data file."}
+{"text": "Musca domestica L.The correct version of the title is: Insecticide Mixtures Could Enhance the Toxicity of Insecticides in a Resistant Dairy Population of The first author Hafiz Azhar Ali Khan should also be affiliated with the institution: Institute of Agricultural Sciences, University of the Punjab, Lahore, Pakistan"}
+{"text": "There are some evidences in Brazil and others countries pointing out insufficient resources and actions to promote prevention and rehabilitation for substance abuse related disorders. Also the lack of professional qualification contributes to this scenario, generating knowledge deficiencies and inadequate practices. The study evaluates the Regional Reference Centre on Drugs of Juiz de Fora, Brazil (CRR-JF). The CRR-JF aims to train professionals of the local health sector (NHS) and social care system increasing their knowledge of screening and brief intervention (SBI) practices on the use of drugs and strengthening health care activities. Five courses are provided: Motivational Counseling and Brief Intervention, Case Management and Social Reintegration of Drug Users, Improvement of Medical Practices about Drugs, and Comprehensive Drug Care for Hospital\u2019s Professionals. Questionnaires were applied measuring participant satisfaction and changes in the practices. The added workload of the courses was 360 hours. A total of 180 professionals attended the courses . According to results, 83.2% of participants were satisfied or very satisfied about the courses attended; 61.3% evaluated the content of the courses as good, 28% as great, and 60% were very satisfied or satisfied with the applicability of the course content. Regarding SBI, the participants showed a significant increase in their level of trust and ability to approach users of psychoactive substances and counsel them to reduce or stop their consumption. Besides providing knowledge acquisition, participation in the CRR-JF enabled greater discussion of the practices carried out, reflecting on the work of professionals in the development of more effective interventions in prevention, promotion, and psychosocial rehabilitation of users of psychoactive substances. Acknowledgments: National Secretary of Policy on Drugs (SENAD), Coordination for the Improvement of Higher Education Personnel (CAPES)."}
+{"text": "E. coli was discussed from the points of view of enzyme level  regulation, and gene level  regulation. Then the effects of the specific pathway gene knockout such as pts, pgi, zwf, gnd, pyk, ppc, pckA, lpdA, pfl gene knockout on the metabolism in E. coli were overviewed from the systems biology point of view with possible application for strain improvement point.Recent metabolic engineering practice was briefly reviewed in particular for the useful metabolite production such as natural products and biofuel productions. With the emphasis on systems biology approach, the metabolic regulation of the main metabolic pathways in  The concept of metabolic engineering has been proposed back in 1991 Bailey, .Escherichia coli, Saccharomyces cerevisiae, Corynebacterium glutamicum, Bacillus subtilis etc.; (4) metabolic pathways available in the strains from the available carbon source(s) to the target metabolite(s), (5) introduction of the heterologous pathways by recombinant DNA technology; (6) reduction of the flux to undesirable by-products; (7) enhancement of precursor metabolites production together with necessary cofactors production; (8) modulation of transporters for exporting the target metabolite(s) to the extracellular medium; (9) understanding the metabolic regulation mechanism by both allosteric regulation of enzymes and transcriptional regulation by global regulators; (10) robust and responsive genetic control system for the desired pathways and the host microbe, (11) methods for debottlenecking the chosen pathways; and (12) ways to maximize yields, titers, and productivities  available raw materials such as cellulosic biomass, algae, and waste materials, which can be converted to glucose, xylose, fructose, galactose, mannitol, and glycerol etc. by the appropriate saccharification methods and their processing costs; (2) enhancement of the substrate uptake rate and co-consumption of multiple carbon sources (for the enhancement of the target metabolite production rate); (3) appropriate host microbes such as E. coli by probably considering the advantages of high cell growth rate and well-known characteristics etc. In the field of biofuel production, much interest has centered on S. cerevisiae. Corynebacterium glutamicum is also frequently employed as platform cell factories in industry in particular for amino acid production. An overview of the recent advances in engineering the central carbon metabolism of such industrially important bacteria as E. coli, C. glutamicum, B. subtilis, Streptomyces sp., Lactococcus lactis has been reported  Fell,  may be ain silico gene knockout simulations for succinic acid fermentation. Trinh et al.  system and the MglBAC system  for the case of using a mixture of multiple carbohydrates, an early attempt was to knockout  Gosset, . Thus Gapgi gene, which codes for the first enzyme of Embden-Meyerhof-Parnas (EMP) pathway, was knocked out, the glucose catabolism occurs exclusively through the oxidative pentose phosphate (PP) pathway. As a result, NADPH is overproduced, and inhibits allosterically the activity of G6PDH, thereby reducing the glucose uptake rate, resulting in the low growth rate  pathway is activated, and the flux through G6PDH is reduced for the gnd mutant .The effect of d mutant  , PEP is accumulated, which causes the activation of Ppc and increases the Ppc flux. This in turn causes the increased fluxes through MDH (reverse direction) and Mez, and the reduced PYR (caused by Pyk disruption) could be backed up by these alternative pathway fluxes  both activate the aromatic amino acid biosynthetic pathways  is regulated by the phosphorylation /dephosphorylation of ICDH by aceBAK, and the decrease in OAA becomes dominant for the activation of glyoxylate pathway due to the importance of cell synthesis.If either the  pathway  . The metabolic flux analysis of lpdA gene knockout mutant indicates that glyoxylate pathway was activated, while glycolysis, the oxidative PP pathway, and the TCA cycle activities were down-regulated  accumulates and in turn glycolysis intermediates accumulate, and thus the glucose consumption rate decreases. Moreover, the accumulation of PYR activates Pox pathway producing acetate, and in turn AcCoA is backed up by ACS pathway from acetate (aceBAK operon was induced to activate glyoxylate pathway. If sucA gene, which codes for subunit of \u03b1KGDH, was knocked out, the metabolism is a little different from the case of lpdA gene knockout (Li et al., If  acetate  (Li et apflA, B gene knockout caused overproduction of lactate (Zhu and Shimizu, pfkA and pykF gene expressions, and thus the glucose uptake rate was increased (Zhu and Shimizu, ldhA gene was knocked out, the fluxes toward the production of acetate, formate, and ethanol were increased as expected (Kabir et al., Under anaerobic or microaerobic conditions, NADH balance and the substrate level phosphorylation for the production of ATP may control the metabolic fluxes at the branch points such as PEP, PYR, and AcCoA (Zhu and Shimizu, E. coli. The metabolisms of other microorganisms have also been investigated by Fuhrer et al. (13C-metabolic flux distributions, where the changes in the metabolic flux distributions are caused by the regulation of enzymes and the intracellular metabolite concentrations. In addition to allosteric regulation, the enzyme activities are controlled by their corresponding gene expressions. Since gene expressions are under control of global regulators or transcription factors, it is quite important to understand how these control the metabolism for metabolic engineering (Matsuoka and Shimizu, The above explanation is for r et al. . The aboAlthough most of the metabolic pathway engineering practices have focused on the modulation of the metabolic pathways of interest, the present analysis indicates the importance of understanding the overall main metabolic regulation in response the specific pathway mutation for the efficient metabolic engineering. It may be also considered to modulate transcription factors for the significant strain improvement."}
+{"text": "Fasciola hepatica on the structures of the blood vessels and biliary tract in the sheep liver.The aim of this study was to evaluate the functional capacity of the liver based on the activity of specific enzymes and bilirubin in serum and also to investigate the influence of mechanical and toxic effects of F. hepatica, corrosion cast technique was used.Blood samples and liver of 63 indigenous sheep of Pramenka breed, slaughtered in the period from March to December 2009 were used. Based on parasitological findings in the liver, all animals were divided into two groups: control (n = 34) and infected group (n = 29). For investigation and description of pathological changes in sheep liver, naturally infected with P\u22640.05) of serum gamma-glutamyl transferase (GGT), total bilirubin (TBIL) and direct bilirubin (DBIL) in infected sheep group comparing with the control group. No significant differences were observed for activity of aspartate aminotranferase (AST) between groups. Vascular and biliary systems of the liver were found to be affected.Biochemical analysis of tested parameters showed a significant elevation (F. hepatica.Results of biochemical analysis are consistent with pathological findings and measuring of tested parameters could be used in early diagnosis of sheep fasciolosis and to test the effectiveness of anthelmintic therapy. Corrosion cast technique is very useful for investigation of pathological changes and neoangiogenesis of vascular and biliary system in sheep liver, caused by mechanical and toxic effects of  Fasciola hepatica , which is mainly localized in the liver, bile ducts and gallblader of domestic and wild ruminants, especially in sheep. In animals, the subclinical and chronic disease usually results in decreased production of meat, milk and wool, secondary bacterial infections, fertility problems and great expenses with antihelmintics (Fasciolosis (Fascioliasis) is one of the most common parasitic disease in domestic animals, with a cosmopolitan distribution, particularly prevalent in countries with developed sheep production and very low socio-economic status, such as Bosnia and Herzegovina. It is caused by the hepatic trematode lmintics .F. hepatica, affect the complex vascular and biliary system in the liver. Properly functioning of these two systems is the most important factor for preservation of normal liver functions.The pathogenic effects of these flukes on the host organism begins with the ingestion of encysted metacercaria with vegetation or freshwater. After migration of juvenile forms through the hepatic parenchyma, flukes reside and graze on the mucosa of the bile ducts, which result in the massive tissue damage , 4. The Due to the complexity of vasular and biliary system examination, there are a number of different laboratory tests, which are based on biochemical analysis of serum parameters. These tests usually include the determination of serum transaminases , which are the most sensitive indicators of hepatocellular injury. Alkaline phosphatase (ALP), gamma-glutamyl tranferase (GGT), serum proteins and bilirubin are also used to evaluate the degree of cholestasis and syntetic capacity of the liver \u20138.Corrosion cast technique is usually used for anatomical investigations of three-dimensional vasculature and ductal architecture of some organs, and it has rarely been used for study of pathological changes in the liver caused by parasites or other pathogens .In only a few studies authors have used a corrosion cast technique for investigation and description of pathological changes in liver in natural and experimental induced fasciolosis in sheep and cattle \u201312.F. hepatica on the structures of the blood vessels and biliary tract in the sheep liver, using corrosion cast technique.The aim of this study was to evaluate the functional capacity of the liver based on the activity of specific enzymes and bilirubin in serum and also to investigate the influence of mechanical and toxic effects of F. hepatica. After that, all examined sheep, based on parasitological findings, were divided into two groups: control (n = 34) and infected group (n = 29).The study included serum and the liver of a total of 63 indigenous sheep of Pramenka breed, slaughtered in the period from March to December 2009. All sheep were from 1 to 3 years of age and body weight ranged 45 - 65 kg approximately. During the study, liver of the slaughtered animals was inspected for presence of PLUS  with commercial kits . Direct bilirubin (DBIL) was determined by spectrofotometer BTS-330 , using modified Jandrassik/Gr\u00f3f method .Before the animals were slaughtered, blood samples for biochemical analysis were collected from the external jugular vein into marked vacuum tubes and transported at +4 \u00b0C to the laboratories of the Veterinary Faculty in Sarajevo. The blood tubes were centrifuged at 3.000 rpm for 10 minutes for serum separation. Due to poor stability of enzymes and bilirubin in the serum, the samples were analyzed within 6 hours. Liver enzymatic activities of aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT) and total bilirubin (TBIL) were measured according to standard procedures using automatic analyzer DIMENSION - Xpand F. hepatica. After dissection and fine preparation the blood vessels were rinsed with saline solution and heparin to remove remaining blood and the clots. The biliary tract was rinsed also. To prepare corrosion cast models, blood vessels and bile ducts of each liver, were injected with acryl resin . Powder and solution of acrylat were mixed in a ratio of 1: 2 and then colored with different Biodur pastes. The portal vein, hepatic arteries, hepatic veins and bile ducts were stained green, red, blue and yellow, respectively. After hardening of resin at room temperature for 24 hours, the livers were macerated in 33% hydrochloric acid for 7-10 days. Later, corrosion casts were washed under tap water and air-dried . Differences were considered as significant when P\u22640.05.All statistical analyzes were performed using Minitab 15 software. Significant differences between infected and control group of animals were determined by Student's F. hepatica infected and control sheep and reference intervals are presented in The mean values of AST, GGT, TBIL i DBIL in serum of F. hepatica, revealed dilated, rough and wrinkled bile ducts. Smaller ducts on the edges of intermediate and cranio-ventral segments of the left lobe were lost  terminal branches  and 3. IFasciola hepatica causes the release of reactive oxygen species producing a damage of cell wall and hepatic tissue necrosis  at the early stage of the infection could be related to the hepatocellular necrosis and degenerative changes produced by migration of juvenile flukes through the liver parenchyma , 17, 18.F. hepatica.Serum GGT values in infected sheep group were significantly higher than in the control group . Some auF. hepatica infected sheep recorded in the present study were confirmed by corrosion cast study.In the present study, concentration of TBIL and DBIL were significantly higher compared to the control group , but theChanges observed on the casts of bile ducts, arterial and venous blood vessels of the sheep liver from infected group, completely correspond to changes described by Rushton and Murray , 12 and According to Rushton and Murray , duct diObserved narrowing of the secondary and terminal branches of portal vein along changed bile ducts is most probably a consequence of exudation and inflammation (edema), as well as, secondary proliferation of connective tissue in the chronic phase of the disease . The samMalformations such as curved (serpentine) shapes, dilations, and loss of continuity on the casts of hepatic artery , we beliF. hepatica.Activities and concentration of AST, GGT, TBIL and DBIL in serum are reliable indicators of the stage of sheep fasciolosis and could be used in early diagnosis and to test the effectiveness of anthelmintic therapy. Corrosion cast technique is very useful for investigation of pathological changes and neoangiogenesis of vascular and biliary system in sheep liver, caused by mechanical and toxic effects of"}
+{"text": "Interest is growing in integrated systems of e-care for the frail elderly. The present project promotes cognitive training and assessment using ICT tools, stimulates the socialization, shares and monitors the situation of the elderly by different professionals, care givers and relatives.Within the frame of the European Commission funded SOCIABLE Project, 348 elderly are participating in the trial.The approach was pilot in seven different sites, across Italy , Greece , Spain (1 University) and Norway .SOCIABLE pilot study is a multi-national, multicenter, non-randomized, placebo-controlled efficacy study. Its primary objective is to evaluate the effects of a computer-based cognitive training and social activation program on the cognition, the affection and the functional abilities of cognitively intact elderly, patients with MCI and patients with mild AD. Conclusions: Two types of models of integrated care delivery for the frail elderly have been tested; one was characterized by group sessions in the pilot center assisted by caregiver or psychologist, another was stipulated in the use of ICT tools by the elderly at home. The first results of the trial will be illustrated.Integrated care delivery can be achieved in various ways. Irrespective of which model is adopted were detected high levels of satisfaction and performance by all groups and an important ability to monitor results by medical experts and care givers."}
+{"text": "In the past few decades the knowledge of the key pathogenic mechanisms of the disease has improved, but it remains far from being fully understood. Traditionally, the diagnosis of AD has been based on clinical symptoms, and accuracy studies of the current clinical criteria conducted in referral have shown high sensitivity for AD. However, identification of the disease, in particular in the early stages, remains difficult as pathological alterations may be apparent several years before the clear-cut clinical picture. Alzheimer's disease (AD) is the most frequent neurodegenerative disease in the elderly. It is characterized by progressive impairment in multiple cognitive domains, in particular memory, leading to severe impairment in daily living followed by progressive physical deterioration and death. The neuropathological hallmark of AD is the presence of cortical intracellular neurofibrillary tangles (NFT) and extracellular There is growing evidence that the use of biomarkers will increase our ability to identify AD earlier in the disease process and with higher accuracy. In addition, biomarkers will help elucidate the underlying biological and molecular changes, improve the detection of patients suitable for specific treatments, research studies or drug trials, and will contribute to a better management of the disease in the clinical practice. In this special issue on early clinical and molecular detection of AD, we have invited manuscripts that specifically address issues related to early and improved diagnosis of AD. The first two articles address the usefulness of current biological and neuroimaging markers for the diagnosis of AD, including genetic variation, plasma, serum and CSF biomarkers, brain atrophy measures, functional MRI measures, and amyloid burden evaluated by PiB compound. The third paper reevaluates the usefulness of common clinical rating scales for AD, frontotemporal dementia, and vascular dementia using factor analysis. In the fourth paper, the sociocultural impacts of novel molecular technologies for the early diagnosis of AD are addressed. The paper outlines three steps to assess sociocultural impacts. First, conceptual analysis of the ideas underlying technological developments shows how these technologies redraw the boundary between AD and normal ageing and between biological and social approaches of ageing. Second, scenarios are designed depicting different possible futures of AD diagnosis and societal ways to deal with ageing. Finally, the paper reviews the possibilities for deliberation on the potential sociocultural impacts. CDKN2A and CDKN2B on AD. Finally, the last paper assesses the effect of siRNAs silencing on gene expression. While commonly studies use RNA interference (RNAi) to investigate the effect of silencing of specific genes on their expression and effect on cell metabolism, the current paper takes this technology further by assessing the effect of allele-specific silencing of a particular mutant allele, in this case mutation L392V in PSEN1.Manuscripts five and six are original research studies assessing the effect of specific genetic variations on AD and AD endophenotypes. While the study by Swaminathan et al. explores the effect of copy number variation (CNV) derived by genome-wide screening in the ADNI cohort on AD and MCI, the study by Tedde et al. explores the effect of genetic variation in Benedetta NacmiasBenedetta NacmiasChristiane ReitzChristiane ReitzThomas ArendtThomas Arendt"}
+{"text": "The other two presenters suggested some practical methods for globalization of SCM on the basis of their experiences. After the three main presentations, there was a panel discussion session for further development of workshop topics, extended by five other external experts. They discussed the benefits, limitations and essentials for globalization of Korean Traditional Medicine, specifically SCM, from bench to bedside.The workshop on \u201cStrategic Approach to the Globalization of Sasang Constitutional Medicine (SCM)\u201d was held in the Korea Institute of Oriental Medicine (KIOM) on September 18, 2009. This workshop was designed to discuss and brainstorm the strategic approach to the globalization of SCM, one of the unique systems in Korean Traditional Medicine, with three topics and an extensive panel discussion. Professor Edwin Cooper, Editor-in-Chief of  This isedicine\" . A brilledicine\" . Among sedicine\" . The othedicine\" , perspecedicine\" , currentedicine\" , the intedicine\"  and curredicine\" . The thredicine\" , the assedicine\"  and the edicine\" . The addedicine\" , quantitedicine\"  and relaedicine\" .The publication of this special issue led to conduct aworkshop on \u201cStrategic Approach to the Globalization of Sasang Constitutional Medicine\". This was held in the KIOM, the unique government-funded institute for Korean Traditional Medicine in Korea, on September 18, 2009, in Deajeon, Korea supported by the Division of Constitutional Medicine, KIOM . This workshop was designed to discuss and brainstorm the globalization of SCM, one of the unique systems in Korean Traditional Medicine, with three presentations and a panel discussion.eCAM, gave a commemorative lecture on publication of the second supplement of eCAM. He made a brief introduction to this supplement and gave a 1-hour lecture about how to globalize SCM. He showed the print version of supplement with beautiful cover of \u201cBanquet of Seowangmo, Joseon dynasty (the name of Kingdom in Korea from 1392 to 1910)\", which was reproduced with the kind permission of the Los Angeles County Museum of Art. He introduced the content of this supplement briefly and introduced SCM as a unique contribution to the growing field of CAM. According to Prof. Cooper, the supplement to eCAM represents a milestone, in that it is the first publication in this area of alternative medical practices. He also described the rigorous peer-review process for the supplement and summarized how SCM represents a potentially fruitful modern approach to an ancient practice that will probably attract more and more attention. In conclusion, he finished his talk with the promise of that this application of an ancient system to international human health would be forthcoming.Professor Edwin L. Cooper, the Editor-in-Chief of Dr. Myeong Soo Lee of KIOM presented practical strategies for the publication of CAM researches in Science Citation Index journals. His main topic and contents were drawn from his personal experience of submission, publication and peer review of other scientist's papers. His talk started with the main factors for successful publication and the procedures for submission and the peer-review process. In particular, he showed several submission platforms of online journals and gave many personal tips for successful publication.Professor Han Chae from Pusan National University focused on how to enhance the publication of Sasang typology based on personal experiences in Korea and the United States. He also discussed how the uniqueness of SCM made publishing articles on the subject really tricky. He highlighted the most common errors that authors make in writing for publication, for example, trying to explain the whole subject in one manuscript, without giving enough reliable references supporting the underlying notions. His issue was the research model and operational definition that should be built up with sufficient references.After the three main presentations, there was a panel discussion session for further development of workshop topics, extended by five other external experts: Profs Young E. Earm , Byung Hee Koh (Kyung Hee University), Heon M. Lim , Kwang-Sup Soh  and Jong Yeol Kim (KIOM). They discussed the benefits, limitations and essentials for globalization of Korean Traditional Medicine, specifically SCM, from bench to bedside.eCAM and the future role of editorial members for eCAM.The next day, I hosted a meeting of the Editorial Board in Seoul. The attendees were Profs Edwin L. Cooper (Editor-in-Chief), IL-Moo Chang (Kyung Hee University), Byung Hee Koh (Kyung Hee University), Sanghoon Lee (Kyung Hee University) and Myeong Soo Lee (KIOM), with Prof. and Dean, Seung-Hoon Choi (Kyung Hee University) as observer. We discussed several topics, including the second quarter's reports from"}
+{"text": "Phosphate plays a central role in the pathophysiology of CKD-MBD and the progression of chronic kidney disease (CKD) and contributes to the disproportionate cardiovascular risk faced by patients with CKD. Adaptation of nephrons attempting to preserve phosphate homeostasis requires endocrine tradeoff that fuel adverse events of hyperphosphatemia in CKD\u2014secondary hyperparathyroidism, calcium and vitamin D derangements, vascular calcifi cation, and metabolic bone disorder.In fact, in advancing CKD there is a multitude of biochemical, physiological, and clinical alterations, and mechanistic understanding of secondary hyperparathyroidism, vascular calcification, and regulation of phosphate metabolism in CKD has advanced significantly in the past five decades. The principal hormones that regulate renal phosphate handling are parathyroid hormone (PTH), which is produced by the parathyroid gland, and fibroblast growth factor (FGF)-23, which is produced by osteocytes and osteoblasts in bone. In healthy individuals, increasing serum phosphate concentration induces secretion of PTH and FGF-23, and Kloto decline.It has been established (and now accepted by nephrologists) that observational studies strongly suggest that phosphorus is associated with cardiovascular risk, and definitive prospective animal studies are supportive. However, prospective studies demonstrating that modulation of the putative risk factor affects clinical outcomes are lacking, and phosphorus, as yet, does not qualify as a cardiovascular risk factor.This special issue provides an identification of the complex mechanisms that determine the phosphorus and calcium metabolism in CKD-3 and CKD-4; a verify the association of serum phosphate and related factors in ESRD-related vascular calcification. It has also addressed mineral metabolism in patients with CKG in the Era of KDIGO Guidelines, the effect of vitamin D on clinical outcomes in chronic kidney disease, and the effect of paricalcitol on vascular calcification and cardiovascular disease in uremia. Finally, were also discussed the effect of the use of non-calcium-phosphate binders in the control of vascular calcifications; the clinical significance of FGF-23 in patients with CKD, the the relationship between arterial stiffness and vascular damage; the treatment of severe metastatic calcification and calciphylaxis in dialysis patients; the clinical impact of hypercalcemia in kidney transplant patients.Biagio Raffaele Di IorioBiagio Raffaele Di IorioMarkus KettelerMarkus KettelerDomenico RussoDomenico RussoAngela WangAngela Wang"}
+{"text": "Health research programs targeting the population of Gabon and Equatorial Africa at the International Center for Medical Research in Franceville (CIRMF), Gabon, have evolved during the years since its inception in 1979 in accordance with emerging diseases. Since the reemergence of Ebola virus in Central Africa, the CIRMF \u201cEmerging Viral Disease Unit\u201d developed diagnostic tools and epidemiologic strategies and transfers of such technology to support the response of the National Public Health System and the World Health Organization to epidemics of Ebola virus disease. The Unit carries out a unique investigation program on the natural history of the filoviruses, emergence of epidemics, and Ebola virus pathogenesis. In addition, academic training is provided at all levels to regional and international students covering emerging conditions  that favor the spread of viral diseases.  The International Centre for Medical Researches of Franceville (CIRMF) was founded in 1974 by His Excellency El Hadj Omar Bongo Ondimba, President of the Gabonese Republic, and Mr. Pierre Guillaumat, the chairman of the petroleum company, Total Gabon. The Centre was inaugurated on December 5th, 1979 with the participation of numerous internationally eminent scientists .In the 1990s, viral hemorrhagic fevers became a focus of attention in Equatorial. The decision to develop a high security laboratory for the study of Ebola virus disease came after a 1996 Ebola virus disease outbreak in Mayibout area, Gabon. The main objective was to develop the potential for rapid and specific diagnosis on viral hemorrhagic fevers and to have a backup for field investigation of severe viral hemorrhagic fever epidemics. Because the unique expertise and interaction of the CIRMF team along with the international World Health Organization (WHO) teams for Ebola virus disease, the Gabonese government agreed to such a project. The first BSL3+ (including negative pressure and glove box) laboratory was built in 1997, mostly financed by the Foreign Ministry of France . This lai.e., Ebola, Marburg, and Crimean-Congo hemorrhagic fever viruses). Research, including isolation and characterization of these highly pathogenic viruses is performed in accordance with international rules defined by WHO on the handling Risk Group 3/4 Agents Updated equipment includes a double door autoclave, thermo regulated cabinet, a high security centrifuge system, a conventional photonic microscope, a virus isolation unit, and two independent rooms the can be shut down alternatively after decontamination when necessary. An uninterruptable controlled electrical supply for refrigeration, computer systems, and other systems is ensured by two back-up power plants. The telecommunication network consists of mobile phones and the Internet through a dedicated satellite antenna. Other service units consist of a Primate Center, the Gorilla and Chimpanzee Study Station in Lop\u00e9 National Park, and the Dienga Health Observatory. Investigators from this observatory conduct field studies on the prevalence of viral and parasitic diseases and their implications for public health [On 45 hectares, the CIRMF campus has a working space of 2,500 square meters composed of a main building, laboratories, service buildings, and living accommodations . The prec health Pan troglodytes), gorillas (Gorilla sp), mandrills (Mandrillus sphinx), guenons (Cercopithecus sp.), collared mangabeys (Cercocebus torquatus), greater spot-nosed monkeys (Cercopithecus nictitans), vervet monkeys (Chlorocebus pygerythrus) and an Asian macaque (Macaca sp.) colony. One of the largest primate centers in Africa, the Primate Center is equipped with level A2 and A3 animal facilities for scientific research protocols. The Great Apes are housed in large open-air facilities. Semi-free living colony of twelve forested hectares harbor about half of the primates at the Primate center. At the Gorillas and Chimpanzee Study Station, researchers study ecological approaches to the emergence of zoonotic diseases, inter-species transmission of pathogens, and disease outbreaks in humans and wild animals [Dedicated to medical research, the Primate Center houses more than 450 primates belonging to ten different African species , Marseille, and other European agencies. The Scientific Council presided by Professor Patrice Debr\u00e9  recommends scientific policy to the Board of Directors .Running costs are funded by the Ministry of Economy, Gabon, the national petroleum company of Total-Gabon, and the Ministry of Foreign and European Affairs, France. Several international agencies participate in a variety of financial supports including scientists\u2019 salaries, equipment, research projects, and academic grants .Technical laboratory training support of Gabonese teams and other African countries has been one of the major aims of CIRMF. The UMVE actively participates in the academic training at the Regional Graduate School and the different State universities of Equatorial Africa. A special relationship with the \u201cHealth Sciences University\u201d of Libreville and the \u201cSciences and Technology University\u201d of Masuku in Franceville encourages collaborative research projects with teachers and supports students of the Faculties of Medicine and Sciences in the preparation of doctoral theses. CIRMF receives doctoral and post-doctoral scientists from other universities of developed countries . Continuing medical education in the form of post-doctoral workshops are held at the CIRMF for discussion and demonstration of modern techniques. As a National reference laboratory, CIRMF has the following roles: diagnosis of suspected cases during outbreaks of viral hemorrhagic fevers or severe clinical infectious syndromes; development of new methods for diagnosing such infections; surveillance of animal fatalities in reservoir or intermediate hosts; and intervention during outbreaks of unknown etiology. CIRMF diagnosed infections of more than 70 pathogens that could not be identified in other biology laboratories throughout the country. CIRMF maintains close ties to several components of the National Healthcare system, such as Amissa Bongo Regional Hospital in Franceville or the Sino-Gabonese Friendship Hospital. i.e.,: Military Hospital, Libreville; General Hospital, Libreville; A. Schweitzer Lambarene Foundation).In order to facilitate national and international scientific exchanges including scientists, equipment, biological specimens, the capital of Gabon, Libreville, is part of CIRMF operational system. Hosted by the University of Health Sciences, Libreville, one laboratory is now operational. Tight connections with other scientific teams in Libreville are under development  to respond to all Ebola virus disease epidemics in Africa. CIRMF aims to use laboratory and field expertise be a regional focal resource in conjunction with local health authorities to organize epidemic responses. CIRMF expertise is also offered from by entering into laboratory-to-laboratory agreements. Also, an informal international laboratory network for the diagnosis and surveillance of severe infectious clinical syndromes includes: the Institut National de Recherche Biom\u00e9dicale, Democratic Republic of the Congo; Laboratoire National de Sant\u00e9 Publique de Brazzaville, Republic of the Congo; Metabiota/Laboratoire des Maladies Emergentes, Yaound\u00e9, Cameroon; Pasteur Institute, Bangui, Central African Republic; Institute of Virology, Bonn University, Germany; and P4 Jean M\u00e9rieux Lyon, France. Exchange of materials, equipment, and personnel is facilitated through memorandums of understanding. CIRMF holds more than 250,000 samples of various origins in a biological repository, which is accessible to the International scientific community. The UVME assists the National Public Health System in consolidating and formalizing microbiological monitoring of the Equatorial African sub-region. Ultimately, CIRMF will be positioned as a Center of Excellence for microbiological surveillance and research in a global network. Developing diagnostic tools and strategies is the main driver to improve surveillance and research of emerging viral diseases. A strategic choice was made to link syndromes to an etiological agent, including hemorrhagic syndromes. To isolate and diagnose highly pathogenic viruses, a progressive and diversified methodology was applied. The first approach used real-time virus-specific PCR (qRT-PCR). If the first approach was not successful, conventional RT-PCR was implemented using degenerate consensus primers targeting conserved regions of the genome. Ultimately, random amplification of nucleotide sequences was directly applied to the original biological material ).Hypsignathus monstrosus, Epomops franqueti, Myonycteris torquata) in Gabon and Republic of the Congo (Rousettus aegyptiacus) in Gabon, suggesting that bats might be reservoirs for filoviruses [UMVE studied the factors implicated in the three steps that led to Ebola virus and Marburg virus diseases emergence in humans. These steps include: the identification of reservoir species, the circulation within the natural host, the crossing to intermediary animal species, and finally the direct transmission to humans from great apes and fruit bats. Antibodies and nucleotide sequences specific for Ebola virus were detected in the liver and spleen of fruit bat belonging to three species , cold chain with the necessity to maintain in situ a unit of liquid nitrogen production (repository), and purified water supply.CIRMF is geographically isolated from the capital of Gabon, Libreville. The Libreville office is essential to the Franceville headquarters as it coordinates visits from staff on field missions, and forwards imported equipment to headquarters. The capital is accessible by a 12-hour ride in a four-wheel drive vehicle or in a train (three times/week schedule) covering 641 km. Due to tropical weather, four weekly domestic plane rotations often fly on an inconsistent schedule. Ultimately CIRMF needs to be largely autonomous in term of electrical power (CIRMF is uniquely suited to study infectious diseases of the Congolese tropical rain forest, the second world\u2019s largest rain forest. As a central point of a North-South transect of the rain forest, the Center is able to study the biodiversity of Africa including animal species, microbes, and parasites. CIRMF is dedicated to conduct medical research of the highest standard, and is the only facility of its type in Equatorial Africa. With unrivalled infrastructure, multiple sites, and multidisciplinary teams, the Center promotes a modern healthcare system in Gabon. CIRMF teams are engaged in trans-disciplinary projects bringing together specialists from the health sciences, biological sciences, veterinary medicine, conservation, the humanities, and environmental sciences. The Center welcomes partnerships from around the world to work on global human health issues."}
+{"text": "Anellovirus genus), and descriptions of new technologies  that have profoundly affected the field of virology. This comprehensive desk reference provides concise definitions of virologic terms; enables quick fact checking; and provides useful, often difficult to find, information\u2014such as the origin of virus names, determination of ICTV-approved virus abbreviations, and locations and sources of viral isolations. An appendix of current ICTV-recognized virus families, subfamilies, genera, and type species is especially useful.Rapidly expanding technologies in the field of virology, identification of novel viral agents, and the 2005 report (8th edition) of the International Congress of Taxonomy of Viruses (ICTV) addressing reclassification of several viruses generated the 20% new material in Mahy\u2019s 4th edition of The Dictionary of Virology. The previous edition of this book was published in 2001; the 2009 edition includes recent advancements, such as newly described viruses  human coronavirus, human metapneumoviruses, bocaviruses, and Rabensburg virus), reclassification schemes of viruses  or viruses (the newly described virophages of mimiviruses). The increasing quantity of information about viruses of vertebrates ranging from fish to primates presented the author with considerable space difficulties. He compensated for this situation, however, by citing literature sources at the end of entries for readers seeking more information. Additionally, considerable cross-referencing enhances the utility of the book. On the basis of inclusion of new information in the field and my personal experience with previous editions of The Dictionary of Virology, I highly recommend this volume to students, virologists, microbiologists, and public health professionals interested in viruses of vertebrate hosts."}
+{"text": "The reoperations in cardiac surgery are technically more difficult, and the mortality and morbidity increased. It is huge importance of operative techniques, preoperative planning and the skills of the surgical team in those cases. We like to detect the different pre- and intra-operative reasons of the elevated morbidity and mortality, and the opportunities, how we could to reduce them.It was 79 REDO cardiac operations in our department during the last 2 years. The previous operations were: mitral valve (n=33), aortic valve (AVR) (n=15), CABG (n=22), AVR and CABG operations (n=4). We recorded the ejection fraction (EF), right ventricular pressure (RVP), intra-operative and postoperative complications, mortality, and postoperative bleeding.The most common reason of major bleeding injuries (MBI) was the damage of right ventricle . In contrast to the literary data, in our cases the MBI were not increased the mortality, and the mean intensive care unit (ICU) time. The early ventricular fibrillation , the MBI  intra-arterial balloon pump application  and mortality  was higher after previous CABG operations. The incidence of non-fatal complications, MBI and the mortality were significant higher in those patients who had lower EF before, or/and higher RVP.The lower EF and higher RVP increases the mortality and elongated the mean ICU time. Due to this objects the REDO operation is indicated in the first time of the detection of necessity. The high RVP increase the possibility of MBI. In those cases the possible serious complications can be prevented by peripheral canulation, and the use of external defibrillator paddles. With proper preoperative planning and meticulous surgical techniques, the mortality and the serious postoperative complications can be reduced."}
+{"text": "Plasmodium falciparum. The efficiency of these treatments is however seriously compromised by the appearance and spread of drug resistance. Resistance is observed today to some extent against every available drug, including recent reports of resistance to artemisinin. Resistant strains of P. falciparum can spread in affected areas if they fare better than sensitive strains over the entire transmission cycle, including within-human and within-vector infection phases. Both hosts likely represent widely different environments for the parasite, particularly in terms of exposure to drugs and host-specific costs of resistance, which could notably affect the outcome of competition between resistant and sensitive strains and ultimately the evolution of drug resistance.Efforts to relieve the burden caused by malaria rely critically on the availability of drugs targeting To investigate this issue we present a model of malaria transmission combining between-hosts and within-hosts (human and vector) dynamics. The latter incorporates the impact of competition, treatment and immunity in a strain-specific fashion.P. falciparum, impact resistant strains . Finally we also investigate the effect of vector control methods on the prevalence of resistance.We show how costs of resistance, particularly within-vector costs, affect the selection for resistant strains. We also explore how different drugs, acting on specific parts of the within-human cycle of Weconclude that the evolution of resistance to antimalarial drugs is affected by biological specificities of the parasite across its entire life cycle, including dynamics within both hosts. Theoretical studies in this framework that incorporates parasites, humans and mosquitoes improve our understanding of the emergence and spread of drug resistance, and provide a better picture to investigate sustainable tools in the fight against malaria."}
+{"text": "Cardiovascular diseases (CVDs) prevalence continues to increase, and it is still the number one killer so far. In 2002, nearly 17 million deaths all over the world were attributable to CVDs, which accounted for almost 30% of the total deaths. Despite treatment with percutaneous coronary intervention (PCI) and many other conventional medicines, CVDs patients are still confronted with certain risk of recurrent acute cardiovascular events, readmission to the hospital, and unfavorable quality of life. In recent years, more and more clinicians have successfully applied complementary/alternative medicine (CAM) in CVDs prevention and treatment based on standardized conventional therapy. Nevertheless, the role of CAM in CVDs still needs more clinical evidence and definite mechanism of actions. In this issue, a collection of several original research articles and reviews are presented that address the clinical application and the mechanism of action of CAM in the treatment of CVDs. These works were submitted by researchers from different parts of the world, including China, Japan, South Korea, Australia, and Sweden. In these studies, the effectiveness of Chinese medicine and some other alternative therapeutic methods in improving symptoms was demonstrated in patients with hypertension, chronic stable coronary artery disease, chronic heart failure, and so forth. Specifically, the use of Chinese herbal medicines was reviewed for the prevention of in-stent coronary restenosis after PCI. The study of Tanshinone IIA, a diterpene quinine extracted from the root of salvia miltiorrhiza, a Chinese traditional herb, was presented as a promising cardioprotective agent. The positive effect of Chinese food and herbal medicines in improving certain moderate dyslipidemias was described. The usefulness of Xuezhikang, an extract from Red Yeast Rice, was reviewed in the treatment of coronary heart disease complicated by dyslipidemia. A pharmacological and mechanistic study showed Naoxintong's effect on cytochrome P450 2C19. Further, one study showed the effect of berberine on improving insulin sensitivity by inhibiting fat store and adjusting adipokines profile in human preadipocytes and metabolic syndrome patients. In the authors' opinion, the clinical research of Chinese medicine and other CAMs for CVDs still faces some major challenges. Issues such as overall quality of medical service and the unmet medical needs in the contemporary society are common to these medicines. A general guideline is required for practicing Chinese medicine and other CAMs, which should be developed based on solid evidence from well-designed and well-executed clinical studies. Such is the direction that the research of Chinese Medicine and other CAM should follow.Ke-ji ChenKe-ji ChenKa Kit HuiKa Kit HuiMyeong Soo LeeMyeong Soo LeeHao XuHao Xu"}
+{"text": "Schistosoma mansoni infection in the northern-most islands of this archipelago, a follow-up survey was conducted to ascertain whether transmission was endemic to this island group, combining parasitological and malacological surveys. Prevalence of intestinal schistosomiasis was again observed to be high, as was intensity of infections which, combined with low reported incidence of treatment, suggests that chemotherapy-based control initiatives are not being maximally effective in this region as high levels of population movement between islands and districts are confounding. The local disease transmission was confirmed by the observations of high abundance of Biomphalaria, as well as field-caught snails shedding S. mansoni cercariae. DNA sequencing of 12 cercariae revealed common mitochondrial cox1 haplotypes, as well as, novel ones, consistent with the high genetic diversity of this parasite in Lake Victoria. Intestinal schistosomiasis is firmly endemic in parts of the Sesse Islands and more broadly, this island group provides an insight into the future challenges to be faced by the Ugandan National Control Programme in regularly reaching these rather remote, inaccessible and largely itinerant communities.The Sesse Islands, in the Ugandan portion of Lake Victoria, have long been considered a low transmission zone for intestinal schistosomiasis. Based on observations of high prevalence of  Schistosoma mansoni which, as part of its life cycle, requires a suitable freshwater snail intermediate host ; the predominantly exposed, sandy beaches of the Sesse Islands, mostly almost devoid of vegetation, were thought to be unfavourable for such snails, thus limiting the potential transmission of the disease. In 2003, the Ugandan Ministry of Health initiated a National Control Programme, consisting of mass drug administration (MDA) with praziquantel (PZQ) to school-age children in high-prevalence and high-risk districts, based on baseline data from rapid mapping surveys [The Sesse Islands, in the Ugandan portion of Lake Victoria, have long been considered a low transmission zone for intestinal schistosomiasis, although until recently, few if any formal surveys had been undertaken in this archipelago. The disease is caused by the trematode parasite  surveys ,2. Kalanhttp://globalnetwork.org/) funded an ambitious study to attempt to survey all islands in the Ugandan part of Lake Victoria which revealed an extremely heterogeneous distribution of intestinal schistosomiasis in school-aged children on the Sesse archipelago [in situ. Moreover, the survey, as well as previous rapid mapping exercises of the Ugandan Lake Victoria shoreline, revealed high levels of community itinerancy, with a substantial percentage of children travelling frequently between islands and the mainland [As part of a larger effort to monitor the efficacy and coverage of the National Control Programme, in January 2010 the Global Network for Neglected Tropical Diseases (GNTTD: hipelago . Notablymainland . As suchS. mansoni eggs. Egg counts were multiplied by 24 for estimation of numbers of eggs per gram of faeces (EPG). Infection intensity classes were based on WHO recommendations, whereby <100 EPG is considered a 'light' infection, 100-400 EPG is a 'moderate' infection and >400 EPG is a 'heavy' infection [To clarify the possibility of high transmission and local endemicity in this part of the Sesse Islands, in November 2010 a combined parasitology and malacology expedition was conducted throughout the northern islands of Bufumira sub-county, revisiting the sites that had been mapped in January earlier in the year. As with the previous survey, a lot quality assurance sampling method (LQAS) was attempted [nfection . Each chThe follow-up survey's findings confirmed the observation of high prevalence of intestinal schistosomiasis in this portion of Bufumira sub-county, based on 11 of the sites first surveyed in January 2010, plus an additional location , their genomic DNA extracted using published protocols [cox1 gene amplified and sequenced [S. mansoni haplotypes from Lake Victoria and Lake Albert [In contrast to the January 2010 survey of Bufumira sub-county, the follow-up expedition also included a malacological element. At 15 sites, 12 of which were associated with a location also examined for prevalence of intestinal schistosomiasis in local school-aged children, the shoreline of Lake Victoria was surveyed for the presence and abundance of rotocols , and theequenced . The edie Albert -10.Biomphalaria were found, at several of the surveyed locations inclusive of numerous other freshwater snail species , as well as, two novel haplotypes, named H139 and H140 (Genbank accession numbers HQ839767 and HQ839768). This is consistent with sampling elsewhere in Lake Victoria, where the high genetic diversity of the parasite frequently results in new haplotypes being observed; the identification of H1 and H23 suggests that the Sesse Islands are part of the wider Lake Victoria 'population' of S. mansoni, as the parasite shows little population genetic structure throughout the region, potentially due to the mixing effects of human population movement and migration [Contrary to previous surveys elsewhere in the Sesse Islands, large numbers of s Figure . The maxBiomphalaria and prevalence of infected snails was tested statistically against the environmental observations also recorded using a multivariate linear regression model; increased abundance of Biomphalaria was positively associated with low turbulence/sheltered habitats, suggesting that the exposed beaches elsewhere in the Sesse Islands might be contributing to the low numbers of snails  seen there. No other variables were significantly associated with abundance or incidence of infected snails.The relationship between abundance of S. mansoni, suggest that Bufumira sub-county may be a local hotspot for intestinal schistosomiasis, and contradicts earlier evidence suggesting that this western portion of Lake Victoria is a much lower transmission environment than the eastern regions [Overall, the combination of parasitological and malacological surveys has clearly confirmed the endemicity of intestinal schistosomiasis to certain parts of the Sesse Islands, and emphasized the importance of maintaining control initiatives in Kalangala District. The high prevalence of the disease, combined with the observation of snails shedding various haplotypes of  regions . In fact regions ,12. SincThe authors declare that they have no competing interests.The study was conceived by CJS, NBK and JRS. Fieldwork was undertaken by CJS, MA, FB and JRS; CJS, MA and FB collected parasitological samples and MA and JRS carried out malacological surveys. Molecular and statistical analyses were done by CJS; the manuscript was prepared by CJS and JRS, and all authors read and approved the final version."}
+{"text": "Charcot neuro-arthropathy (CN) is one of the most devastating complications of diabetes. To date it appears that no clinical tools based on a systematic review of existing literature have been developed for the management of acute CN. Thus, the aim of this paper was to systematically review existing literature and develop an evidence-based clinical pathway for the assessment, diagnosis and management of acute CN.Electronic databases , reference lists and applicable websites were systematically searched for literature discussing the assessment, diagnosis and/or management of acute CN. At least two independent investigators then quality rated and graded the evidence of all identified literature. Consistent recommendations emanating from the included literature was then fashioned in a clinical pathway.The systematic search identified 267 manuscripts, of which 117 (44%) were assessed to meet the inclusion criteria for this study. As hypothesised, most literature discussing the assessment, diagnosis and/or management of acute CN constituted level IV or EO evidence. The included literature was used to develop an evidence-based clinical pathway for the assessment, investigations, diagnosis and management of acute CN.This research has assisted in developing a comprehensive, evidence-based clinical pathway to promote consistent and optimal practice in the assessment, diagnosis and management of acute CN. The pathway aims to support health professionals in making early diagnosis and providing appropriate immediate management of acute CN, ultimately reducing its associated complications such as amputations and hospitalisations."}
+{"text": "The fourth international conference on emerging zoonoses  brought together 180 scientists and healthcare specialists from 18 countries working to control diseases transmitted from animals to humans. The meeting took place under the auspices of the Center of Food Security and Public Health, USA, and the Institute for International Cooperation in Animal Biologics . Brucella isolates from feral swine in coastal South Carolina. Another presentation concerned the increasingly appreciated role of wildlife in the dynamic epidemiology of other zoonotic infections, such as tuberculosis. Scientists also explored the intricate routes prions follow between wildlife and domestic animals; between sheep, cattle, and humans; and between the tongue and brain of infected animals.A multidisciplinary and global approach shed new light on both old and new zoonoses. For example, brucellosis topics covered a wide range of material, from economic aspects of control in Mongolia to characterization of Since most agents of bioterrorism potential are zoonotic, a full session was dedicated to bioterrorism and biodefense. It included a global view, a report on national preparedness by Israeli hospitals, and examples of research that may eventually help experts coping with bioterrorism but would also unfortunately be accessible to persons with malicious intent.Innovative methods for preventing spread of foodborne pathogens were presented, including the use of fluorescence spectroscopy to detect fecal contamination on animal carcasses or the use of vaccination to reduce transmission of zoonotic pathogens and drug-resistant nonpathogens through the food chain to humans. In the field of xenotransplantation, key components of a source-animal production facility were described. The feasibility of breeding pigs free of designated pathogens offers hope for wide use of xenotransplantation in the near future.Mycobacterium avium subspecies paratuberculosis, the etiologic agent of Jhone\u2019s disease in cows, brought some hope in solving the long-lasting dispute on its role in the pathogenesis of Crohn\u2019s disease in humans.Participants also discussed current trends and challenges of protozoan parasitic zoonoses, including cryptosporidiosis, toxoplasmosis, African and Latin American trypanosomiasis, and leishmaniasis. Controversial zoonotic viruses were given an important place in the conference. These included hepatitis E virus, with similar strains causing liver disease in swine and humans; Borna disease virus, causing neurologic disease in various species of animals as well as, debatably, psychiatric disorders in humans; and the recently discovered severe acute respiratory syndrome\u2013associated coronavirus and its yet-undefined animal reservoir. The recent mapping of the genome of The value of using a global, multidisciplinary approach was highlighted in studies on the flow of genes among avian, swine, and other influenza viruses and on the ongoing intercontinental spread of arboviruses, exemplified by the evolving epizootic of equine West Nile encephalitis in the United States. Several papers dealt with the epidemiology of Nipah, Ebola, monkeypox, rabies, and Hantaan viruses.Escherichia coli O157:H7 or by species of Anaplasma, Bartonella, Borrelia, Campylobacter, Coxiella, Francisella, Pasteurella, and Salmonella.A series of presentations demonstrated how genomic fingerprinting and other sophisticated molecular biology techniques allow exceptionally fast development in understanding the epidemiology and pathogenesis of many zoonotic infections, such as those caused by http://www.zoonoses2003.com).The \u201cone-track\u201d meeting, by avoiding parallel and superspecialized sessions, gave an opportunity for fruitful and inspiring interactions among experts from multiple disciplines with a shared goal of mitigating human disease from emerging infections. More details on the meeting can be viewed online (available at:"}
+{"text": "Chinese herbal medicine is increasingly widely used as a complementary approach for control of breast cancer recurrence and metastasis. In this paper, we examined the implicit prescription patterns behind the Chinese medicinal formulae, so as to explore the Chinese medicinal compatibility patterns or rules in the treatment or control of breast cancer recurrence and metastasis.This study was based on the herbs recorded in Pharmacopoeia of the People\u2019s Republic of China, and the literature sources from Chinese Journal Net and China Master Dissertations Full-text Database (1990 \u2013 2010) to analyze the compatibility rule of the prescription. Each Chinese herb was listed according to the selected medicinal formulae and the added information was organized to establish a database. The frequency and the association rules of the prescription patterns were analyzed using the SPSS Clenmentine Data Mining System. An initial statistical analysis was carried out to categorize the herbs according to their medicinal types and dosage, natures, flavors, channel tropism, and functions. Based on the categorization, the frequencies of occurrence were computed.The main prescriptive features from the selected formulae of the mining data are: (1) warm or cold herbs in the Five Properties category; sweet or bitter herbs in the Five Flavors category and with affinity to the liver meridian are the most frequently prescribed in the 96 medicinal formulae; (2) herbs with tonifying and replenishing, blood-activating and stasis-resolving, spleen-strengthening and dampness-resolving or heat-clearing and detoxicating functions that are frequently prescribed; (3) herbs with blood-tonifying, yin-tonifying, spleen-strengthening and dampness-resolving, heat-clearing and detoxicating, and blood-activating with stasis-resolving functions that are interrelated and prescribed in combination with qi-tonifying herbs.The results indicate that there is a close relationship between recurrence and metastasis of breast cancer with liver dysfunctions. These prescriptions focus on the herbs for nourishing the yin-blood, and emolliating and regulating the liver which seems to be the key element in the treatment process. Meanwhile, the use of qi-tonifying and spleen-strengthening herbs also forms the basis of prescription patterns. Breast cancer is one of the most common malignant tumors among women, and the incidence increases every year in both developed and developing countries . Every yToday, the standard therapies for breast cancer include surgery, chemotherapy, radiation therapy, and hormonal therapy. However, even though patients receive systemic treatment, there is still 10% to 30% chance of recurrence and metastasis. Among the patients with local recurrence, 75% to 93% will eventually develop distant metastasis with an extremely low 5-year survival rate . VisceraRecently, the use of natural Chinese herbal medicine with anti-tumor effects is receiving more and more attention from the public . In tradIn Chinese medicinal therapy, experienced Chinese medical practitioners prescribe a medicinal formula\u2014a combination of various single herbs\u2014for the treatment of ailments. According to TCM theories, pharmacological and pharmacodynamic relationship exists among herbs, which is deemed as Chinese medicinal compatibility. The compatibility of Chinese herbal medicine has particular rules and patterns. In Chinese medicinal database, there are over ten thousand medicinal formulae which enclose complicated information. However, a well-established and orderly system for organizing the information of Chinese medicinal formulae does not exist. This implies that a large amount of implicit prescription patterns behind the formulae have not been fully disclosed ,16.LHS\u21d2RHS, where LHS and RHS are sets of items, and the RHS set is likely to occur whenever the LHS set occurs. One of the applications of association rules mining is to mine association rules in medical record data [Association rules mining is one of the methods for discovering meaningful associations or correlations between variables in large databases. It identifies frequent item sets from the data sets, and then uses these frequent item sets to form their association rules. To select meaningful rules from the set of all possible rules, minimum thresholds on support and confidence are the two important constraints. An association rule has the form ord data ,18. Sincord data . The supord data .This study was based on Pharmacopoeia of the People\u2019s Republic of China recordedThere were five types of literature included, including literature: (1) related to clinical research on using Chinese medicine for the prevention and treatment of breast cancer recurrence and metastasis; (2) related to clinical research on using Chinese medicine for the treatment of advanced stage breast cancer; (3) related to clinical research on using Chinese medicine for the prevention of postoperative breast cancer recurrence and metastasis ; (4) with randomized controlled trials as the study design; and (5) where the clinical study aims to prove the efficacy of experimental group with Chinese medicinal treatment over control group.Literature with the following criteria were excluded: (1) small-sample-sized studies with less than 20 cases; (2) studies which primarily aimed to treat complications of operations or to reduce the side effects of chemotherapy; (3) studies without investigation into the use of Chinese medicine for the treatment and prevention of breast cancer recurrence and metastasis; (4) studies which provided only the names of formulae but without descriptions of herbal ingredients; (5) duplicate publications reporting the same group of participants; and (6) literature in which the clinical trial received a Jadad score of less than 2.Association rules mining is a popular and well-researched method for discovering interesting relations between variables in large databases . We usedTwo parameters (support factor and confidence factors) were essential in association rules mining. With regard to support and confidence in discovering the association rules, the user shall set the minimum support (min-sup) and the minimum confidence (min-conf) as critical values providing the baselines for discovery. Only the combinations that satisfy the minimum thresholds on support and confidence were considered to mine meaningful rules. The selection of thresholds (support and confidence) was always an issue. If the minimum confidence is set too high, a lot of useful data will be missed. To find an effective drug compatibility mode, we discovered central tendency of association rules to be more obvious at the support of 0.1 and confidence of 0.6 in the two correlation analysis of these herbs (used pairs of couplet herbs) and the pairs of herbal functions. So the minimum support of 0.1 and the minimum confidence of 0.6 were specified in this study.Based on Pharmacopoeia of the People\u2019s Republic of China, the ingredients of Chinese medicine were listed according to the selected medicinal formulae and were organized to establish a database. The computing software Microsoft ACCESS was used as a storage tool, and then the SPSS Clenmentine Data Mining System was used as a platform to analyze the frequency and the association rules of the prescription patterns. An initial statistical analysis of the database was carried out to categorize the herbs according to their medicinal types and dosage, natures, flavors, channel tropism, and functions. The frequencies of occurrence and use were then computed based on the categorization. In additionthe associations between different functions of Chinese herbs from the formulae were also examined using the association rules mining.The 180 herbs were categorized according to the Five Properties and Five Flavors Table . Based oThe results of the association analysis based on channel tropism theory among 180 herbs Table  showed tThere are 96 medicinal formulae with a total of 180 herbs included in this study. The total cumulative occurrence of 180 herbs appearing in 96 formulae was 1001 times. The following 13 herbs were frequently prescribed (over 20 times):a Principal function in qi-tonifying, including : Huang Qi , Bai Zhu , Gan Cao , Tai Zi Shen (Radix Pseudostellariae), Dang Shen (Radix Codonopsitis Pilosulae)b Principal function in spleen-fortifying and dampness-resolving, including : Fu Ling (Sclerotium Poriae Cocos), Yi Yi Ren (Semen Coicis),c Principal function in heat-clearing and detoxicating, including : Shan Ci Gu (Pseudobulbus Shancigu), Bai Hua She She Cao (Herba Hedyotidis Diffusae), d Principal function in blood-tonifying, including: Dang Gui (Radix Angelicae Sinensis), u e Principal function in yin-tonifying, including: Gou Qi Zi (Fructus Lycii), f Principal function in blood-activating and stasis-resolving, including: E Zhu (Rhizoma Curcuma Phaeocaulis), andg Principal function in qi-regulating, including: Chen Pi (Pericarpium Citri Reticulatae) (Table e) Table .Herbs with tonifying and replenishing , blood-activating and stasis-resolving, spleen-fortifying and dampness-resolving or heat-clearing and detoxicating functions appeared to be most frequently prescribed for the treatment and prevention of breast cancer recurrence and metastasis Table . The topAssociation rules mining was applied to investigate the associations between pairs of herb functions from the formulae, and to examine the Chinese medicinal compatibility patterns Table . The minThe top three pairs of herbal functions with the highest confidence included the blood-tonifying paired with qi-tonifying functions (93.18%), the qi-regulating paired with qi-tonifying functions (93.10%) and the yin-tonifying paired with qi-tonifying functions (92.50%).Couplet herbs are two herbs used in pair to increase the therapeutic effect or reduce the toxic effect. To further examine the compatibility patterns of couplet-medicinal prescriptions, we targeted the herbs for healthy-qi reinforcement , and the herbs for pathogenic-factor elimination , which were frequently prescribed for the treatment and prevention of breast cancer recurrence and metastasis Table . The minFrom the herbal perspective, breast cancer is the local manifestation of a whole-body disease, referred to as an intrinsically deficient but extrinsically excessive syndrome. Based on TCM theories, deficiency of spleen qi, inadequate source of engendering transformation, deficiency of qi and blood, and excess of phlegm-dampness are believed to be the main mechanism responsible for development of breast cancer ,25.The 180 herbs were classified according to the Five Flavors, and herbs that were sweet or bitter were the top two most frequently prescribed herbs in the formulae. In TCM theories, herbs that taste sweet can be used for supplementation, moderation and harmonization, referred to as tonifying and replenishing herbs. Herbs that taste bitter can be used for discharging and downbearing, referred to as heat-clearing and detoxicating herbs. However, sweet tasting herbs with spleen-strengthening functions were prescribed and used more frequently than herbs with a bitter taste for clearing heat.Breast cancer is different from the other cancer types, as the onset of this disease usually peaks at menopausal . The patAmple clinical research of Chinese formulae reinforces the spleen to regulate qi and soothe the liver to alleviate pain. Thus, they do not only resist tumor and strengthen the body, but also have anti-cancer effects on metastatic breast cancer ,28.From the TCM perspective, the etiology of breast cancer is due to deficiency of the healthy qi, which is related to spleen qi deficiency, and liver-kidney depletion. This deficiency will result in malfunctioning of spleen, liver and kidney for transportation and transformation, and free coursing. Without the proper functioning, stagnation and obstruction of the breast collaterals will ultimately be developed and transformed into breast cancer .Restoration of healthy qi is an effective way to treat diseases and to prevent further progression. The use of qi-tonifying and spleen-fortifying herbs is to replenish the source of engendering transformation for qi and blood, and to achieve qi-tonifying, blood-replenishing and harmony of the five visceral functions. This is particularly essential for nourishing the liver and smoothing the qi movement. At the same time, spleen-strengthening and qi-replenishing herbs also have the functions for resolving dampness and dispelling phlegm. Therefore, the formulae prescribed herbs such as Huang Qi, Bai Zhu, and Fu Ling, among others.. From the association rules mining, the results showed that the combination of the herbs should also focus on the functions for qi-tonifying. The use of couplet herbs involving Huang Qi and Bai Zhu is to achieve the effects of spleen-strengthening and qi-replenishing, and dampness-drying and water-draining; the use of couplet herbs involving Bai Zhu and Tai Zi Shen is to achieve the effects of fluid-engendering and lung-moistening; the use of couplet herbs involving Bai Zhu and Fu Ling is to achieve the effects of dampness-resolving. The effectiveness of these tonifying and replenishing herbs on tumor resistance and immunity enhancement has also been proven by clinical studies ,31.The results showed that recurrence and metastasis of breast cancer is considered to have a close relationship with liver dysfunctions. These prescriptions focus on the herbs for nourishing the yin-blood, and emolliating and regulating the liver. Strengthening of liver function seems to be the key to successful treatment. Meanwhile, the use of qi-tonifying and spleen-strengthening herbs also forms the basis of prescription patterns. It is also noteworthy that liver function is promoted by strengthening the spleen.The authors declare that they have no potential and competing interests.YH performed the study; JC was in charge of the study work, advice in the study design and modified in manuscript writing.XZ, CS, ZW, TX, BJ, QY and KT equally conducted and performed the study. LC and WTYL gave expert advice in the study design and participated in manuscript writing."}
+{"text": "To develop an empirically-based framework of the aspects of randomised controlled trials addressed by qualitative research.Systematic mapping review of qualitative research undertaken with randomised controlled trials and published in peer-reviewed journals.Medline, Premedline, Embase, The Cochrane Library, Health Technology Assessment, PsychINFO, CINAHL, British Nursing Index, Social Sciences Citation Index and ASSIA.Articles reporting qualitative research undertaken with trials published between 2008 and September 2010; health research; reported in English.296 articles met the inclusion criteria. They had a wide international authorship. Articles focused on 22 aspects of the trial within five broad categories. Some articles focused on more than one aspect of the trial, totalling 356 examples. The qualitative research focused on the intervention being trialled ; the design, process and conduct of the trial ; the outcomes of the trial ; the measures used in the trial ; and the target condition for the trial . A minority of the qualitative research was undertaken at the pre-trial stage .A large amount of qualitative research undertaken with specific trials has been published, addressing a wide range of aspects of trials, with the potential to improve the endeavour of generating evidence of effectiveness of health interventions. Researchers can increase the impact of this work on trials by undertaking more of it at the pre-trial stage and being explicit within their articles about the learning for trials and evidence-based practice."}
+{"text": "ST among populations, testing population differentiation, and performing principal component analysis (PCA) and correspondence analysis (CA). All analyses revealed a low but significant differentiation between the Amami Islanders and the mainland Japanese population. Furthermore, we examined the genetic differentiation between the mainland population, Amami Islanders and Okinawa Islanders using six loci included in both the Pan-Asian SNP (PASNP) consortium data and the J-MICC data. This analysis revealed that the Amami and Okinawa Islanders were differentiated from the mainland population. In conclusion, we revealed a low but significant level of genetic differentiation between the mainland population and populations in or to the south of the Amami Islands, although genetic variation between both populations might be clinal. Therefore, the possibility of population stratification must be considered when enrolling the islander population of this area, such as in the J-MICC study.Uncovering population structure is important for properly conducting association studies and for examining the demographic history of a population. Here, we examined the Japanese population substructure using data from the Japan Multi-Institutional Collaborative Cohort (J-MICC), which covers all but the northern region of Japan. Using 222 autosomal loci from 4502 subjects, we investigated population substructure by estimating F Uncovering population structure is a crucial step in properly conducting association studies because neglecting to correct for population structure can lead to both false positive results and failures to detect genuine associations It is generally accepted that the modern Japanese population was formed by the mixture of two major ancestral groups who came to Japan by different routes at different times. The mainland population of Japan shows genetic influences from both groups but appears to be predominantly descended from the second ancestral group, whereas two contemporary indigenous groups in Japan, the Ainu and Ryukyu peoples, are recognized as remnant populations descended from the first ancestral group A previous study of the Japanese population substructure, based on genome-wide association study (GWAS) data, revealed the clear differentiation between the Ryukyu and mainland populations and partially confirmed the dual structure hypothesis described above Therefore, the aim of this study is to examine the genetic differentiation between the Amami Islanders and other Japanese subpopulations . For thiGenotype data were obtained from 4514 Japanese subjects in the J-MICC study, which is one of the largest population-based cohort studies in Japan In addition to the J-MICC data, the Pan-Asian SNP (PASNP) consortium genotype data The ethics committees of all participating institutions approved the protocol for the J-MICC study, and all participants provided written informed consent.The participating institutions included:Division of Cancer Registry, Prevention and Epidemiology, Chiba Cancer Center, Chiba, Japan,Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, JapanDivision of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan,Department of Public Health, Nagoya City University Graduate School of Medicine, Nagoya, Japan,Department of Health Science, Shiga University of Medical Science, Otsu, Japan,Department of Epidemiology for Community Health and Medicine, Kyoto, Japan,Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan,Department of Preventive Medicine, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan,Department of Preventive Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan,Department of Preventive Medicine, Faculty of Medicine, Saga University, Saga, Japan,Department of International Island and Community Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan andLaboratory for Genotyping Development, Center for Genomic Medicine, RIKENThe J-MICC data: All genotypes were determined using the multiplex PCR-based Invader assay  at the Laboratory for Genotyping Development, Center for Genomic Medicine, RIKEN 2>0.5; 52SNPs) were excluded from the data set. The remaining polymorphisms had call rates of >90% and were not excluded. Subjects with a call rate less than 90% (12 subjects) were excluded. Thus, the final data set for further analyses consisted of 221 autosomal SNPs and one autosomal indel for 4502 subjects  originally designed for association studies subjects .The PASNP data: We also used all 54794 autosomal SNP genotypes available in the PASNP data. After applying the same filtering procedures used for the J-MICC data to the PASNP data, 46485 SNPs remained. Of these SNPs, only six  were contained in the J-MICC data; thus, these SNPs were used for comparison between populations of the mainland, Amami Islands and Okinawa Islands.Data filtering, the calculation of basic summary statistics, and Hardy-Weinberg equilibrium (HWE) tests were performed with the R package SNPassoc STST estimates were averaged over all loci, and 95% confidence intervals (CIs) of the average FST were calculated by bootstrap resampling with 10000 replications. We used this computational method so that this study would be comparable with that of Yamaguchi-Kabata et al.ST over all loci was also estimated as the ratio of sums of the variance components in the numerator and denominator ST, variance components were estimated to reflect intra-individual, inter-individual and inter-population differences in genetic variation.To measure the differentiation between populations, the widely used statistic FTo test for differentiation between two populations based on multiple loci, Goudet's G statistic was used with 10000 permutations of individuals between populations principal components.A principal component analysis (PCA) was performed to visualize the relationship between populations; this type of analysis summarizes information for multiple loci into a few synthetic variables called For the same purpose, correspondence analysis (CA) was performed on a contingency table of minor allele counts per population. Importantly, as in any analysis carried out at a population level, all information about the diversity within populations is lost in this analysis. In contrast, PCA was performed at the individual level and not at the population level.ST estimations, variance component estimations and tests of population differentiation at multiple loci were all performed with the R package hierfstat FST over all loci and its 95% CI between each pair of subpopulations in the J-MICC data are shown in ST values between the Amami Islanders and other mainland Japanese subpopulations (0.0067\u20130.0086) were much larger than the FST values between mainland Japanese subpopulations (0.0001\u20130.0007).The average FST values for all loci; the resulting distribution is shown in ST and its 95% CI between the Amami Islanders and a population grouped across all subpopulations in the mainland. Once again, a substantially large FST value was observed . Furthermore, this genetic differentiation was statistically significant according to the G statistic (p<0.001) ST was estimated as the combined ratio estimate over all loci  than the Amami Islanders are , and both Islanders groups are similar to each other . The difference in the p-values for comparisons of each Islanders group with the mainland population reflects the different sample sizes of the Islander populations (only 49 Okinawa Islanders vs. 515 Amami Islanders).Next, we examined the genetic differentiation between the mainland population, Amami Islanders and Okinawa Islanders using the same methods used for the J-MICC data. The average FST values with respect to the distance separation among the three groups.The variance component between both Islanders is 0.2%, which is about one order of magnitude less than that between the mainland population and either Islanders group  ST value (\u22480.008) is slightly larger than that obtained in a previous study of the Japanese population substructure based on GWAS data (\u22480.003) In this study, a low but significant FAlthough we can separate the Amami Islanders and the mainland population using correspondence analysis (CA), we cannot separate the two groups using principal component analysis (PCA) because the number of polymorphisms (222 loci) used in this study is not large enough to classify individuals according to the two subpopulations. According to the study that first proposed regression to the principal components of the PCA to correct for population stratification Finally, it should be noted that the low coverage of study areas in this study might exaggerate the sharpness of the observed genetic boundary between the mainland population and the Amami Islanders, although the true pattern of genetic variation might be clinal. Therefore, we think that it is necessary for further studies to include individuals from the southernmost mainland part of Japan (southern Kyushu) and a few other islands between the Amami Islands and the mainland.In conclusion, we have revealed a low but significant level of genetic differentiation between the mainland population and population in or to the south of the Amami Islands, including the Okinawa Islands, although the genetic variation between both populations might be clinal. Therefore, the possibility of population stratification must be considered when enrolling the islander population of this area, such as in the J-MICC study.Figure S1ST values per locusbetween the Amami Islanders and the mainland population (JPEG).Empirical distribution of F(TIF)Click here for additional data file.Figure S2Empirical distribution of heterozygosity per locus for the Amami Islanders and the mainland population (JPEG).(TIF)Click here for additional data file.Figure S3Scree plot of principal component analysis for the mainland population and the Amami Islanders in the J-MICC (JPEG).(TIF)Click here for additional data file.Figure S4Principal component analysis plot for the mainland population and the Amami Islanders in the J-MICC. (a) PCA plot of the first and second principal components, (b) PCA plot of the first and third principal components (JPEG).(TIF)Click here for additional data file.Figure S5Principal component analysis plot of the first and second principal components for the mainland population and the Okinawa Islanders in the PASNP data. Principal component analysis was conducted for the mainland population and the Okinawa Islanders in the PASNP data, using (a) all 46485 loci and (b) 5000, (c) 1000, (d) 900 and (e) 800 loci that were randomly selected from all loci. Scree plots are shown in each figure.(TIF)Click here for additional data file.Table S1(DOC)Click here for additional data file.Table S2(DOC)Click here for additional data file.Table S3(DOC)Click here for additional data file."}
+{"text": "The availability of fully sequenced genomes and the implementation of transcriptome technologies have increased the studies investigating the expression profiles for a variety of tissues, conditions, and species. In this study, using RNA-seq data for three distinct tissues , we investigate how base composition affects mammalian gene expression, an issue of prime practical and evolutionary interest.We present the transcriptome map of the mouse isochores (DNA segments with a fairly homogeneous base composition) for the three different tissues and the effects of isochores' base composition on their expression activity. Our analyses also cover the relations between the genes' expression activity and their localization in the isochore families.This study is the first where next-generation sequencing data are used to associate the effects of both genomic and genic compositional properties to their corresponding expression activity. Our findings confirm previous results, and further support the existence of a relationship between isochores and gene expression. This relationship corroborates that isochores are primarily a product of evolutionary adaptation rather than a simple by-product of neutral evolutionary processes. The genomes of vertebrates are mosaics of isochores, long regions  that are fairly homogeneous in base composition. The isochores belong to a small group of families characterized by different GC levels  -4. In thThe emergence of the isochores is an open debate of relevant evolutionary importance, where in addition to the selectionist model , other in silico compositional analysis of expression vectors and DNA carriers, showed that aside from the GC3 level (GC level in the third codon position) of the coding sequences, the genomic compositional context in which a gene is embedded affects its expression. Additionally, the Human Transcriptome Map (HTM), using SAGE data, revealed domains of highly and weakly expressed genes [Previous studies have investigated the effects of base composition on gene expression, both in human and mouse tissues, through an exhaustive use of expression data from techniques based on sequencing  and/or hybridization  -21, and ed genes , namely ed genes ,25. The ed genes ,27. In aed genes ,29. Nexted genes -32. Moreed genes -36. In ted genes  in orderThe results of aligning each tissue's reads to the reference mouse genome and to the coding sequences are shown in Table GC > 53% -- marked with a vertical line in the red box in Figure Rbrain = 0.72, Rliver = 0.62, and Rmuscle = 0.65 -- see Additional file Additional file R = 0.42). Having shown the positive effect of high GC levels to the isochoric expression and between GC levels and gene density, we also looked into the direct relation between the gene density and the expression level of the individual isochores. We found a positive correlation, with similar coefficients for all tissues .It is well-known that in vertebrates, including the mouse, GC-richer isochores have higher gene densities compared to the GC-poorer ones (see the Background Section). This is confirmed by the positive linear correlation we found between the gene density of the isochores and their respective GC level , and we found a very strong preference for them to be located in the L2 family (over 50% of these genes), with decreasing presence in families of subsequently higher GC  and genic compositional properties in gene expression, in the context of specific tissues or biological processes, and reveal valuable information on the implicated regulation mechanisms.To produce the transcriptome map of the isochores, we used publicly available RNA-seq data of three distinct mouse tissues , obtained in a recent study by Mortazavi et al  using thlog2 of each normalized read count was calculated as a representation of the expression level. This is represented by Equation (1), where EL represents the expression level normalized over the length L of the isochore, Ri the read count of the isochore, Rt the read count of the tissue, and f the scaling factor.To investigate the expression levels of the mouse isochores, the aligned reads were assigned to the isochores containing their mapped location. The locations and GC-spans of the isochores were extracted from . To elimBecause the normalized counts are very small, the logarithm produces negative values, however, higher expression still corresponds to peaks. Details on the isochores' coordinates, GC levels, aligned reads, and expression levels, for each of the three tissues, can be found in Additional file D we denote the gene density of the isochore and by ED the isochoric expression normalized over the gene density, Equation (1) is modified as shown in Equation (2).As we report in the Results Section, the expression levels were also further normalized by the respective gene densities to account for the higher concentration of genes in isochores with higher GC level. If by To investigate the expression at gene level, the coding sequences for the mouse were retrieved from the Consensus Coding Sequence Database (CCDS) . From thECDS) was produced with Equation (3), where RCDS represents the count of aligned reads in the exons of each CDS, Similarly to the procedure followed for the expression levels of isochores, the expression level of a CDS  and their respective expression levels (EL -- Equation (1)) for the brain, liver, and muscle tissues . High expression corresponds to peaks in the lines.Click here for fileCorrelations between GC level and expression activity of the isochores. The correlations between isochoric expression level ) and their GC. The red plot is for brain, the blue plot for liver, and the green one for muscle tissue.Click here for fileIsochoric expression levels for each tissue normalized over gene density. This table reports the name of each isochore, the GC level , the length , the number of genes (CDS-count), the gene density (GeneDensity -- number of genes within an isochore over its length), the count of aligned reads for each tissue , the ratio between the count of aligned reads for each tissue within each isochore over the total number of reads of that tissue , and finally the isochoric expression level normalized over the gene density (LogBr(GeneDens), LogLiv(GeneDens), and LogMusc(GeneDens)).Click here for fileDistribution of the coding sequences across the five isochore families. Within each isochore family, the % of the isochores containing at least one gene (grey bars) and of the isochores with no genes at all (light grey bars).Click here for fileDistribution of the expressed CDSs in the isochore families. For each tissue, the % of the expressed genes (in histogram -- upper panel) within each isochore and the corresponding count (in table format -- lower panel) using as expression threshold \u2265 10 aligned reads per gene. In the histogram, the red bars indicate the genes expressed in brain, the blue bars the genes expressed in liver, and the green ones in muscle.Click here for fileIsochoric expression levels for each tissue normalized over length. This table reports the name of each isochore, the GC level , length , the number of genes (CDS-count), the gene density (GeneDensity -- number of genes within an isochore over its length), the count of aligned reads within each isochore for each tissue , the ratio (%) between the count of aligned reads within each isochore for each tissue over the total number of reads of that tissue , and finally the global isochoric expression level normalized over the isochoric length (LogBr(Length), LogLiv(Length), and LogMusc(Length)).Click here for fileGenic expression levels for each tissue. This table reports the isochoric localization of each coding sequence. Specifically, the first column shows the chromosome, the second indicates the isochore in which the gene is embedded, followed by its GC level and the genomic coordinates (Start (Mb) and End (Mb)). Afterwards comes the id of each coding sequence, the genomic coordinates of the coding sequence (cds_from and cds_to), the level (GC_ccds), the GC3 (GC3_ccds), the length of the coding sequence (Length_ccds), and the count of aligned reads for each tissue  within each coding sequence. The three last columns report the genic expression level for each tissue (LogBr(genic), LogLiv(genic), and LogMusc(genic)).Click here for file"}
+{"text": "Sir,Biceps brachii muscle (BB) is one of the most variable muscles in the human body in terms of the number and morphology of its heads. In contrIn this report, we present a rare case of bilateral hypoplasia of the long head of the BB found during the anatomical dissection of a 58-year-old female cadaver. In both arms, the most remarkable findings were the strange-looking long heads Figure \u2013b, compoAnomalies of the long head of the BB include absence, duplication, deficiency and various origins . Embryolo3The variations of the long head of the biceps tendon could also create diagnostic difficulty in MRI. However, awareness of their existence and MRI appearance can help prevent misdiagnosis, correct prospective MRI diagnosis and avoiding unnecessary surgery."}
+{"text": "The maintenance of highly regulated mechanisms to control intracellular levels of reactive oxygen species (ROS) is essential for normal cellular homeostasis. Indeed, most ROS, including free radicals and peroxides, are produced at low level by normal aerobic metabolism and play an important role in the redox-dependent regulation of many signaling processes. In contrast, excessive accumulation of ROS, resulting from an imbalance between ROS production and scavenging, leads to a condition of oxidative stress that can cause extensive oxidative damage to most cellular components, including proteins, lipids, and DNA, and may have pathophysiological consequences. Remarkably, oxidative stress has been clearly implicated in aging and the pathogenesis of several human diseases, including cardiovascular, metabolic, inflammatory, and neurodegenerative diseases and cancer. Thus, ROS may function as friends or foes of signal transduction depending on specific threshold levels and cell context.To highlight the important topics in this evolving field the Journal of Signal Transduction presents a special issue on the involvement of ROS in physiological and pathological signal transduction processes from prokaryotes to low and high eukaryotes.Neurospora crassa light signal transduction (in the second paper), the interplay between ROS and mitochondria in the control of cell death and aging (in the third and fourth papers) and cancer progression (in the fifth and sixth papers), the role of ROS in nuclear transport (in the seventh paper), the interplay between ROS and Ras GTPases (in the eighth paper), the role of ROS in the crosstalk between integrins and cadherins (in the ninth paper), integrin signaling (in the tenth paper), and skeletal muscle signaling (in the eleventh paper). These articles describe our current understanding of this field. Furthermore, this special issue highlights the importance of gaining a greater understanding of the physiological and pathological role of ROS in the perspective of defining new therapeutic strategies based on redox regulation of signal transduction processes.In particular, the topics covered in this special issue include ROS-mediated signaling in bacteria (in the first paper), the mechanisms by which ROS affect Saverio Francesco RettaSaverio Francesco RettaPaola ChiarugiPaola ChiarugiLorenza TrabalziniLorenza TrabalziniPaolo PintonPaolo PintonAlexey M. BelkinAlexey M. Belkin"}
+{"text": "The aim of the study was to investigate the effect of dietary supplementation with zinc and polyphenol compounds, i.e. resveratrol and genistein, on the effectiveness of chemically induced mammary cancer and the changes in the content of selected elements  in tumors as compared with normal tissue of the mammary gland.Female Sprague-Dawley rats were divided into study groups which, apart from the standard diet and DMBA , were treated with zinc ions (Zn) or zinc ions + resveratrol (Zn + resveratrol) or zinc ions + genistein (Zn + genistein) via gavage for a period from 40 days until 20 weeks of age. The ICP-OES  technique was used to analyze the following elements: magnesium, iron, zinc and calcium. Copper content in samples was estimated in an atomic absorption spectrophotometer.Regardless of the diet , DMBA-induced breast carcinogenesis was not inhibited. On the contrary, in the Zn + resveratrol supplemented group, tumorigenesis developed at a considerably faster rate. On the basis of quantitative analysis of selected elements we found - irrespectively of the diet applied - great accumulation of copper and iron, which are strongly prooxidative, with a simultaneous considerable decrease of the magnesium content in DMBA-induced mammary tumors. The combination of zinc supplementation with resveratrol resulted in particularly large differences in the amount of the investigated elements in tumors as compared with their content in normal tissue.Diet supplementation with zinc and polyphenol compounds, i.e. resveratrol and genistein had no effect on the decreased copper level in tumor tissue and inhibited mammary carcinogenesis in the rat. Irrespectively of the applied diet, the development of the neoplastic process in rats resulted in changes of the iron and magnesium content in the cancerous tissue in comparison with the healthy mammary tissue. The application of combined diet supplementation with zinc ions and resveratrol considerably promoted the rate of carcinogenesis and increased the number of DMBA-induced mammary tumors. DS planned, designed and carried out the experiment, AT coordinated the study. All authors read and approved the final manuscript."}
+{"text": "Increasing evidence indicates that miRNAs are essential in the development, diagnosis, treatment and prognosis of a variety of tumors. The utility of miRNAs as biomarkers for diagnosis and of target molecules for the treatment of cancers is increasingly being recognized. With the discovery of circulating miRNAs, a non-invasive approach for the diagnosis and treatment of cancer has been identified. This review summarizes the role of miRNAs in the development of different tumors, as well as a variety of other biological events. Moreover, this review focuses on analyzing the function and mechanism of gastric cancer-related miRNAs and investigates the importance of circulating miRNAs in gastric cancer, as well as their origin. Finally, this review lists a number of the problems that must be solved prior to miRNAs being used as reliable non-invasive tools for the diagnosis, treatment and prognosis of gastric cancer. The incidence of gastric cancer ranks fourth in males and fifth in females, while the mortality ranks third in males and fifth in females among all cancers worldwide . The incet al observed that in gastric cancer cell lines 17 miRNAs were upregulated and 146 miRNAs were downregulated compared with normal gastric mucosa (microRNAs (miRNAs) are becoming increasingly recognized as important in cancers, including gastric cancer. To date, >1,400 miRNAs have been described in humans . Yu et ac mucosa . miRNAs c mucosa . ConsequC. elegans in gastric cancer cells  Determining the source of circulating miRNAs; ii) validating a classical pathway of circulating miRNA transmittance; iii) clarifying the mechanism of the action of various circulating miRNAs in gastric cancer; iv) determining how the circulating miRNAs in different stages of gastric cancer development are expressed and how miRNAs develop in this development process; v) highly specific and sensitive detection of miRNA pre- and post-operatively, as well as at various stages of gastric cancer; vi) clarifying the mechanism of synergy/antagonism of various circulating miRNAs in the occurrence and development of gastric cancer; and vii) determining the feasibility of certain miRNA target therapies at different stages of gastric cancer according to associated miRNA specificity."}
+{"text": "The classical concept of PTSD has been criticized for many reasons, including its cultural limitations and negligence of long-lasting changes to personality, which has been documented in cases of chronic interpersonal trauma. The concept of complex PTSD has addressed these shortcomings and specifies \u201calterations in self-perception\u201d as one of the characteristic changes in functioning following extreme and chronic trauma. Torture survivors and refugees are a population particularly affected by cumulative traumatization. The experience of torture comprises the deliberate and systematic devastation of values, beliefs, self-concept, and personality development. It has severe effects on the survivors\u2019 fundamental trust, self-identity, and attachment. Meanwhile, refugee trauma involves the long-term experience of discrimination, persecution, helplessness, and humiliation, which also has a significant impact on the individual's personal and collective identity. A number of studies and theories now exist, which describe the psychological effect of torture and refugee trauma on identity. However, the issue of torture and life in exile is generally discussed separately. The present research aims at integrating the two phenomena and focuses on the unique and combined effect that torture and refugee trauma has on the survivors\u2019 identity. The qualitative study comprises narrative in-depth interviews with refugee torture survivors and applies a psychoanalytic framework for interpreting the data."}
+{"text": "The safety of patients is not yet in the priorities of the health system in DRC despite the country is with Nigeria and Ethiopia, the head of the African countries that are at high risk  of complications and maternal mortality against 1.34 10-4 in developed countries. Under these conditions, achieve the Millennium Development Goals to reduce by 2/3 of maternal mortality in 2015 is impossible, unless efforts are made in huge areas.To assess the proportion of hospital infections in maternal morbidity and mortality observed in the maternity Lubumbashi.Descriptive cross-sectional study conducted in two maternity second (10 deliveries / day) and third levels (30 births / day) of the city of Lubumbashi. The relevant parameters are maternal mortality, hospital hygiene, quality of care, performance of biomedical laboratories, supplies of antibiotics.It was noted:In terms of hygiene: sanitary conditions are deplorable with no water points, disinfectants, antiseptics or gloves (unarmed deliveries). In terms of patient safety: No respects procedures during blood transfusions, infusions, injections, often performed cesarean section without asepsis emergency. In epidemiological terms: maternal mortality rate higher in the maternity tertiary level, especially related to the intra-hospital infections after cesarean section despite a higher skill level.Improving patient safety in maternity services in DR Congo through the implementation of emergency measures post-crisis to address issues related to the disruption of the health system, the morale and training of health personnel, and the paucity of hospitals.None declared"}
+{"text": "The global supply of food has led to an increasingly connected planet, not only in terms of food products but also in terms of risks for foodborne diseases. The fourth edition of Morris and Potter\u2019s Foodborne Infections and Intoxications delivers an in-depth look at the global effects of foodborne illnesses, provides pathogen-specific information, and describes processes and policies intended to prevent these illnesses. The text is a well-written and well-referenced guide to foodborne illnesses, containing contributions from >70 experts in epidemiology and the basic sciences of foodborne diseases.The text has been organized into 6 sections. The first section describes the epidemiology of foodborne disease, highlighting the most common illnesses in the United States and abroad with country-specific data as well as the most common outbreak-associated foods and microbial risk assessment. The next 4 sections encompass microbe-specific illnesses; each section comprises chapters on specific pathogens. The sections are organized to include bacterial pathogens, viral pathogens, parasites , and agents involved with food intoxications. Each chapter is specific to a given pathogen and includes a clinical description of the disease, the microbiology of the pathogen, exposure risks, and disease prevention. Escherichia coli O104:H4 infections in northern Germany. This outbreak illustrates the importance of food safety and the critical role of public health officials, clinicians, and scientists in identifying new outbreaks and limiting the spread of newly identified illnesses. The final section of the book outlines prevention of foodborne diseases and discusses food safety and the legal basis for food safety regulation.Chapters have been written by leading researchers in their respective fields and are filled with up-to-date references on each pathogen. One example, in Chapter 8, includes a description of the 2011 outbreak of This edition of Foodborne Infections and Intoxications updates the third edition, published in 2006, with increased emphasis on global disease prevention and a risk-based approach to food safety. This text is particularly valuable for students and practitioners in the fields of public health and food safety. It can also serve as a useful reference for public health investigators and officials."}
+{"text": "This special issue of Nanoscale Research Letters contains scientific contributions presented at the International Conference \"Micro&Nano2010 - Special Symposium on Nanomaterials for sensing and energy harvesting devices\", which was held in Athens, Greece, from December 12-15, 2010.http://www.micro-nano.gr). The Conference aims at gathering together in an interactive forum scientists and engineers working in the challenging field of Microelectronics, Nanoelectronics, Nanotechnologies and MEMs and to stimulate discussions in last achievements and new developments in this rapidly evolving field. One of the key objectives of the Conference is to promote collaboration and partnership between different academia, research and industry players in the field. The Conference combines an extensive scientific programme, including oral and poster sessions, with an exhibition and social events.Micro&Nano2010 was the fourth of a series of Conferences on Microelectronics, Nanoelectronics, Nanotechnologies and MEMs held in Athens-Greece every three years and organized by the \"Micro&Nano\" Scientific Society (Within \"Micro&Nano2010\" a special Symposium was organized on nanomaterials for sensing and energy harvesting devices. A selected collection of papers of this Symposium are found in the present special issue. The full volume of the Proceedings, including micro- and nanomaterials, technologies and devices, will appear as a special issue of the journal \"Microelectronic Engineering\".The guest editor of this issue and Chairperson of \"Micro&Nano2010\"Androula G. NassiopoulouHead of the Nanostructures for Nanoelectronics, Photonics and Sensors Research groupTerma Patriarchou Grigoriou, Aghia Paraskevi153 10 Athens, GreecePresident of Micro&Nano Scientific SocietyDirector of Research, IMEL/NCSR Demokritose-mail: A.Nassiopoulou@imel.demokritos.gr"}
+{"text": "Graves' orbitopathy, despite of the results of recent researches concerning pathomechanism of the disease, is still a therapeutic challenge. Corticosteroids are the treatment of choice for active, moderate to severe Graves' orbitopathy.The aim of the study is to evaluate the effects of treatment of patients with GO with novel protocol of steroidotherapy designed and introduced in Department of Endocrinology, Metabolism and Internal Medicine. The management protocol consists of 3 g of methylprednisolone administered intravenously followed with methylprednisolone injected intramuscularly in divided doses every 3 weeks .The study group consisted of 50 patients. Assessment of efficacy of therapy was performed before and immediately after the therapy and 6 months later. Thyroid function parameters , titers of thyroid autoantibodies , thyroid volume (V) were analyzed. Moreover, ophthalmological findings  and disease activity on magnetic resonance imaging of orbits were evaluated.The therapy significantly improved the degree of soft tissue involvement, CAS, diplopia and decreased the autoimmune disease activity in oculomotor muscles. Moreover, significant decrease of TRAb titer was observed.To conclude, novel protocol of glucocorticoid therapy is effective and safe."}
+{"text": "Nanoscale Research Letters features selected papers presented at the Symposium E: \"Nanoscaled Si, Ge based Materials\" of the EMRS Fall meeting, held in Warsaw, Poland from September 13-h16, 2010.This special volume of The symposium was organized by Fabrice Gourbilleau , Artur Podhorodecki  and Nicola Daldosso . CNANO North West  kindly sponsored the symposium.The goal of the symposium was to describe exciting, state-of- the- art applications of Si or Ge nanoparticle-based materials, doped or not with rare earth ions, in the fields of (i) information storage, (ii) optoelectronic devices, (iii) telecommunications, as well as (iv) life sciences. using the. The origin of such intense research activity in these different domains can be explained by the potential of Group IV nanostructures to lead to either (i) future chips with optical interconnects in which CMOS compatible electronic and photonic and/or biosensing components aree integrated or (ii) the future generation of solar cells with lower cost and/or higher efficiency.The four-day symposium included 13 sessions in which 48 oral and 18 poster presentations gave a comprehensive overview of progress toward a wide range of applications as well as the development of new promising techniques for microstructural investigations at the atomic scale. The papers published in this special volume have been selected after careful peer review, and form an authoritative reference for future applications.The organizers wish to thank the EMRS staff for their help in the organization of the symposium."}
+{"text": "Plasmodium falciparum malaria. ACT combines two effective antimalarial drugs and is the cornerstone of successful malaria control and ultimately, elimination. Fixed-dose combinations (FDC) of ACTs are preferred, as they promote adherence to treatment and reduce the risk of selecting for drug-resistant parasites.The World Health Organisation (WHO) currently recommends the use of five artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated initiative (DNDi), together with the WHO Special Programme for Research and Training in Tropical Diseases (TDR), launched the FACT (Fixed Dose Artesunate Combination Therapy) project in 2002, with original funding from INCO/DEV. The FACT core group also included the Brazilian government-owned pharmaceutical company, Farmanguinhos/Fiocruz, the University of Bordeaux, Universiti Sains Malaysia, Mahidol University and the Shoklo Malaria Research Unit in Thailand, the Centre National de Recherche et de Formation sur le Paludisme in Burkina Faso and the University of Oxford, combining epidemiological and drug development expertise. Additional competencies in clinical studies, clinical supplies and regulatory matters strengthened the core team. Through innovative collaborations with this variety of partners, the FACT project delivered FDCs of Artesunate (AS) plus Amodiaquine (ASAQ), and AS plus Mefloquine (MQ). Key contributions in scale-up, industrial production and regulatory filing were still needed to make the products available to patients, and different strategies were set up for each product. Both strategies were based on an initial development within the public and not-for-profit sector, with an extension to the private sector when a viable product was available, for registration, production and distribution.In order to strengthen the ACT portfolio of FDCs, which at the time was minimal, the Drugs for Neglected Diseases Sanofi took over the last steps of industrial development and regulatory filing for ASAQ and the product was pre-qualified by WHO in 2008. Since then, ASAQ has been registered in over 30 countries, mostly in sub-Saharan Africa and over 120 million treatments have been delivered - making this the second most widely used ACT. Deployment was accompanied by a risk-management plan, together with an extensive training and educational programme developed by Sanofi. ASMQ FDC production was scaled up by Farmaguinhos/Fiocruz and registered in Brazil in 2008. A large intervention study involving over 23,000 patients was performed by the National Malaria Control Programme in Brazil showing the efficacy of the product in real-life conditions. Through a South-South technology transfer, ASMQ FDC production was transferred to the Indian pharmaceutical company Cipla to ensure availability in India and South East Asia. ASMQ FDC was registered in India in 2011 and in Malaysia in early 2012 and is under review for WHO prequalification.The FACT project demonstrates that alternative drug development strategies can make safe, affordable and sustainable treatments available to patients. Diverse partnerships gathering a wide range of expertise, from national programmes ensuring the most appropriate therapy is used in endemic areas to industrial partners for product implementation and wide distribution, were key to success. Both ASAQ and ASMQ FDCs are critical drugs for malaria control across Africa, Latin America and South East Asia."}
+{"text": "The purpose of this article is to reflect on the proceedings of the ALMA working session.In 2009 a total of 153,408 malaria deaths were reported in Africa. Eleven countries showed a reduction of more than 50% in either confirmed malaria cases or malaria admissions and deaths in recent years. However, many African countries are not on track to achieve the malaria component of the Millennium Development Goal (MDG) 6. The African Leaders Malaria Alliance (ALMA) working session at the 15Working methods of the session included speeches and statements by invited speakers and high-level panel discussions.The main bottlenecks identified related to the capacity of the health systems to deliver quality care and accessibility issues; need for strong, decentralized malaria-control programmes with linkages with other health and development sectors, the civil society and private sector entities; benefits of co-implementation of malaria control programmes with child survival or other public health interventions; systematic application of integrated promotive, preventive, diagnostic and case management interventions with full community participation; adapting approaches to local political, socio-cultural and administrative environments.The following prerequisites for success were identified: a clear vision and effective leadership of national malaria control programmes; high level political commitment to ensure adequate capacity in expertise, skill mix and number of managers, technicians and service providers; national ownership, intersectoral collaboration and accountability, as well as strong civil society and private sector involvement; functional epidemiological surveillance systems; and levering of African Union and regional economic communities to address the cross-border dimension of malaria control.It was agreed that countries needed to secure adequate domestic and external funding for sustained commitment to malaria elimination; strengthen national malaria control programmes in the context of broader health system strengthening; ensure free access to long-lasting insecticide treated nets and malaria diagnosis and treatment for vulnerable groups; strengthen human resource capacity at central, district and community levels; and establish strong logistics, information and surveillance systems.It is critically important for countries to have a clear vision and strategy for malaria elimination; effective leadership of national malaria control programmes; draw lessons from other African countries that have succeeded to dramatically reduce the burden of malaria; and sustain funding and ongoing interventions. Dr Gro Harlem Brundtland, the then Director-General of the World Health Organization (WHO), identified Roll Back Malaria (RBM) as a priority project of the renewed WHO and established it as such on 23 July 1998 [In September 2000 the UN added efforts to fight malaria to the Millennium Development Goals (MDGs) . The AfrAt the Abuja Summit in 2006 African Union Heads of State and Government called for universal access to HIV/AIDS, tuberculosis and malaria services by a united Africa by 2010 and for a long-term vision on malaria elimination .In 2008 the Global Malaria Action Plan was developed, and the malaria endemic countries developed road maps to scale up cost-effective interventions towards achieving the MDGs . This inIn September 2009 the 59th WHO Regional Committee for Africa adopted a resolution on Accelerated Malaria Control, Towards Elimination in the African Region, which calls for, among other actions, integration of malaria control in poverty reduction strategies and all national health and development plans and mobilization of local resources for sustainable implementation of the strategies .On 23 September 2009 His Excellency President Jakaya Kikwete of Tanzania, Past Chairman of the African Union, launched the African Leaders Malaria Alliance (ALMA) during the Sixty-fourth Session of the United Nations General Assembly . The purThe ALMA working session at the 15th African Union Summit in Kampala was held 25\u201326 July 2010 in the context of calls for increasing efforts to accelerate progress towards MDGs 4 , 5  and 6  and was in line with the theme of the Summit, \u2018Maternal, Infant and Child Health and Development in Africa\u2019. The session agenda was also well aligned with the issues discussed at the previous satellite session on health financing.The purpose of this article is to reflect on the proceedings of the ALMA working session.The session included speeches and statements by invited speakers and high-level panel discussions. It was chaired by His Excellency Jakaya Mrisho Kikwete, President of the United Republic of Tanzania. The panel comprised the host of the African Union Summit, President Yoweri Museveni of Uganda, President Robert Mugabe of Zimbabwe and ministers of health and officials from African Union Member States. Invited speakers included Mr Raymond G. Chambers, UN Secretary General's Special Envoy for Malaria; Mrs Asha-Rose Migiro, UN Deputy Secretary-General; Mrs. Obiageli Ezekwesili, World Bank Vice President for Africa; Professor Michel Kazatchkine, Executive Director of the Global Fund to Fight Aids, Tuberculosis, and Malaria (GFATM); Mr Kapembwa Simbao, Minister of Health of Zambia and Chairman of the Roll Back Malaria Partnership Board; Dr Luis Gomes Sambo, WHO Regional Director for Africa; and Mrs Johannah-Joy Phumaphi, Executive Secretary of ALMA.In his opening remarks, President Jakaya Mrisho Kikwete, stated : \u201cI see President Kikwete underlined two strategic goals: (i) to achieve universal mosquito net coverage by the end of 2010 and (ii) to eliminate preventable malaria deaths by 2015 by scaling up coverage of all other available interventions .He acknowledged that these were audacious goals, but with more than 680,000 African children dying each year from malaria, audacity was a moral imperative. He strongly advocated for malaria control as a step towards achieving MDGs 4  and 5 . As convener of ALMA, President Kikwete noted the tremendous contribution of the Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM) and the World Bank in helping to finance malaria control in Africa. He expressed ALMA support for the full replenishment of funding to both GFATM and the International Development Association of the World Bank.Finally, President Kikwete called upon African leaders, communities and partners to make a final push to reach universal coverage of interventions against malaria.The UN Secretary General Special Envoy for Malaria focused his statement on the need to achieve universal coverage with essential interventions to end preventable deaths due to malaria . He highThe UN Deputy Secretary-General, addressing the AU leaders, indicated that the fight against malaria was boosting women\u2019s and children\u2019s health . She appThe World Bank Vice President for Africa indicated that the World Bank was making investments in malaria control that would have returns both in terms of lives saved and well beyond the health sector . Those iThe Executive Director of GFATM presented recent evidence on the impact of GFATM supported national programmes in saving lives and contributing to health systems and development . He stroDr Luis G. Sambo informed the session that the African Region accounted for 85% of malaria episodes and 89% of malaria deaths worldwide . He remiDr Sambo reported that over the last decade, African countries had scaled up proven malaria interventions, which include vector control using long-lasting insecticide-treated nets ,20, indoDr Sambo highlighted the encouraging achievements of Botswana, Cape Verde, Eritrea, Namibia, Rwanda, Sao Tome and Principe, South Africa, Swaziland, Zambia and Zanzibar (Tanzania) in reducing the number of malaria cases by at least 50% between 2000 and 2008 . This suHe informed the meeting that some countries were contemplating the transition from sustained control to elimination of malaria owing to their very low malaria transmission levels and based on robust epidemiological evidence and feasibility assessments. Governments contemplating the pursuit of malaria elimination will need to secure adequate domestic and external funding for sustained commitment; strengthen national malaria control programmes in the context of broader health systems strengthening; strengthen human resource capacity at central, district and community levels; establish strong logistic, information and surveillance systems as well as early detection mechanisms for response to malaria epidemics and complex emergencies; and forge effective cross-border and trans national malaria control collaborative initiatives.According to Dr Sambo, the use of oral artemisinin monotherapy was a potential driver in emergence of resistant malaria parasites. In May 2007 the World Health Assembly adopted Resolution WHA60.18, which urged Member States to deploy recommended artemisinin-based combination therapies (ACTs) and withdraw oral artemisinin-based monotherapies. He informed the meeting that by July 2010, 30 countries in the African Region had taken regulatory measures to withdraw oral artemisinin-based monotherapies. He urged the remaining countries to urgently develop similar policies to stop the marketing of oral artemisinin-based monotherapies.Dr Sambo cited a study that estimated at US$ 3 billion per year Africa\u2019s need for global resources to attain international malaria control goals. Financial support to African countries for prevention and control of malaria totals approximately US$1.6 billion per year and comes from GFATM, the US President\u2019s Malaria Initiative (PMI), the World Bank Booster Programme for Malaria Control in Africa, the United Kingdom Department for International Development (DFID), Bill and Melinda Gates Foundation and other agencies and foundations. He indicated that based on the cost of an essential package of interventions, this support represents 53% of the estimated financial resources needed to reach global malaria control targets . He appeHe concluded by appealing to the Heads of State to foster leadership for improved intersectoral collaboration to eliminate malaria as a public health problem in Africa; increase domestic funding for malaria control and accelerate progress towards MDGs 4, 5 and 6; support viable initiatives for local production of quality medicines and other commodities; eliminate taxes and tariffs on antimalarials and other public health essential commodities; and ensure free access to malaria diagnosis and treatment for vulnerable groups such as children and pregnant women, in addition to universal access to long-lasting insecticide treated nets.Mrs Johannah-Joy Phumaphi reported on the ALMA call for immediate acceleration of procurement, shipment and distribution of malaria commodities . She expMrs Johannah-Joy Phumaphi expressed concern that the high tariffs on commodities, such as bed nets and antimalarial drugs, make them expensive and hamper access. She cited the latest data that indicated that only five African countries had completely eliminated these tariffs.In his remarks to ALMA, Mr Kapembwa Simbao, Minister of Health of Zambia , expressZimbabwe, Zambia, Rwanda, Nigeria, Mozambique, Kenya and Mauritius presented their experiences in scaling up of malaria control interventions, cross-border collaboration and malaria elimination challenges. These experiences revealed the link between malaria control and maternal and child health. The debate provided insights on the importance of implementing comprehensive programmes, including community involvement, the need to build adequate capacity for vector control, and the use of rapid diagnostic tests. The role of nongovernmental organizations (NGOs) and public-private partnerships was also covered. The innovative approaches highlighted included involvement of school children and teachers in Mozambique, building capacity of village health workers in Zimbabwe, fostering cross-border collaboration among Mozambique, Swaziland and South Africa, and establishing model health centres in Kenya. Mauritius talked on its efforts to prevent reintroduction of malaria by using active surveillance and enforcing travel health regulations.th October 2010, the ministers of health from the republics of Benin, Cameroon, Central African Republic, Chad, Equatorial Guinea, Niger and Nigeria met in Abuja and signed the Abuja Commitment on Cross-Border Public Health Issues. The countries represented agreed to establish a joint initiative that permits multi-sector involvement in prevention and control of multiple public health problems in participating countries; promote communities-based initiatives on information, education and communication for disease prevention and control; promote cross-border initiatives in early detection of epidemics and improvement of water supply, sanitation and hygiene; advocate for operationalization of the African Public Health Emergency Fund to support emergency and cross-border public health activities; strengthen National Disease Surveillance Systems and share information on cross border health issues; establish National Agency for Drug Control and inter-country multi-disciplinary committees to monitor the quality of medicines and the circulation of counterfeit medicines across borders; provide (on request) technical and logistics support to any of the participating countries in the management of public health emergencies; and appoint focal persons to constitute a committee to follow-up recommendations made in the inter-ministerial meeting [Cross-border collaboration is necessary for malaria control in Africa because of the large negative externalities involved. Elimination of malaria in one country will not be sustained if the neighbouring countries experience high transmission of malaria, as citizens mix freely along borders, re-introducing malaria through travel and migration. Cross-border mechanisms that could be leveraged for controlling malaria already exist in the African Region. There are two recent examples. First, on 18 meeting .th March 2011, the ministers of health of the Republic of Angola, Republic of Congo, Democratic Republic of Congo, Republic of Namibia and Republic of Zambia met in Lusaka and signed a Memorandum of Understanding (MOU) on Cross Border Public Health Issues. The MOU touches on progress towards achievement of health related MDGs; strengthening health systems to support cross border public health issues; prevention and control of cholera and other epidemic prone diseases; polio eradication; surveillance and international health regulations; fake and counterfeit medicines; and monitoring and evaluation of cross border public health issues. Such mechanisms can be used to mobilize domestic and external resources, design, implement, monitor and report on cross-border public health action against infectious diseases [Second, on 18diseases .The country presentations echoed the sentiment of the high-level panel that the burden of malaria should be addressed as a priority health, social and developmental issue and no longer as a fatality threat for Africa. The need of tackling vector, parasite and host factors in the context of specific environmental and climatic conditions also was highlighted during the debate. Speakers at the session emphasized the necessity of multi-pronged approaches as the way forward to sustain the gains in reduction of malaria morbidity and mortality. There was agreement that the old but still valid notion of the pathogenic malaria complex must remain at the core of malaria control and elimination strategies .The main bottlenecks identified by country representatives related to the capacity of the health systems to deliver quality care and to issues of ensuring universal access to diagnostic services and treatment. The participants unanimously agreed on the need for strong, decentralized malaria-control programmes with linkages with other health and development sectors, the civil society and private sector entities. Recent publications highlight the benefits of co-implementation of malaria control programmes with child survival or other public health interventions ,32-34. FHowever, it is important to acknowledge the challenges that have to be overcome in ensuring universal access to malaria prevention and control services; and getting people to use those services once access has been assured. The first challenge is to develop sustainable health financing mechanisms that assure free access to diagnosis, treatment and insecticide treated nets for the poor. Such mechanisms may entail a combination of social health insurance and tax funded health services. In addition, health development partners can complement government efforts by paying social health insurance  premiums on behalf of the poor. Furthermore, partners can reinforce national governments capacities for providing free access for the poor through general budget support. The second challenge draws attention to the fact that even with free access, utilization may be a problem because non-financial barriers to use of diagnostic services and medication can be significant . The nonThe success mentioned above has been made possible by a number of enabling factors. First, existence of a clear vision and effective leadership contributed to improvement in the governance, stewardship and success of national malaria control programmes. Second, high level commitment has ensured relatively adequate capacity in expertise, skill mix and number of managers, technicians and service providers, including for community interventions and case management. Third, national ownership, intersectoral collaboration and accountability, as well as strong civil society and private sector involvement, are important attributes of well-performing malaria control programmes. Fourth, successful programmes have the capacity to adjust to the rapidly changing malaria epidemiology. Fifth, several regional initiatives initiated with the support of AU and regional economic communities contributed in addressing the cross-border dimension of malaria control.The panellist\u2019s emphasized countries that had achieved significant reductions in the malaria burden required support to undertake programme assessments to ensure sustained control and evidence-based transition to elimination of the disease. This requires in-depth programme reviews, strengthening of capacity for surveillance monitoring and evaluation and intensification of cross-border collaboration. It will entail contribution of research and research based institutions in the collection, analysis and dissemination of information for better control, adjustments, and policy guidance.The meeting was informed that the WHO regional framework for the acceleration of malaria control towards elimination and the guidelines on malaria elimination were available to guide the countries in planning, implementation, monitoring and evaluation of malaria programmes . Moreove\u2022 Securing adequate domestic and external funding for sustained commitment to malaria elimination;\u2022 Strengthening national malaria control programmes in the context of strengthening the broader health system;\u2022 Ensuring free access to malaria diagnosis and treatment for vulnerable groups such as children and pregnant women in addition to universal access to long-lasting insecticide treated nets;\u2022 Strengthening human resource capacity at central, district and community levels;\u2022 Establishing strong logistics, information and surveillance systems as well as early detection mechanisms for response to malaria epidemics and other public health threats.A number of conclusions emerged from the discussions. First, ALMA working sessions at the African Union Summit were critically important for sustaining the focus on accelerated malaria control and elimination vision and strategy in support of actions at the country level. Second, there is need for documenting and sharing lessons learnt from African countries that have succeeded to dramatically reduce the burden of malaria. Third, the achievements in some countries clearly indicate that the Abuja and MDG malaria targets are achievable if funding and ongoing interventions are sustained. Lastly, there was a strong indication that the next MDG summits will also offer a forum for strategic projections and consolidation of financing and implementation pledges ,51.ACTS: Artemisinin-based Combination Therapies; ALMA: African Leaders Malaria Alliance; GFATM: Global Fund to Fight AIDS, Tuberculosis and Malaria; MDG: Millennium Development Goal; NGO: Non-governmental Organization; UN: United Nations Organization; WHO: World Health Organization.The authors declare that they have no competing interests."}
+{"text": "As part of a Berlin-based research consortium on health in old age, the OMAHA  study aims to develop a conceptual framework and a set of standardized instruments and indicators for continuous monitoring of multimorbidity and associated health care needs in the population 65 years and older.OMAHA is a longitudinal epidemiological study including a comprehensive assessment at baseline and at 12-month follow-up as well as brief intermediate telephone interviews at 6 and 18 months. In order to evaluate different sampling procedures and modes of data collection, the study is conducted in two different population-based samples of men and women aged 65 years and older. A geographically defined sample was recruited from an age and sex stratified random sample from the register of residents in Berlin-Mitte  for assessment by face-to-face interview and examination. A larger nationwide sample  was recruited for assessment by telephone interview among participants in previous German Telephone Health Surveys. In both cohorts, we successfully applied a multi-dimensional set of instruments to assess multimorbidity, functional disability in daily life, autonomy, quality of life (QoL), health care services utilization, personal and social resources as well as socio-demographic and biographical context variables. Response rates considerably varied between the Berlin and German OMAHA study cohorts (22.8% vs. 59.7%), whereas completeness of follow-up at month 12 was comparably high in both cohorts (82.9% vs. 81.2%).The OMAHA study offers a wide spectrum of data concerning health, functioning, social involvement, psychological well-being, and cognitive capacity in community-dwelling older people in Germany. Results from the study will add to methodological and content-specific discourses on human resources for maintaining quality of life and autonomy throughout old age, even in the face of multiple health complaints. Multimorbidity, e. g. the concurrent existence of multiple health problems in the same person, is a highly prevalent phenomenon in old age and of growing public health impact in aging societies -3. The tDue to methodological challenges and limited epidemiological data, the prevalence, patterns, determinants, correlates, and consequences of multimorbidity are not well researched ,6. A firAgainst this background, the Federal Ministry of Education and Research (BMBF) launched a long term research initiative on 'Health in Old Age'. A total of six research consortia qualified for an initial three-year funding period (2008-2010) to provide insight into the epidemiology and socioeconomic consequences of multimorbidity in older people in Germany . Among tThe population-based AMA subproject OMAHA  aims to develop a conceptual framework and a set of standardized instruments and indicators for continuous monitoring of multimorbidity and associated health care needs in the population 65 years and above. Main specific goals are: (1) to develop an algorithm for the comprehensive assessment of multi- and comorbidity, (2) to analyze patterns, correlates, determinants, and consequences of multi- and comorbidity; (3) to evaluate an innovative instrument for preference-based QoL assessment among elders with multimorbidity; (4) to examine the effectiveness and efficiency of different recruitment strategies and to characterize difficult-to-reach subgroups of the population 65 years and older. We describe here the design, methods, study population, and data base of the OMAHA study.The OMAHA study is designed as a population-based longitudinal epidemiological study of multimorbidity in the population aged 65 years and older. With regard to methods applied for continuous nationwide health monitoring in Germany , the OMAThe study was approved by the local ethics committee at Charit\u00e9 - Universit\u00e4tsmedizin Berlin and conducted in compliance with data protection and privacy regulations as requested by the Federal and Berlin Offices for the Protection of Data. Study participants were informed in detail about the study objectives, interview and examination procedures as well as pseudonymized record keeping and subsequent data analysis. Persons participating in the personal interview and examination gave written informed consent prior to study inclusion. A subset also provided written permission to contact their family doctor for validation of specific self-reported medical conditions . Oral informed consent to study participation was obtained from participants in previous German health telephone surveys before conducting the OMAHA baseline CATI.For the Berlin OMAHA cohort, we drew an age  and sex stratified random sample of 2000 men and women aged 65 years and older from the official register of residents in Berlin-Mitte as of July 15, 2008. All individuals of the population sample who were then verified as alive, still living in Berlin-Mitte and available during the study recruitment period were eligible for the study. Exclusion criteria were: death, permanent change of residence outside of Berlin-Mitte or to an unknown address, and continuous absence from Berlin during study recruitment period. Anticipating an overall response rate of about 20% and an overall proportion of unverifiable contacts of 5-10%, the total sample size was sufficiently large to achieve a study population of n = 300 for the main study and of n = 100 for preceding pre-test evaluation.To assure public support of the study, we communicated the study goals and logistics to members of the Berlin Medical Association via the official journal of the Berlin Medical Association  and to community officials  via telephone contacts.Individuals belonging to the main sample were initially contacted by post. The letters contained a brief description of the study, an invitation to participate, and a prepaid self-addressed envelope together with a return sheet to fill in telephone numbers, preferred contact times, and choice of home or study centre visit for the assessment. Participants were offered a small monetary incentive (\u20ac 10) plus reimbursement for travel expenses. Foreign nationals were offered a brief description of the study in seven different languages .In order to identify and further characterize persons who did not participate, we explicitly asked family members or caregivers to respond in case that an eligible person was not able to participate due to cognitive impairment or severe illness and to consent to proxy telephone interviews.Among persons who did not respond to the initial mailed invitation, we conducted a randomized controlled trial which evaluated the effectiveness and efficiency of three different intensified recruitment strategies: (a) personal visits, (b) telephone calls, or (c) mailed reminder letters including the initial invitation letter and enclosures. Statistical analysis of this comparative evaluation of recruitment strategies is completed and results are currently prepared for publication in a separate paper.German OMAHA cohort was recruited from a pool of persons who had previously participated in the German Telephone Health Surveys 2004 or 2006. Nationwide telephone health surveys have been conducted in Germany annually by the Robert Koch Institute since 2002/2003; sampling procedures and recruitment strategies have been previously described in detail [The n detail . In brien detail . This men detail ; 2682 won detail ). The maOf the total Berlin sample, 519 persons (26.0%) had initially been contacted for preceding pre-test evaluation, leaving a total of n = 1481 persons for the main study  was drawn from the German Telephone Health Survey sample 2007 .N = 1552 participants in previous German Telephone Health Surveys 2004 and 2006 were selected for the OMAHA study  potential consequences of multimorbidity, including impairment of body functions and frailty, autonomy, quality of life, and health care services utilization, (c) personal and social resources likely to modify the association between multimorbidity and outcome measures, (d) socio-demographic and biographical context variables.Within the conceptual framework depicted in Figure Selection of instruments was based on extensive literature review and feasibility pre-testing. Table multimorbidity is composed of two domains: (a) health status as assessed by self-reported physician-diagnosed health conditions, history of surgical procedures, history of fractures past age 50 years, medication use within 7 days prior to the interview, and standardized measures (Berlin cohort only) of height, weight, waist and calf circumference, and blood pressure; (b) self-reported current symptoms and complaints including sensory limitations (vision and hearing problems), urinary and faecal incontinence, constipation, back pain, and joint complaints. Overall, 31 specific health conditions were covered in the CAPI and CATI following a standardized sequence of questions on first and last time of occurrence of symptoms, medical treatment within the past 12 months, and perceived level of condition specific limitation in daily life  was assured by scanning the original containers brought to the examination site for that purpose. All drugs were automatically coded by an underlying software system to the WHO-ATC system. Details on medication use also included self-reported indications, form of administration, frequency of intake, origin of the medicine, and duration of use.Autonomy is conceptualized twofold as (a) absence of disability in daily life and dependence on care, and (b) perceived self-determination. Disability and dependence on care were assessed by standardized CAPI or CATI, covering questions on limitations in activities of daily living , and everyday competence. Questions on subjective self-determination were covered in the self-administered questionnaire and are hence limited to the Berlin cohort.Quality of life comprises the following domains: self-rated health, subjective well-being and vitality, pain, health-related QoL, global life satisfaction, and preference-based quality of life. All of these except preference-based quality of life were assessed in both OMAHA cohorts by validated instruments via standardized interview (CAPI or CATI) or self-administered questionnaire. Preference-based QoL was assessed only in the Berlin cohort by the newly developed tool FLQM  as part of the CAPI. Additional instruments to measure global life satisfaction  and subjective well-being  were administered in the Berlin cohort only.Resources can roughly be divided into personal, social and organizational resources. As facets of personal resources, individual health-related behaviours , educational status, and income as well as housing and environment were assessed in both OMAHA cohorts by standardized self-administered questionnaire or CATI. Proactive coping as another important personal resource was assessed by the Proactive Coping Inventory (PCI) via self-administered questionnaire in the Berlin cohort only, since the PCI is not suitable for administration via CATI. As part of the social resource domain, social contacts were assessed in both OMAHA cohorts by the same validated instrument (MILVA). In lack of a validated instrument for administration by CATI, the assessment of subjective social support (by BSSS) was restricted to the Berlin OMAHA cohort. Organizational resources assessed were health insurance, family doctor, housing and environment, and nursing care level within the German healthcare system. Additional context variables covered age, critical life events, and migration background.Due to the exploratory nature of the study and the multiplicity of outcomes, no power calculation was considered.A statistician supervised, validated, and where necessary corrected the data throughout the process of data-collection. Cleaned final data sets were provided by the statistician within less than 6 months after the completion of data collection. A detailed documentation of the process was continuously accessible to the research team.To achieve a high degree of standardization in the survey, the study nurses for personal interviews (CAPI) were initially trained and continuously supervised. Additional training sessions took place before the 12-months follow-up. Telephone interviewers were highly experienced in carrying out telephone health surveys and received specific training before the baseline interview as well as before the 6-month and 12-month follow-up interviews. Standard operation procedures (SOPs) were supplied for all parts of the computer-assisted interviews (CAPI and CATI), functional assessments, and anthropometric measurements. Quality standards and requirements for internal quality control were developed according to recognized epidemiological guidelines and standards applied in German Health Interview and Examination Surveys .The OMAHA project is a longitudinal epidemiological study in two population-based cohorts of older people aged 65 years or older using different methods of data collection. In the urban cohort (Berlin cohort), an age- and sex-stratified sample of residents of an inner-city district of Berlin was assessed by face-to-face interviews, self-administered questionnaires and measurement of physical functions and body measures. In the nationwide cohort (German cohort), participants of former German Health Telephone Surveys were assessed by telephone interview.Our research is focused on the development of a comprehensive assessment of multi- and comorbidity and the analysis of patterns, correlates, determinants, and consequences of these. Also, an innovative instrument for preference-based QoL assessment among elders suffering from multimorbidity will be evaluated. On the methodological level, we examine the effectiveness and efficiency of different recruitment strategies and will characterize difficult-to-reach subgroups of the population 65 years and older. Data collection comprises four waves in each of the two cohorts: two more extensive waves at baseline and 12-month follow-up, and two very brief waves at months 6 and 18 from baseline assessment. This opens up a wide range of opportunities for analyses on trajectories of health states, longitudinal relationships of outcome determinants, and, most importantly, causal relationships between conditions and trajectories over a period of 18 months.The parallel application of instruments in the two cohorts and modes of administration (CAPI and CATI) will on the one hand allow us to identify those tools that are most suitable for telephone administration. On the other hand, we will also be able to make comparisons between the urban Berlin cohort and the nationwide cohort with respect to selected variables cross-sectionally as well as longitudinally. The wide variety of measures relating to similar constructs allows us to soundly determine the psychometric properties of adaptations and new developments for geriatric and gerontological assessments in older age groups. After the completion of analyses relating to validity and reliability of (1) adaptations of existing measurement tools and (2) the newly developed quality of life assessment tool (FLQM) we will be able to provide a wide-ranged set of instruments and tools for personal and telephone assessment in population-based health surveys.Clearly, the samples are subject to selective inclusion. Within the Berlin cohort, there were considerable differences in sample structure with respect to different major sub-populations, such as migrants or people living in nursing-homes and socio-economically deprived areas. In addition to the specified sub-populations, people suffering from dementia or cognitive impairment and those who are heavily restricted in their sensory capacity are not likely to be adequately represented in both cohorts. Because determining barriers and evaluating recruitment strategies are among our goals, we did not expect the participating sample to be representative. In contrast, analyses of the effectiveness and efficiency of the three different recruitment strategies in the Berlin cohort and detailed analysis of participant/non-participant characteristics in both cohorts will enable us to derive strategies on how to get better access to, and response from, these groups. In future studies, a strategy of oversampling underrepresented, yet notably prevalent and politically important groups could serve as one means to minimize selection bias.OMAHA offers a wide spectrum of data related to health, functioning, social involvement, psychological well-being, and cognitive capacity throughout old age in Germany, opening up new opportunities for further gerontological and geriatric research. Results from the study will add to methodological as well as content-specific discourses on human resources for maintaining high levels of autonomy and quality of life in old age, even in the face of multiple health burdens and morbidity.The authors declare that they have no competing interests.MH and CSN conceptualized and supervised the study, analyzed the data and wrote the final manuscript. JF, MB and PM conceptualized and supervised the study, analyzed the data and made substantial contributions to the writing of the final manuscript. JWelke, JSM, HK, UH assisted in the conceptualization of the study, provided specific knowledge, made substantial contributions to the acquisition and quality assurance of the data and contributed to the final manuscript. RD, NS, IKS, JWiskott provided specific knowledge, made substantial contributions to the acquisition and quality assurance of the data and contributed to the final manuscript. AE assisted in the conceptualization of the study, analyzed the data and contributed to the final manuscript. BG analyzed the data and contributed to the final manuscript. MW made substantial contributions to the acquisition and quality assurance of the data and contributed to the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6963/11/47/prepub"}
+{"text": "MLH1, 206 MSH2, 39 MSH6, 26 PMS2). Carriers of mutations in these genes are at high risk of colorectal, endometrial and other cancers.Literature on the ethics of returning research-generated genetic results to research participants has not reported on the practical experience of this activity. The Colon Cancer Family Registry (Colon CFR) has recruited participants from the US, Canada, Australia and New Zealand. Colon CFR-wide molecular testing has identified deleterious germline mutations in a DNA mismatch repair (MMR) gene for members of 424 families  (see Table The variation in uptake of genetic information could be related to the variation in the potential for insurance discrimination and/or the differences in the cost to consumers of genetic testing in the research and clinic setting.The return of genetic results and collection of uptake data has provided valuable information about the translation of these research findings and has led to translational research proposals. Delivering research-generated genetic results in the research setting, especially when sampling is population-based, provides both challenges and opportunities."}
+{"text": "Leptospirosis is a tropical neglected disease that is highly under-diagnosed and under-reported, mostly because of a lack of diagnosis capacity. The Institut Pasteur International Network includes researchers and physicians that have a recognized expertise in the field of leptospirosis epidemiology and diagnosis. Taking advantage of this international and widespread network of expertise, we currently aim at implementing the diagnosis of leptospirosis in institutes, countries or regions where it was not available. With the financial support of the Institut Pasteur International Network, biologists and researchers from French Guyana, Cameroon, Guadeloupe (West Indies), Cote d\u2019Ivoire, Cambodia, New Caledonia and France currently work at implementing and inter-calibrating leptospirosis diagnosis in their respective institutes.Leptospira spp., the early diagnosis of leptospirosis increasingly relies on PCR. Using its own molecular platform and expertise, each institute implements the PCR or qPCR method of its choice for the detection of pathogenic Leptospira spp. Common Leptospira suspensions are shared to commonly evaluate the sensitivity of the PCR assays.Because of very slow and delicate culture of The serological reference method uses the Micro Agglutination Test (MAT), a method that requires continuous culture of live leptospires and experienced staff for interpretation. Therefore, commercially available serological tests (Elisa for the detection of anti-Leptospira IgM) are used as a first diagnosis approach. The French National Reference Center then validates the results and identifies the infecting serogroup using a reference MAT panel.These diagnostic tools are then offered to patients hospitalized with predefined leptospirosis-like symptoms, as a way to (re-) evaluate the contribution of leptospirosis to non-malarial febrile illnesses in these countries and regions.The global architecture and goals of our Lepto-network will be presented, together with epidemiological research perspectives using the tools and expertise developed through this network."}
+{"text": "They function in metabolic processes, signal transduction, transport of small molecules and polymers across endo- and plasma membranes, and inter-compartmental trafficking of proteins, lipids, and cell wall components. During these highly integrative processes, dynamic interactions of membrane proteins with other membrane or soluble components are thought to provide a high degree of flexibility that usually characterizes higher plants. This concept is supported by the recent release of a first, partial Arabidopsis interactome by the Arabidopsis Interactome Mapping Consortium [Frontiers in Plant Transport and Traffic and Frontiers in Plant Physiology reflects well this outcome of the Arabidopsis Interactome Mapping Consortium. It embraces outstanding current research efforts with a series of reviews and original papers that highlight conserved and plant-specific mechanisms of post-Golgi trafficking, exocytosis and endocytosis and the role of the actin cytoskeleton from an evolutionary perspective. This research topic is comprised of reviews on PILS and AUX/LAX transmembrane auxin carriers and reviews, original articles, and hypothesis and theory articles on plant channels, including potassium channels, slow and quick anion channels, and glutamate receptors. This research topic concludes with an integrated view on how membranes shape plant nodulation and Arbuscular mycorrhizae.With no surprise, this current research topic co-hosted by As such, this research topic is a timely update presenting advances in research in the evolution of membrane signaling and trafficking in plants, encompassed of outstanding contributions that address fundamental questions in these essential processes in plants."}
+{"text": "The development of vaccines is one of the most important public health achievements. However, as the incidence of vaccine-preventable diseases has decreased, the general public has become increasingly concerned about vaccine safety. Vaccine safety is evaluated extensively through animal safety studies, clinical trials, and post-licensure surveillance. Safety monitoring in post-licensure surveillance has relied mainly on passive reporting systems such as the Vaccine Adverse Event Reporting System in the United States and epidemiological studies.Vaccine safety profiles cannot necessarily be generalized to developing countries, where the incidence, type and severity of serious adverse events may differ significantly because of local environmental and genetic influences. With thThe recent and novel use of YF vaccine for preventative mass vaccination campaigns in sub-Saharan Africa has increased the urgency of establishing functional PV systems. Between 2006 and 2013, the YFI will distribute vaccines to residents of high-risk areas in 12 West and Central African countries. A condition of funding from the GAVI Alliance is the implementation of AEFI surveillance. To address this requirement, AMP and WHO have provided technical support, including the development of surveillance tools , the introduction of active case finding methods, and the creation and training of national expert committees to review and classify suspected serious AEFIs. Reference laboratories, including the Institut Pasteur in Cameroon, and the Robert Koch Institute in Germany provided diagnostic test results to facilitate the YF AEFI classification process. Best practices have been shared between different countries and African-based consultants have been trained to become local experts. Their expertise is now being requested for AEFI surveillance of additional vaccines such as the serogroup A meningococcal conjugate vaccine."}
+{"text": "An additional interesting fact is that miRNAs are highly developmental stage-, tissue- and cell-specific, even in adjacent cell types, and mean abundance of these individual species may fluctuate as do the levels of transcription factors which regulate pre-miRNA transcription , and the biological actions of these ribonucleotide entities in the developing, aging, and pathological human central nervous system (CNS) has opened a novel and fascinating vista into our appreciation of human brain epigenetics, the role of sncRNAs on homeostatic and pathogenic gene control, and the potential role of single stranded, 22&nt signals in shaping the transcriptome of the human CNS (Lukiw et al., s Lukiw, . Table 1convergence, and conversely, a single miRNA may interact with multiple mRNAs in a regulatory process known as miRNA divergence (Lukiw and Alexandrov, Another poorly understood layer of complexity in miRNA signaling is that several miRNAs may regulate a single mRNA in a neurogenetic control process known as miRNA"}
+{"text": "This Editorial announces a new section in the Journal of Translational Medicine: Patient-Targeted Molecular Therapies. This section is dedicated to the dissemination of targeted molecular therapies in context of patient-centered outcomes research and evidence-based clinical decisions. The focus on patient-targeted molecular therapies \u2013 spanning small molecules and biomolecules alike \u2013 stems from the unprecedented growth in this arena. This is consonant with the overall objective of the Journal of Translational Medicine, which seeks out to expand firmly to other vast areas of medicine in the domain of translational science, viewed here as the transaction between translational research and translational effectiveness. As we inaugurate this new section in Journal of Translational Medicine, with its mission described in detail in this Editorial, we invite interested scientists to submit their work for publication. Analyses of current limitations and deficiencies in health care in the context of the Affordable care Act, signed into law by President Obama in March 2010 [There has been unparalleled and continuous progress in research and development in broad areas of molecular medicine resulting in novel platform technologies, drugs, biomolecules and companion diagnostics on the market and in development. Additionally, post-approval testing of novel medicines or therapeutic combinatorial modalities with the aim to improve the standard of care has been a steady continuous source of information with impact to the healthcare. Key to these advances is the dynamism of this process, and the magnitude and complexity of resulting informational output, warranting iterative application of appropriate research and evaluation tools across entire domains of medicine, to identify and promote standard of care or outline state of the art.Therefore, innovative models of evidence-based patient-centered molecular-targeted interventions are timely and critical. Evidence-based medicine/dentistry/nursing, through the process of comparative efficacy and effectiveness research and review for clinical practice (CEERAP) pursues the identification of the best available evidence gained from the scientific method to clinical decision-making ,3. CEERAPatient-Targeted Molecular Therapies, which is dedicated to the dissemination of targeted molecular therapies in the context of patient-centered outcomes research and evidence-based clinical decisions. Therefore, the focus on patient-targeted molecular therapies \u2013 spanning small molecules and biomolecules alike \u2013 stems from the unprecedented growth in this arena, fueled by scientific progress in understanding the molecular pathogenesis of disease.In response to this urgency, the Journal of Translational Medicine now inaugurates a new section, entitled Patient-Targeted Molecular Therapies provides avenues for the discussion of translational effectiveness pertaining to diverse therapeutic areas including inflammation, degenerative disorders, cancer, infection, metabolism, neurologic, cardiovascular to genetic disorders. The section considers pathologies that pertain to the micro-environment and local immunoregulation and epigenetics, as well as systems immunophysiology. The section addresses chronic and acute immune-related pathologies, from autoimmune disease, to HIV/AIDS, from immune deficiencies to osteo-immunopathology, from inborn errors of immune metabolism to psycho-neuroendocrine-immune pathologies. This section also considers non-immunological disorders, and conditions that are at the interface with immunopathology with both facets: the drug (or therapeutic intervention) and the companion biomarkers.The section Patient-Targeted Molecular Therapies will be complemented by an interest in prognostic and predictive biomarkers, as well as companion diagnostics as they are a critical tool in the assessment or application of molecular targeted therapeutics, and emphasize patient-targeted research for personalized medicine, now subsumed under the terminology \u201cpatient-centered outcomes research\u201d. As molecular targeted therapies \u2013 through an increased potential for clinical benefit and data-rich clinical design - carry the benefit of yielding informative data sets in individual patients during smaller trials in early development, a focus will be to outline emerging evidence of efficacy or toxicity for innovative drug candidates.The purpose of this new section is consonant with the overall objective of the Journal of Translational Medicine, which \u2013 with traditional and diligent interest in immune therapies - seeks out to expand firmly to other vast areas of medicine. This section on Patient-Targeted Molecular Therapies in Journal of Translational Medicine specifically addresses the best available evidence about the translational effectiveness of biomarkers-guided targeted molecular therapies of established medical and dental clinical conditions.In brief, as the informational output regarding more mature or approved molecular targeted therapies evolves across multiple development programs and studies, the specific content of this section will include research products in the form of systematic reviews, clinically relevant complex systematic reviews and meta-analyses. It will also include reviews of the best available evidence, in the form of critical evidence reviews and evidence-based policies. The scientific focus of this section on With this opening editorial, we announce and inaugurate this new section in Journal of Translational Medicine. We invite interested scientists to submit their work for publication."}
+{"text": "The liver responds to estrogens and growth hormone (GH) which are critical regulators of body growth, gender-related hepatic functions, and intermediate metabolism. The effects of estrogens on liver can be direct, through the direct actions of hepatic ER, or indirect, which include the crosstalk with endocrine, metabolic, and sex-differentiated functions of GH. Most previous studies have been focused on the influence of estrogens on pituitary GH secretion, which has a great impact on hepatic transcriptional regulation. However, there is strong evidence that estrogens can influence the GH-regulated endocrine and metabolic functions in the human liver by acting at the level of GHR-STAT5 signaling pathway. This crosstalk is relevant because the widespread exposition of estrogen or estrogen-related compounds in human. Therefore, GH or estrogen signaling deficiency as well as the influence of estrogens on GH biology can cause a dramatic impact in liver physiology during mammalian development and in adulthood. In this review, we will summarize the current status of the influence of estrogen on GH actions in liver. A better understanding of estrogen-GH interplay in liver will lead to improved therapy of children with growth disorders and of adults with GH deficiency. Growth hormone (GH) is the main regulator of somatic growth, metabolism, and gender dimorphism in liver , metabolic , and sex-differentiated  functions in liver. The influence of estrogens is executed at the level of pituitary GH secretion and the regulation of GHR-JAK2-STAT5-SOCS signaling pathway. Therefore, the complex estrogen/GH interplay is relevant because physiological roles that these hormones have in mammals, and the widespread use of estrogen-related compounds. In the general population, the endocrine and metabolic consequences of long-term exposition to estrogens or novel estrogen-related compounds and their influence on the GH axis are largely unknown. Understanding this complex interaction in physiological and pathological states could contribute to prevent health damage and improve clinical management of patients with growth, developmental, and metabolic disorders.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Because of their evolving nature and inherent scientific uncertainties, outbreaks of emerging infectious diseases can be associated with considerable fear in the general public or in specific communities, especially when illness and deaths are substantial. Mitigating fear and discrimination directed toward persons infected with, and affected by, infectious disease can be important in controlling transmission. Persons who are feared and stigmatized may delay seeking care and remain in the community undetected. This article outlines efforts to rapidly assess, monitor, and address fears associated with the 2003 severe acute respiratory syndrome (SARS) epidemic in the United States. Although fear, stigmatization, and discrimination were not widespread in the general public, Asian-American communities were particularly affected. Public health strategies that deal with rapidly evolving disease outbreaks of new and emerging infectious diseases require a delicate balance between protecting the public\u2019s health and initiating exclusionary practices and treatments that can lead to fear and stigmatization of, and discrimination against, specific populations. The outbreak of severe acute respiratory syndrome (SARS) illustrates these difficulties. SARS spontaneously appeared in the southern province of Guangdong, People\u2019s Republic of China, in November 2002  at the Centers for Disease Control and Prevention (CDC) formed a 14-member, multidisciplinary NCID/SARS Community Outreach Team as part of its emergency response to the global SARS outbreak. While other NCID/CDC response teams dealt with laboratory investigations, surveillance, communication, and clinical infection control practices, the Community Outreach Team worked to implement rapid public health strategies to document, monitor, and assist in ameliorating specific problems associated with fear, stigmatization, and discrimination attributed to the SARS outbreak in the United States.In creating a rapid public health intervention to mitigate behaviors and practices associated with SARS-related fear, the team recognized the need to address the experiences of persons at greatest risk for experiencing SARS-related fear, stigma, and discrimination. The team monitored stigmatizing ideas and behaviors in the general population and the media, particularly toward Asian Americans, who were disproportionately reporting fear, stigmatization, and discrimination compared to the general public. The team began working with Asian-American communities to develop a culturally tailored intervention that 1) promoted community understanding of the facts related to the transmission and prevention of SARS; 2) contributed to the strengthening of community resiliency and capacity to mitigate fear, stigmatization, and discrimination; and 3) encouraged appropriate health-seeking behaviors for those who may have been exposed to SARS and were experiencing early symptoms. The team also worked to dispel myths; keep the general public better informed; prevent discrimination against SARS-affected communities; and provide guidance for institutions, agencies, and organizations hosting international visitors from SARS-affected countries.During the first 3 weeks of April 2003, the NCID/SARS Community Outreach Team conducted a rapid situational analysis to determine the impact of SARS-related fear, stigmatization, and discrimination within the Asian-American community in the United States. The team carried out the following activities: 1) facilitated group discussions with key opinion leaders within the Asian community in the United States; 2) collected and monitored the CDC Public Response Service data; 3) collected and monitored Asian-language newspapers, Internet sites, and other information sources; 4) reviewed polling data and other communication information; 5) conducted community visits, panel discussions, and media interviews; 6) solicited information from state and regional minority health liaisons nationwide; 7) developed ongoing relationships with the Asian-American communities; particularly in major metropolitan areas throughout the United States; and 8) determined new data-gathering strategies as needed.The team conducted group interviews through teleconferences with national, state, and local influential leaders in the Asian-American community throughout the United States. The team also conducted group interviews with Chambers of Commerce and trade association members, school officials and representatives, state public health department staff, academicians at universities, mental health professionals, and others. The 11 teleconferences the team conducted reached more than 70 persons who represented more than 50 agencies, organizations, and communities. The goals of the group interviews were the following: 1) determine the impact of SARS-related fear on the Asian community; 2) document examples of fear, stigmatization, and discrimination; 3) determine strategies for identifying and reaching \u201chidden populations\u201d; 4) develop partnerships with leaders and community members of the affected populations; 5) determine the needs of affected populations; and 6) respond appropriately to those needs through a targeted intervention with activities and Asian-language materials.Five major recommendations were derived from the facilitated group discussions with key informants: 1) develop simple, tailored SARS prevention messages; 2) develop SARS information materials in various Asian languages; 3) disseminate SARS information through multiple and culturally appropriate channels, including (but not limited to) community visits, town hall meetings, and health education and communication channels to complement mass media messages; 4) establish partnerships with local Asian-American community\u2013based organizations to educate the community; and 5) ensure that CDC would continue to provide leadership and coordination in preventing and controlling SARS. The relationships developed during these group discussions allowed team members to monitor and document ongoing stigmatizing situations related to the disease outbreak in real time and to deal more effectively with intentional and unintentional discrimination.CDC operates the Public Response Service (CDC PRS) under contract with the American Social Health Association. This contract provides hotline service to the general public requesting information via telephone and email about bioterrorism and other disease emergencies, including SARS. The NCID/SARS Community Outreach Team worked with the CDC PRS to track a daily sample of incoming SARS-related calls, specifically noting questions associated with fear, stigmatization, and discrimination directed toward the Asian-American community. This system allowed the team to help determine specific answers to frequently asked questions for hotline staff and to develop simple, prerecorded Asian-language messages. Passive data collection of SARS fear-related concerns began on April 29, 2003. During May 2003, 7,327 SARS-related calls were received; 4,013 (54.7%) of these calls were passively sampled. Of these sampled calls, an average of 10% of callers expressed concerns related to fear, stigmatization, and discrimination. A caller could express more than one concern. Major concerns included the following: fear of buying Asian merchandise ; working with Asians ; living near Asians ; going to school with Asians ; and more generic issus such as being on a cruise ship or airplane ; and church, school, or workplace issues . Most SARS calls related to transmission, symptoms, and treatment of disease and travel advisories.One critical component of the team\u2019s activities was determining where members of the Asian-American community were getting SARS-related information. Team members monitored English-language and Asian-language electronic, print, and television media coverage and informal chat rooms in the United States and other countries to stay abreast of changing information about the nature of the SARS outbreak that could influence fear, stigmatization, and discrimination. The assessment showed that many people within the Asian-American community were getting information from Asian-language newspapers, television, and Internet sites directly from China, Hong Kong, Taiwan, and other Asian areas\u2014usually hours ahead of information providers in the United States. The information provided by these Asian-language sources was often inconsistent with newspaper, television, and Internet coverage in the United States, thus creating fear and suspicion that the United States government might not be telling the truth about the outbreak in this country. Independent content-analysis research conducted by InterTrend Communications  compared four of the most popular Chinese language newspapers in the United States with two popular national mainstream English-language newspapers from March 21 to April 3, 2003  advised other SARS emergency response teams on how to minimize the risk of stigmatizing groups in their own communications by focusing messages on the virus and the relevant behavioral risk factors; 2) assisted with developing culturally tailored health education materials; and 3) conducted community visits, panel discussions, and media interviews to positively influence negative behaviors occurring in communities. These visits and other contacts with the Asian-American community allowed CDC to develop ongoing relationships and helped the team determine new data-gathering strategies.During a disease outbreak, information changes rapidly as scientific evidence is collected and analyzed. Vital components of the team\u2019s activities were prioritizing and translating existing information and guidance documents and developing health education materials to address the specific needs of the Asian-American community. An in-house translation service did not exist, and the rapidly evolving scientific evidence challenged the turnaround time for developing, translating, and disseminating information. The team worked to identify priority documents for translation and to ensure Asian-language translation for Web and print products tailored to the Asian-American community. To ensure accurate translations, CDC contracted with professional translation services and had all documents back-translated. Web-based information on SARS included documents in traditional Chinese, simplified Chinese, Korean, Vietnamese, and Japanese, as well as French and Spanish. The team also created brief, recorded educational hotline messages in Chinese and Vietnamese. The main messages for people in the United States were the following: 1) the risk of SARS is low; 2) severe cases of SARS have been uncommon, and there have been no deaths in the United States; 3) methods for disease prevention in the general public are like those of other viral diseases; and 4) although no evidence of community spread currently exists, continued vigilance, aggressive case management, and infection control are needed.Team members conducted field visits to Asian communities in Boston; New York City; Oakland, California; San Francisco; Washington, D.C.; Edison, New Jersey; and Los Angeles to respond to the direct needs of the communities and gather information. The team met with community leaders, toured the communities, informally gathered further information, and gave community SARS presentations in seven cities, reaching approximately 500 persons. Through community visits, the team was able to 1) provide the latest in evidence-based information on SARS with Asian-language education materials; 2) dispel misconceptions, myths, and rumors; 3) act as a catalyst for bringing together a broad spectrum of organizations and persons in the community to create local networks to promote community resiliency; and 4) provide credibility and reassurance to those who felt vulnerable. Speakers also presented a public health model for mitigating fear, stigmatization, and discrimination that could be instituted by public health officials, clinicians, and community members. Through open discussion sessions and informal information gathering in the community, the team found that SARS-related stigmatization was occurring more frequently within the Asian community than from outsiders directed toward the Asian community. The team also found that those persons with SARS-like symptoms who used traditional herbal physicians and pharmacies were less likely to be referred to, or seek out, public health officials, suggesting that further research into strategies to reach this population is needed. Conducting community visits also showed that CDC was responding to the needs of the community at risk for SARS-related fear, stigmatization, and discrimination and was modeling positive behaviors to the public.Other infectious disease epidemics have been associated with specific ethnic groups. Fear, stigmatization, and discrimination plagued Russian Jewish immigrants when the 1892 outbreaks of typhus fever and cholera in New York City were traced to Russian Jewish immigrants from Eastern Europe (Protecting the health of the public while preventing stigmatization of segments of the population during a rapidly evolving disease outbreak is complex. The team\u2019s experience during the recent SARS outbreak demanded anticipatory insight, perceptive planning, and a rapid response to a targeted audience with specific cultural perspectives and influences. It also required us to recognize the distinctive features of SARS in a medical, social, and cultural context. Weiss states, \u201cPreventing fear and stigmatization depends on controlling or treating the target health problem, countering tendencies of those who stigmatize others, and supporting those who are stigmatized through emotional support and social policies\u201d (The data collected during the rapid situational assessment were critical in guiding activities of the team. Both the data and the data collection process assisted the team in establishing interpersonal relationships with community leaders, determining priority needs, identifying responsible intervention strategies, and developing effective communication channels. The team was able to better understand community perceptions and attitudes by identifying the communities\u2019 trusted sources of information. When conducting community visits, the team was able to address discordant information, myths, and rumors; provide simple Asian-language messages and materials; and act as a catalyst to build community resiliency and prepare for the possibility of future emerging diseases. The team was also able to keep CDC/NCID leaders informed and to intervene when they identified discriminatory policies, practices, and actions that were inconsistent with evidence-based public health recommendations and guidelines.Quelling fear-driven stigmatization and discrimination during the SARS outbreak required tailored intervention strategies carried out by the SARS Community Outreach Team. These activities complemented traditional risk communication for the general public. To be effective, behavioral intervention approaches, messages, and materials had to be salient for the affected population, in this case Asian-American communities within the United States. Further, these interventions aimed at promoting an accurate understanding of the epidemic both in the general population and within the affected community, that is, the dynamic nature of the outbreak and its cause, treatment options, and prevention strategies. Through interpersonal connections, the team members worked to promote reassurance and enhance community resiliency.Public health professionals must understand the necessary balance needed to protect the public\u2019s health with appropriate exclusionary practices, while at the same time preventing fear, stigmatization, and discrimination of specific segments of the population. As we prepare for the next new or reemerging disease outbreak, we should also be preparing to deal with the fear epidemic that will likely accompany it. By developing effective behavioral and health education strategies and providing timely attention to the special needs of affected populations, we can ensure that, no matter what the infectious disease, we can limit the associated epidemic of fear and stigmatization."}
+{"text": "One of the most significant features of healthcare-associated infections (HAIs) is the high frequency of multidrug-resistant bacterial strains (MDRBSs). Even modern chemical antimicrobials (CAMs) are not efficient enough; a totally different way of prevention of HAIs caused by MDRBSs is necessary.To develop a monobacteriophage (MBP)-based way of prevention of HAIs caused by MDRBSs.Pseudomonas aeruginosa (PA), methicillin-resistant Staphylococcus aureus (MRSA), Salmonella spp., Shigella spp., and Klebsiella spp. were sprayed on various surfaces in different healthcare settings (HCSs) in the case of spread of HAIs caused by these agents. We compared efficiency of MBPs on different surfaces and in different conditions of phage circulation. Finally, we assessed the influence of the MBPs on incidence and mortality of HAIs caused by MDRBSs. The efficiency of the MBPs was evaluated in the terms of absence of the target bacteria in the environment, that, in turn, was assessed by classical bacteriological methods.MBPs against Salmonella-caused infections, 4-fold reduction of incidence of Shigella-caused infections, and 2-fold decrease of incidence of Klebsiella- and MRSA-caused infections. Finally, CAMs did not influence the efficiency of MBPs, and no side effects were registered.Application of MBPs sprayed on surfaces in hospital environment is significantly more efficient method of elimination of MDRBSs compared to their usage by any other way. MBPs possessed greater efficiency on glass, metal, and plastic surfaces compared to textile and paper. Duration of MBP circulation was determined by time frame, MBP strain, and lytic activity of the MBP, but not by dose of MBP on the surface. The greatest effect was revealed against PA; even the single usage of MBP provided total elimination of PA from the hospital environment. The application of MBPs led to 15-fold decrease of incidence of The MBP-based way of prevention of HAIs caused by MDRBSs has certain advantages over CAMs. It may be used without limitations in different HCSs, particularly in intensive care units, it allows the efficient elimination of MDRBSs from the hospital environment in short terms, it provides termination of the outbreaks caused by MDRBSs, reduces the incidence and mortality from HAIs, and it is much cheaper compared to CAMs.None declared."}
+{"text": "After publication of this work , we noteThe authors declare that they have no competing interests.JvA was responsible for the conception and design of the study, researched data, and wrote the manuscript. HPH contributed to acquisition of data, discussion and reviewed/edited manuscript. MCRFvD contributed to acquisition of data and reviewed/edited manuscript. CPHL and ICCH coordinated inclusion of individuals with CAD and reviewed the manuscript. CJZ coordinated inclusion of individuals with PAD and reviewed the manuscript. MGV contributed to acquisition of data, discussion and reviewed/edited manuscript. BHRW coordinated inclusion of diabetic individuals and reviewed/edited the manuscript. HvG contributed to discussion and reviewed/edited manuscript. JLH was responsible for the conception and design of the study, researched data, contributed to discussion and reviewed/edited manuscript. All authors read and approved the final manuscript."}
+{"text": "Since the late 1990s, natural language processing (NLP) has seen a massive shift from high-precision, low-recall systems based on small sets of hand-written rules, to methods based on the statistical analysis of large corpora. The field of chemoinformatics, likewise, is dominated by statistical and machine-learning approaches. In recent years, however, pharmaceutical companies have been engaging more and more with Semantic Web technologies, which are largely built around the sorts of hand-written systems that NLP has moved away from this century. We discuss where our current text analysis and Semantic Web efforts at the Royal Society of Chemistry are headed and how we're making use of the unreasonable effectiveness of data."}
+{"text": "The total synthesis of natural products, a field of organic chemistry that is both historical and contemporary, has undoubtedly entered a new paradigm over the past decade with the advent of revolutionary new synthetic methods and innovative synthetic concepts. Putting aside the downstream applications of natural-product synthesis in the interrogation of biological processes, elucidation of biogenetic origins, structural assignments and many others, its fundamental and indispensable value as a vehicle for the discovery of new synthetic transformations is well-testified and unparalleled by any other research discipline over the history of chemical science. These transformations, largely concerning carbon\u2013carbon/carbon\u2013heteroatom bond formations, asymmetric induction, and catalysis, constantly expand the repertoire of powerful tools available at the organic chemist\u2019s disposal, and enable more challenging synthetic problems to be investigated. As such, this catalytic cycle of discovery fueled by natural-product synthesis continues to capture and captivate the imagination of both practitioners and students of organic chemistry around the world and will do so far beyond the foreseeable future. In particular, the recent discovery of novel transitional-metal complexes and their associated chemical transformations, and rediscovery of the unprecedented reactivity of previously documented transition-metal complexes with subtle changes in the reaction conditions and the reacting substrate have been extremely fruitful since the turn of the millennium, most notably in promoting reactions of unfunctionalized and unactivated chemical bonds. Furthermore, the application of organic compounds as promoters of chemical transformations has also witnessed increasing sophistication, substrate scope, and efficiency together with new modes of activation, which rival or at times surpass those exhibited by transition metals. Last but not least, the judiciary combination of transition-metal and organic mediators, together with tandem processes encompassing multiple reaction cycles in a programmed sequence, represents a new horizon with vast potentials that have yet to be fully understood and exploited.In this Thematic Series, selected examples of metal- and organic-compound-promoted chemical processes that render the preparation of architecturally complex natural products, natural-product subdomains, or natural-product-like scaffolds, are presented. These illustrative synthetic studies are intended to showcase the most recent developments, at the same time highlight the state-of-the-art and current limitations, and in doing so set the path for the future. It is our great anticipation that this Thematic Series will instigate and inspire further investigations in this field, and challenge the existing technologies and our current mindset in target-oriented synthetic design. Ultimately, we wish that the newly acquired knowledge will translate to further advances in synthetic organic chemistry and provide more enabling tools for synthetic-chemistry-dependent research fields and beyond.David Yu-Kai Chen and Dawei MaSeoul, Shanghai, June 2013"}
+{"text": "Chlamydomonas reinhardtii disrupted for selected target genes. The approach relies on the generation of thousands of transformants followed by PCR-based screenings that allow for identification of strains harboring the introduced marker gene within specific genes of interest. Our results highlight the strengths and limitations of two independent screens that differed in the nature of the marker DNA used (PCR-amplified fragment containing the plasmid-free marker versus entire linearized plasmid with the marker) and in the strategies used to maintain and store transformants.A method was developed to identify insertional mutants of  Chlamydomonas reinhardtii (Chlamydomonas throughout) dCTP by PCR amplification of a 360 bp fragment using the PARAU (5'-GAGGATCTGGACGAGGAGCGGAA-3') and PARAL (5'-CCCTCAGAAGAACTCGTCCAACAGC-3') primers.Isolation and enzymatic digestion of genomic DNA, electrophoretic fractionation of the DNA fragments, transfer of the DNA fragments to a nylon membrane, labeling of specific DNA probes, hybridization of the probes to the immobilized fragments and washing of the hybridized membrane were performed as previously described ,34. LabeThe authors declare that they have no competing interests.DGB is the main intellectual author of this work, has participated in the designing, coordination, construction and screenings of both libraries, collected data from some transformants, and wrote this manuscript. WP has made important intellectual contribution to this work, has participated in the designing, coordination, construction and screening of Library 1, collected data from the sulfate transporters mutants, and participated in the writing of this manuscript. FM, WY, CC, LM, and MP have participated in the construction and screening of Library 1, and collected data from many transformants enlisted in Tables"}
+{"text": "The State of infections acquired during care procedures whose prevalence rate is estimated at about 15% in some benchmark institutions reflects the alarming situation of provision of care and patient safety in DR Congo.Conduct an inventory of patient safety in health facilities in the city Kinshasa.Study conducted using survey and observation checklist covering the different aspects of patient safety: institutional, medical technical equipment, medical devices, blood products, drugs, biological graft, waste management medical needles and treatment materials.At the institutional level: the lack of standards and policies on patient safety except on injection safety; lack of policy on the fight against nosocomial infections; reporting system for adverse events.Technically: Absence of risk management procedures, training non-existent on the quality and safety of patients in Kinshasa (90% of staff) and 89% of patients do not know their rights and lack of association of patient safety care.The implementation of a policy of promotion of hospital hygiene and the fight against adverse events associated with their care requires a partnership challenging multiple states, civil society, communicators, the private sector and international institutions.None declared."}
+{"text": "The advancement of diabetes treatment has gone from crude extracts of insulin and accidental discovery of sulfa-like drugs in antibiotics to the development of drugs based on improved understanding of the pathophysiology of diabetes mellitus. This article will review the history of the discovery and development of insulin. A companion focusing on non-insulin diabetes agents will follow in the next issue of JCHIMP. Ebers Papyrus  and N , were marketed.Because the insulin preparation required several injections daily, investigators worked to find ways to prolong its duration of action. In the 1930s, H.C. Hagedorn, a chemist in Denmark, prolonged the action of insulin by adding protamine . In ToroOnce patients with diabetes started to live longer, chronic complications of diabetes became prevalent. In 1993, the Diabetes Control and Complications Trial showed for the first time without any doubt the linear relation between the degree of glycemic control and complications . To reduTo have an alternative delivery method for insulin, exubera, the first inhaled insulin, was developed by Sanofi-Aventis and Pfizer and marketed by Pzifer in 2006 . The inhThe discovery of pancreatic crude extracts gave hope to patients with diabetes mellitus. The subsequent development of precisely engineered insulin analogs, which are more physiologic, improved diabetes control and reduced or delayed complications. Insulin continues to be the cornerstone of therapy. Newer medications complement and enhance insulin action tailored toward different mechanisms in the pathophysiology of diabetes mellitus.Meanwhile, in the next issue of JCHIMP, we will review the other agents for diabetes care."}
+{"text": "The first Biennial International Symposium on Colorectal Disease held in Phuket, Thailand, from Dec 8 to Dec 10, 2013, was hosted by the governor of the International College of Surgeons, assistant professor and chief of the colorectal department of the Bangkok Hospital Phuket, Dr. Art Hiranyakas on behalf of the International College of Surgeons, the Society of Colon and Rectal surgeons of Thailand, Vachira Phuket Hospital and Bangkok Hospital Phuket. It was undoubtedly a unique opportunity to hear from internationally acclaimed speakers and experience the most exotic and exceptional Phuket beauty. The three-day exhilarating meeting agenda focused on rectal cancer treatment and advances in colorectal surgery. On the first day, a stimulating live surgery session, moderated by Dr Giovanni Milito, Professor of Surgery, Tor Vergata University Hospital, Rome, Italy, was held showcasing parallel laparoscopic and robotic low anterior resections for distal rectal cancer performed by Drs. Steven Wexner and Seon-Hahn Kim, respectively. The cases were followed by a live demonstration of total mesorectal excision specimen examination and an assessment of mesorectal integrity by the expert gastrointestinal pathologist Dr. Mariana Berho, Chairman of the Pathology and Laboratory Medicine, Cleveland Clinic Florida. This lively and highly informative session prompted an excellent exchange among experts and the attendees.The Honorary Lecture on \u201cColorectal Surgical Education\u2014A Prescription for the Future\u201d by Steven Wexner inaugurated the second day of the conference with a comprehensive review of colorectal surgery education and standards of training, followed by an eye-opening exposition of the challenges and goals for future colorectal training around the world. Dr. Steven Wexner\u2019s lecture served as a perfect prelude to the remainder of the day, which highlighted the complex expertise required for state-of-the-art rectal cancer treatment. The multidisciplinary nature of successful rectal cancer was elegantly taken into account throughout the entire meeting with sessions that discussed the complex role of diet in colorectal carcinogenesis, minimally invasive options and outcomes for rectal cancer surgery, radiologic preoperative rectal cancer staging, and pathological staging after neoadjuvant therapy. A sober discussion on sphincter preservation by Dr. Hiranyakas topped the session with a well-balanced review of the oncologic and functional outcomes, highlighting the advantages and disadvantages of this approach. The controversial topic of the benefits of robotic compared to laparoscopic low anterior resection for rectal cancer was presented by Dr. Francis Seow-Choen and was followed by an edifying and interesting debate with excellent audience participation. The challenges of advanced rectal cancer management were also thoroughly discussed including presentations that reviewed the most recent trials and outcomes for the management of stage IV disease by Yik-Hong Ho, cytoreductive surgery and HIPEC for carcinomatosis peritonei and the liver-first approach for metastatic rectal cancer.The program also included a wide-ranging overview of the diagnosis and treatments of frequent anorectal disorders including pelvic floor disorders, fecal incontinence, and complex anal fistulas. These sessions were coupled with a hands-on endoanal ultrasound course taught by Art Hiranyakas and a live LIFT procedure demonstration by Arun Rojanasakul, Chulalongkorn University, Thailand, who initially developed and reported the procedure. Hemorrhoidectomy techniques and indications followed high-yield topics including management options for complex anorectal fistulas and fecal incontinence. The third day of the meeting also included updates on a potpourri of common anorectal and colorectal issues, including rectal trauma, management of anastomotic leak, and an excellent presentation on enhanced recovery after colorectal surgery protocols and updates, presented by Drs. Varut Lohsiriwat, Mahidol University, Thailand, and Fabio Potenti, Cleveland Clinic Florida, respectively. In addition, a poster walk-around session displayed scientific research abstracts from Asia, Europe, and North and South America.The meeting attendance surpassed expectations and absolutely fulfilled the aim of providing an in-depth and stimulating scientific update of rectal cancer management and advances in colorectal surgery. The world-class exchange of knowledge and experience from international leaders in the field of colorectal diseases and live demonstrations made this an outstanding educational meeting. Taken together, with the fascinating natural beauty of Phuket during the most beautiful time of the year, and the finest Thai hospitality, we are all certainly looking forward to participating in the 2015 meeting. Anyone who did not attend in 2013 should indelibly mark the dates of December 9\u201311, 2015, in their calendar. Anyone with an interest in attending a highly informative meeting and in visiting one of the most beautiful areas in the world should plan to attend. The topics for the next meeting include multidisciplinary approach to colorectal cancer, colorectal imaging, histology, genetics and molecular biology, minimally invasive colorectal surgery including robotics and laparoscopy. Controversies in the management of rectal prolapse, advanced surgical management of fecal incontinence, constipation, anorectal fistulas, and hemorrhoids are also a part of the agenda which includes live surgery and hands-on workshops in surgery, imaging, and histology as well. Save the date! (Fig."}
+{"text": "This report is the collective product of word-leading experts working in the branches of integrative medicine by predictive, preventive and personalised medicine (PPPM) under the coordination of the European Association for Predictive, Preventive and Personalised Medicine. The general report has been prepared as the consortium document proposed at the EPMA World Congress 2011 which took place in Bonn, Germany. This forum analyzed the overall deficits and trends relevant for the top-science and daily practice in PPPM focused on the patient. Follow-up consultations resulted in a package of recommendations for consideration by research units, educators, healthcare industry, policy-makers, and funding bodies to cover the current knowledge deficit in the field and to introduce integrative approaches for advanced diagnostics, targeted prevention, treatments tailored to the person and cost-effective healthcare."}
+{"text": "Integration can take a variety of forms at the macro-, meso- and micro-levels. On the macro-level systems aim to deliver integrated care on a high-level of performance to the population they serve. Meso-level systems focus on the integrated care needs of a particular group or population with same diseases or same conditions. Consequently, integrated systems on the micro-level seek to improve care co-ordination for individual patients and carers.Based on experiences from the USA, UK, and Europe the report comprises successful integrated systems and summarizes relevant evidence about high-profile systems.The book is technically divided into five parts. Following usual convention in the literature, the first and the last section include Introduction and Discussion/Conclusion. The three middle sections, however, are each concerned with one specific level of integration: macro-, meso- and micro-level. For reasons of clarity and comprehensibility this review follows this structure.In Chapter I the authors provide a comprehensive overview of the meanings of different terms, diverse forms of integration in health care and their differentiation and interrelationships. Definitions include \u2018fragmentation\u2019, \u2018integration/integrated care\u2019 as well as its forms of organizational, functional, service, clinical, normative, systemic, horizontal, vertical, real, virtual/contractual and commissioner integration.In the report macro-level integration is described using examples from the US. These systems have high levels of organization and tend to perform better than the fragmented forms of care. Each of the described approaches can be categorized as either complete provider and commissioner integration or provider integration or integrated medical groups.Based on a clear and reasonable research structure consisting of a detailed explanation and description of the integrated systems followed by an assessment of the system\u2019s impact in the national health system based on evaluations, survey data and national ranking the following five integrated care programs are examined:Kaiser Permanente: Virtually integrated system in which provider remain distinct organizations that co-operate based on exclusive contracts.Veterans Health Administration/VA: Real integrated system of regionally based integrated service networks across all care settings.Geisinger Health System: Hospital system, partially integrated in terms of provision and commissioning.Mayo Clinic: Multispecialty groups practice consisting of hospitals and medical offices without own health plan.Integrated Medical Groups : Composition of primary, community physicians from diverse specialties that are either directly employed or have an exclusive contract or have the budget responsibility. Kaiser, VA and Mayo Clinic are seen as integrated medical groups.Moreover, the individual systems are compared among themselves and to the NHS in the UK.Meso-level integration seeks to integrate care for particular groups of patients and population. These programs are mostly focused on older people and those suffering from specific conditions.Following this dichotomy the authors present examples of integration for older people and condition-specific integration. As in the 2nd section of the report the structure of description and impact-analysis based on evaluations and performance measures is used to examine nine systems:Program for all-inclusive care for the elderly: US-based integrated provider model aimed at maintaining frail older people in the community.System of integrated services for aged persons: Canadian integrated provider model seeking to overcome fragmented health and social care for elderly. Ended in 2001.PRISMA: Canadian model of integration and co-ordination of services across provider network to ensure functional autonomy.Rovereto: Italian model aimed to integrate medical and social services in a continuum of care using case managers. Pilot in 1990s.Vittorio Veneto: Italian model aimed to improve the integration and co-ordination of older people\u2019s health and social care. Pilot in 1990s.Torbay: UK-based model using integrated health and social care teams proactively managing the care of vulnerable elderly in cooperation with GPs.Disease management programs: Mostly multicomponent, consisting of a variety of different elements and aim to reduce deficits in the care for long-term conditions such as coronary health disease, COPD or diabetes.Chains of care: Swedish-based way of co-ordination and integration of care across organizations and professions. Focused on certain conditions and based on clear care pathways to improve quality of care.Managed clinical networks: Scottish system seeking to broker care across providers from all sectors that does not require the creation of new organizational entities.The first six examples display ways of integration for older people. In addition to the detailed description the authors also provide a very clear table summarizing the key features and impacts of each system.Micro-level integration is focused on the co-ordination of care for individual patients and carers. Responsibility for care co-ordination is often assigned to a specific individual or a team of care providers trying to decrease fragmentation.Six ways of micro-level integration have been identified by the authors:Care planning and care coordinators: Refers to the planning, coordinating, managing and reviewing an individual\u2019s care. The process of care planning is basically done by a care coordinator.Case management: Assignment of a case manager/care team to each patient that is responsible for assessing needs, developing care plans, organization of care, monitoring the quality of care, and the maintaining of the contact with the patient/family.Patient-centred medical homes and virtual wards: US-based system based on an accountable individual/care team and shared information systems and focused on care delivery for individuals with special care needs.Personal health budgets: Shifting of autonomy over care to patients by giving them responsibility to administer own health budget. Also referred to as self-directed care or individual budget.Use of information technology: Facilitates the timely and efficient flow of information across provider.Use of telecare and telehealth: Enable integrated care especially for long-term conditions by focusing on reducing avoidable and costly use of healthcare resources.The final, fifth chapter of the report takes a closer look at the situation in the UK as well as the implications resulting from the examples. The authors clearly state that action is needed at all three levels to ensure that integration and cooperation deliver better outcomes.This report reviews ways of achieving closer integration for individual service users and carers through care coordination. Very positive: Each section closes with a summary of the key messages of the section. This provides a valuable overview to all readers, allowing them to get first useful information in a short period of time.The reader has to be aware that the paper is primarily aimed at NHS personnel confronted with the re-organization of the UK-system. However, this report has a special value for all policy-makers faced with the question of overcoming fragmentation of care."}
+{"text": "The great success in the prevention and treatment of pediatric HIV in high resource countries, and now in low resource countries, has changed the face of the HIV epidemic in children from one of near certain mortality to that of a chronic disease. However, these successes pose new challenges as perinatally HIV-infected youth survive into adulthood. Increased survival of HIV-infected children is associated with challenges in maintaining adherence to what is likely life-long therapy, and in selecting successive antiretroviral drug regimens, given the limited availability of pediatric formulations, limitations in pharmacokinetic and safety data of drugs in children, and the development of extensive drug resistance in multi-drug-experienced children. Pediatric HIV care must now focus on morbidity related to long-term HIV infection and its treatment. Survival into adulthood of perinatally HIV-infected youth in high resource countries provides important lessons about how the epidemic will change with increasing access to antiretroviral therapy for children in low resource countries. This series of papers will focus on issues related to management of perinatally infected youth and young adults. The remarkable success in the prevention and treatment of paediatric HIV infection in high-resource countries has changed the face of the HIV epidemic in children from a fatal disease to that of a chronic illness. With widespread access to antiretroviral therapy in high-resource settings, many perinatally infected children are surviving into adolescence, young adulthood and beyond . With inThese successes pose new management challenges as perinatally infected youth survive into adulthood. There have been significant difficulties in maintaining adherence to life-long therapy, and in selecting successive antiretroviral drug regimens, given the limited availability of paediatric formulations, pharmacokinetic, and safety data in children and development of extensive drug resistance in multi-drug-experienced children. Long-term survival of youth with perinatal HIV infection has been accompanied by unanticipated needs. These include management of long-term complications of therapy, sexual and reproductive health, mental health needs, and issues of higher education and career training ,5.How to transition from complete dependence on adult caregivers and health services provided in paediatric HIV care settings, which are often multidisciplinary, family-centred and include extensive support services, to adult HIV care systems and assuming responsibility for their own care has received little attention . These yTo optimize the psychosocial well-being and treatment outcomes of perinatally infected adolescents and young adults as well as enabling them to lead long, meaningful and productive lives, there is an urgent need to understand the factors that either facilitate or serve as a barrier to the health and well-being of HIV-infected children and youth, and the complications of HIV and therapy as they age. The articles in this series provide a comprehensive evaluation of the issues related to perinatal HIV infection in both high- and low-resource settings.One common theme is the paucity of research in the area of adolescent perinatal HIV infection, including a lack of epidemiologic data to better define this population of youth on a global basis, and the general lack of data regarding potential impacts of gender on HIV disease in this population.Sohn and Hazra discuss the changes in the global paediatric HIV epidemic as children receiving antiretroviral therapy age into adolescence, highlighting our lack of knowledge regarding the global numbers of perinatally infected youth over 15 years of age because global reporting does not differentiate between perinatal and behaviourally infected youth . They diAgwu and Fairlie discuss the multiple challenges of antiretroviral therapy in perinatally infected youth, with a focus on adherence issues and a review of clinical, immune and viral outcomes . ChildreMellins and Malee discuss mental health issues in perinatally infected youth, reviewing the literature in this area, risk as well as protective factors, treatment modalities and need for further research . Infectein utero and behaviourally based, such as substance use). The authors note the paucity of data in infected adolescents and in youth from resource-limited settings.Laughton and colleagues discuss neurodevelopmental issues in perinatally infected youth, noting that infected youth exhibit problems on general cognitive tests, processing and visual-spatial tasks and are at high risk for psychiatric and mental health problems as discussed by Mellins ,13. WhilLipshultz and colleagues discuss the cardiac effects of HIV and its treatment in perinatally infected children and adolescents, including the range of cardiovascular disease in children, the clinical manifestations, pathogenesis and monitoring, including cardiac biomarkers, and treatment . They emBarlow-Mosha and colleagues discuss the myriad of metabolic complications of HIV and its treatment that are being observed in youth . While pPuthanakit and Siberry discuss issues related to the effect of HIV infection and antiretroviral therapy on bone. They discuss normal bone development and non-HIV factors affecting development as well as HIV and treatment-related factors impacting bone, and approaches to detection, prevention and management of these problems in youth . Bone unBhimma and colleagues discuss the problem of kidney disease in youth with perinatal infection . They noA number of studies have found that many perinatally infected adolescents may not be aware of their HIV status in both high- and low-resource settings \u201323. We rWeber and colleagues note the emerging data and high prevalence of chronic lung disease in adolescents with perinatal HIV infection, as well as the need for more detailed prospective studies. They note that bronchiectasis and bronchiolitis obliterans are important problems in these children, with lung function tests showing significant impairment. The importance of co-infection with tuberculosis and the emergence of chronic lung disease is discussed, emphasizing the need for early antiretroviral therapy in children to minimize the risk of chronic lung problems. Lastly, they provide guidance for the evaluation of lung health and the need for more prospective data.This series of articles serves to focus attention on the growing population of perinatally infected adolescents and young adults globally, the complexities of their care, and helps to identify the future research needs. A holistic approach to improve the long-term health of these youth is needed to ensure that our success in achieving survival of HIV-infected children from infancy is maintained into adulthood."}
+{"text": "Questions have been raised in screening, brief intervention, and referral to treatment (SBIRT) research concerning the role the assessment process may serve in contributing to behavior change. However, most SBIRT trials have not been designed in a way to disaggregate the impact of assessment versus the combined effect of assessment plus brief intervention. We describe the design of the National Institute on Drug Abuse-Clinical Trials Network (NIDA-CTN) Screening, Motivational Assessment, Referral, and Treatment (SMART-ED) trial, with a focus on the screening and assessment instruments used and three treatment conditions to which participants have been randomized: minimal screen only (MSO); screening, assessment, and referral to treatment (if indicated) (SAR); or screening, assessment, and referral plus a brief intervention (BI) with two telephone follow-up booster calls (BI-B). The screening and assessment measures are relatively brief in the context of a clinical trial to minimize participant burden and assessment reactivity. The design allows a comparison of the impact of assessment as an independent factor over and above minimal screening (SAR versus MSO) as well as an evaluation of the incremental benefit of the BI with booster calls over and above assessment without BI (BI-B versus SAR). Assessment reactivity is of concern, especially in BI studies, because it may reduce effect size and conceal therapeutic benefit. On the other hand, if found to contribute independently to behavioral change, assessments could be designed to maximize the therapeutic benefit they provide. The design used in the SMART-ED trial will allow an evaluation of the independent and incremental contribution of the assessment process to behavior change."}
+{"text": "Acute respiratory infections remain a leading cause of morbidity and mortality in Sierra Leone; however, similar to other African countries, little is known regarding the contribution of influenza. Routine influenza surveillance is thus a key element to improve understanding of the burden of acute respiratory infections in Africa. In 2011, the World Health Organization (WHO) funded the Strengthening Influenza Sentinel Surveillance in Africa (SISA) project with the goal of developing and strengthening influenza surveillance in eight countries in sub-Saharan Africa, including Sierra Leone. This paper describes the process of establishing a functional Influenza Sentinel Surveillance (ISS) system in Sierra Leone, a post-conflict resource-poor country previously lacking an influenza monitoring system.Sierra Leone utilized a systematic approach, including situational assessment, selection of sentinel sites, preparation of implementation plan, adaptation of the standard operating procedures, supervision and training of staff, and monitoring of influenza surveillance activities. The methods used in Sierra Leone were adapted to its specific context, using the Integrated Disease Surveillance and Response (IDSR) strategy as a platform for establishing ISS.The ISS system started functioning in August 2011 with subsequent capacity to contribute surveillance activity data to global influenza databases, FluID and FluNet, demonstrating a functional influenza surveillance system in Sierra Leone within the period of the WHO SISA project support. Several factors were necessary for successful implementation, including a systematic approach, national ownership, appropriate timing and external support.The WHO SISA project demonstrated the feasibility of building a functional influenza surveillance system in Sierra Leone, integrated into existing national IDSR system. The ISS system, if sustained long-term, would provide valuable data to determine epidemiological and virological patterns and seasonal trends to assess the influenza disease burden that will ultimately guide national control strategies. Influenza remains an important global public health concern. Annual influenza epidemics are estimated to account for 3 to 5 million severe illnesses and 250,000 to 500,000 deaths worldwide . Though In 2011, the World Health Organization (WHO) funded the Strengthening Influenza Sentinel Surveillance in Africa (SISA) project in which eight countries were selected to receive support to implement or strengthen influenza sentinel surveillance (ISS) and improve epidemiological and virological data collection and reporting through the global databases FluID and FluNet ,8. The pThe objectives of this paper are threefold:to describe the approach used in Sierra Leone in the development and implementation of a functional ISS system; to illustrate the challenges and solutions encountered in developing a surveillance system in a resource-poor country previously lacking an influenza monitoring system; and to provide resource-poor countries, external funders and implementers with a better understanding of the opportunities and challenges of developing new surveillance activities.The SISA project was implemented in Sierra Leone using a common methodological framework including development of initial situation assessment and recommendations for improvement; drafting of relevant country-specific surveillance protocols and standard operating procedures (SOPs); training of sentinel surveillance and data management staff; and supervision of surveillance activities . The metAn initial briefing meeting at the start of the project brought together national program managers and other stakeholders concerned with surveillance activities. All relevant information concerning influenza, including the background, situation analysis, objective and proposed process for implementation of the ISS system in the country, was provided. This initial meeting was instrumental in identifying designated personnel to be involved in the assessment exercise and to ensure leadership at the national level. Throughout the course of implementation,particular attention was placed on training and regular supervision of sentinel surveillance staff. Monthly review meetings were conducted to closely monitor and support the initial phase of implementation of ISS activities.The systematic approach followed in establishing a functional ISS system is described below.Initial activity focused on understanding the organization of surveillance function, including data management at various levels, laboratory support services and availability of suitable health facilities for integrating ISS into existing disease surveillance systems. The methods included the review of relevant documents, visits to the National Ministry of Health of Sierra Leone (MOHS), the Directorate of Disease Prevention and Control (DPC), the National Disease Surveillance Programme (NSD), the District Health Management Team (DHMT) of the Western area, the Central Public Health Reference Laboratory (CPHRL) and the health facilities in the district. Figure\u00a0Sierra Leone has implemented the IDSR strategy, coordinated by the National Surveillance Unit (NSU) within the DPC; IDSR promotes the integration of resources through the coordination and streamlining of common surveillance activities. By integrating multiple surveillance systems, limited personnel and scarce resources can be used more efficiently. In the IDSR implementation framework, epidemiologic surveillance is linked with laboratory support in order to produce relevant information for taking public health action . UltimatAt the time of the assessment, it appeared that the IDSR infrastructure was an appropriate platform in which to integrate the ISS system to ensure sustainability. The sustained laboratory support from diverse partners including the WHO, CDC, Association of Public Health Laboratories (APHL), UNICEF and the Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM) had gathered momentum to upgrade the CPHRL laboratory capacity to Bio-safety Level 2 (BSL-2) standards. The laboratory was in the initial stages of conducting testing of bacterial meningitis samples for surveillance and HIV polymerase chain reaction (PCR) testing for the early infant diagnosis of HIV. The available PCR machines could ideally be used to identify influenza viruses. However, prior to initiation of influenza testing, building of laboratory human resource capacity and supply of primers would be required.Based on the findings of the assessment, it was feasible to establish an ISS system in Sierra Leone without delay. Consequently, health facilities for the ISS system were selected based on WHO criteria, which included administrative division, geographical location, public-private mixture, institutional capacity to carry out surveillance activities, and staff interest in participation . RecommeApplying the WHO criteria, the following four health facilities in the Western area of Freetown were selected as initial sentinel sites for implementation of the ISS: Jenner Wright Children\u2019s Clinic, Ola During Children\u2019s Hospital, Lumley Government Hospital, and Blue Shield Hospital (private). Surveillance information flow within the health system, which included upwards transmission of data and reports, as well as communicating feedback to sentinel sites and stakeholders, was as follows:The responsibilities of sentinel site staff included collecting epidemiological and laboratory data, transmitting these data to the District Surveillance Officers (DSOs), and collecting, storing and delivering patient specimens to staff at CPHRL.The molecular unit of the CPHRL served as the National Influenza Reference Unit (NIRU) and was responsible for developing protocols for influenza specimen chain of custody and transport, and for training of sentinel site laboratory personnel in specimen handling, bio-safety measures and cold chain maintenance. The CPHRL was also responsible for collecting samples from sentinel sites, logging information, packing and shipping samples to the Institut Pasteur in Dakar, Senegal, and entering laboratory data into the WHO FluNet database.The NSU was responsible for analyzing the epidemiological and laboratory data supervision and providing feedback to sentinel site staff and other stakeholders. The NSU was also responsible for entering epidemiological data into the global database FluID. The DSOs were in charge of reviewing and compiling weekly sentinel site data.The Sierra Leone national influenza sentinel surveillance protocol and SOPs for influenza sample collection, sample handling, packaging, shipping and transport, and data handling and sharing were developed based on the generic WHO guidelines. Additional protocols were adopted for entering epidemiological and virological data into the global databases, FluID and FluNet, which are key tools in monitoring global influenza trends in real-time. Information from FluID and FluNet is available to health professionals and policy makers to assist in making informed decisions regarding influenza management. Using these databases, surveillance activity in Sierra Leone is incorporated into a global network for influenza epidemiological data collection.Standardized case definitions were adopted to identify influenza-like illness (ILI) and severe acute respiratory infection (SARI) cases. An ILI case was defined as \u201ca person with respiratory illness with a measured temperature greater than 38\u00b0C and an onset of a cough within the last seven days\u201d. A SARI case was defined as \u201ca person with respiratory illness with a history of or measured temperature greater than 38\u00b0C, a cough, and onset of shortness of breath or difficulty breathing that required hospitalization within the last seven days\u201d.The training workshop targeted all staff involved in surveillance, including surveillance officers at the national and district level, clinicians, laboratory technicians, monitoring and evaluation officers in charge of data at the selected health facilities, and staff at CPHRL. The topics covered in the training included an overview of influenza epidemiological patterns, clinical and virological diagnosis of influenza, and specimen collection, handling and transportation. Data management, including data collection, collation, analysis and flow, was also discussed. At the national level, additional information on weekly summary reporting and data analysis using EpiInfo software was discussed.On-site support at sentinel sites covered practical demonstration of nasal swab sample collection, data recording, compilation of weekly summaries, and transfer of samples. Additional support included demonstration for correct sample handling, storage, and assurance of cold chain integrity and usage of sample custody forms.The NSU conducted regular supervision to facilitate smooth operation of the implementation. The DSOs in charge of collecting and compiling weekly sentinel site data also provided additional support to sentinel sites, including cleaning data to maintain data quality and timeliness. Regular review meetings were held, bringing together all staff engaged in sentinel influenza surveillance from sentinel sites, CPHRL, MOHS and WHO. The objectives of the meeting were to determine the progress of implementation, identify challenges, and propose solutions and elaborate subsequent steps in the process of implementation.The sentinel surveillance system formally began on August 19, 2011. The implementation was closely monitored and supported through onsite technical assistance, regular supervision and monthly review meetings.A sampling method was used for ILI cases based on the patient load at health facilities and the capacity of the laboratory to process samples. Accordingly, a nasal swab sample from every fourth ILI patient was collected. For SARI, a nasal swab was collected from all cases. Prior to sample collection, an explanation of the procedure was provided and verbal consent was obtained from the patient or guardian. Nasal swabs were collected according to the procedures described in the SOPs. The following data were recorded for each patient sampled: sentinel site identification number, date of symptom onset, date of specimen collection, date of hospitalization (for SARI cases), sex, age, temperature, pregnancy status, seasonal influenza vaccine status, antiviral use, and any comorbidities.Specimens were stored at sentinel sites in appropriate viral transport media at 2-8\u00b0C until collection by the CPHRL. Sentinel sites notified the CPHRL regarding samples that were collected and ready for pick-up. Samples were picked up by the CPHRL within 48 hours of collection. At the CPHRL, the specimens were logged and packaged for shipment to the Institut Pasteur in Dakar, Senegal.Reverse transcriptase PCR (RT-PCR) testing for influenza A and B was conducted at the Institut Pasteur in Dakar, Senegal. The results were communicated to the MOHS and also back to the sentinel sites from which the sample originated.During the SISA project surveillance data collection period in Sierra Leone, from August to December 2011, 1,235 ILI cases  and 282 SARI cases  were identified in the four sentinel sites \u2022Securing additional funding to cover specimen collection, laboratory costs, consumables, etc.\u2022Close monitoring of progress with update and feedback at regular review meetings\u2022Motivation of staff through recognition and other non-monetary incentivesThe project was implemented using a deliberate systematic approach, beginning with a thorough assessment of Sierra Leone\u2019s existing surveillance system capabilities. The national IDSR network was used as a platform to integrate the ISS and demonstrated that building on an existing framework was the most appropriate approach.Training, which began after all stakeholders were identified and committed to be part of the sentinel site, occurred at multiple levels and ensured that all involved with surveillance activities were properly trained before progressing to the implementation phase. A similar approach was used in data collection. The roles, responsibilities and reporting timelines were clearly defined on the surveillance data flow for each level to avoid confusion and to ensure regular submission of data. Using this approach ensured that the project was fully prepared to successfully implement the sentinel site surveillance.Another important factor for the success of the SISA project was the ownership and active leadership of the government of Sierra Leone. The ISS system implementation began with a briefing at the national level to ensure the participation of decision makers and staff involved in surveillance activities at various levels. Following the initial assessment, a consensus-building meeting was held where important information was communicated and the national action plan was developed using a participatory approach. The monthly review meetings that brought together focal persons from the various sentinel sites, CPHRL, and surveillance officers from the district and national levels served for sharing experiences, providing feedback and troubleshooting problems. Allowing staff members to directly participate in the evaluation and management of the surveillance activities and openly recognizing their work, increased staff motivation and dedication.The timing of the project coincided with the strategic planning for IDSR, which allowed for its integration with the overall surveillance function and provided additional support for the activity. Most importantly, the project benefited from the national leadership, committed partners, team approach and continuous engagement and motivation of all staff involved. The introduction of the SISA project also coincided with the ongoing efforts of partners, such as WHO and CDC, in building the capacity of the CPHRL. Additionally, partnerships such as the Institut Pasteur in Dakar, Senegal, and the Ghana National Influenza Center were beneficial in providing laboratory services unavailable in-country.The focused technical and financial support through the SISA project was critical for the success of establishing the system for ISS in Sierra Leone. However, continuation of project support following the initial phase could have allowed for better consolidation of the achieved results and detailed analysis, including seasonal variation, of the information from the epidemiological and virological data in the country. Despite the above limitation of the project, the integration of the ISS into the IDSR is an effective and efficient approach that will allow for sustainability. These efforts will require the continued support of partners such as WHO and CDC in order for Sierra Leone to maintain generation of influenza surveillance data that is critical for disease control efforts at local and international levels.The WHO SISA project demonstrated the feasibility of building a functional influenza surveillance system in Sierra Leone, integrated into the existing national IDSR system and generating relevant surveillance data within a seven-month in-country project phase and sustained with support of local partners.Although the collaboration with influenza laboratories in the region was a useful initial step, the reliance on an out-of-country laboratory for testing required additional organization, time, and increased funds. Strengthening and accreditation of the CPHRL of Sierra Leone will enable the national ISS system to function more efficiently and independently. Future laboratory related work should ensure a system for efficient specimen handling, regular supply of markers, and participation in quality assurance to ensure that the CPHRL is advanced to the list of National Influenza Center status.Despite the challenges and limitations, the ISS system in Sierra Leone produced valuable results that were incorporated into the global databases FluID and FluNet. Additionally, one year following cessation of active external technical support by SISA, the system continues to be operational and effective in monitoring the burden of influenza. National ownership was demonstrated to be a critical element in the success of the project and is critical for sustainability of the ISS system and other future surveillance activities. The ISS system, if sustained long-term, would provide valuable data to determine epidemiological and virological patterns and trends to assess the influenza disease burden that will ultimately guide national control strategies.APHL: Association of Public Health Laboratories; CDC: US Centers for Disease Control and Prevention; CRHRL: Central Public Health Reference Laboratory; DHMT: District Health Management Team; DPC: Directorate of disease prevention and control; DSO: District surveillance officers; IDSR: Integrated disease surveillance and response; ISS: Influenza sentinel surveillance; MOHS: Ministry of health and sanitation; NSD: National disease surveillance program; RT-PCR: Reverse transcriptase - polymerase chain reaction; SISA: Strengthening influenza sentinel surveillance in Africa project; SOPs: Standard operating procedures; WHO: World Health Organization.CA Steffen works for the Agence de M\u00e9decine Pr\u00e9ventive (AMP), which receives unrestricted support from Sanofi-Pasteur and grant-specific support from Crucell, GlaxoSmithKline, Merck, Novartis Vaccines, Pfizer and Sanofi Pasteur. All other authors have declared that no competing interests exist.SK and IC conceived the study. CA was the overall SISA project coordinator for AMP and provided scientific advice and technical input to the manuscript as well as revision work. SK, IC, CA, IW, and FD organized and coordinated collection of field data. SK, IC, and FK analyzed data. SK drafted the manuscript. SK, CA, WA, and KV finalized the manuscript. AJ, AY, FK provided feedback to the manuscript. All authors read and approved the final manuscript."}
+{"text": "Chronic cough is a very common complaint in clinics throughout China. Clinical and basic science research on chronic cough started late, but in recent years the effort has yielded promising findings regarding the etiological diagnosis, treatment and pathogenesis. We found that inflammation in nonasthmatic eosinophilic bronchitis has some similarities to cough variant asthma but also a number of distinct differences. Recent evidence has also suggested a mechanistic link between airway neurogenic inflammation and and gastroesophageal reflux cough (GERC). Cough-related animal models have been developed, including models for esophageal reflux, nonasthmatic eosinophilic bronchitis and allergic rhinitis. Normal reference values for differential cell counts in induced sputum, cough sensitivity and esophageal 24-h pH monitoring in Chinese healthy subjects have been established. By using a modified algorithm for the etiological diagnosis of chronic cough, the causes of chronic cough have been investigated across a number of cities in China. The most common causes of chronic cough are cough variant asthma, eosinophilic bronchitis, upper airway cough symptoms, atopic cough and GERC, however, there are some regional variations. The Chinese National Guidelines on Diagnosis and Management of Chronic Cough were drafted in 2005, updated in 2009, and have been widely publicized and disseminated through many channels since their publication. In the clinical setting, chronic cough is defined as cough being sole or predominant symptom and lasting for more than 8 weeks with normal chest X-ray. Chronic cough is a common complaint in China, as it is in Europe, America and Japan. An epidemiological study demonstrated a 3.3% incidence of chronic cough among college students in Guangzhou. It is aSince the description of an anatomy-based diagnostic protocol for chronic cough in 1977 by Irwin and colleagues, many studies have been undertaken in America, Europe and Japan, concerning the pathogenesis, etiologic diagnosis and management of chronic cough with the subsequent development of national guidelines-6. Since4), histamine, prostaglandins, and eosinophilic cationic protein (ECP). Despite the similarities between EB and asthma, there are a number of disparities:Airway inflammation in EB shares some similarities to asthma regarding the recruitment of inflammatory cells such as eosinophils (Eos), T lymphocytes and mast cells, as detected using the induced sputum test, bronchoalveolar lavage fluid (BALF) cytology and airway mucosal biopsy. In addition, airway inflammation is attributable to the pro-inflammatory mediators released from these cells, which include leukotriene C4  in induced sputum in both EB and asthma,13. HoweLiu et al. found that gastroesophageal reflux is an independent cause of cough, and that reflux of the distal esophagus may induce cough in most cases with GERC. In patients with GERC, distal reflux episodes accounted for 88.23% of all reflux events during 24-hour pH monitoring, and were positively correlated to the onset of coughs. In guinAnimal cough models include models of isolated cough and those of cough-related diseases. Several specific cough-related animal models currently available in China are described below.Animal models of reflux esophagitis with concomitant inflammation in the tracheal and bronchial mucosa were successfully established in guinea pigs by repeated esophageal infusion of HCL and pepsin. These animal models provide a basis for studies on the pathogenesis of reflux-related respiratory disorders.An eosinophilic bronchitis model in BALB/c mice has been established for the first time. To establish the model of this kind, all the mice were sensitized by intraperitoneal ovalbumin (OVA) and subsequently challenged by either intranasal drip or inhalation of OVA. This moAn allergic rhinitis model was successfully established by sensitizing mice with intraperitoneal OVA and then challenging them with an intranasal OVA drip. In addiEarly studies in Europe and America indicated that the most common causes of chronic cough in specialist clinics were postnasal drip syndrome (PNDS), bronchial asthma and gastroesophageal reflux (GER), which accounted for more than 93.6% of all causes. ReferriThe definition of atopic cough was first proposed in 1989 by Fujimura. In JapaOur previous study showed that about 5% of chronic cough can be attributed to chronic bronchitis. ChronicIn 2003, analysis of differential cell count in induced sputum samples was introduced into the diagnostic protocol for chronic cough in China. This teIn China, the assessment of cough sensitivity is not yet an established part of the diagnostic algorithm for chronic cough, and is available in only a few medical institutions. The normal lower limit of cough sensitivity has been primarily established (C5 \u226562.5 \u03bcmol/L) using a single metered-dose inhalation of capsaicin. IncreasIn the Chinese National Guidelines on Diagnosis and Management of Cough, detection using spirometry and airway hyperresponsiveness is recommended as the first-line tests for the diagnosis of chronic cough. While sAmbulatory 24-h esophageal pH monitoring has some value in the diagnosis of gastroesophageal reflux disease and to assess the association between reflux events and cough episodes. The normal Demeester score is <12.70 for healthy Chinese subjects, slightlThe algorithm for the etiological diagnosis of chronic cough has been re-structured to adapt to the clinical picture of this condition in China Figure, with reNB: 1) ACEI: angiotensin converting enzyme inhibitor; UACS: upper airway cough syndrome; PNDS: postnasal drip syndrome; CVA: cough variant asthma; EB: eosinophilic bronchitis; SPT: skin prick test; IgE: immunoglobulin E; GERC: Gastro-esophageal reflux-related cough; AC: atopic cough. 2) Empirical treatment can be initiated in grass-root institutions or to individuals with low income. Patients who fail empirical treatment should be referred for thorough investigations of underlying etiologies at institutions with sufficient access to medical resources, to prevent a delay in treatment.Along with increasing concern in this field, a series of studies addressing the etiologies and treatment of cough have been conducted in Europe, America and Japan over the past 30 years. These efforts have shed light on the common causes of chronic cough and have given rise to the development of guidelines on the diagnosis and treatment of cough-6. In ChSince their release, the Chinese cough guidelines have been widely publicized and disseminated through journals, newsletters, conferences, internet and many other channels. A Cough Forum has been held annually around China since 2007, which provides a platform to discuss the cough research hot topics. A cough symposium has also been added to the agenda of the Annual Conference of Chinese Society of Respiratory Diseases. In addition, several reputable national journals  have launched columns or published special issues on chronic cough to introduce the state-of-the-art advances in this field worldwide. Furthermore, keynote speakers from America, Europe and Japan are invited to China on a regular basis to share their expertise on chronic cough.Looking to the future, we still have a long way to go until the mystery surrounding chronic cough is unraveled. The closer communication and collaborations between Chinese and international specialists will improve our understanding of the diagnosis and treatment of chronic cough in the future.Chronic cough is a common complaint in the clinic in China. In the last decade, the etiological diagnosis and pathogenesis of chronic cough have been widely studied in China, and promising findings have been reported. The pathophysiology and causes of chronic cough in China have local characteristics. Whether genes, geography and lifestyle diversity contribute to these differences is unknown. We have developed cough-related tests, such as the induced sputum test and capsaicin challenge test. With the release of the Chinese Guidelines on the Diagnosis and Treatment of Cough, we believe many more patients are being correctly diagnosed and receiving the appropriate treatment. However, the cause and pathogenesis of some types of chronic cough need to be further elucidated.The authors declare that they have no competing interests.NSZ and KFL conceived the study. KFL and WL carried out the literature review and drafted the paper, GQZ drafted the paper and provided writing support. All authors read and approved the final manuscript.KFL: M.D. PhD., Professor of Internal Medicine, State Key Laboratory of Respiratory Diseases, 1st Affiliated Hospital of Guangzhou Medical College, and PhD tutor of respiratory medicine.WL: Master Degree in immunology, senior research fellow, State Key Laboratory of Respiratory Diseases, 1st Affiliated Hospital of Guangzhou Medical College.st Affiliated Hospital of Guangzhou Medical College; Editorial Director, Journal of Thoracic Disease.GQZ: M.D., Associate Professor of Medicine, Professor of Editology and Publishing, State Key Laboratory of Respiratory Diseases, 1NSZ: Academician of Chinese Academy of Engineering, Professor of Internal Medicine, State Key Laboratory of Respiratory Diseases, 1st Affiliated Hospital of Guangzhou Medical College, and PhD tutor of respiratory medicine."}
+{"text": "I read with interest the timely article by Rasoli and colleagues, who reviewed the literature on the efficacy of antioxidant vitamins in the management of atrial fibrillation (AF) . Those aInhibiting the major source of excess ROS is a different therapeutic approach that may prove effective in the management of various types of arrhythmia. The major sources of cardiac ROS are nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, the mitochondria electron transport chain, and uncoupled endothelial nitric oxide synthase. Those sources of ROS are interrelated, and the activation of one may result in the increased production of ROS by other sources, particularly by mitochondria (ROS-induced-ROS release) . Under d"}
+{"text": "Rather, the available evidence indicates that these disorders are associated with subtle abnormalities distributed throughout the brain , major depression, bipolar disorder, post-traumatic stress disorder (PTSD), and Alzheimer's disease, and showcases the diverse range of methods used to interrogate these brain changes.This Special Topic of The article by Fornito and Bullmore  overviewThe remaining articles illustrate the application of specific techniques to study different disorders. Independent component analysis (ICA), a popular data-driven technique for decomposing fMRI data into distinct components with characteristic anatomy and temporal dynamics (Calhoun et al., Seed-based techniques are featured in the work of Mills et al. , Mennes In a second study of MDD, Almeida et al.  use dynaGraph analytic techniques are featured in the work of Xie and He  and CollFinally, Lungu and Stip  present Collectively, the research presented in this Special Topic provides the novice reader with exposure to the diverse array of methods available for interrogating brain network structure and function in health and disease, and offers the expert reader prime examples of cutting-edge applications of these methods to understand psychiatric disorders. The continued development of novel connectivity mapping techniques (Bassett et al.,"}
+{"text": "The BITS2011 meeting, held in Pisa on June 20-22, 2011, brought together more than 120 Italian researchers working in the field of Bioinformatics, as well as students in Bioinformatics, Computational Biology, Biology, Computer Sciences, and Engineering, representing a landscape of Italian bioinformatics research.This preface provides a brief overview of the meeting and introduces the peer-reviewed manuscripts that were accepted for publication in this Supplement. The Italian Society of Bioinformatics (BITS)  was founThe main aim of the Society, which is a Regional group of the International Society for Computational Biology (ISCB), is the fostering of Bioinformatics in Italy. Its activities include the organization of an annual scientific meeting, the maintenance of a web site and of a mailing list for the distribution of news of interest for the involved community of researchers, the coordination of educational initiatives in Italy, from bachelor to PhD degrees, the coordination of research activities among members, and the improvement of the participation of Italian researchers, both senior and junior, to international events and projects of relevance.The Eighth Annual BITS Meeting, BITS 2011, was held in Pisa at the Research Campus (Area della Ricerca) of the National Research Council (CNR), on June 20-22, 2011. The meeting was organized by Marco Pellegrini of the CNR Institute for Informatics and Telematics and by Roberto Marangoni of the Computer Science Department of the University of Pisa.Over 120 scientists actively working in bioinformatics and related fields or strongly interested in its development met and discussed their work, state of the art and future perspectives. A total of 98 abstracts were accepted: 23 of them were selected for oral presentation by the Scientific Committee after a well established peer-review procedure based on three reviews and scores per paper. The remaining 75 were presented in the poster sessions.Four keynote talks were given by distinguished scientists. Marie-France Sagot, INRIA-Lyon, France, gave a talk on \"Towards an Algorithmic and Mathematical Exploration of Symbiosis\". \"How not to Become a Systems Biologist\" was the title of the \"Giuliano Preparata\" Lecture given by Arthur Lesk, Penn State University, USA. Bud Mishra, New York University, USA, gave a provocative talk on \"Why we Keep Assembling...\". \"Using the T-Coffee Multiple Sequence Aligner in the High Throughput Era\" was the title of the keynote given by Cedric Notredame, Center for Genomic Regulation (CRG), Barcelona, Spain. The last talk was co-sponsored by the Italian Network for Bioinformatics Oncology (RNBIO).The conference was organized into thematic sessions that reflected the following conference topics: Genomics, Molecular Evolution and Comparative Genomics, Protein structure and function, Proteomics, Transcriptomics, Metagenomics, Systems Biology, Biological Databases, Biobanks, Algorithms for Bioinformatics, Biophysics, and Synthetic Biology.An \"industrial track\" was also organized under the form of a round table focused at opening a dialogue between the industries and the academic world on bioinformatics. The round table was participated by deputies of University of Pisa, CNR, industrial accelerators programs, and computing and/or life sciences companies in Tuscany. It ended with the decision to open a permanent table of discussion on the advancement of bioinformatics in the Innovation Poles in Tuscany.The web site  of the mTwo tutorial lectures were also given on the last day of the meeting at the Computer Science Department of the University of Pisa. Giorgio Valentini, from the University of Milan , gave a tutorial on \"Machine learning methods for gene function prediction\" and Andrea Bracciali, from the University of Stirling , gave a lecture on \"Formal Models in Systems Biology\".Shortly after the conference, 42 papers were submitted for publication in this BMC Bioinformatics Supplement. An Editorial Board was formed, including all members of BITS Programme Committee. Associated Editors are listed here:\u2022 Rita Casadio, University of Bologna, Bologna, Italy\u2022 Gianni Cesareni, University of Rome \"Tor Vergata\", Rome, Italy\u2022 Francesca Ciccarelli, European Oncology Institute, Milan, Italy\u2022 Domenica D'Elia, CNR Institute for Biomedical Technologies, Bari, Italy\u2022 Diego Di Bernardo, Telethon Institute of Genetics and Medicine, Naples, Italy\u2022 Angelo Facchiano, CNR Institute of Food Sciences, Avellino, Italy\u2022 Manuela Helmer Citterich, University of Rome \"Tor Vergata\", Rome, Italy\u2022 Sabino Liuni, CNR Institute for Biomedical Technologies, Bari, Italy\u2022 Roberto Marangoni, University of Pisa, Pisa, Italy\u2022 Marco Pellegrini, CNR Institute for Informatics and Telematics, Pisa, Italy\u2022 Graziano Pesole, University of Bari, Bari, Italy\u2022 Paolo Romano, IRCCS San Martino IST, Genova, Italy\u2022 Giorgio Valle, University of Padova, Padova, ItalyA stringent reviewing procedure was then adopted. Associate Editors handled the process according to their recognized knowledge in specific meeting topics. At least three referees, of a high reputation at an international level, were selected for each submission. Overall, 67 referees from 20 different countries were involved in the selection of papers. We opted for a two step peer review procedure, offering authors the possibility to submit a new version of their paper, revised according to the referees' comments.At the end of this process, 22 papers were accepted and are now included in this Supplement. They cover different aspects of theoretical and applied Bioinformatics. For sake of readability, they are presented in this Supplement grouped by topic.et al [et al. [et al. [In the context of \"Algorithms for Bioinformatics\", we present three contributions. \"Accurate multiple sequence alignment of transmembrane proteins with PSI-Coffee\" from Chang et al  reports  [et al.  presents [et al.  presentset al [In the context of \"Biological Databases and Biobanks\", this Supplement includes the following four papers. \"GIDL: a rule based expert system for GenBank Intelligent Data Loading into the Molecular Biodiversity Database\" by Pannarale et al  presentset al [\"An ICT infrastructure to integrate clinical and molecular data in oncology research\" by Segagni et al  presentset al [\"OREMPdb: a semantic dictionary of computational pathway models\" by Umeton et al  presentset al. [\"Towards Linked Open Gene Mutations Data\" by Zappa et al.  presentset al [et al [et al [In the context of \"Biophysics and Synthetic Biology\", the paper \"Fine-tuning anti-tumor immunotherapies via stochastic simulations\" by Caravagna et al  uses siml [et al  presentsl [et al  offers al [et al  copes wiCarthamus tinctorius and Cynara cardunculus\" [et al [et al [For the \"Genomics\" topic, three papers were selected. In the first one, \"In-silico and in-vivo analyses of EST databases unveil conserved miRNAs from unculus\" , Catalan\" [et al , the autl [et al  describeet al [For the \"Molecular Evolution and Comparative Genomics\" topic, \"Primates and Mouse NumtS in the UCSC Genome Browser\" from Simone et al  describeet al., in \"Intuitive representation of surface properties of biomolecules using BioBlender\" [et al. [et al. [radii. A version of the software running on Linux is also made available for download as supplementary material. The last paper in this topic, by Vangone et al [The topic \"Protein Structure and Function\" had four works selected. Andrei Blender\" , describ [et al. , describ [et al. , describne et al , reportsThe \"Systems Biology\" topic is represented by the work of Fioravanti and co-authors , where set al [et al. [Finally, the \"Transcriptomics\" topic has two papers selected. The work by Consiglio et al  describe [et al.  describeThe next Annual meeting of the Italian Society of Bioinformatics will be held in Catania, May 2-4, 2012. Further information about BITS 2012 is available on its purpose web site , as well"}
+{"text": "The xylem vascular system is composed of fused dead, hollow cells called tracheary elements (TEs) that originate through trans-differentiation of root and shoot cambium cells. TEs undergo autolysis as they differentiate and mature. The final stage of the formation of TEs in plants is the death of the involved cells, a process showing some similarities to programmed cell death (PCD) in animal systems. Plant proteases with functional similarity to proteases involved in mammalian apoptotic cell death (caspases) are suggested as an integral part of the core mechanism of most PCD responses in plants, but participation of plant caspase-like proteases in TE PCD has not yet been documented.Confocal microscopic images revealed the consecutive stages of TE formation in Zinnia cells during trans-differentiation. Application of the caspase inhibitors Z-Asp-CH2-DCB, Ac-YVAD-CMK and Ac-DEVD-CHO affected the kinetics of formation and the dimensions of the TEs resulting in a significant delay of TE formation, production of larger TEs and in elimination of the 'two-wave' pattern of TE production. DNA breakdown and appearance of TUNEL-positive nuclei was observed in xylogenic cultures and this was suppressed in the presence of caspase inhibitors.To the best of our knowledge this is the first report showing that caspase inhibitors can modulate the process of trans-differentiation in Zinnia xylogenic cell cultures. As caspase inhibitors are closely associated with cell death inhibition in a variety of plant systems, this suggests that the altered TE formation results from suppression of PCD. The findings presented here are a first step towards the use of appropriate PCD signalling modulators or related molecular genetic strategies to improve the hydraulic properties of xylem vessels in favour of the quality and shelf life of plants or plant parts. Maintenance and structuring of tissues and organs, homeostasis and defence in biological organisms are controlled by well coordinated and active cellular processes of death and survival. Programmed cell death (PCD) is a cell suicide genetically programmed, developmentally associated and environmentally stimulated mechanism and has been found throughout animal and plant kingdoms -6. PCD iIn vascular plants, PCD is involved in embryogenesis, developmental processes, senescence, hypersensitive response to pathogen attacks and in the response to abiotic stress stimuli ,5,19,27.Zinnia elegans) cell cultures, derived from leaf mesophyll cells, has revolutionized the understanding of the xylem differentiation process butane; (NAA): \u03b1-naphthalene-acetic acid; (BA): NPT and ETI shared their participation in the experimental design of the study, pharmacological analysis, light, fluorescent, confocal and DIC microscopic observations and measurements, DNA analysis, data processing and manuscript drafting. ETI also contributed to manuscript revision. TQ participated in the experimental work as a MSc thesis student. WvI and JHNS acted as daily supervisors of the experimental work. AMCE and OvK were involved in the coordination of the research program on xylogenesis and plant quality, OvK as chair of the Department Horticultural Production Chains and AMCE as chair of the Department of Plant Cell Biology. Both participated in the progress meetings.EJW conceived and co-ordinated the study on PCD in xylogenic Zinnia cultures and drafted and revised the final version of the manuscript. All authors read and approved the final manuscript.Zinnia elegans: from cellular development in vitro to performance in planta\" of which this study is a part. He is currently appointed as Lecturer at the Department of Biochemistry and Biotechnology, Kwame Nkrumah University of Science and Technology (KNUST), Kumasi, Ghana. ETI is qualified in plant physiology with a focus on programmed cell death, cell cultures, phyto hormones, stress and post-harvest physiology. In this study she participated through 21 months EC FP6 Marie Curie Intra-European Fellowship project \"Regulating plant quality by controlling xylem vessel dimensions during xylogenesis\" at Wageningen University, Agrotechnology and Food Science Group (AFSG), Wageningen, The Netherlands. At present ETI occupies a position of Associate Professor at the Institute of Ornamental Plants, Sofia, Bulgaria. TQ participated in the work when she was a MSc student, currently she is a PhD student at Wageningen University. WvI is Assistant Professor at Wageningen University, Department Horticultural Production Chains, his expertise is, among others, in effects of environmental conditions on plant growth and product quality and is an expert in xylem vessel functioning and its relation to quality of detached plant parts. JHNS is Associate Professor in the Laboratory of Plant Cell Biology, with a main expertise in structural plant cell biology and embryogenesis. AMCE is Professor of Plant Cell Biology of Wageningen University with main expertise in cytoskeleton and cell wall formation. OvK is chair holder of the Department Horticultural Production Chains of Wageningen University with main expertise in chain management and non-destructive measurements of processes related to product quality. EJW is Professor in the Department Horticultural Production Chains and project manager at the Wageningen University Research Institute \"Food and Biobased Research\". EJW has a broad background in (postharvest) plant biology and has long term experience in plant programmed cell death research using, among others, different types of cell cultures.PT was employed as a PhD student at Wageningen University, Department Horticultural Production Chains from 2003 to 2007 and successfully defended his PhD Thesis \"Hydraulic properties of"}
+{"text": "Eucalyptus: Collaborating Center in Agriculture Defense Relative to the Biosafety of Genetically Modified (GM) Eucalypts\u201d is to gather, assess and validate the existing information concerning GM and non-GM Eucalyptus and its derivatives in the Brazilian environment, both in laboratories and field test experiments. Accordingly, the purpose of the present research activity is to provide a binary plasmid collection containing different versions of the gene encoding green fluorescent protein (GFP), originally from Aequorea victorea, for the future generation of easily detectable GM plant phenotypes. Using commercially available plasmids encoding blue (ECFP) and yellow (EYFP) versions of GFP for expression in bacteria, the initial strategy was to transfer the coding sequences to the intermediate plasmid pSport1 (Invitrogen) and, subsequently, to pART7 plasmid, which contains the promoter and terminator sequences for gene expression in plants. Although recombinant bacteria have been obtained for both genes, DNA sequencing showed that success was achieved only with pSport1-eyfp. So far, pART7 versions were not obtained. A new cloning strategy was proposed, which involves the binary plasmid pCAMBIA1302 (Cambia). This plasmid already contains one version of the gfp gene for expression in plants. The intention is to replace the gfp gene by ecfp, eyfp and mCherryFP versions. As soon as plasmids are finished, plants will be transformed via Agrobacterium tumefaciens, and their transgenic state will be confirmed by the fluorescence of the encoded proteins. Thus, the fluorescence of the GFP different versions will be used to monitor seeds, pollen, leaves and transgenic plants as a whole in the environment.The main purpose of the \u201cCDA Financial support: Brazilian Ministry of Agriculture, Farming & Supply (MAPA), and The National Council for the Development of Science & Technology (CNPq), Brazilian Ministry of Science & Technology (MCT)."}
+{"text": "Analysis is lacking on the management of vector control systems in disease-endemic countries with respect to the efficiency and sustainability of operations.Three locations were selected, at the scale of province, municipality and barangay (i.e. village). Data on disease incidence, programme activities, and programme management were collected on-site through meetings and focus group discussions.Adaptation of disease control strategies to the epidemiological situation per barangay, through micro-stratification, brings gains in efficiency, but should be accompanied by further capacity building on local situational analysis for better selection and targeting of vector control interventions within the barangay. An integrated approach to vector control, aiming to improve the rational use of resources, was evident with a multi-disease strategy for detection and response, and by the use of combinations of vector control methods. Collaboration within the health sector was apparent from the involvement of barangay health workers, re-orientation of job descriptions and the creation of a disease surveillance unit. The engagement of barangay leaders and use of existing community structures helped mobilize local resources and voluntary services for vector control. In one location, local authorities and the community were involved in the planning, implementation and evaluation of malaria control, which triggered local programme ownership.Strategies that contributed to an improved efficiency and sustainability of vector control operations were: micro-stratification, integration of vector control within the health sector, a multi-disease approach, involvement of local authorities, and empowerment of communities. Capacity building on situational analysis and vector surveillance should be addressed through national policy and guidelines. Vector-borne diseases cause a major burden in the Philippines. Main diseases are malaria, dengue, lymphatic filariasis, schistosomiasis and Japanese encephalitis ,2. The PVector control has the potential to play an important role in reducing transmission of these diseases and in reaching critical low levels of vectorial capacity required for elimination of disease -9. To beThe technical and operational sustainability of vector control is of major concern, given the threat of insecticide resistance -12, and Numerous reports are available on the effectiveness and costs of individual vector control interventions, with some of these interventions having an application value in diverse epidemiological settings ,14. HoweThe World Health Organization promotes the principles and approaches set out in the strategic framework on integrated vector management (IVM) to improve the efficacy, cost-effectiveness, ecological soundness and sustainability of vector control . A recenThis study was initiated on the assumption that lessons could be learnt about operational efficiency and sustainability by studying vector control systems established at different levels of public administration because at each level, distinct conditions for decision-making and integration would apply. The outcomes were evaluated in relation to the five key elements laid-out in the framework on IVM: evidence-based decision-making; an integrated approach; collaboration within the health sector and with other sectors; advocacy, social mobilization and legislation; and capacity building . As the Three locations were selected, at different administrative levels, i.e. province, municipality and barangay; a barangay is the smallest administrative division in the Philippines and is equivalent to a village.The first case study location, Cagayan Valley in north-eastern Luzon, comprises the provinces of Isabela and Cagayan (combined population 2.4 million). This area was selected as an example of a malaria elimination programme showing promising results in the reduction of malaria cases. The programme in Cagayan Valley was implemented under the National Malaria Control Programme, with main support from the Global Fund. The second case study location was the municipality of Mati City , in Davao Oriental province in south-eastern Mindanao. This location was selected because of its known local efforts in developing an epidemic response system for vector-borne disease control. The third case study location, the barangay of Simbalan , in Buenavista municipality, Agusan del Norte province in northern Mindanao, was selected as a known example of a barangay with active involvement of local leaders and communities in vector control.The case studies were conducted on site in June 2011. Data on programme achievements in terms of training, supervision and interventions and data on disease incidence rates were gathered through meetings at health offices at regional, provincial and municipal level. Focus group discussions were held in selected municipalities and barangays with local government officers, barangay health workers and members of civil society to obtain qualitative data on the recent history, structure, organization and management of local programmes.Anopheles flavirostris and Anopheles maculatus, which breed at the edges of streams in foothills, especially near human habitation [The main malaria vectors in Cagayan Valley, as in most of the Philippines, are bitation -20. In 2Plasmodium falciparum. The purpose of the micro-stratification, to be updated every three years, was to aid programme managers in their planning, choice of interventions and efficient use of resources for case detection and vector control in accordance with the disease situation in each barangay.These malaria incidence data have enabled micro-stratification of malaria epidemiology, with the barangay as stratification unit. The micro-stratification, conducted in 2010, categorized individual barangays as having 'stable transmission', 'unstable transmission', 'sporadic transmission' or being 'malaria prone', defined on the basis of monthly patterns of malaria transmission using criteria presented in Table The results showed that the distribution of malaria was highly focal, with 'stable transmission' occurring in less than 1% of the barangays and the majority of barangays being classified as 'malaria prone' , with a population of 2,675, and Mabuno , with a population of 2,640. Both barangays had been malaria hotspots Table . MicroscClose examination of case reports revealed that in Antagan, the malaria cases were mostly male (92%), from 11 to 30 years (77%), occupational loggers (53%) or farmers (32%), and that 65% of all cases occurred during the months of June and July, coinciding with the planting season of rain-fed crops in the hills. Men staying out in the hills to plant and cultivate these crops during the rainy season, or to log trees, are apparently at risk to be infected with malaria, because these are the known habitats where the main mosquito vectors breed. Hence, it is likely that the remaining malaria transmission in Antagan occurred not within the barangay proper but out in the hills. The causes of the recent drop in cases  need further investigation.Conversely, in Mabuno, malaria cases did not decline even with high coverage of LLINs and IRS. Here, the majority of cases were indigenous people, living in make-shift houses in the foothills, which were areas not covered under recent LLIN-distribution campaigns, and reporting to the barangay health centre for treatment when they were ill. This suggests that transmission has continued among indigenous people living unprotected from infectious bites outside of the barangay proper.The examples of Antagan and Mabuno indicate that information other than basic epidemiological data was important for evidence-based decision-making. Entomological data and information on personal protection behaviour among those staying in the foothills could help adapt the malaria control strategy to achieve further reductions in disease incidence. For example, increased attention could be paid to mobile indigenous populations and temporary agricultural workers, developing appropriate control methods , and targeting the interventions at times and places when and where these groups are most at risk of malaria transmission. Also, entomological surveillance to confirm the absence of malaria vectors within the barangay proper will help improve the efficient allocation and use of resources for vector control and personal protection.Summing up, the case from Cagayan Valley demonstrates a model for planning and adapting malaria control strategies to the epidemiological situation in each barangay. The benefits of micro-stratification were three-fold: it resulted in more efficient use of resources; it allowed for more in-depth understanding about malaria transmission within the barangay; and, it stimulated the involvement of local leaders. An important lesson is that this model could be improved further by collecting entomological data and determining which sections of society are most at risk of malaria transmission.The municipality of Mati City has been affected by both malaria and dengue. Malaria control has been well structured through the National Programme, with support from the Roll Back Malaria Project and Global Fund for case finding, treatment, and vector control through LLINs and IRS as well as capability building for local health staff and volunteers. These efforts were accompanied by a decline in malaria prevalence during the period 2005-2010 , began to organize weekly clean-up drives and conduct vector larval surveillance at monthly intervals. Second, a disease surveillance unit was created to enact and coordinate weekly reporting of cases of all notifiable diseases, including vector-borne diseases, from the city's two hospitals and from all 26 barangay health centres. These two measures helped safeguard the regular allocation in City budgeting for the detection and control of vector-borne diseases, notably dengue. In addition, in 2011, the City mayor's office began sponsoring the rapid deployment team, driven in part by the economic burden of dengue, due to costs incurred by the mayor's office for transport, treatment and referral of dengue cases to specialized hospitals.In the event of an increase in dengue cases or a local dengue outbreak, the relevant agencies were alerted to respond. The response consisted of intensified health promotion and weekly rounds of vector surveillance and concomitant source reduction in 100 houses in the vicinity of detected cases. The weekly rounds were repeated for up to 10 times, until the 'house index' (i.e. % of houses being positive for dengue breeding) dropped below the locally set threshold margin of 2-5% and the 'Breteau index' (i.e. the number of positive containers per 100 houses) dropped below the value of 20 . Hence, Aedes larvae are found on their compound. The resolution was adopted by the entire barangay, and the generated income went into a trust fund to treat dengue patients.There were other partners in vector control. The department of education created their own vector control task force with monitoring by brigades at schools. Moreover, barangay chiefs and councillors, having been among those trained on dengue prevention, provided support for health promotion and clean-up drives, issued permits to search people's compounds for vector breeding sites and, in one instance, formulated policy. After four child deaths due to dengue in one sub-barangay in 2009, the local councillor introduced a resolution that households must pay a fine of 50 pesos if Hence, the case of Mati shows how in-kind contributions for malaria control benefited dengue control activities through a joint malaria-dengue system of detection and vector control response. Even though dengue was the only prevalent vector-borne disease at the time of the case study, the system was prepared to respond to outbreaks of malaria and other diseases, thus increasing the efficiency as compared to single-disease systems. To safeguard the operational sustainability, the detection and response system was integrated within the health infrastructure. Cases of dengue fever dropped from 185 in 2010 to 108 in 2011; the coming years will show whether the strategy leads to a further reduction in disease cases and whether the political commitment can be sustained.sitios in a poorly accessible mountainous area. Sporadic cases of lymphatic filariasis were reported in the past, but dengue has been absent.Buenavista municipality has been relatively free from malaria, with the exception of a pocket of 'stable transmission' of malaria around Simbalan, a barangay composed of a number of scattered sub-barangays or sitios, and in that year the number of confirmed malaria cases  was determined at 490 . In recent years, full coverage of the population with insecticidal nets has been achieved, whereas IRS was started in 2010 in the western-most part of the barangay where transmission risk through imported cases was considered to be highest. The number of malaria cases dropped to zero  and evaluation of bed net utilization . Hence, surveillance data were readily utilized. Nevertheless, gaps remained in the evidence base needed for decision-making on vector control. Particularly, data on the cost-effectiveness of stream clearing against irostris , and on irostris ,27, wereng sites , and by ng sites .An integrated approach to vector control, aiming to improve the rational use of resources, was evident in the case of Mati where elements of a multi-disease strategy of detection and response had been established Table . Also, tCollaboration on vector control can improve operational efficiency within the health sector and lead to reduced disease risks in other sectors. Collaboration within the health sector was apparent from the involvement of barangay health workers in vector-borne disease control in each case study, but was most obvious in Mati, where the job descriptions of barangay health emergency response teams were modified and staff reoriented towards vector control and where a central unit was created for weekly surveillance of notifiable disease cases, including vector-borne disease cases Table . Health Advocacy and social mobilization were common features in each case study Table . SpecifiCapacity building is a major challenge to the improvement of vector control systems. The case examples indicate that a national strategy for capacity building on detection and diagnosis of malaria was in place, but competencies on situational analysis and vector surveillance appeared to be inadequate. These aspects should be addressed in national policy and guidelines.Considering the current reliance on external funding support, the operational sustainability of vector control remains uncertain. It will be particularly challenging to sustain vector control during and beyond the elimination of disease, after the public health problem has diminished -8; howevThe case studies have suggested several other mechanisms to sustain vector control: integration within the health sector, involvement of local authorities, and empowerment of communities. In Mati, financial support for dengue control was coming to an end, which prompted the municipal health authorities to incorporate dengue control within their health system, utilizing local infrastructure and safeguarding regular allocation of funds for vector-borne disease control in local budgeting. Yet, many municipalities with dengue prevalence may lack such resources and, thus, sufficient national funds should be allotted to the control of this neglected disease.bayanihan, a common tradition in Philippine towns [The engagement of barangay leaders and existing community structures helped mobilize local resources and voluntary services for vector control. Barangay authorities and the community in Simbalan were actively involved in the planning, implementation and evaluation of malaria control actions, indicative of local programme ownership. Moreover, their vision statement to become independent from external resources for malaria control is particularly relevant in the context of malaria elimination because continued commitment to surveillance and outbreak response will be needed . Neverthne towns . This suMicro-stratification based on epidemiological data resulted in improved efficiency of disease control operations, but should be accompanied by further capacity building on the selection and targeting of vector control interventions at barangay-level. The case studies suggested several mechanisms to improve operational sustainability of vector control: integration within the health sector, a multi-disease malaria-dengue approach, involvement of local authorities, and empowerment of communities. Local programme ownership on vector-borne disease control could potentially be replicated if adequate training and guidance are given.LLIN: Long-lasting insecticidal nets; IRS: Indoor residual spraying; ITN:  Insecticide-treated nets; IVM: Integrated vector management; RDT: Rapid diagnostic test; SARS: Severe acute respiratory syndrome; WHO: World Health Organization.The authors declare that they have no competing interests.HvdB, RV, AE, BHGC, RT, MT and JH all participated in field visits and data collection. JH conceptualized the study. HvdB analysed and interpreted the data and drafted and revised the manuscript. JH, RV, BHGC, AE, RT and MT contributed to revising the manuscript. All authors have read and approved the final manuscript."}
+{"text": "The gamma-secretase complex is an intramembrane aspartyl protease comprised of at least four known subunits: Presenilin (PS), Nicastrin (Nct), Aph, and Pen2. Presenilin is the catalytic subunit of the complex. Mutations in PS1 and PS2, which lead to familial early-onset Alzheimer disease, alter the activity and specificity of gamma-secretase. Investigation of gamma-secretase specificity and development of gamma-secretase based therapies have been a huge challenge because of its nature of intramembranal catalysis and macromolecular complex as well as cleavage of multiple substrates. We have developed an integrated approach of biochemistry, chemical biology and cell biology for the study of gamma-secretase structure and function. We will discuss how to apply this approach to elucidate the role endogenous and exogenous factors in regulation of gamma-secretase. We will focus on the development of chemical probes and utilize them to define the mechanism of action of gamma-secretase modulators."}
+{"text": "Integrated analysis of both methods highlighted the extensive impact of moderate-severe LBP, the paucity of effective interventions, the pivotal nature of the midwife-patient relationship, and physiotherapists\u2019 concerns about using acupuncture for pregnant women, despite their use of it for other musculoskeletal problems. Results informed phase 2  in terms of patient information, recruitment and consent procedures. They also helped shape the training programme for physiotherapists delivering the interventions, to directly address issues of safety and side effects. Findings highlight the role mixed methods can play in preparing for randomised trials and ensuring they are sensitive to the needs of patients and practitioners. The phase 2 pilot trial is currently underway.EASE BACK is an NIHR HTA funded feasibility pilot trial to inform a large randomised trial evaluating the clinical and cost-effectiveness of acupuncture for pregnant women with low back pain (LBP). Mixed methods were employed to generate a breadth of data. In phase 1, interviews and focus groups explored the views of pregnant women with LBP about the acceptability of the proposed interventions, the content and delivery of participant information, important outcomes, and timing of outcome measurement; and the views of health professionals (midwives and physiotherapists) about standard care, using acupuncture for this patient group, proposed trial design, and recruitment methods. A total of 52 individuals were interviewed. In addition, a postal survey of UK based physiotherapists was undertaken (response rate 57.5%:"}
+{"text": "Its unparalleled in vivo and quantitative capabilities offer a broad range of applications covering from noninvasive morphologic measurements, tissue microstructural characterization, hemodynamic and vascular characterization, metabolite measurements, sub-system physiologies, brain functions to monitoring of cell migrational dynamics. This presentation will illustrate these technological developments with some of the ongoing rodent brain MRI projects in our laboratory, highlighting the capacity of MRI as a platform technology to visualize the central nervous system (CNS) in vivo from molecules to systems levels. They include diffusion characterization of neural tissue microstructure; functional study of molecular pathways by spectroscopy; functional study of brain development and injury; monitoring of endogenous neural stem cell activities; and novel contrast agents for brain imaging.With advances in engineering and computing, an extraordinary body of imaging technologies and applications has developed over the last 35 years. One of the most important applications of such technologies is the study of anatomy, physiology, pathology and functions in humans and animal models of human development and diseases. Among the various"}
+{"text": "To the Editor: Norovirus (NoV), the distinct genus within the family Caliciviridae, is a major cause of sporadic cases and outbreaks of acute gastroenteritis in humans . Polymerase chain reaction with specific primers resulted in the identification of astrovirus, rotavirus, sapovirus, adenovirus, and NoV genogroup I (GI) and GII  successful co-infection of a single host, 2) successful co-infection of a single cell, 3) efficient replication of both parental strains, 4) template switching, and 5) purifying selection (The NoV capsid is predicted to be well suited for genotype classification (In conclusion, our results described the genetic characterization of novel, naturally occurring recombinant NoV and increased evidence for the worldwide distribution of recombinant NoV. This report is the first to describe acute gastroenteritis caused by recombinant NoV in China and warns of the threat it poses."}
+{"text": "Although obesity is a risk factor for many chronic diseases, we have only limited knowledge of the magnitude of these associations in young adults. A multiethnic cohort of young adults was established to close current knowledge gaps; cohort demographics, cohort retention, and the potential influence of migration bias were investigated.For this population-based cross-sectional study, demographics, and measured weight and height were extracted from electronic medical records of 1,929,470 patients aged 20 to 39 years enrolled in two integrated health plans in California from 2007 to 2009.The cohort included about 84.4% of Kaiser Permanente California members in this age group who had a medical encounter during the study period and represented about 18.2% of the underlying population in the same age group in California. The age distribution of the cohort was relatively comparable to the underlying population in California Census 2010 population, but the proportion of women and ethnic/racial minorities was slightly higher. The three-year retention rate was 68.4%.These data suggest the feasibility of our study for medium-term follow-up based on sufficient membership retention rates. While nationwide 6% of young adults are extremely obese, we know little to adequately quantify the health burden attributable to obesity, especially extreme obesity, in this age group. This cohort of young adults provides a unique opportunity to investigate associations of obesity-related factors and risk of cancer in a large multiethnic population. In 2007Managed care systems are a unique system to study associations between rare outcomes in young adults due to their large populations and the potential for long passive follow-up periods. However, lack of generalizability due to healthy worker bias  and the potential loss of subjects in epidemiologic studies using members of managed care systems are of concern because these factors can be a major of source of bias. Study subjects may lose their health insurance coverage or migrate out of the coverage area but also may re-enroll based on their employment status or other financial decisions and life events. If subjects who leave the health plan are systematically different from those who remain in the health plan in terms of exposure and the association with health outcomes, the estimates of association between exposure and outcome may be systematically biased. The potential of bias exists in all epidemiologic studies due to low and selective responses to recruitment attempts, survey fatigue, migration of subjects, and other factors. However, the control of this bias can be addressed through careful study design and interpretation of the data. As part of the study design, the potential existence of such bias has to be acknowledged, appropriate measures to assess such bias have to be made, and potential effects of such bias for direction and magnitude have to be estimated. Therefore, these potential biases are extremely important to understand.The long-term goal of this large prospective cohort of young adults is to investigate the relationship between weight class, metabolic syndrome, diabetes, and obesity-related cancers and their risk factors. The analyses presented here show the detailed cohort demographics, as well as cohort retention and the potential influence of migration bias.The present project was initiated to study the consequences of obesity in young adults (OBAYA) including cancer and leverages the resources of the Cancer Research Network (CRN), an ongoThe cohort is followed by passive follow-up through linkage with data extracted from the KP electronic health records. Information on occurrence of cancers comes from linkage of cohort members to KPNC and KPSC tumor registries, which are compliant with data requirements of the NCI Surveillance, Epidemiology, and End Research (SEER) Program and the North American Associations of Central Cancer Registries (NAACCR). Additional data come from probabilistic linkage to the National Death Index (NDI) and to the state cancer registry. The maximum follow-up on December 31, 2010 was four years, the minimum being one year.The study used information that is routinely assessed during most ambulatory and hospitalization visits. This information captures administrative datasets containing membership and benefit information including all medical encounters at Kaiser Permanente facilities, out-of-system claims, laboratory and radiology test results, and dispensed prescription pharmaceuticals. The address information is routinely geocoded to the census block level, providing the ability to link to census-based group-level socioeconomic information. Laboratory data are also available from electronic medical records. Using the cohort members\u2019 unique medical record numbers, incident diseases can be identified from electronic records, internal disease registries such as the cancer registry, and also from the state cancer registry and state death files.Body weight and height are routinely measured during almost every medical encounter and were extracted from the electronic health records. BMI was calculated as weight (kilograms) divided by the square of the height (meters). Based on a validation study including 15,000 patients with 45,980 medical encounters, the estimated error rate in body weight and height data was <0.4%[th, 2011).Population counts for California were retrieved from Census 2010 data for California for individuals who were 20 to 39 years of age , linkage with state death files (restricted to death cases), and linkage with state cancer registries (restricted to those who remain in the state and limited to cancer diagnosis).Planned future research on the young adult cohort will develop these quality measures in order to identify person-level characteristics associated with both variations in services related to cardiovascular disease, diabetes, and cancer in young obese adults and variations in the care they receive and its consequences for incident morbidity, mortality, and health care utilization. This planned research will also examine differences in the effectiveness of that care in demographically and medically defined subpopulations.BMI: Body Mass Index; CRN: Cancer Research Network; NCI: National Cancer Institute; KPNC and KPSC: Kaiser Permanente Northern and Southern California; KP: Kaiser Permanente; IRB: Institutional Review Board; NCI: National Cancer Institute; SEER: NCI Surveillance Epidemiology, and End Research; NAACCR: North American Associations of Central Cancer Registries; NDI: National Death Index.Lawrence H Kushi reports a relevant relationship as Adjunct Professor at the UC Davis Medical School, which is not his primary employment.Design and conduct of the study: CK, LHK; Collection, management, analysis and interpretation of data: CK, LHK, NS, MPM, KH, HAC, AEW; Preparation of the manuscript: CK, MPM, NS; Critical revision of the manuscript for important intellectual content: LHK, KH, HAC, AEW. All authors read and approved the final manuscript."}
+{"text": "Optimization of the clinical care process by integration of evidence-based knowledge is one of the active components in care pathways. When studying the impact of a care pathway by using a cluster-randomized design, standardization of the care pathway intervention is crucial. This methodology paper describes the development of the clinical content of an evidence-based care pathway for in-hospital management of chronic obstructive pulmonary disease (COPD) exacerbation in the context of a cluster-randomized controlled trial (cRCT) on care pathway effectiveness.The clinical content of a care pathway for COPD exacerbation was developed based on recognized process design and guideline development methods. Subsequently, based on the COPD case study, a generalized eight-step method was designed to support the development of the clinical content of an evidence-based care pathway.A set of 38 evidence-based key interventions and a set of 24 process and 15 outcome indicators were developed in eight different steps. Nine Belgian multidisciplinary teams piloted both the set of key interventions and indicators. The key intervention set was judged by the teams as being valid and clinically applicable. In addition, the pilot study showed that the indicators were feasible for the involved clinicians and patients.The set of 38 key interventions and the set of process and outcome indicators were found to be appropriate for the development and standardization of the clinical content of the COPD care pathway in the context of a cRCT on pathway effectiveness. The developed eight-step method may facilitate multidisciplinary teams caring for other patient populations in designing the clinical content of their future care pathways. Standardization of the clinical care process through integration of evidence-based knowledge has proven to be an effective strategy for reducing unwanted variations in treatment and for minimizing the probability of medical errors . HoweverA possible tool to facilitate implementation of evidence into practice is a care pathway. Care pathways are complex interventions for mutual decision making, organization, and standardization of predicTable care for a well-defined group of patients during a well-defined period -8. One oCare pathways induce change at different levels of the organization ; consequently, variability at individual level outcomes may reflect the impact of higher-level complexity processes. To deal with these multilevel effects, cluster randomized designs are strongly recommended when studying the impact of care pathways ,11. ImpoIn 2009, the European Pathway Association (E-P-A) launched the European Quality of Care Pathways (EQCP) study, an international cRCT addressing the impact of a care pathway for chronic obstructive pulmonary disease (COPD) exacerbations [et al.[The clinical content of an evidence-based care pathway for COPD exacerbation was developed based on the process design methodology developed by Berry et al., and theet al., the Woret al. and the et al.. Subsequet al..A set of 38 evidence-based key interventions and a set of 24 process and 15 outcome indicators were developed in eight different steps. Both sets are displayed in Additional file The patient population under study was specified as \u2018Patients hospitalized with COPD exacerbation\u2019. To ensure clinical validity and feasibility of the end product, an expert panel was involved in each step of the development method. This panel was composed of the following: (i) three clinicians with internationally recognized clinical and scientific expertise in COPD exacerbations: a respiratory physician (MD) who is also president of the European Respiratory Society, a physiotherapist (TT) who specializes in pulmonary rehabilitation, and a clinical nurse specialist in COPD (CL); (ii) an epidemiologist (MP) who specializes in organization of primary and secondary chronic care; and (iii) two professors  in patient care management who have extensive clinical and scientific expertise in development and implementation of care pathways ,18-21. ATo identify all available evidence for integration in the evidence-based COPD care pathway, an extensive literature review was conducted by the main researchers, CL and KV Figure . First, http://www.thoracic.org); British Thoracic Society (BTS) (http://www.brit-thoracic.org.uk); European Respiratory Society (ERS) (http://www.ersnet.org); Global Strategy for Diagnosis, Management, and Prevention of COPD (GOLD) (http://www.goldcopd.org); National Institute for Health and Clinical Excellence (NICE) (http://www.nice.org.uk); Scottish Intercollegiate Guidelines Network (SIGN) (http://www.sign.ac.uk); (II) Public resources for evidence-based clinical practice guidelines ; (III) electronic databases including Medline and Embase and Cochrane; (IV) available process flow diagrams founded on evidence-based medicine .The following resources were explored: (I) websites of international respiratory societies: American Thoracic Society (ATS)  \u2018practice guideline\u2019, (ii) \u2018disease exacerbation and patient care management\u2019, and (iii) \u2018outcomes\u2019. For Embase, we used the MeSH terms \u2018chronic obstructive lung disease\u2019 combined with (i) \u2018practice guideline\u2019 and (ii) \u2018disease exacerbation and patient care\u2019, and (iii) \u2018outcomes\u2019. Non-MeSH terms used in Embase were \u2018COPD\u2019 in combination with \u2018exacerbation and management\u2019. Search limit parameters included: (i) published between 2005 and 2011, and (ii) written in English, French, German, Italian or Dutch.Second, we performed a two-phase screening evaluation of publications selected from websites of the respiratory societies, Map of Medicine and the electronic databases. In the first phase, publications were appraised for relevance based on appropriateness of the title and abstract. If relevance was unclear, or if the abstract was unavailable, the publication was included for further appraisal of the full text. In the second phase, two independent researchers (CL and KV) reviewed the full text of the selected guidelines, reviews or process flow diagrams. The following inclusion criteria were used: (i) reportage of clinical processes and outcomes regarding in-hospital management of COPD exacerbation; (ii) evidence was reported in terms of guidelines, process flow diagrams, reviews or overview papers; (iv) published between 2005 and 2011; (v) published in English, French, German, Italian or Dutch; and (vi) quality of underlying evidence can be appraised by in-text references. The literature research revealed initially three guidelines, one process flow diagram, and 2,939 digital records from the electronic medical databases  and 10 of 21 outcome indicators (47.6%). Highest consensus was reached for the process indicators for oxygen therapy (100%), pulmonary rehabilitation (100%), and patient education (94.5 to 88.6%), and for the outcome indicators for understanding of therapy (91.4 to 85.7%) and self-management (88.6 to 88.2%) .First, the list of 58 extracted clinical activities (step 2), together with the Delphi results (step 3), were sent to the clinical experts of the panel  with a request to complete two tasks: (i) to review the 58 identified activities for validity and feasibility; and (ii) if indicated, to propose any additional clinical activity they believe is essential for in-hospital management of COPD exacerbations and which is lacking in the current activity list of clinical activities. Second, a consensus meeting was held with the entire expert panel in order to make a final selection of the clinical activities. As a result, all 58 clinical activities were appraised to be valid and feasible. In addition, 19 clinical activities beyond the 58 original ones were included  clinical activities are inextricably linked to each other ; (ii) clinical activities need to be performed by a specific team member ; (iii) clinical activities need to be performed at a specific time point or within a specific time span of the care process . As a result, the 77 clinical activities were clustered into 38 key interventions, with 9 of them comprising 2 to 15 subcomponents.Second, the key interventions were categorized into three core processes , and subsequently presented by means of a process flow diagram. In addition, within each of three core processes, key interventions were grouped into care blocks based on the overall content of these key interventions . The process flow diagram with the 38 key interventions is displayed in Additional file For each key intervention, the following components were included in the detailed description: (i) rationale, which addresses why it is of crucial importance that the key intervention is performed, and which describes expected impact on patient outcomes; (ii) description, which defines the exact content of the key intervention; (iii) in-text references and reference list; and (iv) grading of evidence. An example of a detailed description of a key intervention on arterial blood gas measurements is provided in Figure Besides the set of key interventions, a set of process and outcome indicators needed to be developed to verify compliance to key interventions and to follow up the impact on outcomes. First, to select the final set of indicators, the expert panel convened for a consensus meeting. The selection process was based on the (updated) literature search step 2), the Delphi survey (step 3), and the developed set of 38 evidence-based key interventions (step 5) . As a re, the Delhttp://www.qualitymeasures.ahrq.gov) and the Joint Commission (http://www.jointcommission.org), each indicator and baseline variable was defined in an indicator protocol by the main researcher (CL). This process included defining of description, rationale or relation to quality, type of indicator , nominator and denominator, data collection method, data elements, data reporting , criteria to meet expected outcomes, and references. An example of an indicator description is detailed in Additional file Subsequently, the selected indicators and baseline variables were operationalized into objective measurements . Based oThe set of 38 key interventions, and the set of 24 process and 15 outcome indicators, were piloted by nine Belgian experimental COPD teams in the context of the EQCP study . The mulSecond, during a workshop in which team members of all nine multidisciplinary COPD teams attended, the process flow diagram, including the 38 key interventions, was presented. Subsequently, all key interventions were extensively discussed. Third, the detailed set of key interventions was provided to the study coordinator of each hospital. We requested all members of the multidisciplinary COPD team to extensively review the key intervention set and subsequently to provide feedback within two weeks. As a result, the feedback given during the workshop and provided after extensive appraisal by all teams showed that teams were very enthusiastic about the process flow diagram and underlying key interventions. Moreover, they agreed by consensus that the set of key interventions was valid and applicable for use in their practice.However, the teams provided four main remarks regarding: (i) usefulness of spirometry during exacerbation because results may be inaccurate due to the compromised condition; (ii) feasibility of referral to pulmonary rehabilitation with regard to condition of the patient and availability of a rehabilitation center; (iii) type of inhaler medications and device ; and (iv) finally content, workload and feasibility of patient education. First, with regard to spirometry, no hard evidence about accuracy and, thus, usefulness of spirometric tests during exacerbation is available and, thus, no specific guidance on whether or not to perform spirometric tests could be provided to the teams. This issue was specifically emphasized in the detailed set of key interventions. Concerning pulmonary rehabilitation, all teams were convinced about the importance of referring patients to rehabilitation, and consequently, during the workshop some alternatives with regard to availability of a rehabilitation center were discussed. Finally, with regard to inhaler therapy and patient education, a teaching workshop was organized and education tools for COPD teams and ready-to-use patient leaflets were provided.Finally, the nine multidisciplinary COPD teams implemented the set of key interventions as an active component of their care pathway for in-hospital management of COPD exacerbation in the context of the EQCP study . Six monA set of 38 evidence-based key interventions for in-hospital management of COPD exacerbation was developed  and pilot testing (step 8). However, results of the Delphi survey and piloting are essential to ensure that the key intervention set is widely, clinically applicable. This is especially important when conducting a cRCT, in which the \u2018same\u2019 care pathway intervention needs to be implemented by different teams at different sites and possibly in different countries . Teams dA surprising finding is that, based on review of the literature (Step 2), the Delphi study, and face-to-face expert opinion, advanced care planning was not included in the set of 38 key interventions. On one hand, this can be explained due to the focus on management of acute COPD exacerbation. On the other hand, it is essential that advanced care planning and end of life discussions are initiated in advance of a life threatening situation, which can arise after COPD exacerbation . TherefoAn important limitation in the current strategy is the lack of patient involvement . PatientWe believe that developing the clinical care pathway content by using this newly developed and validated eight-step method will facilitate adequate integration of evidence-based knowledge into daily practice. Since the beginning of the 1990s, evidence-based clinical practice guidelines for almost all domains of medicine have been available worldwide, accessible more recently via the Internet ,70,71. HFinally, we want to emphasize the potential role of professional medical associations in clinical content development for evidence-based care pathways. Many national and international societies have extensive clinical and research experience in the patient population of their clinical field, comprise a global network of experts in the field, have funding available and, last but not least, have comprehensive understanding and experience in synthesizing evidence-based knowledge and making this knowledge usable for daily clinical practice. Therefore, we believe that professional societies could play a major role in developing the clinical content of future evidence-based care pathways, especially in terms of clinical support, expert networking and input of resources.The set of 38 key interventions and the set of process and outcome indicators were found to be appropriate for the development and standardization of the clinical content of the COPD care pathway in the context of a cRCT on pathway effectiveness. The developed eight-step method may facilitate multidisciplinary teams caring for other patient populations in designing the clinical content of their future care pathways.1: Forced expiratory volume in one second; FVC: Forced vital capacity; GOLD: Global Strategy for Diagnosis Management, and Prevention of COPD; HICPAC: Healthcare Infection Control Practices Advisory Committee; HRQL: Health-related quality of life; LOS: Length of stay; LTOT: Long-term oxygen therapy; NICE: National Institute for Health and Clinical Excellence; QALY: Quality-adjusted life expectancy measure; SIGN: Scottish Intercollegiate Guidelines Network; WHO: World Health Organization.ABGs: Arterial blood gases; ACCP: American College of Chest Physicians; ATS: American Thoracic Society; BMI: Body mass index; BTS: British Thoracic Society; COI: Cost of illness; COPD: Chronic obstructive pulmonary disease; cRCT: Cluster randomized controlled trial; DALY: Disability adjusted life years; E-P-A: European Pathway Association; EQCP: European Quality of Care Pathways; ERS: European Respiratory Society; FEVThe authors declare that they have no competing interests.CL KV, WS, SD and MP contributed to the draft and the final version of the paper. MD supervised and was closely involved in the development of the clinical content of the care pathway intervention. MP, KV and WS have the scientific lead of the EQCP study. KV is international coordinator of the EQCP study. All authors have read and approved the final manuscript.Process flow diagram for in-hospital management of COPD exacerbation. This Additional file displays a process flow chart including 38 key interventions that should be performed for every patient entering the hospital with COPD exacerbation. The key interventions are classified under three core processes: Diagnostic, Pharmacological and Non-pharmacological management.Click here for fileSet of Process and outcome indicators for in-hospital management of COPD exacerbation. This Additional file displays a set of validated process and outcome indicators for audit of care for in-hospital management of COPD exacerbation.Click here for fileExample of description of an indicator. This Additional file displays the detailed description of an indicator according to the guidance of the Agency for Health Care Research and Quality  and the Joint Commission (http://www.jointcommission.org).Click here for file"}
+{"text": "Background: Legislation and regulation of pesticides used in public health are essential for reducing risks to human health and the environment.Objective: We assessed the global situation on legislation and regulatory control of public health pesticides.Methods: A peer-reviewed and field-tested questionnaire was distributed to 142 member states of the World Health Organization (WHO); 113 states completed the questionnaire.Results: Legislation on public health pesticides was absent in 25% of the countries. Where present, legislation often lacked comprehensiveness, for example, on basic aspects such as labeling, storage, transport, and disposal of public health pesticides. Guidelines or essential requirements for the process of pesticide registration were lacking in many countries. The capacity to enforce regulations was considered to be weak across WHO regions. Half of all countries lacked pesticide quality control laboratories, and two-thirds reported high concern over quality of products on the market. National statistics on production and trade of pesticides and poisoning incidents were lacking in many countries. Despite the shortcomings, WHO recommendations were considered to constitute a supportive or sole basis in national registration. Also, some regions showed high participation of countries in regional schemes to harmonize pesticide registration requirements.Conclusions: Critical deficiencies are evident in the legislative and regulatory framework for public health pesticides across regions, posing risks to human health and the environment. Recent experience in some countries with situational analysis, needs assessment, action planning, and regional collaboration has signaled a promising way forward. Major vector-borne diseases such as malaria, lymphatic filariasis, dengue, leishmaniasis, Chagas disease, and Japanese encephalitis, as well as nuisance pests in and around human habitations, cause tremendous suffering and impede the alleviation of poverty and constrain economic development. Thus, attaining the United Nation\u2019s Millennium Development Goals  is diffiInternational Code of Conduct on the Distribution and Use of Pesticides [Food and Agriculture Organization of the United Nations (FAO) 2005], hereafter referred to as the Code of Conduct, and two recent World Health Assembly (WHA) resolutions, WHA 63.25 and 63.26 ]. This is a response rate of 80% of the number of targeted countries  PDFClick here for additional data file."}
+{"text": "Governance and leadership in health development are critically important for the achievement of the health Millennium Development Goals (MDGs) and other national health goals. Those two factors might explain why many countries in Africa are not on track to attain the health MDGs by 2015. This paper debates the meaning of 'governance in health development', reviews briefly existing governance frameworks, proposes a modified framework on health development governance (HDG), and develops a HDG index.et al also does not include macroeconomic and political stability as a separate principle. The Siddiqi et al framework does not propose a way of scoring the various governance domains to facilitate aggregation, inter-country comparisons and health development governance tracking over time.We argue that unlike 'leadership in health development', 'governance in health development' is the sole prerogative of the Government through the Ministry of Health, which can choose to delegate (but not abrogate) some of the governance tasks. The general governance domains of the UNDP and the World Bank are very pertinent but not sufficient for assessment of health development governance. The WHO six domains of governance do not include effective external partnerships for health, equity in health development, efficiency in resource allocation and use, ethical practises in health research and service provision, and macroeconomic and political stability. The framework for assessing health systems governance developed by Siddiqi et al's framework to make it more relevant to the broader concept of 'governance in health development' and to the WHO African Region context.This paper argues for a broader health development governance framework because other sectors that assure human rights to education, employment, food, housing, political participation, and security combined have greater impact on health development than the health systems. It also suggests some amendments to Siddigi A strong case for broader health development governance framework has been made. A health development governance index with 10 functions and 42 sub-functions has been proposed to facilitate inter-country comparisons. Potential sources of data for estimating HDGI have been suggested. The Governance indices for individual sub-functions can aid policy-makers to establish the sources of weak health governance and subsequently develop appropriate interventions for ameliorating the situation. An Editorial in the African Journal of Health Sciences delved into the 'The essence of leadership in health development' . HoweverThe World Health Report 2000  dictionaUnlike stewardship, governance is the sole prerogative of a national government, i.e. the executive policy-making body that exercises political authority over a country. A government through its system(s) rules or governs a country. HarperCollins  dictionaThe United Nations Development Programme (UNDP) five principles of good governance include: legitimacy and voice (participation and consensus orientation), direction (strategic vision), performance , accountability (and transparency), and fairness  .The World Bank's three clusters (with six domains) of governance include: processes by which those in authority are selected and replaced ; ability of government to formulate and implement sound policies (government effectiveness and regulatory burden); and respect of citizens and the state for institutions which govern their interaction (rule of law and control of corruption) .The World Health Report 2000 [The slightly amended World Health Organization  health set al [et al [Siddiqi et al  frameworl [et al  frameworet al [The governance domains of the UNDP and the World Bank are very pertinent but not sufficient for assessment of health development governance. That is understandable since they were developed for assessing general governance. The WHO six domains of governance do not include effective external partnerships for health, equity in health development, efficiency in resource allocation and use, ethical practises in health research and service provision, and macroeconomic and political stability. Siddiqi et al  also doeIn this paper we are arguing for a broader health development governance framework. Why? This is because of the fact that other sectors that assure human rights to education, employment, food, housing, political participation, and security combined have greater impact on health development than the health systems. For example, the significant negative impact of political and macroeconomic instability on health development has been starkly demonstrated in the diminished health indicators of the African countries that have undergone various forms of political and macroeconomic turmoil.et al [et al's framework to make it more relevant to the WHO African Region context.Siddiqi et al  does notet al [Table et al  refers tet al [Third, community participation and responsiveness function has four sub-functions, i.e. participation in NHP and NHSP development process, participation in NHSP implementation, participation in tracking progress in implementation of NHSP, and responsiveness to community's legitimate non-medical expectations -14. Siddet al  principlFourth, effective internal and external partnerships for health function has ten sub-functions, namely: inter-sectoral action ,16, publFive, horizontal and vertical equity in health systems function has three sub-functions, i.e. horizontal equity in access of health services -20, vertEight, evidence-based decision-making function has four sub-functions, i.e. national health research systems ,32; healTen, macro-economic and political stability function is divided into three sub-functions, i.e. link between national economic development plan (NEDP) , PovertyThe health development governance (HDG) framework discussed above has 10 functions and 42 sub-functions. Each of the functions can be measured using a governance thermometer scale of 0% (very poor) to 100% (excellent)  such as leadership responsibilities, existence of health-related legislation, inter-sectoral action, horizontal equity, allocative efficiency, existence of transparent results-oriented reporting and assessment frameworks, bioethics review system, national health research systems, etc.For example, the Leadership Responsibilities index (LR) can be expressed as follows:where LRI is the leadership responsibility index, Actual (LR) is the actual Leadership Responsibility score, Minimum (LR) is the minimum leadership responsibility score, and Maximum (LR) is the maximum leadership responsibility score. For example, assuming the global minimum leadership responsibility score and the global maximum responsibility scores are set equal to 0% and 100% respectively and the actual leadership responsibility score for a hypothetical country in Table The indices for each of the remaining 41 sub-functions can be calculated in a similar manner. And once individual sub-functions indices have been obtained, the overall Health Development Governance Index (HDGI) can be obtained using the following formula:where Since governance is measured on a scale of 0 (or 0%) to 1 (or 100%), the above HDGI of 0.35 implies that the health development governance in this hypothetical country is below average. If instead, the hypothetical country's HDGI was 50%, it would have signified average health development governance. The above formula is similar to that used by the United Nations Development Programme in calculating the Human Development Index . In realThe Governance indices for individual sub-functions can aid policy-makers to locate the sources of poor governance and then to develop appropriate interventions for ameliorating the situation. Those indices could be conducted every two or three years among all countries in the WHO African Region. Therefore, every two or three years, the WHO Regional Committee Ministers of Health from the African Region can have peer review. Since Regional Committee meets every year, there would be no additional cost for organizing the peer review sessions. Such peer review mechanisms would motivate countries to improve health development governance and also share good practises.Countries that choose to estimate the HDGI may need to set up a national multi-disciplinary stakeholder Technical Working Group (TWG) to assess the current status of HDG. In addition, they might consider establishing a Steering Committee (SC) to oversee and facilitate the work. The TWG ought to be made up of appropriately qualified staff from all relevant sectors and programmes that deal with the ten functional domains of HDG. It is critically important for all relevant government sectors , health development partners, civil society organizations, and private health sector to be represented in both the TWG and SC. Wide participation will ensure that the results will be used to improve national HDG.Public health leadership and management: Comprehensiveness of the NHP and NHSP can be assessed by reviewing the two documents against the WHO/AFRO guidelines [Table idelines . The datExistence of health-related legislation can be assessed through review of existing health-related laws. The questions for assessing level of enforcement of health-related legislation may be included in the survey questionnaire for public health leadership and management.Firstly, data for use in assessing the level of community participation in formulation of NHP/NHSP and monitoring their implementation can be generated through administration of a questionnaire among parliamentarians and civic leaders or administrative leaders, e.g. chiefs. Secondly, responsiveness of health service providers to communities' non-medical expectations can be assessed through administration of responsiveness module of the World health survey questionnaire  among saFirstly, data for assessing inter-sectoral action can be generated from in-depth interview with either prime minister's or president's office, depending on who chairs the cabinet. Secondly, review of health-related legislation and interviews with leaders of faith-based and private-for-profits health services providers can yield information on the extent to which legislative and policy environment fosters public-private partnerships.Thirdly, interviews with Ministry of Finance and health development partners could yield information on percentage of aid flows for health development channelled through general government budget support. Fourthly, interviews with ministries of health would yield information on the existence of sector-wide approaches, multi-donor steering committees or equivalent donor coordination mechanisms.th March 2011, about 30 WHO African region countries had reports on the PEFA Secretariat website. Where such information does not exist, there may be need to conduct assessment using the PEFA framework [Fifthly, the Public Expenditure and Financial Accountability (PEFA) initiative  reports ramework .Information on whether there has been sufficient integration of global programmes and initiatives into NHSP can be obtained by conducting interviews with Directors of Policy and Planning at Ministry of Health, health sector focal persons in Ministries of Finance, and country representatives of GAVI and GFATM.The data needed for accountability and transparency in health development should be collected together with that on effective international and external partnership.et al [Estimation of health inequality requires data on health variables (e.g.) and ordinal living standards measure . Equity et al  is an exet al .Malmquist total factor productivity analyses have been carried out in continental Africa national health systems [Estimation of technical efficiency (TE) requires data on quantities of health system inputs, e.g. numbers (or time) of different cadres of health workforce, annual expenditure on pharmaceuticals, annual expenditure on non-pharmaceutical supplies, number of hospital beds; and volume of health service outputs, e.g. number of outpatient curative visits, outpatient preventive visits, community health outreach activities, inpatient admissions, inpatient discharges, and hospital deaths. In order to estimate allocative efficiency (AE), information on average inputs prices is needed in addition to data needed for TE. Calculation of productivity change requires all abovementioned input and output data for a number of time periods, e.g. a number of years. In the African region TE studies have been undertaken in Benin , Burkina systems , Angola  systems , Botswan systems , Seychel systems  and Sout systems . Therefo systems ,64.Firstly, the national health research systems analysis (HRSA) data can be obtained through review of existing HRSA reports. Where such data does not exist, it can be obtained through an assessment of national health research systems using HRSA toolkit -67. SecoData on dissemination of international ethical guidelines for medical practise and health research, bioethics review system, and institutionalization of ethics training should be collated simultaneously with that on HRSA (mentioned above) and using the same toolkit . The modFirstly, the linkage between NEDP, PRSP and NHP/NHSP can be ascertained through a review of those documents. Secondly, a review of Medium-Term Expenditure Framework (MTEF) document will help to determine whether it contains a clear health component derived from NHSP. Finally, a review of the national constitution and in-depth interview with chairperson of the national legal bar association can facilitate identification of the extent to which a non-violent process exists by which those in authority are elected and replaced. This information can be complemented with a review of data on the Economist Intelligence Unit Democracy Index  and the The weak governance and leadership in health development might explain why many countries in Africa are not on track to attain the health MDGs by 2015 ,70,71. TOne of the possible reasons for inadequate governance and leadership in health development in Africa is largely because many health leaders and managers, at various levels of national health systems, were never trained to govern and lead. Thus, whereas they may have had very good training on disease prevention and control, their curricula might not have featured training on governance and leadership. Therefore, there may be need to revise the curricula of schools of public health, medical schools, nursing schools and other schools of health sciences in Africa to reflect the recent developments in health systems performance assessment, including leadership and governance. In addition, leadership and governance should feature prominently in the continuing education programmes for medical and public health practitioners which are organized by the national professional associations .The list of abbreviations include: AE: Allocative efficiency; CTP: Household's capacity to pay; DHS: Demographic and Health Surveys; GAVI: The Global Alliance for Vaccines and Immunization; GFATM: Global Fund to Fight AIDS, Tuberculosis and Malaria; HDG: Health development governance; HDGI: Health Development Governance Index; HDGSFI -Health development governance sub-function index; HE: Household expenditure on health; HFC: Health fairness in financial contribution; HKMS: Health knowledge management systems; HRSA: National health research systems analysis; ICT: Information, communication and technology; LR: Leadership Responsibilities index; LSMS: Living Standards Measurement Study; MDGs: Millennium Development Goals; MICS: Multiple Indicator Cluster Surveys; MTEF: Medium-term expenditure framework; NEDP: National economic development plan; NHIS: National health information system; NHP: National health policy; NHSP: National Health Strategic Plan; PEFA: Public Expenditure and Financial Accountability; PRSP: Poverty Reduction Strategy Paper; SC: Steering committee; TE: Technical efficiency; TWG: Technical Working Group; UNDP: United Nations Development Programme; WHO/AFRO: World Health Organization Regional Office for Africa; and WHS: World Health Surveys.The authors declare that they have no competing interests.JMK and DGK contributed equally to the design, analysis and writing of various sections of the manuscript. Both authors read and approved the final manuscript.JMK has a PhD in economics  from the University of York, UK; MA and BEd in Economics from the University of Nairobi, Kenya; and a Diploma in health economics from the University of Tromso, Norway. DGK holds a MPH from the London School of Hygiene and Tropical Medicine, UK; and a PhD in Public Health from the University of New South Wales, Australia. Currently, JMK works at the World Health Organization, Regional Office for Africa, B.P. 06, Brazzaville, Congo. DGK is CDC/WHO Consultant, P.O. Box 529, Freetown, Sierra Leone."}
+{"text": "The risk of infection and epidemiological surveillance and control of legionellosis depends on the challenges of detecting the Legionella pneumophila DNA in the hospital environment.The aim was to compare the various hospital departments in according to the features of existence of L. pneumophila in the environment of hospitals.We conducted real-time PCR of 963 swabs from 40 objects of the environment, 156 samples of water from the centralized water supply and swimming pools in 27 departments of 10 healthcare setting in the Nizhny Novgorod Region.We have distinguished the following types of the departments.Type 1: territories of high risk of health-care associated legionellosis due to high susceptibility of patients, usage of artificial lung ventilation and moisturing the oxygen and air mixture. It includes intensive care units, surgical, obstetrical departments, operating theaters. Type 1 is characterized by the high contamination of environment by L. pneumophila DNA , by presence of reservoirs \u2013 the oxygen moisturizers and water taps , by a frequent isolation of Legionella pneumophila from water .Type 2: departments with patients suffering from outpatient pneumonias: therapeutic, pulmonological, thoracic departments. They are characterized by the low contamination of environment  and a frequent isolation of L. pneumophila from water .Type 3: departments of high risk of nosocomial legionellosis. They have favorable conditions for L. pneumophila and air-borne mechanism of transmission by means of aerosol-producing facilities. They are balneological departments which have a high contamination of environment ; reservoirs of L. pneumophila such as the Jacuzzi, therapeutic baths and showers ; a rare isolation of L. pneumophila from water .That is, there are different types of hospital departments for the risk of legionellosis depending on the frequency of detection of Legionella DNA the hospital environment, data about patients, their treatment and diagnostics. Different departments require different approaches to organizing and conducting surveillance of legionellosis.None declared"}
+{"text": "One-third or more US adults, and similar numbers elsewhere, use complementary and integrative medicine (CIM). The results of previous systematic reviews of the economic impacts of CIM are limited and now out of date. The purpose of this comprehensive review is to capture and highlight for policy makers what is currently known about the economics of CIM, and to make recommendations for future research.PubMed, CINAHL, AMED, PsychInfo, Web of Science, and EMBASE were searched through December 2010 using a comprehensive search strategy. In addition, bibliographies were searched, and key researchers contacted. All full economic evaluations published 2001-2010 were also subjected to five study quality criteria and one indicator of whether the study\u2019s results were transferable .A total of 340 economic evaluations of CIM were found, of which 206, covering a wide variety of CIM for different populations, were published 2001-2010, and 134 of those were full economic evaluations. Despite the fact that most CIM users utilize more than one type of CIM, almost all (88%) of these studies were of single CIM therapies and only one evaluated coordinated care across CIM and conventional practitioners. Of the recent full evaluations 32 (24%) met all five study quality criteria, and 17 of these also met the minimum criterion for study transferability.This comprehensive review identified a substantial number of economic evaluations of CIM and emerging evidence of cost-effectiveness in at least a few clinical populations. Therefore, instead of more studies, what is actually needed are higher quality studies\u2014both in terms of enhanced study quality  and better transferability (to increase the usefulness of results to other decision-makers in other settings). To this end, eight specific recommendations are made."}
+{"text": "Prevalence of childhood asthma has worldwide increased in recent decades. Different genome-wide studies have identified that more than 100 genes in 22 chromosomes were associated with asthma. Different genetic backgrounds in different environments might modulate the susceptibility of asthma. This has been attributed to industrialized environment such as air pollution and microbial-deprivation ecology that polarize the immune response towards allergy sensitization in perinatal stage. Recently, evidence has shown that allergy sensitization may occur in fetal life, and influence of fetal environment may cause epigenetic programming of diseases in adults. Apparently, asthma is not an exception from the Developmental Origins of Health and Diseases (DOHaD), in which both the pre- and postnatal environments could shape the developmental programming of asthma developed in infancy, childhood, and even adulthood.The association between prenatal environment and disease risk in adults is first demonstrated by Barker showing low birth weight was linked to ischemic heart disease in adult life in 1986 . They alIn this special issue, we included 8 papers depicting effects and potential mechanisms of perinatal environments including intrauterine growth trajectory, maternal exposure of cold and herb medication, perinatal exposure to pets, perinatal gut microbiota, bottle feeding, genetic determinant of cockroach allergy, interaction of parental atopy and genes, and gene-environment interactions on the development of asthma. These papers together have highlighted different epigenetic and genetic effects of perinatal environments and parental genetic backgrounds on the perinatal programming of asthma. As summarized from these articles and shown in Another review article on whether perinatal diets such as vitamins, polyunsaturated fatty acid, protein-hydrolyzed infant formula, or the time and types of complementary foods are protective from the development of asthma is not included in this issue because of its complex controversy and the paper submitted for this issue was not good enough for publication. Neither the hygiene hypothesis for the development of asthma nor the persistence and remission of childhood asthma in adolescents are included in this issue. This guest editor team including K. D. Yang, MD, PhD, from the Department of Medical Research and Development, Show Chwan Health Care System, Taiwan; S.-K. Huang, PhD, from Johns Hopkins Asthma Center, Johns Hopkins University, Baltimore, USA; H.-J. Su, PhD, from Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan; J. Abe, M.D., Ph.D., from the Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo, Japan anticipates that another issue of perinatal programming of asthma including advances in the knowledge of DOHaD depicting influence of nutrition and hygiene on the development and remission of asthma will come not far in order to provide a prospect for early prediction and prevention of childhood asthma."}
+{"text": "All models harbor mutations in relevant tumor suppressors and/or cell-type specific expression of potent oncogenes, which initiate de novo carcinogenesis in the targeted tissues. In all these models deletion of cathepsin B led to suppression of the aggressiveness of the respective cancer phenotype. Cathepsin B is networking with other proteases as it was shown for cathepsin X/Z. In contrast, deletion of cathepsin L was beneficial in the RiP1-Tag2 model, but enhanced tumorigenesis in the APCmin, and the K14-HPV16 mice. A logical consequence of these results would be to further pursue selective inhibition of cathepsin B. Moreover, it became clear that cathepsins B and S derived from cells of the tumor microenvironment support cancer growth. Strikingly, delivery of broad spectrum cysteine cathepsin inhibitors in the tumor microenvironment disrupts the permissive ecosystem of the cancer and results in impaired growth or even in regression of the tumor. In addition, combination of cysteine cathepsin inhibition and standard chemotherapy improves the therapeutic response of the latter. Taken together, the next preclinical challenges for developing cathepsin inhibition as cancer therapy might be the improvement of inhibitor selectivity and targeted delivery to the tumor microenvironment and investigation of the biological context of the individual factors within the complex proteolytic network.Lysosomal cysteine cathepsins belong to a family of 11 human proteolytic enzymes. Some of them correlate with progression in a variety of cancers and therefore are considered as potential therapeutic targets. Until recently, the contribution of individual cathepsins to tumorigenesis and tumor progression remained unknown. By crossing various types of mouse cancer models with mice where specific cathepsins have been ablated, we contributed to this gap of knowledge and will summarize the results in this report. The employed models are the Rip1-Tag2 model for pancreatic neuroendocrine tumors, the K14-HPV16 model for squamous skin and cervical cancers, and the MMTV-PyMT model for metastasizing breast cancer, the KPC model for pancreatic ductal adenocarcinoma, and the APC Cysteine cathepsins are papain-like peptidases of which cathepsin B, C, F, H, L, K, O, S, V, W, X/Z have been identified in the human genome and are well defined in molecular, biochemical, and structural terms  have been used to study the role of cathepsins in early stages of intestinal neoplasia (Moser et al., The focus of this review are studies, in which cathepsin knock-out or transgenic mice with overexpression of cathepsins have been crossed with transgenic mouse models of Hanahan, , the K14Hanahan, , and theHanahan, . All thrmin mice reduced formation of intestinal neoplasia (Gounaris et al., de novo tumorigenesis showed consistently that cathepsin B is a tumor-promoting protease and, therefore, a potential therapeutic target.Accumulating clinical and experimental data indicate that cathepsin B is a cancer-promoting protease (Poole et al., furless mice, which harbor a spontaneous active site mutation of cathepsin L, with APCmin mice increased the multiplicity of premalignant intestinal polyps significantly (Boudreau et al., min and K14-HPV16 models is an impressive example for the context-dependent consequences of a gene knock-out (Kruger, Single deficiencies for cathepsins B, L, S, and H perturbed the development of Rip1-Tag2 pancreatic islet cancers, while deletion of cathepsin C did not affect tumor progression in this model (Gocheva et al.,  Kruger, . The rea Kruger, . The relThe active roles of the tumor microenvironment in carcinogenesis and tumor progression have attracted considerable attention during the past decade. It emerged that tumor-promoting inflammation and induction of angiogenesis are hallmark characteristics of activated tumor stroma (for review, Hanahan and Weinberg, Overexpression and extracellular re-dislocation of cysteine cathepsins have been associated with multiple stages of tumorigenesis and tumor progression (Vasiljeva et al., Despite the important role of tumor cell-derived cathepsins in cancer progression, there is an increasing body of evidence confirming the up-regulation of cysteine cathepsins by macrophages in the tumor microenvironment, such as macrophages (Mohamed and Sloane, Taken together, the accumulated evidence in the literature strongly supports the concept of the use of cathepsins, in particular cathepsin B, as targets for cancer therapy targets. Therefore, inhibitors with improved pharmacokinetic properties and improved selectivity, possibly combined with appropriate delivery systems, and their use in combination with established chemotherapeutic treatment strategies, will have the potential to become valuable therapeutics for the treatment of metastatic malignant disease in the clinic.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Purpose of the study is to define the role of conventional radiology and MRI in the evaluation of pelvic floor hernias in female pelvic floor disorders.A MEDLINE and PubMed search was performed for journals before March 2013 with MeSH major terms 'MR Defecography' and 'pelvic floor hernias'.The prevalence of pelvic floor hernias at conventional radiology was higher if compared with that at MRI. Concerning the hernia content, there were significantly more enteroceles and sigmoidoceles on conventional radiology than on MRI, whereas, in relation to the hernia development modalities, the prevalence of elytroceles, edroceles, and Douglas' hernias at conventional radiology was significantly higher than that at MRI.MRI shows lower sensitivity than conventional radiology in the detection of pelvic floor hernias development. The less-invasive MRI may have a role in a better evaluation of the entire pelvic anatomy and pelvic organ interaction especially in patients with multicompartmental defects, planned for surgery. Pelvic floor disorders represent a significant cause of morbidity and reduction in quality of life that appear to be increasing in frequency during the last few years . PregnanPelvic floor disorders may be associated, with an incidence ranging from 18% to 45%, to the so-called midline pelvic floor sagittal hernias (MPH) that represent the herniation of the peritoneum and/or peritoneal viscera in the Douglas', Retzius', and retrorectal spaces.Although anamnestic and physical examination represents the first approach in the evaluation of the patients with pelvic floor dysfunction, the diagnostic limitation of the pelvic examination alone has led to the need to use more direct and comprehensive diagnostic methods -6.Purpose of the study is to define the role of conventional radiology and MRI in the evaluation of pelvic floor hernias.A MEDLINE and PubMed search was performed for journals before March 2013 with MeSH major terms 'MR Defecography' and 'pelvic floor hernias'. Non-English speaking literature was excluded.Entero-colpo-cysto-defecography (ECCD) is considered the gold standard for the evaluation of the patients with pelvic floor disorders and diagnosis of MPH -9. For tMRI Defecography should be performed on 1.5-T closed magnet using a body-phased-array receiver coil. To ensure an adequate bladder filling, all patients are invited to drink 500-700 ml of water 10-15 min before the examination. The rectum and vagina should be filled with 200 mL and about 25-30 mL , respectThe reference line used for conventional radiology and MRI is the Pubococcygeal line (PCL), extending from the most inferior portion of the symphysis pubis to the tangent of the sacrococcygeal joint.The diagnosis of descent of the bladder, vagina, and rectum is based on measurement of the verticaldistance between the PCL and the bladder base, the vaginal vault, and the anorectal junction, respectively.According to Yang's classification , the limRectocele could be defined as an out-pouching of the anterior rectal wall occurring during evacuation or straining -17 Figu.Pelvic floor hernias could be classified, basing on the content, into enterocele, omentocele, and sigmoidocele, whereas, according to the hernia development they could be classified as elytrocele, edrocele, retrorectal, and Douglas' and Retzius' hernias  Figure .Enterocele, sigmoidocele, and omentocele represent the herniation below the proximal  one third of the vagina of the peritoneal sac containing ileal loops, part of the sigmoid, or peritoneal fat, respectively -21. If tOn evaluation of conventional radiology, the diagnosis of an enterocele/ sigmoidocele/omentocele is made if the picture obtained during evacuation compared with that during rest showed an increase in the distance between the vagina and rectum Figure .This expansion should extend below the PCL reference line and shows a sagittal diameter of more than 2 cm.Anyway, the distinction between sigmoidocele, enterocele, and omentocele is made basing on the presence of contrasted small bowel in the expanded recto-vaginal space for the enterocele, on the presence of distinguishable bowel gas bubbles without contrast for the sigmoidocele alone, and on the absence of contrasted small bowel and bowel gas bubbles in the expanded recto-vaginal space, for the omentocele.-28On MRI-defecography, the relationship between the lowest point of the peritoneal border line and the PCL should be assessed. A descent of parts of the peritoneal content below this line and the identification of herniated contents allowed the distinction in enterocele, sigmoidocele, and omentocele . The herIn our experience, the specificity of MRI versus conventional radiology is of a 100%; the sensibility of MR-D in the detection of an omentocele, sigmoidocele, and enterocele is, respectively, 95%, 82%, and 65%, showing an inferior diagnostic capacity if compared with conventional radiology ,30. The In conclusion, MRI defecography shows lower sensitivity than coventional radiology in the detection of pelvic floor hernias. The diagnostic efficacy of conventional radiology is significantly higher than that of MRI Defecography in the detection of both hernia content (enteroceles and sigmoidoceles) and hernia development .However, the less-invasive MRi defecpgraphy may have a role in a better evaluation of the entire pelvic anatomy and pelvic organ interaction especially in patients with multicompartmental defects, planned for surgery .The authors declare that they have no competing interests.AR: conceived the study, analyzed and interpreted the data, drafted the manuscript.GDG: conceived the study, critically revised the manuscript.GG: critically revised the manuscript.FI: critically revised the manuscript.CR: critically revised the manuscript.MG: analyzed the data and critically revised the manuscript.FC: analyzed the data and critically revised the manuscript.LB: conceived the study, analyzed and interpreted the data, critically revised the manuscript.All authors read and approved the final manuscript.AR: Post-Doctoral Fellow in Radiology at Second University of NaplesGDG: Resident in Radiology Training Program at Second University of NaplesGG: Assistant Professor of Radiology at Second University of NaplesFI: Resident in Radiology Training Program at Second University of NaplesCR: Resident in Radiology Training Program at Second University of NaplesMG: Associate Professor of Radiology, University of FerraraFC: PhD Student at University of PalermoLB: Full Professor of Radiology, University of Molise"}
+{"text": "With its increasingly large pool of expertise across 19 countries including 13 EU member states, Australia, Canada, China, Norway, Thailand and the USA, the consortium provides forums and collaboration platforms on quality control, extraction technology, component analysis, toxicology, pharmacology and regulatory issues of Chinese herbal medicine (CHM), as well as on acupuncture studies, with a particular emphasis on the application of a functional genomics approach. The project officially started in May 2009 and by the time of its conclusion in April 2012 a Europe-based academic society dedicated to TCM research will be founded to carry on the mission of GP-TCM.Traditional Chinese medicine (TCM) is widely used in the European Union (EU) and attracts intense research interests from European scientists. As an emerging area in Europe, TCM research requires collaboration and coordination of actions. Good Practice in Traditional Chinese Medicine Research in the Post-genomic Era, also known as GP-TCM, is the first ever EU-funded 7 Traditional Chinese medicine (TCM), especially Chinese herbal medicine (CHM) and acupuncture, is an ancient medical system used in China and other Asian countries for thousands of years ,2. In cost May 2009. This is a three-year coordination action project funded under the EU Seventh Framework Programme (FP7) with a total budget of \u20ac995,100. The central hypothesis of the consortium is that, using functional genomics technology, which allows high-content observations of whole profiles of molecules at different levels, eg DNA, mRNA, protein and metabolites, and furthermore linking them to clinically relevant biological functions, we might be in a better position than ever before to interpret and validate the scientific value of TCM in a holistic and function-oriented manner [The Good Practice in Traditional Chinese Medicine Research in the Post-genomic Era (GP-TCM) consortium was launched by the European Commission on the 1d manner -11.Focusing on research of CHM and acupuncture, we especially emphasise studies of CHMs, their complex chemical ingredients and their holistic impact on the functional genomics of patients. The overall aim of the consortium is to inform the best practice and harmonise research on the safety and efficacy of TCM using a functional genomics approach through exchange of opinions, experience and expertise among scientists in EU member states, China and other parts of the world. Specifically, we aim to undertake the following objectives:\u2022 Develop a European-Chinese network, collaborating on functional genomics research of TCM;\u2022 Review current practice of TCM research, identify problems and propose solutions;\u2022 Propose standard protocols of methodology;\u2022 Propose priority areas for future research;\u2022 Develop online resources to support and enhance pan-European studies of TCM research;\u2022 Facilitate and foster a sustainable European collaboration by founding a European society dedicated to TCM research.in vitro and in vivo pharmacology (WP4-WP5), clinical studies (WP6), as well as international regulatory issues of CHM (WP7). WP9 is dedicated to organising the Final Conference of the consortium at the end of the project and WP10 is charged to manage consortium-wide matters, such as appointment and coordination of WP leadership, recruitment of additional experts, editing website and newsletters, drafting standard operating procedures, providing scientific and technological support and guidance, organising internal review and quality assurance, as well as liaising with the Commission and other stakeholders and external authorities.As shown in Figure ie funded) partner organisations across ten EU member states  and China, which is an International Cooperation Partner Country (ICPC) of the EU. The consortium has additional 60 non-beneficiary (ie unfunded) collaborating partner organisations as well as two independent experts from Australia, Austria, Belgium, China, Denmark, Finland, Germany, Italy, Luxembourg, the Netherlands, Norway, Thailand, the UK and the USA , the management team (WP10) has coordinated a highly successful team build-up and re-construction. With the ever-strengthening expertise pool, WP10 has developed a number of committees and panels that lead the consortium with clear divisions of labour. WP10 has led the design and updates of the professional GP-TCM website and all WPs have established their homepages and online discussion facilities. Periodic newsletters have enabled members to share information and stay as a united team. Significantly, a series of face-to-face meetings, including consortium and WP kick-off meetings and the 1paozhi (processing) in the production of CHM. WP3 produced a list of toxic plants for further literature study and identified 3 major fields of action: (i) investigation of methods  applicable to toxicity evaluation; (ii) study of toxicological reports available on a series of CHM; (iii) review of pharmacovigilance safety data. WP4 established evaluation criteria for scoring scientific articles and began the creation of an appropriate database of literature encompassing functional genomic applications in CHM research. WP5 performed reviews on CHM literature involving animal models, especially models of cancer and its conclusions have laid a solid foundation for further literature analysis on application of functional genomics in CHM research and proposing good practice in animal studies of CHM. WP6 gathered literature on seminal studies in clinical CHM studies and drafted a guideline on clinical trials of CHM. WP6 and WP8 collaboratively designed an online survey targeting TCM practitioners and the survey is currently undergoing in collaboration with 30 professional acupuncture and TCM organisations. WP7 brought together wide-ranging experiences and expertise in drug development and registration from Europe, China, Australia and North America to discuss the legislative and regulatory issues relevant to CHM. Together they are developing a comprehensive document providing comparisons of different practices on CHM regulations and this will be extremely helpful for the EU to develop its future policies and for companies to develop products for the global market. WP9 discussed the time and format of the Final Conference and preliminary bookings of venue has been made.Noteworthy WP-specific achievements are as follows. WP1 led the creation of a list of nearly 300 species of plants and fungi commonly used in TCM in Europe and China and a priority list of 11 species will be used by all WPs in their initial literature analysis. WP2 worked jointly with WP1, linking quality control, extraction technology and chemical analysis, with special emphasis on the important role of The major difficulty encountered by the consortium is unsurprisingly the language barrier. There is a lack of accessibility to original Chinese publications in Europe, and even if they are available, fast and accurate translation of these materials is impossible, preventing the consortium from extensively studying classic Chinese medical literature and evaluating a great deal of modern Chinese medical literature. While we strongly encourage our members to master both English and Chinese languages, we welcome members from various linguistic, ethnic and cultural backgrounds to work in close collaboration.As the first ever EU-China collaborative consortium dedicated to TCM research, we will continue to promote EU-China dialogues and collaborations in this important emerging supra-disciplinary area. As a network of principal investigators, we will collaborate to train the next generation of scientists who are more comprehensively equipped to study complex drugs such as CHM and personalised medicine such as TCM. As a coordination action involving much literature review and evaluation, we acknowledge the huge importance of good practice in scientific publication and will continue to support open-access publications.As an EU-China collaboration dedicated to TCM research, we are keen to incorporate ourselves into the worldwide landscape of TCM research community and serve as a constructive member. We sincerely support the international TCM community to bundle forces to improve TCM research funding from both the public and private sectors and to help shape the medicine of tomorrow together.CGCM: Consortium for Globalisation of Chinese Medicine; CHM: Chinese herbal medicines; EU: European Union; FP7: Seventh Framework Programme; GP-TCM: Good Practice in Traditional Chinese Medicine Research in the Post-genomic Era; ICPC: International Cooperation Partner Country; ISCM: International Society for Chinese Medicine; TCM: Traditional Chinese medicine; WFCMS: World Federation of Chinese Medicine Societies; WPs: work packages.The authors declare that they have no competing interests.The authors are the Project Manager (HU), the Coordinator (QX), Deputy Coordinators  and Assistant Coordinator (HE) of the GP-TCM Consortium. HU and QX jointly drafted the manuscript. All named authors took part in the revision and approved the final version of the paper."}
+{"text": "Efforts to engage traditional, complementary, and alternative (TCA) health providers in the public health workforce are gaining increasing attention in India. Evidence from studies evaluating the efforts to integrate TCA health providers into the formal public health system highlights numerous lacunae in policy and practice. This study was undertaken to diagnose operational and ethical challenges in the implementation of current policies for integration of TCA health providers in order to derive lessons to strengthen integration strategies.We used qualitative data collection methods and an interpretive policy analysis approach in three states of India: Kerala, Delhi, and Meghalaya. Health policy documents, including bills, acts, orders, inter-institution communications, and publicly available material on TCA health providers, were examined. We also carried out direct observations of healthcare delivery facilities to map the workings of the health system in each of the study states. In-depth interviews were conducted with a range of stakeholders, including policy elites, health administrators, TCA health providers and allopathic (modern medicine) providers appointed in government health facilities, local traditional healers, community health workers, village elders, opinion leaders, and representatives of community organizations. Interviews explored the stakeholders\u2019 experiences and perceptions related to their roles, job responsibilities, and interactions with the various players in the health system. While 73 in-depth interviews were conducted in Kerala and 46 in Meghalaya, data collection is ongoing in Delhi. Further data collection is also planned in Kerala and Meghalaya.Major hurdles in mainstreaming of TCA health providers in essential health service delivery include absence of, or limited, formal communication and coordination between actors representing different systems of medicine; diverse levels of collegiality, ranging from hostility to harmony; and dissonance between the expectations placed on TC.A health providers and the amenities provided to them. Further observations included contestations by different strata of actors on validity and reliability of medical evidence from alternative systems; lack of coherence in the range of medical evidence across different systems of medicine; and weak conformance by state to the national policy in certain states, and limited action in communicating policy directives across the systems of medicines. Conflicting loyalties, to systems of medicine, patients, and the public health system, emerged as a key finding in the experiences and perceptions of TCA health providers in one state. Local health traditions implemented through family-based practice, although acknowledged as resonating deeply with the local culture, were found to have little, if any, place in the official health system. These gaps are compounded by the limited opportunities for formal collaborative work across different systems of medicine.Preliminary findings suggest that on the one hand, national policy articulations are not adequately translated into the state context. On the other hand, these articulations leave unresolved larger ethical questions of validity and reliability of evidence, and inter-system coherence that could more concretely support integration efforts. There is a profound need to understand and amend state-specific health governance processes and institutional capacities, and engender receptivity in mainstream health systems to alternative approaches, for the evolution of a truly integrated workforce for health services in India and other low- and middle-income countries. This may require institutionalizing incentives and opportunities for routine interaction between practitioners across systems of medicine in training, and ideally, in practice.Members of the research team for this study included allopathic (modern medicine) and homoeopathic doctors.This study was funded by the Wellcome Trust Capacity Building Large Research Grant (No. F012/RG/KS/02)."}
+{"text": "Geographic information systems (GISs) with emerging technologies are being harnessed for studying spatial patterns in vector-borne diseases to reduce transmission. To implement effective vector control, increased knowledge on interactions of epidemiological and entomological malaria transmission determinants in the assessment of impact of interventions is critical. This requires availability of relevant spatial and attribute data to support malaria surveillance, monitoring, and evaluation. Monitoring the impact of vector control through a GIS-based decision support (DSS) has revealed spatial relative change in prevalence of infection and vector susceptibility to insecticides and has enabled measurement of spatial heterogeneity of trend or impact. The revealed trends and interrelationships have allowed the identification of areas with reduced parasitaemia and increased insecticide resistance thus demonstrating the impact of resistance on vector control. The GIS-based DSS provides opportunity for rational policy formulation and cost-effective utilization of limited resources for enhanced malaria vector control. In Sub-Saharan Africa, malaria remains a major cause of morbidity and mortality . Its traSince malaria distribution is not homogeneous, much effort needs to be expended towards defining local spatial distribution of the disease  precedenWhile vector control interventions are being deployed according to the World Health Organization-led Integrated Vector Management Straandtegy , 13, 14,Until recently, very few malaria endemic countries had incorporated the GIS technology into operational malaria control programmes, that is, in South Africa and the Lubombo Spatial Development in Mozambique in Southern Africa, where it has been harnessed for case mapping and monitoring of vector control coverage , 19. In An. gambiae s.s, An. arabiensis, and An. funestus, including the comparative impact of main stream vector control interventions, has been conducted in Zambia.The integration of operational and logistical data for malaria control program planning with epidemiological data will serve to strengthen both the epidemiological analysis and the planning and execution of control programs. GIS facilitate the integration of quantitative malaria determination and control data with data obtained from maps, satellite images, and aerial photos. A comprehensive review of data collected through nationally representative malaria indicator surveys and insecticide resistance data in major malaria vectors: 2 (Syngenta and Bayer) and DDT at 2\u2009g/m2 (Avima) at the beginning of the peak malaria transmission period ..32].ad hoc basis driven by limited empirical evidence and undoubtedly resulting in misdirection of the limited resources available.Given the spatial heterogeneity in the distribution of malaria vectors and variations in the inherent malaria risk, GIS has potential applications in deployment and monitoring of interventions. For resource-constrained malaria-endemic Sub-Saharan African countries, like Zambia, the need for a GIS-based malaria information system cannot be overemphasized. Until recently, decisions in the malaria control programmes were taken on an Following the increased funding for malaria control  particulThe use of GIS in Zambia has enabled detection of spatial trends of parasite prevalence following extensive deployment of front line vector control interventions. Cross-sectional prevalence surveys show continuous prevalence increase in children from 2008 to 2010 in Chongwe district. In Kapiri mposhi, Mumbwa, Mazabuka and Kafue districts, prevalence dropped between 2008 and 2009 but increased in 2010. However, progressive reduction in malaria prevalence was detected in Monze, Kabwe, and Chibombo districts from 2008 through to 2010 .The GIS has introduced new dimensions to the understanding, prediction, analysis, and dissemination of spatial relations between disease, time, and space , 44. It An. funestus. At Myooye and Chimoto, ITN deploying sites with high kdr mediated crossresistance to pyrethroids and DDT in An. gambiae s.s, prevalence was reducing and remained at a low level across the three years. However, Rufunsa, another ITN deployment area with high pyrethroid resistance in An. funestus, exhibited constant increase in parasitaemia despite high coverage of ITNs (There was great heterogeneity in prevalence of malaria at sentinel sites relative to detected insecticide resistance in malaria vectors. At Chibombo, prevalence has been reducing despite high pyrethroid resistance detected in  of ITNs . The usefulness of a GIS-based DSS for planning and managing control programmes is dependent on the availability of accurate and raw data on malaria transmission-related parameters. Monitoring and evaluation of malaria interventions and understanding of their true impact on disease burden is essential for measuring performance of a control programme. An effective system for monitoring and evaluation and continuous surveillance requires integration of spatially and temporally explicit data for entomological and epidemiological outcome indicators. This allows for identification of disease prevalence, planning of effective interventions, assessments of reduction of vector exposure and malaria burden resulting from implemented control measures. Continuous surveillance capturing real time data enables routine monitoring and evaluation of programme to demonstrate goals and impact on malaria burden. This is essential to increasing the efficiency and effectiveness of malaria control efforts . The effEffective implementation and monitoring and evaluation of malaria control interventions have resulted in redefinition of stratification of the country in three epidemiological zones for malaria transmission potential in Zambia , 45. ThiIn this case, the GIS-based DSS has not only streamlined evidence-based implementation of interventions, but has improved the tracking of entomological indicators: species characterization and insecticide resistance status, including parasite prevalence and impact assessment of ITNs and IRS. It has been greatly valuable in enabling the display of heterogeneities in malaria risk areas within low transmission intensities , 46, 47.The impact of main thrust vector control interventions on parasite prevalence in children between 1\u201314 years of age has been monitored through annual malaria surveys for three consecutive years at 19 sentinel sites . The useAlthough routine surveillance data have proved inadequate for monitoring control programmes , and havThe ability of GIS-based DSS to deal with large data sets and to incorporate satellite images increases the feasibility of studying transmission determinants of malaria and has resulted in prompt availability of data to support surveillance and policy formulation. The epidemiological mapping of high-risk areas of malaria transmission and insecticide resistance profiles of major vectors has facilitated the recognition of those populations and geographic areas where it is possible to identify the main determinants of malaria morbidity and mortality. The revealed trends and interrelationships have allowed the identification of high risk areas and facilitated decision making and rational utilization of limited resources in a cost-effective manner.In Zambia, an evidence-based decision support has created a more focused and purposeful approach to directing resources to areas of most need with reasonable returns for effort and resources invested. Monitoring the impact of malaria vector control interventions through the GIS-based DSS on relative change in prevalence of infection and vector susceptibility to insecticides over time has enabled measurement of spatial heterogeneity of trend or impact. The revealed trends and interrelationships have allowed the identification of areas with reduced parasitaemia and increased insecticide resistance thus demonstrating the impact of vector control. Targeting interventions based on entomological and epidemiological evidence have not only contributed markedly to the success of the Zambian Malaria Control Programme, but also have provided opportunity for rational decision making in deployment of interventions and cost effective utilization of limited resources for enhanced malaria control."}
+{"text": "High risk prescribing can compromise independent wellbeing and quality of life in older adults. The aims of this project are to determine the prevalence, risk factors, clinical consequences, and costs of high risk prescribing, and to assess the impact of interventions on high risk prescribing in older people.The proposed project will utilise data from the 45 and Up Study, a large scale cohort of 267,153 men and women aged 45 and over recruited during 2006\u20132009 from the state of New South Wales, Australia linked to a range of administrative health datasets. High risk prescribing will be assessed using three indicators: polypharmacy (use of five or more medicines); Beers Criteria ; and Drug Burden Index (a pharmacologic dose-dependent measure of cumulative exposure to anticholinergic and sedative medicines). Individual risk factors from the 45 and Up Study questionnaire, and health system characteristics from health datasets that are associated with the likelihood of high risk prescribing will be identified. The main outcome measures will include hospitalisation ; admission to institutionalised care; all-cause mortality, and, where possible, cause-specific mortality. Economic costs to the health care system and implications of high risk prescribing will be also investigated. In addition, changes in high risk prescribing will be evaluated in relation to certain routine medicines-related interventions. The statistical analysis will be conducted using standard pharmaco-epidemiological methods including descriptive analysis, univariate and multivariate regression analysis, controlling for relevant confounding factors, using a number of different approaches.The availability of large-scale data is useful to identify opportunities for improving prescribing, and health in older adults. The size of the 45 and Up Study, along with linkage to health databases provides an important opportunity to investigate the relationship between high risk prescribing and adverse outcomes in a real-world population of older adults. In older adults, high risk prescribing can be defined as prescribing likely to lead to adverse clinical outcomes or prescribing that does not align with quality use of medicines principles. A range of indicators have been proposed to quantify high risk prescribing in older people. These include multiple medication use or polypharmacy, potentially inappropriate prescribing and exposure to high risk medicines, measured using different risk assessment tools.Although the concomitant use of multiple medicines is often indicated in the treatment and prevention of health problems, polypharmacy is generally considered as high risk prescribing in older adults, and is associated with increased risk of harm -3, incluHigh risk prescribing also includes potentially inappropriate prescribing, defined as the use of medicines whose potential harms to older adults may outweigh the benefits . PotentiHigh risk prescribing may also encompass exposure to \u201chigh-risk\u201d medicines such as those with anticholinergic and sedative properties. A number of anticholinergic and/or sedative scores have been developed to capture the cumulative exposure to these pharmacological classes . One sucStrategies to reduce high risk prescribing, including pharmacist-conducted medication reviews, educational interventions and policy approaches, have been trialled in older adults -22. HoweThe current evidence from pharmaco-epidemiological studies suggests that high risk prescribing increases the risk of adverse outcomes in older adults ,2. Howev1) Estimate the prevalence of high risk prescribing;2) Investigate the risk factors for high risk prescribing;3) Quantify the relationship of high risk prescribing to adverse health outcomes;4) Determine whether associations between high risk prescribing and adverse outcomes vary according to individual and/or health care system specific factors;5) Calculate the economic cost and implications of high risk prescribing to the health care system;6) Investigate whether certain routine medicines-related interventions, including the Home Medicines Review and Chronic Disease Management are associated with reductions in high risk prescribing.The proposed cohort analysis will utilise a population-based dataset combining self-reported questionnaire data  linked to routine administrative health datasets. This project will utilise the following data sources: the 45 and Up Study baseline questionnaire; the Australian Commonwealth Medicare Benefit Scheme (MBS) claims data, Pharmaceutical Benefit Scheme (PBS) claims data, Aged and Community Care Management Information System (ACCMIS) database, National Death Index; and New South Wales (NSW) datasets including the Admitted Patients Data Collection (APDC), and the Register of Births, Deaths and Marriages Figure\u2009.The 45 and Up Study cohort includes 267,153 men and women aged 45 and over from the state of NSW, Australia, randomly sampled from the Medicare Australia database . ParticiMBS and PBS are part of the Australia's national health insurance arrangements . These sst 2012) towards the cost of their medicines. Since all PBS medicines cost more than the concession card holder threshold, they will always attract a Commonwealth subsidy. Therefore medication data from concession card holders are captured consistently in the PBS database. However, the co-payment threshold for general beneficiaries is $35.40 (as at January 1st 2012). There are a range of PBS-listed medicines that cost less than this co-payment threshold. When these medicines are dispensed to a general beneficiary, the general beneficiary is required to pay the full cost of the medicines and the government does not contribute to payment. Consequently, PBS-medicines falling below the co-payment were not captured in the PBS database for general beneficiaries. However, following a policy change, since April 2012 the PBS database now captures all PBS-dispensed medicines, regardless of whether the government contributes to the payment. To manage the potential incomplete capture of PBS-listed medicines dispensed to general beneficiaries we will restrict our analysis to healthcare concession card holders. Recent estimates indicate that over 90% of individuals aged 65\u2009years and over hold a government health care concession card [The PBS database contains information on Commonwealth subsidised claims for prescribed medicines listed on the Schedule of Pharmaceutical Benefits. There are two main groups of PBS beneficiaries, concession card holders and general beneficiaries. The PBS database records only PBS-listed prescription medicines that attract a government subsidy. Concession card holders are required to contribute a co-payment of $5.80  routinely links identifying details  from 45 and Up Study participants to those from the NSW APDC and death records, to provide regular updates to events in the cohort. This is a part of an established program of linkage. Records are matched probabilistically using privacy-preserving current best practice with software , an algoMedication exposure will be measured using the 45 and Up Study predominantly using PBS dispensing data, validated and calibrated against self-reported medication use from the 45 and Up Study questionnaire. As the PBS database does not capture private prescriptions, medicines dispensed to public hospital inpatients, over-the-counter medicines and many complementary and alternative medicines, the extent to which PBS data reliably categorise high risk prescribing is not known. The authors are currently conducting the validation projects to estimate the extent and implications of any under-ascertainment of high risk prescribing using PBS data, compared with self-reported measures from the 45 and Up baseline questionnaire.High risk prescribing will be defined using three indicators: polypharmacy; Beers Criteria; and DBI. Polypharmacy will be defined as the concurrent dispensing of five or more medicines  over a sThe DBI, a measure of exposure to drugs with anticholinergic or sedative effects will be calculated using the equation ,D is the daily dose, and \u03b4 is the minimum efficacious dose , an estimate of the dose required to obtain 50% of the maximal effect. The daily dose will be estimated from the total quantity dispensed, using a standard pharmaco-epidemiological approach [where approach , by multapproach . The minData on individual risk factors from the 45 and Up Study questionnaire , and health system characteristics from linked data  will be obtained to identify factors associated with the likelihood of high risk prescribing.Data on a range of clinical outcomes will be obtained, including: hospitalisation ; all-cause mortality; and, where possible, admission to institutionalised care and cause-specific mortality. Follow-up will be from the date of recruitment, to the last available data on hospitalisation, death or institutionalisation, whichever occurs first. The 45 and Up Study recruitment was from February 2006 to April 2009, giving a range of follow-up duration of 2\u20135\u2009years, by end 2012 (accounting for linked data delays).Changes in high risk prescribing will be evaluated in relation to two health interventions: the Home Medicines Review , and theThe cost analysis will be undertaken from a health system perspective. Total annual health system costs will be estimated overall and for each type of health care resource utilisation for each individual in the 45 and Up Cohort, based on their hospital, Medicare and pharmaceutical utilisation data. Costs will be assigned to each type of resource utilisation based on standard Australian sources . Differences in total and average annual costs will be estimated for the high-risk and non-high risk prescribing groups using each of the definitions of high risk prescribing. Covariates will be included in the cost equations and interacted with a dummy variable for the high risk prescribing group. Differences in total health care costs and for each type of health care resource utilisation will be estimated.The statistical analysis will be conducted using the standard pharmaco-epidemiological methods including descriptive analysis, univariate and multivariate regression analysis , time-varying methods, and controlling for relevant confounding factors using a number of different approaches .To answer the first study objective, analysis will be performed to calculate the high risk prescribing indicators, using the 45 and Up Study cohort, linked to PBS data and restricted to concession card holders. The patterns of high risk prescribing will be summarised using proportions and means. To answer the second and third objectives, analysis will be performed to identify individual and health system based risk factors for high risk prescribing, using the same dataset in aim one. Univariate and multivariate analysis with relevant covariates will be used to quantify the risk for high risk prescribing compared to age and gender-matched controls. Using the same dataset, linked to other data sources, we will investigate the relationship of high risk prescribing indicators with hospitalisations, deaths and institutionalisation, allowing for a range of factors. Analysis related to the fourth objective \u2013 calculation of the economic costs and implications of high risk prescribing to the health care system \u2013 will be performed as outlined in the previous section. To answer the fifth objective, we will perform the analysis to evaluate the possible impact of policy-related interventions on high risk prescribing. In particular, we will compare the rates of high risk prescribing in participants with and without these interventions and the incidence of high risk prescribing before and after each of these interventions, within individuals.before and after the intervention.Using data available to the end of 2012, the project will be highly powered for the main outcomes, with the ability to detect a minimum relative risk of death (the least common outcome) of 1.12, for each of the three high risk prescribing indices  ,15, at 5This study has been approved by the NSW Population and Health Services Research Ethics Committee . In addition, the 45 and Up Study also has overarching in principle ethical approval for data linkage from the University of New South Wales Human Research Ethics Committee , Sydney, Australia and the Department of Health and Ageing, Ethics Committee .The baseline characteristics of the 45 and Up study participants, and concession card holders are presented in Table\u2009High risk prescribing is a term used to describe a pattern of prescribing, which, for theoretical or empirical reasons, has been linked with adverse outcomes in older people. Identifying strategies to minimise high risk prescribing in older people requires a reliable evidence base on the magnitude of the problem and the relationship of high risk prescribing to adverse health outcomes, as well as the effectiveness of routine interventions to improve quality use of medicines. The Australian health system is well suited to this, because of a rich collection of large population-based and administrative databases. The size of the 45 and Up Study, along with linkage to routine health data will allow investigation of the relationship between high risk prescribing and adverse outcomes at the population level, including exploration of confounding, effect modification and intervention effects. In addition, opportunities to utilise other population-based datasets, including general PBS population and Department of Veteran Affairs\u2019 data will also be explored.It should be noted that the administrative datasets are not collected specifically to describe patterns of medicine utilisation or medical care and there are some important limitations to this cohort analysis, including generalisability, validity of data, bias and causality issues. Cohort studies often involve selected groups and produce results based on internal comparisons within the cohort. Theoretical and empirical work have shown these internal comparisons to be valid and reliable ,38, inclWhile the gold standard for evaluating the causal effects of medicines on clinical outcomes is the randomised controlled trial, randomising older individuals to high risk prescribing would be inappropriate. Therefore, observational studies are essential to elucidate the association between high risk prescribing and health outcomes in this population, and to ensure the necessary degree of heterogeneity. However, the quantification of causality requires judicious interpretation of observational data . A centrIn summary, the 45 and Up Study and its linkage with health databases will allow investigation of the relationship between high risk prescribing and adverse outcomes at the population level, which has not been possible in the past. The proposed study will generate an important, unique dataset for the quality use of medicines and will allow the identification of targets for improving prescribing in older people.ACCMIS: Aged and Community Care Management Information System; APDC: Admitted Patients Data Collection; ATC: Anatomical Therapeutic Codes; CHeReL: Centre for Health Record Linkage; DBI: Drug Burden Index; MBS: Medicare Benefit Scheme; NSW: New South Wales; PBS: Pharmaceutical Benefit Scheme; TGA: Therapeutic Goods Administration.The authors declare that they have no competing interests.DG and EB drafted the manuscript. EB, DLeC, SP, AM, RV, SH, DG, FB, and GJ contributed to the design of the study, and DLeC, SP, AM, RV, SH, FB, GJ were involved in reviewing the manuscript. All authors read and approved the final manuscript.Danijela Gnjidic: Faculty of Pharmacy, Bank Building A15, Science Rd, University of Sydney, Camperdown, NSW 2006 Australia.David Le Couteur: Centre for Education and Research on Ageing (CERA), Concord Hospital and University of Sydney, NSW 2139 Australia.Sallie-Anne Pearson: Faculty of Pharmacy, Bank Building A15, Science Rd, University of Sydney, Camperdown, NSW 2006 Australia.Andrew McLachlan: Faculty of Pharmacy, Bank Building A15, Science Rd, University of Sydney Camperdown, NSW 2006 Australia.Rosalie Viney: Centre for Health Economics Research & Evaluation, PO Box 123, Broadway NSW 2007 Australia.Sarah Hilmer: Royal North Shore Hospital and University of Sydney, Level 1, Acute Services Building, RNSH, St Leonards, NSW 2065 Australia.Fiona Blyth: Centre for Education and Research on Ageing (CERA), Concord Hospital and University of Sydney, NSW 2139 Australia.Grace Joshy: National Centre for Epidemiology and Population Health, Australian National University Canberra ACT 0200 Australia.Emily Banks: National Centre for Epidemiology and Population Health, Australian National University Canberra ACT 0200 Australia.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/13/115/prepub"}
+{"text": "Descending necrotizing mediastinitis is a life-threatening complication of an oropharyngeal infection that requires prompt and aggressive medical and surgical therapy. Herein, we report unusual case of man suffering of sub-acute mediastinal infection due to odontoiatric abscess which exacerbated at 3 months after its first presentation. Chest X-ray and CT scan demonstrated soft-tissue swelling of the neck and encapsulated fluid collections with gas bubbles within anterior mediastinum, especially on the right side. Bilateral anterior neck dissections were performed and blunt dissection, irrigation and debridement were carried out to several centimetres below the sternal manubrium. Then, right standard thoracotomy was performed with debridement of the anterior mediastinum. Four tubes were placed in the mediastinum and pleural cavity on the right side, and two tubes were placed in the left thoracic cavity. Follow-up CT scans of neck and chest showed the resolution of infection. Descending necrotizing mediastinitis (DNM) is a life-threatening complication of an oropharyngeal infection that requires prompt and aggressive medical and surgical therapy. Delay of diagnosis and inappropriate drainage of the mediastinum are the main causes of mortality in this life threatening condition ,2. HereiA 50 year-old man was admitted in our institution for neck pain, dysphagia, high-fever, and chest pain. Such symptoms began following infected foot ulcer 7 days before. She had a history of diabetes, and chronic obstructive bronchitis; yet, three months before she was admitted to a local hospital for mediastinal abscess as complication of odontogen abscess. However, the patient refused further investigations, and started antibiotic therapy for a time not better defined. On examination she had bilateral diffuse neck erythema, oedema, and induration. Broad-spectrum antibiotics were initiated empirically. Chest X-ray and CT scan demonstrated soft-tissue swelling of the neck and encapsulated fluid collections with gas bubbles within anterior mediastinum, especially on the right side Figure .After review of the images, the patient was taken to the operating room. Bilateral anterior neck dissections were performed and blunt dissection, irrigation and debridement were carried out to several centimetres below the sternal manubrium. Then, right standard thoracotomy was performed with debridement of the anterior mediastinum. We irrigated the mediastinum and thoracic cavity with copious warm saline  during the operation. Four tubes were placed in the mediastinum and pleural cavity on the right side, and two tubes were placed in the left thoracic cavity. Bacteriologic results from materials obtained from the neck, pleura, mediastinum, pericardium, and blood revealed in all cases a polymicrobial infection, with mixed aerobic and anaerobic organisms. A repeated bronchoscopies were attended ,4. FolloThe most dreaded and probably lethal form of mediastinitis is the diffuse necrotizing variety that occurs as a complication of infection of the oropharynx. The best term of such mediastinitis is DNM; descending because the infection uses fascial planes in the neck to gain access to the mediastinum, and necrotising because the infection is often polymicrobial and gas-producing . InfectiIntravenous broad-spectrum antibiotic therapy alone is not efficient without adequate surgical drainage of the cervical and mediastinal collections, extensive debridement and excision of necrotic tissue, and wide mediastinopleural irrigation -14.The most interesting aspect of the present case, not been reported before, is that our patient suffered of sub-acute mediastinal infection due to odontogen abscess treated with antibiotic therapy for three months. Then, an exacerbation of mediastinal infection is observed with concomitant presence of infected foot ulcer. In theory, the infection of foot ulcer may lead to septicemia which in addition with other risk factors as diabetes, and obesity may then cause the exacerbation of mediastinal infection.In the present case, diagnosis of cervical infection with increasing infectious symptoms, and respiratory insufficiency is clinically obvious; yet, radiological studies show the presence of cervical abscess with diffuse mediastinal collections. Thus, the diagnosis of DNM is confirmed in agreement of diagnostic criteria of Estrera et al. . These cIn reported cases of DNM, successful surgical management involves a combination of cervical and mediastinal drainage with or without open thoracotomy. Endo et al.  proposedIn the meta-analysis by Corsten et al , patientRoberts et al  report tThe authors declare that they have no competing interests.PL : conception and design, interpetration of data, given final approval of the version to be published. F. N.: acquisition of data, drafting the manuscript, given final approval of the version to be published. CC : acquisition of data, drafting the manuscript, given final approval of the version to be published. MD : acquisition of data, drafting the manuscript, given final approval of the version to be published. BA : acquisition of data, drafting the manuscript, given final approval of the version to be published. AG : acquisition of data, drafting the manuscript, given final approval of the version to be published. MV: acquisition of data, drafting the manuscript, given final approval of the version to be published. V.D.C.: critical revision, interpretation of data, given final approval of the version to be publishedPL: Resident in Department of Medicine and Surgery - University of Salerno. FN: Resident in Department of Medicine and Surgery - University of Salerno. CC: Resident in Department of Clinical Medicine and Surgery - University of Naples. MD: Aggregate Professor of Surgery in Department of Clinical Medicine and Surgery - University of Naples Federico II. BA: Associate Professor of Surgery in Department of Clinical Medicine and Surgery - University of Naples Federico II. AG: Assistant Professor of Pediatric Surgery - University of Salerno. MV: Associate Professor of Endocrinology - University of Salerno. VDC: Assistant Professor of Thoracic Surgery - University of Salerno."}
+{"text": "These Centers foster collaboration among transdisciplinary teams of scientists with the goal of accelerating progress towards reducing cancer incidence, morbidity and mortality associated with obesity, low levels of physical activity and poor diet. This presentation will review key opportunities in transdisciplinary research, highlight lessons learned and note future challenges.The increasing recognition of the complex, multidimensional relationship between excess adiposity and cancer risk, coupled with the high prevalence of obesity in the US, has motivated the scientific community to seek new research models and paradigms. Compared to traditional unidisciplinary research, transdisciplinary research is seen as having the potential to accelerate both discovery and its translation to practice, and eventually policy. In response, the National Cancer Institute (NCI) developed a centers grant mechanism in nutrition, energetics, and physical activity; referred to as the Transdisciplinary Research on Energetics and Cancer (TREC) Initiative ("}
+{"text": "In Japan, the Research Committee on Intractable Vasculitides, supported by the Ministry of Health, Labour and Welfare, has been promoting basic and clinical research on vasculitis since 1972. The present Research Committee on Intractable Vasculitides comprises 4 subcommittees under the direction of a Principal Investigator: Basic and Pathological Research Subcommittee, Clinical Research Subcommittee of Small and Medium-sized Vessel Vasculitis, Clinical Research Subcommittee of Large-sized Vessel Vasculitis, and International Cooperation Research Subcommittee. Since 2008, 9 nationwide clinical studies for vasculitis have been conducted and 8 clinical and basic studies are in progress. The Research Committee on Intractable Vasculitides, supported by the Ministry of Health, Labour and Welfare of Japan, has conducted and promoted basic and clinical research on vasculitis since 1972. We study 9 diseases: Takayasu arteritis, temporal arteritis, polyarteritis nodosa, Buerger disease, microscopic polyangiitis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, antiphospholipid syndrome, and rheumatoid vasculitis. Experts from several fields including nephrology, rheumatology, pulmonology, dermatology, cardiology, vascular surgery, pathology, epidemiology, and otorhinolaryngology work cooperatively. The present Research Committee on Intractable Vasculitides comprises 4 subcommittees under the direction of a Principal Investigator (Hirofumi Makino):Basic and Pathological Research Subcommittee of Vasculitis Syndrome (Yasunori Okada), Clinical Research Subcommittee of Small and Medium-sized Vessel Vasculitis Syndrome (Yoshihiro Arimura), Clinical Research Subcommittee of Large-sized Vessel Vasculitis Syndrome (Kazuo Tanemoto), and International Cooperation Research Subcommittee of Vasculitis Syndrome   patients  and a naTo describe the current treatment status and evaluate the effectiveness of these treatments for Japanese patients with all types of antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV), we conducted a nationwide prospective cohort study of remission induction therapy in Japanese patients with AAV (RemIT-JAV). Twenty-two university hospitals and referring hospitals participated in this study; consecutive patients newly diagnosed with AAV were enrolled from April 2009 to December 2010. The criteria of primary systemic vasculitis proposed by the European Medicines Agency (EMEA) algorithm was employed for enrollment [Based on our retrospective study elucidating the risk factors for relapse in patients with myeloperoxidase (MPO)-ANCA positive MPA , we are After RemIT-JAV, we conducted a nationwide, prospective cohort study of remission induction therapy in Japanese patients with ANCA-associated vasculitides and rapidly progressive glomerulonephritis (RemIT-JAV-RPGN) (UMIN000005136) including 47 university hospitals and referring hospitals. Enrollment of consecutive patients newly diagnosed with AAV began in April 2011 and will continue till December 2013. The primary and some secondary outcome measures are the same as those in RemIT-JAV, but pathological analysis of renal involvement and radiological analysis of pulmonary involvement will be added. Further, biological samples  will be collected and offered to the Basic and Pathological Research Subcommittee for Research for identifying candidate biomarkers.We also conducted a nationwide Japanese prospective observational study on the current state and efficacy of therapeutics for large-vessel vasculitis (UMIN000010414). The subjects included patients newly diagnosed with Takayasu arteritis and giant cell arteritis. The study objective was to clarify the current state and efficacy of therapeutics for large-vessel vasculitis in Japan and to evaluate the utility of the current diagnostic criteria and classification for large-vessel vasculitis. The primary outcome measure of this study is remission rate. The study began in November 2012, and patients will be registered until March 2014. Final follow-up will be completed in March 2016.The International Cooperation Research Subcommittee is leading the effort to join some international collaborative clinical research studies: the Diagnostic and Classification Criteria in Vasculitis Study (DCVAS) (NCT01066208), the Plasma Exchange and Glucocorticoid Dosing in the Treatment of ANCA-Associated Vasculitis (PEXIVAS) Study (NCT00987389), and a comparison study of phenotype and outcome in microscopic polyangiitis between Europe and Japan.A genome-wide association study in AAV patients registered in the Japanese clinical studies RemIT-JAV and RemIT-JAV-RPGN, and a prospective study of the severity-based treatment protocol for Japanese patients with MPO-ANCA-associated vasculitis (JMAAV) , is also"}
+{"text": "The disease causes progressive bilateral swelling of the lower legs Podoconiosis is widely distributed in certain countries on three continents: Africa, South America, and Asia Ernest Price, in the early 1970s, conducted extensive research in Ethiopia and in the eastern African region on the aetiology, natural history, distribution, and management of non-filarial elephantiasis In 2002, Gail Davey was first introduced to the problem of podoconiosis in one of the southern districts of Ethiopia. Since then, she has led podoconiosis research using a multi-disciplinary approach, including epidemiology, immunology, mineralogy, genetics, bioethics, social sciences, and economics, to describe the disease and its impacts. In addition to Price and Davey approaching podoconiosis from a multi-disciplinary perspective, Davey went the extra mile by partnering with local and international institutions that translated the research into disease prevention and treatment. Several factors have contributed to the success of Davey's program. Unlike Price, Davey has (i) embraced social science and public health research rapidly applicable to education of community members and clinical management, (ii) included service-providing institutions , and International Orthodox Christian Charities, Ethiopia [IOCC]), (iii) engaged a wider range of academic and other institutions in Ethiopia and from around the world , and (iv) most importantly, included local investigators . Contextual factors that have contributed to the success of this program have been increased awareness of the importance of partnership in North\u2013South research collaborations, and the recent global attention focussed on NTDs.The major accomplishments of the past decade fall into three interlinked categories: scientific research, inclusion of podoconiosis in national and international health agendas, and integration of research findings into clinical management of podoconiosis .de novo clinical staging system that could be used by community workers with little health training HLA\u2013DQA1, \u2013DRB1, and \u2013DQB1 confer risk for podoconiosis Considering first scientific research, the initial group of podoconiosis studies aimed to describe the burden of the disease in Ethiopia in terms of prevalence, economic cost, and social burden. Studies in different regions of Ethiopia have documented prevalence ranging from 2.8% to 7.4% http://www.who.int/neglected_diseases/diseases/podoconiosis/en/). In March 2012, Footwork, the International Podoconiosis Initiative, was launched, with the vision of eliminating podoconiosis (www.podo.org). In 2012, the civil society organizations (CSOs) that had been working on podoconiosis prevention and treatment in Ethiopia for over 20 years formed the National Podoconiosis Action Network (NaPAN), an umbrella organization that coordinates the work of its member organizations to work towards its vision \u201cto see Ethiopia free of podoconiosis.\u201dThe aforementioned research milestones contributed significantly to the second major accomplishment\u2014recognition of podoconiosis in national and international health agendas. In December 2010, the Ethiopian Federal Ministry of Health agreed to prioritize podoconiosis control. Subsequently, podoconiosis was included in the National Master Plan for NTDs and in the modules prepared by the Open University for the upgrading of Ethiopian Health Extension Workers. In February 2011, the World Health Organization included podoconiosis in its list of NTDs  total dependence on CSOs for podoconiosis treatment services and limited involvement of government health services, making disease prevention efforts unsustainable, (ii) limited knowledge of mid- and high-level health professionals in Ethiopia about the causes and clinical management of podoconiosis and differential diagnosis from other causes of lymphoedema, (iii) neglect by global health advocates of non-infectious and non-fatal, but socio-economically devastating, diseases of the poor such as podoconiosis, thereby limiting the amount and sources of funding available for research and interventions, and (iv) absence of comprehensive data on the distribution and burden of podoconiosis  and lack of diagnostic tools, which are necessary for negotiating funding and delivery of treatment and interventions.http://www.who.int/neglected_diseases/diseases/podoconiosis/en/), the Wellcome Trust (http://www.wellcome.ac.uk/News/Media-office/Press-releases/2012/WTVM054822.htm), and the US National Institutes of Health . The successes of the journey demonstrate the impact of ten years of community-oriented, intervention-linked, multi-disciplinary research to positively influence the lives of marginalized patients. It also shows that scientific research in a low-income setting and among marginalized communities can impact policy, raise disease profile, and touch hearts across the world. These rewarding accomplishments have also generated research questions that future enquiry may answer with huge dividends for scientific knowledge, disease elimination, and lessons for other diseases.The accomplishments of the past ten years have drawn podoconiosis from the book shelves where it was buried for a ten-year \u201cDark Age\u201d to some light. Podoconiosis is now a global health topic recognized as such by the World Health Organization (work, the International Podoconiosis Initiative.The success stories of the past ten years and the recent funding of further research projects such as the mapping of podoconiosis in Ethiopia, an evaluation of podoconiosis lymphoedema management, and a trial of behavioural strategies for promoting footwear imply that elimination of podoconiosis is achievable. Mapping of the disease burden of podoconiosis will help target resources, monitor control progress, and advocate for investment in podoconiosis prevention, control, and ultimately elimination. The studies evaluating lymphoedema management and behavioural interventions are a prerequisite for the scale-up of these interventions. Capitalizing on filarial lymphoedema management experience and research outcomes will help update the treatment options for podoconiosis"}
+{"text": "Formed in 2008, the Southern African Centre for Infectious Disease Surveillance (SACIDS) is a One Health consortium of academic and research institutions involved with infectious diseases of humans and animals. Operating in partnership with world-renowned centres of research in industrialised countries, its mission is to harness innovations in science and technology for improving southern Africa's capacity to detect, identify, monitor (DIM) and manage the risk posed by infectious diseases of humans, animals, and ecosystems. The consortium's major capacity development activities include a series of One Health-based Master of Science (MSc) courses and a five-year DIM-driven research program. Additionally, SACIDS organized Africa's first One Health conference, in July 2011. This paper describes these and other major activities that SACIDS has undertaken to improve infectious disease surveillance across southern Africa. The paper also describes the role and collaboration of SACIDS with other national, regional and international consortia/networks that share a vision and interest in promoting novel approaches to infectious disease surveillance and outbreak response. It has become increasingly apparent that the most cost-effective strategy for addressing the high infectious disease burden and risk in southern Africa must be through the sharing of expertise and resources across institutions; through close collaboration between the human and animal health sectors; and, ideally, through an approach that is based on ecological systems, which in Africa often transcend administrative or national boundaries  services the Southern African Development Community (SADC). Operating in partnership with world renowned research institutions in the United Kingdom, United States, and Asia, SACIDS : Burundi, Rwanda, Uganda, Kenya, and Tanzania. Together, the two regional economic communities (RECs) share not only a vision for inter-regional free trade, but also an abundance of wildlife animals in their savannah and forest ecosystems and an intense wildlife-livestock-human dynamic . Thus, sThe headquarters of SACIDS is located at the Sokoine University of Agriculture (SUA), Morogoro, Tanzania. SACIDS operates as a non-profit inter-institutional consortium through the legal framework of the SACIDS secretariat host  and member institutions. At the national level, several virtual centers for infectious diseases have been formed. Collectively, these National Centres for Infectious Disease Surveillance (NatCIDS) form the core of SACIDS see . The undSACIDS seeks to enhance the effectiveness of existing official disease surveillance systems. Thus, at both national and regional levels, SACIDS is underpinned by sector ministries and regional inter-governmental organizations, especially SADC, the New Partnership for Africa's Development (NEPAD), and the African Union. At the national level, each NatCIDS includes as active members representatives of the Ministries responsible for human health, livestock and wild animal health; operates under the patronage of national chief medical and veterinary officers; and is linked to national offices responsible for responding to natural emergencies. At the regional, or SADC level, SACIDS is developing linkages with sections of the SADC Secretariat that deal with human and animal health matters, not only through desk officers but also directly with the communicable diseases and livestock technical committees that advise governments on priority diseases for regional priority.Provide training through two \u201cOne Health\u201d MSc courses, one at Sokoine University, Tanzania, with a focus on molecular biology; the other at the University of Zambia, Lusaka, with a focus on analytical epidemiology. Each course includes core modules on the understanding of key One Health challenges. The courses have been developed and are being delivered in collaboration with regional institutions and the University of London's London School of Hygiene and Tropical Medicine (LSHTM) and Royal Veterinary College (RVC).Develop research capacity, focusing primarily on five disease-driven themes: (i) climate-dependent, vector-borne diseases ; (ii) diseases with potential inter-species concern/spread between wildlife, livestock, and humans ; (iii) diseases of economic and food security importance ; (iv) bacterial rare diseases ; and (v) dangerous emerging diseases . The consortium's research on One Health policy is focused primarily on disease burden in the dry land ecosystems of southern and East Africa and its impact on livestock-dependent communities . AnotherShare expertise and resources across consortium institutions, especially for disease emergency situations See . The valExamine approaches and mobile technologies for improving the efficiency of disease alerts, surveillance and response .The initial focus of SACIDS is on capacity development through employment of the Community of Practice (CoP) principle . A CoP iOnderstepoort Journal of Veterinary Research  is governed by a multi-sectoral steering committee whose members include representatives from the Ministry of Livestock Development and Fisheries, and efforts are underway to establish a veterinary stream of the Tanzania FELTP. TFELTP is a collaboration between MOHSW, Muhimbili University of Health and Allied Sciences (MUHAS), National Institute of Medical Research (NIMR), Centres for Disease Control and Prevention (CDC), World Health Organization (WHO), and African Field Epidemiology Network (AFENET) . It was Mycobacteria strains, the causative agent(s) of tuberculosis (TB), can infect both animals and humans. SACIDS's focus on TB exemplifies not only how SACIDS is focused on developing and implementing a One Health approach to infectious disease surveillance, but also how SACIDS seeks to enhance existing surveillance systems by prioritizing the same diseases that the official organs of SADC prioritize. SADC prioritizes TB because member states carry a disproportionate burden of the dual epidemic of TB and HIV/AIDS compared to the rest of Africa and the rest of the world. The region is home to 25 percent of the sub-Saharan human population but accounts for 50 percent of TB cases reported. The SADC Health Protocol includes a specific Article 12 on TB control, advocating for global and regional partnerships to respond to the TB epidemic in the SADC region , pathogen evolution, travel and trade, changing patterns of land use resulting in increased interactions between humans and both domestic and wild animals, increasing urbanization, population growth, and changing food consumption patterns. Together, these factors will create evolving One Health challenges, such as emerging zoonoses, and an increasing demand for scientific evidence in relevant policy decision-making. The challenges will be made more difficult if policy silos between human health, animal health, and agriculture prevent the type of inter-sectoral, inter-disciplinary collaboration that is needed for One Health infectious disease surveillance and response.But as the burden increases, so too do opportunities for reducing the burden. It is anticipated that SACIDS itself will continue to evolve as an initiative that promotes novel One Health approaches to infectious disease surveillance, such as the application of improved diagnostic and information technologies that can be used in remote rural settings. To be effective, SACIDS will need to strengthen its \u201cengagement\u201d and convening strategy for developing smart, shared-vision partnerships at national, regional, and international levels. CORDS helps to nurture that strength."}
+{"text": "The development of novel, more precise instruments for the delivery of ionizing radiations, the accretive utilization of protons and heavy ions, and the emphasis on hypofractionated irradiation schemes have resulted in major improvements in locoregional tumor control. However, radiation therapy alone is still insufficient to cure locally advanced metastatic tumors. The heterogeneity of neoplasms and their microenvironment also affect the radiosensitivity of cancers. Thus, there is an urgent clinical need for innovative therapeutic concepts that may be translated into novel radio(chemo)therapeutic regimens. In order to develop new therapeutic strategies, a profound knowledge of tumors and their microenvironment is essential.In this e-book, the authors deal with various aspects of interrelationship between neoplasms and their microenvironments, including how high and low dose irradiation affects the immune system, the effects of targeted and non-targeted photon, and particle irradiation on tumor and normal tissues, as well as the impact of epigenetics on irradiation therapy. Furthermore, the authors report on the effects of irradiation on inflammatory pathways and on the microcirculation, two aspects that are highly relevant for the delivery of macromolecules and other therapeutics to irradiated tumors. A major focus of this e-book is to elucidate immunological facets of ionizing irradiation. It is indeed becoming clear that high- and low-dose irradiation elicit distinct immunological effects. Furthermore, the mode of irradiation-induced cell death  has a major impact on anticancer immune responses. Overall, the e-book aims at review the current knowledge on the role of ionizing irradiation in antitumor immunity. This knowledge is instrumental for the development of innovative therapeutic modalities involving the combination of radio(chemo)therapy and immunotherapy in patients with locally advanced tumors."}
+{"text": "Little is known physical health (PH), mental health (MH) and health-related quality of life (HRQOL) adaptation outcomes in AYA with SB, and the factors associated with them. The purpose of this presentation is to 1) describe the PH , MH , and HRQOL outcomes; and 2) delineate the direct and indirect relationships of risk and protective variables in the Ecological Model of Secondary Conditions and Adaptation in SB associated with these outcomes. This model includes SB Context , neuropsychological risk [NPR], and protective processes (adolescent resilience and family resourcefulness).This is an interdisciplinary descriptive cross-sectional study. AYA were between 12-25 years of age and from 4 clinical programs in the USA. They had no other major medical condition, no mental retardation, were English speaking and functioned at approximately grade levels. Parent and AYA report of PH and MH and AYA report of HRQOL outcomes were included. Study measures had reliability and validity data and most had been used in our previous studies. Structural Equation Modelling (SEM) analyses were used to assess the model.Mean parent and AYA basic functional status scores reflect need for supervision; self-management reflects need for substantial assistance. Mean parental report of IBP are higher than EBP and both are in the normative range. However, 13-18% of parent or AYA reports of AYA depressive symptoms were in the clinically significant range.Self-worth and HRQOL were both moderately high. Three SEM analyses revealed different predictive patterns for PH, MH, and HRQOL constructs. In the PH model only LOL was significantly related to FS. NPF mediated the impact of shunt status and LOL on self-management, and age, NPR, and functional status had direct relationships to self-management. In the MH model, SES and family resourcefulness had indirect paths to MH; whereas AYA resilience, secondary conditions, and age had direct paths to MH. In the HRQOL model SES, age, and family resourcefulness had indirect paths to HRQOL through AYA resilience and MH; whereas AYA resilience and MH had direct paths.Different direct and indirect relationships of the conceptual framework variables were identified for the three outcomes. Clinical interventions should be differentiated by outcome and targeted to risk and protective variables."}
+{"text": "Segmented service delivery with consequent inefficiencies in health systems was one of the main concerns raised during scaling up of disease-specific programs in the last two decades. The organized response to NCD is in infancy in most LMICs with little evidence on how the response is evolving in terms of institutional arrangements and policy development processes.Drawing on qualitative review of policy and program documents from five LMICs and data from global key-informant surveys conducted in 2004 and 2010, we examine current status of governance of response to NCDs at national level along three dimensions\u2014 institutional arrangements for stewardship and program management and implementation; policies/plans; and multisectoral coordination and partnerships.Several positive trends were noted in the organization and governance of response to NCDs: shift from specific NCD-based programs to integrated NCD programs, increasing inclusion of NCDs in sector-wide health plans, and establishment of high-level multisectoral coordination mechanisms.Several areas of concern were identified. The evolving NCD-specific institutional structures are being treated as \u2018program management and implementation\u2019 entities rather than as lead \u2018technical advisory\u2019 bodies, with unclear division of roles and responsibilities between NCD-specific and sector-wide structures. NCD-specific and sector-wide plans are poorly aligned and lack prioritization, costing, and appropriate targets. Finally, the effectiveness of existing multisectoral coordination mechanisms remains questionable.The \u2018technical functions\u2019 and \u2018implementation and management functions\u2019 should be clearly separated between NCD-specific units and sector-wide institutional structures to avoid duplicative segmented service delivery systems. Institutional capacity building efforts for NCDs should target both NCD-specific units  and sector-wide organizational units (for building program management and implementation capacity) in MOH.The sector-wide health plans should reflect NCDs in proportion to their public health importance. NCD specific plans should be developed in close consultation with sector-wide health- and non-health stakeholders. These plans should expand on the directions provided by sector-wide health plans specifying strategically prioritized, fully costed activities, and realistic quantifiable targets for NCD control linked with sector-wide expenditure framework. Multisectoral coordination mechanisms need to be strengthened with optimal decision-making powers and resource commitment and monitoring of their outputs. The burden of chronic non-communicable diseases (NCDs) is growing in low- and middle-income countries (LMICs) alongside persistent communicable diseases, poor maternal health, and fragile health systems. NCDs such as cardiovascular disease (CVD), cancers, diabetes, and chronic obstructive respiratory diseases are increasingly affecting people in the economically productive age- groups. NCDs also account for more than 50% of total premature mortality (i.e. deaths in those under 60\u2009years of age) in most LMICs ,2. The aEncouragingly, NCDs are now high on the global agenda with a series of high-level events, such as the Health Ministers' meeting in Moscow and a United Nations High-Level Ministerial summit, held in September 2011. Calls are being made to establish a Global Fund for NCDs and a global facility for NCD medicines . Past exThe organized response to NCD is still in infancy in most LMICs. There is limited published evidence on how this response is structured from governance perspective within the context of overall health systems. We examine the evolving response in terms of institutional structures and arrangements, policy content and development processes, and coordination across different actors and sectors.Although our research is focused on LMICs in the Western Pacific Region (WPR) of the World Health Organization (WHO), we hope the findings may be of wider interest.Governance and leadership is a central building block for health systems . The terGovernance structures: The roles and responsibilities, inter-relationships, and architecture of the institutional structures within Ministries of Health (MOH) that are involved in oversight, management, and planning for NCDs were examined. We conceptualize the institutional structures in two categories: NCD \u2013specific structures whose remit is confined to NCDs only, and the \u2018sector-wide\u2019 structures responsible for \u2018shared\u2019 health functions across different diseases and programs .Policy development and planning: Policies and plans may be NCD-specific and \u2018sector-wide\u2019  covering all the programs and diseases and other sector-wide issues . We examine the extent to which the content, and processes for development of NCD-specific and sector-wide health policies and plans are aligned.Multisectoral coordination, building coalitions and partnerships: Effective regulation of and influence over the life-style and other environmental determinants of NCDs require interventions across multiple sectors and stakeholders increasing the salience of multi-sectoral coordination. We examine the status, nature, roles and responsibilities, and outcomes of multisectoral coordination mechanisms, coalitions and partnerships both within and outside government.In addition, the conceptual framework envisages that the governance of health systems and disease-specific programmes, especially in aid-dependent countries, are influenced by architecture of funding flows, policies, accountability and reporting requirements at global and regional level .A qualitative desk-review of policy and programme documents (published between 2000 and 2011 and available in public domain) covering the health sector and NCDs was conducted for the five selected countries\u2014Cambodia, Fiji, Malaysia, Mongolia and the Philippines. These countries represent a range of contexts from low-income (Cambodia and Mongolia) to lower-middle income (the Philippines) to upper middle income countries . A specific focus of analysis was the most recent national NCD plan and sector-wide national health plan in each of these five countries -22. In aThe paper also draws on data collected in 2004 and 2010 from member states in the WPR as part of the WHO sponsored global key-informant surveys. The surveys assessed the capacity of member states to respond to NCDs in five areas: public health infrastructure for NCDs; the status of policies, strategies, action plans and programmes relevant to NCDs; health information systems, surveillance and surveys; the capacity of health care systems for early detection, treatment and care of NCDs; and health promotion, partnerships and collaboration ,24. BothThis paper also uses other peer-reviewed literature on governance of health systems and NCDs published since 2000 with special reference to Western Pacific Region.An increasing number of countries have established special units or departments specifically for NCDs, giving a clear institutional identity to control and prevention of NCDs within MOHs. Globally, countries reporting such structures increased from 70% to 95% between 2000 and 2010 . In the The location and remit of NCD units within the MOH varies across countries Table\u2009. In MalaCo-existence of different NCDs in a substantial number of patients, and the common risk factors that link major NCDs  warrant integrated multidisciplinary approach to disease prevention and management. Integrated approaches can improve efficiency, which is especially important given the often limited human resources in LMICs. Yet disease- or risk-factor based governance structures, often separate and additional to the overall NCD specific structures described above, have developed over time in some countries. For example in Vietnam, the National Institute for Cardiovascular Disease manages the program on prevention and control of CVD; the National Institute of Oncology  manages the program on prevention and control of cancer; the National Institute of Endocrinology and the National Institute of Psychiatry each manage the separate national programs on diabetes and mental illness, respectively . A similDisease- or risk-factor specific global or regional initiatives seem to have also influenced development of disease- or risk-factor specific organizational structures within MOHs. For example, much stronger global advocacy and funding flow for tobacco control under the WHO Tobacco Free Initiative has led to far more resourced tobacco control teams in LMICs, often separate and under different hierarchical control from the NCD teams described above. Encouragingly, some positive trends are observed in establishment of more integrated NCD programs. The Philippines merged the three vertical programs into an integrated NCD control and prevention program in 2000, and similar trends are seen in other countries such as Mongolia and Malaysia.The global key informant survey in 2010 elicited information about the planning, coordination of implementation, and monitoring and evaluation of NCD initiatives and almost all the member states in the WPR reported NCD-specific units responsible for these functions. However, the relationships and division of roles and responsibilities between NCD units and other sector-wide institutional structures, such as policy and planning units and health information units, are often not clearly specified. In some countries, the NCD related structures seem to function mainly as technical units and not as specific programme management and implementation entities. For example, in contrast to the situation in Vietnam described earlier, structures such as the National Cancer Centre, National Cardiovascular Centre, National Centre for Neurosciences and Psychiatry affiliated with Ministry of Health, Labour and Welfare in Japan and in many other developed countries including Malaysia mainly serve as leading technical and research institutions in their respective fields, rather than as programme management or operational entities .Many LMICs have other major organizational structures with NCD related functions such as health promotion centres and national centres for nutrition, and these are often distinct entities under different hierarchical control. For example, Cambodia and the Philippines have an autonomous National Centre for Health Promotion. In Mongolia the National Centre for Health Development has the key responsibility for health promotion. Many countries including Malaysia, Mongolia, and the Philippines have newly established, or plan to establish, health promotion boards or foundations to provide population-based primary prevention services for NCDs. However, relationships of these newly proposed structures with the existing organization structures for health promotion or the NCD units are not clearly specified. There is a potential overlap in the reported functions and responsibilities, as NCD units also reported health promotion as their key responsibility in the global key informant survey. For example, the National Centre for Health Promotion in Cambodia  is the focal organization for tobacco and alcohol control and is mandated to lead on matters of behaviour change, working across multiple programmes . This soIf the common goals and targets articulated in sector-wide and NCD-specific policies and plans are to be pursued effectively and efficiently, clear specification of roles and responsibilities of each institutional structure involved may be required to align the NCD-related functions, activities and resources located in multiple and distinct organizational structures across the MOH.Neither the global key informant survey nor the qualitative review indicated the presence of formal institutional coordination mechanisms for these different organizational units within the MOH. The Philippines has a Sectoral Management and Coordination Team responsible for the overall development, monitoring and coordination of policies, mechanisms and guidelines for the health sector, but its role in coordinating NCD policies across the Department of Health is not known.Cambodia provides a \u2018typical\u2019 example of the situation witnessed in many countries on how additional \u201cvertical\u201d disease- or program-specific structures were created over time that evolved into self-contained units taking over sector-wide health system functions relative to only that particular disease/program leading to segmented service delivery.In the past, the MOH in Cambodia created special institutions such as the National Centre for HIV/AIDS and STDs, the National Centre for TB and Leprosy Control, the National Centre for Parasitology, Entomology and Malaria Control, and the National Centre for Maternal and Child Health (NCMCH), which respectively became responsible for HIV/AIDS, Tuberculosis, Malaria and immunization services Figure\u2009. These nCurrently, the Department of Preventive Medicine is responsible for NCD control and is expected to facilitate and coordinate the development of NCD policy, conduct surveillance of NCD risk factors, develop treatment guidelines and deliver health promotion, prevention and treatment services and training relevant to NCD prevention and control. Many of the reported functions of this NCD unit overlap with other sector-wide centres/departments that are expected to perform some of these functions across different programmes/services Figure\u2009.If the experience of other disease-specific structures mentioned above is repeated, these NCD-specific structures may start growing by having additional staff with expertise and responsibility in the areas such as planning, management, human resource training, supervision, medical supply, logistics and procurement, and health information systems to become self-contained programme implementation and management entities undermining overall consolidation of these sector-wide functions in MOH. Encouragingly, Cambodia sector-wide health plan recognizes the fragmentation of activities, funding, monitoring and supervision and administrative lines of authority . The NCDIn LMICs in the WPR, the sector-wide national health plans and policies increasingly mention NCDs and included at least one goal or objective related to NCD control, although the level of detail varies. In Malaysia, NCD policy agenda figures high up not only in the health sector plan  or for a specific risk factor such as alcohol or tobacco use, unhealthy diet, obesity, and physical inactivity. In 2010, the highest number of countries reported a policy/strategy for diabetes mellitus (71%) and cancer control (66%) and the lowest number reported for chronic obstructive pulmonary diseases (11%). These developments do not necessarily reflect the relative public health importance of these diseases. For example, the estimated number of deaths from cardiovascular (4.1 million) and chronic respiratory diseases (1.5 million) is much higher than that of diabetes ( 0.2 million) in the WPR ,26. The A qualitative review of sector-wide and NCD-specific polices/plans in five countries showed weak alignment between the two groups of policies in terms of goals and targets, financial resource allocation, and implementation mechanisms, potentially reflecting the largely autonomous development process of these policies involving different constituents. The NCD-specific Plans do not necessarily expand on the directions set in sector-wide national health plan and may be completely independent. The development of NCD-specific plans are for the most part coordinated by the NCD unit in the MOH, the role and influence of the sector-wide policy and planning units in the development of these policies is not very clear.An important factor in ensuring the implementation of NCD-policies and plans is the extent to which political consensus and administrative undertakings to ensure implementation are in place. This might best be achieved by involving key stakeholders at the preparatory stages of NCD strategies but the extent to which this happens is not clear from our qualitative review and practice seems to vary. The 2007 National NCD control program document in Mongolia identifies all the policy actors and their roles, and was explicitly endorsed by the Ministry of Food and Agriculture, Ministry of Finance, and governors of the capital city and provinces , other non-health government ministries (83%), private sector (71%), other international organizations (66%), academe (60%) and UN agencies (51%).The most commonly reported mechanism in the global key informant survey for multisectoral coordination was cross-departmental or inter-ministerial committees (80%). However, the survey does not give details of the composition, roles, responsibilities, and effectiveness of these partnerships, or the extent to which these partnerships influence national strategies, plans and regulations for NCDs.Encouragingly, in all the five countries, both the sector-wide and the NCD specific plans emphasize the importance of multi-sectoral coordination and identify relevant stakeholders. The qualitative review showed that high-level multisectoral coordination committees exist in all these countries Table\u2009. HoweverThe roles and responsibilities, powers and legitimacy of decision-making, and resources of these coordination mechanisms were often unclear. Evidence is already emerging that suggests the limited functionality and effectiveness of these structures in influencing either policies or resource allocation in non-health sectors. For example, although never formally abolished, the national public health council chaired by Mongolia's Prime Minister is not active . A similEffective governance for NCD at national level requires the development of effective partnerships and coalitions to generate the demand for change and to catalyze political action. The range of actors and stakeholders for non-communicable disease control are complex and include food manufacturers and retailers, tobacco and alcohol industries, civil associations, disease/condition specific advocacy groups such as national diabetic associations, and professional associations. Although the multisectoral coordination mechanisms in both Fiji and the Philippines included membership of non-governmental organizations (NGOs) Table\u2009, LMICs mWhile, the implementation of programs for communicable diseases and maternal and child health in LMICs owe much to the financial and technical assistance of external donors, less than 3% of global development assistance for health currently goes to NCDs . DespiteIn the past, many global initiatives had required countries to establish coordination structures for specific health issues as a condition to receive the assistance. For example, the Global Fund required a Country Coordination Mechanism and GAVI Alliance required an Interagency Coordination Committee (ICC), often having similar membership, functions and mandates . SimilarThe analysis in the paper is limited by explicit information available in the public domain and may not be able to capture all the complex consultations or discussions that may be ongoing in the countries more recently. Hence the results should be interpreted in light of this limitation.The evolving response to NCDs in LMICs shows several positive trends. These include increasing institutional recognition of NCDs, a move from disease-based programs to integrated NCD programs, and an increasing inclusion of NCDs in sector-wide health plans. These developments reflect the increasing recognition of the high burden of NCDs, and an explicit acknowledgment of the need for multisectoral actions with the creation of high-level coordination mechanisms. The analysis also suggests substantial influence of supranational initiatives and processes on in-country governance structures and policy development processes, which offers both opportunities and challenges.Notwithstanding the above positive trends, the analysis highlights some areas of concern. Each of these areas of concern and potential strategies to address them are described below.The current directions in development of NCD-specific institutional structures in LMICs with their increasing direct role in planning, management and implementation may lead to segmented service delivery systems for NCDs, especially with increase in NCD-specific external funding, as experienced in the past with scaling-up of programs for immunization, malaria, Tuberculosis, HIV/AIDS.Two key strategies are recommended to pre-empt this undesirable outcome. The first strategy would be clear separation of the \u2018technical\u2019 and the \u2018operational and programme management\u2019 functions between NCD-specific units and sector-wide organizational units , respectively. The NCD-specific structures are justified to build much needed technical capacity for NCDs in MOH and to provide institutional identity and visibility, especially when similar structures exist within the MOH for other public health problems perceived to be important. However, it will be critical that these NCD-specific units are developed only as technical advisory bodies with strengthening of their capacity in analyzing up-to-date technical information, development of clinical guidelines, advising on suitability of different proposed interventions and research. In addition, NCD-specific units should focus on strategizing, guiding, coordinating policies and activities across different stakeholders within and beyond MOH. However, these units should not act as direct implementing bodies for NCD plans and management and delivery of NCD-related services which should be rather left to sector-wide organizational structures.Second, the resources to strengthen institutional capacity to respond to NCDs should not be solely targeted to NCD-specific units, but more importantly to sector-wide organizational units to build their capacity in effectively incorporating NCD-specific requirements in human resources development, health financing, medical supply and logistic and information systems.Three major concerns were identified in the increasingly complex NCD policy landscape in LMICs.First, out analysis suggest that the sector-wide health plans were not entirely informed by critical analysis of local disease burden and health needs. Often local evidence, even when acknowledged in situation analysis, was ignored in favour of global priorities and goals. Hence, NCD-specific units should be fully engaged in the sector-wide health policy and planning process to ensure inclusion of NCDs related activities as appropriate to their epidemiology, morbidity/mortality burden in the sector-wide health plans.Second, our analysis shows weak alignment Tables\u2009 and 3 amThird, NCD specific plans with no information on financial and implementation feasibility and no realistic quantifiable targets, as have been observed in some of the countries examined, may become simply technical papers or 'laundry lists' of desirable activities with limited reference value and no follow-up at the government level .Although the need for multisectoral coordination is acknowledged by most LMICs, the resources needed to organize and manage such coordination mechanisms appear to be inadequate. The inter-ministerial bodies\u2014the most common mechanism reported\u2014seem to be relatively fragile structures in most LMICs with limited effectiveness in influencing the policies, programs and resources allocation in different sectors . In someTo summarize, attention to evolving governance structures and policy development processes for NCDs is vital. It will aid pre-emptive and corrective action at an early stage for the effective, efficient, and sustainable scaling-up of response to NCDs within a health systems context.The authors declare that they have no competing interests.MR conceptualized the paper and wrote the first draft and the final version. SN assisted with the qualitative desk reviews of the data and other literature and reviewed various drafts. LH reviewed the draft of the paper and provided comments and inputs towards the final paper. All authors read, commented, and approved the final version of the manuscript.MR \u2013 Western Pacific Regional Office, World Health Organization SN\u2014University of Auckland, New Zealand LH-- Western Pacific Regional Office, World Health Organization.The views expressed in this paper are solely the responsibility of the named authors and do not necessarily reflect the decisions or stated policy of the organization they work for.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/12/877/prepub"}
+{"text": "A brief history of training of traditional birth attendants (TBAs), summary of evidence for effectiveness of TBA training, and consideration of the future role of trained TBAs in an environment that emphasizes transition to skilled birth attendance are provided. Evidence of the effectiveness of TBA training, based on 60 studies and standard meta-analytic procedures, includes moderate-to-large improvements in behaviours of TBAs relating to selected intrapartum and postnatal care practices, small significant increases in women's use of antenatal care and emergency obstetric care, and small significant decreases in perinatal mortality and neonatal mortality due to birth asphyxia and pneumonia. Such findings are consistent with the historical focus of TBA training on extending the reach of primary healthcare and a few programmes that have included home-based management of complications of births and the newborns, such as birth asphyxia and pneumonia. Evidence suggests that, in settings characterized by high mortality and weak health systems, trained TBAs can contribute to the Millennium Development Goal 4\u2014a two-thirds reduction in the rate of mortality of children aged less than 14 years by 2015\u2014through participation in key evidence-based interventions. Every year, an estimated four million babies die in the first four weeks of life, and a similar number of babies are stillborn. Moreover, half a million women die from pregnancy-related causes. Most of these deaths occur at home during the first postnatal or postpartum week, especially within the first 24 hours of birth. Most occur in developing countries with weak or failing health systems, with South Asia and sub-Saharan Africa being especially hard-hit \u20133. For mAlthough TBAs have been trained since the late 1800s, important milestones over the last century illustrate the shifting policies on TBA training as a global public-health strategy. Credit for the first formal training programme is usually given to a British missionary midwife, Miss M.E. Wolfe, working in Sudan in 1921 . HoweverThe broad goals of TBA training programmes are to reduce maternal and child mortality and morbidity and to improve the reproductive health of women. The objectives include: enhancing the linkages between the modern health system and community, increasing the number of TBA-attended births, and improving the skills and stature of TBAs . TraininThe content of curricula of TBA training also varies. Most TBAs have been trained to upgrade their skills so as to be able to perform safe deliveries. Consistent with the emphasis on extending the reach of primary healthcare, many TBAs have also been trained to take on the expanded functions of prevention, screening, and referral , 13. VerThe answer to the question: is TBA training effective? depends on the objectives and content of a particular training programme and the outcomes measured. From 1997 to 2002, we conducted a meta-analysis of the available published and unpublished studies on the effectiveness of TBA training. We updated this review for selected topics in 2003 and 2004 \u201315. The Details of materials, methods, and statistical analyses have been described elsewhere \u201315. Brieh, representing the standardized difference between the trained and the untrained TBA group on the outcome of interest. The variance-weighted mean effect size for each sub-group of outcomes was then calculated, and homogeneity tests were performed on the distributions of the weighted mean effect sizes. With a few exceptions, homogeneity of variance was rejected (\u03b1=<0.05), and the weighted mean effect size and 95% confidence interval were calculated using formulae based on a random effects model. Sensitivity analysis was conducted to detect the presence of publication bias. In addition, stratified analyses, by study design and sampling procedure, were performed to examine the influence of these potential moderating variables on the weighted mean effect sizes. Lastly, sub-group analyses conducted to date include antenatal care, referral for emergency obstetric care, birthing and newborn-care practices, perinatal and newborn health outcomes.Most outcomes measured were reported as percentages. The percent difference associated with each outcome was converted to a common scale using the effect size index Cohen's The findings of the meta-analysis were positive for the sub-groups of outcomes measured . StratifTBA training is associated with moderate-to-large improvements in behaviours relating to selected intrapartum and postnatal care practices, and small but significant decreases in perinatal mortality and neonatal mortality due to birth asphyxia and pneumonia. The findings are consistent with the historical focus of TBA training on extending the reach of primary healthcare and a few TBA training programmes that have included management of birth asphyxia and pneumonia care. TBA training is also associated with small but significant increases in women's use of antenatal care and emergency obstetric care, suggesting that referral is a multi-faceted process, and influence of TBAs on care-seeking behaviour may be limited.Unfortunately, incomplete reporting by authors resulted in loss of studies and datasets and limited our ability to examine which intervention characteristics were associated with better outcomes, cost-effectiveness, and the association between training and maternal mortality\u2014the rationale for the policy shift away from TBA training. Moreover, due to the variable quality of studies included in our sample, we could not address causality and only the magnitude and direction of the association between training and the outcomes could be measured. More rigorous studies are now being conducted. In a recent cluster-randomized controlled trial from Pakistan, Jokhio and colleagues showed that TBA training, linked to outreach and facility-based care, resulted in a statistically significant reduction of 30% in perinatal mortality . The estMillennium Development Goal (MDG) 4 aims to reduce mortality of children, aged less than five years, by two-thirds between 1990 and 2015. MDG 5 aims to reduce maternal mortality by three quarters during this timeframe. Policy regarding the best strategies to meet these goals, however, swings between community-based care and facility-based care, while safe motherhood and child-survival advocates compete for limited resources . The finIn settings characterized by high mortality and weak healthcare systems, family and community care providers often include a mix of women, family members, TBAs, and other semi-skilled or skilled health workers. In these circumstances, \u201cAre TBAs the best choice, among others, for training in health promotion and delivery care?\u201d There are a number of considerations. One important consideration is the proportion of deliveries assisted by TBAs since this reflects, to a large extent, their number, distribution, role, status, presence of other providers, and preference of women and families. Our analysis of the 1994\u20132004 Demographic and Health Survey data from 44 countries for the period of three years preceding the survey  showed tThe Lancet\u2014eloquently argued that women, newborns, and children all have lefts, and all would greatly benefit from a health system that delivers proven interventions through a continuum-of-care approach, i.e. from pregnancy through labour, birth, and the postpartum and postnatal periods, and into early childhood; and including home, peripheral health facility, and hospital \u2014must include interventions that prevent and treat complications that kill women\u201d . We beliThe meta-analysis of effectiveness of TBA training was made possible through funding support from the World Bank , USAID , USAID, DFID and the Bill and Melinda Gates Foundation (University of Aberdeen/IMMPACT Project), and the Bill and Melinda Gates Foundation (Save the Children/Saving Newborn Lives Project). The views presented here represent those of the authors."}
+{"text": "The obstructive sleep apnea syndrome (OSAS), a form of periodic breathing, is highly prevalent disorder that affects at least 4% of adult male population and 2% of females and is associated with repetitive episodes of complete (apnea) or partial (hypopnea) occlusion of upper airway during sleep. These episodes result, among others, in loud snoring and in daytime symptoms such as excessive sleepiness, morning headache, irritability, cognitive impairment and lead to reduced quality of life. Varying degrees of transient oxygen desaturation follow the upper airway occlusion, and it is a common pathway for the development of several cardiovascular complications. Central Sleep Apnea (CSA) is another form of periodic breathing characterized by lack of respiratory effort during sleep and frequently coexists with OSA. One major underlying mechanism of CSA is unstable ventilatory drive during sleep. Treatment options for sleep apnea include continuous positive airway pressure (CPAP), oral appliances, and weight loss.In this special issue on sleep-related breathing disorders a number of distinguished scientists report on the following: the association between the duration of sleep and cardiovascular and metabolic comorbidities of patients with OSAS, the influence of age on clinical characteristics and polysomnographic findings of patients with OSAS in Greek population, the effect of weight loss by behavioural, pharmacological, or surgical approaches in the management of OSAS, the mechanisms that may trigger cognitive decline in OSA patients, the evaluation of two different mandibular advance appliances and the application of sclerosant agents for treatment of snoring, the presence of Cheyne-Stokes respiration (CSR), a form of central sleep apnea, in patients with radiologically-proven first-ever lacunar stroke, the implication of age in the pathogenetic link between sleep apnea and plasma homocysteine levels.All the above help us to better understand some mechanisms involved in pathogenesis, consequences, and treatment of sleep apnea syndrome and snoring, and clearly this special issue is a great contributor to our knowledge.Manos AlchanatisManos AlchanatisJames MacFarlaneJames MacFarlaneSofia SchizaSofia Schiza"}
+{"text": "Diarrheal illness remains 1 of the top 5 causes of death in low-income and middle-income countries, especially for children <5 years of age. Introduction of universal childhood vaccination against rotaviruses has greatly reduced the incidence and severity of illness in upper-income and lower-income settings. For adults, norovirus is the leading cause of sporadic cases and outbreaks of diarrheal illness and is responsible for nearly 21 million episodes annually in the United States, of which 5.5 million are foodborne. Public health efforts to control and prevent norovirus illness have focused on rapid outbreak detection and source identification and control of transmission in institutional settings. Diarrheal illness remains 1 of the top 5 causes of death in lower-income and middle-income countries (For children <5 years of age, rotavirus is the leading cause of diarrhea-associated illness and death. Fortunately, safe and effective vaccines against rotavirus illness are now available in many countries. Introduction of universal childhood vaccination against rotaviruses greatly reduces the incidence and severity of illness in upper-and lower-income settings (In adults, norovirus is now recognized as the leading cause of sporadic cases (Public health efforts to control and prevent norovirus illness have focused primarily on outbreak detection and control. The implementation of CaliciNet, as described by Vega et al. (Because a large proportion of norovirus illness results from foodborne exposures, considerable effort has gone into development of methods for detecting and eliminating virus contamination from food items, particularly shellfish (Finally, several other viruses, including astrovirus, sapovirus, and as described by Drexler et al. ("}
+{"text": "Translational Neurodegeneration will provide a perfect platform at the global level to share knowledge and experience of the latest research on the epidemiology, etiology, pathogenesis, diagnosis, management and prevention of neurodegenerative diseases.A common feature of current biomedical science is inter-disciplinary research and collaboration. Translational research, the basis for translational medicine, integrates the basic sciences and clinical medicine with the aim of optimizing preventive measures and patient care, is at the cusp for expansion. Translational medicine, in short, is the process of turning appropriate biological discoveries into drugs and medical devices that can be used in the treatment of patients. Vigorous efforts have been made to link basic scientific research with clinical investigations. Notably, in the area of neurodegenerative disorders, more basic and clinical researchers as well as nations have joined forces to explore the interface between basic neurosciences and clinical neurology and psychology. Thus, the newly established journal of Indeed, the prevalence of neurodegenerative disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD), has increased significantly as global populations age. Specifically, the number of cases of dementia in the developed world is projected to rise from 13.5 million in 2000 to 21.2 million in 2025, and to 36.7 million in 2050[The discovery and application of levodopa (L-dopa) is one of the best examples of translational research for neurodegenerative diseases. In 1910s, L-dopa was first isolated from seedlings of Vicia faba; and in 1938, L-dopa decarboxylase was discovered, which can produce dopamine (DA) from L-dopa. In 1959, DA was found enriched in the basal ganglia; and in 1960, a severe striatal DA deficit was demonstrated in PD patients. These major discoveries and a deepening understanding of the neurochemistry of DA and the neuropathology of PD led to the concept of \"DA replacement\" with L-dopa. In 1961, L-dopa was tried in PD patients by i.v. treatment. In 1967, oral administration of L-dopa was reported to produce dramatic improvements in PD patients with increasing amounts over long periods . Since tSubstantial progress has been made in understanding the pathogenesis of neurodegenerative diseases, but we are still a long way from applying it to clinical application. Translational research will definitely help overcome the bottleneck and barriers in 1) identifing and validating biomarkers for early or pre-clinical diagnosis as well as clinical progression; 2) promoting the innovative clinical technologies, such as neuroimaging, stem cell technology and nanotechnology; and 3) developing the novel drug candidates; and more importantly, to gain a multitude of new ideas and contacts back to research. Thus, launching a journal in translational neurodegenerative diseases is essential and timely.Translational Neurodegeneration. Notably, the articles are interdisciplinary and focus on many current issues facing translational neuroscience research.The latest research on the etiology, pathogenesis, potential diagnostic markers and treatment modalities of PD has been presented at the XIX World Congress on Parkinson's Diseases and Related Disorders. Almost 2500 distinguished scientists, clinicians and allied health experts gathered in Shanghai, China, December 11-14, 2011 to enhance collaboration in these important inter-disciplinary research areas. Organized by the Association of Parkinsonism and Related Disorders and the local host, the Department of Neurology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, the congress is the highest level of academic conferences in the field of PD and related disorders. Several speakers and attendees contributed review and original articles for the inaugural issue of Research of gene mutation, especially of alpha-synuclein, has provided important clues in understanding the pathogenesis of PD. In cell models, A53T mutation of alpha-synuclein can increase macroautophagy, which has not yet been detected in patients. Yue Huang et al . It gavePeter A. LeWitt discussed the wide role of norepinephrine (NE) in his review titled \"Norepinephrine: the next therapeutics frontier for Parkinson's disease\" . NE may Jon Stoessl introduced the latest progress in \"Neuroimaging in the early diagnosis of neurodegenerative diseases\" . SPECT aTranslational Neurodegeneration will promote the rapid conversion of basic research to clinical applications benefiting patients better and faster. The concept and spirit of translational research in the field of neurodegenerative disorders will spread through Translational Neurodegeneration and the authors.Translational research and knowledge of neurodegeneration are expanding at a fast pace. The potential to find causes, treatments and cures for many neurological and neurodegenerative diseases are available to us. This congress and our journal highlight the opportunities for interdisciplinary and global collaborations. By offering a high-visibility forum for new insights and discussions of translational research in neurodegenerative diseases, Translational Neurodegeneration; Rui Jin Hospital leaders, colleagues, team members and leaders of Shanghai Jiao Tong University School of Medicine, University of Nebraska Medical Center, Society for Neurology Chinese Medical Association and Chinese Society for Neuroscience, without whose help the success of this undertaking could not have been realized.We thank the authors, referees, and Springer and BioMed Central, our publisher, for their help in making this journal and first issue possible. Special thanks also go to Ms. Robin Taylor from the University of Nebraska Medical Center; Drs. Jianqing Ding and Yuyan Tan, managing Editors of"}
+{"text": "Phaseolus vulgaris L.) is an important source of plant protein, and member of the legume family, which includes soybean, cowpea, and lentils. With its relatively small genome size, well-characterized cytogenetics, and recently sequenced genome, common bean serves as a good model for legume epigenetics. Accumulation of recent and ongoing bean community-wide genomic and transcriptomic sequence data along with advances in sequencing technology enables the further understanding of the roles of histone-DNA interactions, small RNAs, and cytosine methylation in gene regulation in common bean. Till date, there has not been much progress in studying various epigenomic marks in common bean, and therefore, the long-term objective of this research is to identify protein-DNA interaction sites in the common bean genome to include histones, as well as, non-histone proteins such as transcription factors involved in biotic and abiotic stress. The short-term objective of this work is to develop the first reference epigenomes in four common bean genotypes  as related to histone modifications. Common bean genotypes can be broadly classified into those of Andean and Mesoamerican origin, and these genotypes were selected for their importance and use in genomics, as well as breeding. The immediate goal of this work is to identify the hierarchy of binding of histones H4K12ac and H3K9me2 in the common bean genome using Illumina sequencing. To achieve this goal, a chromatin immunoprecipitation (ChIP) protocol was developed for common bean, and chromatin from leaves of these four genotypes was isolated and used for ChIP and ChIP-sequencing (ChIP-seq). Sequence analyses of this data is enabling the understanding of the layout of these histone modifications across the genomes of these four genotypes when compared to the reference genome sequence of G19833. This work serves as the first reference histone-DNA interaction map in common bean and lays a foundation for comprehensive analyses and large-scale studies of histone modifications and global protein binding sites in this important plant species, further facilitating the annotation of the common bean genome.The common bean ("}
+{"text": "Indeed, the remarkable achievements in contemporary integrative oncology only emphasize the need for a patient-tailored strategy of care attuned to the individual's biophysical, psychological, social, cultural, and spiritual needs and concerns. The integrative challenge is how to provide an evidence-based consultation and supportive treatment to patients who confront fear at the moment of breaking the bad news of cancer diagnosis; how to improve their well-being during chemotherapy, radiation, surgical, or palliative treatment; and how to support patients and their care providers along the survivorship pathway or across the threshold of life. In daily practice, integrative oncology may be employed to reduce nausea and vomiting  in contemporary cancer care is an emergent field of clinical practice and research throughout the world. The use of herbs, nutrition, mind-body, and spiritual practices is deeply rooted in the cross-cultural mosaic of Middle Eastern and South Asian nations. The concept of integrative oncology has emerged in the last decade to signify the need to amalgamate traditional and complementary medicine practices with evidence-based research aiming to improve supportive cancer care. The integration of ancient s ginger ), to alls ginger ), and tos ginger ), mood ds ginger ), and maThe paper by H. Zaid et al. featured in this special issue reviews the concept of traditional Islamic medicine with regard to herbs with potential anticancer activity. This paper illuminates the importance of bridging ancient knowledge rooted in Greco-Arabic medicine and contemporary research. But, in addition to the extensive review presented by H. Zaid et al., this paper is also distinctive thanks to the contribution of the two other authors in this collaborative Israeli-Palestinian paper. Notable is the contribution of M. Silbermann, the director of the US National Cancer Institute-affiliated Middle-East Cancer Consortium (MECC), who has succeeded over the last 15 years in promoting supportive care collaborations that have included joint integrative oncology projects between MECC  and other Middle-Eastern countries .  The paper by E. Ben-Arye presents an integrative oncology program operated within conventional oncology services in northern Israel aimed at improving patients' quality of life during chemotherapy and advanced cancer. The authors address barriers to integration of traditional and complementary medicine in supportive care of Arab patients and propose six practical recommendations aimed at improving patients' access to integrative supportive care as well as compliance with treatments. This paper emphasizes the need to base integrative oncology on a sensitive cross-cultural approach that takes into consideration social, cultural, and spiritual elements.The paper by M. Schaltz et al. intensifies this cross-cultural theme by reflecting on palliative care from the perspective of Jewish and Islamic traditions. The collaboration in this paper between M. Schultz and K. Baddarni, two scholars in spiritual supportive care in northern Israel, highlights the richness of therapeutic dialogue between Muslim and Jewish health care providers who share faith in the role of the integrative dialogue. This paper summarizes ethical, religious, and spiritual insights gleaned in the management of patients in the community-centered Al-Taj organization and in the oncology department in Rambam health care campus, which is named for the renowned Jewish physician Maimonides.The paper authored by I. Cantarero-Villanueva et al. from Granada presents the flavor of the ancient cities of southern Spain, the backdrop for the Golden Age of collaborative Muslim and Jewish physicians, including Maimonides and the followers of Ibn-Sina, the most prominent Islamic medicine scholar. In this paper, the authors evaluated, in a randomized controlled trial, the effects of a multimodal exercise and massage program on the well-being of breast cancer survivors. The reduced fatigue, tension, depression, and improved vigor and muscle strength after intervention and 6 months after discharge are remarkable and support the need for other rigorous trials in the integrative oncology field.alternative) to CIM (with emphasis on integrative) that will enable patients and physicians to discuss complementary use in an open nonjudgmental context. Moving from West to East across the Mediterranean and West Asia, the paper by P. Puataweeponge et al. presents the notion of complementary medicine in Bangkok, Thailand. The authors present a study regarding CAM use by a large cohort of cancer patients attending outpatient radiotherapy treatment in Thailand. The high prevalence of CAM use of more than 60% is notable in light of the patient-oncologist communication gap illustrated by the high prevalence (58.3%) of patients who did not disclose CAM use to their doctors. This communication aspect should raise concern when 9.4% of patients in this study reported side effects of CAM treatments. Moreover, this study emphasizes the need for a paradigm shift from CAM (with emphasis on in vitro research elements needed to base any clinical integrative oncology activity. Zhang et al. from China report. the anticancer effects of the photochemical Zerumbone, isolated from the plant Zingiber zerumbet Smith. Although additional rigorous studies are warranted, the promising apoptosis induction effect of this plant on pancreatic carcinoma cell lines may suggest that ginger and related plants may have anticancer properties in addition to their beneficial effect in chemotherapy-related nausea and vomiting. In the paper by Y. H. Liu et al. from neighboring Taiwan, they studied Abrin, a protein purified from the seeds of Abrus precatorius, and reported that prohibitin, a tumor-suppressing protein, plays a role in abrin-induced apoptosis. These findings join the growing number of promising studies in integrative oncology that may support development of new and, in some cases, traditional medicine-based, therapeutic agents and modalities for the benefit of patients with cancer across the globe. Two papers in this issue present the fundamental"}
+{"text": "The Western Palearctic (WP) is composed of Europe, Middle East and North Africa. In this territory, the Mediterranean Sea, and the land under the influence of the Mediterranean Sea is the most important geographical character for both migration and dispersion of organisms; especially for invertebrates including sand flies. Anatolia (Asia-Minor) takes place on the crossroads of this area and these events.The phlebotomine sand flies  are vectors of several infectious pathogens causing leishmaniases and arbovirus infections due to phleboviruses. Several of these diseases have wide geographical distributions in the WP, and give rise to occasional epidemic outbreaks. In numerous countries, increasing risk factors are making sand fly-borne diseases a major public and veterinary health problem. Many studies on phylogenetic relationship among sand fly taxa, their distribution, population structure and diseases of phlebotomine species have been already published, but there are still many gaps waiting to be filled up in, especially, Anatolia. In this point, scientists have to discuss some deficiencies under cover of geography, history and phylogenetic studies to understand the mechanisms of distribution of both sand fly species and their pathogens in Anatolia.In this presentation, updates in distribution of sand fly species with state of art maps of EU-VBORNET project, possible new species, leishmaniasis and phleboviruses epidemiology will be discussed with an emphasis on several studies performed by our group between 2000 and present in Anatolia.Studies were supported by EU-FP7 Edenext project, HU-Scientific Research Foundation and Turkish Scientific and Technical Research Council."}
+{"text": "Water-electrolyte disturbances are one of the most common complications of acute brain injury of various origins, threatening the life of the patient and requiring timely correction. In this work we studied the structure of water-electrolyte complications in patients in the neurological intensive care with acute brain injury.We analyzed 259 cases of water-electrolyte disturbances that developed in patients treated in the Department of Intensive Care of Russian Polenov's Neurosurgical Institute from 2001 to 2012. Patients were between 16 and 55 years old. A total of 142 patients were operated for brain tumor, 72 of them of basal-supratentorial localization; eight severe brain trauma; 62 of the hemorrhagic type of stroke, one herpes encephalitis. We excluded from this study the patients with heart and renal failure receiving diuretics. We measured BP, HR, CVP, hourly and daily urine output, level of K and Na in plasma, brain natriuretic peptide (BNP) one to four times a day, and levels of K and Na in urine in single and daily servings. All patients were receiving dexamethasone at a dose between 8 and 32 mg/day as an anti-edema therapy, and thus levels of ACTH and cortisol were not investigated.Central diabetes insipidus (CDI) developed in 106 patients. Against the background of substitution therapy, we did not observe the development of complications, hypovolemia, hypernatremia, or hyperosmolality. Out of 48 cases of CSWS, in 12 cases the symptoms interleaved with the symptoms of CDI. For 24 patients, CSWS was complicated by depressed consciousness, for three patients by convulsions against the background of hypovolemia, hyponatremia, or hypo-osmolality. No correlation between BPN level and absence of CSWS symptoms was found.In patients with acute brain trauma we observed two syndromes causing water-electrolyte disturbance - CDI and CSWS. CSWS generally is more severe than CDI. We could not determine a correlation between BPN level and the absence of presence of the CSWS symptoms."}
+{"text": "Advanced glycation end-products (AGEs) generated with aging or in the presence of diabetes mellitus, particularly AGEs derived from the glucose/fructose metabolism intermediate glyceraldehyde ), were recently shown to be closely involved in the onset/progression of diabetic vascular complications via the receptor for AGEs (RAGE). TAGE also contribute to various diseases, such as cardiovascular disease; nonalcoholic steatohepatitis; cancer; Alzheimer\u2019s disease, and; infertility. This suggests the necessity of minimizing the influence of the TAGE-RAGE axis in order to prevent the onset/progression of lifestyle-related diseases (LSRD) and establish therapeutic strategies. Changes in serum TAGE levels are closely associated with LSRD related to overeating, a lack of exercise, or excessive ingestion of sugars/dietary AGEs. We also showed that serum TAGE levels, but not those of hemoglobin A1c, glucose-derived AGEs, or N\u03b5-(carboxymethyl)lysine, have potential as a biomarker for predicting the progression of atherosclerosis and future cardiovascular events. We herein introduce the usefulness of serum TAGE levels as a biomarker for the prevention/early diagnosis of LSRD and the evaluation of the efficacy of treatments; we discuss whether dietary AGE/sugar intake restrictions reduce the generation/accumulation of TAGE, thereby preventing the onset/progression of LSRD. Diabetes mellitus (DM) is one of the largest global health emergencies of the 21st century. Increases are reported each year in the number of individuals with this hyperglycemic condition, which may result in life-changing complications. In addition to the 415 million adults (this will increase to 642 million adults by 2040) already estimated to currently have DM (a DM-related death occurs every 6 s), there are 318 million adults with impaired glucose tolerance (IGT), which places them at high risk of developing the disease in the future ,8,9. We Hence, a focus was placed on TAGE and a specific competitive enzyme-linked immunosorbent assay (ELISA) was developed, and the clinical utility of measuring TAGE as a biomarker for evaluating disease activity in LSRD was examined.In vivo AGE generation is affected by sugar concentrations, the rate of turnover of the chemically modified target, and the time available. Increases in glucose concentrations were previously considered to have a major influence on the Maillard reaction; however, glucose is one of the least reactive sugars found in biological organisms  fluorodeoxyglucose-positron emission tomography (FDG-PET) in outpatients in vitro ammation ,82. In aammation ,84,85.in vivo tumor growth of G361 cells . T. T103]. We evaluated the amounts of AGEs and sugars in beverages and foods, which cause the generation of TAGE in the body. We evaluated the amounts of various AGEs in 885 kinds of beverages and 767 kinds of food, and found that the amounts of AGEs derived from Glu-AGEs/Fru-AGEs (particularly Glu-AGEs) more accurately reflected the amounts of AGEs in beverages and foods than those of CML . Our evaet al. prospectively examined the relationship between the consumption of SSB and risk of DM from 17 cohorts  [Imamura n years) . They reThe findings of our studies suggest that sugars  are present at appreciable levels in common beverages , and exoThese findings are promising in that the concept of the restricted intake of AGEs and sugars in beverages and foods may be a new strategy when considering the suppressed generation/accumulation of TAGE and prevention of LSRD.As described above, changes in serum TAGE levels are closely associated with MetS and IR, postprandial hyperglycemia, dyslipidemia, and hypertension, which are related to overeating, the lack of exercise, or excessive ingestion of sugars (HFCS and sucrose)/dietary AGEs . We propThe characteristics of modern dietary habits  promote the generation and accumulation of TAGE in the body, and are strongly involved in the onset and progression of LSRD. Thus, our findings provide a new concept of preventative measures against LSRD, including aging."}
+{"text": "Migration and trauma is a critical and timely area of inquiry given the enormous transnational migration occurring within the past year. The UN estimates there are over 244 million people living outside of their country of origin  offer a unique look at the association between posttraumatic growth and dispositional optimism, perceived social support, and PTSD among 111 refugee and asylum-seeking adolescents. At least some PTG was reported by the sample. PTG and PTSD were not statistically significantly associated, but PTG was associated with higher levels of optimism and social support. This is one of the first studies conducted to explore these associations within an adolescent population and future research, especially longitudinal , People's Republic of ChinaBrian J. Hall Johns Hopkins Bloomberg School of Public Health Baltimore, MD, USA E-mail: brianhall@umac.mo; bhall31@jhu.eduDepartment of Health, Behavior, and Society Department of Psychiatry Academic Medical Center University of Amsterdam Amsterdam, The Netherlands Arq Psychotrauma Expert Group Diemen, The NetherlandsMiranda Olff"}
+{"text": "The seas are continuously pervaded by a broad range of contaminants entering the marine environment from polluted soils, the atmosphere, sewage, water transport or river streams (Shahidul Islam and Tanaka, Biomass transfer among species of a food web can be modeled using allometric scaling rules describing body size, consumption and metabolism (Yodzis and Innes, Geobacter spp. (Mahadevan et al., Shewanella oneidensis (Fredrickson et al., Pseudomonas putida (Nogales et al., The described efforts facilitated generic estimations of contaminant flows in ecosystems, but largely neglected the contribution of microorganisms to pollutant degradation. Specifically, PCBs can be dechlorinated and degraded by a range of bacteria (Borja et al., P. putida. First, the authors conducted an extensive literature review to complement a food web reconstruction (Coll et al., P. putida for constraint-based simulation of microbial PCB degradation. The study integrated two methodologically similar modeling approaches within a reaction-based ecological/microbial network representation, relying on the parallels between representing PCB concentrations and flows on the ecosystem level, and metabolite concentrations and reaction fluxes on the microbial cellular level. Therein, marine species groups resemble the representation of metabolites, while contaminant flows are modeled as reactions. This approach enabled the seamless integration of ecological and metabolic modeling techniques, providing the basis for multi-scale simulations of ecosystems.Taffi et al.  have recP. putida. Further, the impact of different bioremediation scenarios on global and local network indices was assessed. Importantly, the generality of the proposed approach facilitates the integration of measured data, the incorporation of established techniques from ecological and metabolic modeling and the direct application of the methodology to other ecological and microbial networks. Thus, it can be used to guide the selection of appropriate bacteria and consortia (Thompson et al., The modeling approach was used to predict the influence of different microbial bioremediation strategies on the fate and distribution of PCBs in marine species of the Adriatic Sea. The effect of varying oxygen levels on microbial PCB degradation revealed a tradeoff between PCB uptake and growth of The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Objectives: The objective of this post-hoc exploratory analysis was to examine the relationship between age and measures of cortical excitability and inhibition.Methods: Forty-six participants  completed MT, SICI, ICF, and CSP testing in a cross-sectional protocol. Of these 46 participants, 33 completed LICI testing. Multiple linear robust regression and Spearman partial correlation coefficient were used to examine the relationship between age and the TMS measures.Results: In the overall sample of 46 participants, age had a significant negative relationship with motor threshold (MT) in both the right  and left  hemispheres. This significant negative relationship of age with MT was also observed in the sample of depressed youth in both the right  and left  hemispheres, but not in healthy controls. In the sample of the 33 participants who completed LICI testing, age had a significant negative relationship with LICI  in both the right  and left  hemispheres. This negative relationship between age and LICI  was also observed in depressed youth in both the right  and left  hemispheres.Conclusion: These findings suggest that younger children have higher MTs. This is more pronounced in depressed youth than healthy controls. LICI inhibition may also increase with age in youth. Transcranial magnetic stimulation (TMS) measures of cortical excitability and inhibition have shown initial promise as biomarkers and for the study of neurophysiology in youth with attention deficit hyperactivity disorder  which is a single pulse TMS measure and intracortical facilitation (ICF) which is a paired-pulse TMS measure. Prior human pharmacologic studies indicate that the MT is at least partially dependent on voltage-gated sodium channels while ICF is an indirect measure of glutamatergic N-methyl-D-aspartate (NMDA) mediated neurotransmission  and excitability (MT and ICF) were collected during a single session. A subgroup of this cohort completed LICI testing during the same testing session. Study design details have been previously published  and excitability . The TMS measures were log transformed to obtain a more normal distribution (because of skewness).The primary independent variable was patient age in years. Sex and CDRS-R total score were included as covariates in the models to bolster precision in the evaluation of the relationship between age and each measure of cortical inhibitory or excitatory functioning. Some  were used to examine the relationship between age and TMS measures of cortical inhibition  and excitability  in the overall sample, while adjusting for sex and CDRS-R total score, and then separately in depressed youth and healthy controls, while adjusting for sex. The estimated slope from the regression model indicates the mean change in each TMS measure per one-year increase in age, while the sample correlation coefficient indicates not only direction, but also strength of the linear relationship between age and each TMS measure. The Spearman partial correlation coefficient can also be interpreted as the effect size estimator in evaluating the magnitude of the relationship between age and each TMS measure.This was an exploratory study with the aim of investigating the impact of age on measures of cortical inhibition and excitability in youth. Analyses were performed on the entire sample and then on subgroups of healthy and depressed youth. The rationale for this approach was to maximize limited data and with the realization that the impact of depression or depression severity on these neurophysiological measures is not definitively known. Demographic and clinical characteristics for the overall sample of patients and for depressed youth and healthy controls were described using the sample mean and standard deviation for continuous variables and the frequency and percentage for categorical variables. Multiple linear robust regression (with MM estimation) and the Spearman partial correlation coefficient (post-hoc) regression models (similar to that described above) by evaluating the interaction effect of group  with age on the TMS measure. Comparing the regression parameters (slopes) between groups was used to assess if the mean change in the TMS measure per one-year increase in age was different between healthy controls and MDD patients.Regression coefficients found to have statistical significance for each of the two groups in the abovementioned regression analysis, were then tested in subsequent . The level of significance for all tests was set at \u03b1 = 0.05 (two-tailed). We implemented the False Discovery Rate procedure  with MDD completed MT, SICI, ICF, and CSP testing. Demographics of the sample are also characterized our prior publication. In comparing participants with MDD and healthy controls, there were no statistically significant differences in age, sex, or handedness  and left  hemispheres. This significant negative relationship of age with MT, while adjusting for sex, was also observed in the sample of depressed youth in both the right  and left  hemispheres, but not in healthy controls. Note that lower MT values reflect increased excitability. We also present scatterplots of the log transformed MT values (left and right hemispheres) against age, with a fitted regression line and 95% confidence limits, by depressed youth and healthy controls  and left  hemispheres. This negative relationship between age and LICI , while adjusting for sex, was also observed in depressed participants  and left  hemispheres and in healthy controls . Note that lower LICI values reflect increased inhibition. Scatterplots of the log transformed LICI  values (left and right hemispheres) against age, with a fitted regression line and 95% confidence limits, by depressed youth and healthy controls are presented in Figures post-hoc results of the interaction of group with age indicated that the slope of the regression of LICI-200 ms on age was similar for both healthy controls and MDD patients in the left hemisphere  in both the right  the MT was unobtainable with maximum output of the stimulator  had a statistically significant negative relationship with age in depressed youth, but not in healthy control participants. It is important to acknowledge the lack of a relationship may be attributable to low power, given the high degree of variability in the measure in general. Lower LICI ratios signify greater inhibition and increased GABAA receptors decreases from childhood to adulthood  Great Neck, New York; and Pfizer Inc., New York, NY. He has served as a site subprincipal or principal investigator  for Eli Lilly and Co, Indianapolis, Indiana; Forest Laboratories, Inc., New York, NY; Merck and Co, Inc., Whitehouse Station, New Jersey; and Pfizer Inc.Mustafa M. Husain has received research support from the National Institute of Mental Healthy, Stanley Medical Research Institute, Cyberonics, Inc., Pfizer, Inc., Neuronetics Inc., Magstim; has served as a consultant for AstraZeneca; served on speaker bureau for AstraZeneca, Bristol-Meyers-Squibb, and Abbott Laboratories.Graham J. Emslie has received research support from the National Institute of Mental Health, Biobehavioral Diagnostic Inc., BioMarin, Duke University, Eli Lilly, Forest Laboratories, GlaxoSmithKline, Mylan, and Somerset; has served as a consultant for Alkermes, Inc., Allergan, NCS Pearson , Bristol-Myers Squibb, Eli Lilly, Forest Laboratories, GlaxoSmithKline, INC Research Inc., Lundbeck, Merck, Pfizer, Seaside Therapeutics, Shire, the Texas Department of State Health Services, University of Miami, Valeant, and Wyeth; and was on the Speakers Bureau for Forest Laboratories.In the last 5 years, Zafiris J. Daskalakis received research and equipment in-kind support for an investigator-initiated study through Brainsway Inc. and a travel allowance through Merck. Zafiris J. Daskalakis has also received speaker funding through Sepracor Inc., AstraZeneca and served on the advisory board for Hoffmann-La Roche Limited and Merck and received speaker support from Eli Lilly.Drs. Paul A. Nakonezny, Charles P. Lewis, Michael J. Zaccariello, John E. Huxsahl, and Betsy D. Kennard have no disclosures.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "We report our experience in a University Hospital 2012-2013) and in the School of Medicine (2001-2013) in courses committed to promote original thought, to provide basic and operationally useful skills, to teach and to explore the possibilities of setting up networks and existing collaborations. The contribution of ideas, resources, skills and tenacity is the basis for strategic researches aimed at promoting quality, effectiveness and efficiency of health systems. The specific environments and healthcare organizations for which the research is a structural mission need quality and visibility, indicators of quality and efficiency. Vocational training integrated and participated within all the active components with a clinical profile  will facilitate those who wish to plan projects also with international European profile 2-2013 an.1) Actual research ongoing in the individual clinical institutions, by the presentation of projects implemented or under way, regardless of specific funding.2) Strategies of Project Management through an analysis of the context (scenario), feasibility, impact and contingency plans.3) Realistic prospects for fundraising, public and private, building-up overviews of applied research with the contribution of all students. The course implements the explicit use of methodologies of data-mining and the subsequent elemental analysis of usable information:a) predictive models,b) assessments of sensitivity/specificity (diagnostic tests),c) comparative analysis of the risks in case-control or randomized studies, and the calculation of the required number,d) comparison of averages or changes of measures in sequential studies,d) definition of some possibilities for translational research with the development of models.The expertise in clinical research is limited in most institution and not fully oriented toward Predictive, Preventive, and Personalized Medicine (PPPM) concepts and goals. The consequence is that most funded research are addressed to innovative fields but show often limited attention to a shared patient-physician center strategy, to integration and even to outcome. These trainings to be comprehensive and effective must move along PPPM directives; these must be included in the projects that should be independently supported (such as EU funding) within competitive calls. The goal is overcoming the gap among predictive, preventive and personalized medicine training professionals \u2013 not only MDs -, for sustainable and rewarding research projects, including nutrition and lifestyle chance strategies by health psychology tools. The promotion of the professional quality in translational research  is the pre-requisite for innovative best practices and their dissemination of the most high impact information."}
+{"text": "This series of papers focuses on a quality of care framework for maternal health, and systematically reviews the evidence of interventions aimed at improving care at the community-, district- and factility-levels. While the systematic reviews highlight the effectiveness of specific quality improvement efforts on maternal and newborn health, it also illlustrates the dearth of evidence on community-, district- and facility-level interventions, particulary for issues specific to quality of maternal health care and maternal newborn health outcomes. Further evidence is now needed to evaluate the best possible combination of the strategies. Governments, stakeholders and donors need to work together to form these policies and develop models of health care to suit the needs of their own population. This series of papers focuses on a quality of care framework for maternal health, and systematically reviews the evidence of interventions aimed at improving care at the community-, district- and factility-levels. The approaches included in this paper had an effect on process and outcome measures for mothers and newborn health (MNH). Effects on other types of outcomes, while important, are not included in this analysis. In this final paper of the series, we summarize the most critical findings, and highlight the evidence gaps and research priorities identified through the analysis of the scientific literature. We also discuss the methodological quality of the existing evidence and areas for further advancement of the maternal and newborn health agenda, particularly in low and middle income countries (LMIC) -4.At the community-level, home visitation, community mobilization, women\u2019s support groups and the training of community health workers (CHW) and traditional birth attendants (TBA) have shown significant and positive impacts on MNH outcomes. The community-based generation of funds for transportation also had an effect on access to MNH care in resource limited settings of India and sub-Saharan Africa. Mid-level health worker based care (MLHW) has not only demonstrated outcomes comparable to routine non-MLHW care delivery but also reported better results for some of the outcomes. Many of the interventions, including specialized outreach clinics, continuing medical education, problem-based learning, clinical practice guideline implementation and critical appraisal, showed inconclusive and mixed results on the quality of MNH care or MNH outcomes. Table At the district-level, user directed financial incentives have shown to improve quality of care indicators, with conditional cash transfers and maternal voucher schemes having the most significant positive impacts across a range of MNH outcomes.At the facility-level, evidence suggests that standardized or individualized social support programs and continuity of specialized midwifery care throughout pregnancy, labor and postnatal period have the potential to improve a range of perinatal, maternal, and labor specific indicators. To maintain performance and motivation among the healthcare workers, stress management trainings, multidisciplinary meetings and feedback sessions can reduce work related stress and improve performance. There was limited and inconclusive evidence for the impacts of physical environment, exit interviews and organizational culture modification on any MNH process or outcome measures. Table As discussed in paper 1 [\u2022 In-service training and specialty teams have conclusive benefits in improving maternal health outcomes.\u2022 Social support during pregnancy interventions reduce antenatal hospitalization and caesarean delivery\u2022 Strategies to improve professional practice were reported to have a significant positive effect on the desired practice.While the systematic reviews highlight the effectiveness of specific quality improvement efforts on maternal and newborn health, it also illlustrates the dearth of evidence on community-, district- and facility-level interventions, particulary for issues specific to quality of maternal health care and MNH outcomes. This is particularly evident during the most hazardous time period for women (last trimester of pregnancy to the first week post-partum) when the majority of maternal deaths and severe morbidities occur.Community-based quality improvement interventions were widely assessed for their effectiveness in improving MNH outcomes in low and middle income countries (LMIC). At the district-level, evidence from financial incentives was available from both high-income countries (HIC) and LMIC settings. Other interventions at the district-level were mainly evaluated in HIC settings. Given the differences in LMIC and HIC countries\u2019 infrastructure and health systems, there is limited generalizability of findings across countries. There is also an information gap on the effectiveness of these interventions on different population groups that may represent within-country disparities.At the district-level, many of the components of leadership, supervision, health information systems and staffing models had limited evidence of impact on the quality of maternal healthcare, or on MNH outcomes. Overall, very few maternal health specific outcomes were observed at the district-level. Although financial incentives, both user- and provider-directed, have been widely evaluated for their effectiveness in improving MNH outcomes, audits, feedbacks and information systems are mostly evaluated in the context of general health outcomes. Moreover, reviews focusing on MNH specific interventions, like maternal and perinatal mortality audits, require strong, standardized data collection mechanisms to evaluate their effectiveness. Improving the health information systems in countries is necessary for any evaluation of the impact of mortality audits.From the facility-level evidence, most of the findings from social support and specialized midwifery teams programs during pregnancy and labor were limited to HIC. There is limited evidence on the effects of these interventions on maternal and newborn health outcomes in LMIC. There is also a lack of data evaluating the effectiveness of structural and cultural changes, educational interventions, and the facility mix of staff skills. Future research on the impact of these interventions (at the facility-level) on quality of maternal health care and specific maternal health outcomes in LMIC\u2019s is essential in order to make evidence-based recommendations for better policies, programs and practice.Very few of these studies provided evidence on sustainability and scale up, particularly in countries where resources are constrained and health systems are weak. Recent studies in Uganda and Ghana have highlighted the challenges in scaling up interventions that have been proven effective ,6. InterThere are currently several innovative interventions that are being implemented globally to improve the quality of maternal health services. The Maternal Health Task Force, for example, is currently supporting multiple research projects aimed to improve referral systems, increase the use of novel methodologies to train providers, introduce innovative approaches to supportive supervision and mentoring, increase access to blood products, develop professional organizations, among many others. The results of the evaluation of the impact of these programs on the quality of maternal care may fill many of the informational gaps in the Quality of Maternal Care Framework that this systematic review has utilized.Finally, qualitative data describing individual components of the interventions for reproducibility will be invaluable for scale up and sustainability. Further evidence is now needed to evaluate the best possible combination of the strategies. Governments, stakeholders and donors need to work together to form these policies and develop models of health care to suit the needs of their own population. This will further lead to outlining approaches that enable health care providers either in the community or in a facility, and program managers at the district-level, to adopt and implement patient-centered, evidence-based interventions to improve the quality of care during childbirth and the immediate postpartum period.Research and programming priorities are summarised in Table We do not have any financial or non-financial competing interests for this review.All authors contributed in writing the paper.Click here for file"}
+{"text": "The mini-review stemmed from a recent meeting on national aging research strategies in China discusses the components and challenges of aging research in China. Highlighted are the major efforts of a number of research teams, funding situations and outstanding examples of recent major research achievements. Finally, authors discuss potential targets and strategies of aging research in China. China Aging Development Report (2013), the severity of the aging population China faced is rarely seen elsewhere in the world. By the end of 2012, China\u2019s elderly population (aged 60 and above) had totaled 194 million, taking up 14.3% of total population; the elderly population aged 65 and above had reached 123 million\u2014constituting one fifth of the world\u2019s elderly population. By 2030, China\u2019s elderly population is expected to reach 400 million, equivalent to the total population of 15 EU countries. China is the country with not only the world\u2019s largest population, but also a country holds the largest elderly population.According to The increases in age-related diseases and the consequent rise in health care costs caused by the decline in the health status along with the aging of the population have brought increasing pressure and burden to the society, families and individuals  joint research.Research on aging and related diseases in China has received significant support from the National Natural Science Foundation of China (NSFC), the Ministry of Science and Technology of China (MOST), the National Health and Family Planning Commission of China (NHFPC), and local departments over the last decades. NSFC has supported approximately 55 million of US dollars on aging research over the past decade Fig.\u00a0. The supIn recent years, China has made significant progress in the research of aging and anti-aging, and the underlying mechanisms. A number of funding programs, such as \u201cThousand Talents\u00a0Program \u201d, \u201cNational Science Fund for Distinguished Young Scholars\u201d, distinguished professors of \u201cChangjiang Scholars Program\u201d, and \u201cHundred Talents Program of the Chinese Academy of Sciences\u201d have been in place to encourage biomedical research including aging and anti-aging research. A brief of made-in-China achievements and summaries in distinct aging research fields is summarized as the following.CETP 405\u00a0V is protective in Ashkenazi Jews but may be a risk allele against longevity in the Chinese population, and that the gene interaction between CETP and APOE polymorphisms confers higher risk of hypertriglyceridemia on Chinese women  are closely related to the occurrence of aging and aging-related diseases  from Terc\u2212/\u2212 SCNT embryos have stronger differentiation potential and self-renewal capacity compared with that of Terc\u2212/\u2212 iPSCs. It is noteworthy that the telomere lengths in SCNT cloned embryos are significantly lengthened, and the capping function of telomeres in Terc\u2212/\u2212 ntESCs is enhanced. In addition, the mitochondrial function of Terc/iPSCs and their differentiated derivatives is severely impaired, while the mitochondrial function in Terc\u2212/\u2212 ntESCs is considerably improved  technology enables the creation of cell models of progeria and geriatrics in laboratory conditions, for studying disease mechanisms and drug screening. Meanwhile, human pluripotent stem cells and gene targeting technologies can assist the knockout or modification of any protein from human stem cells, therefore facilitating the functional study of the proteins in organisms with aging and diseases  inflames surrounding cells of the same and other cell types leading to tissue degeneration, and continuous accumulation results in irreversible losses of differentiated function and pathological changes of the diseased tissue. Anti-aging is also a process involving corrections and/or removals of damaged molecules, the clearance of senescent cells, as well as proliferation and differentiation of stem/progenitor (precursor) cells. Aging and anti-aging process coexist as aging, anti-aging factors, and injury, repair and regeneration are also in parallel. For instance, interactions of inert and reactive bioactive assemblies and the consequent chemical reaction would free or slowly cross-link the biological molecules, and altered oxidative product may produce damaging molecules precipitating aging of the biological tissues. In addition, aging and damage of cellular organelles may be the pathophysiological basis of many neural aging-related diseases such as Alzheimer\u2019s disease (AD) and Parkinson\u2019s disease (PD), while the replication and regeneration of cells may be the promising approach to vanquish many mitotic aging-related diseases Liu, . MobilizAging of the organism, tissues, and organs is the main cause of functional decline, and the premature aging of tissues and organs is the utmost pathological basis for chronic degenerative diseases. Tissue and organ specificity of aging are common for most chronic degenerative diseases, such as AD, atherosclerosis, pulmonary fibrosis, muscular dystrophy, osteoporosis, obesity, diabetes, menopause syndrome, which are related to the premature aging of tissue-specific cells. Aging of organism, tissues, or cells is a complicated and irreversible process, but the time when it occurs and the pace of the process may be regulated. Facing the need to slow down the aging process of the organism and organs, as well as to prevent common chronic diseases, a fundamental understanding of the cause of aging and the causes of aging developing into diseases is a hot topic in the current medical biological research field  has not been well recognized as the primary factors of most non-infectious chronic diseases. Although the central government has been increasing its research budgets continuously in aging research, contributions from the state governments and the private sections have not been considered as high priority to aging research and development. As a matter of fact, with improved living conditions and life expectancies in China, there are significant demands and interests of the general population in detecting premature aging and delaying aging occurrence. In addition, international collaborations in promoting aging research have until recently been on the agenda including our organizing the \u201cShuangqing\u201d forum and a number of other activities from universities, hospitals, and Chinese Academy of Science. Unfortunately, a national-wide database incorporating information of aging-related resources is yet to be established, which requires urgent actions from aging research organizations and researchers. On the other hand, collaborations between hospitals and basic research institutes are lacking which hinders the development of gerontology and geriatrics. The phenomenon of being more difficult for an aging disease to find its way to geriatrics than for ill children to be sent to pediatrics may well reflect currently poor understandings of the mechanisms and biomarkers of aging bodies for clinical practice, making the translational aging research struggle to develop. While many challenges and weakness of aging research in China may be shared by global situations, we highlight at least but not last the following a few that are particularly sought after for development in China:(1) The impact of particular environmental factors, various foods, and exercise levels on aging and lifespan, (2) Genetic traits and epigenetic specificities affected by stress in premature aging and aging related diseases including metabolic disorder and cancers in liver, digestive tracts, and lung, (3) Effect of endocrine/paracrine/autocrine hormones and cytokines, microorganisms, inflammatory/immune responses on tissue and organ aging, (4) Repair mechanisms of stem cells and key enzyme molecules in aging damages, (5) Tissue- and organ-specific mechanisms of aging and diagnostic markers.Numerous tasks need to be done prior to achieving the final goal of preventing and reducing aging-related diseases. By means of original innovative research, it would be important to achieve 3 major comprehensive objectives. Firstly, at the molecular and cellular levels, it would be important to understand the basis of aging, to clarify the molecular characteristics of different types of cellular aging and their roles in the aging of tissues and organs, regulatory networks, plasticity, and clearance mechanisms; to clarify the regulatory mechanism of the change of sub-cellular structure of eukaryotic cell aging in aging and anti-aging process; to clarify the basic structure and spatial conformation of different key molecules and to analyze the binding structural domain of interacting molecules and small molecules; to analyze direct and indirect (epi-)genetic regulatory network of different genes, especially to identify and control the key transcription factors mediating aging process; to unveil the regulation and effect of key environmental factors, especially the microflora in different tissues (such as intestine), excessive nutrients, toxic molecules, as well as exercises and sleep, etc. on the aging of tissues and organs.Second, at the levels of tissue- and organ-specific aging, it would be important to clarify the transition of aging damage to pathological damage and the composition and structural alteration; to clarify the source, function, and regulatory environment of triggers to aging and aging-related diseases; to clarify the susceptible parts of aging organelle/tissue/organ, and the complicated etiology of aging-related diseases; to rationalize and establish the relationship among the causes, to strengthen the research in the compensatory effect of aging development into aging-related diseases; to set out the mechanism, reagents, and methods for early intervention in the transition from aging to aging-related diseases in the micro environment; to clarify the definition of physiological aging and pathological aging of organisms as well as the definition of healthy lifespan; to clarify the similarities and differences in the lifespan regulation of non-vertebrates, invertebrates, and mammals and to clarify the disease susceptibility and resistance mechanisms of different models to aging-related diseases; to clarify the functional ingredients of natural medicine (including Chinese medicine), the role of new, small molecule compounds and clinical drugs , and the regulatory mechanism of other environmental factors to mammalian lifespan.Third, at the levels of particular diseases, it would be important to clarify the role of signaling pathway impairment and pathological basis in the occurrence and development of aging-related diseases through the analysis of animal/human disease models; to clarify the role of stem (precursor) cells and their aging in aging and different common aging-related diseases; to clarify the molecular biological characteristics and development in the research models of brain aging-related diseases , vascular aging-related diseases, marrow aging-related diseases, lung aging-related diseases, and ovarian aging-related diseases; to clarify the mechanisms of prevention of aging-related diseases via either inhibiting key aging molecules or activating anti-aging molecules, thus providing the basis and strategies for further research on the prevention and treatment.It is possible that senescence of a single or a group of cells in certain tissues and organs seeds tissue specific aging which paves, and is a prelude of, aging-related diseases. Such senescent cells suffer irreversible damages, therefore being amplified to cause loss of normal function of aged tissues and organs. Current aging research in China may need to collaborate with researchers in other countries to integrate the approaches of molecular imaging, stem cell biology, molecular genetics and genomics, molecular pathology, histology and embryology, systematic biology, bioinformatics, and clinical medicine to conduct research at different levels of aging and related diseases. Research of aging and aging-related diseases is a great challenge and opportunity in the 21st century. Although it has experienced a long history, aging research is still limited especially on the transition from aging to aging diseases. In-depth and extensive exploration on key molecules and critical mechanisms are still very much sought after. The complexities of various body tissues and differences in structures and functions bring massive difficulties in human anti-aging research. However, the discovery of stem cell plasticity, and continuous breakthroughs in verification of the causal relationship between molecules and aging-related diseases, for example, using different cell culture systems and animal models, have provided opportunity for collaborative innovation in the research on aging and aging-related diseases."}
+{"text": "Comparison of epidemiological studies of JIA is challenging due to many influencing factors, mainly differences in classification criteria or study designs . Recently, longitudinal cohort studies have provided important contributions to the understanding of the disease course of JIA in the long run. Latest advances in research of incidence and prevalence of JIA will be highlighted and discussed to facilitate understanding the consequences of epidemiological knowledge of the disease.P. Lahdenne Speakers Bureau of: Consultancy and speaker\u2019s fees from Pfizer, Abbvie, Roche, Novartis"}
+{"text": "Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected Children are now available on the AIDSinfo website ( http://aidsinfo.nih.gov/contentfiles/lvguidelines/oi_guidelines_pediatrics.pdf ). These guidelines update the last version of the guidelines published in 2009. They are intended for use by clinicians and health care workers providing medical care for human immunodeficiency virus (HIV)-exposed and HIV-infected children in the United States.The The guidelines include a discussion of opportunistic pathogens that occur in the United States and ones that might be acquired during international travel, such as malaria. The section for each opportunistic infection (OI) includes a brief description of the epidemiology, clinical presentation, and diagnosis of the OI in children; prevention of exposure; prevention of first episode of disease; discontinuation of primary prophylaxis after immune reconstitution; treatment of disease; monitoring for adverse effects during treatment, including immune reconstitution inflammatory syndrome (IRIS); management of treatment failure; prevention of disease recurrence; and discontinuation of secondary prophylaxis after immune reconstitution. Recommendations are rated using a system that indicates the strength of each recommendation and the quality of evidence supporting it.Major changes in the guidelines include 1) greater emphasis on the importance of antiretroviral therapy (ART) for preventing and treating OIs, especially those OIs for which no specific therapy exists; 2) increased information about the diagnosis and management of IRIS; 3) additional information about managing ART in children with OIs, including potential drug\u2013drug interactions; 4) updated immunization recommendations for HIV-exposed and HIV-infected children, including pneumococcal, human papillomavirus, meningococcal, and rotavirus vaccines; 5) addition of sections on influenza, giardiasis, and isosporiasis; 6) elimination of sections on aspergillosis, bartonellosis, and human herpes virus (HHV-6 and HHV-7) infections; and 7) updated recommendations on discontinuation of OI prophylaxis after immune reconstitution in children."}
+{"text": "Development the personalized programs of rehabilitation for inhabitants of industrial cities with Chronic Fatigue Syndrome (CFS) and stress-induced diseases is actual up-to-date problem.85 patients  with combined myofascial pain in the cervical part of the vertebral column and chronic fatigue syndrome were examined. Clinical neurological examination was conducted to identify the role of myotonic neck \u201ctunnel- syndromes\u201d and biomechanically significant biomarkers in the cervical spine for affect the cerebral blood flow. EEG- examination was carried out to assess the state of brain activity, the definition of cortical areas responsive to the effects of stress factors and hemispheric interactions, as correlates of memory. The NEC-method of visualization used to study the biochemical markers \u2013 the level of cerebral metabolism and adaptation possibilities. 15 patients used genetic test for indication genes of metabolism (genes of phase I and phase II).Main complains in patients were: headache, fatigue, memory, sleep problems. Disorders in the cognitive, personal, emotional status had all patients. Neuro-vertebral examination had revealed biomechanical markers-disturbances of muscular coordination, muscular hypertension, rigidity in the shoulder girdle, syndrome of upper aperture, kyphosis, postural displacement and the lymphodinamic disturbances \u2013 edematosity of the axillary and subclavicular areas. EEG and NEC analysis revealed signs of functional inter-hemispheric asymmetry of bioelectrical activity in 80% of patients and different levels of cerebral acidosis as biomarker for brain hypoxia. Genetic tests revealed decreasing genes activity of phase II detoxification in 7 patients. Clinical and instrumental observations allow us to offer some statements. New mechanisms of non-specific base of CFS are: stress \u2013 short term or long term muscle spasm and lack of oxygen increase the density of muscles and lead to 3-level \u201ctunnels\u201d intervertebral (compression of nerves), intramuscular (compression of blood vessels) and intrafascial (compression of lymphatic and nodes), Retrograde lymph flow and intoxication of the intersticial matrix are suppose to be the grain for CFS and specific pathologidcal processes. The personalized integrative schemes of rehabilitation were worked out for patients with different postural, neurovascular and lymphodinamic disturbances for correction of muscle-tonic syndrome in the neck, cranio-vertebral region, for improving the cerebral metabolism and liquorodynamics. Methods of intermitted hypoxia therapy were used in the case of cerebral acidosis; adoptive gymnastics was used for patients with postural problems; nutrigenomic diet was recommended to patients for increasing phase II of detoxification.Comprehensive personalized rehabilitation of the patients with CFS improved their clinical and emotional background, memory and cognitive functions. EEG and NEC examination marked the trends in recovery of inter-hemispheric connections, normalization of the bioelectrical activity in the brain and improvement of cerebral metabolism."}
+{"text": "Nurses are in key positions to plan and implement alcohol screening and brief intervention (aSBI). To simultaneously advance aSBI of nurses in various roles, we developed a self-paced program for Clinical Nurse Leaders, Nurse Informaticists, Nurse Administrators, and Registered Nurses including Advanced Practice Nurses. The content for the program is based on the Centers for Disease Control & Prevention (CDC) 2014 Planning and Implementation Screening and Brief Intervention for Risky Alcohol Use: A Step-by-Step Guide for Primary Care Practices. The objective is to present the results of a cooperative agreement between the Centers for Disease Control & Prevention, Johns Hopkins School of Nursing, and the University of Pittsburgh School of Nursing. The framework used to design the aSBI Program and key aspects of the program will be demonstrated and discussed.The aSBI Program flow, depicted in the CDC guide defined the modules for learning: patient population, assess alcohol consumption, negative screen (and subsequent conversation), positive screen (and assessment of harm and dependence), brief intervention and referral to treatment. The modules were developed using Articulate Storyline, the premier rapid e-learning development platform, and hosted on a learning management system. Special focus was given to the assessment portion of the e-learning modules to ensure learners are provided with authentic assessments that accurately measure their mastery of real-world skills needed to be successful when applying the module educational materials.When finalized, the self-paced aSBI Program, funded by the American Association of Colleges of Nursing through the CDC, will be widely disseminated to the nursing community across the U.S.This easily accessible on-line educational program will bring evidence-based alcohol screening and intervention to current and future nurses."}
+{"text": "Hystrix javanica) and its immunolocalization.To identify the types of endocrine cells in the pancreas of the Sunda porcupine  in pancreatic tissues were detected using the avidin-biotin-peroxidase complex method.Five adult The fusiform, round, and oval form endocrine cells were detected in the islets of Langerhans and exocrine parts. Most of the insulin cells were found in the central area, glucagon cells were identified in the central and peripheral areas, and somatostatin and PP cells were detected in the mantle area of the islets of Langerhans. Glucagon and somatostatin cells were also detected in smaller numbers of peripheral parts of the islet. In all of the islet parts, glucagon endocrine cells were most prevalent cell type and then, somatostatin, insulin, and PP. In the exocrine parts, PP, somatostatin, glucagon, and insulin endocrine cells were found in the inter-acinus part with moderate, moderate, a few and rare numbers, in that order. In the pancreatic duct, glucagon and somatostatin cells were found between epithelial cells in rare numbers.H. javanica) contains four types of major pancreatic endocrine cells with approximately similar distribution patterns to the other rodents, except for abundant glucagon cells in the peripheral area of the islets of Langerhans.The pancreas of Sunda porcupine ( Hystrix javanica, belonging to the genus Hystrix in the family Hystricidae is one of the Old World porcupines [The Sunda porcupine, rcupines . There arcupines ,3.The pancreas is a composite gland consisting of exocrine and endocrine parts. The exocrine part consists of acini that secrete digestive enzymes into ducts. The endocrine part, the pancreatic islets (islets of Langerhans), consists of masses of endocrine cells embedded within the exocrine pancreas, where pancreatic hormones of insulin, glucagon, somatostatin, and pancreatic polypeptide (PP) are distributed into the whole body via blood vessels. The presence, distribution, and immunoreactivities of these regulatory hormones secreted by endocrine cells in the pancreas were well understood by histochemistry , immunofHystrix cristata), which belongs to the subgenus Hystrix of the genus Hystrix [H. cristata were limited on its basic morphology and localization of only 3 kind endocrine cells. There are no other data of pancreas on other porcupine species are available. In this research, the presences and semiquantitative distribution of all major endocrine cells types  in the pancreas of Sunda porcupine, H. javanica which is endemic to Indonesia, were detected by employing the avidin-biotin-peroxidase complex (ABC) method.The recent studies on pancreas of porcupine have been conducted in crested porcupine .H. javanica, about 67 cm in length, were purchased from an extreme food merchant in Tawangmangu, Central java, Indonesia, were used as samples. Pancreatic tissues of H. javanica were fixed for 24 h in Bouin\u2019s solution, dehydrate in ethanol, cleared in xylene, and embedded in paraffin.Five pancreatic tissues of adult Sunda porcupines, 2O2 in methanol for 15 min. Primary antibodies , few (+), moderate (++), and numerous (+++).The presences of positif endocrine cell types were observed in 3 parts of the pancreas, (1) the islets of Langerhans, (2) the exocrine acini, and (3) the pancreatic duct. In addition, the presence and semiquantitatif number of endocrine cells types in the islets of Langerhans were distinguished into three locations: Central, mantle, and peripheral areas. The presence and semiquantitative number of endocrine cells types in the pancreatic duct were distinguished into two locations: inter-epithelial and sub-epithelial cells.H. javanica. Four types endocrine cells were detected in various pancreatic parts and areas with different semiquantitatif numbers as shown in Tables-H. javanica, was fusiform, round, and oval.The research clarified the presence of four types pancreatic endocrine cells including insulin, glucagon, somatostatin, and PP in the islets of Langerhans, exocrine acini and pancreatic duct of H. javanica contain fusiform and round form insulin cells which located in the central and mantle areas with a numerous and moderate numbers, respectively, but not in the peripheral area , has clarified base on the results of this research. They are insulin, glucagon, somatostatin, and PP of the endocrine cells types. The semiquantitatif number of endocrine cell types was grouped according to the pancreatic parts  and the area of pancreatic islets . Specific spreading of endocrine cell types in the pancreatic tissues was also emphasized with references to other already known species.The presence of four main types of endocrine cells in the pancreas of the most exotic Indonesian endemic porcupine, the Sunda porcupine  could exactly be distinguished from each other using immunohistochemical techniques . Previoue region . The preH. javanica, mainly in the peripheral area of the islets.PP cell is the other type of endocrine cell that can be found in the pancreas. It has been known that the location differentiation of PP cells in the pancreas can easily be recognized among species, although the cells, if they occur, were always located in the peripheral area of the islets of Langerhans. PP cells were demonstrated in the peripheral area of the pancreatic islets of the hamster , rat 1717, mouseH. javanica pancreas, insulin, glucagon, and somatostatin cells were found individually, whereas PP cells were detected in a form of cluster cells located between acini. Moreover, glucagon and somatostatin cells were detected in the inter-epithelial cells and sub-epithelial cells of pancreatic ducts, respectively. Unfortunately, the report of Timurkan et al. [H. cristata did not mention about this features. The present result, however, the first evidence on the individual form of insulin, glucagon and somatostatin cells, and cluster cells feature of PP cells in the exocrine parts of porcupines species.In the exocrine part of n et al.  on pancrH. javanica, glucagon cells were found in inter-epithelial cells, and somatostatin cells were detected in sub-epithelial cells. The endocrine parts of H. javanica pancreas contain of those four types endocrine cells with variation on the form, location, and number of the cells depend on the area of the islets of Langerhans but in common is approximately similar to that of other rodents. The research elucidated the exception on the specific location of glucagon cells in the peripheral area in islets of Langerhans of H. javanica which differ from others mammals.The present research clarified the presence of four major endocrine cells, namely, insulin, glucagon, somatostatin, and PP cells in the islets of Langerhans and inter-acinar cells of the exocrine part. In pancreatic duct of TB prepared proposal and managed the research implementation. TB, YHF and GTM carried out the sample collections and laboratory works for histology and immunohistochemistry. TB critically analyzed the histological and immunohistochemical data and prepared the manuscript. All authors read and approved the final manuscript."}
+{"text": "The prevalence of allergies has vastly increased over recent decades due to air pollution and climate change. The present study aims to identify any seasonal variations in the allergens, to help prevent and treat allergic diseases; and investigate any correlations between the reported allergens and other biotic parameters, namely age and sex. The study included 67 subjects  who visit the Department of Pneumology and Oto-rhino-laryngology of the Regional Hospital of Gafsa, between August 2007 and September 2008. The allergic condition of these patients was confirmed by measuring allergen specific IgE levels using the multiple allergen simultaneous test-chemoluminescent assay (MAST-CLA). A total of 30 allergens were tested and classified into seven groups: tree and grass pollen, herbaceous pollen, animal dander, moulds, latex, cockroaches and mites.The seasonal distribution of allergens shows that the frequency of respiratory allergy was mainly observed during spring corresponding to the pollination season. However, the detection of some seasonal allergens, such as olive pollen, outside the pollination season can be explained by the cross-reactivity between allergens. The age range of patients with sensitivity was found to be between 10 and 73 years, with the most sensitive patients aged between 20 and 50 years. The sex variable was significantly associated with the studied allergens since sensitization was present more frequently in women than in men."}
+{"text": "Eosinophilic chronic rhinosinusitis (ECRS) is considered a refractory and intractable disease. Patients with ECRS present with thick mucus production, long-term nasal congestion, loss of sense of smell, and intermittent acute exacerbations secondary to bacterial infections. Despite medical and surgical interventions, there is a high rate of recurrence with significant impairment to quality of life. The recent increasing prevalence of ECRS in south Asian countries and the strong tendency of ECRS to reoccur after surgery should be considered. The majority of cases need repeat surgery, and histological examinations of these cases show eosinophilic-dominant inflammation. The degradation and accumulation of eosinophils, release of cytokines, and mucus secretion have important roles in the pathogenesis of ECRS. ECRS differs from non-ECRS, in which eosinophils are not involved in the pathogenesis of the disease, and also in terms of many clinical characteristics, blood examination and nasal polyp histological findings, clinical features of the disease after surgery, efficacy of medications, and computed tomography findings. This review describes the clinical course, diagnosis, and treatment of ECRS as well as its pathophysiology and the role of eosinophils, mucus, cytokines, and other mediators in the pathogenesis of ECRS. Eosinophilic chronic rhinosinusitis (ECRS) is an inflammatory pathological condition of the nose and paranasal sinuses . PatientMultiple cytokines are involved in the pathogenesis of ECRS. Elevated levels of circulatory eosinophils and tissue eosinophils are prominent features of ECRS. Cytokines are essential for hematopoietic cell development, differentiation, and maturation. Interleukin (IL)-3, IL-5, and granulocyte/macrophage-colony stimulating factor (GM-CSF) are cytokines that are particularly important in regulating eosinophil development . MyeloidEosinophils also function as antigen-presenting cells and they can process and present a variety of microbial, viral, and parasitic antigens . In addiConversely, cytokines that have antagonistic effects, especially on Th2 inflammation, such as IFN-\u03b3 and transforming growth factor (TGF)-\u03b2, are down-regulated in ECRSwNP . The comA number of studies demonstrated that there is an association between peripheral eosinophilia and a high percentage of eosinophil infiltration in paranasal sinuses . EosinopA better understanding of the clinical features and specific characteristics of CT images will facilitate the diagnosis of ECRS. Researchers have found a direct association between the severity of paranasal cavity CT findings and an increase in the circulatory eosinophil count . Thus, aPatients with ECRS exhibit clinical characteristics that include long term nasal congestion, mucus production, olfactory disturbances, bilateral nasal polyposis, and intermittent acute exacerbation of secondary bacterial infections . A combiSince there is no approved medication to treat patients with ECRSwNP completely, surgery is often needed to clear the sinonasal passage, and repeated endoscopic sinus surgery (ESS) is often required . In caseMoreover, the presence of mucosal eosinophilia (>10 eosinophils/high-power field) at the time of ESS consistently predicts less improvement in both disease-specific measures and general quality of life compared to the absence of eosinophilia . AdditioThe effectiveness of low-dose, long-term erythromycin treatment (macrolide therapy) was reported for the treatment of CRS in Japan , 73, 74.As mentioned before, the treatment strategies for ECRS differ from those for non-ECRS; a diagnostic criterion for ECRS is thought to be very useful to decide a treatment strategy in an outpatient setting . If sinuSystemic deregulation of eosinophils is thought to be involved in the pathogenesis of ECRS . Once thAlthough, CRSwNP is characterized histologically by an abundance of eosinophilic inflammatory changes, the levels of leukotriene C4 in patients with recurrent sinonasal polyps after surgery are significantly higher than in healthy controls, and higher leukotriene C4 levels can be an indicator of the risk of recurrence of nasal polyps . Recent In European  and UnitAlessandri et al. showed that AT7519, a novel cyclin-dependent kinase inhibitor, causes apoptosis in human and mouse model eosinophils, indicating that such inhibitors can have a therapeutic role in eosinophil-dominant allergic disorder treatment . A newlyECRS is an intractable and persistent disease of the nose and paranasal sinuses. Eosinophilic degradation and accumulation, the release of cytokines and chemokines, and mucus production have an important role in the pathogenesis of this disease. The clinical features reflect the complicated condition of ECRS that seems to be resistant to the current available medical therapies and has a high rate of recurrence after surgery. Further studies are needed particularly focusing on the function of cytokines, chemokines, and eosinophils and the production of eosinophils to achieve a precise treatment, prevention, and the required outcomes."}
+{"text": "Budgetary constraints - with annual growth rates that peaked at 20% - fuelled by the upcoming economic crisis demanded a change in the pricing model for pharmaceuticals in the Republic of Macedonia. Several neighbouring countries were faced with similar challenges, so the Republic of Macedonia carefully looked into their policies and thus introduced external reference pricing in 2011, which led to a reduction of prices. The specific was that both the Ministry of Health for the \"unique price\" (i.e. the maximum price) and the Health Insurance Fund as a basis for reimbursement performed price comparisons. The country basket for the Ministry of Health includes Bulgaria, Croatia, France, Germany, Greece, the Netherlands, Poland, Russia, Serbia, Slovenia, Turkey and the UK whereas the HIF references Bulgaria, Croatia, Serbia and Slovenia.To show the trend of price reductions achieved for selected pharmaceuticals in the Republic of Macedonia as compared with the non-basket countries Hungary, Czech Republic and Austria.Policies targeted: Analysis of the effects of external price referencing in different countries.Stakeholders: Pricing and reimbursement authorities of the analysed countries.Region covered: International comparison focussing on Central and Eastern Europe countries.Ex-post cross-country evaluation of pricing trends between 2009 and 2014 for selected out-patient medicines that are reimbursed by the Macedonian HIF using the national Macedonian price database and the European Integrated Price Database EURIPID.The prices of the selected medicines were reduced in all analysed countries but the extents of tje decreases were different. It was also notable that some of the initially selected medicines (based on the Macedonian reimbursement list) were not marketed or reimbursed in the countries of comparison.The analysis showed that a more regular exchange of information and pricing policies could generate higher savings for national pricing and reimbursement authorities as the price development of similar products was quite diverse."}
+{"text": "Obesity, insulin resistance, and type 2 diabetes are associated with a substantially increased prevalence of vascular fibrosis and stiffness, with attendant increased risk of cardiovascular and chronic kidney disease. Although the underlying mechanisms and mediators of vascular stiffness are not well understood, accumulating evidence supports the role of metabolic and immune dysregulation related to increased adiposity, activation of the renin angiotensin aldosterone system, reduced bioavailable nitric oxide, increased vascular extracellular matrix (ECM) and ECM remodeling in the pathogenesis of vascular stiffness. This review will give a brief overview of the relationship between obesity, insulin resistance and increased vascular stiffness to provide a contemporary understanding of the proposed underlying mechanisms and potential therapeutic strategies. Vascular stiffness is a consequence of pathophysiological alterations involving endothelial cells (ECs), vascular smooth muscle cells (VSMCs), extracellular matrix (ECM), and other functional elements of the vessel wall  analysis of pulse transit time; (2) wave contour of the arterial pulse; and (3) direct measurement of arterial geometry and pressure that corresponds to regional, systemic, and local determination of stiffness  and sympathetic nervous (SNS) systems are all components of the cardiorenal metabolic syndrome, which is associated with vascular stiffness Sowers, . DysreguExcess adipose tissue, in particular abdominal adipose tissue, has been closely linked to the development of vascular stiffness and cardiovascular disease , and vasoconstrictor substances, such as angiotensin II (Ang II), and thromboxane A2  has a vasodilatory effect and anti-atherogenic properties, including inhibition of VSMC proliferation and migration, platelet activation and adhesion and leukocyte adhesion and migration  and connective tissue growth factor (CTGF) are well-known profibrotic factors that can stimulate synthesis of ECM proteins, such as fibronectin and collagens, under conditions of obesity, insulin resistance, and T2D  expression on the EC surface leading to reduced NO production that is associated with increases in cortical stiffness of the cytoskeleton  oxidase activity and reduction of NO bioavailability, thereby promoting oxidative stress and vascular dysfunction  can protect the vascular cells by immunosuppression, cell contact\u2013dependent suppression, and functional modification or killing of activated protein C (He et al., Vascular stiffness is associated with chronic inflammatory disease in the vessel wall characterized by an activation of both the innate and adaptive immune systems, which are composed of diverse cellular components, including granulocytes, mast cells, monocytes, macrophages, and natural killer cells (Aroor et al., Non-diabetic premenopausal women exhibit lower incidence of cardiovascular complications compared to age matched men. However, this protection is lost under the setting of obesity and T2D (Manrique et al., Although the mechanisms that contribute to vascular stiffness in obese premenopausal women are poorly understood, upregulation of RAAS signaling may be important in this regard (Aroor et al., Vascular stiffness is increased in conditions of insulin resistance and obesity and independently increases the risk of developing hypertension, coronary heart disease, and CVD morbidity and mortality. The underlying pathophysiology of vascular stiffness in insulin resistance and obesity involves activation of RAAS, adipocyte inflammation, abnormalities in vascular cells, ECM and maladaptive immune responses, all of which increase the risk of vascular stiffness associated CVD events Figure . Future The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Neglected tropical diseases (NTDs) affect more than 1,000,000,000 poor and marginalized people worldwide [An important element of targeted NTD intervention is the delivery of mass drug administration (MDA) for treating the five major \u201cpreventive chemotherapy\u201d NTDs, including lymphatic filariasis (LF), onchocerciasis, schistosomiasis, soil-transmitted helminths (STH), and trachoma . MDAs taInnovation to Application article, we describe the creation of an innovative NTD mapping tool (www.ntdmap.org) developed by a consortium of research and program partners for use particularly by program implementers. Its functionality and accessibility have been designed specifically to meet the needs of national programs and international partners. This tool provides an online resource allowing users to visualize and manipulate geographical data on a range of variables for the planning and managing of integrated NTD programs.In this Sharing data is challenging not only because of the complexity of the data themselves but also from the sheer volume of information. In an effort to meet these challenges, the NTD community has developed a range of resources that display epidemiological and treatment data in the form of maps . Data arWhile these disease-specific mapping projects are extremely helpful for visualizing predefined projects, they are of limited usefulness for integrated program planning, primarily because of the inability to customize maps through overlaying multiple variables highlighting cross-disease opportunities. These resources are also time-consuming to maintain, with data needing to be managed manually for each tool. In the rapidly changing NTD environment, the utility of maps erodes quickly with time. To become a useful operational resource, maps must be routinely updated. For NTDs, this need has been addressed in the development of an NTD mapping tool capable of integrating available epidemiological and programmatic NTD data into a single resource, which is both dynamic and easy to use.http://www.thiswormyworld.org/about/gahi-reports). Each platform was reviewed for content, quality, and functionalities offered. Results show that the main functionalities included were (i) ability to add different map layers, (ii) query the data underpinning each map, (iii) zoom and pan in the maps, and (iv) print and save maps.A first step in developing the tool was a stocktaking exercise of existing mapping platforms and an end-user survey to assess the needs of the tool\u2019s intended audiences. The exercise included a \u201cstate-of-the-art\u201d review of existing mapping applications, undertaken by independent consultants, Avia-GIS , provided high-level software expertise. The technical development of the tool included linking Structured Query Language (SQL) databases from multiple partners such as the Global Atlas of Helminth Infections (GAHI) [Finally, a series of meetings were held among partners in March, 2013. These meetings established the minimum criteria for the NTD mapping tool . To assis (GAHI) , Global s (GAHI) , Internas (GAHI) . These dhttp://www.thiswormyworld.org/training/modern-tools-for-ntd-control-programmes). Feedback received included the ability to adjust the order of layers, inclusion of administrative boundary layer, ability to query the source of data, and the ability to change the colors of layers. A second version of the tool was then released to selected partners on September 1, 2013 for additional feedback. The process of requesting feedback from both field managers and partner organizations ensured the usefulness of the tool to the broader NTD community. The completed tool was launched at the NTD Non-Governmental Development Organization (NGDO) Network (NNN) meeting in Brighton, United Kingdom, on September 19, 2013.A beta-version of the tool was piloted at an NTD training course in Nairobi in May 2013  for the different NTDs at the subnational  level, whereas WHO typically reports coverage at the national level. Better understanding of the relationship between these two sources would be useful for filling knowledge gaps on treatment coverage. Third, the NTD Mapping Tool includes data on STH, schistosomiasis, and trachoma, as well as health district maps of access to improved water and sanitation. It is envisioned that in the future, data on LF  and onchwww.thiswormyworld.org). Readers interested in the details of these data can consult this resource and contact this project.A second phase of development on this tool is underway. In the upcoming release, the technical features will be enhanced. This release will include an offline component where users with limited internet access can build their own maps. Users will also have the ability to input their own data into the offline maps, allowing the visualization of private data in the context of the publicly available data included in the tool. Future work will additionally investigate how best to make the data included in the tool available for download; at present, data on STH, schistosomiasis, LF, and Water Sanitation and Hygiene (WASH) can be downloaded from the Global Atlas of Helminth Infection (In conclusion, the NTD Mapping Tool provides an important new tool for the planning, implementation and evaluation of NTD control activities. The tool is simple and intuitive to use, with minimal requirements placed on the users. The development of the tool has brought together partners working on different NTDs and has involved extensive consultation with the global NTD community. Future roll-out of the tool will identify further needs which will guide subsequent revision. The experience of developing the NTD Mapping Tool provides a powerful example of how integrating data, expertise, and resources can provide new resources and tools to help improve decision making in, and implementation of, integrated health programs."}
+{"text": "In 2008, the Global Health Research Initiative (GHRI) invited applications from teams of researchers and decision-makers who were interested in conducting research related to human resources for health and the implementation and use of integrated health information systems in Africa, with special attention to equity considerations. These thematic areas constituted the focus of the Africa Health Systems Initiative - Support to African Research Partnerships (AHSI-RES) program. GHRI is a partnership of three Canadian agencies: Foreign Affairs, Trade and Development Canada (DFATD), International Development Research Centre (IDRC), and the Canadian Institutes of Health Research (CIHR). It is hosted at IDRC.AHSI-RES is a five year, $5.9 million CDN research program (2008-2014) supported by Foreign Affairs, Trade and Development Canada ($5 million) and the International Development Research Centre ($900 000). AHSI-RES is the research component of the larger Africa Health Systems Initiative (AHSI) program. The AHSI program is a 10 year, $450 million CDN commitment (2006-2016) to strengthening national-level health strategies and architecture, and is being implemented by Foreign Affairs, Trade and Development Canada.The AHSI-RES program\u2019s purpose is to support policy relevant research, knowledge translation and exchange in the program\u2019s thematic areas. The AHSI-RES program emphasized the importance of ongoing interaction, collaboration, and exchange of ideas between researchers and decision-makers to maximize the likelihood that research findings would be used to inform programs and policies. A decision-maker was defined as \u2018an individual who makes decisions about, or influences, health policies or practices.\u2019IDRC program officers engage with grantees in framing research problems, improving research designs, and choosing methodologies. IDRC staff and funded researchers work as peers to contribute new ideas and theories, influence practice and policy, and strengthen research networks, bringing together grantees to share research results . This isTeams had to include one African researcher and one African decision-maker, both as co-principal applicants. The co-principal applicants had to be affiliated with an institution located in one of the AHSI-RES geographic areas of focus. Geographic areas of focus included: Francophone West Africa ; Great Lakes and Eastern Africa ; and, Southern Africa . Researchers and decision-makers affiliated with a non-African institution were eligible as co-applicants or collaborators, additional to the African co-principal applicants.Ten teams were selected from 57 proposals following a rigorous merit review process, where the review panel included international researchers and African decision-makers. Research teams that were successful in getting funding had to demonstrate: the ability to engage in interdisciplinary applied research to address complex policy-relevant questions related to the key themes of AHSI-RES; and, the ability to link research, policy, and action to improve health decision-making and programming. Gender, ethics, capacity development, and knowledge translation and exchange were cross-cutting themes that featured in AHSI-RES programming.Human Resources for Health. This supplement focuses on lessons learned from the uptake and impact of research for evidence-based practice.Research teams were based in: Burkina Faso, Mali, Kenya, Tanzania, Uganda, Malawi, and Zambia, and some involved Canadian researchers. Their research focused on two main areas: 1) the recruitment and retention of health workers and the shifting of certain services to less specialized health workers in response to a severe human resources crisis in the health sector in sub-Saharan Africa; and 2) the role of health information in ensuring greater equity in access to health care. The results of AHSI-RES research on the recruitment and retention of health workers is presented in a supplement to Health systems research can enrich the evidence base needed to inform the development and implementation of equity-oriented policies and interventions. The expected outcomes for AHSI-RES include: (i) improved and timely uptake of research evidence for health systems strengthening among decision makers in low- and middle-income countries; (ii) improved knowledge base for health systems strengthening that addresses the needs of vulnerable populations, focusing on priority global health issues in low- and middle-income countries; and (iii) strengthened individual and institutional capacity for doing and using research on health systems strengthening in low- and middle-income countries.. The research ranges from investigation into government policies to retain health workers in underserved areas, to the implementation and validation of health information systems in peri-urban and rural areas.The articles in this supplement present research results from Kenya, Malawi, Mali, Uganda, Tanzania, and ZambiaFindings from these research teams capture the complexity of challenges faced by decision-makers, health system managers, and health human resources in establishing, maintaining, and sustaining effective and functional health systems. The research serves to test, validate, and challenge policies at national and regional levels. Some of the policies and strategies incorporated in this supplement\u2019s research include, amongst others: Kenya\u2019s Community Health Strategy, Uganda\u2019s integrated Community Case Management (iCCM) strategy, as well as the World Health Organization and International Agency for Prevention of Blindness\u2019s program strategy for \u201cVISION 2020: The Right to Sight,\u201d a global initiative to eliminate avoidable blindness.For example, as described in the articles, the policy-relevant results and lessons learned include:\u2022 the Kenya Community Health Strategy is an effective approach to delivering community-based interventions: it can be successfully implemented and sustained in different socio-demographic contexts, with participatory community planning, based on household information, driving the improvement of health indicators. There were significant changes in essential maternal and newborn care practices such as antenatal care attendance and skilled deliveries because household members had been provided with the necessary information to make healthy decisions to be able to respond to maternal and neonatal health needs, based on evidence provided by the community based health information system .\u2022 a better understanding of the quality of eye care at primary health care facilities and influencing factors (e.g. staff turnover and absenteeism) in Kenya, Malawi and Tanzania, are urgently needed before continuing to invest resources in the scale up of the model of task shifting in Africa as it relates to VISION 2020: The Right to Sight, a global initiative to eliminate avoidable blindness. This study demonstrated the negative impact of the high turnover of primary health care workers and absenteeism in providing health services at the community level. This turnover and absenteeism also affects the integrity of research on interventions designed to improve health services .\u2022 in Uganda, specific iCCM training and support to a selected segment of community health workers (CHWs) within larger CHW village teams unexpectedly and negatively impacts \u2018basic\u2019 CHWs\u2019 work motivation, but not necessarily team functioning. The Ugandan Ministry of Health\u2019s national strategy calls for the employment of volunteer CHWs for the implementation of iCCM of common illnesses  affecting children under five years of age. The researchers recommend that CHW programmers should consider minimizing segregation when introducing new program opportunities through providing equal opportunities to participate and receive incentives, while seeking means to improve communication, CHW solidarity, and motivation .The 10 teams supported by the AHSI-RES program worked to connect research with policy and action to improve health decision-making and programming in the sub-Saharan region, paying particular attention to the needs of disadvantaged segments of the population. Grantees benefited from opportunities to strengthen individual and institutional capacity for doing and using research on health systems strengthening. Research teams also benefitted from linking with African decision-makers to make the research collaborative and responsive, enhancing the likelihood of research uptake to inform current and future policies.Adrijana Corluka and Ren\u00e9e Larocque serve as Senior Program Officers, Marc Cohen serves as Program Officer, and Esm\u00e9 Lanktree serves as Program Management Officer, with the Global Health Research Initiative. The Global Health Research Initiative supported the assembly and publication of this supplement. The views expressed in this introductory article are those of the authors alone and do not represent the views of the Global Health Research Initiative, the International Development Centre, the Canadian Institutes of Health Research, nor Foreign Affairs, Trade and Development Canada."}
+{"text": "Tobacco use in India is characterized by a high prevalence of smoking and smokeless tobacco use, with dual use also contributing a noticeable proportion. In the context of such a high burden of tobacco use, this study examines the regional variations, and socioeconomic, demographic and other correlates of smoking, smokeless tobacco and dual use of tobacco in India.We analyzed a cross sectional, nationally representative sample of individuals from the Global Adult Tobacco Survey in India (2009\u201310), which covered 69,296 individuals aged 15 years and above. The current tobacco use in three forms, namely, smoking only, smokeless tobacco use only, and both smoking and smokeless tobacco use were considered as outcomes in this study. Descriptive statistics, cross tabulations and multinomial logistic regression analysis were adopted as analytical tools. Smokeless tobacco use was the major form of tobacco use in India followed by smoking and dual tobacco use. Tobacco use was higher among males, the less educated, the poor, and the rural population in India. Respondents lacking knowledge of health hazards of tobacco had higher prevalence of tobacco use in each form. The prevalence of different forms of tobacco use varies significantly by states. The prevalence of tobacco use increases concomitantly with age among females. Middle-aged adult males had higher prevalence of tobacco use. Age, education and region were found to be significant determinants of all forms of tobacco use. Adults from the poor household had significantly higher risk of consuming smokeless tobacco. Lack of awareness about the selected hazards of tobacco significantly affects tobacco use.There is an urgent need to curb the use of tobacco among the sub-groups of population with higher prevalence. Tobacco control policies in India should adopt a targeted, population-based approach to control and reduce tobacco consumption in the country. Smokeless tobacco use consists of chewing pan , chewing gutkha or pan masala , and mishri (a kind of toothpaste used for rubbing on gums). India has one of the highest tobacco users in the world both in number and relative share. India is one of the fewer countries in the world where prevalence of smoking and smokeless tobacco use are high and is characterised by dual use of tobacco (use of both smoking and smokeless tobacco products) also contributes to a noticeable proportion. Using data from the National Family Health Survey second round , prevalence of tobacco use in India was estimated to be 37 percent among the population of 15 years and above Tobacco is used in India in many forms. Smoking of cigarettes and nd round of the NSS on Morbidity and Private Health Expenditure, conducted between June 1995 and June 1996 by the National Sample Survey Organization (NSSO) of the Government of India, collected information on current regular smoking and chewing of tobacco for all individuals aged 10 years and above. The survey estimated tobacco use prevalence among males to be at 51.3% and among females at 10.3% Establishment of effective tobacco control policies depends on precisely assessing the enormity of tobacco use in the country. Several national level studies have collected information on tobacco use to evaluate the prevalence of tobacco use. Tobacco use is a part of the consumer behaviour component of the National Sample Survey (NSS), held every five years All these studies were mostly limited to collecting some data on tobacco use as a component of health-based surveys. However, there was a lack of a large scale survey with comprehensive data on tobacco use among adults in India. Most of the past research work on tobacco was either based on localized studies with an urban bias or based on non-representative sample surveys with socio-demographic predictors of tobacco related behaviour mostly inadequately understood. These works were frequently limited to specific focus group in terms of their tobacco habit.The recent two rounds of the Global Youth Tobacco Survey were specially designed to collect tobacco related information, although for a very specific age group. The Global Adult Tobacco Survey (GATS) is a standardized household survey that enables countries to compile data on key tobacco indicators and assist states in the formulation, tracking and execution of effective tobacco control interventions and international comparisons as laid out in the MPOWER policy package of the WHO This study is based on the secondary analysis of the Global Adult Tobacco Survey India (GATS-India) 2009\u201310 data. This survey data was released for the general researchers by International Institute for Population Sciences. Global Adult Tobacco Survey is the global standard for systematically monitoring adult tobacco use (smoking and smokeless) and tracking key tobacco control indicators. GATS-India is conducted globally in around 14 countries. The Centers for Disease Control and Prevention (CDC), CDC Foundation, Johns Hopkins Bloomberg School of Public Health (JHSPH), Research Triangle Institute International , the World Health Organization and many countries throughout the world worked together to design and implement GATS. For each participating country, a standard protocol with respect to questionnaire, sample design, data collection and management procedures was used. Survey information was collected using handheld devices. The Ministry of Health and Family Welfare, Government of India, designated the International Institute for Population Sciences, as the nodal agency for conducting GATS Survey in India. The main objectives of the GATS India Survey were to measure the impact of tobacco control efforts through implementation of different provisions of COTPA 2003 and its regulations and to systematically monitor adult tobacco use and track key tobacco control indicators. Further information regarding the guidelines followed to collect the data is available in the GATS-India report GATS-India (2009\u201310) is a nationally representative household survey covering population aged 15 years and above, covering all the 29 states and 2 Union Territories (UTs) in India. Multistage sampling procedure was adopted independently in each state, and within the states, independently in urban and rural areas to select the sample. In the urban areas, three-stage sampling was adopted for the selection of households. At the first stage, a list of wards from all cities and towns of the state/UT formed the urban sampling frame from which a required sample of wards, i.e., primary sampling units (PSUs), was selected using probability proportional to size (PPS) sampling. At the second stage, a list of census enumeration blocks (CEBs) in every selected ward formed the sampling frame from which one CEB was selected by PPS from each selected ward. At the third stage, a list of all the residential households in each selected CEB formed the sampling frame from which a sample of the required number of households was selected. In the rural areas, two-stage sampling was adopted for the selection of households. The PSUs were villages selected using the PPS sampling method. At the second stage, a list of all the residential households in each selected village formed the sampling frame from which a sample of the required number of households was selected. From each eligible household, one respondent was selected.beedis, cigarettes, cigars, cheroots, rolled cigarettes, tobacco rolled in maize leaf and newspaper, hookah, pipes, chillum, and chutta. Smokeless tobacco included tobacco leaf, betel quid with tobacco, sada/surti, khaini or tobacco lime mixture, gutkha, pan masala with zarda, gul, gudaku, and mishri. Final sample included in the analysis were all the 69,296 respondents Complete data is available for 69,296 adult respondents age 15 and above, of which 33,767 and 35,529 were males and females respectively. The survey covered domains like tobacco use (smoking and smokeless tobacco), exposure to second hand smoke, cessation, economics of tobacco, exposure to media messages on tobacco use, and knowledge, attitudes and perceptions towards tobacco use. The survey was designed to provide estimates of the tobacco prevalence at the national and the state levels, and by certain specific background characteristics. Data for tobacco use was collected from the eligible respondents aged 15 years and above. The respondents were asked about their daily and occasional use of tobacco. Smoking tobacco included The main dependant variable in the analysis is the tobacco use categorized into four types, namely, smoking only, smokeless tobacco use only, dual use of tobacco (both smoking and smokeless tobacco use) and non-user of tobacco.The state level variations in type of tobacco use were assessed for the 29 states and 2 UTs of India. The relationship of age with use of tobacco in three forms was assessed by classifying age into age groups of five years. For the further analysis, independent variables used were age (four categories), sex , residence , education (four categories), occupation (four categories), region (six categories), knowledge that exposure to smoking causes heart attack, stroke and lung cancer (Yes/No), smokeless tobacco causes serious illness (Yes/No), and household asset scores (three categories). Six geographical regions, covering 29 states and 2 UTs, were included in the analysis. Included in the North were the states of Jammu & Kashmir, Himachal Pradesh, Punjab, Chandigarh, Uttarakhand, Haryana and Delhi; in the Central region, Rajasthan, Uttar Pradesh, Chhattisgarh and Madhya Pradesh were included; the East included West Bengal, Jharkhand, Odisha and Bihar; the North-east included Sikkim, Arunachal Pradesh, Nagaland, Manipur, Mizoram, Tripura, Meghalaya and Assam; in the West were included Gujarat, Maharashtra and Goa; and finally Andhra Pradesh, Karnataka, Kerala, Tamil Nadu and Puducherry were included in the South region. The household economic status was assessed using the household assets information provided. Since the information of assets was quite limited in nature, the scores of 10 household assets were summed up to give a final score between 0 and 10. These scores were divided into three parts based on their distribution, and households were categorised as poor, moderate and rich.The prevalence of tobacco use for each type namely, smoking only, smokeless tobacco use only, and dual use of tobacco (both smoking and smokeless tobacco use) is defined as the number of persons consuming tobacco in this manner per 100 adult persons 15 years and above. Bivariate analysis was used to estimate the prevalence of tobacco use in three forms by background characteristics. The state level variations in type of tobacco use were assessed by simple bivariate analysis in 29 states and 2 UTs of India. The relationship of age with use of tobacco was assessed by classifying age into age groups of five years. Further prevalence of tobacco use was analysed according to the background characteristics described in the earlier section. Both point estimates and robust 95% confidence intervals were given based on robust standard errors adjusting for strata and clustering at PSU. Multinomial logistic regression is used to estimate and assess the adjusted associations respectively of different socioeconomic, demographic and knowledge related characteristics. Multinomial logistic regression analysis was used to analyze the four outcomes-smoking only, smokeless tobacco use only, dual use of tobacco and non user in a single model. In multinomial regression each outcome is modelled relative to baseline outcome group: non-user of tobacco (in this study). Therefore, relative risk ratios (RRR) are reported rather than risk ratio or odds ratio. The RRR and their 95% confidence intervals were provided in the tables. Models are used after applying the sampling weights and adjusting for multistage sampling designs using svy command in STATA. STATA 11.0 was used to carry out the statistical analysis.GATS-India data provides an ample opportunity to study the tobacco use behaviour in the form of smoking, smokeless tobacco and dual use of tobacco among adults in India. Understanding the type of tobacco use behaviour has important health implications. The estimates of the tobacco use provided by GATS are considered to be reliable and representative enough as the survey was designed to provide only tobacco use indicators in India. The other studies suffer from the most important limitation that they were not designed to collect information on tobacco use. Surrogate responses were used which often produced bias and inaccuracies in the results Tobacco consumption among females was mostly in the form of smokeless tobacco, while that among males was distributed among the three types of uses. Tobacco use in India has been higher among males than among females in India. However, the male-female gap was lower in the case of use of smokeless tobacco. The use of smokeless tobacco was equally high among middle-aged and elderly males and females. This indicates that adult females in India were as vulnerable as males, and at a high risk of using smokeless tobacco, especially in the higher age groups. With an increase in age, the odds of using tobacco significantly increase in India. Elderly and middle-aged females had significantly higher odds of consuming every type of tobacco. Smoking and dual use of tobacco among males were more common in the younger and middle-aged adults. Age has been found to be an important determinant of tobacco use in earlier studies Tobacco use in India varies significantly by states and regions. A comparison of state-wise figures for smoking and smokeless tobacco use among adults aged 15 years and above, provided by another research study for India, beedis per day. Such figures were much higher for the uneducated and the male population Tobacco use in India is clearly a big burden in terms of its magnitude and use in different forms. There is also a need to check the dual use of tobacco in India. Dual users are at much higher health risks than those who consume the individual tobacco product. The higher prevalence of tobacco use among males, the uneducated and the poor is a matter of concern as these people even lack resources to combat the morbidity associated with tobacco use. At a time when India is experiencing a major mortality and epidemiological transition, these subgroups are likely to suffer more from the dual burden of communicable and non-communicable diseases. In addition to the differences in the prevalence of tobacco consumption between disadvantaged and better off groups, the type and amount of tobacco consumption, and its dependency may also vary between these groups, further aggravating the differences in the disease burden attributable to tobacco. GATS report shows that more than 60 percent tobacco users consume first tobacco of the day within half an hour of waking up. An ample proportion of daily smoker consumes more than 10 cigarettes or"}
+{"text": "Journal of Hematology & Oncology is pleased to see the exponential growth in the number of publications from China, especially in hematology and oncology. This editorial calls for putting more weight on the quality of the future scientific output and invites rigorous dialogs among policy makers, granting agencies, academic leaders, physicians, and scientists, followed by concrete actions, to achieve such a goal. The number of scientific publications from China has exploded in the past 10 years. Multiple factors have propelled this exponential growth. Among these factors include but are not limited to a large scientific research base, increases in government funding through Natural Science Foundation of China, acute upholding of the publish-or-perish mantra, monetary reward for publications from local institutions, institutional requirement for publications in quality journals for awarding doctoral degrees, and faculty promotions. Dr. An-mei Deng\u2019s group from Shanghai performed a detailed and focused analysis of hematology research output from China in the past 10 years [China has succeeded in quantitative promotion of scientific research . The nex"}
+{"text": "The development of multidrug resistance (MDR) in an increasing number of pathogens, including Pseudomonas, Acinetobacter, Klebsiella, Salmonella, Burkholderia, and other Gram-negative bacteria is a serious issue. Membrane efflux pump complexes of the Resistance-Nodulation-Division (RND) superfamily play a key role in the development of MDR in these bacteria. These pumps, together with other transporters, contribute to intrinsic and acquired resistance of bacteria toward most, if not all, of the compounds available in our antimicrobial arsenal. Given the enormous drug polyspecificity of MDR efflux pumps, studies on their mechanism of action are extremely challenging, and this has negatively impacted both on the development of new antibiotics that are able to evade these efflux pumps and on the design of pump inhibitors. The collection of articles in this eBook, published as a Research Topic in Frontiers in Microbiology, section of Antimicrobials, Resistance, and Chemotherapy, aims to update the reader about the latest advances on the structure and function of RND efflux transporters, their roles in the overall multidrug resistance phenotype of Gram-negative pathogens, and on the strategies to inhibit their activities.The discovery of antibiotics represented a key milestone in the history of medicine. However, with the rise of these life-saving drugs came the awareness that bacteria deploy defense mechanisms to resist these antibiotics, and they are good at it. Today, we appear at a crossroads between discovery of new potent drugs and omni-resistant superbugs. Moreover, the misuse of antibiotics in different industries has increased the rate of resistance development by providing permanent selective pressure and, subsequently, enrichment of multidrug resistant pathogens. As a result, antimicrobial resistance has now become an urgent threat to public health worldwide  focus on the outer membrane channel OprM of Pseudomonas aeruginosa, investigating the presence of N-terminal modifications. They present a new X-ray structure solved in a new space group, making it possible to model the N-terminal residue of OprM as a palmitoylated cysteine.RND transporters reside in the inner membrane, and in Gram-negative bacteria they form trans-envelope complexes together with periplasmic membrane fusion proteins (MFPs) and outer membrane factors (OMFs). As tripartite entities, these macromolecular complexes are powerful machines that expel multiple antibiotics across outer membranes. In recent years, much of the research efforts have been focused on the structures of the RND, MFP, and the OMF components. The assembly and disassembly of the tripartite efflux pump components is so crucial to their physiological role in resistance, that much research effort has been directed toward both the elucidation of the structures and functional dynamics of individual components and the Wang et al. use AcrAB-TolC of Escherichia coli as model to explore the mechanism of function recovery of the AcrBP223G variant, which compromises AcrB trimerization and drastically reduces the drug efflux activity. Their study highlights how modulation of several critical factors can lead to the proper functioning of the pump. Zgurskaya et al. further analyze how the reaction cycles of transporters are coupled to the assembly of the trans-envelope complexes. Using a combination of biochemical, genetic and biophysical approaches, the authors reconstruct the sequence of events leading to the assembly of transenvelope drug efflux complexes, and characterize the roles of periplasmic and outer membrane proteins in this process. In particular, they propose that OMF recruitment is triggered by binding of effectors (substrates) to MFP or MFP-RND complexes. Bavro and co-workers investigate in detail the architecture and roles of periplasmic adaptor proteins in tripartite efflux pump assemblies . They stress how recognition between the MFPs and OMFs is essential for pump assembly and function, and how targeting this interaction may provide a novel avenue for combating RND pump-mediated multidrug resistance. Picard and co-workers design a new test permitting investigation of the assembly of the MexAB-OprM efflux system of P. aeruginosa with only tens of microgram of protein . The method relies on the streptavidin-mediated pull-down of OprM proteoliposomes upon interaction with MexAB proteoliposomes containing biotinylated lipids. Their study gives clear evidence for the importance of MexA in promoting and stabilizing the assembly of the MexAB-OprM complex and the role of the proton motive force on the assembly and disassembly of the efflux pump.Several factors are critical for the proper function of the tripartite system: drug binding, interaction with MFPs and OMFs, proton relay through the transmembrane domain, and trimerization of the transporter. Regarding the latter process, in vitro work makes sense without an understanding of the occurrence, regulation, and interdependence of the efflux pumps in a physiological setting. Martins and co-workers summarize the current knowledge on RND efflux mechanisms in E. coli, a bacterium responsible for community and hospital-acquired infections, as well as foodborne outbreaks worldwide . They review the knowledge on Acriflavine (Acr), Multidrug Transport (Mdt), and Copper transporting (Cus) efflux systems. Chen and collaborators use clinical Salmonella typhimurium isolates to demonstrate how acquisition of the plasmid-mediated quinolone resistance (PMQR) genes oqxAB and aac(6\u2032)Ib-cr accelerates the development of fluoroquinolone resistance in this bacterium . Their analysis reveals that oqxAB and aac(6\u2032)Ib-cr are encoded on plasmids of various sizes and mediate resistance to ciprofloxacin, ultimately facilitating the selection of ciprofloxacin-resistant S. typhimurium. In their Perspective, Paulsen and collaborators summarize the current knowledge on the Acinetobacter chlorhexidine efflux (AceI) pump, a prototype for a novel family of multidrug efflux pumps conserved in many proteobacterial lineages . The discovery of this family raises the possibility that additional undiscovered intrinsic resistance proteins may be encoded in the core genomes of pathogenic bacteria.Little of the Morita and co-workers identify a novel MexS variant involved in up-regulation of the mexEF-oprN multidrug efflux operon in a clinical isolate of P. aeruginosa displaying multi-drug efflux-mediated resistance to fluoroquinolones, aminoglycosides, and most \u03b2-lactams. Their study constitutes the first genetic evidence that a MexS variant causes mexEF-oprN upregulation in P. aeruginosa clinical isolates. If the road toward understanding of efflux-mediated multi-drug resistance in E. coli, Acinetobacter baumannii and P. aeruginosa is rough, the characterization of efflux pumps in many other prominent pathogens, e.g., the members of the genus Burkholderia, lags even further behind. As in other non-enteric Gram-negatives, efflux pumps of the resistance nodulation cell division (RND) family are the clinically the most significant efflux systems in this genus. Schweizer and co-workers provide an excellent review of the current knowledge about efflux mechanisms in several Burkholderia species .Among the mechanisms that are not fully understood is the genetic regulation of efflux pumps. Venter et al. describe how available biochemical and structural information can be translated into the discovery and development of new compounds that could reverse antimicrobial resistance in Gram-negative pathogens. Opperman and Nguyen analyze in detail the reasons why no compounds have yet progressed into clinical use. One of the major hurdles in the development of EPIs has been the lack of biochemical, computational, and structural methods that could be used to guide rational drug design. The authors review recent reports that have advanced our understanding of the mechanisms of action of several potent EPIs active against RND-type pumps.Last but not least, inhibition of efflux pumps is one of the current strategies being pursued by several groups attempting to reduce the impact of efflux on antimicrobial resistance. Efflux pump inhibitors (EPIs) could be used as adjunctive therapies that would increase the potency of existing antibiotics and decrease the emergence of multidrug-resistant bacteria. In their review, In summary, the articles in this research topic serve as a background to the search for a deeper understanding of the mechanisms by which RND efflux pumps limit the concentration of antimicrobial compounds inside the bacterial cell. This knowledge may in turn pave the way for new, more directed inhibitor and antibiotic design to ultimately overcome antimicrobial resistance in Gram-negative pathogens.All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.www.translocation.eu) and has received support from the Innovative Medicines Initiative Joint Undertaking under Grant 115525, resources that are composed of financial contributions from the European Union's Seventh Framework Programme (FP7/2007-2013) and European Federation of Pharmaceutical Industries and Associations (EFPIA) companies. Work in the lab of KP on multidrug efflux is funded by the Canadian Institutes of Health Research and Cystic Fibrosis Canada.The research of AVV and KMP was conducted as part of the Translocation Consortium (The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Although D&I models identify several potential facilitators and barriers to adoption of evidence-based practices, the contextual characteristics that determine the relative importance of these factors remain largely unknown. The objectives of this study were to identify the most significant facilitators and barriers to innovation and adoption of EBPs as determined by agency and program directors; explore whether facilitators and barriers identified are associated with agency role and pace of adoption; and explore whether consensus on barriers is associated with pace of adoption.Semi-structured interviews were conducted with agency and program directors of 36 New York State-supported mental health clinics. Agencies were classified based on level of participation in different implementation activities ranging from no engagement to participation in a webinar, in-person training, or learning collaboratives. Data were analyzed using grounded theory analytic methods. Intra-organizational consensus was defined as the number of barriers identified by both types of directors divided by the total number of unique barriers.Three interconnected themes relating to barriers and facilitators were identified: costs associated with adoption, capacity for adoption, and acceptability of new practices. Agency directors were more concerned about financial and organizational capacity, and client buy-in and fit, while program directors were more concerned about time for training and staff buy-in. Concerns about cost, time for training, client buy-in, and organizational capacity were inversely associated and concern about reimbursement was positively associated with pace of adoption. Agency consensus on barriers and facilitators was associated with pace of innovation.Organizations assess EBPs and other innovations in terms of costs, capacity and acceptability. This assessment varies by role within an organization and by an organization's level of engagement in implementation activities. Consensus within an organization as to specific facilitators and barriers is a potential predictor of EBP adoption and implementation.NIH-NIMH P30 MH090322."}
+{"text": "Physical activity is a vital component of good health, and it also helps reduce the severity of many chronic conditions . CurrentAlthough the study lacked conclusive evidence regarding the effect of medical school education and counselling knowledge/skill , it is a plausible assumption that doctors, having been taught how to prescribe exercise, would in turn counsel their patients effectively.However, the article does not consider other factors, in addition to medical school education, which can have an impact on physical activity counselling by healthcare professionals.One such factor is patient compliance. Justine et al.  showed tIn addition, the lack of public facilities and initiatives to encourage people to exercise can also limit the amount of physical activity undertaken. From a different perspective, the organisation of the healthcare system of a country may impact the effectiveness of physical activity counselling on patients. For instance, in the United Kingdom, general practitioners (GPs) are the primary point of contact for many chronic conditions, and so educating all GPs about the effects of physical activity could have a greater impact on general health in a nation.These wider factors lie outside the remit of counselling from the clinician and therefore the actual clinical outcomes from educating medical students regarding physical activity counselling remains unknown.In conclusion, educating medical students about the importance of physical activity is an important aspect of the medical curricula, which is being omitted in many universities across the world. However, other factors need to be considered when assessing the clinical benefit of physical activity counselling.Shaan Rashid Imperial College London School of Medicine London, UK Email: sr3011@ic.ac.ukOmer A. Jamall Imperial College London School of Medicine London, UKSheeraz Iqbal Imperial College London School of Medicine London, UKAbeer F. Rizvi Imperial College London School of Medicine London, UKOsman Nayeem Imperial College London School of Medicine London, UKA. M. Hameed Khan Imperial College London School of Medicine London, UK"}
+{"text": "Packenham, Director of the National Institute of Environmental Health Sciences (NIEHS) Office of Human Research Compliance, Clinical Research Program (CRP) and Vice-Chair of the NIEHS Institutional Review Board (IRB); Jane M. Lambert, NIEHS CRP IRB Administrator; and Craig Wladyka, NIEHS, CRP, IRB Protocol Coordinator, for their roles in the review and oversight of the GuLF STUDY. The comments they made during the review process were incorporated into the study protocol and consent documents and played an important role in ensuring ethical and regulatory oversight of the study.The authors regret this omission."}
+{"text": "Escherichia coli, due to the reliability of the host and the ease of protein (over) production, in particular many enzymes, in a compatible host background. Consequently, coliphages such as T4 and lambda served as model phages in the development of molecular tools and the fundamental understanding of phage-host interactions. The advent of new generation sequencing technologies has in recent years provided a vast array of sequence data relating to Gram-positive phages and their hosts, which in turn has permitted the development of analogies between Gram-negative and Gram-positive phages. For example, sequence analysis of Bacillus subtilis and Lactococcus lactis phages SPP1 and Tuc2009, respectively, revealed genomes with a conserved gene and/or functional order relative to lambda, the main model for Siphoviridae phages. While the Gram-negative models have been extremely useful platforms, many questions have remained unanswered owing to the fundamental structural and compositional differences between the cell walls of Gram-negative and positive cells. In response to this knowledge gap, there has been a significant upsurge in research in the area of phages infecting Gram-positive bacteria and in particular, lactococcal phage-host interactions, which have now become one of the leading model systems along with the above-mentioned Bacillus subtilis phage SPP1 and the mycobacteriophage L5.Bacteriophage research has seen many peaks and troughs over the past century ascending with phage therapy and application in the early 1900's; a research peak which was largely overshadowed by the dawning of the antibiotic era, and which has now deservedly regained attention as an approach against the problematic rise in antibiotic-resistant pathogenic bacteria. Following this initial scientific highlight, the advent of molecular biology and biotechnology sparked a renewed interest in phages and their encoded enzymes and promoters, which are still employed as research tools today. Much of this research was conducted using phages of Gram-negative bacteria, particularly Leuconostoc, Oenococcus and Weissella (Kot et al., Listeria and Clostridium spp. (Hagens and Loessner, In the ensuing 11 articles, many key advances that now define our understanding of phage-host interactions of Gram-positive bacteria and their infecting phages are described. We collate these advances and define the current knowledge of cell wall structures that present the target molecule of phage attachment (Munsch-Alatossava and Alatossava, The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The study of the microbial communities in the built environment is of critical importance as humans spend the majority of their time indoors. While the microorganisms in living spaces, especially those in the air, can impact health and well-being, little is known of their identity and the processes that determine their assembly. We investigated the source-sink relationships of airborne bacteria in 29 homes in the San Francisco Bay Area. Samples taken in the sites expected to be source habitats for indoor air microbes were analyzed by 16S rRNA-based pyrosequencing and quantitative PCR. The community composition was related to the characteristics of the household collected at the time of sampling, including the number of residents and pets, activity levels, frequency of cooking and vacuum cleaning, extent of natural ventilation, and abundance and type of vegetation surrounding the building.Diaphorobacter sp., Propionibacterium sp., Sphingomonas sp., and Alicyclobacillus sp. Source-sink analysis suggested that outdoor air was the primary source of indoor air microbes in most homes. Bacterial phylogenetic diversity and relative abundance in indoor air did not differ statistically from that in outdoor air. Moreover, the abundance of bacteria in outdoor air was positively correlated with that in indoor air, as would be expected if outdoor air was the main contributor to the bacterial community in indoor bioaerosols. The number of residents, presence of pets, and local tap water also influenced the diversity and size of indoor air microbes. The bacterial load in air increased with the number of residents, activity, and frequency of natural ventilation, and the proportion of bacteria putatively derived from skin increased with the number of residents. Vacuum cleaning increased the signature of pet- and floor-derived bacteria in indoor air, while the frequency of natural ventilation decreased the relative abundance of tap water-derived microorganisms in air.Indoor air harbored a diverse bacterial community dominated by Indoor air in residences harbors a diverse bacterial community originating from both outdoor and indoor sources and is strongly influenced by household characteristics.The online version of this article (doi:10.1186/s40168-015-0128-z) contains supplementary material, which is available to authorized users. The study of the indoor microbiome  is of critical importance since humans spend the majority of their time indoors and thus regularly encounter microbes in this habitat. Microbes, including those present in indoor spaces, impact human health and well-being , 2. Whil3 of air a day . All additional files supporting the results of this article are included within the article and its additional files."}
+{"text": "The Organizational Process Improvement Intervention (OPII), conducted by the NIDA-funded Criminal Justice Drug Abuse Treatment Studies consortium of nine research centers, examined an organizational intervention to improve the processes used in correctional settings to assess substance abusing offenders, develop case plans, transfer this information to community-based treatment agencies, and monitor the services provided by these community based treatment agencies.A multi-site cluster randomized design was used to evaluate an inter-agency organizational process improvement intervention among dyads of correctional agencies and community based treatment agencies. Linked correctional and community based agencies were clustered among nine (9) research centers and randomly assigned to an early or delayed intervention condition. Participants included administrators, managers, and line staff from the participating agencies; some participants served on interagency change teams while other participants performed agency tasks related to offender services. A manualized organizational intervention that includes the use of external organizational coaches was applied to create and support interagency change teams that proceeded through a four-step process over a planned intervention period of 12 months. The primary outcome of the process improvement intervention was to improve processes associated with the assessment, case planning, service referral and service provision processes within the linked organizations.Providing substance abuse offenders with coordinated treatment and access to community-based services is critical to reducing offender recidivism. Results from this study protocol will provide new and critical information on strategies and processes that improve the assessment and case planning for such offenders as they transition between correctional and community based systems and settings. Further, this study extends current knowledge of and methods for, the study of evidence-based practice adoption and implementation.The online version of this article (doi:10.1186/2194-7899-2-1) contains supplementary material, which is available to authorized users. Screening and assessment are clinical processes used to detect and then determine the extent, pervasiveness, or severity of presenting problems or issues by patients in a variety of health and other service settings. For individuals engaged in criminal justice or correctional systems, these screening and assessment processes should identify and evaluate criminogenic risks, including mental health and drug abuse problems, in order to tailor correctional supervision and rehabilitative services to those who need them  that include individuals in staff and managerial positions from correctional and community treatment agencies. The objectives of this study are threefold: (1) improve the quality of the assessment and case planning processes of correctional-based agencies; (2) assess the effectiveness of an externally facilitated, interagency change team process in implementing targeted process improvements; and (3) evaluate the impacts and determinants of this change process upon staff behavior, attitudes, and quality of assessment and case planning processes.The social significance of this study lies in its context within criminal justice systems and its focus on the processes of offender assessment and case referral, an interagency juncture long recognized to be faulty and ill-devised  from implementation strategies (those activities delivered to organizations and providers delivering the intervention strategy)  while NIATx involves a single agency.The implementation strategy of the OPII is similar to the NIATx model that uses a change team and coach to bring about process improvements in behavioral health settings . The individual designated for this position was expected to have direct line communications to the chief executive officer  of the corrections partner agency in which the OPII was being conducted. The LCTL served as the communication and decision-making pipeline with the corrections agency CEO and facilitated logistical and operational change processes identified by the LCT.The facilitator was an individual who worked with the LCT throughout the organizational improvement process. Each research center, in cooperation with the relevant correctional agency partner, selected facilitators who were under the employ of the RC. In general, facilitators had previously worked directly with agency providers in some capacity and possessed credentials and experience that provided credibility with the LCT.Facilitators helped LCTs stay on track and on task as they engaged in a structured, five-phase model of assessing and improving the quality of their interagency assessment and case planning mechanisms within correctional and community treatment systems. The five structured phases of the OPII and the planned duration of each phase were as follows: (1) Team Development (1\u20132 months); (2) Needs Assessment (3\u20134 months); (3) Process Improvement Planning (3\u20134 months); (4) Implementation (6 months); and (5) Follow-Up/Sustainability (6 months).During the Needs Assessment phase, the LCT engaged in a variety of information gathering and group decision-making techniques to critically examine and prioritize gaps or capacities in four core quality dimensions of their shared assessment and case planning processes: 1) Was the correctional agency using evidence-based and validated means for assessing the needs of offenders? (2) Were these needs identified and prioritized in the resulting case plans developed by the correctional agency? (3) Did the correctional agency share this assessment and case plan information with their referring community-based treatment providers, and did the providers find this information useful? (4) Did the community based agency provide services that addressed the needs of the offenders? The LCT, with assistance provided by the facilitator, used information gathered during the Needs Assessment to identify improvement goals, created a Process Improvement Plan (PIP), and carried out the implementation activities they had set out for themselves  participated in this study, with each RC comprised of correctional/criminal justice (CJ) agencies, community-based treatment agencies, and researchers. The role of each RC in the OPII study was to create and participate in the implementation strategy and to participate in workgroups that addressed issues such as implementation, data collection and quality, analysis, and publication. Resources and incentives provided by the research centers to the CJ and community providers varied across centers, but included opportunity and nominal funding for education (continuing education units), improvements in delivery of services, and development of an implementation process that could be used after the research was completed.Evaluation of the OPII used a multi-site cluster randomized design. Organizational clusters consisted of linked correctional and one or more community-based substance abuse treatment agencies providing correctional and substance abuse treatment services to common clients. Nine research centers contributed at least two clusters both of which were located within the same state. In this design, one cluster was randomly assigned to an early start condition, and the other cluster was assigned to a delayed start condition  introduce a design effect that must be estimated for sample size determinations and incorporated into analyses of study data  of the participating correctional settings served adults, but two of them served juveniles. There are 10 sites (clusters) in each study condition, for a total of 21 study sites.The outcomes of primary interest were those related to change in the intervention being provided to offenders, namely, assessment and case planning processes. Measures of intervention outcomes included congruence between assessed needs and case plan recommendations, quality of the content of the case plan, conveyance of case plans to community treatment providers, and cross-organizational coordination.Also of interest were the implementation outcomes of the facilitated change intervention process itself, which are related to fidelity and acceptability of the activities of the OPII. It was hypothesized that success in achieving process improvement goals, with regard to the assessment and case planning process, were dependent upon commitment to the intervention by members of the LCT, satisfaction with the facilitation, executive management support, interagency collaboration, and the quality and intensity of facilitation.Quantitative data collected for this study included structured ratings of correctional agency offender case plans and surveys of members of the LCT and other organizational staff in the participating agencies.The Assessment and Recommendations for Treatment Rating Form (ART/RF) provided ratings of four quality dimensions of the case plans. These dimensions included: (1) Measurement (the problem or service needs assessed by a given agency); (2) Integration with the Case Plan (the degree to which the case plan targets needs identified); (3) Conveyance (evidence that the case plan was shared with the community based treatment provider); and (4) Services Activation (evidence that the community-based treatment provider delivered services in accordance with the needs identified in the case plan). Case plan ratings were collected before the start of the intervention (baseline), during the intervention , and during the Sustainability/Follow-up phase. In each period, research staff randomly selected five case plans per month from agency records and rated them using the ART-RF. Case plans from the Delayed-Start sites were rated during the same period of time as for the Early-Start sites. Composite scores for each of the four quality dimensions were calculated for the five cases sampled each month, generating four ratings  per month.The Baseline Survey of Organizational Characteristics (BSOC) describes the organizational characteristics, climate, and culture of the participating sites across the three CJDATS studies . The BSOC was adapted from previously developed and validated instrumentation, including the TCU Survey of Organizational Functioning (TCU-SOF)  of the participating agencies were conducted periodically throughout the OPII intervention, specifically at the end of the Process Improvement Planning Phases, the end of the Implementation Phase and at the end of the Sustainability/Follow-Up Phase. Respondent interviews were valuable to understand and clarify the experiences, motivations, and underlying attitudes of participants involved in change projects Tracy . The intInterviews were conducted by members of each research center, either in person or over the phone. Interviews were audio recorded, transcribed, fact-checked, stripped of identifying information, and then analyzed using a multi-part group and individual coding process.The level of congruence between transitional offender assessments and case plans.The level of presence of accepted principles of case plan development in case plans.The percentage of case plans forwarded from correctional agencies to community treatment programs.The level of the use of case plans by community-based substance abuse treatment programs.Staff perceptions of the assessment-case planning process.The primary hypotheses of the study are that enhancements or improvements in each of the following outcomes occur only after the introduction of a specific and structured process improvement initiative (OPII):The degree to which LCTs exhibit fidelity to the designated elements of OPII.The degree of commitment by LCT members to achieving the goals of the plan.The level of staff satisfaction with the implementation strategy.The degree of management support within the organization for the intervention.The strength of the working alliance between the facilitator and the LCT.Secondary hypotheses are concerned with factors affecting the degree of success that LCTs experienced in achieving the goals they established for themselves. LCTs\u2019 success in achieving the goals for their Process Improvement Plans (PIP) were expected to be positively related to:The implementation questions for the OPII study include: (1) How are implementation outcomes related to variations across states in system characteristics, configurations of LCTs, assessment processes, and study implementation? (2) Were the improvements in assessment and case planning procedures identified by each LCT implemented as intended? (3) What does the OPII cost in terms of staff time devoted to designing and implementing the PIP? (4) Are OPII-initiated changes in assessment and case planning sustained following the end of the intervention? (5) In what ways does collaboration between organizations involved in the OPII change over the course of the intervention?Each research center obtained Institutional Review Board approval through an established FWA-recognized entity. In most instances, approvals were also secured from participating correctional and/or treatment agency research/IRB committees. Informed consent was obtained by research participants, including staff and managers of participating agencies, at varying points of time throughout the study, depending upon data collection requirements. Baseline structured staff surveys and corresponding participant consent were administered at the time of the kick off meeting of the early start site for participants of both the Early-Start and Delayed-Start sites. Qualitative interviews occurred after the randomization. ART-RF case ratings samples began six months prior to randomization; since the ratings did not collect personal identifying information, but rather agency documentation patterns, offender consent was not required.The organizational intervention under study in this paper will extend the use of interagency LCTs and externally facilitated organizational coaching to enhance the shared processes of assessment, case planning, service referral, and treatment provision processes between correctional agencies and community based treatment agencies. This study will generate and extend knowledge related to the science of implementation and organizational change in at least four key areas.First, the study will provide some of the first evidence of the effectiveness of change teams and facilitated coaching strategies to bring about changes in organizational processes  within correctional systems. While the utilization of organizational coaching and facilitation has been recognized as an effective organizational change process in correctional systems , but also nearly all of the survey measures, present major risks and challenges to the analysis and interpretation processes. Nonetheless, the focused efforts at construct triangulation, drawing upon multi-methods data collection  provide the potential for advancing measurement sophistication in this nascent field of inquiry. The reflective nature of our intervention design, one in which the speed at which the LCTs progress through the planned phases of the intervention, as well as the targeting of the process improvement goals selected by each LCT, present significant risks and challenges to analysis and interpretation. Finally, given the local setting context within which these LCTs are formed, the potential for spillover or generalization effects between early start and local start sites is an area for concern. For each of these methodological risks and liabilities, we have taken efforts to anticipate and guard against the most egregious risks, and we hope, in the process, to make significant contribution to the study of organizational improvement and implementation in general and within the unique context of correctional settings in particular.aCopies of the Facilitator Manual can be obtained by contacting the corresponding author.bAlthough there were nine (9) CJDATS Researcher Centers, one Center had two sets of study sites in two states, while another Center had a total of three study sites. The remaining seven research centers fielded one cluster each, with two study sites per cluster (n\u2009=\u200914).The CJDATS Assessment Workgroup members who participated in the development of the Assessment protocol are : David Duffee, Cassia Spohn (Arizona State University), Karen McKendrick, , Matthew Hiller, Roger Peters, Ralph B. Taylor, Gary Zajac (Temple University), Wayne Lehman (Texas Christian University), Linda K. Frisman, Colleen Gallagher, Eleni Rodis (University of Connecticut), Steven S. Martin, Cynthia Robbins (University of Delaware), Jamieson Duvall, Erin McNees Winston, Michele Staton Tindall (University of Kentucky), Bennett W. Fletcher ."}
+{"text": "While advances in neuroscience are helping to improve many aspects of human life, inequalities exist in this field between Africa and more scientifically-advanced continents. Many African countries lack the infrastructure and appropriately-trained scientists for neuroscience education and research. Addressing these challenges would require the development of innovative approaches to help improve scientific competence for neuroscience across the continent. In recent years, science-based non-profit organisations (NPOs) have been supporting the African neuroscience community to build state-of-the-art scientific capacity for sustainable education and research. Some of these contributions have included: the establishment of training courses and workshops to introduce African scientists to powerful-yet-cost-effective experimental model systems; research infrastructural support and assistance to establish research institutes. Other contributions have come in the form of the promotion of scientific networking, public engagement and advocacy for improved neuroscience funding. Here, we discuss the contributions of NPOs to the development of neuroscience in Africa. The centralised role of the nervous system in coordinating both conscious and unconscious bodily processes, actions and perceptions makes neuroscience an important discipline in biomedical research Lewis . Yet, adWhile these developments in neuroscience provide hope to improve our understanding of the biological basis of organismal health and development, large proportions of these advances have come from research laboratories in continents that are more developed than Africa  sponsoring promising African researchers for short-term training in leading universities abroad, and (2) awarding scholarships for graduate training abroad , Korle Bu Neuroscience Foundation , NeuroLeadership Institute (https://www.neuroleadership.com), The Dana Alliance for Brain Initiatives (http://www.dana.org) and Seeding Labs (http://seedinglabs.org). We will also highlight how some of these NPOs have partnered with scientific societies, funding agencies and universities in the delivery of their support initiatives, and how other organisations and individuals can emulate such strategies.To ensure that more scientists in Africa benefit from outstanding neuroscience training and are also supported to conduct high-impact research, some science-based non-profit organisations (NPOs) have been partnering the African neuroscience community to provide modern research infrastructure and training courses conducted at African universities. Other contributions have come in the form of promoting pan-African scientific networking, public engagement and advocacy for improved neuroscience funding. In this article, we discuss the contributions of these NPOs to neuroscience capacity building in Africa. This discussion will focus on NPOs that have provided support specifically for neuroscience education and research within Africa. The NPOs, identified through their contributions to the specific areas of capacity building discussed later in the article, include; Teaching and Research in Natural Sciences for Development in Africa  as powerful-yet-cost-effective model organisms for neuroscience research, the annual neuroscience summer courses also provide training in the development of experimental techniques for cutting-edge research , listing the equipment they need and the contact person for correspondence. TReND in Africa volunteers then appeal to leading institutions in Europe and North America which might have these equipment as surplus-yet-functional resources to donate. Upon donation, the equipment are packed and shipped to the African partner university; the receiving institution covers only the shipping cost. This approach provides a cost-effective means for African institutions to obtain research equipment. To date, KIU in Uganda has been the largest beneficiary of this support system, leading to the establishment of an Institute for Biomedical Research  is one of the effective means of building neuroscience capacity in the continent. Learning from this, neuroscientists in Africa (and scientists in other disciplines) can devise similar strategies to develop mechanisms of overcoming the chronic challenges that have caused science in the continent to lag behind other parts of the world. This way, resident scientists in Africa would obtain improved access to urgently-needed tools and materials in order to promote their teaching and research activities. We also call on African governments, industries and other NPOs to increase investments in neuroscience in order to help advance healthcare, education, business, economics and social wellbeing in the continent.IBRO, International Brain Research Organization; KBNF, Korle Bu Neuroscience Foundation; KIU, Kampala International University; TReND in Africa, Teaching and Research in Natural Sciences for Development in Africa; NPO, non-profit organisation"}
+{"text": "The Building Blocks trial [ISRCTN 23019866] assessed the short-term impact of an intensive programme of antenatal and postnatal visiting by specially trained nurses to support young pregnant women. This follow-on study, BB: 2-6, will assess the programmes' impact on longer-term benefits for mothers and children, through the linkage of routinely collected data, with a particular emphasis on the programmes' impact upon child maltreatment.Follow up will be by linked anonymous data abstraction from the Health and Social Care Information Centre (HSCIC), Office for National Statistics (ONS) and Department for Education, National Pupil Database (NPD). These information centres (ICs) will match participants to the information held in their databases, and send to a third party safe haven.Re-consenting of all mothers would have resulted in a drastic loss of participants therefore section 251 support was sought to allow the transfer of identifiers to ICs for matching. This support required participants to opt-out rather than consent in.This project will complete in 2018. What has been achieved thus far is the establishment of a regulatory compliant model of linking health, social care and education data to clinical data. This model of linkage offers the possibility for long term evaluation of trials, at lower cost, and with the potential to extend to other sources of routine data.This presentation will review the approach established in this study, reflect on the dis/advantages of the approach, summarise the conditions of s251 support, information governance compliance, IC requirements and finally the challenges (and solutions) faced thus far."}
+{"text": "Despite the proliferation of evidence-based treatments (EBT), there is little evidence that they are successfully implemented in real world behavioral health systems, fueling an ongoing debate about whether and how systems should invest in infrastructure to support implementation of EBT and the use of data and research to inform policy. Ironically, however, there are few empirical studies of whether and how public systems are living up to the promise of data- and research-based decision-making. The current study used data from the National Association of State Mental Health Program Directors (NASHMPD) Research Institute's (NRI) longstanding effort to compile information on state mental health authorities to examine the degree to which state systems currently invest in EBT and data-driven decision-making, and how such investments have changed over the period from 2001-2012. The study focused on: (1) Rates of implementation of specific EBT programs; (2) Types of state-provided or-facilitated EBT training and workforce support; and (3) State investment in evaluation, data, and research use. Data originated from three NRI projects for which annual or semi-annual data relevant to the above research questions were available: the State Profiles System (SPS), the Revenues and Expenditures Study (R&E), and the Uniform Reporting System (URS). Results found that after an initial increase from 2001-2004, rates of implementation of both child and adult EBTs have been consistently flat for the last decade, with investment in EBTs for adults 2-6 times higher than for children's services. Data also show variability over time in the types of implementation supports being used, with states increasingly emphasizing EBT in contracts with providers, modification of IT systems, and \"awareness building,\" and less on specific budget requests for EBT implementation or financial incentives for EBT use. Of concern, state investment in research and evaluation capacity and database integration efforts appear to be decreasing. Results of this ongoing research initiative are intended to strengthen the D&I knowledge base on the use of research findings in public systems, informing future national priorities and state efforts, promoting additional research, and serving as a baseline metric for reform efforts."}
+{"text": "Dengue outbreaks in the Guangdong province reached epidemic proportions in the last quarter of 2014. According to the Guangdong provincial health and family planning commission (Although dengue, one of the most strongly emerging, neglected tropical diseases worldwide and presently without widely available drugs or vaccines, has a geographical distribution in South China , this ouChina needs to tackle the increase in dengue. The lessons learnt from previous infectious disease outbreaks such as SARS and H7N9 can be of value. The Chinese government has taken the following surveillance and control measures for dengue: strengthening surveillance and situation analysis; reinforcing case management and medical treatment; and conducting risk communication with the public and releasing information. Of note, the Patriotic Health Campaign Committee Office is a government organisation in each city or county, which can organise the resources needed to address issues of community hygiene. The government should also advise travellers to areas with known dengue outbreaks to take precautions such as avoiding mosquitoes.Chengshen JiangMaryland Institute for Applied Environmental HealthUniversity of MarylandCollege Park, MD, USAJohn S. SchieffelinDepartment of PediatricsSection Adult & Pediatric Infectious DiseaseTulane University School of MedicineNew Orleans, LA, USAJian LiDepartment of Biostatistics and BioinformaticsTulane University School of Public Health andTropical MedicineNew Orleans, LA, USAWenjie SunSchool of Food ScienceGuangdong Pharmaceutical UniversityZhongshan, ChinaDepartment of Global Health and Environmental SciencesTulane University School of Public Health andTropical MedicineNew Orleans, LA, USAEmail: wsun3@tulane.edu"}
+{"text": "Tension headache (TH) belongs to most frequent type of the idiopathic cephalalgies. Depression and serotonins metabolism disorders play a leading role in the pathogenesis of TH.Study the dependence of the intensity of the TH of degree of depression, anxiety and levels of serum serotonin.The complex algic, psychometric test and determination of concentration of blood serum serotonin (S) by the method of immunoenzyme analysis were performed in 140 patients with TH.At patients of first group the intensity of episodic TH (44 man) was 56\u00b14,32 mm according to 100-mm visual analogue scale. All patients of this group had high level of reactive anxiety , moderate level of depression and tendency to the decreasing of blood S concentration . The second group consists of 96 patients with chronic TH. Straight correlation between duration and intensity of ache, indices of reactive and personal anxiety , high depression level  and significant decreasing of blood S concentration  was determined in all patients of this group.Concentration of blood serum serotonin depends on duration and intensity of ache, level of depression and anxiety. Therefore, serotonin of blood serum can be used as biomarker of ache intensity, level of depression.No conflict of interest."}
+{"text": "The aim of the present study is to empirically test the theoretical model, Positive Self and Relational Management (PS&RM), for a sample of 184 Italian university students. The PS&RM model specifies the development of individuals' strengths, potentials, and talents across the lifespan and with regard to the dialect of self in relationship. PS&RM is defined theoretically by three constructs: Positive Lifelong Life Management, Positive Lifelong Self-Management, Positive Lifelong Relational Management. The three constructs are operationalized as follows: Positive Lifelong Life Management is measured by the Positive and Negative Affect Schedule (PANAS), the Satisfaction With Life Scale (SWLS), the Meaningful Life Measure (MLM), and the Authenticity Scale (AS); Positive Lifelong Self-Management is measured by the Intrapreneurial Self-Capital Scale (ISC), the Career Adapt-Abilities Scale (CAAS), and the Life Project Reflexivity Scale (LPRS); and Positive Lifelong Relational Management is measured by the Trait Emotional Intelligence Questionnaire (TEIQue), the Multidimensional Scale for Perceived Social Support (MSPSS), and the Positive Relational Management Scale (PRMS). Confirmatory factor analysis of the PS&RM model was completed using structural equation modeling. The theoretical PS&RM model was empirically tested as defined by the three hypothesized constructs. Empirical support for this model offers a framework for further research and the design of preventive interventions to promote decent work and decent lives in the twenty-first century. Across the lifespan, individuals inevitably confront multiple challenges in the domains of work and relationship. While these are longstanding human challenges, recent economic, and social changes related to unemployment, globalization, and the changing nature of work have created a crisis involving underemployment, unemployment, and subsequent loss of financial security. The field of vocational psychology can assume a leadership role in responding to the current crisis by advancing theories, research, and practices that address the impact of these pressing social and economic challenges . Participants were predominantly White Italians from middle-class backgrounds.Participants are 184 Italian students of the University of Florence. Regarding gender, 81 participants were male (44%) and 103 participants were female (56%). The age of the participants ranged from 22 to 27 years  and negative affect (NA), the Positive and Negative Affect Schedule . Concerning ethical standards for research, the study followed procedures consistent with the latest version of the Declaration of Helsinki revised in Fortaleza , NNFI = 0.93, CFI = 0.93.The goodness-of-fit indices for the best model are the following: \u03c7An evaluation of these indices in relation to the results of the analysis for this study reveals good fit and support for the PS&RM model.The aim of the present study was to provide empirical support for the conceptualization of PS&RM (Di Fabio, Structural equation modeling confirmed the hypothesized structure articulated by the three lower order latent constructs: Positive Lifelong Life Management, Positive Lifelong Self-Management, and Positive Lifelong Relational Management. The construct of Positive Lifelong Life Management integrates hedonic and eudaimonic well-being, meaning in life and authenticity. Given that rapid social, economic, technological, and career change can disrupt a sense of meaning, coherence, and well-being Masten, , the capThe second construct Positive Lifelong Self-Management emphasizes self and intraindividual resources considered important for coping proactively with the challenges of the post-modern era (Di Fabio, The third construct Positive Lifelong Relational Management includes personal (e.g., trait emotional intelligence; Petrides and Furnham, In sum, the current study provides empirical support for the conceptualization of PS&RM as Positive Lifelong Life Management, Positive Lifelong Self-Management, Positive Lifelong Relational Management. Considered collectively, the three dimensions consider the importance of advancing a state of well-being that benefits the individual and society and promotes personal skills to adapt to change and uncertainty while integrating and balancing individual, relational, and community concerns and interests. Together, the dimensions are supportive of decent work and decent life.Although the results of the present study test the PS&RM model (Di Fabio, If the PS&RM model is tested and validated in future research with diverse populations, it may offer a useful framework for preventive intervention. As a preventive framework (Hage et al., It is our hope that the preventive and relational framework specified by the PS&RM model can contribute to building decent work and decent lives for many people in the twenty-first century. We propose that life construction (Guichard, AD and MK conceptualized the study, chose the theoretical framework and chose the measures. AD collected the data and with MK wrote the methods and results. Then the authors wrote the paper together and read and revised the manuscript several times.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "To assess different methods for determining cause of death from verbal autopsy (VA) questionnaire data, the intra-rater reliability of Physician-Certified Verbal Autopsy (PCVA) and the accuracy of PCVA, expert-derived  and data-driven  algorithms were assessed for determining common causes of death in Ugandan children. A verbal autopsy validation study was conducted from 2008-2009 in three different sites in Uganda. The dataset included 104 neonatal deaths (0-27 days) and 615 childhood deaths (1-59 months) with the cause(s) of death classified by PCVA and physician review of hospital medical records (the \u2018reference standard\u2019). Of the original 719 questionnaires, 141 (20%) were selected for a second review by the same physicians; the repeat cause(s) of death were compared to the original,and agreement assessed using the Kappa statistic.Physician reviewers\u2019 refined non-hierarchical algorithms for common causes of death from existing expert algorithms, from which, hierarchal algorithms were developed. The accuracy of PCVA, non-hierarchical, and hierarchical algorithms for determining cause(s) of death from all 719 VA questionnaires was determined using the reference standard. Overall, intra-rater repeatability was high . PCVA performed well, with high specificity for determining cause of neonatal (>67%), and childhood (>83%) deaths, resulting in fairly accurate cause-specific mortality fraction (CSMF) estimates. For most causes of death in children, non-hierarchical algorithms had higher sensitivity, but correspondingly lower specificity, than PCVA and hierarchical algorithms, resulting in inaccurate CSMF estimates. Hierarchical algorithms were specific for most causes of death, and CSMF estimates were comparable to the reference standard and PCVA. Inter-rater reliability of PCVA was high, and overall PCVA performed well. Hierarchical algorithms performed better than non-hierarchical algorithms due to higher specificity and more accurate CSMF estimates. Use of PCVA to determine cause of death from VA questionnaire data is reasonable while automated data-driven algorithms are improved. Verbal autopsy (VA) is an indirect method of determining cause of death based on an interview with the caretakers of a deceased individual, which has been widely used to collect information on cause-specific mortality where vital registration systems are lacking and medical information on deaths is incomplete . DiffereThe most widely used method is physician review, known as physician-certified VA (PCVA), in which physicians are trained to review questionnaire data and determine cause of death. Although the validity of PCVA has been evaluated , concernAn alternative to PCVA for determining cause(s) of death from VA data are algorithms. Algorithms can be expert-derived or data-driven. Expert algorithms include a set of pre-defined diagnostic criteria developed by a panel of physicians,based on experience or review of existing literature . AlternaData from a VA validation study conducted in three epidemiological settings in Uganda were used to investigate the performance of different methods for determining causes of death from VA data. We evaluated the intra-rater reliability of PCVA, and also compared the accuracy of PCVA to that of two algorithms; one developed with the input of expert physicians  and another data-driven .The VA data-set used to investigate the performance of different methods for determining causes of death was obtained from a VA validation study that was approved by the Ugandan National Council for Science and Technology, the Centers for Disease Control and Prevention, and the ethics committees of Makerere University Faculty of Medicine, and the London School of Hygiene and Tropical Medicine. Details of the VA validation study method are published elsewhere . BrieflyTwenty percent of VA questionnaires were systematically sampled for assessment of intra-rater reliability. Using a list of sequentially ordered identification numbers for each site, we systematically selected every fifth VA questionnaires with the corresponding COD originally determined by physician review of the data. VA questionnaires were re-evaluated by the original physician a second time. Re-determination of causes of death from VA questionnaires occurred 3\u20139 months after the original assessment, and physicians were blinded to the causes of death recorded in the original VA death certificate.The non-hierarchical algorithms were based on previously published expert algorithms ,21,29\u201331Hierarchical algorithms were developed by ranking the performance of the non-hierarchical algorithms to reach common causes of childhood deaths, including neonatal deaths. Ranking was prioritized based on specificity of causes of death as determined using expert algorithms. The cause of death with the highest specificity wasplaced at the top of the hierarchy while the least specific was placed at the bottom . NeonataOriginal) to the re-determined CSMF (CSMF Repeat).The cause of death determined by physicians upon repeat review of VA questionnaires was compared to the cause of death originally determined by the same physician. The percentage level of agreement and Kappa statistic was calculated using Stata 12  for each physician. Interpretation of Kappa values was based according to the criteria of Landis and Kock , who recA database comprised of responses to closed-ended sections of VA questionnaires, and the reference causes of death derived from medical records were generated. Causes of death determined by non-hierarchal algorithms were derived by applying non-hierarchal algorithms to the closed-ended sections of VA questionnaires. Non-hierarchal algorithms were capable of classifying more than one cause of death. Hierarchal algorithms were also applied to the same VA questionnaire database, generating a single cause of death for each questionnaire.PCVA), non- hierarchical algorithms (CSMFNHA) and hierarchal algorithms (CSMFHA). The difference between the CSMF determined using each of the three methods and the \u2018reference standard\u2019 (CSMFMR) was calculated for the common causes of death. For neonatal and childhood deaths, where algorithms were developed for five and four commonest causes of death respectively, causes of death that did not fit the commonest cause of death list were categorized as \u2018others\u2019 and were factored in all analysis.The sensitivity and specificity of each method for determining cause of death were calculated by comparing the cause of death assigned by each method to the \u2018reference standard\u2019 for causes of death derived from hospital medical records, including malaria, pneumonia, diarrhea, meningitis, malnutrition, and HIV. CSMF estimates of the leading causes of death were also calculated for PCVA , non-hierarchical algorithms , and hierarchical algorithms (1% and 2% difference respectively). Non-hierarchical algorithms (50% difference), and hierarchical algorithms (16% difference) overestimated the CSMF for septicemia deaths compared to PCVA (-3% difference) that performed best. On the contrary non-hierarchical algorithms (5% difference), and hierarchical algorithms (-4% difference) had better CSMF estimates for meningitis deaths compared to PCVA  deviated greatly from the reference standard , with a tendency to overestimate the CSMF for the leading causes of death across all sites. The CSMF estimated by PCVA (CSMFPCVA) and the hierarchal algorithms (CSMFHA) approximated that of the reference standard (CSMFMR) for all cause(s) of death, performing far better than non-hierarchical algorithms. However, overall CSMF estimates of malaria deaths were best approximated by hierarchal algorithms (0% difference), exceeding performance of both PCVA (6% difference) and non-hierarchical algorithms (56% difference), which both overestimated the fraction of deaths attributable to malaria when compared to the reference standard  of death and a marked decline in specificity.Hierarchical algorithms assigning a single cause of death from each VA questionnaire resulted in an increase in specificity of the algorithm in determining causes of death, but at the expense of sensitivity which declined. However, compared to the non- hierarchal algorithms, hierarchal algorithm estimates of the reference CSMF were accurate and as good as those of PVCA for all the common causes of death; a fact attributed to the high specificity levels of hierarchal algorithms. This finding, previously described by Anker et al , demonstSeveral computerized methods premised on different algorithmic methods , probabilistic  approaches have been developed as alternative methods of determining cause(s) of death from VA questionnaires ,33,36\u201338InterVA uses a probability matrix, which was derived from clinical knowledge of group of physicians , and in Our study is not without limitation. Internal evaluation of the performance of the hierarchical algorithm may have biased results, showing good performance of the hierarchical algorithms. However, the results of our analysis are strengthened by the inclusion of three different study sites. Furthermore, the small sample of deaths among some of the causes of the death in both neonates and children, especially when stratified by site, may have undermined our ability to detect representative estimates of measures of performance.Our study provides insights into the performance of different methods for determining cause(s) of death from VA questionnaire data collected in three sites. Importantly, we demonstrate that repeatability of PCVA is high, contrary to expectation, and that overall PCVA performed well. Thus, based on our results and available evidence so far, PCVA remains a reliable method for determining cause of death from VA questionnaire data. Given the lack of consensus on the accuracy of recently developed CCVA methods, PCVA still has a place in determining cause of death in VA, while existing and newer automated data-driven algorithms, which undoubtedly would be more efficient, are further developed, refined, and evaluated."}
+{"text": "A 70-year-old man referred for cataract surgery, had on examination a palette of colored needle-shaped opacities in the cortex and anterior nucleus of the lens, consistent with unilateral Christmas tree cataract. This type of cataract result from the accelerated breakdown of membrane associated proteins. The peptides and amino-acids accumulate in the lumen of the reticular meshwork, and cystine is concentrated beyond the level of crystallization, giving rise to growing crystals."}
+{"text": "Inflammation in the face of harming stimuli protects the organism; as a result, it is an essential route for survival, in which both innate and adaptive immunity are involved. This process must be tightly controlled and terminated in order to warrant the reestablishment of body homeostasis. Therefore, activation of resident inflammatory cells and the recruitment and modulation of migrating inflammatory cells must be ceased. When failure in neutralizing acute inflammation occurs, there is augmented risk of development of chronic inflammation, leading to several metabolic consequences. In the present special issue, original research studies as well as review articles address the inflammatory process as a key contributor to disease onset and progression. In addition, pharmacological and nonpharmacological therapies are examined and the molecular and physiological mechanisms of the treatments are discussed.Among the 24 accepted papers, 7 approach nutritional therapy and inflammation . The selected papers discuss the effects of Macadamia oil supplementation attenuation of adipocyte hypertrophy and of the inflammatory response of adipose tissue macrophages. The protection induced by supplementation of chitosan coacervate whey protein against metabolic changes and obesity-related inflammation is investigated. Other papers examine Jussara supplementation-associated reversal of the adverse effects of perinatal intake of transfatty acids, the beneficial effect of red genistein extract on autoimmune arthritis, and the role of vitamin C in the resolution of inflammation. Finally, the promotion, by nutritional intervention, of the recovery of glucose homeostasis is discussed. In addition, results on the effect of microencapsulated probiotics on alcoholic liver disease are presented. Taken together, these papers show new encouraging results of nutritional therapy in counteracting the symptoms of obesity and insulin resistance.The ability of exercise to modulate chronic inflammation was the center of two papers . These studies report that a community-based exercise program results in decrease or maintenance of inflammatory biomarkers after 1 year and thus presents strong potential in public health approaches for chronic disease prevention.Inflammation and its mechanisms are discussed in the development and progression of many diseases, such as in ectopic fat deposition , acute and chronic kidney disease , and polymicrobial sepsis . The role of interleukin- (IL-) 18 in the regulation of toll-like receptors and mannose receptor expression  is examined. Inflammation in the metabolic syndrome  and the effect of metformin on autoimmune arthritis  are debated. Gut microbiota participation in inflammation is addressed , and its regulation by short-chain fatty acids in diabetes  contemplated. The contribution of circulating LL-37 and inflammatory cytokines in the setting of plaque and guttate psoriasis  is commented on. Other papers consider ionotropic and metabotropic proton-sensing receptors in allergic asthma  and autologous bone marrow stem cell transplantation in myocardial infarction . Flavocoxid and infliximab are examined in the context of classical and nutraceutical therapies . The role of IL-38 and related cytokines in inflammation  is discussed, in addition to gingival inflammation and pregnancy  and the contribution of the immune system in triplet repeat expansion diseases .Collectively, this issue provides insight on the role of acute and chronic inflammation in different diseases and discusses mechanisms and new treatment strategies.M. SeelaenderM. SeelaenderJ. C. Rosa NetoJ. C. Rosa NetoG. D. PimentelG. D. PimentelR. S. GoldszmidR. S. GoldszmidF. S. LiraF. S. Lira"}
+{"text": "Infections of poultry species with virulent strains of Newcastle disease virus (NDV) cause Newcastle disease (ND), one of the most economically significant and devastating diseases for poultry producers worldwide. Biological engagement programs between the Southeast Poultry Research Laboratory (SEPRL) of the United States Department of Agriculture and laboratories from Russia, Pakistan, Ukraine, Kazakhstan, and Indonesia collectively have produced a better understanding of the genetic diversity and evolution of the viruses responsible for ND, which is crucial for the control of the disease. The data from Kazakhstan, Russia, and Ukraine identified possible migratory routes for birds that may carry both virulent NDV (vNDV) and NDV of low virulence into Europe. In addition, related NDV strains were isolated from wild birds in Ukraine and Nigeria, and from birds in continental USA, Alaska, Russia, and Japan, identifying wild birds as a possible mechanism of intercontinental spread of NDV of low virulence. More recently, the detection of new sub-genotypes of vNDV suggests that a new, fifth, panzootic of ND has already originated in Southeast Asia, extended to the Middle East, and is now entering into Eastern Europe. Despite expected challenges when multiple independent laboratories interact, many scientists from the collaborating countries have successfully been trained by SEPRL on molecular diagnostics, best laboratory practices, and critical biosecurity protocols, providing our partners the capacity to further train other employes and to identify locally the viruses that cause this OIE listed disease. These and other collaborations with partners in Mexico, Bulgaria, Israel, and Tanzania have allowed SEPRL scientists to engage in field studies, to elucidate more aspects of ND epidemiology in endemic countries, and to understand the challenges that the scientists and field veterinarians in these countries face on a daily basis. Finally, new viral characterization tools have been developed and are now available to the scientific community. Newcastle disease (ND) is one of the most significant diseases of poultry worldwide. It is caused by virulent strains of Newcastle disease virus (NDV), also known as avian paramyxoviruses of serotype 1 (APMV-1). The presence of virulent viruses in poultry must be immediately reported to the World Organisation for Animal Health . Whether in domestic poultry or wild birds, vNDV strains remain a threat to all producers of poultry.In 1998, the US Department of State (DOS) assisted selected former Soviet chemical and biological weapons scientists to redirect their efforts to peaceful, agricultural research and to help reduce the proliferation of weapons of mass destruction. Almost a decade later, the DOS Biosecurity Engagement Program (BEP) was implemented with the broader mission of providing financial and intellectual assistance to microbiological laboratories to enhance biosecurity, biosafety, and pathogen and disease surveillance, while decreasing biological threats, globally. The collaborations expanded past the former Soviet Union (FSU) to include South and Southeast Asia, the Middle East and Africa. One area of common mutual interest across these regions was scientific collaboration on avian influenza virus (AIV) and NDV, both notifiable and listed diseases to the OIE.In 2000, a long-standing collaboration between the ARS Southeast Poultry Research Laboratory (SEPRL) and Russian counterparts began on avian influenza and NDV and provided unique opportunities for surveillance and research in the region. In 2002, SEPRL began collaborating with partners in Kazakhstan; in 2010, collaborations began with Ukraine, Egypt and Indonesia; and in 2011, with Pakistan. From 2000 to 2015, SEPRL has collaborated on 14 bio-engagement research projects on avian influenza and ND with its global partners mainly funded by the DOS, but also more recently by the Department of Defense\u2009\u2013\u2009Defense Threat Reduction Agency. While most of the initial interactions with foreign laboratories often began with the training of collaborators at SEPRL, formal scientific collaborations often developed subsequently , Food and Agricultural Organization , US AgenDuring the research projects, SEPRL scientists visited their foreign counterparts in Russia, Kazakhstan, and Ukraine 32 times. SEPRL scientists also hosted 30 collaborators for scientific visits involving research and training. Under the auspices of the projects, SEPRL and foreign collaborators participated in over 25 international conferences in the US, Russia, Ukraine, South Africa, Spain, Germany, China, Latvia, the United Kingdom, and Thailand. In addition to the research projects, from 2008 to 2010, SEPRL provided training on molecular techniques to detect AIV and NDV to 57 scientists from 21 countries. Additional informal collaborations with scientists from Israel, Bulgaria, Nigeria, Tanzania, and Mexico have added to the body of knowledge on AIV and NDV epidemiology. Through training and collaborative research efforts, SEPRL has developed an extensive network of scientists around the world working on AIV and NDV.The initial objective of the scientific proposals between SEPRL and the collaborating laboratories included increasing the number of surveillance samples obtained from commercial and domestic poultry species, and also wild birds. Scientists from the participant laboratories processed these samples together with SEPRL scientists, identified and characterized the strains of NDV obtained. Subsequent testing of molecular diagnostic techniques documented if routinely used molecular assays were able to detect all of the viruses isolated. Additional characterization of isolates, such as pathogenesis studies in chickens, vaccine studies, or phylogenetic sequence analysis was performed depending on the scientific interests or industry concerns. The objective of the training was to prepare foreign scientists to be able to accurately and promptly detect vNDV and to identify what avian species the viruses are likely to be obtained from. Those skills were considered to be critical for preventing, containing, and controlling ND outbreaks. Furthermore, efforts were made in promoting safe, secure, and responsible use of biological materials that are at risk of accidental release or intentional misuse as the prevention of accidents improves the quality of life for people from all the countries involved.NDV of low virulence, also known as lentogenic NDV, are widely distributed worldwide and are present in multiple avian species that may be in contact with poultry. Lentogenic viruses are used as vaccines to prevent mortality and clinical disease from vNDV infections in poultry. However, some lentogenic strains produce respiratory infections that decrease productivity in poultry, and have the potential to become virulent upon mutation of the cleavage site of the fusion protein gene. The nucleotide sequence of the fusion gene is used to classify NDV strains into genotypes and the cleavage site sequence of the fusion protein of NDV is the accepted OIE identifier of virulence. Strains that have three or more basic amino acids at positions 113\u2013116 with a phenylalanine at position 117 are by definition virulent \u201310. As mA collaboration project with the National Scientific Center Institute of Experimental and Clinical Veterinary Medicine, Kharkiv, Ukraine was initiated to study the geographic distribution, wild host species distribution, and ecological factors affecting virus transmission of avian paramyxoviruses in Ukraine. Wild-bird surveillance was conducted in Crimea, Kherson, Zaporizhia and the Donetsk regions of Ukraine. The Black and Azov Sea regions are part of an intercontinental (north to south and east to west) flyway, and the similarity of the NDV strains isolated from these regions with other NDV from Northern Europe and Africa confirmed the importance of sampling birds in these regions for the early detection of viruses transported by wild birds .n\u2009=\u20099), APMV-4 (n\u2009=\u20094), APMV-6 (n\u2009=\u20093), and APMV-7 (n\u2009=\u20094) (Surveillance for hemagglutinating (HA) avian paramyxoviruses was conducted during 2006\u20132011 through different seasons of the year on 6,735 wild birds, representing 86 species, from 8 different orders. The presence of HA positive viruses in oral and cloacal swabs was obtained and the serotypes of the APMV were identified by hemagglutination-inhibition tests. The APMV obtained from swabs were serologically characterized and determined to belong to different serotypes as follows: APMV-1 ( (n\u2009=\u20094) . SurprisAs a result of an international collaboration that included the US Geological Survey at the Alaska Science Center in Anchorage, the Southeastern Cooperative Wildlife Disease Study group of The University of Georgia, Athens, GA, USA, the Research Center for Animal Hygiene and Food Safety, Obihiro University of Agriculture and Veterinary Medicine in Inada, Hokkaido, Japan, and the State Research Center of Virology and Biotechnology \u2018VECTOR\u2019, Novosibirsk Region, Koltsovo, Russia, the genetic diversity of APMV-1 isolated from migratory birds connected with Alaska and the continental US was studied . Swabs sAnalysis of the fusion protein sequence data revealed that none of the putative amino acid sequences for the fusion protein cleavage sites were consistent with those of previously identified virulent viruses. Besides the fact that five isolates of genotype I of class II formed a monophyletic cluster exhibiting previously unreported genetic diversity, which met criteria for the designation of a new sub-genotype, the most significant finding of this study was the close genetic relationship among selected isolates from wild-bird isolates from widely divergent geographic location. Close relationships were found among viruses of class II, with Russian NDV strains closely related to North American viruses (class II sub-genotypes Ib and Ic). More specifically NDV strains from Alaska (US) and Japan were related to NDV from Maryland (US), suggesting multiple opportunities where birds from different areas were exposed to each other\u2019s viruses. The relatedness of these viruses provided indirect evidence for possible intercontinental virus spread by migratory birds. Furthermore, the close relationship between NDV from class II genotype I, sub-genotypes Ib and Ic, confirmed that migratory bird movement is one of the possible mechanism for the redistribution of NDV strains . Due to The epidemiological factors responsible for the maintenance and spread of vNDV strains are largely unknown. It is suspected that vNDV may persist in vaccinated animals, however, repeated isolations of vNDV strains in wild birds also suggests the existence of natural reservoirs in birds species that either might not be susceptible to disease or may be partially resistant, such as parrots, cormorants and pigeons. Evaluating surveillance samples of domestic poultry species along with samples from wild-bird populations geographically surrounding them is critical for completely understanding the epidemiology of ND.The BEP collaborations between SEPRL and Pakistan involved two departments of the University of Veterinary and Animal Sciences, in Lahore; 1) Quality Operations Laboratory and (2) the Pakistan Institute of Biochemistry and Biotechnology, and another institution, the Poultry Disease Diagnostic Laboratory in Gakkhar, Gujranwala, Punjab. Efforts were focused on epidemiological studies designed to identify and characterize circulating strains of NDV in Pakistan. The first BEP collaboration with Pakistan characterized eight vNDV strains isolated from the years 1974, 1995, and 2004 through 2008 . Besides Quality The majority of the remaining Pakistani strains grouped with variants of NDV found in pigeons from genotype VIb, often called pigeon paramyxovirus-1 (PPMV-1). PPMV-1 are virulent by definition since they contain three or more basic amino acids at positions 113\u2013116 and a phenylalanine at position 117 of the fusion protein cleavage site and have an ICPI of equal to or greater than 0.7, thus are reportable to OIE  has been gradually replaced by new viruses in some countries of Asia and the Middle East, these older viruses of VIId have continued to circulate worldwide. Three viruses isolated from chickens in Ukraine between 2003 and 2013 have been classified as members of sub-genotype VIId. Interestingly, these viruses resembled NDV isolates from backyard poultry in Bulgaria from 2006 and 2007 (unpublished data). These viruses were closely related to isolates from China from 2003 to 2007 and Serbia from 2007, further providing evidence for the distribution patterns of vNDV.113-R-Q-R/K-R-F-117) and ICPI values ranging from 1.05 to 1.87 .Thus, the evidence suggests that the simultaneous evolution of vNDV strains from multiple genotypes has continued in different locations and different hosts since the first vNDV were identified in 1926. However, increased surveillance, and prompt epidemiological characterization of new strains circulating in developing countries funded by BEP and other international efforts have allowed a better understanding of the evolution of vNDV and has increased awareness that ND is a global problem.One of the goals of the BEP collaborations was the evaluation of current diagnostic methods against new emerging strains of NDV. The constantly developing network of laboratories in different countries around the world, collaborating on the control of the ND, resulted in the increasing number of samples obtained from both poultry  and wild birds. Thousands of collected specimens where tested by various serological, virological, and molecular methods. As a result, more than 350 NDV strains were isolated and most of them have been further studied and characterized. Most currently utilized rapid diagnostic methods based on rRT-PCR were effective in detecting ND viruses. The L-TET rRT-PCR designed to detect class I APMV-1 viruses  and multn\u2009=\u200952) and class II (n\u2009=\u2009135)  , 27 (unpNewcastle disease represents an international problem and a significant threat to poultry industries worldwide. The existence of a large number of countries with endemic virulent ND circulating in poultry and wild birds, the capacity of viruses for rapid intercontinental spread, the ability of viruses to gradually change, and the potential use for bioterrorism, require the development of more internationally funded epidemiological and veterinary research programs. The BEP collaborative projects have effectively contributed to the understanding of the threat and to the development of better tools to identify and characterize this agent.PM, KD, and CA defined the theme of the manuscript. All authors contributed on the data collection, writing of the manuscript and editing the manuscript. KD, PM, and DW-C created the tables. KD created the figure. DW-C, KD, and CA designed primers. All authors have seen and approved the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Sarcopenia and muscular dystrophy are both characterized by the loss of muscle mass and increased intramuscular fibrosis. The two conditions also share several pathophysiological mechanisms, including mitochondrial dysfunction, increased apoptosis, abnormal regulation of autophagy, decline in satellite cell function, increased generation of reactive oxygen species, and alterations of signaling and stress response pathways. Basic science researchers and clinicians working in the areas of sarcopenia and muscular dystrophy in human and animal models contributed to this research topic  may well serve that purpose -dependent signaling , IBM with Paget\u2019s disease of bone and frontotemporal dementia (IBMPFD), and  Krause, . MutatioThe five following contributions explored clinical aspects and evaluation methods. Harris-Love et al.  provide Since a distinction between normal age-related weakening of muscle strength and clinically significant muscle disease is not always obvious, the correct diagnosis is easily missed. Palmio and Udd  performeThe quantitative and qualitative domains of sarcopenia concur to the development of the clinical phenotype, dominated by muscle weakness, poor balance, and slow gait speed. This clinical picture shows substantial overlap with that of physical frailty , nutritional intervention, and physical exercise were discussed.The possibility of counteracting the age-related muscle decline was assessed through electrical stimulation (ES) of the thigh muscles (Kern et al., The origins of sarcopenia are multifactorial and only partly understood. However, protein-energy malnutrition is a well-known cause of muscle loss in advanced age (Calvani et al., Besides the optimization of nutrition, engagement in regular physical activity is widely recognized as an effective measure for preventing and treating sarcopenia (Landi et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Evidence-based, expert-driven, practical statements improve quality and effectiveness of the diagnostic and therapeutic process of patient care. Although the effectiveness of physiotherapy treatment strategies in ICU patients has been described, statements or guidelines of physiotherapy for ICU patients are not available . GuideliFor the development of this evidence statement, we used the EBRO method, as recommended by the Dutch Evidence Based Guideline Development Platform . This meThree expert-based relevant clinical questions were formulated within the physiotherapy clinical reasoning process and were classified according to the International Classification of Functioning, Disability and Health. In a systematic literature search, 129 studies were identified and assessed for methodological quality and classified according to the level of evidence. The final Evidence Statement consisted of recommendations for physiotherapy in ICU patients including safety criteria, a core set of instruments to assess impairments and activity restrictions and effective interventions.The Evidence Statement for physiotherapeutic diagnostics and intervention in ICU patients will contribute to the quality of clinical practice by supporting the clinical decision-making process."}
+{"text": "The circulation of poor-quality medicines continues to undermine the fight against many life-threatening diseases. Anti-malarial medicines appear to have been particularly compromised and present a major public health threat in malaria-endemic countries, negatively affecting individuals and their communities. Concerted collaborative efforts are required from global, regional and national organizations, involving the public and private sectors, to address the problem. While many initiatives are underway, a number of unmet needs deserve urgent and increased multisector attention. At the global level, there is a need for an international public health legal framework or treaty on poor-quality medicines, with statutes suitable for integration into national laws. In addition, increased international efforts are required to strengthen the governance of global supply chains and enhance cooperation between national medicine regulation authorities and law enforcement bodies. Increased investment is needed in innovative technologies that will enable healthcare teams to detect poor-quality medicines at all levels of the supply chain. At the regional level, a number of initiatives would be beneficial\u2014key areas are standardization, simplification, and reciprocal recognition of registration processes and development of quality control capacity in regional centres of excellence that are better aligned with public health needs; improved surveillance methods and creation of a framework for compulsory and transparent reporting of poor-quality medicines; additional support for national medicine regulation authorities and other national partner authorities; and an increase in support for regional laboratories to boost their capabilities in detecting poor-quality medicines. It is vital that all stakeholders involved in efforts against poor-quality anti-malarial medicines extend and strengthen their actions in these critical areas and thus effectively support global health development and malaria elimination programmes. In 2015, an estimated 214 million malaria cases occurred globally, causing approximately 440,000 deaths . Su. Su36]. n Center , 70.TablEnforcement of drug regulations is another area in which collaboration is essential. National-level action against deliberately falsified medicines requires NMRAs to conduct collaborative investigations with police and customs. Operation Storm I and II, conducted in 2008 and 2009 in Cambodia, Indonesia, Laos, Myanmar, Singapore, Thailand, and Vietnam, offered an example of this sort of multisector collaboration. Coordinated by WHO and INTERPOL, these operations involved a synergistic partnership between customs authorities, police, NMRAs, and laboratories in participating countries . EncouraThe Global Fund has established a Joint Interagency Task Force (JIATF) to pro-actively engage with NMRAs and law enforcement authorities, and to provide information on the circulation of falsified medicines , training, and analytic technologies . SupportAction is needed at both the international and national levels to strengthen laws and law enforcement with regard to both falsified and substandard medicines. There have been calls for an international treaty, founded on considerations of public health , to define and differentiate in law the different forms of poor-quality medicines, provide a framework for criminal prosecution (commensurate with the relative seriousness of the offences and intentions of the perpetrator), and harmonize regulatory standards , 18. TheAt the national level, Attaran , 74 receIn 2013, the United Nations urged all states to establish national health and regulatory infrastructures and domestic management capacities to ensure that all citizens have access to medicines that are affordable, safe, efficacious, and of good-quality, and for the international community to continue to assist in achieving this goal . The WHOAccess to good-quality medicines is an essential human right and a top priority in the global fight against many life-threatening diseases including malaria . The coninternational and national political commitment and financing to drive these and other measures necessary to ensure access to quality medicines and thereby protect public health.Confer sustained international, public health-orientated legal framework or treaty on poor-quality medicines, with statutes integrated into national laws.Form a more comprehensive international efforts to strengthen governance of global medicines supply chains, harmonize regulatory standards and related procedures, and facilitate international cooperation between NMRAs and law-enforcement bodies.Provide further regional centres of excellence with common registration documentation, procedures, and decision-making procedures that are better aligned with public health needs.Develop harmonization of registration processes in Nationally, develop NMRAs that are adequately prioritized, resourced, structured, and trained to allow them to perform all regulatory functions  in collaboration with the other national partner authorities.globally and nationally to support anti-malarial initiatives, particularly the detection of poor-quality medicines at all levels of the supply chain, and track-and-trace technologies that ensure a valid product from the manufacturing facility to the consumer.Invest in innovative technologies global and regional support to increase the number of prequalified standardized reference laboratories that can detect poor-quality anti-malarial medicines and also drive the validation and scaling-up of new field technologies for surveillance and analysis, particularly in malaria-endemic countries via appropriate training and resourcing.Arrange specific National and regional surveillance to be linked to effective routine and transparent reporting of incidents followed by an immediate withdrawal of products in the case of major findings by national authorities. Reporting of events should be made compulsory and a data-sharing policy involving public and private sectors, patient representatives, academics, non-government organizations, and international bodies should be developed accordingly.Given the current situation, urgent action is required by the international community across eight key areas:While it is not the intention of this publication to allocate responsibilities to defined organizations and initiatives, questions on strategic roles must be discussed and clearly assigned for future coherent actions. These eight key areas are considered as the priorities for all stakeholders, including the scientific and medical community and health policymakers, and the joint actions of these groups will be critical in driving forward effective malaria elimination programmes and global health development.The continued circulation of poor-quality anti-malarial medicines poses a significant threat to global advances in combating malaria. There are many ongoing initiatives designed to address different aspects of the problem; however, it is imperative that key unmet needs are addressed with urgent multisector action. The role of the international community is vital in extending and strengthening actions across eight crucial areas and reinforcing the fight against malaria."}
+{"text": "Pre-labour Rupture of Membranes (PROM) is an important cause of maternal and fetal morbidity and increased rate of cesarean section delivery.The aim of this study is to investigate the clinical characteristics, PROM-delivery interval, mode of delivery, and early maternal neonatal outcome among pregnant patients presenting with pre-labour rupture of membranes.This prospective case control study is implemented at the Obstetric and Gynecology Clinic of the University Clinical Center of Kosovo. The study included 100 pregnant patients presenting with prelabour rupture of membranes of which 63 were primigravida and 37 patients were multigravida.The incidence of cesarean section in this study is 28 % and the most common indications for cesarean delivery were fetal distress, malpresentation, cephalopelvic disproportion, and failed induction. The most common maternal complications in this study are chorioamnionitis, retained placenta and postpartum hemorrhage. Neonatal infectious morbidity was present in 16 % of cases.PROM is a significant issue for obstetricians and an important cause of maternal and neonatal morbidity and increased rate of cesarean section delivery. Spontaneous rupture of membranes (ROM) is a normal component of labour and delivery , but theThe aim of this study was to investigate the clinical characteristics, PROM-delivery interval, mode of delivery, and early maternal neonatal outcome among pregnant patients presenting with pre-labour rupture of membranes in Republic of Kosovo.This prospective case control study was implemented at the Obstetric and Gynecology clinic of the University Clinical Center of Kosova and included 115 pregnant patients. This study was submitted and approved by the Ethical Review Committee of the University Clinical Center of Kosova and is in adherence to the laws and regulations of the country in which the research was conducted.Inclusion criteria for participant eligibility included that women were between 28-41 weeks of gestational age, not on either antibiotic or corticosteroid treatment, and experienced pre-labour rupture of amniotic membranes were assessed for eligibility. Women were excluded (N = 15) who had hypertensive disorders, diabetes mellitus, fetal malformations or other co-morbidities. The study was thus conducted on 100 women  who met study eligibility criteria. Study participants were divided into two groups according to their gestational age at the time of rupture of membranes: 1) Term PROM with gestational age \u2265 37 weeks of gestation (69 cases), and 2) Pre-term PROM with gestational age 28-36 weeks+6 days (31 cases).After implementing informed consent process a detailed patient history and examination was performed and confirmation of the diagnosis of rupture of membranes was documented. The documenting of the rupture of membranes was done by sterile speculum examination confirming the pooling of amniotic fluid in the posterior vaginal fornix or/and direct visualization of fluid leakage from the cervical canal. A questionnaire and evaluation form was used to collect data at admission. Demographic data, clinical characteristics and data covering PROM \u2013delivery interval, mode of delivery and maternal neonatal outcome were recorded and compared between the two groups. Total hospital stay was also recorded and analyzed.A total of 100 patients with PROM were analyzed in this study. Demographic data, obstetrical risk factors for PROM respectively previous PROM, previous abortions and smoking in pregnancy are presented in The clinical characteristics of investigated patients with PROM are presented in Mode of delivery and maternal- neonatal outcomes are presented in The cesarean section rate was 28 % (N = 28). Comparison of the cesarean section rate between the Term Group and the Preterm Group did not show any significant statistical difference. Neonatal infectious morbidity was present in 16% (N = 16) of cases. Out of the N = 16 neonatal infection cases, 6 of them were in the Term Group and 10 were in the Pre-Term Group, which is a statistically significant difference (p = 0.003). Main maternal complications were chorioamnionitis, postpartum haemorrhage, and retained placenta. Both Term and Pre-Term groups showed similar rates of maternal complications (p = 0.680).Pre-labour rupture of membranes remains one of the important problems in obstetric practice. The etiology of PROM is multi-factorial and in some cases yet unclear. Infection is one of the exogenous etiologic factors thought preventable in some cases with proper antenatal screening and treating of genito-urinary infections. Management of pregnancies with pre-labour rupture of membranes varies depending on gestational age and obstetric status. Recent clinical trials support immediate labour induction in pregnant woman with PROM at term in absence of other maternal and fetal contraindications. Management of Pre-term PROM is more complex and carries risk of prematurity and other related fetal complications.Maternal complications, increased rate of operative delivery, increased rate of neonatal morbidity and mortality in pregnancies with PROM are reported in the literature, and PROM is also more frequent in developing countries. This study was conducted with the aim to evaluate these characteristics, mode of delivery and outcome of pregnancies with pre-labour rupture of membranes in a local setting. This study included one hundred patients of which 63 were primigravida and 37 patients were multigravida. Our findings suggest higher incidence of PROM in the primiparous than in the multiparous patients. The participants in this study had a wide variation in age, from 17 years to 37 years.The literature reports that PROM is associated with an increased risk of cesarean delivery . The resIn this study, fetal distress, malpresentation, cephalopelvic disproportion, and failed induction were the most common indications for cesarean delivery. Two of the 28 cesarean sections performed in this study were done so on the request of the mother. Of the studied cases maternal complications were present in 8% of cases. The most common maternal complications were chorioamnionitis, retained placenta and postpartum hemorrhage. There was no statistically significant different in maternal complication between the Term and Pre-Term PROM groups.Neonatal infectious morbidity was present in 16 cases. Of these cases, observed neonatal infectious morbidity was statistically significantly higher (p = 0.003) in the Pre-term PROM group (62.5 compared to Term PROM Group (37.5 %). In addition to the risk of prematurity the preterm infants of pregnancies with pre-labour rupture of membranes are at higher risk of infectious morbidity.In conclusion, pre-labour rupture of membranes remains an important cause of maternal and fetal morbidity and increased rate of cesarean section delivery. Postpartum haemorrhage, retained placenta, and chorioamnionitis are the most common maternal complications. Neonatal infection related to PROM is also an important factor of neonatal morbidity especially in pre term born infants. Fetal distress, malpresentations, cephalopelvic dispro-portion and failed induction are the most common indications for cesarean section delivery in pregnancies with pre-labour rupture of membranes. The results in this study indicate PROM is a significant issue for maternal and neonatal health in Kosovo. Future studies are warranted to improve maternal-neonatal outcomes."}
+{"text": "There are currently many changes taking place in the health care system in the United States. Major transformations occurring in primary care settings strive to improve efficiency and effectiveness of health promotion and prevention activities, coordination of patient care, and management of chronic diseases. Team-based care is a major component of primary care redesign.The purpose of this study was to gain an in-depth understanding of how primary care practices in the United States are implementing team-based care. The study focused on understanding team-based care approaches, challenges to implementation, and successful strategies.A multidisciplinary research team used qualitative research methods to conduct in-depth case studies of eight primary care practices in various stages of practice transformation. The research team collected data from practices over a sixteen-month period using on-site interviews and structured telephone questionnaires (N=51), observation, and document review. In addition, key informant interviews were conducted with sixteen (N=16) leaders of primary care delivery organizations across the United States to obtain detailed information on team-based care models, such as team composition, roles and responsibilities of team members, and how teams function to meet the needs of their patients.The composition of teams and team member functions vary greatly across health care organizations. Team members typically include one or more providers , registered nurses (RN) or licensed practical nurses (LPN), medical assistants (MA), and administrative staff. In some settings teams include pharmacists, behavioral health specialists, social workers, community health workers, patient navigators and/ or care coordinators. Many organizations recognize the patient as an important member of the team.Organizational culture, values set by practice leaders, and other factors influence implementation of team-based care. Successful strategies for implementation include: leadership support and commitment, a multidisciplinary design and implementation team, careful review and redesign of processes, communication through formal policies and procedures and regular team meetings, and collection and review of performance data. Culture for team-based care models center on shared values and respect for individual team members\u2019 skills and contribution.The future of primary care in the United States will be characterized by many models of care that incorporate different types of health care professionals. Team-based care is a promising method for improving care coordination, medication management, patient education and self-management, and increasing the delivery of preventive services. Team-based care models may also improve productivity and boost employee morale."}
+{"text": "The task force recommendation is based on strong evidence of effectiveness in 1) decreasing the prevalence of tobacco use, 2) increasing cessation and use of available services such as quitlines, and 3) decreasing initiation of tobacco use among young persons.Mass-reach health communication interventions target large audiences through television and radio broadcasts, print media, out-of-home placements , and digital media to change knowledge, beliefs, attitudes, and behaviors affecting tobacco use. The Community Preventive Services Task Force recommends mass-reach health communication interventions to reduce tobacco use and has posted new information about its systematic review at Established in 1996 by the U.S. Department of Health and Human Services, the task force is an independent, nonfederal, unpaid panel of public health and prevention experts whose members are appointed by the Director of CDC. The task force provides information for a wide range of decision makers on programs, services, and policies aimed at improving population health. Although CDC provides administrative, research, and technical support for the task force, the recommendations developed are those of the task force and do not undergo review or approval by CDC."}
+{"text": "Juvenile idiopathic arthritis is a heterogeneous group of chronic inflammatory diseases with high risk of progressive articular damage. Clinical examination is the basis for assessing of the affected joints. Modern radiological techniques provide additional important information about the status of the damaged joints, allow the identification of subclinical inflammation.To investigate the additional capabilities of assessing local activity of finger joints of the hands and wrists in patients with different types of JIA by the modern methods of radiology diagnostic of articular pathology (magnetic resonance imaging (MRI) and ultrasonography (US)) in comparison with clinical research.20 patients with JIA  were studied. Mean age was 12,3 years . Mean disease duration was 21,2 months (range 8-61). On clinical evaluation recorded the tenderness/pain on motion, swelling, limitation of movement. MRI (ESAOTE O-Scan) and US  assessment of fingers and wrists joints was performed with the main focus of research on the signs of local activity: MRI - the presence of fluid in the joint cavity, US - the presence of joint effusion, synovial hyperplasia, power Doppler signal. We compared the results of clinical examination and radiology diagnostics.On clinical examination, synovitis was detected in 103 finger joints of the hands, in 9 wrist joints. On MRI and/or US synovitis was identified in 145 of finger joints of the hands, 13 wrist joints. Thus, by radiological methods subclinical activity was detected in 42 (28.9%) of finger joints of the hands, 4 (30.7%) - of wrists. Of them, 7 joints of the fingers and 1 of the wrists revealed a significant degree of activity on MRI and/or US, including a pronounced increase of vascularization of the synovial membrane (by means of power Doppler).In 20 finger joints clinically indicated only the presence of pain. Of them, in 6 joints revealed clear signs of activity on US: in 4 joints - small or moderate severity; in 2 joints - significant changes .In 2 patients the signs of synovitis associated with manifestations of dactylitis.In the studied group of patients with different subtypes of JIA, the use of MRI and ultrasound possible to detect subclinical synovitis in most patients. The use of modern radiological methods in patients with JIA can verify the exact local activity, improves detection of subclinical synovitis.None declared."}
+{"text": "Spermatogenesis is a complex process of male germ cells proliferation and maturation from diploid spermatogonia, through meiosis, to mature haploid spermatozoa. The process involves dynamic interactions between the developing germ cells and their supporting Sertoli cells. The gonadal tissue, with abundance of highly unsaturated fatty acids, high rates of cell division, and variety of testis enzymes results very vulnerable to the overexpression of reactive oxygen species (ROS). In order to address this risk, testis has developed a sophisticated array of antioxidant systems comprising both enzymes and free radical scavengers. This chapter sets out the major pathways of testis generation, the metabolism of ROS, and highlights the transcriptional regulation by steroid receptors of antioxidant stress enzymes and their functional implications. It also deals with of the advantages of the system biology for an antioxidant under steroid control, the major selenoprotein expressed by germ cells in the testis, the phospholipid hydroperoxide glutathione peroxidase (PHGPx/GPx4) having multiple functions and representing the pivotal link between selenium, sperm quality, and species preservation. Spermatogenesis appears to be a fairly conserved process throughout the vertebrate series. The balance between spermatogonial stem cell self-renewal and differentiation in the adult testis grants cyclic waves of spermatogenesis and potential fertility. These replicative processes imply a highest rate of mitochondrial oxygen consumption and reactive oxygen species (ROS) generation. Enzyme complexes of the respiratory chain of the oxidative phosphorylation, localized on the crests of the mitochondria, as the xanthines, the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and cytochrome P450, represent a source for a variety of ROS. As known, ROS are free radicals and/or oxygen derivatives that include superoxide anion, hydrogen peroxide, hydroxyl radical, lipid hydroperoxides, peroxyl radicals, and peroxynitrite. They have a dual role in biological systems, both beneficial than harmful depending on their nature and concentration as well as location and length of exposure . In this2O by glutathione peroxidase (GPx) or glutathione-S-transferase (GST)  . The SODse (GST) , 6. In ase (GST) .In vertebrates, the spermatogenesis is controlled by a complex network of endocrine, paracrine, and autocrine signals \u201310 Recenin vivo, testosterone promote the expression only, as a consequence of the induction of spermatogenesis (The maintenance of a high redox potential is a prerequisite to maintain the reproductive systems in a healthy state . Reproduogenesis . The stuogenesis , suggestogenesis , 32.The overall objective of our mini-review was to highlight the beneficial and detrimental role of ROS that comparatively determine and influence the cyclic waves of spermatogenesis and the species preservation.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The Materials Science and Engineering Laboratory (MSEL) of the National Institute of Standards and Technology (NIST), the Office of Industrial Programs of the Department of Energy (DOE), and the American Iron and Steel Institute (AISI) co-sponsored a Workshop on Intelligent Processing for Primary Metals held at NIST on August 29\u201330, 1989. Attendance was by invitation and the more than 80 participants were primarily senior technical staff and managers from steel, aluminum, and copper companies.Although the United States is a leading contributor to the world\u2019s materials science base, it is beginning to lag in the cost-effective implementation of this knowledge. U.S. industry does not enjoy leadership in the introduction of new materials technologies into consumer products, as it does in defense systems. Other nations have initiated government-industry programs aimed at the development of advanced processing technology. Advanced manufacturing techniques increasingly demand materials of greater reliability and uniformity at competitive cost. Specific demands for properties and performance can be met by control of the processing of the material from synthesis or raw material production to forming/finishing.Such process control, or \u201cIntelligent Processing of Materials\u201d (IPM), is based on four elements: a process model that relates specific materials properties at each stage of the processing to the final properties; sensors (measurement technology) which can measure the appropriate materials properties in real-time during processing; materials property data which must be coupled with the real-time measurements in the process model; and rapid computational capability for incorporation of sensor data, process model evaluation, and process variable control into an integrated, automated control strategy. The IPM concept differs greatly from conventional automated materials processing. In conventional practice, only the process variables  are automatically controlled to pre-set values which, nevertheless, still allow the microstructure and properties of the material to deviate significantly from the desired values. A critical feature of intelligent processing is the shift from off-line measurements on finished products to on-line measurements in real-time to control processing.The past 5 years have witnessed extensive advances in the enabling technologies needed for intelligent processing of materials. These include: advanced sensors for on-line monitoring of material and process parameters, the knowledge base and materials characterization techniques to develop process models relating process parameters to material properties, and hierarchical computer control strategies for implementing artificial intelligence/expert systems concepts. Several recent national programs have been initiated to integrate elements of these advances to control the processing of advanced materials such as gallium arsenide crystals, powder metals, and composites. Similar opportunities now appear to exist in the primary metals industries.The goal of this industry-led workshop was to highlight the recent advances in sensing, modeling, and process control, to identify areas of need in the primary metals industries, and to develop a strategy for implementation of research results. Industry, university, and government participants assessed information provided by researchers and operating staff from industry to develop a research agenda for coupling the advancing state of materials processing in the primary metals industries.The genesis of this workshop may be traced to two events. First, the signing into law in late 1988 of the Steel and Aluminum Energy Conservation and Technology Competitiveness Act that authorizes DOE and NIST to carry out coordinated programs in support of the primary metals industries, primarily steel, aluminum, and copper. NIST would concentrate on providing instrumentation and measurement R&D. The second event was the January 1989 forum at Northwestern University to identify long-range research opportunities for the North American steel industry. The industry participants concluded that research opportunities could best be addressed in the context of three specific long-range development projects: direct production of liquid steel, near-net shape casting, and finishing and coating operations.To capitalize on these events, planning was initiated through a steering committee, chaired by Lyle H. Schwartz, Director, MSEL/NIST, with representatives from steel, aluminum, and copper trade associations, individual companies, the academic community, and Federal agencies. The consensus was to attempt to address the process control needs of the broad spectrum of primary metal industries and the role of intelligent processing concepts in solving these needs by focusing on three generic areas: primary metal production/refining, production of near-net shape products, and finishing/coating to final properties. Emphasis would be on future, advanced processes and technologies.The Organizing Committee, chaired by James G. Early, MSEL/NIST, was pleased to have participation by representatives of the aluminum and copper industries because the workshop structure is applicable to the processing of these metals. An overlap or commonality of process control needs is likely in some areas of processing. The success of this workshop could lead to other industries using this approach to develop process control priorities. Although the strategy was to achieve a workshop relevant to steel, aluminum and copper, the program contained a strong orientation toward steel-related issues. Since early in this decade, the steel industry has worked to develop a consensus on technical advances needed to improve traditional production practices and on identifying the future steel-making technologies. Thus, the steel industry was particularly well-positioned to play an important role and make major contributions to the workshop resulting in the strong emphasis on steel.Direct Liquid Metal ProductionNear-Net Shape CastingFinishing and CoatingThe core of the workshop was organized into three working sessions:Within these areas, the key elements of intelligent processing were stressed. The relationships between fundamentals and processing were explored through the integration of process modeling, sensor technology, and control strategies. Leading off the first day of the Workshop was an introduction to intelligent processing of materials concepts through applications to aerospace and other advanced materials followed by an overview of the process control research needs for the production of steel and aluminum. The three working sessions, responsible for Direct Liquid Metal Production, Near-Net Shape Casting, and Finishing/Coating, took place in the afternoon of the first day and the morning of the second day to permit a wide range of inputs from the participants. Coordinated presentations were given in these working sessions on the status of sensors, process models, and control approaches, the available technology, and the benefits to relevant research. After the morning sessions on the second day, a brief, verbal synopsis of the deliberations in each of the three working sessions was presented to the assembled workshop participants.Between the first and second days working sessions, Deputy Secretary of Commerce Thomas J. Murrin, spoke to the Workshop on \u201cNew Metals Technologies: Making the Government-Industry Connection Work.\u201d In his remarks, Mr. Murrin discussed the three key issues facing industry as it develops new metals technologies: the need to improve the quality of products and services; the need to take advantage of new technologies being developed overseas; and the need for continued and expanded government-industry-labor cooperation. While the metals industry\u2019s health will be determined primarily by its own efforts, there are appropriate areas in which the Federal Government can contribute. Deputy Secretary Murrin reported on a number of policy initiatives underway related to taxes and tax credits, antitrust laws, and a broad review of technology-innovation policies and programs to determine if other changes are needed.The first session was devoted to a series of invited presentations to prepare the participants in the three working sessions with the necessary background and global view needed to achieve the Workshop goal. The first speaker, W. Barker (DARPA) described the concept of intelligent processing of materials and reviewed the national programs supported by DARPA. In a companion talk, D. Backman  reviewed the application of IPM concepts to advanced aerospace materials. The industry perspective was presented in the final two talks: I. Hughes (Inland Steel) \u201cLong Range Research -North American Steel\u2019s Competitive Edge\u201d; and R. Bonewitz (Alcoa) \u201cSensor, Process Models, and Control Needs in the Aluminum Industry.\u201dA. W. CrambCarnegie-Mellon UniversityJ. KorTimken CompanyCo-Chairmen:The session was organized into two parts: the first part was an information exchange between experts on sensor technology, process control, modeling, and the application of advanced computer decision making techniques, while the second part was to define and prioritize specific needs in the area of intelligent processing of liquid metals. Within each area specific needs were identified. Speakers included: J. Kor (Timken Company); P. Koros (LTV Steel Company); J. Fay ; A. McLean (University of Toronto); D. Hardesty ; C. Alcock (Notre Dame University); Y. Kim (Lehigh University); R. Guthrie (McGill University); M. Shah (IBM); and S. Ray (NIST).The sensor area was considered to be the area of highest importance and it was the consensus of the group that sensor development and implementation should be the major focus of any endeavor. Three separate groups of sensors were distinguished: continuous temperature sensors; continuous chemical sensors for liquid metal and hot, dirty gases; and, physical sensors to measure reaction intensity. The area of process modeling was identified as the second most important area for research at this time. Two separate groups of needs were outlined: Process Control Models; and In-Detail Process Models. In the area of process control there was a concern that current \u201cArtificial Intelligence\u201d techniques might not be applicable to on-line control in a broad sense; however, in certain well-defined circumstances it may be useful. In addition, it was felt that the computer science involved in process control and decision making was sufficiently rapid that a mechanism should be set up so that appropriate advances can be implemented within the industry in a reasonable time frame. Three separate groups of needs were identified: Operator Feedback and Instruction; System Integration; and Technology Transfer. A copper industry participant reported that many of the sensors discussed would also be of use to the copper industry and further identified the sensors that overlapped those needed by the steel industry.W. E. Eckhart, Jr.U.S. Department of EnergyR. SussmanARMCO, Inc.Co-Chairmen:This session was conducted in two parts. The first day was characterized by presentations made by experts in their respective fields. Each presentation generated a modest number of questions within the subject area. It is noteworthy that no process-specific problems were detailed during the first-day presentations, to the disappointment of some of the participants. The second day of this session was started by brief presentations made by individuals having hands-on experience with near-net shape casting of metal. Despite the obvious differences between the various casting methods, needs were categorized into three distinct areas: liquid metal handling, casting, and strip collection. Speakers included: M. R. Moore (USS Division of USX); R. A. Gleixner ; L. T. Shiang (Inland Steel Company); Y. Sahai (Ohio State University); H. N. G. Wadley (University of Virginia); and J. A. Walton .Eight sensors were identified as critical to the successful development of a commercial strip casting process: continuous temperature measurement of the meet; continuous temperature of the substrate surface; rapid on-line strip thickness sensing; on-line hot strip inspection system; continuous topographic sensing of substrate; liquid metal level sensor; liquid metal inclusion sensor; and liquid metal nitrogen sensor. It was recognized that each of these must be employed in a manner in which it could be actively used to control the outcome of the process, and not merely in a passive role to provide information. Attempts were made to determine the range and precision needed for each of the sensors. In many cases, the identified range was quite accurate, but the estimated precision reflected that required of the product; the sensor may require greater sensitivity. In the area of mathematical modeling, it was agreed that most models are process-specific. Nonetheless, there exist many commercially available models of the two principal phenomena involved in near-net shape casting, heat transfer and fluid flow. It was determined after considerable discussion that the industry would benefit from a comprehensive review of such models currently available, along with their respective strengths and weaknesses, and a strategy for implementation of selected models. In the area of process control, it was recognized that the overall state of knowledge of near-net shape casting makes it difficult to design a comprehensive control system at this stage of development. It was determined that it would be meritorious to undertake an intelligent process simulation project to serve as a model for the metals industry. Shortly after the close of the workshop, a participant from the copper industry submitted an analysis that summarized similarities and differences in the sensor/model/control needs for copper and steel near-net shape casting.D. WatanapongseInland SteelA. Van Clark, Jr.NISTCo-Chairmen:The session consisted of two meetings designed to facilitate interaction between national experts and industry experts. The goal of the first meeting was to understand and assess the states of knowledge in intelligent processing; namely, product/process knowledge, process modeling, sensors, integrated process control, and artificial intelligence. The product/process relationships for steel substrates and coated steel were presented along with the needs for future improvements. Subsequent presentations were in sensor development, process modeling, and advanced control. The goal of the second meeting was to address the issues and resolutions that can enhance the success of future research programs to develop and apply intelligent processing technologies. Speakers included: D. Reinbold (Bethlehem Steel); P. Southwick (Inland Steel); S. Denner ; K. Brimacombe (University of British Columbia); J. Monchalin (IMRI Canada); A. V. Clark, Jr. (NIST); L. Lowry (Jet Propulsion Laboratory); and A. Meystel (Drexel University).Although there is a wide range of sensor needs in the finishing and coating processes, five sensors were identified as having highest priority: continuous temperature measurement of strip; on-line measurement of chemical composition and phase identification in coatings; measurement of surface topography and surface chemistry of strip; measurement of lubricant film thickness; and measurement of mechanical properties/microstructure. Further attempts to prioritize among the five or to define specific ranges and accuracy of the sensors were considered inappropriate by the group because sensor requirements must be specified as an integral part of process modeling and control system development. Attempts were made, however, to estimate the developmental time for the sensors based on current understanding of available principles and technologies. In the coating processes, much work is needed to understand and model coating adherence mechanisms for a range of coating materials, steel substrates, surface morphology, and processing parameters. In addition, press performance of coated materials in terms of stampability and powdering characteristics must be studied and modeled. Engineered surfaces and microstructural engineering were cited as the important areas needing further modeling studies. Since intelligent processing involves implementation and also a wide range of multidisciplinary backgrounds, the significance of project team formation, technology transfer, designed-in safety and maintenance were discussed at length. Intelligent processing has definitive roles in the finishing and coating processes, in terms of new product and process design and on-line process control. Specific recommendations are: Develop real-time expert models for control to supplement process models; and develop implementable intelligent processing systems from hot rolling to coating, with emphasis on continuous processing.The research agenda developed at this industry-led workshop is summarized in NIST Special Publication 772, \u201cIntelligent Processing for Primary Metals.\u201d According to the participants, successful development and implementation of advanced processing concepts for the production of steel, from raw steel through finished steel products, will be enhanced through the formation of broad-based, multidisciplinary teams focusing on generalized approaches and solutions to well-defined tasks. Specific recommendations for critically-needed sensors, process models, and control strategies are reported for the three working sessions.For information on collaborative IPM research opportunities at NIST or a copy of the workshop report, NIST Special Publication 772, send a self-addressed mailing label to Dr. James Early, Materials Building, Room B309, NIST, Gaithersburg, MD 20899."}
+{"text": "Health professional mobility in Europe has become a fast-moving target for policy-makers. It is evolving rapidly in direction and magnitude as a consequence of fundamental change caused by European Union (EU) enlargement and the financial and economic crisis.Health professional mobility changes the numbers of health professionals in countries and the skill-mix of the workforce, with consequences for health-system performance. Many of the so-called pull and push factors influencing mobility of individuals are in the remit of countries and organizations. In Europe, these pull and push factors are co-determined by EU policies on free mobility, the qualifications directive and many soft-law initiatives.This presentation is reviewing the current mobility trends in Europe and provides clues on how to strengthen governance for human resources for health at European and country level. A particular reference is made to mobility monitoring, workforce intelligence, workforce policies/ strategies, skills-initiatives and coordination mechanisms across sectors and levels."}
+{"text": "Salmonella enterica typhimurium. The authors thank Dr. Claire Pearson for critical review of the manuscript.The authors thank Professor David Holden, Imperial College London, for the kind gift of GFP-Salmonella enterica typhimurium. The authors thank Dr. Claire Pearson for critical review of the manuscript and The Sir Jules Thorn Charitable Trust for their financial support.The authors thank Professor David Holden, Imperial College London, for the kind gift of GFP-The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The Computer Systems Laboratory (CSL), National Institute of Standards and Technology, sponsored the sixteenth North American ISDN Users\u2019 Forum (NIUF) at its Gaithersburg, Maryland site on October 26\u201330, 1992. About 250 users, implementors, and service providers of ISDN technology attended the meeting. CSL collaborated with industry in 1988 to establish the NIUF to ensure that emerging ISDN applications meet the needs of users. A Cooperative Research and Development Agreement (CRDA) with industry was established in 1991 to govern the management of the forum; the CRDA now has 36 signatories from industry and academia. CSL serves as chair of the forum and hosts the NIUF Secretariat. NIUFmembership is open to all interested users, product providers, and service providers; meetings are held three times a year at various locations throughout North America.International standards for ISDN support worldwide communications for the exchange of voice, data, and image information among users, independent of any manufacturer, service provider, or implementation technology. ISDN standards are developed by the International Telephone and Telegraph Consultative Committee (CCITT) and, for North America in particular, by the Exchange Carriers Standards Association (ECSA) accredited standards committee, T1, under the umbrella of the American National Standards Institute (ANSI).ISDN standards provide a broad variety of options and parameters to meet many potential needs and applications. To ensure interoperability and terminal portability within the ISDN network and its attendant equipment, a uniform subset of options and parameters must be selected for implementation. Each application usually requires only a subset of total functionality available in the standards; for ISDN products and services to work together in a multi-vendor environment, common sets of options must be selected.To cope with this proliferation of choices and to provide practical products and services which meet the needs of users, the standards specification process must be extended to include the development of Application Profiles, Implementation Agreements, and Conformance Criteria which will promote interoperability. The NIUF addresses all of these areas.To promote an ISDN forum committed to providing users the opportunity to influence developing ISDN technology to reflect their needs;To identify ISDN applications, develop implementation requirements, and facilitate their timely, harmonized, and interoperable introduction; andTo solicit user, product provider, and service provider participation in the process.The NIUF seeks to achieve three principal objectives:The actual work of the NIUF is accomplished in two workshops: the ISDN User\u2019s Workshop (IUW) and the ISDN Implementor\u2019s Workshop (IIW). The IUW produces Application Requirements which describe potential applications of ISDN and the features which may be needed. The IIW develops Application Profiles, Implementation Agreements, and Conformance Criteria which provide the detailed technical decisions necessary to implement an application requirement in an interoperable manner. The NIUF Executive Steering Committee coordinates the activities of the two workshops.133 active applications for development of Application Profiles have been accepted;Application Profiles have been completed for 14 applications;12 Implementation Agreements have been completed; and8 Conformance Tests have been completed.Since its inception in 1988, the NIUF has achieved the following:CSL established the NIST Special Publication 823 series, Integrated Services Digital Network Technology Publications, to publish the approved Implementation Agreements, Conformance Tests, and other NIUF documents. Copies of these documents are available for sale by the Government Printing Office, (202) 783-3238 or the National Technical Information Service, (703) 487-4650.The October NIUF focused on finalizing plans for the Transcontinental ISDN Project 1992 (TRIP \u201892) on November 16\u201320, 1992, which marked the advent of National Integrated Services Digital Network . Cosponsored by the NIUF and the Corporation for Open Systems (COS), TRIP \u201892 involved 74 user organizations in 149 locations across North America as well as several international sites. National ISDN-1 is based on national and international standards and is consistent with Implementation Agreements developed by the NIUF.TRIP \u201892 Open Houses across the nation featured demonstrations of ISDN applications available to government and industry such as video/multimedia conferencing, desktop conferencing and screen sharing, LAN-to-LAN bridging, medical imaging, Group 4 facsimile, and image and large data file transfer. NIUF industry partners participating in the demonstrations at the NIST Open House site included AT&T Bell Laboratories, COMSAT, Bell Atlantic, and Northern Telecom. Also featured was a special session for about 170 government and industry executives. Speakers at this session included Robert M. White, Under Secretary for Technology, who presented a government view of national ISDN, and Irwin Dorros, Executive Vice President, Bellcore, who gave the industry perspective.A Catalog of National ISDN Solutions for Selected NIUF Applications and A Generic Model for ISDN Cost Analysis. Both documents resulted from a cross-industry team effort by NIUF members. The catalog focuses on demonstrating solutions for those applications identified as most important by an NIUF survey; most applications are satisfied with basic rate ISDN access and can be implemented using NI-1 solutions. The cost analysis document contains an ISDN checklist of both hard and soft costs and benefits. The document also includes a spreadsheet available in Microsoft Windows and MAC-based Excel, from which users can form the basis for their own customized spreadsheet for an ISDN cost analysis.Other highlights of the October meeting included a demonstration of Remote Message Retrieval Over ISDN by the Messaging and Answering Group and completion, subject to final approval at the NIUF February 1993 meeting, of two significant NIUF documents: For more information about the NIUF and its publications or to obtain conference proceedings, contact the NIUF Secretariat: Dawn Hoffman, Computer Systems Laboratory, National Institute of Standards and Technology, Building 223, Room B364, Gaithersburg, MD 20899-0001; telephone (301) 975-2937 or Fax (301) 926-9675."}
+{"text": "Juvenile arthropathy it\u2019s a term combining heterogeneous group of joints diseases in children, which are characterized by structural, morphological and functional changes of inflammatory nature and non inflammatory disorders. Chronic inflammatory process may be \"driving\" mechanism that is determine the nature of the articular lesions with specific clinical, instrumental and laboratory picture or maybe just one of the features of another pathology. Similarity of clinical and radiological picture, chronic nature of the flow, various of pathogenetic therapy and outcomes of the disease do this group one of the difficult to diagnose.To study the masks of JIA and no rheumatology pathology joint in children of Russian Federation.Clinical, serological, x-ray manifestations, ultrasound, MRI, arthroscopy data were analyzed in more then 300 children which examined in hospital department with presumptive diagnosis JIA.All children were subjected to complete rheumatology examination, and remained under our observation for a long time in order to assess the dynamic of the articular lesion. Children with classic course of JIA were appointed basic anti-inflammatory drugs . In cases when clinically atypical duration or laboratory \"mute\" of arthritis, long persistence monoarthritis and also variants with fever or destructive bones change we were applied deeper imaging methods such as MRI, arthroscopy, 3-phase osteo scintigraphy and other. Over five years were diagnosed six cases of tuberculous lesion of the joints (specific destruction of bone + biopsy), two cases of tuberculous periarthicular soft tissue (cyst formation with tyromatosis), fourteen cases of vascular anomaly , five cases of atypical localization focus of osteoid-osteoma , six cases of pigmental villous and chronic hemorrhagic synovitis of the knee and ankle joint, several cases of the skeletal dysplasia, and in rare cases of histiocytosis, malignant B-cell lymphoma, osteomyelitis and other rare bones disorders. Not one cases of the CRMO. In many cases due to this methods, we were excluded such diagnosis like tumors of the joints, different forms osteochondropathy. Such typical changing of the bones in JIA are usually degenerative nature in chronic uncontrolled inflammation.In some cases in undifferentiated arthritis, time of the diagnosis may determine the success of treatment. Any arthritis after failure of anti-inflammatory and antibacterial therapy should be questioned of rheumatic nature. Application invasive and non-invasive additional imaging methods can reduce the risk of incorrect diagnosis.None declared."}
+{"text": "Narrative approaches and storytelling are emerging as powerful health promotion tools that can spark interest, increase understanding of determinants of health, and translate complex science. A Story of Health, a multimedia e-book with continuing education credits was designed to harness the power of storytelling to increase environmental health literacy. Health professionals are a key audience. They recognize that patients may be suffering from preventable illnesses of environmental origin but often feel ill-equipped to educate individuals and families about risks associated with common exposures. A Story of Health seeks to fill this gap and help readers develop the competencies they need in order to help patients make informed choices, reduce health risks, improve quality of life, and protect the environment. Americans rate nurses and medical doctors as having the highest honesty and ethical standards of all professions. These medical professionals can play a key role in changing patterns of patient behavior and influencing public policies. The e-book provides an easily accessible method of developing environmental health competency. The multimedia format with graphical interpretations allows for quick reviews of topics or for more in-depth analysis via links to additional resources. The CE evaluations have been overwhelmingly positive. A Story of Health multimedia e-book with continuing education (CE) credits was designed to harness the power of storytelling to increase the environmental health literacy of health professionals, policy makers, and health advocates; encourage inclusion of anticipatory guidance in professional practice, and stimulate policy changes.Narrative approaches and storytelling are emerging as powerful health promotion tools that can increase understanding of determinants of health and translate complex science . Case-baA Story of Health capitalizes on the narrative approach to teaching by using fictional stories to convey how multiple environmental factors interact with genetics to affect health across the life span. The first installment of the 150-page peer-reviewed e-book, which includes chapters on asthma (Brett\u2019s story), developmental disabilities (Amelia\u2019s story), and childhood leukemia (Stephen\u2019s story), was released in 2015 and is available online without cost . Free CE credits are offered through the Centers for Disease Control and Prevention (CDC) and the Agency for Toxic Substances and Disease Registry (ATSDR). About two-thirds of the downloads are accompanied by CE registration suggesting that CE credits are an incentive for health professionals to read A Story of Health.The stories explore influences of the natural, built, chemical, food, economic, and social environments on health across the life span\u2014from conception to elder years. The individual stories reveal how these environments are further expressed through education, family structures, housing, nutrition, access to health care, social supports or stressors, and more. Collectively, these multi-level variables interact to create conditions conducive to health and wellness\u2014or vulnerability and disease. Health promoting interventions from the individual level to the policy level are highlighted to encourage action.A Story of Health\u2019s ecological approach is central to the concept of environmental health literacy, a relatively new subdiscipline that \u201ccombines key principles and procedural elements from the fields of risk communication, health literacy, environmental health sciences (EHS), communications\u2019 research and safety culture\u201d , \u201cParents of young children are intensely interested in the impact of the environment on their children\u2019s health. They may look to their pediatrician for guidance about how to evaluate news reports about potential hazards in the air, water, and food\u201d . PediatrA 2015 survey of more than 200 pediatric oncologists, fellows, and nurse practitioners also underscored the need for increased training about environmental health exposures related to cancer . AlthougA recent national online survey of more than 2,500 fellows of the American Congress of Obstetricians and Gynecologists (ACOG) also revealed that routine guidance to patients on the health effects of environmental exposures was not a high priority . AlthougA Story of Health provides an alternative method of developing environmental health competency for health care providers, as it can be easily accessed online and reviewed at the time and pace of one\u2019s choosing. The multimedia format with graphical interpretations allows for quick reviews of topics, or more in-depth analysis via links and references to additional resources. Web-based medical education matches the efficacy of more traditional forms of delivery such as face-to-face conferences and lectures  Toxicity. During a 1-year period, A Story of Health CE course received more than double the registrations of one of the most popular ATSDR/CDC courses.Acquiring the knowledge and skills to counsel patients and families about the risks associated with exposure to environmental toxicants may be challenging for health care providers because of busy schedules, required continuing medical education in their specialties, and the relative scarcity of professional training about environmental health. lectures  without A Story of Health describe the lives of people with different diseases, several common themes resonate throughout the e-book:Although the fictional narratives in Important environmental influences come from the natural, chemical, food, built, and social environments.Although there are exceptions, most diseases, as well as good health, are the result of complex interactions between genes and multiple environmental influences.Early-life experiences, particularly during critical windows of development, can have profound beneficial or detrimental lifelong effects, even into elder years.Preventing disease and promoting health require actions and commitments from the individual, family, community, and society, as they are all interconnected.A Story of Health team is currently developing the fourth story for the e-book on infertility and reproductive health\u2014Reiko and Toshio\u2019s Story\u2014that echo these common themes.A Story of Health is designed to convey complex concepts about multi-level influences on health through a family reunion scenario (scenario . A nesteThe fictional cases are communicated in text, illustrations, graphic images, videos, and links to additional resources and journal references. The stories include the following key concepts:Early origins of childhood and adult diseaseEpigeneticsMechanisms of actionAllostatic loadWindows of susceptibility and opportunityEffect modifiersEnvironmental justice and health disparitiesThe stories weave in relevant information about disease trends and demographics. They also include potential interventions, policy recommendations, and helpful tools, such as environmental exposure checklists, for practical application in the real world.The e-book draws content from the research of the top scientists in their fields and brings the collective expertise of the Pediatric Environmental Health Specialty Units network and the National Institute of Environmental Health Sciences Children\u2019s Environmental Health Centers into the e-book in a variety of ways.A Story of Health was developed through a cooperative effort of the ATSDR, the Collaborative on Health and the Environment, the California EPA Office of Environmental Health Hazard Assessment, the Science and Environmental Health Network, and the Western States Pediatric Environmental Health Specialty Unit. Leveraging the resources and networks of all the partners has also been an important outreach strategy.Promoting the availability of the e-book online via web sites, listservs, newsletters, YouTube presentations, and social media has been essential for reaching key audiences. A Story of Health filled a gap in their skills or knowledge, and > 89% reported they plan to apply the new knowledge to develop strategies and interventions in their practices (Currently, more than 3,300 health professionals, including physicians, nurses, and health educators, have registered for the online course. Evaluations have been overwhelmingly affirming. In an analysis of responses from users in the second quarter of 2015, > 95% indicated that ractices .With additional funding, and with new CE evaluation tools being developed by the CDC, the authors hope to conduct follow-up surveys of those who have taken the CE course to further evaluate the impact of the e-book. Use the following links:A Story of Health: http://wspehsu.ucsf.edu/for-clinical-professionals/training/a-story-of-health-a-multi-media-ebook/To download http://www.atsdr.cdc.gov/emes/health_professionals/index.htmlTo access CE registration:"}
+{"text": "Promoting child wellbeing necessarily goes beyond the clinic as risks to child health and development are embedded in the social and physical environmental conditions in which children live. Pediatricians play a vital role in promoting the health of children in the communities they serve and can maximize their impact by advocating for and supporting efficacious, evidence-based strategies in their communities.To provide a succinct guide for community pediatric efforts to advance the wellbeing of all children and particularly disadvantaged children in a community, we conducted a theory-driven and structured narrative review to synthesize published systematic and meta-analytic reviews of policy-relevant, local-level strategies addressing potent and malleable influences on child health and development. An exhaustive list of policy-relevant, local-level strategies for improving child health was used to conduct a comprehensive search of recent (1990\u20132012), English language peer-reviewed published meta-analyses and systematic reviews in the 10 core databases of scientific literature. Our review of the literature encompassed six key conceptual domains of intervention foci, including distal influences of child health  and proximal influences . We examined intervention effects on four key domains of child health and development: cognitive development, social and emotional competence, psychological and behavioral wellbeing, and physical health.Published reviews were identified for 98 distinct policy-relevant community interventions, evaluated across 288 outcomes. We classified 46 strategies as meeting scientific criteria for efficacy by having consistent, positive outcomes from high-quality trials . Another 21 strategies were classified as having consistent evidence of positive outcomes from high-quality observational studies only, while 28 strategies had insufficient evidence available to assess their effectiveness based on published reviews. We did not limit the review to studies conducted in the United States, but the vast majority of them were U.S.-based, and the results therefore are most applicable to the U.S. context.Based on our synthesis of published literature on community development strategies, we provide an illustration combining a comprehensive set of evidence-based strategies to promote child health and development across a wide-range of child health outcomes. A mounting body of research has documented the social gradient in child health . ChildreGiven the multiplicity of health risks associated with social disadvantage, strategies to promote child health and wellbeing necessarily go beyond the clinic and involve community-wide policy strategies that change the broader environments in which children live. There is a growing understanding that health disparity populations  are overlapping populations suffering avoidable health inequities resulting from unequal distribution of health-damaging and health-protecting exposures in daily life ,11. PoliChild-focused community development initiatives offer great potential to prevent the numerous, potentially life-long and generationally transmitted, health inequities related to SES, race/ethnicity, and neighborhood. Recent efforts in the United States include the Promise Neighborhoods program  modeled Despite sizeable investments in child-focused community development initiatives and the tremendous potential of such efforts to improve social and health inequities, extant enacted policies and programs often do not reflect effective practices based on scientific studies ,16,17. IThe Promise Neighborhoods Research Consortium (PNRC), a network of prevention scientists in the U.S., created a science-based framework to guide comprehensive, community-level efforts promoting development and health among socially disadvantaged children living in distressed neighborhoods . This frIn this paper, we present the results of a synthesis of published systematic reviews or meta-analyses of six intervention domains for protecting and promoting child health. We did not limit the review to studies conducted in the United States, but the vast majority of them were U.S.-based, and the results therefore are most applicable to U.S. context. Based on our synthesis of the published literature, we provide an assessment of the current state-of-the-science regarding community development strategies that influence child health. Finally, we present an illustration of a comprehensive set of evidence-based strategies for child health as guidance for pediatricians and other child health advocates advancing local community development efforts. Scientific evidence on health promotion and risk prevention strategies is diverse, complicated, inconsistent in quantity and quality, and often inaccessible to policymakers, health care providers and other community stakeholders . Our goaWe conducted a theory-driven and structured narrative review of systematic reviews of a comprehensive set of community development strategies for child health. We limited the scope of our narrative review to those strategies that have been assessed in peer-reviewed, published meta-analyses or systematic reviews for three reasons. First, the scope of the conceptual framework guiding our work precludes exhaustive review of individual studies or newly emerging reports on prevention strategies that have yet to warrant systematic review. Second, systematic reviews represent the pinnacle of the \u201clevels of evidence\u201d hierarchy and provide the best practical method for identifying effective interventions . Third, Guided by our conceptual framework Figure\u00a0, scholarWe include summaries of effects on both primary and intermediate child health outcomes. We define primary outcomes to include any measures of cognitive development, social/emotional competence, absence of psychological and behavioral problems, and physical health among children or adolescence. We define intermediate outcomes to include measures of any of the proximal and distal influences on primary child outcomes Figure\u00a0. For exalevel of evidence on a scale of 1 to 3 for each strategy following the standards of evidence for efficacious interventions laid out by the Society for Prevention Research . Gu. Gu15]. Published systematic reviews address 98 policy-relevant strategies with 288 studied outcomes ranging from primary indicators of child health to measures of important physical and social contextual influences on child health. Less than half (46 of 98) intervention strategies meet scientific criteria for efficacy, as defined by the Society of Prevention Research  by havinhttp://promiseneighborhoods.org) displays all policy briefs in a searchable format organized by domain of influence on child health and development. The Consortium is also working actively to disseminate this information to the recent Promise Neighborhoods grantees and others planning community development initiatives.Our primary objective was to organize a very large and diverse literature into a conceptually logical framework that reflects the best of current science, and succinctly summarize large bodies of scientific literature that makes clear to end-users the strength of evidence and size of estimated effects across the whole range of community changes thought to improve child health and wellbeing. Additionally, for each intervention, we created policy briefs to provide pediatricians, local-level policymakers, and other stakeholders with accessible science-based summaries to help identify policies that may effectively address child health needs in their community and facilitate community action around those issues. The Promise Neighborhoods Research Consortium website  of the quality of the reviews. However, narrative literature reviews with no systematic review or meta-analytic methods were excluded from our summary. We critically evaluated the studies included in each published review, classified the level of evidence, and provided a summary of findings. No individual study can definitively answer the question of a policy\u2019s effectiveness across populations and time. Therefore, the accumulation of evidence and meta-analysis of outcomes across studies provides a more accurate assessment of effectiveness than a single study. Finally, the vast majority of studies were U.S.-based, and the results therefore are most applicable to U.S. context. Therefore, one should generalize to other countries with care, especially when considering countries that are quite dissimilar to the U.S.We present a current state of the science in order to (1) inform pediatricians and other child health advocates about policy-relevant community strategies with the most evidence demonstrating efficacy at improving primary child health outcomes, proximal influences of child health and development , and distal influences ; as well as to (2) inform scientists of community interventions that require more empirical attention to determine their efficacy at improving child health and reducing health disparities. It is our hope that continued evaluation and systematic review of child health policies and policy-relevant strategies, in conjunction with translation of the most evidence-based strategies into effective polices and practices, will lead to optimal child outcomes and minimal health disparities.The authors declare that they have no competing interests.KK, AT and AW participated in the conceptualization of the study concept and design. AD and AT participated in the acquisition of data. AT, RO, AD, KK and AW participated in the analysis and interpretation of data. AT, RO, AD and KK drafted the manuscript. KK, AW, RO and AT participated in critical revision of the manuscript for important intellectual content. KK and AT supervised the study. All authors read and approved the final manuscript.Kelli A. Komro, MPH, PhD is Professor of Health Outcomes and Policy in the College of Medicine, Associate Director of the Institute for Child Health Policy, and University of Florida Research Foundation Professor.Amy L. Tobler, MPH, PhD is Assistant Professor of Health Outcomes and Policy in the College of Medicine and Institute for Child Health Policy at the University of Florida.Alexander C. Wagenaar, PhD, is Professor of Health Outcomes and Policy in the College of Medicine and Institute for Child Health Policy at the University of Florida and Associate Director of Public Health Law Research, a national program of the Robert Wood Johnson Foundation, housed at the Temple University Beasley School of Law.Alexis L. Delisle, MS, was an Institute for Child Health Policy predoctoral fellow at the time of this work.Ryan J. O\u2019Mara, MS, is an MD/PhD student at the University of Florida and was a Research Assistant in the Institute for Child Health Policy at the time of this work.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2431/13/172/prepubPolicy-relevant community strategies by level of evidence.Click here for filePolicy briefs for strategies by level of evidence.Click here for file"}
+{"text": "The unfolded protein response (UPR) occurs in response to endoplasmic reticulum (ER) stress caused by the accumulation of unfolded or misfolded proteins in the ER. The UPR is comprised of three signaling pathways that promote cytoprotective functions to correct ER stress; however, if ER stress cannot be resolved the UPR results in apoptosis of affected cells. The UPR is an important feature of various human diseases, including multiple sclerosis (MS). Recent studies have shown several components of the UPR are upregulated in the multiple cell types in MS lesions, including oligodendrocytes, T cells, microglia/macrophages, and astrocytes. Data from animal model studies, particularly studies of experimental autoimmune encephalomyelitis (EAE) and the cuprizone model, imply an important role of the UPR activation in oligodendrocytes in the development of MS. In this review we will cover current literature on the UPR and the evidence for its role in the development of MS. The endoplasmic reticulum (ER) is one of the largest cellular organelles in eukaryotic cells, and consists of two types, rough ER and smooth ER Kaufman, . SecretoThe PERK protein contains an ER transmembrane domain, a cytosolic kinase domain, and a regulatory luminal domain  by its endoribonuclease activity to produce the active transcription factor spliced XBP1 (sXBP1). sXBP1 enhances the expression of chaperones and certain cytoprotective genes, and promotes ER expansion  is a T cell-mediated autoimmune demyelinating disease of the central nervous system (CNS)  is the primary animal model used in MS research that displays many of the clinical, pathological, and immunological features of MS  plays a critical role in the development of MS and EAE  to young adult mice induces a synchronous consistent demyelination  that allows for temporally controlled activation of PERK signaling specifically in oligodendrocytes has been generated  10, elevates the level of p-eIF2\u03b1 exclusively in oligodendrocytes, significantly ameliorates the severity of EAE clinical symptoms, and attenuates EAE-induced oligodendrocytes loss, demyelination, and axon degeneration in the CNS. Oligodendrocyte loss is one of the first signs of pathological changes in EAE and can occur before demyelinating lesions are identifiable. Importantly, the low dose of AP20187 treatment significantly reduces the number of apoptotic oligodendrocytes in the CNS of heterozygous PLP/Fv2E-PERK mice before the onset of clinical disease and the formation of demyelinating lesions (at PID12). Moreover, moderate PERK activation in mature oligodendrocytes does not significantly affect the immune responses in CNS or peripheral immune system during EAE  against inflammatory attacks in immune-mediated demyelinating diseases  suggesting activation of the ATF6 branch of the UPR in oligodendrocytes (Lin et al., PLP1 mutant mice and that CHOP deletion exacerbates the clinical symptom and oligodendrocyte apoptosis in PLP1 mutant mice. It has also been shown that upregulation of CHOP induced by moderate PERK activation in oligodendrocytes of heterozygous PLP/Fv2E-PERK mice does not have a detrimental effect on the cells under normal or disease conditions (Lin et al., PLP/Fv2E-PERK mice with a high dose of AP20187 strongly activates PERK signaling specifically in oligodendrocytes, resulting in strong inhibition of protein biosynthesis and upregulation of CHOP in the cells. Notably, strong PERK activation inhibits the myelinating function of oligodendrocytes in young developing mice by suppressing protein translation, but does not affect oligodendrocyte viability. Intriguingly, strong PERK activation in mature oligodendrocytes of fully-myelinated adult mice had minimal effects on the function and viability of the cells (Lin et al., A large number of studies have demonstrated that CHOP, an effector of the PERK-eIF2\u03b1 pathway, functions as a pro-apoptosis transcription factor in many cell types during ER stress (Tabas and Ron, It is well-documented that the UPR influences the development of a number of human diseases, including inflammatory diseases, neurodegenerating diseases, myelin disorders, and tumors (Zhang and Kaufman, in vitro model of myelination (Lin et al., Using genetic approaches, the studies described above well-documented the cytoprotective effects of the PERK-eIF2\u03b1 pathway on both mature and remyelinating oligodendrocytes in mouse models of MS (Lin et al., The ER is essential for the biosynthesis of myelin lipids and proteins. The volume of the ER increases dramatically in the cytoplasm of oligodendrocytes during the active phase of myelination (Wollmann et al., While the actions of PERK activation in oligodendrocytes in immune-mediated demyelinating diseases have been studied extensively, the underlying mechanisms through which PERK mediates protection remain unknown and deserve further investigation. Moreover, activation of the PERK pathway has been observed in other cell types in MS and EAE demyelinating lesions, including T cells, microglia/macrophages, and astrocytes (Chakrabarty et al., For many years, the focus of MS research has been on T cell-mediated demyelination of the white matter. Recent studies, however, have shown that neurodegeneration is not only an early event but also the primary cause of chronic disability in MS (Dutta and Trapp, In summary, previous studies have demonstrated the cytoprotective effects of the PERK branch of the UPR on oligodendrocytes in models of MS. Future studies will need to assess the role of other branches of the UPR in oligodendrocytes and the roles of individual branches of the UPR in other cell types involved in MS, particularly neurons, in this disease. The knowledge gained from these studies would provide a foundation to develop therapeutic strategies that protects both oligodendrocytes and neurons in patients with MS.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Cats have been transported as human commensals worldwide giving rise to many feral populations. In Australia, feral cats have caused decline and extinction of native mammals, but their time of introduction and origin is unclear. Here, we investigate hypotheses of cat arrival pre- or post-European settlement, and the potential for admixture between cats of different invasion events. We analyse the genetic structure and diversity of feral cats from six locations on mainland Australia, seven Australian islands and samples from Southeast Asia and Europe using microsatellite and mitochondrial DNA data.Our results based on phylogeographic model selection are consistent with a European origin of cats in Australia. We find genetic distinctiveness of Australian mainland samples compared with Dirk Hartog Island, Flinders Island, Tasman Island and Cocos (Keeling) Island samples, and genetic similarities between some of the island populations. Historical records suggest that introduction of cats to these islands occurred at the time of European exploration and/or in connection with the pearling, whaling and sealing trades early in the 19th century. On-going influx of domestic cats into the feral cat population is apparently causing the Australian mainland populations to be genetically differentiated from those island populations, which likely are remnants of the historically introduced cat genotypes.A mainly European origin of feral cats in Australia, with possible secondary introductions from Asia following the initial establishment of cats in Australia is reasonable. The islands surrounding Australia may represent founding populations and are of particular interest. The results of the study provide an important timeframe for the impact of feral cats on native species in Australia.The online version of this article (doi:10.1186/s12862-015-0542-7) contains supplementary material, which is available to authorized users. The deliberate or accidental translocation of species from their native habitat to new environments by humans , 2 may tVulpes vulpes) and the domestic cat (Felis silvestris catus) . All sequence data is available on GenBank, .The microsatellite data sets supporting the results of this article are available in the Dryad repository [Dryad doi:10.5061/dryad.6t066 ("}
+{"text": "Cryptosporidium and Giardia (oo)cysts on environmentally relevant surfaces such as brushed stainless steel, formica, ceramic, fabric, and skin. Parallel experiments were conducted using clean and soiled coupons incubated under three temperatures. The die-off coefficient rates (K) were calculated using first-order exponential formula. For both parasites, the fastest die-off was recorded on fabric, followed by ceramic, formica, skin, and steel. Die-off rates were directly correlated to the incubation temperatures and surface porosity. The presence of organic matter enhanced the survivability of the resting stages of test parasites. The decay rates calculated in this study can be used in models for public health decision-making process and highlights the mitigation role of hand hygiene agents in their prevention and control.The objective of this study was to find out the impact of environmental conditions on the survival of intestinal parasites on environmental surfaces commonly implicated in the transmission of these parasites. The study was performed by incubating  Enterobius vermicularis is more prevalent in temperate areas  of parasites. Although with the present knowledge it is not possible to precisely define the role of environmental variables  in the survival of parasites (oo)cysts, recovery of neglected enteric parasitic (oo)cysts/ova from naturally contaminated hands of children reported previously  coupled"}
+{"text": "Immune reconstitution inflammatory syndrome (IRIS) is originally described in association with antiretroviral therapy (ART) for HIV infected patients. IRIS consists of a broad spectrum of inflammatory diseases, such as infectious inflammatory, neoplastic, and autoimmune diseases, that present after starting an effective ART, leading to CD4+ cells increase and plasma HIV-RNA reduction. IRIS reflects either worsening of an already-diagnosed infection or presentation of previously subclinical infection. Opportunistic pathogens include cryptococcus, mycobacterium, herpesviruses, or also auto-antigens. The paradoxical worsening of clinical symptoms as observed in IRIS is also the phenomenon of drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS). In the course of DIHS/DRESS, cytomegalovirus diseases and herpes zoster are observed coincidently with the increase in lymphocytes or rapid reduction of systemic corticosteroids. Based on the similar manifestations between IRIS and DIHS/DRESS, DIHS/DRESS can be seen in a broad context as another manifestation of IRIS. Although the mechanisms of IRIS is complex and variable, depending on the latent pathogens and shift of immune status, use of the concept of IRIS can help our recognition of various manifestations that occur in the setting of DIHS/DRESS. The understanding of IRIS may improve the morbidity and mortality rates of DIHS/DRESS."}
+{"text": "Engagement with social media, such as Facebook, Instagram, and Snapchat, may lead to negative outcomes for body dissatisfaction and disordered eating due to the appearance focused nature of the online interactions. The aim of this cross-sectional study was to examine relationships between social media photo-related activities and overvaluation of shape and weight, body dissatisfaction, and dietary restraint in adolescent girls. Participants were 101 year 7 girls  who completed measures of social media use and body image and disordered eating via self-report. Significantly higher levels of overvaluation of shape and weight, body dissatisfaction, dietary restraint, and internalisation of the thin ideal were found for participants who regularly shared self-images on social media, compared with those who were not regular sharers. In addition, after controlling for media exposure and internalisation of the thin ideal, higher engagement in manipulation of self-images and greater investment in the self-images prior to sharing were associated with greater overvaluation of shape and weight, body dissatisfaction, and dietary restraint. Findings suggest that self-image related social media activities may contribute to body dissatisfaction and disordered eating and indicate important contemporary targets for social media based intervention for these problems."}
+{"text": "To the Editor: Diphyllobothriosis, infection by tapeworms of the genus Diphyllobothrium (Cestoda: Diphyllobothriidea)  in 2011 and increases continuously. More than 200,000 tons of fresh or chilled fish, which may serve as source of human fishborne diseases if eaten raw or undercooked, are imported to Spain every year. The fourth largest importer is Ecuador, the sixth is Chile, and the seventh is Peru; D. pacificum, in Europe, but it is highly probable that this species can be introduced anywhere through the importation of fresh or chilled fish from the Pacific coast of South America. This has implications for food safety rules and human health risk measures taken by national health and veterinary agencies. Regarding adequate processing of clinical samples and their preservation for morphologic and genetic evaluation, we strongly recommend fixation of positive fecal samples with eggs or segments (proglottids) immediately with 96%\u201399% molecular grade  ethanol for future molecular diagnosis (In the present study, we confirmed human infections with the Pacific broad tapeworm, A summary of Diphyllobothrium and Diplogonoporus cases in Spain, photomicrographs of features of diphyllobothriids, and results of testing for human-infecting Diphyllobothrium spp."}
+{"text": "Poor health systems and structures in countries affected by Ebola virus disease (EVD) have compounded difficulties in access to hospital care for Ebola patients. With this low healthcare access, individuals may be forced to seek alternative remedies for the management of EVD. One major study suggested that the transfusion of whole blood and serum from patients who had recovered from EVD reduces the risk of EVD-related fatality , with adIn the wake of the growing epidemic, it is possible that this alternative may bring new challenges such as the emergence of a black market trading of blood of EVD survivors . This maConcerns about transfusion-related transmission of HIV and hepatitis infection in the sub-Saharan African region are not unfounded. Afolabi et al.  demonstrIn the face of an epidemic with a high fatality rate and low likelihood for access to quality medical care , the proMorenike O. Folayan Institute of Public Health Obafemi Awolowo University Ile-Ife, Nigeria Department of Child Dental Health Obafemi Awolowo University Ile-Ife, NigeriaBrandon Brown Department of Population Health & Disease Prevention University of California Irvine, CA, USA Email: brandon.brown@uci.eduAminu Yakubu Department of Health Planning and Research Federal Ministry of Health Abuja, Nigeria"}
+{"text": "Knowledge translation researchers in the last decade have seen a torrent of publications arguing for the central importance of organizational context in influencing implementation success. The Translating Research in Elder Care (TREC) program investigates the role of organizational context on the use of best practices, provider and resident outcomes in residential long-term care facilities (nursing homes) in three western Canadian provinces. The purpose of this presentation is to present findings from our study examining the influence of organizational context on the use of best practices by healthcare aides.We collected survey data from 36 nursing homes, 103 units and 1262 healthcare aides and used Hierarchical Linear Modeling (HLM) to assess elements of organizational context that predicted best practice use by healthcare aides. Organizational context was measured using the Alberta Context Tool (ACT).In the final models, instrumental use of best practices was predicted by age, sex, shift worked, job efficacy, belief suspension, and the contextual variables social capital, organizational slack, informal interaction frequency, unit type, and profit status; 18% of the variance was explained in the final model. Conceptual use of best practices was predicted by: English language status, job efficacy, belief suspension, intent to use research, number of information sources uses, perception of adequate knowledge, and the contextual elements leadership, feedback processes, organizational slack, availability of resources, and province; 43% of the variance was explained in the final model.Our study identifies several individual and contextual factors that play an important role in healthcare aides' use of best practices in nursing homes. This has important practical implications for designing strategies for dissemination and implementation of best practices to increase healthcare professionals' ability to practice evidence informed care to improve health outcomes.Funded by Canadian Institutes of Health Research (CIHR)."}
+{"text": "Several studies have presented morphological, biochemical and histopathological changes in the paraspinal skeletal muscle of patients with adolescent idiopathic scoliosis (AIS). Some abnormalities have been demonstrated such as an increased amount of type I fibers in the concavity and the decreased number of type II in the convexity, an increase in the intracellular concentration of glycogen and lipids, structural changes in the sarcolemma and myotendinous junction, changes in the activity muscle enzyme, an increase in intracellular calcium concentration.To evaluate the rotator muscle fibers at the apical vertebraof curves of patients with AIS by histological and immunohistochemical analysis.Cross-sectional study.Twenty-one patients with AIS submitted to surgical correction between 2,010 and 2,013 had the spinal rotator muscles biopsied in the concavity and convexity of the apical vertebra of the thoracic curve during the surgery. Serial cryosections were stained with Hematoxylin-Eosin (HE) and Sudan Red. We evaluated muscle atrophy and hypertrophy, fatty proliferation, presence of endomysial and perimysial fibrosis, presence of hyaline fibers, mitochondrial proliferation, muscle necrosis, nuclear centralization and inflammation. Two independent observers evaluated the sections.The average value of the angle of the main thoracic curve was 68\u00b0 Cobb. For analysis of non-parametric paired variables between the concave and convex side it was used the McNemar test with a significance level of 5%. The results of relative frequency and \u201cp\u201d values showed significant difference in both endomysial and perimysialfibrosis and fatty involution when compared to both sides of the apical vertebra.The paraspinal muscles at the apex of the deformity had higher involvement in the concavity when analyzing the fatty involution and fibrosis. However, both sides showed signs of myopathy, muscle atrophy through areas of necrosis and hyaline presence of fibers, mitochondrial proliferation."}
+{"text": "David Stephens and colleagues describe their experience of treating patients with Ebola virus disease at Emory University in the United States. Ebola hemorrhagic fever, or Ebola virus disease (EVD), has emerged in the last year as a global threat and humanitarian disaster for the affected countries of West Africa and has also come to the United States (US) and Europe.The treatment of the first and three subsequent US patients outside of Africa at Emory University provided a number of challenges, as well as strategic and tactical lessons that included detailed planning and team work across multiple academic and health care units, emphasizing biosafety, the importance of institutional communications, addressing unanticipated challenges such as waste management, and the logistics of working closely with governmental agencies and outside collaborators.In providing effective care for individuals, the value of mobilizing a diverse health and academic community to work collaboratively to addressing a global threat is emphasized. This includes dissemination of best practice information; providing education and training about EVD; expansion of new knowledge about the clinical course, complications, and pathogenesis of EVD; the creation of new institutional forums, and engagement in the broader policy and equity issues of contagious health threats.Zaire ebolavirus), began in Meliandou, Guinea, West Africa and soon enveloped neighboring Sierra Leone and Liberia, with cases also in Nigeria, Senegal, and Mali [Ebola hemorrhagic fever, or Ebola virus disease (EVD), is caused by a highly contagious group of enveloped, single-stranded, negative-sense RNA viruses of the family Filoviridae. The disease has historically carried 53%\u201388% mortality \u20133. In Deand Mali \u20135. WHO  hospital in Liberia were evacuated from Monrovia by a specially designed air ambulance to Emory University Hospital (EUH) . Until AThe strategic and tactical lessons and challenges presented by providing care for the first and subsequent US EVD patients at Emory University provide an opportunity to share lessons that may help others. Specific clinical and immunological features and diagnostic and detailed management issues of the patients at Emory are reported separately \u201311. It iEUH is the flagship clinical care facility for Emory Healthcare, staffed by 1,221 Emory School of Medicine faculty physicians, with over 3,600 employees, 25,300 admissions, and 157,000 outpatient visits annually. The hospital has one of the highest case-mix indexes (a measure of complexity of illness treated) among the University Healthsystem Consortium (UHC)-ranked facilities. Emory had established strong programs in health care delivery, quality, infectious diseases (ID), infection control and biosafety, immunology, vaccines, and public health that were important to its ability to respond to this series of events.The Serious Communicable Diseases Unit (SCDU) , Box 1 oThe SCDU was designed  to proviThe SCDU was constructed  within the EUH clinical research unit. The clinical research unit has been in existence for some 60 years and supports clinical research through the National Institutes of Health (NIH)-funded Clinical and Translational Science Awards (CTSA) program. The SCDU offers on-call, highly trained staff operating under standardized, ready-to-go protocols for providing care for patients infected with highly communicable contagious diseases.While not necessary for treatment of EVD, the isolation rooms feature negative pressure air handling, 20 air changes per hour, with laminar flow and high-efficiency particulate air (HEPA)-filtering completed before the air is 100% exhausted outside of the hospital (no recirculation). General and intensive care can be provided. The SCDU was activated on two previous occasions. The first was in 2003 for a CDC worker with concern for having been infected with severe acute respiratory syndrome (SARS) in Hong Kong, China. The second was in 2005 for a CDC employee in Angola with potential Marburg virus hemorrhagic fever. While unit activation has been infrequent, intensive training in this unit to maintain a state of readiness has been continuous for well over a decade, including detailed preparation for transport of patients and the training of nurses and physicians.www.emoryhealthcare.org/ebolaprep [A virtual tour of the SCDU and videos addressing many of the most frequently asked questions, together with access to all SCDU policies and standard operating procedures (SOPs), are available on the Emory education web site: bolaprep .The ID program at EUH was built to provide expertise in hospital epidemiology, antimicrobial management, transplant infectious diseases, and clinical microbiology. For over a decade, Emory University was an active member of the NIH Research Centers of Excellence (RCE) in Biodefense and was the site for the biosafety training program for select pathogens of the Southeast Regional Center of Excellence for Emerging Infections and Biodefense (SERCEB) RCE. This particular program provided invaluable expertise, equipment, and support for the EVD effort. Emory ID and Emory Healthcare (EHC) also created the TravelWell clinic, an outpatient clinic available for assessment and evaluation of pre- and post-travelers and supporting major Atlanta corporations and the CDC. Emory\u2019s TravelWell is part of a 57-site worldwide travel network (GeoSentinel) with a 10-year database of 3,000 entries of those who either had returned ill following travel to Liberia, Sierra Leone, Guinea, or Nigeria or had just emigrated from one of those countries.The request for medical care for the initial patients came from the missionary organizations Samaritan\u2019s Purse and Serving in Mission (SIM) USA and from the patients themselves. The decision was coordinated through the US State Department and the CDC. EUH and EHC leadership made the decision to accept the patients\u2014a decision made quickly but not lightly. The decision was based on the need, confidence in the overall preparedness of EUH, and the more than a decade plus of training and preparation to address highly communicable diseases at EUH . ImportaThe SCDU medical team is led by the SCDU director, an ID trained physician who has spearheaded for over a decade efforts in establishing the protocols, training, education, and operations of the unit in conjunction with the CDC. Three other faculty members of the Department of Medicine, four additional ID physicians, two pathologists, five medical technologists, and 21 critical care nurses also support the unit.An SCDU unit director, clinical nurse specialist, and team coordinator handle logistics, organize training sessions, determine supply needs, and establish nursing schedules. Nurses provide care in 4-hour stretches to minimize donning and doffing of personal protective equipment. The overall effort has directly involved over 125 staff and support personnel.During the care and treatment of EVD patients, there were daily communications between the SCDU medical team and the CDC\u2019s Division of High-Consequence Pathogens and Pathology (DHCPP), the Division of Healthcare Quality Promotion, and the Emergency Operations Center for Ebola established at CDC, and with the US Food and Drug Administration (FDA) and other US federal agencies, as well as frequent communications with other academic units, industry, and providers in West Africa.The primary focus of training was on biosafety for all individuals who provided direct care or handled body fluids. All of these individuals received mandatory education and training, followed by strict competency verification before medical or nursing staffs were permitted to provide care for these patients.Effective and assertive communication was central to the safety of the SCDU team. Use of the buddy system was an essential element of the focus on individual and colleague safety. Because communication was so important, the team developed rules to govern direct patient care communication as well as within daily team huddles. These rules were reviewed each morning during the daily huddle and served as a platform to empower all members of the team, regardless of role, to facilitate communication and to maintain strict SOPs.The hospital support team was led by the CEO of EUH. The chief medical and nursing officers of EHC and EUH, and in particular the vice president of operations of EUH, were also heavily involved in leading the support efforts. During the care and treatment of the EVD patients, an operations team of key administrators and nursing and physician leadership met twice a day. Despite the extensive preplanning, opportunities to refine and improve both clinical and operations were noted, and all aspects of the hospital services were involved. Pharmacy, environmental services, engineering/facilities support, and pastoral care/counseling were especially important.Other ID faculty, including a pediatric ID specialist with experience in EVD, provided support for the frontline medical team. Periodic conference calls focused on support, therapeutic options in treating patients, and issues of postexposure prophylaxis, vaccines, surge planning, protocol development, and discussions of research as it related to EVD. To facilitate the necessary availability of SCDU dedicated ID providers, alternate faculty were recruited to cover the regular duties of the SCDU physicians. ID support also included contacting key national and international research leaders in EVD; evaluating, contacting, and obtaining, through outside groups, experimental vaccines and new drugs for Ebola; and communicating with the CDC, FDA, NIH, and other federal agencies, other university partners, and biotech/industry contacts, all of which were essential in the effort.The Emory Environmental Health and Safety Office (EHSO) was engaged immediately after the call for ongoing support. While clinical care settings are very different from those of labs, EHSO staff included individuals with expertise in training on Biosafety Level BSL 3 and 4 laboratory safety, which was helpful in translating to our clinical care situation. Conversations were conducted by EHSO with other national biosafety leaders in EVD.  attending coverage for critical care management issues including airway management and line placement issues. Other subspecialties, such as renal medicine, were required on a case-by-case basis. The location of the SCDU away from other patient care units of EUH significantly reduced the impact on our other health care delivery and patient operations. DHCPP at CDC provided critical help to the unit for viral loads, specialized assays, and other support.10 RNA copies per ml of serum [Different outside perspectives and guidance were initially provided about the level of biosafety needed for EVD. Ebola viruses have a very low infectious dose, 1\u201310 aerosolized organisms, in nonhuman primate models  and can of serum ), stool,To achieve the lowest risk to health care personnel, the highest level of biosafety was initially employed. This included MAXAIR powered air-purifying respirators (PAPRs), fluid-resistant body suits along with cover aprons, double gloves and shoe covers, and wiping down all surfaces with US Environmental Protection Agency (EPA)-registered disinfectants (no spraying) when doffing PPE. Other key biosafety SOPs developed were autoclaving within the unit for waste management, followed by disposal of regulated medical waste off-site after it had been autoclaved; decontamination; and handling of laboratory samples and waste. The consequences of transmission stressed the need for the highest level of biosafety.The importance of the EHSO office in reinforcing the prior training of personnel and monitoring the clinical staff for consistency and adherence to biosafety from training sessions to practices in real-time clinical care cannot be overemphasized. This included how to \u201cdon and doff\u201d impermeable fluid-resistant body suits, proper use of PAPRs, coordination of the disposal of waste, and the handling and transport of lab samples. EHSO also helped prepare and support the team psychologically, challenging them with spills and other incidents to practice remaining calm in the face of potential unexpected occurrences. Team engagement demonstrated the importance of melding the philosophies of clinical treatment/practice and biocontainment/biosafety. Feedback from frontline physicians, nurses, and hospital staff highlighted the contributions of EHSO to the effort and the value of the EHSO biodefense education and training expertise.Waste management for EVD is a significant hurdle. EVD results in copious amounts of vomit and diarrhea with up to 10 liters of fluid lost by patients each day. Up to 40 large \u201cbags\u201d per day of regulated medical waste were generated by our first two patients. A large-capacity autoclave was mobilized, with postautoclaved waste stored in 32-gallon leak-proof rubber waste containers in the SCDU until removal and incineration. All waste in toilets was disinfected with an EPA-registered disinfectant before flushing. Importantly, no traces of Ebola RNA on \"high-touch surfaces\" such as beds and bathrooms were detected during active care or after patient discharge prior to terminal decontamination with vaporized hydrogen peroxide.Guiding principles for communications included consistent messaging and protecting patient privacy while educating the public. Internal communications with a focus on transparency and education, within the bounds of confidentiality of medical information and protecting our patients\u2019 privacy, were vital. These included meetings with EUH hospital leadership and staff to address concerns, frequent emails and other communications with all faculty and staff at EHC and Emory, making sure instructions/checklists were in place, and facilitating the dissemination of protocols. To avoid unauthorized access to electronic medical records, a chart-warning flag was implemented. Confidentiality of medical information regulations were repeatedly stressed to all medical staff, residents, and fellows.www.emoryhealthcare.org/ebolaprep) [In external communications and interface with the media, the Emory communications teams tirelessly addressed media logistics, developed web and social media material, worked closely with governmental and nongovernmental external groups, developed talking points, and prepared the hospital and SCDU teams for communications venues. To maximize our preparedness and to address national concerns, press conferences and media interviews were conducted, and an EVD Questions and Answers document was developed and posted. The story exploded in broadcast print and social media. Over 84,000 media stories have been written linking Emory and Ebola. Emory communications created an Emory Healthcare Ebola Preparedness Protocols website (olaprep)  to make The admissions heightened Ebola and other bio-threat concerns both locally and nationally. Questions about potential EVD patients began to occur immediately in our health care system and throughout the US. We developed and disseminated flow diagrams, algorithms, and SOPs  for evalAs noted, a highly trained group of faculty, nurses, biosafety support, and other providers staff the EUH SCDU. While no trainees  served on the direct care team, trainees benefitted from the experience of the unit and clinical experience with EVD through conferences and other education venues . An EVD \u201cMicro Vignette\u201d and other educational materials were developed for resident and fellow education. Further, ID and other specialty fellows have been integrated into the management planning for EVD patients, educated on the broader policies and procedures of the unit, are involved with the development of protocols for the management of Ebola patients who present to the Emergency Department (ED) or other clinical settings, and are educated about the collective experiences in treating the patients. In addition, a Massive Open Online Course (MOOC) \u201cEbola at Emory: Patients to Populations\u201d has been launched , an EBOLWork was initiated to better understand EVD pathogenesis and therapeutic options \u201311,15\u201319The event also led to broad faculty engagement across all parts of the institution through the creation of an Emory Ebola Task Force and Ebola Faculty and Community Discussion Forum . The TasEVD has arrived in North America and Europe and impacted us globally. Academic medical centers can be expected to be at the frontline to address EVD and other highly communicable infectious agents in the future. Our experience  with EVDCommunicable infectious diseases will continue to be global threats to human health and have the potential to cause repeated humanitarian disasters.Coordination, detailed planning, and teamwork across governmental, nongovernmental, academic, and health care unitsEnvironmental Health and Safety as a key support team memberPreparedness in training, biosafety, surveillance, and communicationsDonning and doffing of PPEWaste management protocolsDecontamination and containment protocolsSpecimen handling for diagnostic testingEvaluation of provider competency in biosafetyAn organizational structure to solve unanticipated challenges and the logistics of working closely togetherThe rapid dissemination of best practice informationProviding education forums and frequent educational communications  around disease transmission and riskConsistent messaging and protecting patient privacy while educating the publicExpanding new knowledge about the clinical course, complications and pathogenesis, diagnosis, treatment, and preventionEngagement in the broader policy issues of global health care inequitiesOur experience as an academic health center with EVD emphasized the importance of preparation, communications, and implementation:The institutional experience, while providing the opportunity to effectively care for these individuals, has led to best practice information and the education and training of others, created key academic, governmental, and community partnerships, expanded research programs in EVD, and resulted in the development and communication of new knowledge about this emerging disease. Mobilizing our diverse academic community to work collaboratively on this global problem is also an important long-term outcome."}
+{"text": "Tropical diseases remain a major cause of morbidity and mortality in developing countries. Although combined health efforts brought about significant improvements over the past 20 years, communities in resource-constrained settings lack the means of strengthening their environment in directions that would provide less favourable conditions for pathogens. Still, the impact of infectious diseases is declining worldwide along with progress made regarding responses to basic health problems and improving health services delivery to the most vulnerable populations. The London Declaration on Neglected Tropical Diseases (NTDs), initiated by the World Health Organization\u2019s NTD roadmap, set out the path towards control and eventual elimination of several tropical diseases by 2020, providing an impetus for local and regional disease elimination programmes. Tropical diseases are often patchy and erratic, and there are differing priorities in resources-limited and endemic countries at various levels of their public health systems. In order to identify and prioritize strategic research on elimination of tropical diseases, the \u2018First Forum on Surveillance-Response System Leading to Tropical Diseases Elimination\u2019 was convened in Shanghai in June 2012. Current strategies and the NTD roadmap were reviewed, followed by discussions on how to identify and critically examine prevailing challenges and opportunities, including inter-sectoral collaboration and approaches for elimination of several infectious, tropical diseases. A priority research agenda within a \u2018One Health-One World\u2019 frame of global health was developed, including (i) the establishment of a platform for resource-sharing and effective surveillance-response systems for Asia Pacific and Africa with an initial focus on elimination of lymphatic filariasis, malaria and schistosomiasis; (ii) development of new strategies, tools and approaches, such as improved diagnostics and antimalarial therapies; (iii) rigorous validation of surveillance-response systems; and (iv) designing pilot studies to transfer Chinese experiences of successful surveillance-response systems to endemic countries with limited resources. Please see Additional file Effective and timely surveillance and responses tailored to specific settings reflect the ability of a health system to provide reliable and judicious information for public health policy, pragmatic action in infectious disease control and elimination, and efficient sustainable development ,2. TropiDespite growing international funding and logistical support offered by the World Health Organization (WHO), multilateral agencies, philanthropic organisations and a host of new consortia to fight tropical diseases, the public health burden and the challenges facing programmes to achieve sustained control and ultimate elimination of the major NTDs are still enormous ,14. It hThe \u2018First Forum on Surveillance-Response System Leading to Tropical Disease Elimination\u2019 was held on June 16-18, 2012 in Shanghai. The Forum was jointly supported by the National Institute of Parasitic Diseases of the Chinese Center for Disease Control and Prevention (NIPD/China CDC), the Swiss Tropical and Public Health Institute (Swiss TPH) and the WHO. The purpose was to share knowledge and experiences pertaining to the control, prevention and elimination of major tropical diseases and to discuss novel approaches towards the establishment of integrated surveillance-response platforms and networks to assist these efforts. The Forum brought together scientists, public health experts and health policy specialists to explore and discuss promising surveillance-response systems with focus on, but not limited to, malaria, schistosomiasis, lymphatic filariasis and other NTDs. The participants in each session were engaged in in-depth discussion on current challenges, opportunities and measures to foster reliable effective surveillance-response systems as the strategic key for endemic countries moving towards disease elimination.It was felt that the establishment of a conceptual framework to design and implement surveillance-response systems is critical for the elimination of tropical diseases including NTDs. Surveillance-response systems with regard to infectious diseases of poverty have gained traction, particularly in settings where health systems provide an integrated data repository capable of characterising disease dynamics at multiple scales. Evaluating the impact of implemented programme(s) and intervention(s) in public health centres and health services on the population-level towards prevention or control of tropical diseases would benefit by a system for surveillance and response leading towards maximum positive health outcomes. To summarise, the two-fold objectives of this paper were: (i) to establish a platform for resource-sharing and effective surveillance-response systems for Asia Pacific and Africa with an initial focus on elimination of lymphatic filariasis, malaria and schistosomiasis; and (ii) to explore new strategies, with an emphasis on improved and more sensitive diagnostics and antimalarial therapies in elimination programmes.Schistosoma japonicum had declined to an all-time low with less than 300,000 infected people [Before 1955, just after the founding of the People\u2019s Republic of China, many infectious diseases were highly endemic, particularly in the southern parts of the country, similar to the epidemic and pandemic documented in Africa between 1980s and 2000 [d people ,24.Plasmodium falciparum malaria has been eliminated as a public health threat in all provinces except Yunnan. Among the 24 malaria-endemic provinces, annual incidence rates have dropped below 1 per 10,000 in 95% of the endemic counties, and only 87 counties have a rate above this threshold [With regard to malaria, it must be noted that sustained efforts have reined in the endemic areas, which are now considerably smaller with the number of cases in China decreasing from an estimated 30 million in the 1940s to less than 5,000 by the end of 2011 . Today, hreshold ,27. HencKnowledge on the unrelenting control of its many endemic tropical diseases and the growing expertise in other disease-endemic regions of the world has shown that China can harness evidence-based knowledge and information, create innovative approaches and implement large-scale, effective solution for both its own people and the global community. The low-level transmission patterns of infection and re-infection rates in China and other endemic countries underscore that continuing control activities are critical for ultimate success of schistosomiasis and malaria surveillance-response systems. For example, transmission features in schistosomiasis include environmental contamination by eggs excreted by a large number of domestic and wild animal species that contribute to transmission; indeed the proportion of eggs from water buffaloes might account for up to 90% of all eggs found in the endemic areas ,32. In aP. vivax transmission and mixed infections with P. falciparum and P. vivax are documented, respectively [It was documented that active mapping of disease transmission hotspots and molecular characterization of genetic diversity and population dynamics were effective for early detection, allowing prompt treatment using safe and efficacious drugs. Meanwhile, patient compliance and adherence to any effective prescribed regimen is vital for public health management in primary healthcare and minimising the evolution of resistant parasite strains resulting from sub-therapeutic doses and drug selective pressure indicators. There is a pressing need to develop new surveillance tools and strategic responses to shift the focus from control to elimination. With regard to local elimination of malaria in China, specific response packages must be tailored for different settings . For exaectively ,37.Anopheles vectors and transmission [Highly sensitive and specific diagnostic tools  are urgently needed to target mass screening of asymptomatic gametocyte reservoirs in low/moderate endemic areas as well as sub-microscopic parasitaemia and intensive integrated management of hotspots linked to environmental, climatic and ecological appropriateness for smission ,38. Intesmission . Additiosmission ,18.New reliable tools and efficient strategies against other communicable diseases were discussed, such as development of highly sensitive diagnostic assays for early detection of low-transmission settings, MDA, development and validation of vaccines for prevention and drugs for management, improvement of preventive strategies and environmental sanitation, information, education and communication (IEC), community participation and ownership, mechanisation of agriculture, sewage drainage, building of public latrines, waste management and provision of clean water as well as modelling based on a minimal essential database approach Table\u00a0.Health system and health policy makers, and government will require development and implementation of new surveillance-response system policies in the context of infectious diseases elimination towards eradication (e.g. containment of private-sector workers importing parasitic diseases). New policies will include prevention and control, community-based mobilisation, IEC as well as participation and cooperation to re-enforce management, community ownership and development, such as mechanisation of agriculture and food production. For example, in malaria information system, remote sensing, web-based information, eHealth  and mHealth  for health services, information and communication) have proved useful in controlling malaria in remote areas and enhancing active surveillance as well as new and fast ways of gathering geographical, spatial, ecological and meteorological data relevant for the understanding of foci of vector transmission, dynamics mapping for patient follow-up, containment of infections or outbreaks and monitoring resistance -43.In schistosomiasis, veterinary public health and emphasis on the socioeconomic importance of zoonoses are needed along with health education with special reference to farming and the development of a new policy for surveillance-response systems to contain outbreaks and resurgence. In addition to prevention, control and spatio-temporal surveillance tools relevant to the understanding of schistosomiasis transmission dynamics, mapping of infectivity and close monitoring of outbreaks are important ,44-46.Surveillance and response represent the final, crucial steps in achieving effective elimination of a disease , as recognised in many of the ongoing malaria and NTD elimination programmes -49. Intrhttp://www.theglobalfund.org/en/) [P. falciparum, a dry-season, breeding-site mapping and an epidemiological survey were conducted, followed by diagnosis of malaria patients in the community and treatment in combination with integrated vector management  and long-lasting insecticidal net (LLIN) campaigns). In addition, in their move towards elimination of the vicious cycle of poverty and infectious diseases, malaria consortia should continuously provide technical assistance for health system strengthening and the development of innovative tools to improve malaria surveillance and provide national and district staff with the information they need to respond to malaria outbreaks as well as to individual cases [Passive and active surveillance systems have been utilised for different purposes and at different stages of disease control and elimination Table\u00a0. Passiveorg/en/) ,51. Actial cases ,52-54.P. vivax and P. falciparum malaria addressed based on WHO\u2019s global roadmap.The Forum elaborated on a set of effective and essential features to achieve infectious disease elimination, such as (i) political stability and good governance; (ii) commitment to use local resources for elimination activities; (iii) worthy organisational and technical infrastructure coupled with qualified and committed personnel; (iv) adequate general health care services delivery; (v) making communities understand and support the control programmes; (vi) no major uncontrolled population movements; and (vii) The move from morbidity control to interruption of transmission and achievement of elimination requires novel, advanced technologies, either aimed at reducing the infection reservoir or at reducing the rate at which infections spread. This can be done by an innovative research portfolio that is expanded to include NTDs, zoonoses and other socioeconomic determinants in most endemic countries, particularly in sub-Saharan Africa. Important outcomes from the First Forum on Surveillance-Response System Leading to Tropical Diseases Elimination include foremost important lessons from previous outbreaks and resurgences of parasitic diseases in China and elsewhere; second, new surveillance-response platforms capable of further strengthening existing health systems at all levels; third, long-term commitment, which is crucial to achieve sustainability of the elimination agenda; fourth, political will, i.e. commitment to use local resources and implementation of innovative multi-sectoral, integrated approaches; fifth, improved diagnostic tools for early detection of infection and disease; and finally, but not the least, capacity-building, new partnerships and use of innovative technology to render existing surveillance-response systems more effective ,50,52,55The following questions were raised: (i) Do we have, and are we using, the most effective surveillance tools (this is of particular relevance with regard to diagnostics)? (ii) Are we implementing the most effective surveillance-response packages tailored to a given transmission setting? (iii) Is it possible to innovate and incorporate additional surveillance measures to existent interventions? (iv) What are the contributions of private companies to health? (v) How can we be sure that we move in the right direction? The Forum promptly progressed to addressing these questions during different sessions.Participants felt that the Forum provided a stimulating environment for exchange of ideas and experiences giving an impetus for rapid progress towards surveillance and response systems in elimination of tropical diseases that impact on the health and well-being of disadvantaged and marginalised populations in the world. It was concluded that the Forum should be held every 2 years. Hence, at the time of writing the current report, planning for the June 2014 forum is intensifying. The following recommendations for strengthening research on surveillance-response systems for disease elimination were put forward.The Forum recognised that containing the emergence and spread of tropical diseases requires early alertness, active detection and diagnosis of its pathogenic cause. Concerted efforts and effective partnerships are needed to share the roles and responsibilities in defining powerful surveillance-response systems to mitigate the public health burden of tropical diseases thereby ensuring scalability and sustainability.Setting up a genuine coordination and collaboration between Asia Pacific and Africa with regard to public health and control/elimination of malaria and NTDs was encouraged, emphasising surveillance-response systems that rely on an integrated and dynamic approach to risk management with ongoing research, data collection and real-time analysis, thereby driving evidence-informed knowledge translation into policy decisions and action with a feedback process to facilitate continuous advancement and adaptation.Continuous scrutiny of all aspects of infectious diseases occurrence and spread, pertinent to effective control and elimination, requires systematic collection, collation, analysis, interpretation and dissemination of health data and the establishment of a resource-sharing platform for surveillance-response system between Asia Pacific and Africa. Reconvening the Forum every 2 years would provide an opportunity to discuss progress and challenges in implementing local, national or regional surveillance-response system for targeted infectious diseases, discoveries and developments among scientists, public health specialists, politicians and other stakeholders.Importantly, documented limitations call for dispersion of technological advances in most developing countries of Asia Pacific and Africa, so that surveillance-response strategies and rapid diagnostic methods, tools and approaches can be improved. This requires continued innovation, validation and application of efficient, low-cost diagnostic, affordable novel therapeutic agents and vaccines ,5.in vitro sensitivity limitations of currently deployed detection tools (e.g. microscopy and rapid diagnostic tests) have been documented, and hence, there is a need for improved tools in assessing susceptibility [Sensitive diagnostic tools based on molecular methods and advanced biotechnological assays need to be developed as surveillance tools for monitoring and verification of elimination of tropical diseases ,39,52,56tibility ,56.The Forum provided a unique opportunity to discuss surveillance-response systems as the final stage towards elimination of infectious diseases, especially NTDs, based on a \u201cOne World-One Health\u201d perspective. Five research priorities were recommended: (i) dynamic detection and mapping of transmission, particularly low-level transmission, also using eHealth and mHealth; (ii) near real-time monitoring of population dynamics; (iii) modelling to establish minimal essential databases and indicators to be collected in space and time; (iv) design of effective response packages tailored to different transmission settings and levels; and (v) rigorous validation of approaches and response packages with regards to effectiveness within elimination programmes.It was emphasised that regional strategies, innovative data management tools, inter-sectoral, multi-disease control approaches and research framework on control and elimination of infectious diseases of poverty must be strengthened . SurveilChina can provide expert support on the establishment of diagnostic tools and techniques, in providing capacity building and training on tropical diseases to laboratory technicians, medical staff and disease control managers in Africa. Moreover, support in monitoring techniques and conducting collaborative research on all aspects of effective surveillance-response mechanisms can be provided depending on context, nature of endemicity. Assistance can be provided to African countries to complement their own electronic reporting system for infectious diseases , including continuous monitoring and evaluation of disease transmission dynamics through innovative Sino-Africa partnership. China had developed effective surveillance and early warning systems (EWS) for malaria and schistosomiasis based on electronic-based reporting systems ,59 and tP. falciparum and P. vivax  exist. Drug resistance is a very important consideration in malaria control demanding the application of approaches, such as real-time molecular genotyping of sexual and asexual resistant biomarkers from asymptomatic and symptomatic population. This activity is paramount in endemic areas for the monitoring of emerging trends of susceptibility and drug resistance, which are key components of malaria control towards elimination.It is worth noting that China has made significant contributions in the discovery and development of drugs against malaria (e.g. artemisinins), schistosomiasis (e.g. artemisinins and mefloquine) and soil-transmitted helminthiasis (e.g. tribendimidine) -63. The Future global health involvements include the establishment of comprehensive sites for M&E and impact assessment in sentinel sites, focussing on three areas of possible research-action programmes: (i) characterising how demographic, epidemiological and environmental factors influence disease transmission by comprehensive comparison of population prevalence, capacity building in diagnostic ability, effects of integrated vector management between demonstration areas and control areas; (ii) socioeconomic factors and the status of prevailing health systems; and (iii) strategy and measurement assessment, including evaluating intervention effects of a related policy and strategy applied in the interventional areas and further exploration of the external validity of the findings from these areas.The Forum reviewed the action plans of NTD control and elimination articulated in the WHO roadmap and China CDC, as well as the national schistosomiasis elimination programme for China (2009-2015), placing particular emphasis on surveillance-response systems. China\u2019s challenges and needs in tropical disease control, and its experiences and lessons learnt necessitate national governments to build and implement surveillance-response systems to deal with tropical diseases, including imported cases and new outbreaks.The first Forum provided a platform for exchange among participants from different countries and sectors who presented their principles and approaches from disease control to elimination. The reader should, however, be aware that the current report expresses the opinions of the individuals participating in the Forum and does not intend to be an exhaustive exploration of the subject matter or a representation of consensus.During the First Forum on Surveillance-Response System Leading to Tropical Diseases Elimination, a priority research agenda within a \u2018One Health-One World\u2019 frame of global health was developed, including: (i) the establishment of a platform for resource-sharing and effective surveillance-response systems for Asia Pacific and Africa with an initial focus on elimination of lymphatic filariasis, malaria and schistosomiasis; (ii) development of new strategies, tools and approaches, such as improved diagnostics and antimalarial therapies; (iii) rigorous validation of surveillance-response systems; and (iv) designing pilot studies to transfer Chinese experiences of successful surveillance-response systems to endemic countries with limited resources.More than 100 scientists, disease control managers and other stakeholders participated in the First Forum on Surveillance-Response System Leading to Tropical Diseases Elimination. It offered the opportunity for discussions and exchange of ideas and opinions with emphasis on disease elimination and the key role played by surveillance-response systems. Strengths and limitations of national and international strategies for elimination, prevailing strategies, and novel approaches required for elimination, rely on useful surveillance-response platforms. Funding channels should be explored to intensify research and development of new, innovative and effective platforms. Supporting Sino-Africa partnership for control of parasitic diseases will require taking initiatives for global health and the best experiences from China and the international community to Africa. New operational research should be devoted to identify risk factors and hotspots of transmission, monitoring emergence and spread of disease outbreak with enhanced geographical information systems (GIS), health systems, care management and an integrated approach in improving the efficiency of surveillance-response systems.Sustained control can only be made leading to elimination by accelerating breakthroughs in research, while fully understanding inputs, processes, outcomes and impact on transmission. The launch of the WHO roadmap perpetuates the need for effective surveillance-response systems tailored to local settings. Systems effectiveness depends on access to highly sensitive diagnostics, prompt treatment and follow-up as well as quality of care and patient trust. Sensitive tools for surveillance for xenobiotic monitoring and a deeper understanding of which tools and strategies are most suitable to achieve elimination of malaria, schistosomiasis and other NTDs are needed. Moving from classical M&E to surveillance as an intervention and interruption of transmission not only requires high standards in data collection  and appropriate analysis, but also experiences in modelling and validation, verification of elimination and reliable forecasting. Finally, relevant effective intervention science is a must in order to improve the effectiveness of the policies recommended and the public health interventions undertaken.The authors declare that they have no competing interests.ET, XZ, RB, MT, XNZ conceived the review concept. ET, LA, XZ, JHC, XNZ carried out the literature search, developed the structure for the manuscript, and drafted the paper. ET, XZ, RB, JGG, MT, XNZ participated to organize the draft sections, co-wrote sections of the draft, and ET, RB, JU, MT, XNZ edited the overall manuscript. All authors read and approved the final version of the manuscript before submission to Infectious Diseases of Poverty.Multilingual abstracts in the six official working languages of the United Nations.Click here for file"}
+{"text": "The Millennium Development Goals (MDGs) made a marked transformation for neglected and vulnerable communities in the developing countries from the start, but infectious diseases of poverty (IDoPs) continue to inflict a disproportionate global public health burden with associated consequences, thereby contributing to the vicious cycle of poverty and inequity. However, the effectiveness and large-scale coverage of artemisinin combination therapy (ACT) have revolutionized malaria treatment just as the control of lymphatic filariasis (LF) and onchocerciasis have benefitted from harnessing the broad-spectrum effect of avermectin-based derivatives. The paradigm shift in therapeutic approach, effected by these two drugs and their impact on community-based interventions of parasitic diseases plaguing the endemic low- and middle-income countries (LIMCs), led to the Nobel Prize in Physiology or Medicine in 2015. However, the story would not be complete without mentioning praziquantel. The huge contribution of this drug in modernizing the control of schistosomiasis and also some intestinal helminth infections had already shifted the focus from control to potential elimination of this disease. Together, these new drugs have provided humankind with powerful new tools for the alleviation of infectious diseases that humans have lived with since time immemorial. These drugs all have broad-spectrum effects, yet they are very safe and can even be packaged together in various combinations. The strong effect on so many of the great infectious scourges in the developing countries has not only had a remarkable influence on many endemic diseases, but also contributed to improving the cost structure of healthcare. Significant benefits include improved quality of preventive and curative medicine, promotion of community-based interventions, universal health coverage and the fostering of global partnerships. The laudable progress and benefits achieved are indispensable in championing, strengthening and moving forward elimination of the IDoPs. However, there is an urgent need for further innovative, contextual and integrated approaches along with the advent of the Sustainable Development Goals (SDGs), replacing the MDGs in ensuring global health security, well-being and economic prosperity for all. This year's Nobel Prize in Physiology or Medicine, awarded for the discovery of artemisinin and ivermectin, was divided between Youyou Tu \"for her discoveries concerning a novel therapy against malaria\" and William C. Campbell together with Satoshi \u014cmura \"for their discoveries concerning a novel therapy against roundworm infections\" Fig.\u00a0. These pThe burden of persisting and threatening infectious diseases in most developing countries is a complex affair, a fact recognized by The United Nations' Millennium Development Goals (MDGs)  that repArtemisia - qinghaosu - has a long history in Chinese traditional medicine), are broad-spectrum drugs that can be used to cure many more infections than mentioned above; amazingly, the artemisinins have even effect against immature schistosomes, while ivermectin seems to limit the behaviour of the malaria vector. However, it was not evident that a new era had begun until the new drugs were in general use. Trying to pinpoint this historic shift exactly is of course futile, but it can be said that after the large-scale introduction of modern chemotherapy in the 1980s and 1990s, the first decade of the new millennium marks the time that world-wide implementation of mass drug administration (MDA) occurred [The root cause of the infectious diseases of poverty (IDoPs) is the ubiquitous presence of infectious agents. However, social and economic issues play a large role in their transmission and persistence, a fact recognized in both the MDGs and the follow-up SDGs. Still, the transformation of the endemic landscape is almost entirely due to large-scale distribution of the three novel 'wonder drugs' artemisinin, ivermectin and praziquantel, mainly used against malaria, lymphatic filariasis (LF)/river blindness and schistosomiasis, respectively. All three, discovered and developed in the 1970s , LF (Brugia and Wuchereria), hookworm infection  and other soil-transmitted helminthic (STH) infections [The discovery of artemisinin and ivermectin have had, and will continue to have, a long-lasting, strong impact on the IDoPs, the former due to its effect on the parasites causing malaria; the latter because its effect on the different nematodes that cause river blindness  against acute and severe malaria, intermittent preventive treatment and curative with respect also to the asexual plasmodium stages, has provided relief and hope for a large proportion of vulnerable populations in the endemic areas \u201311. Impote drugs , 11, 16 te drugs  in strente drugs .Both acute and severe malaria continues to exert a deep-rooted impact in 109 countries and territories around the world and still constitute a leading risk factor for infant mortality and sub-optimal growth and development in spite of the global malaria elimination campaign programmes (GMECPs) that were in effect in the 1950s to the 1970s , 18\u201320.Artemisia plant extracts could kill P. berghei, a rodent malaria parasite laboratory model. The following year, she succeeded in isolating the active ingredient (qinghaosu), now part of ACT, the most important class of anti-malaria medications [In 1971, at the Pharmaceutical Institute of the Academy of Traditional Chinese Medicine, Youyou Tu showed that ications , 21. Artications , 22, 23.ications . Impressications , 24, 25.ications , 25, 26.The latest decades have witnessed substantial progress in raising awareness and increasing the production, adoption and distribution of existing effective interventions besides the use of ACTs, e.g. indoor residual spraying (IRS) and large-scale distribution of long-lasting insecticidal nets (LLINs) as prescribed by the RBM's universal coverage partnership , 27, 28.William C. Campbell and Satoshi \u014cmura discoveries proved to be a breakthrough in the tenacious fight against infections caused by roundworm parasites, mainly onchocerciasis and LF, dreaded health scourges of the most vulnerable groups of affected populations. The discovery, industrial development and implementation of the active avermectin derivative ivermectin (best known under the brand name Mectizan) led to a significant reduction of onchocerciasis in the endemic areas in central Africa and Latin America as well as of LF and scabies that are also endemic in India and Southeast Asia, thus improving the situation in vulnerable communities in low- and middle-income countries (LIMCs) , 3. In aO. volvulus, is transmitted to humans through bites of infected female blackflies (Simulium spp.). Adult worms can live up to 18\u00a0years in infected human hosts and release up to 1,000 microfilariae daily causing a variety of ailments including skin lesions due to chronic dermatitis, , rashes, intense itching, depigmentation as well as visual impairment due to eye inflammation causing corneal scars eventually leading to irreversible blindness [Onchocerciasis, transmitted by the filarial worm lindness , 32. Thelindness . The Onclindness  and its lindness , 13 at alindness . Intervelindness . As of 2lindness .O. volvulus and reduction of the burden of visual impairment and blindness have been achieved [The Onchocerciasis Elimination Program of the Americas (OEPA) was launched in 1992 under the Pan American Health Organization (PAHO) with the goal of interrupting onchocerciasis transmission in six endemic Latin American countries by 2015 . The WHOachieved , 42. Howachieved , 35, 43.Schistosoma spp. species capable of infecting humans [Echinococcus spp. [Taenia spp. that can infect the brain and muscles with its eggs and larvae (cystocercosis) and food-borne trematodes (FBTs), such as Paragonimus spp., Opistorchis spp. and Clonorchis spp. [Though not recognized for this year's Nobel Prize, the story would not be complete without mentioning praziquantel. Praziquantel, a drug that has modernized the control of schistosomiasis and many other helminth infections in the same way the ACTs and ivermectin worked for malaria and LF/onchocerciasis, respectively , 45. Prag humans , 50\u201352 tcus spp. , whose lFasciola spp., a parasitic worm preferably treated with triclabendazole (sold under trade names Egaten and Fasinex) [FBT transmission is linked to traditional customs, e.g. consumption of dishes containing raw fish, crustaceans and plants in countries where these diseases are sustained by entrenched cultural practices, which are difficult to change. FBTs affect over 56 million people infected in over 70 countries ; this fiFasinex) .Schistosomiasis is acquired through contact with water infested with cercariae, the free-swimming larval forms emanating from the intermediate snail host when infected. The microscopic adult worms live in the veins of abdominal organs, where large amounts of eggs are produced for excretion via faces or urine aimed at hatching and infecting fresh-water snails thus closing the parasite's lifecycle. Large numbers of the eggs are, however, trapped in the tissues and where immune reactions cause damage that varies from subtle to serious. Millions of people suffer from severe schistosomiasis , 44, 53,The global IDoP elimination agenda will require strengthening community, national and regional leadership and commitment to rapidly increase funding and fostering integrated multidisciplinary and inter-sectorial policies. Furthermore, scaling-up of high-impact MDA coverage of available drugs, development and implementation of new, effective vaccines and other novel approaches and tools are needed in addressing the geographical complexity of the panoply of different diseases including malaria, river blindness, LF and schistosomiasis , 57. ThiThe pharmacological and therapeutic paradigm shift discussed here calls for further, strong investments in research and development in the field of drugs and vaccines creating pipelines of new products capable of tackling the challenge of rapid emergence and spread of vectors, parasites and drug resistance. Timely, evidence-based and cost-effective operational approaches and solutions for IDoPs and NTDs are required for dealing with the rise and spread of insecticide resistance, and the environmental impact of climate change. Likewise, development of diagnostics with improved sensitivity and specificity as well as preventive therapeutics and efficient information communication/dissemination mechanisms underscore the quest for novel and innovative approaches. Leveraging on lessons learnt, efficient and integrated intersectoral partnerships as well as collaboration in the development of needed, new diagnostics, drugs and vaccines are much needed. So are also proven and innovative community-based programmes with respect to ownership in health systems, surveillance and new opportunities in elimination interventions packages and eventually in moving forward eradication of IDoP worldwide."}
+{"text": "Depression is a highly prevalent disorder that poses a significant social burden to society. Despite continued advances toward the understanding of the pathophysiology of this disease, its molecular/cellular underpinnings remain elusive, which may be at the basis of the lack of effective treatment strategies. Among the different lines of research, recent literature suggests that impaired neuron and glial plasticity may be a key underlying mechanism in the precipitation of the disorder. Surprisingly, glial cells appear to be involved both in the pathophysiology of major depression and in the action of antidepressants. In particular, several works refer to alterations in the morphology and numbers of astrocytes, microglia, and oligodendrocytes in the context of depression, in human patients, and animal models of depression. These observations are linked to functional evidences, such as impairments in the cross-talk between glia and neurons, changes in the level of neurotransmitter or immunoactive substances, myelination status, and synapse formation, maintenance or elimination.Polyakova et al. begin by suggesting the astrocytic S100B as a novel marker of minor depression, specifically in males, which could help to understand its pathophysiology. The study point outs the possible relevance of glial cells in the modulation of brain neuron-glia networks at least in some types of depression. Rial et al. explore the multiple interactions between glial and neuronal cells at the synaptic level, which may be impaired in depressive-like conditions. The authors address how purines may be used to restore synaptic efficacy by modulating glia-neuron bidirectional communication, possibly reverting depressive-like behaviors. Jo et al. discuss the importance of the glial-mediated immune modulation through cytokine signaling that may trigger depressive episodes, and Branchi et al. highlight that by participating actively in the modulation of the extracellular environment microglia are an integral part of brain plasticity and, therefore, appear to account directly for the precipitation of the depressive disorder. Brites and Fernandes point out that the disruption of secreted extracellular vesicles, an alternative form of neuro-glial signaling, may also underlie depressive behavior. Collectively the research indicates that these novel forms of neuro-glia communication may represent a novel approach for modulation of the brain networks and, thus, its manipulation may allow the development of autologous therapies for depression.This Research Topic highlights the roles played by neurons, astrocytes, and microglia in depressive disorder(s). Di Benedetto et al. suggest a link between fluoxetine modulation of aquaporin four levels in astrocytes with consequences for astrocyte morphology and re-establishment of a functional glia-vasculature interface, which may underlie its antidepressant effect. Interestingly, the decreased levels of astrocyte-specific connexin 43 (Cx43) appear to be related with antidepressant and anti-anxiolytic phenotypes as suggested by Quesseveur et al. Moreover, the authors suggest that the inactivation of Cx43 might induce beneficial effects through an attenuation of the stress response, \u201cavoiding\u201d depressive symptoms. In accordance, Jeanson et al. explored the effect of antidepressants on the functional status of astrocytic connexins, showing a complex pattern of responses that links astrocytes to the mode of action of these drugs. Exploring the use of deep brain stimulation (DBS) as an alternative for treatment-resistant depression patients, Eti\u00e9vant et al. discuss the beneficial role of astrocytes in the process based on the absence of a DBS-effect after pharmacological lesion of astrocytes.In addition to the implication of glia in the pathophysiology (and treatment) of depression, a number of studies associates glia-related pathways to classically accepted antidepressant mechanisms. Specifically, in this Research Topic, Overall, the excellent reflections and novel data sets that make up this Research Topic provide evidence for a role of glial cells, namely microglia and astrocytes, in the mechanisms underlying depression and the effect of antidepressants. Collectively, the data indicates that despite the rapid advancement of the field there is still a long way to go. The study of glial cells will continue to reveal novel and more effective therapeutic mechanisms for depression and its symptomatology.All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.JO and LP received fellowships from the Foundation for Science and Technology (FCT) and their work is funded by FCT (SFRH/BD/101298/2014 to JO and IF/01079/2014 to LP) and Bial Foundation (207/14 for JO and 427/14 for LP) projects. SV is supported by FCT (SFRH/BPD/81627/2011). CG is supported by FCT (SFRH/BPD/63013/2009). This work was co-funded by the Life and Health Sciences Research Institute (ICVS), and Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER) (projects NORTE-01-0145-FEDER-000013 and NORTE-01-0145-FEDER-000023). This work has been also funded by FEDER funds, through the Competitiveness Factors Operational Programme (COMPETE), and by National funds, through the (FCT), under the scope of the project POCI-01-0145-FEDER-007038.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Magnetic resonance imaging (MRI) is an imaging modality widely used in clinical practice.The use of MRI for imaging of the thorax, however, has been historically considered oflimited value, despite the effort of physicists and radiologists to obtain positive andreproducible results in several studies. MRI plays a role in the assessment ofcardiovascular disease, mediastinal lesions and abnormalities of the brachial plexus andchest wall. However, clinical indications are restricted to specific conditions,generally as a problem-solving technique.,2. In more recent years, however, MRI hasevolved from a research tool to a useful modality in the assessment of thoracic disease.Technical advances such as very short echo times and ultrafast turbo-spin-echoacquisitions, that allow breath-hold imaging with full anatomic coverage and help toovercome cardiac pulsation,4, have improved the capability ofthoracic MRI. The use of contrast agents for perfusion MRI and gas imaging forassessment of pulmonary ventilation have further increased the applications of MRI inthe investigation of lung diseases-8.Continuous motion from cardiac and vascular pulsation and respiratory motion are one ofthe major challenges in MRI of the chest as they severely affect imaging quality. Asignificant limitation of thoracic MRI is imaging of the lung due to intrinsiccharacteristics of the pulmonary tissue and the presence of physiologic motion. The lowproton density of the lung parenchyma generates low signal intensity and lowsignal-to-noise ratio when compared to other parts of the body. Furthermore,susceptibility artifacts at tissue-air and liquid-air interfaces of the alveoli greatlyaffect signal intensityRadiologia Brasileira, Hochhegger et al. provide a concise yet comprehensivereview of MRI of the chest. The authors convey an instructive discussion of technicalaspects and challenges of thoracic MRI, including limitations of 3T MRI in the chest,and suggest strategies to overcome some of these obstacles.In the article \"Chest magnetic resonance imaging: a protocol suggestion\", published inthe current issue of ,11 as well as theadvantages of MRI in the staging of lung cancer when compared to CT and 18-FDG-PET/CT.Various studies have demonstrated the value of MRI in the detection and assessment ofdegree of tumor invasion in the mediastinum, pleura and chest wall, thus contributing tothe T descriptor of the TNM staging system-14. The present articlediscuss the role of whole-body diffusion-weighted MRI in the detection of distantmetastases (M staging) and remark the potential role of diffusion MRI in thecharacterization of irradiated lung tissue. The authors also describe the advantages of MRI in themorphological and functional assessment of patients with pulmonary hypertension,including estimation of cardiac function as well as surgical planning,17. Importantly, the use of MRI in the diagnosis of pulmonaryembolism and in the follow up of cystic fibrosis and pneumonia are discussed-20, highlighting the importance of MRI in populations at increasedrisk of ionizing radiation complications such as young patients and in pregnancy. Recentstudies assessing the use of thoracic MRI in cystic fibrosis in particular have shownpromising results, including depiction of morphological changes as well as evaluation ofpulmonary function and respiratory mechanics,21,22. The clinical impact of an accurate ionizingradiation-free modality for a young population requiring frequent imaging assessmentcannot be underestimated.In the first part of the manuscript, the main clinical indications of MRI of the chest ispresented, including recent data regarding the role of MRI in the distinction betweenmalignant and benign pulmonary nodulesThe authors finalize the article providing a basic MRI protocol applicable to most commonthoracic diseases while also suggesting additional sequences to be used in specificthoracic abnormalities. The proposed protocols are suitable to most state-of-art MRIscanners and can be easily implemented.I commend the authors for they effort to present MRI as a valuable modality in theassessment of pulmonary diseases, increasing awareness of the peculiarities andadvantages of this modality to the radiology community as well as for providingobjective tools that can move MRI from an underutilized technique to a modality with thepotential to substantially contribute to thoracic radiology."}
+{"text": "Muscle weakness in corticosteroid myopathy is mainly the result of the destruction and atrophy of the myofibrillar compartment of fast-twitch muscle fibers. Decrease of titin and myosin, and the ratio of nebulin and MyHC in myopathic muscle, shows that these changes of contractile and elastic proteins are the result of increased catabolism of the abovementioned proteins in skeletal muscle. Slow regeneration of skeletal muscle is in good correlation with a decreased number of satellite cells under the basal lamina of muscle fibers. Aging causes a reduction of AMP-activated protein kinase (AMPK) activity as the result of the reduced function of the mitochondrial compartment. AMPK activity increases as a result of increased functional activity. Resistance exercise causes anabolic and anticatabolic effects in skeletal muscle: muscle fibers experience hypertrophy while higher myofibrillar proteins turn over. These changes are leading to the qualitative remodeling of muscle fibers. As a result of these changes, possible maximal muscle strength is increasing. Endurance exercise improves capillary blood supply, increases mitochondrial biogenesis and muscle oxidative capacity, and causes a faster turnover rate of sarcoplasmic proteins as well as qualitative remodeling of type I and IIA muscle fibers. The combination of resistance and endurance exercise may be the fastest way to prevent or decelerate muscle atrophy due to the anabolic and anticatabolic effects of exercise combined with an increase in oxidative capacity. The aim of the present short review is to assess the role of myofibrillar protein catabolism in the development of glucocorticoid-caused myopathy from aging and physical activity aspects. Glucocorticoids, well-known immunosuppressive and anti-inflammatory drugs, have unfortunate side effects upon long-term use and high doses: fast twitch (FT) muscle fiber atrophy and development of myopathy ,2. Glucoet al. [Glucocorticoids, chemically classed as steroids, are hormones that affect the metabolism of carbohydrates. These steroids have an anti-inflammatory effect, but there are also many side effects of catabolic action. The catabolic effect of glucocorticoids depends on individual tissues. In contrast to the loss of protein from skeletal muscle, bone, lymphoid tissue, and smooth muscle, there is an increase in the rate of cardiac, hepatic, and urogenital activities . The catet al. , who aboet al.  are the et al. . A decreet al.  and of tet al. , shows t\u03b1, increases adiponectin and IGF-1 concentrations, and reduces total and abdominal visceral fat [More than four decades ago it was shown that the catabolic action of corticosteroids depends on the state of functional activity of skeletal muscle . Moderateral fat . Increaseral fat  via a maeral fat . The receral fat .Over a lifespan there is a decrease of skeletal muscle mass, primarily as a result of the reduction of FT fibers , accompaMuscle fibers and myofibrils of glucocorticoid-caused myopathic glycolytic muscle are thinner in comparison with the control group and disappeared completely from one fifth of the area of myofibrils of myopathic muscle myosin filaments . The intDuring ageing muscle strength decreases significantly; for example, the hindlimb grip strength in old rats decreases by about 50% due to sarcopenia . GlucocoProtein degradation, particularly myofibrillar protein degradation, is typical for glucocorticoid myopathy. Protein degradation in skeletal muscle fibers, particularly in FT fibers with low oxidative capacity, is mediated by the activity of the ubiquitin\u2013proteosomal and the lysosomal pathways . The actIn the case of corticosteroid myopathy, sarcopenia, and cachexia, the molecular mechanisms of regulation of muscle, metabolism, and induced wasting disorder-related skeletal muscle atrophy is almost similar. Cachexia is characterized by the loss of adipose tissue as a result of an imbalance in lipogenesis and lipolysis, with enhanced lipolysis supported by neuroendocrine activation and tumor-related lipolytic factors .The central question is how to prevent or decelerate skeletal muscle atrophy in the elderly and glucocorticoid myopathic patients. Aging causes a reduction of AMPK activity as the result of reduced function of the mitochondrial compartment . AMPK acMuscle weakness in corticosteroid myopathy is the result of destruction and atrophy of fast-twitch muscle fibers and their myofibrillar machinery. The disappearance of one fifth of myosin filaments from myofibrils and a decrease in MyHC IIb isoform relative content are the reasons for decreased muscle strength and motor activity in the case of corticosteroid myopathy. The higher the degree of muscle atrophy, the lower the muscle elasticity and the higher the tone. A decrease in titin and myosin, and in the ratio of nebulin and MyHC in myopathic muscle, shows that these changes of contractile and elastic proteins are the result of increased catabolism of these proteins in skeletal muscle. Both glucocorticoid-caused myopathic and aging-caused sarcopenic muscle wasting is mainly a result of the decrease and atrophy of fast-twitch muscle fibers. In both cases, the myofibrillar protein synthesis rate decreases. Slow regeneration of skeletal muscle is in good correlation with a decreased number of satellite cells under the basal lamina of muscle fibers. Aging causes a reduction of AMPK activity as the result of reduced function of the mitochondrial compartment. AMPK activity increases as a result of increased functional activity. Resistance-type muscle activity causes anabolic and anticatabolic effects in skeletal muscle: muscle fibers hypertrophy and myofibrillar proteins turn over faster. These changes are leading to the qualitative remodeling of fast-twitch muscle fibers. As a result of these changes, muscle strength is increasing. Endurance-type muscle activity improves capillary blood supply, increases mitochondrial biogenesis and muscle oxidative capacity, and causes a faster turnover rate of sarcoplasmic proteins as well as qualitative remodeling of type I and IIA muscle fibers. As both muscle strength and endurance decrease in the elderly, particularly during glucocorticoid administration, the combination of endurance and resistance training may have the best rehabilitative effect."}
+{"text": "The Manchester Synthetic Biology Research Centre (SYNBIOCHEM) is a foundry for the biosynthesis and sustainable production of fine and speciality chemicals. The Centre's integrated technology platforms provide a unique capability to facilitate predictable engineering of microbial bio-factories for chemicals production. An overview of these capabilities is described. By harnessing the power of predictive SynBio methods, SYNBIOCHEM is driving next-generation sustainable manufacturing processes that are appropriate and commercially relevant for scale-up across many industrial sectors .The Manchester University Synthetic Biology Research Centre (SBRC), SYNBIOCHEM (http://www.mib.ac.uk/) and builds on the MIB's core strategy of uniting teams of interdisciplinary scientists and industrial partners to deliver challenge-led innovation in bio-based chemicals and broader industrial biotechnology sectors. SYNBIOCHEM also builds on a long-term vision and commitment by the University of Manchester in sustainable Industrial Biotechnology, leveraging and integrating world-leading capabilities in MIB Centres of Excellence including: Biocatalysis, Biotransformation and Biocatalytic Manufacture (CoEBio3); Manchester Centre for Biophysics and Catalysis (MCBC); Manchester Centre for Integrative Systems Biology (MCISB) and the Michael Barber Collaborative Centre for MS (MBCMS). SYNBIOCHEM was established in 2014 funded jointly by the U.K. Biotechnology and Biological Sciences Research Council, the U.K. Engineering and Physical Sciences Research Council and The University of Manchester. Led by three directors  the Centre unites a complementary team of SynBio researchers at Manchester in pursuit of SynBio solutions that will deliver wider access to chemical diversity and more rapid and predictable delivery of chemical targets for scalable production/manufacturing. The interdisciplinary team includes not only chemists, biologists and computer scientists, but also investigators from the Manchester Institute of Innovation Research and the School of Social Sciences contributing insight of RRI relevant to the Centre activities. A key challenge includes consideration of the societal impact of SYNBIOCHEM research activities to ensure that the Centre anticipates, prepares for and, if necessary, mitigates the impact of SynBio technology in the wider society, economy and environment [SYNBIOCHEM is located in the Manchester Institute of Biotechnology (MIB; SYNBIOCHEM has established state-of-the-art and fully integrated Design/Build/Test technology platforms for bio-based chemicals production . The plaSYNBIOCHEM has an open and collaborative culture with a strong emphasis on building academic and industry partnerships, both at the national and international levels. Industrial foresight and awareness coupled to translation of SYNBIOCHEM discovery science and technology towards commercial exploitation are at the core of the Centre's strategy. The Centre hosts regular open meetings in a variety of formats, enabling one-to-one discussions with industrial partners, the development of new collaborative projects with external stakeholders, and through an industry club for joint supervision of research studentships in projects that address scientific problems of interest to the club members. Early SYNBIOCHEM programmes have resulted in protection of new intellectual property for the development of tools and microbial factories/hosts relevant to the production of pravastatin , biosynthttp://synbiochem.co.uk.In summary, SYNBIOCHEM is addressing major challenges in SynBio through a foundry concept and an open collaborative ethos with external partners. The Centre's integrated technology platforms provide a unique capability to facilitate predictable engineering of microbial bio-factories for chemicals production. Further information about the Centre and routes to collaboration can be obtained from the SYNBIOCHEM website:"}
+{"text": "This paper presents, from the perspective of technological development andproduction, the results of an investigation examining 61 clinical studies withvaccines conducted in Brazil between 1938-2013, with the participation of the OswaldoCruz Institute (IOC) and the Oswaldo Cruz Foundation (Fiocruz). These studies havebeen identified and reviewed according to criteria, such as the kind of vaccine, their rationale, design and methodological strategies.The results indicate that IOC and Fiocruz have accumulated along this timesignificant knowledge and experience for the performance of studies in all clinicalphases and are prepared for the development of new vaccines products and processes.We recommend national policy strategies to overcome existing regulatory and financingconstraints. Clinical studies are crucial for the development and registration of new products andconstitute today a structured process, mandated by strict legislation involving a growingnumber of participants, in a stepwise strategy.The Oswaldo Cruz Institute (IOC) and the other technical units which constitute the OswaldoCruz Foundation (Fiocruz) are recognised as very important institutions for basic scienceand biological and technological research on tropical diseases in Brazil. Theseinstitutions have a long tradition of clinical studies which have proven to be vitallyconnected to the prevention of infectious diseases of public health importance for Braziland other countries. In this paper, we review and analyse these studies, occurring over aperiod exceeding seven decades, from the perspective of technological development (TD). Theunderstanding, in a historical sense, of the evolutionary stages of these clinical studieswill hopefully provide a better understanding of the processes that were involved and mayhelp policy and decision-makers to conceive of new alternatives and create possibilitiesfor the design of new studies in the future.For the selection of the clinical studies we adopted the following criteria forinclusion: (i) studies conducted in human beings; (ii) prospective; (iii) vaccination asthe basic intervention; (iv) longitudinal and individual follow-up of participants; (v)published in scientific medical journals; (vi) conceived and conducted according toethical and legal criteria for clinical research in human beings, with tolerance to theabsence of formal ethical and regulatory evaluations regarding the older studies; (vii)conducted with participation of at least one unit or professional of Fiocruz/IOC.These restrictive criteria, besides being conceptually acceptable, met the requirementto limit the scope of the research within an acceptable range. Studies which did notmeet these criteria were excluded. These included retrospective studies,clinical-epidemiological studies, seroepidemiological studies, pharmacovigilance studiesand observational studies. Although the latter did not fit into the classical model ofclinical studies, some of them could be classified as clinical studies, in a broadersense definition.For studies conducted at the origin of IOC, which are outstanding and part of itshistory, these criteria were not strictly applied, which is justifiable, consideringthat the legislation on clinical studies came later. However, if they are not formallyperfect, they have been conducted ethically, with the best science and methodologyavailable at the time.The search for papers was done by databases, including PubMed, from the National Centerfor Biotechnology Information, National Institutes of Health, United States of America,and LILACS, the Latin-American database from BIREME-Regional Library of Medicine, fromPan American Health Organization (PAHO)/World Health Organization (WHO). However, mostpapers were found through personal archives, consultations with colleagues, somereference books on the history of vaccines  and otheTo recover original papers, we used, besides PubMed and LILACS, the SciELO database,Capes Periodicals Gateway and the libraries of the National School of Public Health,Bio-Manguinhos/Fiocruz and Mourisco Castle. Photocopies were also obtained from theHinari Programme, from WHO and Oxford Journals.We use terms \"clinical trial\" and \"clinical study\" interchangeably.The period of study extended up to the year 2013 .The clinical studies with vaccines under the scope of IOC and Fiocruz, besides theirrelevance to the public health of Brazil and many other developing countries, havecontributed to the institutional TD.These technical advances built institutional knowledge and skills in vaccinethermostability, new freeze-drying formulation, use of certified inputs, improvement ofquality control methodologies and the skills to incorporate new products throughtechnology transfers, which resulted in scientific breakthroughs and have been landmarksof Fiocruz history.Haemophilus influenzaeType b (Hib) vaccine, measles/mumps/rubella (MMR) androtavirus vaccines [GlaxoSmithKline (GSK)] and shortly themeasles/mumps/rubella/varicella (MMRV) vaccine . Besides leading to theintroduction of new vaccines into the NIP, in a relatively short time, technologytransfers of these vaccines have made possible the creation, expansion and improvementof new platforms, production and laboratories and the creation of a qualified workforcethat is now a most valuable asset of Fiocruz. The positive consequences of theseinnovative processes have been outstanding and should not be minimised. Moreover,transfer of technologies has been feasible because of the intrinsic capacity of theinstitution for absorbing, in a relatively short span of time, the newly involvedtechnologies.Examples of tech transfer include the yellow fever (YF) vaccine (Rockefeller Institute),the polysaccharidic AC meningococcal vaccine (Institut M\u00e9rieux), the poliomyelitis andmeasles vaccines (BIKEN Institute), the The clinical studies of measles vaccines were conducted to evaluate the successfultechnology transfer and implement the regular use of a vaccine to counteract one of themain causes of child mortality in Brazil . The tecThe clinical studies with poliomyelitis vaccines and many additional seroepidemiologicalstudies resulted in changes and improvements in vaccine composition and eventuallyresulted in the elimination of this disease in Brazil and many other Latin Americancountries.oral polio vaccine (OPV) technologywas obtained under the umbrella of the Brazil-Japan Cooperation Agreement. Thetechnology transfer for this vaccine came through the Japanese Poliomyelitis ResearchInstitute. These actions included redesigns and upgrades of facilities, provision ofequipment, \"on the bench\" training within production laboratories, quality control andneurovirulence testing in nonhuman primates. The creation of this highly qualified groupin 1982 allowed Bio-Manguinhos to take the responsibility for the quality controltesting of the OPV vaccine used in the national routine immunisation program or in masscampaigns. Later, this responsibility was transferred to the National Institute forQuality Control. Another great contribution from Bio-Manguinhos was the formulationimprovements of OPV vaccine, including a doubling of the dose of type 3 OPV, required tocontrol poliomyelitis outbreaks in Northeast Brazil. This formulation change wasaccomplished in just two weeks after the decision was made. The highly satisfactoryresults led the PAHO to extend this recommendation to all Latin American countries and,afterwards, WHO recommended the use of the same formulation for all countries.As with the measles vaccine, the The clinical studies with diphtheria, tetanus and pertussis/Hib vaccine drove thetechnology transfer for the Hib portion of the vaccine. This resulted in theintroduction of this vaccine into the routine vaccination schedule, which, in a veryshort time, drastically reduced the incidence of Hib meningitis.Plasmodium falciparum , which needs better protection, and for pertussis and YF, which needimproved safety.Although some of the achievements have been remarkable, we should recognise thatinnovations at IOC and Fiocruz have been incremental and did not change paradigms . The innThe results presented here indicate that, over the last several years, there have beenconsiderable quantitative and qualitative advances in the development of clinicalstudies under the scope of IOC and Fiocruz. These demonstrate that clinical studies nolonger constitute a bottleneck for innovation, in terms of local capacity. However,regulatory and financial constraints still remain. There are also regulatory andoperational issues that need to be addressed, in order to streamline processes withoutloss of safety and quality. Slow decision-making and excessive centralisation ofregulatory and ethical processes may, in fact, decrease the quality of studies and mayresult in loss of opportunities in a competitive world.It should be noted that, although not reviewed here, several clinical studies withmeningococcal vaccines have been conducted at Bio-Manguinhos/Fiocruz, of which threehave been Phase I studies and published in congress annals , b,2010Although several new innovative vaccines are in development, their complexity isincreasing and will certainly require creativity and scientific and technologicalcapacity to achieve a final product.It should also be stressed that if we have been weak in technological innovation so farin Brazil, we have been innovators on the ethical concept that vaccines are a right ofcitizenship and that all people should have free access to them, as to basic sanitaryservices and education. The vaccine schedule of the Ministry of Health has significantlyexpanded and now includes all vaccines used by developed countries . MoreoveThe contribution of vaccines for the improvement of health conditions of the Brazilianpopulation is evident and outstanding. The infectious diseases targeted by vaccination(except TB) are under control. The Brazilian producers of vaccines made these conquestspossible and the clinical studies with vaccines have been an essential part of thisprocess.The review of clinical studies under the scope of IOC and Fiocruz within the period ofthis study indicates the strength and potential of IOC and Fiocruz to conduct all phasesof clinical studies with vaccines. However, the innovation component is still weak andshould be strengthened. To achieve this objective as well as to accelerate the TD of newand innovative vaccines, we suggest: (i) the urgent development of a new legal andinstitutional framework for Bio-Manguinhos/Fiocruz, allowing flexibility and capacity toproduce and to operate in the market. It is necessary to conciliate social commitmentwith speeding up of processes and entrepreneurial capacity, which are essential toindustrial activity and technological competitiveness; (ii) to stimulate intra and interinstitutional partnerships and the exchange of personnel, nationally andinternationally; (iii) to stimulate group and personal cooperation through meetings andcommon projects; (iv) to promote public-private partnerships, leading to technologytransfers, to search for common development of new products and processes; (v) tostimulate innovation and creativity; (vi) to attract new talent, creating an inspiringand receptive atmosphere and environment to innovation and creativity; (vii) to searchfor expertise, wherever it may reside, to solve the technological and organisationalproblems of Bio-Manguinhos/Fiocruz; (viii) to increase the governmental financing forclinical studies and to stimulate the non-governmental financing; (ix) to stimulateexcellence, at all levels."}
+{"text": "Ultrasongraphy (US) is a powerful diagnostic imaging tool for evaluating musculo-skeletal disorders in children. US is relatively cheap, non invasive and does not require sedation thus it is generally well-tolerated. Lack of ionizing radiation and dynamic imaging capabilities are significant advantages compared to CT and MRI too.US is ideally suited to the evaluation of the bone, cartilage and soft-tissue structures, including tendons and ligaments, joints and muscles .The combined use of new generation high frequency transducers and of Power Doppler increases the diagnostic accuracy of US.US is widely used in the diagnosis of hip disorders in children . In deveBesides hip\u2019s disorders, US can be employed in many other pathological conditions of the pediatric musculoskeletal system, including congenital, infectious, neoplastic and inflammatory disorders . ParticuIn acute osteomyelitis US is able to identify early abnormalities in the soft tissues overlying the bone just few days after the onset of symptoms before the appearance of radiographic signs. As infection progresses, US can depict interruption of the cortical profile related to bone destruction and diffuse involvement of subcutaneous tissue with formation of abscesses.Due to the peculiarities of the growing skeleton, the knowledge of musculoskeletal pediatric anatomy and especially of growth-related changes in healthy children is extremely important in establishing whether the US findings reflect pathology or are part of normal development ."}
+{"text": "Indirect contact transmission is considered as the most common mechanism of transmission of microorganisms in healthcare environments. Contaminated medical devices, equipment and surfaces in the environment of the dental surgeries are applied as a vehicle. Microbial contamination (bioburden) of medical devices from the category of critical, semicritical and non-critical was monitored in orthodontic surgeries in this project.The file included 11 dental chair units in Department of Orthodontic, Faculty of Medicine and Dentistry, Palack\u00fd University Olomouc and 11 dental chair units in private orthodontic surgeries. Dental chair units belongs to the category of non-critical medical devices and at the same time is defined as \"patient zone\" there is applicated \"My Five Moments for Hand Hygiene-Dental Care\".Swabs were taken from the following places: headrest, hand lights, armrest, spittoon, terminal of a rotary tool, control panel, and hand control of doctor's chair. orthodontic bands and wires belong to the category of critical medical devices. Orthodontic pliers belongs to the semicritical category of medical devices. Microbial contamination of the above mentioned medical devices was monitored by using of cotton swabs and cultivation in liquid and solid culture medium.Public orthodontic surgeries: Orthodontic bands and wires which included to the critical category of medical devices were contaminated in one case by coagulase-negative staphylococcus.Pseudomonas aeruginosa, from the group of gram-negative bacteria, was demonstrated the most often. Microscopic filamentous fungus Aspergillus sp. was demonstrated from spittoon in one case.Private orthodontic surgeries: Staphylococcus aureus was demonstrated in two cases in the private surgeries on the surface of semicritical medical devices (orthodontic pliers). It is very necessary to follow the recommendations for disinfection or sterilization of the above mentioned critical and semicritical category of medical devices.The public medical facility has a higher incidence of coagulase-negative staphylococcus in category of critical  and semicritical medical devices. None declared."}
+{"text": "Treatment system planning and resource allocation is hampered by the lack of systems-level data and planning frameworks. We developed and pilot-tested a needs-based planning model for substance use services and supports that aligns with the estimated needs of the population of local health regions, takes a broad systems approach beyond the specialized sector, and yields estimates of required treatment capacities for service categories along the continuum of care.Using national population survey data, we estimated, for 94 regional planning areas in Canada, the number of people in need of substance use treatment within a given year, based on five \u2018tiers\u2019 of problem severity. We then estimated the probable help-seeking population for each level of severity, based on a synthesis of the literature. Working with a national expert consensus panel, we estimated the optimal trajectory of clients across several defined categories of treatment services organized by level of care. Integrating steps 1\u20133 yielded the number of people to plan for in each service setting. We piloted the model in nine Canadian jurisdictions, conducting gap analyses that compared the projected and actual service utilization, and supplemented by stakeholder feedback and local indicators of need, such as wait lists and referral data.The model development process and gap analyses at the nine pilot sites yielded important results for local planners, but with national implications. Results indicated that the capacity of moderate-intensity services is adequate in many regions, but that larger gaps exist in low-threshold services  and high-intensity services , providing opportunities for international knowledge exchange."}
+{"text": "Over the past two decades, improved diagnosis, pharmaceutical therapies, and interventional strategies have impressively improved the armamentarium of modern cardiologists in the fight against the most incident and lethal diseases: heart failure, ischemic heart disease, and arrhythmia. The innovations in the field have mostly been enabled by inventions based on hypothesis-driven approaches. The invention and development of key cardiac biomarkers, such as natriuretic peptides and cardiac-specific troponins, may serve as examples. Based on few candidate molecules, the discovery of these markers requires neither high-throughput molecular screening, nor advanced computational methodologies for interpretation and refinement of results.e.g., age, body mass index, and kidney function) in such trials rather neglect the individuality of patients and their diseases. Hence, it is pivotal to enhance the characterization of prevalent and incident cardiovascular diseases, and either better select the appropriate therapy for the individual patient or define the personal drug target in a single patient.What has changed such that authors of this Special Issue on Computational Cardiology propose the requirement of a structured interaction of clinical, molecular, and bioinformatics experts? Evidence-based changes that have been implemented into current guidelines of cardiovascular medicine are mostly due to large-scale randomized clinical trials. Although this approach was hugely successful to improve prognosis of patients, in the future the treatment and outcome net-benefit expected from additional or refined treatments are predicted to become smaller and smaller. To further improve the management of heart disease, it is therefore important to increase personalization of new approaches. While the intricate power of statistics in randomized trials is obvious, the less than handful selection and phenotyping criteria  for existing and upcoming pharmacotherapies and cardiac interventions;\u2022a real-time approach for data integration in the hospital setting and usage of big data on a population level;\u2022prevention of disease by early identification of health hazards;\u2022endorsement of health economic approaches in high-burden diseases, such as heart failure;\u2022improvement of point of care phenotyping and decentralized patient care to relieve the hospital setting;\u2022e.g., that are suited for gene repair;definition of new or personal drug-targets, \u2022automated monitoring of novel treatments for the early detection of treatment success and side effects.One could list the selected foreseen challenges and roles of computational cardiology including:Based on these fields of future innovations, the vision of the future of precision medicine demands for far more than rocket science, namely the simulation of molecular pathways, cells, tissues, organs, and whole organisms. The ignition will be set by advances in molecular and clinical phenotyping in conjunction with the recent developments in bioinformatics methods for integration of multi-level high-throughput and high-content datasets with clinical data. This will pave the way for integrative approaches for patient care in the real sense of personalized medicine.In this Special Issue on Computational Cardiology, we cover some of the exciting insights into new approaches toward a more personalized patient care using computational means. The authors highlight the importance of biobanks and comprehensive data resources, building the basis for future developments of diagnostics and potentially more targeted therapies The authors have declared no competing interests."}
+{"text": "The following Acknowledgements statement is missing from the published article:The authors thank Mani Vembar, CT Clinical Science, Philips Healthcare, Cleveland, Ohio for his comments and suggestions in the preparation of this manuscript."}
+{"text": "The standards of scholarly publications are evolving to meet the ever-growing demands of digital communications globally. Current authors, reviewers, editors, and publishers face numerous challenges, which can be overcome through Continuous Professional Development (CPD) aimed at advancing skills in research reporting and communicating with the global scientific community. The best scientific traditions nurtured by research and academic institutions in the Russian-speaking world over the past centuries may add to the quality of publications in the rest of the world. Conversely, the recent achievements in the systematization of scientific evidence and proper research reporting, made in Anglophone countries, are of great interest to the Russian counterpart, entering the global research competition.European Science Editing journal, and translated the EASE guidelines for authors, which is now the main reference for most Russian-speaking authors from Russia and other European and Asian countries.With that in mind, the Russian Regional Chapter of the European Association of Science Editors (EASE) organized its first seminar on science communication in Moscow on March 25, 2014 . It was chaired by Associate Professor, Dr Sergey V. Gorin and attended by a multidisciplinary group of researchers, journal editors, and experts in bibliographic databases from several leading Russian academic and research institutions in Moscow, Perm, Ryazan, and Yaroslavl. Dr Sergey Gorin opened the Seminar by presenting its aim and introducing lecturers. The aim was to improve research reporting and communication skills of Russian-speaking authors, reviewers, and editors and to facilitate their networking with collaborators from the English-language scientific journals and editorial associations such as EASE. The Russian chapter of EASE already arranged a regional meeting in 2013, published a paper in the The first lecturer, Member of The Russian Academy of Natural Sciences, President of The League of Professional Image Makers, Prof Viktor M. Shepel reflected on philosophy of culture of scientific publications and shared his life-long experience of evaluating style and structure of multidisciplinary research publications. Prof Shepel emphasized the importance of novelty, creativity, and courteous style of research writing. Easily understandable and logical flow of ideas, correctly elaborated hypotheses, as well as brevity and evidence-based writing are all indicative of high culture of the authors. The authors who do not properly use scientific terms and excessively rely on professional slang distract the non-expert readership. Unfortunately, not all researchers are skilled to present details of methodology applicable to the concrete circumstances and aims of their research, which complicates the evaluation of the papers, particularly those written by PhD candidates. The authors should analyze and report whether the materials used for their studies are representative enough for the generalization of the results. Finally, each paper should have a limited, logically justified number of references to link each statement with a relevant scientific evidence or fact. Overly citing literature sources or quoting words of wisdom of eminent scientists do not allow the readership to judge the style of the authors. Generally, Russian-speaking researchers are modest in expressing their own style of writing and expressing ideas, and are too often critical toward their own research work.http://elibrary.ru/), still do not have strict criteria for calculating research performance indicators. This is why the interpretation of the citation counts and related indicators is often prone to bias. The lecturer also touched upon some rampant cases of plagiarism in Russian papers and its detection by reviewers and science editors. The plagiarism-detection software currently employed by journal editors calculates quantitative indicators that do not reflect the real picture of scientific misconduct. Plagiarism in research grant applications still goes unnoticed by most research evaluators. Some Russian scholarly journals lack traditions of peer review, which leads to a wide variability of its models across periodicals. Strangely, there are journal editors who consider \u201coral peer review\u201d as viable as the written models.The second talk was given by Prof Oleg S. Sukharev from the Institute of Economics of the Russian Academy of Sciences. He discussed the current standards of scholarly journal and book publishing, and criticized the widespread \u201cobsession\u201d with the numbers of papers at the expense of their quality. Monographs and other types of books are becoming increasingly unpopular among the authors because of the inappropriate crediting system and unnecessary prioritization of the long lists of publications and large citation numbers. Prof Sukharev reminded the audience of the long-forgotten principle \u201cbetter fewer, but better.\u201d He was also critical of ranking journals based solely on citation indicators and distinguishing the so-called elite journals. Many ground-breaking research papers are not highly cited despite having true impact on science and bringing prestige and even Nobel prizes to their authors. Moreover, not all citations in research papers are correct and relevant. Citation databases, and particularly the Russian Index of Scientific Citations (http://www.ease.org.uk/publications/impact-factor-statement) and the San Francisco Declaration of Research Assessment (http://am.ascb.org/dora/). He stressed the importance of opening access to scholarly publications, which may increase their influence on the global scientific progress. At the same time, Dr Gasparyan referred to the increasing number of retractions in English-language journals, which is largely due to their accessibility through the free full-text digital libraries and repositories. The subscription to periodicals and the distribution through the regular postal services are no longer capable of meeting the increasing demands of updated scientific information worldwide. Digitization, which includes the assignment of Digital Object Identifiers (DOIs), XML encoding for permanent archiving and preservation of scientific literature, indexing and posting full-texts of journal articles on digital platforms, is the requirement of the \u201cbig science\u201d era. Many journals from non-Anglophone countries may improve their visibility and attractiveness for the global scientific community by following the best examples of online journals from Anglophone countries. That said, the authors should be also aware of the \u201cpredatory journals and publishers,\u201d which are listed by Jeffrey Beall on his blog (http://scholarlyoa.com/). The blog contains information on unacceptable practices, which corrupt the open access and waste the authors\u2019 efforts.The second session of the Seminar was run by Associate Professor, Dr Armen Yuri Gasparyan, who presented functional characteristics of bibliographic databases and search platforms, analyzed journal impact indicators, and introduced the EASE Statement on Inappropriate Use of Impact Factors . Prof Zhanna \u0410. \u041cingaleva , Prof Svetlana A. Gusar , Olga V. Kirillova (NEICON School in Moscow), and Elena V. Karpunina (Intereconom Publishing) shared their thoughts on the visibility of Russian journals in international bibliographic databases and reassured that most regional journals are now correcting format of references and upgrading standards of peer review and ethical publishing, which will be helpful for indexing in the future.All the lectures were thoroughly analyzed and commented on by the Seminar participants at the roundtable discussion. The participants were encouraged by Dr Gasparyan to submit their best papers to the journals with wide visibility and international outreach. Some exemplary journals were discussed in detail (eg, The Seminar participants were awarded with certificates credited with CPD credits in research methodology and communication. It was decided to arrange such seminars with international participation annually to discuss matters arising across multidisciplinary journals and to advance science communication skills of non-native English-speaking authors, reviewers, and editors of regional journals."}
+{"text": "There is an urgent need to build Research and Development (R&D) capacity for leishmaniasis and other neglected tropical diseases (NTDs) in the Middle East and North Africa.The neglected tropical diseases are a group of 17 viral, bacterial, protozoan, and helminthic infections that often have high morbidity but low mortality, causing disabilities through their impact on child development and education, pregnancy outcomes, and worker productivity [Leishmania is the most important protozoan infection in the MENA region [NTDs promote poverty and interfere with economic development. Emerging information indicates that the Middle East and North Africa (MENA) region is highly endemic for several NTDs, with increasing levels of poverty and disease in the region . Today, A region . Rapid uA region . Among tA region .http://www.afro.who.int/), have been successful in MENA countries, many have not received such attention.Globally, compared to HIV/AIDS, malaria, and tuberculosis, which receive 42.1% of the funds allocated to overseas development assistance for health, NTDs have generally been ignored, receiving only 0.6% of the budget . StudiesA similar level of neglect for both mass treatment of and R&D for NTDs has been noted for MENA countries. The World Health Organization (WHO) reports that mass drug administration coverage for many NTDs in MENA is low. For instance, the coverage for soil-transmitted helminthic infections in the WHO Eastern Mediterranean Region is less than one-half the coverage in sub-Saharan Africa . In addiAs mentioned previously, leishmaniasis represents a good case study of the challenges facing control of NTDs in MENA. Today, MENA countries exhibit some of the highest incidences of cutaneous leishmaniasis globally , with woIn addition to conferences, by establishing regional R&D and training centers of excellence in the MENA region, we could promote and build long-lasting research skills and capacities and enhance the contribution of research to the control and elimination of NTDs. One such center was suggested recently for southern Europe , but a pLeishmania major), and the second-highest prevalence of anthroponotic cutaneous leishmaniasis (Leishmania tropica infection) [Iran is one of the MENA countries with the highest prevalence of zoonotic cutaneous leishmaniasis (fection) . With mofection) . There aIn the coming years, geopolitical events taking place in the MENA region could promote the emergence or re-emergence of widespread NTDs. Now, more than ever, we need to re-examine the necessity to strengthen and expand existing programs for the control of NTDs in MENA, through improvement of mass treatment coverage for these diseases and identification of innovative ways to enhance R&D capacity in the region."}
+{"text": "The aim of tissue engineering is to promote the repair of functional tissues. For decades, the combined use of biomaterials, growth factors (GFs), and stem cells has been the base of several regeneration strategies. Among these, biomimicry emerged as a robust strategy to efficiently address this clinical challenge. Biomimetic materials, able to recapitulate the composition and architecture of the extracellular matrix, are the materials of choice, for their biocompatibility and higher rate of efficacy. In addition, it has become increasingly clear that restoring the complex biochemical environment of the target tissue is crucial for its regeneration. Toward this aim, the combination of scaffolds and GFs is required. The advent of nanotechnology significantly impacted the field of tissue engineering by providing new ways to reproduce the complex spatial and temporal biochemical patterns of tissues. This review will present the most recent approaches to finely control the spatiotemporal release of bioactive molecules for various tissue engineering applications. Although approved by the US Food and Drug Administration (FDA) in 2002, the high doses of rhBMP-2 used by this device resulted in major adverse side effects, including cancer, spinal cord compression from soft tissue swelling, spinal cord impingement from ectopic bone formation, elevated bone resorption from osteoclast activation, and preferential induction of adipogenesis over osteogenesis   interactions between cells and the extracellular matrix (ECM) have been proven to be crucial to orchestrate tissue formation and regeneration in response to injury. Materials such as hydrogels and scaffolds engineered to emulate the ECM can support tissue healing Hoffman, .Three-dimensional patterning has been defined as the entrapment of biochemical  (PLLA) scaffolds loaded with rhBMP-7 enhanced osteogenesis. Kim et al.  (PLGA) for the controlled release of small bioactive molecules (Pandolfi et al., m et al.  accompliInterface tissue engineering focuses on the development of tissue grafts capable of replacing defective interfaces, such as ligament-to-bone, tendon-to-bone, and cartilage-to-bone (Almod\u00f3var et al., in vitro 2D cell cultures, which fail to reproduce tissue complexity. Recently, 3D cultures on biomimetic materials mimicking the ECM microenvironment are becoming the in vitro models of choice to study the regenerative process of specific tissues. 3D biomimetic cultures are more physiologically relevant than those in 2D and simpler than in vivo models (Hoffmann and West, Most of the current understanding of the regenerative process is based on the use of simplified in vivo (Lee et al., in vitro and in vivo (Gelain et al., Recently, in a very elegant study, the Anseth research group proposed an RGD patterned hydrogel, synthesized through a versatile process of sequential bio-orthogonal click-chemistry reactions (DeForest et al., In vivo, the transient nature of GF signaling is combined with the slow, sustained signals received from the ECM (Lund et al., de novo matrix deposition (Kim et al., However, in the natural ECM, cells not only respond to signals presented on the surface of the ECM but also to soluble stimuli, especially in the regeneration process. Usually, these factors diffuse through the ECM and bind to their specific receptors on cells\u2019 surface, activating specific transduction cascades. in vivo. Altogether, the studies herein reviewed show the potential of 3D biomaterials spatiotemporally patterned with bioactive molecules to recapitulate the complex biochemical milieu of target tissues.In the past decade, significant advances have been accomplished in the design of biopatterned materials able to accomplish temporally and/or spatially controlled release of bioactive molecules. Despite these advances, methods should be further developed to prepare patterns and gradients with controlled shape and kinetics, in order to tune the desired cell mechanisms SM and FT conceived the idea of this review. SM wrote the Abstract, Introduction, and Conclusion sections. LP drafted the first paragraph, FT drafted the second paragraph, and SM and FT revised and finalized the mini-review with the help of ET.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "One of the major concepts of modern epidemiology and disinfectology is prevention and fighting with healthcare-associated infections (HAI).Prophylaxis of HAI in Russia.Epidemiological, statistical.It is one of the largest documented chronic outbreaks of Nosocomial Salmonellosis in the world which occurred (1994-1996) at the big multi-speciality hospital with more than 1,500 beds. The outbreak was active for approximately 3 years and more than 350 surgical and intensive care unit patients fell ill. At that point in time it was impossible to eliminate the outbreak by means of traditional antiseptics and antibiotics used for patients\u2019 treatment.2 of healthcare organization areas. Phagoprophylaxis schemes of patients found in NS effective disease area and undergoing treatment at in-patient hospital, and sanitation and phagoprophylaxis of stuff were developed and described by the author for the first time.For the first time ever in global practice adapted salmonella bacteriophage was used in a combined manner for treatment of NS patients (83 people), phagoprophylaxis of patients admitted to the in-patient hospitals and undergoing treatment there , sanitation and phagoprophylaxis of staff , and biological disinfection of more than 15,000 mThe method of Salmonella Bacteriophage combined use was highly effective, harmless, non-toxic while treating patients with salmonellosis at surgical and intensive care units, it allowed performing effective disease prevention in risk groups and sanitation of staff, it was cost-effective and highly effective in decontamination of surfaces and objects in medical organization. Combined use of adapted salmonella bacteriophage allowed isolating and eliminating of long-existing effective disease area of Nosocomial Salmonellosis for 3 months from the time of bacteriophage\u2019s application.None declared."}
+{"text": "With contributions from USA, Taiwan, Japan, and Korea, this special issue holds great insight. This special issue offers comprehensive knowledge on chitosan and collagen as biomaterials, especially with respect to their basic biological and chemical properties, as well as clinical applications. Two review articles described the preparation and biological application of chitooligosaccharide and its derivatives and the relevance to clinical dentistry of distinct characteristics of mandibular bone collagen. Original articles reported seven experiments: 3 chitosan topics and 4 collagen topics. The former demonstrated the contributions for a proteomic view of chitosan nanoparticle to hepatic cells, the promotion of D-glucosamine to transfection efficiency, and chitin application as skin substitutes. The latter showed the contributions for hydroxyapatite-gelatin nanocomposite, genipin modification of dentin collagen, dentin phosphophoryn/collagen composite for dental biomaterial, and biological safety of fish collagen."}
+{"text": "Human albumin is used for volume expansion and resuscitation and to correct hypoalbuminemia . HypoalbAlbumin mobilizes polyunsaturated fatty acids (PUFAs) from the liver and other tissues, and thus enhances the formation of cytoprotective bioactive lipids \u2013 lipoxins, resolvins and protectins \u2013 that, in turn, suppress production of proinflammatory prostaglandins, free radicals and cytokines. The beneficial actions of albumin thus depend on its ability to mobilize PUFAs and the formation of adequate amounts of lipoxins, resolvins and protectins. For those who have hepatic and tissue deficiency of PUFAs, albumin fails to mobilize PUFAs and formation of lipoxins, resolvins and protectins will be inadequate, which may explain failure of the beneficial actions of albumin in the critically ill.The cell membrane is rich in PUFAs  that give rise to both proinflammatory prostaglandins, thromboxanes and leukotrienes and anti-inflammatory lipoxins, resolvins and protectins  see Fig. BalancePlasma concentrations of TNF\u03b1, interleukin (IL)-6 and macrophage inflammatory protein-2 were significantly lower and the IL-10 concentration higher in the albumin-treated hemorrhagic shock model animals . HypoalbTNF\u03b1 administration to healthy well-nourished rabbits produced hypoalbuminemia  and endoBased on the preceding discussion, I propose that PUFAs need to be administered along with albumin to enhance formation of lipoxins, resolvins and protectins to derive the benefit of albumin therapy in the critically ill ,17.Beneficial actions of albumin are limited by: availability of PUFAs in the liver and other tissues; formation of adequate amounts of lipoxins, resolvins and protectins from PUFAs; activity of cyclooxygenase and lipoxygenase enzymes; circulating levels of TNF\u03b1 and other cytokines that interfere with the formation of arachidonic acid, eicosapentaenoic acid and docosahexaenoic acid and induce hypoalbuminemia; enhanced formation of reactive oxygen species that peroxidize PUFAs and thus reduce their availability; and formation of proinflammatory prostaglandins that antagonize actions of lipoxins, resolvins and protectins ,17 (see Adipose-fatty acid binding protein (A-FABP), which induces insulin resistance and whose levels are increased in the critically ill , is a caA-FABP can be linked to the expression of Toll-like receptors, macrophage activation, synthesis and release of proinflammatory cytokines IL-6 and TNF\u03b1, activation of cyclooxygenase-2 expression and eicosanoid synthesis, events that cause insulin resistance and initiation and progression of inflammation and sepsis. PUFAs and lipoxins, resolvins and protectins suppress A-FABP expression, inhibit macrophage and cyclooxygenase-2 activation, and decrease production of proinflammatory cytokines, and thus decrease insulin resistance and resolve inflammation and augment recovery from sepsis ,19. Henc"}
+{"text": "The gap between what is known and what is practiced results in patients not benefitting from advances in healthcare and unnecessary costs for clients and health systems. The Promoting Action on Research Implementation in Health Services (PARIHS) framework posits 1) strong evidence, (2) context in terms of coping with change, and (3) facilitation as elements influencing successful implementation of new knowledge [ strong eThe development of the Context Assessment for Community Health (COACH) tool departed from the PARIHS framework and was undertaken in Bangladesh, Vietnam, Uganda, South Africa and Nicaragua in six phases; (1) defining dimensions and draft tool development, (2) quantitative and qualitative content validity amongst in-country experts, (3) content validity amongst international experts, (4) response process, (5) translation and (6) evaluation of psychometric properties. The tool has been validated for use amongst physicians, nurse/midwives and community health workers in these five settings.This study indicates that dimensions of context identified to influence implementation in high-income healthcare settings are also relevant in LMICs. Having said this, there are additional aspects of context of relevance in LMICs. The final version of the tool includes 49 items measuring the following eight aspects of context: leadership, work culture, monitoring services for action, sources of information, resources, community engagement, commitment to work and informal payment.Application of the COACH tool will allow for systematic characterization of local healthcare context prior to or as part of the evaluation of implementing new interventions and allow for deepened insights into the black-box of implementation in LMICs."}
+{"text": "Differential interference contrast microscopy is designed to image unstained and transparent specimens by enhancing the contrast resulting from the Nomarski prism-effected optical path difference. Retinitis pigmentosa, one of the most common inherited retinal diseases, is characterized by progressive loss of photoreceptors. In this study, Differential interference contrast microscopy was evaluated as a new and simple application for observation of the retinal photoreceptor layer and retinitis pigmentosa diagnostics and monitoring. Retinal tissues of Royal College of Surgeons rats and retinal-degeneration mice, both well-established animal models for the disease, were prepared as flatmounts and histological sections representing different elapsed times since the occurrence of the disease. Under the microscopy, the retinal flatmounts showed that the mosaic pattern of the photoreceptor layer was irregular and partly collapsed at the early stage of retinitis pigmentosa, and, by the advanced stage, amorphous. The histological sections, similarly, showed thinning of the photoreceptor layer at the early stage and loss of the outer nuclear layer by the advanced stage. To count and compare the number of photoreceptors in the normal and early-retinitis pigmentosa-stage tissues, an automated cell-counting program designed with MATLAB, a numerical computing language, using a morphological reconstruction method, was applied to the differential interference contrast microscopic images. The number of cells significantly decreased, on average, from 282 to 143 cells for the Royal College of Surgeons rats and from 255 to 170 for the retinal-degeneration mouse. We successfully demonstrated the potential of the differential interference contrast microscopy technique\u2019s application to the diagnosis and monitoring of RP. The light-sensing retinal tissue is composed of specially functionalized cell layers including the ganglion cell layer (GCL), the bipolar/horizontal cell layers, and the photoreceptor cell layer. The outer retinal layer, consisting of the outer plexiform layer (OPL), the outer nuclear layer (ONL), and the photoreceptor layer, detects, by means of numerous rods and cones, contrast and color, respectively. The photoreceptors for the initial sensing of light receive the light information of visual objects and transfer signals to retinal ganglion cells and optic nerves in the brain. Photoreceptor degeneration causes retinitis pigmentosa (RP), one of the most common inherited ophthalmologic diseases in vivo, can be useful for early diagnosis. Although there is no approved treatment for RP, vitamin A and docosahexaenoic acid have been reported to delay its progress in vivo, though imaging of rod cells remains a challenge Patients in the early stage of RP usually suffer from night blindness since primary RP incurs rod degeneration. Night blindness symptoms worsen as the disease progresses, followed by constriction of vision and, eventually, central vision loss Differential interference contrast (DIC) microscopy is designed to image unstained, transparent specimens, enhancing the contrast resulting from the optical path difference between two beams that are split from the Nomarski prism. In the present study, we set up a DIC microscopy system and observed photoreceptor cells with RP at the cell level.The DIC microscopy system used in our laboratory is comprised of a polarizer, Nomarski prisms, a condenser, an objective lens, and an analyzer . Light prd/rd) mice, both widely utilized animal models in RP research, were housed and provided with standard chow and water provided ad libitum. Male Sprague-Dawley rats and C57BL/6 (wild type) mice were reared separately as controls. Autosomal recessive RP occurs in the RCS retina due to malfunction of MERTK, a member of the Axl subfamily of receptor tyrosine kinase, which inhibits contact between photoreceptors and the RPE rd mice follows a pattern similar to that in human RP: apoptosis of rod photoreceptors, followed by death of cone photoreceptors rd mice, similarly to some human RP cases, results from a mutation in the \u03b2 subunit of cGMP-dependent phosphodiesterase rd mice aged 3 weeks and 3 months, were prepared . Samples were obtained from both eyes so as to compare, under DIC, retinal flat-mount and histological images of retinal sections stained with Hematoxylin and Eosin (H&E). Specifically, the retina of the right eye was extracted and flat-mounted with buffer solution on slides; the left eyeball was enucleated and fixed with 4% paraformaldehyde overnight and embedded in an optimum-cutting-temperature compound. Ten-micrometer-thick sections were obtained for H&E staining.The use of animals in this study was approved by the Animal Research Committee of Seoul National University Hospital, and complied with the regulations of the Association for Research in Vision and Ophthalmology\u2019s Statement for the Use of Animals in Ophthalmic and Vision Research. Royal College of Surgeons (RCS) rats, and C3H/HeJ retinal-degeneration . This RP-induced decrease agreed well with the closed-loop decremental tendency. Also, the tissue shrinkage could be confirmed by the cell decrement. A number of cells in the photoreceptor sample with RP at 8 weeks were even more decreased, since the RP had completely progressed. Thereby, the automated counting method which needs more validation in future research was demonstrated to be a possible diagnostic method for photoreceptor diseases that tend to manifest cell-number decrements.The DIC images were also analyzed by MATLAB for automatic diagnosis of RP based only on images rd mouse images obtained using the DIC technique well coincided with the measured histological morphologies of the photoreceptors. Also, the clear DIC images made possible the application of an automated counting program (designed using MATLAB) to image analysis and photoreceptor counting. Based on our results, we conclude that the DIC technique is a feasible and effective method of RP diagnosis. Indeed, more generally, the novel application of DIC microscopy to retinal imaging at the cell level potentially can be utilized as a simple and convenient retinal-disease-diagnostic technique. Future research should focus on the potential application of DIC microscopy to in vivo and real-time diagnostics and monitoring of human RP.The images obtained demonstrate that by the DIC technique, we can clearly distinguish RP-affected abnormal retinal tissue from normal retinal tissue. Also, DIC images can be used to estimate the elapsed time of RP. The RCS rat and"}
+{"text": "Stem cells mainly include embryonic stem cells (ESC), pluripotent stem cells (iPS), Epiblast-derived stem cells (Epi-SC), and adult tissue stem cells. ESC are pluripotent, being able to differentiate into the ectoderm, mesoderm and endoderm (Evans and Kaufman, Stem cell treatments include new technologies and therapies that aim to replace damaged tissues and cells in order to treat disease or injury (Lindvall and Kokaia, The ability of stem cells to self-renew and their capacity for differentiation offers significant potential for the generation of tissues with minimal risk of rejection and side effects. A number of stem cell therapies are still in the experimental stages, and are controversial (Francis et al., Stem Cell Treatments is to publish all findings and experiences of stem cell treatments, experimentally and clinically, and to open up new possibilities for the treatment of various diseases such as Alzheimer's disease, traumatic brain injury, heart disease, diabetes, and cancer, etc., that we may promote health and extend the human life span.The goal of"}
+{"text": "High risk behaviors (HRBs) can impact public health. HRB refers to any kind of behavior or reaction that can potentially harm psychological and biological aspects of an individual. These behaviors are hazardous to several areas of human development which include: health, performing duties or tasks commensurate with developmental stage, playing expected social roles, learning the skills, feeling competent and adequate, and preparation for doing tasks . PrevaleAlmost hundred years ago, ADHD was described as a childhood disorder  called hyperactivity. Nearly six decades later, the \"minimal brain damage\" and \"minimal brain dysfunction\" were replaced with hyperactivity. With the introduction of attention deficit as the central feature of this disorder, a significant change occurred in the approaches of etiology and diagnosis of ADHD . CurrentPeople with ADHD, suffer from social and interpersonal problems. Inattention and hyperactive/impulsive behavior can cause social problems in this population , thus, PSymptoms of ADHD, in general, and its comorbidity with other disorders  can increase probability of performing HRBs, but these are not the only determinants of high risk behaviors. Overall, ADHD patients have major problems in decision-making, executive functioning and social cognition. Their decision-making in ambiguous situations has the same features of \"intuitive-existential\" decision-making system . Also, tIn a review of the studies done over a period of 30 years by Uekermann et al. found that ADHD is associated with deficit in social cognition (e.g., face perception, emotional prosody perception . DeficitAlthough our understanding of ADHD and its association with HRBs has increased by the conducted research, there are still questions and issues regarding to hereditary, neuropsychological, developmental, environmental, psychological, social factors of ADHD which should be studied further. Some of the major issues in this regard are listed below.1- The interaction of genetic and environmental factors in the development of ADHD.2- The development of brain networks and circuits associated with ADHD symptoms, impaired executive functions and social cognition of people with ADHD.3- Deficits in executive function as a general capacity and also its components and how executive functions relate to HRBs in children and adults. 4- Studying the effectiveness of drug treatments and psycho-social interventions on executive functions and improving the deficit of social cognition depending on ADHD subtypes and developmental stage of the patients.5- Impact of parenting styles and cultural-social factors on development and maintenance of ADHD symptoms with HRBs, and the impact of ADHD on parental behaviors.6- The role and influence of different situations and emotional states in decision-making of people with ADHD."}
+{"text": "Phase contrast magnetic resonance imaging (PC-MRI) is the current gold standard for blood flow quantification. Using this technique it is possible to quantify cardiac output, stroke volume, shunts and valve insufficiencies. The accuracy of flow quantification is highly dependent on the manual delineation of the vessels of interest. Therefore, the purpose of this study is to develop an automatic method for vessel segmentation in PC-MRI sequences.A total of 211 subjects from a previous study [The stroke volume from the automated method agreed well with manual delineations Figure , with a In conclusion, the proposed method for vessel segmentation results in bias and variability comparable to manual delineations.Swedish Research Council, Swedish Heart-Lung Foundation, Medical Faculty at Lund University."}
+{"text": "Morphogens are secreted signaling molecules that play instructive roles to regulate tissue patterning and cell identity in a concentration-dependent fashion during early embryonic development. Four principal mammalian morphogens include retinoic acid, as well as members of the Wingless-int (Wnt) and transforming growth factor beta (TGF-\u03b2)/bone morphogenic protein (BMP) and sonic hedgehog (Shh) families. Morphogen gradients control a plethora of developmental events related to specification and differentiation, cell and tissue polarity, growth control and regeneration.In the nervous system, neuronal differentiation, the polarized outgrowth of neuronal projections, the pathfinding of axons toward their target cells, and the recognition of pre- and post-synaptic partner cells are fundamental requisites to allow the assembly of functional synapses. During the last decades, a growing body of evidence gathered from invertebrate and vertebrate model organisms has shown that the same morphogens classically known to orchestrate early embryonic development are also involved in the precise wiring of the nervous system.Aviles et al.; Bernis et al.; Berwick and Harvey; Dickins and Salinas; Pinto et al.; Rosso and Inestrosa; Silva-Alvarez et al.; Varela-Nallar and Inestrosa; Aviles et al.; Varela-Nallar et al.), BMP , and Shh  signaling pathways. Research also covers the function of signaling cascades activated by other types of morphogens, including the fibroblast growth factors , the hepatocyte growth factor (HGF) , and netrin . In addition, researchers have contributed with the emerging roles of new molecules, such as the thyroid hormone , SCO-spondin , and vitamin C . Articles are focused on a wide variety of cellular processes involved in the establishment of neuronal connectivity, such as neurogenesis, neuronal specification, and maturation , axonal outgrowth, polarization, and guidance , and synapse formation , either in physiological contexts or in models of diseases affecting the normal function of the nervous system, including epilepsy , Alzheimer's disease , and amyotrophic lateral sclerosis .The aim of this research topic is to highlight the fundamental roles that morphogens play during the establishment of synaptic connectivity. Hence, we have brought together 12 original research articles and eight reviews. They are mainly focused on Wnt (We are confident that this integrative research topic emphasizes the central and pleiotropic roles played by morphogens during neural development. We therefore hope that the original articles and reviews presented here will inspire future directions of research focusing on the diversity of cell signaling mechanisms controlling the assembly, maintenance and regeneration of the nervous system.JH and NO wrote, edited and revised the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "There is an alarming increase in the number of cases of diabetes with the global prevalence rate at 9% for the year 2014 . DiabeteMesenchymal stromal cells are at a forefront of the cell-based therapies and Davey et al. elegantly summarized importance of MSCs for diabetic microvascular complications . The revDr. Rajashekhar further reiterated the importance of MSCs in diabetic microvascular complications in his review by summarizing the critical benefits of MSCs for the treatment of diabetic retinopathy . His artFurthermore, Mizukami and Yagihashi summarized the importance of ASCs in the treatment of diabetic neuropathy  adding tin vivo home to ischemic retina and integrate into retinal vasculature  in diabetic retinopathy . Their sculature .+ cell  levels and restoration of NO helps in correcting CD34 dysfunction  choice of an ideal stem cell type, (ii) rigorous characterization of stem cells, (iii) site of injection and route of delivery, (iv) limited survival, (v) risk of tumors, and (vi) impaired potency, before the cell therapy reaches to the clinic. However, with advancement in research, stem cells will provide effective treatments for diabetic microvascular complications.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Using different modalities of neuroimaging, both structural and functional brain connectivity can be mapped. The connectivity analysis has been widely applied into investigating the brain mechanisms of cognitive functions and neuropathology of different brain disorders. However, there are still some challenges when mapping, analyzing, and modeling the brain connectivity at different scales. This special issue aims at reflecting the advances in studies of brain connectivity, including both modeling methods and applications. In this special issue, different imaging techniques, such as structural MRI, diffusion MRI, and functional near-infrared spectroscopy (fNIRS), were employed in the studies of brain connectivity. The applications addressed hemispheric asymmetry, primary insomnia, and motor training. Also, the computational modeling methods and analysis toolbox of brain connectivity were introduced. The types of papers include review articles as well as original research.With the advent of brain imaging techniques, the study of human brain connectivityFor the modeling methods of brain connectivity, R. C. Sotero (2015) reviews computational models of phase-amplitude coupling (PAC) generation ranging from realistic networks of Hodgkin-Huxley neurons to neural mass models (NMMs) describing only the average activity of the neuronal populations involved and showed that NMMs are rich enough to provide a variety of PAC patterns. For the analysis toolbox of brain connectivity, J. Xu et al. (2015) developed a MATLAB software package that facilitates fNIRS-based human functional connectome data-analysis, which will be useful for the resting-state brain functional connectivity (FC) studies. For the application studies of brain connectivity, N. Shu et al. (2015) investigated the hemispheric asymmetry of brain white matter anatomical network which is constructed by diffusion MRI tractography and demonstrated that the topological asymmetries of the anatomical networks might reflect the functional lateralization of the human brain. L. Zhao et al. (2015) investigated the topological alterations of the structural covariance network for patient with primary insomnia, suggesting that insomnia might be related to underlying increase in brain network integration encompassing the sensory to motor networks, the default mode network, and the salience network and decrease in the integration between the sensory regions and the frontoparietal working memory network.The special issue also contains several review papers: B. Wong et al. (2015) review structural and functional connectivity studies of bilingualism and examined different issues such as whether the language neural network is different for first- (dominant) versus second- (nondominant) language processing; the effects of bilinguals' executive functioning on the structure and function of the \u201cuniversal\u201d language neural network; the differential effects of bilingualism on phonological, lexical-semantic, and syntactic aspects of language processing on the brain; and the effects of age of acquisition and proficiency of the user's second language in the bilingual brain, and how these have implications for future research in neurolinguistics. T. D. Ben-Soussan et al. (2015) review the connectivity studies of quadrato motor training and proposed a general model tying cerebellar function to cognitive improvement, via neuronal synchronization as well as biochemical and anatomical changes.In summary, the papers collected in this special issue cover a wide range of topics that are on the frontier of the methods and applications of brain connectivity."}
+{"text": "Evidence based policy-making has been promoted as a means of ensuring better outcomes but what counts as evidence in policy-making lies within a spectrum of expert knowledge through scientifically generated information. Different actors provide varying degrees of support for and use of different types of evidence in policy development. Since not all forms of evidence share an equal validity or weighting for policy-makers, it is important to understand the key factors that influence their choice of evidence.A retrospective cross-sectional study was carried out at the national level in Nigeria. A case-study approach was used and the Nigerian Integrated Maternal Newborn and Child Health (IMNCH) strategy was selected because it met the criteria of being: (i) recently developed (<10 years old); and (ii) of international prominence. Two frameworks were used for conceptualization and data analysis namely: (i) framework for analyzing the role of evidence in policy making developed by Mirzoev et al., in 2012, and (ii) the policy triangle. They were used to explore the key contextual and participatory influences on choice of evidence in developing the IMNCH strategy. Data was collected through review of relevant national documents and in-depth interviews of purposefully selected key policy and decision makers. Thematic analysis was applied.The breadth of evidence used was wide, ranging from expert opinions to systematic reviews. The choice of different types of evidence was found to overlap across actor categories. Key influences over actors\u2019 choice of evidence were: (i) perceived robustness of evidence - comprehensive, representative, recent, scientifically sound; (ii) roles in evidence process, i.e. their degree and level of participation in evidence generation and dissemination, vis-\u00e0-vis their role in the policy process; and (iii) contextual factors such as global agenda and influence, timeline for strategy development, availability of resources for evidence generation, and lessons from previously unsuccessful policies/plans.Actors\u2019 choice of evidence in policy making is influenced not only by the characteristics of evidence, but on the roles these actors play in the process, their power to influence the policy, and the context in which evidence is used."}
+{"text": "In 1995, Dr.Parker developed the vacuum-assisted breast biopsy technique (using theMammotome\u00ae equipment), to improve the accuracy of biopsies ofmicrocalcifications in adipose breast tissue. Core and vacuum-assisted biopsies were initially greeted withskepticism and even rejected by some medical professionals. Image-guided percutaneousbiopsies, however, would bring changes to the field and gain broad acceptance for use inclinical assessments.In 1989, Dr. Parker started performing percutaneous biopsy, using a core needle and anautomatic deployment device, for the diagnosis of nonpalpable breast lesions, thedetection of which was becoming increasingly more frequent after the advent ofhigh-resolution mammography. In their first study of the topic, published in 1990,Parker et al. compared the performance of core biopsy with that of surgical biopsy,concluding that core biopsy represents a reliable, rapid, and affordable alternativethat is well-tolerated by patients with minimum complications and a low risk ofparenchymal scarring; b) failure to standardize practices after a benignhistopathological result, resulting in patients who should be merely observed undergoingsurgery, and vice-versa; c) lack of technique and tactics in carrying out the procedure,including the incorrect choice of access and faulty spatial reasoning; d) lack ofappropriate documentation of the procedure-the report, the record of the lesion beforeand after the biopsy, and X-rays of the biopsy fragments -leaving the radiologist vulnerable from a legal aspect; e) lack of auditing of the results,making it impossible to evaluate the performance and identify errors to becorrected-8. Items a), b) and c) are certainly the result of gapsin the education of the radiologist. It is extremely important that radiologists whowork with breast imaging procedures frequent institutions that specialize in and arededicated to specific training. Item d) illustrates the distortion in our model of care,in which low rates of pay by the medical insurance companies leads to an excessivenumber of exams per hour. That problem can be solved only by presenting a united frontwithin the Brazilian College of Radiology and Diagnostic Imaging, because individuallywe are impotent. Item e) illustrates the absence of an auditing culture. There is nointerest in the matter, and radiologists do not receive specific training in that. Inaddition, it is difficult to obtain and correlate results in day-to-day practice,because patients are lost in the system.Although the demand for percutaneous biopsies is currently increasing, many problemsarise, resulting in false-negatives, late or delayed diagnosis, and increases in cost.Among the most important problems are the following: a) unawareness of the technicalcriteria for indicating the procedure (on the part of the requesting physician), as wellas of the criteria for recommending and selecting the best type of biopsy (core orvacuum-assisted) and guidance for each lesion (on the part of the radiologist), given that an incorrectindication/choice generates technical difficulties and diagnostic errors, as well asresulting in inefficient allocation of resourcesIn conclusion, the considerations above are points for reflection. The ultimate goal isto improve the experience of patients subjected to breast biopsy."}
+{"text": "In 2014 World Kidney Day (WKD) will focus on chronic kidney disease and aging. The mission of WKD is to raise awareness so that everyone cares for their kidneys and, if appropriate, check to assess if they are at risk for kidney disease. Prevention of kidney disease, early detection, and subsequent kidney protection are critical aims for WKD.Last year, the International Society of Nephrology (ISN) and the International Federation of Kidney Foundations (IFKF), focused the World Kidney Day (WKD) of 2013 on acute kidney injury . VariousGTH and HN contributed as authors of the manuscript.The author declared no competing interests.Ethical issues  have been completely observed by the author.None."}
+{"text": "Undoubtedly, residents play a very important role in the healthcare system of most countries. The process of admission of medical trainees into specialties, residency training and their assessment are key determinants of the future of healthcare.In Canada, according to the 2014\u201315 data, there were 13,439 residents (excluding Fellows) distributed in 42 specialties/sub-specialities.Philips and Barker who systematically examined the occurrence of fatal medication errors over 25 years in the US attribute a significant spike in medication errors in July to the entry of a new cohort of medical residents.4A recent study by Curtis and Dube looked at the characteristics of CMGs, IMGs and CSAs in an era where measures are being taken to alleviate physician shortage.In Canada, the Canadian Resident Matching Services (CARMs), a non-profit, fee-for-service organization, facilitates a fair and transparent process of resident admissions into programs.*The Royal College of Physicians and Surgeons and the College of Family Physicians of Canada play are regulatory bodies that oversee the quality of residency training in Canada. Research into the training process and application of educational principles helps promote training quality. In this edition, Guajardo and colleagues examine the effect of inclusion of patient name and image in virtual patient cases on knowledge acquisition.A large part of resident training involves role modeling by preceptors. In Canada, with its wide distribution of population in rural and remote areas, medical schools train students and residents in these areas under the supervision of preceptors. Piggott, Morris, and Lee-Poy examine the facilitators and barriers to engagement of preceptors in distributed medical campuses. There are several barriers that can be addressed by medical schools such as: provision of training of preceptors in being better teachers, ensuring that preceptors in these areas are aware of curricular objectives, among others. Lubitz, Lee, and Hillier look at the perception of residents to the longitudinal integrated curriculum, a form of training provided in mostly rural areas.With the introduction of the CanMEDs roles, residents are trained and assessed using the CanMEDs framework.A large volume of literature exists in relation to the transformation of trainees from novices to experts."}
+{"text": "The axillary artery presents abnormalities in its origin and course and a variable branching.A rare case of axillary artery bifurcation and branching was observed in a 60-years-old European male cadaver of Greek origin. The right axillary artery at the second part was bifurcated into a superficial and a deep brachial artery. The superficial brachial artery anteromedial to the median nerve and lateral to the ulnar nerve gave off the acromio-thoracic artery and two lateral thoracic arteries. The deep brachial artery behind the median nerve, after giving rise to the anterior circumflex humeral artery trifurcated into a branch that coursed distally, the posterior circumflex humeral artery and the subscapular artery. The latter subdivided into the circumflex scapular artery, a muscular branch for the subscapularis and the thoracodorsal artery. The continuation of the deep brachial artery divided laterally into a humeral nutrient artery and medially into a trunk which trifurcated into the profunda brachii artery, a deep muscular branch and a branch to the posterior compartment of the arm. The profunda brachii artery ended as radial and middle collateral arteries.Deviations from the normal arterial pattern are of immense significance for anatomists, plastic, cardiovascular and orthopedic surgeons, vascular radiologists and interventional cardiologists. The pectoralis minor muscle divides the AA into three parts. The 1) Adachi . Althoug) Adachi . The varIn the present case, a unilateral high bifurcation of the AA into a superficial brachial artery (SBA) in front of the median nerve (MN) and a deep brachial artery (DBA) behind the MN is described. This abnormal division of the artery may have clinical application in hemorrhagic emergencies, where the accurate diagnosis and surgical repair or ligation of the vessels is crucial.During routine dissection of a 60-years-old Greek male donor who died after cardiac arrest, an unusual case of high bifurcation of the AA into two arterial stems supplying the right axilla and the upper limb was observed Figure\u00a0A. The prThe coexistence of abnormalities of the AA  is unusual, while isolated aberrations of the arterial pattern follow a wide range among races  and/or bilaterally (3rd part) (Natsis et al. st part and the 2nd part of the AA was also reported (Huelke rd part of the AA, although the PBA may be absent (Samuel et al. Twenty-three different arterial patterns of the AA have been recognized (De Garis and Swartley A Huelke . The LTA Patnaik  or from  Patnaik . The TDA Patnaik . Moreoved Huelke . In our d Huelke  who obsend part of the AA into SBA and DBA occurred. Other authors (Cavdar et al. rd part, while a rare bifurcation at the 1st part, absence of the SSA and origin of the ATA from the DBA, was also referred (Jurjus et al. The AA high bifurcation into SBA and DBA (Cavdar et al. The variable pattern of the AA is of paramount importance for surgeons and interventional physicians. Although the superficial course of the SBA makes the arterial grafting and cardiac catheterization easier, the high bifurcation of the AA and its abnormal branching pattern may pose problems to clinician during angiographic procedures leading to diagnostic errors. The SBA due to its abnormal origin and position may be more prone to serious injury leading to hemorrhage (Jurjus et al. nd part. Documentation of such rare abnormalities in the axilla is highly significant for aneurysms and trauma surgery (Ortiz-Pomales et al. The present case provides additional information on the branching and distribution pattern of the AA since the high division of the artery occurs at the 2The body donor gave written informed consent before its death for the publication of this case report.K. Natsis - Professor, Director of the Department of Anatomy, Medical School, Aristotle University of Thessaloniki, Greece, natsis@med.auth.grM. Piagkou - Assistant Professor, Department of Anatomy, Medical School, National and Kapodistrian University of Athens, Greece, mapian@med.uoa.grNA. Panagiotopoulos - Research Fellow, Department of Anatomy, Medical School, National and Kapodistrian University of Athens, Greece, panagiotopoulos.nikitas@gmail.comS. Apostolidis - Associate Professor, Department of Anatomy, Medical School, Aristotle University of Thessaloniki, Greece, stlsa@med.auth.gr"}
+{"text": "Caloric restriction (CR), the reduced intake of calories without malnutrition, extends lifespan of many organisms, from yeast to mammals, and delays the progression of age-related diseases. Evidence show that hypothalamus is a crucial brain region for the progress of whole-body aging and the"}
+{"text": "Three hundred and twelve delegates from 73 cities in 16 countries took part in the conference. Actual problems of urogenital tract infection (UTI) including tuberculosis (TB) as a specific infection were discussed, including: nosocomial infections in urology, various aspects of prostate biopsy, epidemiology and diagnosis of urogenital tuberculosis, gender and age related characteristics of urinary tract infections, and male infertility,  The meeting of the ESIU/EAU board at the annual EAU Congress in Paris in 2013 had decided to organize the Conference on Urogenital Tuberculosis (UGTB) in a region with a high prevalence of this disease. As the Novosibirsk Research TB Institute and the TB Department of Novosibirsk Medical University are well-known for their studies in this field, and Siberia is an epidemic region of TB, Novosibirsk was chosen as a place for this Conference. The meeting was organized as a joint event between several medical associations: The European Section of Infection in Urology (ESIU)/European Association of Urology (EAU), International Commission on UTI of the International Society of Chemotherapy for Infection and Cancer (ISC), Russian Society of Urology, Russian National Association of Phthysiologists, Asian Association of Urogenital Tract Infection and Sexually Transmitted Diseases (UTI&STI), Novosibirsk Research Institute for Tuberculosis and Novosibirsk Medical University, Russia. The Organizing Committee was chaired by Professor Truls E. Bjerklund Johansen, Chair of the ESIU, Professor Kurt G. Naber, Past-President of the ISC, and Honorary Chair of the ISC WG UTI, and Professor Ekaterina Kulchavenya, as President of the Conference. The International Conference \u201cUrogenital Infections and Tuberculosis\u201d was held in Novosibirsk, from 24 to 26 October 2013. Three hundred and twelve delegates from 73 cities in 16 countries  took part in the conference, and 191 doctors attended via on-line translation. One of the conference highlights included the World Health Organization (WHO) report which indicated that 8.6 million people suffer from TB in 2012, including 1.1 million cases among people with HIV. In 2012, 1.3 million people died from TB. In 2012, an estimated 450,000 people developed multidrug-resistant TB (MDR-TB) globally and there were an estimated 170,000 deaths occurred from MDR-TB.M. tuberculosis may affect any organ of the human body, and next to the lungs the most common sites of the disease are the urogenital system, bones and joints. Unfortunately, because of delayed diagnosis, urogenital tuberculosis (UGTB) often has a complicated course. UGTB may mimic urogenital tract infection (UTI) with common bacteria, a fact that confuses many doctors who are not familiar with TB. The official opening ceremony was attended by the Minister of Public Health of the Novosibirsk region, Professor Leonid Shaplygin , and theFor three days there were parallel lectures, debates and discussions in two halls\u2014in English and Russian languages with simultaneous translation. The following problems were discussed: latent urogenital infections, their bacteriological diagnosis and therapy; complicated urogenital infections, their prevention and treatment; sexually transmitted infections; infectious diseases of the reproductive system as a cause of infertility and sexual dysfunction; interrelation of infections and tumors of the urogenital system: mistakes in diagnosis and features of combined therapy; standards of examination and treatment of patients with urogenital infections; epidemiology, organization of early detection and follow up of patients with urogenital tuberculosis; classification of urogenital tuberculosis; diagnosis, therapy and surgery of urogenital tuberculosis; multi-organ tuberculosis, and multi-drug resistance (MDR) with extrapulmonary tuberculosis.On the first day of the conference, participants were able to attend sections dedicated to the following topics: bladder leukoplakia, kidney stones, and the problem of non-specific cystitis, chronic prostatitis, and sexually transmitted infections. In the session on bladder leukoplakia, the etiology and pathogenesis of this disease were considered in addition to the role of sexually transmitted diseases. Also, the possibilities of minimally invasive procedures as well as the prospects for recovery of anatomy and physiology of the urothelium were demonstrated. A new method of less invasive intravesical laser therapy for bladder leukoplakia was presented  with evidence of its superiority compared to transurethral resection. Problems of urolithiasis are by no means new to urology, but they are still quite relevant. The latest techniques and the \u201cgold standard\u201d lithotripsy and litholytic therapy were presented and prevention of infectious complications and preoperative preparation were thoroughly discussed . Although the topic of non-specific cystitis in urological practice has been repeatedly considered at various congresses and conferences, the contributions and discussions in this section were again very lively.On the second day of the Congress, the followings topics were discussed: current issues of nosocomial infections in urology, various aspects of prostate biopsy, epidemiology and diagnosis of urogenital tuberculosis, gender and age related characteristics of urinary tract infections, and male infertility. Possibilities of minimally invasive and endoscopic procedures in urology, as well as modern methods of drainage of the urinary tract and wounds were demonstrated to the audience.Ekaterina Kulchavenya  emphasized in her presentation on the classification of UGTB that UGTB remains an important problem, especially in developing countries, because it is often an overlooked disease. Classification includes exact description of forms and stages of the UGTB, because each stage implies a different approach of management. Thus, accurate classification is the basis for good therapeutic results. Kidney tuberculosis (KTB) at stage 1\u20132 should be treated with chemotherapy, KTB at stage 3 requires partial nephrectomy, and KTB at stage 4 is indicated for nephrectomy. A stricture of ureter needs reconstructive surgery in KTB 1\u20133, but nephron-ureterectomy in KTB-4. Male genital tuberculosis (MGTB) should be treated with chemotherapy; fistulas are treated by surgery. Generalized UGTB, combining both kidney TB and male genital TB should be managed depending on the forms and stages of the kidney and male genital TB. UGTB is a tremendously diverse disease. A unified standard approach is therefore impossible. The common term \u201cUGTB\u201d gives insufficient information about therapy needed, e.g., surgery, and prognosis\u2014and makes evaluation of general epidemiology difficult. In contrast, a more detailed clinical classification will also improve the therapy of UGTB.Mete Cek from Trakya University (Turkey) reported the results of a 10-year, worldwide study on the prevalence, structure and characteristics of nosocomial infections in hospitalized urological patients. Besides prevalence and contemporary classifications, also a detailed analysis was presented concerning causes of nosocomial infections, antibiotic resistance patterns of uropathogens, and international practices of antibacterial therapy.Mycobacterium tuberculosis and drug susceptibility testing. According to the author\u2019s data, isothermal microcalorimetry could displace all other culturing methods, since the minimum detection time is only 25 h and the test easily identifies the drug sensitivity of the pathogen. With regards to UGTB, with this technique the growth rate and doubling time of 4 different mycobacteria could be determined in urine simultaneously.Florian Wagenlehner from the University of Giessen  had two presentations, one on complications of prostate biopsy and the other on new antibiotics in urology. Every year in Europe more than 1 million prostate biopsies are performed, and the risk of infectious complications after this procedure is rising. The author proposed a strategy to minimize the risk of infectious complications and justified the need of targeted antibiotic prophylaxis. In his second presentation he analyzed the global bacterial antibiotic resistance in urology in relation to the antibacterial activity of different classes of existing and new antibiotics in the pipeline. Gernot Bonkat from the University of Basle (Switzerland) presented the isothermal micocalorimetry as a new method for identification of Topics of the third day of the conference were prevention of urogenital infections, chemotherapy and surgery of urogenital tuberculosis.Magnus Grabe  discussed the prevention of infectious complications in urological surgery. He encouraged all participants to follow the recent recommendations of the EAU Guidelines.Bj\u00f6rn Wullt  reviewed in his presentation the optimal management of uncomplicated UTI according to the 2013 updated EAU guidelines. Seung-Ju Lee  described the methods of reconstructive surgery in UGTB. Denis Kholtobin  presented his rather huge own surgical experience. He emphasized the necessity of simultaneous extirpation of bladder and prostate in male patients with bladder TB.M. tuberculosis with BACTEC 960 and GeneXpert. According to data of the Novosibirsk Research TB Institute, in 12.5% of patients with prostate tuberculosis that initially showed negative culture results, M. tuberculosis was finally found with these new methods.Anna Mordyk  paid special attention to difficulties of bacteriological confirmation of UGTB. The main reasons are: (i) rare and scant mycobacteriuria and (ii) non-optimal previous antibacterial therapy for \u201curogenital tract infections\u201d, which in fact means overlooked UGTB. Olga Alhovik  presented new techniques for rapid identification of On Wellcome Reception after first day of the Conference some participants who made biggest contribution in this event were awarded with Diplomas and Prizes, We do not know the real incidence and prevalence of UGTB as it includes KTB, MGTB, and female genital TB. All these forms of TB have their own clinical features and require their own approaches to the diagnosis and management. Before anti-TB drugs were created, the prevalence of UGTB was huge. Every fifth urological in-patient had UGTB, more than third of all pyonephrosis were due to TB . NowadayThis first conference brought together urologists and TB specialists not only from the Siberian region, but also from the whole of Russia and other countries as well. The outstanding quality of the presentations and the lively discussions during the congress underlined the high degree of relevance of this event. Participants were able not only to gain useful information, but also to find new partners for further joint research.There are many un-solved problems in TB urology. Unique terminology, classification, and approach to diagnosis, therapy and surgery for patients UGTB are needed. Heated discussions, hot debates and arguments between participants at this Conference resulted in agreement on key points.M. tuberculosis can be found in the ejaculate of half of the TB patients [The take home messages emphasized the need for more awareness regarding UGTB in many regions of the world, considering that UGTB is a sexually transmitted disease, as patients . A betteAfter Conference memory picture of the faculty was made in the hall of the Congress Center ."}
+{"text": "Juvenile scleroderma (JS), represents a rarely seen group of connective tissue disease with multiple organ involvement. Although quite rare in childhood, cardio-vascular and pulmonary involvements are the most important mortality and morbidity factors. Pulmonary arterial hypertension (PAH), the most important sequelae of pulmonary involvement, could be determined by echocardiographic examinations. Early cardio-vascular and pulmonary involvement determination is extremely important in reducing mortality of patients.The aim of the study was to use non-invasive methods  to examine cardio-pulmonary involvement of the disease in patients. Treatment of patients with positive findings in the early stage of the disease possibly reduces the morbidity and mortality.Totally of 35 patients with scleroderma, followed up at Cerrahpasa Medical Faculty, Pediatric Rheumatology Department with diagnosis of juvenile scleroderma were included in the study. Doppler echocardiography was performed at Cerrahpasa Medical Faculty, Pediatric Cardiology Department and pulmonary function tests were performed at Laboratory for pulmonary function tests at Cerrahpasa Medical Faculty. FVC and DLCO were measured in order to investigate pulmonary fibrosis. The assessment of PAP and risk factors for PAH was made by measurement of maximum tricuspid insufficiency (TI), end diastolic pulmonary insufficiency (PI), AT/ET, RAP and contraction of vena cava inferior during inspiration.The values of TI, PI, AT/ET and PAP were found to be normal and statistically sign\u0131ficant different from the pathological values. The results of FVC and DLCO were found to be statistically significant above normal values. In other words, no patient was found to have cardio-pulmonary involvement.Although quite rare in juvenile scleroderma, cardio-vascular and pulmonary involvement is the most important factor in the prognosis of the disease. Early diagnosis, regular follow up and appropriate treatment are important in reducing the cardio-vascular and pulmonary complications of the disease.None declared."}
+{"text": "The authors would like to supply additional information in relation to the study.The characteristics of the sample population included in the study are outlined in the table supplied. The methods pertaining to this are as follows:Informed consent and inclusion into study: Each subject who qualified for the study was explained the purpose and procedures of the research and written informed consent obtained. Questionnaires were used to assess demographics, oral hygiene and diet. Oral hygiene habits were assessed by frequency of brushing, flossing, smoking history and visits to the dentist, while food habits were assessed by routine exposures to one of the four diet patterns: (i) Standard American , pasta and similar dishes, and desserts). (ii) Hispanic and Latino , avocado, olives, fruits, sweet breads, red meats), (iii) Asian  or (iv) not fitting into any of the above categories.The legend for Table S1Ethnicity Table(JPG)Click here for additional data file."}
+{"text": "Selection of appropriate outcome measures is crucial in clinical trials in order to minimize bias and allow for precise comparisons of effects between interventions -3.We aimed to assess the frequency and completeness of outcome measures in randomized controlled trials (RCTs) included in Cochrane systematic reviews (SRs), focusing on evaluations of the efficacy and safety of rehabilitation interventions for mechanical LBP.We performed a cross-sectional study of all RCTs included in all Cochrane SRs (full-text) published on The Cochrane Database of Systematic Reviews in February 2013. Two authors independently evaluated the type and frequency of each outcome measure reported in the full-text of RCTs, the methods used to measure outcomes, and the proportion of outcomes fully replicable based on the reported information  84.7% \u2013 93.7 %), disability , range of motion , and quality of life  measured respectively by 70, 43, 41, 19 different measurement instruments (Figure A large number of outcome measures and a myriad of measurement instruments were used across all RCTs. The reporting was largely incomplete, suggesting better opportunities for the standardization of approaches and reporting."}
+{"text": "The NMC portal allows users to access the experimental data used in the reconstruction process, download cellular and synaptic models, and analyze the predicted properties of the microcircuit: six layers, ~31,000 neurons, 55 morphological types, 11 electrical types, 207 morpho-electrical types, 1941 unique synaptic connection types between neurons of specific morphological types, predicted properties for the anatomy and physiology of ~40 million intrinsic synapses. It also provides data supporting comparison of the anatomy and physiology of the reconstructed microcircuit against results in the literature. The portal aims to catalyze consensus on the cellular and synaptic organization of neocortical microcircuitry . Community feedback will contribute to refined versions of the reconstruction to be released periodically. We consider that the reconstructions and the simulations they enable represent a major step in the development of in silico neuroscience.We have established a multi-constraint, data-driven process to digitally reconstruct, and simulate prototypical neocortical microcircuitry, using sparse experimental data. We applied this process to reconstruct the microcircuitry of the somatosensory cortex in juvenile rat at the cellular and synaptic levels. The resulting reconstruction is broadly consistent with current knowledge about the neocortical microcircuit and provides an array of predictions on its structure and function. To engage the community in exploring, challenging, and refining the reconstruction, we have developed a collaborative, internet-accessible facility\u2014the Neocortical Microcircuit Collaboration portal  13\u201316] somatosensory cortex from sparse data on its cellular and synaptic organization , 11 electrical types (e-types), and 207 morpho-electrical types (me-types); ~7.5 million connections belonging to 1941 unique m-type specific connection types; and ~40 million synapses belonging to six synapse types (s-types) . The synaptic level represents the anatomical and physiological properties of synaptic connections between specific pre-post combinations of m-types, and the complete map of intrinsic input and output synapses , from and to neurons of different types.An interactive browser across three levels: Comparisons between the morphological, molecular, electrical, synaptic, and physiology properties of the reconstruction and its overall circuit anatomy against the published literature.Experimental datasets used in the reconstruction process.Animations of simulated microcircuit activity under a variety of experimental conditions.Images illustrating key steps in the reconstruction process.Tools for analyzing, and simulating the reconstructed microcircuit.Models of neurons, ion channels, and synapses for the NEURON simulation environment.The microcircuit section of the portal contains data computed during the reconstruction process, using methods described in , electrical types (e-types), morpho-electrical types (me-types), and synapse types (s-types), numbers of intrinsic, and extrinsic synaptic connections and associated synapses, and the number of unique synaptic connection types between neurons of specific source and target m-types  in a layer are given  for each layer is given , calbindin (CB), and calretinin (CR)], and neuropeptides  they express is given  back-propagating from the axon , neurotransmitter release probability (U), time constant for recovery from depression , time constant for recovery from facilitation , and the predicted correction factor necessary to account for dendritic filtering (space-clamp artifacts). Physiological data at the connection level summarizes the kinetics and time course of post-synaptic potentials (PSPs). The data provided include onset latencies, peak amplitudes, 20\u201380% rise times, decay time constants, transmission failures, and the coefficient of variation of PSP amplitudes  , a web link to the publication, the name of the contact author, and the names of the persons who undertook the literature search are also provided.The literature consistency contains papers considered in the validation process. For each paper we identified one possible evaluation criterion. Each paper is annotated to show the evaluation criterion, and the result of the validation . Where a paper was not actually used, it is marked as not implemented, or not applicable. Additional annotations describe the species and age of the animals used in the study, the brain region, cortical layer, and cell type concerned, the key finding, and other relevant results. The The evaluation criteria are based on the morphological, molecular, electrical, synaptic, circuit anatomical, and physiological properties of the reconstructed microcircuit. For ease of presentation, papers are grouped according to the class of properties considered in their evaluation criteria.This sub-section presents 64 papers used for the validation of experimentally reconstructed neuron morphologies. The papers provide data for Sholl statistics, dendritic and axonal lengths, dendritic and axonal volumes, soma diameters, and dendritic and axonal segment branch order and path distance statistics. Overall, the properties of the morphologies used in the reconstruction were consistent with the results reported in 17 papers, possibly consistent with 10 papers and inconsistent with nine papers. Six papers whose data were not comparable with the reconstruction  were excluded from the validation process.in silico staining. This sub-section presents six papers providing the necessary data. The papers present data on the expression of the main calcium binding proteins and neuropeptides expressed by neurons of different types.During the validation process, gene expression data associated with specific neuron types was used to perform This sub-section presents 77 papers describing the electrical properties of different cortical neuron types. Data are provided for ion channel kinetics, electrical firing patterns, and passive membrane properties, including the resting membrane potential, membrane time constant, and input resistance. Other data describe electrophysiological features including AP amplitude, AP half-width, firing frequency, inter-spike interval, and dendritic properties including bAP and EPSP/IPSP attenuation.A, and GABAB receptor peak conductances, EPSC/IPSC properties , EPSP/IPSP properties , transmission failure rates, c.v. of EPSP/IPSP amplitudes, short term depression and facilitation, and tonic excitation and inhibition.This sub-section contains 81 publications used to validate the anatomical and physiological properties of synaptic connection types in the reconstruction. The data provided includes spine and bouton densities for different neuron types, as well as data for pairs of neurons belonging to specific m-types: synaptic innervation patterns, number of synaptic contacts per connection, connection probabilities, transmitter release probabilities, AMPA, NMDA, kainate, metabotropic glutamate, GABAThis sub-section presents 43 papers used to validate the anatomical properties of the reconstructed microcircuit. The properties considered include microcircuit thickness, individual layer thicknesses, layer-wise distributions and densities of neurons, total axon and dendritic lengths, total number of synapses and their densities, and layer-wise distributions of bouton densities from thalamocortical axons.This sub-section contains 47 papers used to assess the physiological properties of the reconstructed microcircuit. Relevant properties include the frequency of network oscillations, patterns of propagation of electrical activity across different cortical layers, the physiological properties of thalamocortical synapses, and the balance of excitatory and inhibitory synaptic conductances in different neuron types due to network activity.Over the past two decades, Markram and colleagues have experimentally characterized the cellular, and synaptic microcircuitry of developing (P13-16) rat neocortex, where the anatomical, physiological and synaptic properties are not completely mature  stained coronal slices with annotations of individual layer extents, and spreadsheets summarizing measurements of layer heights.Measurements of individual layer heights.Data are given as microscopy images of NeuN stained slices with annotations of individual layer extents, and spreadsheets summarizing measurements of neuron counts across different layers.Layer-wise distributions and densities of neurons.Data can be obtained as text files containing the expression patterns of calcium binding proteins, and neuropeptides for morphologically identified neurons.Molecular characterization of single neurons based on the expression of calcium binding proteins , and neuropeptides .Data are provided as text files containing 3D representations of neuronal morphologies reconstructed using Neurolucida .More than 1000 morphological reconstructions of neurons of different m-types.Data are given for current stimuli (in pA), and voltage responses (in mV) from whole-cell patch clamp recordings in single neurons acquired using IGOR Pro .More than 1500 electrical recordings from neurons of different e-types.Data are provided for post-synaptic responses obtained from whole-cell patch clamp recordings in synaptically connected pairs of neurons.More than 5000 experiments from synaptically connected neurons.2+. Movies of evoked activity show electrical activity in response to the stimulation of thalamocortical fibers at different levels of extracellular Ca2+. Additional movies visualize the distribution of afferent synapses for a single exemplar neuron for each of the 55 different m-types, and predicted dendritic attenuation of EPSPs and bAPs for 5 exemplars for each of the 207 me-types.The videos section provides movies of simulated spontaneous and evoked activity in virtual cortical slices, obtained from the reconstructed microcircuit under a variety of simulated experimental conditions. Movies of spontaneous activity show electrical activity in the reconstructed microcircuit at different levels of depolarization and extracellular CaNeuroM provides a range of morphometric analyses that allow a user to quantify properties of the axonal and dendritic morphologies of neurons, and provides features that are used in the classification of different neurons into one of 55 m-types. NeuroR utilizes the results of NeuroM to identify and repair arbors that were severed during slice preparation. NeuroC produces clones of the neurons repaired by NeuroR, introducing statistical variations in the arbors of each cloned neuron. This procedure makes it possible to generate a limitless number of unique instances of neurons belonging to a given m-type.The tools section contains three tools used for the analysis, repair and cloning of neuronal morphologies. downloads section provides models of single neurons, synapses, and predicted maps of input-output synapses. Models are available either in the native format used in the reconstruction process, based on the NEURON simulation environment, or in the emerging NeuroML 2.0 , and LEMS . Models of individual neurons (in the NEURON simulation environment) can also be obtained from the me-type fact sheets [see Morpho-Electrical Types (me-types)]. Model packages for individual neurons contain a 3D reconstructed morphological model, models of ion channels and synapses, synaptic model parameter descriptions, and a template model of the electrical type. Additional helper scripts for the NEURON simulation environment are provided to instantiate a morphoelectrical neuron model, distribute ion channel mechanisms on axonal and dendritic arbors, and simulate electrophysiological and synaptic experiments.The in vitro. The shortfall can be overcome by in silico synthesis of axons, utilizing data from in vivo filled neurons  and to enable community-driven refinement of the reconstruction. Newer versions of the reconstruction will be released periodically, consisting of data structures consistent with the current version. We consider that these reconstructions and the simulations they enable represent a major step in the development of in silico neuroscience.The NMC Portal is part of a broad trend toward the development of large repositories of anatomical and physiological data. Other examples include The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Idiopathic scoliosis induces change in coordination between body segments, spinal anatomy, left-right trunk symmetry and gait pattern. Various treatment methods have being used for scoliosis which includes: physical therapy, occupational therapy, osteopathic therapy, casting, bracing and surgery. However, using brace is a commonly used method in this regard. Although, the influence of brace to reduce the scoliosis curve has been investigated in lots of research studies, there is not enough research regarding the influence of brace on performance of scoliotic subjects while walking and standing. Therefore, the purpose of this study was to evaluate the immediate effect of brace on stability performance of scoliotic subjects and the symmetry of the ground reaction force applied on the right and left feet while walking.Then girls aged between 8 and 12 years were recruited in this study. The gait analysis was assessed using a three-dimensional motion analysis and a force plate (Kistler) in two conditions, with and without Boston brace. Moreover their stability was evaluated by use of force plate. The difference of kinetic and stability parameters between two conditions(with and without Boston brace)was checked by use of paired T-test.For scoliotic patients, comparison of in-brace and out-brace situations revealed a significant decrease in postural sway in brace associated with increase of patient stability. But very short-term bracing in AIS has no significant effect on the symmetry of force applied on right and left limbs during walking .Bracing aligned the vertebral column and improved the abilities of the subject to stand and walk."}
+{"text": "A 36-year-old woman, with no remarkable medical or family history, was admitted to thehospital in cardiogenic shock. Transthoracic echocardiography (TTE) revealed severebiventricular dilation and dysfunction. Several mobile masses consistent with thrombi wereattached to the apex and protruding into the left ventricle (LV) beyond the mid-ventricularlevel (Any condition with severe LV systolic dysfunction increases the probability ofintraventricular thrombus formation. Incidence of systemic embolization is low;nevertheless, it increases in cases of large, protuberant and highly mobile thrombi.Therapeutic approach in this scenario is controversial. It is generally agreed thatanticoagulation should be the initial therapy in most of cases, but there are no specificrecommendations regarding thrombolysis or thrombectomy.TTE is the gold standard technique for diagnosis and stratification of embolic risk, sinceit allows accurate assessment of morphology, mobility and point of attachment of theclot.Conception and design of the research and Analysis and interpretation of the data: LorenzoN; Acquisition of data: Lorenzo N, Restrepo JA, Aguilera MC; Writing of the manuscript:Lorenzo N, Rodriguez D; Critical revision of the manuscript for intellectual content:Lorenzo N, Aguilar R."}
+{"text": "C, the founder of the prion protein family, there has been a constant quest to dissect its biological function and that of its two homologs, Doppel and Shadoo. While clues were greatly anticipated from the generation of PrP null mice, alterations appeared quite imperceptible at first examination, beyond the clear-cut resistance to prion infection. Taking a closer look at these knockout mice, together with the generation of mice invalidated for Doppel and Shadoo has in the end yielded much information on the -sometimes overlapping- roles of these proteins. These in-depth investigations have also explored functions of the prion protein family beyond the central nervous system, which was obviously the first focus of interest since prion diseases are neurodegenerative disorders. This Frontiers Research topic on the promiscuous functions of the prion protein family incorporates contributions ranging from the field of developmental biology to that of structure-function, including aspects related to cell biology, signal transduction, and neuronal homeostasis.From the discovery nearly 30 years ago of the cellular prion protein PrPC deletion (Halliez et al., C expression after the brain, i.e., the placenta (Makzhami et al., C expression in human gestational diseases. The review by Allais-Bonnet and Pailhoux is dedicated to the gonads, a unique tissue where PrPC, Shadoo and Doppel are all expressed, raising the question of a potential redundancy between the three proteins, as well as their roles in reproductive functions (Allais-Bonnet and Pailhoux, C and the pathways involved in epithelial to mesenchymal transition, a process associated with major changes in cell adhesion properties and that physiologically takes place during embryonic development, while also involved in cancer metastasis (Mehrabian et al., C to stem cell biology and its recent association with tumor-initiating cells (Martin-Lanneree et al., C, with special emphasis on the protective role exerted by this protein (Sakudo and Onodera, Starting from the embryo, the contribution by Halliez et al. provides a comprehensive review of the impact of PrP invalidation on embryonic development, compiling data from both mice and zebrafish and highlighting the key cellular pathways affected by PrPC and cell signaling. The mini-review by Roucou elaborates on the connection between PrPC dimerization, proteolytic processing and the recruitment of cell signaling cascades (Roucou, C-related signaling and src family kinases, in contexts ranging from embryonic cell adhesion to regulation of NMDA activity (Ochs and Malaga-Trillo, C against NMDA-dependent excitotoxicity is the focus of the review by Black et al, which also discusses the pathophysiological implications of this regulation as to ischemic injury, neuroinflammation, and Alzheimer's disease (Black et al., C as a cell-surface receptor for Abeta oligomers, and follow-up investigations on the contribution of PrPC to Abeta toxicity, which is summarized in the review by Watt et al. (C to zinc homeostasis, and discusses how age-regulated deregulation of the interplay between PrPC, lipid rafts and zinc may contribute to Alzheimer's disease. The fate of PrPC during aging is further discussed in the review by Gasperini and Legname, which notably highlights the changes in the biochemical properties and lipid raft association of PrPC in aged animals (Gasperini and Legname, Several contributions go down to the molecular scale and focus on the relationship between PrP Roucou, . Ochs ant et al. . This reC, Doppel and Shadoo, as well as their specificities, in relation with their propensity to misfold (Rezaei, Further zooming on the molecule itself, the review by Rezaei provides a global view of the biochemical and structural similarities between PrP Rezaei, .Collectively, these works underscore the advance in our understanding of the functions exerted by the prion protein family and underlines their versatile roles according to the cellular context and interacting partners involved. Finally, they provide some future directions for further dissecting how the deregulation of these proteins functions can cause or contribute to pathological conditions.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Building on momentum in five NIH-supported meetings, \"Advancing the Science of Dissemination and Implementation,\" the NIH convened three separate meetings during 2013-4, each addressing an overarching issue: \"Developing a field-based approach to D&I research training\"; \"Measurement & Standardized Reporting\"; and \"Fit between Investigation and Research design?\"Meeting themes were selected by the NIH D&I Workgroup, addressing pressing needs in the field and high-demand topics from prior meetings. Targeted groups of participants were invited to the meetings, each led by a team of researchers and NIH staff.The training meeting yielded a map of current training, a field wide training vision, and a set of tensions--notably training for a rapidly evolving field. The research design workgroup produced a common terminology that crosses diverse fields of medicine and public health as well as disciplines, and categorized 27 different designs that have been used for dissemination and implementation research. The reporting workgroup identified four broad areas, planning, delivery, evaluation, and long-term outcomes as well as cross-cutting issues to provide reporting consistency. The meetings further generated a set of issues that cross-cut the three topics, including how to reflect the evolution of measurement, design and reporting within training programs and how to train reviewers, editors, decision-makers, and practitioners?The three issue-focused meetings provided opportunity to take stock of the field ten years after the initial NIH D&I meeting and generated papers that both synthesize the stimulate important advances for the field.Reporting guidelines improve the overall depth and quality of manuscripts across specialties and journals. No reporting guidelines for Dissemination and Implementation (D&I) research yet exist. We sought to develop a framework from which D&I reporting guidelines can be derived and to identify ideal metrics.The National Institutes of Health held a series of invited state-of-the-science meetings to address key gaps and opportunities in D&I research in 2013. One of these focused on reporting and evaluation/measurement. This workgroup's objective was to identify key areas in need of better measurement and reporting at all stages of D&I research.The workgroup concluded that the existing plethora of reporting guidelines mandated additional exploration before deriving D&I-specific reporting guidelines, and decided that a D&I framework divided into the planning, delivery, evaluation, and long-term outcome phases of research was an essential first-step.The overriding objective of the D&I framework was to improve population health, health equity, social well-being, and health system efficiency. The workgroup identified the following stages to be essential: Planning: D&I intervention's evidence-basis and mechanism of change, setting characteristics like organizational capacity for change and resources, evaluability and scalability of the implementation strategy, key partnerships, and study design. Delivery: reach; adoption; implementation fidelity, dose, adaptation, and costs. Evaluation: primary outcome effectiveness including measured unintended consequences; explicit description of settings and intervention adaptation, including PRECIS criteria for pragmatism, and robustness of implementation effort. Long-term Outcomes: sustainability, evolvability, transportability; conditions under which the findings hold; and an economic evaluation. In addition, participants identified multiple cross-cutting elements extending across all stages, including: multilevel context; multiple stakeholder perspectives; and societal costs. The next step is to contrast existing reporting guidelines with this new D&I framework to highlight overlap or deficiencies relative to complete and consistent D&I research reporting, and to identify appropriate measurement instruments.The fields of medicine and public health have made great progress in determining whether an intervention is efficacious or effective by conducting carefully crafted randomized clinical trials. In contrast to these designs to evaluate an intervention's efficacy or effectiveness, the designs for dissemination and implementation (D&I) research are not yet well established, a factor that has no doubt has impeded developing our knowledge of effective D&I. By its very nature D&I research is intimately connected to understanding how programs, practices, or policies work in different contexts, so there is more attention in D&I research on external validity, as contrasted to the heavy emphasis on internal validity that many of the randomized efficacy and some effectiveness trials address.This presentation is a product of a workgroup meeting of 10 scientists and NIH staff, convened by NIH to facilitate D&I research. This committee addressed differences in terminology and provided a summary of the designs that have been used in D&I research, including both randomized and non-randomized studies. We identified 27 designs and found it useful to categorize these designs into several broad categories. One category of designs involves what can be termed the \"traditional translational pipeline\" of interventions that move step by step from efficacy, to effectiveness, to implementation research. A second major class of designs involves \"hybrid designs,\" which combine elements of effectiveness and implementation research in one single design. Thirdly, we describe designs that are focused on quality improvement as the primary goal, in contrast to producing generalizable knowledge.Several of these latter designs borrow from diverse areas of engineering.We provide illustrations of these alternative designs and discuss cross-cutting issues, including community engagement and ethics in conducting implementation research.Demand for training in the science of dissemination and implementation is high, reflected in oversubscribed registrations for the NIH meetings on Advancing the Science of D&I and applications to existing training programs. D&I training is provided in a small number of national programs, but given local university courses and degree programs and the growth of on-line webinars, a field-wide perspective on training is needed.NIH convened a meeting of representative U.S. and Canadian trainers and trainees to in September 2013 to assess the field, identify cross-cutting themes, and develop a field-based training vision.The training meeting yielded a map of current training, including NIH funded summer training institutes, a handful of Master's and PhD programs, individual graduate courses, CTSA Cores, and on line webinars. Program aims, participants and funding sources vary, as do training deliverables . Training gaps were identified, including programs at the doctoral level and those designed for decision-makers, and practitioners. Several serious challenges were identified, including: shaping and continually evolving training for a rapidly advancing field, establishing boundaries with related fields, targeting appropriate levels of training specificity versus generality, and sustaining high-intensity training. The meeting also generated issues that cross-cut with the measures/reporting and research design meetings. Participants underscored the importance of a regular national meeting to provide an intellectual home for those trained in D&I. Meeting products will include papers for publication reporting a field-based training vision.The meeting yielded a map of current training in dissemination and implementation research as well as gaps and needs to be met through new training initiatives and a repository of training resources."}
+{"text": "The aim of this study was to analyze current scientific impact of Ss Cyril and Methodius University of Skopje, Republic of Macedonia in the Scopus Database (1960-2014).Affiliation search of the Scopus database was performed on November 23, 2014 in order to identify published papers from the Ss Cyril and Methodius University of Skopje (UC&M), Republic of Macedonia. A total number of 3960 articles  were selected for analysis (1960-2014). SCImago Journal Rank (SJR), Source Normalized Impact per Paper (SNIP) and h-index were calculated from the Scopus database.The number of published papers was sharply increased with maximum of 379 papers in 2012 year. The largest number of papers has been published in Macedonian Journal of Medical Sciences, Journal of Molecular Structure, Lecture Notes in Computer Science, Acta Pharmecutica, and Macedonian Journal of Chemistry and Chemical Engineering. The biggest SJR and SNIP has journal Nephrology Dialysis Transplantation. First three places of the top ten authors belong to Dimirovski GM, Gavrilovska L, and Gusev M. Top three places based on Scopus h-index  belong to Kocarev L, Stafilov T, and Polenakovic M. The majority of papers originate from UC&M, but significant numbers of papers are affiliated to Faculty of Medicine, Faculty of Pharmacy, and Institute of Chemistry as members of UC&M, as well as Macedonian Academy of Sciences and Arts. Articles are the most dominant type of documents followed by conference papers, and review articles. Medicine is the most represented subject.Officials of the Ss Cyril and Methodius University of Skopje should undertake more effective and proactive policies for journal publishers and their Editorial Boards in order to include more journals from UC&M in the Scopus database. Scopus is the world\u2019s largest abstract and citation database of peer-reviewed literature with smart tools that track, analyze and visualize research. Easy to use and comprehensive, Scopus is designed to quickly find the information researchers\u2019 need. Scopus indexes over 20,500 titles from 5,000 publishers worldwide; contains 49 million records, 78% with abstracts; includes over 5.3 million conference papers; and provides 100% Medline coverage  and one in Trnava, Slovakia [AF-ID (\u201cUniversity of SS Cyril and Methodius Trnava\u201d 60021677)] which was excluded from analysis.A total number of 3960 articles, all from Ss Cyril and Methodius University , were selected for analysis (1960-2014). SCImago Journal Rank (SJR), Source Normalized Impact per Paper (SNIP) and h-index were calculated from the Scopus database [The number of publication in the period of 1960-1991 year was very small (1-29 papers per year). Starting of 1991 year, the number of published papers was sharply increased with maximum of 379 papers in 2012 year .The largest number of papers from Ss Cyril and Methodius University of Skopje have been published in Macedonian Journal of Medical Sciences (136 papers), followed by Journal of Molecular Structure (79 papers), Lecture Notes in Computer Science (46 papers), Acta Pharmecutica (38), and Macedonian Journal of Chemistry and Chemical Engineering (37 papers). The rest of journals published less than 36 papers  top. TheThe number of papers published by top ten authors is shown in Scopus Hirsh index (h-index) for the top ten authors affiliated to Ss Cyril and Methodius University of Skopje was presented as calculated by Scopus. We can see from the The biggest number of papers belongs to Ss Cyril and Methodius University (3051 papers), but significant number of papers belongs to Faculty of Medicine, Ss Cyril and Methodius University (860 papers), Faculty of Pharmacy, Ss Cyril and Methodius University (145 papers), Institute of Chemistry, Cyril and Methodius University (138 papers), as well as Macedonian Academy of Sciences and Arts (105 papers)  left. MoDocuments by type and documents by subject area are published by Ss Cyril and Methodius University of Skopje, shown in In this paper analysis of documents affiliated to Ss Cyril and Methodius University of Skopje deposited in the Scopus database (1960-2014) is presented. Starting of 1991 year, the number of published papers was sharply increased with maximum of 379 papers in 2012 year. The largest number of papers from Ss Cyril and Methodius University of Skopje has been published in Macedonian Journal of Medical Sciences, Journal of Molecular Structure, Lecture Notes in Computer Science, Acta Pharmecutica, and Macedonian Journal of Chemistry and Chemical Engineering. The biggest SCImago journal rank per year (SJR) and Source Normalized Impact per Paper (SNIP) has journal Nephrology Dialysis Transplantation. First three places of the top ten authors belongs to Dimirovski GM, Gavrilovska L, and Gusev M. Top three places based on Scopus h-index  belongs to Kocarev L, Stafilov T, and Polenakovic M.The majority of papers originate from Ss Cyril and Methodius University of Skopje , but significant number of papers are affiliated to Faculty of Medicine, Faculty of Pharmacy, and Institute of Chemistry as a members of Ss Cyril and Methodius University of Skopje, as well as Macedonian Academy of Sciences and Arts. Most of the papers affiliated to Ss Cyril and Methodius University of Skopje originate from Macedonia, Yugoslavia, United States, and Germany. Articles are the most dominant type of documents followed by conference papers, and review articles. Medicine is the most represented subject. Engineering, computer science, chemistry, biochemistry, genetics and molecular biology, physics and astronomy are represented in more than 10%.From the top 10 journals participating in the Ss Cyril and Methodius University of Skopje publishing, only two of them are published in Republic of Macedonia . The biggest SCImago journal rank per year and the biggest Source Normalized Impact per Paper have the journal Nephrology Dialysis Transplantation, published outside the Republic of Macedonia. Thus, the impact of journals from the Ss Cyril and Methodius University of Skopje participating in Scopus database is very small. Other journals supported, attached or affiliated to mention UC&M as a publisher are not participating at all in the Scopus database. Officials of the UC&M should undertake more effective and proactive policies for journal publishers and their Editorial Boards in order to include more journals from UC&M in the Scopus database.http://www.researcherid.com/) [http://orcid.org/) [Analysis of author rank is very sensitive issue. In this analysis total number of published papers in Scopus database was bigger than the number of papers affiliated to Ss Cyril and Methodius University of Skopje in the same database. These differences are caused by affiliation changes of the top ten authors. For example, Dimirovski GM was affiliated with 121 papers to Ss Cyril and Methodius University of Skopje, and the rest of 139 papers are affiliated to Dogus Universitesi Istanbul, School of Engineering, Istanbul, Turkey. Similarly, Soptrajanov B, Polenakovic M, and Kocarev L have additional profiles  as a result of their affiliation to Macedonian Academy of Sciences and Arts. Additional problems arise when author impact analysis search is used: i) some authors have used different names in different periods of time; ii) some authors transliterate their names in several different ways; iii) some authors add or do not add \u201cv\u201d; iv) some authors use only one of their two surnames; v) there are some identical names and surnames in the world for different researchers . All of id.com/)  and in tid.org/) . IdentifFor the first time in Republic of Macedonia, current scientific impact of academic staff employed at the Institutes of the Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Republic of Macedonia, was analyzed and published. Based on different citation values and citation indexes, it was concluded that Institutes of the Faculty of Medicine are very heterogeneous with three groups of institutes: institutes with higher scientific impact; institutes with intermediate scientific impact, and institutes with low scientific impact . ScientiRecently we presented the results of SCImago Institutions Rankings for R. Macedonia (2009-2012) and show that only Ss Cyril and Methodius University of Skopje were included in the SIR with world rank of 1726 to 1821. Regional rank in Eastern Europe was gradually increased from 156th in 2009 to 127th in 2013 year [In summary, analysis of documents affiliated to Ss Cyril and Methodius University of Skopje deposited in the Scopus database (1960-2014) have shown that the number of published papers was sharply increased with maximum of 379 papers in 2012 year. The largest number of papers from Ss Cyril and Methodius University of Skopje has been published in Macedonian Journal of Medical Sciences. The biggest SCImago journal rank per year and Source Normalized Impact per Paper has journal Nephrology Dialysis Transplantation. First three places of the top ten authors belong to Dimirovski GM, Gavrilovska L, and Gusev M. Top three places based on Scopus h-index  belong to Kocarev L, Stafilov T, and Polenakovic M. Officials of the UC&M should undertake more effective and proactive policies for journal publishers and their Editorial Boards in order to include more journals from UC&M in the Scopus database."}
+{"text": "Development of normal hematopoietic cells is an ordered multi-step process, tightly regulated by a complex network of intrinsic factors and microenvironmental cues that control cell fate decisions within the bone marrow (BM)  has been the most popular systems biology tool for the study of normal and leukemic hematopoiesis. This type of modeling is useful for the time evolving non-linear competition between normal and leukemic cell populations, considering multiple compartments to simulate different maturation stages or multiclonal behavior  acting collectively within a dynamical complex context . By tracking HSC replication, the expansion of the hematopoietic system was apparent from birth to adolescence, when steady-state levels are reached. Stochastic modeling of replication kinetics has shown to be useful to predict cell rebounding upon hematopoietic transplantation or under emerging conditions  proteins, and other molecules produced and expressed by niche cellular elements, may dictate the final fate decision , multi-compartment (differentiation stages), and agent-based  modeling of leukemia pathobiology is a promising tool for the study of feedback pathways in the searching of auxiliary strategies for leukemia treatment, normal hematopoiesis rebounding, and relapse delay. The construction of novel \u201csystems within a system\u201d integrative theoretical models (Figure To this extent, the use of \u201cedge-technology\u201d s Figure  that betJE: Analysis of published data, discussion of the topic-related information, drafting, and writing the paper. LM and RP: Conception and design of the Opinion Article, analysis of published data, discussion of the related information, drafting, and writing the paper. Critical review of the intellectual content.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Following the publication of our article , we notiAG performed the majority of experiments, analyzed the data, and drafted the manuscript. VH provided MDA231 and MDASrc ezrin KD and EZR/WT-expressing cell lines and contributed to the design of experiments. AS performed the TMA staining for Src/Ezrin, image analysis, clinical outcome correlations, and VEGF-A/-C western blots. DL supervised AS in establishing and optimizing the quantification of Src/ezrin in histopathological tissue samples by multi-channel immunofluorescence. MH assisted with the aortic rings experiment and analysis. NL assisted in quantification of angio/lymphangiogenic activity in tumour xenograft H&E sections. KN assisted in design and interpretation of aortic ring assay and analysis. YM collected the clinical outcome data for the in-house human breast cancer cohort and assisted in analysis and interpretation of clinical correlative studies. SS assessed the tumours in our breast cancer cohort and oversaw the construction, staining, and analysis of all TMA-related experiments. BEE conceived the project, supervised experiments & analysis, and contributed to writing of the final manuscript.All authors have made substantial contribution to the design of experiments, data analysis, and drafting of the manuscript. All authors have reviewed and approved the final version of this manuscript and agree to be accountable for all aspects of the work presented herein."}
+{"text": "Introduction: The burden of cervical cancer is large and growing in developing countries, due in large part to limited access to screening services and lack of human papillomavirus (HPV) vaccination. In spite of modern advances in diagnostic and therapeutic modalities, outcomes from cervical cancer have not markedly improved in recent years. Novel clinical trials are urgently needed to improve outcomes from cervical cancer worldwide.Methods: The Cervix Cancer Research Network (CCRN), a subsidiary of the Gynecologic Cancer InterGroup, is a multi-national, multi-institutional consortium of physicians and scientists focused on improving cervical cancer outcomes worldwide by making cancer clinical trials available in low-, middle-, and high-income countries. Standard operating procedures for participation in CCRN include a pre-qualifying questionnaire to evaluate clinical activities and research infrastructure, followed by a site visit. Once a site is approved, they may choose to participate in one of four currently accruing clinical trials.Results: To date, 13 different CCRN site visits have been performed. Of these 13 sites visited, 10 have been approved as CCRN sites including Tata Memorial Hospital, India; Bangalore, India; Trivandrum, India; Ramathibodi, Thailand; Siriaj, Thailand; Pramongkutklao, Thailand; Ho Chi Minh, Vietnam; Blokhin Russian Cancer Research Center; the Hertzen Moscow Cancer Research Institute; and the Russian Scientific Center of Roentgenoradiology. The four currently accruing clinical trials are TACO, OUTBACK, INTERLACE, and SHAPE.Discussion: The CCRN has successfully enrolled eight sites in developing countries to participate in four randomized clinical trials. The primary objectives are to provide novel therapeutics to regions with the greatest need and to improve the validity and generalizability of clinical trial results by enrolling a diverse sample of patients. Cervical cancer is the fourth most common cancer in women worldwide with almost 530,000 cases diagnosed in 2012 , a subsidiary of the Gynecologic Cancer InterGroup (GCIG), is a multi-national, multi-institutional consortium of physicians and scientists focused on improving cervical cancer outcomes worldwide by making cancer clinical trials available in low-, middle-, and high-income countries. In this manuscript, we describe the early activities of the CCRN, with a focus on describing a model of collaborative capacity-building, with the overall goal of promoting cervical cancer research and improving access to novel therapies.The CCRN is a subsidiary of the GCIG, a non-profit network of appointed representatives from international cooperative research groups for clinical trials in gynecologic cancers. The GCIG was established in 1990s with the goal of promoting and conducting high quality clinical trials to improve outcomes for women with cancers of the ovary, uterus, and cervix. The GCIG has been highly successful in completing clinical trials, publishing results, and developing consensus conferences.The CCRN developed to address the lack of cervical cancer clinical trials, increase enrollment on existing trials, and improve the standards of cancer care in low- and middle-income countries. In light of the limited improvement in survival in locally advanced cervical cancer in the decades since chemoradiation became the standard of care, the vision of the CCRN was to provide infrastructure and support for cancer clinical trials in developing nations that have a significant burden of cervical cancer.The CCRN reports to and is guided by the Executive Board of Directors of the GCIG. This Board has regularly scheduled teleconferences and semi-annual meetings. The chair and co-chair of the CCRN are elected for 3-year terms by voting members. The chair of the CCRN serves on the Executive Board of the GCIG and a formal report of activities and progress is made to the membership at the General Assembly at each semi-annual meeting.The mission of the CCRN was formulated by the committee chair and participating members. The literature was evaluated for best practices for clinical trials within gynecologic cancers, with emphasis on methods for low- and middle-income countries in which clinical trial resources are often limited. The CCRN then developed standard operating procedures (SOP) to evaluate potential participating sites to ensure appropriate infrastructure prior to clinical trial enrollment. The principal investigators of the CCRN trials normally select potential sites. The SOP workflow is demonstrated in Figure The SOP includes a pre-qualifying questionnaire to evaluate clinical activity, site resources, clinical trials infrastructure, radiation therapy treatment records, radiotherapy quality assurance, and clinical management documentation Table . AdditioFor potential study sites deemed eligible after the pre-qualifying survey, a site visit must be performed by an audit team to evaluate the appropriateness and readiness to participate in CCRN trials. Infrastructure, the physical plant, and human resources are evaluated to ensure that clinical trial participation can succeed. The audit team typically includes one clinical specialist and one clinical trials manager. Various measures of quality assurance are performed, depending on the requirements of the available clinical trial. To date, the CCRN has received limited funding from the International Gynecologic Cancer Society (IGCS) and the GCIG, as well as support from the NCI.To date, 13 different CCRN site visits have been performed. Of these 13 sites visited, 10 have been approved as CCRN sites including Tata Memorial Hospital, India; Bangalore, India; Trivandrum, India; Ramathibodi, Thailand; Siriaj, Thailand; Pramongkutklao, Thailand; Ho Chi Minh, Vietnam; Blokhin Russian Cancer Research Center; the Hertzen Moscow Cancer Research Institute; and the Russian Scientific Center of Roentgenoradiology. Approval with contingencies has been granted to sites in Cluj, Romania, and Minsk, Belarus.Through significant efforts within the Cervix Cancer Committee at the GCIG, four multi-national cervical cancer clinical trials suitable for both developed and developing nations have successfully been opened.The Tri-weekly Administration of Cisplatin in LOcally Advanced Cervical Cancer Trial , developed by investigators from the Korean Gynecologic Oncology Group (KGOG) and the Thai Cooperative Group, is a randomized phase III study that compares weekly chemotherapy for advanced cervix cancer to every-3-week chemotherapy. Preliminary data from a phase II trial by the KGOG suggest that every-3-week chemotherapy may confer a survival benefit .The OUTBACK Trial is led by investigators from the Australia/NewZealand Gynecologic Oncology Group (ANZGOG). This study is a randomized phase III trial evaluating the efficacy of extended adjuvant chemotherapy in women with advanced cervix cancer compared to the standard of weekly cisplatin chemotherapy and definitive radiotherapy. The OUTBACK chemotherapy consists of four cycles of carboplatin and paclitaxel chemotherapy administered after standard concurrent chemoradiotherapy. The rationale for the study is a meta-analysis of several studies that showed adjuvant chemotherapy to be a promising approach .The INTERLACE Trial is headed by the National Cancer Research Institute (NCRI) from the United Kingdom. This is a randomized phase III study evaluating neoadjuvant chemotherapy prior to concurrent chemoradiotherapy for women with advanced cervix cancer compared to concurrent chemoradiotherapy alone. The goal of this study is to improve compliance with additional chemotherapy by giving it before standard chemoradiotherapy, as opposed to after standard chemoradiotherapy.The SHAPE Trial is spearheaded by investigators from the NCIC Clinical Trials Group in Canada. This randomized phase III trial is evaluating radical hysterectomy versus simple hysterectomy in women with early-stage cervix cancer. The primary endpoint is freedom from pelvic failure.Each approved CCRN site chooses to participate in one or more of the four available clinical trials. To date, 48 patients have been enrolled.The greatest burden of cervical cancer is in developing countries, particularly parts of Africa, Central and South America, Eastern Europe, India, and other parts of Asia . The outThere are many challenges in conducting multi-national clinical trials, particularly in low-resource settings , 15. HumIn spite of these real and complex challenges, there are tremendous opportunities to enhance clinical trials results and improve cervical cancer outcomes through collaboration, creativity, and persistence. Rapid improvements in technology, particularly internet-based approaches, have made communication and quality assurance checks more feasible, timely, and cost-effective. Investments in research training and infrastructure development have the potential to influence not only cervical cancer clinical trial involvement but also standard care and care for other types of cancers. While sophisticated translational trials involving complex imaging and biomarker measurement will be confined to core GCIG settings, pragmatic trials that are aimed at defining worldwide standard of care, as well as trials directed at practices in low- and middle-income countries, are within the capability of the CCRN.In summary, the CCRN has developed a methodology to evaluate potential clinical trial enrollment sites in low- and middle-income countries to make cervical cancer clinical trials available in countries with the highest burden of disease. The CCRN has successfully enrolled 10 sites in developing countries to participate in four randomized clinical trials. The primary objectives are to provide novel therapeutics to regions with the greatest need and to improve the validity and generalizability of clinical trial results by enrolling a diverse sample of patients, with the ultimate goal of improving outcomes from cervical cancer worldwide.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Despite major advances in the treatment of hematological diseases over the last decades, allogeneic hematopoietic stem cell transplantation  still remains the only curative option for many of them. According to the recent survey of the European Society of Blood and Marrow Transplantation (EBMT), nearly 15\u2009000 alloHSCT are currently performed each year across Europe and EBMT-affiliated countries (Approximately 50% of these patients will develop a major late complication \u2013 chronic graft-vs-host disease (cGVHD), a multi-organ allo- and auto-immune disorder affecting the skin, lungs, mouth, liver, eyes, joints, and gastrointestinal and genital tracts -4. As a Chronic GVHD can last for many years causing severe medical, social, and quality of life problems, as well as significantly impacting health-related costs and health care management. A recently published report from the Center for International Blood and Marrow Transplant Research has identified a clear increase in the incidence of cGVHD from 1995 to 2007 due to the more frequent use of peripheral blood graft instead of bone marrow, unrelated donors, and older recipients  Consensus classification was developed in 2005 and prospectively validated ,6-10. HoThe German-Austrian-Swiss cGVHD consortium assessed the usefulness of the NIH criteria in routine clinical practice and reported high rates of acceptance for definitions of cGVHD, as well as overall and organ-specific NIH cGVHD severity scoring among the vast majority of participants . An inteTherefore, there has been significant research activity and renewed interest in cGVHD in the world over the last decade. It is likely that the current better characterization of cGVHD, standardization of research tools, and numerous new treatment opportunities will lead to improved clinical outcomes, such as clinical symptoms, function status, quality of life, morbidity, and survival.However, not a single agent has yet been approved for cGVHD prevention or treatment, neither by the US Food and Drug Administration (FDA) nor by the European Medicines Agency (EMA). The current standard front-line steroid therapy has a 50% failure rate with significant toxicity, and there are no standards for second-line (and beyond) therapeutic options.Croatian Medical Journal presents several excellent articles that are a product of these enhanced international collaborations and efforts by teams across Europe to address cGVHD.The focus now in this field is on further in-depth study of the biology of cGVHD, developing and validating new biomarkers, and pursuing clinical trials of new agents that would eventually develop pathways to their FDA and EMA regulatory approvals. The aim is to develop more effective, less toxic, and more targeted treatments that will not interfere with the beneficial graft-vs-tumor effects. To advance this field and break the 30-year-old suboptimal treatment paradigms, the goal is that each cGVHD patient should be either treated in a clinical trial or at least should be documented within a registry capturing essential clinical data on the course of cGVHD. The tools and opportunities to harness cGVHD and create better and safer alloHSCT are in our hands right now. This issue of the Acknowledgment This work is supported by the Unity Through Knowledge Fund project entitled \u201cClinical and Biological Factors Determining Severity and Activity of Chronic Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation.\u201d The opinions expressed here are those of the authors and do not represent the official position of the National Institutes of Health or the US Government."}
+{"text": "In 2014, the World Health Organization (WHO) declared two \"public health emergencies of international concern\", in response to the worldwide polio situation and the Ebola epidemic in West Africa respectively. Both emergencies can be seen as testing moments, challenging the current model of epidemic governance, where two worldviews co-exist: global health security and humanitarian biomedicine.The resurgence of polio and the spread of Ebola in 2014 have not only exposed the weaknesses of national health systems, but also the shortcomings of the current global health regime in dealing with transnational epidemic threats. These shortcomings are of three sorts. Firstly, the global health regime is fragmented and dominated by the domestic security priorities of industrialised nations. Secondly, the WHO has been constrained by constitutional country allegiances, crippling reforms and the limited impact of the (2005) International Health Regulations (IHR) framework. Thirdly, the securitization of infectious diseases and the militarization of humanitarian aid undermine the establishment of credible public health surveillance networks and the capacity to control epidemic threats.th World Health Assembly address these fundamental issues.The securitization of communicable diseases has so far led foreign aid policies to sideline health systems. It has also been the source of ongoing misperceptions over the aims of global health initiatives. With its strict allegiance to Member States, the WHO mandate is problematic, particularly when it comes to controlling epidemic diseases. In this context, humanitarian medical organizations are expected to palliate the absence of public health services in the most destitute areas, particularly in conflict zones. The militarization of humanitarian aid itself threatens this fragile and imperfect equilibrium. None of the reforms announced by the WHO in the wake of the 68The online version of this article (doi:10.1186/s13031-015-0058-1) contains supplementary material, which is available to authorized users. Margaret Chan, Director General of the World Health Organization (WHO), declared a public health emergency of international concern after consultation with an Emergency Committee of experts convened under the provisions of the revised (2005) International Health Regulations (IHR) . F. Fth rev the BWC , while i the BWC . The pro the BWC , 31.TablThe case of Syria is illustrative of the limitations imposed by UN mandates on the capacity of the WHO to ensure adequate public health responses in areas of civil conflicts . UN agenArmed conflict that flies in the face of international humanitarian law. Civil unrest. Migrant populations. Weak border controls. Poor routine immunization coverage. Bans on vaccination by militant groups. And the targeted killing of polio workers\u201d [The setbacks of the Global Polio Eradication Initiative in its final stage could have been anticipated precisely in those conflict zones where access and trust are paramount. However, new counter-terrorism and foreign policies of Western coalitions are enmeshing humanitarian action into international security agendas, which can discredit the neutrality of all humanitarian actors, for example when relief and health care are provided to secure the acceptance of counter-insurgency operations , 40. Theworkers\u201d . Ironicaworkers\u201d .A consensus has emerged to say that the disastrous situation in Guinea, Liberia and Sierra Leone reflects the disarray of national health systems and a vacuum in global health governance , 44. Witth World Health Assembly consist in: (i) integrating WHO outbreak and emergency response units, (ii) the creation of a global health-emergency workforce, (iii) setting up an emergency contingency fund, and (iv) advancing the research and development of medical products for infectious diseases of epidemic potential, and (v) strengthening health systems. One could muse over the fact that such measures are belated, obvious or simply represent an attempt to resurrect similar assets dismantled by a recent round of crippling reforms. More than with circumstantial resolutions, global health would be served by genuine reforms of the current regime, emphasizing universal health values instead of security and diplomacy interests. This would entail a new constitutional mandate for the WHO. Reflecting on the future of global health governance, Lawrence Gostin has called for a new Framework Convention on Global Health [It is uncertain how the current global health security regime will evolve , particul Health . With a th World Health Assembly address these fundamental issues.The setbacks of the Global Polio Eradication Initiative and the delayed control of the Ebola epidemic in West Africa reflect a fragmented approach to outbreak preparedness. More broadly, they point to profound flaws in the current regime of global health governance, which is guided by foreign affairs and security policies. The securitization of communicable diseases has so far led foreign aid policies to sideline health systems. It has also been the source of ongoing misperceptions over the aims of global health initiatives. With its strict allegiance to Member States, the WHO mandate is problematic, particularly when it comes to controlling epidemic diseases. In this context, humanitarian medical organizations are expected to palliate the absence of public health services in the most destitute areas, particularly in conflict zones. The militarization of humanitarian aid itself threatens this fragile and imperfect equilibrium. None of the reforms announced by the WHO in the wake of the 68"}
+{"text": "In this case, calcium-phosphorus index of animals\u2019 enamel, with high caries resistance, have no significant differences with the calcium-phosphorus index of human enamel rather, it is even lower.Investigation of the structure and morph-chemistry of enamel and dentin should ultimately lead to development of effective caries prevention strategies. Accordingly, we have studied the nanostructure and morph-chemistry of teeth utilizing X-ray microanalysis, scanning electron microscopy and atomic force microscopy and tunneling. The results suggest that the surface of primary and permanent teeth enamel is not as smooth as previously considered. Rather enamel surface has apertures which are conducive to realization of morphological and chemical processes. Detailed examination of the enamel surface reveals that most of anatomical defects/holes do not end blindly; rather, they penetrate the enamel surface (resembling \"tunnels\"), branch and intersect each other to form enamel \"bridges\" in dentin. Examination of enamel using atomic-powered and tunnel microscopy not only confirm the presence of these nanostructures, - but also help discern more refined characteristics. Consequently, it appears that the tunnels intersect one another at 90 degrees angle. The morph-chemical examination of enamel reveals differences in the structure of intact compared to carious enamel and dentin. Calcium and phosphorus - are the main structural elements of enamel and dentin. The amount of potassium, sulfur and chlorine increases respectively in caries pathology, while the concentration of sodium, silicon, and especially magnesium decreases. The same pattern is observed for dentin. These observations suggest that high concentration of magnesium increases, while chlorine and sulfur decrease the effectiveness of the protective properties of enamel thereby leading to alteration of caries resistance. Subsequently, we examined teeth obtained from animals. In beaver\u2019s enamel, the content of magnesium is higher (seven fold) compared to those of human. The concentration of chlorine and sulfur are higher in people\u2019s enamel that confirms our previous researches concerning the impact of these elements on the caries resistance level of enamel. Differences in microelements structure, the prevalence of magnesium in beaver\u2019s enamel, determined the differences in microhardness of the enamel. The content of the elements is 1.5 times higher in tooth enamel of beavers than humansIn conclusion, the novel discovery of structural formations and the morph-chemical structure of human and animal enamel may ultimately lead to identification of a new approach to caries prevention and development of new, more effective formulation of oral hygiene products."}
+{"text": "This special issue of the International Journal of Environmental Research and Public Health includes peer-reviewed publications from investigators who participated in this conference.Health disparities have been defined as a particular type of health difference closely linked with social, economic and/or environmental disadvantage. The National Institute on Minority Health and Health Disparities (NIMHD) at the National Institutes of Health, has a comprehensive portfolio of grants that fund scientific research to improve racial/ethnic minority health and eliminate health disparities. The  The scientific program included general, and concurrent sessions, panel discussions and poster sessions. The conference also included specialized technical workshops; workshops on collaboration, scientific leadership, grantsmanship, and mentoring; and meet the expert sessions focused on career development for early stage investigators planned in collaboration with NIH staff. The conference offered unparalleled opportunities for networking and exchanging ideas, forging new scientific collaborations, resource sharing and opportunities for specialized training.The 2014 Minority Health and Health Disparities Grantees\u2019 Conference was held 1\u20133 December, in National Harbor, Maryland. The theme of the symposium, State of the Science in Achieving Global Health Equity-Past and Present Advances and Future Directions-highlighting best practices in biomedical, behavioral, population and health policy research that contribute to improvements in US and global health equity among populations who carry the burden of health disparities. Collaborative, sustainable, replicable and culturally appropriate research promoting prevention, reduction and elimination of heath disparities were also discussed;Achieving Health Equity Through a Population Health Research Paradigm-highlighting effective population health interventions that are often multi-sectorial and community engaged; Transdisciplinary Social, Behavioral and Clinical Approaches for Understanding and Achieving Health Equity in Cardiovascular, Cerebrovascular, and Related Peripheral-Vascular Diseases-highlighting ethnic- and racial-specific variations and determinants underlying health disparities in cardiovascular, cerebrovascular and related peripheral-vascular diseases; andTransdisciplinary Collaborations: A Call to Action-highlighting evidenced-based transdisciplinary research approaches to reduce health disparities, and the strategies to promote diversity in the biomedical research workforce.Health disparities have been defined as a particular type of health difference closely linked with social, economic, and/or environmental disadvantage. Hence, health disparities adversely affect groups of people who have systematically experienced greater obstacles to health based on their ethnicity or race, gender or sex, age, religion, socioeconomic status, mental health, physical disability, or other relevant characteristics . Health In addition to keynote lectures and panels, 1364 abstracts were presented in thirty concurrent scientific sessions and three poster sessions. Research presented spanned a variety of disease areas-cardiovascular, diabetes, obesity, cancer, mental health, infectious disease, stroke and other diseases that disproportionately impact health disparity populations. Studies examined the etiology of disparities; the intersection of biological and behavioral risk factors, the physical environment, social determinants of health, and public health and health care system factors in addressing health disparities; and multi-level community interventions and other population-based studies to improve minority health and reduce health disparities. International Journal of Environmental Research and Public Health is dedicated to the publication of selected peer-reviewed manuscripts resulting from conference presentations. Highlights on a few of these research papers are as follows:This special issue of the Carriere and collaborators  studied Ala54Thr) polymorphism of the fatty acid binding protein 2 (FABP) on HDL cholesterol in Mexican-Americans with type 2 diabetes (T2D). They found that the Thr54 allele carriers who were heterozygous or homozygous for the threonine-encoding allele had lower HDL cholesterol and higher triglyceride levels at baseline compared to the Ala54 homozygotes. They concluded that the Ala54Thr polymorphism of FABP2 modulates HDL cholesterol in Mexican-Americans with T2D and that Thr54 allele carriers may be responsive in interventions that include dietary changes.Salto and collaborators  conductein-vitro study results that targeting the gain-of-function pathways may improve treatment efficacy when R248Q mtp53 proteins are expressed in TNBC.Shtraizent and collaborators  performeMiranda-Diaz and collaborators  investigIn a retrospective epidemiologic study, Holmes and collaborators  investigUsing the Jackson Heart Study as a model, Addison and collaborators  highlighUsing both GIS and regression analysis models, Mathis and collaborators  conducteWe would like to thank the conference organizing committee, scientific review committee, other conference committees and staff, and the National Institute on Minority Health and Health Disparities leadership and staff for their contributions to making the conference a success and publication of this special issue possible."}
+{"text": "The increase in body weight is a serious global public health problem, with high risk of associated diseases such as diabetes, cardiovascular disease, hypertension, and some forms of cancer. The option for foods with high energy value but poor in micronutrients increases the nutritional status and contributes to the deficiency of important minerals in human health. The use of minerals, among them calcium and magnesium, to control body weight has been the object of several studies.The purpose of this study was to investigate the effect of with the calcium and magnesium supplementation in diets offered to Wistar rats.A biological assay was conducted with 24 animals, distributed in four groups of six. The control group (GI) received feed prepared according to the AIN-93G standard ; the calcium-supplemented group (GII) received this diet containing approximately four times this mineral; the group supplemented with magnesium (GIII) received approximately four times this mineral; and the lipid-supplemented group (GIV) received it with a 14% addition of vegetable oil, but no mineral supplementation. The diets were isocaloric . The variables measured were weight, feed efficiency coefficient, liver and kidney histology, and the following laboratory parameters: total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TG), and serum calcium and magnesium levels.After 35 days, the GII animals showed the lowest level of feed efficiency, when compared with the other groups, and consequently exhibited lower body weight, with a significant increase in VLDL, TG and serum calcium levels and a decrease in serum magnesium. The morphological analysis of liver and kidney revealed tissue damage in all groups that received supplementation.The supplementation with calcium proved a possible resource for body weight control, in contrast with that observed in the animals that received magnesium supplementation, whose results were similar to those of controls."}
+{"text": "Background.\u2003Following the 65th World Health Assembly (WHA) resolution on intensification of the Global Poliomyelitis Eradication Initiative (GPEI), the Nigerian government, with support from the World Health Organization (WHO) and other partners, implemented a number of innovative strategies to curb the transmission of wild poliovirus (WPV) in the country. One of the innovations successfully implemented since mid 2012 is the WHO's engagement of surge capacity personnel.Methods.\u2003The WHO reorganized its functional structure, adopted a transparent recruitment and deployment process, provided focused technical and management training, and applied systematic accountability framework to successfully manage the surge capacity project in close collaboration with the national counterparts and partners. The deployment of the surge capacity personnel was guided by operational and technical requirement analysis.Results.\u2003Over 2200 personnel were engaged, of whom 92% were strategically deployed in 11 states classified as high risk on the basis of epidemiological risk analysis and compromised security. These additional personnel were directly engaged in efforts aimed at improving the performance of polio surveillance, vaccination campaigns, increased routine immunization outreach sessions, and strengthening partnership with key stakeholders at the operational level, including community-based organizations.Discussion.\u2003Programmatic interventions were sustained in states in which security was compromised and the risk of polio was high, partly owing to the presence of the surge capacity personnel, who are engaged from the local community. Since mid-2012, significant programmatic progress was registered in the areas of polio supplementary immunization activities, acute flaccid paralysis surveillance, and routine immunization with the support of the surge capacity personnel. As of 19 June 2015, the last case of WPV was reported on 24 July 2014. The surge infrastructure has also been instrumental in building local capacity; supporting other public health emergencies, such as the Ebola outbreak response and measles and meningitis outbreaks; and strengthening the integrated disease surveillance and response. Due to weak health systems in the country, it is vital to maintain a reasonable level of the surge capacity for successful implementation of the 2013\u20132018 global polio endgame strategy and beyond. In May 2012, the 65th World Health Assembly (WHA) resolved to intensify the Global Polio Eradication Initiative (GPEI) and declared the completion of poliovirus eradication a programmatic emergency for global public health , 4.In October 2011, Nigeria announced the establishment of a Presidential Task Force on Polio Eradication to provide highest-level leadership to the national effort to guide the polio eradication initiative (PEI) back on track. The task force oversaw a number of initiatives aimed at rapidly achieving the goal of interrupting poliovirus transmission within the shortest time possible. However, an in-depth review of the performance of polio eradication activities in the highest-risk states and local government areas (LGAs) indicated that the high-level commitment at federal and state level did not always translate into improved program quality at the operational level . The 23rThe health system in Nigeria faces multiple challenges, including poor healthcare infrastructure, underfunding of programs, frequent strikes by health workers, and weak oversight at the lower levels \u201310. In rFurthermore, in January 2012, Nigerian high level government officials visited India to review factors that contributed to the successes in the polio eradication efforts in that country . One of The World Health Organization (WHO) team in Nigeria has a broad range of public health practitioners comprising physicians, epidemiologists, pharmacists, logisticians, laboratory experts, data managers, communication experts, program managers, and administrative support staff providing technical support for polio eradication, routine immunization (RI), and accelerated control of vaccine-preventable diseases at national and subnational levels. The WHO was uniquely positioned to implement the surge project as per the mandate from 41st WHA and its physical presence in all 36 states of the federation and the federal capital territory . Prior tTo this end, in March 2012, WHO-Nigeria developed a project to substantially increase its technical capacity to support planning, implementation, monitoring, and evaluation of critical PEI activities, particularly in the states, LGAs, and wards (districts) at highest risk for polio transmission, to ultimately achieve interruption of poliovirus transmission within the shortest time possible.In this article, we document the recruitment, deployment, and management processes and how implementation of the WHO's surge capacity project contributed to the improvement of PEI and RI performance indicators.We conducted a retrospective review of publications by global and local PEI partners and working groups, WHO internal documents, secondary sources, and unpublished reports to obtain data for this article.In early 2012, the WHO country office, with input from key stakeholders, submitted a proposal to the Bill and Melinda Gates Foundation to support the implementation of the surge capacity project. Between 2012 and 2015, the Bill and Melinda Gates Foundation allocated $84 million to support the surge capacity project.The surge capacity project focused on 11 states at high risk for polio transmission , selected on the basis of an epidemiological risk analysis. The states were Bauchi, Borno, Jigawa, Kaduna, Kano, Katsina, Kebbi, Niger, Sokoto, Yobe, and Zamfara. The project aimed to support the HR states to achieve and sustain quality supplemental immunization activities (SIAs) required to ensure poliovirus transmission is interrupted, to maintain certification standard acute flaccid paralysis (AFP) surveillance and to improve RI coverage . CriticaThe recruitment process commenced after developing elaborate terms of reference, key performance indicators, and qualification requirements for each position. The WHO communicated the vacancies through internal notices and existing health networks at all levels. Under its overall responsibility, the WHO formed an interagency panel comprising representatives from National Primary Health Care Development Agency, the Nigerian Ministry of Health, and the United Nations Children's Fund to conduct the selection process. The screening included short-listing the applications on the basis of standard scoring criteria, administration of pretraining and posttraining tests, and interviews. Each panel submitted a detailed report on the selection proceedings, along with a list of recommended candidates and their scores, to the WHO central office for approval.The WHO adopted various contract types to facilitate deployment of the surge capacity personnel in the prevailing epidemiological, operational, and security circumstances. Such contract types included staff contracts, characterized by short or fixed terms and mainly involved for central and zonal level staff; special services agreements, which involved nonstaff, were governed by United Nations security regulations, and were used mainly to engage cluster coordinators; and agreements for performance of work, which involved nonstaff , were not governed by UN security restrictions, and allowed flexibility in determining the payment rates and movement of the contract holder.In addition to the training conducted to administer selection tests during the recruitment process, the WHO and partners organized and cascaded trainings. The training package covered topics on the Expanded Program on Immunization and involved field visits to health facilities offering RI and surveillance services, to further perform hands-on practices using the approved RI and surveillance checklists.In 2012\u20132013, the WHO engaged an international consulting firm and conducted a series of management trainings for top- and middle-level managers, including surge capacity personnel with supervisory responsibilities. The training introduced the following concepts: understanding management styles, performance management and accountability, team building and maintenance, objective setting and monitoring performance, handling difficult conversations, coaching for development, and improving creativity and innovative problem solving skills.The WHO officers support efforts to enhance program ownership and oversight, improve immunization operations, and sustain high quality surveillance performance. It is important to provide them with a working environment conducive to providing objective technical and operational guidance to the PEI program. The WHO operational focus is drawn from the national immunization plan, which drives the allocation and deployment of technical assistance, particularly at the field levels. To this end, after close review of the WHO's staffing strength vis-\u00e0-vis the expected technical deliverables, the WHO implemented a series of in-country staff rotation.The WHO used the policy of placing high-quality personnel in the worst-performing LGAs. To this effect, based on a thorough risk analysis conducted in collaboration with national authorities and partners, coupled with the performance assessment results, state- and LGA-level personnel were reassigned biannually to deploy high performers in priority areas .Along with the substantial increase in the number of personnel, it was necessary to strengthen the monitoring and evaluation capability to systematically monitor staff performance. In 2014, the WHO introduced a systematic accountability framework and implemented it in all its field offices, using key performance indicators aided by geographical information systems and mobile device technologies, coupled with periodic supportive supervisory visits to the field . Additional monitoring and evaluation officers, as well as data management personnel, were hired at the central level and in priority zones and states.In March 2012, the WHO made a major adjustment to its functional organogram to establish that adequate technical, managerial, and administrative support systems at all levels to effectively support the enhanced WHO technical infrastructure. The revised structure reflected the WHO's extended presence down to LGA and ward levels after the introduction of the surge capacity. The adjustment further optimized the span of control and supervisory lines.In 2013, the WHO trained 532 cluster coordinators and LGA facilitators and 1 637 field volunteers. Each session took 4 days, using the Expanded Program on Immunization comprehensive package that included polio SIAs, nonpolio SIAs, surveillance, RI, and data management. Specific topics were drawn from the standard operating procedures developed for technical surge personnel . Furthermore, 214 participants received management training, of whom 45 were from government and partner agencies.Following the full implementation of the surge capacity, the human resource strength of the WHO increased by >400%. Table The WHO used agreements for performance of work for >80% of the overall personnel, while 11% and 7% of personnel were engaged under fixed-term and special service agreements, respectively. These cadres possessed a higher technical caliber and were placed in supervisory responsibilities at state, zonal, and central levels.Between August 2013 and July 2014, the WHO undertook various waves of mass rotations that resulted in rotation of 50 high-level technical officers, the majority of whom coordinated zonal and state level activities. The administrative focal points in all 37 field offices were also relocated or reprofiled between December 2014 and February 2015. These periodic movements contributed to enhanced managerial capabilities and fostered staff accountability.Guided by surge capacity deployment optimization analysis and the cumulative feedback during 2014 from the accountability framework, the WHO made necessary adjustments during the 2015 surge capacity deployment. States in northeast zone with persisting security challenges and programmatic priorities were assigned more personnel by shifting staff from states such as Jigawa that had relatively more resources. The current deployment of 2 210 human resources involved in the surge capacity in the 11 HR states is shown in Figure The majority of surge capacity personnel were deployed and became fully functional toward the end of 2012. As highlighted in Figures 3Figure Microplan development is one of the core process indicators for successful and quality immunization campaigns for which the surge capacity personnel are directly responsible. As Figure As of 19 June 2015, cases of WPV infection in the country decreased during 2012\u20132014, with 122 cases in 2012, 53 cases in 2013, and 6 cases in 2014, with the last case reported on 24 July 2014. End-process independent monitoring of polio SIAs showed that 86% of wards achieved 90% vaccine coverage by the end of 2012, which increased to 96% by the end of 2014.With respect to RI indicators, the surge capacity also contributed to the steady improvement in the implementation of fixed and outreach sessions to immunize children. Each state has a goal of conducting 80% of planned fixed and outreach RI sessions. As Figure The WHO reorganized its functional structure, adopted a transparent recruitment and deployment process, provided focused technical and management training, and applied systematic accountability framework to successfully manage the surge capacity project in close collaboration with the national counterparts and partners. The engagement of >2 200 surge capacity personnel has enhanced the WHO's technical capability to contribute to the achievements registered in the intensified PEI and RI activities in Nigeria. Guided by the epidemiological risk analysis and feedback from the accountability framework, the majority (92%) of the surge personnel were strategically deployed in the northern part of the country, which remains a priority from epidemiological, operational, and security perspectives. To facilitate acceptance by the community, the surge capacity personnel were hired from the communities where they resided, using suitable contractual arrangement. The personnel have built up personal relationships with key stakeholders in the community to obtain buy-in for successful implementation of several innovative interventions that have been introduced since 2012.The surge project gave the program an opportunity to use technically competent health professionals who understand the grassroots' cultural and operational context. As such, they are suited to address challenges unique for every local area in the context of the diverse political, social and economic landscape in Nigeria. Their extended presence at LGA and ward levels created the capacity to successfully translate the high-level commitments and strategies into operational levels.The surge capacity is well aligned with the updated WHO functional structure and integrated into the existing health systems in the country. The collaboration with the government and partners in recruitment, deployment of the surge personnel, and collective program reviews at ward, LGA, state, and national levels, coupled with application of WHO's rigorous accountability framework, contributed toward improved program performance. As outlined in the WHO's standard operating procedures, the surge personnel are directly involved in training, planning, implementation, monitoring, and review of the field-level polio campaign performance and timely outbreak investigation and response; active case based surveillance; and intensification of RI activities . Furthermore, the surge capacity personnel have been instrumental in sustaining the program in security-compromised areas, which were not accessible to regular staff.Owing to the weak health system in the country, the surge personnel are also called upon to support other activities, such as nonpolio immunization campaigns, integrated disease surveillance and response, and other disease outbreak investigations and responses .The surge project faces challenges of attrition, mainly because of the implementation of accountability framework and, to some degree, resignations. In 2014, 300 agreements for performance of work were not renewed, because of persistent poor performance  [Despite the challenges in recruitment and maintenance of such a large workforce, the partnership coordination and management architecture put in place contributed to maximize efficiency and accountability from ward to national levels .In conclusion, as recommended in the 24th ERC report and the 2012\u20132013 global polio emergency plan, the WHO responded to the call for action and equipped its personnel, including those involved in the surge capacity, with the standardized tools and knowledge to optimize the substantial investment on the project . As statWe recommend the sustenance of the surge project to maintain the polio program's momentum and successful implementation of the polio endgame strategy in Nigeria , 20. As"}
+{"text": "Abscisic acid (ABA) is the master hormone governing the intricate network of molecular switches and physiological responses of guard cells that determine the degree of stomatal aperture. Once plants sense water deficit, ABA is synthesized, and enters the guard cells triggering a series of signals that result in stomatal closure and preservation of the water status of the whole plant. ABA signaling in guard cells involves several mechanisms sustained by enzymes, small molecules, and second messengers that finally promote the inactivation of inward-rectifying K+  channels, activation of outward-rectifying K+  channel, and activation of slow and rapid-anion channels   is required for ABA-dependent induction of stomatal closure  and (B) negative effects leading to the attenuation of the ABA signaling through the inhibition of key effectors of stomatal closure (inhibition of NADPHox and OST1 by S-nitrosylation). A recently published article adds new in vitro and in vivo evidences showing that the family of ABA receptors PYR/PYL/RCAR is inactivated by nitration of tyrosine residues leading to the degradation of the receptor via proteasome. The non-reversible nitration of tyrosine residues is a post-translational modification of proteins that requires the formation of the strong oxidant peroxynitrite, a compound formed from the fast reaction between superoxide (OAs stated, OST1 is a serine/threonine protein kinase that acts as a positive regulator mediating the ABA-induced stomatal closure through the activation of downstream effectors (Wang et al., Overall, this opinion article tries to recall the already known two sides of the NO \u201ccoin\u201d as a ubiquitous, homeostatic, and synchronizer molecule in cell physiology. Thereby, we highlight here the rationale of NO acting both in promoting and arresting the ABA-induced/phospholipid-mediated signals triggering the stomatal closure, as a way to avoid the exacerbation of a hormonal stimulus. In future investigations, however, it remains to be deciphered if the multi targets of NO are reached simultaneously or through a temporal and spatial pattern of its actions.The analysis, revision of the bibliography and the discussion of the data were conducted by AL, CG, and LL. The manuscript was prepared and written, including round of corrections, by AL, CG, and LL. The design and general supervision was performed by LL.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Microorganisms are common colonizers of superficial (phylloplane) and internal tissues (endophyte) of a variety plant species . PhyllopFor isolation of yeasts, samples leaves, stems and flowers of B. dracunculifolia were colected; 10 g were macered in 90 mL of saline solution  and dilutions of the suspension were spread in solid medium BDA and TSA. After purification and preservation, the isolates were characterized by colony morphology and grouped. Isolates representant of each group were subsequently identified by molecular techniques based on the amplification and sequence analysis of ITS1-5, 8S-ITS2 rDNA. For evaluation and screening of potential enzymes producers, enzymatic activity was performed in solid media . ProteolWere obtained 69 isolates, being 74% of these isolates of yeasts and yeast-like fungi. On the basis of on colony morphology the isolates were grouped into four morphotypes . The majority of the isolates was originating from samples of flowers and showed black colonies on PDA media. By analysis of ITS1-5,8S-ITS2 rDNA sequences in Genbank database, the isolates were identified as members of the species Starmerella bombicola, Aureobasidium leucospermi, A. pullulans, Rhodotorulla mucilaginosa and Occultifur externus. The isolates were promissing for enzyme production, specially for amylolytic and lipolytic activities which were predominant among the isolates. The most promising isolates were belonging to the genus Aureobasidium sp., which showed activities for the five enzymes tested. The isolates identified as promising for the production of enzymes, especially those of the genus Aureobasidium sp. were selected for more specific analyzes aimed at quantification and perfecting of culture conditions that allow greater production and can contribute to to the development of alternatives to enzymes already available in market."}
+{"text": "Under current conditions of development of health care and generally mankind, prevention of healthcare-associated infections (HAI) is one of the global world problems.Prophylaxis of HAI in Russia.Epidemiological, statistical.HAI affect 5-10% of patients staying at in-patient departments and rank the tenth place among the causes of population mortality. Annually according to the data of official statistics in Russia approximately 30,000 of HAI cases are registered but the experts consider their actual quantity to be not less than 2-2,5 mln of people.Under current conditions in Russia \u201cNational Concept of Prevention of Health Care Associated Infections\u201d (2011) was enacted and is valid. The present concept was developed by specialists of Federal Service for Surveillance on Consumer Rights Protection and Human Well-being, famous scientists and health professionals, and it determines the purpose, principles, general architecture, major improvement concepts of national system of health care associated infections prevention, its functioning mechanisms and also expected social-and-economic effect.Taking into account absence of specific means and prevention issues solution methods one of the most important concepts of HAI control is improvement of disinfection and sterilization methods. This concept in Russia is particularly significant due to wide spread of microorganism with high resistance to the effect of majority of antibiotics and antiseptics groups, development of modern technologies , building and reconstruction of centralized sterilization in-patient departments with updated equipment for washing and disinfection of medical products and endoscopic devices.None declared."}
+{"text": "Low levels of bilirubin exert antioxidant effects, but some neonates may develop very high levels of unconjugated bilirubin (UCB), with an increase of the unbound free fraction  at the time of insult exposition is supposed to influence the location of selective brain damage, as well as the severity of consequences . The cliTo avoid neurological consequences, the Clinical Practice Guideline of the American Academy of Pediatrics recommend total bilirubin determination (TSB) on every jaundice infant, both during hospital stay and post discharge follow-up. To this goal, Bilistik , a new mEarly neuronal accumulation of bilirubin in damaged regions and its brain metabolism may have a role in the marked regional differences observed in kernicterus impairment. This hypothesis is supported by the role of brain cytochrome P-450 (Cyp), known to oxidize UCB. In the brain of Gunn rats, an early upregulation of Cyp mRNAs was observed in the unaffected brain regions, cortex and superior colliculus, in contrast to the delayed and slight upregulation observed in the affected regions, inferior colliculus and cerebellum , where Uin vitro and challenged with bilirubin in controlled (concentration/timing) manner, strictly modelling different histopathological aspects of neurological conditions.Clarification of pathophysiology of UCB neurotoxicity, that continues to be an important risk among newborns worldwide, may open new perspectives for therapeutic approaches, focused in protecting directly the brain, the final target of bilirubin toxicity. To this aim the development of new research models, appear of particular relevance. Among them the organotypic brain cultures, living slices of the CSN that can be cultured"}
+{"text": "The clinicalstudies establish the absorbed doses in organs, by improving the compartimental models andallowing the prescription of the activities (amount of radiation) to be administered tohumans. Both in preclinical and in clinical studies, quality control ofradiopharmaceuticals labelling is one of the steps in the quality assurance system, whichis mandatory for registry in the Health Regulatory Agency . Thebiological effects of ionizing radiation in Medicine were identified by biodosimetry inroutine or in non-planned situations. In industrial applications, accidents have beenreported. Treatments of radiological victims in different contexts, includingreconstructive dosimetry for cutaneous radiation syndrome (CRS), should be obligatorydisciplines in the professional curricula of the multidisciplinary teams. The low-intensityred and infrared laser effects are increasing in Regenerative Medicine, nevertheless theassociated risks are unknown and there is a lack of safety requirements. Eight paperspresented in the SBBN Congress were selected to be published in the Brazilian Journal ofMedical and Biological Research, Volume 48(10), 2015.In the last two decades, the applications of ionizing and non-ionizing radiation in Biologyand Medicine have been improved considerably in Brazil. The 2014 SBBN Congress, entitled\"Framework, science and technology for preclinical and clinical studies with ionizing andnon-ionizing radiation\", was held in Caxambu, MG, during the XXIX FeSBE Annual Meeting.About 50 posters were presented in Radiobiology, Radiopharmaceuticals, Radiationprotection, Biophotonics and Photobiology. For new radiopharmaceutical developments, thepreclinical studies were essential because the \"2014 SBBN Congress President"}
+{"text": "To analyze the relations between the meanings of working and the levels of doctors work well-being in the context of their working conditions. The research combined the qualitative methodology of textual analysis and the quantitative one of correspondence factor analysis. A convenience, intentional, and stratified sample composed of 305 Spanish and Latin American doctors completed an extensive questionnaire on the topics of the research. The general meaning of working for the group located in the quartile of malaise included perceptions of discomfort, frustration, and exhaustion. However, those showing higher levels of well-being, located on the opposite quartile, associated their working experience with good conditions and the development of their professional and personal competences. The study provides empirical evidence of the relationship between contextual factors and the meanings of working for participants with higher levels of malaise, and of the importance granted both to intrinsic and extrinsic factors by those who scored highest on well-being. The research focuses on the social, organizational, and psychological effects of new, unstable, and fragmented employment, especially in Latin-American countriesAs the labor world is a fundamental scenario of people\u2019s psychological experience, the social and organizational changes in working conditions similarly affect workers\u2019 labor subjectivity, social working relations, professional ethical values and meanings, occupational health, job satisfaction, and work well-being levels.,Research on the meaning of working, work values, and working life is heterogeneous,,,,,,,,,,The literature about the different types of work well-being is extensive and diverseContemporary work well-being theories are greatly influenced by the ideas of Warr and his ecological modelThese changes,The Brazilian Federal Constitution from 1988 created the foundations of a Unified Health System , which defined health as \u201ceveryone\u2019s right and duty of the State\u201d. However, access to health services is not as easy for every citizen, for multiple reasons, as significant social and economic inequalities, disparities between states, deficit of public investment in health infrastructure, public subsidies to the private sector, double coverage of health services for a privileged minority, and the asymmetric distribution of funding SUS between the public and private sectors. All these features greatly affect the quality of the health system and the conditions of medical workth century, among them the creation of the Ministry of Health, Welfare and Social Security in 1924 and of the National Health Service in 1952. The 1981 Reform condensed and summarized the difficult balance between two conflicting tendencies: the movement for the recovery of public health system eroded by the dictatorship and the neoliberal insistence on cutting public spending. At the beginning of this century, new reforms were implemented concerning social rights in health, reorganization of the hospital network, and universal mandatory health plans regulated by the State. In contrast, funding for the system drags large deficits that involve job insecurity, deteriorating working conditions and low quality of work life for the health professionalsThe Chilean health system has a long history marked with milestones along the 20The Colombian health system of the past decades is the heritage of the strengths and weaknesses of Law 100/1993 and its successive reforms of 2007 and 2011. Law 1,752/2015 introduced a new regulation of the fundamental right to health and a new general social security health system. The underlying problems that have been dragging Law 100 were caused by conflictive visions of health as a source of business and as a fundamental rightFor its part, the current Spanish health system reflects the tension between hardly compatible objectives and strategies: the goal of excellence in managing the health systemMisi\u00f3n Barrio Adentro, which includes modules and Comprehensive Diagnostics Centers (CDI). This policy tried to increase the coverage of health services for the poorest populations. However, it failed to focus on fundamental problems of the Venezuelan health systemThe Venezuelan health system consists of a network of hospitals and clinics financed by the State or by private systems. In the 2000s, the government created a network of health centers and outpatient clinics as part of the The background of the present study consists of the changes in Latin-American and Spanish health systems, the value transformations in health care professionalism, and the growing work overload and job insecurity in flexible jobs within current medical working conditions. In this context, the objective of this research was to analyze the relations between the meanings of working and the levels of doctors work well-being in the framework of their working conditions.This study combined two approaches: one qualitative, with keywords concerning the meanings of working; and one quantitative, using a self-report survey made up of a battery of scales measuring well-being at work and working conditions.Pragmatic and epistemological reasons led researchers to seek a compromise between random and convenience sampling. This study combines a long questionnaire, a target-group with little time available to complete it, and a remarkable diversity of contexts among countries regarding opportunities and restrictions in access to random samples. This set of circumstances would determine a very low response rate in random sampling, with consequent problems of statistical representativeness. Following the principles of Grounded TheoryWe conducted a homogeneous collective concerning type of service  and professional sector (medicine) composed of 305 professionals employed in hospitals or other large and complex health centers in Brazil, Chile, Colombia, Venezuela, and Spain. The collective was also somewhat heterogeneous, as all the participants were recruited by convenience, intentional, and stratified sampling, according to six criteria: gender, generation, country, type of contract, seniority in the organization, and whether they had management responsibilities. About half of this group was male, mean age was 42 years, around 40.0% worked in Spain, and the others belonged to various participating Latin-American countries . Seventy-five percent of the participants had stable employment contracts, the juniors and seniors in the organization were equally distributed, and one third had experience in health care services management.The general tool to collect data was a self-report survey, which also included items concerning sociodemographic information. To analyze the meanings of working, this questionnaire included a free-word association item that invited people to write four keywords defining their current work experience. For the quantitative variables, a standardized battery of scales including the Working Conditions ScaleThe section concerning working conditions included 44 closed items. It was designed according to a theoretical model that configures working conditions around a three-way relationship of the organization with the method, the environment, and the person. A principal component analysis showed the existence of six factors, related to material and social environments, regulation and development methods, organizational adjustment to the person, and adaptation of the person to the organization. The six scales of the theoretical model represented by these factors were rated on an 11-point Likert scale ranging from 0  to 10 .The Questionnaire of General Labor Well-being included a series of 55 closed items organized according to a theoretical model of general work well-being. Factor analysis yielded two independent factors: the first one, called Psychosocial Well-being, comprised three scales measuring affections, skills, and expectations; and the second one, Collateral Effects, contained three scales evaluating somatization, exhaustion, and alienation. The affections and skills scales had a semantic differential format, ranging from 1 to 7; the expectations scale had a Likert format, ranging from 1 (low) to 7 (high). The three collateral effects scales ranged from 0 (never) to 6 .All scales showed high internal consistency, with Cronbach\u2019s alpha values ranging from 0.80 to 0.97. The psychometric study indicated that the overall instrument reproduced the structure of the proposed theoretical models, and that it was a measurement tool particularly sensitive to the psychosocial dimension of working conditions and of work well-being of health care professionals, and to evaluate the bipolar nature of their well-being experience.For the qualitative analysis, we used a dual pathway of textual and content analysis, and for the quantitative analysis, we combined descriptive statistics and factorial correspondence analysis, which shows relationships in a set of categorical variables from the contingency table data.,For the textual analysis of lexical forms associated with working experience, we performed thematic analysis of the corpus of data collected sequentially, combining two procedures: bottom-up data classification without adjusting to existing coding frames and top-down recoding, based on a theoretical framework. The result of this process was a dictionary drawn from all the original words of the questionnaire, which was based on a theoretical perspective, facilitating the analysis and discussion of its contents. This theoretical framework was grounded in the burnout and engagement modelsIn an initial coding level, general codes related to the malaise and well-being axes were constructed. The categories associated with the malaise pole were negative working conditions, discomfort, exhaustion, cynicism (negative attitude towards the organization), depersonalization (negative treatment of people), and (self-)inefficacy. The categories linked to the well-being pole were positive working conditions, well-being, vigor, commitment, good relationships, personalization, and efficacy., exhaustion, lack of commitment, depersonalization, and inefficacy. The remaining 11 codes have positive connotations: good (socioeconomic) conditions, opportunities, satisfaction, well-being, empowerment, commitment, ethics, good relations, plenitude, efficacy, and competences. We created an additional category that grouped a low percentage of non-specific responses.In a second level of categorization, specific codes were designed including words that condensed groups of meanings from the original terms. This list includes 25 codes, 14 of them with negative connotations: overwork, bad management, disorganization, bad  environment, injustice, inappropriate work, lack of resources, instability, dissatisfaction, malaiseThe Ethics Committee of the Autonomous University of Barcelona approved this study. All participants signed an informed consent form. Moreover, in all cases, we applied the international rules on confidentiality of participants and institutions, safeguarding the anonymity of responses, commitment to returning results, and responsible use of information.All the participants tended to associate medical practice experience in their respective health center to a double type of factors: the valuation of their own working conditions ; and a set of semantic codes, value systems and beliefs rooted in local cultures of each country, but also very influenced by the respective socioeconomic and health policy joints of every place and time. In this regard, the data obtained show a picture characterized by the following major trends in assessment of working conditions: (a) general convergence between countries on scoring averages ranging between 5.5 and 7.5, depending on factors and scales; (b) no statistically significant differences between the various Latin-American groups; (c) almost statistically significant differences (p = 0.054) between the respective averages of Latin-American and Spanish professionals concerning working conditions in general (tending to show above the first collective); (d) significant differences between Latin-American  and Spanish  on the general factor \u201corganization and individuals\u201d . This means that the Latin-American group recognized more adaptation of individual professionals to their organization . In addition, they perceived a greater degree of accommodation of the organization to the person . The Chilean group showed a special configuration, evaluating their own working conditions close to those of other Latin-American countries scores, but considering their own work experience very close to the Spanish group terms .The corpus of the meaning of working variable consisted of 161 word forms generated by the participants, with frequencies ranging from 45 to 1 and a total of 769 lexical forms. The distribution quartiles obtained from the responses to the General Labor Well-Being Questionnaire formed the continuous variable well-being. We assigned each response to a category , according to the quartile corresponding to its score on the questionnaire.2 (75) = 148.820, p < 0.001) led to rejecting the null hypothesis of independence between the meaning of working and the malaise-well-being quartiles and to accepting the alternative hypothesis: the meaning of working and the malaise-well-being quartiles were significantly related.A Chi-square test  and well-being (0.470).The highest relative contributions corresponded to malaise (0.903) and well-being (0.900), which showed that they were well placed in the axis. However, the other modalities of normal and risk were not so well placed. Lexical forms that defined the axis and that were found adequately placed corresponded to the variable meaning of working, but other variables that were also well placed did not contribute to its definition., inefficacy, and dissatisfaction. The pole representing the working experience for professionals positioned in well-being quartile included good conditions and plenitude.To facilitate interpretation of dimension 1, malaise-well-being and their lexical forms, the modalities of the two variables were located on an axis in accordance with their coordinates and absolute and relative contributions. The pole consisting of lexical forms that defined the meaning of working experience for those located in the malaise quartile included bad management, overwork, exhaustionThe axis risk and malaise and their lexical forms were characterized by the higher absolute contributions of the lexical forms dissatisfaction (0.149), overwork (0.128), strengthening (0.119), disorganization (0.106), and depersonalization (0.081). The examination of its coordinates showed that at the upper end of the axis were located lexical forms that defined the meaning of working experience as dissatisfaction (1.311), bad management (1.240), depersonalization (1.081), and strengthening (0.656), whereas at the lower end of the axis were mainly located disorganization (-1.236) and overwork (-0.580).Regarding the profile of the malaise-well-being quartiles, as observed in the column profile, the second axis was defined by the modalities risk (-0.337), normality (-0.179) at one extreme, and malaise (0.248) and well-being (0.236) at the other.At the malaise - well-being pole, the highest relative contribution is strengthening (0.474), and, at the normal-risk pole, disorganization (0.586). These scores indicate that these categories were not well placed on the second axis, and neither was the modality normal.To view the interpretation of dimension 2, risk-malaise and their lexical forms, the modalities of the two variables were placed on an axis according to their coordinates and absolute and relative contributions. On this axis, one pole includes the lexical forms that define the meaning of working experience as disorganization and overwork for those in the risk-normality quartiles. On the opposite pole, the meaning of working experience in the malaise-well-being quartiles was associated with dissatisfaction, strengthening, and depersonalization.The meanings of working for the medical group located in the malaise quartile were made up of lexical forms of job discomfort, showing strong evidence of frustration and exhaustion. The set of words included in this category showed that most aspects involve a negative assessment of working conditions and the management of health facilities. Specifically, work experience was described with the terms: bad management , work overload , exhaustion , inefficacy , and dissatisfaction (disappointment).In contrast, the job experience of medical professionals who were located in the well-being quartile, including extrinsic and intrinsic aspects, was described as working with good conditions  and plenitude . Globally, results showed the clear and intense relations between the meanings of working experience and perceived work well-being in the context of specific working conditions.This study overviewed how Latin-American and Spanish doctors construct their experiences and meanings of the complex relationship between work, malaise, and well-being in a changing world of health care systems and services. The research provides information about two main points: (a) the close association between specific working conditions and meanings associated with job well-being and professional performance, and (b) the strong link between the meanings that doctors assign to their professional practice and the general environmental characteristics of the settings and contexts where they work. In this regard, situational diversity explains some differences in meaning, whereas shared contextual background tendencies allows better understanding of detected similarities of work, professional values, and ethical dilemmas.,,-,,The distribution of keywords on the malaise-well-being axis makes evident the relationship between meaning of working and job well-being experienced by medical professionals. On the malaise quartile, work meanings appear closely associated with worse objective and perceived organizational working conditions . In contrast, scores in the well-being quartile were related to perceived good working conditions and to the importance granted to intrinsic  and extrinsic  factors. The discourses on working and well-being from the surveyed physicians were consistent with data from previous empirical studies,,,,,Two single trends in working conditions were reported by most participants as especially problematic common concerns: emerging job insecurity from the temporal instability of job contracts, and the perceived intensification of work due to task overload, which in the health sector was expressed as attendance pressure, the main psychosocial risk factor of professional burnout,,,,,,,,,The results linking the meanings given to professional experience, job well-being, and working conditions are consistent with the strong association reported between the available material resources of hospitals and the mental health symptoms observed in health care professionals (doctors and nurses),,,,,,,,,,,From a sociological and cultural point of view, the data collected suggest an underlying paradoxical process: the historical tension between differentiation and homogenization megatrends. Literature indicates the structural and manifest differences between countries, concerning general economic, social, political, demographic, cultural and historical backgrounds, state and market structures, and health system administration modelsThe joint impact of these conflicting processes is visible in the meanings given by doctors to their professional practice, closely related to their perception of the quality of their own specific organizational environment. Spanish and Chilean participants shared their respective working experiences, commonly described as an overloaded and monotonous agenda, and bureaucratic, politicized, inflexible, and ineffective management. These professionals considered work overload as the worst of their working conditions and as a main psychosocial risk factor of burnout. Another perceived major cause of professional discontent in the daily routine was job insecurity. Spanish participants with unstable jobs (temporary contract) reported lack of career prospects in a public service systemThe professional practice of Colombian doctors also showed their discomfort with temporary contracts, low pay, difficulties of the public health care system, and frustration for failing to provide good service to the community. Thus, they conveyed a critical point of view about the negative working conditions of medical care, affected by some aspects of the reforms carried out during the past few years. They also expressed a shared belief in the need to seek greater coverage and equity in health services for most people.The meanings given by Venezuelan doctors to their work reflected a difficult experience of tension between vocation requirements and the limited resources to carry out their profession, strongly influenced by the progressive deterioration of the national public health system in recent decades, characterized by lack of supplies for diagnostic tests, lack of medicines, infrastructure problems, and precarious working conditions.,,Over the last few years, the Brazilian government invested in health personnel and infrastructures, developing public health policies. In this context, participants of this country showed a confuse representation of work, which some describe as an uncomfortable experience and others as an opportunity to put professional and ethical principles into practice-,Moreover, within this basic diversity, the various countries also share a more or less successful history of health system reforms. Despite their remarkable variety of achievements and strategies, they were oriented toward the similar main goal of increasing the health system efficiency and redesigning the management and direction of the public health system, health care centers, services, and working conditions of medical professionals. This historical innovation has generated new organizational subcultures and professional practices facing a challenging, difficult, and conflicting cultural combination of values, such as efficiency and empathy, cost-benefit analysis and the Hippocratic path, business and humanism, common good and private benefit, commercial and social demands, managerial and professional priorities, market laws and the personal quality of working lifeThis underlying historical background and cultural matrix is an important explanatory key to the similar meanings constructed by professionals living and working in such heterogeneous settings, crossed by conflicting megatrends. They described their experience of reforms as changes, bureaucratization, politization, or reorganization, and noted certain dominant values of the new model of managing health system, such as flexibility, efficiency, competitiveness, demand-resources, financing, profit, client, quality, or cost-benefit. The shared appraisal of the health system reforms by most respondents to the questionnaire provides evidence of an unbalanced process: perceived positive general advances concerning infrastructural and organizational investments and negative outcomes from the new management of an increasing number of patients and health care professionals.,,,-,,In this way, despite their contextual diversity, doctors from different countries tended to acknowledge certain good organizational, material, and technical working conditions, which allow them to work more and better with patients. However, they expressed also discomfort about work overload, time pressure, and certain ethical and professional strains and dilemmas posed by new organizational demands, economical restrictions, and working conditions. They also criticized reform strategies and practices for being insufficient to promote health and well-being policies for medical and other health care professionals. Thus, they showed the discrepancy between the official rhetoric about the need to develop human talent as a strategic resource in health care organizations  and the practical inattention of the psychosocial dimension of medical professional risks and their quality of working lifeAnother link among the common cultural background of the surveyed workers was the manifest centrality of work in their personal and social life and of values of medical professionalism  in the entire sample of participants in the study. Participants showed it independently of their present political context, working conditions, relative job satisfaction, or specific organizational circumstances of their professional practice.,,,-,,,,,,,,,,,Our data are consistent with the information provided by the literaturestricto sensu non-epidemiological research enhances our theoretical understanding of current relevant emerging professional experiences in this population. Moreover, the study performed a combination of qualitative and quantitative methodological strategies, using a design of text dictionary and adopting the bipolar malaise-well-being axis. The empirical work promoted the participation of professionals from five countries, focusing on a profession that involves important psychosocial risks. The results point out some aspects to consider in the preventive political agenda aimed at avoiding, eliminating, or minimizing risk factors as well as promoting healthy organizational conditions of the professional medical practice.The present research has limitations and strengths. The adopted theoretical sampling procedure does not allow statistical generalization of the obtained data to the reference population. However, this"}
+{"text": "Those planning, managing and working in health systems worldwide routinely need to make decisions regarding strategies to improve health care and promote equity. Systematic reviews of different kinds can be of great help to these decision-makers, providing actionable evidence at every step in the decision-making process. Although there is growing recognition of the importance of systematic reviews to inform both policy decisions and produce guidance for health systems, a number of important methodological and evidence uptake challenges remain and better coordination of existing initiatives is needed. The Alliance for Health Policy and Systems Research, housed within the World Health Organization, convened an Advisory Group on Health Systems Research (HSR) Synthesis to bring together different stakeholders interested in HSR synthesis and its use in decision-making processes. We describe the rationale of the Advisory Group and the six areas of its work and reflects on its role in advancing the field of HSR synthesis. We argue in favour of greater cross-institutional collaborations, as well as capacity strengthening in low- and middle-income countries, to advance the science and practice of health systems research synthesis. We advocate for the integration of quasi-experimental study designs in reviews of effectiveness of health systems intervention and reforms. The Advisory Group also recommends adopting priority-setting approaches for HSR synthesis and increasing the use of findings from systematic reviews in health policy and decision-making. Health policymakers and managers (henceforth decision-makers), as well as other stakeholders  involved in health systems worldwide, routinely face difficult decisions around improving health care and promoting equity. Ideally, decisions and recommendations should be informed by the best available research evidence, which typically comes from systematic reviews of research \u20133. SysteThe Alliance for Health Policy and Systems Research (\u201cAlliance\u201d), a partnership housed within the World Health Organization (WHO), is pioneering support for strengthening capacity for synthesis of health policy and systems research through the establishment of systematic review centres in low- and middle-income countries (LMICs). The need for such a resource is especially acute in these settings due to the limited capacity of individuals, teams, organisations and knowledge systems to support the production and use of systematic reviews . To dateThe work of the Alliance centres complements that of other recent global initiatives. The Evidence-Informed Policy Network (EVIPNet) has actively promoted partnerships at the country level between policymakers, researchers and civil society in order to facilitate both policy development and policy implementation informed by the best scientific evidence available . SimilarAlthough there is growing recognition of the importance of systematic reviews to both inform policy decisions and produce guidance for health systems, a number of important methodological challenges remain and there is a need to better understand the processes supporting the transparent use of review findings in complex health system decisions. In addition, there is a multiplicity of initiatives in the field and better coordination is needed. The Alliance therefore convened an Advisory Group on Health Systems Research Synthesis (\u201cAdvisory Group\u201d) to bring together different collaborations, groups and institutions interested in HSR synthesis and its use in decision-making processes .In this paper, we outline the rationale of the Advisory Group, the six areas of work steering its activities and the guidance it provides to the Alliance and beyond; the paper also reflects on challenges in producing complex HSR syntheses and fostering their use in health systems decision-making.Since 2009, a series of consultative meetings led to the development of recommendations to improve international collaboration on HSR synthesis, with a focus on LMIC needs and capacity building Table\u00a0.Table 2EThe consultative meetings also revealed a landscape of research synthesis in which the focus and activities of organisations varied in terms of the following: (1) content , (2) research questions , (3) geographical focus (high-income countries (HIC) or LMIC)), and (4) capacity building (for supply and/or demand for reviews). The Advisory Group was established to play a central role in advancing the science of HSR synthesis and knowledge translation by developing and strengthening networks among individuals, groups, institutions and collaborations that have an interest in this field. Participating organisations include Cochrane and The Campbell Collaboration, numerous academic institutions and governmental and nongovernmental organisations ).The Advisory Group has evolved to include participants from 17 organizations/networks who convene once every 3 to 4\u00a0months to discuss current challenges and advances related to both producing systematic reviews and drawing on them for guidance on strengthening health systems. The group shares information, identifies where further methodological work or training is needed and builds cross-institutional links, and thereby, with its anchoring at the Alliance and WHO, serves as a global focal point for coordination around the issues.The Advisory Group, together with the Alliance more broadly, has contributed to setting priorities for health systems research on a global scale , 18. TheLimited capacity and issues of financial sustainability of groups in LMICs that undertake systematic reviews are further important challenges identified by the Advisory Group. For example, how can these groups secure core funding, ensure the availability of specialised resources such as information scientist support and statistical tools, strengthen their capacity to undertake the wide range of reviews needed to inform health system decisions and improve their engagement with decision-makers in the review process? Discussions on these issues contributed to the development of the new Global Evidence Synthesis Initiative (GESI), led by an international collaborating group of organisationsAnother important challenge identified by the Advisory Group relates to strengthening the capacity of decision-makers and stakeholders to access, assess and apply HSR evidence in decision-making and to create a \u201cuser-pull\u201d for HSR evidence. The Advisory Group advocates for and supports the development of user-friendly summaries of HSR syntheses and recognises the importance of sensitization workshops for users of HSR syntheses, institutionalised mechanisms for researcher-user interactions and knowledge translation activities. The last involves using knowledge translation tools such as evidence briefs for policy and briefing notes and convening dialogue sessions with decision-makers and stakeholders.For a number of areas within the field of HSR, evidence from quasi-experimental studies forms a substantive component of the overall evidence base for questions on the impacts of interventions. Evidence from quasi-experimental studies may be particularly important for reviews of interventions or exposures whose effects are not, often for practical reasons, easily amenable to measurement using designs based on random assignment of participants or facilities to comparison groups under the direct control of researchers. Quasi-experimental studies, such as regression discontinuity designs, , 23 inteHowever, efforts to integrate quasi-experimental studies into effectiveness review frameworks in both HICs and LMICs are, in general, at an early stage of development \u201328. ThisWith the Harvard School of Public Health, the Alliance organized a workshop in 2013 focused on the following: (1) establishing a taxonomy of quasi-experimental study designs, (2) developing guidelines for systematic review authors on incorporating quasi-experimental studies in reviews, (3) devising strategies to build institutional capacity to support the wider inclusion of quasi-experimental studies in reviews, (4) establishing approaches to translate evidence from quasi-experimental studies for policymakers, and (5) strengthening partnerships between researchers in HICs and researchers in LMICs.One of the outputs of the workshop and the background work commissioned by the Alliance is the identification of five quasi-experimental study designs frequently employed in health systems research: natural experiments, instrumental variable analyses, regression discontinuity analyses, interrupted times series studies and difference studies including controlled before-and-after designs, difference-in-difference designs and fixed effects analyses of panel data .Systematic reviews addressing the full range of health system issues may be useful for decision-making Table\u00a0. HoweverThe EPPI Centre is leading a study, funded by the Alliance, on supporting policy-relevant systematic reviews for health systems. Interviews with policymakers and systematic reviewers have emphasised the importance of connecting these two groups and supporting their mutual engagement with formalised procedures and structures, so as to ensure that their motivations for producing and using systematic reviews are aligned in terms of the urgency and generalizability of products .In addition, members of the Advisory Group are conducting scoping reviews to assess the most appropriate knowledge synthesis methods to answer different types of research questions , 34. Thewww.healthsystemsevidence.org), a database for all types of systematic reviews of HSR. In this database, systematic reviews, and links to their included primary studies, are complemented by a range of other policy-relevant documents addressing health systems, including evidence briefs for policymakers, overviews of systematic reviews, systematic review protocols, economic evaluations and descriptions of health system reforms. The database is available in Arabic, Chinese, English, French, Portuguese, Russian and Spanish; it can be searched using country, region and LMIC filters; it includes links to user-friendly summaries written by other groups. These features make the database a particularly powerful resource for health system decision-makers, stakeholders and researchers. HSE also now includes the beta version for an Intergovernmental Organizations\u2019 Health Systems Documents Portal, developed as a complete inventory of all policy-relevant WHO documents about health systems. Another useful repository is PDQ-Evidence (http://www.pdq-evidence.org), which links systematic reviews of HSR and other health research, overviews of reviews and their included primary studies.The Advisory Group acknowledges the utility and promotes the use of repositories of evidence synthesis in this field, such as Health Systems Evidence (HSE) , was established for this purpose but initially included only reviews of effectiveness. The Advisory Group therefore initiated discussions with PROSPERO regarding how the full range of health systems systematic reviews , the international prospective register of systematic reviews  the research domain, for instance human and financial resource constraints for conducting reviews and limited open access to and functionality of databases; (ii) the policy domain, including limited access to HSR systematic reviews and difficulties in assessing both how well evidence syntheses were conducted and how much confidence to have in their findings; and (iii) optimising the linkages between these domains to foster the uptake of findings into policy-making, for instance the alignment of review questions with policy needs and timeliness in the production and uptake of HSR synthesis.Further work of the Advisory Group aims to address these challenges, including capacity development and methods development across these domains. Ongoing work by members of the Advisory Group includes developing norms and standards for qualitative and mixed-methods reviews, building on existing resources , 37 and We argue that early engagement with decision-makers is critical for prioritizing, planning and conducting HSR systematic reviews and for enhancing the relevance and uptake of review findings. In engaging with decision-makers, special attention should be given to the challenge of translating priority policy issues into reviewable HSR questions. Funders of initiatives to strengthen health systems are also a key target audience of the Advisory Group. When designing and funding such initiatives in LMICs, we would suggest that funders take into consideration both available policy-relevant HSR syntheses and the need to build capacity for HSR synthesis.Those conducting reviews should give more consideration, when it is appropriate to do so, to evidence from quasi-experimental studies on the impacts of health systems interventions. Following from this, further development of the methods and standards for incorporating quasi-experimental evidence into reviews is needed. Complementary to developing standards for reviewing is the work of the EQUATOR  initiative, which seeks to improve the reliability and value of health research by promoting transparent and accurate reporting of studies and reviews . Given tOverall, the focus on collaborative priority setting for research, judicious choice of study designs and relying on systematic reviews rather than single studies for making decisions about health systems set this work alongside the movement advocating less waste and greater value in biomedical research , 42. We These efforts need continued collaboration and coordination across different organizations, networks and actors. We believe a coordination mechanism like the Advisory Group can fulfil the need for aligning interests, methods and approaches and for securing interest and investments in the field of health systems research synthesis globally.http://www.who.int/alliance-hpsr/projects/hsrsynthesis/en/index.htmlMore information on the activities of the Advisory Group is available at"}
+{"text": "The flow of fluids in complex geometries like porous media  plays anNIST Tutorial/Workshop on Lattice Gas and Lattice Boltzmann Methods. The organizer was Dr. Nicos S. Martys of the Building Materials Division. The purpose of this workshop was to familiarize NIST scientists and members of industry with the basic ideas of lattice gas and lattice Boltzmann methods and to inform the audience of recent developments in such computational methods.In August 1995, the NIST Center for Theoretical and Computational Material Science  and the NIST Building Materials Division [Building and Fire Research Laboratory (BFRL)] cosponsored a workshop titled The workshop was attended by over 50 participants of which approximately 40 % were from industry, 30 % from academia and 30 % from national laboratories.The Lattice Gas/Boltzmann workshop was held over 2 days and divided into two parts. The first part was a tutorial given by Dr. Hudong Chen of Exa Corporation, Cambridge, Massachusetts. Dr. Chen is a world expert on lattice gas and lattice Boltzmann methods having published over forty papers on this relatively new topic. In this tutorial the basic concepts of lattice gas and lattice Boltzmann methods were introduced. The second part of the workshop was devoted to recent developments in, and applications of, these methods. The following sections include representative sample highlights of the workshop.Dr. Xiaowen Shan of Los Alamos National Laboratory discussed a recently proposed lattice Boltzmann model for simulating multi-component, multi-phase flows by incorporating long-range interactions into the fluid dynamics. It was shown that the equation of state of the fluid could be altered from an ideal-gasto one that matches any specific functional form. When the equation of state is properly chosen, the fluid system will separate into multiple phases each of which still obeys the Navier Stokes equation. The coexistence curve, density profile across a liquid-gas interface, surface tension, and diffusivity in a multi-component system were obtained analytically for this model.Dr. Ray Kapral  introduced a lattice gas model describing the mesoscale dynamics of spatially distributed, chemically reacting systems. Results were presented for two examples of such systems. First, chaotic front dynamics that arise from diffusively driven instabilities were described. Second, the dynamics of catalytic oxidation processes on metal surfaces was discussed. In this case, the metal-catalysed oxidation was preceded by the coupling of the reaction kinetics to surface phase reconstruction, and gave rise to a rich variety of pattern formation processes on micrometer to submicrometer length scales. Consequently one could begin to probe fluctuation effects and the breakdown of mean field theories in these systems.John F. Olson in collaboration with Dr. Daniel H. Rothman of the Massachusetts Institute of Technology presented results from lattice gas simulations of two-phase flow through Fontainebleau sandstone. The three-dimensional rock geometry, obtained by x-ray microtomography, was used to investigate complex flows through a natural medium. Results were compared with earlier studies of flow through artificial porous media, and with recent experimental measurements on the same media. These comparisons illuminated the potential and the limitations of these techniques.Dr. Norman Margolus of the MIT Lab for Computer Science discussed his group\u2019s involvement in research on large-scale cellular automata (CA) modeling of physical systems. This research has been part of a long term effort to better match computations to the constraints of physics, with the ultimate aim of effectively harnessing the potential of computer hardware that can take advantage of the uniformity, simplicity, and spatial locality of cellular automata computations. Recent developments in dedicated \u201cCellular Automata Machines\u201d have significantly advanced their ability to efficiently and flexibly model and analyze large-scale cellular automata systems.Bruce Boghosian of the Center for Computational Science at Boston University described a lattice gas model of the nonequilibrium dynamics of microemulsions. The model was based on the immiscible lattice gas of Rothman and Keller , which iThe NIST Tutorial/Workshop on Lattice Gas/Boltzmann Methods provided an opportunity for NIST scientists to learn about state-of-art techniques for the modeling of many complex flow problems. The workshop also provided an opportunity for interaction with many of the world leaders in the field of cellular automata modeling of fluids.There has been ongoing research in the application of lattice Boltzmann methods in the modeling of single and multi-component flow in porous media  like bui"}
+{"text": "After the MOEA-based model construction is finished, the system automatically generates appropriate scatter plots, quantifies the relationships, finds differences between the two populations of models, and calculates the statistical significance of those differences.Coregulation of ionic current levels, and specifically the changes that appear to take place in such relationships in response to deafferentation  and pyloric dilator (PD), proposed in . In addi"}
+{"text": "BrisSynBio is the Bristol-based Biotechnology and Biological Sciences Research Council (BBSRC)/Engineering and Physical Sciences Research Council (EPSRC)-funded Synthetic Biology Research Centre. It is one of six such Centres in the U.K. BrisSynBio's emphasis is on rational and predictive bimolecular modelling, design and engineering in the context of synthetic biology. It trains the next generation of synthetic biologists in these approaches, to facilitate translation of fundamental synthetic biology research to industry and the clinic, and to do this within an innovative and responsible research framework. BrisSynBio is supported by \u00a313.6 million from Biotechnology and Biological Sciences Research Council (BBSRC)/Engineering and Physical Sciences Research Council (EPSRC), which includes a \u00a33.3 million investment in new state-of-the-art equipment and computing, and significant additional University of Bristol support. BrisSynBio is led by the University of Bristol in partnership with the University of the West of England. It is a multidisciplinary Centre distributed across four Faculties, with an administrative hub in University of Bristol's new \u00a356 million Life Sciences Building . BrisSynBrisSynBio's Director, Professor Dek Woolfson, is one of the U.K.'s leading advocates for advancing and broadening synthetic biology approaches to include biomolecular design and engineering . He has BrisSynBio's scientific focus is on the rational design and engineering of nucleic acids, lipids, peptides and proteins as structural, enzymatic and regulatory components in new biological and bio-inspired systems. BrisSynBio is organized into three research Strands:Strand 1\u2013Enzyme Cascades and Cell Factories: This strand focuses on the isolation, characterization and scalable production of \u2018new-to-science\u2019 natural product-based therapeutics and agrochemicals. A major emphasis is polyketides, the most structurally and functionally diverse family of bioactive natural products known. These molecules represent challenging, frequently intractable targets for synthetic organic chemistry, and as such biosynthesis offers the only generally applicable route to efficient production. Exemplar projects include: engineering Trans-acyltransferase (AT) polyketide synthase (PKS) antibiotic gene clusters to deliver bioactive compounds, led by Willis [Escherichia coli, led by Race [y Willis ; scalabl by Race \u20138; and m by Race .Strand 2\u2013Self-assembled Systems and Minimal Cells: This strand explores using and combining stripped-down biological components and machinery to build virus- and cell-like micro-compartments. It involves the systematic inclusion and networking of engineered biomolecular and cellular components, and gene circuitry to establish biomimetic operations and modules. Achieving this vision depends critically on the construction and design of self-assembled systems, novel representations of synthetic cellularity and re-engineering of minimal cells. Exemplar projects include: developing hybrid peptide-virus nanoparticles for immunology and cell delivery, led by Woolfson [Woolfson \u20134; desigWoolfson ; and engWoolfson .Strand 3\u2013Programming Complexity in Natural Systems: Strand 3 integrates modelling, cell biology and imaging to address the predictable reprogramming and control of single cells, cell populations and cells in multicellular organisms. Applications are envisaged for whole-cell biosensors for the detection, analysis and remediation of aromatic pollutants; the use of engineered cells to control cell populations; and the development of wheat strains with the potential to revolutionize wheat breeding for agriculturally important traits. Exemplar projects include: design and implementation of orthogonal components for transcriptional logic gates, led by Savery [tools for the rational design of synthetic gene circuits [y Savery ; harnessy Savery ; and a sy Savery . The fircircuits .Design and Characterization of Biomolecular Components; Engineering and Modelling across Scales; and Public Engagement and Responsible Research and Innovation. For the second of these, three computational scientists are employed to cover theoretical aspects and computational modelling and simulation. Sophisticated models can help predict the outcome of experiments, and hence inform which experiments are most likely to provide useful outcomes. Additionally, they offer powerful methods for interpreting experimental results. BrisSynBio has built upon existing close relationships between modelling and experimental groups by providing an interface across the scales of modelling that are addressed by different research groups at Bristol so that experimental researchers can readily collaborate with the appropriate group for the scale of problem they are addressing: atomistic molecular modelling and simulation, led by Sessions and co-workers [The Strands are supported by three cross-cutting Themes in: -workers ,3,17; mo-workers ; and coa-workers .fundamental problems, ethics and responsible innovation in the design and engineering of synthetic-biological systems. A philosopher works alongside BrisSynBio researchers, examining what \u2018responsible innovation\u2019 and \u2018ethical science\u2019 mean in practice, as well as fundamental ethical and philosophical questions raised by BrisSynBio's research and synthetic biology activities more broadly. As part of this aspect of BrisSynBio, the Centre and its researchers are proactively involved in a range of public engagement, from traditional science cafes and visits to local schools, to innovations such as Question Time-style panel discussions and supporting a show at the 2015 Edinburgh Fringe [In Theme 3, Kent  leads thh Fringe .All of these research activities are underpinned by major new facilities supported through the Centre grant for: high-throughput molecular biology; NMR spectroscopy and peptide synthesis; high-performance computing; microfluidics; FACS; and advanced microscopy and imaging. And to help pave the way to applications, BrisSynBio's current industrial partners include Bruker, GSK, Syngenta and UCB, through which BrisSynBio aims to realize translational outcomes in the areas of fine and specialty chemicals, medicines and healthcare, and wheat breading."}
+{"text": "The national roll-outs of evidence-based psychotherapies in the Department of Veterans Affairs (VA) afford an unusual opportunity to study both implementation and sustainability. Although unique in some aspects of management and resources, the VA also serves as an excellent laboratory to understand the implementation of best practices as it is a more organized and controlled environment, free of the barriers faced in other more fragmented segments of the U.S. health care system. In a two-year NIMH grant, we utilized a theory-based model to collect baseline data regarding the adoption of two evidence-based treatments for Posttraumatic Stress Disorder (PTSD), Prolonged Exposure (PE) and Cognitive Processing Therapy (CPT), in a national sample of 38 VA PTSD residential treatment programs with over 200 providers. In a subsequently funded NIMH R01, we are extending our investigation with the same population and model to see: (1) how well PE and CPT are sustained over time, (2) what organizational and individual factors influence sustainability, and (3) what effects implementation and sustained use of PE and CPT have on patient outcomes. Implications for implementation in and outside of the VA health care system will be discussed.Updates on measurement of a model of implementation for health care: advances toward a testable theoryOne comprehensive theoretical model for understanding implementation of innovations was initially developed by Rogers (1962) and elaborated on by others . This model construed implementation as a complex process influenced by five broad constructs: (a) perceived characteristics of innovation, (b) potential adopter characteristics, (c) communication and influence, (d) system antecedents and readiness, and (e) outer context. Although a considerable evidence-base was used to develop the model, the authors did not fully operationalize their model, making it difficult to test formally. Our group undertook a systematic review of the literature and, using an iterative process, we examined existing measures and utilized or adapted items. Where no one measure was deemed appropriate, we developed other items to measure the constructs through consensus. The review and iterative process of team consensus identified three types of data that could be used to operationalize the constructs in the model: survey items, interview questions and administrative data. Over three waves of data collection concerning the implementation of two evidence-based psychotherapies disseminated nationally within Department of Veterans Affairs, we have made changes to the quantitative measurement of aspects of this model including the exclusion of the measurement of some constructs  as well as refinement of others . This presentation will review these changes as well as psychometric properties of other constructs and their items.Testing the model using quantitative data for implementation of two evidence-based psychotherapies for PTSD in VA residential treatment programs: outcomes for two yearly time pointsThis study examined the implementation of two evidence-based psychotherapies, Prolonged Exposure (PE) and Cognitive Processing Therapy (CPT), in the Department of Veterans Affairs (VA) residential Posttraumatic Stress Disorder treatment programs. The current analyses focused on continued implementation a year after an initial assessment of implementation and of provider and site variables thought to be related to implementation. Seventy-five providers from 38 programs provided complete quantitative data on both baseline and follow-up. At one year follow-up, there was continued effect of supportive organizational context  on the implementation of both PE and CPT delivered in a group format.Unlike at baseline, effects of perceived characteristics of treatment on implementation of PE and of supportive organizational context on CPT delivered individually were no longer significant. Rather, social connections predicted a lower likelihood of implementation of CPT individually. These effects all remained, even after taking into account baseline levels of implementation.Implementation of two evidence-based psychotherapies for PTSD in VA residential treatment programs: patient-level outcomesThis presentation will discuss the effects of implementation of two EBTs for PTSD (PE and CPT) in the U.S. Department of Veterans Affairs (VA) residential treatment programs on patients' PTSD symptom severity, alcohol and drug use, and treatment satisfaction. The instruments were administered to patients upon admission and four months post-discharge. The short form of the Mississippi Scale for Combat-Related PTSD was used to measure PTSD and alcohol and drug abuse were measured using the composite indexes from the Addiction Severity Index. Controlling for length of stay and baseline symptoms, implementation of PE and CPT predicted improvement in PTSD symptom severity and alcohol use. The implications of these findings are that two EBTs for PTSD can be feasibly and effectively disseminated to routine clinical settings and implementation produces favorable patient outcomes."}
+{"text": "Based on panel data of Chinese listed companies, this paper estimates the impact of low-carbon city policy (LCCP) on enterprise investment efficiency (EIE) by the heterogeneous timing difference in differences (HTDID) method and examines the heterogeneous effect of urban culture on the impact. The results show that LCCP improves EIE, and the research conclusion passes the robustness tests. Mechanism analysis reveals that LCCP mainly acts on EIE along two paths: promoting enterprise technological innovation and easing financing constraint. But the LCCP does not have a significant effect on resource allocation. On urban culture heterogeneity, the ecological wisdoms of green urban culture and Confucian culture, such as benevolence to all beings and the harmony between man and nature, help to enhance the promoting effect of LCCP on EIE. From the perspectives of the synergistic development between formal and informal institutions and of urban cultural governance, this research provides important reference and data support to EIE improvement. Notice on Launching the Pilot Program of Low-Carbon Provinces and Low-Carbon Cities in 2010, kicking off the piloting of low-carbon city development. In the meantime, the Chinese economy is moving from the high-speed growth stage to the high-quality development stage. The further decline of industrial production efficiency has severely bottlenecked the macroeconomic growth of China in recent years. The low-carbon city policy (LCCP) requires cities to clarify their development strategies, principles, and directions during the pursuit of low-carbon development; accelerate the research and development, promotion, and application of low-carbon technologies; build a low-carbon industrial system characterized by greenness, environmental friendliness, and high recyclability; and implement the industrial policies, fiscal and tax policies, and technology promotion policies for low-carbon development, aiming to strengthen the driving role of low-carbon technology innovation on economic development. Enterprises are the most important participant and contributor in the construction of low-carbon cities. Being major emitters of carbon dioxide, enterprises are the core organizers of low-carbon product research and development and need to improve investment efficiency, one of the most effective ways to reduce carbon emissions and lead the construction of low-carbon cities. In the context of China's economic transformation, culture lies at the core of the informal institution and significantly affects economic and social development. The implementation of the LCCP is inseparable from the cultural foundation at the city level. Therefore, it is particularly important to explore the impact of LCCP on enterprise investment efficiency (EIE) and consider the role of urban culture for the implementation of policies. Facing the realistic needs of ecological protection and high-quality development, this paper is aimed at answering the following questions: does China's LCCP help improve EIE? Under the influence of culture, an important informal institution, does the relationship between LCCP and EIE varies with the culture of specific cities?Global warming, a consequence of greenhouse gas emissions, exposes human beings to multiple risks, including sluggish economic growth and worsening living environment. To address these risks, the National Development and Reform Commission of China issued the Rich results have been drawn on the evaluation of the effect of LCCP. Many scholars used the data of Chinese listed companies to evaluate the impact of LCCP on the total factor productivity . For exaBased on the above analysis, this paper intends to reveal the impact mechanism of LCCP on EIE and to empirically test that impact. Taking the LCCP as a quasinatural experiment, the authors estimated the impact of LCCP on EIE, using the heterogeneous timing difference in differences (HTDID) method, and alleviate the endogenous bias through a series of robustness tests. In addition, urban green culture and Confucian culture were taken as examples; the heterogeneous impact of urban culture was examined, revealing the key role of cultural governance in the implementation of LCCP. This is another defining feature of this research. The research findings help to examine the achievements of low-carbon city construction, deepen the understanding of the factors affecting EIE, and provide reliable suggestions for promoting high-quality economic development while implementing low-carbon governance.The main contributions are as follows: firstly, scholars have not reached a consensus on how environmental regulation affects economic efficiency of enterprises \u201311. At tUnder the global trend of carbon reduction, China launched the first batch of low-carbon pilot projects in 2010. Each pilot region was required to explore a low-carbon development model according to its own conditions. Subsequently, the second and third batches of pilot projects were determined in 2012 and 2017, respectively. The pilot regions need to complete the following tasks: establishing a responsibility system for carbon control target, setting up a carbon emission data statistics and management system, formulating supporting policies for low-carbon development, constructing a low-carbon industrial system, and advocating the low-carbon green lifestyle. This paper intends to demonstrate the impact of LCCP on EIE from three aspects: technological innovation effect, financing constraint effect, and resource allocation effect.Specifically, the technological innovation effect refers to the influence of LCCP over EIE via technological innovation. LCCP is an environmental regulation policy proposed by China at the city level to reduce carbon emissions . The infThe financing constraint effect refers to the influence of LCCP over EIE via easing the financing constraint. To integrate the concept of low-carbon development into the production and operation of enterprises, the government has continuously stepped up its support for enterprises. Local governments have made bold explorations and attempts with the help of the autonomy granted by their superiors, such as tax relief, financial subsidies, loan discounts, special funds, and talent incentives, aiming to help enterprises to expand financing channels. Banks and other financial institutions regard the government support and subsidies as implicit guarantees and lower the credit threshold for the enterprises receiving such support and subsidies. For example, the low-carbon urban plans of the pilot regions all cover various financial policies, namely, the special funds for low-carbon development, subsidies for specific industries, preferential loan interest rates, and tax reductions and exemptions. Through capital allocation, these financial policies guide enterprises to reduce investment in polluting projects and invest more funds in green industries and environment-friendly production processes , therebyThe resource allocation effect refers to the influence of LCCP on EIE by affecting enterprise resource allocation. On the one hand, the implementation of LCCP, whether it is the formulation of emission reduction requirements, the collection of pollution taxes, or the trading of pollution rights, will generate new costs, which will cause enterprise production to deviate from the original optimal state. The reason is that environmental regulation will increase the corporate cost of pollution control and system compliance . Some enThrough the above analysis, the following hypotheses were presented.LCCP can promote EIE.LCCP can suppress EIE.LCCP influences EIE via technological innovation effect.LCCP influences EIE via financing constraint effect.LCCP influences EIE via resource allocation effect.Chinese and Foreign Urban Knowledge Dictionary. It is a rather complex and diversified issue. Urban culture, as a way of communication between people and cities, is rooted in the soil of urban historical development and is the characteristic gene of a city. Urban culture has strong regional characteristics, and its development is largely affected by administrative division. Therefore, different cities may vary significantly in terms of culture. As an informal system, culture has an important impact on the economy and enterprise behavior. Urban green development is impossible without the support and guidance of culture. The promotion and implementation of LCCP cannot be detached from the special \u201csoil\u201d of urban culture, especially the green gene in culture. Urban green culture is the value and philosophy of ecoenvironment protection and resource utilization with urban characteristics, both of which gradually form in the process of urban operation and management. As the main body of Chinese traditional culture, Confucian culture has a subtle influence on the behavior of Chinese people. Its ecological ethics and wisdom are highly consistent with modern concepts like ecological civilization and green development. Both urban green culture and Confucian culture carry the gene of green culture, exerting an important impact on the implementation of LCCP. Therefore, this paper takes urban green culture and Confucian culture as examples to explore the different roles of urban culture differences in the implementation of LCCP.Urban culture is mainly defined in two ways: deducing from the definition of culture and defining by the features of the city itself. Concerning the first way, urban culture is defined as the sum of material and spiritual wealth created by people in the city and is the overall form of their living conditions, behavior patterns, spiritual characteristics, and urban features. Concerning the second way, urban culture is defined as a cultural model with urban characteristics jointly created by citizens in the long-term life process and is the sum of urban living environment, lifestyle, and living habits, according to the The Outline of the Tenth Five Year Plan for National Economic and Social Development proposed to break the extensive \u201cblack\u201d development model with GDP growth as the fundamental goal, switching to a resource-saving, environment-friendly, and green path towards sustainable development. Since then, urban green culture has been gradually formed through urban green operation and management and imperceptibly affected the public's values and decision-making. Therefore, Confucian culture and urban green culture are the representatives of traditional culture and emerging culture, respectively, and carry the very gene of green culture. Meanwhile, the two cultures vary greatly from city to city.Confucian culture has a long history of development. After more than two thousand years, Confucian culture has gradually established the core values and moral norms of Chinese culture and has become the ethics of \u201cdaily use without knowing.\u201d With a low per capital ecological wealth, China faces a growing mismatch between the public's pursuit of high-quality life and the insufficient supply of urban development resources. Urban green culture refers to the values and philosophy of ecoenvironmental protection and resource utilization with urban features. These values and philosophy are formed gradually during urban operation and management. Firstly, urban green culture can promote enterprises to generate cohesive and centripetal forces, which are friendly to the environment. By giving play to the guiding role of culture, the awareness of environmental protection can be formed subtly, and employees are encouraged and instructed to care for the environment and make concerted efforts for environmental protection. Secondly, urban green culture will form a binding force in enterprises through institutional norms and responsibility requirements. The social and environmental responsibilities that enterprises should undertake in production and operation will be stressed, motivating enterprises to develop the relevant institutions. Hence, urban green culture will lay a good basis for the promotion and implementation of LCCP and actively shape the influence of LCCP over EIE.The behavior of enterprises is affected by the institutional environment . China iTo sum up, the following hypotheses were presented.The stronger the urban green culture, the more LCCP improves EIE.The stronger the Confucian culture, the more LCCP improves EIE.i and t are the serial numbers of enterprises and years, respectively; Investeffi,t+1 is EIE; LCCi,t is the low-carbon piloting state of the registered city of the enterprise; Xi,t is a series of control variables; \u03bci, \u2211Year, \u2211Industry, and \u2211Province are the fixed effects of individuals, years, industries, and provinces, respectively; \u03b5i,t is a random error; and \u03b2 is the estimate of HDID, the key index of this research.Taking the low-carbon city piloting policy of China as an example, this paper explores how LCCP affects EIE. Since the piloting program starts from different years in different cities, the HDID method was adopted to recognize the influence of LCCP over EIE. The benchmark econometric model can be designed asThe research samples are the nonfinancial Chinese enterprises listed in the A-share board of Shanghai and Shenzhen stock exchanges from 2007 to 2016. Financial enterprises were excluded from the samples, mainly for the following two reasons: firstly, the financial industry, especially the banking industry, is more special than general industries. For example, many banks earn profits from off-balance sheet businesses. Bias is unavoidable if listed banks are analyzed based on the three major financial statements. Secondly, the financial enterprises have different financial statement requirements different from nonfinancial enterprises, because of the difference in business model between the financial industry and other industries. The statement structure and main accounting items of the financial industry are also different from those of general industries. The following samples were also excluded: the samples receiving special treatment (ST) or facing delisting risk (\u2217ST), the enterprises issuing both A-shares and B-shares, and the enterprises with key variables missing. The relevant data were collected from China Stock Market & Accounting Research (CSMAR) database and WIND database.The low-carbon city piloting (LCC) is defined as follows: if the registered city of a listed enterprise implements low-carbon piloting, LCC = 1 in the current and following years; otherwise, LCC = 0. During the sample period, two batches of pilot cities were announced. Hence, the first and second batches of pilot cities were selected as the treatment group. Some cities belong to both batches. As a result, the start time of piloting of a province was taken as that of every city administered by that province.The EIE was measured mainly referring to the research of Biddle et al.  and Choii,t is the investment level of the enterprise in year t, which is measured by the ratio of the cash paid for the purchase and construction of fixed assets, intangible assets, and other long-term investments to the total assets at the beginning of the period, and Growthi,t\u22121, Levi,t\u22121, Agei,t\u22121, Sizei,t\u22121, Cashi,t\u22121, Reti,t\u22121, and Invi,t\u22121 are the growth capacity, debt rate, listing period, company scale, cash holding ratio, stock return, and investment level of the enterprise in year t \u2212 1, respectively.The model can be expressed as follows:\u03b5i,t reflects the inefficient investment expenditure of the enterprise. If \u03b5i,t > 0, then the investment is excessive; if \u03b5i,t < 0, then the investment is insufficient. The absolute value of the residual \u03b5i,t was taken to measure the EIE (Investeff). This value reflects how much the enterprise investment deviates from the theoretical expectation. The greater the value, the larger the deviation and the lower the EIE.The regression residual price-earnings ratio has been used as a key variable to measure investor sentiment, which has been proved to bear on the investment behavior of enterprises through equity financing, catering, manager optimism, debt financing, and other channels. Thirdly, the local government would intervene in the economic operation of enterprises by means of government subsidies, guiding local investment, and changing the investment direction and level of enterprises. Fourthly, the duality of chairman and general manager, as an important allocation mechanism of decision-making power, directly affects EIE. Fifthly, market competition can improve information sharing. In a fully competitive market, owners will have reliable information of managers. Thus, the information asymmetry between shareholders and management is mitigated, so that executives will not expand blindly or get complacent, and the enterprises will invest more efficiently. Sixthly, the sustainable growth rate reflects the sustainability of enterprises. The sustainable growth rate can affect EIE through earnings retention and financial structure.The HDID model controls the key explanatory variables and solves the endogeneity induced by the correlation between time-invariable individual features. But the time-varying individual features should be controlled to reduce the estimation inconsistency arising from missing variables. Referring to the literature, this paper selects the following control variables: enterprise size (Size), price-earnings ratio (PE), government subsidy change (Subchange), holding concurrent positions of chairman and general manager , industry concentration (Hhi), and sustainable growth rate (Sgr). In addition, industrial and provincial dummy variables were included. Reasons for choosing the control variables are as follows: firstly, the existing research has shown that enterprises of different scales have different financing constraints, which affect EIE differently. Secondly, Investeff represents the deviation of enterprise investment from the theoretical expectation, the greater the deviation, the lower the EIE. Hence, the empirical results reveal that LCCP significantly enhances EIE. According to column (5) of Next, EIE was divided into excessive investment and insufficient investment and treated as the explained variable separately. On this basis, model  was regrDki,t is a series of dummy variables, indicating the k-th year since the implementation of low-carbon city piloting . This paper mainly considers parameter \u03b2k . The other variables in formula  between city attribute and time trend to the benchmark regression model, where Sc is the city attribute  and f(t) is the first-order term of the time trend. The cross-term controls the time-varying influence of the intrinsic difference between city attributes over EIE. The regression results are recorded in column (1) of The first batch of low-carbon pilot cities in China was designated by the superior government. As for the second and third batches, application and expert review were added as necessary links of determining low-carbon pilot cities. Thus, the list of low-carbon pilot cities is not determined purely by random. To mitigate the negative effect of nonrandom selection on estimation results, this paper adds the cross-term Sc \u00b7 The approval time of low-carbon pilot cities was moved ahead by 3 years, and variable Before_3 was added to model . The regConsidering the effect of its abnormal value, the explained variable was censored at the 1% and 99% quantiles. The regression results are displayed in column (4) of Per capita gross domestic product (GDP) was added to the benchmark model. The regression results are shown in column (5) of Two cross-terms were designed: the cross-term between whether the city is a new energy demonstration city and the time of approval (Ncity) and the cross-term between the city environmental protection criticized by superiors and the time of criticized (HBYT). The two terms were introduced to model . The regTo increase the similarity between treatment group and control group, this paper further removes the provinces without any pilot cities. The regression results are displayed in column (8) of Regarding the measurement of urban green culture, this paper selects the actual year-end number public vehicles and trams/ to depict the green consumption concept of residents. The samples were grouped by the median of the variable and tested separately. The results are shown in columns (1) and (2) of To rule out the possibility that the above results are caused by government intervention, this paper uses the government-market relationship index compiled by Fan et al.  to measuNational Sustainable Development Plan for Resource-Based Cities (2013-2020), this paper divides cities into resource-based cities and non-resource-based cities and performs regression on each group. The results are shown in columns (5) and (6) of Compared with non-resource-based cities, many resource-based cities in China lag behind in the construction of urban green culture, due to their long-term dependence on resources. According to the Referring to the research of Du , this paUnder the influence of green culture and Confucian culture, enterprises identify with different goals and pursue legitimacy to different degrees. This paper holds that LCCP has a more positive impact on the EIE in high-carbon emission industries than low-carbon emission industries. To test this hypothesis, the industries were divided into high-emission industry, medium-emission industry, and low-emission industry, according to the trisectional quantiles of carbon emissions of all industries in China, in reference of the carbon emission data in 2009. The relevant data come from Carbon Emission Accounts & Datasets (CEADs). The regression results are shown in The impact of LCCP on EIE mainly manifests as three effects, namely, technological innovation effect, financing constraint effect, and resource allocation effect. These effects are tested separately in this paper.The R&D expenditure reflects the willingness of enterprises to invest in technological innovation. Therefore, this paper selects R&D expenditure as a proxy variable for technological innovation and measures the variables with the ratio of R&D expenditure to operating income. The regression results are shown in column (1) of Scholars mainly use KZ, WW, and SA indices to measure the financing constraint of enterprises , 35. AmoThis paper uses capital allocation efficiency as a proxy variable of resource allocation efficiency and designs model  followinThis paper measures the EIE with the Richardson enterprise expectation investment model. The research samples are the A-share listed nonfinancial enterprises in Shanghai and Shenzhen stock exchanges of China from 2007 to 2016. On this basis, the impact of LCCP on EIE was estimated by using HTDID, and the heterogeneous effect of urban culture was also investigated.The main conclusions are as follows:(1) Overall, LCCP improves EIE, and the research conclusion passes a series of robustness tests. (2) Mechanism analysis reveals that LCCP mainly acts on EIE along two paths: promoting enterprise technological innovation and easing financing constraint. But the LCCP does not have a significant effect on resource allocation. (3) The influence of LCCP over EIE varies with urban cultures. The ecological wisdoms of green urban culture and Confucian culture, such as benevolence to all beings and the harmony between man and nature, help to enhance the promoting effect of LCCP on EIEThe policy implications are as follows:First, the positive effect of LCCP on EIE was demonstrated through empirical research. The construction of low-carbon cities is an important means for European developed countries to improve residents' well-being and urban competitiveness. In developing countries, the legal system is relatively weak, and the relevant pilot policies may be difficult to implement. The research results prove that LCCP has the same ideal effect in developing countries like China and can be used as an important means to promote high-quality economic development.Second, strengthening urban cultural governance is of great significance to LCCP promotion. Urban cultural governance focuses on improving the cultural connotation and quality of urban governance. This is particularly true as China witnesses increasing urban scale, rapid construction, the lack of urban culture, and cultural imbalances. Then, it is necessary to highlight the construction of cultural soft power in governance goals and contents. Special attention should be paid to urban cultural governance from the perspective of green development, making cultural governance a powerful guarantee for promoting the progress of urban civilization and green development."}
+{"text": "Health Related Quality of Life (HRQoL) is a cornerstone in the evaluation of modern medicines, healthcare practice and other medical interventions . It is oIn health economics, it is useful to perform cost-effectiveness and cost-utility studies by considering the preferences of patients , 9. The Li et al. have evaluated the global, sex, age, region, and country-specific cardiovascular disease (CVD) burden, along with the trends, risk factors, and implications for the prevention of CVD. This study would help explain the characteristics of the global CVD burden in order to set up more effective and targeted prevention strategies. Lobo et al. have studied the need to address potential caregiver-affecting issues at many stages of health planning, recovery, and policymaking in order to generate the evidence to enable stroke caring engagement. In addition, a thorough understanding of the processes involved in stroke care, available services and individual needs and experiences to develop a more realistic approach toward engagement with whom. Cheng and Jin have investigated the association between smoking and HRQoL among Chinese individuals aged 40 years and older using an instrumental variable probit model. Their findings showed that smoking leads to a smaller probability of having a better quality of life, thereby anti-smoking campaigns are then needed to highlight the negative effect of tobacco use on HRQoL. In a multinational study, Ghazy et al. have also assessed the quality of life and its determinants among healthcare workers living and working in the Arab world. The findings of this study indicate that more attention should be administered to this key group in order to ensure their productivity and service provision. Besides, AlKuwaiti et al. have also explored the physical, social, psychological, spiritual, and lifestyle impact of a positive COVID-19 diagnosis on a sample of the UAE population. The study shows that patients with COVID-19 have perceived very good support in terms of their physical health from the government and health authorities, but need social, psychological, and educational support during the infection period and after immediate recovery and post-recovery.To date, plenty of research is conducted in this field and relates, for example, to the choice of the instrument, methodological development, ability to capture specific health dimensions, and lots more. Our Research Topic was open to the subject area of health-related quality of life in healthcare and in clinical practice. Articles included instrument development, new technologies, application, evaluations and outcomes. For example, Shi et al. have assessed the cost-effectiveness of the same-day discharge (SDD) in comparison to that of regular care for primary total hip arthroplasty patients. This is achieved by analyzing the effect using the Oxford hip score (OHS), medical costs (both out-of-pocket and reimbursed), mean incremental cost-effectiveness ratio (ICER), and quality-adjusted life years (QALYs) at 6-month follow up. By a standard cost-effectiveness analysis (CEA), this study would help physicians, government and health authorities to look at SDD in a more precise and efficient approach. Additionally, Shao et al. have also evaluated the cost-effectiveness of camrelizumab plus chemotherapy to treat sq-NSCLC from the Chinese healthcare system perspective. The findings of this economic evaluation approach would provide evidence for clinicians, government and health authorities in making optimal decisions in general clinical practice.With regards to cost-effectiveness analyses, Kharroubi and Kelleher have developed a novel Bayesian non-parametric model for estimating the utility values of health states defined by a generic descriptive system, to generate quality-adjusted life years and hence to conduct cost utility analysis of healthcare interventions. The new Bayesian statistical model also permits the utilization of evidence from one country as potential prior information for a study in another. The results of this study suggest that existing countries' valuations could be used as informative priors to generate better utility estimates than modeling the data from each country separately. This sort of analysis (borrowing strength from existing countries) could be particularly promising in terms of reducing the need for conducting large surveys in every country, which would in turn reduce the cost of cross-country valuation. This will be hugely important for countries where large-scale evaluation exercises are expensive and hard to conduct, particularly for countries with small population size or low- and middle-income countries.To this end, our Research Topic was sealed with a methodological paper where So as a final word, Health Related Quality of Life in Healthcare has become the focus of health related research and practice especially after the COVID-19 crisis which have unveiled systems weaknesses and the need for future preparedness with more evidence based oriented actions and polices which this topic has aimed for.SK participated in the conceptualization of the idea, the design of the Research Topic, editorial drafting, and the final review of the editorial. IB reviewed and finalized the editorial and participated in the conceptualization of the study. All authors have read and approved the final editorial."}
+{"text": "The COVID-19 pandemic remains a public health problem threatening national and global health security. The socio-economic impact of COVID-19 was more severe on developing countries including Lebanon, especially due to the fragile healthcare system, weak surveillance infrastructure and lack of comprehensive emergency preparedness and response plans. Lebanon has been struggling with plethora of challenges at the social, economic, financial, political and healthcare levels prior to the COVID-19 pandemic. The COVID-19 pandemic in Lebanon revealed gaps and challenges across the spectrum of preparedness and response to emergencies. Despite these challenges, the Lebanese response was successful in delaying the steep surge of COVID-19 cases and hospitalisations through imposing strict public health and social measures. The deployment of the national vaccination plan in Lebanon in February 2021 coincided with the reduction in the number of cases and hospitalisation rates. The aim of this manuscript is to advance the epidemiologic evolution of COVID-19 in Lebanon pre- and post-vaccination, the challenges affecting the response and recovery, and the lessons learned. Since its emergence in December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has been a global public health problem. SARS-CoV-2 has rapidly spread worldwide and accounted for more than 649\u00a0711\u00a0690 cases and 6\u00a0654\u00a0580 deaths until the write-up of this manuscript . Ba. Ba26]. The lifting of PHSMs prior to the availability of COVID-19 vaccines, and specifically during the 2020 holiday season, had a significant impact on the already fragile healthcare system suffering from shortage of medical equipment and medication as well as incentives and livelihood subsidies. This coincided with the detection of the first SARS-CoV-2 variant of concern (VOC), alpha (B.1.1.7) . A sharpThe day 27 January 2021 marked the announcement of the national COVID-19 vaccination plan as well as the launching of an online registration platform, IMPACT, for COVID-19 vaccine registration and reporting of adverse events . The COVThe BNT162b2 vaccine was the first to be delivered to Lebanon followed by the ChAdOx1 vaccine , 37. By Despite all the challenges, the national vaccine campaign was successfully launched and was coupled with a gradual decline in the number of reported cases and incidence rates. The lowest number of reported cases was reported in the period extending between 1 May and 31 July 2021 with an average daily case of 378 and average daily positivity rate of 2.3%  and 2. SWith the emergence of SARS-CoV-2 variants and vaccine escape mutants, several studies reported breakthrough infections among fully vaccinated individuals \u201352. HoweAt the beginning of the pandemic in Lebanon, there was limited capacity in detecting, tracing and isolating confirmed COVID-19 cases. The RHUH was the only hospital designated for testing, quarantining and treating confirmed cases . This reSARS-CoV-2 seroprevalence studies are important to estimate the burden of COVID-19 in a population and to understand the dynamics of disease transmission, risk of infection as well as the evolution of the pandemic . While sMoreover, the lack of concerted efforts between academics and national stakeholders as well as lack of information-sharing system resulted in poor engagement of the scientific community in supporting decision-making. Modelling studies, for examples, are important to inform and help policy makers to implement appropriate public health measures and mitigate virus spread. Few modelling studies were conducted in Lebanon to predict the spread of SARS-CoV-2 as well as the impact of COVID-19 vaccination , 70, 71.unpublished data).Importantly, limited genomic data on circulating SARS-CoV-2 variants have been available in Lebanon due to the lack of national genomic surveillance programmes and the lack of concerted efforts between research institutions and the MoPH to support the latter. SARS-CoV-2 genomic surveillance is important to continuously monitor the circulation and emergence of variants in order to guide national public health policies. Scattered reports on limited number of samples revealed the detection of B.1 lineage (20A clade), B.4 lineage (19A clade) and the B.1.1 lineage (20B clade) in 11 samples collected from hospitalised patients between February and March 2020 . Later aThe structure of the national healthcare system had a major impact on the national response to COVID-19. Approximately, 84% of healthcare facilities are located in large cities and most of them are private healthcare facilities . The numDespite all these challenges, Lebanon was able to delay the exponential rise in COVID-19 cases until January 2021 through intermittent lockdowns and community mobilisation. The latter was translated by the engagement of municipalities in sharing information with the MoPH, albeit later during the course of the pandemic, as well as monitoring home isolation for confirmed and suspected cases under their jurisdiction. Few months into the pandemic, the concerted efforts and collaboration between the MoPH, the Ministry of Interior, the Lebanese Red Cross, the United Nations agencies, the WHO and the Disaster Risk Management Unit resulted in better implementation of the national response against the spread of SARS-CoV-2. Moreover, volunteers were trained for contact tracing nationwide, testing and data collection specifically at points of entry (airport and land borders). The ability of the RHUH to care for COVID-19 patients early during the pandemic, the compliance of the Lebanese community to the implemented national strategies and safety measures, and the deployment of the COVID-19 vaccines contributed significantly to the success of the national response.The COVID-19 pandemic revealed global gaps and brought to the surface the need to reimagine the pillars of global health security. Lebanon, similar to other countries, grappled with a variety of challenges that unravelled the dire need for a national strategy cutting across emergency preparedness, response and recovery from crises. This strategy should be applied and sustainable for any type of threat including agents of potential epidemic threats as well as biological, chemical, radiologic and natural disasters. A prioritised plan of action supporting the development of the national health sector strategy on health security as well as strengthening the existing infrastructure is needed. These efforts require rethinking and reimagining the healthcare system and its components in order to manage crises. The COVID-19 pandemic unravelled many structural obstacles and barriers spanning the entire spectrum of emergency preparedness in Lebanon. The need to enhance surveillance and shift from disease-based surveillance into comprehensive surveillance programmes was clear for timely response to disease outbreaks. While this might seem generic, however, Lebanon has been suffering from political instability for the past five decades; the former hampered the institutionalisation of systemic programmes for disease prevention and care. Consequently, political commitment is needed to invest in sustainable capacity building and strengthening and updating the infrastructure of Lebanon's surveillance system and its healthcare infrastructure through: establishing an organic and sustainable link between the public and private sectors, the development of laboratory networks and decentralised yet linked genomic surveillance programme, robust health bioinformatic system for transparent data sharing while linking epidemiologic data to clinical data and genomics; importantly, the coordination between policy makers and research institutions is critical to advance contextual data that will feed into national needs of national stock supplies and supply chain . While researchers are well represented on national, regional and international committees and task forces on prevention and control of infectious diseases and disaster management and while the former had a positive impact on guiding national policies to control COVID-19 in Lebanon, an inherent lack of trust between policy makers and the community was obvious through lack of compliance of the community and lack of catch-up on vaccination depicted through the current low coverage rates. The development of a strong risk communication and community strategy is instrumental in times of emergencies and allows the engagement of communities in policymaking. This is more critical in Lebanon in order to build trust and engage the public in decision-making.Importantly, the recovery from an emergency must begin during the response and consequently, we recommend the development of a national policy for safe return to work, the establishment of a multisectoral recovery task force to coordinate and implement recovery arrangements , and supporting the MoPH to expand resources to strengthen the medical and public health sectors.Enormous efforts and actions were put in place to respond to the COVID-19 pandemic in Lebanon during a progressively worsening economic and financial situation; however, the COVID-19 pandemic revealed the vulnerability, gaps and needs of the healthcare system in Lebanon including epidemiologic surveillance, genomic surveillance, integrated and concerted data sharing, diagnostic capacity, community mobilisation and risk communication. The national commitment to these important inherent components of a rapid response requires resources and investment in human and technical expertise to reduce inequality in access to information and care."}
+{"text": "According to the American Psychological Association APA, , Health Several issues and factors are still understudied in Health Psychology. Psychological effects of the COVID-19 outbreak, caregiving experiences, work-related stress and life-work balance, quality of life of sexual minorities, health-related orientations and motivations among younger generations, and the impact of the new media on people's mental health are just a few examples of Health Psychology phenomena that need further investigation. A critical issue in Health Psychology is measurement. A variety of crucial psychological constructs, health-related behaviors, and responses to health, illness, and healthcare need to be addressed and measured in Health Psychology research and practice. Intervention programs designed to foster good health by changing negative health behavior, promoting positive health behavior, and enhancing the management of chronic conditions have been of particular interest to Health Psychology since its beginnings as a distinctive discipline. The availability of psychometrically sound measures is crucial to assessing the effectiveness of such interventions and deepening our understanding of the social and psychological processes of health and illness Apple, .We launched the Research Topic \u201cMeasurement in Health Psychology\u201d in this context. Because measures are a critical part of research and practice in Health Psychology, we were interested in providing an overview of up-to-date measurement principles and methods, which could help improve the process of developing valid, reliable, and sensitive instruments to be used in the fields of Health Psychology.Within this Research Topic, we brought together research studies developing new tools or advancing the psychometric study of existing measures relevant to Health Psychology. Twenty-three articles authored by 105 contributors from different countries and continents were accepted. The research contributions published in this Research Topic relate to self-report measures of socio-environmental and psychological/behavioral influences on health and disease, as framed within the biopsychosocial model Engel, , which hZhan and Wang) presented the development of a new measure to assess the subjective evaluation of harmonious family relations as a resource for physical and mental health. Three independent samples of Chinese university students were enrolled, respectively, for item analysis and exploratory factor analysis (EFA) of the initial item pool; confirmatory factor analysis (CFA) and assessment of internal consistency; and relationships to other variables and test-retest reliability over a two-month interval. Results supported a nine-factor model of family harmony, with adequate reliability and validity as evidenced by positive correlations with criterion measures of subjective well-being and family function, cohesion, and adaptability, and negative correlations with loneliness scores.Six articles in this Research Topic addressed constructs belonging to the social domain of the biopsychosocial model. Three papers dealt with the assessment of family relationships. One of them  evaluated the psychometric properties of a Chinese version of the 10-item Family Communication Scale (FCS) to measure positive family communication. EFA and CFA supported a one-factor structure, which showed adequate internal consistency and test-retest reliability and correlated in the expected direction with wellbeing indicators and frequency of communications with family members via Information and Communication Technologies.Another paper  proposed a new short measure to assess the bonding between parents and children under 1 year of age, namely the \u201cMe and My Baby\u201d (MaMB) questionnaire. Factor analyses and Rasch calibration performed on data from 434 mothers provided initial evidence that the MaMB reliably measures infant bonding.Finally, UK researchers . Applying CFA and Rasch analysis, the authors found evidence of a unidimensional structure with adequate reliability. Evidence of validity was provided by relationships with a measure of the risk of physical and psychosocial abuse and neglect by primary caregivers. As for formal caregiving, Italian researchers developed a 20-item scale to assess emotional, informational, appraisal, and instrumental social support by healthcare providers in the oncology setting (Tomai and Lauriola). Scale dimensionality and reliability were tested using exploratory structural equation modeling (ESEM) and Mokken scaling analysis. Evidence of validity and reliability and expected associations with doctor communication skills and trust in the physician supported the use of this new measure of healthcare social support as multidimensional a construct.In the context of caregiving, one paper tested the psychometric characteristics of the Zarit Burden Interview in Peruvian informal primary caregivers of persons diagnosed with intellectual disabilities  tested the validity and reliability of the School Burnout Inventory among Chilean high school students. CFAs on the 8-item Chilean version supported two statistically equivalent first- and second-order three-factor models of school burnout as composed of exhaustion, cynicism, and inadequacy, which showed gender invariance. Internal consistency and test-retest reliability were acceptable, and school burnout scores correlated as expected with study-related emotions, academic psychological capital, and academic engagement.Finally, as for the school environment, one article  tested the psychometric properties of the Farsi version of Perth Alexithymia Questionnaire (PAQ). Based on CFA results, the 5-factor model of the original PAQ replicated well on data from college students, with adequate internal consistency and test-retest reliability. Evidence of associations with other variables  was collected for the Farsi PAQ.Nine papers addressed the assessment of individual characteristics and behaviors relevant to health and illness. Within the field of psychosomatic disorders, Iranian researchers . An 11-item Spanish version with three factors  was obtained using CFA and ESEM and proved to be invariant across gender and age within and between five different study samples. Reliability coefficients were satisfactory, and correlations with relevant criterion measures  provided evidence of convergent and divergent validity.The Work-Related Rumination Scale was tested on a sample of Puerto Rican workers (Lang and Ye) presented a Chinese adaptation of the Self-Objectification Beliefs and Behaviors Scale (C-SOBBS). As a result of exposure to sexual objectification in interpersonal situations and visual media, self-objectification entails viewing one's own body from a third person's perspective and has been linked to poorer women's mental health. The authors found evidence of structural (CFA), convergent, discriminant, and incremental validity, and adequate internal consistency and test-retest reliability for the C-SOBBS. In another paper, Chinese researchers proposed the development and validation of the Psychological Needs of Cancer Patients Scale to identify the psychological care demands of cancer patients . Results of EFA and CFA supported a six-factor model of value and esteem, independence and control, mental care, disease care, belonging and companionship, and security, with acceptable reliability and expected associations with anxiety and depression.As to individual beliefs and expectations, one article . Data from Italian university students were analyzed via EFA and CFA, followed by Rasch analysis. A four-factor model of despair, adjustment, proactivity, and aversion was supported, which was invariant across gender and age and showed adequate reliability. Discriminant and criterion-related validity based on correlations with personality characteristics helpful in coping with disasters and predictive validity on levels of enjoyment and anger 2 months later were also supported. To assess coping strategies to deal with cancer, researchers from Portugal  performed a cross-cultural adaptation and psychometric evaluation of the Perceived Ability to Cope with Trauma Scale (PACT). Results of CFA on data from patients recently diagnosed with early breast cancer supported the original PACT two-factor model of coping flexibility as composed of forward and trauma focus domains, which showed adequate internal consistency and associations in the expected direction with self-efficacy to cope with cancer, quality of life and psychological distress.Two articles addressed situation-specific coping. The Robust Pandemic Coping Scale (R-PCS) was developed to assess coping strategies related to pandemic situations at all stages of the epidemic management cycle  developed a brief scale to assess the affective, cognitive, and behavioral attitudes of youth and young adults toward condom use. Using EFA and ESEM, the authors found support for the hypothesized three-factor model. The scale showed strong invariance across gender, adequate reliability, and expected relationships with sexual risk behaviors and condom use.In the area of health-related attitudes, Chilean researchers  tested the psychometric performance of a very brief measure of problematic internet use, namely the Compulsive Internet Use Scale (CIUS), when used with Lithuanian medical students and resident doctors. Results indicated that the brief, 5-, 7-, and 9-item versions of the CIUS were reliable and valid screening tools to assess the severity of symptoms of problematic internet use in the medical population. Another brief, 6-item scale of excessive use of social networks was adapted for use with Mexican adolescents and young adults . Altogether, the structural properties of the response options fitted the partial-credit model. CFA supported a single domain of addiction to social networks, with measurement invariance across sex, age, and educational campus, good internal consistency, and theoretically consistent associations with sensation seeking and depression.Among health-related behaviors, one study  presented the traditional Chinese version of the Recovering Quality of Life (ReQoL) outcome measure. The ReQoL measures mental health recovery, defined as a self-directed process of healing and transformation, which has received increasing attention in evaluating the outcomes of mental care. The Chinese ReQoL showed good psychometric properties in terms of internal consistency, test-retest reliability, factor structure (CFA), known-group validity, and associations with relevant variables in the general population.A total of eight papers focused on assessing outcomes of the interactive relationships between biological, environmental, and psychological/behavioral factors. Two papers focused on health-related quality of life (HRQoL), which is a primary outcome in the evaluation of interventions' effectiveness on people's health. One article  examined the validity and reliability of the Minnesota Living with Heart Failure Questionnaire in individuals with coronary artery disease. EFA and CFAs supported a three-factor model of physical, social, and emotional disease-specific HRQoL. The Lithuanian version was reliable and showed evidence of convergent validity based on correlations with another measure of HRQoL (SF-36) and with exercise capacity assessed using a standardized computer-driven bicycle ergometer.Lithuanian researchers . CFA confirmed a bifactor model, which was invariant across gender and age in a sample of university students. Based on reliability analyses, the authors advised against the interpretation of specific-factor scores and recommended the computation of a general wellbeing score.Six papers addressed the assessment of indicators of mental health or adjustment to health problems. One of them presented the validation of a Kazakhstani version of the Mental Health Continuum\u2013Short Form to assess emotional, social, and psychological wellbeing  presented the validation study of a multidimensional inventory for the assessment of mental pain after traumatic experiences (FESSTE30) in the German speaking general population. CFA showed a satisfactory fit of a five-factors measuring somatization, depression, intrusive memories, dissociation, and anxiety. The scale showed evidence of reliability and strong correlations with measures of psychological distress, PTSD symptoms, and the extent of traumatic experiences.Another article . Based on the results of PCA and CFA, the authors proposed a revised model (MI-RSWB-R) with general religiosity and connectedness domains reflecting religious and spiritual wellbeing, respectively, and suggested using the remaining subscales  to gain insight into specific, separate facets of wellbeing. All MI-RSWB-R domains showed adequate reliability and relationships with the centrality of religiosity.The Swedish version of the Multidimensional Inventory for Religious/Spiritual Well-Being (MI-RSWB) was psychometrically tested to assess the spiritual wellbeing of a large sample of university students  tested a Brazilian-Portuguese version of the 12-item Infertility-Related Stress Scale (IRSS-BP) to assess adjustment to the infertile condition. ESEM showed a bifactor model with one general and two specific intrapersonal and interpersonal stress factors, which was invariant across Brazilian and Italian infertile individuals. All three IRSS-BP factors showed adequate composite reliability and theoretically meaningful associations with gender, infertility duration, and depression scores.Brazilian and Italian researchers  tested the psychometric properties of the Starkstein Apathy Scale (SAS) to assess apathy in a sample of English speaking people having experienced a stroke. A revised 9-item version of the SAS targeting impairment of apathy/motivation was obtained, which was unidimensional and reasonably reliable, with no substantial item differential functioning across time, age, sex, and education.Using Rasch's partial-credit model, correlation, and regression, one study . Ego integrity in older people is crucial to help them achieving successful aging and a better quality of life. Through a three-step process involving expert validity and piloting, item analysis and principal component analysis, CFA, and assessment of reliability and relations to criterion measures, the authors found acceptable validity and reliability evidence, supporting the use of the Chinese IPB.Chinese researchers developed and tested a 40-item short form of the Inventory of Psychosocial Balance (CIPB-SF) to assess ego development based on Erikson's theory in Chinese older adults (In this Research Topic, we invited researchers from around the world to contribute to measuring key constructs in Health Psychology by sharing the development and improvement of measures to be used by Health Psychology researchers and clinicians.Two-thirds of the accepted papers presented further development and validation of existing instruments for use in different cultural contexts or populations with specific characteristics. This emphasizes that the validation process is never complete but is instead an ongoing process, which involves collecting multiple types of evidence to support the appropriateness and meaningfulness of inferences and decisions made from measurement scores Messick, . Most paAltogether, 23 measures with promising psychometric characteristics are made available to researchers and clinicians to ensure a valid and reliable assessment of psychosocial variables and behaviors that may influence health and illness, as well as to evaluate health outcomes and monitor the effectiveness of Health Psychology interventions. This Research Topic certainly does not exhaust the issue of measurement in Health Psychology. Still, we hope that other colleagues will take new initiatives to further share the development and testing of valid, reliable, and sensitive instruments to be used in Health Psychology research and practice.All authors listed have a substantial and equal contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Measurement-Based Care (MBC) is an emerging healthcare model with a number of potential advantages over traditional approaches for the treatment of substance use disorder (SUD). Despite SUD treatment programs being theoretically well suited for the implementation of MBC, its uptake has been minimal, which in turn limits further research, knowledge synthesis, and translation into clinical practice.The goal of this knowledge synthesis project is to stimulate greater consideration of MBC models in addictions programs, with three interrelated objectives: 1. To summarize the existing evidence from research literature 2. To complement the literature findings with the data from our clinical research and quality improvement projects 3. To explore potential risks and difficulties of MBC implementation in the SUD treatment programsNarrative review. Knowledge synthesis.To date, only two published randomized controlled trials, which along with the data from our pragmatic clinical research, support the wider implementation of MBC in the substance abuse treatment settings, but also indicate the high need for larger-scale clinical trials and quality improvement programs. Potential barriers to the implementation of MBC for SUD are outlined at the patient, provider, organization, and system levels, as well as challenges associated with the use of MBC programs for clinical research. Critical thinking considerations and risk mitigation strategies are offered toward advancing MBC for SUD beyond the current nascent state.The state-of-the-art of MBC in SUD care settings reviewed and the strategies for further development from adminsitrative, clinical, and research prospectives outlined.No significant relationships."}
+{"text": "QEEG is a modern electroencephalography (EEG) analysis that records digital EEG signals, which are processed, transformed, and analyzed using complex mathematical algorithms. When Hans Berger recorded the first EEG of a human brain in 1924, his observations were limited to the time domain. Still, he suggested that frequency analysis would improve the interpretation of EEG signals in the future. QEEG has brought new EEG signal feature extraction techniques: analysis of specific frequency band and signal complexity, analysis of connectivity, and network analysis. The role of QEEG is not necessarily to pinpoint an immediate diagnosis but to provide additional insight in conjunction with other diagnostic assessments for obtaining a precise result and disease severity stage or specific treatment response evaluation. The clinical application of QEEG is extensive, including neuropsychiatric disorders, epilepsy, stroke, dementia, traumatic brain injury, and many others.Neurotechnology establishes strategic connections between various disciplines, from neuroscience and medicine to engineering and artificial intelligence, tackling the more profound understanding of fundamental brain principles and enhancing the advancement of new technological methods in experimental and clinical settings.EUNeurotech, the European University of Brain and Technology, brings together eight leading European universities, partner research institutions, companies, societal stakeholders, cities, and (non) governmental organizations to build a trans-European network of excellence in brain research and technologies to increase the competitiveness of European education, research, economy, and society. In this context, the University of Medicine and Pharmacy Iuliu Ha\u021bieganu (UMFIH), through the Erasmus+ department, developed the first Blended Intensive Program (BIP) within the NeurotechEU Alliance, organizing the QEEG Summer School (QEEGSS). BIP aims to open more opportunities for learners to participate in blended mobilities, supporting the development of transnational and transdisciplinary curricula and innovative teaching methods such as research-based learning and challenge-based approaches.th and 15th, 2022, to promote a basic understanding of QEEG analysis and its applications in a multidisciplinary environment. This innovative event was the first BIP of the NeurotechEU alliance, developed with its academic partners: UMFIH through Erasmus+ department and RoNeuro Institute for Neurological Research and Diagnostic.The first edition of the QEEGSS educational program was conducted in Cluj-Napoca, Romania, between July 11e.g., medical school students, psychologists, neuroscience or PhD students) from six European countries , facilitating multidisciplinary interaction and exchange of skills.The five-day training followed a simple-to-complex approach, from the source and principles of EEG to the most complex types of QEEG analysis. It provided early-stage researchers with a basic yet modern understanding of where QEEG has arrived today and potential avenues for its development. QEEGSS brought together junior researchers with a common interest in QEEG and distinctive backgrounds  and the Society for the Study of Neuroprotection and Neuroplasticity (SSNN)  .This educational and practical event was set up to unfold over 5 days in two locations: UMFIH on the first two days and RoNeuro on the following days for the hands-on sessions. Furthermore, as part of the BIP recommendations, the final lecture was developed as a virtual course with innovative interactive resources. A total of 23 delegates from different countries participated in the intensive program: Germany \u2013 Bonn University (6 delegates), Bulgaria \u2013 Medical University of Sofia (4 delegates), the Netherlands \u2013 Radboud University (3 delegates), Slovenia \u2013 Maribor University (2 delegates), Hungary \u2013 Debrecen University (1 delegate), Romania \u2013 UMFIH (6 delegates), Carol Davila University of Medicine and Pharmacy, Bucure\u0219ti (1 delegate).Participants were given the opportunity to share their knowledge and experience on conventional EEG, discuss and question basic concepts, and analysis of QEEG. Ultimately, the delegates were divided into five teams, and the goal of each team was to develop a project idea that involved the QEEG assessment of subjects with specific pathology. Then, being provided with a potential methodological approach, they were invited to build up a research proposal and an elevator pitch as they were applying for a grant, convincing the evaluation board that their ideas were relevant and feasible.All participants were early-stage researchers with distinctive backgrounds from medical sciences up to psychology, with an interest in the QEEG assessment of neuropsychiatric physiology and pathology.Prof. Dafin Fior Mure\u015fanu opened the QEEGSS with an overview of the new paradigms in neurophysiology research and the importance of extending the knowledge about neuroscience inside an ever-increasing technology in this field.After the introduction, the participants were divided into five teams and encouraged to propose a research hypothesis aligned with their shared interests, which could be tested through QEEG. Each team came up with creative project proposals, such as:The effects of antidepressants on sleep architecture in offspring rodents with a history of prenatal stress;The benefits of mindfulness meditation in young ADHD subjects;The effects of imagination of motor action on mu waves.In the second part of the day, Dr. Livia Popa lectured on the fundamentals of EEG, describing the sources of the electric scalp activity and recording principles  . ThroughThe following presentations focused on spectral analysis, time-frequency decomposition, and various connectivity analyses. First, Dr. Victor D\u0103bal\u0103 presented how a Fourier transformation (FT) works, emphasizing the Fast Fourier Transform (FFT) and the convolution theorem. Next, Dr. Diana Chertic introduced the most used methods for obtaining time-resolved frequency representations of EEG data and for assessing the connectivity in the time domain. Finally, Dr. Hanna Drago\u0219 covered the basics of several connectivity methods such as coherence, phase-locking value, and the Granger causality. By being asked to fixate on a central flashing dot while ignoring the dots existing anywhere else in the visual field, the participants were introduced to the concepts of selective attention and motion-induced blindness as changes in communication structure between brain areas. QEEG applications in daily neurological practice were highlighted through clinical cases that entertained the participants in debates on differential diagnoses from neurodevelopmental to neurodegenerative disorders.The third day occurred at the RoNeuro Institute for Neurological Research and Diagnostic. The institute has a multidisciplinary clinical activity and a research branch driving innovation in neuroscience across sectors. The day started with Dr. Livia Popa offering an interactive and comprehensive presentation about EEG patterns, types of activity, and artifacts. The participants were also instructed on the features of EEG in neurological disorders, comprising a full dive into the complex concept of EEG.Dr. \u0218tefan Strilciuc then coordinated a hands-on experience targeting the Independent Component Analysis (ICA) technique, used for two fundamental QEEG steps: cleansing the data prior to the analysis and identifying the brain sources of specific signal patterns.The hands-on session continued on the fourth day, when the participants could record the EEG of a randomly assigned participant. Afterwards, they were instructed on the preprocessing and analysis of the recorded signal, both activities led by Dr. Livia Popa. Using the EEGLAB software, the time series data was first referenced, filtered, cleared from artifacts and bad segments, and analyzed using FFT and time-frequency decomposition. Some source reconstruction techniques were also employed, and the participants were introduced to the forward and inverse problems.The last day of QEEGSS started with an online lecture, which offered a basic overview of several technologies that can be used in conjunction with QEEG, covering their development, functions, mechanisms, and research applications. Therefore, concepts like transcranial magnetic stimulation (TMS), functional magnetic resonance imaging (fMRI), functional near-infrared spectroscopy (fNIRS), eye tracking (ET), magnetoencephalography (MEG), transcranial direct-curent stimulation (tDCS) and transcranial alternating current stimulation (tACS) were developed through innovative interactive virtual resources by Dr. Irina Vlad.QEEG participants had the opportunity to enrich their local experiences by attending various leisure and cultural activities, such as familiarizing with the Romanian culture and language, exploring the Turda Salt Mine (recently considered for UNESCO heritage inclusion), sharing a multicultural dinner, experiencing a deep dive into the history and architectural landmarks of Cluj-Napoca through a guided visit to the city's historical center, and, lastly, exploring the Alexandru Borza Botanical Garden.The QEEGSS lectors and participants  contribuEU. As quantitative electroencephalography is becoming a reliable tool for experts in the interconnected fields of neurosciences and biotechnology, the event cleared a possible pathway regarding the interest of future generations in exploring the boundaries of their field of expertise.The first edition of QEEGSS marked the beginning of BIP educational events within the alliance of NeurotechConsidering the critical significance of international collaboration and the continuous need for multidimensional and multidisciplinary approaches for neurotechnology applications in research settings, the QEEGSS offered a peak into QEEG and its potential to drive developments in clinical neuroscience and beyond."}
+{"text": "Dear Editor,Along with the increasing administration of COVID-19 vaccines, in the last months, the detection of potential adverse skin reactions has increased, highlighting the possibility that not only SARS-CoV-2 infection but also COVID-19 vaccines can induce cutaneous manifestations.A 61-year-old Caucasian woman presented to our department with a 3-month history of ten, symmetrical, whitish, xerotic and sclerotic plaques, with a diameter ranging between 5\u202fcm and 12\u202fcm localized in the abdominal area, lower limbs, back and upper limbs A. Her faGM is identified by more than four plaques, at least 3\u202fcm, that involves two or more anatomical regions and differs from scleroderma by the absence of Raynaud phenomenon, sclerodactyly, facial involvement, nail fold involvement, and specific autoantibodies.None declared.Giovanni Paolino: Study concept and design; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; writing of the manuscript or critical review of important intellectual content; final approval of the final version of the manuscript.Matteo Ricardo Di Nicola: Writing of the manuscript or critical review of important intellectual content; final approval of the final version of the manuscript.Nathalie Rizzo: Study concept and design; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; final approval of the final version of the manuscript.Santo Raffaele Mercuri: Study concept and design; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; final approval of the final version of the manuscript.Nathalie Rizzo and Santo Raffaele Mercuri share the co-last authorship.None declared."}
+{"text": "Exosomes are a class of extracellular vesicles (EVs) comprising a heterogenous population of biological nano-vesicles enclosed by a lipid bilayer . All eukShpigelman et al., at the University of California, San Diego, CA, United States, are reporting a pioneering study developing a reporter cell line for quantitative measurement of EV release from antigen-presenting cells (APCs) in a phenotypic high-throughput screening format. They show that the new, dual-reporter cell line exhibits robust responses and has the potential to become an excellent research tool for the screening of compounds that induce or inhibit EV release by APCs. An article by Shukla et al., at the University of California, San Diego, CA, United States, aimed at identifying small molecules that could induce EV release in a human monocytic leukemia THP-1 reporter cell line. They described a process of screening the EV release that could add a new dimension to structure-activity relationship studies of vaccine adjuvant activity. A study by Olivero et al., at the University of Genoa, Italy, addresses the important question of whether exosomes are actively released from presynaptic nerve terminals. Their findings provide strong evidence supporting the release of EVs from presynaptic structures and indicate an increased EV release upon exposure of synaptosomes to a depolarizing stimulus.Alsop et al., from the group of one of our Research Topic Editors, Dr. Kendall Van Keuren-Jensen at the Translational Genomics Research Institute, Phoenix, AZ, United States, together with multiple collaborators, have generated an atlas of small RNAs from 30 different tissues and three different blood cell types. They analyzed various tissues for the enrichment of small RNA sequences, assessed their expression in different human biofluids  in cell-free circulation as well as from EVs  on the miRNA cargo in cerebrospinal fluid-derived EVs and to determine if AD risk factors have an impact on EV-associated miRNA expression patterns. Their study showed that APOE-\u03b54 and female sex, two known risk factors for the disease, influence EV-associated different miRNA levels in the CSF of patients with AD. Bilousova et al., at UCLA, CA, United States, led a multi-omics study analyzing putatively microglia-originating small EVs from cryopreserved human brain tissue in search of novel biomarkers for Alzheimer\u2019s Disease. The analysis included lipids, proteins, and miRNAs in microglia-originating small EVs from human brain tissue and indicated the release of neuronal and myelin materials via EVs. Another important finding was a significant decrease in docosahexaenoic acid levels in AD, which potentially could be used as a biomarker. A review article by Ghosh and Ghosh from the Indian Institute of Technology Jodhpur, India, described in detail the role of small EVs as pathogenic agents transmitting toxic protein forms that propagate neurodegenerative disorders throughout the CNS. It is becoming increasingly evident how small EVs can be harnessed in identifying neurodegenerative disease biomarkers , Milan, Italy, demonstrated that EVs isolated from the plasma of patients with COVID-19 harbor SARS-CoV-2-related protein materials. They observed that EVs recovered from patients with mild symptoms effectively modulated antigen-specific CD4-positive T-cell responses. The study also suggested that the patient-derived EV-associated proteins not only induced an immune response, but also the EV cargo could help identify the pathological state of patients in the acute phase of the disease.A timely study by Moros et al., at the Universidad de Zaragoza, Zaragoza, Spain, and Istituto di Scienze Applicate e Sistemi Intelligenti, Pozzuoli, Italy, isolated EVs from the freshwater cnidarian polyp Hydra Vulgaris and investigated their biochemical, morphological, and functional characteristics. The analysis showed that EVs released by this species transfer protein and major components of axial patterning, modulating foot and head regeneration. A review article by Fang et al., China Agricultural University, Beijing, China, and Dr. Brett M. Tyler Oregon State University, Corvallis, OR, United States compiles information regarding recent research on the biogenesis of EVs and their pathobiological functions in organismal communication of microbes. The authors highlighted key questions related to the transfer of genetic materials between species which requires further exploration in this direction.Kutchy et al., at the University of Nebraska Medical Center, Omaha, NE, United States, and collaborators in Grenada and China showed that EVs could be used as a vehicle for the effective delivery of drugs to the brain. The authors investigated the biodistribution of ultra-small, iron oxide-labeled, mouse astrocyte-originating EVs after intranasal perfusion in mice and suggested that engineered EVs could be utilized for targeted delivery of therapeutics into several organs including the brain. In another review article, Zheng et al., from Fudan University, Shanghai, China, summarized the current research advances on the involvement of EVs in the pathogenesis, diagnosis, and treatment of the autoimmune disease, systemic lupus erythematosus (SLE) and lupus nephritis (LN). In this article, the authors have discussed the role of several immune cell-originating EVs in the regulation of the innate immune responses and highlighted the necessity of further research to fully understand the involvement of EVs in the pathophysiological mechanisms of SLE and LN.The delivery of therapeutics across the blood-brain barrier for brain disorders has remained challenging despite recent progress . A studyKang et al., at the University of Illinois, Chicago, IL, United States, studied the effects of the inflammatory cytokines on mesenchymal stem cell-derived EV-mediated immunomodulation. They concluded that TNF\u03b1 preconditioning of human mesenchymal stem cells results in the generation and release of EVs that can alter the phenotype of macrophages, both in vitro and in vivo. Corsello et al., at the University of Texas Medical Branch at Galveston, TX, United States, investigated the presence of innate immune mediators, including interferons in EVs, released from airway epithelial cells infected with the respiratory syncytial virus. The study found significant levels of soluble and EV-associated interferon \u03bb in nasopharyngeal secretions (NPS) and NPS-derived EVs from children with respiratory syncytial virus infections.While EVs have been extensively studied in the field of cancer  and someOverall, this Research Topic covers broad aspects of extracellular vesicle biogenesis, their isolation and characterization strategies, involvement in intercellular communication, and the roles EVs play in different human diseases. The topic also includes articles that investigated and discussed the possibilities of using small EVs as potential disease biomarkers and opportunities for therapeutic applications. These basic, translational, and clinical studies demonstrate the importance and high potential of EVs in human health and diseases including neurodegenerative disorders and cancer, as well as in understanding intercellular communication in low organisms, including microbes and polyps. Future scientific efforts to fully understand the mechanisms of EV-mediated cell-cell communication in health and different disease states are expected to provide critical insights into basic biological processes, development of biomarkers, identification of therapeutic targets, and harnessing EVs as a vehicle for drug delivery."}
+{"text": "From ancient times to the present, mankind has experienced many infectious diseases, which have mutually affected the development of society and medicine. In this paper, we review various historical and current infectious diseases in a five-period scheme of medical history newly proposed in this paper: (1) Classical Western medicine pioneered by Hippocrates and Galen without the concept of infectious diseases (ancient times to 15th century); (2) traditional Western medicine expanded by the publication of printed medical books and organized medical education (16th to 18th century); (3) early modern medicine transformed by scientific research, including the discovery of pathogenic bacteria (19th century); (4) late modern medicine, suppressing bacterial infectious diseases by antibiotics and elucidating DNA structure as a basis of genetics and molecular biology ; and (5) exact medicine saving human life by in vivo visualization and scientifically verified measures (after the 1990s). The historical perspectives that these five periods provide help us to appreciate ongoing medical issues, such as the present COVID-19 pandemic in particular, and remind us of the tremendous development that medicine and medical treatment have undergone over the years. From ancient times to the present day, the most important mission of medicine and medical care has been to diagnose and treat illnesses. It is well known that medicine before the 18th century was fundamentally different both in medical perception and medical scientific technology from what followed . Until tAfter recent studies on the history of medical education ,4, we neSince the beginning of the year 2020, the COVID-19 pandemic caused by SARS-CoV-2 has not only inflicted severe damage on the world economy but also caused indescribable suffering to people around the world. Although this experience has been a very disastrous one, it has also provided us with an opportunity to once again reaffirm the relevant roles of medicine and medical care for the world. At the same time, it is also relevant to recall the emergence of these great infectious diseases that have occurred one after another in history as part of the common experience of humankind.The Western medical tradition began in ancient Greek and Rome since 5th century BC, long before the discovery of infectious pathogens and without the concept of infectious diseases. The medical documents of Hippocrates and Galen were handed down and compiled into medical textbooks in the Middle Ages. From the records they contain of several devastating plagues, their causative pathogens have been investigated and interpreted by modern researchers from the symptoms and the modes of progression described therein.Corpus Hippocraticum) . Phy. PhyTheopeatedly .Box 1Theoria (theory of medicine), the theoretical foundations of medicine in five subdivisions, including Physiologia, Pathologia, Semeiotica, Hygiena, and Therapeutica(A) Practica (practice of medicine), the individual illnesses(B) Anatomia et Chirurgia (anatomy and surgery), the structure of the human body as a basis of medicine, and its application to surgical operations(C) Botanica et Pharmatica (botanics and pharmaceutics), botanical remedies, utilizing botanical or herb gardens for education and research(D) Practica books dealt with the diagnosis, therapy, and prognosis of individual illnesses, including both the regional illnesses a capite ad calcem (from head to toe) and systemic illnesses such as fevers [Practica books, indicating there was no collective concept of infectious disease at that time , gastrointestinal symptoms (diarrhea and vomiting), respiratory symptoms (cough and dyspnea), and so on, were confused with the diseases and represented the illness. In the 19th century, the pathological changes of organs found by postmortem autopsy were regarded to be the cause of diseases, or the illness itself. There are several diagnostic innovations observed during this time  Box 2)..Box 2).Box 2Jean-Nicolas Corvisart: Discovery of the diseases of the heart and great arteries conducted in vivo diagnosis using the chest percussion maneuver (1806).Ren\u00e9 Th\u00e9ophile Hyacinthe La\u00ebnnec: Development of indirect auscultation and discovered pulmonary diseases supported by observations made during autopsy (1819).Richard Bright: Discovery of the kidney diseases by autopsy of dropsy patients after scarlet fever (1827), which came to be known as Bright\u2019s disease.Rudolf Ludwig Carl Virchow: Cellular pathology (1858) and recommended histopathological diagnosis, which improved the accuracy of pathological diagnosis.Surgery up to the 18th century had high risks of developing bacterial infections peri- and post-operationally, and its application was limited to the treatment of wounds and tumors on the body surface. The British surgical scientist Joseph Lister proposed a disinfection method using carbolic acid in the 1870s and later developed a surgical sterilization method. In the mid-19th century, ether anesthesia was performed in a public surgery in the United States (1846), and the anesthesia method spread rapidly to Europe and the United States. These innovations enabled surgical operations of visceral organs deep in the body, such as the digestive, respiratory, and reproductive organs .Box 3Joseph Lister: A disinfection method using carbolic acidin the 1870s and later developed a surgical sterilization method.TheodorBillroth: Pyloric resection (1881) and gastrectomy (1885)William Halsted:Development of radical mastectomy for breast cancer (1889)Harvey Cushing: Apioneer of brain surgery (from 1912)With the Industrial Revolution and urbanization in the 19th century, the water-borne diseases of dysentery and cholera became common causes of death in many countries  see Sup.contagio\u201d (contact) had been used since the 16th century [In the mid-19th century, the causes of plagues and epidemics were still obscure, and miasma (contaminated air) and contagion (disease seeds) were discussed as possible causes of diseases. The German anatomist Jakob Henle (1840) classified the causes of diseases into miasmas, contagions, and miasmatic-contagions . The con century .Bacillus anthracis [Mycobacterium tuberculosis (M. tuberculosis) (1882) [Vibrio cholerae (V. cholerae) (1884) [Yersinia pestis (Y. pestis), the pathogen of the plague (1894). Bacteriology was the mainstream state-of-the-art science, leading to the discovery of numerous pathogens during this period   and reventhracis , Mycobac) (1882) , and Vib) (1884) , all thrs period .specielle Pathologie\u201d in German, and \u201cpathologie interne\u201d in French. In these textbooks, the diseases of organs were arranged according to individual organ systems in addition to systemic diseases. As the most popular textbook in this period, Niemeyer\u2019s Lehrbuch der speciellen Pathologie und Therapie (1858) [In the 19th century Europe, medical textbooks dealing with the diagnosis, therapy, and prognosis of individual diseases were published under various titles such as \u201cpractice of medicine\u201d in English, \u201ce (1858)  recognizIn the 20th century, the increased international mobility and the worldwide wars spread serious airborne infectious diseases, such as influenza and tuberculosis. On the other hand, medical science succeeded in overcoming the infectious diseases by antibiotics against bacterial pathogens and by identifying specific pathogenic viruses.The investigation of antimicrobial agents began with the discovery of pathogenic bacteria at the end of the 19th century. Salvarsan and sulfonamides were produced by chemical synthesis in 1911 and 1935, respectively . AlexandStaphylococcus aureus (S. aureus) was, however, reported in 1942, the same year of the introduction of Penicillin G [S. aureus (MRSA) was first reported in 1961 [Bacterial infectious diseases were significantly suppressed by antibiotics, and deaths from infectious diseases such as tuberculosis and gastroenteritis decreased sharply after World War II . Penicilcillin G . This le in 1961 , and rap in 1961   [At the end of the 19th century, while bacteria were discovered, viruses such as influenza and smallpox were not yet known. Tobacco mosaic virus was the first virus to be discovered in 1892 by Dmitri Ivanovsky . Dutch ms fluid) . At the s fluid) .The electron microscope, invented in 1938 by German scientists Max Knoll and Ernst Ruska, enabled the observation of virus morphology . During By the mid-19th century, the records of six influenza pandemics remained  ,42, and Principles and Practice of Medicine  [In the early 20th century, infectious diseases increasingly attracted the attention of researchers after the discovery of pathogenic bacteria at the end of the 19th century. The contents of medical textbooks in this period generally listed the infectious diseases at the top, followed by diseases of organs in various organ systems, as exemplified by the most notable textbook of the time, Osler\u2019s n, 1920)  , initially introduced in 1977 for the treatment of herpes simplex virus infections caused by HSV-1 (herpes simplex virus type 1) ,47. SoonSeen from the perspective of the history of medical science, current medicine obtained robustness in the diagnosis and treatment of infectious diseases. Even though human society faces emerging issues such as the ongoing pandemic, the global burden of antimicrobial resistance remains one of the most urgent health threats. AIDS is still the leading cause of death across Sub-Saharan Africa, although antiviral drugs have been developed. Since the beginning of the 21st century, three coronavirus pandemics  have emerged, the present one of which is still ongoing  see Sup.The outbreaks occurring prominently during the period of exact medicine are associated with interactions between humans and domestic and wild animals. In fact, approximately 75% of emerging human diseases in the period of late modern medicine and exact medicine have been zoonotic ,51. One Harrison\u2019s Principles of Internal Medicine, 20th edition (2018) [Since the end of the 20th century, various novel categories of diseases were recognized in addition to infectious diseases and diseases of the organs, including malignant tumors, autoimmune diseases, endocrine and metabolic disorders, and diseases caused by environmental factors. These topics were included in the medical textbooks in this period as exemplified by the widely adopted, best-selling American textbook n (2018)  (see SupBy following the history of medicine since the ancient Greek and Roman period and the severe experiences with various infectious diseases, we can better appreciate the current state of medical scientific achievement. When seen through the historical viewpoint on infectious diseases, advanced \u201cexact medicine\u201d has greatly minimized the impact of COVID-19, which has caused significant damage to society and humanity. The fear of COVID-19 has been remarkably reduced thanks to exact medicine, and human civilization must continue to co-exist with SARS-CoV-2. The world in the post-COVID era may never be the same as before, as the historical infectious diseases changed society, economy, and human life in each epoch. It is evident that novel world health issues will continue to emerge. In 2022, as the COVID-19 pandemic continues, monkeypox outbreaks have been reported from non-endemic and endemic countries in widely disparate geographical areas . Further"}
+{"text": "Cultural competence and related terms began to appear in the 1960s in the context of the development of civil rights movements in many countries. The importance of research of cultural competence among mental health professionals is raised with the globalization trends of the modern world, when the growth of ethno-cultural diversity, internal and external migration, temporary movement of people lead to intensification of intercultural interaction.The current study aims to reveal contemporary tendencies in cultural competence understanding and development.Theoretical analysis and systematization of research publications in order to clarify concepts, models and applications of cultural competence.The following tendencies were revealed. Cultural competence continues to attract significant attention of researchers and practitioners, especially among the mental health specialists  who work with representatives of different cultures. A number of similar concepts and their components have been proposed: cultural competence, intercultural communicative competence, cross-cultural competence, cultural intelligence, cultural awareness, cultural acceptance, intercultural sensitivity, intercultural adaptation, multicultural competence, multicultural orientation. The difficulties and limitations of existing models noted: a shift of attention to a specialist, but not to a client; borrowing static and absolutistic ideas about cultures, without consideration of cultures development and interaction.There is a trend in contemporary global world for broad research and development of cultural competence that improve professional qualities of healthcare professionals and provide psychological assistance to representatives of different ethnic and culture groups, confessions and minorities. The reported study was funded by the Russian Foundation for Basic Research, project number 17-29-02506.No significant relationships."}
+{"text": "The current research examined how the associations between the level and changes in the Big Five personality traits and different types of health outcomes  differ across ages over the lifespan  and during the aging process  in particular. Using data from the two large longitudinal studies, we observed three important patterns based on the results. First, levels and changes in personality traits demonstrated substantial effects on health across different life phases, with the effects observed even in very old ages. Second, overall, the prospective relations between personality traits/changes in personality traits and health outcomes increased in strength in mid adulthood and/or early stages of late adulthood; however, the strength of their connections diminished in very old ages. Finally, there were some trait-specific and health outcome-specific patterns in the age-differential associations between personality and health."}
+{"text": "The paper uses the analytic hierarchy process (AHP), spatial autocorrelation analysis, and geographic detectors to reveal the spatial pattern of agricultural production space suitability in China, explores the impact mechanism of agricultural production development, and explores the optimization and promotion strategies for the development of regional agricultural production in various regions in the future. The results show that the resource and environmental carrying capacity, and the agricultural production space suitability under the direction of China\u2019s agricultural production function, show a \u2018polarization\u2019 development trend in space, with high levels in the southeast and low levels in the northwest, with significant spatial agglomeration. The factors influencing the suitability of agricultural production have significant spatial differentiation laws in the Nine Agricultural Areas of China. Climate change factors are the dominant factors affecting the areas with poor resource endowment and traditional agricultural areas in the northwest. Factors that reflect the level of urbanization are the main factors that affect the agricultural production space suitability in the middle and lower reaches of the Yangtze River and South China. China\u2019s agricultural production spatial suitability areas can be divided into nine types of suitable geographical areas. In the future, the impacts of climate change and urbanization on agricultural production space should be considered, and strategies should be taken, according to local conditions, in different regions to improve their suitability. For a long time, the one-sided pursuit of economic growth in urban development, the extensive development mode of urban construction land expansion and the one-way unbalanced flow of urban and rural factors have greatly squeezed the production space of agriculture . At the Agricultural production space is a complex system, affected by social, economic, cultural, institutional and other dimensions, as well as the interaction of national and local top-down multi-scales ,11. The China is the world\u2019s largest food producer and also the country with the fastest urbanization rate. In the context of climate change and urbanization, studying the suitability of China\u2019s agricultural production space has important enlightenment significance for agricultural production and layout of other developing countries in the world, and can provide useful experience for coordinating urbanization and agricultural development. This paper attempts to identify the dynamic evolution process of agricultural production space suitability in China by constructing a comprehensive index evaluation system for agricultural production space suitability evaluation, and analyzing the impact mechanisms and optimization strategies of different scales, locations and types of agricultural production space. This paper seeks to fill the gap in the existing research on the suitability of agricultural production space, which has neglected the impact of climate change and urbanization. By filling this gap, this paper helps in explaining and understanding the evolution trend and law of agricultural production space in China, and provides a reference for the optimization and adjustment of agricultural space and sustainable agricultural development in the future.The main structure of this paper is as follows: In order to analyze the agricultural production space, this paper first constructs the evaluation index of agricultural production space suitability. Based on the conceptual definition and understanding of the spatial suitability of agricultural production ,35,36, tIn order to analyze the relationship between the suitability of agricultural production space and urbanization and climate change, this paper starts from the connotation of urbanization and climate change, and combines the relevant research on the impact of urbanization and climate change on the suitability of agricultural production space . Six indq-statistic. The calculation formula is as follows:In this paper, geodetectors are used to analyze the factors affecting the spatial suitability of agricultural production. Geodetection is a quantitative research method that detects spatial differentiation characteristics and reveals the driving factors and influencing factors behind spatial differentiation ,40, and h = 1, \u2026, L is the number of secondary regions. In the formula, q is . When q = 0, it indicates that the spatial distribution of agricultural production space suitability in China is in a random distribution state. An increase of q shows that the influence factors of independent variables have a greater impact on agricultural production space suitability in China. This paper selected five indicators, population density, night light index, added value of secondary production, water and heat balance index, and annual average temperature, to detect the impact of urbanization and climate change on the spatial pattern of agricultural spatial suitability in China.The threshold range of According to the regional conditions, development orientation, resource and environment carrying capacity, suitability degree of agricultural production space and other factors of different agricultural production spaces, and referring to the traditional naming method of regional types , this paChina Statistical Yearbook (County-Level). The mean elevation was derived from the SRTM 90 m DEM Digital Elevation Database. The soil erosion degree and the spatial distribution index data of China\u2019s annual 1 km vegetation index (NDVI) were obtained from the website of the Resources and Environment Science Data Center, Chinese Academy of Sciences . The Chinese water system vector shp data came from the National Geomatics Center of China . Meteorological data, such as precipitation, accumulated temperature, and temperature, were derived from the China Regional Surface Meteorological Element-Driven Dataset of the National Tibetan Plateau/Third Pole Environment Data Center . The land use data were derived from the China Multi-period Land Use Land Cover Remote Sensing Monitoring Dataset (CNLUCC). The traffic data came from the geographic data sharing service platform  of the College of Urban and Environment Sciences, Peking University. The vegetation net primary productivity data  came from the Google Earth Engine platform .The social and economic data, such as the fertilizer application amount and the total power of agricultural mechanization, in the comprehensive evaluation system of agricultural production space suitability were mainly acquired from the The Nine Agricultural Areas of China reflect agricultural development conditions, agricultural production conditions and agricultural spatial patterns in a certain period, and are the result of a planning and implementation process that integrates elements of nature, society, economy and ecology ,43. Its The spatial distribution characteristics of the suitability of agricultural production space were obtained by overlaying and processing the grid data of the indicators of the spatial suitability of agricultural production from 1), night light index (X2), land-average secondary industry added value (X3), water\u2013heat imbalance index (X4), average annual temperature (X5), and crop water demand (X6), were detected. The matching degree of spatial characteristics was analyzed for four first-level suitability indicators, including resource environmental bearing capacity (Y1), spatial form (Y2), location conditions (Y3), and production conditions (Y4). In addition, based on the detection of influencing factors, this paper selected the three most powerful factors for each first-level index of suitability for spatial matching , the average secondary production value added (0.407), population density (0.373), night light index (0.177), crop water requirements (0.018) and water\u2013heat imbalance index (0.014). The agricultural production space suitability in China was mainly affected by factors such as the average annual temperature, the average industrial added value of the land, and the population density , land-average secondary production added value (0.407), population density (0.373), night light index (0.177), crops\u2019 water demand (0.018) and hydrothermal imbalance index (0.014). The agricultural production space suitability was mainly affected by factors such as the average annual temperature, the average industrial added value of the land, and the population density.The agricultural production space suitability is subject to the comprehensive disturbance of multi-dimensional factors, such as climate change and urbanization. This paper selected three indicators, population density, night light index and land-average added value of secondary production, which reflect the development level of urbanization, and reflect the degree of climate change. The water\u2013heat imbalance index, the average annual temperature and the crop water demand, and a total of 6 indicators, were used to conduct in-depth exploration and research on the formation mechanism of the spatial pattern of agricultural production space suitability in China. Using the classification of the agricultural production space suitability in China and the classification results of each influencing factor, coupling matching analysis was carried out, and the distribution results of the agricultural production space suitability in China, and the spatial matching of elements in 2018, were obtained . The q sq statistic for each influencing factor and the first-level indicators of resource and environmental carrying capacity, spatial form, location conditions and production capacity. The spatial matching degree between the top 3 influencing factors of the force and the 4 first-level indicators was analyzed ; Lower suitability zone, dominated by severe cold temperatures in Qinghai Tibet Plateau (II); Higher suitability zone, dominated by the optimization of water\u2013heat matching degree in the Northeast China Plain (III); Higher suitability zone, dominated by warming and drying in Loess Plateau (IV); Higher suitability zone, dominated by industrialization in Huang-Huai-Hai Plain (V); Medium suitability zone, dominated by topography in Sichuan Basin and surrounding regions (VI); High suitability zone, dominated by comprehensive factors in the Middle\u2013lower Yangtze Plain (VII); High suitability zone, dominated by the altitude difference in Yunnan-Guizhou Plateau (VIII); High suitability zone, dominated by population agglomeration in Southern China (IX) . An optiThe differences in resource endowment, socio-economic conditions, location conditions, and government policies, of the different types of agricultural areas resulted in different suitability characteristics and development paths among the various types of agricultural areas. There were also significant differences in the mathematical characteristics of resource and environmental carrying capacity conditions, spatial form conditions, location conditions, production conditions, and suitability characteristics . Based oLand resources, water resources, climate conditions and environmental conditions are the basic factors that affect agricultural production and play a decisive role in the suitability of agricultural production space. First of all, climate change leads to changes in planting systems and crop production layout. Global warming has led to an increase in the temperature in middle and high latitudes of China, leading to an earlier crop sowing date, a later winter season, an overall extension of the growing season, and an increase in the accumulated temperature during the winter, which may lead to changes in planting systems. More northern and high-altitude regions can carry out multi-cropping production and planting, and the planting areas expand northwards. The multiple cropping index increased, and the suitable planting area was further expanded . SecondlThe rapid progress of urbanization and industrialization has brought China many conveniences, such as economic development, social progress and industrial upgrading, as well as positive and negative effects on the suitability of agricultural production space. First of all, the urbanization process has brought a lot of agricultural transfer population, and the modern non-agricultural sector has absorbed a large amount of labor from rural areas, which has brought about the non-agricultural transfer of agricultural production subjects and optimized the allocation of urban and rural resource elements. Secondly, the rapid progress of urbanization has led to extensive and disorderly expansion of construction land, which has had a far-reaching impact on agricultural production subjects and space, leading to reduction of the quantity and quality of cultivated land, the occupation of high-quality cultivated land and permanent basic farmland, and great reduction in the suitability of agricultural production space. For example, in the middle and lower reaches of the Yangtze River, where there is a high degree of economic and social development, and, likewise, in the southeast coastal areas, agricultural production space has become fragmented and decentralized due to the interference of high intensity human activities; thus, affecting the suitability of agricultural production space. Finally, urbanization has driven the development of urban industry and technological progress, and has had multiple effects on agricultural production space. On the one hand, the development of urban industry drives the innovation of agricultural technology. Industrialization provides more advanced and convenient mechanized production tools for agricultural production, effectively saves the labor input cost of agricultural production , improveIn addition, price mechanism, livelihood mode, policy guarantee and technology input are also auxiliary factors that affect the suitability of agricultural production space in China. First, the market price mechanism affects farmers\u2019 willingness to plant, and the fluctuation of market price affects the income of agricultural producers engaged in agricultural production activities, thus, affecting the enthusiasm of agricultural producers engaged in agricultural production activities. This then affects the way agricultural production entities engage in agricultural production and operation activities, causing changes in the quality of agricultural production space, and, ultimately, leading to changes in the suitability of agricultural production space. Second, the shift of the main agricultural production body\u2019s part-time livelihood mode is also an important factor affecting the suitability of agricultural production space. Areas such as the middle and lower reaches of the Yangtze River and South China have conditions conducive to production, such as high matching of water and heat resources, flat terrain for farming, and abundant labor force. However, these areas often have a high level of economic development, and the labor income of central cities is significantly higher than that of rural areas. Farmers, based on the consideration of rational economic people, tend to move to cities and the surrounding areas to engage in other occupations with higher returns. As a result, a large number of agricultural production subjects, mainly young and middle-aged people, have turned to non-agricultural production modes, which has caused problems, such as aging and feminization of agricultural production subjects , and, thBased on the background of the era of urbanization, industrialization and climate change. and the major strategic needs of rural revitalization, sustainable agricultural development and food security, this paper integrated multidisciplinary theories and research methods, and deeply developed the spatial and temporal pattern, evolution process, influencing factors, type of differentiation and coping strategies of agricultural production space suitability in China. The specific conclusions are as follows:First, the proportion of each region in each suitability degree did not change much and was relatively stable in 2000, 2009 and 2018. The areas with poor suitability are mainly located in the Qinghai-Tibet Plateau and the northern arid and semi-arid regions, which have improved a lot in the past 10 years, mainly due to the increase in precipitation in the middle and high latitudes, which has improved the suitability of agricultural planting in this region. From the perspective of the spatial differentiation pattern, the agricultural production space suitability in 2000, 2009 and 2018 showed a polarized distribution, with high levels in the southeast and low levels in the northwest. The agricultural production space suitability in each county in China is significantly affected by the suitability of neighboring counties, showing a significant positive correlation.Second, the factors influencing the agricultural production space suitability in China have significant spatial differentiation laws in the nine agricultural areas in China. Climate change factors, such as annual average temperature and the water\u2013heat imbalance index, are the dominant factors affecting areas with poor resource endowment and traditional agricultural areas in the northwest. Factors that reflect the level of urbanization, such as population density and nighttime light index, are the main factors that affect the agricultural production space suitability in the middle and lower reaches of the Yangtze River and South China with relatively high levels of economic development, good water and heat matching, and favorable location conditions.Third, based on geographical location, the dominant influencing factors of the agricultural production space suitability, the degree of agricultural production space suitability in 2018, and the types of agricultural production space suitability in China can be divided into the following zones: Medium suitability zone, dominated by water\u2013heat imbalance in Northern arid and semi-arid region; Lower suitability zone, dominated by severe cold temperatures in Qinghai Tibet Plateau; Higher suitability zone, dominated by the optimization of water\u2013heat matching degree in the Northeast China Plain; Higher suitability zone, dominated by warming and drying in Loess Plateau; Higher suitability zone, dominated by industrialization in Huang-Huai-Hai Plain; Medium suitability zone, dominated by topography in Sichuan Basin and surrounding regions; High suitability zone, dominated by comprehensive factors in Middle-lower Yangtze Plain; High suitability zone, dominated by the altitude difference in Yunnan-Guizhou Plateau; High suitability zone, dominated by population agglomeration in Southern China.Fourth, agricultural production is a production process that is highly dependent on climatic resources, and, at the same time, is subject to comprehensive disturbances by its production subject and other related subjects. Differences in resource endowment, socio-economic conditions, location conditions, and government policies have resulted in different suitability characteristics and development paths among various types of agricultural areas. The natural conditions, environmental conditions and location conditions of regional agriculture reflect the macro background value of agricultural development in the region. The scientific application of strategies, such as the rational development and utilization of regional agricultural resources, the improvement of acquired technologies and policy guidance, are \u201clate remedy\u201d measures and important approaches for the rational utilization of regional agricultural resource conditions and sustainable agricultural development. In the future, optimization and improvement strategies should be given for the agricultural production space in different regions according to local conditions.This paper enriches the empirical research on spatial adaptability of agricultural production and agricultural sustainable development. It also provides important reference for agricultural regional planning and high-quality agricultural development in other developing countries. Limited by the availability of data, the frequency of natural disasters, farmers\u2019 livelihood choices and market food prices have not been considered, which is also the shortcoming of the paper. As climate change and human activities disturb the agricultural production space more and more intensely, more and more experts and scholars have begun to consider how agricultural production can reduce the frequency of external disturbances and improve the system resilience of agricultural production to actively respond to disturbances. On the one hand, the indiscriminate use of agricultural chemicals worldwide in the last century has increased crop yields to a certain extent, but, at the same time, has brought great damage to terrestrial and aquatic ecosystems. Nanomaterials, biomass charcoal and nitrogen fertilizer, and other new materials, could reduce the disturbance of agricultural production to the outside world. They could also improve the diversification of crops, organic agricultural production, large-scale planting and irrigation in water-deficient arid and semi-arid areas. The resilience of agricultural production could be improved by means of technological upgrading and other means. Therefore, it is urgent to classify the agricultural production space caused by different influencing factors, and to explore the future agricultural development path of each regional type."}
+{"text": "Mental health literacy (MHL) could be defined as a knowledge of mental health, comprehension of its importance, adequate attitude to information about mental health, possession of skills and abilities to provide assistance and self-help to maintain and promote mental health.The aim of the present study is to identify possible relationships between the components of mental health literacy and the manifestations of the emotional sphere of the respondents.The sample consisted of 220 young people from 16 to 23. Emotional Empathy Questionnaire , self-assessment of mental states (G. Eysenck), questionnaire from the study of Reavley et al., and the custom MHL questionnaire were used.Most significant of relationships revealed by Pearson\u2019s Product-moment correlation analysis: Adequate actions of respondents in a mental health-threatening situation inversely correlates with anxiety , aggressiveness , frustration , rigidity . Comprehension of the importance of specialized care inversely correlates with frustration . Helping others in difficult situations correlates with empathy .A low level of the behavioral component of MHL is often manifested with high anxiety, aggressiveness, rigidity, frustration. Correlation between the cognitive component and frustration may indicate that sufficient level of this component does not allow the individual to fall into a state of deep frustration in mental health-threatening situations. Individuals with low level of anxiety, rigidity, aggression are more inclined to understand the importance of seeking professional help. An individual with lower frustration and aggressiveness will less likely choose destructive behaviors .No significant relationships."}
+{"text": "In addition, at least a quarter of the total direct cost impact of healthcare interventions affects other economic sectors. International methods and tools are lacking for the rigorous and comparable assessment of the costs and outcomes of (public) health care from a societal perspective. The H2020 PECUNIA project (grant No 779292) brought together ten partners from six countries (AT/DE/ES/HU/NL/UK) between 2018 and 2021 aiming to improve the comparability and feasibility of multi-sectoral, multi-national health economic evaluations in Europe. A multi-step, mixed methods approach was used following a new harmonized costing concept to develop new methods and tools for the standardised identification, definition, measurement and valuation of costs in multiple sectors  justice, education, employment and productivity, and patient, family and informal care), and for the broader, harmonised, supra-national assessment of outcomes using selected mental disorders as illustrative examples. This presentation will summarise the relevant advances in costing methods, give an overview of the developed tools that are now publicly available ("}
+{"text": "Emerging and reemerging plant diseases can be defined as those diseases caused by new or reappearing pathogens which, due to their intrinsic characteristics, have the ability to spread rapidly and cause epidemics in certain agro-climatic contexts. In recent years, both DNA and RNA viruses have been implicated in important disease outbreaks in plants. The different forms of mutation, recombination and other types of genetic exchange, considered as the basis of the evolutionary forces of viruses, have undoubtedly given rise tothe genetic diversity found in plant virus populations. In this context, environmental factors play an important role in driving virus evolution. In addition, the rapid expansion of human activity in the world of commerce, agriculture, anthropization of natural ecosystems and climate change have further contributed to the instability between hosts and virus populations, favouring the emergence of viruses with mutant and/or recombinant forms, with potentially negative impacts on plants, vectors and ecosystems.Lal et\u00a0al.), an important group of emerging viruses with a destructive potential on many crops; capable of causing serious social and economic losses , currently causing major losses in rice production mainly in sub-Saharan Africa (SSA). This review deals with the molecular characteristics of RYMV: the genomic structure, function and gene diversity, and RYMV-host interactions. In particular, the review sheds light on mechanisms related to the qualitative resistances, controlled by three recessive genes RYMV1, RYMV2 and RYMV3, and quantitative resistances, with the description of several QTLs found in Oryza germplasm. Finally, since RYMV shows high genetic variability and some Oryza germplasm has low or non-durable resistance, the review suggests possible genetic improvement strategies for a significant enhancement of rice protection through the use of assisted selection with molecular markers and by employing genome editing to impair susceptibility.The second review addresses the problem of yellow mottle rice virus (YMRV) , with particular reference to the contribution provided by high-throughput sequencing (HTS). The work takes into consideration the period 2011-2020, during which 45 new viruses have been described in tomato, 14 of these identified by HTS. Based on the data present in the literature and in the databases, the authors list 312 viruses, satellite viruses, or viroid species (in 22 families and 39 genera) identified in tomato. This represents the highest number of viral and viral-like agents described in a single botanical species. The work also underlines the importance of the application of HTS for epidemiological studies, in particular for the identification of the virome of weeds and other wild plants, or for the identification of viruses in vectors, irrigation water or wastewater and soil. The HTS analysis of environmental samples helps to greatly improve the understanding of epidemiology and ecology of tomato-infecting viruses and can facilitate virus disease forecasting in order to prevent virus disease outbreaks in tomato. Finally, the review outlines the main tomato viruses, highlighting their potential threat and impact. Newly emerged viruses, such as tomato brown rugose fruit virus (ToBRFV), are capable of overcoming the Tm-22 resistance gene used to contain tobacco mosaic virus (TMV) and tomato mosaic virus (ToMV) infections in greenhouse tomatoes. Tomato spotted wilt virus (TSWV) easily overcomes the resistance mediated by the Tsw hypersensitivity gene in pepper with increasing temperatures. A group of emerging geminiviruses, of subtropical and tropical origins, including tomato leaf curl New Delhi virus (ToLCNDV) and tomato leaf curl virus (TYLCV), mostly are virulent at high temperatures. Their vector, Bemisia tabaci, is notoriously thermophilic and a highly invasive species.The final review concerns the progress on tomato virome research . The work also highlights progress in the detection of ToBRFV, mainly regarding sensitivity, compared to previous methods. This paper also emphasizes the practical advantages deriving from the use of LAMP, since it can be applied by poorly equipped laboratories and unskilled persons at official country points of entry, providing a new diagnostic tool for phytosanitary investigations and management of ToBRFV. The second work describes an RT-qPCR assay for the diagnosis of parietaria mottle virus (PMoV), based on a specific TaqMan\u00ae probe ,. PMoV is considered an emerging pathogen in the Mediterranean basin on tomatoes and peppers. This virus has recently expanded its natural host range  assays, both real time and visual, for the diagnosis of ToBRFV on leaf samples and seeds of tomato and bell pepper  and desmodium leaf distortion virus (DesLDD) and two deltasatellite. This is the first report of (i) a monopartite New World begomovirus found in a host other than tomato and (ii) deltasatellites found in C. siliquosus, thus extending the host and helper virus ranges of this recently recognized class of DNA satellites.The paper of Crinivirus, family Closteroviridae) (ToCV) is expanding its geographical and host ranges associated with the emergence of whiteflies of the Bemisia tabaci complex  (genus Fabavirus in the family Comoviridae), an emerging virus in economically important crops worldwide. They investigated the BBWV2-pepper (Capsicum annuum L.) pathosystem, using two distinct BBWV2 strains, PAP1 (a severe strain) and RP1 (a mild strain). Upregulation of several genes associated with pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) and ethylene signaling were associated only with the severe PAP1 strain, with high ethylene emission detected. Authors conclude that the activation of PTI-associated defense responses increase symptom development during BBWV2 infection in a virus strain-specific manner.Tomato chlorosis virus (genus  complex . Fortes Phaseolus vulgaris L.) in the North-Western Himalayan region of India by Rashid et\u00a0al. Three viruses were identified: bean common mosaic virus (BCMV), bean common mosaic necrosis virus (BCMNV), and clover yellow vein virus (ClYVV), with BCMV more widespread and BCMNV and ClYVV new records from India. In another paper , applied HTS to characterize the virome of Pseudostellaria heterophylla, generated data on three novel carlaviruses and one novel amalgavirus.HTS analysis has been applied to study the diversity of virus(es) associated with common bean  and papaya ringspot virus (PRSV) in cucurbits with a novel recombination pattern detected in the HC-pro. Despite the origin from interspecific recombination, they proposed that these viruses still belong to ZTMV according to their genome characteristics; their results provide insights into the prevalence and evolution of ZTMV and PRSV in cucurbits.Vo et\u00a0al.). ToLCNDV-ES hardly infects tomato and some isolates would not at all. Nonetheless, ToLCNDV-ES in the presence of TYLCV proves to be able to multiply and infect tomatoes. In addition to the known risk of formation of recombinants between geminiviruses, this work highlights the risks of a possible expansion of the natural hosts for this group of emerging viruses thanks to the phenomena of assistance and complementation between viruses.The last paper concerns a complementation phenomenon between TYLCV and ToLCNDV-ES, first observed in the field and then demonstrated in the laboratory with agro-inoculations of infectious clones (Emerging and Reemerging Viruses in the Context of Global Change. We are deeply grateful to all the authors and reviewers who with their exceptional work have made possible the realization of this special issue. We believe that this collection will increase knowledge and awareness about the importance of emerging and reemerging viral diseases in order to improve the monitoring and the possible control that derives from them, with the aim to prevent epidemics in agricultural crops.In summary, this Research Topic provides cutting-edge methodologies, research, observations and knowledge on the current scenario of All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
+{"text": "Risk levels of spring pollen allergy for tourists in different assessment units were revealed by combining the green zone allergenicity index model and three-dimensional risk assessment matrix. The results showed that: (1) There were seven primary pollen-allergenic plants in the Summer Palace, including Platycladus orientalis, Sabina chinensis, Salix babylonica, Pinus tabulaeformis, Populus tomentosa Carr, Morus alba L. and Fraxinus chinesis, among which Platycladus orientalis and Salix babylonica were the highest allergenic. (2) Among 18 spots, tourists faced the highest risk level of pollen allergy in spring at three spots, namely the Hall of Serenity, Hall of Benevolence and Longevity, and Gallery of Literary and Prosperity. (3) The two routes of the Long Corridor and Longevity Hill scored high on the risk level. (4) Among four areas, risk levels of the Front-hill and Rear-hill areas were high. Given the increasing spatial-temporal uncertainty of pollen allergy and tourist behaviors under global warming and urbanization, the related monitoring should be strengthened in the future. Furthermore, the dynamic and improved assessment of pollen-allergy risk should be institutionalized and be integrated into the evaluation of tourism experience quality. Tourism administration should make full use of relevant assessment results and conduct more effective risk communication.Pollen allergy has already been an increasingly prominent ecosystem disservice in tourism attractions. However, few studies have assessed the tourist risk of pollen allergy through integrating multidisciplinary knowledge of ecology, medicine, phenology, and risk management. Basing on the conceptual framework of risk assessment proposed by UNISDR, we first established an index system of pollen-allergy risk for tourists in attractions and outlined assessment methods 18 available indexes were put forward to cover three aspects: hazard of plant allergen, tourist vulnerability, and resilience of assessment units. Subsequently, taking the Summer Palace as the case study area, we conducted a tourist risk assessment of pollen allergy. Values of nine available indexes were obtained  Pollinosis is a \u201cnational disease\u201d around the world. It can cause allergic rhinitis, conjunctivitis, hay fever or asthma, urticaria, and allergic dermatitis, etc. Patients may suffer from shock and have a risk of sudden death, when correlated symptoms are severe. In developed countries, 20\u201330% of the population is allergic to pollen , while tStudies on pollen allergy came from medicine, ecology, phenology, and some other disciplines. Among them, medicine focused on the difference in the allergenicity and emissions of various pollens, the association between its incidence and the demographic characteristics of patients, and seasonality changes of airborne pollen . EcologySabina chinensis, Populus tomentosa, Fraxinus chinensis, Rhus Typhina, Syringa reticulata, and the latter includes Chrysanthemum morifolium and Brassica rapa. Despite their undeniably benefits of the adaptability to local climatic conditions, the ease of management, and the ability to enhance the landscape, allergenic plants make tourism attractions uncomfortable seasonally for the human respiratory system. Under the background of nature tourism and outdoor education becoming more and more popular, people' exposure to the allergenic environment is increasing.Tourism attractions play a key role in tourism and have become more and more important with the continuous enhancement of Chinese travel desire and payment capability. In 2021, the number of National A\u22125A level tourism attractions in China reached 14196, and their tourism revenue increased to 2.92 trillion yuan, up 31.0% over 2020 . CompareMorus, Robinia and Cerasus yedoensis across many regions have already advanced , factor (B), category index (C) and bottom index (D). The pollen-allergy risk of tourists in attractions was defined as the target (A). According to the risk conception and the pollen-allergy formation mechanism, the target was determined by three factors on the B layer, including the hazard of plant allergen, tourist vulnerability, and resilience of assessment units. As for the hazard of plant allergen, its category indexes and bottom indexes were selected considering both the biological and ecological characteristics of allergenic species. With reference to the meanings of risk exposure and the resistibility of human body in the assessment theory of natural disaster risks , 30, catvia phenological observations and airborne allergen monitoring. Concerning the third category index of tourist exposure, we selected two basic indexes (tourist amounts and dwell time) used in most studies on tourist behaviors. More tourist amounts and dwell time mean greater tourist exposure. According to previous studies, tourist amounts can be obtained via the sampling survey, GPS tracking survey  model  model , 31 , S = vertical crown projection area covered (m2), H = canopy height (m), ST = total surface area of the assessment unit (m2).Where k = number of pollen allergenic species, NRisk level matrix is another convenient fundamental tool used to assess risk , 30, 38.2, in which 357.20 km2 are parks , canopy breadth and canopy height of every allergenic plant were measured by DBH ruler, tape measure, and laser rangefinder, respectively. During the investigation course, The DBH was measured at the height of 1.3 m, and the canopy breadth was calculated as described by Liu et al. .Platycladus orientalis, Sabina chinensis, Salix babylonica, Pinus tabulaeformis, Populus tomentosa Carr, Morus alba L, and Fraxinus chinesis. Their phenological observation data were obtained from the Chinese Phenological Observation Network . Records of first flowering dates (FFD), full blooming dates (FBD) and end of flowering dates (EFD) of them in 2021 were extracted from the dataset, whose observation process conformed to the traditional criteria in China . By use of a search engine developed by Sichuan University  was revealed by combining the data mining of visitors' check-in on Sina Weibo and the dwell-time analysis. Among the 18 scenic spots, the Hall of Benevolence and Longevity, East Palace Gate, Gallery of Literary Prosperity and North Palace Gate were most visited in the spring of 2021. Therefore, tourist vulnerabilities of them were the highest. In contrast, the scenic spots of the Marble Boat, Chamber of Cultivation, Hall of Happiness and Longevity, Chamber of Clearness, and West Palace Gate had low tourist vulnerabilities. Among the five scenic routes, the tourist vulnerabilities of the Long Corridor route and the Longevity Hill route were very high and high, respectively, while those of the West and East Causeway routes were both low. As for the scenic areas, the tourist vulnerability of the Front-hill area was very high, while that of the East-lake area was the lowest . OverallBecause all the six medical centers are located near the gates of the park, the distances from the assessment unit to the nearest gate have great influence on their resilience. Among the 18 scenic spots, four scenic spots had the poorest resilience, namely the Garden of Farming and Weaving, Chamber of Clearness, Marble Boat, and Hall of Serenity . AccordiAccording to the assessment results of the three-dimensional risk matrix, tourists in three scenic spots  had a very high risk of pollen allergy, whose governance should be given the top priority . In the 2 would increase the likelihood of seasonal allergies throughout the continental USA, with end-of-century emissions being increased up to 200%  shows that heat waves will significantly increase the risk of morbidity and mortality, and have a profound impact on population behavior patterns and transportation choices for travel . David M2.5 concentration  model and three-dimensional risk assessment matrix to assess and map the risk levels of spring pollen allergy in 18 scenic spots, five scenic routes and four scenic areas. The results showed that: (1) There were 7 primary pollen-allergenic plants in the park, among which Platycladus orientalis and Salix babylonica had the highest allergenic hazard. (2) Among 18 spots, tourists faced the highest risk level of spring pollen allergy in three spots, namely the Hall of Serenity, Hall of Benevolence and Longevity, and Gallery of Literary Prosperity. (3) The two routes of the Long Corridor and Longevity Hill scored high on the pollen-allergenic risk level. (4) Among four areas, the Front-hill and Rear-hill areas were high risky for tourists.Climate change has already affected human health directly and indirectly in China. From the perspective of tourism management, it is imperative to assess the pollen-allergy risk of tourists and visualize it by risk mapping. For this purpose, we established an assessment index system consisting of 18 available bottom indexes, which covered three aspects of allergen hazard, tourist vulnerability and resilience of assessment units. The quantification and coupling of assessment indexes were also outlined. Taking the Summer Palace as the case study area, we obtained the values of nine representative indexes 2 concentration, and extreme events. Urbanization will also affect the local climate, thermal environment and PM2.5 concentration. As a result of these two driving forces, greater uncertainty of pollen allergy risk may occur subsequently in the future. Therefore, under the policy background that Chinese government has placed increasing emphasis on the construction of ecological civilization and the improvement of human wellbeing and public health, the high-quality development of tourism attractions should attach importance to the risk impact of local thermal environment, climate comfort and air pollution  and the National Key Research and Development Program (Grant No. 2018YFA0606102).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "In low- and middle-income countries, facility-based neonatal care practices can be improved using a collaborative cross-learning quality improvement approach incorporating remote mentoring, coaching, and supportive supervision. Combining a training package to improve the knowledge and skills of health care workers in managing sick and preterm neonates with point-of-care quality improvement skills successfully reduced the unindicated use of oxygen, antibiotics, and phototherapy while increasing the use of enteral feeds.Despite a significant reduction in the use of 2 lifesaving medical interventions\u2014oxygen and antibiotics\u2014no increase in mortality or short-term adverse outcome was observed, indicating an overuse of these interventions in the preintervention period.A strategy of combining professional training activities and coaching in continuous quality improvement methods can successfully improve the health care of sick and preterm neonates. With the rapid expansion of access to facility-based neonatal care, it is important to monitor for both overuse and underuse of evidence-based interventions. We evaluated the efficacy of training health care workers (HCWs) in point-of-care quality improvement (POCQI) and a preterm newborn health care package (PHCP), followed by remote mentoring and supportive supervision in improving health care practices, neonatal survival, and morbidities in special neonatal care units (SNCUs).This pre- and postintervention quality improvement study was conducted at 3 SNCUs in Madhya Pradesh, India from February 2017 to February 2019. Clinical care teams comprising doctors and nurses from the study sites were trained in POCQI and the PHCP. The teams identified, prioritized, and analyzed problems and designed quality improvement initiatives at their respective health facilities. Change ideas were tested by the local teams using sequential plan-do-study-act cycles. Facilitators maintained contact with the teams through quarterly review meetings, fortnightly videoconferencing, on-demand phone calls, and group chat service. State SNCU coordinators made follow-up visits to supplement coaching. Study research staff independently collected data on admissions, health care practices, and outcomes of neonates.A total of 156 HCWs were trained in the POCQI methodology and PHCP. Sixteen quality improvement projects were formulated and implemented. Among 13,821 enrolled neonates , improvement was seen in reduction of use of oxygen , antibiotics , and dairy milk . Enteral feeds were started within 24 hours of admission in a larger number of neonates, resulting in fewer days to reach full feeds. There was no effect on survival at discharge from the hospital .A collaborative cross-learning quality improvement approach with remote mentoring, coaching, and supportive supervision was successful in improving the quality of care at SNCUs. Special newborn care units (SNCUs) at district hospitals provide FBNC to about 0.9 million neonates every year, on approximately 16,000 beds across India.\u2013Although the SNCUs have adequate infrastructure and supplies, concerns have been raised about suboptimal knowledge and poor skills of the health care workers (HCWs) that staff them.Can combining knowledge and skills augmentation activities with problem-solving skills improve HCWs\u2019 ability to adapt and adopt evidence-based practices and improve health outcomes in SNCUs?\u2013Our study evaluated whether the implementation of an intervention package to improve the knowledge and skills of the HCWs in providing clinical care as well as undertaking QI activities would improve health care practices, neonatal survival, and morbidities in the SNCUs. To test this hypothesis, we developed a theory of change that formed the basis of the package of interventions .14 The tThis before-and-after study was conducted from February 2017 to February 2019 in the SNCUs of 3 district hospitals and a medical college in the state of Madhya Pradesh, India . All livThe study was coordinated by the All India Institute of Medical Sciences, New Delhi, the Postgraduate Institute of Medical Education and Research, Chandigarh, and the Government Medical College Hospital, Chandigarh. Institutional ethics committees at the 3 coordinating sites and the Indian Institute of Public Health, Hyderabad approved the study protocol. National Health Mission, Madhya Pradesh also approved the study protocol. Written informed consent was obtained from parents of the enrolled neonates, HCWs at the study sites, state SNCU coordinators, and state child health consultants.The study intervention was guided by a theory of change and the work plan was divided into preintervention and intervention phases.\u2013The preintervention phase had 2 components\u2014formative assessment and baseline neonatal data collection. The formative component started with the development of a theory of change  based onBOXImprove oxygen administration methodsMonitor and promote the use of continuous positive airway pressure and surfactantOptimize oxygen use:Minimize amount of blood samplingRestrict use of blood productsEffective use of phototherapyReduce exposure to blood products:Early initiation and rapid advancement of enteral feeding with breast milkImprove nutritional status:Improve aseptic techniques at birth and during hospital admissionReduce sepsis:Hypothermia preventionKangaroo mother carePain controlReduce noise and light exposureIncrease parental involvement in careImprove developmental care:www.pretermcare-eliminatingrop.com) were developed and reviewed by 35 neonatologists and nurses from across the country. The Point of Care Quality Improvement (POCQI) tool, developed in collaboration with the World Health Organization South-East Asia Regional Office (WHO-SEARO), guided the training for conducting QI projects.In parallel, we assessed the baseline levels of knowledge, skills, attitudes, and practices of SNCU health care personnel, state SNCU coordinators, and child health consultants. This preassessment focused on the clinical care pathways including the drivers of improvement identified in the theory of change. We also assessed the problem-solving and QI skills of the HCWs. Results of this formative part of the study are being reported separately. Based on this formative phase, we designed, pilot-tested, and finalized a collection of interventions with 2 components: (1) improvement in knowledge and skills of the HCWs in neonatal care and (2) improvement in the ability of staff to practice the knowledge and skills gained by conducting QI activities at their respective SNCUs. The content for training HCWs on best practices in preterm care was called the preterm newborn health care package (PHCP) and included 10 modules composed of brief webinars, videos, case studies, posters, job aids, and key messages. The content of each module was divided into specific learning objectives, with a self-assessment in the form of multiple-choice questions following each objective. The evidence-based content and materials in the PHCP . Activities for knowledge and skill augmentation included small group discussions, skill practice, and simulated clinical scenarios. The second part consisted of clinical data presentation from each SNCU, choosing target areas of improvement, forming QI teams, analyzing the root causes of the problem, and outlining the QI project activities. Each SNCU team not only worked on the development of its own QI project but also reviewed and gave feedback on the QI projects of other SNCUs. During the study, selected HCWs from each SNCU underwent a total of 5 in-person sessions that covered all the modules developed under the PHCP.Ongoing support: In addition to the training in the remaining modules during successive in-person workshops, all the training materials were available online for ongoing training and review. Skill training corners were also established in each SNCU, and a skill lab was established in the mentoring medical college.QI projects and mentoring: The theory of change guided the selection of QI projects. Doctors and nurses working in each SNCU selected specific problems to be addressed by a QI project and decided the goal and outcome measures for each project based on the 4 criteria outlined in the POCQI guide\u2014importance to patient outcomes, affordability in terms of time and resources, ease of measurement of outcome, and whether the identified problem was under the control of team members. Following the workshop, the SNCU teams returned to their units and started working on their respective QI projects. We held web meetings every two weeks to review progress and provide guidance for any bottlenecks encountered. Team members presented their completed projects in subsequent on-site workshops after which they developed and conducted new QI projects. The intervention period continued from September 2017 to February 2019 and over this period each SNCU conducted 3\u20135 QI projects .A study research nurse at each of the 3 SNCUs collected the health outcome data of the admitted neonates. The primary outcome of the study was the proportion of neonates who survived without developing severe ROP. Secondary outcomes included death before discharge, adverse outcomes , hypothermia at admission, neonatal hyperbilirubinemia needing phototherapy or exchange transfusion, and duration of hospital stay. Various care processes reported include enteral feeding practices, use of oxygen and antibiotics, and screening for ROP.The primary outcome of the study was the proportion of neonates who survived without developing severe ROP.We defined the composite primary outcome as neonates discharged alive from SNCU and not found to have severe ROP on screening examination before discharge or during follow-up. We defined severe ROP as ROP needing laser ablation or surgery to prevent loss of vision. Although estimates of mortality among SNCU admissions are available, no such information is available about the incidence of severe ROP, the second component of the composite primary outcome. Therefore, the sample size was calculated for the incidence of mortality among SNCU admissions. With an estimated enrollment of 3,000 neonates in the preintervention period and 10,000 neonates during the intervention period, the study had 90% power to detect an absolute reduction of 2% in mortality (from 10% to 8%) with a 2-sided alpha of 0.05.P value of less than .05 was considered statistically significant and no adjustment was made for multiple comparisons.Study nurses prospectively collected data from the bedside clinical records and entered it into a custom-built Android application. We then analyzed the data using Stata 16.1. Categorical data are presented as numbers and percentages. Normally distributed numerical data are presented as mean and standard deviation, and skewed numerical data are presented as median with interquartile range. We used a mixed-effects regression model to estimate the effect of the intervention, with SNCU site as random effects and other covariates  as fixed effects. The covariates included in the model were based on biological plausibility and significant differences between the preintervention and intervention periods. We conducted a post-hoc secondary analysis to account for the possible effect of a secular trend in the preintervention and intervention periods. For this, we aggregated the data for each month and then analyzed the data using the interrupted time-series regression method which separates the effect of intervention from the preintervention trend. A Supplement, Table S1 and Table S3). All the doctors and >90% of nurses in the study SNCUs received training over the period of intervention. All the learning modules were covered over the 5 in-person sessions and the continuous online training and mentoring. The flow of online modules on the web portal ensured that the participants were able to proceed to the subsequent module only after successfully completing the knowledge assessment of the current module. The skill check activities were directly observed. Due to the midway change in the mentoring medical college, preintervention data were not available from the SNCU in Bhopal and so data from this site were not included in our primary analysis. Throughout the study, the 3 SNCUs were mentored by investigators from outside the state of Madhya Pradesh.Over the study period, a total of 5 in-person sessions were held and 156 HCWs were trained. A total of 16 QI projects were completed at the 3 study SNCUs of the district hospitals and 1 SNCU of a medical college . Antenatal care was almost universal, with 87% of mothers having had at least 3 antenatal check-ups and 11.2% having had cesarean delivery. A high proportion (43.6%) of neonates were preterm (<37 weeks of gestation). Over the study period, the profile of enrolled neonates remained similar , althougA total of 343 (10.2%) neonates died during the preintervention period and 1,106 (10.6%) during the intervention period . As gravely sick neonates may be referred for tertiary care or taken home by parents for compassionate care, we also calculated the rate of adverse outcomes including death, referral to a higher center, or left the hospital against medical advice. No difference was observed in the incidence of adverse outcomes .P<.01), and very preterm  gestation. The duration of oxygen therapy also decreased .Several health care practices improved during the intervention period . These iecreased . A signiecreased . The proThe use of many interventions, including oxygen and antibiotics, declined, indicating overuse in the preintervention period.Supplement, Figures S1 and S3). The trend-adjusted analysis showed no significant change in other health care practices, death, or adverse outcomes .The interrupted time-series analysis adjusting for the preintervention trend showed a significant reduction of 2.2%  per intervention month in the proportion of neonates who were started on oxygen at admission and a significant reduction of 5.1%  per intervention month in the proportion of neonates who received antibiotics . An additional challenge was the state government practice of measuring performance evaluation of the SNCUs by the number of admissions and use of various medical interventions. In our formative evaluation, this was associated with unnecessary admissions, delayed discharge, and overuse of medical interventions. During the intervention period, the SNCU teams identified and ran QI cycles to address these issues. Combined with the PHCP to improve the knowledge and skills of HCWs in managing sick and preterm neonates, the QI cycles successfully reduced the use of oxygen, antibiotics, and phototherapy while enteral feeds were initiated earlier resulting in a shorter time to reach full enteral feeds. Significant reduction in the use of 2 lifesaving but double-edged interventions like oxygen and antibiotics without a concomitant increase in the incidence of death or referral to a higher center supports our preintervention assessment of overuse. Alternatively, the profile of admitted infants may have changed over time, resulting in a lower use of oxygen and antibiotics. However, this alternate explanation is refuted by the similarity of baseline variables and significant effect size obtained even after adjusting for biologically plausible prognostic factors. Rather, the case mix in the intervention period had a higher proportion of preterm and male neonates and lower use of antenatal steroids, all of which are risk factors for increased sickness and mortality.,We evaluated the efficacy of a novel package of interventions in improving the health care practices and outcomes in district level-2 neonatal care units. We observed significant improvement in the health care provided to sick or preterm neonates at admission and during the hospital stay. However, we did not observe any improvement in neonatal survival. Our study intervention was based on the assumption that unexplained variation in the care provided to neonates admitted to the SNCUs is related to the quality of care. During the baseline period of observations, we found that many health care interventions were often being used without clear indications. These included administration of oxygen, intravenous fluids, antibiotics, and phototherapy. The root causes of injudicious use of these interventions were lack of standard operating procedures and fear of adverse outcomes in absence of use , it is not able to address the gaps in the structure of the health system .The study has certain limitations. The first major limitation is that due to the lack of consistent availability of ophthalmologists at the district hospitals, only a subset of eligible preterm neonates could be screened for the development of ROP. Therefore, the study was not able to report any change in the incidence of severe ROP, a component of the composite primary outcome of the study. Second, being an uncontrolled study, the role of secular trends and external influences cannot be ruled out. We used an interrupted time-series regression analysis to control for the preintervention trend. Although this reduced the number of practices that were found to have improved significantly, this can be explained by reduced power as aggregated data were used in the analysis instead of individual patient data. Third, working on 1 QI project could have led to improvement in another clinical domain and the confounding effect of QI projects on each other cannot be removed. However, the QI teams at each SNCU worked on only 1 QI project at a time and only after completing the project took up the next QI project using the new baseline level of performance at that time. Fourth, the QI activities in the study focused only on the health care processes within the SNCUs. Obstetric practices, resuscitation, and, if outborn, care during transport, have a major influence on neonatal mortality and morbidity. This limitation may be a major reason for the study intervention not resulting in improved neonatal survival. Fifth, the study did not formally evaluate the sustainability of the effects of the intervention package. It is possible that the withdrawal of the external collaborators could result in reverting to previous health care practices. Lastly, we have not evaluated the cost-effectiveness of the intervention.Focusing only on health care processes within the SNCUs may be a major reason that the study intervention did not result in improved neonatal survival.An intervention package based on a situational analysis, consisting of a novel combined training and problem-solving approach and driven by HCWs, was able to significantly improve neonatal health care practices and reduce the injudicious use of many potentially harmful therapies. Future studies should target QI efforts at the full continuum of fetal-neonatal care including childbirth, resuscitation, transport, and postdischarge follow-up.Authors in the Retinopathy of Prematurity-Quality Improvement India Study Group: All India Institute of Medical Sciences, New Delhi, India, Department of Pediatrics: Ashok K. Deorari and Anu Thukral; Postgraduate Institute of Medical Education and Research, Chandigarh, India, Department of Pediatrics: Praveen Kumar, Sourabh Dutta, Sundaram Venkataseshan, and Shiv Sajan Saini; Postgraduate Institute of Medical Education and Research, Chandigarh, India, Department of Ophthalmology: Mangat Dogra and Deeksha Katoch; Government Medical College and Hospital, Chandigarh, India, Department of Neonatology: Deepak Chawla, Suksham Jain, and Meenakshi Sharma; Government Medical College and Hospital, Chandigarh, India, Department of Ophthalmology: Subina Narang; Indian Institute of Public Health, Hyderabad, India: Rajan Shukla, G.V.S. Murthy, Snigdha Das, and Ammaji Ch; National Health Mission, Bhopal, India: Rajashree Bajaj and Manish Singh; and London School Hygiene & Tropical Medicine, London, United Kingdom, Department of Clinical Research: Clare Gilbert, International Centre for Eye Health."}
+{"text": "Among various regenerative cues, including chemical, biological, optical, magnetic and mechanical factors, the implementation of advanced pharmacological approaches, electrical and mechanical stimuli have long been underestimated in regard to their potential for the development and improvement of bioengineered and biological tissues, such as the bone, cartilage, muscle, heart, and nerve.The primary mission of tissue engineering and regenerative medicine (TERM) is to mimic the architectural and functional nature of impaired tissues . TERM hain vitro studies. Long-term evaluation on the reparative potential of mechanically and electrically conductive biomaterials is the key to identifying a translational approach to advance the field of mechano- and electro-active tissue regeneration therapies.Mechanical and electrical activities play a crucial role in a series of physiological phenomena in the living body and are important for the functionality of mechano- and electro-active tissues, such as bone, cartilage, muscle, heart, brain, spinal cord, and peripheral nerve. Therefore, it is vital to focus on the application of conductive scaffolds and their regulation on endogenous electrical activities in the process of tissue regeneration, with or without exogenous mechanical and electrical stimuli of different paradigms . Positive outcomes have been reported in previous literature, but it is poorly understood how electrical phenomena affect cell physiological function-behavior, metabolism, signaling transduction, and gene expression, or how the combination of engineered conductive scaffolds with the specific delivery of therapeutic drugs boosts the regenerative capacity of tissues. For instance, the inter-cellular communication between neurons or glial cells influenced by electrically conductive scaffolds is not well elucidated in nerve tissue engineering. Some preliminary findings were obtained from In this Research Topic, we have covered the latest advances in the modulation of electrophysiological activities of cells, tissues, and organs by conductive biomaterials and their regenerative signaling mechanisms. This has ultimately led to a comprehensive display of papers .Liu et al. stressed the involvement of osteoclasts and osteoblasts in the activation of various mechanical transduction pathways and discussed changes in the differentiation, formation, and functional mechanisms under multiple forms of mechanical stress to bone tissues. Mei et al. designed a mesoporous bioactive glass biomimetic scaffold to enhance cellular adhesion and to improve osteogenic/cementogenic differentiation in human periodontal ligament cells.Some papers focused on physiological and metabolic response of excitable and non-excitable cells and tissues on electrically active substrates under mechanical and electrical stimuli in normal and tissue injury environments. Wang F et al. proposed a conductive adhesive and anti-bacterial Zwitterionic hydrogel dressing to repair full-thickness skin wounds. In their study, modulation of electrical paradigms facilitated intercellular communication and transcriptional signaling, mechanical stimulation for angiogenesis and skin development and function supported by conductive scaffolds. Tian Y et al. claimed pro-healing effects of mechanically conductive tissue engineering strategy with bardoxolone methyl on nucleus pulposus cells and tissues by inhibiting extracellular matrix (ECM) catabolism and promoting ECM anabolism. In addition to traditional electrical stimuli, in vitro and in vivo evaluation of wound healing and tissue regeneration technologies of combined electrical stimulation and smart materials also yielded some promising results, including novel electroactive scaffold design and user-friendly application .Jiang Y et al. reported the Netrin-1 modified adipose-derived stem cells and the combined application of such in vitro and in vivo tissue engineering strategies to accelerate or improve the development and function of bioengineered endovascular tissues. In addition, there are some research papers concerning novel biomaterial design, fabrication and application for mechanobiology/electrobiology and interfacial characterization of these biomedical materials in bone and nerve regeneration .The improvement in tissue regeneration, either in functionality or morphology, largely depends on the increasing knowledge of the properties of mechano- and electro conductive tissues and organs. The purpose of physical stimulation is generally to simulate the nature of the living tissue and organ itself. For instance, microenvironmental remodeling in nerve repair is essential and influenced by the spatial and temporal changes after nerve injury. This also greatly affects the scaffold design and physiochemical factors of the nano- and micro-scale biomaterials . The rec"}
+{"text": "In contemporary context the difficulties of making sense of social ambiguity becomes one of the most important appeals for seeking the psychological help. This grounds the importance of studying the mechanism underlying the quality of mentalization and its individual variations.The objective of the study was to find empirical relations between the quality of mentalization and its cognitive, emotional and expressive mediating factors.(1) The Adult Attachment Interview, scored using Social Cognition and Object Relations-Global rating method for mentalization ability. (2) Group embedded figures test. (3) New Tolerance-Intolerance to ambiguity and (4) Toronto alexithymia scale questionnaires. Twenty participants, aged 18-38, looking for psychological consultation, took part in the study.Correlation analysis suggests positive relation between field-independency and tolerance to ambiguity . The complexity of representations of the mind positively correlates with the understanding of social causality . The affective quality of relationships\u2019 representations positively correlates with the ability to emotionally invest into relationships , and with the understanding of social causality . The ability of emotional investment into relationships also positively correlates with the understanding of social causality . There is a negative link between the severity of alexithymia and the presence of long-term relationships with a partner .Mentalization should be understood as a system, with underplaying cognitive, expressive and emotional factors.No significant relationships."}
+{"text": "The sudden changes in daily routine due to the containment measures adopted for facing the COVID-19 pandemic have had an impact on the mental health of the general population. In particular, young adults are exposed to a higher risk compared to the general population to suffer from the consequences of the pandemic, in terms of anger and irritability, depressive symptoms and somatic complaints, insomnia, lack of motivation and loneliness. In particular, loneliness can be particularly pronounced during young adulthood.This study aimed to describe the levels of loneliness in a sample of Italian young people during the national lockdown in 2020, evaluating clinical and socio-demographic differences and the role of coping strategies and levels of resilience.A sub-analysis of a sample of adults aged 18-34 years has been drawn on a larger cross-sectional observational national trial  in which, among other psychopathological dimensions, the levels of loneliness have been assessed by the UCLA scale short version.Levels of loneliness were particularly severe in a third of cases , in association with depression, anxiety, stress, OCD symptoms, higher rates of suicidal ideation, sleep disturbance and excessive use of Internet. Levels of loneliness tended to increase over time.Overall, during the Italian COVID-19 lockdown young people have experienced quite high levels of loneliness: this dimension could represent a useful domain to assess in routine clinical practice.No significant relationships."}
+{"text": "Cannabidiol (CBD) has been gaining increased attention in contemporary society but seems to have been little explored in dentistry. This scoping review mapped the scientific and technological scenarios related to the use of CBD in dentistry. Peer-reviewed publications were searched in five international databases, patents were searched in five technological platforms. In total, 11 articles and 13 patents involving CBD in dentistry-related applications were included. The countries contributing to most articles were Brazil (27.3%) and USA (18.2%). The studies involved experiments on animals (63.6%) and/or using bacteria or cells (36.4%), and no clinical study was found. Three different applications of CBD were observed: periodontal therapy (45.4%), aid for bone regeneration (27.3%), and general use in oral therapies (27.3%). Patent inventors were based in China (53.8%) or USA (46.2%). The patent claims were mainly compositions for oral care, tooth whitening, injury repair, antifungal, anti-inflammatory, and analgesic effects. A total of 76.9% of the patents were filed in association with a company. In general, research suggests that CBD has promising biological properties for applications in dentistry, whereas patents indicate that the current interest of industry relies on compositions for oral care. There appears to be extensive room available for research and technological applications of CBD in dentistry. Endocannabinoids are naturally occurring molecules in mammals produced in the endocannabinoid system ,2, whichCannabidiol (CBD) is a compound without psychoactive activity derived from Cannabis sativa plant . CBD hasIncreasing research and development of CBD and its medical applications have been undertaken due to financial support by various private and governmental organizations in the past years. The global CBD market is expected to reach approximately USD 30 billion by 2025 . CBD hashttps://osf.io/yk65c/ (accessed on 10 October 2022). For the mapping, the following parameters were selected: (i) Population\u2014articles and technological products; (ii) intervention\u2014use of CBD or its synthetic analogs; (iii) comparison: other substances or treatments that may have been tested (if applicable); (iv) dental and oral medicine applications, (v): articles or patents. One general question guided the review: What scientific applications and technological products based on CBD or its synthetic analogs are being used in dentistry at present?This scoping review has been reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Extension for Scoping Reviews guideline . The stuThe inclusion criteria consisted of in vitro or in vivo studies and patents that have evaluated or reported the use of CBD for dental applications or subjects . Studies that evaluated the use of CBD alone or associated with other substances  or biomaterials in dentistry were included. In addition, studies that evaluated other synthetic analogs  were also included. The search was restricted to documents published in English without restriction on date. Case reports, case series, pilot studies, opinion articles, letters, and conference abstracts were excluded due to the high risk of bias associated to these articles. Reviews were excluded to concentrate the analysis to original articles. Studies on the use or smoke of cannabis plants and other cannabinoids also were excluded. Patents including CBD were excluded when its application or scope of patents was not related to dentistry or oral medicine.The searches in literature databases were performed by two independent reviewers (CD and AE-H) and patent tools (CD and AB), with no starting date and continuing through to December 2021. The research for articles was carried out in five international databases: PubMed/MEDLINE, Scopus, Web of Science, Embase, and Cochrane Library. The search strategy was based on the MeSH terms of PubMed and the specific terms of the other databases, using the search strategies presented in All records identified were imported into the EndNote program . The independent researchers identified articles and patents by first analyzing titles and abstracts for relevance and eligibility criteria using the online system Rayyan QCRI . Retrieved records were classified as included, excluded, or uncertain. Full-text versions of the included and uncertain records were selected for further eligibility screening. Discrepancies in a screening of titles/abstracts and full texts were resolved by discussion. In case of disagreement, the opinion of a third reviewer (RRM) was sought.We created two spreadsheets in the Microsoft Office Excel 2013 software  for data extraction from articles and patents. The spreadsheets were pilot tested by three reviewers  to reach a consensus on which data to collect and how. Two independent reviewers  extracted the main relevant data, specifically focusing on the outcomes in dentistry, and influence of CBD on the dental applications. The following items of data were collected for articles: year, first author, journal, study design, country of the corresponding author, CBD dosage, route of administration, CBD presentation, manufacturers, applications , and sponsors of the studies. From patents, the following data were collected: patent numbers, year, title, inventors, country of inventors, main claims, and company. The mapping of research findings and patents was carried out considering the application of CBD in different dental subjects.A total of 2312 unique articles and 989 patents were identified  with 229Characteristics of the 11 original studies included are presented in Characteristics of the 13 patents included are shown in The main applications of CBD and its synthetic analogs in dentistry are illustrated in The anti-inflammatory properties of CBD also made it a suitable alternative for the prevention and treatment of oral mucositis, by reducing the inflammatory process and the severity of lesions ,19. CBD This scoping review mapped the available literature and patents on the use of CBD for dentistry-related applications. Most of the peer-reviewed literature suggested that the positive effects of CBD could be attributed to its anti-inflammatory, analgesic, antimicrobial, biological, and osteoinductive properties. The patents also seemed to rely on these properties to offer technological applications of CBD in dentistry. The dental subjects mainly involved in the literature and patents reviewed were periodontology, oral medicine, and oral surgery. These subjects, the potential technological applications of CBD, and future research challenges on the topic are discussed as follows.CBD has anti-inflammatory properties and was shown to be capable of reducing alveolar bone loss in induced periodontitis ,25. PharThese anti-inflammatory and analgesic properties of CBD have been reported to be dose-responsive, without ideal doses having been established for a possible antioxidant and anti-inflammatory action ,21,26. TIn an in vivo study , the synPorphyromonas gingivalis and Filifactor alocis, which are key components of subgingival microbiota [CBD showed effective antimicrobial properties in the reduction of colonies of bacterial strains against oral bacteria and two biofilms . High docrobiota . Dental crobiota . Howevercrobiota .CBD has shown favorable biological and osteoinductive properties. When used alone or in combination with other substances, CBD was sufficiently effective and reliable to produce cell migration and bone differentiation ,7,26 andIn line with the recent literature on the use of CBD in dentistry, our findings also revealed an increasing interest in technology and appropriation relative to dental applications of CBD in recent years. Despite the increasing progress in filing these patents, only one patent  dating bA number of limitations relative to research and technological applications of CBD in dentistry can be cited. One limitation is the absence of clear regulations governing the supervision of the quality of CBD , which cStudying of the behavior, dosage, and mechanisms of action of CDB used in dentistry-related clinical conditions;Acceptability of CBD-based treatments among dental patients;Standardization of the methods used for extraction of CBD and standardization of in vitro and in vivo tests with this compound ;Evaluation of the cytocompatibility of CBD in order to develop safe products;More basic studies are needed to increase safety of CBD for use in dental patients;Since CBD has been approved for use in patients in many countries, clinical studies with patients are also needed in dentistry, which means that the available evidence is of low quality, low certainty, and prone to risk of bias.The scientific articles reviewed indicated challenges to the current clinical use of CBD in dentistry and a potentially extensive field for research and products using CBD and its synthetic analogs, including:Cannabidiol has been gaining increasing attention in contemporary science and society but seems to have been little explored in dentistry-related research and patents to date. Dental research evidence suggests that CBD has anti-inflammatory, analgesic, antimicrobial, biological, and osteoinductive properties for potential periodontal, oral surgery, and oral medicine applications. Patents available indicate that at present, the interest of industry relies on compositions for oral care products including toothpaste, mouthwash, and dental floss. There appears to be extensive room available for research and technological applications of CBD in dentistry, especially as far as the lack of clinical trials is concerned."}
+{"text": "Dear editor,Melkersson-Rosenthal syndrome (MRS)/orofacial granulomatosis is characterized by the triad of recurrent orofacial edema, recurrent peripheral facial palsy, and fissured tongue.The cause of MRS is unknown. The authors of the present study demonstrated an increase in the expression of HLA A*02, HLA DRB1*11 to HLA DQB1*03 and a decrease in the levels of HLA A*01, HLA DRB1*04, HLA DRB1*07, and HLADQB1*02 in patients with MRS when compared to the control group, indicating genes that may predispose to or protect against the disease.The histopathological findings of MRS include non-caseating granulomas similar to CD, which may suggest that MRS and CD might be part of the same clinicopathological spectrum.4The present report describes seven cases of MRS in children and adolescents, drawing attention to a possible association with CD.The analyzed data from the cases diagnosed with granulomatous cheilitis/MRS/orofacial granulomatosis were: sex, age, lesion location, neurological impairment, and colonoscopy exams . The diaThis sample represents the largest case series of children with MRS in Latin America.There was a predominance of male patients; the only female patient noticed symptoms at age 15. The cases reviewed by Savasta et al. showed a prevalence of female patients.Only patient 6 reported a previous bout of facial palsy, having also had an episode observed by the authors. Facial palsy affected 61/116 (52.6%) of the previously reported pediatric cases.Cases 4, 5, 6 and 7 had fissured tongue; cases 4 and 6 had geographic tongue  and FUNADERSP \u2012 (29/2016).Camila F\u00e1tima Biancardi Gavioli: Statistical analysis; approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.Yasmin da Silva Amorim City: Statistical analysis; approval of the final version of the manuscript; drafting and editing of the manuscript; collection, analysis, and interpretation of data; effective participation in research orientation; critical review of the literature.Giovanna Piacenza Florezi: Design and planning of the study; collection, analysis, and interpretation of data; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature.Silvia Vanessa Louren\u00e7o: Statistical analysis; approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.Marcello Menta Simonsen Nico: Statistical analysis; approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.None declared."}
+{"text": "Plant-derived antioxidants are a large group of chemical compounds that include the secondary metabolites of plants  and the substances formed in food during processing . These compounds are widely distributed in fruits and vegetables, as well as their derived products. Natural antioxidants have been gaining increasing interest, mainly due to the association between their consumption and the prevention of cardiovascular disease, cancer, neurodegenerative disorders, diabetes, and some other illnesses. Many research studies on plant-derived antioxidants have shown that these compounds exhibit a wide range of biological effects, including anti-aging, anti-inflammatory, anti-atherosclerotic, and anti-cancer. The bioavailability and bioefficacy of plant-derived antioxidants, including polyphenols, carotenoids, and tocopherols, are dependent on their molecular structure, food matrix, the occurrence of other substances, and their digestion pathways. Recent evidence suggests that the pharmacokinetics and metabolism of bioactive compounds are crucial to understanding their role and function in human health. However, the exact mechanisms of action, effects, and bioavailability of plant antioxidants are still not fully recognized.This Special Issue consists of 18 articles focusing on the field of fortified and functional foods, the impact of technological processes on the content and transformation of bioactive components and the antioxidant activity of food, as well as in vitro and in vivo studies of the bioavailability, bioaccessibility, and bioactivity of plant-derived antioxidants, and explaining the effect of metabolism and pharmacokinetics on the efficacy of plant antioxidants and other potentially health-promoting mechanisms.Lactobacillus casei, and pork sausages [The scientific literature provides many examples of the use of plant raw materials rich in antioxidants and by-products of their processing to obtain fortified or functional foods, especially products that are poor in antioxidants in traditional formulations. A rich source of many active substances with health-promoting properties is sea buckthorn. Among them, antioxidants, phytosterols, essential fatty acids, amino acids, and vitamins C, K, and E should be mentioned. Sea buckthorn shows antimicrobial and antiviral properties and is a potential nutraceutical or cosmeceutical. Moreover, it has been proven to help treat cardiovascular diseases, cancer, and diabetes, as well as gastrointestinal and skin problems. Sea buckthorn is the most often used in the production of foods such as juices, jams, wines, pies, and liquors. There are also known examples of the addition of this fruit or its preparations for the enrichment of frozen yoghurt, soy drinks fermented by sausages . Anothersausages  determinsausages . Waste osausages  used appsausages .Polyphenolic extracts, which could be used as functional food ingredients and whose qualitative\u2013quantitative composition and properties depend on the extractant used, can be obtained from grape pomace. A study by Caponio et al.  showed tBrassica oleracea var. gongylodes) were used as research material. The study indicated that UVB irradiation could induce an overall alteration in metabolite composition. Increased levels of secondary metabolites, such as anthocyanins and phenolic acids and ABTS free radical scavenging ability were observed during UVB irradiation [The cultivation conditions and the type and parameters of the production processes used affect the chemical composition and properties of raw materials as well as semi-finished and finished products. Research into the effect of UVB radiation on changes in the composition of primary and secondary metabolites in plants was conducted by Yeo et al. . Purple adiation .Thermal processes can cause changes in the chemical composition, structure of compounds, and the bioactive properties of food. For example, roasting affects the qualitative and quantitative composition of polyphenols, the formation of Maillard reaction products and, consequently, the antioxidant potential of carob kibbles . ThermalO-glucoside (C3G) showed a low bioavailability of this compound and confirmed its significant instability under intestinal conditions [O-glucoside binds in the vicinity of the catalytic site of \u03b1-amylase and lipase. In contrast, in the case of \u03b1-glucosidase and lipoxygenase, no direct contact with catalytic amino acids was found. However, further research involving biological assays is needed to confirm the possibility of using this extract as a natural agent to treat and reduce the incidence of MS [The bioavailability, bioaccessibility, and bioactivity and, consequently, pro-health potency of plant bioactive compounds depend on their molecular mass, chemical structures, concentration in food, as well as food matrix and digestion pathways. Studies provided by Fraisse\u2019s team using a simulated gastrointestinal tract model on the bioavailability of cyanidin-3-nditions . The decnditions . Other hnditions . The anace of MS .Humulus lupulus L.), their bioavailability and their biological activity. It reports the most important results obtained so far in the primary and secondary prevention of several non-communicable diseases, such as cancer and MS, understood as a cluster of risk factors for diabetes mellitus and cardiovascular diseases  in the presence of central obesity [A review article authored by Zugravu et al.  describe obesity .Triticum spelta L. cv. Ostro), the highest relative bioavailability of p-coumaric acid and trans-ferulic acid showed seeds subjected to enzymatic treatment and then fermentation. These processes also allowed for the improvement of the antioxidant activity of the tested material [Talaromyces amestolkiae [The bioavailability of phenolic compounds contained in food matrices can be enhanced by the prior application of various bioprocessing techniques. In the case of spelt seeds -epicatechin and only in stem bark extract: (+)-catechin) and nine phenolic acids  were identified in the extracts). All of the tested extracts showed antioxidant and DNA-protective potential, most visible in the case of extracts from flower parts and leaves [Andonova et al.  conducted leaves .Carotenoids are colored compounds with lipophilic properties and poor solubility during digestion, resulting in low and variable bioavailability. On the other hand, they are characterized by high antioxidant activity affecting several health benefits. The effect of frequently consumed proteins , gelatin, GEL; turkey and cod) on carotenoid bioavailability and cellular uptake was studied. The food content after joint digestion in the gastrointestinal tract of these proteins with food matrices rich in carotenoids (tomato and carrot juice and spinach) was studied in Caco-2 cell models. The matrices containing higher amounts of non-polar carotenes after protein addition were characterized by better fractional bioavailability during simulated digestion in the gastrointestinal tract than analogous systems of matrices rich in more polar xanthophylls. The digestion of matrices in the presence of protein promoted the cellular uptake of carotenes  and counteracted the negative effect of proteins on the bioaccessibility of xanthophylls by improving the cellular uptake of lutein + zeaxanthin (up to 12%), especially in the presence of WPI and SC proteins .n = 16) conducted by \u00c1vila-G\u00e1lvez [Flavanones are consumed in our diet almost exclusively with citrus fruits and, to a lesser extent, with some herbs or tomatoes. Hesperidin is the main flavanone present in oranges, and eriocitrin in lemons. The available scientific evidence shows that the intake of flavonoid-rich citrus fruits is associated with a lower risk of stroke and the occurrence of certain types of cancer. However, the low solubility of hesperidin hinders its bioavailability. A randomized human crossover pharmacokinetic study n =  conducteThe LC-ESI-LTQ-Orbitrap-MS was used to study the distribution of oleaceins (OLEA), oleocanthalu (OLC), and their metabolite derivatives in rat plasma and organs/tissues  after the acute intake of refined olive oil. Unmetabolized OLEA was detected in the stomach, small intestine, liver, plasma and, above all, in the heart. OLEA metabolites, in turn, were mostly distributed in the liver, heart, spleen and lungs. OLC was detected only in gastrointestinal samples, while its metabolites were widely distributed in rat tissues, with the small intestine and liver being the most important metabolizing organs. The obtained results may partially explain the mechanism of the beneficial effect of extra virgin olive oil consumption. However, further detailed pharmacodynamic studies are needed to link the ingested concentrations of OLEA and OLC and the composition of their metabolites with the frequency of the intake and the effect on the human body ,18."}
+{"text": "Background: The impacts of health inequities on healthcare access, utilization, and outcomes have been highlighted by the COVID-19 pandemic, but these issues have been ongoing, yet understudied, in infectious disease epidemiology. Health inequities affect access to care, quality of care, and health outcomes in all healthcare settings. One healthcare setting that has yet to be fully studied in the context of health inequities is nursing homes. Nursing homes have a host of facility and population-specific issues that differ from other healthcare settings, making the impacts of health inequities likely unique and imperative to understand. The impacts of health inequities on nursing homes are unclear, and they likely have downstream effects on trends in morbidity, mortality, and transmission of multidrug-resistant organisms (MDROs) and other pathogens. Method: Here, we present a descriptive analysis, integrating multiple datasets relating to nursing home facility factors (data from the CMS Provider of Services and the CDC NHSN), nursing-home staffing trends , and social vulnerability . We conducted a spatial analysis of nursing-home locations and the social vulnerability of the area. Results: Investigations of facilities and health inequities are best conducted in small spatial geographies. Analyses with less detailed spatial geographies miss high levels of heterogeneity in social vulnerability. Figure Conclusions: These findings highlight that health inequities affect the quality and quantity of care of in nursing homes and that research conducted at larger geographical scales may overlook important mechanistic factors. This work will inform epidemiological models for disease transmission in nursing homes, accounting for the impacts of health inequities on transmission. Abating health inequities in all healthcare settings is a necessity to improve public health for the entire United States.Funding: NoneDisclosures: None"}
+{"text": "Lipids are crucial components of cellular function owing to their role in membrane formation, intercellular signaling, energy storage, and homeostasis maintenance. In the brain, lipid dysregulations have been associated with the etiology and progression of neurodegeneration and other neurological pathologies. Hence, brain lipids are emerging as important potential targets for the early diagnosis and prognosis of neurological diseases. This review aims to highlight the significance and usefulness of lipidomics in diagnosing and treating brain diseases. We explored lipid alterations associated with brain diseases, paying attention to organ-specific characteristics and the functions of brain lipids. As the recent advances in brain lipidomics would have been impossible without advances in analytical techniques, we provide up-to-date information on mass spectrometric approaches and integrative analysis with other omic approaches. Last, we present the potential applications of lipidomics combined with artificial intelligence techniques and interdisciplinary collaborative research for treating brain diseases with clinical heterogeneities. This review article explores lipid alterations in brain diseases and provides insight for future brain lipidomic research. With an increase in the aging population worldwide, brain diseases such as neurodegenerative diseases, psychiatric diseases, and brain tumors are being increasingly recognized as leading causes of morbidity and death . NoBrain cholesterol accounts for 25% of the total cholesterol found throughout the body. Cholesterols, which are mostly generated from astrocytes, are transferred to neurons through the formation of cholesterol-rich lipoproteins, including apolipoprotein E (APOE)  (fig. S1) (N-acetyl-\u03b1-neuraminidase 3 (Neu3)  and phospholipase D (PLD) , a neuronal protein that affects the regulation of synaptic vesicles and neurotransmitter release, the subsequent production of Lewy bodies , and the loss of dopaminergic neurons (HTT) gene is a well-known cause of HD  is an inherited progressive brain disease characterized by abnormal motor functions (chorea and dystonia), psychiatric complications (anxiety and depression), and cognitive functions (dementia)  spectrometry, fluorescence assay, and MS  and software tools have been developed for monitoring large-scale datasets, for performing the compositional and structural profiling of numerous lipids, and for analysis of their molecular networks . LIPID MAll these developments in MS-based analytical platforms and software tools for data interpretation have led to the availability of increasing reference data for lipidomic research, thereby facilitating large-scale studies. In recent years, these analytical tools and DBs have been used for brain lipidomics. However, many brain lipids are still unknown, increasing the need for their global and in-depth characterization.Brain diseases, such as neurodegenerative diseases  and psychiatric diseases, commonly exhibit molecular and clinical heterogeneities, which makes the development of diagnosis and treatment strategies quite difficult. Multi-omics is a powerful and useful approach to unravel the molecular mechanisms of diseases  gene GBA (one of the genetic risk factors for PD), and lipid substrates of GCase, such as glucosylceramides, ceramides, and sphingosines, is explored using the CSF of patients with or without gene mutations . IThe fundamental agenda in brain research involves understanding the structural and functional characteristics of molecular organization in the brain, starting from the genes to the whole organ, and the development of treatment approaches for brain diseases and psychiatric diseases. To achieve this goal, the use of human resources is inevitable because animal models used often demonstrate limitations in reflecting the physiological state of humans owing to the differences in the genotype and life cycle. In addition, interdisciplinary collaborative research between different fields such as neuroscience, mathematics, physics, computer science, engineering, and medicine is required for the systematic investigation of brain functioning and the practical application of research results . Unlike"}
+{"text": "Building on the importance of family and friends as sources of social connectedness in later years of life, we conducted a contextual examination of their independent and interactive roles in predicting mental health, using a compensatory social convoy model. In a sample of older Korean Americans, we anticipated that friend networks would be a more important predictor of mental distress when strong family relationships were absent. Data were from 2,140 participants in the Study of Older Korean Americans, a multi-state survey of Korean immigrants age 60 and older . To identify family types, latent profile analysis (LPA) was performed with 17 variables assessing family networks, positive and negative interactions with family members, and incidence of mistreatment by family. Linear regression models of mental distress then examined the direct effects of family type and networks of friends, as well as their interactions. LPA on family-related items identified three family types: close-knit, mixed, and dysfunctional. Membership in the close-knit group and a larger network of friends were associated with lower levels of mental distress. In addition, a significant interaction was found between dysfunctional family type and friend network , where the positive effect of friend networks was most pronounced in the context of dysfunctional family relationships. These findings support the use of a compensatory social convoy model. Substituting for family resources, friend networks yielded compensatory mental health protection for those with dysfunctional family relations."}
+{"text": "Approximately 30 years after the publication of the first Sicilian checklist of macrofungi, a new updated version is presented here. The census of macromycetes was carried out through periodic observations in different agricultural and forest ecosystems, in urban areas, in public and private gardens, and in botanical gardens. The 1919 infraspecific taxa included in 508 genera belonging to 152 families were collected in the Sicilian territory. Ectomycorrhizal fungi are the most represented ecological category, followed by saprotrophs on wood, saprotrophs on litter, and terricolous saprotrophs. The interest in this rich group of organisms is evidenced by the nutritional and therapeutic value of a high percentage of species. The actions linked to the National Recovery and Resilience Plan and The Network for the Study of Mycological Diversity will further increase the number of macrofungi for Sicily in the future. The checklists are modern tools for evaluation of fungal diversity and valuable papers to highlight ecological data, and tips for management and exploitation of protected areas, agro- and forest ecosystems. Relevant studies were published around the world\u2014in Europe and in Italy ,5,6,7,8.The assessment of fungal diversity in the Italian regions is still incomplete and needs further investigation. In most Italian regions, it is difficult to document the exact number of mushrooms due to lack of mycologists. Even greater difficulty is faced in the evaluation of the presence of hypogeous macrofungi as few research groups have dogs trained to harvest.The territories included in the Med-Checklist consider the Italian peninsula as a separate region from a floristic point of view, and its two major islands, Sicily and Sardinia, are separately coded . The envOn the basis of literature data reported from 1814 to 1991, a preliminary survey on fungal diversity in Sicily was carried out by Venturella , with anFrom 1991 to present, the study of macromycete diversity has continued unabated through an intensive exploration of forest ecosystems, natural parks, nature reserves, public and private gardens, botanical gardens, cultivated and uncultivated lands.Based on data collected during 30 years of long-term observation, an up-to-date assessment of fungal diversity of Sicily is reported in this paper.The physiographic uniqueness of Sicily  coupled with the paleogeographic vicissitudes, over time have determined the progressive evolution of a rich vascular flora (ca. 3000 species) and the presence of a number of rare species or in any case of considerable taxonomic significance . In agreQuercus ilex L. subsp. ilex, Q. coccifera L., and Q. suber L. as well as semi-evergreen oaks Quercus pubescens Willd. s.l. and Q. virgiliana (Ten.) Ten. In the warmer areas near the sea, forests can be replaced by aspects of Mediterranean maquis such as those characterized by Juniperus turbinata Guss., J. oxycedrus L. subsp. oxycedrus, J. macrocarpa Sm., Pistacia lentiscus L. and other sclerophyllous shrubs such as Cistus creticus L., C. salvifolius L. and C. monspeliensis L.The forest area of Sicily corresponds to 512,121 hectares and includes 58 types of forest vegetation . The coaAmpelodesmos mauritanicus (Poir.) T. Durand & Schinz and other types of grassland and shrub communities. Even rarer are the natural forests of Mediterranean conifers such as Pinus halepensis Mill., P. pinea L. and P. pinaster Aiton, which are considered pioneer plants. In the hills, the natural forest vegetation, in the hottest and driest conditions, consists of mixed forests of deciduous oaks with dominance of Q. pubescens, while in cooler climatic conditions, with a marked oceanic climate, are more diffused Q. cerris L., Q. petraea (Matt.) Liebl and the endemic Q. gussonei (Borz\u00ed) Brullo. These species have in some cases been replaced for agricultural purposes or for the use of wood by Corylus avellana L., Fraxinus ornus L., and Castanea sativa Mill. The degradation aspects are represented by mesophilic shrubs dominated by different taxa belonging to the family of Rosaceae such as Pyrus pyraster. (L.) Burgsd. and P. amygdaliformis Vill. The forest vegetation of the mountain area is characterized by forests of Fagus sylvatica L. sometimes mixed with Acer pseudoplatanus L., Quercus petraea (Mattuschka) Liebl., Taxus baccata L. and llex aquifolium L. An exclusive characteristic of Sicily is the presence of forests of Q. ilex that reach an altitude of 1500 m well above the maximum elevation found in other parts of Italy. Of considerable interest is also the presence of different endemic trees and shrubs and evidence of relict forest vegetation such as Abies nebrodensis (Lojac.) Mattei, Betula aetnensis Raf., Celtis aetnensis (Tornab.) Strobl, Populus tremula L., Pinus laricio Poir., Quercus gussonei (Borz\u00ec) Brullo, Zelkova sicula Di Pasquale, Garfi & Qu\u00e9zel, and Genista aetnensis (Raf. ex Biv.) DC. Upland shrubs such as Sorbus graeca (Spach) Schauer and Berberis aetnensis C. Presl. are found in some areas lacking tree forest vegetation. Woody species that vegetate above the edge of the forest are found only on Mount Etna, but also in the Madonie. This vegetation is dominated by the shrubs of Astragalus nebrodensis on the Madonie and by A. siculum on Mount Etna.In the areas most subject to disturbance, the vegetation is currently represented by Fagus sylvatica L. in Sicily can therefore be considered a remnant of the glaciations, when conditions had to be favorable even at lower altitudes.The presence of Salix pedicellata Desf., S. alba L. and S. purpurea L., associated with Populus nigra L., P. alba L., Laurus nobilis L., Sambucus ebulus L., Cornus sanguinea L., Prunus mahaleb L. and Alnus cordata (Loisel.) Desf. , cupules of Castanea sativa Miller [Lanzia echinophila (Bull.) Korf], and cladodes of Opuntia ficus-indica [Pleurotus opuntiae (Durieu & L\u00e9v.) Sacc.] complete the list.Ectomycorrhizal fungi (637 taxa) are the most represented ecological category , followeFungi are recognized worldwide as fundamental components in every type of ecosystem . After aThe climatic features of Sicily are favorable to the development of basidiomata and ascomata of different fungal species. The observations carried out during the present study showed a constant presence throughout the year of macrofungi in ecosystems. Most species are collected in fall, although the presence of macrofungi appears to be strongly affected in some years by prolonged periods of drought. In the woods of the hinterland, it is possible to have optimal conditions of temperature and humidity able to favor the appearance of macrofungi even in the summer. In Sicily, spring is not a season of abundance for fungal fruiting and ascomycetes predominate among species. In winter and summer, pathogenic basidiomycetes and wood saprotrophs can be predominantly observed.Due to the presence of the three major regional parks  in these territories, the largest number of infraspecific taxa is found in the provinces of Palermo, Messina and Catania. In the other provinces, reafforestations are prevalent and thus the composition of fungal coenoses is reduced in quality and quantity.Marasmius bulliardii while it is very common to observe Fistulina hepatica at the base of chestnut trees. In Quercus ilex forests, fungi responsible for wood decay  are observed on stumps and trunks. Compared with other oak forests, fewer macrofungi are reported Quercus suber forests and in the maquis. This is due to the greater state of degradation of the forest coenosis due to frequent fires that cause a significant reduction in the number of mycorrhizal species and saprotrophs, the latter negatively affected by the drastic reduction in plant residues. In pastures, grasslands, and garrigues, the number of mycorrhizal species is limited to those of shrubs of the genus Cistus (Lactarius cistophilus and Leccinellum corsicum). Saprotrophs on litter and lignicolous species are widespread in riparian vegetation.The greatest number of species is found within beech forests. The low night temperatures, the summer storms and the presence of occult precipitations determine, starting from the second decade of August, the early appearance of macrofungi that are generally found, at lower altitudes, in autumn within the forest ecosystems. A rich number of lignicolous species, mostly pathogenic and to a lesser extent saprotrophic, has also been surveyed within beech forests, growing on trees, branches of different sizes that have fallen to the ground and stumps. A similar condition of prevalence of mycorrhizal species is found in oak and holly forests and in chestnut groves. In the latter type of forest, an important role in the decomposition of the abundant litter layer is provided by The high percentage of mycorrhizal species within the natural forests and reforestations of Sicily allows to exclude at the moment a decline in forest ecosystems. In some forested areas, frequent fires cause a reduction in mycorrhizal species and saprotrophs on litter due to the drastic reduction in plant residues. Conversely, silvicultural practices and the resulting failure to remove woody debris of different sizes promote the appearance of crusty, shelf-like, or gelatinous lignicolous macrofungi.Pleurotus ssp.) represent a valuable example for the economic enhancement of fungal diversity in Sicily. Of great interest is the presence on the Sicilian territory of rare species classified according to IUCN criteria as Vulnerable (Alessioporus ichnusanus) [Poronia punctata) [Pleurotus nebrodensis) [Grifola frondosa, Ganoderma lucidum, and Ericium erinaceus, with proven pharmacological activities including antibacterial, antifungal, antiviral, cytotoxic, immunomodulating, anti-inflammatory, antioxidative, antiallergic, antidepressive, antihyperlipidemic, antidiabetic, digestive, hepatoprotective, neuroprotective, nephroprotective, osteoprotective, and hypotensive activities.The presence of prized and edible truffles, especially within the holm oak and pine woods, is of relevant interest especially for the areas of the Sicilian hinterland characterized by a depressed economy . These pnusanus) , Least Cunctata) , and Endodensis) . MushrooPleurotus and Tuber species, can provide an important income in agroecosystems, especially in rural or marginal areas.Although the number of fungal species is still in constant flux, Sicily is among the Italian regions with the highest diversity of fungal species, many of which are of potential applicative interest and economic interest. Therefore, it is necessary to raise the level of knowledge and attention on the part of local communities towards this group of organisms. The data reported in this survey strongly increase the knowledge on distribution and ecology of macromycetes in Sicily and may help better valorize such non-timber products. The outcome of the checklist carried out in Sicily could provide the Regional Administration with useful information for the conservation and exploitation of fungi in natural habitats, with particular reference to forest ecosystems. Legislation should limit the level of danger existing for the conservation of fungal diversity and support such strategies with more rigorous limits against wild edible mushroom overharvesting. The cultivation of some prized edible mushrooms, i.e., The National Recovery and Resilience Plan (NRRP) and The Network for the Study of Mycological Diversity (NSMD), recently launched, will contribute to implement the monitoring of mycological biodiversity within national terrestrial habitats.These actions will be carried out with the contribution of institutions such as the Higher Institute for Environmental Protection and Research (ISPRA) of the Italian Ministry of Ecological Transition and the Working Group for Mycology of the Italian Botanical Society through an Open Science initiative."}
+{"text": "Next, the microstructure and properties after the selective laser melting fabricating process which act as an emerging technology compared to conventional manufacturing techniques are also enlightened. Thereafter, the development of multi-scale simulation and machine learning (ML) in material design is illustrated with typical examples and the great concerns in PHSS research are presented, with a focus on the precipitation techniques, effect of composition, and microstructure. Finally, promising directions for future precipitation hardening stainless steel development combined with multi-scale simulation and ML methods are prospected, offering extensive insight into the innovation of novel precipitation hardening stainless steels.Precipitation hardening stainless steels have attracted extensive interest due to their distinguished mechanical properties. However, it is necessary to further uncover the internal quantitative relationship from the traditional standpoint based on the statistical perspective. In this review, we summarize the latest research progress on the relationships among the composition, microstructure, and properties of precipitation hardened stainless steels. First, the influence of general chemical composition and its fluctuation on the microstructure and properties of PHSS are elaborated. Then, the microstructure and properties under a typical heat treatment regime are discussed, including the precipitation of B2-NiAl particles, Cu-rich clusters, Ni Precipitation hardening stainless steel (PHSS) has a long history and is widely employed in aerospace industries, marine environment applications, and nuclear reactor fields due to its ultra-high strength, satisfactory ductility, and excellent anti-corrosion properties ,2,3,4,5.The microstructure and distinguished properties of ultra-high strength stainless steels have been characterized through experimental techniques in the past decades ,9,10. ThVarious martensite variant microstructures with significant anisotropy features were demonstrated based on first principles calculation and phase-field simulation methods, which is in acceptable agreement with experimental results ,25. The In this review, we concentrate on recent progress in the advancement of PHSS, including the ultra-high strength steel not limited to the precipitation hardening steel (PHS) and PHSS, in regard to the modeling of composition-microstructure-properties relationships, especially in the hot working process, as well as the effects of compositions on the microstructure and properties of PHSS steels. Although the PHSS has a relatively long history, we would like to present how to establish a quantitative model of composition-structure-property to quickly discover novel high-performance PHSS. We start by summarizing the composition development and property features of PHSS, the microstructures and properties under representative heat treatments, and then discussing the microstructures and properties of the PHSS prepared by the selective laser melting (SLM) method. Finally, the strategies of alloy design and tailored property optimization of PHSS are prospected. This work is devoted to providing useful insight into the design strategies that are used to develop novel high-performance PHSS, specifically for engineering applications.Many investigations on PHSS have been carried out, and most of them focus on mechanical and corrosion behavior ,30,31,32The first-generation precipitation hardening martensitic stainless steel was designed in the 1840s . PHSS haPHSS is mainly strengthened by the precipitation of various nanoprecipitates during the aging treatment ,48, whicThe alloying elements in ultra-high strength stainless steel are mostly concentrated in transition metallic elements, and the corresponding frequency of alloying elements is displayed in 3Ti phases; Ni acts as a stabilizer of the austenitizing element, which promotes alloys with enhanced properties , a, a150], Generally, the traditional material design method based on trial and error is very cumbersome; therefore, it is urgent to carry out the modeling optimization. In recent years, the multi-scale calculation and simulation methods of materials have been developed rapidly and widely harnessed in the material design and mechanism research of new materials, which provides an efficient way for the development of new PHSS. The obtained FDM is determined through a numerical strategy. Physical characteristics of fluid flow, temperature, entropy optimization, and concentration have been illustrated. Variations of parameters are graphically investigated . The micAs shown in There are many types of alloying elements, and the additional content of alloying elements as well as the interaction between various elements would increase the complexity of the experiment. The traditional trial and error approaches are simple in facing the dilemma of low efficiency. C.E. Campbell et al.  establisWith the vigorous development of computational science, it is a new trend to examine the influence of alloying elements on the properties of materials by leveraging algorithms to model rationally. Additionally, common ML algorithms were adopted to investigate the intrinsic relations of materials especially in steels, including random forest (RF), linear regression (LR), support vector regression (SVR), multi-layer perceptron (MLP), convolutional neural network (CNN), and K-nearest neighbor (KNN) ,185,186.3Ti nanoprecipitates coupled with thermodynamic calculations and PM theories [Physical metallurgical (PM) method has been employed as an efficient strategy to develop distinguished mechanical properties and illustrate the mechanisms of strength increment. Furthermore, Chunguang Shen et al.  introductheories . Meanwhitheories . Therefotheories ,189. 3Ti phase, Cu-rich clusters, and other strengthening phases. A novel material with multiple co-existing particles was indicated to achieve comprehensive performance. In the present work, we focus on the establishment of the composition-microstructure-properties model of PHSS to urgently develop novel precipitation hardening stainless steels with superior mechanical properties. We over-reviewed the development history of representative PHSS. The influence of the composition fluctuation of general alloying elements on the microstructure and properties is discussed, and the research progress of the microstructure and properties of PHSS after the heat treatment process is summarized and illustrated, especially in the aspects of mechanical properties to guide the optimization of the heat treatment process. The relationships between precipitation strengthening nanoparticles and the microstructure and properties of steel were revealed, including typical B2-NiAl precipitates, NiCompared to traditional fabrication techniques, the advancement of AM in terms of machine capabilities and process parameters has resulted in the development of parts. The emergence of AM techniques provides strong support for the manufacturing and application of PHSS parts, especially for improving the microstructure and performance of PHSS steel prepared by SLM. At present, the AM technology of alloys is still in the immature stage. The parallel development of AM technology based on the traditional method of fabricating alloys provides convenience for the application of PHSS. There is still an enormous space for SLM to fabricate steel parts due to the drawbacks of PHSS, such as anisotropy, macro and micro defects, and residual stress after the existing processes.The development of new techniques and new approaches ensures the future exploration of PHSS with application potential. Moreover, it is necessary to employ ML strategies in materials science to extract the data from the results of experimental physical metallurgy and multi-scale simulation approaches, rather than trial-and-error methods, to comprehensively and efficiently design tailored PHSS with excellent mechanical properties. Additionally, future investigations will focus on developing reliable and robust databases and modeling the assessable correlations of chemical composition, hot work processes, microstructure, and properties. Machine learning and multi-scale simulation methods are used to reveal the relationship among the fraction and features of precipitates, processes, and properties to achieve accurate regulation of the precipitates. Meanwhile, attention should be paid to the precision heat treatment parameter control that takes into account fluctuations in composition by combining intelligent algorithms.Therefore, ML coupled with multi-scale simulation approaches and experimental methods undoubtedly exhibits a high-efficiency direction toward the development of novel PHSS with high performance, since ML has a strong capability to solve the intrinsic quantitative relationship between the microstructure of composition/process properties in the PHSS system. The prosperity of ML applications in PHSS design is poised to provide the perspective for a novel paradigm in integrated multi-scale computational materials science as a whole."}
+{"text": "Polycystic Ovarian Syndrome (PCOS) is the most frequent hormonal/endocrine disorder in women of reproductive age and is one of the most common causes of infertility. Approximately 20% of Danish women of reproductive age are diagnosed with PCOS, and yet only a little attention has been paid to the psychological symptoms appearing in women with PCOS. The present study investigated anxiety, depression, and lower quality of life among Danish women of reproductive age who are diagnosed with PCOS.This was a cross-sectional survey study among 326 Danish women who self-reported as being diagnosed with PCOS. The Hospital Anxiety and Depression Scale (HADS) was used to measure anxiety and depression, and the PCOS-QOL scale was used to measure the quality of life. Chi-square tests and logistic regression analyses were used for analyzing data.Sixty-six percent of women were found to have anxiety (n = 216), 41% of women had depression and 70% of women had low quality of life The most frequently reported symptoms were irregular menstrual cycle (86%), overweight (73%), and mood swings (65%), and irregular menstrual cycle, overweight and infertility were the were perceived of having higher severity. After adjusting for age, ethnicity, education, and income, the severity of symptoms, namely irregular menstrual cycle, infertility, overweight, and hirsutism, were independently and positively associated with depression, and severity of symptoms, namely irregular menstrual cycle, mood swings, and hirsutism, was independently and positively associated with anxiety. Lower quality of life was independently associated with both anxiety and depression.Women with PCOS are at higher risk of anxiety, depression, and consequently, lower quality of life. Clinicians and other healthcare professionals should pay attention to the importance of mental health support in women with PCOS and work towards promoting it.\u2022\u2002Women with PCOS are at higher risk of anxiety and depression, and lower quality of life.\u2022\u2002Health care professionals working with women with PCOS should be aware of this and be prepared to offer necessary support."}
+{"text": "The interest in membranes and membrane bioreactors for health and life sciences is rapidly growing thanks to their wide applications in advanced therapies and biotechnologies. Therapeutic approaches include the integration of membranes and membrane bioreactors for tissue regeneration and repair, for drug testing and drug delivery, and for cell therapy. Innovative biotechnologies employ membranes and membrane bioreactors for the production and selective separation of biological and bioactive molecules, for the design of diagnostic systems, and for the development of new drugs and pharmaceutical compounds.This Special Issue collects six original research articles by renowned experts, highlighting the current advances and new trends in membrane preparation, the membrane separation process, membrane bioreactors, and membrane applications in tissue engineering and biotechnologies. A new sequential fabrication route of wet spinning combined with UV curing has been presented by Yin et al.  for the z-axis and forming a multi-layered epidermis. This strategy represents an attractive tissue engineering approach for the creation of specific human epidermal strata to test the effects and toxicity of drugs, cosmetics, and pollutants.The use of membranes is of key interest in the development of engineered tissues. Membranes provide adaptable biomimetic microenvironments that can emulate the essential characteristics of the physiological ones, including tissue-specific extracellular matrix interactions. Surface properties trigger specific cell responses dictating the cell fate in terms of cell growth, migration, proliferation, differentiation and functional activation. Salerno et al.  developeDesign optimization of membrane bioreactors for tissue engineering applications and upscaling analyses requires an in-depth knowledge and understanding of the mass transport of nutrients to ensure uniform distribution and to solve critical limitation issues. Wang et al.  investigThe global biopharmaceutical market for therapeutic proteins, vaccines, and gene vector manufacturing requires reliable and efficient separation processes to ensure the safety, potency, and efficacy of the therapeutics. Membrane ion-exchange chromatography promises several advantages over column chromatography, including low operating pressure and fast flow rates, ease of use, and elimination of cleaning and validation costs in single-use applications. To this end, Lemma et al.  developeMembrane emulsification is a promising methodology in cosmetic and pharmaceutical biotechnology, with unique properties in terms of precise manufacturing of emulsion droplets under mild operating conditions, suitable to preserve the stability of bioactive labile components. Piacentini et al.  used memNovel approaches in membrane technology aim to overcome the main drawback of filtration and separation processes, i.e., membrane fouling. This phenomenon, caused by the accumulation of solutes on the membrane surface or within the membrane pore structure, irreversibly affects the performance of the membranes and increases the overall operational cost due to the need for regular membrane-cleaning procedures. Among the different antifouling strategies that have been employed, magnetic responsive membranes allow for the control of solute-membrane interactions through a reversible adjustment and modification of physicochemical properties of the membrane surface, which translate into tuneable permeate fluxes and superior antifouling characteristics. Upadhyaya et al.  developeIn conclusion, the different contributions collected in this Special Issue highlight the multifunctional role of membranes and membrane bioreactors in health and life science applications, addressing critical issues and aspects of the field. Membranes for their help and support during the review process.As guest editors, we would like to thank all the authors for their outstanding contributions. We sincerely feel that overall these papers offer innovative approaches and new trends that could stimulate future research in membrane science applied to the biomedical and pharmaceutical field. We would also like to thank the reviewers for their valuable contributions and the editorial staff of"}
+{"text": "Viral hepatitis is a major global public health problem that affects hundreds of millions of people and is associated with significant morbidity and mortality. Five biologically unrelated hepatotropic viruses account for the majority of the global burden of viral hepatitis, including hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV), and hepatitis E virus (HEV). Omics is defined as the comprehensive study of the functions, relationships and roles of various types of molecules in biological cells. The multi-omics analysis has been proposed and considered key to advancing clinical precision medicine, mainly including genomics, transcriptomics and proteomics, metabolomics. Overall, the applications of multi-omics can show the origin of hepatitis viruses, explore the diagnostic and prognostics biomarkers and screen out the therapeutic targets for viral hepatitis and related diseases. To better understand the pathogenesis of viral hepatitis and related diseases, comprehensive multi-omics analysis has been widely carried out. This review mainly summarizes the applications of multi-omics in different types of viral hepatitis and related diseases, aiming to provide new insight into these diseases. Viral hepatitis is a major global public health problem that affects hundreds of millions of people and is associated with significant morbidity and mortality. Five biologically unrelated hepatotropic viruses account for the majority of the global burden of viral hepatitis, including hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV), and hepatitis E virus (HEV). Despite that HAV does not develop into a chronic infection, HBV, HCV, HDV and occasionally HEV may cause chronic infections, of which HBV and HCV have a significant association with chronic incidence. Most deaths from viral hepatitis are due to HBV and HCV infections. According to the statistics, it was estimated that 296 million people were infected with hepatitis B, 58 million people were infected with hepatitis C and 1.1 million people died as a consequence of viral hepatitis infections in 2019 . In 2015The advances in technology have created a variety of new fields of study, commonly referred to as omics. Omics is defined as the comprehensive study of the functions, relationships and roles of various types of molecules in biological cells. The multi-omics analysis has been proposed and considered key to advancing clinical precision medicine, including genomics, transcriptomics and proteomics, metabolomics and so on . GenomicTo better understand the pathogenesis of viral hepatitis and related diseases, comprehensive multi-omics analysis has been widely carried out. Hence, this review summarizes the applications of multi-omics in different types of viral hepatitis and related diseases, aiming to throw light on the development of these diseases.Hepatitis A virus is a positive-strand RNA virus, which is transmitted through the fecal oral route. HAV outbreaks are often associated with poor sanitation, overcrowding or contamination of food and water . HAV infUsing genomics, To better understand the biogenesis of quasi-enveloped HAV (eHAV) virions, Hepatitis B virus is the most common cause of acute and chronic liver diseases worldwide, and approximately 4 million people are infected with HBV every year, especially in Asia and Africa . About 1By comparing the genomes of ancient African strains and HBV, As the DNA virus, HBV is different from other RNA hepatitis viruses since its viral genome can be integrated into the host liver cell genome. HBV integration is considered to lead to the occurrence of HCC, and the study of its structure is of great significance to the occurrence and development of HBV-related HCC. Advances in genomics have deepened the understanding of the diagnosis, prognosis of HBV-related HCC. The detailed genetic analysis of liver tissue provides important information for tumorigenesis and progression . The finThe applications of proteomics are of great significance in hepatitis B and related diseases . ProteomThe applications of proteomics provide new strategies for the occurrence, progression and replication of HBV. Based on yeast proteomics, In addition to the traditional HBV markers HBsAg and anti-HBs, the applications of proteomics have also expanded the development of diagnostic markers. Two differential proteins, VWF and C8B were considered to have the potential to distinguish HBV infection genotypes B and C and could provide precise guidance for HBV genotyping . The pepIn CHB patients, fibronectin levels in plasma have been demonstrated to be a predictor of HBsAg clearance . Long-teIn recent years, the applications of proteomics in HBV-related cirrhosis have also been reported. Autoantibodies recognized aminoacylase-1 (ACY1) were considered biomarkers to differentiate HBV-related cirrhosis and CHB patients by serum proteomic detection . ProteomProteomics also plays an important role in HBV-related liver failure. As HBV is a risk factor for the development of HCC, the applications of HBV-related HCC proteomics have also been paid more and more attention. O-glucoside was confirmed to inhibit HBsAg and HBV replication through mechanisms involving mitochondria  infection . CHC infE-cadherin is a mediator of HCV entry into host cells and is closely related to HCV-induced epithelial-mesenchymal transition. Through functional genomics, Proteomics matters in hepatitis C and related diseases . ProteomDiagnostic and prognostic biomarkers of HCV-related HCC can be discovered by proteomics. Through the comprehensive metabolomics analysis, Through the genome-wide miRNA functional screening and transcriptomic analysis, Hepatitis D virus is only found in humans currently. It is a satellite virus, which is assembled, released and entered by the envelope protein of HBV. It is the smallest known RNA virus, encoding a single protein.Using meta-transcriptomics, Hepatitis E virus (HEV) is an important zoonotic virus that can infect various hosts. It has 7 main genotypes. Patients with HEV infection are mostly asymptomatic, some patients will present jaundice and symptoms of acute hepatitis . Besidesin vitro HEV exposure, which was beneficial for the study of the interaction between HEV and host cells. Three different strains of porcine HEV were identified by The study by In conclusion, the applications of multi-omics have shown the origin and development of the hepatitis virus and provided new strategies for the diagnosis, prognosis and treatment of viral hepatitis and related diseases . There aBesides, multi-omics applications are not limited to genomics, proteomics, metabolomics and transcriptomics, and other omics are also developing, including radiomics, viromics, and so on. The joint application of these omics is believed to provide new insight into viral hepatitis and related diseases.ZX and JL had the idea for the manuscript. ZX and DL performed the literature search and data analysis. XX and XW drafted and critically revised the work. All authors contributed to the article and approved the submitted version."}
+{"text": "The uncertainty of COVID-pandemia, vital danger and disruptions in the habitual social contacts can be paralleled to the experiences of severe emotional stress and violence, usually found in the people with Borderline Personality Disorder. Both can be regarded as hampering the ability to categorize and express thoughts, feelings and experiences. The implementation of distant forms of psychological counseling may accentuate the mentalization deficiency.To develop a theoretical framework for an empirical typology of impairments of mentalization.The model of consciousness proposed by L.S. Vygotsky was used for theoretical generalization of the levels of categorical structures of mentalization observed in previous empirical studies.The following structures were identified: (1) the syncretic type of mentalization with low differentiation and complexity of object representations, their negative affective tone, autistic, chaotically mutable motivation and low emotional investment in relationships were described in patients with schizotypal disorders; (2) the \u201ccomplex\u201d type, with literal, non-generalized, field-dependent and rigid, or unstable, representation of the self, others and relationships as a result of the \u201cfusion\u201d of cognitive representations with the current emotional states. Similar types of mentalization were previously described in people with BPD and self-harming behavior .The \u2019syncretic\u2019 and \u2019complex\u2019 types of mentalization produce affective-cognitive distortions of the image of a psychotherapist, hamper the understanding of the conditional and metaphorical character of the therapeutic process, render difficult the de-traumatization of the unbearable experiences, and lessen the effectiveness of consultations of people with BPD.No significant relationships."}
+{"text": "Systematic research efforts have been focused on the development of low-dimensional structures, such as nanotubes (NTs), because of the potential of their use in nanodevices and in applications in nanoelectronics and biomedicine. After intense investigation on carbon nanotubes (CNTs), nanotubes made up of elements other than carbon, called non-carbon nanotubes (N-CNTs), have also attracted research attention, as they can be more suitable for electronic and optical engineering applications than their carbon counterparts. Success in assembling CNTs and N-CNTs together has opened the perspective of integrating these innovative complex structures into advanced NT-based systems. As experimental studies on the mechanical behaviour of CNTs and N-CNTs are limited by experimental difficulties in characterizing nanomaterials at the atomic scale, theoretical, analytical and numerical studies to predict the mechanical properties of NTs are of great importance.This Special Issue, comprised of a total of five research articles, is dedicated to recent developments in the modelling and numerical simulation of the mechanical properties of graphene sheets ; CNTs anThe next two research articles ,3 of theThe research article of Pereira et al.  is dedicThe last article by Sakharova et al.  providesThe works of this Special Issue promote research for the evaluation of the mechanical properties of carbon and non-carbon nanotubes and CNT-based structures by mostly numerical approaches. As a Guest Editor, I believe that the overall quality of the methodologies and achievements presented in this Special Issue contributes to the progression in our understanding of the mechanical behaviour of carbon and non-carbon nanotubes, aiding the future design and optimization of advanced nanotube-based structures."}
+{"text": "Due to volatile, uncertain, complex, and ambiguous (VUCA) project context, human decision-making behaviors can affect the performance of engineering project. Therefore, understanding the process of perception, cognition, and decision caters to minimizing the risks that attribute to behaviors . Peng et al. focused on safety behaviors in transportation systems. They introduced theories of electroencephalogram (EEG) and the utilization of EEG in scenarios of fatigued driving, distracted driving, and emotional driving. Lastly, Wang et al. utilized bibliometric methods to summarize the interdisciplinary applications of neuroscience tools in building construction. The results show that EEG and eye-tracking techniques are the predominant neuroscience tools in building construction studies, while functional near-infrared spectroscopy (fNIRS), functional magnetic resonance imaging (fMRI), and trigeminal nerve stimulation (TNS) are still at the adoption stage .Amongst the non-original research articles, Fan C. et al. regard EEG signals as the gold standard of cognitive status and proposed an end-to-end brain-computer interface framework named EEG-TNet for mental workload estimation of workers. The event-related potential (ERP) is a kind of real-time EEG signal related to the stimuli events , etc.] to promote management efficiency in the engineering industry. EEG, for instance, has been used in five of all thirteen original research articles. Among them, Qu et al. proposed a method to identify human-computer interaction intention and cognitive state based on eye movement and EEG parameters to solve the unsmooth and inefficient problems in human-computer interaction. Equipment teleoperation is a powerful solution for hazardous construction environments and attracted researchers' attention. Fan J. et al. investigated the effect of eye movement on teleoperation performance in excavating tasks. They built eye-tracking heatmaps with virtual annotations, representing operators' visual attention allocation. Based on these heatmaps, they concluded that visual attention is influenced by the excavating tasks and the shape of virtual annotations plays a critical role in visual attention allocation.Two studies using eye-movement parameters were presented in the Research Topic. Hu and Shealy  used fNIRS to measure the neuro-cognition changes of the engineers when they were asked to evaluate the implementation of conventional stormwater and green stormwater design options. So as to test whether design engineers think about the environmental and social sustainability benefits of green infrastructure can influence what attributes engineers consider and how they weigh these attributes during the design decision-making process. Ding et al. focused on the problem of the increasing hazards caused by construction and demolition (C&D) waste in the construction industry. In order to explore measures that could mitigate the problem, fNIRS has been used to investigate whether the media can influence consumers' willingness to pay for C&D waste recycling products and thus increase consumers' choices.The association between engineering decision-making and neuro-cognition was examined in two studies using fNIRS. Yang et al. attempted to explore the role of the right temporoparietal junction in the effects of the CEO-to-employee pay ratio on potential investors' perceived investment potential in the construction industry. The mechanisms underlying these effects of tDCS in the right temporoparietal junction on the perceived investment potential are also explored in the study.Zhao, Ao, et al. found that the experience of home-based learning significantly influenced the attitudes of university students of civil engineering, which in turn had a positive influence on their intention to continue online education. Chen et al. developed a whole-process digital management system platform and used a variety of advanced digital construction hardware and three-dimensional model software to coordinate the measurement, design, construction, and inspection work in the process of highway engineering construction. Zhao, Wang, et al. explored the key influencing factors of urban intelligent transportation construction and proposed a root cause analysis method based on a fuzzy cognitive map to model the construction process.Lastly, three papers in this Research Topic use different tools to explore the measures to increase the efficiency of engineering education and the construction industry. We appreciate the contributions of all the authors, the reviewers, and the editorial board members for contributing to this Research Topic. We hope that this Frontiers Research Topic can enrich the body of knowledge and encourage the utilization of cognitive neuroscience theories, methods, and tools in the Architecture, Engineering, and Construction Industries.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Multiple hospitalisations towards the end of life is an indicator of poor-quality care. Understanding the characteristics of patients who experience hospitalisations at the end-of-life and how they vary is important for improved care planning.To describe socio-demographic and clinical characteristics of patients diagnosed with serious mental illness who experienced multiple hospitalisations in the last 90 days of life.Data for all adult patients with a diagnosis of serious mental illness who died in 2018-2019 in England, UK were extracted from the National Mental Health Services Data Set linked with Hospital Episode Statistics and death registry data. Variables of interest included age, gender, marital status, underlying and contributory cause of death, ethnicity, place of death, deprivation status, urban-rural indicator, and patient\u2019s region of residence. The number of hospitalisations and patient\u2019s sociodemographic & clinical were described using descriptive statistics and percentages, respectively.Of the 45924 patients, 38.1%  had at least one hospitalisation in the last 90 days of life. The median number of hospitalisations was 2. Most of those hospitalised , died in a health care establishment . There were marked geographic differences in the proportions of hospitalisations.The North West region of England recorded the most hospitalisations , compared to other regions.Further analysis is needed to understand factors independently associated with hospitalisations in people with serious mental illness. Funding: This project is supported by the National Institute for Health Research (NIHR) Applied Research Collaborations (ARC) South London."}
+{"text": "Gliomas are the most common and aggressive intra-axial primary tumours of the central nervous system (CNS), arising from glial cells. The poor prognosis of these tumours partly results from a lack of significant advances in early diagnosis and treatments prolonging life .Most of the available local treatment options, including radiotherapy and neurosurgery, heavily depend on precise knowledge of the type, location, and extent of the tumour. Visual assessments of medical imaging represent a unique possibility for the detection, characterization, and monitoring of diseases. Qualitative evaluations still represent the modality for intraoperative assessments using ultrasound (ioUS) and/or optical coherence tomography (OCT) to identify lesions and potential residue, analyse the vascularization pattern, and characterise the nature of the mass. Technological advances in both structural and functional imaging (MR and PET imaging) also enables defining several images features, through multiparametric and quantitative evaluations of gliomas ,3.In the field of quantitative imaging, the main issues regard the acquisition/reconstruction parameters, tissue segmentation, feature extraction/selection, and the appropriate statistical analysis of data .Radiomics analysis, considered to be the most advanced development inimage quantification, may provide valuable diagnostic, prognostic, and predictive information of tumours. However, its role in gliomas is still undefined. Numerous studies have demonstrated the correlation between the heterogeneity of the tissues and the radiomics features, which can obtain relevant information not conventionally assessable in medical imaging ,6. FuturThere is still a need to validate the advanced use of MR and PET techniques, as the diagnostic methods increasingly utilized in clinical and research settings ,8,9,10. Diagnoses, disease extensions, vascularization patterns, differential diagnoses between low-grade and high-grade gliomas, and definitions of disease status after treatment remains the main issues of medical imaging in gliomas. This Special Issue will focus on developing in vivo quantitative and qualitative imaging , also considering the novel application of radiomics-based analysis to improve the current role of imaging in the management of gliomas.We invite authors to submit contributions of novel findings or reviews that comprehensively highlight the latest discoveries in the field."}
+{"text": "The Second International Conference on Rail Transportation (ICRT), initiated and hosted by Southwest Jiaotong University, completed its agenda after two days of academic reports and seminars, and came to a successful end on 6 July 2021, in Chengdu, China. The conference chairman was\u00a0Professor Wanming Zhai from Southwest Jiaotong University.\u00a0The conference received tremendous support from multiple co-sponsors including National Natural Science Foundation of China, Transportation & Development Institute of ASCE, National Innovation Center of High Speed Train of China, University of Illinois at Urbana-Champaign, Tongji University, Delft University of Technology, China Academy of Railway Sciences, Royal Institute of Technology (KTH), Central South University, Politecnico di Milano, Central Queensland University, Beijing Jiaotong University and University of Technology Sydney.The 2nd ICRT covered a variety of railway research fields such as rail vehicles, infrastructures, traction power, operation and maintenance, environment impacts, sustainable development, etc. Affected by the COVID-19 epidemic, the conference was held in a combination of online and live ways. As one of the largest gatherings of railway researchers, engineers, and technicians, this conference has attracted more than 70 well-known experts to join the conference committees, over 300 Chinese representatives to meet in Chengdu, and thousands of scholars from 22 countries to participate online. After a rigorous peer review process, the conference has accepted 120 full-length papers from 18 countries, and 96 oral presentations have been selected in the conference program.Railway Engineering Science is published for the extended versions of six plenary presentations, which are related to design of locomotive, wheel-rail interaction, train-bridge interaction, railway track structure and subgrade. The following are brief introductions of the six articles:Prof. Maksym Spiryagin from Central Queensland University, Australia, systematically presented the problems, assumptions and solutions in locomotive design, traction and operational studies and summarized the existing major challenges in the future developments of locomotive traction science and digital twins.The research team led by Professors Yunmin Chen and Xuecheng Bian of Zhejiang University, China, focused on the mud pumping problem in high-speed railway. On the basis of the numerical simulation, in-situ soil core test, and full-scale physical model of ballastless track, the formation of mud pumping in roadbed of ballastless track was revealed, and the effectiveness and engineering application of the polyurethane injection on mud pumping remediation was verified.Prof. Buddhima Indraratna from University of Technology Sydney, Australia, presented the mechanical behaviors of four recycled rubber products applied in railways and developed a rheological track model to reveal the energy dissipation capacity of the track with these applications, which may promote environmental sustainability and more affordable ballasted tracks.Prof. Ant\u00f3nio Gomes Correia from University of Minho, Portugal, proposed a geomechanics classification for subgrade coupling the stiffness (resilient modulus) and permanent deformation behaviour, which could be a potentially useful tool in the evaluation and modelling of the foundation of railway structures.The research team led by Prof. Zili Li of Delft University of Technology, the Netherlands, presented new insights into the friction modifiers (FMs) by experimentally investigating the effects of two types of top-of-rail FMs, and their application dosages on wheel\u2013rail dynamic interactions with various angles of attack.Prof. Yongle Li from Southwest Jiaotong University, China, presented a comprehensive literature review of research works on train\u2013bridge systems under external excitations including crosswinds, waves, collision loads, and seismic loads, and provided some valuable suggestions for further research on train\u2013bridge coupling vibrations under external excitations.Particularly, nine distinguished railway experts from different research fields were invited to deliver plenary presentations, who shared the state-of-the-art academic research and engineering practices. This Special Issue of These papers collectively present the recent progress, new insights and in-depth discussions in the aspect of essential challenging issues from rail transportation industry, which are expected to provide useful guidance and inspiration for the above research subjects.We would like to sincerely appreciate all contributing authors, involved peer reviewers, management and technical teams for their effort, time and collaboration to guarantee the high-quality publications of this Special Issue."}
+{"text": "Genomics, transcriptomics and metabolomics are increasingly generating key insights for the development of precision approaches in heath and disease. Omics technologies have unlocked the high-throughput discovery of diagnostic biomarker and the systems-level evaluation of the efficacy and toxicity of novel therapies.In the subfield of sport medicine and sport science, the application of -omics methods is relatively recent; yet, the number of peer-reviewed original research articles has seen a steady rise over the last years.Athletic performance can be affected by a combination of endogenous and exogenous factors, including genomic and metabolomic profiles, as well as diet, medicament/drug intake, training regimen, and exercise. In this respect, the application of omics approaches encompassed, for instance, the multi-parametric assessment of training efficacy, injury predisposition, and the identification of robust biomarkers for the indirect detection of potentially \u201cinvisible\u201d forms of doping. In addition, multi-omics integration approaches in sport medicine and doping sciences hold a clear promise for better understanding of the molecular/system levels of athlete\u2019s pathophysiology.What we believe should be indispensable to maximize the potential benefit that such approaches promise, is the promotion of cross-disciplinary and collaborative science, beyond the individual laboratories and research institutions.If we wish to ensure that evidence-based, multi-omics studies, will be complementing efficiently, omics data and the associated meta-data should be available without delay in curated repositories. The availability of omics data generated in independent studies, will enable results validation in the context of distinct populations of subjects/athletes , and allow to gauge unprecedented insight from genome-wide association studies (GWAS) to identify associations between genotypes and phenotypes and how this reflects on performance and drug testing. Meta analyses of literature data would indeed allow to assess and possibly validate any cause-effect relationships emerged from new studies, also, but not only, allow replication and confirmation of the results.In this first volume of the special research topic \u201cOMICS-Based Approaches in Sports Research\u201d, we welcomed submissions tackling 1) integrated omics in sport physiology and pathophysiology, 2) predictive biomarkers associated with improved athletic performance and on sport related risks on athlete\u2019 heath and injuries, 3) investigation of hormones and growth factors for improved anti-doping tests, 4) identification of novel biomarkers for the detection of sport doping, 5) novel statistical/modelling approaches for omics data integration, interpretation and doping detection. The feedback we received was beyond our most optimistic expectations: 57 scientists responded to our call with eight full length, high quality original articles. All published contributions are now available \u201copen access.\u201dThese studies covered different subfields of sport medicine and physiology of exercise, ranging from the interaction between mitochondrial function and the microbiome, to novel, indirect methods for the detection of doping.Khoramipour et al. applied metabolomics to compare metabolic profiles and movement patterns between different male basketball player positions, with focus on relationships between indicators of internal and external loads during elite basketball games. The integration of video-based time motion analysis (VBTMA) with metabolomics of saliva samples and multivariate data analysis demonstrated distinct metabolic profiles of backcourt and frontcourt players, with significant changes involving aerobic/anaerobic pathways.Mach et al. addressed the impact of endurance exercise on the functionality of mitochondria and on the composition of the gut microbiome in elite horses. The authors used transcriptomics, metabolomics and fecal microbiome analysis before and after hose endurance race. Their results show the association between energy metabolism, oxidative stress and inflammation with butyrate-producing bacteria, suggesting the possibility of enhancing/improving athletic performance by targeting the gut-mitochondria axis.Narduzzi et al. used steroidomics and complete blood count analysis to tackle one among the most debated topics in doping testing, that is the detection of the intake of low doses of human growth hormone (GH) in association with recombinant erythropoietin. GH intake affects human hematopoiesis and steroidogenesis. Thus, the authors analyzed the complete blood count and the steroidomics profile in healthy, physically active young males and demonstrated that leukopoyetic and steroidal biomarkers in conjunction with classical endocrine biomarkers allow the accurate detection of the intake of micro-doses of recombinant GH.Al-Muraikhy et al. dissected the influence of age and high intensity endurance on the effect of aerobic exercise on the complement system. Using peripheral blood, they show that high endurance elite athletes exhibit lower levels of complement components C2, C3b/iC3b and adipsin, and this observation is age-independent.Al-Menhali et al. studied the proteomic responses of the heart to exercise training in mice by high resolution mass spectrometry. Proteomics analysis revealed specific changes in proteins involved in the respiratory electron transport chain and implicated in glutathione conjugation. These results represent a further step towards the full understanding of the molecular mechanisms underlying the beneficial effects of exercise on the heart.Al-Muraikhy et al. addressed the issue of biological aging and its correlation to alterations in the metabolic pathways, specifically characterizing the metabolic activity in relation to telomere length in elite soccer players.Lima et al. investigated whether whole blood in long-term storage and whole blood left over from standard hematological testing in short-term storage could be used for transcriptomic analysis, despite lacking RNA preservation; their result show that quantity, purity, and integrity were not significantly compromised from short- or long-term storage in blood storage tubes lacking RNA stabilization, indicating that transcriptomic analysis could be conducted using anti-doping samples collected or biobanked in absence of RNA preservation.Sellami et al. outlining the state of the art and the expected forthcoming developments of molecular big data and omics-disciplines in sports sciences.Finally, the first volume of this special research topic was closed by a perspective article by We thank all the Authors for the time and energy dedicated to the preparation and submission of the articles published in \u201cOMICS-based Approaches in Sport Research\u201d, and we look forward to welcome submissions of new articles for the second volume."}
+{"text": "The \"Law on Doctors of the People's Republic of China,\" which was officially implemented on March 1, 2022, emphasizes the requirements for rational drug use and the necessity for appropriate management of off-label drug use. The safety and ethical considerations related to off-label drug use are different in children than in adults. There is so far no management guideline for pediatric off-label use of drugs in China, and the applicability of foreign guidelines is limited. Establishing a localized evidence-based management guideline for pediatric off-label use of drugs to support the national legislation and clinical practice is of critical importance.We established a guideline working group, including experts from a broad range of disciplines and developed recommendations following the guidance of the World Health Organization Handbook and the Chinese Medical Association. The following themes were identified by questionnaires and expert interviews to be of great concern in the management of off-label drug use in children: general principles and characteristics of management of pediatric off-label drug use; establishment of expert committees; evidence evaluation; risk\u2013benefit assessment; informed consent; monitoring and assessment of the risk; and monitoring and patient education. Two rounds of Delphi surveys were organized to determine the final recommendations of this guideline. We graded the recommendations based on the body of evidence, referring to the evaluation tool of the Evidence-based management (EBMgt) and the Oxford Center for Evidence-Based Medicine: Level of Evidence (March 2009).We developed the first guideline for the management of pediatric off-label use of drugs in China.The guideline is to offer guidance for pediatricians, pharmacists, medical managers, policymakers, and primary care physicians on how to manage off-label drug use in pediatrics and to provide recommendations for Chinese healthcare policy in the future.The online version contains supplementary material available at 10.1186/s12887-022-03457-1. Off-label use refers to the use of drugs beyond the scope of the drug instructions and labels provided by the manufacturer and approved by the National Medical Products Administration of China . DiffereThis guideline was developed by the Chinese Society of Pediatric Clinical Pharmacology, the Chinese Medical Association, the National Clinical Medical Research Center for Child Health and Disease , and the Chinese GRADE Center. Methodological support was provided by the Chinese GRADE Center, the World Health Organization (WHO) Collaborating Center for Guideline Implementation and Knowledge Translation, and the Institute of Health Data Science, Lanzhou University. The guideline was launched on April 12, 2021, and finalized on December 24, 2021. The guideline followed the methodology proposed by WHO  and the Experts from a broad range of disciplines including pediatrics, pharmacy, management and health policy, and evidence-based medicine, as well as parents of children participated in the development of the guidelines. The participants were divided into the steering committee, a secretarial team, an evidence team, a consensus team, and an external review team. A full list of members is provided at the end of this article. All members completed a declaration of interest form and stated that they had no economic conflicts of interest directly relevant to this guideline.This guideline is registered at the International Practice Guideline Registry Platform (Registration no. IPGRP- 2021CN088). The guideline protocol is available on request from the registration platform.The target audience of this guideline includes pediatricians, pharmacists, medical managers, policymakers, and primary care physicians. The management population of the guideline is children and their guardians.The themes of this guideline were determined during one round of a questionnaire-based survey and two rounds of expert interviews. At the beginning, the working group identified 11 themes by analyzing published guidelines relevant to the topic and interviewing pharmaceutical specialists. Subsequently, we developed a questionnaire to evaluate the importance of these themes and ask suggestions for additional themes. Sixty-six themes were obtained through the feedback from the survey. After de-duplication, merging, and discussion with the consensus team meeting, eight themes were finally selected to be included.We performed a systematic literature search for each question through PubMed, Web of Science, Embase, China Biomedical Literature Database (CBM), WanFang Data, and China Knowledge Network database (CNKI) to identify literature published from inception to August 13, 2021. We used the search terms \"pediatric*\", \"paediatric*\", \"child*\", \"infant*\", \"adolescent*\", \"neonat*\", \"newborn*\", \"teen*\", \"off-label\", \"off label use*\", \"unlabeled use*\" and \"unlicensed medicines\"   combinedBased on the summary table of the available evidence for each theme and consideration of patients' preferences and values, fairness, and the implementation ability of the management measures, we drafted initial recommendations on off-label drug use for children. Two rounds of Delphi surveys on recommendations were then conducted on November 4, 2021, and November 8, 2021, respectively, and a total of 19 suggestions from experts were collected. Recommendations were considered to have reached a consensus when 80% of the voters agreed to the recommendation.The secretariat prepared the first version of the guideline in accordance with the RIGHT checklist and sent the full text to the external review committee. All opinions and recommendations of the review committee were taken into consideration in the revision and creation of the final draft of the guideline.This guideline is planned to be updated within three to five years based on emerging relevant evidence, following the Reporting Items for Updated Clinical Guidelines: Checklist for the Reporting of Updated Guidelines (CheckUp ) checkliThe guideline entitled \"Management Guideline for the Off-label Use of Drugs in China 2021)\" focuses on the definition of off-label use of drugs, evidence grading standards, management of informed consent, monitoring of adverse drug reactions and adverse events, main responsibilities of hospitals and manufacturers, conditions for reimbursement by social health insurance, and the national approval system, resulting in recommendations in nine thematic areas  of health care workers did not follow the \u201cExpert Consensus on Off-label drugs in pediatrics in China\u201d guidance document, with 52.6% of the reasons being \"no expert group on off-label use\" .To ensure the rationality of off-label use of drugs to treat children, the process of protocol development and safety monitoring requires the discussion and collaboration of experts from various disciplines, including pediatricians, pharmacists, and nurses \u201317. In aGuidelines and consensus statements on the management of off-label use of drugs for children from China and abroad emphasize that off-label drug use should be evidence-based. Most clinicians, however, lack the necessary skills and time to conduct systematic reviews of existing evidence . EvaluatClinical experts in the corresponding diseases.Non-clinical experts in medical technology, such as professionals in clinical testing, pathology, imaging, or ultrasound.Experts in the field of essential medicine, such as biologists and pharmacologists. In complex clinical cases involving, the expert committee can be expanded if the expertise of the regular committee does not cover all aspects related to the actual situation of the patient. Under the principles of individualized medical model and precision medicine, we suggest that the expert groups should be expanded on a case-by-case basis to include non-clinical medical technologists and basic medicine specialists when discussing off-label treatment of children who have comorbidities or need to take multiple drugs off-label at the same time. For example, we suggest including microbiologists for questions regarding the off-label use of drugs to treat infectious diseases; and radiologists for questions related to ultrasound and MRI contrast agents in children.Formulating and regularly updating the list of drugs commonly used off-label for children in their respective medical institution;Participate in consultations for off-label drug use in children;Promptly release data on serious adverse events or adverse reactions(ADRs) related to off-label drug use. Evidence from adults can be used as indirect evidence;In the lack of high-quality pediatric clinical evidence, an extrapolation of evidence from adult trials can help mitigate the impact of limitations caused by insufficient sample size, disruption of equilibrium, and heterogeneity in pediatric clinical trials . Both thWe suggest assessing the evidence by systematic reviews in cases when there are not yet any approved indications for children, but there is evidence for both adults (in China) and children (anywhere).When there exists evidence only from Chinese adults evidence and no high-quality evidence is available for the pediatric population, we suggest using these findings with caution. A comprehensive analysis of all available information and data is required prior to use, including differences in organ function in specific age groups, the impact on pharmacological characteristics, knowledge of the disease, epidemiological conditions, non-clinical trial data, pharmacokinetics (PK), pharmacodynamics (PD), clinical effectiveness, and safety differences between adult and pediatric populations for drugs with the same or similar mechanism.Evidence from similar diseases in children can be used as indirect evidence;Evidence from pharmacokinetic or pharmacodynamic equivalency modeling studies on pediatric populations can be used as indirect evidence.Evidence from similar diseases may need to be considered for some specific types of disease, such as rare diseases in children , 30 or pIt is not suitable to adopt the adult dose directly for children based on the child's age and weight alone . InsteadBenefit and risk assessment is an appropriate method to judge the rationality of off-label drug use , 5. In rThe severe shortage of drugs for neonates is a worldwide problem , 40, maiCompared with adults, assessing the benefit-risk of off-label use of drugs in children is more complicated . BecauseInformed consent is a crucial tool for doctors and patients to defend their legitimate rights and interests. Although children have a limited ability to estimate risks, signing informed permission is vital for children's mental health and treatment participation. Article 19 of the Civil Code of the People's Republic of China  stipulatEvidence-based drug databases and drug directories, such as the Micromedex Pharmaceutical Database, the British National Formulary for Children (BNF-c) , the DutCurrently, awareness on the principles of adequate off-label drug use is poor among clinicians . For halThe World Health Organization  categoriCurrently, adverse drug response events are being monitored and reported through the National Adverse Drug Reaction Database of the State Drug Administration in China . HoweverWhile clinicians, pharmacists, and nurses should individually assess the risk of children taking off-label drugs during the process of monitoring adverse drug reactions, we suggest seeking help from parents or guardians of children, especially of children who are incapable of autonomous behavior , 72.Pediatricians should consider whether or not their child patients have the ability to be independent during drug education. 83.5% of medical working groups believed that the family members or guardians of children should be informed when they use off-label drugs . As a reComprehensive drug education is essential to the safety of off-label use of drugs for children. For example, for children and adolescents who use psychotropic drugs beyond the label, a list of information on overdose drug instructions is required . The druEffective drug education enhances doctor-patient communication, promotes public knowledge of safe drug use, and reduces misunderstanding-related doctor-patient confrontations , 81. BecAlthough the guideline is the first Chinese evidence-based guideline for the management of pediatric off-label use of drugs, there were certain difficulties in the application of evidence-based methodology in the area of health care. Because of the diversity and heterogeneity of the types of research on each topic, we were unable to produce systematic reviews of evidence.Off-label use of drugs in children is common globally, also in China. This guideline provides 21 recommendations grouped into 8 themes and a list of evidence on the common types of off-label use of drugs in children, in order to assist the management of pediatricians, pharmacists, medical managers, policymakers, and primary care physicians on off-label use of drugs in pediatrics, as well as provide recommendations for future healthcare policies in China.Additional file 1: Supplementary 1. Management Guideline for the Off-label Use of Drugs in China (2021).\u00a0Supplementary\u00a02.\u00a0A list of common types pediatric off-label use of drugs, evidence levels, and recommendations."}
+{"text": "Empoasca onukii and Trialeurodes vaporariorum. Ecological shading significantly affected the composition of soil microbial communities in tea plantations, in which WS significantly reduced the diversity of soil microorganisms.Ecological shading fueled by maize intercropping in tea plantations can improve tea quality and flavor, and efficiently control the population occurrence of main insect pests. In this study, tea plants were intercropped with maize in two planting directions from east to west ) and from north to south  and west shading (WS)) to form ecological shading, and the effects on tea quality, and the population occurrence and community diversity of insect pests and soil microbes were studied. When compared with the non-shading control, the tea foliar nutrition contents of free fatty acids have been significantly affected by the ecological shading. SS, ES, and WS all significantly increased the foliar content of theanine and caffeine and the catechin quality index in the leaves of tea plants, simultaneously significantly reducing the foliar content of total polyphenols and the phenol/ammonia ratio. Moreover, ES and WS both significantly reduced the population occurrences of  Camellia sinensis (L.), is a subtropical perennial evergreen crop, and it is one of the main cash crops in China /EGC (%) \u00d7 100  . The pheEmpoasca onukii and Trialeurodes vaporariorum, as being the main insect pests in the tea plantation, were selected to assess the effects of ecological shading by intercropping maize on the population occurrences of insect pests. Moreover, the Shannon\u2013Wiener index (H), Pielou evenness index (E), Margalef richness index (D) and Simpson dominance index (C) of the insect community were calculated based on the species and numbers of sampled insects on tea plants. The formulas are as follows:The field investigation was conducted every 10 days after the intercropped maize plants were taller in height than tea plants, i.e., from the last ten days of July to the last ten days of October in 2019 and 2020, respectively. Three tea plants were randomly selected for each treatment of the ecological shading  and its respective control (WECK for ES and WS and SSCK for SS) to count the number of insects, and the species of collected insects were also identified and classified. Cameras, insect nets, and suction-implements were used as methods of insect collection and statistics. In this experiment, two key insect pests, Shannon\u2013Wiener diversity index:Pielou evenness index:Margalef richness index: Simpson dominance index:iP: relative abundance of insect species i; iN: number of individuals for species i; N: the total number of individuals of all species in the community; S: the number of species in the community; Hmax: Maximum species diversity index.Chao1 index, Shannon\u2013Wiener diversity index (H), Pielou evenness index (E), and Simpson dominance index (C). The latter three formulas were same as in Chao1 = S + F12/2F2), F1 and F2 are the count of singletons and doubletons, respectively.On 2 October 2020, three sampling sites were randomly selected in each treatment of ES, WS, SS, WECK and SSCK, and the surface soil (depth: 0\u201320 cm) near the tea tree plants was collected. The collected soil samples were sent to Shanghai Personal Biotechnology Co., Ltd. for the 16S rRNA gene sequencing study. Initial screening was performed on the original off-board data of high-throughput sequencing based on sequence quality and retested the problem samples. The library and samples were divided according to the index and barcode information of the original sequence of an initial quality screening, and then the barcode sequence was removed. We performed sequence denoising or operational taxonomic units (OTUs) clustering, according to the QIIME2 DADA2 analysis process or V-search software analysis process. The specific composition of each sample (group) at different taxonomic levels was displayed to understand the overall situation. In order to compare the differences in microbial composition among the samples and display the distribution trend of species abundance of each sample, a heat map was used for species\u2019 composition analysis. The heat map was drawn using abundance data from the top 20 genera with an average abundance. The horizontal and vertical coordinates of the heat map plotted the clustering tree ordering according to the correlation between the samples, i.e., plotted the clustering heat map. The diversity indices of soil microbial communities for different samples were counted, including the E. onukii and T. vaporariorum, and the dynamic values of the community diversity indexes  for the insects in the tea plantations. Additionally, one-way ANOVAs were used to analyze the effects of ecological shading treatment on the diversity indices of soil microbial communities in the tea plantation. Furthermore, the significant differences between/among treatments were analyzed by the LSD test or t-test at p < 0.05.SPSS 25.0  and GraphPad Prism 7  were used for the statistical analysis. The latter was used for making line and column charts. A two-way repeated measures ANOVA was used to analyze the effects of sampling year (2019 vs. 2020), ecological shading treatment  and their interaction (with sampling time as repeated measures) on the measured indexes of foliar soluble nutrients, functional components and quality indexes of the tea leaves, the population dynamics  of the key species of The ecological shading treatment and sampling year both had significant effects on the foliar contents of soluble sugars and free fatty acids, while it had no significant effect on the foliar content of the soluble protein in tea plants . When coThere were no significant differences in the contents of the foliar soluble nutrients of the tea plants among the three ecological shading treatments of SS, ES and WS . AdditioEcological shading treatment, sampling year and their interaction had significant effects on the foliar contents of the functional components  of tea plants. When compared with the respective control no-shading treatment , the ecological shading treatments of SS, ES and WS significantly reduced the foliar content of polyphenols, and significantly enhanced the foliar contents of caffeine and theanine in the tea plants .The foliar polyphenol content of the tea plants in the control no-shading treatment of EWCK was significantly higher than that in the control no-shading treatment of SSCK, and the trend was just opposite for the foliar theanine content, while there was no significant difference in the foliar caffeine content of tea plants between the two control no-shading treatments of SSCK and EWCK . MoreoveEcological shading treatment, sampling year and their interactions had significant effects on the leaf quality indexes  of tea plants, except for the effect of sampling years on the phenol/ammonia ratio of tea leaves. When compared with the respective control no-shading treatment (SSCK or EWCK), the ecological shading treatments of SS, ES and WS significantly increased the catechin quality index, and significantly decreased the phenol/ammonia ratio in the leaves of the tea plants . MoreoveT. vaporariorum and E. onukii on tea plants, except for the effect of sampling year on the population dynamics of E. onukii fed on tea plants. When compared with their respective control no-shading treatment (SSCK or EWCK), the ecological shading treatments of ES and WS significantly reduced the population dynamics of T. vaporariorum and E. onukii on tea plants, while the ecological shading treatment of SS significantly increased the population dynamics of T. vaporariorum on tea plants . Additionally, the ecological shading treatment significantly influenced the values of the Margalef richness index (D), and the sampling year significantly impacted the values of the Simpson dominance index (C), describing the insect community in tea plantation , and the ecological shading treatments of ES and WS both significantly increased the value of the Margalef richness index (D) of the insect community in the tea plantation (H), describing the insect community in the ecological shading treatment of ES, was significantly higher than that in the ecological shading treatment of SS (When compared with their respective control no-shading treatment (SSCK or EWCK), the ecological shading treatments of ES significantly enhanced the value of the Shannon\u2013Wiener index , and Acidothermus, Acidibacter, AD3, Subgroup_2, WPS-2 and IMCC26256 were the six dominant bacterial genera , Pielou evenness index (E) and Simpson dominance index (C)) in the tea plantation , Pielou evenness index (E) and Simpson dominance index (C) of the soil microbial microorganisms, while the ecological shading treatments of SS and ES did not significantly affect the community diversity indexes of the soil microbial microorganisms in the tea plantation (H), Pielou evenness index (E) and Simpson dominance index (C) of the soil microbial microorganisms in the control no-shading treatment of EWCK were significantly higher than those in the control no-shading treatment of SSCK , Pielou evenness index (E) and Simpson dominance index (C) of the soil microbial microorganisms in the ecological shading treatment of ES were significantly higher than those in the ecological shading treatments of SS and WS, and these three community diversity indexes of soil microbial microorganisms in the ecological shading treatment of SS were significantly higher than those in the ecological shading treatment of WS  in the shade treatments (ES and WS) decreased and the insect diversity index increased. It is speculated that the shading effect of maize might have caused the changes of the content of secondary metabolites in tea leaves, and indirectly affected the occurrence of pests. Studies have shown that secondary metabolites affect insects\u2019 food selection, feeding and utilization, and thus affect insects\u2019 growth, behavior, and population biology [A large number of studies have found that the incidence of plant diseases and insect pests in the compound cultivation mode of tea plantation was relatively mild . When cobaccarum . Our fin biology . Prior s biology ,40,41. OSoil microbes decompose organic matter, participate in soil nutrient cycling and plant nutrient supply, and the composition of their community structure is a major indicator for assessing soil quality and fertility . Some scProteobacteria, Acidobacteria, and Actinobacteria were the relatively large microflora in farmland soil, and intercropping had an effect on their proportion in the community. In this experiment, the ecological shading of maize affected the composition and distribution of the soil microbial community.The results of this experiment showed that the Chao1 index, Shannon\u2013Wiener index, Pielou evenness index and Simpson dominance index of soil microbial community were decreased by the western shading of maize, i.e., the richness, diversity, evenness and dominance of the soil microbial community were decreased. It must be mentioned that the shade was the most intuitive feeling for people when intercropping with corn in tea plantation. However, the causes for the changes of tea detection indexes and quality were closely related to the changes in the soil microbial structure and field temperature, the occurrence of plant diseases and insect pests, and the changes of tea garden biodiversity after the shade formation. The changes in tea quality were the combined result of shading, pest reduction and changes in soil structure. This is an important point in pastoral landscape design: it is not a separate existence but a mutual influence. Agroforestry combines the use of trees with annual crops or fodder plants on the same piece of land that build up synergies, which leads to a higher resilience and allows crops to maintain long-term productivity .The effects of the ecological shading formed by intercropping maize on tea foliar soluble nutrients, foliar functional components, quality indicators, insect occurrence in tea plantation, and soil microbial diversity were summarized from different planting directions \u00a0Table A2"}
+{"text": "Data was collected using a structured questionnaire and analyzed with Microsoft Excel software.one hundred and fifty-one (151) health facilities with a total bed capacity of 3089 were enrolled into the study. Overall, the least prepared infection prevention and control, water and sanitation core components in ascending order were the coordination committee structure (13.19%), guidelines and SOPs (21.85%), vector control (22.02%), staff management (30.63%), and training received (33.64%). The best prepared components in descending order were integrated disease surveillance and response capacity (69.83%), medical waste management system (57.12%) and infrastructure compliance (54.69%).the findings of this study which is comparable to those of other studies in similar settings validates the perception that Infection Prevention and Control/Water, Sanitation, and Hygiene (IPC/WASH) capacity and readiness is inadequate in South Sudan. To scale up these core components, we recommend development and implementation of a comprehensive and long-term infection prevention and control strategic plan as part of the country\u2019s broader health sector recovery planning. Infection Prevention and Control (IPC) is aimed at preventing avoidable infection of patients and healthcare workers at health facility and community levels . It is aWater, Sanitation, and Hygiene (WASH) plays an essential role in IPC, particularly in healthcare settings. Infection prevention and control and WASH are two sides of the same coin; thus, safe WASH contributes to enhanced IPC, patient, and health workers\u00b4 safety, and vice versa . A robusSouth Sudan experiences recurrent incidents of emergencies regularly; a significant number of these emergencies are outbreaks of infectious diseases which often results in high morbidity and mortality. The country\u2019s southern parts sit in the ecological zone of the EVD and yellow fever, which is contiguous with the same zone in neighboring Democratic Republic of Congo (DRC) and Uganda . The couSouth Sudan scaled up IPC/WASH interventions due to the increasing threats of disease outbreaks, however, there is a paucity of reliable data on the status of IPC/WASH interventions in the country. This is a major constraint to evidence-based prioritization, planning, implementation and monitoring of IPC/WASH interventions. Thus, IPC interventions are often ad-hoc rather than proactive and systematic. Furthermore, the technical knowledge and capacities of national and international agencies involved in implementing IPC/WASH interventions in the country are often weak, affecting both the quantity and quality of interventions. Given the exposure of South Sudan to threats of cross border importation of EVD, recurrent outbreaks of infectious diseases and the ongoing COVID-19 outbreak, which require effective IPC/WASH interventions for prevention and control, the importance of having reliable data for evidence-based planning, implementation and monitoring of interventions cannot be overemphasized. An IPC/WASH study was thus conducted in selected health care facilities in the country.The objective of the study were to assess the readiness and capacity of the core components of IPC/WASH in health facilities to effectively respond to and contain potential outbreaks of EVD and control the ongoing COVID-19 outbreak in the country and to establish baseline information for planning, implementation, supervision, monitoring, and evaluation of short- and long-term IPC/WASH interventions. The study also sought to raise awareness about and provide evidence for advocating for more investments in IPC/WASH in the country. In this research article, we present and discuss the key findings, conclusions, and recommendations of the study.Study design and sampling method: a descriptive cross-sectional study on the capacity and readiness of the core components of IPC/WASH to respond to infectious disease outbreaks was conducted in health facilities in six high-risk States of South Sudan from February 2020 to December 2021. The three Equatoria States were initially enrolled into the study in 2020. With the report of the first case of COVID-19 in the country on April 5, 2021 and subsequent declaration of an outbreak, three more States, namely, Western Bahr el Ghazal, Lakes and Jonglei, classified as high risk for both EVD and COVID-19 transmission, were enrolled into the study. A purposive sampling method was used to identify between 14 to 16 health facilities per State. Inclusion criteria were any operational health facility with permanent structures and at least two or more healthcare workers.Study setting: South Sudan, a country experiencing a chronic humanitarian crisis, is bordered by Uganda in the South, DRC in the South West, Central Africa Republic in the West, Sudan in the North, Ethiopia in the East and Kenya in the Southeast. These borders are porous with free population movements between the neighboring countries for economic and sociocultural reasons. The country has a 2021 population of 11.4 million and landmass of 619,745 km2 [(Annex 1) adapted from the WHO guidelines on core components of IPC programmes at the national and acute health care facility levels [Data collection: quantitative data was collected using a structured questionnaire y levels  and Watey levels  both of Data analyses: the data was cleaned, entered and analyzed with Microsoft Excel software. Twelve indicators identified based on expert consensus were analyzed . The aveEthical clearance and approval: administrative clearance for this study was provided by the Ministry of Health of South Sudan. World Health Organization provided the ethical clearance (WHO e-Pub no: ePub-IP-00331783-EC).One hundred and fifty-one (151) health facilities with a total bed capacity of 3089 in six States were enrolled into the study. Almost half (49%) of the surveyed health facilities were PHCCs while the rest were PHCUs (25%) and hospitals (14.51%) . WesternThis study sought to establish the capacity and readiness of the core components of IPC/WASH in health facilities to prepare for and respond to disease outbreaks and enhance the safety of patients and health workers in South Sudan. To the best of our knowledge which is based on an exhaustive literature review, it is the first documented study that comprehensively assessed the status of IPC/WASH in health facilities in the country thus, its findings will form the baseline for planning, supervision, monitoring, and evaluation of IPC/WASH interventions moving forward. The findings showed a lack of readiness of most IPC/WASH components to prevent disease outbreaks except for IDSR capacity, infrastructure compliance and medical waste management system. There was a generally poor readiness of IPC/WASH committee structure, vector control and IPC/WASH supplies components across most of the study area. The study showed weak IPC readiness in the three Equatoria States which had the highest risk for EVD transmission.et al. in their study of IPC in eight conflict-affected countries [et al. and Fofanah et al. in Sierra Leone [et al. in Liberia [The general lack of readiness of most IPC/WASH components that were observed in this study is similar to the findings of Lowe ountries  and thosra Leone ,24. Thisra Leone . Likewis Liberia .et al. and Forrester et al. in their assessment of IPC in Liberia [The high scores observed in the IDSR capacity, infrastructure compliance and medical waste management system components may be associated with ongoing health interventions before and during the study period. As part of efforts to respond to the chronic humanitarian crisis in the country, humanitarian partners led by WHO made massive investments in an Early Warning Alert and Response System (EWARS) to address the need for good quality and real-time data for timely detection and response to epidemics. The EWARS built a foundation for improving disease surveillance which resulted in significant improvements in IDSR capacity all over the country . Similar Liberia ,29.et al. which showed that low income countries were less likely to have functional IPC/WASH programmes [et al. in Sierra Leone [The IPC/WASH committee structure which requires minimum funding and efforts to implement was the weakest among all the IPC/WASH components which is corroborated by the findings of Tartari ogrammes . This fira Leone . Inadequet al. [The below average score observed in the vector control component across all the States points to gaps in the malaria control programme, which is primarily responsible for this component hence the need for strengthening the national malaria prevention and control programmes and ensuring greater coordination and collaboration between it and the the IPC/WASH programme at all levels. Although similar to the findings of another study conducted in Uganda , the belet al. .Limitations: the above findings should be interpreted within the context of three key limitations. Only six and seven health facilities were sampled in Jonglei and Lakes States due to access constraint. Given this small sample size, the findings in both States may not be a true reflection of the IPC/WASH readiness. The purposive sampling method used may have resulted in selection bias in which the more readily accessible and possibly the most functional and good performing health facilities were selected. Lastly, the involvement of some Ministry of Health IPC/WASH officials in the data collection process may have introduced interviewer bias. The data collectors may have focused on their predetermined perceptions which may affect their assessment of the various components of IPC/WASH. This bias was addressed by rigorous screening, selection, training and supervision of the data collectors and physical verification of the responses.The findings of this study which is comparable to those of other studies in similar settings validates the perception that IPC/WASH capacity and readiness is inadequate in South Sudan. This observation is confounded by the fact that the massive IPC/WASH investments made during the EVD preparedness programme of 2018 to 2020 and the ongoing COVID-19 response programme seem not to have yielded the anticipated outcomes. The inadequate capacity and readiness of the IPC/WASH programme observed in this study are mainly due to the chronically weak health system, lack of a comprehensive national IPC/WASH strategy and inadequate knowledge and funding of IPC/WASH interventions in the country. Other factors include weak capacity for IPC/WASH planning, implementation, supervision, monitoring and evaluation in the country. Furthermore, most of the international IPC/WASH norms and standards may not be realistic in view of the peculiar context of South Sudan.Moving forward, we propose four main recommendations based on our findings. First, the results of this study should be used to develop and implement a long-term IPC/WASH strategic plan for the country as part of the broader health sector strategic, health system recovery and annual humanitarian response planning. This strategic plan should have a clear monitoring and evaluation framework based on the baseline established by this study and should be actualized through annual IPC/WASH operational plans. Second, the study results should be used to scale up advocacy and resources mobilization for IPC/WASH in the country. Third, international IPC/WASH norms, standards and guidelines should be adapted to suit the South Sudan context. For instance, it may be practically impossible to constitute IPC/WASH committees in every health facilities due to inadequate staffing hence the need to innovate. Fourth, establishment of national and State level platforms for IPC/WASH coordination is critical to coordinate and monitor progress.Infection prevention and control/water, sanitation, and hygiene (IPC/WASH) is a critical component of outbreak preparedness, response, prevention and control in humanitarian settings such as South Sudan;There is inadequate evidence-based information for the planning, implementation, supervision, monitoring and evaluation of IPC/WASH interventions in the country;Despite the exposure of the country to threats of disease outbreaks, the readiness of the IPC/WASH programme to adequately respond to these outbreaks is unknown.This study identifies the key gaps in the readiness and capacity of IPC/WASH programme in the country to prevent and control diseases outbreaks;The study further provides baseline information for future planning, supervision, monitoring and evaluation of IPC/WASH interventions at health facility level."}
+{"text": "The current ecosystem services of karst protected areas cannot fully enhance human well-being, and the value of eco-products cannot be effectively realized. Research on eco-products and ecological civilization is conducive to the regional sustainability. The results of a statistical analysis of 258 related articles indicate: (1) the number of published articles has increased rapidly after slow growth, indicating that this research field has become a research hotspot and has broad research prospects; (2) the research content mainly involves five aspects, such as eco-product supply, eco-product value realization, eco-industry, ecological civilization, and monitoring and evaluation; (3) the articles research area is mainly distributed in the karst areas with a fragile ecological environment in China and the eco-product value realization and ecological civilization pilot areas; (4) the research frontiers are revealed from four aspects of eco-product supply ability, eco-product value realization, the driving force of eco-product value realization on the formation of eco-industry, model and effectiveness of ecological civilization; (5) it is necessary to deepen the research on the improvement mechanism of eco-product supply capacity, the classification systems and value accounting standards of eco-products, the formation mechanism of eco-industries under ecological threshold constraints and the driving mechanism of eco-industry to ecological civilization. The 2030 Agenda for Sustainable Development, adopted at the 70th session of the United Nations General Assembly, marks the beginning of a new era for humanity to move toward a sustainable society . Ecologi2, accounting for about 15% of the land area [The distribution area of modern carbonate rocks in the world reaches 22 million kmand area , affectiand area ,14. Karsand area .In March 2022, the Convention on Biological Diversity (CBD) proposed to expand the coverage of protected areas under the global biodiversity framework, and it is planned that the total area of protected areas will reach 30% of the global land area by 2030 . The proThe construction of ecological civilization in karst protected areas is an important measure to protect the eco-environment of karst protected areas and enhance the well-being of karst communities. How to effectively realize the value of eco-products has become a hot issue of common concern for governments and scholars. The purpose of research on eco-product value realization is to solve the externality problem in supply and protect the functionality and integrity of ecosystems , and theScholars have three main understandings on the connotation of ecological products. The first view equates eco-products with ecosystem services, and believes that they are the well-being that natural ecosystems provide to humans ,21. The https://www.webofscience.com), Foreign Journal Resource Service System (http://fpd.juhe.com.cn/) and China National Knowledge Infrastructure (CNKI) (https://www.cnki.net/). The searching date was on 12 November 2021. To identify relevant studies, a search was conducted based on the platforms including Web of Science (WOS) , Linbo Zhang (5), Yihong Zhou (5), Weiming Li (5), Shuilin Qiu (4), Hongxing Zhang (4), Zhiyun Ouyang (4), Huiyi Yu (4), Shuzhong Gu (4) and Jinnan Wang (3). When calculating the number of published articles by authors, all authors in the articles were accounted regardless of the author\u2019s order.In 1990, ecological civilization was first systematically proposed in Ecological Awareness and Ecological Civilization . In 2005The contents of the articles are shown in We conducted an interpretation and analysis of the distribution of organizations by using the occurrence frequency of each institution of related articles as the basis, and then sorted them from high to low. The statistical results show that the studies are mainly distributed in the following three types of research institutions. (1) Institutions that have long been engaged in the related research on ecological civilization and sustainable economic development, and have good relevant research foundation and experience, such as: the Chinese Academy of Natural Resources Economics, Environmental Planning Institute of the Ministry of Ecology and Environment and Development Research Center of the State Council. (2) Institutions in finance and resources directly related to the subject of the research, such as Lanzhou University of Finance and Economics, Central University of Finance and Economics and Hebei University of Economics and Business. (3) Institutions in the areas where the national eco-product value realization mechanism pilots are located, such as: Shandong University, Zhejiang University and Lishui College. Moreover, senior colleges and universities with majors related to agriculture and forestry are also the main camp of research institution articles with related studies, such as China Agricultural University and Beijing Forestry University, Renmin University of China. In general, research foundation and experience, professional connection and geographical advantages are the main factors affecting the distribution of articles research institutions.The \u201cmeta-rule\u201d of territorial spatial planning is the preservation and appreciation of natural resources . At the Ecological design and product full-cycle environmental management have become important links in the research and development of eco-products. To quantitatively evaluate eco-product design, Ng  proposedThe environmental cost in the process of economic development has caused a prominent contradiction between the supply and demand of eco-products. It is urgent for us to improve the ecological environment, increase the total supply of eco-products and enhance the supply capacity . The supThe core of expanding consumption demand of eco-products is to coordinately promote the whole of society to form ecological values, green lifestyles and green consumption models . The useThe calculation method of eco-product value usually adopts the calculation method of ecosystem service value, which is divided into two stages of functional volume accounting  and monetary value volume accounting according to the studies by Daily et al. and Ouyang et al. ,38,39. UEcological banks such as forest banks, wetland banks and water banks are new platforms for value realization. These ecological banks can promote the capitalization and make eco-products become productive forces. So, they can change resources into assets. The operation process of ecological banks includes resource investigation, project planning, value evaluation, circulation reserve and operation . These eEco-products have diverse and complex characteristics, so the value realization paths are also different. The property rights of purely public eco-products (such as clean water) are common. The economic value of them, which is difficult to realize through market transactions, mainly relies on governmental paths. Value payments of them are in the form of transfer payments, ecological compensation  and specEntering the era of ecological civilization, the classical division of labor among the three industries can no longer meet the needs of industrial development in the era of ecological civilization. Ye and Han  proposedEco-resources must be fully relied on to realize ecological industrialization, and regional characteristics must be found to promote industrial ecologicalization . Both ecThe eco-industry chain of protected areas is the input\u2013output relationship of material, value and information. Based on the input\u2013output perspective of eco-products, the eco-industry chain structure model includes four links: the eco-product industry chain, the derivative industry chain, the product demand market and the supporting industry chain . The heaDue to the differences in natural and socio-economic resource endowments, the specific models and paths for ecological civilization vary from place to place. Bao  believesThe development level of ecological civilization is usually measured by eco-efficiency , ecologiThe contradiction between the supply shortage of eco-products and the demand for high-quality eco-products has become increasingly prominent . It is uFrom the perspective of eco-product value formation, the biological and physical structure of the ecosystem and the process of material, energy and information flow form the ecosystem functional units. Each functional unit ensures the supply of ecological material products and ecological service products. Under certain conditions, when material products and service products of the ecosystem meet human needs, the monetization value assessment can be conducted. Coupled with the design of a reasonable transaction mechanism, the value of eco-products can be realized . TherefoKarst protected areas should analyze the particularity of consumers\u2019 demand for eco-products under the influence of karst culture on the premise of understanding the impact of karst fragmented landscape pattern and dual structure on ecosystem functions, and then clarify the mechanism for improving the supply capacity of karst eco-protection products.Scholars have different views on the concept and classification of eco-products. Due to the differences in the concept of eco-products, the classification systems and value accounting standards of eco-products are also different, which directly affects the accuracy and comparability of the value accounting, and hinders the process of value realization. Many scholars directly use Gross Ecosystem Product (GEP) to calculate the value of eco-products, and include agricultural products, forestry products, animal husbandry products and fishery products into eco-products ,56. GEP With rapid economic and social development, many protected areas are facing the dual pressure of eco-protection and economic development. Eco-industries give full play to the advantages of natural resources and economic resources have strong survival, expansion and competitiveness. It is necessary to establish a coupling model between ecological carrying capacity and eco-industries, and clarify the interaction between the two. The ecological control mechanism for the formation and optimization of eco-industries is also important. The first is to analyze the unique attributes of karst protected areas, improve the accounting indicators and methods of GEP and calculate the functional and monetary value of karst eco-products. The second is to collect and optimize the fragmented management rights and use rights of eco-resources, expand the paths for value realization and explore the value-added mechanism of eco-products. The third is to build trading systems including eco-products certification system, clarify the driving factors for the formation of eco-industries, optimize the industrial structure and clarify the formation mechanism of the eco-industries.In the critical period when human society is entering the ecological epoch and realizing the improvement of ecological environment quality from quantitative change to qualitative change, the important position of eco-industries in strongly promoting ecological civilization is becoming increasingly more prominent . Due to For example, based on ecological industrialization of karst reserves and industry ecologicalization of buffer zones, the driving mechanism for ecological industries extension on the eco-economic system is to be explored. Based on eco-cultural gene mapping, eco-brand culture shaping and ecological value enhancement, the driving mechanism for ecological culture inheritance on the eco-cultural system is to be elucidated. The driving mechanism for the multi-subject participation of eco-industry management on the eco-responsibility system is to be revealed. The driving mechanism for trade-offs, synergies and compensation of eco-industrial benefit distribution to the eco-system is to be clarified. The inner logic for the five systems of ecological civilization is to be analyzed, the driving framework for eco-industries to the eco-security system can be conducted and the driving mechanism for eco-pattern formation to the eco-security system can be proposed.In this paper, we conducted a systematic literature review by analyzing 258 articles retrieved from the Web of Science, CNKI and Foreign Journal Resource Service System of Guizhou Normal University Library. The main conclusions are as follows: (1) studies on eco-protection product value realization and ecological civilization are increasing rapidly, showing a broad research prospect; (2) among the studies on eco-product supply, value realization, eco-industry, ecological civilization and monitoring and evaluation, the studies on eco-product value realization are most common, mainly focusing on mechanisms and paths for value realization; (3) the related research has mainly been conducted in China. After analyzing the main developments and landmark achievements, the paper proposed four scientific issues to be addressed.The reasons for more literature written in the Chinese language than in English may be as follows: (1) the concept of ecological products has been put forward in China by the Chinese, and some pilot projects in China have formed models that are worth learning from; (2) international scholars use the concept of ecosystem services more than ecological products. The eco-products related academic research is still in the exploratory stage. Some scholars even confuse the concepts of eco-products and ecosystem service, believing that the two are the same.In fact, the two concepts are different. Ecosystem service has been widely studied internationally. The concept of eco-products was proposed based on ecosystem service, but is an extension to it. Ecosystem services emphasize the benefits of natural ecosystems to humans, while eco-products emphasize the human\u2013nature life community. Ecosystem service value emphasizes the value of ecology and arouses the awareness of human beings to protect nature and protect ecology. The value of eco-products emphasizes the value of products and services jointly created by man and nature, and emphasizes the value created by the behavior of human beings to protect and restore ecology.The future directions of eco-products and ecological civilization can be conducted based on the following aspects: (1) the mechanism of improving the supply capacity of eco-products based on eco-products (ecosystem structure and process) and the ecological market (consumer demand); (2) the classification systems and value accounting standards of eco-products; (3) the formation mechanism for ecological industries under the constraints of ecological thresholds based on the carrying capacity of ecosystems; (4) the driving mechanism for eco-industries on ecological civilization. These future research topics are especially suitable for protected areas, such as natural world heritage, geoparks, nature reserves and scenic spots, due to the high-grade eco-products in these areas.Through the study of the characteristics and supply of the ecosystem, the attributes of eco-products, the mechanism for improving supply capacity and the mechanism for value realization are clarified. The industrialization of eco-products produces eco-industries, which directly drives the construction of the eco-economic system and eco-cultural system, and then promotes the construction of the eco-institutional system and eco-responsibility system, thereby building the eco-security system and realizing the goal of ecological civilization.Ecological civilization acts on ecosystem supply through ecological protection and ecological restoration, and acts on ecosystem demand through ecological demand expansion. Through research on the formation mechanism for the eco-industry and the driving mechanism for eco-industry to ecological civilization, the model and paths of ecological civilization based on ecological protection can be conducted to provide the basis for the construction of ecological civilization and sustainability in karst protected areas."}
+{"text": "This editorial sets the scene for our Special Issue on the growing problem of sedentary behavior and physical inactivity in the Asia-Pacific region. In many societies, more than 40% of the adult population and growing numbers of children are insufficiently physically active to safeguard their health. This is contributing to high rates of cardiovascular disease, obesity, and other deleterious health outcomes across the region. The Asia-Pacific is heterogeneous and complex, with diverse social, cultural, and environmental barriers that affect intentions and opportunities for regular physical activity. Recently, the problem has been compounded by the acceleration of population aging, the worsening effects of anthropogenic climate change, and the ongoing COVID-19 pandemic. Without strong leadership, enduring funding support, and innovative interventions that cut across policy and society, we may yet be facing a century of unmitigated expansion of morbidity across the Asia-Pacific. Many adults and children across the Asia-Pacific region are not sufficiently physically active to support their health ,2. This Diverse factors are conspiring to reduce opportunity, time, and motivation for physical activity across the Asia-Pacific region. These include lack of appropriate and consistent infrastructure, inequities in access to sports facilities, poor work-life balance, changing modes of learning and leisure, COVID-19 pandemic restrictions, increasing risk aversion, and others ,12. At tThis Special Issue of the International Journal of Environmental Research and Public Health brings together cutting-edge research that explores a diversity of topics related to inactivity in the Asia-Pacific. The carefully curated selection includes manuscripts concerning reductions in children\u2019s play, later life activity declines, the rise of metabolic disease risk factors, unequal distribution of behavioral impacts associated with the ongoing COVID-19 pandemic, and other thought-provoking contributions. It is hoped that this Special Issue will inform ongoing debate and stimulate new research, policy, and interventions to promote higher levels of activity across the life course in this rapidly changing region.The Asia-Pacific region has several geographical definitions, which typically comprise over 50 nations across Oceania and the Pacific, South and South-east Asia, North-east Asia, and Central Asia. This region is arguably the most populous, rapidly aging, culturally diverse, and economically disparate area of the globe . This exConsiderable discrepancies have been reported in the measurement of physical activity across the Asia-Pacific region. This may be due to a lack of standardized measurement, which has been well documented in largescale review studies of regional data . Indeed,Mortality and morbidity data across the region also provide indirect evidence of deleterious lifestyle behaviors. For example, despite being highly preventable cardiovascular diseases (CVD) remain the leading cause of death  across the region . PacificThe regional problem of inactivity is potentially influenced by the mega-trends of population aging and anthropogenic climate change, which will define health and behavioral outcomes in many societies over the 21st century. Population aging refers to a demographic transition from a younger to an older age structure whereby growth in older adult cohorts significantly outpaces changes among cohorts of children and younger adults due to long-term reductions in fertility and increases in longevity . Across Beyond population changes, the progression of anthropogenic climate change is also likely to affect opportunities for physical activity at a population level. Anthropogenic climate change refers to long-term changes in temperature and weather patterns linked to human industrial activities and the burning of fossil fuels . The resThe ongoing COVID-19 pandemic has added to the challenge of regional inactivity in several ways. Enforced lockdowns, quarantine and self-isolation, home-based and online modes of work and learning, social distancing, cancellation of sport and group exercise, and the permanent closure of businesses serving recreational physical activity needs are some of the ways in which the pandemic has altered the regular behavior of children and adults across the region. At the time of writing, the world is entering the third year of the pandemic and a seventh wave of infection with no signs of abatement despite the wide availability of relatively effective vaccines and booster shots. The historic and lingering nature of this pandemic is leading to long-term changes in physical activity patterns at a population level. This has been shown in cross-national studies using objective activity (step count) data collected from smartphone accelerometry and GPS data . Such stPersistently high levels of physical inactivity in the Asia-Pacific region portend poorly for the management of obesity, cardiovascular disease, and other deleterious health conditions in the coming decades. Population aging, climate change, and the ongoing COVID-19 pandemic are adding to the current crisis of inactivity with no near-term solutions in sight for these emerging problems. In order to tackle this complex issue, interventions at multiple levels will be required, along with strong government leadership and enduring funding commitments. International and national guidelines for physical activity have been clearly established for decades based on a robust evidence base , and theThree areas for potential action that hold some promise for arresting activity declines include a renewed focus on school-based physical education, community interventions led by health professionals, and urban environmental remediation strategies. Across the Asia-Pacific, physical education programs that were once a staple of school and university life are being reduced or replaced with academic subjects at an alarming rate . The val"}
+{"text": "As an early warning strategy for coronavirus disease 2019 (COVID-19), environmental detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in wastewater was integrated into pandemic responses in Australia, Germany, New Zealand, the United Kingdom of Great Britain and Northern Ireland, and the United States of America.  is a pervasive global health concern, complicating treatment of infectious diseases and routine medical procedures. The Philippines has experienced increasing numbers of infections resistant to specific antibiotic combinations, for example, carbapenem resistance in New molecular diagnostic laboratories established for the detection of SARS-CoV-2 in the Philippines could be used for other emerging infectious diseases and, thus, contribute to improved resilience during future epidemics. This article discusses how the strengthened monitoring and surveillance capacity developed for SARS-CoV-2 in the Philippines provides opportunities for environmental surveillance of emerging infectious diseases and AMR.Environmental surveillance, specifically WWS, could be used as an adjunct to clinical and laboratory diagnosis of individuals for the detection of local outbreaks. Similar to clinical testing, WWS utilizes reverse transcription-quantitative polymerase chain reaction (RT-qPCR). .It is possible for WWS to detect and analyse chemical or biological compounds to understand the health status of communities. (The Philippines has recently increased its molecular laboratory testing capacity for SARS-CoV-2. The number of public and private sector laboratories with the ability to detect SARS-CoV-2 using polymerase chain reaction (PCR) increased from one in the first quarter of 2020 to 247 by the end of April 2022. , with RITM, can develop, implement and study the cost\u2013effectiveness of multidisciplinary WWS in the response to emerging infectious diseases.Bringing Filipino institutions and multidisciplinary professionals together with experience in environmental and clinical surveillance could be a starting point for a national One Health integrated surveillance system where clinical and environmental samples from human health systems, animal health systems, food systems and the environment can be analysed and correlated. This system could inform hygiene, sanitation and infection prevention strategies to reduce the risk of spreading AMR and infectious disease outbreaks of pandemic potential. A One Health integrated surveillance system could increase its reach by building on the growing capacity of Filipino medical technologists in the use of RT-qPCR as they handle more samples due to the surge of COVID-19 cases. Capacity building could also be supplemented by online training from experienced global researchers through today\u2019s communication technology. The Philippine Interagency Committee on Antimicrobial Resistance (ICAMR), established in 2014 and comprising the DOH, Department of Agriculture, Department of Science and Technology, Department of Interior and Local Government, and Department of Trade and Industry, could oversee the One Health integrated surveillance system, as the committee is already strengthening surveillance and laboratory capacity for AMR. (As epidemics continue to affect the Philippines, improved preparedness, response and resilience to emerging infectious diseases including AMR could be supplemented by a One Health integrated surveillance system. To implement such a system, the country would need to develop capacity in environmental surveillance, including WWS, making use of existing infrastructure and expertise while exploring possibilities for collaboration with global experts and international partners. National agencies and committees, such as the DOH, RITM and ICAMR, would have to take on responsibility for overseeing and leading this initiative. A multidisciplinary approach and the identification of relevant Philippine institutional partners would be needed to sustain this initiative and prepare for emerging infectious diseases and chronic health-system challenges."}
+{"text": "The utilization of crop straw biomass resources is highly emphasized by governments and academia in recent decades. Based on the core databases of the literature in China National Knowledge Infrastructure (CNKI) academic journals, CiteSpace software is used to analyze and process the hotspots, and this study proposed the primary coverage and evolutionary trends of research on the utilization of crop straw resources. The thesis proposes the research development trend for improving the institutional mechanism of the utilization of crop straw resources, strengthening technology research and development, exploring the economic model of green cycle agriculture, accelerating the construction of the industrial system, and designing new paths of resource utilization in multiple ways, which helps estimate the development trend of the utilization of crop straw resources and provide inspiration and direction for future research and practices. Straw feed processing methods mainly include straw bulking, ammonification, pellet feed, straw silage, straw compaction, and straw microstorage. The integration and optimization of the aforementioned technologies are effective means to promote the utilization of straw for feed. Technological progress is mainly achieved through the optimization of the main body, process, facilities, and auxiliary parts. .3) The SAt present, straw energy utilization modes mainly include straw to biogas, straw centralized gas supply, straw power generation, and straw solidification molding .The utilization of biomass to generate energy is an important source of energy in the future. There are various ways of energy utilization, but the utilization technology needs to be further explored. At present, the main modes of straw energy utilization include biogas production, straw-fired cogeneration, and densified corn stover briquetting fuel .4) Straw Raw Materialization and Base Materialization UtilizationPractice shows that the efficiency of straw-fired cogeneration is low while the cost is high . Current2 emissions and saving energy  The systems and mechanisms should be improved for using crop straw as resources. Under the leadership of the government, professional teams were organized to conduct in-depth research; the policy obstacles in the utilization of crop straw as resources were clarified, and targeted policies about financial support, technical assistance, incentive system, and performance assessment for the utilization of crop straw as resources were formulated.2) Research on the resourcization technique of crop straw should be strengthened. The backward technology of straw recycling results in high production costs and small scale of straw-consuming enterprises. Strengthening the technical level of straw industrial utilization is the most important task at present.3) It is necessary to adhere to the concept of carbon peak and carbon neutrality to explore the green circular agricultural economic model. Governments should promote the recycling of crop straws, especially the economical and intensive utilization of straw resources, and explore the suitable mode of green agriculture and recycling agriculture.4) The construction of an industrial system should be accelerated for the utilization of crop straw resources. Countries all over the world, especially developed countries, should guide the exploration of diversified industrial utilization of crop straw, such as fertilizer, energy, feed, and raw material. The straw resource utilization industrial system should be constructed to get rid of crop straw resource utilization of small scale and low benefit predicament.5) The utilization paths of crop straw are designed in diverse ways. In view of the needs of rural revitalization, beautiful countryside construction, and territorial space planning in the new era, a diversified design of the crop straw resource utilization path is carried out so as to explore a low-carbon and high-efficient regional straw resource utilization path tailored to local conditions.The implementation of a series of national strategies such as new countryside construction, beautiful countryside construction, territorial space planning and rural revitalization, efficient utilization of resources, ecological environment protection, and high-quality economic development has become the theme of China\u2019s development. Based on the analysis of the current predicament and research progress of crop straw resource utilization, the authors assume that more attention should be paid to the following area:The raw data supporting the conclusions of this manuscript will be made available by the authors, without undue reservation, to any qualified researcher."}
+{"text": "Semiconductor heterostructures form the basis of modern electronics and optoelectronics, and the study of physical phenomena in them, along with the development of technological methods for their manufacture, is actively carried out all over the world to ensure progress in the output parameters of devices. The most important trends in the development of semiconductor heterostructures are both the development of new systems of materials and the continuous decrease in the size of active regions of various types of heterostructures, including superlattices, quantum wells, and quantum dots, down to the nanometer level, corresponding to the thickness of few monolayers and even less . Technological methods for growing heterostructures are constantly being improved, and along with the study of self-organized heterostructures (such as quantum dots), methods are being developed for obtaining structures with an ordered complex surface topology. An important role in achieving the desired properties of heterostructures and developing new technological methods is played by the development of various analytical methods for studying the structural, optical, and electrophysical properties of quantum-sized heterostructures. Seven articles of this Special Issue reflect almost all of the above areas of research on semiconductor heterostructures.In this Special Issue, Davydov et al.  describe0.52Al0.48As/In0.53Ga0.47N quantum well structure with two quantum-confined electron states and two hole sub-bands. The properties of this structure were studied by measuring photoluminescence spectra in a wide temperature range (10\u2013300 K). The authors determined the energy position of localized states in such quantum wells using phenomenological analysis based on experimental measurements of the Fermi edge singularity and its analysis in terms of the line shape model with key physical parameters, such as the Fermi energy, the hole localization energy, and the band-to-band transition amplitude.In the next article, Ahn et al.  consider2 islands were used by Mintairov et al. [Measurements of the magneto-photoluminescence spectra of single-electron quasi two-dimensional InP/GaInPv et al.  to find The following articles of the Special Issue are devoted to solving various technological problems in the implementation of various semiconductor heterostructures for light-emitting devices and transistors.Novikov et al.  describeThe problems of selective growth of InGaAs quantum wells on GaAs substrates by metalorganic chemical vapor deposition were analyzed by Shamakhov et al. . They co18 cm\u22123 can be achieved in the p-GaN/AlN-IL/AlGaN structure.Dai et al.  describeIn the last article of this Special Issue , the autIn general, the Special Issue includes seven articles from different groups devoted to the study of the basic properties and technological peculiarities of various semiconductor heterostructures, including quantum wells, quantum dots, and superlattices, grown by metal\u2013organic vapor deposition or molecular beam epitaxy. These structures are designed to implement various devices, such as InGaAs semiconductor lasers, quantum electronics devices, high-power UVC emitters with electron beam pumping, Ge(Si) infra-red emitters, and various types of HEMT."}
+{"text": "For more than 40 years, under the leadership of four editors and two publishers, The International Journal of Aging and Human Development (IJAHD) has featured multidisciplinary scholarship related to aging processes and older adults. With the publication of eight issues a year, with over 800 pages of scientific content, the IJAHD places emphasis upon psychological and social studies of aging and the aged. However, the Journal also publishes research that integrates observations from other disciplines that illuminate the \"human\" side of gerontology. A more recent focus includes midlife development, as well. About half (47%) of the publications in the IJAHD are from international colleagues. This presentation will discuss tips for both international and US-based scholars for ensuring timely reviews and positive decisions for manuscript submissions, including such areas as key words, suggesting unbiased reviewers, formatting, writing mechanics, clearly-articulated methods, and a sound theoretical basis."}
+{"text": "Entering the twenty-first century, the centenary neurosurgery has entered the era of network neurosurgery, along with the development of brain research \u20133, the dNetwork neurosurgery is based on the topological characteristics of the brain networks, using multimodal intelligent neurological imaging and minimally invasive surgical techniques. In the process of diagnosing and treating neurological diseases, network neurosurgery can protect and remodel the patient\u2019s functional brain networks and thus improve the level of diagnosis and treatment of refractory neurological disorders. Network neurosurgery will be the nexus for translational research in the field of human brain science.In the early twentieth century, neurosurgery gradually became an independent clinical specialty by a deep understanding of brain neurophysiology and functional localization. The centenary history of neurosurgery can be divided into three stages: classical neurosurgery, microneurosurgery, and minimally invasive neurosurgery. The three dimensions of brain anatomy and cognitive discovery, leap development of biomedical imaging, and the update of surgical instruments are the driving force of the continuous development of neurosurgery.In the late nineteenth century, surgeons began to engage in the surgical treatment of intracranial tumors, brain abscesses, epilepsy, spinal cord compression, and trigeminal neuralgia. In 1870, Fritsch and Hitzig firstly proved the functional localization of the parietal cortex. Subsequently, Flechsig mapped the functional areas of movement, sensation, and vision in human brains and established the examination methods of the nervous system. The diagnostic techniques of pneumoencephalography (1917), cerebral angiography (1927), electroencephalogram (EEG) (1929), and other specialized methods detecting the location of intracranial lesions have laid the foundation for neurosurgery. In 1919, Cushing (1869\u20131939), a neurosurgeon, proposed and established the neurosurgery. During this stage, the neurosurgery solved the patients\u2019 increased intracranial pressure and neurological deficits caused by intracranial lesions.From the 1950s to the late twentieth century, the successive appearance of computerized tomography (CT), magnetic resonance imaging (MRI), and digital subtraction angiography (DSA) provided reliable imaging evidence for early detection and accurate localization of intracranial lesions. The surgical microscope and microsurgical instruments, such as high-speed cranial drill, controllable operating table and skull frame, automatic retractor, ultrasonic suction, and bipolar coagulation, solved the problems of lighting, narrow field, and hemostasis that interfered with the process of neurosurgery. The new procedure of microsurgery, especially the transcranial approach, can accurately remove the brain lesions while effectively protecting the normal brain structure.The minimally invasive neurosurgery was capable of early and accurate diagnosing neurological disorders and locating the functional areas based on modern diagnostics imaging. The neurosurgical equipment of navigation systems, neuro-endoscopy, cerebral blood flow, and electrophysiological monitoring have provided more reliable guarantees for the accurate detection of lesions and avoidance of neurological impairment during surgery. Endovascular interventional techniques and stereotactic radiosurgery have become new modalities for minimally invasive neurosurgery.Entering the twenty-first century, the research boom of brain science, the digitization of medical imaging, and the emergence of modern technology in hybrid surgery have promoted neurosurgery to the era of networks neurosurgery.The human brain is the most complex object in the known universe. Understanding the structure and function of the brain is the most challenging frontier scientific problem in the twenty-first century. Brain research has important clinical significance for the effective diagnosis and treatment of brain disorders. Brain science research reveals the theory of cerebral networks and promotes neurosurgery in the era of networks neurosurgery.Modern digital neuroimaging, such as functional MRI (fMRI), DSA, single photon emission computed tomography (SPECT), positron emission tomography (PET), and other multimodal neuroimaging technologies, has achieved the leap from anatomical neuroimaging to functional neuroimaging. The structural brain imaging and functional networks have laid a solid foundation for networks neurosurgery.The modern neurosurgical hybrid operating room is equipped with intraoperative MRI and cerebral angiography equipment, which provides real-time imaging data and thereby guides the operation. Intraoperative waken-up anesthesia, frameless stereotaxic robots, intraoperative neurophysiological monitoring (IONM), and other technologies have established a technological platform for networks neurosurgery.In the procedure of networks neurosurgery, the neural network and its relay station can be precisely positioned. The intraoperative resection of intracranial lesions and implantation of electrodes are accomplished with neuroengineering, nanotechnology, brain-computer interface, and other technologies. Networks neurosurgery not only treats brain tumors and neurovascular diseases but also opens new avenues for chronic pain , movement disorders , epilepsy, mental disorders, hearing impairment, vision loss, and other refractory neurological disorders.The vast majority of brain hubs in the human brain functional networks have only a few connectivities, while a few hubs have a great many connectivities, known as the key hubs of the brain networks. The structure and function of the networks will be seriously affected if the key hubs were damaged . ExploraThe blood supply and the structure of brain networks are strongly linked to functional connectivity \u201310. AlthRevascularization contributes to the recovery of brain functional networks in patients with ischemic stroke. Chronic cerebral hypoperfusion affects the structure and function of fiber tracts in adult patients with moyamoya disease (MMD) , and theThe prediction of recovery in brain network connectivity is available after the revascularization by brain network analysis, which may contribute to predicting the selection of surgical management. Prospectively, the preoperative evaluation will no longer be limited to the degree of ischemia in the management of cerebrovascular diseases. The surgical indications and prediction of surgical outcomes are determined regarding the status of brain network connectivity.The generation and regulation of consciousness and cognition exist at the level of neural circuit. The cerebral cortex plays a central role in consciousness and cognitive functions. There may be complex neuronal subsets in the single brain region. Central circuit is the core circuit that generates, maintains, and regulates the consciousness. The core structure of central thalamus is a key target for deep brain stimulation (DBS) in consciousness disorders. The functional connectivity and neural oscillatory characteristics of the central thalamocortical circuit are strongly associated with loss and recovery of consciousness. Different frequencies of electrical stimulation can awaken the state of loss of consciousness. Therefore, it is a key way to resolve individual differences, increase the rate of awakening, and shorten the awakening duration, by developing an adaptive approach of closed-loop neuromodulation based on the regulatory mechanisms and theories and forming an effective clinical practice for DBS awakening in consciousness disorders. Besides, it provides novel ideas for analyzing the \u201cPrinciples of Brain Cognition and Neural Mechanisms of Consciousness.\u201dBy directly measuring the pathological brain activity and providing adjustable stimulation, DBS is feasible to treat neurological and psychiatric disorders related to abnormal circuit function. The brain electrodes and pacemaker , 16, whiBrain-computer interface (BCI) establishes a new communication and control channel between the brain and the external environment that is independent of peripheral nerves and muscles. Thus, it is practicable to accomplish the direct interaction of the brain and external devices. BCI can be used as an auxiliary communication and control method for patients with severe movement disorders. By utilizing the signals of the motor cortex, patients can precisely control the external robotic arm and manipulator and restore motor dysfunction. Obtaining and analyzing the EEG signals of patients with chronic consciousness disorders through BCI equipment, the diagnosis and assessment, prognosis evaluation, and even communication of consciousness disorders can be achieved. Further clinical research on neurodegenerative diseases  is warranted.In the twenty-first century, brain research has advanced by leaps and bounds, targeting the network neurosurgery. Therefore, actively and rationally constructing the new discipline is an arduous task for the neurosurgery community ."}
+{"text": "The National Institutes of Health\u2019s Asian American, Native Hawaiian and Pacific Islander Health Scientific Interest Group (NIH AANHPI-HSIG) provides a viewpoint on developing approaches to enhance research on health and wellbeing for Asian American, Native Hawaiian, and Pacific Islander ethnic populations, in order to advance racial equity amongst such populations. Asian American (AA), Native Hawaiian and Pacific Islander (NHPI) populations are highly heterogeneous racial/ethnic groups with diverse health disparity concerns including hepatitis B and chronic liver disease, diabetes without obesity, various types of cancer, and stroke etc. , 2. AA aAsian American, Native Hawaiian, Pacific Islander (AA and NHPI)\u201d to describe the populations in an Executive Order (14031) on May 28, 2021, which reinstated and reinvigorated the White House Initiative (WHIAANHPI) on improving the quality of life and opportunities to participate in federal programs for AAPI proclaimed in an earlier Executive Order (13125) on June 7, 1999 [The National Institutes of Health Asian American Pacific Islander Health Scientific Interest Group (NIH AAPI-HSIG) was established in April 2021 with approval from Dr. Michael M. Gottesman, the NIH Deputy Director for Intramural Research . The groe Order 1031 on Marder 1312 on June In just over 1 year, the NIH AANHPI-HSIG has initiated several projects to integrate NIH-wide efforts to enhance knowledge and awareness of health disparity and assess the research needs for AA and NHPI populations , 6. We hMental health issue facing the AA and NHPI community is another important topic that was discussed at the 1st NIH AANHPI Mental Health and Well-Being Seminar Series hosted by the NIH AANHPI-HSIG . As partThrough these initiatives we have recognized that in order to advance health equity, more research on health disparities specific for the AA and NHPI racial/ethnic subgroup is needed. To address this need, a NIH-wide AANHPI Research Priority Recommendation Working Group has been formed. The Working Group led the effort to publish the first NIH Request for Information (RFI) (NOT-CA-22-047) specifically focusing on actionable priority recommendations to improve research on health and well-being of AA and NHPI populations in line with the White House [To celebrate the AANHPI-Heritage Month, AANHPI-HSIG successfully organized its inaugural AA and NHPI Health Research Conference on May 4\u20135th, 2022, with a central theme of \u201cFrom Mechanism to Translational Research: Improving the Health and Therapeutic Outcome for AA and NHPI Populations\u201d . Dr. LawAll of Us research project using intentional community engagement efforts and the multilevel AANHPI engagement strategy, and the New York Genome Center\u2019s Polyethnic-1000 program that enrolls ethnically diverse and underserved cancer populations in New York City were highlighted. Participants of the conference also stressed the need of data disaggregation for AA and NHPI subgroups, discussed the language accessibility problem for AA and NHPI populations in seeking medical care or involving in clinical research, and addressed the effect of anti-Asian hate/discrimination on health. The conference not only enhanced the awareness of AA and NHPI heritage and highlighted scientific achievements in AA and NHPI health-related research, but also informed NIH leadership of the current research needs and priorities.The two-day conference, which included participants from across the HHS, had for scientific sessions on Cancer; Diabetes and Other Diseases; Other Health Conditions; Mental Health, Community Health Care, Caregiver and Indigenous Medicine, respectively; each followed by a Panel Discussion and Summary session . Many isIn summary, advancing AA and NHPI health research is an integral part of the NIH\u2018s charge on minority health and health disparities research. The NIH AANHPI-HSIG can contribute to the WHIAANHPI on advancing equity, justice, and opportunity for AA and NHPI communities in the United States in many areas, including data disaggregation for AA and NHPI subgroups, language access, promoting inclusion, capacity building and community engagement, through enhancing research focusing on the health and well-being of AA and NHPI populations . The res"}
+{"text": "This presentation highlights the development of Age-Friendly care interactive modules to prepare the future healthcare workforce to care for older adults in Age-Friendly Health Systems. To date, there is a gap in the educational preparation of nurses, advanced practice nurses, and other health professionals to work in Age-Friendly Health Systems upon entry into practice. This project, funded by a faculty innovation grant at Seton Hall University, provides undergraduate and graduate nursing and interprofessional students with the background knowledge to care for older adults in Age-Friendly Health Systems. The aim of this project was to develop five interactive modules to embed in undergraduate and graduate nursing and interprofessional curricula focusing on the provision of care to older adults using the evidence-based 4Ms Framework: What Matters, Medication, Mentation, and Mobility. Faculty collaborated with instructional designers in development of the modules using Articulate 360 to embed them in curricula. The first module focuses on the background of the Age-Friendly Health Systems movement, how health systems may become an Age-Friendly Health System, and the evidence for the 4Ms Framework. The second module focuses on assessment and act on strategies related to What Matters to older adults including advance care planning strategies. The third module covers crucial information related to Medication such as avoiding potentially inappropriate medications, deprescribing, and antibiotic stewardship. The fourth module focuses on Mentation and covers assessment and act on strategies for depression, delirium, and dementia. The fifth module focuses on Mobility such as promoting mobility and decreasing fall risk."}
+{"text": "Yao et al.) Emerging diseases and health issues, lifestyle and diet changes urge us in seeking novel bioactive substances and formulations from plant sources (The investigation on plants that are both medicinal and edible is rooted in different ethno-medicinal systems ( sources . RelatedAlong with the strong increase in the publication of medicine food homology study , researcIn this Research Topic, we have provided a discussion forum for the community, and received 47 full length article submissions, with 17 papers published, which covers cultivation and pharmacognosy of medicinal and food plants, ethno-pharmacological practices and pharmacological investigation, food function and safety evaluation of selected plants; identification of novel pharmacological and biological effects of plants, strategy on the development of pharmaceutical, nutraceuticals and functional products, reviews as well as general methodology and research advancement , 2.This Research Topic provides a platform and community space for sharing and enlightening the state-of-art discovery and scientific understanding in edible and medicinal plants . Efforts"}
+{"text": "A sustainable approach in asphalt pavement engineering should focus on materials, design methods, and technologies that can contribute to minimizing environmental impacts through a reduction in energy consumption and natural resources, while ensuring that all performance standards and requirements are met.The decision-making process should be appropriately updated by adopting suitable tools and methodologies, such as LCCA and LCA, to measure the potential economic and environmental impacts associated with the adoption of sustainable solutions.This Special Issue includes recent and original studies that address the design and construction of sustainable asphalt pavements performed by several researchers belonging to different universities. The scope of the presented studies is extensive and multidisciplinary, covering many aspects related to (i) recycled and renewable materials for the production of asphalt concrete, (ii) low-energy and low-emission technologies, (iii) long-life design solutions, and (iv) green urban development.(i) Recycled and renewable materials in asphalt pavements may be employed for the modification of asphalt binders and/or for the full or partial replacement of natural aggregates and mineral filler in asphalt mixtures ,2. In th(ii) Cold-mix asphalt technologies, including water-foamed asphalt and emulsion-based mixtures, have been extensively used for their energy-saving and emission-reducing features. The study of  focused (iii) Durability and performance life are recognized to be critical factors in the sustainability of road pavements . The SpeComposite admixtures of lignin and glass fibers have been successfully used as additives to improve the performance of asphalt mixtures, in terms of moisture susceptibility and thermal cracking resistance . The env(iv) The construction of a sponge city is a major green innovation that can be used implement the concept of sustainable development. The study of  addresseThe editors give special thanks to the authors and the editorial team of Materials for the collaborative and peer-review process. We hope you enjoy reading this Special Issue and find new concepts for future and present research."}
+{"text": "Sexual and reproductive health (SRH) among young people, aged 10\u201324 years, in Sub-Saharan Africa (SSA) remains a major public health challenge, with evident gaps in access to SRH services and increased risk of poor SRH , 4. HoweTemin et al. open this collection by exploring HIV-related risk determinants from the perspective of foreign migrant adolescent girls and young women in South Africa who participated in an evidence-based female-focused intervention\u2013\u201cGirls Club Project.\u201d They provide recommendations for more inclusive HIV prevention programming that reaches foreign migrant adolescent girls and young women. With a similar focus on risk factors, Envuladu et al. assessed the covariates of sexual activity and consistent condom use among adolescents in Plateau State, Nigeria. Their results suggest a need for gender-tailored interventions. Taking a broader perspective, tailored interventions that are contextually appropriate can enhance the acceptability and adoption of SRH interventions.Yuya et al. assessed the level and predictors of knowledge of reproductive rights among Haramaya University students in Ethiopia. The study revealed that lack of awareness/information on reproductive health issues and absence of reproductive health services utilization were important predictors of participants' knowledge of reproductive rights. This warrants further investigations on whether knowledge of reproductive rights can promote uptake of sexual and reproductive health services. Lawrence et al. shared the work undertaken by the team as part of the Public Health Adolescent Services Evaluation, which is a national evaluation of adolescent HIV services in Kenya. The evaluation revealed a preference for adolescent autonomy in seeking sexual and reproductive health services and contacting healthcare workers for sexual and reproductive health information. This study confirms the value of adolescent and youth-friendly health services and the need for contextually appropriate strategies to enhance uptake and adoption.Two authors highlight knowledge and uptake of Youth Sexual and Reproductive Health services with helpful insights. Bridging the Research-to-Practice gap, three articles highlight the application of implementation science in young people's sexual and reproductive health. Mgoli Mwale et al. evaluate the sustainability of the Community Score Card to improve Adolescent Sexual and Reproductive Health in Ntcheu, Malawi. Their work provides compelling evidence of the importance of agents and context in the sustainability of interventions. They specify real-world facilitators, barriers, and opportunities in promoting sustainability within resource-constrained settings. Libous et al. offer a new generalizable approach to guide intervention adaptation that builds on existing infrastructure, culture, and resources to inform implementation strategies. Their work focused on the adaptation of a trauma-informed cognitive behavioral therapy intervention addressing mental and sexual health for adolescents and young adults living with HIV guided by the ADAPT-ITT framework. Obiezu-Umeh et al. presented compelling findings from a systematic review of 23 articles on the implementation outcomes and implementation strategies of youth-friendly sexual and reproductive health services in sub-Saharan Africa. The authors underlined the need to develop rigorous studies further to understand better which and what combination of implementation strategies would lead to more gain in promoting the uptake and sustainment of youth-friendly sexual and reproductive health services. These articles provide concrete suggestions for community and young people's engagement in intervention development, adaptation, and implementation processes, to foster co-creation and ownership within communities. These are critical for the adoption, scale-up, and sustainability of interventions as we seek to bridge the research-to-practice gap.Echoing the call for Individually, these contributions address an array of critical issues. Collectively, they provide momentum on the importance of contextually appropriate, youth-friendly, and youth-engaged approaches to enhance the uptake, scale-up, and sustainability of young people's SRH interventions in SSA. We acknowledge that articles presented in this collection are not exhaustive of the work in the field. Nevertheless, the findings, insights, and perspectives discussed in each paper could inspire new research and interventions.This special issue continues to highlight substantial structural, social, and individual barriers that limit the uptake of SRH services. Nonetheless, a few articles highlight the importance of active community engagement and active youth participation to circumvent these barriers. Community engagement and youth participation can enhance the uptake, appropriateness, and sustainability of SRH intervention and can help move us closer to the goal of bridging the research-to-practice gap in promoting SRH among young people in SSA. Participatory approaches such as crowdsourcing that involve community members in solving a problem and then publicly sharing innovative solutions could provide an opportunity to co-create with young people and community members , 7. ThisAll authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Original Research, one Hypothesis and Theory, and one Perspective have addressed this issue by studying possible microbiota involvement and modulation in the case of psoriasis, epilepsy, depression, and a possible correlation with environmental exposure to glyphosate and glyphosate-based herbicides with neuropsychiatric conditions. In all these publications, diet, probiotics, and lifestyle changes represent also valid support for ameliorating health conditions.In the last decade, the gut-skin-brain axis has emerged as a research field offering more and more evidence on the way foods and intestinal microbiota can affect the development of intestinal/skin diseases , and neuSun et al. considered two physiological body barriers, i.e. skin and gut, and investigated the relationship between intestinal microbiota and psoriasis development with an epidemiologic analysis and an experimental approach. In psoriatic patients, the incidence of gastrointestinal discomfort symptoms was significantly higher than in healthy subjects and the gut microbiota was improved when patients received therapy of oral acitretin and narrow-band ultraviolet B, with an evident decrease in their psoriasis area and severity index (PASI) score compared to untreated subjects. The transplantation of fecal microbiota from psoriatic patients or healthy controls into mice after the application of imiquimod cream confirmed that psoriatic microbes delayed recovery of psoriasiform dermatitis and induced a lesser decrease of IL-17A, a key proinflammatory psoriatic cytokine, thus validating the epidemiologic data. This study represents an excellent example of the translational integration of preclinical and clinical investigations and helps in better defining the complex association between dysbiosis and psoriasis with the final aim of developing microbiome-based therapeutic options for dermatologists.The original research by Wang et al. for epilepsy, a disease imposing low quality of life for millions of people. The hypothesis of a possible gut dysbiosis has been considered by the authors based on the published studies about the regulating role of bacteria in neuroinflammation and oxidative stress. Under this perspective, the administration of probiotics, Bifidobacterium and Lactobacillus strains, prebiotics, inulin, and synbiotics, the combination of bacteria and inulin, were administered to kainic acid-induced epileptic rats, and both clinical manifestations and biochemical markers of the supposed involved mechanisms were collected. This pre-clinical results obtained show a decreased frequency and duration of seizures, an extended latency period with a major effect due to synbiotics, together with an improvement in cognitive impairment. The biochemical markers of lipid peroxidation, DNA damage, diminished total antioxidant ability, inflammation, and the release of IL-1\u03b2, IL-6, and TNF-\u03b1, confirm the authors' hypothesis and pave the way for finding new therapeutic agents.The connection between the gut and brain has been investigated by Ghannoum et al. provide a Hypothesis and Theory contribution shedding light on the potential link between the gut microbiome and depression, exacerbated by the COVID-19 pandemic. The authors provided clinical evidence suggesting that integrative management of depression may also include microbiome modulation. Despite this issue deserves further data to be fully comprised, the possibility to help people to understand the causes of their mental problems and to avoid the use of antidepressant drugs, often without real positive effect or coupled with strong side effects and costs, is worth to be investigated.Perspective opinion made by Barnett et al., the reader enlightens by the descriptive evidence of how glyphosate, which was designed to combat threatening weeds competing for nutrients and resources for crops production, induces alterations of the gut microbiota diversity, associating with neuropsychiatric conditions like anxiety, depression, autism, and important maladies like Parkinson and Alzheimer's disease. The discussion of the topic walks through a narrative describing how sub-toxic exposure to glyphosate and glyphosate-based herbicides is reported to perturb the abundance of important species in the microbial intestinal biome, which include commensals like Lactobacillus spp., Bacteroides spp, Bifidobacterium spp., Butyricoccus spp., Clostridium spp., and members of the family Ruminococcaceae, among others. The changes in the abundance of these bacterial species are the results of their susceptibility to the antimicrobial properties of glyphosate and result in the reduction of important microbial metabolites many of which are neurotransmitters, necessary for mental health and wellbeing acting through the gut-brain-microbiome axis. On the other hand, there is a selection of glyphosate-resistant microbes with the potential to increase the production of pro-inflammatory cytokines and reactive oxygen species which may result in dysfunctional hypothalamic-pituitary-adrenal axis activation, with deleterious consequences in neuronal homeostasis. The authors finish with a discussion of the benefits that the use of glyphosate and glyphosate-resistant plants brought to crop production in the world, which permits us to understand the need for the development of alternative methods for weed control.In the In conclusion, the published works evidence that perturbations of the gut microbiota uncouple the function of the Gut-Skin-Brain Axis which is evidenced by the development of diseases in humans or its preclinical models. A full comprehension of the involved mechanism, like high oxidative stress, DNA damage, impaired cell signaling, and associated dysbiosis, will open the way to offer alternative healing methods to drugs but above all, the possibility to prevent the onset of the associated diseases through a correct lifestyle and diet; all in all with the ultimate goal to promote patient's health.AF wrote the introduction and the conclusion. All authors summarized the contributions and added comments to the cited papers. All authors approved the submitted version."}
+{"text": "Many existing and newly constructed bridges are made of reinforced and prestressed concrete. Advanced concrete materials play an increasingly important role in concrete bridges, facilitating the strengthening and repair of existing bridges, fast replacement solutions for parts of existing bridges, and for the design of novel challenging bridge projects. The development of advanced concrete materials and their structural applications is, thus, an important topic in the built environment.The articles presented in this Special Issue bring together research insights, practical applications, and discussions on how to develop better structural concrete materials for bridge engineering practices. Since articles were written both by materials scientists and bridge engineers, a wide view on the topic is presented.One example of an advanced structural concrete material is ultra-high-performance fiber-reinforced concrete (UHPFRC). With research on this topic having reached a high level of maturity, practical applications of this material are becoming increasingly more common. A key practical issue is related to the resulting fiber content, fiber orientation, and efficiency factor of the structural elements, particularly relevant for thin elements. This property determines the post-cracking tensile strength of the UHPFRC. In , the autAdvances in steel-fiber-reinforced concrete include the development of steel-fiber-reinforced expanded-shale lightweight concrete (SFRELC) . In partAnother example of an advanced structural concrete material is concrete with an MgO expansive agent and steel fibers added to the mix. This improved concrete mix  was applFor the prefabrication industry, a better understanding of the structural behavior can result in the optimization of the resulting prefabricated elements. A topic of particular interest is the interface bond strength and anchorage performance of the steel reinforcement (ribbed and plain bars) in the prefabricated concrete. The experimental study of  resultedFor existing bridges, the first challenge is often the proper assessment of the structure; the information is important for the evaluation of various possible solutions, such as for the strengthening of the structure. In , the autOn the topic of strengthening existing bridges, various advanced structural concrete materials are proposed. Experiments on reinforced concrete beams strengthened with textile-reinforced concrete (TRC) and fiber\u2013textile-reinforced concrete (F/TRC) showed the beneficial effects of this strengthening technique at the ultimate limit state, as well as in the serviceability limit state . A seconUHPFRC is also proposed for the strengthening of existing bridges . ExperimPolyvinyl alcohol fiber-reinforced engineering cementitious composites (PVA-ECCs) are proposed in another paper , where tAnother novel method for strengthening was proposed in , in whicUltimately,  proposesMaterials, who helped handle the manuscripts of this Special Issue, as well as the journal staff, who provided expert assistance to the development of this Special Issue at every step of the way.These presented papers provide insight into the current state-of-the-art of advanced structural concrete materials in bridge applications, and show the way towards the practical application of these materials. I appreciate all author contributions and sincerely value the time and effort spent in preparing these articles. I would also like to thank all reviewers who contributed to this Special Issue for their time, effort, and valuable remarks to the articles. Finally, I would like to thank the academic editors of"}
+{"text": "A 28-year-old male farmer from the rural zone of Alagoas, seropositive for HIV and not adhering to antiretroviral therapy, was admitted to an infectious disease service in northeast Brazil with continuous fever, asthenia, cough with bloody expectoration, and loss of 20 kg in 30 days.2 93%, and whitish plaques on the tongue. Complementary tests revealed upper gastrointestinal bleeding on endoscopy; interstitial infiltrate, lymph node enlargement, and bronchial thickening on chest radiography; and visceromegaly on abdominal ultrasound. The laboratory profile revealed severe anemia and thrombocytopenia and mild leukocytosis , besides intracellular structures in neutrophils suggestive of Histoplasma capsulatum in the blood smear , with a high rate of morbidity and mortalityAs definitive diagnosis of histoplasmosis can be difficult and time-consuming, the need to expand access to other tests becomes relevant and may be useful in deciding the initiation of empirical therapy for histoplasmosis. Thus, in the present case description, we highlight the relevance of performing microscopic examination of peripheral blood smear, allowing direct viewing of the fungus and the final diagnosis of histoplasmosis."}
+{"text": "Chronic kidney disease (CKD) is a leading public health problem that affects a significant proportion of the population worldwide. It is a complex multifactorial disease and approximately 13% of the world population are affected by this disease . The numThe use of experimental models represents a valuable tool to understand the underlying pathophysiological mechanisms of kidney diseases and exploring novel therapeutic targets. Model organisms, in particular rats and mice, represent an invaluable resource for both fundamental and applied research, allowing prediction studies, modeling, and the identification of action mechanisms. Drug development requires tests on model organisms before the clinical trials and this makes these organisms essential for progress within the field.This Research Topic encompasses two research articles and two review articles. These articles introduced cutting-edge research on diabetic nephropathy (DN) and the role of cellular senescence in CKD. In addition, the role of extracellular vesicles (EVs) in acute kidney injury (AKI), CKD, DN and renal tumors has been discussed. However, drug/chemical-induced nephrotoxicity and other models of AKI were not discussed in these articles. The guest editors are pleased to present a compendium of these articles as follows:Hou et al., the investigators utilized the connectivity map (CMap) with renal tubulointerstitial transcriptomic profiles of biopsy-proven early- and late-stage DN, a leading cause of CKD, to identify novel treatment candidates. The therapeutic potential of the suggested candidate drugs was evaluated in vivo in streptozotocin-induced CD-1 mice, and in vitro utilizing HK-2 cells and immortalized bone marrow-derived macrophages (iBMDMs). CAY10603, a specific inhibitor of histone deacetylase 6 (HDAC6), was defined as a potential drug and the experimental findings showed its ameliorative effect on renal dysfunction, inflammatory cell infiltration, tubular injury and tubulointerstitial fibrosis in diabetic mice. These effects were associated with the inhibition of NLRP3 and pyroptosis as revealed by the studies on HK-2 cells and iBMDMs.In the research article by Wang et al. summarized and discussed the findings of the studies showing the effects of the active constituents of Rheum ribes on key signaling pathways implicated in the pathogenesis of renal fibrosis. The conducted analysis revealed the beneficial effects of Rheum ribes constituents against the development of renal fibrosis and their value as drug candidates.In another article, Zhao et al. summarized the common features and the interaction between CKD and renal senescence, and the therapeutic approaches, including senolytics, senomorphics, and immunomodulation. This review article highlighted the value of renal senescence as a promising target for therapeutic intervention of CKD.Etiology, pathological changes, phenotype, and outcome are among the similarities that renal senescence shares with CKD. Given these numerous similarities, is not clear whether renal senescence is a trigger or a consequence of CKD. In this review article, Xiang et al. summarized the latest studies showing the role of EVs in renal diseases and highlighted their value as therapeutic targets. EVs are cell-derived membrane structures released by most cells and play a role in cell-cell communication and as vehicles for information transmission. The association between EVs and renal diseases has been acknowledged. This review highlighted the updated progress in understanding the role of EVs in the progression of renal diseases and the possible therapeutic application of stem cell-derived EVs.The editors anticipate the published articles in this Research Topic to be of interest to the readers and expect researchers to benefit from achieving further progress in understanding the mechanisms underlying renal diseases and the development of novel therapeutics."}
+{"text": "In this paper, we propose a method to identify different varieties of raisins by combining near-infrared (NIR) spectroscopy and machine learning algorithms. The direct averaging of the spectra taken for each sample may reduce the experimental data and affect the extraction of spectral features, thus limiting the classification results, due to the different substances of grape skins and flesh. Therefore, this experiment proposes a method to fuse the spectral features of pulp and peel. In this experiment, principal component analysis (PCA) was used to extract baseline corrected features, and linear models of k-nearest neighbor (KNN) and linear discriminant analysis (LDA) and nonlinear models of back propagation (BP), support vector machine with genetic algorithm (GA-SVM), grid search-support vector machine (GS-SVM) and particle swarm optimization with support vector machine (PSO- SVM) coupling were used to classify. This paper compared the results of four experiments using only skin spectrum, only flesh spectrum, average spectrum of skin and flesh, and their spectral feature fusion. The experimental results showed that the accuracy and Macro-F1 score after spectral feature fusion were higher than the other three experiments, and GS-SVM had the highest accuracy and Macro-F1 score of 94.44%. The results showed that feature fusion can improve the performance of both linear and nonlinear models. This may provide a new strategy for acquiring spectral data and improving model performance in the future. The code is available at  Raisins are rich in dietary fiber, vitamins, carotenoids and polyphenols . StudiesIn the existing studies, Mostafa et al. used raisins images combined with support vector machine (SVM) and linear discriminant analysis (LDA) to identify fifteen kinds of raisins, with the highest average accuracy of 69.78%  and , respectively. In the GA algorithm, the ranges of C and g were within  in skin spectra of the different varieties of raisins were more obvious than that of flesh spectra; the differences of characteristic peaks of fatty acids, amino acids and carbohydrates  in flesh spectra were more obvious than that of skin spectra. Studies have shown that skin and flesh are more susceptible to climate and content of water in the external environment, and only recording spectral data on the skin will limit the model classification performance [In the experiment, the spectrum shows that the differences of characteristic peaks of lipids and phenols Click here for additional data file.S1 File(ZIP)Click here for additional data file."}
+{"text": "Dear Editor,A six-year-old female patient presented with hyperchromic confluent papules on the trunk and face , followiOn dermoscopy, the lesions were non-specific with a homogeneous brownish color and with structures similar to follicular crypts or openings .Figure 2Histopathological examination  showed aBasaloid follicular hamartoma (BFH) consists of the proliferation of multifocal basaloid cells, with frequent connection to the epidermis.The main differential diagnosis of BFH is basal cell carcinoma (BCC). Both consist histopathologically of basaloid strands of cells in a fibrous stroma, but the BCC is not folliculocentric and can be seen in the interfollicular dermis.3Acquired BFH can show a linear pattern, following the lines of Blaschko - occurring due to mosaicism - or in a generalized form - commonly associated with autoimmune diseases.In the case described herein, BFH clones were distributed along the Blaschko lines, representing ectodermal development patterns, which is a rare distribution. When a somatic mutation or chromosomal nondisjunction occurs during embryogenesis, affecting an epidermal progenitor cell, the affected offspring cells proliferate and migrate along the lines of Blaschko.Currently, there is no standard treatment for BFH. Correct identification prevents patients from undergoing unnecessary surgery and also allows periodic monitoring to detect malignant transformations. Lesions that increase in size or change in appearance should be biopsied whenever detected. If associated with an autoimmune disease, treatment of the comorbidity may lead to the regression of the associated skin lesions.In summary, BFH is a rare type of benign skin tumor, with different presentations, which can be congenital or acquired. Its main differential diagnosis is basal cell carcinoma, and histopathology should be performed for differentiation. There is yet no standard treatment for this condition and, in most cases, it is not necessary.None declared.Gabriela Martins de Queiroz: Collection, analysis, and interpretation of data; design, planning, drafting and writing of the manuscript; critical review of the literature; critical review of the manuscript; approval of the final version of the manuscript.Tayla Cristina Lopes: Collection, analysis, and interpretation of data; design, planning, drafting and writing of the manuscript; critical review of the literature; critical review of the manuscript; approval of the final version of the manuscript.Maria Clara Dantas Valle Soares: Analysis and interpretation of data; drafting and writing of the manuscript; critical review of the literature; critical review of the manuscript; approval of the final version of the manuscript.Carlos Bruno Fernandes Lima: Analysis and interpretation of data, design and planning of the manuscript; critical review of the literature; critical review of the manuscript; approval of the final version of the manuscript.None declared."}
+{"text": "Alcohol withdrawal delirium is severe complication of alcohol withdrawal leading to high mortality. Early identification of severe course of psychosis and complications threatening the patient\u2019s life is the most important problem in the treatment of these patients.Under supervision were 690 men, dependent on alcohol, in the state of withdrawal with acute psychotic disorder ; the average age - , the average age of alcohol abuse - . The patients were examined in a dynamics after a re-hospitalization after 5-7 years. This allowed us to verify the differential diagnostic approach to acute psychotic disorders in a state of abandonment, to investigate the impact of chronic acute psychotic disorders on the course of alcohol dependence, including the formation of deficits.clinical, clinical and psychopathological, methods of quantified scales and mathematical statistics.There were estimated factors influencing the severity of alcohol withdrawal with delirium: total amount of alcohol consumed per week, drunken alcoholics, persistent alcohol abuse, social disadaptation, cognitive impairment, psychological disorders, reducing the quality of alcohol consumed, food pattern characterized total calorie mostly due to alcohol, life trajectory, severe or chronic somatic diseases, rate of progression of alcohol dependence.The severity of acute psychotic disorder in the state of alcohol withdrawal mostly depended situational factors such as the number of days of severe drinking before a psychotic disorder, the pattern of nutrition, the quality and quantity of alcohol consumed, the presence of acute somatic diseases.No significant relationships."}
+{"text": "Rhipicephalus appendiculatus Subolesin, and a cross-species-effective vaccine formulation. As the next step, a controlled vaccine field trial has been approved by Ugandan state regulatory authorities, the Uganda National Council for Science and Technology (UNCST) and the National Drug Authority (NDA), to evaluate the efficacy and effectiveness of the vaccine formulation for the control of cattle tick infestations under field conditions. The results of this trial may lead to the approval of the vaccine for application in Uganda to improve cattle health and production while reducing the use of acaricides.A collaboration program was established between the group of Health and Biotechnology (SaBio) of the IREC Institute of Game and Wildlife Research  and the National Agricultural Research Organization of Uganda (NARO) for the development of vaccines for the control of cattle ticks in Uganda. Controlled pen trials identified a tick protective antigen,  Ticks parasitize livestock and wild animals with a higher prevalence in the warm tropics and sub-tropics while humans are accidental hosts, with all at risk for tick-borne diseases . EconomiRhipicephalus appendiculatus), blue ticks (R. decoloratus), bont ticks (Amblyomma variegatum), and red ticks (R. evertsi) , where NTV is the number of adult female ticks in the vaccine-treated group, and NTC is the number of adult female ticks in the control (adjuvant-only-treated) group.The candidate vaccine effect on the tick weight (DW) = 100[1 \u2212 (WTV/WTC)], where WTV is the average adult female tick weight in the vaccinated group, and WTC is the average adult female tick weight in the control (adjuvant-only-treated) group.The candidate vaccine effect on oviposition (DO) = 100[1 \u2212 (PATV/PATC)], where PATV is the average weight of the eggs per survived tick in the vaccine-treated group, and PATC is the average weight of the eggs per survived tick in the control (adjuvant-only-treated) group.The candidate vaccine effect on egg fertility (DF) = 100[1 \u2212 (PPLOV/PPLOC)], where PPLOV is the average weight of the larvae per gram of eggs in the vaccinated group, and PPLOC is the average weight of the larvae per gram of eggs in the control group.Finally, calculate the vaccine efficacy (E) = 100[1 \u2212 (CRT \u00d7 CRO \u00d7 CRF)], where CRT = NTV/NTC, CRO = PATV/PATC, and CRF = PPLOV/PPLOC, which is a representation of the reduction in the number of adult female ticks, oviposition, and egg fertility as compared to the control group, respectively.In conclusion, if vaccine efficacy and effectiveness are supported by the results of the trial, Ugandan state regulatory authorities will consider the approval of the vaccine for prospectus licensure for vaccine commercialization. These results will represent a key step for the Ugandan cattle industry with a positive impact on society and the economy."}
+{"text": "Cancer is increasingly recognized as an extraordinarily heterogeneous disease featuring an intricate mutational landscape and vast intra- and intertumor variability on both genetic and phenotypic levels. Prostate cancer (PCa) is the second most prevalent malignant disease among men worldwide. A single metabolic program cannot epitomize the perplexing reprogramming of tumor metabolism needed to sustain the stemness of neoplastic cells and their prominent energy-consuming functional properties, such as intensive proliferation, uncontrolled growth, migration, and invasion. In cancerous tissue, lipids provide the structural integrity of biological membranes, supply energy, influence the regulation of redox homeostasis, contribute to plasticity, angiogenesis and microenvironment reshaping, mediate the modulation of the inflammatory response, and operate as signaling messengers, i.e., lipid mediators affecting myriad processes relevant for the development of the neoplasia. Comprehensive elucidation of the lipid metabolism alterations in PCa, the underlying regulatory mechanisms, and their implications in tumorigenesis and the progression of the disease are gaining growing research interest in the contemporary urologic oncology. Delineation of the unique metabolic signature of the PCa featuring major aberrant pathways including de novo lipogenesis, lipid uptake, storage and compositional reprogramming may provide novel, exciting, and promising avenues for improving diagnosis, risk stratification, and clinical management of such a complex and heterogeneous pathology. Cancer is increasingly recognized as an extraordinarily heterogeneous disease featuring an intricate mutational landscape and vast intra- and intertumor variability on both genetic and phenotypic levels. The complexity of cancer is reflected in a high level of diversity in terms of the underlying mechanisms and drivers of carcinogenesis, manifestation and progression of the disease, spectrum of metabolic and functional modifications of the affected tissue, variety of cellular processes and involved molecular actors, an array of disrupted regulatory circuits, and, finally, clinical outcomes. Furthermore, cancer represents a dynamic system that evolves over the course of qualitatively distinct states regulated by a wide range of entities operating on multiple spatial and temporal scales ,2,3.Under physiological conditions within intricate hierarchical systems, cells receive, send, and process sets of signals that condition the precise coordination of their behavior with the aim of preserving the stability and integrity of a complex structure such as a multicellular organism. Following comprehensive communication and control mechanisms, cells differentiate, grow, divide, and, finally, die when that serves the organism\u2019s well-being. The formation of a malignant phenotype is due to changes that affect the control systems of cell proliferation, senescence and longevity, relationships with other cells, and capacities to evade the surveillance and defense activities of the immune system. The interplay between genetic alterations and environmental factors modulates the expression of both oncogenes and tumor-suppressors, thus orchestrating the nonlinear progression of the neoplastic disease . With unConceptualization of the set of shared biological attributes of malignantly altered cells represents a theoretical framework for distilling the complexity of neoplasia as well asa heuristic tool for research and a better understanding of cancer biology. Key hallmarks of cancer cells are the maintenance of proliferative signaling, avoidance of exogenous growth suppressors, resistance to mechanisms of programmed cell death, replicative immortality, induction of angiogenesis, ability to invade and colonize distant sites reserved for other cells, alteration of cellular bioenergetics, i.e., metabolism reprogramming, and evasion of immune system-mediated destruction . These aThere is a mounting body of evidence underpinning the significance of malignancy type and tissue-specific metabolic alterations, fluctuations in bioenergetic sources, and oxidative stress modulation in supporting the anabolic requirements of tumor biomass production and cancer progression. It is evident that a single metabolic program cannot epitomize the perplexing reprogramming of tumor metabolism needed to sustain the stemness of neoplastic cells and their prominent energy-consuming functional properties, such as intensive proliferation, uncontrolled growth, migration, and invasion . Each ceMost solid tumors exert the so-called Warburg Effect, a phenomenon described in the mid-19th century with the pioneering works by Otto Warburg, the Nobel Prize winner, whereby cancer cells take up glucose at substantially higher rates than the surrounding non-transformed normal tissue and shift their dominant adenosine triphosphate (ATP)-producing pathway towards aerobic glycolysis. In such circumstances, even under normoxia and with completely functioning mitochondria, the glucose-derived carbon is preferentially converted to lactate rather than being oxidized as pyruvate within the tricarboxylic acid cycle (TCA) . It has Nevertheless, aerobic glycolysis is only one element of the cancer-related metabolic reprogramming puzzle. To engage in limitless replicative division, cancer cells require a continuous supply of both glucose and glutamine, representing the principal and most abundant extracellular nutrients, for the metabolic pathways governing the synthesis of the three major macromolecule classes .GlutaminFunctionally interdependent with cancer-specific glucose and glutamine catabolic pathways, reprogramming of the lipid- and cholesterol-associated metabolisms encountered in malignancy are of exceptional importance for the pathogenesis of cancer. Although their relevance was disregarded in the past, they now represent a topic of burgeoning scientific interest. Cancer cells exert pronounced avidity for lipids, which are derived endogenously from citrate or taken up from exogenous sources. In normal adult mammalian tissues, de novo lipogenesis is rather low with the exception of lipogenic tissues such as liver, adipocytes, and mammary epithelium during lactation. Conversely, tumorigenesis is associated with a remarkable amplification of lipid production . ExcessiContrary to their normal counterparts, whose survival and proliferation are dependent on specific signaling prerequisites based on adhesion and growth factors, cancer cells foster oncogenic alterations to circumvent dependence on these external inputs. Several aberrant oncoproteins and tumor suppressors, such as phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR)signaling pathway, hypoxia-inducible factor-1 alpha (HIF-1A), MYC, and p53, have been associated with the regulation of the metabolic adaptation that favors tumorigenesis by facilitating cellular proliferation, access to vasculature, and stress resistance . The modProstate cancer (PCa) is the second-most prevalent malignant disease among men worldwide . The incPCa treatment requires an individual approach to each patient, and the decision is made depending on the stage of the disease while respecting the wishes and preferences of the patient. Active surveillance, surgery, and radiotherapy are reserved for localized PCa, with hormone therapy, chemotherapy, and target therapy being used in locally-advanced, advanced, or metastatic PCa.18F-fluorodeoxyglucose (FDG) cannot provide accurate differentiation between healthy and cancerous prostates [Benign prostatic tissue exerts a specific metabolic profile in baseline circumstances. Conventionally, mammalian cells energetically depend on aerobic respiration and, therefore, rely on citrate oxidation as a crucial step in the TCA cycle. Nevertheless, one of the major biochemical functional features of the glandular epithelium in the peripheral zone of the prostate is its exceptionally high citrate production and its subsequent secretion into the prostatic fluid. The unique metabolic programming of benign prostate cells to produce rather than oxidize citrate is biologically determined by another extraordinary feature: their capability to accumulate large intracellular concentrations of zinc. Increased zinc levels exhibit an inhibitory effect on the activity of m-aconitase, the mitochondrial enzyme catalyzing the stereospecific citrate conversion to isocitrate within the Krebs cycle. In other cell types, such inhibition is lethal, but in healthy prostate tissue, it enables secretion of citrate into the semen, where it serves as the buffering agent and energy source for spermatozoa as well as afree radical scavenger and chelating agent for zinc and calcium ions ,37. By crostates .In order to support proliferation concomitantly with the shift toward citrate-oxidizing metabolism, malignant prostate cells display the lipogenic phenotype. As opposed to most normal somatic cells, which predominantly utilize the lipids from exogenous sources, de novo fatty acid biosynthesis is reported to be exacerbated in various cancer cells irrespective of the abundance of the extracellular lipid content and circulating fatty acids . The sigThere is a complex interplay between the androgens and the modulation of the lipogenic program. In neoplastic prostate cells, androgen-regulated gene expression operates via common transcription factors of several genes significant for fatty acid synthesis and the cholesterol biosynthetic pathway. SREBPs have the central role in the synchronized cascade mechanism of highly coordinated androgen-mediated control of lipid metabolism in this oncopathology. It has been demonstrated that SREBP cleavage-activating protein (SCAP), compulsory for the nuclear translocation and activation of SREBP, FASN, and several lipid-modifying enzymes, including those implicated in the mevalonate-pathway, are upregulated in an androgen-dependent manner . FurtherSignaling pathways that elicit cancer lipogenesis culminate with the formation and accumulation of LDs. Accurate, controlled, and precise synchronization between factors of lipogenesis and lipolysis defines the net amount of lipids stored intracellularly. De novo synthetized or acquired lipids in the malignant tissue are commonly incorporated in triacylglycerols and cholesterol esters, and are then deposited within LDs. Anelevated abundance of LDs is the representative characteristic of various aggressive cancers, including PCa. The final step in the biosynthesis of triacylglycerols is catalyzed by acyl-CoA:diacylglycerol acyltransferase (DGAT) enzymes; the overexpression of DGAT1 was found in PCa neoplastic cells compared to normal epithelium . FurtherAlthough the endogenous de novo lipogenesis is considered to be the dominant source of fatty acids in neoplastic cells, it has been acknowledged that, under metabolic stress, cancers may adopt additional means to obtain lipids, including scavenging from the extracellular milieu. Such aberrant metabolic routs, coupled with the proficient de novoformation machinery, fuel the pervasive upregulation of lipid abundance and accommodate the increased demand of the progressing neoplasia . FurtherIn addition to lipogenesis, reprogramming of the fatty acid composition patterns was acknowledged in the cellular pool and membrane phospholipid profile. Fatty acid desaturation, catalyzed by the family of stearoyl-CoA desaturases (SCDs), and elongation, depending on the activity of elongases, may have a significant role in PCa progression. SCD1 overexpression was demonstrated on both mRNA and protein levels in specific PCa cell lines and human tissue specimens, where it correlated with a higher Gleason grade and worse clinicopathological features . FurtherDeregulation of cholesterol metabolism is another hallmark of the PCa pathogenesis. Featuring an amphiphilic and virtually planar structure, cholesterol molecules represent major constituents of the cellular membrane, supporting its integrity and regulating itsfluidity and permeability. In the TME, both intrinsic and extrinsic cues trigger cholesterol metabolism alternation, thus supporting carcinogenesis and suppressing the antitumoral activity of the immunological landscape . PCa celThe lipidomics approach, involving comprehensive identification, structural characterization, and quantitation of the complex networks and pathways of cellular lipids and their interactions with other moieties in vivo, represents a platform of exceptional potential in PCa research. As a metabolome subset, ubiquitously present lipid species display multifaceted and diverse roles in both the etiology and sequelae of various pathologies. Exploration of lipid alterations in translational contexts and clinical settings serves not only to advance the fundamental comprehension of the biological processes underlying disease onset and trajectory, but also to assist in developing personalized risk-assessment models that may guide curative interventions . ProvidiIn summary, comprehensive elucidation of the lipid metabolism alteration in the PCa, the underlying regulatory mechanisms, and their implications in tumorigenesis and the progression of the disease are gaining growing research interest in contemporary urologic oncology. A better understanding of the unique metabolic signature of PCa, featuring major aberrant pathways including de novo lipogenesis, lipid uptake, storage and compositional reprogramming, may provide novel, exciting, and promising avenues for improving diagnosis, risk stratification, and clinical management of such a complex and heterogeneous pathology."}
+{"text": "Additive Manufacturing of Polymer\u2013Fiber Composites is a newly open Special Issue of Materials, which aims to publish original and review papers on new scientific and applied research, and make great contributions to the finding and understanding of the fabrication of fiber-reinforced polymer composites using current advanced additive manufacturing techniques. This Special Issue also covers fundamentals, characterization, and applications of fiber-reinforced polymer composites.The technology of the additive manufacturing (AM) process has significantly piqued the interest of researchers and industrial players from various areas ,2,3,4,5.Studies on fiber-reinforced polymer composites for the additive manufacturing process have been carried out by many researchers and become an interesting topic to be explored in the additive manufacturing industry. The aims of the inclusion of fiber in the polymer-based feed stock materials are to reduce the percentage of polymers and consequently reduce the harmful substances that may emit during the fabrication process in AM. Moreover, fiber-reinforced polymer composites could improve the properties of the dominant materials and exhibit good performance in the final products. Employment of the fibers in the AM process should consider the type of fiber, fiber treatment, fiber size, fiber loading, and fiber characteristics. It is important to understand the composition of fibers to ensure their compatibility with the polymer, and how they could produce good resultant composites for AM.The AM process starts from the preparation of the feed stock until the disposal of the fabricated parts . The impIn this Special Issue, we aim to capture the cutting edge of the state-of-the-art research pertaining to advancing additive manufacturing of fiber-reinforced polymeric materials. The topic themes include advanced fiber-reinforced polymeric material development, processing parameter optimization, characterization techniques, structure\u2013property relationships, process modelling, etc., specifically for AM."}
+{"text": "In contemporary Poland, Universities of the Third Age are the most visible institutional forms of active aging. These lifelong-learning institutions that are specifically for retirees often cultivate ideals of independence through workshops and classes that teach new, and potentially transformative, skills and hobbies . Universities of the Third Age in Poland emerged out of the fields of andragogy, pedagogy, and social work, fields that have regional intellectual roots in the late 19th/early 20th-century presocialist era, and are based on radically different ideals of personhood, relationality, and care than those of the contemporary postsocialist neoliberal era . This paper analyzes 1) historical data from institutional archives of two Universities of the Third Age in Poland, and 2) secondary sources on histories of andragogy, pedagogy, and social work, to create a locally grounded intellectual history of active aging in central and eastern Europe. The Polish case offers an opportunity to think across divergent political-economic eras, in which assumptions about the value of a person to society have shifted. By tracing how the fields of andragogy, pedagogy, and social work have shaped active aging in Poland, this paper finds that 1) dichotomies of East/West, socialist/capitalist, and individual/collective are insufficient to explain the history of contemporary practices of active aging, and 2) intellectual history can reveal complex relations between political-economic change, and ideals and practices of aging. These findings have implications for advancing gerontological theories of 1) active aging in cross-cultural contexts, and 2) how active aging relates to sociopolitical change."}
+{"text": "Defined as, \u201cstereotype, prejudice, and discrimination directly towards people because of their age\u201d, ageism may contribute to adverse health outcomes, accelerate aging process, and increase the burden on health and social services. Little is known about the ageism impact on biological aging. Secondary analysis of the American Health and Retirement Study (2012 and 2016 waves) was carried out. Participants were asked: the self-perception of aging (SPA), the causes of receiving discrimination, including ageism as one of the causes, and the frequency of receiving such discrimination. The aging rate was measured using two distinct measurements: homeostatic dysregulation  and epigenetic aging clocks . The influence of perceived ageism (current or previous waves) on the aging rate was modelled with linear models using biological aging (aka. homeostatic dysregulation and epigenetic age) as the dependent variable (outcome), ageism as the exposure, with considering confounders: sex, depressive symptom. The results show that more negative SPA, either from the previous (2012) or the same wave (2016), is associated with elevated homeostatic dysregulation  and increasing epigenetic age . The association between the ageism receiving frequency and biological aging is similar but less significant. The results demonstrate that ageism is associated with accelerated biological aging. More interventions are called to combat ageism and foster the health and wellbeing of the older adults."}
+{"text": "The coronavirus disease of 2019 (COVID-19) pandemic has led to increases in intimate partner violence (IPV), a leading cause of women's homelessness. Although the Canadian Government provided emergency funding to the violence against women and housing and homelessness sectors in response to COVID-19, Canada lacks a national legislative and funding framework to support coordinated prevention efforts. We review the context of IPV and homelessness among women and international policy exemplars. We then propose several starting points for developing a Canadian strategic framework, including adopting inclusive definitions of IPV and homelessness as well as evaluating a broad continuum of IPV-housing options and intersectoral partnership models. The intersections of intimate partner violence (IPV), homelessness, and the coronavirus disease of 2019 (COVID-19) pandemic necessitate a coordinated public health response strategy. As in prior infectious outbreaks, the COVID-19 pandemic has been associated with higher risks of violence against women, including IPV . In addiIn this activist/advocate note, we outline the context of gender-based violence and homelessness in Canada prior to COVID-19 and how the pandemic has exacerbated structural vulnerabilities for women. We propose that Canada needs a national legislative and funding framework that supports intersectoral coordination to maximize prevention efforts for women's homelessness and IPV during and beyond the pandemic. We discuss several starting points for building this framework based on successful local examples and international approaches, including adopting inclusive definitions of IPV and homelessness and evaluating a broad continuum of structural solutions. The COVID-19 pandemic has highlighted the gaps in public health policy for marginalized communities and presents a critical opportunity to restructure for a more equitable future of public health. Doing so requires countries to not only reflect inwards, but to consider successful policy and practice internationally, including areas of implementation that can be further improved.Although people of all genders experience IPV, women and gender-diverse populations tend to experience more severe IPV and more physical, psychological, and socioeconomic impacts . IPV is Most specialized housing supports available to women experiencing IPV in Canada are mandated for short-term stays  . Few optEmerging evidence from the COVID-19 pandemic indicates that IPV has increased over the last year due to stressors like income loss or precarious employment, service disruptions, and lockdown measures . In CanaChanges in the risk and severity of IPV are exacerbated by a collision of structural vulnerabilities disproportionately impacting women during this pandemic, as in prior public health emergencies . These gDespite the gender-based and intersectional impacts of the COVID-19 pandemic, Canada paused development of its National Action Plans on gender-based violence and Missing and Murdered Indigenous Women and Girls as well as the National Indigenous Housing Strategy during the first 6 months of the pandemic. The Federal Government committed financial support in response to women's experiences of homelessness and violence in May 2020: $76 million for violence against women shelters (including off-reserve Indigenous shelters), sexual assault centers, and nonprofit gender-based violence organizations; and $10 million for shelters supporting Indigenous women and children fleeing violence on reserves . The houAs the Canadian Government recommits to developing its National Action Plan on gender-based violence , as well as New Zealand, which likewise implemented national legislation and is in the process of designing its National Action Plan to prevent family and sexual violence . As a reDespite a lack of large-scale investment in coordinated responses to IPV-related homelessness in Canada, locally practitioners have successfully committed to delivering longer-term options. For instance, a small-scale evaluation of Housing First adapted for women's homelessness needs in the province of Ontario found that six of 10 participants who had experienced complex histories of homelessness, violence, and trauma were housed at the end of the 2-year funding period, although the evaluators highlighted the need for a stronger integration with community services . EvaluatTo advance a coordinated intersectoral approach to preventing gender-based homelessness and violence in Canada, inclusive and standardized definitions of IPV and homelessness should be applied across (and within) jurisdictions, including in national funding streams. Legal definitions of IPV currently vary across Canada, often barring survivors from critical supportive services  if they have not experienced specific definitions of physical or sexual violence . RegardiMoving forward, policies and programs related to homelessness should explicitly adopt an intersectional gender-based definition of homelessness that understands women's unique experiences, based on multiple and intersecting social locations: gender, sexual identity, race/ethnicity, Indigeneity, class, disability, and age . This muCanada's national strategies on housing and gender-based violence should be coordinated to provide the necessary legislative and funding infrastructure for key sectors to collaborate in developing, implementing, and innovating across the full continuum of intersectoral interventions. For instance, Canada's National Action Plan on gender-based violence should be developed with linkage points to the National Housing Strategy, including investment in long-term supportive housing solutions that account for the unique needs of IPV survivors . This muStrengthening intersectoral action to prevent gender-based homelessness and violence against women in Canada must address the disproportionate burdens faced by Indigenous women and girls due to historic and ongoing structural harms at the intersections of colonization, misogyny, and racism . This inThe COVID-19 crisis has demonstrated the consequences of siloed and chronically underfunded social care systems worldwide. Now more than ever, policymakers must mobilize the coordination of Canada's national infrastructure to address the structural causes and outcomes of gender-based violence and homelessness. This is a critical time to draw lessons from local and international examples of coordinated intersectoral action to strengthen Canada's systems-level response to gender-based violence and homelessness\u2014especially as the national government restarts the development of its National Action Plan for gender-based violence. Intersectoral action is essential for addressing the structural determinants of gender-based health inequities and strengthening the response to IPV during and beyond the COVID-19 pandemic."}
+{"text": "Dear Editor,Betacoronavirus genus), responsible for the COVID-19 pandemic, can potentially cause severe acute respiratory syndrome (SARS), affect other organs, and trigger autoimmune events as a result of the cytokine storm.Infection caused by Coronavirus 2 , followed by UVB (narrow band). Two weeks after household contact with COVID-19, she developed a maculopapular rash . After 1The role of environmental factors and infectious agents as triggers or promoters of the development of CTCL is not yet fully established. Moreover, autoimmune disorders can generate a favorable environment for the risk of CTCL. Theories about the pathogenesis of MF and SS include increased Th2 activity, and reduced Th1 activity, the antitumor cytotoxic response of CD8 lymphocytes, the dendritic cell population, and the production of interleukin-12 and interferon-alpha.4The immunological dysregulation present in COVID-19 favors the reduction of the functional activity of regulatory T lymphocytes and an imbalance in the production of cytokines, in addition to the elevation of C-reactive protein and D-dimer serum levels.Although most patients with indolent or controlled CTCLs are not predisposed to viral infections, conditions at risk for infection and severe symptoms of COVID-19 are considered: aggressive or advanced CTCLs, ongoing immunosuppressive therapy, lymphopenia, chronic organ failure, coexisting comorbidities, advanced age.This unprecedented report of previously controlled MF, with exuberant and sudden cutaneous recurrence after SARS-CoV-2 infection, indicates viral immunogenic mechanisms as potential triggers of immune dysregulation in CTCLs.None declared.\u00c9derson Valei Lopes de Oliveira: design and planning of the case study; data collection, or analysis and interpretation of data; writing of the article or critical review of the intellectual content; collection, analysis and interpretation of data; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied case; critical review of the literature; approval of the final version of the manuscript.Ligia Magnani Landell: collection, analysis and interpretation of data; intellectual participation in the propaedeutic conduct of the studied case; approval of the final version of the manuscript.Cacilda da Silva Souza: design and planning of the study; analysis and interpretation of data; writing of the article or critical review of the intellectual content; collection, analysis and interpretation of data; critical review of the literature; approval of the final version of the manuscript.None declared."}
+{"text": "The COVID-19 pandemic has had unprecedented and potentially irreversible impacts on health and health care globally. Many complex issues and factors therefore need to be accounted for as we look at the long-term impact of COVID-19 on humanity and society and how this ongoing crisis continues to affect health and health care outcomes for different populations. There are significant health disparities and sex inequalities associated with the COVID-19 pandemic. Sex-responsive interventions are imperative to address widening sex gaps resulting from the pandemic. Although many researchers have studied the impact of the COVID-19 pandemic on health disparities, there is a lack of research on the sole and joint association of the pandemic or sex differences and their specific impact on health and health care. The study examined the association of the COVID-19 pandemic, the association of sex, and the joint association of sex and the COVID-19 pandemic with health communication, physical activity, mental health, and behavioral health. We also highlighted the application of Bonferroni corrections when conducting multiple hypotheses testing simultaneously.To examine the association of the COVID-19 pandemic, the association of sex, and the joint association of sex and the COVID-19 pandemic with health communication, physical activity, mental health, and behavioral health.We drew data from the National Cancer Institute's 2020 Health Information National Trends Survey (HINTS). We described and compared the characteristics of social determinants of health, physical activity, mental health, alcohol use, patterns of social networking service use, and health information data sharing. Analyses were weighted to provide nationally representative estimates. Multivariate models  were used to assess the sole and joint association with sex and pandemic. In addition, we applied the Bonferroni correction to adjust p-values to decrease the risks of type I errors when making multiple statistical tests.Females were more likely to use mobile health and health communication technologies than males, and the difference increased after the pandemic. The association between sex and mental health was significant after the COVID-19 pandemic. Females were more likely to experience depression or anxiety disorders. Both males and females had a slight decrease in terms of the quantity and intensity of physical activity and females were less likely to perform moderate exercise and strength training regularly. Males were likely to drink more alcohol than females.The COVID-19 pandemic amplifies the differences between males and females in health communication, physical activity, mental health, and behavioral health. Intersectional analyses of sex are integral to addressing issues that arise and mitigating the exacerbation of inequities. Responses to the pandemic should consider diverse perspectives, including sex."}
+{"text": "Drowning and near-drowning are the consequences of recreational activities and natural disasters. The purpose of this study was to review the microbiology literature on drowning and near-drowning and to understand its applications in the diagnosis and treatment of these injuries and diseases.This study is the result of a short review on publications extracted by searching in scientific databases including Google Scholar, PubMed and Semantic Scholar in the period from 1961 to 2021, using the keywords \"Microbiology\" and \"Drowning\" or \"Near-Drowning\".A search in scientific databases revealed 184 articles related to \"drowning\" and \"microbiology\" and 84 articles related to \"near-drowning\" and \"microbiology\", of which 65 and 28 articles have been published in the last twenty years, respectively. Of these, 43 articles were used for this study. Regarding the microbiology of drowning and near-drowning, no study was conducted in the Islamic Republic of Iran in this field. The findings of the present study showed that:\u2022 Near-drowning in its victims causes physical and mental injuries, and invasive polymicrobial and fungal pneumonia, brain abscesses, and sepsis.\u2022 They are mainly associated with numerous bacterial agents e.g. Aeromonas spp., Nocardia spp., Vibrio spp., Photobacterium spp., Burkholderiapseudomallei, Pseudomonas spp., Plesiomonas shigelloides, and Shewanella spp. and Fungal and Protozoan pathogens are limited to Aspergillus spp., Scedosporium apiospermum, and Rhizopus spp., and Cryptosporidium parvum (rare), respectively.\u2022 If bacterial, fungal, and protozoa infections are not properly diagnosed and treated in drowning victims, they can lead to death in intensive care units and even long after discharge from the hospital.\u2022 Deaths from drowning and near-drowning are candidates for organ transplants, especially lung, bone, liver, and heart.\u2022 Clinical, environmental, forensic, and eco-microbio-epidemilogy studies in pre-and post-mortem drowning victims are being developed using cultured-based and molecular methods such as PCR, LAMP, NGS, and Metagenomics, etc. to determine the drowning microbiome pattern.Several cases of infections and diseases caused by drowning and near-drowning have been reported among the victims of recreational activities and natural disasters in different countries. Therefore, eco-microbio-epidemiological study of drownings in our country, where there is an average of 1,200 annual drownings on the north and south coasts and inland waters is essential. Even predicting tsunami and destructive storms on the shores of the Caspian Sea and the Oman Sea are very important in determining the microbiome pattern of natural aquatic areas and the role of microbes in diseases and complications caused by drowning. Finally, a national protocol should be developed for microbial monitoring of drowning victims from the scene of water accidents to the hospital bed and on the autopsy table.Microbiology, Microbiome, Drowning, Near-Drowning, Natural Disasters"}
+{"text": "Gliomas are invasive brain tumors characterized by high rates of recurrence and mortality. Glioblastoma (GBM), a grade IV brain tumor, is known for its heterogenicity and its resistance to the current treatment regimen. MicroRNA (miRNAs) are small non-coding sequences of RNA that regulate and influence the expression of multiple genes. The detection of certain types of micro-RNA in tissues and blood serum can be used for diagnosis and prognosis, including the response of a particular patient to therapy. The purpose of this review is to analyze studies and experimental results concerning changes in microRNA expression profiles characteristic of gliomas. Furthermore, miRNAs also contribute to autophagy at multiple stages. In this review, we summarize the functions of miRNAs in GBM pathways linked to dysregulation of cell cycle control, apoptosis and resistance to treatment, and the possible use of miRNAs in clinical settings as treatment and prediction biomarkers. The posThis review considers the possibility of using miRNAs as prognostic markers and therapeutic targets in gliomas.2Many recently published works have confirmed the association of microRNA with chemotherapy and radiation resistance of patients' tumors  13].Fig.Fig13].FCSF  allows to differentiate glioblastomas and brain metastases with high accuracy (91\u201399%) on the test dataset. Nevertheless, the authors note that the search for additional microRNA biomarkers and subsequent analysis of large cohorts of patients will help to increase the accuracy of the approach [Radiation resistance, often caused by the spread of CSCs in gliomas, remains one of the main difficulties in the treatment of glioblastoma. In the context of radiation resistance of gliomas, miR-21 is one of the most actively discussed microRNAs. Blocking this microRNA with anti-miR-21 promotes the formation of phosphorylated histone g-H2AX (an indicator of double-stranded DNA breaks) and suppression of phospho-Akt expression, activation of autophagy and apoptosis (including by inhibition of Cdc25A expression) after irradiation in cell lines gliomas ,14. MiR-3The principle of therapeutic targeting of micro-RNAs is based, on the one hand, on increasing their expression due to the introduction of synthetic micro-RNAs (micro-RNA mimetics) to inhibit oncogenes; on the other hand, on the inactivation of endogenous micro-RNAs using inhibitors (antagomiRs or anti-micro-RNA) in order to increase the expression of tumor suppressors . Effecti4Expression profiles of certain types of microRNA in gliomas repeat the changes characteristic of other types of malignant neoplasms. Similarly, to genes proper, subdivided according to their effect on tumor pathogenesis on tumor suppressors and oncogenes, by now it is already possible to distinguish classes of microRNAs that also play opposite roles in the pathogenesis and progression of gliomas - oncogenes  and tumor suppressors . Studies of microRNA expression profiles have expanded our understanding of the mechanisms of progression of gliomas/glioblastomas, providing valuable information on the pathogenesis of these tumors and potential therapeutic targets  . DetectiNone.Albert Sufianov and Sema Begliarzade conceptualized and designed the study. All authors participated in the acquisition, analysis and interpretation of the data. Tatiana Ilyasova and Yanchao Liang drafted the manuscript. Ozal Beylerli contributed to critical revisions of the manuscript. All authors agreed on the journal to which the article would be submitted, gave final approval for the version to be published, and agreed to be accountable for all aspects of the work.The authors declare that no conflicts of interest exist."}
+{"text": "Hysterical disorders were considered separately in the context of the dynamics of the course of either endogenous affective diseases or schizophrenia, without attention to the conjugation and interaction of issues of hysterical symptoms and affective or psychotic syndromes.To test the psychopathological structure and provide a typology of the conjugation of hysterical symptoms with other psychopathological syndromes.120 patients (82 women and 38 men) with schizophrenic and affective disorders with associated hysterical symptoms were examined by a clinical psychopathological method.Three variants of conjugation were identified. In the group of hysterical disorders associated with affective diseases  the structure and dynamics of hysterical symptoms directly influenced the developing affective phase: the low intensity of hysterical symptoms contributed to the development of an apatho-adynamic type of depression, and bright and spontaneous hysterical manifestations formed an anxious-hypochondriac type of depression. Hysterical disorders formed in the structure of the psychotic state  influenced the nature, structure, dynamics and content of delusional, hallucinatory and paranoid disorders. \u201cCaste\u201d hysterical symptoms  revealed a lack of connection with affective and psychotic states. Hysterical symptoms were characterized by persistence, stability, invariability of manifestations, long-term psychotherapeutic and psychopharmacological resistance.Clinical and psychopathological analysis of endogenous mental diseases of the affective and schizophrenic spectrum, occurring with hysterical symptoms, showed that the parameter of the conjugation of hysterical symptoms with other psychopathological syndromes is prognostically significant.No significant relationships."}
+{"text": "The International Classification of Functioning, Disability and Health (ICF) provides a framework rooted in patient-centered care and the biopsychosocial model that facilitates a comprehensive description of a person\u2019s health and their level of societal participation. The importance of the ICF for assessing the needs of individuals with mental health problems (MHP) and intellectual disabilities (ID) is growing, especially in the social medicine.To describe the benefits and limitations of the ICF in clinical practice, pertaining to the assessment of healthcare needs and societal participation in persons with MHP and ID.Comprehensive literature search in medical databases using the Keywords: ICF, mental health, intellectual disabilities, social and occupational participation.ICF-based instruments such as the Mini-ICF-APP, with which impairments and competencies in social and occupational participation can be described, are playing an increasingly important role in healthcare and rehabilitation. In Germany, for example, in accordance with the Federal Participation Act, the entitlement to disability support benefits is assessed using ICF-based instruments, which therefore play a decisive role in social medical care.The functional descriptions of the ICF provide the opportunity for a standardized, yet individualized assessment of medical needs, general health and societal participation, thus facilitating the provision of a comprehensive package of care and support for people with disabilities. ICF-Core Sets and the Mini-ICF-APP are effective tools to describe level of function. It would be clinically valuable to further develop these instruments for use in persons with ID and MHP in the field of social medicine.No significant relationships."}
+{"text": "There are about 1.5 million internally displaced persons (IDPs) in Ukraine, which requires an assessment of their mental health.To develop a psychoeducational program aimed at informing about the clinical manifestations (markers of symptoms) of mental disorders, the possibilities of preventing their formation and options for action in conditions of the formation or exacerbation of a mental state.270 IDPs were examined. Methods: clinical-psychopathological, psychometric, statistical.Evaluation of the mental state of IDPs with symptoms of mental disorders (risk group (31.92%)) indicates the presence of various emotional disorders that formed individual syndromes \u2013 asthenic (41.18%), agrypnic (45.59%), somato-vegetative (30.88%), anxiety-depressive . The risk factors for the development of mental disorders in IDPs were identified - the older age is from 50 to 59 and the average age is from 40 to 49 years; lack of a complete family, lack of work, low level of social employment, lack of satisfactory living conditions, a significant decrease in the level of well-being, the preservation of the significance of factors of mental trauma, the presence of certain prenosological syndromes. The proposed psychoeducational program is built on the principle of thematic seminars with elements of social and psychological training.The implementation of the program provides a comprehensive impact on the cognitive, emotional, psychophysiological, behavioral and social aspects of personality functioning."}
+{"text": "The inter-organelle interactions, including the cytomembrane, endoplasmic reticulum, mitochondrion, lysosome, dictyosome, and nucleus, play the important roles in maintaining the normal function and homeostasis of cells. Organelle dysfunction can lead to a range of diseases , Parkinson\u2019s disease (PD), and cancer), and provide a new perspective for drug discovery. With the development of imaging techniques and functional fluorescent probes, a variety of algorithms and strategies have been developed for the ever-improving estimation of subcellular structures, organelle interaction, and organelle-related drug discovery with accounting for the dynamic structures of organelles, such as the nanoscopy technology and molecular dynamics (MD) simulations. Accordingly, this work summarizes a series of state-of-the-art examples of the recent progress in this rapidly changing field and uncovering the drug screening based on the structures and interactions of organelles. Finally, we propose the future outlook for exciting applications of organelle-related drug discovery, with the cooperation of nanoscopy and MD simulations. Cellular organelles with specific morphology and functions are highly dynamic in maintaining the normal operation of eukaryotic cell life activities , and theOrganelle bioimaging can aid our understanding of the organelle functions and the development of organelle-targeting therapy for various diseases. Conventional fluorescence microscopy (FM) opens the door to fine structural details of cellular architectures and dynamics, while the resolution is limited to approximately 200\u00a0nm because of the light diffraction . As the With the status of interactions between organelles in the improvements of pathogenesis and therapeutics, related articles are emerging as an endless stream. Recent advances in organelle-targeted fluorescent probes (FPs) provide us with a more suitable selection and high resolution scale under SRM . MeanwhiPrecise imaging of intracellular and subcellular structures and their dynamic processes are crucial to fundamental research in biology and medicine . Super-rWith the technical advancements in SRM, in practice, however, many factors can influence the achievable resolution, including the excitation and detection schemes, the properties of fluorescent probes (FPs), as well as the labeling and sampling density of FPs. SRM technologies have also enhanced the requirements of FPs, which need especially low cytotoxicity, high photostability, photobleaching resistance , and spevia STED method.The search for new therapies is a tedious process with long cycles and high risks . In the A receptor)   Figure  can obseeceptor) . The esteceptor) ] and deteceptor) ]. The tweceptor)  (Nakane eceptor)  and 2) ceceptor)  (Ng and eceptor) . In cryoeceptor) . The cryeceptor)  is a receceptor) . HoweverVia IPET and FETR, the adverse effect caused by the inclination error can be effectively limited, and the macromolecular center can be found more accurately, thus greatly improving the resolution of reconstruction results  is the most common malignant primary brain tumor in adults. However, existing treatments, such as surgery and chemotherapy, have little effect on glioblastoma stem cells (GSCs)  . After hAlthough the dynamic process of organelle interactions can be obtained by nanoscopy, it is still necessary to analyze the evolution behavior at the all-atom level. Molecular dynamics (MD) simulations could obtain structural and dynamical insight into organelle interactions at the all-atom level . MD simuin vitro. The rebalancing MD simulation force fields, based on experimental data on LLPS and without limiting specific coarse-particle sizes, not only perfect the interaction between proteins, but also correct the potential energy surface, improving the reliability of modeling interactions between membraneless organelles  techniques enable the observation of fluorescence images of subcellular organelles beyond the diffraction limit and arouse the discovery of mitochondrial lysosome contact (MLC), providing a new perspective on the drug screening and the treatment of diseases . HoweverThe ideal of organelle interaction research is to capture a series of atomic resolution images in active state in chronological order, construct the dynamic structures during the interaction processes, and deeply understand the details of conformational transitions and \u201cenergy motion\u201d transformation mechanism. Due to the limitation of current nanoscopy techniques, SRM and cryo-EM analyses cannot reach the atomic resolution or look at how a particular change over time trends. The two deficiencies could be partially compensated by molecular dynamics (MD) simulation. Although the computational power of MD simulation is far from being able to replace the experiments, through careful design, especially constrained by the key dynamic spatial and temporal data provided by nanoscopy (SRM and cryo-EM), it can provide sufficient information for the construction of the initial model. Combined with Coarse-Grained MD and all-atom MD simulations, it is expected to not only connect the dynamic evolution process of organelle interaction on a large scale (the application of CG models sacrifices degrees of freedom), but also analyze the evolution behavior of key dynamic nodes at the all-atom level , then summarize the physical characteristics and laws of the structure-activity changes of the system, and establish the correlation between the dynamic structure and function of organelles .With the continued advances in SRM, cryo-EM, and MD simulation, the combination of the three techniques and the cooperation of super-resolution time series and cryo-EM structure information will be an effective solution for the in-depth investigation of large-scale dynamic structural evolution and will provide new insight for the organelle interaction and drug discovery. It is promising to see the breakthroughs with this approach in the field of organelle-related drug discovery."}
+{"text": "Dementia is a neurodegenerative condition characterized by cognitive decline and increased functional dependency. With most persons living with dementia (PLWDs) residing at home, home-based interventions provide a convenient and individualized alternative for person-centered care. Most of the evidence focused on specific interventions or exercise-based activities; there remains a gap in understanding the impacts of a broader range of non-exercise interventions on PLWDs and their caregivers. This review aimed to understand the impacts of home-based, non-exercise interventions on the behavioral, functional, cognitive, and mood outcomes of PLWDs, and their caregiver's quality of life (QoL), burden and mood.Search for studies published up to June 2020 was conducted on CINAHL, PsycArticles, PubMed, SAGE Journals, Science Direct, and Web of Science. A search was also done manually based on the bibliographies of selected articles. The inclusion criteria for the systematic review were: (i) participants with a medical diagnosis of dementia, (ii) participants who resided at own home, (iii) intervention in the home setting, (iv) investigate interventions other than physical exercise, (v) randomized controlled trials (RCTs) or quasi-experimental studies, and (vi) full-text study published in English and in a peer-reviewed journal.Eighteen studies consisting of 14 RCTs and 4 quasi-experimental studies were included. Interventions included were occupational therapy, cognitive rehabilitation, tailored activity program, cognitive stimulation therapy, personalized reminiscence, music therapy, reality orientation, biobehavioral and multicomponent interventions. Results were mixed, but important intervention features were highlighted. Personalized activities for PLWDs that are aligned to their interest and ability appeared to contribute to intervention effectiveness especially in reducing behavioral symptoms and improving functional status. Involvement of caregivers in interventions is another feature of effective interventions for both the PLWDs and the caregivers' QoL, provided it is not deemed demanding or challenging to the caregivers. The inclusion of caregiver's education was effective in reducing caregivers' burden, particularly when the interventions improved the PLWD's functional status. Dementia is a neurodegenerative condition marked by cognitive decline that interferes with activities of daily living  leads to a decreased functional ability to live independently overtime  is PLWDs and their caregivers. The target intervention type is home-based, non-exercise interventions for dementia. N comparator factor (C) is being considered. The outcome variables (O) are PLWDs' behavioral symptoms, functional status, cognition and mood, as well as the impact on their caregivers in terms of caregivers' quality of life, their burden and mood. The study designs (S) included are randomized controlled trials and quasi-experiments.The reporting follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRIMA) guideline for systematic reviews and meta-analyses  were used to identify potential articles within the databases. In addition, the reference lists of all relevant full-texts and review articles were hand-searched for eligible articles.Studies were identified and retrieved from the beginning of time up to 30 June 2021 from the following electronic databases: CINAHL, PsycArticles, PubMed, SAGE Journals, Science Direct and Web of Science. A combination of Search terms with truncation and Boolean operators . Next, the full-text articles were screened for final inclusion in the systematic review by the same three reviewers. If no consensus was reached among the three reviewers, the plan was to discuss the case with the fourth author (DGH) until a final consensus was reached; but this option was not required.The inclusion criteria for the systematic review were: (i) participants with a medical diagnosis of dementia, (ii) participants who resided at home in the community, (iii) use of individualized intervention in the home setting for participants, (iv) investigate interventions with treatment components other than physical exercise, (v) randomized controlled trials (RCTs) or quasi-experimental studies, and (vi) full-text study published in English and in a peer-reviewed journal.Studies were excluded if (i) the intervention was conducted in group setting, (ii) the intervention was conducted in institutionalized settings, and (iii) the study focused solely on exercise-related intervention.The quality of each included study was examined independently by two reviewers among BMB, CS, and MML using the Joanna Briggs Institute (JBI) Critical Appraisal Tool Checklist for randomized controlled trials . The characteristics extracted were experimental design, participants' demographics, intervention protocol and components, outcome measures, and findings. After independent data extraction, the accuracy of the data was verified by one other reviewer. The data was analyzed and synthesized on the qualitative directionality of the effects reported in the included studies. The effects on the PLWDs were grouped into: (i) behavioral disturbance, (ii) cognition, (iii) mood, (iv) functional status. The effect on the caregivers of PLWDs in terms of (i) quality of life, (ii) mood, and (iii) burden were also analyzed.A total of 3,882 studies were identified through the screening of the different databases, with 2,444 studies remaining after duplicates were removed. After the advanced search filter (abstract and/or title) was used, 148 studies were screened, with 97 full-text studies obtained and assessed for eligibility. Eighty-five studies were excluded, with reasons such as the type of study design, ongoing studies, settings of the studies and interventions that were unrelated to the research topic. This resulted in a total of 18 studies being included. The PRISMA flow diagram for the current review is illustrated in Fourteen studies were RCTs and four studies were quasi-experimental studies. Among the 18 studies included n = 3), tailored activity programme or TAP (n = 3), cognitive stimulation, (n = 2), occupational therapy (n = 2), reminiscence (n = 1), music therapy (n = 1), reality orientation (n = 1), biobehavioral intervention (n = 1), and multi-component intervention (n = 4).The studies covered interventions that include cognitive rehabilitation , music therapy, ICST, reality orientation, cognitive rehabilitation and multicomponent interventions. Outcome measures consisted of Neuropsychiatric Inventory, Revised Memory and Behavior Problem Checklist, and Agitated Behavior in Dementia Scale.Studies using TAP reported significant reduction of behavioral disturbance when compared to the control groups , Caregiver Assessment of Function and Upset Scale (CAFU), Bristol Activities of Daily Living Scale (BADLS), Alzheimer's Disease Cooperative Study Group Activities of Daily Living Scale (ADCS ADL), Functional Independence Measure (FIM), Direct Measure of Training (DMT), Disability Assessment for Dementia (DAD), Independent Living Scale (ILS), Instrumental Activity of Daily Living Scale (IADLS), Barthel Index (BI), Assessment of Motor and Process Skills (AMPS), Interview of Deterioration of Daily Activities in Dementia (IDDD) and a 3-point scale on competence, questionable and ineffective steps and deficits.The interventions included in these studies were TAP , cognitive rehabilitation, reality orientation, memory rehabilitation with caregiver psychoeducation, and a multicomponent intervention. Outcome measures used across studies were the Rivermead Behavioral Memory Test, Alzheimer's Disease Assessment Scale\u2014Cognition, MMSE, Weschler Memory Scale-Revised, Behavioral Assessment of the Dysexecutive Syndrome, Dementia Rating Scale-2, Test of Everyday Attention, 8-Words Test and Memory Awareness Rating Scale.Significant benefit to cognition were reported in two studies  albeit the direction of change was counterintuitive.With a growing need to provide interventions for home-dwelling PLWDs, this review is the first of its kind to investigate the impact of home-based, non-exercise interventions on the behavioral disturbance, functional status, cognition and mood of PLWDs as well as caregivers' QoL, burden and mood.Tailored activities for PLWDs that are aligned to their interests and abilities appeared to contribute to intervention effectiveness especially in reducing behavioral disturbance and improving functional status. Involvement of caregivers in interventions is another feature of effective interventions for both the PLWDs and the caregivers' QoL and burden, particularly when the interventions are improving the PLWDs' functional status and provided the involvement is not deemed demanding or challenging to the caregivers. Longer duration of intervention and measurement are also critical in observing effectiveness.A reduced number and frequency of behavioral symptoms were reported in studies where the interventions were tailored toward the interests and abilities of the PLWDs  benefits cognition by delaying deterioration in cognitive reserves of PLWDs through intellectual and social stimulation (Duan et al., The current review also did not find evidence of home-based cognitive rehabilitation benefitting cognition as a secondary outcome despite improvement in functional abilities (Clare et al., All included studies were based in the Western context, hence the transferability of the findings to Asian contexts may be affected given the presence of different sociocultural factors in dementia care. The inclusion criterion of only using studies published in English could have further limited Asian studies published in different languages from being reviewed.The studies had used varied outcome measures for specific outcomes. For example, caregiver burden was measured using various outcome measures such as the Zarit Burden Scale and the Caregiver Burden Inventory. Hence the lack of standardization might have affected the accuracy of analyzed results.There are mixed findings on the evidence of home-based, non-exercise interventions in alleviating PLWD's behavioral symptoms, functional status and cognitive decline as well as their caregivers' QoL. Evidence for improving the PLWDs' mood and their caregivers' burden and mood is limited.Interventions that were tailored to the interest and abilities of the PLWDs alleviated their behavioral disturbance and functional decline. Longer interventions that incorporated reinforcement of strategies and involvement of caregivers in interventions benefits the PLWDs' cognition.When interventions actively involved caregivers and included caregiver education and concurrently yielded a positive impact on the functional abilities of the PLWDs, benefits to the caregivers' QoL and burden were observed. However, the caregivers' involvement must not be overly intensive or causing inconvenience lest increasing their burden.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.DT, BB, CC, and MT conceptualized the presented work. BB, CC, and MT conducted the systematic search, the title and abstract screening, the full text screening, extracted the data, conducted the reporting quality assessment, and drafted the first version of the manuscript as a report. DT supervised the project during each stage of the work. DT and B-SW drafted the manuscript for submission. All authors revised the manuscript for intellectual content and approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Complex neuro-immune-vascular interactions play key roles in the development of both neuroinflammation (an inflammatory response within the nervous system) and neurogenic inflammation (sensory nerve-released neuropeptides inducing inflammation in different tissues). Both phenomena have a substantial importance in the pathogenesis of several diseases and might be targets for pharmacological interventions.Therefore, the present Research Topic was designed to collect papers on the molecular mechanisms and pharmacology of pathological processes affecting neuro-immune-vascular interfaces, focusing on neurodegeneration, stroke, headache, neuropathic and other types of pain, as well as peripheral inflammatory diseases, such as arthritis or dermatitis. In addition, interactions between the peripheral and central nervous systems have also been explored.Neuroinflammation is usually accompanied by vascular reactions, including opening of the blood-brain barrier. In the present Research Topic, Inflammasomes were in the focus of the work of Inflammatory reactions may affect the peripheral nervous system as well. Inflammatory neuropathies are characterized by leukocyte infiltration of peripheral nerves, demyelination and axonal degeneration. Therefore, inflammation and pain control in chronic neuropathies is essential to improve the outcomes of the disease. Somatostatin released from capsaicin-sensitive peptidergic sensory nerve endings leads to anti-inflammatory and anti-hyperalgesic actions at distant parts of the body, through activation of the somatostatin receptor subtype 4 (SST4). Based on this knowledge, A specific subgroup of neuropathies, immune axonal neuropathies are described in the review of Finally, the paper of Altogether, as a result of the common effort of the Frontiers in Pharmacology team and the five guest editors, a balanced collection of original and review papers have been included in the Research Topic. Nine articles originating from six different countries cover a wide thematic range focused around inflammatory processes affecting the central and peripheral nervous systems."}
+{"text": "Over the last few decades, various adsorption functions of polymer hydrogels for the removal of hazardous pollutants have been developed. The performance of hydrogel adsorbents depends on the constituents of the gels and the functions produced by the polymer networks of the gels. Research on hydrogels utilizing the characteristic functions of polymer networks has increased over the last decade. The functions of polymer networks are key to the development of advanced adsorbents for the removal of various pollutants. No review has discussed hydrogel adsorbents from the perspective of the roles and functions of polymer networks in hydrogels. This paper briefly reviews the basic requirements of adsorbents and the general characteristics of hydrogels as adsorbents. Thereafter, hydrogels are reviewed on the basis of the roles and functions of the polymer networks in them for the removal of hazardous pollutants by introducing studies published over the last decade. The application of hydrogels as adsorbents for the removal of hazardous pollutants is discussed as well. Conservation of water environments and water resources is a critical issue of this century. Efficient purification technology to reduce water pollution is essential, along with the promotion of reduced emission of pollutants. In the treatment and remediation of large water bodies, adsorption is an effective method for the separation of low-concentration pollutants. In the treatment of wastewater containing hazardous substances, the adsorption method is also a candidate process owing to its simplicity and cost-effectiveness. Various cost-effective solid adsorbents such as zeolites, activated carbon, modified clays, and ion-exchange resins have been developed for water treatment. Inevitably, the efficiency of the adsorption process relies on the performance of the adsorbent. Organic polymer hydrogels comprising a three-dimensional polymer network and a solvent have been shown to act as adsorbents for heavy-metal ions, dyes, and other organic hazardous pollutants because of their high performance, simplicity of use, and diversity in adsorbent design. Over the last few decades, the development of hydrogel adsorbents that effectively utilize the functions of polymer networks has increased ,4,5,6,7.In this short review, the basic requirements for adsorbents and the general advantages and challenges in the application of hydrogels as adsorbents are first reviewed. Then, the characteristics, advantages, and subjects of hydrogels as adsorbents are reviewed based on the roles and functions of the polymer network of gels, with an overview of studies published in the last decade. This review offers engineers and researchers an opportunity to gain more knowledge on hydrogels as adsorbent candidates.The design and use of adsorbents in the adsorption separation process are essential for adsorption separation technologies. Adsorbents that meet requirements like material cost, minimal environmental impact, stability, uptake rate, reusability, and adsorption capacity for target adsorbates will be selected in practice. In the modern design of adsorbents, the physicochemical structure of the adsorbent can be tailored to target pollutants. In the design of the adsorption separation process, the parameters of both the adsorption equilibrium and the mass transfer in adsorbents are crucial ,9. The aThe typical approach for improving the adsorption capacity is micronization and increasing the specific surface area of the adsorbents. Fibrization of adsorbents, as observed in non-woven fabrics, has also been used in recent years ,11. A coFrom an adsorption engineering point of view, the adsorption performance depends on operational conditions such as the adsorber reactor type, solid\u2013liquid ratio, and solution\u2013adsorbent contact time ,9. When Some adsorbents include a local gel phase. In most cases, only an adsorbent in which the entire adsorbent consists of a gel phase is called a gel adsorbent. Polymer hydrogels have several advantages in their application as adsorbents. The polymer networks create percolation pores with the desired solvent content and pore size. The specific surface area of polymer hydrogels is not typically discussed because of their network structure with a large amount of solvent. Open pores created by the polymer networks in the gels enable adsorbates to percolate deep inside the gels quickly, thus facilitating the adsorption capacity of the gels. Gels with high solvent content exhibit excellent diffusional permeability toward a range of substances. The diffusivity of solutes in gels has been extensively studied, both experimentally and theoretically. Various mathematical models used to determine the diffusion coefficient in gels have been developed and summarized in studies published in the 1990s ,17. NeveHowever, hydrogels have some drawbacks. Mechanical strength is a significant issue in many applications of the gels. The mechanical strength is an essential factor for the practical use of hydrogels. Thus, the strength of hydrogels has been improved by polymer selection and the structural design of polymer networks, such as the use of stiff polymers, an increase in the degree of polymerization, and the crosslinking method. Composites have successfully resolved the subject of strength through immobilization in a stiff porous matrix, the introduction of fiber materials such as nano-cellulose ,37,38, pApplications in which these functions are suited have been explored in many fields. Studies reviewing gel adsorbents in the last decade are introduced as follows.Naseem et al. (2018) reviewed microgels as adsorbents for the removal of aqueous pollutants such as heavy metals, nitroarenes, organic matter, and toxic dyes . The micMany studies on natural polymer gels as adsorbents have been reported. Various adsorbents using natural polymers and biomass, such as alginate ,43, chitLim et al. (2019) reviewed molecular gels as adsorbents for environmental remediation and water treatment and indicated the advantages of molecular gels with large selective capacities for pollutant sorption and recovery . MoleculHande et al. (2015) reviewed ion-imprinted polymer gels (IIPs) . MethodoSamiey et al. (2014) reviewed organic\u2013inorganic composite adsorbents for heavy-metal ions based on the composite structure of the adsorbents . The merPolymer gels as adsorbents were classified based on the roles and functions of the polymer networks in their applications as follows. The simple use of hydrogels is for the immobilization of supports and carriers. Even in this simple application of hydrogels, they have various advantages. The incorporation of diverse materials, simple solid\u2013liquid separation, stabilization of the immobilized substances maintaining high dispersion, accumulation and enrichment of target substances inside the gels, and the size control of stable solvent droplets with the size of gels are distinct advantages of the gels. The difference between hydrogels and emulsions or liquid immobilizing capsules is that water is immobilized in the polymer network with percolating open pores, and mass transfer across the surface of the gels is not restricted. The size of gels and pores are controllable, and mass transfer in the gels is not reduced, owing to the large amount of water and the percolating open pores in the hydrogels, which are also effective for the immobilized microorganisms and macromolecules, such as antibodies and enzymes, to maintain their activity over a long time. Furthermore, gels can produce a hierarchical reaction field because zoning of embedded substances can be achieved owing to the immobilization property of the polymer network.co-acrylonitrile) composite gel immobilizing magnetic CoFe nanoparticles for the removal of Cr3+, Cd2+, and dyes  acrylamide) copolymer hydrogels [N-[3-(dimethylamino)propyl]methacrylamide (DMAPM)-co-N-tert-butyl acrylamide (TBAM) nanogels and applied them for the separation of carbon dioxide [N-isopropylacrylamide-N-tert-buthyacrylamide) copolymer gel slurry system [Ka shift is expected to yield a high-performance gel. To use this property, the mechanical strength of the gels to withstand repeated swelling operations is required. In addition, the gels must be micronized for a rapid response and adsorption. This process is energy-consuming when thermoresponsive gels are used because of the temperature-swing operation of the entire system. Therefore, it is crucial to devise methods to reduce energy consumption in practical applications. Effective utilization of the heat generated in chemical factories, steel mills, incinerators, etc. would increase the feasibility of these processes. Thin membranes fabricated on porous supports with nanosized particles of TBAM gels successfully achieved the energy-saving separation of carbon dioxide [Changes in the dissociation of ionic groups on the polymer networks occur depending on the volumetric change in the crosslinked polymer hydrogels. Weak acid-type or weak base-type ionic groups on the polymer chains undergo a shift in their dissociation equilibrium p the gel . This phydrogels . Honda e dioxide . Nagasawy system . A molec dioxide .3O4 nanoparticle-immobilized poly(3-acrylamidopropyl trimethylammonium chloride) microgels for the removal of AsO43\u2212 [3O4 nanoparticles effectively absorb oil spreading on the water surface, and the gels can be easily collected from the surface by the application of a magnetic field [Composite or conjugated forms of hydrogel adsorbents can increase the performance of the gel and the availability of the gels as adsorbents, considering the advantages of their use, cost, and material sharing from an ecological point of view. Adsorbents that exhibit advanced functions have been developed based on composite design. An example is the hydrogel embedding of magnetic nanoparticles . Solid\u2013lf AsO43\u2212 . The magic field . 2O), acrylamide\u2013acrylic acid sodium copolymer, and CuS for the storage of solar heat energy by light-to-thermal conversion  developed light-to-thermal conversion phase-change composite hydrogels consisting of sodium acetate trihydrate  matrix for immobilization of nano- and microsubstances, (2) scaffold for the strategic immobilization of functional groups, (3) stimuli-responsiveness of the polymer network, (4) contaminant uptake by self-assembly and gelation processes, (5) ionic and molecular imprinting, (6) integrated reaction field, and (7) dissociation control of ionic groups via volumetric control of the gel. Hydrogels have the diversity of creating various adsorbents suitable for capturing potential pollutants using the available functions as indicated in this review. Hydrogel adsorbents have the potential to create a functional adsorption process with a small environmental impact by integrating multiple functions into the gels. The variety of structural designs and functions of gel adsorbents would continue to expand their application. This is an era of comprehensive design of adsorbents and adsorption processes. In the life cycle of an adsorbent, green technology based on both adsorbent design and the optimum adsorption process is required. However, this effort is still in its infancy."}
+{"text": "The human microbiota is equivalent to the major organs of the adult human body like the brain and liver, in terms of weight ~1.5 kg) and functionality. The gut, oral cavity, skin, and vagina are major residing homes of the human microbiota. The human microbiota comprises bacteria, viruses, archaea, fungi, and protozoans. Recent studies have revealed the presence of functional microbiota in blood, atherosclerotic plaques, adipose tissues, and other organs. Microbiota and their metabolites play a key role in insulin resistance, atherosclerotic plaque formation, inflammation, oxidative stress, and the metabolism of drugs and chemicals  is becoming predominant among heart failure conditions. Hence, Shen et al. review its relationship with gut microbiota. A wide range of data on different microbial metabolites such as short-chain fatty acids, trimethylamine-N-oxide, and their molecular pathway leading to thrombus formation are discussed. In addition, the future therapeutic perspectives based on intervention in microbiota are elaborately presented.Atherosclerosis is the thickening of the blood vessel that aids different cardiovascular diseases. Aside from the different molecular pathways proposed for the formation of atherosclerotic plaques, recent research also suggests the role of microbial metabolites in this process . The bloYang et al. employed the in vitro and mice models to investigate the impact of Chinese rice wine metabolites on gut microbiota and subsequent impacts on diabetic cardiomyopathy. The mice treated with rice wine polyphenols and polypeptides led to a proliferation of Akkermansia and depletion of Desulfovibrio genera. A significant correlation was observed between the cardiac markers and microbiota profile, indicating the microbiota-mediated therapeutic impact.Dietary exposure, environment, and host genetics are the key players in shaping the microbiota of a human . The impIonescu et al. provide a comprehensive review of the studies related to microbiota and miRNAs and propose the mechanisms for the synergism between gut microbiota and host miRNAs during cardiovascular diseases.The gut microbiota interacts with numerous host factors and thereby influences host physiology and pathology. Numerous studies have revealed the role of microRNAs (miRNAs), the small, non-coding RNAs of mammalian origin that negatively regulate gene expression at the post-transcriptional stage. During the past decade, several studies have revealed the role of gut microbiota and miRNAs in different cardiovascular diseases . IonescuShanmuganathan et al. investigate the variation in the microbiota of human intervertebral disc tissue of healthy donors and patients with cardiovascular diseases undergoing surgery. The study reveals the abundance of proteobacteria (particularly the Pseudomonas genus) and firmicutes phyla in the degenerated disks. There is a significant loss in microbial diversity with an abundance of pathogenic bacteria in the degenerated disks.Recent studies explored the presence of microbiota in traditionally considered sterile tissues such as the liver, pancreas, breast tissue, and bone in both healthy and cancer tissues . In contOverall, this Research Topic provides different dimensions on the role of human microbiota during cardiovascular and other metabolic diseases. The major drawback in microbiota and disease studies is the non-exploration of the chicken and egg hypothesis, i.e., the cause and effect. At this moment, further studies are needed to explore the etiology of changes in the microbiota. We are hopeful that microbiota-based therapeutic approaches discussed here including fecal microbiota transplantation, probiotics, and prebiotic intervention with plant-derived metabolites will evolve into routine clinical practice in the near future.All of the contributors contributed to the Editorial process and approved this Editorial article."}
+{"text": "A mental health (MH) assertive community treatment (ACT) is always designed expecting for a decrease in the pressure (visits and readmissions) in inpatient services and to increase care quality. An appropriate management of ACT provision can be crucial to develop a balanced community-based MH ecosystems.To assess the impact of the ACT on the performance of the MH ecosystem of Bizkaia .The ecosystem is structured by 19 MH areas, supported by 5 ACT teams. Here ACT provides high intensity mobile outpatient care to people suffering from severe mental disorders. The impact of these teams on the ecosystem performance was assessed by Monte-Carlo simulation, the Data Envelopment Analysis (DEA) and fuzzy inference. The input variables were the availability, number of psychiatrics, nurses and total of professionals of ACT services in each area. The outputs were: frequentation, incidence and prevalence of ACT services in each MH area. Performance indicators were: relative technical efficiency (RTE), statistical stability and entropy.The global ecosystem performance was high , the stability was medium-low  and the entropy was medium-high .Results highlighted a positive impact of ACT in Bizkaia. Nevertheless, stability and entropy levels showed the existence of a high structural variability in ACT services due to the necessity of adjusting them to the user\u2019s specific needs.No significant relationships."}
+{"text": "GNAS and TP53 mutations, and the diagnosis of OS arising from FD was strongly supported. This case highlights the characteristic images and molecular features of the malignant transformation of FD.Fibrous dysplasia (FD) is a benign fibro-osseous lesion that frequently involves the craniofacial bones and femur. Malignant transformation of FD is a rare occurrence. We report a 38-year-old woman with osteosarcoma (OS) arising from FD of the femur. Magnetic resonance imaging revealed a well-defined lesion in the medulla of the femur, with cortical thinning and local bone destruction. Wide excision of the femur was performed. Grossly, the inner part of the mass was hard and tan-gray in color, and the outer part of the mass adjacent to the cortex showed myxoid discoloration with infiltrative borders. Microscopically, most of the tumor consisted of curvilinear woven bone and fibrous stroma with bland spindle cells, which transitioned to the outer portion of the tumor, showing cellular proliferation of pleomorphic cells with frequent mitotic activity. Next-generation sequencing revealed"}
+{"text": "In conclusion, the presence of OSA does not increase the need for glaucoma management.We try to evaluate glaucoma management numbers in patients with both glaucoma and obstructive sleep apnea (OSA) using the National Health Insurance Research Database (NHIRD) of Taiwan. A retrospective cohort study was conducted and patients with glaucoma were enrolled and divided into the OSA and non-OSA populations. A total of 11,778 participants were selected in both the OSA and non-OSA groups. The primary outcomes were the number of anti-glaucomatous medications each year and the total number of glaucoma laser and glaucoma surgeries. The Cox proportional hazard regression was utilized to produce the adjusted hazard ratios (AHR) with corresponding 95% confidence intervals (CI) between the two groups. After a study period of 18 years, 286 and 352 events of laser and surgeries for glaucoma were found in the OSA and non-OSA groups, respectively. After considering the effect of potential confounders, no significant difference concerning the numbers of laser trabeculoplasty, trabeculectomy and tube shunt surgery, cyclodestructive procedure and eyeball removal were found between the two groups . In addition, the multiple anti-glaucomatous medication usages were similar between the two groups (all  Glaucoma is a prevalent ocular disease that causes large numbers of visual impairments and legal blindness worldwide ,2. AccorRegarding the risk factors of glaucoma, old age is a well-established predisposing factor for glaucoma, and individuals aged older than 40 years are under a higher risk of glaucoma development and the prevalence of glaucoma reached 3.3% percent in those aged more than 70 years old ,7,8. RefObstructive sleep apnea (OSA) is a disease resulting from impaired ventilation , which cThe purpose of the current study is to survey the management numbers of glaucoma between OSA and non-OSA patients using the National Health Insurance Research Database (NHIRD) of Taiwan. The management of glaucoma is based on the number of anti-glaucomatous medications, arrangement of laser treatment and performance of glaucoma surgery.The NHIRD contains claims data of the National Health Insurance of nearly all inhabitants in Taiwan between 1 January 2000 and 31 December 2018. Our study obtained these data from the Longitudinal Health Insurance Database 2005 (LHID 2005), which is a sub-database of NHIRD and contains the records of nearly 2 million patients, which were randomly sampled from the NHIRD registry in the year 2005, and their data were connected from 2000 to 2018. Both the Ninth and Tenth Revisions of International Classification of Diseases were used for disease diagnosis in the NHIRD/LHID 2005. The accuracy of diagnosis is dependent on the physicians who enter the codes, and the system also provides the demography, time of medical visit, department codes, insurance codes of examination and codes of medications.We defined individuals as having glaucoma if their medical documents revealed (1) the presence of a glaucoma diagnosis; (2) the arrangement of intraocular pressure (IOP) measurement before glaucoma diagnosis; (3) the arrangement of visual field test, optical coherence tomography or fundoscopy before or on the same day of glaucoma diagnosis; and (4) the receipt of glaucoma diagnosis in ophthalmic outpatient department (OPD) and received treatment by an ophthalmologist. The index date was the date that the glaucoma diagnosis was entered into the NHIRD/LHID 2005. The exclusion criteria in this study were illustrated as follows: (1) receipt of legal blindness diagnosis before the index date; (2) receipt of an ocular tumors diagnosis at any time; (3) receipt of endophthalmitis or severe ocular trauma diagnoses at any time; and (4) outcome develops before the index date. Then, the patients with OSA were selected from the whole glaucoma population based on these criteria: (1) the presence of an OSA diagnosis, (2) the arrangement of polysomnography before the OSA diagnosis, and (3) the OSA diagnosis was entered by a thoracologist, otorhinolaryngologist or neurologist. After that, each individual with both OSA and glaucoma was matched to one glaucoma patient without OSA via the propensity score-matching (PSM) method according to demographic data, co-morbidities and medications listed in the following sections, and the non-OSA population constructed the control group. Subjects in the OSA group that could not be matched to one non-OSA patient were excluded from this study. A total of 11,778 patients were enrolled in both the OSA and non-OSA groups after the selection process. In addition, participants in the study population were categorized into OAG, NTG and ACG subgroups according to the diagnostic codes and differences in outcomes of these subgroups between OSA and non-OSA populations were analyzed. The flow chart of subject selection is revealed in The performance of glaucoma treatments, which were the primary outcome of our study, was defined as the following: (1) the number of topical anti-glaucomatous medications used, which included beta-blockers, alpha agonists, carbonic anhydrase inhibitors, prostaglandin, and miotic agents; (2) the arrangement of laser trabeculoplasty; (3) the arrangement of trabeculectomy and tube shunt surgery; (4) the arrangement of cyclodestructive procedure; and (5) the arrangement of eyeball removal. To prevent the overestimation of the primary outcome, the primary outcome was considered to develop only in patients who received introductory diagnostic codes, medical prescriptions and surgical treatments from an ophthalmologist.To make secure that the health status and the potential risk factors of advanced glaucoma between the OSA group and non-OSA group are sufficiently comparable, we investigated the influence of enrollment years, age, sex, urbanization, education level, and the following morbidities and medications in the multivariate model: hypertension, DM, ischemic heart diseases, hemodialysis, cerebrovascular disease, uveitis, cataract, refractive error, and steroid application including topical and systemic prednisolone, methylprednisolone, hydrocortisone, triamcinolone and dexamethasone. We longitudinally followed the data from the index date until the date of each outcome achievement, subject withdrawal from the National Health Insurance program, or till the end date of NHIRD/LHID 2005, which is 31 December 2018.p < 0.05, and p values less than 0.0001 were presented as p < 0.0001.The SAS version 9.4  was applied for all the analyses. After PSM of the OSA and non-OSA groups at a 1:1 ratio, descriptive analyses were used to show the difference of basic characters between the two groups, and the absolute standardized difference (ASD) between the two groups was also calculated and an ASD < 0.1 was regarded as a similar value. Then, the incidence rate and the adjusted hazard ratios (AHR) with corresponding 95% confidence intervals (CI) of primary laser and surgical outcome between the two groups were yielded through Poisson regression and Cox proportional hazard regression. The Cox proportional hazard regression incorporated the demographic data, systemic comorbidities, ocular comorbidities and steroid utilization. In the subgroup analyses, we stratified the OSA and non-OSA groups via age, gender, glaucoma subtypes , the duration of OSA, and the presence of OSA-related surgery . We then compared the incidence of laser trabeculoplasty, trabeculectomy and tube shunt surgery, and cyclodestructive procedure via the Cox proportional hazard regression again. Of note, the eyeball removal was not compared at this stage due to insufficient patient numbers. We produced the Kaplan\u2013Meier curve to illustrate the cumulative incidence of laser and surgical management between the two groups, and used log-rank test to determine the significance between two survival curves. For the anti-glaucoma medications, the percentage of any anti-glaucomatous medication usage and the percentage of more than one type of anti-glaucomatous medication applications between the two groups in every year was analyzed via independent T test and presented as a line chart. The statistical significance was regarded as The baseline characteristics between the OSA and non-OSA groups are shown in p > 0.05). Regarding the numbers of anti-glaucomatous medications, both the percentage of any anti-glaucomatous medication usage and the percentage of multiple anti-glaucomatous medications application showed similar values between the OSA and non-OSA groups   .In the subgroup analyses, the glaucoma patients aged more than 60 years and with OSA received significantly fewer trabeculectomy and tube shunt surgery compared to the glaucoma patients aged more than 60 years without OSA . However, the incidence of glaucoma laser and surgical managements demonstrated similar values in all other subgroups stratified via age, gender, glaucoma subtype including the OAG, NTG and ACG, OSA duration, or presence of OSA-related surgeries  .In our study, we found that co-existing OSA in glaucoma patients does not increase the incidence of advanced glaucoma management such as laser treatment and glaucoma surgery. Moreover, the percentage of patients with more than one anti-glaucomatous medication usage is similar between the OSA and non-OSA populations. On the other hand, the ratio of trabeculectomy and tube shunt surgery is lower in those glaucoma individuals with OSA and aged more than 60 years old.The association between OSA and glaucoma has been evaluated for decades . GeneralThe current study illustrated that the percentage of multiple anti-glaucomatous medication applications, the incidence of glaucoma laser therapy, and the ratio of glaucoma-related surgeries are similar between the OSA and non-OSA groups after adjusting multiple potential risk factors including steroids. To our knowledge, few studies have surveyed this issue concerning glaucoma severity and concurrent OSA before. Although some studies have proposed that glaucoma severity was associated with OSA ,21,22, tIn the subgroup analyses of this study, the impact of OSA on glaucoma management did not alter with different conditions. The only significant finding is the lower incidence of trabeculectomy and tube shunt surgery in the OSA population older than 60 years old than in the non-OSA population with the same age interval. The possible explanation is that the OSA-induced ocular surface irritation and retinal diseases meant that the patients came to the ophthalmic department more frequently ,32, and Regarding the demography between the OSA and non-OSA groups, the majority of covariates revealed similar distribution between the two groups even though OSA was diagnosed more commonly in males and those with metabolic disorders ,35,39. TThere are several limitations presented in the current study. Firstly, the claimed database nature of our data source meant that many important indexes could not be accessed, which included the polysomnography results throughout the OSA management, the application of continuous positive airway pressure device, the arrangement of weight-loss therapy, the details of the OSA treatment course, the results of glaucoma-related examination including the visual field optical coherence tomography, the fluctuating of IOP after treatment in both the OSA and non-OSA groups, the controlling of IOP and glaucoma damage progression after glaucoma management, and the exact severity of glaucoma and other ocular diseases. Because the IOP value was unknown in the NHIRD/LHID 2005 and the main mechanism of OSA-related glaucoma could be hypoxia and ischemia ,13,19, wIn conclusion, the presence of OSA does not affect the management numbers of glaucoma concerning anti-glaucomatous medications, laser treatments and glaucoma-related surgeries. Furthermore, the insignificant effect of OSA on glaucoma management is universal in different types of glaucoma including OAG, NTG and ACG. Consequently, the therapeutic program of newly diagnosed glaucoma should not be altered in those with OSA. A further large-scale prospective study to evaluate the effect of continuous positive airway pressure devices on the severity and management of glaucoma in OSA individuals is mandatory."}
+{"text": "Globally, cancer ranks among the most common causes of death, especially among people under 70 years of age . With thAfrica is considered the most vulnerable continent in the world with regards to the availability of resources for optimal health care provision and comprises about 85.2% of countries that belong to the low-income/lower-middle-income economies . Also, mWe examine the implementation status of AI platforms for cancer outcomes in Africa and provide pointers that could maximize their utilization.The uptake of technology-driven systems available in developed regions is slower in Africa than in other parts of the world, as these platforms are often generated from integrative variables that may not be available for external validation and clinical application in many African settings. For oncology, this may be further challenged by the variation in molecular or etiological subtypes, as well as infrastructural and ethnocultural peculiarities of cancer management in the African region ,8. A preGenerally, the development of AI tools for assisted decision-making among patients with cancer in Africa can be considered a recent endeavour, with many models being reported from 2018 (Relative to the different subregions in Africa, the pattern of AI penetrance mirrors the ongoing economic and infrastructural development in the continent ,27. As sMoreover, oncological AI-based models in Africa were being considered for outcome determination among patients with breast, cervical, and colorectal carcinomas (The technical aspects of the development and validation of cancer-related AI models in Africa is generally satisfactory (The performances of the set of models proposed for use in African oncological settings so far were satisfactory to excellent upon validation -12,14,18Applying AI in developing credible tools for the prediction of cancer outcomes in Africa is a relatively recent endeavour. Model construction in the continent reflected the degree of technological advancement among the nations, as well as the availability of electronic health records and digitized clinical investigations. None of the models developed locally and internationally have been assessed for their impact and efficiency in automated assistive clinical decision-making and risk stratification. Hence, this should represent the phase of AI implementation to be addressed soon, especially in numerous remote areas of the low- and lower-middle-income areas. Likewise, for these settings, it is expected that the future will see the integration of AI-based prediction and other digital health technologies to mitigate the challenges of reduced manpower, substandard facilities, and lack of access to care currently experienced in cancer diagnosis and management in Africa."}
+{"text": "Even though numerous studies on the systemic administration of antimicrobial drugs can be found in the literature, they still have many shortcomings related to the site-specific drug delivery, unwanted side effects and even potential toxicity. To overcome the above limitations, it is necessary to explore new approaches for the administration of active principles with antimicrobial properties.In this Special Issue, original papers have been published that bring new perspectives in the development of novel pharmaceutical formulations for antimicrobial applications. Active principles with antimicrobial properties, such as antibiotics ,2,3,4,5,A first study, in which the Chapman University School of Pharmacy, Chapman University Irvine, USA and the Department of Ophthalmology School of Medicine, University of Pittsburgh School of Medicine, USA collaborated, was designed to evaluate the stability of vancomycin eye drops in normal saline solution, phosphate-buffered saline (PBS) and balanced salt solution (BSS), while being stored for 7, 14 and 28 days at room temperature or refrigerated [Two other research teams from the Interdisciplinary Excellence Centre, Faculty of Pharmacy, Institute of Pharmaceutical Technology and Regulatory Affairs, University of Szeged, Hungary and the School of Engineering, Institute for Materials and Processes, University of Edinburgh, UK studied the preformulation of poly(vinylpyrrolidone)-based nanofiber mats loaded with ciprofloxacin (CIP) for oral administration . The aimAnother study involving researchers from Turkey, UK and Romania presents the fabrication of bacterial cellulose (BC)/polycaprolactone (PCL) patches loaded with different antibiotics (amoxicillin (AMX), ampicillin (AMP) and kanamycin (KAN)) for transdermal delivery . The obtC. trachomatis serovar D laboratory strain and the clinical isolate C. trachomatis serovar F. All tested liposomes efficiently delivered AZT to HeLa 229 cells infected with the laboratory Chlamydia strain, showing minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of AZT even 4\u20138 times lower than those obtained with free AZT. Also, AZT-loaded liposomes were effective against the clinical Chlamydia strain by decreasing the MIC values by two-fold compared to free AZT.A multidisciplinary research team from Hungary and Croatia managed to prepare and test several new formulations based on elastic liposomes loaded with azithromycin (AZT), which differ in surface charge  . Their aThree Research Institutes from M\u0103gurele, Romania and three other Departments from the Faculty of Biology, University of Bucharest, Romania developed composite materials based on bioglass/ciprofloxacin/poly(methyl methacrylate) as multifunctional thin films for hard tissue implants . BrieflyCandida albicans infection.A stable and highly skin-permeable topical delivery system for itraconazole (ITZ) was obtained and tested by a multidisciplinary research team in Korea . This toAnother study that sought to obtain pharmaceutical formulations based on antifungal drugs was published following collaboration between researchers from Saudi Arabia and Ethiopia. Butenafine hydrochloride nano lipid carrier (NLC) formulations were obtained and optimized . The optLactobacillus acidophilus, Bifidobacterium animalis) combined with actives from Helianthus tuberosus and Plantago ovate as herbal prebiotics. The results obtained are encouraging and attest to the great potential of the obtained nutraceutical formulations for their designated purposes, recommending them for further in vivo studies.As is known, modulation of the immune system refers to a certain alteration in the immune response in the form of stimulation, amplification, expression or inactivation of some stage of the immune response. A material which exhibits a modifying immune system response to a threat is an immunomodulatory and this concept currently underlies the development of functional foods. The study of a group of researchers from Romania  aimed toS. aureus and K. pneumonia, but low activity for P. aeruginosa and E. coli, and may be considered non-cytotoxic. The swelling behavior, the mechanical properties, and the antimicrobial activity recommend the use of this biocomposite in biomedical applications as wound or oral dressings.Another group of Romanian researchers proposes a new type of full-IPN hydrogel, based on chitosan and poly, obtained by combining two cross-linking methods: covalent and physical. In fact, the authors obtained a biocomposite consisting of silver nanoparticles dispersed in the matrix of IPN, designed to exert a synergistic antimicrobial activity through the action of both chitosan and silver . The bioS. aureus, E. coli, and K. pneumonia.The same type of matrix (with hydrogel character), but covalently cross-linked with glutaric aldehyde, was used to disperse ZnO particles in order to obtain a biocomposite proposed for the treatment of bacterial infections . The incA review discusses the possibility of using plant materials in the management of many inflammatory diseases, including periodontitis\u2014one of the most serious oral diseases which affects tissues, being caused by pathogenic bacteria and environmental factors . It is wStaphylococcus aureus and Escherichia coli, and high selective antiviral activity against the H1N1 influenza virus, with minimum host toxic effects.In another paper of this issue, harmala alkaloid-rich fraction (HARF) (which is hydrophobic) was included in 2-hydroxy propyl-\u03b2-cyclodextrin to obtain a host\u2013guest complex; by doing so, the water solubility and bioavailability of HARF was improved . The com2 and grafted with poly [Escherichia coli was eradicated at pH 6\u20137 and humidity 45\u2013100%, conditions in which most bacterial and fungal strains thrive.The last paper of the issue concerns the preparation of ligand brush nanocapsules, based on poly(vinyl pyrrolidone), coated with SiOum salt) . The ligPharmaceutics, titled Pharmaceutical Formulations with Antimicrobial Properties, are researchers with decades of experience in the field of controlled drug release, and they consider these articles reporting recent results concerning the obtaining of polymer\u2013drug systems, their properties and their biomedical applications justified and useful.The editors of this Special Issue of Pharmaceutics with the results of their recent research.The editors express their gratitude for the kindness and cooperation of the contributors, who are reputable researchers in the field and have responded to our call to contribute to this Special Issue of"}
+{"text": "Sensitive indicators of nursing quality focus on the core elements of nursing quality management. Nursing-sensitive quality indicators will play an increasingly important role in the macro and micro management of nursing quality in my country.  This study were aimed at formulating the sensitive index management of orthopedic nursing quality based on individual nurses for improvement of the quality of orthopedic nursing.  Based on the previous literature, the existing challenges in the early application of the orthopedic nursing quality evaluation index were summarized. Moreover, the management system of the orthopedic nursing quality-sensitive index based on individual nurses was devised and implemented, including monitoring the structure and result indices of individual nurses on duty and sampling the process indicators of patients managed by individual nurses. At the quarter-end, the data analysis was performed and fed back to determine the key points of the changes in the quality of specialized nursing affecting the individual, and the PDCA method was utilized for persistent improvement. The changes of sensitive indices of orthopedic nursing quality before (July-December 2018) and 6 months after implementation (July-December 2019) were compared. P < 0.05).  There were significant differences in other indices  ( The formulation of an individual-based orthopedic nursing quality-sensitive index management system modifies the traditional quality management model, improves the specialized nursing level, contributes to the accurate core competence training of specialized nursing, and improves the quality of specialized nursing of individual nurses. Consequently, there is an overall improvement in the specialized nursing quality of the department, and fine management is attained. The sensitive indicators of nursing quality are nursing guidelines, regulations, procedures and methods formulated according to the content, characteristics, processes, management requirements of nursing work, and the characteristics and needs of nursing staff. Sensitive indicators of nursing quality are also yardsticks for measuring nursing work. The establishment of a systematic, scientific, and advanced nursing standardization system is conducive to improving the quality of nursing and nursing management and promoting the development of nursing disciplines and the training of nursing talents. On the basis of the above standards, each hospital formulates basic nursing quality standards, critically ill patient nursing quality standards, nursing documentation quality standards, and other standards but lacks specialist nursing quality standards. In the field of orthopedic nursing, domestic and foreign countries only focus on the evaluation of certain orthopedic diseases or individual nursing problems and lack comprehensive and overall orthopedic nursing quality standards. Sensitive indicators of nursing quality focus on the core elements of nursing quality management, and nursing-sensitive quality indicators will play an increasingly important role in the macro- and micromanagement of nursing quality in my country. Quantitatively identify nursing practices that are most relevant to patient outcomes in an effort to improve patient safety and quality of care , 2. The Previously, indicator management was based on the integrity level of wards, departments, and hospitals \u20138; howevThe Department of Orthopedics of our hospital is a national key construction discipline, integrating trauma, joint, and spine surgeries, bone oncology, microsurgery, sports medicine, and other specialized disease treatment disciplines. Seventy-seven orthopedic nurses were included as the study participants, with the age ranging from 22 to 42  years; title: one deputy chief nurse (1.30%), 13 chief nurses (16.88%), 51 nurse practitioner (66.23%), and 12 nurses (15.58%); working years: 29 (37.66%) with <5 years, 30 (38.96%) with 5\u2013 10 years, seven (9.09%) with 11\u2013 15 years, and 11 (14.29%) with >15 years; and posts: 19 nursing team leaders or specialized nurses (24.68%), 22 senior nurses (28.57%), and 36 junior nurses (46.75%).The following are the inclusion criteria: (i) clinical practical nurses registered with the Provincial Health Commission, (ii) clinical practical nurses registered with the Provincial Health Commission, (iii) clinical practical nurses registered with the Provincial Health Commission, with at least orthopaedic nursing work (1 year). The following are the exclusion criteria: (i) nursing managers (head nurses), nurses without a nursing practice certificate were excluded; (ii) working in orthopaedics for <1 year, with long-term leave; and (iii) sick leave, maternity leave; or studying abroad for more than 15 days (nurse).P < 0.05). Structural indicators  Establishment of a Specialist Nursing Quality Control Group. In January 2019, a specialist nursing quality control group was established. The group members comprised the department nursing director, district nursing director, and specialist nurses, with a total of 10 members. The inclusion criteria for team members were bachelor degree or above; rigorous scientific fact-finding attitude; rich nursing expertise, strong thinking, and judgment; experience in nursing quality evaluation; 10 or more years of experience in orthopedic nursing or management; and intermediate level or above. The responsibilities of the team members include organizing core competency training based on sensitive indicators and performing individual nursing quality personalized management  for individual nurses based on sensitive indicators.(2) Core Competency Training Based on Sensitive Indicators. The core competency training of orthopedic nurses includes the theoretical knowledge and practical skills related to sensitive indicators which are included as important elements of clinical practice competency. From January to March 2019, pretraining on personalized management of nursing quality of orthopedic nurses is organized and implemented. Content of the training included overview and interpretation of orthopedic nursing quality sensitive indicators, the connotation of indicators theoretical knowledge, nursing processes, and standards and application of orthopedic nursing quality sensitive indicators for nursing quality management; methods of training and assessment: theoretical lectures, case teaching, operation demonstrations, business visits, objective structured clinical examinations, skill training, and assessment; training hours: 120\u2009h/person.(3) The Specialist Nursing Quality Control Team Performing Individualized Monitoring and Improvement of Indicators. Individualized monitoring of structural indicators (nurse-patient ratio) and some outcome indicators  are conducted, that is, monitoring the nurse-patient ratio and outcome indicators during the shift of the responsible nurse. Patients who were under the charge nurse's supervision throughout the hospital stay were monitored for outcome indicators (patient satisfaction at discharge). To investigate satisfaction, the hospital's revised \u201cPatient Satisfaction Questionnaire\u201d was distributed at the time of discharge, which included patient satisfaction with the medical environment, quality of care, professional skills of nurses, and service attitude of nurses. The survey forms were placed in the satisfaction survey box by patients or family members to reduce human interference factors. The process indicators including accuracy of blood circulation assessment in limbs, the accuracy of neurological function assessment, the accuracy of pain assessment, the passing rate of postural care, and accuracy of rehabilitation behavior training of the patients under the charge of this responsible nurse were sampled, and record forms were filled out. Moreover, members of the quality control team served as quality inspectors, and each nurse was continuously sampled for each indicator five times/quarter, and the total number of times each nurse sampled for the five indicators was 25 per quarter. The quality of the nurses' process of implementing specialized care was assessed to determine if the content was comprehensive, the method was correct, and the results were consistent with the quality inspector's evaluation. When the two evaluation results were inconsistent, another quality inspector made a judgment, and if necessary, the competent professor of the patient was asked to implement the evaluation and provide guidance.Quarterly data entry of quality evaluation was performed to establish a database of sensitive indicators of orthopedic nursing quality based on individual nurses. At the end of each quarter, the quality management team analyzed the above data by calculating each nurse's indicator value, comparing the growth rate of each nurse's indicator value to the previous quarter, comparing the difference in indicator values between nurses at the same level of position, comparing the difference between each nurse's indicator value and the indicator target value for nurses in the same level of position, and providing feedback to the individual nurse on the results of the analysis and the individual finding the impact of individual specialty nursing The results of the analysis are fed back to the individual nurse, and the individual identifies priorities for continuous improvement that affect individual specialty care changes. Simultaneously, targeted training is provided at the ward and unit level for nurses with large differences in indicator values and fluctuating indicator values, and specialty nursing core competency training is implemented based on individual nurses. For example, the pain assessment accuracy of a nurse's patients was the lowest among the process indicators and lower than the pain assessment accuracy of nurses in the same level of positions. The individual detected that the reasons affecting his low pain assessment accuracy were his lack of mastery of the use of different pain assessment scales, subjective judgment during pain assessment, and lack of timely assessment after implementing pain interventions. The individual proposed improvement measures, including changing the concept of pain, believing in the patient's chief complaint, learning relevant knowledge, and writing a case report on pain assessment in conjunction with the case; asking the district nurse manager or pain specialist nurse for bedside guidance; and self-evaluating the accuracy of pain assessment and comparing it with the evaluation results of the QI officer.\u03c72 test was used to compare the differences between the two groups with a test level of \u03b1 = 0.05. The types of diseases in which nurses performed care before and after implementation included extremity fractures, multiple injuries, pelvic fractures, brachial plexus injuries, hand trauma, osteoarthritis of the knee, femoral head necrosis, femoral neck fractures, femoral trochanter fractures, knee ligament injuries, knee meniscal injuries, lumbar disc herniation, cervical spondylosis, scoliosis, spinal cord injury, spinal fracture, extremity bone tumor, and sacral tumor. The differences in patients' sex, age, diagnosis, surgery, and condition classification were comparable and not statistically significant (P > 0.05). The results of the discharge patient satisfaction survey were selected for statistical analysis from the questionnaires completed by patients who had implemented the process index evaluation.Statistical analysis was performed using SPSS 20.0 software to compare changes in orthopedic nursing quality sensitivity indicators before implementation (July-December 2018) and 6 months after implementation (July-December 2019). Percentages were used for descriptive analysis and the P > 0.05). The incidence of external fixation complications in high-risk patients was 0.65%, the incidence of deep vein thrombosis was 0.52%, and the incidence of respiratory obstruction was 0.13%. In high-risk patients, the incidence of deep vein thrombosis was 0.13% and the incidence of respiratory obstruction was 0. Comparing the process indicators of nurse management at different levels with the results of patient discharge satisfaction, all indicators except the accuracy rate of neurological function assessment of patients in the nursing management of level 3 and the satisfaction rate of discharged patients from nursing group leaders or specialist nurses have statistics difference in science (P < 0.05). See Tables 2There was no significant difference in the nurse-patient ratio of nurses in charge of the same post before and after the intervention (With the gradual formation of a consensus on the concept of \u201cevidence-led improvement to replace evidence-based management,\u201d nursing-sensitive quality indicators will play an increasingly important role in the macro- and micromanagement of nursing quality in my country . In receOur study found no statistically significant difference in the proportion of nurses and patients in the same post before and after the intervention. The incidence of external fixation complications in high-risk patients was 0.65%, the incidence of deep vein thrombosis was 0.52%, and the incidence of respiratory obstruction was 0.13%. In high-risk patients, the incidence of deep vein thrombosis was 0.13% and the incidence of respiratory obstruction was 0. The reason for the analysis is as follows: Because of the relatively stable nurse-to-patient ratio, the level of professional care in the department is reflected in the difference between the quality of the process and the outcome . The evaOur study found that when comparing the process indicators of nurse management at different levels with patient discharge satisfaction outcomes, all patients except for the accuracy of neurological function assessment and patient satisfaction at discharge from nursing group leaders or specialist nurses in level 3 nursing management All indicators were statistically different. The reasons for the analysis are as follows: the assessment and management of nursing quality should be based on professional standards of nursing . NursingBased on individual nurses, this study implemented the management of sensitive indicators of orthopaedic nursing quality, and further explored the application value of sensitive indicators of specialized nursing quality. Facts have proved that both managers and individual nurses can accurately find the weak links in nursing according to the changes in the indicator data, thereby improving the professional nursing quality of individual nurses, thereby improving the overall professional nursing quality of the department, and achieving refinement. This study was limited to the orthopaedic ward in our hospital, and future research may include a multicenter study to further improve the management of sensitive indicators of orthopaedic care quality based on individual nurse practice."}
+{"text": "The main components in the machine complexes responsible for generation and functions of these epi-markers have been characterized in recent years. These components display tissue-specific and delicate spatiotemporal patterns, and their fine-tuned orchestration contributes to the precise and dynamic regulation of the epigenomic and the epitranscriptomic landscapes, ensuring the normal growth, development, and reproduction. More importantly, the emerging evidence links the aberrant regulation of these epi-markers to pathogenesis of multiple diseases, potentially translatable to clinical applications for therapy.Dynamic and precise regulation of gene expression is orchestrated genetically and epigenetically in accordance with developmental stages and in response to environment stimuli. Aberrant genetic or epigenetic events could devastate gene expression, contributing to pathogenesis of disease. Epigenetic markers of base modifications such as 5-cytosine (5-mC), 5-hydroxycytosine (5-hmC) and adenosine methylation mThis Research Topic mainly focuses on the epigenomic and epitranscriptomic basis of human diseases. The aim of the topic is to provide a broad overview of current research on epigenetic aspect of development and pathogenesis of human diseases.Xu et al., found that deficiency in TET1, one of the erasers for base demethylation impairs learning and memory. In addition to neurological disorder, methylation status is also linked to cancers. One research article addresses the critical role of histone methyltransferase KMT5B on initiation of glioblastoma (GBM) via epigenetically regulating a subset of GBM-related genes associated with hypermethylation and 5-hmC loss of genomic DNA Lopez et al.Total 13 of articles published in this Research Topic focus on epigenetic regulation of learning and memory, immunological functions, and tumorigenesis. Two of them are related to base modification and human disease. Wang et al. found that dynamic histone modifications could activate a subset of genes involved in lipogenesis, energy metabolism and inflammation under the high-fat diet (HFD) conditions, addressing the contribution of the eating habits to the related pathology via histone modification.Histone modifications are associated with lipogenesis and obesity by repression or activation of gene expression. Two research articles are related to the link of histone modifications with metabolic disorders and autophagy involved in pulpitis. Yin et al., screened several groups of writers and erasers for histone methylations under TNF\u03b1 treatment, providing important information on the epigenetic regulation of autophagy genes during pulpitis, and more importantly this study could be translated to a novel clinical therapy.Autophagy is regulated epigenetically as well during development. epigenomic and epitranscriptomic basis of development and human diseases.As a summary, the research and review articles published in this Research Topic provide important scientific information in a convenient manner that is targeted toward readers with interest in the"}
+{"text": "This Frontiers in Veterinary Science Women in Veterinary Neurology and Neurosurgery collection of scientific articles presents the innovative work of female neurologists working in the UK, Europe, and North America. The series comprises 13 articles showcasing original research and case reports in various fields of Veterinary Neurology and Neurosurgery, including advances in diagnostic imaging techniques and novel neurosurgical procedures.Boudreau et al. describes DWI MRI findings of spontaneous canine CVA in relation to the time of clinical onset, the DWI type (EPI vs. non-EPI), and the presence or absence of a haemorrhagic component of the lesion. The results of this study help to inform the appropriate clinical interpretation of these sequences by veterinary neurologists and neuroradiologists.Diffusion MRI is a specific sequence that detects and quantifies water diffusivity, which is the molecular motion (Brownian movement) of water and represents an intrinsic feature of tissues. Diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) are MRI sequences routinely used in the diagnostic investigation of suspected cerebrovascular accidents (CVA) in people . There iRemelli et al. highlights the usefulness of low and high-field MRI in complementing clinical and laboratory findings in the diagnosis of SRMA. In this retrospective study, including 70 dogs with SRMA, the MRI showed abnormalities in 98.6% of dogs, with the majority (87.1%) being MRI features suggestive of meningeal inflammation. T1W FAT-SAT sequences were particularly useful in detecting meningeal enhancement. In addition, the contrast enhancement of the synovium of the cervical articular facets and the epaxial muscles was detected in 48.6% of dogs.Steroid-responsive meningitis-arteritis (SRMA) is an inflammatory disorder of probable immune mediated origin, commonly recognized in dogs . It typiLaws et al. describes the clinical and diagnostic findings, treatment , and outcomes of dogs with SEE that were presented to five referral hospitals in the UK. This study provides detailed information on the presenting clinical signs, MRI findings, laboratory investigation results, treatment, and long-term outcomes. The results of this study inform client communication and clinical decisions on canine SSE management.Spinal epidural empyema (SEE) is characterized by the \u201caccumulation of purulent material in the epidural space of the vertebral canal\u201d . It can Goffart et al. shows that end-on fluoroscopy, with or without inversion, is a highly accurate technique for the intraoperative evaluation of bicortically placed Steinmann pins' position in the canine thoracolumbar vertebral column. Three-dimensionally printed patient-specific drill guides have been used to improve the accuracy of implant placement in the canine spine  of the central and peripheral nervous system.The author confirms being the sole contributor of this work and has approved it for publication."}
+{"text": "Using the technique of Force Field Analysis, the co-developer of CAPABLE examined drivers and restrainers of dissemination for the CAPABLE program. This generated 19 distinct drivers including robust research findings, demonstrated clinical and economic utility, and high value to older adults. The environmental shift toward value-based approaches in Medicare and Medicaid also increased the perceived value of CAPABLE. In addition, there were 8 restrainers, including component complexity, siloed health and housing sectors, and the operational lift needed to build the program. Lessons are offered from this case study to move from research to embedded practice."}
+{"text": "In the CNS, microglia is the major resident immune cell. Recent efforts have revealed the diversity of the cell types and the heterogeneity of their functions. The refinement of the synapse structure was a hallmark feature of the microglia, while they are also involved in the myelination and capillary dynamics. Another promising feature is the modulation of the synaptic transmission as synaptic plasticity and the intrinsic excitability of neurons as non-synaptic plasticity. Those modulations of physiological properties of neurons are considered induced by both transient and chronic exposures to inflammatory mediators, which cause behavioral disorders seen in mental illness. It is plausible for astrocytes and pericytes other than microglia and macrophage to induce the immune-triggered plasticity of neurons. However, current understanding has yet achieved to unveil what inflammatory mediators from what immune cells or glia induce a form of plasticity modulating pre-, post-synaptic functions and intrinsic excitability of neurons. It is still unclear what ion channels and intracellular signaling of what types of neurons in which brain regions of the CNS are involved. In this review, we introduce the ubiquitous modulation of the synaptic efficacy and the intrinsic excitability across the brain by immune cells and related inflammatory cytokines with the mechanism for induction. Specifically, we compare neuro-modulation mechanisms by microglia of the intrinsic excitability of cerebellar Purkinje neurons with cerebral pyramidal neurons, stressing the inverted directionality of the plasticity. We also discuss the suppression and augmentation of the extent of plasticity by inflammatory mediators, as the meta-plasticity by immunity. Lastly, we sum up forms of immune-triggered plasticity in the different brain regions with disease relevance. Together, brain immunity influences our cognition, sense, memory, and behavior  Cyclostomatas). On the other hand, innate immunity existed long before the advent of vertebrates. The complement system has been found in ascidians and sea urchins, and Toll-like receptors are already present in cnidarians , pathogen-associated molecular patterns (PAMPs), and neurodegeneration-associated molecular patterns (NAMPs), and the mediators play distinct roles in both physiology and pathology in the CNS  , activates microglia through Toll-like receptor 4 (TLR4), a pattern recognition receptor. Exposure to LPS facilitates the vesicular release at hippocampal excitatory presynaptic terminals , which intensifies the intrinsic excitability of Purkinje cells  of intrinsic excitability, as the increase in the firing frequency of action potentials, and facilitate synaptic transmission in Purkinje neurons of juvenile rodents . In contrast, spontaneous events are recorded without TTX. When the amplitude of miniature EPSC and IPSC changes, it indicates changes in postsynaptic responsiveness.It is noteworthy that, generally, in synapses, there are two sites for modulation: pre- and post-synapses. The modulation of presynaptic release is identified by the increase and decrease in the frequency of miniature EPSC and inhibitory postsynaptic current (IPSC) of the excitatory and inhibitory synapses, respectively. Miniature EPSC and IPSC are the synaptic events recorded under voltage-clamp in the presence of a blocker of voltage-sensitive Navia downregulation of SK channels  and the microglia activation reduces the intrinsic excitability of layer 5 (L5) and L2/3 pyramidal neurons  mediated by TrkB signaling, associated with the neural pain , transient receptor potential cation channel subfamily A member 1 (TRPA1), interleukin-1 receptor 1(IL-1R1), and presynaptic ionotropic glutamate receptor [N-methyl-D-aspartate receptor (NMDA receptor)]  released from microglia induces depolarization of anion reversal potential and modulates the driving force of inhibitory GABAergic channels via innate immune responses. The related inflammatory cytokines and the mechanism for induction have numerous variations. In the following sections, we discuss the roles of inflammatory mediators, cytokines, in synaptic and non-synaptic plasticity (Roles of Inflammatory Cytokines and Lipid Mediators in Synaptic and Non-synaptic Plasticity). And we describe modulations by chemokines . Lastly, we discuss the possible involvement of the immune-triggered plasticity in psychiatric diseases (Plasticity Triggered by Inflammatory Cytokines and Relevance to Psychiatric Diseases).The modulation of synaptic transmission and intrinsic excitability by immunity is expected to exist in CNS regions other than the cerebellum and cerebral cortex. Here, we show summary tables of the immune-triggered modulation of the synaptic efficacy and intrinsic excitability of neurons in different brain regions , 2. TablA receptors  was identified in 1975 as a factor causing hemorrhagic necrosis in tumors planted in mice , which binds to the same receptor but does not convey a signal. IL-1 signal induces the expression of IL-8 and IL-6 by activating NF\u03baB and AP-1 In vivo, administration of LPS to the fourth ventricle impaired hippocampal memory tasks  are synthesized by many cell types, including macrophages, as pre-pro-TGF\u03b2 (pre-propeptide), and the pre-propeptide is cleaved in the endoplasmic reticulum and secreted as an inactive dimer bound as a latent complex, tethered by the extracellular matrix. Serum proteinases and matrix metalloproteinases (MMPs) liberate the latent form, and TGF\u03b2-binding to transforming growth factor beta receptors (TGFBRs) transduce the signaling in the SMAD-dependent and SMAD-independent manners  and LTP in hippocampal perforant path-dentate gyrus synapses  are the physically active lipid mediators, which are produced in almost all tissues and involved in the induction of plasticity in the brain  ligand 1  suppressed the induction of the LTD of parallel fiber-Purkinje cell synapses  or HCN channels, would be another potential target for the drug administration, while we should note that inflammatory mediators could be modulators of not only fast synaptic transmissions and the intrinsic excitability but also metabotropic receptors of monoamine, mGluRs, GABABR, and other G protein-coupled receptors, which are also involved in the plasticity induction.Despite the difficulty in interpreting the biological significance of behaviors, learning, and cognition, the interaction of immune cells with neurons is a quite important feature of brain functioning. The immune-triggered plasticity and related meta-plasticity are expected to be involved in psychiatric disorders evoked by aberrant immunity, specifically at the stage of neurodevelopment and maturation of brain vasculatures . The funders had no role in the study design, decision to publish, or preparation of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "In 2013, about 60% of the urban sample economic growth and carbon emissions showed signs of tapping into potentials and increasing efficiency (absolute decoupling) and intensive expansion (relative decoupling). In old industrial cities, the proportion of relative decoupling shows a fluctuating upward trend. In the future, the government should accurately select its own development orientation and actively seek the \u201cbest balance\u201d between economic growth and a green and low-carbon path.Based on a literature review and theoretical mechanism, this paper takes the implementation point of the adjustment and transformation policy for old industrial cities as the breakthrough point, and uses a regression model to explore the impact of the adjustment and transformation policy of these old industrial cities on urban carbon emissions. This paper also robustly tests the effective mechanisms and environmental hypotheses. Overall, the implementation of the adjustment and renovation policy has significantly reduced the carbon emissions of old industrial cities by about 0.068 units. Compared with the control group cities, the pilot cities reduced carbon emissions by an average of about 310,000 tons after the implementation of the policy. Based on a summary of the excellent Chinese case experience and an empirical analysis, it can be concluded that improvements in the green innovation capacity of old industrial cities, the agglomeration of high-end service industries, and the strengthening of ecological restoration are important mechanisms that lead to reduced carbon emissions. There is no subsequent exacerbation of the carbon intensity of neighboring cities, and there is insufficient evidence to prove pollution via neighboring transfers and use of the beggar-thy-neighbor policy. The extended analysis shows that the \u201cinverted U-shaped\u201d CO General Secretary Xi Jinping has repeatedly emphasized that China\u2019s carbon dioxide emissions will peak before 2030, and the country will strive to achieve carbon neutrality before 2060. Activities related to industrial production and energy consumption are the main sources of carbon dioxide production. Vigorous promotion of carbon emission reduction in the industrial and energy fields is key to the successful implementation of new environmentally friendly development concepts, and to accelerate the construction of a modern industrial system, which in turn will help achieve carbon peaking, and then carbon neutrality. The old industrial cities have made historical and significant contributions to the formation and improvement of an independent and complete industrial system and national economic system in China, and have been indispensable in the post opening-up reform era, and during the current wave of modernization.The old industrial city, as a basic unit, still faces many difficulties and challenges with the existing institutional mechanisms, policy systems, and governance methods. The past problems remain prominent and cause difficulties for the old industries to adapt to the requirements of the industrial green and low-carbon transformation. Through an in-depth study of the adjustment and transformation of old industrial cities, in the face of today\u2019s good conditions, this paper aims to help accelerate the reform of high-quality economic development and promotion of green and sustainable development of the industrial economy. Promoting regional coordination and complementarity in order to reduce carbon emissions and pollution, are important to the success of building a beautiful, more affluent, healthier society. The policy of adjustment and reconstruction of old industrial bases across the country can be considered a starting point to achieving the environmentally friendly targets. This paper can provide operational, replicable, and scalable experience and practices for the low-carbon development of other industrial cities, and explore new ways for the green and low-carbon transformation of industrial cities across the country.Old industrial cities were once the engines that drove rapid economic development in Europe and the USA. \u201cDe-industrialization\u201d in the developed countries led to a severe recession. Similarly, due to market system changes, or the over-specialization of industries, old industrial cities will become prominent in developing countries, which will cause serious ecological and environmental problems . How to Due to the characteristics of the industrial development cycle, it is harder to achieve green transformation in old industrial cities . They maThe process of urbanization and industrialization in China differs from that of Western countries. The analysis of evolution elasticity theory shows that the economic growth rate and industrial structure of old industrial cities can be differentiated . Based oThe existing literature mainly comprises a factual elaboration and theoretical summary of the old industrial cities, and discusses their implementation path and future direction from the perspective of case analyses. However, less empirical attention has been given to the net impact of the adjustment and comprehensive transformation of old industrial cities on regional green and low-carbon development.(1)Evaluate the low-carbon effects and spatial spillover effects with the adjustment and renovation policies of old industrial cities.(2)Effectively identify the transmission mechanism by which the adjustment and transformation of old industrial cities can help reduce carbon and pollution.(3)Test whether a curve is significantly established in the old industrial city sample based on the Kuznets inverted U-curve theory of carbon dioxide.(4)To analyze the degree of decoupling of old industrial cities.Given this, the possible contributions of this paper are:We give a flow chart of the research framework of the article. The flow chart of the research framework is shown in Achieving carbon peaking and carbon neutrality are necessary to solve the outstanding problems of resource and environmental constraints, and to ensure sustainable development, in turn nurturing China\u2019s lucid waters and lush mountains. China\u2019s \u201cNotice of the State Council on Printing and Distributing the Action Plan for Carbon Peaking Before 2030\u201d identified the need to establish an economic system of green, low-carbon, and circular development by 2025. The Notice also specifies that carbon dioxide emissions per unit of GDP will drop by 18% compared to 2020, and that substantial progress will have been made in the comprehensive green transformation of economic and social development, with carbon dioxide emissions reaching a peak and achieving stable and moderate declines by 2030. The government encourage key fields such as energy, industry, transportation, and construction to formulate special plans for peaking, and promote key industries such as steel, building materials, nonferrous metals, chemicals, petrochemicals, electric power, and coal to put forward clear peaking goals and formulate peaking action plans. By 2060, the goal of carbon neutrality will be successfully achieved, and a green, low-carbon, and cyclical economic system and a clean, low-carbon, safe, and efficient energy system will be fully established, creating a new realm of harmonious coexistence between man and nature.Old industrial cities face dual pressures in the process of carbon reduction due to their own unique realities. The proportion of traditional industries is still relatively high, and it is increasingly difficult to tap the potential of energy conservation. The coal-biased energy structure, inefficient energy utilization, and low utilization of clean energy remain apparent. The lack of advanced technology reserves, the shortcomings of energy-saving and efficiency-enhancing technological innovation, the tight time window for carbon peaking and carbon neutralization, and the arduous task of realizing the green and low-carbon transformation of old industrial cities, are the unwanted features that still dominate old industrial cities.In order to promote energy conservation, emission reduction, and the sustainable development of old industrial cities, the reform plan for renovating these cities should focus on transforming the mode of economic growth and promoting sustainable development. The government focusing on transforming the mode of economic growth and promoting sustainable development, focusing on the new competitive advantage of re-engineering the industry, taking promoting green and low-carbon development, and enhancing innovation support capabilities as an important focus, promote the comprehensive, coordinated, and sustainable development of old industrial bases, building it into an important new low-carbon industrial base for the country and a key growth pole for the high-quality development of the regional economy.By considering the success rate of the measures taken by 94 old industrial cities after the implementation of the adjustment and renovation policy, their transmission path is proposed. Representative cities in the eastern region , central region , and western region  were then selected for case analysis.Industrial green innovation. The continuous innovation of urban intelligent green manufacturing technology can help transport an industry to the high end of the value chain, change the existing unsustainable technology and production system, and improve the level of informatization and automation of the manufacturing industry. The government can deepen the degree of coupling between the innovation chain and the industrial chain; increase the transformation of innovation achievements and the research and development, as well as the application of green and low-carbon cutting-edge technologies; accelerate the upgrading of low-carbon products and technologies; and form new manufacturing processes and equipment that are efficient, energy-saving, environmentally friendly, and recyclable, building a green zero-carbon manufacturing system, thereby greatly reducing carbon emission intensity. Industrial technological innovation can broaden the depth and breadth of the development and utilization of renewable clean energy and promote a revolution in energy consumption. Industrial green innovation also reduces excessive dependence on fossil fuels, optimizes energy industry structure and energy use ways, and improves the efficiency of the optimal allocation of energy industrial cities. The government accelerate the conversion of old and new kinetic energy in cities, and continuously overcome key energy-saving technologies in major energy-consuming fields of industry, so as to reduce total carbon emissions from the source .Environment for innovation activities. An environment conducive to innovative scientific research and the construction of innovative service networks plays an increasingly important role in carbon emission reduction. Scientific research includes technological projects in the fields of energy conservation and environmental protection, low-carbon production, and clean energy, and forces and/or motivates enterprises to develop advanced production technology. The people in old industrial cities participate in and popularize the practice of green production and life, actively advocating green, low-carbon, and simple lifestyles in the whole society, and indirectly reduce the scale of carbon emissions .Efficient division of labor. Emerging high-end industrial clusters can reduce production and trade costs through the specialized division of labor and advantageous resource endowments, in turn effectively promoting business exchanges between enterprises. This will help reduce the volatility of demand for green and low-carbon products, deepen the division of labor in the industrial chain, and promote the extension of the industrial chain towards high added value .Element sharing. The agglomeration of high-end industries is conducive to promoting the effective allocation of production factor resources and recycling urban infrastructure. Element sharing helps to reduce the transportation distance, expenditure cost, and time search cost in old industrial cities. Element sharing can improve the government\u2019s treatment and utilization efficiency of pollutants, reduce the decentralized consumption of energy, improve the utilization efficiency of energy and elements, and thus promote the rapid reduction of urban carbon emissions.Spillover effect. The complementary effect of the modern low-carbon industry and its related industries will produce increasing returns to scale, resulting in the multiple effects of urban collaborative innovation, cutting-edge ideas, and spillover enhancement effects. The spillover effect will help to enhance the rooting and cohesion of the low-carbon industry, and increase the communication, interaction, and cooperation between enterprises and other related industries. The diffusion of urban clean technology will accelerate, and upstream and downstream enterprises will be promoted through exchanges and interaction along the industrial chain. In addition, other companies will benefit from the agglomeration of high-end low-carbon industries .2 emissions [Firstly, ecosystem protection and restoration can significantly increase the coverage of natural vegetation, prevent soil erosion and dust storms, increase soil fertility, expand the total amount of forest and grass resources, maintain biodiversity, and effectively improve regional air quality. Ecological governance can change local albedo, turbulent energy, and mitigate natural disaster losses. Ecological governance can promote the enhancement of the carbon sequestration and carbon absorption capacity of forests and wetlands, and effectively reduce the total carbon emissions of cities. Afforestation programs that promote increased terrestrial carbon storage are an important means of helping to gradually reduce atmospheric COmissions .The research on forest carbon sinks of Peking University also shows that for every cubic meter of forest growth, it absorbs about 1.8 tons of carbon dioxide on average, especially in the peak season of tree growth, the forest can absorb 1.6 kg of carbon dioxide per square meter per day. The United Nations Intergovernmental Panel on Climate Change estimates that the global forest carbon storage will exceed 11,000 tons. In order to achieve carbon neutrality, cities require conservation as well as sustainable management to increase carbon sink. Therefore, old industrial cities must formulate policies against deforestation and deforestation, promote scientific research on carbon sinks, actively build forest parks, and promote afforestation activities . ResearcSecondly, the expansion of the regional green area can optimize the urban ecological space pattern, enrich the urban connotation and functional quality, and continue to attract new workers. Profiting from their industrial heritage resources, cities can provide a high-quality creative environment and atmosphere through exhibitions and projects, creating green and low-carbon development ecological places, tourist attractions, and idyllic scenery complexes. Ecosystem protection will help cities fundamentally transform their original industrial structure of high energy consumption, high pollution, and high emission industries, realizing the integrated and diversified development of primary, secondary, and tertiary industries, continuously improving the \u201cgreen content\u201d of emerging industries, and accelerating the realization of low carbonization .DID model. The difference-in-differences method is an important scientific research tool for evaluating the effect of a project or policy implementation. This method can not only exclude unobservable individual heterogeneity among samples, but also account for the influence of unknown factors that change over time. The difference-in-differences method ensures unbiased estimation of policy effects and effectively controls the effect of the interaction between the explained variable and the explanatory variable. Based on the pilot list of old industrial cities, the benchmark regression model is constructed as follows:by Athey  is used Panel quantile regression model. The basic idea of this model is to minimize the distance between the dependent variable and the fitted value, which can effectively eliminate the assumption of a normal distribution for the unobserved residuals based on the minimum residual squared and panel model, and better measure the independent variables in the variation trends and distribution shapes at multiple quantiles, which reflect the rich information of all samples.The parameter estimation method of the panel quantile regression model is as follows:Lnco2). Referring to the calculation method of Wu Jianxin [Perco2  and land average carbon emissions Aerco2  are both estimated as dependent variables.Explained variable: total urban carbon emissions . The carbon emission of urban transportation is based on the methods of Zhang Yan [4 kg/TJ (as CO2). The net calorific value of gasoline is 44.3 TJ/Gg, which is 44.3 \u00d7 10\u22126 TJ/kg. The diesel emission factor is 7.41 \u00d7 104 kg/TJ (as CO2). The net calorific value of diesel is 43 TJ/Gg, which is 43 \u00d7 10\u22126 TJ/kg. The emission coefficient of raw coal is 9.46 \u00d7 104 kg/TJ , and the net calorific value is 25.8 TJ/Gg, which is 25.8 \u00d7 10\u22126 TJ/kg. The urban public transportation uses diesel as the main fuel, and the density of diesel is 0.835 kg/L. Taxis use gasoline as fuel, and the density of gasoline is 0.725 kg/L. The urban thermal energy data were not taken into account due to the large area of missing values in the total urban heating supply and heating area.Direct energy carbon emissions are obtained by multiplying the total urban natural gas and LPG supply by the relevant conversion factors provided by IPCC2006. The COhang Yan  and Zhaohang Yan . It is aCore explanatory variables. Pergdp), as measured by the ratio of urban real GDP to total urban population. GDP is an important factor affecting CO2 emissions in old industrial cities. With the continuous increase in the total economic volume and output scale, the new emission of pollutants has become prominent, which has brought great pressure on the emission reduction of old industrial cities. Investment level (Oinvest), as expressed by the ratio of the whole society\u2019s fixed asset investment and real GDP. The impact of investment levels on the green and low-carbon development of old industrial cities is uncertain. On the one hand, old industrial cities have increased investment to attract \u201chigh energy consumption, high pollution, high emissions, low added value\u201d enterprises to enter, and constantly reduce the quality of the city\u2019s green development. On the other hand, the increasing investment in environmental protection has provided effective financial support for eliminating the pollution stock and reducing the pollution increment. The government\u2019s efficient environmental protection investment can promote the reduction of the county\u2019s pollution emission intensity. Education scale (Oeduc), which is represented by the ratio of the number of students in regular high schools in the city to the urban population. The scale of education can significantly reduce the scale of carbon emissions in old industrial cities and increase the carbon sequestration of regional vegetation. Education has a reinforcing effect on public environmental protection behavior in old industrial cities. Education carries the universal function of social values and can increase knowledge about ecological and environmental protection. Industrial structure (Upais), as represented by the advanced index of urban industrial structure, that is, Dmarket), as represented by the ratio of the number of private and individual employees in the city to the total number of employees in the city. The improvement of market demand is conducive to the public consciously transforming green concepts into actual consumption actions and building a social action system for low-carbon consumption. To a certain extent, it is conducive to industrial structure adjustment and independent innovation, and guides enterprises to actively adapt to the requirements of green and low-carbon development. Communication facilities (Teleinst), as represented by urban fixed telephone users and mobile users. The rapid increase in the coverage of communication facilities can prompt the public to spontaneously monitor the environmental pollution around living areas, exert high pressure on local governments, and increase the quality and scope of government environmental pollution information disclosure. The multicollinearity test found that the largest covariate VIF was 2.56, 1/VIF was 0.91, and the mean VIF was 1.83. There was no serious multicollinearity problem.Other explanatory variables: Economic development  statistical yearbooks over the years. If there was a problem of missing data, the CSMAR database and EPS database were used as alternatives. The descriptive statistics of the variables are shown in By selecting the time series data from 2006 to 2019, the annual change trend in urban carbon emissions in the treatment group and the control group was analyzed before and after the implementation of the policy. According to This paper considers the impact of the adjustment and renovation policies of old industrial cities on regional carbon emissions. The benchmark regression estimation results in Before the implementation of the old industrial city adjustment and renovation policy, the old industrial city exceeded the threshold of the carrying capacity of the social environment through the excessive consumption of energy resources, and substantial investment in related factors of production, which all reduced the stability and service functions of the regional ecosystem. Following policy implementation, the original economic development model of the old industrial city has been gradually broken. The old industrial cities, according to the resource endowment conditions and the main function positioning, anchors the green and low-carbon development plan, leading to deeply adjusting the industrial structure and making every effort to promote industrial energy conservation and emission reduction. The old industrial cities can accelerate industrial innovation and low-carbon construction projects, strengthen the hard constraints of the ecological environment, and promote the elimination of backward and excess production capacity. Old industrial cities actively explore new models of low-carbon industrial development and vigorously develop low-carbon modern service industries. Additionally, old industrial cities are accelerating the continuous reduction of energy consumption per unit of product, strengthening their recycling capacities and comprehensive utilization of resources, and promoting manufacturing and supply of green products. Old industrial cities can strictly abide by the red line of urban ecological protection, increase the carbon sinks in the ecosystem, resolutely curb the blind development of high energy consumption, and optimize the layout of land and space development and protection areas. To sum up, the implementation of the policy can effectively reduce the emission intensity of carbon dioxide pollutants in cities and promote the green and low-carbon development of cities.According to The implementation of the new development concept has enabled old industrial cities to gradually incorporate ecological civilization education into the national education system, which has strengthened innovation capacity building and talent training, incited green and low-carbon social actions, and popularized basic knowledge of carbon peaking and carbon neutrality. With the implementation of the new development concept, old industrial cities have gradually incorporated ecological civilization education into the national education system, strengthened innovation capacity building and talent training, and led to green and low-carbon social actions. People\u2019s consumption habits, ecological awareness, and market demand are constantly changing, resource conservation is increasing, and the degree of public participation is orderly. The coverage network of regional communication infrastructure can significantly enhance public participation in environmental governance, and enhance the environmental protection demands of informal forces. The advancement of communication facilities has significantly improved people\u2019s ideas and ways of thinking and boosted the rapid flow and efficient dissemination of diverse information. The coverage network of regional communication infrastructure can improve the availability of products and services in the region and help enterprises to make optimal production and sales decisions, thereby improving industrial production efficiency and reducing urban carbon emissions. In addition, the extensive way of economic development in old industrial cities negatively increases the pollution of the ecological environment and significantly increases the total regional carbon dioxide emissions. With the continuous increase in the total economic volume and output scale, the lagging industrial structure and the increasing risk of spatial layout, the synergy of the development of modern low-carbon industries needs to be improved, and the pressure of new pollutant emissions is prominent. With the weakening of environmental protection, the overall coordination of ecological protection has increased, and the comprehensive deepening of the reform has not yet formed a system integration effect.According to Overall, at the lower quantiles, the old industrial cities lack protection from mountains, rivers, forests, fields, and lakes, and the ecological space is instead constantly being eroded and occupied. High development intensity comprises the expansion of urban construction land, increased traffic density, continuous population growth, and intensification of the area of natural vegetation. Per capita consumption of energy-intensive products continues to rise, increasing the city\u2019s carbon emission levels. With the continuous increase in quantiles, the old industrial cities should start from improving the overall competitiveness of the region, clarify their own ecological function positioning, and strengthen the dual control of carbon emission intensity and total amount. The old industrial cities can adhere to the combination of industrial transfer and sustainable development, innovate the way and platform for undertaking industrial transfer, and improve the layout management of low-carbon industrial development and the ecological space within the region. Old industrial cities can optimize the carrying capacity of resources and environment, implement integrated protection and restoration, and consolidate the role of ecosystem carbon sequestration, thereby producing a positive green and low-carbon effect. At the highest quantile, the old industrial cities have heavy work tasks to reduce production capacity, adjust their structure, and change their methods, as there are serious historical problems, and the process of industrial transformation, upgrading, and optimization is relatively slow. The land use, energy consumption, water consumption, factor allocation, and pollutant discharge standards undertaken by the industry are relatively weakened, and it is easy to \u201cturn one eye and close one eye\u201d in order to continue to \u201cgive the green light\u201d for pollution-transfer enterprises. Old industrial cities neglecting the quantity and quality of investment promotion will lead to the misallocation of production factor resources and bring about regional ecological and environmental crises.Following the omitted variable test, the replacement variable test , the beAs old industrial cities differ with regards to geographical location, administrative level, social endowment, and regional attributes, the impact of policy implementation on urban carbon emissions will also differ. Therefore, in terms of geographical location, the cities were divided up into the eastern region, central region, and western region; in terms of administrative levels, they were grouped by size as large cities, medium-sized cities, and small cities; in terms of convenience, they were divided into cities with high-speed rail and cities without high-speed rail. The estimated results are shown in Compared with cities in the eastern and western regions, the adjustment and renovation policies of old industrial cities in the central region have not produced significantly positive regional green and low-carbon effects. Due to the complexity and particularity of the old industrial cities in the central region in terms of geographical location and social environment, it is easy to undertake the transfer of polluting industries and increase the level of carbon emissions. Overcapacity and low-efficiency in central cities still plague the process of industrialization reform. Influenced by interestism, the central region government relaxes environmental control and lowers the regional requirements for environmental quality, thereby ignoring ecological and environmental planning and protection in the region.The challenge of ecological environmental protection is thus increasing; hence, there is no evidence of positive pollution and carbon reductions. The old industrial cities in the eastern region actively exert their own resource endowment advantages, strengthen industrial environmental protection awareness and low-carbon concepts, and accelerate their industrial innovation capabilities and the training of high-quality talents. Old industrial cities in the eastern region are strengthening the research, promotion, and application of major low-carbon technologies to overcome the commonalities and key core technologies. In addition, the estimated effect coefficient generated by the implementation of the old industrial city policy in the western region is the largest. The old industrial cities in the western region are striving to promote the green, circular, and low-carbon development of the industry, actively exploring the environmental supervision, regulation mechanism, and innovative transformation path of the industrial wasteland, and steadily promoting the formation of a new model of green, low-carbon, and sustainable development. The western region is generally establishing a resource-saving and environmentally friendly development mode to further strengthen the main functions of the different regions.For large old industrial cities, the implementation of adjustment and renovation policies can have a very significant effect on reducing pollution and carbon in the region. Therefore, large-scale city governments are using \u201ccarbon peaking and carbon neutrality\u201d as the guide, and green and low-carbon industrial clusters as the carrier. In taking this approach, large cities will continue to adjust and optimize the regional layout of industrial productivity, guide a rational and orderly transfer of industries, have efficient and clean agglomeration, improve the coordination and supporting system of the industrial chain, create a circular industrial entity, and improve the level of industrial informatization. Large cities are accelerating the research, development, and promotion of industrial low-carbon technologies, exploring and innovating low-carbon industrial development models, enhancing independent innovation capabilities, improving industrial technology innovation mechanisms, promoting in-depth implementation of industrial green manufacturing, and developing an innovative green economy. Large cities are turning \u201cgreen\u201d in the \u201cbackground\u201d of industrial production, taking the lead in achieving carbon peaks with a more proactive attitude.Compared to old industrial cities without high-speed rail, those with high-speed rail have a significantly \u201cnegative shadow\u201d impact on their urban carbon emissions, which is conducive to reducing carbon levels and pollution, reducing costs, and increasing efficiency in the region. The reason is that the opening of high-speed rail can improve the accessibility level and location advantages of a city. Transportation times and efficiency increase the potential of agglomeration and economies of scale in the central area, and change the spatial distribution pattern of the urban industrial economy. High-speed rail cities continue to effectively promote the optimization of the industrial division of labor, and the complementation of comparative advantages in the region promote the continuous conversion of new and old kinetic energy, thereby greatly reducing the intensity and total amount of carbon emissions.Grinnov). Patents have become a popular way for researchers to measure green and low-carbon innovation. Therefore, with reference to Zhang [Green innovation quality , drawing on the practice of Xuan [Agglomeration of modern industries ( of Xuan  to buildEcolores). This indicator is measured by the degree of urban green vegetation coverage [Ecological restoration and reconstruction  refers to the fact that with the growth of the regional economy, there is a specific extreme point in the emission of carbon dioxide, which is an \u201cinverted U-shaped\u201d curve relationship that first increases and then decreases.2 environmental Kuznets curve (EKC) in old industrial cities, and the \u201cinverted U-shaped\u201d hypothesis is clearly established. When the cubic term of per capita income is added to the continuous increase in per capita income in old industrial cities, carbon dioxide emissions still show a clear \u201cinverted U-shaped\u201d relationship, which initially increases slowly, and then continuously decreases; the \u201cN-shaped\u201d curve hypothesis does not hold. In reference to the general framework test of Lind [Pgdp is found to be significantly larger than the threshold, and the extreme value point tested is within the range of the sample data. The null hypothesis is rejected at the 10% significance level Overall, the adjustment and renovation policies can produce a positive low-carbon and carbon-reduction effect, with an average reduction of about 0.068 units of carbon emissions. Compared with the average value, the implementation of the policy can reduce the urban carbon emissions by an average of about 310,670 tons. The policy implementation can effectively promote carbon reduction and pollution reduction in the middle quantile. There is no significant evidence that policy implementation leads to the transfer of pollution from old industrial cities to neighboring cities. The phenomenon of \u201cblaming the neighbors\u201d for serious pollution has not occurred, and thus the implementation of the policy can realize low-carbon regional development.(2)The adjustment and renovation policies of old industrial cities have had a distinct and negative effect on pollution reduction and carbon reduction for sample cities in the eastern and western regions, large cities, and cities connected to high-speed rail.(3)On the basis of summarizing excellent Chinese cases and conducting empirical estimates, it is found that after policy implementation, the innovation and improvement of urban green quality, the expansion of high-end industrial agglomeration scale, and the increase in ecological environment reconstruction are important mechanisms to reduce urban carbon emissions.(4)2 EKC in old industrial cities, but the \u201cN-shaped\u201d curve hypothesis does not hold. There are quite a few old industrial cities that have yet to cross the turning point of the EKC.There is a significant \u201cinverted U-shaped\u201d CO(5)During the implementation of the policy, in 2013, about 62% of the old industrial cities showed a state of relative decoupling and absolute decoupling. As the years pass, the trend of an increasing fluctuation of this ratio becomes more prominent, thus reversing the rapid growth of carbon dioxide in old industrial cities.The following conclusions are drawn:Based on the empirical results and conclusion analysis, the following policy recommendations are put forward:First, the city government should rationally design a dynamic path for carbon emission reduction to achieve absolute decoupling between economic growth and carbon emissions. City governments should fully integrate carbon peaking and carbon neutrality goals into medium- and long-term planning for economic and social development, and clarify the goals and outcomes of carbon reduction and carbon reduction tasks. City governments should cross the inflection point of the CKC curve as soon as possible; vigorously support cities with endowment conditions, key industries, and key enterprises to take the lead in peaking carbon emissions; and should not implement campaign-style carbon reduction. The government of the old industrial city should strengthen the top-level system design and promote the participation of diversified subjects, such as the government, society, and public, to realize the linkage of carbon emission reduction from top to bottom.Second, the government should take various measures to achieve green and low-carbon development. The government should strengthen the leadership of cutting-edge innovation in the industrial base, cultivate compound green and low-carbon talents, implement key core technology innovations, cultivate green and low-carbon emerging industries, promote cross-sector and cross-industry collaborative innovation, and accelerate industrial low-carbon transformation and digital transformation. The government should further increase the proportion of renewable energy production and consumption, and provide an important guarantee for the construction of a zero-carbon green energy system. The government should cultivate advantageous high-end industrial clusters; improve the coverage of regional communication infrastructure; strengthen regional division of labor and efficient cooperation; broaden the rational flow of production factors and channels; strengthen the coupling and linkage of green and low-carbon industries; and promote the advanced industrial foundation of industrial cities, the specialization of industrial division of labor, and the modernization of industrial chains. The government should speed up the transformation of the original extensive and high-carbon development mode; strengthen the restoration and management of the geological environment and vegetation coverage; enhance the ability to conserve water sources and soil; and realize the coordination and unity of the economic, ecological, and social benefits of resource development.Third, the government should build a cross-regional environmental coordination mechanism. The government should compile and apply a negative list for environmental access; implement an implementation plan for coordinating joint prevention, joint governance, and comprehensive governance; promote the simultaneous coordination of environmental regulations in adjacent areas; and strengthen the industrial division of labor and complementary advantages. The government should break the administrative level restrictions; build a cross-regional pollution-reduction and carbon-reduction coordination mechanism, and a cooperation platform; and achieve regional high-efficiency and integrated governance. The government should focus on the environmental effects of policy reforms in the central region cities, cities without high-speed rail, small cities, and medium-sized cities."}
+{"text": "This evidence synthesis aimed at assessing the effectiveness of Faith-Based Organisations (FBOs) on Maternal and Child Health (MCH) outcomes; and explore the perceptions and experiences of the users and providers of MCH services delivered by FBOs in Africa. This review considered studies from African countries only. Both reviews and primary studies focusing on MCH services provided by FBOs were considered. Quantitative, qualitative, and mixed methods reviews were included with no restriction on the date and language. Primary outcomes included maternal mortality ratio, neonatal mortality, infant mortality, child mortality, quality of care, views, experiences, and perceptions of users of FBOs. We searched up to November 2020 in the Joanna Briggs Institute (JBI) Database of Systematic Reviews and Implementation Reports, the Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, PROSPERO register, PDQ-evidence, Health Systems Evidence, CINAHL, EMBASE, and PubMed. We searched references cited by similar studies that may be potentially eligible for inclusion. We then updated the search for primary studies from December 2009 - October 2020. One systematic review and six primary studies met the eligibility criteria for inclusion. Methodological quality varied. These observational and qualitative studies found that FBOs offered the following MCH services - training of healthcare workers, obstetric services, health promotion, sexual education, immunization services, and intermittent preventive therapy for malaria. Maternal and Child Health (MCH) services provided by FBO suggest a reduction in maternal morbidity and mortality. Increased uptake of maternal healthcare services, and increased satisfaction were reported by users of care. However, costs of providing these services varied across the studies and users. This review shows that FBOs play an important role in improving access and delivery of MCH services and have the potential of strengthening the health system at large. Rigorous research is needed to ascertain the effectiveness of FBO-based interventions in strengthening the health systems in Africa. The Worve visit . To achive visit .et al. [The complex social, political, environmental and economic determinants of health calls on health systems to look beyond the provision of care by a single entity such as the public healthcare services . A privaet al.  argue thet al. -10.An FBO is defined as an \u201corganization, with or without non-profit status that provides social services and is either motivated by religious faith or belief or have affiliations with religious groups\u201d . More reA number of published studies on the role and contribution of FBOs on maternal, newborn, and child health (MNCH), HIV/AIDS and other health issues have focused on understanding the different roles of FBOs in healthcare delivery, their reach, costs, and satisfaction from beneficiaries ,12,14. CThe protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO): CRD 42020153300 [Criteria used to consider studies for inclusion: we included systematic reviews and primary studies  on MCH services provided by FBOs. We considered any level of care and facilities providing either maternal or child services or both by any health provider regardless of cadres. The comparison was of other types of organizations or health care services providers that are not faith-based such as government-owned healthcare facilities and non-governmental organizations. We defined maternal health as the health of women during pregnancy, childbirth, and postpartum (the first 42 days after delivery) [elivery) . Child helivery) . MCH seret al. 2015 [Secondary outcomes included utilization of MCH services, the proportion of live births, percentage of births attended by skilled health personnel, uptake of intermittent preventive treatment (IPT) for malaria, the proportion of HIV pregnant women on prevention of mother to child transmission (PMTCT), immunization coverage, maternal and child morbidity, stunted children, the proportion of children receiving treatment of childhood infectious diseases, like pneumonia, cost-effectiveness, access to care, client\u00b4s satisfaction, quality of care and continuity of care as reported in the studies. Systematic reviews are defined as reviews with the following characteristics as described by Moher al. 2015 : clear dSearch methods for identification of studies: the first search used a comprehensive search strategy to identify systematic reviews. It was developed for PubMed and adapted for other databases, with the assistance of an information specialist (Annex 1). We did not apply any date or language restrictions. The following key words were used with key terms such as 'systematic' or 'meta-analysis' in the title or abstract fields: 'delivery of care/economics', 'organization and administration', 'community health centres', \u2018faith-based organizations', 'faith-inspired interventions', 'hospitals/religious', 'quality of care', 'public-private partnerships', 'SDG3' and 'health services/research', 'faith-based facilities', 'religious programmes\u00b4, \u2018local faith communities', 'humanitarian care', 'faith-based aid'. We searched up to November 2020 in the JBI Database of Systematic Reviews and Implementation Reports, the Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, PROSPERO register, PDQ-evidence, Health Systems Evidence [Annex 1). We searched in the JBI Database of Systematic Reviews and Implementation Reports, CINAHL, EMBASE, and PubMed.Evidence , CurrentSelection of studies, data extraction, and management: two authors (Chinwe Juliana Iwu-Jaja and Jeannine Uwimana Nicol) independently screened titles and abstracts of the records from the first search on CovidenceR software. The records were rated as 'or exclusion', 'for inclusion', or 'potentially eligible' accordingly.The full text of systematic reviews judged as 'for inclusion' or 'potentially eligible' were then assessed against the inclusion criteria independently by the two authors. Disagreements were resolved be through discussions and when consensus was not reached, a third author (Taryn Young) was consulted for arbitration. In the second round of screening to identify recent primary studies (from 2009-2020) five reviewers  independently screened titles and abstracts of the records in Covidence. The full text eligibility assessment was independently done by the same four reviewers. Disagreements were resolved through discussions and when consensus was not reached, two of the reviewers (Jeannine Uwimana Nicol and Chinwe Juliana Iwu-Jaja) resolved the conflicts. Data were extracted using a pre-defined form which included key characteristics of included studies such as first author name, year of publication; objectives, number of included studies; countries, characteristics of participants, study type, types of interventions, intervention intensities, setting, and context where the study was conducted, outcome assessed, instruments used to assess outcomes ; comparisons of performed and results. Additionally, extracted data included the phenomenon of interest .Assessment of methodological quality, data analysis, and synthesis: two authors (Chinwe Juliana Iwu-Jaja and Jeannine Uwimana Nicol) independently, and in duplicate, assessed the quality of systematic reviews using the AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews) tool [ws) tool , qualitaws) tool . For priws) tool  and the ws) tool  for qualws) tool  and guidResults of the search: a total of 13,810 article citations were identified through both stages of database searching, of which 12,844 were screened for titles and abstracts after de-duplication. These articles were a combination of primary studies and systematic reviews. After titles and abstracts screening, 64 studies (59 primary studies and three systematic review) were considered potentially eligible. We included one systematic review and eight primary studies ( studies .Characteristics of included studies: the systematic review included six primary studies conducted in eight countries in Africa (1987-2007), while the eight additional primary studies were conducted from 2012-2020. The systematic review conducted by Widmer et al. [r et al.  assessedr et al. -31; thesr et al. ,29,31-33r et al.  and two r et al. ,28. The The FBOs included Baptist Church, Christ Apostolic Church, Presbyterian Church, Catholic Church, Protestant Church, Catholic Church, Muslim organizations, Catholic Medical Services, Uganda Protestant Medical Bureau, Uganda Muslim Medical Bureau, the Christian Health Association of Malawi which includes Malawi Council of Churches and the Episcopal Conference of Malawi, the Kenya Conference of Catholic Bishops, Lutheran Church, and the Seventh-day Adventist Church. The services that were offered by these FBOs covered: capacity building: training of healthcare workers, community health workers, and volunteers in the community such as church/faith leaders, women leaders and others; health education and promotion; immunization services; obstetric and neonatal care services: births, management of neonates related complications, births and managing complications in newborns; sexual reproductive health and antenatal care: family planning services, antenatal care services including HIV testing for pregnant women, caesarian section and vaginal delivery, birth related complication and post-natal care up to 6 weeks after delivery; health education and promotion: hygiene, breastfeeding and immunization, family planning, counseling on family planning and HIV, malaria prevention including IPT, and Education on HIV prevention strategies; other primary health care services such as treatment of minor ailments, home-based care, community outreach programmes, among others; the reproductive services offered include safe motherhood (SMH) which comprise antenatal care (ANC) attendance, caesarian section and vaginal delivery, birth related complication and post-natal care up-to 6 weeks after delivery.The methodological quality of included studies: the methodological quality of the systematic review by Widmer et al. [apriori; there was no duplicate study selection and data extraction; no list of excluded studies; no risk of bias assessment; and no source of funding declared . The key methodological aspects that were not described include the identification of potential confounders and how these confounders were controlled in the analyses. The quality of two qualitative studies [Annex 2). The methodological areas of concern included the lack of reflectivity of the researcher(s) and whether the data reached saturation. Vossius et al. [Annex 3 and Annex 4.Four cross-sectional studies met six of the eight JBI criteria for quality -33 whileet al.  met all  studies ,28 was fs et al.  study coEffects on FBOs on maternal and child health outcomes: the key findings on MCH services provided by FBOs are presented in When comparing government, FBOs, and private health facilities in terms of MCH services frequently rendered in the community, most government and FBO facilities provided obstetric services and prenatal care. The majority of FBOs (88.6%) and the government facilities (98.7%) offered prenatal care. There were higher immunization levels among women and children in the FBO facilities than government facilities offering similar services. Faith-Based Organizations (FBOs) had more supplies of health commodities than government facilities . In addiOne of the included studies in the review  assessedA descriptive report  includedet al. [From the qualitative studies, Aristide et al.  highlighet al.  highlighIn this study, we synthesized research evidence on FBOs providing MCH programs including HIV in Africa. The findings provide important insights into the contribution and potential impact of FBOs in the delivery of MCH services in Africa. Improving the utilization of antenatal care services, such as getting more mothers to attend professional healthcare visits while pregnant, is critical to improving maternal and child health . During High cost of health services has been described as a major limitation to accessing care . The cosWomen preferred the services run by the FBOs to those by the government facilities . These wet al. [et al. patient satisfaction is so critical that it has been used to assess the quality of care and health-related outcomes and behaviors [A study by Mwarey et al.  conducteet al. . Apart fet al. . Accordiehaviors . These pet al. [One systematic review and six additional primary studies met the inclusion criteria - consisting of cross-sectional, qualitative, economic evaluation and pilot studies. Methodological quality appraisal of these studies raised some concerns such non-reporting confounding factors and how these confounding factors were controlled ; non reporting of the reflexivity of the authors/researchers ; and lack of clarity on incremental costs and only the provider point of view was considered in the economic evaluation. It\u00b4s important to note that the scarcity of reviews and poor methodological quality of the included studies is not an isolated situation for the African continent, but it has been highlighted in other systematic reviews conducted among Latinos and Black Americans ,48 Kagawet al. , in theiWe followed a pre-specified protocol, conducted a comprehensive search, without language restrictions, covering various electronic databases, and we searched for on-going and unpublished systematic reviews. Two reviewers independently applied pre-defined eligibility criteria to select studies for inclusion, extracted data and evaluated the methodological quality of each included study. PRISMA 2020 reporting guidelines were followed . Only obet al. (2004) in their review assessing the effectiveness of FBO based health programs indicate that there is an urgent need for collaboration between FBOs and researchers to facilitate capacity building of FBOs in conducting research and routine health information systems to improve the quality of scientific papers produced. Additionally, Derose and Rodriguez [With regards to policy and public health implications, strengthening health systems in Africa through public private partnerships (PPP) such as FBOs, further research is needed to ascertain the effectiveness and impact of FBO based interventions on MCH outcomes and other global health programs. This will require capacity building of FBOs, partnerships of FBOs and academia/research agencies and increased funding to support a pipeline of evidence generation that will enhance informed decision making and the attainment of SDGs at large in developing countries. DeHaven odriguez  argue thFaith-Based Organisations (FBOs) play an important role in health systems strengthening and their presence could contribute to MCH through the reduction in maternal mortality and morbidity, increased uptake of maternal health care services, increased satisfaction by users of care, provision of HIV/AIDS services and an overall improvement in health outcomes. Future research need to carefully consider the questions to be addressed and refine these, based on existing evidence to avoid unnecessary duplication ,50. AdheFunding statement: this systematic review was supported by the funding from Stellenbosch University, Faculty of Medicine and Health Sciences-Early Career Research funding 2018. Award/grant number is not applicable. The funder did not have any role in the review process.There is high burden of maternal deaths in the African region which is common amongst the poorest and most disadvantaged population groups;Faith based organizations (FBOs) deliver between 30-70% of health services in low- and middle-income countries in Africa, including maternal and child health services;The role of the FBOs and their impact on maternal health outcomes in Africa need to be clearly understood.Faith-Based Organisations (FBOs) play an important role in improving access and delivery of maternal and child health care services;Experiences of participants using services provided by FBO are variable;Further research is needed to ascertain the effectiveness of FBO-based interventions in improving maternal and child health outcomes and ultimately strengthening health systems in Africa."}
+{"text": "Dear Editor,A seven-month-old female patient presented with a history of a congenital, violaceous, fast-growing lesion located on the right plantar surface. Dermatological examination disclosed the presence of a firm spherical tumor, with dilated vessels on the surface, and central ulceration with friable, bleeding tissue, and hematic crusts A. The chMagnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) disclosed a well-vascularized solid mass, with the involvement of the underlying muscles and extending to the anterior aspect of the foot. Diffuse contrast enhancement was observed throughout the lesion, with no signs of arteriovenous shunts or a cluster of tortuous vessels (nidus), thus ruling out the diagnosis of a vascular tumor, including kaposiform hemangioendothelioma A and 2B.The patient was submitted to neoadjuvant chemotherapy  to reduce tumor size C, followCIF is a rare malignant tumor of childhood; however, it is the most common soft tissue sarcoma in children under one year of age.Fibrosarcomas are malignant neoplasias composed of mesenchymal fibroblasts. The infantile variant shares histopathological characteristics with adult fibrosarcoma but has a better prognosis. Although local recurrences are common, the rate of CIF metastasis is less than 10% and the ten-year survival rate is up to 90%.5The histopathological findings of CIF include the proliferation of dense fusiform cells and vascularized areas. Immunohistochemistry is positive for vimentin and, in some cases, for desmin, smooth muscle actin, and cytokeratin.5The diagnosis of CIF should always be considered in the presence of a congenital, spherical, bleeding extremity tumor in children, aiming to avoid treatment delays.None declared.Luciana Baptista Pereira: Design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; critical review of the manuscript; approval of the final version of the manuscript.Jo\u00e3o Renato Vianna Gontijo: Critical review of the manuscript; drafting and editing of the manuscript; approval of the final version of the manuscript.Marcelo de Mattos Garcia: Critical review of the manuscript; drafting and editing of the manuscript; approval of the final version of the manuscript.Karine Corr\u00eaa Fonseca: Critical review of the manuscript; drafting and editing of the manuscript; approval of the final version of the manuscript.None declared."}
+{"text": "The approach to evaluating the effectiveness of psychosocial rehabilitation (PSR) of mentally ill patients implies a multidimensional, hierarchical consideration of mental pathology with the inclusion of clinical and psychopathological, socio-environmental and personal indicators when setting goals and objectives of PSRDevelopment of algorithms and models for evaluating the effectiveness of PSR taking into account: clinical, socio-demographic, psychological characteristics of the patient and the characteristics of the family environment, as well as factors of psychiatric care.Clinical, statistical, algorithms of the analytical hierarchy process (AHP) [1].Numerical estimates of changes (before and after the PSR program) in the main areas of patient\u2019s functioning disorders, such as motivation, cognition, compliance, coping strategies, family, skills, immediate environment, and others, are proposed as particular criteria for evaluating the effectiveness of PSR. Quantitative estimates for particular criteria are obtained on the basis of rank estimates, which are converted into numerical ones based on AHP algorithms [1]. Quantitative integral estimates of the effectiveness of PSR are obtained on the basis of partial estimates, taking into account the weight of the corresponding areas of impaired functioning of patients.S.S. Korsakov Journal of Neurology and Psychiatry. 2019; 119(2): 49-54The developed approach opens up prospects for obtaining numerical, partial and integral estimates based on various rank scales, which are of interest from the point of view of forming criteria-indicators (markers) of the effectiveness of psychosocial, rehabilitation, psychoeducational and psychotherapeutic measures. References: 1. Mitikhin, V.G., Solokhina, T.A. No significant relationships."}
+{"text": "A 73-year-old male patient developed a poorly differentiated squamous cell carcinoma in the anal canal nine months ago. He was treated with two cycles of 5-fluorouracil and cisplatin and concomitant radiotherapy , with complete remission. Since forty-five days he presentes a painful perianal and intergluteal erosion with circinate pustular borders. Light microscopy showed pseudoepitheliomatous hyperplasia of the epidermis with microabscesses of inflammatory cells (neutrophils and eosinophils) and acantholytic keratinocytes . Indirect immunofluorescence was positive for IgG, with an intercellular pattern, 1:80 titer. The diagnosis of radiotherapy-induced pemphigus vegetans was established and there was significant regression with oral prednisone (40 mg) and topical betamethasone. A 73-year-old male patient developed a vegetating lesion in the anal canal nine months ago; the histopathology showed a non-keratinizing poorly differentiated squamous cell carcinoma. He was treated with two cycles of 5-fluorouracil and cisplatin and concomitant radiotherapy , with complete remission. The control colonoscopy and endoscopy after six months of treatment were normal. Forty-five days before coming to the clinic again, he had a painful perianal and intergluteal erosion with circinate pustular borders and some isolated pustules, with surrounding erythema . He was a)Ulcerated herpes simplex associated with immunosuppressionb)Ulcerated radiodermatitisc)Pemphigus vegetansd)Tinea associated with immunosuppressionThe histopathological findings were suggestive of pemphigus vegetans, which may present with acantholytic clefts associated with polymorphonuclear microabscesses,There was no therapeutic response to systemic antibiotics and antivirals initiated before the results of the investigation, and there was significant regression with oral prednisone (40\u2009mg) and topical betamethasone. After seven days, the pustular border disappeared, and there was total symptom regression, with the appearance of some hyperkeratotic and verrucous central areas . Later, There are several reports of radiotherapy-induced pemphigus vulgaris, but not of the vegetans variant. Reported cases are restricted to the irradiated area,The mechanism of induction of autoimmune acantholytic diseases by radiotherapy must be complex. One possibility is the antigenic alteration by radiation;This case demonstrates the possibility that pemphigus vegetans lesions may occur locally on a previously irradiated area.None declared.Hiram Larangeira de Almeida Jr.: Approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.Ant\u00f4nia Larangeira de Almeida: Approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.Pedro Henrique Evangelista Martinez: Approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.Ana Let\u00edcia Boff: Approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; critical review of the literature; critical review of the manuscript.None declared."}
+{"text": "Trypanosoma brucei. Despite important advances in the reduction or disappearance of HAT cases, AAT represents a risky reservoir of the infections. There is a strong need to control AAT, as is claimed by the European Commission in a recent document on the reservation of antimicrobials for human use. Control of AAT is considered part of the One Health approach established by the FAO program against African Trypanosomiasis. Under the umbrella of the One Health concepts, in this work, by analyzing the pharmacological properties of the therapeutic options against Trypanosoma brucei spp., we underline the need for clearer and more defined guidelines in the employment of drugs designed for HAT and AAT. Essential requirements are addressed to meet the challenge of drug use and drug resistance development. This approach shall avoid inter-species cross-resistance phenomena and retain drugs therapeutic activity.Human African Trypanosomiasis  and Animal African Trypanosomiasis (AAT) are neglected tropical diseases generally caused by the same etiological agent,  Trypanosoma brucei (T. b.) gambiense, present in Western and Central African countries, and the zoonotic T. b. rhodesiense, found in over 13 countries of Eastern and Southern Africa regions , with implications for both livestock and wildlife, and Human African Trypanosomiasis (HAT), also known as \u201csleeping sickness\u201d. HAT is caused by the etiological agent  regions . AAT is Glossina sp.) in tsetse-inhabited areas. On the other hand, socio-economic instability, and geopolitical disputes compromise the fragile disease surveillance systems , , and the disubstituted compound . Isomethamidium can bind the kDNA with high affinity with an unconventional sideways geometry. The drug is preferentially accumulated in the mitochondrion (gamma-subunit of ATPase). Mutation of the ATP synthase subunit is sufficient to cause a substantial level of resistance. It is mainly prescribed to treat early infections caused by oma spp. . It is aoma spp. . It is poma spp. . IsometaT. b. evansi in camels and horses . Po. PoT. b.st T. b. . This wo and NMT . An addi and NMT . The mos and NMT   profile, and very good selectivity [3 was able to cure the 60% of mice in a systemic model of HAT, and it can successfully cross the BBB. However, it was unable to clear parasitemia in a CNS model of the disease. Following the same approach, diaminopurines were also identified as compounds with antitrypanosomal activity. Optimization of hit-compounds led to a new promising entity with improved absorption, distribution, metabolism and excretion (ADME) properties  and the efforts of international partners to engage other ministries and the community in the implementation of control strategies. The success of this strategy is largely attributed to the engagement of stakeholders and strategies including the use of insecticides to treat cattle as live bait for tsetse, therefore breaking the transmission of trypanosomes to both humans and animals [T. b. gambiense is still a problem [An effective and sustainable control of African Trypanosomiasis will be directly reflected on agricultural development and veterinary and public health, therefore contributing to poverty alleviation and population wellbeing. Animal health, public health, and economic needs sustain the urge to control Trypanosomiasis in sub-Saharan Africa. Since treatment of AAT reduces the animal reservoirs of zoonotic vector-borne programs . As a cldesiense . Controld to HAT . The ina animals . This fi problem .Trypanosoma spp. between animals and humans must be carefully monitored [Resistance to trypanocidals is becoming common, cross-resistance between classes has been identified, and resistant trypanosomes may pass from animals to humans. Since human\u2013animal proximity increases the risk of spill over and crossing species barriers, the interchange of onitored . Part ofTrypanosome species, for which the underlying mechanisms are yet to be discovered. Genetic combinations among different breeds and the introduction of trypanotolerant phenotypes may result in a balance between productivity and resistance to Trypanosomiasis, leading to a sustainable production and economical benefit [Trypanosoma spp. life cycle must prioritize collaboration and coordination of efforts at national, provincial, and district levels to integrate human health and veterinary and agricultural sectors together with wildlife and natural resources advocates, epidemiologists, policy makers, researchers, the pharmaceutical industry, and all those involved in epidemic preparedness. A framework must be designed in order to achieve: (i) depletion of parasite reservoirs through active case detection  and treatment of the infected humans and domestic animals; (ii) ensure the best available treatment is employed and is adequate for the disease stage; (iii) reduction in the tsetse fly population and human and animal contact with tsetse flies by protecting population health vulnerabilities; (iv) reduction in human\u2013wildlife and livestock\u2013wildlife contact; (v) detection of both human and animal cases; (vi) development of effective communication strategies between all intervenors and implementation of guidelines and training opportunities for health workers; (vii) translation of research findings to solutions in order to support the development of new safer drugs for HAT and AAT prevention, more advanced treatments, and field-friendly techniques for an early diagnosis [Regarding vector control measures, both chemical  and biological interventions  and genetic control of these flies (releasing sterile insects into the wild) have been attempted. The interventions did not give effective results, and caused severe environmental consequences, besides the selection of insecticide-resistant tsetse flies . At the  benefit . From thiagnosis ; and  an effective surveillance of infection among wildlife, domestic animals, and humans; (ii) implementation of a vector surveillance system and control measures; (iii) implementation of an effective system for disease notification in both animals and humans; (iv) implementation of effective, sensitive, and fast diagnostic tools applicable to field conditions; (v) creation of an effective network linking communication between stakeholders, medical and veterinary departments, and government and policy makers; and, finally, investment in the development of safer and more easily available HAT and AAT therapies and prophylactics. Cooperation among different actors will make this approach feasible and sustainable."}
+{"text": "The aforementioned educational event together with the 5th Teaching Course on Rare Neurological Diseases brought together a lively audience of over 1400 participants in a hybrid format, both online and on-site.The first day of the Summer School included presentations on the latest and most exciting or pressing issues in Neurology.The event started with a welcome address by Dafin Muresanu (Romania), Natan Bornstein (Israel), Volker Homberg (Germany), and Wolfgang Grisold (Austria).Wolfgang Grisold held a short presentation on the World Federation of Neurology (WFN) institution and activities. The World Federation of Neurology encompasses 6 regions and 123 member societies worldwide. As the World Health Organization approved the Global Action Plan to address epilepsy and other neurological disorders, the 10 years intersectoral action plan of the WFN was addressed, which is set to target:Followingly, Policy;Diagnosis and treatment;The implementation of strategies for promotion and prevention;Fostering research and innovation;Strengthening of public health approaches.The WFN activities include communication with regional and member societies, increasing the impact of international cooperation, education programs, development of publications, and international adaptation.Volker Homberg (Germany) and Dafin Muresanu (Romania) introduced the first session and covered topics such as neurorehabilitation, post-stroke deficits and post-stroke recovery.Volker Homberg (Germany), President-Elect of the World Federation of Neurorehabilitation (WFNR), presented a future perspective for neurorehabilitation, also highlighting the pillars of WFNR, namely (1) improvement of science, (2) improvement of services, and (3) improvement of education in neurorehabilitation. In the context of the global situation, where over 1 billion people live with some form of disability (and the number is increasing), prof. Homberg highlighted the differences in the availability of trained staff among different income countries and discussed high-tech and low-tech options for neurorehabilitation. Prof. Homberg pinpointed the strategies for neurological rehabilitation (restoration vs. compensation): replacement of dead tissue, \u201cwake up\u201d alternative structures, teaching bypass strategies, replacing functions by aiding devices, and adapting the environment to patients. He presented exciting avenues of technology for rehabilitation, such as rehabilitation robots, VR/AR technology, and brain-computer interfaces, putting an emphasis on the role of motivation in neurorehabilitation and the prospect of serious games, which can have a decisive role in therapeutic strategies. In contrast, the importance of more available low-tech options and the role of enriched environments were also marked, and the limitations and opportunities for both high-tech and low-tech undertakings were discussed. Pharmacological options for recovery and the latest achievements in neurorehabilitation were also addressed.Dafin Muresanu (Romania), Chairman at the Department of Neurosciences, Iuliu Hatieganu University of Medicine and Pharmacy in Cluj-Napoca (Romania), presented advances and updates in neurorecovery after stroke, pinpointing the need for better evidence-based approaches in stroke, supported by the following 3 pillars:Theory and basic research;Evidence-based parameters;External validity.According to Prof. Muresanu, the whole science and practice of neurorecovery are based on the pillars above. The burden of neurological disorders in Europe was also discussed, with stroke being a significant component of the disease burden. Prof. Muresanu showcased the AHA/ASA guidelines, the role and advantages of the GRADE system, as well as the similarities with EAN guidelines. The role of multimodal agents in contrast to neuroprotectants for neurorehabilitation was also approached.Michel Brainin (Austria), Emeritus Professor of Neurology and Chair at the Department of Clinical Neurosciences and Preventive Medicine of Danube University in Krems (Austria), centered on cognitive deficits after stroke. Prof. Brainin's first message was that the most common manifestation of vascular diseases is not reflected in stroke but in cognitive impairment and dementia. Furthermore, he took a more focused glance at vascular cognitive impairment and what cognitive domains it affects. He discussed the risk and protective factors for dementia and stroke, presenting a case study. He also approached several topics, such as small vessel disease, strategic infarct, preexisting vascular damage, and preexisting Alzheimer's disease.The last presentation of the session was held by The second session was introduced and coordinated by Michael Brainin (Austria) and Natan Bornstein (Israel).Wolfgang Grisold (Austria), President of WFN, who discussed the educational activities of the World Federation of Neurology (WFN). Prof. Grisold discussed the IGAP , which centers around developing education training, structures for training, making research attractive, and promoting a public health perspective. He then presented the mission and current WFN educational activities, including accredited training centers, department visit programs, junior travelling fellowships, WFN grants, eLearningHub, and Young Neurologist programs.The first to present was Johannes Vester (Germany), Head of Biometry & Clinical Research at the Institute for Data Analysis and Study Planning (IDV) in Gauting (Germany) then presented \u201cA new gold standard to improve TBI clinical research \u2013 the multidimensional approach\u201d. The gaps in traditional trial designs and the need for multidimensional approaches were highlighted to capture the global status of TBI patients as accurately and comprehensively as possible. He outlined current approaches and different scales used in research, pinpointing the more accurate picture of outcomes that the multidimensional analysis offers in contrast to the often employed one-criterion paradigm, which has been the standard in the research of neuroprotective treatments over the past decade. To support his point, he discussed the meta-analysis of the CAPTAIN trials, trials based on multidimensional approaches.David Vodusek (Slovenia), Emeritus Professor of Neurology at the Faculty of Medicine from the University of Ljubljana (Slovenia), presented \u201cNeurological and neurophysiological evaluation of the lower sacral segments\u201d. Prof. Vodusek discussed steps in the diagnostics, the difficulty of assessing lesions affecting the peripheral nervous system in contrast to central nervous system (CNS) evaluation, methods, the testing of the motor function along with some issues in reflex testing, diagnosis of neurological lesions in sacral segments through different tools (including electromyography) and many other inspiring subjects.rd session of the day was introduced by Antonio Federico  and Tudor Lupescu (Romania), addressing neuropathies and neurosciences in migrant populations.The 3Antonio Federico , Emeritus Professor of Neurology at the Department of Medicine, Surgery and Neurosciences from the University of Siena in Siena  firstly discussed aspects of neurology and neurosciences in migrants and refugees, describing the global situation and the effects of immigration, both positive and negative, and pinpointed the phenomenon of \u201cbrain drain\u201d \u2013 the migration of highly educated individuals- in certain territories. Furthermore, Prof. Federico outlined the relationship between refugee status and migration with the health system and the aspects which link migration and neurosciences . He discussed the specific brain diseases in immigrants and refugees, showcased the influence of migration on brain development, and outlined some protective factors encountered in migrants which mediate cognitive disturbances. Finally, the needs and limitations of approaching the neurological health of migrants and the impact of migration on children were also topics touched upon.Max Hilz (Germany), from the Icahn School of Medicine at Mount Sinai, New York (USA) and University Erlangen-Nuremberg (Germany) offered an insightful presentation on \u201cDiabetic autonomic neuropathy\u201d, discussing the complications of diabetes and the relationship of diabetes with neuropathies, highlighting the importance of making an early diagnosis to prevent fatal outcomes. In addition, he discussed the fluctuation of heart rate and blood pressure with age, how to diagnose cardiac diabetic neuropathy and offered recommendations for assessment and diagnostic criteria.Tudor Lupescu (Romania), the Head of the Neurology Department from Agrippa Ionescu Hospital in Bucharest (Romania), presented diagnostic approaches to neuropathies. Differential diagnostics, profiling, timing assessment, types of neuropathies and their symptoms were the topics covered and presented in an inspiring case study.th session was introduced by Marc Fisher (USA) and Urs Fischer (Switzerland).The 4Marc Fisher (USA), Professor of Neurology at Harvard Medical School (USA) showcased his presentation \u201cRepurposing neuroprotection (Cyto) and recovery enhancing drugs in the thrombectomy era\u201d, where he discussed the ischemic penumbra as the target of acute stroke therapy, the relevance of combining cytoprotection with reperfusion, and the need for multi-targeted interventions, as well as the factors for multi-targeted approach. Decompressive surgery was also addressed as a topic. Further on, Urs Fischer (Switzerland), the Chairman of the Department of Neurology at the University Hospital in Basel (Switzerland) presented the \u201cManagement of spontaneous intracerebral haemorrhage\u201d. Prof. Fischer underlined the need for more recent evidence-based guidance in the global burden of stroke, discussed therapeutic approaches and the importance of lowering blood pressure, and showcased international randomized control trials, presenting their outcomes.Natan Bornstein (Israel), Professor of Neurology at Tel-Aviv University, Sackler Faculty of Medicine (Israel) discussed \u201cDiabetes and Stroke\u201d. One hundred years after the discovery of insulin, his insightful presentation began with a mention of diabetes as the leading risk factor for stroke and a short reminder of the increasing global burden of stroke (12/2 million new stroke cases per year with a significant proportion of DALYs). It repeatedly highlighted the critical role of primary and tertiary prevention for stroke. Type 2 diabetes will increase the risk of stroke and double the risk of stroke occurrence, stroke outcomes being significantly worse in patients with diabetes. Prof. Bornstein highlighted that diabetic patients have a risk of stroke similar to people without diabetes who are 25 years younger. Furthermore, Prof. Bornstein discussed the role of gut hormones and incretin-based therapies, presenting randomized control studies, and presented the role of new therapies that demonstrated protective effects in patients with type 2 diabetes and higher risk of cardiovascular complications or with established cardiovascular disease (SGLT 2 inhibitors: GLP \u2013 1 RAs). Moreover, he talked about the importance of neurologists in managing patients with type-2 diabetes mellitus, controlling diabetes and other risk factors to prevent initial stroke and stroke occurrence, and the importance of preventing atherosclerosis both for stroke and dementia prevention. He mentioned that controlling risk factors through medication and lifestyle modification can reduce the risk of stroke by 90%. Following his presentation, Laszlo Csiba (Hungary), Professor of the Department of Neurology at the Debrecen University in Debrecen (Hungary) discussed interesting cases from daily practice.th International Summer School of Neurology, the \u201cPsychiatry Perspectives in Neurocognitive Disorders\u201d parallel session, and the 5th Teaching Course on Rare Neurological Diseases will be highlighted in future materials.Other information and further details on the 17"}
+{"text": "Under circumstances of pervasive global aging combined with weakened traditional family elder care, an incremental demand for institutional elder care is generated. This has led to a surge in research regarding institutional elder care. Rural residents\u2019 institutional elder care is receiving more attention as a major theme in social sciences and humanities research. Based on 94 articles related to rural institutional elder care, this study identified the most influential articles, journals and countries in rural institutional elder care research since 1995. This was done using science mapping methods through a three-step workflow consisting of bibliometric retrieval, scoping analysis and qualitative discussion. Keywords revealed five research mainstreams in this field: (1) the cognition and mental state of aged populations, (2) the nursing quality and service supply of aged care institutions, (3) the aged care management systems\u2019 establishment and improvements, (4) the risk factors of admission and discharge of aged care institutions, and (5) deathbed matters regarding the aged population. A qualitative discussion is also provided for 39 urban and rural comparative research papers and 55 pure rural research papers, summarizing the current research progress status regarding institutional elder care systems in rural areas. Gaps within existing research are also identified to indicate future research trends , which provides a multi-disciplinary guide for future research. The rapidly aging population combined with the weakening of traditional family aged care support ,2,3,4 haThe contribution of this study to the research field of rural institutional elder care is as follows: (1) The selection method of the literature samples covered in this paper is relatively comprehensive, and the high-frequency keywords related to rural institutional elder care extracted from the literature samples can reflect current research topics; (2) This paper presents high-impact articles, journals, countries, and authors related to rural institutional elder care; (3) This research explores the research evolution in the field of rural institutional elder care by using a scoping analysis method, and discusses the gaps within existing research, to identify future research topics. It should be noted that this review is a summary of the global research on rural institutional elder care, and in order to ensure the comprehensiveness of the review, it is not based on any country\u2019s definition standard of \u201crural\u201d and \u201curban\u201d. The division of \u201crural\u201d and \u201curban\u201d in this review follows the division criteria in the original literature samples. In other words, this review distinguishes between \u201crural\u201d and \u201curban\u201d based on the results of the search formula TS =  and the specific content of the literature sample. Meanwhile, among the 94 literature samples, 39 comparative studies of urban and rural institutional elder care were retained, assuring enough relevant rural sample for conclusions.The remainder of this paper is organized as follows. The following section describes the overall research methods of science mapping and qualitative discussion. The third section shows the visualized scientific atlas and the results of the scoping analysis. The fourth section expands on the above analysis results and discusses the research gaps and trends in this field. The final section summarizes current research as identified and described in this review.Introduced by Pritchard , bibliomPain deterioration within 1 year predicts future decline of walking ability: A 7-year prospective observational study of elderly female patients with knee osteoarthritis living in a rural district; Multidrug-resistant organism infections in US nursing homes: A national study of prevalence, onset, and transmission across care settings and 1 October 2010\u201331 December 2011, Prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in patients in long-term care in hospitals, rehabilitation centers and nursing homes of a rural district in Germany [Telerehabilitation for older people using off-the-shelf applications: Acceptability and feasibility and Assessing end-of-life preferences for advanced dementia in rural patients using an educational video: A randomized controlled trial [The Web of Science combines a traditional citation index with advanced Web technology and multiple and unique functions that accurately retrieve targeted literature. Moreover, it contains comprehensive literature information . As such Germany ; Other eed trial ,14. FurtVOSviewer, a text-mining tool developed by Van Eck and Waltman , was adoQualitative discussion is the final step required following a bibliometric search and scoping analysis. Qualitative research is always helpful to provide readers with more in-depth and useful insights ,19. An iGenerally speaking, scholars pay limited attention to rural institutional elder care. From This study systematically analyzes the source journals of 94 research articles on rural institutional elder care. The results are shown in Journal of Rural Health is found with the highest literature output, followed by Journal of the American Geriatrics Society, with both the second highest literature output and average citation times. From the perspective of average normalized citation, journals such as Collegian and JAMA Network Open are rated with the highest annual average influence.In The minimum number of documents of an author and the minimum number of citations of an author set in VOSviewer are 2 and 15, respectively. Of the total 357 authors in the literature sample, 22 met the selection criteria. Literature influence was assessed using Norm. Citations. As shown in Chinese researchers indicated by the red clusters in the co-authorship map contributed the highest value of Norm. These citations focused on exploring the relationship between social support and mental health and health-related quality of life in rural nursing homes in China and the gender differences in institutional care choices. For example, Zhang, et al.  construcThis study identified those countries active in rural institutional elder care research, with the United States, Australia, and China standing out. Using VOSviewer, these countries\u2019 contribution to rural institutional elder care research is identified and evaluated. When drawing the map of countries conducting research in rural institutional elder care research, the minimum number of documents of a country and the minimum number of citations of a country were both set to 1. Finally, 23 out of 25 countries met the conditions. Keywords spotlight the main topic content of studies and depict the themes that have been focused on within a given domain . A netwoBased on the connection strength between keywords, VOSviewer divides 35 keywords into five clusters with different colors for distinction: red, green, blue, purple, and yellow see . It can Of the 94 identified research studies on rural institutional elder care, 39 offer relevant research conclusions based on comparative analyses between urban and rural institutional elder care, while the remaining 55 provide a more in-depth investigation specific to rural institutional elder care. According to the five mainstream research topics presented in the map of co-occurrence of keywords, studies on rural institutional elder care are classified.When exploring the present situation of institutional elder care in rural areas from urban\u2013rural comparative studies, a series of similarities and differences between rural and urban institutional elder care are identified. To provide clarity for readers, the primary trend of urban\u2013rural comparative studies is also discussed individually from the five research mainstreams identified from the keyword analysis, including (1) the cognition and mental state of the aged population, (2) the nursing quality and service supply of aged care institutions, (3) aged care management systems\u2019 establishment and improvement, (4) the risk factors of admission and discharge of aged care institutions, and (5) healthy institutional elder care and deathbed matters of the aged population.In the comparative studies of rural and urban institutional elder care on the cognition and mental state of the aged population, the happiness, satisfaction, depression, and cognitive level of residents and related personnel in rural old-age care institutions are the main research objects. Generally speaking, the happiness of the elderly in rural old-age care institutions is lower than that found in urban old-age care institutions . The satIn the meantime, from the comparative studies of rural and urban institutional elder care on the nursing quality and service supply of aged care institutions, it is generally believed that the level of nursing quality and service supply in old-age care institutions in urban areas is higher than in rural areas . This faLikewise, for rural and urban institutional elder care comparison concerning the elderly care management systems\u2019 establishment and improvement, the main research focus lies in the characteristics and recruitment paths of certified nursing assistants. Although both the staff of nursing homes in urban and rural areas rely heavily on relatives and friends in order to obtain recruitment opportunities, rural nursing staff are more likely to receive training in nursing institutions than those in urban nursing homes that might be trained by community colleges or websites .Furthermore, the differences between admission and discharge status of urban and rural residents and the exploration of related influencing factors remain a main focus. In the research on the status quo of admission to nursing homes, in general, the rural elderly tend to care for nursing homes better than the urban elderly ,62,63,64In the comparative studies of rural and urban institutional elder care on the healthy institutional elder care and deathbed matters of the aged population. There are two main emphases, one health and disease, and the other end-of-life decisions and care. In addition, in the contrastive research of health and diseases of the elderly between urban and rural institutional elder care, on the one hand, the significant regional differences in the level and quality of health services of residents in nursing homes between urban and rural areas are confirmed across many quality indicators . On the Studies on rural institutional elder care are more specific in scope than comparative studies. Certain characteristics unique to the rural setting can be found. To provide readers with structured and systematic insights, the discussion is also unfolded from the five research mainstreams identified from the keyword analysis, namely (1) the cognition and mental state of the aged population, (2) the nursing quality and service supply of aged care institutions, (3) the aged care management systems\u2019 establishment and improvement, (4) the risk factors of admission and discharge of aged care institutions, and (5) the healthy institutional elder care and deathbed matters of the aged population.In rural institutional elder care studies on the cognition and mental state of the aged population, scholars have described the cognition and mental state of rural institutional elder care-related groups, such as residents, family members and staff ,79,80. FFor the nursing quality and service supply of aged care institutions, the influence of facilities and service conditions of rural nursing homes on the quality of life, physical health, mental health, and social relations of the elderly has been confirmed . For theFor the rural aged care management systems\u2019 establishment and improvement, research topics can be roughly divided into two streams, staff management and institution management. In terms of staff management, there are a range of problems leading to the ineffective implementation of management systems. Some of these shortcomings are as follows: inadequate consideration of family members\u2019 opinions by management and staff , lack ofIn studies of rural institutional elder care on the risk factors of admission and discharge of aged care institutions, related factor analysis has always been a research priority. A high social capital level influences family members\u2019 familiarity with nursing homes in rural communities . In turnRegarding healthy rural institutional elder care and deathbed matters regarding the aged population, two main themes are identified: health and disease and end-of-life decision and care. In the field of health and diseases, the main concerns are adverse drug reactions in old-age care institutions , microbiAlthough the number of published research studies on institutional elder care in rural areas is relatively small, significant research gaps can be summarized by analyzing the existing literature to inform related stakeholders of future research directions. Based on the discussion of mainstream research topics and gaps, the framework of near-future directions in rural nursing homes is proposed and shown in Nowadays, comparative studies between urban and rural institutional elder care are an evident priority, where differences between urban and rural depressed and demented elderly are among the most commonly adopted research themes ,78,116. Compared with urban institutional elder care, the resource allocation of rural institutional elder care shows great room for improvement. Thus, scientific and rational resource allocation is needed for rural institutional elder care. Future research on staffing and capital investment is recommended. Furthermore, the rural institutional elder care system should be standardized, so that the innovation research of rural institutional elder care models is required for accumulation. In recent years, intelligent nursing homes , telemedThe essence of the nursing home is an institution, and its management mode is the core. According to the present research situation, the management mode of rural nursing homes is backward, so further research on management mode innovation is needed to promote the development of rural elder care.Descriptive and empirical research on influence factors of the admission and discharge of nursing homes pave the way for countermeasure research. The significance of countermeasure research lies in the accumulation of policy planning. With a global trend of an aging population, many countries have attached great importance to planning and developing old-age care policies , suggestOverall, the health level, illness condition, and end-of-life status of the elderly in rural old-age care institutions are worse than those in urban old-age care institutions. Furthermore, the improvement of healthy institutional elder care and end-of-life status is called for by society.Journal of Rural Health, Journal of the American Geriatrics Society, Collegian and JAMA Network Open. (2) Keywords are determined by co-occurrence keyword analysis, and the mainstream research keywords of institutional elder care in rural areas can be classified into five aspects: the cognition and mental state of the aged population; the nursing quality and service supply of aged care institutions; aged care management systems; risk factors of admission and discharge of aged care institutions, and healthy institutional elder care and deathbed matters of the aged population. (3) Co-authorship analysis reflects the most frequently cited articles from Yang et al. who have the highest Norm. Citations, with their work mainly exploring the relationship between social support and mental health, and health-related quality of life in rural nursing homes in China, as well as the gender differences in institutional care choices. (4) The countries active in carrying out research on rural institutional elder care include the United States, Australia, and China, significantly contributing to this research field.This study of rural institutional elder care follows a bibliometric research paradigm, employing scoping and qualitative analysis to find the current research scope and future directions. A total of 94 related articles are selected as samples for analysis with results listed as follows: (1) The influential journals that publish papers on rural institutional elder care include According to the outcomes of scoping analysis, this study further identifies gaps within this research field. Consequently, a systematic framework for further research is proposed: (1) There are only a few multi-dimensional comparative studies, and in the future, more attention should be paid to rural institutional elder care comparisons between developed countries and developing countries, comparison of various indicators of institutional old-age care in urban and rural areas, and comparison between ordinary old-age groups and special old-age groups; (2) Compared with urban institutional elder care systems, rural institutional elder care models and technology have greater room for improvement, and both the market and the government should actively encourage innovative research on rural institutional elder care; (3) Studies on urban institutional elder care have offered many notable recommendations, but those addressing rural areas and their circumstances are limited, and the sustainable development of rural institutional elder care model remains absent. In order to identify developmental pathways and provide practical policy recommendations, further efforts to upgrade and revitalize rural institutional elder care are needed.This study focuses on the research progress of rural institutional elder care, with the research results limited by the scope of the research literature samples but not specifically listed and selected the definition of urban and rural research. Furthermore, this research sample is derived from Web of Science Core Collection only, which may limit the scope of the review. In defining the literature sample, the completeness is constrained by the keyword indicators on which the sample selection is predicated so future research could expand the search query. Moreover, only journal papers were selected, excluding minutes, letters, etc., which ordinarily offers limited insight, but this remains an assumption. This study only contains English literature, and does not analyze the research output published in other languages, which also may result in the omission of important references in related fields."}
+{"text": "Advances in Perovskite Quantum Dots and Their Devices\u2019 is a new open Special Issue of Materials in which original and review papers on the novel findings of synthesis, deep understandings of properties, and advanced potentials of applications in perovskite quantum dots are reported and published.\u2018Owing to their prominent properties including tunable bandgaps, strong absorption, efficient emission, and long carrier diffusion lengths, perovskites composed of metal-halide have rapidly emerged as materials with great potential in the last decade. Thus, their wide applications in solar cells, light-emitting diodes, lasers, photodetectors, X-ray scintillators, and catalysis have attracted the attention of researchers and captivated the broad scientific community.Furthermore, with the adaption of bulk perovskites to nanoscale ones, quantum dots exhibit a vast size-dependent optoelectronic performance, suggesting promising commercialization ability . For insThe research interests of this Special Issue include, but are not limited to, the following: the exploration of preparation methods; the scientific understanding of structures and optoelectronic mechanisms; the optimization of properties; wide-ranging applications; and the fabrication and performance enhancement of devices based on perovskite quantum dots."}
+{"text": "Dear Editor,Acute localized exanthematous pustulosis (ALEP) is an atypical variant of acute generalized exanthematous pustulosis (AGEP), a rare drug reaction.3) and serum C-reactive protein. The pustule secretion culture was negative. The skin biopsy revealed intraepidermal subcorneal pustules and a superficial perivascular lymphocytic infiltrate  is a particular form of AGEP. Approximately 25 reports have been published in the literature, confirming that it is a rare drug reaction.5As ALEP is a self-limited disease, the mainstay of treatment is the withdrawal of the suspected drug, promoting symptom improvement within a few days. Support therapy with topical or oral corticosteroids may be appropriate for the treatment of pruritus and inflammation in prolonged cases.In conclusion, ALEP is an unusual drug-induced skin reaction, and the majority of published cases were secondary to the use of antibiotics. However, it is important to emphasize that chemotherapeutic agents of the taxane class may also be responsible for this skin reaction.None declared.Ana Carolina Tardin Rodrigues de Medeiros: Statistical analysis; design and planning of the study; drafting and editing of the manuscript; intellectual participation in the propaedeutic and therapeutic conduct of the studied cases; critical review of the literature.Juliana Lopes Correa: Collection, analysis, and interpretation of data; drafting and editing of the manuscript; critical review of the literature.Ademar Schultz Junior: Collection, analysis, and interpretation of data; design and planning of the study; drafting and editing of the manuscript.Karina Demoner de Abreu Sarmenghi: Approval of the final version of the manuscript; effective participation in research orientation; intellectual participation in the propaedeutic and therapeutic conduct of the studied cases; critical review of the manuscript.None declared."}
+{"text": "The biogeochemical roles of microbes in the Earth system are relatively well known , but theMagnetospirillum of Alphaproteobacteria: M. magneticum AMB-1 and M. gryphiswaldense MSR-1 [MTB are a group of morphologically, phylogenetically and metabolically diverse prokaryotes , affiliase MSR-1 ,8. Consiet al. [To solve this problem, Jinhua Li and co-workers developed a general strategy for identifying and characterizing uncultured MTB from natural environments at the single-cell level . In receet al. , they fuThis study links, apparently for the first time, the production of magnetic minerals to specific genes in MTB at the species/strain level, building on earlier observations that the genes associated with magnetosome formation  vary among different MTB clades . This inmamABEIKMPQ) and the phylum-specific genes  related to magnetosome formation. Interestingly, the genes mamL and mamO, which were previously thought to be core genes [mad and man genes may be involved in the growth of bullet-shaped magnetosome magnetite. These findings provide genetic evidence for the phylum-specific morphology of magnetosomes, which indicates that magnetofossil crystal morphology from the ancient geological record has the potential to be a reliable proxy for the taxonomic lineage of ancient MTB and their paleoecology.First, confirmation of the core genes  are responsible for diverse chain configurations among MTB clades. For instance, the copy number, arrangement and homology of the mamK gene may influence the magnetosome chain structures in magnetotactic Pseudomonadota, and the Mad24 and Man5 genes may be involved in the assembly of multiple magnetosome chains in MTB of the Desulfobacterota and Nitrospirota phyla, respectively. This study further proposes a general model for the gene networks that control/regulate magnetosome biomineralization, including magnetosome membrane formation, protein sorting, iron transportation and magnetite nucleation, crystal mineralization, and chain assembly, in diverse MTB clades. This finding will further our understanding of magnetosome biomineralization in multiple bacterial clades and could pave the way for use of magnetofossils in paleoecology, paleoenvironment and evolution research.Second, demonstration of the key role of assembly ,9, suggeYet, the general model proposed here remains incomplete and will require refinement. Further investigation of more phylogenetically diverse MTB is needed in order to achieve a deep understanding of magnetosome biomineralization at the molecular level. Nonetheless, the new results of Jinhua Li and co-workers significantly expand our knowledge of the genetic basis for magnetosome biomineralization and will likely serve as a guiding framework for future molecular-scale studies of biogenesis and chain assembly of magnetosomes. The linkage of minerals to genes in MTB systems achieved in this study offers an excellent example for other fields of geomicrobial research."}
+{"text": "The COVID-19 pandemic is having an unprecedented detrimental impact on mental health in people around the world. It is therefore important to examine factors that may buffer or heighten the risk of mental health problems in this context.This study explores the buffering effects of different flows of compassion  and the magnifying effects of fears of compassion on the impact of perceived threat of COVID-19 on depression, anxiety and stress, and social safeness.4057 adult participants collected from the general community population across 21 countries from Europe, Middle East, North America, South America, Asia and Oceania, completed self-report measures of perceived threat of COVID-19, compassion, fears of compassion, depression, anxiety, stress, and social safeness.Self-compassion moderated the impact of perceived threat of COVID-19 on depression, anxiety and stress, whereas compassion from others moderated the effects of fears of COVID-19 on social safeness. Fears of compassion moderated the impact of perceived threat of COVID-19 on psychological distress. Only fears of compassion from others moderated the effects of fears of COVID-19 on social safeness. These effects were consistent across countries.Our findings highlight the universal protective role of compassion, in particular self-compassion and compassion from others, in promoting resilience by buffering against the harmful effects of the COVID-19 pandemic on mental health and social safeness. Furthermore, our results reveal that fears of compassion have a magnifying effect on the damaging impact of the COVID-19 pandemic on mental health and social safeness.I wasn\u2019t able to add the full list of authors above. Please add the full list as described below."}
+{"text": "The relationship and mechanism between agricultural low-carbon technology application and farm household returns are not yet clear, especially the lack of evidence from developing countries. This paper takes large-scale farming households in Jiangxi Province, China, from 2019 to 2020 as the research object, and obtains relevant data from field research to explore the intrinsic impact of agricultural low-carbon technology application on the returns of large-scale farming households. Based on the relevant theoretical analysis, the division dimensions of agricultural low-carbon technologies were proposed, and agricultural low-carbon technologies were subdivided into ten specific low-carbon technologies according to six dimensions: tillage system, breeding, fertilization, irrigation, medicine application, and waste treatment. Relevant questions were designed and researched to obtain data on the application status of low-carbon technologies in agriculture and the income cost status of large-scale farmers. Based on the theoretical analysis, the research hypotheses were proposed, and an empirical analysis was conducted based on the obtained data from large-scale farmers. The application of seven low-carbon technologies in agriculture: conservation tillage system, direct sowing technology, selection of compound fertilizer/organic fertilizer/controlled-release fertilizer, soil formula fertilization technology, deep fertilization/irrigation fertilization, sprinkler/drip irrigation/wet irrigation/intermittent irrigation, and straw resourceization significantly improved the income level of large-scale farmers. Furthermore, the application of biodegradable agricultural membranes, biopesticides, and new pesticide-controlled release technologies did not have significant effects on the income level of large-scale farmers, due to their low application and penetration rate. Based on the findings of the paper, the government should strengthen the promotion and subsidies of agricultural low-carbon technologies, especially those technologies that have no significant impact on large-scale farmers\u2019 income, such as biodegradable agricultural membranes, biopesticides, and new pesticide controlled-release technologies, so as to achieve a win-win situation of reducing carbon emissions and increasing farmers\u2019 income. The history and current status of economic development show that economic development is a function of the dual-factor of technological progress and input factor addition . CompareThe existing literature focuses on the carbon reduction effect and driving factors of specific agricultural low-carbon technologies, and pays less attention to the economic consequences of the application of agricultural low-carbon technologies, which limits the popularization and application of agricultural low-carbon technologies to a certain extent ,11,12,13This paper has the following three contributions relative to the previous literature: (1) the existing literature on low carbon technologies in agriculture mainly focuses on the drivers of low carbon technologies in agriculture, but less on the economic consequences of low carbon technologies in agriculture. This paper explores the impact of agricultural low-carbon technologies on the returns of large-scale farmers and provides theoretical support for the long-term sustainable diffusion of agricultural low-carbon technologies. (2) The existing literature on low-carbon technologies in agriculture focuses on specific technologies, such as drip irrigation and soil testing and fertilization, and there is less literature on low-carbon technologies in agriculture in a holistic manner. This paper constructs an agricultural low-carbon technology index based on the characteristics and application of agricultural low-carbon technologies as a standard to measure the degree of application of agricultural low-carbon technologies. The construction of the agricultural low-carbon technology index can help solve the problem that agricultural low-carbon technologies are complex and difficult to measure. (3) This paper adds evidence with Chinese characteristics to the study of agricultural low-carbon technologies by taking the field surveyed large-scale farmers in Jiangxi Province, China, as the research object. Jiangxi Province is a representative agricultural province in central China. Jiangxi has a high forest coverage and a relatively low level of economic development, which represents the situation of major underdeveloped regions in China. Therefore, it is highly representative to carry out agricultural low-carbon technology research in Jiangxi Province. Conducting a study on the impact of its agricultural low-carbon technology application on returns is conducive to revealing bottlenecks in the diffusion of agricultural low-carbon technologies in developing countries, as well as promoting the application of agricultural low-carbon technologies.Based on the discussion and analysis of existing literature, this paper puts forward the research hypothesis of agricultural low-carbon technology driving the income of large-scale farmers. Combined with the survey data of large-scale farmers in Jiangxi Province, China, empirical research and draws corresponding conclusions and policy suggestions are carried out. This paper is structured as follows: Part II is a literature review and the formulation of research hypotheses; Part III is a dimensional classification of low-carbon technologies in agriculture; Part IV is an empirical study, including descriptive statistics of the sample and research hypotheses.2 emissions [Numerous scholars have worked on specific agricultural low-carbon technologies and their impacts. Agricultural low-carbon technologies are a collection of technologies that can reduce agricultural carbon emissions in the production stage of agricultural products (cradle-to-farm gate), such as biochar technology, the in-use of agricultural waste, and cropping systems ,15,16. Bmissions . Low carmissions . Agriculmissions . Meanwhimissions ,23. Thermissions ,25.Some other scholars have conducted in-depth studies on the drivers of low-carbon technologies in agriculture. Farm household characteristics, such as size, age, and gender, have important effects on low-carbon technology adoption . For exaIncreased energy consumption due to economic growth is an important cause of carbon emissions, and thus carbon reduction targets may severely reduce agricultural output ,37,38. AAccording to the theory of technological progress, innovation and application of technology are the core drivers of economic development. Agricultural low-carbon technologies are different from traditional high-carbon technologies, which can not only reduce the level of agricultural carbon emissions, but also increase the output and quality of agricultural products. From the perspective of specific agricultural low-carbon technologies, conservation tillage systems, soil testing and formula fertilization, sprinkler irrigation and drip irrigation and other agricultural low-carbon technologies not only reduce the cost of fertilizer and irrigation water for farmers, but also help to improve the yield and quality of crops. At the same time, ecological and low-carbon agricultural products are more likely to be welcomed by consumers, which helps to improve farmers\u2019 income. The economic benefits generated by the organic combination of various production factors need to be based on a certain scale, that is, economies of scale. Therefore, when studying the economic benefits of agricultural low-carbon technology, we investigate and use farmers with a scale of more than 100 mu, so as to improve the credibility of the research. Therefore, the basic hypothesis of this paper is that the application of agricultural low-carbon technologies has a positive impact on the returns of large-scale farmers, which is analyzed as follows.Tillage systems include no-till, minimum-till, and conventional tillage, among which no-till and minimum-till are conservation tillage systems. The conservation tillage system has significant economic and ecological benefits compared with the traditional conventional tillage system, which can achieve high quality, high efficiency, and high yield in agricultural production . FirstlyHypothesis\u00a01.The conservation tillage system can reduce production costs and help to improve the returns of large-scale farmers.Direct sowing and transplanting are the two main methods of rice cultivation in China at present. Direct sowing refers to the direct sowing of dry seeds or seeds that have been soaked and germinated; transplanting includes the basic processes of germination, seedling raising, and transplanting. As a new rice planting technology in recent years, direct sowing saves labor and energy compared with traditional transplanting, and the yield is not much different from that of transplanting, which can reduce the cost and obtain better economic benefits. Based on the above analysis, Hypothesis 2 is proposed.Hypothesis\u00a02.The application of direct sowing technology can reduce costs and promote the income of large-scale farmers.The agricultural membranes are one of the important carbon sources in the agricultural production process, and crops are often covered with agricultural membranes at the beginning of planting for drought and frost resistance. As a new low-carbon technology in agriculture, the use of biodegradable agricultural membranes can effectively reduce the carbon emissions of agricultural membranes. However, the cost of biodegradable agricultural membranes is relatively high compared to traditional agricultural membranes, and the difference in efficacy between traditional agricultural membranes and biodegradable agricultural membranes is not significant, which increases the cost and is not conducive to economic efficiency. Therefore, the promotion and application of biodegradable agricultural membranes should rely on the government to provide corresponding subsidies to make the use cost of large-scale farmers lower than that of traditional agricultural membranes, in order to effectively improve the utilization degree and realize low-carbon agriculture. Based on the above analysis, Hypothesis 3 is proposed.Hypothesis\u00a03.The application of biodegradable agricultural membranes will increase the cost and reduce the income level of large-scale farmers.The choice of fertilizer type can have a large impact on crop production. Reducing the application of nitrogen fertilizers and increasing the application of organic fertilizers and compound and controlled-release fertilizers can effectively reduce the greenhouse gas emissions of chemical fertilizers. Studies have shown that the application of compound fertilizers and controlled release fertilizers has a longer and more balanced nutritional effect than the application of nitrogen alone, and can increase yields. In addition, when determining the amount of fertilizer to be applied, the use of soil testing and fertilizer application technology can effectively reduce the waste of ineffective fertilizers, reduce costs and reduce the source of fertilizer carbon. In terms of fertilizer application method, deep application and irrigation fertilization can deliver effective fertilizer nutrients to the lower layer of soil and crop roots, and improve the utilization rate of fertilizer. Based on the above analysis, Hypotheses 4 to 6 are proposed.Hypothesis\u00a04.The application of compound fertilizer, controlled-release fertilizer, and organic fertilizer can enhance the profit level of large-scale farmers.Hypothesis\u00a05.The adoption of soil testing and fertilizer application technology can reduce costs and increase the returns of large-scale farmers.Hypothesis\u00a06.Deep fertilization and watering fertilization can improve the utilization rate of chemical fertilizers and enhance the profit level of large-scale farmers.Irrigation methods include conventional irrigation as well as the new sprinkler, drip, wet irrigation, and intermittent irrigation. Sprinkler irrigation is the use of decentralized nozzles for rotary water spraying irrigation; drip irrigation is the irrigation method through fine pipes to irrigation water to the roots of the crop; wet irrigation is to make the field near saturation of water, but does not establish a water layer of irrigation; intermittent irrigation is a certain interval of time, using intermittent water supply to the furrow or border in successive water supply, the use of wave surge flow in the furrow border to advance to wet the soil Irrigation method. Too much water in the soil may lead to problems such as low ground temperature, which may affect the normal growth and development of crops. Compared with the traditional large water irrigation the above four irrigation methods can achieve significant water saving, reduce irrigation water, improve irrigation efficiency, maximize the crop growth water demand and increase yield. In addition, the above four irrigation methods consume less power than traditional pumping flood irrigation, thus reducing carbon emissions. Based on the above analysis, Hypothesis 7 is proposed.Hypothesis\u00a07.The scale farmers using sprinklers, drip, wet irrigation as well as intermittent irrigation can achieve better economic benefits.The use of pesticides is another important source of carbon in agricultural production. Excessive pesticide application not only increases carbon emissions and agricultural production costs, but also threatens food safety and causes environmental pollution. Biopesticide is a general term for a series of new modern pesticides, mainly including biomass pesticides and biochemical pesticides. Compared with traditional pesticides, biopesticides are derived from animals, plants, or microorganisms and can repel pests without increasing the burden on crops, improving the quality and yield of agricultural products. The adoption of new pesticide-controlled release technologies can slow down the volatile process of pesticides, increase efficacy, reduce the use of pesticides, and lower the cost of agricultural production. Based on the above analysis, Hypothesis 8 and Hypothesis 9 are proposed.Hypothesis\u00a08.The adoption of biopesticides can enhance the level of returns of large-scale farmers.Hypothesis\u00a09.The adoption of new pesticide-controlled release technologies can reduce the cost of agricultural production and increase the level of returns of large-scale farmers.The treatment of agricultural waste is a key aspect of low-carbon technology application in agriculture, the most important of which is the fertilizer/feed utilization of straw. Returning straw resourceization can improve soil fertility, maintain soil temperature, inhibit water evaporation and increase crop yields. Burning straw not only leads to air pollution and a large increase in carbon emissions, but also reduces soil fertility and is not conducive to increasing crop yields. Based on the above analysis, Hypothesis 10 is proposed.Hypothesis\u00a010.Straw composting/overstocking can improve soil fertility, increase yields, and raise the level of returns for large-scale farmers.After the questionnaire design, questionnaire surveys were conducted successively: first, the subject group members went to Fuzhou city and Ganzhou city from 15 July to 15 August 2019, and with the assistance of the agricultural bureaus of Fuzhou city and Ganzhou city, they selected key townships in the counties where large-scale farmers were concentrated to conduct field interviews in the countryside; second, with the help of Jiangxi Province\u2019s Second, with the help of the \u201cOne Village, One Product\u201d college student project carried out in Jiangxi Province, members of the research team selected large-scale farmers who came to study at the College of Continuing Education of Jiangxi Agricultural University to conduct interviews from 20 December to 25 December 2020; Third, they went to the Jiangxi Provincial General Survey Team and Jiangxi Provincial Bureau of Statistics to access the information needed for the study. The total number of questionnaires obtained was 350, of which 322 were valid, as shown in As can be seen from y); the independent variables are the 10 agricultural low-carbon technology variables set above; and five additional control variables are set as population.\u03b11 to \u03b115 are variable coefficients, and \u03b8 denotes residuals.In Equation (1), y represents the net profit per mu for large-scale farmers. The average age of household heads in the research area was 47 years old. Only three households were under 30 years old, accounting for 0.9%; 63 households were under 40 years old, accounting for 19.62%; and 87 households were between 40 and 45 years old, accounting for 27.1%. This indicates that the farmworkers of large-scale farming households are generally older, mainly distributed over 40 years old, and these people have greater difficulties in accessing new knowledge and generating new ideas. In addition, 138 of the household heads are party members and cadres, accounting for 43%, a high proportion, indicating that party members and cadres play a pioneering and exemplary role in carrying out large-scale agricultural operations, or it may be that there is a shortage of young and strong rural laborers, and the older generation of laborers who remain in rural areas take up the main administrative work in rural areas. In terms of education level, the education level of heads of large-scale farm households is mainly distributed in high school and below, accounting for 87% of the total, with only 13% share of the university and above, and the largest number of heads of households with junior high school education level. This indicates that the education level of large-scale farm household heads is generally not high, and even university education has many informal full-time graduates, and the overall cultural level is low, which is not conducive to the acceptance and application of new agricultural low-carbon technologies. In terms of household size, the total household size of the studied large-scale farming households is five persons on average, and the labor force is 2.7 persons on average, and the agricultural labor force is 2.2 persons on average. It can be seen that the agricultural labor force is less than half of the total household size, and part of the labor force has been diverted to non-agricultural jobs.An important aspect of the production characteristics is the scale of planting. The object of this paper is the scale of farmers, defined as farmers with a planting area of 100 mu and above, and in the research process we focused on the selection of local large grain growers, as shown in As can be seen from The sample size farmers are mainly large grain farmers, and rice sales are their main source of income. In order to ensure the comparability of data, we only counted the sales income and production cost of rice. The relationship between income cost and land size is shown in It can be seen from Based on the complexity and systematic nature of low carbon technologies in agriculture, identifying and quantifying low carbon technologies in agriculture is the core problem to be addressed in this paper. The academic research on agricultural low-carbon technologies generally follows the traditional technology research paradigm, which simply classifies agricultural low-carbon technologies into binary variables of adoption/non-adoption, on the basis of which the influencing factors of agricultural low-carbon technologies are studied. Pathak and Aggarwal (2012) systematically studied the cost, classification, and improvement directions of agricultural low-carbon technologies, taking wheat and rice as an example in the Indus-Ganges plain of India, which provides an important reference for China . The 10 Low-carbon technologies in agriculture are applied throughout the whole process of agricultural production, and they are reflected in different cropping patterns and crops. Therefore, there is no unified academic standard for the classification of low-carbon technologies in agriculture, but some core classifications are mostly the same. In the process of agricultural production, fertilizers and pesticides are used as the main carbon sources, and the technologies for fertilizer and pesticide application are also used as the core agricultural low-carbon technologies, in addition to breeding, irrigation, and transportation. Scholars have put forward different classifications of agricultural low-carbon technologies. Although they are referred to in different ways, the basic connotations are similar, mainly around breeding, fertilizer, pesticide, irrigation, waste, cropping systems, and machinery, covering the whole process of agricultural production. Based on the basis and consideration of scholars\u2019 research, this paper divides agricultural low-carbon technologies into the following seven dimensions according to the agricultural production chain, as shown in The quantification of agricultural low carbon technologies is the basis for conducting a study on the drivers of agricultural low carbon technology applications on the returns of large-scale farmers. After the dimensional division and explicit classification of low carbon technologies in agriculture, 10 nominal variables for low carbon technologies in agriculture are set based on the design problem. After obtaining data on the application of low carbon technologies in agriculture, the level of application of agricultural low-carbon technologies is reflected by the mean value of each agricultural low-carbon technology application, as shown in Equation (2).ith agricultural low-carbon technology, i-th agricultural low-carbon technology (expressed as 0/1) of the j-th scale farm household, and N represents the number of sample scale farm households. The mean value of each agricultural low-carbon technology was calculated by this formula, and the specific application levels are shown in In Equation (2), As can be seen in The adoption of low-carbon technologies in agriculture not only reduces the level of agricultural carbon emissions, but also improves the efficiency of agricultural operations and increases income. Conservation tillage systems can increase soil moisture retention and nutrients, and improve yields. The application of organic fertilizers, compound fertilizers, and controlled-release fertilizers can improve the utilization efficiency of chemical fertilizers and increase soil fertility; soil testing and fertilizer application can maximize yields according to local conditions; deep fertilizer application and irrigation application can improve the utilization efficiency of fertilizers. New irrigation technologies such as sprinkler and drip irrigation can improve irrigation efficiency and increase yields. New pesticide-controlled release technology and bio-pesticides can control pests and diseases more environmentally friendly and improve the growing environment of crops. Straw resourceization can improve soil fertility, moisturize and increase temperature, and increase yield. Based on the questionnaire data, a linear regression of the model was conducted and the results are shown in As can be seen in As can be seen in 2O, the majority of the P2O5, and a portion of the N in chemical fertilizers. Promoting the return of straw to field has a great potential to reduce the use of chemical fertilizer, air pollutant emission, and environmental burden [The survey data from large-scale farmers in Jiangxi Province, China show that the application of agricultural low-carbon technologies such as conservation tillage system, direct sowing technology, the use of controlled-release fertilizer, deep fertilization, soil testing, and formula fertilization, drip irrigation, sprinkler irrigation, and straw resourceization have a significant positive impact on the income of large-scale farmers. (1) Consistent with Afshar and Dekamin (2022), the results show that conservation tillage systems can reduce the cost of agricultural production, improve income, and increase the returns of large-scale farmers . The conl burden .However, the adoption of new pesticide-controlled release technologies and biopesticides has no significant impact on the returns of large-scale farmers, mainly because the adoption of biopesticides and new pesticide-controlled release technologies in the actual production process is very small and difficult to form a scale. Most large-scale farmers do not know about biopesticides, and the practical application is more difficult. New pesticide-controlled release technology is also relatively small, scale farmers in the use of pesticides generally do not consider the use of controlled release agents, mainly on the function and role of pesticide controlled release agents and cost-effective understanding is not in place. In addition, new pesticide-controlled release technologies and biopesticides are still immature, which also limits their low-cost promotion and application ,54.Furthermore, the increase in household size can raise the income level, and the expansion of the planting scale reduces the unit income level. The increase of labor force can enhance the fine management of unit farmland and increase the unit output, while the expansion of planting scale reduces the level of fine cultivation of unit farmland and lowers the unit output. The effects of increasing household size and expanding planting scale on the level of returns of large-scale farmers are logically consistent intrinsically.The impact of low-carbon technologies in agriculture on the returns of large-scale farmers is systematically explored in this work. Based on the characteristics and application of low carbon technologies in agriculture, an agricultural low carbon technology index is constructed to measure the application of these technologies. Then the impact of low-carbon technologies on the returns of large-scale farmers in Jiangxi Province, China, was investigated through a field survey.The application of seven low-carbon technologies in agriculture: conservation tillage system, direct sowing technology, selection of compound fertilizer/organic fertilizer/controlled-release fertilizer, soil formula fertilization technology, deep fertilization/irrigation fertilization, sprinkler/drip irrigation/wet irrigation/intermittent irrigation, and straw resourceization could significantly improve the income level of large-scale farmers. However, the application of biodegradable agricultural membranes, biopesticides, and new pesticide-controlled release technologies did not have significant effects on the income level of large-scale farmers, probably because the application of the above three agricultural low-carbon technologies in the actual agricultural production process was relatively small and the penetration rate was not high, and the effects on income were not significant. Based on the findings of the paper, some suggestions are proposed.(1)Promote conservation tillage systems. Conservation tillage systems include no-till and minimum tillage, which can enhance soil carbon storage and significantly reduce the carbon emission level of farmland compared to traditional conventional tillage systems, and are key agricultural low-carbon technologies that return farmland from a carbon source to a carbon sink. In addition, a conservation tillage system increases soil organic matter content, regulates soil temperature, enhances soil moisture retention capacity, and improves yield, while reducing tillage costs and increasing economic benefits. Therefore, conservation tillage systems have significant synergistic effects between achieving low carbon agriculture and modernizing agriculture. In the actual production process, most farmers do not have a high awareness of the conservation tillage system, and they are still stuck in the traditional farming mindset that \u201cyou get what you put in, you get what you harvest\u201d, and that more tillage is necessary for high yield. To promote the conservation tillage system, on the one hand, we should strengthen the technical training of farmers, through technology in the countryside, centralized lectures, and other ways to make farmers aware of the advantages of the conservation tillage system; on the other hand, through the agricultural cooperatives, family farms and other local agricultural organizations of scale, so that the majority of farmers see the conservation tillage system can generate real income, driving the implementation of the conservation tillage system.(2)Promote direct sowing technology and encourage the use of biodegradable agricultural membranes. Although there is some decrease in yield compared to the traditional transplanting method, the overall benefit of rice cultivation is significantly increased. In addition, direct sowing technology eliminates the tedious process of traditional seed breeding and reduces the carbon emissions of the breeding process. The adoption rate of direct sowing technology in rice cultivation is gradually expanding, but there is still a significant proportion of large-scale farmers who have not yet used direct sowing technology. The reason for this may be that there are some problems with direct seeded rice technology, such as the increase in weeds, the climatic risk of inversion, and the high mechanization requirements for sowing and harvesting, so the acceptance is not yet high enough. The promotion and application of direct sowing technology should, on the one hand, strengthen the education and training efforts and the application of large households to drive the efforts, and on the other hand, actively solve the problems arising from the application of direct sowing technology, and improve the applicability of direct sowing technology. The popularity of biodegradable agricultural membranes is low mainly because the application of biodegradable agricultural membranes has little effect on improving economic efficiency, and the cost is high compared with traditional agricultural membranes. To promote the application of biodegradable agricultural membranes, it is necessary to strengthen the policy subsidies, improve the tax preferences and subsidies in production and use, reduce the production and use costs of biodegradable agricultural membranes, and make large-scale farmers take the initiative to adopt biodegradable agricultural membranes through government regulation and market-oriented approach.(3)Improve the science and efficiency of fertilizer application. Fertilizer is the first major source of carbon emissions from agriculture, to reduce agricultural carbon emissions, mainly from the use of chemical fertilizers to think of ways. But the growth of crops cannot be separated from chemical fertilizers, which have a great impact on the production results of crops. China is the largest fertilizer user in the world, and for every ton of fertilizer applied, the agricultural output value will increase by 1,245,910,000 RMB. Therefore, improving the science and efficiency of fertilizer application is the only way to achieve low carbon fertilizer use and high-efficiency income. First of all, in fertilizer selection, the use of compound and controlled release fertilizers, as well as organic fertilizers in the selection of fertilizers reduces the application of traditional nitrogen fertilizer. The use of compound fertilizer and organic fertilizer can balance soil nutrients, improve soil fertility and increase yield, while reducing carbon emissions, and the application of controlled-release fertilizer can prolong fertility and reduce the application of chemical fertilizers. Secondly, in the application method, deep fertilization or watering fertilization is used instead of the traditional spreading of fertilizer. Deep fertilizer application and irrigation fertilization can improve the efficiency of fertilizer utilization and reduce the amount of fertilizer, while increasing the yield. Finally, soil testing and fertilizer application techniques are used to determine the amount and type of fertilizer to be applied. Traditional fertilizer application is based on the amount of fertilizer applied in previous years or the amount of fertilizer applied by other local farmers, ignoring the nutrient demand of the soil. Soil formula fertilization can meet the individual needs of the soil, while reducing the waste of useless chemical fertilizers, lowering the soil burden, increasing yields, and improving economic benefits. In the actual production process, large-scale farmers have low awareness of the scientific nature of fertilizer application, and the lack of science in the amount of fertilizer used, the type of fertilizer applied, and the way of fertilizer application has made chemical fertilizer the number one source of carbon in agriculture, and also reduced economic benefits. To improve the science and efficiency of fertilizer application, we should strengthen the training of farmers on fertilizer application and raise their awareness of environmental protection. At the same time, agricultural extension personnel should also go deep into the farmers, go into the fields to give scientific guidance to large-scale farmers, and lead them to apply fertilizer scientifically to realize the synergy of agricultural economic benefits and environmental benefits.(4)Promote the use of new irrigation technology. Compared with the traditional large water irrigation, sprinkler irrigation, drip irrigation, moist irrigation, and intermittent irrigation can improve water use efficiency, reduce water use costs and improve economic benefits. In the sample study area, it is not common for large-scale farmers to adopt new irrigation technologies, and almost no farmers use sprinkler and drip irrigation, while some farmers use wet irrigation and intermittent irrigation. The cost of sprinkler and drip irrigation is higher than that of wet irrigation and intermittent irrigation, and the cost of water saved is not enough to compensate for the equipment cost of sprinkler and drip irrigation, thus the popularity rate is low. To promote new irrigation technologies, we should increase policy support and provide greater subsidies for sprinkler and drip irrigation equipment, so that farmers can afford to buy and use them. At the same time, strengthen the irrigation technology training for large-scale farmers, deepen the concept of new irrigation, and gradually reverse the backward irrigation situation in rural areas.(5)Promote the application of biopesticides and pesticide-controlled release formulations. Pesticide application is one of the important aspects of the agricultural production process and one of the important elements in the transformation of traditional agriculture to modern agriculture. The massive use of modern chemical pesticides on the one hand has greatly reduced crop pests and diseases, ensuring high agricultural yields and providing us with abundant agricultural products; on the other hand, it has also brought about serious environmental pollution, including a large increase in agricultural carbon emissions. As early as 1962, the American scholar Rachel Carson shockingly revealed in Silent Spring the great threat posed by the excessive use of pesticides to the human living environment in modern society. Controlling the excessive application of pesticides can not only reduce the cost of pesticide application for large-scale farmers, but also reduce agricultural pollution and carbon emissions, which is conducive to achieving a deep synergy between the economic and ecological benefits of agriculture. The promotion and application of biopesticides can significantly improve the current situation of pesticide pollution, and the elimination of pests and diseases through biological laws and mechanisms is the future development direction of agriculture. The new pesticide-controlled release technology can extend the efficacy of traditional pesticides, reduce the overuse of pesticides, and reduce the environmental risks brought by pesticides. In the actual agricultural production process, the application of biopesticides is very little, and the adoption of emerging pesticide controlled release technology is also less, mainly because the technology of biopesticides is still in the formative stage, is not mature, the application cost is very high, emerging pesticide controlled release technology also has a high application cost, the scale of farmers on emerging pesticide controlled release technology has not been really recognized. Promote the application of biopesticides can be emerging pesticide control release technology, on the one hand, the drug to strengthen basic research, improve the applicability of biopesticides, and pesticide control release technology to reduce costs; on the other hand, to strengthen the publicity and education of large-scale farmers, so that biopesticides and new pesticide control technology in the vast rural areas to gain recognition; and finally to strengthen policy subsidies to improve the application of large-scale farmers biopesticides and emerging pesticide The enthusiasm of controlled release technologies.(6)Improve the application rate of straw resourceization. The traditional way to deal with straw is to burn or abandon it regardless, which not only wastes the nutrients of the straw itself, but also greatly increases agricultural carbon emissions. Straw resourceization can improve the soil organic matter content, while regulating soil temperature, enhancing moisture storage capacity, and can increase yields without raising costs, improving economic efficiency. Eighty percent of the survey respondents have returned straw resourceizations, indicating that straw is commonly returned to the fields in the actual agricultural production process. For the application of straw resourceization of large-scale farmers, on the one hand, enhance the technical training of straw resourceization, improve the scientific nature of straw resourceization of large-scale farmers, improve the efficiency of straw utilization, and maximize the utility of returning to the field; on the other hand, further promote the application of straw resourceization, improve the popularity of straw resourceization, and strive to achieve the popularization of straw resourceization.(7)Improve the research and development innovation of agricultural low-carbon technologies, and provide a number of agricultural low-carbon technologies with low cost and good benefit. The promotion and application of low-carbon technologies in agriculture are not only conducive to enhancing the economic benefits of large-scale farmers, but also can achieve agricultural carbon emission reduction, which is the only way to achieve sustainable development of modernized high-carbon agriculture. To promote the application of low-carbon technologies in agriculture, farmers are the main body, the government is the leading, and technology is the key. The government should play a leading role in promoting the application of low-carbon technologies in agriculture and provide support for the promotion and application of various low-carbon technologies in agriculture. First, promote the research and development innovation of agricultural low-carbon technologies, and provide a number of agricultural low-carbon technologies with low cost and good benefit. Second, promote the construction of agricultural carbon sink market, and at the same time provide measurement support for farmers\u2019 carbon emission reduction, provide a carbon trading platform for large-scale farmers to achieve carbon emission reduction, and enhance the enthusiasm for large-scale farmers\u2019 carbon emission reduction. Third, drive the application of agricultural low-carbon technologies with new agricultural business entities . Fourth, strengthen the publicity and education for farmers to raise the low-carbon awareness of large-scale farmers. Fifth, propose a national development plan for low-carbon agriculture to provide legal support for the promotion and application of low-carbon agricultural technologies. Sixth, strengthen the construction of rural financial markets, encourage the development of new agricultural financial organizations, and provide financial support for the promotion and application of low-carbon agricultural technologies."}
+{"text": "Editorial on the Research TopicHighlights in diagnostic and therapeutic devices 2021/22Developing flexible systems that monitor human health and deliver feedback therapy are the unmet medical needs for applications of personalized medicine and digital healthcare , 2. Sevei.e., United States, United Kingdom, Germany, Canada, France, Italy, Spain, Israel, Turkey, and Thailand) and nominated universities/institutions , University of California, Los Angeles (UCLA), University of Pennsylvania (UP), Tufts University, and Weill-Cornell Medicine,). Herein, we provide a brief introduction of these published articles and welcome readers to refer to these publications and their associated references for more details on this Research Topic.We are pleased to see the quality of the research submitted to our topic in diagnostic and therapeutic devices. This Research Topic finally contains six research and two review articles that address the recent advances and insights in diagnostic and therapeutic devices from scholars in a variety of countries  from sole pressure and flow waveforms by using SYNCSMART software and that the results are within the inter-rater variability, providing a reliable assessment of patient-ventilator asynchrony. Afra et al. offer a comprehensive evaluation of the Vagus nerve stimulation (VNS) therapy system technology for drug-resistant epilepsy, including the technological evolution of the VNS with device approval milestones and a comparison of conventional open-loop and closed-loop generator models. This review could potentially serve as a valuable resource as this anti-epileptic neuromodulation technology continues to evolve. Basnet et al. report examining the field of energy-based medical therapies based on the analysis of patents, indicating an increasingly important role for energy-based therapies in the future of medicine. Prezelski et al. propose a novel multi-point injection cannula for achieving broader volume distribution than current single-needle designs and validate this system in benchtop studies of trypan blue convention enhance delivery in agarose brain phantoms, demonstrating a significant increase in volume distribution compared to single-needle delivery, while significantly reducing the total duration of the procedure. Schumayer et al. present an interesting three-dimensional masking process and demonstrate its successful application for the partial coating of a scleral contact lens electrode. Such techniques could open up more applications, including the mass production of brain electrodes or the structuring of microfluidic systems. Sringean et al. demonstrate the technical feasibility of using multisite wearable sensors to quantitatively assess early objective outcome measures of the ability of patients with Parkinson's disease to get out of bed, which significantly correlates with axial severity scores, indicating that axial impairment could be a contributing factor in difficulty getting out of bed.The articles published on this Research Topic cover a broad spectrum of research in wearable/implantable diagnostic and therapeutic devices that will bring new solutions and perspectives for the next-generation medical devices. We sincerely thank all the authors for their contributions to this Research Topic. It is also essential to acknowledge all the reviewers' time and assistance in ensuring the scientific validity and quality of the work submitted to this Research Topic."}
+{"text": "Terminologies can seem very abstract to end-users. While most health professionals will be familiar with some terminologies , the controlled vocabulary thesaurus used for indexing articles for PubMed or ICD-10, WHO's terminology for disease coding), fewer will be aware of the depth and range of terminologies used in healthcare, nor of the central importance of multilingual standard terminologies in health care interoperability. Following a brief introduction to the use of terminologies, the integration of the International Classification for Nursing Practice (ICNP) the Systematized Nomenclature of Medicine - Clinical Terms (SNOMED CT) will be presented, as an example of the use of terminologies, and their ongoing curation, maintenance and development."}
+{"text": "Social isolation and loneliness are related but distinct constructs. A number of studies have examined these two constructs separately; however, the combined and interactive effects of social isolation and loneliness on health outcomes have rarely been studied. Using the most recent data of the Health and Retirement Study (HRS 2020) collected during the pandemic, this study aimed to explore the latent classes of social isolation and loneliness among adults aged 60 and older  and to examine the associated psychological well-being. Social isolation was measured by five indicators, including living alone, no membership in any organizations, and less than once a month contact with children, relatives, and friends. Loneliness was measured by the 3-item UCLA scale. Four classes were identified by the Latent Class Analysis (LCA): neither isolated nor lonely , living alone and lonely , no social participation and lonely , and highly isolated and lonely . The results of multivariate regression indicated that compared to respondents who were neither isolated nor lonely, those who were in the class of living alone and lonely and the class of highly isolated and lonely had more depressive symptoms, stress, anxiety, worry, loneliness during the pandemic. The latent class of no social participation and lonely was associated with more depressive symptoms and covid-related stress. This study emphasizes the importance of specialized intervention strategies targeting the unique needs of older adults with different experiences of social isolation and loneliness."}
+{"text": "The massive production and use of organohalides resulted in their worldwide contamination in soil, sediment and other environmental matrices . In addition, the debromination extent and rate of BDE183 could be enhanced by amendment of the BDE47. This study provides knowledge on new capabilities of Dehalococcoides and its potential in bioremediation of sites contaminated by both DBE47 and BDE183.In a Cimmino et al. deciphered the stoichiometry of pceABCT individual gene products in OHRB of Firmicutes. Notably, in contrast to a previously proposed model, results showed the formation of a membrane-bound PceA2B that could be devoid of PceC. These results provide unprecedented insight into the electron-accepting complex in PCE-dechlorinating OHRB of the phylum of Firmicutes.Reductive dehalogenase is the key enzyme to catalyze halogen removal from organohalides. Based on both transcription and translation analyses, Matturro et al. employed both 16S rRNA gene amplicon sequencing and metagenomic analyses to elucidate the microbial interactions among Dehalococcoides, Methanobrevibacter and Methanobacterium for the efficient dechlorination of trichloroethene (TCE) and reduction of Cr(VI) in a BES. In addition, at sites contaminated with chlorinated ethenes, abiotic factors  could determine the fate of chloroethenes by affecting organohalide respiration of OHRB. Li et al. reported that FeS enhanced Dehalococcoides-mediated reductive dechlorination of TCE by formation of FeS nanoparticles and up-regulation of tceA transcription. These results could guide efficient bioremediation of sites contaminated by chlorinated ethenes and other contaminants.Bioelectrochemical systems (BES) hold great potential for bioremediation of sites co-contaminated by organohalides and heavy metals. With the success of the two volumes of this Research Topic, we would like to thank all the authors and reviewers for their valuable contributions. These papers significantly improve our understanding in organohalide-respiring bacteria and their electron transport chains, as well as in dehalogenating microbiome and bioremediation implications. Notably, several research gaps were also highlighted in this Research Topic, and awaited future studies: (1) contribution of microbial reductive dehalogenation to attenuation of organohalides in natural environments; (2) cycling of organohalides in varied environmental matrices and associated functional microorganisms and enzymes; (3) reciprocal interactions of the commonly co-existing abiotic processes with the OHRB-mediated reductive dehalogenation process. We hope that this collection of reviews and original research articles will be helpful for researchers and engineers seeking information on organohalide respiration and bioremediation applications.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
+{"text": "On the basis of complex clinical anamnestic, clinical psychopatological, pathopsychological research, data were obtained about reasons and conditions of formation, abnormal clinical psychopathological structure, syndrome peculiarities of emotional disfunctions for patients with episodic paroxismal disorders, generalized anxiety disorders and mixed anxiously depressed disorders.To realize the aim and tasks of the research, 145 patients were examined with anxiety disorders, that passed the stationary course of treatment.The purpose of the research was to discover emotional disturbance peculiarities for anxiety disorder patients with different origins of pathological syndromes.The basic method was a group psychotherapy with the elements of rational, positive, suggestive and family psychotherapy. In relation to disfunctions of emotional sphere, cognitive-behavioral therapy (CBT) was used for the phobic-depressive and anxious-depressed disorders.Decrease in general level of anxiety and internal anxiety was obtained for most patients. No spontaneous emergence of fear was practically observed. While active interviewing, patients stated that their former worries and fears have lost actuality and apparent emotional colouring, somatic-vegetative correlates of anxious states disappeared. Up to the end of the therapy course, a sense of calmness was attained as a base-line for the background emotional state. Considerable reduction of symptomatic of the depressed circle also took place. Patients\u2019 mood increased, their interests broadened, patients started to feel joy and optimism.To correct emotional disfunction of patients with episodic paroxismal disorders, generalized anxiety disorders and mixed anxiously depressed disorders, psychotherapeutic correction system is optimal to use, which is built based on stepwise and multimodal principles."}
+{"text": "Among non-communicable diseases, cardiovascular disease (CVD) is the leading cause of mortality worldwide, which is associated with increased morbidity and hospitalization . To dateMa et al. creatively conduct an overview of EV research in CVD via a bibliometric analysis. The authors systematically collect the last 20 years of research on Web of Science Core Collection and perform a bibliometric analysis with visual tools (Citespace and Vosviewer). The results demonstrate that increasing attention was significantly paid to the capacity of EV in CVD from 2017 onwards, indicating the increasing popularity of the subject in this field. Furthermore, the authors conclude most of these studies focused on EV as biomarkers for CVD diagnosis, delivery vehicles, and a potential strategy for treating myocardial infarction.In this issue, Yao et al. prospectively performs atrial fibrillation (AF) modeling in Canines and investigates the function of EV in AF development. The authors reveal that blocking the release of small EV by GW4869 could alleviate AF by reducing atrial fibrosis. Mechanistically, EV-enclosed miR-21-5p targets the downstream TIMP3/TGF-\u03b21 pathway and induced fibrosis. Inhibiting the release of EV may be a potential strategy for AF treatment, which may help accelerate new clinical trials of AF treatment. Chen et al. systematically review the role of EV and EV-enclosed non-coding RNAs (NcRNAs) in the diagnosis and treatment of AF in more detail. Notably, EV-enclosed NcRNAs may also play a crucial role in the progression of AF.The study of Liu et al. and Yang et al. explore the role of adipose-derived EV in lipid metabolism, which is closely associated with vascular homeostasis. Epicardial adipose tissue (EAT)-derived EV-enclosed miR-3064-5p is identified as a key molecule in regulating lipogenic differentiation.The EV-mediated interaction between adipose tissue and blood vessels may play an important role in CVD. In this Research Topic, Hu et al. investigate the crosstalk between macrophages and cardiomyocytes. The authors reveal that ambient particulate matter could promote the release of EV and subsequently activate macrophages. EV-enclosed TGF-\u03b2 derived from macrophages promotes the fibrotic alteration of cardiomyocytes, ultimately leading to cardiac dysfunction. This study sheds light on the underlying mechanism and potential therapeutical strategy for air pollution-associated cardiovascular disorders.Interestingly, EV is proven to be involved in air-pollution-associated cardiac injury. Wei et al. summarize the role of platelet-derived EV in mediating intercellular communication, which contributes to arterial thrombosis. This review provides a new horizon as platelet-derived EV could provide promising biomarkers for the diagnosis of CVD.Notably, increasing evidence shows that platelet-derived EV are a crucial component of circulating nanoparticles in blood, indicating that platelet-derived EV play important roles in multiple pathological processes. In this Research Topic, Overall, this Research Topic provides a relatively comprehensive understanding of the role and potential application of EV in CVD, including a bibliometric analysis, overviews, and some surprising experimental articles. These studies identify a novel cargo and signaling axis  in the development of CVD and provide a novel way of using different sources of EV and EV-enclosed cargo in diagnosing CVD. Nevertheless, EV-associated basic, translational, and clinical studies are still on the way. Here we sincerely hope that this Research Topic can provide readers with different viewpoints and new horizons in EV & CVD diagnosis and treatment, inspiring future studies on the therapeutical application of EV. In addition, we also hope the work can help to stimulate novel ideas in associated fields and improve the research progression of CVD.HW, YH, and JX are the topic editors of this issue and they have contributed to the writing and revising of the article. XZ, MZ, and YL contributed to drafting the Editorial. All authors approved it for publication.This work was supported by grants from the National Key Research and Development Project (2018YFE0113500 to JX), the National Natural Science Foundation of China (82020108002 and 81911540486 to JX and 82000253 to HW), the grant from Science and Technology Commission of Shanghai Municipality (20DZ2255400 and 21XD1421300 to JX), the Dawn Program of Shanghai Education Commission (19SG34 to JX), the Sailing Program from Science and Technology Commission of Shanghai (20YF1414000 to HW), Chenguang Program of Shanghai Education Development Foundation, and Shanghai Municipal Education Commission (20CG46 to HW).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "About 29\u201381% of post-stroke survivors suffer from dysphagia, which is characterized by varying degrees of eating disorders, choking cough, salivation, and abnormal pronunciation. Dysphagia is associated with increased risk of malnutrition and pneumonia and leads to prolonged hospital stay, poor prognosis, and mortality . For PAS, some studies used both liquid and semi-solid measurements and further produced two different PAS results  and Dysphagia Grade (DD) in the meta-analysis. The reasons are unclear. DD is mainly assessed using questionnaires, whereas PAS requires the collection of video images for assessment by the Fiber Endoscopic Evaluation of Swallowing (FEES) or the Video Fluoroscopic Swallowing Study (VFSS). The Standardized Swallowing Assessment (SSA), Functional Dysphagia Scale (FDS), and Mann Assessment of Swallowing Ability (MASA) are commonly used as measurements of swallowing function, and some trials using these outcome indicators have been missed. Moreover, a trial  instead of standard deviation (SD). We note that Khedr et al.  and KhedWe added a randomized controlled trial , p = 0.04]. Heterogeneity also greatly reduced  compared with Yang et al. . Subgroup analysis was conducted according to different frequencies. The efficacy of high-frequency stimulation  and low-frequency stimulation  in the treatment of dysphagia after stroke was greater than conventional rehabilitation, which was completely different from Yang's results. The results showed that rTMS was superior to conventional rehabilitation in the treatment of post-stroke dysphagia regardless of stimulation frequency. We emphasize the importance of carefully examining the data extraction and reviewing the results of the meta-analysis.As shown in In conclusion, we urge readers to be cautious about the quality and validity of the review analyzed by Yang et al. The study omitted several important trials and produced extraction/synthesis errors in the meta-analysis, leading the authors to underestimate the efficacy of rTMS in patients with post-stroke dysphagia.Y-lX, SW, and Y-hX conceived the idea and wrote the manuscript. QW and YW analyzed the data. All authors reviewed the final manuscript.YW was supported by Sichuan Medical Research Project Plan (Q18038). QW was supported by Development Project of Affiliated Hospital of North Sichuan Medical College (2021ZD014). Y-lX was supported by the North Sichuan Medical College of Medical Sciences Postgraduate Research Scholarship.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "The COVID-19 pandemic has highlighted the need for resilient health systems with the capacity to effectively detect and respond to disease outbreaks and ensure continuity of health service delivery. The pandemic has disproportionately affected resource-limited settings with inadequate health capacity, resulting in disruptions in health service delivery and worsened outcomes for key health indicators. As part of the US government\u2019s goal of ensuring health security, the US Centers for Disease Control and Prevention has used its scientific and technical expertise to build health capacity and address health threats globally. We describe how capacity developed through global health programs of the US Centers for Disease Control and Prevention in Cameroon was leveraged to respond to coronavirus disease and maintain health service delivery. The health system strengthening efforts in Cameroon can be applied in similar settings to ensure preparedness for future global public health threats and improve health outcomes. The ongoing COVID-19 pandemic was declared a public health emergency of international concern by the World Health Organization (WHO) on January 30, 2020  began work in Cameroon during 1998 by establishing an HIV laboratory and research program. The presence of CDC in Cameroon evolved to an established country office in 2004, providing technical expertise and support to the Ministry of Health (MOH) to strengthen disease control efforts and develop sustainable public health capacity. In 2007, an agreement was signed between the US and Cameroon governments, establishing a partnership to prevent and control HIV/AIDS, avian influenza, and other infectious diseases. Consistent with the International Health Regulations (2005) that states WHO member states should develop, strengthen, and maintain their capacity to respond promptly and effectively to public health emergencies of international concern  was activated for the response. The PHEOC is a state-of-the-art facility constructed and established with support from the US Defense Threat Reduction Agency and CDC and handed over to the government of Cameroon in June 2019 to ensure coordination and management of health emergencies , an established command structure to manage emergency responses . CoordinThe CDC-established Field Epidemiology Training Program  supportehttps://anab.ansi.org), meeting international standards for quality management systems and competence for medical laboratories  . Rapid tThe COVID-19 pandemic overwhelmed health systems globally and adversely affected health programs because available resources were focused on responding to the pandemic  and tuberculosis treatment dispensation, and HIV viral load sample collection in the community. Clinical implementing partners collaborated with community-based organizations and satellite health facilities for HIV testing, linkage, and treatment dispensation. CDC conducted weekly virtual clinical program and data reviews with implementing partners and health facilities and held quarterly virtual sessions to review program performance and share best practices. Establishing virtual trainings and weekly granular site management (HIV service provision and program performance decreased in many President\u2019s Emergency Plan for AIDS Relief\u2012supported sub-Saharan African countries during the COVID-19 pandemic (The COVID-19 pandemic called attention to health system gaps and underscored the need for resilient health systems to effectively respond to health threats while ensuring continued health service delivery. The effect of the pandemic has been serious in central Africa and other resource-limited settings, largely caused by the limited health infrastructure and capacity in the region. Building on the strong partnership with the Cameroon MOH, capacity established through global health programs of CDC was leveraged to support the COVID-19 response in Cameroon while implementing innovative strategies such as differentiated service delivery and granular site management to mitigate the effect of the pandemic on health programs. In addition to the need for strengthened disease preparedness and response capacity, key lessons learned from the response in Cameroon to the pandemic include the need for a well-trained and fit-for-purpose health workforce, timely mobilization of resources, and the need for coordination of multiple stakeholders to effectively manage response efforts.Despite ongoing security and humanitarian crises in Cameroon, efforts of CDC have helped to strengthen the health system and improve health outcomes by ensuring continuity of HIV and tuberculosis services during the COVID-19 pandemic and maintaining programmatic gains. Through support of CDC, Cameroon has accelerated progress to reach the 95\u201395\u201395 targets and is positioned to be the first country in West and Central Africa to achieve HIV epidemic control. As part of the mission of the US Government to improve health globally, CDC continues to provide support to Cameroon to respond to the COVID-19 pandemic and prevent and control other public health threats. The lessons learned from Cameroon might be applicable to other resource-limited settings and conflict-affected areas to respond to COVID-19 and prepare for future pandemics.Members of the Centers for Disease Control and Prevention Cameroon Team: Leonard C. Keleko, Ebako Takem, Christopher Coox, Adebowale Okunrinboye, Fabrice D. Nembot, Edwin Sah, Mohamadou Awalou, Yvan D. Mouzong, Anula C. Acho, Alexandre Forbin, Jeannette E. Bessem, Sidouanne Signing, Marie G. Dima, Peter T. Atonkah, Yaya N. Sale, Eric Kamleu, Richard Olemba, Johnson Teboh, Chrysantus Egbe, and Keanu Renee-Glover."}
+{"text": "Strengthening organization quality-specific immune is the key linkage to improve the quality performance of intelligent manufacturing enterprises. organization quality-specific immune is constructed by selecting four state variables of organization quality cognition, monitor, defense, and memory. Based on the perspective of self-organization, self-organization theory and methods are used to construct the evolution model of organization quality-specific immune. According to four state variables, the evolution of organization quality-specific immune of fourteen typical intelligent manufacturing enterprises is studied, and the conclusion is drawn according to the relaxation coefficient. The empirical results show that self-organization theory and self-organization methods can effectively analyze the evolution of organization quality-specific immune and provide new inspiration for organization quality improvement and quality management of intelligent manufacturing enterprises. The finding results will present the framework for practicing engineering managers of intelligent manufacturing enterprises to enhance organization quality performance and organization quality-specific immune performance and promote organization quality-specific immune evolution. Industry 4.0 advocates the fourth industrial revolution, transforms the manufacturing industry to intelligence, actively develops intelligent manufacturing enterprises, continuously improves the intelligence level of manufacturing enterprises, and promotes intelligent production, intelligent technology, human-computer interaction, intelligent management, intelligent network, and the intelligent resources of intelligent manufacturing enterprises. Quality is the core element of the intelligent manufacturing enterprise , 2. QualScholars home and abroad adopt interdisciplinary research ideas and methods to transplant, integrate, and map immunology to the quality management field; derive analogy and metaphor research results; and generate the connotation, function, classification system, and construction elements of organization immune; organization immune includes organization-specific immune and organization nonspecific immune; organization-specific immune is the core architecture of organization immune \u201355. Lv aQuality is the life of intelligent manufacturing enterprise, on the basis of relevant research results of organization immune \u201355, 62; By drawing lessons from the relevant theoretical concepts of biological immunology, the scholars put forward the definition of organization quality immune, that is, enterprises find out the harmful factors that threaten product quality and organizational health, take the initiative and take immunization measures to deal with and eliminate the factors that threaten the quality, and generate the memory function as for the immunization process at the same time, in order to maintain the whole process healthy, quality performance, and stable development of enterprise , 57\u201363. Through the analysis, it is found that scholars at home and abroad mainly analyze organization quality-specific immune through system structure, system function, and function mechanism according to organization immune. There is a lack of qualitative and quantitative methods to probe into the evolution of organization quality-specific immune. Therefore, this study constructs theoretical framework of organization quality-specific immune evolution model; organization quality-specific immune is composed of four construct elements of organization quality cognition, organization quality monitor, organization quality defense, and organization quality memory by drawing lessons from absorbing a large number of relevant literature and conducts empirical analysis of organization quality-specific immune evolution model according to self-organization methods.Organization quality-specific immune refers to the systematic concept, which is a system. Organization quality-specific immune is divided into four components of organization quality cognition, organization quality monitor, organization quality defense, organization quality memory, which can dominate and determine the evolution of organization quality-specific immune \u201352, 56.Organization quality cognition includes two parts of perception and discovery. The organization subject collects the object and quality-related information actively through organization quality cognition behavior, which is the expression form of organization initiative consciousness . ThroughOrganization quality monitor is an important link, and it is an important tool for senior managers to detect damage to product quality and health in time. The tool can help the enterprise to monitor the quality environment all the time so that the enterprise has been in a stable quality environment . ThroughOrganization quality defense mainly includes three parts of variation, selection, and coordination. The defense process is carried out on the basis of effective monitoring of the organism, which refers to the process that the organization actively eliminates harmful factors of affecting quality in the organism . DefenseOrganization quality memory is the whole process of summarizing and digesting the immune process through memory behavior after a series of immune behavior . The memSelf-organization mainly studies the self-motion process of how the related subsystems of the system integrate into the regular structure , 73. TheThe principle of self-organization refers to the evolution theory within the system, which itself is a form of evolution . Self-orThe organization quality-specific immune is a system, it is necessary to explore the organization quality-specific immune from the perspective of the system. In this study, the relevant theory and methods of self-organization are used to study the evolution process. The scope of the research system and degree of grey correlations between the calculations are determined to find out the order parameters of the system , 74, 75.(1)Determining the Order Parameters of the System. The order parameter is a parameter at the macrolevel, and the order parameter can better express the behavior of the system. Order parameters are mainly used to express the disordered and ordered state of the system. Its core is the change of two phases after the phase transition occurs, and the order parameter is to describe the different physical quantities between two phases. The order parameters determine the direction of system evolution. Ha introduced the concept of order parameters into synergetics knowledge, that is, the variables that discovered and determined the formation and evolution of the system 2 \u2212 4\u2211j=14aijxj(1)(t)]2. According to the extreme value condition of multivariate function, the conclusion is drawn.According to the principle of least square method, There are various multiple relationships among the internal factors of organization quality-specific immune. To study its evolution system, it is necessary to analyze the scope of organization quality-specific immune and get the correlations among the factors so as to find out the order parameters of the system accurately.State variables of organization quality-specific immune evolution refer to organization quality cognition, organization quality monitor, organization quality defense, and organization quality memory.According to the evolution model, we calculate the grey correlation degree and get the correlation degree of each variable according to the numerical value so as to get the state variable of the system. In this study, fourteen representative large-scale intelligent manufacturing enterprises in eastern China are taken as the evaluation objects, and four subsystems are constructed, including organization quality cognition, monitor, defense, and memory. This study makes out dynamic evaluation on the organization quality-specific immune evolution of intelligent manufacturing enterprises in eastern China.X1\u2013X14) in eastern China are selected as samples. The questionnaire is divided into two parts of the basic information of the object and the score of the questionnaire. Among them, the basic information part of the survey object requires the survey object to fill in the personal information, and the scoring part will affect the four state variables and further affect the evolution of the system. This study uses organization quality cognition C1, organization quality monitor C2, organization quality defense C3, and organization quality memory C4 to score. Among them, 1\u20132 indicates weak influence on the evolution of organization quality-specific immune, 3\u20135 indicates average influence, 5\u20136 indicates higher influence, and 7\u20138 indicates strong influence.By the form of on-site distribution questionnaire, fourteen representative benchmark intelligent manufacturing enterprises XXi(t) represent the data  of the first index of the t enterprise, and the data sequence after dimensionless processing is Xi(0)(t) as shown in Let variable Xit) is treated with AGO and recorded as Xi(1)(t)  represents the synergistic and competitive effect of state variables on i variables.The external synergy among the system elements is recorded as 1)(t) is , 95, 96(bijxj(1)(t); the competition is expressed as aij(Xj(1)(t))2; fi(t) represents the external interference factors. \u2212bii=bi, then the nonlinear equation can be deduced toAmong them, the synergy is expressed as Xi(1)(t)/dt=Xi(1)(t) \u2212 Xi(1)(t \u2212 1)=Xi(0)(t).Assuming that dAccording to the principle of least square method, it can be concluded as follows:According to the extreme value condition of multivariate function, it can be concluded as follows:t=2,3,\u2026, 14, separate into the above formula, yN=BiPi.Substitute Bi to obtain B1, B2, B3, and B4 and replace the cumulative added data into yi to obtain y1, y2, y3, and y4; the results are as follows [Replace the dimensionless data into  follows \u201396, 98: is the relaxation coefficient of each index system in the organization quality-specific immune system. According to the coevolution model, the relaxation coefficient of each index system is obtained: C1\u2009=\u20091.7480, C2\u2009=\u20090.5125, C3\u2009=\u20091.1552, and C4\u2009=\u20090.8899. The relationships among the relaxation coefficients of each index system are as follows: C2\u2009<\u2009C4\u2009<\u2009C3\u2009<\u2009C1.The relaxation coefficient represents the influence degree of the state variable on the evolution of organization quality-specific immune, that is, the smaller the relaxation coefficient is, the greater the effect and influence on the evolution of organization quality-specific immune is, and the greater the relaxation coefficient is when the state variable has a slight effect on the evolution of organization quality-specific immune. According to the empirical analysis results, organization quality monitor has the greatest influence on the evolution of organization quality-specific immune, organization quality memory has the greater influence on the evolution of organization quality-specific immune, organization quality defense has a general influence on the evolution of organization quality-specific immune, and organization quality cognition has the least influence on the evolution of organization quality-specific immune.The related theory and methods of self-organization are introduced into the evolution model of organization quality-specific immune of intelligent manufacturing enterprises. With the help of self-organization theory and methods , 74, thiAccording to the relaxation coefficient, it is concluded that different state variables have different influences on the evolution of organization quality-specific immune, that is, organization quality monitor has the greatest effect on the evolution of organization quality-specific immune, organization quality memory has the greater influence on the evolution of organization quality-specific immune, organization quality defense has a general effect on the evolution of organization quality-specific immune, and organization quality cognition has the least effect on the evolution of organization quality-specific immune. It is urgent to enhance organization quality-specific immunity in accordance with local conditions on the weak points of the evolution of organization quality-specific immune . The purTheoretical research framework of this study can be used by practicing engineering managers; engineering managers of intelligent manufacturing enterprises can understand the key role and significance of quality in the process of engineering management and organization management; comprehensively examine quality management problems from the perspective of immune; strengthen the soft and hard elements of quality management practice; activate the function and vitality of hard and soft elements of organization quality defense; develop institutional and social measures; focus on the core practice and basic practice of quality management; realize quality improvement cycle; form the virtuous cycle and context system of mutual promotion, coordination, correction, and feedback among organization quality cognition, organization quality monitor, organization quality defense, and organization quality memory; enhance organization quality trial and error ability; promote organization quality-specific immune evolution ; and improve organization quality competitiveness, quality innovation ability, quality management ability, customer satisfaction, organization operation efficiency, and organization finance performanceIn terms of the theoretical research framework of this study, engineering managers of intelligent manufacturing enterprises can also judge and examine quality management issues from the perspective of system and evolution; put emphasis on the functions of organization quality cognition, organization quality monitor, organization quality defense, and organization quality memory; activate and dredge the function of organization quality-specific immune; prevent hypersensitivity and hyperimmunity; enhance organization quality-specific immune response rate; continuously increase quality performance and core competitiveness; improve organization quality improvement efficiency, market share, productivity, and final product quality qualification rate; and reduce product quality assurance cost, total quality cost, and quality defects compared with competitorsThe empirical analysis results of this study can be applied by practicing engineering managers; engineering managers of intelligent manufacturing enterprises can recognize that organization quality-specific immune is a system; actively promote the orderly evolution of organization quality-specific immune; drive organization quality-specific immune to maintain the good evolution trend and development tendency; prompt the spiral upgrading, function optimization, and function renewal of organization quality-specific immune; introduce negative entropy flow; make organization quality-specific immune get into the virtuous cycle process and track; stimulate the niche change of organization quality system; enhance the maturity, survivability, robustness, disaster tolerance, and buffer capacity of organization quality-specific immune system; and reduce the vulnerability and redundancy of organization quality systemIn terms of the empirical analysis results of this study, engineering managers of intelligent manufacturing enterprises can also identify the key factors, dominant slow variables, and order parameters of organization quality-specific immune evolution; emphasize on the obstacle factors and weak links of organization quality-specific immune development; excavate the bottleneck factors that hinder the evolution of organization quality-specific immune; refine the operation paths of organization quality-specific immune evolution according to the relevant parameters of organization quality cognition, organization quality monitor, organization quality defense, and organization quality memory; actively guide the evolution direction of organization quality system; and complete organization quality strategy and missionThe practical implications for engineering managers of intelligent manufacturing enterprises lie in the following:"}
+{"text": "Dysbiosis of gut microbiota plays a fundamental role in the pathogenesis and development of chronic kidney disease (CKD) and its complications. Natural products from plants and microorganisms can achieve recognizable improvement in renal function and serve as an alternative treatment for chronic kidney disease patients with a long history, yet less is known on its beneficial effects on kidney injury by targeting the intestinal microbiota. In this review, we summarize studies on the effects of natural products from plants and microorganisms, including herbal medicines and their bioactive extracts, polysaccharides from plants and microorganisms, and phytochemicals, on the prevention and treatment of chronic kidney disease through targeting gut microflora. We describe the strategies of these anti-CKD effects in animal experiments including remodulation of gut microbiota structure, reduction of uremic toxins, enhancement of short-chain fatty acid (SCFA) production, regulation of intestinal inflammatory signaling, and improvement in intestinal integrity. Meanwhile, the clinical trials of different natural products in chronic kidney disease clinical practice were also analyzed and discussed. These provide information to enable a better understanding of the renoprotective effects of these effective natural products from plants and microorganisms in the treatment of chronic kidney disease. Finally, we propose the steps to prove the causal role of the intestinal microflora in the treatment of chronic kidney disease by natural products from plants and microorganisms. We also assess the future perspective that natural active products from plants and microorganisms can beneficially delay the onset and progression of kidney disease by targeting the gut flora and highlight the remaining challenges in this area. With the continuous deepening of studies in recent years, it has been proved that gut microbiota is a potential target of natural active products derived from plants and microorganisms for chronic kidney disease treatment. Fully understanding the functions and mechanisms of gut microbiota in these natural active products from plants and microorganisms is conducive to their application as an alternative therapeutic in the treatment of chronic kidney disease. Chronic kidney disease (CKD) has become an increasing public health problem with a wide range of complications and high risk of mortality. The worldwide prevalence of CKD (8%\u201316%) brings a heavy economic burden for middle- and low-income countries in particular . Due to Proteobacteria and Actinobacteria and a decreasing level of beneficial microbes such as Lactobacillaceae  has an important influence on obesity  and Sophora japonica L. (SL) lowered the F/B ratio in spontaneously hypertensive rats  in the normal group. The expansion of Proteobacteria abundance is considered a hallmark for dysbiosis  mice. A. membranaceus and S. miltiorrhiza   , Astragaccharide , Coptidiccharide , and a rccharide  enhanced Nx rats . The abumia mice . Shenqi mia mice .Lactobacillus and Bacteroides enriched in the diabetic mice, which were significantly reduced by QiDiTangShen granules  that increased in the 5/6 Nx group was found to be associated with kidney injury , claudin-1, and occludin, play an indispensable role in maintaining the permeability of the intestinal epithelial barrier. Once the expression of tight junction proteins in intestinal mucosa decreases, the paracellular permeability would increase and the tight junctions would be destroyed, resulting in intestinal barrier damage . Decreasmy model . Higher my model . Fermentmy model . Astragaccharide , rhubarbccharide , the comacterium  and alisacterium  treatmen mycelia , Bupleurupleurum , and Mouupleurum  improvedupleurum  and curcupleurum  and the upleurum  protectetoxicity . Thus, iIntake of choline, tyrosine, and tryptophan increases the amounts of trimethylamine (TMA), IS, hydrogen sulfide, and indole produced by intestinal bacteria. After absorption, these compounds are further metabolized in the liver to generate the typical uremic toxin trimethylamine N-oxide (TMAO), PCS, and p-indoxyl sulfate. These toxins, which cannot be removed efficiently even by hemodialysis and would accumulate in advanced CKD patients , are higBacillus, thereby reducing the accumulation of IS and PCS in CKD mice (via colonic irrigation (ECI) remodeled gut microflora and decreased the levels of urea and IS in CKD rats  (Abelmoschus moschatus) inhibited the tryptophan transport in the main indole-synthesizing bacteria Enterobacteriaceae, resulting in the decease of uremic toxin IS production in CKD rats  could disturb microbiota-mediated indole production by inhibiting the transport of exogenous tryptophan into indole-synthesizing bacteria and further reducing indole biosynthesis (Supplementation with amylose resistant starch HAM-RS2  could re longum)  complete longum) . The com longum) . Oligofr longum) . FurtherCKD rats . HuangkuCKD rats . As a naynthesis . To sum Enterobacteriaceae, Vibrionaceae, and Pseudomonadaceae, was found to increase significantly in the CKD patients  are generated from the fermentation of various types of cellulose by SCFA-producing gut microbiota such as nditions   of systemic inflammation in hemodialysis (HD) patients  could increase fiber intake, reduce IL-6 and IS plasma levels  was effective in reducing IS in patients affected by advanced CKD  in a randomized, double-blind, placebo-controlled, crossover trial , and resistant starch, are utilized as prebiotics that are selectively digested by host microorganisms, which could stimulate the growth of one or a limited number of beneficial bacteria and reduce the uremic toxin released in the colon. However, common side effects including mild diarrhea and gassiness were often accompanied with administration of these fibers , proteomics, metabolomics, and cultureomics. These strategies have pushed the development of novel disease-related probiotics, prebiotics, and functional proteins for the treatment of CKD by targeting the dysbiosis of the gut microbiota in recent years  animals, and antibiotic treatments. Additionally, to understand how natural products from plants and microorganisms affect the gut microbiota in CKD patients and to develop new alternative therapies for CKD treatment, the strain- and molecular-level connections between the gut microbiome, natural products from plants and microorganisms, and host CKD phenotype should be established in future research based on the hypotheses developed from these correlative studies . The sysnt years . The synvia targeting gut microbiota. These natural products from plants and microorganisms have an impact on the biogenesis and progression of CKD and its relative metabolic complications through alteration of the diversity and composition of the gut microbiota. More research should be carried out to prove the causal role of intestinal microflora in the treatment of CKD by natural products from plants and microorganisms based on these associative studies.In summary, the literature analyzed in this review suggests a great advantage in the adoption of natural products from plants and microorganisms to treat CKD"}
+{"text": "Ferroptosis, a new type of cell death, is mainly characterized by intracellular iron accumulation and lipid peroxidation. The complex regulatory network of iron metabolism, lipid metabolism, amino acid metabolism, p53-related signaling, and Nrf2-related signaling factors is involved in the entire process of ferroptosis. It has been reported that ferroptosis is involved in the pathogenesis of neurological diseases, cancer, and ischemia\u2013reperfusion injury. Recent studies found that ferroptosis is closely related to the pathogenesis of COPD, which, to some extent, indicates that ferroptosis is a potential therapeutic target for COPD. This article mainly discusses the related mechanisms of ferroptosis, including metabolic regulation and signaling pathway regulation, with special attention to its role in the pathogenesis of COPD, aiming to provide safe and effective therapeutic targets for chronic airway inflammatory diseases. In 2012, Dixon . The morThe mechanism of ferroptosis is shown in Iron is an element necessary for lipid peroxide accumulation and ferroptosis. Excessive iron load promotes the production of ROS through the Fenton reaction and iron-binding proteins, thereby promoting the occurrence of ferroptosis , 9, 10. Lipid metabolism is critical for regulating cellular susceptibility to ferroptosis. Because plasma membrane damage caused by iron-dependent excess accumulation is an important feature during ferroptosis , reducinFerroptosis caused by abnormal amino acid metabolism is mainly related to the abnormal metabolism of GSH. GSH is a key substance in amino acid metabolism in ferroptosis and is mainly synthesized from cysteine, glutamate, and glycine . ExtraceCystine/glutamate anti-transport system Xc- (System Xc-) on the cell membrane transports extracellular cystine and intracellular glutamate in a 1:1 ratio. Cells mainly acquire cystine from the extracellular space through System Xc-, where cystine is reduced to cysteine to participate in the synthesis of GSH, and erastin acts on System Xc- to inhibit the uptake of cystine by the cell membrane, thereby reducing the synthesis of GSH and further contributing to the accumulation of ROS . BecauseThe process of ferroptosis is affected by different signaling pathways. As a tumor suppressor gene for cell cycle inhibition, apoptosis, and senescence, p53 is also one of the main signaling pathways of ferroptosis in cells , 27. RelNuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of cellular antioxidant activity, and its targets play important roles in iron and lipid metabolism , 36. StuThe pathogenesis of COPD is based on the response of the body to inhalation of harmful particles and gases, and it is complex and has not been fully elucidated. Smoking is the main cause of COPD, and the pathogenesis of COPD is mostly related to inflammatory mediators, inherent immunity, oxidative stress, and protease/antiprotease imbalance , 44. AmoCigarette smoke (CS) and harmful particles induce the body to produce highly reactive molecules such as ROS and reactive nitrogen species (RNS), thus inducing oxidative stress. The accumulation of neutrophils and macrophages in airways and pulmonary blood vessels causes the release of a large number of inflammatory mediators, which induces an inflammatory response and leads to lung tissue damage and protease/antiprotease imbalance, ultimately accelerating the progression of COPD . OxidatiOxidative stress is an important pathogenic factor in COPD, and the presence of a large amount of ROS in the inflammatory response inactivates antiproteases and leads to lung tissue damage. Excessive secretion and accumulation of neutrophils lead to the production of a large amount of reactive oxygen species (ROS). The accumulation of ROS reduces the activity of histone deacetylases (HDACs) and increases the activity of histone acetyltransferases, leading to further accumulation of neutrophils, which exacerbates oxidative stress .Iron homeostasis may be disrupted in inflammatory diseases, resulting in the production of excess reactive oxygen species with deleterious effects on cells and tissues. Epithelial cells and macrophages in lung tissues produce iron metabolism-related proteins, which regulate iron homeostasis and prevent the occurrence of oxidative stress . DisruptLipid peroxidation is the loss of hydrogen atoms of intracellular lipids under the action of peroxidase or free radicals, resulting in oxidation, fragmentation, and shortening of carbon chains as well as lipid-free radicals, malondialdehyde (MDA), and 4-hydroxy-2-nonenal (4-HNE) peroxidation products, which eventually oxidatively degrade lipids and damage the lipid bilayer structure of cell membranes.  CurrentlSmoking increases the content of lipid peroxidation in the body, and lipid peroxidation is closely related to the pathological progression of COPD . A surveThe role of ferroptosis in COPD is shown in In vivo studies showed that CS causes lung injury in COPD rats, increases inflammatory cell infiltration, increases inflammatory cytokine secretion, and induces ferroptosis in lung tissue cells of COPD rats. In vitro and in vivo studies showed that CSE/CS increases the MDA content, increases the iron content, downregulates GPX4, decreases ferritin heavy chain levels, and upregulates transferrin receptor levels and also reported that curcumin reverses CS-induced lung inflammatory damage and epithelial cell ferroptosis . These findings suggest new options for the treatment of patients with COPD.Morphological aspects of ferroptosis mainly manifest as mitochondrial shrinkage, reduction or disappearance of mitochondrial cristae, and increased mitochondrial membrane density. Liu et al. found that dihydroquercetin (DHQ) inhibits CS-induced ferroptosis in the pathogenesis of COPD by activating the Nrf2-mediated pathway and attenuating CSE-induced mitochondrial morphological changes . In vitrNrf2 is a key factor in maintaining the oxidative/antioxidative balance, which can prevent the occurrence of COPD by resisting oxidative stress and lung inflammation. Recent studies reported that CpG hypermethylation in the promoter causes downregulation of Nrf2 expression in the lung tissue of patients with COPD . Zhang ein vitro and in vivo studies, Liu et al. found increased levels of M2 macrophages, MMP9 expression, and MMP12 expression in patients with COPD, CS-exposed mice, and THP-M cells cocultured with CSE-treated human bronchial epithelial (HBE) cells, suggesting that NCOA4 and ferroptosis are involved in the pathogenesis of COPD , deferiprone, and deferasirox. DFO is one of the drugs that have been approved by the FDA for the treatment of iron overdose . In addiresponse . Howeverresponse . Anotherresponse . Throughresponse . TherefoOxidative stress is an important cause of airway inflammation, lung parenchyma destruction, and lung function decline in COPD, mainly induced by inhalation of air pollutants such as CS/CSE and dust. The acute exacerbation of COPD is closely related to oxidative stress and oxidant/antioxidant imbalance in the blood . Studiesin vitro and in vivo studies showed that ferroptosis is closely related to a variety of disease processes, and appropriate intervention in ferroptosis can treat the disease and delay the progression of related diseases. Although some progress has been made in the role of ferroptosis in lung cancer, ALI, and pulmonary fibrosis, the role of ferroptosis in COPD is not fully understood, and further clinical and experimental studies are needed. Although the existing ferroptosis inducers are effective, the therapeutic modalities for ferroptosis are still insufficient and only include iron inhibitors, iron chelators, and antioxidants. Identifying effective diagnostic markers of COPD may aid in the treatment of ferroptosis in COPD. For example, the known important regulator of iron metabolism, hepcidin, and its receptor, Fpn1, have been demonstrated to be effective diagnostic markers for COPD, and they may be promising targets for future drug development. In conclusion, with increasing studies on ferroptosis, new related regulators and their functions are constantly being explored. Considering ferroptosis as an entry point to develop COPD treatment regimens and targeted drugs has important clinical value.Ferroptosis, a new type of cell death, is involved in the pathogenesis of various diseases. Ferroptosis is a process involving abnormal metabolism of iron, amino acids, and lipids, which are involved in cell proliferation and differentiation. The metabolic process of ferroptosis is complex, and its mechanism has been preliminarily studied. Both The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.DM and CZ wrote the manuscript. RJ and ZL provided language assistance. WW proofread the manuscript. SS was involved in the design and review of this study. All authors contributed to the article and approved the submitted version."}
+{"text": "Multidrug-resistant organisms (MDRO) are bacteria that exhibit acquired resistance to multiple antibiotics, reducing the efficacy of antimicrobial therapies. The spread of MDRO is currently one of the most important threats for public health, and it is associated with a remarkable burden in terms of increased morbidity, mortality, healthcare costs, and antibiotic use ,2,3.The extensive and, in most cases, inappropriate uses of antimicrobials, at both human and veterinary levels, contribute to the selective pressure at the basis of MDRO diffusion. Different factors contribute to the spread of resistant bacteria to humans and animals, including poorly prepared food, proximity, and inadequate hygiene. Resistant bacteria can be spread in the environment and food through contaminated wastewater or through wildlife. The best strategy to contrast the spread of MDRO is the implementation of a One Health approach, which involves the collaboration of multiple sectors to improve public health outcomes as defined by the World Health Organization .This Special Issue includes a collection of ten research articles, communications, and reviews focused on the epidemiology and pathogenicity of MDRO. Enterococcus spp isolates were investigated. Their results established the presence of nosocomial-associated clonal complex 17 and a variety of mobile genetic elements among the enterococci from backyard chickens, suggesting the possibility of their dissemination in backyard farms and related environments [Alzahrani and coworkers investigated the role of backyard healthy chickens as a potential reservoir for MDR and virulent enterococci. In this study, antimicrobial resistance and virulence determinants, biofilm formation, plasmid content, and the clonality of ronments .Escherichia coli (ExPEC) lineages. Meanwhile, rabbits were a source of resistant and virulent E. coli pathogens with acquired colistin resistance determinant mcr-1 [Animals, community, hospital, and industrial settings (including food-production) have been investigated as possible sources of Antimicrobial Resistance (AMR) by Massella and coworkers. Their article reaffirmed the role of food-producing animals as a reservoir of potential zoonotic pathogens, with variable antimicrobial and virulence traits among the sources investigated. In particular, rabbits and poultry represented the most concerning sources, carrying the highest number of antimicrobial resistance genes (ARGs) and virulence-associated genes. Poultry was associated with potential extraintestinal pathogenic nt mcr-1 .Enterobacterales (ESBL-E), carbapenemase-producing Enterobacteriaceae (CPE), and methicillin-resistant staphylococci (MRS) in a companion animal clinic in Switzerland. The study documented the plasmidic dissemination of blaOXA-48 in a companion animal clinic with low infection prevention and control (IPC) standards. This poses a worrisome threat to public health and highlights the need to foster standards in veterinary clinics to prevent the spread of MDRO into the community [The role of animals in the spread of MDRO has also been described by Schmitt and coauthors, who reported extensive environmental contamination with extended spectrum \u03b2-lactamase-producing ommunity .To reduce the circulation of MDRO, the programs of surveillance should be combined with the implementation of efficient disinfection protocols that employ various biocides. Geraldes and coworkers in the paper titled \u201cEvaluation of a Biocide Used in the Biological Isolation and Containment Unit of a Veterinary Teaching Hospital\u201d tested a recently developed biocide (Virkon\u2122S), presenting a complex formulation  with mainly oxidative activity. Their results suggested that this novel biocide presented efficient antimicrobial activities against representatives of different bacterial species isolated from the Biological Isolation and Containment Unit (BICU). However, organic matter could interfere with its antimicrobial activity, and a slight change of antimicrobial susceptibility was observed in four enterococci, which is probably related to a general stress-induced response promoted by the sub-lethal levels of Virkon\u2122 S .Klebsiella pneumoniae clinical isolates in order to help the control and management of associated infections and to limit their spread in the hospital environment. In addition, the characterization of the emerging high-risk clones can support the implementation of protective actions and infection control procedures [The ability to produce biofilm and its correlation with antibiotic resistance was also reported by Fasciana and coauthors in their communication. The authors underlined the need to characterize the genetic diversity and biofilm formation properties of ocedures .K. pneumoniae and Acinetobacter baumannii in the intensive care unit (ICU) and of E. coli in non-intensive care units (non-ICUs). The authors stressed the importance of the implementation of large community-level programs to prevent bacteremia caused by MDRO. The authors observed that local surveillance and the implementation of educational programs remain essential measures for slowing down the spread of resistance and, consequently, for increasing antibiotic lifespan [A retrospective investigation from Southern Italy on the prevalence of Gram-negative bacteria (GNB) and their resistance in hospitalized patients by age, sex, and units from blood cultures (BCs) was conducted by Di Carlo and coworkers. The authors reported a higher prevalence of lifespan .Gentile and coworkers reported the importance of surveillance programs for nosocomial drug resistance. They suggested that whole-genome sequencing (WGS) proved to be a useful tool for elucidating the spreading dynamics of MDRO and can help in limiting their diffusion. According to the authors, the analysis of resistome and virulome by WGS, if available in real-time, could help to survey the alert nosocomial pathogens by directing the infection control team to focus its attention and resources in departments where surveillance is more necessary .To reduce the diffusion of MDRO, the use of an appropriate antibiotic therapy is of paramount importance. Fiore and coworkers in a systematic review and meta-analysis titled \u201cCeftolozane-Tazobactam Combination Therapy Compared to Ceftolozane-Tazobactam Monotherapy for the Treatment of Severe Infections: A Systematic Review and Meta-Analysis\u201d reported that combination therapy with ceftolozane-tazobactam (C/T), compared to C/T monotherapy, may reduce all-cause mortality in infections due to Gram-negative bacteria but did not increase the rate of clinical improvement .Helicobacter pylori. It is very important to have a good understanding of regional antibiotic resistance patterns of H. pylori for the implementation of effective empirical eradication therapies and adequate rescue therapies. The study conducted by Park and coworkers investigated the antibiotic resistance patterns of H. pylori and their impact on eradication in Seoul in recent years [H. pylori eradication in Korea.The rate of multidrug resistance is also increasing in nt years . Their rH. pylori and the consequent limited therapeutic options available against this pathogen represent an important topic in gastroenterology. The aim of the review presented by Krzy\u017cek and coworkers was to list compounds showing the ability to enhance the antimicrobial activity of classically used antibiotics against H. pylori. The antimicrobial properties, such as minimal inhibitory concentrations and minimal bactericidal concentrations, dose- and time-dependent mode of action, and, if characterized, anti-biofilm and/or in vivo activity of these compounds are also reviewed [The increasing spread of antibiotic-resistant reviewed . In conclusion, this Special Issue collected articles and reviews that underlined the need for robust surveillance systems that are essential for combating antibiotic resistance at both hospital and environmental levels, emphasizing the necessity of an \u201cOne Health\u201d approach. The importance of both phenotypic and genotypic approaches for the characterization of MDRO, and the necessity of novel effective antimicrobials and biocides active against MDRO was also emphasized."}
+{"text": "Primary care stresses the importance of the relationship between physicians and patients . AccordiMoh et al.). Many infectious diseases such as malaria, tuberculosis, and human immunodeficiency virus (HIV) are major issues for the health system in C\u00f4te d'Ivoire, mainly because health resources remain inaccessible and inefficient, especially in rural areas . To solve this problem, Moh et al. conducted a study in three locations to improve the integration of HIV, malaria, and tuberculosis prevention. This project was planned for a duration of 3 years, including 2 years of field activities with six main activities . Through this project, Moh et al. proposed some strategies to improve the integration of HIV, malaria, and tuberculosis prevention, including selecting and strengthening the capacity of community health workers to provide care for these three diseases, providing monthly animation of village health committees by target groups, and using application and tablets for data collection.The studies collected on this topic cover a wide range of research on family medicine and primary care, including systematic review and meta-analysis of the prevalence and risk factors of disease, research exploring factors associated with disease, strategies aimed at improving the healthcare system, effects of different guidelines on mortality risk of disease, development of measurement technology, evaluation the price, availability, and affordability of essential medicines, as well as distribution of health problems. We expect that the research on this topic or the evidence they provide will act an informative role in family medicine and primary care. Community Health Workers (CHWs) are a key component in promoting population health and improving health systems, especially in many low- and middle-income countries  with 17,708 subjects aged 45 years and older in 2011\u20132012, to examine the change in the prevalence and mortality, if the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) hypertension guideline were adopted for Chinese adults. The study found that if the 2017 ACC/AHA guideline was adapted for Chinese adults aged 45 years or older, the hypertension prevalence would increase, which was mostly attributable to the change in the definition of systolic diastolic hypertension . However, the difference was minuscule in the proportion of people recommended for antihypertensive treatment among people with isolated diastolic hypertension or isolated systolic hypertension. Also, the study has found that the adoption of the 2017 ACC/AHA might be applicable to improve the unacceptable hypertension control rate for Chinese adults aged 45 years or older .This topic also collected a study regarding the policy for patients with hypertension in China, which highlighted how different guidelines would have an impact on the effects of primary care and patients' health outcomes. Specifically, the China Hypertension League (CHL) guideline is different from the guidelines in the United States , 7. TherLiu Z. et al. conducted a systematic review to explore the status quo of BP measurement technology and development trends of BP measurement. In general, the technology of auscultatory, applanation tonometry, and volume clam methods are mature, and new control methods of volume clamp are developing . However, the study found limitations and challenges in existing finger-end BPM technologies as well , indicating that further research on new technologies is still needed to facilitate the development of daily multi-scenario and multi-frequency BPM technologies and provide a basis for realizing long-term personal BP management strategies.Another study covered in this Research Topic also focused on primary care for blood pressure in the Chinese population. Previous research suggests that routine blood pressure (BP) monitoring may help predict mortality , 9. TherWang et al. based on the adjusted World Health Organization and Health Action International methodology. This study found that the Medication Possession Ratio (MPR) for lowest-priced generics (LPGs) was generally decreasing between 2016 and 2020 . In addition, the median availability of generic medicines increased in 2018 . These results indicated that the National Essential Medicines Policy (NEMP) has proceeded relatively well in the primary healthcare institutions (PHIs) in Jiangsu . In addition, this Research Topic also contains other related studies, including a systematic review on dyspnea measurement in acute heart failure , research exploring factors associated with childhood asthma and wheezing in Chinese preschool-aged children , a systematic review and meta-analysis of the prevalence and risk factors of depression in type 2 diabetes patients in China , and a cross-sectional study exploring the distribution of health problems at the general outpatients' clinic of the University of Hong Kong-Shenzhen Hospital . It has long been documented that characteristics such as gender, race, and socioeconomic status are associated with the use of healthcare services in routine care, which might further bring health disparities in health outcomes (As more and more new medicines become available, healthcare systems face considerable challenges in regulating drug prices, affordability, and affordability for primary care . To evaloutcomes \u201313. As toutcomes , 15. Furoutcomes . At lastXX, GL, XJ, HM, and KL conceived the idea for the editorial and wrote the initial draft. All authors approved the final version of the editorial."}
+{"text": "Thyroid dysfunction such as hypothyroidism, is connected with numerous neurological and psychiatric disorders. However, the importance of assessing the interaction between brain, psyche and thyroid in clinical practice is often underestimated, and this has a direct impact on the planning of therapeutic interventions and treatment efficacy in patients with primary hypothyroidism.We examined 132 patients with primary hypothyroidism.Assessment of the presence and severity of psychopathology was performed using the technique SCL-90-R (questionnaire severity of psychopathology).The results showed the highest scores on the scales of somatization , depression , interpersonal anxiety , phobias . High rates of somatization scale showing a violation of bodily dysfunction of various body systems-cardiovascular, gastrointestinal, respiratory and headache, muscular discomfort and other unpleasant sensations in different parts of the body and manifest themselves in a complaint of patients. Scale depression revealed the presence of dysphoria, anhedonia, low affect, loss of vitality and interest in life. Relatively high on a scale of phobias indicate the presence in these patients persistent fear responses to certain situations and objects that are irrational and inadequate and lead to avoiding behavior. General index of severity of symptoms (GSI) and the index of an existing symptomatic distress (PSDI) were significantly higher in the following patients than in hypothyroid patients without mental disorders.Thus, these results should be taken into account when determining treatment strategy both in psychopharmacotherapy and different methods of psychological correction.No significant relationships."}
+{"text": "Due to the many factors involved, the treatment of cancer by Chinese medicine is very complicated: it is not only a variety of components of Chinese herbal medicines but also a complicated cancer network among tumor cells, tumor microenvironment, human interior milieu, and the environment. In addition, the interaction between the gut microbiota and the host also has a potential impact on cancer progression. The complexity of Chinese herbal medicines and the pathogenesis of cancer makes it difficult to understand the pharmacological effects of anticancer Chinese herbal medicines, especially when the treatment is in the form of a mixture of multiple compounds, such as Chinese herbal formulas.To address such a high level of complexity, advanced approaches are needed. Thanks to the advent of systems biology and advanced OMICs techniques, including genomics, transcriptomics, proteomics, metabolomics, and bioinformatics, novel systems-based approaches have been developed and widely used in the research of Chinese medicine, leading to the rapid progress of this research field and more comprehensive understanding of the pharmacological mechanisms of Chinese herbal medicines in cancer treatment.Albuca Bracteata (Thunb.) J.C.Manning & Goldblatt in a colon cancer model. They found that the change of intestinal microbiota and therefore production of beneficial short-chain fatty acids might contribute to the anti-tumor effect of Albuca Bracteate Polysaccharides when used alone and in combination with the chemotherapeutic agent 5-fluorouracil Yuan et al. Another study by Shi and others performed 16S rRNA gene sequencing and metabolomics to study the mechanism of action of Siwu-Yin, a formula used in traditional Chinese medicine for the treatment of esophageal precancerous lesions and esophageal cancer. They found this formula traditionally used to replenish blood and nourish Yin improved the composition of intestinal flora by regulating the synthesis and secretion of bile acids. This action of Siwu-Yin contributed to the modification of the tumor microenvironment and inhibited the occurrence of esophageal precancerous lesions . These studies have provided us insights into the application of combined OMICs technologies in the pharmacological studies of botanical drugs.In this special collection, we aimed to highlight the application of OMICs and other advanced approaches in understanding the mechanisms of action of medicinal botanical drugs as a mixture of multiple components in the treatment of human diseases, especially gastrointestinal cancer. We have received 16 submissions by authors from mainland China, Macau S. A. R., and Hong Kong S. A. R, including both original articles and reviews, and seven of them are accepted for publication. Among these published studies, Yuan and others innovatively combined multiple OMICs platforms to analyze the modulation of gut flora metabolites by the polysaccharides extracted from a Chinese botanical drug Dai et al.). Li and others focused on the application of OMICs technologies as useful tools for deciphering the role of botanical drugs as an adjuvant therapy, both to improve therapeutic outcomes and to reduce the side effects of conventional therapies, in the treatment of gastrointestinal cancers. They highlighted that OMICs approaches can efficiently reveal potential key molecular targets and intracellular interaction networks of herbal medicines in gastrointestinal cancer, therefore guiding future research Li et al. Guo and others particularly reviewed the application of metabolomics in investigating herbal therapies against gastrointestinal cancers by targeting metabolism. They systematically summarized the actions of herbal compounds, extracts, and formulas on the metabolism of carbohydrates, lipids, amino acids, and nucleotides, as well as on other metabolic pathways, and highlighted the usefulness of metabolomics in guiding the further development of botanical drugs as novel and efficient adjuvant therapeutics against gastrointestinal cancer . In addition, Coptidis Rhizoma  and Chinese Medicine-based carbon dots were introduced by He et al., and Li et al., respectively, as examples for a better understanding of the application of OMICs in pharmacological studies of herbal products. He et al. reviewed the broad pharmacological effects of Coptidis Rhizoma (C. Rhizoma) against cancers, highlighted recent studies on the botanical drugs, including the application of OMICS, novel drug delivery systems, combination therapy and clinical research, and provided new scientific and clinical evidence for future clinical use of the botanical drugs in treating gastrointestinal cancers . Li et al., reviewed the progress in Chinese herbal medicines-derived carbon dots for the treatment of hemorrhagic diseases and also discussed the application of nanomaterials, OMICS and other advanced technologies in the research and development of charcoal drugs against other refractory diseases, e.g., cancers Li et al.This special issue has also collected expert opinions and reviews on the application of OMICs technologies in the pharmacological studies of botanical drugs. Dai and others reviewed the state of art and provided their future perspectives on OMICs applications in studies on herbal treatment of gastrointestinal cancers. They highlighted how single and multiple OMICs approaches may facilitate unravelling signalling interaction networks and key molecular targets of botanical drugs with anti-gastrointestinal cancer potential. Their review suggested that, towards precision medicine, extensive application of high-throughput sequencing technologies to unravel tumor heterogeneity is urgently needed for stratified diagnosis of gastrointestinal cancers and better-targted herbal treatment (In conclusion, the applications of single and combined OMICs technologies, systems biology, and other advanced methodologies have been very useful in studying botanical drugs. We wish readers will enjoy reading articles in this special collection, which represent the state of the art of OMICs-based pharmacological studies of botanical drugs. As shown in"}
+{"text": "The African region faced a large-scale public health crisis, with the outbreak of coronavirus disease 2019 (COVID-19). As of February 16, 2022, the region recorded 7,944,049 confirmed cases with case fatality of 2.1 percent [The WHO African region adopted and implemented the new WHO ACT-Accelerator strategy in its response to the pandemic . New ACTThe countries mounted and implemented several actions in response to the outbreak. Some actions entailed the use of innovative strategies in addressing transmissibility and spread of the virus, reaching the populations with vaccines, diagnostics, and therapeutics. Others were on surveillance and testing, infection prevention and control, public health and social measures as well as contact tracing, among others. The Incident Management Support Team (IMST) of the WHO AFRO further enabled the countries with evidence-driven innovations and guidelines in responding to the COVID-19 pandemic.Several experiences were gathered that could be useful for future public health interventions. This special issue of the Pan African Medical Journal documents the of the key lessons and experiences gathered from response to the COVID-19 pandemic in countries as well as the WHO AFRO IMST. The papers, written by those who were actively engaged in response to epidemics in countries, cover critical topics from preparedness and response to disease outbreaks, strengthening surveillance systems and integration as well as strengthening health workforce against pandemics. The comprehensive analysis of the success stories made in pandemic response will no doubt enhance response to future public health events within and outside the region. These articles therefore constitute a case of turning tragedy to gains!"}
+{"text": "The inspiring digital event brought together international speakers and presented a multidisciplinary approach to one of the less-addressed topics in neurology. The event it was coordinated by Antonio Federico , Professor of Neurology at the Department of Medicine, Surgery and Neurosciences from the Medical School at the University of Siena , and Dafin Muresanu (Romania), EFNR President, and was divided into 4 sessions over the course of the day.The Antonio Federico  and Dafin Muresanu (Romania), with the two highlighting the increased interest of stakeholders in this subject from neurology.The Teaching Course on Rare Neurological Diseases began with a welcome address by Kailash Bhatia (UK) and Antonio Federico . A presentation entitled \"Rare Neurologic Diseases, a Pandora Box for Neurology and Neurosciences\" was introduced by the latter, Antonio Federico , Professor of Neurology at the Department of Medicine, Surgery, and Neurosciences from the Medical School at the University of Siena . About 300 million people are affected by a rare disease \u2013 3.5\u20135.9% of the population \u2013 with a majority having genetic pathogenesis and more than half of the cases involving the central or peripheral nervous system and muscles. Prof. Federico firstly discussed what makes a disease rare, namely the standards for classification. Moreover, he went over why rare diseases and orphan therapies lead to many unacceptable inequities in the health systems, from trouble finding experts on the disease, limited availability of therapies, and the issue of pharmacological companies having little interest in developing drugs. Prof. Federico stated the crucial role of neurologists in diagnosing and treating rare diseases in general, as many affections present with neurological manifestations. Furthermore, he discussed the universal challenges faced by those living with a rare disease, mentioning the broad diversity of disorders and relatively common symptoms that can hide the correct diagnosis. He talked about the commonality of misdiagnosis and the variability of symptoms from one patient to another in the context of the same rare disorder. Prof. Federico also tackled in his presentation the importance of research and international collaboration of researchers and clinicians, as well as the involvement of multiple stakeholders, mentioning recent developments in Europe concerning networks aiming to improve the diagnosis and treatment of rare diseases. He further approached the European Reference Networks, especially those for rare diseases, underlining the European Brain Council Research Project \u2013 The \"Value of Treatment (VOT) for brain disorders\". Moreover, Prof. Federico highlighted the World Health Organization's (WHO) highly active endeavour on revising the ICD-10 Diseases of the Nervous System Chapter from a rare disease perspective. Lastly, he mentioned the problem of expensive orphan drugs leading to equity issues in rare diseases. He ended his presentation by stating the necessity for comprehensive global action to improve the quality of diagnosis and care.The first session was presided over by Kailash Bhatia (UK), Professor of Clinical Neurology at the Sobell Department of Movement Neuroscience \u2013 Institute of Neurology, UCL, in Queen Square, London (UK), discussed the \"Rare presentation of Parkinson's diseases and dystonia\". Prof. Bhatia covered several case studies on various disorders with variable presentations, from language and calculation difficulties to gait imbalance and cerebellar features of parkinsonism. He showcased imaging clues for different types of parkinsonism, the difficulties in diagnosis, and pointed to different affections, signs, and triggers to be avoided. Rare diseases causing movement disorders are a significant subset of conditions as they represent a substantial proportion of movement disorders. The importance of recognition and awareness of the treatable forms and the treatment implications were also discussed. Finally, Prof. Bhatia highlighted that many rare neurological disorders provide vital insight into the pathophysiology of more common movement disorders.Max Hilz (Germany), from the Department of Neurology, Icahn School of Medicine at Mount Sinai in New York (USA), discussed, during his presentation \"Evaluating autonomic dysfunction in Rare Neurologic Diseases \u2013 a diagnostic tool and predictor of increased risk\", about hereditary sensory & autonomic neuropathies (HSAN Types I-VIII), the steps in the assessment and consideration for the diseases' epidemiology and their timelines, along with prominent clinical features. Moreover, he presented HSANs types 1, 2, 3, 4, and 5, with insight into the sural nerve pathology, in addition to diagnostic steps to determine the type of HSAN, including history, clinical examination, motor & sensory nerve conduction studies, quantitative sensory testing, assessment of the sudomotor function, of sympathetic or parasympathetic deficits, and many more.Michelangelo Mancuso , began by introducing Michelangelo Mancuso , the Head of the Centre of Neurogenetics and Expertise for Mitochondrial Diseases and Rare Diseases \u2013 Department of Clinical and Experimental Medicine at the Neurological Institute, University of Pisa , with his presentation \"Stroke and Rare Neurologic Diseases. An EAN Consensus\". Prof. Mancuso discussed the importance of awareness and minimizing diagnostic delays. Moreover, he offered insight into cerebral small vessel diseases , along with some related issues. Prof. Mancuso followed the Delphi methodology to provide recommendations and proposed \"red flag\" features suggestive of the diagnosis of monogenic disease and discussed specific recommendations for the particular forms of monogenic cSVD. He further approached some rare diseases, including Fabry disease, CADASIL, and MELAS, and highlighted the EAN management and recommendations, pointing out that the EAN consensus provides a valuable framework to guide diagnosis and management.The second session, presided by Marianne de Visser (the Netherlands) and Marianne de Visser (the Netherlands), Senior Neurologist at the Amsterdam University Medical Center in Amsterdam (the Netherlands), presented \"HyperCKemia: from common to rare\". Dr. de Visser discussed asymptomatic and paucisymptomatic hyperCKemia, the most common causes, the steps leading to a differential diagnosis, and the most appropriate diagnostic tools. In addition, she offered a glimpse into variations of the disease in different populations and presented insightful case studies from her practice. One crucial point was the role of complex diagnostic assessment, including detailed family history and ancillary investigations , offering a lively and engaging presentation with interactive exercises for the public.Antonio Federico , Professor of Neurology at the Department of Medicine, Surgery and Neurosciences \u2013 Medical School from the University of Siena in Siena , then discussed \"Rare Neurologic Diseases mimicking a multiple sclerosis like phenotype\" through the presentation of a comprehensive set of disorders , mentioning the McDonald Diagnostic Criteria. For multiple sclerosis (MS), several genetic conditions need to be considered in the differential diagnosis. Prof. Federico offered a complex and all-encompassing view of this large set of disorders and offered the public a glance, through case studies presentation, into the fascinating world of rare neurological disorders.Davide Pareyson , the Head of Rare Neurodegenerative and Neurometabolic Diseases Unit at the Dept. of Clinical Neurosciences, IRCCS Foundation, Neurological Institute Carlo Besta in Milan , presented \"Clinical and diagnostic approach for diagnosis of rare forms of peripheral neuropathies\", discussing the time to consider them as a diagnosis and ways to diagnose these diseases, pinpointing that the most important forms are hereditary and immune-mediated neuropathies. He talked about the role of early diagnosis in detecting diseases and initiating early treatment, and also approached clinical phenotypes for acute neuropathies, chronic sensory-motor demyelinating/axonal, relapsing, pure motor neuropathy, and sensory ataxic or painful neuropathies. Next, Prof. Pareyson presented the steps for diagnosis and the use of next-generation sequencing in certain diseases and hereditary TTR-related amyloid neuropathies in non-endemic countries. Lastly, he discussed Charcot-Marie-Tooth and other chronic immune-mediated or neoplastic neuropathies and underlined the fact that various neuropathies are represented by different phenotypes.Session 3 was overseen by Wolfgang Grisold (Austria) and Jean-Marc Burgunder (Switzerland). Firstly, Wolfgang Grisold (Austria), President of the World Federation of Neurology (WFN), presented on the Paraneoplastic Neurological Syndromes, with mentions about the history of the syndromes, different types of most-likely cancers, their mechanisms, therapy, and prognosis. He also discussed the classification of paraneoplastic antibodies based on cancer risk and offered insight into Lambert Eaton Syndrome. One crucial point of his presentation was that the diagnosis of paraneoplastic syndrome is a diagnosis of exclusion.Dafin Muresanu (Romania), President of the European Federation of NeuroRehabilitation Societies (EFNR) and Chairman at the Department of Neurosciences from Iuliu Hatieganu University of Medicine and Pharmacy in Cluj-Napoca (Romania), offered an inspiring glimpse into the neurorehabilitation for rare neurologic disorders in the context of rare causes of stroke, discussing the concepts of post-lesional brain regulation following two sequences (1) neuroprotection and (2) neurorepair. Prof. Muresanu mentioned that \"when neuroprotection is active, neurorecovery is silent\" and vice versa, showcasing that neurorehabilitation is represented by a mixture of neurorestorative and compensation capacities. He further discussed the intricacies of endogenous defense activity. Neurorehabilitation is a multidisciplinary concept aiming to improve biological function by creating therapeutic learning situations. Prof. Muresanu pinpointed the role of a specialized multidisciplinary neurorehabilitation team . Moreover, the 3 essential components of neurorehabilitation, (1) motor, (2) cognitive, and (3) mood, were discussed, and noteworthy examples of neurorehabilitation effects on different pathologies were presented.Maria Judit Molnar (Hungary), the Director at the Institute of Genomic Medicine and Rare Disorders Semmelweis University in Budapest (Hungary), on \"New therapies for Rare Neurologic Diseases\". Prof. Molnar discussed different therapeutic options, their mechanisms on various levels  and how pharmacological or surgical approaches can influence the phenotype. She focused on gene therapy, ARN-based methods, and protein modification therapies, mentioning the importance of allogeneic hemopoietic stem transplantation in monogenic neurogenetic disorders. Her presentation showcased general applications of therapeutic gene transfer, gene delivery methods, approved gene therapies, future gene therapeutic approaches in neuromuscular disorders, and valuable lessons from clinical trials. Genetic therapies are increasing extremely fast, opening new options for patients with neurological disorders. Still, there are some limitations, such as the high prices and the ways in which clinicians can support the development of drugs and therapies.The last session of the day, Session 4, presided by Holm Graessner (Germany) and Maria Judit Molnar (Hungary), began with a presentation of Jean-Marc Burgunder (Switzerland), Professor of Experimental Neurology at the Faculty of Medicine, the University of Bern in Bern (Switzerland), discussed updates in neurogenetics and therapy. First, he offered examples of different diseases , discussed variations related to the age of onset, and presented an inspiring case study on hereditary spastic paraplegia in twins. The second part of his presentation was structured around the concept of gene therapy, the use of vectors for the restoration of dopamine production and the use of antisense oligonucleotides to modify gene expression. As neurology has a vast number of rare disorders (>7000), with many different genes, pathways, and pathophysiology, there is a dire need to better understand the presented concepts.Holm Graessner (Germany), Coordinator of the European Reference Network for Rare Neurological Diseases based at the University Hospital in Tubingen (Germany), showcased in his presentation \"Undiagnosed Rare Neurologic Diseases and the ERN Role\" the European reference networks for complex diseases. One insightful point was that the rareness of disease could refer to the rareness of:Patients;Experts;Care structures of knowledge;Therapies.He discussed the large number of expert centers in 25 EU countries which aim to improve care for patients with neurological diseases . They create added value based on the youth partnership plan built to integrate patient representatives and organizations in a structured manner. Moreover, these expert centers monitor the care to sustain improvements, offer e-health for cross-border care, work on expert opinion-based recommendations and provide guidelines.This awe-inspiring event stands as proof of the significant need for international collaboration and dissemination of knowledge in neurosciences overall, but even more direly for the fascinating yet less addressed topic of rare diseases. As rare neurological diseases can lead to significant inequities in the healthcare system and heavily impact the affected patients, it is paramount to find sustainable solutions, through joint efforts, to address these biases and provide an improved standard of diagnosis and care. It is important to remember that rare diseases not only reflect a reduced incidence but rather the fundamental problems identified by several speakers, namely the lack of specialists, resources directed for the research and development of pharmacological treatments, and the increased chance of misdiagnosis. All of these are completed by a lack of comprehensive understanding of the disease and the best treatment avenues to ensure a high quality of life for the patients."}
+{"text": "This Special Issue aims to highlight the usefulness of microRNA (miRNA) as diagnostic and prognostic markers of gastroenterological cancer (GC). GC is one of the leading causes of cancer death worldwide. Despite advances in GC therapy, the prognosis of those patients remains poor due to the high incidence of recurrence. A better understanding of the pathogenesis during GC development brings effective outcomes for the diagnosis and treatment at the early stages.Over the past two decades, researchers have unveiled the association between miRNA and the biology of GCs. In fact, the critical role of miRNAs in the developmental process of GCs is increasingly evident. Aberrant miRNA expression in tumor tissue and blood of GC has been implicated in disease diagnosis, prognosis, and therapeutic efficacy in different tumor types ,2. It isThis Special Issue contains three review articles and three original papers, amounting to six in total, on the biological roles of miRNAs in different tumor types of GC and their potential clinical applications. For example, inhibition of miRNA-122, a representative liver-specific miRNA, promotes drug resistance by increasing the expression of oncogenes in hepatocellular carcinoma  and faciIn addition, miRNAs are released into circulation. Circulating miRNAs include the following four types: (1) miRNAs encapsulated in exosome, which have recently been recognized as promising, noninvasive, and stable biomarkers (2) miRNAs bound to protein and lipid, (3) miRNAs in apoptotic body, (4) miRNAs leaked from the cell . RecentlThe main aim of this Special Issue is to contribute to the current development and future prospects of tissue and circulating miRNAs as biomarkers of carcinogenesis, progression, metastasis, or drug resistance to chemotherapy in GCs. In addition, through the contributions to this special issue, we clarify how these GC-related miRNAs are involved in the mechanism of GC proliferation and development, and how these miRNAs can be applied to various biomarkers and GC therapies. Further data accumulation and clinical trials are needed to implement clinical applications."}
+{"text": "Clear documentation of the understanding of the problem, development process, and content of interventions is essential to understand why interventions succeed or fail. Transparent reporting will enable future researchers to build on previous evidence and replicate or adapt interventions for new contexts. This paper describes the theory- and evidence-based systematic development of the Bloom Trial - a home-based intervention to promote healthy weight development among infants and children in Denmark.Development of the intervention is guided by the six-step planning tool the Intervention Mapping protocol. Step 1: Needs assessment including identification of risk factors in infancy and existing interventions, interviews with parents, and an organizational capacity assessment. Step 2: Development of program theory and matrices. Step 3: Selection of theoretical methods and practical applications for modifying personal and environmental determinants. Step 4: Development of intervention tools. Step 5: Planning of program adoption, implementation, and sustainability. Step 6: Generation of an evaluation plan.The Bloom intervention is universal but with a strong focus on families with low socio-economic position and non-Danish ethnic background. It is aimed at first-time parents and addresses early risk factors for child overweight such as parental skills and healthy habits related to food and meals, movement, screen time and sleep, and introduce a new theme: sense of security in the family. It will be integrated in existing services delivered by community health nurses supplemented with extra elements such as telephone consultations, family groups and a video library.The transparency of the developmental process and theoretical, empirical, and contextual foundation of the Bloom Trial may enable future studies to build on our findings and accumulate knowledge to promote healthy weight development among infants and children.The development process resulted in a complex intervention addressing known risk factors for child overweight e.g., meals, movement, screentime and sleep, and introduce a new theme: sense of security.Transparency of the developmental process may enable future intervention studies to build on our findings and accumulate knowledge to promote healthy weight development among infants and children."}
+{"text": "Burnout occurs in every stage of a medical graduation and career. In the first years of graduation, is affects 35-45% of medical and dentistry students. This has severe consequences, such as: higher levels of suicidal ideation, substance abuse, medical errors and medical neglect; lower levels of empathy and self-compassion - essential to the quality of healthcare. Students with certain personality traits  are more vulnerable to emotional dysregulation when facing stressors of daily life. Our recent studies proved that mindfulness and self-compassion can attenuate the effect of perfectionism on psychological distress.To present the rational, materials, methodology and preliminary results of our project COMBURNOUT, aimed to develop, implement and assess the efficacy of a mindfulness and self-compassion-based intervention to prevent burnout in medical and dentistry students.Students with high levels of burnout, psychological distress and perfectionism will be randomly assigned to intervention (8 weekly sessions) or control groups. The sessions will be composed by psychoeducation about burnout, mindfulness and self-compassion practices, within and between sessions. The follow up will include three assessment moments until a year after the intervention.We expect that the experimental group will present significantly lower levels of burnout, psychological distress and perfectionism, and higher levels of emotional regulation skills.The facilitators training and the manualization are guaranties of standardization and sustainability. If the positive impact of COMBURNOUT is verified, we intend to provide the program to medical/dentistry students from all over the country."}
+{"text": "Despite being disproportionately impacted by health disparities, Black, Hispanic, Indigenous, and other underrepresented populations account for a significant minority of graduates in biomedical data science-related disciplines. Given their commitment to educating underrepresented students and trainees, minority serving institutions (MSIs) can play a significant role in enhancing diversity in the biomedical data science workforce. Little has been published about the reach, curricular breadth, and best practices for delivering these data science training programs. The purpose of this paper is to summarize six Research Centers in Minority Institutions (RCMIs) awarded funding from the National Institute of Minority Health Disparities (NIMHD) to develop new data science training programs. A cross-sectional survey was conducted to better understand the demographics of learners served, curricular topics covered, methods of instruction and assessment, challenges, and recommendations by program directors. Programs demonstrated overall success in reach and curricular diversity, serving a broad range of students and faculty, while also covering a broad range of topics. The main challenges highlighted were a lack of resources and infrastructure and teaching learners with varying levels of experience and knowledge. Further investments in MSIs are needed to sustain training efforts and develop pathways for diversifying the biomedical data science workforce. The National Institutes of Health (NIH) has had long-term strategic interests in bolstering the diversity of the biomedical and behavioral research communities . While eData science has grown tremendously in the past several years due to its great potential to transform industries, economies, and scientific discoveries. Many data science initiatives from the NIH, e.g., All of Us Precision Medicine, Bridge to Artificial Intelligence (BRIDGE2AI), are largely focused on the generation of flagship data sets to accelerate health research and improve the health of racial and ethnic minority populations ,7. AlthoThis paper aims to summarize all the NIMHD-funded RCMI institutions and their efforts with the development, deployment, and delivery of their respective data science training programs. We evaluate and highlight the reach, breadth, and feedback of these training programs with a particular emphasis on the targeted population and topics covered in the curriculum, as well as challenges & successes faced while designing and implementing these programs. Specifically, we utilized a cross-sectional survey to measure the demographics of learners served, curricular topics covered, methods of instruction and assessment, challenges, and recommendations by program directors. In what follows, we provide an overview of the RCMI program and the funding announcement from the NIMHD. We then provide an overview of survey questions and report on the results using descriptive methods. We conclude with a discussion on challenges and recommendations highlighted by project directors and link these results with the broader literature on developing and sustaining training programs with the stated goal of enhancing diversity.The study design consisted of a cross-sectional survey administered at six minority-serving institutions awarded supplements from the NIMHD to develop new data science training programs. This included RCMI programs at the University of Puerto Rico\u2014Medical Sciences Campus, Meharry Medical College, Jackson State University, the University of Hawaii at Manoa, Howard University, and the RCMI coordinating center at the Morehouse School of Medicine.The Research Centers in Minority Institutions (RCMI) Program is a congressionally sponsored program initiated by the NIH in 1985 and administered by the National Center for Research Resources (NCRR) [Since its establishment, the RCMI program has proven itself as a research powerhouse, with extraordinary strength across the spectrum of translational medicine, health disparity research, and minority research participant enrollment. As noted by Ofili et al., between 2000 and 2015 RCMI investigators from 18 sponsored institutions leveraged $805 million in RCMI program funds into $3.7 billion in additional awards, including 1643 R01  awards, with >14,000 publications and >500 patent disclosures [To address a lack of diversity in biomedical data science and to be better positioned for the challenges posed by the complex, highly dimensional, and inherently transdisciplinary nature of health disparities, the National Institute of Minority Health Disparities (NIMHD) issued a notice of special interest (NOSI) to invite applications for administrative supplements from eligible RCMIs. This funding opportunity is aimed at enhancing data science capacity at recipient institutions and fostering further collaborations between RCMI-funded researchers and data scientists .The emphasis of the supplement was placed on the development of data science skill-building activities. In the notice, the activities of interest included the development of new modules focused on data analysis with health disparities datasets. Additionally, the NOSI cited interest in the integration of datasets representing \u201cmultiple levels and domains of influence in the NIMHD Research Framework\u201d .The survey consisted of 25 questions and focused on understanding the breadth of the curriculum marshaled at each program. They survey was modified to assess additional criterion, such as program-specific data, including demographics of trainees, knowledge areas covered in training programs, mechanisms for instruction, and assessed competencies. The questions in this survey were based on an ACM Data Science Task Force questionnaire administered to academic and industry participants to understand the landscape of curricular offerings in data science . The surDescriptive analysis was performed on all quantitative survey data, including frequencies and percentages. Additionally, themes were identified in open ended questions around challenges and recommendations inductively.Six NIMHD-funded RCMIs were awarded to increase data science capacity for resource-constrained, minority-serving institutions. These institutions included the Medical Sciences Campus at the University of Puerto Rico, Meharry Medical College, Jackson State University, the University of Hawaii at Manoa, Howard University, and the RCMI-Coordinating Center located at the Morehouse School of Medicine.The specific aims of each of these training programs are detailed below:University of Puerto Rico\u2014Medical Sciences Campus: To enhance and build capacity for investigators and students from biomedical informatics and other disciplines in DS/AI/ML topics such as Jupiter Hub, coding with R, RStudio, and Python, using ML libraries and other cutting-edge techniques to mitigate Hispanics\u2019 health disparities. To accomplish this aim, we developed of a new course \u201d), focused on data analysis using Hispanics datasets, that represents multiple levels and domains of influence in the NIMHD Research Framework.Meharry Medical College: Develop authentic and sustainable collaborations between Meharry\u2019s RCMI researchers and data scientists within Meharry\u2019s new School of Applied Computational Sciences. Enhance Meharry\u2019s RCMI capacity by providing data science training to the community. Assess the learning and data analytics skills of the RCMI investigators, post-docs, staff, and/or graduate students and research capacity enhancement of the RCMI program.Jackson State University (JSU): With the overarching goal to train the next generation of scientists to address the monumental challenge associated with the curation, integration, analysis, and interpretation of biomedical big data, the specific aims of the Biomedical Data Science Training Program (BDS-TP) at JSU are to foster collaborations between data scientists and biomedical, socio-behavioral, and/or clinical researchers at the RCMI Center for Health Disparities Research at JSU; and build the capacity of JSU and other Historically Black Colleges and Universities (HBCUs) in Mississippi  in biomedical data science by developing the biomedical data science skills of science, technology, engineering, and mathematics (STEM) faculty, students, and post-doctoral research fellows.University of Hawaii at Manoa: Provide education and training of data science-related skills to RCMI Researchers and their collaborators. Enhance collaborations between RCMI-funded researchers and data scientists. In addition to training RCMI investigators and their collaborators in a group in Aim 1, we will also offer individual data science training for investigators to foster collaborations between investigators and our data science experts.Howard University: To develop a new and targeted intensive data science modular training workshop focused on data analysis with minority health and health disparities datasets. To develop hands-on experience in the utilization of data science in minority health and health disparity research, which includes: (a) develop mentored summer research projects for undergraduate, graduate, and post-doctoral trainees and, (b) host product driven Codeathon events to address an issue or issues related to minority health or health disparity research. To promote and support the institutionalization of data science efforts at Howard University by: (a) developing train-the-trainer programs that provide targeted training opportunities for HU educators and encourage them to incorporate data science principles and exposures in their class offerings; and (b) developing a train-the-researcher program that provides training opportunities for HU RCMI researchers with emphasis on junior faculty to effectively incorporate cutting-edge data science techniques and capabilities into their research efforts.RCMI-CC at the Morehouse School of Medicine: To enhance the data science capacity of RCMI investigators across the RCMI consortium by collaboratively developing a project-based curriculum and organizing workshops introducing data science fundamentals and tools, as well as NIH-funded resources and datasets relevant to minority health disparities. To stimulate data science collaborations across U54 centers, as well as between U54 and non-RCMI institutions by organizing Data Science and Health Disparities Demo Days and launching enrichment awards to support the development of collaborative research projects.Each program recruited a diverse cohort of trainees at differing stages in their careers, ranging from undergraduate students to postdoctoral fellows and early-stage investigators and senior faculty see . The parInstitutions utilized existing resources, created new resources, and invited instruction from outside faculty see . Funded Survey respondents were asked to enumerate the top three challenges faced when designing and implementing their training programs , generally. The responses were varied but focused on similar themes, summarized in Examples of these recommendations were \u2018training-the-trainer\u2019 models of didactics, embedded multi-level coursework inside training programs , and investments in diverse faculty and mentorship to broaden the interdisciplinary reach at partnering institutions.The purpose of this study was to shed light on the reach, curricular breadth, and best practices in data science training at resource-constrained, minority-serving institutions by summarizing the efforts of six NIMHD-funded RCMI programs that received funding to develop data science training programs. The programs surveyed shared curricular goals around the application of cutting-edge data science techniques to different data types and training development around data science resources and tools. The average program used four tools and discussed over ten (>10.6) computing knowledge areas over the course of their curriculum. Together, the programs targeted building capacity at every point in the higher-education process (from undergraduates to continuing education for professors). The shared goals of the RCMI programs were to increase training capacity, professional development, and institutional collaboration. These goals have been highlighted across several RCMI initiatives and in the evaluation of RCMI programming ,14,15.The survey results also emphasize several pertinent themes around challenges in, and recommendations for, designing, implementing, and sustaining training programs to enhance diversity in data science training. Notably, the challenges and recommendations were reflective of issues of long-term planning and investment. For instance, the need for broad infrastructure was a recurring theme in survey responses; the possibilities for infrastructure development to bridge the chasm in data generation, analysis, access, and distribution has been echoed for several years ,16,17. AWhile the recommendations were diverse, the most agreed upon recommendations can be summarized by the prioritization and development of long-lasting resources. Program directors independently recognized the ways that diverse data set development, training for learners at various levels of erudition, and a multiplicity of training options  would provide a better outlook for future generations of diverse investigators with robust data science skills. A plethora of educational modalities for healthcare researchers at various stages of education have demonstrated comparable performance and increased the reach of educational objectives ,21,22 anThere are three limitations of our study that are worth considering: first, the six RCMI programs considered are not a random sample of RCMI institutions. The programs covered were awarded grants through a competitive process, which limits the generalizability of our findings. Second, the funding opportunity from the National Institute for Minority Health disparities did not require a formal evaluation plan. As such, the programs evaluated did not utilize the same approaches to evaluating their respective programming. While our analysis attempted to develop a better understanding of who took part and what would be required to sustain the program over time, future studies should incorporate a formal evaluation of the data science programs using an existing framework like RE-AIM . FinallyThis article adds to the literature on investments in minority-serving institutions with the twin aims of enhancing capacity in these resource-constrained environments and contributing to the diversification of the scientific workforce. Our descriptive study provides insight on federally funded data science training programs leveraging the breadth and depth of the NIMHD-funded RCMI network. Our results support the need for increased diversity in data sets, increased curricular materials and work sets reflective of the diverse audiences served, and further diversity of personal and professional exposure for underrepresented professionals in biomedical data science. Investment and funding efforts to build and sustain increased capacity at RCMI and minority-serving institutions are necessary and may prove increasingly so as the diversity of the nation continues to outpace the diversity reflected in NIH-funded datasets and research. Taken together, there is strong evidence for building capacity in biomedical data science at RCMI institutions and the downstream impact for enhancing diversity in the biomedical research and data science workforce."}
+{"text": "Frontiers in Microbiology to describe the state of the art, recent developments, major accomplishments, as well as the challenges and potential directions to move the fields of Microbiological Chemistry and Geomicrobiology forward.As the pivotal players in all the ecosystems, microbes drive the biogeochemical processes that are of both fundamental and practical significance. Microorganisms exert multiple ecosystem services which are crucial for the pressing issues such as biodiversity conservation, remediation of environmental pollution, global climate change, food production, and public health , the group of enzymes catalyzing hydroxylation of medium\u2014to long-chain length alkanes, focusing on the arrangement of the electron transfer proteins that activate AlkB. In the most extensively studied model organism, Pseudomonas putida GPo1, the alkB gene occurs on the OCT plasmid within an operon containing all the genes necessary for the transformation of alkanes to fatty acids and AlkB activation occurs via electron transfer from a flavin reductase and an iron-sulfur protein. Although this mechanism is well-established, the authors note that the OCT operon is not common in sequenced microbial genomes that contain alkB and describe other alkane-oxidizing strains that employ alternative electron-transfer arrangements. The authors review the biochemistry of the electron-transfer proteins and speculate about their biological significance. They also propose future avenues to enhance the mechanistic understanding of AlkBs in terms of their in vivo and in vitro characterization, structural information and alternative substrates.Alkanes originating from a variety of sources represent an important component of the global carbon cycle on Earth. While selective activation of the non-polar carbon-hydrogen bonds is energetically challenging, a variety of aerobic microorganisms are capable of oxidizing alkanes. Takamiya et al. report ultra-small cells inhabiting the grain boundaries of metal sulfide  mineral assemblages in samples collected from extinct chimneys located in the southern Mariana Trough. Combined nanoscale secondary ion mass spectrometry (NanoSIMS), transmission electron microscopy coupled with electron diffraction (TEM-SEAD), Raman spectroscopy, fluorescence microscopy, and in-situ biosignature analysis allowed visualization and identification of ultra-small cells coated with copper nanoparticles in the chimney interior. Taken together these analyses support the occurrence of a distinct microbial community in the oligotrophic and anoxic extinct chimney. This study of ultra-small cells inhabiting the interior of a chimney suggests that photosynthesis-independent microbial ecosystems in submarine metal sulfide deposits could have existed billions of years ago on the early Earth.Genetic evidence provided by high-profile sequencing, parallel geochemical coupled with microscopic and spectroscopic analyses provide convincing evidence for the microbe-environment nexus, especially for organisms that are challenging to be cultivated. Liu et al. investigated the interplay of light, minerals, and microbes that could occur in the marine euphotic zone. Based on a suite of mineralogical and photoelectrochemical analyses, photoreduction and electron conversion were demonstrated for goethite (\u03b1-FeOOH), a representative and widespread semiconducting natural mineral. The experiments simulating light-illuminated marine euphotic zones showed photoreduction of goethite and release of reduced Fe(II) which affected the structure and diversity of the mineral-associated microbial community. The results suggest that light-induced interactions between semiconducting minerals and microorganisms may regulate microbial carbon cycles in the marine euphotic zone.Increasing evidence has demonstrated the importance of previously unrecognized reaction pathways in biogeochemical processes comprised of synergistic abiotic and biotic reactions. One example is the photoelectric conversion system, in which natural semiconducting minerals  act as catalytic shuttles to sustain electron and energy flow from light to non-phototrophic bacteria. Chen et al. investigate the microbial composition and the ecological processes controlling community assembly shaped by different cropping strategies. Amplicon sequencing, functionality prediction, statistical analyses and modeling demonstrated that various cropping treatments influenced microbial communities, interspecies interactions, and the ecological processes that shaped the community composition in different soil-plant compartment niches. Crop rotation intensified the interspecies competition and decreased heterogeneity of the rhizosphere via strengthened selection force. Furthermore, the indicator species significantly influenced by intercropping and crop rotations potentially facilitated nitrogen/phosphorous cycling and degradation processes, respectively. The results suggest appropriate agricultural management may improve farmland soil fertility, crop yields, biomass growth, and economic benefit.Insightful understanding of microbe-environment interactions can also facilitate practical applications such as agriculture management and treatment of hazardous algal blooms. Coyne et al. provide a comprehensive review on algicidal interactions to control harmful algal blooms. Bacteria are capable of driving algicidal or algistatic effects through physical contact (direct mode) or generation of algicidal compounds (indirect mode), which result in a wide range of reversible and irrevocable outcomes for the target algae. The range of algicidal interactions, including specificity of bacterial control, mechanisms for activity, and chemical and biochemical characterization of the algicidal mode, were discussed. Considering the constraints on the spectrum and concentrations of bacteria and target algal species in laboratory-scale experiments, the research and strategies to enhance the efficacy of algicides and stability of the algicidal microbial cohorts under environment-relevant conditions were emphasized. The avenues for future research of alternative applications of algicidal bacteria in biotechnology, their ecological effects on non-target species, characterization and optimization of novel algicides to control hazardous algal blooms were also proposed and discussed.Finally, Taken together, the reviews and articles published in this issue cover different aspects of microbiological chemistry and geomicrobiology, from insights on genetic and biochemical mechanisms of biogeochemical processes in unique ecosystems to advancing fundamental knowledge for practical applications . Active research in these areas and many more exciting discoveries ahead of us will pave the way toward a more comprehensive understanding of biogeochemical processes in diverse ecosystems and integral to support sustainable development goals and the wellbeing of human populations.Both authors contributed to the article and approved the submitted version.via China University of Geosciences (Wuhan). BT acknowledges research funding received from the U.S. National Science Foundation on grants EAR 2122086 and CHE 2120408.YD appreciates the funding support from National Natural Science Foundation of China under the contracts 92051111, 41877321, and 91851211 and the Fundamental Research Funds for the Chinese Central Government The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "The burden of cirrhosis is increasing in North America where a significant proportion of the population (~20%) is comprised of recent immigrants and refugees. However, the incidence of cirrhosis among this population has not been described.The aim of this study was to describe the incidence of cirrhosis among recent immigrants and refugees to Ontario, Canada stratified by cirrhosis etiology and region of origin and compare incidence rates to those of Canadian-born and long-term residents.This is a population-based cohort study from Ontario, Canada from 2000-2017 using healthcare data housed at ICES. Individuals with incident cirrhosis using a 5-year lookback were identified along with cirrhosis etiology using validated algorithms. Recent immigrants and refugees to Ontario (since 1985) and their World Bank region of origin were defined based on linkage to the Immigration, Refugees, and Citizenship Canada\u2019s Permanent Resident database. Adjusted incidence rates of cirrhosis by immigration status, etiology, and region of origin were calculated and differences in rates were compared between recent immigrants and refugees to long-term residents (born in Canada or arriving before 1985) using age and sex adjusted Poisson regression to calculate rate ratios (RR).In total, n=25,054 recent immigrants/refugees with incident cirrhosis were identified. 59% were male, median age was 49 years (IQR 39-61), 99% resided in urban areas and 31% resided in neighbourhoods of the lowest income quintile. The most common regions of origin were East Asia and Pacific , South Asia , Europe and Central Asia  and Latin America/Caribbean . The majority had NAFLD cirrhosis , followed by HBV , ALD , and HCV . Cirrhosis incidence stratified by etiology varied by region of origin, with HBV highest among the East Asia and Pacific and Sub-Saharan Africa cohort , HCV among Sub-Saharan Africa and South Asia , ALD among European/Central Asia and South Asia , and NAFLD among the Latin America/Caribbean, Middle East/North Africa, and South Asian populations . When comparing age and sex adjusted incidence of cirrhosis by etiology and immigration status, rates were lower among recent immigrants/refugees for all causes compared to long-term residents  with the exception of HBV where it was over 4-fold higher .Rates of HBV cirrhosis are substantially higher among migrants to Ontario while rates of all other causes of cirrhosis are lower, likely explained by the healthy immigrant effect. NAFLD has emerged as the most common etiology of cirrhosis among migrants with rates approaching those of Canadian-born and long-term residents. These data add to our understanding of the evolving epidemiology of cirrhosis and the contribution of other etiologies outside of viral hepatitis among immigrants.NoneNone Declared"}
+{"text": "Tourism eco-efficiency is a performance basis for evaluating green total factor productivity and sustainable development.The objective of this study was to measure tourism eco-efficiency in Inner Mongolia and explore its influencing factors. The aim was to provide an accurate reference for improving the quality and efficiency of tourism in Inner Mongolia and promoting the sustainable development of the regional economy and society.Tourism eco-efficiency in Inner Mongolia from 2009 to 2019 was calculated using a super-slacks-based measure (SBM) model with an undesirable output. The spatial variation function was used to explore the spatial evolution pattern of tourism eco-efficiency in Inner Mongolia, and the influencing factors of the spatial evolution were analyzed by geographically weighted regression.Tourism eco-efficiency in Inner Mongolia is relatively low. Eco-efficiency values among cities in Inner Mongolia vary, and their distribution is not balanced. The structural eco-efficiency of tourism in Inner Mongolia has been consistent from 2009 to 2019. The degree of homogenization in the overall direction is relatively good. Furthermore, its spatial distribution form and internal structure evolution show a certain regularity and continuity. The pattern evolution of tourism eco-efficiency in Inner Mongolia is jointly driven by the economic level, environmental regulation, industrial structure, traffic conditions, resource endowment, and tourism reception facilities. These influencing factors show obvious spatial heterogeneity.From the perspective of Inner Mongolia, the difference in the tourism eco-efficiency value from 2009 to 2019 was relatively large, but the number of effective areas in the efficiency frontier generally showed a fluctuating growth trend. The range parameters of tourism eco-efficiency showed a decreasing trend, and the spatial correlation effect of tourism eco-efficiency in Inner Mongolia showed a decreasing trend under the influence of structural and spatial differentiation. Tourism is one of China's strategic pillar industries. In addition to helping regional economic growth and poverty alleviation, tourism contributes significantly to aesthetics and ecological civilization in China . In receSchaltegger first proposed the concept of eco-efficiency in 1990 , and thevia exploratory spatial data analysis  method.2, with abundant grasslands, forests, mountains, rivers, and deserts among other natural resources and Manchu and Mongolian culture, ethnic customs, border ports, and other human tourism resources. In recent years, Inner Mongolia has made a significant effort to create the brand image of \u201cbright Inner Mongolia is in the north of the motherland.\u201d In 2020, Inner Mongolia planned to promote epidemic prevention and control and cultural tourism, the year-round reception of domestic tourists and domestic tourism revenue reached 125 million people and 240.406 billion yuan (RMB), indicating that the development of tourism has developed well  and Y(xi+k) are the observed values Y(x) of the geographic variables at the points xi and xi+k,N(k) are the sample sizes of the k segmentation distance.Geographically weighted regression focuses on the local effects of spatial objects. Based on the principle of regression, it attempts to explore the relationship between spatial variables under the premise of considering the spatial correlation of the samples. Based on this, the spatial variation and driving factors of the research object are extended forward, and the characteristics and laws of spatial variation are analyzed \u201346. The yi refers to the global dependent variable; xik is the independent variable; (uivi) is the coordinate of the capital city of the i region; \u03b2k is the spatial unit value of the continuous function in the i region; \u03b5i is the random error term,\u03b20 and \u03b2kare the parameters; and kis the number of regions.Where Based on the super-SBM model of the variable return scale (VRS) with an undesirable output, tourism eco-efficiency in Inner Mongolia from 2009 to 2019 was statically evaluated and obtained . OverallTourism eco-efficiency is a static measure that is independently measured yearly. Therefore, to determine the mobile changes in the tourism eco-efficiency levels in Inner Mongolia from 2009 to 2019, it is necessary to measure its growth rate. In this study, the VRS model was used for the measurement analysis considering the machine learning (ML) index, which refers to the growth rate of tourism eco-efficiency when the desired output is increased and the undesired output is reduced in equal proportion. The ML index includes two indicators: tourism eco-technical efficiency growth rate (EC) and tourism eco-technical progress growth rate (TC) . The ML First, the projection coordinate system of Inner Mongolia was measured, then the spatial variation function of 2009, 2013, and 2019 Inner Mongolia tourism eco-efficiency was measured, and finally, the optimal model for measuring the fractal dimension of each direction was selected. Ultimately, the Kriging interpolation simulation was performed to comprehensively analyze the evolution process of the spatial pattern of tourism eco-efficiency in Inner Mongolia. According to the results of the spatial variation value of tourism eco-efficiency in Inner Mongolia , the GauFrom the fractal dimension of the spatial variation function , the oveThe Kriging interpolation simulation of the variation function of tourism eco-efficiency in Mongolia  shows thui, vi) as a i coordinate, the GWR model of tourism eco-efficiency is expressed as follows:Based on the objectivity of the spatial heterogeneity of the influencing factors of tourism eco-efficiency, the GWR method was used to measure the regression coefficients of the influencing factors in each region. Data from 2009, 2013, and 2019 were selected to construe the spatial evolution law of the influencing factors on the eco-efficiency level. Considering , industrial structure (tertiary industry share), traffic condition (ratio of the length of graded highways to the urban area), resource endowment (the weighted score of high-level scenic spots), and environmental regulation , respectively, in the period J of the region i.Where ArcGIS10.4 was used to calculate GWR, and the regression coefficients of each influencing factor were divided into five levels ranging from the high-value area to the low-value area based on five levels of natural fracture points . In termThis study uses a super-SBM model with an undesirable output to assess and analyze tourism eco-efficiency during 2009\u20132019 in Inner Mongolia. Then, using the spatial variation function analysis of the spatial and temporal evolution characteristics of tourism eco-efficiency in Inner Mongolia and based on the GWR analysis of the influence of factors of tourism in Inner Mongolia on eco-efficiency, the following conclusions were drawn.The average tourism eco-efficiency in Inner Mongolia is 0.74, which is relatively low. Furthermore, the tourism eco-efficiency values of the provinces vary significantly, and their distribution is unbalanced. In addition, technological progress contributes significantly to the growth rate of tourism eco-efficiency in Inner Mongolia, indicating that technological innovation has a relatively high impact on tourism eco-efficiency. The differences in tourism eco-efficiency from 2009 to 2019 in Inner Mongolia were relatively large, but the number of effective areas in the efficiency frontier generally showed a fluctuating growth trend. The results of this study echo previous studies. Jun shows that the extensive economic growth mode restricts the improvement of tourism eco-efficiency in Inner Mongolia . The impThe range parameters of tourism eco-efficiency showed a decreasing trend, and the spatial correlation effect of tourism eco-efficiency in Inner Mongolia showed a decreasing trend under the influence of structural and spatial differentiation. Tourism eco-efficiency in Inner Mongolia showed consistent structural characteristics in different periods. The general homogenization degree of tourism eco-efficiency is relatively good, and the spatial difference in the local direction is relatively obvious. The spatial distribution pattern and internal structure evolution of tourism eco-efficiency have a certain regularity and continuity, showing a high-value concentrated distribution, and low-value scattered contiguous distribution. Yuanyuan and Yuxiang pointed out that the spatial variation function can deeply describe the randomness and structure of regional variables and measure the degree of variation of the spatial pattern of economic units . The strThe pattern evolution of tourism eco-efficiency in Inner Mongolia is jointly driven by the economic level, environmental regulation, industrial structure, traffic conditions, resource endowment, and tourism reception facilities, and there is obvious spatial heterogeneity among the influencing factors. The spatial and temporal patterns of the impact of environmental regulation on tourism eco-efficiency are generally consistent with those of economic factors. The spatial and temporal patterns of the influence of traffic conditions and resource endowment on tourism eco-efficiency are generally consistent with those of the influencing factors of industrial structure. Zhilong and Diyun emphasized that the economic level, industrial structure, resource endowment, infrastructure, and environmental regulation are the key factors affecting tourism eco-efficiency , 41. TheThis study first constructs a tourism eco-efficiency evaluation index system based on Inner Mongolia and then explores the evolutionary path and spatial pattern of tourism eco-efficiency in Inner Mongolia from the perspective of the geographic spatiotemporal dimension. To provide an accurate reference for improving tourism quality and eco-efficiency in Inner Mongolia and the sustainable development of the regional economy and society.First, the study presents research on tourism eco-efficiency from the perspective of ecological and environmental protection, which conforms to the connotation of developing an ecological civilization and meets the requirements of high-quality economic development. This is of great significance for enriching the theory of ecological civilization construction and expanding the applicable category of ecological civilization construction. Second, tourism eco-efficiency is the application of the theory of tourism eco-efficiency. Tourism eco-efficiency can combine the development of the tourism economy with its environmental impact, which can also provide some academic reference for the study of eco-efficiency in other industries. Finally, this study tries to determine the temporal evolution path and spatial pattern of tourism eco-efficiency, which is the basic paradigm of geographic spatiotemporal analysis. With respect to research, this study incorporated the undesired output in the tourism eco-efficiency measurement and constructed a relatively scientific, systematic, and perfect tourism eco-efficiency evaluation index system. In addition, the rules of spatiotemporal evolution and the characteristics of tourism eco-efficiency based on Inner Mongolia were analyzed. This provides additional insight into the correlation between geographical spatial patterns and the ecological environment, and promotes the cross-integration of tourism economics and tourism geography and other marginal disciplines. With respect to research methods, this study adopts the super-SBM model with the undesirable output to calculate tourism eco-efficiency in Inner Mongolia from 2009 to 2019, and comprehensively uses the Malmquist\u2013Luenberger index to break down tourism eco-efficiency. The spatial variation function and GWR analysis describe its spatiotemporal evolution characteristics and allow the integration of econometrics, spatial geography, and other disciplines.Tourism eco-efficiency is an essential index for the formulation of a tourism development plan, the evaluation of tourism management, and the promotion of the sustainable development of the tourism destination. The evaluation of tourism eco-efficiency, the description of the time evolution path, the outline of the spatial distribution pattern, and the discussion of its dynamic correlation with the development of the tourism economy have significant practical value. In the face of increasing tourism energy consumption and the worsening of the ecological environment, Inner Mongolia tourism eco-efficiency evaluation can effectively reflect the relationship between economic activities and the ecological environment. This is validated by the development of the worsening situation of the tourism ecological environment, can boost sustainable blossom of the province tourism such as national macro policy takes root provides the beneficial reference. The exploration of the time evolution model and the outline of the spatial pattern of tourism eco-efficiency in Inner Mongolia elucidate the sustainable development of the entire region's tourism in Inner Mongolia from a macro perspective and provide scientific guidance for the \u201ctop-down\u201d decision and \u201cbottom-up\u201d policy of tourism ecological protection in Inner Mongolia. Moreover, this study explores the spatial and temporal patterns of tourism eco-efficiency and its influencing factors in Inner Mongolia, which provides a reference for the optimization of tourism eco-efficiency and the sustainable development of tourism in other regions.Under the national macro context of constructing an ecological civilization, Inner Mongolia should change its tourism development model, enhance tourism eco-efficiency, and promote the sustainable development of tourism. Therefore, this study proposes the following. In view of the performance of tourism eco-efficiency in Inner Mongolia, the environmental ecology of tourism in Inner Mongolia needs to be improved, and environmental protection needs to be considered while developing the tourism industry, to enhance the sustainable development of tourism , 18. FirThis study explores in depth the spatial pattern and influencing factors of tourism eco-efficiency in Inner Mongolia. The study provides a reference for future research on tourism eco-efficiency and sustainability in Inner Mongolia and other regions. However, this study has certain shortcomings that should be addressed. First, regarding the design of the index system, carbon emissions as an undesirable output of tourism eco-efficiency reflect the negative impact of tourism on the environment. However, related theoretical and empirical research is insufficient; the travel coefficient of carbon emissions for Inner Mongolia has not been evaluated. Therefore, the measurement results of tourism eco-efficiency may be slightly conservative , 22. SecThis study first constructs the tourism eco-efficiency evaluation index system and then explores the evolution path and spatial pattern of tourism eco-efficiency in Inner Mongolia from the perspective of the geographic spatiotemporal dimension. Inner Mongolia has a relatively low tourism eco-efficiency value, with an average value of 0.74. Furthermore, the tourism efficiency values of the provinces vary and their distribution is unbalanced. The range parameters of tourism eco-efficiency and the spatial correlation effect of tourism eco-efficiency in Inner Mongolia under the influence of structural and spatial differentiation showed a decreasing trend.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.XW contributed to all aspects of this work. YW wrote the main manuscript text and analyzed the data. Both authors reviewed this manuscript, read, and agreed to the published version of the manuscript."}
+{"text": "Microbial biofilms are spatially organized communities of microorganisms attached to different surfaces and embedded within a self-produced matrix composed of extracellular polymeric substances (EPS). The formation of biofilms frequently occurs in the food industry, due to available nutrients, large areas for microbial growth, and the complexity of processing facilities. Microbial biofilms have represented an outstanding survival strategy against stressful conditions for both spoilage and pathogenic bacteria during food processing  the mechanisms underlying the formation of mixed-species biofilms; (2) the persistence and resistance under food processing environments; (3) the development of appropriate methods to study mixed-species biofilms; and (4) the potential novel strategies to control the formation of mixed-species biofilms. This Research Topic comprises 4 original research articles from Austria, China, Canada, and South Korea, contributed by 24 authors. Two contributions focused on the evaluation of mixed-species biofilm formation, and the others designed potential effective methods to control the formation of multi-species biofilms.Voglauer et al. described the complexity of mixed-species biofilms formed in water hoses of a meat processing environment by high-throughput 16S rRNA gene sequencing, with Comamonadaceae and Pseudoxanthomonas being most abundant in biofilms. Opportunistic pathogens, including the genera of Neochlamydia, Legionella, and Pseudomonas, have also been detected with different abundances. However, knowledge of the effects of environmental factors on the formation of biofilms in water hoses is limited. The authors also stated that control strategies have to be taken to prevent the colonization and biofilm formation in water hoses in order to assure water safety for the health of workers and consumers. In another study, Nan et al. evaluated the formation and transfer of mixed-species biofilms by Escherichia coli O103:H2 and lactic acid bacteria or spoilage bacteria at different temperatures, storage time, and humidity conditions. They stated that the formation of mixed-species biofilms may increase or diminish the risk of beef contamination by E. coli O103:H2, depending on the bacteria community and environmental conditions in beef processing environment.Yan et al. confirmed the high antibiofilm efficiency of lightly acidic electrolyzed water by preventing surface adhesions and impairing biofilm cell membrane integrities, and the antimicrobial activity highly depends on its storage time. This study also investigated the inhibitory effect of slightly acidic electrolyzed water on mixed-species of Listeria monocytogenes Scott A and Staphylococcus aureus for the first time.It is generally believed that mixed-species biofilms exhibit higher resistance to biofilm control strategies in food processing facilities when compared to single-species biofilms  the mechanisms underlying the formation of multi-species biofilms by omics, and (2) the development of appropriate methods to study multi-species biofilms and still needed for a better understanding of multi-species biofilms.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.This research was financially supported by the Natural Science Foundation of Jiangsu Province (BK20210814) and China Postdoctoral Science Foundation (2021TQ0274).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Dear Editor,Acquired generalized idiopathic anhidrosis (AGIA) is a rare disease without a defined etiology, non-related to dysautonomia or neurological abnormalities.A 20-year-old military male, of non Asian descent, without comorbidities, had developed diffuse anhidrosis for eight months, not affecting the palmoplantar and axillary regions, associated with multiple small normochromic papules, with an erythematous base, affecting the face, trunk, back region and upper limbs . The rasAGIA clinically presents as the absence of sweating after stimulation. The symptoms of heat intolerance and cholinergic urticaria are associated, corroborating the predominance in individuals whose work activity involves exposure to heat. Preserved palmoplantar and axillary sweating is justified by the adrenergic innervation and the predominance of apocrine sweat glands, respectively.The diagnosis is clinical, and pathological examination may reveal the presence of perieccrine lymphocytic inflammatory infiltrates.The differential diagnosis of anhidrosis includes congenital and acquired causes . Three sDespite reports of therapeutic success with corticosteroid use, there are no clinical studies to prove its efficacy. There is no consensus on the method of administration, dose, and duration of treatment.4None declared.Maisa Aparecida Matico Utsumi Okada: Design and planning of the study; data collection, or analysis and interpretation of data; drafting of the manuscript.Let\u00edcia Santos Dexheimer: Critical review of important intellectual content; approval of the final version of the manuscript.Renan Rangel Bonamigo: Critical review of important intellectual content; approval of the final version of the manuscript.Renata Heck: Critical review of important intellectual content; approval of the final version of the manuscript.None declared."}
+{"text": "The application of human factors engineering for rehabilitation robots is based on a \u201chuman-centered\u201d design philosophy that strives to provide safe and efficient human-robot interaction training for patients rather than depending on rehabilitation therapists. Human factors engineering for rehabilitation robots is undergoing preliminary investigation. However, the depth and breadth of current research do not provide a complete human factor engineering solution for developing rehabilitation robots. This study aims to provide a systematic review of research at the intersection of rehabilitation robotics and ergonomics to understand the progress and state-of-the-art research on critical human factors, issues, and corresponding solutions for rehabilitation robots. A total of 496 relevant studies were obtained from six scientific database searches, reference searches, and citation-tracking strategies. After applying the selection criteria and reading the full text of each study, 21 studies were selected for review and classified into four categories based on their human factor objectives: implementation of high safety, implementation of lightweight and high comfort, implementation of high human-robot interaction, and performance evaluation index and system studies. Based on the results of the studies, recommendations for future research are presented and discussed. Stroke is a cerebrovascular disease that causes significant morbidity, disability, and mortality, often leading to motor dysfunction or permanent disability , 2. WithRehabilitation robotics is a specific branch that focuses on helping patients restore or reestablish motor function. Rehabilitation robotics can be used in many aspects of physical therapy. It attempts to combine multiple technologies to maximize the physical rehabilitation training needs of patients, making extensive advances in robotic prostheses and other fields . Thus, iThe direct target of rehabilitation robots is the patient, and human factors goals such as safety, comfort, reliability, and adaptability are key considerations. Some rehabilitation products, such as HAL-5, Lokomat, and Hero Arm, have entered the market . But in The above-given context raises the question of how far the research application of human factor engineering in rehabilitation robotics has progressed. In the field of rehabilitation robotics, review articles \u201318 can pTo this end, this study focuses on the specific connotation of human factors goals, analyzes and composes the four human factors goals currently focused on research from the perspective of the system level and characteristics, explores the shortcomings of existing human factors goals and research contents and technical solutions in terms of research depth and breadth, and provides supplements and suggestions for further research contents. This study is crucial for further securing and improving the effect of stroke or postoperative rehabilitation treatment and enhancing the human-robot interaction experience. In the long run, this work can also improve the quality and overall level of rehabilitation medical equipment and help the development of rehabilitation equipment iterations.In this regard, this study has the following contributions in various aspects: (1) the research progress of robotic rehabilitation systems is analyzed from a brand new perspective, such as human factor engineering, and this is used as an innovation and entry point to analyze and sort out the four human factors objectives that are currently the focus of research. (2) The importance of human factor engineering in rehabilitation robotics research is clarified by highlighting the motivation and challenges of improving the adaptability and user experience of rehabilitation robots through human factor engineering research. (3) Suggestions are offered from the perspectives of the connotation categories of human factors goals and key technology solutions to provide a theoretical foundation and a direction for future study. (4) The results of various datasets and available sources are explained to support the classification of human factors goals, and tables are provided comprising all relevant datasets.This study is organized as follows. In order to address our research topic, we conducted a systematic review of the literature related to this topic, drawing on the methodology and process of Bal et al. In the study of , a literA systematic search was conducted to collect and summarize all research on human factor engineering in rehabilitation robotics as the research topic. We searched for the literature in three steps. First, databases, such as Web of Science, ScienceDirect, IEEE, EI, SCOPUS, and SpringerLink, were selected and searched, with the database time limit set from January 2011 to May 2022. These databases were systematically searched using Boolean algebra. Three columns of search terms were freely combined: the first and second columns were synonymous with rehabilitation robotics and human factor engineering, respectively. The third column of search terms is a paraphrase of the \u201chuman factor engineering\u201d connotation due to the broad scope of \u201chuman factor engineering.\u201d A total of 510 Boolean-configured search terms were composed and examined in each database. A complete view of the search terms can be found in The studies need to be empirical and examine the human factor engineering research component of rehabilitation-oriented robots. For this purpose, quantitative, qualitative, and mixed methods studies were considered.The research needs to involve research that enhances the human factors suitability of rehabilitation robots, such as safety, comfort, light weight, human-robot relationships, task allocation, the naturalness of human-robot interaction, and system performance evaluation. The research also needs to include technical solutions and measures.The research needs to be an academic paper. However, as the emerging field of human factor engineering research in rehabilitation robots is thus far in its infancy, we decided to expand the journal research to include book chapters and conference papers.Studies that met the following selection criteria were included in the review, and studies that failed to meet any of the following criteria were excluded:Following the initial screening, the subject staff critically assessed qualitative , quantitData extraction was carried out in two main ways. First, the essential characteristics of the final included studies were sorted to include the date of publication, the study's country, and the literature type. Correspondingly, the research design and data collection methods used in the selected studies were summarized, and information on the study participants was added to count the number of participants in the study. Second, under the human factor engineering connotations category, we report the human factor engineering research components involved in the studies reviewed, using specific human factors targets as the basis for classification.We found that in human factor engineering research on rehabilitation robots, the achievement of the same research goal maps to multiple dimensions of rehabilitation robot system design; similarly, the design of the same dimension of a rehabilitation robot system affects the achievement of multiple human factors embedded goals under the category of human factor engineering. To provide a clear and intuitive overview of the results of human factor engineering research on rehabilitation robots, the results of the data analysis have been reviewed using the former classification approach. This approach summarizes and integrates the current state of research on each human factors goal within the human factor engineering research scope of the selected studies in a multifactor and multimethod classification of one human factors goal.This study used the style of systematic reviews and meta-analyses guidelines illustrated in In addition, 10 studies were quantitative, 2 were qualitative, and 9 were based on mixed methods. All of these studies were experimental. 18 studies used actual experiments, basically choosing healthy people or rehabilitation patients with motor dysfunction as experimental subjects; 7 studies used virtual simulation in the form of experiments, of which 4 studies used a combination of both simulation and actual experiments and controls, while none of the more subjective research methods, such as questionnaires, were involved.We found that in human factor engineering research on rehabilitation robots, the achievement of the same research goal maps to multiple dimensions of rehabilitation robot system design; similarly, the design of the same dimension of the rehabilitation robot system affects the achievement of multiple human factors embedded goals under the category of human factor engineering. To provide a clear and intuitive overview of the results of human factor engineering research on rehabilitation robots, the results of the data analysis are reviewed using the former classification approach. This approach summarizes and integrates the current state of research on each human factors goal within the scope of human factor engineering research on rehabilitation robots in the selected studies in a multifactor and multimethod classification of one human factors goal.As a typical human-robot interaction device, safety design is a primary consideration. There are two central safety control schemes in everyday use today: an external control system scheme based on external monitoring and an internal control system scheme based on the robot's body design. Pan et al.  designedThere is still room for weight reduction in the quality of existing rehabilitation robots, and portability and wearability need to be improved. In recent years, research has increased into reducing the structural weight of rehabilitation robots and enhancing wearer comfort.Using lightweight composite materials plays an active role in reducing the structural weight of rehabilitation robots and improving the wearing comfort. For example, using materials such as polyethene and polypropylene can significantly achieve lightweight designs for rehabilitation robots. One study  reduced Weight reduction can also be achieved by simplifying complex structures and softening rigid structures. In addition, it has been found that using the principle of gravitational balance to balance some of the weight in terms of structural simplification makes the exoskeleton simple, lightweight, and well-followed, minimizing the physical footprint while maximizing mechanism isotropy and device functionality , 45. AnnThe rational weight distribution configuration, i.e., improving the drive layout and optimizing the drive method, can also achieve lightweight and comfort goals. Some studies have reduced the total weight by using a cord and pneumatic drives \u201349 whileFlexible exoskeleton robots can be said to combine all three of these aspects: eliminating the rigid frame of traditional exoskeletons, optimizing the actuation methods  based on the use of lightweight materials \u201358, and A rehabilitation robot is a human-robot collaborative intelligence system with a human core. Good human-robot interaction performance includes flexibility, coordination, adaptivity, on-demand assistance, and pathological adaptability of rehabilitation movements, all of which are prerequisites for efficient human-robot collaboration. Many factors affect human-robot interaction performance, including human-robot interaction control, anthropomorphic structure, human-scale adaptability, motion planning, and many other aspects, mainly involving control systems, mechanical systems, software systems, and others.The suppleness of human-robot interaction is influenced by the interaction control, but it also focuses on three main aspects mapped on the drive mechanism, structure, and interface connection components of the rehabilitation robot . RegardiDrive mechanisms are essential for realizing flexibility, with the series elastomeric actuator (SEA) becoming the most popular drive option . The SEALi et al.  proposedThe variation in the rehabilitation solutions required by different patients or the same patient at different stages of rehabilitation places a demand on adaptive on-demand assistance for robotic rehabilitation systems. Adaptive control strategies can provide many benefits for exoskeletons, as the controller can automatically adjust for the variability between each patient and the changing needs of individual patients. Adaptive control of rehabilitation exoskeletons is currently immature . Two stuThe coordination of rehabilitation movements is based on precisely recognizing the patient's movement intentions. EMG signal control is noninvasive, flexible, precise in the patient's movement intentions, and highly operable and safe. At present, the application of surface electromyography signals in rehabilitation robotics has been increasingly studied \u201387, suchEMG-based control methods can usually be divided into two types: neuro-fuzzy control methods based on EMG  and muscle model-based EMG control methods, in which a matrix is associating the user's joint torque with a specific muscle is used to obtain the boost torque . For theEffective performance evaluation methods and indicators are the basis for optimizing the performance of human-machine equipment. A total of eight papers deal with performance evaluation studies, mainly focusing on ergonomic comfort, stability of muscle activity and movement, compatibility, fit, and other aspects of human-robot effectiveness performance evaluation.Safety is a critical evaluation index for human-robot interaction devices and is an essential prerequisite for transforming experimental results into clinical applications. The safety evaluation of rehabilitation robots aims to achieve safe interaction between patients and rehabilitation robots and currently focuses on the safety performance of the rehabilitation robot system itself during human-robot interaction. Wang et al.  defined As a wearable device that acts directly on the surface of the human body, comfort is the critical performance of human-robot interaction. The comfort of rehabilitation robots is mainly evaluated in terms of their appearance, materials, operational comfort, and wear fatigue. The main methods for evaluating the comfort of rehabilitation robots are subjective evaluation and objective experimental methods, with subjective evaluation usually taking the form of questionnaires and objective evaluation mainly taking the form of pressure distribution and physiological electrical signal experiments.Two studies dealt with comfort evaluation. De Rossi et al.  applied There is no unified index system for evaluating human-robot efficacy performance. Four studies evaluated the motion performance of rehabilitation robots, such as matching, compatibility, and stability, and one involved the evaluation of human-robot ergonomics. Zhang et al.  and Di NIn this study, we conducted a systematic review of human factor engineering research on rehabilitation robots and classified the human factors research content from the perspective of human factors objectives. The research mainly focuses on human factors objectives and content, such as safety, weight and comfort, human-robot interaction, and performance evaluation of rehabilitation robots.Research on human factor engineering in rehabilitation robots has already achieved some milestones, which not only solves many drawbacks, such as low efficiency of rehabilitation by traditional rehabilitation methods but also achieves high efficiency, high precision, and personalized rehabilitation treatment to a certain extent. Therefore, applying human factor engineering in rehabilitation robots is a necessary technical means to achieve effective rehabilitation treatment in the future. However, some critical human factors issues regarding safety, lightness and comfort, human-robot interaction, and performance evaluation have not yet been carried out or require in-depth research. On the basis of an analysis of the aforementioned human factor engineering research for rehabilitation robots, it is proposed that safety protection mechanisms, individual difference compatibility mechanisms, human-robot interaction incentive mechanisms, and human-robot system evaluation indicators and systems can be further developed in future research.The safety design of the rehabilitation robot should include two levels: (1) the rehabilitation robot and the human being are in the same movement space to jointly complete the corresponding task, and it is necessary to prevent the robot from colliding with the human body to ensure the user's safety. (2) The safety of the rehabilitation training mode, intensity, and range of motion for the patient's current disease condition. In terms of safety protection mechanisms, most of the current safety research focuses on the internal control system designed by the rehabilitation robot itself, with little research involving the external control system between human and robot and a lack of safety assessment of the functional parameters of rehabilitation training for the patient's pathology.To achieve multiple protections for patient safety, future research should focus on two critical aspects of the rehabilitation robot: mechanism design (hardware) safety and control system (software) safety. Regarding robot hardware safety, limit blocks can be used for mechanical protection. At the same time, the mechanical structure design can fully avoid the invasive design of the robot to the human body by establishing the robot's kinematic model and analyzing the robot's reachable space. Regarding robot software safety, the stability of the existing closed-loop system for the interactive control of rehabilitation robots should be addressed with emphasis due to the dynamical uncertainty of the robot system and the fact that some action conflicts often occur during the physical human-robot interaction. At the same time, the damping response performance of the system should be improved.Although some studies have been conducted on adaptive aids and postural and motor adaptations, there is a lack of systematic and targeted research. The number of rehabilitation patients is growing annually, and the parameters of the rehabilitation programs vary greatly depending on the individual's posture, degree of motor impairment, pathology, and stage of rehabilitation. In response to individual differences in body shape and pathology, rehabilitation robots should be individualized in configuration, control systems, movement trajectories, training modes, and functional parameters. In this regard, further research should be conducted on the adaptive mechanism of individual and pathological differences, the adaptability and stability of the control system, the application of sensor technology, and the design of control algorithms so that the rehabilitation robot can sense the state information of the patient's force and position and adopt the corresponding training mode, control strategy, and matching training parameters. In addition, the flexibility of the structure should be considered, and modular designs can be utilised to make the structure and size of the rehabilitation robot adaptable to individual differences.Patients can interact with robots in a secure, pleasant, and natural environment if interaction control is effective. Impedance control and hybrid force/position control are the most common control mechanisms employed in the former case. In the latter, the most widely used strategies are myoelectric signal control and EEG signal control. The principles, advantages, and disadvantages of various interactive control methods are shown in . Among tIn addition to the HCI performance factors mentioned above, HCI strategies can also affect the HCI experience and rehabilitation outcomes. In the case of rehabilitated patients, the weak motor skills of the affected limbs and the lack of motivation to participate in a rigid, boring, and repetitive training paradigm will directly lead to poor rehabilitation efficiency and effectiveness. A robust incentive mechanism is a way forward for human-robot interaction in rehabilitation. Future research should combine rehabilitation robots with virtual reality (VR) technology to integrate task-oriented training paradigms. While exciting and diverse virtual scenarios can effectively increase patients' motivation for rehabilitation training, the immersive VR environment can also effectively stimulate mirror neurons in the motor cortex of the human brain and promote neural recovery.As a typical human-robot interaction system, the human factors evaluation of the rehabilitation robot only stays in the study of human comfort or the performance of the equipment from a single aspect in the human-robot system. It has not yet involved a comprehensive, systematic, and in-depth study of human-robot adaptability issues, such as safety and comfort, human-robot fit, pathological adaptability of movement patterns, and trajectories from the mapping matching relationship of human-robot characteristics and lacks perfect evaluation indexes and evaluation systems. Therefore, future research should effectively integrate psychological, subjective evaluation, and physiological human response parameters to achieve a comprehensive human-robot suitability evaluation of rehabilitation robots using geometrical and functional characteristics as direct inputs, which is essential for optimizing the overall performance of rehabilitation robots, developing more targeted training methods and maximizing human-robot matching.On the one hand, human factor engineering research for rehabilitation robots is cross-disciplinary research. In human factor engineering research for rehabilitation robots, there is a one-to-many cross-mapping relationship between human factors goals and rehabilitation robot system design. For example, the realization of the same human factors goal is mapped to multiple levels of rehabilitation robot system design, and the design of the same system level is also mapped to various human factors goals. Therefore, the categories of \u201chigh safety implementation,\u201d \u201clightweight and high comfort implementation,\u201d and \u201chigh human-robot interaction implementation\u201d in this study are based on the human factors goals and system levels. The contents of the three classifications will inevitably overlap. On the other hand, these classifications are derived from a series of processes, such as literature search, review, evaluation, and statistics, to arrive at high-frequency terms  safety and control system (software) safety are small dimensional suggestions based on the general direction of \u201csound safety protection mechanism.\u201dThis review provides an exhaustive review of research advances in human factor engineering in rehabilitation robotics through a series of methodological processes, including literature search and screening, quality assessment, and data extraction. This study classifies existing human factors research in the context of the rehabilitation robotics field, using specific human factors goals as the classification criteria. Based on the four categories of human factors goals, the research progress in rehabilitation robotics is systematically sorted, and the benefits of the corresponding technical solutions for the practical use of rehabilitation robots are analyzed in detail. This systematic review focuses on the lack or inadequacy of current research in terms of the connotation categories of human factors goals, and suggestions are made for subsequent human factors research.The application of human factor engineering in rehabilitation robots can guarantee that rehabilitation robots can better replace rehabilitation therapists in providing patients with safe, comfortable, and efficient human-robot interaction training. Under the scope of human factor engineering connotation, this study innovatively provides information on human factors goals and technical solutions related to rehabilitation robots, emphasizing the benefits, challenges, goals, and recommendations for the application of human factors in rehabilitation robots, further improving the scope of human factors research on rehabilitation robots and helping to promote rehabilitation robots to maximize the \u201crobots fits human.\u201dFuture research should give full attention to the characteristics of human factor engineering in the development of rehabilitation robots and explore the solutions of sound safety protection mechanisms, human-robot interaction incentive mechanisms, individual difference adaptation mechanisms, and human-robot suitability evaluation systems from multiple perspectives, for example, from the dual dimensions of institutional design (hardware) safety and control system (software) safety. For example, the safety protection mechanism can be improved from both institutional design (hardware) safety and control system (software) safety. At the same time, through multidisciplinary collaboration and the combination of various research techniques, the hypotheses and solutions can be verified to enhance the safety, usability, ease of use, and inclusiveness of the rehabilitation robot as a new rehabilitation tool and instrument. This is important for developing a harmonious human-robot relationship, enhancing rehabilitated patients' motor function and quality of life, and assisting rehabilitation robots in gradually becoming practical, mature, and finally achieving large-scale application."}
+{"text": "Having a child with autism spectrum disorder can have significant psychological effects on parents. This systematic review summarizes the current state of literature underscoring the impact of autism spectrum disorder (ASD) on parents in Arab countriesA systematic search of seven databases  was performed, which identified 24 studies  that included 3,299 parents or caregivers of children with ASD. These studies were conducted in 10 Arab countries .The majority of the included studies found that ASD has a significant negative impact on the mental health and wellbeing of Arab parents. It was found that parents of children with ASD have a poor quality of life (QoL) and an increased risk of psychological disorders. These findings were in contrast to findings of parents of typically developing children and children with other developmental disorders. Challenges faced by parents of children with ASD were associated with several child- and parent-related factors. The most common coping strategy used by parents was religious coping.The impact of ASD on parents has only recently gained traction among researchers in Arab countries. Despite several knowledge gaps, published studies have provided useful information outlining the impact of ASD on parents in some of these countries. Further research comprising larger random samples and using varied research and data-collection methods is required to understand the multifaceted challenges experienced by parents raising children with ASD in Arab countries. Autism spectrum disorder (ASD) is a lifelong neurodevelopmental disorder that intersects racial, ethnic, and socioeconomic boundaries, and is characterized by persistent impairments in social interactions, verbal and non-verbal communication, as well as restricted and repetitive patterns of behavior, interest, or activities  and the United Kingdom (UK)  of the included articles. Disagreements among the authors were resolved through discussion. Finally, the information was analyzed to identify themes and gaps in the literature and to suggest implications for future research and practice.The authors developed a coding form to assist with the data extraction. The coding form comprised sections designed to obtain information regarding the author(s), publication year, country, purpose, methods, and key findings. Thereafter, the first author used this chart to extract data from the included articles. The second author independently extracted data for 29% (Twenty publications (84%) were quantitative studies, which were mostly cross-sectional, while four publications (16%) were qualitative studies. The samples used in eight of the studies included only mothers , the Depression, Anxiety and Stress Scale (DASS-21), the Perceived Stress Scale (PSS), the 36-Item Short Form Survey (SE-36), the Brief Version of the Coping Orientation to Problems Experienced Inventory (Brief -COPE), the Hospital Anxiety and Depression Scale (HADS), Oberst Caregiver Burden Scale time and difficulty subscales (OCBS-T and OCBS-D), Bakas Caregiving Outcome Scale (OCBS), Zarit Burden Interview (ZBI-12), Patient Health Questionnaire (PHQ)-9, Parenting Stress Index\u2014Short Form (PSI\u2014SF), Ways of Coping Checklist-Revised (WCC-R), Beck's Depression Inventory (BDI), the Standard Recall Short Form 36 (SF-36 v2), Family Stress and Coping Interview-Adapted Scale (FSCI-A), the Satisfaction with Life Scale (SWLS), Interpersonal Support Evaluation List (ISEL), General Health Questionnaire (GHQ-12), and the Positive Reappraisal Coping (PRC) Subscale of the Cognitive Emotion Regulation Questionnaire (CERQ).n = 16, 67%) were conducted between 2017 and 2021.The included studies were all published in the past 10 years and most of these studies (In total, 3,299 parents or caregivers, namely, 2,415 parents or caregivers of children with ASD and 884 controls, were included as participants in these studies. The total number of mothers and fathers of children with ASD was 813 and 327, respectively. Eleven studies comprising 1,275 parents or caregivers of children with ASD did not specify the gender of the parent and referred only to the term \u201cparents\u201d (Kheir et al., Data from studies included in this review revealed that parents raising children with ASD in Arab countries experience considerable stress and strain. Nine studies reported high levels of parental stress (Dababnah and Parish, In six studies, parents raising children with ASD were compared with parents raising children with other disabilities and children without any disabilities (Fido and Al Saad, Factors associated with psychological disorders and the burden experienced by parents of children with ASD were explored in some of the studies. These studies found that several factors were associated with the impact of ASD on parents, including the severity of ASD, social support, economic status, maternal education, financial hardship, marital status, parental age, and the gender of the child (Al-Kandari et al., Limited studies have investigated coping strategies used by parents raising children with ASD in Arab countries. Religious coping was the most common coping strategy found in some of these studies (Dababnah and Parish, Only two studies examined the psychological resilience of parents. Dababnah and Parish  reportedThis systematic review was conducted to identify studies that addressed the impact of ASD on parents in Arab countries. The included studies were reviewed in terms of participants, general characteristics, methodology used, and the main findings. This review found that the impact of ASD on parents and caregivers has only recently gained traction among researchers in some Arab countries. Approximately 80% of the studies included in this review were conducted in Saudi Arabia, Jordan, Egypt, Kuwait, and Bahrain. Most of these studies used cross-sectional study designs and included non-random samples. Furthermore, the study participants of the included studies comprised more mothers than fathers. Moreover, most of the included studies did not distinguish between the different subtypes of ASD.The majority of studies found that ASD has a significant negative impact on the mental health and wellbeing of Arab parents. This finding is consistent with previous studies conducted in several countries, suggesting that parents of children with ASD experience significant levels of stress, depression, and anxiety (Loukisas and Papoudi, Studies exploring the factors associated with stress in parents and caregivers of children with ASD are limited in Arab countries. These factors include the severity of ASD, social support, economic status, maternal education, financial hardship, marital status, parental age, and the gender of the child. Overall, these results are consistent with literature indicating a relationship between the impact of ASD on parents and various characteristics among the child and extended family (Karst and Van Hecke, Furthermore, studies addressing the coping strategies used by parents raising children with ASD are even more limited in Arab countries. Although limited, these studies found that the most common coping strategy used by parents was religious coping followed by acceptance, positive reframing, withdrawal from the community, denial of the ASD diagnosis, increasing social interactions, and accessing information. Moreover, two studies found high levels of resilience in parents and caregivers. However, since the studies are limited, these results should be interpreted with caution. Moreover, most of the studies used self-report questionnaires and lacked a qualitative measurement. As a result, socially desirable responses may have been provided by the parents and caregivers, underscoring the limitations of the data collection methods used.The findings of this systematic review have several important implications for future research in Arab countries. Parents that have a child with ASD are severely impacted (Picardi et al., Furthermore, further research is required to underscore the difference in the experience of the burden associated with raising a child with ASD between mothers and fathers. While several studies have indicated that mothers of children with ASD suffer from increased levels of mental health challenges and burdens compared to fathers, some studies have yielded mixed results (Picardi et al., Moreover, the majority of the studies included in this review used small non-random samples based on a limited number of countries. Consequently, this limited the generalizability of the findings to all parents in the Arab region. Thus, future research including larger random samples is required.Several limitations should be considered when interpreting the findings of the current review. First, only studies published in English in peer-reviewed journals were included in this review. The researchers excluded literature published in the Arabic language due to the severe lack of Arabic electronic databases. Furthermore, conducting a comprehensive manual search would have been a formidable task (Alkhateeb and Alhadidi, This systematic review summarized the results of studies underscoring the impact of ASD on parents in Arab countries. Twenty-four studies met inclusion criteria and most of the included studies were quantitative studies that were conducted within the last 5 years in Saudi Arabia, Jordan, Egypt, Kuwait, and Bahrain. Furthermore, most of the identified studies found that ASD has a significant negative impact on the mental health and wellbeing of Arab parents. Moreover, significant gaps were found in the evidence base, including research on coping strategies and interventions aimed at reducing stress and burden among parents and caregivers. However, this review contributes valuable insights for future studies on parents of children with ASD in Arab countries.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.JA conceptualized the manuscript and research questions, performed the initial article search, and reviewed all articles identified during the search. MH and WM participated in the acquisition of data, analysis, and manuscript drafting. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "A relationship was found between the use of breast milk and infant formula milk and a decrease in the incidence and number of clinical complications caused by hypoxic-ischemic encephalopathy hypoxic-ischemic encephalopathy.To assess the efficacy and safety of breast milk and infant formula milk in terms of reducing of hypoxic-ischemic encephalopathy, the level of morbidity, the severity of damage to brain structures, the time before switching to full-fledged enteral nutrition and the frequency of detecting feeding intolerance in premature infants.Prospective observation of the development of 254 premature babies were treated up to six months of corrected age at the Department of Neurology of Early Growth in 2016-2018. The effect of breast milk and formula milk on neurological status was compared.In comparison, breast milk and formula milk didn\u2019t show any effect on the frequency of severe hypoxic-ischemic encephalopathy , the severity of brain damage. Breast milk showed a statistically significant effect in terms of reducing the average number before switching to full enteral nutrition .Breast milk and formula milk does not affect the frequency of development of hypoxic-ischemic encephalopathy, the severity of brain damage. Breast milk significantly reduces the frequency of feeding intolerance, accelerates the transition to enteral nutrition, reduces the duration of hospitalization in premature infants.No significant relationships."}
+{"text": "Multiple sclerosis (MS) is a chronic inflammatory, demyelinating, and neurodegenerative disease of the central nervous system. This condition is enhanced by stress. In turn, stress symptoms are a risk factor for the onset and progression of MS. However, knowledge about predictors of stress in patients with MS is scarce.This preliminary study aimed to verify whether the number of relapses, fatigue, physical disability (MS characteristics), experiential avoidance and self-judgment (emotion regulation processes) predict stress symptoms in patients diagnosed with MS.A convenience sample of 101 patients diagnosed with MS and without other neurological diseases participated in this study. Participants completed the Depression Scale of the Depression, Anxiety and Stress Scales-21, Analog Fatigue Scale, World Health Organization Disability Assessment Schedule-12, Acceptance and Action Questionnaire-II, and Self-Judgment Subscale of the Self-Compassion Scale.All predictors initially hypothesized and years of education have significant correlations with stress symptoms. Simple linear regression analyses showed that the variables significantly predicted stress symptoms and were, therefore, included in the multiple linear regression model. This model explained 51.8% of the variance of the stress symptoms and showed that years of education, the number of relapses, fatigue, and experiential avoidance significantly predicted those symptoms.The promotion of mental health mental in patients with MS must develop functional skills to deal with stress induced by years of education (possibly responsible for the degree of awareness about MS and its consequences), recurrence of relapses and fatigue, and should minimize emotion regulation strategies focused on experiential avoidance."}
+{"text": "Schizophrenia spectrum disorders are related with prolonged stay in hospital and high cost for treating them. As a consequence, the determination of the factors that affect the duration of hospitalization is essential.The purpose of the study is the determination of the psychosocial characteristics of inpatients in a public psychiatric hospital and their association with the duration of hospitalization.A total of 103 patients with a diagnosis of Schizophrenia (according to ICD-10) participated in the study. The socio demographic characteristics were recorded and the following psychometric tools were used: NEO- Five Factor Inventory, Connor-Davidson Resilience Scale (CD-RISC25), Multidimensional Scale of Perceived Social Support, Multidimensional Scale of Perceived Social Support (MSPSS), Positive and Negative Syndrome Scale (PANSS), Global Assessment of Functioning scale (GAF).All instruments were adapted to greek population. All statistical analysis was performed using SPSS v.25.The median length of hospital stay was 40,7 days. The number of previous admissions , the type of admission (compulsory or voluntary) , the physical restrain , the duration of restrain  as well as the existence of social support networks and in particular social support from friends , seem to affect the duration of hospitalization.The present study underlines the signification of the psychosocial factors that could contribute to the prediction of longer hospitals stays, the planning of appropriate interventions and as a result the reduction of hospital costs."}
+{"text": "The fifth health sector directors\u00b4 policy and planning meeting for the World Health Organization (WHO) regional office for Africa convened to focus on building health system resilience during the COVID-19 pandemic to ensure continuity of essential health services, primary health care (PHC) revitalization, and health system strengthening towards achieving universal health coverage (UHC). In this paper, we present short summaries and experiences shared by 18 countries, for which their practices and outcomes have been documented in this manuscript. These actions are aligned with six key themes: (i) defining and making more essential health services available, (ii) increasing service coverage targeting hard to reach populations, (iii) financial risk protection, (iv) improving user satisfaction with services, (v) improving health security, and (vi) improving coverage with health-related sector services. It is through these shared country experiences that lessons are learned that can influence the region\u00b4s work and advancement to achieve UHC through a PHC approach. Universal health coverage (UHC) is central to the 2030 sustainable development agenda, and the employment of a comprehensive PHC approach is critical for its attainment. Looking to the heightened prominence of UHC, entailing \u201call people have access to the health services they need, when and where they need them, without financial hardship\u201d , COVID-1The influence of piecemeal initiatives remains limited to catapulting action towards attainment of UHC and other health related SDG targets . Such plCase study: country lessons sharedDefining, and making more essential health services availableBurundiPractice: Burundi held a national conference on primary health care revitalization on 16-18 September 2019 to take stock of the implementation of the country\u00b4s commitments related to PHC and the health-related SDGs.Outcomes: the government, in collaboration with its partners, made relevant recommendations with the establishment of a unit to monitor the implementation of these recommendations at the presidential level. These include: focusing on leadership and governance to improve intra, inter, and multi-sectoral coordination, international aid, develop a health in all policies strategy, and others; ensuring sustainable, quality, integrated and person-centred PHC that takes into account the needs of individuals, families, and communities in all policies is relevant; improving health human resources through strengthening training, ensuring equitable distribution of providers across the country, and ensuring the strengthening of mechanisms for the remuneration, motivation, and retention of specialized personnel; and ensuring individual and community empowerment through their participation at all stages of public health interventions, joining the UHC global compact 2030, establishing multi-stakeholder platforms to ensure heightened participation in regular policy dialogue, strengthen the performance of community health worker groups and other community-based associations, and others.CameroonPractice: established the UHC national technical group in 2015 and performance-based financing (PBF) was implemented to improve the coverage and quality of maternal and child health services by purchasing quantity and quality bonuses from health facilities. This has been ongoing since 2012 with 14 pilot demonstration sites in three regions  and implemented in the 10 regions of the country. The focus has largely been on maternal and child health and adolescent health indicators , among other key country indicators. Interventions implemented included: signature of performance contracts; purchase of cover; quality control by higher level stakeholders; and common verification.Outcomes: performance-based financing  found that it improved: maternal and child health vaccination rates (which are now over 17%), direct payment of radiology and laboratory fees , direct payment of illegal service fees , quality of services with respect to the technical platform, and the overall satisfaction of women (improving 8.6% points). However, no improvements were recorded for the quality of care in terms of technical and interpersonal quality.ComorosPractice: Comoros established a vision (2015-2024): \u201can efficient national health system that enables the entire population, particularly the most vulnerable and disadvantaged, to have access to quality health care, with the effective involvement of all public and private actors and stakeholders, in a spirit of solidarity, equality, equity and social justice\u201d. In alignment with this vision, various initiatives and steps have been carried out, including: assessing financial flows; joining the International Health Partnership; receiving the commitment of the head of state; adopting a law establishing health insurance; hosting a capacity-building workshop; undertaking a feasibility study; revising the national pharmaceutical policy; undertaking construction for a 600-bed university hospital centre; providing free services to those with HIV, TB, leprosy and malaria; providing services targeting maternal and neonatal health, children under five years of age, those with neglected tropical diseases, and those with non-communicable diseases; and many others.Current steps for improvement and/or ongoing challenges faced: despite the several actions taken, challenges remain, such as around: strengthening effective coordination and sectoral dialogue mechanisms; weak technical and institutional capacity of the national health information system; implementation of the legal and regulatory provisions of the new health code; development of the public-private partnership; weak mobilization of financing for the implementation of generalized health insurance; and implementation of a national community health strategy in alignment with the Astana declaration.Increasing service coverage targeting hard to reach populationsAlgeriaPractice: undertook a twinning study (instituted and regulated by the government) which sought to: provide care to patients in the southern regions and the highlands whose specialties and/or skills are in short supply; provide training to medical, paramedical, administrative and management staff on a cyclical basis; establish links and networks between institutions to organize the transfer of complex cases for their certified education program (CEP) at the pilot institution level; and avoid the displacement (travel) of patients to university cities, by having the teams move to these populations in these health structures which generally have the necessary equipment.Outcomes: the work resulted in numerous twinning agreements and developments, including: 109 public hospitals, 101 agreements signed, and 45 agreements in the process of being signed. As well, embraced a strong stakeholder communication strategy  and drew commitment from the state with 100% matched funding. However, challenges remain around telemedicine and exchange programs which are increasingly developed in healthcare institutions to support remote local teams in helping patients with diagnosis or CEP and distance education for health professionalsSouth SudanPractice: South Sudan has implemented a community health strengthening strategy, the \u201cboma health strategy\u201d, which trained community health workers in over 55 counties deliver a package of health promotion, disease prevention, and selected curative maternal and child health services.Outcomes: numerous successes have been realized, such as increasing access and demand for health services in the community. Due to the availability of health services within the community, families no longer have to walk long distances to access health services at distant health facilities, nor are they financially impacted, as these services are provided free of charge. Additionally, available health services (including drugs) have improved demand for services, more community members have utilized health services, and drug consumption has increased. Service delivery has been regular with minimal disruption due to continued partner support. However, challenges remain around: the sustainability of free services ; limited ownership of the program by the community and local authority; quality of care ; need to adopt the patient safety strategy and associated development of guidelines and protocols; and select locations not yet fully implementing the service package.Republic of CongoPractice: establishment of the national health policy designed to improve equitable access of the population to packages of essential and quality services. For which the priority is to strengthen PHC, through the revitalization of the health districts to move towards UHC and achieve Sustainable Development Goal (SDG) 3 .Current steps for improvement and/or ongoing challenges faced: an evaluation of WHO support to the ministry of health in the 12 districts in 2020 is underway and will show the evolution of the 18 indicators selected in the monitoring and evaluation plan. However, to-date, 50% of cases of yaws have been detected and notified by the community relays. The indigenous population is concerned about prevention and protection against all forms of violence. To address this, since 2017, 200 indigenous community relays have been trained in order to improve the social demand for the use of health services. Further, health workers in health facilities are aware of the principle and importance of non-discrimination against indigenous people in public and private health care structures. While equitable access to quality essential care and services for vulnerable populations  remains a challenge in the Republic of Congo, the country has embarked on a process of decentralization for the implementation of PHC to address this challenge.Financial risk protectionGhanaPractice: Ghana has worked towards achieving FRP through scaling up various interventions, including: electronic mobile phone renewal of national health information system membership, increased recruitment of community health nurses, improved claims reimbursement time, investment into health facilities at the primary level  and nurses and midwives, supply chain management systems, and reforms .Outcomes: numerous successes have been realized in Ghana, such as: increased active membership in the insurance scheme (over 40.5% of the population), over 60% of beneficiaries in the scheme exempt from fees, improved health service utilization, over 90% of out-patient department services provided at the primary level , reduction in malaria fatality rate (from 0.51% in 2015 to 0.1% in 2019), and others. Additional successes have been realized in four key areas: physical access to essential health services, financial access to essential health services, demand for essential health services, and resilience of health systems.RwandaPractice: Rwanda\u00b4s efforts have focused on financial risk protection (FRP) and have accordingly introduced a Community-Based Health Insurance (CBHI) scheme to improve access to healthcare services and reduce significantly out-of-pocket expenditures, in particular, for the poor and most vulnerable. 90% of the population was covered by health insurance . Interventions that have been scaled up to facilitate improved FRP: insurance coverage for the informal sector through CBHI; moving from flat to stratified premiums according to socio-economic categories; fully subsidizing the poor and most vulnerable population in Ubudehe Category I; access to broadened benefit package over time ; reduced fragmentation of CBHI pooling risks from 31 pools to one single pool; and increased CBHI revenues for financial sustainability.Outcomes: efforts on FRP have resulted in successes in four key domains: physical access to essential health services through improved health worker density, effective referral system, task-shifting of select services at the community-level, establishing non-communicable disease clinics in hospitals and health centres, and ensuring one health post in every administrative cell to reduce travel time; financial access to essential health services though increasing the sources of revenue for CBHI to ensure sustainability, full subsidization of select populations, moving from flat to stratified premiums by socioeconomic status, and others; demand for essential health services has increased, as the utilization rate for CBHI beneficiaries has increased from 0.3 to 2.05 visits per capita (from 1997-99 to 2018/19); and quality of care through pursuing accreditation programs, digitalization of health services through scaling up electronic medical records, improving claim management, and enhancing the pharmaceutical supply chain.MauritaniaPractice: despite efforts to reduce the burden of current health expenditure on households in Mauritania, it remains at 52% of health expenditures as of 2017. Mauritania carried out specific interventions to address this. In 2020, a national program aimed at strengthening social security coverage and direct income for the most vulnerable families, financing: free resuscitation for all; a 55% reduction in the amount of the Obstetrical Package with the extension of the package to all the needs of pregnancy and postpartum and everywhere in public structures; free medical transportation during referrals and treatment of road accidents; and ongoing medical insurance for the poorest households on the social register.Current steps for improvement and/or ongoing challenges faced: a program to improve social supply and support demand was launched by the public authorities in 2020, and is investing more than $45 million over 30 months through nine health projects to help reduce financial and geographic barriers to access to health services for the poorest, accelerate progress towards UHC, regulate the sector, strengthen geographic coverage, and improve health system resilience. This financing should be sustainable after 30 months by being integrated into the public financing of the sector in order to make progress towards UHC. An additional budget line of 7.7 million dollars has been included in the 2020 finance law to reimburse health facilities for expenses incurred for this free service. The anticipated outcomes include: reducing the share of direct payments in current health spending; contributing to the reduction of the poverty rate; and faster progress toward UHC.Sierra LeonePractice: while about 60% of Sierra Leoneans live below the poverty line, over 60% (2018) of total health expenditure come from households (while the government contributes around 4% and donors account for about 36%). As such, Sierra Leone selected to address the high out-of-pocket payments at points of service delivery. Accordingly, the Social Health Insurance Law was passed in 2017 and was to be implemented as a prepayment health insurance scheme with the government providing the major source of funding.Current steps for improvement and/or ongoing challenges faced: various initiatives have been undertaken and are ongoing in Sierra Leone, including: completing the UHC Roadmap to be implemented through the National Health Strategic Plan, to make quality health care accessible to all, everywhere, and at all times; abolishing user fees for pregnant women, lactating mothers, children under five years of age, and Ebola victims under the Free Health Care Initiative; revisiting school health; engaging over 30,000 community health workers, especially in rural and challenged communities; increasing health human resources by 4,000 people (40%) and receiving approval for the recruitment of another 3,000; implementing mandatory social health insurance; engaging the community for partnership and ownership through the revised primary health care handbook; and continued commitment to the global quality of care network.Improving user satisfaction with servicesBurkina FasoPractice: Burkina Faso undertook an evaluation to assess response to needs with attention to select characteristics: dignity; autonomy; confidentiality; prompt decisions; access to social support services; quality of basic amenities; and the choice of health care providers. Based on the analysis carried out, Burkina Faso adopted a reform of its healthcare system based on quality management, the integrated person-centered care approach (ASICP), and patient safety. Specific interventions carried out included: National Strategy Combining Quality, Country Policy and Institutional Assessment (CPIAA), and patient safety; ASICP tools; Regulatory Quality Charter; quality reference; certification/accreditation; community watch; management of adverse care events; traditional medicine interface; and community health.Outcomes: the implementation of these approaches has improved access and demand through free health care, universal health insurance, taking into account the needs of users, the involvement of other profiles in health care , and the involvement of the population in self-management . Health care channels and networks have been created and strengthened. It also made it possible to strengthen the resilience of the health system for continuity of care in insecure areas and in the context of COVID-19. However, Burkina Faso experiences difficulties with the inclusion of people-centered care indicators in the reporting of the national information system.EswatiniPractice: following various client satisfaction surveys, a client satisfaction and feedback mechanism (CSFM) was developed and deployed in 2019 in all health facilities across the country to strengthen capacity of health managers to manage client feedback. It consists of questions in multiple choice form and responses are used by healthcare workers to improve the quality of the healthcare service provision. Between 4th February and 31st August 2020, a total number of 12,677 respondents/customers have given feedback. Outcomes: the CSFM has resulted in numerous outputs, including: customers satisfied with service provision (ranging from 85 to 90% between February to August), availability of drugs (ranging from 64 to 76% in this same period), average waiting time , cleanliness in the health facility (majority of respondents indicating very good and good), and attitude of health care workers (majority of respondents indicating very good). However, some challenges remain, such as some clients who are reluctant to share mobile numbers, no offline version in case of power/network interruptions, need to fund the CSFM through government, insufficient feedback mechanism to the client that submitted the issue of concern, and inadequate practice of \u201cclient first\u201d culture in entire continuum of health care.GabonPractice: Gabon undertook an assessment of user satisfaction levels to identify areas of dissatisfaction, in order to improve health system performance. The evaluation of the service's response to needs involves the following characteristics: dignity, autonomy, confidentiality, prompt decisions, access to social support services, quality of basic amenities, and the choice of health care providers. Gabon elected to focus on the reception of patients in health facilities, as users raised concerns about the quality of basic amenities, confidentiality, and wait times.Outcomes: the Ministry of Health has therefore initiated several reflections to improve the quality and supply of care. As such, numerous interventions were introduced, including: adopting a law that considers the rights of patients, dissemination of this charter to all health facilities, creating centralized services to receive patients, establishing mobile screening units in all health regions, mass awareness campaigns, and others. This required investments made to improving essential health services through access, demand, resilience, and quality of care. Improvements measured included: mass awareness campaigns for several years during the month of October for female cancers has enabled the population to adopt more responsible habits for monitoring their health ; the realization of CAP and socio-anthropological studies on cancer and other pathologies has led to a better understanding of the determinants of the population's demand for care; mobile screening units considerably improved the geographical accessibility of patient care ; and others.ZimbabwePractice: Zimbabwe implemented the first generation of RBF which was aligned with and supportive of the National Health Strategy of 2010-13 by design. This included: user fee removal to improve access and utilization of health services; rebuilding basic standards of health services delivery-capital investment in facilities; strengthening the referral system from primary to secondary; and a strong thrust towards PHC. The RBF was piloted in two front runner districts (Zvishavane and Marondera). After evaluation, it was scaled-up initially to 18 districts in 2012 and all additional 42 districts.Current steps for improvement and/or ongoing challenges faced: the RBF has resulted in: enhanced capacity to accurately report and utilize data, decentralized planning and investments of subsidy earnings for performance improvement at facility and district levels, significant improvements in coverage of maternal and child health indicators , significant improvement in the quality of select antenatal care services, and notable improvements in uptake of vouchers in past quarters. However, not all indicators show relative improvement under RBF. In the future, additional attention should be afforded to: careful selection of indicators to maximize efficiency in spending, revisiting how quality of care is measured and incentivized under RBF, combine RBF with complementary investments in quality improvement, and involve community health workers through a package of indicators and enhance demand through various initiatives.Improving health securityLesothoPractice: the main health security issue/policy problem Lesotho faced amidst COVID-19 was rising co-morbidities and excess mortalities from communicable and non-communicable diseases. This included the: inadequate integration of health system strengthening and health security efforts; inadequate coordination of efforts between ministry of health and partners; low level of community awareness and engagement; and weak information systems.Outcomes: to combat this, Lesotho scaled up interventions to facilitate the protection of populations from health risks  and vaccines). This work was due to successes with multi-stakeholder collaboration , which led to enhancing health security and better targeting susceptible populations.GuineaPractice: Guinea drew on experiences from the Ebola epidemic to make necessary investments to strengthen their health system. Some of these investments include: developing strategic frameworks, plans, and policies; setting up a coordination framework; strengthening community health; significantly increasing the number of health structures; increasing health human resources at the health and community structure level; increasing the health care budget; modernizing the National Health Information System; and strengthening the supply chain and system for health products.Current steps for improvement and/or ongoing challenges faced: strengthening the health system has increased access, demand creation, resilience, and quality of care. However, challenges remain around maintaining the quality of health care and services and early recovery through state ownership.Democratic Republic of the Congo (DRC)Practice: established a strategic framework and undertook a review of essential health services, including: vaccination, maternal and child health, HIV/AIDS, bed net usage, and tuberculosis.Outcomes: determined various successes, including: vaccination coverage is greater than 80% (as of early May 2020), more pregnant women received prenatal care from a trained health professional (88% in 2013 compared to 80% in 2007), childbirth assisted by a health personnel (80% in 2013 compared to 64% in 2007), households had and used impregnated mosquito nets (9% of households in 2007 compared to 70% in 2013), and decreased deaths due to malaria . Challenges remain around: health financial resources are limited and efficient use needs to be improved; frequent and health emergencies related to Ebola virus and the COVID-19 pandemic tend to inhibit progress and the ongoing work and interventions being undertaken to reach UHC; the persistent insecurity in various regions; and health in all policies, as health interventions and progress are dependent on other sectors.SenegalPractice: Senegal incorporated the Primary Health Care Performance Initiative approach , adjusted their targets based on these various ODD as well as their strategic plan, and established a multi-sectorial compliance plan in the response to the COVID-19 pandemic to ensure continuity of health services .Outcomes: the ministry of health and advocacy began improving the quality of healthcare services through various experiences at hospitals and health centers (centres de sant\u00e9 and the laboratories). This initiative is designed to assist and help develop an environment in which health system\u00b4s actors will know what to do in order to provide quality health care, have the competence to do so and that they stay engage with available resources. These numerous initiatives, policies and actions resulted in better health indicator outcomes, including a decrease in maternal mortality  and infant mortality . The ministry of health and advocacy will continue to improve PHC performance through developing more community approaches, multidisciplinary strategies, and using health information.Cross-country experience sharing opportunities provide an opportunity for peer learning, experience sharing and assessment of the direction of systems development amongst countries of the region. It aims to build a common understanding, and knowledge on taking forward the UHC agenda in the region. Across the three six themes highlighted, it has emerged clearly that countries in the region are making progress towards attainment of these goals of improved health security; defining, and making more essential health services available; increasing service coverage targeting hard to reach populations; improving financial risk protection; and improving user satisfaction with services. Against the background of a rapidly changing context of health, driven by the COVID-19 pandemic, countries have all faced significant and un-anticipated challenge to their health system capacities. Together with this, the Astana Declaration on Primary Health Care and the adoption of the SDG 3 Global Action Plan all call for a re-think of the design, focus and monitoring of health systems development in the WHO Region for Africa. The experiences shared have demonstrated that countries are actively rethinking policies and actions to re-align with the current needs of their health sectors to make them fit for purpose in the current and future health environment and in regard of the overall 2030 agenda. Beyond these experiences sharing sessions, WHO AFRO continues to provide technical support to countries in health systems strengthening, through the UHC flagship program, and implementation of the regional framework for primary health care operationalization. One key aspect of this support, particularly in the context of the COIVID-19 pandemic, is the support for strengthening health systems to ensure continuity of essential health services. Tools including health facility assessments for readiness and service capacity have been implemented across the region, as well as support for embedding measures for assessing health service resilience in routine health information systems.The country experiences shared here provide evidence of the importance of lessons sharing to galvanize action and improve knowledge of ongoing work towards the 2030 agenda. Through such platforms, south-south collaboration across countries can be strengthened. While these interventions are not completely exhaustive, this paper has been designed to pull together high-level actions and lessons for policy consideration. Having these ideas presented through the experiences of countries in the African Region, action is within grasp to achieve UHC through PHC."}
+{"text": "Oil is the mainstay revenue for a number of African countries. However, extraction can result in multiple impacts on the health and wellbeing of communities living in oil-rich areas. This review explored evidence of oil industry-related social exclusion on community health and wellbeing on the African continent.We used a systematic approach guided by PRISMA to search six databases for empirical and descriptive sources focused on oil industry impacts, in any African country, between 1960 to 2021. Findings were grouped according to four dimensions of the Social Exclusion Knowledge Network (SEKN) framework: political, social, economic, and cultural.Fifteen articles were identified, of which 13 articles focused on Nigeria; while one focused on Sudan, and one on C\u00f4te d'Ivoire and South Africa. Evidence relating to political aspects of social exclusion encompassed marginalization of indigenous communities through land grabs and unequal representation in political decision making. Limited compensation for environmental damage and livelihood displacement caused by oil-extraction, and high rates of unemployment and poverty were key themes of the economic dimension. Evidence of social impacts included lack of government, or oil-industry investment in social infrastructure; poor health and wellbeing linked to land, air, and water pollution; homelessness and lack of social cohesion. The cultural dimension of social exclusion was comparatively underexplored and only six sources included data collection with indigenous residents, and comparatively more sources were written by non-citizens or non-residents of oil-industry affected areas. Major themes included impacts on collective identity, ways of life and values, particularly where loss of ownership or access to land was experienced.Oil industry activities in African countries are clearly associated with multiple exclusionary impacts. However, the narrow body of empirical research limits understanding of the lived experiences and management of social exclusion by residents of oil-rich areas themselves and is an area deserving of further attention. Oil is among the most impactful of the various extractive industries globally and in Africa. In 2020, 10 African countries were identified as being the top oil producers  despite  of Nigeria over the past 30 years shows that four million barrels of oil spilled between 1991 and 2011 and a further 12,381 spilled between 2011 and 2019 . AlongsiResource extraction activities degrade the environment, reducing residents' ability to farm, fish and live in an unharmed environment , 17. Lossocial exclusion  methodology and was guided by the six steps of the Arksey and O'Malley Framework for conducting a scoping review. This systematic process included identifying research questions, identifying, and selecting all relevant studies, charting the relevant data, collating, summarizing, and reporting the results . This apSix electronic databases were searched for both peer-reviewed papers and gray literature: Scopus, Psyinfo, Pubmed, Medline, Proquest platform and Web of Science. In consultation with a university librarian, search terms were refined, and a search strategy devised that included four rows of search terms focusing on \u201coil industry\u201d and like terms; African countries; \u201csocial exclusion\u201d and like terms, and \u201ccommunity wellbeing\u201d and like terms . Following title and abstract review and application of inclusion and exclusion criteria, 51 full text articles were assessed, and 8 studies met the inclusion criteria. Following manual scanning of reference list seven additional records were identified. A total of 15 records are included in the final review.The identification and screening process is summarized in n = 6) were read in full by the first author; theses and dissertations were evaluated, and specific chapters selected and read based on their relevance to the review topic. Categorization of data in each dimension was initially based on examples of previous applications of the SEKN framework and iteratively adapted in consultation with co-authors as data extraction progressed. Natural overlap in some areas of impact  were discussed and assigned based on consensus. The details of each of the 15 selected studies are summarized in All works, except for theses and dissertations  in Nigeria or elsewhere in Africa between 1960 and 2004.Of the articles identified, 13 of the total of 15 focused on Nigeria , 38, 40 n = 10 of 15) discussed political aspects; more than half the sources also mentioned discussed economic dimensions (n = 11) and social dimensions (n = 9) while comparatively fewer sources identified cultural dimensions of social exclusion (n = 6).Nine studies used qualitative methods , 36\u201339 tn = 8) and published peer reviewed papers (n = 3). Nine of the empirical works used qualitative methods and two used mixed methods. Most empirical works (n = 10) were focused on Nigeria . Empirical works included theses and dissertations  were focused on Nigeria  and published peer reviewed papers (n = 3). Three of the empirical works used mixed methods and six used qualitative methods. Most of the empirical works (n = 8) focused on Nigeria  include lack of basic social infrastructure reduces communities' ability to engage in traditional social activities such as team fishing and family farming , 32, 33.n = 3) and published peer reviewed papers (n = 3). Four of the empirical works used qualitative methods and two used mixed methods. Most of the empirical works focused on Nigeria  framework to explore oil industry social exclusion in Africa.Although the empirical literature identified was not as extensive as expected, sources identified clearly pointed to significant social, economic, political and cultural social exclusion impacts of the oil industry in African countries, but Nigeria in particular. Most of the empirical literature in this review (13 of 15 sources) focused on Nigeria and the Niger Delta Region with one additional source focused on multiple countries including Nigeria. This reflects, in part, the longer history of oil-related industry activities in that country as well as the attention that local conflict over oil industry presence has garnered in recent years. Indeed, at the screening stage of this review we found many articles focused on describing oil-related civil conflict and violence in the Niger Delta region . ConcernOverall, the review highlighted multiple aspects of political, economic, social and cultural exclusion that interact and influence each other to the detriment of local communities. For example, in the political dimension, articles reported how political marginalization and unequal representation of community interests in the Niger Delta region, interacted with unequal wealth sharing and loss of livelihoods in the economic dimension to exacerbate the exclusion of local communities , 34, 39.cultural aspects of social exclusion, which were comparatively under-explored in the sources identified in this study . The review also highlights a need to conduct research that promotes a better understanding the links between cultural aspects of social exclusion and political, social and economic marginalization and of the different types of responses of residents to these experiences of social exclusion.Notwithstanding the evidence of political, social and economic forms of social exclusion, this review revealed that there is still limited empirical work on the topic of social exclusion given the long history of oil extraction on the continent, and in particular, limited research that centers the lived experiences of residents or communities in oil-rich regions. A range of non-empirical sources  not included in the formal review , 43\u201345 mThis review was conducted using thorough and systematic search approach with assistance from a research librarian. Deliberately inclusive date ranges were adopted to try to ensure all potentially relevant literature dating back to the inception of oil-industry activity in Africa was capture. Nonetheless, our primary reliance on academic data bases and restriction to English language sources means it is possible that some studies may not have been identified which could have added further depth of understanding to the topic being explored. Another limitation was the exclusion of literature specifically focused on oil conflict which prevented deeper reflection on the role of oil conflicts themselves on social exclusion and its implications. Furthermore, because of the extensive nature of gray literature, our gray literature search was necessarily targeted, and important sources kept in local repositories that the authors were unaware of may have been missed.Oil industry activities in African countries are clearly associated with multiple exclusionary impacts. This review provides evidence of how oil industry activities affect the political, social, economic, and cultural lives of oil communities' residents in Africa and impact on health and wellbeing. Exploring the perception of the residents toward oil industry-related social exclusion on political, social, economic, and cultural aspect of their lives would enhance the understanding of the impacts of social exclusion on the health and wellbeing of oil communities and thus, help to inform effective policies toward improving inclusion in oil communities in Africa. However, the narrow body of empirical research limits understanding of the lived experiences and management of social exclusion by residents of oil-rich areas themselves and is an area deserving of further attention.The original contributions presented in the study are included in the article/AN, ST, and WL: conceptualized the study. AN: wrote first draft, data search, and extraction. AN, ST, and SD: data analysis. AN, SD, ST, and DO: critical edits. All authors approved final version.This study was conducted with support of a James Cook University Postgraduate Research Scholarship to (AN) and the College of Public Health, Medical and Veterinary Sciences (CPHMVS) Higher Degree by Research Enhancement Scheme (HDRES) Publication Grant.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Falls are the leading preventable cause of death and disability in older adulthood. Subjective experiences of aging could facilitate fall prevention and adaptation to post-falls life. We use data from the 2008-2018 waves of the Health and Retirement Study to follow self-perceptions of aging (SPA), health-domain control (HDC), and physical activity (PA) in 12,000+ adults  to examine trajectories of subjective experiences and health behaviors preceding and following a fall. In total, 57% experienced falling. Both SPA and HDC were lower among fallers. Spline growth models showed that HDC, SPA, and PA significantly decreased over time. Additionally, the rate of decline in HDC and PA increased following the fall. After falling, the protective effect of HDC amplified, while positive SPA dampened change in PA. Our study illustrates the importance of subjective experiences of aging on adaptation and recovery in the context of falling."}
+{"text": "The achievements made by scientists in the fast-growing field of COVID-19 have been exceptional over the last 2 years, leading to major advancements in understanding and managing the new disease, but also transforming the fields of infectious diseases and public health in general. Following the SARS-CoV-2 outbreak and subsequent pandemic, the multi-disciplinary work of researchers worldwide has provided an in depth understanding of COVID-19 pathogenesis, of clinical treatments and outcomes, of models and dynamics governing disease spread, period of infectivity and containment interventions. Immunological research focused on the understanding of acquired immunity, and development of innovative vaccines and effective vaccination schemes, which have greatly improved disease outcomes across the globe. The required rapid processing and dissemination of scientific information would not have been possible if not for the special focus and attention given by scientific journals such as Frontiers in Public Health and Frontiers in Medicine.Following on from the success of the first Frontiers COVID-19 Research Topic, featuring 400 original research articles , a dedicTo provide a backdrop, at the time of the launch of this Research Topic in June 2021, the first wave of the rollout of population-wide SARS-CoV-2 vaccinations with two doses was nearing completion in most European countries, while a severe lack of vaccine availability was still recorded for resource-restricted settings. Following the vaccination successes in Europe and North America a gradual relaxation of public health restrictions was afforded while many countries worldwide were preparing for resurgences. In total, 176 manuscripts were submitted, 83 (47%) of which were accepted. As of August 2022, the special topic achieved approximately 255,000 views and 31,000 article downloads, with readership distributed across the globe. Frontiers made a significant contribution to the timely generation and distribution of peer-reviewed COVID-19 publications as the publisher of this special topic, as well as many other related topics. At the time of writing, the top five most viewed Research Topics on COVID-19 published in Frontiers in Medicine and Frontiers in Public Health , followed by Clinical Management (19), Epidemiology (14). Pathophysiology (12) and Screening Methods (12). The accepted submissions comprised of Original Research (50), Brief Research Report (11), Reviews (8), Opinion (5), Case Report (4), Methods (2), Community Case Study (1), Hypothesis and Theory (1) and Perspective (1).Lu et al.), the Czech Republic , Germany , Portugal , Romania , Saudi Arabia  and the USA . Awareness about the virus transmission within public education settings and protective practices were also examined in the studies by Lordan et al., Middleton et al., Sombetzki et al., and Qin et al., as well as within areas of precarious housing conditions by Zimmermann et al..The understanding and comparison of public health responses has been vital in the design and quick adaptation of effective mitigation strategies. A number of manuscripts shared details of investigations of SARS-CoV-2 transmission patterns and non-pharmaceutical control interventions implemented in defined geographies, such as China . Some of these early data was summarized by the systematic review of Norhayati et al. The perspectives and responses of different communities toward COVID-19 were considered, such as pharmacists being both vaccinated and vaccinators ; of patient groups being vaccinated ; as well of wider communities within specific geographical areas . Related to the safety of vaccination programs and providing a holistic view of the subject within this special topic, were also the studies describing vaccine reactions in the USA, EU (Montano) and China . Finally, the protective properties of breast milk for infants from COVID-19 were outlined in the Hypothesis and Theory study by Quitadamo et al..As population-wide vaccination programs were implemented across the world, a number of studies emerged considering the overall COVID-19 vaccination acceptance, providing survey-based quantitative estimates  and pancreatitis . Various approaches to assessing prognostic factors and indicators were reported. Enocsson et al. looked at soluble urokinase Plasminogen Activator Receptor (suPAR) as a specific prognostic biomediator. On the other hand, Ranard et al., looked at a wider set of indicators reporting different patient endotypes that might be prognostic for COVID-19. One study by Kurban et al., provided examples of simple triage tools that can be used to predict severe disease.The topic of COVID-19 was approached from a clinical management perspective as well, with Masi\u00e1 et al.); the effect of tocilizumab monotherapy on biomediators ; the infusion of umbilical cord mesenchymal stromal cells ; the use of A2 adrenergic receptor agonist ; as well as the case report of blood purification for 5 severely ill patients . Regarding the prevention of symptoms or at least the reduction of symptom severity, studies looked into the supplementation with vitamin D  and zinc (Hardigan and Gordon). The breadth of topics covered demonstrate the multitude of approaches still being considered in the effort to improve the current standard of care for COVID-19, as well as indicating the many clinical specialties involved in those investigations. This aspect of plurality in COVID-19 treatments was captured well in the meta-analysis of randomized control trials by Zhang et al., while W\u00fcstner et al., looked into the clinical evidence informing treatment guidelines, specifically on repurposed drugs for hospitalized patients during the early waves of the COVID-19 pandemic, including for corticosteroids, anticoagulants and other.Among the articles with a primary focus of clinical management, another main area of interest was the evaluation of various new or concomitant therapies with respect to benefits for COVID-19 progression and outcome. Treatments evaluated included the addition of baricitinib to standard care  and specifically, as they relate to chronic fatigue syndrome . Frontiers journals have initiated distinct special topics on COVID-19 sequelae, especially on emotional/mental health and post COVID syndrome assessment , the Ecuadorean army , the Colombian army , South Korea , China , as well as the incidence in cannabis users . In order to complement the picture on symptomatic case identification, Syangtan et al. focused their systematic review on investigating asymptomatic cases. Finally, the study by Yadav et al. described an outbreak of Nipah virus concurrent to COVID-19 in India, reminding that COVID-19 is cumulative to existing pathogen pressures in many countries.Of the articles primarily focused on Epidemiology, disease surveillance remained an area of focus in order to elucidate the geographical, demographic and behavioral distribution of confirmed cases at specific time points (or over time). As such, there were studies regarding COVID-19 epidemiologic patterns in Burkina Faso , Morfeld et al. provided an estimate of the excess mortality attributable to acute COVID-19 and highlighted limitations of routine demographic surveillance systems. The goal of these investigations was to achieve a better understanding of the individuals/groups with increased risk, and thus, prioritizing any public health interventions to decrease the transmission risk to susceptible populations.Accurate disease surveillance remains a cornerstone for healthcare systems for the timely implementation of public health measures as warranted, and for resource and treatment planning relative to available service capacity. Thus, a clear area of interest remained the modeling and testing of prediction models that might be implemented in subsequent waves of the pandemic. These included work by Chua et al.), at schools , at healthcare facilities . As with any diagnostics, a greater than acceptable threshold of false-positive or false-negative outcome, can cause considerable damage both at individual and public health levels. Therefore, a number of studies focused on the evaluation of the individual performance of such test and/or methodologies . The investigation of saliva as a suitable detection fluid was discussed by Pierri et al.; while the implementation of ELISA-based seroprevalence for the understanding of asymptomatic transmission levels was considered by the studies of Sherman et al., and Breedon et al..Asymptomatic and pre-symptomatic transmission of SARS-CoV-2 has introduced a greater degree of difficulty and uncertainty for monitoring the spread of the infection into new clusters. Thus, population-wide or high-risk group screening policies have been implemented at various scales in many countries. The studies included in this special topic describe the implementation of such screening policies at national borders (Hayes et al. provided a scoping review of over 100 persistent symptoms of long COVID-19; while the study by Cheng et al. described a text clustering method to identify symptom clustering. The systematic review by Sodeifian et al. looked into the drug-induced liver injury in COVID-19 patients; and Zhang et al. investigated liver fibrosis scores and clinical outcomes in COVID-19 patients. There were two Opinion papers in this special topic, one by Kozlakidis, considering the relative lack of evidence of genomic recombination for SARS-CoV-2; and another by Dubina, considering a potential non-immune prophylaxis against COVID-19 by targeting tolerance for Angiotensin II.Understanding the pathophysiology of COVID-19 and its many clinical manifestations is crucial in dealing with the severe forms of the disease, identifying individuals with increased risk, and taking timely action toward development and/or implementation of appropriate treatments. Teshome et al. investigated the impact of vitamin D on COVID-19 infection; while Chen et al. investigated the relationship between plasma vitamin C and COVID-19 susceptibility and severity. The investigation of such relationships allows the deeper understanding of molecular mechanisms and their link to clinical outcomes. The relationship between platelet count and COVID-19 mortality was investigated by Yang et al.; while another relationship, between cellular and humoral immune responses after two doses of vaccination were studied by Mangia et al. The brief research report by Jimah et al. focused on the monitoring of COVID-19 positive pregnant women. Finally, Holm-Jacobsen et al. investigated the clinical implications of rectal SARS-CoV-2 shedding in Danish patients.The link between vitamin intake and COVID-19 clinical outcomes remains a focal point of research. To this end the systematic review by As the COVID-19 pandemic continues and as the SARS-CoV-2 virus continues to evolve and produce a greater number of variants, it is likely that the case numbers and hospital admissions will persist their fluctuations globally. Thus, it is not surprising that epidemiological studies continue to feature strongly in the published scientific literature as understanding of the changing dynamics of COVID-19 remains a public health priority. To this end, the greater emphasis on public perceptions, attitudes and behaviors is a welcome development, further strengthening public health responses and gradually involving an active participation of \u201ccitizen scientists\u201d as advocated previously .Building on understanding the pathophysiology and epidemiology of the disease, the development of efficacious vaccines and treatments have made a clear difference in addressing severe forms of the disease and mitigating its public health impact. More contagious and/or virulent variants of the virus that are able to evade acquired immunity may continuously emerge, and their widespread dissemination is of concern in the near future. Novel and/or improved virus screening methods, therapeutics and vaccines are likely to remain key tools toward pandemic mitigation. The cumulative burden of \u201clong COVID\u201d sequelae as well as psychological/psychiatric impact of the disease and its control measures are crucial topics to study for guiding long term medical and public health management. Therefore, concerted research efforts on current topics remain a crucial part of the continued fight against COVID-19.ZK compiled/wrote the first draft. MS contributed to the outline. Both authors reviewed and edited for final revisions. All authors approved the final version for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "The process of recovery of mental reactions in children after acute traumatic brain injury is determined by complex methods with an interdisciplinary approach. Studies of emotional, communicative and behavioral reactions are based on an assessment by a psychiatrist and a teacher-defectologist.To study mental reactions and identify predictors of positive recovery of consciousness after acute brain injury in children in early rehabilitation.48 children (14\u201336 months) with acute severe traumatic brain injury who were admitted for treatment and rehabilitation (in CRIEPST). Methods: psychiatric and pedagogical examinations; also - neuroimaging data and others.Three groups of children were identified, depending on the different severity of emotional, communicative and behavioral indicators: Group 1 (11%): The level of consciousness is minimal positive. Reactions: stable gaze fixation; emotional reaction to sound (smile) and the face of an adult; short-term tracking of the gaze of the object; the ability to touch an object and hold it; sits himself. Group 2 (33%): The level of consciousness is minimal positive / negative, with an advantage of positive. Reactions: unstable gaze fixation; emotional reaction and involuntary movements to sound; reflex seizure of an object; sits with support. Group 3 (56%): The level of consciousness is minimal negative. Reactions: no emotional reactions, low motor and sensorimotor activity.Predictors of emotional-communicative and behavioral indicators of recovery of the level of consciousness were identified: sensory and motor, cognitive and socially-oriented. These predictors are the basis for choosing a rehabilitation program with interdisciplinary support and a treatment strategy."}
+{"text": "Dear Editor,Since the beginning of the new coronavirus SARS-CoV-2) pandemic, several cases of extrapulmonary involvement have been reported, including cardiovascular, gastrointestinal, neurological, and cutaneous manifestations. A wide variety of dermatological conditions related to COVID-19 infection have been reported; pandemic4A 56-year-old male patient complained of pruritic lesions that appeared on his lower limbs six months before. He mentioned that the lesions appeared approximately one week after the onset of COVID-19 infection symptoms, which was confirmed by RT-PCR. The patient had a mild respiratory clinical picture, without the need for hospitalization, and used ivermectin and hydroxychloroquine, prescribed at the service where he was originally treated. After the rash appeared, he used oral fluconazole and topical ketoconazole, with no improvement. The patient had a history of HIV infection, with an undetectable viral load for several years, without other comorbidities and with negative serology for syphilis, hepatitis B, and hepatitis C. He was undergoing regular treatment with lamivudine (3TC), tenofovir disoproxil fumarate (TDF) and dolutegravir (DTG), without recent changes in medications.On dermatological examination, the lesions were clinically and dermoscopically compatible with LP . He had Lichen planus is an immune-mediated dermatosis of unknown cause, which affects less than 1% of the population, mainly middle-aged adults, and may affect the skin, hair, nails, and mucous membranes.4A possible association between HIV infection and LP has already been reported. In the present case, we consider that the LP was triggered by the COVID-19 infection, since the patient had been diagnosed with HIV 24 years before, without changes in the medications of chronic use, with the appearance of lichenoid lesions timely associated with COVID-19. SARS-CoV-2 infection can stimulate cytotoxicity by TCD8+ lymphocytes and Th17 cells, changes that also participate in the pathogenesis of LP, and this can persist even after the resolution of the triggering viral infection.We report a case of annular LP that appeared one week after infection with COVID-19, suggesting an association between the diseases. There is a scarcity of reports of lichenoid lesions associated with COVID-19, with only one other report of the rare LP annularis variant triggered by SARS-CoV-2 infection having been identified.4None declared.Laura Murari Mondadori: Design and planning of the study; data collection, or data analysis and interpretation; statistical analysis; drafting and editing of the manuscript or critical review of important intellectual content; collection, analysis, and interpretation of data; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature.Helena Barbosa Lug\u00e3o: Design and planning of the study; data collection, or data analysis and interpretation; statistical analysis; drafting and editing of the manuscript or critical review of important intellectual content; collection, analysis, and interpretation of data; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; approval of the final version of the manuscript.Fernanda Andr\u00e9 Martins Cruz Perecin: Design and planning of the study; data collection, or data analysis and interpretation; statistical analysis; drafting and editing of the manuscript or critical review of important intellectual content; collection, analysis, and interpretation of data; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; approval of the final version of the manuscript.Marco Andrey Cipriani Frade: Design and planning of the study; data collection, or data analysis and interpretation; drafting and editing of the manuscript or critical review of important intellectual content; collection, analysis, and interpretation of data; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; approval of the final version of the manuscript.None declared."}
+{"text": "Editorial on the Research TopicPeriod povertyEach month, half of the world's female population, estimated at 1.9 billion individuals, experience menstruation . MenstruThe American Medical Women's Association defines period poverty as the lack of accessibility or affordability of menstrual hygiene tools and educational material, such as sanitary products, washing facilities, and waste management . The terPeriod poverty does not only affect menstruating people in lower income countries; it also affects them in higher income countries . It is eSwe et al.). These findings were similar to those highlighted in the systematic review by Patel et al. on period poverty in lower and middle income countries, which included three emerging themes:1.Availability and affordability of menstrual products, and accessibility to water, sanitation and health (WASH) services,2.Availability of support system and coping with \u201cperiod poverty,\u201d and3.Gender dimensions of menstrual hygiene management.Age appropriate education, using innovative approaches such as interpersonal practical guidance (IPG) as face-to-face communication and mediated practical guidance (MPG) as social and behavior change communication (SBCC), was successful in improving menstrual health and hygiene management (MHHM) knowledge, attitudes, and practices in India, while addressing the existing menstrual health challenges in similar settings . Another country that suffered drastically from the consequences of period poverty amidst an economic recession and political turmoil was Lebanon .The gap in the literature and the lack of data on period poverty is a continuous challenge to measure its deteriorating impact on women's health. The following special issue aimed to address this gap by including a diverse set of qualitative, cross-sectional, and review studies exploring the menstrual experiences of girls and women from different regions across the world. For instance, the menstrual health challenges reported by adolescent girls in Myanmar ranged from access to information and social support, to behavioral restrictions, stigma surrounding menstruation, and difficulties managing menstrual bleeding and pain . Similarly, adults working with U.S-based communities of color revealed tension between school responsibility and family authority in providing menstruation and puberty education in schools, school- and teacher-related delivery challenges, and inadequate and disengaging menstruation and puberty content .When it comes to the United States, low-income menstruating adults were seen to be disproportionately affected by period poverty during the COVID-19 pandemic because the pandemic acted as a barrier to period supplies and an underlying factor for missing work due to the lack of such products (Social, physical, and mental issues imposed by period poverty and encountered by females globally are inhumane and require immediate attention of policymakers and healthcare professionals to attain positive and sustainable menstruation outcomes. Findings from this issue will provide the readers with an overview about the current situation of period poverty in high-income and low-income countries. It will also guide research experts in the design and implementation of interventions seeking to address structural, social, and individual factors among populations impacted by such a phenomenon."}
+{"text": "Zoonotic diseases account for at least 60% of all infectious diseases and no less than two-thirds of new emerging ones, which underlines the importance of monitoring them as early as possible. Understanding the nature of the animal-to-human transmission of zoonotic diseases is a fundamental requirement for their effective anticipation and control. The SARS-CoV-2 pandemic, and more recently, the monkeypox epidemic, have revealed our limited preparedness against a diversity of emerging and re-emerging pathogens. There are different modes of transmission of zoonotic diseases: direct or indirect contacts, vector-borne, or environmental , making their monitoring more complex. Effective control of zoonotic diseases requires early detection of the source of the disease and the factors that contribute to its spread. Combining wildlife, farm animal, and domestic animal health monitoring with human health monitoring can greatly reduce the risk of major epidemics or pandemics of zoonotic origin.The changes in our environment caused mainly by human activity and the evolution of human\u2013animal interactions are and will undoubtedly be responsible for several new health crises. These crises will be manifested in particular by an increase in the frequency and intensity of epidemics and epizootics. Numerous factors favor the increase in interactions between humans, animals, and their environment, such as the increase in animal and human population movements, or the demographic increase in the human population and its expansion into new geographical areas (ultimately increasing human/wildlife interactions). Over half of known human pathogenic diseases can be aggravated by climate change, including warming, precipitation, and floods . These pThe links and analogies between animal health and human health have been known since Antiquity, particularly with the transposition of anatomical knowledge from animals (particularly from dissections) to humans. This notion was expressed more concretely in the mid-1800s by a Prussian pathologist, Rudolf Virchow, who emphasized the lack of distinction between animal and human medicine. The \u201cOne Health\u201d concept has since developed by basing the study of these issues on multidisciplinary and multisectoral approaches . Its genEscherichia coli), and parasites  [In this Special Issue, we invite colleagues to submit original research articles and scientific reviews to assemble a collection of papers highlighting the progress in our understanding of all aspects related to surveillance and control of zoonotic diseases, including (1) the development of new diagnostic tools, (2) outbreak investigation and surveillance programs of emerging pathogens , and 3) understanding the mechanisms of pathogen emergence. The first 10 papers published in this Special Issue address topics related to viruses , bacteria ( understasmodium) ,7,8,9,10"}
+{"text": "Beach waste is an important pollutant in the Bohai Sea and coastal cities around the Bohai Sea and has raised many social and environmental concerns in China. The semi-closed characteristics of the Bohai Sea, the well-developed tourism, the special industrial structure and residents\u2019 living habits endow the beach waste around Bohai sea with a unique character that should be explored. This study investigated changes in the sources and composition of beach waste in coastal cities around the Bohai Sea of China during the tourist peak and off-peak seasons. Beach waste from twenty beaches in thirteen coastal cities around the Bohai Sea was sampled and analyzed in March and August 2021, respectively. The results showed that beach waste around the Bohai Sea was characterized by large quantities and small weights and was greatly affected by human coastal activities. The sources and composition of beach waste from different coasts and different seasons varied, whereas the overall trend was consistent. In terms of composition, beach waste in both the tourist peak season and off-peak season was mainly composed of plastics, fabrics and paper, which accounted for more than 70% of the total in weight. Meanwhile, the proportion of plastics in the total quantity of beach waste was greatest (maximum of up to 71%) and exhibited seasonal fluctuations, trending higher in the tourist peak season than in the off-peak season. In contrast, trends in the proportion of paper and fabrics in the total quantity and total weight of beach waste were relatively stable in different seasons. In terms of sources, beach waste mainly derived from human coastal activities, the proportion of which in the total quantity of beach waste in the tourist peak season reached 70.55% and was 11% higher than that in the tourist off-peak season. Shipping/fishing activities were the second largest source of beach waste, and their proportion in the total quantity of beach waste in the tourist peak season was 5% lower than that in the tourist off-peak season, as the tourist peak season around the Bohai Sea coincides exactly with the fishing moratorium. The quantity of smoking-related waste only accounted for 9.35% and 7.73% of beach waste in the tourist peak and off-peak seasons, respectively. The special semi-enclosed structure of the Bohai gulf, surrounded by land on three sides, aggravated the accumulation of beach waste on the coast. Source reduction and classified recovery, collaborative management of marine waste and beach waste, and joint prevention and control mechanisms of three provinces  and one municipality (Tianjin) were suggested for comprehensive management of beach waste in coastal cities around the Bohai Sea of China. This study provided valuable information for beach waste management in coastal cities around the Bohai Sea of China. The world\u2019s oceans have been overexploited. Human activities are greatly affecting the marine and coastal environment and coastal ecosystems . Large qBeach waste is very complex and mainly composed of plastics, woods, metals, glass, rubber, clothing, foam and other materials ,12. Beac2, a mainland coastline of 2796 km, and an average water depth of 18 m. There are about forty rivers along its coast, including the Yellow River, Liaohe River and Haihe River. The Circum-Bohai-Sea region is an important strategic region for the coordinated development of Beijing, Tianjin and Hebei province in China, a significant ecological region for marine biodiversity protection as well as a vital functional region for the lives of local residents. Liaoning, Hebei, Shandong and Tianjin surround the Bohai sea, and their total gross marine output reached CNY 2621.9 billion, accounting for 31.4% of the national gross marine output of China. For decades, the Bohai Sea has paid a great price in its resources and environment to support the economic development around the Bohai region and has become the most degraded coastal area in China [Bohai Sea is the sole semi-closed marginal sea in China, with a sea area of about 78,000 kmin China . In partin China .At present, most research studies concerning the environment around the Bohai Sea region have focused on its seawater quality , marine 2, accounting for 1.63% of the total territorial sea area of China. The Bohai Sea includes Liaodong Bay, Bohai Bay, Laizhou Bay, Central Sea Basin and Bohai Bay. It is surrounded by thirteen coastal cities  belonging to Liaoning, Hebei, Tianjin, and Shandong provinces. The Bohai Sea has a unique natural ecology, obvious geographical advantages and a prominent strategic position. Meanwhile, it is confronted with many challenges, including unstable environmental quality, a degraded ecosystem and high environmental risks. The Bohai Sea is a major ocean dumping area, accounting for 20.3% of the total amount of marine waste dumped in China, as shown in The Bohai Sea is a semi-closed, shallow sea located deep inside the Chinese mainland , as shown in The sampling points are shown in After collection, samples of beach waste from each sampling point during the tourist peak and off-peak seasons were sorted, counted and weighed, respectively. The composition of these beach waste samples was divided into nine categories: plastic, wood products, paper, metal, polystyrene plastic foam, rubber, fabric, glass, and others. According to the Northwest Pacific Organization, the sources of beach waste were divided into five categories : human cThe composition of beach waste obtained from twenty beaches in thirteen coastal cities around the Bohai Sea of China during the tourist off-peak and peak seasons is shown in Following plastics, paper waste and fabrics were also major components of beach waste around the Bohai Sea. In terms of average quantity, the proportion of waste paper in beach waste from twenty beaches in the tourist off-peak and peak season reached 18.32% and 17.97%, respectively. These waste paper components in beach waste mainly included food packaging, towels and cigarette boxes discarded by tourists. Meanwhile, in terms of average weight, the proportion of fabrics in the tourist off-peak and peak season remained relatively stable, reaching 28.65% and 27.28%, respectively. Polystyrene foam is a key material in fishing net buoys and life vests and is often found in beach waste. The percentages of polystyrene foam in beach waste from twenty beaches in thirteen coastal cities were highly variable and random. Among them, the percentages of polystyrene foam by weight and quantity were highest in Dongjiang Construction and Development Memorial Park of Tianjin, reaching 21.40% and 24.44% in the tourist off-peak season and 10.81% and 34.15% in the tourist peak season, respectively. The perniciousness of polystyrene foams to the marine environment and marine organisms is not less than that of plastic waste. The polystyrene foams are broken up and disintegrated into many pieces of micro-plastic by mechanical (wind and wave), biological (microorganisms) and chemical (ultraviolet radiation) degradation . Waste wThe sources of beach waste in samples obtained from twenty beaches in thirteen coastal cities around the Bohai Sea of China during the tourist off-peak and peak seasons are presented in The second greatest source of beach waste was shipping/fishing activity. This mainly included buoys, ropes and fishing nets. By quantity and weight, the average proportions of beach waste from shipping/fishing activity on these twenty beaches during the tourist off-peak season reached 19.12% and 27.75%, respectively, which were higher than their levels during the tourist peak season . One reason was that the tourist peak season between July to September for coastal cities around Bohai Sea coincided exactly with the seasonal fishing moratorium on the Bohai Sea. At that time, shipping/fishing activities were greatly decreased, which reduced their contribution as a source of beach waste. Meanwhile, the frequency of beach pollution cleanup operations was much higher during the tourist peak season than during the tourist off-peak season. These buoys, ropes and fishing nets washed ashore by the seawater would not stay on the beach for very long before they were cleaned up during the tourist peak season. Moreover, during the lengthy tourist off-peak season, a great deal of marine waste (including many buoys and fishing nets) would be washed ashore by strong winds, waves and ocean currents.Counting as the third greatest source of beach waste were other discarded materials, including construction waste and other debris from unidentifiable sources. In terms of average quantity and weight, the proportions of other discarded materials in beach waste during the tourist off-peak season on these twenty sampled beaches were also higher than their levels during the tourist peak season. Many waste materials were degraded into unidentified debris by waves. In particular, by weight, the proportions of other discarded materials in total beach waste at Panjin Jinbotan Beach, TDC&DM Park, Binzhou Shell Island and Yantai No. 1 Bathing Beach even reached above 40% during the tourist off-peak season. From 2, and the average density was 1849 kg/km2. It was reported that plastic waste (75.9%) was the overwhelming type of beach waste. China has been highly attentive the issue of marine waste pollution and has already issued a series of relevant laws, regulations and documents concerning marine environmental protection and marine waste management, as shown in Currently, marine and beach waste are important pollutants for the Bohai Sea and its surrounding coastal cities and have spurred many social and environmental concerns in China. Due to the semi-closed nature of the Bohai Sea and its low water exchange ability with the outer sea, marine waste and beach waste are exchanged only within a certain range of time and space. Thus, marine and beach waste should be taken into account together. According to the 2021 China Marine Ecological Environment Status Bulletin , the ave2/cycle; that was the lowest in four major sea areas  of China [The quantitative proportions of different components and sources of beach waste on twenty beaches during the tourist off-peak and peak seasons were averaged to approximate the beach waste situation for the whole year in these thirteen coastal cities around the Bohai Sea of China, as shown in of China . In receAs shown in The waste scattered on beaches has a major negative impact on the natural landscape and the ecological environment of the coastal region. The high mobility of beach and marine waste materials due to frequent winds, waves, ocean currents and tsunami has further magnified their perniciousness.In particular, the Bohai Sea is the sole semi-closed marginal sea in China. There are about forty rivers along its coast, including the Yellow River, Liaohe River and Haihe River. The Bohai Sea is surrounded by Liaoning, Hebei, Shandong and Tianjin and is a vital functional region for the lives of local residents as well as a significant ecological region for marine biodiversity protection. The semi-closed nature of the Bohai Sea, the well-developed tourism, the special industrial structure and residents\u2019 living habits endow the beach waste around Bohai Sea with a unique character. In order to control the beach and marine waste pollution of coastal cities around the Bohai Sea, a series of suggestions are proposed as follows:(1) Source reduction and classified recovery. The production, sale and use of disposable plastic products should be further restricted. Reusable tools and products should be encouraged in shipping and fishing activities. The behaviors of individuals (tourists and marine industry practitioners) and relevant enterprises must be well-regulated. The random waste dumping into the sea and on beaches must be strictly prohibited. The identification of the sources, components and distribution of beach waste around the Bohai Sea should be well-investigated. The classified recovery of beach waste is indispensable. Valuable components and materials in beach waste should be recycled.(2) Collaborative management of marine waste and beach waste. Marine waste and beach waste will exchange positions within a certain range of time and space. Beach waste management should also be incorporated into the comprehensive governance of the Bohai Sea. Laws and regulations concerning collaborative management of marine waste and beach waste should be established. Deeper insights into the whole life cycle of beach waste combined with marine waste should be developed.(3) Joint prevention and control mechanisms in three provinces  and one municipality (Tianjin). The Bohai Sea is surrounded by Liaoning, Hebei, Shandong and Tianjin. These four regions must keep pace in the comprehensive governance of marine waste and beach waste in the Bohai Sea. The joint prevention and control mechanisms of the three provinces and one municipality for marine waste and beach waste pollution are indispensable. With the efforts of the government, enterprises, institutions, environmental protection organizations and the public, the three provinces and one municipality will form a leading force for beach waste prevention and control.Beach waste around the Bohai Sea was characterized by large quantities of small, lightweight materials and was greatly affected by human coastal activities. The sources and components of beach waste from different coasts and in different seasons were varied, whereas the overall trend was consistent. In terms of composition, beach waste in both the tourist peak season and off-peak season mainly of plastics, fabrics and paper, which together accounted for more than 70% of the total in weight. Meanwhile, the proportion of plastics in the total quantity of beach waste was the greatest (up to a maximum of 71%) and exhibited seasonal fluctuations that were higher in the tourist peak season than in the tourist off-peak season. In contrast, the percentages of paper and fabrics in the total quantity and total weight of beach waste maintained relatively stable trends across different seasons. In terms of sources, beach waste was mainly derived from human coastal activities, which accounted for 70.55% of the total quantity of beach waste during the tourist peak season, 11% higher than that in the tourist off-peak season. Shipping/fishing activities were the second largest source of beach waste, and their share of the total quantity of beach waste during the tourist peak season was 5% lower than that during the tourist off-peak season, as the tourist peak season around the Bohai Sea coincides closely with the seasonal fishing moratorium. Smoking-related waste only accounted for 9.35% and 7.73% of the quantity of beach waste during the tourist peak and off-peak seasons, respectively. The special semi-enclosed structure of the Bohai gulf surrounded by land on three sides aggravated the accumulation of beach waste on the coast. Source reduction and classified recovery, collaborative management of marine waste and beach waste, and joint prevention and control mechanisms of the three provinces  and one municipality (Tianjin) were suggested for comprehensive governance of beach waste in coastal cities around the Bohai Sea. Although this study provided valuable information concerning sources and components of beach waste in coastal cities around the Bohai Sea, the physical, chemical and biochemical properties of beach waste are still not clear. In the future, the characteristics of beach waste should be further investigated, and the treatment technologies should be taken into consideration."}
+{"text": "Art-therapy  is a promising and acceptable management strategy of eating disorders (ED). It has the potential to improve well-being and therapeutic alliance, targeting psychological dimensions of ED, and dealing with difficulties of expression and rationalization of patients. Nevertheless, the efficacy of this approach is difficult to evaluate because of the lack of studies in this area.We sought to provide an overview on the efficacy of art therapy in the management of ED, by a systematic review of all controlled trials using art therapy on patients with ED.This systematic review included all controlled trials using art-therapy on a population of adolescent and adult patients with ED. The effect of art therapy on clinical indicators such as anthropometric variables, symptoms and dimensions of ED was evaluated.Of the 1286 screened records, only four respected inclusion criteria. These four trials evaluated plastic art therapy, music therapy, writing therapy, and dance-movement therapy. A large number of bias and strong heterogeneity of inclusion criteria, techniques and variables prevented any attempt of quantitative synthesis. Music therapy appeared to have a significant effect on post-prandial anxiety, while dance-movement therapy showed an effect on body dissatisfaction.The generalizability of the results found is weakened by the high heterogeneity of trials. Replication studies and a rigorous methodologies are necessary for more reliable conclusions. Art therapy could help improving some specific dimensions of ED.No significant relationships."}
+{"text": "Explosive growth in computing power has increased by orders of magnitude the complexity of data structures and the number of analyses that may be performed per unit time. Contemporary gerontology utilizes diverse data ranging from continuous longitudinal assessments (e.g. motion capture) to complex single-timepoint assessments (e.g. bioimages) to systems-level administrative descriptions of the healthcare delivery environment. Paradoxically, this abundance of resources presents a considerable challenge, as the availability of information threatens to overwhelm mechanistic models of aging supportive of intervention development. To inform precision medicine, gerontological biostatistics therefore embraces the opportunity of collaborating with allied quantitative disciplines to bolster the coherence, reproducibility, and generalizability of findings. This presentation will demonstrate the salient advantages of such interdisciplinary collaborations using the example of design and analysis of an intensely longitudinal study of wearable and environmental sensors, conducted with teams in exercise science and architectural design."}
+{"text": "Dear Editor,Cutaneous Pseudolymphoma (CPL) refers to reactive lymphoid proliferation simulating cutaneous lymphomas. CPL may occur in response to many kinds of foreign antigens or factors, such as injected substances, tattoos, arthropod bites, and so on.A 31-year-old man presented with a 3-month history of two asymptomatic subcutaneous nodules on his back. He was otherwise healthy and there was no history of preceding illness, injected substances, vaccination, or insect bite. Physical examination revealed two coin-sized subcutaneous nodules palpable on his back . The skiCutaneous Pseudolymphoma (CPL) is not an uncommon condition, which considers a group of benign cutaneous lymphoproliferative disorders and very rarely progresses to lymphoma. The clinical presentation of CPL has a wide spectrum. The most common clinical manifestations are red to violaceous nodules, papules, or plaques on the exposed areas, especially on the face and neck. Subcutaneous nodules, as in our case, are the uncommon presentation of CPL, which have been described in several cases occurring secondary to feline scratches or injection of vaccines.None declared.Ying Wang: Approval of final version of the manuscript; conception and planning of the study; drafting and editing of the manuscript.Sitong Li: Approval of final version of the manuscript; participation in the design of the study.Yanping Bai: Approval of final version of the manuscript; conception and planning of the study.Zhancai Zheng: Approval of final version of the manuscript; conception and planning of the study; drafting and editing of the manuscript; critical review of the literature; critical review of the manuscript.None declared."}
+{"text": "The COVID-19 pandemic caused dilemmas for the most vulnerable populations around the world. This article describes the gendered effects of the pandemic on Ugandan women\u2019s rights and wellbeing and provides suggestions for local and international practice. Mandatory lockdowns and movement restrictions created negative implications for women\u2019s attainment of economic, social, cultural, political and civil rights and intensified pre-existing gender inequalities between women and men. The findings of intensified gender inequities, gender-based violence, sexual abuse, scanty access to reproductive health services and social justice, and barriers to participation in education, employment and politics indicate that response measures were not aligned with the government\u2019s legal and policy framework for addressing gender inequities. This research indicates that governments, civil society organisations and the international community must undertake proper gender analysis in designing response measures and guidelines not only for COVID-19 but also in other emergencies. All response measures during emergencies must be coordinated, monitored and evaluated to ensure efficient and effective protection of the vulnerable and conformity to human rights standards. The Sustainable Development Goals (SDGs)\u2014a plan to achieve 17 goals with 169 targets in 15\u00a0years evolved in 2015. These cover all aspects to transform lives. The goals provide hope that the world can transcend biting poverty, food insecurity, unhealthy lives and discriminatory gender practices and achieve equality and women empowerment and sustainable and inclusive development. The corona virus disease (COVID-19) pandemic emerged while international partners were struggling to redress imbalances as set out in the SDG plan to secure good futures for their populations. This global enemy was declared a public health emergency by the World Health Organisation (WHO) on 30 January 2020.In March 2020, Uganda reported its first confirmed COVID-19 case and cases gradually increased to 163,301 as of March 2022  Women, Based on a comprehensive literature review, this article describes the impact of the pandemic on women\u2019s rights and wellbeing. It explains the recurrence of gendered inequalities from the COVID-19 crisis. This research contributes to global attempts for strengthening women\u2019s capacities and rights. It is expected that national response teams across sectors will consider the gendered implications of COVID-19 and put in place a broad and gender-responsive COVID-19 prevention and response plan to reduce conditions of vulnerability and strengthen resilience across various disadvantaged groups.The article begins with a brief description of methods and provides the legal and policy context of the rights and management of COVID-19 in Uganda. The second part analyses the gendered effects of COVID-19 on women\u2019s rights and wellbeing under six themes: the implications of COVID on women\u2019s economic rights, COVID-19 and its effects on women\u2019s unpaid work, COVID-19 and women\u2019s health needs, COVID-19 and gender-based violence (GBV), COVID-19 implications on the young women\u2019s right to education and COVID-19, discrimination and the legal protection of women\u2019s rights. The final section provides local and international implications for practice.Uganda has made some advancements in the achievement of women and girls\u2019 rights in the political, economic and social spheres. For instance, the Universal Primary Education (UPE) programme increased the overall enrolment of women from 2.7 million in 1995 when it was rolled out to the recent 4. 4 million in 2017 (Uganda Bureau of Statistics (UBOS), Women have progressively become visible in leadership and public decision-making. The Ugandan Constitution provides for the reservation of one seat for a woman member of parliament for every district and at least one-third of local council seats are reserved for women. Women's reproductive health packages have also been promoted by the government and women\u2019s organisations and this facilitates their participation in the productive economy and ability to meet their survival needs. For example, the total fertility rate declined from seven to five children per woman between 1995 and 2016 UBOS, .Despite these achievements, research indicates high school dropout rates for girls in primary and secondary education, increased gender disparities in enrolment and completion rates and more women than men in low-paid occupations NPA, . BesidesUganda has a rich legal framework that addresses gender-responsive planning and programme design at the national, regional and international levels. Uganda\u2019s Constitution guarantees equality of all people under the law in all spheres of political, social and cultural life and the enjoyment of equal protection by the law in all aspects. Chapter four of the constitution lays down fundamental rights and freedoms of women and fair representation of marginalised groups, freedom from discrimination, and proposes affirmative action in favour of marginalised groups based on gender or any other reason created by tradition or customs  is mandated to spearhead and coordinate sectors to ensure that the concerns and experiences of women and men are fully integrated into the design, implementation and monitoring and evaluation policies and programmes.With this initiative, the GOU has mainstreamed gender issues in several policies and programmes including, the Gender Equity Budgeting Policy, the National Priority Gender Equality Indicators 2016), the National Policy on the Elimination of Gender-based Violence in Uganda, the Uganda Vision 2040, the Third National Development Plan (NDPIII) 2020/21 \u2013 2024/25, the Uganda Gender Policy 2007 (UGP), the Gender in Education Policy, the Education Sector Strategic Plan (ESSP) 2007\u20132015 and the Business, Technical, Vocational Education and Training (BTVET) Strategic Plan (2012/3- 2021/2) to improve the status of women and girls. For instance, Gender Education Policy promotes the implementation of universal and compulsory education, engendered education curricula, gender equality in teacher recruitment, and deployment, sex education, re-entry into formal education for young mothers and advocacy for stay-in-school campaigns for girls (Ministry of Education and Sports (MoES), , the NatIn addition, Uganda is a signatory to regional instruments that promote gender equality and empowerment including the East African Community (EAC) Treaty (2000), the Common Market for Eastern and Southern Africa (COMESA) Gender Policy , the Protocol on the Rights of Women in Africa , the Inter-Government Authority on Development (IGAD), Gender Policy and Strategy , the New Partnerships for African Development (NEPAD) and the AU Heads of State Solemn Declaration on Gender Equality . Internationally, the country ratified the Convention on Elimination of All Forms of Discrimination Against Women , the Beijing Declaration and Platform for Action (1995), the International Conference on Population and Development (1994) and the United Nations Declaration on Violence Against Women .This allegiance obliges the government to enact programmes to enhance women\u2019s human rights and wellbeing. In 1997, the government enacted a National Gender Policy (NGP) which was revised in 2007. The NGP presents strategies focused on developing and implementing livelihood interventions that respond to diverse gender needs, address women\u2019s rights and access to justice, strengthen women\u2019s participation in administrative and political processes and address gender inequalities in macro-economic policy formulation, and implementation and evaluation  2020/21 \u2013 2024/25. The NGP stresses that all national programmes must advance equal gender relations by eliminating gender discriminatory practices, norms and values, preventing and responding to gender-based violence, executing sexual and reproductive health rights programmes, implementing legal literacy programmes for women, supporting social protection for vulnerable women, promoting time-saving technologies, developing incentive frameworks for poor women and eradicating exploitation of women and girls.This article is based on policy documents and published literature on COVID-19 and its impact on women and girls. It draws on official GOU documents about the management of COVID-19, international human rights instruments, national health and development policy documents, WHO publications and reports and journal articles covering COVID-19 and its impacts on women and girls. The majority of these documents were accessed from the government of Uganda websites. The first search for journal papers resulted in thirty-eight (38) papers but only nineteen (19) that were judged to be of high quality were included in the review covering Africa and other parts of the world. Literature published between 2005 and 2022 was considered for inclusion with a high number focused on the period 2020 and 2022 when the COVID-19 pandemic was confirmed.The policy documents were analysed using content analysis Bryman, . The proUganda confirmed the first COVID-19 case in March 2020, and the number of cases has since then increased to 163,301 as of March 2022 , In addition, all government ministries, agencies and departments were directed to work out plans to ensure that only essential staff would physically report for duty in the offices. Additional public health measures to contain the pandemic were instituted such as the closure of the country\u2019s borders, quarantining of individuals  of healthy persons who may have been exposed to the virus and immediate suspension of public transport to minimise movement and contact among people. , The GOU recognises gender inequality as a constraint to growth in the country NPA, . Gender To ensure growth and prosperity, states are required to pursue progress in a fair way that grants women equal rights with men in the political, social, economic and cultural life of their countries. Gross inequalities in work and wages, unpaid women\u2019s work, discrimination in public decision-making, violence and exploitation of women and girls, harmful practices and unequal access to universal reproductive rights and health need to be exposed and eliminated. Elimination of these would foster equal rights and empowerment of women and lead to sustainable and inclusive development.The National Development Plan III (2020/2021\u20132024/2025) guides the establishment of strategies to increase household incomes and improve the quality of life of all people. Women have equal rights as men, to participate in the economic life of their countries at all times and in all contexts. Under this initiative, States must create an enabling environment where women and men are empowered to join gainful employment. This obligation requires a gender sensitivity lens to recognise different situations and needs of women and men throughout the decision-making processes. For instance, some women may require affirmative action to balance their roles both in the monetised and non-monetised sectors of the economy.However, Uganda\u2019s COVID-19 response measures did not take into account the economic and livelihood needs of women and girls. Previously, there has been marked gendered segregation of Ugandan women in the formal sector with many being concentrated in client-facing roles, leisure, travel and hospitality business \u00a0 revealedAlthough an economic shutdown of predominant female sectors has affected women in both developed and low-income states Peck, , women iUganda\u2019s National Equal Opportunities Policy 2006 envisioned a just, free and fair development process and establishment of affirmative action where imbalances exist  compared to men (11%) left their jobs/careers to attend to household needs Peck, . Though The pandemic has worsened maternal health outcomes globally. Uganda has registered an increase in maternal deaths due to involuntary confinement and resultant financial uncertainty   exacerbates maternal mortality and morbidity and increases the risks of early and unwanted pregnancies, HIV and other sexually transmitted diseases.A situation analysis of the impact of COVID-19 on school-going girls and young women in Uganda by the United Nations Children's Fund (UNICEF) reported a 22.5% increase in pregnancy among girls aged 10\u201324 seeking first antenatal care from 80,653 to 98,810.The National Policy on Elimination of Gender-Based Violence in Uganda aimed to eliminate gender-based violations and impunity  ; UN WomeIn the public sphere, market women were forced to sleep on the job due to curfew with some being humiliated, injured and arrested by security personnel  suffered , The decision to close schools possibly saved learners worldwide NPA, ; howeverArticle 2 of the CEDAW imposes an obligation on states to establish effective legal protection of the rights of women on an equal basis with men. Women need protection from exploitation and discrimination especially because emergencies intensify violence and disrupt existing protective structures  and sexual harassment MOFPED, . For exaThe pandemic risked women\u2019s rights because services in different ministries and institutions including the health sector, justice sector, internal security, local government (districts) and non-government organisations services were disrupted due to limited financial and human resources. This restricted monitoring, evaluation and coordination efforts for apprehending perpetrators and support to victims. For instance, at a certain point, MoGLSD lacked funds to support GBV prevention and response while the closure of the court system  delayed justice and GBV-related legislation  revised and stringent roadmap. For example, the EC banned political rallies and processions and made the entire process unaffordable for the poor. Expensive restrictions  and curfew rules curtailed general participation in these elections Babirye, . Women, The foregoing discussion shows the gendered effects of the COVID-19 pandemic on women\u2019s economic and education rights, unpaid work and health needs and indicates a resurgence of gender-based violence (GBV) and discriminatory practices against women and girls. This is concerning because they are happening with minimal or no protection because available resources are highly prioritised in the management of the pandemic. This raises an important question: how to stitch these gaps to protect rights and improve the wellbeing of women, girls and other marginalised populations during crises like the COVID-19 pandemic?At the outset, the GOU, civil society organisations and the international community need to re-examine COVID-19 measures and guidelines and ensure that they are gender-responsive and conform to human rights standards. To ensure that COVID-19 responses are gender-responsive, various social protection measures must be in place to shelter the most disadvantaged (such as the provision of food relief and cash transfers) and most importantly, women must be represented in professional and technical COVID-19 task forces. Given that most of the COVID-19 containment efforts are largely funded by development partners, they should avail sustainable and prompt funding to facilitate the formation of country-specific functional gender-sensitive management committees to promote gender equality initiatives and women\u2019s rights.It is also important to anticipate the gendered impacts of the lockdowns and stay-at-home orders on women and girls and other vulnerable groups. This is necessary to establish policies, systems, structures and practices that meet their specific needs and priorities, for example, measures to minimise delays in accessing specialised health care  and affordable legal protection. Sustainable recovery strategies may involve recognition of women\u2019s unpaid work, provision of equal opportunities and social protection schemes UN, .Furthermore, affirmative action as enshrined in legal and human rights instruments must be pursued to bridge gender gaps and address historical and present forms of discrimination against women and girls in the economic, social, political and cultural spheres. For instance, social security protection measures to cover informal workers or capital and economic stimulus packages and emergency measures as implemented in other countries UN,  can be aThe role of professionals in different ministries and institutions including the health, education, justice, internal security sectors and local governments must not be overlooked. This research has revealed several issues including violation of women\u2019s rights, gender-based violence and discrimination and their consequences on individual women and national development. Health workers, social workers, counsellors, lawyers and other professionals must provide seamless practice in terms of needs assessments, information sharing, management and referral. For example, probation officers are versed in human rights. They could form useful partners for assessing risks associated with response measures (such as lockdown and restrictions on movement) and monitoring the COVID-19 situation in communities and providing required individual and group counselling.Professionals over the world need to innovate ways of advocacy to ensure that the voices of disadvantaged groups reach COVID-19 management task forces in all contexts, for example, social workers can aid the transformation of the education system to integrate teaching methods that can address the special needs of traumatised or teenage mothers. This will ensure prioritisation of their rights and needs for safety, health and wellbeing and foster inclusive development in the long run.Gender equality is not only a right but also a necessity for the achievement of further development goals. The COVID-19 containment measures adopted by GOU have impaired women\u2019s rights and escalated unequal power relations causing high levels of violence against women and girls, death, disability, teenage/early pregnancies and school dropouts. Mandatory lockdowns and movement restrictions created negative implications for women\u2019s attainment of economic, social, cultural, political and civil rights and intensified pre-existing gender inequalities between women and men.The oversights (in the design and implementation of COVID-19 control measures) discussed in this article are great lessons for upgrading the management of ongoing and future pandemics. Uganda\u2019s government planners and development partners need to design and implement comprehensive and integrated response services to safeguard the wellbeing and survival of vulnerable populations. Such interventions must also consider and address their routine challenges.This research has indicated a need for policymakers, community leaders and service providers to apply gender analysis in the delineation of public health measures and standard operating procedures on women\u2019s wellbeing and rights.https://www.health.go.ug/https://www.unicef.org/uganda/press-releases/prioritize-re-opening-schools-secure-childrens-well-being"}
+{"text": "Immunogenic cell death (ICD) is a type of cell death that leads to the regulation and activation of the immune response, which is marked by the exposure and delivery of damage\u2010associated molecular patterns (DAMPs) in the tumor microenvironment. Accumulating evidence has revealed the significance of ICD-related genes in tumor progression and therapeutic response. In this study, we obtained two ICD-related clusters for glioblastoma (GBM) by applying consensus clustering, and further constructed a risk signature on account of the prognostic ICD genes. Based on the risk signature, we found that higher risk scores were associated with worse patient prognosis. Besides, the results illustrated that ferroptosis regulators/markers were highly enriched the high-risk group, and ferroptosis were correlated with cytokine signaling pathway and other immune-related pathways. We also discovered that high-risk scores were correlated to specific immune infiltration patterns and good response to immune checkpoint blockade (ICB) treatment. In conclusion, our study highlights the significance of ICD-related genes as prognostic biomarkers and immune response indicators in GBM. And the risk signature integrating prognostic genes possessed significant potential value to predict the prognosis of patients and the efficacy of ICB treatment. Immunogenic cell death (ICD) is a form of cell death that leads to the regulation and activation of the immune response, which is characterized by the exposure and release of damage\u2010associated molecular patterns (DAMPs) in the tumor microenvironment such as calreticulin (CRT), secreted HMGB1and ATP . These mGlioblastoma (GBM) the most fatal brain cancer with a median survival time of 12 to 18 months and 5-year survival rate of less than 10% . At preshttp://www.tcga.org/ ). For the validation dataset, the RNA-Seq data were obtained from TCGA. The information about the response of tumor patients to anti-PD-1 checkpoint inhibition therapy was acquired from the Gene Expression Omnibus (GEO) datasets GSE67501 and GSE78220.For the training set, the RNA-Array data and corresponding clinicopathological information of GBM patients were retrieved from TCGA , progression free survival (PFI), and disease-specific survival (DSS) of patients in different clusters or risk groups. ROC curve was utilized to estimate the predictive performance of different classification methods in various aspects, including 1 -, 3 -, and 5-year survival, GBM subtypes, and IDH status.The DEGs between different risk groups were identified by utilizing the R package \u201cLimma\u201d. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of the aberrantly expressed genes were determined by the gene set variation analysis (GSVA), which compared the variation levels of gene sets between groups . We alsoESTIMATE  is an implement to estimate tumor purity and the presence of infiltrating stromal cells/immune cells in tumor tissues utilizing gene expression according to the enrichment analysis of single sample gene set .The immune infiltration heterogeneity between groups was estimated by the R package integrating six state-of-the-art algorithms, which include TIMER , MCP-couhttp://tide.dfci.harvard.edu/) assessed two different indexes of tumor immune escape, including dysfunction of cytotoxic T lymphocytes (CTLs) and rejection of CTLs by immunosuppressive molecules (Tumor immune dysfunction and exclusion (TIDE) analysis was performed to evaluate the potential response to ICB treatment. TIDE  collects numerous cell drug sensitivity information and drug disturbance-based cell expression signature, which provides specific information for integrating a large number of drug sensitivity and genomic data to promote the discovery of novel therapeutic biomarkers for cancer treatment (The Genomics of Drug Sensitivity in Cancer (GDSC) database was utilized to locate the drugs with the specific target potential as anti-cancer candidates based on the correlation between the risk score and drug response AUC. GDSC database  were compared in both the TCGA array  , the key molecules mediating antigen presentation in cancer immunotherapy, were upregulated in the high-risk group (at/home) . NotablyThen, we applied the GDSC1 and GDSC2 databases to assess potential effective anti-cancer drugs based on risk scores and the AUC values of drugs. We identified 341 and 175 kinds of potential drugs in GDSC1 and GDSC2 databases respectively, and 15 kinds of them were overlapped whose AUC values were negatively correlated with risk scores (http://gepia2.cancer-pku.cn/#index)   to obtai#index)   can be found in the article/SF, XX, and QC made substantial contributions to the design of this study. XL, JL, ZL, and ZW carried out the analysis and interpreted the data. SF, XL, and XX made contributions to the drafting of the manuscript. HZ, ZD, PL, and JZ made contributions to the review of previous literature. SF, XX, XL, and QC contributed substantially to the revision of the manuscript. All authors contributed to the article and approved the submitted version.This work was supported by the National Natural Science Foundation of China ; Hunan Provincial Natural Science Foundation of China ; Hunan Provincial Health Committee Foundation of China (NO.202204044869); Natural Science Foundation General Program of Changsha City (kq2014290); and Xiangya Hospital Central South University postdoctoral foundation.All authors thank TCGA and GEO database for providing the wothy patient cohort data for research, and we also thank Central South University for providing the High Performance Computing Center.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Maintaining low ecological consumption and high well-being while making economic progress and thus achieving sustainable development is a significant issue facing the world today. Ecological well-being performance (EWP) is one indicator that tracks this progress. Although EWP has been typically assessed at the national, provincial and urban levels, investigations into EWP units in the Great Lakes region are lacking. This study applied the two-stage super-efficiency slack-based measure (Super-NSBM) model and DEA window analysis to evaluate the EWP and sub-stage efficiency in the Poyang Lake (largest freshwater lake in China) area and analyzed its spatial differences at the local level. Redundancy analysis was conducted to explore the EWP improvement paths of different counties in the Poyang Lake region and Dagum\u2019s Gini coefficient was applied to clarify the policy priorities of coordinated regional development. Results showed that the EWP of the Poyang Lake area presents an improving trend from 2007 to 2019, although the overall level is still low. The Poyang Lake area mainly faces the incongruity of ecological and economic development, which is the main reason for the low overall level of EWP. Excessive resource input and severe environmental pollution are common in most counties, but the focus of measures to improve EWP differs from county to county. The expansion of spatial differences in eco-economic efficiency leads to the spatial differences of EWP in the Poyang Lake area being still apparent at the local level. Reducing inter-basin disparities while alerting the widening of intra-basin differences is the policy focus for the future coordinated development of the Poyang Lake area. Achieving economic prosperity and social progress within ecological limits is the essential requirement of sustainable development for improving human well-being . Daly  [4 [7] firIn recent years, scholars have successfully conducted numerous sustainable development studies through EWP. They have mainly used two methods to evaluate EWP, namely, ratio and the efficiency model . HDI 1313 and liSome scholars have argued that the ratio method presents two limitations . On the In addition, regional differences are a popular part of EWP research and have been studied extensively by scholars. For example, Wang et al. (2021)  applied Although EWP has been successfully applied, it can still improve in the following aspects. First, most studies on spatial differences in EWP have been conducted under the large-scale levels of regions, provinces and cities and there is a lack of spatial difference analysis at the local level of the Great Lakes region. Second, studies typically consider ecological inputs but ignore nonecological inputs, such as scientific and technological expenditures and human capital inputs, in the process of indicator selection. These elements are indispensable intermediate means of converting ecological consumption to human well-being. Finally, existing studies only consider EWP as a simple direct conversion process from ecological consumption to well-being output and lack the analysis of sub-stage efficiency.Compared with previous studies, the main objectives of this study are presented as follows. First, nonecological inputs, such as science and technology expenditure and human capital input, are included in the evaluation index system to assess the level of EWP in the Poyang Lake area comprehensively and accurately. Second, the spatial differences of EWP and its sub-stage efficiency in the Poyang Lake area at the local level are analyzed and the Dagum Gini coefficient is used to explore the characteristics and sources of spatial differences. Third, the redundancy analysis is used to reveal what measures each county should take to enhance EWP. We hope that the analysis of this study can provide scientific policy reference for the local level of the Poyang Lake area to enhance EWP in a coordinated manner.The specific study area identified in this thesis includes 25 counties (districts or cities) within the Poyang Lake area, given the availability of data. Notably, Yujiang County was renamed Yujiang District in 2018, Jiujiang County was renamed Chaisang District in 2017, Dongxiang County was renamed Dongxiang District in 2016, Xingzi County was renamed Lushan City in 2016 and Xinjian County was renamed Xinjian District in 2015. However, this adjustment only changes the name and district boundaries remain the same. Names of administrative divisions after the adjustment are used in this study to ensure uniformity in presentation. The two main regional classification methods for the Poyang Lake area in the literature are \u201ccenter\u2013periphery\u201d  and \u201cby The Poyang Lake area is divided into two parts: the lakeside area and the peripheral area around the lake. Poyang Lake basin belongs to the lakeside area and Ganjiang River basin, Xinjiang River basin, Raohe River basin, Xiuhe River basin, Yangtze River basin and Fuhe River basin belong to the peripheral area around the lake.On the basis of Long (2019)  and WangThe evaluation index system of EWP in the Poyang Lake area is presented in Output indicators of the first stage also include both desired and undesired outputs. If the process of converting ecological inputs into economic outputs results in environmental pollution, then it can harm public health . TherefoHDI has been commonly used to measure the well-being output in existing studies. However, sub-indicators of the HDI cover only economic and social dimensions but ignore the importance of environmental well-being. Xiao and Xiao (2021)  incorporNotably, the indicators of environmental pollution and total well-being output in this study are selected in large numbers, while the number of decision making units (DMUs) is small. This study adopts the entropy value method to accurately measure the EWP of each county (district or city) within the Poyang Lake area and reduce the dimensionality of environmental pollution and total well-being output. Finally, the indices of environmental pollution, economic well-being and social well-being are obtained.Data for the selected indicators are extracted from the 2008\u20132020 China County and the Jiangxi Provincial Statistical Yearbooks. Data for average years of education are obtained from the sixth and seventh national census bulletins published by the government of each county (district or city). Data on nighttime lighting were obtained from the Harvard Dataverse platform . Data foWe calculated the EWP of 25 counties (districts or cities) in the Poyang Lake area using MAXDEA 6.0 software. We then applied MATLAB R2015b  to estimate spatial differences of EWP in the Poyang Lake area.km and kv represent the input and output of the stage k, respectively; k\u03c6 represents the number of intermediate indicators;  represents the connection from stage k to stage h; x, y, z and represent the input, output and intermediate output, respectively; k\u03bb represents the model weight of stage k; and k\u03c9 represents the weight of stage k; k\u2212s represents the slack variables of input indicators; and gks and bks represent the slack variables of desired and undesired outputs, respectively.This study adopted a two-stage Super-NSBM model  to measuThe DEA window analysis was adopted in this study to measure EWP in the Poyang Lake area and analyze differences in EWP and trend of efficiency changes in each county (district or city) comprehensively. This method first treats the same DMU in varying periods as different DMUs for efficiency calculation. The efficiency of each year in other windows is then weighted and averaged to obtain the final efficiency value of the evaluated DMU. Notably, this method can increase the number of DMU and compare the efficiency in both horizontal and vertical dimensions . On the G) of EWP in the Poyang Lake area is decomposed into intra-regional (intra-basin) differences (jjG), inter-regional (inter-basin) differences (Gjh) and super-variable density (tG) and satisfy: G = jjG + jhG + tG.The Dagum Gini coefficient method improved the shortcomings of the traditional methods of measuring spatial differences and solved the problem of cross-over between samples . It can \u03bc represents the mean value of EWP in each region, n represents the number of counties (districts or cities) in Poyang Lake area, k represents the number of regions, jn(hn) represents the number of counties (districts or cities) in the j(h) region (basin) and jiy(hry) represents the EWP of the i(r) counties (districts or cities) in the j(h) region (basin).jjG denotes the Dagum Gini coefficient of the j-th region (basin), jhG denotes the inter-regional (inter-basin) Dagum Gini coefficient of the j-th and h-th regions, jhD denotes the relative impact of EWP between the j-th and h-th regions (basins), jF(hF) is the cumulative density distribution function of the j-th (h-th) region (basin) and jhd denotes the differences of EWP between regions (basins). The Dagum Gini coefficient varies between 0 and 1. Spatial differences of EWP among counties (districts or cities) in the Poyang Lake area are small as the value of the Dagum Gini coefficient approaches 0 and vice versa.The formula for measuring the Dagum Gini coefficient can be expressed as follows:EWP is still at a low level from the overall perspective despite its rapid improvement in the Poyang Lake area . The aveSpecifically, among 25 counties (districts or cities) in the Poyang Lake area, only Duchang County, Poyang County and Gao\u2019an City demonstrate a decreasing trend of EWP, thereby indicating that the overall EWP in the Poyang Lake area is improving. Among them, Nanchang County, De\u2019an County, Xinjian District and Yongxiu County rank in the top four in terms of annual growth rate at 16.453%, 14.089%, 13.183% and 13.067%, respectively, and all achieved the relatively effective DEA. However, the overall level of EWP in the Poyang Lake basin is pulled down due to the low EWP in Lushan City, Xinjian District and Hukou County and the decreasing trend of EWP in Duchang and Poyang Counties. Similar to that of Duchang and Poyang Counties, the EWP of Gao\u2019an City also exhibits a decreasing trend with an average annual decrease of 1.529%. The average annual growth rate of EWP in Anyi and Wuning Counties was only 1.210% and 0.141%, respectively; hence, the Xiuhe River basin showed the lowest average annual growth rate of EWP among the seven basins.The significantly high results of the Super-SBM model, which takes into account the undesired output from a single-stage perspective, indicated that the two-stage Super-NSBM model selected in this study is accurate and reasonable. Moreover, this study can provide a methodological reference for similar studies that measure multistage efficiency.The EWP of counties (districts or cities) in the Poyang Lake area was generally at a low level in 2007. Only the EWP of Duchang and Poyang Counties were located on the production front surface. At this time, differences in EWP between the lakeside and peripheral area of the lake are small. The range of high EWP counties (districts or cities) in the Poyang Lake area showed an expanding trend in 2011. EWP of Jinxian County, Fuliang County, Leping City, Wuning County and Yujiang District improved. However, the EWP of Duchang and Poyang Counties dropped below 1. The scope of high EWP counties in the Poyang Lake area continued to expand in 2015. The EWP of counties (districts or cities), such as Nanchang County, Guixi City, Yujiang District and Fuliang County, improved significantly. EWP in the Poyang Lake area improved significantly in 2019 and counties (districts or cities) with low-level EWP are mainly located in the peripheral area of the lake. The EWP of De\u2019an County, Yongxiu County and Xinjian District improved to the efficiency frontier surface and the overall level of EWP of the lakeside area was significantly higher than that of the peripheral area of the lake. Thus, the EWP of the Poyang Lake area shows this spatial distribution pattern\u2014\u201chigh EWP counties spread from the lakeside area to the peripheral area of the lake and the EWP of the lakeside area is higher than that of the peripheral area of the lake\u201d\u2014from 2007 to 2019.This study further analyzed the sub-stage efficiency of EWP and the redundancy of input-output indicators in the Poyang Lake area to open the \u201cblack box\u201d of EWP in converting ecological consumption into well-being output.As can be seen from Specifically, the improvement of EWP in the Lakeside area is mainly constrained by the efficiency of economic well-being. Compared with the peripheral area of the lake, the economic level of the lakeside area results in a significantly higher value for eco-economic efficiency because the area is more developed, more technologically advanced and presents stricter environmental protection policies. By contrast, the low EWP in the peripheral area of the lake is mainly due to constraints of eco-economic efficiency. Only the Xinjiang River basin in the region shows higher eco-economic efficiency than economic well-being efficiency. Among the 25 counties (districts or cities), only Poyang County achieved DEA relative effectiveness in both eco-economic and economic well-being efficiencies in 2019. Notably, Dongxiang District\u2019s economic well-being efficiency improves yearly and achieved DEA comparative effectiveness in 2019 despite an eco-economic efficiency of only 0.280. Dongxiang District must improve its eco-economic efficiency to enable coordinated economic, ecological and social development. Jinxian County achieved an effective DEA for economic well-being efficiency but faced the same problem of incompatible economic and environmental development. The eco-economic efficiency of Yogan County, Nanchang County, De\u2019an County, Xinjian District, Yongxiu County and Yujiang District increased beyond the production frontier surface and the efficiency of economic well-being needs further improvement.Although some counties achieved an effective DEA for EWP in 2019, the majority still present a low EWP. Therefore, this study selected 2019 as the time point for redundancy analysis. This section focuses on the redundancy of input-output indicators in counties (districts or cities) with low EWP. Lushan City and Hukou County not only spend too much on education but also produce a large amount of carbon and wastewater emissions in the development process and thus have a low EWP. Low land resource use efficiency, high PM2.5 concentration and per capita sewage discharge and a severe shortage of sanitation technicians in Xinkan County are the main reasons for its low EWP. Zhangshu City, Gao\u2019an City and Dongxiang District not only have higher land consumption, water consumption and pollution discharge but also have redundancy in education expenditure. Guixi\u2019s low EWP is caused by low land resource use efficiency and per capita public finance expenditure, while education expenditure and per capita sewage discharge are too high. There is redundancy in education expenditures in Anyi County and the efficiency of water resources utilization, sewage treatment rate and per capita social security and employment expenditures are below average. Wuning County has excessive consumption of land and water resources and the economic output efficiency of education and science and technology expenditure needs to be improved. Chaisang District and Ruichang City are overly redundant in terms of energy consumption, land consumption, water consumption and spending on science and technology. Their PM2.5 concentration and per capita sewage discharge are also much higher than average. In addition, Chaisang District needs to improve its forest cover and sewage treatment rate to contribute to the improvement of environmental well-being.The analysis results demonstrated that the efficiency of EWP and its sub-stages in the Poyang Lake region differ significantly at the local level. Therefore, this study applied the Dagum Gini coefficient to analyze EWP\u2019s characteristics and sources of spatial differences in the Poyang Lake area.As shown in We decomposed the spatial differences of EWP in the Poyang Lake area in a basin division according to Equations (3)\u2013(11) to illustrate the characteristics and sources of spatial differences further. The annual average values of inter-basin differences in EWP in the Poyang Lake area from 2007 to 2019 are listed in Finally, we analyzed the intra-basin differences of EWP in the Poyang Lake area. The Dagum Gini coefficient of the Fuhe River basin is 0 from 2007 to 2019 given that it only contains Dongxiang District; therefore, the intra-basin differences of EWP in the Fuhe River basin are not shown in The sustainable development status of the Poyang Lake area has attracted considerable research attention since the State Council of China approved the Poyang Lake Eco-economic Zone Plan in 2009. However, there is no study in existing research to analyze the sustainable development of the Poyang Lake area through EWP. In this study, a two-stage Super-NSBM model was applied to divide the process from resource input to well-being output into two stages and then analyzed the EWP of the Poyang Lake area. Compared with the study of Long (2019) , who alsAlthough the EWP of the Poyang Lake area demonstrates an improving trend from 2007 to 2019, the overall level is still low. Most counties have problems of over-input of natural resources and environmental pollution. At the same time, counties should beware of over-investment of funds, which fails to improve EWP significantly and may lead to increased debt. Specifically, each county and region should apply differentiated measures. Lushan City and Hukou County must reduce excessive spending on education, introduce advanced technology and promote the green transformation of industries. Xinkan County should improve land use efficiency, increase the number of health technicians and strictly limit PM2.5 and wastewater emissions from enterprises. Zhangshu City, Gaoan City and Dongxiang District must reduce land and water consumption, minimize education expenditure redundancy and limit pollution discharge. Guixi City should improve land use efficiency and public finance expenditure, reduce education expenditure redundancy and limit wastewater discharge. Chaisang District and Ruichang City must reduce the consumption of various resources and pollution discharge and increase the forest coverage and sewage treatment rate. Anyi County should pay attention to the utilization of water resources and wastewater treatment, improve the efficiency of education expenditures and increase social security and employment expenditures. Wuning County must reduce the consumption of land and water resources and excess spending on education, science and technology.The differences of EWP and its sub-stage efficiency and indicator redundancy among counties and districts confirmed that EWP in the Poyang Lake area indeed has spatial differences at the local level. The widening spatial differences in eco-economic efficiency are a significant reason why the spatial differences of EWP in the Poyang Lake area are still apparent. Meanwhile, we found that inter-basin differences are the primary source of spatial differences in EWP in the Poyang Lake area. Therefore, the policy focus of the future coordinated development of the EWP region in the Poyang Lake area should be to introduce a cross-regional collaboration mechanism. Regions with advantages in production efficiency, technology level and resource endowment are targeted to help lagging areas to smooth their development mode and realize green economic transformation. The government should also actively help lagging regions increase their income, improve infrastructure construction and social security systems and enhance people\u2019s well-being. Finally, strengthening the construction of ecological civilization within each basin, establishing regional environmental regulatory agencies and establishing long-term cooperation for sustainable development are crucial to avoid intra-basin spatial disparities from widening while narrowing inter-basin differences.However, this study also has some limitations. Regarding the selection of well-being indicators, due to the lack of survey data on subjective well-being in the Poyang Lake area, we can only select objective well-being indicators. Our future research direction is to investigate residents\u2019 subjective well-being in the Poyang Lake area and then analyze EWP by combining subjective and objective well-being indicators. Besides, applying the system dynamics method to the analysis of EWP in the Poyang Lake area is also worth exploring.The main conclusions of this research are as follows.First, the EWP of the Poyang Lake area shows an improving trend from 2007 to 2019, but the overall level is still low. The EWP of all seven basins failed to achieve DEA effectiveness. The spatial distribution of EWP in the Poyang Lake area shows this apparent pattern\u2014\u201cthe high EWP counties spread from the lakeside area to the peripheral area of the lake and the EWP in the lakeside area is higher than that in the peripheral area of the lake.\u201dSecond, there is a complex problem of uncoordinated development between the economy, ecology and society in the Poyang Lake area as a whole. The low eco-economic efficiency mainly constrained the improvement of EWP in the Poyang Lake area and the redundancy of resource input and environmental pollution were more severe in all counties and districts in general. The eco-economic efficiency of the lakeside area is higher and the primary goal is to coordinate the relationship between economy and well-being to promote the efficiency of economic well-being. The redundancy analysis revealed that measures to improve EWP varied across counties.Third, the spatial differences of EWP in the Poyang Lake area are gradually decreasing and show the overall trend of coordinated development. However, the spatial differences of eco-economic efficiency are progressively expanding, resulting in the spatial differences of EWP in the Poyang Lake area at the local level being still evident. Inter-basin differences are the primary source of spatial differences in the Poyang Lake area\u2019s EWP. Reducing the inter-basin differences of EWP in the Poyang Lake area while avoiding the elevated intra-basin disparities is crucial."}
+{"text": "S\u20136. Se.g.iologies , 8.Alkabie and Budrham reviewed the methodologies used for the testing of the two most common antibody-associated demyelinating myelitis, namely myelin oligodendrocyte glycoprotein antibody-associated disease (MOG-AD) and aquaporin-4 (AQP4) positive neuromyelitis optica spectrum disorders (NMOSD). They compare the performance of fixed and live cell-based assays, the yield of antibody detection in different specimens , and address the important topic of antibody titer cut-offs, which is particularly relevant for diagnostic accuracy of MOGAD. This latter point is also at the core of the original research of Manzano et al., who investigated the positive predictive value of serum anti-MOG antibody testing in a real-world institutional cohort, using well-established live cell-based assays. While on one hand the authors identify an assay cut-off 1:40 as the one yielding the highest positive predictive value, they also noted a sizeable number of cases with phenotype aligned with typical MOGAD that would have been missed with the use of such threshold, underscoring the need for further work in the optimization of diagnostic assays.For this Research Topic, the characteristics of different immune-mediated myelopathies and common associated diagnostic tests have been extensively reviewed. Cacciaguerra et al. provide an overview of the key imaging features, pitfalls and mimics of the most common demyelinating syndromes and of some rare, recently characterized immune-mediated myelopathies. Recent years have seen an exponential rise in the number of biological agents that can be applied for the treatment of systemic inflammatory disorders and malignancies, and neurologists are increasingly challenged by possible secondary neurological manifestations of these treatments. This expanding field of iatrogenic myelopathies is the focus of the review of Gritsch et al., which provides useful recommendations for workup and management, while Passeri et al., provide an in-depth discussion of paraneoplastic myelopathies. Recognizing these rare but important causes of myelopathies has important treatment implications, and is now particularly relevant as the testing for many of the associated antibodies has become commercially available in the United States. Lastly, Fadda et al. compare the typical evolution, clinical and radiological short and long-term outcomes of spinal cord involvement in multiple sclerosis, MOGAD and AQP4 antibody positive NMOSD, emphasizing the importance of accurate diagnosis and prompt treatment initiation to alter the disease course of these disorders.These articles altogether highlight how, even in the presence of useful biomarkers, the diagnosis of immune mediated myelopathies rests on clinical acumen, and the recognition of characteristic disease features remains the fundamental step to achieve diagnostic accuracy. To aid clinicians in the differential diagnosis of inflammatory myelopathies, Our knowledge on many of the immune-mediated myelopathies discussed in these articles is still at its early stages, and many spinal cord syndromes observed in clinical practice continue to be labeled as idiopathic. While this field will likely continue to evolve in the upcoming years, physicians should familiarize with the current landscape of immune mediated myelopathies, as prompt recognition of these syndromes and early and targeted therapies are often key to provide the most optimal patient outcomes.GF, EF, and ES: study concept, design, and drafting the manuscript and figures. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "The first part of the SSNN Summer School of Neurology 2022, which covered the first day's events, is highlighted in a previous publication.Natan Bornstein (Israel) and Dafin Muresanu (Romania). The beginning session of the day, Session 5, started with Natan Bornstein (Israel), the Director of the Brain Division and Chairman of the Israeli Stroke Society (ISS), and his two presentations: \"Secondary Stroke Prevention \u2013 The DAPT Story \u2013 A Journey of 25 Years\" and \"Post-stroke cognitive decline \u2013 current concepts and treatment approaches\". Prof. Bornstein firstly stated the importance of tertiary prevention of stroke with the syntagm \"don't let stroke strike twice\", as stroke represents a major cause of long-term disability, and went further into discussing current guidelines and the long-term story of Dual Antiplatelet Therapy (DAPT) research, beginning back in 1996. His second presentation discussed treatment options following ischemic stroke, highlighting the lessons from double-blind randomized trials in patients with acute mild ischemic stroke or high-risk Transient Ischemic Attack (TIA). Moreover, as post-stroke depression (PSD) represents the most frequent non-cognitive neuropsychiatric complication and is associated with higher mortality, poorer recovery and decreased quality of life, the investigation of its mechanisms remains a subject of utmost importance. Due to this, approaches should be multidimensional, involving a multidisciplinary team for the best results.The second day of the congress was introduced by Dafin Muresanu (Romania), President of the The European Federation of NeuroRehabilitation Societies (EFNR), presented microcirculation and stroke and discussed the 3 crucial pillars in neurorehabilitation and brain protection and recovery:Developing a solid theory and strong hypothesis, validating the ideas with basic research;Testing the effectiveness of the intervention;Using evidence-based parameters.He then pinpointed two critical aspects of rehabilitation: the limit of the disability and the individual biological reserve. In addition, the importance of creating promising paradigms and protocols for treatments and aligning the mechanisms of action with the design was showcased, and the two anticorrelated sequences of post-lesional brain regulation (NEUROPROTECTION and NEURORECOVERY) were also highlighted. Moreover, Prof. Muresanu discussed endogenous defence activity, damage mechanisms, and the levels of central nervous system (CNS) endogenous modulation. One crucial point touched upon was the importance of the proportion and interactions as more relevant factors than the separate effects of each function. Furthermore, he offered an in-depth view of the anticorrelated processes of 3 different levels, discussing the vertical correlation between functional and gene networks. The principal therapeutic approach in acute ischemic stroke was also outlined, which refers to:Arterial revascularization;The substantial predictive effect on clinical outcomes of the final recanalization;The factors on which brain tissue perfusion depends.European Federation of NeuroRehabilitation Societies (EFNR).In his comprehensive presentation, he discussed the combination of approved methods, avenues for enhancing thrombolysis, and the role of Cerebrolysin in inhibiting endogenous inflammatory pathways. Prof. Muresanu closed the session with a lesson on performing neurorestorative treatments with extended therapeutic windows and recommended that specialists work together in integrative approaches, highlighting the role of the th session, hosted by Dafin Muresanu and Adina Stan, began with the presentation of Jesse Dawson (UK), Professor of Stroke Medicine at the Institute of Cardiovascular and Medical Sciences in Glasgow (UK) on \"Stimulation (neuromodulation) for post-stroke recovery\". Prof. Dawson highlighted that there are many mechanisms for upper limb impairment, therefore, many avenues for recovery. As a result, the interventions should be related to the cause of impairment. The approach in stroke rehabilitation refers to causing task-specific plasticity, as neuro-connectivity and activity are altered post-stroke. Also, with plasticity being task-specific, neuromodulation \u2013 the alteration of neuro-activity to target the delivery of a stimulus to specific neurological sites \u2013 encompasses both advantages and disadvantages, showcased in his presentation. Prof. Dawson discussed different types of stimulation and their respective roles and effects, as well as approached VNS (vagus nerve stimulation) after ischemic stroke for upper limb motor function, highlighted in his research.The 6Andreas Winkler (Austria), Medical Director and Head of Department in Neurological Rehabilitation at Klinik Bad Pirawarth in Vienna (Austria), presented \"How can we be more efficient in motor recovery after stroke?\". Prof. Winkler discussed the possibility of improving endogenous plasticity and introducing a new window of opportunity to obtain a better neurological outcome for the patient. He approached the enhancement of post-stroke plasticity and the limitations of current undertakings, including selective serotonin reuptake inhibitors (SSRIs), and discussed three clinical trials to highlight his previous point. Moreover, he showcased the usefulness of Cerebrolysin in stroke patients as outlined by different medical societies and the shift from past approaches to this innovative agent, underlining the positive effects of Cerebrolysin on neuroplasticity. The role of Brain-derived neurotrophic factor (BDNF) as a biomarker in stroke and the enhancement of post-stroke plasticity through electrical stimulation were also tackled. One important point of his presentation was combining different approaches to boost plasticity.Adina Stan (Romania), Primary Neurologist and Lecturer of Neurology at the University of Medicine and Pharmacy Iuliu Hatieganu in Cluj-Napoca (Romania), presented a case study on stroke, showcasing the disease progression and process of examination, discussing the affections of the patient, and engaging the public to suggest the most probable diagnosis based on the available information. She also tackled the differential diagnosis, discussed the TOAST classification of stroke subtypes and underlined the role of stroke prevention. Following her presentation, Hanna Dragos (Romania), from Cluj-Napoca Emergency County Hospital (Romania), offered an inspiring approach to a rare disease, discussing the symptoms, disease progression, medical history examinations, and, similarly, asked for public input on the most likely diagnosis. Finally, after covering multiple aspects, she touched upon the molecular genetic diagnostic pathway for stroke-like episodes and the management of the disease.th session, presided by Cristina Tiu (Romania) and Rodica Balasa (Romania), Cristina Tiu (Romania), Head of the II Neurology Department and Head of the Neurology Discipline at the Neurology Clinic from the Bucharest University Emergency Hospital in Bucharest (Romania), introduced the public to her presentation \"About immunosenescence and inflammaging in multiple sclerosis (MS). Therapeutic options in older patients\". With elderly patients being a challenging population and real-life patients differing from those presented in clinical studies, complex and multimodal approaches to diagnostics and treatment are needed. Prof. Tiu discussed the prevalence of MS and various epidemiological characteristics, the immunosenescence of innate immune systems, the meningeal inflammation, and the influence of age on the pathophysiology of MS and imaging features for identifying comorbidities. Two scenarios were tackled: (1) diagnosis at older age vs. (2) patients with known MS who are aging naturally, with particularities detailed for each. Finally, she argued whether the discontinuation of immunomodulatory therapy is recommended in patients over 60 years of age from a therapeutic perspective, pinpointing the aspects of biological age, epigenetic factors, and lifestyle strategies.During the 7Mihaela Simu (Romania), Professor and Chairman of the Neurology Department II \u2013 the University of Medicine and Pharmacy Victor Babes in Timi\u0219oara (Romania), presented \"Cognitive impairment in MS \u2013 from theory to practice\". Historical notes, statistical facts, and the science of cognition and neuropsychology were discussed first. The presentation then focused on statistical data on cognitive deficits in MS and various neuropsychiatric aspects of the disease, with an outline of the neuropsychological patterns in MS cognitive impairment according to phenotypes and the similarities of cognitive profiles of different MS phenotypes. Further on, Prof. Simu offered a view into the types of cognitive deficits, assessment of MS, and the prevalence of cognitive deficits in MS depending on the subtype, mentioning the pediatric population. The classification of MS and the various tests and screening methods were also discussed, and the presentation ended with recommendations for cognitive impairment (CI) evaluation in MS, as CI is a common feature of MS, which direly impacts patients' quality of life, with 40\u201370% of patients affected at any time during the course of the disease.Rodica Balasa (Romania), the Head of the Neurology 1 Clinic at the Emergency Clinical County Hospital of Mures (Romania), ended the session with \"Plasmatic exosomal microARN from brain cells in the evaluation of immunological treatment in multiple sclerosis patients\". During her presentation, Multiple Sclerosis (MS) was discussed, its impact \u2013 as the leading cause of chronic neurological handicap in young adults \u2013 was showcased, and the difficulty in treatment due to its heterogeneity and the unknown aetiology as a probable result of the interplay of several different factors were touched upon. Prof. Balasa tackled the role of inflammation in demyelination and axonal loss, the processes of neurodegeneration and remyelination, and highlighted disease-modifying therapies, underlining that the best choice for the patient is based on the specific biological mechanism of CNS inflammation. As a result, the best-suggested response is precision medicine.Hari Shanker Sharma (Sweden), the Director of Research at the International Experimental Central Nervous System Injury & Repair (IECNSIR) from the University Hospital, Uppsala University (Sweden), presented \"Methamphetamine exacerbates Alzheimer's disease pathology\". Neuroprotective effects of nanowired Cerebrolysin with Neprilysin, discussing the particularities of the blood-brain barrier in the Alzheimer's disease and the effect of methamphetamine. As Alzheimer's disease (AD) represents a devastating neurological affection leading to lifetime disability, investigating the risk factors, which can accelerate the pathogenesis of AD, including substance abuse, is of utmost importance. Prof. Sharma also focused on the effects of methamphetamine intoxication on the spinal cord and the rapid morphological changes after acute intoxication, highlighting his research on the matter.The last session of the day, Session 8, was introduced by Hari Shanker Sharma (Sweden) and Xianshuang Liu (USA). First, Xianshuang Liu (USA), Associate scientist at the Department of Neurology from the Henry Ford Hospital, Detroit (USA), offered his presentation together with Michel Chopp (USA), Vice Chairman for Research of the Department of Neurology and Scientific Director at the Henry Ford Neuroscience Institute, Detroit (USA), on \"Exosomes enhance the coupling of neurogenesis and angiogenesis by transfer of microRNA\", where the functions and uses of exosomes were explained, the process of neurogenesis and angiogenesis described, and the impact of stroke on their association was tackled.Ioana Mandruta (Romania), the Head of the Epilepsy Monitoring Unit at the University Emergency Hospital of Bucharest (Romania), presented \"Semiology of epileptic seizures \u2013 the new glossary of terms\". Prof. Mandruta discussed epilepsy, its subtypes, the classification of seizures, the need to address the terminology, and presented a case with epilepsy. She explained the definition of myoclonic jerks, offering examples, discussed seizures with focal onset and the appearance of seizure symptoms based on the affected part of the brain, and provided a glossary definition of elementary motor signs. Further on, Prof. Mandruta presented complex motor behaviors, subjective ictal symptoms, also called \"aura\", autonomic events, and the localization of seizure generators. Moreover, she exemplified another case of seizures with impaired consciousness and the exploration of the patient. Finally, she discussed temporal lobe epilepsy and posterior cortex epilepsy, ending with additional case studies on patients with epilepsy.Peter Jenner (UK), Emeritus Professor at the Institute Of Pharmaceutical Sciences from the Faculty of Life Sciences and Medicine at King's College in London (UK), presented \"Can we develop non-dopaminergic approaches to the treatment of Parkinson's disease?\" and began his lecture with a discussion on \"breaking out of the dopaminergic box\", highlighting the need for more complex approaches to PD and suggesting a multimodal pharmacological perspective as the best way in the future. Dopaminergic approaches dominate the field as they are highly effective for this disorder but can lead to complacency, considering there are still some needs in PD that cannot be treated with a dopaminergic approach. He suggested that although the dopaminergic treatment helps non-motor symptoms it is not the complete solution, and discussed safinamides as a treatment option. An essential point of his presentation was that there are non-dopaminergic components to both motor and non-motor symptoms of Parkinson's disease. Cristian Falup-Pecurariu (Romania), the Head of the Department of Neurology at the County Clinic Hospital from Brasov (Romania), presented \"Autonomic dysfunction in Parkinson's disease\", discussing the spectrum of dysautonomia symptoms in PD and the prevalence of different symptoms (dependent on study methodology). Parkinson's Disease (PD) has a wide variety of non-motor symptoms and one of the frequently encountered ones \u2013 autonomic nervous system dysfunction \u2013 direly impacts the quality of patients' lives. In advanced stages, dysautonomia significantly impacts the activities of daily living. He then discussed the relationship between disease progression and survival rates of autonomic dysfunction and dysautonomia in patients with a high risk of PD, pinpointing on the autonomic dysfunction and disease severity. Methods of dysautonomia assessment and specific symptoms were additionally presented. Comprehensive approaches to treatment management were showcased.Alla Guekht (Russia), Director at the Moscow Research and Clinical Center for Neuropsychiatry in Moscow (Russia), presented \"Post-stroke cognitive impairment and dementia \u2013 Treatment challenges\", addressing epidemiology, the populations at risk, potential targets, prevention, treatment, and current strategies and perspectives. As the population is growing older, people 65 and over represent the fastest growing group, posing several issues, with post-stroke cognitive dysfunction representing an important factor of morbidity. With shifting demographics, increased post-stroke survival and life expectancy can also mean an increased number of patients with post-stroke cognitive impairment. Prof. Guekht discussed the importance of implementing results for clinical trials in different groups and addressing the challenges and unresolved issues in post-stroke cognitive decline. For this, the trajectory is of utmost importance. The complexity of the affection requires combined approaches and assessment at different time points, as well as consideration of the emotional and cognitive problems. She presented some risk factors that increase the magnitude and speed of post-stroke cognitive decline, highlighting early seizures after stroke and the post-stroke development of epilepsy. The relationship between stroke location and cognitive outcomes, the association of cognitive impairment with early seizures, and the multidomain lifestyle interventions to prevent cognitive decline after stroke were also subjects touched upon. Moreover, Prof. Guekht encouraged integrative approaches in diagnosing and treating neurological disorders and discussed the need for increased research and more clinical trials to address the best strategies for post-stroke cognitive impairment.Jozsef Szasz (Romania), Associate Professor at the Department of Neurology at George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures (Romania). He described the Romanian context for testing and initiating therapy by means of a multicenter study from 9 university teaching hospital centres on 113 patients. The presented research demonstrated the effects of therapy on patients with advanced Parkinson's disease. Prof. Szas detailed his research on the matter, highlighting, through video presentations of the patients over the years, the effects of the treatment.Next, Session 10, presided by Jozsef Szasz (Romania) and Cristian Falup Pecurariu (Romania) was introduced with a presentation on \"Management of advanced Parkinson's disease with Levodopa intestinal gel\" by Dafin Mure\u0219anu (Romania), the president of the European Federation of NeuroRehabilitation Societies (EFNR) and Chairman at the Department of Neurosciences from Iuliu Hatieganu University of Medicine and Pharmacy in Cluj-Napoca (Romania), then presented \"Is neurorehabilitation useful in Parkinson's Disease?\". Prof. Muresanu began with an introduction to brain functions and the shifting paradigm in neuroscience, offering a brief parallel between the physics and biology approaches in neuroscience. He further discussed the three circuitries of the nervous system, namely the limbic, the associative, and the sensorimotor, underlining the importance of said mechanisms working in harmony. Next, Prof. Muresanu masterfully described the \"small-world\" network organization of the brain, the endogenous modulation based on balancing anticorrelated processes, and the interrelation between the brain's levels of organization. Further on, he discussed basal ganglia and behavior regulation, the relationship between dopamine and executive dysfunction, and the relationship of rehabilitation with the biological reserve, highlighting the differences between the classic medical model and the rehabilitation model. Moreover, prof. Muresanu pinpointed the role of restoration versus compensation in neurorehabilitation, the specialists needed for developing a comprehensive rehabilitation team, and the functional rationale for neurorehabilitation in Parkinson's Disease. Prof. Muresanu also discussed guidelines for occupational therapy in PD, mentioned the importance of cueing in the rehabilitation process, and ended on a brief note on neurorehabilitation in different PD stages.Stanislav Groppa (Moldova), Head of Neurology Department at the State University of Medicine and Pharmacy Nicolae Testemitanu in Chisinau (Republic of Moldova) presented \"Nonconvulsive Status Epilepticus \u2013 A Complex and Often an Under-Recognized Entity\". Prof. Groppa discussed status epilepticus as a neurological emergency and a challenge of modern neurology, as the condition is difficult to delimit, and current clinical options remain unsatisfactory. This affection is often unrecognized, leading to delays in diagnosis and treatment, mostly due to failure to request an electroencephalogram (EEG). He showcased issues in diagnosis, the role of EEG on epidemiology, and pinpointed \"borderline syndromes\" where electrographic convulsive activity appears without obvious clinical seizures. The discussion then centered around the primary forms (nonconvulsive and convulsive), their causes, the trigger factors, clinical manifestations \u2013 including chameleon presentation and mimic disorders. Furthermore, he approached the management, complications, and treatment recommendations for this disorder, the need for tailored interventions, the importance of research with prospective studies on the effects of extended continuous EEG monitoring on outcomes and cost-effectiveness strategies for early identification and treatment.Adina Roceanu (Romania), Primary Neurologist and Research Scientist at the Neurology Department from the University Emergency Hospital Bucharest (Romania), on migraine treatment. Beginning with the definition and symptoms of migraines, she offered insight into one of the most common affections for the larger population. Prof. Roceanu discussed the classifications of migraines with and without aura, highlighting specific criteria for each of the two presentations. She underlined related affections, including chronic migraines and medication-overuse headaches, while also showcasing the clinical phases of migraines and the role of specific agents in their treatment. Dr. Roceanu ended her presentation with a mention of some non-pharmacological approaches which are appropriate in situations where pharmacological treatment proves ineffective.The following session, Session 11, introduced by Adina Roceanu (Romania) and Corina Roman (Romania), began with a presentation by Corina Roman (Romania), the Head of the Neurology Department at the County Hospital Sibiu (Romania), approached case presentations on secondary headaches. Prof. Roman discussed the international classification of headache disorders, the general principles, and the pharmacological agents that can cause headaches. She described red flags suggestive of secondary aetiology of headache in patient history and introduced clinical case presentations on headaches attributed to arteriovenous malformation, headaches caused by cerebral tumors, and patients with MS with associated secondary trigeminal neuralgia. Prof. Roman suggested that headache is prevalent and headache disorders are among the most common signs of nervous system disorders, making it vital to consider the patient history, neurological examinations, and the SNOOP mnemonic as the best predictors of pathology.Vitalie Vacaras (Romania), Lecturer of the Neurology and Pediatric Neurology Discipline at the Iuliu Hatieganu University of Medicine and Pharmacy in Cluj-Napoca (Romania) presented \"When headache hides neurocysticercosis \u2013 Case presentations\", an interesting clinical case with some unexpected characteristics. He began by discussing cysticercosis \u2013 what it is, what some of the risk factors and its most common manifestations are \u2013 and followed with the specific case, detailing the diagnostics and examination of the patient, the prognosis of the disease, initial treatment, evolution, and outcomes, discussing the implications and rationality for choosing the previously mentioned case.Catalin Jianu (Romania), Professor of Neurology, Head of the First Department of Neurology, and Head of Advanced Research Centre for Cognitive Research in Neuropsychiatric Pathology at the Victor Babes University of Medicine and Pharmacy in Timisoara (Romania), \"An integrated approach on the diagnosis of cerebral veins and dural sinuses thrombosis\", in which Prof. Jianu began by offering the public information on the epidemiology of the disease. Then, he discussed cerebral veins anatomy, the anatomy of intracranial dural sinuses, the aetiology and risk factors, genetic and acquired thrombophilia, the most common risk factors, and the impact of COVID-19. Next, he covered the pathophysiological mechanisms leading to the clinical presentation of cerebral venous thrombosis (CVT), and also discussed clinical diagnosis, the importance of laboratory data and tests, and imaging methods. Further on, Prof. Jianu presented the experience of the hospitals, an analysis of 70 patients admitted between 1998 and 2021 and the results, as well as a review of an integrated approach to the diagnosis of cerebral veins and dural sinuses thrombosis. He then showcased another case review on cavernous sinus thrombosis in a woman with inherent thrombophilia and one on acute isolated lateral sinus thrombosis. One important takeaway from his presentation was that a comprehensive clinical spectrum with an often-misleading presentation might cause diagnosis delays.The last session of the event, Session 12, presided by Catalin Jianu (Romania) and Vitalie Lisnic (Republic of Moldova), was introduced with the presentation of Mihail Gavriliuc (Republic of Moldova), Professor of Neurology and Chairman of the Neurology Department from the State University of Medicine and Pharmacy Nicolae Testemitanu in Chisinau (Republic of Moldova), presented on Neuroborreliosis, an antropozoonosis also known as Lyme disease. Prof. Gavriliuc discussed the aetiology of different species of Borrelia, the biological basis and different presentations, Lyme disease vectors, and the deer tick's life cycle. He approached epidemiology, pathogenesis and pathophysiology, and clinical manifestations for early and late neuroborreliosis. He highlighted the Bannwarth triad symptoms and outlined differential diagnosis of Lyme neuroborreliosis, diagnostic workup, the management of the disease in the early and late stages and the importance of individualized therapies.Vitalie Lisnic (Republic of Moldova), Professor of Neurology at the Nicolae Testemitanu State University of Medicine and Pharmacy in Chisinau (Republic of Moldova), ended the congress with his presentation \"Wilson disease \u2013 a constellation of phenotypes\". First, he discussed the history of the disease, its aetiology, prevalence, and other epidemiological aspects and highlighted the clinical picture and the existence of a delay in diagnosis. Further on, Prof. Lisnic described hepatic, psychiatric, ophthalmic, and neurological manifestations, followed by methods of diagnosis. Lastly, he presented clinical cases and treatment with different cure options for various presentations and discussed new treatment avenues. One fascinating insight of his proceedings is an algorithm for treating Wilson's disease. He ended by stating the importance of investigating Wilson Disease (WD) in any patient with neuropsychiatric manifestations of unknown cases. The disease can be fatal without therapy, yet treatment has an excellent prognosis.The conclusions of the event were drawn by Dafin Mure\u0219anu (Romania), Natan Bornstein (Israel), Volker Homberg (Germany), and Wolfgang Grisold (Austria), with Prof. Muresanu sharing his hopes for an in-person next edition of the Summer School of Neurology. Prof. Muresanu touched upon the possibility of future hands-on programs and extended his gratitude to everyone who contributed to the development of the program."}
+{"text": "Dear Editor,Plasma Cell Cheilitis (PCC) is a rare inflammatory disorder of unknown origin within the spectrum of plasma cell mucositis. Clinically, it manifests as a circumscribed, flat to slightly raised, eroded erythematous plaque or patch involving the lower lip of elderly male patients.An otherwise healthy 52-year-old man, an agricultural worker, was referred to our hospital with a ten-year history of painful erythematous erosion on the lower lip. Physical examination revealed an erythematous plaque with diffuse desquamation along with erosions and crusts A. DermosOne of the main differential diagnoses in the context of our patient was Actinic Cheilitis (AC) or even progression to Squamous Cell Carcinoma (SCC). Dermoscopy could be a useful tool to help differentiate these entities. We found some similarities between our case and the previously reported regarding border regularity and vascular enlargement and proliferation.Although PCC is considered a benign disorder is usually refractory to various topical treatments, including topical and intralesional corticosteroids, topical calcineurin inhibitors, antibiotics, and antifungal agents.None declared.Daniella Truffello: Approval of the final version of the manuscript; critical literature review; data collection, analysis, and interpretation; intellectual participation in propaedeutic and/or therapeutic management of studied cases; study conception and planning.Carolina Cevallos: Approval of the final version of the manuscript; critical literature review; effective participation in research orientation; manuscript critical review; preparation and writing of the manuscript; study conception and planning.Claudio Escanilla: Approval of the final version of the manuscript; critical literature review; effective participation in research orientation; intellectual participation in propaedeutic and/or therapeutic management of studied cases; manuscript critical review; study conception and planning.Pauline Morgan: Approval of the final version of the manuscript; data collection, analysis and interpretation; intellectual participation in propaedeutic and/or therapeutic management of studied cases.None declared."}
+{"text": "Based on the panel data of thirty-one provinces in China from 2003 to 2020, we constructed an evaluation index system of urban-rural integration development level from the perspective of factor flow. The combined weighting model of GI and CRITIC were used to evaluate the regional urban-rural integration development. The coefficient of variation and panel fixed effect model was used to explore convergence, absolute convergence, and conditional convergence. The impact of capital, labor, and technology factor flow on the convergence of urban-rural integration development level was further investigated. In addition, the difference analysis in time scale and impulse response function analysis was performed to explore the regular pattern of factor flow on the convergence of urban-rural integration development. The main conclusions were as follows: first, the growth of urban-rural integration development had an absolute convergence trend and tended to conditional convergence faster. Second, the capital flow positively affected the convergence of urban-rural integration development, while labor and technology flow had a slowing effect on the convergence of urban-rural integration development at this stage. Third, the impact of factor flow on the convergence of urban-rural integration development was dissimilar during different phases. The convergence rate of urban-rural integration development after 2012 was drastically slower than before. The urban-rural disparity is a critical headspring of social structure differences. For a long time, \u201cUrban bias\u201d has existed and been popular due to people's wrong concepts and restrictions of development. In recent years, problems have become more and more apparent, like the gap between rural and urban economic development is increasingly widening, and the rural economy has been aggravating in some areas. The proportion of urban population and output rises due to the \u201cSiphoning effects.\u201d Agriculture has languished and lost development vigor, and rural areas face the issue of growing depopulation . The ecoOne of the important performances is the unbalanced development between urban and rural areas and inadequate development in rural areas. Promoting the integrated urban-rural development is the key to alleviating the unbalanced and inadequate development between urban and rural areas and the objective requirement of ensuring common prosperity between urban and rural residents. Urban and rural integration breaks the contrary state of the urban-rural dual structure and gradually realizes the rational flow and optimal combination of factors in urban and rural areas. Urban-rural coordinating development had been proposed as a strategy as far back as 2002. \u201cPromote the integration of urban and rural development\u201d was proposed in 2012. Furthermore, on this basis, integrated urban and rural development was proposed in 2017, emphasizing the interaction of urban and rural factors. The evolution of the policies might fully embody the development of cognition on urban-rural relations [Factor mobility between urban and rural areas might change the fundamental structure of urban and rural elements, influence the evolution of urban-rural relations, and then affect urban-rural integration development. At the micro-level, factor flow might put idle resources to work, promote balanced marginal returns growth in urban and rural elements, and realize complementary functional advantages and maximization of integral benefit . At the Along with the development of urban-rural relations, the concept of urban-rural integration is continually developed . FurtherIn recent years, the study on the flow of urban and rural factors has been roughly divided into three aspects . Some stIt is normal to have a certain degree of development gap in social and economic development , 22. HowIn short, other studies on the overall development of urban and rural areas and their index systems cover three dimensions: society, economy and ecology, mainly adopting the ratio of urban and rural indicators, and then making a descriptive analysis of the results. The research on the combination of urban-rural integration and factor flow focuses on the internal logic and relationship, lacking specific empirical research. The possible marginal contributions of this paper are as follows: Firstly, given that urban and rural areas are two different social forms, the state indicators and dynamic indicators showing the integrated of urban-rural development are added on the basis of the mainstream of urban-rural comparative indicators in the past; the spatial integration dimension is added to the indicator system for the closer spatial connection between urban and rural areas. Secondly, from the perspective of factor flow, this paper analyzes the regional gap and convergence of the integrated urban-rural development. It also further explores the differences of labor, technology, and capital factor flow on the integrated urban-rural development convergence, which not only provides reference for further promoting integrated urban-rural project but also provides theoretical support for guiding the free and orderly flow of factors. Thirdly, by means of using provincial data, this paper examines the distribution and convergence of the overall integrated urban-rural development at a macro level, and explores the influence of the flow of factors between urban and rural areas in different provinces on the overall integrated urban-rural development and regional economy.From the perspective of spatial evolution, the difference of factor resource endowment between urban and rural areas is the initial reason for the low level of urban-rural integration development. With the advancement of industrialization, the centripetal force formed by the city's market effect and price index effect makes the factors gather in the urban area, which gradually improved the production conditions and quality of life in urban area. The flow of factors promotes rapid urban economic growth. At the same time, this process also accelerates the process of element agglomeration. Once the accumulation of factors in urban reached a specific size, the cost of living and production in cities is gradually rising, which might create centrifugal forces and crowding effect, and progressively transfer factors to rural areas, promote rural economic development, narrow the development gap between urban and rural areas, and improve the development level of urban-rural integration. By promoting the two-way flow of urban and rural factors in various regions, urban-rural integration development gradually balances. Finally, the convergence of urban-rural integration is realized. Our growth function of urban-rural integration development level is as follows:yt+1i \u2212 ln\u2009\u2009yti) is affected by the urban-rural integration development level (yti) of the region and the gap between areas ) and other factors (xti). The gap between areas is affected by the stock and flow of labor, capital, and technology. Based on this, Hypothesis 1 is proposed in this study.\u2009 H1: factor flow might play a critical role in converging urban-rural integration development.As shown in the above formula, the growth of urban-rural integration development level Hti indicates the natural growth (WHti \u2212 WHtj/WHts) and suggests the transfer ratio caused by the reward gap of H factors between regions. The scale of labor mobility increases with the increase of the pay gap. However, there is an upper limit on labor transfer. The congestion function is defined as m = Ht + (Lt/Nt)Nt+1 = (1 + \u03c6)Nt, indicating that the regional population capacity limits the proportion of labor mobility. Similarly, the meaning of the labor mobility equation is similar to that of H. When the pay gap between regions of H factor is higher than that in L, its proportion of labor transfer is also higher. With the increase H, the scale of subsequent labor flow is limited in places of influx and finally the number of H and L reaches a balance in the process.The above formula /Rts). The former fixed capital transfer is multiplied by the realization coefficient t based on this proportion. Therefore, the simplified form of capital transfer equation is as follows:The capital transfer is affected by the differences in regional interest rates. It is worth noting that fixed and new capital transfer speed is different. It is assumed that the transfer proportion of new capital i is lower than in region j, the item (Rti \u2212 Rtj) becomes negative. Currently, the elements in the j area show a trend of backflow. Affected by the difference of interest rates between regions, the capital flow might promote the capital flow, which affects both the regional economic development and the urban and rural integration and development. Based on this, hypothesis 2b is proposed:\u2009 H2b: capital flow has a critical impact on the convergence of urban-rural integration development.As shown in the above formula, when the interest rate in region Technology transfer is affected by the proportion of science and technology funds in financial expenditure (the rate of technology investment). Like the above capital transfer equation, the simplified form of the technology transfer equation is as follows:i is lower than the regional technology input rate of region j, (Tti \u2212 Ttj), it becomes negative. The elements of the j area show a return trend. Affected by the difference in technology input rate, technology flows between regions, affecting regional economic development and urban-rural integration development. Based on this, hypothesis 2c is proposed:\u2009 H2c: technology flow has a crucial impact on the convergence of urban-rural integration development.The setting of the above formula does not limit the inflow and outflow places. When the interest rate of region Based on the abovementioned, promoting the integrated urban-rural development is actually promoting the two-way flow of elements between urban and rural areas. For a long time, a large number of productive factors in rural areas have continuously flowed into cities unidirectionally, resulting in serious \u201cblood loss\u201d in rural areas. In the new relationship between urban and rural areas, rural elements flow to cities, and urban elements also flow to rural areas, which will form a virtuous circle of two-way flow of urban and rural elements. It is essential to guide the factors to flow freely and orderly between urban and rural areas, and activate the endogenous power of rural development through \u201coptimizing the combination effect of factors,\u201d \u201cspillover effect of knowledge dissemination technology,\u201d and \u201cexpanding market scale effect by division of labor,\u201d so as to promote the integrated development of urban and rural areas.The growth level of urban-rural integration development. Based on Chang et al. , the difDevelopment level of urban-rural integration, labor flow, capital flow, and technology flow. The development level of urban-rural integration is measured by establishing an index system and calculating the urban-rural integration development index. We construct an evaluation index system for urban-rural integration development, following the scientific and creative principles. Labor flow equals the ratio of the number of employees in this province and the average number of employees in other regions in the current year. Capital flow equals the balance of the number of capital formation rates to the average value of capital formation rate in the current year in other provinces. Technology flow equals the ratio of this province's science and technology expenditure (R&D expenditure) to the average science and technology expenditure of other regions.Per capita GDP (logarithm), fiscal decentralization, and rural financial services in this region. The higher the regional GDP, the better the regional economic development, which could drive regional urban-rural growth and impact urban-rural integration development. The higher the level of fiscal decentralization, the more autonomy the local government has, which could reasonably arrange urban and rural resources, promote resource allocation, and promote regional urban-rural integration and development. Rural financial services mean financial support for rural areas. The more thoughtful rural financial services are, the more funds might be provided for rural development, which could accelerate the speed of urban-rural integration and development. The above control variables are measured by the proportion of local government income in total income and per capita agriculture-related loans (logarithm).The econometric model selected in this study refers to the research on the setting of the convergence model by Bakbak and Kansu  and Cholyi,t is the development level of urban-rural integration in the region i during the periodt, yi,t\u2212T is the development level of urban-rural integration in the region i at the beginning of the intervalT. Due to the short observation period, this study investigates the growth rate of urban-rural integration development in one (1/T)ln year. The average annual growth rate of the development level of urban-rural integration in the region \u03b2 is the convergence rate of the development level of urban-rural integration in the region. Variable Z includes fiscal decentralization, rural financial services, industrial structure, and other factors that might affect the growing convergence of urban-rural integration development. At the same time, to avoid simultaneous errors of variables, we deal with the first-order lag of critical investigation variables and control variables.Among them, yi,t \u2212 ln\u2009\u2009yi,t\u22121 refers to the growth of regional urban-rural integration development level in the year; yi,t\u22121 is the development level of urban-rural integration that lags behind the first stage; Ki,t\u22121 is the factor flow that lags behind the first period in the region, including labor flow lm, capital flows cf, technology flow tf; Xi,t\u22121 is a series of control variables that affect the growth of regional urban-rural integration development; ui refers to the individual effect; vt indicates the time effect; \u03bei,t is a perturbation term.According to formula , the fol\u03c3 convergence model belongs to the concept of convergence in neoclassical economic growth theory. If there is \u03c3 convergence in the level of urban-rural integration, then the urban-rural integration converges in absolute value and finally realizes the balanced development of urban-rural integration. The coefficient of variation was used to measure the convergence of urban-rural integration, as shown in the following formula:The Values were expressed as mean\u2009\u00b1\u2009SD.https://olap.epsnet.com.cn, accessed on December 16, 2021)). Some missing data are supplemented by interpolation. Due to the lack of data from Hong Kong, Macao, and Taiwan, 31 provinces and cities are selected as the research objects. The following table is the basic descriptive statistics for the samples. To avoid the objective deviation caused by experts' subjective judgment and incomplete data statistics and make up for the lack of single weighting, we adopt the combination of the G1 method and critical subjective and objective weighting method. Taljaard and Mare [The data used in this study are from the relevant years of \u00abChina Financial Statistics Yearbook\u00bb, \u00abChina urban and rural construction statistics yearbook\u00bb, provincial statistical yearbooks, EPS database , rural financial services (L. lnrfs), and per capita GDP (L. lnpgdp). Before the empirical analysis, the unit root inspection was carried out on the panel data, and the results demonstrated that the variables were stable. There are three models for panel data model estimation: mixed regression model, fixed-effect model, and random effect model , 31. TheThe fixed effect was estimated for the panel data to validate whether there was absolute convergence of the development level of urban-rural integration. The benchmark regression results are exhibited in \u03b2 Convergence trend in the growth of urban-rural integration development in China with provinces and cities as samples by using the fixed effect estimation of panel model \u03b2. After controlling the time effect in model (2), the coefficient of L. lny was still negative, indicating that this result was relatively robust. After adding variables such as fiscal decentralization (FD), rural financial services (Lnrfs), and per capita GDP (lnpgdp), the regression coefficient of L. lny was still negative regardless of whether the time effect was controlled. The convergence rate in model (3) was 0.087 percentage points higher than that in model (1), and that in model (4) was 0.053 percentage points higher than that of model (2). These data indicated a trend of absolute convergence in the growth of regional urban-rural integration development. Moreover, this growth might tend to conditional convergence at a faster speed.As shown in We next investigate the convergence of factor flow on the growth of urban-rural integration development, the interaction terms of capital flow and urban-rural integration development, labor flow and urban-rural integration development, technology flow, and urban-rural integration development were introduced into the model, respectively. The benchmark regression results are shown in As shown in As shown in As shown in \u03c3 convergence verification, we first understood the improvement process of regional urban-rural integration development. Here, we depicted the density diagram of urban-rural integration development before and after the year of the promulgation of the policies of \u201ccoordinating urban-rural economic and social development,\u201d \u201cpromoting urban-rural integration,\u201d and \u201curban-rural integration.\u201dBefore the \u03c3 convergence) of regional urban-rural integration development and factor flow was measured by the variation coefficient of urban-rural integration development and factor flow. As shown in \u03c3 convergence). The coefficient of variation of factor flow was greater than that of urban-rural integration. From big to small, the coefficient of variation of factor flow among provinces and cities was technology flow, labor flow, and capital flow [As shown in tal flow .Affected by the implementation of the policy, the impact of factor flow on the growing convergence of the development of urban-rural integration in provinces and cities might be diverse during different phases. After the proposal of \u201ccoordinating urban-rural economic and social development\u201d in 2002, the relationship between urban and rural areas had changed from Urban-Rural separation to urban-rural integration. \u201cPromote urban-rural integration\u201d was proposed in 2012. It is reasonable to believe that there might be pronounced period heterogeneity in the impact of factor flow on the growth of urban-rural integration development in different provinces and cities. It is necessary to further explore the time difference of factor flow on the convergence of urban-rural integration development in China. Here, the two-way fixed effect model of panel data were employed to investigate the situation in different regions in 2003\u20132011 and 2012\u20132020, respectively. The results are shown in As shown in Impulse response function could directly reflect the dynamic interactive relationship and effect between variables and urban-rural integration development. To avoid orthogonalization dependence caused by the order of variables, VAR models of general impact response between variables and the development speed of urban-rural integration were established, respectively. The impact results of impulse response are shown in To test the robustness of the above empirical results, the independent weight coefficient method is used to recalculate the regional urban-rural integration development index, which is substituted into the two-way fixed effect model of the panel data model for re-estimation. The results are shown in As shown in Provinces and cities with the extreme growth trend of urban-rural integration development might have substantial heterogeneity and significantly impact the empirical results. Therefore, to overcome the possible impact of this situation, the top and bottom five provinces and cities in the urban-rural integration development were excluded, and the robustness of the above empirical conclusions was assessed. As shown in \u03b2 convergence model. We further explored the time difference of factor flow on the growing convergence of regional urban-rural integration development and assessed the robustness. The main conclusions were as follows:Based on the perspective of factor flow, we constructed the evaluation index system of urban-rural integration development using the panel data of 31 provinces in China from 2003 to 2020. The combined weighting model of GI and CRITIC were used to evaluate the regional urban-rural integration development. The impact of capital, labor, and technology factor flow on the convergence of urban-rural integration development was evaluated using the coefficient of variation and The growth of urban-rural integration development had an absolute convergence trend and tended to conditional convergence faster. The variation coefficient of urban-rural integration development and the regression coefficient of L. lny in model (1) was negative, indicating a definite convergence trend in urban-rural integration development. Furthermore, the estimated coefficient was still negative after controlling the time effect, indicating that the conclusion was stable. After introducing the variables such as fiscal decentralization (FD), rural financial services (Lnrfs), and per capita GDP (lnpgdp), the regression coefficients of L. lny were negative regardless of whether the time effect is controlled. The convergence rate of model (3) was 0.087 percentage points higher than that of model (1). Moreover, the rate of model (4) is 0.053 percentage points higher than that of model (2), implying that the growth of regional urban-rural integration development had the trend of absolute convergence, and it might tend to conditional convergence at a faster speed.Nowadays, the capital flow has a positive effect on the convergence of urban-rural integration development, while labor flow and technology flow have a slowing effect on the convergence of urban-rural integration development. After adding the interaction term between capital flow and urban-rural integration development, the coefficient of urban-rural integration development in the base period was negative, whereas the coefficient of interaction term was positive, and the convergence rate increased. Capital flow positively affected the growth and convergence of urban-rural integration development. After adding the interactive term of labor mobility and urban-rural integration development, the coefficient of urban-rural integration development in the base period and the coefficient of the interactive term was negative, and the convergence rate decreased. After adding the interaction term between technology flow and urban-rural integration development, the coefficient of urban-rural integration development level in the base period and the coefficient of interaction term were negative, and the convergence speed also decreased. Labor and technology mobility slowed the growth and convergence of urban-rural integration development at this stage.There were time differences in the impact of factor flow on the convergence of urban-rural integration development. The convergence rate of urban-rural integration development after 2012 was markedly slower than before. Before and after the proposal of \u201cpromoting urban-rural integration\u201d in 2012, the growth of urban-rural integration development of provinces and cities in China showed a convergence trend, and the convergence rate was about 0.030 percentage points lower than before 2012. We also found significant differences in the impact of factor flow on the convergence of regional urban-rural integration and development around 2012. The convergence rate of urban-rural integration development before 2012 is higher than after 2012. Furthermore, the interaction coefficient of capital flow, technology flow, and urban-rural integration development also showed the opposite direction before and after 2012. However, the interaction coefficient of labor flow and urban-rural integration development had not changed before and after 2012.We should further promote the rural revitalization strategy and the two-way flow of urban and rural factors. The core of the rural revitalization strategy is talent revitalization. Establishing an institutional mechanism for the rational flow of urban and rural populations could attract rural and urban labor to stay in rural areas and start businesses to build rural areas. Establish and improve the introduction and training mechanism of professional farmers, cultivate new agricultural business entities, and improve the labor skills and quality of the rural population by establishing a talent training and exchange platform, strengthening the contact and cooperation between urban and rural talent markets, and establishing an information-sharing mechanism to provide institutional basis and policy guarantee for the rational flow and optimal allocation of urban and rural resources. Build the benefit-sharing mechanism for factor subjects, build a mechanism combining the complementary functions of the government and the market, and build the endogenous development mechanism of rural areas to promote the two-way flow of urban and rural factors, which guide the flow of production factors to rural areas.Develop the financial allocation capacity of local governments and guide financial funds flow to rural areas. Financial support is the first element to develop a new countryside. Coordinating urban and rural development is a systematic project, which might not be realized only by market mechanism regulation. We should develop the positive guiding role of government funds, increase capital investment, leverage financial funds and social resources, and speed up the construction of a new countryside. We should increase fiscal expenditure on rural education, agricultural science, and technology; insist education as the foundation and technology as a means; improve the actual productivity of rural areas; and attract more talents to participate in rural construction. Establish and improve the government investment guarantee system to increase the public budget for agriculture and rural areas to fill the lack of agricultural and rural development. We should plan new financing ideas, strive for external progress, tap internal potential, and raise funds through multiple channels. Through the cross-regional transaction of land-saving indicators, more funds will be attracted to rural areas, and more rural people will share the urban development.Focus on areas with slow urban-rural integration development and seek novel points. Promote the development of regional urban-rural integration, which tends to high-level convergence. We should promote the equalization of basic public services between urban and rural areas, improve the benefit-sharing mechanism for residents, and enable urban and rural residents to share the development of new urbanization. We might build basic public service facilities in urban and rural areas following unified allocation standards; further improve the security system for the elderly, the weak, the sick, and the disabled; and promote the integration of health care, old-age care, education, and employment. Promote the integration of urban and rural undertakings, increase investment in rural preschool education, and consolidate and enlarge teachers' teams. Insist overall consideration, individual breakthroughs, suit local conditions, fully consider the different stages of urban-rural integration development in different regions and the vast differences between diverse rural areas, and form a unique and practical development model of urban-rural integration."}
+{"text": "Knowledge of the main markers of bipolarity, clinical features and the course of depression within BPAD in men and women will contribute to the correct diagnosis, prog- nostic assessment of the disease course and administration of an adequate therapy.The aim of the investigation was to study the clinical features of depression in men and women with BPAD in order to identify markers of bipolarity, facilitate a diagnostic search and determine therapeutic tactics.The study was conducted from 2018 to 2020 in outpatient and inpatient conditions of the S. S. Korsakov Psychiatric Clinic of Sechenov University. 100 patients (50 women and 50 men) with a diagnosis of F31.3-F31.5 according to ICD-10 were examined by the clinical method.In the structure of the depressive phase in men, the following were more common: pronounced seasonality (with deterioration in autumn-winter) and daily fluctuations in the state (with improvement in the evening), anesthesia of the senses, depersonalization-derealization syndrome, decreased libido, difficulty falling asleep and increased appetite and / or body weight, comorbid depression, panic attacks and alcohol and surfactant abuse. Depression within the BPAD in women was characterized by a more frequent presence of apathy, tearfulness, self-harm, dysmorphophobic inclusions, decreased appetite.The revealed features of psychopathological symptoms and correlations between some characteristics and factors, taking into account gender differences, can be used as markers of bipolarity, which will allow for an earlier and more accurate diagnosis of BPAD and adequate therapy.No significant relationships."}
+{"text": "This study aimed to investigate the effect of self-management behavior on the rehabilitation of stroke patients to lay a theoretical basis for using patient-reported outcome (PRO) for rehabilitation evaluation of stroke patients.t-test and analysis of variance. Bonferroni method was used for multiple comparison correction. The correlation between rehabilitation results and patients\u2019 basic conditions and self-management was investigated through Pearson correlation analysis. The main factors for self-management behaviors were studied through multiple stepwise regression analyses.396 patients hospitalized in the Department of Neurology of 4 tertiary general hospitals in Datong from August 1st 2018 to March 31st 2020 were included in accordance with the inclusion and exclusion criteria. The included patients were randomly assigned into a self-management intervention group and a control group. Only the control group received the clinical pathway intervention of stroke rehabilitation. The stroke patients in the intervention group received the self-management intervention in addition to the clinical pathway intervention of stroke rehabilitation. The self-management status and rehabilitation results of the patients were evaluated in 24 h and 3 months after the patients were enrolled, respectively. Statistical description and analysis were conducted using SPSS20.0 statistical software. The general data of the patients were expressed by percentage. The data regarding patients\u2019 self-management and rehabilitation results were statistically described by percentage, mean and standard deviation. The comparison between groups was drawn through P < 0.01). In this study, there was no statistical difference in different genders and medical insurance status (P > 0.05). The total scores of self-management behaviors and the scores of the respective dimension were positively correlated with the health education, exercise intervention, functional training, psychological intervention, food intake, living habits, and functional training of stroke patients at the recovery stage. Educational level and marital status were positively correlated with the rehabilitation results of patients. The PRO questionnaire for the stroke scored higher in married patients and highly educated patients, and there were statistically significant differences (P < 0.01). Family history was negatively correlated with the rehabilitation results of patients. Exercise intervention and functional training were positively correlated with the rehabilitation results of patients.The total scores of self-management behaviors of the investigated subjects achieved statistical significance in different ages, occupations, educational levels, income levels, exercise intervention, past medical history, BMI, as well as marital status (Education level, health education, food intake, exercise and rehabilitation training, sleep, and psychological intervention were the main factors for self-management behavior in stroke patients at the recovery stage. Self-management interventions can effectively increase the health education level of stroke patients, strengthen their self-confidence in disease self-management, facilitate the establishment of effective self-management behavior of patients, and improve their quality of life and subjective well-being. Stroke PRO scale can be used to evaluate the clinical intervention effect of self-management on stroke patients in multiple dimensions, especially evaluating the improvement of subjective mental and psychological state of patients, thus revealing the intervention effect of self-management on stroke patients comprehensively. The rehabilitation of stroke patients at the recovery stage (2 weeks to 6 months after onset) is a vital factor in the prognosis and quality of life of stroke patients . ExistinThis study gained approval from the Medical Ethics Committee of Shanxi Datong University. A total of 396 patients with a stroke at the recovery stage from August 1, 2018 to March 31, 2020 in the Fifth, Third, and Second People\u2019s Hospitals of Datong City, Affiliated with Shanxi Datong University and Tongmei General Hospital of Datong City were included as the subjects for investigation.The inclusion criteria of subjects are elucidated below: \u2780 Patients meeting the diagnostic criteria established at the Fourth National Academic Conference on Cerebrovascular Diseases in 1996  and confThe exclusion criteria of subjects included patients with severe illness, the degree of ADL deficiency  was BI \u2264 20 and BI = 100,unclear consciousness  , or cognThe general demographic characteristics, lifestyle, health status, treatment and intervention of the subjects were investigated and evaluated by the self-made questionnaire. The PRO scale for the stroke developed by Wei Xiaoyuan of Shanxi Medical University was used to evaluate the rehabilitation results of patients. The PRO scale was investigated using the self-rating scale method, and its reliability, validity, and feasibility were examined, which confirmed its high reliability, validity, fairness, and feasibility .The serious and responsible medical staff in the neurology department should be recruited as the investigators for unified training. Subjects with a consistent baseline were included in accordance with the inclusion and exclusion criteria. \u2780 Patients were randomly assigned to a control group and a self-management intervention group by computer random number method, with 198 patients in the respective group. The patients\u2019 condition was evaluated within 24 h and 3 months after the patients were enrolled by the self-made general questionnaire and the PRO Scale for the stroke. \u2781 The patients in the control group received the clinical pathway intervention of stroke rehabilitation in a standard hospitalization period of 22\u201328 days. According to the specific type, course and main complications of stroke, appropriate clinical treatment measures were selected according to the Clinical Diagnosis and Treatment Guidelines \u2013 Neurology; during the standard hospitalization period of 22\u201328 days, the patients in the intervention group received self-management education while receiving the clinical pathway intervention of stroke rehabilitation. On the day of admission, the third week of hospitalization and the day of discharge, the nurse in charge of the patient carried out self-management education in the ward  to improve the patient\u2019s self-efficacy, daily functional activities, and eliminate negative emotions. Methods: The form of mobile phone WeChat official account combined with bedside nursing was used for propaganda and education . \u2782 The st-test and analysis of variance. Bonferroni method was used for multiple comparison correction. The correlation between rehabilitation results and patients\u2019 basic conditions and self-management was investigated through Pearson correlation analysis. The main factors for self-management behaviors were studied through multiple stepwise regression analyses. When P < 0.05, the difference is statistically significant.After the questionnaire was collected, the data of study materials were entered into an Excel spreadsheet by two people and two computers, and a database for logical examination and correction was built. The statistical description and analysis were conducted using SPSS20.0 statistical software. The general data of patients were statistically denoted as percentages. The data regarding patients\u2019 self-management and rehabilitation results were statistically described by percentage, mean and standard deviation. The comparison between groups was drawn through t-test or one-way analysis of variance. The results indicated that the total scores of self-management behaviors of patients at the recovery stage of stroke achieved statistical significance in different ages, occupations, educational levels, income levels, exercise intervention, comorbidities, BMI and marital status (P < 0.01), whereas they did not achieve any statistical difference in different genders, family histories, stroke type and medical insurance (P > 0.05), as listed in No data loss in the study, for the 396 subjects included, 176 were male (44.5%), and 220 were female (55.5%), aged from 31 to 97 years, with an average age of 65.8 12.5. The demographic data of patients included  and exercise intervention), which may affect the self-management behavior of stroke patients at the recovery stage, were investigated through independent sample The PRO scale for the stroke used in this study included four domains and 10 dimensions, including the physiological domain , psychological domain , social domain  and therapeutic area (satisfaction), which involved a total of 46 items. Stroke PRO scale items were all scored using the Likert five-stage scoring method. All negative scores of the respective dimension were converted and then added with the positive scores to develop the total score. The higher the score, the higher the quality of life will be . Table 2P > 0.05). Statistical difference was found in the PRO scores of the self-management intervention group and the control group after the self-management intervention (P < 0.05). After Bonlemmi correction, the PRO scores of the self-management intervention group and the control group after the implementation of self-management intervention were statistically different (P < 0.017), and the differences between the other groups were not statistically significant . There was no statistical difference in the PRO scores of the self-management intervention group and the control group before the self-management intervention  were compared in the included patients at the rehabilitation stage of stroke .P > 0.05). After the 3-month self-management intervention in the behavioral period, there were statistically significant differences in the scores of self-management behaviors of the two groups (P < 0.05). After Bonlemmi correction, there was a statistical difference between the self-management intervention group and the control group in the scores of self-behavior dimensions after the implementation of self-management intervention (P < 0.013), and there was no statistical difference between the other groups . Before the self-management intervention, there was no significant difference in the scores of self-behavior dimensions among different groups (The correlation analysis was conducted between the total score of self-management behavior and scores of the respective dimension and a total of 10 dimensions in four fields of the PRO questionnaire. The results indicated that health education, exercise intervention, psychological intervention, food intake, living habits, and functional training of stroke patients at the recovery stage were positively correlated with the total score of self-management behavior and scores of the respective dimension.Taking the total PRO score of stroke patients as the dependent variable, and introducing the above factors into the equation, a multiple linear regression model was established. The results indicated that there was a relationship between educational level, marital status, family history, exercise intervention, and functional training and the rehabilitation results of stroke patients. Educational level and marital status were positively correlated with the rehabilitation results of patients. Married patients and highly educated patients had high scores in the stroke PRO questionnaire and the differences achieved statistical significance. Family history was negatively correlated with rehabilitation results. The total rehabilitation scores of patients with a family history of stroke were lower than those of patients without a family history, and the differences were statistically significant. Participation in exercise intervention and functional training was positively correlated with the rehabilitation results of patients. Active exercise intervention and functional training can lead to higher scores of rehabilitation results of patients and significant differences. Stroke recovery patients with a better self-management ability and having mastered several systematic, scientific and effective methods and relevant knowledge and basic rehabilitation skills required for self-management can improve their confidence in self-management of their diseases and play their subjective initiative. They are capable of increasing the rehabilitation results by actively establishing correct self-management behavior patterns .In this study, there were differences in scores of different dimensions of self-management behavior, and the self-management of food intake was the best, probably because of the traditional concept of \u201cdisease entering from the mouth\u201d and the significant treatment effect of diet control for patients. Moreover, the medical staff emphasized the role of the healthy nutrition concept and the significance of long-term adherence during the patients\u2019 hospitalization and discharge education, so the patients\u2019 management of food intake can be effectively performed. The self-management of living habits, exercise intervention, health education, and functional training was better, probably arising from the strengthening of hospital education for patients and popular science education on stroke-related knowledge via the media, newspapers, television and community. Patients developed an awareness that excessive intake of tobacco and alcohol, unreasonable dietary structure, lack of exercise, and emotional abnormalities were significantly correlated with the occurrence and development of stroke. The management time and economic cost in diet, daily life and other aspects were reported to be low and acceptable, thus enabling patients to actively change their dietary structure, conduct the moderate exercise and functional training and maintain a relatively stable and optimistic mood . SpecialSeventy-three percent of the patients surveyed in this study had educational culture below junior middle school level, and their understanding of disease-related knowledge and mastery of rehabilitation training skills were poor, thus resulting in their poor knowledge level of stroke and preventing them from effectively implementing self-management and monitoring of the disease. Accordingly, nursing staff should increase health education for the stroke patients and pay more attention to health education regarding common chronic non-communicable diseases of the elderly and training in rehabilitation skills, so as to help patients understand the significance of self-management after stroke. Furthermore, they should carry out targeted guidance on systematic knowledge and skills in accordance with the patients\u2019 age, educational level, and economic situation, enhance the patients\u2019 behavioral abilities of self-management and scientific rehabilitation training after illness .The results of multiple regression analysis indicated that marital status of being married, active physical exercise and rehabilitation training were the protective factors for self-management scores of stroke patients; family history, past medical history and complications were the risk factors for self-management of stroke patients. The self-management score of married patients was higher than that of unmarried/divorced/widowed patients. The family relationship and family income of married patients were reported to be relatively stable, and they were significantly supported and encouraged. The patients\u2019 emotions were stable, and they faced stress with a positive attitude, thus improving their self-management ability. The rehabilitation scores of patients actively doing physical exercise were higher than those of patients not doing physical exercise. Regular and appropriate physical exercise improved the physical quality of patients and the rehabilitation of the diseases of stroke patients . The resThis study aimed to investigate the effect of self-management on stroke patients at the recovery stage. Due to the constraints of test time and test conditions, patients from the community and rehabilitation pension institutions were not included, and the sample representation was not comprehensive. When choosing the self-management evaluation scale, no more comprehensive reliability and validity evaluation was conducted due to the test conditions.The information was acquired directly from the patients based on the clinical outcomes reported by them, in which the explanation by the medical staff and any other staff was excluded. The information of this study can provide a more valuable reference for doctors in diagnosis and treatment of stroke, and it is of great significance in the clinical treatment practice. For patients at the post-stroke rehabilitation stage, medical intervention in accordance with the feelings and wishes directly from the patients can be the starting point for smooth work.Education level, health education, food intake, exercise and rehabilitation training, sleep, and psychological intervention were the main factors for self-management behavior in stroke patients at the recovery stage, which revealed that medical staff should improve the health education level of stroke patients and give more support to patients with lower educational levels. Self-management interventions can effectively increase the health education level of stroke patients, help them gain self-confidence in disease self-management, and facilitate the establishment of effective self-management behavior of patients, which is conducive to improving the quality of life and subjective well-being of patients. Stroke PRO scale is a novel sensitive and effective efficacy evaluation tool, which is capable of evaluating the clinical intervention effect of self-management on stroke patients from multiple dimensions, especially evaluating the improvement of the subjective psychological state of patients and thus revealing the intervention effect of self-management on stroke patients comprehensively.First, this study is only a multicenter study of a regional Grade III hospital, and did not include inpatients in the department of neurology of hospitals below Grade III in the region during the same period; Second, in order to facilitate research, we only used the PRO scale, no other scale is used, such as SF36 scale; Third, the cognitive function of the subjects was only evaluated with MoCA and MMSE neuropsychological evaluation scales, without further hierarchical evaluation. This requires us to further expand the sample in future research. On the basis of operational research, we should try our best to select various evaluation tools to comprehensively evaluate the research object, compare them with other similar research tools, and select the evaluation tool with the best reliability and validity.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Medical Ethics Committee of Shanxi Datong University. The patients/participants provided their written informed consent to participate in this study.YSS, NPZ, and XZ proposed the idea of the article, formulated the inclusion and exclusion criteria, and wrote the first draft of the manuscript. DBY and JM conducted literature retrieval and screening. YSS and JM conducted data analysis and result writing. CGM and XZ reviewed the first draft of the manuscript. CJL revised the manuscript. All authors contributed to the article and approved the submitted version."}
+{"text": "In order to improve the overall structural stability and thermal insulation capacity of existing buildings in severe cold areas, green energy-saving ecological transformation methods of existing buildings in severe cold areas are proposed. The concrete stress analysis method of the joints in the frame is used to calculate the bearing capacity and prestress of the beam-column joints. Based on the method of parameter analysis, the calculation model of shear capacity is established. The embedded anchoring method is adopted to realize the equal strength connection of beam-column joints. Increase the unbalanced moment between reinforcement and steel plate, and improve the stability and reliability of beam-column joint fixation. The overall structural optimization method of joint shear performance is adopted to reduce the distance between lap reinforcement and steel plate, so as to realize the green energy-saving ecological transformation design of existing urban buildings in severe cold areas. The test results show that the service stress and tensile resistance of the reconstructed existing building area are higher than 60, the tensile capacity is good, and the slip of the lap reinforcement is effectively controlled. At the same time, this method improves the stability of beam-column elements and the overall thermal insulation performance of existing buildings in cities in severe cold areas. The next research will focus on the transformation of other structures. In recent years, with China's great emphasis on the ecological environment, the concepts of low-carbon cities and green energy-saving buildings have been gradually popularized. With the constant improvement of China's green energy-saving construction, the growth of building energy consumption has been effectively restrained. However, there are still some problems, such as people's ignorance of building energy-saving ideas, imperfect building energy-saving renovation methods and technologies, lack of energy-saving ideas in building construction , 2, and At present, for residential units, there are often some problems, such as unreasonable layout of residential buildings, inefficient use of space, ventilation and lighting of residential buildings failing to meet the requirements of residents, wasting a lot of energy and so on. Therefore, the application of low-carbon concept and low-carbon technical measures in planning and architectural design to build energy-saving green communities and energy-saving buildings is not only of great significance to China's energy conservation and utilization \u20136, but aChina's research on the application of low-carbon energy-saving theory and space syntax in building energy-saving renovation is still insufficient, and the current research results in this area are also lacking, and have not formed a complete system. This study systematically sorts out the application theory of low-carbon energy conservation and the practice method of spatial syntax by analyzing the Reference, reports and excellent cases of the implementation and application of low-carbon energy conservation concepts at home and abroad, perfecting and enriching the energy conservation theory of existing residential areas and residential buildings, and supporting the construction of low-carbon energy-saving communities in China. In this study, the spatial syntax theory is applied to the quantitative and visual analysis of existing residential areas, which can more intuitively analyze the energy-saving transformation of residential areas and buildings. The comprehensive application of space syntax and low-carbon energy-saving theory will provide a new direction and path for the renovation of low-carbon energy-saving residential areas in the future. The design of green energy-saving ecological transformation of existing buildings in cold regions is based on the optimization design of mechanical parameters of beam-column joints of existing buildings in cold regions, and the optimization of green energy-saving ecological transformation of existing buildings in cold regions is realized by combining numerical simulation and mechanical analysis. At present, for the green and energy-saving ecological transformation methods of existing buildings in cities in severe cold areas, the anchor joint fixing method, the foundation pit fixing method, and the tensile steel bar strain stability fixing method are mainly adopted, and the double steel plate concrete composite wall design method is adopted to realize the stability control of beam-column joints of existing buildings in cities in severe cold areas.Reference  proposedThe vast majority of existing buildings belong to non-energy-saving high-energy buildings. In the energy-saving transformation of existing buildings, local practices basically focus on large-scale public buildings and government office buildings with high-energy consumption, as a breakthrough in energy-saving transformation. Therefore, this paper proposes a green and energy-saving ecological transformation method of existing buildings in cities in severe cold regions based on the overall structural optimization of node shear performance. Firstly, in assembling the integral shear wall structure, the concrete stress analysis method of the joints in the frame is adopted, the embedded anchorage method is adopted, and the prestressed reinforcement degree analysis and yield response analysis are combined to realize the equal strength connection of the beam-column joints of the existing urban buildings in severe cold areas. Then, the static monotonic tensile test method is adopted to increase the moment of force between steel bars and steel plates, improve the stability and reliability of the beam-column joints, and the overall structural optimization method of the shear performance of the joints is adopted to reduce the distance between the overlapping steel bars and steel plates. Finally, the experimental test shows the superior performance of this method in improving the green energy-saving ecological transformation ability of existing urban buildings in severe cold areas.Parameter analysis method is widely used in various reservoir parameters. Through cluster analysis and discriminant analysis, the types of flow units in the study area are reasonably divided, and the discriminant functions of various flow units are established to identify the unit types. These parameters mainly include porosity, permeability, median grain size, shale content, formation coefficient, net-gross ratio, saturation, conductivity coefficient, storage coefficient, pore throat radius, pore throat ratio, and cross-well flow capacity index.Cans identifies the flow unit by using the cross-well flow capacity index Interwell Flow Capacity Index (IFCI). IFCI is defined as the ratio of flow between two adjacent wells. The denominator is the flow rate of high permeability layer. The results show that if the two wells are located in the same flow unit, the ratio of formation coefficient of the two wells has a good correlation with its flow rate ratio. Otherwise, the correlation is poor. Therefore, the distribution range and connectivity of flow units can be judged.Identification of flow unit by repeated formation test and tracer test. The main principle is to identify the flow unit according to the measured pressure change and tracer concentration change.Prediction of flow unit by production pressure difference. According to the flow of fluid in oil\u2013water two-phase obeying Darcy's law, the calculation formula of production pressure difference of flow unit is established. This method can avoid the contradiction between resource waste caused by shut-in pressure measurement and less pressure measurement data by layers, and its accuracy depends on the accuracy of parameter selection and the reliability of flow unit division.Fluid Inclusion Stratigraphy (FIS) is used to identify oil\u2013water interface and seepage barrier, and production logging and pressure data are used to identify flow units. It is worth noting that when the physical and chemical properties of fluid inclusions between adjacent wells are different, it can indicate the existence of barrier layer. However, when there is no difference in physical and chemical properties of fluid inclusions between adjacent wells, it cannot be concluded that the barrier layer does not exist.Based on the research and analysis of domestic and foreign cases, it is concluded that domestic green low-carbon energy-saving residential communities usually pay attention to the application of low-carbon energy-saving concept from the early planning and design stage. In the construction stage, domestic residential areas also adopt construction methods such as assembly to reduce energy consumption and waste of resources in the construction stage. Many technologies and methods are also used in the residential operation stage, which play a substantial role in the energy conservation and utilization of the whole residential area, but the public participation is not high and the enthusiasm is not strong. Compared with foreign low-carbon energy-saving communities, they have invested a lot of financial resources and manpower in the active energy-saving and passive energy-saving design of residential areas, and paid great attention to public participation and the cultivation of residents' low-carbon energy-saving concept in the whole process, which is very worthy of our reference \u201314. CombVerify through the node count in the software. If the value of node count is positive, it indicates that the drawing is correct, and the color of the line segment is green. If the value is negative, the model is wrong and the color of the line segment is red.Using reinforced concrete raft as foundation, combining embedded anchoring and embedded anchoring methods, the anchoring connection module of beam-column joints of existing buildings in cities in severe cold areas is established. According to three anchoring forms, double steel plate concrete composite wall configuration method is adopted, and bolts on both sides of beam-column joints of existing buildings in cities in severe cold areas are used to achieve anchoring. Considering raft foundation, embedded steel plates of beam-column joints of existing buildings in cities in severe cold areas are perforated. The cracks of reinforced lap specimens are fixed by anchor bolts, and the ribbed steel bars are lapped in concrete by embedded anchorage. Through strain detection and mechanical parameter analysis of tensile steel bars and steel plates, the wall-reinforced concrete foundation parameters of beam-column joints of existing buildings in cities in severe cold areas are determined. Based on the code for design of building thermal insulation (GB 50011-2010), the thermal insulation design of beam-column units of existing buildings in cities in severe cold regions is carried out. In AISC N690-12, the tensile reinforcement is configured in combination with the technical standard requirements of cylindrical head welding nails for arc stud welding (GB/T 10433-2002).Through field investigation, case comparison and spatial syntax model analysis, this paper analyzes the constitutive relationship of beam-column joints of existing buildings in severe cold regions.In order to comprehensively consider the green energy-saving design level of buildings in residential areas and the maintenance degree of green environment in residential areas, the building materials of residential buildings and the property management of residential areas are also analyzed. In the assembled integral shear wall structure of existing buildings in cities in severe cold areas, the concrete stress analysis method of the joints in the frame is adopted, and the spatial structure, planning layout and traffic flow lines of two existing residential areas are analyzed at the macro level. For the overall layout and traffic, through the axis model of two existing residential areas, it is analyzed according to two indicators: selectivity and integration. According to the axis model established by the urban road network, the roads represented by each axis have corresponding index values. The values are arranged according to the size, and the color is attached for visual analysis. In the model, the red, yellow and blue axes represent high, medium, and low index values in turn. Among them, the main syntactic index of axis: Choice\u3009 indicates the potential of axis to attract crossing traffic. Integration represents the traffic accessibility of the axis. In assembling the integral shear wall structure, the concrete stress analysis method of the joints in the frame is adopted to calculate the bearing capacity and prestress of the beam-column joints of the existing buildings in cities in severe cold areas, and the constitutive model of the materials of the beam-column joints of the existing buildings in cities in severe cold areas is constructed \u201317. The Vt1 represents the internal force of tensile reinforcement configuration of existing buildings in cold regions relative to the node performance, Vu1 represents the standard anchorage length of reinforcement, and \u0394Vt represents the distance between lap reinforcement and steel plate of existing buildings in cold regions. The static loading test method is adopted to analyze the correction factor of lap reinforcement diameter as follows [dei is the hysteretic coefficient of the cross-section and steel plate of the existing building specimen in the cold area city, and dpti represents the buckling relation of large local deformation. The template parameters on both sides of the existing building concrete pouring in the cold area city, and the stress parameters of the anchoring reinforcement are:\u03bb is the index of compression and tensile damage of existing buildings in cities in severe cold areas, and t is the volume stirrup ratio of energy-saving ecological renovation of existing buildings in cities in severe cold areas. Considering the size and loading capacity of the loading device, it is found that the index coefficient of tensile damage of beam-column joints of existing buildings in cities in severe cold areas satisfies u : I \u00d7 IRd\u27f6IR, and the elastic modulus of concrete of existing buildings in cities in severe cold areas is:s \u2265 0, 1/p=1/p1+1/p2=1/p3+1/p4. The index coefficients of compressive and tensile damage of existing building concrete in cities in severe cold areas are analyzed. When \u2203x0 \u2208 R2, the tensile damage index of concrete in steel tube:P(Y|\u03bbj) is the biaxial compressive yield strength of existing urban buildings in severe cold areas, P(Y|\u03bbj) is the uniaxial tensile stress of existing urban buildings in severe cold areas, and P(Y|\u03bbT) is the initial elastic modulus. If a > 1, the constitutive relation model of beam-column joints of existing urban buildings in severe cold areas is established, and the constitutive relation analysis of beam-column joints of existing urban buildings in severe cold areas is realized under uniaxial stress.In the above formula,  follows :(2)di=deP is the applied prestress, \u03c6x is the anchor parameter of the existing buildings in the cold region, v is the prestress, b is the structural fitting parameter, a is the yield response of ecological design, and t is the constitutive model parameter.On the basis of the above-mentioned constitutive relation model of beam-column joints of existing buildings in cities in severe cold areas, the overlapping force transmission analysis of beam-column joints of existing buildings in cities in severe cold areas is carried out by adopting the arrangement of overlapping steel bars, and the stress parameter analysis model of beam-column joints of existing buildings in cities in severe cold areas is established by analyzing the bearing capacity, stiffness, and other parameter information of beam-column joints of existing buildings in cities in severe cold areas. Steel plates are welded at the bottom of steel plates, Calculate the stress parameters of the anchorage zone between column and foundation, build the calculation model of shear bearing capacity, adopt the embedded anchorage method, and combine the analysis of prestressing tendons and yield response to obtain the longitudinal strength of the beam-column joints of existing urban buildings in severe cold areas, and establish the finite element model of the beam joints . The comThe calculation model of shear capacity includes the main influencing factors, such as beam geometric size, shear span ratio, stirrup ratio, axial prestress, concrete strength, load form, and so on. During the construction, 987 beams without web reinforcement were selected, including 531 beams with web reinforcement, 136 beams without web reinforcement, and 42 beams with web reinforcement under uniform load. Other prestress, bearing capacity, concrete strength, load, and other parameters are set in the test.Therefore, combined with the finite element analysis of composite frame joints, the relationship between compressive stress and compressive strain is shown in aii is the stress\u2013strain joint distribution characteristic of green energy-saving ecological transformation of existing buildings in cold regions, bi is the deviation value of green energy-saving flow potential of existing buildings in cold regions, xjk)( is the strain corresponding to uniaxial compression of green energy-saving ecological transformation of existing buildings in cold regions. According to the analysis of the overall structural parameters of shear performance of beam-column joints of existing buildings in cold regions, the standard anchorage length of steel bars is calculated by the method, and the influence of anchorage length on the performance of beam-column joints of existing buildings in cold regions is analyzed.According to the relationship between compressive stress and compressive strain of green energy-saving ecological renovation of existing buildings in cities in severe cold areas shown in Is is the vertical and horizontal spacing, \u03bcj is the distribution of compressive stress\u2013strain relationship, Aj is stress\u2013strain under uniaxial compression, W\u2032 is the parameter value of uniaxial tension descending section, F is the biaxial compressive yield strength.By adopting the static monotonic tensile test method, the moment of force between steel bars and steel plates is increased, and the lap joint model of beam-column joints of existing buildings in cities in severe cold areas is constructed . The indF is 0.1, the biaxial compressive yield strength obtained satisfies:\u03bbn is the uniaxial tensile strength of beam-column joints of existing buildings in cities in severe cold areas [fvk is the standard value of the parameter value of uniaxial tension descending section, \u03c9 is the deviation value of flow potential; Ac, Aw are the cross-section parameters and distribution area of concrete restrained by stirrups, and \u2211Af is the stiffness recovery coefficient. N is the initial elastic modulus of steel [When ld areas , 22, fvkof steel , 24.According to the supporting sequence of the bolt body, the concrete supporting column project is adopted to realize the analysis of the stress structure parameters of the beam-column joints of existing buildings in cities in severe cold areas. In the steel-inserted anchorage joints, the bearing capacity of the specimens is analyzed, and the specific operation process is shown in To sum up, to realize the equal strength connection of beam-column joints of existing buildings in cities in severe cold areas, the static monotonic tensile test method , 26 is aIn the experimental test of green energy-saving ecological transformation of existing buildings in cities in severe cold areas, the strength grade of steel bars is set to HRB400, and the ultimate strength detection model of beam-column joints of existing buildings in cities in severe cold areas is established by using I-beam, steel tube, and internal reinforcement design method. The yield prestress degree is 234.1\u2009MPa and 232.0\u2009MPa. See According to the parameter evaluation index system in In According to the stress analysis in The steel bars are planted on the brick wall at the post-cast strip. The depth of the holes for planting steel bars is 200\u2009mm, and the spacing is 300\u2009mm. An 8-screw with an implanted depth of 150\u2009mm is arranged in the hole, which is anchored by pouring steel bar glue, and 180\u2009mm is thrown out of the hole. Eight long-length steel bars are placed in the post-cast strip, and the long-length steel bars are tied together with the bolts implanted in the wall. At the same time, the hooks of the embedded steel bars at the bottom of the precast reinforced concrete slab hook the long-length steel bars. This test is loaded in the vertical and horizontal directions, and a jack is used to apply a constant vertical force of 30\u2009t to the steel beam. The load is transmitted to the concrete loading beam at the top of the test body through the loading steel beam, and then to the specimen to ensure that the axial force is evenly transmitted to the specimen. Load horizontally with electrohydraulic servo actuator and adopt displacement control, and get the comparison of force characteristics of existing buildings in cities in severe cold areas after green energy-saving ecological transformation, as shown in According to the analysis of The yield response of beam-column joints of green buildings is tested. The comparison of cloud pictures of green energy-saving ecological transformation of existing buildings in cities in severe cold areas is shown in In It can be seen from This paper puts forward the green energy-saving and ecological transformation methods of existing buildings in cities in severe cold areas. The connection model between concrete foundation and double steel plate composite wall of beam-column joints of existing buildings in cities in severe cold areas is established, which improves the bearing capacity of buildings. Combined with embedded anchoring and embedded anchoring methods, the mechanical reliability of beam-column joint fixation is optimized. The embedded anchoring method improves the stability and thermal insulation performance of the building.Since the weather environment in most cities in China is hot in summer and cold in winter, this study is only aimed at the reconstruction of existing buildings in cities in cold regions. Therefore, the next research will start from the energy-saving transformation of the building envelope, energy-saving transformation of existing buildings in hot summer and cold winter areas."}
+{"text": "There is a paucity of research on the impact of caregiving on the quality of life of unpaid caregivers for older adults aged 60 years or older with visual impairments (VI). The purpose of this study is to test multimodal interventions to improve quality of life and well-being in unpaid caregivers of older adults with VI. The objectives were: (1) to implement multimodal interventions targeted towards improving the quality of life of family caregivers of older adults with a VI; (2) to evaluate the efficacy/effectiveness of the interventions in improving the quality of life of older adults with a VI. The outcomes of interest include: quality of life, health, stress, burden, problem-solving, and barriers. For this study, a 10-week virtual intervention was implemented with 12 caregivers and eight older adults with visual impairments, for a total of 20 participants. The intervention was held for one hour for 10 consecutive weeks and included activities such as tai chi, yoga, meditation, music, nutrition, and other de-stressing techniques. Participants completed a series of questionnaires before and after the intervention period. These questionnaires include: Satisfaction with Life Scale, Living Arrangement and Indicators of Social Interaction survey, Caregiver quality of life (EQ-5D), the Perceived Change Index, and the Geriatric Depression Scale. Findings from the data analysis show excellent caregiver engagement throughout, including participation in the pre and post surveys. Results show the benefits of multimodal interventions for caregivers as well as older adults with VI. Future studies should focus on interventions that are most promising."}
+{"text": "Give Peace a ChanceJohn Lennon 1969ICONS-5, organized during from August 31 to December 02, 2022, was the fifth edition of the on-line magnetic resonance conference series called Konstantin Ivanov InterCONtinental Magnetic Resonance Seminar, named after our untimely deceased colleague and friend. The ICONS conferences are an off-shoot of the weekly Intercontinental NMR Seminar Series that started on April 8, 2020. This seminar series has enabled the communication and dissemination of research ideas among the magnetic research community in the times of the COVID-19 pandemic and will continue to do so beyond. In the framework of the ICONS series, until now, more than 130 scientists from five different continents have presented their recent results. While the weekly seminar series gives both early-stage and experienced researchers an opportunity to give seminar talks and interact with colleagues from all over the world, the ICONS conference is a platform for experienced researchers. The ICONS-5 conference attracted registrations from nearly 200 people from 30 countries  and spanned 17 time zones from Japan over Europe to the US West Coast. The meeting talks were broadcast across the Zoom and YouTube platforms. The average combined attendance was around 120.The ICONS seminar series is open to all areas of magnetic resonance and covers the full range of Magnetic Resonance, i.e., EPR, NMR, MRI, and their various hybrids. While the summer ICONS conferences  and its pros and cons compared to other hyperpolarization techniques. Then he reported on recent developments on the application of DNP towards studies of RNA ribozymes and discussed the application potential of DNP for the simplification of crowded spectra of biomolecules. At the end, he gave an overview of 1\u03c1. At the end, he reported a combination of REDOR and VT-NMR studies of side-chain dynamics of proteins.Paul Schanda, Austria, gave a fascinating overview of recent developments in the investigation of protein dynamics in the solid state employing a combination of solid-state NMR and molecular dynamics simulations. At the start of his presentation, he explained why relaxation is intrinsically multi-exponential. Then he discussed the effects of deuteration on the relaxation times and gave a Redfield analysis of RThomas Theis, USA, first gave an introduction into Parahydrogen-based hyperpolarization techniques in Chemistry, Biochemistry, and medical imaging. He then discussed the advantages of reversible PHIP (SABRE), in particular in bio-related questions, owing to the large number of available metabolites of interest that are or are likely to become SABRE active, and showed a number of recent results from his group. Next, he gave a fascinating overview about the construction and physical principles of a RASER NMR setup in his group and demonstrated the astounding coherence length and spectral resolution of this system and the resulting line resolution.Jamie Walls, USA, discussed the application potential of diffusion NMR for the investigation of NMR diffusion experiments for the analysis of the pharmaco-kinetics of emulsion-based formulations of drugs and its application to isoflurane, a widely employed common anesthetic. He discussed the kinetics employing Bloch-McConnell model.Patrice Bertet, France, gave a fascinating introduction into recent results in the detection of small numbers of electron spins employing micro-waves in a miniaturized resonator. He explained how the relaxation properties of the spins are optimized and discussed the SMPD device for the detection of the signals. Then he showed the tremendous improvements obtained in the last twelve month where the detection limit was increased from 1000 to one spin. Finally, he showed a number of basic experiments, such as Rabi oscillations on these systems.N). By CEST  an excited state of the protein was detected, whose structure was studied via 1H-15N RDCs .Ashok Sekhar, India, discussed the application of NMR for the investigation of order/disorder phase transitions in intrinsically disordered proteins, employing the cytidine repressor, which binds its cognate operator DNA through the N-terminal DNA-binding domain  for the processing of diffusion NMR spectra.Jean-Pierre Korb, France, reported on recent studies of water dynamics in protein hulls, employing a multi-scale approach. From the combination of the experimental dispersion of the NMR relaxation data and theoretical modeling he investigated the surface water diffusion in hen egg-white lysozyme (LZM) and bovine serum albumin (BSA) solutions and the influence of the addition of different salts on these dynamics. He found an excellent agreement between experiments and modeling over 4 decades in Larmor frequency (10\u00a0kHz to 110\u00a0MHz).Eva Meirovitch, Israel, gave an intense theoretical introduction into the combination of the slowly relaxing local structure (SRLS) approach for the analysis of NMR relaxation from proteins and molecular dynamics (MD) simulations and the application of these techniques towards the study of NH-bonds.Thomas Barbara, USA, gave a fascinating historical overview about the development of NMR relaxation theories. In this overview, he showed that already Felix Bloch had developed a full density matrix approach for the description of relaxation, which later fell into oblivion in favor of Redfield's simpler semiclassical approach and how this old approach by Bloch is related to the recent rediscovery of the Lindblad master equation.Organization and future developments: The conference was organized by Daniel Abergel , Gerd Buntkowsky , and P. K. Madhu . Suman Saurav, TIFR Hyderabad, provided technical assistance. The conference and seminar series were sponsored by Alexander von Humboldt Foundation, Wiley, Springer, HyperSpin, and Adani. Following the scheme of a general MR conference in summer alternating with a specialized conference on cutting-edge topics in winter, there are already plans for a specialized ICONS-6 in spring of 2023. For updates and the schedule of upcoming talks, see the home page of the meeting ICONS-Seminar."}
+{"text": "In addition to the global negative impact on mental health of general population, as well as psychiatric patients, Covid-19 pandemic affected significantly research. Initially, lockdowns and restrictions of human contacts temporarily disrupted clinical research activities, but the unprecedented health crisis also provided unique opportunity to study epidemiology of mental disorders, direct and indirect effects of the pandemic on psychiatric disorders, underlying pathophysiological mechanisms, or long-term neuropsychiatric consequences. Research has refocused now on better understanding of the causes, presentations, outcome trajectories, and therapy of mental illnesses. New research topics are followed by the surge in publications covering Covid-19 and mental health and/or psychiatric disorders and treatments. The impact of the pandemic on research and publications is also evidenced by the results of a survey among psychiatric researchers.No significant relationships."}
+{"text": "Database of Journal Citations in Science Education to collect studies on teacher education published from 2015 to 2019 and analyzed the issues described therein. Fifteen categories of issues described therein. Regarding our suggestions for future research on teacher education, this study recommends strengthening the body of literature on the following themes: (1) the professional development of preservice teachers, (2) teacher education for special education, (3) quality assurance for teacher education, (4) the career development of preservice teachers, (5) teacher education for experimental education and rural schools, (6) the sociology of teacher education, and (7) the operation of teacher education centers. Our findings may serve as a reference in efforts to improve the quality of teacher education, and promoting the sustainable development of Taiwan's education system.In this study, the researchers analyzed the issues in teacher education research after the implementation of the 12-Year Basic Education policy and developed suggestions to improve the quality of teacher education in Taiwan. The researchers used Taiwan's http://w1.dorise.info/JCSE/. The implementation of education affects a country's development and success, and a key component of an effective education system is the cultivation of high-quality teachers. The quality of education often depends on the quality of teachers, and teachers' professional development is closely linked to teaching effectiveness and student learning outcomes. In discussions on teacher education reform, high-quality teachers are often considered the foundation of student achievement, and the cultivation of high-quality teachers depends on research-based teacher education. Practice and theory must be integrated to ensure high-quality teacher education. Theory can improve practice, and practice can be used to revise theory; that is, teacher education theory can guide the implementation and thus improve the quality of teacher education. The development of the theoretical basis of high-quality teacher education requires extensive research on teacher education. Studies on teacher education can contribute to the development of the theoretical basis of teacher education , promote best teaching practices in the workplace, and enhance the quality of teacher education  in November 2014. The New Curriculum reflects the idea that the 12-year basic education curriculum guidelines should be based on the principle of holistic education, incorporating the ideas of \u201ctaking initiative\u201d, \u201cengaging in interaction\u201d, and \u201cseeking the common good\u201d. The practice of the New Curriculum is based on \u201ccore competency\u201d as its main axis and consists of three dimensions: \u201cautonomous action\u201d, \u201ccommunication and interaction\u201d, and \u201csocial participation\u201d  preservice teacher education courses; (2) international comparison; (3) teacher education policy; (4) student teachers; (5) teaching materials, methods, and practicums; (6) educational issues; (7) practices in teacher education; (8) test construction; (9) professional development of preservice teachers; (10) teacher education for special education; (11) quality assurance of teacher education; (12) career development of preservice teachers; (13) experimental education and teacher education; (14) sociology of teacher education; and (15) operation of teacher education centers. The number of articles related to each issue is presented in Regarding the studies on teacher education courses, one study discussed the development strategy of the teacher education system through the lens of the religious concept of servant leadership Chang, . AnotherOne study examined the possibility of offering capstone courses, which are widely offered by universities, as part of the teacher education system , which comprises the \u201cWork Values Scale for Teachers\u201d, \u201cSituational Judgment Tests for Teachers\u201d, and \u201cPersonality Scale for Teachers\u201d. The TAA involves conducting tests close to the actual teaching site; exploring students' teaching quality, emotions, and behavioral performance in the context of work; and supplementing the content that cannot be measured using cognitive test performance and academic achievement. The TAA can be used for preservice teacher selection and to evaluate whether preservice teacher education courses are useful. Finally, the TAA can also be used to evaluate the performance of student teachers  in teacher education research after the implementation of 12-Year National Basic Education in Taiwan. The researchers offer the following suggestions for future research on teacher education.No consensus has been reached on teachers' professional ethics in Taiwan. Professional ethics courses are rarely offered in preservice teacher education programs. According to the standards of professional competence for preservice teachers announced by the Ministry of Education in 2019, teachers' recognition and practice of professional ethics are necessary. However, further research on the alignment of teachers' professional ethics with 12-Year Basic Education is warranted.Schools have trended toward an integrated education approach for the education of special education students at the senior high school level and below. Teachers play a key role in protecting these students' right to learn. Therefore, teachers' knowledge of special education and of how to cooperate with special education teachers and students' parents are crucial. Although preservice teacher education programs at most teacher education centers offer 3-credit \u201cIntroduction to Special Education\u201d courses, few studies have been conducted on improving the quality of teachers' knowledge in special education.Taiwan's teacher education system is superior to those of many countries in its recruitment and selection process and elements of quality assurance  remain crucial concerns in Taiwan. In addition, various major social issues, including a decreasing birth rate, an aging population, diversified interactions between ethnic groups, rapid development of the Internet and information technology, emergence of new job types, increasing democratic participation, growing awareness of social justice, attention to ecologically sustainable development, and transformations brought about by globalization and internationalization, pose numerous challenges to education and contribute to the need for reform to ensure that Taiwan's education system can keep pace with changing social needs and global trends. In addition, Taiwan, a small island in the western Pacific Ocean, has been influenced by international tendencies in terms of its politics, economics, academic research, etc., and the development of teacher education is no exception Huang, .Since the implementation of the 12-Year Basic Education in 2014, many major educational reforms and corresponding reforms in teacher education have been enacted. After the implementation of the New Curriculum in 2019, preservice teacher education courses have also moved toward competency-based curriculum reform. Broadly speaking, the teacher education reforms enacted in response to 12-Year Basic Education span four key areas: (1) implementation of the development and design of competency-based preservice education courses; (2) guidance of teacher education universities in the development of school-based teacher education characteristics; (3) encouragement of teacher education universities to ensure the quality of preservice teachers and teaching experience; and (4) development of preservice teachers' inquiry and practical abilities, cross-disciplinary teaching, and international mobility. Therefore, teacher education in Taiwan is closely related to the 12-Year Basic Education curriculum, and the findings of this study may serve as a reference in the effort to promote the quality of teacher education in Taiwan and the sustainable development of Taiwan's education system within the context of the curriculum's implementation.This study collected the relevant research on teacher education in Taiwan from 2015 to 2019, evaluated the developments in research on teacher education, and analyzed the themes that have been emphasized in this body of research so far. The main research issues were as follows: (1) preservice teacher education courses; (2) international comparison; (3) teacher education policy; (4) student teachers; (5) teaching materials, methods, and practicums; (6) educational issues; (7) practices in teacher education; (8) test construction; (9) professional development of preservice teachers; (10) teacher education for special education; (11) quality assurance of teacher education; (12) career development of preservice teachers; (13) experimental education and teacher education; (14) sociology of teacher education; and (15) operation of teacher education centers.Overall, the research on teacher education reflects the focus on curricula and the Taiwanese system of teacher education. However, it still fails to consider all aspects of system reform, such as teacher education for special education and experimental education and quality assurance of teacher education. In addition, studies on the career development and professional development of preservice teachers have remained scarce. Finally, research on teacher education for rural schools, the sociology of teacher education, and the operation of teacher education centers should be prioritized. Regarding our suggestions for future research on teacher education, the body of literature on the following research issues must be further developed: (1) the professional development of preservice teachers, (2) teacher education for special education, (3) quality assurance for teacher education, (4) career development of preservice teachers, (5) teacher education for experimental education and rural schools, (6) sociology of teacher education, and (7) operation of teacher education centers. Our findings may serve as a reference in improving teacher education, and promoting the sustainable development of Taiwan's education system as well as for future research on the theoretical basis and quality of teacher education worldwide.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.Conceptualization, methodology, investigation, resources, data curation, writing-original draft preparation, and writing-review and editing: R-JW and Y-HS. Formal analysis: Y-HS. All authors have read and agreed to the published version of the manuscript.This study was funded by the Taiwan Ministry of Science and Technology (Grant No. 110-2420-H-002-003-MY3-Y11014).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "In China, studies on the regional risk assessment of hazardous chemicals have been carried out for only a few years, and there are few studies on hazardous chemicals leaking into seas. Previous regional-risk-assessment methods considered a single risk factor for most assessment targets, and comprehensive considerations of risk sources and sensitive resources for a study area are not sufficiently included. Based on previous work, this study established a regional-risk-assessment method for hazardous chemicals leaking into seas. This method considered the hazards of hazardous chemicals and the tolerance of the regional environment by means of a case study in Tianjin. The results showed that the risk level of the enterprise was Grade I, classified as a high-risk source of hazardous chemicals; the main reasons were the strong toxicity and large quantity of hazardous chemicals. This method provides technical support for scientifically assessing marine-environmental-risk levels for hazardous-chemical-leakage areas and for carrying out risk-prevention and restoration assessments of hazardous chemicals leaking into seas. The chemical industry has gradually become the leading industry in China. While the use of many chemicals improves production quality and quality of life, their inherently dangerous properties also pose a great threat to human health and the natural environment . At the In the 1960s and 1970s, developed countries enacted laws on the management of chemical substances, which prompted United Nations agencies to gradually establish and implement relevant international conventions . InitialResearch outside China on the risk assessment and prediction of hazardous chemical accidents began earlier, and it is more systematic in both theory and method. In terms of policy, many developed countries have incorporated environmental risk assessment into the scope of environmental management, with policies such as the guidelines on \u201cControlling Accidents Affecting People inside and Outside Factories and Major Environmental Hazards\u201d issued by the Department of Environment and Science of the World Bank in 1985; the European Union (EU) legislation from 1987, which stipulates that environmental risk assessments must be carried out for factories that may be at risk of chemical accidents; and the Appel Plan (APELL), developed in 1988 by the United Nations Environment Programme (UNEP), which is used to deal with environmental pollution accidents that are difficult to prevent and may cause serious harm to human health and the ecological environment [In 1996, the EU published the first edition of the Technical Guidelines for Risk Assessment (TGRA), applicable to various chemicals , which dBP International, a well-known British multinational company, absorbed the methodology of major-accident-risk management used by multinational oil companies and formed a set of major accident risk-management processes . Marhavi(1)Theoretical research on risk assessment of hazardous chemicals. At present, risk-assessment research on major sources of hazardous chemicals mainly focuses on four aspects: multiobjective fuzzy theory , grey th(2)Qualitative-risk-assessment technology for hazardous chemicals. In March 2013, the Ministry of Environmental Protection issued the Guidelines for the Preparation of Environmental Risk Assessment Reports for Hazardous Chemicals under Key Environmental Management  , and in (3)Quantitative risk-assessment technology for hazardous chemicals. Li Qiujin et al.  conducte(4)The innovative application of computer technology in the risk assessment of major sources of hazardous chemicals. In terms of the risk assessment of major hazards in petrochemical enterprises, Liang Chenghao and L\u00fc Dong  used theThe research status of risk-assessment technology used for hazardous chemicals in China can be divided into the following aspects:In summary, regional-risk-assessment research on hazardous chemicals in China started late, and there has been less research on the methods for assessing the leakage of hazardous chemicals into the sea. In the existing regional-risk-assessment methodology, most of the assessment objects are single risk factors, and there is a deficiency in that the comprehensive impact of other risk sources and sensitive resources in the study area is not fully considered.In this study, to carry out the risk assessment and zoning of hazardous chemicals leaking into seas, we developed a regional-risk-assessment index system for hazardous chemicals spilling into the sea, focusing on the whole coastal area of China.Due to the insufficient accumulation of risk data in the environmental field in China, it is difficult to scientifically define the risk level of each evaluation index. Therefore, by comprehensively drawing on the grading methods from previous research at home and abroad, based on the responsibilities of the Ministry of Natural Resources, this study initially established a risk-grading index system  that incR is the regional-risk-assessment score, iC is the weight value of the specific indicator, and iS is the score of the indicator.Considering that environmental risks may arise from defects in any link in the risk system, the comprehensive evaluation of risk zoning adopts a combined algorithm of weighted summation and weighted multiplication. In the calculation of the criterion layer from specific indicators, different specific indicators represent different aspects of the same risk factor, and the weighted summation method is used to calculate the criterion layer following Equation (1). In addition, the analytic hierarchy process (AHP) and Delphi method (Delphi) are used to determine the weights, the weight coefficients between the criterion layer and each specific indicator are then determined, and the sum of the coefficients is maintained as 1 when determining the weights between specific indicators.The hazard assessment of hazardous chemicals should comprehensively consider the types of risk sources involved in hazardous chemicals, the types of hazardous chemicals, and the quantity of hazardous chemicals. The details are as follows:H1. Risk-source type: The probability of environmental accidents in various industry types is different, and we devided into three types: high-risk-industry types (H1. 1), medium-risk-industry types (H1. 2) and low-risk industry types (H1. 3). High-risk-industry types include chemical raw materials and chemical manufacturing, crude-oil processing and petroleum-product manufacturing; medium-risk-industry types include medicine, printing and dyeing, coatings, metal surface treatment and hot processing; low-risk industry types include steelmaking and steel rolling.H2. Hazardous chemical types: Different types of hazardous chemicals have different degrees of impact on the environment, and internationally, the European Standard Behaviour Classification System  is generally used to classify the physical behavior of chemicals after entering the sea . AccordiH3. Toxicity of hazardous chemicals: The Joint Group of Experts on the Scientific Aspects of Marine Pollution (GESAMP) comprehensively considers the bioaccumulability, stability, and aquatic biological toxicity of hazardous chemicals and divides the ecotoxicity of hazardous chemicals into grades 1 to 6 ,36,37,38H4. Quantity of hazardous chemicals: Refers to the number of hazardous chemicals used, stored, and produced in the region. Based on the division of the \u201cList of Hazardous Substances and Critical Quantities of Environmental Emergencies\u201d of the Ministry in Environmental Protection\u2019s \u201cGuidelines for Risk Assessment of Environmental Emergencies in Enterprises ,\u201d considering the critical amount of hazardous chemicals in the region, it is divided into three levels: high, medium, and low.Regional risk tolerance is divided into two factors: disaster bearer and disaster-mitigation capacity. Disaster bearer comprehensively considers the background values of characteristic pollutants in the marine environment, the impact of topography and geomorphology, the connection to the ocean, the category of sensitive resources, and the distance from sensitive resources. Disaster-reduction capacities should take into account regional-risk-control capacities. The specific instructions are as follows:E1. Diffusion condition: Refers to the drift diffusion of hazardous chemicals after they enter the sea; the wider the scope of the diffusion, the greater the degree of its impact on the marine environment. The spread situation is divided into open sea, semi-enclosed bay, and harbor pool, and its impact on the marine environment is open sea > semi-enclosed bay > port pool.E2. Sensitive-resources category: With reference to the marine-water-quality standard , sensitiE3. Distance from sensitive resources: The distance from sensitive resources reflects the degree of damage caused by environmental accidents. After a spatial analysis of environmental risk sources and surrounding sensitive points through GIS, the distance from the most direct leakage point to the nearest environmentally sensitive point according to the risk source is divided into 3 levels: <3 km, 3 to 10 km, and \u226510 km.E4. Enterprise safety-production-standardization level: According to the provisions of the Administrative Measures for the Evaluation of Enterprise Safety Production Standardization  , the safTo make the weights determined more representative and maximize the sample size, the relevant experts of the First Institute of Oceanography of the State Oceanic Administration, Xiamen University, Beijing Normal University, Beijing University of Chemical Technology, Dalian Maritime University, CNOOC Safety Technical Service Company, Beihai Environmental Monitoring Center of the State Oceanic Administration, and other units were invited to comprehensively construct a judgement matrix of expert scores to determine the relative importance of weights of each layer of indicators .According to the hazard scores of hazardous chemicals, the hazards of hazardous chemicals were divided into four levels .According to the regional-risk-tolerance scores, the regional risk tolerance was divided into four levels .According to China\u2019s current administrative management system, with the county (district) as the unit, a regional risk assessment was carried out, and the assessment scope was 10 km on the seaward side of the coastline and, on the landward side, up to the maximum-high-tide line, focusing on the risk sources for sources of dangerous chemical leakage into the sea, such as hazardous-chemical enterprises located within 1 km of the coastline on the landward side or adjacent to rivers entering the sea. The risk-assessment-level relationship of dangerous chemicals leaking into the sea area is shown in To test the applicability of the risk-source-assessment-index system, a typical enterprise in Tianjin Binhai New Area was selected as a research case for risk-source-level assessment. First, basic information, such as the geographical location coordinates, the types and quantities of hazardous chemicals involved, and the level of the enterprise\u2019s safety-production standards, was collected and sorted. Second, according to the \u201cTianjin Marine Functional Zoning\u201d (2011\u20132020), the conditions for the potential diffusion of chemicals into the sea from the company, the types of sensitive resources nearby, and their distance from sensitive resources were determined. Finally, the scores for each risk factor were calculated according to the established risk-assessment method for the leakage of hazardous chemicals into the sea . The comBy applying the recent research conducted at home and abroad to comprehensively consider the hazard and regional risk tolerance of hazardous chemicals, this study established a regional-risk-assessment-index system for hazardous chemicals spilling into the sea, including the type of risk source, the types of hazardous chemicals, the quantity of hazardous chemicals, the toxicity of hazardous chemicals, the diffusion conditions, the types of sensitive resources, the distance from sensitive resources, and the level of enterprise-safety-production standards. At the same time, a combination of the AHP and the Delphi method was used to determine the weights of the indicators, and comprehensive expert scores were assigned to the indicators. The index system not only takes into account the scientific rationality of index-setting and weight assignment, but also considers the applicability of the operationalization of risk assessment in the area in which hazardous chemicals are leaked into the sea. Unquestionably, there are still deficiencies in the risk assessment of hazardous chemicals leaking into the sea. The indicator system needs to be further adjusted and screened, the weight assignment needs to be further optimized and improved, and it is still difficult to obtain some indicators, such as the quantity of hazardous chemicals and the level of enterprise-safety-production standards.In the next step, we will select the Bohai Sea area, carry out the application of the risk-assessment methods for hazardous chemicals leaking into the sea, further improve the assessment method and indicator system, and provide good technical support for the comprehensive management of the Bohai Sea."}
+{"text": "Neisseria gonorrhoeae and gonorrhoea treatment failures were increasing, a response plan to control and manage multidrug-resistant N. gonorrhoeae (MDR-NG) in Europe was published in 2012. The three main areas of the plan were to: (i) strengthen surveillance of antimicrobial resistance (AMR), (ii) implement monitoring of treatment failures and (iii) establish a communication strategy to increase awareness and disseminate AMR results. Since 2012, several additional extensively drug-resistant N. gonorrhoeae (XDR-NG) strains have emerged, and strains with high-level ceftriaxone resistance spread internationally. This prompted an evaluation and review of the 2012 European Centre for Disease Prevention and Control (ECDC) response plan, revealing an overall improvement in many aspects of monitoring AMR in N. gonorrhoeae; however, treatment failure monitoring was a weakness. Accordingly, the plan was updated in 2019 to further support European Union/European Economic Area (EU/EEA) countries in controlling and managing the threat of MDR/XDR-NG in Europe through further strengthening of AMR surveillance and clinical management including treatment failure monitoring. The plan will be assessed biennially to ensure its effectiveness and its value. Along with prevention, diagnostic, treatment and epidemiological surveillance strategies, AMR surveillance is essential for effective control of gonorrhoea.Because cefixime and ceftriaxone resistance in  Neisseria gonorrhoeae (NG) has developed antimicrobial resistance (AMR) to all classes of therapeutic antimicrobials, most recently to third-generation cephalosporins [N. gonorrhoeae across Europe, but the degree of representativeness is affected by suboptimal isolate numbers and low completeness of reporting [Gonorrhoea is the second most commonly reported bacterial sexually transmitted infection (STI) in the European Union/European Economic Area (EU/EEA), with 117,881 cases reported in 2019, representing an increase of 17% since 2018 [osporins . Surveilosporins . Euro-GAosporins . Additioosporins . A revieeporting .Response plan to control and manage the threat of multidrug-resistant gonorrhoea in Europe in 2012 [As a response to the emergence of in vitro resistance to cefixime and to treatment failures with cefixime and subsequently ceftriaxone in the EU/EEA and internationally , ECDC an in 2012 . Similar in 2012  and by n in 2012  and by t in 2012 . In addi in 2012 .Regular monitoring of the gonococcal AMR situation and AMR response plan indicators, and evaluating, reviewing and subsequent updating of national and international response plans are essential. Since the 2012 ECDC response plan  was publDecreasing azithromycin susceptibility and sporadic resistance to ceftriaxone threaten the effectiveness of dual-therapy and ceftriaxone monotherapy regimens . CeftriaOur aim was to describe the evaluation of the 2012 ECDC response plan, by analysing the progress of indicators from 2012 to 2017, as well as the subsequent review and update of the response plan to further support EU/EEA countries in implementing national strategies and interventions to control the threat of multidrug-resistant (MDR)- and XDR-NG in a multidisciplinary approach.The main goal of the 2012 ECDC response plan was to mitigate the impact of MDR-NG on the prevention and control of gonorrhoea by serving as a guide for EU/EEA countries . Three mTo evaluate the effectiveness of the 2012 ECDC response plan , membersWe also assessed indicators related to Euro-GASP . The numDecreasing susceptibility to azithromycin, along with increasing reports of ceftriaxone-resistant strains and gonorrhoea treatment failures and of MDR/XDR-NG, made an evaluation, detailed review and update of the 2012 ECDC response plan imperative . The 201N. gonorrhoeae isolate data to the epidemiological and clinical data of the gonorrhoea cases.There are three main components in the 2019 ECDC response plan . FirstlyN. gonorrhoeae isolates should be collected and ideally reported promptly to ECDC. Where possible, N. gonorrhoeae XDR or ceftriaxone-resistant isolates and those from suspected treatment failures should be shared with the Euro-GASP hub for further verification, including whole genome sequencing, in order to inform the European guideline on the diagnosis and treatment of gonorrhoea [N. gonorrhoeae strain before and after treatment and to identify the presence of AMR determinants in treatment failure cases, but additionally has a role in improving AMR surveillance by providing a genomic background to monitor the molecular epidemiology of circulating strains , to detect new and emerging AMR determinants, to ultimately predict AMR and to investigate the genetic relatedness of isolates from national and international outbreaks [Secondly, a national agreement on adopting the treatment failure case definitions proposed in the 2019 ECDC response plan  and an onorrhoea  and to mutbreaks .Thirdly, the effectiveness of the 2019 ECDC response plan should be monitored at the national and European level . More deN. gonorrhoeae is imperative. The 2019 ECDC response plan should assist in controlling and managing the threat of MDR/XDR-NG in Europe through strengthening AMR surveillance and clinical management including treatment failure monitoring. The effectiveness of the 2019 ECDC response plan should be monitored regularly to identify and address areas for improvement promptly. Control of AMR in N. gonorrhoeae is ineffective without a comprehensive approach, therefore the 2019 ECDC response plan needs strong support from comprehensive management and control strategies nationally and internationally, including appropriate STI prevention (e.g. promotion of condom use), diagnostic and testing algorithms (e.g. triple-site testing in men who have sex with men), treatment, test of cure, notification and treatment of partners and robust epidemiological surveillance to identify key groups at risk of gonorrhoea and gonococcal AMR.Preventing further emergence and spread of AMR in"}
+{"text": "Plants have developed a complex biochemical system for interacting and coping with dynamic environmental challenges throughout their whole life. Plant secondary metabolites are specifically produced and accumulated in low quantities in response to numerous factors such as bacteria, viruses, fungi, nematodes, insects and herbivores, as well as to climatic factors and seasonal fluctuations, soil and water parameters, etc.To optimize secondary metabolites production, plants have fine-tuned early signal systems for differentiating general mechanical damage from an attack by an insect/herbivore, for example. In addition, plants distinguish the degree of damage caused by herbivore feeding guilds, insect oral secretions, oviposition fluids, etc. The consecutive steps of the production of the respective defense secondary metabolites is mediated by cellular messengers and events such as metabolic changes, gene activation, jasmonic acid (JA) accumulation, kinase cascades, hydrogen peroxide production, cytosolic calcium ion fluxes, as well as membrane potential changes  and refeThe key role of secondary metabolites for plant survival also underline the pharmacological roles that these substances play in mammalian organisms and hence their applicability in veterinarian and humanitarian medicinal practices. Plant cell tissue and organ cultures are based on the \u201ctotipotency\u201d of the plant cell and its capability to regenerate up to a whole integral organism. The technique allows for the cultivation of separate cells, tissues, differentiated organs, or integral plants in a growth medium in sterile conditions and out of the indigenous natural environment of the plants. The contemporary development of the method has nowadays led to its routine use as a supplementary to conventional plant breeding for an array of applications such as the rapid and disease-free micropropagation of plantlets, independent of seasonal, climatic, and geographic factors; the rapid testing and practical introduction of new cultivars using conventional or genetic engineering selection approaches. An important and rapidly developing field of the application of plant biotechnology is its use for the yield of plant secondary metabolites, allowing for the standardization of the levels of the secondary metabolites produced due to the capability of tissue culture techniques to optimize culture conditions and obtain the desired environment for the production of the target compounds.Plants dedicated to \u201cPlant Tissue Culture and Secondary Metabolites Production\u201d. The present collection aims to provide readers with up-to-date research dedicated to the scientific accomplishments in the production of plant secondary metabolites of different chemical types through the development of plant cells, tissues, and organs in diverse in vitro culture systems.Considering the importance of plant secondary metabolites and the high relevance of the establishment of scientifically based approaches for their biotechnological production, we are pleased to present this Special Issue of We have received seven scientific research papers on tissue culture development and secondary metabolite production of medicinal and aromatic plants of different regions of the world.Bidens pilosa L. (Asteraceae), dominated by chlorogenic acids consisting of caffeoyl and feruloyl derivatives of quinic acid. Xanthones production in differentiated shoot cultures of the endangered Gentianella lutescens (Gentianeceae) was evaluated for the first time by Krsti\u0107-Milo\u0161evi\u0107 et al. [Daucus carota, Apiaceae) callus culture experimental design of a combination of the components of the Gamborg [3:NH4 ratio affected carotenoid accumulation. In this work, changes to the medium other than N, such as microelements, vitamins, growth regulators, and sucrose, had no effect on callus growth and carotenoid accumulation. Mamdouh et al. [Lycium schweinfurthii (Solanaceae). Investigations on genetic stability, phenolic, flavonoid, ferulic acid contents, and antioxidant activity were performed, leading to the selection of an effective protocol for the in vitro propagation of plant material with desired quality. Erst et al. [3, as well as NH4:K+ ratio and the cytokinins BAP and naphthylacetic acid (NAA) on the growth and production of total phenolics callus culture of Rhodiola rosea (Crassulaceae). The study of Pieracci et al. [Artemisia caerulescens L. (Asteraceae) demonstrated the potential of the tissue culture technique for both the ex situ conservation and production of essential oils and phenolic compounds of this species.Ramabulana et al.  establis\u0107 et al.  in an ex\u0107 et al.  proposed Gamborg  and Mura Gamborg  culture  Gamborg  establish et al.  developet et al.  studied i et al.  on shoot"}
+{"text": "Allium sativum L., Persea americana Mill., Moringa oleifera Lam., Mangifera indica L., and Allium cepa L. are the five most utilised plant species. The preferred plant parts include the leaves (36%), roots (21%), barks (14%), fruits (7%), and seeds (5%), which are mostly prepared by decoction. Benin, Mauritius, Nigeria, South Africa, and Togo had the highest reported use while most of the investigations were on diabetes and hypertension. Despite the nutraceutical advantages of some of these MPs, their general toxicity potential calls for caution in their human long-term use. Overall, the study established the need for governments of SSA countries to validate the efficacy/safety of these MPs as well as provide affordable, accessible, and improved modern healthcare services.Cardiovascular diseases (CVDs) are the leading cause of global mortality, including deaths arising from non-communicable diseases in sub-Saharan Africa (SSA). Consequently, this study aimed to provide details of medicinal plants (MPs) employed in SSA for the treatment of CVDs and their related risk factors to open new avenues for the discovery of novel drugs. The extensive ethnopharmacological literature survey of these MPs in 41 SSA countries was based on studies from 1982 to 2021. It revealed 1,085 MPs belonging to 218 botanical families, with Fabaceae (9.61%), Asteraceae (6.77%), Apocynaceae (3.93%), Lamiaceae (3.75%), and Rubiaceae (3.66%) being the most represented. Meanwhile,  Cardiovascular diseases (CVDs), a group of disorders involving/affecting the heart and blood vessels, are the chief cause of death in the world ,2,3,4,5.2  were used.An extensive literature retrieval, principally from published scientific journals, was used to obtain the required ethnopharmacological information. This was based on studies from 1982 to 2021 with the application of single or combinations of keywords such as medicinal plants, cardiovascular diseases and treatment, diabetes, hypertension, obesity, stroke, and the different names of SSA countries. Major scientific electronic databases , as well as other internet sources, were consulted. To verify the scientific names and families of the identified MPs, other databases such as The Plant List and The World Flora Online [Based on the goal/theme of the review, information gathered from the literature survey, which include the name of the MPs , family, plant part used, modes of usage/preparation, therapeutic use, and the SSA countries involved, were analysed, as well as grouped accordingly.Descriptive statistical analysis of the ethnopharmacological data obtained was achieved using Microsoft Excel software  while a readily available bioinformatics web tool  was usedA. sativum is the most employed MP, which indicates its obtainability in many parts of the region and suggests the presence of potent bioactive compounds in the plant against the development of these diseases.To aid the research on CVDs and production of novel drugs, this comprehensive ethnopharmacological review provides the necessary details of MPs used for the treatment of CVDs and their associated risk factors in SSA. The study revealed that SSA has a rich history in the use of MPs for the treatment of the diseases of focus and a wealth of knowledge in TM, which some individuals in the region rely on for their health needs. The results showed that there are five dominant botanical families of MPs that have been used in SSA for CVD treatment, with some of the MPs having nutraceutical applications because of their edible parts. The ease of collection of MPs\u2019 leaves contributing to their high percentage use shows that the availability of effective and affordable drugs for the treatment of these diseases in the region would assist in encouraging the use of modern medicine. This will also safeguard consumers against the unexpected risk of certain toxic compounds in these MPs and the possible negative effects of overdoses arising from unregulated use. The reliance on decoction as a mode of preparation of these MPs (despite its inherent short shelf-life disadvantage), as well as the major focus on diabetes and hypertension, call for enlightenment, scientific engagements, and urgent government intervention to reduce the number of people suffering from CVDs in the region.Most importantly, the investigation points out the need for governments of SSA countries such as Nigeria and South Africa, with the high percentage use of MPs reported for these diseases, to provide affordable/accessible high-quality modern healthcare services for the populace. Validation of the claimed medicinal/pharmacological potentials and safety assessment of MPs used in the region for CVDs treatment are also encouraged."}
+{"text": "The problem of coexistence of heteroaggression and autoaggression most clearly manifests itself in the field of forensic psychiatry. For example, in Russia, about 25% of criminals who committed aggressive actions had a history of suicide attempts.Identification of specific personality traits in individuals with multidirectional aggression.In a continuous one-step study, relatively sane adults of both sexes were examined: 38 persons undergoing forensic examination with multidirectional aggression and 34 violent criminals. A wide range of forensic psychological techniques is used to identify aggression, suicidogenic and inhibitors of aggression. Nonparametric statistical methods were used: Spearman rank correlation coefficient (r) and Mann-Whitney (U).The leading role in the genesis of multidirectional aggression, in contrast to other types of aggression, playing the combination (p<0.01) to the presence of motivational aggressiveness  and the willingness to show negative feelings at the slightest arousal , along with suicidal personal qualities, which is combined with the deficiency of auto- and heteroaggression inhibitors . However, the psychological mechanisms of multidirectional aggression are relatively non-nosospecific and are similar in mentally healthy individuals and individuals with personality and organic mental disorders.Multidirectional aggression in view of the increased risk of recidivism and personal and public danger should be taken into account by forensic experts when recommending psychocorrective measures in places of deprivation of liberty.No significant relationships."}
+{"text": "As a urinary dysfunction disorder, stress urinary incontinence (SUI) is more common in women than in men. Acupuncture, a traditional minimally invasive technique, has potential efficacy in the treatment of SUI. The purpose of this overview is to critically assess the available evidence on acupuncture for the treatment of SUI in women.  Two researchers searched seven databases for systematic reviews (SRs)/meta-analyses (MAs) of randomized controlled trials (RCTs) on acupuncture for SUI. Two researchers assessed the included SRs/MAs using the Assessment of Multiple Systematic Reviews 2 (AMSTAR-2), the Risk of Bias in Systematic (ROBIS) scale, the list of Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA), and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system.  Eight published SRs/MAs were included in our overview. According to the results of the AMSTAR-2 assessment, all SRs/MAs were of very low quality. According to the ROBIS evaluation results, no SR/MA was assessed as low risk of bias. According to the results of the PRISMA checklist assessment, no SR/MA was fully reported on the checklist. According to GRADE, a total of 27 outcomes extracted from the included SRs/MAs were evaluated, and only 1 was rated as high quality.  Acupuncture may be an effective and safe complementary treatment for SUI in women. However, further standard and comprehensive SRs/MAs and RCTs are needed to provide an evidence-based medical rationale for this. As a form of dysfunction disorder, stress urinary incontinence (SUI) is the most common type of urinary incontinence. It is defined as the involuntary flow of urine due to physical exertion or effort, coughing, or sneezing . SUI hasThe main treatment modalities for SUI include lifestyle interventions, electrical stimulation, pelvic floor muscle training (PFMT), medication, and surgery . The AmeAs a minimally invasive treatment method, acupuncture has a history of more than 2,500 years in China and is gaining more and more international attention in the field of healthcare . With itThe methodology of this study follows the Cochrane manual, as well as the study methods of some high-quality SRs/MAs overviews \u201312.The criteria for inclusion of SRs/MAs in this overview are as follows: (1) Study design: This overview includes SRs/MAs of randomized controlled trials (RCTs) of the acupuncture on SUI; (2) Type of participants: Female subjects diagnosed with SUI based on any authoritative national or international diagnostic criteria regardless of race, age, gender, time of onset, and source of cases; (3) Intervention: The control group received the following treatments: Conventional medication (CM), rehabilitation training (RT), sham acupuncture (SA), and placebo. The intervention group received acupuncture treatment, including plum blossom acupuncture, fire acupuncture, electro-acupuncture, body acupuncture, manual acupuncture, warm acupuncture, or acupuncture therapy in combination with the treatments received by the control group; (4) Outcome indicators: Outcomes assessed in this overview include: Effective rate, 1-hour pad test, international consultation on incontinence questionnaire short form (ICIQ-SF) score, visual analog scale (VAS) score, and adverse reactions.The criteria for exclusion of SRs/MAs in this overview are as follows: (1) Animal studies; (2) Network MAs, research protocols, narrative reviews, overviews, dissertation, and conference abstracts.Literatures were retrieved from PubMed, Cochrane Library, EMBASE, Chongqing VIP, Wanfang Database, CNKI, and SinoMed on 1 January 2022. We adopted a search strategy combining keywords with free words, and the keywords include acupuncture, urinary incontinence, systematic review, and meta-analysis. The literature search strategy shown in  of the PThe literature screening (HS-S and LZ-Z) and information extraction (WB-L and ZC-W) were performed independently by two researchers. We firstly input the retrieved documents into Endnote X9 document management software, and then removed the duplicates. The literatures that potentially met the inclusion and exclusion criteria were then obtained by reading the titles and abstracts. Eventually, we finalized the included SRs/MAs by reading the full text. A standardized data extraction form was adopted to extract relevant information for the inclusion of SRs/MAs. The following information was extracted from each SR/MA: First author, year of publication, author nationality, number of RCTs included, sample size, intervention group measures, control group measures, tools used to assess the risk of bias, and main findings.Two researchers (PL-L and D-W) independently assessed the methodological quality and certainty of quality of the included SRs/MAs.The methodological quality of the included SRs/MAs was assessed by the Assessment System for Evaluating Methodological Quality 2 (AMSTAR-2) . Seven (The Risk of Bias in Systematic Review (ROBIS)  scale waThe quality of each SR/MA report of the included SRs/MAs was evaluated by the list of PRISMA  which coThe certainty of quality for each SR/MA outcome was evaluated by The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) , and fivA total of 166 publications were retrieved from seven electronic databases. Nine publications were retrieved for full-text evaluation after the duplicates removal and title/abstract screening. One paper  was exclThe characteristics of the 8 SRs/MAs included in our final evaluation were summarized, as shown in Regarding the methodological quality of the included SRs/MAs, all were considered to be of very low quality because more than one key item was missing from the SRs/MAs included in the quality assessment. Methodological quality limitations come from the following items: Items 2  was the most common downgrading factor, followed by risk of bias (n\u2009=\u200913), inconsistency (n\u2009=\u200913), imprecision (n\u2009=\u20099), and indirectness (n\u2009=\u20090). GRADE specific assessment details are shown in The 8 SRs/MAs included 27 outcomes related to the effectiveness of acupuncture for SUI. For all the outcome indicators, 1 was rated as high quality, 10 moderate, 6 low and 10 very low by means of the GRADE evaluation. Publication bias  SRs/MAs were published in the last five years, indicating that acupuncture had received increasing attention as an important intervention modality for SUI in women.Based on the results of the AMSTAR-2, ROBIS, and PRISMA evaluation in this overview, the methodological and reporting quality of the SRs/MAs were unsatisfactory. Only two SRs/MAs contained initial research protocol registrations, the lack of which could lead to non-standardization of the research process, increase the risk of bias and impact the rigor and credibility of the final SRs/MAs results. All of the included SRs/MAs lacked a search of the gray literature, which made it difficult to ensure the comprehensiveness of the literature search and tended to generate publication bias. None of the SR/MA provided a complete list of exclusions for each study, which may affect the reliability of the results and assessment of publication bias. The provision of a list of exclusion researches can be a stronger demonstration of the rigor of the literature screening process. No SR/MA reporting was included in the RCT's funding resources, which may increase the bias in clinical trials as the results of corporate-funded studies may be biased in favor of the funder. None of the SR/MA provides comprehensive search strategies, which reduced the reproducibility and credibility of the study. In addition, the lack of reporting of conflicts of interest also potentially affected the credibility of the article.Based on the GRADE assessment, publication bias was deemed as the most significant downgrading factor. Further analysis revealed a risk of publication bias for the outcome indicators included in the SRs/MAs, which may be related to incomplete searches and the insufficient number of RCTs included in the relevant outcomes. In addition, other reasons for the downgrading risk of bias included: Most of these RCTs mentioned randomization without giving the randomization method; most didn't conceal allocation; and most didn't use blinding method or just used single blinding. Declining certainty of quality due to inconsistency may stem from substantial clinical and methodological differences in the included RCTs, which could be avoided by standardizing the inclusion and exclusion criteria as well as the literature screening process.Descriptive analysis suggested that acupuncture was an effective treatment for SUI in women with a high safety profile. However, due to the low methodological quality and certainty of quality of the included studies, these findings may deviate from the actual results. Therefore, caution should be exercised when recommending acupuncture as a complementary intervention for SUI in women.Featuring unique advantages, acupuncture therapy plays an integral role in the treatment of urinary incontinence. Acupuncture works by repeatedly stimulating the points within the body by needling the control points of the bladder and sphincter muscles, thus effectively repairing and improving the body's various control functions .This paper gave a comprehensive assessment of all aspects of the included SRs/MAs using AMSTAR-2, PRISMA, ROBIS, and GRADE, and the methodological quality and certainty of quality were found unsatisfactory. As implied, there is still considerable scope for addressing the quality issues in the process of conducting SRs/MAs. When selecting topics for SRs/MAs, investigators should register or publish study protocols in advance to minimize the risk of bias and ensure the standardization of SRs/MAs. The search for gray literature, complete search strategy and the list of excluded literature need to be supplemented in SRs/MAs, which can reduce publication bias and improve the certainty of quality. A list of funding for RCTs and declarations of conflicts of interest need to be provided to increase the credibility of SRs/MAs. In addition to this, the specific nature of acupuncture treatment makes it difficult to perform a blinded acupuncture-related RCT. However, patients, care providers, and outcome evaluators should be blinded whenever possible to minimize the risk of bias. A well-designed and rigorously executed RCT is believed to be the gold standard for evaluating interventions to minimize or avoid bias . AcupuncOur overview is the first to use AMSTAR2, ROBIS, PRISMA, and GRADE to evaluate SRs/MAs regarding acupuncture for the treatment of female SUI. The evaluation process revealed clear limitations of the current relevant SRs/MAs and RCTs, which may help boost the quality of future clinical studies. However, the overview may have some limitations due to the subjectivity of the evaluation. Although our evaluation had been assessed and reviewed by two independent reviewers, different reviewers may have their own judgments about each factor, so the results may vary. In addition, for different SRs/MAs included in this overview, the definition of effective rate is not mentioned.In conclusion, acupuncture is a beneficial and safe way to treat SUI in women. However, due to the generally low methodological quality and certainty of quality in the included SRs/MAs, clinicians should approach these findings with caution in their practice."}
+{"text": "Having valid information on mortality within a country is of great importance for public health planning. This includes knowing the causes of death (CoD) within a population. However, these data are not always suitable for Burden of Disease calculations from the start and hence, need some realignment in advance. The CoD statistics in Germany include a relatively high share (26% in 2017) of ill-defined deaths (IDD) - using the definition of the Global Burden of Disease Study. Additionally, only the underlying CoD is included in the national statistics and no multicausal data are available yet. As part of the German Burden of Disease project BURDEN 2020 we redistributed IDD to valid CoD using a process of proportional redistribution. To do so, we made use of the distribution of the valid ICD-codes in the data. In the proposed presentation, we use examples of stroke, diabetes, and heart failure to illustrate how IDD were reallocated. After redistribution, the largest increases for both women and men were seen for lower respiratory infections, diabetes mellitus, and stroke. The numbers of deaths for these causes more than doubled after redistribution. Within this project, we carried out the first comprehensive redistribution of IDD for German CoD statistics."}
+{"text": "Sedation and analgesia (SA) management is essential practice in the pediatric intensive care unit (PICU). Over the past decade, there has been significant interest in optimal SA management strategy, due to reports of the adverse effects of SA medications and their relationship to ICU delirium. We reviewed 13 studies examining SA practices in the PICU over the past decade for the purposes of reporting the study design, outcomes of interest, SA protocols used, strategies for implementation, and the patient-centered outcomes. We highlighted the paucity of evidence-base for these practices and also described the existing gaps in the intersection of implementation science (IS) and SA protocols in the PICU. Future studies would benefit from a focus on effective implementation strategies to introduce and sustain evidence-based SA protocols, as well as novel quasi-experimental study designs that will help determine their impact on relevant clinical outcomes, such as the occurrence of ICU delirium. Adoption of the available evidence-based practices into routine care in the PICU remains challenging. Using SA practice as an example, we illustrated the need for a structured approach to the implementation science in pediatric critical care. Key components of the successful adoption of evidence-based best practice include the assessment of the local context, both resources and barriers, followed by a context-specific strategy for implementation and a focus on sustainability and integration of the practice into the permanent workflow. Optimal sedation and analgesia (SA) management are critical components of care in the pediatric intensive care unit (PICU) and an essential piece of the ICU Liberation ABCDEF Bundle , 2. SedaSeveral studies have examined the impact of SA regimens on clinical outcomes in critically ill infants and children over the past decade  5\u201316). \u201316. 5\u201316A variety of outcomes were considered in these studies. Exposure to SA medications was the most common outcome assessed after the implementation of an SA regimen. Of the 13 studies included in this review, 12 92%) studies had interventions examining initiation and titration of SA medications and 8 (62%) included a sedation/analgesia weaning protocol. In total, 11 studies 85%) demonstrated a significant reduction in either duration or total dose of opiates, benzodiazepines, or another sedative of interest. Patient-centered benefits were explored in some of the studies with variable results % demonst, 9\u201314. M2% studieImplementation strategies were described in 11 (85%) studies and predominantly included educational modules, visual aids, and bedside local champions. The majority of implementation strategies center around educational efforts, despite the fact that educational efforts are known to be relatively weak interventions . Some stRandomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE), a multicenter unblinded cluster-randomized trial that included 31 PICUs in the United States , was theThe 2022 Society of Critical Care Medicine Clinical Practice Guidelines on Prevention and Management of Pain, Agitation, Neuromuscular Blockade, and Delirium in Critically Ill Pediatric Patients With Consideration of the ICU Environment and Early Mobility (PANDEM guidelines) reviewed many of these studies , inability to engage non-verbal patients with non-pharmacologic interventions, concerns about medication effects on long-term neurocognitive outcomes, and the need to balance the depth of sedation with patient safety (such as unplanned extubations or line/tube dislodgment events) . ProtocoThe evidence for best SA practices remains scarce with respect to patient-centered outcomes, which may limit provider buy-in, even in the context of increased interest or motivation to change practice. The lack of newer effective drugs with acceptable pediatric safety profiles limits our choice of sedative agents. For example, the use of propofol as a long-term sedative agent is declined in children over the past decade due to concerns for propofol infusion syndrome and increased mortality . MidazolAdditionally, most of the interventions in this cohort relied on weak implementation methods, such as educational modules. Several studies recognized the importance of providing bedside clinical decision support (CDS), particularly in the early phase post-implementation, to ensure compliance and sustainability beyond the immediate implementation period , 10, 12.Further barriers in implementation include cultural context barriers, i.e., readiness of the local environment for change, as well as other practical limitations, such as resource requirements, staffing models, lack of PICU or institutional leadership investment, and lack of effective teamwork and collaboration skills , 28. TheThe studies of SA regimen efficacy in the PICU highlight an important gap in IS in pediatric critical care. IS addresses the effective translation of evidence-based guidelines into bedside practice and is an emerging field of study in critical care . SpecifiIn pediatric critical care, barriers to effective implementation of new guidelines are multifactorial and span different levels of the healthcare delivery system. A recent study using the integrated Promoting Action on Research Implementation in Health Services (iPARIHS) framework across 58 professionals in 8 United States PICUs utilized structured interviews to examine barriers, facilitators, and processes for change . Common In addition to continuing clinical research studies targeted at understanding best SA practices in pediatrics, there should be a parallel effort to specifically examine the adoption and sustenance of the intervention using IS-specific methodology. In addition to the development of an evidence-based intervention, strategically ensuring the successful implementation and sustainment of the intervention is critical to short-term and long-term success. Successful implementation may require effective education, ongoing just-in-time CDS, continuous feedback and evaluation, and strategic planning based on local contextual factors. IS seeks an understanding of why or how an intervention is successful. For example, although the comprehensive ICU Liberation Bundle highlights guidelines related to early mobility, SA practices, and daily extubation readiness assessment for improving patient outcomes, successful implementation has not been consistently demonstrated, and current investigations focus on barriers, such as culture change , 28, 30.Implementation science methodology includes tools, such as implementation mapping, traditional quality improvement (QI) tools, education, and concept mapping , 31. ImpA recent review provides an overview of the associated theories, models, and frameworks of IS . The autAnother potentially useful tool for IS is the Dissemination and Implementation (D&I) Models in Health Research and Practice available through the National Institutes of Health . The D&ISince many protocols and materials rely on team-based approaches, educational material should emphasize the role clarity of team members, as well as identify and employ specific skills and knowledge unique to each team member. This requires an interdisciplinary approach at all stages of implementation, from intervention design to execution to auditing, maintenance, and accountability . Common There is heightened interest in employing best practices related to SA regimens in pediatric critical care. There are several studies that have examined the role of evidence-based novel SA regimens in the PICU population, and this area of research has the promise to achieve improvements in patient outcomes. The existing literature on the subject could be significantly enhanced by emphasis on the systematic implementation of the interventions. Research in SA protocol implementation is met with numerous challenges . The intYY and NM conceived the design of the manuscript. YY performed the review of the studies and prepared the manuscript draft. AG, KM, and NM reviewed and edited the manuscript. All authors approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "The proceeding focused on case studies of patients with diverse affections, mainly depression, cognitive impairment, and discussed the role of neurotrophic factors.Within the \"17th year of intense collaboration, benefitting from a strong endorsement from the World Federation of Neurology (WFN), World Federation of Neurorehabilitation (WFNR), European Federation of NeuroRehabilitation Societies (EFNR), European Academy of Neurology (EAN), and many other organizations. Prof. Muresanu made a stance on working together on a significant topic at the European level, namely the concept of \"brain health\", which presumes a close collaboration between neurology and psychiatry, outlining his belief that the future would bring together the two disciplines due to the fantastic advances, with a strong accent being placed on the interdisciplinary approach.Prof. Dafin Muresanu, the EFNR President, delivered his thoughts on the 17Adela Ciobanu (Romania), Habilitated Professor of Psychiatry at Carol Davila University of Medicine and Pharmacy in Bucharest (Romania), and Head of 1st Clinical Department at Professor Dr. Alexandru Obregia Hospital (Romania), presenting the management of treatment-resistant depression in the elderly. Prof. Ciobanu followed the case of a 75-year-old woman with a depressed mood, anxiety, and insomnia, describing behavioral traits, treatment history, and symptoms. A very in-depth presentation of the mental state examination was provided, the diagnosis \u2013 including differential diagnosis \u2013 and the treatment approach. One crucial point of her lecture was that treatment-resistant depressive disorders often occur in current medical practice, raising issues on differential diagnosis. Moreover, Prof. Ciobanu stated that these clinical cases must be addressed individually and highlighted the role of Cerebrolysin as adjuvant therapy for addressing treatment resistance.The first session of the day introduced Brindusa Focsaneanu (Romania), Senior Lecturer at the Department of Psychiatry from the Faculty of Medicine at Titu Maiorescu University of Bucharest and the Head of the Psychiatry Department VIII within the Hospital Prof. Dr. Al. Obregia (Romania), presented the topics of depression and cognitive impairment, discussing therapeutic approaches for a case report on a 60-year-old woman experiencing a depressive episode with anxiety, behavioral and mood imbalance, somatic symptoms and others. She discussed the public health and epidemiological aspects of mental and neurological disorders in older adults, signalling the role of neurotrophic factors in the modulation of synaptic transmission and their part as a therapeutic strategy in certain neurological disorders. The fascinating presentation showcased a descriptive insight into the patient's pathway in the medical system. Dr. Focsaneanu compared the expected and actual outcomes and pinpointed the importance of cognitive testing, obtaining a detailed patient history, and implementing longitudinal follow-up. Moreover, Dr. Focsaneanu discussed the risks of dementia for older people with depression and the role of neurotrophic factors in aiding neurorecovery and the preservation of cognitive function.Andreea Szalontay (Romania), Associate Professor of Psychiatry at Grigore T. Popa University of Medicine and Pharmacy and Head of Clinical Psychiatry VI from the Socola Institute of Psychiatry in Iasi (Romania), presented a case of mild cognitive impairment after infection with SARS-CoV-2. Offering an epidemiological context on SARS-CoV-2 and cognitive decline, Prof. Szalontay mentioned the effects of COVID on bodily systems and highlighted the cognitive decline and the persistence of symptoms in patients with the infection. One point of her presentation was that the pandemic might contribute to the future increase in the world dementia burden. Her insightful and comprehensive case studies showcased the importance of multidimensional approaches and the effect of neurotrophic factors, such as Cerebrolysin, in the treatment of cognitive deterioration.Romeo Dobrin (Romania), Associate Professor of Psychiatry at Grigore T. Popa University of Medicine and Pharmacy and Head of Section IX at the Socola Institute of Psychiatry in Iasi (Romania), approached the efficacy of neurotrophic factors in neurocognitive disorders. Prof. Dobrin discussed the concept of senescence and dementia, presenting the stages of the disease and highlighting the symptoms and manifestations. Furthermore, based on a case report on mixed dementia, he highlighted the importance of comprehensive approaches, including mental state examination, Alzheimer's assessment, anamnesis, differential diagnosis and clinical data, showcasing the disease progression and presenting therapeutic objectives and further assessment. Finally, he outlined essential points on the management and perspectives of dementia, pinpointing the importance of a larger-picture approach, including research, medicine, and public health perspectives.Mihai Mutica (Romania), Psychiatrist at Elisabeta Doamna Psychiatry Hospital in Galati (Romania), ended the session with \"Mild Cognitive Impairment in a Patient with Polymorphic Symptoms\". Dr. Mutica showcased a case study with complex presentation and favorable outcomes, discussing the results of psychiatric examination, the effect of the treatment, and the management of the patient, pinpointing the importance of individualized approaches for anxiety affective symptoms presenting with cognitive impairment, advising the audience to take precautions when making assumptions about psychiatric disorders and their relation to future dementia.Virgil Enatescu (Romania), Habilitated Professor of Psychiatry at the Victor Babe\u0219 University of Medicine and Pharmacy in Timisoara (Romania), who presented \"The Efficacy of Neurotrophic Factors in A Case Of Minor Cognitive Disorder Comorbid With Bipolar I Disorder And Sequelae Of Cerebral Infarctions\". Prof. Enatescu discussed, based on a case study on bipolar disorder presenting with mild cognitive symptoms, the prognosis of bipolar disorders, genetic vulnerabilities, and comorbidities. Furthermore, he described the patient's pathway and the outcomes, pinpointing the impact of cognitive dysfunction on the psychosocial outcomes in patients with bipolar disorder. Cerebrolysin, as the potential aid in the treatment of a variety of debilitating neurological conditions, was also an important topic touched upon.The second session introduced Catalina Giurgi-Oncu (Romania), Senior Lecturer in Psychiatry at the Department of Neuroscience from Victor Babes University of Medicine and Pharmacy of Timisoara (Romania), presented \"A significant improvement of affective symptoms and Theory of Mind abilities in a patient treated with neurotrophic factors for a Mild Cognitive Disorder\". Dr. Giurgi-Oncu discussed mild cognitive impairment and the risk of developing further dementia, approached the impact of emotional health on social functioning, and glimpsed through the effect of depressive disorders on social interactions, highlighting the \"Theory of Mind\" concept encompassing affective and cognitive components. An exciting case study was presented, highlighting diagnostic criteria for mild cognitive impairment, epidemiology and risk factors, procedures of screening, evaluation, and early detection, and recommendations for follow-up and prognosis.Adriana Mihai (Romania), Associate Professor at the Psychiatric Department from the University of Medicine, Pharmacy, Science and Technology George Emil Palade in Targu Mures (Romania) and Director of the Centre of Psychotherapy and Personal Development (IPPD), showcased her presentation \"Vascular neurocognitive disorder \u2013 presentation of a clinical case with language disturbances\", highlighting cognitive disorders, especially vascular dementia, as a common cause of neurocognitive disorders post-Alzheimer's disease. Furthermore, Prof. Mihai presented epidemiological aspects and the characteristics of vascular dementia and introduced a fascinating clinical case presentation of acute psychotic disorder. Lastly, prof. Mihai discussed the importance of collecting comprehensive information on patients, especially on cases with less common manifestations, as the paradigm for treatment in psychiatry is a symptomatic one.Claudia Anghel (Romania), Psychiatrist at the Psychiatric Hospital Dr. Gh. Preda in Sibiu (Romania) and President of the NGO Psychiatric Hospital Association Dr. Gh. Preda, focused on \"Electroconvulsive therapy \u2013 between necessity and stigma\", discussing the mechanisms of electroconvulsive therapy and the impact of technological advancements while mentioning the possible complications and contraindications when using this therapy. For a better understanding, Dr. Anghel pinpointed the history of ElectroConvulsive Therapy (ECT) therapy in their hospital and the issues related to stigma and the portrayal of ECT in media, urging for improved education on this therapy. Lastly, in a case study on undifferentiated schizophrenia, the impact of ECT was highlighted. In the end, she invited the public to reflect on some aspects of ECT, including the avenues for changing societal perception of this medical technique.Doina Cozman (Romania) underlined the importance of showing great attention to mild cognitive impairment in people over 50 years of age, as this syndromologic diagnostic is chameleon-like, taking many possible forms and, in some cases, leading to dementia or depression, or even causing several psychiatric or somatic issues. Other critical points showcased were the relevance of the Montreal Cognitive Assessment (MoCA) test in cognitive assessment, the vital role of multidisciplinarity, and the interrelations of psychiatry and neurology. The parallel psychiatry session from the 17th International Summer School of Neurology stands as an example of the importance of transdisciplinary perspectives in neurosciences.In the form of discussions and final remarks,"}
+{"text": "RSC Advances article due to concerns with the reliability of the data in the published article. The authors confirmed that the western blot images in Fig. S3A had been inappropriately manipulated. Given the significance of the concerns about the validity of the data, the findings presented in this paper are no longer reliable.The Royal Society of Chemistry, with the agreement of the named authors, hereby wholly retracts this Fang Liu, Jing Wang and Xiu-Wei Yang were contacted but did not respond.Signed: Qi Zhao, Rui Yang, Dan-Dan Hu and Fei LiDate: 23rd January 2023RSC AdvancesRetraction endorsed by Laura Fisher, Executive Editor,"}
+{"text": "Mental disorders in Europe represent the leading cause of disability and the third leading cause of overall disease burden, following cardiovascular disease and cancers. As future healthcare professionals, with an imminent role in tackling this global health issue, we acknowledge that Mental Health is not adequately included in the medical curriculum. To address this gap, this workshop was created to equip medical students with the knowledge and skills that will empower them to lead a pioneering role in advocating for mental health for their patients, peers, and communities.By the end of the workshop, all participants should have: - Increased their knowledge in the field of Mental Health disorders - Increased their skills in the field of Mental Health  - Explored the relations between stigma, vulnerability, and Mental Health - Strengthened the international perspective and global understanding concerning mental health issuesThis workshop utilized principles of non-formal education and was planned according to the 4MAT system to meet all four learning styles through theory blocks, space for reflection, practical application of knowledge, and future opportunities for application of content. This was achieved through various methodologies including presentations, self-discovery activities and exercises, roundtable debates, simulations, and role-playing.obtainedThis workshop highlighted the importance of building the capacity of medical students to tackle the burden of Mental Health globally and within the region, and how similar student-led initiatives can further empower them to be change agents and impactful advocates for better Mental Health in their own communities."}
+{"text": "To examine links between Adverse Childhood Experiences (ACE) categories and diagnosis of antisocial personality disorder (ASPD) in this population; it is predicted that there will be a positive association between number of ACEs and ASPD. The effectiveness of high secure hospital admission and treatment in reducing number of risk incidents was also examined. ACEs are known to impact significantly on the development of the personality and future psychiatric risk. Currently, research into links between distinct ACE categories and the diagnosis of ASPD in the high-secure inpatient population is limited.Data were collected from a sample (n = 221) including all patients in the Mental Health, Personality Disorder and Women's Services at a high-secure hospital. Records were examined for evidence of abuse/neglect during childhood, and a number of markers of household dysfunction. The statistical relationship between each ACE category and subsequent diagnosis of ASPD was examined through paired t-tests. Frequency of incident reports (IR1s) involving violence was compared in the first, third and fifth years post-admission.Significant associations with adult diagnosis of ASPD were seen in categories of childhood physical abuse, sexual abuse, divorced/separated parents, Looked After Child (LAC) status and parental substance misuse, and total number of ACE categories present overall. Significant reductions in frequency of IR1s were seen in all services between first- and fifth- year post admission.A significant association between ACEs in specific domains and ASPD in adulthood was found. The importance of detailed exploration of childhood circumstances in this group is highlighted, as well as the need for further investigation of the psychological and social mechanisms underlying."}
+{"text": "Parkinson\u2019s disease (PD) is taking a staggering toll on healthcare systems worldwide, with the bulk of the expenditures invested in the late stages of the disease. Considering the rising life expectancy and the increasing prevalence of PD across the globe, a clear understanding of the early signs and treatment options available for advanced PD (APD), will facilitate tailoring management programs and support services. This task is complicated by the lack of both global consensus in defining APD and standardized care guidelines. This perspective prepared by a panel of movement disorder specialists, proposes to extend and optimize currently accepted PD coding to better reflect the diverse disease manifestations, with emphasis on non-motor features. The panel seeks to promote timely diagnosis by adjustment of evaluation tools for use by community neurologists and suggests modification of eligibility criteria for advanced therapy. Moreover, it advocates multidisciplinary assessments of APD patients to drive personalized, patient-centered and holistic management. Overall, earlier and more targeted intervention is expected to markedly improve patient quality of life. Parkinson\u2019s disease (PD) currently affects 41 in 100,000 individuals between the ages of 40 and 49 and 1,607 in 100,000 individuals over the age of 80 . In IsraHistorically, motor syndrome was the main recognized clinical manifestation of PD and the prevalence of severe disability and mortality within 5 and 10 years of onset was 25 and 65%, respectively . Yet, sivia pumps, are needed to improve response fluctuations.This stage is characterized by moderate to severe motor deficits (Hoehn & Yahr stage III-V during off periods), generally accompanied by troublesome motor and non-motor symptoms: fluctuations, dyskinesias, frequent off-periods, postural instability leading to frequent falls with increased risk of fractures, sleep disturbances, hallucinations, and cognitive decline, among others. However, with close support, patients are not entirely dependent at this stage and are still capable of independent activity, and may be effectively managed by timely adjustment of the treatment. As PD patients progress to the advanced stage, they typically require intensive and individualized multidisciplinary pharmacological and non-pharmacological care to manage disease and treatment-related complications . FurtherDespite the wealth of knowledge of PD pathology and its natural course, there is a lack of global consensus regarding the precise definition of APD. This is largely due to its heterogenic origins, the vast variety of subphenotypes, variable trajectories and prognostics, as well as the absence of robust biomarkers for disease progression. In turn, it has challenged development of standardized care guidelines, and has brought to a lag in appropriate alignment of diagnostic instruments and grading scales for classification of disease severity and evaluation of treatment and management strategies. Furthermore, it has stymied early APD identification, and tailoring of interventional programs and appropriate allocation of funds. The most popular assessment tools use PD duration as an anchor and primarily focus on cardinal overt motor features. They have been proven to lack universality due to different phenotypes and rates of disease progression and generally fail to recognize the true weight of non-motor features on patient performance and quality of life . Recent In line with the global efforts to moderate PD impact on quality of life, the authors, representing a panel of Israeli movement disorders specialists, propose to define APD in the International Classification of Disease 11th revision (ICD-11) as a unique health entity that demands adjusted healthcare provider attitudes and relevant social services. Modification of the ICD-11 PD coding should include severity- and fluctuation-based subcodes that accurately capture APD and distinguish it from early-stage PD. While very few diseases have been assigned severity-based subcodes in ICD-10 , the growing evidence of the distinct clinical manifestations and medical needs of this patient subpopulation, justifies reconsideration of its coding status.In addition, we call for optimization of the Delphi criteria by extending them to include a more extensive list of non-motor features, such as autonomic disturbances , pain, daytime somnolence, and apathy. Furthermore, in the opinion of the Israeli panel, the Delphi criteria for APD from motor fluctuations, regardless of their duration and severity, should be the main eligibility criteria for advanced therapy. Evaluation of PD patients should be based on a structured questionnaire applied as a preliminary tool geared to be implemented by community neurologists or case managers . Patients with suspected APD should undergo multidisciplinary evaluation, ideally in specialized APD centers, to define the extent of disability, outline an individualized treatment program, and weigh the need for rehabilitation and social support services. Routine evaluations should be adequately sensitive to allow for timely diagnosis of palliative-stage PD, which should be addressed by end-of-life palliative/hospice referral .Management protocols should implement personalized patient-centered and holistic approaches to target the heterogenic manifestations and course of PD. These should include tools for timely diagnosis and treatment of osteoporosis. Furthermore, patients should be informed of opportunities to participate in relevant clinical trials. In addition to the clinical benefits of integrated and coordinated care , such prThe panel also suggests standardization of DAT eligibility and prioritization of its use to early-stage APD patients, while minimizing its use in palliative-stage patients. Furthermore, integration of telemedicine and nurse practitioners can tighten surveillance and improve treatment optimization efforts.These can be further supported by establishment of a network of community physicians, led by movement disorder specialists, to promote case-sharing, research dissemination and exchange of professional know-how.Expanded APD-geared health baskets clearly outline eligibility for reimbursement for a part/full time paid attendant, mobility allowance, and rehabilitation services. In parallel, attention should be paid to informal and non-specialized caregivers by providing them PD-specific education and support . PatientIn summary, the globally rising life expectancy has increased the prevalence of PD in general, and of APD, in particular. Appreciation of the heterogeneity of PD etiology and manifestations has underscored the need for updated PD coding. Precise and standardized definition and evaluation of APD will promote earlier APD identification and timely referral to adequate therapies and specialists. Moreover, it will enhance holistic management, which is expected to markedly improve APD patient quality of life. Future works should focus on validating the proposed extension of the Delphi APD criteria, and on tailoring treatment to APD phenotypes.TG: draft preparation and literature search. All authors conceptualized, critically revised, and approved the submitted version."}
+{"text": "Advances in Theranostics: Novel Nanotools for the Treatment and Diagnosis of Tumors\u201d presents a small series of articles reporting the most exciting research, novel application studies and scientific progress in the field of nanostructures and functional materials used in the field of oncological theranostics. The limitation in the effectiveness of traditional approaches in treating cancer are largely demonstrated in this Topic Research Topic, providing examples of stimuli-sensitive and technologically advanced novel nanoplatforms  that, in a multidisciplinary and collaborative approach, involve the contribution of different disciplines ranging from material sciences, biology, immunology, medicine as well as diagnosis. Nanotechnology platforms that can combine both therapy and diagnosis are especially interesting, as this approach allows combining targeted therapy and monitoring of efficacy with minimal invasiveness and systemic toxicity. Multifunctional nanomedicines combining responsiveness to tumor microenvironment, targeting, therapy, sensitivity, and early-stage detection are highly advantageous and are most likely the future clinical direction of cancer management. The high number of views obtained by the articles published in this Research Topic Collection shows a clear interest of the scientific community for nanomedicine and theranostics and motivated the edition of this Topic Research Topic. Our goals are to facilitate access to thematically related papers and draw attention to the current activity and trends in addressing remaining challenges, ultimately serving as a valuable resource to the biomedical and pharmaceutical science community and beyond. The Research Topic is comprised of four selected peer-reviewed manuscripts  derived from the fields of (bio) materials science and engineering, pharmaceutics, and biology.The Research Topic entitled \u201cCong et al. opens this Topic Research Topic by overviewing the abnormal pathophysiological characteristics of the tumor microenvironment, including acidosis, overexpression of special enzymes, hypoxia, and high levels of ROS, GSH, and ATP. These characteristics are exploited in drug delivery systems (DDSs) design to trigger the spatial and temporal control of drugs and/or diagnostic agents in tumor tissues. The latest advances in the field of DDSs responsive to stimuli found in tumor microenvironment are highlighted in this review paper, emphasizing their ability to effectively realize tumor-site specific drug, decrease the injected dose and systemic toxicity. Finally, a critical analysis of the existing bottlenecks to the clinical translation of these technologies are also critically discussed and include, among others, DDS complexity, sub-optimal biocompatibility, patient biological heterogeneity, leading to varying response, size control and immune system reaction.The review paper by Xu et al., who proposed a nanoparticle-based platform for the effective presentation of sonosensitizers to hypoxic tumor tissues. In this work, a core-shell structured nanoparticle (IR780/PLGA@MnO2NPs) loaded with IR780 and manganese dioxide (MnO2) was developed as a nanocarrier to transport the sonosensitizer IR780 and the generated oxygen into the tumor tissue. The MnO2 shell layer of IR780/PLGA@MnO2NPs was designed to respond to tumor microenvironment, by releasing IR780 and generating reactive oxygen species in response to tumor acidity and excess of H2O2. As a result, the generated oxygen relieves tumor tissue hypoxia and kills tumor cells, while the generated Mn enhances magnetic resonance imaging (MRI) signal intensity by acting as a contrast agent for MRI. The developed multi-layer core-shell nanostructure was validated in vitro and in vivo on a breast cancer mice model, providing a promising strategy for cancer diagnosis and sonodynamic treatment, with potential future application in cancer theranostics.An example of stimuli-sensitive nanoDDS for tumor diagnosis and treatment if offered by Ranjbari et al. described nanostructure two-dimensional Mxene as potential materials in the diagnosis and treatment of breast cancer. Different synthetic methods for producing biocompatible Mxenes and their application to the detection and therapy of breast cancer are overviewed. The authors point out the high biocompatibility profile of. MXenes\u2019 and their surface modification flexibility, leading to multifunctional properties, such as preferential agglomeration at tumor sites for photothermal treatment by the non-covalent reactions on the MXene surface with PEG, CS, SP, and PVP materials. The synthetic MXenes could be potentially applied in the fields of, antimicrobial materials, attributes, drug delivery, engineering of tissue, and extensive near-infrared sorption.Wang et al., dealing with the assessment of the diagnostic value of 18F-NaF PET/CT in diagnosing bone metastases in patients with nasopharyngeal carcinoma (NPC) using, for the first time, visual and quantitative analyses. The study was carried out retrospectively, analyzing 164 patients with NPC who underwent 18F-NaF PET/CT between 2017 and 2021. They showed that visual analysis of 18F-NaF PET/CT findings is accompanied by high sensitivity and specificity for the diagnosis of bone metastases in NPC. Furthermore, the quantitative analysis of PET/CT (SUVmax), displaying the advantage of higher objectivity and reproducibility than visual qualitative analysis, was demonstrated a valuable tool for the differential diagnosis between bone metastases in NPC and benign bone lesions.Breast cancer is also tackled in the original research article by In conclusion, this Research Topic Collection represents a small cross-section of the research work performed around the topic of novel nanotools for the treatment and diagnosis of tumors, having the scope to promote ideas, show new technologies, present the state of the art in the field, and critically discuss current challenges still existing in this area and possibilities for overcoming these challenges. We are convinced that this article Research Topic will be significantly relevant to the scientific community and beyond to spotlight cutting edge studies and start initiatives and collaborations among scientists in this field.This Research Topic aims at collecting recent advances in theranostic nanoplatforms, with a special emphasis on originally designed systems. Nanoplatforms combining drug delivery, targeting, and tumor monitoring approaches could be of particular interest when designed to address the challenge to specifically reach tumors in specific body districts, or treat tumors of different stages."}
+{"text": "Background: Six diverse Demographic Development and Environmental Surveillance System (DDESS) sites were established in urban slum, urban resettlement, peri-urban, rural, and tribal areas located in Northern, North-East, Eastern, and Southern regions of India from June 2020 to March 2022. Understanding the community dynamics and engaging people in the community is critically important in the process of establishing DDESS. We ascertained the barriers, challenges, and facilitators during the establishment of multiple DDESS sites across India. Methods: This was a cross-sectional descriptive mixed-methods study. Results: Multiple barriers and challenges encountered were reported in the process of community engagement (CE), such as geographical inaccessibility, language barriers, adverse weather, non-responsiveness due to perceived lack of individual benefit or financial gain, fear of contracting COVID-19, COVID-19 vaccine hesitancy, etc. Facilitators in the CE process were pre-existing links with the community, constitution of community advisory boards, community need assessment, concomitant delivery of outreach health services, and skill-building facilities. Conclusion: Most community barriers in the development of DDESS sites in resource-limited settings can be overcome through a multipronged approach, including effective community engagement by focusing on demonstrating trust at the local level, enlisting community mobilization and support, utilizing pre-existing community linkages, initiating community diagnosis, and meeting perceived community health needs. Demographic Development and Environmental Surveillance Systems (DDESS) enable the development of novel, innovative, and real-world solutions for achieving healthier, prosperous, and sustainable communities in resource-limited settings ,2,3. In Globally, there are over thirty demographic surveillance sites across Asia, Africa, and America . For obtAccording to the Centre for Disease Control (CDC), community engagement (CE) is the process of working collaboratively with and through groups of people affiliated by geographic proximity, special interest, or similar situations to address issues affecting the well-being of those people . Local cThere is a paucity of evidence towards understanding the real-world strategies and solutions that enable effective CE in public health and developmental research . MoreoveStudy Design: This was a cross-sectional descriptive mixed-methods study. Baseline data were collected from the ongoing multi-site DDESS project in India.Study Setting: Six diverse DDESS sites across India established during the period from June 2020 to March 2022 were included .All these sites were pre-existing field practice areas of the concerned medical colleges and research organizations. At each site, data were collected on the type of settlement , demographic, and health characteristics from both DDESS surveys and non-DDESS secondary data sources, such as previous local surveys, census data, community and facility-based research studies conducted in the area, and medical and health records from the local government primary care facilities. Description of the study sites (DDESS): The six DDESS sites were slated to be developed by six respective institutions: MAMC, Gokulpuri, New Delhi; CHRD-SAS, Dakshinpuri, New Delhi; INCLEN, Mawphlang and Sohiong, Meghalaya; ICMR-RMRC, Bhubaneswar, Tigiria, Cuttack, Odisha; AMC, Vishakapatnam, Andra Pradesh; and PIMS, Marakanam-Villupuram district, Chitamur-Chengalpet district, Tamilnadu, and Muthialpet in U.T. Puducherry). The basic sociodemographic characteristics of the study population are reported in The Gokulpuri DDESS is an urban low-income neighbourhood in the North-East district of Delhi comprising an urban resettlement colony, urban slum, and a village. Of the total population, 91.6% are literate, 94.94% belong to the Hindu religion, and 52.28% belong to the scheduled caste. The settlement has very few  health care facilities, while the nearest referral health facility is around 6\u20137 km away.The Dakshinpuri DDESS is an urban low-income neighbourhood located in the Southern district of Delhi. A total of 99.55% of the population is urban and 78.91% follow the Hindu religion, followed by the Muslim and Sikh religions. The settlement has 3 healthcare facilities for local residents.The Mawphlang DDESS spreads across the 364.48 Sq Km area in the Mawphlang and Sohiong administrative blocks of the East Khasi Hills district of Meghalaya state. The site is predominantly occupied by the Khasi tribal community (99.5%). In total, 80.7% of the population are Christians and the site has very high literacy rates (82.8%). There are 2 community health centres, 1 primary health centre and 9 sub-centres.The Tigiria DDESS is a predominantly rural area (89.2%). A total of 95.17% of people belong to the Hindu religion, followed by other minority communities. The majority belong to the upper caste (83.4%), followed by the schedule caste (13.2%) and the schedule tribe (3.4%). Cultivation is the main occupation. While the site has 2 community health centres, 4 primary health centres and 13 sub-centres, the referral health centre is around 15\u201320 km away.The Simhachalam DDESS is located in the western part of Visakhapatnam and is predominantly peri-urban. A total of 95.9% of the population belong to the Hindu religion. The scheduled caste (7.6%) and scheduled tribe (14.3%) constitute one fourth of the population. Occupations are mostly service or running small businesses. The site has the fair availability of 92 hospitals in the urban setting and 13 hospitals in the rural setting, respectively. The Marakanam, Chitamur, and Muthialpet DDESS is predominantly rural, with the average literacy rate being 65.2%. The major occupations are agriculture and fishing. The site has an availability of 48 hospitals in the rural setting, compared to only 2 hospitals in the urban facilities for the residents.Sample size and sampling strategy: A universal sample (census) of all the households located in the DDESS sites were included in this study through a standardized house-to-house survey process. Data collection (quantitative) was conducted following a systematic process followed for the establishment of comprehensive community-based surveillance sites . BroadlyData entry: All 6 DDESS sites used Android-based electronic questionnaires called \u2018SOMAARTH 1 & SOMAARTH 3\u2019. The enumerator asked the respondent questions in a face-to-face interview and the responses were recorded by the enumerator directly into their data collection tablet. Data were securely saved in the Amazon Web Service (AWS\u00a9) server. Data analysis: Data were downloaded from the server and cleaned using STATA Version 15  and IBM SPSS Statistics for Windows, Version 25.0. . Data related to key sociodemographic characteristics of the study populations were reported as frequency and percentages.Written transcripts were prepared for the interviews as part of this study. Thematic analysis was used for identification of recurrent themes, all of which had been identified a priori from a comprehensive review of the literature. Key findings from each of the sites were centrally analysed using qualitative synthesis techniques, such as textual narrative and framework synthesis for the identification of the key barriers, facilitators, and coping strategies in community engagement during the establishment of DDESS sites. Analytical conceptual framework: The CE activities undertaken by the study teams were classified within a conceptual framework comprising the previously validated five stages of the CE continuum ,18, whicThe locations of six DDESS sites included in this study are presented in (A)Limited or lack of understanding of locally spoken languages: India is the world\u2019s most linguistically diverse country. Absence of familiarity with the locally spoken language and dialect posed challenges for investigators and project staff, especially in remote and tribal regions with predominantly indigenous populations. For instance, Khasi, an Austroasiastic language, is predominantly spoken in the tribal areas of Mawphlang and Sohiong blocks of the North-Eastern state of Meghalaya, having just over 1 million speakers. This caused difficulty for site investigators unfamiliar with the local language to communicate with members of the local community that precluded effective CE and the data collection processes.Poor road connectivity and difficult terrain: Some DDESS sites were located in areas  that were not connected with all-weather motorable roads and caused difficult access. The survey team had to travel considerable distances by foot to reach these remote villages. The interior areas located in forest and hilly terrain were difficult to reach, and more so during the rainy season.Inclement weather and extreme climatic conditions: While DDESS sites in Meghalaya were the wettest, the site of Odisha is near the riverine regions. Such sites are prone to flood and difficult to carry out field activities in during the rainy seasons. The temperature extremities (summer in southern DDESS sites and winter in the northern part) and heavy rainfall were also detrimental to conducting routine project activities.Expectation for financial benefits: Some community members had expectations of financial gain or compensation for participating in or facilitating the project and research activities in their sites. In the absence of provision for any direct financial benefit, such members were disinclined to participate or consent.Fear of wage loss: Some family members, especially the adults who were mainly involved in earning livelihoods for their family, could not afford to spend time with the team during their working hours.Migration: Some people migrate in search of jobs, even with their family. This causes a loss in follow-up of the registered population and a challenge to DDESS sustainability.Dispute over land ownership: Households with prevailing legal disputes about their land ownership were initially found to be resentful and reluctant to share any of their personal information as part of the study. In hilly areas, even the village councils are involved in disputes over the village boundaries, and some of them do not agree with the inter-village boundaries given in the government records.Pandemic and fear of COVID-19 infection: The COVID-19 pandemic created a lot of panic among the community, and the imposed restrictions created hindrance for initiating interactions with outsiders in the sites. The unavailability of hospital beds for COVID patients during the COVID peak resulted in non-cooperation of the community with the research team.Distrust for COVID-19 vaccination: Communities, particularly rural and tribal communities, were reluctant to accept COVID-19 vaccination. They were panic-stricken and agitated at the prospect of engaging with people working in the health sector or associated with hospitals. There was also resistance among communities against the implementation of non-pharmaceutical measures, such as social distancing and following COVID norms. Dissatisfaction with suboptimal functioning of primary care facilities during the pandemic, reduced staffing, and services as a result of the pandemic were a major issue faced by the surveillance team.Unpleasant past experiences: Some of the community members had unpleasant experience of supporting governmental or non-governmental activities in the past, resulting in non-cooperation. For instance, no personal benefits were received by the community members for previous participation in other surveillance activities. Some community members had unpleasant experiences of not receiving any financial or other benefits promised to them for their participation in prior community-based research activities conducted in their areas, which further compounded their unwillingness to participate in the present research project.Engagement of locally hired people in the enumeration team may bring undue demands and interference from the local community, such as mounting pressure to hire undeserving candidates, negotiations for the payment amount or rolling back the termination order, etc.Barriers encountered during community engagement (CE). The significance of CE exists both during the establishment of the DDESS and ensuing quality data collection from the sites. The research teams encountered many barriers and challenges in the process of ensuring adequate CE. While some common challenges were observed in multiple sites, some were site-specific:(B)Pre-existing community links with the research teams by virtue of being the field practice areas of the respective institutions; b. broadcasts of the activities conducted by the SOMAARTH DDESS among the public by the village council through the public announcement system; c. involvement and engagement of community-level frontline health workers ; and d. involvement of village volunteers were helpful in ensuring community engagement activities.Enablers to achieve CE: Many enabling factors were noticed that facilitated CE, which are described below.(C)Formation of a community advisory board (CAB) at each DDESS site: Each study site formed a CAB by identifying and recruiting significant stakeholders following a common CAB charter for better functioning of the DDESS site. Meetings among the members of the advisory committee were held to identify and address existing community-level issues to achieve trust and better community involvement and participation. The CAB helps in supporting advocacy, sensitization campaigns related to the project, and mitigation of any conflict, while ensuring that beliefs and cultural disparities among community members are respected. The CAB gives advice and recommendations to the research team but has no administrative or legal responsibilities. The research team informs the CAB before carrying out any new activities. The board provides guidance and assistance in planning and implementing the activities of the project by ensuring that the activities are conducted in an informed and transparent manner that is acceptable to the community.Identifying and involving community volunteers: Some of the DDESS sites identified and involved local community volunteers, such as Panchayati Raj Institution (PRI) members, schoolteachers, ASHA, Anganwadi workers, etc. These community volunteers were engaged during the community mobilization process. They provided enormous support during community consultation, village boundary mapping, and for health awareness initiatives towards strengthening surveillance activity. In order to avoid the interference of the community in the recruitment and research processes, a detailed SOP for the village volunteers\u2019 recruitment was developed and followed by the sites. The formal recruitment process for the engagement of village volunteers included vacancy announcements in all the site villages/localities, organization of written examinations and tablet tests at clusters for ensuring the participation of volunteers from the villages which are far from the office location, followed by face-to-face interviews with the successful candidates. A merit list was prepared and publicly displayed for the transparency of the process and recruitment of the village volunteers was carried out on the basis of the merit list.Community consultations involving key stakeholders: Prior to data collection, the population was consulted and appraised of the project objectives. During the meetings, key stakeholders, such as local health care providers, schoolteachers, and community leaders were also involved. Many stakeholders played a role as a link between the community and researchers. This improved the trust among the people to participate and support the project\u2019s activities.Undertaking other health-related activities: Apart from the project-related activities, the DDESS sites also organized some other health initiatives, such as health camps, COVID-19 Serosurveys, screening for non-communicable diseases (NCDs), and oral health problems. Community awareness and sensitization programs based on prevailing key health issues, such as the COVID-19 pandemic situation, prenatal/postnatal care, multidrug-resistant tuberculosis (MDR-TB), and vector-borne diseases, such as dengue, chikungunya, etc., were supported by the community stakeholders.The participatory mapping and data collection approach helped in gathering updated relevant information in the manner in which the community perceived them. In villages where boundaries were not available in the government census maps, research teams were able to gather information through the community consultation process.Strategies adopted for better community engagement: In view of the existing barriers, challenges and enablers, various site-specific strategies were undertaken in order to achieve better community engagement .FormatiThe barriers and enablers encountered for CE, and the strategies adopted to achieve better CE, are depicted as a conceptual framework .A comparison od the barriers and enablers encountered, and strategies adopted for better community engagement, across the six DDESS sites, is presented in The establishment of DDESS is important to study a population cohort through collecting data longitudinally and monitoring their health and wellbeing. This helps to understanding the community dynamics, the existing challenges, and barriers better to developing appropriate disease-control and prevention strategies. These sites enable epidemiological surveillance through prospective data collection on population dynamics and health measures in a specific geographical area, generating data on a country\u2019s vital statistics related to disease burden and demographic information that instructs and advances public health policy formation .There is growing global recognition of the role of CE in facilitating and accentuating research activities planned and conducted within communities. However, there is a lack of global consensus guidelines on assessing the quality of CE processes . FurtherIn this study, all the participating organizations had been functioning in their respective sites for >10 years and were engaged in various public health services, and this activity helped the research team to acquire knowledge and understand the beliefs and socio-cultural practices of the local population. Operational challenges for the sustained functioning of the DDESS sites are evident from the requirement of frequent updating of population data prospectively often resulting in research fatigue amongst respondents . InaccesSome DDESS sites are being developed amongst vulnerable communities, such as tribals, rural, and urban poor, necessitating the need for community consultation to identify community concerns which may influence community participation. In this regard, Community Advisory Boards (CABs) were frequently used to support CE by helping research teams honour the community values, and frequently also guide decision-making when deliberating on the choice of community-based research and supportive activities ,28,29. AFurthermore, the suboptimal functioning of existing health surveillance systems in the more geographically inaccessible remote, rural, and tribal locations renders the monitoring and detecting of the vital events and associated data management difficult ,32. All Effective community mobilization and collaboration with motivated community partners are also crucial towards identifying the prevalent social determinants of health that impact population health ,6. In thThe establishment of DDESS sites intends to bridge the health- and demography-related data gaps necessary for informing and strengthening public health policies in developing countries. The specific challenges encountered in establishing DDESS sites in different areas, and the approaches and strategies implemented to overcome these, may be instructive in developing comparable platforms under similar conditions. Most community barriers exist in the development of DDESS sites in resource-limited settings, but most can be overcome through effective community engagement by focusing on enlisting local community trust, mobilization and support, utilizing pre-existing community linkages, community diagnosis, and meeting health needs. The study underscores the need for rigorous community mobilisation and regular stakeholder participation, for a better understanding of community dynamics, and aiding community engagement."}
+{"text": "Screening and brief intervention (SBI) is a low-intensity, time-limited psychosocial treatment for substance misuse. The therapeutic principle is grounded on the social cognitive theory encompassing different combinations of personalized feedback, styles of motivational interviewing (MI), decisional balance, advice, identifying and managing high-risk situations, and providing a personalized menu of options to reduce or stop substance use . SBI couAlthough there are several screening instruments to detect and monitor substance misuse, the validity of those screening tools across countries, age groups, and study settings are not yet consistent . For insThe effectiveness of alcohol BI among adults in primary and general healthcare is consistent and robust , 12. HowThe implementation gap of BI is possibly much wider than the evidence gap, especially for alcohol misuse. The practice of alcohol BI in clinical settings, despite the support from policymakers, is sub-optimal. Scandinavian countries, the UK, and Italy, which have integrated alcohol BI into their healthcare system, show only a minority population are screened (10\u201337%) for alcohol use by their primary care physicians, and a further minority receive advice to cut down . The posLevy et al. examined the uptake and preliminary outcomes of a teleconsultation model for pediatric primary care. The teleconsultation program from Massachusetts, US, provides an implementation model for SBI in children and adolescents in a limited resource context. Another electronic health record system-based study from the USA tested the changes in unhealthy alcohol use pre- and post-pandemic. The authors identified vulnerable subgroups and suggested using telehealth to reach out to these groups. Al Mahmud et al. explored the format and themes of another digital self-help option for alcohol cessation, the YouTube videos. In another study, the authors explored the need for brief counseling and intervention based on a theory-driven approach in the context of sexualized drug use, also known as Chemsex. Future studies on BI in special populations and contexts might use a theory-driven, tailor-made approach . Finally, a South African study proposes screening for suicidal behavior in persons with heroin misuse- increasing the ambit of screening in SBI.This Research Topic revisits the evidence of alcohol BI in the criminal justice system and the integration of alcohol intervention into general healthcare settings. The latter study focuses exclusively on sub-Saharan Africa. These two studies aim to review and update the evidence of alcohol BI in non-primary care and low-resource settings. This Research Topic highlights the evidence and the implementation gap of SBI in substance misuse. This unpacking of the research gaps may motivate further research on SBI. It may provide directions to funders and policymakers.AG, SM, and DN-B jointly conceived the idea of the Research Topic and the editorial. AG wrote the first draft. SM and DN-B reviewed and edited the draft. All authors reviewed the final draft and approved it.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "A 46-year-old female patient came to the Dermatology outpatient clinic complaining of asymptomatic breast lesions for ten years. She reported a weight gain of approximately 50\u202fkg during this period and reported being an active smoker with a tobacco load of 42 pack/year. Dermatological examination showed erythematous to violaceous reticulated lesions on both breasts. Some areas showed shallow ulcerations .Figure 1Histopathology revealed a rectified epidermis and proliferation of small vessels, more intense in the upper dermis, but extending to the middle dermis without cell atypia . The imma)Kaposi's Sarcomab)Low-grade angiosarcomac)Diffuse dermal angiomatosis of the breastd)CalciphylaxisBased on the clinical-pathological correlation, a diagnosis of diffuse dermal angiomatosis of the breast was made. Laboratory tests including ANF, lupus anticoagulant, anticardiolipin, anti-beta-2 glycoprotein, C and S proteins were normal. The CT angiography excluded venous or arterial thrombosis. The patient lost 20\u202fkg in one year and there was complete regression without any medical or surgical treatment . DespiteDiffuse dermal angiomatosis of the breast (DDAB) is a poorly described entity that affects exclusively middle-aged, obese women with macromastia and who are smokers.The pathogenesis likely involves tissue ischemia leading to an increase in endothelial growth factors and neoangiogenesis.The management of DDAB requires treatment of the underlying cause of tissue ischemia. The investigation to exclude the causes of ischemia is mandatory. Advice on weight loss, smoking cessation, and control of cardiovascular risk factors such as hypertension or hyperlipidemia are essential. Drug therapy includes the use of isotretinoin, anticoagulants, acetylsalicylic acid, pentoxifylline, and oral corticosteroids, but responses are variable.None declared.Bruno de Castro e Souza: Drafting and editing of the manuscript; critical review of the literature.Esio Pessoa Caracas de Souza: Collection, analysis, and interpretation of data; drafting and editing of the manuscript; critical review of the literature.Neusa Yuriko Sakai Valente: Design and planning of the study; drafting and editing of the manuscript; critical review of the literature; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied case.Jos\u00e9 Antonio Sanches: Design and planning of the study; drafting and editing of manuscript; critical review of the literature; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied case.None declared."}
+{"text": "The coronavirus pandemic (COVID-19) has affected the functioning and capacity of healthcare systems worldwide. COVID-19 has also disproportionately affected older adults, including those living with dementia. In the context of COVID-19, decision-making surrounding place of care and place of death in this population involves significant new challenges.To explore key factors that influence place of care and place of death decisions in older adults. A secondary aim was to investigate key factors that influence the process and outcome of these decisions in older adults. To apply findings from current evidence to the context of COVID-19.Rapid review of reviews, undertaken using WHO guidance for rapid reviews. Ten papers were included for full data extraction. These papers were published between 2005-2020. Data extracted was synthesised using narrative synthesis, with thematic analysis and tabulation.Papers included discussed actual place of death, as well as preferred. Results were divided into papers that explored the process of decision-making, and those that explored decision-making outcomes. Factors such as caregiver capacity, the availability of multidisciplinary teams, cultural appropriateness of care packages and advanced care planning were found to be key.The process and outcomes of decision-making for older people are affected by many factors \u2013 all of which have the potential to influence both patients and caregivers experience of illness and dying. Within the context of COVID-19, such decisions may have to be made rapidly and be reflexive to changing needs of systems and of families and patients."}
+{"text": "Cancer, the second leading cause of death worldwide, continues to represent an impressive challenge for researchers and clinicians. Indeed, radiotherapy and chemotherapy are still the main therapeutic options, associated, however, with undesirable toxicity. Furthermore, chemotherapy is frequently accompanied by the appearance of the drug resistance, which, in turn, further limits the overall success of the therapy. In the last decades, much work has been devoted to the development and/or implementation of strategies of cellular and molecular targeted therapies. For instance, Tamoxifen, which specifically targets the estrogen receptor in breast cancer, is the first drug approved by the Food and Drug administration (FDA) in 1977 as cellular targeted therapy for the treatment of metastatic breast-cancer-affected patients . On the In the \u201cTargeted Therapies for Cancer\u201d Special Issue, six original articles, one perspective article and three reviews intend to provide an overview on the state-of-the-art of targeted therapies for cancer, covering some of the aspects of this broad field. This Editorial briefly summarizes findings and highlights derived from the published manuscripts.Jebali and colleagues  focused The involvement of Lamin A/C (LMNA gene) in the tumorigenesis and progression of glioblastoma multiforme (GBM) was instead investigated by Gatti and colleagues . It was In addition, the study conducted by Yu and colleagues  is focusThe implication of Nuclear factor erythroid-2 related factor-2 (Nrf2) in breast cancer (BC) responses to chemotherapy was instead investigated by Bovilla and colleagues . The expEliseev and colleagues  focused Rango and colleagues  investigFresnais and colleagues  presenteA new and interesting approach of cancer therapy consisting in the targeted osmotic lysis (TOL) was presented by the review article of Gould and Paul . This apAdvances and limitations in the development of Antibody-Drug Conjugates (ADCs) are discussed in the review article from Mckertish and Kayser . ADCs arThe review article by Wolf  focuses,"}
+{"text": "Traumatic Brain Injury (TBI) represents a major medical, healthcare, and socioeconomic problem worldwide and one of the most important causes of disability and mortality. Over 700 participants from various countries attended the much-expected educational event, which aimed to set the stage for lively debates on a plethora of aspects under the broad domain of neurosciences. Thrilling lectures and presentations took place over two days and the event included 6 sessions and 4 interactive panels held by 26 speakers.The 20The event brought together a lively audience with diverse backgrounds, such as neurology, psychology, neurosurgery, neurorehabilitation, psychiatry, psychotherapy, and public health. The Congress was opened by the steering committee, which included Klaus von Wild (Germany), Dafin F. Muresanu (Romania), Johannes Vester (Germany), Nicole von Steinb\u00fcchel (Germany), and Volker H\u00f6mberg (Germany).Session one introduced the audience to the topic of TBI research and was structured into two presentations. The former, by Johannes Vester (Germany), the AMN president and Associate Professor at the Department of Neuroscience from Iuliu Hatieganu University of Medicine and Pharmacy in Cluj-Napoca (Romania), was centered around the multidimensional approaches in TBI research and presented insights from the Cerebrolysin Asian Pacific Trial in Acute Brain Injury and Neurorecovery (CAPTAIN) I and II trials. Moreover, Prof. Vester discussed the limitations of the dichotomization of results, of binary thinking in TBI research, and the importance of full-scale analysis.e.g. Intelligent Mechanical Training Devices, Gaming Technology for motor and cognitive training, Brain-Computer Interfaces, Neuromodulation) in contrast to low-tech options , comparing their limitations and benefits. Furthermore, Prof. H\u00f6mberg offered insight into the role of digital communication strategies in allowing the dissemination of knowledge and skills to larger populations.The second presentation, by Volker H\u00f6mberg (Germany), Chairman of AMN Scientific Program Committee and President-Elect of the World Federation for Neurorehabilitation (WFNR), approached the vast and complex subject of neurorehabilitation, discussing future approaches. Neurorehabilitation of TBI represents a vast topic, ranging from early rehabilitation of patients to support and reintegration into the social and professional environment. Therefore, discussing solutions for neurorehabilitation is of utmost importance, especially considering the gap experienced in low- and middle-income countries (LMIC) with regard to meeting the needs of the patients, as well as the disruption caused by the COVID-19 pandemic. Prof. H\u00f6mberg discussed the role of high-tech options , ended the session with a presentation entitled \u201cNew developments in TBI clinical research from a C-RETURN study\u201d highlighting the importance of continuous research in the domain of neurotrauma. Prof. Muresanu suggested that the functional effects of lesions on brain networks require a change in our approach to neurorehabilitation, shifting the emphasis of treatment and restorative trials towards modulating the activity levels in preexisting networks and showcased the role of multimodal drugs in both neuroprotection and neurorecovery. Moreover, Prof. Muresanu discussed the importance of the CAPTAIN trials in TBI research as the first series of trials with multidimensional approaches based on full outcome scales, and the vital role of the C-RETURN study.Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI). The inspiring CENTER-TBI is a longitudinal prospective study describing Intensive Care Unit (ICU) admission policies, management, and outcome for TBI patients. Prof. Maas showcased the importance of care in the initial phase at the emergency scene and the post-acute care phase. The necessity for the CENTER-TBI study was two-fold, first, the need for improved characterization and classification, and secondly, the issue of the heterogeneity of TBI as a disease, which motivated the search for best practices. Moreover, the importance of guidelines was discussed, as well as the shift towards multimodal approaches in treatment, the disparities in care, and the risk of incomplete recovery following a mild TBI. Lastly, the presentation ended with a statement on the importance of the CENTER-TBI study.The second session, having Prof. Johannes Vester (Germany) and Prof. Andrew Maas (Belgium) as chairpersons, further discussed the role of research in TBI. The session began with a presentation by Andrew Maas (Belgium), Emeritus Professor of Neurosurgery at the Antwerp University Hospital and University of Antwerp (Belgium), on the continuity of care in the trauma chain, presenting the experience of Furthermore, the session was followed by an insight into the CAPTAIN trial from Christian Matula (Austria), Professor and Vice-Chairman at the Department of Neurosurgery from Medical University of Vienna (Austria). In the past years, a few studies significantly impacted the management and outcomes of TBI. The CAPTAIN trial reveals impactful insight into the effect of the pharmacological agent Cerebrolysin. After discussing the neuroprotective and neurorecovery mechanisms of the brain following an acute lesion, he highlighted the importance of neurotrophic factors in the process of protection and recovery. Moreover, Prof. Matula discussed the objectives of the CAPTAIN trial while showcasing the problems of reductionist approaches, and the importance of multidimensional analysis in providing a new direction for clinical and statistical thinking. The results of the trials could be a door opener for future guidelines. Lastly, the grim realities of post-TBI depression encountered in nearly half of all TBI patients were discussed, highlighting the need for proper approaches. As proof of the necessity of multimodal approaches, he ended the presentation with a glimpse into the exciting Neurotrauma Treatment Simulation Center from Vienna, a training program focusing on the patient pathway to recovery.The final presentation offered an immersive incursion into the tools and instruments necessary for developing and providing the best practices in neurotrauma care by Mark Bayley (Canada), Program Medical Director and Psychiatrist-in-Chief at UHN-Toronto Rehabilitation Institute (Canada), underlining the constant need to improve existing therapies and find new treatments. Prof. Bayley aided the participants in discovering evidence-based resources to support TBI care and rehabilitation, including reviews and clinical practice guidelines, navigating web-based resources developed in Canada, providing demonstrative cases, and, lastly, using the TRICORDRR (Toronto Rehabilitation Institute Concussion Outcome Risk Determination & Rehab Recommendations) tool for the identification of patients most likely to require long-term special care for conclussions.rd session, having Prof. Nicole von Steinb\u00fcchel (Germany) and dr. Juan Carlos Arango-Lasprilla (Spain) as chairpersons. The session centered around neuropsychological aspects of TBI as well as TBI rehabilitation.The first day of the online AMN Congress of 2022 was completed by the 3Firstly, Nicole von Steinb\u00fcchel (Germany), Director of the Institute of Medical Psychology and Medical Sociology of the University Medical Center at Georg-August-University of Goettingen (Germany), outlined the domains and new trends in neuropsychological rehabilitation. The presentation started with an incursion into the past, presenting a reality that remains in place to this day, respectively that only a minority of patients suffering a stroke or traumatic brain injury receive adequate rehabilitation aid. This reality supports the need to enhance and personalize the post-TBI treatment and rehabilitation, especially regarding cognitive function, but also in treating psychiatric, psychological, and daily life problems arising after neurotrauma. With physical treatment receiving more attention in TBI, it is essential to consider the need for proper neurorehabilitation. The sequelae of TBI can be complex and could hamper the reintegration of patients into society, as well as their quality of life. With depression, anxiety, and Post-Traumatic Stress Disorder (PTSD) presented in a significant number of patients early on after a TBI and persisting up to one year, the need for systematic longitudinal evaluation and therapy is apparent. Prof. von Steinb\u00fcchel described how neurological rehabilitation aims to improve functions through restitution, substitution, activation, or integration, with each of the above-mentioned requiring specific evaluation and therapeutic strategies in the context of a multidimensional perspective. Recent years have brought the development of new therapeutic technologies, the improvement of neuroimaging techniques, as well as the development and implementation of international multicenter studies to address the gaps in information on neuroimaging and analytic algorithms, the influence of biomarkers on outcomes, the multidimensional outcome assessment, thus paving an encouraging road towards comprehensive neurotrauma care and rehabilitation.Secondly, Marina Zeldovich (Germany), Dr. rer. nat. at the Institute of Medical Psychology and Medical Sociology in G\u00f6ttingen (Germany), discussed the results of the CENTER-TBI study on patient-reported and neuropsychological outcomes after TBI. Patients after a TBI often report anxiety, depression, PTSD, post-concussion symptoms, and a decreased quality of life. In addition to clinical diagnosis tools, the patient-reported outcomes offer a more comprehensive image of the subject. To assess modifications in cognitive functions, information on performance-based outcomes provides relevant insight into patient status after a TBI. Dr. Zeldovich presented the findings of the CENTER-TBI studies, highlighting the need for multimodal outcome assessment, the inclusion of health-related quality of life evaluations, and evaluation of cognitive performance.The presentation was followed by a glimpse into the complexity of rehabilitation after mild traumatic brain injury, by Nada Andelic (Norway), Head of Research and Development at the Department of Physical Medicine and Rehabilitation from University Hospital in Olso (Norway), describing evidence-based recommendations for the treatment of physical, cognitive, and emotional symptoms following a mild TBI. Prof. Andelic familiarized the audience with strategies for treating physical, cognitive, and emotional consequences post mild TBI as well as facilitating the return to pre-morbid functioning. Mild TBI is characterized by the level of consciousness at the time of the injury or half-hour post-injury, along with the presence of other neurological symptoms. Rehabilitation aims to optimize function and reduce disability in patients, as stated by the World Health Organization (WHO). Prof. Andelic pinpointed the effectiveness of rehabilitation efforts in the acute phase, highlighted the importance of comprehensive assessment, and supported the use of biopsychosocial conceptualization in the rehabilitation of persistent symptoms encountered after mild TBI. The importance of contextual factors stems from their interaction and the possibility to negatively or positively impact the outcome and brings forward the need for patient-centered rehabilitation models and evidence-based treatments. Further aspects on neuropsychological rehabilitation, focusing on memory and attention after traumatic brain injury and new technologies were also discussed by Juan Carlos Arango-Lasprilla (Spain), Research Professor at BioCruces Vizcaya Health Research Institute in Bilbao (Spain).The last presentation of the session approached the topic of neurorehabilitation of psychiatric sequelae after TBI and was conducted by Katrin Rauen (Switzerland), Consultant in Neurology, Psychiatry & Psychotherapy at the Department of Geriatric Psychiatry from University Hospital of Psychiatry Zurich (Switzerland). Nowadays, traumatic brain injury scientifically becomes more important, however, the society is still unaware of its significant medical and healthcare implications and neuropsychiatric repercussions for the patients. Therefore, neuropsychiatric complications are one of the most important factors to consider, as they represent a constant challenge for all medical specialties and can significantly impact the lives of patients and their families. Most TBI patients are seen by GPs  rather than TBI specialists, underlining the neglected relevance of the disease in the field of Neuropsychiary. Some of the most important aspects to consider are depression, anxiety, fatigue, and insomnia, as well as PTSD and the increased risk of suicide. It is of utmost importance to detect patients with neuropsychiatric sequelae early on and consider the importance of quality-of-life assessment after neurotrauma. The Quality of Life after Brain Injury (QOLIBRI) instrument comes as a solution to this problem. Finally, Dr. Rauen pinpointed strategies for cognitive rehabilitation and the importance of psychiatric diagnosis and rehabilitation in TBI guidelines.\u2013 how to minimize the risks of failure?\u201d, where a respected set of panelists, including Michael Chopp (USA), Karin Diserens (Switzerland), Andrew Maas (Belgium), and Johannes Vester (Germany) had a lively discussion on fitting approaches for the challenges of TBI research. TBI research can be difficult as there is tremendous variability when considering the best approaches. A comprehensive approach should consider the best models, the outcomes and mechanisms, and have a thorough understanding of the selected population. A multidimensional approach from research teams members of varying specialties  could offer a more complex vision of the problems and lead to innovative solutions.The AMN Congress introduced the first Panel, \u201cResearch in TBI is full of challenges \u2013 what should be done to offer effective treatment solutions?\u201d, having Nada Andelic (Norway), Juan Carlos Arango-Lasprilla (Spain), Peter Lackner (Austria), Katrin Rauen (Switzerland), Nicole von Steinb\u00fcchel (Germany) and Marina Zeldovich (Germany) as panelists, highlighted approaches to treatment for the cognitive problems resulting from neurotrauma. Cognitive problems are often developed following a TBI and can affect attention, learning, memory, concentration, speech, problem-solving, and planning. As attention is the basis for higher cognitive skills , impairment in attention can lead to a wide array of manifestations, from understanding information, following directions, reacting, managing tasks, learning and remembering, making informed decisions, or understanding social boundaries.The impact of the cognitive impairments can reflect significantly on the personal and professional lives of those who have experienced TBI due to difficulty in carrying out executive tasks, distractibility, and difficulty in conversations. The issue of post-TBI cognition is complex and multidimensional, having a substantial impact on the patient and their social circle . For this, early identification of the individual at risk and the development of effective treatment solutions, as well as having a follow-up of the patient is of utmost importance.The impact of the cognitive impairments can reflect significantly on the personal and professional lives of those who have experienced TBI due to difficulty in carrying out executive tasks, distractibility, and difficulty in conversations.The second Panel, \u201cThe incidence of post-TBI cognitive problems is known etc.). For this, early identification of the individual at risk and the development of effective treatment solutions, as well as having a follow-up of the patient is of utmost importance.The issue of post-TBI cognition is complex and multidimensional, having a substantial impact on the patient and their social circle (family, employers, healthcare providers,"}
+{"text": "International Journal of Molecular Sciences, entitled \u201cNon-Covalent Interactions in Coordination and Organometallic Chemistry\u201d, is to cover the most recent progress in the rapidly growing field of non-covalent interactions in coordination and organometallic chemistry. Both experimental and theoretical studies, fundamental and applied research and any types of manuscripts are welcome for consideration.Non-covalent interactions are one of the key topics in coordination and organometallic chemistry. Examples of such weak interactions are hydrogen, halogen, and chalcogen bonds, stacking interactions, metallophilic contacts, etc. Non-covalent interactions play an important role in materials science, catalysis, and medicinal chemistry. The aim of this Special Issue of  Non-covalent interactions are one of the key topics in coordination and organometallic chemistry. Examples of such weak interactions are hydrogen, halogen, and chalcogen bonds, stacking interactions, metallophilic contacts, etc. Non-covalent interactions control the structure of solids , as well as the properties of supramolecular systems in liquid and gas phases, in addition, the elementary stages of chemical reactions are due to such weak inter- and intramolecular contacts. In the context of bio(organic/inorganic)chemistry, non-covalent interactions are necessary for the formation and folding of the three-dimensional structure of proteins and nucleic acids as well as their metal complexes and ligand-protein binding. These inter- and intramolecular interactions have a significant effect on the properties of polymers, gels and membranes, on the dissolving abilities of liquids and their boiling points. Non-covalent interactions play an important role in materials science, catalysis, and medicinal chemistry. Information about inter- and intramolecular interactions can be obtained experimentally, for example, based on X-ray diffraction analysis data, from phonon spectra and elastic characteristics of crystals, using thermogravimetric analysis and measurements of sublimation energies, from spectral characteristics . At the same time, these experimental methods provide only indirect information, largely mediated by the experimental conditions, and often do not allow one to establish the nature  and the energy of non-covalent interactions, what can be the goal and task for computer modeling and computational chemistry. In particular, the most promising theoretical methods in this context are the topological analysis of the electron density distribution within the formalism of Bader\u2019s theory (QTAIM) using additional auxiliary methods: visualization of van der Waals potential, Interaction Region Indicator (IRI) analysis, Independent Gradient Model (IGM) analysis, Density Overlap Regions Indicator (DORI) analysis, localized orbital locator (LOL) analysis, electron localization function (ELF) analysis, reduced density gradient (RDG) analysis, etc.); visualization and mapping of non-covalent interactions  analysis) and the study of the degree of influence of crystal packing on the structure of isolated molecular associates stabilized by non-covalent contacts using Hirshfeld surface analysis; analysis of orbitals and charges, in particular, within the formalism of Weinhold\u2019s theory (NBO); study of energy and charge decomposition within the formalism of EDA and CDA theories, respectively. Thus, the most adequate, comprehensive, and promising approach to the study of non-covalent interactions in chemical compounds and their supramolecular associates seems to be a combination of experimental observations and computer simulation results using the latest advances in quantum and computational chemistry. Finally, processing of large amounts of data , machine learning and artificial intelligence  is very promising goal for data scientists.International Journal of Molecular Sciences, entitled \u201cNon-Covalent Interactions in Coordination and Organometallic Chemistry\u201d, is to cover the most recent progress in the rapidly growing field of non-covalent interactions in coordination and organometallic chemistry. Both experimental and theoretical studies, fundamental and applied research and any types of manuscripts are welcome for consideration.The aim of this Special Issue of -experimental studies of non-covalent interactions;-theoretical modeling of supramolecular systems;-1D, 2D, 3D coordination polymers;-weak contacts in bio(organic/inorganic)chemistry;-non-covalent interactions in material science;-application of machine learning and artificial intelligence in studies of non-covalent interactions.This Special Issue will address the following topics:We welcome researchers to contribute their works to our Special Issue. We hope that the materials of this Special Issue will prove valuable and useful to a wide range of readers and researchers and will serve as a starting point for new fruitful work in the field of non-covalent interactions in coordination and organometallic chemistry. All types of manuscripts  are welcome for consideration."}
+{"text": "The study reviewed the progress and outcomes of rolling out IDSR in South Sudan.this descriptive cross-sectional study used epidemiological data for 2019, 2020, and other program data to assess indicators for the five surveillance components including surveillance priorities, core and support functions, and surveillance system structure and quality.South Sudan expanded the priority disease scope from 26 to 59 to align with national and regional epidemiological trends and the International Health Regulations (IHR) 2005. Completing the countrywide rollout of electronic Early Warning Alert and Response (EWARS) reporting has improved both the timeliness and completeness of weekly reporting to 78% and 90%, respectively, by week 39 of 2020 in comparison to a baseline of 54% on both timeliness and completeness of reporting in 2019. The National Public Health Laboratory confirmatory testing capacities have been expanded to include cholera, measles, HIV, tuberculosis (TB), influenza, Ebola, yellow fever, and Severe Acute Respiratory Syndrome 2 (SARS-COV-2). Rapid response teams have been established to respond to epidemics and pandemics.since 2006, South Sudan has registered progress towards using indicator and event-based surveillance and continues to strengthen IHR (2005) capacities. Following the adoption of third edition IDSR guidelines, the current emphasis entails maintaining earlier gains and strengthening community and event-based surveillance, formalizing cross-sectoral one-health engagement, optimal EWARS and District Health Information Systems (DHIS2) use, and strengthening cross-border surveillance. It is also critical that optimal government, and donors\u2019 resources are dedicated to supporting health system strengthening and disease surveillance. Public health security is essential to minimizing the impact of acute public health events and is critical for countries\u2019 social and economic stability and transformation . Health Numerous years of civil strife in South Sudan and inadequate public health and healthcare investments have contributed to the increased risk of outbreaks and insufficient capacities to detect and respond to public health threats. Within this context, in 1998, South Sudan experienced a relapsing fever outbreak that is estimated to have resulted in more than 400,000 cases, including 2,000 deaths CFR 5 0.5%) [ 0.5% [5]Since the adoption of IDSR by the WHO Africa (WHO-AFRO) Region in 1998, the strategy has been implemented successfully in stable countries. The strategy has been used to improve capacities to respond to cholera, meningitis, Ebola Virus Disease (EVD) and other outbreaks or public health events. In this present paper, we share the experiences and impact of using IDSR to strengthen national surveillance and response systems in a country experiencing a protracted grade 3 humanitarian crisis that has persisted since 2014 with a scale that warrants major support from WHO and other United Nations Agencies . These eAnnex 1). The surveillance system components assessed include the availability of a list of priority diseases, conditions, and events for surveillance; the structure of the surveillance system; the core and support functions; and the quality of the surveillance system (Annex 1) [Annex 1) [This was an observational, descriptive cross-sectional study that used the quantitative program and aggregate epidemiological data for all the epidemiological weeks in 2019 and 2020 to document the progress of implementing IDSR and building national surveillance and response capacities in South Sudan. Additionally, other IDSR program data from 2006, were compared with program benchmarks to document the implementation progress. The study used Ministry of Health (MoH) IDSR and Early Warning Alert and Response Network (EWARN) data collected routinely at the health facility, county, and state levels or from periodic program monitoring reports during the study period. Program reports, including monitoring, training, support supervision, and periodic assessment reports, were reviewed to obtain the information on the program performance indicators (Annex 1) . We idenAnnex 1) . We usedThe periodic indicator measures were compared to the program targets during the study period to document quantitative and qualitative changes that demonstrate program performance concerning set indicator-specific targets. Quantitative changes in program performance indicators entailed absolute measurements, proportions, or rates. These descriptive analyses were undertaken in Microsoft Excel. We used aggregate data from routine Ministry of Health epidemiological bulletins and program reports with no personal identifiers, and therefore, an ethical review was not warranted for this present study.Ethics approval and consent to participate: administrative clearance for publication of this paper was provided by the Ministry of Health of South Sudan and WHO (WHO e-Pub no: ePub-IP-00331294-EC).We present the performance on indicators aligned to the five surveillance system components starting with the surveillance priorities, then the core and support functions, and surveillance system structure and quality.Surveillance priorities: South Sudan adopted the IDSR strategy in 2006, but systematic implementation aimed at establishing national surveillance structures aligned to the strategy started in 2009. These initiatives were further buttressed when South Sudan became a WHO Member State on 27 September 2012 and after the country committed to the IHR (2005) on April 16, 2013.Objectives for disease surveillance: the national surveillance goals are aligned to the IHR (2005) and the IDSR strategy for the African region 2020-2030. Thus, the South Sudan Ministry of Health adapted the third edition IDSR guidelines and training materials during a 5-day WHO-facilitated workshop from October 21, 2019. The Government eventually adopted these guidelines on November 13, 2019 thus paving the way for their dissemination and use by counties, health facilities and communities. Based on these guidelines, the main objective of the national surveillance system is to improve the country\u00b4s capacities to detect, report, confirm, and effectively respond to priority diseases, conditions, and events. The updated guidelines are explicit on one-health surveillance for zoonotic diseases, the use of eHealth to enhance surveillance, cross-border surveillance strengthening, and surveillance in humanitarian contexts.Prioritization of diseases for surveillance: as part of the revised 2019 national IDSR guidelines, the priority list was updated from the 26 diseases, conditions, and events prioritized in the 2012 guidelines to 59 diseases, conditions, and 19 events for indicator and event based surveillance (Annex 2 and Annex 3). The broad categories include diseases, conditions, or epidemic-prone events, diseases targeted for eradication or elimination; other major diseases of public health importance; and diseases or events of international concern (Annex 2 and Annex 3). The top cause of morbidity in South Sudan in 2019 was malaria that accounted for 75.9% of outpatient consultations and hence is top on the priority list  and the National Health Sector Development Plan (2017-2022) to facilitate the implementation of IDSR in South Sudan. However, the public health bill and the animal health bill have not been enacted as Acts of Parliament as of writing this report.Legislation to facilitate outbreaks and emergency response: the overall mandate for regulation and provision of healthcare and health emergency response is constitutionally vested in the national and state governments. Consequently, the Minister of Health has sanctioned the formation of national and state-level outbreak task force committees to control outbreaks of cholera, measles, hepatitis E, and other public health events in recent years. In the same way, presidential orders were issued to establish the National COVID-19 task force to provide the overall policy, strategic, and oversight guidance and coordination of the national COVID-19 response.Designation of National International Health Regulations Focal Point: in line with the IHR (2005) requirement, the office of the Director General International Health and Coordination in the National Ministry of Health is the designated IHR (2005) National Focal Point (NFP) for coordinating IHR (2005) core functions implementation in collaboration with other sectoral focal points.Functioning International Health Regulations communication facilities: while the National IHR Focal Point has been designated, staffing and communication logistics remain inadequate for the office to meet functional and communication objectives. Official communication email and telephone facilities have not been designated for efficient communication with the other sectors and the WHO IHR focal point.International notification of outbreaks to World Health Organization: in compliance with the IHR (2005), an outbreak of yellow fever in Sakure, Nzara County and measles outbreaks in 20 counties were notified to WHO as potential Public Health Emergencies of International Concern (PHEIC) in 2019.National Integrated Disease Surveillance and Response and Early Warning Alert and Response Network Coordination: the Emergency Preparedness and Response (EP&R) department under the Directorate of Preventive Health Services in the national MoH is the designated IDSR coordination unit at the national level. It is supported by state-level surveillance focal points in the respective state MoH  and the health promotion department. The committee also provides strategic and operational guidance on strengthening IDSR core and support functions at all levels. The EP&R committee convenes weekly to review and support preparedness for anticipated outbreaks and public health emergencies; coordinates initial investigations and responses to new and ongoing suspect or confirmed outbreaks and other public health emergencies. In 2019, there were 14 (27%) documented weekly EP&R meetings with minutes on the record.Evidence of sharing resources: to optimize IDSR functional capacities at all levels, integrated use of resources occurs through detection and reporting of acute flaccid paralysis (AFP), Guinea worm, other vaccine-preventable diseases (VPDs) to the respective vertical programs for case-based investigations. The integrated use of IDSR rapid response teams (RRTs) and surveillance focal points to investigate and respond to AFP, Guinea worm disease (GWD), and other VPDs. The use of IDSR/EWARS reporting resources to support reporting needs under the DHIS2 has also been initiated. Further, influenza sentinel surveillance resources under IDSR have been used to support Ebola virus disease, yellow fever, and COVID-19 investigations and laboratory testing.Intersectoral collaboration, networking, and partnership: effective control of outbreaks like cholera, Rift Valley Fever, Ebola virus disease, and COVID-19 requires the competencies of a designated intersectoral committee for systematic risk assessment, contingency planning, and effective response. However, South Sudan lacks a formalized multisectoral platform to take on this role. Moreover, recent intersectoral engagements are timebound and restricted to the active phase of outbreaks and emergencies. During the cholera outbreaks of 2014-2017, the Ministry of health and partners worked alongside the Ministry of water and irrigation and Juba City Council to implement water quality surveillance and improve access to safe water sources. In the same way, the Ministry of Livestock and Fisheries (MLF) has worked with the Ministry of Health and partners under the task force constituted to respond to the Rift Valley Fever (RVF) outbreak of 2017.Existence of functional laboratory networks: South Sudan has one National Public Health Laboratory (NPHL) that was founded in 1974 but was not inaugurated until 2014 and has capacities to test for cholera, measles, human immunodeficiency virus (HIV), tuberculosis (TB), influenza, Ebola, Marburg, yellow fever, severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), and routine water quality testing . The committee members share disease surveillance information regularly, and a social media platform was created to complement the other official communication channels. The tripartite cross-border surveillance committee meets annually and has conducted one joint cross-border outbreak response simulation exercise on the Ebola virus in 2019. The committee has also conducted two cross-border outbreak investigations on Rift Valley Fever and yellow fever in 2019 and 2020, respectively. The later investigation resulted in the confirmation of a yellow fever outbreak in Kajo-keji county in March 2020. Synchronized yellow fever vaccination campaigns were implemented on either side of the international border by October 2020. Alongside Uganda, the Democratic Republic of Congo (DRC), and Uganda, South Sudan has participated in the Goma cross-border surveillance initiative. The initiative strengthened cross-border surveillance to mitigate the risk of cross-border spread during the 2018/ 2019 Ebola virus disease (EVD) outbreak in North Kivu and Ituri, DRC. South Sudan is also participating in intercountry meetings to strengthen regional health security. In May 2019, WHO-AFRO convened an intercountry meeting in Kigali, Rwanda, to strengthen regional health security for operational readiness and surveillance in response to the EVD outbreak in DRC. The meeting involved the four high-risk countries  bordering DR Congo.Case detection and registration: South Sudan is implementing both indicator and event-based surveillance to detect and register new cases of priority diseases or other public health events. As part of strengthening indicator-based surveillance, case definition charts and booklets have been printed and disseminated for use at health facilities. In 2019, 3,540 case definition booklets and charts were printed and distributed to the 1,260 functional health facilities. This number of case definition job-aids translates into at least three case definition job-aids distributed per functional health facility. As part of community-based surveillance, the Boma health workers (BHW) and community health workers (CHW) use simplified and translated community case definitions for case detection and registration at the community level. These simplified community case definitions are included in the case definition booklets. Indicator-based surveillance is complemented by event-based surveillance, which entails informal alerts of potentially serious public health events from the community, health facility, county, state, or national level. The log of rumors and suspect outbreaks is used for recording new alerts or suspected outbreaks. In 2019, at least one log of rumors and suspect outbreaks was distributed per functional health facility. A national toll-free center hotline exists in the call center and is used to report community alerts. Additionally, the electronic Early Warning Alert and Response (EWARS) reporting platform includes an event based platform that facilitates alert recording, verification, and risk assessment by health facility, county, and state surveillance officers and watch officers in the Public Health Emergency Operations Center (PHEOC).In 2019, 3,184 alerts were detected and reported through the national event-based disease surveillance system using EWARS. The alerts reported in 2019 are four times higher when compared to the alerts (771) reported in 2018 . The sigCase confirmation and response to outbreaks and other public health emergencies: during 2019, at least 104 suspect outbreaks were reported and investigated, with 35 (33.65%) confirmed. Of the 35 confirmed outbreaks; 4 (11.4%) were due to Hepatitis E virus; 20 (57.1%) were due to measles; 9 (25.7%) were due to rubella;1 (2.9%) due to yellow fever; and 1 (2.9%) due to mass casualty (burns) ( (burns) . Since tReporting, data analysis and feedback: all priority diseases and events should be reported to the next high level either immediately, weekly, or monthly to facilitate appropriate public health action. Since the adoption of IDSR in South Sudan in 2006, routine IDSR reporting relied on a combination of paper-based, Microsoft Excel or Access datasets transmitted by email or radio calls to the next level. These approaches were fragmented, incomplete, and were associated with reporting errors and delays. Hence, in 2017, WHO, through the Global EWARS project, initiated support to the Ministry of Health and partners to streamline reporting. The support entailed modular training and technical support to facilitate the Early Warning Alert and Response System (EWARS) deployment. The EWARS is a web-based desktop and mobile application that can be rapidly configured and deployed to support early warning, alert management, and outbreak response. The EWARS mobile reporting has been deployed to support reporting in at least 1,260 functional health facilities in 10 States and three administrative areas. As part of the EWARS rollout from January 2019 to March 2020, WHO, in collaboration with the local governments and partners, has trained over 1,500 frontline health workers and distributed 21 \u201cEWARS in a box\u201d kits to facilitate real-time submission routine IDSR and disease outbreak reports. Each EWARS in a box kit contains 60 mobile phones with SIM cards, 25 solar power banks, and 60 EWARS quick start guides.The completion of electronic EWARS reporting rollout has positively impacted the timeliness and completeness of weekly IDSR reporting from the health facilities. The average timeliness for submitting weekly IDSR reports from the health facilities by the end of week 39, 2020 was 78%  compared to 54%  by week 39, 2019, representing an increase of 24%. In the same way, the average completeness rate of reporting from the functioning health facilities across the country by week 39, 2020 was 90%  as compared to 54%  in week 39, 2019 representing an increase of 36%. Overall, the completeness of weekly reporting from the health facilities by county improved in 2020 when compared to 2019 and 2020 . Early wEpidemic preparedness: epidemic preparedness and contingency plans are developed and updated within national and state-level efforts to improve public health security. The updated preparedness and contingency plans include cholera, epidemic meningitis, yellow fever, Rift Valley Fever, and floods. Emergency funds are incorporated into the overall MoH budget to facilitate the implementation of the plans for providing primary health care as defined in the basic package for nutrition and health (BPNH). Epidemic preparedness and response is also incorporated into humanitarian response in prioritized populations and supported using the Country-Based Pooled Funds (CBPF) and through the ongoing support to IDSR implementation by ECHO and USAID.Response and control: with support from the WHO, the MoH has established a national multi-hazards rapid response team and state rapid response teams in each of the 10 states with regular multi-hazard training and simulation exercises. The operations of the rapid response teams are guided by standard operating procedures that define the team composition, roles of each team member, and the procedure for activation, mobilization, and deployment in response to suspect and confirmed outbreaks. Once an outbreak is confirmed, the Minister of Health designates a task force committee to coordinate the overall response in liaison with other sectors and stakeholders.Performance on support functions: in November 2019, the South Sudan MoH adapted and adopted the third edition of IDSR technical guidelines. The guidelines are expanded to include guidance on event-based surveillance, cross-border surveillance, the use of information technology to enhance surveillance functions, guidance on surveillance in the humanitarian context, and the one-health approach. The initial training of trainers on the third edition IDSR technical guidelines have been completed. The cascade county county-level training plan has been finalized though the implementation was delayed and modified in the context of COVID-19. A dedicated national IDSR plan of action is updated annually and incorporates all the activities required to implement the support functions and strengthen the core functions at all levels. However, the plan of action is primarily donor-supported, thus raising sustainability issues in the medium to long term.The present study assessed performance for five core surveillance components to document the impact and experiences of deploying IDSR in a humanitarian context. Through the implementation of the IDSR strategy, South Sudan has registered significant progress towards strengthening the national disease surveillance system as demonstrated from the performance on key surveillance indicators for each of the surveillance components assessed in the present study.Objectives of disease surveillance: in line with the IHR (2005) and the regional strategy for IDSR 2020-2030, the South Sudan Government adopted the IDSR to expand and strengthen the national surveillance and response system. Over the years, the Government adapted the requisite guidelines, expanded the priority disease list, and provided technical oversight to establish surveillance focal points, train and equip them, and monitor the implementation of IDSR functions at all levels [l levels . Howeverl levels . Achievil levels ,11. SincIDSR structure: the South Sudan Ministry of Health has established coordination structures and technical focal points to optimize IDSR functions at the community, health facility, county, state, and national level. The cross-sectoral engagement has been exploited in response to recent cholera outbreaks (2014-2017), Rift Valley Fever (2017), and COVID-19. However, these efforts are timebound and confined to the active outbreak phase. Furthermore, these efforts need to be formalized and should be extended to span the entire epidemic and emergency management cycle. Hence, as part of the NAPHS, there are plans to formalize cross-sectoral linkages with relevant line Ministries [nistries . Furthernistries .Existence of laboratory networks: laboratory capacities are critical to the IDSR function of detecting and confirming public health hazards [ hazards . South S hazards . Over th hazards . This wiCross border collaboration: the regional outbreaks of EVD in West Africa in 2014 spread to at least five countries in West Africa. Moreover, exported cases were reported in Europe and the United States in 2014 and 2015. Cross border EVD spread was again reported during the 2018 DRC Ebola outbreak in Ituri and North Kivu that spread to Uganda. These incidents highlight the need to enhance cross-border surveillance and response [Performance on core and support functions: in line with the third edition IDSR technical guidance, South Sudan is expanding community and health facility-based surveillance using the indicator and event-based surveillance [eillance ,9. Boma eillance . Gaps ineillance . Reportieillance -19. A noeillance ,20.The limitations of this study entail incomplete program and epidemiological data and the cross-sectional nature of the study that is not ideal for demonstrating the program\u2019s impact. Therefore, we used multiple sources of data to triangulate information and reduce data gaps. Also, we used standardized program performance indicators to document progress on core and support IDSR functions.Since the adoption of IDSR in 2006, South Sudan has registered progress towards strengthening the national disease surveillance system. In compliance with the IHR (2005) and IDSR, the priority disease scope has been expanded, with indicator and event-based surveillance used to detect and report alerts and suspect cases. In addition, the countrywide rollout of electronic EWARS reporting has improved the reporting performance. Further, laboratory capacities continue to be strengthened following the inauguration of the National Public Health Laboratory, which now possesses capabilities for confirming priority bacterial and viral pathogens supported by a countrywide network for specimen referral. To facilitate investigation and response to suspect and confirmed outbreaks, national and state rapid response teams have over the years been trained, drilled, and deployed to support investigation and response to outbreaks of cholera, Rift Valley Fever, yellow fever, viral hemorrhagic fevers, and COVID-19. Epidemic preparedness is effectively supported through the national EP&R team. In contrast, the response to confirmed outbreaks is supported by task force committees of experts from varied disciplines and sectors using the incident management system (IMS) principles. The rollout of the third edition IDSR guidelines will further bolster this progress. The rollout will facilitate formal cross-sectoral one-health engagement, enable optimal use of EWARS and DHIS2, and allow effective cross border engagement. In collaboration with the health cluster partners, the MoH will continue using the IDSR to address fragile, vulnerable, and conflict-affected populations\u2019 surveillance and response needs. To ensure that these investments in IDSR are optimized and sustained, budget support towards strengthening the health system and surveillance system must be optimized. To address the challenge of high healthcare workers turnover, the working conditions of health workers in public health facilities must be enhanced. The NAPHS, which embodies IHR (2005) and IDSR priorities, should be implemented to enhance national and international health security. Finally, as the country works towards emerging from decades of conflict and economic downturn, donor support to the IDSR program must be sustained to reduce morbidity and mortality from priority health diseases, conditions, or events and enhance national and international health public health security.The integrated disease surveillance and response (IDSR) strategy provides a framework that countries in the WHO African region are using to attain core capacity requirements for the international health regulations (IHR (2005)). The member states in the African region have demonstrated that IDSR is a cost-effective strategy for effective preparedness, detection, investigation, response and control of epidemics and pandemics in the African region.Whereas the IDSR strategy has largely been used in stable settings, in this paper, we have demonstrated how the IDSR functions can be used to support Early Warning Alert and Response (EWARN) in humanitarian settings where the performance of surveillance systems is sub optimal. The sustained investment of resources towards IDSR implementation has improved the program reporting performance, thus allowing detection of major outbreaks, and averting morbidity and mortality;Program funding from domestic resources is critical for sustainability in the long-term."}
+{"text": "Patients with lepromatous or borderline leprosy may present two types of vasculonecrotic reactions: Lucio\u2019s phenomenon (LP) and necrotic erythema nodosum leprosum (nENL). These are serious conditions, which mostly lead to life-threatening infectious and thrombotic complications. The authors report the case of a patient with leprosy recurrence associated with an atypical type II reaction with LP characteristics on histopathology. M. leprae to dapsone, rifampicin and ofloxacin. The patient was submitted to a new regimen of multibacillary multidrug treatment (MB-MDT), prednisone 80\u202fmg/day and systemic antibiotic therapy, with significant clinical improvement after three weeks.A 32-year-old man with a history of multibacillary leprosy under treatment for ten years with negative bacilloscopy at discharge reported the appearance of erythematous papules on the upper limbs. He used prednisone 40\u202fmg/day on his own for five months and, when it was discontinued, pustules, vesicles, painful crusts and bullae with purulent content appeared on the plantar region , togetheMycobacterium leprae.Leprosy is a chronic granulomatous infectious disease with polymorphic manifestations caused by None declared.Larissa Daniele Machado G\u00f3es: Approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.Patr\u00edcia Motta de Morais: Approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.Paula Frassinetti Bessa Rebello: Approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.Ant\u00f4nio Pedro Mendes Schettini: Approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.None declared."}
+{"text": "Constipation is a common disorder of gastrointestinal motility, which usually causes infrequent stools, and difficulty in the passage of stools. Many aspects, including genetic predisposition, daily diet and behavior, socioeconomic status, and other biological and clinical factors are considered to be associated with the pathogenesis of constipation . ConstipBacillus coagulans BC01, Bifidobacterium lactis TY-S01, and Lactobacillus plantarum KFY02 increased the fecal moisture and gastrointestinal transit rate in mice . Furthermore, the authors found that these strains can promote the homeostasis of gut microbiota in the constipated mice . Bifidobacterium lactis TY-S01 and Lactobacillus plantarum KFY02 increase the community richness and bacterial diversity. More importantly, the structure and composition of intestinal flora in the constipated mice are markedly changed by these three strains, and the change in the abundance of special species depends on the strain specificity of probiotics. The mechanisms underlying these effects on constipation are summarized as follows.This Research Topic mainly focuses on the attenuation effect and potential mechanism of new probiotics on constipation. To date, five papers, including four research articles and one review article have been collected in this Research Topic. Bifidobacterium lactis TY-S01 increases the content of SCFAs, such as isobutyrate acid, butyrate acid, acetic acid, valeric acid, and propionic acid, in the feces of the constipated mice . These SCFAs may inhibit the growth of pathogenic bacteria by reducing the pH in the small intestine, and improve gut motility by increasing colonic smooth muscle contraction, therefore contributing to the amelioration of constipation symptoms (Ara\u00fajo and Botelho).Yi et al.). The destruction of gut barrier may result in the further invasion of pathogenic bacteria and their toxins, which aggravates intestinal inflammation. The maintenance of gut barrier integrity can inhibit the adherence of pathogens bacteria and their metabolites and facilitate stool passage (Ara\u00fajo and Botelho). Zhou et al. reported that the nuclear factor (NF)-\u03baB signaling-mediated inflammation in the small intestine of mice with constipation is inhibited by Bacillus coagulans BC01. Bifidobacterium lactis TY-S01 decreases the mRNA expression of colonic inflammatory cytokines in the constipated mice . Furthermore, the expression levels of gut barrier-associated key genes, including transient receptor potential vanilloid-1, mucin 2, stem cell factor, claudin-1, occludin c-kit, and glial cell line-derived neurotrophic factor are significantly regulated by Bifidobacterium lactis TY-S01 and Lactobacillus plantarum KFY02 , indicating that these probiotics have the potential ability to restore the gut barrier.The imbalance of intestinal bacteria can cause the release of inflammatory cytokines, thereby damaging the integrity of gut barrier . These intestinal hormones can regulate intestinal peristalsis and improve constipation symptoms . Besides, Zhou et al. reported that Bacillus coagulans BC01 reduce the production of vasoactive intestinal peptide and somatostatin in the constipated mice, contributing to the slowing down of intestinal transit time and the relief of constipation.The content of motilin, 5-hydroxytryptamine, and substance P in the constipated mice is increased by Zhang et al. examined the regulatory effect of synbiotic consisting of Bifidobacterium lactis BL-99 and fructooligosaccharide (FOS) on the intestinal flora from constipated individuals in vitro. They found that this synbiotic enhances the level of acetic acid, but also changes the structure of intestinal flora, and increases the abundance of beneficial bacteria. However, human and animal studies evaluating the improved effect of synbiotics on constipation are scarce (Ara\u00fajo and Botelho).Apart from the regulation of gut microbiota in the constipated mice by probiotics, in vivo studies and mechanism of synbiotics on constipation.In summary, although the above-mentioned probiotics show a good efficiency in improving the constipation of mice, randomized clinical trials are needed to further confirm their anti-constipation effect. The molecular mechanisms underlying probiotics effect on constipation, including the identification of key metabolites and their mode of action need to be further investigated. In addition, it is necessary to further strengthen the JS wrote the whole manuscript. XZ, K-yP, and HS provided some valuable comments. All authors contributed to the article and approved the submitted version."}
+{"text": "Psychological health problems, especially emotional disorders, have become an important topic of considerations for many scientists, because the epidemiology of these disorders is strongly influenced by stressful events, such as the SARS-CoV-2 coronavirus pandemic.The aim of this study was to evaluate selected parameters of psychosocial functioning as well as socio-demographic correlates of depression, anxiety, sleep disorders and perceived stress among the residents of the West Pomeranian Voivodeship.An online questionnaire was completed by 323 participants, in whom the parameters of psychosocial functioning were assessed: symptoms of depression (PHQ-9), anxiety (GAD-7), severity of sleep disorders (AIS) and perceived stress .The majority of the respondents (75.2%) scored high on the Perceived Stress Scale, almost half of the respondents (47.1%) had sleep disorders and 26% of the participants had no depressive symptoms. Age statistically significantly correlated with the severity of depressive symptoms and sleep disorders. Parental status statistically significantly correlated with the severity of depressive symptoms. There was a strong correlation between the severity of depression and anxiety and a strong correlation between depression and sleep disorders.Age and parental status contributed to the severity of depressive symptoms and the occurrence of sleep disorders among the residents of the West Pomeranian Voivodeship during the SARS-CoV-2 pandemic. Some of the residents of the West Pomeranian Voivodeship showed high levels of stress or insomnia. The severity of depressive symptoms significantly influenced the levels of anxiety and perceived stress, as well as the occurrence of sleep disorders.No significant relationships."}
+{"text": "The challenges of supporting the health and social needs of older adults and caregivers in rural and frontier areas are well-documented. It is common for rural older adults to experience barriers in accessing geriatric specialists, care coordination services, and caregiver support and education programs. The Wyoming Geriatric Workforce Enhancement Program (WyGWEP) is an innovative partnership comprising an academic geriatrics program, primary care delivery sites, single-unit on aging representing community-based organizations, and a tribal health program. This partnership, funded by the Health Resources and Services Administration, provides the infrastructure to assess needs, provide education and training, create programs to address gaps in care, implement practice innovation, and advocate for needs of rural older adults. This symposium includes five presentations detailing the unique projects of the WyGWEP partnership and the impact of this collaborative work on a variety of stakeholders. The results of a mixed-methods evaluation of the WyGWEP partnership will describe the benefits to the partners and areas for growth. A collaborative effort to assess the needs of older adults informs recommendations to support rural aging in place. Schenck et al. will describe the adaptation of the widespread ECHO model for use with dementia caregivers in rural and remote locations. Representatives from Wyoming\u2019s only Program for All-Inclusive Care of the Elderly (PACE) will explain the cost of a recent decision to de-fund and close this important program. Finally, the impact of a novel Chronic Care Management implementation program will be discussed, including sustainable billing revenue produced by rural primary care clinics."}
+{"text": "The number of patients with ocular disorders has increased due to contributing factors such as aging populations, environmental changes, smoking, genetic abnormalities, etc. Age-related macular degeneration (AMD) is one of the common ocular disorders which may advance to loss of vision in severe cases. The advanced form of AMD is classified into two types, dry (non-exudative) and wet (exudative) AMD. Although several therapeutic approaches are explored for the management of AMD, no approved therapy can substantially slow down the progression of dry AMD into the later stages. The focus of researchers in recent times has been engaged in developing targeted therapeutic products to halt the progression and maintain or improve vision in individuals diagnosed with AMD. The delivery of anti-VEGF agents using intravitreal therapy has found some success in managing AMD, and novel formulation approaches have been introduced in various studies to potentiate the efficacy. Some of the novel approaches, such as hydrogel, microspheres, polymeric nanoparticles, liposomes, implants, etc. have been discussed. Apart from this, subretinal, suprachoroidal, and port delivery systems have also been investigated for biologics and gene therapies. The unmet potential of approved therapeutic products has contributed to several patent applications in recent years. This review outlines the current treatment options, outcomes of recent research studies, and patent details around the novel drug delivery approach for the treatment of AMD. Age-related macular degeneration (AMD) is one of the common causes of irreversible loss of vision in individuals above 65 years ,2. AccorBased on pathophysiologic features, AMD is majorly classified into dry and wet-type. The initial presentation of the disease is the dry or non-exudative type, which may further advance in the later stage into wet or neovascular AMD ,15. AlthThe pathologic mechanisms involved in the development and progression of AMD are mainly related to the impairment and degeneration of RPE . The risApart from the difficulty in developing novel therapeutic agents due to the complicated pathophysiologic processes involved in the disease progression, the currently available therapies are limited due to safety, efficacy, and delivery issues . AMD affSeveral attempts have been made to develop reliable therapeutic and diagnostic tools for the effective management of AMD. The investigated therapeutic approaches as depicted in The inhibition of the complement system is one of the approaches which involves the suppression of complement proteins to downregulate the complementary pathways and the formation of the membrane attack complex . The comIn AMD patients, the visual cycle involving enzymatic reactions in the RPE and photoreceptor cells of the retina along with phototransduction cascade events may produce significant inflammatory and metabolic waste. The progressive build-up of these wastes culminates in GA and retinal impairment . Visual The transplantation or implantation of the cell can be an alternative therapy in AMD. Although a substantial number of cells of RPE may be damaged in AMD patients, other cells such as photoreceptors, ganglion cells, bipolar cells, etc. may sustain efficient retinal connections . TherefoInflammation has been reported to play a major role in the progression and pathogenesis of AMD . TherefoNeuroprotection involves the use of therapeutic agents to enhance neuronal endurance by protecting the anatomical and physiological features of the neurons. The neuroprotective agents in AMD are very important along with other therapeutic strategies for slowing down the progression and preventing the loss of vision ,63. ElamThe pathogenesis of AMD involves complicated pathways pertaining to fluctuations in angiogenesis and pro-angiogenesis factors, such as; (i) VEGF overexpression, (ii) pigment epithelium-derived factor (PEDF) deficit, (iii) the reduced expression of the extracellular domain of VEGF receptor 1, and (iv) the inhibition of pro-angiogenic factors ,67. TreaDespite the high efficacy of intravitreal therapy, it is associated with the burdens of frequent injections, high treatment costs, and is associated with the risk of an increase in intraocular pressure . RGX-314The delivery devices of anti-VEGF based on the port delivery system allows for their sustained release into the eyes. Ranibizumab (anti-VEGF antibody fragment) has been formulated and encased in sustained-release devices. The devices were able to achieve similar treatment outcomes with a considerably reduced frequency of administration ,77.The delivery systems used for therapeutic agents against AMD primarily revolve around using either implantable devices or intravitreal injectable liquids. Recently, scientists have made considerable attempts at improving the potential of therapeutic agents used for AMD by designing novel carriers that can reduce invasiveness at a low cost ,79. DespIntravitreal space is the most employed route for the delivery of therapeutic agents for AMD. The main reason behind the popularity of this route is its high safety, minimum invasiveness, convenient application, and adequate efficacy . Table 1The mesoporous silica nanoparticles (MSNs) functionalized with 3-aminopropyltriethoxysilane (3-aminopropyl) triethoxysilane (APTES) and mPEG-succinimidyl carboxymethyl ester (mPEG-NHS) were also reported to show improvement in the anti-VEGF potential of bevacizumab. In vitro studies showed that MSNs were effective in inhibiting proliferation, migration, and tube formation of endothelial cells induced by VEGF. Furthermore, the MSNs exhibited in vivo inhibition of corneal and retinal neovascularization . BevacizVollrath et al. developed sustained-release solid lipid implants of ranibizumab using the twin-screw extrusion method. The implant could load a high amount of protein (3 mg/implant) with consistently sustained release profiles for 120 days. The implant showed a predominantly high release of the monomeric form >95%) of the ranibizumab initially, followed by the formation of the hydrophobic type upon the completion of 18 weeks. The stability of the ranibizumab in the implant was exceptional with no signs of aggregation or alterations in secondary structures . PLGA mi% of the The researchers used a similar delivery system for the encapsulation of aflibercept. The rate and extent of release of aflibercept was also in a controlled manner depending upon the concentration of the cross-linking agent and the loaded microspheres. The drug released from the microspheres showed no signs of cytotoxicity from its degraded byproducts, and bioactivity was maintained throughout the complete release period . The preThe region between the RPE layer and the photoreceptors is considered as a subretinal space which allows the direct delivery of drugs to the RPE and photoreceptor cells. The subretinal injections utilize trans-scleral and trans-corneal routes in animal studies for attaining the required desired concentration of a drug in subretinal space ,114. It \u00ae) based on an equine infection-causing anemia virus was developed for delivering two anti-angiogenic genes (endostatin and angiostatin) to the retina to suppress angiogenesis and enhance the vision of patients [\u00ae was studied for subretinal delivery for the management of wet-AMD. The amount of endostatin and angiostatin increased after subretinal administration in rabbit eyes throughout the study. Ocular inflammation was reduced with 1 month of continuous dosing, with no considerable changes in electroretinograms and intraocular pressure [Gene therapy is one of the effective approaches for dealing with AMD by incorporating healthy genes in the cells of patients to avoid or treat defective genetic pathways. The benefit of using gene therapy is that it provides long-lasting treatment and enables targeted ocular regions to generate their protective agents . Streptopatients . RetinoSpressure . The recpressure . A phasepressure . Lambertpressure .The novel drug delivery techniques have facilitated better access to the suprachoroidal space for the treatment of ocular diseases. The drugs administered through the suprachoroidal space allow the attainment of higher concentrations in the retinal region, thereby reducing the undesirable delivery to the anterior ocular areas . A novelThe suprachoroidal graft of autologous cells was also proposed as a treatment for dry AMD, owing to its impact on the enhancement of visual acuity and microperimetric responses. The technique involved the implantation of adipose stem cells in the suprachoroidal space to stimulate the secretion of growth factors. The outcome was a significant improvement in visual acuity after six months, along with the maintenance of growth factor secretion and choroidal flow . The resImplantation containing adipose tissue-derived mesenchymal stem cells was evaluated for its safety and efficiency in patients with dry AMD. There were no occurrences of systemic or ocular complications in any of the patients with improvement in the visual field, visual acuity, and mf-ERG recordings . Zhang eA port delivery system (PDS) encompasses a robust reservoir fabricated for the prolonged delivery of the drug into the vitreous cavity after being implanted. The ability of PDS to release the anti-VEGF medication for a longer duration helps in reducing the overdependency on intravitreal injections for the treatment of AMD. PDS is applied through the surgical insertion of the device into the scleral space through conjunctival peritomy. After implantation, the drug diffuses from the release control element in a sustained manner into the vitreous, which can be filled again once emptied . A phaseSeveral studies have explored the utilization of some of the less preferred routes of administration to combat the limitations associated with existing therapies. Some of the routes reported in recent times chosen for drug delivery for AMD are the subconjunctival, topical, oral, etc. The subconjunctival region is located under the conjunctival membrane covering the sclera. The subconjunctival space is mostly chosen for delivering drugs to anterior ocular regions . A depotNumerous efforts were also made to deliver drugs and biologicals through the topical route owing to convenient and non-invasive administration . A topicAlthough the oral delivery of drugs provides a means of convenient and non-invasive administration, it is rarely chosen for the treatment of AMD due to the presence of ocular barriers, preventing effective delivery to the posterior regions. The phase II trial of an oral tablet formulation (X-82) containing anti-VEGF/PDGF agents was conducted to examine the efficacy of wet AMD. Although the product showed comparable improvement in visual acuity at higher doses, the limitations in safety and tolerability of the formulation resulted from the halt in further development. A case-control study reported the correlation between the oral administration of metformin and a reduction in the chances of developing AMD. The assessments indicate that metformin may possess therapeutic potential for AMD. However, there is a need for a comprehensive clinical study to assert the benefits of oral metformin therapy in preventing AMD development . StewartAMD management involves continuous observation, regular follow-up, and documentation for timely recognition of visual function, or else the condition leads to mortality. Several studies reported on the management of AMD, as presented in the previous section, both with the safety and efficacy of formulations alone and in combination with treatments such as photodynamic therapy. Practical therapeutics strategies for a complex disease such as AMD require the combination of multiple factors, including diet, lifestyle, and improved pharmacological interventions, and the direct development of not only effective but also safe treatment strategies. The systemic quality, safety, and efficacy of many investigated products after successful clinical trials leads to the granting of such patents, indicating the extreme necessity of these products . BesidesThis section is included to provide an outline of the patents granted or applied in recent years related to the use of novel delivery approaches for the treatment of AMD. A recent US patent application of mesozeaxanthin for the management of macular diseases, specifically AMD, proposed that the supplementation of mesozeaxanthin (dosage 0.5 and 50 mg/day) either alone or in combination with other carotenoids and vitamins may increase macular pigments . AnotherExpert opinion on the patent registered by Borodic for the administration of botulinum-toxin as an extra ocular infusion avoiding the risk of direct intraocular injections and complications associated with the patent indicated that co-administration with proteins such as hemagglutinin and monoclonal antibody makes a novel system for the development of the combined approach in the management of AMD . MoreoveOcular barriers pose challenges in the treatment of AMD, leading to therapies with suboptimal efficacy. To overcome this, there is a requirement for the development of novel therapies and drug delivery strategies to fulfill the unmet need. This review was focused on discussing drug delivery in AMD concerning currently available therapeutic approaches, emerging therapies, and the situation of patents. The intravitreal space is the most targeted route for AMD treatment for the delivery of anti-VEGF agents such as bevacizumab, ranibizumab, aflibercept, etc. The studies have also reported the use of novel delivery systems such as polymeric nanoparticles, liposomes, implants, microspheres, etc., which could help in enhancing therapeutic efficiency. The efforts were mostly towards controlling/sustaining release, prolonging residence time, reducing the incidence of adverse events, improving stability, etc. Subretinal and suprachoroidal routes were also investigated for cell-based and gene therapies for dry and neovascular AMD. The PDS of Ranibizumab is another interesting prospect for sustained delivery of the therapeutic agents, allowing for the reduction in dosing frequency. Lastly, the current patent situation included in the review showed that the suppression of the VEGF system is the major target for the treatment of AMD."}
+{"text": "Domains of social privilege are predictive of a number of key aging outcomes, such as physical and cognitive functioning. However, less is known about the dynamic interplay of - related but distinct- domains of privilege and how they are associated with cognitive and physical functioning. In the following project, we aim to close this gap by examining the role of multidomain identity and social background factors for initial levels and subsequent changes in psychological, cognitive and physical functioning. Specifically, we identified predefined social privileges within the Berlin Aging Study II (BASE-II) sample  and related these categories, interactively, to markers of physical health (multimorbidity), perceptual speed (digit symbol), and psychosocial functioning (loneliness). Results highlight the dynamic interplay  of multidomain identity and social background factors with aging related outcomes across a number of key domains."}
+{"text": "RecentlKosten et al.). Huang et al. reviewed fMRI papers of small animals under the state of stimulation categorized into electrical, visual, olfactory, auditory and other ways, and analyzed the similarities and differences, advantages and disadvantages of the stimulation sites, electrodes, and stimulation methods. The study provided invaluable comparative information on brain fMRI of small animals combined with stimulation .It is difficult to expound brain function at cellular, systematic and functional levels. Multimodal neuroimaging approaches are able to combine techniques such as calcium imaging, optogenetics, electrophysiology, chemogenetics with functional magnetic resonance imaging (fMRI) and help scientists uncover the relationship between neuronal activity and vascular network dynamics, which would promote our knowledge of the brain from the level of single cells or circuits to the whole brain  implantable monopolar carbon electrodes were used to treat alcohol use disorder. This method of implantation generates smaller MRI artifact and serves clinical and basic research . In terms of data processing, Bao et al. constructed an automatic method for individual parcellation of rat brain MEMRI images, which further benefited case-control statistical analysis and improved the accuracy of ROI-based imaging analysis.Maharjan et al.). At the same time, resting state fMRI of AD mice after electroacupuncture(EA) at Baihui and Shenting indicated that the ReHo value of local neuronal integration in hippocampus, entorhinal cortex and other brain regions increased, as well as the number of functional connectivity and neural fiber connections between entorhinal cortex and hippocampus increased, suggesting that EA intervention may be an effective strategy to treat memory defects in AD recognition .Alzheimer's disease (AD) is the most common cause of dementia. Many clinical and basic studies have aimed at improving effective identification strategies for AD .Hippocampus is closely associated with cognition and emotion. Sepsis associated encephalopathy (SAE) has been identified as a common complication of sepsis. SAE-induced pathological changes in the hippocampus may lay the foundation for the development of cognitive dysfunction and affective disorders. Pan et al. used 18F-FDG PET/CT to identify the subregions of the posterior splenic cortex, the role of RSCDS and RSCGS in the coding process of rat contextual fear conditioning model, and the underlying brain network mechanism. The results showed that the role of rat RSCS in the formation of scene fear memory mainly depends on the RSCDS rather than the RSCGS.Chen et al.).In segmental sampling of rat's sciatic nerve imaging in DTI, RS-5 EPI sequence-derived FA and RD may be highly sensitive quantitative biomarkers for detecting histopathological changes of sciatic nerve in rats. These findings provide some reference value for the optimization of DTI sequence in the future peripheral nerve MRI research (We hope that the aforementioned studies which were included in this special topic can inspire new studies and novel future applications of small animal MRI in the fields of data acquisition, analysis methods, pre-clinical applications, biomarker detection and can contribute in more accurate prediction of disease progression and bring us a step close to clinical applications.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
+{"text": "The impact of COVID-19 on older adults goes beyond a higher risk for serious infection to long-term consequences such as decreased well-being and disability. In 2020, we formed an international and interdisciplinary research group and adopted a biopsychosocial model as a conceptual framework to guide our collaboration. Our ultimate goal is to mitigate the long-term health consequences of the pandemic and utilize affordable technology-based interventions to enhance the quality of life for older adults in Hong Kong, Singapore, Thailand, and the US. Five empirical studies will be presented with topics ranging from quality of life, fear of falling, attitudes toward technology, and the utilization of technology-based interventions. A path analysis from the first study indicated that physical frailty was the strongest direct power on quality of life followed by depressive symptoms, and life-space mobility. The second study found that fear of falling was predicted by falls risk, resistance, COVID fear, and health conditions. The third study revealed a strong connection between the COVID severity and positive attitudes toward technology, and social support facilitates the adoption of technology. The fourth study reported the benefits of using a technology-based body-mind intervention to alter a mismatch between fear of falling and actual fall risk and to increase the accessibility of the fall intervention. The final study indicated that utilizing an alternative online exercise program during the pandemic increased exercise regularity and enhanced motivation. Together, all five studies contribute to strategic implications on global mitigating long-term health consequences and essential issues for further research."}
+{"text": "COVID-19 has caused unprecedented disruptions to health, social and economic systems in countries worldwide including Ireland. Weaknesses in Public Health capacities have undermined health system resilience compounding the effects of the pandemic. The Essential Public Health Functions (EPHFs) provide a comprehensive, cost-effective approach to operationalising public health and a means to build health systems resilience. As Ireland looks to recovery, the Department of Health engaged the World Health Organization (WHO) to undertake a mapping of the current state of delivery of EPHFs to identify opportunities for improvement and support wider health system strengthening towards resilience.A strategic review of the delivery of EPHFs in Ireland was conducted with respect to policy, infrastructure, service provision and coordination and integration. Findings were reported in the context of international lessons identified through experience with COVID-19 and major health system challenges within the Irish context.There are significant capacities present within the Irish context to support the delivery of the EPHFs though they are limited in strategic cohesion, coordination and implementation. These include a high level of Public Health expertise, an agile and resourceful workforce, a strongly engaged community and significant evidence generation and synthesis capacities. Gaps recognised included ICT infrastructure and capacity, workforce resourcing and support, pandemic planning and public health governance, visibility, legislation, strategy and resourcing. COVID-19 has led to the development and strengthening of mechanisms to leverage a whole-of-government and -society approach to health that should be sustained to tackle ongoing and future stressors.The use of the EPHFs within the Irish setting provides a comprehensive approach to strengthening capacities for public health and enhanced population health and wellbeing."}
+{"text": "Mitochondria are organelles that serve as a central hub for physiological processes in eukaryotes, including production of ATP, regulation of calcium dependent signaling, generation of ROS, and regulation of apoptosis. Cancer cells undergo metabolic reprogramming in an effort to support their increasing requirements for cell survival, growth, and proliferation, and mitochondria have primary roles in these processes. Because of their central function in survival of cancer cells and drug resistance, mitochondria are an important target in cancer therapy and many drugs targeting mitochondria that target the TCA cycle, apoptosis, metabolic pathway, and generation of ROS have been developed. Continued use of mitochondrial-targeting drugs can lead to resistance due to development of new somatic mutations. Use of drugs is limited due to these mutations, which have been detected in mitochondrial proteins. In this review, we will focus on genetic mutations in mitochondrial target proteins and their function in induction of drug-resistance. Mitochondria consist of double membranes, the outer mitochondrial membrane (OMM) and the inner mitochondrial membrane (IMM), with intermembrane space in between. Invagination of IMM into the mitochondrial matrix results in formation of cristae, a structure that is essential for the function of mitochondria. Mitochondria serve as a central hub for physiological processes in eukaryotes, including production of adenosine triphosphate (ATP), regulation of calcium dependent signaling, generation of reactive oxygen species (ROS), and regulation of apoptosis  and defects of mitochondrial enzyme leading to tumorigenesis and tumor progression due to abnormalities of the metabolic pathway or resistance to apoptosis  domains, through control of mitochondrial outer membrane permeabilization (MOMP). Among the members of the BCL-2 family, anti-apoptotic proteins such as BCL-2, BCL-XL, and MCL-1 induce inhibition of apoptosis leading to tumor promotion  with G101V, F104C, F104L, and D103Y mutations in the MCL-1 with L267V mutation detected in myeloma patients, the mutation does not interfere with binding of MCL-1 inhibitors such as S63845 and AZD-5991 to MCL-1, rather it prevents displacement of pro-apoptotic proteins by the drug, resulting in disruption of the process of apoptosis  occurs upon induction of apoptosis, leading to an increase of MOMP, resulting in loss of membrane potential and release of cytochrome c  is the first step of glycolysis. ATP-dependent phosphorylation of glucose is catalyzed by HK for generation of glucose-6-phosphate (G6P) which is also utilized in OXPHOS and the pentose-phosphate pathway  most likely has an anti-apoptotic function. which might be responsible for its overexpression in most cancers. HK2 is bound to the outer membrane protein VDAC in mitochondria and probably gives HK2 an advantage regarding access to ATP generated during OXPHOS , a selective inhibitor of mIDH2, displays a potent inhibition of 2-HG production in the context of the ROS, a byproduct of normal metabolism of oxygen in cells, are highly reactive oxygen-containing molecules that react readily with other molecules in cells. Production of ROS occurs through recurring biochemical reactions during OXPHOS in the ETC with passage of electrons through a series of proteins in order to finally reach oxygen in mitochondria. Increased levels of ROS detected in cancer cells has long been regarded as tumorigenic through promotion of genomic instability. A moderately increased level of ROS in cancer cells can promote tumorigenesis and progression through activation of signaling pathways responsible for regulation of cellular proliferation, metabolic alterations, and angiogenesis as well as induction of DNA mutation  and induction of apoptosis by release of cytochrome c by BAX/BAK  harboring the T14634C mutation of ND6 that showed no change in expression of ND6  of complex II. Upon gaining electrons, ubiquinone is reduced to ubiquonol in order to supply electrons to complexes III and IV Cecchini . InteracMitochondrial dysfunction is a major cause of tumorigenesis and tumor progression in many cells. Many anticancer drugs that target dysfunctional mitochondrial metabolism and apoptosis pathways have been developed Fig. . HoweverPositive combination therapy can have a synergistic effect on efficacy (Duarte and Vale Therefore, selection of an optimal mitochondria-target in order to minimize drug toxicity, identification of patients who show resistance to the drug to be administered, and design of an alternative strategy for treatment in patients who show resistance are important. Combination drug therapy or another single drug capable of evading resistance might be an alternative strategy. Finally, as various anti-cancer drug therapies have been developed, cases of resistance to the drug have also been reported; thus, conduct of many clinical studies is still required in various cases in order to achieve a successful treatment outcome for cancer patients."}
+{"text": "Osteoporosis (OP) is a systemic bone disease characterized by the decreased bone mass and destruction of bone microstructure, which tends to result in the enhanced bone fragility and related fractures, as well as high disability rate and mortality. Exercise is one of the most common, reliable and cost-effective interventions for the prevention and treatment of OP currently, and numerous studies have revealed the close association between gut microbiota (GM) and bone metabolism recently. Moreover, exercise can alter the structure, composition and abundance of GM, and further influence the body health via GM and its metabolites, and the changes of GM also depend on the choice of exercise modes. Herein, combined with relevant studies and based on the inseparable relationship between exercise intervention-GM-OP, this review is aimed to discuss the moderating effects and potential mechanisms of exercise intervention on GM and bone metabolism, as well as the interaction between them.The online version contains supplementary material available at 10.1186/s12967-022-03700-4. Osteoporosis (OP) is a kind of systemic metabolic bone disease characterized by descending bone mass and destruction of bone microarchitecture, predisposing to the enhanced bone fragility and associated fractures, as well as the high disability rate and mortality \u20133. AccorCurrently, a variety of drugs with different mechanisms of action have been applied in preventing and treating OP. Nevertheless, in the process of integrated management of OP, the pivotal contribution of exercise intervention still cannot be ignored , 7. In tIn addition, as the largest and most complicated micro-ecosystem in human body, the gut microbiota (GM) and its metabolites play a critical role in the regulation of host metabolism, nutrition, immunity, and so on . MeanwhiImportantly, exercise is of great significance for the maintenance of whole-body health. On one hand, exercise can directly act on various tissues and organs of the body to regulate different functions. On the other hand, exercise could significantly alter the structure, composition and abundance of GM, and further affect the body health through GM and its metabolites . Meanwhi14 orders of magnitude bacteria are colonized in the intestine, and the number of genes in the genome of GM is about 150 times that of the total number of genes in human genome [As the largest micro-ecosystem in human body, more than 10n genome . The GM n genome . Currentn genome . Especian genome . MeanwhiFirmicutes and Bacteroidetes. Fuhrman et al. [Clostridium and Bacillus were positively related to urinary estrogen metabolites, and the diversity of GM also increased with the enhancement of proportion of hydroxylated estrogen metabolites in urine. Meanwhile, the use of probiotics and prebiotics could change the composition, structure and abundance of GM, indicating the benefits of probiotics and prebiotics for bone metabolism. Regarding this, a previous randomized controlled trial conducted by Nilsson et al. [10 CFU of Lactobacillus reuteri ATCCPTA 6475 had a significantly lower reduction in BMD than individuals in control group after 12 months of treatment. Lei et al. [Lactobacillus casei Shirota for a period of 6 months. Moreover, van den Heuvel et al. [Transgalactooligosaccharides was able to enhance the intestinal calcium absorption in postmenopausal women, thus enhancing the bone mass and preventing OP.Specifically, in terms of the clinical studies, Wang et al.  conducten et al.  examinedn et al.  suggestei et al.  observedl et al.  showed iAs for the animals\u2019 studies, by constructing the mice model of postmenopausal OP induced by ovariectomy (OVX), Tu et al.  revealedTaken together, there is a close link between GM and OP, and a healthy intestinal microenvironment state has a significant protective effect on the bone. Importantly, GM mainly affects the balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption, which plays a vital role in the regulation of bone metabolism and provides a novel target of intervention for the prevention and treatment of OP. Nevertheless, the relevant studies on the association between GM and OP are still in the initial stage, and more researches are needed to further clarify its deep-level mechanisms and explore more effective conditioning measures.As a kind of homeostatic stimulus, exercise intervention may diversify the GM and increase the number of beneficial microbial communities in gut. Exercise intervention contributes to enhancing the gastrointestinal peristalsis of body and promotes the timely excretion of feces, so as to reduce the contact time of intestinal mucosa with pathogens and harmful substances, further affect the characteristics of the intestinal contents and alter the composition of GM , 41. MeaThe dynamic balance between GM and host physiological function determines the possibility of host morbidity caused by GM imbalance. However, several previous studies have revealed that long-term chronic moderate-to-low intensity exercise has beneficial effects on body , 51. MorAkhmann mucophilus and Clostridium praevia, and these bacteria have been verified to be anti-inflammatory bacterial species [Verrucomicrobia, Verrucomicrobiaceae, Akkermansia and Dorea in the feces of the sedentary and overweight women increased after 6 weeks of moderate-to-low intensity power cycling training. Therein, Akkermansia and Dorea were verified to be able to ferment with dietary fiber as the substrate to generate the butyric acid. Besides, Hamasaki et al. [Enteric acidophilus, Bifidobacteria and Lactobacillus in their intestines increases, resulting in a decrease of the content of malondialdehyde and an increase of the activity of antioxidant enzyme, so as to improve a variety of metabolic processes in the body and then promote health [In addition, compared with the sedentary women, the premenopausal women who exercise continuously at the low intensity are equipped with the increased abundance of  species . Moreove species  also indi et al.  also coni et al. , 64. Fore health , 66. HenNevertheless, different from the moderate-to-low intensity exercise, in the case of acute/vigorous exercise, the ischemic effects of intestinal mucosa and the enhancement of intestinal permeability resulting in the intake of bacteria and toxins could induce the inflammatory response of body . Accordi2max might reduce the visceral blood flow by 60\u201370%, and when the blood flow was reduced by 50%, the exercise-induced ischemia may result in the increased intestinal permeability. On the basis of this, the blood flows from the gastrointestinal tract via surrounding organs may also result in the loosening of tight junction proteins (mainly expressed by zonula occludens-1 (ZO-1) and Occludin), so as to further damage the intestinal mucosal barrier [With regard to this, Zouhal et al.  suggeste barrier . Moreove barrier  observedFirmicutes and Bacteroidetes. Li et al. [Autonomous exercise is a significant part of the structure of exercise modes. With regard to this, Matsumoto et al.  first obi et al.  also sugAgrobacterium  reduced significantly in autonomous exercise group, suggesting that exercise intensity and exercise amount might be the variables influencing the function of GM. In addition, the changes in GM caused by exercise also seem to depend on the physiological state of individuals. A previous study conducted by Gordon et al. [In animal models, the most common type of forced exercise is the forced treadmill exercise. Compared with the autonomous exercise, the forced exercise has significantly different influence on the GM of experimental animals. With regard to this, in the mice model of colitis, Cook et al.  observedn et al.  indicateThe musculoskeletal system plays an indelible role and significance in the human health. In addition to acting as a scaffold for body, it also continuously communicates with other organs through the biochemical signals, and has basic neural, immune and endocrine regulatory functions , 86. TheFirmicutes and Bacteroides. Moreover, in terms of the clinical practice, Ilesanmi-Oyelere et al. [Recently, there have been research reports that the promoting effects of exercise on the bone is closely associated with GM. In a previous study, McCabe et al.  focused e et al.  conductee et al.  concludee et al. \u2013101.Blautia, Roseburia, Anaerostipes, Butyricicoccus) in the intestine of athletes under high intensity exercise conditions. Butyric acid can directly supply the energy to the intestinal epithelial cells and repair injury, thereby reducing the injury to intestine of body caused by high intensity exercise training [Veillonella isolated from the feces of marathon athletes into experimental mice, and the exercise endurance of mice was significantly improved. Besides, several studies have also reported that the production of butyric acid is related to the production of heat shock protein 70 (HSP70) [As one of the significant metabolites of GM, SCFAs are mainly composed of the carboxylic acids and small hydrocarbon chains , 103. SCtraining , 111. Metraining  suggestetraining  transpla (HSP70) , 115. HSBacteroides enterica and Escherichia coli were involved in the production of secondary BAs in the colon, and exercise may increase the level of secondary BAs by increasing the contents of beneficial bacteria. Meanwhile, Meissner et al. [In addition to SCFAs, the metabolic disturbance of bile acids (BAs) is also involved in the occurrence and progression of OP. As a kind of signal molecule, BAs not only play a significant role in the absorption, transport and distribution of fat and fat-soluble vitamins, but also participate in the regulation of energy metabolism, thereby inhibiting the excessive proliferation of GM . Fukiya r et al.  also revr et al.  showed tr et al. , 121. ItDifferent exercise amount and exercise intensity may have different effects on the intestinal mucosal barrier and mucosal immune function, and regular moderate exercise may reduce the incidence of infection in body . MeanwhiIn addition, the long-term aerobic exercise can enhance the adaptability of body to exercise, and the intestinal mucosal barrier function can also be significantly improved under the long-term exercise intervention . Kang etOn one hand, GM is involved in immune maturation and anti-infection protection of the body, and in this process, the microorganisms are involved in immune system to recognize and distinguish between the beneficial and harmful bacteria . On the Lactobacillus and Bifidobacterium [Lactobacillus yeast, while the levels of IgA, IL-4 and IL-12 in saliva were not significantly changed. Furthermore, as a kind of indigestible polysaccharide, the prebiotics can stimulate the activation and growth of one or more beneficial bacteria in intestine. Similarly, Drakoularakou et al. [Galactooligosaccharides (GOS). Regular supplementation of Fructooligosaccharides (FOS) is also related to increased serum intestinal peptide concentrations and decreased circulating C-reactive protein (CRP) levels [In addition, the supplementation of probiotics/prebiotics also has a crucial impact and repercussion on exercise-mediated immune regulation. Athletes might also benefit from the regular probiotic supplementations, while with certain strain specificity , 143. Practerium , 145. Practerium \u2013148. Beracterium  revealedu et al.  revealed) levels . As a re) levels , more anFirmicutes and Bacteroidetes, induce the proliferation of beneficial bacteria and metabolites, and improve the function of intestinal mucosal barrier, so as to further modulate the bone metabolism. Hence, the appropriate exercise has indelible effects on prevention and treatment of OP. However, there are still various issues need to be negotiated in the researches on relationship between exercise, bone metabolism and GM and its metabolites, specifically including: (1) The mechanisms of exercise-related GM and its metabolites directly regulating bone metabolism needs to be further improved; (2) Whether the exercise-related GM and its metabolites have the linkage effects with other important organs in body to indirectly modulate bone metabolism; (3) Paying attention to and screening out the specific GM suitable for different races around the world and the specific flora for improving the motor function may provide the novel insights for the healthy development of motor system and the improvement of motor function level. Nevertheless, with the increasing maturity of microbiome technologies and the wide application of sterile or GF animals, it is believed that further in-depth exploration might provide new perspectives for the researches on link between exercise, GM and its metabolites, and bone metabolism, and also promote the interdisciplinary and integrated researches of exercise physiology, microbiology and metabolomics.In general, there is increasing evidence that exercise is an independent factor of external environmental stressors that affects the composition and diversity of GM, and improves the body metabolism and immune system. The imbalance of GM has a direct impact on the normal physiological function and the health status of host. Exercise can enrich the abundance and diversity of GM, improve the proportion of Below is the link to the electronic supplementary material.Supplementary Material 1Supplementary Material 2"}
+{"text": "The Inner Mongolia Autonomous Region ranks first among the five major pastoral areas in terms of lamb breeding of China. The Inner Mongolia Autonomous Region has a vast territory, with many famous grasslands and thousands of forage plants and multiple local high-quality lamb breeds. After hundreds of years of artificial breeding and improvement, Mongolian sheep have developed many varieties. Different diets, feeding and treatment methods have effects on the production performance, lipid deposition and flavor composition of mutton sheep. Therefore, understanding the relationship among Inner Mongolian lamb, meat quality, and flavor will improve the production of high-quality mutton. The regulation of meat quality and flavor will have a profound impact on the deep processing and income-generating capabilities of mutton. Non-genetic factors affect the quality and flavor of mutton, which are more intuitive than genetic factors. In this review, we cover the contributions made by scientists to explore and improve the quality and flavor of Inner Mongolia lambs through non-genetic means, compare the differences between grazing and drylot-feeding in detail, and summarize some feed additives. We hope that based on our review, we can provide some inspiration to improve the meat quality of Mongolian sheep. China is the world's largest producer of mutton. Among the five major pastoral areas in China, the Inner Mongolia Autonomous Region ranks first in the mutton industry in the country, accounting for 33% of the country's total mutton production . There aAccording to geographical distribution and genetic relationship classification, there are Tibetan sheep, Mongolian sheep and Kazakh sheep in China. Mongolian sheep is a short fat-tailed sheep, which is the most abundant and widely distributed sheep breed in China, and is suitable for extensive management of nomadic grazing throughout the year . MongoliMutton is an indispensable source of high-quality protein in the human diet . The conlongissimus thoracis, biceps femoris, and triceps brachii) are mainly glycolytic type II B fibers. With the increase of months, the muscle fiber has a trend of I \u2192 IIA \u2192 IIB. The diameter and cross-sectional area of muscle fiber gradually increase with the number of months, but the increase is slower after the age of 6 months , and whole-drylot-feeding . As the longissimus thoracis muscle of the grazing group were significantly higher than those of the drylot-feeding group; the fat content, slaughter, net meat rate, and redness value of the drylot-feeding group were higher than those of the grazing group . Th. Thlongiopposite  57, 58), 58longiopposite . The expas lower . The n-3as lower . Of couras lower . The maias lower . Owing tas lower . The umaas lower . Althougsemitendinosus and longissimus thoracis muscle of the grazing group and the heat denaturation temperature were higher than those of the drylot-feeding group . After sheep have eaten odorous forages, and are then fed without odorous forages for 7\u201314 days, the odor can be eliminated  produce significantly higher volatile indole content in the rumen than those grazing on other types of pastures, so their flavor is poor , indicating that A. mongolicum polysaccharide has an immunomodulatory effect on sheep peripheral blood lymphocytes  in the diet reduced the crude fat, SFA, and SA content of mutton and increased crude protein, crude ash and dry matter, MSFA, and PUFA, among them, the content of ALA increased by 13.89%, and no heavy metal residues were detected (Jujube) in the diet can effectively promote the immunity, growth and development of Bamai sheep, and increase the crude fat content and IMP content in Bamei mutton.Chinese herbal medicine is based on natural animals, plants, and minerals; contains many flavor substances and antibacterial ingredients; and has dual functions of nutrition and medicine , 131. Itdetected , 136. Gadetected  pointed Lycopene is a carotenoid, mainly found in tomato pulp. This natural plant pigment has strong antioxidant properties, can regulate cell growth and metabolism, and enhances the body's immunity. The polyunsaturated double bond structure of lycopene has the effect of scavenging free radical groups, so that lycopene has strong antioxidant properties. Ma et al.  found thAlfalfa and silage are considered important feeds for herbivores, providing abundant feed protein and physically effective neutral detergent fibers. Alfalfa saponin is one of the most valuable plant secondary metabolites. Saponins are composed of a fat-soluble core with a steroid or triterpene structure and are amphiphilic. This structure gives saponins membrane-dissolving activity and explains their antibacterial, antitumor, and anti-inflammatory properties in animals. In addition, saponin can act on cholesterol and control lipid metabolism through its ability to bind cholesterol in the intestine and other tissues  put forward different requirements for the tenderness, intermuscular fat content, flavor, and other attributes of lamb. Therefore, the identification of mutton in different regions should be made through two aspects. On the one hand, the local government should regulate the mutton industry chain  in accordance with policies as soon as possible; On the other hand, the identification of sheep grazing in different grasslands depends on the whole-process traceability technology and the correlation between different geographical environment characteristics and local meat quality.Factors such as livestock age, gender, castration, tail docking, feed additives, nutritional level of the diet, grazing and drylot-feeding all affect the quality and flavor of mutton, which are more intuitive than genetic factors. Feed is a key factor in improving the quality and flavor of mutton; the rumen fermentation process and biohydrogenation have a great influence on the composition of intramuscular fatty acids; antioxidant levels of lamb during storage and cooking are also worth investigating. Through the combination of appropriate breeding methods, nutritional control factors and scientific management, the quality and flavor of mutton can be improved, the mutton taste problem of mutton can be fundamentally controlled, and the needs of consumers can be met.YL: writing\u2014original draft and writing\u2014review and editing. RL and YY: writing\u2014review and editing. YZ and YH: resources. HW: supervision and funding acquisition. KL: supervision. All authors contributed to the article and approved the submitted version.This research was funded by the Science and technology projects in Inner Mongolia Autonomous Region (No. 2021GG0029) and Central Public-interest Scientific Institution Basal Research Fund (Nos. 1610332022013 and 1610332022009).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "PRESENT . Moreover, the two Panels of the second day brought together respected specialists who discussed the focus of the AMN as a society and on TBI in low- and-middle-income countries.The second day of the 2022 Academy of Multidisciplinary Neurotraumatology (AMN) Virtual Congress began with Session 4, with Prof. Karin Diserens (Switzerland) and Dr. Pieter Vos (the Netherlands) as chairpersons. The day encompassed a plethora of presentations on TBI, with the speakers approaching subjects such as disorders of consciousness, the role of Brain-Derived Neurotrophic Factor (BDNF), diffuse axonal injury, the impact of TBI on the Alzheimer's Disease, personalized approaches to TBI management, traumatic brain hemorrhage, the role of oxiracetam nanodelivery for the enhancement of memory, the complications of decompressive craniotomies following TBI, neurovascular therapies and the innovative The first presentation regarded the modern concepts of disorders of consciousness, where Karin Diserens (Switzerland), Head of the Acute Neuro-rehabilitation Unit at the Department of Clinical Neurosciences from Lausanne University Hospital (Switzerland), shared her expertise on neurotrauma. The pathologic alteration in consciousness represents one of the most challenging aspects of TBI since the simple definition of consciousness during history proved to be problematic from a scientific point of view and from a philosophical one. The evolution of medicine has led to better outcomes secondary to brain injuries, prolonging survivability. Several aspects of the disorders of consciousness have led to a better and deeper understanding of the Disorders of Consciousness (DOC) from an anatomical, biological, and functional perspective.In modern medicine, the concepts of DOC have changed with the help of electroencephalogram (EEG) or functional Magnetic Resonance Imaging (MRI) studies and translational neurology. These concepts are a mirror to the continuous development of medicine.Secondly, Anton \u00c1lvarez (Spain), Director at Medinova Institute of Neurosciences and Clinical Research and Director at QPS-JSW Life Sciences (Spain), presented an intriguing insight into the role of Brain-Derived Neurotrophic Factor (BDNF) in clinical and basic research. BDNF represents the most abundant neurotrophin in the brain with an essential role in synaptic plasticity, cell differentiation and survival, playing a vital role in neuropathology and treatment and exerting a positive influence on TBI neurorecovery by promoting endogenous processes of regeneration, thus enhancing survival, and improving TBI outcomes. It is, therefore, essential to enhance BDNF in the brains of TBI patients to improve cognition and prevent dementia after TBI. Lastly, it is crucial to consider the shift from acute neuroprotection to sub-acute and chronic neurorestoration.Moreover, Pieter Vos (the Netherlands), Neurologist at the Department of Neurology at Slingeland Hospital in Doetinchem (the Netherlands), conducted a fascinating presentation regarding diffuse axonal injury. Diffuse axonal injury is one of the significant complications of TBI that can lead to impairment and death. With an unknown incidence, this insult to the brain leads to malfunction of the neuronal networks, affecting various functional structures of the brain. Diffuse axonal injury is found mainly in severe TBI cases, predominantly affecting the white matter of the frontal and temporal lobes and the structures of the brainstem and corpus callosum. The definitive diagnosis is made post-mortem, although imagery like Computed Tomography (CT) or MRI can identify various lesions secondary to diffuse axonal injury. Therefore, Dr. Vos highlighted that for TBI patients with diffuse axonal injuries, preventing secondary injuries and providing physical, neuropsychological, and pharmacological rehabilitation is of utmost importance in decreasing morbidity and mortality.The session ended with a presentation by Alexandru V. Ciurea (Romania), Vice President of the Romanian Ministry of Health Neurosurgical Committee, Chief of Neurosurgery and Scientific Director at Sanador Medical Center Hospital in Bucharest and Professor of Neurosurgery at Carol Davila University in Bucharest (Romania), on the role of TBI as a trigger or aggravating factor in Alzheimer's disease. Several pathophysiological aspects of TBI remain an enigma. Thus, the gap between translational and clinical research represents a need, an opportunity, and the future of TBI. A close collaboration between clinicians and translational researchers will lead to the further development of this field, mainly by finding comparable data between human and animal models. Prof. Ciurea presented a current study on Alzheimer's Disease and TBI on 19 patients, from 2013 to 2022, showcasing that TBI is an aggravating factor for Alzheimer's disease, as it affects synaptic transmission. Prof. Ciurea discussed further prevention strategies for Alzheimer's Disease.th session, Prof. Christian Matula (Austria) and Prof. Martin Rakusa (Slovenia) represented the chairpersons, and exciting topics related to neurosurgical aspects of TBI and inspiring approaches towards TBI were showcased.During the 5At the beginning of the session, Felix Brehar (Romania), Head of the Stereotactic and Functional Neurosurgery Department at Bagdasar Arseni Clinical Emergency Hospital in Bucharest and Associated Professor at Carol Davila University of Medicine and Pharmacy in Bucharest (Romania), presented current and future trends toward a personalized approach to TBI management. A successful individualized approach should pinpoint the presence, the severity, the possibility that the patients would recover on their own, the best treatment option, and what the long-term disability would be. A personalized approach integrates clinical diagnosis, multi-omics approach, and tailored treatment. The multi-omics integrates data on genomics, epigenomics, transcriptomics, proteomics, and metabolomics. Prof. Brehar showcased the role of biomarkers in TBI in the diagnosis, stratification, delivery of targeted therapy, and prognosis. A take-home conclusion from the presentation regards the variability in TBI, the need for further research and the importance of multimodality and interdisciplinary efforts in the approach of TBI.th session of the Congress ended with the skillful presentation of Prof. Stefan Florian (Romania), Head of the Department of Neurosurgery at Cluj County Emergency Hospital and Vice President of the Romanian Society of Neurosurgery. Prof. Florian delivered a detailed perspective regarding the complications of decompressive craniectomy in TBI.Bringing forth another inspiring approach, Martin Rakusa (Slovenia), Consultant Neurologist in the Division of Neurology and Head of the Medical Research Department at University Medical Centre Maribor (Slovenia) discussed the topic of traumatic brain hemorrhage. Prof. Rakusa pinpointed the rarity of traumatic hemorrhage in TBI, with a more common occurrence in more severely affected patients, as well as the lack of association of anticoagulants with hemorrhage. An equally insightful presentation was that of Hari Shanker Sharma (Sweden), director of Research at the International Experimental Central Nervous System Injury & Repair (IECNSIR) at Uppsala University. Prof. Sharma discussed on the role of oxiracetam nanodelivery for the enhancement of memory, functional recovery, and induction of neuroprotection following a concussive head injury. The 5The last session of the AMN Congress, Session 6, having Prof. Michael Chopp (USA) and Prof. Hari Shanker Sharma (Sweden) as chairpersons, discussed neurovascular therapies and the innovative TBI registry, PRESENT. The first speaker of the session, Michael Chopp (USA), Vice Chairman for Research of the Department of Neurology and Scientific Director of the Henry Ford Neuroscience Institute in the USA, discussed the topic of exosomes and neurotrophic factors in Neurovascular Therapy. On a microscopic level, exosomes represent a valuable structure with various functions. For example, they can assure intercellular connection by transporting different nucleic acids, proteins, or lipids. Prof. Chopp further discussed on the progression of diseases, and potential biological markers of different lesions.It was dr. Iulia Vadan (Romania), Neurologist at RoNeuro Institute for Neurological Research and Diagnostic in Cluj-Napoca (Romania), who then discussed the status of PRESENT. PRESENT, short for Patient Registry, Short Essential Neurotrauma, has been developed as an international, multidisciplinary longitudinal, prospective registry. The registry represents an electronic platform for TBI patients, covering the patient's pathway during the hospital stay and discharge, with possibility of implementation at national and international levels. PRESENT will be able to mirror the multimodal treatment in TBI. One of the main characteristics of TBI is the heterogeneity of mechanisms, causes, and types of brain injuries, as well as the patient's particularities that lead in a first phase to the primary injury and then to secondary injuries. Furthermore, the patient's rehabilitation after TBI is of utter importance by influencing the degree of posttraumatic disability and the patients' quality of life, as well as their families. Based on an electronic platform, it is a valuable tool in obtaining a TBI patients database that will cover several elements from epidemiology to the pathway of care, outcomes, treatments, and rehabilitation measures.Finally, Prof. Andriy Huk (Ukraine), Chief of the Department of Endoscopic and Craniofacial Neurosurgery at Romodanov Neurosurgery Institute, painted an inspiring portrait of the role of PRESENT in the multimodal treatment following a TBI.rd Panel \u201cThe AMN is an ambitious medical society-what should be its focus?\u201d, Volker H\u00f6mberg (Germany), Jongmin Lee (South Korea), Johannes Vester (Germany), Lynne Lucena (The Philippines), Christian Matula (Austria), Nicole von Steinb\u00fcchel (Germany), Pieter Vos (The Netherlands) and Dafin Muresanu (Romania) discussed the focus of AMN as a modern medical society. The AMN aims to advance research, practical application, and education in neurotraumatology and is determined to become a leading example of multidisciplinary cooperation. However, considering the complexity of TBI, especially with the fast-growing advancement of research and innovation, finding the right path for scientific societies can be a challenging pursuit.During the 3The AMN Congress was finalized with the last of the panels, respectively Panel 4 \u201cTBI in low- and middle-income countries \u2013 what are the specifics, what are the pragmatic solutions for improvements\u201d, where panellists like Felix Brehar (Romania), Volodymyr Golyk (Ukraine), Ignacio Previgliano (Argentina) and Tarek Lotfy (Egypt) alongside members of the AMN board and specialists from Romania, including Andriy Huk (Ukraine), Johannes Vester (Germany), Nicole von Steinb\u00fcchel (Germany), Stefan Strilciuc (Romania), Razvan Chereches (Romania), Irina Vlad (Romania), Iulia Vadan (Romania), Constantin Radu (Romania) showcased the specific problems of neurotrauma in low- and middle-income countries (LMIC), as well as discussed possible approaches.LMIC are more affected by TBI than more resourceful ones and experience specific challenges in practice and research, the availability and reliability of data. Pragmatic solutions, such as PRESENT are needed to obtain more profound knowledge about TBI.Moreover, it is crucial to consider the needs and particularities of the specific countries when discussing TBI research and consider the patient's pathway through the medical system. Therefore, having an \u201cecological\u201d approach and considering the larger picture when approaching TBI remains of utmost importance.AMN website.The exciting event showcased insight into a wide-range of TBI-related themes, offering a glimpse into the complex and intricate world of neurotraumatology. The multidisciplinary principle of the AMN is reflected in the variance of perspectives presented, standing as the cornerstone of future research and medical practice. In a fast-changing and unpredicted environment, collaboration and dissemination of knowledge, skills, and innovation support the pursuit of science and bring optimistic perspectives for the future. More information on the congress can be found on the"}
+{"text": "In the United States most adults have a preference to die at home and is an indicator of good end-of-life care. In the context of dementia, family members and caregivers are decision makers and part of good and equitable care involves understanding cultural variation in attitudes and social norms related to dementia, death and dying, and the meaning of a good death. This symposium explores racial and ethnic variation in lifetime dementia diagnosis and end-of-life care quality indicators. The first presentation examines racial, ethnic, and geographic variation in the rarely discussed lifetime prevalence of dementia and survival time from dementia diagnosis to death using national Medicare data. The second presentation describes the relationship between end-of-life care planning and satisfaction with end-of-life care using data from the Health and Retirement Study. The third presentation describes variation in place of death, a key indicator of end-of-life care quality, by dementia diagnosis and race/ethnicity using national Medicare data. The fourth presentation examines variation in hospice use, another indicator of end-of-life-care quality, and place of death by dementia diagnosis, race, and ethnicity using national Medicare data. The symposium concludes with a presentation examining the relationship between place of death and satisfaction with care received using data from the Health and Retirement Study. The Institute for Healthcare Improvement\u2019s Triple Aim  serves as a lens for discussing policy and practice implications of the major findings from each presentation."}
+{"text": "Participatory action research (PAR) is a promising approach to engage older adults in self-determined research that influences policies and practices; however, the voices of older adults are very often missing from most PAR projects. The purpose of this paper is to reflect upon the challenges and opportunities of engaging lesbian, gay, bisexual, transgender, and queer (LGBTQ+) elders of color in PAR during the Covid-19 pandemic. Data were generated through interviews with LGBTQ+ elders of color and their caregivers and analyzed thematically. Findings illustrate several barriers and facilitators of conducting PAR during the pandemic. Barriers included feelings of distrust toward research(ers), pandemic related issues and illnesses, and competing priorities and interests. Facilitators included leveraging community connections and participating in community-based activities. Study findings have the potential to advance a critical turn in gerontology that is committed to the liberation of marginalized older adults in aging research, policies, and practices."}
+{"text": "The COVID-19 pandemic was declared a Public Health Emergency of International Concern on January 30, 2020. The government of Zimbabwe through the Ministry of Health and Child Care set up the COVID-19 national preparedness and response plan in which the laboratory was a key pillar. The implementation of PCR testing, genomic sequencing, and the establishment of quality management systems during the COVID-19 response strengthened the capacity of the public health laboratory system in responding to the pandemic. Here we present the different strategies taken by the government that strengthened laboratory capacity, the lessons learned during the COVID-19 response, and recommendations on how the capacity can be sustained and leveraged for outbreak response in the future. On the 30The development of the National COVID-19 Laboratory testing strategy and the review of the National Health Laboratory Strategy and policy documents in the context of COVID-19 played an important role in strengthening the laboratory in Zimbabwe. Tools for guidance and standard operating procedures for use during implementation were developed, reviewed, and approved as a matter of urgency, adopting WHO guidelines for SAR-CoV-2 infection detection.th of March 2020 [Typical of health systems in sub-Saharan Africa, the capacity to respond to the COVID-19 pandemic in Zimbabwe was low due to inadequate funding and a lack of trained personnel to conduct COVID-19 testing and genomic sequencing . Zimbabwrch 2020 . The govThe Ebola virus disease (EVD) outbreak in West Africa provides useful lessons on how emergency responses can impact health systems, . Novel tThe Ebola virus disease (EVD) outbreak in West Africa provides useful lessons on how emergency responses can impact health systems, . Novel tThe emergency use listing of two Ag-RDT, Abbott and SD Biosensor by WHO in September 2020  led to tThe COVID-19 response demanded strict adherence to quality when performing COVID-19 testing to ensure accuracy, reliability, and timely release of results. Before the COVID-19 pandemic in Zimbabwe, a few government and private laboratories were participating in external quality assessment programs (EQA) such as proficiency testing (PT). During the COVID-19 pandemic, the MoHCC and partners through the DLS facilitated the setting up of quality management systems (QMS) and participation of laboratories in PT programmes offered by organisations such as the WHO, Thistle (South Africa), and One World Accuracy (Canada). To standardise laboratory testing of COVID-19, Africa CDC in collaboration with ASLM and PanaBIOS as technical leads, introduced the COVID-19 Laboratory testing certification Program (CoLTeP) to ensure accuracy, and reliability of test results and that testing procedures be conducted under appropriate biosafety and biosecurity conditions . A totalThe COVID-19 response brought about collaborations and partnerships in the form of inter-governmental, government to private, government to institutions and institution to institution collaborations. These partnerships strengthened the public health laboratory system in Zimbabwe in areas of the supply chain and logistics, training of laboratory personnel, sequencing, QMS, and outbreak response. Different partners came aboard to support the pandemic response by providing technical support for SARS-CoV-2 testing, outbreak response, building sequencing capacity, buying of reagents, and capacitating laboratory personnel e.g. the WHO, the Jack Ma Foundation , BiomediEarly response to the COVID-19 pandemic in Zimbabwe was slowed due to a lack of skilled personnel to perform SARS-CoV-2 molecular testing among other reasons. Many laboratory cadres also lacked training and skills in disease outbreak response. Collaborative efforts with organisations such as the Kwazulu-Natal Research Innovation and Sequencing Platform (KRISP), QIB in the United Kingdom, and the Africa CDC facilitated the training of Zimbabwean scientists in genomic sequencing and bioinformatics analysis. It will be important to retain the trained staff through improving remuneration and working conditions and supporting continuous improvement towards building a resilient public health laboratory system capable of responding to future outbreaks.The COVID-19 response in Zimbabwe generated capacity and strengthened the public health laboratory system. However, the implementation of various strategies was not devoid of challenges. We propose recommendations to address some of the challenges and to maintain and improve existing capacity. Beyond the COVID-19 pandemic, a robust public health laboratory system will be important to address existing public health problems as well as respond to the next pandemic. 1)There is a need to maintain existing partnerships between the government and different local and international partners beyond the COVID-19 pandemic to enhance disease surveillance and cooperation in areas of public health interest. The government must maintain the existing partnerships with local private laboratories and research institutions to improve the overall surveillance and response efforts to disease outbreaks. The government through the DLS can play a role in supporting private laboratories to set up sustainable quality management systems with the goal of certification and accreditation. 2)The COVID-19 pandemic exposed the low capacity for genomic surveillance in Zimbabwe. There is an urgent need to invest in next-generation sequencing (NGS) platforms with high throughput and training of many laboratory cadres in performing sequencing and bioinformatics analysis of sequencing data [st century.Before the COVID-19 pandemic, several deficiencies characterized the public health laboratory system in Zimbabwe. For instance, there were a few PCR and sequencing platforms as well as trained and skilled personnel in the areas of sequencing and bioinformatics analysis. However, during the pandemic, a significant shift in the paradigm of strengthening the public health laboratory system occurred characterised by improved laboratory infrastructure, training of laboratory cadres, and setting up of QMS and participation in EQA programmes, decentralised Ag-RDT testing, and important partnerships between the government and various organisations. In the post-pandemic period, further gains in strengthening the public health laboratory system can be achieved by constant capacity building in molecular techniques training, bioinformatics analysis, and setup maintaining of quality management systems. The current experiences have strengthened the public health laboratory system in Zimbabwe and this has laid the foundation for a significant post-COVID-19 transformation so that the public health laboratory system can be better prepared to address existing public health problems and the next global threat(s) of the 21"}
+{"text": "Over the last two decades, imaging techniques have become irreplaceable tools in nanotechnology: electron microscopy techniques are routinely used to observe the structural features of newly manufactured nanoconstructs, while light and electron microscopy, magnetic resonance imaging, optical imaging, positron emission tomography, and ultrasound imaging allow dynamic monitoring of the biodistribution, targeting and clearance of nanoparticulates in living systems, either for the whole organism or at the level of single cells, tissues and organs .The first Special Issue, \u201cMolecular Imaging in Nanomedical Research\u201d, contained five research articles and two reviews on diverse imaging techniques applied to the development of novel nanoconstruct-based strategies for diagnosis and therapy . In thisChang and co-workers  used polSu and co-workers  aimed toMagnetic iron oxide nanoparticles are potential contrast agents for magnetic resonance imaging and magnetic particle imaging. Baki and co-workers  modifiedWo\u017aniak and co-workers  reviewedDopamine-related tracers are a powerful tool used to assess the status of presynaptic nigrostriatal terminals in the brain; Palermo and co-workers  illustraAptamers are short, single-stranded, non-coding DNA or RNA nucleotides that specifically bind molecular targets and may be functionalized via radioisotope labeling for use as diagnostic and therapeutic agents. Due to their high specificity and adjustable binding affinities, aptamers targeting HER2 are promising agents in nuclear medicine for the early detection, diagnosis and potential treatment of HER2-positive breast cancer. In their review, Vi and co-workers  describeAfter describing the concepts and characteristics of general optical coherence tomography systems, Wang and co-workers  describeAmong the existing contrast agents for magnetic resonance imaging, smart nanoprobes that respond to selective stimuli  may provide information on tissue and cell functional features. This subject was reviewed by Wang and co-workers , who focElucidating the interactions between the nanoconstructs and the biological environment is crucial in nanomedicine, and transmission electron microscopy provides direct evidence of the uptake and biodistribution of nanoparticles, as well as of their relationships with the cell and tissue components. My paper  presentsOverall, this Special Issue confirms the key contribution of molecular imaging techniques, which support and foster the creativity and inventiveness of scientists engaged in nanomedical research."}
+{"text": "The magnitude and exceptional opportunity to research the psychological distress of shelter in place resulted in a publication frenzy on a smorgasbord of research studies of variable scientific robustness. Confinement, fear of contagion, social isolation, financial hardship, etc. equated to stratospheric stress levels. The decline in protective factors as a function of quarantine anecdotally reflected historic rates of anxiety and depression.In this study, we combined 12 variegate datasets and developed an algorithm to build a model to identify key predictors of pandemic-related stress with high accuracy and generalizability.This study reports on existing published data. We first describe the International  and then the Italian dataset . The time-frame (first wave of lockdown), method (survey), measurement tool , and outcome measures were extremely similar to enable consolidation of datasets . The Flesia et al., (2020) data set was integrated into the Adamson et al., (2020) dataset as the first step towards data validation construction of the ML predictive model.We aim to demonstrate the strength of combining cross-cultural datasets, and the applicability of ML algorithms to facilitate the process and generate a predictive model that identifies and validates key predictors of pandemic-related stress and accommodates for interaction with demographic, cultural, and other mitigating factors while concurrently having high generalizability.We believe our model provides clinicians, researchers, and decision-makers with evidence to investigate the moderators and mediators of stress, and introduce novel interventions to mitigate the long-term effects of the COVID-19 pandemic.No significant relationships."}
+{"text": "Community-based treatment of possible serious bacterial infection (PSBI) in young infants, when referral to a hospital is not possible, can result in high treatment coverage and low case fatality. However, in Ethiopia, the coverage of PSBI treatment remains low, worsened by COVID-19. To understand the challenges of delivery of PSBI treatment and design and test adaptative strategies to mitigate the impact of COVID-19 on neonatal mortality, we did implementation research (IR) employing Implementation Research Logic Model (IRLM). In this paper, we describe IRLM application experiences in designing, implementing, and evaluating strategies to improve community-based treatment of PSBI during the COVID-19 pandemic in Ethiopia.This IR was conducted between November 2020-April 2022 at Dembecha and Lume woredas of Amhara and Oromia regions, respectively. We employed narrative reviews, formative assessment and facilitated stakeholder engagement to develop the PSBI treatment IRLM to identify barriers, understand the conceptual linkages among determinants, choose implementation strategies, elicit mechanisms, and link to implementation outcomes. In addition, we used the IRLM to structure the capture of emerging implementation challenges and resulting strategy adaptations throughout implementation.This IR identified COVID-19 and multiple pre-existing contextual factors. We designed and implemented implementation strategies to address these challenges. These adaptive strategies were implemented with sufficient strength to maintain the delivery of PSBI services and improve mothers\u2019 care-seeking behavior for their sick young infants.The IRLM offers us a clear process and path to prioritize implementation challenges, choose strategies informed by mechanisms of action, and where the adaptive implementation of community-based management of PSBI would lead to high-implementation fidelity and change in mother behavior to seek care for their sick young infants. The IRLM was also an effective tool for stakeholder engagement, easily explained and used to structure discussion and decision-making during co-design meetings.The use of the IRLM helps us to specify the conceptual links between the implementation challenges, strategies, mechanisms of action, and outcomes to explore the complex community-based management of PSBI during complex contexts to improve high-fidelity implementation and integration of PSBI treatment in the primary healthcare delivery systems through active engagement of stakeholders.The online version contains supplementary material available at 10.1186/s12913-022-08945-9. Possible serious bacterial infection (PSBI) was identified as a leading cause of mortality in young infants (0\u201359\u00a0days of age) in Sub-Saharan Africa, contributing to 37% of the 2.1 million neonatal deaths \u20136). The Ethiopia introduced community-based newborn care (CBNC) in its flagship Health Extension Program (HEP) to improve access to and use of appropriate treatment for neonatal sepsis when a referral was not possible in 2012 . HoweverThere is limited evidence of the level of impact of the COVID-19 pandemic on care-seeking for neonatal sepsis programs in Ethiopia. Implementation research (IR) was conducted between November 2020-April 2022 in Dembecha and Lume districts of Amhara and Oromia regions, respectively. The research was carried out by JSI Research & Training Institute Inc./The Last Ten Kilometers (L10K) Project, funded by the Bill & Melinda Gates Foundation. The aim was to understand the demand- and supply-side challenges of delivery of PSBI treatment during the COVID-19 pandemic and to develop and test adaptative strategies to mitigate the impact of COVID-19 and other barriers on community-based management of PSBI implementation and uptake. Implementation research is the scientific study of methods to promote the systematic uptake of research findings and other evidence-based practices into routine practice, to improve the adoption, high-fidelity implementation, and maintenance of quality, effective, evidence-based practices in health care services . The ImpIn this paper, we describe the use of the IRLM for stakeholder engagement and incorporate formative research to inform the design, implementation, and evaluation of strategies to improve community-based management of neonatal bacterial infection during the COVID-19 pandemic. The utilization of the IRLM in Ethiopia represents important insights into using this tool and IR to inform adaptive implementation, engaging key stakeholders, and generating generalizable knowledge to inform the broader, context-adapted implementation of PSBI treatment.This implementation research was conducted between November 2020-April 2022 in Dembecha and Lume woredas of Amhara and Oromia regions Fig.\u00a0 DembechaWe employed narrative review, formative assessment, and facilitated stakeholder engagement to develop the management of PSBI IRLM. The work was designed to articulate determinants, choose implementation strategies, and link these through mechanisms to targeted implementation outcomes. In addition, during the implementation phase, we captured ongoing implementation challenges and adaptations of strategies using a tracker. We applied the Framework for Reporting Adaptations and Modifications to Evidence-based Implementation Strategies (FRAME-IS) . We alsoIn April 2021, we conducted a narrative review of existing literature to quickly identify the overview of previously described barriers and facilitators of community-based management of PSBI implementation in Ethiopia. One author (GT) searched Google Scholar and PubMed for publications in English between 2012 to 2021, starting after the initiation of CBNC services in Ethiopia. Search terms used included: possible serious bacterial infection, community-based management of newborn illnesses, neonatal sepsis, uptake, utilization, barriers, facilitators, determinants, and Ethiopia. The title or abstract of the article was downloaded. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) diagram   frameworWe conducted a cross-sectional population-based household survey of 4,242 mothers who gave live birth 2\u201314\u00a0months before data collection and resided in the two woredas. Survey captured information including household and sociodemographic characteristics, experiences related to using maternal and newborn health services across the continuum of care, care-seeking for sick infants and children, and Knowledge and risk perception of COVID-19. A structured questionnaire translated into local languages (Amharic and Oromiffa) was used to capture the data using a web-based mHealth platform (SurveyCTO) using smartphones , development partners (4), direct service providers (16), and community volunteers (8). The interview guide was designed using CFIR to understand what factors facilitate or hinder community-based management of PSBI implementation, including characteristics of the health system, intervention, individual, inner, and outer settings.We engaged stakeholders throughout the research process as a keystone of our implementation research in the selection, prioritization, and operationalization of tailored and appropriate implementation strategies to improve the adoption, implementation, and sustainment of community-based management of PSBI. For this purpose, we followed a rigorous and thoughtful development process to systematically plan for the implementation strategies by facilitating a national stakeholder consultation which expanded on adapted expert recommendations for implementing change (ERIC) protocol  employinFollowing the formative assessment and exploration of potential strategies from the literature, we developed an initial IRLM. Then, we conducted a national co-designing workshop on May 11\u201312, 2021. The workshop involved the Ministry of Health (MOH), National Child Health Technical Working Group, including program managers and development partners; it also included the National RMNCH-N Research Advisory Council Child Health and Immunization group, including their program managers, academics, researchers, and development partners. The workshop also included development partners active in neonatal care in Ethiopia. The workshop\u2019s primary aim was to share the assessment findings and design tailored solutions to address implementation challenges.On the first day, the research team presented an overview of implementation research and formative assessment findings, followed by a discussion on the barriers to community-based management of PSBI implementation. On the second day, the research team presented the draft IRLM, including the identified determinants and preliminary implementation strategies from the literature. Next, the team facilitated a group process of identification and prioritization of implementation strategies. The research team then populated the determinants and strategies of the IRLM raised through an iterative discussion with stakeholders and used the matrix to understand the conceptual links between determinants, implementation strategies, mechanisms, and outcomes.In the last week of May 2021 and the first week of June 2021, we conducted a woreda-level co-creation workshop with regional health bureaus, zonal health departments, woreda health offices, facility-level managers, service providers, kebele managers, and HEWs. Through the co-creation workshop, L10K and participants contextualized and validated the nationally co-designed implementation strategies, identified additional local contextual community-based management of PSBI implementation challenges that had not been captured during the national co-design phase, designed relevant strategies, and developed micro-plans to improve PSBI treatment implementation. All HPs and health centers in the two implementation woredas developed micro-plans.  of childhood illnesses and newborn care, particularly for sick young infants (SYI). A higher proportion of mothers who resided in Dembecha (11%) compared to Lume woredas (5%) reported symptoms of severe neonatal infection in their infants. Communities in Dembecha demonstrated lower care-seeking behavior compared to Lume woreda, with only 52% of mothers receiving antibiotics for neonatal sepsis there compared to 70% of mothers in Lume. Most women sought care for their SYI at health centers and bypassed the HPs. Additionally, the following pre-existing factors were identified as external barriers to the delivery of PSBI treatment: phase-out of partner support, low community care-seeking behavior, negative community attitudes toward services for neonatal illness and PSBI, lack of community trust in HEWs\u2019 capacity to manage PSBI, and low functionality of organized female community volunteers called Women Development Armies (WDAs).The following characteristics were identified as barriers to HEW management of PSBI implementation: lack of competency and confidence in their PSBI knowledge and skills; lack of training, mentoring, and coaching; low motivation, attendance, and engagement regarding PSBI care implementation; competing workload and engagement in non-health activities; and fear of contracting COVID-19. In Dembecha, HEW knowledge of all PSBI signs was lower than in Lume, with 33% and 41%, respectively. Likewise, a higher number of HEWs untrained in the basics of PSBI were identified in Dembecha compared to Lume.Process: The formative assessment, as well as the stakeholder consultation, identified the following implementation process barriers to PSBI care: poor integration of management of PSBI services in the woreda health system, weak coordination, ownership, and stakeholder engagement, and a weak culture of learning.Previous implementation research on the management of PSBI when referral was not feasible conducted in Ethiopia, Malawi, Nigeria, Bangladesh, Pakistan, and India identified several strategies critical to supporting effective implementation at the individual, community, facility, and systems levels. At the individual and community level, these included: training health care workers, in-field technical support, performance reviews , and comDuring the stakeholder engagement, based on the formative assessment and narrative review findings, we grouped major management of PSBI implementation challenges that existed before COVID-19 and were exacerbated by the pandemic into the following categories: 1) low competency, confidence, and motivation of HEWs; 2) weak primary health care system; 3) suboptimal community engagement; 4) other systemic factors ; and 5) weak coordination and integration. We also presented results from the literature review and formative assessment. In consultation with stakeholders, we adopted and adapted a number of the strategies from the literature and developed new ones, including reflecting on COVID-19 -related challenges to enhance the adoption, acceptability, and high-fidelity implementation of community-based management of PSBI interventions, with the aim of further integration and scale up.As presented in Table Using the IRLM, we described the mechanisms of action that the proposed strategies would operate to influence the desired outcomes. For example, building the organization's capacity for better integration, coordination, and stakeholder engagement would lead to strong district-level operational management and high-fidelity intervention delivery during/after study to maintain strategies. Adoption of the strategies, training and supportive supervision increased skills and interest in delivering PSBI treatment effectively and with higher fidelity. It also strengthened referral systems, addressed community knowledge and fears while increasing fidelity, effectiveness, and adoption Fig.\u00a0.Fig. 3ThReach: number of newborns identified and visited by community health workers, percentage of treatment coverage, and percentage of referral refusal; Effectiveness: recovery, and case fatality rate; Fidelity: percentage of patient adherence to antibiotic treatment, percentage of patients who received follow-up care, percentage of classification errors, and percentage of patients who received correct antibiotic; Acceptability: number of parents/family who refused referral but accepted community-based PSBI treatment, barriers and facilitators of acceptability and care-seeking, percentage of PSBI cases who accepted the referral, and rate of adherence to outpatient treatment. We developed a matrix of indicators and data sources for adaptive implementation of PSBI treatment during COVID-19 in Ethiopia  from 42 HPs reported participation in at least one PHCU level PRCMM in the last six months  HPs treated at least one sick young infant in the previous six months, significantly improving from 36% in the last six months.During implementation, we tracked ongoing implementation challenges and adaptive strategies. We used the IRLM framework to capture these emerging or persistent challenges and adapted strategies to articulate the mechanisms of action and link them to outcomes Fig.\u00a0.During the implementation, adaptive implementation strategies were also incorporated, including facilitating the redistribution of gentamicin 20\u00a0mg/ml, intensifying the support and monitoring visits, and increasing offsite PSBI treatment training of HEWs and their supervisors at HPs in Dembecha. Due to the civil war in the northern part of the country, a regional emergency decree was issued on October 31, 2021, halting the regular services of public institutions. This subsequent shift in attention and resources away from the management of the PSBI program emerged as a challenge in Dembecha. We provided one round of supervision when the national and regional situations improved. The district health office conducted monitoring visits, performance reviews, and corrective measures to reestablish prior support for community-based management of PSBI services and strengthen their implementation.In the Lume district, NGO support for maternal and child health was identified as a facilitator for the management of PSBI service during implementation. In addition, the MOH introduced a digital version of the PSBI/iCCM module into the electronic Community Health Information System (eCHIS) in Lume in August 2021. The eCHIS was developed to replace the paper-based information system, a family folder containing household information, registration for incoming and leaving household members (member registration), data regarding service provision, and referral services rendered. The eCHIS incorporated job aids to support service provision, improve quality of care, and improve data use for decision-making. As such, digitization of the PSBI/iCCM treatment module aided HEWs as a decision support tool. It also facilitated digital referral, identification, and registration of newborns and SYI in the app during household visits, leading to improved delivery of community-based management of PSBI services Table .Table 5AWe successfully employed implementation research frameworks in designing, implementing, and evaluating the adaptive implementation of PSBI treatment during COVID-19 in Ethiopia. The RE-AIM and CFIR frameworks were used to design the COVID-19 pandemic that needed to be addressed to improve the reach, adoption, fidelity, and uptake of community-based management of PSBI services. In addition, we populated an initial IRLM. We used the framework to meaningfully engage stakeholders to systematically develop, identify, categorize, and prioritize implementation strategies to address identified and newly emerged barriers. We found that using an increasingly used framework, which combines CFIR and RE-AIM using concept mapping, effectively identifies strategies by integrating existing evidence and stakeholder engagement and expertise.The learnings demonstrated the unprecedented challenges of the COVID-19 pandemic, and the pre-existing health system-level barriers exacerbated the fragile community-based management of PSBI in Ethiopia. Previous studies revealed significant service disruptions in outpatient care and child vaccinations ; a decliUsing implementation research methods to inform the evidence synthesis using narrative review and formative assessment helped us better identify the challenges and provide an initial understanding of the conceptual links between determinants, implementation strategies, mechanisms, and outcomes. The use of concept mapping is essential in informing the choice of implementation strategies and is associated with more effective implementation , 37. StaThroughout our implementation research, we employed IRLM and expanded the adapted ERIC protocol and concept mapping technique to engage stakeholders to gain insights and clarity for developing the PSBI IRLM. This allowed for the systematic planning and application of the community-based management of PSBI implementation strategies that consider determinants, mechanisms, and outcomes. Consequently, we bridged implementation gaps by selecting strategies that improved the implementation process, increased adoption, and sustained effective intervention uptake . CurrentThe IRLM enabled the development of adaptive implementation strategies based on an in-depth understanding of the barriers and facilitators. The application of the framework also allowed us to identify implementation challenges, strategies, and mechanisms of action for adaptive implementation of PSBI treatment to increase implementation fidelity, reach, and adoption. Furthermore, these adaptive implementation strategies elucidated changes in the care-seeking behavior of mothers for their sick young infants. IRLM helped guide the measurement of the activities, intermediate outputs, and outcomes and synthesizing lessons from implementation.During implementation, we tracked ongoing implementation challenges and adaptive strategies, using the IRLM framework to conceptualize the mechanisms of action and outcomes. We also employed this framework to document the implementation learnings and share them with the broader community. This allowed us to examine what happened during the implementation and accurately report the hypothesized relationships we observed. For instance, the digital version of the iCCM module, which is a mobile health  solution for HEWs that incorporates job aids\u2014 to counsel mothers on essential newborn care and educate them on danger signs of PSBI, assess newborns for possible signs of infection, diagnosis, treat and counsel mothers to adhere to treatment protocols\u2014improved the delivery of PSBI treatment. Specifically, it facilitated identifying and registering newborns and sick young infants and aided clinical and referral decisions and adherence to PSBI treatment protocols. This is in contrast to the responses from the data in Dembecha, where the iCCM module was not incorporated into eCHIS and where few or none of the above advantages from eCHIS were reported. At the same time, close monitoring and timely corrective measures to address emerging contexts like the effect of civil war are critical.We continued using this framework to share examples of our work in the cross-country community of practice with the community-based management of PSBI Kenya and India teams to cross-map implementation strategies, adaptations, mechanisms of action, and implementation outcomes. We also explored efficient ways to capture contextual factors to build on our IRLM to inform the management of PSBI work at scale. This has informed our continued work across country projects to identify areas that could benefit from standardized processes, approaches, methods, and metrics.Despite our efforts of exploring all possible challenges, co-designing and implementing strategies with active engagement of stakeholders, capturing ongoing challenges, and adapting strategies throughout the implementation period, we might not include all possible barriers affecting the community-based management of the PSBI program in the model. In addition, some of the determinants of this study may have been affected by social desirability and recall biases which would, in turn, affect the logical links between each component of the IRLM. Though the IRLM provides formats for a standard IR study that include multiple contexts and comparative implementation, it doesn\u2019t explicitly show how to synthesize and report implementation outcomes across various contexts to compare variations in implementation processes and influences across contexts for understanding what works for whom, and how .In conclusion, we found that the IRLM used in this research helped us organize the formative work and facilitate stakeholder engagement to specify the conceptual links between the implementation challenges, strategies, mechanisms of action, and outcomes to design and strengthen the management of the PSBI program under complex contextual factors, including COVID-19, as well as an existing health system and community barriers. The capturing of ongoing implementation challenges and document modifications of strategies during implementation allowed us to update the IRLM to provide better generalizable knowledge on adapting and implementing management of PSBI in similar and different settings.The participatory design and implementation of adaptive COVID-19 strategies effectively maintained the quality delivery of PSBI treatment during the pandemic. These approaches effectively engage community volunteers, HEWs, and the primary health care system and better integrate PSBI treatment for sustained implementation and scale up. Continuous support and feedback systems, continuous supply of essential drugs, and strategies to alleviate HEWs\u2019 workload to deliver quality services should be prioritized.Additional file 1.Additional file 2.Additional file 3.Additional file 4.Additional file 5.Additional file 6."}
+{"text": "Driven mostly by an aging population, the utilization of spine surgery has increased exponentially over the last decades . ChronicPatient-centered care and the use of multidisciplinary collaborations inside and outside of the operating room is a cornerstone of safe and effective management of spinal disorders. Multiple studies have shown the benefits of multidisciplinary case conferences, tumor boards, and shared-decision making in the management of these conditions ,10. NaidThe second strategy to improve safety and outcomes includes the use of advanced techniques and enabling technologies. Anand et al. reported a 13-year experience treating severe adult spinal deformity with minimally invasive circumferential strategies without posterior osteotomies ,15. EchtThe third aspect that will most likely improve the safety and outcome of complex spine surgery is the use of advanced predictive analytics, particularly artificial intelligence. Machine and deep-learning algorithms can offer high predictive capability and can aid in complication prediction, survival prediction, and the identification of high-risk patients ,17,18,19The field of spinal surgery is rapidly changing and we must adapt to it. As specialists dealing with such complex conditions, we must focus on providing humanized and personalized high-quality care to our patients. The use of the approaches described herein will most certainly help us achieve that."}
+{"text": "Urban production energy consumption produces a large amount of carbon emissions, which is an important source of global warming. This study measures the quantity and intensity of carbon emissions in 30 provinces of China based on urban production energy consumption from 2005\u20132019, and uses the Dagum Gini coefficient, kernel density estimation, carbon emission classification and spatial econometric model to analyze the spatial and temporal distribution and driving factors of quantity and intensity of carbon emissions from China and regional production energy consumption. It was found that the growth rate of carbon emission quantity and carbon emission intensity of production energy consumption decreased year by year in each province during the study period. The imbalance of carbon emission was strong, with different degrees of increase and decrease, and there were big differences between eastern and western regions. The classification of carbon emissions differed among provinces and there was heterogeneity among regions. The quantity and intensity of carbon emissions of production energy consumption qwre affected by multiple factors, such as industrial structure. This study provides an in-depth comparison of the spatial and temporal distribution and driving factors of quantity and intensity of carbon emissions of production energy consumption across the country and regions, and provides targeted policies for carbon emission reduction across the country and regions, so as to help achieve China\u2019s \u201cdouble carbon\u201d target quickly and effectively. The massive emission of greenhouse gases has led to an increase in global temperature and an accelerated frequency of extreme hot weather, which has seriously damaged ecological health , and hasAs a region where human activities are concentrated, China has seen a significant increase in carbon emissions due to the production of various industries in the process of urbanization and industrialization, and the contradiction between economic development and resource consumption and environmental pollution problems has become more and more prominent ,13,14,15There are many factors affecting carbon emissions, mainly in economic development, energy use, population structure, urban development, etc. Relevant studies show that China\u2019s carbon emissions have a strong correlation with the level of economic development, and China\u2019s industrial carbon emissions show an inverted U-shaped non-linear relationship with the level of economic development . MeasuriThe influence of different indicators on carbon emissions shows the diversity of carbon emission pathways, and in the process of economic and social development, large consumption of energy is one of the important sources of carbon emissions. Existing study shows that energy consumption and carbon emissions show a certain spatial correlation , and theIn addition, scholars have conducted a lot of research on the regional nature of carbon emissions. Chen et al. (2022) used the Theil index and the Moran index to conduct spatial analysis of China\u2019s carbon emission intensity and found that the spatial differences of carbon emission intensity from 2000 to 2019 were obvious, mainly intra-regional, with significant spatial correlation and local agglomeration characteristics . Yang etIn general, the existing studies on carbon emissions are rich, but there are still certain shortcomings. Firstly, existing studies have deeply analyzed the relevant influencing factors of carbon emissions, which can clearly sort out the theoretical relationship between carbon emissions and related influencing factors. However, carbon emissions have a spatial nature, and current studies lack discussion on the spatial relationship between carbon emissions and their influencing factors. Secondly, carbon emissions in China come from a wide range of sources, and carbon emissions from energy consumption are a key source in the process of industrialization and urbanization in China, so research on carbon emissions from energy consumption is necessary, and most existing studies have been conducted on carbon emissions from energy consumption. Energy consumption can be divided into rural energy consumption and urban energy consumption, and the corresponding urban energy consumption is divided into production energy consumption and domestic energy consumption. A more detailed division of energy consumption sources and the study of its carbon emission nature and influencing factors can propose more targeted energy saving and emission reduction policies. Thirdly, carbon emissions are spatially imbalanced, but the degree of imbalance and how it evolves still need to be measured and analyzed further in order to clarify the regional differences and spatial distribution characteristics of carbon emissions. Based on the above three analyses, this paper decided to measure the carbon emission quantity and carbon emission intensity of urban production energy consumption, and analyze the spatial and temporal distribution of carbon emissions and the driving factors. The carbon emissions of urban production energy consumption refer to the carbon emissions generated by the energy consumption of production activities in industries, raw materials and materials, construction, transportation, storage, postal services, wholesale and retail trade, and accommodation and catering, in addition to agriculture. After measuring carbon emission quantity and carbon emission intensity, the national and regional imbalance and spatial distribution characteristics of carbon emissions from urban production energy consumption were further measured and analyzed using the Dagum Gini coefficient and its decomposition and kernel density estimation, and, finally, the driving factors of carbon emissions and the regional heterogeneity of the driving factors were investigated using spatial econometric models. The results of this paper aim to provide quantitative support for the formulation of national and regional carbon emission reduction policies, so as to achieve China\u2019s \u201cdouble carbon\u201d target quickly and effectively.In this paper, the carbon emission quantity and carbon emission intensity of urban production energy consumption were used to measure the regional carbon emission level, and the carbon emission quantity of urban production energy consumption was calculated using energy in industry, raw materials and materials, construction, transportation, storage, postal industry, wholesale, retail trade, accommodation, catering production and other end consumption.At present, there are many accounting methods for carbon emissions from energy consumption, including the IPCC measurement method, field measurement method and model estimation method . In thisiE is the energy consumption, iNCV is the average low level calorific value of the fuel, iEF is the carbon content per unit calorific value of the fuel, iO is the oxygen content, and 44/12 is the conversion factor for converting C to 2CO.In Formula (1), The carbon emission intensity of urban production energy consumption is the carbon emission of urban production energy consumption per unit of GDP. The calculation formula of carbon emission intensity is as follows:In Formula (2), secondary industry refers to the mining industry (excluding mining auxiliary activities), manufacturing , electric power, heat, gas and water production and supply industry, and construction industry. The third industry, or tertiary industry, refers to the service industry, including wholesale and retail, transportation, warehousing and postal services, accommodation and catering industries, etc.The Gini coefficient and its decomposition are important methods to study regional differences, and the sample is divided into three parts: between-group differences, within-group differences and hyper-variance density to explore regional differences and their sources in depth ,52. In tk is the number of research subjects grouped. In this paper, it was divided into three regions: eastern, central and western China, containing a total of n research subjects. The values ijy and mry are the carbon emission levels of the j(r)th province in the i(m)th research region, and \u03bc is the average value of carbon emissions of all provinces.The value The intra-regional Gini coefficient measures the difference in carbon emission levels within each region, and the inter-regional Gini coefficient measures the difference in carbon emission levels between regions. The specific formulae are as follows:iiG is the intra-regional Gini coefficient, imG is the inter-regional Gini coefficient, in (m) and i\u03bc (m) are the number of research objects in region i (m) and the mean carbon emission level of provinces in region i (m).The overall Gini coefficient is decomposed to further measure the contribution of intra-regional differences, inter-regional differences and supervariable density to the overall differences. The formulae are as follows:wG, nbG and lG are the intra-regional, inter-regional and hypervariable density difference contributions, respectively. imD is the relative impact of carbon emission levels between regions i and m, imd is the difference in carbon emission levels between regions i and m, i.e., the mathematical expectation of the sum of all sample values of ij \u2212 ymry > 0 in regions i and m, and imp is the hypervariable first-order matrix, i.e., the mathematical expectation of the sum of all sample values of ij \u2212 ymry > 0 in regions i and m.Kernel density estimation is an important nonparametric estimation method, which can further explore the absolute differences and dynamic evolution of regional carbon emissions ,54. In tiy is the carbon emission level of province i, p is the sample size, h is the bandwidth, and K is the Gaussian kernel function.To explore the changes of carbon emission levels of urban production energy consumption and their carbon emission types from 2005 to 2019, the carbon emissions of urban production energy consumption were divided into four categories, namely high-high (high carbon emission quantity-high carbon emission intensity), high-low (high carbon emission quantity-low carbon emission intensity), low-high (low carbon emission quantity-high carbon emission intensity) and low-low (low carbon emission quantity-low carbon emission intensity), using the average value of carbon emission quantity and carbon emission intensity as the measure. Those above the average value were high carbon emissions, and those below the average value of carbon emissions were low carbon emissions.It is considered that the carbon emission level of urban energy production consumption in provincial in China may have the characteristics of spatial correlation. This paper proposed to test the drivers of carbon emission levels of production energy consumption in towns using the spatial error model (SEM), spatial lag model (SLM) and spatial Durbin model (SDM). The spatial correlation of carbon emission levels of urban production energy consumption in China was tested using the global Moran index  . If the (1)Spatial error model (SEM)(2)Spatial lag model (SLM)(3)Spatial Durbin Model (SDM)i, j represents a province, t represents the year, itCE is the carbon emission level of the ith province in year t, \u03b2 is the coefficient of the explanatory variable, i\u03bc is the individual fixed effect, t\u03b7 is the time fixed effect, w is the spatial weight matrix, \u03bb is the spatial error term coefficient, \u03c1 is the spatial autocorrelation coefficient, x is the explanatory variable, and \u03b3 is the coefficient of the explanatory variable of the neighboring province affecting the home province.In the formulae, In this paper, the spatial weight matrix used the adjacency space weight matrix, and the neighborhood under the spatial structure was represented by 0 and 1. If the spatial units had a non-zero common boundary, they were considered to be spatially adjacent and represented by 1; otherwise, they were considered to be non-spatially adjacent and represented by 0.The driving factors of carbon emissions from urban production energy consumption are complex. In this paper, 11 explanatory variables were selected for analysis from five dimensions as the driving factors of carbon emissions from urban production energy consumption: urban economic level, living standard of urban residents, urban energy consumption level, urban population size and urban development level.(1)Urban economic level. The transformation of industrial structure can be realized through the upgrading of industrial structure and the rationalization of industrial structure to reduce carbon emissions, so industrial structure is an important influencing factor of carbon emissions ,58. Fore(2)Living standard of urban residents. Wen and Zhang found that per capita disposable income has a significant impact on carbon emissions . Therefo(3)2 emissions, and the proportion of coal consumption to total energy consumption was used to measure the energy consumption structure.Urban energy consumption level. Studies have shown that the high proportion of coal consumption in China directly determines the energy consumption structure, which, in turn, is the driving factor of carbon emissions . Therefo(4)Urban population size. As the main body of economic development, the population structure has a profound impact on carbon emissions. Labor force and dependency ratio are important demographic indicators, and have significant space differences in the impact of carbon emissions . In addi(5)Urban development level. Studies have shown that the green coverage of built-up areas has a significant impact on provincial carbon emissions in China . The spaThe urbanization rate was measured by the proportion of urban population in the total population, and the education level was measured by the average years of education: number of primary school students *6+ number of junior middle school students *3+ number of senior high school students *3+ number of junior college students and above *16/number of people aged 6 and above. Technological innovation was measured by the turnover of the technology market. The original data of all the explanatory variables were obtained from China Statistical Yearbook and China Energy Statistical Yearbook from 2005\u20132019, and individual missing data were completed using the trend prediction method and interpolation method. The abbreviations, definitions, and data sources for variables are shown in The carbon emission level of production energy consumption varies widely among different regions, and this paper divided China into three study regions: the eastern region, including Beijing, Tianjin, Hebei, Liaoning, Shanghai, Jiangsu, Zhejiang, Fujian, Shandong, Guangdong, and Hainan; the central region, including Shanxi, Jilin, Heilongjiang, Anhui, Jiangxi, Henan, Hubei, and Hunan; the western region, including Inner Mongolia, Guangxi, Chongqing, Sichuan, Guizhou, Yunnan, Shaanxi, Gansu, Qinghai, Ningxia, Xinjiang. The study area is shown in The results of calculating carbon emissions of urban production energy consumption in inter-provincial in China from 2005 to 2019 showed that carbon emission levels have obvious spatial distribution characteristics . Carbon (1)Overall differencesIn order to explore in-depth the overall regional differences and sources of carbon emissions from urban production energy consumption, this paper used the Dagum Gini coefficient and its decomposition to calculate the overall Gini coefficient of carbon emissions and further decomposed this to measure the Gini coefficients of eastern region, central region and western region.The overall difference of carbon emission quantities is shown in (2)Intra-regional differencesThe intra-regional differences in carbon emission quantity and their evolution trends are shown in Since 2012, the intra-regional difference in carbon emission quantity in the central region decreased, while the intra-regional difference in carbon emission quantity in the western region increased, so that the intra-regional difference in the western region was much higher than in the central region by 2019. As shown in (3)Inter-regional differencesThe inter-regional differences in carbon emissions and their evolution trends are shown in Based on the Dagum Gini coefficient and its decomposition, the overall differences and evolution trends of carbon emission levels were analyzed, and the relative differences of regions were identified. In order to further study the dynamic distribution characteristics of carbon emission levels and absolute regional differences, this paper used Kernel density estimation to study the overall pattern and dynamic evolution of carbon emission distribution in China and each region. Matlab software was used to draw a three-dimensional perspective view of carbon emission levels in China and each of its regions from 2005 to 2019.(1)The evolution of carbon emission quantity dynamicsAs shown in The above analysis showed that the imbalance of carbon emission quantities in China deepened, and there was a trend of polarization, with large differences between regions and an increasing trend of differences between provinces within each region. The largest differences between provinces were within the eastern region, followed by the central region, and with polarization within the western region, but the polarization was gradually decreasing.(2)The evolution of carbon emission intensity dynamicsAs shown in The above analysis showed that the imbalance of carbon emission intensity of urban production energy consumption in the country weakened, but the deepening of the polarization phenomenon indicated an obvious gradient effect. Compared with the eastern region and western region, the central region had the weakest imbalance, followed by the eastern region, and the western region had the strongest imbalance. The emergence of side peaks in the eastern region and central region also showed a certain polarization phenomenon. There was an obvious gradient effect, namely most provinces\u2019 carbon intensity decreased obviously and became gradually numerically close, but there were still some provinces where the decrease in carbon emission intensity was small and there was a large gap with the carbon emission intensity in most provinces, so the phenomenon of multi -polarization was generated.The carbon emission classification of urban production energy consumption inter-provincially is shown in In the previous section, the analysis of carbon emission levels of urban production energy consumption inter-provincially found that there were significant spatial distribution characteristics. In order to further explore the strategies to reduce the carbon emission levels of production energy consumption, it was necessary to conduct an in-depth study of the driving mechanism. By calculating the global Moran\u2019s I index of carbon emissions for spatial correlation analysis , it was As shown in Carbon emission intensity was also affected by multiple factors, as shown in The results of the analysis of carbon emission driving factors of urban production energy consumption in the three major regions of China are shown in As can be seen from In order to test the feasibility and robustness of the research results, this article adopted a replacement indicator method for a robustness test. The per capita disposable income of important indicators was replaced by per capita consumption expenditure. The robustness test results are shown in the This study measured the carbon emission levels (carbon emission quantity and carbon emission intensity) of urban production energy consumption in inter-provincial areas in China based on data from 2005\u20132019. The study measured and decomposed the overall regional differences in carbon emission levels using the Dagum Gini coefficient, analyzed the dynamic characteristics of the distribution of carbon emission levels and absolute regional differences using the Kernel density estimation method, and used a spatial econometric model to analyze the driving factors of carbon emission levels in the whole region and three regions . The main research findings are as follows.First, the carbon emission quantity increased year by year during the study period, but the growth rate decreased, and the carbon emission intensity had an obvious decreasing trend. Besides this, the carbon emission quantity and carbon emission intensity showed obvious spatial differences, i.e., the carbon emission quantity showed the characteristic of eastern region > central region > western region, while the carbon emission intensity, on the contrary, showed the characteristic of western region > central region > eastern region, and the spatial characteristics were more obvious as time went on.Second, the overall difference of carbon emission quantity showed a decreasing trend. The intra-regional difference of carbon emission quantity evolved from eastern region > central region > western region to eastern region > western region > central region, and the overall difference of carbon emission intensity showed an increasing trend, and the intra-regional difference of carbon emission intensity was always western region > eastern region > central region. The imbalance of carbon emission quantity increased in the country, and the imbalance of carbon emission quantity increased in different degrees in the eastern region, central region and western region. There was a significant gradient effect in the carbon emission intensity, and there was also a trend of multi -level differentiation in the provinces in various regions. From the perspective of carbon emission classification, the inter-provincial carbon emission classification had some changes from 2005 to 2019, but most of the carbon emission provinces were in the low-low category.Third, carbon emission level was influenced by multiple factors, among which carbon emission quantity was mainly influenced by industrial structure, per capita disposable income, energy consumption structure, urbanization rate, cultural level, scientific and technological innovation. Carbon emission intensity was mainly influenced by industrial structure, foreign direct investment, energy consumption structure, the dependency ratio of elderly population and scientific and technological innovation. Different regions had heterogeneity, and the level of driving factors was different. Industrial structure, per capita disposable income, energy consumption structure, urbanization rate were the important driving factors of regional carbon emissions.Based on the above findings, this paper proposes the following recommendations to reduce carbon emissions from urban production energy consumption in China, to promote the achievement of carbon peaking and carbon neutral goals, and to realize green and sustainable economic and social development.2 emissions [First, on a national scale, the energy consumption structure has more room for transformation. On the one hand, China\u2019s natural resource profile of \u201ccoal-rich and oil-poor\u201d has influenced the energy consumption structure, so China\u2019s current production energy consumption is still coal-based fossil energy, which leads to a large amount of COmissions . On the missions . AdjustiSecondly, the regional differences should be balanced to achieve dual balance between carbon emission quantity and carbon emission intensity. The regional differences in carbon emission quantity and carbon emission intensity of urban production energy consumption reflect imbalance in intra- and inter-regional economic development and energy utilization. The eastern region as a whole has a relatively developed economy and higher technology level, but its internal imbalance is also stronger. Therefore, important provinces in the eastern region, such as Shanghai and Zhejiang, should actively play the role of central cities to strengthen the economic and technological radiation to the surrounding areas, improving the economic levels of the surrounding provinces while reducing the differences in the level of carbon emissions of production energy within the region. The eastern region should give full play to its advantages in high and new technology, and transport technical talents to the central region and western region, so as to provide important support for the industrial development and upgrading of the central region and western region. The difference of carbon emission level and economic development within the central region is smaller, therefore, as an important hub between the eastern region and western region, the central provinces should play a good role as a mediator, while maintaining a stable and positive development. The western region should pay more attention to economic construction and low-carbon development of secondary and tertiary industries, while industrial structure transformation is crucial to strengthen the upgrading of low-end manufacturing industries to high-end manufacturing industries, accelerate the transfer from labor and capital-intensive industries to high-tech-intensive ones, and narrow the economic differences with the eastern region and central region, so as to reduce the carbon emission intensity of production.Finally, the construction of new urbanization should be strengthened. The increase of urbanization rate has significant heterogeneity for regions, and the urbanization rate is higher in the eastern region and central region at the present stage. Further increasing the level of urbanization rate will raise the level of production of carbon emissions, so the transformation of new urbanization should be accelerated, and new urbanization should play an important role in revitalizing the economy, while being a key step in the coordinated development of economic and ecological environments . Therefo"}
+{"text": "Pregnant women frequently use prenatal screening and diagnostic tests to detect fetal structural and chromosomal anomalies; however, the regulation and financing of these examinations differ substantially across countries. In this paper we focus on the provision, financing and setting of the following tests in selected European countries: First Trimester Screening (FTS)/Combined Test (CT), Non-invasive Prenatal Test (NIPT), second-trimester ultrasound screening for fetal anomalies, amniocentesis/chorionic villus sampling.We chose 6 European countries that differ in various criteria  to illustrate the range of possible regulations and forms of funding: Germany, Switzerland, Netherlands, United Kingdom, Norway, Italy. We conducted a comprehensive hand search and consulted experts from the 6 countries using a questionnaire.The results are based on 11 completed expert questionnaires and 22 published sources. The heterogeneity of the provision, regulation and financing of the tests concerns in particular the choice of the first-line screening test for fetal trisomies , the implementation of the NIPT, the reimbursement of the tests, the uptake of the examinations, but also the professional groups responsible for antenatal care . There are some similarities between countries, e.g., concerning the provision and financing of invasive tests and of the ultrasound screening for fetal anomalies in the second trimester.The results highlight the significant heterogeneity between European countries regarding prenatal screening and diagnostic testing for fetal anomalies. Due to the many ethical aspects of the topic, a broad societal discourse with the relevant interest groups and stakeholders seems to be necessary. Decision-makers should pay particular attention to high-quality and non-directive counselling.European countries take different approaches to offer and fund prenatal screening and diagnostic tests for fetal anomalies.The implementation of screening strategies should focus in particular on the importance of high-quality counselling to enable informed decision-making."}
+{"text": "Working conditions at universities are often considered precarious. Employees complain of fixed-term contracts and extensive unpaid overtime . Studies from various fields of work show that occupational groups with a high workload suffer particularly from a conflictual compatibility of work and family.The aim of this study was to assess the WFC in the context of working conditions.N=844 university employees  were asked about the burden of work/life balance using Work-family-conflict (WFC) - Family-work-conflict (FWC) -Scales (Netemeyer 1996). The dichotomously formulated question on overtime worked was supplemented by a five-step scaled item on the burden of overtime. The correlation analyses were calculated according to Spearman.Overtime performed by 83% of the total sample and 64% feel burdened by it. 95% of the scientists and physicians, 68% of the administrative staff, 63% of the service providers work overtime and 90% of the physicians and 72% of the scientists feel burdened by it. Significantly high correlations were found between the burden of overtime and the conflict of compatibility. The higher the burden of overtime, the higher the WFC and FWC. The highest correlation was found among physicians (r=.649), followed by scientists (r=.533), administration (r=.451), services .The additional work and strain caused by this, as well as the connections with the problem of compatibility, show need for action for employers regarding the working conditions of physicians and scientists. Especially with regard to reducing overtime and improving the compatibility of work and family."}
+{"text": "This symposium engages diverse methods and analyses to discover and reimagine possibilities for individuals aging with and into disability. The presentations advance an understanding of the diversity of service/care needs as well as of social capital, with exploration into assistive technologies, educational attainment, and assessment of successful aging. In the first presentation, the authors delineate key informant interview data identifying capacity-building needs in professional skills, organizational operations, service/care models, and public policies to effectively serve older adults aging with and into disability. The second presentation offers a content analysis of how researchers conceptualize, measure, and apply social capital to developmental disability throughout the life course, reviewing peer-reviewed articles from 5 disciplines, across more than 20 years. In the third presentation, using National Health and Aging Trends Study data, the authors investigate the longitudinal associations between disabilities, assistive technologies, and subjective well-being among older adults. In the fourth presentation, the author uses multivariate regression analysis to analyze National Health Interview Survey (NHIS) data, building on prior research analyzing the association between educational attainment and the perceived need for future help with activities of daily living (ADLs), often measuring disability in the literature. In the fifth and final presentation, the authors use the National Health & Aging Trends Study data to understand successful aging from the perspectives of those who experience disability, integrating subjective components of self-rated health and well-being, and providing insights on subjective perceptions on successful aging among older adults with disabilities."}
+{"text": "The food supply chain operates in a complex and dynamic external environment, and the external uncertainties from natural and socio-economic environment pose great challenges to the development of the food industry. In particular, the COVID-19 pandemic and Russia\u2013Ukraine conflict have further exacerbated the vulnerability of the global food supply chain. Analyzing the dynamic impacts of external uncertainties on the stability of food supply chain is central to guaranteeing the sustainable security of food supply. Based on the division of food supply chain and the classification of external uncertainties, the TVP-FAVAR-SV model was constructed to explore the dynamic impacts of external uncertainties on food supply chain. It was found that the impacts of external uncertainty elements were significantly different, the combination of different external uncertainty elements aggravated or reduced the risks of food supply chain. And some uncertainty elements had both positive and negative impacts in the whole sample period, as the magnitude and direction of the impacts of various uncertainties in different periods had time-varying characteristics. Food security is the guarantee for human survival, economic development, and social harmony. The outbreak of the global food crisis in the early 1970s and in 2008 caused food insecurity in many countries and induced great tension in the world ,4, whichStudies on the food supply chain from different perspectives has played an important role in promoting the development of food supply chain. Based on the general supply chain theory, Ouden et al.  found a The food supply chain usually faces complex challenges from external economic, social and natural environment when maintaining stability ,32. ThusChina is the largest grain producer and importer. Limited by the natural environment, China has to ensure food and nutrition security of 18% of the world\u2019s population with only 9% of the world\u2019s cultivated land and 6% of the world\u2019s water resources . China aResearch on the impacts of external uncertainties (or risks) on food supply chain is of great significance to eliminate global hunger and achieve sustainable security of food supply . The resTo improve these deficiencies, this paper first divides the main sectors of the food supply chain and selects a large number of indicators from the two aspects of natural and socio-economic environment to measure the external uncertainties, which serves as entry points for the study. Then, the TVP-FAVAR-SV model is constructed, and the common factors reflecting the external economic environment uncertainties are extracted through latent factor extraction method. With the help of the three-dimensional impulse response of the representative variables in the sectors of the food supply chain to all external uncertainty elements, this paper studies the dynamic impacts of a single external uncertainty element on the food supply chain, and the different impacts of the combination of multiple external uncertainty elements on the food supply chain. Compared with existing research, the three-dimensional impulse responses based on the TVP-FAVAR-SV model can depict the dynamic and complex impacts of external uncertainties more clearly. The impulse response results show the time-varying characteristics of the uncertainties\u2019 impacts, and reveal that the combination and transmission of various uncertainties\u2019 impacts are the main reason for aggravating or reducing the food supply chain risks.In this section, first, we divide the major sectors of food supply chain and classify the external uncertainties, which serve as entry points for the study. Second, the impact mechanisms of external uncertainties on all sectors of the food supply chain are identified. Finally, the construction of empirical model and data sources are introduced.The food supply chain comprises multiple sectors and sub-elements, and each sub-element is independent but closely linked . The synThe external uncertainties include economic uncertainties, social and natural public emergencies ,19,22. TThe impacts caused by the external uncertainties on the primary agri-products supply sector are mainly reflected in labor force reduction, disaster area increase, agricultural production input increase, variety selection, premature harvesting, policy changes, and subsidy shortage ,57,64,65The impacts caused by the external uncertainties on the food production sector are mainly reflected in the impacts on the cost, inventory, production strategy, support services and financial risks of food production enterprises (including agri-products processing enterprises and food manufacturing enterprises) ,67,68, wThe impacts caused by the external uncertainties on circulation and trade sector are mainly reflected in the impacts on food supply, operation costs, market selection, market access, market sanctions, and trade agreements in the food market, which lead to price volatility, consumption fluctuation and trade fluctuation ,22,69,70In the consumption sector, the decision-making behavior of consumers on food purchase is the main content. The impacts of external uncertainties on consumption are mainly realized by changing consumers\u2019 purchasing power, consumption habits, and expectations . In the The external uncertainties to be investigated in this paper cover many indicators, especially 67 economic indicators are used to measure the economic uncertainty, and which cannot be fully included for analysis. In order to show as many of the impacts of external uncertainties as possible, it is necessary to be more prepared to grasp the time-varying characteristics of various impacts, and to improve the ability to explain the relationship among the variables in the system, so it is crucial to analyze with the help of an appropriate model. Considering that the characteristics of some indicators can be described by the common part, the dimensionality reduction of indicators can be achieved by extracting the common part . Kazi etIn order to study the time-varying quality of the parameters, the model needs to be extended to a time-varying parameter form. The basic expression of the time-varying parameters factor-augmented VAR (TVP-FAVAR) model takes the form:According to the methods of Primiceri  and NakaStacking the row vector of Following the assumptions as Koop et al. , for eacThus, Equation (1) can be rewritten as:Inserting Equation (10) into (9) can obtain the final TVP-FAVAR-SV form:Monthly data are selected in this paper to describe the external uncertainties as carefully as possible and maintain the consistency of data frequency. Considering data availability, the sample interval selected in this paper is from March 2005 to June 2020. In primary agri-products supply sector, primary agri-products trade includes vegetable products and animal products, and the specific product types and corresponding HS codes are shown in This paper draws on the latent factor extraction method proposed by Bernanke et al.  to extraIn p-value of ADF-statistic, all variables have passed the unit root test.Since this paper studies the relationship between time series, before empirical analysis, this paper uses unit root test to examine the stationarity of all variables in the TVP-FAVAR-SV model, in order to eliminate the influence of random law differences in non-stationary series ,81. The Based on the common factor extraction and unit root test, this paper further explores the three-dimensional impulse responses of representative variables in each sector of food supply chain to positive shocks of public health emergencies (PHE), disaster emergencies (DE), interest rate uncertainty factor (IRU), financial uncertainty factor (FU), social development uncertainty factor (SDU), and consumption uncertainty factor (CU).The impulse responses of primary agri-products purchase price (PAPP)The positive shocks of external uncertainties mainly have positive impacts on PAPP. FU and DE have relatively large impacts, while that of CU is the smallest. The impacts of DE have obvious intermittence.From October 2009 to September 2010, IRU had great impacts on PAPP, and the Chinese government implemented moderately loose monetary policies to cause an increase in the positive impacts of IRU on PAPP ,82. WhenFrom April 2007 to February 2008 and from May 2009 to March 2010, FU had great positive impacts on PAPP, because the agri-products price rose rapidly with the high liquidity of domestic currency and assets in these two periods .From February 2009 to October 2010, the impacts of SDU on PAPP increased remarkably, mainly due to the significant growth of PAPP driven by the \u210cfour trillion\u210d economic stimulus plan implemented by the Chinese government ,82. FromFrom November 2008 to April 2011, the positive impacts of CU on PAPP were significantly greater than that in other periods. Reasons include the high level of consumer confidence and expectation, and the depreciation of CNY exchange rate. Therefore, strong demand in both domestic and international markets significantly increased PAPP .The continuous heavy rainfall in the Yangtze River Basin from July to August 2010 seriously impacted agricultural production, which led to the increase of PAPP from October 2010 to February 2011, due to the lagging effect of agricultural production on prices. From March 2015 to September 2016, due to severe droughts and floods in North China, Northeast China, and Northwest China, as well as the Yellow River and Yangtze River Basins, PAPP increased significantly during this period.From March 2010 to August 2010, the positive impacts of PHE on PAPP decreased significantly, because the outbreak of influenza A (H1N1) at the end of 2009 reduced consumption of livestock products and pork . Moreove2.The impulse responses of production value of primary agri-products (PVPA)The positive shocks of external uncertainties have both positive and negative impacts on PVPA, with the greatest impacts being of SDU, followed by DE, and CU has the least impacts .Before 2006, IRU mainly had negative impacts on PVPA due to the downturn of the primary agricultural product market, and the rise of interest rate further increased the loan pressures of agricultural enterprises, agents, and purchasers . After 2FU increases PVPA by improving the financing environment of agricultural enterprises and raising primary agri-products price , and hasSince 2006, the Chinese government has implemented a series of agricultural support policies, which have made great contributions to ensuring agricultural production, narrowing the income gap of farmers and maintaining the number of rural laborers ,54,89. TCU has negative impacts on PVPA first, and then positive impacts, but the overall level of impacts is small. With the improvement of residents\u2019 income level, people will increase the consumption of durable goods, high-end goods, or luxury goods, resulting in the negative impacts on PVPA; meanwhile, people\u2019s consumption upgrading can also stimulate agricultural production value ; thus, CDE has negative impacts on PVPA first, and then positive impacts. The occurrence of DE, especially natural disasters, has relatively great negative impacts on PVPA in the short term. Meanwhile, due to the support and protection of agricultural policies, primary agri-products will quickly resume production after disasters, so PVPA will experience compensatory increase in the long term ,90. Due PHE has negative impacts on PVPA first, and then positive impacts, but both positive and negative impacts are small. It reflects that policies implemented by the Chinese government to support and protect agriculture, as well as the emergency prevention and control measures have effectively reduced the impacts of PHE on PVPA.3.The impulse responses of primary agri-products export (PAE)The positive shocks of IRU mainly have negative impacts on PAE, while FU, SDU, and CU, DE, and PHE have both positive and negative impacts. Among them, DE has the greatest impacts on PAE, followed by FU and FU, while CU has few impacts .The increase of IRU means the increase of loan interest rate or price index. On the one hand, it affects PAE by influencing the borrowing costs of exporters ; on the FU first has short-term negative impacts, followed by long-term positive impacts. The reason for the short-term negative impacts is that the FU raised the price of agri-products, thus reducing the price competitiveness of its exports. The long-term positive impacts are realized by improving the financing environment of export enterprises .SDU increases PAE by improving quantity and quality of agricultural production, and strengthening interregional agricultural trade consultation . HoweverCU increases PAE by raising the exchange rate of foreign currency to CNY, and reduces PAE by stimulating consumption when the exchange rates are relatively stable, such as the time from October 2009 to October 2012 .DE and PHE first have great negative impacts on PAE, followed by positive impacts. It indicates that the occurrence of DE and PHE reduce PAE in the short term , but when the disaster passes and agriculture production recovers, PAE will experience compensatory growth .4.The impulse responses of primary agri-products import (PAI)The positive shocks of financial uncertainties, CU and PHE, mainly have positive impacts on PAI. IRU, SDU, and DE have both positive and negative impacts. DE has the greatest impacts on PAI, followed by SDU, and FU has the least impacts . IRU incSDU reduces the dependence on agri-products imports by increasing domestic supply and applying relevant trade policies . It is also found that during the implementation of the \u201cfour trillion\u201d economic stimulus plan (from February 2009 to October 2010), SDU had significant positive impacts, which reflects the strong orientation of the plan . The impDE and PHE have significant positive impacts on PAI, and impacts of DE are relatively great. It indicates that DE is still the main factors affecting the PAI compared with the impacts of economic uncertainties.The impulse responses of sales price of food enterprise (SPFE)The positive shocks of external uncertainties mainly have positive impacts on SPFE, with the greater impacts of FU and SDU, and the smallest of DE . IRU hasThe positive impacts of SDU on SPFE increased significantly from April 2007 to February 2008 and from May 2009 to March 2010. CU has greater pulling effects on SPFE in time of high liquidity, and the impacts of CU on SPFE decreased with time. The continuous heavy rainfall in the Yangtze River Basin from July to August 2010 led to the unstable supply of primary agri-products, so the impacts of DE on SPFE also increased significantly during this period.PHE mainly has positive impacts on SPFE, but it had significant negative impacts from January 2010 to October 2010. The outbreak of influenza A (H1N1) from October 2009 to April 2010 led to a significant decrease in the consumption of poultry and pork products , which f2.The impulse responses of production value of food industry (PVFI)The positive shocks of external uncertainties have both positive and negative impacts on PVFI, with the greatest impacts of DE, followed by PHE, and IRU having the least impacts . The priThe positive shocks of FU increase PVFI by improving the food enterprises\u2019 financing environment and raising food price. The impacts of FU on PVFI will increase in time of high liquidity . SDU hasDE and PHE first have great negative impacts on PVFI, followed by positive impacts. It shows that when DE and PHE occur, PVFI will decrease in the short term; after the disaster pass and enterprises resume production, PVFI will experience a compensatory increase .3.The impulse responses of profit margin of food industry (PMFI)The positive shocks of IRU mainly have negative impacts on PMFI. The positive shocks of SDU mainly have positive impacts. FU, CU, DE, and PHE have both positive and negative effects. DE has the greatest impacts on PMFI and IRU have the smallest impacts .IRU increases food enterprises\u2019 production and operation costs, so IRU mainly has negative impacts on PMFI. FU increases the production costs of food enterprises in the short term, which have negative impacts on PMFI. In the long term, it has positive impacts on PMFI by improving the financing environment and reducing financial risks. In time of high intensity of agricultural policies, the impacts of FU are greater . SDU hasWith the continuous improvement of consumption level, people\u2019s eating habits are constantly upgraded , and fooDE and PHE first have great negative impacts on PMFI, and then have positive impacts. When DE and PHE occur, PMFI will greatly reduce through direct and indirect impacts in the short term. After food enterprises resume normal production, the profit margin will recover .The impulse responses of food retail (FR)The positive shocks of FU and SDU mainly have positive impacts on FR, while positive shocks of IRU, CU, DE, and PHE have both positive and negative impacts. The impacts of DE and PHE are relatively large, while the impacts of IRU are the smallest .In the period of high liquidity (from April 2007 to December 2007 and from October 2009 to September 2010), due to the income effect of savings, people increased food consumption considerably, resulting in positive impacts on IRU during this period. If the money liquidity is at a moderate level, people increase savings due to the substitution effect of savings. Therefore, IRU mainly had negative impacts after 2012 ,96.FU increases FR by raising food prices. Meanwhile, it also stimulates food consumption by increasing residents\u2019 income. SDU increases FR by improving residents\u2019 income and enhancing food market construction . The impDE and PHE rapidly increase FR in the short term by changing consumer expectations ; however2.The impulse responses of food products export (FPE)The positive shocks of IRU mainly have negative impacts on FPE. SDU mainly has positive impacts, while FU, CU, DE, and PHE have both positive and negative impacts. DE and SDU have greater impacts on FPE, while CU has the least impacts .IRU has negative impacts on FPE by affecting the borrowing costs of export enterprises and raising domestic food prices. After 2016, with the rise of loan interest rate and the continuous growth of agri-production material price index, the negative impacts of IRU on FPE increased. In the short term, FU can raise food prices, which causes negative impacts on FPE; in the long term, FU has positive impacts on FPE by improving the financing environment of food exporters ,88.SDU increases FPE by improving food quality, diversifying food supply, and improving the trade environment of food enterprises and the development prospects of food exporters . SimilarDE and PHE first have great negative impacts on FPE and then have positive impacts. When DE and PHE occur, FPE decreases greatly in the short term; after the disasters or pandemics, FPE will experience a restorative growth .3.The impulse responses of food products import (FPI)FU mainly has positive impacts on FPI, and other external uncertainties have both positive and negative impacts. DE has the greatest impacts on FPI, followed by SDU, and IRU having the least impacts . In the FU mainly increases FPI by improving the credit level and financing scale of import enterprises . With thDE and PHE first have positive impacts on FPI, and then negative impacts. The increase of FPI caused by the influenza A (H1N1) outbreak in October 2009 and H7N9 in December 2016 was significantly greater than that caused by COVID-19; considering the safety of imported food, global outbreaks of infectious diseases will strengthen quarantine on imported goods and reduce the food products import.Since the sales amount in the food market equals the purchase amount of consumers , and the impacts of external uncertainties on food retail have been discussed in the circulation and trade section, this section is devoted to analyzing the impacts of external uncertainties on the food consumption price.The impulse responses of food consumption price (FCP)The positive shocks of FU and CU mainly have positive impacts on FCP, while IRU, SDU, DE, and PHE have both positive and negative impacts . IRU hasThe positive impacts of DE on FCP have great volatility. PHE has positive impacts on FCP first and then negative impacts, but both positive and negative impacts are small, reflecting the Chinese government\u2019s effectiveness of food prices regulation.The impacts of IRU on the sales price of food enterprises and food consumption price are significantly greater than that on the purchase price of primary agri-products. On the one hand, this difference is because the food products are at the end of the supply chain, and prices are directly affected by IRU shocks, as well as the transmission of impacts that caused by IRU on other sectors. On the other hand, the price support and protection policies implemented by the Chinese government have effectively restrained the fluctuation of primary agri-products price.IRU affects the production value of primary agri-products, production value, and sales profit of food enterprises by changing production, sales, and operating costs. In the time of high liquidity, positive shocks of IRU lead to a significant decline in the sales profit margin of food enterprises, despite the increase in its production value.aThis phenomenon causes by the sensitive responses of production costs and loan costs to changes in the interest rate.IRU affects food retail through income effect and substitution effect of savings. The substitution effect is dominant during periods of moderate liquidity, while the income effect plays a major role during periods of high liquidity.IRU has an impact on trade of primary agri-products and food products by affecting the agri-production material price and enterprise credit costs, and the impacts on exports are greater than that on imports. It indicates that preferential loan interest rate policy for export processing enterprises can effectively improve their resistance against risks in primary agri-products and food products exports, which is consistent with the conclusions of Qu and Kang  and NordFU increases the purchase price of primary agri-products, sales price of food enterprises, and food consumption price through financialization. The impacts on the sales price and food consumption price are greater than that on the purchase price of primary agri-products. Because the purchase of agri-products is at the front of the supply chain and is less affected by risk transmission from other sectors. And price support and protection policies implemented by the Chinese government reduce the price volatility of primary agri-products, and the results verify the findings of Assefa et al. .FU affects the production value of primary agri-products by changing the financing environment of primary agricultural producers and raising the price level of primary agri-products, and affects the production value and sales profit margin of food enterprises by changing the sales price, financing environment, financial risks, non-operating income, etc. FU has greater impacts on the sales profit of food enterprises. It shows that internal operation management of the enterprises reduces the risk transmitted from sales profit to production value, consistent with Kuiper and Lansink  and GoliFU has great impacts on primary agri-products exports and small impacts on primary agri-products imports and food products trade, indicating that the relevant policies by the government and financial institutions to support the financing of agricultural export enterprises are important measures to increase agri-products exports. And this is consistent with Nordhagen et al.  and ZhanSDU has greater impacts on the sales price of food enterprises and food consumption than on the purchase price of primary agri-products. This is caused by the differences in risk transmission from other sectors and the implementation of agricultural protection policies. The Chinese government has implemented policies such as grain supporting procurement and agricultural production subsidies, which are of great significance to stabilize the price of agri-products. Especially from 2008 to 2013, the steady implementation of the minimum purchase price policy for wheat and rice, temporary purchase and storage policy for corn, soybean and cotton, and the substantial increase of agricultural production subsidies led to corresponding increase in the response value of agri-products purchase price during this period.SDU has positive impacts on production value of primary agri-products, production value, and sales profit margin of food enterprises through the agricultural policies to protect primary production and improve farmers\u2019 income , as well as a series of positive policies to support food enterprises , and have a greater impact on the sales profit margin. It indicates that the preferential policies implemented by the Chinese government to support the development of food enterprises have effectively reduced the internal operation costs and risks of food enterprises, and can significantly improve the profit margin. The results verify the findings of Golini et al.  and NordSDU increases sales by increasing consumers\u2019 income and improving construction of food market. The purpose of improving construction of food market is to promote the diversification of consumers\u2019 dietary structure and to meet their needs for balanced nutrition.SDU increases the export of agri-products and food products by improving product quality, increasing varieties, and improving the trade environment, and has negative impacts on agri-products import . However, economic development also brings about upgrading of the consumer market, which increases the import of high-quality and diversified food products.CU has positive impacts on the purchase price of primary agri-products, sales price of food enterprises and food consumption price by increasing consumer confidence and expectation. The positive impacts are more significant in time of high liquidity.Due to the necessity of agricultural production and the rigidity of food demand, the impacts of CU on production value of primary agri-products and food industry are volatile, but the overall impacts are small; these findings are consistent with Davis et al. .CU first has negative impacts on the profit margin of the food industry and then positive impacts. The reason for this change is the mismatch between food supply and consumer demand caused by upgrading dietary habits. The shift from negative to positive impacts is also the process in which new products are produced and then accepted by the market, and finally growth of sales profit is achieved. This result verifies the finding of Dania et al. .The impacts of CU on food retail have significant volatility. Especially when zoonotic infectious diseases occur , the positive impacts on food retail sales are significantly reduced. This phenomenon is affected by consumers\u2019 attitudes toward the risk perception, which is consistent with the conclusions of Lobb et al.  and SeegCU increases the export of primary agri-products and food products by increasing the exchange rate of foreign currency to CNY, and increases the import of primary agri-products and food products by stimulating consumption.The impacts of DE on the purchase price of primary agri-products are greater than that on the sales price and consumption price. Agricultural production has features of periodic planting and the concentrated harvest, so the occurrence of natural disasters has relatively great impacts on the price of primary agri-products. Food enterprises can reduce the transmission of domestic agri-product price fluctuations to food prices through imports, so DE has smaller impacts on the sales price of food enterprises.With the end of the disaster and the implementation of agricultural protection policies and risk response measures, the production value of primary agri-products, the production value, and profit margin of food enterprises will gradually recover, which is consistent with Zhan and Chen . AlthougDE changes consumers\u2019 consumption expectations and increases food reserve in the short term to ensure future living needs, which lead to increased food retail. Consumption of reserved food after the disaster leads to a decline in food retail.DE significantly reduces exports and increases imports of agri-products and food products in the short term. After the disaster, exports of agri-products and food products experience restorative growth, and their imports declined significantly. With the continuous improvement of agriculture-related policies, agri-products trade  is gradually affected by policies, while the impacts of DE are gradually reduced.The impacts of PHE on the purchase price of primary agri-products are smaller than that on sales price and food consumption price, which is consistent with Nordhagen et al. . This diPHE has relatively small impacts on the production value of primary agri-products, mainly due to the series of agricultural support and protection policies, as well as the emergency prevention and control measures. PHE first has great negative impacts on the production value and profits of the food enterprises, and then have positive impacts. Especially after the occurrence of zoonotic infectious diseases, the negative impacts on the production value and profit margin increase, and the positive impacts decrease. After the pandemic, the production value recovers rapidly, but sales profit margin recovers slightly, which may lead to the long-term loss of enterprises, and it is consistent with Nordhagen et al. . TherefoThe impacts of PHE on food retail sales are much greater than that on the production value, price and profit margin of the food industry, reflecting that China\u2019s food supply chain has a certain resilience, and this result verifies the findings of Fan et al. . MeanwhiPHE significantly reduces export and increases imports of agri-products and food products in the short term, but export of agri-products and food products experiences restorative growth after the pandemic. Import of food products can be reduced during the global infectious diseases (such as COVID-19 in 2020), and the terms of trade will be more stringent (such as strengthening quarantine and screening import markets), because of concerns over the safety of imported goods.This study divided the main sectors of the food supply chain and fully considered the time-varying quality, complexity, and high-frequency occurrence of external uncertainties as the entry points, then selected a large number of monthly indicators to measure the external uncertainties, and used three-dimensional impulse responses based on the TVP-FAVAR-SV model to depict the dynamic impacts of external uncertainties on food supply chain. The impacts of combination of various uncertainty elements and the transmission of these impacts among various sectors of the food supply chain are the focus of this study. It was found that the impacts of all external uncertainty elements were significantly different: social and natural public emergencies had great impacts on aspects of retail sales, profit margin, and international trade, while economic uncertainties had great impacts on aspects of price, production, and international trade. It was also found that the combination of different external uncertainty elements aggravated or reduced the risks of food supply chain. With the continuous improvement of the agricultural policy system, the negative impacts of economic uncertainties on the food supply chain were gradually diminished, and the appropriate liquidity improved the positive impacts of relevant policies. The integrated emergency measures and complete market systems reduced the negative impacts of disaster emergencies and public health emergencies on the production sector, and shortened the time for food enterprises to resume operation and end the profit losses. Unlike risks, some uncertainty elements had both positive and negative impacts in the whole sample period. The magnitude and direction of the impacts of various uncertainties in different periods had time-varying characteristics, and the time-varying characteristics were caused by the impacts of combination of various uncertainty elements and the transmission of these impacts.This paper recognizes and acknowledges that some limitations are still in variable selection and content analysis when analyzing the dynamic impacts of external uncertainties on the food supply chain, which provides approaches for future research. When identifying the external uncertainties of the food system, the paper tried to summarize the socio-economic environment and natural environment, and finally selected many indicators from public health emergencies, disaster emergencies, and economic uncertainties to measure the complexity of external uncertainties. However, the uncertainty risks of the food system are multifaceted, and especially in recent years, the pressure of resources, environment, and energy consumption has seriously challenged the sustainable stability of the food system. This paper is short of risk analysis from the aspects of resources, environment, and energy. Moreover, the Chinese government has implemented a series of policies and measures to achieve the carbon peak and neutrality goals. These policies and measures also have long-term and important impacts on the sustainable development of the agri-food system. However, this paper is short of the uncertainty analysis of relevant policies and measures. ITo comprehensively analyze the impacts of external uncertainties to ensure the sustainable stability of the food system, future research could focus on: (1) selecting impact factors from energy and environment as important indicators and summarizing them into the external uncertainty system, such as energy prices, production, trade, as well as carbon emissions, land use, agricultural material consumption, and other elements; (2) using a variety of quantitative methods to study the impacts of relevant policies and measures implemented by the Chinese government on the food system, such as data crawling technology, event and text analysis method, etc., to achieve multi-scale research on the sustainable security of the food supply chain."}
+{"text": "High-quality talent cultivating Internet of Things (IoT) Engineering is the basis for the rapid development of IoT technology. To train high-quality application-oriented IoT technical talents, guided by educational psychology, this article conducts in-depth research; analyzes the characteristics of IoT Engineering; makes professional talent cultivating programs and cyclical adjustment plans; builds a high-quality teaching system based on the professional knowledge system of the IoT; explores the \u201cspiritual level\u201d and \u201cpsychological level\u201d characteristics of teachers and students in teaching; highly integrates \u201cIndustry-University-Research-Competition\u201d from the perspective of students, teachers, and colleges; infiltrates positive psychological cues appropriately; formulates the construction method of the \u201cstudent teaching assistant\u201d auxiliary system to enhance the efforts to promote learning by learning; and finally innovates the talent cultivating system for the IoT Engineering. The implementation results show that the students trained by this system have a solid foundation of knowledge related to IoT Engineering and strong engineering practice application, adaptability, and innovation ability. Based on sensing technology, information recognition technology, communication technology, and control technology, the Internet of Things (IoT) realizes the connection among things and is one of the global strategic emerging industries. At the fifth session of the 11th National People\u2019s Congress on 5 March 2010, the IoT was written into the Government Work Report for the first time. Since then, the industrialization process of IoT technology has been fully promoted, combining the development strategies of energy conservation, consumption reduction, green and low carbon with the sustainable development industry, food safety, disaster monitoring, modern logistics, intelligent transportation, and other industries as the entry point. The research and development of IoT technology promotes the development of devices, chips, materials, services, and other industries; forms an industrial cluster effect; promotes the integration of the undertaking of traditional industries and the independent innovation of emerging industries; and leads to the enduring demand for IoT technical personnel in the talent market. The talent cultivation of IoT has become the key to the sustainable and rapid development of the IoT.To train technical talents for the IoT, universities in China have started to offer the major of IoT Engineering successively since 2010, and our university (Luoyang Institute of Science and Technology) also added the undergraduate major of IoT Engineering in 2014. Compared with the traditional established major, this major is an interdisciplinary subject, involving the integration of computer, automation, communication engineering, and other multidisciplinary knowledge. The development time is short, and the talent cultivation scheme is not mature. Therefore, the talent training system of IoT Engineering must be constantly improved and perfected based on the development needs of society and school .Educational psychology  mainly slanding.zhaopin.com and 51job.com), we can learn the types and levels of current demand for IoT talents, get the multidisciplinary demand for IoT technology, and determine the industry fields for talent cultivation. According to the college development plan, the key points of talent cultivation are determined: talent cultivation of IoT technology with big data in building materials industry. Questionnaires are used to obtain feedback on graduates\u2019 employment, such as industry and salary. Shortcomings of existing talent cultivation programs are found while exploring the space for improving the quality of talent cultivation.In view of the characteristics of interdisciplinary integration, the development of talent cultivation programs for IoT Engineering majors needs to fit social needs, school positioning, and teacher-student status analysis based on educational psychology. By investigating official websites of government departments, public institutions, large enterprises , and recruitment websites Meet the needs of the development of innovative talents, with all-round development of both political integrity and ability, showing good humanistic quality, professional ethics, and social responsibility.(2)Have a solid mathematical foundation and a good basis of natural science.(3)Master the professional knowledge and skills of the IoT; be able to analyze, research, and design solutions; solve the application problems of the IoT in the research and development of building materials with big data; have strong engineering practical ability and unique thinking mode of the IoT Engineering; and become the technology backbone.(4)Have engineering organization ability, teamwork ability, and international vision.(5)Have lifelong learning ability and be able to update and expand their knowledge and ability through appropriate ways.Curriculum system is the core of higher education, reflecting social needs, scientific knowledge, and ability development . The conConstructivism holds that \u201clearners do not transfer knowledge from the outside world to memory, but construct new understandings based on existing experience through interaction with the outside world.\u201d To cultivate high-quality application-oriented talents, the curriculum system must be able to cultivate students with correct world outlook, outlook on life, and values.To cultivate students majoring in IoT Engineering to have a good sense of appreciation, be rich in knowledge and experience and get excellent ability, at present, the curriculum system of this major should include four categories, namely, general courses, basic engineering courses, professional basic courses, and professional courses, as shown in General courses mainly include Ideological and Political Theory Courses, Physical and Mental Development Courses, Language and Tool Courses, and Quality-Oriented Education Elective Courses. At present, the Ideological and Political Theory Courses in our college include Morality and Law, Basic Principles of Marxism, Introduction to Mao Zedong Thought and the Socialist Theory with Chinese Characteristics, and Outline of Contemporary and Modern Chinese History. Physical and Mental Development Courses include Physical Education, Military Theories, Mental Health Education for Undergraduate, Career-Ready Skills with Innovation, and Entrepreneurship Practice. Language and Tool Courses include College English and College Applied Writing. Quality-Oriented Education Elective Courses include courses about humanities and art, social science, natural science and technology, economic management, and general development of foreign languages .Basic engineering courses for IoT major mainly include mathematics and physics. Mathematics courses include Advanced Mathematics I, Linear Algebra I, Probability and Statistics I, and Discrete Mathematics. Physics courses include College Physics II and College Physics Experiment.Professional basic courses mainly focus on the basic theory and program design of IoT technology, aiming to train the student to gain IoT technology learning foundation and prepare for the study of knowledge required by the design and development of IoT systems. This type of course covers Electrical and Electronic technology, Program Design of C Language, Computer Organization and Architecture, Data Structures, Database Systems and Applications, Computer Networks, Operating Systems, and Digital Logic.Professional courses are divided into professional required courses and professional elective courses, which mainly train students to have the ability of IoT system design, development, management, and maintenance; to serve the IoT application in building materials industry; and to provide direction for employment and further study. Professional required courses for IoT mainly include Specialty Introduction for IoT Engineering, Java Programming, Information Security, IoT Communication Technology, Embedded System, IoT Identification Technology (college-enterprise), IoT Application Software Development for Building Materials Industry, and IoT Engineering Design and Implementation. The professional elective courses are divided into two directions: Direction One (Cloud Computing-IoT): Cloud Computing Technology (college-enterprise), Big Data Technology, Smart City System, and IoT VR Design; Direction Two : Artificial Intelligence, Linux-C Programming, IoT Middleware Development, and Smart Agriculture System.At present, the curriculum system of IoT Engineering major in our college highlights the knowledge that students of this major should master in quality-oriented education and engineering education. Professional basic courses constitute the most core basic knowledge of this major, and the setting of professional courses reflects the common requirements of IoT technology application ability  and the training focus of IoT Engineering major in our college.Our college is positioned as application-oriented, and its teaching activities focus on \u201capplication,\u201d aiming at cultivating high-quality application-oriented talents with strong social adaptability and competitiveness. IoT Engineering itself is closely related to practical application, so practice teaching is the key to make students digest kinds of theoretical knowledge  and applThe application ability of students majoring in IoT Engineering includes engineering practice ability and innovation and entrepreneurship ability . Around The IoT Comprehensive Experiment Center of our college is one of the Experimental Teaching Demonstration Centers in Henan Province. It has an IoT experience experiment platform, a communication experiment system, a smart experiment platform of agricultural machinery, Cisco network routers and switches, high-performance servers and computers, optical fiber fusion splicers, IoT Comprehensive testers, FLUKE network testers, and embedded experiment boxes and provides experiment environment for professional experiments such as a single-chip microcomputer, embedded system, RFID, wireless sensor networks, communication and switch, upper computer, cloud, and AI. We utilize educational psychology to set up three-level experiment courses. These courses incorporate the application of the IoT in the building materials industry, smart agriculture, and advanced manufacturing industry. Step by step, they can mobilize the initiative of students in the experiment/experimental training and can cultivate engineering practice ability in cement production simulation, smart livestock farm, industrial Internet, and other industries, highlighting the characteristics of the IoT Engineering major of our college and the good teaching quality.Experiment is the foundation for cultivating ability to apply knowledge flexibly, and practical training is the basis for students to improve their personal abilities and possess engineering practice and innovation/entrepreneurship capabilities. By rationally setting up on-campus practical training courses, using educational psychology scientifically to analyze students\u2019 practical training status and arrange corresponding practical training details, students can consolidate their learned knowledge and cultivate their practical ability in the actual trial production environment. Based on educational psychology, our college guides students to contact, understand, and serve the society through reasonable planning of corporate training, IoT project engineering design, and graduation project; and cultivate students\u2019 IoT comprehensive practical ability, especially the service and innovation capabilities of IoT in building materials industry with big data. Our college has set up a practical training center for IoT and further built practical training and scientific research platforms such as \u201cCisco Network Technology Institute,\u201d \u201cHuawei Institute of Information and Network Technology,\u201d \u201cRenesas Electronic Joint Laboratory,\u201d and \u201cShuguang Ruiyi Big Data Innovation Center.\u201d At the same time, our college has signed eight off-campus practice bases with Shenzhen Xunfang Communication Technology Co., LTD., Wuxi NIIT (China) Institute of Service Outsourcing, and other related enterprises, to ensure the quality of on-/off-campus practical training courses in terms of software, hardware, and teachers.\u201cIndustry-College-Research-Competition\u201d (ICRC) refers to the cooperation between colleges and enterprises , which iTo achieve the deep integration of ICRC Student perspective: In four years of college, complete a scientific and technological research in the field of IoT independently, complete several experimental projects related to the needs of enterprises and competition, participate in scientific research activity for teachers at least 1 time, participate in enterprise IoT projects at least 2 times, complete a comprehensive innovative experimental project cooperatively, and participate in IoT-related competition at least 1 time.(2)Teacher perspective: Link their own scientific research with enterprises College perspective: Establish good and stable college-enterprise cooperation with IoT-related enterprises, take the market demand as the guidance, serve Luoyang economy and building materials industry, explore the cultivation mode based on the ICRC integration for the training of high-quality applied talents, improve multi-evaluation subsystem reflecting the characteristics of ICRC with respect to the curriculum system, teaching team, college-enterprise joint practice bases and competition training mode, and construct the talent cultivation subsystem of ICRC integration, carrying out efficient and high-quality teaching work.The relevant theories of educational psychology point out that the teacher\u2013student relationship is the most basic and important interpersonal relationship when implementing teaching activities, and the teacher\u2019s attitude toward students affects the quality of teaching directly. Therefore, the cultivation of high-quality application-oriented talents is dependent on the harmonious teacher\u2013student relationship and the smooth development of student-centered teaching activities . At presBy studying the cooperative learning theory in educational psychology, our college has set up a mechanism \u201cStudent Teaching Assistant (STA)\u201d . This meCourse assistants are responsible for maintaining classroom discipline; supervising pre-class preview, after-class review, and homework; and organizing flipped classrooms. CAs\u2019 solid efforts in learning are conducive to creating a good atmosphere for class learning. They assist teachers to detect students\u2019 psychological changes timely; promote healthy competition in learning in the class; encourage all students to develop good habits for listening to classes, previewing and reviewing; improve the utility of flipped classroom teaching activities such as teaching video watching and cooperative discussion; organize curriculum knowledge of IoT Engineering in series by mind mapping and other methods; and organize course knowledge competition. CAs give full play to the role of mentoring and guiding poor students and make progress together. They are selected within the same grade. Each course has 3\u20134 CAs, and each CA is responsible for a study group of less than 10 students. With the help of CAs, the phenomenon of \u201cphubber\u201d in class, homework copying, etc., can be reduced. Good college study habits can be established, and students are more active and solid in learning the theoretical knowledge related to IoT, which is many, complex, and difficult.In addition to experimental classes, our college has an open system to facilitate students to use the laboratory to complete practical tasks after class. One role of PA is the laboratory-assisted management. PAs assist teachers to urge students to maintain a good experimental environment and follow laboratory discipline consciously, and this mechanism cultivates students\u2019 sense of ownership about the laboratory. Another role of PA is to assist teachers to guide various IoT-related experiments, internships, and practical training courses. PAs take the initiative to solve common problems in practice for other students, promote mutual assistance among students, discover and summarize problems, and give feedback to teachers to solve them in a timely manner. PAs are produced from the students in senior grades and the same grade, among which the PAs from senior grades assist in the practice and training and the PAs from the same grades assist in course experiments. With the help of PAs, the interaction between teachers and students is enhanced, so that detailed practical guidance can cover each student, which is conducive to the cultivation of students\u2019 practical ability.Competition and research assistants are mainly responsible for the collection and promotion of competition information, the auxiliary organization of competition training, the leading participation of enterprise projects, and teachers\u2019 scientific research projects (such as IoT software coding and project data collation). They assist teachers to optimize the allocation of personnel and resources for competition and scientific research and shorten the distance between competitions/projects and students. Besides, they take themselves as examples to drive all the students majoring in IoT to learn the frontier knowledge. The selection of such assistants is based on the awards of the competition, and their responsibilities are determined according to the award level. Students with low levels of awards provide introductory training to lower grade students . High-level award-winning students assist teachers in training and guiding IoT technology competitions . In addition, all CRAs participate in the project as team leaders responsible for the implementation of sub-tasks and the management of student members. With the help of CRAs, students are encouraged to form a healthy and upward competitive psychology and stimulate their innovative consciousness. In this way, competitions and participation in scientific research activities can become the norm for the IoT Engineering major, and students can develop their ability to discover, analyze, and solve engineering application problems.In 2014, our college started to recruit students for the IoT Engineering and followed the above methods to build a talent cultivation system. At present, certain results have been achieved in cultivating high-quality applied talents.To check students\u2019 subjective initiative, questionnaires for students\u2019 self-evaluation in learning are released at the 1/4 semester, 1/2 semester, 3/4 semester, and the end of the semester.  The scores of the questionnaires from 2014 to 2021 were sorted out, and the results are shown in The execution quality of experiment and practice directly affects the quality of IoT Engineering talent cultivation. Collecting the assessment results of experiments and practice sessions, the average proportions of excellent, good, medium, and poor grades are calculated separately according to Eq. 1 every year from 2015 to 2021, and m and n are the number of courses and practice sessions, respectively; Exp Li and Pra Lj are the number of students who gain grade L in experiments attached to course i and practice session j separately; and Ci and Pj are the number of students attending the course i and practice session j, respectively.where Participating in competitions and teachers\u2019 scientific research is an effective way to enhance the core competitiveness of students. We counted the number of students who take competition and scientific research in IoT Engineering, with results shown in Students are the objects of talent cultivation and the core of teaching activities, and their psychology directly affects the training quality. To this end, we can use educational psychology with student learning psychology as the core to improve the cultivation quality of application-oriented talents in IoT Engineering.The construction of a high-quality application-oriented talent cultivation system for IoT Engineering involves many aspects. We analyze the existing knowledge architecture of IoT technology according to educational psychology. Based on the characteristics of the IoT major, we provide the formulation and adjustment strategies of talent cultivation programs and then put forward the idea of building a high-quality talent cultivation teaching system based on constructivism. Considering the psychological characteristics of teachers and students, we explore the deep integration mode of industry, college, research, and competition. Finally, we construct an STA auxiliary mechanism using a positive energy psychological hint. To sum up, all of these conduct the cultivation of high-quality application-oriented talents for IoT Engineering.The rapid and sustainable development of IoT technology determines that it is a long way to cultivate high-quality application-oriented talents for IoT Engineering. In the future, efforts should be made to integrate educational psychology and teaching practice to obtain more efficient and high-quality methods of training application-oriented talents.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.YN: investigation, writing original draft, data analysis, and method design. HW: applied research in educational psychology, investigation, and method design. BL: editing, writing, checking, and data collection. SY: implementation plan of educational psychology. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "The nanopatterning of bionic materials, performed by means of laser processes that utilize pulsed laser sources with short and ultrashort pulse durations, is a rapidly growing field. The method\u2019s applications are varied, being used mainly to tailor special industrial, medical, and scientific applications. This process is significantly driven by the exciting properties of micro- and nanopatterned materials found in natural biological species. These include being self-cleaning, capable of adapting color and reflectivity, the possession of pronounced adhesive and anti-adhesive properties, the aptitude for wetting and directional fluid transport, reduction of wear and friction, control of cell growth, and antimicrobiotic properties .This Special Issue, entitled \u201cNanopatterning of Bionic Materials\u201d, represents an extension of the former review and includes a collection of recent top-quality articles in this research area. Particular attention has been devoted to the functionalization of medical implants and other surfaces, relevant for biomedical applications owing to the widespread need for improved approaches in medicine in our aging society. A comparable scenario applies for miniaturized sensors concerning the sensitivity of small traces of biologically hazardous or metabolic gases.(i)Functionalization of Ti-based medical implants by means of laser-induced micro- and nanostructures for cell repellence as well as for osteoblastic proliferation and differentiation ,3,4;(ii)Polymer surfaces with antimicrobiotic and antiadhesive properties induced by laser-induced periodic surface structures (LIPSS) in connection with nanofibers or nanowires ,6,7;(iii)The generation of novel hybrid carbon nanotube materials for biosensing applications by means of laser-induced forward transfer (LIFT) .Herein, only original research articles have been considered for publication. The present Special Issue includes contributions on the following research topics:Overall, I am grateful to all the authors for their fine contributions to the present Special Issue, and hope that the published studies will pave the way for the novel real-world applications of nanomaterials in medicine and biotechnology."}
+{"text": "A 34-year-old female was referred to our department, complaining of multiple asymptomatic lesions that appeared two weeks previously. The patient had active nephritis with nephrotic syndrome and was treated with immunosuppressive therapies. Physical examination revealed multiple well-circumscribed rounds of flat brownish plaques with slightly elevated borders, some of which were covered by scales. The number of lesions was nine in total. Skin biopsy specimens showed dyskeratotic cells in the thinned epidermis with cornoid lamella, and the absence of a granular cell layer. The development of porokeratosis was considered to be related to immunosuppressive therapy or the activity of nephritis. Dear Editor,A 34-year-old female was referred to our department, complaining of multiple asymptomatic lesions that appeared two weeks previously. Physical examination revealed multiple well-circumscribed rounds of flat brownish plaques with slightly elevated borders, some of which were covered by scales . The numEruptive porokeratosis is characterized by rapid onset of porokeratosis, which occasionally presents with more than 100 lesions involving multiple regions, in association with paraneoplastic, immunosuppressive, inflammatory, and other conditions.None declared.Masato Ishikawa: Designed the study; performed the research and contributed to analysis and interpretation of data; wrote the initial draft of the manuscript; read and approved the final version of the manuscript.Toshiyuki Yamamoto: Designed the study; assisted in the preparation of the manuscript; read and approved the final version of the manuscript.None declared."}
+{"text": "Vector-borne diseases (VBDs) are a major threat to human health. Climate change has a significant impact on VBDs. To clarify the complex effects of climate change on VBDs, we concluded the effects of climate on the transmission and spread of VBDs from an ecological perspective and summarized VBD changes in response to climate change, specifically including: the nonlinear effects of local climate  on VBD transmission, especially temperature showing n-shape effects; regional climate (the El Ni\u00f1o\u2013Southern Oscillation and North Atlantic Oscillation) has time-lag effects on VBD transmission through indirect impact on local climate; and the u-shaped effect of extreme climates can lead to the geographical spread of VBDs. In terms of non-climatic factors, land use and human mobility through the interactions with climatic factors, will affect transmission and spread of VBD. We further explored the uncertainty of the impact of climate change on VBDs under the COVID-19 pandemic. A systematic understanding of the impact of climate change on the transmission and spread of VBD can provide insights and suggestions for future research on VBD prevention and control.Climate change affects ecosystems and human health in multiple dimensions. With the acceleration of climate change, climate-sensitive vector-borne diseases (VBDs) pose an increasing threat to public health. This paper summaries 10 publications on the impacts of climate change on ecosystems and human health; then it synthesizes the other existing literature to more broadly explain how climate change drives the transmission and spread of VBDs through an ecological perspective. We highlight the multi-dimensional nature of climate change, its interaction with other factors, and the impact of the COVID-19 pandemic on transmission and spread of VBDs, specifically including: (1) the generally nonlinear relationship of local climate  and VBD transmission, with temperature especially exhibiting an n-shape relation; (2) the time-lagged effect of regional climate phenomena (the El Ni\u00f1o\u2013Southern Oscillation and North Atlantic Oscillation) on VBD transmission; (3) the u-shaped effect of extreme climate  on VBD spread; (4) how interactions between non-climatic (land use and human mobility) and climatic factors increase VBD transmission and spread; and (5) that the impact of the COVID-19 pandemic on climate change is debatable, and its impact on VBDs remains uncertain. By exploring the influence of climate change and non-climatic factors on VBD transmission and spread, this paper provides scientific understanding and guidance for their effective prevention and control. Climate change, which has affected the world since the last century, has caused a general rise in temperatures over the period of 1906\u20132005  and poseThe ten publications in this Special Issue illuminate the impacts of climate change on ecosystems and human health from different perspectives in diverse disciplines, including phytology, biology, epidemiology, pathology, and molecular biology. In phytology and biology, the geographical ranges of plants and animals have been shown to be affected by climate change ,7,8. In As a climate-sensitive type of disease, VBDs are assessed on a global scale with the aim of shedding light on possible future trends, particularly given the increased likelihood of climate change . The impThe influence of climate factors on the transmission and spread of VBDs can be considered at the levels of local climate, regional climate, and extreme climate. Local climate, represented by temperature, rainfall, and wind, mainly affects the transmission of VBDs by affecting their vectors ; regionaThe effects of local climate factors  on VBD transmission are generally nonlinear. These factors can affect the distribution range, population dynamics, and virus transmission ability of vectors , and henThe non-linear effect of temperature on VBD transmission generally follows an n-shape . Under sPrecipitation has also demonstrated a nonlinear effect on VBD transmission in many studies. A suitable level of precipitation may be beneficial for the formation of vector breeding habitats , especiaHigh wind speeds hamper mosquitos in their flight, can decrease the density of mosquitoes, and make them less likely to stand on and bite their hosts. An example to support this view is the finding that high wind impeded the rate of West Nile virus transmission; conversely, there is no obvious negative trend in the effect of low wind speed on mosquitoes. ,45. ThisClimate change has an important impact on the transmission of vector-borne diseases, which in general will expand the climate-adaptive transmission zone of vector-borne diseases. In Europe, climate change is likely to expand ticks into higher latitudes and altitudes, thereby increasing the incidence of tick-borne diseases . In SoutRegional climate mainly exerts its influence on VBDs through local climate factors, which in turn affect the ecological habitat, distribution, and population dynamics of the vectors , and henNumerous studies have concluded that local climate has a time-lag effect on VBD transmission in the short term. For rodent-borne diseases, many studies have also demonstrated a time-lag effect of regional climate, such as on renal hemorrhagic fever ,57, leptTime-lag effects of regional climate have wider ranges and longer timespans than local climate effects, and hence are more relevant to making predictions for disease prevention in advance. ENSO is the most significant example of quasi-periodic climate variability on an interannual scale that can affect weather all over the world . The patWith the frequency of climate extremes increasing as climate change accelerates, it is increasingly important to understand the impact of climate range edges and limitations on VBDs A. Most eDifferent types of extreme climate events  have different effects on the distribution expansion of VBDs. The impact of heat waves on mosquitoes depends on the onset time and duration; such events usually promote mosquito population growth in early developmental stages, but often suppress the entire life cycle . Thus, uAedes aegypti can expand its distribution in mountainous areas by up to 4215 km2, which would put over 12,000 people at risk of disease [Ixodes ticks in Europe, especially Northern and Central Europe; however, extreme weather is expected to expand the distribution of Ixodes ticks in Europe by 3.8% during 2040\u20132060, and tick-borne encephalitis (TBE) is expected spread to high altitudes and latitudes [Thus, in the context of climate change, climate extremes are increasingly expected to create additional risks and possibilities for the spread of VBDs ,89. When disease . In Indi disease . Extremeatitudes . In New atitudes .Beyond climate factors alone, the interactions of non-climatic factors (land use and human mobility) and climate factors are important to consider for their impacts on VBD spread ,28,94. The interaction of land use and climate change will provide opportunities for pathogen exchange among geographically isolated wildlife, and thus in some cases will promote disease spillover . ProjectHuman mobility is also a major factor in the global spread of VBDs ,97. With2 emissions was found to weaken the aerosol cooling effect, which can lead to warming [The impact of the COVID-19 pandemic on climate change is debatable in the short term ,100,101; warming . These pBesides climate change, lack of vector testing and control activities ,105,106 However, lockdown policies have greatly reduced imported cases and blocked sources of VBD transmission ,111,112.In this paper, we summarized the different impacts of multiple climatic factors on the transmission and spread of VBDs in the context of climate change. Local climate exerts non-linear direct effects, resulting in rapid transmission in suitable conditions and decline in an unsuitable environment, with local temperature in particular showing a clear n-shape. Regional climate has an indirect impact on VBDs, affecting transmission through its effects on local climate, which by necessity produces a certain time-lag for the effect on disease transmission. Extreme climate events can increase the spread of disease, leading to the expansion of VBD distributions. Moreover, land use and human mobility have an important interaction effect on VBD spread, increasing the possibilities for spread and spillover. The impact of the COVID-19 pandemic on how climate change affects VBD transmission and spread is yet uncertain.Quarantine policies during the COVID-19 pandemic successfully blocked the import of VBD cases; this effective prevention and control policy is worth adopting and applying in the field of VBDs. Meanwhile, the impact of COVID-19 on climate change is controversial, and its potential effect on VBDs may gradually become clear in the future. Accordingly, it remains necessary to further explore the potential of COVID-associated climate change to drive effects on VBDs. Meanwhile, the improvement of surveillance systems in relation to the COVID-19 pandemic and the construction of a surveillance network are also worthy of application in VBD surveillance. With the continuous improvement of monitoring systems, it also becomes necessary to adopt methods from the fields of machine learning and artificial intelligence to handle large databases with complex algorithms in the future.There is still a lot of research worth undertaking with regard to climate change and VBDs. One important research direction is to integrate multidisciplinary factors to analyze the impact of climate change on VBDs, especially with reference to the fields of computer science, zoology, entomology, ecology, and epidemiology. Through the integration of multiple disciplines, we can not only better understand the impacts of climate change on VBDs, but also develop a deeper understanding of the occurrence and development mechanisms of these infectious diseases. Such findings could contribute to achieving a better understanding of how climate change drives effects on VBD risk and spread, thereby improving the prevention and control of VBDs and so improving human health."}
+{"text": "Recognizing an urgent need to understand the dynamics of the pandemic\u2019s severity, this longitudinal study is conducted to explore the evolution of complex relationships between the COVID-19 pandemic, lockdown measures, and social distancing patterns in a diverse set of 86 countries. Collecting data from multiple sources, a structural equation modeling (SEM) technique is applied to understand the interdependencies between independent variables, mediators, and dependent variables. Results show that lockdown and confinement measures are very effective to reduce human mobility at retail and recreation facilities, transit stations, and workplaces and encourage people to stay home and thereby control COVID-19 transmission at critical times. The study also found that national contexts rooted in socioeconomic and institutional factors influence social distancing patterns and severity of the pandemic, particularly with regard to the vulnerability of people, treatment costs, level of globalization, employment distribution, and degree of independence in society. Additionally, this study portrayed a mutual relationship between the COVID-19 pandemic and human mobility. A higher number of COVID-19 confirmed cases and deaths reduces human mobility and the countries with reduced personal mobility have experienced a deepening of the severity of the pandemic. However, the effect of mobility on pandemic severity is stronger than the effect of pandemic situations on mobility. Overall, the study displays considerable temporal changes in the relationships between independent variables, mediators, and dependent variables considering pandemic situations and lockdown regimes, which provides a critical knowledge base for future handling of pandemics. It has also accommodated some policy guidelines for the authority to control the transmission of COVID-19. Coronavirus disease 2019 (COVID-19) is a public health crisis that has afflicted more than 225 countries all over the world ,9,10,11.Furthermore, the socioeconomic makeup and institutional structure of a country can influence pandemic severity, human mobility, and the rigor of various lockdown measures. Our previous research investigated the complex relationships between the COVID-19 pandemic, lockdown measures, and people\u2019s social distancing and mobility behaviors . HoweverIn the preceding study , we empiConsidering that the early effort was limited by the cross-sectional nature of the analysis, where each population sample was observed at a single point in time, the present study situates the clinical, behavioral, social, and institutional aspects of the pandemic in a broader temporal context and examines sampled countries repeatedly at different periods to detect seamlessly any changes in the variables and parameters in different phases of the pandemic. Moreover, the availability of time-series data would ensure the dynamic properties and stability of our model, which is critically important to assess the vigor of the pandemic and better empower the world for effective action under changing socio-politico-medical contexts. Despite meaningful insights from the previous study after a few months of the pandemic, a longitudinal study comprising of time series data is necessary to capture the temporal aspects of the pandemic, how they evolve and influence the mobility of the people, and how people adjust with the changing environment. This spatial-temporal data analysis is critical to mitigating the pandemic efficiently by taking data-driven decision-making .What are the impacts of various lockdown measures on reducing people\u2019s mobility patterns and the severity of the pandemic?What are the consequences of the pandemic severity on mobility patterns and, therefore, on the practice of social distancing of people?What are the impacts of human mobility on the severity of the pandemic?What are the effects of socioeconomic factors of domestic populations and institutional arrangements and dispositions on population mobility and on the pandemic severity?Thus, this longitudinal study aims to investigate the evolution of complex relationships between the incidences of the COVID-19 pandemic, lockdown measures on populations, and their social distancing and mobility behaviors throughout the time of the pandemic from March 2020 to February 2021 across 86 countries of the world. Thanks to the integrated analytical framework of SEM, the following four research questions are formulated to understand the evolution of these intertwined relationships in different waves of the pandemic:The rest of the paper is organized as follows. A number of studies have investigated the complex relationships between the COVID-19 pandemic, lockdown measures, social distancing, and human mobility patterns. The following sub-sections summarize and discuss the associations between the conditions related to this pandemic after critically reviewing and analyzing previous studies.The COVID-19 pandemic has drastically changed mobility systems due to enacted lockdown and confinement measures, social distancing practices, and personal hygiene requirements, most strikingly with an increase in private travel modes  and a decrease in public transport  ,21,22. SHaving compiled mobility data of mobile phone users by country/region/sub-region/city, Apple Inc., Cupertino, CA, USA, has estimated changes in human mobility around the world . CompareMany studies have investigated the impacts of COVID-19 on human mobility patterns in more detail. For example, Bucsky  calculatSimilarly, observing travel patterns of 1439 people in Switzerland, researchers in  estimateSome studies also investigated how transport accessibility and human mobility may have stimulated the spreading of the COVID-19 virus. For example, researchers in  quantifiHadjidemetriou, Sasidharan  investigFrom the above discussion, it is conceived that COVID-19 and human mobility influence one another . A higheWhile the fear of infection and of serious health complications has gripped the state of mind of many segments of human societies, lockdown and confinement measures adopted by governments during the COVID-19 pandemic may have tangibly influenced travel patterns of people. A number of empirical studies have investigated and compared the movement of people before, during, and after the lockdown regimes to understand the impacts of NPIs on travel patterns ,37,38,39Saha, Barman  investigResearchers in  investigIn Australia, Beck and Hensher  noticed 2 of 0.998. The model indicated that, after 6 weeks of the lockdown measures, confirmed cases had dropped threefold below the initial level, which sanctions the effectiveness of control measures to mitigate the severity of the pandemic. As a whole, lockdown and confinement measures may play a critical role in curtailing the transmission of viruses by reducing human mobility, contacts, interactions, and social gathering. Several studies have investigated the effectiveness of lockdown and confinement measures for travel restrictions on COVID-19 transmission in cities and regions. For example, applying a data-driven epidemic model, researchers in  investigIn the same geographical context of India, Gupta, Mohanta  used an Oum and Wang  determinLockdown and confinement measures tend to curtail human mobility immediately, however, they may do so differentially according to trip purposes. In addition, incubation would delay the damping of infection cases and deaths by one or two weeks , hence, The socioeconomic status of people, living environments, and community structures are very important factors in viral diffusion. Much research has been conducted on the socioeconomic factors of COVID-19 transmission. These studies also investigated the temporal and spatial dependence in the associations of these factors with COVID-19 transmission. For example, Andersen, Harden  studied Maiti, Zhang  exploredSome studies also investigated the impacts of urban form  on COVID-19 transmission. For example, Carten\u00ec, Di Francesco  found thSome studies have also evaluated COVID-19 incidence in different environmental and climatic conditions. For example, researchers in  quantifiHowever, adjusting for city-level socioeconomic and disease control factors , researchers in  found onJust as the COVID-19 pandemic is conditioned by socioeconomic and spatial factors, so may human mobility, including aspects of travel mode choice, travel distance, and travel time. Some studies also investigated the variations in the mobility of people from diverse sociodemographic backgrounds and geographical contexts. For example, Molloy, Schatzmann  observedCollecting travel flow data from 1436 administrative areas of mainland France, researchers in  noticed Based on the comprehensive review of the extant literature summarized above, a conceptual framework is developed to study the relationships between lockdown measures, mobility patterns, pandemic severity, and socioeconomic and institutional factors of countries across all world regions . The conTo test and validate the conceptual model internationally at the scale of countries and determine the relative strength of the complex relationships between the factors outlined in Data related to changes in human mobility due to lockdown measures  were collected from Google Mobility Reports ,75. ThisThe total daily number of coronavirus infection cases and death cases for the study period were sourced from Our World in Data, a research project at the University of Oxford . They coSEM is used to investigate the causal relationships between socioeconomic and institutional factors, lockdown variables, coronavirus infection and death rates, and social distancing measures and validate the model depicted in Human mobility : TS, RR, WP, and RDPandemic severity: l_case and l_deathLockdown measures: NL, WPC, SH, and SISocioeconomics and institutional factors: MA, AGE65, KOFGI, AE, SE, HE, FS, EI, and IDV.Based on exploratory factor analysis (EFA) and extant theories reviewed in the previous section of this article, latent dimensions are created to reduce dimensions and easily understand the data and represent underlying concepts. The following four latent dimensions are constructed: Moreover, a path diagram is constructed to graphically represent the interdependencies of the independent variables, mediators, and dependent variables in the model specification. Finally, a set of fit indices  are estimated to establish the goodness-of-fit of the model. Two models evenly spaced on the timeline are estimated from each month from March 2020 to February 2021, to capture the temporal aspects of the pandemic, how they evolved and influenced the mobility of people, and how people learned and adjusted to the changing environment . Hence, The models were calibrated using the SEM Builder on the STATA 15 platform . The maxThe robustness of the calibrated models was assessed with several goodness-of-fit statistics, as presented in The Chisq/df values of all models presented in The direct, indirect, and total effects of lockdown and confinement measures on human mobility  from 17 March 2020 to 28 February 2021 are depicted in In addition to their direct effect on social distancing patterns, lockdown measures can also have an indirect impact  on humanThe impacts of lockdown and confinement measures on each of the factors of human mobility patterns  can be estimated by the same token d. OveralConsidering the direct and indirect effects discussed so far, The impacts of COVID-19-related lockdown and confinement measures on overall pandemic severity, COVID-19 confirmed cases, and deaths, are presented in The direct, indirect, and total effects of the pandemic on human mobility over the study period are captured in The indirect impact b of the Drilling down deeper into human engagement in various activities, Combining direct and indirect impacts, The indirect impact b of humaCombining direct and indirect impacts, the overall trend c shows tThe direct, indirect, and total effects of socioeconomic and institutional factors on social distancing  are presented in The indirect effects b of sociThe total impact of socioeconomic and institutional factors on social distancing measures c shows aThe direct, indirect, and total effects of socioeconomic and institutional factors on pandemic severity are shown in Indirect effects b of sociThe overall impacts c of sociConsidering the direct and indirect effects and their temporal variation, this study reported a negative association between lockdown measures and human mobility at the onfall of the pandemic from March 2020 to mid-May 2020. People maintained strong social distancing  when the government imposed strict lockdown measures and restrictions on mobility. On the other hand, citizens defied social distancing practices when authorities eased lockdown measures between mid-May and mid-October 2020, and they aspired to go back to normal life and break the dullness of their confined life. However, a further reduction in human mobility was observed from November 2020 to mid-January 2021 due to the reinstatement of lockdown measures induced by the sharp rise in coronavirus cases and deaths. Thus, strict lockdown measures significantly reduced human mobility across countries, which upholds the findings from our previous study , where wWe have also shown that lockdown and confinement measures indirectly influence the COVID-19 pandemic by moderating social distancing/human mobility patterns. The study findings indicate that the pandemic severity intensified in some countries from March to May due to the inadequate practice of social distancing and from mid-October to February due to the increase in human mobility induced by relaxed lockdown measures and people\u2019s eagerness to return to normal life. However, the study noticed that adequate and timely adopted lockdown measures reduced the severity of the pandemic from June to mid-October, which corroborates the findings from previous studies ,86,87,88Socioeconomic and institutional conditions encourage people to practice social distancing , considering the greater vulnerability of the elderly, higher treatment costs, higher level of globalization, increasing employment in the service sector, decreasing employment in agriculture, and the degree of independence in national societies. These factors also motivate people to maintain social distancing while the pandemic is more severe and lockdown measures are more strict, considering the greater risk of COVID-19 infection due to fragile public health conditions, higher risk of infection from globalization, and open interactions. Thus, socioeconomic and institutional factors have significant impacts on maintaining social distancing to reduce the severity of the pandemic ,90,91.This study also found a significant impact of socioeconomic and institutional factors on the severity of the pandemic. Considering direct and indirect impacts, we observed that socioeconomic and institutional factors increased the severity of the pandemic due to a higher number of elderly people who are physically susceptible to COVID-19, a higher level of globalization, increasing employment in the service sector, a reduction in agriculture, and a higher degree of independence in society. Thus, socioeconomic and institutional factors increase the severity of a pandemic by reducing social distancing practices and increasing human mobility for essential and non-essential purposes ,90,91,92The study found mixed effects of the COVID-19 pandemic  on maintaining social distancing. The negative association at the early stage of the pandemic (March to June) indicates that the increasing severity of the pandemic reduced human mobility and increased time spent at their residence. Early on, people reduced their movement due to lockdown measures and self-awareness induced by fear of infection, which endorses the findings from previous studies ,26,93,94Investigating the impact of human mobility on pandemic severity, we observed a strong negative and sustained impact of mobility/social distancing on pandemic severity throughout the study period compared to the baseline scenario, with the greatest impacts in late December 2020 and early January 2021. The study showed that countries with a sharper reduction in personal mobility had experienced an increased severity of the pandemic due to the absence of other NPIs and the possibility of infection from other family members while home confinement. Thus, maintaining social distance lessens the severity of the pandemic  by reducing human trips to retail and recreations, transit stations, and workplaces and encouraging people to stay at home, which confirms the results from previous studies ,95,96. HGiven the adverse effects of the COVID-19 pandemic, there is a pressing need to understand the root causes of the pandemic, associated risks, and conditions that exacerbate its impacts and promising mitigation measures. This study intended to perform a longitudinal study spanning a great diversity of countries, with data from March 2020 to February 2021. The main objective of this longitudinal study was to explore the evolution of complex relationships between the incidence of the COVID-19 pandemic, lockdown measures on populations, and their social distancing and mobility behaviors in 86 countries. A conceptual framework was developed  to hypotThe study results indicate that implementation of lockdown and confinement measures are necessary to reduce human mobility and encourage people to stay home to control COVID-19 transmission through community infection. However, delayed implementation of lockdown measures, relaxation of lockdown measures, and people\u2019s failure to maintain social distancing and their travel for work and discretionary activities can worsen the pandemic. Thus, it is suggested to evaluate mobility changes after the implementation of lockdown measures, which can guide policymakers on when to implement stricter lockdown measures or ease them, to curtail the diffusion of coronavirus. The study also found that national context defined by socioeconomic and institutional factors influences social distancing patterns and the severity of the pandemic. Additionally, this study observed an intertwined two-way association between the COVID-19 pandemic and human mobility. Higher severity of the pandemic reduces human mobility and on the other hand, higher human mobility increases the severity of the pandemic. However, the impact of human mobility on pandemic severity is stronger and more significant compared to the reverse relationship. Overall, the study displays considerable temporal changes in the relationships between independent variables, mediators, and dependent variables considering pandemic situations and lockdown regimes.Several policy decisions have been outlined based on the analysis. The timely implementation of strict and comprehensive lockdown and confinement measures is critical to mitigating the severity of the pandemic by reducing the movement of people and person-to-person interactions. Moreover, estimating the changes in human mobility during lockdown periods is an effective policy option to evaluate the social distancing patterns of people. If necessary, a targeted campaign among the less responsive communities or individuals could be effective in enhancing social distancing practice, in addition to vaccine administration at a large scale ,100. SinAlthough this study has revealed the changing faces of the pandemic and provides significant policy implications, adopting an SEM using actual longitudinal data  and showing temporal effects in path diagrams could reveal complex causal relationships between COVID-19 pandemic, lockdown measures, and human mobility . Since mThe goodness-of-fit statistics of the models  showed a"}
+{"text": "Decision Support Systems (DSS) are appropriate tools for guiding policymaking processes in Mental Health (MH) management, especially where a balanced and integrated care provision is required.To assess the performance of a MH ecosystem for identifying benchmark and target-for-improvement catchment areas according to the Balanced Care model.The MH provision, distinguishing inpatient, day and outpatient main types of care, has been assessed in the Mental Health Network of Gipuzkoa  using a DSS, integrating Data Envelopment Analysis, Monte-Carlo Simulation and Artificial Intelligence. 13 catchment areas, defined by a reference MH centre, are the units (universe) for the analysis. The indicators for MH ecosystem performance were: relative technical efficiency, stability and entropy, for identifying both benchmarking and target-for-improvement areas. The analysis of the differences between the two groups can be used to design organizational interventions.The Mental Health Network of Gipuzkoa showed high global efficiency scores, but it can be considered statistically unstable . For a global performance improvement, it is recommended to reduce admissions and readmissions in inpatient care, increase workforce capacity and utilization of day care services and, finally, increase the availability of outpatient care services.This research offers a guide for evidence-informed policy-making to improve MH care provision in the main types of care and provide aftercare. The characteristics of the area to be improved are critical to design interventions and assess their potential impact on the MH ecosystem.No significant relationships."}
+{"text": "The coronavirus disease (COVID-19) presented a unique opportunity for the World Health Organization (WHO) to utilise public health intelligence (PHI) for pandemic response. WHO systematically captured mainly unstructured information  for public health intelligence purposes. WHO used the Epidemic Intelligence from Open Sources (EIOS) system as one of the information sources for PHI. The processes and scope for PHI were adapted as the pandemic evolved and tailored to regional response needs. During the early months of the pandemic, media monitoring complemented official case and death reporting through the International Health Regulations mechanism and triggered alerts. As the pandemic evolved, PHI activities prioritised identifying epidemiological trends to supplement the information available through indicator-based surveillance reported to WHO. The PHI scope evolved over time to include vaccine introduction, emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, unusual clinical manifestations and upsurges in cases, hospitalisation and death incidences at subnational levels. Triaging the unprecedented high volume of information challenged surveillance activities but was managed by collaborative information sharing. The evolution of PHI activities using multiple sources in WHO\u2019s response to the COVID-19 pandemic illustrates the future directions in which PHI methodologies could be developed and used. The World Health Organization (WHO) uses public health intelligence (PHI) as one element of its approach to improve population health. A PHI approach encompasses the detection, verification, risk assessment and investigation of events that pose a potential risk to human health, and communicating this information for effective decision making and action -3. PubliEvent-based surveillance involves the detection, triage and verification of new public health threats and changes in ongoing events. Signals, defined as raw data or information with potential acute human health risk , are detOne of the tools used by WHO for PHI to monitor all hazards, including COVID-19, is the Epidemic Intelligence from Open Sources (EIOS) system . Here, pWith the emergence of COVID-19, additional event-specific criteria were established and adapted over time to reflect the pandemic\u2019s evolution and the evolving response needs. These additional criteria were determined as a result of a discussion between a team of WHO epidemiologists who took into account surveillance objectives and scope, the epidemiological context in which the pandemic took place, and available human resources. The criteria were continuously reassessed every several months, or when the characteristics of the pandemic changed. COVID-19 PHI provided a more complete understanding of disease dynamics rather than relying on IBS alone.The EIOS system was one component key for WHO PHI activities during the COVID-19 pandemic. EIOS is an adaptable, user-oriented and constantly evolving web-based system designed to support, augment and accelerate PHI activities. It is used by communities and organisations from national to international levels . The EIOPrior to the detection of COVID-19, the WHO was conducting standardised EBS daily, employing an all-hazards approach and using official government reports, EIOS and other sources of information. Building on this established mechanism at the onset of the pandemic, the WHO intensified EBS to track initial cases and deaths from COVID-19 while an IBS system was being established to complement International Health Regulations (2005) reporting mechanisms. Due to the volume of information, the number of analysts dedicated to screening for COVID-19-related events was increased. In addition, a separate set of filter criteria was created within the EIOS system exclusively for monitoring information related to COVID-19, which reduced the volume of articles on the routine EBS boards. Systematic information sharing for COVID-19-related signals and events was put in place among WHO country offices, Regional offices and headquarters.Since the first detection of COVID-19 cases, the processes and scope for COVID-19 EBS activities have evolved to reflect changing response priorities. During the early months of the pandemic, EBS complemented official COVID-19 case and death reporting according to the International Health Regulations (2005)  and trigThe scope of PHI evolved over time to include vaccine introduction, emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, unusual clinical manifestations, upsurges in cases, hospitalisations and deaths at subnational level. Granular information collected through PHI provided valuable contextual information, which is not always available through IBS sources alone, including the burden on the health system and at-risk and vulnerable groups such as healthcare workers, rapid response teams, indigenous populations, children, pregnant women, elderly people and refugees.The PHI approach combined signals detected via EBS and IBS along with contextual information which provided WHO response teams that supported the assessment and interpretation of COVID-19 epidemiological situations at national and subnational level. Analysts working on COVID-19 PHI activities validated and risk-assessed relevant signals, and communicated them through internal and external information products, including WHO Regional weekly briefing documents and the WHO\u2019s weekly epidemiological update on COVID-19 . In addiBetween 31 December 2019 and 31 December 2021, 4,794 COVID-19 signals were detected and followed up by the WHO at the global level using the EIOS system .In May 2021, the WHO developed a situational alert system to support the early detection of countries where immediate action may help to mitigate the impact of a COVID-19 surge on morbidity and/or mortality. From May 2021 to June 2022, a collaborative, multi-disciplinary, mixed-methods process took place weekly, integrating information and input from teams across the three levels of the organisation. The first stage of the situational alert system employed an automated statistical risk assessment algorithm, based on daily incidence of cases and deaths, to predict COVID-19 disease severity within the near future. This produced an initial alert level for each country. The second stage integrated a PHI-based qualitative context assessment, which provided important information including pressure on the healthcare system; the impact of other concerning epidemiological signals such as concurrent outbreaks and large changes in circulating variants of concern; and the impact of factors affecting response activities such as acute events resulting in insecurity, or mass gatherings and population movement. This was combined with information on vaccination coverage, public health and social measures, and an assessment of the trust in available data for each indicator to produce a standardised recommendation for whether a country should be maintained at the initial alert level, or whether it should be updated. Based on this, teams at WHO global and regional levels jointly agreed on a final classification where the process supported a shared understanding of risk and operational priorities across the COVID-19 incident management teams at different levels of the organisation and, for specific contexts, the rapid release of response funds, distribution of oxygen, distribution of testing supplies, and technical support.WHO was able to effectively adapt its PHI processes and systems including EIOS to align with surveillance strategies across different WHO offices as the pandemic evolved. An example of the unique adaptations implemented at the regional level was seen in the Western Pacific Region. Here, a media statement on cases of \u2018unknown viral pneumonia\u2019 in China (the first detection of COVID-19 cases) was detected through routine EBS processes on 31 December 2019 . EIOS piAdditionally, the WHO and partners conducted PHI for mass gathering events from December 2019 to December 2021, including the Union of European Football Associations championship that took place in 11 countries in Europe, the Tokyo Olympic and Paralympic Games in Japan, Hajj in Saudi Arabia, Al-Arbaeiin in Iraq and the World Handball Championship in Spain.There are many strengths to the COVID-19 PHI activities implemented by WHO during the pandemic. WHO was able to develop a PHI approach throughout the course of the pandemic, used the findings to guide response activities and later to contextualise and supplement information derived from EBS and IBS as processes were established. The WHO\u2019s PHI activities have remained flexible, scalable and resilient, adapting to the changing epidemiological context and availability of the WHO and partners\u2019 person-time. Furthermore, the location of COVID-19 PHI activities within WHO\u2019s Health Emergencies Programme and the Incident Management Support team structure was essential for coordinating and collaborating with key technical experts, ensuring relevancy and usefulness of information gathered, in order to better support Member States.While the WHO\u2019s experience with PHI during the COVID-19 pandemic illustrates its value for the timely detection of health threats  using muIn response to these limitations and challenges, several initiatives have been developed to improve EBS activities for COVID-19 and other public health events. WHO offices established a COVID-19 PHI working group to strengthen collaboration, maximise resources and brainstorm solutions. From 31 March 2020 to 31 December 2021, the working group initiated a collaborative use of the EIOS system as one tool for detecting relevant information. The working group also provided regular feedback to further improve the process, including enhanced signal detection and verification, broadening of source types, geographical and language coverage and the use of tools to optimise shared workflows in rapid signal detection and monitoring. In addition to establishing the working group, WHO increased the number of personnel working on PHI, added and formalised trainings on PHI activities for COVID-19 and conducted a survey-based assessment of the system to further understand its strengths and weaknesses.Public health intelligence is a rapidly evolving approach that is necessary for WHO and Member States . The COV"}
+{"text": "Rhizopus microsporus var. microsporus through culture for fungi and PCR examination.COVID-19 disease caused by the SARS-CoV-2 coronavirus causes a wide range of clinical manifestations, ranging from mild to severe, with the main ones affecting the respiratory tract, such as pneumonia. In patients with greater severity, the high frequency of bacterial and fungal coinfection stands out, a situation related both to the patient's pre-existing comorbidities and due to the hospitalization itself. Cases of mucormycosis associated with COVID-19 were highlighted in the lay and scientific media, with the increase in mycosis cases being directly and indirectly attributed to the viral infection. This report describes a case of rhino-orbito-cerebral mucormycosis in a diabetic patient hospitalized for COVID-19, whose diagnosis was confirmed by identifying the agent  Rhizopus sp.  reported eye pain and a decrease in visual acuity on the right eye for ten days, which started during a recent hospital stay in another hospital for COVID-19. His medical file reported treatment with corticosteroids, unspecified antibiotic therapy, and respiratory physical therapy. He was discharged from this hospital and immediately sought the service with edema and intense erythema on the right conjunctiva, mild erythema on the upper eyelid , and ocuopus sp. . The colRhizopus and Mucor genera.5Mucormycosis is a rare, opportunistic, globally distributed fungal disease whose physiopathology is centered on angioinvasion that leads to tissue necrosis. Among the most often described etiological agents are the coenocytic fungi of the In a study conducted before the COVID-19 pandemic, 71% of the world's cases of mucormycosis were reported in India.SARS-CoV-2 also promotes changes in the host, especially in the severe forms of infection, favoring the development of mucormycosis agents. Among them are the direct damage to pancreatic cells, causing acute DM and ketoacidosis, the use of corticosteroids, which alter glycemic homeostasis and indirectly favor the progression of mycosis, the alteration of iron metabolism leading to an internal environment with high rates of ferritin, a key factor for the development of the fungus, and finally, endothelitis caused directly by the virus, facilitating fungal angioinvasion.The case described herein maintains the classic line of mucormycosis presentation, the rhino-orbito-cerebral type, in a patient with a history of DM, who shares another severity factor, COVID-19 infection. Prompt and correct treatment with antifungals and surgical approaches resulted in a disfiguring outcome, but with the preservation of the patient's life in this serious and fatal disease.None declared.Sandy Daniele Munhoz: Design and planning of the study; data collection; analysis and interpretation of data; drafting and editing of the manuscript; obtaining, analyzing, and interpreting data; critical review of important intellectual content; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature.Rute Facchini Lellis: Analysis and interpretation of data.Ana Paula Carvalho Reis: Analysis and interpretation of data.Gilda Maria Barbaro Del Negro: Obtaining, analyzing and interpreting data.Maria Gl\u00f3ria Teixeira Sousa: Analysis and interpretation of data.John Verrinder Veasey: Design and planning of the study; data collection; analysis and interpretation of data; drafting and editing of the manuscript; critical review of important intellectual content; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; approval of the final version of the manuscript.None declared."}
+{"text": "Biomolecules demonstrates the almost unlimited possibilities of modern protein engineering in gene expression, protein production and modification, as well as the design and creation of new proteins. The research teams behind the articles included in this Special Issue deal with a variety of proteins of possible medical and/or biotechnological interest, but all of these proteins apply state-of-the-art protein engineering techniques in their research. These techniques include the engineering of chimeric bispecific antibodies, modification of protein stability, enzyme activity and specificity, multiple mutagenesis to analyze the role of amino acid residues in functionally important regions of proteins, etc. This Special Issue of Developing the theme of the membrane-active properties of cytochrome c, Chertkova R. and coworkers  evaluateXenopus oocytes and three of them showed enzymatic activity. RhoPDE from Choanoeca flexa exhibited the highest value of light/dark activity ratio. Protein engineering of natural enzymes can be used to improve their properties for optogenetic applications. For example, point mutations in the SrRhoPDE catalytic domain demonstrated the reduced dark activity of this enzyme. Rhodopsin phosphodiesterases (RhoPDEs) possess light-regulated enzyme activities towards cGMP and cAMP and can be used as optogenetic tools. Tian et al.  expresseRybchenko V. et al.  describePseudomonas sp. E2-15 [Exiguobacterium sibiricum (EsOgl) [Extremophilic enzymes are of special interest for biotechnology due to their unusual properties and activity in specific conditions. The Special Issue includes two papers in which new examples of such enzymes are reported, including a novel esterase Est19 from the Antarctic bacterium p. E2-15  and a coIn the paper by Khan et al. , new bioT. thermophilis and similar chaperones, their domains and mutants obtained in their laboratory and described in the literature, and discussed their possible biotechnological applications for scientific and biotechnological purposes.In their review, Yurkova M. and Fedorov A.  describeBiomolecules includes research and review papers that use the best methods of modern protein engineering to modify and investigate proteins of biomedical importance. The studied proteins include therapeutic antibodies, cytochrome c, GroEL, extremophilic enzymes and others. The data obtained may be of great interest for a better understanding of the structure and structural\u2013functional relationships in proteins and their possible use for the development of new therapeutic and biotechnological forms.To conclude, this Special Issue of"}
+{"text": "The active development of psychosocial rehabilitation (PSR) has been taking place in Russia within latest two decades. In this regard, analysis of the accumulated experience and problems\u2019 identification in the PSR field is relevant.Conducting a sociological study in the Volga Federal District (VFD) to work out measures for further PSR system development.Sociological, statistical, original semi-structured questionnaire on PSR application, including 26 questions.63 institutions providing psychiatric care in 14 large regions of the VFD participated in the study. Achievements in the field of PSR include: introduction of new forms of rehabilitation care, modern psychosocial interventions; development of the volunteer sector and others. A number of systemic problems were also identified: more pronounced decrease in the availability of psychiatrists in VFD compared to the Russian Federation (RF) as a whole ; insufficient provision with psychotherapists, psychologists, social workers, which varies considerably in different territories (up to 10 times); insufficient use of non-profit organizations\u2019 (NPOs) potential; lack of a unified system for assessing PSR effectiveness.Measures for development of PSR were proposed: improving staffing levels and qualifications of employees, introducing psychosocial interventions with proven effectiveness; dissemination of successful experience of NPOs, development of methodological tools for assessing effectiveness of PSR, its standardization and others."}
+{"text": "Program targets professionals from Ministries of Health, including Immunization and Screening Program Managers, and cervical cancer stakeholders.Under the framework of the Global Strategy to Accelerate the Elimination of CC as a Public Health Problem, The University of Texas MD Anderson Cancer Center (MD Anderson), the US National Cancer Institute (NCI), and the Pan American Health Organization (PAHO) partnered to develop the Project ECHO for the elimination of CC in Latin America (ECHO ELA). ECHO ELA is modeled on Project ECHO\u00ae  a hub-and-spoke knowledge-sharing approach where expert teams lead virtual didactic lectures and case discussions, building capacity for participants to deliver best-practice programs to their regions.In the first year of the program (2020-2021), 294 participants from 22 countries were registered. Fourteen sessions were held averaging 77 participants per session on topics spanning comprehensive program planning, presenting country experiences on HPV vaccination strategies, new technologies for screening and treatment. Eighteen participants completed the post survey addressing priorities, capacity, and desired outcomes, and two focus groups collected facilitators/barriers to achieving goals.ECHO ELA is potentially an effective tool to enhance collaboration and support countries\u2019 progress towards the elimination of CC."}
+{"text": "Editorial on the Research TopicDigital health adoption: Looking beyond the role of technology By Kyratsis Y, Scarbrough H, Begley A and Denis J-L. (2022) Front. Digit. Health. 4: 989003. doi: 10.3389/fdgth.2022.989003Accelerating the adoption of proven digital health technologies and advancing their embedding into routine care operations has the potential to revolutionize human health by boosting efficacy, driving costs down, and increasing access to and capacity for care delivery . It can Shaw and Donia propose a broader socio-technical approach to the ethics of digital health, which spans domains from software, devices and supply chains to inter-personal relationships, organizational and government policies. They emphasize issues of social justice, the need to address inequalities in digital access and advocate anticipatory forms of governance to minimize potential negative consequences. Greenhalgh et al. discuss a conceptual framework\u2014PERCS\u2014used to evaluate remote healthcare consultation services in the UK. The authors focus attention on digital maturity and digital inclusion, examining seven inter-related domains, spanning from the reason for consultation, to patients, care delivery, home and family and the wider system. They identify tensions and contradictions along these domains and elaborate on related practical ethical issues. Shaw et al. analyze the accelerated implementation of video consulting during the COVID-19 pandemic. Using comparative and interpretive policy analysis, the authors identify key variations across the four UK health systems in terms of enabling and limiting conditions at both policy and delivery levels. The authors also caution against inequalities in accessing video consulting services.Reflecting on adoption Nantume et al. explore the commercialization of a wearable vital signs monitor in low resource settings and argue for a holistic implementation perspective, from idea and product design to market. They highlight implementation being intertwined with development and evaluation, involving local stakeholders as co-creators. The authors also stress the role of social dynamics, such as trust in regulatory authorities, and public misperceptions about the technology. Rainey et al. in their survey study explore perceptions of AI by UK radiographers for successful application and integration into clinical practice. The authors highlight important aspects of the professional roles of clinicians, and the need for learning, capability-building and de-mystification of the opacity of AI-in use. Bouabida et al. evaluated two platforms for remote patient monitoring following hospital discharge in the context of COVID-19 in Canada. The authors highlight issues of social acceptability by diverse stakeholders during adoption, maintaining human contact and balancing concerns for confidentiality and data security. They underline the need for user participation in technology development and deployment, also bringing to the fore organizational, social and ethical aspects.Bennet et al. describe the experience of ID-Liver implementation and use in northern England for integrated, pro-active management of patients at risk of developing chronic liver disease. From setting up to piloting and using ID-Liver, the authors argue for the need to mobilize a network of collaborators including commercial partners, healthcare organizations and professionals. Yan et al. in their commentary on digital therapeutics raise the broader question of cost and reimbursement. The authors identify a set of dilemmas for policy-makers, which are related to the specificities of digital therapeutics including the ability of patients to afford and use technological devices and the possibility of reimbursing these therapeutics. Cripps and Scarbrough present a perspective on a sustainable approach to digital applications in the UK's NHS. The authors argue to shift the focus from the technology itself to considering the motivations of users and constraints within specific contexts. They advocate for a wider approach to change that incorporates clinical and behavioral insights, process engineering and knowledge management.Co-creating through digital inclusion and user engagement. (b) Bridging local and trans-local stakeholders including partners from the wider economy and the private sector. (c) Adapting to ethical issues and social forces, beyond technical and clinical aspects, such as public (mis-)perceptions, professional and organizational dynamics, regulatory elements, as well as issues of cost and reimbursement. (d) Demystifying the opacity  of digital health applications and assessing digital maturity in practice.The papers' contribution can be grouped into four themes, which highlight key non-technology related aspects of digital health adoption : (a) Co-five key levers that can help drive more effective digital health technology adoption.1.Understanding and responding to the needs and preferences of diverse individuals and communities is critical . A number of authors  highlight inequalities in digital health. While inequality is often considered at the point of care in terms of the ability of patients and clinicians to use technology, inequalities also arise when more marginalized groups are unable to voice their concerns and preferences upstream, and to influence the development and evaluation of digital innovations. Aptly, the question of co-creation underpins many papers in the collection.2.Early and active stakeholder engagement in both design and technology use . This highlights the need to partner with and incentivize innovators (including the private sector) to bring in their technical expertise , as well as effective collaboration with patients, healthcare providers and commissioners.3.Building the capability and confidence of all actors to acknowledge and raise quality, privacy, security and safety concerns relating to digital health care . Reskilling, learning and modifying professional roles play a vital role in adoption as the Rainey et al. paper illustrates.4.Adopting a holistic, rather than a piecemeal approach to build a supportive ecosystem. This suggests the need for a long-term strategy, appreciating politics, the regulatory groundwork, reimbursement mechanisms, cost .5.Considering seriously the wider ethical implications of digital health  to establish and maintain trust, transparency and accountability.Reflecting on implications for policy and practice, the papers in this Research Topic highlight"}
+{"text": "The Silk Road, a historical network of interlinking trade routes across the Afro-Eurasian landmass, was of great importance to the transport of peoples, goods, and ideas between the East and the West. Although its main use was for importing silk from China, traders moving in the opposite direction carried to Central China jewelry, glassware, and other exotic goods from the Mediterranean, jade from Khotan, and horses and furs from the nomads of the Steppe. In historical records, communication between China and Central Asia has been unbroken ever since the opening of the Silk Road in the Han Dynasty. However, relics unearthed from archaeological sites indicate that communication between people along the Silk Road began during the Bronze Age. The Silk Road brought together the achievements of the different peoples of Eurasia to advance the Old World as a whole.Ethnic groups with different religions, cultures and customs inhabited the Ancient Silk Road and experienced complex histories. Patterns in genetic variation between individuals can tell us about the population history of these groups. In recent years, using relatively direct means of studying ancient samples through osseous material, alongside indirect means of analyzing the genomes of modern populations, demographic history\u2014migrations, expansions and colonizing events - have been progressively revealed in numerous genetic studies of early human populations. However, until the present, the origins of the populations along the Ancient Silk Road and relationships have been examined in far less detail.Kairov et al.; Allen et al.; Guarino-Vignon et al.) or microarray technologies , or various kinds of markers, including mtDNA , Y chromosome , forensic STRs , SNPs , and InDels data  For example, a novel 6-dye direct and multiplex PCR-CE-based typing system has now been validated and could be considered as a reliable tool for human identification and intercontinental population differentiation In this special editorial, we collected 15 genetic investigations involving the populations living along or related to the Silk Road from ancient times to the present day. These studies approach academic and public Research Topic  of the targeted populations through genome-wide sequencing .The eastern end of the Silk Road lies on the middle reaches of the Yellow River. The Shimao site in Shaanxi Province is an important Neolithic archaeological culture in this area. To further reconstruct the genetic structure of Silk Road-related populations, it is necessary to understand the genetic compositions of such early local populations as these. The Shimao population showed a mostly local origin and showed a maternal affinity with Taosi site, a Longshan culture population in the middle Yellow River valley . The former site dates back to the Han Dynasty (118BCE-191CE) and the latter to the Wei - Jin Dynasties and Sui and Tang Dynasties (220CE- 907CE). For the two sites, from the paternal Y-chromosome perspective, all male individuals showed the Sino-Tibetan speaking origin of Yellow River-related populations, while Foyemiao samples demonstrated a higher proportion of an Altaic speaking and North Eurasian ancestral component, alongside a small proportion of southern East Asian ancestry. From the maternal perspective, female Heishuiguo individuals showed a northeast Asian origin and revealed a sex-biased migration from the middle and lower reaches of Yellow River to Hexi corridor. This was consistent with evidence in historical records, especially unearthed slips  and was an integral component of the eastern section of Silk Road. Heishuiguo site and Foyemiao site lie in the central and western portion of the Hexi corridor, respectively  Another site, Shichengzi, a Han Dynasty agricultural garrison, also located in ancient Xinjiang, has revealed to us genetic makeup of a Frontier population in early imperial China . Archaeogenomics at Shichengzi has revealed two subgroups with East Asian origin and Northeast Asian origin, respectively, occupying a single burial space. Interestingly, stable isotope analysis showed that dietary patterns among site inhabitants could be split among agro-pastoral and agricultural groups. Considering ancient DNA and stable isotope evidence together, it has been argued that Northeast Asian origins of Altaic pastoralists and East Asian origins of Han agriculturalists lived together in the Shichengzi military outpost.Population admixture also can be observed in the Western Regions (present Xinjiang), where individuals at the Xiabandi reveal genetic flow from Central Asian populations and thus the influence of Middle and Late Bronze Age steppe pastoral cultures , Kazakh , Hui , Dongxiang , Bonan , Yugur , Salar , Mongol , and Manchu  groups have been investigated using genetic markers and/or genome sequencing at the population level. Generally speaking, population from the same language group exhibit a closer genetic affinity. Furthermore, the Turkic-speaking population from China and Kazakhstan both present a closer genetic relationship to Central Asian populations, while Hui and Tungusic-speaking populations had a significant admixture with Han Chinese. Mongolian\u2019 mitochondrial genomes show a dominant East Asian related ancestry, an outcome of Bronze Age events and Mongol Empire expansion along the Silk Road.The Altaic language family is divided into Mongolic, Tungusic and Turkic language groups. Altaic speaking nomads played an important role in shaping the northern steppe Silk Road. However, their history is often only recorded sporadically in ancient writings of surrounding civilizations. In this special edition, the genetic history of Uyghur .In addition to the northern steppe Silk Road, the Tea and Horse Ancient Road or South Silk Road were another part of the ancient Silk Road. Beginning at approximately 1200\u00a0years ago (Tang Dynasty), the Tea and Horse Ancient Road emerged as a famous caravan road system for tea, salt and horse trading in Southwest China. Guizhou Province, located near the Tea and Horse Ancient Road has been documented as a critical depository of substantial sociocultural, genetic, and linguistic diversity for studying southern Silk Road related populations. The southern Han constitute the majority ethnic group within Guizhou. Guarino-Vignon et al.). The use of recent aboriginal paleogenomes, combined with the genomes of related modern humans, will help us to understand further details of the genetic history of regional populations.At the western end of the Silk Road, Guarino-Vignon et al. found that a bronze age individual from Oxus Civilization  at the Ulug-depe site in Turkmenistan, shared genetic affinity with a local BMAC population, and further revealed that modern Central Asian Indo-Iranian\u2013speaking populations primarily harbored ancient BMAC related ancestry (In summary, this special edition focuses on the population history along the Silk Road, covering the eastern limits of the Silk Road, the Western Regions, the northern steppe, and southern Tea and Horse Ancient Road, and western end. The genetic diversity and population structure of modern populations in these regions are dissected using ancient forensic markers. Moreover, combined with modern human DNA data, ancient DNA researches discuss the formation of targeted populations in greater detail. In future work, fine temporal-spatial scales using enlarged sample sizes should be considered when outlining changes in population dynamics along the ancient Silk Road."}
+{"text": "Diagnostics of Apocalyptic variant of end-world Delusion with Religious Content (ADRC) in schizophrenia is related with insufficient exploration and recognizability, despite the severity of the state, social risks and resistance to psychopharmacotherapy.To define psychopathological and phenomenological features of ADRC in schizophrenia, to identify the clinical dynamics of delusional disorders due to specifics of the delusional behavior, and to develop diagnostic and prognostic criteria.28 patients with ADRC in schizophrenia were examined . Clinical-psychopathological and statistical methods were applied.Delusional ideas of end-world, Apocalyptic variant, occurred in the structure of affective-delusional state . Two types of ADRC were identified: with the predominance of acute sensory delusions of perception and with the predominance of visual-figurative delusions of the imagination. These types differed in the severity and depth of psychotic manifestations and in the specifics of a delusion formation, were characterized by the mono- or polythematic delusional disorders.Cases of ADRC differ both in the clinical-psychopathological specifics of delusional constructions, and in the socio-behavioral aspect. Among these cases, there is a high risk of delusional destructive behavior, with auto-aggressive, suicidal attempts and hetero-aggressive behavior. In cases with ADRC the strong persistence of delusional pseudo-religious beliefs occurs, with the refusal of any medical and psychological assistance, as well as implication of socially dangerous acts associated with the spread of delusional ideas and their induction of religiously inclined persons, which leads to the emergence of pathological pseudoreligiosity .No significant relationships."}
+{"text": "I believe that business is nothing more than a group of people trying to make a difference.\u201d\u201c\u2014Sir Richard BransonAntimicrobial Stewardship and Healthcare Epidemiology (ASHE) journal is a momentous step for the scientific mission of the Society for Healthcare Epidemiology of America. All of us on the editorial team are both honored and deeply excited about the future of ASHE. Before looking forward, it is important for us to pause and reflect on the multiple events of the last year and the coronavirus disease 2019 (COVID-19) pandemic to gain a better perspective on and clear commitment to what lies ahead.The launch of the open-access The COVID-19 pandemic affected us in multiple ways. As healthcare epidemiologists and healthcare providers across varied components of the healthcare delivery spectrum, we faced tremendous challenges in infection prevention, patient quality and safety antimicrobial stewardship, disinfection, the use of personal protective equipment, diagnostic testing and the clinical management of SARS-CoV-2 infected patients. All of this was coupled with rapid scientific discovery and dissemination in the medical literature.The COVID-19 pandemic further exposed the many weaknesses in the fabric of society, including significant healthcare disparities by race and inequalities in access and outcomes for individuals with COVID-19. The tragic death of George Floyd reignited an intense awareness of racism, diversity, justice, equity, and intersectionality. The year 2020 also witnessed an explosion of misinformation  across multiple spheres including medicine and politics. More than ever, the medical infodemic underscored the important role of epidemiologists as both content experts and scientists to drive an evidence-based public health response in critical times.These unique times shaped the vision of ASHE. The journal is committed to the rapid dissemination of high-quality, timely, evolving science in antimicrobial stewardship and healthcare epidemiology in an open-access model, to serve both developed and low- and middle-income countries. To do so, we are committed to diversity in professional backgrounds, nationalities, and gender across the editorial team, such that journal leadership reflects not only the membership of the Society for Healthcare Epidemiology of America but also the antimicrobial stewardship and healthcare epidemiology community at large. Next, we will seek innovative original science, reviews, and commentaries that represent a diversity of perspectives, issues, evolving challenges, and controversies in the varied field of healthcare epidemiology and antimicrobial stewardship, with the ultimate goal of maximal content accessibility to a worldwide readership. Additionally, SHEA members will benefit from a highly discounted rate and the journal will waive publishing costs for invited reviews.Authors submitting to ASHE will find that the journal provides constructive peer review, competitive turnaround times, immediate online publication, and social media promotion. As a fully gold open-access journal, ASHE readers will benefit from free and easy access to all journal content, bringing the widest possible impact, reach, and discoverability for our authors and readers. The journal is engaged in efforts to ensure that article processing charges (APCs) are not a barrier to publication. Our publisher, Cambridge University Press, has recently signed a number of read-and-publish agreements with hundreds of institutions worldwide, which will cover APCs for corresponding authors from those institutions. APCs for authors from low- or middle-income countries will be waived or discounted through initiatives like Research4LifeAs we move forward and view the COVID-19 pandemic in the rearview mirror, we must not forget the valuable lessons learned from scientific responsiveness and the publication of high-quality science, under a vigorous peer review, in an open-access manner. With a diversity of both content and contributors, ASHE will aim for a global audience for advancing patient safety, antimicrobial stewardship, and healthcare epidemiology, with the aspiration of making a difference."}
+{"text": "The Yellow River basin spans nine provinces and autonomous regions and plays an important role in China's economic and social development and ecological security. However few studies have integrated the concept of carbon neutrality into research to evaluate the carbon-neutral development level. This paper calculates the comprehensive evaluation value of the provincial carbon-neutral capacities comprehensive evaluation index in the Yellow River basin through the driving-force-pressure-state-impact-response (DFPSIR) index system and the global entropy method based on provinces data between 2008 to 2019. The final results indicated that from 2008 to 2019, the carbon-neutral capacities of the provinces in the Yellow River basin were in a state of rapid development and had achieved a grade leap. However, seven provinces had carbon-neutral capacity levels at the Grade III standard in 2019, thereby leaving scope for substantial improvement. Through the above research, we identified the changes in the trend and driving mechanisms of the carbon-neutral capacity of the Yellow River basin and provide a theoretical reference value for a comprehensive realization of carbon neutrality in China in 2060. Unchecked emissions of greenhouse gases lead to global warming and aggravate problems such as ecological and environmental deterioration and energy crises. Therefore, an increasing number of countries have switched to developing low-carbon economies as an effective way for sustainable development since the advent of the twenty-first century. As a special low-carbon development mode, carbon neutrality promotes the balancing of carbon emissions and carbon absorption through the innovation and reform of technologies and systems, industrial transformation and upgrading, and the promotion and utilization of clean energy. Finally, the coordinated development of society, the economy, the environment, and energy is being emphasized. The terrain of the Yellow River basin is high in the west and low in the east. The western region of the basin is covered with snow throughout the year. Its central area is covered with loess; therefore, the soil and water losses are significant in this region. The eastern region of the basin is comprised mainly of the alluvial plain of the Yellow River. The Yellow River basin spans nine provinces and autonomous regions and plays an important role in China's economic and social development and ecological security. Therefore, the objective and comprehensive evaluation of the carbon-neutral development level of the Yellow River basin is of high significance for the sustainable development of the provinces and cities in the Yellow River basin.3, regional low-carbon economy5, low-carbon transportation6, evaluation of ecological level7 and analysis of influencing factors of carbon emissions are mature. The evaluation indicators are roughly divided into three categories: basic indicators, core indicators, and different orientation indicators according to the research purpose9. There are some differences in the selection of indicators by different scholars11. Jing et al.12 collected a set of 21 indicators covering the economic, social and environmental levels, constructed an indicator system, and proposed the comprehensive TOPSIS-ORM method to evaluate the sustainable development performance of shrinking cities in northeast China. Chaofeng et al.13 established a low-carbon city construction and evaluation index system in view of the carbon emission problem in urban construction and development. Yuzhao et al.14 studied the ecological security index system of the river basin, proposed the improved DPSIR model, and verified the applicability and importance of the improved DPSIR model in the ecological security assessment of the river basin scale. Guo et al.15 established the evaluation index system of ULCC from the perspective of driving force and resistance, respectively used the principal component analysis method and cluster analysis method to evaluate and classify the ULCC of Wuhan metropolitan area, and tested the results with fuzzy analytic hierarchy process to find out the problems existing in the city. Duan et al.16 constructed the evaluation system of Dalian's low-carbon economic development level based on AHP\u2009+\u2009entropy weight method. The comprehensive evaluation index of the development level of low-carbon economy in Dalian from 2005 to 2014 was calculated. Cheng et al.17 used correlation analysis, fuzzy rough set and entropy weight methods to select and analyze 21 indicators and construct a regional green competitiveness index. The above studies are all studies on evaluation indicators and evaluation methods between low-carbon and related industries or economies in different regions. However, in the evaluation of multi-provincial regions, river basins and heterogeneous regions, the characteristic indicators increase, and further research on the index system and evaluation methods is also needed.There are few researches on the development level of carbon neutrality, but the establishment and methods of sustainability evaluation system18 constructed an evaluation index system including 20 indicators at six levels. An improved TOPSIS method is proposed for analysis and calculation, and the results show that the use of renewable energy, the maintenance of ecological environment quality and low carbon technology are the important factors affecting the carbon neutrality ability of China. Liu et al.19 used China's provincial panel data from 2004 to 2016 and the Dubin spatial model based on the Stippart model to empirically analyze the impact of the three subsystems of ecological civilization on carbon emission intensity. Cao et al.20 proposed an evaluation model based on the improved matting element extension cloud model to evaluate China's ecological and environmental performance in 2019, taking Jiangsu Province as an example. Wei et al.21 adopted the PSR method to identify the influencing factors of China's carbon emissions. Jiang et al.22 respectively studied the impact of structural changes in internal and external inputs on global carbon emissions, and used structural decomposition analysis to decompose changes in global carbon emissions into six factors: carbon emission intensity, domestic input structure, international input structure, consumption pattern, consumption and population. Wei et. al.24 took Xiamen City as an example to establish a calculation method for the carbon footprint accounting of urban buildings. Ghaffar et. al.25 establishes baseline information on urban energy use and CO2 emissions. Built-up areas verify the increment of urban CO2 sources.In terms of carbon neutrality capacity evaluation and its influencing factors, Niu et al.In summary, the current research results show that the DPSIR model can effectively represent the concept and structure of the composite system, and can be well applied to the evaluation of low-carbon or carbon neutral development levels in river basins or multi-province regions. However, there are the following problems in the research: (1) most of the research objects of low-carbon development are urban areas or single industries, and there are few studies on the evaluation of low-carbon development level in river basins, multi-provincial or multi-heterogeneous regions. (2) At present, most of the research focuses on the field of low-carbon economy. (3) At present, most of the evaluation indicators of low-carbon development level are aimed at both carbon emission and carbon absorption, and no evaluation indicators have been established for the process of carbon transmission.In view of the shortcomings in the above studies, this paper builds the DPSIR analysis model of carbon neutrality capacity evaluation on the basis of the existing studies, and integrates the ecological evaluation index according to the actual situation of carbon emission, carbon absorption, economy, population, technology, resources and environment in the Yellow River Basin. Improve the driving mechanism analysis, pressure measurement, state assessment, impact analysis, response evaluation and other index systems of the carbon neutrality evaluation system in the Yellow River Basin. Combined with statistical data, the analytic hierarchy process and entropy weight method are used to evaluate the carbon neutrality capacity of the nine provinces in the Yellow River Basin. To verify the applicability and importance of DPSIR model in the evaluation of carbon neutral development level in the Yellow River Basin, and to provide theoretical reference for promoting the sustainable development of the Yellow River Basin.The driving-pressure-state-impact-response (DPSIR) model has evolved from the pressure-state-response (PSR) model proposed by the Organization for Economic Cooperation and Development and the driving-pressure-response (DPR) model proposed by the United Nations Commission on Sustainable Development. It is comprehensive, systematic, holistic, and flexible. The model can reveal the causal relationship between the environment and economy. The DPSIR model divides the system into five factors: driving, pressure, status, impact, and response. Figure\u00a0TO objectively and scientifically evaluate the carbon-neutral capacity of the Yellow River basin, this study follows the principles of the DPSIR model: science, system, compatibility, regional, hierarchy, operability, and regional economic and social development. The evaluation index system includes three levels: the target layer, subsystem layer, and index layer. The determined index layer comprises 37 specific indicators. It determines its attributes as positive (+) or negative indices (\u2212) for the index characteristics. The specific carbon-neutral-capacity evaluation index system is listed in Table The research objects of this paper are nine provinces in the Yellow River basin, mainly including Qinghai, Sichuan, Gansu, Ningxia, Inner Mongolia, Shaanxi, Henan, Shanxi,and Shandong. As shown in Fig.\u00a0The data on economic and social development were mainly sourced from China Statistical Yearbooks from 2008 to 2019 and included data for nine Yellow River basin provinces. The data on the use of resources were sourced mainly from the China Energy Statistical Yearbooks from 2008 to 2019. The data on environmental quality and environmental governance were sourced mainly from the 2008\u20132019 China Environmental Statistics Yearbooks, China Bulletin on the Status of the Marine Environment and the Department of Ecology and Environment of the nine Yellow River Basin provinces. The indicator data on per capita carbon emissions, annual average temperature change rate, GDP proportion of secondary industry, tertiary industry GDP proportion, and provincial health cities were calculated using their respective formulas from the index description and explanation given in Table Standardized processing of index data Because the original data of the N index may have different units and dimensions, these data must be standardized to obtain standardized data Normalization of index standardization data:Calculate the information entropy of each index Calculate the redundancy of each index Calculate the weights of each index After the evaluation index system was established, an appropriate evaluation method was selected to evaluate the development level of the system. Commonly used comprehensive evaluation methods include hierarchical analysis, fuzzy comprehensive evaluation, main component analysis, factor analysis, and entropy methods. The entropy method is an objective empowerment method that calculates the degree of numerical dispersion among the indicators. However, the traditional entropy method can handle only cross-sectional data. It cannot handle the panel data of a multi-index system spanning years. Therefore, this study used the global entropy method to determine the weight of the evaluation index system for the provincial carbon-neutral capacity of the Yellow River basin.d), pressure subsystem evaluation value (Sp), state subsystem evaluation value (Ss), impact subsystem evaluation value (Si), and response subsystem evaluation value (Sr).The DPSIR model subsystem layer evaluation formula is as follows:dpsir) of the DPSIR subsystem layer was determined using the expert evaluation method. The five subsystem weights were as follows: driving (wd), pressure (Wp), state (Ws), impact (Wi.) and response (Wr) weights.The weight  was obtained asConsidering the score of the comprehensive evaluation index of the provincial carbon-neutral capacity of the Yellow River basin and referring to the relevant comprehensive index classification method at home and abroad and the actual situation of this study, the grading standards for establishing provincial carbon-neutral capacities in the Yellow River basin are listed in Table Driving subsystemThe evaluation values of the carbon-neutral capacity driving subsystems in nine provinces in the Yellow River basin generally exhibited an upward trend, as depicted in Fig.\u00a0Pressure subsystemAlthough the evaluation values of the carbon-neutral pressure subsystems in the nine provinces of the Yellow River basin decreased slightly in some years during 2008\u20132019, the overall trend exhibited a small increase, as depicted in Fig.\u00a0State subsystemFigure\u00a0Impact subsystemFigure\u00a0Response subsystemFigure\u00a0The DPSIR subsystem was thoroughly analyzed by comparing the evaluation values of the carbon-neutral capacity DPSIR subsystem of the nine provinces in the Yellow River basin from 2008 to 2019 and combining the characteristics of resources and environment and the specific characteristics of the basin.Overall, the provincial carbon-neutral capacities in the Yellow River basin were gradually enhanced.the State Council on Printing and Distributing the National Sustainable Development Plan for Resource-based Cities (2013\u20132020) was issued. The development plan for sustainable economic development in the next seven years was introduced. From 2013 to 2019, nine provinces responded positively to state calls. Governments at all levels need to rationally develop and use environmental resources and strengthen environmental governance and protection in accordance with relevant work arrangements. The strong development of the response subsystem and gradual comprehensive and stable implementation of the regulation measures improved the quality of economic development, the pressure and negative impact on the ecological environment of the Yellow River basin decreased continuously, and the CCCEI increased rapidly.During 2008\u20132019, the provincial carbon-neutral capacities in the Yellow River basin were continuously enhanced, and the CCCEI exhibited an upward trend. Since 2013, the concepts of a low-carbon economy and sustainable development have attracted wide attention from society and governments at all levels. In 2013, However, driven by the ever-increasing population and economic aggregate, the increases in the coal-dominated industrial energy consumption structure and cars per capita ensure that the evaluation values of the pressure and impact subsystems fluctuate, thereby impeding the development of the provincial CCCEI in the Yellow River basin.The development of carbon-neutral capacity in the Yellow River basin varies.Qinghai and Inner Mongolia have relatively good ecological environments, large vegetation coverage areas, and underdeveloped economies. Therefore, the provincial CCCEIs were above 0.8 in 2008.From 2008 to 2012, the provincial CCCEI values of Henan, Shanxi, Ningxia, and Shandong were less than 0.8. The overall levels of the carbon-neutral capacities of these provinces were level II, which were poor. Economic development leads to the destruction of resources and the environment. The evaluation values of the driving, pressure, and state subsystems were low.The provincial CCCEIs of Qinghai and Inner Mongolia were the first to attain level IV in 2017, which indicated that their carbon-neutral capacities were good. In 2019, the provincial CCCEIs of Sichuan, Shaanxi, and Gansu were above 1.1, i.e., slightly lower than the lower limit of the standard of IV. These provinces entered the initial stage of development with good carbon-neutral capacities. However, owing to the environmental damage and reduced green areas caused by economic development, the carbon-neutral capacities of Shanxi, Ningxia, Henan, and Shandong are relatively low. In 2019, their provincial CCCEIs were higher than 0.95 but lower than 1.1, thereby indicating their middle development stage of standard III.The provinces in the Yellow River basin have significant development potential.During 2008\u20132019, the carbon-neutral capacities of provinces in the Yellow River basin achieved a grade leap. However, there is a huge scope for development beyond the upper limit of standard IV. Furthermore, no province has reached standard I, thereby leaving scope for further development of provinces. Ningxia and Shanxi are important coal carbon bases in China, and the coal energy industry is an important industry. With the development of green energy technology, the carbon-neutral capacities of these provinces will be significantly improved. Shandong and Henan Provinces have large populations. A small cultivated land area per capita, a small proportion of renewable energy power, and a large proportion of secondary industry lead to increased pressure on carbon-neutral capacities in these provinces. Therefore, it is necessary to increase the utilization of new energy, vigorously develop tertiary industry, strengthen carbon-capture technology, and strive to achieve the sustainable development goal of carbon neutrality at first.The provincial CCCEI in the Yellow River basin from 2008 to 2019 is depicted in Fig.\u00a026. The index system is scientific, complete, and easy to obtain and provides a basic framework for a comprehensive analysis of the causal relationship between carbon neutrality and social and economic activities in the Yellow River basin.A carbon-neutral-capacity-evaluation index system for the Yellow River basin is established based on the DPSIR model. The index system has three levels and 37 indicators13, the practicability of DPSIR model and the scientificity of the result are further verified.The global entropy method was used to calculate the capability evaluation value of each subsystem of the DPSIR, the CCCEI model of the Yellow River basin was constructed, and a classification standard for the carbon-neutral capability was proposed. This method can be used to perform quantitative analysis on each subsystem of the carbon-neutral capacity of each province in the Yellow River basin. It can dynamically describe the evolution trend of the subsystems and objectively measure the level and future development scope of the carbon-neutral capacity of each province. Compared with referenceThe comprehensive evaluation of carbon neutrality capacity in the whole Yellow River basin shows a significant upward trend, showing the spatial difference of the comprehensive evaluation of carbon neutrality capacity in the middle and lower reaches of the river basin than that in the upper reaches of the river basin. The evolution trend of spatial differences among each subsystem is basically consistent with the evolution trend of comprehensive evaluation.Based on DPSIR model and global entropy method, the comprehensive evaluation Index (CCCEI) of provincial carbon neutrality capacity in the Yellow River Basin was established to evaluate the carbon neutrality capacity of the Yellow River Basin from 2008 to 2019. The logical relationship among subsystems in DPSIR model and the spatial and temporal differences of each province are revealed, and the dynamic evolution trend of carbon neutral capacity of each province is analyzed.From 2008 to 2019, the carbon neutrality capacity of the provinces in the Yellow River Basin was in a state of rapid development and achieved multi-level leapfrog, but there is still a great room for improvement. The carbon neutrality capacity of each subsystem shows two time differences: fluctuation and rise from 2008 to 2019. Driven by the continuous growth of population and economic aggregate, the continuous fluctuation of the evaluation index of pressure subsystem and influence subsystem hinders the consubstantial growth of the comprehensive evaluation index of carbon neutrality capacity of provinces in the Yellow River Basin to a certain extent.The index system based on the DPSIR model is capable of evaluating the impacts of economic and social developments in various provinces on their carbon-neutral capacities, as well as those of positive measures adopted to achieve carbon neutrality. The proposed index system is broad based and can be extended to the carbon-neutral assessments of other river basins.Provinces have actively developed emerging industries, strengthened ecological and environmental protection in the Yellow River basin, formulated and implemented low-carbon development plans, and effectively eliminated obstructive indicators. The carbon neutrality status of most provinces in the Yellow River Basin is relatively severe, and the resource and environment problems in the middle reaches are prominent. To improve the carbon neutrality capacity of the Yellow River basin, the resources and environment in the Yellow River basin need to be further rationally utilized, managed and protected. It is necessary to establish a reasonable resource and environmental utilization mechanism, strictly control the emission of industrial pollutants, advocate public transportation, promote the implementation of low-carbon economic development plans, and improve the comprehensive capacity of carbon neutrality in the provinces along the Yellow River Basin.The distribution of the middle and lower reaches of the Yellow River provincial carbon neutral pressure generally larger, strengthen the response and the implementation of the policy, increasing factors of flow across the land, digging in the middle and lower reaches of the Yellow River and Yangtze river along the Banks of the leading type carbon neutral city experience, give full play to their ability of carbon neutral spillover effect and is a progressive effect, formation of the carbon cycle in the Yellow River urban agglomeration, It will drive the improvement of provincial carbon neutrality capacity in the form of urban agglomeration. Based on the development advantages of each region, the differences in factors hindering carbon neutrality shown by each region should be solved.While dredging economic development, the government should constantly coordinate the contradiction between environmental protection and economic development, improve the overall coordinated development level at the material level such as industrial support and the accumulation of development factors, and formulate relevant policies according to local conditions.Combined with the research and analysis, it is not difficult to see that the carbon neutrality capacity level of the provinces in the Yellow River Basin has been significantly improved. The evaluation of carbon neutrality capacity shows obvious regional heterogeneity and distinct regional characteristics. Accordingly, according to the provincial characteristics and differences carried by different river basins, policy suggestions are put forward to promote the carbon neutrality capacity of the Yellow River Basin as follows:"}
+{"text": "The most frequent and severe non-cognitive disorders in dementia are hallucinatory-paranoid disorders (HPD), which cause social dysfunction and financial burden of this pathology.To study the features of HPD in vascular dementia (VD), an approach using clinical-psychopathological, psychometric, psychodiagnostic and mathematical-statistical methods was used.The study was based on the examination of 75 patients with HPD in VD and 63 patients with VD without HPD.In patients with VD in the middle stage of development in the structure of clinical manifestations was dominated by frequent paranoid and paranoid disorders  with a systemic delusional plot  material damage, robbery, theft , relationships  and jealousy , which ran in the form of paranoid delusional disorder (63.4%), acute paranoia (12.2%) and hallucinations (24.4%). In patients with VD in the late stage of development, the clinical and psychopathological structure of GPR was characterized by a predominance of frequent, hallucinatory disorders  in the form of healthy , tactile  and auditory  hallucinations, which took the form of hallucinations , confusion  and paranoid delusional disorder .The study of the clinical and psychopathological structure of HPD in patients with dementia of different stages of development revealed their dependence on the stage of development of the pathological process."}
+{"text": "To evaluate the global research productivity in the field of discectomy for lumbar disc herniation (LDH) through bibliometric analysis and mapping knowledge domains.A systematic literature search was performed on the Web of Science (WoS), including the Science Citation Index Expanded (SCIE) database and PubMed. The number of publications, countries of publications, journals of publications, total citation frequency, impact factors of journals, and Institutional sources were analyzed by Microsoft Excel 2019, the Online Analysis Platform of Bibliometrics, and VOSviewer. Hotspots were also analyzed and visualized based on VOSviewer.Spine has published the largest number of papers (289) in this field with the most citation frequencies . Hotspots could be divided into three clusters: surgery, lumbar disc herniation, and diagnoses. The most recent topic that appeared was symptomatic re-herniation.A total of 2,066 papers were identified. The United States ranked first in the number of total citations . China ranked first in the number of publications , which has surpassed the United States in terms of the number of publications published annually since 2016. Wooridul Spine Hospital published the most papers (43). For journals, The United States is the most significant contributor to the development of discectomy for LDH. The current research focus of discectomy on LDH was the comparison between surgical approaches and evaluation of current minimally invasive discectomy. At present, minimally invasive techniques, such as endoscopic discectomy, cannot completely replace non-endoscopic discectomy (open discectomy and microdiscectomy) through bibliometric analysis and mapping knowledge domains. Sciatica in adults is mostly caused by lumbar disc herniation (LDH) , leadingBibliometrics is a method to assess the trends in global research productivity based on literature databases and literature metrology characteristics. Moreover, its application has become more and more mature in various medical disciplines in recent years, including spinal surgery \u201317. BaseA systematic literature search was performed on PubMed, Web of Science (WoS), and the Science Citation Index Expanded (SCIE) database. The search terms were as follows: theme\u2009=\u2009((discectomy) AND (lumbar disc herniation or lumbar disk herniation OR LDH)) AND publishing year\u2009=\u2009 based on MeSH on PubMed. Original articles and reviews were identified.Two researchers extracted the data from databases and imported it into Microsoft Excel 2019 independently. The data were imported as follows: number of publications, countries of publications, journals of publications, authors of publications, total citations, impact factors of journals, and institution sources. Disagreements between the two researchers were resolved by consensus after discussion.http://bibliometric.com/) was also used for analyzing and visualizing the data extracted from databases as a complement.The number of publications, contributive countries of publications, contributive journals of publications, total citation frequency, and impact factors of journals and institution sources were analyzed by Microsoft Excel 2019 , which were visualized by GraphPad Prism 8 . VOSviewer  is used for visualizing the bibliometric mapping, including literature coupling, co-citation, collaboration, and co-word analysis . VOSviewA total of 2,066 papers were identified in this analysis. An overview of global publications in discectomy on LDH over the past 20\u00a0years is shown in Spine has published the largest number of papers (289) in discectomy on LDH with the most citation frequencies . World Neurosurgery ranked second in the number of publications (163). European Spine Journal ranked second in citation frequencies (2586).The top 10 contributing countries, institutions, and journals by the number of publications are shown in The top 20 keywords sorted by frequency of occurrence are shown in The citation status of papers in discectomy on LDH is shown in With the improvement of patients' requirements for prognosis, discectomy continued to improve as the treatment for symptomatic LDH under the general trend of minimally invasive surgery. By 2020, China ranked the first in the number of publications in the field of discectomy in worldwide , followed by the United States . However, the citation frequency of Chinese articles was less than that of the United States. In terms of time, China has surpassed the United States in terms of the number of publications published annually since 2016. China started to get involved in the research of discectomy on LDH relatively late, whereas the incidence rate and absolute value of LDH are relatively high in China based on great population, which could provide great number of clinical data. China has considerable experience in the application of various discectomy approaches to LDH. However, none of these surgical approaches to discectomy was invented by the Chinese. China was not as contributive as other countries such as the United States and South Korea, when it came to the creation or renewal of surgical techniques. Similar situations existed in the research institutions. Among the top 10 institutions that contributed the most publications, the number of citations from Chinese institutions was relatively small compared with institutions in other countries. These findings in this study suggest that the United States is the most significant contributor to the development of discectomy in LDH. China developed rapidly in discectomy on LDH but lack of research depth and citation.Spine (118 citations)   (Spine (198 citations) (Spine (172 citations)  (Advances in Neurosurgery (81 citations) (Techniques in Neurosurgery (80 citations) (Neurosurgery (65 citations) (Spine (87 citations)    , Carragetations) , and Mixtations) , Ruettentations) , and Maytations) . Clustertations) , Mauricetations) , and Pertations) . Clustertations) , Cinottitations) , and Swatations) \u201330. WherIn the top 20 keywords sorted by frequency of occurrence, half were associated with surgical techniques and the research of minimally invasive surgery occupied a quite dominant position. In the bibliometric map generated by VOSviewer, clusters 1 and 4 mainly focus on surgical techniques and postoperative clinical outcomes in A consensus has been reached that the operation for re-herniation is associated with more cost and is less effective \u201337. HencThe objective of this study was to evaluate the global research productivity in the field of discectomy on LDH through bibliometric analysis and mapping knowledge domains. Previous published studies have investigated the quantity and quality of articles in the field of full-endoscopic spine surgery . The advThe United States is the most significant contributor to the development of discectomy for LDH. Some countries developed rapidly in the number of publications but lacked research depth and citations, such as China. The current research focus of discectomy on LDH was the comparison between surgical approaches and evaluation of current minimally invasive discectomy. At present, minimally invasive techniques such as endoscopic discectomy cannot completely replace non-endoscopic discectomy (open discectomy and microdiscectomy) through bibliometric analysis and mapping knowledge domains. One of the research hotspots in the future is the control of the recurrence rate and the solution of symptomatic re-herniation after lumbar discectomy."}
+{"text": "Internationally, an increasing body of scholarship has focused on the experiences of transgender individuals when accessing gender-affirming healthcare. However, the experiences of transgender individuals who belong to the foreign background population in Finland have rarely been studied. This study aims to fill the gap in research and contribute to the understanding of the experiences of acquiring gender-affirming healthcare among those, who fall into the intersections of transness and also identify of foreign origin in Finland.Fourteen semi-structured qualitative interviews were conducted and analyzed with reflexive thematic analysis (RTA), through the framework of intersectionality. The interviews were part of a broader sample of qualitative data, collected about the experiences of sexual and gender minorities among the foreign origin populations in Finland.The analysis showed two main interconnected themes. Firstly, perceived barriers when accessing gender-affirming care. In this theme, the intersections of transgender identity, foreign background, class, and age affected the experiences of the individuals. Secondly, the necessity of \u201cperforming identities:\u201d the intersections of class, transgender identity, and race affected those.The findings of the current study suggest that the intersectional aspects of individual identities create structural inequalities in the Finnish gender-affirmation healthcare system. To tackle these inequalities, further research is needed on the healthcare experiences of gender minorities in Finland both within and outside the scope of transgender-specific healthcare.\u2022\u2002Intersectional aspects of individual identities create structural inequalities in accessing gender-affirming healthcare.\u2022\u2002Further research is needed on the healthcare experiences of gender minorities that examines health and wellbeing using an intersectional lens."}
+{"text": "Neurodegenerative diseases (NDDs) are associated with the accumulation of a range of misfolded proteins across the central nervous system and related autoimmune responses, including the generation of antibodies and the activation of immune cells. Both innate and adaptive immunity become mobilized, leading to cellular and humoral effects. The role of humoral immunity in disease onset and progression remains to be elucidated with rising evidence suggestive of positive  and negative  outcomes. In this study, we review advances in research of neuron-targeting autoantibodies in the most prevalent NDDs. We discuss their biological origin, molecular diversity and changes in the course of diseases, consider their relevance to the initiation and progression of pathology as well as diagnostic and prognostic significance. It is suggested that the emerging autoimmune aspects of NDDs not only could facilitate the early detection but also might help to elucidate previously unknown facets of pathobiology with relevance to the development of precision medicine. Neurodegenerative diseases (NDDs) are chronic incurable disorders of the Central Nervous System (CNS) characterized by a progressive decline of synaptic functions and irreversible neuronal loss, with devastating personal impact and overwhelming socio-economical costs. With aging as the main risk factor, the most prevalent NDDs such as Alzheimer's disease (AD), Parkinson's disease (PD), Dementia with Lewy bodies (DLB), Frontotemporal Lobar Neurodegeneration (FTLD), Amyotrophic Lateral Sclerosis (ALS), and Vascular Dementia (VD) are currently on the rise 2+ homeostasis Amongst shared features of NDDs, deposition of misfolded proteins and fragments across CNS, neuroinflammation, dysregulation of glutamatergic signaling, oxidative stress with cytotoxic effects are the most prominent, contributing to neurological and psychiatric symptoms with behavioral impairments. Disruption of neuronal activity, synaptic transmission, and plasticity mechanisms are thought to be caused primarily by the accumulation of aggregation-prone toxic amyloid proteins in the CNS and dysregulation of CaCurrently, there is a major unmet need for low-cost, non-invasive, and reliable methods for the early detection of CNS diseases. With advances in sensing technologies, it is expected that new approaches will be developed to facilitate the accurate diagnosis of NDDs and timely interventions Antibodies (Ab) are large Y-shaped proteins used by the immune system for recognizing and neutralizing foreign materials, through activating the complement system and phagocytosis. Abs are generated by two types of B lymphocytes: B1 and B2. B2 cells produce Abs in follicles of secondary lymphatic organs, which in their majority are regular proteins derived after specific antigenic stimulation As natural immunoglobulins (Ig), Aabs occur in three isotypes: IgM, IgG, and IgA. IgM recognizes and binds post-apoptotic antigens and markers of cell senescence CNS is considered immunologically privileged with very limited exposure to antigens and restricted infiltration of Abs taking place under physiological conditions. This is due to physical and molecular barriers at the blood-CNS interface  and elaborate system of meningeal lymphatic vessels (mLVs) which control the concentration and isoforms of Abs entering the CNS and guide immune cells out to cervical lymph nodes Many disorders affecting CNS, including NDDs, are associated with the disintegration of BBB, which may lead to an out-of-control outflow of neuronal and glial proteins with activation of autoimmune response Gaskin et al. presented the first evidence for A\u03b2 Aabs in the peripheral circulation of AD patients Using an affinity purification approach, Mruthinti et al. found a higher titer of IgG binding A\u03b242 peptide in plasma of AD Microtubule-associated protein tau, which in AD becomes hyperphosphorylated (p-tau), is the main constituent of neurofibrillary tangles. An increase in the level of p-tau in the brain and CSF has been considered as one of the key biomarkers of AD Using circulating IgGs, it was shown that they can recognize modified tau variants, which differ in their characteristics Neurofilaments (NFs) belong to a family of intermediate filaments with their diameter (~10 nm) falling between two other cytoskeletal polymers, i.e., microtubules (~25 nm) and actin (~6 nm). Based on their gene sequence and structural characteristics, NFs are divided into six types (I-VI) NF deposits were found to co-localize with tau tangles in brains affected by AD Soussan et al. compared NF Aab profiles in serum of AD patients and healthy controls. Unlike controls showing equal binding for different isoforms of NF-H  without changing their specificity during aging, in AD, the levels of Aabs against ventral root cholinergic NF-H was higher than those directed against dorsal root NF-H. The phosphoserine content analysis of NFs showed its higher levels in ventral as compared to that of dorsal root NF-H, with Aabs from AD patients binding more effectively phosphorylated epitopes, which show higher prevalence in ventral root NF-H Accumulation of insoluble and misfolded \u03b1-syn in neurons leads to synaptic failure with the build-up of fibrils constituting Lewy bodies (LB) and neurites of DLB and PD The results of the analysis of \u03b1-syn Aabs in the blood of PD patients and comparison with controls vary considerably Table . While sDespite two decades of in-depth research and major progress in developing biomarkers for CNS disorders, the definitive diagnosis of NDDs remains a major challenge. The current diagnostic gold standard - positron emission tomography (PET) - has low sensitivity and is of limited availability, due to high costs and requirements for specialized infrastructure and skilled staff, as well as potential health risks related to the use of radioactive tracers. Substantial drawbacks are also associated with the use of CNS tissue as well as CSF-based assays involving biopsies and lumbar puncture, which necessitates invasive procedures and related major health risks. The emerging Aabs based blood tests seem to offer a specific, rapid, and affordable approach for diagnosis of NDD without major risks and adverse effects. Nevertheless, significant challenges and questions remain, which impede their effective translation and widespread clinical use, calling for further research and optimization in clinical trials. One of the key difficulties is imposed by the discovery of significant amounts of neuronal Aabs in the peripheral circulation in healthy subjects, inferring their potential physiological role, and questing the specificity of selected Aabs for a particular NDD. Another major challenge is imposed by the results of comparative studies, which demonstrate considerable variations of Aabs levels in the peripheral circulation of NDDs that frequently deviate from changes in Aabs titers in CSF. These observations also substantiate the highly complex nature of the immune response to NDDs and underscore the potential shortcomings of utilized detection methods. Together with numerous conflicting reports and outstanding methodological issues, the above-listed considerations call for revision and improvements of sample preparation and standardization of sensing methods. They also highlight the need for more stringent stratification of target groups and profiling of Aabs, to ensure accurate and specific detection and quantification of Aabs. In this context, the use of genetic methods is especially warranted, given the causative and predisposing effects of specific genes in NDDs. Because of the association of NDD with genetic alterations"}
+{"text": "There has been increasing interest in functionalised mineral materials in terms of both scientific research and the development of the world economy. This arises from the growing interest in clean manufacturing technologies that use mineral sorbents, and is related to current issues in environmental and civil engineering, which are receiving significant attention both in the European Union and in international legislation. The price paid for technical progress and economic development in the 20th century was environmental pollution. In the 21st century, modern approaches based on functionalised mineral material technologies are an opportunity for world economic development and for increased industrial competitiveness in global markets while improving environmental conditions. These issues address the challenges faced by industry in protecting the environment, and in the rational use of natural resources in the creation of modern economies and in the development of industry. From the point of view of the world economy, it is important for researchers to create innovative production technologies. To meet these goals, close cooperation between science and industry is needed; thus, studies on the properties and uses of functionalised mineral materials are important.The great focus placed on functionalised mineral materials by modern science and industry is due to their particular properties, knowledge of which interdisciplinary. The interaction of sorbents with organic and inorganic substances, and the use of mineral materials in ceramics, foundries and metals, are the subject of many publications, patents and industrial practices. These effects are fuelled by technological progress and growing demand for increasingly efficient and cost-effective technologies. Moreover, they enhance the capacity of researchers to determine the mineral and chemical composition of mineral materials, as well as their structure and texture. The second group of reasons for the developing interest in functionalised mineral materials is the progressive threat to and degradation of the environment, which demands new means of reducing the impact of industry.Functional minerals are materials inspired by geological systems originating from Earth\u2019s several billion-year-long history. Each of them has a unique chemical composition and structure that determine its properties and possible functions. Natural, synthetic and anthropogenic minerals, both in their original and modified forms, serve as agents in environmental and industrial applications. The functions of mineral materials include: cation and anion exchange, sorption, immobilisation, energy storage, use as catalysts and photo-activity. Layered clay minerals, zeolites and zeolite-like structures, layered double hydroxides (LDHs), are particularly suited to such functions. Modifications of minerals to obtain functional mineral materials include: surface modification, functional loading, intercalation, grafting, doping and structure reformation. This Special Issue, in which we will discuss topics from interdisciplinary studies, aims to highlight the current top trends in the innovative functionalisation techniques of mineral materials. Additionally, reports on unique properties of functionalised materials and their expected applications are presented.The mineralogical and chemical characteristics of Ukrainian volcanic tuffs from the Khmelnytskyi region were determined in . Their p2MnSnS4 (CMTS) acknowledged as an alternative to traditional semiconductors, two different sources of sulphur have been successfully used to synthesise CMTS particles via solvothermal methods [The main objective of  was to s methods . The expIron-Based Water Treatment Residuals (WTRs) are an extremely interesting material, formed as a result of de-ironing and de-manganising drinking water . The higS. saccharatum (L.) biomass, and its application significantly reduced the heavy metal content of S. saccharatum (L.) biomass. Based on data reported in the literature, Ref. [The aim of the  was to ere, Ref.  presents"}
+{"text": "Dear Editor,Melanocytic matricoma is a rare benign cutaneous adnexal tumor that recapitulates the early anagen hair follicle.A 60-year-old man with HIV under antiretroviral therapy presented with a 2-month history of a rapidly growing papule affecting his left preauricular area. Physical examination showed a well-defined 6\u202fmm papule with an uneven coloration ranging from pink to grey . CompletMelanocytic matricoma typically presents as a sharply demarcated, small  unevenly pigmented papule or nodule, arising on sun-damaged skin of elderly individuals, with a male predominance.Clinical differential diagnosis of this entity includes malignant melanoma, pigmented Basal Cell Carcinoma (BCC), and hemangioma.Despite being considered a benign tumor, the clinical behavior of melanocytic matricoma remains unknown because of the few reported cases and the lack of long-term follow-up.5None declared.I\u00f1igo Aranguren-L\u00f3pez: Approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.Sara Ibarbia-Oruezabal: Approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.Nerea Segu\u00e9s-Merino: Approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.None declared."}
+{"text": "Alpine grassland on the Tibetan Plateau (TP) accounts for about 62% of the total area of the TP . These gClimate changes have been evident across the TP since the beginning of the 1970s . For insIn the past 20 years, numerous efforts have been done to explore the patterns, functions, and processes of alpine grassland ecosystems, including transect surveys, field observations, model simulation, comprehensive meta-analyses, and literature reviews. These studies have following characteristics: (i) with the improvement of testing methods, a diversity of technologies have been applied at the technical level such as remote sensing, model simulation, large-scale transect sampling survey, aerial filming, and long-term observation. Scales of these studies range from regional, landscape, ecosystem, and community to micro-molecular and genomic levels; (ii) the observation indexes have evolved from basic to comprehensive, which includes moisture, soil, biology, watershed, and climate; (iii) various factors such as the environmental, natural, human activities, and the impact of the whole habitat on alpine ecosystems were taken into account, and (iv) studies have evolved from trophic levels, food webs, and independent processes of ground and underground to the integration of above and below ground processes of the whole ecosystem. Despite remarkable knowledge gains, there are still some areas that require in-depth research, such as the driving mechanism of the impact of global change alpine ecosystems with new technologies and theories.To advance our understandings of the patterns, functions, processes, and mechanisms of alpine grassland ecosystems responding to changing environments ., we organized a Special Issue (SI) entitled \u201cPatterns, Functions, and Processes of Alpine Grassland Ecosystems under Global Change\u201d. This SI comprises 49 articles, sharing new ideas, techniques, and findings about this subject from field experiments, large-scale transect surveys, alongside remote sensing . These sThe spatial-temporal patterns and drivers of alpine grassland ecosystem under the changing environment are the top priority for the grassland conservation. Due to the scale of the TP, remote sensing is critical for studies on the spatial and temporal heterogeneity of the grassland. Four papers in this SI discuss the spatial-temporal patterns and drivers of alpine grassland ecosystem under the changing environment based on patch, landscape or pixel based remote sensing observations. Seven papers in this SI assess the variations of alpine ecosystem functions, and the response and feedback of ecological processes using long-term simulated experiments and large-scale transect surveys. Some of the studies used the entire TP as the study area and evaluated the complex biodiversity-ecosystem function relationships , the effClimate change and human activities dominate the recent changes in grassland patterns and processes on the TP, thus affecting the ecosystem functions and services. Many of the articles in this SI reveal the driving mechanism of the impact of climate change and human activities  on alpinSeven papers in this SI explored the mechanisms of alpine ecosystem dynamics using new analytical methods, e.g., artificial intelligence learning, network analysis , Bayes aIt is well known that human activities and their feedbacks affect regional sustainable development, but relevant policy measures have rarely be evaluated at the household level. Although some findings on the ecological system of TP may still be somewhat preliminary, all studies included in this SI have undoubtedly promoted our understanding of the patterns, functions, and processes of alpine grassland ecosystems in the context of global change. Some important questions remain unanswered, though. Further explorations need to focus on the following two aspects: (i) more long-term localized observations and manipulative experiments should be employed to reveal long-term change of coupling of plant-soil-livestock-human system and its driving mechanisms. Two TP-wide programs, namely, the Alpine Fence Observation Net (AFON) and the Alpine Climate Change Observation Net (ACON) were established in 2020 and 2022, respectively Figure\u00a01JS, YW, SL, and JL drafted the story line of the editorial. SL, HZ, GW and NH refined the story line and contributed references and insights to the impact of the papers included in this editorial. All authors contributed to the article and approved the submitted version.This work was supported by the National Natural Science Foundation of China (No. 41871040), the National Natural Science Foundation of China Joint Fund Project (U21A20186), the Joint Research Project of Three-River-Resource National Park Funded by the Chinese Academy of Sciences and Qinghai Provincial People\u2019s Government (LHZX-2020-08), Qinghai Natural Science Fund Innovation Team Project (2021-ZJ-902).We thank all the authors who submitted their work to this Research Topics, the professional editorial staff at Frontiers in Plant Science for their support in creating this Research Topic, and the invaluable help of reviewers in manuscript evaluation.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Saudi Arabia\u2019s ambitious Vision 2030 project was launched in 2016 as a strategy for economic development and national growth, with 11 Vision Realization Programs put in charge of its implementation. The backbone of its Transformation Program for the Health Sector has been the definition of a new Model of Care aiming to deliver 42 coordinated interventions across 6 Systems of Care, with the development of clinical guidelines identified as a key cross-cutting intervention to foster the use of national, evidence-based practices across KSA, reduce care variation, and promote accountable care. This article provides an overview of the history, progress to date, and future outlook of the recently initiated National Guidelines Center in Saudi Arabia, established in collaboration between the Health Holding Company and the Saudi Health Council represented by its National Center for Evidence-based Medicine. The lessons learnt from previous guideline initiatives are grouped under the Center\u2019s design principles of high quality, relevance, practical implementation, and sustainability. Aspects setting the project apart from previous endeavors have been its focus on extensive engagement with key stakeholders in the Saudi guideline ecosystem, the co-development of evidence-based recommendations with aligned key performance measures, and the implementation of guideline recommendations in the clinical workflow via integrated electronic order sets. Nine activity streams aim to enable the Center to take its place among the leading regional and global guideline developing organizations and to optimally support clinicians and patients, Saudi Arabia\u2019s health sector transformation, and the work of guideline communities worldwide. Saudi Arabia (KSA) has one of the highest healthcare expenditures in Gulf Cooperation Council countries (GCC), as well as one of the highest densities of medical professionals per thousand residents . This alHowever, non-communicable diseases, particularly diabetes and obesity, continue to burden the kingdom, and are a major target of preventive care screening policies. It has been estimated that the obese population will reach 73% by 2025 . ConversIn response to this situation in 2016, Saudi Arabia launched the ambitious Vision 2030 project as a strategy for economic development and national growth. Eleven Vision Realization Programs (VRPs) have been put in charge of its implementation, including a dedicated VRP and Transformation Program for the Health Sector .The backbone to healthcare transformation is the definition of a new Model of Care that, among other objectives, aims to deliver 42 coordinated interventions across 6 Systems of Care  responsible for the delivery of all health services Fig.\u00a0 5]. The. The5]. Key to achieving the healthcare transformation within the kingdom\u2019s Vision 2030 program was to promote the use of national, evidence-based practices across KSA to reduce care variation and promote accountable care, through regular adaptation/development, alignment, training, and dissemination of localized clinical practice guidelines.In close collaboration with the Saudi Health Council (SHC) represented by its National Center for Evidence-based Medicine, the Health Holding Company (HHC)\u2014established by the Saudi Ministry of Health to drive its Model of Care Health Sector Transformation strategy\u2014has initiated a National Guidelines Center to guide clinical practice and be the advocate for evidence-based medicine, thereby improving the wellbeing of its nation in a sustainable, standardized, and accountable manner.The SHC was established by a Royal Decree issued in June 2002, with its council under the chairmanship of the Minister of Health and whose current members include all health care providing sectors in the kingdom like Ministry of Health, Military hospitals, Saudi Red Crescent Authority and the special regulatory entities i.e Saudi Food and Drug Authority (SFDA), Council of Collaborative Health Insurance (CCHI ) and Saudi Commission for Health Specialties (SCHS) and other ministries like the Ministry of Economy and Planning, the Ministry of Labor and Social Development and the Ministry of Finance. Key among its many tasks of the SHC was to prepare the healthcare strategy in KSA, issue appropriate regulations to ensure that hospitals run by the Ministry of Health and other government agencies are operated in adherence to the principles of economic management as well as performance and quality standards and development and approval of policies for the coordination and integration between all healthcare providing authorities.Over the last few decades, numerous organizations across Saudi Arabia have independently undertaken the task to create documents aimed at guiding clinical decisions, such as guidelines, consensus documents, pathways, and protocols . DespiteTable Important aspects setting our project apart from previous endeavors and aiming to inform similar endeavors worldwide include its focus on extensive engagement with key stakeholders in the Saudi guideline ecosystem, the co-development of evidence-based recommendations with aligned key performance measures, and the implementation of national guideline recommendations in the clinical workflow at the point of care via integrated electronic order sets.As of October 2022, several milestones have been reached including: (i) documentation of the Center\u2019s vision and mission, charter, goals, processes, and policies; (ii) extensive stakeholder engagement with organizations active in the Saudi guideline ecosystem; (iii) confirmation of the SHC National Center for Evidence-Based Medicine as the most suitable entity to host the center following consultation among 19 stakeholder organizations using a RACI (Responsible/Accountable/Consulted/Informed) framework; (iv) based on a data-driven impact/effort analysis, selection of the initial 12 guideline topics as follows: Chronic kidney disease, Dental caries, Community-acquired pneumonia, Cesarean section, Stroke, Sepsis, Acute gastroenteritis in children, Low back pain in adults, Mechanical ventilation, Chronic obstructive pulmonary disease, and Depression; (v) Recruitment of Clinical Leads and multidisciplinary Task Forces for all topics; and (vi) Development of a multi-component dissemination and implementation strategy.Over the upcoming months, work will focus on (i) completing the Center\u2019s first 12 guidelines; (ii) approving the guidelines by the National Center for Evidence-Based Medicine\u2019s Scientific Committee; (iii) disseminating the guidelines via multiple channels including a website, mobile apps, and educational events; (iv) implementing national guideline recommendations at the point of care through localized order sets embedded in the electronic health record at selected pilot sites; (v) finalizing the Center\u2019s internal team and infrastructure; (vi) disseminating guidance on the GIN criteria for giving a seal of approval as national guidelines to those developed by other guideline organizations ; (vii) d"}
+{"text": "Stress is defined as the state of threatened homeostasis. It has been associated with dysregulation of the stress system, consisting of the Hypothalamic-Pituitary-Adrenal (HPA) Axis and the Locus Caeruleus-Norepinephrine/Autonomic Nervous Systems (LC-NE/ANS), as evidenced by altered central and peripheral biomarkers of this system  of the stress system, as evidenced by altered concentrations of stress-related biomarkers and brain changes in individuals with anxiety disorders, post-traumatic stress disorder (PTSD), and depression . The study demonstrated positive associations between low-normal thyroid function at the 2nd and 3rd trimesters of pregnancy and postpartum with anxiety, depression, and OCD scores. These findings are in close relation with the third article of this Research Topic, the mini-review examining the relations of prenatal maternal stress with thyroid function and neurodevelopment of the offspring, by Anifantaki et al. Indeed, both the HPA and the Hypothalamic-Pituitary-Thyroid (HPT) axes are involved in stress responses, whereas, their final effectors, the Glucocorticoids (GCs) and the Thyroid Hormones (THs), mediate several fundamental processes involved in neurodevelopment. It is well established that growth and neurodevelopment of the fetus depend on maternal hormones, especially during the first half of pregnancy. Altered concentrations of both GCs and THs can cause abnormalities in the neuronal and glial structures and functions, with subsequent effects on postnatal neurocognitive function. Experimental studies demonstrate that increased GC concentrations, related to maternal stress, may reduce maternal and, consequently, fetal circulating THs, either directly or through modifications in the expression of placental enzymes responsible for regulating fetal hormonal concentrations.The study of Konstandi et al. suggest that stress plays a central role in the regulation of drug bioavailability in the body, granted that pharmacotherapy may be a potential threat to homeostasis. Thus, stress may contribute to determining a drug's pharmacokinetic profile, as it regulates various enzymes that catalyze the metabolism of the majority of drugs.One opinion article of the Research Topic summarizes neuropharmacological aspects of stress. Makris et al. critically summarized the existing data on stress system alterations in children and adolescents with Autism Spectrum Disorder (ASD). This review focused on the variations of circadian rhythms of cortisol and alpha-amylase, as peripheral biomarkers of the HPA axis and LC-NE/ANS system, respectively, and on stress system responses to different stressors. This review article also included imaging and immunological findings that have been associated with stress system dysregulation in ASD youth. Finally, the article discussed the possible contribution of early life stress in ASD pathophysiology and the developmental trajectory of the stress system in ASD individuals. Similarly, Payen et al., in their systematic review, analyzed existing data on peripheral biomarkers of the gut and the heart in ADHD, the most prevalent NDD in childhood. The article provided a broader view of stress system components, including task-related heart rate reactivity (HRR) and gut microbiota data in children with and without ADHD. Lo Iacono et al., in their review, summarized evidence on the psychobiological effects of childhood sexual abuse, which has been considered a major traumatic experience in childhood. The authors provided data on specific alterations in the endocrine and immune systems, as well as data on epigenetic modifications related to child sexual abuse.Four articles of the Research Topic focus on peripheral neurobiological measures in children and adolescents. Giannopoulos et al. investigated early life sensorimotor sex/age differences using Electroencephalographic (EEG) recordings to measure muscular and neural acoustic startle response (ASR) in a healthy young population. ASR is a cross-species indicator of sensorimotor and inhibitory mechanisms, showing distinct signature in cognitive aging, sex and psychopathological characterization. Neural ASR was assessed by two different analyses, Event-related Potentials (ERPs) and First-derivative Potentials (FDPs). In this study, the modulation of ASR by PPI and PPF was associated with biological sex and internal/external traits in childhood and adolescence, potentially useful to guide symptomatology and prevention of psychopathology.Finally, the research paper by The articles of this Research Topic highlighted the pivotal role of the stress system in neurodevelopment, either as a contributing environmental factor interacting with a genetic background, or as a major physiological mechanism of adaptation in individuals with neurodevelopmental disorders. Various neurobiological measures of stress have been analyzed and discussed by the authors, however, this is only a limited view of the role of the Stress System in the pathophysiology of NDDS. More data are needed to further elucidate and increase our knowledge on the longitudinal role of stress in brain development and in adaptation to everyday and novel/unexpected stressful stimuli.PP wrote the initial draft. AA and GC critically reviewed the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "People with coronavirus disease (COVID-19) may frequently require treatment with psychotropic medications, but the underlying medical condition and possible interaction with medical treatments might pose serious safety issues.To review the direct and indirect evidence on the safety of psychotropic drugs in people with COVID-19 and provide practical recommendations for frontline clinicians.An international, multi-disciplinary working group was established with the aim of producing evidence-based recommendations on the management of psychotropic medications in people with COVID-19, following the WHO Rapid Advice Guidelines methodology in the context of a public health emergency. Evidence retrieved was focused on the risk of respiratory, cardiovascular, infective, hemostatic, and consciousness alterations related to the use of psychotropic medications. Furthermore, drug-drug interactions between psychotropic and medical treatments used in people with COVID-19 was reviewed and critically discussed by the working group.The analysis of available evidence, although indirect, showed that all classes of psychotropic medications might carry relevant safety risks for people with COVID-19. The working group produced a set of 12 recommendations to support clinicians in the assessment of the anticipated risk of psychotropic-related unfavourable events, and how to practically manage this risk, including when it is appropriate to avoid, withdraw, switch, or adjust the dose of the medication.The present evidence-based recommendations will improve the quality of psychiatric care in people with COVID-19, allowing an appropriate management of the medical condition without worsening the psychiatric condition and vice versa.No significant relationships."}
+{"text": "As the scale of foundation pit projects of subway stations in Shenzhen becomes larger, and the construction constraints become more and more complex, there is an urgent need for intelligent monitoring and safety management of foundation pits. In this study, an integrated intelligent approach for monitoring and management of a deep foundation pit in a subway station was proposed and a case study based on the Waterlands Resort East Station Project of Shenzhen Metro Line 12 was used for validation. The present study first proposed the path of intelligent foundation pit engineering. Based on geotechnical survey and building information modeling, a three-dimensional transparent geological model of foundation pit was constructed. Multi-source sensing technologies were integrated, including micro electromechanical system sensing technology, Brillouin optical frequency domain analysis sensing technology, an unmanned aerial vehicle and machine vision for real-time high-precision wireless monitoring of the foundation pit. Moreover, machine learning models were developed for predicting key parameters of foundation pits. Finally, a digital twin integrated platform was developed for the management of the subway foundation pit in both construction and maintenance phases. This typical case study is expected to improve the construction, maintenance and management level of foundation pits in subway stations. In recent decades, various advanced technologies, such as artificial intelligence (AI), internet of things (IoTs), digital twin (DT), and machine learning (ML), have been successfully applied in various activities of civil engineering, such as slope stability analysis ,2, geoteFoundation pit engineering, as one of civil engineering branches, needs to adapt to increasingly complex urban environmental conditions  and striIn this study, 35 published papers related to foundation pit engineering were collected for knowledge mapping. The input keywords in the Scopus search engine included foundation engineering, foundation pit, foundation excavation, foundation construction, BIM, monitoring and automation. A knowledge map of the relationship between the keywords among those literatures was obtained using VOSviewer, as shown in Based on the keyword relevance analysis atlas of intelligent foundation pit engineering, and the analysis of previous engineering cases, it was found that the research content of intelligent foundation pit engineering is often limited to a certain part of the project. For example, through the establishment of computer in-situ 3D transparent geology of the foundation pit, soil information can be retrieved and managed with high accuracy , and theThis study was based on the project of Waterlands Resort East Station of Metro Line 12, Shenzhen, China. The first intelligent foundation pit integrating \u201ctransparent geology multi-source perception deep learning digital twin\u201d was done through in-situ testing, BIM, multi-source perceptions, ML, and DT. This innovation can significantly enhance the design, operation, and management of foundation pit projects for metro stations.This study was based on the project of Waterlands Resort East Station of Metro Line 12, Shenzhen, China. An overview of the project is shown in Through a geotechnical engineering investigation , on-site engineering geological basic information data was obtained. The three-dimensional geological information and foundation pit engineering structure in the current project were modeled with BIM technology to form a three-dimensional transparent foundation pit engineering infrastructure. Based on the deep foundation pit of Waterlands Resort East Station Project of Shenzhen Metro Line 12, this study carried out six in-situ tests, including a double bridge static penetration test, a three-bridge static penetration test, a pressure meter test, a flat shovel lateral expansion test, a vane shear test and a full flow penetration test. The change laws of the strength, permeability coefficient and mechanical parameters of the stratum soil mass, and the fine division of the soil layer and relevant geotechnical parameters, were analyzed based on the test results. As shown in Through multi-source sensing technologies, including MEMS, BOFDA distributed optical fiber, UAV and MV, a safety monitoring assessment of foundation pit engineering was carried out. MEMS technology is mainly characterized by miniaturization and integration . SensorsOptical fiber sensing technology meets the requirements of high precision, long-distance and long-term measurement. Distributed optical fiber sensor, represented by BOFDA, achieves continuous spatial distributed measurements with accurate measurement results and small errors , and is At present, UAV  and MV  technoloDue to the depletion of the sensor itself, the measurement accuracy declines after a period of time, which affects the accuracy of the monitoring results. Different from the traditional single engineering monitoring method, this study uses MEMS sensing technology, BOFDA distributed optical fiber sensing technology, a UAV and MV technology to monitor the working parameters of the foundation pit, including but not limited to axial force, stress, temperature and displacement, to give reasonable play to the advantages of various sensors and make up for the shortcomings of various sensors, and ensure the accuracy and reliability of monitoring parameters.Based on the foundation pit project of Waterlands Resort East Station, an intelligent monitoring platform of foundation pit based on deep learning algorithms and BIM was developed.The back propagation (BP) neural network algorithm is composed of three-layer networks of input layer, hidden layer and output layer. Its core idea is to transmit the output error back to the input layer by layer through the hidden layer in some form ,58. BaseThese four neural network models were used to train the axial force, settlement and displacement dataset of the support system of the deep foundation pit over the past one year and then develop prediction models. The reliability of the proposed models was assessed using root mean square error. The proposed models are expected to be used for the early warning and safety assessment of deep foundation pits. By calculating the relative average error, we found these four ML models can accurately predict the axial force, settlement and displacement. Furthermore, the GA-BP algorithm has the best prediction performance due to the smallest error.The intelligent monitoring platform of the foundation pit was constructed using IoTs technology and a three-dimensional geographic information system . Figure At present, the platform has only been used to monitor the key parameters during the foundation pit construction stage. It is necessary to complete the monitoring of the whole life cycle of the subway station project using other platforms. Based on the related research of traditional foundation pit engineering monitoring and management, the platform was developed by the Future Underground City Research Institute of Shenzhen University in conjunction with Jinan Bimu Digital Software Technology Co., Ltd. , which is convenient for enterprise users to monitor and calculate their own projects. Based on the cast modeling platform of Huawei Kunpeng cloud, the platform completes the application and development of BIM graphics and subsequent multi-source heterogeneous data. The parametric model data is uploaded and downloaded through the cast without loss. The platform supports repeated editing and modification of BIM models and can add/delete monitoring equipment models for many times. The real-time synchronization of the platform is conducive to the monitoring and management of the BIM model at different stages, and the reuse of one modeling for many times greatly improves the application value of the model. The platform provides an open cloud computing framework, supports the loading of third-party algorithms, and is used to calculate and analyze the collected data of different monitoring devices online, and predict the future development trend with one click. At the same time, an algorithm back test function is provided to directly compare the predicted value with the measured value. The accuracy of the prediction result is evaluated and the most appropriate algorithm according to the data type is selected. As shown in Based on Waterlands Resort East Station Project of Shenzhen Metro Line 12, this study developed a DT app terminal open platform integrating intelligent construction and management of rail transit foundation pit. Unity3D was used to realize intelligent upgrading of two-dimensional drawings. The platform accomplished the integration of a station building drawing and model, and all current project drawings of the enterprise could be viewed in the start page. The current platform was divided into two parts: intelligent construction and intelligent management.As shown in This app is currently applied only to the integrated intelligent construction and management project of Waterlands Resort East Station Project of Shenzhen Metro Line 12. If it is to be applied to other projects, it needs to import relevant information. At the same time, the compatibility problem of the app still needs to be improved. Currently, it can only be used for mobile phones equipped with the Android system. Different from the traditional DT platform, the app includes three major functions: three-dimensional visualization, full life cycle monitoring and predictive analysis. Three-dimensional visualization breaks the traditional mode of integrating building information through plane drawings, and maps the building model of the physical real world through 3D modeling technology. The information integration of DT from planning and design to construction to operation and maintenance stage ensures the integrity and consistency of data and runs through the whole life cycle of the subway station. The introduction of DT technology provides a basis for predictive decision-making and analysis. The key parameters are monitored by the sensors, and the data collected by the monitoring sensors are analyzed with the help of the deep learning algorithm, and the safety level is predicted at the same time.Augmented reality combines real world information and virtual world information. Through real-time imaging, three-dimensional and other technologies, it projects physical information that is difficult to experience in a certain time and space range of the real world into a real world in the form of virtual information, so as to be directly captured by human senses and achieve a perceptual experience beyond reality. The working principle of AR includes video capture, graphics system, video synthesis, and video output. As shown in Through on-site geological investigation, refined geological information of the on-site soil layer was obtained. Three-dimensional transparent geology was then developed on the BIM platform to facilitate information management of the on-site soil layer and effectively control the construction risk;Through MEMS sensing technology, BOFDA distributed optical fiber sensing technology, laser radar, UAV and machine vision technology, the key parameters of the foundation pit, including but not limited to axial force, displacement, strain, temperature, etc., were obtained. The accuracy and reliability of monitoring data were greatly improved using a variety of monitoring methods and multi-source sensing technology;An intelligent monitoring platform of foundation pit based on BIM of independent intellectual property rights was developed using a cast modeling cloud platform to realize integrated monitoring and management of the foundation pit during construction. Four ML neural network algorithms were used to predict the key parameters of the foundation pit. It was found that the algorithm with the smallest error in the project was the GA-BP algorithm;A DT app terminal open platform integrating intelligent construction and operation and maintenance of rail transit was developed using DT means, which included three major functions: three-dimensional visualization, full life cycle monitoring and predictive analysis. Based on app and augmented reality technology, BIM 3D model, facilities, equipment and other operation and maintenance data were combined with the current real tunnel scenario to realize the DT of subway stations.This study advances a new idea for an integrated intelligent approach for monitoring and management of a deep foundation pit in a subway station, which is divided into four modules: the implementation path of intelligent foundation pit engineering, field investigation and in-situ test, multi-source perception technology, ML prediction algorithm and DT integration of foundation pit construction and operation and maintenance. This innovative idea was implemented in the foundation pit engineering of the Waterlands Resort East Station Project of Shenzhen Metro Line 12. The main conclusions are as follows:At present, the data obtained from the in-situ test reflect the real parameters of rock and soil to the maximum extent. The stability of different types of sensors is different, resulting in high cost and long time-consuming of the monitoring platform with multi-source information fusion. Different from the traditional foundation pit project management scheme, this research achieved the integration of construction, operation and maintenance and management of intelligent foundation pit project through four modules of \u201ctransparent geology multi-source perception deep learning digital twin\u201d, which intuitively displays the soil layer information, monitoring data, prediction results and three-dimensional models of construction and electromechanical, greatly improving the project management efficiency of engineering personnel."}
+{"text": "Alcohol is frequently used in association with cannabis, with co-use now perceived as normative with expanding cannabis legalization. Cannabinoid products are increasingly used for a number of medical and recreational purposes, including to enhance alcohol-reinforcing properties or in some cases to substitute for alcohol. Rates of alcohol use disorder (AUD) are higher among cannabis users relative to nonusers, with approximately 60% of individuals with current cannabis use disorder also meeting criteria for current AUD.This research review series approaches cannabinoid\u2013alcohol co-use through the lens of complex interactions between biological, psychological, and environmental factors. Basic science research reviewed in this topic series highlights the role of the endogenous cannabinoid or endocannabinoid (eCB) system in alcohol-related behaviors. The eCB system, which regulates cannabis reinforcement, is also involved in modulating alcohol reinforcement, motivation to consume alcohol, excessive alcohol consumption, AUD,Cannabinoids may reduce harmful effects of AUD, in part, by conferring beneficial effects on the gastrointestinal and immune systems.This translational research series strives to elucidate the cannabinoid\u2013alcohol interactions by synthesizing findings across animal studies as well as human laboratory and epidemiological designs from community and clinical samples. From synapse to policy, the reviews in this series reflect the current state of the science on the reciprocal impact of alcohol and cannabinoids on an individual and the society at large. Several comprehensive reviews summarize findings from preclinical and human studies on the effects of alcohol exposure on the eCB system as a whole34This topic series aligns with the research efforts discerning the shared impact of cannabinoids and alcohol on health undertaken by the Collaborative Research on Addiction at the National Institutes of Health (CRAN) partnership between the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse (NIDA), and the National Cancer Institute. Elucidating effects of cannabis and alcohol co-use on health, policy, and economy is also a key research priority identified by the Cannabis Policy Research Workgroup of the NIDA National Advisory Council on Drug Abuse (NOT-DA-22-003). The empirical literature on cannabis and alcohol co-use has grown fourfold in the last decade alone, reflecting burgeoning interest in this topic. As summarized in the articles in this series, more research is needed to improve our understanding of the mechanisms underlying the functioning of eCBs in relation to alcohol in order to advance the development of eCB-based pharmacological treatments of AUD and related conditions. Clinical data examining the role of specific cannabinoids in alcohol-related human behavior also are critically needed to inform clinical guidelines for individuals engaged in AUD treatment and/or people who drink heavily and co-use cannabis. The authors lend crucial insights and make specific recommendations for future research endeavors on alcohol and cannabis interactions, taking into account between-person and within-person variability across time and contexts. All together, these findings will have important implications for the development of policy concerning alcohol in the context of the changing cannabis sociopolitical landscape."}
+{"text": "Currently, there are no ideal medications for treating anorexia nervosa (AN) and bulimia nervosa (BN). This is due to the variety of symptoms from the mental and somatic spheres.Describe the modern methods of psychopharmacotherapy AN and BN.Data from available publications on the topic of psychopharmacotherapy AN and BN, and long-term practical experience of research staff the Department of psychiatry and medical psychology RUDN University, Moscow.Therapy includes antidepressants (AD) - serotonin reuptake inhibitors (SSRIs), antipsychotics and tranquilizers. AD groups of SSRIs reduce most of the symptoms AN and BN - depressive disorders, anxiety, obsessive and compulsive symptoms, episodes of overeating and purifying behavior, suicidal thoughts, and reduce the frequency of relapses. With severe and persistent dysmorphophobia, a high degree of impulsivity, and psychopathic behavior second-generation antipsychotics Quetiapine, Olanzapine, Risperidone and Aripiprazole are used. Benzodiazepine tranquilizers (Lorazepam) are used in small doses and as additional therapy. Data from the European national guidelines for the treatment of AN and BN very different, and the world Federation of societies for biological psychiatry (WFSBP) does not provide specific recommendations at all. There are many reasons for disagreement and lack of specificity regarding drug selection, including the lack of an equally solid evidence base, that reflects the modern state of research on the psychopharmacological treatment of eating disorders.In General, therapy AN and BN should be comprehensive - psychopharmacotherapy, psychotherapy, diet therapy, social rehabilitation. Treatment should be carried out both in the hospital and on outpatient basis and should be decided individually.No significant relationships."}
+{"text": "Most passengers and goods in Canada travel by road. The trucking industry is the backbone of the tangible goods economy. However, the health and well-being of this aging workforce is in jeopardy. Recent data reveals that 86% of the truckers\u2019 community are 50 years old and over, 4% are female and 5% are immigrants. Moreover, 75% of the male truckers self-reported one or more health condition . Despite, the high prevalence of risk factors  and preventable chronic diseases among truckers, in New Brunswick and elsewhere in Canada, there is a lack of on-the-road accessible lifestyle change programs. Therefore, tailored interventions are needed to appropriately support them adopt healthy behaviors. Using the Re-AIM Framework, we carried out 23 semi-structured interviews to inform the development of tailored educational material. The aims were: to describe the needs and challenges and to design a truckers-sensitive educational intervention. The theoretical foundation of this qualitative study is articulated around concepts extracted from cognitive and behavioural theories . Qualitative analysis of verbatims identified four major themes: Lifestyle challenges, Social and individual representation of healthy behaviors, Health education strategies and communication and Motivational and engagement strategies. Drawing upon these findings we developed tailored educational material and pre-validated them with a small group of professional truck drivers. Our findings informed the development of an educational intervention to support truckers manage and improve their mental health and self-management of chronic diseases. The next step is to implement a randomized clinical trial to test and assess acceptability, feasibility, and effectiveness of our intervention.Improving mental health of professional truck drivers is an urgent public health issue.Format and content of mental health and chronic disease self-management need to be adapted at the cognitive  and capacity  level."}
+{"text": "Peste des petits ruminants virus (PPRV) is an important agent of contagious, acute and febrile viral diseases in small ruminants, while its evolutionary dynamics related to codon usage are still lacking. Herein, we adopted information entropy, the relative synonymous codon usage values and similarity indexes and codon adaptation index to analyze the viral genetic features for 45 available whole genomes of PPRV. Some universal, lineage-specific, and gene-specific genetic features presented by synonymous codon usages of the six genes of PPRV that encode N, P, M, F, H and L proteins reflected evolutionary plasticity and independence. The high adaptation of PPRV to hosts at codon usages reflected high viral gene expression, but some synonymous codons that are rare in the hosts were selected in high frequencies in the viral genes. Another obvious genetic feature was that the synonymous codons containing CpG dinucleotides had weak tendencies to be selected in viral genes. The synonymous codon usage patterns of PPRV isolated during 2007\u20132008 and 2013\u20132014 in China displayed independent evolutionary pathway, although the overall codon usage patterns of these PPRV strains matched the universal codon usage patterns of lineage IV. According to the interplay between nucleotide and synonymous codon usages of the six genes of PPRV, the evolutionary dynamics including mutation pressure and natural selection determined the viral survival and fitness to its host. Morbillivirus, family Paramyxoviridae, and order Mononegavirales (Peste des petits ruminants (PPR) caused by peste des petits ruminants virus (PPRV) is a highly contagious, acute and febrile viral disease of wild and domestic small ruminants, and poses a great threat to the ruminant industry in the world . PPRV waavirales . This isavirales . H and Favirales .The PPR outbreaks can cause high morbidity and mortality, resulting in severe economic losses in the developing countries. Hence, the analysis of epidemic tendency and evolutionary dynamics of PPRV for prevention and control remains particularly important. A Bayesian phylogenetic analysis of all PPRV lineages (I-IV) identified an ancestral PPRV and individual lineages of Nigeria for PPRV and Senegal for lineage I, Nigeria/Ghana for lineage II, Sudan for lineage III and India for lineage IV . In addiThe 45 whole genome sequences of PPRV strains available were downloaded from the National Center for Biotechnology (NCBI) Genbank database, accessed on 1 September 2017 . Based oAs for the nucleotide usage bias at gene levels of the 45 PPRV strains, the normalized information entropy over the frequencies of different nucleotides in a given gene was presented by the below formula :fi is the probability of the specific nucleotide (Fi), and Fi is the total number of occurrences of the specific nucleotide in the target gene . The value of Entropy for nucleotide usage bias ranges from 0 to 1, representing how the dispersed contribution of these four types of nucleotides is: the higher the value is, the more uniform the nucleotide usage is; in contrast, a lower value reflects a more biased usage of nucleotides.where To further compare the nucleotide usage biases in the six coding sequences, the overall nucleotide usage biases, and the nucleotide usage biases at the 1st, 2nd, and 3rd codon positions were estimated by One-way ANOVA method in SPSS 16.0 software, respectively.The relative synonymous codon usage (RSCU) values for the given coding sequences of the PPRV strains were calculated to quantify synonymous codon usage bias without the confounding influence of amino acid usage patterns or the length of different gene samples . Of noteD was introduced into this study  is defined as a cosine value of an included angle between A and B special vectors, meaning that the evolutionary distance between gene A and gene B at the aspect of 59 RSCU values, ai is defined as the RSCU value for a specific codon in 59 synonymous codons of gene A, and bi is termed as the RSCU value for the same codon of gene B. Here, the lower the D value is, the higher the extent of similarity of codon usage patterns between gene A and gene B.where http://genomes.urv.es/CAIcal, calculated the CAI for a group of viral sequences using the specific host reference set and included a complete set of tools related with codon usage adaptation. The host reference set required to calculate the CAI can be introduced in the codon usage database of the host. The synonymous codon usage patterns of host as reference, the synonymous codon usage bias with high extent represented the highest relative adaptation to the host, and coding sequences with higher CAI values should be regarded preferred over those with lower ones  were selected as the reference set, and the related data was obtained from the Codon Usage Database (The codon adaptation index (CAI) analysis of PPRV coding sequences were carried out depending on the CAIcal server , which wwer ones . The synDatabase .Rij)   was intrandXi is the standard deviation of the Euclidean distance between each point (Bi) in the ith group and the centroid (Ai) of the ith group; Xj means the standard deviation of the Euclidean distance between each point (Bj) in the jth group and the centroid (Aj) of the jth group, Tiand Tj standard for the total numbers of points in the ith group and in the jth group, respectively. Mij is the Euclidean distance between the centroids (Ai and Aj) of the ith group and the jth group. The smaller the Rij value is, the stronger the interaction between the two groups.p-value was <0.05. Linear regression was used for modeling the relationship between a scalar dependent variable and one independent variable using the software GraphPad Prism 6 for Windows.One-way ANOVA method was used to compare the means of two or more groups containing numerical response data using the software SPSS 16.0 for Windows, and significant difference can be identified when P < 0.0001). Generally, the nucleotide usage patterns represented the gene-specific compositional trends rather than the similar compositional trends with the overall content of nucleotides  analysis also found highly similar extent of synonymous codon usage in viral genes of the three groups (Although the PPRV strains from China (2007\u20132008), China (2013\u20132015) and other countries generally shared a similar synonymous codon usage pattern , the dife groups  based one groups . In addie groups . These rOvis aries) cellular machinery. Based on the classification of gene types, a strong significant difference was found (Ovis aries) based on RSCU data for Ovis aries  and AAU (Asn) in F gene, UCA (Ser) in H gene, UUG (Leu), UCA (Ser) and AAU (Asn) in L gene, CUA (Leu) and UCA (Ser) in M gene and UCA (Ser) in P gene. These synonymous codons likely mediated and regulated the relevant viral genes translation due to its low corresponding tRNA abundance in the host.The CAI analysis were performed to estimate the correlation between the synonymous codon usage bias and the expression efficiencies of gene samples of PPRV, implying that the strong codon adaptation of the viral genes fit the host  indicated that despite the obvious effects of nucleotide usage biases at different codon positions on the overall codon usage bias of PPRV coding sequences, nucleotide usage biases at the first and second codon positions played more vital roles than that at the third codon position in the codon usage bias for the coding sequences  . AnotherPreviously, the major bottleneck limiting in better understanding of the genetic features of PPRV was their dependence on nucleotide usage variation. Although nucleotide usage variation can be regarded as evolutionary dynamics of PPRV genome, synonymous codon usage patterns of PPRV coding sequences carry more genetic information, including viral adaptation to hosts, viral gene expression, and effects on the biological functions of viral protein.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/Conceptualization: XW, F-yP, and F-qX. Methodology: F-yP, F-qX, XW, and D-rZ. Software: XW and F-yP. Formal analyses: F-yP, D-rZ, XW, and JS. Writing-review and editing: XW, JS, and F-qX. All authors contributed to the article and approved the submitted version.This work was supported by Department of Science and Technology of Gansu Province Nature and Science Fund [21JR1RA141], Cuiying Scientific and Technological Innovation Program of Lanzhou University Second Hospital , Cuiying Postgraduate Student Supervisor Culture Plan [CYDSPY202005], Innovation Foundation for Higher Education Institution of Gansu Province [2020B-022], and Gansu Province Science and Technology Fund [20JR10RA737].The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Rural households are facing severe challenges while adapting to existing and emerging risks of various kinds, including the effects of unprecedented shocks that affect individuals and families in terms of lack of income, reduced consumption and the sale of assets. Health shocks, i.e., unpredictable diseases that undermine people's health status, are the most common unprecedented shocks and the most pressing causes of families falling into poverty. When an illness or injury impairs the health of a family member or causes the income of the family to be reduced or even lost, the family is faces high levels of vulnerability due to the costs of medical treatment as well as the lack of income caused by incapacity for work. Health shocks, together with economic ditto, thus place a heavy financial burden on families and are, de facto, one of the most important factors related to poverty in these regions.Risk adaptation and coping has become necessary activities for families living in rural areas of low and middle income countries, but this is also taking a significant share of their income. Consequently, understanding these risks and related coping strategies is crucial for policymakers. This is also reflected in the Global Development Report entitled Risks and Opportunities, which examines how families can cope with the wide range of risks they face.The focus of this special issue addresses the effects of COVID-19 on rural areas in the Low- and Middle - Income Countries. Several researchers submitted a significant number of high-quality papers for consideration in this special issue, which went through a rigorous peer-review process, with an acceptance rate of 50%. Finally, 16 quality contributions were published, and among them were the following papers:COVID-19's Impact on China's Strategic Emerging Industries: An Observation of Policy Difficulties studies the influence of the COVID-19 on R&D investment and foreign exchange development of China's most important emerging industrial firms.Analysis of Preventive Behaviours of Rural Tourism Hosts in the Face of COVID-19 Pandemic: Application of the Health Belief Model discusses preventive behaviors of rural tourism hosts and the COVID-19 utilizing the HBM model.Investigating the Adoption of Precautionary Behaviours Among Young Rural Adults in South Iran During COVID-19 investigates the factors affecting youth intention and preventive behavior with respect to COVID-19, also using the HBM.Besides of those the issue also discussed the following topics:Social, Environmental and Economic Impact Assessment of COVID-19 on Rural tourism.Dynamic conservation in risk society: A case study of COVID-19 pandemic risk in Kashan Qanat Irrigated Agriculture.Tourism development during the pandemic of coronavirus (COVID-19): Evidence from Iran.The impact of COVID-19 pandemic on food security, and food diversity of Iranian rural households.How do collective efficiency and norms influence the social resilience of Iranian villagers against COVID-19? The mediating role of Social leadership.Impacts of COVID-19 pandemic on micro and small enterprises (MSEs): Evidence from Rural Areas of Iran.Developing a paradigm model for resilience of rural entrepreneurial businesses in dealing with the COVID-19 crisis; application of grounded theory in western of Iran.We hope that the papers presented in this special issue will be useful and stimulating for further understanding of risks, vulnerabilities, and counter mechanisms available to deal with a wide range of health and economic shocks faced by rural households and to properly design and develop social safety nets.https://www.frontiersin.org/research-topics/41035/addressing-the-effects-of-covid-19-on-rural-areas-in-low-and-middle-income-countries-volume-2.Due to the good response from the researchers to this Research Topic, the journal has decided to initiative, the Volume 2 with the same editorial team. Further information can be found at: All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Prefabricated construction is one of the solutions to the problem of balancing environmental improvements with the new buildings in the construction industry. Some work originally done on site is transferred to the front end, and the occupational health risks to industrial workers during the production of prefabricate concrete components are thus aggravated. This study aims to propose a framework to simulate the occupational health risks of workers in prefabricate concrete component plants from the perspective of risk identification, risk assessment, and risk control. Through the following 4 steps, including environmental release monitoring, diffusion and human inhalation mechanism analysis, occupational health risk evaluation, and full-path health risk simulation, this study maps physical entities to virtual reality. The proposed method tends to address the root causes behind occupational health risks, such as the lack of measurement, assessment and prevention criteria, and providing new ideas for theoretical research and innovative practice of HSE management and risk management in the construction industry. Green Building Action Plan released in 2013. In 2018, the Chinese government further made the vigorous development of prefabricated buildings a key task and overall requirement for the future. In 2021, the Chinese government released the Action Plan for Carbon Peaking by 2030, which aims to accelerate the application of prefabricated buildings and the industrialization of construction. Even under the influence of the epidemic, the total building area of new prefabricated building in China reached 740 million square meters in 2021, accounting for about 25% of total area of new construction with more than 500,000 workers employed.The construction industry faces the problem of balancing economic growth and environmental impact. The concept of prefabricated building is an innovative solution to this problem. Compared to traditional forms of construction, prefabricated building has the advantages of increasing efficiency, shortening periods, lowering costs, saving energy, reducing consumption, reducing environmental pollution and sustainability in the production, construction and use processes , 2. TherPrefabricated buildings can be divided into concrete structures, steel structures, bamboo and timber structures according to the type of structure, among which prefabricated internal/external wall panels, prefabricated floor slabs, prefabricated staircases and prefabricated balconies as the main components of prefabricated concrete structures are the most common, accounting for over 90% of the market share . Unlike Occupational Health and Safety Management System Guide in the UK, the Occupational Health and Safety Management System in the US, the Occupational Health Inspection Management Regulations in China, the Occupational Health and Safety Management System General Guide in Australia, the Occupational Health and Safety Management System Guidelines in Japan and the international standard Occupational Health and Safety Management System Requirements and Guidelines for Use. However, the risk regulation system and standards for the assembly construction industry, which lies between manufacturing and construction industry, are still immature and require systematic theoretical research results to support the development of risk evaluation criteria and the control of the overall process.The environmental protection authorities in most country will review the environmental assessment before the project goes into operation. However, the focus is on the impact of the plant's emissions on the external environment, while neglecting the occupational health of workers. For example, although a certain prefabricated concrete (PC) component manufacturer acquired ISO 9001 and ISO 14001 certification and meet the 17 elements of environmental management, there are only a few words of discussion concerning the occupational health of workers. In addition, through the preliminary site survey and visits, some PC component production enterprises, especially the small plants, have problems such as dust, noise and odor, and workers lack the necessary protective measures and awareness of health protection, which exposed them to serious occupational health risks. A series of occupational health-related laws and regulations are enacted worldwide, including the Thus, this article is grounded in the intersection of engineering, environmental, and health management. A logical framework of occupational health risks was formed using risk management concept to identify the full pathway process of environmental release, combined with a personal exposure assessment method to form a simulation model of occupational health risk assessment for the whole process workers. It is also applied to real-life cases to form a complete set of long-term management models of occupational health risks caused by environmental release, providing a new paradigm for research in the field of occupational health risk management.The environmental release in this study refers to the hazardous substances or energy spilling, leaking, emitting or escaping into the external environment in physical or chemical form. The construction phase is long with many upstream and downstream industries, complex construction elements, and huge amounts of construction materials, machinery and energy, thus generating various types of environmental release at all stages of building production, transportation, construction, decoration and renovation . The maiTraditional building products, especially concrete components, are mostly cast on site in an outdoor open environment, and the resulting harmful environmental release are easily dissipated into the atmosphere, so the exposure concentration/intensity of industrial workers is relatively low. The production of PC components is conducted in industrial plants, and the production process produces various harmful environmental release, such as dust, noise and VOCs. Industrial workers have long been in this semi-enclosed space with high environmental release and high intensity, suffering serious potential threat to the health in the short or long term.\u201cOccupational health risk\u201d refers to the possibility of work-related diseases or occupational diseases caused by workers' exposure to occupational hazard factors in the process of occupational activities, and its health damage consequences have specific probability and severity . OccupatOccupational health risk assessment can be divided into qualitative, semi-quantitative and quantitative risk assessment methods. In the 1990's, European and American countries and international organizations successively issued occupational health risk assessment guidelines or norms to assess and manage the risk of hazardous substances in the workplace, For example: ICMM Operational Guidelines for Occupational Health Risk Assessment, Occupational Exposure Limits Evaluation Methodology, New Guidance on Inhalation Risk Assessment, Simple Elements of Chemical Occupational Hazard Classification and Control Techniques, Romanian Risk Assessment Methodology for Occupational Accidents and Occupational Diseases, Australian Guidance on Occupational Health and Safety Risk Assessment Management, International Council on Mining and Metals Occupational Health Risk Assessment Guidance, Risk Assessment Methodology for Occupational Exposure to Toxic Chemicals, ICI Mond Toxicity Index Evaluation Method and so on \u201333. In aThe United States National Institute for Occupational Safety and Health (NOSH) research report indicated that there are as many as 39 categories related to occupational health and safety in the construction industry, such as: sandblasting, blood lead, asbestos, asphalt, carbon monoxide, eye diseases, high temperature and pressure, quartz, skin exposure, noise and so on. At present, in addition to Australia, Sweden, Germany and other countries with good occupational health management, there are still some countries in the world with relatively weak research on occupational health management in the construction industry, and there is still a great room for improvement in occupational health management in the construction industry.Previous research OHSAS and HSE management system as the core, aiming at comprehensive evaluation of the construction industry practitioners of occupational safety and health risks. In fact, multi-source harmful environmental release is one of the causes of occupational health risks. From the perspective of building types, studies mainly focus on traditional building forms and their construction processes, while studies on prefabricated buildings, especially the PC component production are relatively few. In terms of the type of emissions, the vast majority of studies focus on emissions of carbon dioxide and other greenhouse gases that have profound effects on human health and the environment. However, there are few studies on environmental release such as dust, noise and VOCs that pose acute/chronic threats to the health of construction workers. In addition, previous studies lack real-time and long-term monitoring and dynamic optimization of emission sources and their surrounding environment, resulting in the lack of universality of static data obtained from a single measure, and the lack of referential results and conclusions.The Life Cycle Assessment (LCA) can be used to assess the impact on human health of various pollutants emitted from the entire process of product production, with emphasis on a long term and cyclical evaluation concept . Risk MaThe risk identification is divided into three parts through the investigation and literature review to understand the mechanism of environmental release from the perspective of LCA. In the Risk Assessment stage, the occupational health risk assessment method and a simulation model adapted to the PC component production phase are built, so that the risks can be can be quantified and optimized. Finally, the modeled risk assessment system is put into empirical analysis. We will control the risk status of all aspects accurately and put forward policy advice. With the records of the database, the effect of measures on risk reduction are tracked and monitored, and the information is feedbacked to the risk evaluation and risk management system to achieve dynamic risk control .Given that the uncertain factors occur as probabilistic phenomenon, the individual exposure assessment method is used in this study. The individual exposure assessment method is used to simulate the probability of inhalation, exposure and exposure to hazardous environmental release during a worker's long-term work, and thus to assess occupational health risks . It can CDIi denotes the chronic daily inhalation/intake of emission i (mg/kg/d), Ci is the concentration of emission i (mg/m3), IR is inhalation rate (m3/h), ED represents exposure duration (h/d), EF is exposure frequency (d/a), EL is years of exposure, BW is body weight (kg), and AL is average life cycle (years).Where In the available health risk assessment literature, hazardous compounds are usually classified as non-carcinogens or carcinogens . For carCRi denotes carcinogenic risk of emission i, ISFi is inhalation slope factor for emission i (kg\u00b7d /mg), HQi means Hazard Quotient, namely the ratio of the concentration of emission i to its reference concentration RfCi in a given time period, with HQi \u22651 indicates that the emission concentration is high enough to cause chronic non-carcinogenic effects. RfCi symbolizes the reference concentration factor of emission i (mg/m3). ISFi and RfCi are captured in the US Integrated Risk Information System (IRIS).Where DALY) is used to quantify the disease burden and injuries in human populations in the Global Burden of Disease Study and perform a quantitative assessment of health damage (DALY as shown in Equation (4)  .YLL denotes the year of life lost. YLD is the year of life lived with a disability. It is a time-based measure that combines the time lost due to premature mortality and the duration of disability caused by illness in survivors.Where According to the three stages of risk management theory, this study builds an occupational health risk framework, starting from the three stages of risk identification, risk assessment and risk control, including research content, technical roadmap and methods, as shown in Identifying the source of environmental release and confirming the emission characteristics. Specifically, it includes the following two contents: (1) Sorting out the current production process and process characteristics of typical prefabricate concrete component plants assembly lines. (2) Determining the type, location and extent of environmental release resulting from operations such as material fugitive, energy consumption and mechanical equipment operation during the production of prefabricate concrete components. Taking PC exterior wall panels as an example, their production contains more than 30 processes such as cleaning the mold, installing reinforcement cages, pouring and vibrating, and spray release agent, etc. The potential harmful environmental release during the process mainly contains dust, noise, and VOCs, as shown in Detection and analysis of environmental release properties in precast concrete components plants includes: (1) Field sampling of dust, VOCs gas and other aerosol substances using cyclone particulate collectors, vacuum sampling pumps, Teflon filter membranes, etc. Samples collected in the field are sent to the laboratory under light-free, low-temperature and dry conditions. (2) The material class and particle size interval of the solids in the filter membrane, and the composition and proportion of the gas in the sampler, respectively, with the aid of gas chromatography/mass spectrometry (GC/MS), according to the standard test method provided by the National Institute for Occupational Safety and Health Research (NIOSH). (3) Toxicological and human potential damage analysis was conducted for all detected substances, and the substances with a large proportion and heavy hazard were finally selected as the final environmental release types .Based on the source emission characteristics, the diffusion and dispersion mechanisms of environmental release are analyzed using spread and dispersion laws as follows: (1) Using monitoring equipment such as laser dust meter, acoustic meter and photo-ionization detector to monitor the emission sources and the surrounding environment at fixed points to obtain real-time data on the change in concentration of dust or gas emissions during the production of prefabricate concrete components and the change in intensity of noise, respectively. (2) Collecting and measuring data on potential influencing factors such as spatial boundaries, wind speed, wind direction, temperature and humidity within the plant during the same production time period using temperature/humidity meters, anemometers and so on. (3) Establish an environmental release propagation/diffusion model, and simulate the transport trajectory, diffusion path and concentration distribution of dust and gas, as well as the propagation distance and decreasing degree of noise, respectively, with Fluent software. (4) Determine the propagation or dispersion pattern of various types of environmental release during the production of prefabricate concrete components.The human intake mechanism of environmental release includes the following four steps: (1) Real-time monitoring of noise intensity and emission concentration data at the ear, mouth and nose of workers of different job types during production operations by requiring workers to wear portable devices. (2) Deploy RFID sensor devices at designated locations to collect and record data on workers' job characteristics, behavioral habits, movement range and other potential influencing factors. (3) Modeling the inhalation/exposure dose of workers to simulate their inhalation, exposure dose, or exposure level to short-lived environmental release under specific constraints. (4) Determine the way of environmental release from human intake during the production of prefabricate concrete components. A number of instruments and equipment are used in these processes, which are highly specialized and sophisticated. The main instruments and equipment mentioned above are shown in On the basis of the risk identification and assessment methods, the simulation model was established to establish the \u201cEmission-Transmission-Inhalation\u201d whole process of worker occupational health risk simulation and evaluation model. The simulation module of each part is established, specifically including: (1) Establish a basic simulation module of prefabricate concrete component production process and emission source location based on building information model. (2) Establish a numerical simulation module based on computational fluid dynamics to simulate the propagation and dispersion of environmental release in component plants. (3) Establish a multi-intelligence-based worker production behavior and health injury simulation module. (4) Create a multiple sources database module containing information on environmental release monitoring, worker health data, emission factors and so on. (5) The application development platform is selected to integrate the above simulation modules and database to build a quarriable, editable and calculable occupational health risk simulation and evaluation model, as shown in Based on the life cycle risk management evaluation method, combined with the above simulation model, the long-term control of occupational health risks caused by environmental release is formed. For the identification of risk control strategies, the target case analysis takes into account the results of risk evaluation and identifies control strategies based on the classification of carcinogenic risk and chronic disease risk respectively. Then, based on the Critical success factors (CSF) analysis method, the key success variables of environmental release risk control are searched from three aspects: emission sources, transmission paths and recipient individuals.Drawing a fishbone diagram to identify, define and develop specific measures included in the above three CSFs, such as reducing dust/gas release due to handling, disturbance or vibration of parts, installing sound insulation and noise reduction equipment, installing sprinkler systems, optimizing ventilation systems, temperature and humidity regulation systems, regular cleaning and decontamination, requiring workers of specific jobs to wear protective equipment, strictly setting daily/yearly working hours for workers of certain special jobs, adopting a job rotation system on a regular basis, etc. Fishbone diagram through critical success factor analysis, the gray correlation algorithm is used to determine the gray correlation between the above measures and to develop the optimal combination strategy. The process is shown in SM is the simulation model, PE is physical entity, VE is virtual entity, SS is service, DB is data, and CN is the connection between the parts.The simulation model contains five key elements as shown in Equation (5), where: PE is the basis for building the simulation model. In the project, a single PC component production machinery and equipment can be regarded as a unit-level PE, which is the smallest unit for function realization; a full set of PC component production line can be regarded as a system-level PE, which can complete the component production task; the whole plant composed of production line, environmental Emission and workers can be regarded as a system-level PE, which is a comprehensive system including material flow, emission flow and information flow, including four parts of human-machine-material-environment, as shown in Equation (6).Physical layer element identification and data acquisition. The accurate analysis of Hp describes the scope of action and behavior of industrial workers in the production process of components, and the data are obtained through RFID and image recognition technologies; Mp describes the operation of production machinery and production lines, and is portrayed and simulated through preliminary research and continuous probability events; Pp describes the production process of PC components, and is built through the material flow model; Ep describes the intensity and propagation law of environmental release, and is measured through sensors and portable devices.Model layer model building and rules making. The establishment of the model layer is the core of the simulation technology. The digital model of this project includes geometric model, behavioral model and rule model, which describes and portrays each physical entity in the production process of PC components from multiple time scales and multiple space scales, as shown in Equation (7).Gv is a 3D model describing the geometric parameters and relationships of PE, with good spatial and temporal consistency with PE, which can be realized by Fluent 3D modeling software with Revit and Auto CAD; Bv describes the real-time response and behavior of PE under the joint action of external environmental impact and internal operation mechanism in different time scales, using a multi-intelligence-based simulation model. Rv describes how physical entities operate, including rules based on historical data, experience based on tacit knowledge summaries, and process flow standards, enabling VE to map the PC component production process and environmental release in real time.Bs). At the same time, the service (Fs) needs of PC component manufacturing enterprise managers for environmental release and worker health risk information acquisition are met through application software and clients, as shown in equation (8).Functional and business module design of the service layer. The service layer is designed to encapsulate various types of data, models, algorithms, and results in the simulation model in a service-oriented manner, to support the operation of the internal functions of the model and to provide functional services .Database establishment and data are interconnected in the data layer. The establishment of the database in the data layer is the key to realize the information linkage and transmission among other layers, mainly including Dp mainly includes physical element attribute data reflecting PE specifications, functions, performance, relationships, etc., as well as dynamic process data reflecting PE operating conditions, real-time performance, environmental parameters, sudden disturbances, etc., which can be collected through testing equipment, sensors and other equipment; Dv mainly includes data related to geometric models, physical models, behavioral models and rule models in VE, as well as simulation data based on the above models Ds mainly includes data related to Fs  and Bs .CN) between the above four layers is shown in Equation (10).Inter-layer connection method design. After the above four layers are established, how to connect the layers together is another key technique to realize the proper operation of the simulation model. The connection  Integrate the multi-objective model with the simulation model, combine simulation experiments with parallel experiments, and establish environmental release and worker occupational health risk evaluation criteria for PC component production for different products  and different types of work , respectively. (2) Determine the number, location and scope of environmental release monitoring points according to the standards, set the concentration/intensity monitoring thresholds for different categories of emissions, and establish a multi-level risk warning system for workers' carcinogenesis and chronic diseases. (3) Compare the monitoring data of several PC component plants, summarize the characteristics of environmental release and workers' health risks, further optimize the monitoring program of monitoring points, thresholds and types of work, and form evaluation standards with high timeliness and universality, and promote and apply them in the whole industry.The occupational health risks of construction industry workers have been much higher than the social average. With the growing scale of prefabricated buildings, the work originally required to be done on site is shifting to the front end, and the health risks of on-site construction workers are shifting to industrial workers in prefabricate concrete component plants.Based on the intersection of engineering, environmental, and health management, this study tries to solve the root problems behind occupational health risks from risk identification, risk assessment, and risk control, the three processes such as the lack of measurement, assessment, and prevention standards. Through mapping physical entities to virtual simulation, feeding back the quantification and optimization results to practical applications, and then expanding individual projects to the whole industry, this study provides new ideas for theoretical research and innovative practice of HSE management and risk management in the construction industry. Firstly, the logical framework of occupational health risk is formed using the concept of life cycle risk management, which provides a new paradigm for the research in the field of occupational health risk management. Secondly, identifying the characteristics of the source of emissions and analyzing the diffusion propagation law and diffusion mechanism to understand the whole path process of environmental release. Afterwards, clarifying the human intake mechanism combined with the personal exposure assessment method that considers uncertainty factors. Finally, the simulation model of occupational health risk assessment for the whole process workers is formed, and finally it is applied to real cases to form a complete set of long-term management model of occupational health risks caused by environmental release.A reasonable risk assessment simulation model and a long-term management model are proposed in this study. In the future, more empirical researches need to be verified in the model to improve the measurement accuracy, refine the human exposure assessment method, and adjust the simulation parameters, and so as to help decision makers to formulate occupational health risk policy. Furthermore, the production of PC components is only one phase of the assembled building industry. Transport, construction and other phases also include a large number of workers whose health risks need to be considered in future studies.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.PC led the overall study. HZ, ZD, and XJ conducted the analysis. HZ, ZD, XJ, PZ, and SZ drafted the manuscript with input from the other authors. All authors contributed to the concept and design of the study, the interpretation of data, revision of the manuscript for important intellectual content, and have read and approved the final version of the manuscript.This research was funded by Jiangsu Natural Science Fund (BK20200782) and Innovation and entrepreneurship training program for college students in Jiangsu Province (202110298026Z).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Studies of the cognitive and behavioral factors of perpetuation and quality of life in patients with somatoform disorders are important for identifying targets for psychological interventions and risk groups .To reveal beliefs and behavior in patients with somatoform disorders associated severity of somatic complaints and poorer subjective well-being.125 patients with somatoform disorders 17-68 years old filled Screening for Somatoform Symptoms , Cognitions About Body And Health Questionnaire , Scale for the Assessment of Illness Behaviour , and Quality of Life Enjoyment and Satisfaction Questionnairie-18 .Severity of somatoform symptoms is higher in patients with catastrophization of bodily sensations, autonomic sensations, belief in their bodily weakness, somatosensory amplification, scanning for bodily symptoms, and disturbances in daily activities due to illness . Adjusting for the severity of somatoform symptoms, subjective well-being was lower in patients with higher belief in their bodily weakness and somatosensory amplification, autonomic sensations, expression of symptoms, and changes in daily activities due to illness .The results suggests that regardless of symptoms severity poorer quality of life in patients with somatoform disorders is associated with beliefs about body and body perception that could be addressed in psychotherapy."}
+{"text": "Broadly speaking, psychology is the scientific study of behavior and mental processes, while criminology is the scientific study of crime and criminal offenders. Psychological criminology (or simply as psycho-criminology), which combines the two, is generally concerned with the use of psychological knowledge and skills to explain, describe, and potentially prevent or deal with deviant and criminal behavior Hollin, . More spIn this Research Topic (RT), the focus lies on the application of psycho-criminological approaches and constructs to crime, criminal and civil law, and the influence of law on mental health and behavior. This RT aims to advance our understanding of psycho-criminological mechanisms  associated with different criminal behavior in the intersections of mental health and the law. The 10 articles included in this RT explore varied aspects of crime and criminal behavior through the application of psychological concepts and theories to increase our understanding of crime, delinquents and criminal offenders, and their behavior. The highlight of this RT is the range of contribution conducted with six sampling populations, namely Spanish, mainland Chinese, Hong Kongers, Americans, Germans, and Italians. Besides, the collection of these articles addresses the different aspects in the criminal justice system  from a psycho-criminological standpoint.Pecino-Latorre et al.. Using a sample of 448 homicides, this article examines the effectiveness and validity of the Action System model to distinguish thematically between the structure of the homicides and to generate a homicide typology in Spain based on the relationships between the modus operandi, and victim and offender characteristics. Four homicide typologies were identified: Expressive, Adaptive, Integrative, and Conservative. Next, Zhu and Shek investigate the effect of individual dimensions and the global positive youth development (PYD) measures on adolescent delinquency, individually; and the underlying mediating effect of life satisfaction. Employing a two-wave longitudinal data collected from 2,648 mainland Chinese adolescents, findings are found to be consistent with the general theoretical prediction of the PYD approach; in which different PYD attributes  are inversely related to concurrent and future adolescent delinquency. Moreover, the negative predictions are mediated by the adolescents' life satisfaction. Also recruiting mainland Chinese adolescents, Xiong et al. construct a moderated mediation model to test the mechanisms underlying the relationship between perceived discrimination and proactive and reactive aggression in a longitudinal data of 470 mainland Chinese migrant students (aged 11\u201317). They observed that perceived discrimination fosters negative emotions, which in turns increase reactive aggression. Furthermore, socioemotional support reduces the negative impact of perceived discrimination on reactive aggression by weakening the relationship between perceived discrimination and negative emotions.This RT begins with an empirical study of testing a typology of Spanish homicides by Chan sampled 1,171 young adults (aged 18\u201340) to explore the psychosocial risk factors of risky sexual behavior (RSB) by testing the theoretical propositions of several criminological theories . Relative to females, males possess significantly higher mean levels of general, penetrative, and non-penetrative RSB; and negative temperament, use of alcohol and other drugs, and paraphilic interests. Males and females are generally sharing a similar set of psychosocial risk factors  for their involvement in general, penetrative, and non-penetrative RSB. Similarly exploring risky behaviors, M\u00e9ndez et al. explore the different adaptation profiles  in adolescents based on their interpersonal risk factors on drug use. Analyzing 1,201 secondary school students (aged 11\u201318 years) in Spain, a latent class analysis generated three different types of adaptation: Maladjusted group, At-risk group, and Adjusted group.In Hong Kong, Acklin and Velasquez argue that Structured Professional Judgment (SPJ) methods can be a corrective approach for unstructured clinical judgment that prone to evaluator bias and suboptimal levels of inter-rater reliability. The authors propose a SPJ model for criminal responsibility evaluations translated from violence risk assessment methodology. Sampling 230 patients in 13 forensic psychiatric hospitals in Germany, B\u00fcsselmann et al. measure the patients' quality of life in forensic psychiatric hospital using the Measuring the Quality of Prison Life (MQPL) questionnaire. They found that the adapted MQPL questionnaire demonstrates good internal reliability and construct validity. The next article by Titze et al. examine the self-reported acculturation processes and associated individual and social factors in a similar sampling population of 235 forensic psychiatric patients with a migration background in 11 forensic hospitals in Germany. The findings indicate that the patients oriented themselves more toward the culture of admission and less toward the country of origin than the reference sample did.Next, Rossetto et al. retrospectively compared 42 readmitted with 48 non-readmitted females in an Italian forensic psychiatric hospital through a minimum of 42 months follow-up (ranges from 3.5 to 10 years). Their findings indicate that readmitted females were positively associated with the presence of substance use disorders and a primary diagnosis on Axis II. The final article of this RT is authored by Brown et al.. They examine the fetal alcohol spectrum disorder (FASD) by proposing a renewed focus on applying and adapting the Risk-Need-Responsivity (RNR) approach to individuals with FASD in criminal justice settings. The authors argue that the use of RNR approach can better determining the needs and interventions in reducing the propensity of offender recidivism.In Italy, With studies conducted in Spain, Mainland China, Hong Kong, the USA, Germany, and Italy, the 10 articles in this RT collectively demonstrate the importance of applying psycho-criminological knowledge and skills to better understand the underlying mechanism  associated with different criminal behavior in the intersections of mental health and the law. Having studies from different cultures and jurisdictions have clearly demonstrated that a combined etic-emic approach is arguably more appropriate when studying crime and criminal behavior, and developing culturally sensitive assessments and interventions (Ho and Cheung, The author confirms being the sole contributor of this work and has approved it for publication."}
+{"text": "Dear Editor,Tricho-rhino-phalangeal syndrome (TRPS) type I is a rare condition first described by Giedion in 1966. The main characteristics are sparse and slow-growing hair, a pear-shaped nose and coned epiphyses on the medial phalanges of the hands. The hair shafts are thin and miniaturized, as in androgenetic alopecia. There is a down-regulation of the TRPS1 gene in the baldness area, and the decrease of the same protein can impair endochondral cartilage differentiation and cell interactions in the development of hair follicles.Short stature, Legg-Calve-Perthes Disease , shortening of the toes (clinobrachydactyly), dystrophic nails, long philtrum, thin upper lip, and thinning of the distal third of the eyebrows may occur.2TRPS type I often shows an autosomal dominant pattern inheritance, but autosomal recessive inheritance can occur. Type II occurs sporadically, associated with mental retardation and multiple exostoses.The aim of this study is to report the investigation of a case of TRPS in an eleven-year-old girl with mechanical arthralgia in the knees for three years, without morning stiffness, she presented also shortening of the toes and ulnar deviation of the second, third and fifth fingers, bilateral osteochondromas in the supracondylar region, hair rarefaction, and three episodes of convulsive crisis. The neuropsychomotor development was normal. Parents were non-consanguineous and there was no history of repeated abortions. Regarding family history, the father is being treated for epilepsy, and siblings do not have any signs suggestive of genetic syndromes.On physical examination, bilateral hypermobility and deformity of the interphalangeal joints, thickening of the wrists, thinning of the skull, collapse of the nasal bridge, thin upper lip, pear-shaped nose , and higThe cranial tomography showed no changes. The knee radiography revealed a well-defined sclerotic lesion along the medial cortex of the distal diaphysis of the right femur. The patient is undergoing clinical follow-up with the Orthopedics team. The hand radiography showed a widening of the base of the middle phalanx from the second to fifth fingers, bilaterally . The ophThe diagnosis of TRPS type I is attained through typical clinical findings  and radiographic findings of coned epiphyses, or the identification of a heterozygous pathogenic variant of TRPS1. For type II, the diagnosis is attained through typical findings of TRPS II and a contiguous chromosome 8 deletion that includes the genes TRPS1, RAD21 or EXT1.Treatment includes supportive measures from a multidisciplinary team .None declared.Evelyn Freitas Rodrigues: Statistical analysis; approval of the final version of the manuscript, design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.Lisa Gava Baeninger: Statistical Analysis; approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.Caroline Romanelli: Statistical analysis; approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.None declared."}
+{"text": "Mindfulness-based interventions have received growing attention over the last years for the treatment of various mental disorders, including schizophrenia spectrum disorders (SSD), demonstrating their transdiagnostic validity. However, no study has examined the relationship of probable mechanisms underlying the therapeutic effects of mindfulness in SSD.The current study examines the relationship between mindfulness, depression, anxiety, and quality of life in individuals with SSD through quantitative measures.A total of 83 participants with SSD were recruited at the in- and outpatient facility of the Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin in Germany. Participants completed the Southampton Mindfulness Questionnaire, Comprehensive Inventory for Mindful Experiences, and Freiburger Mindfulness Inventory, the Depression, Anxiety, Stress Scale, and the World Health Organization Quality of Life Questionnaire. PROCESS analysis examined the relationship between mindfulness and quality of life and the mediating role of depression and anxiety.Indicated a significant positive association between mindfulness and physical health, psychological and environmental quality of life. Depression and anxiety were found to mediate this relationship, with higher depression and anxiety scores being related to lower mindfulness and quality of life. In this relationship, however, depression was found to be the stronger predictor.The findings of this study provide insight into the mechanisms of mindfulness. Initial evidence for the transdiagnostic and process-based clinical relevance of MBIs for SSD has been found and future studies can further explore the role of mindfulness for central therapeutic processes of change by employing longitudinal designs.No significant relationships."}
+{"text": "Metamaterials for Wireless Power Transfer is a new open Special Issue of Materials, which aims to publish original and review papers on new scientific and applied research and make great contributions to the finding and understanding of the use of metamaterials for wireless power transfer (WPT) and related fundamentals, characterization, and applications. WPT technology is becoming an important topic for the wireless industry , which hMetamaterials for Wireless Power Transfer includes, but is not limited to, the following: low-frequency metamaterial-based WPT systems, electromagnetic compatibility in metamaterial-based WPT systems, wireless energy harvesting (WEH), theoretical research for metamaterial-based WPT systems, magneto-inductive and resonant waves in WPT systems via metamaterials, programmable metamaterials and metasurfaces for WPT systems, and SWIPT systems based on information metamaterials and metasurfaces.The research interest for the Special Issue"}
+{"text": "\u0421ognitive deficit significantly affects the quality of life of patients. Aims of research was detection of cognitive impairments of varying degrees in epilepsy, and as well as studying the results of complex treatment in conditions of University clinic, physical and psychological rehabilitation, cognitive training and VNS included.We studied the features of clinical and psychopathological manifestations of cognitive impairments in patients suffering from epilepsy.The study was attended by 100 patients (35 men and 65 women) who were inpatient care. The following psychodiagnostic techniques were used: the Toronto Cognitive Assessment TorCA, the test of 10 words of Luria, the MOCA test, the M\u00fcnsterberg test, the quality of life scale, the Hamilton scale of depression and anxiety.MCI was observed in 88 % patients, dementia in 12 % . We used non-pharmacological rehabilitation methods for correction of cognitive impairment in epileptic patients with MCI and mild dementia during 3 mounth.. Improving of cognitive function was observed in 48 % patients, stable level of cognitive function - in 36 %, progressing of cognitive imparment - in 16 % patiens with epilepsy.The results of the conducted research indicate the need for further study of the features of cognitive disorders in pharmacologically treatment resistant epilepsy and implementation of training aimed at improving cognitive function and preventing the progression of cognitive impairment in complex treatment of those patients."}
+{"text": "In recent decades, numerous studies provided consistent and convincing evidence that the adoption of healthy plant-based dietary patterns is a valuable strategy to reduce the risk of most non-communicable diseases ,2. SeverAmong the most recent areas of research, the potential action of polyphenols in the central nervous system and related diseases, including neurodegenerative disorders, is of major interest . Diet haIn our Special Issue entitled \u201cPolyphenols and Polyphenol-Rich Foods in Neurodegenerative Disorders\u201d, several articles are published that provide further evidence on the potential role of polyphenols in brain health. The study of Al-Musharaf et al.  investigOverall, the Special Issue provides interesting insights on the role of certain polyphenols, especially underrated polyphenols such as phenolic acids, and brain health for the prevention of neurodegenerative diseases. Additional studies are encouraged for submission to further explore this research topic and broaden the field of exploration of polyphenols on the benefits for the human brain."}
+{"text": "As a research hotspot, deep learning has been continuously combined with various research fields in medicine. Recently, there is a growing amount of deep learning-based researches in orthopedics. This bibliometric analysis aimed to identify the hotspots of deep learning applications in orthopedics in recent years and infer future research trends.We screened global publication on deep learning applications in orthopedics by accessing the Web of Science Core Collection. The articles and reviews were collected without language and time restrictions. Citespace was applied to conduct the bibliometric analysis of the publications.Nature has the highest impact factor in the cited journals. The current hot keywords are convolutional neural network, classification, segmentation, diagnosis, image, fracture, and osteoarthritis. The burst keywords are risk factor, identification, localization, and surgery. The timeline viewer showed two recent research directions for bone tumors and osteoporosis.A total of 822 articles and reviews were finally retrieved. The analysis showed that the application of deep learning in orthopedics has great prospects for development based on the annual publications. The most prolific country is the USA, followed by China. University of California San Francisco, and Skeletal Radiology are the most prolific institution and journal, respectively. LeCun Y is the most frequently cited author, and Publications on deep learning applications in orthopedics have increased in recent years, with the USA being the most prolific. The current research mainly focused on classifying, diagnosing and risk predicting in osteoarthritis and fractures from medical images. Future research directions may put emphasis on reducing intraoperative risk, predicting the occurrence of postoperative complications, screening for osteoporosis, and identification and classification of bone tumors from conventional imaging. As a subset of machine learning, deep learning has broken the limitations of traditional machine learning, and can implement more accurate classification and segmentation of images to extract feature elements , 2. It iMost musculoskeletal diseases in orthopedics require a large degree of help from images. Given the advantages of deep learning in image processing, there has been a growing number of researches on the application of deep learning in orthopedics in recent years . BibliomCurrently, no bibliometric analysis has been conducted to quantitatively analyze the progress and current status of deep learning in this emerging field. Herein, this study aimed to elucidate the research hotspots, key fields, and trends of deep learning applications in orthopedics in recent years by using Citespace, Moreover, the research direction and references for further exploration were shown as well.* OR orthopedic* OR \u201csports medicine\u201d) OR TS = , #2: TS =\u201cdeep learning\u201d OR TS = \u201cconvolutional neural network*\u201d). There is no limit to the publication year. The type of literature was selected as articles and reviews without language restriction. Literature not relevant to this topic was excluded, and duplicate literature was removed by Using Citespace (5.8 R3). Finally, a total of 822 articles were retrieved and exported for records in the format of plain text files. Meanwhile, we also obtained the number of annual publications and the amount of publication of the journal.Since the details of the documents in the Web of Science are more accurate than other databases, such as Scopus, PubMed, Embase, etc. We retrieved all literature from the Web of Science Core Collection. The retrieval was completed within 1 day on March 29, 2022 to reduce changes due to frequent updates to the bibliographic database. The searching strategy was as follows: #1 and #2 (#1:WC = (orthopedics) OR TS =  were identified. The number of studies published in each year can help us understand the general trends in the relevant research. Since 2022 has just begun, the number of documents in 2022 cannot show the overall publication situation. Therefore, the analysis only included the publication from 2015 to 2021. As shown in We used Citespace to conduct co-citation analysis of the countries (or regions) and institutions. The country or region distribution map consisted of 56 nodes and 53 links. As demonstrated in A total of 250 authors were involved in the cooperative map . As showSkeletal Radiology (33 times) had the highest number of outputs, followed by IEEE Access (28 times), Scientific Reports (25 times), Computer Methods and Programs in Biomedicine (19 times), Applied Sciences Basel (17 times), Diagnostics (17 times), International Journal of Computer Assisted Radiology and Surgery (15 times), Journal of Digital Imaging (14 times), Medical Image Analysis (14 times), and Sensors (14 times). The co-occurrence analysis of cited journals obtained from Citespace was shown in Lecture Notes in Computer Science (345 times), In Proceedings of The IEEE Conference on Computer Vision and Pattern Recognition (324 times), Medical Image Analysis (287 times), Radiology (280 times), IEEE Transactions on Medical Imaging (274 times), Scientific Reports (197 times), Nature (190 times), Journal of Digital Imaging (185 times), PLoS One (179 times), and American Journal of Roentgenology (149 times).The 822 articles retrieved in this study were published in 308 journals. As shown in A total of 464 nodes and 733 links presenting the co-citation relationship of the references formed the cited reference network in The high-frequency keywords the article can help us understand the main research hotspots of the filed. Keyword co-occurrence analysis was performed by Citespcace. The co-occurrence network of keywords had a total of 265 nodes and 404 links . The higThe clustering of keywords can present the structural system of related research fields. The sixteen different clusters made through Citespace were shown in The strong burst keywords can help us explore the development trends of the filed. We use Citespace's burst function to analyze keywords that have attracted much attention from academia. The burst keywords were shown in This study utilized the principles of bibliometrics analysis and the method of Citespace visualization. In the application of deep learning in orthopedic filed, the annual number of articles, countries (or regions) and institutions, authors and cited authors, journals and cited journals, and keywords were extensively analyzed to reveal the current research hot-spots and trends in this field.Based on an analysis of countries (or regions) and institutions, the USA and China were the two most documented countries, but there was a lack of international cooperation between them. More international cooperation is needed for China  to jointly promote development in this field. England, Australia, and Canada had high centrality and publications, suggesting that these countries might play an essential role in bridging research. At the same time, most of the top ten institutions with the most centrality and publications are from China and the USA, but these institutions basically cooperate with other institutions in their countries. Therefore, from the perspective of cooperation networks, we hope that there will be more cooperation between different countries.Through the analysis of the author cooperation network, we found that the top ten authors mainly constituted three cooperative networks. In the cooperation between the two authors in the deep learning field, VALENTINA PEDOIA  and Sharmila MAJUMDAR , the most cited literature showed that the improved U-net can automatically segment cartilage and meniscus from MRI . PAUL H As to the analysis of a network of cited authors, the most frequently cited author-LeCun Y believed that deep learning is good at processing high-dimensional data, and can accurately identify and classify targets in image recognition tasks . SimilarAccording to the journals and co-cited journals in Among top ten co-cited references, these references are usually the basis of relevant knowledge fields and play an important role in knowledge structure. For three proceedings papers, Ronneberger O, He KM, and Huang G built new models for deep learning in 2015, 2016, and 2017, respectively, which strengthened the ability of deep learning to process images. These models are deep residual learning, densely connected convolutional networks, and U-net . ArticleKeywords are the cores of a paper that reflecting the concerns of relevant field. By analyzing the high-frequency keywords and strong-burst keywords, we can explore the hot-spots and research trends. The main research hotspots and research trends are as follows:After the first report of deep learning in fracture by Olczak et al. , the numFor upper extremity fracture, deep learning is commonly applied to distal radius fracture and humeral fracture \u201326. Gan In lower limb, hip fractures attracted much attention. Cheng et al. proved that deep learning model can automatically identify femoral neck fracture and trochanteric fracture through pelvic X-rays, with 98% sensitivity and 91% accuracy . Mutasa Moreover, studies showed that deep learning can also help to reveal vertebrae fracture as well. Murata et al. accurately identified vertebral fractures on plain thoracolumbar radiography . UsuallyOsteoarthritis is the most common musculoskeletal disorder, which mainly affects the hip and knee joints with large weight bearings, especially the knee joint. Initially, a proceedings paper showed the use of CNN to analyze Kellgren & Lawrence (K&L) grades based on knee radiographs . Then, TDeep learning is often applied to the classification and diagnosis of diseases. However, with the development of deep learning, this technique will also be applied to perioperative management of orthopedic surgery. Nowadays, deep learning is being gradually explored in the study of orthopedic surgery. Since the visual field in arthroscopic surgery is often affected by different angles of the joint, which requires repositioning in different visual fields, automatic localization under the arthroscopic field of view is urgently needed. Recently, Banach A et al. collected arthroscopic videos and performed deep learning on video sequences at four different knee angles, and the results showed that deep learning performed well in arthroscopic field of view . BesidesFrom the timeline viewer of keywords, we found that the study of fractures and osteoarthritis gradually began to study in-depth from 2016 to 2019. We also paid special attention to the direction of gradual in-depth research after 2019, such as osteoporosis, and bone tumors (osteosarcoma). Osteoporosis often occurs in older or postmenopausal women, and is usually detected because of fractures, thereby screening for osteoporosis may help prevent osteoporotic fractures in many patients. Deep learning can help predict osteoporosis and the possible fracture risk , 51. AltSeveral limitations remain in this study. First, as the literature in the Web of Science Core Collection is constantly updated, and there is currently no uniform regulation on keywords related to the literature, the results of this study may differ from the actual number of documents included. Second, deep learning first appeared in seminars or conferences, and then gradually appeared in journals in the form of article. Since we consider that article has more systematic research, so it is strictly regulated in literature inclusion, which may introduce certain bias to this study. However, it is believed that literature-based visual analysis has undoubtedly laid a foundation for investigators to quickly understand the research hot-spots and development trends of deep learning applied in orthopedics.In conclusion, according to the annual publication curve, the research on the application of deep learning in orthopedics has developed rapidly, and there is a good research prospect. Accordingly, researchers in the field of deep learning and orthopedics may benefit this study. The USA is the country with the largest amounts of articles in this field. University of California San Francisco, the institution with the largest amounts of articles, is also from the USA. However, cooperation between different countries is markedly insufficient. The application of deep learning in orthopedic research has been published in journals of various discipline categories, and multidisciplinary communication conforms to the mainstream of today's world. The current research hot-spots mainly focused on the classification and diagnosis of orthopedic diseases that rely heavily on medical images, such as fractures and osteoarthritis. The application of deep learning to reduce intraoperative risk, predict postoperative risk, screen osteoporosis, and identify, classify, and segment bone tumors may be at the fore-front of the future. At the same time, with the rapid development of deep learning applications in orthopedics, researches in this field will continue to evolve toward multicentric data and more perfect deep learning algorithms.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.CF: investigation, data analysis and visualization, and writing\u2014original draft preparation. XZ, HW, YH, and ZL: investigation and editing. CT: conceptualization, supervision, and writing and revision. All authors have read and agreed to the published version of the manuscript.This work was supported by grant from the National Natural Foundation of China (81902745), Hunan Provincial Natural Science Foundation of China (2022JJ30843), the Science and Technology Development Fund Guided by Central Government (2021Szvup169), Hunan Provincial Administration of Traditional Chinese Medicine Project (No. D2022117), and Clinical Research Center for Medical Imaging in Hunan Province (2020SK4001).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "The European\u2013Latin American Consortium towards Eradication of Preventable Gallbladder Cancer, EULAT Eradicate GBC, is collecting high-quality data and samples in four Latin American countries with high gallbladder cancer incidence  to build a unique biorepository integrated into a tailored IT platform, to identify, validate, and functionally characterize new risk biomarkers, and to develop prediction models that integrate epidemiological and genetic\u2013molecular risk factors. We decided to develop an application for electronic data collection to facilitate the retrieval of sociodemographic, clinical, lifestyle, dietary, and sample-related information from 15,000 Latin American study participants. The application EULAT eCollect will facilitate the work of study nurses, reduce time spent by participants, limit the use of paper and ink, minimize costs and errors associated with filling out written forms and subsequent digitisation, and support the monitoring of local recruitment rates and data quality. We describe in this article the design and implementation of the EULAT eCollect application, which started with the specification of functional and non-functional requirements, and ended with the implementation and validation of four separate application modules: Socio-Demographic Interview, Sample Information, Case Report Form, and Food-Frequency Questionnaire. We present both general and technical results, and our experience with the free and open-source software, Open Data Kit (ODK), which may be of interest for future related research projects, especially those on personalised cancer prevention carried out in low- and middle-income regions. Gallbladder cancer (GBC) is the most common neoplasms of the biliary tract ,2. GBC tAmong the risk factors associated with GBC, female gender, age, gallstones (cholelithiasis), genetic ancestry, obesity, multiparity, and socioeconomic and educational levels are the most important ,4. The lCurrently, there are no tests that reliably detect GBC early enough to be useful as screening tools ,7. Due tA European\u2013Latin American research consortium towards eradication of preventable GBC\u2013EULAT Eradicate GBC\u2014has been established with funding from the European Union\u2019s Horizon 2020 programme to identify factors related to the development of GBC, to find biomarkers in blood, saliva, urine, and faeces that allow individual risk prediction and early diagnosis of the disease, and to facilitate the development of better primary, secondary, and tertiary prevention strategies . The conThe stated goals of the EULAT Eradicate GBC project can only be achieved through collaboration between European and Latin American researchers, clinicians, governmental authorities, and representatives of cancer-patient societies. We plan to leverage samples and data from European cohorts and registries, and collect and analyze data and samples from 15,000 Latin American participants to build a unique European\u2013Latin American GBC biorepository complemented by a customized IT platform applying a translational and multidisciplinary approach. It is challenging to collect high-quality socio-demographic, clinical, lifestyle, dietary, and sample-related information for this large number of study participants, mainly from low-income regions in four South American countries, which led us to develop a customized computer application to support not only the data-collection process but also the monitoring of local recruitment rates and data quality. The application for electronic data collection in the EULAT Eradicate GBC project (EULAT eCollect for short) was designed to facilitate the work of study nurses by, for example, displaying different questions depending on the characteristics of patients and samples, reduce the time invested by study participants in the interview, which is particularly important for patients in poor health, limit the use of paper and ink, and minimize costs and errors associated with the written completion of forms and subsequent digitisation by medical documentalists. Important requirements for EULAT eCollect were the ability to collect and store data without a stable internet connection, and the secure transfer of data to the storage server when the internet is available.This article describes the process of designing and developing the application EULAT eCollect to facilitate the collection, storage and future analysis of high-quality information from patients and their families. EULAT eCollect consists of four separate modules: Socio-Demographic Interview, Sample Information, Case Report Form, and Food-Frequency Questionnaire. We first present the specification of the functional and non-functional requirements, then the design of the application architecture, and conclude the manuscript with a description of the four implemented modules and the usefulness of EULAT eCollect to monitor recruitment rates and data quality.The process of designing and developing an information technology (IT) infrastructure for electronic data collection was based on typical software engineering methodology . The defEULAT eCollect was designed to support patient-data collection by incorporating the functional and non-functional requirements needed to make it easy and secure for the recruiting personnel. Study participants are interviewed by trained nurses before surgical gallbladder removal at the participating hospitals, or in the participant\u2019s home . After the complete process of informed consent, which includes a detailed description of study objectives and participant rights, clarification of any questions or concerns the potential participant may have, and signing of the consent form, recruitment personnel apply a socio-demographic questionnaire. Interviews are always conducted in a private room to protect data confidentiality.The specification of functional requirements see  includedThe non-functional requirements refer to technical aspects of the web application, such as usability, information security, access to and quality of the internet, and the hardware performance . RegardiThe project contemplates collecting, storing, and analysing sensitive information to reach the project\u2019s objectives, which implies a significant challenge of keeping confidentiality and protecting participants\u2019 data. The information collected to improve the prevention and early diagnosis of GBC in Latin America contains sensitive data. Part of the data collected is considered clinical information, and the legislation of the participating countries mandates that this type of information is stored, processed, and used appropriately . AccordiThe application EULAT eCollect for electronic retrieval of patient and sample information was developed and is currently being applied to guarantee standardized data collection at all project recruitment sites. The following complementary activities were also carried out to ensure the establishment of a harmonized project biorepository: development and application of technical operational guidelines, training of recruitment staff in biobanking and biorepository procedures, establishment of a data and sample quality assurance programme, and development and establishment of automated quality control and standardized data-management procedures.EULAT eCollect was organised into four separate modules, taking into account that the ultimate objective of the EULAT Eradicate GBC project is to identify major modifiable dietary and lifestyle risk factors , body size/shape measurements, and reproductive and hormonal factors, and to evaluate possible differences by gender and ethnicity. In a first step, the association between dietary and lifestyle characteristics and GBC risk will be assessed using multiple conditional logistic regression models. Biologically plausible effect-modifiers will then be considered  by investigating potential interactions between biomarkers and dietary/lifestyle risk factors. With these goals in mind, the following application modules were considered:Module 1: Socio-Demographic Interview. The development of this module combined our own experience from previous GBC research [research  with theresearch .Module 2: Sample Information. The aim of this module was to facilitate the collection of relevant information on different types of samples . The type of samples collected depends on the type of study participant, and our application simplifies the work of staff processing study samples by asking for participant-specific information. The data collected includes transport, processing, and storage conditions, which greatly facilitates the automatic generation of pre-analytical sample quality indicators.Module 3: Case Report Form. This module was developed to collect clinical patient information, the characteristics of resected gallbladder specimens, and treatment information. We tried to incorporate the research interests of all collaborating clinicians, and also took into account the latest guidelines for pathology reporting [eporting .Module 4: Food-Frequency Questionnaire. This module was based on a validation study of a self-administered food-frequency questionnaire for Argentina, Chile, and Uruguay [ Uruguay .The four modules were implemented using the free and open-source software ODK . The widAfter creating an application prototype, EULAT eCollect modules were validated with the help of an R script developed for this purpose, which was used to calculate quantitative and qualitative indicators for the data collected. In June 2021, we analyzed a pilot dataset using both the R script and manually calculated indicators. The few discrepancies  were identified and corrected, leading to the final version of EULAT eCollect, which is now fully operational and has been used for almost a year to recruit gallstone and GBC patients in Argentina, Bolivia, Chile, and Peru, with a positive experience so far. A bioinformatics engineer (J.G.D.) was responsible for the technical deployment with the active support of the head of the Biomedical Informatics Laboratory at the Universidad de Talca (S.G.M.). The project coordinator (J.L.B.) and the project manager in Latin America (C.B.P.) were in charge of formulating and verifying the application requirements, with excellent support from the Biobank of the Universidad de Chile during the validation phase. The entire team spent six months creating the application prototype and another two months making the necessary modifications during the validation phase.A fundamental input for the design of EULAT eCollect was the requirements identified and listed in After defining the functional and non-functional requirements for EULAT eCollect, we started its design and implementation. The application was developed under a model\u2013view\u2013controller architecture to separate the views of the data model and the business logic . Figure EULAT Eradicate GBC data can also be collected via a web browser on a desktop or mobile device  and to guarantee consistency with the Chilean National Health Surveys. Standard answers were formulated to avoid typing errors and mandatory fields were defined to limit the amount of missing information.After the informed consent, recruitment personnel enter their authentication credentials and select the type of participant. The application EULAT eCollect displays specific questions for four types of participants: (1) cholelithiasis patient, (2) GBC patient recruited before any treatment , (3) GBC patient recruited after treatment, and (4) first-degree relative  of a GBC patient (proband) in a family with multiple members affected by GBC.The patient interview is structured into eight to nine sections: (I) basic information, e.g., participant code, recruiter identifier, and type of participant, (II) demographic information, (III) socioeconomic information, (IV) lifestyle factors, (V) individual health history, (VI) family health history, (VII) body measurements, (VIII) physical activity, and (IX) gynaecological information (for women only). In Bolivia and Peru, an additional item on coca-leaf use was included in the interview. Visual aids are used when conducting the interview, especially for questions on lifestyle and physical activity , to stanAfter biospecimen collection, samples are processed, aliquoted, and stored in compliance with all relevant ethical and legal regulations for biomedical research, and to the standardized operating procedures of the EULAT Eradicate GBC research project. The second module of the EULAT eCollect application facilitates the electronic retrieval of sample information from the donation of blood, urine, faeces, and saliva, through transport to the laboratory, to sample processing and storage, enabling the automatic creation of customized sample inventories for shipment, receipt, and further processing, including pre-analytical quality indicators for the different types of stored samples . Recruitment staff collect different biospecimens depending on the type of participant. For example, only saliva is collected from GBC patients who have been cholecystectomised or started chemotherapy. In contrast, cholelithiasis patients donate blood, urine, and faeces before cholecystectomy. After authentication, the staff responsible for sample processing and storage, which may be different from the staff who collected the samples, selects the type of sample in EULAT eCollect, which then displays specific questions depending on the type of sample and previous answers . For exaThis module of the application facilitates the collection of clinical patient and anatomical\u2013pathological gallbladder information, taking into account the research interests of participating clinical partners , particularly in view of future studies on early diagnosis, predictive and prognostic biomarkers, and personalised treatment. To illustrate, information collected on GBC patients includes method of diagnosis, tumor stage, lymph node involvement, presence and location of metastases, histological type of the tumor, and comorbidities, as well as information on surgical procedures  and treatment . Central to the design and implementation of this module were the latest guidelines for pathology reporting . The casThe fourth module of EULAT eCollect enables the electronic application of a food-frequency questionnaire  validateAn important feature of EULAT eCollect is its usefulness for real-time tracking of patient recruitment in each recruitment site of the EULAT Eradicate GBC project using qualitative and quantitative indicators. Briefly, the forms sent by recruitment personnel to the project\u2019s secure server are processed using R scripts to generate 19 indicators on the number of patients recruited, and on the quality of collected samples and socio-demographic, clinical, and dietary information.Quantitative indicators include the cumulative number of forms collected; stratified by form type ; the number of patients with all forms completed, as pathology reports required to complete case report forms are usually available 3\u20134 weeks after cholecystectomy; the distribution of participants according to participant type at interview , the total number of recruited participants per month; the distribution of participants according to type/s of donated samples ; and the distribution of patients according to anatomy reports . In addition to reports in tabular format , R scripts also generate useful figures that facilitate comparison of the recruitment progress between recruitment sites .Qualitative indicators include the proportion of patients with all forms completed, the proportion of incomplete, non-compulsory fields in the four modules of EULAT eCollect , and the proportion of samples showing deviations from the sample processing protocol. Thresholds were defined and validated for specific indicators  and indicators are highlighted in the monitoring reports when thresholds are exceeded.Research on GBC has been largely neglected, as this aggressive disease is relatively rare in most high-income countries. Several South American regions including northeaster Argentina, Bolivia, Chile, and southern Peru, have a high GBC incidence ,4,5. InhDefining functional and non-functional requirements was the first step in designing the application EULAT eCollect. Functional requirements included minimizing interview time, especially for frail study participants, avoiding errors when creating the sample inventory using barcode readers or mobile phone cameras, taking into account the latest pathology guidelines and applying previously validated food-frequency questionnaires. Non-functional requirements comprised the ability to collect data without internet connection and the secure transfer of data, which takes place via HTTPS protocols. Digest authentication with an encrypted form of the password stored on the server is used to secure username and password authentication.EULAT eCollect enables electronic data collection for the EULAT Eradicate GBC project via mobile devices . Once the application is installed, staff recruiting study participants and processing samples can download, fill in, and send the four forms developed for the project. The first module of EULAT eCollect facilitates the recording of the main established and potential GBC risk factors in accordance with the Chilean National Health Surveys. The second module of the application facilitates the electronic retrieval of sample information from biospecimen donation to sample storage, enabling the automatic generation of sample inventories that include pre-analytical quality indicators. A practical feature of the third module of EULAT eCollect is the ability to upload images and PDF files of blood tests and pathology reports for case report forms. Finally, the Food-Frequency Questionnaire embedded in EULAT eCollect allows for efficient collection of comprehensive nutritional information. An important activity in the EULAT Eradicate GBC project is the monitoring of patient recruitment, which is greatly facilitated by the automatic generation of quantitative  and qualitative indicators  through the EULAT eCollect application.The free and open-source ODK software was chosen for the implementation of EULAT eCollect. ODK provides convenient tools for developing a data-collection system with an integrated database . The fleThe collection, storage and analysis of sensitive information to reach the objectives of the EULAT Eradicate GBC project is a major challenge\u2014confidentiality must be maintained, participants\u2019 data must be protected, and the participating countries have different legislation for the use of sensitive patient data. Therefore, we have paid special attention to information security in the development of EULAT eCollect. The four application modules were built in such a way that the identity of the patients remains anonymous\u2014components of data records that would allow participant identification are replaced by pseudonyms on-site, and only treating physicians know patient identity. In addition, data are transferred via HTTPS protocols for which a key and certificate are generated based on regulatory requirements, firewalls restrict access to the servers where data are stored, and administrative access is limited to the management of the institution\u2019s intranet.The EU-funded project EULAT Eradicate GBC is collecting high-quality data and samples from 15,000 study participants to identify geographic, environmental, lifestyle, ethnic, and molecular differences in GBC risk and prognosis, and to translate the results into optimised GBC-prevention programmes considering the specificities of national health systems. The collection of high-quality information for this large number of participants in low- and middle-income regions is challenging and motivated the design and development of a customized computer application, EULAT eCollect, which we describe in this article.EULAT eCollect can be easily adapted or used directly for electronic data collection in similarly oriented research projects, and we explicitly offer our support in this direction. For example, current and future research projects on the prevention of gastric, colorectal, and biliary malignancies in Latin America could benefit from our experience in designing and implementing the application. Modules 1, 2, and 3 will probably require some modification to take into account established and potential risk factors for the disease under investigation, the type of samples and aliquots collected in the project, and clinical characteristics according to generally accepted guidelines, but Module 4 could be used directly after clarification of data storage. We also offer to share, interested researchers, our list of quantitative and qualitative indicators for monitoring of the participant recruitment."}
+{"text": "The skeletal system is generated and maintained by its progenitors, skeletal stem cells (SSCs), across the duration of life. Gradual changes associated with aging result in significant differences in functionality of SSCs. Declines in bone and cartilage production, increase of bone marrow adipose tissue, compositional changes of cellular microenvironments, and subsequent deterioration of external and internal structures culminate in the aged and weakened skeleton. The features and mechanisms of skeletal aging, and of its stem and progenitor cells in particular, are topics of recent investigation. The discovery of functionally homogeneous SSC populations with a defined cell surface phenotype has allowed for closer inspection of aging in terms of its effects on transcriptional regulation, cell function, and identity. Here, we review the aspects of SSC aging on both micro- and macroscopic levels. Up-to-date knowledge of SSC biology and aging is presented, and directions for future research and potential therapies are discussed. The realm of SSC-mediated bone aging remains an important component of global health and a necessary facet in our understanding of human aging. A remarkable proportion of healthcare costs are attributed to skeletal disease . In 1990Fundamentally, the vertebrate skeleton is a remarkably dynamic and complicated organ. Throughout life, nearly every bone in the body continually deconstructs and regenerates itself in order to maintain structural and mechanical integrity . This hiThroughout life, adult stem cells are responsible for replenishing and restoring tissues of the body. Evidently the natural process of aging diminishes the capability of adult stem cells to maintain these systems in a youthful and resilient state. In the skeletal system, aging corresponds to a decline in the regenerative and restorative potential of its progenitor cell population, and through replicative exhaustion, chromatin remodeling, and changes to the intra- and extracellular transcriptional landscape, the skeleton becomes less capable of maintaining its dynamic stability .The foundation for skeletal integrity lies in the cellular progenitors of the skeletal system supplying bone tissue with its building blocks of mature cell types. Significant effort has been made in identifying the bona fide progenitors of bone- and cartilage-forming cells, and indeed much debate remains over the precise cellular identity and definition of such progenitors ,10. A loOnly within the past decade have advances in lineage tracing and cell sorting using multiple surface markers revealed more functionally homogeneous populations of self-renewing, lineage-restricted progenitors of bone, cartilage, and stromal cells that have the unique capacity to effectively reconstitute the skeletal niche in-vivo \u201321. ThesIn search of the transcriptomic identity of SSCs, the apparent features of aging in the skeletal system reveal itself . In agedIn many regards, biological aging itself is a process that is poorly understood. Theories on the causes of aging point towards genomic instability and progressively deleterious epigenetic modifications that produces an aged, unstable cellular phenotype . EvidencThe mechanisms of aging in SSCs remain less clear but are under current investigation, with focus on relating the functional differences between young and aged cells. A summary of gene pathways altered in aged cells and their effect on SSCs and skeletal tissues is provided in Within the skeletal niche, hematopoietic stem cells (HSCs) reside alongside skeletal cell types and share an age-related decline in lineage diversity potential . A hallmLastly, evidence of age-related differences of SSCs in the histone deacetylation protein Sirtuin1 suggests a mechanism for epigenetic control of SSC differentiation . In thisCurrent approaches to treating age-related decline in bone and cartilage health rely almost exclusively on maintaining the balance of bone resorption and production by targeting osteoclast and osteoblast activity . TreatmeDirected application of stem cell therapies in humans remains largely under investigation, but provides an enticing avenue for minimally disruptive, highly regenerative treatment . StudiesAccumulation of senescent SSCs may play a role in age-related skeletal regeneration deficiencies, and indeed in-vivo studies in mice have demonstrated a reversal of age-related bone loss by eliminating senescent cells . RemodelIn general, our understanding of aging among organisms remains elusive. While the role of aging in nature is not clearly delineated, evidence of unusually long lifespans in the animal kingdom, the longest of potentially 300 or more years belonging to the Greenland shark, suggests the potential for expansion of the human lifespan, and the potential to reverse or elongate youthful features of human tissues through targeting of stem cells ,66. MuchIndeed, the loom of aging evades no known animal. Regardless, the prospect of delaying or reversing the effects of aging serves as motivation to understand the systems that generate our bodies. Much progress has been made in recent years to reveal the process by which the skeleton is generated and maintained. The discovery of functionally homogeneous SSC populations identified by a combination of surface markers has therefore unveiled the potential for directed and reliable studies into the nature of the progenitor cells of the skeletal system. Moreover, the complexities of skeletal aging can more readily be elucidated by studying the changes in cellular function and expression profile across age groups. Several studies have already identified key features of SSC aging and its components, but more work is needed to better clarify cellular mechanisms that, in aggregate, generate an aged and dysfunctional skeletal niche, and subsequently an aged and dysfunctional skeletal system."}
+{"text": "Historically, the science of Psychology and the practice of psychological assessment in Africa have been influenced by Western ideologies and practices , Frontiers or do not support faculty with the APC. That researchers are often restricted by lack of funding to publish their work in high impact outlets like Frontiers is highly problematic and undermines our collective efforts in overcoming some of the limitations in hegemonic psychological theory, research, and praxis.To diversify the pool of potential contributors, we invited as many Africa-based and Africa-focused researchers and practitioners as possible through the use of: (1) the professional networks of the guest editors; (2) websites of African departments; (3) Africa-based and Africa-focused journals, books, and book chapters; and (4) invitations to individuals whose previous work appeared consistent with the goals of this RT. We invited a total of 269 prospective contributors, out of which 212 were unresponsive, 23 declined our invitation, 20 withdrew, and 14 confirmed their participation. We accepted 15 abstracts and expected additional 2 manuscripts from researchers who requested permission to submit after the deadline for receiving abstracts had elapsed. Of the 17 expected submissions, we received 12 full manuscripts. We accepted seven of these for publication. Unfortunately, the response to this RT was negatively affected by the Article Processing Cost (APC), given that many African universities do not have institutional agreements with van der Merwe et al.), a perspective , development of ethical guidelines for online mental health screening tools (Hassem and Laher), an evaluation of an adaptation to a self-directed format of the Grade 9 Career Guidance Project , and application of approaches to construct validity .The seven (7) papers accepted for publication in this RT were mostly authored by South African and Ghanaian researchers. More recently, Serpell et al.  reportedvan der Merwe et al. and van Vuuren et al. provide guidance on how to approach the process of contextualizing assessment tools as well as the factors that influence the assessment process in the African context. For instance, van der Merwe et al identified contextual factors, the school learners' test-taking skills/familiarity and prior learning, and the school learners' cognitive abilities that affect the applicability of the test instrument when imported into other settings. Similarly, van Vuuren et al. raised the concerns of culture and language in the development of psychological tests, highlighting the challenges associated with test adaptation and translation and offered some guidance on how to navigate cultural and language issues in the development, adaptation, and translation of tools assessing intelligence and similar constructs.Together, the work by Hassem and Laher and van Schalkwyk et al. provided guidance on how to contextualize intervention programme or guidelines in the South African context. In this regard, Hassam and Laher presented guidance to researchers on the practical steps required to either contextualize an existing ethical guideline or develop new ones using a two-phase in-depth interview with mental health experts. On the other hand, van Schalkwyk et al. provided evidence via a mixed-methods design to evaluate teachers' support for the use of a self-directed manualised booklet to assist Grade 9 learners to explore their career interests and their knowledge of self. The reliance on teachers' evaluative feedback serves as key approach to assessing implementability of similar programmes. In particular, the assessment of relevance, appropriateness of methods of adaptation, and suggestions for improvements are important standards for evaluating any ethical guidelines.Further, Anum; Khumalo et al.; Tadi et al.) sought to provide evidence of construct validity using different approaches. Tadi et al. employed the theory-consistent group differences approach  and LCA to investigate the validity of the dual-continua model among young adults from Ghana, Kenya, Mozambique, and South Africa who completed the Mental Health Continuum\u2014Short Form (MHC-SF) and PHQ-9. Both studies are exemplary as they utilized CFA , LCA, large sample sizes, and cross-national samples to enhance the validity evidence they produced. Finally, Anum employed appropriate developmental changes and theory-consistent group differences approaches to investigate the relative impact of age and socio-economic status (SES) on fluid and crystallized intelligence. He showcased that the type of school attended (private or public) can reasonably be used as a proxy for SES among young children and offered practical steps on the use of appropriate developmental changes approach to construct validity.The last set of studies (Gregory,  to examiWe hope that this RT will inspire Africa-based researchers and practitioners to become more conscious of the need to adapt or generate context-responsive assessment tools, show preference for validated versions of tools, and contribute to culturally appropriate guidelines and testing practices in Africa and the Global South.SO developed the first draft. RA, GH, JK, and SO edited and improved it until a final version was agreed upon. All authors contributed to the article and approved the submitted version."}
+{"text": "Differentiated thyroid carcinoma (DTC) is on the rise worldwide and ranks first among endocrine cancers . The surMajor efforts have been made to reduce the surgical burden in low-risk tumours and in diagnostic procedures. Other surgical contraventions, such as the role of central neck dissection, especially prophylactically, has been questioned given its risk-benefit ratio; the role of active survival in low-risk DTC; non-surgical interventions such as radiofrequency and thermal ablations are among the studies included in these current Research Topics. Other aspects relate to the use of technology to minimise potential complications and adverse outcomes of thyroid surgery - use of intraoperative nerve monitoring to reduce recurrent laryngeal nerve injury, remote surgical approaches that avoid visible neck scars, and more.After completion of primary treatment, patients with DTC can usually remain healthy and return to their former lives , 4. HoweIn addition to objective factors that have an obvious impact on quality of life, such as postoperative complications, recurrence, etc., subjective quality of life, i.e. patient-centred factors in treatment options for DTC, has become an important topic in recent clinical trials \u20134. This Factors influencing the quality of life of DTC patients include physical and psychological symptoms, self-efficacy and social support , 3. ClosThe more severe the symptoms in DTC patients, the greater the psychological distress, the lower the physical and social functioning and the poorer the overall quality of life . Social The concept of quality of life is currently gaining importance in the evaluation of treatment procedures . When coPhysicians should discuss the expected outcomes after thyroid surgery with patients in order to increase patient satisfaction and quality of life through detailed information.AK, OC and GD: writing and revising the manuscript. All authors contributed to the article and approved the submitted version."}
+{"text": "RNA-Seq and mass spectrometry-based studies generate omics data tables with measurements for tens of thousands of genes across all samples in a study. The success of a study relies on the quality of these data tables, which is determined by both experimental data generation and computational methods used to process raw experimental data into quantitative data tables. We present OmicsEV, an R package for the quality evaluation of omics data tables. For each data table, OmicsEV uses a series of methods to evaluate data depth, data normalization, batch effect, biological signal, platform reproducibility and multi-omics concordance, producing comprehensive visual and quantitative evaluation results that help assess the data quality of individual data tables and facilitate the identification of the optimal data processing method and parameters for the omics study under investigation.https://github.com/bzhanglab/OmicsEV, and the source code is released under the GPL-3 license.The source code and the user manual of OmicsEV are available at  RNA-Seq and mass spectrometry (MS)-based proteomics provide global measurements of the abundance of genes and their protein products in samples of interest. These measurements are usually stored in quantitative data tables for downstream analysis. The success of an omics study is largely determined by the quality of these tables, which in turn depends on the quality of both experimental data generation and computational methods used to process raw experimental data into quantitative data tables. Omics data processing involves multiple steps, and many algorithms, software, and workflows have been developed for these essential tasks.Optimal selection of tools, algorithms and parameters is critical to ensure reliable and accurate estimation of gene or protein quantification , by grant CPRIT [RR160027] from the Cancer Prevention & Research Institutes of Texas, by funding from the McNair Medical Institute at The Robert and Janice McNair Foundation. B.Z. is a CPRIT Scholar in Cancer Research and a McNair scholar.Conflict of Interest: none declared."}
+{"text": "Observational outcomes of recent studies indicate the notion of the gut microbiota's contribution to the host's physiological, immune, neurological, and metabolic health. In dysbiotic conditions, gut microbes could contribute to the development of a wide spectrum of diseases including metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), irritable bowel syndrome (IBS), and inflammatory bowel disease (IBD) , 2. HoweIn this regard, the special issue of \u201cGut Microbiota and Gastrointestinal Disorders\u201d appeared highly topical, wherein the aim was to provide novel insights on the central role of the gut microbiota in gastrointestinal disorders and seek innovative therapeutic and predictive applications of selected microbial species.Hu et al. reviewed the genetic, immunological, and microbial risk factors for UC pathogenesis. They enumerated potential microbiome-based approaches to restore and preserve intestinal microbial homeostasis and subsequently resolve UC. In another review, Wang et al. focused on gastrointestinal microbial dysbiosis and its contribution to the development of NAFLD, ranging from steatosis to non-alcoholic steatohepatitis (NASH). In this study, the special association of periodontopathic bacteria, mainly Porphyromonas gingivalis, to the pathogenesis of NAFLD was highlighted through clinical and basic research.Considering the profound influence of the gut microbiota on the development and progression of ulcerative colitis (UC), Tavakoli et al. during the treatment procedure of IBD patients. Observational findings suggested a substantial decrease in microbial diversity of Crohn's disease (CD) patients compared to UC patients. This, in principle, leads to the interdependence of treatment strategy and microbial dynamic comparing CD and UC patients. Although most studies associating the gut microbiota with human health and disease have focused on the analysis of bacterial and archaeal components, the importance of the mycobiota, the microbiota's fungal portion, is now recognized. The analysis of the mucosa-associated mycobiota in CD patients by Olaisen et al. revealed the enrichment of Malassezia and the depletion of Saccharomyces, along with a higher proportion of Candida albicans and Malassezia restricta, compared to healthy controls. Notably, the mycobiota structural differences between the inflamed and proximal non-inflamed ileum within the same individual may contribute to CD pathogenesis. Moreover, the identification of intraindividual and interindividual differences in microbial composition can be utilized as predictive biomarkers. Tian et al. exhibited the abundance of Alistipes and Eubacterium and the impoverishment of Roseburia species in patients suffering from slow transit constipation. The enrichment of fatty acid biosynthesis, butanoate metabolism, and methane metabolism pathways along with microbial alteration might be potential biomarkers for slow transit constipation. Another predicting strategy was provided by Vincentis et al., evaluating the clinical improvement of patients receiving rifaximin therapy. Although inaccurate in predicting gut microbiota alterations, their electronic multi-sensorial systems constituted of e-tongue and e-nose, could effectively predict clinical improvement.The significance of microbial species in the progression and emission of gastrointestinal disorders has led to the evaluation of longitudinal bio-psychological dynamics by Nakajima et al. in C57BL/6 male mice. Nicotine administration prior to the induction of DSS-induced colitis elevated indole concentration in the distal colon and rectum while short-chain fatty acid (SCFA) values presented insignificant differences, compared to the control cohort. The high level of indole concentration, as well as the increased proportion of Clostridioides and Porphyromonas genera, were presented as the underpinning mechanism of DSS-induced colitis suppression following nicotine administration. Similarly, Zhou et al. reported the potential for a ginger extract to attenuate the susceptibility to DSS-induced colitis by preventing weight loss, colon shortening, inflammation, and intestinal barrier dysfunction. Ginger administration to mice models for 4 weeks following antibiotic exposure increased bacterial diversity and the relative abundance of Helicobacter species while decreasing the relative abundance of Peptococcaceae rc4-4.In the context of IBD research, a treatment strategy for dextran sodium sulfate (DSS)-induced colitis was evaluated by Ishikawa et al. for UC patients following triple-antibiotic therapy. This study protocol presented a double-blinded, randomized, placebo-controlled, parallel assignment trial that primarily should evaluate the Total Mayo Score at 8 weeks after the FMT procedure. Furthermore, the comparison of clinical features, microbial structure, and metabolic profile, as well as post-FMT 2-year follow-up constitute other endpoints of this study protocol.Another therapeutic approach for restoring the inherent microbial composition is fecal microbiota transplantation (FMT), which was proposed by Yang et al. assessed the efficacy and safety of FMT combined with biofeedback for mixed constipation. They reported insignificant differences in side effects, yet the combined therapy presented a substantial enrichment in the proportion of probiotic species namely Prevotella and Bifidobacterium. Considering FMT as a stopgap, yet effective and safe, microbiome-based therapeutic strategy for the remission of gut dysbiosis and gastrointestinal disorders, Savigamin et al. presented four primary steps for initiating FMT in developing countries including: 1. Finding a perfect stool donor; 2. Initiating a clinical trial; 3. Establishing a stool standard for use in other research trials; 4. Establishing a clinical center for the transplantation of fecal microbiota. They further discussed and provided insightful suggestions for the first two steps.In conclusion, the studies published in this Research Topic further shed light on the critical contribution of the gut microbiota in the pathogenesis of gastrointestinal disorders and its potential capacity in developing efficient biomarkers and therapeutic strategies. In this field of study, the knowledge gaps to be filled and the bottlenecks to be surpassed include deciphering the contribution of hundreds of as-yet-unknown metabolites and their related signaling pathways to the host's physiological and metabolic health and disease.AN-R wrote the first draft of the manuscript. AY, JO-R, TO, and Y-DW revised the manuscript. All authors read and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "The COVID-19 pandemic has substantially affected global communities and health systems in both high- and low-income countries. Many nations have been experiencing very high population burdens that implies the importance of strengthening responses systems and mobilizing communities in pandemic preparedness and control. The shortage of resources in LMICs is well-documented prior to COVID-19 and it has been worsened with the surge of COVID-19. In many LMICs, testing capacity remains inadequate, the number of ICU beds is far less than required, access to drug treatments such as dexamethasone is limited, and the supply of therapeutic oxygen and ventilators is insufficient . ImportaZhang studied the experience of public health system construction in China's COVID-19 prevention and identified key lessons for other countries to confront unprecedented pandemic. The paper not only pointed out several advantages of China's public health system construction in response to COVID-19, such as adequate supply of health resources and improved affordability of health care, but also discussed China's deficiencies, including low utilization efficiency of health resources, unequal ability to pay for medical expenses, and late disclosure of virus information in the early stage of the outbreak of COVID-19. Given that Nepal is facing a flood of COVID-19 cases after the lockdown was lifted in July 2020, Rayamajhee et al. provided critical insights on response of the government, highlighting the need to increase testing, tracing, and isolation capacity, and to set up quality quarantine centers throughout the nation to address the rise in COVID-19 infection cases. As cases have continued to fluctuate over a year into the pandemic in Indonesia, Mahendradhata et al. reviewed the current capacity of the healthcare system to respond to COVID-19 and emphasized the need for the Indonesian Government to ramp up the country's healthcare capacity in order to absorb and accommodate the varying healthcare demands during the pandemic. Saha and Gulshan provided a systematic analysis of the overall patterns in terms of number of cases, number of deaths, and impacts of COVID-19 in Bangladesh. The authors also shed light on the underlying causes that resulted in a continuous outbreak while discussing possible measures, effectiveness of the preparedness, implementation gaps, and their consequences to gather vital information and prevent future pandemics. Abd El Ghaffar et al. investigated the situation in some of the COVID-19 screening hospitals in Egypt in terms of inpatient beds, ICU beds, and ventilator utilization rates. Results from this paper, which indicated a shortage of resources, would help policymakers make informed resource reallocation decisions in Egypt, or other developing countries, which suffered from a lack of resources and a weak health system prior to the pandemic. Coumare et al. discussed the challenges and experiences in preparation and responses to the ongoing COVID-19 pandemic at a tertiary teaching hospital situated at Puducherry, India. Tran et al. examined factors associated with the intention to participate in COVID-19 frontline prevention activities among Vietnamese nursing students. The finding suggested that socioeconomic characteristics of participants, their source of COVID-19 related knowledge, and their perception and attitude toward participating in COVID-19 frontline activities were associated with intention to participate. Given resource-scarce settings of most LMICs, these countries are challenged by their limited capacity for manufacturing test kits, limited budgets for equipment and reagents, and scant ability to make competitive bids for global supplies. Gyawali and Mohammad Al-Amin et al. advocated for recognition of the almost insurmountable obstacles that face the implementation of non-pharmaceutical interventions for COVID-19 management in Asian LMICs and called for a global commitment to the equitable distribution of therapeutants and vaccines. Although the World Bank is making available more than $160 billion funding to LMICs to purchase and distribute COVID-19 vaccines, tests and treatment and mitigate the health, economic, and social shocks, and philanthropic organizations such as the Global Alliance for Vaccines (GAVI) have received billions of dollars in donations, much more will be required for LMICs to combat COVID-19 and mitigate the expected economic downturn. In the long term, LMICs will need to develop their own capacity to manufacture and distribute vaccines, as well as strengthen primary health centers to manage the impact of the pandemic.The following studies summarized experience of LMICs in managing the surge of COVID-19 in terms of capacities and responsiveness of health systems and communities. Muhammad Nur Amir et al.. described the workforce mobilization from the National Institutes of Health (NIH) to the other public healthcare facilities within the Ministry of Health (MOH) in the early phases of the COVID-19 pandemic management in Malaysia. The paper demonstrated how this workforce mobilization team efficiently mobilize the healthcare workforce and fulfill requests received for human resource aid, resulting in reduced infected COVID-19 cases throughout the country. Nguyen D. N. et al. provided evidence for reforming the training programs to prepare medical students, a potential task force with the capability to support the stretched health sector, for COVID-19 responses in Vietnam. This study suggested that the training curriculum should include both theoretical approaches  as well as other contextual approaches to achieve efficient epidemic control in specific regions. Le et al. illustrated the potential and feasibility of intersectoral collaboration in epidemic preparedness and response at grassroots levels in the threat of COVID-19 pandemic in Vietnam, which ensures sufficient resources for urgent cases and helps to inform a determined response framework.In addition to capacities and responsiveness of health systems and communities to respond to the pandemic, numerous studies have highlighted the importance of strategic planning and resource mobilization to maintain essential health services and maximize human resource capacity to address COVID-19 situation and its associated disruptions. Shewade et al. reported that the estimated COVID-19 deaths in India after adjusting for the coverage and quality of the routine death surveillance may be 5.5\u201311 times the reported COVID-19 deaths. Hence, this study further discussed the routine deaths surveillance in India, the rationale for adjusting the reported COVID-19 deaths for coverage of the routine death surveillance and its implications on the estimated infection fatality ratio (IFR) for India in order to make meaningful and reliable comparisons. Mansab et al. highlighted the disparity in oxygen provision for COVID-19 patients between 26 nations included in the study and suggested that there was an association with higher national mortality rates in those nations that pursued a conservative oxygen strategy. Abbasi-Kangevari et al. sought to determine the priorities of the Iranian public toward the fair allocation of ventilators during the COVID-19 pandemic. Participants stated that socioeconomic factors, except for age > 80, should not be involved in prioritizing mechanical ventilators at the time of resources scarcity. Front-line physicians and nurses of COVID-19 patients, pregnant mothers, mothers who had children under 2 years old had been given high priority.Given the speed and spread of transmission of COVID-19, assessing the effectiveness of epidemiological monitoring and surveillance of the epidemics is critical to control the expansion of the epidemics and avoid the collapse of health care systems. Vo et al. demonstrated how social distancing measure had been implemented in Vietnam and further discussed factors associated with the high compliance of Vietnamese with social distancing measures. Tam et al. discussed the evidence on the effectiveness, and rationale for community mass masking to prevent the COVID-19 transmission in Vietnam. Sun et al. showed that the proper management of inbound travelers from outbreak areas had a significantly positive effect on the prevention and control of the virus and suggested that effective measures taken by Yunnan province may provide an important reference for preventing the COVID-19 outbreak in other regions. As the prevalence of psychological stress among healthcare workers (HCWs) in Vietnam during the COVID-19 pandemic was high, Nguyen P. T. L. et al. sought to understand COVID-19-related, psychological stress risk factors among HCWs, their concerns and demands for mental health support during the pandemic period. The author recommended psychological interventions involving web-based consulting services to provide mental health support among HCWs. Nguyen A. N. et al. assessed the knowledge and practices regarding the prevention of the COVID-19 among the HCWs in Vietnam to identify the ways of disseminating information to maximize the safety of these essential workers. Findings from this study suggested that future education initiatives should centre initially on the COVID-19 virus aerosols with the primary focus on doctors, especially those in emergency and the intensive care departments. In addition to epidemiological and psychosocial interventions, Nguyen H. T. T. et al. described economic recovery solutions implemented by the Vietnam government to manage the fiscal deficit, such as focus on effectively implementing domestic stimulus, use the savings from falling international oil prices to curb the crisis, earn funding from the World Bank WB and the International Monetary Fund, etc.Many articles in this Topic focused on evaluating the effectiveness of epidemiological, psychosocial and economical interventions to prevent the importation, spreading and relieve the impact of COVID-19 pandemic in LMICs. Vietnam has achieved initial results in flattening the curve and slowing the spread of COVID-19 transmission in the community, which is attributable to a high-level adherence with social distancing measures, accompanied with contact tracing, mass testing, and mandatory isolation. Klement pointed out that journalism, politics, and medicine involved within the COVID-19 crisis have maintained a simple narrative and reductionist thinking and emphasized the need for systems thinking during the outbreak. A survey by Raza et al. was conducted to understand knowledge, attitudes, and practices related to COVID-19 among the students in Lahore, Pakistan. This survey showed that most of the students were well informed about COVID-19 and exhibited a proactive approach during the outbreak, suggesting an effective public health campaign of the local government to deliver public health knowledge in the community. Chatterjee et al. focused on highlighting some of the key aspects of digital healthcare during the times of COVID-19 pandemic in South America. This study shed light on the role of Artificial Intelligence and the Internet of Things role in resource optimization along their potential applications like clinical decision support systems and predictive risk modeling, especially in the direction of combating the emergent challenges due to the COVID-19 pandemic. Mat Dawi et al. examined the influence of e-government and social media on the public's attitude to adopt protective behavior and suggested that during the COVID-19 outbreak, public health decision makers may use e-government and social media platforms as effective tools to improve public engagement on protective behavior. Although Nguyen, Nguyen, Le, et al. demonstrated a high level of agreement among the general population toward the importance and necessity of national response measures to combat the COVID-19 epidemic in Vietnam, Nguyen, Nguyen, Nguyen, et al. expressed concern about the impact of fake news on the adherence of national response measures during the lockdown period in Vietnam. In response to fake news, the government had made early predictions and concrete strategies, such as passing a cybersecurity law or establishing official communication channels, which may also have important lessons for other nations in the fight against COVID-19.Several studies have raised important points regarding the impact of perceptions and attitudes toward the COVID-19 crisis on the improvement of both public health and individual well-being and highlighted how digital health care and social media may influence public's attitude during the COVID-19 outbreak. Specifically, Gyawali and Mohammad Al-Amin et al.; Mahendradhata et al.; Rayamajhee et al.; Tran et al.; Zhang). Ensuring sufficient healthcare workforce, training more health providers, and recruiting volunteers would help to increase vaccine availability, distribution, and monitoring. In addition to healthcare workforce capacity, vaccine acceptance and hesitancy remain a significant barrier to increase vaccination rate. Perceptions and attitudes play an important role on the improvement of both public health and individual well-being, which significantly influenced by Internet and social media . Thus, governments could establish awareness-building initiatives using community and mass media to manage inaccurate information about vaccines, lack of information, and lack of trust in the government and pharmaceutical companies. Lastly, governments should consider to increase budgets for COVID-19 vaccine purchase and delivery to scale up COVID-19 vaccination and offer access to all populations; however, this has not been discussed in the collection of papers in this topic.Besides efforts to mitigate pandemics in LMICs from medical staff training and monitoring to system modernization, it is also important to consider potential barriers that arise during the COVID-19 vaccine rollout in LMICs and how to address these difficulties in resource-scarce settings. Recent studies have reported several challenges for vaccination faced by LMICs, including vaccine hesitancy , inadequThe COVID-19 pandemic has challenged the healthcare capacity of many countries. The collection of papers in this topic provides insight on the opportunities and challenges in strengthening health system and community responses to confront COVID-19 pandemic in resource-scarce settings. Lessons learned in terms of strength and limitations from the latest evidence on health sectors and community responses to control the COVID-19 pandemic in LMICs would suggest implications to improve the effectiveness of current policies and facilitate development of new strategies to strengthen the capacity and efficiency of healthcare systems in the fight against COVID-19. Governments will continue to play an important role in responding to the coronavirus pandemic and providing access to care for communities in resource-constrained countries with limited human, infrastructural, and financial resources and that are behind the curve in the spread of the pandemic.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.Research was supported by the Vingroup Innovation Foundation (VINIF) in project code VINIF.2020.Covid-19.DA03. The article processing charge for journal is financed by NUS Department of Psychological Medicine (R-177-000-100-001/R-177-000-003-001/R177000702733) and NUS iHeathtech Other Operating Expenses (R-722-000-004-731).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "This study aimed to identify a set of newborn signal functions (NSFs) that can categorize health facilities and assist policymakers and health managers in appropriately planning and adequately monitoring the progress and performance of health facilities delivering newborn health care in Bangladesh and similar low-income settings.A modified Delphi method was used to identify a set of NSFs and a cross-sectional health facility assessment among the randomly selected facilities was conducted to test them in public health facilities in Bangladesh. In the modified Delphi approach, three main steps of listing, prioritizing, and testing were followed to identify the set of NSFs. Then, to finalize the set of NSFs and its variables, a total of five Delphi workshops and three rounds of Delphi surveys were conducted. Finally, 205 public health facilities located in 41 randomly selected districts were assessed for the availability and readiness of finalized NSFs using the updated tool of Bangladesh Health Facility Survey (BHFS) 2017.Twenty NSFs were identified and finalized, nine of which were categorized as primary NSFs, 13 as basic NSFs, 18 as comprehensive NSFs, and 20 as advanced NSFs. Almost all district hospitals (DHs), Upazila health complexes  and maternal and child welfare centres (MCWCs) performed the primary NSFs in the last three months. However, around one-third of the union health and family welfare centres (UH&FWCs) and very few community clinics (CCs) performed them during the same period. The basic, comprehensive, and advanced NSF readiness was inadequate and inappropriate across all types of facilities, including DHs and UHCs.In the absence of internationally or nationally agreed-upon NSFs to measure a health facility's service availability and readiness for providing newborn care, this study becomes the first to identify and finalize a set of NSFs and to incorporate relevant variables in the health facility assessment tool which can be used to monitor the availability and readiness of a newborn care facility. The identified NSFs can also be adapted for the countries with similar contexts and can serve as a standard base to determine a global set of NSFs. In the last decade, commendable progress has been made in improving maternal and newborn health globally. During the Millennium Development Goals (MDG) era 1990-2015), the global neonatal mortality rate (NMR) declined from 36 19 deaths per 1000 live births; the decline in NMR 47%) has been much slower than that of the post-neonatal under-five mortality rate (58%) [990-2015,7% has beConsidering this high burden, the government of Bangladesh is highly committed to achieving the SDG targets of newborn mortality by 2030. In response to the global Every Newborn Action Plan (ENAP), it developed the Bangladesh Every Newborn Action Plan (BENAP) with specific strategies for averting newborn mortality and morbidity. Following up on these commitments, newborn health has been included as one of the priority activities in the fourth health sector program (2016-2022) of Bangladesh, while the operation plan has a separate programme called the National Newborn Health Programme and Integrated Management of Childhood Illness (NNHP&IMCI) for implementing the newborn health interventions targeting the major causes of newborn death in Bangladesh .Since most of these interventions involve specialized and facility-based treatment, a robust health infrastructure is needed to provide the necessary services ,7. ServiEmergency obstetric care (EmOC) signal functions  have been used to assess the availability and quality of maternal care . The latA set of signal functions is crucial in planning policy and programs for correctly identifying health facilities that provide newborn services. Acknowledging the necessity and significance, NNHP & IMCI Program of the Directorate General of Health Services (DGHS) has designated the identification of newborn signal functions (NSFs) as a priority task for successful planning and scaling-up of newborn interventions in Bangladesh . This stThis cross-sectional study was carried out from October 2017 to February 2020. It adopted the Delphi method to seek expert consultation and built consensus for identifying the NSFs and their relevant variables as well as adapting the assessment tool. The Delphi method, mainly developed by Dalkey and Helmer at the Rand Corporation in the 1950s, is well adapted for building consensus due to its evident potential for revealing underlying assumptions and searching out new perspectives that can contribute to consensus among different respondents . The DelThree main steps of the Delphi process  were followed, with each step being divided into two sub-steps, as illustrated in To identify the leading causes of neonatal mortality, relevant interventions, indicators, and possible functions (skills and resources needed to provide an intervention), a comprehensive desk review of the available literature (both written and unpublished) was undertaken. We develop a list of existing maternal, newborn, and child health strategies, action plans, monitoring frameworks, standard operating procedures (SOPs), and national and global guidelines on interventions/functions to avert major causes of newborn deaths. A group of International Centre for Diarrhoeal Disease Research, Bangladesh  researchers systematically reviewed relevant five global and ten national documents from the list. Table S1 in the Besides desk review, a total of six key informant interviews (KIIs) were conducted with Ministry of Health & Family Welfare (MoHFW) program managers and newborn health experts from professional bodies such as Bangabandhu Sheikh Mujib Medical University (BSMMU) and Bangladesh Neonatal Forum (BNF) to identify additional interventions and functions needed to deliver newborn care in a health facility setting. The interviews helped to identify an additional 11 newborn interventions/functions that were added to the primary list of 79 newborn interventions/functions.The National Technical Working Committee for Newborn Health (NTWC-NBH) (established by MoHFW) formed a group of newborn expert panels with a specific Term of Reference (ToR). A total of 48 newborn experts, representing 22 organizations such as the MoHFW, professional bodies, United Nation (UN) agencies, and development partners engaged in newborn health, became part of the newborn expert panel  tools: Averting Maternal Death and Disability (AMDD), Health Facility Census (HFC), Service Provision Assessment (SPA), Rapid Health Facility Assessment (R-HFA), Service Availability Mapping (SAM), and Service Availability and Readiness Assessment (SARA) . The 201The variables present in the 2017 BHFS tool (n\u2009=\u200945) and the variables present in the other HFA tools (n\u2009=\u200916) were automatically included in the final variable list. Variables identified from interviews with the newborn Delphi experts were validated before they were included in the final variable list. Project research physicians (PRPs) measured the variables\u2019 construct and content validity by field testing them in seven different public health facilities. The operational definition of these validity measures is described in the published protocol . ContentThe questionnaire adaptation for the 2017 BHFS tools took place in August 2019. A consultative meeting with the stakeholders especially from National Institute of Population Research and Training (NIPORT), visits to the service provision sites for pre-testing the tools, and a day-long questionnaire adaptation workshop elicited the feedback needed to adapt the questionnaires. Based on the feedback, the validated variables were incorporated into the BHFS 2017 tool, and finally, the tool was updated and finalized for the assessment of service availability and readiness of NSFs in Bangladesh. The updated 2017 BHFS had two types of data collection tools as facility Inventory questionnaire and the health care provider interview questionnaire.12 PRPs were recruited for the HFA who received five days of training on the updated BHFS 2017 tool in September 2019, in Dhaka.Four data collection teams were formed, with one data collector on each team assigned the role of a team leader. Data collection was conducted from November to December 2019. On average, data collection took two days for each health facility. And was conducted using paper-based Facility Inventory and Health Care Provider Interview questionnaires. The data collectors interviewed the most knowledgeable person about the facility and its services; if collected from other persons, the information was validated by direct physical observation and/or some facility record review.Two medical doctors monitored the overall data collection process and supervised the team. They conducted periodic visits to ensure the quality of data collection and provide onsite training.To assess the service availability and readiness of the public health facilities for the NSFs, a precision-based sample size was measured. With a 10% error margin, the study aimed to cover maximum variance (50%) as there is no estimate available. The required sample size was 101 public health care facilities, assuming a non-response rate of about 5%. We were able to conduct a cross-sectional facility assessment in 205 registered public health facilities across all eight divisions to provide the most representative results for Bangladesh  tools .To analyse each Delphi survey outcome, central tendency (mean) and a measure of distribution (interquartile range (IQR)) were measured. Additionally, the average expert agreement (AEA) for every intervention/function was calculated from the ratio between the frequency of mode and the number of responses in each survey. As experts recommended, consensus and agreement were stable when the AEA value was 50 or more for any intervention/function. Kappa statistics with a >0.75 cut-off were used to report on the construct validity of the newly added variables in the HFA tool. The BHFS tabulation plan was followed to analyse the HFA data.Ethical approval was obtained from the Research Review and Ethical Review Committee (ERC) of icddr, b (PR-17089). Written and informed consent was sought from the health facilities and each participant before the assessment or interviews.Based on the pre-defined cut-off values and scoring guidelines recommended by the newborn Delphi experts, we identified 20 NSFs from the shortened list of 37 interventions/functions for Bangladesh. The summary of the average score for each intervention/function and the cut-off values to identify four categories of NSFs is presented in The AEA of the Delphi experts on newborns was checked based on each category of NSFs on the pre-defined cut-off values  supplementation function. Almost all district hospitals (DHs), Upazila health complexes  and maternal and child welfare centres (MCWCs) provided IFA supplementation in the last three months, while around one-third of union health and family welfare centres (UH&FWCs) and less than 10% of community clinics (CCs) provided IFA supplementation in the same period.One-fourth of the facilities did not perform hand washing each time before touching the baby. All DHs, MCWCs, and UHCs performed hand washing each time before touching the baby, whereas around half of the UH&FWCs and less than 10% of CCs performed hand washing each time before touching the baby.About 73% of the facilities performed immediate drying. Moreover, all DHs, MCWCs, and UHCs performed the immediate drying of the newborn, while around half of the UH&FWCs and less than 10% of CCs performed this function.About 73% of the facilities performed delayed umbilical cord clamping approximately one to three minutes after birth. All DHs, MCWCs, and UHCs performed delayed umbilical cord clamping approximately one to three minutes after birth, whereas the function was performed by around half of the UH&FWCs and less than 10% of CCs.About 72% of the facilities performed a clean cord-cutting function. Nearly all DHs, MCWCs, and UHCs performed clean cord-cutting. However, around half of the UH&FWCs and less than 10% of the CCs performed this function.About 73% of the facilities performed a single application of 7.1% chlorhexidine to the umbilical cord followed by dry cord care. All DHs, MCWCs, and UHCs performed the single application of 7.1% chlorhexidine to the umbilical cord followed by dry cord care, while only around half of the UH&FWC and less than 10% of the CCs performed this function.About 68% of the facilities performed neonatal resuscitation. All MCWCs, nearly all DHs, and about 93% of the UHCs performed this function.About 72% of the facilities performed early initiation of breastfeeding within one hour. All MCWCs and UHCs performed this function whereas 2% of DHs did not perform this function.About 73% of the facilities performed skin-to-skin care for two hours. While all DHs, MCWCs, and UHCs performed the clean cord-cutting (clean/sterile thread) function, only 53% of the UH&FWC and 10% of the CCs performed this function.Only 58% of all facilities performed tetanus toxoid function. The function was performed by over 80% of the DHs, MCWCs, and UHCs, but by less than one-third of the UH&FWCs.One-third of the total facilities performed suction of newborns. All DHs and nearly all UHCs and MCWCs performed this function, but less than 50% of the UH&FWCs performed it.Only 12% of the total facilities provided oral antibiotics for infections. Across facilities, the performance of this function was lower than 25%, and no CCs performed this function.Only 24% of the total facilities provided injectable antibiotics (intramuscular (IM)) for infections. Besides, none of the UH&FWCs and CCs performed this function.Only half of the total facilities provided antibiotics for premature rupture of the membrane (PROM). Nearly all the DHs provided antibiotics for PROM, while none of the UH&FWCs and CCs performed this function.About 60% of the total facilities provided oxygen therapy. However, only 78% of the DHs, 56% of the UHCs, and 39% of the MCWCs performed this function.Only 35% of the total facilities provided injectable antibiotics (intravenous (IV)) to the newborn. Besides only 78% of the DHs, 56% of the UHCs, and 39% of the MCWCs performed this function.Less than 30% of the total facilities provided phototherapy. Moreover, about 88% of the DHs and less than 10% of the UHCs and MCWCs performed this function.Only 28% of the total facilities provided kangaroo mother care (KMC) for pre-term and low birth weight (LBW) babies. Only 63% of the DHs, 39% of MCWCs, and less than one-third of the UHCs performed this function.Only 37% of the total facilities provided ACS for preterm birth. Only 78% of the DHs and around 50% of the MCWCs and UHCs performed this function.Only 10% of the total facilities performed incubator functions. Only half of the DHs and 2% of the UHCs performed this function, while none of the MCWCs performed this function.Overall, almost all the MCWCs, 90% of the UHCs, and 85% of the DHs performed all primary NSFs, while only 39% of the UH&FWCs and 5% of the CCs performed those in the previous three months of the assessment. Only 5% of DHs performed advanced NSFs.Using the adapted Delphi method, a clear, evidence-based, and low-cost technique combining scientific methods and expert opinion -19, thisIn identifying a set of valid and agreed-upon NSFs, this study followed all relevant steps of a Delphi study including defining consensus. A Delphi study must have a pre-defined meaning of consensus for their study, if not, the credibility of the outcomes will not be considered as valid . VariousThe utilization of RAND-modified Delphi in this study improved the validity and generalisability of the identified NSFs . The resThe identified valid NSFs can capture the service availability, readiness, and functionality of a range of relevant newborn interventions/functions at different facility levels, which can help identify the causes of the high burden in newborn mortality and the recent halt in the reduction in newborn morbidity. In this study, a total of 20 interventions were accepted and 17 were rejected, with a focus on impact, reliability, actionability, priority, and feasibility of data collection during the scoring and ranking process. A similar attempt undertaken in Zimbabwe identified 11 obstetric and newborn signal functions, three of which were for routine newborn care, six for basic emergency newborn care, and two functions for comprehensive emergency newborn care . To finaThese 20 identified NSFs can be captured as part of a health facility assessment survey or as a routine monitoring system by health managers at any health facility level. When reviewing existing HFA tools, we found that most NSFs are not collected through health facility surveys. The 2017 BHFS tool only measured the availability and readiness of one newborn indicator (newborn resuscitation) as part of Basic Emergency Obstetric Care (BEmOC) of public and private health facilities in Bangladesh, which was insufficient to accurately measure the health facility's availability and readiness to provide newborn care and to assess the status of identified NSFs. All these NSFs are not routinely collected or reported in the existing health information system. Having an agreed list of functions made it relatively easy to identify and finalize the list of variables required to measure the service availability and readiness of these functions at a health facility level. The results of the survey conducted by the updated HFA tool contributed to assessing the health facilities for the NSFs and will assist policymakers and health managers in planning and monitoring their performance and progress regarding newborn health services . The preThe HFA of this study revealed that the functionality of NSFs for neonatal infection management such as oral antibiotics, injectable antibiotics (IM), and injectable antibiotics (IV) was poor, especially in primary referral facilities. Infections such as sepsis, pneumonia, tetanus, and meningitis account for about 22% of overall newborn deaths worldwide and around one-quarter of newborn deaths in Bangladesh ,30. The This research study and its findings primarily aimed to influence national policy and programs. From the study\u2019s initiation, the NNHP & IMCI Program of the DGHS was co-leading the study activities with icddr,b . All theTen years have left to achieve the ambitious Sustainable Development Goals (SDGs) of ending preventable neonatal deaths, accelerated efforts are needed to improve access to and quality of care for all mothers and newborns -3. As moThis is the first study to identify widely agreed upon NSFs for Bangladesh by adopting the validated and widely used Delphi methodology to synthesize experts\u2019 knowledge and experiences. The MOHFW of Bangladesh, various associations, academics, and development partners have endorsed the identified NSFs. The existing health facility assessment tool has been updated to test the NSFs in public health facilities for further use. In the future, the updated health facility assessment tool will be used for the national health facility assessment in Bangladesh.This is a resource-intensive and long-time study. It took us longer than anticipated to ensure the participation of numerous Delphi experts during each workshop and survey. Some Delphi experts were unable to participate throughout the whole process.There are currently no internationally or nationally recognized signal functions that are widely accepted and can be used to measure a health facility's service availability and readiness to provide newborn care. We developed a widely agreed-upon set of NSFs that assisted in updating the national HFA tool. The findings of the survey helped to determine whether health facilities are adequately ready to provide newborn health care services. The results contributed to categorizing newborn care health facilities as primary, basic, comprehensive, and advanced. The identification of the NSFs will guide health managers and policymakers towards appropriate planning and adequately monitoring of the progress and performance of health facilities delivering newborn health care in Bangladesh."}
+{"text": "Legumes and cereals, which provide different nutrients, are cultivated as coupled crops in most centers of plant domestication worldwide. However, as the only legume domesticated in China, the spatio-temporal distribution of soybeans and its status in the millet- and rice-based agricultural system of the Neolithic and Bronze Ages remains elusive. Here, archaeobotanical evidence of soybeans (n=254), millet (n=462), rice (n=482), and zooarchaeological evidence of fish (n=138) were synthesized to elucidate the phenomenon of coupled or decoupled cereals and legumes in prehistoric China. During the Neolithic and Bronze Ages, soybeans was mostly confined to northern China and rarely found in southern China, serving as a companion to millet. In contrast, fish remains have been widely found in southern China, indicating a continuous reliance on fish as a staple food besides rice. Thus, an antipodal pattern of millet-soybeans and rice-fish agricultural systems may have been established in northern and southern China since the late Yangshao period  respectively. These two agricultural systems were not only complementary in terms of diet, but they also exhibited positive interactions and feedback in the coculture system. Consequently, these two systems enabled the sustainable intensification of agriculture and served as the basis for the emergence of complex societies and early states in the Yellow and Yangtze Rivers. Zea mays) in Mesoamerica was accompanied by the common bean (Phaseolus vulgaris) (Triticum aestivum) and barley (Hordeum vulgare) in southwest Asia had a series of companion legumes, including lentil (Lens culinaris), pea (Pisum sativum), chickpea (Cicer arietinum), and broadbean (Vicia faba) (Oryza sativa subsp. indica) in south Asia was associated with the mungbean (Vigna radiata) (Glycine max) seem to be merely associated with broomcorn (Panicum miliaceum) and foxtail  millets in northern China, while no companion legumes to rice (Oryza sativa subsp. japonica) have been discovered in southern China.Optimal foraging theory in anthropological studies suggests that energy constraints and nutrient requirements are vital to the origin and evolution of agriculture  . As essulgaris) , wheat (ia faba) , and ricradiata) . HoweverGlycine soja) in far eastern Russia, China, Korea, and Japan, a variety of regions have been proposed as candidate sources , Early Yangshao period , Late Yangshao period , Longshan period , and Bronze Age  . SubsequBased on the previous investigations on the distribution of millet, rice, and mixed farming sites , the milMylopharyngodon piceus), grass carp (Ctenopharyngodon idella), and crucian carp (Carassius carassius)   . Besidesephalus) .In terms of meat acquisition strategies, fishes were clearly an important component of diets in the Yangtze River throughout the Neolithic Age, whereas they seemed to be less significant in the Yellow River . A detaiIn addition to fishes, shellfishes were also regarded as an important source of protein, which was mostly confined to the coastal regions, especially the Liaodong and Shandong peninsula to the northeast and Fujian and Liangguang region to the southeast with hundreds of shell middens existed during 7000\u20135000 cal BP . HoweverGiven that soybeans and fish served as an important source of protein for ancient humans in northern and southern China, antipodal patterns of a millet-soybean and rice-fish agricultural system may have formed in the Neolithic and Bronze Ages. During the Peiligang period , only wild soybeans was discovered along the marginal mountains of the Loess Plateau and Inner Mongolian Plateau , while fDuring the Longshan period  and Bronze Age , the soybeans began to spread in four directions . HoweverIn summary, antipodal patterns of a millet-soybeans agricultural system in northern China and rice-fish agricultural system in southern China may have been established since the late Yangshao period , which sustained the nutritional requirement of both starch and protein. To a certain extent, the cultivation and domestication of soybeans in the Yellow River may compensate for the possible lack of protein due to the transition from hunting wild animals to the rearing of livestock. However, the relative abundance of diverse animals and fish species in the Yangtze River may promote ancient humans to continue fishing and hunting rather than reliance on soybeans domestication , and ultIn most centers of origin of agriculture in the world, legumes and cereals have been cultivated as coupled crops except for southern China. Soybeans, generally considered to be domesticated in the middle and lower Yellow River, was mostly confined to northern China and served as a companion to millets. In contrast, fish had been intensively exploited in southern China and rarely recovered from the Yellow River. Thus, since the late Yangshao period , an antipodal pattern of millet-soybeans and rice-fish agricultural systems may have been established in northern and southern China, respectively. On one hand, these two systems are dietary complementation of starch and protein, providing balanced requirements of energy and nutrient; on the other hand, the systems exhibit agronomic compensation that soybeans fix atmospheric nitrogen and improves the soil fertility while millet uses soil nitrogen up, and fish reduce rice pests and rice favors fish by moderating the water environment. Positive interactions in these two systems enabled sustainable intensification in agriculture and provide the basis for the emergence of complex societies and early states in the Yellow and Yangtze Rivers.The original contributions presented in the study are included in the article/HL designed the research. XY and KH assisted the analysis of archaeobotanical and zooarchaeological data. XY and CS contributed to the discussion sections. KH compiled the figures. KH and HL wrote the manuscript. All authors contributed to the article and approved the submitted version.This research was supported by the National Natural Science Foundation of China , and China Postdoctoral Science Foundation (Nos. 2020M670444).www.editage.cn) for English language editing.We sincerely thank Xue Yan, Xiaoqu Zheng, Yuqian Wang and YM for their assistance with data collection. We would like to thank Editage (The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.The handling editor YG declared a shared affiliation with the authors KH, XY, HL at the time of review.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Background: As the world prepared for and responded to the COVID-19 pandemic in early 2020, a rapid increase in demand for personal protective equipment (PPE) led to severe shortages worldwide. Acquisition of PPE in the general market was an integral part of pandemic response, along with the safeguarding of hospital supplies. We seek to quantify the difference in cost per unit (CPU) of PPE during the first wave of COVID-19 compared to prepandemic prices. Methods: We performed a retrospective review of market prices for PPE during the first surge of the pandemic in Chicago. Cost of PPE was tabulated and compared with prepandemic prices. The maximum cost per unit (CPU) of PPE was tabulated for each week, and the average cost throughout the pandemic was calculated. Disposable gowns, washable gowns, N95 respirators, face masks, and gloves were included in our analysis. Results: PPE prices were significantly higher during the pandemic compared to prepandemic prices (Figure Conclusions: Market prices for PPE were significantly elevated during the first weeks of the pandemic and remained high throughout the first wave of COVID-19. Multiple factors likely contributed to high prices, including demand shock, disrupted supply chains, and a rush to acquisition by healthcare systems and the general population alike. The impact of COVID-19 on prices highlights the importance of supply chains and national stockpiles for pandemic preparedness.Funding: NoDisclosures: None"}
+{"text": "This article presents a brief history of public policies to address sexually transmitted infections (STI) in Brazil. It also discusses deficiencies and challenges to be considered by the country to formulate and implement future policies.STI remains a global public health issue. In 2016, the World Health Organization (WHO) estimated a 376.4 million incidence of curable STI in people aged 15 to 49. There were 127.2 million cases of chlamydia, 86.9 million cases of gonorrhea, and 6.3 million cases of syphilis. In the Region of the Americas, an estimated 29.8 million cases of chlamydia, 13.8 million cases of gonorrhea, and 2 million cases of syphilis were reportedThese estimates indicate a high STI incidence and warrant the WHO global strategy and the establishment of priority measures to achieve STI elimination goals by 2030. This strategy focuses on (i) gonococcal antimicrobial resistance and chlamydial co-infection risk, (ii) congenital syphilis elimination, which requires increased testing and treatment of pregnant women and specific populations, and (iii) human papillomavirus (HPV) infection, with a focus on immunization to eliminate cervical cancer and anogenital wartsThe Pan American Health Organization's (PAHO) Plan of Action for the Prevention and Control of HIV/STI (2016-2021) aims at expediting the elimination of the human immunodeficiency virus (HIV) and STI epidemics as public health issues in the Region of the Americas by 2030In Brazil, acquired syphilis, syphilis in pregnant women, and congenital syphilis cases are compulsorily notifiableBrazilian nationwide-covering STI prevalence studies reveal the scale of the problem. Parturients attended in public maternity hospitals had a 9.8% prevalence of chlamydia and 1.0% of gonorrhea in 2011The publishing of the first Clinical Protocol and Therapeutic Guidelines (PCDT) for Comprehensive Care for People with STI, approved by the National Committee for the Incorporation of Technologies in the Brazilian National Health System (Conitec), in 2015, is noteworthyIn the period 2015-2016, the Ministry of Health's partnership with the Federal University of Santa Catarina and sentinel sites for the elaboration of a gonococcal resistance study (SenGono Project) made possible the first Brazilian gonococcal antimicrobial susceptibility surveillance program. The nationwide surveillance research analyzed gonococcal strains at seven sentinel sites  and found high tetracycline, penicillin, and ciprofloxacin resistance in the bacteriaNeisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium, and Trichomonas vaginalis, in urethral discharge samples; and herpes simplex virus types 1 and 2, Treponema pallidum and Haemophilus ducreyi, in genital ulcer samples.In 2018, a new phase of the SenGono Project started with installing more collection sites and the inclusion of two new antimicrobials (spectinomycin and gentamicin) in the analyses. Within the SenGono Project, the following are undergoing research: The SenGono Project results led to the publication, on June 17, 2020, of Ordinance GM/MS no. 1.553/2020, by which the Ministry of Health instituted the sentinel surveillance of male urethral discharge syndrome to monitor data in qualified health unitsConsidering the global and national penicillin supply shortage and the difficulties for its acquisition by states and municipalities in the period 2014-2016, the publication of the 'Strategic Actions Agenda for Syphilis Reduction in Brazil' in 2016Following the HPV vaccination inclusion in SUS, the need for monitoring the impact of such immunization on the specific population was perceived. Research on HPV prevalence in Brazil was scarce until thenNeisseria gonorrhoeae to several antibiotics threatens the efforts for controlling this infection. 66% of the 67 countries participating in the Gonococcal Antimicrobial Surveillance Programme have already shown increased clinical and in vitro resistance to broad-spectrum cephalosporins in 2009-2014, and it is the only remaining first-line monotherapy for gonorrhea controlThe fast antimicrobial resistance growth of Treponema pallidumSome challenging goals in syphilis control include eliminating vertical transmission, improving case surveillance, developing more accurate tests to diagnose active syphilis, neurosyphilis, and congenital syphilis, increasing access for the most vulnerable populations, and developing alternative oral drugs and vaccines against ,,Lack of knowledge and fake news on immunization are examples of contributing factors to low vaccination coverage for HPV. Health care integration with schools and communities is central to achieve better indicators since well-informed adolescents are potential communicators of such information to their parentsChallenges and deficiencies persist in the formulation and implementation of public policies in IST in Brazil. In such a scenario, there is a permanent need for (i) strengthening the role of primary health care in comprehensive care to people with STI and their sex partners, (ii) ensuring adequate vaccination coverage against HPV and viral hepatitis A and B, (iii) promoting health information, education, and communication, (iv) expand access to STI testing and treatment, with emphasis on the most vulnerable populations, (v) notify sex partners, and (vi) qualify health professionals' approach to sexual health matters, in addition to screening for asymptomatic, prevention, clinical-laboratory management, and surveillance of sexually transmitted infection cases."}
+{"text": "Food microbiology studies the microbiota of food products. It is a very diverse area within the field of microbiology because it deals with microorganisms that may have both beneficial and deleterious effects on food quality and safety, comprising fermentative, probiotic, spoilage, and pathogenic bacteria, moulds, yeasts, and other microorganisms.The survival and growth of these diverse microorganisms is very much influenced by a wide range of environmental factors, which include the hugely diverse composition of the different food matrices.Among the submitted manuscripts that pretty much covered all aspects of food microbiology, eight research articles were selected by external experts to enter this annual special issue of BioMed Research International.Micromeria fruticosa serpyllifolia plants, growing in different regions of Palestine, screening for their antioxidant and antimicrobial activities.Salameh et al. did a comparative study on the volatile oils of Gebru and Sbhatu studied a collection of probiotic lactic acid bacteria (LAB) isolated from Korean Kimchi and Ethiopian spontaneously fermented Teff and evaluated the effect of LAB on the phenolic content of Teff during fermentation.Cordyceps kyushuensis, a parasitic fungus, for their immunomodulatory and antioxidant actions and concluded that these could be considered potential candidates for functional foods and therapeutic agents.The work by Su and coworkers evaluated the water-soluble polysaccharides of Staphylococcus aureus and Acinetobacter baumannii.Hassan and colleagues studied the probiotic properties of lactobacilli isolated from traditional Pakistani yoghurt and evaluated the antimicrobial activity of their bacteriocins against foodborne pathogens, such as Staphylococcus aureus and Escherichia coli resistant isolates, highlighting the public health consequences associated with the consumption of these unhygienic food products.Jaja et al. reported a high-level contamination of meat with Salmonella enterica.The article by Tenea described the role of peptide extracts from native LAB as promising food antimicrobials against Bacillus megaterium-coated diets on the growth, digestive enzyme activity, and gut microbial diversity of Songpu mirror carp.Finally, Luo and colleagues described the beneficial effect of The authors come from nine different countries, one European (United Kingdom) and eight non-European, namely, Ethiopia, Pakistan, Saudi Arabia, South Africa, Nigeria, China, State of Palestine, and Equator.BioMed Research International find this Food Microbiology 2020 special issue of relevance to their research field.We are happy to launch this special issue, which includes eight manuscripts that reported new findings mainly on the antimicrobial and antioxidant activities of food microbiota or their secondary metabolites. We hope that the readers of"}
+{"text": "The global aging of the population, combined with shifts in the structure and composition of families, has led to increased attention to the role of family and social relationships in the aging experience. The importance of family in determining healthy aging, however, may largely depend on the social, political, and economic context in which individuals are embedded. Cross-national investigations offer a unique opportunity to understand how family relationships and family caregiving influence health and well-being among older adults by comparing family dynamics across different sociocultural contexts. The HRS-family of surveys, which have been harmonized within the Gateway to Global Aging, provides remarkable opportunities for cross-national comparative analysis. The papers in this session use harmonized data from the Gateway to compare the influence of family on health across different social dimensions in multiple countries from around the world, including examinations of: 1) the impact of grandparenting on health of older adults in Europe and China; 2) psychological well-being among European older adults whose partners receive formal care; 3) the influence of parent-child relationships on health and well-being of older adults in China and the U.S.; and 4) how loneliness among older adults is patterned according to their living arrangements and relationship quality. The discussion will highlight the promises and challenges of cross-national research on families and aging and how harmonized aging data facilitates international comparisons."}
+{"text": "This systematic review aimed to analyse the performance of the Integrated Disease Surveillance and Response (IDSR) strategy in Sub-Saharan Africa (SSA) and how its implementation has embraced advancement in information technology, big data analytics techniques and wealth of data sources.HINARI, PubMed, and advanced Google Scholar databases were searched for eligible articles. The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols.A total of 1,809 articles were identified and screened at two stages. Forty-five studies met the inclusion criteria, of which 35 were country-specific, seven covered the SSA region, and three covered 3\u20134 countries. Twenty-six studies assessed the IDSR core functions, 43 the support functions, while 24 addressed both functions. Most of the studies involved Tanzania (9), Ghana (6) and Uganda (5). The routine Health Management Information System (HMIS), which collects data from health care facilities, has remained the primary source of IDSR data. However, the system is characterised by inadequate data completeness, timeliness, quality, analysis and utilisation, and lack of integration of data from other sources. Under-use of advanced and big data analytical technologies in performing disease surveillance and relating multiple indicators minimises the optimisation of clinical and practice evidence-based decision-making.This review indicates that most countries in SSA rely mainly on traditional indicator-based disease surveillance utilising data from healthcare facilities with limited use of data from other sources. It is high time that SSA countries consider and adopt multi-sectoral, multi-disease and multi-indicator platforms that integrate other sources of health information to provide support to effective detection and prompt response to public health threats. Despite scientific development to strengthen the health system to protect and promote human health, Sub-Saharan Africa (SSA) continues to be confronted by longstanding, emerging, and remerging infectious disease threats , 2. The Before 1998, most countries in Africa implemented surveillance systems through vertical programmes of specific diseases of national and /or international priority. These included malaria, HIV/AIDS, tuberculosis and vaccine-preventable diseases. Epidemiological data were collected mainly at the health care facility level and in outreach health service settings . This siIDSR functions are categorised into core and support functions. The core functions include identification of cases, investigation and confirmation, registration, case notification/reporting, data analysis and interpretation, response to the situation, communication and provision of two-way feedback, evaluation of the interventions, and preparation for emergency occurrences. The support functions include guidelines, laboratory capacity, supervision, training, resources and coordination at all health system levels . The IDSDuring the past 20\u00a0years, the IDSR framework has been used in 94% (44/47) of the countries in the WHO African region to enhance capacity for surveillance for priority diseases, conditions, and events \u201316. In mOver the years, the IDSR has relied heavily on the routine health management information system (HMIS) implemented at the facility and district levels of the health systems . HoweverThis review was guided by the following overarching question: Does IDSR generate information that drives early detection of and response to infectious disease outbreaks? Specific questions were: (i) Has IDSR improved health data quality and utilisation during its 20\u00a0years of implementation in SSA?; (ii) What are the challenges and opportunities for IDSR to improve early detection and prompt response to infectious diseases in SSA? The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols 2015 checklist . Three dThe review involved two-stage screening, title/abstract screening and full-paper screening. The inclusion criteria were: the study must involve at least one of the SSA countries, clearly describe the evaluation of the IDSR system, focuses on at least one of the IDSR functions and/or systems attributes. The review excluded studies with abstracts without full text, not in English, reviews and newsletters. Two of the authors (IRM and LEGM) extracted eligible articles independently, and any disagreements between them on inclusion or exclusion were resolved by discussion and consensus. The linked descriptive search requests that were developed and search results from each database are presented in Table A total of 1,809 articles were initially identified using the key search descriptors. A large number of articles  were irrelevant or duplicate and were excluded. The 498 remaining abstracts were screened further, and 412 were excluded based on the inclusion/exclusion criteria. Of the remaining 86, full-text articles were screened, and 45 studies met the inclusion criteria and hence, were selected for detailed reviews  disease control programmes; implementation of standard surveillance, laboratory and response guidelines; improved timeliness and completeness of surveillance data, as well as increased national-level review and use of surveillance data for the response , 15. HowImprovements in IDSR system attributes such as completeness and timeliness of data reporting have been observed in Uganda, Malawi and Ghana , 49, 51.Studies in Ghana, Tanzania, and Zambia have reported that several health facilities lack copies of the IDSR Technical Guidelines for Standard Case definitions; and that laboratories are ill-equipped to provide confirmation of any suspected priority notifiable infectious disease , 25, 60.In terms of IDSR support functions, of the 47 countries in the WHO Africa Region, 94% were implementing the IDSR strategy, and 45 (85%) have initiated training at the sub-national level . Thirty-This review indicates that in most countries, data generated through the routine HMIS, which is the key source of IDSR, are rarely assessed for their quality, analysed and used to support decision-making . SeveralIn Ethiopia, Liberia and Tanzania, assessments of the HMIS have identified some data quality issues and lack of use of the generated data , 60, 75.A few countries  have reported analysing and used routine HMIS data at sub-national levels , 74. In For the integrated system to be efficient, it requires strong coordination and communication, a clear organisation structure, adequate resources , 81, andIn SSA, several government ministries, agencies, and academic and research institutions are involved in managing different aspects of the health information systems. The ministries of health run the routine HMIS as the major source of information for decision making and planning. National Statistical Offices are responsible for most of the nation-wide household demographic and health surveys as well as population census . Other kA warning of an impending epidemic can help relevant authorities and communities to prepare and take immediate actions to reduce morbidities and mortalities. Many of the epidemic diseases are highly sensitive to long-term changes in climate and short-term fluctuations in weather. Meteorological data are made available daily by the National Meteorological Agencies, yet they are rarely used to monitor the occurrence of diseases. Meteorological data can be combined with geospatially referenced data, population densities or road networks to generate estimates of environmental indicators relevant to infectious diseases . HoweverIt is critical for a good and efficient surveillance system to incorporate other sources such as mortality data from demographic surveys, environmental data, vital statistics and civil registration, antimicrobial resistance, systematic surveys, meteorological data and research data. In most countries, despite an enormous amount of data generated by these systems, they run in parallel and independently, not well-coordinated, and sharing of information between them is minimal. Each of the existing systems operates its data collection and utilization framework. Moreover, much of the information is generated outside the health sectors \u2013 making it not readily available for disease surveillance purposes. It is a fact that the innovations, including the use of big data and artificial intelligence, could transform infectious disease surveillance and response and complement the existing traditional disease surveillance systems and improve detection and response to epidemics .Laboratories play an important role in the prompt diagnosis of infectious diseases. The findings of this review have shown that IDSR is challenged by inadequate diagnostic capacities at all levels of the health system, especially in terms of staff levels, skill sets and infrastructure. It is critical, therefore, that countries support the efforts to strengthen laboratory capacities for the detection of a wide range of pathogens in relation to the IDSR priority diseases. Moreover, laboratory networking should be encouraged and should involve both national, regional and research reference laboratories. To address the gaps in knowledge, it is important to strengthen the laboratory management information systems (LIMS), recruit adequate staff who are well trained and motivated as well as the need for periodic support supervision of the surveillance activities. The plan by the African Centres for Disease Control and Prevention to establish and operationalize a Regional Integrated Surveillance and Laboratory Network is commended. This network is expected to coordinate and connect the continent\u2019s analytical, surveillance, and emergency-response assets .An effective epidemic intelligence should contain both indicator-based and event-based surveillance. Globally, with the use of information technologies, an event-based surveillance approach is being promoted to complement the traditional \u201cindicator-based\u201d surveillance approach as part of the components of epidemic intelligence . There hThere is growing interest in using digital surveillance approaches to improve monitoring and control of infectious disease outbreaks . HoweverWith the proliferation of information technologies and increased ownership of mobile phones in SSA, there are large amounts of data on social media blogs, chatrooms, and local news reports that may provide governments and other stakeholders\u2019 clues about disease outbreaks time and place daily. Such data are essential raw materials for DDS. Advancements in information technology and information sharing give rise to infodemiology \u2013 defined as the science of distribution and determinants of information in an electronic medium, specifically the internet . To dateCommunity-based surveillance (CBS) is defined as the systematic detection and reporting of events of public health significance within a community by community members . CommuniThe WHO Technical Guidelines on IDSR , 17 highAs part of an effective global response to diseases transmitted between animals and humans , there hIn 2019, the Tripartite organisations \u2013 the Food and Agriculture Organization of the United Nations, the World Organisation for Animal Health, and the World Health Organization \u2013 developed the Tripartite Zoonoses Guide (TZG). The aim is to help the countries develop a capacity to address zoonoses in a coordinated manner, linking to existing international policies and frameworks and supporting efforts for global health security. The TZG includes three operational tools to support national authorities: (i) the Multi-sectoral Coordination Mechanism, (ii) the Joint Risk Assessment, and (iii) the Surveillance and Information Sharing operation tools .The emerging and re-emerging infectious diseases in Africa underline the urgent need to integrate public health surveillance systems . As infeThe importance of using both formal and informal data sources for timely and accurate infectious disease outbreak surveillance has been emphasized . EvidencModern technologies such as artificial intelligence and machine learning are widely applied in analysing a significant volume of data to assess the status and forecast future dynamics of diseases , 124. A This review indicates that most countries in SSA rely mainly on traditional indicator-based disease surveillance utilising data from healthcare facilities with limited use of data from other sources. However, the traditional indicator-based disease surveillance approaches face several challenges, including data quality and inefficient early warning systems, because they are less sensitive than event-based surveillance approaches. They most often miss information from populations who do not access health care or do so through informal channels, thus unable to detect new, potentially high-impact disease outbreaks. Moreover, there is a dearth of information on IDSR data quality, analyses that utilise advanced methodologies and use in the detection and response of infectious disease outbreaks in the region. Over the years, data-use and data-process have not been given adequate attention. This analysis indicates that future efforts to address disease surveillance systems should consider data quality, multi-source data analysis and triangulation, data use and data integration. Capacity building for health workers at the national and sub-national levels in data management is critical.This review highlights the untapped opportunities for integrating community-based, digital surveillance through a one health approach that could improve public health surveillance in SSA. It is high time that the region explores and adopts the integration of several surveillance programmes into hybrid systems that combine traditional surveillance data with data from the public health laboratories, community, research settings, search queries, social media posts, and crowdsourcing. Improved performance requires the merging of current gains, strong collaboration from all stakeholders, supervision and regular evaluation of the surveillance system to identify and address challenges as they emerge. The introduction of innovative ways to further strengthen the surveillance and response system in SSA countries is critical to enhancing early detection and reporting of suspected cases of priority diseases, conditions and events.To address the challenges of the IDSR system, there is a need to develop an electronic platform that will combine data from multiple relevant databases such as HMIS, research programmes, laboratory management information systems (LMIS), population-based surveys, digital disease surveillance, sentinel surveillance, OH surveillance and community-based surveillance initiatives to allow their interoperability. The aim is to make optimal use of community, facility and research-based epidemiological information in preparing the community to act before a health emergency happens, as well as to provide high-quality evidence to guide policy development and resource allocation at the national level. With this platform, a continuing analysis and review of scientific publications, social media, routine health data and demographic statistics can be established to feed different decision-making units. Composite and multi-sourced indicators that comprise information from various sources can be generated, analysed and monitored. The goal is to make data readily available and help speed up dissecting the information and putting programmes in place to detect and promptly respond to epidemics. The platform will foster improved utilisation of surveillance data for action and avoid delays in response to emergencies by linking health indicators with other information such as climate data that can add value to inform health risks accurately. A multi-sectoral approach should be used to pursue a common strategic goal of developing a workforce that can support public health surveillance and response."}
+{"text": "The COVID-19 pandemic and global lockdown have had drastic socioeconomic and psychological effects on countries and people, respectively. There has been limited access to health care and education. These negative consequences have had a significant impact on the well-being of children and adolescents. Therefore, the EAP and the ECPCP are requesting state, health, and education authorities as well as European pediatric societies and the healthcare professionals that special attention be given to this population and the problems they face as a result of the pandemic. The COVID-19 pandemic has caused unprecedented changes in people's way of life and social relationships. Global public health measures, including a worldwide lockdown, have affected socioeconomics, health care, education, and public mental health . This haTo highlight this issue, provide guidance, and offer strategies for the prevention or minimization of the detrimental effects of the pandemic and associated lockdown on young people, the European Academy of Paediatrics (EAP) and the European Confederation of Primary Care Paediatricians (ECPCP) present this position paper and recommendations directed to state, health authorities, European pediatric societies, and the European healthcare professionals involved in the care of the pediatric population. This statement does not focus on the care of children and adolescents with COVID-19 disease.The course of SARS-CoV-2 infection is rarely severe in children and adolescents \u201310. HoweThe lockdown has also affected the availability of well-child care and the administration of childhood inoculations for vaccine-preventable diseases. Many children, especially those from lower-income households, have not received scheduled routine vaccinations and the overall immunization rate has dropped significantly \u201327. ThisLimited access to mental health services for children and adolescents has resulted in the intensification of preexisting problems and an increase in the prevalence of depression and anxiety disorders \u201330.The new situation has led to weakened communication, deprivation of personal peer relations, lack of physical activity, and reduced sensory stimulation. The consequences of this can include psychological deterioration, anxiety, frustration, stress disorder, adjustment disorders, grief, loss of appetite, and sleep problems , 31, 32.Social distancing and limited interpersonal contact can lead to development delays, impaired social skills, anxiety, and depressive symptoms . The lenThe transference of social activity exclusively to the Internet can result in digital technology overuse, abandonment of other activities, exposure to inappropriate content, and cyberbullying , 47.The prolonged school closures are likely to have detrimental effects on learning outcomes \u201350. In yThe lockdown exacerbates socioeconomic inequalities. In the context of education, this can mean that children from poorer families are likely to have inadequate access to appropriate IT tools, insufficient intellectual support from caregivers, and fewer educational opportunities beyond school. As they do not receive meals at school during the lockdown, these children are also at increased risk of malnutrition , 52. MorFor teachers, the pandemic has been a challenge related to the crisis of competence. Educators have had to develop and improve objective methods of assessing learning progress. Remote education has also weakened teacher-student relationships , 53.The EAP and the ECPCP strongly believe that action is necessary to reduce the negative effects of the pandemic on young people. The following measures are advised:For state, health, and education authorities- Establish a framework on how to mitigate the impact of COVID-19 on children and adolescents needing essential services in a variety of healthcare settings.- Consider strategies to reduce preventable illness during the COVID-19 pandemic in young people with non-COVID-19 diseases and injuries.- Guarantee the staffing, adequate drug, and material supply, especially for personal protective equipment for essential pediatric services.- Implement secure and flexible reopening and maintenance of kindergartens and schools based on the rights of children and adolescents.For European pediatric societies:- Keep members updated in the area of risks for child and adolescent health during the COVID-19 pandemic.- Encourage members to make all possible efforts to maintain curative and preventive high-quality services for children and adolescents.- Initiate and coordinate European-wide surveys regarding the temporary impact of the COVID-19 pandemic on pediatric health services.- Analyze the experiences with telemedicine in the area of pediatric care, screening, follow-up, and drug prescribing.- Support the EAP campaign \u201cVaccinate your child,\u201d to restore routine immunization of children .For the providers in the primary, secondary, and specialized pediatric care- Increase vigilance and diligence about the risks of non-personal appointments when conducting remote health assessments of children and adolescents.- Encourage face-to-face visits when presenting symptoms require them to rule out life-threatening diseases. Provide postnatal care in person wherever possible.- Ensure hygienic measures and personal protection for all staff and patients. Make appropriate adjustments and appointments to avoid crowding in outpatient services. Limit the quantity of accompanying persons.- Communicate personally and in public with caregivers to reassure the trust in essential health services and the unlikely danger of COVID-19 infection in the health care system. Clarify any public misinformation.- Reinforce the capacity of parents and adolescents for self-management and timely presentation in case of alarming signs and symptoms.- Make every effort to maintain essential pediatric health services by facilitating open access to curative services for the acute and the chronic ill children and adolescents.- Maintain preventive health services as well as child checks and vaccinations. Use recall and other motivational reminder systems to catch-up with missed visits.- Increase surveillance and screening for emotional, social, and behavioral disorders and provide age-appropriate guidance at any given opportunity.- Engage to maintain mental health services and social services in the community, with special focus on lower-income households.- Encourage adolescents to discuss non-pharmacological COVID-19 interventions such as social distancing, hygiene, and the use of face coverings. This will enable them to identify and minimize behavioral infection risks, which may be detrimental even in areas with high vaccination rates.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.\u0141D, AM, and AH: study design. \u0141D, IR-W, and GH: data collection. \u0141D, IR-W, GH, ZG, AM, ST, SB, AC, and AH: data analysis and interpretation, manuscript preparation, and critical revision. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Dear EditorWe had a case of Krukenberg tumor (KT) of the right ovary, which extended to pelvic zone M;18*13*10 cm in a 40-year-old virgin woman who had no history of previous cancer. The patient received five courses of chemotherapy before surgery, and because of the chemotherapeutic effect on the ovarian stroma, spindle cells of stroma were plump, hyperchromatic, with mild pleomorphism. The number of signet cells was low, and they were scattered between spindle cells, mostly with eosinophilic cytoplasm. Spindle cell tumors such as pelvic rhabdomyosarcoma (with scattered eosinophilic rhabdoid cells) also gastrointestinal stromal tumor (GIST) with signet ring-like change were in the differential diagnosis in frozen section examination and permanent sections. Because of the increasing use of preoperative chemotherapy in the management of ovarian malignancy, pathologists should be aware of changes in cellular morphology induced by chemotherapy, which may cause problems in tumor typing and grading and the identification of ovarian epithelial tumors or metastatic tumors to the ovary such as breast and lung cancers .Effects of chemotherapeutic drugs on the cellular stroma of the ovary were seen in the literature previously, which can cause apoptotic depletion of follicles . ChemothAge of women at menopause show duration of estrogen deficiency which can cause health problems . The tumThen, correct interpretation requires exact evaluation of the morphology of tumoral cells and stromal cells, patient history, and confirmation of diagnosis with immunohistochemistry such as anti-cytokeratin and anti-histiocytic antibodies."}
+{"text": "This study systematically reviewed processes and educational programs for self-management of health and diseases that are the subject of public health attention. This systematic review of the literature (SRL) is relevant to recognizing the characteristics of the educational processes in self-managing chronic diseases in contexts where technology did not play a significant role. Following the PRISMA protocol, the authors independently reviewed full-text articles from several databases using the following criteria: (1) intervention studies evaluating the effects of self-management health programs; (2) educational process of disease self-management; (3) studies that included at least one control group, and (4) peer-reviewed studies. In addition, the Scottish Intercollegiate Guideline Network measurement tool was used to assess the risk of bias in each trial. In the final sample, 38 articles were included. The findings regarding health education methods of self-care, using community-based care and technological tools, are considered fundamental. Among the conclusions, the relevance of the pedagogy that health education processes demand improvement in post-pandemic program effectiveness stands out. Educational processes in public health seek to ensure the populations\u2019 right to health by promoting improved living conditions, welfare, and development . Public Health education interventions have traditionally focused on prescriptions and lifestyle restrictions . This apTherefore, educational actions developed in public health contexts and reported by research mainly focus on disease self-management and the appropriation of self-care skills . MedicalAccess to medical and health education programs include mechanisms to counteract their low participation rates. According to health institutions and research worldwide, low community participation is mainly related to socioeconomic conditions, transition effects over time, and a low level of health experts in educational training . AdditioThe importance of working on the aspects that affect people\u2019s willingness to participate in educational programs and daily, personal, collective activities to control and treat disease is evident. In this regard, improving self-regulation and self-management requires immediate feedback to modify behavior . Thus, tLikewise, health education programs have various innovative educational strategies that focus on the subject and his/her context to facilitate the formative effectiveness of the programs . EducatiOther health education initiatives have reflected on the role of health education professionals to ensure that there are no gaps in access to educational programs . FurtherEducational approaches involving technological tools in training processes in healthcare are in an exploratory phase, given the possibilities of improvement offered by technology . This syThis systematic review was conducted according to the preferred reporting items for systematic reviews and meta-analyses, or PRISMA, guidelines . To idenOne author performed the initial eligibility assessment by reviewing the titles and abstracts. Then, two authors independently reviewed full-text versions of 92 articles using the following criteria: (1) intervention studies evaluating the effects of self-management health programs; (2) studies including at least one control group; and (3) peer-reviewed studies.Data extraction was performed independently by the authors. The following data were extracted from each study: first author, date and place of publication, study design, population served, analysis of the program effectiveness, EdTech used, and pedagogical strategy. Extracted data were entered into standardized MS Excel files. Any disagreements were resolved by discussion among the authors.The Scottish Intercollegiate Guideline Network (SIGN) measurement tool was used to assess the risk of bias in each study in this review. SIGN was developed in 1993 to improve healthcare quality for populations in Scotland by reducing variation in practice and outcomes by developing and disseminating national clinical guidelines with recommendations for effective practice based on current evidence . This toA total of 3114 records were found in the database search. These search results were imported using Parsifal, and 1428 duplicates and 81 records marked as ineligible by automation tools were removed. A detailed flow chart of the selection process is shown in After the elimination of duplicates, 1605 records were examined. Subsequently, we searched for papers citing any of the initially included studies. However, no additional articles meeting the inclusion criteria were found in these searches. Finally, 38 full-text papers were reviewed.n = 14), Asia (n = 13), North America (n = 8), Africa (n = 3), and Oceania (1). Twenty-five studies involved adults aged between 35 and 60 years, while ten studies reported educational programs for self-management of health and disease with young adult participants between 18 and 35. In a smaller proportion, programs involving follow-up and control of people >65 years (n = 2) and accompanied by health professionals (n = 2) were identified. The general characteristics of the studies are presented in It was identified that, while some articles met the inclusion criteria, they evaluated performances in regular professional training processes in health ,27, leavDisease self-management programs link different pedagogical strategies and learning methodologies developed to contribute to the knowledge and control of chronic diseases. It was highlighted that 16% of the investigations ,34,47,48Similarly, methodologies that allowed discussion and knowledge exchange among patients in collaborative groups in contextual intervention programs were recognized. We also found analyses of patient perception through the accompaniment of a professional or the majoritarian use of qualitative analysis tools. This review showed that 29% of the texts studied ,54,55,57It was emphasized that the analysis of technological tools, which contributed to self-management of diseases, were contemplated where technology was not an indispensable tool for their management, as reflected in 71% of the investigations that do not report the mediation of technology in their educational process. This point becomes relevant for identifying lessons learned and best practices of current educational processes that aim to meet educational challenges during and after pandemics, where technology is the main instrument for transmitting knowledge.According to the SIGN checklist, 18 of the studies ,45,49,55In interpretating the findings, we were careful about generalization due to the number of studies reviewed and their open-access character. However, the results allowed us to answer the guiding research question and identify the educational process characteristics of self-management of health in public healthcare. The results aligned with recent research on the innovation needs of medical and health education programs reported by health institutions and agencies worldwide ,30. The While public health processes aim to prevent diseases, promote and maintain health and quality of life, the above is interpreted as a call to public health and medical and health education to diversify their objectives and educational strategies for the prevention, promotion, maintenance, and monitoring of population health. Doing so aligns with the recommendations of the World Health Organization (WHO). It invites broadening of the clinical and therapeutic perspective of healthcare and health education through strategies that build frameworks of trust, social support, and learning which respond to the needs of individuals and communities for health and welfare beyond the health-illness binomial .Thus, it seems that health education programs continue to emphasize informative actions on the self-management of diseases, leaving at a low priority the training and monitoring of learning and the appropriation of knowledge and skills for self-care and self-management of health in the daily activities of families and communities . Some reThe findings of this review indicate that health education programs in public health face significant challenges in guaranteeing program access, participation, and permanence and improving the effectiveness of the learning processes. The programs studied mainly address objectives for the self-management of diseases, remaining at the level of health maintenance, and lacking educational processes for disease prevention, promoting integral health, and monitoring people\u2019s quality of life and welfare. Some studies emphasized the importance of involving the participants in the design of the educational sessions and using tools, such as dialogue and other interactive methods, to improve participation . Thus, mRegarding technological tools, electronic education has become crucial in the information era and, therefore, it is also incorporated in medical and health education processes. Our results identify that technologies have offered robust mechanisms that support the self-management of health and guarantee a lasting educational experience for people, any time and place , with neThe findings report that educational processes for self-management of health hold promise for public health intervention when technology supports it. This review suggests recognizing and integrating the transformative possibilities of community education methods coupled with the use of technology. In addition, it is relevant to consider the pedagogical character of health education processes to improve the effectiveness of the programs. To this end, it is essential to strengthen the educational training processes for health professionals and structure evaluation goals for the teaching-learning process in these programs. The assessments should cover content, teaching strategies, appropriation of knowledge, and self-management of health in populations. Concerning technologies in the training processes, their functionality and usability, with regard to achieving the expected learning, should be evaluated.The findings regarding health education methods of self-care as part of community-based care and how technological tools are used are fundamental to this review. Consequently, we urge future research to focus on studying the barriers and facilitators that arise when using technological tools as mediators of learning in health education programs, mainly in terms of access to infrastructure, generational gaps, cultural factors, levels of digital literacy, and economic disadvantages .One limitation of this systematic review is language bias, as we only included studies published in English. Therefore, studies published in other languages, such as Chinese and Japanese, were not included in this review. In addition, the review did not include research from grey literature, which could exclude important unpublished pieces produced by non-governmental organizations. Finally, it should be noted that the analyses performed represent a partial view of the phenomenon under study and, therefore, the generalizability of the data is not considered. Despite these limitations, this literature review study increased the understanding of self-management health education processes and identified opportunities for improvement.This review began with the question, \u201cwhat are the characteristics of educational processes of self-management of health in public health care?\u201d. We identified that the most relevant characteristics respond to objectives focused on self-management of diseases, primarily chronic, and mitigating disease signs and symptoms. There is a focus on remedial education for the maintenance of health that is typical of hospital environments, which, in the public health context, is limited. In this regard, institutions and researchers propose innovative medical and health education processes to improve training and contribute to the prevention, promotion, care, maintenance, and monitoring of integral public health.The innovative processes highlight social and community-based learning characteristics that involve peers, caregivers, families, and professionals in training actions. In addition, some initiatives highlight socio-emotional characteristics of education and the need for contextual learning in daily life practices. Finally, there are characteristics oriented around using technological tools in the teaching-learning process as an area of opportunity to improve their effectiveness and increase their coverage.Future research is invited to examine the barriers and facilitators in medical and health education programs using socio-community and technology-enhanced educational strategies. Furthermore, the contributions of innovative processes for public health education toward long-term improvements in self-management of health and diseases should be evaluated. These research needs are especially relevant due to the COVID-19 health crisis because the fundamental medium of knowledge transmission for the formulation and implementation of health education programs, which recognize the health, economic, social, and cultural realities of communities, has become technology."}
+{"text": "On physical examination, erythematous papules and pustules were observed on the abdomen , on the sternum, the back, and the lateral surface of the buttocks Pruritic folliculitis of pregnancyb)Polymorphic eruption of pregnancyc)Bacterial folliculitisd)Acneiform eruptionPruritic folliculitis of pregnancy (PFP) was originally described in 1981 by Zoberman and Farmer.3This is the least common pregnancy-specific pruritic dermatosis.In the 1999 study by Vaughan Jones et al., a cohort of 200 women with gestational dermatoses (GD) with a two-year follow-up identified PFP in 14 patients (7%).In 2006, Ambros-Rudolph et al. carried out a retrospective study by analyzing the medical records of 505 pregnant women. PFP was diagnosed in only one patient (0.2%), with a history of eczema in childhood and a family history of atopy in two first-degree relatives. The authors proposed a new classification of GD, introducing the term atopic eruption of pregnancy (AEP) which encompasses PFP, prurigo of pregnancy, and eczema of pregnancy.As described in the literature and observed in the present case, patients respond well to topical treatments based on 5% or 10% benzoyl peroxide and 1% hydrocortisone.Pruritic folliculitis of pregnancy is a rare, benign and self-limited gestational dermatosis that does not interfere with maternal-fetal morbidity and mortality. It is essential that pregnant women be adequately diagnosed and advised, and followed-up with specialized care.None declared.Maria Rita Carvalho de Freitas Amorim: Collection, analysis and interpretation of data; writing of the manuscript; obtaining, analysis and interpretation of data; critical review of the literature and approval of the final version of the manuscript.Flavia Amorim Meira Cavaliere: Critical review of important intellectual content; effective participation in research orientation; intellectual participation in the propaedeutic and therapeutic conduct and approval of the final version of the manuscript.Esther Oliveira Xavier de Brito: Critical review of important intellectual content and approval of the final version of the manuscript.Amanda Nascimento Cavalleiro by M. Mota da Silva: Design and planning of the study; critical review of important intellectual content; intellectual participation in the propaedeutic and therapeutic conduct and approval of the final version of the manuscript.None declared."}
+{"text": "Increasing the number of specialized human resources for health is paramount to attainment of the United Nations sustainable development goals. Higher learning institutions in low-and middle-income countries must address this necessity. Here, we describe the 5-years trends in accreditation of the clinical and non-clinical postgraduate (PG) programmes, student admission and graduation at the Muhimbili University of Health and Allied Sciences (MUHAS) in Tanzania, highlighting successes, challenges and opportunities for improvement.This was a retrospective longitudinal study describing trends in PG training at MUHAS between 2015\u00a0and\u00a02016 and 2019-2020. Major interventions in the reporting period included university-wide short course training programme to faculty on curricula development and initiation of online application system. Data were collected through a review of secondary data from various university records and was analyzed descriptively. Primary outcomes were the number of accredited PG programmes, number of PG applicants as well as proportions of applicants selected, applicants registered (enrolled) and students graduated, with a focus on gender and internationalization (students who are not from Tanzania).The number of PG programmes increased from 60 in 2015-2016 to 77 in 2019-2020, including programmes in rare fields such as cardiothoracic surgery, cardiothoracic anesthesia and critical care. The number of PG applications, selected applicants, registered applicants and PG students graduating at the university over the past five academic years had steadily increased by 79, 81, 50 and 79%, respectively. The average proportions of PG students who applied, were selected and registered as well as graduated at the university over the past five years by gender and internationalization has remained stably at 60% vs. 40%  and 90% vs. 10% , respectively. In total, the university graduated 1348 specialized healthcare workers in the five years period, including 45 super-specialists in critical fields, through a steady increase from 200 graduates in 2015-2016 to 357 graduates in 2019-2020. Major challenges encountered include inadequate sponsorship, limited number of academic staff and limited physical infrastructure for teaching.Despite challenges encountered, MUHAS has made significant advances over the past five years in training of specialized and super-specialized healthcare workforce by increasing the number of programmes, enrollment and graduates whilst maintaining a narrow gender gap and international relevance. MUHAS will continue to be the pillar in training of the specialized human resources for health and is thus poised to contribute to timely attainment of the health-related United Nations sustainable development goals in Tanzania and beyond, particularly within the Sub-Saharan Africa region. Building stronger health systems in paramount to attainment of the United Nations sustainable development goals (SDGs). The World Health Organization (WHO) recognizes six major health systems building blocks including human resource for health (HRH), service delivery, information, commodities, financing, leadership and governance as pivotal components for maturing health systems to reach their full potential \u20133. Of thIn Tanzania, this large and growing demand for HRH is apparent and is driven in part by the recent changes of disease patterns in the country such as the emergency of the new burden of non-communicable diseases (NCDs) \u201311. In aEver since its founding in 1963, the Muhimbili University of Health and Allied Sciences (MUHAS) and its predecessors have produced the largest share of specialized (Master\u2019s degree level) HRH in Tanzania in fields such as internal medicine, obstetrics and gynecology, pediatrics and surgery, and was the sole producer of such specialists in the country before establishment of other medical universities from the late 1990\u2019s. To date, MUHAS is the only university in Tanzania offering training in super-specialized fields of clinical medicine  such as cardiology and nephrology. With the existing and growing demand, and in line with its vision, MUHAS needs to continue to play the leading role in producing an increased output of HRH, especially in the diverse specialized and super-specialized fields, without compromising quality.In order to ensure equitable socio-economic development, higher learning institutions have the obligation to maintain narrow gender gaps by fostering unbiased enrolment and training of the specialized healthcare workforce . MUHAS hSince its existence, MUHAS has faced several challenges in providing specialized training to healthcare workers. Notable challenges include limited sponsorship for postgraduate students which contributes to inability of up to 35% of the selected students to register for studies, inadequate number of qualified academic staff where over half of the 313 currently available full-time academic staff are in the junior ranks of Tutorial Assistant and Assistant Lecturer, and limited physical infrastructure for teaching. Here, we describe trends in development and accreditation of postgraduate programmes, student admission and graduation at MUHAS over the past five years. We highlight successes and provide new windows into challenges and opportunities faced by academic institutions in low- and middle-income countries (LMIC) which can inform other similar efforts.This was a retrospective longitudinal study describing trends in postgraduate degree training (Master and PhD) at MUHAS over the past five academic years (2015-2016 to 2019-2020).To date, MUHAS has seven academic units, comprising five Schools; , two academic Institutes;  and 11 directorates; . Besides postgraduate programs reported in this article, the University also runs 6 diploma programmes, 1 advanced diploma programme and 15 undergraduate (bachelor) degree programmes. Currently all MUHAS academic units offer postgraduate training with exception of the Institute of Allied Health Sciences. The total enrolment at the University is currently 4423 students, out of whom 1332 are postgraduate students. In the five\u00a0years period under current report, the university undertook two major interventions including training of faculty on curricula development with the aim to increase the number of postgraduate programmes and initiated an online application system with the aim to increase the number of applicants for postgraduate programmes, especially from outside Tanzania.This study was based on review of documents (secondary data) to obtain information on accredited programmes, academic staff available for teaching, applicants for postgraduate programmes, applicants selected, applicants registered (enrolled), students who obtained sponsorship as well as students who graduated at MUHAS between 2015 and 2016 and 2019-2020. The sources of data included postgraduate admission records, records from the Students\u2019 Academic Report Information System (SARIS), graduation books, minutes of academic committee meetings and annual reports from relevant academic and administrative units.Data were analyzed descriptively. Numerical data were summarized in frequencies and percentages and were presented in Tables and Figures. Outcomes of interest in this study were the trends in number of postgraduate programmes, academic staff available for teaching, admission processes , sponsorship for postgraduate programmes, together with graduation . In analyzing the trends in admission and graduation by gender and internationalization, the number of students in the relevant group  was divided by total number of students in appropriate category  and multiplied by 100, and proportions for individual academic years were presented for each group with error bars indicating standard deviation. Data were analyzed using Prism 4 .The total number of postgraduate programmes at MUHAS has steadily increased from 60 in the academic year 2015-2016 to 77 in the academic year 2019-2020. Major contributors to this increase were the SOM which initiated 10 new programmes  and SPHSS which initiated 3 new programmes  in the five-year time span. The SON also initiated 3 new programmes in 2019-2020 , registering a 100% increase in the number of its postgraduate programmes, from 3 in the preceding year to 6 in 2019-2020. Other increase was in the SOD, which initiated 1 new programme (Master of Dentistry in Orthodontics) in 2019-2020 , Master of Science  and Master of Science-super-specialization . Currently, there are 17 accredited Master of Science-super-specialization degree programmes or subspecialties in various fields of medicine . The SON offers MSc programmes . The SOD offers Master of Dentistry degree programmes  and the ITM offers MSc in Traditional Medicines Development which runs for 2\u2009years, recruiting diverse bachelor\u2019s degree holders with background in science  and Doctor of Philosophy (PhD). These are distinguished from coursework programmes in having intense research component culminating in a defendable thesis. Apart from the written thesis, other graduation requirements include course credits in research methodology, biostatistics, bioethics and scientific writing (15 for MSc R&P and 30 for PhD), published articles in peer-reviewed journals (2 for MSc R&P and 4 for PhD) and presentations in scientific meetings (2 for MSc R&P and 4 for PhD).Currently, the University has a total of 313 full-time academic staff. Most academic staff are aged 50\u2009years and below (81%) and are in junior academic ranks of Tutorial Assistant and Assistant Lecturer (52%). Detailed description of the academic staff by age, gender and academic rank is provided in Table\u00a0There was a steady increase in the number of applicants for postgraduate degree programmes over the past five years, from 543 in academic year 2015-2016 to 970 in 2019-2020 (79% increase). Similarly, the number of applicants selected to join the various postgraduate programmes increased over time from 470 in 2015-2016 to 853 in 2019-2020 (81% increase), which is concordant with the increase in the number of selected students who registered/enrolled at the university, from 358 in 2015-2016 to 536 in 2019-2020  to purse studies at MUHAS was 62, 79, 68, 127 and 159 in academic years 2015-2016, 2016-2017, 2017-2018, 2018-2019 and 2019-2020, respectively.The total number of students graduating at MUHAS had steadily increased over the past five years, from 200 in 2015-2016 to 357 in 2019-2020 (79% increase). The SOM and SPHSS contributed the largest number of graduates in each of the past five academic years . Here we aimed to describe the trends in initiation of specialized programmes, enrolment and graduation at the Muhimbili University of Health and Allied Sciences (MUHAS), the premier health sciences university in Tanzania. We show that, compared to five years ago, the MUHAS has made noteworthy strides by initiating 17 new specialized and super-specialized degree programmes, increasing student enrolment by 50% and increasing the number of graduating Tanzanian and international health specialists by 79% whilst maintaining a narrow gender balance. Overall, the University graduated 1348 specialized healthcare workers in the five years period, including 45 super-specialists in critical fields. These advances will have significant positive impact in strengthening health systems in Tanzania and Sub-Saharan Africa at large.MUHAS has a notable strength in the large number of specialized degree programmes in health sciences. Over the past five years, this strength has been emphasized by initiating 17 new competence-based and demand-driven programmes. The super-specialized programmes, also known as subspecialties, have been established in collaboration with partnering institutions in-country, including the Jakaya Kikwete Cardiac Institute, Muhimbili National Hospital, Muhimbili Orthopedics Institute and Ocean Road Cancer Institute, as well as universities in South Africa, Australia, United Kingdom, Germany, Sweden, Norway, Canada and USA that provided technical assistance as well as expertise in teaching as visiting scholars, adjunct faculty and through opportunities for international clinical attachments. This model has been used successfully in other countries in Sub-Saharan Africa and has proven to be effective for the transfer of skills to LMIC . The incThe WHO estimates that Sub-Saharan Africa would need to scale up its production of healthcare workforce by 140% in order to meet the international development targets . In the Besides training of Tanzanian healthcare workforce, and in line with the obligation for regional and international integration , 26, MUHNotwithstanding achievements made, there have been several challenges that were experienced over the past five years. Firstly, close to 35% of selected students in each academic year did not register due to lack of sponsor, being called back by employer due to staff shortages and other personal reasons. In addressing this challenge, the University continues to work closely with the Tanzania government through the Ministry of Health\u00a0as well as Ministry of Education, Science and Technology and other stakeholders in advocating for increased sponsorship to postgraduate students. Secondly, the University has inadequate number of qualified academic staff. The University is tackling this challenge by increasing recruitment of academic staff and soliciting scholarship opportunities for training of the junior staff towards PhD. Lastly, with the expansion of programmes and enrolment, the University is currently facing limitation of physical space for teaching. In addressing this challenge, the University is working to expand the physical infrastructure including extension of the dental facility at the SOD which is underway. Furthermore, the University has acquired 3800 acres of land in Mloganzila area, Dar-es-salaam, where a new campus will be built. To date, a 571-bed state-of-the-art hospital has been built in the area and construction of the Centre of Excellence in Cardiovascular Sciences - a research and teaching facility - is near completion. Next in plan is construction of lecture halls, laboratories, student hostels, administrative buildings, library, and other supporting units.Despite challenges encountered, the MUHAS has made significant advances in the past five years by increasing the number of programmes, enrolment, and graduation of specialized and super-specialized healthcare workforce for Tanzania and beyond, whilst maintaining a narrow gender gap. These milestones occurred amidst challenges of inadequate sponsorship, limited number of academic staff and limited physical infrastructure for teaching. The proposed improvements will further cement its leading role in training of the specialized and super-specialized healthcare workforce for Tanzania and Sub-Saharan Africa by enhancing the diversity of programmes, enrolment, gender equity and internationalization thus contribute positively towards timely attainment of the SDGs for Tanzania and the region."}
+{"text": "At the launch of this issue, then newly discovered COVID-19 seemed to be faltering, and the collection of papers gathered in this publication was bound to be both a reminder and a relatively final display of domains and aspects of human functioning that were somehow affected by the corona crisis. Meanwhile, the health situation in the world has shown us the full breadth of the impact that the coronavirus has left or still leaves in almost all fields of human behavior. Overall, bibliographic mapping shows that most of the papers, framed within the scientific study of coronavirus and its societal impact, were in the field of medicine and psychology , mental health , and positive  and negative affects  during the COVID-19 outbreak. Taking a more differential approach, papers dealing with the socio-cognitive factors related to the COVID-19 crisis build the next larger group of the collected articles . The third group includes papers dealing with preventive and protective behaviors, such as adherence to epidemiological recommendations . A final group of studies conferred deals with the way of mitigating psychological distress  during the coronavirus crisis. In the following paragraphs we have grouped these studies according to overarching topic, with their main findings summarized.As in the case of other health crises in the human history, our research collection has placed an emphasis on the effects of this pandemic on our emotional and cognitive behaviors, as well as attempts to prevent or mitigate its destructive effects. Indeed, most of the collected papers revealed the affective side of living with the pandemic. These studies cover topics of anxiety Fear of COVID-19, Stress, and Anxiety in University Undergraduate Students: A Predictive Model for Depression Anxiety and Social Support as Predictors of Student Academic Motivation During the COVID-19 The Influence of Personality, Resilience, and Alexithymia on Mental Health During COVID-19 Pandemic (Mehuli\u0107 and Kamenov)Mental Health in Affectionate, Antagonistic, and Ambivalent Relationships During the COVID-19 Pandemic: A Latent Profile Analysis The Relationship Between Quarantine Length and Negative Affect During the COVID-19 Epidemic Among the General Population in China: The Roles of Negative Cognition and Protective Factors .The Moderation Effects of Comparative Thinking Between Gratitude and Negative Affect During the COVID-19 Outbreak Analytic Thinking and Political Orientation in the Corona Crisis Who Believes in COVID-19 Conspiracy Theories in Croatia? Prevalence and Predictors of Conspiracy Beliefs The Relationship Between Perceived Stress and Subjective Cognitive Decline During the COVID-19 Epidemic .Individual Differences Facing the COVID-19 Pandemic: The Role of Age, Gender, Personality, and Positive Psychology  vs. non-pharmacological measures differ, which should also be considered when planning communication strategy. These are the studies dealing with the above topics:Lep et al.)One Hundred and Sixty-One Days in the Life of the Homopandemicus in Serbia: The Contribution of Information Credibility and Alertness in Predicting Engagement in Protective Behaviors Boldness Personality Traits Are Associated With Reduced Risk Perceptions and Adoption of Protective Behaviors During the First COVID-19 Outbreak .Trust in Science, Perceived Vulnerability to Disease, and Adherence to Pharmacological and Non-pharmacological COVID-19 Recommendations , it is advised to avoid some self-guided techniques (such as expressive writing) in the context of the COVID 19 pandemic\u2014as suggested by the following studies:Rivera et al.)Autogenic Training Improves the Subjective Perception of Physical and Psychological Health and of Interpersonal Relational Abilities: An Electronic Field Survey During the COVID-19 Crisis in Spain Reduction of COVID-19 Anxiety Levels Through Relaxation Techniques: A Study Carried Out in Northern Spain on a Sample of Young University Students .Effectiveness of Expressive Writing in the Reduction of Psychological Distress During the COVID-19 Pandemic: A Randomized Controlled Trial  and three continents testified about the efforts made world-wide to better understand its impact and mobilize inter- and intra-individual resources in combating its negative consequences.We have found commonalities of psychological responses of fear, anxiety, conspiracy, resiliency, and support across countries and cultures. We have also seen strong individual and group differences responding to COVID-19 related stress due to age, gender, and culture. This Research Collection provides examples of the many ways in which evolutionary principles can help advance psychological and behavioral science applied in a pandemic context. The Topic provides scientific evidence of effective coping strategies to protect from stress and negative emotions, such as:- Build trust in science and lower the sense of political helplessness- Increase optimism, cognition, uncertainty tolerance, and social support- Mindfulness, relaxation, and writing to reduce stress.This Research Topic was envisioned as an evidence-based reminder of the times of crisis caused by the new and then little-known coronavirus. By clearly identifying areas of research important for our coping with the pandemic and its effects, this Research Topic has outgrown its primary purpose. It can now be viewed as a tool for generating new valuable research ideas, consolidating the existing findings, and testing future treatment strategies.AV has drafted the article. All authors have contributed to the final revision to the editorial.Part of the effort was supported by United States National Institute of Health AG060608 to YJ.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "World Heritage sites, Biosphere reserves and UNESCO Global Geoparks are three primary categories of UNESCO-designated sites. As irreplaceable sources of life and inspiration, heritage is our legacy from the past, what we live with today, and what we pass on to future generations . StrengtTaking into consideration the interdisciplinary nature of heritage studies, scientists, engineers, managers and relevant stakeholders with diverse knowledge advocate a more cooperative approach to develop comprehensive, yet practical, solutions and applications. Space technologies, including remote sensing, Geographic Information System (GIS), Global Navigation Satellite System (GNSS), along with big data, cloud computation, artificial intelligence, 5G communications etc., provide a new paradigm of scientific and technological innovation, with the potential to transform the way of social production and people\u2019s life.The relevance and performance of space technologies in managing and monitoring heritage sites has already been established. Applications for space technologies in heritage conservation enable innovative solutions primarily in three aspects. First, the core elements of heritage ontology along with surrounding environments can be digitalized to develop seamless virtual representations that help to archive valuable archaeological assets, improve resource management, enable digital forensic studies and data intensive investigations utilizing modern analytical techniques and methods. Secondly, space-air-ground stereoscopic observation enables high resolution monitoring of heritage sites to sense minute changes and perceive historical and ongoing transformations in near real-time providing comprehensive information to develop practical solutions. Third, multisource spatiotemporal data and models can be collected, and integrated into a smart management system.Additionally integrating big data analytics, along with simulation/prediction, virtual reality/augment reality, socio-economic and geo-science process model, enhances the capacity to optimize management countermeasures to ensure sustainable development of these heritage sites. These technological resources also help to promote the Outstanding Universal Value (OUV) of heritage sites through digital communication platforms improving knowledge, education, awareness, and recognition of the OUV, and improving community involvement sustainable conservation of UNESCO-designated sites, ensuring a transformation towards a resilient society.The International Centre on Space Technologies for Natural and Cultural Heritage (HIST) under the auspices of UNESCO was proposed to UNESCO by the Chinese Academy of Sciences (CAS) in May 2007. The proposal was approved by the 35th General Conference of UNESCO in October 2009, and ratified by China\u2019s State Council in April 2011. On 24 July, 2011, the launching ceremony of HIST was held in Beijing. HIST is devoted to developing and utilizing space technologies for the identification, conservation, monitoring and management of UNESCO-designated sites to support UNESCO and its Member States in the implementation of the World Heritage Convention and providing support for the implementation of the UN 2030 Agenda for delivering Sustainable Development Goals (SDGs).Introduction to Space Archaeology (Chinese Version), which is the first book of its kind that reviewed space information technology applications for archaeology and introduced different space information techniques used for archaeology application and discussed the potential to establish a new discipline: Space Archaeology. Another prominent case is that HIST worked with other international scientists to make the discovery of 10 new archaeological sites in Tunisia dating to ancient Rome using Chinese space technology, which won the plaudits from Tunisian Ministry of Culture and Chinese Academy of Sciences. In addition, HIST has also expanded its global network with more than 30 UNESCO Member States and international organizations such as IUCN, ICOMOS, ICCROM. In the past decade, HIST has\u00a0made outstanding achievements, received international recognition and wide praise from UNESCO and other international organizations as well as relevant governments and institutions across the globe.Since its inauguration in July 2011, HIST has played a vital role in assisting UNESCO and its Member States in the conservation of UNESCO-designated sites. It has conducted 70 international conservation projects such as Remote Sensing for Environment of Angkor Site, Monitoring Landscape Evolution and Abnormal Deformations of the pagodas in Bagan World Heritage site, Monitoring and Analysis of Changes in the Forest Cover Loss in Asian Elephants\u2019 Habitats in Sri Lanka, Digital Characterization and Preventive Conservation of the Ming Great Wall with 20 UNESCO Member States, like Cambodia, Tunisia, Italy, Brazil, and strengthened capacity building through cultivating 20 doctoral students from developing countries and training 300 heritage site managers, technicians, researchers and decision-makers from UNESCO Member States. Meanwhile, HIST has pioneered the building of a new discipline-Space Archaeology. One of the landmark achievements is the publication of the Heritage Science, part of Springer Nature, to launch the special issue (article collection) to commemorate its 10th anniversary. This special issue presents the latest academic achievements from HIST researchers and its international partners. It groups a selection of eleven papers to illustrate the uses of space technology in the characterization, monitoring and assessment of heritage sites. These research studies not only highlight the necessity of this technology by emphasizing its benefits in first-hand data collection at macro\u2013micro scales, but also reveals its advantages in sustainable conservation of heritage properties by means of spatiotemporal analysis and scientific findings.Supported by the Bureau of International Cooperation, Chinese Academy of Sciences, HIST has joined hands with As the one of the four ancient civilizations worldwide, the\u00a0Chinese civilization is quite unique and one that has lasted continuously for thousands of years. Cultural heritage sites are witnesses to our history, a mirror to reflect upon our past. Yan et al.  utilizedOn site or space-based monitoring and surveillance is the most effective way to evaluate the condition of heritage sites as well as their surrounding environment. For those inaccessible locations , the prominent role of remote sensing for heritage monitoring is essentially important and irreplaceable. Owing to the technological advance of active and passive Earth observation sensors along with intelligent processing chains  and the emerging of open-source data , remote sensing has been applied as a systematic observation tool for stakeholders to map drastic or slowly driven landscape changes towards the better management of these sites and their surroundings . In caseThe paradigm of scientific discovery has transformed from statistical modelling to the data-driven and knowledge mining in the era of big data. Considering the transboundary and interdisciplinary characteristics of heritage studies, the potential of big data science in the sustainable conservation and smart management of heritage sites needs to be fully exploited. In Liang et al. , the spaIn general, the digital technology and data aggregation are the foundation for the data-driven knowledge mining. In the smart management of Mount Lushan project, Cai et al. evaluated the performance of digital technologies including oblique aerial photography, 3D laser scanning and 360-degree panorama imaging and synergistically utilized them to integrate all elements  into a virtual tourism subsystem. This pilot application is a representative demo to overcome the shortcoming of heritage protection and heritage tourism marketing .Looking forward, future researches on the application of space technologies to heritage conservation will be conducted in six major fields: (a) heritage-related multi-source data access, big data processing and analytic techniques, (b) fine-precise heritage conservation methods; (c) digital heritage technological system based on high and newly emerging technologies; (d) blending and presentation techniques for heritage utilization; (e) the formulation of different standards for heritage property conservation and digital conservation; (f) participatory heritage education, social governance pathways and methods.In the next decade, HIST would like to strengthen partnerships with UNESCO and its Member States and advisory bodies as well as other international organizations to meet strategic demands for the conservation and sustainable development of UNESCO-designated sites. It calls for global stakeholders to make concerted efforts to integrate science, technology and engineering to develop a system of theoretic framework and technological methodology, to further build space archaeology paradigm, to construct an international digital world heritage platform for scientific research and technological application by integrating database, monitoring, evaluation, presentation and decision support, and to establish a whole chain of digital heritage with a mix of data access, processing, analysis, presentation, application and industrialization, thus helping UNESCO and its Member States to achieve heritage-related SDGs."}
+{"text": "Religiosity and spirituality are commonly supported and viewed as essential elements of well-being in old and very old age, particularly at end of life. These essential elements often include the exploration of the meaning in life, inner peace, belonging, contentment, and near-end-of-life-completion. The positive outcomes of religious and spiritual beliefs and practices have been well established. However, these experiences and related positive outcomes may not always include a diverse array of older adults. The spiritual care of older adults is becoming more culturally diverse and includes differing perspectives on what constitutes spiritual care, both in approach and practice. This symposium will explore the current state of spiritual care for older adults through a lens of cultural diversity and inter-religious/spiritual perspectives. A focus on the current practices of spiritual care for older adults and future implications will also be considered. Recommendations pertaining to future gerontological inquiry in the importance of spiritual care, as well as diverse approaches within gerontological practice will be highlighted and discussed."}
+{"text": "The current increase in the number of publications on the use of artificial intelligence (AI) technologies in neurosurgery indicates a new trend in clinical neuroscience.The aim of the study was to conduct a systematic literature review to highlight the main directions and trends in the use of AI in neurosurgery.Using the PubMed search engine, 327 original journal articles published from 1996 to July 2019 and related to the use of AI technologies in neurosurgery, were selected. The typical issues addressed by using AI were identified for each area of neurosurgery.The typical AI applications within each of the five main areas of neurosurgery  were defined.The article highlights the main areas and trends in the up-to-date AI research in neurosurgery, which might be helpful in planning new scientific projects. In the first part of this systematic review : 106), using topic modeling, we determined the main topics featured in publications on artificial intelligence (AI) in five important fields of neurosurgery: neuro-oncology, functional, vascular, spinal neurosurgery, and traumatic brain injury. The second part of the review presented here discusses the main issues addressed by the authors to test and evaluate AI methods.The review was conducted using PRISMA  guidelines .The analysis covered journal articles and international conference proceedings that met the following criteria:the publication was an original research article;the publication referred to a disease and/or a treatment directly related to neurosurgery;the authors analyzed the use of AI technology for solving clinical problems of diagnosis, treatment, prognosis, rehabilitation, or prevention of a nervous system disorder;neurosurgery was a potential or actual field of application for the AI technology analyzed in the study.(https://www.ncbi.nlm.nih.gov/pubmed/). The search query was phrased to find all documents, in which the terms \u201cneurosurgery\u201d or \u201cneurosurgical procedures\u201d were coupled with terms related to specific AI technologies  in all database fields. The exact and complete query in the PubMed search engine is given below:The literature search for this systematic review was performed with PubMed US National Library of Medicine search engine system  OR \u201cneurosurgical procedures\u201d[All Fields] OR \u201cneurosurgery\u201d[All Fields] OR \u201cneurosurgery\u201d[MeSH Terms]) AND .The search results from PubMed were reviewed to select original articles that met the inclusion criteria in this systematic review. The selected articles were classified according to the relevant fields of neurosurgery. The topics in these studies were preliminary outlined by experts and their number was counted. The selection process and the technical tools used in this systematic review have been detailed in Part I.In accordance with the inclusion criteria, 327 papers published between 1996 and July 2019 were selected. A complete list of the 327 publications is presented in the Appendix. Below, we analyze the application of AI technologies in each field of neurosurgery in more detail; typical publications illustrating the study objectives are shown in brackets. Approximately 41% of the selected studies provide examples of using AI technologies in neuro-oncology (see Appendix). Most of data for these works were obtained from medical images  as well as from genomic sequencing and histology.The main tasks in neurosurgical oncology attempted to be solved using AI technologies were:segmentation and volumetry of brain structures , 3;noninvasive tissue and molecular genetic differential diagnosis \u20137;predicting complications and treatment outcomes , 9.One of the unconventional AI applications in neuro-oncology was the analysis of research trends in neuro-oncology based on scientific publications. An interesting task to be solved was concerned with the brain shift during neurosurgery. The solution to this problem is of great importance for the developing technologies of intraoperative neuro-navigation. Approximately 19% of articles on the use of AI in neurosurgery address the issues of functional neurosurgery, including epilepsy surgery (see Appendix). The data in these studies were obtained from electroencephalography and electrocorticography, magnetoencephalography, medical imaging , as well as deep brain stimulation, video monitoring of patient\u2019s condition, medical records, biochemical and genetic analyses, wearable devices.Among the typical tasks approached by researchers in these studies, there were:diagnosis of epilepsy, ictal and interictal activity, seizure predictors \u201312;functional tractography ;search for epileptogenesis biomarkers ;patient selection for epilepsy surgery ;predicting outcomes of epilepsy treatment ;Parkinson\u2019s disease diagnostics ;study of functional compensatory mechanisms in patients with Parkinson\u2019s disease ;study of movement disorders in Parkinson\u2019s disease ;electrophysiological identification of postural tremor and voluntary movements with essential tremor ;detection of targets, planning and modulating of deep brain stimulation ;prediction of postoperative side effects ;predicting the outcomes of microvascular decompression in hemifacial spasm ;search for electrophysiological correlates of neuropathic pain ;diagnosis of neuropsychiatric disorders ;research of episodic and semantic memory mechanisms ;speech-based identification of hemisphere dominance ;detection of the epileptogenic focus and segmentation of brain structures .This section of neurosurgery is characterized by a greater variety of research tasks as compared with neuro-oncology. Predominantly, attention was paid to epilepsy and movement disorders. The principal source of data was the electrical activity of the brain as recorded not only from the scalp, but also from the cortex and deep brain structures including specific neural ensembles. Using intracranial microelectrodes, researchers were able to directly measure the electrical activity in the brain and then analyze that in studies on memory and speech. Research in vascular neurosurgery accounted for 14% of the entire pool of retrieved publications on AI in neurosurgery (see Appendix). Most of the data were retrieved from medical images  followed by the data from medical information systems, bedside monitor recordings, electroencephalography, stereolithography, blood tests, and social/demographic questionnaires. A non-typical source of data in this field was a study on environmental pollution.The key tasks of the above studies were:identification of patients with aneurysms ;diagnosis of unruptured aneurysms ;risk factors and risk assessment for aneurysm rupture  and spontaneous intracranial hemorrhage ;risk assessment for cardiac disorders after aneurysmal subarachnoid hemorrhage ;predicting outcomes of ruptured aneurysms ;predicting ischemia after aneurysmal subarachnoid hemorrhage ;grading the severity of intracranial vascular stenosis ;diagnosis of atherosclerotic plaques ;predicting a persistent decrease in blood pressure after carotid stenting and angioplasty ;risk assessment for stroke after carotid artery stenting ;predicting perfusion deficiency ;segmentation of blood vessels and arteriovenous malformations ;predicting adverse events and outcomes of treatments for arteriovenous malformations ;definition, classification, and segmentation of intracranial/intracerebral hemorrhage ;discovering the genesis of intracranial hematomas ;predicting an increasing volume of hypertensive intracerebral hematoma ;risk assessment for intracerebral hemorrhage ;predicting functional outcomes of intracerebral hemorrhage ;predicting consciousness impairment in hemorrhagic stroke .Despite the substantially smaller number of publications as compared to neuro-oncology, the field of vascular neurosurgery earned a fairly wide range of AI applications. Most of these tasks can be summarized as (i) diagnosing pathological vascular formation and (ii) predicting complications and treatment outcomes. The use of AI in the field of spinal neurosurgery was discussed in 8% of the publications (see Appendix). The main sources of data in this area were medical images , as well as the data obtained from limb motion sensors. Special data were derived from video recordings of the surgeon\u2019s movements, as well as articles from the US National Library of Medicine. The main tasks addressed in this area of research included:prediction of complications ;prediction of treatment outcomes ;hospital discharge options ;transformation of images into different modalities ;segmentation of bone tissue and the spine ;grouping of patients and interventions for spinal deformation surgery ;assessing the motor function in patients with cervical spine disease and lumbar stenosis of the spinal canal , 54;assessing the foot drop in lumbar radiculopathy ; visual predicting the long-term use of opioids after surgery ;predicting the development of osteoporosis .The unusual research in this category included two studies on predicting changes in the intracranial pressure in patients during spinal surgery and predicting the surgeon\u2019s actions during the intervention , 60. In 8% of the selected studies, AI was used for issues of neuro-traumatology (see Appendix). The reported data were extracted from medical images , electroencephalography, patient monitoring devices , clinical examinations, eye movement recordings, and genetic studies.With a relatively small pool of AI-associated articles, traumatic brain injury is an area with multiple data sources and quite a few challenging problems related to prognosis. The main objectives of the analyzed studies were:assessing the severity of traumatic brain injury ;diagnosis of impaired consciousness ;quantitative assessment of intracerebral changes ;search for biomarkers of traumatic brain injury ;prediction of secondary injuries, classification of adverse events and complications ;predicting outcomes, searching for prognostic factors ;evaluating autoregulation of cerebral blood flow ;noninvasive assessment of intracranial pressure . About 10% of the studies on AI application in neurosurgery were concerned with general issues relevant to a number of neurosurgical conditions or non-specific for any disease. In these studies, medical imaging data, electrophysiological data, and other sources described above were used. For example, an analysis of infectious complications in patients in the neuro-intensive care unit.Non-standard sources of data in this area included photographs of patients\u2019 faces, information from smartphone , and texts of scientific publications. In the above studies, both traditional approaches to classification and prediction  and the most recent methods  were used. Thus, almost the entire spectrum of modern AI technologies was involved in these studies.According to our literature review, the majority of data concerning the use of AI technologies in neurosurgery come from neuroimaging, genome sequencing, invasive and non-invasive biosensors, and medical information systems (including unstructured data). Along with that, much less attention has been paid to the AI-based analysis of medical texts .Current technologies of text analysis allow one to explore the content of medical records, highlight relevant information, and test scientific hypotheses. AI technologies can not only extract data from medical texts but also create diagnostic and predictive models based on this data . An archImportantly, electronic medical libraries represent an invaluable source of \u201cbig\u201d data for research tasks. Today, generalization and critical assessment of research results using the criteria of evidence-based medicine are carried out by experts who write systematic reviews and meta-analyses . As a ruToday, a common limitation of AI-assisted research in neurosurgery is a relatively small sample size  compared to the \u201cbig data\u201d that has been processed by machine learning in other branches of science and industry. This data insufficiency calls into question the scalability of AI-powered solutions, even though it performs well in isolated studies. That is why research projects using AI technologies are beneficial and productive for medical research organizers who own the resource of big data.In our opinion, when planning research using AI technologies, it is important to adhere to the principles of evidence-based medicine, which ensure the scientific validity of the obtained results and, therefore, increase their benefit to patients. Research planning and the choice of methodology are of fundamental importance and should be adequate to achieve the study objective while minimizing potential biases. In addition, technologies for analyzing large amounts of data can, to a certain extent, compensate for the methodological limitations of research in neurosurgery .With a wide range of tasks demonstrated in this review, the application of the AI technologies can be reduced to two major areas \u2014 research and clinical practice.In research, the AI potential involves its ability to extract a lot of useful information and knowledge by making this extraction most efficient and by reducing the time of investigation. This approach overcomes the limitations of traditional mathematical statistics, which test hypotheses using much fewer data.In clinical practice, AI can be instrumental in solving tasks of medical activities automation, i.e. accelerating, simplifying, and increasing the reliability of diagnosing diseases, making clinical decisions, and predicting possible complications and outcomes of medical interventions. Thus, AI is expected to bring an economic effect by reducing human labor costs and the time for decision-making in medicine.A good understanding of the AI technologies perspectives justifies the efforts to develop and test these methods in research and clinical medicine. The term \u201cartificial intelligence\u201d can be intuitively  understood as \u201ca machine capable of thinking\u201d, and in the context of medicine \u2014 literally \u201ca robotic doctor\u201d. Neuroscience has not yet reached the understanding of human intelligence, and AI technologies have not come close to creating an \u201cartificial brain\u201d. At present, the methods united by the concept of \u201cartificial intelligence\u201d, solve rather traditional and pragmatic tasks, but using entirely novel technologies. Calculations based on AI methods, like the results of traditional statistical analysis, are interpreted by a medical doctor. Despite the similarity between the principles of mathematical algorithms and human intellectual activity, the AI methods cannot yet imitate consciousness, conscience, reflection, and other abilities of the human mind, which allow the doctor to make informed and responsible decisions. Like robotic navigation systems, microscopes, and linear accelerators, AI technologies are new tools in the doctor\u2019s arsenal. Today, they have the potential to become routine, but, for now, they cannot replace a clinician. This work includes a large number of publications reflecting major trends in using AI in neurosurgery without addressing the issues of efficacy, safety, or economic feasibility of specific technologies under specific conditions. Thus, the authors limit their scope to stating the facts of using AI methods in various tasks without assessing the quality of these studies.To date, research using artificial intelligence technologies has been carried out mainly in five major areas of neurosurgery: neuro-oncology, functional, vascular, and spinal neurosurgery, and the area of traumatic brain injury. The main sources of data in these studies were neuroimaging, genome sequencing, biosensors, and medical records. The use of artificial intelligence is becoming a global scientific trend in neurosurgery, therefore, an assessment of their efficacy, safety, and applicability in the clinic is highly important."}
+{"text": "Mycobacterium tuberculosis DNA in a cutaneous fragment, through polymerase chain reaction, the diagnosis of gummatous tuberculosis was confirmed, probably secondary to hematogenous dissemination from an intestinal focus.As the treatment of infectious and parasitic diseases improved, the prevalence of these conditions declined. However, with the expansion of the use of immunobiologicals, opportunistic infections have emerged, especially under atypical presentations. The present study reports the case of a patient treated with infliximab for Crohn's disease, who presented diarrhea, weight loss, abdominal pain, fever, and subcutaneous erythematous nodules that evolved with spontaneous fluctuation and ulceration. With the finding of alcohol-resistant bacilli and  Immunobiologicals were introduced in the 1990s to treat inflammatory bowel diseases.A 26-year-old female patient was diagnosed with Crohn's disease (CD) due to stomach enterorrhagia and abdominal colic. After therapeutic failure with prednisone, mesalazine, and azathioprine, infliximab 5\u202fmg/kg was initiated. Despite the initial improvement in symptoms, she gradually worsened. After 14 months on infliximab, she maintained an active disease and weight loss, in addition to daily feverish peaks. She presented three subcutaneous erythematous nodules on the posterior region of the right thigh, of approximately 3\u202fcm in diameter, without fluctuation or drainage. Subsequently, these lesions ulcerated, with well-defined edges and a necrotic background . HistopaYersinia pseudotuberculosis was raised. The treatment with gentamicin and ceftriaxone was ineffective, with the onset of a new erythematous cutaneous nodule on the left thigh, which revealed the presence of AAFB on histopathological examination (Mycobacterium tuberculosis by the rapid molecular test, confirming the diagnosis of gummatous tuberculosis. Computed tomography of the chest showed nonspecific nodules, and pulmonary involvement was not ruled out. Treatment with rifampicin, isoniazid, pyrazinamide, and ethambutol was instituted for six months. The ulcerated nodules healed completely after the third month, with no recurrence after one year of follow-up.Due to the characteristics of the granulomas, the hypothesis of infection with mination  and geneCutaneous TB accounts for approximately 1% of the cases of the disease.6Gummatous tuberculosis is rare and affects mainly immunosuppressed and malnourished children. It is characterized by subcutaneous erythematous nodules, which evolve with intense central necrosis, fistulization, and ulceration. It results from the acute hematogenous spread of a primary outbreak during periods of bacillemia. The tuberculin test is usually negative. Histopathology shows extensive necrosis, formation of loose granulomas, and high bacillary load. Molecular techniques also contribute to the diagnosis.None declared.Lucas Campos Garcia: Approval of the final version of the manuscript; drafting and editing of the manuscript; collection, analysis, and interpretation of data; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature.Everton Carlos Siviero do Vale: Approval of the final version of the manuscript; drafting and editing of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.Maria de Lourdes Ferrari: Approval of the final version of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases.Lauro Damasceno de Carvalho Faria: Approval of the final version of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases.None declared."}
+{"text": "This Special Issue on Development of Laser Welding and Surface Treatment of Metals contains as many as twenty-two research articles mainly related to the application of lasers, but also on other welding processes that may be competitive to laser technologies under specific conditions. Despite the introduction of lasers for material processing in the 1960s, the continuous development of laser devices also leads to the development and expansion of laser technology applications. This Special Issue is a compendium of knowledge in the field of fusion welding, the manufacturing of surface layers and coatings with increased wear resistance and tribological characteristics, as well as corrosion resistance and the characterization of coatings and surface layers. The topics of the presented research articles include aspects related to laser welding (eight articles), especially technological conditions, the properties of different types of joints, and analytical and numerical aspects of modelling the laser heat sources. The second dominant issue concerns laser cladding and laser surface treatment of different ferrous and nonferrous metallic and composite materials (six articles). In addition, there are interesting results of the study of fusion welding under forced cooling of the deposit or underwater conditions (four articles), results on the characterization of wear resistance coating produced by different technologies that can be competitive for laser cladding (three articles), and an original study on local strengthening of the thin-walled structure by laser treatment (one article). This Special Issue provides very wide and valuable knowledge based on theoretical and empirical study in the field of laser and fusion welding, laser and related coating technologies, characterization of coatings, and wear phenomena. Striving for sustainable development as well as limiting the harmful impact on the environment, including the reduction in COructures ,2,3.Therefore, new materials are being developed with higher mechanical properties, higher wear resistance and thus higher operating parameters. The conventional welding methods and technologies usually do not provide satisfactory results in applications such as joining and cladding of modern materials, e.g., high strength steel, nonferrous metals and alloys, composite materials, and nanostructured and hybrid materials ,5,6,7,8.The main disadvantages of typical methods of welding and cladding such as conventional arc or plasma arc methods are excessive heat input and the relatively large volume of the molten pool. This leads to overheating of the material, internal stresses and deformations, and unfavorable grain growth or dissolution of the reinforcing phase particles, e.g., carbides or nitrides. Therefore, the attention of researchers and industry is focused on the search for methods of joining and processing materials that ensure a minimum thermal effect on the material and the ability to precisely control the amount of heat and the thermal cycle of the process ,11,12,13One of the dynamically developed areas of material processing technology in recent years is laser material processing technology. In the area of joining materials, laser welding shows several advantages because it provides high-power densities and low diameter of the laser beam spot, and thus high penetration depth, high welding speed, and low, precise, and controllable heat input. The above features are particularly important for the joining of modern and advanced alloys such as ultra-high-strength steels (UHSS), advanced high-strength steels (AHSS), modern stainless duplex and super duplex steel, nonferrous metals, and light metals, e.g., titanium and aluminum alloys ,15,16,17Another area of laser beam application that is currently being intensely developed is the shaping of the properties of surface layers and the production of coatings for enhanced wear characteristics such as corrosion resistance, tribological properties, abrasive resistance, thermal and mechanical fatigue resistance, and resistance to impact load ,6,7,8,18In the area of surface treatment and cladding, the laser beam as a heat source is also advantageous. The most significant advantages include low and controllable heat input, and thus limited thermal impact on the substrate, reduced internal stresses, minimized distortions, high solidification and cooling rates, low penetration depth, and low dilution of the clad layer by the substrate material. Low heat inputs and related high cooling rates during laser processing are beneficial in many applications of surface treatment and cladding as they provide high quality clads and surface layers. Usually, surface layers are characterized by superior metallurgical bonding and a fine-grained and refined microstructure, which are decisive for providing superior tribological characteristics, high abrasive or erosion wear resistance, and corrosion or fatigue resistance ,8,18.It is worth noting that laser-made clads and surface layers show higher functional properties compared to surface layers made by plasma arc (PTA) or conventional arc cladding processes, even if the same additional materials are applied. This is due to intense grain refinement caused by very fast cooling and solidification of the molten pool, typically an order of magnitude higher than plasma (PTA) and conventional arc cladding  ,12.Thanks to the advantages mentioned above, lasers are used in different processes of surface treatment such as laser surface hardening (LSH), melting (LSM), shocking (LSS), texturing (LST), alloying (LSA), cladding (LSC), remelting (LSR), and surface deposition (LSD), and in additive manufacturing processes such laser metal deposition (LMD) or selective laser sintering and melting (SLS/SLM) .2 and solid-state rod type Nd:YAG laser generators used for the last few decades, new generations of solid-state lasers are currently available such as high-power diode lasers (HPDL), disk lasers, and fiber lasers [2 gas lasers and disk lasers, as well as fiber lasers [Continuous development of laser generators and related improvement of laser radiation and laser beam characteristics enable further development in the field of laser material processing, including laser welding and laser surface treatment. In addition to the gaseous COr lasers ,15,16,17r lasers ,17,18. There has also been significant progress in the design and construction of fiber generators in the last decade. Modern fiber lasers are also beneficial due to their compact design, high wall plug efficiency, low beam divergence, and possibility to focus the beam into a very small spot, even at relatively high power . MoreoveAnother interesting example of dynamic development in the field of material processing technology is hybrid processes. According to the definition, the hybrid process combines at least two different machining processes which must be carried out simultaneously and in the same processing area . In the case of welding, the laser beam is often combined with the arc, e.g., laser + GMA , laser + GTA (gas tungsten arc) or laser + PTA (plasma tungsten arc). Such combinations of two different heat sources allow taking the advantages of both welding methods. The laser beam is responsible for deep penetration of the material, while the arc processes provide additional heat and material to fill the gap. Consequently, it is possible to weld at high speed and ensure the correct shape of the weld at high depth. Hybrid processes are also being developed in the field of surface treatment and coating applications, ensuring higher functional parameters or the possibility of producing coatings with special properties ,18.The Materials and Methods should be described with sufficient details to allow others to replicate and build on the published results. Please note that the publication of your manuscript implicates that you must make all materials, data, computer code, and protocols associated with the publication available to readers. Please disclose at the submission stage any restrictions on the availability of materials or information. New methods and protocols should be described in detail, while well-established methods can be briefly described and appropriately cited.-Study of technological conditions of laser welding, investigation of test joints properties ,24,25,26-Analytical and numerical models of heat sources of laser beam and arc welding processes ,20,22,23-Study of laser cladding and investigations of the coating\u2019s properties and tribological characteristics ,31,32,33-Study and development of fusion welding processes, investigation of properties of the deposit produced under forced cooling or underwater conditions ,35,36;-Study of cladding, surfacing, and thermal spraying processes of wear-resistant coatings, characterization of the coatings ,38,39;-Study of application of local strengthening of the thin-walled structure by laser treatment .This Special Issue, entitled \u201cDevelopment of Laser Welding and Surface Treatment of Metals\u201d, is a complementary and valuable resource of knowledge in the following fields:In the work presented by Wang et al. , plates Kik  presenteIn the second article, Kik  presenteThe study presented by G\u00f3rka  was focu2 laser welding of lap joints of low-carbon structural steel. They determined hardness profiles and weld geometry for the welds produced at different parameters. They also provided detailed analysis of the metallographic structure of fusion zone (FZ) and heat-affected zone (HAZ), as well as a quality assessment of the tested joints. The laser welding process was also investigated by Danielewski and Skrzypczyk . They prThe study presented by Landowski et al.  concerneThe results of the study presented by Pa\u0144cikiewicz et al.  also conAnother study on laser welding was presented by Tofil et al. . They coThe topic of laser surface treatment and cladding begins with Lisiecki\u2019s article  on the s4C particle on the microstructure and chosen properties was investigated and determined. A highly interesting study on laser surface modification of an aluminum alloy by boron carbides was carried out by Sroka et al. . The fibAnother interesting study on laser cladding was performed by Li et al. . In theiThe next study, presented by Majkowska-Marzec et al. , is relaA comparative study of laser and plasma cladding was presented by Czupry\u0144ski et al. . The coaAnother study on the effect of laser treatment on tribological properties was presented by Lubas et al. . They an2C-WC carbides across the coating. The thematic series on laser surfacing and cladding ends with the article presented by Lisiecki and \u015alizak  on hybriAnother very novel and interesting subject related to arc welding processes was presented by Szczucka-Lasota and Szymczak et al. ,35. The Some manuscripts dealt with other arc processes and technologies, but the presented solutions were very innovative. An example of a highly interesting subject was presented by Tomk\u00f3w et al. . They inThe study presented by Mician et al.  was relaThe second study presented by Czupry\u0144ski  was focuThe next article provided by Czupry\u0144ski  presenteAnother original issue was presented in the study by Kapustynskyj et al. . They foThis Special Issue was very successful due to the valuable articles that were submitted, the wide variety of topics and research problems that were undertaken, and in-depth analysis of the state of the art in different fields of laser and related processes. This Special Issue contains a significant number of research articles ; however, the entire number of manuscripts submitted to this Special Issue was half that higher. Unfortunately, some of the manuscripts have not gone through a very rigorous review process. Such a large interest and quantity of articles shows the importance of the issue and themes. It should also be emphasized that each research article in the field of materials processing is the result of tedious, long-term, and interdisciplinary research, usually conducted by a team of scientists. The topics of the articles were mainly focused on laser welding, laser cladding, and laser surface treatment, as well as related processes of fusion welding and manufacturing of coatings. The wide range of experimental, numerical, or analytical study conducted and presented by 58 authors, representing 19 academic or research centers and 3 industrial centers from 5 countries  and 16 cities, proved the topicality and importance of this Special Issue."}
+{"text": "Artificial intelligence (AI), together with robotics, sensors, sensor networks, internet of things (IoT) and machine/deep learning modeling, has reached the forefront towards the goal of increased efficiency in a multitude of application and purpose. The development and application of AI requires specific considerations, approaches, and methodologies. This special issue focused on the applications of AI to environmental systems related to hazard assessment in Urban, Agriculture and Forestry. A total of ten papers were published in this special issue, with topics ranging from reviewing the current climate-smart agriculture approaches for smart village development  to the iThe development of smart villages in Europe requires a framework to secure sustainability based on climate-smart agriculture. As argued by Adesipo et al. , these cOne of the detrimental effects of reduced green infrastructure is the contamination of waterways and water networks. The study by Lu\u010din et al.  proposedFor agricultural systems, novel digital technologies were applied for farm animal welfare assessment based on weather information and cow data to predict milk productivity and quality through supervised machine learning . The modClimate change effects include the increased incidence, number and severity of climatic anomalies such as heatwaves and bushfires. These climatic anomalies have a specific impact on viticulture and winemaking, specifically with bushfires producing smoke contamination on leaves and berries, which are later passed to the wine through the fermentation process. These have been investigated in two studies focused on implementing digital technologies and machine learning modeling using low-cost electronic noses  and nearFinally, low-cost electronic noses and near-infrared spectroscopy were also implemented to assess the infestation of insects in plants and the insect-plant interaction . This st"}
+{"text": "Zienkiewicz and Zienkiewicz). Because of the vital role of lipid metabolism in photosynthetic organisms, exploring lipid processes is very important for engineering crops to obtain better agronomic traits including productivity, nutrition, stress tolerance and resilience.Lipids are the essential building blocks of cellular membranes, and they play fundamental roles in numerous biological activities such as photosynthesis, protection, environmental and cellular communication, and storage of carbon and energy. Lipid metabolism is a dynamic and complicated process that includes lipid biosynthesis, transport, accumulation, turnover, and excretion, acting to regulate plant development and tolerance to various environmental stresses. Understanding how lipid metabolism regulates the development and growth in response to adverse conditions raises many interesting questions. Communication between membrane and storage lipids has been observed during the progress, for example, membrane degradation accompanied by lipid droplet (LD) accumulation. Recently, autophagy has been connected with lipid metabolism in plants and algae under stress conditions . As the major reservoir of cellular carbon and energy, TAG is packed in LD, a dynamic organelle at the center of cellular metabolism. The review also compares the LD degradation in plants and algae , while Liao et al. show the roles of two rice acyl-CoA-binding proteins, OsACBP4 (plasma membrane and ER) and OsACBP5 (apoplast), in the intra- and extracellular transport of acyl-CoA esters, respectively  leaves ; together with the specificities of extraplastidial acyltransferase enzymes, the olive OeFAD2-2 and OeFAD2-5 regulate the oleic/linoleic acid ratio in the mesocarp of olive cultivars . The Research Topic also highlights the significance of lipid metabolism in environmental stress response and tolerance  that catalyzes the biosynthesis of very-long-chain fatty acid (VLCFA) in Citrus sinensis , reduces water loss and ion leakage and increases tolerance to drought and salt stress ; Arabidopsis phospholipid:diacylglycerol acyltransferase 1 (AtPDAT1) promotes the activities of acyl-CoA:lysophosphatidylcholine acyltransferase (LPCAT) and acylCoA:lysophosphatidylethanolamine acyltransferase (LPEAT) and improves resilience to heat and cold exposure . In Vaccinium corymbosum L., cv. Duke (Duke blueberry), intermittent warming treatment of the fruit regulates its lipid metabolism such as increases in phosphatidylcholine, linoleic acid, and oleic acid, which enhances the low-temperature tolerance in the fruit . In the roots of maize, integrated lipidomic and transcriptomic analyses reveal the membrane lipid remodeling and gene regulations under saline-alkaline  or cold stress , which are applicable for engineering the crop for better performance under these stress conditions.This Research Topic includes 10 original review and research articles, with a special focus on lipid metabolism in crops. The review by nd algae . Lookingectively . Other cultivars  (Hern\u00e1ndolerance . In ArabThe collection of articles in this Research Topic demonstrates the significance of lipid metabolism in various biological processes and the findings will contribute to engineering agronomic traits of crops for the increasing demand for food and bioproducts.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Objectives: To assess the quality of health facility documentation related to maternal deaths at health facilities in Afghanistan.Methods: Analysis of a subset of findings from the 2016 National Maternal and Newborn Health Quality of Care Assessment in Afghanistan. At each facility, maternity registers were reviewed to obtain data related to maternity caseload, and number and causes of maternal deaths in the year preceding the survey. Detailed chart reviews were conducted for up to three maternal deaths per facility. Analyses included completeness of charts, quality of documentation, and cause of death using WHO application of International Statistical Classification of Disease to deaths during pregnancy, childbirth and the puerperium.Key findings: Only 129/226 (57%) of facilities had mortality registers available for review on the day of assessment and 41/226 (18%) had charts documenting maternal deaths during the previous year. We reviewed 68 maternal death cases from the 41 facilities. Cause of death was not recorded in nearly half of maternal death cases reviewed. Information regarding mode of birth was missing in over half of the charts, and one third did not capture gestational age at time of death. Hypertensive disorders of pregnancy and obstetric hemorrhage were the most common direct causes of death, followed by maternal sepsis and unanticipated complications of clinical management including anesthesia-related complications. Documented indirect causes of maternal deaths were anemia, cardiac arrest, kidney and hepatic failure. Charts revealed at least eight maternal deaths from indirect causes that were not captured in register books, indicating omission or misclassification of registered deaths.Conclusion: Considerable gaps in quality of recordkeeping exist in Afghanistan, including underreporting, misclassification and incompleteness. This hampers efforts to improve quality of maternal and newborn health data and priority setting. The World Health Organization defines maternal death as the death of a woman while pregnant or within 42 days of termination of pregnancy, irrespective of the duration and site of the pregnancy, from any cause related to or aggravated by the pregnancy or its management but not from accidental or incidental causes . MaternaMaternal mortality in Afghanistan has significantly declined from 1,600 deaths per 100,000 live births in 2002  to 638 dDespite these challenges, the Ministry of Public Health (MoPH) in Afghanistan remains committed to reducing preventable maternal mortality and has set a national target for mortality reduction , consideMaternal death surveillance and response (MDSR) is widely implemented in low- and middle- income countries, as one strategy to identify and address health system weaknesses contributing to maternal deaths . In AfghHowever, while national guidelines for maternal and neonatal death surveillance and response exist, authorities acknowledge that maternal death audits have been poorly performed in Afghanistan and gaps exist in the quality of reported data , 15. BeyPrevious studies in Afghanistan have assessed accuracy and validity of maternity care records and quality of cesarean section-related documentation, but none have examined the availability and completeness of documentation of maternal deaths , 17. We National Maternal and Newborn Health Quality of Care Assessment, a cross-sectional health facility assessment conducted in 2016. The assessment was designed to examine health facility readiness for basic and comprehensive emergency maternal and newborn care, and assess quality of routine antenatal care, childbirth and postpartum care, and management of selected obstetric and newborn complications , and a random sample of facilities with fewer than five births per day (n = 149). The sample size for low-volume facilities was calculated to provide a representative sample of the 1,736 public facilities with < five births per day, with a 10% margin of error, 5% alpha error, design effect of 1.5 due to stratification of facility types, and 5% oversampling for potential inaccessibility due to geography or insecurity. In addition, 20 private health facilities were purposively selected to provide a snapshot of care at private sector facilities in all regions of the country.The Data collection was conducted by 32 female doctors and midwives trained on assessment objectives, data collection techniques and research ethics. Data collection methods for this paper included use of a facility inventory and record review tool to verify caseload, availability of relevant data and guidelines, as well as review of patient's folders or mortality charts. Data collection at health facilities with an average of at least five births per day was completed between May 14th, and August 3rd, 2016. Data collection at health facilities that averaged fewer than five births per day was completed from November 5, 2016, to January 5, 2017. At each facility, maternity registers were reviewed for information on the maternity caseload and number and causes of deaths in the year preceding the survey. Detailed chart reviews were conducted for up to three maternal deaths per facility; charts were requested for the three most recent maternal deaths in the previous year. For each chart, data collectors extracted information on client characteristics, location and mode of childbirth, timing and causes of death, and newborn outcomes. Data collectors reviewed charts for any information on factors contributing to maternal death and noted if women experienced any of the following: delayed arrival to health facility, delayed transfer to appropriate level of care, delay in care due to lack of supplies, delay in care due to absence or non-attendance on part of the health professional, delay in correct diagnosis . All datData was exported from CommCare to Excel for cleaning and analysis. We used visual inspection and descriptive statistics methods to analyze quality of documentation and completeness of charts, and case review methods to classify causes of death using WHO Application of ICD-10 to deaths during pregnancy, childbirth and the puerperium (ICD-MM coding). Facility types were defined as follows: (1) Specialized, Regional, and Provincial Hospitals; (2) District Hospitals (DHs) with an average of five or more births per day; (3) DHs and Comprehensive Health Centers (CHC) with an average of fewer than five births per day; and (4) Basic Health Centers (BHC), Sub Health Centers (SHC), Family Health Houses (FHH), and other primary health care facilities.The 2016 Afghanistan National Maternal and Newborn Health Quality of Care Assessment protocol was approved by the ethical review boards of the Afghanistan Ministry of Public Health (361533) and the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland . Written permission for data collection was also obtained from the in-charge of each facility.Review of maternity registers showed an average number of 194 births per month at public facilities and 67 births per month at private facilities in the Afghan calendar year preceding the assessment (April 2015 \u2013 March 2016). An average of 175 antenatal care visits per month were reported at public and 107 antenatal care visits per month at private facilities . Of publSpecialized, Regional, and Provincial Hospitals which reported an average of more than 8500 births per year , recordeWe reviewed patient charts for 68 women from 41 facilities , who died from direct or indirect causes related to the pregnancy, childbirth or clinical management. Seventeen charts did not record the age of the woman who died and 21 did not indicate gestational age. In more than half (39) mode of birth was not recorded. Seventeen did not record timing of death in relation to childbirth . Approximately half of the charts reviewed (35 of 68) recorded cause of death .Of the 51 charts with the woman's age recorded, four were <20 years old, 31 were between the age of 20 and 35 years and 16 were over 35 years of age. Of the 52 charts with birth location recorded, most (46) were facility births, whilst four women gave birth at home, and two women on the way to the health facility. Mode of birth was only recorded for 29 cases: 18 women gave birth vaginally and 11 by cesarean section. Fourteen women were referred from lower level health facilities and private sector to higher levels of care. Of the 51 charts with timing of death recorded, 33 were deaths occurring postpartum, 13 intrapartum and 5 antepartum.The review of patient's charts showed that the main causes of mortality were obstetric hemorrhage (17), hypertensive disorder, preeclampsia and eclampsia (16), amniotic fluid embolus (2), unanticipated complication of management such as anesthesia (2), sepsis (1), and ectopic pregnancy (1). Fifteen charts indicated no indirect causes of maternal death, while 37 did not record any information on indirect causes. The causes of death listed in 16 cases reporting indirect causes were cardiac, respiratory, liver and kidney disorders (9), anemia (4) and anemia with heart and kidney disease (2), and shock (1) . SixteenThe 68 maternal mortality charts reviewed included 59 singleton pregnancies and 9 twins . Of the Fifty-five of the 68 maternal mortality charts reviewed included information on factors contributing to maternal deaths . Thirty-Our study shows remarkable weaknesses in quality of documentation and record keeping, at both public and private facilities in Afghanistan. We found glaring gaps in completeness of recordkeeping. Critical information on characteristics of deceased were missing in nearly half of the records. Our results are in line with other studies from Afghanistan that have indicated that quality of medical record keeping is extremely low , 17, 22.Charts reviewed suggest that the most commonly reported direct causes of maternal deaths were obstetric hemorrhage, eclampsia, and abortions; fewer cases were recorded on maternal sepsis and complications of anesthesia. Hence, urgent effort is needed to first address these immediate causes of death for many women, while putting in longer-term efforts to strengthen the health system and working on social determinants that lie outside the realm of the health sector, in a multifaced approach , 3. As pAccurate classification of causes of maternal mortality is vital for decision making and provision of care; otherwise there could be misclassification and under-identification of maternal deaths at facilities, where a woman of reproductive age may die in a medical or surgical ward with an undiagnosed obstetric complication . For proNotably, reliability of facility level data will become even more important when frontline clinicians accurately record clinical activities and related outcomes in charts. Information on the medical records can be used to improve health service quality , 27. MorThe private health sector in Afghanistan is dynamic, rapidly expanding, and largely unregulated . Very feIn Afghanistan, the poor quality of medical records, lack of knowledge and skills, staff turnover, lack of coordination, the culture of blame and inadequate resources are barriers to conducting effective death reviews , 31, 32.Providing targeted refresher training on clinical record keeping, improved compliance by health care providers, staff support and fostering a culture of secrecy and professional protectionism, and non-punitive responses on medical errors, and strong leadership at national level and at lower levels of governance will lead to accuracy, reliability and completeness of medical records , 22, 31.There are some examples of successful large-scale implementation of MDSR in low- and middle-income countries, including in Malaysia, Sri Lanka and India. Evidence suggests that such implementation requires considerable efforts to identify and address maternal deaths and associated factors . In counMDSR remains a vertical intervention in Afghanistan, operated in parallel to the country's disease surveillance system. A study in Ethiopia has emerged the importance of MDSR embedment within the existing disease surveillance system as a routine practice rather than a stand-alone system, with a greater supervisory support to improve the reporting and response mechanism .There are considerable methodological shortcomings of surveys to measure maternal mortality in Afghanistan, exacerbated by the fragile context. Efforts should be redirected to improve access to and quality of routine maternal health data to obtain real time-insights, with increased longer-term investment in civil registration and vital statistics .The use of electronic medical records (EMR) in Cameroon and Malawi has shown an increase in completeness and accuracy of medical records , 36. A sOur study is not without limitations. It was designed to assess the quality of broader maternal and newborn health services. Therefore, only three most recent patients' charts per facility were reviewed, not all deaths in the previous year, so data on case characteristics and causes of death cannot be considered representative of all maternal deaths in Afghan health facilities. The private-sector snapshot provided only a limited picture of maternal mortality in private health facilities in Afghanistan and cannot be compared with nationally representative data from public health facilities. Despite these limitations, our study shines a light on the deplorable quality of record keeping and documentation of maternal health outcomes, and highlights challenges in relying on facility records for estimations of maternal mortality.Our study identifies considerable concerns with regard to the quality of record keeping in Afghanistan. These encompass under reporting, misclassification, and incomplete documentation. Improvements in record-keeping and health management information systems are critical to improve maternal and newborn health outcomes. Improving the quality of maternal and newborn health data requires robust political support and investment at various levels to support real-time clinical and political decision making and priority setting. This paper serves as a call to improve documentation and analysis of causes of maternal deaths amidst insecurity in Afghanistan, and to systematically improve accountability for coordinated, data-driven efforts to address factors associated with preventable maternal mortality.Data is available from the principal investigator or upon reasonable request or signature of a data use agreement.The studies involving human participants were reviewed and approved by the ethical review boards of the Afghanistan Ministry of Public Health (361533) and the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland (6799).FM served as co-trainer for the 2016 Afghanistan National Maternal and Newborn Health Quality of Care Assessment, wrote the first draft of this manuscript, led data analysis, interpretation and revision of this article. TvdA contributed to the writing and revision of the manuscript. JS served as a study advisory board member and contributed to the review and revision of the manuscript. HT served as principal investigator, led the data analysis, and contributed to the interpretation of study findings and revision of the manuscript. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "People with substance use disorders may be at a greater risk of contracting COVID-19 infection and developing medical complications. Several institutional and governmental health agencies across the world developed ad hoc guidance for substance use disorder services and care of individuals misusing substances. We aimed to synthesise the best available recommendations on management and care of people with or at risk of substance use disorders during the COVID-19 pandemic from existing guidelines published in UK, USA, Australia, Canada, New Zealand, and Singapore.th 2021). We summarized the extracted data as answers to specific clinical questions.We systematically searched existing guidelines and websites from 28 international institutions and governmental bodies in the context of the COVID-19 pandemic (May 4We organised the available recommendations from 19 sources in three sections. First, we focused on general advice and recommendations for people who misuse alcohol or drugs during the COVID-19 pandemic, the design of contingency plans, safeguarding issues for children and families of service users and advice to the public, patients, and carers. Then, we summarised specific guidelines for people who use illicit drugs and related services, such as opioid substitution treatment and needle and syringe programmes. Finally, we provided a synthesis on specific recommendations for services supporting people who misuse alcohol and key topics in the field, such as management of alcohol detoxification and safe transition between supervised and unsupervised consumption.Available guidance reflected different approaches, ranging from being extremely cautious in providing recommendations other than generic statements to proposing adaptation of previously available guidelines to confront the challenges of the COVID-19 pandemic. After the early phase, guidance focused on reduction of infection transmission and service delivery. Guidance did not provide advice on infection prevention via vaccination programmes and service access strategies tailored to individuals with substance use disorders.The online version contains supplementary material available at 10.1186/s12888-022-03804-7. The corPeople with SUD may be more susceptible to developing COVID-19. They may have a higher burden of comorbid medical and mental health conditions, be less likely to be tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), and live in social conditions which make it difficult to comply with home isolation  \u201310. PeopGovernmental health agencies across the world have rapidly developed additional guidance on treatment services, with adaptations to national legislation and policies, to try and meet the specific needs of patients with SUD during the COVID-19 pandemic . HoweverTo aid the busy clinicians in rapidly accessing reliable sources of existing guidelines in this area, we systematically searched and synthesised the best available guidance of both governmental and non-governmental agencies in the UK, USA, Australia, Canada, New Zealand, and Singapore, focusing on treatment of SUD during the COVID-19 pandemic and its aftermath.th 2021:Governmental institutions: Public Health England (PHE), Centers for Disease Control and Prevention (CDC), US Department of Labor, Singapore Ministry of Health (SMH), Health Canada (Government department), Australian Government Department of Health, Substance Abuse and Mental Health Services Administration (SAMHSA), and Canadian Society of Addiction Medicine (CSAM).Professional bodies: Royal College of Psychiatrists (RCPsych), Royal College of Nursing (RCN), Royal College of Physicians (RCP), American Psychiatric Association (APA), Singapore Psychiatric Association (SPA), Singapore Medical Association (SMA), Canadian Psychiatric Association (CPA), Royal Australian and New Zealand College of Psychiatrists (RANZCP).Health Technology Agencies (HTA): The National Institute for Health and Care Excellence (NICE), Healthcare Improvement Scotland.International agencies: World Health Organization (WHO), Inter-Agency Standing Committee (IASC), UNICEF, European Monitoring Centre for Drugs and Drug Addiction (EMCDDA).Scientific societies: The National Association of Psychiatric Intensive Care and Low Secure Units (NAPICU), RCPsych with British Geriatric Society and European Delirium Association, Massachusetts General Hospital Psychiatry, World Psychiatry Association (WPA), British Association of Psychopharmacology (BAP), Scottish Health Action on Alcohol Problems (SHAAP).A multidisciplinary team  within the Oxford Precision Psychiatry Lab  systematFurther sources were hand-searched from the references of each website. Given that summarising data from primary studies was beyond our scope, we did not search reference databases . Nonetheless, should we come across a particularly relevant publication, either supporting or in disagreement with available recommendations, we included it to better outline the context of a specific question. A search on Google was also completed using keywords relevant to COVID-19 , substance and alcohol use disorders and related treatments , and guidelines . Queries or disagreements were resolved by discussion with a third researcher (AC), and the team collaborated with international experts in the field  to keep the guidance global, focused, and comprehensive. We incorporated the feedback of clinicians and mental health professionals, and the final synthesis of guidelines was grouped in a questions and answers format for ease of consultation, with key sentences highlighted in bold. The recommendations were classified as \u201cGeneral advice and recommendations\u201d, when applicable to the whole population potentially accessing healthcare services due to substance or alcohol misuse, or \u201cspecific guidelines\u201d when tailored to distinct sub-groups of service users. Finally, we appraised the identified recommendations according to type of source organisations and institutions , international agencies, scientific societies).n\u2009=\u200911, 58%%) were from governmental institutions , healthcare technology agencies (n\u2009=\u20092), professional bodies (n\u2009=\u20092), and scientific societies (n\u2009=\u20091). The identified sources focused on promoting telepsychiatry in routine care, providing detailed recommendations on how to deliver digital assessments to abide by the social distancing requirements. Moreover, available guidance emphasised the potential benefits of digital services, such as an increased level of anonymity for consultancy services, though inevitably some services require face-to-face interaction. A blended or mixed approach was thus recommended, such as in-person assessments delivered for people with a moderate level of dependence. Where possible, an increased level of flexibility was prompted in the provision of take-home treatments.We collected recommendations from 19 sources, \u201334 of whThe full guidance is reported in Table We have summarised the available guidelines published in English-speaking countries on several key topics relevant to the management of people with substance or alcohol use disorders and misuse of drugs or alcohol during the COVID-19 pandemic. Identified sources were primarily from governmental institutions. Available guidance reflected several changes to standard practice and care that occurred due to the impact of the COVID-19 pandemic on substance and alcohol use disorders treatment services. Key changes in recommendations focused on the role of telepsychiatry and increased flexibility in dispensing take-home treatments.Identified guidelines widely promoted the use of digital consultations and telepsychiatry to maintain social distancing when delivering substance and alcohol use services whilst minimising perceived social isolation. The social distancing restrictions in several countries prompted a rapid implementation of telehealth and the dissemination of digital mental health practices at an unprecedented pace . TeleheaIn the early phase of the COVID-19 pandemic, detoxification services needed to adapt the management and delivery processes of their activities. However, these changes to usual practice came with some drawbacks. Service disruptions and unmet support needs have been recorded as a direct result of the impact of the COVID-19 pandemic , 38, 39.In some cases, the initial adaptation of policies and recommendations to the COVID-19 pandemic significantly deviated from usual care. For instance, in the UK requirements for opioid substitution therapy prescription were relaxed. Drug testing was suspended as a requirement for buprenorphine prescription and, in the case of methadone, limited to individuals without a clear history of opioid use and tolerance and known patients with evidence that opioids have been used in the previous 24\u00a0h . In-persAs the pandemic has progressed, focus has shifted from immediate management and reduction of transmission to prevention via licensed COVID-19 vaccines. A key area of concern is vaccine hesitancy, in those with mental health difficulties more generally,  and specOur work has some potential limitations. The search process was restricted to English language sources to synthesise available guidance from a list of English-speaking countries. The recommended resources in this paper are primarily limited to the UK and USA, whilst laws and policies regarding the treatment of and resources for people with SUD may differ between countries. For instance, this is indeed the case with regards to the treatment of opioid use disorder. Nonetheless, given the global nature of the COVID-19 pandemic, international collaborators have produced translations of our synthesis of guidance in several foreign languages and adapted it for local use , 13. SinSubstance and alcohol misuse services had to rapidly and profoundly change to limit disruptions for service users and, where possible, continue the treatments previously in place. At the same time, the demand for services increased. More than 8 million adults in the UK are drinking at high risk, and a surge in the number of people addicted to opiates seeking help have been recorded . Mental In the initial phase of the COVID-19 pandemic, regulatory agencies and professional bodies quickly provided guidance to address urgent issues. This rapid response was inherently based on limited evidence and resulted in several different approaches. Some sources of guidance were more conservative and limited to generic recommendations, whilst others suggested temporary amendments of pre-COVID-19 guidelines. Since then, a vast volume of scientific literature has been published on COVID-19, which present the opposite challenge of quickly synthesising available evidence. Future guidance should shift focus from acute restrictions to longer term management, such as the implementation of a comprehensive vaccination programme with equitable access and managing the mental health consequences of COVID-19. To do so, guidelines should source their recommendations from the growing body of literature by leveraging newly developed frameworks to provide up-to-date syntheses of the available evidence .Additional file 1.Additional file 2."}
+{"text": "As of early May 2021, there have been more than 4.67 million cases of coronavirus disease 2019 (COVID-19) and nearly 126,000 deaths reported in Africa.American Journal of Tropical Medicine and Hygiene.To understand COVID-19 knowledge, attitudes, and practices and their impacts on health, nutrition, and education, the Africa Research, Implementation Science, and Education (ARISE) Network conducted a telephone survey at six sites  in Burkina Faso, Ethiopia, and Nigeria between July and November 2020.,,There have been wide variations in the levels of knowledge of COVID-19 symptoms and modes of transmission among adolescents, adults, and healthcare workers. Although the level of knowledge of common symptoms and the perception of personal risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were relatively low among adolescents, prevention approaches  were commonly practiced.These surveys revealed many worrisome findings. The majority of adolescents had greatly decreased communication with family and friends, were no longer attending school because of closures, could not continue their education during the pandemic, and anticipated not being able to catch-up with what they missed after the pandemic.In addition to the adverse effects on education and food security, the survey found partial or complete interruptions in the delivery of basic maternal and child healthcare services, including pediatric immunization services, vitamin A supplementation, and access to preventive nutrition services and malnutrition treatment.Although these studies had several limitations, including differences in consent processes between countries (in-person informed consent was required in Ethiopia but not elsewhere), a lack of generalizability beyond the study communities, variations in sampling frameworks across the study locations, and the availability of completed surveys only from willing individuals with mobile telephones, there were also several strengths. Diverse samples of the general population in rural and urban areas were recruited across three countries, there was a focus on the impact on adolescent health and education, and data were disaggregated by age and sex. Additionally, mobile telephone surveys represent a potentially low-cost strategy for data collection in contrast to in-person household surveys.This three-country telephone survey revealed varying levels of knowledge of COVID-19 symptoms and how this disease is transmitted, although most adults and healthcare workers reported using effective preventive measures. However, the more concerning findings were related to the negative adverse effects of the COVID-19 pandemic on routine health services, access to education for adolescents, and food security and dietary diversity. The short-term impacts of undernutrition and impaired access to basic healthcare for children, adolescents, and adults are likely to be substantial. These problems are likely to be further exacerbated by the ongoing second wave of the pandemic, which appears to be more severe in sub-Saharan Africa. The combination of food insecurity leading to undernutrition and major challenges regarding completing education may have long-term negative effects on adolescents and younger children who may be greatly impacted by food insecurity and reduced dietary diversity in terms of their future health, nutritional status, and potential for economic development."}
+{"text": "The Omnibus Budget Reconciliation Act (OBRA) of 1987 included provisions for the Preadmission Screening and Resident Review (PASRR) program, which requires states to create and maintain systems to assess persons with serious mental illness (SMI) seeking NH care. The prevalence of SMI in NHs is increasing, and little is known about the effectiveness of the PASRR program intervention. We conducted 20 interviews with state and national PASRR stakeholders, including assessors, hospital discharge planners, mental health advocates, geriatricians and geriatric psychiatrists. Interview data were triangulated with state provided materials on PASRR collection and implementation. Based on these interviews, we identified four themes: 1) variation in the implementation of federal PASRR legislation across states and jurisdictions, 2) the need for investment in professional development and workforce capacity, 3) lack of usefulness of PASRR in ongoing care planning, and 4) the need to consider the role of age, race/ethnicity, and stigma on quality of care for NH residents with SMI. Stakeholders agree that PASRR legislation was well intentioned, but also expressed concern regarding the completion of PASRR as an issue of compliance versus meaningful assessment. More work is needed to determine how best to develop and support the care needs of people with SMI, while being mindful of the original goals of deinstitutionalization that prompted OBRA passage. In order to assess the impact of the PASRR program on quality of care and mental health outcomes, further research should take an evaluative approach through meaningful use of PASRR data."}
+{"text": "IUCrJ.Henry Chapman and Xiaodong Zou have recently been appointed as Main Editors of  IUCrJ. Henry Chapman, who was already a Co-editor of IUCrJ, will succeed the late John Spence in leading the journal section on Physics and Free Electron Laser Science and Technology. Xiaodong Zou will lead a new section on Electron Crystallography, which will act as a home within the IUCr journals for high-quality, high-impact papers in this field. We are assembling a team of Co-editors to work with Xiaodong Zou and details of this section will be provided in the next issue of IUCrJ.Henry Chapman of the Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, and Xiaodong Zou of the Department of Materials and Environmental Chemistry, Stockholm University, have recently been appointed as Main Editors of Henry Chapman is a physicist who is a world leader in exploiting modern high-brightness X-ray sources for high-resolution structure determination and imaging of soft matter or biological systems. His work in developing experimental methods and analysis for coherent diffractive imaging of non-periodic objects includes the first experimental demonstration of X-ray ptychography, as well as his pioneering work in serial femtosecond crystallography. His international status in these FELS fields also includes his association with multiple world-class high-brightness coherent X-ray source developments around the world. Henry completed his PhD in 1992 at The University of Melbourne, Australia, for which he was awarded the Bragg Gold Medal from the Australian Institute of Physics. He explored lensless X-ray imaging at Stony Brook University , and first demonstrated X-ray flash imaging while at Lawrence Livermore National Laboratory in California where he also contributed to the development of extreme ultraviolet lithography. He joined DESY and the University in Hamburg in 2007 as a founding director of the Center for Free-Electron Laser Science. He was awarded the Leibniz Prize of the German Research Foundation (DFG), the Roentgen Medal, and an honorary doctorate of Uppsala University, and is a Fellow of the Royal Society (FRS).Xiaodong Zou is a leading expert in electron crystallography and porous materials. Her research interests have been developments of electron crystallographic methods and design of novel porous materials. She is one of the pioneers in establishing electron crystallography as an important technique for accurate atomic structure determination of unknown 3D crystals. Her group has demonstrated the power of electron crystallography in studying complex structures including zeolites, metal-organic frameworks, pharmaceuticals and proteins. Professor Zou has also made key contributions in design, synthesis and applications of novel zeolites and metal-organic frameworks. Xiaodong is a full professor in structural chemistry and deputy head of the Department of Materials and Environmental Chemistry, Stockholm University. She received her BSc in Physics at Peking University in 1984, and PhD in structural chemistry at Stockholm University in 1995. One of her main research interests is method development for accurate atomic structure determination of nano-sized crystals by electron crystallography. Her group has solved a number of complex structures of zeolites and mesoporous crystals by transmission electron microscopy. She is also working on synthesis, structure determination, topology analysis and applications of inorganic open-framework materials and metal-organic frameworks. She has received several prestigious awards given by the Royal Swedish Academy of Sciences. She is an elected member of the Royal Swedish Academy of Sciences (KVA), member of the Royal Swedish Academy of Engineering Sciences (IVA), Fellow of the Royal Chemical Society (FRCS) and council member of the International Zeolite Association."}
+{"text": "Healthy ageing has become a popular topic worldwide. We investigated the role of sleep, leisure activities, and socioeconomic inequalities in relation to cognitive decline, wellbeing, and quality of life in data from the English Longitudinal Study of Ageing (ELSA), Chinese Health and Retirement Longitudinal Study (CHARLS), and Japanese Study of Aging and Retirement (JSTAR), national representative samples of England, China and Japan, respectively. We found an inverted U-shaped association between sleep quality and memory in English adults and a positive dose-response association in Chinese older adults (Brocklebank). In another examination, we found that younger English individuals playing games had lower quality-of-life than older participants who game, and this association is more pronounced for widowed individuals than others (Almeida-Meza). Cognitive impairment and dementia represent significant challenges worldwide. In a cross-country investigation, we found that the prevalence of MCI was twice as great in England compared with Japan, but that the two nations differ slightly across socioeconomic correlates (Gireesh). In another cross-country comparison between England and China, we found that the rate of memory change appeared socioeconomically patterned, primarily by education and area-based characteristics , with a more substantial impact on rural China inequalities compared to England (Cadar). Our results indicate more robust educational and geographical disparities in China and increased occupational impact among English and Japanese participants. Our findings highlight the imperative need for policy interventions and tailored strategies to protect those particularly disadvantaged in England and China."}
+{"text": "Mortality burden in South Africa since the mid-1990s has been characterized by a quadruple disease burden: HIV/AIDS and tuberculosis (TB); other communicable diseases (excluding HIV/AIDS and TB), maternal causes, perinatal conditions and nutritional deficiencies; non-communicable diseases (NCDs); and injuries. Causes from these broad groupings have persistently constituted the top 10 causes of death. However, proportions and rankings have varied over time, alongside overall mortality levels.To provide evidence on the contributions of age and cause-of-death to changes in mortality levels in a rural South African population over a quarter century (1993\u20132018).Using mortality and cause-of-death data from the Agincourt Health and Socio-Demographic Surveillance System (HDSS), we derive estimates of the distribution of deaths by cause, and hazards of death by age, sex, and time period, 1993\u20132018. We derive estimates of life expectancies at birth and years of life expectancy gained at age 15 if most common causes of death were deleted. We compare mortality indicators and cause-of-death trends from the Agincourt HDSS with South African national indicators generated from publicly available datasets.Mortality and cause-of-death transition reveals that overall mortality levels have returned to pre-HIV epidemic levels. In recent years, the concentration of mortality has shifted towards older ages, and the mortality burden from cardiovascular diseases and other chronic NCDs are more prominent as people living with HIV/AIDS access ART and live longer. Changes in life expectancy at birth, distribution of deaths by age, and major cause-of-death categories in the Agincourt population follow a similar pattern to the South African population.The Agincourt HDSS provides critical information about general mortality, cause-of-death, and age patterns in rural South Africa. Realigning and strengthening the South African public health and healthcare systems is needed to concurrently cater for the prevention, control, and treatment of multiple disease conditions. Ongoing characterization of mortality and disease patterns is required in different settings in order to set locally relevant health and development priorities, identify critical elements for strengthening of health systems, and determine the focus of health services and programmes. During the first half of the twentieth century, populations in high-income countries moved from periods of high, fluctuating mortality rates dominated by epidemics of infectious diseases, famines, and wars to periods of progressive reductions in mortality rates and the emergence of degenerative diseases as the major causes of morbidity and death . They suIn South Africa, overall mortality levels were declining, and life expectancy was steadily improving from the 1960s until the early 1990s . From thThe dramatic increases in overall mortality and reductions in life expectancy from the mid-1990s to the mid-2000s were driven mostly by increases in mortality caused by the HIV/AIDS epidemic and lack of treatment programmes ,23\u201325. AWe used mortality and cause of death data collected from 1993 to 2018 as part of annual updates of vital events of the population of the Agincourt Health and Socio-Demographic Surveillance System (HDSS) in rural northeast South Africa ,28. SimiThe most probable cause-of-death was generated using the InterVA-5 probabilistic model (version 5.1) . For eacUsing the person-year file, we estimated the hazards of death by age, sex and time-period using logistic regression models . ThereafWe split the calendar years into the following time periods: 1993\u20131997, 1998\u20132000, 2001\u20132003, 2004\u20132007, 2008\u20132010, 2011\u20132013, 2014\u20132016 and 2017\u20132018 to contextualize the dynamics of the HIV epidemic and the rollout of prevention of mother-to-child transmission (PMTCT) and antiretroviral treatment (ART) services. Where possible, we compared the indicators of mortality and cause-of-death trends from Agincourt with South African national indicators generated from publicly available datasets as a way of assessing the generalizability of our findings. We compared estimates of life expectancy at birth from the Agincourt HDSS with estimates of life expectancy at birth for South Africa obtained from the World Bank data archive . We alsoAll analyses have been conducted using Stata version 14.1 .A total of 17 934  deaths were recorded in 2 210 631  person-years of follow-up in the Agincourt HDSS surveillance population over the period 1993\u20132018. Panel (a) of Trends in mortality levels in children under the age of 5 years show progressive increases between 1993\u20131997 and 2001\u20132003 and decreases thereafter (Panel (b) of Trends in life expectancy at birth exhibit a similar pattern to trends in overall mortality for both males and females (Panel (d) of Panel (d) of Owing to the significant contribution of HIV/AIDS and TB to the mortality profiles of the Agincourt HDSS population in the last two and a half decades, Building on the finding that cardiovascular diseases have progressively gained prominence among the leading causes of death, A clear understanding of the levels and patterns of mortality and diseases in different sub-populations is continuously needed in order to formulate and implement locally relevant policies and programs to improve population health. However, effective responses to this need for populations in the most resource-poor settings are hampered by a lack of comprehensive, reliable, population-based data on health risks, exposures, and outcomes. One of the viable alternatives to addressing this lack of data has been the establishment of HDSSs in some resource-poor settings. HDSSs enumerate populations in geographically well-defined areas and prospectively collect detailed information on the core components of population change  as well as complementary information on health, social and economic indicators . In thisUnlike prior research ,30,54,55While there have been impressive reductions in mortality levels in Agincourt since 2007, the COVID-19 pandemic that has been underway in South Africa since March 2020 may well induce some reversal through both direct and indirect mortality, the latter resulting from reduced provision and utilization of health service for NCDs, HIV/AIDS, TB, antenatal care and vaccine-preventable diseases in children under 5\u00a0years . The extA previous study showed broad similarity in major cause of death categories despite low agreement of cause attribution at the individual level between the causes of death in the South African national data that are determined from death notification forms (Form BI-1663) completed by clinicians or death reports (Form BI-1680) completed by authorised traditional leaders when clinicians are not available, and causes of death in the Agincourt HDSS population determined from verbal autopsies using the InterVA model . The strThis study has a number of limitations. First, the sensitivity of our findings to different computer-based models for assigning causes of death other than the InterVA model, such as Tariff  and InSi61Our findings show that the population in Agincourt, a rural area of South Africa adjacent to southern Mozambique, has experienced significant shifts in mortality levels and the associated contributions of age and various causes of death over a quarter century of tremendous health, population and social change. The findings also illustrate that the general mortality and cause of death transition experienced in the Agincourt area largely reflects the mortality, age, and cause of death transition experienced in South Africa, although the magnitudes may differ from one setting to the other. Most importantly, the mortality and cause-of-death transition presented in this paper highlights the increased importance of CVD and other chronic NCDs as leading causes of death in recent years as more people living with HIV/AIDS access ART and attain prolonged survival. Therefore, there is a need for realigning and strengthening of the public health and healthcare systems in South Africa to concurrently cater for the prevention, control, and treatment of multiple disease conditions."}
+{"text": "The aim of the present study was to provide an overview of gingival crevicular fluid (GCF) bone turnover markers (BTMs) concerning the physiology of orthodontic tooth movement (OTM) and assess their potential contributions to regulating bone remodeling, that could prove useful in designing future approaches to modulating orthodontic tooth movement.Multiple electronic databases  were searched up to October 1st, 2020. Randomized controlled trials (RCTs), controlled clinical trials, observational studies of prospective and retrospective designs, and cross-sectional studies reporting on levels of BTMs in GCF were eligible for inclusion. The quality of the included RCTs was assessed per the revised Cochrane risk of bias tool for randomized trials (RoB 2.0), whereas the risk of bias of the included cohort studies was assessed using the Risk Of Bias In Non-randomized Studies of Interventions tool.Five RCTs, 9 prospective cohort studies, and 1 cross-sectional study fulfilled the inclusion criteria. The risk of bias was deemed as high for the RCTs and 4 of the prospective studies and moderate for the rest of the studies. The following biomarkers for bone formation were assessed: bone alcaline phosphatase (BALP), alcaline phosphatase (ALP), and osteocalcin (OC). For bone resorption, the following BTMs were assessed: deoxypyridinoline (DPD) and pyridinoline (PYD), N-terminal telopeptide (NTX), osteopontin (OPN), and tartrate-resistant acid phosphatase (TRAP). The follow-up period ranged mainly from baseline to 45 days, although one study had an expanded follow-up period of up to 16 months. The results of the included studies comparing different BTMs were heterogeneous and qualitatively reported.Current evidence continues to support the potential for BTMs to provide clinically useful information particularly for adjusting or standardizing the orthodontic stimulus. The present systematic review has retrieved studies of high, overall, risk of bias, and has unveiled a substantial clinical and methodological heterogeneity among included studies. Further data of the relationships between the clinical assays and the physiological or pre-analytical factors contributing to variability in BTMs\u2019 concentrations are required.CRD42020212056.The online version contains supplementary material available at 10.1186/s13643-021-01860-w. Orthodontic tooth movement (OTM), as a biological process, encompasses a series of histological and biochemical reactions ; these lA reflection of these phenomena can be found in the gingival crevicular fluid (GCF) of moving teeth, with significant elevations in the concentrations of its components. The noninvasive nature and the convenience of repetitive sampling of GCF are considered of great importance for identifying the periodontal changes followed by orthodontic force application .There are three main methods of collecting GCF: (a) the gingival washing technique, which consists of perfusing the GCF with an isotonic solution of fixed volume; the fluid collected represents a dilution of crevicular fluid, containing cells and soluble constituents, as plasma proteins; (b) insertion of capillary tubes, with specific diameter, into the entrance of the gingival crevice; the fluid then migrates into the tube by capillary action. (c) The most common method, however, of collecting GCF is with the use of absorbent sterilized paper strips. The paper strips are inserted into the gingival crevice and left in situ for 5 to 60 s to allow the GCF to be adsorbed by the paper .Several substances can be collected from GCF and are considered biomarkers. The term \u2018biomarker\u2019 depicts a substance that is measured and evaluated objectively as an indicator of normal biological processes, pathological processes, or pharmacological responses to a therapeutic intervention .Numerous protein or protein derivative biomarkers are released during bone remodeling by osteoblasts or osteoclasts and are generally described under the term of bone turnover markers (BTMs) . BTMs laBTMs have been studied for over 30 years, and they are separated into two groups: markers of bone formation , osteocalcin (OC), and bone alkaline phosphatase (BALP)) and markers of bone resorption  and N-terminal telopeptide of type I collagen (NTX)) . HoweverIn orthodontics, biomarkers related to bone turnover may introduce new possibilities for understanding bone growth and remodeling. Knowledge of the ongoing process occurring in periodontal tissues during orthodontic and orthopaedic therapies can lead to proper choice of mechanical loading with the aim of shortening the period of treatment and avoiding adverse effects associated with orthodontic treatment .The aim of the present study was to provide insights into possible GCF BTMs concerning the physiology of orthodontic tooth movement and assess their potential contributions to regulating orthodontic processes that could prove useful in designing future approaches to modulating orthodontic tooth movement.The latest (2021) Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) were adopted throughout the process of the present systematic review , 10.Participants (Population):orthodontic patients of any age and sex.Intervention: any type of removable or fixed orthodontic appliance resulting in OTM.Comparisons: any control group was accepted ).Outcomes: quantitative and qualitative analyses of bone remodeling biomarkers detected in GCF; measurement units were nanograms per microlitre (ng/\u03bcl), international units per microlitre (IU/\u03bcl), units per milligram (U/mg), picograms per millilitre (pg/ml), and milliunits per sample (mU/sample). Receptor activators or mediators not considered as exclusive bone remodeling biomarkers were excluded. Follow-up: All observation periods were accepted.Study design: Any study design was considered eligible for inclusion in this review, including randomized clinical trials (RCTs), non-randomized or quasi-randomized controlled trials, and prospective and retrospective studies.Exclusion criteria: animal and in-vitro studies, case reports or studies reporting less than 5 patients, studies including patients with systemic disorders affecting periodontal and orthodontic therapy, preclinical studies/ abstracts/ letters to editors/ narrative reviews, insufficient/unclear information not allowing data extraction, and no author response to inquiry email for data clarification.Detailed search strategies were developed and appropriately revised for each database, considering the differences in controlled vocabulary and syntax rules by the last author (DK). No language or publication date restrictions were applied.The Cochrane Central Register of Controlled Trials (CENTRAL) ;MEDLINE (PubMed) ;Ovid MEDLINE ;Ovid Embase ;LILACS On October 1st, 2020, we updated and searched the following electronic databases to find reports of relevant published studies:The search strategy of all databases is shown in Additional files http://www.clinicaltrials.gov), the multidisciplinary European database (http://www.opengrey.eu), the National Research Register, and Pro-Quest Dissertation Abstracts and Thesis databases (https://about.proquest.com).In order to further identify potential articles for inclusion, grey literature was searched in the register of clinical studies hosted by the US National Institutes of Health , who were not blinded to the identity of the authors of the studies, their institutions, or the results of their research. Study selection procedure comprised of title-reading, abstract-reading, and full-text\u2013reading stages. After exclusion of non-eligible studies, the full report of publications considered by either author as eligible for inclusion was obtained and assessed independently. Disagreements were resolved by discussion and consultation with the third author of the review (IS). A record of all decisions on study identification was kept.The first two authors (LK and IG) performed data extraction independently and in duplicate. Disagreements were resolved by discussion with the last author (DK). Specifically designed Excel collection forms were used to record the desired information. Data extraction was piloted in five random included papers between the two first authors. The following data were collected: author/title/year of study, design of study, number/age/gender of patients recruited, type of orthodontic treatment, method of GCF collection, tooth site of GCF collection, control group, observation period (follow-up of patients), changes of biomarkers in GCF, biological consequence, and clinical significance.If stated, the sources of funding, trial registration, and publishing of the trial\u2019s protocol was recorded. This information was used to aid assessment of heterogeneity and the external validity of the included studies. In case of missing data, it was attempted to contact the corresponding author. Studies without enough data for meta-analyses were kept in the systematic review, but excluded from the meta-analyses.The methodological quality of all included studies was assessed by the first two review authors (LK and IG) independently and in duplicate. For interventional, randomized controlled trials (RCTs), the Risk of Bias 2.0 tool was used . For intMeta-analyses would have been conducted if included studies reported similar interventions and comparable outcomes in homogeneous population (i.e. in the case of limited heterogeneity). For continuous variables, mean differences and standard deviations would be used to summarize the data from each study. For dichotomous data, number of participants with events and total number of participants in experimental and control groups would be analyzed. Regarding meta-analysis for dichotomous data, risk ratios and their 95% confidence intervals (Cls) would be calculated. For continuous data, mean differences and 95% Cls would be calculated.2 test and the I2 statistic.Clinical and methodological heterogeneity were assessed by examining the characteristics of the studies, the similarity between the types of participants, the interventions, and the outcomes as specified in the inclusion criteria for considering studies for this review. Statistical heterogeneity would have been assessed using a ChiReporting biases arise when the reporting of research findings is affected by the nature or direction of the findings themselves . PotentiAs no sufficient data existed, subgroup analyses based on study characteristics or sensitivity analysis based on the risk of bias were not conducted.We anticipated that some of the included studies presented data from repeated observations on participants, which could lead to unit-of-analysis errors. In such cases, we followed the advice provided in section 9.3.4 of the Cochrane Handbook for Systematic Reviews of Interventions : we woulIn total, 1051 studies were identified from the electronic searches as relevant. After exclusion of all duplicates and assessment of the title and abstract of the reports, 64 studies were considered eligible for inclusion in this review. Out of the 64 studies, another 49 studies were excluded after full-text assessment, leaving 15 studies fulfilling the inclusion criteria , according to the Newcastle-Ottawa Quality assessment scale  , alcaline phosphatase (ALP), and osteocalcin (OC).The following biomarkers for bone resorption were assessed: deoxypyridinoline (DPD) and pyridinoline (PYD), N-terminal telopeptide (NTX), osteopontin (OPN), and tartrate-resistant acid phosphatase (TRAP). The follow-up period ranged mainly from baseline to 45 days. One study had an expanded follow-up period of up to 16 months   and alcaline phosphatase (ALP)\u0392ALP was examined in one study . AlthougOsteocalcin (OC)OC was assessed in 4 out of 55 studies , 26, 29.Deoxypyridinoline (DPD) and pyridinoline (PYD)DPD was evaluated in two studies , 29. AccN-terminal telopeptide (NTX)NTX was investigated in 2 out of 5 studies , 26. AlfHowever, in the Isik et al. study, NTX values were found to be below the detection limit with a few readings which showed large variations between subjects and stages of tooth movement .Osteopontin (OPN)OPN was investigated in 4 studies , 21, 22.Tartrate-resistant acid phosphatase (TRAP)TRAP was detected only in one study . In the The aim of the present systematic review was to provide an updated summary of the available evidence regarding the collection of biomarkers in GCF, so as to guide and facilitate future research projects. The included studies demonstrated high heterogeneity, regarding methodological, clinical, and statistical issues. Clinical heterogeneity among studies included considerable variations in participants  as well as in interventions , whereas the diversity in the measurement units of the biomarkers indicated considerable methodological heterogeneity. The aforementioned forms of heterogeneity precluded the possibility for a valid meta-analysis.The inclusion criteria for most of the studies were good general health, no history of antibiotic therapy during the previous months or anti-inflammatory drug use within 1 month before GCF collection in periodontally healthy nonsmokers. One week to 1 month prior to GCF collection, the participants underwent a session of professional supra- and sub-gingival scaling and also received repeated oral hygiene instructions , 27.Most studies evaluated the biomarkers in GCF samples before, during, and after canine distalization in cases of first premolar extractions , 27, 29 Isolation of the sites of GCF collection (most often with cotton rolls),Method of GCF collection ,Depth insertion of paper strips,One single or repeated measurements,Time that paper strips remain inside the gingival sulcus (e.g. 30 or 60 s),Time slot of the day for the collection,Incubation solution which was used for the GCF sample ,Biochemical assay used for the analysis of biomarkers .There was no agreement between the studies regarding GCF sample collection and management. Several differences were identified during the following stages:The fluctuation of the levels of biomarkers in GCF is suggestive of underlying intricate biological remodeling processes in bone and periodontal tissues related to OTM . MechaniThe increase of these pro-inflammatory cytokines results in chronic leukocyte recruitment and tissue destruction and seems to play a crucial role in periodontal remodeling during tooth movement, preventing pathological destruction of the bone and PDL . The amoIn the past two decades, there has been significant interest in the development of noninvasive oral and systemic diagnostic biomarkers by large-scale protein analysis. Whole saliva, parotid secretions, and GCF samples have been collected for diagnostic biomarker discovery. The notion to use GCF as a source of diagnostic biomarker is not uncommon; however, the possibility of using a panel of independent disease-related proteins has recently emerged. In this respect, the ability to highlight a large number of proteins with local tissue/cell specificity and to define their relative levels in health versus disease have become of major interest.The use of BTMs for the monitoring of treatment requires a baseline assessment with a repeat measurement at some defined point during orthodontic treatment. In order to do this effectively, it is important to assess the expected level of alteration. Thus, it is important to monitor treatment effect in the individual, the imprecision of the measurement, as well as the intra-individual variability which may be influenced by factors such as timetable of sampling, fasting status, adherence to instructions, etc..Some limitations do exist in the present review. Ideally, only randomized trials with control groups would be included in this review. However, due to the scarcity of available studies in the field, non-randomized designs were also considered for eligibility. Inter-rater reliability during data extraction was not tested; nevertheless, this has probably low impact as consensus was reached with the last author, when needed. The lack of blinding and generally the methodological heterogeneity in the included studies may have also introduced uncertainty in the results. However, the main strength of this review is that it gathers information about GCF collection and BTM values so that the future studies can be conducted under standardized conditions, with the sole purpose of using BTM in regulating orthodontic tooth movement.The diversity in expressing the released quantities and the use of different units hindered this review. To allow unequivocal interpretation and comparison between different studies, it is recommended to express quantitative release data in standardized units. The use of internationally agreed decision limits and target values for these markers requires that measurements are universally comparable. Standardization and establishment of a reference system for the BTMs is the route to achieve this , 37.The limits for detection/quantification of each analyzed eluate are essential for the interpretation of the results, and should therefore always be mentioned. Compounds that could not be detected, may still have been released, but in concentrations below the detection limit. It would thus not be correct to assume that they are not released in the GCF.Contamination may lead to false-positive detection of compounds, and great care should be taken to avoid any contamination. All studies should report if the necessary measures were taken in order for contamination from saliva to be avoided.In summary, the available studies relating BTM changes after an orthodontic stimulus are promising. Based on the results of this literature review, several guidelines for standardization may be suggested:Too often, the materials and methods failed to mention necessary information about the GCF collection procedure. Information such as the volume of incubation solution, the percentage of solvent in case of dilutions, the pH of the solution, and the brand of paper strips should be always stated.As BTMs may show significant responses to the orthodontic treatment, their response to treatment may allow the best choice of a possible future chemical or pharmacological agent. They may also help with the proof of principle and help establish the mechanism of action. This could potentially alter the actual orthodontic treatment modalities.Current evidence continues to support the potential for BTMs to provide clinically useful information particularly for adjusting or standardizing the orthodontic stimulus, and in the future for modulating the orthodontic tooth movement. The present systematic review has retrieved studies of high, overall, risk of bias, and has unveiled a substantial clinical and methodological heterogeneity among included studies. Further data of the relationships between the clinical assays and the physiological or pre-analytical factors contributing to variability in BTMs\u2019 concentrations are required.The review protocol was specified in advance and registered at PROSPERO , No. CRD42020212056.Additional file 1. PRISMA 2020 for Abstracts Checklist.Additional file 2. PRISMA 2020 Checklist.Additional file 3 Search strategy, MEDLINE/PubMed, assessed as up to date: 01.09.2020.Additional file 4. LILACS, Cochrane Library, MEDLINE, and Embase search strategies.Additional file 5. List of excluded studies."}
+{"text": "A growing body of evidence suggests that nucleus accumbens (NAc) plays a significant role not only in the physiological processes associated with reward and satisfaction but also in many diseases of the central nervous system. Summary of the current state of knowledge on the morphological and functional basis of such a diverse function of this structure may be a good starting point for further basic and clinical research. The NAc is a part of the brain reward system (BRS) characterized by multilevel organization, extensive connections, and several neurotransmitter systems. The unique role of NAc in the BRS is a result of: (1) hierarchical connections with the other brain areas, (2) a well-developed morphological and functional plasticity regulating short- and long-term synaptic potentiation and signalling pathways, (3) cooperation among several neurotransmitter systems, and (4) a supportive role of neuroglia involved in both physiological and pathological processes. Understanding the complex function of NAc is possible by combining the results of morphological studies with molecular, genetic, and behavioral data. In this review, we present the current views on the NAc function in physiological conditions, emphasizing the role of its connections, neuroplasticity processes, and neurotransmitter systems. A group of morphologically and functionally related brain structures receiving and interpreting stimuli associated with satisfaction, positive feeling, and addiction is commonly defined as the brain reward system (BRS). This system consists of subcortical mesolimbic structures, such as the nucleus accumbens (NAc), ventral tegmental area (VTA), amygdala (Amg), striatum (Str), and septum (Spt). It also includes several meso-corticolimbic regions, such as the hippocampus (Hip), prefrontal cortex (PFC), para-hippocampal, entorhinal, and motor function-related cortical areas . NAc is NAc contains predominantly small and medium-sized spiny neurons (MSNs) ,8. AmongEach part of NAc, namely shell and core, has different molecular characteristics considering the type of released neurotransmitters and their receptors. Levels of neurotransmitters, such as dopamine (DA), serotonin (5-HT), and norepinephrine (NE) are different in the two parts of NAc ,13. WhilIn humans, the concentration of NE is different in various portions of NAc. Tong et al. reported three-fold higher concentration of this neurotransmitter in the caudomedial portion than in its caudolateral part, and 12-fold higher in the caudal fragment compared to the rostral . DA leveApart from the internal functional specialization within NAc, high concentrations of NE and DA in the same area may suggest an interrelationship between both neurotransmitter systems and their reciprocal modulatory function upon controlled processes. On the other hand, the 5-HT content is higher in the shell compared to the core, although its utilization is greater in the latter . High leThe degree of morphological differentiation of neurons in NAc, their molecular characteristics, as well as the development of their spino-dendritic system determine the optimal adaptation of this brain structure to the integrative function which it plays within the BRS.A functionally important feature of NAc is its extensive system of connections with numerous brain areas. These can be divided into structural levels of cortical, hemispheric subcortical, diencephalic, and brain stem areas b. This hSignificant differences in the topography of connections between the two parts of NAc can be explained by their functional diversity  2,3,4].,3,4.2,3,The target areas of projections originating from the shell are limbic structures, such as extended Amg (Amgex), Spt, basal forebrain (BF), ventral pallidum (VP), and diencephalic areas involved in the regulation of vegetative and limbic functions, such as lateral preoptic area (LPa), lateral hypothalamus (LHTh), and lateral habenular nucleus (LHn) ,3,4. TheThe NAc core is a source of efferent projections targeting areas of the basal ganglia related to the limbic and motor systems, e.g., VP, external and internal parts of globus pallidus . Neurons located in the core also project to pars reticulata of substantia nigra (SNpr) ,6,30.Altogether, both parts of NAc have extensive ascending and descending connections which allow this nucleus activity to be coordinated with several cortical areas related to the association, limbic and projection functions  27]. Th. Th27]. The role of NAc as an important integrating center in the elaboration of behavioral reactions of the limbic, motor and vegetative systems is possible due to projection pathways using several neurotransmitters, of which DA, Glu and GABA could be considered as of primary importance, although serotoninergic and noradrenergic projections also contribute to the specific NAc functions.Numerous studies indicate a crucial role of receptors representing all the main neurotransmitter systems in physiological and pathological processes in NAc ,42,43,44The sources of dopaminergic projections that reach the NAc shell and core are VTA and SN, two mesencephalic structures involved in functioning of the limbic and motor systems, respectively ,46,47. WThe DA released in NAc affects many physiological processes. The level of this neurotransmitter increases in this brain area with the reward approaching, which reflects the awaiting state for its achievement. DA in NAc has also a positive effect on motivation for reward-achievement behaviors and reward-driven learning. Finally, it enhances learning of prediction errors, important in planning new adaptive behaviors . RegulatThe modifying effect of DA on synaptic plasticity is based on changes in receptors\u2019 activation and on the stimulating or inhibiting character of their response, changing the probability of neurotransmitter release and cell excitability, as well as on triggering synaptic potentiation or depression . LocatedOne of the most important functions of DA in NAc is its modulatory effect on the processes of short- and long-term homeostatic synaptic plasticity ,60. HoweApart from the essential physiological functions, the dopaminergic system plays fundamental role in development of addiction  which isGlutamatergic projections terminating in NAc originate from Hip, Sub, Amg, thalamus (Th), VTA, and from the mPFC and prelimbic cortical areas ,72,73,74Action of Glu on NAc is associated mainly with the development of LTP ,80. HoweActivation of different types of glutamatergic receptors in NAc induces the development of dendritic spines in the MSNs. During maturation, they go through the stage of \u201csilent\u201d synapses with NMDARs, but not AMPARs . Later oAs mentioned before, the mechanism of drug addiction is associated with the modification of iGluRs , which is based on changes in their number and function . First-tAltogether, the role of glutamatergic projection in the functioning of NAc involves various types of receptors, although the contribution of AMPARs and NMDARs is probably the most significant. Changes in the expression of these receptors correlate with morphological modifications of the spino-dendritic system, contributing to the development of synaptic plasticity and playing an important role in the processes of both short- and long-term synaptic potentiation.The main target of GABA-ergic projection from NAc is pallidum (predominantly VP) ,32,98. OThe role of GABA-ergic projection and relevant receptors, necessary for the functioning of NAc and the whole BRS, have been raised in several excellent publications ,42. AmonSome evidence suggests the presence of functionally diverse GABA pools in the axonal endings of neurons in NAc . Newly sThe GABA-ergic receptors play an important role in controlling Glu release in NAc . The parGABARs also play a significant role in the regulation of mechanisms related to the consequences of alcohol consumption. The reinforcing effect of ethanol in the NAc\u2019s shell can be modulated by activation of GABAARs and GABABRs, together with 5-HT3 receptors . InteresFurthermore, GABARs play a crucial role in the regulation of addiction processes induced by psychostimulant drugs. For example, activation of GABAARs, but not GABABRs, modulates the reinforcing effects of morphine in NAc . The GABAdditionally, the GABA-ergic system in NAc is involved in alleviating the effects of stress and emotions. Activation of the GABABRs in NAc ameliorates spatial memory impairment after stress exposition , and exeIn summary, GABA-ergic receptors in NAc have important regulatory functions associated with direct inhibition of other cell populations and controlling the release of several neurotransmitters. Regulation of NAc activity via GABA-ergic receptors enables precise control of processes occurring in the BRS.Large projections originating from the small population of neurons concentrated in the raphe nuclei complex  deliver 5-HT to the BRS. This monoamine neurotransmitter is involved essentially in all physiological processes controlled by NAc. The 5-HT function in this brain area depends on the dynamic balance between other neurotransmitters\u2019 systems and concentrations of the relevant neurotransmitters. One of the important functions of 5-HT in NAc is its role in motivation. This function is closely related to the facilitating activity of DA. Impairment of interactions between the serotoninergic and dopaminergic systems may result in anhedonia, lack of motivation, and finally in depression . InteresAnother important function of 5-HT in NAc is the regulation of prosocial interactions and behaviors, which is closely related to the rewarding effect of such interactions . AdditioThe role of 5-HT in NAc is also associated with the reinforcing effect of ethanol. This effect is further enhanced by DA release, which leads to an increased reward experience and impulsivity. In combination with some drugs, such as mephedrone, 5-HT and DA can increase the susceptibility to alcohol abuse, due to their increased release in NAc and mPFC . The incThe serotonergic system has a complex influence on NAc. This is due to the large number of receptors, their distribution on many types of cells, and to the use of several neurotransmitters. Among different types of receptors, at least two representing the 5-HT2R group  play an important role in control of addiction mechanisms. Taking into account the fact that development of addiction is associated with an increase in DA released in the NAc, it has been suggested that the role of these receptors is based on a regulation of the DA concentration . They caApart from the aforementioned agonists and antagonists of the serotonergic receptors, other drugs such as partial agonists of serotonergic receptors, inhibitors of the 5-HT transporters and multiple neurotransmitter uptake inhibitors also act on the serotonergic system ,145. TheIn addition to all the above-mentioned functions, 5-HT also plays a regulatory role in the metabolic processes in NAc, leading to an increase in glucose blood levels . StudiesAlthough stimulation of different types of 5-HT receptors in NAc can enhance the effect of some addictive substances such as alcohol, stimulation of other types of receptor in this brain area leads, paradoxically, to a lower likelihood of addiction in response to the other psychostimulants ,126. TheNE, as one of the most important brain neurotransmitters, is also represented in the BRS. Its sources are neurons localized in TegB, mostly in LC. Extensive projections of this relatively small population of neurons allow the distribution of NE to almost all brain regions. Under stressful and rewarding stimuli, NE is released in NAc and mPFC . The amoAnother study has shown that cocaine administration enhances the release of NE, DA, and 5-HT in NAc . The dynIn addition to the abovementioned functions, increasing evidence points to NE involvement in the mechanism of alcohol addiction. Karkhanis et al. reported that chronic early-life stress resulting from social isolation has an impact on the behavioral risk of alcoholism manifested by a greater tendency to alcohol self-administration . This coAltogether, NE via its action in NAc, as well as in other BRS structures, regulates a wide spectrum of physiological processes and plays a role in the development of addiction. Moreover, cooperation with other neurotransmitters, such as DA or 5-HT, determines the NE action upon NAc and its regulatory role in these processes.NE plays a role in several processes, such as concentration of attention, wakefulness, drug addiction, and psychostimulants relapse. Action of this neurotransmitter within NAc is based mainly on its interaction with the \u03b11-adrenergic receptor (\u03b11AR) . A rare In summary, the release of neurotransmitters in NAc is precisely adjusted to the cause of activation, the goal to be achieved, and the origin of the activated projection. The action of a neurotransmitter depends on its concentration in NAc and its binding to specific receptors. The important role of neurotransmitter receptors the NAc functioning is related to changes in their expression level, subunit composition, and externalization or displacement within the plasma membrane or outside the synapses. The cooperative effect and synergistic action of receptors representing different neurotransmitter systems are critical for motivation, learning, and addiction.The proper functioning of the BRS requires cooperation among all morphological elements of brain tissue. Structural and functional relationships occurring between neuroglia and neurons form the basis not only for processes of motivation and reward-aimed behaviors, but also for the development of addiction and mental diseases . As can 2+ ion-dependent signaling pathways [Astrocytes are an important element of the brain tissue involved, together with neurons, in the regulation of reward and addiction mechanisms . An impopathways ,162. As pathways . Finallyad libitum. On the other hand, an increase in the dendritic spine density correlates with compulsive seeking behavior [Interesting data about the role of microglia in NAc come from animal studies. Microglia activation has been reported in mice fed with a high-caloric chocolate cafeteria diet . Apart fbehavior . In casebehavior . This reOligodendrocytes, like other neuroglial cell subpopulations, play an important role in the BRS, both in physiological conditions and pathology. Their role in myelin metabolism is important for the functioning of the brain tissue. Through controlling myelin metabolism, oligodendrocytes can influence the plasticity processes related to transmission efficiency of excitatory stimuli along the neuronal fibers. Consequently, myelin metabolism seems to be a good indicator of the BRS status during stress or anxiety. Down-regulation of myelin genes and oligodendrocyte-specific genes in NAc and PFC was recorded after four weeks of stress exposure in mice . SimilarAnother important issue represents myelination disorders and changes in myelin synthesis, resulting in impairment of the brain function observed in the course of some mental illnesses. The major depressive disorder (MDD) is associated with changes in the myelin content in several brain regions, but in particular in structures of the limbic system, including NAc . FurtherResults of a postmortem study showed myelination impairment in several brain areas, including NAc, after chronic cocaine abuse . DysreguTo conclude, neuroglia participates in a wide spectrum of processes occurring in NAc and other areas of the BRS. Its role includes modulation of synaptic transmission and signaling pathways within tripartite synapses, as well as regulation of energetic metabolism by astrocytes. It also takes part in the regulation of the BRS activity, through the release of inflammatory mediators by activated microglia. Finally, these cell populations regulate myelin metabolism, expression of oligodendrocyte-specific proteins and, consequently, the efficiency of stimuli conduction along the neuronal fibers. The modifying effect of neuroglia upon the BRS activity (including NAc) involves both physiological processes and a wide spectrum of pathologies associated with addiction, neurodegeneration, and mental illnesses. Further studies on the role of neuroglia in these processes are needed.In the 1980s, Mogenson and colleagues formulated a hypothesis that NAc functions as an interface between the limbic and motor systems . More reDifferences in functioning of the two parts of NAc have previously been reported ,186,187.The core of NAc is involved in responses to motivational stimuli , impulsiLike other brain regions, NAc undergoes characteristic morphological and functional changes during ontogenesis. At the subsequent stages of development, changes in the cellular structure, formation of connections with other brain areas, along with development of neurotransmitter systems and signaling pathways, as well as development of structural and functional plasticity, occur ,201. NumThe action of the above-mentioned factors at different stages of ontogenesis results in development of behavioral disorders and mental dysfunctions either during adolescence or in adulthood. This could be a consequence of an impairment in functioning of the endocrine system , disturbances in the functioning of neurotransmitter systems , as well as changes in the expression of neurotrophic factors  and transcription factors  ,207,208.During early development, due to an incomplete development of endocrine regulatory mechanisms, stress hormones (glucocorticoids) may be harmful to immature NAc, and induce abnormal behavioral responses ,210. DefAdolescence is the period in NAc development characterized by the final formation of connections, shaping balanced functional relations between neurotransmitter systems, as well as stabilization in the production level of neurotrophic factors and balanced gene expression. In addition, the development of hormonal maturity related to the HPA axis, both in terms of controlling stress reactions and achieved sexual maturity, is important for the functioning of the reward system during that period. Despite these changes, during adolescence there is a greater susceptibility to stressful and aversive stimuli than in adulthood . This caThe susceptibility of NAc to the harmful effects of addictive substances during development can be illustrated by the effects exerted by nicotine. Exposure to this commonly consumed psychostimulant has been linked to NAc impairment. The most important research includes the effects of early exposure to nicotine and its long-term consequences, the effects of nicotine withdrawal during development and adolescence, and mechanisms shaping the reward feeling triggered by nicotine during development. It has been shown that exposure to nicotine already in the fetal period affects the expression of genes of growth factors, death receptors, and some kinases related to the regulation of cell death or survival in adolescence . MaternaNicotine withdrawal has different effects on the functioning of NAc in adolescence as compared to adulthood. Studies have shown that discontinuation of nicotine in juveniles causes less side effects than in adults . This maThere are premises indicating involvement of different mechanisms triggering the reward and satisfaction feelings at various ages . These cAdolescence is a period of development associated with intensive learning, gaining various types of experience, as well as developing a responsiveness to stressful stimuli resulting from action of environmental factors and social interactions . All of Chronic juvenile (pre- and adolescent) stress of different nature has a significant impact on development of many brain areas, including NAc and the prefrontal cortex, important for shaping of the reward processing and the executive functions. Disturbances in the functioning of these areas resulting from impact of stressful stimuli on the immature structures may manifest in psychopathological symptoms during development and in adulthood, and sometimes may lead to the development of mental illnesses .Some evidence indicates that early-life adversity experiences like poverty, chaotic environment, maternal separation or poor parental care may significantly contribute to dysfunction of the BRS . They maThe plasticity processes occurring during adolescence in the shell and core of NAc not only have different dynamics but also reveal a different involvement in rewarding and aversion effects, thus emphasizing the functional differentiation of both parts of this nucleus . Some auOverall, the presented data indicate the complex character of the NAc function in the rewarding or aversive responses. This implicates the existence of different regulatory mechanisms depending on the situational context of the shaped reaction, which are disturbed in the course of such pathological processes as addiction, stress, depression or mental disorders.The importance of dendritic spines in the NAc neurons results not only from their involvement in synaptic transmission and plasticity, shaping motivational behavior and reward feeling, but also from their role in the development of addiction. Morphology of dendritic spines in NAc, predominantly bearing excitatory synapses, is determined by processes that occur both in the prenatal and postnatal period . The devDrugs of abuse, such as cocaine, change the number and structure of dendritic spines in NAc ,44,246. In summary, both external and internal stimuli can initiate morphological changes in dendritic spines in NAc and other regions of the BRS. The importance of dendritic spine modifications results from their involvement in the synaptic transmission and neuroplasticity processes. These modifications are accompanied by activation of signaling pathways contributing to an increase in efficiency of synaptic transmission, which enables specific behavioral reactions. The modifications occur not only in physiological processes, but also in pathological processes, such as addiction, mental, and neurodegenerative diseases.Growing evidence shows the relationship between stress, taken psychostimulants, and some mental disorders and changes in the synapto-dendritic system of the reward-involved brain structures ,44,89,95Some addictive substances can also induce molecular changes in the BRS. Cocaine and morphine induce a decrease in content of Homer1 protein and postsynaptic density of protein 95 (PSD95) in the BRS ,262. TheA recent study found a correlation between drug addiction and dysregulation of the circadian rhythm of sleep and wakefulness . These dFurther research on the molecular basis of plasticity mechanisms in the spino-dendritic system in the BRS is warranted, since it might contribute to a better understanding of the causes of numerous pathological processes and to the development of new and more effective therapies.The main role of neurotransmitter transporters in the CNS is removal of the appropriate mediators from the synaptic cleft . TherefoFrom a practical point of view, the effects of inhibition of the individual transporters are of great importance, on the one hand affecting the dynamics of psychopathological disorders such as depression, anxiety, obsessive-compulsive disorder, attention deficit hyperactivity disorder (ADHD), and addiction . On the DAT plays an important role in eliminating DA from the synaptic space, ensuring physiological homeostasis in the neurotransmitter system . By inhiBahi et al. reported the crucial role of DAT in ethanol-seeking behavior, as well as acquisition and retrieval of ethanol contextual memory in mice . ConsequApart from the receptors, Glu transporters also play an important role in the efficiency of synaptic transmission in NAc . Their fActivity of GABA-ergic neurons and release of GABA have a significant impact on the activity of projection neurons and, thus, indirectly on the concentration of DA in NAc . This prExpression level of vesicular GABA transporter (vGAT) and vesicular glutamate transporter 2 (vGlut2) in NAc of the adolescent and adult rats after ethanol exposure shows a characteristic ontogenetic pattern with lower vGlut2/vGAT ratios in adolescents compared to adults . The preAs shown by studies performed in mouse experimental models, chronic unpredictable mild stress is often associated with development of major depression . During Results of a recent study have shown that SERT deletion contributes to the protection against the development of behavioral sensitization by increasing serotonergic neurotransmission, which is accompanied by dendritic remodeling of the MSNs in NAc . These rResults of the study by Verheij and Karel have shown that changes in NE content do not have a decisive influence on the enhancement of cocaine intake in the SERT knockout rats . In the Studies on the mechanisms of reward, stress, depression and addiction involve animal knock-out models of serotonin and dopamine transporters  ,285,286.The dopamine transporter (DAT) is responsible for removing the neurotransmitter from the synaptic cleft to the presynaptic terminal. The DAT ko mice show symptoms resulting from the increased DA content . The useSome authors emphasize the importance of brain-derived neurotrophic factor (BDNF) for proper functioning of connections between structures of the BRS, such as VTA, NAc, and PFC ,292,293.The relationship between changes in BDNF expression and altered functioning of the limbic system\u2019s structures  has been documented in several mental disorders such as depression, schizophrenia, and drug-induced addiction ,298,299.Data presented in this review show a wide range of NAc functions, not only under physiological conditions but also in pathological processes. The unique role of NAc among the structures of the BRS is a consequence of: (1) a widely distributed hierarchical system of connections with other brain regions, (2) cooperation with the limbic and motor functional systems in regulating the state of consciousness and behavioral reactions, and with the vegetative system, in coordinating metabolic, endocrine, and autonomic nervous systems functions, (3) cooperation among several neurotransmitter systems, (4) well-developed morphological and functional plasticity processes enabling control of the short- and long-term synaptic enhancement, and (5) supportive role of the NAc neuroglia in physiological and pathological processes.Changes in NAc functioning contribute to the development of several CNS diseases, such as depression, schizophrenia, and AD. In all these cases, the NAc dysfunction should be analysed in the context of its hierarchical connections with the other CNS structures and functional systems, impairment of the neurotransmitter systems and neuroplasticity processes. Further research on the structure and function of NAc will provide relevant information, useful not only for a better understanding of the mechanisms regulating motivation processes and striving for reward-achievement but possibly also for the development of effective therapies for some CNS diseases."}
+{"text": "In recent years, cardiovascular disease (CVD) continues to be the leading cause of global disease burden. Extensive efforts have been made across basic, translational, and clinical research domains to curb the CVD epidemic and improve the health of the population. The successful completion of the Human Genome Project catapulted sequencing technology into the mainstream and aroused the interests of clinicians and scientific researchers alike. Advances in single-cell RNA sequencing (scRNA-seq), which is based on the transcriptional phenotypes of individual cells, have enabled the investigation of cellular fate, heterogeneity, and cell\u2013cell interactions, as well as cell lineage determination, at a single-cell resolution. In this review, we summarize recent findings on the embryological development of the cardiovascular system and the pathogenesis and treatment of cardiovascular disease, as revealed by scRNA-seq technology. In particular, we discuss how scRNA-seq can help identify potential targets for the treatment of cardiovascular diseases and conclude with future perspectives for scRNA-seq. Cardiovascular disease (CVD), primarily ischemic heart disease and stroke, remains the leading cause of mortality and morbidity across the world . Recent With the completion of the Human Genome Project and the rapid development of sequencing technologies, there has been a growing interest in single-cell genomic and transcriptomic studies. Single-cell sequencing investigates biodiversity and heterogeneity at a single-cell resolution . Since iIn contrast, single-cell RNA sequencing (scRNA-seq) is used to detect the mRNA level of individual cells . In the Compared to adult hearts, embryonic and neonatal cardiac tissues are easier to digest and isolate single cardiomyocytes with higher viability. The lineage and heterogeneity of various cells in the process of cardiac development can be comprehensively analyzed by scRNA-seq . In 2016In addition, scRNA-seq contributes to the identification of factors responsible for the spatial development of the heart. Recently, uniquely expressed genes responsible for the development of the cardiac conduction system were identified in an embryonic mouse . SimilarAs for human vascular cells, scRNA-seq can comprehensively provide mRNA information of each cell in the heart and blood vessel in disease states, which can enable the discovery of new therapeutic targets for CVDs . In a moBecause of the large size of intact adult cardiomyocytes, researchers have used nuclei extracted from myocytes for scRNA-seq, so-called snRNA-seq. Coming to blood vessels, In addition, smooth muscle cells were reported to transition to macrophage- and fibrochondrocyte-like cells during atherosclerosis, a phenomenon regulated by the retinoic acid pathway . RecentlIn recent years, cardiovascular cells differentiated from human embryonic stem cells or hiPSCs have provided a new source of cells for repairing or regenerating the injured heart. Transplantation of cardiovascular cells was found to improve wall stress, cardiac metabolism, and contractile performance in a porcine heart model of MI . Geneticin vitro and the complexity of differentiated cardiomyocyte subsets are still unsolved questions  is the basis for the development of scRNA-seq and spatial RNA sequencing (spRNA-seq), the latter two can offer transcriptional information at a single-cell level or near single-cell level . In addiscRNA-seq provides a powerful tool for studying cell heterogeneity, tracking cell dynamics, and subsequently finding new therapeutic strategies for CVDs. It has, thus, opened a fresh chapter in the field of modern cardiovascular research. With constant improvement in scRNA-seq technology and the combination of multiomics and spatiotemporal analysis, scRNA-seq will play a greater role in the field of cardiovascular research. In particular, the comprehensive study and analysis of genomics, epigenomics, and transcriptomics at the single-cell level holds promise for the elucidation of gene regulatory mechanisms at a single-cell resolution, contributes to individualized therapy of CVD in clinical practice, improves therapeutic efficacy and clinical outcomes, and facilitates the practice of precision medicine."}
+{"text": "ABSTRACT IMPACT: As scientific research is trending towards greater interdisciplinary and collaboration in order to meet the challenges of contemporary science, which has led to increased recognition of the importance of Team Science, this study will promote team science research within NJ ACTS Consortium as well as across the country. OBJECTIVES/GOALS: The objective of this study is to assess the feasibility of using the NIH Reporter database for developing and tracking team science metrics within the CTSA-funded NJ ACTS Consortium, which consists of RU, PU, and NJIT. The NIH Reporter database provides detailed information on single-PI and multiple-PI R01 grants funded by NIH. METHODS/STUDY POPULATION: 58 multi-PI projects and 344 single-PI projects are currently funded within the NJ ACTS consortium. We will use information from the database on funding levels, institutional composition of projects , numbers of publications, impact factors of publications, and funding supplements obtained to quantify and track NIH R01 Team Science activity in the consortium. RESULTS/ANTICIPATED RESULTS: Preliminary analysis suggests that it will be both feasible and efficient to use the NIH reporter database to develop Team Science metrics and to augment information in the database with information on PI characteristics such as department/center/school/university, academic discipline, and rank/tenure status, as well and detailed composition of research teams, such as the mix in terms of senior and junior scholars. DISCUSSION/SIGNIFICANCE OF FINDINGS: This study will make an important contribution to this movement by demonstrating the feasibility of using the publicly available NIH Reporter Database to quantify the level and success of Team Science in the form of single-PI and multiple-PI R01 grants funded by NIH, which represent extremely important Team Science activities at universities."}
+{"text": "The outbreak of COVID-19 has posed a huge threat to global health and economy. Countermeasures have revolutionized norms for working, socializing, learning, and travel. Importantly, vaccines have been considered as most effective tools to combat with COVID-19. As of the beginning of 2021, >200 COVID-19 vaccine candidates, covering nearly all existing technologies and platforms, are being research and development (R&D) by multiple manufacturers worldwide. This has posed a huge obstacle to the quality control and evaluation of those candidate vaccines, especially in China, where five vaccine platforms are deployed in parallel. To accelerate the R&D progress of COVID-19 vaccines, the guidances on R&D of COVID-19 vaccine have been issued by National Regulatory Authorities or organizations worldwide. The Center for Drug Evaluation and national quality control laboratory in China have played a leading role in launching the research on quality control and evaluation in collaboration with relevant laboratories involved in the vaccine R&D, which greatly supported the progression of vaccines R&D, and accelerated the approval for emergency use and conditional marketing of currently vaccine candidates. In this paper, the progress and experience gained in quality control and evaluation of COVID-19 vaccines developed in China are summarized, which might provide references for the R&D of current and next generation of COVID-19 vaccines worldwide. Consequently, >200 companies and institutions quickly put together plans for the research and development (R&D) of COVID-19 vaccines, covering almost all technology platforms available for preparing vaccines.3 Currently, COVID-19 vaccines from 19 developers have entered phase III clinical trials, and 12 related vaccines have been approved for conditional marketing or emergency use worldwide , quality control system, analytical methods, and qualification/validation data and validation data for assays used to evaluate critical vaccine qualities, such as purity, identity, and potency for all stages of manufacturing should be clarified and provided.40 While promulgating the technical guidelines for the R&D of COVID-19 preventive vaccines, China has formulated the technical guidelines for the pharmaceutical research of COVID-19 preventive mRNA vaccines to address and meet the growing interest in the R&D of new mRNA vaccines.37 These technical guidance documents have played an important role in the development and approval of vaccines for emergency responses globally. However, most of the above guidelines are based on the existing experience in vaccine development, which need to be updated and revised in a timely manner based on new data and trends arising from the research on the produce, quality control, preclinical, and clinical trials related to COVID-19 vaccines.To guide and standardize the R&D of COVID-19 vaccines, global health organizations or regulatory authorities, including WHO, NMPA of China, FDA of the United States, EMA of the European Union, and PMDA of Japan, have issued a framework for the evaluation of clinical studies and guidelines related to emergency use of COVID-19 vaccines Table .34\u201345 AsIn addition, in view of the emergence of new problems and challenges, it is necessary to formulate contingent technical guidelines that can be tested quickly and adopted for standardization. For example, WHO and FDA are currently developing guidelines on testing the impact of mutant strains on the efficacy of protection of vaccines. Relevant departments in China are also working on preparing supplemental guidelines and policies to assist and streamline responses to rapidly evolving situations during pandemics.Countries all over the world had to rush to come up with countermeasures to mitigate the impact of the COVID-19 pandemic. Companies and institutions scrambled for the development of vaccines. The resulting tight R&D time lines, adoption of numerous platforms for the development of vaccines, participation of multiple enterprises, and inadequate scale-up, as well as production facilities severely impacted the setting up and implementation of standards to guide the development of COVID-19 vaccines through the various stages of R&D and production. For instance, in China itself, currently, there are >50 R&D enterprises working on five different vaccine platforms. Among the candidates being studied and developed, 17 products have entered clinical trials. Standardization of the various processes developed by many companies posed a huge challenge to the Chinese regulatory authorities. To address this, the Chinese Center for Drug Evaluation (CDE) has released multiple publications on guiding principles for vaccine development, recommendations on methods, and the statutory standards for the quality control at each step of R&D. Furthermore, the national laboratory of China, National Institutes for Food and Drug Control (NIFDC), worked closely with several laboratories conducting research on vaccines to establish a series of quality control and reference standards for the purposes of evaluation, which provide valuable support for vaccine development.The purpose of recommending guidelines for vaccine quality is primarily to ensure the safety and effectiveness of vaccines. To aid the rapid development of vaccines for emergency use, parameters related to quality control and their specifications should, at the minimum, include the basic requirements of safety and effectiveness, while keeping in mind the urgency in rolling out vaccines for epidemic prevention and control. In view of the limited data generated during the R&D of quality control methods for new vaccines, some leeway should be permitted on the condition that specifications are continuously improved and validated in the subsequent R&D efforts.In terms of quality control methods and specifications, China has set forth technical requirements on key items like viral strains, cells, purified bulk, and final bulks to final lots for vaccine production by each platform. These form part of the quality control effort and require registration of related products that are specifically used in the development of vaccines from any of the five technical platforms.For a variety of cell lines involved in the production of COVID-19 vaccines, the relevant international guidelines were closely integrated with the Chinese pharmacopoeia, in order to formulate comprehensive recommendations on the quality control measures for the processes using cell lines in the production of vaccines. The numbers of new methods available for monitoring a range of parameters related to cell cultures for guaranteeing the quality have surged recently. For instance, a variety of methods for detecting contamination and misidentification of cell lines like multiplex polymerase chain reaction (PCR), DNA barcoding, and STR mapping are now available for rapidly identifying problems and quality issues with cell lines. In particular, the newly established methods for the rapid detection of exogenous contamination (such as the Touchdown PCR detection method for mycoplasma) not only guarantee the safety of the vaccine, but also solve the problem of lack of cell detection technology, which can save considerable time for vaccine R&D, while providing strong support for the quality of production processes during technical reviews.For vaccines made up of recombinant protein Fig. , the tar37 The quality control of the mRNA bulk targets steps like mRNA identification, mRNA sequence length, sequence integrity and accuracy, etc. Research for enhancing the quality of nanoparticles should focus on optimization of encapsulation rate, particle size distribution, surface charge, stability and immunogenicity, etc. Biological activity of the final products should be demonstrated in vitro, as well as in vivo tests.For vaccines based on mRNA technology Fig. , there i46 it also puts forward relevant requirements for vaccine design. For example, the rationale for the selection of the target antigen(s), encoded proteins  and the inflammatory nature of the given mRNA, the quality, quantity and bias of the immune responses  cell phenotype), biostability, etc. should be clarified.In addition, in the general guideline for RNA vaccines newly formulated by WHO in 2020,One of the key challenges in COVID-19 vaccine development that remains unaddressed is the drafting and acceptance of criterion for the evaluation of the efficacy of vaccines by all stake holders. In the early stages of COVID-19 vaccine development, NIFDC of China successfully prepared and established the SARS-CoV-2 neutralizing antibody (NtAb) standard, created the pseudovirus detection method as a substitute for tests involving use of live SARS-CoV-2 and ACE2 transgenic mice models for in vivo testing of the efficacy and safety of the vaccine. It is mandatory for the emergency use vaccines to provide data related to the use of these standards and methods in the preclinical studies before entering the clinical trials, leading to their subsequent approval for emergency use.47 In addition, the preparation of serum has also helped some vaccine development companies to establish a vaccine antigen detection method.SARS-CoV-2 recombinant RBD protein was used to immunize goats and rabbits to successfully prepare several anti-goat and anti-rabbit sera against the virus. The highly potent sera were distributed to several Chinese manufacturers of SARS-CoV-2 inactivated vaccine, which solved the technical bottleneck of identification of the virus specifically and detection of exogenous virus-related factors.For the first generation of coronavirus vaccines being developed and approved for emergency use, in vivo efficacy testing remains the main rate-limiting step for licensure. The traditional methods for establishing the efficacy of the vaccine rely on the collection of blood samples for the detection of antibodies 1 month after immunization. Based on the results from previous research, it is proposed that both the inactivated and recombinant protein vaccines should be tested for binding antibodies 14 days after the administration of the first dose of vaccine. After successful demonstration of the required titer of antibodies, the candidate vaccine for emergency use can successfully complete the registration requirements in the first attempt and quickly enter the clinical trial.Many R&D enterprises that developed inactivated vaccine and recombinant protein vaccine adopted their own antigen detection methods, which make it difficult to compare the active content of vaccines across the manufacturers. Recently, a team of scientists extensively screened monoclonal antibody libraries to obtain antibodies suitable for establishing a double antibody sandwich ELISA-based kit for the universal detection of antigens, which showed good correlates between vaccines developed from different platforms and different systems (unpublished date). Such a kit would be used for the evaluation of the in vitro efficacy of recombinant protein vaccines and inactivated vaccines.48Elicitation of neutralizing antibodies is one of the main measures of vaccine pharmacodynamics during clinical trials. Plaques reduction and microcytopathic methods are the gold standards for the detection of NtAb at present. But, the application and popularization of these methods are greatly limited due to the need of live virus. In the early stage of the outbreak of COVID-19, Wang et al. constructed the SARS-CoV-2 pseudovirus using the VSV pseudovirus system and established the pseudovirus neutralization method. This method of detection of neutralizing antibodies offers several advantages like objectivity, sensitivity, and accuracy. Most importantly, there is no need for a P3 laboratory for performing tests using this method. Consequently, it has been used in many vaccine R&D enterprises and institutions, solving the key issue of detection of NtAb evoked by COVID-19 vaccine, and providing strong technical support for ensuring effectiveness of the process of evaluation for the vaccine.49Animal models are key tools for evaluating the amount of protection conferred by vaccines in preclinical studies. Using CRISPR/Cas9 knock-in technique, Sun et al. constructed a transgene mouse model that could express human ACE2 (HACE2) receptor. Compared with wild-type C57BL/6 mice, both young and old HCE2 mice maintained higher viral loads in the lungs, trachea, and brain during nasal infection. At the same time, increased interstitial pneumonia and cytokines were observed in SARS-CoV-2-infected HCE2 mice. At present, this model is being used in the preclinical pharmacological evaluation of several vaccines, providing a crucial tool for evaluating the ability of vaccine to confer protection against viral challenge.51 Synchronous R&D of the vaccine by different manufacturers helped establish, authenticate, and validate the processes and methods for QC during preclinical and clinical immunogenic evaluation of vaccines produced by different manufacturers,60 which ensured the accuracy and comparability of vaccine, and aided the marketing and application of EV71 vaccines.61Standard materials are yardsticks for ensuring the safety, effectiveness, and produce consistency of the vaccines. The use of rational, reliable, stable, and uniform standard materials is necessary to ascertain that the internal, as well as external regulatory QC requirements are met. These attributes also play a role in the evaluation of vaccines of different kinds originating from different regions or institutes involving various methods used for their appraisal. Such as enterovirus 71 (EV71) vaccines, methods for QC and establishment of standard reference materials for EV71 vaccines were done in the early stage of development to guarantee accurate evaluation of vaccines.Compared to EV71 vaccine, which was developed using only one technical platform, the establishment and application of standard materials for COVID-19 vaccines that have been developed from multiple platforms would be more challenging. Given the importance and need for unifying protocols for ease of comparison of different COVID-19 vaccines, the guiding principles on establishment and use of standards could greatly reduce the burden and challenges, surrounding approvals for these new vaccines.62 This standardized reference also plays an important role in assuring adequate QC measures for vaccines developed from different platforms and by different manufacturers. Importantly, it provides a reference point for comparison of NtAb titers evoked by different vaccines. WHO established the first WHO international standard for anti-SARS-CoV-2 immunoglobulin  in December 2020, and it was assigned an international unitage of 250\u2009IU/ampoule. The standard was a result of an international collaborative effort with laboratories from all over the world participating in the calibration of the standard, leading to a uniform international standard for the estimation of antibody titers.63NtAb response is a key measure of immunogenicity and efficacy of vaccine. To assist in the evaluation of the efficacy of COVID-19 vaccines during the R&D stage, Hou et al. employed convalescent sera of COVID-19 to develop a national standard for SARS-CoV-2 NtAb with an assigned unitage of 1000\u2009U/ml.64 Therefore, RBD protein content is the key of the whole virus inactivated vaccine and other forms of recombinant protein vaccines developed using various expression systems. Presence of correctly folded RBD ensures efficacy. To establish a uniform reference to quantify effective components in vaccine, Liang et al. selected a CHO-expressed RBD antigen that had a moderate antigen activity from different candidates. This RBD protein was distributed to 11 labs for collaborative calibration. The results indicated that this candidate standard showed good parallelism and linearity with inactivated antigen and S or RBD antigens produced from CHO cells, yeast, Escherichia coli, or sf9 cells, which demonstrated that this candidate standard could be used as a uniform antigen standard for inactivated or recombinant vaccines. The standard is expected to provide a uniform benchmark for the quantification of effective components in vaccine.RBD is a universally accepted active domain of SARS-CoV-2 vaccine.The outbreak of COVID-19 has been catastrophic for human health, and its epidemiology posed a great challenge for global regulators and vaccine industry. In order to promote the R&D of vaccines and ensure the safety and effectiveness of vaccines, global regulators have formulated a series of guiding principles for the R&D of this new vaccine, including quality control, evaluation, and licensure. Among them, China is facing the biggest challenge due to the complicated and diverse vaccine R&D situation. In China, as a part of the national supervision system for vaccine development, CDE and NIFDC have played a leading role in launching the research on QC and evaluation at the earliest stages in collaboration with relevant laboratories involved in the vaccine R&D, which supported and accelerated the process of conditional marketing and emergency use of different vaccines with high quality.In this process, the Chinese National Regulation Authority believes that the establishment of national and international unified evaluation methods and standards is extremely important for the QC and evaluation of these new vaccines. So, QC and evaluation methods, including psedovirus-based NtAb detection method, and NtAb standard, were rapidly developed, established and used in the quality control and evaluation of COVID-19 vaccines. Those accomplishments relied on the close communication and collaboration between Chinese regulatory authorities and international organizations , and the close cooperation among institutions with supervisory roles in China, and the direct communication among supervisors and manufacturers. These works unified projects, methods, and standards for QC of vaccines using same platforms to great extent, which ensures the consistency, comparability, and objectivity of quality control and evaluation of different kinds vaccines or same kinds vaccines developed by different manufactures.66 More innovative technologies and ideas, such as research on heterologous prime-boost strategy of combining different vaccine candidates, next-generation vaccines capable of evoking more potent and effective immune responses against mutants, monovalent or multivalent vaccines, and the monitoring for tendency of the virus mutation should be studied if it can help mitigate these issues. At the same time, how to constantly adjust the standards and technical requirements of vaccines according to the changing situation, so as to ensure the safety and effectiveness of vaccines is a common challenge faced by global regulatory agencies. Active and close international cooperation and exchange is the only way to solve the problem to better prevent and control of the epidemiology of SARS-CoV-2 worldwide.Recently, COVID-19 inactivated and adenovirus-vectored vaccines have been approved for marketing. However, there has been variability in their protective efficacies, which needs to be further investigated. Furthermore, the recent variants documented in South Africa and Brazil might escape the protective immune responses elicited by these vaccines."}
+{"text": "Nucleic acids underlie the storage and retrieval of genetic information literally in all living organisms, and also provide us excellent materials for making artificial nanostructures and scaffolds for constructing multi-enzyme systems with outstanding performance in catalyzing various cascade reactions, due to their highly diverse and yet controllable structures, which are well determined by their sequences. The introduction of unnatural moieties into nucleic acids dramatically increased the diversity of sequences, structures, and properties of the nucleic acids, which undoubtedly expanded the toolbox for making nanomaterials and scaffolds of multi-enzyme systems. In this article, we first introduce the molecular structures and properties of nucleic acids and their unnatural derivatives. Then we summarized representative artificial nanomaterials made of nucleic acids, as well as their properties, functions, and application. We next review recent progress on constructing multi-enzyme systems with nucleic acid structures as scaffolds for cascade biocatalyst. Finally, we discuss the future direction of applying nucleic acid frameworks in the construction of nanomaterials and multi-enzyme molecular machines, with the potential contribution that unnatural nucleic acids may make to this field highlighted. Nucleic acids demonstrated very unique properties and advantages to be used for constructing nanomaterials and scaffolds of multi-enzyme systems. For example, the structures of nucleic acids are well determined by their sequences, which allows straightforward control of their structures by customized sequence design . The feamachines . In recemachines . Hopefulin vitro and in vivo are summarized and discussed. A perspective on future development and application of novel nucleic acid frameworks in building nanostructures and multi-enzyme systems is provided in the end, with the potential contribution of unnatural nucleic acids highlighted.In this review article, we start from a brief introduction of the molecular structures and properties of natural and unnatural nucleic acids. Then the approaches and recent progresses on fabricating and applying complex nanostructures and multi-enzyme systems with nucleic acid scaffolds de novo synthesis of DNA and the invention of polymerase chain reaction (PCR) technology for exponential amplification of DNA have already laid the technical foundations for large-scale preparation of DNA, which is the prerequisite to extensively use DNA as a structural material  has greatly expanded the genetic alphabet . Introduormation . Moreovereagents .in vivo replication, transcription, and even translation , and the ssDNA was then reverse transcribed from the RNA by HIV reverse transcriptase, which was recruited by HTBS  effector staple proteins , four-way junction (4WJ), kink-turn motif, hairpins, pseudoknot, C-loops, right-angle motifs, tetraloop-receptors, paranemic motifs, and kissing loops, which can be directly employed in the design and construction of RNA nanostructures . Early emedicine . Mao andmedicine . Hermannmedicine . Since tmedicine . With inmedicine . In anotmedicine .in vivo construction and application of nanostructures more feasible. Geary et al. designed RNA tiles fabricated with a single-stranded RNA, and these RNA tiles can self-assemble into hexagonal lattices , for the treatment of triple negative breast cancers (TNBCs) . AlternaEfforts have also been made to fabricate RNA and DNA structural units together to produce novel RNA-DNA hybrid materials that possess characteristics, properties, and functions of both RNA and DNA. For example, Hermann and co-workers reported a self-assembled RNA-DNA hybrid polygonal nanostructure, the formation and stabilization of which were highly dependent on the binding of the DNA aptamer integrated in the nanostructure with its ligand AMP . Afonin in vivo production of RNA nanostructures via co-transcriptional assembly has also been demonstrated by several groups, which suggested the potential use of RNA as a scaffold material for organizing functional molecules in living cells. For example, Delebecque et al. assembled programmed RNA scaffolds in vivo, and applied them to guide the spatial organization of proteins , which mimicked peroxidase , which was composed of AMP and Ce3+ . The NCP3+ . Other t3+  20 oligonucleotide, was attached to the surface of the DNA tile in between these two enzymes, and behaved as a swinging-arm that facilitated hydride transfer between G6PDH and MDH 20 oligonucleotide had an obvious negative impact on the catalytic activity. Later, they expanded this work to the construction of an artificial 2D enzyme network of G6PDH and lactate dehydrogenase (LDH), in which the enzymes were immobilized on the nodes of a wireframe DNA origami grid, and the cofactor NAD+-coupled duplex swinging arms were immobilized halfway between each pair of G6PDH and LDH  and a malic dehydrogenase (MDH) were co-immobilized on a DNA double-crossover tile scaffold, and a NAD and MDH   and xylitol dehydrogenase (XDH) of xylose metabolic pathway on DNA origami nanostructures with different distribution patterns of protein binding sites  Ngo et . While Xin vitro construction of multi-enzyme systems, presumably due to the fact that RNA is not as stable and cheap as DNA. However, there are some examples of using RNA scaffolds for the in vivo construction of multi-enzyme systems, taking advantage of easy in vivo production of RNA via transcription and efficient co-transcriptional assembly of RNA nanostructures, which will be introduced in next section. Unnatural nucleic acid scaffolds have also not been used for the construction of multi-enzyme systems yet, since the efforts on the development of efficient tools to produce, amplify, and manipulate them, including unnatural nucleic acid polymerases, although already fruitful, are still in progress. The great potential of this field will be discussed in the end of this article.There is barely any example of using RNA scaffolds for the via in vivo construction of multi-enzyme systems with key enzymes in the metabolic pathways  cells. After being expressed in the cells, the zinc finger protein-fused enzymes spontaneously assembled onto the scaffold plasmid. They then optimized stoichiometric ratios of the enzymes and intervals between the enzymes for higher L-threonine production. With the optimal system, the production time of L-threonine was reduced by over 50%, and the growth rate of the host cells was also enhanced, presumably due to reduced accumulation of toxic intermediates. Chen and coworkers reported the application of similar strategy on spatial modulation of pathway enzymes for improved production of N-acetylglucosamine in Bacillus subtilis (in vitro or in vivo by simply fusing enzymes with TALE proteins and immobilizing them onto a DNA scaffold with multiple TALE binding sequences. Zhu et al. reported the in vivo construction of TALE-based multi-enzyme system for the synthesis of indole-3-acetic acid (E. coli (Whole cell biocatalysts have been broadly used in bioindustry for the production of valuable chemicals, and their catalytic efficiency can be significantly improved pathways . Biomacr ligands . Many of ligands  (Lee et  ligands . Plasmidsubtilis  (Liu et subtilis . The zinsubtilis  (Conradosubtilis . TALEs asubtilis . Taking tic acid . In this(E. coli . After oin vivo construction of multi-enzyme systems have been reported yet, mainly due to the lack of efficient and user-friendly methods for in vivo production and assembly of singles-stranded nucleic acid components, as well as methods for in vivo immobilization of enzymes of interest site-specifically onto these nanostructures. Sliver et al. pioneered an effort to construct multi-enzyme systems in vivo based on RNA nanostructures (in vivo constructed 2D RNA scaffolds for enhanced pentadecane and succinate production (Up to now, not many examples of applying complex nucleic acid nanostructures for ructures . RNAs wioduction .in vitro and in vivo.In the past decades, a variety of elegant artificial structures based on nucleic acids have been designed and constructed, and some of them have found broad application in the construction of elegant nanomaterials or as highly programmable scaffolds for multi-enzyme systems. In this article, we started from the introduction of basic characteristics and properties of natural and unnatural nucleic acids, which demonstrated the uniqueness and superiority of nucleic acids to be used as structural materials. The progress in the development of polymerases for the efficient synthesis of nucleic acids with unnatural moieties, which are essential for broader application of unnatural nucleic acids, was also discussed. We then summarized representative approaches in the application of DNA, RNA, and unnatural nucleic acids for the construction of various artificial nanostructures, ranging from simple one or two-dimensional structures to complicated 3D origami nanostructure assemblies. In the end, we reviewed the construction of multi-enzyme systems using nucleic acid structures as scaffolds, as well as the application of these multi-enzyme systems for efficient catalysis of cascade reactions, both de novo synthesis technology, will facilitate the acquirement of more and better oligonucleotide sequences to be used as components for the construction of nucleic acid nanostructures in the future (Rapid development of DNA and RNA nanotechnology has enabled the construction and broad application of various nucleic acid nanostructures. However, more efforts still need to be made to make the procedures and the computational programs for the design and construction of complicated nanostructures more robust and user-friendly . Recentle future .in vitro or in vivo. However, these systems are still far from perfect, and a lot of efforts need to be made to further improve their performance. For instance, new chemistry may be developed to achieve efficient site-specific immobilization of the enzymes onto the scaffolds and precise control of the orientation of the enzymes, which is obviously very important for the accessibility of substrates or intermediates to the active sites. Smarter nucleic acid nanostructures may also be designed for better regulation of the stoichiometric ratio and relative positions of the enzymes based on their kinetic parameters to achieve optimal overall catalytic performance. Development of better computational tools to assist the design, assembly, and behavior simulation of versatile nucleic acid nanostructures will also greatly promote these efforts (in vitro, complex DNA origami nanostructures are rarely used as scaffolds for in vivo construction of multi-enzyme systems. Most of the nucleic acid scaffold-based multi-enzyme system constructed in vivo are still simply based on the immobilization of DNA-binding protein elements on linear double strands of DNA. Further exploitation of methods for constructing complicated nucleic acid nanostructures in vivo and combining these nanostructures with well-designed nucleic acid-binding proteins may lead to much better scaffolds for in vivo assembly of highly programmable multi-enzyme systems, and facilitate the engineering of cellular metabolic pathways.In order to immobilize and organize two or more enzymes for efficient catalysis of cascade reactions, multi-enzyme systems have employed various materials to fabricate the scaffolds, including inorganic materials, organic frameworks, and biological materials. Among those, nucleic acid has proven one of the most promising scaffold materials. Numerous artificial structures have been constructed with nucleic acids, and many of them are already well suited for the construction of multi-enzyme systems for efficient catalysis of cascade reactions  efforts . Despitein vitro application of unnatural nucleic acids, the efforts on construction of semi-synthetic organisms have opened the gate for in vivo application of unnatural nucleic acids (in vitro and in vivo.Although natural nucleic acid frameworks have already been broadly used in the construction of nanomaterials or as the scaffolds of multi-enzyme systems, there still remain many challenges in the construction and application of better nucleic acid scaffolds that fulfill the requirements of more programmable and robust nanostructures or multi-enzyme systems. For example, the number of nucleobases in natural DNA and RNA is quite limited compared to the number of amino acids in protein, which results in limited sequences, structures, and designability of DNA and RNA. Moreover, natural nucleic acids have low tolerance against nuclease degradation and reduced stability under various chemical or physical conditions, which restricts the application of nucleic acid nanostructures or multi-enzyme systems with nucleic acid scaffolds in biological solutions or harsh environments. The fast development of unnatural components has provided a generous toolbox for the structural and functional expansion and augmentation of nucleic acids, and thus offered a great potential for the design and construction of better nucleic acid-based nanostructures and multi-enzyme scaffolds. As mentioned above, newly developed unnatural base pairs are already able to pair, replicate and transcribe as efficiently as natural base pairs . The intic acids , so we c"}
+{"text": "Rates of suicide are elevated in middle- and late-life, yet studies focusing on suicidal ideation and behavior in older adults are limited compared to research in younger adults. The studies included in the present symposium offer valuable findings on suicide in older adults across the span of late-life. Owsiany et al. focus on age differences between older and younger adults in the association between anxiety symptoms and suicide risk. In Heisel et al., an online intervention is assessed for improving the outcomes of psychological well-being and suicide risk in older adult men who are transitioning into retirement during the COVID-19 pandemic. Crnek-Georgeson and Wilson reviewed the link between retirement patterns and psychological effects, including suicidal behaviors, among older adults. Additionally, this review includes recommendations for policy makers and employers in an effort to assist older adults with the transition into retirement. Utilizing baseline data from the Helping Older Adults Engage study, Fenstermacher et al. research the association between volunteering and suicidal ideation in a predominantly lonely older adult sample across the span of late-life. Together, these studies provide foundation for future research on suicide in late-life to build upon. Future studies should continue to focus on risk and protective factors for suicide in older adults and aim to improve screening and intervention for suicidal thoughts and behaviors in this population. Yeates Conwell, M.D., Director of Geriatric Psychiatry and Co-Director of the Center for the Study and Prevention of Suicide at the University of Rochester Medical Center, will serve as discussant."}
+{"text": "Internally Displaced Persons (IDPs) in the camps face many reproductive health challenges. They should meet their needs timely to save their lives. This paper outlines a systematic review to discuss the challenges of reproductive health management in the camps of internally displaced persons.For this research, electronic databases including PubMed, Science Direct, Scopus, Pro Quest, Google Scholar and Cochrane Library till January 1, 2020 were searched. A threestage screening process was used for the selection of literature due to PRISMA checklist. Finally, a thematic synthesis approach was applied to analyze the data.In total, 133 articles were identified; 11 articles met the inclusion criteria for entering the process of final analysis. The findings were demonstrated in six main categories of availability and accessibility of reproductive health services, sexual and gender-based issues, human rights, social and cultural issues, coordination and collaboration, and mental health issues. The remarkable result of this study highlighted that the main challenges are lack of access to health services, violence against women and lack of household education.Results of this systematic review present valuable advice for policy makers and managers to prepare and respond effectively and timely to reproductive health challenges of internally displaces persons. Disaster preparedness plans and contingency plans for maintaining and developing reproductive health in IDPs camps are recommended. Every year, millions of people around the world miss their homes as a result of conflicts and disasters and become internally displaced within their own countries . A totalInternally Displaced Persons (IDPs) have the same health needs as non-displaced people. Women accounted for around half of the IDPs in 2010 . They arReproductive health is a state of complete physical, mental and social well-being and not merely the absence of disease and infirmity, in all matters related to the reproductive system and to its functions and processes . Many stThe purpose of this systematic review study is to determine the reproductive health challenges of IDPs in disasters and emergencies.Search strategy and selection criteria: Six electronic databases were searched to identify studies from published and grey literature on productive health problems and challenges of IDPs. The populations of interest were persons who had been internally displaced. The search was done on January 1, 2020 and not limited to a specific time frame. The bibliographic databases searched were PubMed, Scopus, Science direct, ProQuest, Cochrane Library for English literature and Google Scholar for Persian ones. The search terms adopted include:  AND  AND  AND (Disasters). Reference listings of identified articles were also independently hand-searched for more specific articles. The numbers of articles/abstracts generated from the various databases are indicated in Study screening and selection: A three-stage screening process was undertaken for the selection of literature for the study. Initially, the authors conducted independent searches based on the search strategy. Secondly, title and abstract of founded articles were screened independently by the authors to assess their eligibility for inclusion in the review. This stage was conducted using the inclusion and exclusion criteria. Finally, the available full texts of the selected articles were reviewed to confirm that the studies met the research question of this review. The process for selecting and reviewing the articles has been indicated in Inclusion and exclusion criteria: All the studies with different study designs and methodologies that reported the reproductive health challenges of IDPs were included. Studies with no data on the scope of the research question of this review were excluded alongside books, guidelines, peer-review and online articles and reports. Also, the articles that whose full texts were not available or were in other languages other than English and Persian were excluded. Furthermore, time, age and sex were not factors considered for exclusion in this study.Data extraction: The full texts of eligible studies for this review were independently screened and summarized according to designed forms for descriptive and thematic analysis. Information about the author, country in which the study was carried out, study year, study design, objectives and key study results were extracted from the descriptive analysis. Another form was applied for extracting the challenges of reproductive health in IDPs and categorizing them. Finally, the manuscript was evaluated by PRISMA checklist.The screening process yielded a total of 133 citations/abstracts (Stage 1). The duplicated studies were removed, and of 119 studies after reviewing the titles and the abstracts, a total of 90 of these were rejected because they were not relevant to reproductive health challenges of IDPs, or the study populations were done in either refugees or unrelated populations (Stage 2). A total of 29 articles were left for the full-text review (Stage 3). Subsequently, 18 studies were discarded because they did not meet the inclusion criteria .Descriptive results: By reviewing the eleven included articles, it was declared that the largest numbers of papers were from Africa (36%), followed by Asia (18%) and United States (18%). Other studies were from Europe and South America. The descriptive analyses of the most important included articles in this study are summarized in Analysis: Classification of reproductive health management challenges of IDPs in disasters are shown in The database search yielded 101 papers . Of thesThe 11 included studies reported on reproductive health management in IPDs focusing on lack of access to certain services , violencThe main challenges were described and categorized in the field of reproductive health management in the humanitarian settings for IDPs at this stage. Availability and accessibility of reproductive health services, sexual and gender-based issues, human rights, social and cultural issues, coordination and collaboration, and mental health issues were the main categories  22,23).,23.22,23This review identified a limited evidence base on the main IDPs challenges of reproductive health management in the humanitarian settings with available studies covering divergent settings. Available studies revealed that there are many fundamental challenges to IDPs reproductive health management ,21.Availability and accessibility of reproductive health services: The first important challenge in this category was lack of access to certain services (services \u201316. Lackservices \u201327, but services . Neglectservices ,17,19, uservices ,14,17, pservices , 17 and services , 15\u201318 mA woman has many reproductive health needs, through the different stages of reproductive life such as access to a full range of family planning services, safe abortion care, and prenatal, delivery and postnatal care . ReproduThere are some health concerns of women and infants in disasters . UnplannSexual and gender-based issues: In disasters and emergency situations, overall levels of violence increase (increase . Women aincrease . Communiincrease  and inteincrease .Human rights: Some studies mentioned that women in IDP camps suffer diminished human rights and dignity ( dignity . This is dignity . Nationa dignity . Humanit dignity . Also, S dignity .Social and cultural issues: Lack of household education is one of the main reproductive health management challenges of IDPs in disasters. Most of the studies had focused on this issue (is issue ,15,19,20is issue . Disasteis issue . To asseis issue . Therefois issue .Women in IDP shelters suffer from reproductive health challenges and their activities are mainly influenced by cultural taboos and community beliefs . The heaCoordination and collaboration: One of the challenges was lack of adequate standards for managing the reproductive health. One of the active roles of the government and humanitarian assistance organizations is to provide adequate standards of living and social security for IDPs. This is in complete agreement with previous studies ( studies . Minimum studies \u201350. Deve studies . Also, mMental health issues: Mental disorders after disasters reported in previous studies. Depression especially in women are recognized as a common mental disorder. Post disaster suicide-attempt rates and depressive disorders are higher in internally displaced population (pulation . Violencpulation , and accIn general, IDPs in camps face with many reproductive health challenges. In this systematic review, we provided a comprehensive discussion and summarized all aspects of these challenges. Developing disaster preparedness and contingency plans, estimating the immediate reproductive health needs using the MISP, increasing the knowledge of women about their rights, and addressing the mental and psychosocial needs are important approaches to decrease these challenges. Also, planning for gender-based violence prevention, developing referral programs, using female officers in the IDP camps, creating standards of living and social security for IDPs and increasing the access to a full range of family planning services are some recommendations to decrease the reproductive health management challenges of IDPs in disasters."}
+{"text": "The quality of meat and dairy products can be evaluated from the perspective of the farmer seeking high yields and profits or the consumer for whom sensory characteristics are the most important, although health and ethical aspects, such as animal welfare and the environmental impact of the production system, are increasingly becoming concerns worldwide. Animal nutrition is one of the most important environmental factors that significantly influences the quality of meat, milk, and other dairy products; therefore, emphasis is often placed on improving the quality of feed. A main target for improving the nutritional characteristics of meat and dairy is the enhancement of lipid quality, which can be achieved by increasing the content and improving the composition of beneficial fatty acids (FAs)\u2014n-3 polyunsaturated FA (PUFA) and conjugated linoleic acid (CLA)\u2014and decreasing the n-6:n-3 PUFA ratio. Factors such as the forage:concentrate ratio, dietary fat supplements, pasture, etc. have a crucial effect on dairy and meat quality. Some studies have shown that meat and dairy from ruminants grazing on pasture are enriched with bioactive substances of natural origin like phenolic compounds, fat soluble vitamins, terpenes, and lipid components. These animals are also able to consume increasing amounts of by-products or \u2018unconventional\u2019 animal feedstuffs, which can improve the health-giving properties of products. In addition, dietary manipulations favouring polyunsaturated FA in dairy and meat lipids increase the risk of lipoperoxidation, which can be efficiently prevented by the use of antioxidants in the diet. Furthermore, the search for biomarkers that link the composition of animal products to livestock feed has become a target of scientific research; these biomarkers allow for traceability from farm to fork, based on the herbivore diet and geographical origin. In this context, the Special Issue \u2018Better Animal Feeding for Improving the Quality of Ruminant Meat and Dairy\u2019 aims to provide an integrated analysis of the major aspects of the nature and composition of ruminant meat and dairy  and the effect of better animal feeding on the improvement of nutritional and sensory qualities and functional properties beneficial to human health. This Special Issue comprises seven valuable works of original research on product quality; four studies were conducted on pasture-based systems , two on alternative feedstuff-based systems , and one on conventional concentrate-fed animals .Of the articles on pasture-based systems, three compared grass-fed regimes with conventional concentrate-fed regimes. Serrapica et al.\u2019s  study onIn the Mediterranean region, high amounts of by-products are available that can be used as alternative feedstuffs for ruminants, lowering feed costs, and enhancing farm sustainability, while reducing the environmental impact of livestock production. Monllor et al.  determinIn the last paper of this Special Issue, Barahona et al.  studied In summary, the Special Issue provides evidence that production systems based on grass and forages produce healthier products with better sensory attributes, thereby promoting the consumption of healthier foods. At the same time, as suggested by several authors, high amounts of by-products can be used as alternative feedstuffs for ruminants, enhancing farm sustainability while improving the health-giving properties of products."}
+{"text": "The rapid evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emergency involved Italy as the first European country. Meanwhile, China was the only other country to experience the emergency scenario, implementing public health recommendations and raising concerns about the mental health of the population. The Italian National Institute of Health [Istituto Superiore di Sanit\u00e0 (ISS)] reviewed relevant scientific literature in mental health to evaluate the best clinical practices and established the collaboration with the WHO, World Psychiatry Association, and China to support the public health system in a phase of acute emergency. This process permitted the definition of organizational and practical-operational Italian guidelines for the protection of the well-being of healthcare workers. These guidelines have been extensively disseminated within the Italian territory for maximum stakeholder utilization. Starting from February 2020, Italy was the first European country facing the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emergency. On March 8, 2020, several Northern Provinces of Italy were placed under lockdown, and on March 10, 2020, at 00:30, any movement of people across the whole Italian national territory was forbidden, unless motivated by compelling reasons of health or work. All Italian people suddenly experienced confinement at home, physical distancing, while simultaneously receiving dramatic news from all media concerning the pandemic evolution and hospital emergencies, with potential negative impacts on the mental health of the people, as shown in a recent German study ] consequently elaborated specific guidelines for COVID-19 diagnostic and care procedures, particularly for individuals in the autistic spectrum and/or with intellectual disabilities, to optimize the management of sharp changes in the living and working environment and daily routine of such individuals. The main areas addressed by the ISS guidelines included strategies to promote the training of professionals, reorganize clinical and care activities through the development and maintenance of remote interventions, scheduled interventions in the presence, and patient management in the long-term facilities.Finally, frontline health workers found themselves exposed to biological risk factors, social isolation from family members, and subsequently, intensified challenges of recovery from physical and emotional distress . Only China, at that time, was devoted to face the COVID-19 pandemic and its consequences on the mental health of the people. The ISS researchers reviewed relevant scientific literature in mental health to evaluate the best clinical practices. We established the collaboration with the World Psychiatric Association Action Plan 2021\u201323 Working Groups on Intellectual Developmental Disorder and Autism Spectrum Disorder, consolidating a working group that formulated advice to tackle mental distress for people with intellectual disability and autism spectrum disorder, SIDiN (https://www.iss.it/en/rapporti-iss-covid-19-in-english/). This ISS report is freely available and has been extensively disseminated within the Italian territory for maximum stakeholder utilization. The report provides guidelines to organize the roles and activities of workers, ensure training , promote material in support of interventions, and monitor psychological well-being such as individual support strategies, monitoring of reactions related to discomfort, activate psychological and psychiatry support, psychological, psychiatric, and psychopharmacological interventions (as shown in The Research Coordination and Support Service of the ISS collaborated with the Nottingham Ningbo GRADE Center and researchers of the Shanghai University of Traditional Chinese Medicine, and Children's Hospital of Fudan University to translate and adapt the aforementioned guidelines for an Italian context, with consideration of contextual and cultural differences. The translation of Chinese guidelines has been useful in the preparation of the organizational and practical-operational guidelines for the health workers report \u201cInterim guidance for the appropriate support of the health workers in the SARS-CoV-2 emergency scenario,\u201d developed by the ISS Mental Health and Emergency Working Group COVID-19, which is accessible on the institutional ISS website (via an e-meeting organized by the WHO working in Ethiopia on Mental Health and COVID-19. This document describes an evidence-based process that can be taken as an example for future international collaborations to support the public health systems.The collaboration between Italy and China, established in a phase of acute emergency, has been fundamental as a basis for the definition of Italian guidelines dedicated to public mental health and promotion of the well-being of health workers, whose protection is a key component of public health measures in addressing the COVID-19 epidemic . The proMLS: conceptualization and funding acquisition. MLS, FS, GG, and JX: writing the original draft preparation, writing the review and editing. All authors have read and agreed to the published version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Dear Editor,Pure Neural Leprosy (PNL) is a form of leprosy characterized by neural involvement without any skin lesions.M. leprae and the diagnosis of tuberculoid leprae with PNL was made. Antibodies against phenolic glycolipid-1 antigen (anti-PGL antibody) were negative. A therapy based on a combination of three drugs  associated with prednisone 25\u202fmg and gabapentin 300\u202fmg (2 cp/die) was started with improvement of symptoms.A 78-year-old man, a professional missioner in the Philippines and Papua New Guinea, has presented sensory loss  of left foot and pain of left hand present over a period of 4 years. A physical examination revealed dorsal flexion deficit of the left foot, superficial paraesthesia, and dysesthesia of toes associated with impaired deep sensitivity. In addition, he presented paraesthesia and dysesthesia to the IV and V fingers of the left hand. The left ulnar nerve was palpable and enlarged on the left elbow and no cutaneous lesions were found. The research of Acid-Fast Bacillus (AFBs) in the nasal swab and the slit skin smears from earlobes and left elbow was negative. Motor and sensory action potential of the left ulnar nerve, left peroneal nerve, left anterior and posterior tibial nerves are suggestive of mono-neuritis multiplex. Magnetic Resonance Imaging (MRI) of the left elbow showed the enlarged ulnar nerve partially damaged by entrapment within the fibro-osseous tunnel. Neurosurgery allowed the debridement of the ulnar nerve and, at the same time, the scraping of the perineural tissue. ZN stain and PCR of the scraping were positive for the presence of To the best of our knowledge, this is the first case of PNL diagnosed through scraping, ZN staining, and PCR test. Scraping is a technique that allows obtaining a clinical specimen rubbing a part of the body, in our case myelin sheaths of a nerve. The surface is scraped with a 15 Bard-Paker blade held at a right angle to the incision. Upon scraping, perineural tissue is obtained and examined by ZN staining and PCR test. Traditionally, diagnostic criteria for the diagnosis of PNL consist of nerve tissue samples obtained out of a nerve biopsy, analysis of PCR, and measure of anti-PGL-1 antibody levels.None declared.Ilaria Trave: Conception and planning of the study; elaboration and writing of the manuscript; approval of the final version of the manuscript; obtaining, analyzing, and interpreting the data; effective participation in research orientation; intellectual participation in propaedeutic and/or therapeutic conduct of the cases studied; critical review of the literature; critical review of the manuscript.Alberto Cavalchini: Conception and planning of the study; elaboration and writing of the manuscript; approval of the final version of the manuscript; obtaining, analyzing, and interpreting the data; effective participation in research orientation; intellectual participation in propaedeutic and/or therapeutic conduct of the cases studied; critical review of the literature; critical review of the manuscript.Gianfranco Barabino: Conception and planning of the study; elaboration and writing of the manuscript; approval of the final version of the manuscript; effective participation in research orientation; intellectual participation in propaedeutic and/or therapeutic conduct of the cases studied; critical review of the literature; critical review of the manuscript.Aurora Parodi: Conception and planning of the study; elaboration and writing of the manuscript; approval of the final version of the manuscript; obtaining, analyzing, and interpreting the data; effective participation in research orientation; intellectual participation in propaedeutic and/or therapeutic conduct of the cases studied; critical review of the literature; critical review of the manuscript.None declared."}
+{"text": "In 2021, NIH funded six high-priority research networks designed to develop resources to support and advance the study of emotional well-being (EWB) and its core components. These research networks aim to advance the field by facilitating transdisciplinary research in the social, behavioral, psychological, biological, and neurobiological sciences. The National Institute on Aging (NIA) co-sponsored the RFA, and provided funding for NEW Brain Aging, because of the central importance of EWB to health trajectories across the adult lifespan. In this presentation, Dr. Simmons, Chief of the Individual Behavioral Processes Branch within the NIA Division of Behavioral and Social Research (BSR), will discuss how EWB research fits within NIA priorities. She will then facilitate open discussion about NIA and BSR\u2019s vision for the EWB \u2018network of networks,\u2019 the synergy of NEW Brain Aging with other members of the larger network, and the opportunities these networks will provide for investigators interested in EWB."}
+{"text": "The National Health and Aging Trends Study (NHATS) is a nationally representative sample of Medicare beneficiaries aged 65 and older. From 2011 through 2020, annual in-person interviews have collected data in many areas, including health, environment, wellbeing, cognition, and function. With a decade of follow-up, including replenishment samples, NHATS is an ideal setting to investigate trends and trajectories of aging. Aging is heterogeneous and understanding the myriad of factors and functions that impact health and wellbeing is critical to developing interventions and care to promote health and wellbeing. Considering a multifactorial, wholistic approach to aging will provide a deeper understanding to create an impact. This symposium features pivotal research conducted using NHATS data, while highlighting overall strengths of the dataset for future research. The first presentation of this symposium investigates the factors that define cognitive profiles associated with dementia diagnosis over a period of five years. The second presentation investigates the role engagement in personally meaningful activities play in cognitive, emotional, functional, and health-related outcomes in older adults. The third presentation investigates the association between sleep medication use and fall risk among older adults with and without dementia. The session concludes with an investigation of end-of-life communication in persons with dementia and hearing impairment."}
+{"text": "Nipah virus (NiV) first emerged in 1998 in Malaysia, causing an outbreak of respiratory illness and encephalitis in pigs. Pig-to-human transmission of NiV associated with severe febrile encephalitis was described, and it was thought to occur through close contact with infected animals. The first outbreak was reported in India in Siliguri, West Bengal in 2001 followed by Nadia, West Bengal and adjoining areas of Bangladesh in 2007, where an intermediate animal host was not identified, suggesting bat-to-human and human-to-human transmissions. Although it is extremely difficult to document the spillover event and ascertain crossing of trans-natural boundaries by bats and bringing new viruses in an unexposed population, efforts for source identification are important to understand the epidemiology of disease. As the disease transcends beyond one species and has shown to infect humans, it therefore requires the \u2018One Health approach\u2019 in which multiple sectors coordinate and work together to achieve better public health outcomes.We summarize the re-emergence and response of the Nipah virus outbreaks (NiVD) in Kerala, India, about 1800 kms away, a decade later in 2018 and 2019. The paper recapitulates involvement of various stakeholders from the Ministry of Health and Family Welfare, Directorate of Health Research, Indian Council of Agricultural Research, State Health Department, State Animal Husbandry, District Administration, and multidisciplinary response mechanism during the NiVD outbreaks of 2018 and 2019.Information was collected from the Press Information Bureau (PIB), media/weekly alerts from the Integrated Disease Surveillance Programme (IDSP), news articles from print and electronic media, newsletters, advisories from the National Centre for Disease Control (NCDC), Disease Outbreak News (DON), World Health Organization (WHO), and published papers from various stakeholders.The evidence of NiV in humans and bats, with samples collected from the outbreak sites, was laboratory confirmed. The multidisciplinary response mechanisms during the 2018 outbreak helped in further understanding the importance of the One Health approach for systemic and streamlined response utilizing existing surveillance systems. This was of utmost help in the subsequent outbreak of the disease that occurred during 2019, wherein there was no documented spread of disease from the index case and no mortality was observed. This success reiterates the need for institutionalizing the involvement and cooperation of various departments and organizations during public health emergencies, especially of Zoonotic diseases, using the One Health approach. Nipah Virus (NiV) belongs to the family paramyxovirdae genus Henipavirus with a broad host range. NiV was initially identified to be responsible for outbreaks of febrile respiratory illnesses among veterinary stock. Selected species of bats are being increasingly recognized as reservoir hosts for viruses that can cross species barriers to infect humans, other domestic, and wild mammals. NiV infection in humans causes a range of clinical presentations, from asymptomatic infection  to acute respiratory infection and fatal encephalitis .Fruit bats of the Pteropodidae family are the natural host of NiV . The infWe summarize the re-emergence of the Nipah virus disease (NiVD) outbreaks (2018 and 2019) in Kerala, India about 1800 kms away, a decade later from the previous ones West Bengal (2001) and adjoining areas of Bangladesh (2007). We also recapitulate the systemic and combined efforts of various stakeholders, including Central as well as State authorities, for effective and timely management of these recent outbreaks. The steps taken by all the stakeholders to mount an effective response led to successful containment of the outbreak and prevented its spread to other neighboring districts and states, limiting it to a localized event. This success also reiterates the need for involvement and cooperation of various departments and organizations during public health emergencies, especially of Zoonotic diseases and dealing with them using the One Health approach. The One Health approach aims to establish an inter-sectoral coordination mechanism at National, State, and District levels, and utilizes the existing surveillance systems of various stakeholders to detect early warning signals of impending outbreaks for timely and effective public health response; also, it facilitates sharing of relevant information within the stakeholders for taking necessary action.After reports of an emergence of NiVD cases in Kerala in (2018 and 2019), a multi-disciplinary Central team was deputed, at the direction of the Union Health Minister, to review and respond to the situation of the NiVD in Kerala. Multi-disciplinary central teams were deployed at the sites to provide assistance to the local state authorities in investigating and responding to both the outbreaks; they consisted of public health experts, microbiologists, neurologists, and other infectious disease experts. These experts came from several organizations, including the National Centre for Disease Control (NCDC), Delhi and Calicut, Emergency Medical relief (EMR), MoHFW Delhi, All India Institute of Medical Sciences (AIIMS), Delhi, National Institute of Mental Health and Neuro-Sciences (NIMHANS), Bangalore, and National Institute of Virology Pune (NIV). Experts from the National Institute of High Security Animal Diseases (NIHSAD), Bhopal were also involved, along with the local Animal Husbandry Department 56.5Figure 1 and Table 1.As the state had a very recent experience in dealing with the NiVD outbreak, resulting in an already existing network of inter-sectoral coordination in 2018, an available set of guidelines and an expert team of doctors with past experience were already at hand for handling the outbreak of 2019 . The varThe first outbreak of NiVD was reported in India in District Siliguri, West Bengal in 2001 (66 probable cases and 45 deaths) followed by an outbreak in District Nadia, West Bengal and adjoining areas of Bangladesh in 2007 (5 probable cases and 5 deaths). As any intermediate animal host was not identified, bat-to-human and human-to-human transmissions were suggested 9.The unusual event apparently started with the death of a 26-year-old male resident of Block Perambra at the PHC-Changaroth on 5 May 2018, who was clinically diagnosed with viral encephalitis at the Government Medical College Hospital, Kozhikode on 4 May 2018. Two weeks later, two members of the same family reported with similar symptoms, deteriorated rapidly and died while in treatment at a private tertiary care hospital. Then, a cluster of three cases of viral encephalitis was reported from the same area. Subsequently, six more persons succumbed to similar symptoms, including a staff nurse of the taluk hospital involved in treatment of the primary/index case. All the affected cases were found to be epidemiologically linked with a confirmed case/death. Laboratory testing of throat swabs, urine, and blood samples collected from four suspected patients was conducted by the National Institute of Virology, Pune; three of the four reported deaths were confirmed positive for NiV by real-time polymerase chain reaction (RT-PCR) and IgM Elisa for NiV, and thereafter many more. A total of 19 cases and 17 deaths were reported through 3 June 2018 1112. The11On 30 May 2019, a 23-year-old male resident of Vadakkekara Village, Paravur Block, Ernakulam District, Kerala, having fever with altered sensorium, was referred to a private hospital at Eranakulam. A throat swab, CSF, blood, and urine samples were collected. The samples tested positive and were confirmed for NiV  by NIV Pune. A total of 330 contacts were traced and samples from all the 13 suspected cases were tested and found negative for NiV 16. ErnakFor early detection, monitoring, and response to epidemic-prone disease outbreaks (including NiVD), the Government of India is doing surveillance through the Integrated Disease Surveillance Program (IDSP) and providing technical and financial support to all states under the National Health Mission (NHM). The NiVD guidelines for case definitions  and contacts, advisories for healthcare personnel, information for the general public, treatment guidelines, sample collection, and transport guidelines were framed by IDSP and NCDC 19.The District Rapid Response Teams, along with the central multidisciplinary team, investigated the outbreaks in 2018 and 2019. House to house active case searching and contact tracing was done. Nipah cell of the state was established for contact tracing and ensuring home quarantine. Control rooms were set up at the State Headquarters and District Headquarters. Core committee daily review meetings were held under the chairmanship of the State Health Minister and District Collectors. Central teams reviewed the treatment procedure, infection control practices, use and availability of personal protective equipment (PPE), and availability of drugs, particularly in the designated hospitals 56.5Standard contact, droplet, and airborne precautions were emphasized during patient care and aerosol generating procedures to prevent human to human transmission while managing probable/suspected or confirmed cases of NiVD . To cont23The NiVD outbreak in 2018 was a major event with a very high case fatality rate (CFR), as characteristic of NiVD; however, the subsequent outbreak can be termed as a minor event. The primary cases in both outbreaks could have been infected by an accidental spillover from NiV infected bats or food sources contaminated by their secretions. However, in the 2018 outbreak, the initial spillover event may have been amplified by person-to-person transmission in the hospital settings, as subsequent cases were either close family contacts or hospital contacts. These two episodes are likely to be isolated/localized incidents.The unexpected sudden death of an otherwise healthy young male during the 2018 outbreak could have generated early warning signals only if such unusual events were reported diligently. As all the cases were epidemiologically linked to the index case, , subsequent infection/mortality could have been prevented if the infection control practices and BMW management practices at various levels of healthcare centers  were stringently followed. Thus, adequate quantities of PPE and other logistics were ensured in the district at the earliest. Standard precautions and safe BMW practices were also emphasized while handling the deceased, patient specimens, used PPE, linen, clothing of patients, cleaning, and waste disposal activities at all levels of healthcare centers.Lack of an upgraded virus testing laboratory in the state, especially for dealing with BSL-3 or 4 pathogens, poses an additional burden of sample transportation with biocontainment precautions and delayed response during such outbreak situations . The neePteropus giganteus bats were found positive for NiV by RT-PCR [Pig-to-human transmission of NiV associated with severe febrile encephalitis has been described in past NiVD outbreaks . Human-ty RT-PCR .Pteropus sp were positive for anti-NiV IgG antibodies. As per genetic analysis of NiV conducted by ICMR- NIV (Pune) and NIV , a distinct cluster of NiV sequences suggested the circulation of a new genotype (I-India) in South India, which is different from the Bangladesh and Indian northeast NiV strains [During the 2019 outbreak, one rectal swab sample (out of 141 swab samples of bats) and 3 bat visceral organs (out of 92 bats) were found positive for NiV. Interestingly, 20.68% (12/58) of  strains . No clinIn absence of a clearly identified primary source of infection to the index/primary case, many unscientific and misleading reports  on the possible transmission of disease from fruits, such as mangoes, lychees, dates, bananas, etc., created fear and trepidation in the community . Due to The establishment of strong surveillance and multidisciplinary response mechanisms during the 2018 outbreak was of utmost help in mounting a systematic and organised response rapidly and effectively during the 2019 outbreak, preventing significant human transmission and mortality.The clinical care of patients with suspected or confirmed highly pathogenic infectious diseases is a real challenge for healthcare facilities . A separThe conventional clinical diagnostic procedure required for confirmation of highly infectious disease requires advanced biocontainment laboratories, high-end (and costly) instruments, an expert technician for operation and result interpretation, and longer turnaround time. The technical advancements in research and translation to development of PoCT facilities must be encouraged, which will elevate the clinical diagnostic scenario in resource-limited settings.As per the ensuing bat breeding season, NiVD advisories must be issued to clinicians in affected areas for high index of suspicion and appropriate infection control practices both in public and private sectors . The timPrint and electronic media, social activists, community leaders, and nongovernment organizations play an active role in early case reporting, social mobilization, and the raising of public awareness, which is essential in the rapid control of any outbreak. To prevent the spread of false information, officers must be designated to give authentic information to the media. Correct information helps in managing panic amongst the general public, which can otherwise affect the containment efforts of authorities. A grassroots approach to public health was exercised with success in the NiVD outbreak through consistent public health messages delivered at the community level and steered at the state level, with strategic co-ordination by central government and collaboration with local government .The district, subdistrict, and block-level administrations, along with elected people\u2019s representatives, should be involved in discussions not only during outbreaks, but also prior to the season, to highlight the possibility of an outbreak from endemic- and epidemic-prone diseases. Possible prevention measures can be discussed at routine intersectoral monthly meetings chaired by district or sub-district administrators, leading to better coordination and cooperation at the community level .As spring is the probable breeding season for bats and the preliminary observations with regards to time of occurrence of both events is May\u2013June, this indicates a higher probability of the presence of the virus among bats, and therefore a spillover, during breeding season . FurtherWhen NiV infections are suspected, standard contact and droplet precautions and infection control practices must be promptly strengthened to avoid spillovers in healthcare facility settings, both public and private. Further, in view of emerging NiV infection in the last decades in newer areas, countrywide strengthening of existing disease surveillance systems and multidisciplinary response mechanisms is necessary to enable rapid detection of rare zoonotic diseases, such as NiVD, as is the institution of appropriate control measures with One Health strategy."}
+{"text": "The myth of a \u201ctypical\u201d mitochondrial genome (mtDNA) is a rock-hard belief in the field of genetics, at least for the animal kingdom . The firThe present Special Issue is an attempt to set and assess the state-of-art of mitochondrial genomics, with special reference to the suitability of mtDNAs for phylogenetic inference. The work by Formaggioni and colleagues  opens thOvis nivicola) using the well-exploited mitochondrial gene cytochrome b.Furfaro and Mariottini ,9 demonsTheileria parva are identified using mitochondrial single nucleotide polymorphisms in the work by Mwamuye and colleagues [Unio crassus from Eastern Europe is unraveled by Kilikowska and colleagues [Crassostrea angulata is addressed by Chiesa and colleagues [Arrenurus (Micruracarus) novus by means of morphology interwoven with the sequence of mitochondrial genes cox1 and cytb at different life stages.Several example of mtDNA-based population genetics are provided. Different strains of the cattle protozoan parasite lleagues ; the poplleagues  using onlleagues . Converslleagues  provide Aedes, who found a strong and consistent incongruence between nuclear and mitochondrial phylogenetic inference , whose disentanglement is thoroughly discussed. Finally, Xia [Mitochondrial phylogeny and comparison with nuclear data is the main purpose of the work by Zhao and colleagues  on two slly, Xia  reports Pseudocercospora fijiensis (Ascomycota: Pezizomycotina), as well as the phylogenetic reconstruction of the family Mycosphaerellaceae, providing clues for multiple invasions on introns within mitochondrial genes. Conversely, Johansen and colleagues [Stichodactyla haddoni, that shows group I introns harboring expressed open reading frames and supernumerary genes, and challenges current views of the Actiniidae taxonomy.Furthermore, new complete mtDNAs are hereby reported. Arcila-Galvis and colleagues  present lleagues  present Concluding, the present Special Issue highlights the effectiveness of mitochondrial-based analyses in different fields of evolutionary biology, on one hand, while highlighting future, promising perspectives of research in the field of mitochondrial genetics, on the other hand, a field where unexpected is expected and the exception is the rule."}
+{"text": "Nodularia douglasiae, while the other was N. nipponensis.We determined the complete mitochondrial sequences of female-transmitted (F) mitogenomes of two unionid specimens from the Lake Biwa system, Japan. Their gene contents and orders agreed with those of the typical F mitogenome of freshwater mussels. Molecular phylogenetic analysis using 20 previously identified partial COI and seven (five previously identified and two newly determined) whole mitogenome sequences revealed that one of the two mitogenomes was that of  Nodularia species in Japan: Nodularia douglasiae  and N. nipponensis , the former occurring on Kyushu and Honshu Islands in the area along the Sea of Japan, and the latter being endemic to northern Honshu and Hokkaido. Before the new classification, however, two subspecies were recognized in Japan under the name, Unio douglasiae Gray, 1833: Unio douglasiae nipponensis Martens, 1877 and Unio douglasiae biwae Kobelt, 1879, with the latter endemic to the Omi Basin (Lake Biwa and adjacent area) on Honshu and the former occurring widely in Japan with the exception of the Omi Basin  are burrowing, filter-feeding bivalves. They occur in lakes and rivers worldwide but are now declining in many countries , under the registration numbers LBM-1300014505 and 1300014533. Genomic DNA was isolated from foot muscle tissue, and sequenced using Illumina MiSeq and HiSeq X Ten sequencers (Illumina). The resultant reads were assembled using CLC Genomic Workbench . Contigs were annotated by alignment with the two female (F)-transmitted mitogenomes of N. douglasiae (LC496352 and NC_026111) . The phylogenetic positions of the two mitogenomes indicated that one was that of N. nipponensis , while the other was the new N. douglasiae. This result demonstrated that there are two mitogenome lineages of Nodularia in the Omi Basin, unlike the previous classification hypothesis of Kondo (U. douglasiae biwae).The resulting supermatrix tree  containeof Kondo , which r"}
+{"text": "Objective: The efficacy and safety of adjunctive magnetic seizure therapy (MST) for patients with schizophrenia are unclear. This systematic review was conducted to examine the efficacy and safety of adjunctive MST for schizophrenia.Methods: Chinese  and English  databases were systematically searched.Results: Two open-label self-controlled studies (n = 16) were included and analyzed in this review. In these studies, the Positive and Negative Syndrome Scale (PANSS) total scores and Brief Psychiatric Rating Scale (BPRS) total scores significantly decreased from baseline to post-MST , without serious adverse neurocognitive effects. Mixed findings on the neurocognitive effects of adjunctive MST for schizophrenia were reported in the two studies. A discontinuation rate of treatment of up to 50% (4/8) was reported in both studies. The rate of adverse drug reactions (ADRs) was evaluated in only one study, where the most common ADRs were found to be dizziness  and subjective memory loss .Conclusion: There is inconsistent evidence for MST-related adverse neurocognitive effects and preliminary evidence for the alleviation of psychotic symptoms in schizophrenia. Schizophrenia is a severely disabling psychiatric disorder affecting ~1% of the population worldwide . The ecoECT is the most effective treatment for individuals suffering from schizophrenia , 23 and MST is a novel neurotherapeutic intervention that induces therapeutic seizures based on high-frequency rTMS \u201334. MST To date, no systematic review on the efficacy and safety of adjunctive MST for schizophrenia has been published. Therefore, the target of the current study was to investigate the efficacy and safety of MST as an adjunctive therapy in schizophrenia.PICOS criteria. Participants: adult subjects with a diagnosis of schizophrenia based on any standardized diagnostic instruments. Intervention vs. Comparison: treatment as usual (TAU) plus MST vs. TAU plus ECT (RCTs); MST added to TAU . Outcomes: in this systematic review, the primary outcome was the improvement of psychotic symptoms, as measured by the Positive and Negative Syndrome Scale (PANSS)   or Brief (PANSS) . Key secTwo investigators (XYZ and XHY) independently searched English  and Chinese  databases from the date of inception until October 6, 2021 for studies on adjunctive MST for schizophrenia using the following search terms: (\u201cmagnetic seizure therapy\u201d[Mesh] OR magnetic seizure therapy OR MST) AND . Similarly, two independent investigators (XYZ and XHY) evaluated whether the potentially relevant studies fulfilled the inclusion criteria of this systematic review, and the senior author (WZ) was consulted in case of any differences of opinion.Two investigators (XYZ and XHY) independently extracted data from each included study. Any discrepancies in data entry between the two investigators (XYZ and XHY) were discussed, and the senior author (WZ) was consulted as needed. We contacted the first and/or corresponding authors to acquire any missing information as necessary. The quality of each included RCT and open-label prospective trial was evaluated by two independent investigators (XYZ and XHY) using the Cochrane risk of bias  and the As shown in n = 16) (The characteristics of the two open-label self-controlled studies (n = 16) , 21 are n = 16) , and then = 16)  and a flThe Cochrane risk of bias was not used because no RCTs were included in this systematic review. The NOS scores of the two self-controlled studies , 21 werePs<0.05). In Jiang et al.'s study , but no such decrease was found using the MATRICS Consensus Cognitive Battery (MCCB), Trail Making Test (TMT), Stroop Test or Verbal Fluency using the Controlled Oral Word Association Test (COWAT), and Montreal Cognitive Assessment (MoCA)  ( > 0.05) .In both studies, discontinuation of MST for any reason was reported for 50% (4/8) of the participants , 21. TheThis article is the first systematic review on the efficacy and safety of MST as an adjunctive therapy for schizophrenia. Only two open-label self-controlled studies , 21 wereThis systematic review shows there is preliminary evidence for the antipsychotic effects of MST in schizophrenia and negligible neurocognitive adverse effects. As reported in the two included studies , 21, theAs for other neurotherapeutic strategies, such as tDCS, DBS, or ECT, the main objective in investigating MST is to monitor the effects on neurocognition. The findings of this systematic review are that MST has little to no adverse neurocognitive effects, supporting the findings of an early study . HoweverThis systematic review is limited for the following reasons. First, only two open-label self-controlled studies , 21 withThere is inconsistent evidence for MST-related adverse neurocognitive effects and preliminary evidence for the alleviation of psychotic symptoms in schizophrenia. RCTs with an optimal sample size need to be performed on the use of adjunctive MST for schizophrenia to confirm and extend these findings.The original contributions presented in the study are included in the article/X-YZ and X-HY selected studies and extracted the data. WZ reviewed all the data and helped mediate disagreements. X-YZ, WZ, and D-BC wrote the first draft. All authors contributed to the interpretation of data and approved the final manuscript.This study was funded by the National Natural Science Foundation of China (82101609), Scientific Research Project of Guangzhou Bureau of Education (202032762), Science and Technology Program Project of Guangzhou (202102020658), the Science and Technology Planning Project of Liwan District of Guangzhou (202004034), Guangzhou Health Science and Technology Project (20211A011045), Guangzhou science and Technology Project of traditional Chinese Medicine and integrated traditional Chinese and Western medicine (20212A011018), China International Medical Exchange Foundation (Z-2018-35-2002), Guangzhou Clinical Characteristic Technology Project (2019TS67), science and Technology Program Project of Guangzhou (202102020658), and Guangdong Hospital Association (2019ZD06). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "OBJECTIVES/GOALS: The University of Rochester CTSI Research Education Hub is designed to: 1) connect the local research community with essential internal and external educational resources; 2) create a community of inquiry and collaboration across the translational science workforce pipeline within the university. METHODS/STUDY POPULATION: The Research Education Hub (RE-Hub) utilizes the university\u2019s widely used Learning Management System (LMS), Blackboard, and accessible to anyone at the university with a BlackBoard account. The RE-Hub greets users with an overview, an introduction of key local faculty experts in relevant research methodologies, and links to institutional research programs and helpdesks. Users are provided with curated educational resources organized by topic areas including, but not limited to, research methodology, statistical analysis, and grantsmanship. Discussion boards were created for users to ask general research questions and to connect with others in the translational research community. RESULTS/ANTICIPATED RESULTS: The RE-Hub was designed in Fall 2019 with the purpose of increasing utilization of university resources, including workshops, seminars, methods forums and consultation resources to improve translational science at the university. The RE-Hub was designed to be flexible and responsive to the changing needs of the local research community. User feedback will be used to identify improvements in the organization and content of the RE-Hub. Future improvements will include additional topic areas that span translational competencies, additional materials added to existing topic areas, and facilitation of better collaboration and integration of career development programs and grantsmanship resources. DISCUSSION/SIGNIFICANCE OF IMPACT: The Research Education Hub provides the University of Rochester translational science research community with a space to explore educational resources, to interact with colleagues and ask research related questions, and to help develop and/or improve other educational programs at the university."}
+{"text": "Although polyhydroxyalkanoates were discovered over 100 hundred years ago, and have been used for many applications , the majTo solve these bottleneck barriers, large members of research institutes and industries have contributed their endeavors in this developing field. Other than polyhydroxyalkanoates, semi-synthesized polylactic acid (PLA) has become another bulk commercialized biopolyester with acceptable unit cost and promising material properties . Other nMoreover, the diversity of bio-monomers has increased in recent years . In addiNduko and Taguchi have provided insights into the history for the development of lactate containing polyesters/oligomers, and the applications of variable lactate containing polyesters/oligomers (as macromonomer building blocks). Relating to the use of non-food feedstocks in the bioproduction of polyesters, Sun et al. and Moriya et al. present their updated studies on the microbial production of poly(3-hydroxybutyrate) from a broader-range of non-food substrates. Relating to the microbial production of medium chain-length polyhydroxyalkanoates, Scheel et al. reported a fermentation protocol which can be applied to control the copolymer composition to exhibit increased flexibility and elasticity in a series of medium chain-length poly. Harada et al. present a study on the microbial production of medium chain-length poly by application of an engineered polyhydroxyalkanoate synthase, which significantly improved the 3-hydroxyhexanoate (3HHx) fraction in the copolymers. Dartiailh et al. studied the effects of monomer composition on the thermal and mechanical properties of medium chain-length polyhydroxyalkanoate synthesized by Pseudomonas putida cultured with different substrates.In this Research Topic, a number of experts contributed their updated research outcomes or opinions regarding the strategies to improve the microbial production of polyester. From the perspective of microbial production of novel lactate containing polyesters and oligomers, It is hard to forecast the future of polyester industries, but we believe biopolyesters will have a promising future, based on: the availability of renewable and sustainable bio-feedstocks to support the bioproduction of polyesters; consumer demand for biodegradable and bioassimilatable materials based on renewable biopolymers; industries and research institutes that are eager to develop renewable and degradable polyester products; and the increasing application of advanced biotechnologies  and materials science techniques  that are being applied in this field.Enjoy reading!"}
+{"text": "Waste electronic and electrical equipment (e-waste) consists of used and discarded electrical and electronic items ranging from refrigerators to cell phones and printed circuit boards. It is frequently moved from developed countries to developing countries where it is dismantled for valuable metals in informal settings, resulting in significant human exposure to toxic substances. E-waste is a major concern in Africa, with large sites in Ghana and Nigeria where imported e-waste is dismantled under unsafe conditions. However, as in many developing countries, used electronic and electrical devices are imported in large quantities because they are in great demand and are less expensive than new ones. Many of these used products are irreparable and are discarded with other solid waste to local landfills. These items are then often scavenged for the purpose of extracting valuable metals by heating and burning, incubating in acids and other methods. These activities pose significant health risks to workers and residents in communities near recycling sites. E-waste burning and dismantling activities are frequently undertaken at e-waste sites, often in or near homes. As a result, children and people living in the surrounding areas are exposed, even if they are not directly involved in the recycling. While toxic substances are dangerous to individuals at any age, children are more vulnerable as they are going through important developmental processes, and some adverse health impacts may have long-term impacts. We review the e-waste situation in Africa with a focus on threats to children\u2019s health. How to safely dispose of waste products coming from human activity is a global problem. Often in countries without adequate regulation, wastes are simply discarded. Most countries put wastes into landfills, but without adequate control landfills stink, leachate coming from the landfill can contaminate water and methane escaping from degradation of organic material contributes to climate change. In addition, landfills often attract vermin than can cause and spread disease. In many poor countries, people\u2014including children\u2014scavenge landfills for items of value, increasing risk of injury, infection and exposure to dangerous substances. Incineration is an alternative to landfills, but if incinerators are not operated with appropriate controls, they release toxic metals and dioxins that have the potential to cause significant harm to human health ,2. The harm to the environment is made worse when the discarded material is not readily degradable, as is the case with plastics that now contaminate land, lakes, streams and even the ocean. About eight million metric tons of plastics enter the oceans each year . HazardoThe term electronic and electrical waste (e-waste) refers to \u201celectrical or electronic equipment, which is waste, including all components, subassemblies, and consumables, which are part of the equipment at the time the equipment becomes waste \u201d. E-wastIn 2019, the world generated an estimated 53.6 million metric tons (Mt) of e-waste, or an average of 7.3 kg per person . FurtherThe value of the raw materials in global e-waste is estimated to be 57 billion USD, with iron, copper and gold contributing the most . In someE-waste includes many substances that are dangerous to the health of humans and the environment if released in an unsound manner. E-waste recorded in 2019 contained as much as 50 tons of mercury and 71 kt of brominated flame retardants . The impWhile there is significant exposure risk to all individuals who are involved in informal e-waste recycling  childrenPeer-reviewed publications within the past 15 years related specifically to e-waste in Africa were assembled based on searches on academic research publication databases including PubMed, Science Direct, and Google Scholar. Publications, governmental and regulatory agency reports, and guidelines, were obtained through formal and informal sources. Keywords used to search the literature were: e-waste in Africa, WEEE in Africa, used electronic equipment in Africa, African e-waste management, e-waste regulations and guidelines in Africa, health effects of e-waste chemicals in Africa, African children\u2019s exposure to e-waste chemicals and impacts, countries exporting e-waste to Africa, and African countries most affected by e-waste. Tsydenova and Bengtsson  reviewedLandfills in African countries containing e-waste have shown elevations of many different potentially hazardous metals . Soils aE-waste is recognized as a resource as it contains valuable materials . HoweverThese methods result in severe air pollution containing many toxic substances around e-waste recycling areas. Particulates and other air pollutants are inhaled by workers and nearby residents. In addition, chemicals escape and may contaminate dust, soil, and water in communities around dump sites leading to additional routes of exposure, such as dermal contact and consumption of contaminated food and water . E-wasteLead: Lead is a well-known neurotoxin . Ho. Ho11]. The care and management of e-waste in African countries is either poor or non-existent. The management of e-waste in African countries is a major contributing factor to high levels of pollution and hence the adverse effects on humans, animals, and the environment . Few AfrOn the Ban of the Import into Africa and the Control of Transboundary Movement and Management of Hazardous Wastes within Africa, was set up in 1991 to ban the importation of toxic substances from developed countries into African countries. The East Africa Communication Organization (EACO), formed in 2012, has developed working groups to address e-waste issues in its member nations. EACO has held a range of regional conferences and has produced several reports and strategies addressing e-waste management, awareness, and the status of e-waste in member nations. EACO also aims to train national representatives in better e-waste management, facilitating interventions, and the development of more reliable regional and national statistics. At a national level, the e-Waste Association of South Africa (eWASA) was formed in 2008 to establish sustainable and environmentally friendly ways of managing e-waste. Its members include electronics manufacturers, importers, and retailers. eWASA has struggled to affect the import of e-waste in South Africa. One reason for this is that e-waste and its economic benefits have been championed by business-people who may not consider or be aware of short- and long-term health impacts due to exposure of inappropriately recycled e-waste [The Bamako Convention,  e-waste . At the  e-waste . In Marc e-waste . Other S e-waste . Interventions targeting e-waste are desperately needed in African countries. At international and regional levels, interventions need to target the illegal importation of e-waste, including the better training of inspection officers and better management techniques, without depriving recyclers of their source of livelihood. The International Labor Organization (ILO) has produced strategies on ensuring the safety of e-waste workers that can be adapted to African contexts . At natiAwakening environmental awareness, increased environmental regulation and associated disposal costs in developed countries in the 1970s and 1980s led to incidents of uncontrolled transboundary movements of hazardous wastes and, at times, intentional dumping in developing countries, including in the African region. In response, the global community adopted the Basel Convention on the Control of Transboundary Movements of Hazardous Wastes and Their Disposal on 22 March 1989 and entered into force in 1992. The main objective of the Basel Convention is the protection of human health and the environment against the adverse effects resulting from the generation management, transboundary movement, and disposal of hazardous and other wastes.E-waste can fall under several entries in the annexes to the Basel Convention. In 2019, the \u201cBan Amendment\u201d to the Basel Convention entered into force, prohibiting the transboundary movement of hazardous wastes controlled under the convention destined for final disposal operations from parties listed in Annex VII (Organization for Economic Co-operation and Development (OECD), the European Commission countries and Liechtenstein) to all other States. The Ban Amendment also prohibits transboundary movement of hazardous wastes controlled by the convention except for those considered or defined as hazardous by the national legislation destined for reuse, recycling, or recovery operations. The entry into force of the Ban Amendment has significant political weight, acting as a flagship of international efforts to ensure that those countries with the capacity to manage their hazardous wastes in an environmentally sound manner take responsibility for them, while still allowing parties wishing to receive wastes required as raw materials for recycling or recovery industries. The Basel Convention was followed by other important conventions designed to deal with hazardous wastes, as outlined in The Bamako Convention is a treaty of the African countries to ban the import into Africa and to control the transboundary movement and management of hazardous and radioactive wastes within Africa. The need for the Bamako Convention was based on the realization that many developed nations were exporting toxic wastes to Africa. This convention was adopted in Bamako, Mali in 1991 and came into effect in 1998 . The majOstrava DeclarationLegal status: Legally bindingAdoption: 13\u201315 June 2017Entry into force: 15 June 2017Parties: 53 Member States of the WHO European Region (as of July 2021)Objectives: to improve outdoor and indoor air quality as one of the most important environmental risk factors in the region through actions towards meeting the WHO air quality guideline values in a continuous process of improvementScope: to shape policies and actions on environment and health, support the implementation of effective evidence-based policies and advance actions on environment, health, and well-being in the WHO European Region (as of February 2021)Key provisions:Improve air quality for all by ensuring access to safe drinking water, sanitation, and hygiene. Minimize the adverse effects of chemicals. preventing, and eliminating the adverse effects of waste management and contaminated sites. Strengthen adaptation to and mitigation of climate change. Build environmentally sustainable health systemsThe Basel, Rotterdam, Stockholm, Bamako Conventions, and the Ostrava Declaration are multilateral environmental agreements, which share the common objective of protecting human health and the environment from hazardous chemicals and wastes. Meanwhile, membership of any of the above conventions is not universal and compliance for some countries remains a challenge. For example, while most European countries have signed the Basel Convention, there is evidence that some 352,474 metric tons of e-waste are shipped from EU countries to developing countries each year . Therefoadvocacy including awareness raising and campaigns; knowledge and best practice sharing; and the development of a joint intervention model for the implementation of e-waste work at the country level [In 2018, the E-waste Coalition, a group of international organizations working globally and supporting national governments to address the e-waste challenge more effectively and across health and environment, climate and development agendas, signed a letter of intent. The E-waste Coalition has three core functions: ry level . As a mery level . The pilThis article proposes that actions can be taken at the local, national, regional and international levels to combat hazardous exposure to e-waste. At the local level, the health sector can play an important role by working with other sectors, such as labor, education, policy and environment, identifying specific needs within e-waste-affected communities, educating local communities on the health risks of exposure to e-waste and communicating methods to reduce exposure where possible, recognizing and monitoring health effects of exposure to e-waste and prescribing appropriate solutions. At national, regional and international levels, governments and policy-makers need to ratify appropriate conventions, such as the Bamako and Basel Conventions, that regulate and restrict the transboundary movement of hazardous waste, including e-waste, and implement World Health Assembly Resolution 69.4 on the role of the health sector in the Strategic Approach to International Chemicals Management towards the 2020 goal and beyond. At the regional level, countries need to work together to develop more robust data, build capacity and train those responsible for identifying illegal e-waste exports and to ensure that restrictions on transboundary movement of hazardous waste are enforced. National governments need to develop and implement effective waste management legislation that addresses hazardous waste, such as reducing the use of the most hazardous components in electronic and electrical equipment and encouraging safer and more efficient methods of recycling, develop health-related targets and actions for current and future e-waste policies and conduct research on e-waste and its potential health effects in a variety of contexts and locations, and to evaluate the efficacy of interventionsAt national and international levels, the health sector can play an important role by advocating and lobbying policymakers to incorporate strong health protection measures into national waste management policies and new electronics manufacturing initiatives. Across all levels more research is needed to monitor exposure to e-waste, to better understand the health outcomes associated with e-waste and to implement, and provide evaluation, of e-waste interventions. Research is key to providing national governments and international conventions with evidence of the dangers of e-waste exposure, the urgent need for greater regulation and informing effective legislation and controls. At the local level the health sector should be informed and empowered to raise awareness of the risks of e-waste recycling and prescribe appropriate solutions, work with communities at the primary health-care level to educate and engage key agents and implement and monitor the success of interventions that aim to reduce e-waste exposure.E-waste is a global problem due to the desire of people to have the latest electronic device, the rapid development of new devices and the short lifecycle of many electronic devices, such as computers and mobile phones. While almost all electronic and electrical items contain valuable materials, especially metals such as copper, the cost associated with extraction of these valuable materials from most devices in a safe manner and then disposing of the remainder often exceeds the value of the materials that are extracted. This has made recycling of electronic equipment questionably cost effective in most developed countries, leading to illegal exportation to and exploitation of less developed countries that do not have stringent safety regulations. At the same time the informal recycling of e-waste has provided necessary income for many people in developing countries. Workers, nearby residents and especially children living in or near the sites of informal e-waste recycling are being exposed to a variety of dangerous chemicals that impact cognitive function and increase the risk of many different diseases, including respiratory diseases and cancer. African countries have tried to address these problems through the Bamako Convention and a number of regional interventions, but lack of national action, legislation and enforcement has resulted in serious harm to e-waste workers, nearby residents and especially to the health of children. Stronger action and awareness are needed at international, regional, national and local levels to ensure that the health of people, especially children, and the environment is protected from hazardous chemicals found in e-waste."}
+{"text": "Infections are a major cause of premature death. Fast and accurate laboratory diagnostics of infectious diseases is a key condition for the timely initiation and success of treatment. Potentially, it can reduce morbidity, as well as prevent the outbreak and spread of dangerous epidemics. The traditional methods of laboratory diagnostics of infectious diseases are quite time- and labour-consuming, require expensive equipment and trained personnel, which is crucial within limited resources. The fast biosensor-based methods that combine the diagnostic capabilities of biomedicine with modern technological advances in microelectronics, optoelectronics, and nanotechnology make an alternative.The modern achievements in the development of label-free biosensors make them promising diagnostic tools that combine rapid detection of specific molecular markers, simplicity, ease-of-use, efficiency, accuracy, and cost-effectiveness with the tendency to the development of portable platforms. These qualities exceed the generally accepted standards of microbiological and immunological diagnostics and open up broad prospects for using these analytical systems in clinical practice directly at the site of medical care provision .A wide variety of modern biosensor designs are based on the use of diverse formats of analytical and technological strategies, identification of various regulatory and functional molecular markers associated with infectious pathogens. The solution to the existing problems in biosensing will open up great prospects for these rapidly developing diagnostic biotechnologies. The most terrible tragedies of mankind in recent centuries have been associated with the outbreaks and spread of pandemic infections that have claimed hundreds of millions of lives. Despite the obvious success of the global health care system, the risk of epidemics of known, new, and recurring infections remains a serious threat to the world\u2019s population. The bacterial and viral infectious diseases with the fecal-oral mechanism of infection claim about 2 million lives annually. The recent outbreaks of Ebola, Zika, Dengue, Middle East respiratory syndrome, severe acute respiratory syndrome, and H5N1 influenza, as well as the increasing resistance of bacteria to antimicrobial drugs, increase the urgency of searching for new effective diagnostic tools aimed at early and rapid detection of pathogens .With broadening our knowledge on the complex biochemical processes underlying the pathogenesis of infectious processes, it has become necessary to develop more sensitive and highly specific diagnostic strategies. They are based on the identification of molecular markers, profiling of microorganisms without cultivation, enrichment, and isolation of pure cultures. These methods will become ideal analytical tools for controlling pathogenic microorganisms and make a basis for identifying the relationship between molecular structures and biological processes , 4, 5.Classical microbiological and immunoserological methods, as well as modern diagnostic platforms such as ELISA and chemiluminescence analysis, PCR, flow cytometry, and mass spectrometry (MALDI) adopted in recent decades, prevail when accurate verification of infectious agents is needed in centralized laboratories of medical hospitals and centers. However, these diagnostic tools require expensive equipment, long testing times, and qualified personnel, and are not always available for small hospitals, especially under limited economic resources and the decentralized infrastructure of medical facilities , 6, 7.The biosensor technologies that have emerged over recent years and are actively developing serve as innovative platforms for analyzing biomarkers of the infectious process have a high potential to become affordable, fast and reliable in operation, highly specific and sensitive tools for timely and true diagnosis of bacterial and viral diseases , 9. The In the global practice of infectious disease diagnostics, the point-of-care strategy is becoming increasingly important, based on modern molecular diagnostic technologies, including laboratory testing by the medical personnel at the patient\u2019s bedside or self-monitoring of certain laboratory parameters by patients at home , 9.The diagnostic platforms-precursors of this innovative strategy include qualitative and semi-quantitative test systems for identifying specific antigens  and antiStreptococcus pneumoniae and Legionella pneumophila urinary antigens with the LFIA method. This has increased the popularity of the universal technology that is equally effective in the sandwich analysis format for both high-molecular antigens of microorganisms and antibodies to them in biosubstrates and low-molecular analytes .According to the definition of IUPAC  , biosensThe idea of developing biosensors appeared more than half a century ago, and putting it into practice started , 35. TheIn the modern world, a considerable growth of interest is observed in biosensor technologies, which are rightly considered to be one of the rising trends in the scientific and technical sphere , 38\u201340. Structurally, biosensors are a complex consisting of three main functional segments:a bioreceptor (a biosensing component) with the elements on the sensor plate for recognizing target analytes (target molecules) contained in the biosubstrates;a transducer operating on physical and chemical principles ;an electronic device for signal processing, recording, and displaying data in a convenient  form for the researcher .The analysis of the literature demonstrates interest in the development and use of these analytical devices in ecology, toxicology, agriculture, biosafety, and medicine, including the clinical diagnosis of infectious diseases and septic conditions. Over the decades of the development of the biosensing technology, a large number of structurally different sensors and attempts to systematize them have been proposed , 41\u201343.Currently, the biosensor classification is based on the nature of the biochemical component used, the analytical tasks to be solved, the type of signal transducer, the intended application field, and the generated signal. The technical strategies conditioning the ways of further detection (transduction) of the signal/event determine the basic principle of differentiation of the analytical devices , 44.According to this principle, in one of the proposed IUPAC classifications , all bio2 are immobilized on a solid sensor substrate (matrix) by covalent binding or biotin-avidin interaction. They serve for selective binding and identification of target analytes (ligands) in biological fluids  [The recognition elements (bioreceptors) are common to all types of biosensors used in biomedical diagnostics: immunoglobulins (antibodies), enzymes , nucleic acids  \u201347, micrxtracts) , 49\u201351.When designing highly sensitive biosensors, the correct choice of the matrix and conditions for immobilization of bioreceptors is of key importance. When using non-covalent binding, the receptor is retained on the sensor substrate of the transducer due to electrostatic, van der Waals, or ion interactions that hold the biomolecules fairly firmly. The main advantage of this type of immobilization is that the matrix does not affect the biological properties of the receptor , 26. WitThe new-generation devices more often comprise nanomaterials, the unique catalytic efficiency and adsorption properties of which are ensured by the optimal physical and chemical characteristics of the sensor substrate surface , 40, 54.The mechanism of transmitting a ligand-receptor interaction signal and its transduction is another important functional element of biosensors. Transmission is carried out with electrodes  and graphite pastes , 56, 57.The principle of operation of bioreceptors can also be represented as three consecutive stages: recognition of the target ligand in the biosubstrate by a specific bioelement located on the touch panel; transduction of information about the biochemical reaction into the form of an electrochemical signal; transduction of this signal into a form convenient for reading or processing by the researcher , 55, 56.For example, in the biosensors, where the enzymes immobilized on the sensor plates serve as a recognition element, the substrates from the biomaterial in the presence of catalysts enter a biochemical reaction with them. The resulting product is determined with the aid of an electrode that transduces the biochemical reaction into an electrochemical signal, the magnitude of which is proportional to the amount of substrate in the studied biomaterial , 57, 58.In recent decades, the key task of interdisciplinary research into the design of modern biosensors  has been to improve the parameters of close interaction of biochemical and physical functional elements in order to increase their sensitivity, selectivity, and reduce the detection limits of target analytes , 59, 60.The progress in the development of biosensor diagnostics of bacterial and viral infections has been achieved mainly due to modern improvements in the methods used for the identification of specific markers , 61\u201364.Escherichia coli or Staphylococcus aureus) integrated on the sensory substrate assimilate target organic compounds from biosubstrates , they themselves acting as a sensitive mechanism [Together with the already used analytical devices, where immunoglobulins and enzymes in the form of bacterial homogenates are applied as bioreceptors, in recent years, whole-cell microbial biosensors have been introduced, in which live natural or engineered microorganisms  and its relationship with the patterns of metabolism and growth of microbes were described. These fundamental studies were confirmed in subsequent years by studying the role and structure of DNA and other reporter genes, such as xylE and tfdA, which are currently used actively as a biophysical model for environmental research [The use of reporter genes to identify factors that trigger genetic response in living microorganisms was proposed in the middle of the last century , 35 whenresearch , 66, 67 E. coli, S. aureus, Pseudomonas aeruginosa, and Staphylococcus epidermidis) with concentrations ranging from 102 CFU/ml. Besides, this sensor enabled the differentiation between live bacteria and dead ones.Liu et al.  reportedS. aureus, where a bacteriophage with a detection range of 4\u00b7108 CFU/ml was used as a receptor [Another group of researchers proposed a biosensor design for highly sensitive and rapid identification of receptor .Further improvement of microbial biosensors has been due to the emergence of regulatory biosensing associated with advances in molecular genetic technologies and the discovery of new mechanisms for detecting various extracellular and intracellular signals, as well as their subsequent optical and electrochemical transduction , 69, 70.With the development of modern technologies in infectious disease diagnostics and epidemiology, label-free biosensors have become increasingly more widespread. They enable screening of intermolecular interactions and cellular reactions, provide detailed information about the selectivity of bacterial exotoxins and the specificity of antimicrobial agents, the interaction of antigen with antibody, as well as the kinetics of the inflammatory process, immunological and serological reactions , 73.Currently, there is a wide range of analytical devices for analyzing biospecific ligand-receptor interactions in label-free biosensors. In these highly sensitive and functional systems, the binding reactions of the target analyte to the bioreceptor can be studied without the use of any enzyme, radioactive, or fluorescent labels , 74, 75.This type of biosensor requires only one recognition element, which simplifies the analysis scheme, reduces its duration, and the cost of reagents. The current generation of label-free biosensors allows quantitative measurements of biomolecular reaction products in real time, which makes it possible to perform continuous data recording that enables kinetic monitoring of the parameters of the recognition process in ligand-receptor interactions , 78.An important advantage of using label-free biosensors is that the target analytes are detected in their natural form, without labeling or chemical modification, which means that they can be saved for further analysis .In recent decades, numerous studies have been conducted to develop new types of receptors , 68, 73 The optical, (piezo)electrical, or (micro)mechanical transducers are among the promising methods for recognizing ligand-receptor interaction signals in label-free biosensors used for the diagnosis of various infectious diseases. These biosensing methods are enhanced by surface plasmon resonance (SPR) , surfaceThe biosensors with optical transducers, considered as the main tools for signal perception, are one of the most powerful detection and analysis tools widely used in biomedical research and practical medicine , 88, 89.Due to a variety of detection methods using optical transducers in label-free biosensors, the authors of the review limited themselves to the devices that have proved successful in the detection of infectious disease pathogens. The cutting-edge technologies in the design of label-free optical biosensors with the focus on the diagnosis of bacterial infections are associated with the development of modern methods of transduction  and new recognition elements (molecular-imprinted polymers) , 90\u201392 .Among the modern technologies used for the clinical diagnostics of bacterial and viral infections, the development of electrochemical methods of optical biosensing based on nucleic acids presents interest. The recognition elements used in these types of analytical devices include DNA, RNA, PNA, and aptamers. For example, nowadays the sensor technology of DNA hybridization based on electrochemical (impedance spectroscopy) and optical methods which recognizes the complementary target DNA chain of a pathogenic microorganism is gaining popularity, , 93, 94.The appearance of aptamer-based biosensors (aptasensors) and recombinant nucleic acids as recognition elements has resulted from the development of new technologies and advances in synthetic aptamer biology , 40, 48.For example, in a recent study by Sheng et al. , they reS. aureus, selected as the target pathogen for their aptosensor in food and water. The quantitative assessment of ligand-receptor interaction in the proposed biosensor variant was performed with specific fluorescent dyes for nucleic acids (Sybr Gold and Sybr Green I). It is noteworthy that rapid detection of the pathogen did not require special sample preparation .The authors  demonstrThese modern innovations make optical biosensors more versatile than other types of sensor technologies , 74, 76.In optical biosensors, the use of the transduction method based on the surface plasmon resonance effect and the phenomenon of total internal light reflection is common , 84, 90.If gold (or silver) is sprayed on a hydrogel plate, then another phenomenon occurs associated with the presence of free electrons in this metal(s), which are exposed to the alternating electric field when illuminated. These electrons can collectively vibrate and resonate, adjusting to the frequency of incident light M. tuberculosis biomolecules and non-tuberculosis CFP10 and MPT64 mycobacteria, which, among numerous mycobacteria antigens, interact most strongly with related anti-CFP10 and anti-MPT64 antibodies on the immunosensor matrix.Among the family of optical label-free biosensors, SPR is one of the most accessible, developed, and most successfully used technologies in recent years for the diagnostics of infectious diseases and septic conditions. This is due to the high sensitivity and versatility of this type of sensors, which also allow real-time detection and direct measurement of the kinetics of molecular ligand-receptor interaction , 80. ForThe only drawback of optical label-free biosensors that use prismatic light refraction and SPR effects is their relatively large size, which is incompatible with mobile use in the point-of-care mode , 81. TheM. tuberculosis, mycobacterial proteins, and IFN-\u03b3 cytokine as the most important markers in the early diagnosis of tuberculosis.Label-free optical biosensors have been consistently used for characterization and screening of molecular interactions in clinical laboratories. For example, Golichenari et al.  presenteThe majority of modern biosensors intended for the detection of infectious pathogens are based on electrochemical conversion of the signal. These sensors are based on measuring changes in the current, electrochemical potential, and impedancemetry as a means of conversion of biochemical reactions , 47, 85.The advantages of these devices include portability and simple measuring equipment. Together with their cost-effectiveness, high sensitivity, and large linearity detection range, the electrochemical sensors are capable to work with small sample volumes. Moreover, the result is not affected by sample turbidity, unlike the optical methods based on spectroscopic transduction , 100.The analysis of the research results published in recent years has shown that the development of molecular biology methods with the aid of nanotechnology opens up broad prospects for designing new biosensor platforms with highly efficient, highly sensitive, and highly selective detection of molecular infectious biomarkers.Medical biosensors as a new type of diagnostic tools are at the initial stage of their development. However, the first decades of practical application of these analytical devices in healthcare have shown their absolute attractiveness and prospects for detecting bacterial and viral pathogens. The development and implementation of biosensor technologies in clinical laboratory practice is a modern non-alternative strategy for reducing infectious diseases in the regions with a low level of healthcare, where cheap and highly effective diagnostics can play a key role in timely verification of pathogens. The development of inexpensive and affordable analytical devices for clinical diagnostics with lower detection limits for pathogens is necessary due to the importance of diagnosing infectious diseases at the preclinical stage. In this regard, successful experiments in designing and using biosensors for the detection of spore and uncultivated bacteria with an assessment of their viability pose interest , 87, 101This review focuses on a large group of biosensors that are more available and do not need labels for the reproduced signal, but have rather complex transduction systems. However, the future is for simpler and more portable diagnostic analytical systems that do not require complex conversion platforms (surface plasmon resonance and surface Raman spectrometry) and can detect multiple pathogens simultaneously on the base of multiplex analysis. Such biosensors will be able to solve the global problem of effective control of infectious diseases.Modern trends in the development of biosensor medical technologies are associated with the development of new materials for designing transducers and conditions for more effective ligand-receptor interaction. The prospects for expanding the practical applications of biosensor technologies are related to clinical diagnostics which meets the requirements of personalized medicine, and are equally attractive for doctors and patients, particularly when verifying pathogens of infectious diseases.in vivo metabolites, drugs and molecular markers of the infectious process will soon play a leading role.Moreover, one of the key modern trends in the development of clinical laboratory diagnostics is non-invasive testing, which does not involve blood sampling. In this regard, highly sensitive, miniature, and portable medical biosensors with their capability to continuously monitor"}
+{"text": "Dear Editor,Psoriasis is a chronic, immune-mediated and complex inflammatory disease. The immunopathogenesis of the disease involves interferon-gamma (IFN-gamma), tumor necrosis factor (TNF), and specific interleukins (ILs) that coordinate the interaction between inflammatory cells and keratinocytes.IL inhibitors represent a new group of biological agents with greater specificity for the treatment of psoriasis, as they selectively target inflammatory pathways.Ustekinumab is a fully human monoclonal antibody that binds with high affinity and specificity to the p40 protein subunit, shared by cytokines IL-12 and IL-23.43) in patients with no history of recurrent infections and no secondary causes.Benign constitutional neutropenia is an asymptomatic condition characterized by mild chronic neutropenia  of 13, Psoriasis Area and Severity Index (PASI) of 12.9 (3.A 44-year-old dark-skinned male patient started follow-up at a dermatology referral service 10 years ago due to severe psoriasis, without joint involvement. He had a previous diagnosis of familial constitutional leukopenia 17 years ago, with a mean leukocyte count of 2600\u00a0mm of 12.9  and, conAfter undergoing the initial tests before starting the immunobiological treatment, which were all within the normal range, treatment with ustekinumab 45\u00a0mg was introduced, with the induction phase taking place in weeks 0 and 4 and then every 12 weeks, associated with calcipotriol, twice a day. The patient showed significant lesion improvement after12 weeks, with residual macules only and currently with PASI 0 . The patEvidence indicates that neutropenia during therapy with ustekinumab is rare, and when it occurs it is mild; therefore, periodic monitoring is recommended.None declared.Jessica Vianna Starek: Approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; collection, analysis and interpretation of data; critical review of the literature; critical review of the manuscript.Mariana Reis and Rocha Dultra: Approval of the final version of the manuscript; drafting and editing of the manuscript; collection, analysis, and interpretation of data; critical review of the literature; critical review of the manuscript.Cristina Santos Ribeiro Bechara: Approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; critical review of the manuscript.Juliana de Morais Fernandes Krakheche: Approval of the final version of the manuscript; design and planning of the study; collection, analysis, and interpretation of data; effective participation in research orientation; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.None declared."}
+{"text": "For years, restrictive cardiomyopathies have remained poorly understood and resulted in significant morbidity and mortality. These cardiomyopathies are often difficult to diagnose and can be considered orphan diseases that often lack definitive therapies. In the last several years, however, exciting innovation and treatment, particularly in the field of amyloidosis, has spiked new interest and hope for patients and families affected by these diseases.In this issue, we aim to provide a comprehensive update to our readers regarding restrictive cardiomyopathies and also focus on two of the most common restrictive cardiomyopathies, amyloidosis and sarcoidosis. This issue is of special interest to us as guest editors because we both treat patients with these specific conditions, and we appreciate the opportunity to share answers to many clinically relevant questions through the reviews written by experts in the field.The terminology and classification of restrictive (and infiltrative) cardiomyopathies often leads to much confusion. In the introductory article, Drs. Imad Hussain, Smitha Narayana Gowda, and Hyeon-Ju Ali abate the confusion in their broad overview of the definition and classification of restrictive cardiomyopathy (RCM), defined as a heterogeneous group of diseases that cause increased myocardial stiffness leading to impaired ventricular relaxation and severe diastolic dysfunction. While it is the least common type of cardiomyopathy, it can be a diagnostic challenge given varied pathogenesis, clinical presentation, and diagnostic evaluation. In this review, they provide an overview of the rarer etiologies of RCM (excluding amyloidosis and sarcoidosis) and their diagnostic and treatment approaches.The next reviews focus on amyloidosis. Dr. Daniel Judge and colleagues provide a comprehensive overview of the epidemiology, genetics, and prognosis of transthyretin amyloid cardiomyopathy (ATTR-CM). This is an underdiagnosed disease characterized by pathologic accumulation of extracellular protein arising from unstable TTR tetramers. The authors break down the two distinct forms of ATTR-CM, hereditary and wild-type, and summarize the most common genotypes and their phenotypic heterogeneity. In addition, they give an overview of high-risk clinical features and factors that help predict prognosis.Following the ATTR-CM discussion, Dr. Kelty Baker reviews the epidemiology of light chain amyloidosis, the staging systems, and the concomitant prognostication that is critical in determining the appropriate treatment.Dr. Ahmad Masri and colleagues then review the clinical, imaging, and electrocardiographic clues that should raise suspicion for cardiac amyloidosis. They provide a simplified diagnostic workup algorithm to ensure an accurate diagnosis. The evolution of the noninvasive diagnosis of cardiac amyloidosis has significantly influenced our understanding of disease prevalence, presentations, and outcomes. However, clinical recognition of clues and red flags remains the most important factor in advancing the care of patients with cardiac amyloidosis.Multimodality imaging is becoming the crux of recognizing and diagnosing cardiac amyloidosis. Dr. Mouaz Al-Mallah and colleagues highlight the role of several known and innovative cardiac imaging techniques\u2014including echocardiography, cardiac magnetic imaging, and nuclear imaging\u2014that aid in the evaluation of cardiac amyloidosis.Treatment options used to be limited; however, the last decade has seen significant advances in disease-modifying therapies. Drs. Jignesh Patel and Lily Stern provide an excellent overview of current and experimental treatments for both light chain and ATTR amyloidosis.After these excellent review articles that keep us up to date on present diagnosis and treatment of cardiac amyloidosis, Dr. Barry Trachtenberg explores where the field is heading and what the future might hold for therapeutics and diagnostics. This topic includes the goal to develop anti-fibril therapies that will be safe and effective at removing deposited amyloid fibrils and restoring organs to their pre-amyloid state, as well as the potential for genetic editing to cure variant ATTR even before patients develop clinical signs of the disease.While several landmark studies have been done in amyloidosis, cardiac sarcoidosis is an emerging landscape for well-designed clinical trials. Several areas remain unexplored, particularly in the pathogenesis, genetics, newer imaging modalities, biomarkers, and treatment. Research and innovation are definitely needed in this area. The last two reviews of our special edition focus on this orphan condition.Cardiac sarcoidosis (CS) is a widely underdiagnosed yet clinically significant form of granulomatous myocarditis associated with significant morbidity and mortality. Clinical presentation ranges from clinically silent disease to cardiomyopathy or sudden cardiac death. Diagnosis of CS remains challenging due to the lack of sensitivity of any single diagnostic method, underscoring the importance of elevated clinical suspicion and the use of multimodality imaging to guide diagnosis and treatment. In this review, Dr. Yogita Rochlani and her colleagues discuss the epidemiology, pathogenesis, clinical features, and diagnosis of this clinically evasive disease.Sarcoidosis is a heterogeneous disease with various treatment indications, pulmonary and extrapulmonary. In this review, Drs. Ilias Papanikolaou, Emmanouil Antonakis, and Aggeliki Pandi provide a state-of-the art review on treatment indications and various agents whose use is supported by clinical trials.We are grateful for the opportunity to compile this special edition and provide you with a current overview of restrictive cardiomyopathies in general, with an added focus on the two specific cardiomyopathies. Clearly, the last decade has been exciting, particularly in the arena of cardiac amyloidosis. We anticipate additional advances that will come with new innovations in bioinformatics, imaging modalities, and drug development.Methodist DeBakey Cardiovascular Journal express our thanks to Dr. Trachtenberg and Dr. Kassi for their enthusiasm and dedication in curating this issue on infiltrative and restrictive cardiomyopathies.The editorial team of the Barry Trachtenberg, MD, is a cardiologist specializing in cardio-oncology, cardiology, heart failure, and transplantation cardiology. He is board certified in internal medicine, cardiovascular disease, echocardiography, and advanced heart failure and transplant.Dr. Trachtenberg received his BS degree from the University of Pennsylvania and attended medical school at the University of Texas-San Antonio. A native Houstonian, he completed his residency in internal medicine at Baylor College of Medicine prior to his cardiology training at the University of Miami School of Medicine.His clinical experience includes heart failure and heart transplantation, mechanical support pumps, cardiomyopathies, cardiac amyloidosis, and cardio-oncology. He has contributed to many publications related to advanced heart failure, cardio-oncology, amyloidosis, and ventricular assist devices.Dr. Trachtenberg is a member of the Amyloidosis Working Group of the International Cardio-Oncology Society of North America and serves on the Cardio-Oncology Council of the American College of Cardiology. He serves as the Heart Failure chair for the Texas Chapter of the American College of Cardiology. Currently, Dr. Trachtenberg is a heart failure/transplant cardiologist at Houston Cardiovascular Associates and a member of the Houston Methodist DeBakey Heart & Vascular Center and Methodist J.C. Walter Transplant Center.Mahwash Kassi, MD, is an advanced heart failure and transplant cardiologist at the Houston Methodist J.C. Walter Jr. Transplant Center and the Houston Methodist DeBakey Heart & Vascular Center. An assistant professor of cardiology at the Houston Methodist Academic Institute and Weill Cornell Medical College, she also is an assistant clinical member of the Houston Methodist Research Institute.Dr. Kassi received her medical degree from Aga Khan University in Karachi, Pakistan. She completed fellowships in cardiology at Houston Methodist Hospital and in advanced heart failure and transplant at Mayo Clinic, Rochester, Minnesota, in 2017.Her clinical interests include inherited and inflammatory cardiomyopathies, particularly cardiac sarcoidosis. She has numerous publications in peer-reviewed journals and her research interest includes computational fluid dynamic modeling in patients with left ventricular assist devices, for which she received the Texas A&M Presidential Award. In addition, Dr. Kassi is leading research efforts in cardiac sarcoidosis."}
+{"text": "Coronaviruses in wild and domestic animals have a long history of spillover between species . These examples emphasize the need for wider mobilization of veterinary skills and expertise within national and international task forces in countering SARS-CoV-2 transmission and future epidemics.At national and international levels, veterinary professionals, their representative associations and animal health regulatory bodies have played roles in protecting the public\u2019s health during the COVID-19 pandemic due to their knowledge and first-hand experiences with animal coronaviruses. The United States Agency for International Development\u2019s Emerging Pandemic Threats, the Pandemic Preparedness for Global Health Security (PREDICT) project, was managed by the School of Veterinary Medicine at the University of California, Davis, and was headed by wildlife veterinarians. Through this project, bio-surveillance of SARS-CoV-2 in animals and humans was conducted. The program underscores the significance of veterinarians and their capacities in coronavirus surveillance and control. Another example of the human-animal-ecosystem endeavor is the establishment of the World Organisation of Animal Health (OIE) \u201cAd Hoc Group on COVID-19 at the Human-Animal Interface.\u201d The Group is led by Dr. William Karesh, president of OIE\u2019s Working Group on Wildlife, and joined by collaborating groups to identify research priorities, assess and disseminate surveillance information, and provide guidance on veterinary services that are COVID-19-relevant in animal health and veterinary public health. In Ireland, veterinary epidemiologists work with medical and research colleagues of the National Public Health Emergency Team\u2019s modeling advisory group to counter COVID-19 (Ferri and Lloyd-Evans http://www.primate-sg.org/covid-19). As a precaution against COVID-19 spillover, the IUCN Group recommends biosecurity measures to prevent and control coronavirus transmission from humans to wild great apes, including guidelines on physical distancing, mandatory use of medical masks and various bans on visitation. Further examples of veterinarians researching, producing and following statements can be found at the Center for Disease Control, COVID-19 Safe Industry Plan for Zoos and Aquariums by the Australia Zoo and Aquarium Association, and OIE guidelines to prevent spillover of coronavirus around humans, terrestrial and aquatic animals (www.cdc.gov/coronavirus)  Species Survival Commission (SSC) and the Wildlife Health Specialist Group collectively produced \u201cGuidelines for Working with Free-Ranging Wild Mammals\u201d, among other risk assessments and preventive measures for care of captive wildlife. The IUCN SSC recommends that during the COVID-19 pandemic, no great ape reintroductions or translocations should take place . In addition, the US Centers for Disease Control and Prevention (US-CDC) co-funded the development of a Field Epidemiology Training Programme for Veterinarians (FETPV) in Indonesia in 2017 which helps Indonesia to gatekeep against emerging animal coronavirus epidemics. Current surveillance systems were found to be inadequate in a number of countries when COVID-19 emerged. Surveillance for infectious agents in farmed animals and wildlife is both underfunded and often inconsistent, with reduced interest in disease during inter-epidemic periods. There have been strong calls for enhanced wild animal surveillance to determine the extent and nature of the threats posed and for appropriate action to be taken , and in turn, EID prove to be very costly, both monetarily and environmentally  have provided veterinarians with insights into ways to address the COVID-19 pandemic and also to prevent future spillovers. Transmission of coronaviruses between species and adaptive changes have occurred on many occasions and appear to have accelerated in the past 20\u00a0years. Anthropogenic factors such as biodiversity loss, environmental degradation and inappropriate farming and selling practices, though contending at contribution levels, must be investigated and addressed to reduce and mitigate future spillover and pandemics (Roche et al. Veterinarians\u2019 expertise and knowledge, particularly experiences in epidemics that involve multiple hosts, primary, secondary and evolving pathogens, can improve One Health approach to this disease and other emerging diseases (McNamara et al."}
+{"text": "Bile duct cancer (BDC) has been identified as a highly aggressive cancer arising from epithelial cells of the bile duct, including intrahepatic, perihilar, and extrahepatic . TogethePalliative chemotherapy with cisplatin and gemcitabine (GEM) has been the standard of care for patients with unresectable cancers since 2010 and no breakthrough progress in this challenging disease in the era of targeted therapy and immunotherapy , clinicaIn recent years, scientists have established many omics profiles to reveal underlying mechanisms and networks in cancer. This omics-based approaches can be used and integrated for further basic and clinical research. Chang et al. reviewed the integration of genomics, epigenomics, transcriptomics, proteomics and metabolomics in BDC and provided the views of the application of omics in tumorigenesis, identification of prognostic factors, and investigation of novel targets for current and future drug development .TP53 encoding p53 protein, the guardian of the genome [One famous tumor suppression gene, e genome , has beee genome .Emerging evidence demonstrated that miRNAs regulate tumor responses to chemotherapy and targeted therapy. Huang et al. provided an overview of the current knowledge about the miRNA-mediated regulatory mechanisms underlying drug resistance among BDC, discussed the application of miRNA-based therapeutics to BDC, and provided the basis for innovative treatment approaches . Pan et Based on the comprehensive reviews and studies of various aspects in BDC from this special issue, to elucidate the successful strategy to overcome GEM resistance and innovate future novel treatment could be envisioned. All the efforts on BDC will help clinicians and researchers to beat such tough disease in the future."}
+{"text": "Brassicaceae plants are of great interest for human consumption due to their wide variety and nutritional qualities. Of the more than 4000 species that make up this family, about a hundred varieties of 6\u20138 genera are extensively cultivated. One of the most interesting aspects is its high content of glucosinolates, which are plant secondary metabolites with widely demonstrated anti-oncogenic properties that make them healthy. The most relevant Brassicaceae studies related to food and melatonin are examined in this paper. The role of melatonin as a beneficial agent in seedling grown mainly in cabbage and rapeseed and in the postharvest preservation of broccoli is especially analyzed. The beneficial effect of melatonin treatments on the organoleptic properties of these commonly consumed vegetables can be of great interest in the agri-food industry. Melatonin application extends the shelf life of fresh-cut broccoli while maintaining optimal visual and nutritional parameters. In addition, an integrated model indicating the role of melatonin on the organoleptic properties, the biosynthesis of glucosinolates and the regulatory action of these health-relevant compounds with anti-oncogenic activity is presented. N-acetyl-5-methoxytryptamine) is an indolic bioamine derived from tryptophan as a precursor in its biosynthesis. Since its discovery in 1958 in the pineal gland of cow .,65.Elongnstrated . An overnstrated , and thaA. thaliana, Chinese cabbage seedlings and broccoli florets, the promoting role in glucosinolate biosynthesis has been demonstrated. Melatonin treatments induce the accumulation of total aliphatic and indole glucosinolates, increasing specific glucosinolates, including GER, GRA, GBS and NGBS, among others  to know better the effects of melatonin on primary metabolism, specifically on the photosynthetic, respiratory and carbohydrate transformation pathways ; (ii) to form a better understanding of the regulatory mechanism of melatonin on glucosinolate metabolism ; (iii) to know the possible effect of melatonin on mineral, dietary fiber and vitamin composition in plants and cabbages; (iv) postharvest, to better understand the effect of melatonin on the metabolism of ethylene and other plant hormones in broccoli; and (v) to study the effect of melatonin in other postharvest products of the Brassicaceae family such as cauliflower, Romanesco, kohlrabi, red cabbage and leafy vegetables."}
+{"text": "Gryllus bimaculatus) during storage. Four antioxidants and two packaging methods were used. The effects of different antioxidants and packaging methods on composition of fatty acids, contents of free fatty acids (FFA), peroxide value (PV), and thiobarbituric acid reactive substances (TBARSs) value of deep fried Gryllus bimaculatus were analyzed during 150 days of storage. The composition of fatty acids changed and the content of FFA, PV, and TBARs value also increased with the extension of storage time, indicating that the lipid oxidation dominated by oxidation of unsaturated fatty acids could occur in deep fried Gryllus bimaculatus during storage. In the same storage period, the total content of FFA, PV, and TBARs value of samples treated with antioxidants and vacuum-filling nitrogen packaging were lower than those of controls, suggesting that antioxidants and vacuum-filling nitrogen packaging have noticeable effects on inhibiting lipid oxidation and improving the quality of deep fried crickets, and dibutyl hydroxyl toluene (BHT) was found as the most effective antioxidant in this study. The results may provide a reliable reference for processing of deep fried edible insects.This study aimed to investigate the effect of processing methods on inhibiting lipid oxidation of deep fried crickets ( Insects are a biological group with the largest number of species, huge biomass, fast reproduction capability, and high food conversion rate on earth. Insects are highly nutritious, containing a large amount of high-quality proteins, high levels of unsaturated fatty acids, and high levels of essential trace elements, such as iron and zinc . AlthougBrachytrupes membranaceus, Gryllus similis, Gryllus bimaculatus, Gryllotalpa orientalis, and Acheta domesticus . These studies demonstrated that different degrees of lipid oxidation and decomposition may occur in edible insects during processing and storage, which are similar to other animal foods. Lipid oxidation is an important factor, influencing the quality and shelf-life of animal foods.Compared with other meat products, such as pork , beef 33, and goPhyllanthus emblica polyphenols have activities such as scavenging free radicals and anti-lipid oxidation [Phyllanthus emblica polyphenols (PEP), were used for the investigation in this study. The analysis results of free fatty acids content and PV value show that the antioxidant effects of BHT and TBHQ are better than that of ET and PEP, while the antioxidant effects of BHT, ET, and PEP are better than that of TBHQ in the analysis results of TBARs, in which the most effective antioxidant is BHT. Although some studies have reported that the antioxidant effects of some natural antioxidants in meat products are equivalent to BHT [Antioxidants inhibit the oxidation of lipids by scavenging the peroxide reaction matrix, complexing metal ions, reducing the concentration of active oxygen and blocking the dehydrogenation of fatty acids ,42. Syntxidation . Therefot to BHT , and evet to BHT , the antGryllus bimaculatus, four antioxidants were added to the palm oil used for deep frying, and the non-vacuum sealed packaging and vacuum-filling nitrogen packaging methods were used. Besides, the composition of fatty acids, contents of FFAs, PV, and TBARs value of samples that were treated with different methods during 150 days of storage were analyzed. The results showed that the contents of UFAs decreased, while the contents of SFAs increased. Meanwhile, the total content of FFAs, PV, and TBARs value increased during 150 days of storage, indicating that the lipid oxidation dominated by oxidation of UFAs could occur in deep fried Gryllus bimaculatus during storage. Additionally, at the same storage time, there were significant differences in the contents of UFAs and SFAs, as well as the total content of FFAs, PV, and TBARs value of samples treated with different methods. The total content of FFAs, PV, and TBARs value of samples treated with antioxidants and vacuum-filling nitrogen packaging were lower than those of the control, suggesting that antioxidants and vacuum-filling nitrogen packaging could significantly inhibit the lipid oxidation in deep fried Gryllus bimaculatus, which is an effective method to improve the quality and shelf-life of deep fried crickets, and BHT was found as the most effective antioxidant in the present study.In order to study and inhibit lipid oxidation in deep fried"}
+{"text": "Chronic kidney disease (CKD) is a serious public health problem worldwide, leading to a series of physical and psychological comorbidities, in addition to costly treatments, lifestyle and dietary restrictions. There is evidence that mindfulness-based interventions (MBIs) offer complementary treatment for people with chronic illnesses, including CKD, with the aim of improving overall health, reducing side effects and treatment costs. This review aims to investigate the MBIs impact on people with CKD undergoing hemodialysis, and to identify the methodological quality of the current literature in order to support future studies.We ran searches in five databases  in July 2020. The papers were selected and evaluated by two reviewers independently, using predefined criteria, including the Cochrane Group's risk of bias tool and its recommendations (CRD42020192936).Of the 175 studies found, 6 randomized controlled trials met the inclusion criteria, and ranged from 2014 to 2019. There were significant improvements in symptoms of anxiety, depression, self-efficacy, sleep quality, and quality of life (n=3) in the groups submitted to the intervention, in addition to physical measures such as blood pressure, heart rate and respiratory rate (n=1).MBIs can offer a promising and safe complementary therapy for people with CKD undergoing hemodialysis, acting on quality of life and physical aspects of the disease. For Embase, the search was carried out with the filter \"all fields\", Web of Science was filtered by \"topic\" and Scopus through \"title, abstract and keywords\". For the other databases, no filter was used. The reference lists of the included studies was also analyzed in order to identify a possible flaw in the original search. The articles included in the search had no definition of an initial period and were extracted until July 2020.The research included keywords indexed in Health Sciences Descriptors (DECS) and Medical Subject Headings (MeSH Terms) such as: Renal Dialysis; Dialysis; Chronic Kidney Failure; Peritoneal dialysis; Chronic Kidney Failure; Nephropathies; Mindfulness; Mindfulness Meditation; Mindfulness-Based Intervention; MBI; Mindfulness Based Stress Reduction; MBSR; Mindfulness Based Cognitive Therapy; MBCT; Mindful Eating. The synonyms present in each keyword listed were included in the search. The choice of adding synonyms to the search strategy was applied in order to unify the key used in the different databases and expand the search. All potentially eligible studies were reviewed, regardless of primary outcome or language.We included only MBI studies in people with chronic kidney disease, over 18 years old on hemodialysis treatment, and written in English. Systematic reviews and meta-analyses, MBI together with other interventions, incomplete texts and themes other than the objective of the study were excluded.All citations retrieved from electronic databases were imported into an Excel spreadsheet. Two reviewers (BNR and MFR) analyzed independently and blindly, where the researchers first selected the titles and abstracts, and then the full texts, applying the inclusion and exclusion criteria established in the protocol.Data from the included studies were independently extracted by the same two reviewers using a standardized form. The extracted data included: main author, year of publication, design, participants , inclusion criteria, information about the intervention  and control group , post-intervention follow-up evaluations, evaluation measures and main results.The methodological quality of the included studies was independently assessed by the same two reviewers using The Risk of Bias 2 (RoB 2) tool, in its updated version for ECRs (and its variation for ECRs in crossover format)-,,We found 175 potential studies in the database searches. After removing 77 duplicate studies, we coded 98 titles and/or abstracts. Following the application of the exclusion criteria  showed that 49% of the participants were married, 50% lived with a family and 46% used psychiatric medications. Four studies described comorbidities associated with CKD, with hypertension and diabetes being the most prevalent-,The six clinical trials involved a total of 264 participants with CKD and a mean age of 57.34 years (\u00b1 9.8), ranging from 15 to 63 participants among the studies. Except for the study by Nejad et al. (2018),,,-,,Most of the studies evaluated used well-established protocols such as mindfulness-based stress reduction (MBSR),Two studies adapted the MBSR protocol to be performed through videoconference and in groups (tMBSR), the first and the last face-to-face meeting and the rest were online-,,The practices described in the cited studies ranged from body scanning practices, conscious breathing, raisin practice, gentle arm movement, mindfulness in daily activities and self-compassion, in which participants were invited to adopt a gentle and non-judgmental attitude to respect for experience throughout practices. In addition to the practices carried out in the weekly meetings, most studies encouraged participants to practice at home and keep records over the weeks,Thomas et al. (2017)Since this review aims to investigate the impact of interventions based on mindfulness and chronic kidney disease in a broad way, the outcomes found throughout the studies were described as a majority, being mental health outcomes such as depression, anxiety and self-efficacy, physical measures of fatigue, pain, sleep, blood pressure, sympathetic activity, respiratory rate, and psychosocial measures of quality of life See .,,Three studies associated the effects of MBIs on anxiety and depressionSolati et al. (2019)Gross et al. (2017),Two studies assessed sleep quality. The authors used different scales to assess this outcome. Gross et al. (2017)Park et al. (2014)Two studies assessed quality of life using different scales. Solati et al. (2019),,,,,,,The quality of the studies was measured using The Risk of Bias 2 (RoB 2), in its updated version,,In the domain referring to the measurement of outcomes, all studies cited the psychometric properties of the instruments used, as well as the justification for implementing the adopted measures. Only two studies did not have enough information about the outcome and whether the intervention could have been interfered from the responses,,,,,,,,..) The attrition rate was described in two studies, being 13% for each group,,,MBIs have grown worldwide as a complementary therapy in the treatment of chronic diseases, including CKD,,,,The results of the six studies are encouraging for the domains of mental health, physical measures and quality of life. There were significant improvements in the symptoms of anxiety, depression, greater self-efficacy, sleep quality and quality of life in the groups submitted to the intervention-,In addition to psychological and psychosocial stressors, the presence of comorbidities associated with CKD, such as hypertension, is very prevalent in people with CKDThis review enabled a broad understanding of the impacts of MBIs on CKD patients undergoing hemodialysis and employed a rigorous methodological strategy to research and evaluate the literature on this topic. Two reviewers were involved in the screening and evaluation of studies eligible for inclusion, with in-depth discussions regarding the proposed evaluations, and with the help of a third reviewer, when necessary. The methodological quality of the studies was carefully assessed according to the recommendations in the Cochrane Manual (Cochrane Collaboration 2020)The fact that MBIs originate from ancient Eastern traditions, and the resource constraints for translations in languages \u200b\u200bother than English, may have biased our findings. In addition, the low methodological quality of three studies together and the general heterogeneous nature of the evaluations/outcomes of the analyzed papers made it impossible to carry out a quantitative meta-analysis.,,,,,,,Reilly-Spong et al. (2015)In some studies, the authors used instrument subscales to assess their secondary outcomes, such as the item related to pain inserted in the SF-12,,,Although most of the papers evaluated used MBIs based on well-established protocols and certified mindfulness instructors, two studies did not specify the information on the protocol base of the program adopted, making it difficult to generalize the resultsFuture studies involving MBIs in patients with CKD should be carried out on larger scales, and with the implementation of robust methodologies; examine both physical and psychological measures, quantitatively or qualitatively, in order to further explore the clinical implications of interventions in this population. The sociodemographic characteristics, disease stages and associated comorbidities, sample stratifications, and issues regarding the necessary adaptations for the application of appropriate MBIs to the hemodialysis context, whether individually, in groups or online.Although the evidence is limited, this review indicates that MBIs may offer a promising, safe and non-invasive complementary therapy for patients with CKD on hemodialysis, specifically in relation to mental health, quality of life and the physical aspects of the disease. The implementation of these interventions must consider the certification of instructors and details of the protocols, ensuring their reliability. The potential impacts of MBIs for people with CKD require studies with higher methodological quality, clarifying the feasibility of different formats of interventions presented, and long-term evaluations."}
+{"text": "BACKGROUND: Host factors expressed by individual past medical history of hypertension, stroke, and myocardial infarction may have a relationship with colorectal cancer.METHODS: As part of the Japan Collaborative Cohort Study (JACC Study) for the Evaluation of Cancer Risk sponsored by the Ministry of Education, Science, Sports and Culture of Japan (Monbusho), we conducted a follow-up study of 110,792 Japanese inhabitants aged 40-79 years to reveal the relationship of past medical history of hypertension, stroke, and myocardial infarction at the baseline in 1988-1990 with colorectal cancer death for about 10 years up to the end of 1999.RESULTS: Past medical history of hypertension associated with an increased risk of female rectal cancer when analyzing all cancer cases with adjustment for age, body mass index, and exercise . Past medical history of myocardial infarction was also an increased risk for female rectal cancer . Females who had a medical history of stroke had increased risk of rectal cancer without statistical significance.CONCLUSION: There was a positive association of past medical history of hypertension and myocardial infarction and an increased risk of rectal cancer in women. These common risk factors may contribute to the positive association between the above circulatory diseases and colorectal cancer.We reported a positive association between past medical history of hypertension and colorectal cancer in a case-control study in early 1980,Therefore, we conducted a cohort study to reveal the relationship in the Japan Collaborative Cohort Study (JACC Study) for the Evaluation of Cancer Risk sponsored by the Ministry of Education, Science, Sports and Culture of Japan (Monbusho).3,4 Briefly, the study population was 110,792 Japanese inhabitants aged 40-79 years at 45 study areas in 1988-1990. Subjects completed a self-administered questionnaire including past medical history of hypertension, stroke, and myocardial infarction. A response to the medical history questions was selected from four alternatives such as \u201chave never suffered from the disease\u201d, \u201chave suffered from the disease with present treatment\u201d, \u201chave suffered from the disease with treatment\u201d, and \u201chave suffered from the disease without treatment\u201d. Therefore, subjects with positive medical history of hypertension, stroke and myocardial infarction were defined as those who had suffered from hypertension, stroke and myocardial infarction, respectively, irrespective of past and present treatment.The study population, procedures for conducting the baseline survey using a self-administered questionnaire, and follow-up methods in the JACC Study have been described previously.5 by verifying computer-stored data in the Ministry of Health, Labour, and Welfare with permission. A diagnosis of colon cancer was defined by code C18, while rectal cancer was C19 and C20, in the above classification.5The follow-up survey was conducted using population registries in local municipalities to determine the vital and residential status of the cohort in each area. All subjects that moved out of the study areas were treated as censored subjects. All deaths that occurred in the cohort were ascertained by death certificates from local public health centers in the study areas with the authorities\u2019 permission from the Director-General of the Prime Minister\u2019s Office . The causes of death were coded according to the International Statistical Classification of Diseases and Related Health Problems, 10th Revision2, and no answer) and exercise  for all colorectal cancer cases and cases except for those who had died within the first two years of the follow-up period. Body mass index (BMI) was calculated as weight (kg) divided by height (m) squared provided in the self-administered questionnaire at the baseline.The risk of colorectal cancer was evaluated by hazard ratios (HRs) and 95% confidence intervals (CIs) estimated by the Cox proportional hazards model. Sex-specific HRs were computed after adjustment for age in all colorectal cancer cases and cases except for those who died within the first two years of the follow-up period. Sex-specific HRs were also computed after adjustment for age, body mass index (BMI)  and for cases except for those died within the first two years of the follow-up period . Past medical history of stroke and myocardial infarction had a positive association with female rectal cancer, although there was no statistical significance. Past medical history of hypertension, stroke, and myocardial infarction also showed a positive association with male colon cancer, although none were not statistically significant. There were no other significant relationships among past medical history of hypertension, stroke, and myocardial infarction with colorectal cancer death by sex or site of cancer (colon/rectum).Sex-specific HRs and 95% CIs of colon cancer and rectal cancer adjusted by age, BMI and exercise are shown in 1,2 The present study showed a positive association between past medical history of hypertension and female rectal cancer. Females who had a medical history of hypertension had an increased risk of rectal cancer. This result supports the idea of the presence of common risk factors between colorectal cancer and hypertension. Obesity and physical inactivity are risk factors for hypertension.6 Obesity7,8 and physical inactivity8,9 are also risk factors for colorectal cancer. However, the risk of rectal cancer still existed when BMI and exercise were adjusted. Therefore, there may be common risk factors other than BMI and exercise involved in the link between hypertension and rectal cancer deaths. Females who had a medical history of myocardial infarction also had increased risk of rectal cancer when BMI and exercise were adjusted. Females who had a medical history of stroke had increased risk of rectal cancer without statistical significance. This may be accounted for by hypertension, as myocardial infarction and stroke are both closely related to hypertension.There are no consistent epidemiologic reports on the relationship between past medical history of hypertension and colorectal cancer.10 We proposed this hypothesis because the average value of plasma homocysteine of patients with colorectal cancer was significantly higher than of healthy controls in a clinical case-control study.10 Except for folic acid deficiency, oxidative stress may contribute to the relationship. We have already reported that higher levels of serum oxidized low-density lipoprotein, which is believed to play a role in the development and progression of atherosclerosis,11 were associated with risk of colorectal cancer as part of the JACC Study.12 Therefore, our findings that past medical history of hypertension and myocardial infarction increased the risk of female rectal cancer could be a secondary association due to folic acid deficiency and /or oxidative stress.There is a hypothetical correlation between circulatory diseases and colorectal cancer, shown in There is a major limitation in interpreting the present results. As we conducted a cohort study, some of the subjects who did not have a medical history of hypertension at the time of the baseline questionnaire survey may have developed hypertension and then subsequently colorectal cancer during the follow-up period. Therefore, the relationship between past medical history and colorectal cancer death might have been underestimated.There were no consistent results by sex or site of cancer (colon/rectum) in our study. These differences should be carefully addressed by considering factors other than folic acid deficiency and /or oxidative stress, such as hormonal background.The present investigators involved, with the co-authorship of this paper, in the JACC Study and their affiliations are as follows: Dr. Akiko Tamakoshi (present chairman of the study group), Nagoya University Graduate School of Medicine; Dr. Mitsuru Mori, Sapporo Medical University School of Medicine; Dr. Yutaka Motohashi, Akita University School of Medicine; Dr. Ichiro Tsuji, Tohoku University Graduate School of Medicine; Dr. Yosikazu Nakamura, Jichi Medical School; Dr. Hiroyasu Iso, Institute of Community Medicine, University of Tsukuba; Dr. Haruo Mikami, Chiba Cancer Center; Dr. Yutaka Inaba, Juntendo University School of Medicine; Dr. Yoshiharu Hoshiyama, Showa University School of Medicine; Dr. Hiroshi Suzuki, Niigata University School of Medicine; Dr. Hiroyuki Shimizu, Gifu University School of Medicine; Dr. Hideaki Toyoshima, Nagoya University Graduate School of Medicine; Dr. Shinkan Tokudome, Nagoya City University Graduate School of Medical Science; Dr. Yoshinori Ito, Fujita Health University School of Health Sciences; Dr. Shuji Hashimoto, Fujita Health University School of Medicine; Dr. Shogo Kikuchi, Aichi Medical University School of Medicine; Dr. Akio Koizumi, Graduate School of Medicine and Faculty of Medicine, Kyoto University; Dr. Takashi Kawamura, Kyoto University Center for Student Health; Dr. Yoshiyuki Watanabe, Kyoto Prefectural University of Medicine Graduate School of Medical Science; Dr. Tsuneharu Miki, Kyoto Prefectural University of Medicine Graduate School of Medical Science; Dr. Chigusa Date, Faculty of Human Environmental Sciences, Mukogawa Women\u2019s University ; Dr. Kiyomi Sakata, Wakayama Medical University; Dr. Takayuki Nose, Tottori University Faculty of Medicine; Dr. Norihiko Hayakawa, Research Institute for Radiation Biology and Medicine, Hiroshima University; Dr. Takesumi Yoshimura, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Japan; Dr. Akira Shibata, Kurume University School of Medicine; Dr. Naoyuki Okamoto, Kanagawa Cancer Center; Dr. Hideo Shio, Moriyama Municipal Hospital; Dr. Yoshiyuki Ohno, Asahi Rosai Hospital; Dr. Tomoyuki Kitagawa, Cancer Institute of the Japanese Foundation for Cancer Research; Dr. Toshio Kuroki, Gifu University; and Dr. Kazuo Tajima, Aichi Cancer Center Research Institute."}
+{"text": "The immature immune system at birth and environmental stress increase the risk of infection in nursing pigs. Severe infection subsequently induces intestinal and respiratory diseases and even cause death of pigs. The nutritional and physiological conditions of sows directly affect the growth, development and disease resistance of the fetus and newborn. Many studies have shown that providing sows with nutrients such as functional oligosaccharides, oils, antioxidants, and trace elements could regulate immunity and the inflammatory response of piglets. Here, we reviewed the positive effects of certain nutrients on milk quality, immunoglobulin inflammatory response, oxidative stress, and intestinal microflora of sows, and further discuss the effects of these nutrients on immunity and the inflammatory response in the offspring. During gestation and lactation, maternal nutrition is a predominant factor to regulate the growth and immunity of piglets , 2. SincMaternal infection or inflammatory exposure during pregnancy impairs the innate response of newborns and increases their susceptibility to infection . During As indigestible carbohydrate, dietary fiber (DF) is partially or completely fermented by microorganisms in the large intestine, which could be categorized into insoluble and soluble fiber . InsolubBifidobacterium) of sows  has been reported to activate the immune system  and prom of sows . A recen of sows . Similar of sows .Chitosan oligosaccharide (COS) has good water solubility and performs antioxidant , anti-inSugar peat pulp (SBP) contains large amounts of soluble fibers such as pectin and dextran . FeedingEnterobacteriaceae in sow feces at delivery and the number of Escherichia coli in piglet feces at weaning (Seaweed extracts (SWEs) mainly consists of seaweed polysaccharide (SDP), laminarin, and fucoidan . Supplem weaning . These b weaning .Lactobacilli and decrease the abundance of Bilophila spp in intestine. Importantly, IL-10 and TGF-\u03b2 levels were increased in piglets, which avoids over-activated immune system in piglets , derived from the cell wall of Saccharomyces cerevisiae, has been used as a prebiotic for a long time . Recent diarrhea .Besides soluble fiber, insoluble dietary fiber also plays a crucial physiology role in sow. Insoluble dietary fiber accelerates gastrointestinal motility, reduces constipation and increases satiety of sows . Wheat bHowever, excessive level of dietary fiber could negatively affect total tract nutrient digestibility in pigs . As soluDuring late pregnancy and lactation period, sows require more nutrients and energy for fetal growth and milk synthesis. Oil supplementation in sow diets could prevent excessive mobilization of body reserves , shortenTLR-4, TLR-9 and MyD88) in the ileum  is rich in long-chain n-3 polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which have anti-inflammatory effects both in vitro   is rich in monounsaturated fatty acids , as wellIt is worth noting that high fat-induced obese sows have lower number of live-born piglets , piglet During late pregnancy,rapid fetal development increases the metabolic burden and induces systemic oxidative stress of pregnant sows .Severe oVitamin E, one of the most effective antioxidants, could directly react with free radicals and stimulate the expression of antioxidant enzyme genes, like GSH-Px and CAT . In addiForsythia suspensa extract (FSE) is a medicinal herb extract that mainly consists of forsythiaside A, forythialan A, phillyrin and phillygenin. FSE has been shown to perform antioxidant  and liver of neonates . Furthermore, administration of HMSeBA decreased the gene expression of IL-1\u03b2, IL-6 and IL-8 in placentas and IL-6 serum concentration in neonatal piglets. Therefore, HMSeBA supplementation in sows during late pregnancy increased the antioxidant capacity of piglets and reduced maternal and fetal inflammation  is incorporated into selenopsroteins and subsequently prevent intestinal inflammation by alleviating oxidative stress . In addiammation . Similarammation . MoreoveTaurine (Tau), a metabolite of methionine and cysteine, have anti-inflammatory and antioxidant properties , 117. TaOxidized \u03b2-carotene (OxBC) is a complex mixture produced by complete and spontaneous oxidation of \u03b2-carotene. The addition of OxBC (8 mg/kg) to the perinatal diet (G85-L21) improved the litter weight and individual body weight of the weaned piglets. This might be due to OxBC increased the immune status of sows, which further affect the growth of piglets. This is evidenced by decreased levels of cytokines (TNF-\u03b1 and IL-18) and increased levels of immunoglobulin  in colostrum .In this section, we describe some other nutrients which are advantageous to regulate the immunity and inflammation of piglets when supplemented in sow diets such as rare earth elements, lysozyme, and yeast nucleotides etc Table\u00a03.Christensenellaceae and Ruminocococaceae) and decreased abundance of opportunistic pathogenic bacteria (Proteus and Campylobacter) were also found in the intestinal tract of piglets (Rare earth elements (REEs) includes 15 elements such as lanthanum (La) and cerium (Ce) . In addi piglets .campylobacter in the feces (Lysozyme (LZM) is a natural antibacterial enzyme found in the tears, saliva and milk of mammals . Previouhe feces .Nucleosides could promote the growth and development of intestinal epithelial cells . The addSpray-dried plasma (SDP) is a protein-rich feed additive that contains immunoglobulins, peptides, glycoproteins and other active ingredients . PreviouDietary fiber regulates inflammatory and immune response in the offspring by modulating the maternal intestinal microflora and milk immunoglobulin content. The antioxidant substances could directly react with the free radicals and enhance the maternal antioxidant capacity, thereby indirectly reducing infection in the offspring. The oil and fat products not only provide adequate energy to sows, but also supply functional fatty acids to alleviate infection and enhance the immune function in the offspring by exerting the anti-inflammatory and anti-oxidant effects. In summary, maternal nutrition intervention is an effective way to regulate the inflammatory response and immunity in the offspring.in vitro cell experiments are required to clarify the potential mechanism. Lastly, whether the metabolites of these nutrients were involved in the regulation of immunity and inflammation in the offspring is still unclear and require more research.In this review, we mainly focus on the positive effects of nutrients in the regulation of immunity and inflammatory response of sows and piglets during pregnancy and lactation. It worth noting that these effects would be affected by timing and/or dosage of nutrient supplementation. Moreover, it is well known that excessive addition of fat usually has a negative effect on pigs. The toxic effects of excessive addition of other products, such as vitamin E and selenium  are alsoQL, SZ, and MR initiated the idea, the scope, and the outline of this review paper. QL, SY, XZ, XL, ZW, YQ, WG, MR, and SZ studied and analyzed all of the publications cited in this paper and were involved in the manuscript preparation. SZ and MR conducted the final editing and proofreading. All authors contributed to the article and approved the submitted version.This study was financially supported by the National Natural Science Foundation of the P.R. of China (No. 31872364 and No. 31802067), Guangdong Basic and Applied Basic Research Foundation (No. 2021A1515010440), Science and Technology Program of Guangzhou (No. 202102020056), Anhui Provincial Science and Technology Major Special Project (201903a06020002).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Carbon-based nanomaterials have been increasingly used in the design of sensors and biosensors due to their advantageous intrinsic properties, which include, but are not limited to, high electrical and thermal conductivity, chemical stability, optical properties, large specific surface, biocompatibility, and easy functionalization. Therefore, the final aim of this Special Issue is to share new data concerning the novel exploitation strategies of these nanomaterials in order to support the development of improved (bio)sensing tools. Focus is mostly placed on the usage of graphene but also on carbon dots and carbon nanotubes, as well as on the preparation and characterization of new (nano)composites. The tailoring of the (bio)sensor surface is the common approach of the different reported schemes when optimizing the (bio)sensor design. Simulation tests are also performed .The research community has shown rising and commendable interest in searching for and applying greener synthesis methodologies, with different studies ,3,4 explMoreover, for those researchers seeking an overview of the state of the art of the use of carbon-based nanomaterials for (bio)sensors\u2019 development, three review papers targeting different topics are included in this Special Issue. Pan et al.  revised,The incorporation of carbon-based nanomaterials, independent of the detection scheme and developed platform type , has demonstrated a major beneficial effect on the sensitivity, specificity, and overall performance of (bio)sensors. Consequently, carbon-based nanomaterials have brought about a revolution in the field of (bio)sensors with the development of increasingly sensitive devices."}
+{"text": "OBJECTIVES/GOALS: Hepatitis B and C virus causes inflammation of the liver and can lead to cirrhosis, liver failure, and hepatocellular carcinoma. The aim of this study is to generate a modeled estimate of changes in hepatitis B and C prevalence, and future sequelae, that accounts for recent mass migration to the European Union stemming from 50 high-emigration countries. METHODS/STUDY POPULATION: Total migrant population from 2013-2017 was obtained from the Eurostat population database. Demographics including country-of-origin, sex, and age distributions were used to determine migrant contributions to HBV and HCV prevalence where available. Undocumented migration estimates were obtained from the Institute of Migration database. Country-of-origin HBV and HCV prevalences were obtained for the select 50 country-of-origin nations from the Polaris Observatory and from systematic reviews. Disease progression was estimated using HBV and HCV outcome data for total populations from treatment guideline publication from the European Association for the Study of the Liver. RESULTS/ANTICIPATED RESULTS: Between 2013 and 2017, a total of 11,030,786 documented migrants born outside the EU arrived to the 30 nations. Germany, United Kingdom, and Spain received the greatest influx of persons and the majority of migration stemmed from countries in West Asia, the Middle East, and Africa. A significant proportion of total migration was driven by conflict-related crisis in Syria, and East and North Africa. The most significant increases in estimated total hepatitis case numbers, national prevalence increases, and future sequelae were seen in Germany and Sweden. DISCUSSION/SIGNIFICANCE OF IMPACT: Mass migration has significantly changed HBV and HCV disease burden in Europe over the past 5 years. Consequently, long-term outcomes of cirrhosis and HCC are also expected to increase. These increases are likely to disproportionally impact individuals of the migrant and refugee communities. HBV and HCV surveillance and management programs must strategically focus on individuals from high-burden age cohorts and nations. Screening and treatment would aid WHO elimination efforts while benefiting both the vulnerable individuals and host nations through reduction of morbidity, mortality, and associated healthcare expenses."}
+{"text": "One of the distinctive strengths of WLS is the availability of Henmon-Nelson IQ scores on all participants while in high school, followed by prospective collection of data through cognitive batteries of varying size and sophistication. Launched in 1993, the initial longitudinal cognitive testing included 8 abstract reasoning items followed by the administration of larger cognitive batteries in 2004 and 2011 comprised of a 10-item word recall test, digit ordering task, phonemic and category fluency, as well as repeated and new items from the WAIS-R similarities task first administered in the 1993 survey. In 2018, with R01 funding from NIA, the scope of cognitive testing expanded significantly and includes administration of a phone-based cognitive screening measure, and a comprehensive in-person neuropsychological assessment for individuals identified at risk for dementia targeting a range of cognitive domains, including memory, language, attention, visuospatial abilities, and executive functioning."}
+{"text": "The pandemic profoundly affected the care of older adults in long term care communities (LTCC) across the world. More than one third of pandemic deaths were linked to nursing homes. Most nations and states had strict guidelines on visitation, with many, especially in the United States, totally prohibiting visitation for over an entire year. Well-intentioned measures to protect through isolation caused a profound ethical tension between safety and self-determination. The aim of the project was to examine this dilemma using a case study and the Madison Collaborative Ethical Reasoning in Action Framework. Eight key questions of fairness, outcomes, rights, responsibilities, character, liberty, empathy, and authority were applied in the context of federal and state mandates in the US and Australia. Results highlighted issues of ageism, paternalism vs empathy, regulatory vs family authority, a focus on short-term outcomes while forfeiting long-term outcomes, community responsibilities to the resident trumped individual resident rights, the potential loss of community character in lieu of basic care provision, a loss of personal freedoms, and the emphasis of physical well-being over holistic well-being. The results of this analysis can inform future policy and provide lessons learned for the future."}
+{"text": "The advances in the field of gene therapy have significantly improved the possibility for nucleic acids as highly promising agents for the treatment of both inherited and acquired human diseases. Substantial progress has been made in the development of different types of nucleic acids, including plasmid DNA, mRNA, microRNA, small interfering RNA, and antisense oligonucleotides. Nevertheless, despite the immense pharmacological potential of these molecules, the successful clinical application of genetic material-based strategies remains dependent on the generation of safe and effective delivery systems that have the ability to overcome the numerous biological barriers associated with the gene delivery process. Up to now, the large majority of gene therapy clinical trials have been based on the use of viral vectors, namely due to features such as high levels of transduction, or the efficient and stable integration of exogenous DNA into the host genome. However, several drawbacks have been associated with viral vectors, such as immunogenicity, carcinogenesis, the size limit of exogenous DNA, and the difficulty of large-scale production. Non-viral gene delivery systems have the potential to overcome these limitations, allowing not only a safe but also efficient gene delivery process into the target cells.The aim of this Special Issue was to highlight the current progress in non-viral gene delivery systems. Six original papers and six review articles were published.The publication by Guan and Chen et al.  focused Mart\u00ednez-Negro and Junquera and coworkers  developeOn the other hand, Saher and Zain et al.  evaluateIbaraki and Seta et al.  used a nNagachinta and de la Fuente et al.  aimed toThe potential of cell penetrating peptides (CPPs), also recognized as protein transduction domains (PTDs), to be used as non-viral gene delivery systems was the focus of the review article by Taylor and Zahid . In thisRoma-Rodrigues and Fernandes et al.  providedpiggyBac (PB) transposon, one of three transposon systems  and Tol2), namely the diverse roles of PB in gene delivery and strategies to improve its performance. This work highlights the potential of PB, which promotes the chromosomal integration of the delivered transgenes, to overcome the referred limitations associated with non-viral gene delivery systems.On the other hand, Sato and Nakamura et al.  reviewedCarvalho, Cordeiro and Faneca  presenteCarballo-Pedrares and Rey-Rico et al.  performeOn the other hand, Aulicino, Capin and Berger  focused Egorova and Kiselev et al.  develope"}
+{"text": "Most brain diseases are fatal with no effective therapeutic solutions currently available, contributing to major health issues globally. One of the major obstacles in overcoming the pathologies of these diseases is the existence of the blood-brain barrier (BBB), which physically separates the brain and the bloodstream . The BBBIn the past decades, various strategies including drug modification, novel delivery systems, transiently opening the BBB by physical or chemical methods and bypassing the BBB through intracranial or intranasal delivery  have beein vitro and in vivo, and the application of nanoparticles for treating various brain diseases.This Frontiers Research Topic brings together contributions in new advancements in the mechanisms of the BBB regulation, the development of novel nanoparticles with the capability to be traced Wang et al showed that microRNAs (miRNA) could either inhibit or enhance the expression of tight junction molecules, thereby directly regulating the BBB. In addition, miRNAs affected the structure and function of brain endothelial cells, including the cytoskeleton, channels and transporters of brain endothelial cells. Furthermore, miRNAs also targeted inflammation molecules and other molecules often used in the crosstalk between brain endothelial cells and the other cells of the neurovascular unit. The profound effect of miRNAs on BBB function and integrity makes them a promising target for treatment of brain diseases. Additionally, improvement of brain vascular function may benefit the treatment of brain diseases. In the article by Zhu et al, the authors developed amorphous selenium nanoparticles (A-SeQDs) for treating chronic isocarbophos poisoning through the protection of endothelial function. They showed that A-SeQDs inhibited inflammation while increasing oxygen saturation, leading to sodium hydrogen exchanger 1-dependent reduction of endothelial apoptosis. Consequently, isocarbophos-induced vascular dysfunction was inhibited.Brain diseases are often associated with a dysfunctional often disrupted, BBB . Therefoin vivo drug monitoring. Chung and Zhang developed a novel colloidal stable and non-toxic fluorescent probe, an iron oxide and carbon dot-based nanoparticle, to deliver chemotherapeutics for killing of cancer cells. This new type of nanoparticle was low in toxicity and able to respond rapidly for quantitative imaging. Transparent cranial implants provided a possibility for chronic brain imaging, thereby facilitating brain research. Halaney et al analyzed the optical properties of a ceramic, nanocrystalline Yttria-Stabilized Zirconia (nc-YSZ)-based transparent cranial implant. The optical properties of the implant were critical to the design of optical systems for imaging the brain and for interpreting imaging outcomes.The development of nanoparticles with the capability for imaging is critical to disease diagnosis and Ngowi et al summarized the unique properties of nanoparticles for diagnosis and treatment of brain diseases, including brain tumor, ischemic stroke, amnesia, and amyotrophic lateral sclerosis. The small size of nanoparticles, usually less than 100\u00a0nm, enables them to cross the BBB for delivering therapeutics and diagnostic probes to the brain parenchyma. In addition, nanoparticles can be modified for improved solubility, bioavailability and specificity of conventional drugs. To accelerate clinical translation, the authors highlighted the importance of determining the toxicity and bioaccumulation of nanoparticles in clinical settings. Khan et al discussed the application of various nanoparticles in treating Alzheimer\u2019s disease (AD). They focused on the formulation of nanoparticles employed for this purpose, including organic, lipid-based, as well as metallic nanoparticles. The authors contended that the development of nanoparticles with multi-therapeutic capacities would be the research direction of future AD nanomedicine. Finally, in this special issue Li et al summarized the application of nanomedicine in AD and Parkinson\u2019s disease by focusing on the pathogenic targets of nanoparticles, such as oxidative stress, protein fibrillation, and inflammation.Nanoparticles have been employed to transport therapeutic agents to the brain, providing a safe and effective approach to improve brain drug delivery . Ngowi e"}
+{"text": "According to the cognitive discrepancy theory, although the discrepancy between actual and desired social resources may result in loneliness, Perlman and Peplau (1998) suggested that cognitive processing and attributional style also impact the interpretation of social information. Previous empirical research investigating predictors of loneliness have not assessed a wide range of cognition and attribution factors, so this study filled this gap by examining how protective  and exacerbating , and experiences of age-based discrimination) factors influence and moderate the experience of loneliness cross-sectionally and longitudinally using a sample of 3,345 Americans aged 50 years and older from the 2008 and 2012 waves of the Health and Retirement Study. Optimism , mastery , purpose in life , depression , control constraints , negative SPA , and experiences of ageism  were significantly related to loneliness cross-sectionally and longitudinally, respectively. Optimism buffered the negative impact of poor functional social resources  on loneliness cross-sectionally while control constraints, negative SPA, and experiencing ageism exacerbated the relationship between low functional social resources and loneliness cross-sectionally. None of the protective or exacerbating factors modulated the relationship between functional social resources and loneliness longitudinally. These findings have important implications for the development of interventions that target loneliness. Targeting maladaptive cognitions may be particularly effective in reducing loneliness."}
+{"text": "Scientific Reports 10.1038/s41598-021-82844-7, published online 15 February 2021Correction to: The Acknowledgements section in the original version of this Article was incomplete.\u201cWe are grateful for the constructive comments received from Andrzej Baranski, Sanjeev Goyal, Agne Kajakaite, Byungkyu Lee, Georgia Michailidou, Rebecca Morton, Nikos Nikiforakis, Daniele Nosenzo, Wojtek Przepiorka, Ernesto Reuben, and Marie Claire Villeval as well as the participants of the 2019 Winter Experimental Social Sciences Institute at NYU Abu Dhabi, International Meeting on Experimental and Behavioral Social Sciences at the University of Utrecht and the participants of the Networks and Time speaker series at Columbia University. We also thank the anonymous reviewer for generous comments that helped improve the paper.\u201dnow reads:\u201cWe are grateful for the constructive comments received from Andrzej Baranski, Sanjeev Goyal, Agne Kajakaite, Byungkyu Lee, Georgia Michailidou, Rebecca Morton, Nikos Nikiforakis, Daniele Nosenzo, Wojtek Przepiorka, Ernesto Reuben, and Marie Claire Villeval as well as the participants of the 2019 Winter Experimental Social Sciences Institute at NYU Abu Dhabi, International Meeting on Experimental and Behavioral Social Sciences at the University of Utrecht and the participants of the Networks and Time speaker series at Columbia University. We also thank the anonymous reviewer for generous comments that helped improve the paper. This work was supported by the NYUAD Center for Interacting Urban Networks (CITIES), funded by Tamkeen under the NYUAD Research Institute Award CG001 and by the Swiss Re Institute under the Quantum Cities\u2122 initiative.\u201dThe original Article has been corrected."}
+{"text": "For more than 40 years, under the leadership of four editors and two publishers, The International Journal of Aging and Human Development (IJAHD) has featured multidisciplinary scholarship related to aging processes and older adults. With the publication of eight issues a year, with over 800 pages of scientific content, the IJAHD places emphasis upon psychological and social studies of aging and the aged. However, the Journal also publishes research that integrates observations from other disciplines that illuminate the \"human\" side of gerontology. A more recent focus includes midlife development, as well. About half (47%) of the publications in the IJAHD are from international colleagues. This presentation will discuss tips for both international and US-based scholars for ensuring timely reviews and positive decisions for manuscript submissions, including such areas as key words, suggesting unbiased reviewers, formatting, writing mechanics, clearly-articulated methods, and a sound theoretical basis."}
+{"text": "To evaluate the clinical and histopathological effects of natural extracts in the treatment of oral ulcers induced in animal experimental models.We carried out a search in the Medline, Scopus, WoS and Embase databases from the start of the databases to December 2020, and also made a manual search of the references. The search and selection were carried out by two researchers independently. The inclusion criteria were: experimental studies in animal models, in english, which complied with the study object.Jasminum grandiflorum, Ficus deltoidea, curcumin and Bixina orellana provoked a significantly greater reduction in the size of the ulcer. Extracts of Salvatora persica, Musa acuminate, Ganoderma lucidum mycelia and Bixina Orellana, as well as preparations of Kouyanqing Granule and curcumin, were able to reduce levels of pro-inflammatory cytokines and increase the expression and serum levels of growth factors and anti-inflammatory cytokines. Extracts of Piper sarmentosus, Cannabis sativa and Bletilla striata provoked a reduction in the severity of the histological inflammation. No significant differences were observed compared to controls in the treatments with extracts of Cannabis sativa, Aloe barbadensus Miller and Malva sylvestris in reducing the area of the oral ulcers.A total of 705 articles were identified. After selection by title, abstract and full text, 19 articles were finally included. Natural extracts of Most of the natural extracts described in this review presented a positive clinical and histological effect on the cicatrisation of oral ulcers induced in animal models. Key words:Recurrent aphthous stomatitis, oral ulcer, plants, herbs, extracts, medicine, treatment. An oral ulcer is defined as a tissue loss that alters the epithelium and the underlying connective tissues . Its aet-Review protocolThe systematic review protocol was registered in the international prospective register of systematic reviews (PROSPERO) of the National Institute for Health Research database (www.crd.york.ac.uk/prospero), reference code number CRD42020209352. This review was prepared according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline .-Search strategyA search was carried out in the MEDLINE, WoS, SCOPUS and EMBASE databases. A manual reference search was also carried out. The database search strategy is detailed in -Selection criteriaThe inclusion criteria were: experimental studies in animal models; in english; available from the beginning of the databases until december 2020; studies that aimed to evaluate the effect of natural extracts in the treatment of oral ulcers.in vitro studies; studies to evaluate effect of natural extracts on other pathologies of the oral mucosa.The exclusion criteria were: reviews, clinical trials, case series, case reports; published in other languages; human or -Study selectionAll the references identified were exported to the Mendeley\u00ae reference manager to facilitate the elimination of duplicates. The articles were reviewed by two authors independently ; when necessary, a third author (SW) resolved conflicts. Articles were selected first by title and abstract and then by full text, using the Rayyan tool.-Data extractionTwo data extraction Tables were prepared with the following information: first author and year of publication; total number of subjects and animal species; distribution of the experimental groups; method of induction of oral ulcers in animal model; type of treatment applied  cont.; n-Risk of biasTwo authors  independently assessed the risk of bias of the articles finally included. A third author resolved conflicts (ES). The Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) guideline  was usedA total of 705 articles were obtained; 47 were selected by title and abstract, and 19 articles were finally included by full text -48. All -Extracts usedGanoderma lucidum   and IL-6 in tissues, and the excessive release of adrenocorticotropic hormone (ACTH) and corticosterone (CORT). It has been shown that lack of sleep can activate the hypothalamus pituitary adrenal (HPA) axis . KYQG ha placebo . Extractdiflorum , Bixina orellana , Musa acorellana ,40, Blet striata , curcumi striata , Ficus dlization ,31,44,47lization , less selization , and betlization ,44 and 1gel used . Extractix (ECM) . Cannabiix (ECM) . Freeze-ix (ECM) . It is aJasminum grandiflorum, Bletilla striata, Ficus deltoidea, curcumin, Bixina orellana, Chamomilla recutita and Musa acuminate provoked a positive effect in ulcer contraction, re-epithelialization, and serum levels of molecules that promote repair or accelerate the healing rate. No significant differences from the control groups were observed with the use of treatments based on cannabidiol, Aloe Vera and Malva sylvestris in the area of the oral ulcers.Extracts of"}
+{"text": "Antimicrobial resistance (AMR) is a global public health concern because of its fast spread. India, one of the world\u2019s top consumer of antibiotics and second most populated country has its unique constraints of social, cultural and economic strata. The continual self-medication, use of antibiotics for the growth promotion in animals, and accumulation of residual antibiotics in the environment challenge the implementation of AMR containment policy. Hence, the present review attempts to delineate the influence of antibiotics abuse on the human, animal and environmental health under the realm of one health. It was based on the literature search using public databases to highlight the rapid surge in the burden of AMR in India affecting various sectors and/or ecosystems in India. It was found that the irrational and overuse of antibiotics in different sectors have led to the emergence of extended antimicrobial resistance wherein the environment acts as a reservoir of antibiotic resistance genes (ARGs); completing the cycle of contamination and recontamination. There are efforts by government policy makers to reduce the burden of AMR in the country to reduce the health risks, through the One Health approach. Parallel efforts in educating healthcare professionals, strict legislation for pharmacies and pharmaceutical companies should be prioritize. At the same time surveillance of newly emerged AMR pathogens, prioritising research focusing on AMR, and awareness camps or programs among the local population is critical while addressing the consequences of spared of AMR in India. Discovery of the antimicrobial agents in the early twentieth century was a breakthrough to safeguard the public health from the microbial infection. Propensity of these compounds to kill pathogens influenced the discovery of novel antimicrobials. However, since the 1970s, soon after the discovery of the fluoroquinolones, no major antibiotics have been introduced , 3. The Bacteria are ubiquitous in nature; thriving in soil, water and air and, interconnectedness of ecosystems, featuring human, animals and environment collectively indicates that the burden of AMR is multifaceted in nature . AntibioblaNDM-1  and associated controversy necessitated the policymakers to initiate the development of AMR containment-related policies for India in 2011 . Mo. MoAcineectively . Thus, rc health , 29.Fig.E. coli or Salmonella species. Furthermore, there have been molecular investigations suggesting extended-spectrum beta-lactamase (ESBL)-producing and colistin-resistant E. coli from the poultry [The ever-increasing demand of animal-based food products compelled the producers to increase the usage of antibiotics and growth-promoting factors in the animal feed. The higher usage of antibiotics aids the better health of animals and also enable industries to abandon the responsibilities of maintaining hygiene and sanitation. Such ill-usage of antibiotics in the animal feed leads to bioaccumulation which was supported by observed traces of antibiotics in animal-based food products . Majorit poultry . Moreove poultry . The ant poultry . MoreoveStaphylococcus aureus have been isolated from the animals suffering from mastitis [Vibrio species and members of family Enterobacteriaceae [MDR strains like Vancomycin-resistant mastitis . Furthermastitis , 36. Mormastitis . Similarmastitis . Excessimastitis , 17. Stueriaceae , 17. Preeriaceae . Additioeriaceae \u201317, 33.The finding of antimicrobial-resistant microorganisms in humans, poultry, cattle and fishes reveal possible transmission and sharing of such microorganisms and antibiotic resistance genes (ARGs) between these organisms. However, the underlying mechanism of transmission and establishment of AMR is not well understood . Thus, ablaNDM-1, blaOXA-48, blaCTX-M and mcr-1 genes [NDM-1 genes are responsible for the development of drug resistance in pathogens and also provide an advantage to evolve as a superbug [Sewage plants receiving untreated or inadequately treated hospital and industrial effluents are a potential reservoir of AMR and ARGs. Discharge of untreated sewage into the rivers is a another major factor contaminating the river and facilitating the spread of AMR. Recent studies from India have indicated that the hospital waste carries significantly higher proportion of antibiotic residues, particularly the traces of broad-spectrum antibiotics . In the -1 genes \u201343. blaNsuperbug . Similarsuperbug , 41. Thesuperbug .blaNDM-1 were monitored during the seasonal pilgrimage on the bank of Ganga. The authors reported a 20-fold increase in prevalence during the pilgrimage [Acinetobacter, Corynebacterium and Brevibacterium which was isolated during the event show higher antimicrobial resistance [Corynebacterium godavarianum, a novel bacterium isolated during the Kumbh Mela 2015, was found to confer resistance against an array of antibiotics supporting the observed increase in antimicrobial resistance during the mass bathing event [India is a country of festivals involving several cultural events during the year, one such event is the Kumbh Mela. It is considered as the world\u2019s largest mass gathering event attracting millions of pilgrims for the duration of three months , 46. Thelgrimage . Similarlgrimage , 50. Antng event .Neisseria meningitidis serogroup W135 in 1968, 1987, 2000 and 2001, H1N1 pandemic in 2009, Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in 2012, etc. Additionally, such a large participation also elevates the risk of stampedes or crush injuries, hence necessitates intensive planning and preparedness of the event to minimize the risk to the public health [India is one of the\u2009~\u2009184 countries that take part in Hajj pilgrimage at the Mecca, Saudi Arabia. Participation of pilgrims from these diverse countries has been associated with the morbidity and mortality at the event. In past, the Hajj has witnessed the burden of communicable diseases like, c health \u201354. Massc health , 52, 55.c health , 52. ThuThe striking observations of threatened humans, animal husbandry and fishery and, environment health due to growing antimicrobial resistance raise a serious concern Fig.\u00a0. Self-meTo address the ever-growing challenge of antimicrobial resistance and to safeguard public health, officials keep on upgrading the local policies by following the strategies outlined by WHO. The controversies related to the NDM-1 drew the attention of policy makers to initiate the National Policy on Containment of AMR in 2011 . The MinSimilarly, to safeguard the animal health, Food Safety and Standards Authority of India (FSSAI) has developed norms for the rational use of antibiotics. The FSSAI has banned the use of several antibiotics that could harm the fisheries and those used in the seafood processing . FurtherThe irrational and overuse of antibiotics in different sectors of India i.e., humans, food, animals and environment are responsible for the ever-increasing antimicrobial resistance (AMR), however, it has received little attention compared to its drastic impacts. Mitigation of the growing antimicrobial resistance would require strategies focusing on the one health approach. Initiative of the Indian government such as NAP-AMR policy along with the continued surveillance, awareness camps, and cross-continental research and training would enable combating the issue of AMR. Initiatives like designated AMR repositories by the Department of Biotechnology, Government of India at the National Centre for Cell Science, India would be helpful to generate and validate the emergence of AMR-related data in different sectors of India."}
+{"text": "The Coronavirus disease 2019 (COVID-19) outbreak in Ghana is part of an ongoing pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). The first two cases of COVID-19 were confirmed in Ghana on 12th March 2020. COVID-19 was consequently declared a Public Health Emergency of National Concern, triggering several response actions, including enhanced surveillance, case detection, case management and contact tracing, closure of borders, suspension of international flights, ban on social gatherings and closure of schools. Preparedness and response plans were activated for implementation at the national, regional, district and community levels. Ghana's Strategic approaches were to limit and stop the importation of cases; detect and contain cases early; expand infrastructure, logistics and capacity to provide quality healthcare for the sick; minimise disruption to social and economic life and increase the domestic capacity of all sectors to deal with existing and future shocks. The health sector strategic frame focused on testing, treatment, and tracking. As of 31st December 2020, a total of 535,168 cases, including 335 deaths (CFR: 0.61%), have been confirmed with 53,928 recoveries and 905 active cases. All the regions have reported cases, with Greater Accra reporting the highest number. The response actions in Ghana have seen high-level political commitment, appropriate and timely decisions, and a careful balance of public health interventions with economic and socio-cultural dynamics. Efforts are ongoing to intensify non-pharmaceutical interventions, sustain the gains made so far and introduce COVID-19 vaccines to reduce the public health burden of the disease in GhanaNone declared The Coronavirus disease 2019 (COVID-19) outbreak in Ghana is part of an ongoing pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARSCoV-2).6Most infections are asymptomatic, or patients present with mild symptoms, but some progress to a severe Acute Respiratory Distress Syndrome (ARDS), which is likely to precipitate a cytokine storm.The droplets may fall onto surfaces, and people could become infected by touching contaminated surfaces and touching their faces afterwards.Spread is highest during the initial three days after symptoms, but the spread is possible before the onset of symptoms and from asymptomatic individuals.22th of January 2020, several measures were instituted in Ghana as part of preparedness for COVID-19.th March 2020 and the confirmation of first two cases in Ghana on the 12th of March 2020 led to the declaration of COVID-19 as a Public Health Emergency of National Concern by Minister for Health, triggering a series of emergency preparedness activities to prevent and protect against COVID-19 in Ghana. This report provides an overview of preparedness and response to COVID-19 pandemic in Ghana over the period January to December 2020.Following the declaration of COVID-19 a Public Health Emergency of International Concern (PHEIC) by the World Health Organization (WHO) on the 30Preparations were initially health sector driven and included infrastructure, equipment, logistics and human resource capacity development and enhancement, public education and sensitisation, public and stakeholder engagements. There were press releases and media engagements to solicit the media's support, collaboration, and participation in providing updates and information to the public. Key activities for preparedness included the training of healthcare workers on the disease based on existing knowledge. Training also focussed on surveillance using developed case definition on COVID-19, Infection Prevention and Control for diseases spread by droplet infection and the appropriate use of Personal Protective Equipment (PPE).At the regional and district levels, preparedness and response plans for public health emergencies were revised, and Public Health Emergency Management Committees (PHEMCs) were activated. Rapid response teams were also activated and trained. The National Technical Coordinating Committee (NTCC) and the Emergency Operations Centre (EOC) were activated at the National level. The NTCC was constituted by Ministries, Departments and Agencies with a direct role in the response. The membership of the NTCC also included international organisations such as the WHO; Research institutions such as the Noguchi Memorial Institute for Medical Research and School of Public Health at the University of Ghana. The EOC was the operational arm of the NTCC and had four thematic areas- Surveillance, Laboratory, Case Management and Risk Communication. The NTCC was responsible for coordinating the preparedness and response for COVID-19 with the EOC leading in the implementation of preparedness and response plans at the national level. At the regional and district levels, the respective PHEMCs and Rapid Response Teams (RRTs) played the roles of the NTCC and EOC, respectively. All regions and districts activated their respective RPHEMCs and District Public Health Emergency Management Committees (DPHEMC) with daily meetings.Other preparedness actions were the development of case definitions for COVID-19 based on the WHO recommendations. Ghana adopted an extremely sensitive case definition to reduce the risk of missing a case. A health declaration form was adapted from the Ebola Virus Disease (EVD) form for use at all points of entry (PoEs). Appropriate testing kits were also provided to facilitate confirmation of COVID-19 cases in Ghana. The procurement of other logistics such as PPEs was also undertaken. Additional measures implemented as part of preparedness for COVID-19 included the use of thermal scanners and non-contact thermometers at POEs, the introduction of health declaration forms at POEs, restrictive entries (non-entry from countries with more than 200 cases), and ban on government officials from travelling.The Government of Ghana's response was driven by three key principles: All of Society Approach, All of Government Approach, and Data and Science.nd March 2020; a partial lockdown in the Greater Accra and Greater Kumasi Metropolitan areas from 30th March 2020 for three weeks; the banning of social gatherings including religious activities and funerals, and the closure of schools.Initial response actions to the confirmation of COVID-19 in Ghana were the closure of borders to neighbouring countries  and suspension of international flights from 22th of April 2020; and EI 164 on 15th June 2020. These provided the legal basis for restricting movements and social gatherings and mandatory wearing of face masks, among other measures. The response was also driven by a political framework based on the involvement of all ministries and agencies across all levels of governance from the community, through the districts, regions, to the national level. At the national level, the health sector, in collaboration with other sectors whose function impact on the response, together with development partners , activated the national public health emergency plan Limit and stop the importation, detect and contain the virusSlow down and manage community spreadProvide adequate medical and psychosocial care for COVID-19 casesStrengthen Governance, Coordination and Accountability of COVID-19 ResponseMinimise the impact of COVID-19 on Social & Economic LifeIncrease Domestic Capacity and Self-Reliance including building and strengthening capacity for health research and InnovationsGhana's response actions harnessed the appropriate legal framework, including the Public Health Act 2012 (Act 851) of 2012, which grants powers to the Minister for Health in Public Health emergencies; the Imposition of Restrictions Act 2020 (Act 1012); Executive Instrument (EI) 68 of 2020 on the 17The coordination of the COVID-19 pandemic response at the national level was subsequently elevated to the Presidency with daily emergency operation meetings chaired by His Excellency the President of Ghana with the Vice President, entire Cabinet, and a team of experts in attendance. Leadership by the President provided assurance, a sense of ownership and commitment at the highest level in preparedness for the pandemic response in Ghana. An Inter-Ministerial Presidential Taskforce on COVID-19 was set up chaired by the President of Ghana. The President initiated a whole-of-government approach including Ministries of Health, Information, Interior, Communication, Education, Local Government, Trade and Industries, Environment and Sanitation, Environment Science and Technology, and Aviation. Each ministry was assigned specific tasks in the national COVID-19 response effort. The President appointed a Coordinator for COVID-19 at the Presidency and established a command centre for COVID-19.A team of public health experts, medical laboratory scientists and expert Physicians were involved in the rigorous assessment and review of data to inform decision and policy. Processes were started for early and frequent engagements with institutions such as the Schools of Public Health, the Ghana Academy of Arts and Sciences, Professional Groupings including the Ghana Medical Association, Non-Governmental Organisations (NGOs) and Civil Society Organisations (CSOs) such as Occupy Ghana.At the time of confirmation of the first two cases of COVID-19 in Ghana, only two laboratories, the Noguchi Memorial Institute for Medical Research (NMIMR) and the Kumasi Centre for Collaborative Research in Tropical Medicine (KCCR) could test for COVID-19. This presented challenges to the response with increasing numbers of suspected cases requiring testing leading to a backlog of samples. An aggressive drive to increase the capacity of the existing laboratories to test was instituted. This included recruiting additional staff and the institution of 24-hour workdays for the laboratories to reduce the backlog. In addition, other laboratories within and outside the health sector, such as the Veterinary Services Department laboratory came onboard to support testing and reduce the waiting period between sample collection and testing. Private laboratories were also assessed and accredited to provide testing for COVID-19 that further increased the capacity for testing and significantly reduced the waiting time. Thus, from two testing laboratories in April 2020, the number of laboratories capable of PCR testing for COVID-19 increased to 16 [4 private all in Greater Accra and 12 Public facilities ; Ashanti ; Volta ; Northern , Western (Veterinary Services Department Laboratory), Upper East . Six GeneXpert sites for SARS-CoV-2 testing were initially established with two functional at Cape Coast Teaching Hospital and Effia Nkwanta Hospital. Other GeneXpert facilities yet to be operational are Sunyani, Bolgatanga, Wa Regional and Sefwi Wiawso Municipal Hospitals. Thirty-two more sites were identified and are to be equipped to provide GeneXpert testing services for COVID-19.The laboratory component of the response also saw a significant increase in the human resource capacity for PCR testing in Ghana. Biomedical scientists and other laboratory staff received training from the NMIMR and the KCCR to provide PCR testing services. A laboratory network was also established at the national level, with a Coordinator appointed to oversee the work of the network, including the management of logistics for sample collection, transport and testing.Laboratory testing policy, guidelines and job-aids were developed, and staff were trained on them for immediate use. Real-time Reverse Transcription Polymerase Chain Reaction (RT-PCR) has been the mainstay of diagnosis and laboratory confirmation. Initially, testing was based on case definition, testing of close contacts, enhanced contact tracing (community screening). Prioritised testing of suspected cases, contacts, exposed health workers, students and at-risk groups was later adopted as part of the laboratory response strategy. The testing policy required initial PCR and double exit testing to assess recovery and discharge from the caregiving pathway. Following the revision of the National discharge and recovery policy, the mandatory exit testing was stopped. The pooling method was adopted initially but was suspended when the test positivity rate increased. Rapid diagnostic testing at Kotoka International Airport (KIA) using Immuno-fluorescent assay technology was introduced as part of measures to re-open KIA. Part of the laboratory response measures included evaluating the Rapid Diagnostic Test kit by the Food and Drugs Authority (FDA) in collaboration with the Noguchi Memorial Institute for Medical Research (NMIMR). At the end of December 2020, a total of 70 test kits had been evaluated. All 70 kits did not meet the set criteria for acceptability and use in Ghana for COVID-19 testing.Surveillance was a key component of the preparedness phase for COVID-19 in Ghana. It remains a useful component of the response phase. It includes routine surveillance through case definitions, enhanced surveillance and contact tracing to ensure early case detection and management. At the onset of the outbreak globally but before the recording of the first two cases of COVID-19 in Ghana, the working case definition adopted was:Suspected Case: A person presenting with fever (>38\u00b0C) or a history of fever and symptoms of respiratory tract illness, e.g., cough, difficulty in breathing AND in the last 14 days before symptom onset, a history of travel to China or any other affected countryORAND in the last 14 days before symptom onset, close contact with a person who is under investigation or confirmed for 2019-nCoV.A person with fever (>38\u00b0C) or a history of fever and symptoms of respiratory tract illness, e.g., cough, difficulty in breathing Confirmed Case: A suspected case with laboratory confirmation of 2019-nCoVFollowing the confirmation of cases in Ghana and the subsequent establishment of community spread in Ghana, the case definition was appropriately amended as:Suspected Case: A person presenting with fever (>38\u00b0C) or a history of fever and symptoms of respiratory tract illness e.g., cough, difficulty in breathing OR other symptoms such as loss of sense of smell, loss of sense of tasteORAND the last 14 days before symptom onset, close contact with a person who is under investigation or confirmed for COVID-19A person with fever (>38\u00b0C) or a history of fever and symptoms of respiratory tract illness e.g., cough, difficulty in breathing or loss of sense of taste and/or smell Confirmed Case: A person with laboratory confirmation of SARS-CoV-2 with or without symptomsst and 22nd March 2020, 105 were positive for COVID-19 . Mandatory quarantine ceased temporarily when international flights were banned but was resumed when the government approved evacuations which lasted till 1st September 2020.The overall objective of surveillance was to limit and stop the importation of cases among foreign travellers and reduce the local spread of the disease. Several activities were implemented as part of surveillance measures, including training of port health and other PoE staff , closure of all borders  and introduction of mandatory quarantine. Mandatory quarantine for 14 days was enforced during the early phase of the pandemic in Ghana. This involved initial laboratory testing, daily monitoring for signs and symptoms of COVID-19 and exit testing at the end of the 14-day quarantine. Out of the 1,030 passengers who were quarantined upon arrival at KIA on the 21Development of surveillance and contact tracing guidelines, standard operation procedures (SOPs), and job-aidsTraining of health staff on the implementation of the guidelines and SOPsEnhanced contact tracing Use of call centres and toll-free emergency phone linesRegional Rapid Response Teams were trained, provided with enablers and rendered operationalContact tracing was decentralised and was conducted by district teams with the support of regional and national level teamsSurveillance Outbreaks Response Management and Analysis System (SORMAS), an open-source online mobile e-Health system that processes disease control, outbreak management procedures, disease surveillance, early detection of outbreaks and also software for management for epidemiological data, was deployed and scaled up nationwide for real-time electronic data collection and transmissionA barcode system to link surveillance and laboratory data was developed and implementedAdditional measures implemented to aid detection and containment of cases were the:th of March and 31st December 2020, the surveillance system confirmed 55,168 cases of COVID-19 from a total of 672,364 tests performed, giving a positivity of 8.2%. Among these were 705 cases recorded among international arrivals at the Kotoka International Airport. A total of 335 deaths were reported among the confirmed cases of COVID giving a case fatality rate of 0.61%. Ghana recorded the first major wave of COVID-19 cases between June and August 2020 with the 2nd of July 2020 recording the highest number of cases in a day (774). The trends in COVID-19 cases reported in Ghana between the 12th of March and the 31st of December 2020 are shown in Between the 12st of December 2020. The regions reporting the most cases were the Greater Accra, Ashanti, Western, Eastern and Central Regions. The Greater Accra region alone accounted for more than 50% of the reported cases. The North East Region recorded the lowest number of cases,22. The cumulative COVID-19 cases by region from 12th of March 2020 to 31st December 2020 is as shown in All 16 regions had reported cases of COVID-19 as of the 31st of September 2020. As part of measures to ensure the safe opening of the airport and to reduce the risk of COVID-19 transmission at the airport, the following measures were undertaken:Re-configuration of infrastructure to ensure adequate physical and social distancingLogistics for hand hygieneInstallation of operational booths for Port Health staffInstallation and establishment of an electronic data collection system for the health declaration form (HDF) and network connection of the HDF with the testing laboratory at the KIAWorkshops for airline operators on the guidelines on COVID-19 safety for international travelsSimulation exercises on planned passenger flow for airport re-openingRecruitment of additional staff such as nurses, doctors, disease control officers and clinical psychologists to strengthen their capacityEstablishment of a laboratory at KIA to conduct COVID-19 testing using immune-fluorescent antigen technologyEstablishment of a holding area for COVID-19 positive casesProvision of ambulances to transfer confirmed cases to designated treatment centresThe closure of the airport to international travel was the initial response to the pandemic in Ghana. After months of closure, the Kotoka International Airport (KIA) was re-opened on the 1Other activities implemented at KIA included completing the Electronic Health Declaration, an inspection of PCR test results from the country of origin for arriving passengers, temperature checks and disclosure of COVID-19 test results, isolation and transfer of COVID-19 Positive cases and contact tracing for passengers arriving at KIA.For three weeks, the Enhanced Contact Tracing strategy was adopted to ensure early case detection and establish the extent of community spread, especially in high burden regions and partial lockdown areas in the Greater Accra and Greater Kumasi regions. Teams were trained, resourced, and deployed to test, track and link cases to care. All identified and traced contacts of confirmed cases during the lockdown period were contacted and tested for COVID-19. Approximately 150,000 tests were undertaken during the lockdown period. Multisector contact tracing teams involved national security, immigration, and health workers. Heat maps were developed, and these provided evidence of community spread.Risk communication and social mobilisation was a key thematic area in Ghana's preparedness and response strategy. The Ministry of Information led this thematic area in collaboration with the Health Promotion Division of the Ghana Health Service and the National Commission for Civic Education, among others. Several strategies were adopted as part of risk communication and social mobilisation. At the highest level, regularly scheduled broadcasts by the President of the Republic were employed to update the public on measures implemented by the government in response to the outbreak. These broadcasts by the President were also used to announce health policy initiatives and other critical non-health government interventions. The broadcasts by the President of the Republic were very insightful, and the origin of the now popular expression \u2018Fellow Ghanaians\u2019, which was a call to action by all, can be traced to those Presidential updates.In addition to Presidential broadcasts, regular press briefings were part of the risk communication and social mobilisation strategies. The Ministry of Information, the Ghana Health Service, and other stakeholders provided the general public with scheduled media briefings. Subject matter experts and partners, including the Ghana Medical Association, Academia and the Ministry of Communications, were active participants in the press briefings at various points in time. One key message from such briefings was the refrain \u2018the virus only moves when people move\u2019, which helped emphasise the critical role of all Ghanaians during the critical lockdown period. Parliamentary briefings by the Minister of Health and/or Director-General of the Ghana Health Service were also implemented as part of the communication strategy.The risk communication strategy also included developing and disseminating key messages on COVID-19 to the general population. Public education on COVID-19 across regions, districts and at the community level using traditional and social media have been key components of the risk communication strategy. Other strategies employed included the broadcast of COVID-19 related messages on screens at PoEs, media engagements  providing information on the disease and its prevention, media monitoring to identify challenges and misinformation on COVID-19, tour of media personnel to PoEs to provide them with a clear understanding of the operations of the Port Health Unit of the GHS and the engagement of other key stakeholders such as the National and Regional Houses of Chiefs.Ghana adopted two main approaches towards case management. The first approach was isolating persons with COVID-19 at designated treatment centres , all Teaching Hospitals, all Regional Hospitals, and some District Hospitals). The second approach was home isolation for asymptomatic and mild cases with no underlying medical conditions such as diabetes mellitus or hypertension.Development of case management protocols, guidelines, and job-aidsStaff training on the protocols and guidelines and capacity building, including infection prevention and controlExpansion of infrastructure for holding suspected cases and isolation of confirmed cases in all health facilitiesExpansion of isolation centres and provision of equipment, PPEs, medication, and consumablesInclusion of clinical psychology services for patient supportRe-assignment and deployment of selected staff of teaching hospitals with expertise in critical areas like intensive care and acute medicine to various treatment centres to facilitate the care of critically ill patients.In preparation for case management and care of the sick, the following were put in place to provide healthcare and appropriate health interventions for persons with COVID-19:Case containment was a critical component of the Case Management strategy. Various activities were implemented to ensure containment, which is key to reduce the risk of disease spread.All health facilities were directed and supervised to establish and operate designated holding rooms for suspected cases of COVID-19.Metropolitan, Municipal and District Assemblies (MMDAs) partnered with the Ghana Health Service to provide quarantine facilities in their respective districtsThe national policy and guidelines on quarantine made provisions for mandatory and self-quarantine under supervision. Provisions for mandatory quarantine were enforced when conditions for self-quarantine could not be met.Public-Private partnerships were used to secure more facilities  for quarantine and isolation (with designated Isolation centres such as Pentecost Convention Centre (PCC), TUC (buildings in Accra and other regions), and the Ghanaman Centre of Excellence  in Prampram)Designated Treatment Centres included Tema General hospital, Ga East Municipal Hospital, Greater Accra Regional Hospital, Korle-Bu Teaching Hospital, Kumasi South, Komfo Anokye Teaching Hospital, Frimpong Boateng Medical Centre, and the Nyaho Medical Centre) Newly constructed Ghana Infectious Diseases Centre (100 bed capacity) at Ga East Municipal Hospital, AccraThe following were some critical components of measures aimed at case containment in Ghana's response to COVID-19:The National Ambulance Service supported the response by providing ambulances at vantage locations, including the Kotoka International Airport, to transport suspected and confirmed cases. The drone delivery services were also employed in the delivery of test samples.The health system also set out to ensure prompt linkage to care for schools. To improve school health efficiency and quality, the schools were linked with the District Health Management Teams (DHMT) and nearest health facilities. All senior high schools were supported to establish or upgrade their infirmaries, and these were linked to health facilities in the respective districts. Training of heads of schools, teachers and school health staff was undertaken.A strategic effort was initiated for incremental procurement and stockpiling of essential supplies of PPEs. Measures were also started for local production of PPEs. More PCR machines, laboratory testing kits, infection prevention and control logistics such as hand washing facilities and equipment were procured and distributed. An active drive was initiated to expand infrastructure by identifying and converting facilities such as Ga East hospital to a treatment centre. Other facilities used as treatment centres were the Debrah Ward at 37 Military Hospital, University of Ghana Medical Centre (UGMC) and Frimpong Boateng Medical Centre in the Ashanti region. With these measures, the bed capacity for case management, which was 13 , now increased to about 1,000 beds, including Intensive Care Units (ICUs) and High Dependency Units (HDUs).involvement of private health facilities in the management of public health emergencies saw significant improvement as several private health facilities and laboratories have been accredited and licensed to provide COVID-19 testing and manage cases to complement the efforts of government facilities.The private sector support of Ghana's response extended to establishing the first Ghana Infectious Disease Centre (GIDC) at the Ga East Municipal Hospital. This well-equipped centre was constructed and furnished with funds solely from the private sector and handed over to the Government of Ghana to manage COVID-19 cases. This was a useful addition to Ghana's COVID-19 response and had the potential to be used to manage any future outbreaks of infectious diseases.Non-governmental organisations were also involved in the public education drive for COVID-19, including the development and dissemination of information on COVID-19 safety and the provision of billboards and other communication media. The private sector contributed significantly to the Ghana COVID-19 National Trust Fund established by the government to provide a channel for resources from the non-governmental sector to be pooled in support of the government's efforts towards COVID-19 response. Resources mobilised by the Fund have been useful in the COVID response supporting several activities, including procurement of personal protective equipment and other essential logistics.A team led by the Ministry of Health's Policy Planning Monitoring and Evaluation Directorate mobilised resources for Ghana's COVID-19 response. One major activity of this team was developing a COVID-19 Strategic Plan and Budget (2020\u20132024) with an estimated budget of over 600 million USD. The plan's development involved all relevant stakeholders and included the thematic leads from the laboratory, surveillance, case management, infrastructure, risk communication and social mobilisation. This plan was the basis of the development of the first Project Appraisal Document for the World Bank, for which an initial amount of 100 million dollars was raised to cover all the thematic areas.During the outbreak, mentorship and partnership with academia and other experts were also established. Furthermore, retired clinical and public health experts were engaged to provide technical support to the COVID-19 response. The retired consultants were also involved in monitoring, mentoring and evaluation of the response. Outputs from the engagements informed policy decisions.The government of Ghana instituted several social interventions as part of the response efforts for COVID-19. Among the many social interventions were:Provision of food to some residents in the Greater Accra and Greater Kumasi areas:During the lockdown in Greater Accra and the Greater Kumasi Areas in March and April 2020, the government provided hot meals to about 400,000 vulnerable individuals and homes.The meals were distributed at designated points within the cities, such as the Efua Sutherland Children's Park in Accra. In addition, the government also provided dry food packs for some 470,000 families.25Absorption of Water bills and Subsidy on Electricity bills:The government absorbed the water bills for all consumers for six months from April 2020. In addition, public pipe-borne water stands and water tanker distribution services were provided. The government also provided a 50% rebate for all consumers of electricity and provided free electricity for customers on the lifeline tariff for nine months from April to December 2020.26Tax exemption and other social interventions for healthcare workers: as part of response measures, the government also exempted payment of tax on the employment emoluments of healthcare workers from April 2020 to December 2020. In addition, healthcare workers working directly in the COVID-19 response classified as frontline healthcare workers received a 50% of their basic pay as a top-up to their monthly earnings from April to December 2020. Frontline healthcare workers were also provided insurance cover of up to 350,000 Ghana Cedis per worker. In addition to these, free transportation was provided for some healthcare workers in Accra, Kumasi, Tema and Kasoa.27Despite the many useful actions undertaken as part of health sector preparedness and response to the COVID-19 pandemic in Ghana, several challenges were identified. Key among these challenges were sporadic shortages of PPEs, geographical limitations in testing for COVID-19, delays in receipt of COVID-19 tests, lack of staff to manage treatment centres and shortage of COVID-19 laboratory reagents. The shortage of PPE was addressed through the increased procurement of PPEs and the streamlining of the distribution of PPE through a sub-committee of the NTCC, the Commodities Sub-committee. This sub-committee was also instrumental in addressing laboratory reagent challenges. On staffing challenges, staff training to provide critical care services was undertaken in addition to the secondment of specialised clinical care staff from teaching hospitals to treatment centres. The expansion of laboratory testing services to include private laboratories improved the turnaround time for sample processing to about 48 hours compared to several weeks during the early phases of the pandemic, causing a reduction in the pressure brought to bear on the main testing sites, NMIMR and KCCR. The expansion of laboratory testing services also improved geographic access to COVID-19 testing, although a significant proportion of testing laboratories are in Accra. Some of the interventions to alleviate the pandemic's adverse social and financial challenges, like distribution of food during lockdown, had operational challenges resulting in dissatisfaction.The numerous useful lessons from Ghana's response to the COVID-19 pandemic must be further studied and integrated into routine preparedness planning in Ghana. Key issues such as multisectoral collaboration, high-level political commitment, mobilising whole of government and society, private sector involvement and continuous engagement of the general population are useful, and high impact approaches for pandemic response and management of other public health emergencies.Emerging and re-emerging infections pose major threats to global health security. The COVID-19 pandemic has demonstrated the need for adequate and updated preparedness, with the availability of minimum core capacity for preparedness and response to epidemics. It is always difficult to predict when and where the next pandemic will emerge. Pandemic management and complex public health emergencies require multiple disciplines, sectors, and government apparatus. Additionally, good governance and leadership are crucial for effective, efficient, and successful management of pandemics and other complex public health emergencies, and Ghana's experience has demonstrated this."}
+{"text": "According to Brown and Cai, Thyroid hormones (THs) have been considered \u201cthe first developmental morphogen ever discovered\u201d . This asXenopus tropicalis metamorphosis, both the cross-talk of THs and glucocorticoids and the intestinal morphogenesis are explored using state-of-the-art functional genomic and developmental biology approaches by Buisine [This article collection highlights the role of THs in different tissues, taking into account data from classical and novel models. The work of Esposito et al., gave an insight on the evolution of THs signalling comparing the homologies of the available sequences of TPO, DIOs, and THRs. Thus, their study supports the hypothesis of the evolutionary adaptation of a functional thyroid hormone signaling in non-vertebrate chordates . Nittoli Buisine  and Shib Buisine , respectThroughout these articles the roles and mechanisms of action of THs are covered in different fields of interest including non-mammalian models. Taken together, these contributions should be of wide interest for both scientists of fundamental fields and physicians for translational approaches."}
+{"text": "On July 15, 2021, the Secretary of Health of Honduras (SHH) was notified of an unexpected number of mucormycosis cases among COVID-19 patients. SHH partnered with the Honduras Field Epidemiology Training Program, the Executive Secretariat of the Council of Ministers of Health of Central America and the Dominican Republic (SE-COMISCA), Pan American Health Organization (PAHO), and CDC to investigate mucormycosis cases at four geographically distinct hospitals in Honduras.Mucormycosis is a severe, often fatal disease caused by infection with angioinvasive molds belonging to the order Mucorales. Risk factors for mucormycosis include certain underlying medical conditions  and the use of certain immunosuppressive medications ,Given the severe outcomes associated with mucormycosis, clinicians should remain vigilant for this disease during the COVID-19 pandemic, including in immunocompetent patients. Early mucormycosis diagnosis is possible, even in resource-limited settings ("}
+{"text": "Venous thromboembolism, a complex disease combining deep vein thrombosis (DVT) and its most dangerous complication, pulmonary embolism (PE), strikes millions of people worldwide. For example, in the United States only, DVT develops in up to 600,000 individuals annually, and 100,000\u2013180,000 deaths from VTE are estimated each year .Studies in the field of venous thrombosis cover several aspects of the disease. Discovery of the mechanisms of thrombosis initiation and propagation could help prevent its development in individuals at risk. Exploration of the routes of thrombus resolution is essential to reduce deleterious effects of the formed clot. Finally, search for specific biomarkers is necessary for both verification of the diagnosis and, importantly, prediction of the probability of thrombosis. A review by Anghel et al. in this issue Journal presents a set of previously known as well as novel biomarkers of venous thrombosis and discusses their potential benefits and limitations in diagnosis and building the treatments strategy for DVT .Separate mechanisms of DVT in certain pathological conditions are relatively well understood. For example, the role of tissue factor in cancer-related DVT has been established . Howevervasa vasorum and receives oxygen and nutrients from the blood inside the vessel. Blood flow stagnancy results in limited supply of oxygen and local hypoxia of both endothelium and subendothelial layers, which leads to formation of reactive oxygen species (ROS) [Venous wall does not contain es (ROS) . An impoes (ROS) . In thises (ROS) . AuthorsAccording to the currently predominant concept, PE develops when a thrombus or its part gets dislodged from the site of initial formation  and travels all the way to the lungs where it occludes branches of the pulmonary artery. However, clinical evidence suggests that in many cases, clots in the lungs are observed in the absence of primary thrombosis elsewhere. Porembskaya et al. discuss an alternative scenario, in which systemic prothrombotic and proinflammatory milieu could mediate the development of thrombi in lungs in situ independently of DVT . AccordiThe coverage of VTE-related topics would be incomplete without its clinical aspects. Patel et al. present a comprehensive analysis of existing approaches for diagnostics and prediction of VTE . The artIt is known that pulmonary hypertension (PH) is frequently observed and serious complications of PE . A studyIn conclusion, this Special Issue presents new data and state-of-the-art overview of major aspects of venous thrombosis, such as its development, resolution, diagnosis, and potential biomarkers. This information may be useful to both basic scientists and clinicians dealing with this debilitating and life-threatening disease."}
+{"text": "Linguistic phenotypes of individuals with Fragile X (FXS) and Williams (WS) syndromes exhibit various degrees of pragmatic impairment, involving difficulties in social communication and in adapting to conversational principles. The goal of the present study was to explore syndrome-specific pragmatic profiles of adults with FXS and WS based on the assessment of the observance of Gricean maxims of conversation. The participants were 12 Spanish-speaking adults (6 FXS/6 WS), without a diagnosis of ASD, whose extensive naturalistic conversations  were transcribed and coded with the CHILDES/TALKBANK tools and the PREP-CORP pragmatic protocol. Violations of the maxims of conversation were analyzed, and indexes of cooperation and conversational response were obtained. Both groups showed reduced verbal production and repetitive dysfluencies; prominent features in the FXS profile were higher proportion of non-contingent language, perseverations of topic and form, and impulsive conversational responses; in the WS profile, salient characteristics were higher proportion of tangential utterances, reformulations, and conversational responses reflecting overly literal interpretation. Pragmatic profiles of violation of conversational maxims reflect specific communication skills impaired in adults with FXS and WS and raise the need for assessment and intervention methods that specifically address their social communication abilities. Fragile X syndrome (FXS) and Williams syndrome (WS) are neurodevelopmental genetic disorders characterized by specific phenotypical profiles of relative strengths and weaknesses in the neurocognitive domain, including intellectual disability and a range of behavioral problems ,2,3,4,5.FXS is the most common identified cause of inherited intellectual disability. It is caused by the mutation of the Fragile X Mental Retardation gene (FMR1) at the chromosome Xq27.3 and the consequent lack of the Fragile X Mental Retardation Protein (FMRP), which is predominantly expressed in neurons [WS is a rare neurodevelopmental disorder caused by the heterozygous deletion of 25\u201327 genes at chromosome 7q11.23, which has a complex genomic architecture, and its multisystemic phenotype is characterized by mild to moderate intellectual disability, cardiovascular disease, and distinctive facies .As expected for an X-linked disorder, males with FXS tend to exhibit more cognitive and behavioral problems relative to females with FXS, and most of the research on FXS has targeted males . ConversThe phenotypical outcomes have implications for language profiles in both syndromes, which present within-syndrome and cross-syndrome differences. Within-syndrome analyses typically display uneven profiles of relative strengths and weaknesses. In parallel, cross-syndrome analyses reveal profiles with shared and syndrome specific features ,9,10,11.Despite marked differences in social orientation, FXS and WS share asynchronous profiles of pragmatic weakness that arise in social communication contexts ,10,11. HPragmatic skills have been investigated independently in both syndromes or in contrast with other neurodevelopmental disorders, such as Down syndrome, in search for specific profiles , but to Pragmatic impairment was primarily considered a symptom of autism in early studies, although it was soon differentiated from autism and included, within the Language Development Disorders, as a Semantic-Pragmatic Disorder (SPD) when it occurred \u201cwithout autism\u201d . SPD wasFinally, it was included in the latest version of DSM-5 as the diagnostic category of \u201cSocial (Pragmatic) Communication Disorder (SPCD)\u201d . SPCD isIndividuals with FXS and WS exhibit pragmatic difficulties in social interaction and communication, including problems in maintaining a conversation topic, perseveration, repetitive language, impulsivity, and inappropriate responses . ResearcNarrative skills are a crucial aspect of social communication and provide a means for investigating aspects of the microstructure  and macrostructure  of discourse as it is produced in natural contexts. Those aspects of narratives have been addressed in several studies of individuals with WS or FXS alone or compared with other populations with neurodevelopmental disorders, such as Down syndrome, revealing specific weaknesses in macrostructure aspects  ,34,35,36Even more scarce are the studies on conversational discourse both in FXS and in WS. In one of the first conversational analyses of males with FXS, Sudhalter et al.  reportedIn addition to perseverative speech, individuals with FXS exhibit tangential language, defined as personal and highly idiosyncratic associations of words, phrases, or topics that are not pertinent to the thread of conversation . DysflueIn contrast with FXS, social cognition of adolescents with WS was described initially as a strength, as they showed awareness of listener needs, engagement to the listener, and affective expression in narratives . Their cSubsequent analyses of conversations of individuals with WS indicated that more than 25% of the utterances were inappropriate, which in half of the cases were due to problems of expressive syntax and semantics and insufficient quantity of information provided . Social Pragmatic difficulties in social interaction and communication are often described as autistic symptoms in individuals with intellectual disabilities of genetic origin ,50. AutiAutistic symptoms in FXS might then differ from those of non-syndromic ASD . Social Individuals with WS were initially characterized by a profile of hypersociability and were thus considered to represent the polar opposite of autism in the social and communicative domain . Only inASD comorbid diagnosis in neurodevelopmental disorders may have clinical utility to characterize phenotypic variability, although it is partially based on pragmatic impairments that are not clearly differentiated from those also observed in FXS without autism. If RRB-like features are not present, a more accurate characterization of pragmatic impairment in many individuals with intellectual disability of genetic origin might be provided by DSM-5 diagnosis of Social (Pragmatic) Communication Disorder (SPCD) .The assessment of the pragmatic profile in individuals with intellectual disability is frequently oriented to comorbid diagnosis of ASD, especially in the case of FXS. Therefore, it is based in many cases on instruments designed for autism screening, such as the ADOS-2, ADI-R, Autism Screening Instrument for Education Planning (ASIEP-3), Social Communication Questionnaire (SCQ), and the Social Responsiveness Scale (SRS-2) ,73,74,75Oral language sample analysis is considered the most valid procedure for pragmatic evaluation , such asTaking into account the scarcity of studies on pragmatic impairment and of instruments for its assessment in neurodevelopmental genetic syndromes, the present study had two main objectives: (1) to explore the pragmatic profiles of adults with FXS and WS based on analyses of conversations; (2) to determine the feasibility of the PREP-CORP protocol for assessing pragmatic features in speech corpora.-Maxim of quality (MQL): truthfulness and adjustment to world reality.-Maxim of relation (MRL): non-related, tangential, and perseverations of topic.-Maxim of quantity (MQT): redundant, vague, excessive, and reduced utterances.-Maxim of manner (MMN): repetitions, reformulations, perseverations of form, and alterations of the syntactic order.-AVI of cooperation: aggregate index of violations of all the maxims.-AVI of conversational response: incomprehension, literal interpretation, impulsivity, and echolalia.The PREP-CORP protocol includes a section that allows the coding and quantification of the observance of Grice\u2019s cooperation maxims in conversational utterances. Consequently, the specific objectives of the study were focused on calculating aggregate violation indexes (AVIs) and conducting between-group and within-group comparisons of the following maxims and types of violations:Analyses were expected to yield within-syndrome differences  in the types of violations of conversational maxims; and also, cross-syndrome comparisons were expected to show profiles with overlapping and syndrome-specific conversational features.The conversational speech samples were elicited from two groups of Spanish-speaking participants: 6 adult males with FXS  and 6 adults  with WS . The total size of the speech samples collected was 71,859 words . The participants belong to a larger sample from the SYNDROLING Project . InclusiThe transcripts were coded using the PREP-CORP Pragmatic Evaluation Protocol , adapted(a)Maxim of Quality (MQL)*INV: and what are you working on here nowadays?*PAR: on nothing.%xepr:$i5:MQL:IMP(b)Maxim of Relation (MRL)*INV: (that cap) do you know which team it belongs to?*PAR: of basketball.%xepr:$i5:MRL:TNG:ICOM:LIT(c)Maxim of Quantity (MQT)*INV: why she was called so?*PAR: she was called so.%xepr:$i5:MQT:RUT:ECH(d)Maxim of Manner (MMN)*INV: what happened to the wolf and the stones?*PAR: and then what else? (.) and then (.) and then something else (.) and then something else (.) and then something else yet (.) and then something else yet about stones.%xepr:$i5:MMN:REP:PER_FThe following are examples of PREP-CORP coding for each of the maxims:Speech samples were collected in spontaneous dyadic conversations with an experienced researcher using audiovisual recordings .A certain degree of standardization was introduced by the researcher prompting common topics to all participants, in line with the procedures developed by Abbeduto et al. . The topt-test for independent and related samples. In addition to significance tests, estimates of the magnitude of the observed effects were calculated according to criteria and procedures provided by Ellis [r family (based on correlations), and d family (based on mean differences). Although d is recommended to generalize the impact, r is considered a more flexible and ecologically valid statistic when the sample is small. Therefore, a multiple perspective using both r and d was adopted [In order to control for the differences in grammatical complexity and lexical diversity, mean length of utterances in words (MLUw) and number of different words (NDW) were calculated for both groups. The frequency of the different types of violation of the maxims was also calculated using the CLAN software from the CHILDES project. In order to control for the differences in the size of the transcripts, violation indexes (VI) were calculated: frequency of each type of violation per thousand words. The sum of the VIs provided aggregate violation indexes (AVIs) of each maxim. In turn, the four AVIs were added to obtain an AVI of cooperation (AVIofCOOP), as a global pragmatic measure. An AVI of conversational response (AVIofCONRES) was also calculated from the optional tags. The between-group and within-group differences in the VIs and AVIs were analyzed using the Student\u2019s by Ellis . There a adopted .t-tests, were not statistically significant: MLUw ; NDW .Differences between the two groups on the previous control variables of grammatical complexity (MLUw) and lexical diversity (NDW), assessed with t-test comparisons. The FXS group presented a significantly higher proportion of violations than the WS group in the maxim of relation (MRL) and, specifically, in the topic perseverative utterances (PER_T). Concerning the types of violation of the maxim of manner (MMN), the FXS group presented a significantly higher proportion of violations in perseverations of form (PER_F), while the WS group presented a significantly higher proportion of violations in reformulations (REF). No significant between-group differences were observed in the aggregate measure of violation of the cooperation (AVIofCOOP).t = \u22123.229; p = 0.023; d = \u22121.986; r = \u22120.704) and NRL < PER_T ; in the WS group, NRL < TNG  and NRL < PER_T .In the types of violations of the MRL , within-group comparisons yielded the following statistically significant differences: in the FXS group, NRL < TNG , VUT > EVP , and RVP > EVP  and in the WS group, RUT < VUT  and VUT > EVP .In the types of violations of the MQT , within-group comparisons yielded the following statistically significant differences: in the FXS group, RUT > EVP  and REP > ORD  and in the WS group, REP > ORD , REP > PER_F , REF > ORD , REF > PER_F , and ORD > PER_F .In the types of violations of the MMN , within-group comparisons yielded the following statistically significant differences: in the FXS group, REP > REF ; MQL < MQT ; MQL < MMN . In the WS group, within-group differences were MQL < MQT , MQL < MMN , MRL < MQT , and MRL < MMN .t = \u22122.352; p = 0.041), IMP , and ECH . Within-group differences were found only in the FXS group between ICOM > LIT  and IMP > LIT .t = \u22123.827; p = 0.008; d = 2.44; r = 0.77).The sum of the VIs resulted in a global measure of conversational response (AVIofCONRES) for each syndrome: FXS group  and SW group . These differences were statistically significant  as a significant marker of the speech disorder of individuals with WS, which has been explained considering the cognitive and linguistic demands of the narrative and conversational tasks, in terms of language processing and planning . ReducedBetween-syndrome comparisons of the global index of violation of conversational cooperation in the FXS and the WS groups yielded no statistical differences. However, the present study found some similarities and a number of important differences in their profiles of pragmatic impairment. In both groups, violations of the maxims of quantity and manner were particularly high, while violations of the maxim of quality were less frequent. These findings may suggest an asynchrony between the pragmatic profiles and the underpinning lexical and grammatical skills. The inadequate use of language in conversation, with regard to the informative needs of the interlocutor, might not be consistent with the relative strengths observed in the lexical and grammatical levels, especially in WS ,9,10,11.The most striking difference between the profiles was a significantly higher index of violations of the maxim of relation in the adults with FXS, which indicates that their utterances tended to be more inappropriate or non-contingent. More specifically, regarding the contextual relevance, participants with FXS produced more tangential utterances and, above all, more topic perseverative utterances. These findings are consistent with the results of Roberts et al.  indicatiDespite the fact that violation of the maxim of manner reached similar levels in both groups, prominent differences were also observed concerning the types of violation. On the one hand, perseveration of form  was significantly higher in the FXS group, which confirms a great tendency to topic and phrase perseveration as the most salient feature of conversational discourse in people with FXS, as it had been observed in previous studies ,41,43. IThe analysis of the conversational response also revealed differences between the FXS and the WS groups, and it was significantly more impaired in the FXS group, also showing a more differentiated within-syndrome profile. In both syndromes, impulsivity and incomprehension were the more frequent characteristics of inadequate responses, accounting for more than 70% of the index, while participants also exhibited a tendency to an overly literal interpretation of utterances. Such pragmatic difficulties in processing syntax and semantics in context have been commonly observed in atypical populations, including FXS, WS, and ASD, and have been linked to theory of mind and metapragmatic deficits, which may reflect a failure to integrate a situation model including the speaker\u2019s intent and the rest of the communicative context ,98,99. QThe participants with FXS showed a much higher index of impulsivity, which is associated with ADHD and considered part of the core behavioral phenotype of the syndrome ,103. ResResponses indicating incomprehension of the conversation topic were also significantly more frequent in the participants with FXS, which could suggest an area of weakness, as it was observed in early communication by Roberts et al.  using a Echolalic responses were significantly higher in the FXS group, albeit far less frequent than self-repetitions, which is consistent with previous studies indicating a profile of low proportion of echolalia in individuals with FXS vs. high proportion in ASD ,109. TheThe results of the present study show that individuals with FXS and WS without a diagnosis of ASD may exhibit different degrees and profiles of pragmatic impairment ,86, and It is important to acknowledge several limitations of the present study. The sample size was small and did not control for gender differences, for which reason the objectives were defined as exploratory. The consequent lack of statistical power and of adjustment for multiple comparisons may have influenced the assessment of differences. However, the conversational sample sizes were adequate and could have partially compensated for this limitation, as can be noted in the effect sizes. Different settings in which the speech samples were taken  and the very different age ranges may have affected the results. The focus on group means\u2019 differences and similarities rather than individual differences is also a source of limitations. Stojanovik et al.  found stAdult participants with FXS and WS in the present study showed violations of all the maxims of conversation to varying degrees, which may have an impact on their pragmatic skills. The profiles of cooperation resulting from the assessment of such pragmatic impairment using the PREP-CORP shared some characteristics, including reduced verbal production (maxim of quantity), repetitive dysfluencies (maxim of manner), and similar degree of violation of the maxim of quality. Syndrome-specific features were also observed: in the FXS profile, higher proportion of non-contingent language (maxim of relation) and perseveration of topic and form (maxims of relation and manner); in the WS profile, higher proportion of reformulation (maxim of manner). Conversational response showed increased levels of impulsivity, incomprehension, and echolalia in FXS. Thus, both profiles presented different degrees and forms of pragmatic impairment in the absence of a diagnosis of comorbid ASD, which raises the need for assessment and intervention methods that specifically address the social communication skills of adults with FXS and WS."}
+{"text": "The Research Centers in Minority Institutions, (RCMI) Program was established by Congress to address the health research and training needs of minority populations, by preparing future generations of scientists at these institutions, with a track record of producing minority scholars in medicine, science, and technology. The RCMI Consortium consists of the RCMI Specialized Centers and a Coordinating Center (CC). The RCMI-CC leverages the scientific expertise, technologies, and innovations of RCMI Centers to accelerate the delivery of solutions to address health disparities in communities that are most impacted. There is increasing recognition that the gap in representation of racial/ethnic groups and women is perpetuated by institutional cultures lacking inclusion and equity. The objective of this work is to provide a framework for inclusive excellence by developing a systematic evaluation process with common data elements that can track the inter-linked goals of workforce diversity and health equity. At its core, the RCMI Program embodies the trinity of diversity, equity, and inclusion. We propose a realist evaluation framework and a logic model that integrates the institutional context to develop common data metrics for inclusive excellence. The RCMI-CC will collaborate with NIH-funded institutions and research consortia to disseminate and scale this model. The National Academies report, titled \u201cRising Above the Gathering Storm: Energizing and Employing America for a Brighter Economic Future\u201d, noted that, in order for the United States (U.S.) to maintain global leadership and competitiveness in science and technology, it must: 1) invest in research; 2) encourage innovation; and 3) grow a strong, talented, and innovative science and technology workforce [ invest i encourag grow a sThis paper provides evidence of the impact of the National Institutes of Health (NIH) investments in the Research Centers in Minority Institutions (RCMI) Program, and, the premise that the RCMI Coordinating Center (RCMI-CC) is well positioned to evaluate, disseminate and scale NIH\u2019s Diversity, Equity and Inclusion (DEI) initiatives.The NIH has long recognized that achieving diversity in the biomedical and behavioral research workforce is critical to ensuring that the best and brightest minds have the opportunity to contribute to the achievement of our national research goals. The RCMI Program was established in 1985 in response to committee report language (House Report 98-911) attached to H.R. 6028, the Departments of Labor, Health and Human Services, and Education and Related Agencies Appropriation Act, 1985, to \u201cestablish research centers in those predominantly minority institutions which offer doctoral degrees in the health professions or the sciences related to health\u201d ,11. SubsThe Department of Health and Human Services (DHHS) action plan to reduce racial and ethnic health disparities  and the Despite long-standing efforts by the NIH and other entities across the biomedical and behavioral research landscape to increase the number of scientists from underrepresented groups ,16, GintThe COVID-19 pandemic added to the urgency, by uncovering glaring health inequities and the devastation of structural racism on the health of African Americans, Latinx, Native Americans, Native Hawaiians, and Pacific Islanders .At its core, the RCMI Consortium embodies the trinity of diversity, equity, and inclusion (DEI). The central role of the RCMI Consortium in addressing the NIH-linked objectives of workforce diversity and health equity was highlighted in three keynote presentations delivered at the RCMI Translational Science 2017 Conference in Washington, DC. During the opening plenary keynote, NIH Director Dr. Francis S. Collins, recognized the RCMI community as the brain trust to help develop novel solutions on health disparities . During An analysis of 18 RCMI Centers with active awards between 2002 and 2015 documented RCMI impact, as published in our seminal paper, titled: The Research Centers in Minority Institutions (RCMI) Translational Research Network: Building and Sustaining Capacity for Multi-Site Basic Biomedical, Clinical and Behavioral Research . This puSimilarly, RCMI Clinical Research Centers (CRCs) at Charles R. Drew University, Howard University, Meharry Medical College, Morehouse School of Medicine, University of Hawaii at Manoa, and University of Puerto Rico Medical Sciences Campus collectively enrolled over 16,000 diverse research participants between 2008 and 2016. There was broad representation across health disparity populations, including three quarters women; almost half were Black or African Americans; one third were Hispanics. Native Hawaiians, Whites, Asians, and Native American/Alaska Native were also represented in these clinical research studies. These clinical research centers also supported the training and career development of over 600 new clinical and translational research scholars over the same time period ,24,25. TThis manuscript will describe how the RCMI Consortium will build on its track record by developing and implementing consortium wide data collection processes and evaluation framework that will serve as a best practice for NIH DEI initiatives.The overarching purpose of this work was to understand how a context-based evaluation framework can serve as a blueprint for establishing data standards and common metrics for inclusive excellence (IE). We explored how the centralized data model of the RCMI Consortium can support the evaluation of the RCMI U54 Centers, and ultimately to disseminate and scale the RCMI DEI model.We hypothesized that the RCMI Consortium of institutions and the communities they serve provide a context-based and health equity-centered lens for a realist evaluation (RE) framework of IE.Rationale: Despite the urgent need for diversity in NIH-funded institutions, data confirm that institutional cultures lacking the necessary elements of inclusion and equity consistently send the message that certain groups do not belong in science ,27,28,29The theoretical framework of the RCMI Consortium is the Community of Practice and Stakeholder Engagement model ,33, whicThe RCMI-CC goals include evaluating the RCMI U54 Centers and the RCMI Consortium. The RCMI-CC integrates the Community of Practice and Stakeholder engagement in its needs assessment as described in the methods section. Given the diversity of research resources across the RCMI Consortium institutions, we propose the realist evaluation (RE) framework ,35,36, wThe Community of Practice Stakeholder-Engagement Framework ,46 is a Current NIH diversity programs lack the evidence for a standardized DEI evaluation framework . This prWith funding support, the RCMI-CC will collaborate with NIH-funded research networks, such as the Clinical and Translational Science Award (CTSA) and Institutional Development Award (IDeA) consortia, to disseminate and scale the adoption of the RCMI DEI model across various institutional contexts, from research-intensive to resource-limited settings ,38,39,40We have implemented a centralized RCMI database for baseline and longitudinal RCMI investigators data collection. We are also integrating the open-source central data repository, Dataverse , to sharThe needs assessment was conducted between 18 September and 11 December 2019, and designed to define the priorities, and identify resource gaps, for each RCMI U54 Center. Each U54 Center identified areas of expertise, and opportunities to strengthen its Center\u2019s capacity for inter-institutional research collaboration, by prioritizing access to the following resources: research studio/investigator development; biostatistics expertise; bioinformatics expertise; community engagement expertise; human subjects recruitment expertise; letters of support; finding collaborators ; technology transfer; institutional review board; samples/biorepository/laboratory methods; industry clinical trials; NIH multi-site studies; collaborative pilot project funding; RCMI Program National Conference; minority health and health disparities research training; national research mentoring network resource.The organization of the RCMI Consortium, its stakeholders, and governance are shown in For example, the Administrative Core Consortium includes the RCMI-CC Contact PI Steering Committee Chair and all the U54 Centers principal investigators/program directors. The Evaluation Consortium resides within the Administrative Core of each RCMI U54 Center and the RCMI-CC. The Community Engagement Core Consortium, Investigator Development Core Consortium, and Research Infrastructure Core Consortium are similarly configured to include the directors from the respective cores and the RCMI-CC MPIs.The objective of the stakeholder engagement was to: (1) develop a theory-based evaluation protocol, agree on common metrics, and standardize data collection process; (2) engage RCMI Centers directors in a continuous process improvement and sharing of best practices on investigator development, community engagement, resource sharing, and collaborations, relevant to their respective U54 Center goals and scientific activities; (3) agree on a process to monitor and share outcomes annually. We conducted two full days of Consortium-wide research retreat and strategy sessions followed by breakout sessions. The strategy and breakout sessions were followed by full day workshops for the respective Consortium Core leaders. The workshops were conducted during the RCMI Annual Scientific Conference, with full participation of all 21 active U54 Centers. Each Core Consortium provided direct input to the RE logic model being developed by the Tracking and Evaluation Consortium.We used a modified Delphi method , where tGiven that evaluation, common metrics, and data standardization are goals of this work, we referenced evaluation programs, as well as lessons learned from the CTSA program ,51,52,53To maximize the potential for improved inter-institutional engagement and collaboration, the RCMI-CC established a centralized database to support research collaboration and data collection across the RCMI Consortium. The searchable database can be used for finding investigators, and groups with specific areas of expertise, as well as search publications ,38,39. TCapitalizing on a centralized research-centric system to track productivity is essential to streamline the process for tracking research productivity and inter-institutional collaborations, especially when working with large research networks such as the RCMI Consortium. Using the centralized database as a systematic approach to track productivity at various levels yields consistent, objective, and standardized results across all the RCMI U54 Centers. Two of the most used key performance indicators (KPI) to assess scientific productivity are the number of publications and the number of awarded grants, both of which are routinely (quarterly) captured by the RCMI-CC centralized database. By harnessing the power and capabilities of the underlying relational database management system (RDBMS) of the centralized database, the RCMI-CC will be able to produce a quantitative representation of research activities (publications and grants) over time, at the individual (researcher) level as well as at the institution and consortium levels. In addition to the number of corresponding publications/awards, the centralized database captures other data elements such as: (1) How relevant the concepts of publications to the overall topic? (2) How long ago the publications were written? (3) Was the person the first or senior author, and how many other people have written about the same topic? The data can also identify shifts in research focus over time or reveal gaps in research productivity. The centralized database provides visualizations and timelines that show the dates of publications, top concepts, and concept clouds to emphasize keywords that make a person\u2019s research unique, illustrating changes in the primary topics over time. Other visualizations display cluster and radial graphs of authors, co-authors, and co-authors of co-authors. The graphs illustrate the proportional number of a person\u2019s publications and a proportional number of publications that they share with co-authors.In addition to the centralized database, we are also implementing an open-source central data repository, Dataverse , to sharThe 21 RCMI grantee institutions are located across 12 States, the District of Columbia, and Puerto Rico . Each RCThe results of the needs assessment showed that all (100%) RCMI U54 Centers prioritized community engagement expertise. Other prioritized resources were: 94% letters of support; 89% pilot project funds; 83% access to biostatistics expertise; bioinformatics expertise and finding collaborators for multi-PI research funding opportunities and publications; 78% investigator development research studios, NRMN resources, RCMI Annual Conference, and health disparities training; 72% technology transfer and innovation; 67% human subjects resource/institutional review board. These results bolster the DEI focus of the RCMI Evaluation framework and will be prioritized for common data elements in the logic model. The priorities identified in the needs assessment are included as data elements in the research resources and knowledge resources, which are inputs for the RE logic model. The needs assessment also show that RCMI Consortium members are interested in collaborations with RCMI and non-RCMI investigators. The dissemination and implementation of the RCMI DEI evaluation framework will benefit from this robust collaboration capacity. The fostering of collaboration among young and early investigators, seasoned investigation internal and external to each U54 RCMI, and bi-directional relationship between academic and community partners underscore the RCMI Program\u2019s commitment to inclusion and community focused priorities that impact health outcomes.The centralized database includes existing active, and newly registered investigators. The newly registered investigators were on-boarded between January through 22 April 2021. This sample is from scientific abstracts accepted for presentation at the 2021 RCMI Annual Conference. Our group published the paper titled \u201cUsing a Virtual Community  to Support Early-Stage Investigators Pursuing Grant Funding\u201d . This woThe RE logic model\u2019s inputs, activities, outputs, outcomes, community and health equity impact will track the four pillars that drive sustainable interventions see  34,35,3,335,36. Influence of the external environment including at the agency, state, region, or national policies may be standardized where feasible for purposes of comparative analysis.In this article, we present the design and RE logic model for a context-based evaluation framework of IE, by developing a systematic process with common data elements that align with the inter-linked goals of workforce diversity and health equity. We demonstrate that the mission, goals, and track record of the RCMI Program positions it to develop and standardize common data elements relevant to IE. The RCMI-CC centralized database and Dataverse open-source data-sharing model support collaboration capacity, and support users to disseminate and scale the model. The RE places our study in the larger context of NIH DEI initiatives. The logic model, common data elements, and data standardization will serve as a blueprint for adapting the model to diverse NIH-funded institutions, from research intensive to resource limited settings. The NRMN use case demonstrates the capacity of the RCMI Consortium to support national initiatives on DEI. The RCMI-CC governance and evaluation objectives support future collaboration that can disseminate and scale the RE model. By developing baseline common data elements that can apply across institutions, as well as investing in the Dataverse platform for secure and privacy protected data sharing, the RCMI-CC is establishing a RE grounded logic model for transparent and comparative evaluation of IE at RCMI Centers as well as across NIH funded institutions, regardless of the institution size, resources, public, or privately funded. The RE logic model and common data elements serve to establish a transparent and accountable process to collect and refine baseline data that will support DEI and IE processes and outcomes.This work aligns with the commitment and statement of NIH Director Collins, who declared, on 1 March 2021, that NIH stands against structural racism in biomedical research: \u201cto those individuals in the biomedical research enterprise who have endured disadvantages due to structural racism, I am truly sorry. NIH is committed to instituting new ways to support diversity, equity and inclusion, and identifying and dismantling any policies and practices at our own agency that may harm our workforce and science\u201d. Adding action to words, he announced a new NIH initiative called UNITE, unveiled a website on Ending Structural Racism , and issThe evaluation framework and common metrics represent the first step in the RCMI DEI blueprint for IE. A next step is to complete the implementation of the model in coordination with RCMI U54 Centers. The next step will include establishing benchmarks for publication and research excellence outcomes, that incorporates the RE logic model resource inputs. Our goal is to standardize outputs, based on the baseline data that will populate the RE logic model (anticipated completion in 2022). We will publish this work, to support dissemination and scaling in collaboration with NIH research consortia, including CTSA, NRMN/DPC, and IDeA programs. In addition, we are exploring innovative data collection and analysis methods by leveraging the EQ collaboratory , to engaThis work confirms our hypothesis that the RCMI Consortium context-based and health equity-centered evaluation of IE can serve as a blueprint for NIH DEI initiatives. As the NIH embarks on efforts to address structural and systemic racism, DEI initiatives should prioritize context-based evaluation and common data elements that transparently track and publicize individual, institution, as well as system level outcomes. The RCMI Consortium welcomes a bidirectional outreach and collaboration with NIH-funded institutions and research consortia, as we seek to collectively engage and support the best and the brightest underrepresented investigators in biomedical research."}
+{"text": "The number of older adults who live in long-term care (LTC) is expected to increase worldwide. The COVID-19 pandemic has caused serious consequences in Canadian LTC homes, while homes in China and Japan reported minimal infection and death rates in residents. The differences in LTC policies may be one of the contributors. The purpose of this literature review was to identify elements of the LTC policies that might have impacted COVID-19 outcomes in LTC homes in Canada, China, and Japan. A scoping review was conducted following the framework proposed by Arksey and O\u2019Malley. Scholarly articles and grey literature published between January 2015 and June 2020 were identified in six databases, four in English , one in Chinese (CNKI), and one in Japanese (CiNii), using MeSH terms for LTC and health policy. Grey literature was identified using Google. Data were extracted, summarized and common themes identified through content analysis. A total of 52 articles and 26 grey sources were included in the review based on determined inclusion criteria. They were research articles, reviews, government or association reports, policy briefs, policy documents, and guides. Four common themes of challenges emerged: caregiver workforce, service provision, funding, and physical environments. Three sub-themes were identified for caregiver workforce and service provision. Differences in COVID-19 consequences in LTC homes in the three countries seem to be related mainly to the challenges with the caregiver workforce and the lack of funding. The result suggests Improvements of LTC policies are required, especially in Canada."}
+{"text": "In addition to cancer-related death, malignant progression also leads to a series of symptoms and side-effects, which would detrimentally affect cancer patients' the quality of life, adversely influence their adherence to treatments, and, therefore, negatively affect their long-term survival. Acupuncture and electroacupuncture (EA), as two classic treatment methods in traditional Chinese medicine, have been widely employed to cure various diseases. Recently, the clinical application of acupuncture and EA in cancer patients has received great attention. In this review, we summarized the clinical application of acupuncture and EA in alleviating the cancer symptoms, reducing the cancer treatment-related side-effects, and relieving the cancer pain. The symptoms and side-effects discussed in this review include fatigue, insomnia, chemotherapy-associated dyspepsia syndrome (CADS), pain, xerostomia, and anxiety and depression. The underlying mechanisms of the therapeutic effects of acupuncture and EA might be related to the regulation of the mitochondrial function, coordination of the activity of the nervous system, adjustment of the production of neurotransmitters, and alleviation of the immune responses. In conclusion, acupuncture and EA have been proved to be beneficial for cancer patients. More research, however, is required to clarify the potential mechanisms behind acupuncture and EA for widespread adoption in clinical application. Carcinoma is the leading cause of global morbidity and mortality, so cancer prevention and treatment have become the key research topic in the medical field. In addition to death, the progression of cancer is also accompanied by a series of symptoms and side-effects that is caused by not only cancer itself but also cancer-related therapies, such as surgery, chemotherapy, radiotherapy, etc. These symptoms and side-effects will severely impact the life quality and treatment adherence of cancer patients, and, therefore, adversely affect their long-term survival. Recently, complementary and alternative medicine (CAM), including acupuncture, deep breathing exercises, massage therapy, meditation, naturopathy, and yoga, has been increasingly adopted by cancer patients for seeking relief from cancer-associated symptoms Acupuncture has been defined as the insertion of fine needles into specific acupuncture points (acupoints) in the human body. In Eastern Asia, acupuncture has been widely employed to treat various diseases for over 2,500 years. Notably, the benefits of acupuncture in treating various diseases have been gradually recognized by Western society. For example, the World Health Organization (WHO) and the National Institutes of Health (NIH) released a report on acupuncture in 2003, suggesting more than 100 types of diseases and conditions could be treated by acupuncture Electroacupuncture (EA) is developed around the mid-1900s and is a modified approach of acupuncture that applying weak electronic currents through the needles after conventional acupuncture procedure. Although it is still controversial, EA has been shown to achieve similar or even better effects compared to acupuncture. Moreover, the efficacy of acupuncture mainly depends on the manipulation technique of the acupuncturist, but EA can be practiced more reproducibly and is more suitable for both basic and clinical research. In this review, we introduced the effects of acupuncture and EA on cancer-related symptoms and side-effects, the possible mechanisms behind acupuncture, and the hindrance against the wide application of acupuncture and EA in cancer-related treatment.Cancer and cancer treatments are frequently associated with a lot of symptoms and side-effects including fatigue, insomnia, chemotherapy-associated dyspepsia syndrome (CADS), radiation-induced xerostomia (RIX), pain, vomit and nausea, cognitive impairment, distress, anxiety, depression, etc. Because some of those symptoms and side-effects are tightly related, we mainly discussed the therapeutic potential of acupuncture and EA in some of those symptoms and side-effects in this review.Cancer-related fatigue (CRF) has been recognized as one of the most common cancer-related side-effects The effective treatment options for CRF are limited, consisting of non-pharmacologic interventions like physical activity and psychosocial and mind-body interventions. However, a recent clinical trial, including 302 breast cancer outpatients, showed that acupuncture could significantly relieve CRF Insomnia, also called sleeplessness, is recognized as the most prevalent sleep problem worldwide. The reported prevalence of insomnia in cancer patients is up to 50%, which is three times higher than that in the general population Chemotherapy is routinely employed in combination with radiotherapy, surgery, hormone therapy, or immunotherapy for treating many types of cancers. Despite the effectiveness in reducing tumor burden, chemotherapy also unavoidably raises many irreparable side-effects, such as chemotherapy-associated dyspepsia syndrome (CADS). CADS is defined as a collection of gastrointestinal symptoms after receiving chemotherapy, including early satiety, anorexia, diarrhea, nausea, and vomiting Acupuncture has been commonly employed in China to treat gastrointestinal symptoms for thousands of years and the possible mechanisms behind might be through the altering acid secretion, GI motility, and visceral pain Pain is the most common symptom of cancer and is reported in 90% of cancer patients at various progression stages Acupuncture and EA have been widely employed to relieve non-malignant acute and chronic pain Salivary glands are significantly sensitive to radiation therapy and will be irreversibly damaged at doses higher than 50 Gy Anxiety and depression are common complications of cancer, influencing cancer patients' quality of life, their adherence to treatment, and their survival Although many efforts have been made to understand the effects of acupuncture and EA in the treatment of cancer-related symptoms and side-effects, the mechanisms by which acupuncture and EA achieve therapeutic benefits remain largely unknown. The main focus has been on investigating the mechanisms of the analgesic effects of acupuncture and EA. In the early 1970s, Han's group, for the first time, strongly suggested the involvement of central chemical mediators in the analgesic effect by acupuncture. They transferred the cerebrospinal fluid of acupunctured donor rabbits into recipient rabbits and achieved analgesic effects in recipients The studies on mechanisms of acupuncture and EA for treating other cancer-related symptoms and side-effects are limited. A previous study has shown that EA can improve chronic fatigue by reducing mitochondrial oxidative stress and increasing ATP synthesis Table 1). We also simply introduced the potential mechanisms involved in the therapeutic effects of acupuncture and EA (Table 2). Given that the actual mechanisms of acupuncture and EA remain largely unknown, more basic and clinical studies are needed to endorse the broad clinical application of acupuncture and EA in the treatment of cancer-related symptoms and side-effects.This review summarized the application of acupuncture and EA in cancer patients for improving cancer-related symptoms and side-effects, such as fatigue, insomnia, chemotherapy-associated dyspepsia syndrome (CADS), radiation-induced xerostomia (RIX), anxiety and depression, and pain ("}
+{"text": "Cochrane Cameroon is the fourth geographical group of Cochrane in sub-Saharan Africa, following Cochrane South Africa (1997), Cochrane Nigeria (2006) and Cochrane Kenya (2021). All are part of the Cochrane Africa Network, formally established in 2017. Cochrane Cameroon is based in the Centre for Development of Best Practices in Health, at the Yaound\u00e9 Central Hospital in Cameroon, and is the base of the Francophone hub of Cochrane Africa [June 30Cochrane is a not-for-profit international network aiming to have evidence at the heart of health decision-making world-wide. Cochrane does not accept commercial or conflicted funding which is vital for generating authoritative and reliable information, unconstrained by commercial and financial interests. Cochrane Cameroon responds to the needs to expand evidence-based decision-making and Cochrane activities to French speaking Africa  and to aIn collaboration with Cochrane Africa, Cochrane Cameroon will continue to support the production of high-quality systematic reviews, make relevant Cochrane evidence accessible (through translation of plain language summaries and evidence assessments), advocating for evidence (by raising awareness and stakeholder engagement) and contributing to the sustainability of the network (by supporting mentors and mentees). In recognition of the need to enhance health equity by involving stakeholders and end-users in priority setting , CochranConclusion: this letter is an open invitation to researchers, health care providers, journalists, policymakers, and consumers in the region to visit our website and engage meaningfully in the production and use of high-quality locally relevant and accessible health evidence."}
+{"text": "The growing number of survivors of childhood cancer, with many years of life ahead, demonstrates the increasing clinical and public health relevance of investigating the risks of social and socioeconomic impairment after a childhood cancer diagnosis and the life-saving treatment. To enrich understanding of the mental, social and socioeconomic difficulties that childhood cancer survivors may face during their life-course, identify particularly vulnerable survivors and overcome the limitations of previous research, we initiated the Socioeconomic Consequences in Adult Life after Childhood Cancer in Scandinavia (SALiCCS) research programme.This Nordic cross-border research programme is a collaboration between the Danish Cancer Society, the Finnish Cancer Registry and Karolinska Institutet to investigate a broad range of mental, social and socioeconomic conditions in long-term childhood cancer survivors in Denmark, Finland and Sweden. SALiCCS is based on a registry-based matched cohort design, comprising five-year survivors of cancer diagnosed at ages 0\u201319 years , age-, sex- and country-matched population comparisons and sibling comparisons who were followed over time. Outcomes of interest included mental disorders, educational achievements, employment and profession, family life and the need of social security benefits. Individual-level data linkage among various national registries provided the data for the research programme.The SALiCCS core population comprises 21,292 five-year survivors, 103,303 population comparisons and 29,644 siblings as a second comparison group. The most common diagnoses in survivors were central nervous system tumours, leukaemias and lymphomas.SALiCCS is the largest, most comprehensive population-based research initiative in this field, based on high-quality registry data with minimal risk of bias. The findings will be informative for evidence-based survivorship care targeting not only somatic late effects but also psychosocial impairments. Childhood cancer is of increasing public health concern, as approximately 35,000 new cases are diagnosed yearly in children and adolescents in Europe, and about 500,000 European Union citizens are childhood cancer survivors, with complex needs for medical and psycho-social care . AlthougThe experience of cancer during childhood and adverse somatic or mental health conditions may also have consequences for social and family life and for socioeconomic achievement later in life. Previous research has shown that childhood cancer survivors are at increased risk of several adverse socioeconomic and social outcomes, including scholastic difficulties, such as requiring special education or attending learning disability programmes, lower levels of attained education and lower income than their peers . There aThe current evidence is limited by methodological shortcomings. Most previous research is based on self-reported information from surveys and are thereby susceptible to non-participation, which might have affected the outcomes. Further, many studies included survivors of only one or a few specific childhood cancer types, did not involve repeated measurements of social and socioeconomic outcomes throughout the life-course or suffered from substantial loss to follow-up. Further limitations of previous studies include insufficient sample size of survivors and short follow-up. The mechanisms that lead to adverse social and socioeconomic conditions, especially in vulnerable subgroups of survivors, are still poorly understood , 26, andThe Socioeconomic Consequences in Adult Life after Childhood Cancer in Scandinavia (SALiCCS) research programme was initiated to address these gaps and enrich understanding of the impairments and social and socioeconomic difficulties that survivors of childhood cancer may face during their life-course. This Nordic research programme is a collaboration among the Danish Cancer Society Research Center, the Finnish Cancer Registry and Karolinska Institutet in Sweden.In 2020, Denmark, Finland and Sweden had populations of 5.8, 5.5 and 10.3 million, respectively . The NorThe welfare systems of the three countries are largely comparable. Citizens are entitled to an education free of charge, from primary schooling, which is compulsory, to advanced tertiary educational levels . AdditioIn general, all citizens of the Nordic countries have equal access to government-subsidized primary health care services provided by general practitioners and specialised health care in hospitals or provided by specialist physicians. Out-of-pocket expenses and reimbursement schemes vary, however, in the three countries \u201338. The As childhood cancers are a heterogeneous group consisting of very different diseases, survival and developments in survival over time differ widely by cancer type . Since tCurrent therapy for some malignancies is highly intensive, and, while survival has gradually increased, the risk of treatment-related acute toxicity and late effects may also be increasing. The aim of many current protocols is to identify subgroups of patients for whom the intensity of therapy can be reduced to decrease toxicity.Collaborative clinical trials to standardise childhood leukaemia treatment protocols in all Nordic countries began in 1981 , 40, 43,The SALiCCS research programme is a Nordic register-based cohort study of social and socioeconomic consequences in long-term survivors of childhood cancer in Denmark, Finland and Sweden. SALiCCS is based on the Nordic research programme Adult Life after Childhood Cancer in Scandinavia (ALiCCS), which investigates late effects of cancer therapy in children to better understand the risk and mechanisms of treatment-induced somatic disease . Data frThe main objectives of the SALiCCS research programme are:to ascertain hospital contacts for mental disorders in childhood cancer survivors;to examine how survivors of childhood cancer transition from childhood to adulthood by determining the following social and socioeconomic conditions and attainments: scholastic achievements, attained educational level and educational delays, income, employment, occupational position and professional attainment, leaving the parental household to live independently, cohabitation with a partner, getting married and founding a family; andto assess the socioeconomic burden of childhood cancer and treatment on survivors by determining the uptake of social security benefits, such as unemployment benefits, social assistance, sickness allowance, disability pension and rehabilitation benefits.The SALiCCS research programme is based on a registry-based matched cohort design. Denmark, Finland and Sweden have civil registration systems with numerous national administrative registries \u201347 that The infrastructure of the population-based registers in the Nordic countries, with longstanding, high-quality, comprehensive health, socio-demographic and socioeconomic data, are an ideal, unique basis for large-scale epidemiological studies of childhood cancer survivorship. None of the Nordic countries, however, has a sufficiently large population to provide adequate statistical power for a detailed assessment of social and socioeconomic outcomes in childhood cancer survivors in a life-course perspective, particularly not for determining the underlying mechanisms of adverse social and socioeconomic outcomes and identifying particularly vulnerable groups of survivors. Combination of data from several Nordic countries is required for such purposes. As the Nordic countries have longstanding, largely standardised diagnostic and treatment procedures and similar welfare systems, it was considered reasonable to combine data on childhood cancer survivors across Nordic countries.The SALiCCS core population comprises all five-year survivors of a first childhood cancer  diagnosed at ages 0\u201319 years in Denmark (1971\u20132008), Finland (1971\u20132009) and Sweden (1971\u20132011) .The cancer diagnoses were classified according to the International Classification of Childhood Cancer, in which tumours are classified into 12 major diagnostic groups and detailed subgroups according to the nomenclature of the International Classification of Diseases \u2013 Oncology \u201369.We established two independent comparison groups. We randomly sampled five population-based comparisons per survivor from the populations of Denmark, Finland and Sweden from the national population registries. Survivors and population comparisons were individually matched by year of birth, sex and country of residence   for somatic and mental disorders and the respective discharge diagnoses. We obtained information on prescribed drugs from the nationwide prescribed drug registries, whereby prescription data from Finland was limited to contraceptive medications, antidepressants, pain killers, and psychiatric drugs.Apart from diagnostic data from the national cancer registries, clinical and treatment information was overall sparse. The Finnish Cancer Registry included limited and non-validated treatment information on surgery, radiotherapy and chemotherapy (with incomplete coverage). The treatment information is given on binary level for curative, palliative or unknown intention . For DenWe collected basic socio-demographic and socioeconomic information for the biological and adoptive parents  of the childhood cancer survivors, the population comparisons, and the sibling comparisons. Furthermore, to account for the increasing number of reconstituted families in the Nordic countries, we also defined the \u201csocial parents\u201d for the Danish and Swedish SALiCCS populations, for whom we collected the same socioeconomic and socio-demographic information as for biological parents. In Denmark, social parents were defined as individuals living at the same address with the index person the year before the reference year, at least 16 years older and not a full or half sibling of the index person. In Sweden, social parents were defined as individuals registered by Statistics Sweden as a parent or guardian in the same household in which the index person was defined, the year before the reference date. Social parents could be identified from 1980 onwards in Denmark and from 1990 onwards in Sweden. Corresponding information was not collected for the Finnish SALiCCS population. The SALiCCS research programme has been approved by Statistics Denmark, the Regional Ethical Review Board in Stockholm, Sweden , Findata (Dnro THL/5543/14.06.00/2020) prolonging the former approvals by the National Institute for Health and Welfare and Social Insurance (KELA) and Statistics Finland (TK-53-394-17) in Finland. For the European Union General Data Protection Regulation (GDPR), the SALiCCS project is listed in a local archive (2018-DCRC-0044) at the Danish Cancer Society Research Center, which provides an accurate, updated overview of ongoing projects and of ongoing research projects involving personal data under the GDPR. The 2018-DCRC-0044 replaces the former notification from the Danish Data Protection Agency.The SALiCCS research programme is conducted in compliance with the requirements of the GDPR and other applicable laws in the respective countries, as well as the respective procedures at Statistics Denmark, the Danish Cancer Society Research Center, Karolinska Institutet and the Finnish Cancer Registry. All data have been stored, linked and pooled and are analysed at a secure remote platform at Statistics Denmark, with controlled remote access only for individually approved SALiCCS project members. Personal identification numbers were replaced by pseudonymised ID numbers, and the key code is kept only by the original register holders or at the respective statistical institutes. All the results of the statistical analyses will only be presented as aggregated data.The core SALiCCS population comprises 21,292 five-year survivors, 103,303 population comparisons and 29,644 siblings as the second comparison group. The distribution of diagnostic characteristics differed only slightly in Denmark, Finland and Sweden Table\u00a02.The SALiCCS core population is defined by individuals who survived the five-year survival point. To describe this population, the survival probabilities of all children diagnosed with cancer in Denmark, Finland and Sweden, their population comparisons and siblings are shown in This SALiCCS core population will serve as the basis for individual studies of the objectives of the SALiCCS research programme, as outlined in section 1.3. Additional inclusion and exclusion criteria may be applied to the core population in individual SALiCCS studies, which may be restricted to specific time periods, depending on the respective research objectives and register coverage.The growing number of survivors of childhood cancers diagnosed at a young age, with many years of life ahead, indicates the increasing clinical and public health relevance of investigating the long-term social and socioeconomic consequences of the cancer diagnosis and the life-saving treatment. Some previous evidence points to higher risks of impaired social functioning and adverse socioeconomic outcomes in adult life. Nevertheless, additional research is urgently required to fully understand the long-term social consequences of a diagnosis of cancer in childhood, to identify vulnerable survivors at particular risk for adverse social and socioeconomic impairments in adulthood and ultimately to provide scientific knowledge for evidenced-based survivorship care that addresses not only somatic late effects but also psychosocial impairments.Data linkage among various population-based registries in Denmark, Finland and Sweden gave us the unique possibility of setting up the largest, most comprehensive population-based research initiative on the social and socioeconomic consequences of childhood cancer so far, comprising more than 21,000 five-year childhood cancer survivors and two independent comparison groups. The large number of survivors will enable detailed analyses, allowing for identification of vulnerable subgroups in terms of e.g. diagnostic or socio-demographic characteristics. Use of high-quality population-based register data with high coverage, virtually no loss to follow-up and no self-reporting or non-participation allows reliable estimation of the social and socioeconomic outcomes with minimal risk of bias in countries with similar welfare systems and generally equal access to education and other services. Particularly valuable strengths of the SALiCCS research programme include annual information on social and socioeconomic outcomes, facilitating the study of trajectories and enabling a comprehensive long-term follow-up, as well as the availability of detailed information on hospital contacts, allowing stratified analyses by somatic or mental late effects. A limitation of the SALiCCS research programme is the lack of comprehensive and three-countrywide information on cancer treatment and other relevant clinical characteristics such as subtype of disease and tumour stage or grade. Such information would have been of considerable value for assessing the underlying mechanisms leading to adverse social and socioeconomic conditions, and to identify survivors of childhood cancer that are particularly vulnerable to adverse outcomes. For instance, especially cranial radiation therapy has been associated with various somatic late effects, including long-term neurocognitive impairment, as well as with adverse educational attainments, higher risk of unemployment and low income . UnderstThe novel findings resulting from this research programme may serve as a basis for recommendations on interventions for vulnerable subgroups of survivors. Such recommendations may not be limited to the Nordic countries, with their extensive welfare systems, but may also be applicable to other countries, especially within Europe.jeanette@cancer.dk), the Principal Investigator of the SALiCCS research programme, for further questions about data access.The data that support the information of this article were accessed remotely on a secure platform at Statistics Denmark. Pseudonymised individual-level data were obtained from national registry holders after ethical approval (where applicable) and secrecy assessment. According to Danish, Finnish and Swedish laws and regulations, individual-level sensitive data can only be made available for researchers who fulfil legal requirements for access to personal sensitive data. Please contact Jeanette Falck Winther , Findata (Dnro THL/5543/14.06.00/2020) prolonging the former approvals by the National Institute for Health and Welfare and Social Insurance (KELA) and Statistics Finland (TK-53-394-17) in Finland. For the European Union General Data Protection Regulation (GDPR), the SALiCCS project is listed in a local archive (2018-DCRC-0044) at the Danish Cancer Society Research Center, which provides an accurate, updated overview of ongoing projects and of ongoing research projects involving personal data under the GDPR. The 2018-DCRC-0044 replaces the former notification from the Danish Data Protection Agency.FE and JW developed the concept and outline of the manuscript. All authors contributed to the acquisition and preparation of data. FE, LF, HM, NM, L-MM-H, MF, and JW developed the strategy for the descriptive analysis and presentation of the study population. FE, LF, HM, and JW drafted the manuscript. All authors provided critical feedback, critically reviewed the manuscript for important intellectual content, and revised the manuscript. All authors approved the final manuscript as submitted and agreed to be accountable for all aspects of the work.This work was supported by NordForsk under grant 76111, the Danish Childhood Cancer Foundation under grant 2016-0293, Aarhus University under fellowship 43239402, the Swiss National Science Foundation under grant P2LUP3_175288 , the T\u00f8mrermester J\u00f8rgen Holm og Hustru Elisa F. Hansens Mindelegat under grant 20088 and the Swedish Childhood Cancer Foundation under grant PR2020-0130. The funding sources had no involvement in the content or preparation of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "The invasive behavior of glioblastoma is considered highly relevant for recurrence. However, the invasion zone is difficult to visualize, typically lies outside the resected and irradiated area, and is protected by the blood brain barrier, posing a particular challenge for treatment. We present biological features of invasive growth accompanying tumor progression and invasion based on associated metabolic and transcriptomic changes in patient derived orthotopic xenografts (PDOX) and corresponding patients.1H-MR spectroscopy and imaging . Tissue obtained at surgery was transplanted orthotopically into immune-compromised mice. Longitudinal follow-up was performed by 1H-MRS/I (14.1T) on the injected and the contralateral side. The PDOX, the corresponding contralateral side, and the original human tumors underwent RNA-sequencing.Patients with suspected glioblastoma were enrolled (NCT02904525) and underwent 1H-MRS derived metabolite signatures, reflecting temporal changes of tumor development and invasion in PDOX, revealed high similarity to spatial metabolite signatures of combined multi-voxel analyses of the patients\u2019 tumors. Associations between the metabolite profiles and the combined transcriptome of the xenografts and the host, reflected molecular signatures of invasion, comprising extracellular matrix degradation and reorganization, growth factor binding, and vascular remodeling.The temporal changes of the metabolite profiles characterized the kinetics of invasive growth of PDOX, and were patient specific. Comparison of in vivo monitoring of progression in the non-enhancing tumor infiltration zone and provides insights into the remodeling of the extracellular matrix that is essential for cell-cell communication and regulation of cellular processes. The changes of the structural and biochemical properties of the extracellular matrix are of importance for the biological behavior of the tumors and may be subjected to therapeutic targeting.Integrating metabolic profiles and gene expression of highly invasive PDOX allows"}
+{"text": "Background: The social isolation of older people is a growing public health concern. The proportion of older people in society has increased in recent decades, and it is estimated that ~40% of the population will be aged 50 or above within the next few decades. This systematic review aims to summarize and renew knowledge of the effectiveness of existing interventions for alleviating social isolation of older adults.Methods: Relevant electronic databases, including Cochrane Library, CINAHL, SCOPUS, and Web of Science, were searched by a systematic evaluation method. Eligible randomized controlled trial (RCT) studies were published between 1978 and 2021 in English or Chinese. The primary and secondary outcomes were social isolation and loneliness. The quality of the included RCTs was scored by the Cochrane risk-of-bias tool to assess their quality. Two independent reviewers extracted data, using a standardized form. Narrative synthesis and vote-counting methods were used to summarize and interpret study data.Results: Twenty-four RCTs were finally included in this review. There was evidence of substantial heterogeneity in the interventions delivered. The overall quality of included studies indicated a low-to-medium risk of bias. Eighteen of 24 RCTs showed at least one dimension effect on reducing social isolation. The interventions with accurate targeting of clients in social and public places had more obvious effect. The interventions in which older people are active participants also appeared more likely to be effective. In addition, group intervention activities and individual intervention interviews were effective in improving structural social support; mixed intervention, and group intervention on training support significantly improved functional social support.Conclusions: This study suggests that group and mixed intervention targeting of older adults could be helpful for alleviating social isolation problems. The use of modern technology for remote services could also present good results. More well-conducted RCTs of the effectiveness of social interventions for alleviating social isolation are needed to improve the evidence base. Especially as the debating results of remote interventions, further research in this field should be conducted. Social isolation is a major threat to the health of older adults. There are many risk factors in social isolation in old age, including the lack of family members, rare or no daily communication with friends, depression, and a solitary lifestyle , CINAHL databases, SCOPUS, Web of science, China National Knowledge Infrastructure (CNKI), and Wanfang Data Knowledge Service Platform (WANGFANG). Another search retrieved social isolation and/or loneliness in the review and has been included in the study of the reference literature; retrieval from the University of Southern California Social Work Institute database, evidence-based medicine research center of Lanzhou University, and Population Research Institute of Southwestern University of Finance and Economics. Contacts were made with scholars within the network of the authors to obtain information about ongoing studies. Search words used were as follows: older/elder/senior/aged/geriatric, isolation/isolate/isolated, lone/loneliness/alone/solitude/solitary, social support/network/relations, psychosocial intervention, treatment/therapy, clinical trial, explanatory trial, pragmatic trial, and randomized controlled trial. Search terms used were as follows: (isolation/isolate/isolated) or  or  and (older/elder/senior/aged/geriatric) and  or . The search terms in different databases were slightly different. Therefore, we also searched through the reference lists of systematic review articles on social isolation.According to the research topic and summary, two researchers (FT and CLY) made a preliminary identification of study criteria. The third researcher (FF) read the abstract of the indeterminate literature and determined the specific discussion about the disagreement. A pair of independent raters selected abstracts for full review based on inclusion/exclusion criteria. Two independent reviewers extracted data, using a standardized form. Due to the heterogeneity of different outcome indicators , meta-analysis is not suitable for use. According to the analysis method of the three previous evaluations  older adults over 50 years of age with no mental illness or cognitive impairment; (ii) the purpose of the intervention was to alleviate social isolation or loneliness; (iii) the results of social isolation intervention were reported; (iv) there were randomized controlled trials but no drug trials; and (v) the paper was written in Chinese or English. Exclusion criteria for the study: (i) study samples aged younger than 50 years; (ii) not used a randomized controlled trial (RCT); (iii) drug intervention was used; and (iv) outcomes reporting only on loneliness but no social isolation.Because of the heterogeneity of the intervention types and results of the trial, quantitative analysis of data was not used in the review, so the method of narrative synthesis was applied to analyze the effect of interventions. In the quality evaluation of open randomized controlled trials, we chose not to use the Jadad standard Berger,  as this About 746 items were found in the related research, with 452 duplicates removed, 268 of the studies excluded as they did not meet the selection criteria. Two studies were excluded because of high-bias risk. Twenty-four studies were eventually included .A total of 24 randomized controlled trial studies were included with a total of 4,078 subjects, each involving 26\u2013708 cases. Of all the studies, there were only two studies from mainland China : The Evidence Reorganization, Conversion, and Enlightenment Research of Evidence-based Social Work Intervention on Long-term Care of older adult.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Introduction: Melodic intonation therapy (MIT) is one of the most studied speech and language therapy (SLT) approaches for patients with non-fluent aphasia, although the methodological quality of the studies has been rated as low in previous reviews. The aim of this study is to update current evidence on the possible efficacy of MIT for the treatment of non-fluent post-stroke aphasia.Methods: A systematic review and meta-analysis. We selected randomized clinical trials (RCT) that included adult patients over 18 years of age with non-fluent post-stroke aphasia, whose intervention was MIT vs. no therapy or other therapy. We excluded non-RCT studies, mixed populations including patients with aphasia of non-stroke etiology, studies with no availability of post-stroke aphasia-specific data, and incomplete studies. Three sections of communicative ability were analyzed as outcomes: functional communication, expressive language (naming and repetition), and comprehension.Results: We identified a total of four eligible RCTs involving 94 patients. Despite the heterogeneity in the psychometric tests employed among the trials, a significant effect of MIT on functional communication  was found . In addition, a positive effect of MIT on expressive language (repetition) was found . No significant effects on comprehension measurements were found, despite a lack of significant statistical heterogeneity.Conclusion: This systematic review and meta-analysis shows a significant effect of MIT on improving functional communication and on repetition tasks. Future larger RCT specifically addressing those outcomes should provide the definite evidence on the efficacy of MIT on post-stroke aphasia recovery.Systematic Review Registration:PROSPERO-URL https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020144604. Aphasia is a disorder that is the result of an injury to the brain areas that control the production and understanding of language as well as its components . Aphasia is common after stroke, with an estimated frequency of 30 and 34% for acute and rehabilitation settings, respectively . TherefoA Cochrane meta-analysis published in 2016 showed the effectiveness of SLT for post-stroke aphasia as compared to no therapy, in terms of better functional communication, reading, comprehension, writing, and expressive language . To dateMelodic intonation therapy is a widely used therapy in clinical practice, and therefore, it is necessary to understand whether there is evidence of its efficacy. MIT has been proposed mainly for patients with significant defects in language production, poor verbal agility, poor repetition of sentences, exaggerated prosodic pattern of sentences, and relatively preserved auditory comprehension  \u20138. PatieThe mechanisms underlying the effects of MIT on aphasia recovery are not well-known, although it seems to stimulate brain plasticity by promoting the neuroplastic reorganization of language function, the activation of the mirror neuron systems, the utilization of shared features of music and language (such as pitch and rhythm) reflecting common or associated processing pathways, and improving the patient's motivation and mood . Indeed,A systematic review published 8 years ago reviewed the literature on the effect of musical elements in the treatment of patients with neurological language and speech disorders . The autOur aim is to update current evidence on the possible efficacy of MIT for the treatment of non-fluent post-stroke aphasia in adult patients on functional communication, expressive language, and comprehension.This systematic review and meta-analysis is reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) recommendations for systematic reviews and the Cochrane guidelines for systematic reviews , 20. TheOur PICO  question to guide the systematic review was formulated as follows: in adult patients over 18 years of age with non-fluent aphasia due to ischemic stroke, does the MIT, as compared to no therapy or other therapy, improve functional communication, expressive language (naming and repetition), and comprehension?http://clinicaltrials.gov/), and Clinical trials results . We also performed a manual search of reference lists in other prior systematic reviews on the same topic as well as in guidelines to identify further potentially eligible studies.The following databases were searched: Cochrane Central register of Controlled Trials (CENTRAL), PUBMED, EMBASE, Clinical trials gov. . Duplicate records were deleted. Those separate reports from the same study were linked and evaluated as a single study. Studies analyzed in previously published systematic reviews were manually included when not obtained by the database search . Only puThe evaluation of study eligibility was performed by two authors (AHM and CPA) with the supervision of the review coordinator who identified all potentially relevant articles. After examining the titles and abstracts, clearly irrelevant reports were discarded and the full text of potentially relevant reports was reviewed.The following information was included in the data collection form: eligibility of the study and/or the reason for exclusion, study design, study duration, allocation and blinding process, possible sources of bias, total number of participants, study setting, diagnostic criteria, age, sex, relevant comorbidity, dates of the study, total number of intervention groups, specific interventions, outcome definitions, time-point of reported outcomes related to stroke onset, number of participants allocated to each study group, number of outcomes in each study group, missing data (lost to follow-up), summary data for each intervention group and outcome .For the analysis of the extracted data, we used the Review Manager 5 software .The quality of the included studies and the risk of bias of each study were evaluated following Cochrane Collaboration recommendations available in the Cochrane handbook of systematic reviews of interventions:  sequenceUnder the coordination of the principal investigator, the entire team participated in this stage. Publication bias was assessed with the help of funnel plots. The results of the data analysis were imported into the GRADEpro Guideline Development Tool .Three areas of communicative ability were analyzed as outcomes: functional communication, expressive language (naming and repetition), and comprehension.The main outcome was improvement in language skills or in functional communication constructs as measured by a formal evaluation with validated tools including the Boston Diagnostic Aphasia Examination (BDAE) , the AacI2 test. Sensitivity analyses were performed for each diagnostic tool to better identify possible sources of heterogeneity.Collected data for each outcome were mean and standard deviation after the treatment period as well as the number of participants in the experimental and control groups. Standardized mean difference (SMD) was the summary statistic chosen, given that it allowed for the comparison of various psychometric scales. Data were analyzed on a random-effects basis. Results were summarized as standardized mean differences (SMD) and 95% confidence intervals (CIs), and the results from tests evaluating the same outcome were pooled in forest plots for a more comprehensive analysis of the global effect across studies. Heterogeneity across the studies was evaluated considering clinical reasoning and statistical measurements such as the chi-squared and the Finally, we used the GRADE approach to rate the quality of evidence, and we summarized the results in an evidence profile using the GRADE Pro tool.Our search for articles in the databases produced a total of 226 results. After removing duplicates, 88 articles remained. The abstracts of these articles were analyzed, and 40 potentially eligible studies remained. Of those 40 studies, six studies were selected for full-text evaluation. Two were excluded: one for being a topic review  and the Van der Meulen et al.  conducteVan der Meulen et al.  also useHaro et al.  was a raThe risk of bias assessments are summarized in This systematic review and meta-analysis, compared to the 2016 Cochrane review which included only one RCT on MIT involving 27 patients,  providesResearch on post-stroke aphasia faces two main challenges that limit the internal validity of this study: (1) scarcity of published studies that meet the high standards of well-designed clinical trials, leading to a low number of included studies for the present meta-analysis; (2) heterogeneity in outcome measurements. In this meta-analysis, four randomized clinical trials were included and only two of them, conducted by the same research group, used the same endpoints. Due to the heterogeneity in the outcome measurements of the included studies, in those studies in which several outcomes were described, the most appropriate test for each of the outcomes considered in this review was chosen. Thus, for the functional communication outcome, the ANELT test was chosen over the Sabadel for the Van der Meulen et al.  and Van Functional communication represents the ability to successfully communicate in daily interactions, which should be the main goal for patients with post-stroke aphasia to ensure their social reintegration. However, less than half of clinical trials on SLT have focused on functional communication . In receSLTs can be considered complex interventions per the definition of the Medical Research Council Framework for the Development and Evaluation of RCTs for Complex Interventions . Post-stThe main limitations we faced were the small sample sizes in those trials as well as the heterogeneity in outcome measurements that prevented a pooled analysis. Nevertheless, we were able to show an effect of MIT on the CAL measurements and in the repetition tasks. Despite the randomized design of all the included trials and the lack of high-risk of bias, none of the clinical trials were sufficiently powered to demonstrate the efficacy of MIT. Therefore, the quality of evidence is moderate.In conclusion, this systematic review provides updated evidence on the efficacy of MIT in improving functional communication and repetition in post-stroke non-fluent aphasia. Future larger RCT specifically addressing those outcomes should provide the definite evidence on the efficacy of MIT on post-stroke aphasia recovery.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.AH-M and BF: conception of the work, acquisition, analysis and interpretation of data, draft of the manuscript, and approval of final version to be published. CP-A: acquisition, analysis and interpretation of data, draft of the manuscript, and approval of final version to be published. JS-C: analysis and interpretation of data, draft of the manuscript, and approval of final version to be published. ED-T: conception of the work, interpretation of data, and approval of final version to be published. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "The Care Ecosystem (CareEco) model is a telephone-based dementia care program providing standardized, personalized and scalable support and education for caregivers and persons living with dementia (PLWD), medication guidance, and promotion of proactive decision-making. It has demonstrated improvement in quality of life for PLWD and reduced unnecessary healthcare expenditures. We initiated a pragmatic, embedded randomized pilot trial of an adapted CareEco model for nurses who provide high-risk care management and are embedded in primary care practices within a large healthcare system. Outcomes include feasibility of collecting emergency department visits, usability and acceptability of the intervention by nurse care managers, caregiver strain, behavioral symptoms of dementia and healthcare expenditures. Challenges of implementation include engaging key care management leaders, adaptation of the CareEco training modules for nurses, identification of primary caregivers, training and reinforcing knowledge and skills of the nurses, embedding clinical assessments into care manager workflows and integration with the EMR."}
+{"text": "Objective: To investigate the impact of the severity of age-related hearing loss (ARHL) and tinnitus, presence of ARHL and/or tinnitus, and physical frailty on the health-related quality of life (HRQoL) and domain-specific HRQoL in Chinese community-dwelling older adults.Design: This was a cross-sectional study of a community-based cohort.Participants: We evaluated Chinese older adults  aged \u2265 58years.Measurements: The severity of HL and tinnitus were measured using pure-tone audiometry and the Tinnitus Handicap Inventory (THI), respectively. Physical frailty was measured using the five-item Fried scale. HRQoL was assessed using the Assessment of Quality of Life-8-Dimension (AQoL-8D) multi-attribute utility instrument (35 HRQoL items and eight domain-specific HRQoL subcategories). Low HRQoL (HRQoL score or subscores in the highest quintile) was used as a dependent variable in logistic regression analyses adjusted for demographic (Model 1) and health-related (Model 2) and psychosocial (Model 3) confounders.Results: Age-related hearing loss severity was an independent determinant of senses in the physical dimension of HRQoL after adjusting for all covariates. Tinnitus severity was significantly associated with HRQoL and with independent living, senses, and pain in the physical dimension after adjusting for demographic and health-related covariates and was still associated with independent living and senses after adjusting for all covariates. The presence of ARHL and/or tinnitus was significantly associated with independent living and senses in the physical dimension after adjusting for all the covariates. Physical frailty was an independent determinant of HRQoL, independent living, and pain in the physical dimension and with mental health, happiness, and coping in the psychosocial dimension after adjusting for demographic and health-related covariates. The association with HRQoL, independent living, and pain in the physical dimension, and with happiness and coping in the psychosocial dimension remained significant after adjusting for the covariates. Depressive symptoms, social dysfunction, and a number of comorbidities were critical determinants of psychosocial HRQoL.Conclusion: Physical frailty has a stronger and more profound effect on HRQoL, particularly on independent living and pain in the physical dimension and on happiness and coping in the psychosocial dimension. Domain-specific HRQoL should be considered in the management of patients with ARHL with tinnitus and physical frailty.Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT2017K020. Age-related hearing loss (ARHL) is the most common chronic disorder of the sensory system . PhysicaThe severity of ARHL  and tinnThe negative effect of the severity of ARHL and tinnitus and the presence of ARHL and/or tinnitus on HRQoL varies according to the assessment instruments used  and confounders , 16. OveThe older population has more complex multimorbidity due to the overlap among physical frailty, comorbidity, and chronic physical and mental health diseases . PhysicaThis study aimed to determine whether these associations were different and independent of demographic, health-related, and psychosocial factors. We hypothesized that the association of physical frailty with HRQoL and specific domains in community-dwelling older people is different from that of ARHL with tinnitus.In total, 429 community-dwelling Chinese older adults (age \u226558 years) were recruited from our previous cross-sectional cohort study on ARHL with tinnitus and general health . The numAll the participants underwent cognitive function, hearing and tinnitus severity, QoL, and comprehensive geriatric assessments. The inclusion criteria were:  permanenHealth-related quality of life was assessed using the 35-item Assessment of Quality of Life (AQoL-8D) self-report questionnaire. The questionnaire covers three physical  and five psychosocial dimensions  . The senThe severity of ARHL and chronic subjective tinnitus  was assessed using pure-tone audiometry and the Tinnitus Handicap Inventory (THI), respectively. The pure-tone average (PTA) in the better ear was calculated using the.5-, 1-, 2-, and 4-kHz thresholds. The participants were then divided into four groups based on their hearing levels  .Tinnitus was classified into three categories by severity . The patients were also scored based on the presence of ARHL and/or tinnitus .Cognitive performance was assessed using the global cognitive screening test; Mini-Mental Status Exam (MMSE); and normative z-scores of the neuropsychological test battery, including executive or attention, language, and memory domains , 25. Phy2). The medical questionnaire included self-reported smoking, alcohol intake, and chronic comorbidities ; adjusted for covariates in Model 1 and other health covariates (Model 2); and adjusted for covariates in Model 2 and psychosocial factors, including social dysfunction, depression, and neuropsychiatric symptoms (Model 3). These models were run for low HRQoL scores and then separately for each low domain-specific subscore, which was used as a dependent variable. All the statistical analyses were performed using SPSS version 18.0, and P < 0.05 was considered statistically significant.Continuous variables were expressed as medians and quartiles, and non-normally distributed variables were tested using the Kolmogorov\u2013Smirnov test. Meanwhile, categorical data were expressed as proportions and compared using the Patient characteristics stratified by ARHL, tinnitus, and the presence of ARHL and tinnitus are shown in The results of the multiple logistic regression models on the relationships between the severity of ARHL and high HRQoL (low scores) or low subscores in the physical dimensions of HRQoL are shown in For the physical dimensions, after adjusting for all the covariates in Model 3, absence of ARHL  and subclinical ARHL  were significantly associated with a higher probability of better HRQoL in senses domain. Meanwhile, mild ARHL  showed a marginal association. In Model 3, physical frailty had no effect on senses, while social dysfunction  was associated with significantly worse senses. Lack of physical frailty  and pre-physical frailty  were associated with significantly higher probability of independence and less pain after adjusting for all the covariates . Other iAge-related hearing loss severity showed no significant association with all the five psychosocial dimensions . No physThe results of the multiple regression models on the relationships between tinnitus severity and HRQoL or physical dimensions of HRQoL are shown in Among the five psychosocial dimensions, depressive symptoms were independent risk factors for worse psychosocial dimensions, and social dysfunction was an independent risk factor for worse mental health, happiness, and relationship. Tinnitus severity was not directly associated with the psychosocial dimensions . AbsenceThe relationships of presence of ARHL and/or tinnitus with HRQoL or physical dimensions of HRQoL in the different multiple regression models are shown in p = 0.076, respectively) and relationships  after adjusting for the covariates in Model 2 and in relationships  after adjusting for all the covariates in Model 3. Depressive symptoms were the major determinant of all the five psychosocial dimensions, and social dysfunction was an important determinant of mental health, happiness, and relationships. Age, education level, smoking, and CVD were also independent risk factors for mental health after adjusting for all the covariates.The presence of ARHL and/or tinnitus was not associated with any of the five psychosocial HRQoL domains . Those wThe impact of the presence and severity of ARHL and tinnitus, ARHL, tinnitus, and physical frailty on the HRQoL and its specific domains in community-dwelling older adults is yet to be clarified to date. This study found an association of ARHL severity with the senses domain of HRQoL, and the association remains significant after adjusting for demographic, health-related, and psychosocial covariates. Tinnitus severity is negatively associated with HRQoL and with three physical dimensions, but the association is no longer significant for HRQoL and pain after adjusting for all the covariates in Model 3. The presence of ARHL and/or tinnitus is only significantly associated with independent living and senses, and the association remains significant after adjusting for all the covariates. The severity of physical frailty is significantly associated with worse HRQoL (high scores) and independent living and pain (high subscores), and the associations remain significant after adjusting for all the confounders. Moreover, the severity of physical frailty is also significantly associated with the psychosocial domains of mental health, happiness, and coping, and the association is only decreased for mental health after adjusting for the psychosocial covariates in Model 3. The use of a multidimensional HRQoL questionnaire and the three models, with successive adjustments for different covariates, provided original information on these relationships.These results extend our understanding of the association among the severity of ARHL , 9, tinnThe effects of age-related auditory disorders (ARHL and tinnitus) on the specific domains of HRQoL were significantly different from those of physical frailty. Previous studies have indicated that ARHL, tinnitus, and the presence of ARHL and/or tinnitus were significantly associated with physical function , frailtyOur study also showed that psychosocial factors, such as social dysfunction and depressive symptoms, were independent determinants of the psychosocial dimensions of HRQoL. In a large cross-sectional population-based study of individuals aged >19 years, hearing loss with tinnitus had a significant impact on all five dimensions  of HRQoL . In contSeveral studies have shown that frailty, including physical frailty, is significantly associated with worse HRQoL in the community-dwelling older people , 14. AmoAside from ARHL, tinnitus, physical frailty, education level, BMI, alcohol intake, disability in basic activities of daily living, multicomorbidity, chronic diseases, cognition, and depressive symptoms also influence HRQoL , 26, 35.To our best knowledge, this cross-sectional study is the first to report the different effects of the severity of ARHL, tinnitus, and physical frailty, and the presence of ARHL and/or tinnitus on overall HRQoL and its specific domains. The use of a multidimensional HRQoL instrument, in combination with several self-report and objective covariates, in the assessment improved the robustness of the data collected. However, there are also some limitations to this study. First, participation was voluntary, which could have led to selection bias. Second, the cross-sectional design limited the analysis of causal relationships. For example, ARHL and tinnitus are associated with depressive symptoms , 29, 34 In conclusion, ARHL severity is an independent determinant of senses, while tinnitus severity is an independent determinant of independent living and senses in physical HRQoL. Physical frailty is an independent determinant of overall HRQoL, of independent living and pain in the physical dimension, and of happiness and coping in the psychosocial dimension.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.The studies involving human participants were reviewed and approved by the Ethics Committee of Huadong Hospital, Fudan University. The patients/participants provided their written informed consent to participate in this study.QR, ZY, and ZH conceived and designed the study. QR wrote the article. WZ, JR, RZ, MZ, XH, and ZY conducted the investigation and data analysis. All authors contributed to the article and approved the submitted version.This study was supported by the Medical Science and Technology Support Project of Shanghai Science and Technology Commission (Grant Nos: 18411962200 and 20Y11902300), Shanghai Municipal Key Clinical Specialty (Grant No: shslczdzk02801), and the National Key Research and Innovation Project (2018YFC2002000).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Royal Society Open Science [We introduce the Life Sciences New Talent collection, comprising invited papers which showcase emerging fields of cross-disciplinary life sciences research and some of the exciting work funded by the Royal Society. The collection is part of a series of commissioned New Talent collections originally started with the Chemistry New Talent collection  which ha Science .Royal Society Open Science, commissioned this collection with the aim of expanding the breadth of these New Talent collections to showcase early career investigators in the Life Sciences.We, the Editors of the Biochemistry, Molecular & Cellular Biology, and Genetics & Genomics sections of The papers published in this collection were invited from recent awardees of a Royal Society University Research Fellowship (URF) , Sir HenParamecium bursaria, opening the door to the investigation of its nascent endosymbiotic relationship with a green algae partner [We have enjoyed reading and preparing these manuscripts, which highlight the extraordinary breadth of new talent in the UK Life Sciences research community. Yulia Yuzenkova, a Royal Society URF at Newcastle University, reviews the fast-developing field of non-canonical RNA capping, highlighting the prevalence of this RNA modification across the domains of life . Lu-Ning partner . Michael partner . Benjami partner .Wolbachia bacterial strains in populations of the mosquito Anopheles gambiae in Guinea\u2014findings that identify further candidate strains that might be used in the future for malaria biocontrol strategies [Helge Dorfmueller, a Sir Henry Dale Fellow at Dundee University, contributes a review of recent developments in the understanding of Group A Streptococcus pathogenesis and the implications for vaccine development . Kok-Lunrategies . Christorategies .At the time of writing, we also hope to include the following contributions to our New Talent collection: Andrew Hitchcock, a Royal Society URF at the University of Sheffield, and colleagues review the state of our understanding of the catalytic function, substrate recognition and regulation of two key enzymes which are critical to the final stages of (bacterio)chlorophyll biosynthesis. Benjamin Steventon, a Sir Henry Dale Fellow at the University of Cambridge, reviews the current state-of-the art in the study of pattern formation in static and motile cellular environments, looking ahead to challenges and the approaches that may surmount them. Maria Christophorou, a Sir Henry Dale Fellow at the Babraham Institute, reviews citrullination and its consequences for cell physiology. Joe Grove, a Sir Henry Dale Fellow at the Centre for Virus Research, Glasgow, surveys processes of viral entry to cells and mechanisms of inhibition by antibodies.https://royalsocietypublishing.org/topic/special-collections/life-sciences-new-talent [We hope that readers of the journal will explore this collection and find something of interest. These papers are all curated at w-talent ."}
+{"text": "Colorectal carcinoma is a highly prevalent and heterogeneous gastrointestinal malignancy. The emergence of organoid technology has provided a new direction for colorectal cancer research. As a novel-type model, organoid has significant advantages compared with conventional tumor research models, characterized with the high success rate of construction and the high matching with the original tumor. These characteristics provide new possibilities to study the mechanism of colorectal carcinogenesis and improve the treatment effects. The present literature would mainly summarize the characteristics of tumor organoids and the up-to-date technique development of patient-derived organoids (PDOs) and application in colorectal cancer. Colorectal cancer (CRC) is a highly prevalent and incurable tumor in the population, which is recognized as the third riskiest cancer of death worldwide and the second most deadly cancer in the United States . There aRegarding traditional models in CRC research, APC(Min/+) mice are mainly used to study the effect of the interaction between APC and other related genes and pathways on the origin and progression of intestinal adenomas , 7. Adenin vitro. It has apparent advantages, such as simple operation, fast proliferation, short culture cycle, high success rate, high reducibility to the physiological properties of tumor tissues, and self-renewal ability.In addition, cell lines, patient-derived xenograft (PDX), and tumor organoids were created for studies of each stage of CRC. However, the limitation of cell lines and PDX lies in their loss of heterogeneity of CRC genes, which was inaccurate in the study of advanced CRC , 10. Duein vitro in 2009 , which promotes the proliferation of cancer cells. Noggin protein, a bone morphogenetic protein (BMP) inhibitor, regulates cell differentiation and prevents bone metastasis in CRC. R-spondin1, a Wnt pathway activator, promotes proliferation and metastasis of cancer cells. Prostaglandin E2 (PGE2) and nicotinamide both provide nutritional support to the organoid that maintains long-term activity. Two more compounds, A83-01 (TGF-\u03b2 inhibitor) and SB202190 (p38 inhibitor), are both often used to inhibit the migration of cancer cells and help maintain the stability of the tumor organoid  and growth factors that regulate signaling pathways are all necessary for culture. After preparing the required organoid materials, the culture process Figure\u00a02organoid . Furtherorganoid , 28.Up to the present day, there are still some challenges in the construction of organoids. In terms of the extracellular matrix, there are shortcomings such as high cost, complex specific composition, poor controllability, and limitations in the application. Besides, the tumor organoid after tissue implantation into Matrigel by digestive enzymes contains only epithelial cells and lacks mesenchymal cells, immune cells, and other non-cancerous cells, while the proliferation and differentiation of tumor tissues are affected by the microenvironment containing epithelium and mesenchyme , and theIn conclusion, materials and techniques for the construction of CRC organoids still need to be optimized and constantly upgraded and created to better satisfy the practical needs of clinical implementation.in vitro culture conditions. In 2011, the team of Sato  along with collagen as the core material, which can compensate organoids for the ability of personalized treatment assessment to some degree.Nevertheless, incomplete replication of the models for the biological environment of the intestine as the limitation of models may not be conducive to the development of organoids in CRC; the current research , 40 idenin vivo experiments by verifying in vitro that PDOs are highly concordant with the genes and histological properties related to the source tumor and to better guide clinical use of drugs and personalized treatments by uncovering the diversity of tumor responses to drugs. Initially, van de Wetering et al. , microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and sawtooth-like pathway . Therefoet al. , especially high (MSI-H), occurs inextricably with DNA mismatch repair (MMR) gene silencing, commonly MLH1, MSH2, MSH6, and PMS2 . In contmutation  and abnomutation , often tmutation  verifiedf Takeda establishf Takeda  that 90%V600E as well as MLH1 mutation organoids and successfully modeled the characteristic lesions related to serrated colorectal adenocarcinoma, such as infiltrative growth of serrated tissue with mucus cap, and detected an increased frequency of CpG methylation, which verified that the serrated pathway activation has a strong correlation with BRAF V600E, MSI, and CIMP. It can be supposed that the organoid can still maintain high fidelity to the CRC environment, which provides a piece of important evidence for extensively studying the molecular pathways of CRC in the future.As unique colorectal carcinogenesis pathways, both CIMP and the serrated pathway are relevant in most cases. CIMP, generally interpreted as CpG island methylation, inhibits the normal transcription of genes and thus downstream genes for their normal expression. It is mostly positively expressed in serrated colorectal adenomas, often occurring in collaboration with both BRAF mutations and MSI . The LanIn summary, CRC organoids are competent to recapitulate the relationship between genes and signaling pathways and validate the complexity, diversity, and association between pathway mechanisms of oncogenesis. Applications of tumor organoids can promote research in predicting the development of CRC prognosis based on genetics and in innovating oncology drugs to regulate the interaction among pathways.Due to the phenomenon of tumor heterogeneity, the response of tumors induced by different pathways to drugs may also differ, so the development of various antitumor drugs is inseparable from the study of tumorigenesis and development mechanisms. Furthermore, the preclinical, experimental stage is necessary to ensure that the efficacy of drugs in clinical applications can still achieve the expectation in basic research, which requires the support of a majority of suitable models. On the one hand, CRC PDOs can be used to establish a biological sample bank and preserve the heterogeneity of CRC, providing abundant preclinical models that can be used to predict drug response and efficacy; on the other hand, organoids can be functional in estimating the effect of drugs on genes or signaling pathways referring to the mutation characteristics of colorectal oncogenes and screen out suitable anti-CRC drugs referring to patients\u2019 clinical\u2013pathological data.et al.  and programmed cell death-ligand 1 (PD-L1) are popular immunotherapeutic targets in CRC . By incuUp to now, as the concept of personalized medicine is gradually kept in mind, the space for organoid technology continues to grow. The use of CRC organoid culture technology has broadened the horizons of diagnosis and treatment of CRC and reminds us to target more breakthroughs in medical healthcare and drug selection of CRC.Major progressions of organoids from 2009 to 2020 are supplemented in JL, XH, BZ, and WT conceived of the study and participated in its design and coordination and helped to draft the manuscript. JL, XH, LH, JH, DL, LL, YD, LZ, BZ, and WT made a significant contribution to the work about the analysis, writing, and interpretation. All authors contributed to the article and approved the submitted version.This research was funded by the Guangxi Clinical Research Center for Colorectal Cancer (Guike: AD19245197); Research Basic Ability Improvement Project for Guangxi Young College Teachers (2021KY0087); Innovation Project of Guangxi Graduate Education (YCSW2021133); Guangxi Medical University Autonomous Region-level College Student Innovation Training Project (202110598177); Guangxi Natural Fund Facial Project (2021JJA140081); Guangxi Medical and Health Appropriate Technology Development and Promotion Project (S2021016); and The project of improving the basic ability of scientific research of young and middle-aged teachers sponsored by the Education Department of Guangxi Zhuang Autonomous Region (2021KY0086).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Background: Dance interventions are considered beneficial for older patients with mild cognitive impairment in many aspects. We conducted a comprehensive systematic review and meta-analysis to assess the effects of dance on different aspects  of this population.Methods: A systematic search of PubMed, Web of Science, the Cochrane Central Register of Controlled Trials, Embase, American Psychological Association PsycInfo, ProQuest, Scopus, Cumulative Index to Nursing and Allied Health Literature, the Chinese BioMedical Literature Database, the VIP Database for Chinese Technical Periodicals, China National Knowledge Infrastructure, and Wanfang Data database was performed. Two reviewers independently assessed the study quality.Results: Fourteen studies were retrieved from the databases for analysis. The pooled results showed that dance interventions significantly improved global cognition , rote memory , immediate recall , delayed recall  and attention . No significant improvement was found in executive function, language, depression, anxiety, dementia-related behavioral symptoms, motor function, and quality of life.Conclusion: Dance interventions benefit most aspects of cognitive functions. The evidence for the effects of dance on psycho-behavioral symptoms, motor function and quality of life remains unclear. More trials with rigorous study designs are necessary to provide this evidence. The Lancet reported that approximately one-fifth of the older population, aged over 65 years, experience MCI  was first proposed by Reisberg et al. , to descThe intervention methods for MCI can be pharmaceutical or non-pharmaceutical. Current reviews have found that acetylcholinesterase inhibitors  used to treat Alzheimer's disease (AD) have proven ineffective in the MCI treatment group , lifestyle, emotions, and social functions, thereby improving the quality of life (QOL) of the research subjects ; to establish a general summary of the existing literature; and to provide a basis for follow-up studies in this field.This work adhered to the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines and was prospectively registered with the International Prospective Register of Systematic Reviews (CRD42021230159).RRID:SCR_004846), Web of Science, the Cochrane Central Register of Controlled Trials , Embase , American Psychological Association PsycInfo , ProQuest , Scopus, Cumulative Index to Nursing and Allied Health Literature, the Chinese BioMedical Literature Database, the VIP Database for Chinese Technical Periodicals, China National Knowledge Infrastructure, and Wanfang Data. To ensure the comprehensiveness of the included studies, we used combinations of Medical Subject Headings  and free text words without language restrictions from inception to November 12, 2020. We also retrieved the reference lists of all eligible studies and other relevant studies using alternative approaches . The complete search strategy is provided in We searched the following electronic bibliographic databases: PubMed ; dance not limited to the frequency or duration of the intervention; dance performed under the guidance and supervision of trained professionals or by the participants themselves.We defined dance intervention by the following principles: systemic movements of the body that are needed to be observed and imitated, are focused on physical flexibility and expression of emotion, and are accompanied with music.Including but not limited to drug treatment, regular therapy, and educational programs.At least one measure of cognitive function , motor function , psycho-behavioral symptoms , and QOL.Studies that included the following tests were included in the review: Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) to assess the global cognition level; Trail Making Test Parts A (TMT-A) mainly to evaluate rote memory of patients; Trail Making Test Parts B (TMT-B) primarily to assess executive function; Logical Memory I (LM-1) and Rivermead Behavioral Memory Test (RBMT) to measure immediate recall; Logical Memory II (LM-2) to assess delayed memory; the Symbol Digit Modalities Test (SDMT) or Test of Everyday Attention (TEA) to assess attention; the Boston Naming Test (BNT) to assess the language function in patients with cognitive impairment.Studies that included the following tests were included in the review: Psycho-behavioral symptoms evaluated using Neuropsychiatric Inventory (NPI) to assess the 12 behavioral disorders occurring in patients with dementia such as delusions, hallucinations, agitation, dysphoria, anxiety, apathy, irritability, euphoria, disinhibition, aberrant motor behavior, night-time behavior disturbances, and appetite and eating abnormalities; degree of anxiety mainly measured by the Hospital Anxiety and Depression Scale (HADS); the Geriatric Depression Scale  and HADS to test depression.Studies that included the following tests were included in the review: Berg Balance Scale (BBS) to evaluate balance; the Timed Up and Go (TUG) test to test functional mobility.Studies that used the following two scales for QOL evaluation were included in the review: Quality of Life in Alzheimer's Disease (QOL-AD) and the 36-item Short Form Health Survey (SF-36).Studies that were randomized controlled trials (RCTs) or quasi-experimental trials were included in this review.Two reviewers  worked independently to identify studies that met the inclusion criteria briefly by screening the abstracts. If the abstract did not provide sufficient information, the full text was obtained to determine the study's eligibility for inclusion in this review. Any disagreements were resolved after discussions with a third reviewer (JYC). We excluded studies for which complete information could not be obtained despite our best attempts.RRID:SCR_014001) and NoteExpress.For each eligible study, information about the first author's name, country, number of participants, age, male to female ratio, control group intervention, intervention characteristics , and outcome measures were extracted using a self-designed standardized form . Two revTwo reviewers  independently assessed the study quality according to the Cochrane Handbook for Systematic Reviews of Interventions  to perform the meta-analysis. Since all data were continuous, we selected the mean difference (MD) with 95% confidence intervals (CIs). When different scales were applied to measure the same outcome, we used the standardized mean difference (SMD). Heterogeneity in the included studies was tested by the Cochrane Q statistic and quantified by the IUsing the search strategy, 1,534 articles were identified from 12 databases . After en = 7)        Yi, , USA , and other studies described their dance interventions as choreography, poco-poco dance, and standard dance-based aerobics format. The poco-poco dance course was guided by experienced professionals who gradually increased the difficulty and intensity of the dance both for acceptance and safety. BAILAMOS\u00a9 program was professionally guided based on the BAILAMOS\u00a9 guidebook. The researchers constantly adjusted the dance content in conjunction with the difficulty of the steps and safe limit of each of the participants. The dance used props (Velcro bracelets of different colors) to help participants remember their movements. Chinese square dancing, which originated in China, involves a variety of dance forms, but is also easy to learn. Dance rug is a modern aerobics game that is simple and easy to operate, allowing participants to learn at home without outside guidance. Yangko is a traditional Chinese folk-dance form. This dance mainly involves the twisting of various parts of the body; this unique form of exercise has particular advantages.The data for the risk of bias in the included studies is provided in P < 0.00001; Twelve studies examined the effects of dance interventions on global cognition. Analysis of global cognition at the end of the intervention demonstrated a significantly higher post-intervention global cognition level in the dance group than in the control group. The pooled SMD showed a statistically significant increase in global cognition , we performed a sensitivity analysis. When we excluded the four quasi-experimental trials . Another study .Two studies were pooled for the BNT results. One study illustrated that a structured modular ballroom dance intervention can improve language among older people with MCI . However, another trial . Four studies . One study . Another study .Eight studies compared the dance intervention group with non-dancing controls to evaluate the effectiveness of dance intervention on depression in 577 older adults. Two trials . In contrast, another RCT .Two studies . Another study indicated that a 48-week ballroom dance program could improve these symptoms in older people with MCI . However, both studies demonstrated no significant differences in dementia-rated behavioral symptoms between the two groups.Two . Another RCT .Two studies . However, one RCT . One study .QOL scores were available for 136 participants from three trials. Two trials . Furthermore, we performed a descriptive analysis  for those results of the meta-analysis with more significant heterogeneity (>50%).The aggregate results of MMSE and MoCA evaluations showed that the dance intervention group was better than the control group in terms of overall cognition, and the results were durable and stable when sensitivity analysis was performed. Dance intervention as an aerobic exercise maintains the integrity of cerebral vessels by providing blood, oxygen, and nutrients and influences cognition by increasing brain-derived neurotrophic factor levels and synapses, promoting the growth and survival of neurons , Nursing science, a key discipline project of Jiangsu Province during the 13th Five-Year Plan period (sjy [2016] No. 9), Project Studies on Construction of Core Competency Model and Development of Assessment Tool for Nurses of Hospice Care supported by NSFC (72004099), and Project Comparative study on hospice care mode between China and Canada (2017SJB0295) supported by Philosophy and Social Science Foundation of universities in Jiangsu Province.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Area Agencies on Aging (AAAs) have played an important and well-documented role in meeting the nutritional and wellness needs of older adults during COVID-19. To better understand the continued impact of COVID-19 pandemic on AAA services, partnerships, and clients, the National Association of Area Agencies on Aging surveyed the nation\u2019s 618 AAAs in February 2021, with a 27% response rate. As a result of COVID-19, most AAAs reported both increased numbers of new clients and needs of existing clients; three-quarters of AAAs developed new external partnerships; and over half are implementing strategies to address equity and inclusion regarding their services and clients. Nearly 80% of AAAs are involved with COVID-19 vaccine outreach and delivery, from scheduling appointments to administering the vaccine to homebound clients. We will describe these and other transformations of services, partnerships, and client needs; discuss challenges and opportunities; and provide examples and video vignettes from AAA directors."}
+{"text": "Social isolation and loneliness are detrimental risk factors to older adult\u2019s physical and psychological well-being and quality of life. Given the current situation of the COVID-19 pandemic, social isolation has risen. Social isolation affects younger adults as well and may increase the chances of depression and anxiety. In this study, we tested the acceptability and feasibility of an Intergenerational Bonding (IGB) Program with older and younger adults. Participants include students aged 19-29 at the University of Nebraska at Kearney and older adults above the age of 60 residing in the community. First, we surveyed younger and older adults to determine their interest level in participating in an IGB Program. Both groups of participants rated their interest in different activities. The most popular activities among both groups included engaging in conversations, board games, and an exchange of skills. Neither of the groups was in favor of participating in free housing opportunities or sports-related activities. Response rates were high in young adults but low in older adults, due to lack of trust. Then, in a pilot study, we measured the feasibility and acceptability of the IGB Program. Older adults residing in independent dwellings, assisted living environments, nursing homes and members of community groups were invited to participate in the intergenerational program. Response rates of older adults were low. Further, establishing collaboration with institutions such as nursing homes was not easy despite initial interest. Building trust and working with community activity group facilitators would be beneficial in recruiting older adults."}
+{"text": "While the US-Mexico border region has had increasing restrictions due to coronavirus 2019 (COVID-19), the economically and socially integrated region continues to facilitate necessary movement between the two countries. Binational partners representing universities, government, and health delivery worked together to develop a COVID-19 Virtual Seminar for the US-Mexico Border Region, which consisted of weekly sessions in Spanish designed to better facilitate communication and collaborative systems between border states. In total 835 participants registered for the virtual seminar with attendance ranging from 394 in Session 1 to 269 in Session 6. From evaluation surveys (n\u2009=\u2009297), organizers observed a large plurality of healthcare professionals, followed by students, researchers, and government employees. The seminar\u2019s contribution to increasing collaborative and communication systems identified major needs in the region surrounding surveillance and monitoring; increased resources for migrant shelters to control outbreaks; an increase in personal protective equipment; tracking binational cases. Coronavirus-19 (COVID-19) has had a major impact on population health and health systems across the globe, with the WHO reporting approximately 108.2 million cases and over 2.3 million deaths globally [The US-Mexico border region stretches for approximately 2000 miles along the southern end of the US and most northern area of Mexico. It consists of the US states: California, Arizona, New Mexico, and Texas; and the Mexican states: Baja California, Sonora, Chihuahua, Coahuila, Nuevo Leon, and Tamaulipas. The interdependence of the two countries has continued manifest into a tightly woven region that shares economic, cultural, social, and behavioral ties, regardless of the increased politicization of the border region in recent decades . OverallIn order to better facilitate communication and collective action to monitor and prevent COVID-19 across border region, the US-Mexico Border Health Commission, the University of Arizona, and El Colegio de la Frontera Norte established a virtual seminar series. The series conducted in Spanish shared the state of COVID-19 along the border region, public health prevention efforts, and actions taken by every state government to mitigate the impact of the virus. The seminar series was specifically designed for health personnel and providers, academics, students, among others interested in the topic. The overall objectives of the seminar series to promote information exchange, enhance monitoring processes, identify mutual issues,and promote discussions surrounding solution-based approaches.The COVID-19 Virtual Seminar Series for the US-Mexico Border Region was designed as six weekly 90-min sessions with experts in the field invited to present for approximately 20\u00a0min. The formAll sessions were conducted in Spanish using Zoom with only presenters having permission to share video and audio, while participants had access to a chat feature for questions, reflections, and/or comments on the seminar. Participants were asked to register prior to sessions. All registered participants were able to attend all sessions, given they were subsequently were notified and provided information for every weekly session. At the conclusion of the seminar series, registered participants received an online evaluation form. As no personal or identifiable information was collected, and the investigators are reporting the findings of an open public seminar, US-Mexico Border Health Commission exempted from review.As seen in Table Surveillance and monitoring of suspicious and positive cases, along with tracking of contacts to decrease the spread of the virusIncreasing the diagnostic capacityAcquiring of supplies including personal protective equipment for essential workers and healthcare workers.Strengthening and standardizing of mental health care programsControlling the outbreaks among vulnerable populations specifically, indigenous communities and migrant farm workersIdentification and tracking of cases, as well as exchange of information at the binational level, particularly to address the transmission through binational cases.The last seminar brought together decision-makers across the region to discuss issues across states in the US-Mexico border region, along with collaborative efforts to increase surveillance and control of COVID-19. Identified challenges discussed across the US-Mexico border region:As seen in Table Given the fluidity of the border region, both in crossing of people, goods and services, the Virtual Seminar highlighted the importance of continued communication and collaboration in impeding the epidemic in the US-Mexico border region. As most countries around the world, the US and Mexico, were not an exception to the unpreparedness in addressing the magnitude of this pandemic.In 2011, an infusion of resources was distributed to states across the US and Mexico through the US-Mexico Border Health Commission, which was establish and approved by both federal governments for prevention efforts and public health emergencies , 8. ThesIn addition, there still lacks a cohesive effort by border states to collectively define binational cases. As such, there is an opportunity to recommend at the very least the importance of revisiting collective binational surveillance efforts at both federal and state levels, regardless of political affiliation. These cases that move seamlessly back and forth across the international boundary need to be properly and promptly addressed to curve current pandemics along the border region. This also has critical implications for contact tracing\u2014improved implementation of communication and surveillance systems can immediately identify binational cases through contact tracing to rapidly mitigate community spread on both sides of the border. In addition, this can be extended to migrant shelters and communities that have seen consistent outbreaks, and are in urgent need of additional resources to combat COVID-19 transmission. Lastly, the Operational Protocol for Binational Communication and Coordination between Mexico and the United States on Disease and Outbreak Notifications should be updated, implemented, and serve as policy for improving practice in communication sharing and forging opportunities for collaboration with the current pandemic and future events that require early detection and response."}
+{"text": "With the application of engineering management in smart city construction under Industry 4.0, the intelligent design of urban street landscape has attracted extensive attention. Affected by the low intelligent level of traditional landscape design, the existing urban landscape composite system has difficulty in meeting the needs of smart city construction. Therefore, this paper proposes the construction of street landscape big data-driven intelligent decision support system based on Industry 4.0. Based on the complex network theory, this paper analyzes the structure, links, nodes, driving forces, and functional requirements of urban street landscape and then puts forward the construction content and implementation method of urban street landscape intelligent decision support system. The system consists of four aspects: intelligent infrastructure, service, protection and maintenance, and management and evaluation system. Its implementation not only reflects the cooperation and effective application of intelligent technology in each stage of street landscape construction, but also provides reference for the application of engineering management in other fields under Industry 4.0. Based on the connectivity provided by the Industrial Internet of Things (IIoT) and the use of a variety of digital technologies such as cloud computing, big data, and artificial intelligence, Industry 4.0 is proposed as a new stage of industrial maturity , 2. ThesAs an important part of smart city construction, landscape architecture is also facing opportunities and challenges brought by the intelligent process. Smart gardens changing the construction, operation, and management modes of traditional gardens can effectively improve the efficiency in landscape garden industry, realizing the normalization, standardization, digitization, networking, and intelligence of garden construction . The typIn the construction of urban street landscape intelligent system, \u201curban street\u201d refers to the urban road equipped with sidewalks, municipal utilities, and various buildings on both sides in the overall length or most sections. As one of the subsystems under the future urban open complex giant system, the nature, function, form and structure of urban street are more complex than traditional urban road. Urban street serving as the most basic public urban space focuses on the citizens' life and humanized experience, which facilitates the interpersonal communication and interactions via emotional sustenance as well as playing an irreplaceable role in shaping the urban charms and vitalizing the economic development , 10.Relying on the complex network theory and \u201cInternet +\u201d thinking, the smart landscape cooperates with new-generation information technologies such as Internet of Things, big data cloud computing, mobile Internet, remote sensing, and information intelligent terminal, obtains time-domain advantages, and responds quickly to social and natural activities carried in the landscape space. Integrating the spatial domain of modern ecological landscape into the large database achieves the intelligent connection between scattered social activities and needs of human beings, nature and landscape space for the interactive perception, and cognition and communication and improves the utilization and sharing rate of various scattered landscape resources, thus promoting the intelligent construction, service, and management of landscapes , 12.The design of intelligent street landscape systems shall be based on the comprehensive consideration of user needs, greening landscapes, and basic street functions, through the Internet of Things, web services, and virtualization technology. The basic attributes, characteristic parameters, status, and other information of various street landscape elements are dynamically and intelligently sensed and accessed in real time, to build street space intensively. Through processing the information perceived by the landscape intelligent system, data collection, integration, analysis, processing, and feedback are realized under the mapping of landscape resources in urban streets. On the premise of ensuring the basic functions of the road, people's travel safety, life, and social security should be guaranteed, which provides conditions for the scientific, rapid, comprehensive, and visual development of urban street landscape design and management.The construction of intelligent systems for urban street landscape based on complex network theory and the integration of smart landscape concept into the traditional urban street landscape indicate further improvement, which shall meet the requirements for intensive intelligent spaces, multiple interactive experience, and green ecology of energy conservation , 14.In order to cope with the multiple landscape needs under the complex system of urban streets, the intelligent street landscape system based on the complex network realizes the intelligent supply-demand matching of street landscape space services from the three levels of landscape facilities Internet of Things, service Internet, and user Internet.The construction of street landscape intelligent system mainly involves four aspects: intelligent infrastructure, intelligent service, intelligent protection and maintenance, and intelligent management and evaluation.Intelligent infrastructure is the physical layer and the foundation of street landscape intelligent systems. The infrastructure of street landscape intelligent systems shall proactively provide the information and services desired in addition to the basic functions and be available to correlate with other facilities and even users for the formation of a complete intelligent network featuring information interaction and function linkage, thus completing the virtualization and service-oriented information interaction and functional linkage of the intelligent information system.Information infrastructure is the basis of intelligent street landscape, covering the electric information screen shown in Data cognition is the core of intelligent street landscape development. The data infrastructure is used to collect and integrate street landscape data, achieving the intelligent street landscape construction by providing the users and managers with comprehensive and intuitive information based on the integration and analysis of multisource data (basic/business/service databases).Basic database clarifies the spatial location and surrounding environment of urban street landscape for the precise positioning of smart landscape. Business database has multiple subdatabases covering the special data, system planning and management, monitoring management, and industry management available for the precise and whole-process collection of street landscape data. Service database can provide the popular science knowledge about smart street landscape for the public and facilitate the review of various urban green spaces and scenic spots by potential travelers .Based on the ecological requirements of the street landscape intelligent system construction, ecological observation of the street is an effective measure to achieve this goal. Using RFID (radio frequency identification) technology, the real-time update of spatial ecological information of street landscape can be realized, and the location of vegetation, structures, and buildings can be monitored online. Special sensors and wireless sensor networks for street landscape ecological observation can effectively realize real-time data acquisition and transmission. Real-time monitoring of the street green space ecosystem can help with maintenance and management of the green landscape. Furthermore, the obtained ecological econometric characteristic data can aid in the formation of quantitative analysis results of the street landscape space, resulting in better landscape and ecological effects from green space maintenance and management, The service object of the intelligent street landscape systems is the streetscape users. The construction of intelligent service system is based on Internet functions, which can realize the dynamic matching of the user's needs. From the perspective of users, in the process of system construction, our goals and demand motivation can be evaluated, and the service content can be derived dynamically.In terms of qualitative or quantitative data, managers could be provided with genuine feelings, opinions, and suggestions generated by the public in the service experience. With the help of dynamic characteristics analysis of smart infrastructure, a reliable method for demand forecast management is provided. Thus, public involvement can be achieved, and the quality of the service improves continuously .Network service platforms are the basis for intelligent service and the guarantee for intelligent linkage with other service facilities. The construction of portals serving the public shall cover various services such as bus routes, e-maps, traffic notices, travel tips, and road service calls. In addition, the construction of mobile-based network service platforms  shall also be emphasized to ensure the real-time content update and provide mobile users with street information services based on the shared portal resources.Basic street services are mainly the traffic, lighting, and other necessary basic services. For instance, the smart parking management system achieves the real-time monitoring of parking spaces and the intelligent guidance about available parking spaces based on the information inquiry of parking lots and spaces through various intelligent terminals such as smart phones. The construction of public transportation system shall ensure the timely release of bus information and certain functions  in combination with the special bus signal system for important bus corridors and the intelligent bus stations. The streets with heavy traffic flows shall be equipped with smart toilets, which are available for the information inquiry of location and real-time usage through various intelligent terminals . In addition, the intelligent lighting system subject to the independent sensing, timing, voice control, or remote control of intelligent terminals shall also be arranged for the smart control of landscape lighting in different areas , Figure The intelligent terminals  and multilanguage terminals for self-service navigation shall be arranged to facilitate the inquiry of street and surrounding-area e-maps and tour route planning as well as the scenic spot/plant introduction using QR code/RFID technologies .An interactive information system shall be established to provide life, service, business, and medical information for citizens, with various network service platforms serving as the channels for street information release, covering the street information, real-time road conditions, toilet usage, spare parking spaces, restaurant usage, and other basic information; climatic information  and health information such as negative oxygen ion content in key areas Figures Personalized services available at various network service platforms can meet the street use demands of different people , for insCompared with the traditional consulting/complaint services, the services provided through the intelligent system are more convenient and efficient, and multiple channels  are available for the public. The intelligent system of linkage service can achieve the unified receipt and instant feedback/response to consultations and complaints from telephones and network terminals.In order to improve the user experience, a multimedia experience center focusing on historical districts shall be constructed using multiple technologies  for the display of historic landscapes, original natural features, and historical changes. The 3D panorama/reality enhancement display technology and 360\u00b0/720\u00b0 real-life photos or videos can be utilized to create the virtual blocks for digital virtual tours that are available at portals and terminal devices  , 21.Intelligent protection and maintenance are the function expansion of the user Internet based on the Internet of Things of landscape facilities. Dynamically generate landscape maintenance needs based on smart infrastructure, and dynamically match landscape maintenance needs with landscape maintenance services through the Internet of Things technology. Realize the informatization and intelligence of the protection and maintenance process, provide visual guidance on daily maintenance process and key technology, and the responsible personnel and stages could be specified for the real-time recording of maintenance process and information .Green space protection and maintenance are the key to intelligent protection and maintenance, covering the digital recording, monitoring, and control of boundaries and green resources including the main plants and facilities. The important spots and key facilities shall be equipped with 3D scenes for inspection and comparison via intelligent terminals, mainly involving the plant irrigation and fertilization, pest and disease and freezing damage management, and intelligent cultivation.Environmental monitoring and intelligent irrigation system can provide effective services for intelligent plant irrigation and fertilization management. The digital data processing of soil nutrients can maximize the effects of water-saving and precise irrigation, scientific management, and low-carbon maintenance , 24. TheThe GPS positioning and FRID technologies shall be adopted for the control of plant diseases and pests, with the dynamic tracking system established to ensure the dynamic protection and monitoring of green plants as well as help technicians locate the areas of pests and diseases at first time. The implementation of \u201cprevention-first\u201d principle by each institution responsible for plant management and protection targeting the necessary early warning of pests and diseases within all periods can greatly reduce the prevention costs and probability of large-scale pests and diseases . Early wThe intelligent technology-based seedling planting and cultivation shall make full use of the IoT and spatial information integration technologies. The partitional measuring of regional soil quality, hydrological conditions, and microclimate factors at the stage of planting planning provides the definite data basis for breeding and rapid formulation of cultivation schemes. At the same time, a tree full cycle database shall be established for plant tracking and data sorting in the whole process, as well as the records of seedling archives, tree transplantation, and maintenance information. Intelligent cultivation can effectively prevent the challenges faced by the traditional seedling cultivation .Both natural heritage and cultural heritage involve heritage protection and maintenance, including ancient and famous trees and cultural relics. For the ancient and famous trees, the high-definition photos shall be obtained based on the precise coordinate positioning via monitoring and RFID technology in addition to the normal maintenance measures, and mastering relevant detailed information will facilitate the data calling, plant protection, document management, maintenance, and rejuvenation monitoring. Digital modeling based on the growth environment of ancient and famous trees also facilitates the accurate analysis of protection measures Scientific and comprehensive management measures are an important prerequisite for realizing the sustainable development of streetscapes. Quantitative evaluation mechanism is an effective objective to judge the effectiveness of streetscapes.How to effectively integrate various scattered landscape management resources and coordinate various quantitative evaluation parameters to achieve the best match between street landscape management and demand is the key problem. Hence, quantitative data-driven evaluation and control system is ultimately conducive to the continuous optimization of landscape effects.The comprehensive and scientific management shall take account of internal office work, gardening business, street security, and other related factors.Office automation (OA) system can improve the overall efficiency of internal office work, covering process management, e-mail, document management, document circulation, approval management, working calendar, notice announcement, personal information maintenance, conference management, and attendance management.In terms of the gardening business management, video monitoring, RFID, and infrared sensing technologies shall be adopted for the real-time perception of changes in street green resources, infrastructure, and traffic flows, as well as the automatic collection, adjustment, and update of street landscape data. The real-time monitoring of street landscape can achieve precise management and prevention against vandalism and damage caused by natural disasters.Street security cannot be neglected considering the special traffic function of urban street with public spaces. The construction of integrated street control platform makes the daily operation monitoring and emergency command and dispatching possible, providing basic support for navigation and guidance based on the location services of GIS and satellite positioning systems . NowadayThe evaluation of self-diagnosis by intelligent evaluation system aims to provide reference for further development. Moreover, reasonable performance evaluation can not only measure the achievements of street landscape construction and find out the existing problems, but also provide important guidance for the continuous improvement of street landscape intelligent system.Establishment of the complete, scientific, and effective evaluation system shall be based on the existing urban gardening standards, with the relevant street smart landscape indicators integrated into the system by means of spatial layers, forms/tables, document uploading, and image attachments for real-time computing and result judgment/analysis , Table 1How to manage, digitize, and integrate information from scattered roads efficiently and precisely, in order to realize the effective distribution and dynamic overall grasp of the streetscape service capabilities.How to coordinate the relationship between the geographic space, data flow, time distribution, hardware network, and user needs of the streetscape intelligent system, in order to realize the spatial mapping between complex streetscape resources and intelligent system service capabilities .Intelligent technology refers to a specific technology or method used in the construction of an intelligent urban streetscape system. Internet of Things, spatial information integration, virtual reality and visualization technology, digital technology, etc. can solve the following problems in the construction of streetscape system under the condition of urban complex giant system:Emergence of the most representative IoT technology in the intelligent process has led the transformation of information age into an intelligent era. The all-inclusive IoT technology involving radio frequency identification (RFID), infrared sensor, and sensor-laser scanner solves numerous urban problems via interconnection of things after the Internet-based information connection .Spatial information reflects the spatial distribution characteristics of geographic entities, and the spatial information integration technology involving remote sensing (RS), geographic information system (GIS), and global positioning system (GPS) can reflect the topographical features of all sites more concretely and objectively at the macro level and achieve precise quantification and data digitization for in-depth research and analysis .VR technology integrates multiple techniques features in good experience of immersion, interaction, and conception, covering the real-time 3D computer graphics, 3D wide-angle (wide-field) display, tracking of the viewer's head/eyes/hands, tactile/force feedback, stereo effects, network transmission, and voice input/output .The basic process of digitization involves the transformation of all complex and changeable information into measurable data, digital data modeling for binary code conversion, and input into the computer for unified processing . At presTo achieve the successful construction of street landscape intelligent systems, the mutual mapping of complex system and complex network of street landscape needs to be realized. Therefore, the above intelligent means must be implemented combined with the actual stages of street landscape construction in practice.The early stage of planning and design provides direct guidance for the mid-term construction and post-management of landscape construction. The application of intelligent means such as the Internet of Things, virtual reality, and visualization technology at the planning and design stage can realize more scientific and rational street landscape design.In terms of on-site investigation, the traditional investigation methods have large workload and large error, and most of them are completed on the basis of on-site inspection and surveying and mapping, combined with the existing data. In addition, the traditional street design focusing on-site plane lacks the 3D-space and humanized thinking in terms of vertical design, construction scale, and detailed design. On the contrary, the intelligent landscape construction can realize the targeted integration of IoT and spatial information technologies into the site survey, with the precise positioning of street location and surrounding land uses utilizing the IoT sensing nodes ; moreoveThe construction quality directly affects the smooth implementation of the preliminary design and the cost of later maintenance and management. Due to the problems of inaccurate calculation of quantities, unconstrained construction, and limited professional quality of most construction personnel in traditional garden construction, there are often some deficiencies in construction quality compared with the expected effect.The intelligent street landscape construction can ensure the rational resource allocation and construction efficiency through the in-depth survey of on-site environmental factors  using the sensing and RFID systems of IoT technology and the corresponding construction schemes and regulations. The application of spatial information integration technology and sensing system makes precise and rapid data positioning based on construction drawings possible at the stage of fixed point setting-out. The multispace model using VR technology enables the construction personnel to understand the design intention in an intuitive manner during construction, thus ensuring the realization of design effects. The application of IoT sensing system upon project acceptance for data measurement and quantitative analysis of engineering effects, combined with the direct data transmission to the auditor's mobile devices using mobile Internet technology, guarantee the strict project acceptance , Figure Conservation management can maintain and guarantee the landscape effects after gardening construction. The traditional plant cultivation and conservation have certain shortcomings, e.g., unsatisfactory professional quality of management personnel and conservation measures of low technical contents.The intelligent plant cultivation and conservation integrating IoT technology ensure the effective improvement of conservation efficiency and effects with reduced cost. In order to make proper use of local conditions, the sensors shall be used to measure environmental factors  at the cultivation stage, and the original manual sprinkling shall be replaced by the sprinkling/drip irrigation system with time-frequency sensors to detect the soil moisture and facilitate the intelligent control . In termApplying intelligent means in urban street landscape design and integrating street landscape intelligent system into smart city construction can actively promote urban development. Procedures starting from scheme design and project construction to maintenance management, technology introduction, and formulation of comprehensive and effective strategies are the key to the successful construction of street landscape intelligent system based on complex network. In addition, the construction of street landscape intelligent system also provides a platform for public participation and governance. The public can easily and quickly obtain information through such intelligent systems and use improved consultation/complaint services to give timely feedback to managers, which indicates that public participation has been significantly improved , 38, 39."}
+{"text": "Cancers, experts in this field will review the current approaches for diagnosing and managing patients with the spectrum of GI cancers, and suggest innovative solutions fit for the diagnosis and  the management of these cancers in light of the new challenges and abundance of innovations [Gastrointestinal (GI) cancers remain high on the list of the leading causes of death worldwide; however, the recent emergence of new and ongoing global healthcare threats, such as the COVID-19 pandemic, has led to a temporary reduction in elective endoscopic procedures . InnovatThe SI is a showcase of a fine collection of articles that underpin the continuing research and innovation approaches in GI endoscopy. In the Global Burden, Risk Factors, and Trends of Esophageal Cancer : An AnalIn another paper of this SI, Verra et al. present their work on a robotic-assisted colonoscopy platform with a magnetically actuated soft-tethered capsule . Almost The SI is not short of high-quality reviews in the field of GI endoscopy. Finocchiaro et al. provide their elaborate and highly pictorial revision on the current and future perspectives in training simulators for GI Endoscopy . ConventA high-quality negative screening colonoscopy was related to diminished CRC incidence and mortality for up to 17.4 years . HoweverAlso, in this SI, Marlicz et al. aimed at providing a timely review of robotic gastroscopes and related technologies supporting professional skills in clinical practice . Authors"}
+{"text": "A substantial scientific advance has recently been made in the elucidation of the molecular mechanism by which unusually folded, self-associating tau proteins drive the neuropathology of several common types of human neurodegenerative disease. This group consists of about ~25 different, invariably lethal age-related tauopathies that include prominently, Alzheimer's disease (AD), argyrophilic grain disease (AGD), chronic traumatic encephalopathy (CTE), corticobasal degeneration (CBD), Parkinson's disease (PD), Pick's disease (PiD), and progressive supranuclear palsy (PSP) as well as familial British dementia, familial Danish dementia, primary age-related tauopathy, and several other more rare tauopathies. Normally neuron-abundant microtubule-associated protein tau (MAPT) proteins are involved in the organization and stabilization of the internal microtubule system of brain cells and are involved in the maintenance of overall neuronal shape, cytoarchitecture, and synaptic organization. Each of the tauopathies are defined by the progressive accumulation in the brain of MAPT proteins as complex, multi-component fibrillar aggregates, and their incidence and prevalence correlate strongly with the degree of dementia , The Brown Foundation, Joe and Dorothy Dorsett Innovation in Science Healthy Aging Award; the Louisiana Biotechnology Research Network (LBRN) and NIH grants NEI EY006311, NIA AG18031, and NIA AG038834 (WJL).The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "The majority of nursing home (NH) residents have Alzheimer\u2019s Disease or Related Dementias (ADRD). However, the association of ADRD prevalence and NH quality is unclear. The objective of the current study is to understand the association of NH characteristics, including the proportion of ADRD residents, with the prevalence of NH complaints as an indicator of quality of care and quality of life. We merged data from the ASPEN Complaints/Incident Tracking System with national NH data from the Certification and Survey Provider Enhanced Reports, the Minimum Data Set, the Area Health Resource File, and zip-code level rural-urban codes in 2017. Three groups of NHs were created, including those whose proportion of residents with ADRD was in the top decile ) and those whose proportion of ADRD residents was in the lowest decile ). Bivariate results revealed high-ADRD NHs had higher percentages of Medicaid-paying residents, were less likely to be for-profit and chain-affiliated, had lower staffing hours and lower percentages of Black, Hispanic, and Asian residents. Using NHs in the middle deciles as reference, negative binomial regression models showed that having a low proportion of ADRD residents was significantly associated with higher numbers of total complaints (p<.001) and substantiated complaints (p<.001), whereas having a high proportion of ADRD residents was significantly associated with lower numbers of substantiated complaints (p=.001). The findings suggest the proportion of residents with ADRD in NHs is associated with quality, as measured by complaints. Policy implications of these findings will be discussed."}
+{"text": "The present review summarizes the data on the cerebellar dopaminergic system including its involvement in associative and projective circuits. Furthermore, this study also briefly discusses the role of the cerebellar dopaminergic system in some neurologic and psychiatric disorders and suggests its potential involvement as a target in pharmacologic and non-pharmacologic treatments.In the central nervous system (CNS), dopamine (DA) is involved in motor and cognitive functions. Although the cerebellum is not been considered an elective dopaminergic region, studies attributed to it a critical role in dopamine deficit-related neurological and psychiatric disorders . Data on the cerebellar dopaminergic neuronal system are still lacking. Nevertheless, biochemical studies detected in the mammalians cerebellum high dopamine levels, while chemical neuroanatomy studies revealed the presence of midbrain dopaminergic afferents to the cerebellum as well as wide distribution of the dopaminergic receptor subtypes (DRD In the mammalian cerebellum, the neurotransmitter systems traditionally involved in the synaptic and extrasynaptic interactions may include the excitatory glutamatergic system  and noradrenaline (NA); as a result, until now, the functional role of dopamine (DA) in the cerebellum has been widely disregarded.In studies using histofluorescence , mainly by means of the serotonergic receptors 5-HT2+ elevation , which can regulate the threshold of regenerative cycles of Ca2 adrenergic subtype receptor  revealed a significant presence of selective dopamine transporter ligands (DAT-Ls) , the synaptic vesicles transporter of monoamine neurotransmitters such as DA, NA, 5-HT, and histamine (HIS)  makes use of direct antisera against DA and of -DA in the contralateral caudate nucleus and decreasing such release in the ipsilateral caudate nucleus. Moreover, the electrical stimulation of the fastigial nucleus increased only the release of [3H]-DA in the ipsilateral caudate nucleus , Milardi et al.  carried The interconnection studies conducted with invasive methods in non-human mammals, and the analyses carried out in humans by means of tractographic neuroimaging methods highlight the presence of relevant interconnections of the cerebellum with the traditional dopaminergic areas of the brain. Moreover, this may likely suggest double direct functional DA interactions between the cerebellar dopaminergic system described in this review and the traditional DA cell groups system of the CNS . In addiThough several studies suggested an involvement of the cerebellum in dopaminergic related neurologic and psychiatric disorders as PD  has been found  animal model, increases in the DA level and its metabolites in the anterior cerebellum and as well as a decrease in the caudate-putamen have been detected  during PD remains unclear , and VMAT2  produced downstream changes in neuronal activity in the frontal cortex (Schutter et al., 8-A10; Ikai et al., The present review extensively evidenced the available morphological, chemical, and functional data on the existence of a cerebellar dopaminergic system in mammals including humans, which consist of extrinsic fibers which originate mainly from the midbrain cerebellar dopaminergic nuclei (AIn addition, this review evidenced the presence of direct dentate-SNpc and dentate-VTA interconnections (Milardi et al., Finally, we suggest that the cerebellar dopaminergic system and its interconnections may represent an ideal candidate for innovative non-invasive treatments such as electrical or magnetic stimulations in neurological and psychiatric disorders (Demirtas-Tatlidede et al., PF designed the study, performed the experiments and the analysis of the experimental data, and participated in the writing of the manuscript. PL and DG shared the study project and participated in the writing of the manuscript. GB, ABi, SBe, JB, SBi, and ABr participated in the writing of the manuscript. GG, MG, and GA performed the analysis of the experimental data, participated in the writing of the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "With the increasing number of people with neurodegenerative disease world-wide, novel directions and paradigms are sought to understand disease-specific neuronal death and to offer novel therapeutic strategies to patients. The ability to transform a differentiated cell into a pluripotent state and to differentiate again to a defined target cell type , identifying the limitations of these approaches, including the variable genetic backgrounds, off-target effects of genetic corrections or targeting, the lacking cellular maturity, and the heterogeneity of differentiation techniques. This latter point is further detailed by Ghaffari et al. whom provide an impressive deep-dive into the different means of differentiation of specific neuronal and glial subtypes in detail, and compare and contrast IPSCs and direct conversion. Despite these challenges, the use of patient-derived tissue is strongly recommended in disease-modeling and preclinical ALS studies for drug discovery and development .In the context of ALS and Frontal Temporal Dementia (FTD), Guo et al. summarize the disease-specific phenotypes in patient-derived IPSC-derived neurons and the variability between reports . The importance of how a gene may cause disease and whether that mechanism remains present in iPSC-derived neurons is also of relevance in the context of the regulation of the gene SNCA, encoding for the protein alpha-synuclein, in Parkinson's Disease . Piper et al. describe in-depth the different ways SNCA may genetically cause disease, as well as how SCNA may be regulated. The authors stress the importance of the understanding of temporal and cell type-specific regulation of SNCA in disease, and in disease-models .With the epigenetic markers of cellular maturity lost when cells are converted to iPSCs , this Research Topic's contributions span the increased understanding of pathophysiology, testing of novel therapeutics, and the transplantation of cells as a potential therapeutic.Naphade et al.). They found that MMPs' endogenous inhibitors are decreased in HD cells and are elevated by TGFb treatment , illustrating a potential new direction for HD therapeutic strategies. Rindt et al. used a similar technique to assess the potential of the pre-mRNA repair of mutant Huntingtin, and also identified a beneficial response in HD-derived IPSC neural models . Subsequnetly, Masnata and Cicchetti describe the evidence for seeding of the Huntingtin protein in in vitro cultures of HD, including by IPSC disease modeling, and find sufficient evidence to suggest that this occurs, prompting the conclusion that in vivo assessment is now needed to further assess this (Masnata and Cicchetti). Al-Gharaibeh et al. transplanted IPSC-derived neural stem cells as a potential therapeutic into the striata of aged HD model mice (YAC128) and observed a striking protective effect on pathology and behavior in these animals , indicating the potential for neuronal replacement therapy in HD.Naphade et al. used patient-derived, isogenic, and control-corrected IPSCs to generate neural stem cells to assess the role of matrix metalloproteinases (MMPs) and their inhibitors in HD . They delineate what constitutes an iNeuron, describe the benefits of each stage of differentiation per neurological disease, discuss whether generating subtype-specific iNeurons is critical to the disease-related features of these cells, and subsequently explain the biomedical potential and limitations of the use of these cells . In addition, Omais et al. summarize an alternative potential cells to model neurodegenerative disease; adult neurogenesis in the olfactory bulb .To understand the potential and limitations of the use of non-primary neurons, Drouin-Ouellet et al. summarize the use of inducible neurons (iNeurons), which are derived from direct differentiation from somatic cells (Han et al. Open Science refers to the transparency of the research and is illustrated by Open Lab Notebooks Durcan, and the sharing of resources, including patient-derived stem cell lines (Gan-Or et al., To accelerate the discovery and development of novel therapeutic strategies for patients, the Montreal Neurological Institute has adopted an \u201cOpen Science\u201d model, as described by The author confirms being the sole contributor of this work and has approved it for publication.KS is employed by company Staats Life Sciences Consulting, LLC."}
+{"text": "Ecological science focuses on the structure and function of the natural environment. However, the study of ecological environments primarily focuses on single-element research and lacks a comprehensive perspective. To examine ecological environmental trends on different scales, the present paper selected Yunnan Province as the study area. Chemical oxygen demand, rocky desertification, forest coverage, natural disaster data and spatial analysis methods were used to obtain the ecological environmental characteristics of each county and construct a comprehensive evaluation method of the ecological environment. The present paper revealed that the environmental capacity in Yunnan Province was at a moderate level, the ecological environment fragility was remarkable, the significance of the ecological environment was very high, natural disasters occurred frequently, and spatial differentiation between ecological environments was obvious. The province may be divided into three functional areas: the comprehensive-balanced area, the efficiency-dominated area and the environment-dominated area. Central Yunnan was a key development zone and the main area for the manufacturing and service industries, which were built as a modern industrial system in Yunnan Province. The ecological environment in northwestern Yunnan and southern Yunnan is of high significance, and this region was an ecological environment protection area that was important area for the construction of the modern agricultural system in Yunnan Province. To achieve sustainable development of the ecological environment, the spatial characteristics of the ecological environment must be determined at the county scale. The development of the world economy has exacerbated problems with the ecological environment since the 1990s. Scholars believe that the cost to the ecological environment of achieving economic growth is increasing, which has led to serious deterioration of the ecological environment that continues to intensify. The ecological environment has become a focus of political and academic concerns. Considerable ecological environment research was performed in the last 30 years, and this field has grown rapidly in the last 20 years. Research results are primarily published in journals, dissertations, conference papers and monographs. Research on the ecological environment is systemic and represents an important basis for the development of sustainable resource utilization, economic and social planning and ecological environment protection.Research on the ecological environment primarily focuses on analyses of the water environment, atmospheric environment, soil environment, engineering technology, environmental protection technology, policy guidance, and industry technical guidance and determining solutions to typical regional ecological environment issues . Many reIt is evident that recent developments in the geotechnologies of GIS and remote sensing have had a substantial impact on ecological environment research in the second decade of the 21st century and provided spatial data and associated information to enable further understanding of ecological systems . Remote Remote sensing and GIS have ensured their continuing input and significance in the field of ecological environments . SatelliResearch indicated significant spatiotemporal heterogeneity between economic development and the ecological environment . EcologiWater environmental capacity is defined as the maximum amount of pollutants that a water body can hold and still meet water quality standards , 59. WatResearch on the fragility of the ecological environment began in the 1960s. Research on ecological fragility has been a hot topic ever since 2000, and there were more empirical studies than theoretical studies. Studies in the early period used the city as the data unit. After 2000, a boom of theoretical reviews and initial signs of comprehensive research appeared, and the Grid GIS came into being. In response to requests from governments to show how the environment provides challenges and opportunities for human development, Global Environmental Outlook: Environment for Development gave the concept of vulnerability a central place. Vulnerability is the outcome of multiple stressors and multiple actors in multiple contexts that may occur at various spatial and time scales . Eco-envThe ecological importance showed spatial heterogeneities across and within the regions. Protected area zoning has become an effective tool in recent decades to divide regions into different zones with different protection and development strategies, and it has considerably contributed to biodiversity conservation and the harmonious coexistence of multiple activities . For theThe study of ecological risk assessment started in the 1970s. Ecological risk assessment is a powerful tool for quantifying ecological risk. Ecological risk assessment calculates the possible ecological damage arising from exposure to one or more pollution components . PresentResearch results on the ecological environment are not uncommon. However, this research is basically performed in a specific area and specific year. Therefore, the results reflect only the basic situation of the local area in that year and primarily focus on the study of a single element of the ecological environment. These studies are static. Therefore, the temporal and spatial changes in the ecological environment are difficult to identify. The present paper selected Yunnan Province as the research area to perform a spatial analysis of the ecological environment. The geographical environment of Yunnan Province is highly fragmented, and a single-element evaluation cannot provide a comprehensive explanation of the spatial differentiation characteristics of the environment. In light of the current status of research focusing on a single element of the ecological environment, such as environmental capacity, which can identify the water quality and water pollution status of an area, fragility reflects the sensitivity of the regional ecological environment to the outside world. Significance identifies locations for ecological environment protection, and hazards provide early warnings for earthquake prevention and disaster reduction. The present paper used Yunnan Province as the spatial scale. Focusing on ecological environment theory, this paper constructs a comprehensive evaluation system of the ecological environment and explores the spatial differentiation characteristics of the ecological environment in Yunnan Province to provide a spatial and practical basis for ecological environment research.This paper combines environmental capacity, fragility, significance, hazards and GIS and innovatively proposes a comprehensive research method. Section 2 shows the calculation process for the comprehensive research method. Section 3 presents the application of this method in the study of the ecological environment in Yunnan Province. Section 4 provides suggestions for the sustainable development of the ecological environment in Yunnan Province. Section 5 presents the conclusion.2, the area of Yunnan Province accounts for approximately 4.11% of the area of China, and mountain areas account for more than 84% of the total area of Yunnan. The total population was 48.3 million in 2018, which accounted for approximately 3.46% of the country. The population density was 121.8 people/km2, and the GDP was 1,788,112 million yuan, which accounted for approximately 2% of the GDP of China. Yunnan Province is located in the Chinese frontier area and has the second largest forest area in China. It is an important area for maintaining the stability of the overall ecological environment of China. The forests in this area are mostly distributed in the source area of the river system and the upper and middle reaches of the river basin. The quantity, quality and distribution of the forest are closely related to the ecological environment of a partial area or the entire river basin. The concentrated distribution areas of forests represent the last habitats of the main wild animal and plant resources in Yunnan. As a typical representative border region in China, the supporting capacity of the ecological environment has changed significantly with the development of the economy in mountainous areas, and regulating the deterioration of the ecological environment foundation has become increasingly difficult. Future prospects are not optimistic. Ecological environmental protection has significant benefits in the contemporary era and for future generations. As a source of large rivers in southwestern China, Yunnan Province should place greater emphasis on the ecological environment. Therefore, the maintenance function and social value of the ecological environment in Yunnan Province are far greater than the economic value of these environments. Environmental protection and development in this area must be considered from the perspective of ecological security of the entire river basin and country and the sustainable development of the social economy.As shown in Major Function-Oriented Zone Planning in Yunnan Province (http://www.yn.gov.cn/zwgk/). The soil erosion and rocky desertification data were obtained from the Report on the State of Yunnan Provincial Environment (http://sthjt.yn.gov.cn/hjzl/). The ecological protection data were obtained from the List of Natural Reserves in Yunnan Province (http://sthjt.yn.gov.cn/zrst/). The earthquake and debris flow data were obtained from the Yearbook of Disaster Reduction in Yunnan Province (http://yndzj.gov.cn/yndzj/sy1/index.html), Yunnan Earthquake Prevention and Disaster Reduction Bureau, Department of Ecology and Environment of Yunnan Province. Relevant data were standardized.Chemical oxygen demand (COD) and ammonia nitrogen capacity data for rivers were obtained from the Humans are the main body in the ecological environment, and other living creatures and nonliving objects are a complex of environmental elements . Traditional single-element assessment methods for the ecological environment focus more on analyzing the spatial and temporal distribution characteristics of a single element. Under diversified social development, ecological environment research has obvious comprehensive and holistic characteristics, and the interaction between basic elements of the ecological environment and their associated influence is becoming increasingly obvious. Combined with the objective requirements of developing scientific concepts, ecological environment research aims to overcome the limitations of traditional single-element assessment methods. This paper innovatively constructs a multielement comprehensive evaluation method and emphasizes the possibility of coordinating the balance of the internal system with the external environment.According to the special geographical environment of Yunnan Province, the following comprehensive evaluation system model of the ecological environment is proposed:L) = environmental capacity index (E)+fragility index (Y)+significance index (P)+hazard index (DH).Comprehensive evaluation index system of the ecological environment ((1) Water environmental capacity index system. Japanese scholars proposed the concept of environmental capacity, and the term is rarely used by European and American scholars. Chinese research on environmental capacity began in the 1970s. Environmental capacity is the maximum load of pollutants that the environmental system can accommodate within a certain time frame, and it is the upper limit of the carrying capacity according to the resource and environmental conditions at the development scale. This paper calculated the water environmental capacity using COD and ammonia nitrogen data for the river section at the county level in Yunnan.Ecod is the environmental capacity of COD (t/a), Ccod is the concentration of COD (mg/L), qcod is the amount of COD flowing into the river (t/a), En is the environmental capacity of ammonia nitrogen (t/a), Cn is the NH3-N concentration (mg/L), qn is the amount of NH3-N flow into the river (t/a), Q is the average water volume (t/a), and \u03b1 is the water resource utilization coefficient, which has a value of 0.4.(2) Fragility index system. Scholars determined that sensitivity and instability were the most important characteristics of ecologically fragile areas. The fragility of the ecological environment means that the ecological environment is affected by external interference and factors beyond its own adjustment range. Therefore, the ecological environment shows varying degrees of sensitivity to external interference. The ecological environmental fragility coefficient of Yunnan Province was calculated using the following formula:Y is the ecological environment fragility coefficient, Pi is the dimensionless value of the i-th index, and Wi is the weight value of the i-th index.(3) Significance index system. Ecological significance is an evaluation index for dividing restricted and prohibited development zones within the main functional zone of the province. Many scholars evaluated the importance of ecosystems by analyzing their composition and quantitative service value within a certain national space. Based on the area of nature reserves above the provincial level, this paper calculated the proportion of ecologically important areas in each county.Pi is the ratio of the assessment of regional biodiversity protection areas and ecologically important areas, Ni is the area of an important ecological environment, and Ti is the total area of the region.(4) Hazard index system. The single-element evaluation of natural disaster risk is thorough, and the method of risk assessment shifted from qualitative analysis to comprehensive quantitative evaluations that combine natural and social science. This paper used Graham\u2019s method to evaluate natural disasters.Di is the single-element risk index of natural disasters, Li is the average probability of occurrence of disasters, Ei is the time of recipient affected by the disasters, and Ci is the possible loss caused by disasters.\u03bb is the disaster index weight, and Di is the disaster risk index.(5) Comprehensive ecological environment evaluation index system. Using 124 counties as the basic geographical unit, a comprehensive value measurement algorithm was adopted after standardizing the water environmental capacity index (E), fragility index (Y), importance index (P) and hazard index (DH). The score range of each indicator was no more than 10.Ki is the index weight, and Ai is the index score.https://desktop.arcgis.com/zh-cn/) data show that the water environmental capacity in Yunnan may be divided into 5 levels, which are shown in Based on the minimum value of the remaining amounts of COD and NH3-N in the river section of each county in Yunnan, the results of the study showed that the ecological environment capacity was moderate in Yunnan Province, with 91 counties above the moderate level and 33 counties below the low level. Using the natural classification method, the results using Arcview  Hazardous area: Gengma, Midu, Yao\u2019an and Ludian, with an area of 8,730 km2, which accounted for 2.24% of the total area. Earthquake disasters and landslides and debris flows occurred in Gengma and Midu. The earthquake disasters in Yao\u2019an and Ludian were very obvious in recent years. (3) Generally hazardous area: Yuxi, Chuxiong, Zhaotong(except Ludian), Honghe, Pu\u2019er, Baoshan, Lincang, Dehong, Dali, Lijiang and partial areas of Diqing, covering an area of 142,397 km2, which accounted for approximately 36.51% of the total area. Earthquakes and debris flows occur in Zhaotong. Landslides and debris flows are seen frequently in Honghe, and earthquake disasters often occur in western Yunnan Province.As seen in As shown in Comprehensive-balanced area: Baoshan, Xishuangbanna, Qujing, Nujiang, Pu\u2019er and Lincang. The natural geographical environment in these areas was good, and the ecological benefits and the environmental quality were relatively balanced. With a water environmental capacity of more than 6500 (t/a), Nujiang, Pu\u2019er and Lincang are rich in water resources and have a high water environment capacity. Baoshan and Xishuangbanna have abundant biodiversity and higher stability of surface vegetation, and the ecologically important regions account for 21.04% and 13.62% of the whole area, respectively, which indicates that these cities have the highest ecological significance.Efficiency-dominated area: distributed in the central Yunnan urban agglomerations, including Kunming, Qujing, Yuxi and Chuxiong. This type of area had the most developed economy, high resource utilization efficiency, relatively high technical level, good cultural environment, and ecological benefits that exceeded the environmental quality. Economic development created pressure on the ecological environment. Kunming (with a GDP of 520.69 billion yuan), Qu Jing (with a GDP of 201.34 billion yuan), Yuxi (with a GDP of 149.30 billion yuan) and Chuxiong (with a GDP of 102.43 billion yuan) are economically developed regions in Yunnan Province, and the economies of these cities ranked first, second, fourth and sixth in Yunnan in 2018, respectively. Kunming, Qujing, Yuxi and Chuxiong are neighboring areas, and these cities form the central Yunnan urban agglomeration. The GDP of the central Yunnan urban agglomeration accounted for 54.46% of the GDP of Yunnan Province, which made it the economic growth pole of Southwest China. The ecologies of Kunming, Qujing, Yuxi and Chuxiong showed limited fragility and strong resistance to external interference. The rapid development of urbanization and industrialization led to a backward environmental quality. The water environmental capacities of Chuxiong  and Yuxi  were relatively low. The water environment capacity of the Dianchi Lake Basin in Kunming is extremely low. Therefore, maintaining ecological benefits and improving environmental quality are key points for constructing ecological civilizations in Kunming, Qujing, Yuxi and Chuxiong.Environmentally dominated areas primarily included Wenshan, Dehong, Lijiang, Diqing, Honghe, Dali and Zhaotong. With good natural environmental quality, the sustainable development of these cities was dominated by environmental quality, moderate natural resource utilization rates, and low ecological benefits. The energy consumption per 10,000 yuan of GDP in these areas was not high, the proportion of the secondary industry was low, the proportion of the primary and tertiary industries was large, the GDP per capita was low, and the utilization rate of ecological resources was insufficient. These areas have many biodiversity-protected areas, and the ecological environment was important. The water environmental capacity was greater than 3500 t/a, the ecology was moderately fragile, and vegetation recovery was difficult, as shown in From the perspective of the overall ecological environment, the ecological environment foundation of Yunnan Province was relatively good. However, due to the complexity of the mountainous geographical environment, challenges remain in improving the ecological environment of certain areas. An evaluation of the four indicators of environmental capacity, ecological fragility, ecological importance and natural disaster hazard indicated obvious spatial differences, with the ecological environment in the northwest and southwest areas of Yunnan Province being relatively good and the northeast and central areas of Yunnan relatively weak.Ecological science is the study of the structure and function of the natural environment. The present paper used the relevant principles of ecology to address the current situation of single-element research on the ecological environment, constructed a comprehensive evaluation method of the ecological environment from the perspective of system theory, focused on the prefectural scale, and examined the ecological environment and spatial differentiation characteristics of Yunnan Province. This research has certain theoretical significance and provides a theoretical perspective and practical basis for the construction of ecological civilization space in Yunnan Province. Based on the overall ecological environment, the ecological environment foundation of Yunnan Province was relatively good. However, the geographical environments of mountainous areas are very complex. The environmental capacity, ecological environmental fragility, ecological environmental importance and natural disaster hazards indicators were evaluated, and we found obvious spatial differences, with the ecological environment in the northwestern and southwestern regions of Yunnan being relatively good and that the northeastern and central regions of Yunnan Province being relatively weak.This study found that Yunnan had a moderate environmental capacity, a relatively fragile ecological environment, high ecological environment importance, and frequent natural disasters. The ecological environment had obvious spatial differences, which were divided into three functional areas: comprehensive-balanced area, efficiency-dominated area, and environment-dominated area. Ecological environmental research provides an important basis for the formulation of sustainable economic and social development plans and ecological environmental protection countermeasures. Although the ecological environment was mildly fragile in central Yunnan, this area is a key development zone and the main area for the manufacturing and service industries, which were built as a modern industrial system in Yunnan Province. The ecological environment in northwestern and southern Yunnan is of high significance, and this region is an ecological environment protection area and an important area for the construction of the modern agricultural system in Yunnan Province. According to the environmental capacity, the water quality of Shangri-La, Jingdong, Yongshan, Qiaojia, Tengchong, Baoshan, Dali, Lincang and Pu\u2019er was good and the water pollution in Kunming Dianchi Lake was serious. According to the environmental fragility analysis, the ecological environments of Deqin, Shangri-La, Weixi, Weixin, Zhenkang, Gengma, Mojiang, Honghe, Hekou, Maguan, Wenshan, Malipo, Xichou, Qiubei, Guangnan and Luoping were most obviously affected by external influences. According to the significance analysis, the key areas of ecological environment protection in Yunnan Province included Deqin, Shangri-La, Weixi, Gongshan, Ninglang, Yuanmou, Tengchong, Zhenkang, Yongde, Cangyuan, Jinghong, Mengla, Honghe, Hekou, Luquan, and Funing. These locations had the most ecological environmental protection zones. The hazard analysis identified areas with frequent natural disasters and hidden hazards in Yunnan Province. For example, mudslides were more likely to occur in Dongchuan and earthquakes were more likely to occur in Ludian and Yao\u2019an. Ludian experienced an earthquake in 2014, and Yao\u2019an experienced an earthquake in 2009. Hazard research results have important reference value as disaster warnings.As a hot research field, the ecological environment has obvious comprehensive and systematic characteristics. A comprehensive evaluation system for the ecological environment was constructed as an exploratory research method, and it showed regional characteristics. Particular emphasis should be placed on the selection of indicators for different research spaces in the future.A number of methods are used in environment-dominated areas, including a new round of ecological civilization construction plans, the construction and improvement of a dynamic monitoring network for vegetation coverage, strict implementation of forestland reserves, promotion of forest planting and grassland planting, and scientific development of aboveground and belowground spaces to realize potential land uses and increase surface vegetation coverage. Wenshan, Dehong, Lijiang, Diqing, Honghe, Dali and Zhaotong could gradually improve the level of ecological benefits by enhancing the level of technology and management and increasing the utilization rate of ecological resources.From the perspective of ecological environmental protection, the comprehensive-balanced area could set goals for sustainable economic and social development. Qujing should actively develop its light industry and service industry to prevent hidden dangers caused by the rapid development of highly energy-consuming industries. Baoshan, Xishuangbanna, Nujiang, Pu\u2019er and Lincang could earnestly implement the target responsibility system and accountability system of environmental protection and actively perform paid use of pollution discharge rights and trading pilots. This work would emphasize that the development and protection of the comprehensive-balanced area should work together to improve environmental quality and capacity.The resource-environment dependence path of economic development in efficiency-dominated areas is obvious, and the carrying capacity of the ecological environment hinders the speed of economic and social development. By promoting economic and social development transformation through \"reform\", Kunming, Yuxi, and Chuxiong are capable of breaking through the restriction of the ecological environment on economic and social development to change the traditional resource-dependent development model and transfer the mode of production to promote economic transition and realize the transformation of economic and social development and the ecological environment from \"investment\" to \"reform\".The comprehensive-balanced area, efficiency-dominated area and environment-dominated area should thoroughly implement sustainable development, fully promote law-based governance of the ecological environment, adhere to promoting environmental development, strengthen efforts to promote the ecological environment legal system, and create a good social atmosphere for protecting the ecological environment. The monitoring function of grassroots environmental protection organizations should be supported to provide guarantees for the sustainable utilization of the ecological environment.S1 Data(RAR)Click here for additional data file."}
+{"text": "Over the past 60 years, evidence has accumulated on the fundamental role of supportive social relationships in individual health and longevity. This paper first summarizes the results of 23 meta-analyses published between 1994 and 2021, which include 1,187 longitudinal and cross-sectional studies with more than 1,458 million participants. The effect sizes reported in these meta-analyses are highly consistent with regard to the predicted link between social support and reduced disease and mortality; the meta-analyses also highlight various theoretical and methodological issues concerning the multi-dimensionality of the social support concept and its measurements, and the need to control potential confounding and moderator variables. This is followed by an analysis of the experimental evidence from laboratory studies on psychobiological mechanisms that may explain the effect of social support on health and longevity. The stress-buffering hypothesis is examined and extended to incorporate recent findings on the inhibitory effect of social support figures  on fear learning and defensive reactions alongside evidence on the effect of social support on brain networks that down-regulate the autonomic nervous system, HPA axis, and immune system. Finally, the paper discusses the findings in the context of three emerging research areas that are helping to advance and consolidate the relevance of social factors for human health and longevity: (a) convergent evidence on the effects of social support and adversity in other social mammals, (b) longitudinal studies on the impact of social support and adversity across each stage of the human lifespan, and (c) studies that extend the social support framework from individual to community and societal levels, drawing implications for large-scale intervention policies to promote the culture of social support. Evolutionary biologists did not anticipate the continuing rise in life expectancy in high-income countries  they are cared for and loved, (b) they are esteemed and valued, and/or (c) they belong to a network of communication and mutual obligation. Both Cobb and Cassel considered that social support protects people by buffering the health consequences of life stresses.In 1976, two seminal reviews were published on the concept of social support and its effects on health and mortality .Two electronic databases (Scopus and Web of Science) were searched for meta-analysis studies using the following combination of terms:  and . The electronic searches were restricted to studies published in English with adolescent or adult human participants. They had to include at least one measure of social support as independent variable and at least one outcome measure of longevity/mortality/health/disease as dependent variable. Additional complementary search strategies were used by checking cross-references between the meta-analyses and relevant systematic reviews.A total of 23 meta-analyses published between 1994 and 2021 complied with the inclusion criteria. They were checked to ensure that they followed the PRISMA protocol and that the final list of primary studies across the 23 meta-analyses did not include duplicate studies or participants. The 23 meta-analyses covered 1,187 non-duplicate primary studies with more than 1,478 million participants. Six meta-analyses used correlation as effect size measure, and the remaining 17 used proportion ratios . In the six meta-analyses with effect sizes based on correlation see , the outThe 23 meta-analyses displayed in the three tables obtained highly consistent results, with significant effect sizes confirming the association between social support  and individual health/longevity (regardless of the type of outcome measure). However, as also observed in these tables, the strength of the association depends on numerous factors, including type of effect size, type of outcome, type of social support, and type of moderator variable. In this section, the results are discussed in relation to the type of effect size and type of outcome. The impact of the social support measures and moderator variables are discussed in the following two sections.strong, consistently positive relationships between social support and health outcome measures. They stressed the need for further refinement of social support measures in future research. It is also noteworthy that the most recently published meta-analysis also used correlation as effect size measure  across five continents, used functional and structural measures of social support, analyzed multiple moderator variables, and obtained markedly higher effect sizes .The six meta-analyses in The 10 meta-analyses in post-partum depression , and the heterogeneity of effect sizes for primary studies, weakening, or extinguishing the strength of a true association. However, both problems can be addressed and evaluated by applying meta-analysis methodology.Examination of the social support measures listed in the three tables illustrates the conceptual and methodological diversity described in the Introduction. Twenty-six different social support measures are reported, including: quantitative and qualitative social support; received and perceived social support; enacted social support; network social support; material, informational, and emotional social support; social engagement; and social integration. Only two of these meta-analyses used the recommended functional-structural classification , six structural measures , and a combination of both types of measure. Among the structural measures, the complex measure of social integration was the most highly predictive of the mortality risk, with an effect size of 1.91, whereas living alone was the least predictive, with an effect size of 1.19. Among the functional measures, perceived social support and loneliness were the most predictive measures, with effect sizes of 1.35 and 1.45, respectively, whereas received social support did not even reach statistical significance.The relevance of perceived social support as a predictor of health and longevity is confirmed in five additional meta-analyses in In general, these data show that the measures that best reflect the multidimensionality of the social support concept  are the most accurate predictors of a reduced risk of disease and mortality.Correlational studies are based on a non-randomized selection of participants. Evidently, people cannot be randomly assigned to groups for social isolation or divorce. In both cross-sectional and longitudinal studies, the non-randomized selection of participants involves the presence of third variables that can make the association spurious. It is well-known that age, socio-economic status, or physical and mental health at the initial evaluation can influence health status and longevity. Age is by far the most important risk factor for many chronic diseases and disabilities  or substantive . In meta-analyses, the influence of these variables is evaluated and controlled by means of sub-group analysis and meta-regression. Overall effect sizes are usually adjusted for the influence of these variables (covariates) or reported separately for specific sub-groups of interest. The evidence provided by the 23 meta-analyses remains consistent after controlling for confounders and mediators, thereby conferring convergent validity to the predictive role played by supportive social relationships in health and longevity. However, while confounding variables may reverse the causal pathway between social support and longevity, and moderator variables can modify its strength, other variables affecting the causal pathway play a different role acting as mediators between social support and outcome. This is the case of psychobiological mechanisms and, in particular, of the variables involved in dampening the stress response according to the stress-buffering hypothesis.Multiple pathways may link social support with health and longevity. Informational and instrumental support, including financial and material assistance, can help individuals to cope with health problems. Likewise, integration within a supportive social network can prevent health problems by providing positive health role models and reinforcing healthy behaviors , and ending in autonomic, endocrine, and motor effectors whose function is to protect the organism from the threat (fight-or-flight response). The result is a state of maintained or intermittent activation of physiological and endocrine responses that can, over the long term, compromise the normal functioning of the organs involved and increase the risk of disease and mortality. Two neurobiological subsystems are especially relevant in the above sequence: the hypothalamic-pituitary-adrenocortical (HPA) axis and the sympathetic-adreno-medullar (SAM) axis. Activation of both axes in response to a stressor increases the circulation of glucocorticoids (cortisol) and catecholamines  in the bloodstream to allow energy to be released for the fight-or-flight response, even after the stressor has disappeared.According to the stress-buffering hypothesis, social support is beneficial for health and longevity because the presence of a bond with social partners attenuates or eliminates the adverse consequences of prolonged HPA and SAM activation. This hypothesis was first formulated by Bovard , 1962 anExperimental investigation of the stress-buffering hypothesis in humans has been particularly intensive over the past two decades. The experimental tasks have usually employed laboratory-based stressors, such as public speech, threat of mild electric shock, or exposure to painful stimuli. In children, the tasks may consist in natural stressors such as vaccination injections or exposure to clowns or toys  and comparing with control pictures . The first three studies used the standard startle probe paradigm to confirm that attachment figures elicit a genuine positive emotional response that is not confounded by familiarity or undifferentiated emotional arousal  in comparison to faces of strangers or known people or neutral objects. The results obtained demonstrate that in comparison to faces of strangers and neutral objects, social support faces, either presented alone or paired with control faces, act as safety signals with the following capacities: (a) to inhibit their own fear conditioning  and fear of social rejection (the other) as the two main ancestral fears. Likewise, the main safety signals with capacity to inhibit fear and defense reactions are also other people: attachment and loved figures.The brain structures at the core of the defense motivational system are two subcortical areas within the temporal lobes: the amygdala and the bed nucleus of stria terminalis . Knowledge of these structures derives from animal and human studies on defense reactions and fear conditioning LeDoux, . The amyProlonged activation of the defense system leads to a cardiovascular and autonomic imbalance in which the sympathetic tone is high and the parasympathetic tone is low, a condition associated with increased morbidity and mortality , which stimulates production of adrenocorticotropic hormone (ACTH) by the anterior pituitary and its release into the general circulation. The ACTH then stimulates the production and release of glucocorticoids (cortisol) by the adrenal cortex, whose main function is the mobilization of energy to cope with environmental challenges. Brain control of the HPA axis uses the same structures as those involved in cortical and subcortical regulation of the cardiovascular system: orbitofrontal and medial prefrontal cortex, anterior cingulate, amygdala, and bed nucleus of stria terminalis . The results highlighted the emotional component of social support, principally from family and friends, which is identified as love. Love is embedded in the first and most cited definition of social support proposed in 1976: on Cobb, , describon Cobb, . ImportaNevertheless, research on social support and longevity needs to incorporate recent developments within the field that are helping to expand evidence on the link between social support and health/longevity, to advance knowledge on its underlying neurobiological mechanisms, and to translate this knowledge into the design and implementation of large scale preventive public health interventions that increase the culture of social support. These new developments derive from three different perspectives: the evolutionary, the life span, and the systemic.Mama's last hug (de Waal, Recent comparative studies between human and non-human social mammals have demonstrated that measures of social support and integration in non-human social mammals are strong predictors of health and survival, as observed in humans, with odds ratios between 1.23 and 1.72 (Snyder-Mackler et al., de Waal, , primateThe developmental approach to the stress buffering hypothesis adopted by Gunnar and Hostinar  represenThe systemic approach to social support and longevity, recently defended by Holt-Lunstad et al. , 2015 anLoneliness, the perception of social isolation, is reaching epidemic proportions among the elderly in developed countries and is expected to increase further over the next few decades Cigna, . Social The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "This study examined the association between age and preparedness for the continuation of COVID-19. The moderation effects of three types of social support, namely, emotional, financial, and instrumental assistance were also tested. Using a sample of 443 adults in Dallas county which has the most confirmed cases in Texas, results of multiple linear regressions showed that compared to those aged between 18 and 64, older adults aged 65 and reported better preparedness for the continuation of COVID-19. Receiving emotional, financial, and instrumental assistance were respectively more important for older people to get better prepared than for younger adults, which is consistent with the socioemotional selectivity theory. Our findings directed attention to the strengths and resilience of older adults during COVID-19 from a life course perspective and highlighted the importance of social support and social relationship in their post-disaster recovery and ongoing preparedness."}
+{"text": "Increasing attention is growing towards advanced multiscale metamaterials and nanostructures, due to recent developments in nanoscience and nanotechnology. Smart nanoscale systems with unconventional features are attractive subjects for many applications, such as electronic, optical and magnetic devices, involved in many areas such as aerospace and mechanical engineering, medicine, biology and sound and heat control. The modeling, characterization and synthesis of innovative materials and structures are, thus, needed to explore new challenging scientific applications.The Special Issue (SI) Multiscale Innovative Materials and Structures provides new insights concerning the modeling and realization of advanced nano-reinforced materials, carbon nanotube-based systems, tensegrity structures, periodic lattices and multiscale composites. Theoretical and experimental outcomes collected in the SI provide original and significant contributions in the field of nano-composites, nano-systems and nano-devices.The first work of the SI  deals wiIt is our hope that the works collected in Multiscale Innovative Materials and Structures will provide scientific community with novel and significant contributions to the topic."}
+{"text": "Chest X-rays (CXR) and computed tomography (CT) are the main medical imaging modalities used against the increased worldwide spread of the 2019 coronavirus disease (COVID-19) epidemic. Machine learning (ML) and artificial intelligence (AI) technology, based on medical imaging fully extracting and utilizing the hidden information in massive medical imaging data, have been used in COVID-19 research of disease diagnosis and classification, treatment decision-making, efficacy evaluation, and prognosis prediction. This review article describes the extensive research of medical image-based ML and AI methods in preventing and controlling COVID-19, and summarizes their characteristics, differences, and significance in terms of application direction, image collection, and algorithm improvement, from the perspective of radiologists. The limitations and challenges faced by these systems and technologies, such as generalization and robustness, are discussed to indicate future research directions. The rapid spread of the COVID-19 worldwide developed into a global pandemic, leading to a large-scale medical system burden and economic crisis. The detection and diagnosis of COVID-19 rely on the positive results of the reverse transcription-polymerase chain reaction (RT-PCR); however, false-negative results may occur due to the influence of various factors such as low viral load . HoweverHerein, the application, existing problems, and possible solution of machine learning and artificial intelligence systems based on medical images are introduced, such as diagnosis and classification, treatment decision-making, curative effect evaluation, prognosis prediction, and other relevant aspects for patients affected by COVID-19. By conducting a rapid review of published studies and the existing experience of DL and AI in COVID-19 radiological examinations, the aim of this article is to evaluate the feasibility and the effectiveness of available COVID-19 diagnostic tools, which may be helpful to develop better intelligent models by medical experts and technical researchers.A combination of three group of keywords including disease, imaging examinations, together with algorithm technology was used to search for articles in four databases: PubMed, Web of Scicence, Elsevier/SD, and IEEE; all types of research were evaluated, including case reports, original research, clinical guidelines, and systematic reviews. Through reading abstracts and reviewing the references of included studies, the published studies were finally screened and classified. We set the criteria for inclusion and classification. Only research written in English was included; preprints that were not peer-reviewed were excluded. The application and effectiveness of these systems were discussed from the perspective of radiologists. Although the types and development of algorithms were not the focus of this review, they were not excluded Chest X-ray and CT are widely used to diagnose and screen COVID-19 patients from suspected patients and make differential diagnosis from patients with other lung diseases ,7,8. QuaAlthough CT was recommended in the diagnosis of COVID-19 at different stages of the disease in mainland China, the British Society of Thoracic Imaging and the American College of Radiology currently recommend CXR as the first line of COVID-19 imaging ,16. As aDL and AI systems can extract massive amounts of valuable clinical decision information by analyzing medical images and clinical data from COVID-19 patients, thus revealing the great potential for the use of chest X-rays and CT for quantifying the lesions and assessing progression and related medical indicators. Zhang et al.  used quaA large number of clinical parameters and imaging data, which are generated during the diagnosis and treatment of COVID-19 patients, can be compared and correlated through DL and AI systems. Zhang et al.  selectedThe effectiveness of DL and AI systems in diagnosing COVID-19 is a basic condition for clinical application and is often compared with the diagnostic performance of radiologists. Murphy et al.  used datIt can be seen from these studies that the detection and diagnosis performance of AI models based on COVID-19 CXR or CT images is similar to that of experienced radiologists and may help improve the reliability of physicians\u2019 diagnoses, especially for junior radiologists and nonradiologists.Objectively quantifying the degree of disease by the percentage of COVID-19 lesions in the lung parenchyma is currently the most important application of AI in the evaluation of the COVID-19 patient, which can contribute to evaluating and monitoring the progression of the disease. In order to further analyze the clinical and radiological characteristics that lead to critical illness, it is necessary to develop artificial-intelligence-assisted models to estimate clinical prognosis. Shan et al.  used theAlthough numerous studies report the efficacy evaluation and prognosis prediction of COVID-19 based on imaging, there are relatively few studies on imaging risk factors for poor prognosis of COVID-19 ,34. ReseDL and AI systems can be used to monitor and quantify disease progression and understand the time evolution characteristics of COVID-19 lesions, reducing the subjectivity of radiologists in comparing chest CT images before and after treatment. They are also conducive to accurate treatment. Although there are currently many studies focusing on the evaluation of the radiology and clinical physiological outcomes of recovered COVID-19 patients ,36, therMany biological data have been accumulated with the spread of the COVID-19 epidemic and numerous infected patients generating epidemic contact history, clinical data, laboratory examinations, and imaging data. Researchers have constructed various multimodal DL and AI systems from different angles to fully mine the information contained therein, and then transform the data into reliable and referable information in the diagnosis and treatment of COVID-19 . Li et aDue to the lack of standard requirements for datasets, there are significant differences in the dataset sources used by different studies and the image scanning conditions of each medical center or database. Researchers studied the performance of various algorithms under different data sources. Shiri et al.  used ultThe most common use of deep learning and artificial intelligence based on medical images is for diagnosing and evaluating COVID-19 patients. In addition to using medical image data , DL and After the COVID-19 outbreak, data-driven DL and AI research made a breakthrough in the field of medical imaging. These studies all claimed that these algorithms could diagnose or predict COVID-19 based on CXR and CT images. Although some medical centers or medical imaging alliances have disclosed some COVID-19 dataset resources  Table 2Table 2, With increasing research on the application of AI systems in COVID-19, there are increasingly more studies using similar methods.Partial code access of COVID-19 DL and AI models based on radiology images were listed in The construction of a highly standardized database is essential to improve the accuracy and generalization of the model. In addition, the development of DL and AI algorithms greatly depend on the close communication between engineer, radiologist, and clinicians, and strengthened multidisciplinary communication and cross-complementation. The establishment of multilabel and/or hierarchical classification technology evaluation and benchmark solutions will greatly promote the prevention and control of infectious diseases.Since the outbreak of COVID-19, numerous researchers worldwide have extensively studied how to quickly and correctly diagnose COVID-19 and evaluate and control the condition. Machine learning and artificial intelligence with high reliability and huge potential in various applications were adopted by numerous healthcare providers. From multiple angles, this article introduced studies that explored DL and AI technologies based on medical imaging data so as to solve the troubles and challenges encountered in reality and directly point out the limitations of current studies. Overcoming these challenges may lead to significant progress in the use of artificial intelligence technology to combat COVID-19 and future epidemics."}
+{"text": "Caregivers with diverse backgrounds make up an important part of the landscape of caregiving in the US. Their unique experiences have been traditionally under-researched in the field of social sciences and underrecognized by society. To further understand the impact of race, ethnicity, class, gender and sexuality onto caregiving, the National Alliance for Caregiving (NAC) and the AARP Public Policy Institute commissioned an in-depth analysis of the dataset collected from the Caregiving in the US 2020 study, which segments populations based on ethnic and sexual identity, geographic location, and income level. Utilizing survey interviews with 1,392 caregivers in the US, this study found differences amongst the African-American, Latinx, and Asian American-Pacific Islander populations in relation to age, time spent caregiving, ADL/IADLs, caregiving strain and intensity, receipt of formal and informal support, and financial impact. In consideration of the distinct challenges presented by diverse caregiving throughout the lifespan, this presentation will also feature results from a 2020-2021 Diverse Elders Coalition and NAC commissioned study on the unmet caregiving needs in diverse communities. 11 virtual listening sessions were held with 400 caregivers of color, including American Indian/Alaska Native caregivers, and LGBTQ caregivers across the nation. Presentation attendees can expect to learn new insights into the experiences of diverse caregivers, while also gaining a fresh understanding of informal and formal support preferences with a multicultural lens. Finally, this presentation will provide recommendations to further prioritize the needs of historically marginalized caregivers in policy and practice."}
+{"text": "Noncommunicable diseases and injuries (NCDIs) are the leading causes of premature mortality globally. Ethiopia is experiencing a rapid increase in NCDI burden. The Ethiopia NCDI Commission aimed to determine the burden of NCDIs, prioritize health sector interventions for NCDIs and estimate the cost and available fiscal-space for NCDI interventions.We retrieved data on NCDI disease burden and concomitant risk factors from the Global Burden of Disease (GBD) Study, complemented by systematic review of published literature from Ethiopia. Cost-effective interventions were identified through a structured priority-setting process and costed using the One Health tool. We conducted fiscal-space analysis to identify an affordable package of NCDI services in Ethiopia.We find that there is a large and diverse NCDI disease burden and their risk factors such as hypertension and diabetes (these conditions are NCDIs themselves and could be risk factors to other NCDIs), including less common but more severe NCDIs such as rheumatic heart disease and cancers in women. Mental, neurological, chronic respiratory and surgical conditions also contribute to a substantial proportion of NCDI disease burden in Ethiopia. Among an initial list of 235 interventions, the commission recommended 90 top-priority NCDI interventions  for implementation. The additional annual cost for scaling up of these interventions was estimated at US$550m (about US$4.7 per capita).A targeted investment in cost-effective interventions could result in substantial reduction in premature mortality and may be within the projected fiscal space of Ethiopia. Innovative financing mechanisms, multi-sectoral governance, regional implementation, and an integrated service delivery approach mainly using primary health care are required to achieve these goals. Noncommunicable diseases (NCDs) are the leading cause of premature mortality in lower- and middle-income countries (LMICs), accounting for 60% of deaths . InjurieNoncommunicable diseases and injuries (NCDIs) have become a major public-health problem in Ethiopia, resulting in 44% of total annual mortality . EthiopiSDG 3.4 requires countries to commit to reducing premature mortality from NCDs by a third, through prevention and treatment .Despite commitment pledged by countries in the 2011 UN political declaration on the Prevention and Control of NCDs (UN high-level meeting), progress to combat NCDs has so far been slow, particularly in regards to populations living in extreme poverty ,11. To cNCDI disease burden: We retrieved data on NCDI disease burden and the concomitant risk factors from the Global Burden of Disease (GBD) Study, complemented by a systematic review of published literature from Ethiopia. We searched the following databases using a mix of search terms: Global Burden of Disease/IHME, PubMed, Cochrane, HINARI, Google Scholar, EMBASE, The World Bank, WHO Regional Databases and local journals, including grey literature. We included articles published from 1990 to December 2017 that had clear objectives and methodologies and addressed the major NCDIs and their risk factors. We summarised the evidence for each NCD, injury and risk factor. Where several prevalence studies of similar populations were found, we used a weighted average. In this review, community- and institution-based studies and some hospital-based studies were used to show population prevalence, whilst mortality studies and hospitalisation studies were used to indicate disease severity and outcomes.Priority setting process: Following identification of the major NCDIs in Ethiopia, interventions were selected and prioritised in a four-step process. Firstly, priority-relevant evidence from national and international studies was collected, critically reviewed, and supplemented with expert judgements. Secondly, this evidence, along with the WHO principles, was used to prioritise interventions, ranking them in three categories  , not targeting the worse off in health and low FRP.entions) . The WHOentions) . Thirdlyentions) . Fourth,Estimation of costs and fiscal space: Cost by intervention was estimated using OneHealth Tool version 4.5 using the software's default data on cost of drugs and supplies and the default population model for Ethiopia  Study, complemented by a systematic review of published literature from Ethiopia. The GBD data showed that in 2017 44.4% of total mortality in Ethiopia was due to NCDIs  .Our review of studies of common NCDs and their risk factors in Ethiopia revealed a large and diverse burden that varies according to socioeconomic factors  and 2. TThe burden of common NCDIs such as hypertension  and diabetes (3.2%\u20138% of the adult population) was high, as was the burden of less common but more severe NCDIs such as rheumatic heart disease  and cancers in women ,43\u201363. HCancer, especially breast and cervical cancer, is a staggering public-health problem in Ethiopia. There were an estimated 65,000 cancer cases in Ethiopia in 2015, based on projections from the population-based cancer registry in Addis Ababa, and it was estimated that two-thirds of the cancers occurred in women . These fMental, neurological and substance-use disorders in Ethiopia account for 25.6% of all years lived with disability (YLD) in 2017, affecting nearly 30% of the Ethiopian population at any given time \u201371. In aFurthermore, injuries \u2014 particularly road traffic accidents, falls and interpersonal violence - accounted for 8% of total DALYs lost in Ethiopia in 2017 \u201375. The Economic impact of NCDIs: For individuals and their households, NCDs can have devastating long-term economic consequences. A systematic review of the economic effect of NCDs on households in LMICs showed that NCDs placed a substantial economic burden on patients and their families in all socioeconomic strata, particularly in the poorest sector of the population. Direct medical expenses for drugs, diagnostics, outpatient visits and hospitalisation were the major components of out-of-pocket (OOP) costs (P) costs . The cosP) costs . A lack P) costs .There is a shortage of resources for health care in Ethiopia, with a per capita expenditure of US$33 in 2016/2017 . ReliancPriority setting for essential interventions for NCDIs: A task faced by many LMICs is identification of high-priority interventions for NCDIs and fair prioritisation of introduction or scale-up of these interventions. The gap between health requirements for NCDIs and economically feasible provision is a substantial challenge for LMICs, and likewise for Ethiopia. Health care for chronic diseases has largely been neglected, in comparison with interventions that prevent, diagnose and treat malnutrition, infection and maternal and childhood diseases.After establishing the major NCDI conditions in Ethiopia, the Commission identified an initial list of 235 potential health-sector interventions for implementation or scaleup in the Ethiopia health system. The commission used the WHO Consultative group on Equity and Universal Health recommendations to prioritize NCDI interventions: cost-effectiveness, fair distribution (priority to the worse-off) and FRP . EvidencAdditionally, multi-sectoral interventions designed to reduce population-level behavioural and environmental risk factors  are available in the commission's report . Many ofEstimated health impact of NCDI interventions: The Commission made a conservative estimate that, if fully implemented, the Highest Priority Package for NCDI services  could raise life expectancy at birth from 64.4 to 65.2 (i.e. by 0.8 years), and avert approximately 41,000 premature deaths by 2030 , the Commission estimated that by the end of the first five-year period (2023), there will be US$2.40 extra per capita for NCDI services from the government budget. However, in a best-case scenario of GDP growth of 7%, total government health expenditures of 6% of the GDP and NCDI expenditure 30% of the total health expenditure, there would be an extra US$4.50 for the toppriority package of NCDI services. The potential fiscal space per capita in this best-case scenario approximates the estimated per capita cost of US$4.70 (needed in the year 2023) for the recommended top-priority NCDI services. The three variants for possible targets and budget expansion paths for total (THE) and government health expenditures (GHE) that would be compatible with a commitment to move towards UHC are illustrated in Recommendations from the Ethiopia NCDI commission: Ethiopia is facing a substantial burden from NCDIs such as ischaemic heart disease, stroke, diabetes, major depressive disorders, cancer and chronic respiratory diseases, the incidence of which is increasing at an alarming rate  system in Ethiopia is mainly organised around acute care delivery. In recent years the concept of chronic care has been introduced in PHC facilities through HIV service delivery, from which several implementation lessons could be learned for the delivery of NCDI services. These lessons include implementing decentralised care in the PHC, a multidisciplinary approach to care through task-shifting and task-sharing, simplification of protocols and guidelines, use of standardised essential drugs and diagnostic packages, laboratory networking, harmonised recording and reporting systems and facilitated referral mechanisms. The main strategies for prevention, treatment and care of HIV/AIDS are early detection and monitoring of risk factors, population-based interventions, a care continuum, regular monitoring of treatment adherence and psychosocial interventions. These are well-established strategies for chronic care, which could inform NCDI services. Investment in a health-system approach to NCDIs should be the way forward, as fragmented, disease-based approaches will not enable the country to respond to these emerging health problems. Substantial constraints are anticipated across each of the six key health-system components during NCDI services integration and scale-up in Ethiopia. Governance and technical support for NCDIs should be devolved and capacitated at the regional level in order to ensure appropriate decision-making and implementation of NCDI initiatives. Furthermore, the wide-ranging risk factors and the impact of NCDIs on Ethiopian society, as well as the fact that prevention and control of NCDIs require the involvement and commitment of the government and all stakeholders, including the community, call for the establishment of a national multisectoral committee on NCDIs chaired by the Prime Minister or Deputy Prime Minister, in order to guide and organise NCDI efforts. The Ministry of Health has a critical leadership role in spearheading the government's commitment. A summary of the Commission's recommendations is presented in Box 1.Box 1: Key recommendations by the National NCDI commission.Policy, planning and oversight Establish a national multisectoral committee on NCDIs, chaired by the Prime Minister or Deputy Prime Minister, to guide and organise NCDI effortsStrengthen the NCD Prevention and Control Unit at federal levelEstablish NCD Prevention and Control Units at regional levelProtect the implementation of public-health policies for NCDI prevention and control against interference by vested interests through comprehensive legislation and enforcement of national laws and regulations.FinanceAllocate an increased percentage of gains from economic growth to health; rapidly move government spending on health towards 5% of GDPMobilise additional resources, including improved efficiency, improved taxation and sin taxes , and specifically consider tax on sugar-sweetened beveragesMove towards allocating 30% of total government spending (GHE) to NCDIs by 2030Plan for reduced external funding (at least in relative terms), as the country develops economically and transitions to the status of lower-middle-income countryReduce out-of-pocket to a maximum of 20% of total health expenditureHarmonise community-based health insurance, and if possible social health insurance, with public health-sector prioritiesDevelopment of partners for engagement in generating evidence and supporting implementation of costeffective and equitable interventions for NCDs and injuries, based on national needs, in order to maximise the effectiveness of aidService integrationStrengthen the health system at all levels, emphasising primary care, and finance the national set of NCDI services, interventions and health promotion, focusing on prevention and early detection, as well as curative, rehabilitative and palliative careLow-resource countries such as Ethiopia can prevent and manage NCDs and injuries by integrating a high-priority package of interventions into existing platforms; the package's interventions should be cost-effective, target the worse-off and provide financial risk protectionImplement scale-up of health personnel as planned in HSTP, with a special emphasis on the resources needed for NCDI servicesImprove the training of health workforces and the scientific basis for decision-making through NCD-related research and partnershipsDevelop, train and implement the top eleven clinical guidelines for NCD and injury services Strategic information, target-setting, monitoring and evaluationStrengthen integrated national surveillance systems for NCDIs, including vital registration systems capable of reporting cause of death, cancer registers and risk-factor monitoringRefine existing NCDI indicators and expand to include other priority NCDIs in future revisions of HIS in order to monitor the epidemiology and service coverage of NCDIsTrack results of NCDI interventions by monitoring and reporting on the attainment of the 9 national targets .Mobilise and track domestic and external resources for NCDI prevention and control. Improve NCDI subaccounts in next round of National Health Accounts report.Education and advocacy: Achieving global as well as local commitment and action against NCDIs requires sustained advocacy. Alongside actions directed at changing social, environmental and economic conditions that impact health, mobilising the public and educating them on a healthy lifestyle will substantially contribute to the prevention of NCDIs. Advocate for improved NCDI resources and services.There is shortage of well-trained health professionals in Ethiopia, where there are only 0.96 per 1000 population, which is far less than the 4.45\u2030 recommended in order to meet the SDG health targets. Besides the shortage of human resources, inadequate knowledge and skill in NCDI case management are among the expected challenges for the health workforce during decentralisation of NCDI services. The shortage will be more pronounced in terms of staff attrition, with trained staff with their NCDI skills leaving institutions, leading to compromised case management and inconsistent completion of client-NCD risk-assessment forms, which may exacerbate the long-term monitoring of NCD risk factors. Even though the general provision of health-care professionals relative to the population is low, recent studies suggests that there is much to be gained by improving the efficiency of health facilities in Ethiopia ,90. A stGeneration of sufficient resources is critical to the delivery of health-care services. The fiscal-space analysis conducted by the Commission demonstrates that with more commitment from the government, attainment of 30% coverage of high-priority interventions is possible in the best-case scenario. In addition to economic growth, there are other ways of increasing fiscal space for government health expenditure to 5\u20136% of GDP. They include increased mobilisation of domestic resources, intersectoral reallocation and efficiency gains. As for increased mobilisation of domestic resources, particularly important options to be considered are improved taxation and other forms of revenue collection, including increased taxation of tobacco and alcohol . Such anThe NCDI burden in Ethiopia is increasing and is expected to grow at an alarming rate in the next couple of decades. A targeted investment in cost-effective interventions could result in substantial reduction in premature mortality and may be within the projected fiscal space of Ethiopia. Innovative financing mechanisms, multi-sectoral governance, regional implementation, and an integrated service delivery approach mainly using primary health care are required to achieve these goals."}
+{"text": "Saccharum officinarum, Saccharum spontaneum, and other wild relatives. Sugarcane breeding programmes are broadly categorized into germplasm collection and characterization, pre-breeding and genetic base-broadening, and varietal development programmes. The varietal identification through the classic breeding programme requires a minimum of 12\u201314 years. The precise phenotyping in sugarcane is extremely tedious due to the high propensity of lodging and suckering owing to the influence of environmental factors and crop management practices. This kind of phenotyping requires data from both plant crop and ratoon experiments conducted over locations and seasons. In this review, we explored the feasibility of genomic selection schemes for various breeding programmes in sugarcane. The genetic diversity analysis using genome-wide markers helps in the formation of core set germplasm representing the total genomic diversity present in the Saccharum gene bank. The genome-wide association studies and genomic prediction in the Saccharum gene bank are helpful to identify the complete genomic resources for cane yield, commercial cane sugar, tolerances to biotic and abiotic stresses, and other agronomic traits. The implementation of genomic selection in pre-breeding, genetic base-broadening programmes assist in precise introgression of specific genes and recurrent selection schemes enhance the higher frequency of favorable alleles in the population with a considerable reduction in breeding cycles and population size. The integration of environmental covariates and genomic prediction in multi-environment trials assists in the prediction of varietal performance for different agro-climatic zones. This review also directed its focus on enhancing the genetic gain over time, cost, and resource allocation at various stages of breeding programmes.Sugarcane is a C4 and agro-industry-based crop with a high potential for biomass production. It serves as raw material for the production of sugar, ethanol, and electricity. Modern sugarcane varieties are derived from the interspecific and intergeneric hybridization between  The genetic architecture was incorporated into the kinship matrix by assigning the suitable weight to the markers identified through genome-wide association studies (GWAS) and additionally improved by removing the duplicate trait-specific markers associated with the same , Canal Point, Florida, and the Indian Council of Agriculture Research (ICAR)-Sugarcane Breeding Institute, Coimbatore, India. About 1,002 accessions and 3,345 accessions of Saccharum species clones were used in the development of breeding lines in sugarcane  genome-wide association studies in germplasm and identification of elite accessions with more number of desirable genes/trait-specific accessions; (ii) hybridization between elite accessions with noble S. officinarum clones or commercial sugarcane varieties; (iii) identification of true interspecific hybrids through genomic/cytoplasmic/5S rRNA/Inter Transcriber Spacer specific markers; (iv) optimization of the training and testing populations at each generation or back cross programmes which generally requires 3\u20134 generations of backcrossing/crossing with commercial sugarcane varieties; (v) genomic prediction model building and retraining of the genomic prediction models to optimize and predict the genotype with the highest Genomic Estimated Breeding Value (GEBV) for utilization in the next generation of backcrossing or crossing. The genomic prediction model could also be able to help in the swift development of genetic stocks in pre-breeding and genetic base-broadening in sugarcane.Pre-breeding, a bridge between crop improvement and plant genetic resources, provides an opportunity for introgression of desirable genes with minimal linkage drag and enhances the adaptability of the cultivars , site regression model (SREG), shifted multiplicative model (SHMM), genotype regression model (GREG), and completely multiplicative model (COMM), are used for partitioning of the G \u00d7 E interactions into more than one factor  interactions. The repeatable G \u00d7 E factors in multi-environment trials are estimated through single dimension based statistical models such as ANOVA and regression approaches. The ANOVA based statistical model partitioning the G \u00d7 E interactions into the main effect of genotypes, environments and their interactions as fixed effects/variables and residuals/error components as random variables  sandy soils have high discriminative powers in differentiating the environments and genotypes  size, composition and design of training and validation populations, (ii) plot size for breeding experiments varies with stages of breeding programmes, such as parental selection, early and advanced testing, and (iii) the number of replications within and across the environments (Lorenz and Nice, The genomic selection in the early stages of segregating the population is a trade-off between the cost of genomic selection and trait heritability and family size. The phenotypic selection in a large segregating population with highly heritable traits is highly efficient, whereas low heritable traits, such as yield in a large segregating population, require the molecular markers to assist in the selection of desirable plant types. Further, yield measured on the single plant basis in segregating population is inaccurate in most of the crops (Heslot et al., The recurrent selection procedure is effective in augmenting the frequency of favorable alleles in the breeding population. The marker- or genomic-assisted selection helps to reduce the number of breeding cycles and the number of individuals evaluated in each selection cycle. The marker-assisted recurrent selection scheme aims at gene pyramiding after identifying the QTL (Servin et al., The multi-environment trials are the final phase of cultivar identification and need robust statistical analysis with optimum resource allocation. The resource allocation depends on the number of replications, locations, number of test entries, etc. An adequate number of replications are required for each location to control the microenvironment variations and experimental design such as Alpha design, which is very efficient in accounting for the micro-environment variation (Gonz\u00e1lez-Barrios et al., The unbalanced design or sparse testing refers to the multi-environment trials where all the genotypes are not tested in all environments and sparse testing saves the resources. Unbalanced sparse testing with an appropriate genomic prediction model enhances the prediction accuracies and saves the resources (Endelman et al., Saccharum germplasm with genome-wide markers captures the total genomic diversity of gene bank and assists in the formation of core germplasm and genomic prediction to identify the genes associated with cane yield, CCS, and tolerances to biotic and abiotic stresses. The genomic selection in pre-breeding and genetic base-broadening programmes helps in the precise introgression of genes into the parental clones and genomic-assisted recurrent selection is useful in augmenting the favorable alleles in the population. The genomic prediction for characterization of parental clones for their general and specific combining ability leverage the breeders in selecting the elite parents and progenies combined with favorable alleles for cane yield, CCS, and tolerances to biotic and abiotic stresses. The integration of environmental covariates into genomic models predicts the better performing varieties for target environments and deployment of varieties. Genomic selection is an evolving science; appropriate genomic models and breeding strategies strengthen the prediction accuracies and enhance the genetic gain in sugarcane.Sugarcane is a C4 crop with a great potential for high biomass production and a major source of raw material for sugar production and bioenergy. Its crop improvement has many bottlenecks such as the long cycle of breeding duration, complex polyploidy, high degree of heterozygosity, narrow genetic base, and fewer basic germplasm utilized in pre-breeding and linkage drag during wide hybridization and limited financial and manpower resources. The genomic selection schemes are highly helpful in reducing the duration of breeding cycles, population size, and selection of desirable parents and development of varieties. The characterization of CM conceptualized, wrote, and reviewed the draft. KA wrote, revised, provided inputs on molecular markers, SNPs, genomic selections, and resource allocations. CA, GS, PV, HM, RV, GH, GA, and BR provided inputs on molecular markers, genomic schemes, and resources allocations. All authors read and approved the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Insects are crucial for ecosystem functions and services and directly influence human well-being and health. Insects are among the most diverse classes of the animal kingdom, and therefore it is not surprising that they contain an immense degree of virus diversity, which remains largely unexplored. Until recently, investigations of insect virus diversity were focused on insect species of economic, veterinary, or medical importance. The deployment of high-throughput sequencing technologies has allowed for studies of virus diversity in a wider range of insect species and has led to an explosion in the discovery of new viral sequences in insect hosts, both from known virus groups and from entirely novel families. These studies have, in turn, inspired a re-assessment of the evolutionary relationships among, and taxonomic classification of, insect viruses. It is now clear that further studies of the biological effects of viruses on their insect hosts are required to understand the impact of diverse insect viromes on their host\u2019s physiology, reproduction, and the potential of host insects to be viral vectors.Acheta domesticus) [Neohydatothrips variabilis) [Scathophaga furcata) [Aedes aegypti) from the Amazon basin [Apis mellifera) [Andrena spp.) [Varroa destructor mites, which are closely associated with both Western and Eastern honey bees  [Diabrotica undecimpunctata and D. virgifera) [Matsumuraeses phaseoli, an important legume pest, were also presented [The aim of this Special Issue was to invite research articles focusing on recent advances in virus discovery and the elucidation of virus diversity in insect hosts. The published papers illustrated the effectiveness of high-throughput sequencing approaches for the comprehensive analysis of virus communities, identification of novel virus variants, and discovery of novel viruses. This includes the discovery of previously unknown RNA viruses in house crickets (esticus) , soybeaniabilis) , termiteiabilis) , dung flfurcata) , mosquiton basin , hematopon basin , honey bllifera) ,8,9 and na spp.) , and evectively) . Reportsrgifera)  and a beresented .V. destructor and honey bees (A. mellifera) [Sequence data on the novel viruses identified in high-throughput sequencing studies could be a starting point for further analysis of virus\u2013host interactions. Notably, some of the published papers already present such analyses, including the investigation of viral inter-species transmission between wild and managed honey bees  and betwllifera) , and anallifera) ."}
+{"text": "Emerging Topics in Life Sciences entitled \u2018Current Topics in Stem Cells and Regenerative Medicine\u2019 brings together expertise from a collaborative organisation known as the Mercia Stem Cell Alliance (MSCA). The alliance was established initially by Professors Sue Kimber (University of Manchester) and Jon Frampton (University of Birmingham) just over 10 years ago and now has multiple regional centres of excellence across the Midlands and North West of the UK, including Aston University, University of Chester, Keele University, Manchester Metropolitan University, Lancaster University, University of Leicester, University of Liverpool, Liverpool John Moore's University, Loughborough University, University of Nottingham, University of Oxford, University of Sheffield, University of York. Many of these centres have contributed reviews to this issue. The MSCA also partners with industrial and clinical organisations, including the NHS, and is active in bringing stem cells and regenerative medicines to a meaningful translational endpoint (see: http://www.msca.manchester.ac.uk/).This special issue of  The concept of using cell spray technologies to deliver stem cells to the CNS in the treatment of neurological trauma and pathology, e.g. following spinal cord injury, has been described and discussed by Chari and co-workers (Keele University) [The reviews published in the special issue cover key areas in stem cell biology and regenerative medicine, from aspects of basic stem cell research through to the use of stem cells and tissue engineering to model human pathophysiology and for drug development through to clinical applications of adult stem cells and other regenerative medicines. Dogan and Forsyth (Keele University) have reported how epigenetic mechanisms influence telomerase activity, which plays an essential, although not fully understood role in regulating pluripotent stem cell proliferation, differentiation, tissue repair and cancer . Walczakversity)  (Universversity) . The neeversity)  (Universversity) . Finallyversity)  (RJAH OrEmerging Topics in Life Sciences and Portland Press for inviting the reviews, which have been written in such a manner that they are broad in outlook, whilst deep in content. One of the main objectives of the MSCA is to help basic researchers and translational scientists learn and work together, both to increase our fundamental understanding of the molecular and cell biology that underpins this exciting field and also to successfully develop new stem cell therapies. Hence, it is hoped that the special issue will provide a useful resource to many current and next generation investigators as they progress in their careers in stem cell research.We are grateful to"}
+{"text": "Dear EditorA 27-year-old female patient presented with a six-month history of a persistent and painful nodule on the chin. She referred occasional purulent exudate. There was no history of fever or systemic symptoms. Several courses of oral antibiotics had been ineffective. In the extraoral examination she presented an erythematous nodule with an important surrounding retraction . UltrasoOCF is the result of an abnormal canalization originating from chronic periapical infection. Usually, bacterial infection from the dental pulp drains into the oral cavity. However, when the inflammatory process is severe and long-standing, it may destroy the alveolar bone, spread to the surrounding soft tissue, and eventually drain to the skin.The diagnosis of OCF is usually made based on panoramic radiograph and computed tomography that show the damage of the alveolar process. However, these tests require considerable time and money to perform and may have side effects. Skin ultrasonography is a noninvasive and emerging technique with proven usefulness in localized lesions.Skin ultrasound is a safe and accessible tool for the diagnosis of OCF. The characteristic image of a hypoechoic sinus tract enhanced by color Doppler enables its diagnosis. Hence, neoplastic lesions are rapidly discarded, and many inappropriate treatments are avoided.None declared.Arcadi Altemir-Vidal: Approval of the final version of the manuscript; study conception and planning; preparation and writing of the manuscript; data collection, analysis, and interpretation; effective participation in research orientation; intellectual participation in propaedeutic and/or therapeutic conduct of studied cases; critical review of the literature; critical review of the manuscript.Maribel Iglesias-Sancho: Approval of the final version of the manuscript; study conception and planning; preparation and writing of the manuscript; data collection, analysis, and interpretation; effective participation in research orientation; intellectual participation in propaedeutic and/or therapeutic conduct of studied cases; critical review of the literature; critical review of the manuscript.Monica Quintana-Codina: Approval of the final version of the manuscript; study conception and planning; preparation and writing of the manuscript; data collection, analysis, and interpretation; effective participation in research orientation; intellectual participation in propaedeutic and/or therapeutic conduct of studied cases; critical review of the literature; critical review of the manuscript.None declared."}
+{"text": "The AGEC Accreditation Handbook and Self-Evaluation Guide has been revised several times since the first drafts were produced in 2016 and 2017. The Handbook contains information for accreditation applicants, AGEC reviewers, and members of the Board of Governors responsible for administering AGEC policies and procedures. It includes the accreditation standards, eligibility for accreditation, timelines, and self-study and site visit guidelines. It is the central document for the AGEC accreditation process. Handbook revisions, drawn from the experience of accrediting programs, have been for the purposes of clarifying expectations and simplifying the application process. This presentation highlights modifications included in the 2020 Handbook, which simplify the self-study outline and site visit guidelines, and the 2021 modifications, which clarify the \u201cMapping Course Matrix\u201d (displaying AGHE competencies covered in program courses) and add an \u201cAssessment Matrix\u201d for measuring acquisition of the competencies and improving the program as needed."}
+{"text": "Chemotherapy-Induced Peripheral Neuropathy (CIPN) is a common dose-limiting side-effect of taxane-based chemotherapy, causing progressive and often irreversible pain/sensitivity in the hands and feet. Prevention/treatments for CIPN are not well-developed and urgently needed. Limb cryocompression during chemotherapy has demonstrated promising early data of preventing/reducing CIPN severity. Currently there are no medical devices available that are dedicated to the specific requirements of CIPN prevention. As part of our ongoing development of a dedicated CIPN-prevention limb cryocompression system, this study documents the design & development of the wearable arm wrap, a central component of the system, from initial concept to a trial-ready prototype. A collaborative and multidisciplinary approach was adopted to address the complex and high-risk nature of this SME -centered medical device design & development process. The complementary collaboration unites multidisciplinary expertise spanning the scope of the project. Alongside the clinical, academic, and design & development expertise, the integration of commercial expertise is imperative to promote the market viability, and ultimate success, of the development. As the global leading experts in scalp cooling specializing in the prevention of chemotherapy-induced alopecia, UK-based SME Paxman Coolers Ltd is optimally positioned to support the commercial and regulatory dimensions. Development and adoption of a novel mixed-methodology (HudPAX) facilitated the integration of evidence-based and user-centered techniques to optimize the design & development approach and ensure integration of all critical design inputs. Alpha prototypes were designed through evidence-based approaches, with data from existing clinical trials utilized to determine the preliminary design inputs, alongside 3D ergonomic data. Investigations utilized computer-aided design, rapid prototyping, additive manufacturing, sketch modeling, and fast ideation. User-based approaches facilitated stakeholder-feedback through expert focus groups, informing further design & development and projecting the design into the next stage, Beta prototyping, for use in large-scale efficacy trials and upscaling manufacturing. This paper demonstrates a novel mixed-methods approach, which promotes cross-sector multidisciplinary collaboration, to address the complex multi-layered challenges posed by an early-stage medical device design & development process. Chemotherapy-induced peripheral neuropathy (CIPN) is a common debilitating and dose-limiting non-hematological toxicity of taxane-based chemotherapy. Symptoms of CIPN include paresthesias, dysesthesia and pain in the hands and feet, which can be persistent and irreversible even several years after completion of chemotherapy \u20133. A metAt present, dose modification of the chemotherapy itself remains the most successful approach for the management of CIPN, and symptomatic pharmacological treatment is limited to pain killers. Prevention/treatment for CIPN are not well-developed and urgently needed. Several potential neuroprotective agents have been tested in clinical trials but none have proven effective . RecentlInspired by scalp cooling for preventing chemotherapy-induced alopecia (CIA) , limb crLimb cryocompression during chemotherapy, has demonstrated potential for decreasing the incidence of CIPN \u201319. CryoDue to the emerging scientific and efficacy evidence, there is an imminent demand for a limb cryocompression device, designed specifically for use during chemotherapy infusion for the prevention of CIPN, and this is currently in development. The pilot studies by Bandla et al. facilitated data gathering of user requirements and design inputs for development of a CIPN-specific cryocompression device to facilitate enhanced treatment efficacy . The devIt is acknowledged that the design and development of medical devices is a complex, multilayered and high-risk process, with pitfalls including stringent regulation and commercial challenges. Between 80\u201390% of new product launches fail and the complex challenges specific to medical device development are likely to increase the failure rate further . Small MSelection of the optimal design methodology ensures progress through the complex, collaborative and stringent process of medical device design and development. An optimized methodology promotes collaboration across different disciplines and perspectives, and ensures that user needs are comprehensively identified through means suited to the context of the product being designed. An extensive range of design and development methodologies exist that companies can adopt during product development processes, however there is no standard method, and guidance is lacking on the selection and application of the appropriate methodologies for medical device design and development . Due to This study documents the design & development of an arm cryocompression wrap from a concept to a trial-ready prototype using the HudPAX approach. Prototype development is essential to managing individual expectations within a project, aiding tangible feedback and justifying the cost and time invested in their development. This study explores the Alpha prototyping stage. The Alpha prototype is the initial attempt at designing and fabricating the product to meet the Product Requirements Specification; the Beta prototype development follows on from this and incorporates the design refinements found in Alpha development and implements them into production. This study generated an Alpha prototype of CIPN-prevention cryocompression arm wraps as a medical device in the feasibility, pre-clinical stage, addressing the complex challenges posed, through a mixed-methods approach.- The Double Diamond process, by the Design Council: a strategic and incremental process encompassing four stages; Discovery, Define, Develop and Deliver ;- Reflective Practice, by Donald Schon: Promoting the reflection on our actions in design so as to engage in a process of continuous learning ;- Design Science: an evidence/outcome-based methodology used to bridge the practice\u2013academia divide by developing actionable knowledge that is grounded in evidence ;- Design Thinking: This user-based approach is a procedure for investigating potential product-users wants and needs, that culminates in a design brief identifying an opportunity for developing a new product .The research method designed and applied in this study supports the delicate balance within the project, between the distinct needs of medical device design, commercial feasibility and the stringent regulatory control. In addition, it ensures a comprehensive range of design inputs (user requirements) are successfully gathered and addressed through design outputs. This approach, named HudPAX , integraIntegration of the design principles of the Double Diamond process with Design Science (evidence-based approach) and Design Thinking (user-centered approach), through the mixed-methods HudPAX approach, promoted the establishment of an iterative design process which successfully led to the selection of an initial concept for pre-clinical prototyping.The HudPAX method was developed in-line with the scope of medical regulatory standards, to ensure resulting medical devices are fully compliant with international regulations and to ease the eventual regulatory approval processes. ISO 13485:2016 is the Regulatory Quality management system for medical devices, and the incremental milestones defined by ISO 13485:2016 act as a core element within the HudPAX process, to which all other methods tether.This study concentrates primarily on the feasibility stage, Phase 1 (Discover) and Phase 2 (Define) . There iThe HudPAX research method is designed specifically to address the challenges associated with a collaborative, SME-centered, cross-sector medical design and development project, providing an optimized approach for academic and industrial collaboration. Tools including regular reviews, reports and quarterly board meetings help assess progress and ensure that the needs of all stakeholders are continually addressed.Design inputs and initial user requirements were gathered from previous pilot clinical studies, conducted by the Singapore team, to investigate the safety and feasibility of cryotherapy devices in preventing CIPN. These proof-of-concept studies investigated two cryotherapy modalities using existing class-I cooling devices designed for generic injury and therapeutic purposes. The cryotherapy modalities tested were continuous-flow cooling , and cryocompression . Pilot studies involved healthy volunteers first, to investigate safety, tolerability and optimal parameters, and subsequently studied in cancer patients undergoing chemotherapy for efficacy in preventing CIPN \u201319. ThesDesign inputs were gathered from various stakeholders including the healthy volunteers and patients who participated in the study and, nurses and bioengineers who administered the cryotherapy. Design inputs gathered through the Design Science/evidence-based approach included scientific and clinical data which set the parameters for prototyping. Observations were made on the safety (discomfort or cold burns), temperature tolerability (intolerance to cooling and compression), therapeutic efficacy  and comfort (fit and ease of use over extended duration of usage). These observations were made for both intra-cycle  and over multiple cycles of chemotherapy.Global medical device regulations are very similar and invoke a patient-protective, risk-based system where each device is classified into 1 of 4 categories. The higher the perceived risk, the more stringently the regulations are applied up to the highest risk where a full design dossier review is required.With the exception of the Regulatory Quality management system (ISO 13485:2016), which forms the core of the HudPAX method, integration of regulatory standards is strategically limited during early-stage feasibility investigations of medical product design, in order to permit the full exploration of ideas to ensure the eventual selection of the optimal design. In accordance with the management system, regulatory standards should be fully addressed and applied in the later development stages  where IEC 60601-1 was assessed for general requirements for basic safety and essential performance;- IEC 14971 was assessed for applications of risk management to medical devices;- IEC 62366 was assessed for applications of usability engineering to medical devices.Safety and usability testing is considered in all aspects including, but not limited to:While integration of regulatory standards is not required at this feasibility stage of the investigation, awareness of relevant impending regulations is important to ensure a smooth transition to the next development stage and to optimally position the development for eventual regulatory compliance. Regulatory standards which have been considered during this feasibility study include:This study documents the design & development of an arm cryocompression wrap from a concept to a trial-ready prototype. The mixed-methods HudPAX approach promoted the strategic implementation of multiple complementary research methods, through the process of input gathering, ideation and prototyping and designing for manufacture, ultimately producing an Alpha prototype and facilitating a user-centered focus group study.Design inputs were generated based on clinical evidence, which was gathered from over 400 cycles of cryotherapy using the two modalities: continuous-flow cooling, and cryocompression \u201319. ThesThe HudPAX method integrates a well-established commercial product design & development framework, the Double Diamond design process, an incremental ideation approach to explore the full range of potential concepts. With the evidence-based design inputs as a foundation, Phase 1 (Discover - Research) and Phase 2 (Define - Ideate) were explored , primariAn initial design concept was selected by the team, where ergonomic aspects were explored. The ergonomic foundation of this design was adjustability which allows the wraps to fit a wide variety of users' arm types/sizes, tightening it to different contours, and loosening if patients experience discomfort or sensitivity to the cold, in addition it provides easy removal for toilet breaks or in emergencies. The arm wrap will cover a large portion of the arm, hence many variables were to be addressed including: finger, palm and wrist size, forearm girth and arm length. Design mechanisms were used to allow for the required levels of adjustability including Velcro\u00ae and flaps for extending or reducing individual zones of the arm wrap. This development phase also involved the analysis of: suitable materials, exploration of potential manufacturing methods, testing, technical requirements (including flow rates and cooling efficiency), safety, regulatory standards, comfort, and aesthetics.The ergonomic design concept was implemented in the initial designs , 5 whereApart from evidence-based ergonomic inputs, the initial designs also included considerations of the optimal therapeutic parameters (best tolerable temperature and pressure ranges), based on pilot clinical trial efficacy data \u201319. FeatBased on the knowledge, from our pilot studies, that the forearm is able to tolerate lower temperatures than the fingertips, a feature of thermoregulating different zones was investigated through a concept which utilized three separate cooling bladders per arm .Further exploration led to a concept with a single bladder which utilized a bottleneck design to reduce flow and adjust temperature incrementally from low, medium and high , through zones based on our clinical data on temperature tolerability . This siThe initial concept was then selected for pre-clinical investigation . PrototyThe prototypes were created for a focus group testing with users and stakeholders , 9.The developed Alpha prototypes were presented to a stakeholder focus group to gather user-centered and ergonomic based feedback. The user-centered focus group study was conducted at the Clinical Research Facility, Leeds teaching hospital, Leeds, UK and involved healthcare professionals and patient and public involvement (PPI) groups. Engagement of PPI groups ensures that patients, public and caregivers are actively involved early on in the medical device design process and their insights and perspectives are taken into account. This user perspective also aims to mitigate any possible oversights at an early stage in the medical device development process.The focus group, consisting of 12 healthcare professionals and PPI group members, acknowledged the unmet clinical need and appreciated the concept of a wearable device to prevent CIPN. Participants were informed on the usability aspects of the wrap design including compression and cooling aspects, correct fit, intravenous cannula monitoring, ease of removal, optional pressure on the cannulated arm and instructions for use. Participants were encouraged to try on the prototype wraps alongside examples of existing non-CIPN specific cooling devices. The following user-centered development aspects were explored:The focus group appreciated the idea of an intravenous cannula site window providing visual access to the healthcare professionals to monitor any extravasation or adverse reactions that might occur during the chemotherapy infusion. At the same time, this allows for the cannulated arm to receive the benefit of cryotherapy. The placement and size of the intravenous cannula site window in the Alpha prototype was suggested to be modified to fit cannulation practices in the UK, as the earlier placement was catered to practice in Singapore, based on the pilot clinical trial evidence. This highlighted a key user-centered design aspect to be taken into consideration. Using these key inputs, we applied the data from the focus group to develop a concept prototype including multiple adjustable flaps throughout the wrap, as shown in The focus group suggested incorporation of a design feature for the intravenous feed to fit through the wrap without dislodging the cannula. This would allow for the healthcare professionals to remove the wrap without removing the cannula to facilitate toilet breaks.The focus group considered the reusability of wraps and a suitable biocompatible material which would allow for disinfection and reuse over different chemotherapy cycles and in different patients.The Velcro\u00ae flaps were reported to be simple, easy and convenient to use, especially for quick wrap and unwrap during toilet breaks. The focus group was comfortable with the fit of the prototype wraps which catered to various sizes of arms and ease of adjustability. They also indicated that there was sufficient \u201cbreathing\u201d space around the palm area to allow fingers movement during the extended period of application. A concern was that the wrap may be too long for smaller sizes of arms. The group also considered the weight of the device exerted on the patient's limbs as a factor of comfort through the entire duration of cryotherapy.The next stages of prototype development will involve the production of functional or proof-of-concept prototypes which allow the retention and flow of liquids and air pressure, thus allowing the evaluation of fluid dynamics, temperature control, pressure and temperature tolerability. The feedback gathered in this study was adopted as design inputs into the design development process. This further led to the developed Following on from this feasibility study, in phase 2 and phase 3 of the methodology, the design for manufacture becomes a more dominant consideration. In phase 2, we collaborate with several manufacturing companies with different specialist areas to make Alpha prototypes and low-volume prototyping for validation testing and clinical trials. Considerations include the materials, methods and the costs associated with one-off or low-volume manufacture. The later stages will increase the focus on the design for manufacture, specifically regarding tooling, where rapid tooling and hard tooling will be considered depending on volumes, quality and constraints for both the external limb-wrap and the internal coolant-containing-bladder. Due to the many parallels between this device and Paxman's established scalp cooling device, the existing industry expertise and infrastructure for prototyping, supply and material usage  provides a readily-available framework which can be adopted and modified to the unique requirements of this project.For the manufacture of the internal bladder for the functional prototype, Radio-Frequency (RF) welding has been selected. RF welding uses high frequency electromagnetic energy to generate heat, thus bonding sheets of plastic together . TechnicThis study documents the design and development of arm wraps as a central component of a CIPN-prevention limb cryocompression system. Using the HudPAX method, design input requirements were gathered from existing clinical pilot studies, and design outputs were developed in an iterative process, with user-centered approaches providing vital stakeholder feedback and propelling the development into its next stage. This research demonstrates the importance of cross-sector multidisciplinary collaboration, mixed-methodology adaptation and the integration of stakeholder consultation, in addressing these challenges, particularly with SME-centered developments where resources and research and development infrastructures are limited.Development of a Beta prototype - based on the findings of this study, generating a near-final design for use in the subsequent clinical trials;A healthy volunteer trial to determine safety will be conducted using the Beta prototype;A clinical trial in cancer patients undergoing chemotherapy will be conducted, to prove efficacy;Regulatory approval will be obtained;The \u201cdetailing and final prototype\u201d stage in collaboration with industry will finalize the product;The final product will be launched to an international market, through Paxman's existing infrastructure.Our ultimate aim is to generate a complete four-limb cryocompression system for CIPN prevention, which can be utilized by patients worldwide, alongside the existing Paxman scalp cooling system. The roadmap of milestones to ensure the continuation of this successful development includes:The method adopted in this project was developed to address the complex and high-risk nature of SME-centered medical device design & development projects and supports the equilibrium between the distinct needs of medical device design, user needs, commercial feasibility and stringent regulatory standards. The complex challenges encountered within medical device development demands a multidisciplinary approach; in which experts from all fields of relevant research collaborate to address unmet clinical needs. In this project, early-stage clinical trials generated the evidence-based inputs and ensured the feasibility of the potential solution. The subsequent ideation phase engaged the expertise of designers and engineers, who utilized the scientific evidence to generate potential concepts. Qualitative assessment of the concepts, from users, was then essential to progress the development into the next stages, where opinions and motivations are explored. This fundamental communication between Design Science and Design Thinking methods is the foundation for establishing early success in medical device design & development.As we have explored in this paper, medical device design & development is complex. The development process needs to be adaptable and multifaceted to ensure the commercial viability. A crucial consideration for any development, during the discovery phase (Phase 1 - Research), is a market analysis to assess the market for existing products, state-of-the-art technology and industrial feasibility. A comprehensive literature review identified key commercial aspects including market size, freedom to operate, problem definition, user behavior, opportunities and needs, together with the integration of academic aspects.Ultimately this development aims to achieve MDSAP  approval, which is medical device compliance encompassing HC, FDA, ANVISA, EC, ATG and PMDA, and represents six different medical device markets: Australia, Brazil, Canada, Europe, Japan and the United States. Regulatory approval for additional markets will also be strategically pursued. Utilizing the existing knowledge and infrastructure available from the commercial partner, the future challenges associated with obtaining regulatory compliance, which commonly account for new medical devices' market failure, will be mitigated.Approximately 30,000 patients in the UK, and 1 million worldwide, can be affected by CIPN annually. Scalp-cooling prevents CIA, which occurs alongside CIPN and therefore the market already exists. Collaboration with Paxman Coolers Ltd integrates into the project an existing route-to-market with the synergies facilitating improved productivity and economies-of-scale to be achieved. Limitations specific to this CIPN prevention device include the additional medical time required to attach/detach/monitor the therapy; the additional space required for the device within hospital/clinics; and also potential low adoption of the therapy due to current low-level awareness amongst patients of CIPN as a side-effect of chemotherapy. Identification and consideration of potential limitations by the multidisciplinary team and stakeholders, at this feasibility stage, facilitates early mitigation.Medical requirements; Technical requirements; Stakeholder and user requirements; Regulatory requirements; Multidisciplinary team varied expectations; Commercial viability; and Market awareness and accessibility.This paper has addressed the challenges posed by early-stage medical device design & development, including the following challenge areas: Through the development of a limb-hypothermia arm wrap Alpha prototype for CIPN prevention, cross-sector collaboration has united multidisciplinary expertise from clinical, academic and commercial backgrounds, with the combined regulatory and market-awareness knowledge providing a strong foundation which proves central to the development's ultimate viability.Development and implementation of a mixed-methodology has promoted a flexible approach addressing the complex design challenges and optimized to the cross-sector needs and expectations of the collaborating partners. This mixed-methodology has also demonstrated the equal importance of evidence-based and user-centered inputs, primarily for setting the clinical and technical parameters and secondly for integrating user requirements. Our work highlights the necessity for stakeholder consultation in the early stages of medical device development, specifically when multiple user-types (nurses/patients) exist, to ensure user-inputs comprehensively reflect the user-needs. Continuation of the mixed-methods approach will propel the device through the next stages of the development including Beta prototyping, clinical trials and eventual market launch.The original contributions generated for the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by School Research Ethics and Integrity Committee (SREIC), University of Huddersfield, UK. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.JB, EU, PB, RP, RS, and AB contributed to the conception and design of research. JB and AB contributed to the implementation of the research, acquisition, and interpretation of data. JB, EU, JC, and AB drafted the manuscript. PB, RP, and RS revised the manuscript critically and for important intellectual content. All authors read and approved the final manuscript.JB and PB are employed by Paxman Coolers Ltd. RP partially owns Paxman Coolers Ltd. EU, RS, and AB have received research or travel funding from Paxman Coolers Ltd. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This work was supported by Paxman Coolers Ltd., UK. The funder was involved in the commercial design decisions as this project is a commercial product design and development , but the academic and research team independently made decisions for data collection, analysis, interpretation of data, the writing of this article and the decision to submit it for publication."}
+{"text": "Despite being among the most common psychiatric disorders worldwide, and a leading cause of disability including work and school absences, anxiety disorders have been relatively under-represented in recent research of novel pharmacologic agents, compared to major depressive disorder (MDD) and schizophrenia. Panic disorder (PD), generalized anxiety disorder (GAD), and social anxiety disorder (SAD) are commonly treated with either medications and/or psychotherapy, while specific phobias (SP) are usually treated with behavioral therapy alone. While there is support for certain forms of psychotherapy to treat anxiety disorders, there remains concern about lower efficacy of psychotherapies compared to medications , and incThe purpose of this Research Topic was to collect original papers and review articles exploring promising novel medications on the pipeline for anxiety disorders, primarily GAD, PD, SAD and SP, after first reviewing the current state of psychopharmacological treatments available. The topic aimed to explore more unique pathways for targeting treatment response in anxiety disorders, including the glutamate system, neurosteroids, the hypothalamic-pituitary-adrenal (HPA axis), neuropeptides, cannabinoids, and phytochemicals.Lijffijt et al. reported a protocol for a randomized, placebo-controlled proof-of-mechanism trial of a n-methyl-d-aspartate (NMDA) receptor antagonist lanicemine for 24 adults with symptoms of post-traumatic stress disorder (PTSD) ]. The study was included in this Research Topic despite being a trial on participants with PTSD symptoms because of its potential application to anxiety disorders. In the protocol, participants are to receive 5 days of intravenous (IV) injections of lanicemine or placebo and be monitored with anxiety-potentiated startle and CAPS scores. Lijffijt et al. are building upon previous research of another NMDA antagonist, ketamine, which has also been tested using IV infusions in patients with treatment-resistant depression , and its interactions with GABA, the primary CNS inhibitor, in anxiety disorders. Building from an overview of circuitry and receptor pathways, and a review of preclinical research describing the role glutamate plays in anxiety, Nasir et al. then describe the current state of glutamatergic and GABAergic drug research in anxiety disorders. The GABA modulators discussed in the paper, most of which are clinically used as anticonvulsants , have limited support due the absence of larger, randomized, double-blind, placebo-controlled trials, with the exception of pregalabin, which was approved for GAD in Europe in 2006 , SSRIs, and benzodiazepines may normalize hyperactivity of the HPA axis. Tafet and Nemeroff cite evidence that these antidepressants may modulate glucocorticoid receptors in the brain and benzodiazepines may have an inhibitory effect on corticotrophin releasing factor (CRF). Taken together, the findings support an expansion of research beyond serotonin and norepinephrine and may spur exploration of novel agents targeting the HPA axis directly.Understanding stress response and hormone regulation may provide further clarity about newer pharmacological treatments, and Garakani et al., along with other authors, presented an overview of the current state of treatment of anxiety disorders, which is discussed above, followed by a review of novel pharmacologic treatments for PD, GAD, SAD, and SP. Several serotonergic agents that were originally investigated for depression have been studied and showed potential, but these trials did not lead to FDA approval and there are limited ongoing investigations. There are also trials of psilocybin and lysergic acid diethylamide (LSD) for anxiety but primarily in those with life-threatening diseases (like cancer)  , 18. Ket cancer) . Studies cancer) , 21, andTaken as a whole, the Research Topic did in fact show both promises and disappointments in the research of novel pharmacotherapeutics for anxiety disorders. As expected, the pathways and novel compounds hypothesized to treat anxiety were hampered by lack of efficacy (perhaps due to poor study design), small sample sizes or other mitigating factors. With any hope, this Topic should not discourage ongoing exploration beyond serotonin, norepinephrine and GABA, and instead bolster the efforts to expand on our understanding of the complex neurobiological pathways of anxiety and how to translate this work into novel agents that perhaps can complement the ongoing research into psychotherapeutic treatments of anxiety.AG wrote the original draft of the manuscript. AG, RF, and JM contributed to critical manuscript revisions. All authors reviewed and approved the final draft of the manuscript and made substantial contributions to this study.JM disclosures: In the past 5 years, JM has provided consultation services and/or served on advisory boards for Allergan, Boehreinger Ingelheim, Clexio Biosciences, Fortress Biotech, FSV7, Global Medical Education (GME), Impel Neuropharma, Janssen Research and Development, Medavante-Prophase, Novartis, Otsuka, and Sage Therapeutics. JM was named on a patent pending for neuropeptide Y as a treatment for mood and anxiety disorders and on a patent pending for the use of ezogabine and other KCNQ channel openers to treat depression and related conditions. The Icahn School of Medicine (employer of JM) was named on a patent and has entered into a licensing agreement and will receive payments related to the use of ketamine or esketamine for the treatment of depression. The Icahn School of Medicine is also named on a patent related to the use of ketamine for the treatment of PTSD. JM was not named on these patents and will not receive any payments. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The Acute Life interventions Goals and Needs Program (ALIGN) is an inter-professional team of medical and social work providers dedicated to offering time-limited intensive ambulatory care to the most complex, high cost, high needs older patient population at Mount Sinai Hospital in NYC. During the 2020 COVID19 pandemic, ALIGN pivoted to focus on emergency planning actions. Such actions included language and culturally concordant goals of care discussions with patients and family, completion of electronic Medical Orders for Life Sustaining Treatment, reassessment of patient\u2019s social determinants of health, determination of adequate access to food, medication, and emotional support to those alone and isolated, and assistance with video telemedicine. ALIGN\u2019s model of care has shown how adaptable this program and others were during the height of the pandemic."}
+{"text": "The regulation of ROS and RNS levels is indispensable to preserve cellular homeostasis. Low ROS and RNS levels stimulate immune responses, cell proliferation, apoptosis, differentiation, and stress-responsive pathways. High ROS and RNS levels damage lipids, proteins, and DNA  [S-transferases) can neutralize ROS directly or with the help of metal cofactors  [N-acetyl cysteine and lipoic acid) act as cofactors for some enzyme systems or neutralize the production of free radicals by transition metals [Knowledge on the plants that express the greatest concentration of antioxidant molecules of interest,Pedoclimatic conditions and cultivation stages that make most of their levels available in plants,Extraction methods that can properly maximize their recovery,The potential preventive and/or therapeutic effect of each chemical class of antioxidants,Pharmaceutical delivery systems that allow for the full advantage of their actions in the body.Oxidative stress happens when the levels of reactive species made from oxygen and nitrogen exceed the body\u2019s antioxidant capacity. Exogenous agents  and endogenous processes   generates-links) . Antioxis-links) . Some en and Zn) . The ant and Zn) . The secn metals . In recen metals ,9,10. Fon metals . Moreoven metals . UnfortuThis work comprises original research papers and reviews on antioxidant molecules in food, the agricultural practices that maximize their levels in plants, the potential preventive effects of selected classes of antioxidant molecules, their potential use in functional foods, and the pharmaceutical delivery systems that maximize their potential activity when used as supplements. Finally, the recovery of food antioxidants from food waste is discussed, considering the need to reduce waste to protect the environment as an issue of primary importance ."}
+{"text": "Atherosclerosis is a chronic and progressive inflammatory disease of the arteries initiated by the functional and structural alteration of the endothelial layer responsible for promoting the subendothelial retention of modified low-density lipoproteins (LDL), which in turn generate an active proinflammatory state in which environmental factors, such as oxidizing agents, growth factors, cytokines, monocyte-macrophages and smooth muscle cells (SMCs), work in cooperation to promote the formation of plaque. Despite substantial progress in the prevention, diagnostics, and treatment of atherosclerosis, it remains the leading cause of mortality worldwide, approximately resulting in 18.6 million deaths in 2019 [This Special Issue contains a selection of research articles and reviews written by experts in the field, focusing on the molecular biology of atherosclerosis, the impact of different risks factors and the mechanisms by which they can influence the development of this disease.As briefly mentioned above, atherosclerotic disease arises as a consequence of the subendothelial retention and modification of LDL, sparking an inflammatory state and promoting the formation of fatty streaks, the earliest visible signs of atherogenesis. There is extensive evidence that increased plasma levels of proatherogenic lipid species are causally associated with atherosclerosis, and that lipid-lowering therapies can substantially reduce the lifetime risk of cardiovascular disease . In thisAnother important event contributing to the development of atherosclerosis is the recruitment of circulating monocytes to the vessel wall, their transendothelial migration and their phenotypic polarization towards proinflammatory macrophages that acquire the capability to rapidly secrete a wide range of inflammatory mediators, influencing the development and extent of atherosclerosis. Wu et al. investigated the molecular mechanisms involved in mononuclear cell (MNC) activation and endothelial dysfunction in atherosclerosis, suggesting that circulating fatty-acid-binding protein 4 (FABP4) is capable of altering monocyte cell adhesion and endothelial functions via the upregulation of ERK/JNK/STAT-1 signaling and the downregulation of the eNOS and SDF-1 pathways. Consistently, they also showed that the inhibition of FABP4 attenuates the effect of oxLDL on monocyte adhesion to ECs through the downregulation of the integrin pathways in MNCs and human coronary endothelial cells (HCAECs). Nevertheless, the paper by Chang et al. demonstrates that the selective inhibition of the C-C chemokine ligand (CCL4), an inflammatory chemokine highly expressed in atherosclerotic patients, is able to restore the endothelial adhesive properties and reduce the activity of metalloproteinase-2 and -9, as well as the production of TNF-\u03b1 and IL-6 in stimulated macrophages through the nuclear factor NF-\u03baB pathway. In the context of vascular inflammation and atherosclerosis, the role of neutrophils has been underappreciated for many years; more recently, however, neutrophils have emerged as important contributors to atherosclerosis due to their ability to release neutrophil extracellular traps (NETs). In this regard, it has been demonstrated that NETs are present in the atherosclerotic plaques of both human and animal models, where they induce endothelial cell dysfunction and apoptosis, oxidative stress and the oxidation of high-density lipoproteins; thus, reducing their capability to promote cholesterol efflux from foam cells ,4. Da SiThe health benefits of acetylsalicylic acid (ASA) and diminazene aceturate (DIZE) have also been investigated with respect to the atherosclerotic plaque development and phenotype. Acetylsalicylic acid (ASA), also known as aspirin, was first successfully synthesized in 1899 and widely used to reduce pain, fever and inflammation until the 1970s, when it became the cornerstone of therapy for the secondary prevention of cardiovascular events by the virtue of its antithrombotic properties ,6. In thThe review by Giglio et al. provided a clear overview of the molecular effects of novel nutraceuticals, hypolipidemic agents and hypoglycemic drugs on atherogenesis. Siew and colleagues provided valuable insight into the advances, applications and potential pitfalls of the CRISPR/Cas9 system in the context of atherosclerosis. An interesting interaction between the endothelial cells of coronary arteries (CA) and internal thoracic arteries (ITA) upon coronary artery bypass grafting (CABG) surgery was proposed by Shishkova et al. to explain the molecular mechanism underlying the increased resistance of ITA grafts to atherosclerosis and restenosis."}
+{"text": "Da Costa et al., Druege et al., Mhimdi and P\u00e9rez-P\u00e9rez proposed AR formation as the default state of root development in plants, highlighting that root initiation from non-root tissues might be considered as an ancestral trait, as ARs are formed by default in lycophytes and ferns. According to the same authors, in many angiosperms, AR formation seems to be repressed through mechanisms that maintain competent cells in a quiescent state. Activation of competent cells is triggered by environmental conditions to which the cuttings or intact plants are exposed, like exogenous auxin treatment, wounding, waterlogging, or light exposure and mineral nutrition determining the activation of a complex network of signaling, metabolic, and transport pathways  formation. The first is known as the induction phase, in which high auxin levels are required for reprogramming of competent cells toward root development, which is further linked to other biochemical changes  genes, on the control of auxin or jasmonic acid conjugation, and the PIN, AUX/LAX, and ABCB genes, on the control of auxin transport.The articles of Aux/IAA and ARF genes that encode auxin signaling repressors and their target auxin response factors respectively. Downstream, genes of transcription factors (TFs) from the GRAS, SHORTROOT (SHR), SCARECROW (SCR), WUSCHEL RELATED HOMEOBOX (WOX), LATERAL ORGAN BOUNDARIES-DOMAIN (LOB) and APETALA2/ETHYLENE RESPONSIVE ELEMENT BINDING (AP2/ERF) gene families, control the auxin-dependent establishment of the AR founder cell and the new root apical meristem, the maintenance of the quiescent center (QC) and subsequent establishment and differentiation of the AR primordium . A coordinated change of expression of genes controlling the modulation of the cell wall, such as EXTENSIN and CYS ENDOPEPTIDASE genes, may probably also be involved (Li). Even though these reviews present different perspectives, they stay in line to each other in pinpointing to the core function of plant hormone crosstalk on regulating AR formation, within a process involving a hierarchy of transcription factors, that is linked to epigenetic modulation events, with reactive oxygen species (ROS) also being involved as messenger molecules.Important molecular factors that determine auxin signaling are specific Vilasboa et al. highlight the capacity to efficiently modulate redox conditions though high activity of SOD and soluble GPRX, as the main factor defining AR ability in Eucalyptus. The role of phenolic compounds acting as synergistic or antagonistic in AR formation has long been known, and its role as a species-dependent parameter was also highlighted by Vilasboa et al.The involvement of enzymes from ROS-scavenging mechanisms, and phenolic compounds working as a non-enzymatic antioxidant system, have been investigated across a diversity of plant species during the AR formation process. The activity of ascorbate peroxidase (APX), superoxide dismutase (SOD), and catalase (CAT) have been associated with improved rooting ability . The importance of ROS on AR formation was also explored by studying the involvement of the alternative oxidase (AOX), a key enzyme in the alternative respiratory pathway, using semi-hardwood cuttings .Within the different ROS molecules, the focus has been given to HAbarca suggested the epigenetic control of miR160/167-modulated auxin signaling, the TARGET OF RAPAMICINE (TOR) and possibly RETINOBLASTOMA-RELATED (RBR) dependent metabolic and auxin control of the cell cycle, and the non-cell autonomous regulation of WOX11/12 expression by CLAVATA3/EMBRYO SURROUNDING REGION-RELATED (CLE) peptides, as three molecular checkpoints for the age-related decline in AR induction. In their original article, Pizarro and D\u00edaz-Sala compared hypocotyl cuttings excised from Pinus radiata seedlings with different ages to identify genes that control the cell wall-plasma membrane-cytoskeleton continuum in the basal stem, in relation to rooting competence. The RECEPTOR-LIKE KINASE (RLK) and MECHANOSENSITIVE CHANNEL (MSC) genes, as well as genes encoding downstream regulators of the small GTP-binding protein family, were associated with rooting competence, probably via acting on the control of cell wall sensing and membrane disturbances during the essential cellular reorganization .The loss of rooting capacity with plant aging , a major problem in breeding and propagation of many tree species, has also been investigated. Regarding the relevant literature, Bannoud and Bellini, Abarca).Despite all the research carried out and the information achieved in the last years, the mechanisms underlying maturation-induced rooting recalcitrance and environmentally mediated rooting, as well as several other aspects of the AR formation process, are still far from being fully understood . The work of UD was funded by the German Federal Ministry of Food and Agriculture (BMEL) based on a decision of the Parliament of the Federal Republic of Germany, granted by the Federal Office for Agriculture and Food .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "At Robert Koch Institute\u2019s Department of Infectious Disease Epidemiology, approaches for applying the principles of evidence-based public health (EBPH) have been particularly successfully implemented in the Immunization Unit and in the Unit for Healthcare-associated Infections, Surveillance of Antibiotic Resistance and Consumption. Furthermore, both units participated in the international Project on a Framework for Rating Evidence in Public Health (PRECEPT) which has been funded by the European Centre for Disease Prevention and Control (ECDC).The Immunization Unit hosts the Executive Secretariat of the German Standing Committee on Vaccination (STIKO). In 2011, STIKO has adopted a new Standard Operating Procedure (SOP) for the development of vaccination recommendations. Main aim was to provide a methodological framework to guide this process by applying the principles of EBPH. The SOP comprises ten consecutive steps, starting with a prioritization process of relevant topics, and ending with the publication of the recommendation and a related paper on the scientific background. Following the principles of EBPH, systematic reviews and meta-analyses are performed to address key issues. The methodology of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group is a core element of the SOP and is used to assess the quality of evidence on vaccine efficacy/effectiveness and safety, including population effects. In addition, STIKO has started to use Evidence-to-Decision Tables to support the decision-making process. Since 2012, ten recommendations on new vaccines or revisions of previous recommendations have been successfully developed using the SOP, accompanied by publication of background papers and of the respective systematic reviews in peer-reviewed journals .At the Unit for Healthcare-associated Infections, Surveillance of Antibiotic Resistance and Consumption, the EBPH approach has been used to perform systematic reviews on the burden of healthcare-associated infections . As an eThe latter review was part of the PRECEPT project. PRECEPT defined a methodology for evaluating and grading evidence in public health, with a particular focus on infectious disease epidemiology, prevention and control, taking different domains and question types into consideration . The met"}
+{"text": "Empirical data regarding Covid pandemic impact on the Nevada Adult Protective Services (APS) Program clients, casework, and staff was gathered and analyzed as part of a multi-faceted program evaluation. Key findings include: 66% of the staff agreed or strongly agreed that the pandemic made their jobs more challenging. Respondents reported Covid-related challenges faced by clients, the program, and themselves as social workers serving older and vulnerable adults. Adverse client impacts observed included increased social and emotional isolation, loss of housing, exacerbation of symptoms of mental illness, necessary services being cut from clients subsequent to testing Covid positive, and fear and reluctance to allow needed visiting service providers, such as home health aides, into their homes. We will discuss the implications of the findings on APS services and clients, and on related health and human services designed to promote the wellness and independence of older and vulnerable adults."}
+{"text": "The public health emergency response workforce has experienced unrelenting pressureduring the past decade. Countries in the Western Pacific Region have responded tosignificant outbreaks of avian influenza, Zika virus disease, Middle East respiratorysyndrome, vaccine-derived poliovirus, measles and the coronavirus disease 2019(COVID-19) pandemic, as well as natural disasters; they also supported the response toEbola virus disease in West Africa during 2014\u20132016. . are a keyactivity for strengthening health security by developing vital technical expertise inthe existing workforce. (In 2019, we interviewed public health emergency response experts on topics that includedworkforce support. The experts discussed the challenge of inexperience and noted that anemergency response surge workforce was frequently based on availability rather thanappropriate skills and experience. (To support the technical and leadership needs of the surge workforce during the COVID-19pandemic in Australia, the Public Health Association of Australia and the AustralasianEpidemiological Association rapidly established a pilot mentorship programme for surgeresponders, in which mentors provided both professional and personal support to menteesremotely. (The Australian mentorship programme supported front-line pandemic surge response workersat a time of great need. The main recommendation of the evaluation was to design apurpose-built programme for supporting emergency response workers. (Fig.\u00a01.A similar programme in the Western Pacific Region, based on the experience of theAustralian programme, (Such a support programme could be used in public health emergency response both locallyand globally. It could increase the effectiveness of the workforce, add to professionalknowledge, provide less experienced responders with skills and reduce stress andburn-out. (The first objective of the WHO Global Strategy on Human Resources for Health is tooptimize the quality of performance and the impact of the workforce. ("}
+{"text": "Dear Editor,Papio papio), the name Baboon syndrome (BS) was suggested for these cases.In 1984, Andersen et al.This is the report of a 56-year-old male patient complaining of lesions on the inguinal and axillary regions that were slightly pruritic and not associated with other systemic symptoms. He reported a two-day use of paracetamol, exclusively, and a condition identical to the current one in previous exposures. Upon physical examination, well-delimited, erythematous, wine-colored lesions were observed, without signs of excoriation, with a bilateral and symmetrical distribution on the axillary, inguinocrural, gluteal regions, and lateral aspect of the thighs, including the popliteal region . HistopaTherefore, the clinical, dermatological, and histopathological data allowed the diagnosis of paracetamol-induced SDRIFE. The lesions disappeared within a few weeks after drug discontinuation and the use of topical corticosteroids.In 2011, Miyahara et al.5The pathogenesis is not completely understood, but, as in allergic contact dermatitis, the picture suggests a delayed hypersensitivity reaction mediated by T cells. A greater density of eccrine sweat glands in skinfold regions would explain their restricted or predominant manifestation in intertriginous locations, where the excretion of the sensitizing drug would precipitate the dermatosis. Treatment involves suspicion and interruption of the drugs being used. Topical or systemic steroids can speed up resolution. Case reports and identification of the triggering drug are useful from a instructive and epidemiological viewpoint.None declared.Joana Alexandria Ferreira Dias: Approval of the final version of the manuscript; design and planning of the study; critical review of the literature.Luana Moraes Campos: Approval of the final version of the manuscript; critical review of the manuscript.Juliano Vilaverde Schmitt: Approval of the final version of the manuscript; collection, analysis and interpretation of data; critical review of the manuscript.Silvio Alencar Marques: Approval of the final version of the manuscript; drafting and editing of the manuscript; critical review of the literature; critical review of the manuscript.None declared."}
+{"text": "The United States of America reports almost double the number of cancer cases relative to India that has a much larger overall population. Accurate insights into such differences in cancer rates may be provided by a better understanding of the genetic and lifestyle influences on tumor growth, progression, heterogeneity, and the underlying stressors that prompt pre-clinical dormant lesions to progress into malignant tumors, as well as by synchronizing the cancer surveillance protocols in the two countries. Toward this goal, an Indo-American Cancer Consortium was conceived. The consortium brings together global transdisciplinary teams of basic cancer researchers, oncologists, epidemiologists and surveillance experts who are well equipped with the experience, diagnostic and therapeutic tools, infrastructure and collective resources. The participating institutes include Government and non-Government organizations: Manipal Academy of Higher Education, Saroj Gupta Cancer Centre and Research Institute, and Tata Memorial Centre in India, and the Mayo Clinic Cancer Center, and University of Kentucky Markey Cancer Center in the United States. The genesis of the consortium dates back to 2017. In person visits of Markey Cancer Center teams and Mayo Clinic faculty to the cancer research institutions in India, and joint cancer conferences held in 2017 and 2018 provided strong motivation to formalize the interactions by founding this Consortium. Facilitated by monthly planning meetings beginning mid-2020 and a first retreat in December 2020, held virtually due to COVID-19 travel restrictions, the consortium has been regularly organizing various interactive sessions. These include fortnightly research presentations by faculty and trainees of participating institutions, invited guest lectures from other institutions, and a quarterly mini-symposium in topical areas of cancer. Concerted efforts to mentor the next generation of scientists saw the introduction of didactic courses in basic cancer biology, translational oncology and epidemiology, for Masters, Ph.D., Pharm.D., and MD students offered by Markey Cancer Center faculty; a certificate Program in Precision Medicine: Oncology Genomics; and a virtual tumor board to guide oncologists on treatment options for precision oncology. These activities led to organic multidisciplinary collaborations involving teams of oncologists, basic scientists, pharmacists, pathologists, and epidemiologists focused on research projects. When the travel restrictions are lifted, there will be an exchange of basic science and clinical faculty and students across the participating institutions to further foster and strengthen the partnership in cancer research and training. The consortium initiatives, supported by the parent institutions and a CRDF-Global-NCI Cancer Research Training Travel Award to exchange knowledge and enable technology transfer, have already resulted in joint peer-reviewed publications. Thus, through its multi-faceted research, education, training and outreach programs, the consortium will build infrastructure, expand capacity and strengthen global cancer research leadership and healthcare at the participating institutions.The significance of collaborative team science cannot be overstated. Unlike the days when scientists worked in silos, and laboratory bench findings were rarely translated to the clinic, the era of team science in the last few decades have underscored the value of interdisciplinary teams of investigators with diverse expertise to tackle critical questions of clinical relevance. Such an approach is particularly essential in cancer care, where, for instance, intricate details about the genetic mutations in the patient\u2019s tumor requires the combined expertise of basic and translation scientists as well as clinicians, to not only select the precise treatment for the patient but also maintain a readily available backup strategy in case the tumor develops therapeutic resistance.Cancer is the second leading cause of mortality worldwide. According to GLOBOCAN, there were an estimated 19.3 million new cancer and about 10 million cancer deaths worldwide in 2020 . In the Strategies to improve the impact of cancer research for patients have been widely discussed in India and United States over the past several decades. One confounding factor that restraints progress is the complexity of the disease associated with significant biological heterogeneity among cancer patients with diverse genetic predisposition, lifestyle, and environmental factors. Another impediment is the translation of basic research findings imposed by structural, financial and logistic limitations in facilitating interactions and workflow from the laboratory to the clinic. Some of these issues can be addressed by cohesive multi-disciplinary teams of basic and translational scientists and oncologists working together through multi-institutional cooperation to develop bench-to-bedside projects complemented by epidemiology data and community outreach efforts. Such teams are likely to be more effective in motivating scientific and administrative policy decisions that positively impact patient care. Based on this ideology, the Indo-American Cancer Consortium was formed by academic institutions in India and the United States. These institutions include  Manipal Academy of Higher Education (India), Markey Cancer Center, University of Kentucky (USA), Mayo Clinic Cancer Center (USA), Saroj Gupta Cancer Centre and Research Institute (India) and Tata Memorial Centre (India).This is the first collaborative initiative involving multiple government-supported and non-government cancer centers from India and the United States. The purpose of this consortium is to develop meaningful collaborations among the participating faculty of the cancer centers in key areas of cancer research and treatment, education, and community outreach activity. The partnership is expected to bring together stakeholders with interest in basic cancer biology, translational and precision oncology, cancer prevention programs and public health policy related to cancer. The consortium has identified several thematic areas to allow physicians, scientists, health care workers, and trainees to work together toward the common agenda of cancer research, education, and healthcare. The research collaboration of the cancer centers leverages each institution\u2019s strengths to develop premier research programs focused on key types of cancers that are most prevalent in the United States and India. Even though the interactions are primarily academic, the participating institutions have entered into a mutually acceptable confidentiality agreement to protect intellectual property. Any exchange of research materials is conducted under separate inter-institutional Material Transfer Agreements. This format enables the collaborations to jump-start without initial impediments, and a more involved Memorandum of Understanding (MoU) is developed based on the scope of each project.Working together, the cancer centers in the consortium form an integrated interdisciplinary network. Strong inter-institutional cooperation, cutting edge research concepts and state-of-the-art research infrastructure provide an excellent environment for translational and clinical research, as well as for mentoring of MSc, PhD, PharmD, and MD trainees and junior faculty. The consortium focuses on three themes: Theme 1, Cancer Biology; Theme 2, Translational Oncology; and Theme 3, Cancer Epidemiology, Surveillance, and Community Outreach, and brings together over 30 faculty with active research programs in basic science, clinical and translational research, and public health sciences related to cancer. The consortium faculty are chosen for each theme using criteria that include the strength of their research programs, history of mentoring domestic as well as international students and postdoctoral fellows, activity in co-publishing with other program faculty, and most importantly, passion to facilitate multidisciplinary training in global cancer research.The research aims incorporate plans to: (1) Identify critical signaling molecules, pathways, and mechanisms (Basic Sciences); (2) Discover new compounds and repurposed drugs that target key proteins involved in treatment resistance and discover biomarkers for treatment response ; (3) Develop new or repurposed drugs, or combine existing drugs for clinical trials ; (4) Enhance cancer surveillance and conduct cancer disparities research to promote cancer prevention behaviors . These aims support the objectives of: (a) Mentoring the next generation of medical oncologists interested in academic careers in cancer to become active participants in interdisciplinary cancer research; (b) Enhancing the academic and clinical success of clinicians, scientists, and research faculty; (c) Providing life science, cancer biology or pharmacy track students the requisite didactic training in the basic science of cancer and translational science of cancer biology and epidemiology including opportunities for interaction with clinicians/oncologists; (d) Strengthening global cancer research leadership and mentorship at the participating institutions.Prior visits of Markey Cancer Center teams and Mayo Clinic faculty to the cancer research institutions in India, and the intellectually stimulating breast cancer conferences organized jointly by the Markey Cancer Center, Manipal Academy of Higher Education and Tata Memorial Center in 2017 and 2018 provided the impetus to formalize the interactions by founding the Indo-American Cancer Consortium. The consortium activities started in mid-2020 and were facilitated by monthly virtual planning meetings. These interactions led to the first retreat in December 2020, held virtually due to COVID-19 travel restrictions, that provided an overview of the structure, organization, and programs at each of the participating cancer centers, an introduction to faculty research programs, and the consortium action plan. Since then, the consortium has been regularly organizing the following events:i) Research presentations by faculty and students of participating institutions (oncemonthly). ii) Thematic mini-symposium (occurring quarterly). iii) Featured seminar series with invited guest speakers (once monthly). iv) Didactic courses in: (1) Basic Cancer Biology, and (2) Translational Oncology andEpidemiology, for Masters, Ph.D., Pharm.D., and MD students. v) Certificate Program in Precision Medicine: Oncology Genomics for faculty atparticipating institutions; vi) Virtual tumor board meetings and discussions on tumor next-generation sequencingdata to guide oncologists on treatment options for Precision Oncology. vii) Multidisciplinary team collaborations \u2013 small group meetings involvingoncologists, basic scientists, pharmacists, pathologists, and epidemiologists todevelop focused research projects. viii) Scheduled exchange of faculty and students next year to further strengthen thepartnership in cancer research and training.The impact of the consortium is already apparent in the number of MSc, PhD, PharmD, and MD students from Manipal Academy of Higher Education, Saroj Gupta Cancer Center and Research Institute, and Tata Memorial Center registered for academic credit in cancer biology, epidemiology and therapy courses offered by the Markey Cancer Center; a CRDF-Global-NCI Cancer Research Training Travel Award to train consortium scientists from India at cancer centers in the United States; and joint research publications -10. The"}
+{"text": "Following publication of the original article  two errobold.The incorrect and correct information is listed below; the changes are shown in Abstractsignificant decline in sharp-curettage , and a decline in the duration of hospitalization of patients admitted for PAC .The implementation of PAC strategy in Kinshasa referral hospitals has resulted in the utilization of WHO recommended uterine evacuation method MVA , a Plain English summarysignificant decline in sharp-curettage , and a decline in the duration of hospitalization of patients admitted for PAC .The implementation of PAC strategy in Kinshasa referral hospitals has resulted in the utilization of WHO recommended uterine evacuation method MVA , a Abstractnon-significant decline in sharp-curettage , and a decline in the duration of hospitalization of patients admitted for PAC .The implementation of PAC strategy in Kinshasa referral hospitals has resulted in the utilization of WHO recommended uterine evacuation method MVA , a Plain English summarynon-significant decline in sharp-curettage , and a decline in the duration of hospitalization of patients admitted for PAC .The implementation of PAC strategy in Kinshasa referral hospitals has resulted in the utilization of WHO recommended uterine evacuation method MVA , a"}
+{"text": "Aging in Latin America is occurring rapidly, in a context of high levels of poverty and inequality. This symposium is focused on population health and the heath-disparities found in some of Latin America\u2019s largest middle-income countries, Mexico, Brazil, and Colombia. This symposium contains presentations on different health-related issues affecting older adults, which can have further implications for wellbeing, health, and disease risk. The papers in this symposium examine a variety of health-related dimensions and disparities among older Latinos that include physiological functioning, cognition, and oral health. Using the Mexican Health and Aging Study (MHAS), Sheehan investigates the associations between personal and familial educational attainment on sleep quality. Also using MHAS, Milani. Using data from the Brazilian Longitudinal Study of Aging, Farina examines the relationship between race and cognition. Garcia uses data from the Colombian Survey of Health, Well-Being, and Aging to study the relationship between Motor Cognitive Risk Syndrome (MCRS) and cognition and frailty. Using the same dataset, Osuna examines variation in oral health in Colombian older adults and the impact this has on their wellbeing. Results indicate which population subgroups in Latin American have increased risk for poorer health and which dimensions of health have gender, race and socioeconomic disparities. The findings highlight the importance of understanding the conditions under which Latin American older adults are aging and the implications this can have in the future."}
+{"text": "In parallel, Bangladesh Medical Research Council (BMRC) has announced the launch of \u2018Bangladesh Cancer Genome Atlas (BCGA) project with support from the ICGA teams. Teams from United States - National Cancer Institute (NCI) office of TCGA and Centre for Global Oncology, Institute of Cancer Research, London, United Kingdom are interested in extending their collaborations to these large-scale initiatives by acting as knowledge partners.The Cancer Genome Atlas (TCGA) is a landmark cancer genomics program that molecularly characterized over 20,000 primary cancer and matched normal samples spanning 33 cancer types. On similar lines, the establishment of an nd TCGA conference and workshop in India was organised with the theme of \u2018Towards Team Science for Multi-omics Studies in South Asia\u2019 on December 3\u20135, 2020. Over 1,500 delegates comprising of onco-clinicians, basic researchers, bioinformaticians, geneticists, translational researchers, big-data and machine-learning scientists, bioethicists and regulatory experts from across the globe attended the event. The conference agenda focused on the vision, design and plans of the ICGA project with regards to common standard operating protocols (SOPs), operations, logistics, bioethics, policy and governance models. More importantly, conference sessions were planned around the central theme of building a culture of team science for undertaking mega-cancer research projects in India and neighbouring countries. Experts from the globe deliberated on the latest technical aspects of data/biospecimen/multi-omics studies and applications of Precision Oncology in clinical cancer management.With this background, an online version of the 2 Over the last 15 years, The Cancer Genome Atlas (TCGA) program has characterized over 20,000 primary cancers and matched normal samples across 33 cancer types. By networking interdisciplinary researchers from across the world, TCGA has generated a massive 2.5 petabytes of genomic, epigenomic, and transcriptomic data. These data, not least through their publicly availability, have already led to significant and potential translatable benefits in the diagnosis, treatment, and prevention of cancer. The importance of the project and its participants was recently recognized with the prestigious 2020 American Association of Cancer Research \u2018Team Science Award.\u2019There are an estimated 800,000 new cancers cases in India each year  and, recTo this end, the \u2018Indian Cancer Genome Atlas (ICGA)\u2019 was initiated in 2020 by forming a national consortium of government agencies, cancer hospitals, academic institutions, and private sector partners in India, led by the Council of Scientific and Industrial Research (CSIR). The ICGA will be a long-term collaborative effort between cancer scientists, basic researchers, onco-clinicians, data scientists, and technology providers to facilitate precision medicine and improve translational cancer research in India.The ICGA\u2019s mission is to create an indigenously developed, open-source, comprehensive database of multi-omics profiles of all possible cancers in Indian populations. The goal is the genomic, transcriptomic, epigenetic, and proteomic characterization of Indian cancers using advanced, next-generation multi-omics technologies. High quality meta-data of cancer patients and their biospecimens  will be carefully and ethically collected from across the country. After standardized multi-omics profiling, data will be curated and analyzed in clinicopathological contexts, with the curated databases open-sourced to the Indian and global cancer research communities. To facilitate the uniformity, sanctity, and integrity of the meta-data and biospecimens collected from across India, a pan-India consortium of partners will operate as a \u2018hub-and-spoke\u2019 model in the form of the not-for-profit ICGA Foundation.-National Cancer Institute\u2019s (US-NCI) TCGA has formally agreed to serve as a knowledge partner and will provide technical, operational, troubleshooting, and quality assurance expertise to the ICGA. The Institute of Cancer Research (ICR), UK has formally agreed to help generate and analyze the data and share the data in real-time in a public database.The USAst TCGA conference organized in 2019 in India with the theme of \u201cMulti-omics Studies in Cancer: Learnings from The Cancer Genome Atlas (TCGA)\u201d. In addition to discussing the global trends in multi-omics research, the conference proceedings were focused on the need for developing a national mission program for multi-omics profiling of Indian cancer. These discussions laid the foundation of the ICGA project.The 1nd TCGA 2020 conference was organized in a virtual and online format to discuss these five main domains of the ICGA project. Highlighting governmental support for the conference and the ICGA, the Hon\u2019ble Dr Harshavardhan  presented the conference keynote address. In his keynote address, Dr. Jean Claude Zenklusen  shared his experiences of the genesis and implementation of TCGA and highlighted the need for a multi-disciplinary team approach for success of the ICGA.With this background, the 2There was strong multidisciplinary interest in the conference, with over 1500 delegates representing basic science, translational and clinical research, genomics, bioinformatics, biostatistics, and computational science and biology from academia, clinical medicine, industry, and governmental agencies. Delegates attended remotely from 36 countries around the world.The event  was held over three days: (1) a one-day hands-on pre-conference workshop, where TCGA experts mentored attendees on various aspects of TCGA data mining; (2) conference presentations discussing global trends in multi-omics cancer research, particularly with respect to the technical aspects of clinical multi-omics studies and applications of precision oncology in the clinic; and (3) a full day of discussion between key ICGA stakeholders on the vision, design, and implementation of the ICGA with regards to common standard operating procedures, operations, logistics, and governance models. The conference sessions were planned around the central theme of building a culture of team science for undertaking mega-cancer research projects in India and neighboring countries.nd TCGA conference laid the foundation for the ICGA, and there was a wide consensus that the ICGA consortium will unite diverse expertise in cancer research in India and beyond. Given the high prevalence of breast cancer and unanswered questions around clinicopathological features of the disease in Indian women, the ICGA will begin its efforts with the large-scale multi-omics profiling of breast cancer patients in India. With this focus, the ICGA will develop and validate all protocols and ethical guidelines for subsequent sharing with the entire consortium to ensure uniform data generation and quality. It is anticipated that the economy of scale of the meta-analysis of all cancer data generated in India will help deliver cost-effective cancer research and accelerate bench-to-bedside translation to significantly positively impact the overall cancer burden in the country.The 2In an encouraging development, and motivated by the ICGA project, the Government of Bangladesh has also announced the creation of a Bangladesh Cancer Genome Project (BCGP) modeled on the TCGA and ICGA programs. This partnership will see two parallel large-scale cancer genomic projects span the Indian sub-continent to cover large populations in South Asia.nd TCGA 2020 Conference brought together the global cancer research community through a common goal to accelerate multi-disciplinary, collaborative, and nationwide initiatives in South Asia, which promises to transform clinical cancer research across the region. The 3rd TCGA Conference in 2021 will report progress on the ICGA and BGCP projects. Overall, these efforts are anticipated to deliberate on the emerging trends in precision oncology in the developing world.The 2The conference proceedings were partially funded by Bajaj Auto Ltd and DBT-Wellcome Trust India Alliance.The authors have no conflicts of interest."}
+{"text": "Personal stories provide insight into the experience of illness as it intersects with one\u2019s identity. Prior studies by the first author examined identity as manifested in personal accounts of U.S. World War II veterans with and without dementia. The current study examines identity as revealed through written memoirs of middle-aged and older adults who have aphasia, from a cross-section of North American, European, and Australian cultures. The abrupt onset of stroke and associated aphasia, and the subsequent path toward re-engagement in life with an often-chronic communicative impairment, provide a unique window into the nature and evolution of the identity of the writer. The written modality offers an opportunity for reflective formulation that is not afforded to the memoir-writers in their verbal expression. Nineteen memoirs and biographical accounts of individuals with aphasia from a range of primarily individualistic cultures were examined for content reflective of the identity of the author, focused on post-stroke phases of restitution and quest. Primary authors were people with aphasia or rarely their close family member. Some were professional editors, poets or authors. Gender and life backgrounds were varietal. Manifestations of personal identity, its reinforcement, and its evolution were evidenced in: the provision of lessons learned from living with aphasia; content of letters exchanged with friends; engagement with family in life and recovery; fictional and poetic expression; spiritual insight; renewed or altered occupational pursuits; and comments on facing one\u2019s mortality. Findings hold implications for the cross-cultural practice of narrative medicine with the older adult population."}
+{"text": "The National Institutes of Health (NIH) recognizes that, despite HIV scientific advances, stigma and discrimination continue to be critical barriers to the uptake of evidence-based HIV interventions. Achieving the Ending the HIV Epidemic: A Plan for America (EHE) goals will require eliminating HIV-related stigma. NIH has a significant history of supporting HIV stigma research across its Institutes, Centers, and Offices (ICOs) as a research priority. This article provides an overview of NIH HIV stigma research efforts. Each ICO articulates how their mission shapes their interest in HIV stigma research and provides a summary of ICO-relevant scientific findings. Research gaps and/or future opportunities are identified throughout, with key research themes and approaches noted. Taken together, the collective actions on the part of the NIH, in tandem with a whole of government and whole of society approach, will contribute to achieving EHE\u2019s milestones. Stigma and discrimination are human rights and public health issues in the United States and worldwide. They are among the most ubiquitous and consequential challenges to successful HIV prevention, treatment, and care \u20134. HIV-rRecognizing that preventing and reducing HIV-related stigma is a critical part of fighting the HIV pandemic and a key aspect of ending the HIV epidemic in the United States, the National Institutes of Health (NIH), an agency under the U.S. Department of Health and Human Services (HHS), designates HIV-related stigma research as a cross-cutting research priority in its HIV research program. This article discusses the NIH\u2019s approach to, and investment in, this priority area and its relevance to the Ending the HIV Epidemic: A Plan for America (EHE) initiative .The mission of the NIH is to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability.Within that mission, NIH has a robust and structured HIV research program that strives to advance rigorous and innovative research to end the HIV pandemic and improve the health of people with, at risk for, or affected by HIV across the lifespan .NIH has a significant history of supporting HIV-related stigma research across its Institutes, Centers, and Offices (ICOs) as a fundamental and cross-cutting research priority. Below is a brief overview of HIV-related stigma and discrimination research efforts NIH ICOs are leading and undertaking.Stigma is a key research area within the NIH HIV Research Program as stated in the FY 2021 \u2013 2025 NIH Strategic Plan for HIV and HIV-Related Research  and as rThe Lancet on developing a research agenda to address stigma and global health ) , 12.Journal of the International AIDS Society (JIAS) a series of papers examining the state of the science and identifying the key gaps in measurement, methods and intervention research [In 2013, NIMH and partners published in the In 2016, the White House Meeting on HIV Stigma was convened by the NIH Office of AIDS Research (OAR), the National Institute of Mental Health (NIMH) and the Office of National AIDS Policy (ONAP) . The meeBMC Medicine in 2019. The 2017 workshop also helped inform the design and launch of FIC\u2019s new grant program in 2018, Reducing Stigma to Improve HIV/AIDS Prevention, Treatment and care in Low- and Middle-Income Countries (LMICs) (PAR-18-732 and PAR-19-326), which encourages multi-level intervention and measurement research, as well as the examination of HIV comorbidities/coinfections and intersectionality [In 2017, FIC and NIH partners hosted a three-day workshop in 2017 entitled \u201cThe Science of Stigma Reduction: New Directions for Research to Improve Health .\u201d Sixty ionality .In 2018, NIMH and NIH partners released the PRISM three RFAs (RFA-MH-19-410/411/412), Promoting Reductions in Intersectional StigMa (PRISM) to Improve the HIV Prevention Continuum . This RFIn 2020 and to date, NIH continues its investments in HIV-related stigma research and spearheading such key activities as the NIH OAR and NIMH sponsored 3-phase virtual workshop on HIV-related intersectional stigma and discrimination held in 2020 , its ongIn 2020, the National Institute on Drug Abuse (NIDA) and NIMH issued two RFAs (RFA-DA-21-001/002), under the title \u201cReducing Stigma Related to Drug Use in Human Service Settings.\u201d These RFAs supported early stage, domestic intervention trials or pre-intervention research to reduce stigma in the context of HIV prevention and care .The Office of the NIH Director (OD) is the central office at NIH for its 27 Institutes and Centers (ICs). The OD is responsible for setting policy for NIH and for planning, managing, and coordinating the programs and activities of all the NIH components. OD program offices include the OAR among others within the OD\u2019s Division of Program Coordination, Planning, and Strategic Initiatives (DPCPSI).NIH has 27 ICs, the majority of which have dedicated HIV research investments. ICOs undertake HIV research activities both independently and in partnership with other NIH ICOs and non-NIH stakeholders.The NIH OAR is an Office in the NIH OD within DPCPSI . OAR oveOAR actively initiates and develops cross-collaborations with stakeholders to inform and advance HIV prevention and treatment science, including the assessment of the impact of stigma on efforts to address HIV. The OAR has championed an HIV-related stigma research agenda, which has more than doubled since FY2015, with expanded research across the ICOs. OAR collaborates closely with HHS agencies including the Centers for Disease Control and Prevention (CDC), HRSA, Indian Health Service (IHS) and Substance Abuse and Mental Health Services (SAMHSA), as well as other strategic federal and bilateral partners such as the President\u2019s Emergency Plan for AIDS Relief (PEPFAR) and the Joint United Nations Programme on HIV/AIDS (UNAIDS) to expand the impact of HIV-related stigma research. These collaborations involve strategies to measure and monitor stigma both nationally and internationally, sharing of plans and activities to address stigma among underserved populations, and discussions about how to fill gaps in the HIV-related stigma and discrimination research agenda. OAR seeks input from, and collaborates with, academic institutions and community members through dynamic listening sessions conducted across the U.S., and recently in international settings. The overall purpose of these listening sessions is to increase engagement with a diverse set of stakeholders representing various organizations, groups, populations, and individuals from the research, public health, and HIV-affected communities in order to enhance the framing of emerging, or unaddressed, issues to initiate new approaches and solutions. HIV-related stigma has been a recurring theme across listening sessions in all settings in recent years. In addition, focused conversations with local community constituents involved with HIV programs and services have provided a range of perspectives that contribute to building an extensive HIV stigma research portfolio. The OAR has also conducted HIV-related stigma scientific briefings as part of a series it conducts for NIH science staff on prescient HIV issues and research topics.The NIH HIV-related stigma research portfolio includes projects currently underway that support the EHE initiative goals to drive HIV incidence down by 75% by 2025 and 90% by 2030 . These iThe NIH Office of Behavioral and Social Sciences Research (OBSSR)  was estaOver the course of the HIV epidemic, research-informed knowledge about HIV, early public disclosures of HIV status, destigmatization efforts by public figures, and community-driven advocacy campaigns collectively have contributed to both changes in HIV-related stigma and behavior changes , 29. HisThe NIH Office of Research on Women\u2019s Health (ORWH)  serves a-OD-20-048) to facilitate the inclusion of U3 women and rigorous research on questions relevant to the health of women, including populations of women that experience stigma and health disparities or are otherwise socially or medically vulnerable [ORWH supports multidimensional, intersectional approaches to understanding and mitigating HIV-related stigma, as stigma manifests differently across cultural contexts and social settings. In the U.S., a disproportionate number of women diagnosed with HIV are members of ORWH-defined understudied, underrepresented, and underreported (U3) populations, including rural women, transgender women, women living at/near/below the poverty line and Black and Latina women \u201336. Recolnerable .2019\u20132023 Trans-NIH Strategic Plan for Women\u2019s Health Research [EHE will require the inclusion of women as a matter of scientific rigor, health equity, and policy planning. The Research  describeThe NIH Sexual and Gender Minority Research Office was established in 2015 to coordinate, support, and help develop NIH-wide research and related efforts that advance the health of sexual and gender minorities (SGMs) . Many diSGMs are also disproportionately affected by certain health conditions and diseases . There aThese issues highlight the urgent need to improve existing paradigms and develop novel strategies to tackle health-related concerns and disparities stemming from or exacerbated by stigma related to HIV and SGM status and achieve health equity for all SGMs. There are significant data and training gaps on HIV stigma in SGM populations. This could be addressed, at least in part, through expanded collection of data on sexual orientation, gender identity, and sex (particularly with regard to intersex people and people with differences in sex development) in HIV-related stigma research, as well as in relevant research efforts in HIV and stigma individually. There is a concerning dearth of HIV, stigma, and HIV-related stigma research focusing on those SGM subgroups currently most affected by HIV . There is also a need to adapt and create stigma measures focused on and appropriate for members of the SGM community, incorporating their input wherever possible. In addition, SGM-specific cultural competency training for those who conduct research in HIV stigma-relevant fields and/or who provide healthcare to SGMs is crucial for avoiding further stigmatization and encouraging engagement in both areas by SGM people. Finally, SGMs comprise a highly diverse and heterogeneous community. Intersectional research that incorporates individual and structural factors is necessary to attend to the many dimensions that may contribute to or help ameliorate the impact of HIV stigma in SGMs. Pursuing these opportunities could greatly improve the health and well-being of SGM people facing HIV stigma. SGMRO is taking a leadership role in educating the NIH ICOs on these issues, promoting HIV-related stigma research through OD-level SGMRO initiatives, and in partnering with other ICOs in this important area.The Offices discussed above are noteworthy for their involvement and investments in HIV-related stigma research. These and other activities and partnerships are taking place among and across the OD offices. One example of this is the NIH Office of Disease Prevention (ODP) . HIV-relNIMH mission is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery, and cure. The NIMH Division of AIDS Research interest in HIV-related stigma research and discrimination has been shaped by NIMH\u2019s emphasis upon basic behavioral and social science research, and NIH OAR\u2019s emphasis upon ending the HIV pandemic and improving health outcomes for people living with HIV , 51. NIMNIMH-funded research has advanced stigma models, measurement, mechanisms of action and interventions. A groundbreaking HIV stigma model led by Turan and colleagues is not only recognized in the HIV stigma research field, but it is also being adapted and applied to other health-related stigmas . A greatIn 2018, NIMH aimed to harness new tools and frameworks that move beyond a single focus on HIV stigma to examine HIV-related intersectional stigma and discrimination. A new funding opportunity announcement, \u201cPromoting Reductions in Intersectional StigMa (PRISM) to Improve the HIV Prevention Continuum (RFA-MH-19-410/411/412)\u201d was launched, which resulted in eight research awards  funded by NIMH and NIH partners . NIMH alFICs mission is to support and facilitate global health research conducted by U.S. and international investigators, to build partnerships between biomedical research institutions in the U.S. and foreign countries, and to train the next generation of scientists to address global health needs . Over thAdditionally, it is also widely recognized that stigma is a global phenomenon and affects individuals across geographic locations, cultures, social structures and health statuses with the same effects on PLWH. Recognizing this need to break the cycle of HIV transmission by counteracting stigma, FIC initiated a new program, \u201cReducing Stigma to Improve HIV/AIDS Prevention, Treatment and Care in Low and Middle- Income Countries (R21)\u201d in 2017 to stimulate research to develop interventions to reduce HIV-related stigma and its impact on the prevention and treatment of HIV and on the quality of life of PLWH . To dateGiven the similarities between some LMICs and high-burden U.S. settings targeted by EHE initiative, and the similarities among stigma-related issues across global contexts, the research and research capacity building portfolio initiated for HIV-related stigma in LMICs can offer valuable lessons to the stigma research community in the U.S. and inform the EHE efforts. Over the past few years, FIC has collected case examples of interventions developed abroad that have been successfully transferred from LMICs to the U.S., with a focus on understanding the scientific processes by which these interventions have been adapted. In October 2020, FIC hosted a webinar titled \u201cTransferring HIV and Stigma Reduction Interventions from LMICs to the U.S.,\u201d which provided the scientific community with lessons learned from abroad, frameworks for intervention transfers, and key barriers and facilitators to HIV stigma-reduction research and implementation . The actThe National Heart, Lung, and Blood Institute's (NHLBI) mission is to promote the prevention and treatment of heart, lung, and blood diseases and enhance the health of all individuals. One of its strategic vision seeks to advance translational research and optimize clinical and implementation research to improve health and reduce disease for all, including stigmatized populations of PLWH and across the translational spectrum of HIV comorbid diseases . To addrCardiovascular healthcare disparities in vulnerable, underserved populations of PLWH worsen when they suffer from stigmas related to individual factors  and social determinants. The intersections of multiple marginalized identities and multiple social positions of disadvantage affect the health of Blacks, Indigenous people, and people of color (BIPOC) who are also sexual and gender minorities , 101. AsAlthough HIV, mental illness, and physical disability health status intersect with other forms of stigma related to social identities such as race, gender, and sexuality \u2013110, litThe National Institute of Allergy and Infectious Diseases (NIAID) mission is to support basic and applied research to better understand, treat, and ultimately prevent infectious, immunologic, and allergic diseases. Its HIV research priorities include development of new HIV prevention, treatment, and cure products and strategies . The HIVSeveral key HIV prevention studies have illuminated the fact that HIV-related stigma is a powerful motivator for behavior, even in the more controlled setting of clinical trials. The results of the VOICE trial (MTN 003), which was testing Truvada daily oral pills, Tenofovir daily oral pills, and Tenofovir vaginal gel used daily in women for use as PrEP made very clear that HIV-related stigma played a significant role in participant behavior in the trial . One reaNIAID funds HIV clinical trial networks and the Centers for AIDS Research (CFAR) focused on Improving of HIV treatment, prevention, and cure . These nEunice Kennedy Shriver National Institute of Child Health and Human Development. Leads research and training to understand human development, improve reproductive health, enhance the lives of children and adolescents, and optimize abilities for all [The  for all . In 2020 for all . In addiScientific findings of NICHD HIV stigma research address our U.S. populations of interest through several different areas, including disclosure, family planning, healthcare transition, and technology. As willingness to disclose HIV status is often negatively associated with misconceptions about HIV transmission and stigma, interventions to support caregivers and families with the disclosure process address such barriers . RelatedFuture directions for NICHD HIV stigma research will continue to leverage several ongoing research programs and networks to improve HIV health outcomes among NICHD populations of interest. For example, the Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) is the only domestic, multicenter research network devoted to the health and well-being adolescents and young adults at risk of and with HIV. Intended to support coordinated research efforts amongst investigators, community-based partners, and youth and young adults, the ATN develops, implements, and adapts its research agenda to respond to the HIV epidemic in the United States, including the role of stigma in HIV transmission. NICHD will continue to utilize such programs and databases to further its work in the area of HIV-related stigma research.The mission of the National Institute of Dental and Craniofacial Research is to improve dental, oral, and craniofacial (DOC) health . Across It is clear that unmet dental needs are a common challenge among people living with HIV, and the likelihood of an individual having an unmet dental need seems to increase with time since HIV diagnosis . Among oAcross the healthcare system, there is immense need for structural, social, and behavioral approaches that maximize the uptake of currently available tools for the prevention and treatment of HIV. Stakeholders in the dental community have long recognized potential roles for dental care providers in reducing the burden of HIV, though research and clinical practice have been slower to realize that vision. In an effort to advance research in this area and accelerate improvements in clinical practice, NIDCR has developed a new initiative to support research on how to optimally engage the dental workforce in meeting the unique needs of individuals living with or at risk of contracting HIV . Each ofNational Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) mission is to conduct and support medical research and research training and to disseminate science-based information on diabetes and other endocrine and metabolic diseases; digestive diseases, nutritional disorders, and obesity. Several health conditions addressed by the mission of NIDDK are associated with stigmas that often have negative impacts on psychosocial, educational, professional, and healthcare outcomes . Most noHow stigma associated with HIV impacts the development, exacerbation, and effective management and treatment of CCCs within NIDDK\u2019s mission remains poorly understood and needs to be better elucidated. There are several significant areas that could be explored. For example, stigmas often interact and, as discussed above, CCCs may be associated with specific stigmas of their own. Moreover, research focused on specific vulnerable populations needs to address how rather societal stigmas interact with the stigmas associated with HIV and CCCs. Understanding these pathways is a critical component of EHE, since PLWH with poorly managed CCCs may have poor patient engagement related to viral load monitoring and adherence to antiretroviral therapy. For example, NIDDK issued a research announcement with a focus on how societal factors, environmental barriers, and/or stigmas intersect with food insecurity and/or interventions for food insecurity in the context of CCCs, especially in vulnerable populations such as racial or ethnic minorities, sexual or gender minorities, sex workers, unaccompanied youth, older people, people with disabilities, rural residents, or people living alone .The National Institute on Drug Abuse\u2019s mission is to advance science on the causes and consequences of drug use and addiction and to apply that knowledge to enhance individual and public health including efforts to improve the prevention and treatment of substance use disorders . Stigma NIDA recognizes that drug use-related stigma is common in healthcare, social service and other settings related to HIV prevention and care and the drug use field has long acknowledged the presence of stigma as a barrier to adequate participation in prevention and care services, including those directed at HIV. Stigma in human service settings and self-stigma among PWUD can lead to insufficient access to substance use disorder treatment and harm reduction, as well as insufficient access to screening and care for co-occurring disorders such mental illness and HIV . ProvideStigma and Global Health conference that identified gaps in disease-associated stigma research and FIC-led program announcements to stimulate new research [NIDA is committed to informing and assisting EHE and other public health efforts through developing HIV stigma reduction interventions; supporting pilot, feasibility, implementation, and other studies; and testing new or adapted interventions to reduce stigmas that impede the effective provision, uptake, and utilization of HIV care and prevention services . The Insresearch . NIDA alThe National Institute on Minority Health and Health Disparities leads scientific research to improve minority health and reduce health disparities  HIV/AIDSNIMHD understands that stigma related to HIV, race/ethnicity, and SGM status ultimately contributes to and maintains HIV disparities through its manifestations at the structural and individual levels; and it is a barrier to the prevention, care and treatment of HIV. NIMHD-funded stigma research has focused on the impact of intersectional stigma and other social determinants of health as they relate to HIV prevention, care and treatment for our populations of interest. We have also focused our attention on patient-clinician interactions and stigmatizing attitudes and beliefs held by health care providers; and interactions of cultural attitudes. In addition, NIMHD supports measurement research on SGM-related constructs, including intersectional and structural stigma and discrimination.NIMHD is focusing future research on interventions to prevent HIV in health disparity populations in geographic areas with high rates of new infections. Future directions for NIMHD include research initiatives that focus on the role of structural stigma and discrimination in causing and sustaining health disparities; as well as interventions to reduce stigma and discrimination.The National Institute of Nursing Research\u2019s mission is to promote and improve the health of individuals, families, and communities . This brLove, Sex and Choices which follows the lives of five women navigating relationship scenarios against a text messaging control [NINR supported the development and clinical trial of a digitally-delivered, private HIV education intervention that draws on the experiences of African American and Latina women living in urban U.S. cities. Investigators developed and tested a streaming, web-based intervention called  control . The int control \u2013149. Ano control . The stu control . The int control .Looking forward, NINR recently awarded several research projects focused on the development and testing of community health worker strategies to improve self-management and durable viral suppression among people living with HIV who are out of care or struggling to maintain daily medication routine leading to viral suppression. The initiative is supported through OAR strategic funds and the research is in a geographically diverse set of EHE jurisdictions . As thisThe ICs discussed above are noteworthy for their involvement and investments in HIV-related stigma research. HIV-related stigma research activities and collaborations are taking place among and across these and other NIH ICs, at times with the involvement of OD offices as well. These partnerships and collaborations have and are strengthening the range and depth of the HIV-related stigma research being conducted at the NIH.Achieving EHE\u2019s goals will require a whole-of-society effort. As part of this, EHE is leveraging\u00a0critical scientific advances in HIV prevention, diagnosis, treatment, and care by coordinating the highly successful programs, resources, and infrastructure of many HHS agencies and offices, including the NIH.Developing and testing adaptations to improve interventions that have demonstrated efficacy in reducing HIV-related stigma and improving HIV outcomes across relevant settings, including health and public health contexts involved in HIV prevention and care services;Developing and testing interventions that address self-stigmas that impede people\u2019s use of HIV prevention or care services;Training healthcare, social service, and other providers during key points in their professional development, including their professional or specialty training  to adopt non-stigmatizing approaches;Developing and testing interventions that enable AIDS and other service organizations to address potential sources of stigma and increase their reach of HIV prevention and care;Developing organizational or structural intervention approaches to reducing HIV-related stigma and improve HIV outcomes;Evolving the understanding of and interventions for HIV-related intersectional stigma and discrimination; and,Advancing new approaches to address multi-level factors  that foster stigma and impede the use of HIV prevention and care services.Within this effort, it is recognized that HIV-related stigma is a dynamic and ubiquitous factor that must be considered and addressed in its many forms if EHE and other local and national efforts like it are to fully and robustly succeed. Given that HIV-related and other stigmas can occur at the individual, interpersonal, organizational and/or structural levels, and can be intersectional, there is still much to learn and to address. Key approaches the NIH is taking in the name of HIV elimination in the U.S. and around the world that specifically entails foci on HIV-related stigma include:Reducing HIV-related stigma and discrimination in healthcare settings;Improving communication competencies, integration of community voice and leadership, and partnership engagement overall;Taking whole person and whole society approaches;Understanding and addressing the challenges and needs of the stigmatized and those who stigmatize;Recognizing and addressing the impact of socio-structural dynamics and psychological factors driving HIV-related stigma;Improving models, measures, and mechanisms; andUnderstanding HIV-related stigma in context of other social determinants of health.As noted throughout this article, areas and themes needing further research, intervention, and implementation include:In closing, the broad span of the federal government itself has a role in addressing HIV as well as other stigmas and discrimination. Across the federal government, multiple agencies play a role in enforcing federal civil rights protections, providing technical assistance for carrying out the mandates of the American for Disabilities Act and other laws, and developing and disseminating information about civil rights and protections. While some Departments have authority to enforce these protections, nearly all can disseminate relevant information about protecting the rights of persons living with HIV and to take steps to confront and reduce HIV-related stigma.These actions on the part of the NIH, in tandem with the needed whole of government/whole of society approach, will contribute to achieving the EHE milestones and 2030 goal as well as work towards fulfilling the National HIV/AIDS Strategy: Updated to 2020 vision, that \u201cThe United States will become a place where new HIV infections are rare and when they do occur, every person regardless of age, gender, race/ethnicity, sexual orientation, gender identity or socio-economic circumstance, will have unfettered access to high quality, life-extending care, free from stigma and discrimination .\u201d And as"}
+{"text": "The cerebroplacental ratio (CPR) is an important index for predicting adverse pregnancy outcomes in small-for-gestational-age and appropriate-for-gestational-age fetuses.To find out whether there is an association between the CPR level and the blood cord gases analysis in appropriate for gestational age fetuses.This cross-sectional study included 347 pregnant women at the gestational age of 37-40 wk. Patients had an appropriate-for-gestational-age fetus confirmed from their first ultrasonography results. Participants were divided into two groups based on their CPR, measured before delivery. Finally, after delivery, arterial blood gas level and the incidence of emergency cesarean section, intrapartum fetal distress and neonatal intensive care unit admissions were compared between the two groups.Fifty-four (15.6%) cases had a CPR below the detection limit of the assay. The incidence of fetal distress, emergency cesarean section, neonatal hospitalization in the neonatal intensive care unit, and pH The third-trimester CPR is an independent predictor of stillbirth and perinatal mortality and morbidity. The role of UA/MCA Doppler and the CPR in assessing the risk of adverse pregnancy outcomes should be evaluated prospectively. The cerebroplacental ratio (CPR) is an important index for predicting adverse pregnancy outcomes in small-for-gestational-age (SGA) and appropriate-for-gestational-age (AGA) fetuses. The CPR is calculated by dividing the pulsatility index (PI) of the middle cerebral artery (MCA) by that of the umbilical artery (UA) (1).The CPR, which was first introduced in 1987, is recognized as a more sensitive Doppler index to predict perinatal outcomes, as it shows the status of both the placenta and fetus. Doppler indices for CPR measurements include the resistance index, the PI of the UA, and Doppler waveform indices of MCA. However, the CPR is not routinely measured in clinical practice (2).Intrapartum hypoxia is the cause of nearly 10-15% of cases of cerebral palsy. Despite the clinical importance of this condition, antenatal identification of fetuses at risk of cerebral palsy and other hypoxia-related outcomes remains a challenge. Hence, a prediction of fetal blood gas imbalance could be helpful for identifying the associated risks and preventing their consequences. Fetal CPR, measured within 72 hr after delivery, can help identify fetuses that are likely to require obstetric intervention for intrapartum fetal compromise (3).In this study, we aimed to determine the correlation between the CPR and neonatal outcomes in AGA fetuses.This cross-sectional study was conducted from December 2016 to February 2018 on young pregnant women referred to Dr. Shariati Hospital, a referral hospital affiliated to Tehran University of Medical Science, Tehran, Iran.A total of 403 pregnant women were recruited who were at the gestational age (GA) of 37-40 wk and had an AGA fetus according to their first ultrasonography. The exclusion criteria were a history of multiple pregnancies, history of preterm birth, fetal growth restriction, and fetal abnormalities. However, 56 women were later excluded due to a lack of sampling and other limiting conditions.Finally, participants were divided into two groups according to their CPR level, as measured before delivery. After delivery, the arterial blood gas (ABG) level, and the incidence of emergency cesarean section, intrapartum fetal distress and neonatal intensive care unit admissions were compared between the two groups.Color Doppler sonography of the UA and MCA was performed by a perinatologist before delivery via ultrasonography device . The CPR was calculated by dividing the PI of the MCA by that of the UA.The ABG was measured in the hospital's laboratory and the total number of cases who were admitted to the neonatal intensive care unit (NICU) was recorded. Fetal distress was evaluated with FHR monitoring.This study was approved by the ethics committee of Tehran University of Medical Sciences (Code: IR.TUMS.MEDICINE.REC.1396.4301). All patients provided informed consent prior to the study.t test. Differences in the pregnancy outcomes of the two groups were analyzed using the Chi-square test. P Data analysis was performed using Social Sciences statistical package v. 19 . Descriptive analyses were performed including means, and standard deviations. The baseline characteristics of the two groups were compared using the student's In this study, 403 pregnant women who met the inclusion criteria of the study were enrolled. During the study, 56 of these women were excluded .Patients were divided into two groups based on their CPR level (cut-off: 0.67 MOM).Participants in the two groups did not differ significantly in terms of demographic characteristics including maternal age, GA at the time of ultrasonography, and GA at the time of delivery (Table I).The incidences of fetal distress, emergency cesarean section, neonatal hospitalization in the NICU, and pH The results of all variables were different between the two groups. Based on the findings, it can be concluded that a low CPR is associated with a low Apgar score, low pH in the ABG of the neonate, and an increased rate of emergency cesarean section and NICU admission. As a result the third-trimester CPR is an independent predictor of stillbirth and perinatal mortality and morbidity.Numerous studies have shown that a low CPR indicates redistribution of fetal blood flow (brain-sparing) and predicts adverse outcomes in neonates. The abnormal fetal growth velocity, NICU admission, emergency cesarean section for fetal distress, intraventricular hemorrhage, hypoxic ischemic encephalopathy, necrotizing enterocolitis, bronchopulmonary dysplasia, sepsis, and even death are some of the adverse fetal outcomes (4-6).Term infants weighing The CPR is a preliminary diagnostic measure of pregnancy complications, which can be compared to the biophysical profile score and UA/MCA Doppler studies. The CPR can be used as an independent tool in evaluating of third-trimester fetuses, regardless of UA and MCA findings (1).Detection of stillbirth in prolonged pregnancies is linked to late placental insufficiency and fetal hypoxemia. Therefore, fetal Doppler monitoring may improve the management of fetal condition, although the literature suggests conflicting results. The CPR can help to detect fetal hypoxemia through two mechanisms of reduced resistance in MCA (brain-sparing effect) and increased placental resistance. The CPR has been shown to be more important than Doppler indices of MCA and UA alone in predicting adverse fetal outcomes, associated with growth restriction and prolonged pregnancy (10-12).There is much literature in this field, discussing the pros and cons of the CPR calculation and its features. A number of studies have shown an association between the CPR and growth rate as well as birth weight .Moreover, some researchers showed that the CPR is a major independent predictor of stillbirth and perinatal mortality, and the CPR has the highest sensitivity in the prediction of both intrapartum abnormal fetal heart rate and adverse neonatal outcomes in prolonged pregnancies .However, some believe that there is no relationship between pregnancy outcomes and CPR in prolonged pregnancies (10).The literature suggests that fetuses with CPRs They revealed that the CPR is a marker of impaired fetal growth velocity and adverse pregnancy outcomes, even in fetuses whose size is considered appropriate based on conventional biometry .The findings of this study demonstrate that a low CPR in AGA fetuses is an important marker of low neonatal pH.The CPR is an important factor in predicting the morbidity and mortality of infants. And a low CPR, even in normal weight fetuses, can be a sign of hypoxemia and placental insufficiency. However, this claim needs further investigation.The authors declare that there is no conflict of interest."}
+{"text": "Nanotoxicology, a discipline transpired by the need to assess the human and environmental safety of nanoscale materials, has evolved over the past 15 years into a mature area of toxicology. Early on, nanotoxicology studies established a necessary understanding of dose-response relationships of nanomaterials using typical in vitro toxicology models, provided crucial information on interferences induced by nanoparticles (NPs) in the conventional toxicity assays and how to overcome these, and demonstrated that due to their unique physical\u2013chemical properties, nanomaterials act via different toxicological mechanisms than the bulk counterparts of the same materials. For example, ZnO, known as a water-insoluble compound in bulk form, was shown to exert toxicity through released Zn-ions in the case of ZnO NPs, and the cellular uptake pathways of NPs were discovered to depend on the size, shape, and surface properties of nanoscale particles. As the knowledge on NP toxicity mechanisms and behavior in the environment and organisms has accumulated, nanotoxicologists have acknowledged the need for improved understanding about the NP interactions with biological systems at the molecular level to better predict the potential toxicity of novel nanomaterials and ensure safe and sustainable development of nanotechnology.Accordingly, recent trends in nanotoxicology include incorporation of high-throughput screening approaches to establish structure-activity relationships using libraries of NPs with different properties and in vitro screening assays combined with computational analysis; omics- approaches, including metabolomics, proteomics, and transcriptomics, to discover molecular-level effects of NPs at low, sub-lethal NP concentrations, and method development to include sensitive toxicity assays for early detection of toxic effects. Environmental nanotoxicology is moving towards the direction of enhancing the relevance of testing conditions  to these relevant to the environment and organism physiology, because NP toxicity has been proven to depend on the interactions with natural organic matter, anions and cations, the level of pH, and other environmental factors. Another major direction of nanotoxicology which has gained momentum in the recent years is the safety assessment of nanomaterials designed for applications in biotechnology, environmental bioremediation, wastewater treatment, agriculture, and nanomedicine. Thus, nanotoxicology has a substantial role not only in the risk assessment of unintentionally or intentionally produced nanomaterials but also in ensuring successful nanoinnovation across broad applications and enabling safe-by-design approach in nanotechnology.This Special Issue covers a range of topics regarding the latest research trends in nanotoxicology. The collection includes 10 research articles and 5 reviews by authors from 16 countries, spanning four continents, which illustrates the global significance of nano-enabled technology and its safety assessment. It is worth noting that, in addition to guest editors who both are female scientists, most of the lead authors of the papers of this Special Issue are female scientist which is an important tendency in the STEM areas. The topics of the research articles and review papers address both environmental nanotoxicity as well as human health and nanomedicine safety aspects, providing an excellent overview of the current status of these important sub-areas of nanotoxicology.2 nanospheres and TiO2 nanotubes to two freshwater algae with different morphology [2 nano-spheres and nanotubes was different from the toxicity of single exposures and depended on the microalgal species. Aravantinou et al. assessed the long-term toxicity of ZnO NPs to microalgae using a modeled natural water treatment system with a semi-continuous supply of NPs [Scenedesmus rubescens was used as a model due to its presence in municipal wastewater and its potential use for biofuel production. The study showed that low concentration (0.081 mg/L) of ZnO NPs, supplied at lower hydraulic retention time, slightly inhibited algal growth but enhanced the lipid content of S. rubescens, highlighting the need for further studies of NP-biota interactions in environmentally relevant conditions. The importance of considering the presence of natural organic matter in nanotoxicity studies has been well illustrated in the article by Bondarenko et al. who assessed the ecotoxicity of magnetite NPs in a plant and unicellular eukaryotic model, assessing the influence of humic acid on the toxicity of the NPs as well as Fe(II) and Fe(III) ions [Eisenia andrei, to study the toxicity mechanisms of nanoscale zero-valent iron (nZVI).The original research articles regarding environmental nanotoxicology address aspects that have been less explored in the nanotoxicology studies so far, such as combination toxicity and long-term toxicity of NPs. For example, Wang et al. investigated the toxicity of the binary mixture of TiOrphology . They foII) ions . In anotII) ions . DevelopII) ions . They us2 NP toxicity, and specifically clarified the mechanism of cell death caused by the combined exposure to UVA and TiO2 NPs [2 NPs  under UVA irradiation in HeLa cells and showed that the abnormal membrane integrity and the ultrastructure of HeLa cells, together with the decreased viability induced by TiO2 NPs under UVA irradiation, were due to cell necrosis rather than caspase-dependent apoptosis.The method development and application of novel omics approaches, which can provide molecular-level information about NP biological effects, were also the focus of research articles regarding the human health and nanomedicine safety. Enea et al. applied an innovative and sensitive approach\u2014metabolomics\u2014to compare the in vivo toxicological effects of gold nanospheres versus gold nanostars of similar ~40 nm diameter, coated with 11-mercaptoundecanoic acid, 24 h after an intravenous administration to Wistar rats . Using aTiO2 NPs . They inSeveral articles in the Special Issue discuss the beneficial properties on NPs and the associated mechanisms as well as safe environmental application of NPs. In their research paper, Sguizzato et al. report on the development of a formulation for caffeic acid cutaneous administration . The nanStaphylococcus aureus (MRSA) and biofilm eradication in clinical settings [Clinical applications of NPs and associated safety concerns have been discussed in three review articles. Mosselhy et al. review recent advances in nanotheranostics focusing on the issue of detecting methicillin-resistant settings . The autsettings . A specisettings . The autIn summary, the article collection in this Special Issue addresses important recent trends in nanotoxicology, both from the environmental and human health safety aspects. The articles illustrate the directions where the toxicity studies of NPs  are headed: employing novel and sensitive methods which provide molecular level information about the mechanisms of action of NPs, focusing on the NP-biomolecule interactions, development of biomarkers for early detection of NP toxicity, and guiding safe-by-design strategies for NPs."}
+{"text": "Lacazia loboi in the cutaneous and subcutaneous tissues, with the presence of isolated nodular and coalescent keloidal lesions. Malignant degeneration is rare. This case report describes a 64-year-old male patient with JLD for 30-years who showed a change in the aspect of a lesion in the left lower limb. Histopathological examination confirmed the progression to well-differentiated squamous cell carcinoma (SSC). JLD is highly prevalent in tropical and subtropical regions, requiring monitoring concerning the transformation into SSC in long-term lesions.Jorge Lobo\u2019s disease (JLD) is a chronic, granulomatous fungal infection caused by the traumatic implantation of the fungus  Lacazia loboi.Lacazia loboi (Jorge Lobo\u2019s disease (JLD) is a chronic granulomatous infection of the skin and subcutaneous tissue, without visceral dissemination, which is caused by the fungus ia loboi . Left inJLD, first described in 1931 by Jorge Lobo in a patient from the Amazon region, is a typical infection in tropical and subtropical areas, more common in men aged 20 to 40 years.5None declared.Arival Cardoso de Brito: Approval of the final version of the manuscript; design and planning of the study; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.Maraya de Jesus Semblano Bittencourt: Approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; effective participation in research orientation; critical review of the manuscript.Thain\u00e1 da Silva Gon\u00e7alves: Approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature.Renata Henriques Cavalcante: design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature.None declared."}
+{"text": "The Support at Home pilot program provided financial support for home care services by middle-income adults with disabilities in San Francisco to support aging in place. This presentation reports the results of the mixed-methods evaluation of the program, which incorporated administrative records, surveys of clients and comparison group members, surveys of informal caregivers of clients, surveys of the care providers hired by clients, and focus groups with clients and with informal caregivers. Outcome measures included the Older People\u2019s Quality of Life Questionnaire, Patient Health Questionnaire-2, an adapted Burden Scale for Family Caregivers, and self-reported falls, emergency department visits, and hospitalizations. Analyses included pre-post chi-squared and t-test comparisons and comparisons of changes between the client and comparison groups. Multivariate regression analyses were conducted to control for demographic differences between the groups. An economic analysis was conducted to learn whether changes in costs associated with medical appointments, emergency department visits, and hospitalizations were greater than the costs of the program, including both voucher and administrative costs. Results indicated statistically significant positive changes in personal stress and financial stress, but not in the composite quality of life score. There also were statistically significant reductions in attendance at medical appointments, falls, emergency department visits, and hospitalizations. The focus group data supported the findings regarding personal and financial stress, and also indicated that clients and their caregivers perceived positive quality of life benefits. The economic analysis indicated substantial cost savings from the program due to reduced use of medical services."}
+{"text": "ABSTRACT IMPACT: Development and implementation of a parent navigator program to help parents of justice-involved youth could assist parents in navigating the justice system, improve engagement with court and probation, and ultimately improve outcomes for youth involved in the juvenile justice system OBJECTIVES/GOALS: The goals of the study are to (1) develop a parent-peer navigator program utilizing community-based participatory design; and (2) implement and assess the feasibility of a parent peer navigator program in an urban juvenile justice system. METHODS/STUDY POPULATION: The EPIS framework will guide development and implementation of the navigator program as well as measurement of the implementation process, including measurements of feasibility and acceptability. In the Exploration phase, qualitative interviews with juvenile justice staff, parents of justice-involved youth, and members of the local family advisory board will inform program needs. In the preparation stage, I will work closely with the family advisory board to develop the actual parent navigator program protocol, including a training plan for navigators and their specific roles. I will conduct an open trial in the implementation phase, measuring program feasibility and acceptability among parents, navigators, juvenile justice staff, parents, and youth utilizing mixed methods. RESULTS/ANTICIPATED RESULTS: Results will inform feasibility of implementing the program as well as acceptability of the program based on mixed methods data from parents of justice-involved youth, juvenile justice staff, family advisory board members, and other community stakeholders. Results will potentially inform conduct of a larger scale pilot hybrid implementation-effectiveness study. DISCUSSION/SIGNIFICANCE OF FINDINGS: Development and implementation of a parent navigator program to help parents of justice-involved youth could assist parents in navigating the justice system, improve engagement with court and probation, and ultimately improve outcomes for youth involved in the juvenile justice system."}
+{"text": "There has been little focus on designing tailored diabetes management strategies in developing countries. The aim of this study is to develop a theory-driven, tailored and context-specific complex intervention for the effective management of type 2 diabetes at a tertiary care setting of a developing country. We conducted interviews and focus groups with patients, health professionals, and policymakers and undertook thematic analysis to identify gaps in diabetes management. The results of our previously completed systematic review informed data collection. We used the United Kingdom Medical Research Council framework to guide the development of the intervention. Results comprised 48 interviews, two focus groups with 11 participants and three co-design panels with 24 participants. We identified a lack of structured type 2 diabetes education, counselling, and collaborative care of type 2 diabetes. Through triangulation of the evidence obtained from data collection, we developed an intervention called VICKY (patient-centred collaborative care and structured diabetes education and counselling) for effective management of type 2 diabetes. VICKY comprised five components: (1) patient-centred collaborative care; (2) referral system for patients across transitions of care between different health professionals of the diabetes care team; (3) tools for the provision of collaborative care and documentation of care; (4) diabetes education and counselling by trained diabetes educators; and (5) contextualised diabetes education curriculum, educational materials, and documentation tools for diabetes education and counselling. Implementation of the intervention may help to promote evidence-based, patient-centred, and contextualised diabetes care for improved patient outcomes in a developing country. Type 2 diabetes is a global public health problem and an economic burden to nations, particularly developing countries . It contIneffective management of type 2 diabetes has been associated with poor clinical outcomes, which include disease progression, and increased health services utilisation, such as repeated hospitalisations and high all-cause mortality ,6,7. In Patient-centred collaborative care and the use of culturally tailored interventions, including behavioural interventions, can improve diabetes care in low-income countries ,24,25. EThe aim of this study was to develop a theory-driven, tailored, and context-specific complex intervention for the effective management of type 2 diabetes at a tertiary care setting of a developing country.The study was undertaken at the diabetes centre of a tertiary teaching hospital  in Addis Ababa, Ethiopia. Diabetes care is provided at the diabetes centre of the hospital by endocrinologists, endocrinology fellows, internal medicine residents, and nurses . Each moThe United Kingdom Medical Research Council (UK MRC)  frameworDeveloping a complex intervention involves three steps : (1) ideThe first stage in the development of a complex intervention is to identify an existing, relevant evidence base . We undeIdentification and development of appropriate theory in intervention design is key to understanding the possible processes of change ,44. The We used a co-design panel comprising patients, health professionals, and policymakers at TASH and the Ministry of Health of Ethiopia with a representative of the Ethiopian Diabetes Association and incorporated the findings from the systematic review , interviThe first co-design workshop involved health professionals, policymakers from TASH and the Ministry of Health of Ethiopia, and a professional officer from the Ethiopian Diabetes Association . During We conducted the second co-design workshop with patients with type 2 diabetes . The purWho needs to perform the behaviour?What do they need to do differently to achieve the desired change?When do they need to do it?Where do they need to do it?How often do they need to do it?With whom do they need to do it?A joint workshop was undertaken with a nominated patient, health professionals, policymakers, and a professional officer from the Ethiopian Diabetes Association. The workshop involved examining the defined problem related to the effective management of type 2 diabetes and the selected potential target behaviours during the two separate workshops (workshop I and II). The workshop panel members specified the target behaviours that were agreed upon. In workshop III, the panel members discussed and reached a consensus on the defined problem related to effective management of type 2 diabetes and the selected potential target behaviours at workshops I and II . The criThe co-design panel worked through stage one to stage three of the behaviour change intervention design process . The steThis stage involved four steps  47]. St. St47]. Decide what \u2018intervention functions\u2019 to apply: education, persuasion, incentivisation, coercion, training, restriction, environmental restructuring, modelling, and enablement;Select implementation strategy: fiscal policy, legislation, regulation, environmental planning, communications, service provision, and guidelines development. This stage involves the use of the behavioural diagnosis  to: DeciDevelop a detailed intervention plan by selecting from among a range of specific behaviour change techniques (BCTs) . Michie Create the detailed intervention specification covering all aspects of content and delivery of the intervention structured around the chosen BCTs and modes of delivery. The focus of the third stage is to:Appropriate intervention functions, BCTs, and intervention contents were determined through discussion between the co-design panel and the research team and using the APEASE criteria . The APEModelling of a complex intervention  helps toIn this study, we operationalised the intervention functions and BCTs into a complex intervention to improve the effectiveness of type 2 diabetes management. The researchers collaborated with the co-design panels in operationalising the intervention functions and BCTs into the mode of care delivery using the BCW framework . We usedWe undertook interviews with 48 participants and two focus groups (n = 11) with patients with type 2 diabetes, health professionals, and policymakers from TASH and the Ministry of Health of Ethiopia  comprisiEvidence from the interviews and focus groups we have undertaken, previous findings ,12,13,60Lack of resources, such as medications, laboratory, and diagnostic tests;Lack of continuity of care, such as prolonged follow up clinic visits;Lack of knowledge and awareness of patients about type 2 diabetes and its complications;Lack of self-care activities;Low level of type 2 diabetes education and counselling services;Low competence and experience of health professionals providing diabetes care;Inefficient collaboration among health professionals  in the care of type 2 diabetes;Absence of involvement of clinical pharmacists, dietitians or nutritionists, and psychologists in the care of type 2 diabetes.We identified through interviews, focus groups, and co-design workshops that had challenges for the effective management of type 2 diabetes related to:Our findings from interviews and focus groups demonstrated that the problem of the effective management of type 2 diabetes can be addressed through multiple behaviours targeted in a complex intervention. These include: ensuring continuity of care; enabling provision of structured type 2 diabetes education and counselling by competent health professionals; providing collaborative care of type 2 diabetes, involving clinical pharmacists, dietitians or nutritionists, and psychologists in type 2 diabetes care; improving health professionals\u2019 competency, commitment and professional ethics; and improving the referral system of patients with type 2 diabetes between TASH and other health institutions . The co-Provide structured diabetes education and counselling with competent health professionals;Enable collaborative care of type 2 diabetes;Involve clinical pharmacists, dietitians or nutritionists, and psychologists in the care of type 2 diabetes as members of the collaborative care team;Improve health professionals\u2019 competency, commitment, and professional ethics through trainings.During the co-design workshop, the co-design panel prioritised the potential target behaviours, out of which the four potential target behaviours are listed from highest to lowest priority:Similarly, the co-design panel in workshop II identified and prioritised the following potential target behaviours for intervention in descending order of priority.Ensure continuous availability of medications;Ensure continuous availability of laboratory and diagnostic tests;Involve clinical pharmacists, dietitians or nutritionists, and psychologists in the care of type 2 diabetes as members of the collaborative care team;Enable collaborative care of type 2 diabetes;Integrate all type 2 diabetes care services at the diabetes centre.Given the evidence from the interviews, focus groups, and previous findings ,30,61, bThe co-design panels confirmed that there was no involvement of clinical pharmacists, dietitians or nutritionists, and psychologists in the provision of type 2 diabetes care. It was found that there was a profound deficiency of the collaborative care of type 2 diabetes at the diabetes centre of TASH. A collaboratively working care team is more likely to be responsive, efficient, and provide improved care . As multAfter the selection of the potential target behaviours for intervention, the co-design panel in workshop III specified the two target behaviours, namely to enable the provision of structured type 2 diabetes education, counselling, and collaborative care of type 2 diabetes. These details are found in the table of The findings of the interviews, focus groups, and co-design panel workshops indicated the need for the involvement of physicians, nurses, clinical pharmacists, dietitians or nutritionists, psychologists, and peer diabetes educators in the provision of structured diabetes education and counselling with patients or family members (caregivers) to improve the care of type 2 diabetes at TASH. The structured diabetes education involved the education of patients with type 2 diabetes about the condition, its complications, and management and self-care activities .In enabling the collaborative care of type 2 diabetes, physicians, nurses, clinical pharmacists, dietitians or nutritionists, and psychologists would work in coordination with patients and their families (caregivers), administrative bodies of the hospital, and the Ministry of Health of Ethiopia. A collaborative care team would be organised at the diabetes centre of TASH. The duties and activities of each member of the diabetes care team are described in the table of We used the COM-B system  to identThe provision of structured diabetes education and counselling at TASH was hampered by a lack of availability and involvement of trained and qualified multidisciplinary health professionals in diabetes education and counselling (C). Insufficient time for the consultation of patients (O) and inadequate space (O) led to a lack of physical opportunity to provide structured diabetes education and counselling about type 2 diabetes. Patient adherence to diabetes educations sessions (O) negatively affected the provision of type 2 diabetes education at TASH. A triangulation of evidence from the interviews, focus groups, systematic review , co-desiTime shortages and inappropriate space (O), poor communication among health professionals (O), lack of commitment and motivation of health professionals and policymakers (M), and absence of policies and guidelines for collaboration (O) contributed to a lack of collaborative care of type 2 diabetes at TASH. We triangulated the findings from interviews, focus groups, the co-design panel workshops, and the research team discussions and performed the behavioural analysis using the COM-B . We analIntervention functions appropriate to the context of TASH and that help to improve the management of type 2 diabetes were determined using the APEASE criteria  Table S.We used the BCW  mapping We linked the COM-B components of the collaborative care of type 2 diabetes  with intervention functions using the BCW  mapping After identification of the intervention functions, we evaluated the appropriate policy categories that support the delivery of the intervention functions using the APEASE criteria . GuideliFeedback on behaviour;Self-monitoring of behaviour;Prompt/cues;Salience of consequences;Instruction on how to perform the behaviour;Demonstration of the behaviour;Restructuring the physical environment;Restructuring the social environment;Adding objects to the environment;Goal setting behaviour;Action planning;Social support (unspecified).Behaviour change techniques are active components of an intervention designed to change behaviour  that helWe operationalised the identified BCTs and identified modes of delivery for the provision of structured education and counselling with trained diabetes educators and collaborative care of type 2 diabetes and developed a complex intervention . We creaThe complex intervention (VICKY) consisted of five components .The following 13 BCTs were linked to the intervention functions for the target behaviour in the collaborative care of type 2 diabetes .Self-monitoring of behaviour;Prompt/cues;Feedback on behaviour;Instruction on how to perform the behaviour;Restructuring the physical environment;Restructuring the social environment;Adding objects to the environment;Demonstration of the behaviour;Goal setting behaviour;Action planning;Social support (unspecified);Social support ;Problem solving.We used the logic model  to link This paper describes a systematic development of a tailored complex intervention to improve the effectiveness of the management of type 2 diabetes in a tertiary care setting of a developing country. To our knowledge, the complex intervention is the first theory-driven and context-specific intervention designed using the first stage of the UK MRC framework and the BCW and co-design approaches for the management of type 2 diabetes in Ethiopia.Our intervention addresses an organisational level intervention that involves multiple stakeholders and multifaceted approaches, such as the training of health professionals, provision of educational materials, collaborative care, and patient involvement in the care process. Multifaceted approaches have been demonstrated to be successful in improving healthcare in resource-limited settings, including SSA ,70,71,72Implementation science offers opportunities to design novel healthcare approaches to ensure the utilisation of resources for evidence-based healthcare delivery in developing countries, including SSA ,77. EffoThe MRC framework  guided tThere have been tailored complex interventions ,48 desigWe designed an organisational level intervention to improve the effectiveness of type 2 diabetes management. There is a broad range of evidence internationally in support of organisational interventions to improve the care of type 2 diabetes and patient outcomes ,55,56. SDiabetes care models of developed countries are evidence-based, patient-centred, team-based, and guided by contextually tailored diabetes management guidelines and educational materials, where diabetes education by trained diabetes educators are essential elements of care ,96,97. SOur proposed intervention involves the collaborative care of diabetes, diabetes training of health professionals, and diabetes education by a trained team of health professionals. Evidence also indicates that the diabetes care team needs to incorporate a multidisciplinary group involving physicians, nurses, clinical pharmacists, dietitians or nutritionists, and psychologists ,63,64,65This study has some limitations. We did not include the views of nutritionists or dietitians, psychologists, and laboratory personnel in the intervention design. The intervention was designed at a single healthcare setting, requiring feasibility and piloting prior to evaluation and implementation. Nevertheless, the information obtained can be transferred to other similar settings.This paper indicated the usability and applicability of the UK MRC framework and the BCW to designing tailored and evidence-informed behaviour change interventions in SSA. We developed the UK MRC-guided intervention called patient-centred collaborative care and structured diabetes education and counselling (VICKY) using the BCW. VICKY, which is a tailored intervention to the context of a tertiary care setting of a developing country, is a complex intervention for diabetes management to be tested for feasibility and effectiveness in later phases of this project. This intervention will help to manage diabetes effectively by addressing the current practice gap existing at the hospital, and the country in general. VICKY is a comprehensive diabetes care model co-designed by key stakeholders involving consumers, healthcare providers of various disciplines, and policymakers using multiple evidence sources. This model, if found effective, may serve as a springboard to design similar tailored interventions for other non-communicable diseases in the country."}
+{"text": "The European Union Directives stipulate mandatory tests for the presence of any infections in donors and donations of substances of human origin (SoHO). In some circumstances, other pathogens, including fungi and parasites, may also pose a threat to the microbial safety of SoHO.The aim of the two systematic reviews is to identify, collect, and evaluate scientific evidence for the presence of fungal and parasitic infections in donors and donations of SoHO, and their transmission via transfusion and transplantation.An algorithmic search, one each for fungal and parasitic disease, was applied to 6 scientific databases . Additionally, manual and algorithmic searches were employed in 15 gray literature databases and 22 scientific organization websites. The criteria for eligibility included peer-reviewed publications and peer-reviewed abstract publications from conference proceedings examining the prevalence, incidence, odds ratios, risk ratios, and risk differences for the presence of fungi and parasites in donors and SoHO donations, and their transmission to recipients. Only studies that scrutinized the donors and donations of human blood, blood components, tissues, cells, and organs were considered eligible. Data extraction from eligible publications will be performed independently by two reviewers. Data synthesis will include a qualitative description of the studies lacking evidence suitable for a meta-analysis and a random or fixed-effect meta-analysis model for quantitative data synthesis.This is an ongoing study. The systematic reviews are funded by the European Centre for Disease Prevention and Control, and the results are expected to be presented by the end of 2021.The systematic reviews will provide the basis for developing a risk assessment for fungal and parasitic disease transmission via SoHO.PROSPERO International Prospective Register of Systematic Reviews CRD42020160090; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020160090 ; PROSPERO International Prospective Register of Systematic Reviews CRD42020160110; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020160110DERR1-10.2196/25674 Trypanosoma cruzi) [The European Union Directives have set safety interventions to prevent transmission of infections through substances of human origin (SoHO) ,2. The sa cruzi) .Surveillance data on the presence and transmission of pathogens via cells, tissue, and blood are currently collected at the national and European Union levels. However, no such data are yet available for organ transplantations . GloballThe systematic review protocols are registered with PROSPERO ; registration numbers: CRD42020160090, CRD42020160110 ,9. The PWe will employ the FINER  approach  to test A pilot search demonstrated an adequate number of studies for inclusion in the systematic reviews. The algorithmic search in the PubMed database retrieved 2320 and 1895 publications on the relevant fungal and parasitic infections, respectively. Additionally, the technical expertise of the review team, the time allocation, and the available funding guarantee its successful completion.The research questions are interesting as the systematic reviews aim at providing vital information on mitigating the risk of fungal and parasitic diseases transmission via SoHO. This is significant because fungal diseases kill >1.5 million and affect >1 billion people annually globally , while pThe systematic reviews will confirm or reject the earlier findings and produce new findings on the fungal and parasitic infections transmission risks via SoHO donations or contaminations, which would be used to develop future preventive interventions.There are no ethical concerns regarding the current systematic review processes, as it will be entirely based on evidence accumulation from earlier studies.The research questions are relevant to current scientific knowledge, clinical practices, and health policies.The selection of the information sources was based on the relation of scientific topics to the systematic review research questions and information retrieved from analysis regarding the optimal database combination for biomedical systematic reviews . The revScientific databases for peer-reviewed publications included PubMed, EMBASE, Web of Science, Scopus, Cochrane Library , and CINAHL.Databases for gray literature included JSTOR, OpenGrey, ROAR, ROARMAP, OpenDOAR, GreyNet, British Library, TextRelease, APO, bioRxiv, arXiv, Google Scholar, Infectious Disease Advisor, Healthfinder, and TRIP (Turning Research into Practice).Scientific organization websites for identifying peer-reviewed publications, technical reports, and guidelines containing original data included World Health Organization; European Commission; ECDC; Centers for Disease Control and Prevention (CDC); National Health System, United Kingdom; International Foundation for Care; National Health Information Center; Agency for Toxic Substances and Disease Registry; Food and Drug Administration; Indian Health Services; National Center for Chronic Disease Prevention and Health Promotion; National Center for Emerging and Zoonotic Infectious Diseases; National Center for Health Promotion and Disease Prevention, Veterans Health Administration; National Center for Human Immunodeficiency Virus, Sexually Transmitted Disease, and Tuberculosis Prevention, CDC; National Institutes of Health; National Institute of Environmental Health Sciences; Office of Public Health Genomics, CDC; American College of Preventive Medicine; Robert Koch Institute; Australian Department of Health and Aging; National Notifiable Diseases Surveillance System; and ClinicalTrials.gov.The search strategy was based on the guidelines of the Cochrane Library , while rThe official searching procedure for the gray literature databases and the organizations' websites was accomplished by three members of the review team . Following the selection process, a search for the reference lists of systematic reviews, meta-analyses, technical reports, and guidelines relevant to the research questions will be done. Finally, the reference lists of the eligible publications will be screened to identify any research questions\u2013related publications missed out in the initial searching.The inclusion criteria are set for the types of studies, types of participants, and extracted data items.The review team identified the following types of studies to be included as eligible in the systematic review: (1) peer-reviewed experimental, epidemiological studies of any methodological design and case reports that examined the prevalence, incidence, odds ratios, risk ratios, and risk differences of the presence of the fungal and parasitic infections in SoHO from an infectious donor or contaminated donation to recipients; (2) peer-reviewed in vitro studies that explored the presence of fungi and parasites in SoHO donors and donations, and transmission via SoHO to humans; (3) technical reports or guidelines by any relevant organizations, where eligible peer-reviewed publications and related original data can be detected; (4) articles from any organizations that investigated disease prevention  relevant to the research objectives; (5) outputs in any language; (6) no date limits will be applied in the selection of eligible publications; (7) only peer-reviewed conference proceedings will be eligible from the gray literature, as failure to recognize trials reported in conference proceedings may impose a risk of bias in the effect estimates .The type of participants in the eligible studies will be humans. The term \u201csubstances of human origin\u201d  refers to blood, blood components, tissues, cells, and organs. As a result, therapeutic  and diagnostic products derived from humans will not be included in the systematic review. Therefore, the interventions to be considered will be blood and blood components\u2019 donations and transfusions in humans, and tissue, cell, and organ donations and transplantations in humans.The other data items that will be extracted from the databases include the following: (1) population demographics from eligible studies; (2) number of cases and percentages of fungal and parasitic infections in SoHO donors and donations, and their transmission via SoHO donations; (3) the prevalence of fungal and parasitic infections in SoHO donors and donations, and transmission via SoHO donations; (4) odds ratios, risk ratios, and risk differences of the fungal and parasitic infections among SoHO donors and donations, and their transmission risks via SoHO donations between intervention  and control groups ; (5) associations of donor derived SoHO\u2013related fungal and parasitic disease transmission with demographic characteristics of the population and with any other factor susceptible to the infections; (6) diagnostic methods for the transmissions associated with the relevant SoHO donations (not those related to other exposures); (7) medications received by patients before and during diagnosis; (8) follow-up measures including hospitalizations and deaths; (9) risk factors of the fungi and parasitic infections or contaminations in SoHO donors and donations, and transmissions via SoHO donations; (10) type of infection screening tests in SoHO donors; and (11) country and continent of the population of eligible studies.The exclusion criteria will be: studies not identifying the transmission of the fungal and parasitic diseases via SoHO donations; animal studies; in vitro studies; reviews, systematic reviews, and meta-analyses; letters to editors and opinion papers; theses and dissertations; and gray literature besides the published peer-reviewed conference proceedings relevant to the systematic reviews\u2019 research questions.Two members of the review team will select the eligible publications independently. A referee investigator will be asked to decide in case of a disagreement between the two reviewers. The Cohen kappa test will be used to measure the interrater agreement in selecting the eligible publications . A studyAn individual data extraction form (Cochrane Library model)  will be The priority of the outcomes of this systematic review are as follows: (1) intervention type ; (2) the association of the presence of fungal and parasitic infections in SoHO donors, donations, and their transmission through SoHO donations with any physiological and demographic characteristics of the populations, including aspects such as environmental conditions; (3) the prevalence of the presence of fungal and parasitic infections in SoHO donors, donations, and transmission via SoHO donations; (4) odds ratios, risk ratios, risk differences, and hazard ratios of fungal and parasitic infections or contaminations in SoHO donors, donations, and their transmission via SoHO donations; (5) cause of the infection in donors or the contamination of donation; (6) the type of screening test of infection and the donor types; (7) hospitalizations and deaths; (8) region (country and continent); and (9) diagnostic method.The review team will use the methodological design of each eligible publication to determine the risk of bias assessment. Three appropriate tools are going to be used: the Cochrane Library tool  for the The eligible studies with data not suitable for meta-analysis will be summarized into a qualitative description. In the case of the eligible studies with pertinent data for meta-analysis, a random or fixed-effect meta-analysis model will be used to account for heterogeneity due to differences in study populations, types of infections, interventions, study durations, and other factors. All meta-analyses will be conducted using the RevMan 5.3 software  .The prevalence for meta-analysis will be calculated using the following formula Standard errors for the meta-analysis will be calculated using this formula Standard errors will then be used for weighted proportions, and the RevMan 5.3 software  will be I2 statistic. The results for heterogeneity will be considered statistically significant at P<.10, while the I2 index interpretations will be made based on earlier guidelines [The 95% CI and heterogeneity between studies will be evaluated using the idelines . Small sidelines . The risidelines . Finallyidelines .The reporting of the eligible publications will be checked independently by two review team members, while a referee will make the final decision in case of a discrepancy between them. The interrater agreement in the evaluation results will be tested using the Cohen kappa test . The 25-Two reviewers will independently appraise the implications and applicability of the findings of the systematic reviews using the GRADE  analysis . The GRAThis is an ongoing study. The systematic reviews are funded by the ECDC, and the results are expected to be announced by the end of 2021.The two systematic reviews aim to identify the scientific evidence on transmission risks of fungal and parasitic diseases via SoHO globally. The retrieved evidence would assist an evidence-based risk assessment of the fungal and parasitic transmission through SoHO donations and evaluating the available prevention strategies within the European Union. The study results will be used to create an evidence pool containing the geographical data for transmission risks, genetic, physiological, and demographic characteristics of the infected populations, the infection cause and the type of screening tests for donors, and diagnostic methods of the infections. It is also possible that a meta-analysis of these data will be incorporated, which will further strengthen the evidence-based risk assessment approach.The systematic review process has many strengths. The protocol followed the PRISMA-P guidelines. The searching procedure used robust algorithms with standardized indexing terms to retrieve records that had different words to describe the same concept and information beyond the words in the title and abstract . We willThe systematic review process has limitations too. We excluded gray literature, incorporating a publication bias. Nevertheless, the inclusion of gray literature may itself introduce bias, and one reason to include the gray literature is the absence of peer-review sources . AnotherThese systematic reviews will form the basis for developing a risk assessment of fungal and parasitic disease transmission via SoHO."}
+{"text": "In 2019, the Fondazione Italiana Linfomi research team proposed a new project to summarize the evidence on late sequelae after treatment of classical Hodgkin lymphoma and diffuse large B cell lymphoma in long-term survivors (>5 years free of disease). Six systematic reviews were conducted. Clinical research questions focused on the incidence of late toxicities, comparison of toxicities with different chemotherapies, radiotherapies and autologous stem-cell transplantation, and evidence on early detection and long-term follow-up of late sequelae. The six reviews investigated the late impact of treatment on cardiological diseases, secondary neoplasms, metabolic and endocrine, neurological and psychological disorders, preservation of fertility and reproductive status, and the effect of lifestyle and nutrition. The literature search was conducted on Pubmed, Embase, and Cochrane Library databases up to 2020. This project summarized current evidence in order to see which course of action was best applicable for the clinical management of long-term survivors after Hodgkin lymphoma and diffuse large B cell lymphoma, and highlighted the gaps in the field.Advances in diagnosis and treatment of hematological malignancies has boosted attention on optimal follow-up care of survivors after cancer. To collect evidence that could inform the development of an optimal model for Italian hematology centers and the scientific community, Fondazione Italiana Linfomi (FIL) commissioned an analysis of the international follow-up approaches for long-term survivors after classical Hodgkin lymphoma (cHL) or diffuse large B-cell lymphoma (DLBCL). FIL set up multidisciplinary teams, representing all different skills relevant for cancer survivors. They conducted a series of systematic reviews focused on three main aspects: incidence of long-term toxicity; comparison of old or standard therapies and more recent ones; and evidence on specific follow-up approaches. The teams applied this framework to cardiological, endocrine-metabolic, neurological/cognitive, and psychological disorders, secondary cancers, fertility preservation, and lifestyles. Each team conducted comprehensive literature searches on PubMed, Embase and Cochrane Library databases up to 2020. Screening followed the PRISMA statement for reporting systematic reviews. The reviews report the results of this wide project covering the main areas of late toxicity and conditions in the long-term survival of cHL and DLBCL patients and their follow-up. From a clinical point of view, the series confirmed that the evidence on follow-up tended to focus on solid tumors with scant evidence on hematological malignancies. Advances in the diagnosis and treatment of hematological malignancies has boosted attention on the optimal follow-up care of long-term survivors. International medical societies and health authorities have developed follow-up programs to support patients after complete remission to improve quality of life (QOL) and monitor long-term sequelae of cancer treatments. Europe\u2019s Beating Cancer Plan, launched by the European Commission in early 2020, focused on follow-up care, in addition to prevention, early diagnosis, and treatment .The essential components of survivorship care include prevention and surveillance of new tumors or relapses of primary diseases and long-term sequelae, as well as the management of the effects of therapies. Survivorship care requires the collaboration of specialists and primary care providers, ideally in multidisciplinary teams. Several out-patient models have been developed: multidisciplinary survivorship clinics, as for instance those dedicated to the long-term follow up of cancers developed in childhood or adolescence; disease-specific survivor clinics, focused on a given disease, for instance, breast or colorectal cancer; and general survivorship clinics, providing services for a broad spectrum of diseases ,3.To manage future health care needs, cancer survivors require a structured survivorship care plan (SCP). Several organizations who coordinate oncological care have developed them\u2013for instance, the American Society of Clinical Oncology . SCPs ofIn 2013, the UK National Health Service (NHS) promoted a document called \u201cLiving with and beyond cancer: Taking action to improve outcomes is intended to inform the direction of survivorship work in England to 2015\u201d [Most of the research and clinical experience on the management of cancer survivors come from breast cancer and childhood leukemia. In recent years, however, interest in hematological malignancies has grown. For instance, an SCP was applied to lymphoma patients at the Cancer Free Clinic of Mayo Clinic-Rochester Hospital . From NoOne review described updated evidence on survivorship care models, identifying current gaps . The autWide heterogeneity emerged between the studies, considering the components of the survivorship care models, the type of neoplasm for which survivors had been treated, and the length of the follow-up.Data from survivorship care models are still lacking, particularly the advantages of different models, the impact on survivors\u2019 health outcomes, barriers to offering survivorship care, assessment of available programs, and the costs and benefits of this model . To helpInteresting experiences focused on lymphoma survivors included the nurse-led lymphoma survivorship clinic with a tailored SCP ,9, and tIn Italy, there is a growing number of out-patient cancer programs focused on lymphoma survivors. The first started in the 1990s at the Centro di Riferimento Oncologico in Aviano and the Humanitas Research Hospital in Milan. A recent survey mapping the current follow-up of the growing numbers of Italian lymphoma survivors showed broad heterogeneity and several multidisciplinary approaches .To collect the evidence to inform the development of an optimal model for Italian hematology centers, the Fondazione Italiana Linfomi (FIL) commissioned an analysis of the international follow-up approaches for long-term survivors after classical Hodgkin lymphoma (cHL) or diffuse large B-cell lymphoma (DLBCL). These two cohorts form the prevalent population of long-term lymphoma survivors.The specific aims of the proposed series of systematic reviews were to understand the best applicable model for the clinical management of long-term survivors after cHL or DLBCL, highlight the gaps in long-term monitoring and follow-up, and provide suggestions on further research in the field. The overall goal of this project is to help decision-makers and clinicians to plan follow-ups for lymphoma survivors in the near future.FIL launched its project in 2019. The first step involved setting up a multidisciplinary research team, representing all the different expertise relevant for the comprehensive management of long-term lymphoma survivors. The final research team comprised eight onco-hematologists, two cardiologists, two radiotherapists, a gynecologist, an endocrinologist, a psychologist, and a nutritional biologist. These researchers were part of one or more review teams and were supported by a methods team, comprising three experts in clinical research methodology and systematic reviews .The research group had a brainstorm meeting in March 2019 to define the clinical areas of interest and the research questions to be addressed by each review team. Six areas were identified: cardiological, endocrine-metabolic, neurological/cognitive and psychological disorders, secondary cancers, fertility preservation, lifestyles, and tailored survivorship care plans. The focus of the project was limited to cHL or DLBCL survivors treated as adults and in remission for more than five years from first- or second-line treatments, including autologous hematopoietic stem cell transplant.The meeting included the presentation of the methodological approach and a training session for the review teams. The proposal was to conduct a series of systematic reviews, one for each area, sharing a common structure but flexible enough to account for the specifics of the different clinical settings. First, evidence was collected on late effects after treatments in order to understand their incidence in relation to the previous therapeutic approaches. Second, the best approaches to monitoring any long -term sequalae related to toxicity of previous treatments were identified. The review teams were trained on the basic elements of a systematic review according to the Cochrane approach  which inThe reviews were structured around three aspects: (i) the incidence of specific long-term toxicity; (ii) the comparison of old or standard therapies (for which more data are available) and more recent therapies (including modern radiation therapy); (iii) the best method for early detection and monitoring of long-term sequelae.This framework was applied with minimal adaptations by the teams on cardiological, endocrine-metabolic, neurological/cognitive disorders, and secondary cancers. The groups focusing on fertility preservation and lifestyles and tailored survivorship care plans took a different approach, as the objective of their analysis was slightly different.Each review team defined the relevant clinical questions and divided them into researchable questions through the population, intervention, comparison, outcome study design (PICOS) framework. This lays the basis for the definition of the inclusion and exclusion criteria of the reviews and for literature searches. Considering the aim of the project, the review team agreed on the inclusion of clinical trials, controlled observational studies (prospective and retrospective), and systematic reviews.With the support of the methods team, each review team conducted comprehensive literature searches on the following scientific databases: PubMed, Embase, Cochrane Library. Clinical study registries such as Clinicaltrial.gov, and hand-searched references of these studies were done to maximize the sensitivity of the searches. Titles and abstracts were screened by at least two independent reviewers, and the selected full-text publication was examined to confirm eligibility. Discrepancies were resolved by discussion with a third reviewer or a member of another review team. The screening process was reported using the PRISMA flow-chart .A study was considered eligible if information pertinent to one or more PICOS item was abstracted in a tabular format. The key elements can be summarized as: study design, duration, population, sample size, interventions, comparators, follow-up, outcome measures, main results and main conclusions, and reference. The evidence was summarized qualitatively as a meta-analysis was not considered adequate in this setting. Each review team assessed the risk of bias in randomized trials using the Cochrane risk of bias tool v1 , the quaTo our knowledge, this is the first comprehensive assembly of evidence on clinical management of long-term survivors after cHL or DLBCL. We hope our results will support guideline development and prioritization of research funding allocation, providing the evidence base on which recommendations may be developed, following a transparent and robust methodology. Specifically, it should inform the definition of optimal programs to support patients after complete remission of lymphoma and highlight the gaps where specific research programs are now important. The initiative started with bottom-up input from health professionals involved in the care of long-term lymphoma survivorship, who acknowledged a research priority and set up a project to respond to specific issues. The integration of different competences in a joint, coordinated effort is a major achievement in view of the multidisciplinary approach needed for long-term survivors. The project highlighted several gaps still not covered that could be taken into consideration in new research projects promoted by FIL or other funders (such as scientific societies).The following series reports the results of a wide project covering the main areas of late toxicity and conditions in the long-term survival of cHL and DLBCL patients and their follow-ups.While each article in the series will report detailed considerations, some main clinical and methodological conclusions can be drawn from an analysis of the evidence.From a clinical point of view, our series confirmed that the evidence on follow-up pathways focused mainly on solid tumors with scant information on hematological malignancies. cHL and DLBCL patients can be considered a separate population from those with other hematological diseases due to their good prognosis and life expectancy, the novel chemo-immunotherapy and PET/CT-guided approach during chemo-radiotherapy for patients with cHL, and the improved diagnosis of DLBCL .The improved survival of these patients calls for tailored follow-up specific to their characteristics based on treatments received and their disease history. This is in line with guidelines on solid tumors, such as the National Comprehensive Cancer Network (NCCN) for survivorship and the European Society for Medical Oncology (ESMO) guidelines for monitoring cardiac toxicity in survivorship ,19. FollA recent analysis reviewed cancer survivorship models, with a particular focus on those aimed at integrating primary care providers into the care of cancer survivors . AlthougLike other surveillance programs, the management of long-term lymphoma survivors must assess the potential overuse of diagnostic procedures or treatments. The international initiative Choosing Wisely reports a generic recommendation to start surveillance testing after cancer treatment only after providing the patient with a survivorship care plan to help in transitioning to long-term surveillance, avoiding unnecessary services, and seeking appropriate care and decision support . ChoosinThe overuse of diagnostic procedures or treatments may be associated with side effects, including the possible psychological distress caused by the status of being a \u201ccancer survivor\u201d. In the broader context of a patient-centered perspective on cancer, the development and implementation of survivorship plans should include a transparent approach to shared decision making, where patients\u2019 preferences are taken into consideration.From a methodological point of view, our series pointed out two main limitations. The first regards the indirectness of the results. Most of the evidence refers to mixed populations that include different hematological tumors and, in some cases, even solid tumors, so a good number of studies had to be excluded. The lack of stratification between solid and hematological malignancies and thorough evaluation of the differences precludes robust identification of the most adequate features in each setting. When trials and observational studies only assessed lymphoma survivors, they usually included groups of participants with different disease histories. In general, there is a lack of data on DLBCL patients and those who utilize second-line treatments such as transplants for both cHL and DLBCL. Other papers reported data on populations including children as well as adults, or mixed long-term survivors and patients still receiving treatment together without stratification. The study populations in almost all the studies varied as regards treatment received, age at diagnosis, and timing of the survivorship (intended as time after diagnosis).The second issue regards the overall quality of the evidence. Studies were seldom sufficiently powered to detect long-term sequalae as primary or secondary outcomes, and follow-up was generally too short to detect relevant medical issues in prospective observational and randomized controlled trials. Studies often had major methodological flaws and employed inadequate comparators.This project, promoted by FIL, summarized current evidence to find the best model for the clinical management of long-term survivors after cHL or DLBCL and offered suggestions on further research in the field. It also built up a new multidisciplinary research group, including hematologists with other relevant figures such as experts in radiotherapy, endocrinology, nutrition, and psychology, and research methodology. This group could support decision-makers in preparing sustainable evidence-based guidelines such as SCP, on an Italian national level, and help to fill research gaps through new projects covering unmet medical needs for lymphoma patients."}
+{"text": "Difficult times ask for innovative and daring solutions to complex issues. In the interest of the health, safety, and well-being of all registered attendees and the general public, the Society for the Study of Neuroprotection and Neuroplasticity (SSNN) Board of Directors has decided to extend last year\u2019s decision regarding all upcoming events and hold the conferences in a virtual environment. We are committed to supporting public health authorities globally in their effort to slow and contain the spread of COVID-19. We must stay positive, healthy, and united more than ever to overcome this crisis.th European Teaching Course on Neurorehabilitation (ETCN) (17\u201318 September 2021) and the 16th International Summer School of Neurology (19\u201321 September 2020) will be offering outstanding opportunities for education, dissemination of scientific research, and the exchange of best practices, through a brand new online platform that has been tailored to promote lively interaction between participants.Our well-established conferences \u2013 the 11The current virtual events benefit from the active support of some of the longstanding partners like the European Federation of Neurorehabilitation Societies (EFNR), World Federation of Neurorehabilitation Societies (WFNR), the European Academy of Neurology (EAN), Iuliu Hatieganu University of Medicine and Pharmacy from Cluj-Napoca, Romania, the RoNeuro Institute for Neurological Research and Diagnostic, and the Journal of Medicine and Life.The ETCN is one of the most acclaimed events organized by the SSNN. This year\u2019s second online edition, out of eleven so far, promises to rise to participants\u2019 expectations and serve as a platform for disseminating and exchanging up-to-date scientific knowledge on neurorehabilitation and providing a space for teaching-oriented workshops. Each year, the event reaches a broader audience interested in this steadily expanding and exciting field .The event\u2019s focus is on rehabilitation and neurorecovery, along with identifying new avenues in science, education and delivery of service \u2013 the Scientific Program Committee, conducted by Volker H\u00f6mberg President-Elect of the World Federation Neurorehabilitation (WFNR) and Vice-President European Federation of Neurorehabilitation Societies (EFNRS), carefully curated the program developed on submissions from our top-grade international faculty.The event\u2019s objectives are (1) to further the development and improve quality of neurorehabilitation in Europe, (2) to enhance collaboration in neurorehabilitation between professionals, (3) to encourage and facilitate the exchange of knowledge and scientific research in rehabilitation professionals, and (4) to contribute to the development of cooperation and communication networks between national and international neurorehabilitation societies.th edition, coordinated by Natan M. Bornstein and Dafin F. Muresanu, the virtual event will address topics such as the COVID-19 impact, challenges of evidence-based medicine, stroke recovery monitoring, the right of patients for the suitable device aided therapies, and cost-effectiveness of interventions for neurorecovery after acute ischemic stroke.The International Summer School aims to facilitate the interaction between young neurologists-in-training and an internationally established faculty with extensive expertise in basic and clinical neuroscience. The pillars for this event were set in 2005 together with professors Natan Bornstein (Israel) and Ovidiu Bajenaru (Romania) to fulfill the need of young specialists and practitioners for connection with the latest developments in the field of neurosciences. This pursuit led to the development of a dynamic environment that promotes connection and learning. In the 16The 2020 SSNN virtual events will set the stage for five days of intensive talks and debates between over a thousand participants from 25 countries on a broad range of problems in neurosciences. An exciting achievement of this year is represented by the guideline on pharmacological support in early motor rehabilitation after acute ischaemic stroke. The guideline aims to support the clinical decision-making of healthcare professionals involved in the recovery of stroke patients. They were developed using the Grading of Recommendations, Assessment and Evaluation (GRADE) framework to identify early pharmacological interventions for stroke rehabilitation delivered alongside neurorehabilitation. This guideline provides clinicians with information regarding existent pharmacological support in post-acute stroke neurorecovery intervention, highlighting an exciting avenue for research and development.Despite the societal changes caused by the ongoing global pandemic, we are enthusiastic about finding innovative pathways of adapting to the current context. In our pursuit, we ought to work together to overcome these trying times and build a brighter future."}
+{"text": "The Up-and-Coming-Scientist section of the current issue of the Journal of Membrane Biology features the invited essay by Dr. Mercedes Alfonso-Prieto, Assistant Professor at the Forschungszentrum J\u00fclich (FZJ), Germany, and the Heinrich-Heine University D\u00fcsseldorf, Vogt Institute for Brain Research.Dr. Alfonso-Prieto completed her doctoral degree in chemistry at the Barcelona Science Park, Spain, in 2009, pursued post-doctoral research in computational molecular sciences at Temple University, USA, and then, as a Marie Curie post-doctoral fellow at the University of Barcelona, worked on computations of enzyme reactions and modeling of photoswitchable ligands targeting neuronal receptors. In 2016, she joined the Institute for Advanced Science and the Institute for Computational Biomedicine at the FZJ, where she pursues research on modeling and simulation of chemical senses. The invited essay by Dr. Alfonso-Prieto discusses state-of-the-art modeling of molecular receptors involved in chemical sensing \u2013 the senses of taste and smell. These receptors, and computational methods to study them, are the focus of Dr. Alfonso-Prieto\u2019s research. Recently, Dr. Alfonso-Prieto and colleagues have presented a new methodology to predict ligand binding poses for GPCRs, and extensive computations that deciphered the ligand selectivity determinants of bitter taste receptors. These developments inform our current understanding of how taste occurs at the molecular level. In contrast with vision or hearing, the senses of taste and smell (or olfaction) involve the detection of chemicals present in the environment and thus are considered as \u201cchemical senses\u201d. They inform about the aroma and flavor of food and beverages and act as warning system for toxic substances. Hence, these two chemical senses strongly affect human well-being, food acceptance and intake  are extremely chemically diverse . The GPCR superfamily is the largest in the human genome, with approx. 800 genes, of which half correspond to chemosensory receptors  and is distributed among several databases (Marenco et al. The interplay of experimental and computational approaches has enabled a deeper molecular characterization of bitter taste and olfaction. However, the lack of experimental structures of bitter taste and olfactory receptors is still a hurdle that limits the accuracy of the computational structural models that can be generated. Moreover, a more extensive characterization of the physiological and pathological roles of extraoral TAS2Rs and extranasal ORs is required to exploit their potential as novel drug targets. In addition to computational molecular modeling and data science approaches, systems biology is expected to contribute to further understand the connection between ligand-receptor recognition and the subcellular response of the corresponding type II taste cell or olfactory sensory neuron."}
+{"text": "Pyrazoles are also found in a variety of agrochemicals  and are versatile compounds for synthetic manipulations. Their structural features , and diverse applications, have stimulated the work of several research groups towards the synthesis and functionalization of pyrazole-type compounds and study of their properties, and has inspired this Special Issue that aims to provide a broad survey of the most recent advances in pyrazole\u2019s chemistry.Pyrazoles and their reduced form, pyrazolines, are considered privileged scaffolds in medicinal chemistry, owing to their remarkable biological activities, physicochemical properties and occurrence in many low-molecular-weight compounds present in several marketed drugs . They discussed the most common size of the metallacycles\u2019 ring depending on the metal and analyzed the stability of different ring sizes dec-1-en-5-ium chloride pyrazoles pyrimidines were reviewed by Portilla et al., who have also highlighted the anticancer potential and enzyme inhibitory activity of these compounds, thus providing important insights for the rational and efficient design of new drugs bearing the pyrazolopyrimidine core [In this Special Issue, nine original research articles and seven reviews covering some of the most recent advances in the synthesis, transformation, properties and relevant applications of pyrazoles are reported. Two articles deal with the synthesis and computational study of metallacycles formed by pyrazolate ligands and the coinage metals M = Cu(I), Ag(I) and Au(I). Elguero and Alkorta reported a computational study of metallacycles formed by pyrazolate ligands and the coinage metals (pzM)ng sizes . By usinatalysts . Alam et luminol . Currentine core . Tu et aine core . Brullo ine core . Lee et ine core . In the ine core . Kokorekine core .In conclusion, pyrazoles\u2019 chemistry is undoubtedly a current and pertinent topic of investigation. Several research groups have contributed to the advancement of this topic by designing novel pyrazole-type compounds and developing synthetic strategies for the preparation and post-functionalization of pyrazoles, or by studying their structures, properties and potential applications. Herein, important advances in pyrazoles\u2019 chemistry have been disclosed. We thank all of the authors for their valuable contributions to this Special Issue, all the peer reviewers for their valuable comments, criticisms, and suggestions and the staff members of MDPI for the editorial support."}
+{"text": "Background: The cranio-orbito-zygomatic (COZ) approach is a workhorse of skull base surgery, and each of its steps has a precise effect on target exposure and surgical freedom. The present study overviews the key techniques for execution and tailoring of the COZ approach, focusing on the quantitative effects resulting from removal of the orbitozygomatic (OZ) bar, orbital rim, and zygomatic arch. Methods: A PRISMA-based literature review was performed on the PubMed/Medline and Web of Science databases using the main keywords associated with the COZ approach. Articles in English without temporal restriction were included. Eligibility was limited to neurosurgical relevance. Results: A total of 78 articles were selected. The range of variants of the COZ approach involves a one-piece, two-piece, and three-piece technique, with a decreasing level of complexity and risk of complications. The two-piece technique includes an OZ and orbitopterional variant. Superolateral orbitotomy expands the subfrontal and transsylvian corridors, increasing surgical freedom to the basal forebrain, hypothalamic region, interpeduncular fossa, and basilar apex. Zygomatic osteotomy shortens the working distance of the pretemporal and subtemporal routes. Conclusion: Subtraction of the OZ bar causes a tremendous increase in angular exposure of the subfrontal, transsylvian, pretemporal, and subtemporal perspectives avoiding brain retraction, allowing for multiangled trajectories, and shortening the working distance. The COZ approach can be tailored based on the location of the lesion, thus optimizing the target exposure and surgical freedom and decreasing the risk of complications. The cranio-orbito-zygomatic (COZ) approach is an extension of the pterional approach, involving the adjunct of orbitozygomatic (OZ) osteotomy to allow wider exposure of the anterior and middle skull base and upper retroclival region. It provides advantages in giant aneurysms of the anterior communicating artery (ACoA) and distal basilar artery, tuberculum sellae, large anterior clinoidal, spheno-orbital meningiomas, large craniopharyngiomas, giant pituitary adenomas, cavernous hemangiomas of the hypothalamus, and crus cerebri of the midbrain. Over the years, a wide range of terms has been used to describe this approach, each of which refers to the key steps of the bony work of a specific variant. Similarly, many technical notes of the COZ approach have been reported to make its execution easier and decrease the risk of complications ,13,14,15The herein presented PRISMA-based literature review strives to exhaustively summarize the spectrum of possible technical variations of the COZ approach, particularly focusing on the different quantitative effects resulting from removal of the entire OZ bar, orbital rim, and zygomatic arch. The reported data constitute the key elements for rational tailoring of the COZ approach aimed at optimizing the volume of exposure of the target, augmenting surgical freedom, and decreasing the risk of complications.https://pubmed.ncbi.nlm.nih.gov access date 15 February 2022) and Web of Science (https://www.webofscience.com access date 17 February 2022) online databases. The keywords \u201ccranio-orbito-zygomatic\u201d, \u201corbitozygomatic\u201d, \u201corbitopterional\u201d, \u201czygomatic\u201d, \u201corbitozygomatic\u201d, \u201corbitocranial\u201d, and \u201corbitofrontomalar\u201d were combined with text words \u201capproach\u201d, \u201ccraniotomy\u201d, and \u201costeotomy\u201d. Articles in English or translated, without temporal restriction, were selected. Editorials, comments, case reports, and letters were excluded. Eligibility of the articles was limited to neurosurgical relevance, and the results were reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines . Th. Th11]. 2.Orbitopterional Craniotomy (Al-Mefty Technique)The orbitopterional two-piece COZ approach includes two zygomatic cuts involving the anterior and posterior root of the zygoma, respectively. The zygomatic arch is mobilized inferiorly without detachment of the masseter muscle, thus avoiding the risk of postoperative masticatory imbalance. The other steps are those of the one-piece variant of the COZ approach, where all the cuts are carried out extracranially  3]..3].The three-piece COZ approach consists of a combination of both two-piece variants. It involves zygomatic osteotomy without detachment of the masseter, inferior mobilization of the zygomatic arch, pterional bone flap, and orbital osteotomy as separate piece entailing the superolateral orbital rim and the orbital roof .The dura is opened parallel to the posterior ramus of the Sylvian fissure, and two further curvilinear cuts are performed on the frontal and temporal side. This type of opening decreases the risk of damage to the Sylvian veins, especially in the case of swelling of the brain.The COZ approach allows for four different corridors: (1) subfrontal, (2) transsylvian, (3) pretemporal, and (4) subtemporal. The transsylvian and pretemporal corridors are related to four well-defined deep windows to the infratentorial region through the opening of the Liliequist membrane. The deep windows are as follows: (1) optic-carotid, (2) carotid-oculomotor, (3) supracarotid, and (4) oculomotor-tentorial.The galea-pericranium can be used as a double-layered autologous patch graft in the case of duraplasty or also if cranialization of the frontal air sinus is necessary. Preplating before proceeding to zygomatic osteotomy aids osteosynthesis and avoids the risk of postoperative facial asymmetry. Care should be taken in reconstruction of the orbital roof to limit the risk of enophthalmos. Low-profile titanium plates and 4 or 5 mm self-tapping screws are used for osteosynthesis of the bone flap. The temporalis muscle is reapproximated to the myofascial cuff at the level of the superior temporal line. An interrupted suture with 3/0 vicryl stitches is used for the superficial temporal fascia and galea. Subcutaneous drainage is left in place for 2 days to prevent blood collections. Skin suture can be optionally executed with 3/0 silk stitches or metallic agrafes.A large basilar apex aneurysm was incidentally found in a 54-year-old female patient. On digital subtraction angiography, the aneurysm was superior projecting and presented with a dome-to-neck ratio of 1.5. Both P1 segments of the posterior cerebral arteries arose from the partially calcified neck. Basilar bifurcation was low riding, lying 8 mm below the dorsum sellae. The patient underwent a two-piece COZ approach inclusive of orbitopterional craniotomy, zygomatic osteotomy, extradural anterior clinoidectomy, lateral mobilization of the internal carotid artery (ICA), and posterior clinoidectomy. Posterior clinoidectomy expanded the carotid-oculomotor window and allowed for control of the midbasilar trunk. Given the pattern of low-riding basilar bifurcation, the additional exposure resulting from the COZ approach and posterior clinoidectomy was paramount for temporary clipping. Anterior clinoidectomy and lateral mobilization of the ICA led to expanding the optic-carotid window, which was used to dissect the neck and the thalamoperforating arteries resulting from P1, and to definitively clip the aneurysm. The transsylvian, pretemporal, and subtemporal corridors were used in combination. The patient was discharged without deficits on the fifth post-op day .A 48-year-old female was diagnosed with an incidental large anterior communicating artery aneurysm. The left A1 segment of the anterior cerebral artery was hypoplastic, and both A2 segments originated from the ACoA. The aneurysm was anterior\u2013superior projecting, and the superolateral orbital rim hindered visualization of the left A2 segment. The patient underwent an orbitopterional approach, which allowed expanding the subfrontal corridor and the angular exposure of the aneurysm neck. Better visualization of the left Heubner artery and hypothalamic and subcallosal perforating arteries was also possible. The aneurysm was successfully clipped and the postoperative course was uneventful .The present review summarizes the key techniques for tailoring the amount of surgical exposure provided by the COZ approach, which is today considered a workhorse of skull base surgery. A gradual shift from the one-piece technique to the two-piece or three-piece technique occurred over the years .The reasons consist of easier execution of the latter two variants, as well as better functional and cosmetic outcome ,11,29,30In particular, for the basilar apex and posterior clinoid, the removal of the orbital rim and zygomatic arch as separate steps results in an increase of exposure of 28% and 22%, respectively  32]..32].Based on these data, the COZ approach can be tailored depending on the location and size of the lesion, as well as the specific corridor deemed more suitable for the target exposure ,46. ManyWhile subtraction of the orbital rim is useful for high-riding aneurysms of the basilar apex, the shallower operative field resulting from zygomatic osteotomy enhances the pretemporal, subtemporal transtentorial, and subtemporal transpetrosal (Kawase\u2019s) approaches in cases where the basilar tip aneurysm originates at the level of low-riding basilar bifurcation . An anatComplications of the COZ approach can be functional, aesthetic, or of both types. Some of the most frequent are injury of the frontotemporal branch of the facial nerve, atrophy of the temporalis muscle, masticatory imbalance, enophthalmos, diplopia, visual impairment, and cerebrospinal fluid leakage. The subfascial technique avoids deficit of the frontotemporal branch of the facial nerve, whereas compulsive subperiosteal blunt and \u201ccold\u201d (avoiding electrocauterization) dissection of the deep temporal fascia prevents postoperative atrophy of the temporalis muscle ,24,27,41In the one-piece COZ approach, zygomatic osteotomy is generally less generous, involving mainly the frontal process. Therefore, the one-piece COZ approach is theoretically more suitable for parasellar and orbital tumors where wider mobilization of the zygomatic arch does not add real advantages in target exposure. Conversely, the one-piece COZ approach is less indicated in ruptured aneurysms, hyperostotic spheno-orbital and sphenoid meningiomas, and large intraorbital tumors with raised intraocular pressure. In ruptured aneurysms, the coexistent brain edema increases the risk of parenchymal damages during extracranial osteotomy of the orbital roof. In tumors characterized by severe hyperostosis of the roof and lateral wall of the orbit, the fracture of the one-piece bone flap can accidentally give rise to force vectors involving the optic canal and sphenoid sinus with a consequent risk of damage to the optic nerve and cerebrospinal fluid leaks. In the case of intraocular hypertension, the greater manipulation of the eyeball, equired to cut the orbital roof from the extracranial intraorbital side, increases the risk of blindness, as well as dangerous bradyarrhythmia deriving from elicitation of the trigeminal oculocardiac reflex. The two-piece variant fits most other lesions for which the COZ approach is indicated thanks to its wide intrinsic versatility that characterizes both the Zabramski and Al-Mefty techniques. The Al-Mefty technique should be preferred for malignancies affecting the temporal and infratemporal fossa since this variant avoids detachment of the masseter muscle, thus eliminating an adjunctive risk for mastication. These tumors often involve the masticatory space apart from the middle fossa. Despite its greater facility of execution, the three-piece variant is considered disadvantageous in children where the physiologic growth of the facial skeleton can be compromised by the fixation devices. Furthermore, in pediatric and extremely thin patients, where the thickness of the facial soft tissues is reduced, the greater number of miniplates and burr hole covers required for reconstruction can be sources of poor aesthetic outcome. Apart from the aforementioned aspects, which should be considered as indicative rather than imperative, the preferences and the personal experience of the surgeon also have to be considered in the choice of a specific technique of execution.The present study has some limitations that can be summarized in its retrospective nature, the intrinsic bias of the different studies involved, and the type of morphometric and quantitative studies selected which were performed only on cadavers in most cases.The spectrum of variants of the COZ approach involves a one-, two-, and three-piece craniotomy, with a decreasing level of technical complexity and risk of complications.Superolateral orbitotomy expands the subfrontal and transsylvian corridor and raises surgical freedom to the basal forebrain, hypothalamic region, interpeduncular fossa, and basilar apex.Zygomatic osteotomy shortens the working distance to the main targets of the pretemporal and subtemporal route.Removal of the OZ bar eliminates the need for brain retraction and allows for multiangled trajectories.The COZ approach can be tailored based on the location and extension of the lesion, thus optimizing target exposure and decreasing the risk of complications."}
+{"text": "The evolution of antibiotic resistance in Escherichia coli (E. coli) hampers the treatment of UTIs, mirroring the global public health concerns around antimicrobial resistance. Pivmecillinam, an oral prodrug of mecillinam (a \u03b2-lactam antibiotic), is used as first-line treatment for uUTIs in Denmark. Here, we examine the use of, and the prevalence of resistance to, mecillinam in Denmark in the primary care setting.www.danmap.org). Prevalence estimates of resistance reported by DANMAP 2019 were obtained from the Danish Microbiology Database (MiBA).Nationwide data on the use of and resistance to pivmecillinam  was extracted and examined from the Danish Integrated Antimicrobial Resistance Monitoring and Research Programme (DANMAP) 2019 report . In general, in spite of increasing use in Denmark, the development of resistance to pivmecillinam has remained low. In fact, a slight decline in pivmecillinam resistance was observed over the past decade.Despite the rising number of UTIs and the increasing use of pivmecillinam for uUTI in Denmark, over the past decade, the development of resistance to pivmecillinam remains low.Anne Santerre Henriksen, MS, Advanz (Consultant)Shionogi BV (Consultant)UTILITY Therapeutics (Consultant)"}
+{"text": "In the context of fair trade and protection of consumer rights, the aim of this study was to combat adulteration, counterfeiting, and fraud in the tea market, and rebuild the image of high-quality Taiwan teas. Experts at the Tea Research and Extension Station, Taiwan (TRES), are engaged in promotion of the systems of origin identification (AOC) and grading for authentication of Taiwan\u2019s premium teas. From tea evaluation competitions , the flavor descriptions and consumers\u2019 perceptions were deconvoluted and characterized for the eight Taiwan specialty teas, namely, Bi-Luo-Chun, Wenshan Paochong, High-Mountain Oolong, Dongding Oolong, Tieh-Kuan-Yin, Red Oolong, Oriental Beauty, and Taiwan black tea. Then, according to the manufacturing processes, producing estates and flavor characters, the specialty teas were categorized into six sensory wheels. The flavor descriptors of the sensory wheels were also recognized in consumers\u2019 feedback. In recent years, the performance of international trade in tea also demonstrates that the policy guidelines for authentication of specialty teas are helpful to the production and marketing. Furthermore, the development of sensory wheels of Taiwan\u2019s specialty teas is the cornerstone to the establishment of the Taiwan-tea assortment and grading system (TAGs) for communication with the new generation consumers, enthusiasts, sellers, and producers. Camellia sinensis) is also one of the main agricultural commodities in international trade [Tea is the most popular beverage in the world after water, and the tea leaf  . SpecialSince 1991, the import quantity of Taiwan\u2019s tea has rapidly surpassed the export quantity, as shown in Food authentication is the process of verifying compliance with a food label instruction. Whether from a business perspective or a legal perspective, food authentication has aroused significant interest. Labeling and ingredient regulations may vary by country or region for food safety issues or prevention of criminal activities . Many beNumerous technological approaches have also been utilized to profile the characteristic fingerprint of beverages with physical or chemical data ,13. HoweConsumers make purchasing decisions based on a variety of quality cues (brand reputation and price) controlled by marketing . The autIn tea purchases, consumers often need to try individual teas, and determining a favorite flavor is time-consuming. However, consumer preference for a tea flavor is difficult to state, and words used in professional evaluation are too artistic and metaphysical  for others to understand. A recent study noted that the problem stems from the gap between the sensory perceptions of tea beverages by younger consumers and professional opinions in tea marketing . The appWith the aim of authenticating Taiwan tea to protect consumer rights and ensure trade fairness, numerous fast and accurate analytical techniques have been developed to combat tea counterfeiting, adulteration, and fraud . The aroThis aim of this study was to establish a systematic sensory lexicon to certify the flavor characteristics of specialty teas with high-quality, as flavor authentication. As the major official institute involved in the promotion of the tea industry in Taiwan, TRES must coordinate manufacturers, tea traders, and consumers to establish a functional medium with well-certified guidelines to reduce the gaps in traditional tea culture. Using an expert taster who evaluated the appearance, color, smell, taste, and mouthfeel, the overall impression of the quality of the tea infusion was obtained with a balance based on defect-free and sensory properties. Furthermore, the official sensory wheels of Taiwan specialty teas were developed for the tea industry to serve as communication and quality control tools to enhance the marketing of Taiwan tea for consumers, and to strengthen the core competitiveness of tea farmers. In this study, the characteristic flavors of Taiwan specialty teas were clearly identified based on consumers\u2019 perception using the flavor attributes of the sensory wheel.The main structure of this research consists of the eight specialty teas and six categories of sensory wheels, which have the flavor attributes of infusion color, taste, and aroma in the consumers\u2019 perception. Since the inception of TRES, the lexicon of flavor perceptions on teas has been dynamically reviewed by the professional staff. Our study uses the concept of identifying tea flavors to develop a sensory wheel with flavor terms in detail, and then verifies the accuracy of the flavor terms in each sensory wheel associated with the Taiwan specialty teas.Based on the sensory wheel, tea traceability establishes flavor clues in authentication, and can be used to express the flavor and quality perceptions of Taiwan specialty tea as a marketing tool. The official sensory wheels can be promoted to participating tea merchants, producers, and tea farmers to understand the basic quality requirements and flavor items in the evaluation. The protocols, including sensory evaluations and consumer surveys in this study, are certified as an exempted approval (document number: 1103408809) by the institutional review of TRES according to Article 5 of the Human Subjects Research Act (2 January 2019) of the Ministry of Health and Welfare, Taiwan. All identified data have been delinked for participants\u2019 anonymity and confidentiality before analysis.The flavor wheel working group and the sensory evaluation panel are composed of 25 professional researchers engaged in tea manufacturing and tea sensory evaluation at TRES, Taiwan. The panelists were recruited from certificated referees with qualifications obtained from training courses and practice assessments conducted by TRES for top-level tea sensory appraisers. The certification system of tea sensory appraisers in Taiwan is developed and classified in five levels, namely, elementary, junior, senior, advanced, and special appraisers. Certified appraisers must obtain the qualifications of appropriate training courses and assessments for tea sensory evaluation at different levels, consistent with the ISO 8586:2012 guidelines for sensory analysis [The development of the tea sensory wheel was used to standardize the flavor description and sensory evaluation of premium tea, so the high-quality tea samples were collected from tea evaluation competitions conducted from 2019 to 2020 in Taiwan. The flavor attributes of Taiwan green tea were assessed and graded using 40 samples of Bi-Luo-Chun green tea. The flavor attributes of the fragrant strip-type Paochong tea were assessed and graded using 50 samples of Wenshan-Paochong tea. The flavor attributes of the fragrant ball-type Oolong tea were assessed and graded using 73 samples of High-Mountain Oolong produced in locations including Nantou, Chiayi. The flavor attributes of the heavy roast ball-type Oolong tea were assessed and graded using a total of 210 samples of Dongding Oolong (169 in Nautou), Tieh-Kuan-Yin (19 in Muzha), and Red Oolong (22 in Taidong). The flavor attributes of Oriental Beauty tea were assessed and graded using 62 samples. The flavor attributes of Taiwan black tea were assessed and graded using a total of 60 samples of Sun-Moon-Lake black tea (20 in Nautou), Small-leaf black tea (20), and Honey-flavor black tea .The tea infusions were prepared as a liquor extraction with dry tea leaves, as described in the international standard ISO 3103:1980 . The teaResults of sensory evaluation in terms of color, flavor, taste, and aroma were conducted with hedonic scaling and a ranking test to determine a suitable grade based on the flavor attributes of the tea samples.To explore the feedback of consumers regarding the official sensory wheels of Taiwan specialty teas, participants were randomly invited to participate in a questionnaire survey at the Taiwan International Tea Expo on 11\u201316 November 2020 at the Taipei Nangang Exhibition Center. Participation was voluntary; participants had given verbal informed consent before the trial and could withdraw freely at any stage. A total of 90 valid questionnaire responses were obtained, including those of four foreigners with a questionnaire in English. Of the total number of respondents, 61% were male and the median age was 45 years old. Although the sensory wheel has different color attributes and the same taste attributes of tea infusions, it is difficult to analyze using questionnaires. Therefore, this questionnaire analyzed a total of 25 aroma attributes in six sensory wheels to profile the aroma characteristics of various Taiwan specialty teas. The design of the questionnaire used the Check-All-That-Apply method to verify the recognition coverage of consumer perception of the flavor attributes of Taiwan specialty teas.Based on the questionnaire data, the recognition percentage of an aroma attribute according to a consumer\u2019s perception was calculated and transformed into a 5-point scale, named the acceptance index of aroma attribute. For an aroma attribute with a recognition percentage of 45% or more, 5 points were given, 44.4\u201335% were given 4 points, 34.4\u201325% were given 3 points, 24.4\u201315% were given 2 points, and 14.4\u20131% were given 1.1 points. Those not recognized are not presented.Based on the production estates, the unique manufacturing process, and consumer impressions of the premium teas, the TRES focus group selected eight Taiwan specialty teas to characterize their flavor attributes. According to the tea manufacturing process, the color of tea infusion deepens with the degree of fermentation, as shown in Jacobiasca formosana), which feeds on leaves, stems, and buds without pesticide residues. The tea plant induces the secretion of the monoterpenediol and hotrienol, which gives the tea its unique flavor [Taiwan is the main producing area of partially fermented Oolong tea in the world , so the e flavor . Becausee flavor .Green tea is an unfermented tea made with relatively low processing, but differences in processing nonetheless have a significant impact on the flavor (mainly aroma) and appearance . Based osinensis var. assamica) with a high level of catecholamine are suitable for the flavor of black tea, and small-leaf cultivars (C. sinensis var. sinensis) with a low level of catecholamine are suitable for the flavors of green tea and partially fermented teas [According to the basic processes of tea manufacturing, as shown in ted teas . Due to ted teas , green tFrom the perspective of the producing estate, well-managed tea trees can be harvested for at least 30 to 40 years, and specific varieties are also suitable for planting and growing in the producing area of the specialty tea. Thus, the regeneration of tea planting varieties is very slow . HoweverTaiwan black tea is dominated by large-leaf cultivars. Characteristic Honey-flavor black tea is predominantly produced at the Hualien estate and made from Large-leaf Oolong, which is a tea tree of a small-leaf cultivar. Production of partially fermented teas, such as Paochong tea or Oolong tea, uses common small-leaf cultivars of Chin-Shin-Oolong and TTES No. 12 (Jhinhsuan). Because the catechin content of tea leaves in summer is too high and the flavor is too bitter for partially fermented teas , ten yeaFlavor affects the acceptance and choice of food intake, and helps people identify potentially harmful compounds. Based on the unique flavor attributes and consumer impressions, the sensory wheel working group further developed six sensory wheels of the flavor categories of specialty teas, which are Taiwan green tea (TGT), the fragrant strip-type Paochong tea (FSPCT), the fragrant ball-type Oolong tea (FBOT), the heavy roast ball-type Oolong tea (HRBOT), Oriental Beauty tea (OBT), and Taiwan black tea (TBT), as shown in The official sensory wheel has the function of setting standards and guidelines for each of Taiwan\u2019s specialty teas for the development of Taiwan tea industries, consumer behavior, and trade. The design framework of the sensory wheel has distinctive appearance, context, flavor lexicon, and sensory information, and includes the infusion color and an image representing the tea. Sun-Moon-Lake black tea, Small-leaf black tea, and Honey-flavor black tea are the three representative teas of TGT in Flavor studies ,36 utiliFlavor profiling identifies individual sensory attributes that contribute to the overall sensory impression of the tea infusion and evaluates its strength to establish a description of the flavor and aftertaste, such as in the case of mouthfeel, shown in The TRES is an official professional institution providing counseling for tea industry development and plays the role of guidance and supervision in the marketing of Taiwanese tea. However, flavor descriptions and standards of Taiwan teas are currently lacking a means of authentication compared to the international classification standards ,37 of ChThe official sensory wheel can be used not only as the flavor standard of the Taiwan specialty tea and an auxiliary tool for marketing, but also as teaching material for personnel training and the dissemination of tea-related knowledge on sensory evaluation. The six sensory wheels standardize the flavor lexicon for aroma and taste attributes, and provide a color atlas as a visual reference, as listed in From the comparison of the flavor components of the two extremes in In the future, the main challenge of psychological measurement will be to find a scale with proportional characteristics that is not affected by other factors used in the surrounding environment . Thus, aFlavor profiling includes formal procedures to describe and evaluate the taste, smell, mouthfeel, and flavor, in addition to an underlying complex of sensory impressions of a product in a reproducible manner. Taste is the sensation experienced by taste receptor cells located on the taste buds when stimulated by certain soluble substances. The sense of taste is combined with the olfactory and trigeminal system to produce an overall flavor . HoweverAccording to the results of the consumer questionnaire, the aroma descriptors in the sensory wheels were used to profile the characteristics of Taiwan specialty teas by fuzzy algorithm ,43, as sSensory evaluation techniques of QDA , consumeThe development of a variety of tea processed products has changed the culture of people drinking tea. In particular, the product concept of ready-to-drink tea has created a new tea culture . Tea is As shown in Nevertheless, this study is limited to specific areas and objects and cannot be accurately projected into the larger commercial tea or beverage markets. The quantitative data of flavor description are regarded as representing the objectivity and scientific statement of sensory evaluation . The medFor a long time, tea has been an important daily drink for East Asians. Drinking tea will make people feel happy because of its unique aroma, flavor, and taste. However, the sensory wheels are constructed with the criteria that were proposed by professionals for premium Taiwanese teas, and might not accurately project the consumer\u2019s perception of teas in general markets, such as the aroma attributes of root crop-nutty and bean-vegetal, which have lower acceptance in the consumer survey in From the perspective of the industrial development of beer, wine, coffee, and other popular beverages, professional knowledge education, product contests, media propagation, cultural links, and studies of health benefits can expand the penetration of tea beverages in society . The firIn summary, the development of premium teas has gradually dominated the international trade trend and supply chain structure of the entire tea industry in Taiwan. However, the expansion of the supply chains and the diversification of products have led to the prevalence of illegal business practices in the tea industry. Consumers\u2019 impression and perception have gradually faded for the high-quality Taiwan teas. Therefore, promoting the authentication of specialty teas is an urgent issue for the tea industry. Due to the generational differences of food culture and the rise of international industrial specialization, the flavor information of tea products must be dynamically updated and adjusted for the consumer groups whose lifestyle changes.The implementation of flavor authentication can be used to prevent the forgery of labeling in a traditional certification system of beverages, and the flavor lexicon can also expand consumers\u2019 interest in premium tea via assessor training for sensory evaluation. Further, the analytical techniques should be developed to establish an accurate and quantitative evaluation about the tea flavor. If the scientific clues of a flavor compound are identified, it can be applied to discriminate the quality, origin, and harmful residues of tea. The flavor profiling of the sensory wheels can be applied on the identification of specialty tea with Taiwanese label from general markets. The gap between industrial standards and consumer demand could be repaired with the development of sensory evaluation on tea flavors. Therefore, the use of quantitative descriptions of sensory evaluation, chemical analysis technology, and consumer testing to characterize the most important flavors of Taiwan specialty teas will help establish flavor standards, product traceability, and responsibility."}
+{"text": "Regional framework for action on implementation of the End TB Strategy in the Western Pacific, 2016\u20132020 in countries and areas in the World Health Organization Western Pacific Region.To assess the implementation of the We used a mixed methods approach to assess the framework\u2019s measurable and perceived impact. We conducted an analysis of national tuberculosis strategic plans, a cross-sectional survey of senior staff of tuberculosis programmes, key informant interviews and some country case studies.Of the 37 countries and areas of the Western Pacific Region, 14 had a national tuberculosis strategic plan, including all countries and areas with a high incidence of tuberculosis. Most senior tuberculosis programme staff who responded to the survey (16/23) found the regional framework useful when developing their national targets and grant applications. Programmatic challenges identified included financing, human resources, public\u2013private mix, active case finding, and paediatric and drug-resistant tuberculosis. Most of the 17 key informants thought that the regional framework\u2019s categorization of actions  was useful, but that the added value of the regional framework over other relevant documents was not obvious because of overlap in content.The regional framework influenced national level tuberculosis control planning and implementation in a positive way. A future regional framework should provide a longer-term strategic horizon and specifically address emerging trends and persistent problems faced by countries or areas of the region. The framework included 16 subtopics linked to proposed actions with defined regional targets and indicators. In view of the diversity of the region, a tiered approach was proposed with actions for all settings, specific settings and pre-elimination settings.We undertook a mixed methods evaluation to assess the implementation of the regional framework and progress towards its targets and indicators. We conducted the evaluation in collaboration with the End TB unit of the WHO Regional Office for the Western Pacific, WHO country offices, national tuberculosis programmes and other stakeholders. The main objectives of the evaluation were to: (i)\u00a0assess progress against the targets and indicators defined in the regional framework; (ii)\u00a0determine how the regional framework has been adopted at the country level; (iii)\u00a0ascertain the perceived value of the regional framework in achieving its objectives; and (iv)\u00a0describe country-level challenges and success stories, the influence of the regional framework and future challenges. For the first objective, our findings have been reported in a separate paper,We chose this comprehensive mixed methods approach to obtain multiple perspectives and critical real-life insights. We carried out the evaluation (including data collection/interviews) between July and December 2019.We developed several evaluation tools which included a data extraction guide for the policy review ,We did not require ethical approval for this quality improvement exercise. Countries and areas voluntarily provide their data to the WHO Global TB Programme, as part of standard reporting practices.Only 14 of 37 countries and areas of the region had a national tuberculosis strategic plan , includiThe four countries that had national tuberculosis strategic plans that were clearly informed by the regional framework were Kiribati, Lao People's Democratic Republic, Malaysia and Mongolia . The spehttp://www.who.int/bulletin/volumes/99/5/20-268060), provides a summary of the main objectives, indicators and targets in the national tuberculosis strategic plans of the seven priority countries of the region. The strategic plans of Cambodia, China, Papua New Guinea, Philippines and Viet Nam were mostly aligned with the WHO End TB Strategy,Implementing the End TB Strategy: the essentialsTowards tuberculosis elimination: an action framework for low-incidence countries.We received 23 of 37 completed surveys from senior staff members of national tuberculosis programmes and 19 respondents indicated that they had read the regional framework or part of it. Of these 19 respondents, 16 found the regional framework helpful in the development of their national tuberculosis strategic plan. Eleven of 22 respondents said that their national tuberculosis strategic plans were wholly or greatly guided by previous or current regional strategies. Other documents identified by respondents that guided the development of national tuberculosis strategic plans included: national development plans; national surveys and reports; the End TB Strategy; the MDGs; the SDGs; documents from the United States Centers for Disease Control and Prevention; the results of operational research; and other WHO documents including Respondents indicated that the distinction between guidance for all, specific and pre-elimination settings was useful and ensured that the regional framework could serve as a resource for all countries and areas. Programmatic hurdles that the respondents thought needed to be considered when planning technical assistance or developing future regional frameworks included financing, human resources capacity, public\u2013private partnership, active case finding, management of paediatric and drug-resistant tuberculosis and general health system challenges. Of 12 programmatic areas assessed, the senior tuberculosis staff thought that the regional framework provided the most relevant guidance on the treatment and care of adult tuberculosis patients, the development of adequate laboratory capacity to guide treatment of drug-resistant cases, and treatment and care of children with tuberculosis .We contacted 24 key informants for critical reflection on the value of the regional framework and we interviewed 17 of the informants contacted. Interviewees were with the main organizations and technical agencies working on tuberculosis control in the region and high-level national tuberculosis programme representatives in certain countries (list of organizations and agencies available in the data repository).Box\u00a01Successes: strong focus on active case finding; general laboratory improvement and expanded networks for drug-resistant tuberculosis diagnosis and treatment, including the use of Xpert Ultra\u00ae, line probe assay and whole genome sequencing; low number of multidrug-resistant tuberculosis cases among new casesRemaining challenges: maintenance of Xpert\u00ae MTB/RIF equipment and subsequent loss of skills in smear microscopy; scaling up of detection and treatment of paediatric tuberculosis; low case finding and treatment success for drug-resistant tuberculosis; inadequacy of efforts to find missing casesSuccesses: removal of the category two regimen; availability of child-friendly water-dispersible fixed-dose combination tablets; better patient support to reduce catastrophic costs; implementation of short-course regimens for management of MDR and rifampicin-resistant tuberculosis; access to bedaquiline and delamanid as requiredRemaining challenges: poor patient-centred care ; scaling up of detection and treatment of drug-resistant tuberculosis with high loss to follow-up; high cost of some medicines for multidrug-resistant tuberculosis which are not included in national drug lists and low treatment successSuccesses: better awareness of tuberculosis prevention and new WHO guidelines on infection prevention and control Remaining challenges: screening, prevention and treatment of latent tuberculosis infection; lack of commitment to provide preventive therapy to household contacts in high-incidence settings, even to vulnerable childrenSuccesses: on track to reach targets but much left to do; relatively low caseload of multidrug-resistant tuberculosis Remaining challenges: improvement in documentation to obtain funding; strengthening of surveillance and use of data for field-based research to provide scientific evidence for policy-makingSuccesses: more and better quality research undertaken, e.g. inventory studies, patient cost surveys, new diagnosticsRemaining challenges: strengthening of research capacity and securing fundingSuccesses: improved collaboration and better partnerships, and community engagement; improved private sector and donor engagement; more collaboration with other groups on tuberculosis care Remaining challenges: still insufficient engagement of the private and non-public sector; insufficient engagement of civil society in tackling tuberculosis; overwhelming of national programmes by international partnersSuccesses: increased funding from government; health system improvements, e.g. decentralized care; more attention on universal health coverageRemaining challenges: difficulty in using funding; regulatory barriers, e.g. excessive bureaucracy; strengthening of health-care delivery system; better trained human resources; large funding gaps for national tuberculosis plansSuccesses: improved commitment and top-level engagement after the UN high-level meeting on tuberculosis in 2018Remaining challenges: better cross-regional collaboration and harmonization between the WHO Western Pacific and South-East Asia regions; maintaining political advocacy at the top level following the UN high-level meetingMDR: multidrug-resistant; UN: United Nations; WHO: World Health Organization.Notes: Each success or challenge does not necessarily apply to all the countries and some refer to the region more broadly. Key informants were senior advisers from international donor and technical organizations, tuberculosis programme managers and senior tuberculosis consultants or programme staff in selected countries.Countries included in the case studies were Australia, Cambodia, China, Papua New Guinea, Philippines, Solomon Islands and Viet Nam. The focus of the cases studies was on key lessons learnt. Tuberculosis control in Papua New Guinea and the Philippines was facing significant challenges such as rising numbers of cases of multidrug-resistant tuberculosis and cases in children, while achievements such as productive research collaborations and a new social protection scheme were noted in Viet Nam. ,,,The framework aimed to assist the translation of the End TB Strategy to the national and regional context in the WHO Western Pacific Region. As such, the framework outlined ambitious tuberculosis targets for the region aligned with the End TB StrategyThe success of any global or regional tuberculosis strategy is based on its translation into national strategic plans and actual on-the-ground implementation.,Our analyses showed substantial gaps in case finding and access to treatment in all country case studies, especially for people with drug-resistant tuberculosis. The need for focused strategies to tackle tuberculosis in high-risk subpopulations was highlighted during key informant interviews. In 2018, WHO, the Stop TB Partnership and the Global Fund launched a joint initiative (FIND. TREAT. ALL. #ENDTB) to urgently scale up tuberculosis case finding.,,Responses from national tuberculosis programme managers and key informants highlighted several areas to consider in a future regional framework. Several technical and programmatic problems were highlighted including laboratory capacity, large-scale case finding for active tuberculosis, drug-resistant tuberculosis care, scaling up of preventive therapy and a lack of national research capacity to address key research questions specific to the country context. Health system challenges noted included the need for universal health coverage (UHC) and the integration of tuberculosis services into primary health care, especially for children, with adequate financing mechanisms in place.Of the seven priority countries of the Western Pacific Region, Papua New Guinea and the Philippines have the biggest challenge because of large numbers of undetected cases and health system inefficiencies.Our evaluation has some strengths and limitations. We used both quantitative and qualitative approaches and explored the perceptions of national tuberculosis programme managers and key informants. However, the scope of our evaluation was broad and captured mainly people\u2019s opinions: validation of findings was limited, except in some country case studies. Furthermore, we were unable to validate the specific effect of the regional framework on policies and activities. We also found some inconsistencies between the different components of the evaluation; for example, in the survey of national tuberculosis programme managers, most respondents said that their national tuberculosis strategic plan was influenced by the regional framework, but only four countries published new national tuberculosis strategic plans after the regional framework. Managers might have thought that the regional framework would have influenced their national tuberculosis strategic plans if it had been available at the time, or that it is influencing current plans in development. Determining the real effects of the regional frameworks and strategies is challenging given the large number of priorities, needs, strategies, documents, organizations and funders that influence disease control programming. Although the scope of our evaluation did not cover all aspects of policy development and implementation, preparation of the regional framework included comprehensive consultation with countries and areas, and the formation of a regional tuberculosis technical advisory group has provided a strong platform to develop, disseminate and monitor future regional frameworks.Thirteenth general programme of work, 2019\u20132023 of WHO, and the document: For the future: delivering better health in the Western Pacific Region.,For the future: towards the healthiest and safest region.Overall, the regional framework has had a positive influence on national tuberculosis programmes in the Western Pacific Region, where tuberculosis incidence and mortality are slowly declining. The findings of our evaluation will inform the development of a future regional framework. This framework will be aligned with the priorities of countries and areas, the"}
+{"text": "Susac syndrome (SS) is a rare microangiopathy that involves arterioles of the brain, retina, and cochlea. Diagnosis is extremely difficult because of the rarity of the disease and because the signs and symptoms often occur at different times. Multidisciplinary approaches and multimodal images are mandatory for diagnosis and prompt therapy. In this report, we describe a case of SS and the application of multimodal retinal imaging to evaluate the ophthalmologic changes and to confirm diagnosis. Early diagnosis and therapy based on the associations of steroids and immunosuppressants are necessary to limit the sequelae of the disease. Susac syndrome (SS) is a rare autoimmune syndrome characterized by microvascular alterations involving the precapillary arterioles of the brain, retina, cochlea, and semicircular canals . This diIn this paper, we considered the application of the multimodal retinal imaging approach to describe a case of SS.A 33-year-old man was admitted to the emergency unit for headaches, a referred visual field loss, dizziness, and weakness of the limbs. The patient had a history of malignant external otitis , hearingAlthough the clinical trio including focal neurological deficits, hearing defeat, and retinal arterial occlusions is considered pathognomonic, the whole clinical manifestation occurs in only 13% of patients at onset ,3. The mIn conclusion, MRI and FA are the main diagnostic instruments and may lead clinical ophthalmologists to the correct diagnosis of SS; however, new diagnostic instruments such as OCTA and wide-field color retinal photography may provide an advantage in early diagnosis and follow-up of SS, offering an effective alternative to standard FA; in evaluating microvascular changes in all capillary plexuses; and in monitoring retinal vessel density alterations during prompt therapy without dye injection."}
+{"text": "The purpose of this symposium is to highlight the mental health needs and factors associated with mental health among informal caregivers of older adults in Asia. The symposium consists of five papers. The first paper explores the perceived role, needs, and rewards of informal caregiving among caregivers of residents in independent long-term care facilities in South India. The second paper presents a systematic review and meta-analysis on the association between long-term care service use and informal caregiver burden, depression, and health status. The third paper examines the association between caregivers\u2019 characteristics and quality of life among informal caregivers of older adults with cognitive impairment in China. The fourth paper examines the association between coping strategies and caregiver burden and depression among Chinese caregivers of older adults with cognitive impairment. The last paper examines the association between cohort, meaning making, and depression among adult caregivers during the COVID-19 pandemic in Hong Kong. Taken together, these five papers underscore of the mental health needs and protective and risk factors of mental well-being among caregivers in Asia. Findings of those papers inform the development and adaptation of culturally sensitive interventions to improve mental health outcomes among informal caregivers in Asia. The disccuant will comment on the strengths and limitations of these papers in terms of their contributions to the theory, research, and practice on mental health among informal caregivers in Asia."}
+{"text": "Meteorological disaster monitoring is an important research direction in remote sensing technology in the field of meteorology, which can serve many meteorological disaster management tasks. The key issues in the remote sensing monitoring of meteorological disasters are monitoring task arrangement and organization, meteorological disaster information extraction, and multi-temporal disaster information change detection. To accurately represent the monitoring tasks, it is necessary to determine the timescale, perform sensor planning, and construct a representation model to monitor information. On this basis, the meteorological disaster information is extracted by remote sensing data-processing approaches. Furthermore, the multi-temporal meteorological disaster information is compared to detect the evolution of meteorological disasters. Due to the highly dynamic nature of meteorological disasters, the process characteristics of meteorological disasters monitoring have attracted more attention. Although many remote sensing approaches were successfully used for meteorological disaster monitoring, there are still gaps in process monitoring. In future, research on sensor planning, information representation models, multi-source data fusion, etc., will provide an important basis and direction to promote meteorological disaster process monitoring. The process monitoring strategy will further promote the discovery of correlations and impact mechanisms in the evolution of meteorological disasters. As an important source of potential damage, natural disasters have long received universal attention in the field of disaster prevention and reduction. The mitigation of natural disasters is a key factor in ensuring people\u2019s livelihood. According to a sigma report published by the Swiss Re Institute, the total global economic losses from natural disasters reached 105 billion USD in 2021, again exceeding the average for the previous 10 years ,4. ThereIn recent years, along with the rapid development of sensor technology, aerospace platform technology, and data communication technology, the global observation capability of satellite, aircraft, and land integration has been greatly enhanced ,7,8. Rem(1)What are the objectives of meteorological disaster process monitoring?(2)How are remote sensing approaches being used for meteorological disaster process monitoring?(3)What are the current gaps in remote sensing-based meteorological disaster process monitoring?According to the fifth Climate Report of the United Nations Intergovernmental Panel on Climate Change (IPCC), climate warming will intensify in the future . At the The rest of the paper is organized as follows: Disaster is a general term for objects that have destructive effects on human beings and the environment on which human beings depend for their survival . As one For the remote sensing monitoring of meteorological disasters, the aim is to meet the disaster management needs of disaster prevention and mitigation, and to obtain various pieces of disaster information in different periods in time . FollowiAfter determining the arrangement for the remote sensing monitoring of meteorological disasters, it is possible to follow the relevant requirements to perform monitoring tasks and begin to extract various types of disaster information from remote sensing data. Disaster is the product of the comprehensive effect of three factors: pregnant environment, causing factor, and disaster-bearing body ,22. For Although different meteorological disasters present different patterns and ever-changing situations in disaster factors, the occurrence of meteorological disasters is always a gradual, evolutionary process ,26,27. IThe roadmap of meteorological disaster process monitoring based on remote sensing is shown in In the monitoring of meteorological disasters, it is first necessary to reasonably and comprehensively determine the monitoring tasks to clarify the monitoring timescale, carry out sensor planning and construct the conceptual model of monitoring information. The accurate representation of monitoring tasks is the basis and premise of accurately and effectively obtaining disaster information.As an important branch of geography, the meteorological disaster system has the dual attributes of \u201cnatural\u201d and \u201csocial\u201d, and it is also \u201cscale\u201d dependent on nature. On the one hand, the dependence is manifested in the significant timescale effect of disaster factors. With the introduction of the timescale, when conducting meteorological disaster monitoring, the time boundary to be monitored should first be determined according to the time extent, and the disaster monitoring is limited to a certain period . To undeThere are three main types of sensor planning solutions: single sensor, multi-sensor in single platform, and multi-sensor in multiple platforms. For the planning of a single sensor, due to the small number of sensors, the data processing steps are relatively simple, and the data specifications between the multi-period data are unified . For insHowever, most sensor planning is based on the technical conditions of the sensor itself, which lacks the planning based on the meteorological disaster process monitoring; thus, this kind of planning method would not obtain detailed and specific solutions . For exaIn disaster management, the use of multi-period, multi-area, multi-source, and multi-department meteorological disaster monitoring information has gradually become normal. If there is no uniform standard for meteorological disaster information, it will be difficult to share information in disaster management, which is disadvantageous to efficient monitoring and emergency warning . TherefoThe unified management of the distributed sensors and data resources by establishing metadata model specifications has become an important method for disaster information modeling. Considering the universality of the model, it is usually divided into the general metadata model and the dedicated metadata model. General metadata models include Common Alert Protocol (CAP), Emergency Data Exchange Language Distribution Element (EDXL-DE) and EDXL-rm . The dedThe knowledge representation method can provide semantic integration among people, heterogeneous systems, and people-to-systems. The following related techniques are gradually being introduced to disaster information modeling: 1) Ontology. Ontology is helpful in expressing the concept of disaster and eliminating semantic heterogeneity. After the foundation of standardized geographic ontology proposed by Kolas et al. , more spIn summary, the existing disaster information models rarely consider the spatio-temporal factor; most of them record spatio-temporal information as common attributes . A meteoThe pregnant environment is the natural and human environment that causes disasters. The monitoring of the pregnant environment, mostly before the disaster occurs, and the monitoring results can help to evaluate the disaster risk and predict the disaster. For meteorological disasters, monitoring the pregnant environment is mainly carried out by the extraction of surface environmental information from the lithosphere to the atmosphere. There is a lot of information regarding the pregnant environment, such as altitude, slope, river, road, formation lithology, fault zone, etc., which can be divided into two categories: surface parameters and land cover.The methods of extracting surface parameters using remote sensing methods mainly include the empirical model method and the physical model method. The empirical model method is mainly implemented by establishing an empirical regression model between remote sensing observation signals and surface parameters . To imprThe main strategies for retrieving surface parameters based on physical models are as follows: (1) on the basis of considering the influence of local terrain on the imaging geometry, the surface parameters are extracted using a physical model that is suitable for a flat surface ; (2) on To improve the accuracy of remote sensing extraction of land cover information, it is necessary to involve as much multi-source and multi-temporal remote sensing information and existing knowledge as possible, and also to develop scientific methods to effectively fuse heterogeneous information and eliminate redundancy ,71. A vaIn recent years, with the acceleration of global urbanization, a great deal of infrastructure construction has rapidly changed land cover in a few decades or less . The impThe cause of meteorological disasters is the weather phenomena that may cause disasters. The characteristic parameters of meteorological disasters can reflect the genetic characteristics, structural characteristics, and development process characteristics of disasters and are an important basis for the monitoring and evaluation of the causes. The monitoring of causes based on disaster-characteristic parameters focuses on the type of characteristic parameter on the one hand and on the method of extraction used for each characteristic parameter on the other hand. The extraction of information regarding the causes of different meteorological disasters is discussed in the following parts.In principle, remote sensing approaches to drought monitoring can be divided into two categories: 1) the change in soil moisture can cause changes of soil spectral characteristics; 2) the change in plant physiological processes caused by drought can change the spectral properties of leaves and significantly affect the spectral properties of plant canopy. Sensors for drought remote sensing include a visible light band, near-infrared band, thermal infrared band, microwave band, etc. The common approaches include the soil thermal inertia method, soil moisture inversion method, vegetation index method, surface temperature method, and composite index method .Precipitation is the comprehensive result of atmospheric dynamic and thermal actions, which determines the external shape of precipitating cloud. Precipitation monitoring is mostly used to calculate the precipitation indirectly by detecting the cloud temperature or cloud particle information. This is not the same as directly observed precipitation but is currently one of the most difficult to observe atmospheric variables. Sensors for remote sensing of precipitation include visible light band, infrared band, active/passive microwave bands, and a combination of multiple sensors. Due to the different remote sensing data and retrieval algorithms, the precision of precipitation retrieval is different. The research focus has gradually turned to the fusion of precipitation products retrieved by multiple sensors to obtain more accurate precipitation information .Snow cover, as the most common upper boundary condition during freezing and thawing, directly affects the distribution and migration of soil moisture, soil temperature, freezing rate, freezing depth, etc. Snow cover has the unique spectral characteristics of a high reflection of visible light and a low reflection of short-wave infrared. Additionally, the snow particle size and the content of optical impurity affect the snow spectrum reflection. Sensors for the remote sensing of snow include a visible-light band, near-infrared band, far infrared band, and microwave band. Using the spectral characteristics, remote sensing approaches for snow cover monitoring can be divided into two categories: (1) binary snow identification (judging whether there is snow or not); (2) sub-pixel snow cover mapping in the form of area percentage, also known as snow coverage .Haze is a mixture of particles with different diameters. The scattering and absorption of electromagnetic waves change the radiative transmission process and affect the quality of remote sensing data. Remote sensing approaches to haze monitoring include four categories: spectral-feature-based method, image-preferential-based method, aerosol optical-thickness-based method, and multi-source remote sensing stereo-monitoring method .As the temporal and spatial resolution of the weather satellite has improved, satellite imagery has become the primary means of monitoring typhoons . The satDust particles contain a lot of minerals and have strong backscattering to solar short-wave radiation. This changes the long-wave infrared radiation and seriously affects the visibility of the atmosphere. Thus, the spectral characteristics of dust are significantly different from those of clouds and the underlying surface . HyperspFor the disaster-bearing body, as the main body of human society that is directly affected and damaged by disasters, the core content of information extraction is used to analyze the damage to or recovery of personnel, social wealth, lifeline systems, etc. The target detection and scene classification approaches in remote sensing processing are mainly used to extract information on disaster-bearing bodies of different types.For the extraction of information on the disaster-bearing body, the target object is all kinds of ground objects that are affected by meteorological disasters. According to the morphological characteristics of the object features, typical objects are generally classified into linear objects, blob objects, and complex objects. A large number of target detection methods have been accumulated, including statistical-based detection methods , but changes in the internal features of the scene cannot directly lead to changes in the type of scene. It can be concluded that there is a \"spatio-temporal semantic gap\" between the low-level changes in objects and the high-level changes in scene semantics. An instance of this is provided in Presently, pixel-level change detection is mostly used to detect various kinds of land surface indexes, object-level change detection is used to detect the damage degree of buildings, and scene-level change detection is used for flood mapping .Monitoring of disaster occurrence area. The determination of the disaster occurrence area is based on the construction of a comprehensive disaster index, which considers the intensity of the causing factor, the damage degree of the disaster-bearing body, and the impact of the disaster. On the basis of multi-temporal comprehensive disaster index inversion using remote sensing images, on the one hand, the disaster occurrence area where the disaster index changes are obtained by comparing the pre-disaster and post-disaster images; on the other hand, by comparing the images of different times, the change process of the disaster occurrence area is simulated .Monitoring the degree of disaster. The disaster degree is mainly expressed by disaster grade, building damage degree, casualty, economic loss, etc. . Remote Disaster rescue progress monitoring. Restoration and reconstruction are based on a comprehensive assessment of disasters, and the transitional resettlement of the victims is carried out. According to the post-disaster recovery and reconstruction plan, housing construction, infrastructure construction, public service facilities construction, disaster prevention and mitigation, ecological restoration, and land-use recovery are carried out . A compaDifferent types of meteorological disasters have different causes and effects, but they will evolve with the changes in disaster-causing factors and disaster carriers. Effective monitoring of the evolutionary process of meteorological disasters can not only promptly obtain the real-time status of the current disasters but also provide an objective basis for the prediction and early warning of the next disaster. Based on the above analysis, most research focused on monitoring a specific phase or a certain disaster factor ,192. HowRegarding the methods for the remote sensing monitoring of meteorological disasters, most are multiple static spatiotemporal observations using multi-temporal remote sensing data. At present, machine-learning regression methods have advantages in terms of time dynamics, such as artificial neural networks with hidden layers, which can predict the temporal and spatial changes in geographic phenomena. As a typical geographical phenomenon, meteorological disasters can be used to compensate for the differences between disaster monitoring and disaster evolution at different timescales. Machine learning methods can be used to extract relevant information about the development process from the ever-increasing meteorological disaster monitoring data stream. This can not only simulate the evolution process of meteorological disasters, but also gain a further understanding of the scientific problems of the meteorological disaster system. Together, the theory and method research into meteorological disaster process-monitoring needs a further breakthrough.Based on the characteristics of meteorological disasters, the requirements of the monitoring cycle, monitoring type, and monitoring range for different types and periods of meteorological disasters are determined. On the one hand, the applicability of existing sensors to disaster monitoring is clarified. For example, space-based remote sensing, mainly consisting of polar-orbiting satellites and geostationary satellites, has a wide range of coverage, a strong capacity for repeated observations, and is suitable for all-weather monitoring and early warning of large-scale dynamic changes in the pregnant environment and causing factors; space-based remote sensing, which is mainly based on aircraft, unmanned aerial vehicles and aerostat, has strong mobility and high resolution and is suitable for the dynamic monitoring of sudden meteorological disasters and the rapid assessment of the physical quantity of losses in the disaster-bearing body in key areas. On the other hand, to evaluate the combined effect of different sensors to acquire data, sensor planning can be obtained quickly and accurately in the actual monitoring of meteorological disasters, and the effectiveness and feasibility of the planning scheme are also guaranteed.With the rapid development of big data technology, the availability of various types of data has been continuously broken, creating conditions for the comprehensive monitoring of meteorological disaster processes. Most of the recorded remote sensing data regard the natural environment of the earth\u2019s surface, but the perception of changes in the social environment is scarce, and there is a lack of semantic attribute information. The fusion of multi-source data is not limited to the remote sensing data, but needs to be combined with more types of information to make up for the shortcomings of remote sensing monitoring. Social media, such as Twitter, Facebook, and Weibo, has become an effective means for government departments to keep abreast of disaster developments, with its wide participation and multi-source communication channels . In the The purpose of meteorological disaster process-monitoring is to perform a semantic analysis of various types of disaster information in multi-temporal remote sensing data. The existing meteorological disaster monitoring, due to the decentralization of its tasks, makes it possible to obtain one-sided disaster information. It is necessary to construct a standardized meteorological disaster process-monitoring information model and organize all kinds of information obtained from meteorological disaster monitoring in a standardized and integrated way.The objects of meteorological disaster monitoring include the interaction law, spatial distribution and evolution process of various phenomena in the disaster system, with specific spatio-temporal characteristics. In the field of geographic information science, the geographic, spatio-temporal modeling methods mainly include the temporal snapshot model, event spatio-temporal model and process spatio-temporal model. (1) The temporal snapshot model represents geographic phenomena with continuous dynamic changes as a set of discrete objects with time stamps, displaying time as a property of space . As onlyThe process-oriented spatio-temporal modeling method can provide an important reference for the meteorological disaster process-monitoring information model. Moreover, the evolution mechanism of meteorological disasters is also reflected in the spatio-temporal process of disasters. Therefore, for information modeling in meteorological disaster process-monitoring, it is necessary to use time and space as the framework. This can formally describe the disaster content and mutual relationship among various disaster elements to provide an in-depth analysis, forecasting and early warning, disaster prevention, and relief.By abstracting the disaster state, which is complex and difficult to directly perceive, the information visualization methods can effectively express the change in the morphological characteristics and attribute information of the disaster elements. These methods also can directly and show live the influence degree and development trend of disasters, and help people acquire knowledge and discover patterns. In the present and future, it is important to realize the visual display of disaster monitoring information to assist in disaster simulation, analysis, and emergency rescue decision-making.Due to the diversity and persistence of meteorological disasters, the interrelation of all kinds of disaster information is complicated. The visualization of meteorological disaster monitoring information not only needs to deal with disaster data from different sources and complex disaster elements, but also needs to look at the key information of different users at various stages to develop visualization tasks. In the existing visualization research, no complete and universal method can accurately the characteristics of all meteorological disaster scenes and meet the needs of visualization information in different stages. In summary, visualizing the meteorological disaster monitoring information and displaying the evolutionary process of meteorological disasters is an urgent problem to be solved.The occurrence and decline of meteorological disasters occur in a cyclic evolution process, and the remote sensing monitoring of meteorological disasters is essential for disaster prevention, disaster control, disaster resistance, disaster relief, and other disaster management. As meteorological disaster monitoring has the characteristics of variable timescales, diverse monitoring objects, and complex monitoring content, it is extremely challenging to obtain information on meteorological disasters efficiently, accurately and comprehensively. Based on the analysis of the basic concepts and methodology of remote sensing monitoring in meteorological disasters, this paper reviews and studies the research status of remote-sensing monitoring for meteorological disasters from the perspective of different meteorological disaster remote sensing tasks. The reasonable and comprehensive determination of monitoring tasks is a prerequisite for accurate and effective access to disaster information. In compliance with the requirements of the monitoring task, based on the extraction of surface parameters, land-cover information extraction, target recognition and other remote sensing processing approaches, information on the pregnant environment, causes and disaster-bearing body is extracted. Furthermore, by detecting and analyzing the changes in multi-temporal meteorological disaster information, the comprehensive monitoring of meteorological disaster evolution processes, such as disaster occurrence scope, degree of disaster effects, and disaster relief progress is realized.Meteorological disaster monitoring is based on the time characteristics of the disaster process and analyzes the state changes in disaster content in each disaster element under a certain timescale. Although many remote sensing approaches were successfully used for meteorological disaster monitoring, there are still gaps in process monitoring. In the future, from the perspective of the process of meteorological disasters, the sensor-planning method and the information model of multi-temporal, remote sensing data should be studied. The improvement in various methods such as disaster information extraction abilities, the effective integration of multi-source data, and monitoring information visualization must be emphasized. More importantly, it is necessary to thoroughly study the objective internal laws of various disaster objects and disaster contents in meteorological disasters over different timescales, to reveal the relationship and influence mechanism of various pieces of disaster information in the evolution of meteorological disasters. This not only conforms to the logic and sequence of human understanding of meteorological disasters, but also provides support for the in-depth analysis of the evolution mechanism of meteorological disasters."}
+{"text": "S. aureus adhesion on pristine PMMA, HA-5% lysozyme in The authors regret to inform that, the representative images of waterborne The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "Objectives: To investigate the epidemiological characteristics and infection routes of new cases in order to provide information for preventing COVID-19 resurgence in areas initially under control.Methods: The information of new symptomatic and asymptomatic patients in Chinese mainland was collected. The location distribution, epidemic course, infection routes and patients' characteristics of outbreaks were described and analyzed.Results: There were 43 new outbreaks with 3,795 symptomatic patients in Chinese mainland from March 21, 2020 to June 13, 2021. These outbreaks mainly occurred in central, border and coastal port cities. The main infection route of first generation indigenous patients was contact with imported cases and contaminated goods or environments. The infection routes of secondary generation patients mainly included family transmission, indoor social gathering infection, nosocomial infection and other infection routes. Family transmission was the most common infection route, and indoor social gathering was the most important reason for the large-scale outbreaks.Conclusions: Strengthen the management of imported patients and staff in high-risk posts was the key point to avoid the first generation indigenous patients. Adequate family isolation, prompt management policies for indoor public place and monitor of population at risk of infection were key strategies for preventing COVID-19 resurgence in areas initially under control. The coronavirus disease 2019 (COVID-19) pandemic, which began at the end of 2019, has been a worldwide epidemic of infectious disease . Over 17Therefore, to understand the epidemiological characteristics and main routes of the new outbreaks of COVID-19 in areas initially under control, we analyzed the epidemiological characteristics and infection routes of the outbreaks in different regions of Chinese mainland in recent 1 year, which will provide the basis for the corresponding preventive strategies.The daily new indigenous symptomatic and asymptomatic patients, start date, duration, patient number and clinical subtype were collected from the official documents released by the Health Commission of the People's Republic of China and the provinces \u201318. The The definitions of first and secondary generation indigenous patients were referred to guidelines for epidemiological investigation of COVID-19 release by the Chinese Center for Disease Control and Prevention .First generation indigenous patients were defined as the earliest symptomatic or asymptomatic patients in the epidemiological investigation of epidemics. According to the occupation of patients, the possible infection sources were investigated, including imported cases, imported goods or related environment contaminated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).Second generation indigenous patients were defined as symptomatic or asymptomatic patients contacted with the first generation indigenous patients within 14 days without other potential sources of infection. After identifying the first generation patients, the infection routes of the second generation patients were determined by investigating the contacts with the first generation patients, and were classified into family transmission, indoor social gathering infection , nosocomial infection and other infection routes. The definitions of other secondary generation of patients were similar.The number of symptomatic and asymptomatic patients, start date, duration and clinical subtype of patients in different epidemics were summarized in the descriptive epidemiological analysis. The numbers of daily symptomatic patients were used to describe the epidemic curves of different outbreaks. Statistical map was used to describe the location distribution of outbreaks, in which the area of the circle was proportional to the number of patients. The infection routes of first and secondary generation patients were extracted and summarized from the epidemiological investigation to identify the key infection routes of patients.On March 21, 2020, the first indigenous patient cause by imported patient was reported in Guangzhou, who did not cause further transmission. However, in the past year, there have been some new outbreaks with a large number of indigenous confirmed cases in Harbin, Beijing, Urumqi, Dalian and other cities . In ApriIn May, four outbreaks also occurred in Yingkou, Lu'an, Guangzhou and Shenzhen. Among them, the outbreaks in Yingkou and Lu'an belonged to the same transmission chain, and the source might be cold chain food in Yingkou, resulting in 24 symptomatic and 23 asymptomatic patients in both cities. On May 21, a new indigenous patient was reported in Guangzhou, which leaded to rapid spread of COVID-19 through family transmission and indoor gathering, resulting in fifth generation of transmission and 139 symptomatic cases. On the same day, one indigenous asymptomatic patients was reported in Shenzhen, and four symptomatic and 12 asymptomatic patients were reported in the next few days, who were all employees of an international freighter operation company and their close contacts.By June 13, 2021, 43 new indigenous outbreaks have occurred in Chinese mainland, mainly distributed in central cities, border cities in the inland areas and coastal port cities . The citIn the new indigenous outbreaks, the infection routes of the first generation patients were mainly direct or indirect contact with imported patients, goods or environments contaminated by SARS-CoV-2. Therefore, the indigenous patient included staff or nearby residents contacted with imported cases in quarantine hotels, families infected by imported cases during home quarantine, and staff contacted with contaminated imported cold chain food or environment of inbound aircraft and freighter.The infection routes of secondary generation patients included family transmission, indoor social gathering infection , nosocomial infection and other infection routes . Family Prevention of COVID-19 pandemic is the top priority in the world. After the outbreaks have been controlled in some countries or areas, the normal work, life and foreign exchanges should be restored. Therefore, the focus of prevention in these countries was to prevent the resurgence of COVID-19 epidemic due to imported patients. In this study, we analyzed the epidemiological characteristics and infection routes of new indigenous outbreaks in Chinese mainland in recent 1 year after the pandemic in Wuhan was controlled. The results showed that the new indigenous outbreaks mainly occurred in central cities, border cities in the inland areas and coastal port cities. The main infection routes of first generation patients were direct or indirect contact with imported cases, imported goods or related environment contaminated by SARS-CoV-2. The infection routes of the secondary generation patients mainly included family transmission, indoor social gathering infection, nosocomial infection and other infection routes. Although these outbreaks have been controlled in a short time, there were still some gaps in community prevention and nosocomial infection control in new COVID-19 outbreaks.The first generation patients were the source of COVID-19 resurgence and the focus of preventive strategies. The first generation patients of 15 outbreaks  were related with imported patients, suggesting the necessity of stricter isolation management of entry personnel \u201325. The The first generation patients of seven outbreaks  were related with the contaminated imported goods or environments, including cold chain food, container, freighter, aircraft and so on \u201328. TherCompared with the first generation patients, the infection routes of secondary generation patients were more diversified, and there were a large number of asymptomatic patients, which increased the difficulty of prevention , 32. In Nucleic acid test was an important method for etiological diagnosis of COVID-19, especially for asymptomatic and atypical patients. However, false negative results were found in some imported patients, indigenous symptomatic and asymptomatic patients before diagnosis. In addition to the low viral load in some patients' nasopharynx, it may also be related with the process of collection and transportation of specimens , 38. TheIn summary, the prevention of new indigenous epidemic in areas initially under control was an important issue during the pandemic of COVID-19. We analyzed the new indigenous outbreaks in Chinese mainland, and found that these outbreaks mainly occurred in central, border and coastal port cities. The first generation patients were mainly infected by contacting imported patients, contaminated goods and environment, and secondary patients were mainly infected through family transmission, indoor social gathering and nosocomial infection. Strengthen the management of imported patients and staff at high-risk of SARS-CoV-2 infection was the key point to avoid the first generation indigenous patients. When the new indigenous epidemic occurred, prompt management of indoor public place and monitoring of population at risk of infection using big data can avoid large-scale epidemic.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.YL: investigation, visualization, and writing\u2014original draft preparation. KY: investigation, data curation, and writing\u2014reviewing and editing. SZ: investigation, methodology, and writing\u2014reviewing and editing. LW: investigation, writing\u2014reviewing and editing, and conceptualization. RC: conceptualization and writing\u2014reviewing and editing. All authors contributed to the article and approved the submitted version.This work was supported by the Emergency Research Project of COVID-19 of Zhejiang University (grant number: 2020XGZX024).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Despite the preventability of cervical cancer, the global burden remains high with 604,000 cases and 342,000 deaths estimated in 2020 . IncidenWith the political momentum in place to eliminate the disease over the next decades via national scale-up of the triple  intervention strategy, we would like to highlight the current situation in the Newly Independent States (NIS) of the former Soviet Union.Opportunistic annual cytology screening of broad age groups \u2013 frequently using Romanowsky-Giemsa staining \u2013 remains a common practice in many NIS ; while nUsing the national and subnational cancer registry data from four NIS for the period 2008\u20132017, we examined the time trends in recorded age-standardised (world) incidence rates of invasive cervical cancer. Rates are uniformly high, and trends appear either stable or slightly increasing over the 10-year period . Given tAs a way forward towards cervical cancer elimination in the region, we advocate a radical shift in national policies in the NIS, away from opportunistic screening towards population-based, quality-assured HPV vaccination and HPV-based screening programmes. IARC partners with WHO Regional Office for Europe to improve screening policies and practices in the NIS, and to build capacity for quality assured screening and for population-based cancer registries, thus enabling the benchmarking of national progress in HPV-related cancer control in the forthcoming decades.Where authors are identified as personnel of the International Agency for Research on Cancer / World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer / World Health Organization.The authors report no declarations of interest."}
+{"text": "This study used Latent Class Analysis to examine patterns of social participation among older adults in the US, the UK, and China, from the three nationally representative surveys conducted in 2018-2019: The Health and Retirement Study, the English Longitudinal Study of Ageing, and the China Health and Retirement Longitudinal Study. Although the profiles of social participation were distinctively different, several common patterns were found: Comprehensive Participants, Occasional Participants, and Deficient Participants. It was estimated that less than 10% of older adults from these countries were extensively engaged in social participation. Seventy-seven percent of Chinese older adults were shown being \u201cDeficient Participants\u201d, and the percentages were 29% and 20% in the US and the UK, respectively. The findings showed positive associations of levels of participation with socioeconomic status and health. The magnitudes of these associations varied across the nations. Actions are needed to promote levels of participation for Chinese older adults."}
+{"text": "For 15 years, the Annual African Vaccinology Course (AAVC) hosted by the Vaccines for Africa Initiative, has been at the forefront of vaccinology training in Africa. The AAVC was developed in 2005 in response to the growing demand for vaccinology training in Africa. To date, 958 policy makers, immunization managers, public and private health practitioners, scientists, postgraduate and postdoctoral students have been trained. These participants are from 44 of the 54 African countries. The course content covers diverse topics such as considerations for new vaccine introduction, mathematical modelling, and emerging and re-emerging vaccine preventable diseases. As the landscape of vaccinology continues to evolve, the AAVC aims to expand the reach of vaccinology training using blended learning approaches which will incorporate online and face-to-face formats, while expanding access to this popular course. Ultimately, the AAVC endeavours to develop a big pool of vaccinology expertise in Africa and to strengthen regional ownership for immunization programmes. Immunization programmes in Africa have achieved remarkable progress since the introduction of the Expanded Programme on Immunization (EPI) in 1974 ,3. The sAims of the course: the aim of the AAVC is to: (i) broaden understanding of the challenges and opportunities in vaccinology at regional and global levels, (ii) equip participants with essential expertise to support national immunization programmes, (ii) build sustainable research capacity for vaccine development including the conduct of high quality phase I-IV vaccine trials in Africa, (iv) explore the roles and challenges of National Immunization Technical Advisory Groups (NITAGs) in strengthening immunization policies in Africa, and (v) foster collaboration and networking among African vaccinologists.Course content: since the inception of the AAVC in 2005, the course content has evolved in response to the rapidly growing field of vaccinology and the increasing demand for developing vaccinology expertise in Africa. Further information on the AAVC course content may be sourced from the VACFA website [ website . BrieflyFormat of the course: this is usually a five-day face-to-face course taking place in the last quarter of the year. While previous versions of the AAVC were held in several African countries [ountries , this waountries . The onlth AAVC in 2018, the NITAG workshop was held over 1.5 days. Attendees of the workshop included core members and secretariat of NITAGs from nine African countries, namely; Angola, Cameroon, Ghana, Nigeria, Rwanda, South Africa, Tanzania, Togo and Uganda. Discussions were facilitated by representatives from VACFA and the World Health Organization (WHO) [As part of VACFA\u00b4s initiative to strengthen the vaccine policy and decision-making landscape in Africa, the scope of the AAVC was extended in 2018 to include a workshop dedicated to exploring the roles of, and challenges faced by NITAGs. The workshop is a networking opportunity and explores possible technical and scientific support mechanisms for NITAGs in Africa. In its first offering during the 14on (WHO) . This waCourse participants: a report on the participants and faculty members of the AAVC held between 2005 and 2010 was previously published [ublished . BetweenCourse faculty members: about 116 faculty members have given talks in the AAVC between 2011 and 2019. On average, 33 faculty members regularly give talks at the AAVC each year. The AAVC faculty is well-represented by local, regional and international experts from relevant fields across the vaccinology cascade, including academia, global health agencies, non-governmental agencies and the pharmaceutical industry  for vaccines and immunization, integration of health economics and mathematical modelling in EIDM, Covid-19 vaccine rollout, and vaccine safety monitoring. In addition, the AAVC may be adapted to meet specific training needs of NITAGs. As we move towards the Immunization Agenda 2030 , the AAV"}
+{"text": "The Omnibus Budget Reconciliation Act (OBRA) of 1987 included provisions for the Preadmission Screening and Resident Review (PASRR) program, which requires states to create and maintain systems to assess persons with serious mental illness (SMI) seeking NH care. The prevalence of SMI in NHs is increasing, and little is known about the effectiveness of the PASRR program intervention. We conducted 20 interviews with state and national PASRR stakeholders, including assessors, hospital discharge planners, mental health advocates, geriatricians and geriatric psychiatrists. Interview data were triangulated with state provided materials on PASRR collection and implementation. Based on these interviews, we identified four themes: 1) variation in the implementation of federal PASRR legislation across states and jurisdictions, 2) the need for investment in professional development and workforce capacity, 3) lack of usefulness of PASRR in ongoing care planning, and 4) the need to consider the role of age, race/ethnicity, and stigma on quality of care for NH residents with SMI. Stakeholders agree that PASRR legislation was well intentioned, but also expressed concern regarding the completion of PASRR as an issue of compliance versus meaningful assessment. More work is needed to determine how best to develop and support the care needs of people with SMI, while being mindful of the original goals of deinstitutionalization that prompted OBRA passage. In order to assess the impact of the PASRR program on quality of care and mental health outcomes, further research should take an evaluative approach through meaningful use of PASRR data."}
+{"text": "Forests are key components of European multifunctional landscapes and supply numerous forest ecosystem services (FES) fundamental to human well-being. The sustainable provision of FES has the potential to provide responses to major societal challenges, such as climate change, biodiversity loss, or rural development. To identify suitable strategies for the future sustenance of FES, we performed a solution scanning exercise with a group of transdisciplinary forest and FES experts from different European regions. We identified and prioritized fifteen major challenges hindering the balanced provision of multiple FES and identified a series of potential solutions to tackle each of them. The most prominent challenges referred to the increased frequency and impacts of extreme weather events and the normative mindset regarding forest management. The respective solutions pointed to the promotion of forest resilience via climate-smart forestry and mainstreaming FES-oriented management through a threefold strategy focusing on education, awareness raising, and networking. In a subsequent survey, most solutions were assessed as highly effective, transferable, monitorable, and with potential for being economically efficient. The implementation of the solutions could have synergistic effects when applying the notion of leverage points. Seven emerging pathways towards the sustainable supply of FES have been identified. These pathways build on each other and are organized based on their potential for transformation: (1) shifting forest management paradigms towards pluralistic ecosystem valuation; (2) using integrated landscape approaches; (3) increasing forest resilience; (4) coordinating actions between forest-related actors; (5) increasing participation in forest planning and management; (6) continuous, open, and transparent knowledge integration; and (7) using incentive-based instruments to support regulating and cultural FES. These pathways can contribute to the implementation of the new EU Forestry Strategy to support the balanced supply of multiple FES.The online version contains supplementary material available at 10.1007/s11625-022-01111-4. European forests are ecosystems that deliver manifold benefits to society via so-called Forest Ecosystem Services (FES) . On the first day, each thematic group prioritized and characterized the respective subsets of thematic challenges resulting from the exploratory survey. The prioritization included, for each challenge, a general assessment of the urgency , their impact , the types of FES affected, scale, and the inter-relations between each of these challenges and all the thematic areas. Accordingly, each thematic group reduced the list of challenges to the five most relevant. At the end of the first day, the number of challenges was reduced through a series of anonymous majority voting rounds in plenary to the three most pressing challenges for each thematic area. During the second day, the thematic groups reconvened to formulate and characterize strategic solutions for each of the three selected challenges. The characterization consisted of a description of the solution, the feasibility of implementation, a time frame, and the resources needed for application. A detailed account of the whole process, including the definition, framing and prioritization of the challenges (first day of the workshop); and the identification and characterization of the strategic solutions (second day of the workshop) can be found in S3.During the third phase, the identified solutions were evaluated in an online survey distributed to all participants in January 2021 (S2). The respondents rated each solution according to five different criteria of optimal solutions, adapted from the concept report on climate policy-mix optimality Gorlach  see Box was usedThe participants in the solution scanning process were 24 experts from academia, policy, and practice working directly on FES in Europe. Most participants (90%) were related to the EU Horizon 2020 funded projects SINCERE and InnoForESt,\u00a0both dealing with the promotion of FES-related innovations. A team of three facilitators selected from both projects supported the implementation of the solution scanning exercise. About expert participants, particular attention was paid to balance backgrounds between academia and practice, disciplines, geographic foci, seniority level, and gender (S4).Most of the selected experts worked at research organizations at the interface between science, policy, and practice (41%). The covered areas of knowledge of the forestry sector were broad, including experts on forest ecosystem services governance and innovation, urban forestry and European forest policy. Partly because the coordination of both of the Horizon 2020 projects is based in Germany, most of the participants worked at German organizations (41%). However, seven other European countries were also represented in the exercise, namely Spain, Italy, Austria, Belgium, Switzerland, Finland, and Sweden. A balanced gender representation was achieved and consciously maintained along the process.This solution scanning exercise synthesizes the currently fragmented views on forest challenges and targets suitable solutions to foster the sustainable provision of FES. The organization of the exercise into three well-defined phases allows a clear and transparent communication among the coordinators and experts, facilitating a smooth iterative process. Due to COVID-19 restrictions, the participatory process was conducted entirely online. Two important aspects of this sequential participatory method have been the regular communication with the group to ensure a shared understanding of the process, the use of preparatory materials before and after each workshop through two surveys (S1 and S2), and the presentation of the state of the work at the beginning of each phase of the solution scanning session. However, we must emphasize that the results highly depend on the participant contributions and the specific timing of the survey and workshops, which is a limitation of our approach.After the prioritization process, 15 challenges were selected, three per thematic area, based on their urgency and impact . The suitability of each solution was subsequently assessed and ranked based on the following six criteria: social\u2013ecological effectiveness, economic efficiency, readiness, feasibility, and transferability potential (Box 1). Table Sustainability Area: Environment; Challenge 1\u2014Increasing frequency and intensity of extreme weather eventsClimate-smart forestry is a targeted approach to manage forests in response to climate change  should be consistently supported by cross-scale European and national policies similar to those in place for timber and biomass production . These strategies are often coupled with a philosophy of embracing innovations towards improved forest management for the provision of FES bundles, especially for regulating and cultural FES, for the promotion of ecological and societal transformation, and for the sustainable use of public goods. Public forests would be used as niches of innovation Geels  of, for Sustainability Area: Socio-culture; Challenge 13\u2014Homogenization of perceptions of forest values by societyUnderstanding forests as a mean to solve economic problems is a reductionist standpoint. In the pursuit of sustainable forest management, increased identification and inclusion of cultural bonds is crucial. To achieve a deeper understanding of the mutual constitution of the society\u2013forest relation, it is also necessary to recognize the multi-layered spectrum of forests\u2019 contributions . European studies of public perception  for business model implementation to strengthen their adaptation to each specific context. For example, by refocusing on forest protection measures . These types of solutions would normally require long-term commitment, institutional changes, and socio- political will . Furthermore, they directly or indirectly interfere with long-established cultural elements or strong economic interests . These solutions can be considered as aiming for or being dependent on larger, perhaps even fundamental system changes which require the alteration of existing paradigms, institutions , and actors\u2019 behaviors.A closer look at the solutions\u2019 definitions and prioritization suggests a possible sequence of implementation. Inspired on the notion of leverage points, where solutions can induce shallow or deep changes connection between people and nature. Forestry education at all levels, forest management, and policies need to pursue a shift from the consideration of instrumental values, to increasingly considering intrinsic and especially relational value dimensions , or through user-financed PES in those areas where there is sufficient willingness to pay for a specific FES Supplementary file2 (XLSX 15 KB)Below is the link to the electronic supplementary material."}
+{"text": "H\u00f4pital D\u2019instruction des Arm\u00e9es de Cotonou Centre Hospitalier et Universitaire]) laboratory in Benin launched a quality improvement programme in alignment with the World Health Organization Regional Office for Africa\u2019s Stepwise Laboratory Improvement Process Towards Accreditation (SLIPTA). Among the sub-Saharan African laboratories that have used SLIPTA, few have been francophone countries, and fewer have belonged to a military health system. The purpose of this article was to outline the strategy, implementation, outcomes and military-specific challenges of the HIA-CHU laboratory quality improvement programme from 2015 to 2018.In 2015, the Army Teaching Hospital\u2013University Teaching Hospital (HIA-CHU [The strategy for the quality improvement programme included: external baseline SLIPTA evaluation, creation of work plan based on SLIPTA results, execution of improvement projects guided by work plan, assurance of accountability via regular meetings, training of personnel to improve personnel competencies, development of external stakeholder relationships for sustainability and external follow-up post-SLIPTA evaluation.Over a period of 3 years, the HIA-CHU laboratory improved its SLIPTA score by 29% through a quality improvement process guided by work plan implementation, quality management system documentation, introduction of new proficiency testing and internal quality control programmes, and enhancement of personnel competencies in technical and quality management through training.The programme has yielded achievements, but consistent improvement efforts are necessary to address programme challenges and ensure continual increases in SLIPTA scores. Despite successes, military-specific challenges such as the high mobility of personnel have hindered programme progress. The authors recommend that further implementation research data be shared from programmes using SLIPTA in under-represented settings such as military health systems. H\u00f4pital D\u2019instruction des Arm\u00e9es de Cotonou Centre Hospitalier et Universitaire]) of the Benin Army Health Service in Cotonou is a reference health centre known for the quality of its services and training. The HIA-CHU laboratory plays a leading role in the public healthcare continuum by providing diagnosis, screening, and initial and follow-up treatment as well as preventative care.1 Therefore, the HIA-CHU laboratory prioritises quality, in that it promotes the accuracy, reliability and timeliness of results.The Benin Army Health Service provides healthcare to army personnel, their families and civilians across Benin. The Benin Army Health Service is involved in disaster response and supports the Beninese public health system, with approximately 75% \u2013 80% of its services provided to the civilian population. The Army Teaching Hospital\u2013University Teaching Hospital  15198:2012 standard, \u2018Medical Laboratories\u2013Particular requirements for quality and competence\u2019, serves as a standard for the laboratory quality management system (QMS) \u2013 a formalised system that outlines required structures and functions for medical laboratories. Progress made on the ISO 15189 standard can help a laboratory prepare for accreditation through a recognised agency; this allows the laboratory to demonstrate to clients, partners and staff that it has attained a high level of technical competence, thus instilling confidence in stakeholders on the accuracy and reliability of its results.In recent years, there has been an emphasis on improving medical laboratory services globally. Health priorities have been set forth by public declarations, such as the International Health Regulations and the Maputo Declaration (2008), in which signatories pledged to address and strengthen laboratory and health services.3 Though progress has been made, most clinical laboratories in sub-Saharan Africa remain under-equipped, under-funded and far from attaining international norms and standards. Few laboratories are accredited to international quality standards, and most of these internationally accredited laboratories are based in South Africa.4 Quality assurance, which comprises QMS including the existence of a quality manual, use of internal quality controls (IQC) and participation in external quality assessment (EQA), is poorly implemented and often unavailable in many laboratories in sub-Saharan Africa.7 In the absence of quality assurance, there is the risk of laboratory errors, which could adversely impact patient care.In sub-Saharan Africa, the clinical laboratory remains a weak link in the healthcare chain.8 The African Society of Laboratory Medicine serves as the secretariat of the World Health Organization Regional Office for Africa SLIPTA programme. The SLIPTA framework guides improvement of performance, measures and evaluates the progress of laboratories towards ISO 15189 international accreditation and awards a certificate of recognition from zero to five-star ratings.9To alleviate these challenges and support awareness of the importance of achieving quality standards in medical laboratories in sub-Saharan Africa, the World Health Organization Regional Office for Africa developed in 2009 a phased laboratory quality management evaluation system called the Stepwise Laboratory Quality Improvement Process Toward Accreditation (SLIPTA).The HIA-CHU in Cotonou, Benin, has a staff consisting of military and civilian personnel and includes a clinical pathologist, 12 medical laboratory scientists and support staff. The services provided include medical fitness evaluation, disease prevention, treatment and care, and teaching and research in medical, biological, pharmaceutical, paramedical, odontological and veterinary specialities. Laboratory services at HIA-CHU are versatile and the laboratory manages, on average, 20 000 patient files and 50 000 tests per year.In January 2015, the HIA-CHU laboratory service initiated, for the first time, a quality improvement (QI) programme in alignment with the SLIPTA framework. The QI programme goal was to improve laboratory services related to disease diagnosis and monitoring via the implementation of QMS using SLIPTA framework. The QI programme aimed to provide training for laboratory personnel on quality management concepts and practices, monitor laboratory quality and adherence to quality systems, conduct laboratory test method validation and provide proficiency testing panels for HIV, tuberculosis and other critical tests \u2013 successful implementation of the QI programme ensures that laboratory stakeholders and end-users have confidence in laboratory data which informs clinical decisions and optimises patient care.The HIA-CHU laboratory QI programme was launched through a collaboration with the US Department of Defense HIV/AIDS Prevention Program (DHAPP). As of 2015, the Benin Army Health Service already had a long-standing collaboration with DHAPP, which had been funding laboratory equipment and reagents, specifically to support HIV diagnosis and treatment monitoring. Over the years, both parties recognised that laboratory tests and equipment alone are not sufficient to demonstrate test result quality; tests and equipment must be accompanied by laboratory quality practices implemented by properly trained and motivated personnel. To address this recognised need, DHAPP began supporting the Benin Army Health Service in the execution of the HIA-CHU laboratory QI programme in 2015, with implementation assistance provided by the United States-based global health company Global Scientific Solutions for Health .The purpose of this article is to report on the implementation of the QI programme at the HIA-CHU laboratory from 2015 to 2018.The laboratory QI programme began in January 2015 with initial programme planning among stakeholders  and the facilitation of a comprehensive baseline evaluation of the HIA-CHU laboratory by GSSHealth using the World Health Organization Regional Office for Africa SLIPTA checklist, version 2:2015. The baseline SLIPTA evaluation allowed the assessment of the 12 quality management sections: organisation and personnel, management reviews, process control and internal quality assessment and EQA, information management, corrective action, equipment, purchasing and inventory, documents and records, occurrence management and process improvement, internal audit, client management and customer service, and facilities and safety.Following the evaluation, leaders from HIA-CHU, DHAPP and GSSHealth convened for a collaborative session to review findings, identify priority QI areas and develop a tailored QI approach for each priority area.A tailored QI approach was developed to strengthen HIV testing processes \u2013 the focus of the funding agency DHAPP; it covered the identification of key quality indicators to track and improve upon over time and the development and execution of the QI work plan.The key indicators identified to measure laboratory improvement based on ease of collection and relevance to the work plan included:SLIPTA: Percentage improvement in total and by section.EQA: Percentage score in PT programme.IQC: Accuracy of quality control results.Personnel training: Percentage change in theoretical test scores for training workshops.Laboratory documentation: Number of documents created and adequately implemented to standardise laboratory practices and formalise the commitment to the QMS.The laboratory-set targets were: continual improvement in the SLIPTA score through the establishment and implementation of improvement projects tracked by work plans, participation in EQA and PT and improvement of performance where the score is less than 100%, participation in IQC activities and improvement of processes in case of discrepancies between expected and obtained results, strengthening of laboratory quality management processes guided by well defined documentation, and the advancement of laboratory personnel competencies through training and mentorship workshops.The HIA-CHU laboratory supervisor facilitated work plan development in collaboration with partners  and laboratory staff. The work plan included high-level QI goals, specific objectives for each goal and details of specific, measurable, achievable, realistic, and timely, or \u2018SMART\u2019, tasks and deliverables to meet set targets within defined timeframes see .The work plan was progressively implemented and updated through improvement project execution, progress monitoring, ongoing data collection and review, and continual alignment with the funder\u2019s priorities. Staff were engaged in the work plan implementation through their appointments to specific QI projects with oversight by the laboratory supervisor, and through continuous engagement in recurring collaborative work plan update meetings to promote accountability. Quality improvement activities conducted in the context of the work plan included: nomination of new QMS personnel roles , targeted laboratory personnel training and mentorship, implementation of EQA and IQC, definition of essential QMS processes and development and use of associated documentation, and coordination of a follow-up SLIPTA evaluation to measure progress.From the baseline SLIPTA evaluation, the identified priority issues, which correspond to low-scoring SLIPTA sections, include the following: the lack of a quality manual or safety manual, the lack of standard operating procedures for all processes and technical procedures, the lack of PT and quality control for tests, the lack of equipment maintenance and repair logs, the lack of temperature monitoring processes, and the lack of mistakes or error logs.The initiation and implementation of a QI programme at the HIA-CHU laboratory yielded numerous positive changes as perceived by HIA-CHU hospital leadership, laboratory management and staff, and partners . Positive changes included the establishment of a laboratory quality management team, achievement of designated QI projects resulting in SLIPTA score improvements, the improvement of IQC and EQA test result accuracy, the development and implementation of over 50 standard operating procedures, and the strengthening of personnel competencies through targeted QMS training and mentorship. Throughout the years of the QI programme, support from funding partner DHAPP and implementing partner GSSHealth ensured continuous evaluation of processes via the internal and external evaluations and the update of work plans and associated QI projects.The engagement of laboratory staff was key to the establishment and implementation of the laboratory QI work plan at HIA-CHU. To encourage staff commitment to the QI approach and ensure staff in-depth orientation to quality management concepts and testing processes, the laboratory QI approach prioritised staff training and mentorship.Over 50 technicians participated in training workshops on QMS co-organised and co-facilitated by the Benin military health system and GSSHealth. All training sessions consisted of didactic and interactive sessions and tests were administered pre- and post-training to evaluate knowledge change among the trainees. The median change in test score from pre-training to post-training for all the trainees increased from 15% to 40% . ImproveIn the first year of the programme, two quality workshops were held for laboratory staff with GSSHealth facilitators. The objectives of the workshops were to improve the competency of laboratory staff in the areas of quality assurance, QMS and HIV and tuberculosis testing. These topic areas were priorities for the laboratory director and DHAPP \u2013 the funder, whose focus is the prevention and control of HIV and HIV comorbidities. The first workshop took place in April 2015 with a focus on quality management concepts for equipment management, document writing and EQA. Staff received guidance and mentorship on HIV rapid testing. A second workshop took place in September 2015, with a focus to increase staff competency on laboratory supply chain and stock management. At the end of the first year, a follow-up SLIPTA evaluation was conducted.In 2016, the QI programme continued with an updated work plan, and laboratory staff participated in a national biosafety and biosecurity workshop hosted by the Ministry of Defense and the Ministry of Health. The second year concluded with a poster presentation by the HIA-CHU laboratory supervisor on the quality programme at the African Society of Laboratory Medicine international conference in December 2016.In 2017, the laboratory quality team updated their quality work plan, worked with laboratory personnel on QI projects, implemented the use of quality controls for CD4 testing, and organised an internal SLIPTA evaluation. In April 2017, one laboratory staff member from HIA-CHU was sponsored to attend a multi-country, 5-day training workshop in Senegal. The workshop covered essential aspects of laboratory quality management, including document management and standard operating procedure writing; equipment management and maintenance; error occurrence management, prevention and corrective action, and quality indicators. Finally, a follow-up external SLIPTA evaluation was conducted in October 2017 to re-evaluate the laboratory system, measure progress since the previous external SLIPTA evaluation, and update the QI programme.As the QI programme moved into its third year in 2018, the laboratory again updated its work plan, based on the previous evaluation, and revised and updated key documentation including the laboratory quality manual and biosafety manual. In April 2018, a joint Ministry of Defense and Ministry of Health laboratory biosafety and quality management workshop was organised, to increase staff competency on principles and ISO standards for biosafety and biosecurity.Through its ongoing commitment to training personnel in both technical and quality management topics, the laboratory has observed significant improvements in staff competencies and performance. For example, the SLIPTA sections in which the laboratory achieved the most significant quality improvements correspond to the quality management topics covered during training workshops. Data from the QI programme showed that post-training, personnel knowledge was improved and retained . AdditioThe laboratory document management system has been developed gradually over time and has included the creation and implementation of a quality manual, a biosafety manual, a sample collection manual and more than 50 standard operating procedures, technical instructions, forms and logs . The laboratory supervisor and designated quality manager took the lead in developing documents, executing a document management process, and introducing new documents into circulation in the laboratory. Laboratory personnel were oriented to new documents and procedures during regular laboratory meetings, facilitating the understanding and proper use of new documents. The availability of procedures and other documents helped laboratory management ensure that personnel observed standardised processes across the pre-analytical, analytical and post-analytical phases, and simplified the training of new personnel. Furthermore, to ensure that only correct and updated documents were available in the laboratory, processes to control document revision, approval and version release were instituted by the laboratory supervisor and quality team.In September 2015, the HIA-CHU laboratory enrolled and participated in an annual PT programme for HIV serology with commercial EQA provider Thistle quality assurance, and later with the Benin Ministry of Health, to promote sustainability. During the four EQA events for HIV serology, nine technicians participated, and PT scores of 100% were obtained. No corrective action was needed to improve proficiency; laboratory personnel were nonetheless oriented on root-cause analysis, and corrective and preventive action in case of future instances of lower EQA scores.In 2018, the HIA-CHU laboratory participated in two commercial haematology EQA programmes with Human Quality Assessment Services. The laboratory results for the first haematology EQA test were in the acceptable range for all analytes except for monocytes or mid cells, due to a reporting error. As a corrective action, the laboratory established a system for the supervised recording of results, in which the laboratory section supervisor verifies the accuracy of test results entered manually by technicians, after which results are entered into a computer by a secretary and printed for final validation. This process has helped reduce transcription errors.The HIA-CHU also began an IQC programme in biochemistry for the first time, in which the laboratory used high, normal and low commercial controls on equipment daily. When control values are outside the acceptable range, the laboratory staff will conduct a root-cause investigation and analysis. Elements to be investigated include reagents , room temperature, quality of distilled water, quality of the control product, etc. If the issue persists after the above steps, the equipment is then recalibrated. All corrective actions and measures taken are documented and recorded.Overall improvement of the laboratory\u2019s quality system was demonstrated by a 29% increase in SLIPTA score, from 16% at baseline evaluation in 2015 to 45% at the follow-up evaluation in 2017 see .Since 2018, reliance on the Ministry of Health National HIV Reference Laboratory for the administration of an HIV serology PT programme has allowed the HIA-CHU laboratory and other military laboratories to ensure a more sustainable and affordable PT option.Several important factors can explain the successes achieved during the QI programme. The laboratory leadership and staff benefited from the strong support of the hospital management, thus underpinning laboratory staff motivation to sustain quality improvements. Also, the implementing partner provided support in the execution of work plans, drafting of procedures, funding of training visits and organisation of regular teleconferences to track progress. The implementing partner provided sound advice for the appropriation of the quality approach and the implementation of improvement steps.8 Military health systems face unique challenges that impact their laboratory QI efforts; the challenges and associated responses of HIA-CHU laboratory may be relevant to other military laboratory programmes or to non-military laboratories that have limited funds to invest in QI efforts. Regardless of improvements made, QI is a never-ending process and the sustainability of gains is not guaranteed.10 Despite the quality advancements made over the past several years, challenges remain, requiring corrective action to ensure the efficacy of the ongoing programme.13 The issue of the high mobility of military personnel has made it difficult to fully and consistently integrate staff into quality laboratory operations and maintain the laboratory QMS. As a result of high staff turnover \u2013 a key facet of the military system \u2013 all members of the starting laboratory quality team are no longer in service at the HIA-CHU laboratory in Cotonou. Continuous staff turnover in part explains the slowdown in progress observed between the 2016 and 2017 follow-up evaluations. Staff mobility has also negatively impacted the timelines for the execution of planned activities such as management reviews, internal evaluations and inventory processes, for all of which personnel must be properly trained and oriented to ensure their execution per SLIPTA and ISO 15189 requirements.Although SLIPTA is an adaptable structure and was used to guide the HIA-CHU laboratory\u2019s quality successes, its formal implementation in francophone African countries and military contexts has been limited.Although the laboratory QI programme has incorporated training workshops, the programme would benefit from the establishment of a structured framework for continous personnel training allowing the laboratory to maintain a pool of trained and dedicated personnel.Going forward, the ambition of HIA-CHU laboratory is to continue advancing in laboratory quality using the SLIPTA guideline, to ultimately achieve a five-star SLIPTA rating and become internationally accredited to the ISO 15189 standard. The HIA-CHU laboratory also has the support of the Benin military health system authorities to expand the QI programme to multiple laboratory sites, prioritise the accreditation of clinical laboratories, and to integrate accreditation programmes into health sector policy and development programmes. To date, the HIA-CHU laboratory has expanded the QI programme to military clinical laboratories in Ouidah, Porto-Novo and Parakou. Military laboratory leaders envision the further expansion of the QI programme to additional military sites using a network approach."}
+{"text": "Noradrenaline (NE) is a catecholamine acting as both a neurotransmitter and a hormone, with relevant effects in modulating feeding behavior and satiety. Several studies have assessed the relationship between the noradrenergic system and Eating Disorders (EDs). This systematic review aims to report the existing literature on the role of the noradrenergic system in the development and treatment of EDs. A total of 35 studies were included. Preclinical studies demonstrated an involvement of the noradrenergic pathways in binge-like behaviors. Genetic studies on polymorphisms in genes coding for NE transporters and regulating enzymes have shown conflicting evidence. Clinical studies have reported non-unanimous evidence for the existence of absolute alterations in plasma NE values in patients with Anorexia Nervosa (AN) and Bulimia Nervosa (BN). Pharmacological studies have documented the efficacy of noradrenaline-modulating therapies in the treatment of BN and Binge Eating Disorder (BED). Insufficient evidence was found concerning the noradrenergic-mediated genetics of BED and BN, and psychopharmacological treatments targeting the noradrenergic system in AN. According to these data, further studies are required to expand the existing knowledge on the noradrenergic system as a potential target for treatments of EDs. The Central Nervous System (CNS) produces and utilizes a series of neurochemical transmitters (or neurotransmitters), binding to different receptors to stimulate intracellular signaling pathways. These molecules are synthesized by a limited number of neurons pertaining to specific brain nuclei, and project their extensive ramifications to widespread CNS regions, regulating signals form external and internal stimuli . The catNE is synthesized in neurons, containing the dopamine-b-hydroxylase enzyme, catalyzing the conversion of DA to NE . The maiDespite dopaminergic control of eating and feeding-related reward remaining the most extensively studied issue in this field, a series of relevant studies have investigated the noradrenergic regulation of feeding behavior. In a classic study of Grossman , the injSuccessively, researchers have investigated the potential effect of variations in the noradrenergic activity on feeding behavior. Desmethylimipramine, a noradrenalin uptake antagonist, has been injected into the prefornical hypothalamus of satiated rats, thus promoting eating behavior . SibutraTogether, this evidence suggests the relevant role of the noradrenergic system in the regulation of feeding behavior, indicating the possible specific actions of endogenous and exogenous NE in influencing human nutrition.Besides its relevant direct, hypothalamus-based actions on feeding regulation, the noradrenergic system is indirectly implied in various endocrine networks controlling humane nutrition. Namely, ghrelin, neuropeptide Y (NPY), cholecystokinin (CCK), leptin, oxytocin, and insulin, six hormones involved in the regulation of feeding and satiety, may interact with noradrenergic peripheral networks . PeripheEating Disorders (EDs) are psychiatric disorders characterized by persistent disturbances of eating behaviors, resulting in the altered consumption or absorption of food and significantly impair physical health or psychosocial functioning . EDs areCurrent research suggests that multiple pathogenetic factors are involved in the development of EDs. Genetic and neurodevelopmental factors have been hypothesized to explain the significant comorbidities between EDs and a series of psychiatric disorders, such as Anxiety Disorders, Mood Disorders, and Autism Spectrum Disorder ,32. AddiThe role of the catecholaminergic systems in the pathogenesis of EDs has been addressed by a series of studies; in particular, a relevant systematic review by Kontis and Theochari assessed the involvement of dopamine in the development and management of Anorexia Nervosa (AN) . The autDespite the evidence on the links between catecholaminergic transmission and feeding behavior, no specific review has systematically addressed the relationship between the noradrenergic system and EDs.This systematic review aims to highlight the existing literature on the role of the noradrenergic system in the pathogenesis, transmission and treatment of EDs. The research questions addressed include: (1) Is there documented evidence of involvement of the noradrenergic system in the pathogenesis of EDs? (2) Is there a documented theorical background for the development and testing of treatments for EDs acting on the noradrenergic system?This systematic review was performed in August 2021 by browsing the following databases: Medline (PubMed), Cochrane Library, Clinicaltrials.gov. Research was enhanced by searching the most relevant websites of guidelines and clearinghouses and in the most important etextbooks sites.The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA) flowchart  was usedInclusion criteria: Date: published between January 2000 and July 2021. Population: humans or non-human mammals; Language: English; Study Design: RCT, cohort studies, cross-sectional studies, retrospective studies, case reports; Outcomes: reported.Exclusion: Population: other than humans or non-human mammals; Language: other than English; Study design: descriptive studies, reviews, protocols; Outcomes: unreported.Search string: ((noradren* OR norepinephrine[MH]) AND (eating disord* OR bulimia nervosa OR binge-eating disorder OR anorexia nervosa OR avoidant/restrictive food intake disorder)).A total of 341 original articles were identified with the initial search and checked by two independent investigators (J.P. and D.M.C.), and disagreements among reviewers were resolved through a mediator (M.L.). Thirty-five studies were included in the final analysis after 306 studies were excluded on the basis of exclusion/inclusion criteria. The flow chart of the study is reported in A detailed description of the selected articles is reported in Along with preclinical and clinical research unveiling the link between noradrenergic regulation and feeding behavior, a series of studies have investigated the role of noradrenergic dysregulation in the pathogenesis of EDs.The effect of the serotonin and noradrenaline reuptake inhibitor (SNRI) sibutramine, an anti-obesity treatment, was studied in 10 rats by Tallet and colleagues . The autBello and colleagues  measuredIn a further study, the same group  tried toRomano and colleagues  assessedRecently, Hicks and colleagues  examinedGenetic studies have documented possible contributions of polymorphisms in NE transporters in the pathogenesis of ED.Urwin and colleagues  hypothesThese results were further examined by a second study from the same group . The autRelevantly, Hu and colleagues  tried toIn addition to these studies, a series of authors have investigated the presence and modifications of noradrenaline and its metabolites in the plasma and urine. The most relevant metabolite of noradrenaline in primates is 3-methoxy-4-hydroxyphenylglycol (MHPG), and MHPG in brain tissue, cerebrospinal fluid, plasma, and urine reflects the turnover of noradrenaline .In a large study on the prevalence of migraine and the tyrosine metabolism in patients with EDs, D\u2019Andrea and colleagues  measuredPlasma levels of NE, together with a series of other neurotransmitters and measures of autonomic system activity, were assessed in a group of patients with AN and HC by Lechin and colleagues . VariablThe same group  investigThe activity of NE and the autonomic nervous system was also studied by Yoshida and colleagues . Nine paBrambilla and colleagues  assessedIn a relevant study by Bartak and colleagues , an in vIn another microdialysis study on adipose tissue NE concentration, Nedvikova and colleagues  investigDostalova and colleagues  investigVaz-Leal and colleagues  analyzedZheng and Yang  administRigaud and colleagues  investigNo brain imaging study meeting the criteria of this review was identified investigating the noradrenergic system in patients with ED.Relevant research has provided a theoretical framework for treating these patients with NE-based drugs. The studies of Kaye and colleagues  have dirAs for the studies included in this systematic review, a series of pharmacologic treatments influencing the NE system have been found to have an effect of disrupted food regulation and symptoms of EDs. Thus, studying the mechanism of action of these drugs may contribute to understanding the role of NE in the pathogenesis of EDs.Milano and colleagues  studied Venlafaxine, a SNRI acting as a weak NE reuptake inhibitor at low doses (75 mg/day)  indicateDuloxetine, a SNRI indicated in the treatment of depressive and anxiety disorders, as well as chronic pain, has been investigated by a series of articles in the field of EDs; Bernardi and Pallanti  reportedLeombruni and colleagues  assessedGuerdjikova and colleagues  investigSimilar evidence has been documented for milnacipran, a dual-acting antidepressant that blocks both serotonin and noradrenaline reuptake., in the treatment of 16 outpatients with BN by El-Giamal and colleagues , showingFurther data are available on the effects of reboxetine, a selective norepinephrine reuptake inhibitor (NRI), in the treatment of ED. A case report published by Willeit and colleagues  documentIn the same year, El-Giamal and colleagues  documentSimilarly, Fassino and colleagues  conducteThe effect of reboxetine has been studied by Silveira and collaborators  on the tRelevant data may be found in studies assessing the effect of dasotraline, a novel serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI), in the treatment of EDs.Mattingly and colleagues  investigAtomoxetine, a highly selective norepinephrine reuptake inhibitor associated with weight loss, was studied in a randomized, double-blind, placebo-controlled, flexible dose trial, assessing reduction in binge frequency in 40 patients with BED. Compared with placebo, atomoxetine was associated with a greater reduction in binge frequency, BMI, and psychopathology, showing efficacy in the treatment of BED .Relevantly, desipramine, an antidepressant medication inhibiting the reuptake of noradrenaline and, to a lesser extent, serotonin, appears to reduce binge eating and improve comorbidities in short-term treatments ,74. The This systematic review assessed the role of the noradrenergic system in the pathogenesis and treatment of EDs. A total of 35 studies were included, of whom 5 were preclinical trials on rats, and 29 were clinical studies on humans.The human nutrition encompasses a complex series of biological, genetic, and cultural factors ,76. EDs Preclinical studies have agreed in documenting a significant role of the noradrenergic system in the pathogenesis of EDs under experimental conditions. Relevantly, binge eating has been found to activate the mPFC in stressed rats, an effect that could be reduced by alpha-2A adrenergic agonist guanfacine , while dGenetic studies included in this review have reported conflicting evidence. The research by Urwin and colleagues documented the hypothesis that receiving specific NET and MAOA variants and may increase the genetic risk to develop ANR ,42. NoneClinical studies assessing variations of NE in bodily fluids and tissues have produced conflicting evidence. Plasma NE has been found to be reduced at baseline in AN and BN in a series of studies, both as absolute levels  and whenNo brain imaging (magnetic resonance or positron emission tomography) study was found investigating the noradrenergic system in patients with EDs. Since a series of studies on this field exist on the roles of dopamine, as documented by a recent systematic review , future A number of pharmacological studies have documented the effect of drugs influencing the noradrenergic transmission in the CNS on the management of different EDs. SNRIs represent the most frequently studied molecules, with specific research targeting the effects of sibutramine, venlafaxine, duloxetine and milnacipran. SNRIs have been documented to have a positive effect in reducing binge frequency and psychopathology in BED ,56,57,58Taken together, these results indicate that psychopharmacologic therapies modulating the noradrenergic activity, namely SNRI, NRI, and SNDRI, may serve as effective treatments for binge and purge frequency, weight alterations, and psychopathology for BN and BED. No recent data concerning the use of these drugs in patients with AN was found. Research in this field is urgently needed, since scientific evidence exists supporting only a few molecules in the treatment of AN ,80,81.This study has some limitations. A major point to be considered when assessing the biochemical dysregulation in psychiatric disorders is the difficulty to clearly determine whether the documented modifications represent a causal factor or consequence of the disease. This can be particularly challenging when considering the field of EDs, since malnutrition and the metabolic imbalance determined by the underlying disorder may potentially alter endocrine and neuropsychological systems in the body . S\u00f6derstAs a second limitation, although we aimed at defining the evidence of involvement of the noradrenergic system in the pathogenesis of EDs, different studies did not concern all clinical entities of EDs. Namely, genetic studies were related to ANR only, as well as no clinical study assessing body concentrations of NE was found. Relevantly, no study was identified concerning preclinical or clinical aspects of the relationship between the noradrenergic system and the avoidant/restrictive food intake disorder. Thus, a further thorough systematic review in this field should include new research assessing both preclinical and clinical variables in these less studied conditions.The present systematic review identified a series of key data on the relationship between the noradrenergic system and EDs. EDs represent a group of complex conditions with a multifactorial pathogenesis, and no specific review has systematically addressed the relationship between the noradrenergic system and EDs so far. According to our results, preclinical studies in rats demonstrated the involvement of the noradrenergic brain system in binge-like behaviors, with a key mediating role played by the activation of stress circuits. Genetic studies documented conflicting evidence in the possibility of a noradrenergic-mediated, genetically transmitted increased risk to develop AN. Clinical studies on body fluid concentrations reported non-unanimous evidence for the existence of absolute alterations in plasma NE values in patients with AN and BN. Pharmacological studies documented an efficacy of SNRIs, NRIs, and SNDRIs in the treatment of BN and BED. Still, insufficient evidence is available concerning the noradrenergic-mediate heritability of BED and BN, and psychopharmacological treatments targeting the noradrenergic system in AN. Further in vivo experimental studies and psychopharmacological randomized controlled trials are urgently needed to provide solid scientific evidence in the treatment of these expanding and increasing psychiatric and metabolic disorders."}
+{"text": "As a result, gene therapy treatments have been developed, and for some of the more prominent blood disorders these have reached the clinic and even market approval. Presently, the most advanced approaches are based on herapies ; 2021b, herapies . Permaneherapies . TherefoMutation-Specific Gene Editing for Blood Disorders covers an exceptional selection of contributions on mutation-specific gene editing in particular, and more generally on the development of associated concepts, protocols, technologies and corresponding regulatory and socio-economic conditions. The featured reviews and original articles offer expert perspectives on HSC-based therapies and particularly editing for hemoglobinopathies, on bone marrow failure syndromes and blood malignancies, on editing platforms, pathways and delivery methods, on targeted insertion of therapeutic transgenes and on the assessment of off-target activity of gene editing tools:To address these particular shortcomings of mutation-specific therapy and to enhance efficiency of treatments in general and thus to lower dosage requirements and risks to patients, therapy development for blood disorders needs novel strategies as much as it needs incremental improvements to existing protocols. In this respect, this Special Issue on Klaver-Flores et al. briefly cover HSC biology and gene editing platforms, before evaluating key areas of necessary improvement, the status quo of HSC engineering for therapy and the requirement for regulatory harmonization. In a different approach, Ferrari et al. comprehensively cover clinical development of homology-directed repair (HDR)-based editing for blood disorders, from editing platforms over HDR optimization, cyto-/genotoxicity and manufacturing protocols up to the post-treatment molecular follow-up. They also touch on the relationship of gene addition with conventional integrating vectors and the emerging gene editing therapies, and on the challenges of creating safe and efficient advanced therapies that are also financially sustainable. With further emphasis on clinical translation, Papanikolaou and Bosio review the current efforts and regulatory frameworks in the commercialization of advanced therapies, and provide an insightful perspective on the ongoing improvements to safety and efficacy, required for successful introduction of gene editing-based therapies.Several reviews give independent views on the state of the art and the path ahead for gene editing and therapies based on HSCs. In their perspective on the genetic engineering of HSCs, Zittersteijn et al. include mechanisms underlying globin expression, introductory to an up-to-date view on gene addition and on gene editing approaches and platforms for treatment of hemoglobinopathies. Insights into globin regulation are expanded by Mussolino and strouboulis, whose review places particular emphasis on regulatory complexes and therapeutic targets for epigenetic treatment of \u03b2-hemoglobinopathies. With focus on primary sequence editing for \u03b2-hemoglobinopathies, Barbarani et al. give an overview of editing strategies employed for treatment and point out the significance of reproducing naturally occurring therapeutic modifier mutations, of DNA double-strand break (DSB)-independent editing technologies, and of finding a suitable balance between efficiency and the level of precision required for editing. In this context, original research by Benitez et al. shows how modification of DNA repair factors and in particular their tethering to Cas9 can shift the balance between different DSB repair mechanisms, and thus editing outcomes, for the mutation causing sickle cell disease.Paradigmatic for application of editing to HSCs is the prolific and clinically most advanced field of gene editing for hemoglobinopathies. In their review covering both \u03b1- and \u03b2-hemoglobinopathies, Pavani and Amendola illustrate the extreme versatility of the TI approach, which is based on the insertion of promoterless transgenes behind endogenous promoters or on the insertion of promoter-driven transgenes in safe-harbor loci. TI enables a range of applications, including the deactivation of disease modifiers and the delivery of chimeric antigen receptors (CAR) in the production of CAR cells for adoptive immunotherapy.Controlling repair outcomes is critical for the safety and efficacy of localised sequence modifications, but also for the targeted insertion (TI) of therapeutic transgenes, which combines the safety of gene editing with key benefits of gene addition, including the ability to address multiple mutations with one and the same therapeutic tool. In their review, Antoniou et al.The alternative precision editing technologies of base and prime editors are then comprehensively assessed for their initial and latest developments, for their advantages and disadvantages and for their specific applications to blood disorders by Koyunlar and de Pater point out, these include inherited bone marrow failure syndromes caused by GATA2 mutations, of which 90% are found in the open reading frame and thus depend on precision edits, in the absence of a universal modifier as alternative target. Here, the consistent accumulation of additional oncogenic somatic mutations in other genes and the paucity of HSCs as the substrate for gene editing present particular challenges, representative of what holds true also for other blood disorders, such as Fanconi and Diamond Blackfan anemia. Importantly, many blood malignancies are based on and need to be addressed by changes in mesenchymal stromal cells (MSCs) instead of HSCs, as reviewed by Banjanin and Schneider, who in addition to the option of cross-correction of MSCs by modification of HSCs point out the specific challenges of in vivo and ex vivo editing and validation for MSCs.Taken together, research into shifting the balance of different DSB repair pathways towards precision edits and for TI, or into the employment of DSB-free precision editors has bearing on many diseases. As Simmons et al. demonstrates the utility of CRISPR/Cas9-based editing for the characterization of gene function and the development of Slc48a1-mutant mice as putative models for human SLC48A1-linked idiopathic iron disorders.For many of the rarest blood disorders, understanding of the underlying biology and availability of disease models are limiting. In this respect the original research article by ex vivo editing in HSCs by electroporation was in large part enabled by advances in synthetic CRISPR/Cas guide RNAs, as reviewed by Allen et al. Pointing out an editing technology alternative to protein and ribonucleoprotein-based editors, F\u00e9lix et al. address the concept and framework parameters of polypurine reverse Hoogsteen hairpin technology for editing, and its application to a selection of specific mutations causing different blood disorders. As an alternative to the delivery of naked editing molecules, virus-like nanoparticles conceptually enable ex vivo and in vivo application and make the exploration of editing, also using novel Cas9 flavors, accessible to any laboratory familiar with the production of viral vectors. Gutierrez-Guerrero et al. demonstrate in their primary research article efficient duplex-DSB-based excision and targeted insertion of an adeno-associated-virus\u2013encoded HDR donor into the Wiskott-Aldrich syndrome locus of T, B and CD34+ cells by delivery of CRISPR/Cas with virus-like Nanoblades.Vectors and delivery technologies are critical to the success of therapies based on gene editing, and the recent achievement of near-saturated Blattner et al., whose review comprehensively surveys biased and unbiased detection technology for off-target activities of different editing platforms, including the issue of translocation detection and remaining challenges, such as robust assays that can be applied in therapeutically relevant cells.For any editing application but even more so for the development of CAR and other technologies potentially drawing on multiple DSBs for editing, off-target activity of editing tools is of particular concern. This point is addressed by Driven by the rapid and ongoing development of gene editing tools, protocols and applications, editing technology is fast approaching such efficiency, accuracy and ubiquity, that clinically relevant mutation-specific applications for many diseases are within reach. We hope that the original research and authoritative reviews we had the privilege of putting together in this Special Issue will be a further step to making this exciting prospect a reality."}
+{"text": "The emergence of COVID-19 and social distancing requirements have resulted in disruptions to daily life, reduced opportunities for social engagement, and diminished resource access for millions of older adults. Individuals with cognitive impairments (CI) are particularly vulnerable to risk for social isolation. This presentation will discuss the PRISM-CI pilot trial, which aims to examine the feasibility and potential efficacy of the PRISM-CI software system on enhancing connectivity and quality of life among a diverse sample of 50 older adults aged 65 and over with a CI. PRISM-CI, adapted from the PRISM system (developed by the Center for Research and Education on Aging and Technology Enhancement) for this population, is intended to support social engagement, memory, and access to resources and information. We will present data regarding the feasibility and perceived value of PRISM-CI and discuss the challenges, and strategies used, to adapt the PRISM-CI trial during the pandemic. We used a multi-modal approach to provide remote training and specialized tablet instruction that includes individualized training sessions tailored to individuals\u2019 learning needs, hobbies, and prior technology use. The adapted protocol also involves the use of remote access software for troubleshooting. We will also discuss how participant feedback guided the inclusion of additional features, such as Zoom videoconferencing and virtual library access, for the PRISM-CI application. Finally, we will demonstrate how the adaptation of the PRISM-CI protocol holds promise for the use of flexible, remote technology approaches to reach socially isolated older adults to foster psychosocial well-being."}
+{"text": "Substandard and falsified (SF) medicines have important but neglected consequences including increased morbidity and mortality, economic losses, and diminished public confidence in health systems. SF antimicrobials, particularly those containing reduced quantities of active pharmaceutical ingredients (APIs), may also be key but overlooked drivers of antimicrobial resistance . SubstanAccording to a recent report from the World Health Organization (WHO), approximately 10% of medicines circulating in low- and middle-income countries (LMICs) are either substandard or falsified . The issThe Coronavirus Disease 2019 (COVID-19) pandemic has heightened the risk for SF medicines reaching patients by disrupting pharmaceutical production and supply chains, impeding regulatory inspection, and causing great economic hardship, making it difficult to afford genuine medicines. A surge of SF medical product cases has been reported, especially in settings with already vulnerable supply chains \u201310. In eMedicines Regulatory Authorities (MRAs) are the keystones for many of the interventions to prevent, detect, and respond to SF medicines. However, national MRA, international procurement agencies, and wholesaler/distributor medicine inspectors performing post-marketing surveillance (PMS) have to largely rely only on their own senses and knowledge to detect circulating SF medicines . SuspiciPLOS Neglected Tropical Diseases Collection, typically, inspection of medicines quality is conducted by medicine inspectors from the Bureau of Food and Drug Inspection (BFDI) within the Ministry of Health. Inspectors undertake routine inspection of pharmacies bi-annually, focusing on adherence to legislation  and drug registration. Convenience sampling of certain medicines, especially antimalarials and antiretrovirals, is undertaken as part of specific vertical program projects supported by donors. In convenience sampling within a province, medicines are purchased from a selection of pharmacies in each district and brought back to a central location where they undergo initial screening using the Minilab  of the implementation of the 6 devices tested in the field evaluation for PMS in Laos was conducted. The fifth article discusses the results presented in the series, highlights the evidence gaps, and provides recommendations on the key aspects to consider in the implementation of portable devices and their main advantages/limitations.The Collection is composed of 5 articles. This Editorial represents the first of these, introducing the background and rationale for the Collection. Twelve devices were first evaluated in a laboratory setting  to provide information on their performances to identify SF medicines and to select the most field-suitable devices for further preliminary evaluation of their utility/usability  by medicines inspectors  with the devices in an office setting, allowing more scrutiny by the observers. The GPHF-Minilab was also tested by the chemists in the laboratory evaluation, and by FDQCC technicians, already trained in Minilab use, at their laboratory, in line with its current routine use in Laos.Using results of the above studies, the fourth article presents a CEA of implementing the 6 devices selected for the field phase experiments. Key criteria for each device such as cost per sample analysis, the sensitivity and specificity of each device, and experiment time were utilized to estimate the cost-effectiveness of using the devices under 2 scenarios of high and low prevalence of SF antimalarials in circulation. The results include a variety of device sampling strategies and multiway head-to-head comparisons.In the fifth article, these 4 components are synthesized and discussed, and recommendations are made. This is based on the discussion in a multi-stakeholders meeting held in April 2018 in Vientiane. The meeting included 53 participants from MRAs from 7 Asian and African countries and international health and funding organizations. Hands-on sessions with devices and group discussions about the promises and pitfalls of the devices were held during this 2-day meeting. The advantages/disadvantages, cost-effectiveness, and optimal use of medicine quality screening devices in the medicine supply chains were discussed. Based on the results from this multiphase study, we list policy recommendations for MRAs and other institutions who wish to implement screening technologies, as well as gaps of scientific knowledge to be filled.As far as we are aware, this multiphase study is the first collaborative independent investigation listing the advantages and disadvantages from diverse chemical, economical, and regulatory points of view. The overall study assesses and compares device accuracy, describes potential barriers, and evaluates the costs versus the benefits of the implementation of a wide diversity of portable medicine quality screening devices in a public health perspective. The series also highlights the difficulties and barriers to perform screening devices research and the important remaining gaps of scientific evidence."}
+{"text": "Cardioembolism is one of the most frequent causes of ischemic stroke, accounting for at least 20% of all ischemic strokes. Moreover, cardioembolic stroke entails higher severity and poorer outcome compared to other etiologies. Atrial fibrillation is the most frequent underlying disease, although several other cardiac disorders such as ventricular akinesia, valvular heart disease, acute myocardial infarction, endocarditis, monogenic diseases with cardiac involvement, or complicated interventional cardiac procedures can also be involved in the development of cardioembolic stroke. Direct oral anticoagulants have revolutionized stroke prevention in patients suffering from atrial fibrillation, however, more knowledge is needed regarding the long-term outcomes in patients treated with these drugs.In recent years, much attention has been paid to the search for hidden cardioembolic sources for ischemic stroke, and the \u201cembolic stroke of unknown source\u201d (ESUS) concept was raised to improve the detection of occult embolic diseases, mainly paroxysmal atrial fibrillation. However, the failure of direct oral anticoagulants in recent clinical trials with patients diagnosed with ESUS has raised concerns regarding the appropriateness of a low-intensity diagnostic workup and points to the return of the diagnostic concept of cryptogenic stroke. This highlights the need to increase the search for potential hidden etiologies through advanced diagnostic procedures.This Research Topic issue provides an up-to-date collection of manuscripts focused on the challenge of diagnosis and management of cardioembolic strokes.Pagola et al. highlighting the potential application of Point of Care UltraSound (POCUS) as a helpful screening method at the Stroke Unit. Furthermore, Arnold et al. provide a comprehensive review on the most promising biomarkers for the diagnosis of cardioembolic stroke, including blood-based, genomic, transcriptomic, metabolic, electrocardiographical, echocardiographical, and advance cardiac imaging biomarkers. They discuss the existing evidence for possible clinical applications in risk stratification and in accelerating etiological classification as well as optimal management, from a perspective of the forthcoming implementation of personalized medicine in stroke management.The role of echocardiography is reviewed by Viedma-Guiard et al. provides an excellent and up-to-date overview of the role of aortic sources of embolism in ischemic stroke, focusing on the diagnostic challenges and the current evidence for the optimal treatment in stroke prevention.The importance of atherosclerotic plaques in the aortic arch as a potential cause of embolic stroke has been underestimated in the majority of the etiological classifications of stroke, being relegated in most of them to stroke of undetermined origin, mainly because of a clear recommendation for its systematic search in the stroke patients has not been established. The narrative review by Wan et al. also provides new data on this atherosclerotic-lookalike clinical profile in a prospectively collected series of 119 acute ischemic stroke patients. To deepen the current controversy surrounding the ESUS concept, Fuentes et al. list several arguments against the use of the ESUS concept in clinical practice, advising stroke physicians to be smart in the search for underlying causes of ischemic stroke, optimizing advanced diagnostic procedures according to the patient's and stroke's characteristics, attempting to find the correct diagnosis for stroke patients and reducing rates of cryptogenic stroke diagnosis.Recently the ESUS concept has been called into question. This concept was proposed in 2014 by the Cryptogenic Stroke/ESUS International Working Group under the rationale of the common underlying thromboembolism mechanism in the group of patients with non-lacunar ischemic strokes in which the basic diagnostic approach did not found any undoubtable cause for the stroke. This concept included minor-risk or covert cardiac sources , paradoxical embolism and non-occlusive atherosclerotic plaques in the aortic arch, cervical or intracranial arteries  showing a low frequency of bleeding complications, with no significant differences between anticoagulant drugs at long-term follow-up (of up to 3 years from a stroke). Besides, they provide new insights on the main reasons for switching oral anticoagulant drugs in clinical practice, being the majority of them due to stroke recurrences and labile INR. The other manuscript on stroke prevention is the protocol for LASER  a randomized clinical trial and an associated registry of early anticoagulation with edoxaban after ischemic stroke in patients with atrial fibrillation. It is aimed at recruiting 150 patients with ischemic stroke and atrial fibrillation who will be randomized within 5 days of stroke onset to early or delayed edoxaban initiation .In the field of stroke prevention in cardioembolic strokes, this Research Topic issue includes two interesting manuscripts. The prospective multicentre RESTAIC Registry by Sarti et al. highlighting the relevance of atrial appendage morphology on patients with atrial fibrillation and resistant stroke despite adequate anticoagulant therapy.Finally, this issue also includes a case report by We would like to thank all the contributing authors for their manuscripts in this challenging time in which the COVID-19 pandemic has severely impacted stroke care and research, limiting the number of the expected manuscripts for this Research Topic issue. We hope that the pandemic will soon disappear, and we can refocus all our efforts on fighting stroke, one of the leading causes of death and the first cause of disability worldwide.All authors contributed by drafting the work or revising it critically for important intellectual content and all of them provided approval for publication of the content.BF: Advisory Board (Bayer); Spearker's honoraria ; Travel grants to attend scientific meetings , Participation in clinical trials . GN: Speaker fees/Advisory Boards/Research support from Amgen; Bayer; BMS/Pfizer; Boehringer-Ingelheim; Elpen; European Union; Galenica; Sanofi; Winmedica. JP: Research funding: Helsinki and Uusimaa Hospital District, Academy of Finland, Business Finland, St Jude Medical, Pfizer. Research collaboration: Nokia Technologies, Bittium, BcB Medical, Vital Signum; Speaker's honorary: Boehringer-Ingelheim, BMS-Pfizer, Bayer, Abbot; Advisory Board: BMS-Pfizer, Boehringer-Ingelheim, Bayer, MSD, Portola. Other: ESO guideline working group: Post-stroke hyperglycemia, secondary prevention in patients with AF. Finnish Duodecim guideline working group: ischemic stroke and TIA; Terve Media: Visiting editor."}
+{"text": "Amputation of the upper limb brings heavy burden to amputees, reduces their quality of life, and limits their performance in activities of daily life. The realization of natural control for prosthetic hands is crucial to improving the quality of life of amputees. Surface electromyography (sEMG) signal is one of the most widely used biological signals for the prediction of upper limb motor intention, which is an essential element of the control systems of prosthetic hands. The conversion of sEMG signals into effective control signals often requires a lot of computational power and complex process. Existing commercial prosthetic hands can only provide natural control for very few active degrees of freedom. Deep learning (DL) has performed surprisingly well in the development of intelligent systems in recent years. The significant improvement of hardware equipment and the continuous emergence of large data sets of sEMG have also boosted the DL research in sEMG signal processing. DL can effectively improve the accuracy of sEMG pattern recognition and reduce the influence of interference factors. This paper analyzes the applicability and efficiency of DL in sEMG-based gesture recognition and reviews the key techniques of DL-based sEMG pattern recognition for the prosthetic hand, including signal acquisition, signal preprocessing, feature extraction, classification of patterns, post-processing, and performance evaluation. Finally, the current challenges and future prospects in clinical application of these techniques are outlined and discussed. For human, the worth of hand is indisputable. The hand is the most diverse and dexterous part of the human body, which can execute various activities to interact with the environment by adopting a variety of different motion strategies  and deep learning (DL). ML, which is the method based on feature engineering, could learn and perform tasks from the data input of automatic modeling. For conventional machine learning algorithms, there are limitations in processing raw data, because they could not effectively train on inconsistent, noisy, abstract, and high-dimensional data  we comprehensively analyze the overall structure of DL in sEMG-based gesture recognition; (2) we comprehensively review the latest methods and technologies of sEMG based gesture recognition; (3) we raise the existing challenges and promising research prospects of sEMG based on motion intention recognition in prosthetic hand field.The approaches of gesture recognition model are very similar, but the method of each stage is different; in addition, not all studies use all stages of standard structure. Considering this, we propose a standard approach composed of six parts, which are data acquisition, data preprocessing, feature extraction, classification of patterns, post-processing, and performance evaluation. The sEMG signals are collected from sEMG sensors, which could adopt two different acquisition criteria, sparse multi-channel sEMG and high-density sEMG (HD-sEMG), in the density of the employed electrodes of view  traditional manual feature extraction method is used to increase the data density of sparse multi-channel sEMG; (2) the raw sEMG signal is directly input into the network to realize end-to-end learning.For the traditional feature extraction methods, many researchers are devoted to propose new features based on professional knowledge , mean absolute values (MAV), integrated EMG (iEMG), histogram (HIST), root mean square (RMS), zero crossings (ZC), standard deviation (SD), slope sign change (SSC), Willison amplitude (WAMP), variance (VAR), V-order (V), simple square integral (SSI), and so on, which are often used in combination. The detailed information is shown in Frequency domain features: The FD features are calculated by Fourier transform of the autocorrelation function of sEMG signal and estimated by periodogram or parameter method. The common frequency domain characteristic of sEMG signal is frequency ratio (FR), total power (TP), mean power (MP), median frequency (MDF), mean frequency (MNF), power spectrum (PS), and so on. The detailed information is shown in Time-frequency domain features: The TFD features are expressed as locating the energy of sEMG signal both in time and frequency, which is usually an important approach in feature extraction. The typical representative of time-frequency analysis is wavelet transform  is the mother wavelet, and \u03c4 is the translation parameter. ni is the length of the ith level decomposition coefficient ci ; \u03bc is the mean of ci , average power of the coefficient ci (APOCi), standard deviation of the coefficient ci (STDOCi), ratio between MOACi+1 and MOACi.where Parameter model: The basic principle of the parameter model is to regard it as a time series based on sequence information in the raw sEMG. Because sEMG signal is steady on short notice, the coefficients and intercept of the fourth-order autoregressive model are often selected as the characteristic values  is the most extensive applications for DL architecture based on sEMG gesture recognition. Park and Lee  proposedOne of the most important advantages of CNN is that it can automatically learn spatial features from input data or extract unlabeled features. However, the sEMG is the form of time series signal essentially, which is more suitable for recurrent neural network (RNN) that has dominant position in processing temporal or otherwise sequential information , whose goal is to recover the original data as lossless as possible from the abstract data; the other is probabilistic restricted Boltzmann machine (RBM) and its improved algorithm deep belief network (DBN), whose goal is to maximize the probability of the original data appearing when the RBM reaches a stable state. AE are data compression algorithm, which use efficient data encodings to map noisy input data into clean output Le, . VujakliApart from the above methods, there are many other DL methods applied to sEMG pattern recognition. Because of the simplicity of the structure, fully connected neural networks , skin conditions  , what amputee can do after training (which is a reflection of behavior in life and working environment) (de Vet et al., This review paper briefly introduces the advances of DL-based sEMG pattern recognition techniques for the prosthetic hand in recent years. Through the literature survey of DL application in sEMG recognition, some of the core techniques are highlighted, some of the most common challenges to be solved are analyzed, and some of the most possible development prospects are discussed. It could be found that gesture recognition techniques based on DL has great potential in using sEMG signal to accurately interpret amputee's motion intention, which is of great significance to the development of intelligent prosthetic hand. However, their individual difference, real-time usability, and long-term stability are still being highly limited by many complex factors in these approaches. The high variability of sEMG, the lack of existing data, the limitation of hardware resources, and the lack of clinical evaluation conditions seriously affect the progress of pattern recognition techniques based on DL. In addition, the natural movements of the upper limbs are independent, continuous, and proportional activations of multiple DOFs, while the existing techniques can only use a limited number of patterns for discrete classification. These should be well-improved in the future real-time application of prosthetic hands.WL and PS wrote this paper. PS and HY suggested the methodology. PS supervised the entire project. All authors reviewed the manuscript, read and agreed to the published version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "For organic Cu speciation, an improved anodic stripping voltammetry (ASV) method, employed to eliminate the surface-active substances (SAS) interference on the voltammetric signal, was used in samples containing high organic matter concentration. Fulvic acid was used as a model of natural organic matter and the method was applied for Cu speciation in samples collected in the Arno River estuary  . The binding of Cd(II), Pb(II), and Zn(II) by silica nanoparticles was studied using a combination of the electroanalytical techniques Scanned Stripping ChronoPotentiometry (SSCP) and Absence of Gradients and Nernstian Equilibrium Stripping (AGNES). The experimental system was chosen as a representative model for the role of natural and anthropogenic nanoparticles in the fate and behavior of trace metals in aqueous environmental systems .Several examples of speciation of metal cations in aquatic environment are reported in this Research Topic. The speciation of trace metals aquatic systems includes the determination of free ions, metal complexes, colloidal species, etc., as well as the total dissolved concentration. The integrated assessment of free ions and labile metal complexes can be obtained by Diffusive Gradients in Thin-films (DGT), a dynamic speciation technique. The determination of the organic pools of trace metals in freshwaters and the characterization of organic and inorganic complexes in sea waters were obtained by this procedure (Berto and Alladio). The investigation of the interaction of phytate ligand with biologically relevant cations, namely Mg2+, Zn2+, Fe2+, Cu+, and Cu2+ revealed that alkaline earth metals interact with different binding sites than the transition metals. Experiments with Cu+, and Cu2+ confirmed similar complexing behaviors, depending mainly on the ionic radius .Speciation studies on the interaction of metal cations with ligands having multiple binding sites, such as tannic acid, a natural polyphenolic compound, and phytate ligand, are very important for the fate of those metals. In the study regarding tannic acid, the approach used combines UV-vis and fluorescence spectroscopy with chemometrics, namely Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) and Parallel Factor Analysis (PARAFAC) . The necessary degree of specificity in discriminating all the species of a given element in a sample can be attained by ultrahigh-resolution mass spectrometry based on the Fourier transformation, Orbitrap and Ion Cyclotron Resonance (ICR) cell. The case of the speciation analysis of the products of selenium metabolism by FT ICR MS was described . Metal speciation can be also performed by MALDI-MS and tandem mass spectrometry (MS-MS). The results obtained for Ca2+ interaction with biologically relevant ligands, as cysteine, D-penicillamine, reduced glutathione, and oxidized glutathione obtained by potentiometry and 1H-NMR spectroscopy were confirmed by MALDI-MS and MS-MS, elucidating also the mechanism of interaction .Metal speciation can be also performed by Electrospray Ionization Mass Spectrometry (ESI-MS). In this field, MS-MS approach guarantees exceptional sensitivity, as well as the use of high-resolution sectors, capable of well-resolving isotopic clusters. A further development is the merging of ESI-MS information with data obtained Migliore et al.).Speciation studies also include the search for novel drug delivery systems able to improve the performance of old-generation antibiotics. For example, the capability of two micellar polycationic calix[4]arene derivatives to recognize and host ofloxacin, chloramphenicol, or tetracycline in aqueous solution was investigated by nano-isothermal titration calorimetry, dynamic light scattering, and mono- and bi-dimensional NMR. Results evidenced that the formation of the chloramphenicol\u2013micelle adduct is enthalpy driven, whereas entropy drives the formation of the adducts with both ofloxacin and tetracycline. NMR spectra confirmed ITC data about the positioning of the antibiotics in the calixarene nanoaggregates . Different methodologies are employed for soil remediation. Among them, the use of chelating agents is one of the most promising method for removal of metal ions preserving the most meaningful properties of the original soils. One of these methodologies, the Nurchi's method, an extension of the Reilley procedure for EDTA titrations, is based on speciation studies, namely on the knowledge of the related protonation and complex formation constants. Its employment in biomedical and industrial applications is also discussed, namely in the evaluation of the role of different biomolecules such as bacterial metallophores, in metal uptake and homeostasis in living organism .Speciation studies are also very useful for the development of techniques for the decontamination of natural waters and soils containing toxic metals. In recent years, many efforts have been made to discover new technologies that are effective, robust, cost-effective and easy to handle for the decontamination of downstream water without endangering human health. Among nanomaterials and nanostructures proposed in the remediation field, graphene-based materials (G), are particularly suitable for the development of reliable water decontamination treatments, in particular for arsenic remediation . Ultra-trace urea in synthetic and real milk samples was determined by sensitive and selective methods using Fe/N-codoped carbon dots (CDFeN) and a probe with surface-enhanced Raman scattering (SERS), resonance Rayleigh scattering (RRS), and fluorescence (FL) signals . Novel methods for the monitoring of microcystins (MCs), one of the most common and harmful cyanotoxins, involve the use of aptasensors (aptamer-based biosensors) and immunosensors (antibody-based biosensors) for rapid, portable, easy-to-use, and on-site determinations . Early diagnosis of diabetes on entire blood samples was performed via near-infrared spectra (NIRS) combined with a support vector machine (SVM) and aquaphotomics .Determination of organic analytes such as urea or biotoxins in environmental and food samples using novel, advanced and combined analytical techniques was also performed. More in detail, the determination of saxitoxin in seawater samples was made by a novel flow injection microfluidic immunoassay system which allows Risoluti et al.).Quality of milk was assessed by an innovative MicroNIR and chemometric platform for the on-site and contactless monitoring of the samples (via indirect proxies) those specific chemical species in waters, soil solutions, biological fluids and food products, that provide the most relevant information in human health and environmental safety research. Altogether, these studies point to the wide possibilities underlying the combined use of active/passive sampling strategies, fractionation methods, orthogonal or hyphenated techniques and advanced multivariate analysis for the improvement of the accuracy and specificity of speciation data obtained in complex matrices.This Research Topic emphasizes the recent methodological improvements made in quantifying and identifying (either explicitly or All authors wrote the Editorial and reviewed it.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "DDD698, and American Association of State Highways Transport Officials (AASHTO). Slight modifications to the measurement procedures (such as the use of different surcharge loading and custom-made consolidation rings) reflecting special laboratory testing conditions and for the purposes of comparisons, are also reported.Most of the damaging geo-hazards recorded in modern history are caused by soil swelling or expansion. Therefore, proper evaluation of a soil's capacity to swell is very crucial for the achievement of a secure and safe ground for civil infrastructures and related land developments which are founded on the soil. In order to simulate as well as estimate the heave that can occur under field conditions, laboratory one-dimensional oedometer vertical swell-strain testing are most frequently used. Hence, in this brief, one-dimensional swelling tests adopted to measure soil swelling on laboratory-engineered and natural soils covering various regions on the globe are reported. The testing standards and procedures followed in the measurement of one-dimensional swelling are those enumerated in the American Standards for Testing of Materials (ASTM) DDD698, Turkish Standards (TS), American Association of State Highways Transport Officials (AASHTO)and a combination of both standard and modified efforts. A total of 395 data samples on soil swelling potential are reported. With regards to the corresponding soil properties, a total of 219 data records of soil specific gravity, 321 data records of initial moisture content, 163 data records of void ratio, 273 data records of dry unit weight, 347 data records of liquid limit, 347 data records of plastic limit, 395 data records of plasticity index, 209 data records of activity index, 339 data records of clay content, 174 data records of silt content, 246 data records of optimum moisture content, 228 data records of maximum dry density and 347 data records of Unified Soil Classification System (USCS) are presented. Finally, the dataset of one-dimensional soil swelling described herein are intended to aid geotechnical engineers and researchers who are involved in statistical correlation studies, data analytics, and machine learning predictions using soft computing methods mostly aimed at evaluating soil expansion especially during the preliminary phases of soil investigation and foundation design.Corresponding soil properties characterising the dataset includes moisture content, void ratio, specific gravity, unit weight, liquid limit, plastic limit, plasticity index, clay content, silt content, maximum dry unit weight, optimum moisture content, and soil activity index, all of which are known to bear either direct or indirect influences on soil. Determination of the state of compaction of the soils where applicable, are carried out based on the American Standards for Testing of Materials (ASTM)  This dataset references studies spanning over 5 decades leading back to the period when important discourse on soil swelling-related disasters were first considered. The dataset consists of both naturally occurring (disturbed and undisturbed soils) and a mix of laboratory-engineered-soils. Based on the nature and format of reporting from the different sources, the soils are divided into groups with each having properties collated from the same experimental methods. The dataset for each group are saved in individual tabs within the .xlsx file with the tab names (notations) corresponding to the descriptions on 2Rigorous systematic literature studies were conducted to obtain the dataset. The literature search included data spanning across research articles and reports with experimental investigations conducted on various soil samples. The methodology of data collection involved thorough screening of articles\u2019 titles, keywords and abstracts that met the criteria of one-dimensional swelling for both compacted and non-compacted soils. Most of the collected data were derived from article tables and where data were only presented on graphs, WebPlotDigitizer Relevant data of soil properties not included in the original data such as the Plasticity Index (OrIn areas where soil Activity index, (To allow for an easy and extensive assessment and analysis of the degree of swelling of the different soils and their properties obtained from various sources, entries into each column of the dataset should be manually synchronised to account for missing data through the removal of such affected rows.The authors declare that the present work did not include experiments on human subjects and/or animals.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.Eyo E. U: Conceptualization, Methodology, Software, Data curation, Writing \u2013 original draft. Uche Onyekpe: Visualization, Investigation, Writing \u2013 review & editing.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."}
+{"text": "Dear EditorThe new corona disease COVID-19) is very contagious and features a high risk of vast outbreak and infection. The World Health Organization (WHO) declared a global public health emergency condition on 30 January 2020 and a universal epidemic afterwards by given its rapid epidemic worldwide  empowerment of economic, cultural, and political infrastructures as well as national and local policies, 2) entry of non-governmental and impartial organizations like Red Cross and Red Crescent into the exchange of healthcare and treatment equipment to the countries inflicted with sanctions, 3) decisive entry by the UN into the arena of the dismissal of all sanctions, 4) convergence of the neighboring and regional countries to respond the COVID-19 and overcome the sanctions, 5) concentration on healthcare and empowerment of domestic economy, 6) corroboration of the foreign policy to get prepared for post-COVID-19, 7) complete enforcement of the international agreements and conventions, including Joint Comprehensive Plan of Action (JCOPA), 8) arrangement of moderated political relations between Iran and the US by the UN, 9) the experiences transfer on the fight against sanctions by the allied countries, 10) the third intermediation and impartial countries to remove sanctions such as Switzerland, 11) the sanctions threats transformation to proper opportunities by politicians, 12) change in the power of pharmaceutical and healthcare-related productions by European and American countries, China, and India, 13) exercising realism on display of the sanctions effects and concentration on the local and national interventions in Iran, and 14) institutionalization of the national beliefs in the countries\u2019 self-reliance.National and international collaborations for preventing and controlling COVID-19 are very important by considering the daily increasing spread of the COVID-19 pandemic around the globe. Nevertheless, sanctions have exerted a considerable effect on COVID-19 control through weakening the economic resources and creating disruption in the process of drug and equipment transfer. However, national efforts play more considerable and vital role in COVID-19 management. Hence, healthcare policymakers and decision-makers in Iran and other countries afflicted with sanctions should elevate their national empowerment, make firm decisions, corroborate and concentrate on research and development as well as health-oriented and pharmaceutical industries, engage in acculturalization to take steps towards controlling and managing COVID-19, and become the new global players with the maximum influence in the area of COVID-19 management."}
+{"text": "Powder bed fusion of thermoplastic polymers is a powder based additive manufacturing process that allows for manufacturing individualized components with high geometric freedom. Despite achieving higher mechanical properties compared to other additive manufacturing processes, statistical variations in part properties and the occurrence of defects cannot be avoided systematically. In this paper, a novel method for the inline assessment of part porosity is proposed in order to detect and to compensate for inherent limitations in the reproducibility of manufactured parts. The proposed approach is based on monitoring the parameter-specific decay of the optical melt pool radiance during the melting process, influenced by a time dependency of optical scattering within the melt pool. The underlying methodology compromises the regression of the time-dependent optical melt pool properties, assessed in visible light using conventional camera technology, and the resulting part properties by means of artificial neural networks. By applying deep residual neural networks for correlating time-resolved optical process properties and the corresponding part porosity, an inline assessment of the spatially resolved part porosity can be achieved. The authors demonstrate the suitability of the proposed approach for the inline porosity assessment of varying part geometries, processing parameters, and material aging states, using Polyamide 12. Consequently, the approach represents a methodological foundation for novel monitoring solutions, the enhanced understanding of parameter\u2013material interactions and the inline-development of novel material systems in powder bed fusion of polymers. Laser-based powder bed fusion of polymers (PBF-LB/P) is a powder-based additive manufacturing process of polymer components that is subject to a variety of process influences. These include exposure parameters , varyingLaser-based powder bed fusion of polymers is characterized by the iterative execution of the three consecutive process steps powder coating, laser-based exposure, and the subsequent consolidation of the molten polymer . ResultiIn order to enhance the understanding of underlying physical mechanisms and to enable the monitoring of the powder bed fusion process, several approaches have been proposed. Thermographic approaches for monitoring PBF have been demonstrated for use in metal-based PBF ,18,19 anSummarizing existing monitoring approaches, monitoring of PBF-LB/P predominantly focuses on the thermographic and optical investigation of the energy input. Although the consolidation step, characterized by the viscous flow of the material ,27, accoThe application of machine learning for modeling complex dependencies in powder bed fusion, specifically of polymers, has been adopted in various applications . ApplicaZhang et al. (2019)  proposedThe use of artificial neural networks as a specific machine learning method has been proven especially useful for modeling complex dependencies when given sparse, high-dimensional datasets ,43. DeepTo date, the inline monitoring of the powder bed fusion of polymers is limited to the image-based detection and classification of defects. The presented approach aims to overcome the limitations of existing concepts by correlating optical data, derived by means of inline monitoring, and resulting part properties. The technological basis compromises the combination of time-resolved optical inline process monitoring and subsequent data processing using deep residual neural networks. The applied neural network is designed to model a regression of optical melt pool properties and the resulting, spatially resolved part porosity. The porosity of manufactured parts significantly influences the resulting part quality, as it directly affects resulting mechanical properties  and is, Image post-processing of raw data, displayed in n, the contours of distinct cross-sections are detected using the Canny edge detector algorithm , In spite of the high variance of experimentally obtained porosity values in the validation step, the satisfactory modeling of structural defects can be demonstrated. Furthermore, morphologies that are described specifically for thin-walled samples  can be mThe explanation of the underlying mechanisms of neural-network-based modeling is significant to assess the reliability of the underlying regression . Given tThe application of SHAP on exemplary datasets indicates the mutual dependence of the optical input values and the resulting contribution on the obtained porosity value. Displayed in Considering the applied process layout, increased energy density values are correlated with reduced part-specific layer times. Therefore, the divergent mechanisms determining the part-specific porosity values are expected to not exclusively rely on divergent processing parameters. However, depending on the applied process parameters, structural deviations in the contribution of distinct time steps on the resulting part property, derived by the neural network, are observed. The parameter-dependent contribution of distinct time steps on the resulting porosity value indicates the implicit distinction of divergent process states. The recognition of specific process states is considered essential for enabling the previously demonstrated ability of the network to model varying part-specific porosity values, influenced by variations of process parameters and material aging states. Consequently, underlying mechanisms for the in situ prediction of part-specific porosity values compromise the implicit recognition of superposed process influences.A novel approach for quantifying part porosity in the powder bed fusion of polymers based on optical data, assessed in situ, could be demonstrated within the present paper. The presented approach applies a deep residual neural network that allows for the process-integrated porosity analysis of PBF-LB/P based on the analysis of time series. Temporal changes in optical properties of exposed powder bed sections, representing the input data for the monitoring approach, are characterized by a quasi-monotonous, temporal decay of the radiance of the melt pool, correlated with a time dependency of the occurrence of scattering centers within the melt pool. Varying processing parameters lead to a variation of the time-resolved anisotropic radiance of the melt pool, representing the physical foundation of the subsequent regression, hence allowing for the determination of component properties both on component-specific and mesoscopic scales. The successful inline modeling of the part porosity could be demonstrated for the application of divergent processing parameters, part geometries, and the use of aged Polyamide 12 powder. By determining the influence of distinct optical input values on the corresponding porosity value, the predominant influence of the whole consolidation phase on the derived value was identified. Furthermore, the observed parameter-dependency of the numerical contribution of distinct time steps indicates the implicit distinction of process states, such as insufficient and excessive energy input into the melt. Future work will include enhancing the prediction accuracy and the robustness towards divergent geometries, materials, and processing parameters by enlarging the training dataset. Furthermore, the application of the demonstrated regression network in the real-time process monitoring and the automated, material-specific identification of optimized process parameters embeds relevance for future industrial applications. Considering the possibility of assessing the time-resolved evolution of part properties by determining the resulting part properties at distinct time steps, the proposed approach embeds a novel concept for enhancing the understanding of the consolidation step.Consequently, the presented deep learning-based approach represents the foundation for various applications, including the enhanced understanding of parameter interactions and the vastly accelerated development of novel materials in polymer-based powder bed fusion by means of in-process optimization of process parameters."}
+{"text": "Despite decades of professional, academic, and policy interest in person-centered long-term care (LTC), the field continues to be challenged by the absence of a comprehensive depiction of the concept and a lack of consistency reflected across studies and measures. In response, a participatory action, research-focused, partnership between an institution of higher education and an LTC community (the University of Maine Center on Aging and The Cedars), with funding from The Mayer-Rothschild Foundation, is identifying and mapping the landscape of person-centered LTC in nursing homes and assisted living communities. A collaborative, ongoing, exploratory scoping literature review and evidence mapping has compiled a database of 663 academic and 115 grey literature articles through 65 systematic searches reviewing over 4,296 articles. An iterative process from both the resident and organizational perspectives revealed nine core domains  and two substantive research gaps . For mapping purposes, domain content was analyzed categorically based on concept, information revealed about resident, family, and staff experience, and operations applicability. The identified person-centered LTC domains, categorical analysis, identified gaps, and visual representation via mapping will contribute to generating research ideas, supporting the development of effective operationalization for LTC settings, and contributing to an understanding of the theoretical scope and concrete elements of a person-centered care model that aims to improve the wellbeing and quality of life of older adults in long-term residential settings."}
+{"text": "Western Journal of Emergency Medicine, co-sponsored by the Council of Emergency Medicine Residency Directors (CORD) and the Clerkship Directors in Emergency Medicine (CDEM), serves as a snapshot of the current state of emergency medicine (EM) education research and focuses on relevant topics published by a diverse group of education scholars. Our field has seen marked increases in scholarship, publication venues, funding, and training opportunities for EM education research over the past decade.This special issue of the"}
+{"text": "The number of older adults who live in long-term care (LTC) is expected to increase worldwide. The COVID-19 pandemic has caused serious consequences in Canadian LTC homes, while homes in China and Japan reported minimal infection and death rates in residents. The differences in LTC policies may be one of the contributors. The purpose of this literature review was to identify elements of the LTC policies that might have impacted COVID-19 outcomes in LTC homes in Canada, China, and Japan. A scoping review was conducted following the framework proposed by Arksey and O\u2019Malley. Scholarly articles and grey literature published between January 2015 and June 2020 were identified in six databases, four in English , one in Chinese (CNKI), and one in Japanese (CiNii), using MeSH terms for LTC and health policy. Grey literature was identified using Google. Data were extracted, summarized and common themes identified through content analysis. A total of 52 articles and 26 grey sources were included in the review based on determined inclusion criteria. They were research articles, reviews, government or association reports, policy briefs, policy documents, and guides. Four common themes of challenges emerged: caregiver workforce, service provision, funding, and physical environments. Three sub-themes were identified for caregiver workforce and service provision. Differences in COVID-19 consequences in LTC homes in the three countries seem to be related mainly to the challenges with the caregiver workforce and the lack of funding. The result suggests Improvements of LTC policies are required, especially in Canada."}
+{"text": "Despite the increasing burden of mental disorders, a lot of people worldwide suffer a gap in receiving necessary care in these countries. To close this gap, the WHO has developed mhGAP training modules aimed at scaling up mental health and substance use disorders services, especially in low- and middle-income countries. This article presents the experience of implementing the Mental Health Gap Action Programme (mhGAP) in Ukraine, Armenia, Georgia, and Kyrgyz Republic. Data were gathered from an electronic questionnaire administered to representatives from higher educational institutions where the Mental Health Gap Action Programme Intervention Guide (mhGAP-IG) was implemented in existing curricula for medical students, interns, and residents in family medicine and neurology, practicing physicians, and master\u2019s program in mental health students. More than 700 students went through the programs that provided the feedback. Evaluations of program effectiveness mainly involved standard discipline tests or pre- and post-tests proposed in the mhGAP trainer manual. This finding suggested that mhGAP-IG can be successfully adapted and implemented both on undergraduate and on postgraduate education levels and among medical and nonmedical specialists. Future evaluations need to more definitively assess the clinical effectiveness of mhGAP-IG implementation. Mental and behavioral disorders are highly prevalent across the globe. The World Health Organization (WHO) states that one in four people could have a mental health disorder during their lifetime . In 2016While mental and behavior disorders increase risk for noncommunicable diseases, and injuries ,7, indivUkraine, Armenia, Georgia, and Kyrgyz Republic are former Soviet republics, which have walked down different pathways after gaining independence in 1991.Ukraine is located in Eastern Europe and is the second largest country in the European region. It has a population of 42.0 million . After gGeorgia is a country in the Caucasus region located at the crossroads of Western Asia and Eastern Europe. The population of Georgia is 3.7 million . Since iArmenia is located in the Western Asia, South Caucasus region. The population of Armenia is 2.9 million . The iniThe Kyrgyz Republic is a lower-middle-income country of 6.5 million people in Central Asia. Since independence in 1991, the country has experienced instability, with political and social upheavals in 2005 and 2010 .Additional information on the countries can be found in Development of mental health systems in the Eastern Europe and the Asian region is characterized by gradual decentralization, with often disproportionately slow growth of community services . In manyThe estimated prevalence and burden of mental health and substance use disorders in Ukraine, Georgia, Armenia, and Kyrgyz Republic are shown in Mental health gaps remain high in the region ,4. The rIncorporation of mental health into specialized and primary care services could be a possible solution to existing challenges and could reduce the burden associated with mental disorders ,29,30,31In order to scale up mental health and substance use disorders services, WHO, in 2008, launched the Mental Health Gap Action Programme (mhGAP). To assist in implementation of mhGAP, WHO developed the Mental Health Gap Action Programme Intervention Guide (mhGAP-IG), which provides evidence-based guidelines, tools, and clinical decision-making protocols for integrated management of priority conditions. The mhGAP-IG has been developed for use by healthcare providers working in nonspecialized healthcare settings, with adaptation to meet national and local needs ,34.According to a recent systematic review by Keynejad and colleagues, the mhGAP-IG was successfully used by clinicians, government ministries, trainers, educators, and academics in a range of LMICs . Forms aThere were several initiatives in Ukraine to implement the mhGAP program. In 2017, at the request of the Ministry of Health of Ukraine, WHO supported the launch of capacity-building activities for the mhGAP Humanitarian Intervention Guide in Eastern Ukraine. In 2019, it expanded the program and trained primary healthcare workers on Version 2.0 of the mhGAP Intervention Guide in the Donetsk region . HoweverAt the same time, ongoing and sustainable development of a mental health workforce should include strengthening of institutional capacity to implement training programs effectively . One of Ukraine, Armenia, Georgia, and Kyrgyz Republic work together towards strengthening mental health education within the framework of the Ukraine-Norway-Armenia (UNA) Partnership. The UNA Partnership initially included higher education institutions (HEIs) from Ukraine, Norway, and Armenia. Later, UNA Partnership activities were joined by Tbilisi State Medical University (Georgia) and Kyrgyz-Russian Slavic University (Kyrgyz Republic). Among other initiatives, the UNA Partnership focused on mhGAP-IG implementation in selected HEIs.The initiative of WHO mhGAP-IG implementation in pre-service training was discussed and developed during three consultative meetings in 2018, which took place concurrently with the 23rd World Congress of the International Association for Child and Adolescent Psychiatry and Allied Professions, the 18th WPA World Congress of Psychiatry, and the 2018 mhGAP Forum held at WHO\u2019s headquarters in Geneva, Switzerland.Later in 2018, in Kyiv, Ukraine, a three-day introductory mhGAP course brought together decision makers and clinical educators from postgraduate and undergraduate teaching institutions to discuss how mhGAP-IG can be used to strengthen pre-service training and to provide training on mhGAP-IG, with special emphasis on the module on child and adolescent mental and behavioral disorders. There were 20 faculty members from medical universities in Ukraine, Georgia, Armenia, and Kyrgyz Republic. Each University went through a preparation and adaptation phase, when specific modules and required number of hours were decided based on the existing curriculum and needs .This article provides a one-year follow-up on the implementation of mhGAP-IG in educational settings in Ukraine, Armenia, Georgia, and Kyrgyz Republic after initial assessment .The aim of this study was to collect one-year follow-up data on implementation of mhGAP-IG in education settings in Ukraine, Armenia, Georgia, and Kyrgyz Republic. The objectives were to collect information about curriculum changes of existing courses, development of new ones, teaching processes, and number of students one year after mhGAP-IG implementation; to collect information about evaluation methods used to assess effectiveness of mhGAP-IG implementation in education settings, and to gather recommendations from faculty members who have implemented the mhGAP-IG. We believe that information on the practical realities of implementing standardized training modules in different world regions is essential in optimally planning how to prepare the diverse global workforce of healthcare providers who have the potential to address a critically important healthcare need.A cross-sectional descriptive study was conducted from October 2019 to February 2020. Data were gathered from an electronic questionnaire.Participants were at HEIs in Ukraine , Armenia , Georgia , and Kyrgyz Republic .For the purpose of the study, a self-administered electronic questionnaire was developed. The questionnaire consisted of 20 questions, both open- and closed-ended, divided into four sections: (a) background ; (b) current use of mhGAP-IG in education settings ; (c) evaluation of effectiveness of mhGAP-IG implementation in education settings ; (d) recommendations .Descriptive data are presented as case examples and in tabulated form.Implicit consent was provided when respondents completed the questionnaire.Cumulative results are presented in Background: The official WHO Ukrainian translation of mhGAP-IG has been available since 2019. Kyiv Medical University implemented the mhGAP-IG-enhanced curriculum in September 2019. The existing training curriculum on Psychiatry and Narcology for 4th-year medical students was revised in several steps to implement mhGAP-IG. The mhGAP-IG was presented to the staff of the department of Neurology, Psychiatry and Physical Rehabilitation of Kyiv Medical University, and possible changes in the curriculum were discussed. Necessary changes have been introduced, and the updated curriculum on Psychiatry and Narcology was approved by the Scientific Council in June 2019 and signed by vice-rector of the Kyiv Medical University in August 2019. Additionally, in 2019, following the example of undergraduate curriculum, the curriculum for Neurology residents was updated using mhGAP-IG.The following modules were selected: dementia, epilepsy, substance use disorders, and child and adolescent mental and behavioral disorders. The introduction of the mhGAP-IG allowed reduction of didactic sessions while maintaining the same number of hours spent on interactive practical sessions and emphasizing self-study of mhGAP-IG online materials . The resThe mhGAP-IG has been received very well by the students, clinical instructors, and clinical administrators. Identified benefits include improved trainee knowledge about mental disorders.The program was evaluated based on students\u2019 and residents\u2019 performance , which showed improved knowledge, compared to in the standard curriculum, about mental disorders. Additionally, faculty members discussed their perceptions on the updated program at Scientific Council and expressed positive attitudes towards the mhGAP-IG.The students and residents were given the survey to assess their level of involvement and feedback about strengths and weaknesses of the modules of mhGAP-IG implemented in the program. In their feedback, both students and residents reported acquisition of better knowledge and skills to identify and manage mental disorders. On the other hand, teachers using different assessment measures  found improvement of the students results on the topics after implementation of the mhGAP-IG modules concerning their ability to recognize the symptoms, to put the correct diagnosis, and to provide appropriate treatment of mental diseases.The implementation of mhGAP-IG was effective at both undergraduate and postgraduate levels of medical education. Well-structured information and visual materials have been identified as the main advantages of the mhGAP-IG training and implementation process. The program was evaluated based on students\u2019 and residents\u2019 performance and feedback surveys.The working group of the department initiated the translation of the textbook into Armenian. Staff members of Yerevan State Medical University, Department of Medical Psychology, developed and implemented programs for both undergraduate and postgraduate training levels. Adaptation of the mhGAP-IG-based curriculum took approximately 1 month.The pre-service curriculum for the second-year undergraduate students was updated with mhGAP and included eight academic hours for child and adolescent mental and behavioral disorders (with emphasis on attention deficit and hyperactivity disorder), depression, and suicide. Two modules of a continuing medical education (CME) for senior and mid-level medical professionals have also been developed as two-week, 60-h courses entitled \u201cMental Health of Children and Adolescents\u201d and \u201cMental Health of Primary Care for Children and Adolescents.\u201d The programs were attended by 11 pediatricians and 30 specialists  from 11 orphanages and social services centers for the elderly and disabled. Additionally, a CME course on psychological aspects of palliative care was adapted using mhGAP-IG and attended by 27 oncologists. Additionally, it is planned to develop a CME course in conjunction with the Yerevan State Medical University Department of Family Medicine for doctors and nurses in the primary care setting. Three topics from mhGAP were also included in the curriculum of Psychology courses at American University of Armenia. Furthermore, several mhGAP topics were included as part of the training curriculum of military psychologists from the Ministry of Defense of the Republic of Armenia.The program was evaluated based on students\u2019 and trainees\u2019 performance (tests). Additionally, feedback questionnaires for 2-year students were used and showed that more than 85% of trainees found the course to be very useful .The program was evaluated based on students\u2019 and residents\u2019 performance and feedback surveys. Feedback from participants showed that mhGAP-IG pretraining can be successfully implemented in various conditions with different students (doctors and nurses) and can be adapted to meet the unique needs of each institution. It can be assumed that the introduction of mhGAP-IG techniques and approaches is possible and acceptable, with adequate preparation and under certain conditions.In 2018, Georgia joined the UNA (Ukraine\u2013Norway\u2013Armenia) partnership project. mhGAP-IG has been translated into the Georgian language and included into the pre-services curriculum and accredited CME courses for medical doctors of different specialties. The initial adaptation into the pre-service curriculum took around 1 week.The mhGAP-IG has been integrated into the medical student curriculum at Tbilisi State Medical University and into the Medical Academy curriculum for fourth- and fifth-year students. Accredited CME courses for primary healthcare professionals have been prepared. The mhGAP-IG has been integrated into the psychiatry clerkship and psychiatry internship syllabus. The chapters on psychoses, depression, dementia, self-harm/suicide, and child and adolescent mental and behavioral disorders were added to the curriculum of the mental health master\u2019s program at Ilia State University. In general, the learning process using the WHO mhGAP-IG was highly interactive. All students had the opportunity to actively participate in the discussion and role play process, which they liked very much.For knowledge assessment, the questionnaires from the mhGAP module for psychoses and child and adolescent mental health were used only as post-tests. The comparison of pre- and post-tests was not conducted. The average score on post-test was 82%. After each semester, the university usually assesses the satisfaction of students with the course. This year, the highest marks were received, even though only online classes were provided. Students stated that the WHO mhGAP-IG is a well-structured tool with practical mhGAP-IG supplementary materials that helped them to understand and realize the difficulties and consequences of mental health problems. The personal stories gave them clear messages regarding patients\u2019 and families\u2019 challenging experiences. The video instructions were very helpful in terms of learning interviewing skills, which the students could practice with the role-playing exercises. At the same time, students pointed out that they lacked sessions with real patients.mhGAP-IG was successfully incorporated on different levels of education, including in specialized mental health courses. Well-developed manuals and supporting materials make mhGAP-IG easy to implement. Support from the university leadership is necessary during the implementation process. The program was evaluated based on students\u2019 and residents\u2019 performance  and feedback surveys.The mhGAP guideline was translated into the Kyrgyz language. A seminar on adaptation and implementation of mhGAP was conducted. Order No. 749 of the Ministry of Health of the Kyrgyz Republic of 7 July 2019 was signed, approving the usage of mhGAP in the training of medical personnel in universities of the country at the graduate and postgraduate levels. At the first stage, 20 trainers were trained to further teach the mhGAP program. Then, in the capital of the republic, a pilot mhGAP training was conducted, in which 15 general practitioners, 10 psychologists, and 15 nurses providing outpatient mental healthcare from 10 pilot regions participated. The training was evaluated and recommended for implementation in education settings. With support from the Ministry of Health, mhGAP was implemented in the educational sector at the graduate and postgraguate levels.Before the approval of the program by the Government of the Kyrgyz Republic for the protection of mental health of the population for 2018\u20132030 and the introduction of mhGAP in the country at the undergraduate and postgraduate levels, training in the subject of psychiatry only involved study of the following: the main criteria of the ICD-10; the main psychopathological symptoms such as disturbances in perception, thinking, emotions, motor function, and consciousness; psychopharmacology. After Government approval of and implementation of the mhGAP, the emphasis in teaching psychiatry shifted to practical management of the patient and provision of comprehensive care, including psychoeducation, stress management, and psychosocial care. In the final exam for medical students, questions related to mental health or to the study of behavioral sciences are almost not included. This absence creates a steady depreciation of psychiatric or psycho-educational skills among medical students. In Kyrgyzstan there is no system to reward general practitioners for identifying and treating patients with mental disorders. Recently, a program of monetary incentives for doctors has been developed; however, it is currently at the stage of pilot testing.Four topics were selected to implement the mhGAP guidelines in Kyrgyzstan: depression, suicide/self-harm, childhood and adolescent mental and behavioral disorders, and substance abuse. mhGAP topics have been included in the curriculum of medical institutes and universities . The Department of Family Medicine of the Kyrgyz State Medical Institute of retraining and advanced training provides postgraduate training for family doctors and nurses.The evaluation is based on post-training feedback questionnaires as well as pre- and post-tests from mhGAP. Evaluation of the training showed that 75% of general practitioners rated mhGAP guidelines as relevant and necessary for their practice. In addition, training was also evaluated based on medical records. Detection of depression and suicide among the population from regions where practitioners participated in the pilot training increased by 17%. Based on these results, it was recommended to include mhGAP-IG in the curriculum of medical HEIs.The mhGAP-IG was successfully implemented on under- and postgraduate levels. The program was evaluated based on students\u2019 and residents\u2019 performance  and feedback surveys. Additionally, efficacy of practitioners training was evaluated based on medical records. Implementation of the mhGAP-IG contributed to increased awareness about mental health and recognition of mental health professionals.The mhGAP-IG has been successfully implemented in all four countries at both undergraduate and postgraduate levels. In all cases, the importance of support and recognition by the administration was pointed out. In one case (Kyrgyzstan), legislative changes and support were needed to permit the introduction of mhGAP-IG in educational programs at the country level.At the undergraduate level, the program was introduced into existing curricula for students of different years of study, including second year (Armenia), fourth year (Ukraine), and sub-internship year (Georgia). At the postgraduate level, existing programs were revised or new ones created based on mhGAP-IG. In two countries (Armenia and Kyrgyzstan), mhGAP-IG has been included in postgraduate programs for general practitioners. In Ukraine and Armenia, postgraduate programs for doctors of other specialties  were developed based on or using mhGAP-IG. In one country (Armenia), a postgraduate educational program for nonmedical specialists  was developed based on mhGAP-IG. Only in one country (Kyrgyzstan), educational programs including mhGAP-IG targeted for both family doctors and nurses. In one country (Georgia), mhGAP-IG modules were included in the educational program of psychiatry specialists .All countries implemented modules on depression, suicide, and child and adolescent mental and behavioral disorders. Three countries implemented the module on substance use disorders, and two countries  implemented modules on dementia. Only Ukraine implemented the module on epilepsy. Only Georgia implemented the modules on psychosis and other significant mental health complaints.The scope and nature of evaluating the effectiveness of introducing mhGAP-IG into educational programs varied from country to country , but maiThe study is limited in its inclusion of only four countries, united by similarities in socioeconomic background and implementation of mhGAP-IG during a similar timeframe. It is envisioned that this description of the process of implementing mhGAP-IG in these countries can help other countries that may be interested in introducing what appears to be a helpful tool in advancing the population\u2019s access to mental healthcare. There is also the possibility of self-reporting bias, as the questionnaire were self-administered.This study shows that the mhGAP-IG can be successfully adapted and implemented on both undergraduate and postgraduate education levels for medical and allied specialties."}
+{"text": "Surfactants, especially non-ionic surfactants, play an important role in the preparation of nanocarriers and can also promote the enzymatic hydrolysis of lignocellulose. A broad overview of the current status of surfactants on the immobilization of cellulase is provided in this review. In addition, the restricting factors in cellulase immobilization in the complex multiphase hydrolysis system are discussed, including the carrier structure characteristics, solid-solid contact obstacles, external diffusion resistance, limited recycling frequency, and nonproductive combination of enzyme active centers. Furthermore, promising prospects of cellulase-oriented immobilization are proposed, including the hydrophilic-hydrophobic interaction of surfactants and cellulase in the oil-water reaction system, the reversed micelle system of surfactants, and the possible oriented immobilization mechanism. Bioethanol, as a renewable, economically affordable, and environmentally safe energy material, will gradually become a substitute for fossil fuels. It has far-reaching research significance and application value for the development of a sustainable energy strategy . Due to In general, lignin-derived inhibition is the major physical obstacle restricting the enzymatic hydrolysis of cell wall polysaccharides . More imTo overcome these barriers, immobilization is usually used to improve enzyme stability and even activity or selectivity when properly designed, which can also facilitate the reuse of enzymes and effective cost of catalytic processes . The chaMoreover, the immobilization of cellulase has been achieved based on physical adsorption, covalent binding, or affinity interactions , includiThe surfactants have been widely used for the preparation of nanocarriers as shown in The basic physical and chemical properties of surfactants, such as micelle formation, dispersing, emulsifying, and solubilizing, have made them widely useful in the field of nanotechnology . SeveralSurfactants can also change the surface properties of nanocarriers, such as their morphology, magnetic properties, dispersion, and catalytic performances . This moThe structure and properties of carrier materials have great influence on the properties of immobilized cellulase, such as internal geometry , specific surface area, superficial activation degree, mechanical resistance, and pore diameter . MeanwhiThe physical effects of nanocarriers on immobilized cellulase are as follows: 1) The pore size and effective surface area of the nanocarriers. Not all porous carriers can be used for immobilization of cellulase due to the limitation of pore size, which should be larger than or equal to that of the cellulase to reduce steric hindrance. The effective surface area occupied by the enzyme determines the maximum load of the immobilized cellulase . When a 2). Moreover, the hydrophilic properties of the C-MNPs play an important role in the preparation of oriented-immobilized cellulase based on the SRM system. The conventional immobilization of cellulase molecules on a single magnetic nanocarrier is simple, the chitosan was usually first coated on the magnetic nanocarriers for further combination with cellulase , which are easier to co-precipitate with cellulase  distributed at different ends. In the water-oil (W/O) system, the surfactants are dissolved in the nonpolar organic solvent when a trace of water is provided, and the reversed micelles are formed when the concentration exceeds the CMC (The SRM system has been widely used in the preparation of immobilized enzymes . The spe the CMC . In reve the CMC . Accordi the CMC .Multipoint covalent attachment is likely the most effective strategy for immobilization, but it is difficult to allow the immobilization of enzymes at a well-defined position since the proteins are usually attached to the solid surface by uncontrolled chemical bonds . The uncCellulase plays an important role in the production of fuel ethanol by the enzymatic hydrolysis of lignocellulose, and the immobilization of cellulase on the nanocarriers is an effective way to improve hydrolysis efficiency. However, the nanocarrier structure characteristics, solid-solid contact obstacles, external diffusion resistance, limited recycling frequency of nanocarriers, and nonproductive combination of enzyme active centers restricted the further improvement of hydrolysis efficiency in the complex multiphase system. Surfactants can promote the enzymatic hydrolysis of lignocellulose and play an important role in the preparation of nanocarriers. The special SRM system caused by the amphiphilicity in the oil-water reaction system can provide effective protection to obtain the immobilization of single-layer cellulase, which can effectively prevent the immobilization of cellulase and increase the effective attachment of immobilized cellulase and solid substrates."}
+{"text": "Ferroptosis is a new form of programmed cell death due to iron-dependent excess accumulation of lipid peroxides and differs from other programmed cell deaths in morphological and biochemical characteristics. The process of ferroptosis is precisely regulated by iron metabolism, lipid metabolism, amino acid metabolism, and numerous signaling pathways, and plays a complex role in many pathophysiological processes. Recent studies have found that ferroptosis is closely associated with the development and progression of many lung diseases, including acute lung injury, pulmonary ischemia-reperfusion injury, lung cancer, chronic obstructive pulmonary disease, and pulmonary fibrosis. Here, we present a review of the main regulatory mechanisms of ferroptosis and its research progress in the pathogenesis and treatment of lung diseases, with the aim of providing new ideas for basic and clinical research of lung-related diseases. Ferroptosis is a new type of iron-dependent programmed cell death caused by lipid peroxidation (LPO), which differs from other programmed cell deaths in morphology and biochemical characteristics. In terms of morphology, there is no chromatin agglutination and nuclear fragmentation as opposed to the process of cell apoptosis, nor the formation of autophagic vacuoles with two-layered membrane structures seen during autophagy, or swelling of organelles and rupture of the plasma membrane during necrosis. Its main morphological characteristics are mitochondrial shrinkage and increased mitochondrial membrane density, accompanied by the reduction or disappearance of mitochondrial cristae and outer membrane disintegration . The corLPO is the key link in triggering ferroptosis. Excessive accumulation of LPO will cause plasma membrane damage and eventually lead to cell ferroptosis. Polyunsaturated fatty acids (PUFAs) are more prone to oxidation to produce peroxy groups due to their labile double bonds, and are also one of the key mechanisms of ferroptosis. When PUFAs are present in large amounts, more lipid peroxides are produced, aggravating the degree of ferroptosis . With th2+ in cells, which is composed of transferrin receptor (TfR), divalent metal ion transporter-1 (DMT1), transferrin, ferroportin1 and ferritin (Ft), etc   system. The IRP system can sense the concentration of free FeFt), etc . Fe3+ inol (LIP) . LIP can(LIP)  is located in the cytoplasmic membrane and exerts an anti-ferroptosis effect through its N-terminal myristoylated motif. It is the redox of NADPH-dependent coenzyme Q (CoQ) oxidoreductase. FSP1 maintains the reduced form of CoQ at the plasma membrane, which antioxidant activity is not dependent on GSH. The reduced form of CoQ traps lipid peroxyl radicals and prevents the diffusion of LPO . In GPX4Nuclear transcription factor-2 (Nrf2) is a critical regulator of antioxidant response . Under nVarious types of cell death have been implicated in the regulation of inflammation. When ferroptosis occurs, it can mediate inflammation immunogenically, intervening in the immune system to dispose of dying cells. Intracellular components undergoing ferroptosis can release ATP, nucleotides, and pro-inflammatory cytokines from pro-inflammatory damage-associated molecular patterns (DAMPs) to promote the development of necroinflammation . In addiin vitro model of IR generates a large amount of ROS, which may recruit pro-inflammatory leukocytes and destroy the membrane integrity of plasma endothelial and epithelial cells  is a disease with airflow obstruction as the main pathological change, which can cause irreversible lung injury. The etiology of COPD is not clear, and it is currently believed to be related to the abnormal inflammatory response of harmful gases and harmful particles. Cigarette smoke (CS) has an important effect on iron homeostasis in the lung. Exposure of mouse and human bronchial epithelial cells to CS increased the concentrations of iron, Ft, serum ferritin and non-heme iron in lung cells . EndoplaPulmonary fibrosis (PF) is an interstitial lung disease that develops from long-term inhalation of dust, the use of drugs such as amiodarone, bleomycin, or lung injury caused by radiation therapy. The formation of fibrotic foci is a prominent pathological feature of PF . Collage2+, ROS and mitochondrial superoxide, which inhibits ferroptosis by acting as a competitive endogenous RNA. It is also observed that overexpression of lncRNA LINC00336 limits ferroptosis induced by GPX4-inhibitor RSL3 in lung adenocarcinoma cells , macrophages to accumulate in the airways and release inflammatory factors leading to chronic airway inflammation. In a highly oxidized microenvironment, H2O2 can up-regulate Th2-driven airway inflammation by influencing the secretion of Th1 and Th2 cytokines and enhancing the airway\u2019s hyperreactivity, which makes the above symptoms prolonged and aggravated . Airway rticoids . In hypeMycobacterium tuberculosis (Mtb), the macrophages in the alveoli are the first to secrete large amounts of IL-1, IL-6, and TNF-\u03b1, allowing lymphocytes and monocytes to aggregate, forming combined granulomas to limit the spread of Mtb. Th1 cells play an immune protective role and promote the function of macrophages. The contest between Mtb and macrophages determines the direction of tuberculosis. Studies have found that Mtb-induced macrophage death was associated with decreased GSH and GPX4 levels and increased free iron, mitochondrial superoxide, and LPO. The destruction of macrophages by Mtb was reduced after Ferrostatin-1 treatment. Similar manifestations were also seen in necrosis of the lung, demonstrating that ferroptosis is the primary mechanism of necrosis in Mtb infection  is an infectious inflammatory disease. In the early stage of infection, the symptoms are mostly fever, cough, muscle aches, and fatigue . Severe The pathological changes of COVID-19 mainly include hemoglobin damage, hypoxia, methemoglobinemia, and cellular iron overload . Iron isIron chelator has immunomodulatory and anti-inflammatory effects, and can bind to several receptors used by SARS-CoV-2 to prevent it from entering host cells. The therapeutic mechanism of iron chelators also includes down-regulation of hepcidin, binding of free iron, or depletion of iron from Ft, thus interfering with virus replication . After SReducing the concentration of intracellular iron and increasing the level of reducing agents is the most fundamental treatment to alleviate the redox and ROS damage of cells, especially in severe COVID-19 cases like ARDS. The correct selection of chelating agents and reducing agents to prevent the early formation of ROS is an important control measure.Ferroptosis is a new way of programmed cell death caused by the excessive accumulation of iron-dependent LPO, involving various metabolic pathways such as amino acid metabolism, lipid metabolism, and iron metabolism. With the progress of ferroptosis research, more and more influencing pathways and regulatory factors have emerged, forming a complex network of ferroptosis occurrence and development. A large number of experimental studies have revealed that ferroptosis is involved in the morphological changes and pathological processes of various diseases. In ALI, IR, COPD, and pulmonary infectious diseases where ferroptosis is clearly involved in the injury mechanism, intervention at a certain point in the ferroptosis network may play a role in the early prevention of the disease. This would lead to the improvement of clinical symptoms and control of the development of the disease course. In the future, we can also try to explore whether the combined use of ferroptosis inhibitors in various ways will achieve better therapeutic effects. Therefore, in the context of the many achievements in animal model experiments, it is essential to perform more in-depth studies on the mechanisms and targets of action of ferroptosis inhibitors. More efficient and specific modulation of cellular ferroptosis is key for future research."}
+{"text": "Betula platyphylla Suk. is one of the most widely distributed temperate deciduous tree species in East Asia and has important economic and ecological value. Based on 231 species distribution data points of Betula platyphylla Suk. in China and 37 bioclimatic, soil, and topography variables (with correlation coefficients < 0.75), the potential geographical distribution pattern of Betula platyphylla Suk. under Representative Concentration Pathway (RCP) climate change scenarios at present and in the 2050s and 2070s was predicted using the MaxEnt model. We analyzed the main environmental variables affecting the distribution and change of suitable areas and compared the scope and change of suitable areas under different climate scenarios. This study found: (1) At present, the main suitable area for Betula platyphylla Suk. extends from northeastern to southwestern China, with the periphery area showing fragmented distribution. (2) Annual precipitation, precipitation of the warmest quarter, mean temperature of the warmest quarter, annual mean temperature, and precipitation of the driest month are the dominant environmental variables that affect the potential geographical distribution of Betula platyphylla Suk. (3) The suitable area for Betula platyphylla Suk. is expected to expand under global warming scenarios. In recent years, due to the impact of diseases and insect infestation, and environmental damage, the natural Betula platyphylla Suk. forest in China has gradually narrowed. This study accurately predicted the potential geographical distribution of Betula platyphylla Suk. under current and future climate change scenarios, which can provide the scientific basis for the cultivation, management, and sustainable utilization of Betula platyphylla Suk. resources.Climate is a dominant factor affecting the potential geographical distribution of species. Understanding the impact of climate change on the potential geographic distribution of species, which is of great significance to the exploitation, utilization, and protection of resources, as well as ecologically sustainable development.  Climate plays a major role in species distributions on regional and global scales, influencing the biodiversity and the potential geographical distribution of species \u20133. GlobaBy studying the relationship between species distribution and environmental variables, we can explore the dominant environmental variables that affect the geographical distribution of species, determine the potential geographical distribution range of species, and analyze the impact of climate change on species distribution , 15. BasBetula platyphylla Suk. is one of the most important pioneers and associated tree species in the Larix forest community in East Asia . The boundary was obtained from Natural Earth . Based on the principle of national and territorial integrity, we have modified and adjusted the vector boundary.DEM was obtained from National Tibetan Plateau Data Center ((TIF)Click here for additional data file.S1 Table(XLSX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file."}
+{"text": "Dear Editor,A 60-year-old female patient with a history of chronic liver disease, portal hypertension, polycythemia vera, hypothyroidism, and type 2 diabetes mellitus, presented to the Emergency Section of a University Hospital reporting the appearance of painful purpuric lesions in the lower limbs three days before. She denied fever, chills, arthralgia, or trauma. She denied the use of new medications. She reported receiving the second dose of the COVID-19 vaccine (Oxford-AstraZeneca) approximately eleven days before. She denied a similar previous clinical picture. On physical examination, she had purpuric lesions and palpable papules, which did not disappear on digital pressure .Figure 1She reported daily use of propranolol, metformin and levothyroxine. She described stability of the polycythemia vera since December 2015. She was submitted to two lower-limb skin punch biopsies for histopathological analysis and immunofluorescence (IF). Prednisone (1\u202fmg/kg/day) was started once a day. The histopathological examination showed a mixed inflammatory infiltrate with predominantly perivascular fragmented neutrophils associated with extravasated red blood cells a\u2013c. IF sImmunization is a highly important resource in the fight against pandemics, especially the current one caused by COVID-19. However, possible side effects have not yet been fully described. As portrayed by Cohen et al. 2021) and Bostan et al. (2021), there are reports in the literature that point to leukocytoclastic vasculitis following the application of the COVID-19 messenger ribonucleic acid (mRNA) vaccine, such as the vaccine produced by Moderna and Pfizer.021 and BIt is unclear whether the COVID-19 vaccine can reactivate or trigger autoimmune diseases.None declared.Matheus Fritzen: Statistical analysis; approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.Gabriella Di Giunta Funchal: Statistical analysis; approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.Mariana Oliveira Luiz: Statistical analysis; approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.Giovanna Steffenello Durigon: Statistical analysis; approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.None declared."}
+{"text": "We assess the differences in the effect of traumatic brain injury (TBI) on the decline in cognitive status and the risk of Alzheimer\u2019s disease and related dementia (AD/ADRD) between veteran and non-veteran respondents of the Health and Retirement Study (HRS) and measure the sensitivity of these differences to the incremental introduction of controls for associated risk factors. Three groups of AD/ADRD risk-related variables were used: i) demographic/socioeconomic factors, including gender, race, marital status, education, income, and the number of limitations in activities of daily living; ii) comorbidities, including co-existing depression/post-traumatic stress syndrome (PTSD), substance  abuse, diabetes mellitus, stroke, and heart failure; and iii) genetic factors, including the presence of at least one pair of the APOE4 allele and a series of polygenic risk scores associated with AD hallmarks. The dynamics of changes in cognitive impairment in response to TBI, PTSD, and mild cognitive impairment were validated against respective measures estimated using the Department of Defense Alzheimer\u2019s Disease Neuroimaging Initiative (DoD-ADNI) data. The results of the analyses showed that TBI and PTSD were strongly associated with cognitive decline and the risks of AD/ADRD in both veteran and non-veteran subpopulations in HRS data and the difference between them was not statistically significant. Effect magnitude decreased with the addition of risk-related control variables but remained associated with the increased risks. Prevalence of mild cognitive impairment was associated with TBI at baseline in DoD-ADNI data, but no cognitive decline was observed during one year of follow-up."}
+{"text": "IEEE Open Journal of Engineering in Medicine and Biology focuses on the major interrelated components of Rapid Acceleration of Diagnostics (RADxSM) Tech, a National Institutes of Health (NIH)-funded program launched on April 29, 2020 to accelerate development, validation, and commercialization of innovative point-of-care and home- based tests, as well as improvements to clinical laboratory tests, that can directly detect SARS-CoV-2, the virus that causes COVID-19. RADx Tech was implemented and coordinated by the Consortia for Improving Medicine with Innovation & Technology (CIMIT) in its role as the Coordinating Center for the Point-of-Care Technologies Research Network (POCTRN) in conjunction with the NIH and the four POCTRN Centers This Special Section of the Likened to a mini-Manhattan Project by Sen. Lamar Alexander et\u00a0al.), the expert review panels , the unique facilitation provided to the funded applicants , the POCTRN Cores that evaluated the technologies at the benchtop and in actual use , and the support for large-scale manufacturing and deployment of diagnostic tests . The final paper describes the impact of RADx Tech on future med-tech entrepreneurs and developers .This Special Section provides operational details for the key components and processes of RADx Tech that have proven to be vital to its success: software platforms that enabled the program's infrastructure and processes (Collins On behalf of POCTRN and as Co-Principal Investigators for the POCTRN Coordinating Center, we are grateful to NIH leadership for their invaluable support and guidance, especially National Institute of Biomedical Imaging and Bioengineering director Bruce Tromberg and NIH director Francis Collins, and are privileged to present this collection of outstanding papers from a group of dedicated colleagues committed to serving our nation, which we humbly suggest represents a new paradigm for medical technology development and a validated model for the United States to use and adapt when challenged by another national healthcare emergency.Steven C. Schachter, Guest EditorCo-PI of the Coordinating Center for POCTRNChief Academic Officer of CIMITBoston, MA 02114 USAsschacht@bidmc.harvard.eduJohn A. ParrishCo-PI of the Coordinating Center for POCTRNChief Executive Officer of CIMITBoston, MA 02114 USA"}
+{"text": "Primary biliary cholangitis (PBC) is a chronic autoimmune cholestatic liver disease that can progress to liver fibrosis and cirrhosis, and requires timely diagnosis, optimal treatment, and risk stratification. Several guidelines for the management of PBC have been published, including the American Association for the Study of Liver Disease (AASLD) and European Association for the Study of the Liver (EASL) Clinical Practice Guidelines, which include goals for standards of PBC care. However, recent audits have identified deficiencies in real-world PBC care. In addition, the global coronavirus (COVID-19) pandemic has generally reduced access to care, diminished healthcare resources and accelerated the use of remote patient management. There is therefore a need for simple, actionable guidance that physicians can implement in order to maintain standards of care in PBC in the new environment.A working group of ten PBC specialists from Europe and Canada were convened by Intercept Pharmaceuticals in January 2020 with the aim of defining key criteria for the care of patients with PBC.Following the outbreak of the COVID-19 pandemic, based on these criteria, a smaller working group of six PBC specialists developed practical recommendations to assist physicians in maintaining standards of care and to guide remote management of patients.Figure 1).The working group defined five key criteria for care in PBC, encompassing PBC diagnosis, initiation of first line therapy with ursodeoxycholic acid (UDCA), risk stratification on UDCA, symptom management, and initiation of 2L therapy. The group developed 21 practical recommendations for the management of patients with PBC in the COVID-19 environment including modality, frequency and timing of investigations and monitoring. (The delivery of PBC care during the COVID-19 pandemic carries significant challenges. These consensus criteria and practical recommendations provide guidance for the management of PBC during the pandemic era and beyond.NoneIntercept Pharmaceutical"}
+{"text": "Anal canal and peri-anal squamous cell carcinomas (ASCCs) are relatively rare cancers that affect approximately 8000 patients per year in the United States. The rate appears to be rising, which is potentially attributable to the increasing incidence of oncogenic Human Papilloma Virus (HPV) infection. Historically, patients were treated with abdominoperineal resection with resulting permanent colostomy dependence. Through landmark efforts and sequentially designed clinical trials, the majority of patients with localized disease are now effectively treated with radiotherapy and chemotherapy, or in select cases, sphincter-preserving surgery, with favorable outcomes. However, continued efforts are needed to gain a better understanding of ASCC disease biology and to continue improving cancer control while maximizing the quality of life for patients. The purpose of this Special Issue is to discuss the historical perspectives of surgery, radiotherapy, and systemic therapy; the evolution of therapy over time; and current areas of investigation to advance our understanding of the multi-disciplinary management of patients with ASCC.This Special Issue consists of six articles that provide an in-depth overview of contemporary practice and future areas of investigation. First, Dee et al.  and PossIn conclusion, this Special Issue presents an in-depth discussion of the evolution of therapy for patients with ASCC, highlights the importance of multidisciplinary collaboration, and introduces numerous areas of active investigation to help improve outcomes for our patients."}
+{"text": "The development of metal nanoparticle-based facile colorimetric assays for drugs and insecticides is an emerging area of current scientific research. In the present work, polypropylene glycol was used for stabilization of gold nanoparticles (AuNPs) in a simple one-pot two-phase process and subsequently employed it for the specific detection of cephradine (CPH). The characterization of the prepared PPG-AuNPs was conducted through various analytical techniques such as UV-visible spectrophotometry, Fourier transform infrared spectroscopy, atomic force microscopy (AFM), zeta potential and zetasizer techniques. As the major target of the study, the stabilized PPG-AuNPs were employed for colorimetric detection of CPH and other drugs. Typical wine-red colour of PPG-AuNPs disappeared immediately and surface plasmon resonance band quenched by addition of CPH in the presence of several other interferents  and in real samples. PPG-AuNPs permitted efficient, selective, reliable and rapid determination in a concentration range of 0.01\u2013120 mM with a detection limit (LoD) of 11.0 mM. The developed sensor has the potential to be used for fast scanning of pharmaceutical formulations for quantification of CPH at production facilities. The coupling stoichiometry between PPG-AuNPs and CPH as obtained by Job plot is found to be 1 : 1, The efficiency of any developed method must be validated in the presence of other interfering drugs and salts in the context of real sample analysis. The developed sensor for CPH in this study was found to be robust in the presence of several other interfering drugs and salts. The presence of other drugs namely aspirin, ibuprofen, ampiciline acid, paracetamol, clindamycin, aminophylline, cephalexin, salbutamol, phenytoin, isoniazid, azithromycin, cefixime, cefuroxime, DL tryptophan, theophylline and salts namely potassium bromide, calcium carbonate, calcium bicarbonate and sodium chloride having concentration equal to CPH did not have any pronounced effect on the efficiency of the developed colorimetric CPH sensor, CPH analysis has been reported using many instrumental techniques such as HPLC, ELISA, voltammetry, NMR and GC-MS in different environmental and biological samples, All the above studies were carried out in DI water. Moreover, the authenticity of interference study and validity of PPG-AuNP-based proposed assay for CPH in context of real samples was evaluated by employing the optimized protocols for tap water, urine, serum and blood plasma samples. Immediate disappearance of wine-red colour of PPG-AuNPs and quenching of the typical UV-Vis peak confirms the applicability of the proposed CPH assay for all real samples in the presence of natural interferents, c. The amount of CPH as obtained by the calibration curve is fairly close to the manufacturer claim and analysis of the same sample by independent HPLC-UV and UV-Vis spectroscopy, As the next step, the developed CPH assay was used for quantification and quality control of commercial drugs containing CPH. An appropriate amount of the commercial drug as per claims of the manufacturer was added to the PPG-AuNPs. The immediate disappearance of the wine-red colour of the PPG-AuNPs gave the first indication of the presence of CPH. The next step is the evaluation of the quantitation capability of the proposed colorimetric sensor. The extent of quenching in the UV absorption band, evaluated by the absorbance after addition of the drug, is compared with the calibration curve, figure\u00a07The proposed colorimetric assay for CPH in this study is robust and applicable to samples containing different interfering species and for quick quality control in the production facilities. The advantages of the proposed colorimetric assay for CPH include fast, facile, on-spot analysis of drug contamination in environmental and biological samples without any involvement of high-tech instrumentation.. 4The uniquely developed colorimetric sensing based on PPG-AuNPs has proved to be a rapid and sophisticated one-pot quantitative assay for CPH. Characterization of PPG-AuNPs, CPH and PPG-AuNPs/CPH was done through zeta sizer, AFM, FT-IR and UV-visible spectroscopy. The synthesized PPG-AuNPs were found to be resistant to various external variables such as temperature, pH and the presence of electrolytes. Typical wine-red colour of AuNPs immediately disappears by the addition of CPH and SPR band of AuNPs quenched. The proposed method has a linear dynamic range from 0.025 to 120 mM with a limit of detection of 11.0 mM. The presence of other drugs and ions did not have any pronounced effect on the sensing ability of the PPG-AuNP-based assay for CPH. The proposed method can be used for environmental, biological and pharmaceutical samples. Reasonable selectivity, the simple procedure of preparation and application, a relevant dynamic range and limit of detection demonstrate the potential of PPG-AuNP-based CPH detection method for practical applications without any involvement of high-tech instrumentation. Furthermore, the proposed method can be employed for a quick screening of pharmaceutical formulations in the context of quantification of CPH on production facilities.Click here for additional data file."}
+{"text": "Sambucus nigra L.) attracts attention due to its easy cultivation and high availability of bioactive compounds. Most of the available data concerning black elder\u2019s therapeutic action are focused on its effects such as activation of immune processes and anti-inflammatory processes  and regulation of hormones and their receptors in cancer cells. The effects of elderberry on reproduction have been poorly investigated so far. Nevertheless, conducted studies so far demonstrate the stimulatory influence of black elder extract and its constituents, such as rutin, anthocyanins and agglutinins, on the viability and steroidogenesis of healthy ovarian cells as well as their ability to promote apoptosis and reduce the viability and proliferation of ovarian cancer cells. Furthermore, the action of black elder extract and its constituent biomolecules, such as anthocyanins and lectins, on embryogenesis and the embryonal estradiol-estradiol receptor system have also been reported. The available information, despite limitations, suggest the applicability of black elder constituents for improvement of reproductive processes in animal biotechnology, animal production and assisted reproduction, as well as for prevention and treatment of reproductive disorders (including cancer) in veterinary and human medicine.The present review summarizes the current knowledge concerning provenance, properties, physiological and therapeutic actions of elderberry and the bioactive molecules present in the plant, with emphasis on their action on female reproduction. Elderberry or black elder ( The search for new regulators of reproduction is important for the solution of various problems of modern society. Intensive animal production is associated with growing incidences of farm animal infertility . The occThe majority of reproductive dysfunctions have similar causes and mechanisms\u2014the ability of various adverse environmental factors to induce oxidative stress\u2014including the accumulation of reactive oxygen species, which are deleterious to DNA and proteins, ovarian folliculogenesis and embryogenesis. Oxidative stress can be prevented by antioxidants . The mosSambucus nigra L.). Due to its health-promoting and sensory properties, elderberry is used primarily in the food and pharmaceutical industries [One of the promising and widely accessible sources of antioxidants and other biologically active substances affecting reproductive and non-reproductive processes and health could be the black elderberry  are rich sources of dietary phytochemicals, such as carbohydrates, lipids, terpenoids, flavonoids, phenolic acids, alkaloids, etc. ,20. The The characteristic aroma of elderberries is a result of (E)-\u03b2-damascenone, dihydroedulan, ethyl-9-decenoate, 2-phenyl ethanol, phenylacetaldehyde and nonanal. Alcohols, esters and aldehydes are frequently identified volatile groups in elderberries. Other major secondary metabolites comprise approximately 1% triterpenes  and about 1% sterols . In addition, pectins, tannins and phenolic acids are found in the flowers ,36. EldeTherefore, various parts of the elderberry plant demonstrate the presence of high amounts of biologically active molecules with a wide spectrum of effects\u2014from antioxidative and phytoestrogenic polyphenols to toxic aldehydes and glycosides. The presence of these molecules could explain the physiological and therapeutic effects of this plant, as well as the variability in its action on different targets listed below.Elderberry is widely used in folk medicine through its pharmacological properties . CurrentElderflowers have been used in traditional medicines for the management of inflammation, skin disorders such as diuretic, colds, fevers and other respiratory disturbances ,64,65. FNo substantial adverse side effects of black elderberry have been reported so far . MoreoveIt is widely accepted that elderberries\u2019 curative capacity is due to the presence of high amounts of polyphenolic compounds, primarily flavonols, phenolic acids and anthocyanins. The presence of polyphenols, which assure the defense of plants against pathogenic microorganisms, can also explain the ability of black elderberry to suppress the activity of viruses ,53,54 anPlant polyphenols are known free radical scavengers and are able to protect the human body against oxidative stress and peroxidative processes ,76,77,78There is evidence that the positive action of elderberry on vascular health is due to the presence of anthocyanins, especially cyanidin-3-O-glucoside ,62. MoreIt may, however, be noted that search for an active compound of any plant, including elderberry, is difficult because the tested commercial and non-commercial dietary supplements usually contain multiple ingredients. In addition, substantial differences are often found between labelled and actual ingredients or their amounts . FurtherAs mentioned above, several curative effects of elderberry could be explained by high contents of antioxidants, which can either directly eliminate free oxygen species or promote antioxidative enzymes within the cells ,76,77,78kappa B (NF-\u03baB) and interleukin 8 (IL-8). Some similar signaling substances were changed during curative elderberry action on skin photoaging and inflammation. This effect was associated with a decrease in matrix metalloproteinase-1 (MMP-1) expression, secretion of inflammatory cytokines, mitogen-activated protein kinases/activator protein 1 (MAPK/AP-1) and NF-\u03baB signaling pathways and skin inflammation. In addition, elderberry extract improved nuclear factor E2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) signaling to increase oxidative defense capacity, enhanced transforming growth factor beta (TGF-\u03b2) signaling activation to promote procollagen type I synthesis and blocked extracellular matrix degradation [Furthermore, the antioxidative and anticancer effects of elderberry anthocyanins are associated with the downregulation of promoters and markers of inflammation, such as monocyte chemoattractant protein-1 (MCP-1), transcription factor nuclear factor radation . The protective effect of elderberry flavonoids and pectins against the influenza virus is probably mediated by stimulating the immune system of the host through enhancing the production of inflammatory cytokines such as interleukins IL-6, IL-8 and tumor necrosis factor (TNF) ,68,83 anIn addition, black elderberry anthocyanins can improve vascular health by promoting the production of nitric oxide, which in turn promotes vascular permeability and vasodilation and reduces blood pressure . On the Finally, elderberry can influence some physiological processes via changes in steroid hormones and their receptors. Elderflower extracts promoted estradiol release, downregulated estrogen receptor alpha and upregulated progesterone receptor expression in cultured breast cancer cells, which are involved in the control of cell proliferation . The endTaken together, the available data suggest that the non-reproductive effects of black elderberry are mediated by changes in oxidative, inflammatory, and regenerative processes, as well as angiogenesis, steroid hormones and their receptors. The functional interrelationships between these processes are possible. At least, the influence of oxidative stress and antioxidants on inflammatory processes, which in turn trigger cancerogenesis/carcinogenesis, has been suggested . FurtherOur recent in vitro study demonstrated the promising stimulatory effect of elder-berry extracts on the viability of human ovarian granulosa cells . This inThe role of a particular elderberry molecule responsible for its effect could be detected by comparison of the effects of the whole elderberry extract and its particular constituents. The most known biologically active constituents of elderberry are rutin, anthocyanins and agglutinins. The most abundant polyphenol in elderflower and elderberry is the flavonoid rutin ,26. The In contrast to healthy ovarian cells, in the case of cultured cancer cells, native and hydrolyzed rutin exerted in vitro inhibitory activity against human ovarian adenocarcinomas by suppression of the viability and proliferation of OVCAR-3 ovarian carcinoma cells ,93. AddiThe present observations suggest the stimulatory influence of black elderberry substances on the viability of healthy ovarian cells and the ability of elderberry to promote apoptosis and reduce the viability of cultured ovarian cancer cells. These phenomena suggest that this plant can be principally useful for stimulation of healthy ovarian cells and suppression of cancer ovarian cell functions. The comparison of the action of elderberry and its constituents indicates that its action on ovarian cell viability and proliferation can be due to the presence of rutin, anthocyanins and/or agglutinins.Our recent study demonstrated the influence of both elderberry extracts from dark purple elderberry fruits, as well as from elderflowers on steroid hormone release by cultured human granulosa cells. The release of both progesterone and 17\u00df-estradiol by the cells was increased after supplementation by either elderflower extract or extract from the berries of the shrub. The results of this study demonstrated the benefits of elderberry extracts prepared from different parts of plant (flowers and fruits) in the upregulation of biosynthesis of ovarian steroid hormones in vitro . According to the above-mentioned hypothesis, the black elder constituents responsible for the elderberry\u2019s effects on ovarian steroidogenesis are to be suggested on the basis of the similarity of effects. Such similarity in elderberry and rutin has been reported. In vivo and in vitro studies on rats demonstrated the ability of rutin to promote the plasma luteinizing hormone (LH) level, expression of ovarian follicle-stimulating hormone (FSH) receptors, steroidogenic enzymes, ovarian folliculogenesis and fecundity ,91. In iThe current literature does not portray evidence concerning anthocyanins\u2019 action on ovarian steroidogenesis, although the phytoestrogenic effects of anthocyanins, especially of cyanidin and delphinidin, have been reported ,100. TheAgain, the current literature does not demonstrate the changes in ovarian steroidogenesis under influence of agglutinins. Therefore, there is no evidence so far that elderberry action on ovarian steroid hormones could be due to anthocyanins or agglutinins. On the other hand, the high similarity in stimulatory action of elderberry extract and rutin on healthy granulosa cell viability and steroidogenesis suggests that plant action on ovarian cells can be due to the presence of the most abundant plant flavonol rutin. Furthermore, the steroid-promoting effect of elderberry indicates the potential applicability of this plant and its constituent rutin for the promotion of steroid-dependent non-reproductive and reproductive events including ovarian folliculogenesis and fecundity.Xenopus laevis [Schr\u00f6der et al.  did not s laevis  or on ths laevis . TherefoOther black elder constituents, such as anthocyanins , and herIn contrast to elderberry anthocyanin, elderberry lectins blocked receptors of vascular endothelial growth factor (VEGF) in embryonal tissue, which is responsible for embryonal angiogenesis  . These dSchr\u00f6der et al.  also stuTherefore, the available publications indicate both stimulatory and inhibitory actions of elderberry extract and its constituents rutin, anthocyanins and lectins on regulators of embryogenesis, embryonal cancerogenesis and steroidogenesis. The ability of steroid hormones to promote both embryo development  and maliAlthough numerous signaling pathways are involved in elderberry action on non-reproductive processes, research enabled the identification of only some pathways mediating the effect of black elderberry on reproduction, and less studies have been performed to detect mediators of this plant\u2019s action on female reproductive processes.The direct action of the elderberry extract on reproductive organs and the ability to affect cultured ovarian  and embrThe ability of elderberry constituents rutin ,91 and aElderberry extract affected steroid hormones release by ovarian granulosa cells  and embrThe current literature does not contain evidence concerning the intracellular mechanisms of the whole elderberry extract action on ovarian cells; however, there are some reports concerning the key elderberry constituents  on cultured ovarian cells and cancer cells, which could help to understand the mediators of elderberry actions on either healthy or malignant cells. Treatment of mice with rutin boosted ovarian follicular health and ovarian cell proliferation, increased the number of active mitochondria and the intracellular level of the antioxidant glutathione, reduced ovarian cell ROS level and markers of apoptosis (PTEN/FOXO3a) pathway and mitigated the toxic effect of cisplatin on ovarian functions .The other elderberry constituents, namely anthocyanins  includin(1)Black elderberry agglutinin activates the signaling pathways of AKT and ERK1/2, which promotes de-phosphorylation of dynamin-related protein-1 (Drp-1).(2)Upon its translocation to the mitochondrial fission loci, Drp-1 induces fragmentation of the mitochondrial membrane.(3)Mitochondrial outer membrane permeabilization results in the generation of ROS and cytochrome-c release into the cytosol\u2014the signs of mitochondrial apoptosis.(4)These changes may result in cell cycle arrest before the G2/M phase and programmed cell death.A similar mechanism of action on ovarian cancer cells was reported for black elderberry agglutinin. Chowdhury et al.  demonstrResults of the study also demonstrated that black elderberry and its constituent rutin could promote healthy ovarian cell functions through the upregulation of gonadotropins, gonadotropin receptors, steroid hormones, antioxidants, reduction in oxidative stress and apoptosis, which in turn improves ovarian cell viability and fecundity. In contrast, in the case of ovarian cancer cells, elderberry and its constituents, rutin, anthocyanins and agglutinin, can suppress cell viability and functions via the downregulation of the similar mechanisms\u2014AKT- and ERK1/2-dependent intracellular signaling pathways\u2014promoters of cell proliferation and by induction of ROS-induced cytoplasmic/mitochondrial apoptosis. Understanding the causes of opposite action of elderberry and its molecules on healthy and cancer ovarian cells via similar intracellular mechanisms require further studies. Such studies could be helpful for possible application of elderberry for stimulation of healthy ovary and reproductive processes and suppression of ovarian cancer (see below). Available evidence concerning the possible regulators of female reproductive processes affected by black elderberry and its constituents are summarized in The reported effects of black elderberry and its constituents on female reproductive processes summarized here indicate that these plant preparations could be stimulators of healthy ovarian cells and embryogenesis. It is not to be excluded that these preparations can support ovarian folliculogenesis, oogenesis, fecundity, embryogenesis and gravidity, to relieve the age-related reproductive insufficiency and menopause-related problems. As promoters of release and reception of gonadotropins and steroid hormones, as well as phytoestrogens, they could be useful in veterinary and human medicine for the treatment of disorders induced by a deficit of these hormones\u2014age-related reproductive insufficiency, menopause-related problems, osteoporosis and polycystic ovarian syndrome. The ability of elderberry and its molecules to promote reproductive processes and fecundity could be useful in the induction of ovulation and superovulation in biotechnology in animal production and assisted reproduction. On the other hand, the ability of black elderberry substances to downregulate cell proliferation and viability of ovarian and trophoblast tumor cells indicates the potential ability of these substances for prevention, mitigation and treatment of ovarian and embryonal cancers. Efficiency of elderberry\u2019s polyphenols could be increased by search of its safe and effective dosage, and the improvement of its stability, bioavailability and delivery by using nano-emulsion and nanoliposome systems, which can enhance the biological and therapeutic activity of these plant molecules ,112. Analysis of the available literature performed here shows that black elderberry contains several biologically active substances with different, sometimes opposite, actions. Some elderberry constituents could be toxic see . Some otThe reproductive effects of black elderberry extract and its constituents have been investigated insufficiently. Nevertheless, the published reports demonstrate the stimulatory influence of black elderberry extract and its constituents\u2014rutin, anthocyanins and agglutinin\u2014on steroid hormones and their receptors in ovarian and embryonal cells. The stimulatory influence of anthocyanins on embryogenesis has also been reported. On the other hand, rutin, anthocyanins and agglutinins can suppress ovarian and embryonal cancer cell functions. The effects of black elderberry and its molecules could be mediated by intracellular signaling pathways regulating cell proliferation, oxidative processes, cytoplasmic/mitochondrial apoptosis and viability, as well as by estrogen and estrogen receptors and angiogenesis. The available evidence indicates the potential usefulness of black elderberry extract and its constituents rutin and anthocyanins as biostimulators of female reproductive processes, as well as the potential applicability of whole elderberry extract, with rutin, anthocyanins and agglutinins, for the treatment of ovarian cancer and other reproductive disorders in animal biotechnology, animal production, assisted reproduction and veterinary and human medicine.Nevertheless, the current state-of-art research invokes more queries concerning black elderberry action on female reproduction than answers. All biologically active constituents of black elderberry remain to be identified, and their biological activity remains to be investigated. The action of black elderberry extract has not been studied in in vivo experiments, whilst the reproductive effects of elderberry constituents were studied mainly in in vitro experiments and in a few animal studies. Adequate clinical studies have not been reported yet. Moreover, characteristics and mechanisms of action and biological activities of several elderberry constituents have not been compared in the same experiments yet. The conclusions concerning mechanisms of action of elderberry and its molecules are made mainly based on observations of changes in some signaling molecules after treatment, but the physiological role and functional interrelationships between particular signaling molecules remain rather hypothetical. Therefore, although the influence of black elderberry and its constituents on female reproductive processes has been demonstrated, its actions and potential applications require further studies."}
+{"text": "In this article, we \u2013 the Bacterial Viruses Subcommittee and the Archaeal Viruses Subcommittee of the International Committee on Taxonomy of Viruses (ICTV) \u2013 summarise the results of our activities for the period March 2020 \u2013 March 2021. We report the division of the former Bacterial and Archaeal Viruses Subcommittee in two separate Subcommittees, welcome new members, a new Subcommittee Chair and Vice Chair, and give an overview of the new taxa that were proposed in 2020, approved by the Executive Committee and ratified by vote in 2021. In particular, a new realm, three orders, 15 families, 31 subfamilies, 734 genera and 1845 species were newly created or redefined (moved/promoted).The online version contains supplementary material available at 10.1007/s00705-021-05205-9. Given the revived interest in bacterial and archaeal viruses and recent enormous increase in the number of characterized isolates and need for creation of numerous taxa to classify them, the Executive Committee (EC) voted on the creation of two separate Subcommittees , formally starting their mandates after EC52 (October 2020). The new Bacterial Viruses Subcommittee is chaired by Evelien Adriaenssens, supported by Dann Turner as the Vice Chair, and the new Archaeal Viruses Subcommittee is chaired by Mart Krupovic. Both Chairs were elected for three-year terms ending in 2023. As a result, this taxonomy update summarises both bacterial and archaeal virus proposals for the last time, reflecting the fact that proposals were submitted prior to the formal reorganisation of the original Subcommittee.Bacteriophage and archaeal virus taxonomy has been formally under the auspices of the ICTV Bacterial and Archaeal Viruses Subcommittee, which, at its inception in 1966, was named the Viruses of Prokaryotes Subcommittee, led by David E. Bradley , regional representatives and general members. We would like to welcome new members Jesca Nakavuma (Uganda), Alejandro Reyes (Colombia), Cristina Moraru (Germany), Susan Lehman (USA), C\u00e9dric Lood (Belgium) and Andrey Shkoporov (Ireland) and would like to thank those who have left the Subcommittee for their service.Halopanivirales SG, chaired by Hanna M. Oksanen (Finland), oversees the taxonomy of evolutionarily related viruses of the order Halopanivirales, which includes two families of viruses infecting archaea (Sphaerolipoviridae and Simuloviridae) and one family of bacteriophages (Matsushitaviridae). Thus, the latter SG bridges the two Subcommittees. Additional SGs will be created in the near future, in particular, to develop the taxonomy of archaeal members of the class Caudoviricetes; only a handful of isolated representatives of this highly diverse and expansive group of archaeal viruses are currently classified.In the framework of the Bacterial and Archaeal Viruses Subcommittee, all taxonomic proposals dealing with archaeal viruses were handled by a single SG. The new Archaeal Viruses Subcommittee currently includes 11 SGs . Instead, below we provide a brief overview of the most notable changes.We had a record year of submissions of taxonomy proposals in 2020, with 188 proposals submitted, of which all but one were approved and ratified (Supplementary Table S1). The changes at each of the taxonomic ranks in use for bacterial and archaeal viruses are summarised in Table Adnaviria, was created for classification of archaeal filamentous viruses with dsDNA genomes that adopt the A-form conformation within their virions [Tristromaviridae, Rudiviridae and Lipothrixviridae, which are evolutionarily related to each other, but not to any other known group of viruses. The families Rudiviridae and Lipothrixviridae were already grouped together in the order Ligamenvirales [Primavirales, has now been created for the family Tristromaviridae. The two orders are unified in the class Tokiviricetes, kingdom Zilligvirae and realm Adnaviria.Recently, the taxonomic framework of the ICTV has been expanded from five to 15 ranks, with the highest-level rank, realm, being equivalent to the domain rank used for cellular organisms , 3. This virions , 5. The nvirales , and a sPodoviridae. The family Salasmaviridae, named in honour of Margarita Salas Falgueras, comprises the existing subfamily Picovirinae, which includes the classical bacillus phage \u03c629 and a range of related Bacillus-infecting phages with genomes between 18 and 27 kb in size. The family Rountreeviridae, named in honour of Phyllis Margaret Rountree, groups Enterococcus-infecting phages with genomes between 17 and 19 kb in size, whereas the family Guelinviridae, named after Antonina Guelin, groups Clostridium-infecting phages with genome sizes between 16 and 19 kb.We delineated three new families of short-tailed phages with small genomes that were formerly assigned to the family Schitoviridae, named after Giancarlo Schito, is the formalisation of the group of N4-like phages defined by the presence of a large virion-associated RNA polymerase, described in more detail in reference [The new family eference .Zobellviridae, named after Claude Zobell, groups a set of globally distributed podoviruses associated with marine ecosystems first proposed by Bischoff and colleagues [The new family lleagues .Leviviridae was elevated to the rank of class, named Leviviricetes (replacing the class Allassoviricetes), and expanded to include two orders  and six new families: Fiersviridae , Atkinsviridae, Duinviridae, Solspiviridae, Blumeviridae and Steitzviridae. A detailed description of the new taxa will be published separately.Based on the investigation by Callanan and colleagues on the expansion of known ssRNA virus genomes , the famAutolykiviridae formalises the group of non-tailed dsDNA bacteriophages discovered and described by Kauffmann and colleagues [The new family lleagues , combiniSphaerolipoviridae, which includes icosahedral tailless viruses with internal membranes, consisted of three genera, Alphasphaerolipovirus, Betasphaerolipovirus and Gammasphaerolipovirus. The first two of these genera included viruses infecting halophilic archaea, whereas the last one included phages infecting thermophilic bacteria [Betasphaerolipovirus and Gammasphaerolipovirus have been renamed and moved from the Sphaerolipoviridae into new families, Simuloviridae and Matsushitaviridae (named after Isao Matsushita), respectively. The order Halopanivirales now contains a family of bacterial viruses, Matsushitaviridae, and two families of archaeal viruses, family Sphaerolipoviridae and Simuloviridae. As mentioned above, the order is under purview of a single Study Group, which is part of both the Archaeal Viruses SC and the Bacterial Viruses SC.Until recently, the family bacteria . Althougbacteria , they diPaulinoviridae addresses the challenge of defining family demarcation criteria for phages with small genomes, where members of the same family would share at least two orthologous proteins. Informed by prior work on a gene-content network of predicted filamentous prophage sequences [Bifilivirus and Thomixvirus from the family Inoviridae to the family Paulinoviridae.The new family equences , we movehttp://ictv.global/report, and summaries of the chapters on each virus family are published in the Journal of General Virology. In 2020, four new chapters on bacterial and archaeal viruses were produced by members of the Archaeal Viruses SC and Bacterial Viruses SC, namely, on the families Herelleviridae [Spiraviridae [Ovaliviridae [Finnlakeviridae [Virus Taxonomy: The Classification and Nomenclature of Viruses - The Online (10th) Report of the ICTV is freely accessible at eviridae , Spiraviaviridae , Ovaliviiviridae  and Finneviridae .This past year has been extremely productive in terms of new bacterial and archaeal virus taxa described. It would not have been possible without an active pool of scientists, both within and outside the subcommittee and its study groups, who scour databases, perform analyses and submit proposals. We continue to encourage people to contact us to formalise new discoveries into the taxonomic framework and will keep reaching out to interested parties. Finally, we would like to acknowledge one person in particular, Prof Andrew Kropinski, the Subcommittee Chair from 2014-2020, who authored, co-authored and/or assisted with the majority of proposals that have been approved in the last decade.Supplementary file1 (PDF 175 KB)Below is the link to the electronic supplementary material."}
+{"text": "In the future, AI technologies will likely be used for collecting, processing, and organizing patient-related datasets to provide patient-centered, individualized dental treatment.(1) Background: The rapid pace of digital development in everyday life is also reflected in dentistry, including the emergence of the first systems based on artificial intelligence (AI). This systematic review focused on the recent scientific literature and provides an overview of the application of AI in the dental discipline of prosthodontics. (2) Method: According to a modified PICO-strategy, an electronic  and manual search up to 30 June 2021 was carried out for the literature published in the last five years reporting the use of AI in the field of prosthodontics. (3) Results: 560 titles were screened, of which 30 abstracts and 16 full texts were selected for further review. Seven studies met the inclusion criteria and were analyzed. Most of the identified studies reported the training and application of an AI system ( The principle is to simulate the transfer of information through a neuron: weighted nodes receive the inputs (representing the synapses), sum them to produce an activation (representing the axon), and pass this activation to a nonlinear function called activation or transfer function, in order to generate the output signal. Each neuron acts as an elementary processing unit. The output signal of one unit will feed the other units, organized in layers, and so on, forming an artificial neural network (ANN)\u201d . There aMachine learning (ML) is part of weak AI; by recognizing patterns, the computer system is able to learn and make predictions ,17. AfteAI technologies are well suited for repetitive work using large datasets. The greater the workload, the more precise the performance of AI becomes . Since dThe domain of AI in  medicine is image data processing in radiological workflows, especially for detection of caries and periapical endodontic lesions , as wellTherefore, the aim of this systematic review was to analyze the recent scientific literature on the diagnostic performance and the clinical applications of AI in applied prosthodontics. The remainder of this systematic review was structured as follows: (a) introduction of the search strategy and related inclusion criteria for data extraction; (b) summary of the obtained findings of the identified and included studies; (c) critical discussion of the results; (d) conclusions.This systematic review was conducted in accordance with the guidelines of PRISMA  .Based on the PICO criteria, a search strategy was developed and an electronic search was conducted. The PICO question was formulated as follows: What are the current clinical applications and diagnostic performance of AI in the field of prosthodontics?A systematic electronic search of PubMed MEDLINE, EMBASE, and CENTRAL was performed for English-language publications; in addition, Google Scholar was reviewed. Search syntax was categorized into population, intervention, comparison, and outcome (PICO). Each category was assembled from a combination of Medical Subject Headings (MeSH Terms) as well as free-text words in simple or multiple conjunctions: ((Prosthodontics [Mesh]) OR (prosthetic treatment) OR (reconstructive therapy)) AND  OR ) .Additional manual searches of the bibliographies of all full-text articles and related reviews selected from the electronic search were also performed. Furthermore, manual searching was conducted in the following journals: Journal of Prosthodontic Research, Journal of Prosthetic Dentistry, Clinical Oral Implants Research, International Journal of Oral Maxillofacial Implants, Clinical Implant Dentistry and Related Research, Implant Dentistry, and Journal of Implantology.Studies at all levels of evidence, except expert opinion;Articles published in English;Articles published in the last 5 years (up to 30 June 2021).Inclusion criteria for the studies were defined as follows:Review articles, letter to editors and case reports involving less than 5 cases;Animal studies;Full-text not available/accessible.Exclusion criteria for the studies were defined as follows:Two reviewers (S.B. and T.J.) independently screened the titles and abstracts that were identified in the searches according to the defined inclusion and exclusion criteria. If sufficient information could not be extracted from titles and abstracts, the full text was consulted. The full texts of potentially relevant articles were obtained and reviewed in detail by both reviewers, from which the final list of articles was selected for further analysis. Disagreements were resolved by discussion.Author(s), year of publication, country, study design;Total number of patients/datasets;Training/validation datasets;Test datasets;Aim of the study;AI application; andOutcome.The following information was collected from selected articles:http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp (Accessed on 7 September 2021)) to assess the quality of the studies ;Not a study in the field of AI application in prosthodontics (n = 3);Not a clinical study (n = 1);Full text not available (n = 1).Missing information on AI technology .n = 7). Although automated detection of caries has been investigated in AI dental imaging diagnostics a few years ago, the use of AI technology in prosthodontics is (still) rare. Prosthodontics itself is a diverse and complex area of dental medicine and one that may benefit from the routine application of AI technologies. Long-term success relies on good prognosis of abutment teeth (and/or implants) in all facets of periodontal, endodontic, operative and reconstructive principles, and include patient-specific factors, such as load situation, personal and medical issues, and supportive care [The overall number of eligible studies investigating AI applications in prosthodontics was relatively low  dentists in choosing appropriate removable prosthetic options . Such suThe combination of AI technologies in the field of prosthodontics could lead to a wide variety of novel options, such as AI systems for generating occlusal surface design for crowns accounting for existing intraoral wear facets, as automatic set-up designers for complete dentures, for determining the emergence profile in implantology, or in automatic framework designs for removable partial dentures . FinallyIn principle, there are no limitations to using the power of AI in prosthodontics. In many cases, however, it is (unfortunately) financial factors that trigger the development and standard implementation of new AI technologies in the most economically profitable areas\u2014and tend to prevent interesting dental applications because a market appears too small for the dental industry. Nevertheless, future developments and research on AI can be eagerly awaited.Although this seems to be very promising, the obstacles of AI systems should not be ignored. Based on this systematic literature search, the identified trials must be seen as pilot studies and experimental, and the technologies used in these studies are not yet suitable for everyday clinical routine in the focus of prosthodontics. At the moment, AI is mainly used in undergraduate dental education and for academic research. Improvements in the technology and user interfaces is needed before the techniques can be implemented into routine dental practice. Some intermediate steps still need to be developed to make AI attractive and helpful for its routine implementation. Beyond the technical possibilities, the cost\u2013benefit ratio and ethical aspects of the use of patient-specific data also need to be critically examined in future research on AI technology in (reconstructive) dentistry .While the number of studies reporting the use of AI in prosthodontics identified in this systematic review was relatively low (inclusion of seven out of sixteen full-texts), these studies reflect an honest overview of the latest developments in AI focusing on diagnostics, predictive measures, classification, and identification tools. Prosthodontics is the dental discipline with the greatest variance in terms of diagnostics and, in particular, treatment options. Therefore, it does not seem surprising that the results of this systematic review are comparably diverse and heterogeneous.In addition, dentistry is (still) lagging behind medicine in terms of routine use of AI technology. Nevertheless, AI applications in prosthodontics have the potential to open up a wide range of opportunities for clinicians and patients, and could be used as a supplementary future basic tool for collecting, processing, and organizing patient-related datasets to provide patient-centered, individualized, and personalized treatment. Possible applications of AI algorithms are very diverse in prosthodontics and one can eagerly await further research foci and developments.The step-by-step implementation of digital applications (in dentistry) is linked to the necessary technical development and is dependent on the flexibility of the users in everyday life. The willingness to learn new treatment protocols and to trust computerized applications has been proven as a strong negative driver for dentists . In addiA critical topic and crucial factor for the successful rehabilitation of complex prosthetic cases is the correct clinical definition of vertical and horizontal maxillo-mandibular relationships. AI technology could be used for automatic registering of jaw relationships based on radiological landmarks in cone-beam computed tomography. In this context, the configuration of virtual dental articulators could be synchronized with the radiological situation to simulate individual patient movements for treatment simulation and final fabrication of prosthetic reconstructions.The use of AI technologies in prosthodontics is conceivable in many ways (and absolutely desirable) from the clinicians\u2019 point of view, but not least the demand and the economic efficiency will decide whether the MedTech industry will push AI in prosthodontics as fast and to what extent."}
+{"text": "ABSTRACT IMPACT: Using network analysis and a systems science lens, UTMB\u2019s Institute for Translational Sciences is able to quantify the evolution of REACH (its Community-Campus Partnership) as measured by the creation of new partnerships among member entities, promoting the translation and sharing of ideas and resources, and formalization of relationships among members. OBJECTIVES/GOALS: o Present how network analysis and systems science can inform evaluation of community-campus partnerships o Describe results from our experience with evaluating the REACH coalition o Summarize lessons-learned and likely improvements we are considering for our methodology METHODS/STUDY POPULATION: In 2016, we administered a network survey to core members of the Research, Education, and Community Health (REACH) coalition. The survey captured attributes about each organization, including size, populations served, etc. The survey also captured data on the relationships among these organizations, including joint meeting attendance, joint event planning, shared tangible resources, shared information, and formal legal agreements between organizations. These data were analyzed using network analysis methods. The survey was again repeated in 2018, and comparisons were made to evaluate how the network structure had evolved from 2016 to 2018. RESULTS/ANTICIPATED RESULTS: Joint meeting attendance was high in both 2016 and 2018; however, there was evidence of increased sharing of information and tangible resources in 2018. We also observed an increase in joint event planning among partnering agencies. Most strikingly, we observed that the number of formalized agreements  between agencies more than doubled between 2016 and 2018. By measuring the evolution of our network of partners, we are able to document the evolution of a community-campus partnership over time. DISCUSSION/SIGNIFICANCE OF FINDINGS: Over the course of 2 years, the coalition signaled an increase in deeper collaborations beyond simply meeting together. The use of network analysis demonstrated utility and provided another dimension for evaluating the development of teams, partnerships, and coalitions."}
+{"text": "Teaching points: Gastroduodenal intussusception is an infrequent cause of abdominal pain in children, for which a lead-point is nearly ubiquitous, which imposes endoscopic reduction as the first line of treatment. Figure 1a), in the axial plane at the level of the stomach body , and the pancreatic head  showed multiple enhancing gastric polyps (arrows), along with intussusception (arrowheads) of the stomach within the proximal portion of the duodenum. There was no compromise of the gastroduodenal wall enhancement. The CT findings were confirmed on subsequent gastroduodenal endoscopy carried out for air insufflation, resulting in successful reduction of the intussusception.A 16-year-old girl presented in the emergency department afebrile with hypogastric abdominal pain, nausea, and vomiting. The patient was known to have Peutz-Jeghers syndrome (PJS) with multiple hamartomatous gastrointestinal polyps since the histological analysis of a 50 cm small bowel resection, which occurred at the age of four in the course of acute ileo-ileal intussusception. A contrast-enhanced abdominal computed tomography (CT) on coronal curved reformation through the stomach and duodenal axes  resulting in gastroduodenal and ileo-ileal intussusception, and mucocutaneous pigmentation predominantly on the lips and around the mouth. The diagnosis of PJS is based on histological analysis of the polyps, family history of PJS, or mucocutaneous lesions [Patients with PJS present with recurrent and variable degrees of abdominal pain due to intestinal occlusion, infarction, or gastrointestinal bleeding caused by the endoluminal polyps . Our patUltrasound is the first modality of choice when assessing abdominal pain in PJS . In our As 95% of intussusception occurs in the small bowel, gastroduodenal intussusception is an extremely rare occurrence, even in patients with PJS . An unde"}
+{"text": "The overall aim of ICare was to establish a novel, comprehensive and effective model of mental health service delivery. ICare encompasses mental health promotion, risk detection, disease and relapse prevention of common mental health disorders (CMHD) and guided self-help for eating disorder (ED) patients as well as caregivers of people with an ED delivered through a common online platform.This supplement consists of two parts. The first part summarizes current research on Internet-based treatment and prevention for some of the most CMHD. The second part of the supplement is dedicated to the ICare Stakeholder Survey.Part I\u2014Evidence: As an introduction to the topic, Taylor et al. present an overview of existing systematic reviews and meta-analyses on Internet-based interventions for the treatment of depression, anxiety, EDs and substance abuse. The authors identified important research gaps including the need for more evidence on how to increase engagement, on more tailored interventions for various populations and on interventions delivered by mobile phones. The next article by Buntrock et al. summarizes the evidence on economic evaluations of Internet- and mobile-based interventions for substance use disorders. The results regarding cost-effectiveness of these interventions are promising. However, the authors emphasize that more economic evaluations are needed. The article of D\u00edaz-Garc\u00eda et al. presents a systematic review on the theoretical adequacy, methodological quality and efficacy of Internet-based interventions to promote well-being and resilience. They found a tendency for larger effects of programmes with a clear assessment theory, which underlines the need of strong theoretical foundation of Internet-based interventions. Finally, Zeiler et al. and Nacke et al. present systematic reviews evaluating reach, adoption, implementation and maintenance of Internet-based interventions to prevent EDs in adolescents and adults, respectively. Both reviews revealed a lack of reporting of external validity indicators. Overall, the results of the articles in the first part of this supplement show that Internet-based interventions are feasible and effective adjuncts to face-to-face interventions in order to deal with the increased need for mental health promotion and treatment. However, they identified also a range of research gaps, the need for better theoretical foundation and the need for higher reporting rates for external validity indicators in research studies.Part II\u2014ICare Stakeholder Survey: In their introductory paper on the stakeholder survey, Nitsch et al. describe in detail the development of the overall design of the ICare stakeholder survey which followed a mixed-methods approach to collect data from a range of different stakeholders in the healthcare, university and school settings. The next three papers deal with the results of the stakeholder survey in the healthcare, the university and the school setting, respectively. The first of three articles by Kuso et al. presents stakeholders\u2019 perspectives regarding Internet-based interventions to prevent mental health disorders in adults implemented into healthcare systems in Austria, Germany, Switzerland and Spain. Irish et al. describe the results of the stakeholder survey regarding Internet-based interventions to prevent mental health disorders in students implemented in universities in Austria, Germany, UK, Spain, Switzerland and The Netherlands. Zeiler et al. report on the perspectives of key stakeholders in Austria and Spain on Internet-based interventions to prevent mental health problems implemented in schools. The last two articles shift the focus to guided self-help interventions in the context of the treatment of EDs, targeted either to individuals who currently meet diagnostic criteria and are on a waitlist for treatment(to bridge waiting time), or to carers  of patients currently in treatment. The results are presented country-specific. The perspectives of stakeholders\u2019 views on self-help programmes for EDs patients and caregivers implemented in the healthcare system in Germany are presented by Schmidt-Hantke et al. and for the UK by Yim et al.To the best of our knowledge, this was the first comprehensive stakeholder survey focusing on Internet-based mental illness prevention which was conducted concurrently in several countries and various settings. Overall, 36 focus groups with representatives from the target groups of ICare interventions and 75 interviews with ED patients and carers and policymakers across the three settings  and participating countries were conducted. Furthermore, 423 potential facilitators/enablers filled in an online questionnaire. The findings are in accordance with the existing literature regarding barriers and facilitators for dissemination and implementation of Internet-based treatment in the healthcare system,Following the outbreak of the Covid-19 pandemic, a significant increase in the prevalence of mental health disorders is to be expected,This project has received funding from the European Union\u2019s Horizon 2020 research and innovation programme under grant agreement No. 634757.Conflicts of interest: None declared."}
+{"text": "Rhizobium-legume symbiosis. It is characterized by inverted tip growth of the plant cell wall, resulting in a tunnel that allows invasion of host cells by bacteria during the formation of the nitrogen-fixing root nodule. Regulation of the plant-microbial interface is essential for infection thread growth. This involves targeted deposition of the cell wall and extracellular matrix and tight control of cell wall remodeling. This review describes the potential role of different actors such as transcription factors, receptors, and enzymes in the rearrangement of the plant-microbial interface and control of polar infection thread growth. It also focuses on the composition of the main polymers of the infection thread wall and matrix and the participation of reactive oxygen species (ROS) in the development of the infection thread. Mutant analysis has helped to gain insight into the development of host defense reactions. The available data raise many new questions about the structure, function, and development of infection threads.The intracellular infection thread initiated in a root hair cell is a unique structure associated with  Frankia Pssym33 gad walls B in the sym33-3) . In somesym33-3) . There wP. sativum symbiotically-defective mutant RisFixV (Pssym42), callose deposition (Rhizobium infection as part of the defense response. Another striking feature of RisFixV (Pssym42) was the encapsulation of ineffective bacteroids with de-esterified HG, as detected by JIM5 immunolabelling. This mutant demonstrates unique defense reactions for symbiotic mutants [The deposition of callose  in plant cell walls is an important aspect of many processes associated with developmental physiology, pathogenesis, or stress. In the position C,D was a mutants .The process of tissue and cellular infection is accompanied by the differentiation of plant cells originating from the apical meristem. The differentiation of host cells in the nodule cortex is associated with the release of bacteria into the plant cell as organelle-like structures termed symbiosomes, which are still bounded by a plant membrane that is structurally equivalent to the plasma membrane .The exact mechanism triggering the transition of rhizobia from the extracellular space (apoplast) to intracellular existence within organelle-like symbiosomes surrounded by a plant membrane is not yet known, but it is associated with further remodeling of the host cell wall and cell membrane. In indeterminate nodules of temperate legumes, the release of rhizobia occurs from infection droplets that lack a covering of cell wall material ,236,259.Phaseolus sp., bacterial release occurs at the tips of short intracellular infection threads [Lupinus angustifolius L. showed that rhizobia bud off from infection threads and are enclosed in membranes of plant origin [Sometimes, for example, in  threads . A studyt origin . The relt origin .Presumably, the release of bacteria occurs due to the absence of a cell wall in the infection droplet and the possibility of close contact between the plasma membranes of the plant and rhizobia ,197,263.BacA controls the modification of the bacterial cell wall, including the development of Lipid -A derivatives with long-chain fatty acids [On the part of rhizobia, the gene ty acids . During ty acids ,268, whity acids . Evidencty acids .Senescence of nodule tissue is the final stage of symbiosis. There is autolysis of infected cells, and the nutrients stored in the nodules are recycled by the host plant . ProximaThe extent of nodulation and the efficiency of symbiotic nitrogen fixation can be influenced by environmental conditions, such as temperature, humidity, aeration, pH, salinity, soil structure, imbalance of nutrients in the soil . Other factors affecting nodulation include diseases and insects, as well as anthropogenic influences in the form of fertilization, soil and water pollution with pesticides, chemicals, and heavy metal ions ,276. EnvMost plants have two types of tip-growing cells: Pollen tubes and root hairs. Infection threads represent a third type of tip growth for the deposition of cell wall material. The infection thread is an inwardly growing tube in which polar  growth is topologically inverted relative to the tip growth of root hairs or pollen tubes. The following model  summarizRhizobium bacteria and altered transcriptional activity in the host cell nucleus. Among other things, this leads to the synthesis and deposition of new proteins in the microdomains of the plasma membrane of the infection thread. Vesicles derived from the ER and GA fuse with the plasma membrane at the tip of the infection thread, releasing their contents into the wall and extracellular matrix. This process is apparently controlled by a range of proteins, including: PI3K, GmVAMP721d, EXO7OH4, PvNod22. Targeted secretion from vesicles  is the driving force behind the growth of the infection thread. Glycoproteins, proteins, and polysaccharide components of the infection thread matrix include the following: AGPEs, HRGPs, ENOD2/11, LOX, DAO and RG-II. In addition, H2O2 probably plays a role in cross-linking AGPEs and changing the biophysical properties of the infection thread matrix. Vesicles derived from the GA also contain cellulose synthases, xyloglucan and pectins . HG is synthesized in a highly esterified methyl form and may be transported along with PME/PMEI complexes (pectin methylesterase/pectin methylesterase inhibitor). All these components and other cell wall remodeling enzymes are released into the apoplast.The initiation and growth of the infection thread are the consequence of signal exchange with the infecting 2+ ions, thus increasing its rigidity. RG-I is present in the infection thread wall, and RG-II is also present in the form of dimers with the borate ion. The wall also contains extensins, AGPs, and expansins. Additionally, callose and phenolic compounds such as suberin can accumulate as part of defense reactions in response to an ineffective symbiosis.In the nascent wall of the infection thread, cellulose synthases are incorporated into the membrane and deposit the crystalline cellulose. At this stage, highly methyl-esterified HG is the major component of the infection thread wall. At its mature stage, the main polysaccharide components are: cellulose, xyloglucan, and HG with varying degrees of methyl-esterification. HG having a low level of methyl-esterification binds with CaMany enzymes are involved in the modification and degradation of the cell wall during the growth of an infection thread and the formation of an infection droplet. These include: MsPG3, LjNPL, MtPER, and endo-\u03b2-1,4-glucanases. Polar growth of the infection thread is mediated by the actin cytoskeleton, and the alignment of microtubules creates a constraining tunnel for infection thread growth. Within the lumen, bacterial polysaccharides play an important role: EPS, KPS, LPS, cyclic \u03b2-glucan, RosR, and Rhizobia-induced peroxidases (Rip1-10).Following the release of bacterial cells from the infection droplet, several plant proteins are associated with the symbiosomal membrane. These include: Lectin-like glycoprotein (PsNLEC1), synaptotagmin (MtSyt1/2/3), syntaxin (MtSYP132), inositol-containing phospholipid (JIM18 antigen), and AGP with a GPI anchor (JIM1 antigen). Within the symbiosome compartment, rhizobial cells differentiate into nitrogen-fixing bacteroids: They lose their exopolysaccharide capsule, and the structure Lipid-A and O-antigen groups of LPS becomes modified, partly as a result of the action of the protein BacA.From an evolutionary perspective, the nature of the legume-rhizobial symbiotic interface has become progressively more intimate and complex. On the one hand, it incorporates novel aspects of cellular morphogenesis, in particular the infection thread and the symbiosome compartments. On the other hand, there is a precise system for suppression of host defense responses. As with the other forms of tip-growth observed in root hair cells and pollen tubes, growth of the infection thread is due to the targeted deposition of cell wall and cell membrane material at the apex. However, there is an important distinction. Whereas the extension of root hairs and pollen tubes is driven by cell turgor, the driving force behind the growth of an infection thread is the synthesis and directed secretion of the extracellular matrix material into the lumen of the infection thread and the division of bacteria inside. Polar growth of the infection thread requires a high degree of coordination between many cellular and extracellular processes, including calcium dynamics, apoplastic reactive oxygen species, the cytoskeleton, and vesicular transport.The cell wall that surrounds the infection thread is a dynamic structure that performs both structural and defense functions. While the localization and distribution of the main pectins of the infection thread wall have been recently studied , the rolExperiments designed to investigate these questions will provide new insights into how an infection thread grows. Furthermore, these studies will help to elucidate the more general patterns of plant cell wall development during growth and differentiation. New probes targeting cell wall components will permit a more detailed analysis of the biochemistry and biomechanics of the cell wall of the infection thread. A major problem in studying the infection thread is that it is a dynamic and continually changing system. Its structure at an early stage in a root hair or root cortical cell may be very different from that in a host cell embedded deep in the tissue of a maturing nodule. These differences could affect the remodelling of the cell wall . The chaRhizobium is the relationship between intercellular and intracellular modes of infection. An interesting model has recently been developed based on interaction of L. japonicus with different strains capable of infecting the host plant either via intracellular or via intercellular modes [Rhizobium infection and endomycorrhizal symbiosis [One of the intriguing questions regarding the infection of legume tissues by ar modes . Furtherar modes  and the ymbiosis ,283 clea"}
+{"text": "The need for widely usable bioactive lipids and natural antioxidants continues to grow. Methods used for oil extraction may alter minor constituents that have functional properties and contribute to oil stability. In recent years, consumer demand for cold pressed oils as an alternative to conventional products has increased. This is probably due to the perception of these oils as natural, nutritional, and safe food products with better nutritive and healthy properties.Cold pressed oils are easy to obtain. The process does not involve heat treatment or solvent extraction. Therefore, the cold pressing technique results in a product that is free of organic solvents. Mechanical pressing does not require much energy and meets well the needs of small- and medium-sized companies. Cold pressed oils are promoted as specialty oils and are usually available on the market at a higher price. Cold pressed oil products are reported to contain pro- and anti-oxidative compounds.In recent years, consumption of cold pressed oils has been increasing. The international market already includes numerous cold pressed oils . However, due to high prices of cold pressed oils, they are exposed to adulteration with cheaper and lower-quality refined oils of vegetal origin. Several strategies have been applied to monitor and control the authenticity of cold pressed oils for reasons of both human health and demand, as well as concern for controlling product quality in industrial laboratories. Among these, new frontiers are open toward the use of rapid analytical methods and chemometrics.This Research Topic aims to report on recent advances in cold pressed oils as specialty oils, mainly focusing on their composition, physicochemical characteristics, organoleptic attributes, nutritional quality, oxidative stability, food applications, and functional and health-promoting traits.The main explored topics are as follows: (i) evaluation procedures and quality attributes , yield, quality parameter, and physicochemical properties, sensory and color attributes; (ii) compounds of nutritional and nutraceutical characters in cold pressed oils; (iii) oxidative stability; (iv) impact of cold technologies: extracting and processing parameters; (v) storage and shelf life evaluation; (vi) adulteration and authenticity; (vii) cold pressed cake as functional and value-added product; (viii) consumer perception; (ix) health benefits; (x) safety aspects and potential adverse reaction evaluations; (xi) conventional and innovative fields of applications; (xii) food composition database and dedicated databases; (xiii) regulatory challenges; and (xiv) current and future applications and research needs.Fratianni et al. described the fatty acid composition, antioxidant, and in vitro anti-inflammatory activity of five cold pressed Prunus seed oils and their anti-biofilm effect on pathogenic bacteria. Another example is given by Wang et al. who compared the antioxidant and antibacterial activities of camellia oil from Hainan with camellia oil from Guangxi, olive oil, and peanut oil. Gharby and Charrouf reviewed the chemical composition, extraction process, and quality control of argan oil.Tsao et al. on the application of OXITEST for the prediction of shelf-lives of selected cold pressed oils. Results first revealed that the UFA (Unsaturated Fatty Acid) portion was partially correlated with the shelf-lives of selected expeller-pressed seed oils as estimated by the OXITEST. Benincasa et al. reported the identification of phenolic compounds in spray-dried olive mill wastewater; the study showed that the use of dehumidified air as a drying medium, with the addition of maltodextrin, results an effective way to obtain a phenol-rich powder.It is worth mentioning the study of All the authors listed made a substantial, direct, and intellectual contribution to the article and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Pneumonia is the leading cause of under-five child deaths globally and in Bangladesh. Hypoxaemia or low (<90%) oxygen concentration in the arterial blood is one of the strongest predictors of child mortality from pneumonia and other acute respiratory infections. Since 2014, the World Health Organization recommends using pulse oximetry devices in Integrated Management of Childhood Illness (IMCI) services , but it was not routinely used in most health facilities in Bangladesh until 2018. This paper describes the stakeholder engagement process embedded in an implementation research study to influence national policy and programmes to introduce pulse oximetry in routine IMCI services in Bangladesh.Based on literature review and expert consultations, we developed a conceptual framework, which guided the planning and implementation of a 4-step stakeholder engagement process. Desk review, key informant interviews, consultative workshops and onsite demonstration were the key methods to involve and engage a wide range of stakeholders. In the first step, a comprehensive desk review and key informant interviews were conducted to identify stakeholder organisations and scored them based on their power and interest levels regarding IMCI implementation in Bangladesh. In the second step, two national level, two district level and five sub-district level sensitisation workshops were organised to orient all stakeholder organisations having high power or high interest regarding the importance of using pulse oximetry for pneumonia assessment and classification. In the third step, national and district level high power-high interest stakeholder organisations were involved in developing a joint action plan for introducing pulse oximetry in routine IMCI services. In the fourth step, led by a formal working group under the leadership of the Ministry of Health, we updated the national IMCI implementation package, including all guidelines, training manuals, services registers and referral forms in English and Bangla. Subsequently, we demonstrated its use in real-life settings involving various levels of  stakeholders and worked alongside the government leaders towards carefully resuming activities despite the COVID-19 pandemic.Our engagement process contributed to the national decision to introduce pulse oximetry in routine child health services and update the national IMCI implementation package demonstrating country ownership, government leadership and multi-partner involvement, which are steppingstones towards scalability and sustainability. However, our experience clearly delineates that stakeholder engagement is a context-driven, time-consuming, resource-intensive, iterative, mercurial process that demands meticulous planning, prioritisation, inclusiveness, and adaptability. It is also influenced by the expertise, experience and positionality of the facilitating organization.Our experience has demonstrated the value and potential of the approach that we adopted for stakeholder engagement. However, the approach needs to be conceptualised coupled with the allocation of adequate resources and time commitment to implement it effectively. Pneumonia is the leading cause of childhood mortality, accounting for around 16% of 5.2 million under-five deaths globally . In addi2) [Hypoxaemia, defined by low (<90%) oxygen saturation in the arterial blood, is common among children with pneumonia and is one of the strongest predictors of mortality caused by pneumonia and other lower acute respiratory tract infections -12. Earl2) . In high2) . However2) -16.Bangladesh was one of the sites in the Multi-Country Evaluation of IMCI coordinated by WHO . Based oEngaging a wide range of stakeholders is a key step for ensuring the relevance of research studies and improving the utilisation of research findings in local health systems settings ,25. As aStep-1:Identification and prioritisation of stakeholders for subsequent sensitisation, involvement and engagement. Step-2:Sensitising the majority of stakeholders regarding the context, rationale, importance and process of the proposed research to build interest, confidence and trust. Step-3:Involving key stakeholders in planning, ensuring agreement regarding the implementation process and solidifying commitments for shared responsibilities. Step-4:Engaging the stakeholders at every stage of design, development, implementation and evaluation.Stakeholders are individuals, organisations, or communities that can influence or are affected by a project's process and outcomes, research or policy . StakehoIn Bangladesh, health services are provided by two directorates under the Ministry of Health and Family Welfare. They are the Directorate General of Health Services and Directorate General of Family Planning. Each directorate has a dedicated programme for child health, which manages the child health services, including IMCI services in Bangladesh. In addition, several other programmes are also related to child health services. Besides the government programmes, several development partners and professional societies support the Government of Bangladesh in managing and implementing child health services, including IMCI services. The National Newborn Health and IMCI Programme under the Directorate General of Health Services of the Ministry of Health and Family Welfare is responsible for coordinating with all partners and ensuring the delivery of IMCI services in Bangladesh.First, comprehensive desk review was conducted on IMCI related documents and eight key informant interviews to identify national and district level stakeholders related to IMCI implementation in Bangladesh , district level family planning manager , all (five) sub-district health managers  and all sub-district level family planning managers . In addition, managers from the National Newborn Health and IMCI Programme attended the event. They presented the importance of identifying hypoxaemia in pneumonia assessment and classification and discussed the operational feasibility of introducing pulse oximetry in real-life settings.Subsequently, we organised five such sensitisation workshops in each sub-district, with 14 participants in each workshop, including IMCI service providers such as doctors, nurses and paramedics  and their respective supervisors. For each sub-district level workshop, the respective sub-district health managers gave the keynote presentation.Lastly, 71 enlisted national and local level NGOs actively working in Kushtia district were identified, of which 21 had strong community acceptance and health-related activities. We organised another sensitisation workshop with representatives from these 21 organisations. The district health manager gave the keynote presentation, and all the sub-district managers contributed to the subsequent discussions. All participating NGO partners agreed to raise awareness regarding pneumonia and hypoxaemia and promote appropriate care-seeking practices in the local communities.Like the previous sensitisation phase, we organised workshops at the national, district, and sub-district levels to involve stakeholder organisations representing the high power and high-interest group, discuss a strategy, and develop a mutually agreed plan for introducing pulse oximetry in routine IMCI services of Bangladesh. At the national level, the Programme Manager of the National Newborn Health and IMCI Programme chaired the workshop. All the participants discussed and developed a national action plan to introduce pulse oximetry in routine IMCI services in Bangladesh. The roles of all key stakeholder organisations were clarified and defined in this comprehensive action plan. The National Newborn Health and IMCI Programme agreed to lead this process, and WHO, UNICEF, Save the Children and icddr,b committed to providing technical assistance and implementation support. The National Newborn Health and IMCI Programme also decided to update the National IMCI Implementation Package based on the updated WHO recommendations, including introducing pulse oximetry in pneumonia assessment and classification. This National IMCI Implementation Package consists of guidelines, registers, referral forms, reporting forms, job aids, monitoring checklist, list of essential equipment, medicine and logistics and training manuals. It was also decided that the development partners will be initially responsible for the procurement and supply of pulse oximetry devices in some demonstration facilities. The National Newborn Health and IMCI Programme declared to include pulse oximeters in the national procurement plan if the demonstration is successful.A small working group was formed with technical experts from each stakeholder organisation with high power-high interest to update the implementation package. The small working group recommended assessing the feasibility of implementing the updated implementation package (including pulse oximetry) through an implementation research study. icddr,b volunteered to lead this implementation research study in Kushtia district. The working group members identified the evidence gaps and finalised key research questions for the implementation research through a consultative process. Further, at this workshop, it was also decided that the experience gathered through this implementation research would assist the Government of Bangladesh in taking evidence-based decisions for a national scale-up.A planning workshop was organised in Kushtia district headquarter, which was chaired by the district health manager and attended by all sub-district health managers. At this workshop, the participating stakeholders decided that the implementation research would include all types of health facilities providing IMCI services. Hence, the Kushtia District Hospital, all five Upazila Health Complexes and one Union Health and Family Welfare Centre from each sub-district were selected as demonstration sites for the implementation research study. A district-level action plan was jointly developed outlining the roles of different district level stakeholders and the key activities, including training, distribution of pulse oximetry device, revised IMCI registers, referral forms and reporting forms, supportive supervision visits and assessments. Subsequently, a planning workshop was organised in each sub-district with the supervisors of IMCI service providers. The respective sub-district managers chaired this event and shared guidance on developing a sub-district level implementation plan for introducing pulse oximetry. A preparatory and planning meeting followed in each demonstration facility with IMCI service providers, respective supervisors, and facility managers, leading to the finalisation of a facility-specific implementation plan (with a timeline) to introduce pulse oximetry minimally impacting their routine services and existing practices.In this stage, National Newborn Health and IMCI Programme and icddr,b worked closely with the high power-high interest stakeholders on the following steps to update the IMCI implementation package and implement it in the demonstration facilities in real-life settings.Formation of a working group: The Line Director of Maternal, Newborn, Child and Adolescent Health Programme of the Ministry of Health and Family Welfare formed a small working group with 13 IMCI experts representing the five high power-high interest groups to review and update the National IMCI Implementation Package  and shared their feedback.Afterwards, the updated training package was pre-tested among IMCI service providers, including doctors, nurses, and paramedics. The National Newborn Health and IMCI Programme organised the training, the national master trainers facilitated the sessions, and icddr,b conducted assessment and evaluations. A total of 40 doctors, 91 nurses and 67 paramedics received training in 10 batches. We collected feedback from the IMCI providers on the National IMCI Implementation Package, including the training manuals, registers, job aids and reporting forms. Finalisation of the National IMCI Implementation Package: Following the training workshops with master trainers and IMCI service providers, the working group updated the national implementation package based on their feedback. Then National Newborn Technical Working Committee for Newborn Health and the National IMCI Technical Working Committee, the highest-level technical committees regarding newborn and child health in Bangladesh, reviewed the updated package and shared feedback. The National IMCI Implementation Package was finalised after incorporating their feedback and inputs.Incorporation of the use of pulse oximetry and hypoxaemia in the national health service records: Over a series of six consultative workshops, the National Newborn Health and IMCI Programme convinced the Management Information System (MIS) department of the Directorate General of Health Services to update the national IMCI dataset  based on the updated monthly reporting form (including updated pneumonia classification and hypoxaemia status). icddr,b provided technical assistant and secretarial support in organising these events.Involving national-level stakeholders in the implementation research: A co-design and co-creation approach was adopted to develop the implementation research protocol. icddr,b led the process and engaged the National Newborn Health and IMCI Programme and other stakeholder organisations representing the high-power and high-interest group to prioritise research questions and finalise the research design, data collection methods, and data collection instruments. Additionally, one of the Deputy Programme Managers of the National Newborn Health and IMCI Programme joined the research team as a Co-Investigator.Local-level involvement in the implementation research: A district advisory committee was formed to guide the implementation research study in Kushtia-district. The district health manager chaired the committee, and all the sub-district level health managers were included as members. First, the advisory committee was oriented regarding the research questions and study design. Later, the committee developed a macro plan to introduce pulse oximetry in the selected facilities and conduct quantitative and qualitative assessments as outlined in the research protocol. Subsequently, a planning meeting was organised in each facility with respective IMCI service providers and their supervisors to review the macro plan and develop a micro plan with a timeline. A dissemination meeting was organised with the district advisory committee after the baseline and each round of data collection. icddr,b provided technical assistance and secretarial support throughout the process.Resuming study activities during the COVID-19 pandemic: The Government of Bangladesh declared a nationwide lockdown in the last week of March 2020 to prevent the surge of COVID-19 infections and deaths. Unfortunately, all the implementation research-related activities were suspended due to the strict restrictions imposed during the lockdown period. In August 2020, the government started to reduce restrictions. The National Newborn Health and IMCI Programme issued an official order to resume the research activities with appropriate infection prevention and control measures. A series of meetings were organised in Kushtia-district with the district health manager and sub-district health managers to resume the suspended activities and revise the implementation plan (both macro plan and micro plan) accordingly.Desk Review: A total of 37 documents with approximately 2507 pages were reviewed to identify the stakeholders and update the National IMCI Implementation Package. It required around 120 person-days of effort by medical graduates with basic IMCI training.Resource person interview: A total of eight interviews and a group discussion was organised with IMCI experts to identify and prioritise the stakeholder organisations, requiring ten person-hours for interviewing and an additional 30 person-hours for transcribing and analysis.Document development, editing and formatting: The National IMCI Implementation Package containing 24 documents with 1685 pages were updated, which required approximately 140 person-days of reviewing, editing and formatting to prepare the final versions.Workshops: At the national level, 30 workshops were organised to sensitise (step 2), involve (step 3) and engage (step 4) the stakeholders, requiring approximately 416 person-days of involvement by IMCI experts and stakeholders. In addition, about 42 person-days of investment was needed from icddr,b for taking preparation and organising the events. Furthermore, around 30 person-days was required to prepare and approve the meeting notes for official documentation.At the district level, 45 meetings were organised, requiring approximately 183 person-days of involvement by IMCI service providers, 86 person-days by their clinical supervisors, and 101 person-days by district, sub-district and facility managers.Travel and transport: To sensitise (step 2), involve (step 3) and engage (step 4) stakeholders at the district level, extensive travel and transport were required. A total of 97 person-days of travel and transportation were needed from central-level staff and 312 person-days from local-level staff to organise and participate in the stakeholder engagement related eventsStep 1-Identify: This process began in October 2018 and continued till December 2018.Step 2- Sensitise: At the national level, the sensitisation process started in January 2019 and continued till the end of that year, while at the district level, the sensitisation activities went on from October 2019 till February 2020.Step-3-Involve: At the national level, the involvement process took place in June 2019 and at the district level, the process took place in March 2020.Step 4-Engage: The national-level engagement process started in June 2019 and ended in January 2021. The district-level engagement process began in December 2020 and ended in July 2021.2 assessment for improving pneumonia assessment, classification, and management. As a result, the Government of Bangladesh decided to introduce pulse oximetry in routine IMCI services in Bangladesh.The Government of Bangladesh and all the key stakeholders acknowledged the importance of identifying hypoxaemia through SpOThe National Newborn Health and IMCI Programme formed a national-level working committee with high power-high interest stakeholder organisations related to IMCI implementation in Bangladesh. This high-level working committee updated the National IMCI Implementation package including the chart booklet, register, referral form, reporting form, monitoring checklist and training manuals and incorporated specific recommendations to use pulse oximetry in relevant sections. Further, three hypoxaemia related indicators were included in the national IMCI data set in DHIS2. The Government of Bangladesh trained 4872 IMCI service providers from across the country based on the updated National IMCI Implementation Package.The Government of Bangladesh decided to scale up the use of pulse oximetry in routine IMCI services in a phased manner. As a result, the National Newborn Health and IMCI Programme revised its existing plan and decided to procure pulse oximetry devices for the IMCI corners in approximately 200 Upazila health complexes. In the next phase, the National Newborn Health and IMCI Programme is planning to procure pulse oximetry devices for the remaining of the IMCI corners in the Upazila Health Complexes (approximately 250) and other union-level facilities (approximately 5000). Additionally, UNICEF has committed to support the Government of Bangladesh\u2019s national scale-up endeavour by introducing pulse oximetry in eight districts. icddr,b has committed to support in two districts, and Save the Children in one district. Moreover, WHO has supported the government by printing the updated IMCI registers for all facilities..We present the key learnings from the stakeholder engagement activities based on the SWOT analysis approach ,37. The Context-driven: Our implementation research study primarily aimed to influence the national policy and programmes. Based on the context and prior experience, we adopted a framework with four steps for stakeholder engagement and prioritised only the high power-high interest stakeholder organisations. The framework guided the whole process and all related activities, and the prioritisation helped maximise the use of limited resources. Therefore, any implementation research study aiming to engage stakeholders need to adapt and modify the framework based on the objective and context.Country ownership, government leadership and multi-partner involvement: The Government of Bangladesh demonstrated leadership in forming and leading the national working group, chairing the workshops, developing the strategic plans, and bringing multiple partners together for building national consensus on introducing pulse oximetry in routine IMCI services in Bangladesh. All the major non-government organisations and development partners related to IMCI implementation in Bangladesh committed to using the updated National IMCI Implementation Package in their respective health system strengthening initiatives.Expertise, experience and relationships of the facilitating organisation: The technical expertise and experience of icddr,b in the introduction and scale-up of IMCI services in Bangladesh and pre-existing relationships with other high power-high interest stakeholder organisations substantially contributed to the identification, sensitisation, involvement, and engagement of other high power-high interest stakeholder organisations. Moreover, the communication, and organising skills of icddr,b contributed to facilitating the stakeholder engagement process efficiently. Therefore, the positionality of implementing organisations needs to be considered before adopting a particular approach for engaging stakeholders.Time-consuming: It took more than two and a half years to implement the stakeholder engagement related activities and achieve the objective of incorporating the use of pulse oximetry in national policy and programme. Numerous workshops were organised based on the availability of all high power-high interest stakeholders, which was difficult considering their busy schedules, especially during ongoing COVID-19 pandemic. Extensive deskwork and preparations were necessary before organising these workshops, which called for several days or weeks of preparation. Hence, engaging the stakeholders effectively is time-consuming and will require patience and commitment by the facilitating organisation.Resource-intensive: The initial stage involved reviewing a significant number of documents to identify stakeholders and update the National IMCI Implementation Package, which required a substantial amount of person-time involvement of project staff. In addition, organising workshops at national, district and sub-district levels required numerous person-days of involvement from IMCI experts, managers, service providers and project staff. It also required extensive travelling by the project staff. Since stakeholder engagement is a resource-intensive process, it is important to have a planning and specific budgetary allocation for stakeholder engagement at the outset of any project.Iterative: Reviewing, editing, and formatting several lengthy documents were essential for updating the National IMCI Implementation Package. Some of these documents required numerous rounds of editing and formatting to address and incorporate the feedback of all the stakeholders across the national, district and sub-district levels before finalisation. For example, IMCI chart booklet had 23 rounds of iteration and IMCI registers had 19 rounds of iteration before finalisation. Hence, the facilitating organisation need to have dedication and attention to details to effectively steer the stakeholder engagement process.Mercurial: The power-interest matrix of the stakeholders does not stay static and could change at any given time. For example, during the engagement process, one of the stakeholders with high power and low interest unexpectedly turned into a high power-high interest actor and started posing a risk to the process. Therefore, some part of the stakeholder engagement process was adapted based on the agenda of that particular stakeholder. In addition, during the stakeholder engagement process, there can be changes in leadership positions. For example, the National Newborn Health and IMCI Programme manager was changed twice, and the district health manager was changed three times during the engagement process, owing to administrative transfers. It required investing additional time and efforts to sensitise the new stakeholders and garnering their active buy-in to introduce pulse oximetry in routine IMCI services. Hence, stakeholder engagement is an adaptive process and will require flexibility in revising, updating and changing the plan based on the context and circumstances.COVID-19 pandemic- general awareness regarding hypoxaemia: The COVID-19 pandemic has raised awareness among the health care provider and care receiver for using pulse oximetry in measuring the oxygen saturation level and assessing the severity of pneumonia. This opportunity has facilitated the implementation process more easily.COVID-19 Pandemic- lockdown and restrictions: The stakeholder engagement related activities and plans required extensive modification and revision due to the COVID-19 pandemic. During the first lockdown period between March and August 2020, all project-related activities were suspended. The team advocated with the National Newborn Health and IMCI Programme to resume project activities after the COVID-19 related restrictions were eased.Other national and programme priorities: The engagement process and project-related activities were also interrupted by unanticipated events, such as implementing the national Measles-Rubella campaign, which kept the district and sub-district health managers and IMCI service providers occupied during February and March 2021. Therefore, the potential impact of an emerging threat on the overall outcome and timeline of the stakeholder engagement process must be acknowledged and should have the flexibility of modifying the plan to take course corrective measures.Our experience has demonstrated the value and potential of the approach that we adopted for stakeholder engagement. Our engagement process contributed to the national decision to introduce pulse oximetry in routine IMCI services and update the national implementation package, which are steppingstones towards scalability and sustainability. However, our experience also reveals that stakeholder engagement is a context-driven, time-consuming, resource-intensive, iterative, mercurial process that demands planning, prioritisation, inclusiveness and adaptability. It is also influenced by the expertise, experience and positionality of the facilitating organisation. However, the approach needs to be conceptualised coupled with the allocation of adequate resources and time commitment to replicate its impact and implement it effectively in other settings."}
+{"text": "In 2010, the University of Utah Gerontology Interdisciplinary Program first offered GERON 5240/6240: Aging and the Arts. This course was developed to enrich program curricula by addressing a gap in content specific to the arts and humanities. The purpose of this presentation is to focus on identifying the opportunities and challenges experienced teaching this course over the past decade. Opportunities will highlight competency mapping, internal and external partnerships, the benefits of bridging disciplines, and innovation in teaching and problem-solving. Challenges experienced include addressing various needs , tuition differentials, and varying levels of enrollment. A stand-alone course is one method of increasing humanities, arts, and cultural gerontology within curricula. It has the potential of enhancing student interest in gerontology while also demonstrating how the arts and humanities can improve work across disciplines."}
+{"text": "Ukraine has an extensive experience on creating and maintaining National Medical Networks.A variety of examples include:The National Register of the persons suffered from the Chernobyl disaster: Net of the Sanitary and Epidemiological Service of the Ministry of Health.The National Medical Network for monitoring oncology patients: this links Regional Oncology Dispensaries with Institute of Oncology.Ukraine has a membership to \"EuroTransplant\" and National Medical Network in this effort has linked Regional Centres with the National Informational Centre on Transplantation.Regional databases from Regional Venereologic Dispensaries, used for monitoring diseases, have been extended to include cases of AIDS.The Telemedical Cardiology Centre in Kharkiv, with trans-telephone ECG. All equipment, including portable ECG amplifiers and modems, is developed in the Ukraine.Teleconsulting Medical Centres, in Kiev, for the analysis of MRI images.The centre \"Patholog\", in which oncologists - cytologists carry out work.The Ukrainian Association of Computer Medicine (UACM) has created (http: //www.uacm.cit-a.net) WWW- server , which has become a nucleus of the Corporate medical network permitting to exchange the information to 78 institutional members and over 900 individual members. The UACM has created affiliate Web - EHTO-UKRAINE server on national language (http://www.ehto-ukr.cit-ua.net). Ukraine took part in the \"Telemedecine Medical Care Networks within the Baltic Region\" programme. Also, Ukraine started the Ukrainian- American project on the monitoring of birth defects.The National Telematics Medical Corporate Network 'UkrMedNet' is under construction on the basis of existing the HealthNet and some other autonomous medical networks, with the newest of telecommunication technologies, used in Internet. This project also envisages the integration of all existing separate medical nets, universities and R&D institutes into one 'UkrMedNet', as well as the creation of a common informational space and its integration into the European one.'UkrMedNet' has a three-level structure. The first level consists of the National and four Inter-Regional nodes, which have a similar structure and service 5 or 6 Districts. All Inter- Regional nodes are directly connected to: a) National node and b) one of Inter-Regional ones. Such connection layout ensures the \"doubling\" of the connections of the first level nodes. The second level is formed on the basis of the District Healthcare Departments. Nodes are connected to the nearest Inter- Regional node. They ensure connection to the net of medical organisations located in the district. The third level is Regional nodes and end users. They are connected to the District nodes.The goal of the \"UkrMed- Net' is to supply an infrastructure for all medical networks and Telemedicine Centres in Ukraine. It accelerates the integration of the country into the world informational space."}
+{"text": "Occupational statements on death certificates of 2,457 males aged 25-64 who died from bladder cancer in selected coastal and estaurine regions of England and Wales during 1965-1980 were studied. Excess mortality was found for deck and engine room crew of ships, railway workers, electrical and electronic workers, shoemakers and repairers, and tobacco workers. An excess of cases also occurred among food workers, particularly those employed in the bread and flour confectionary industry or involved in the extraction of animal and vegetable oils and fats. Use of a job-exposure matrix revealed elevated risk for occupations in which most workers were exposed to paints and pigments, benzene and cutting oils."}
+{"text": "During 1982\u20131992, the Maternal and Child Health Family Planning (MCH-FP) Extension Project  of International Centre for Diarrhoeal Disease Research, Bangladesh , in partnership with the Ministry of Health and Family Welfare (MoHFW) of the Government of Bangladesh (GoB), implemented a series of interventions in Sirajganj Sadar sub-district of Sirajganj district. These interventions were aimed at improving the planning mechanisms and for reviewing the problem-solving processes to build an effective monitoring system of the interventions at the local level of the overall system of the MOHFW, GoB.The interventions included development and testing of innovative solutions in service-delivery, provision of door-step injectables, and strengthening of the management information system (MIS). The impact of an in-built monitoring system on the overall performance was assessed during the period from June 1995 to December 1996, after the withdrawal of the interventions in 1992.The results of the assessment showed that Family Welfare Assistants (FWAs) increased household-visits within the last two months, and there was a higher use of service-delivery points even after the withdrawal of the interventions. The results of the cluster surveys, conducted in 1996, showed that the selected indicators of health and family-planning services were higher than those reported by the Bangladesh Demographic and Health Survey (BDHS) 1996\u20131997. During June 1995-December, 1996, the contraceptive prevalence rate (CPR) increased by 13 percentage points (i.e. from 40% to 53%). Compared to the national CPR (49%), this increase was statistically significant (p < 0.05).The in-built monitoring systems, including effective MIS, accompanied by rapid assessments and review of performance by the programme managers, have potentials to improve family planning performance in low-performing areas. Inadequate basic management skill among health teams at the implementation level is one of the main constraints in providing primary healthcare (PHC) in developing countries . LiteratPathfinder International, a Rural Service Delivery Partnership (RSDP), was a part of the National Integrated Population and Health Programme (NIPHP) of the MoHFW, GoB. The RSDP collaborated with the University of North Carolina (UNC) at Chapel Hill, United States of America (USA), to introduce a local-level monitoring system through an action-plan intervention for strengthening team work and developing the competence of health and family-planning managers and frontline supervisors at the levels of sub-district and below. The RSDP complemented the government efforts to increase the accessibility and use of the MCH-FP programme by rural families in the context of the NIPHP . The actIn Bangladesh, the delivery of health and family planning services for 300 000 rural populations is coordinated from the sub-district (upazila), the lowest administrative structure with substantial responsibilities for planning and implementation of all development activities in rural areas . The DirThe MCH-FP Extension Project , in collaboration with the MoHFW introduced a local-level monitoring system during 1982\u20131992 in Sirajganj for improving the management capability where the programme managers had reviewed the progress of the performance of service providers on a few selected indicators from monthly service statistics using the MIS in various meetings. The FWA Register was designed as a longitudinal record keeping system for the FWA. Under the leadership of MIS Unit of the DFP, it provided a foundation for the monitoring of FWA activities through supervisory field-visits [The study was conducted to assess the impact of an in-built monitoring system on the sustainability of a few selected indicators of MCH-FP after the withdrawal of the interventions.A cross-sectional study design was followed. Both quantitative and qualitative methods were used for collecting data on selected indicators. A rapid survey methodology was developed to provide administrators with quick information on problems faced at the community level. The cluster sampling procedure has been used throughout the world in immunization surveys. The EPI (Expanded Programme on Immunization) 30-cluster rapid assessment survey was used as the quantitative method for collecting data on selected indicators. Multi-stage, simple random sampling was used \u2013 one in July 1995 and the other one in December 1996 \u2013 in order to minimize the sample size required. A list of villages of all unions (one sub-district consist 8\u201310 unions having average population of 25 000\u201330 000) was used as a sampling frame. Twenty villages were selected, covering all the unions of the sub-district. Selection of the number of villages from each union was proportional to the size of the union. A cluster of 30 MWRA from each village was selected that yielded a sample of 600 MWRA for interview. Female interviewers received seven days' intensive training on data collection using various research methods and techniques. They interviewed 600 MWRA under the supervision of a field research officer who had more than seven years' experience in field research work and had supervisory and monitoring skills. The interviewer asked the responsible person of the sample village to select a primary school or mosque/temple/church/pagoda (a place of worship). One household from one specific corner of the worship place or primary school was selected as an index household. The corner was specified beforehand and was constant for all the selected villages. Interviews of neighbouring permanent residence MWRA, following the one in the index household, continued until interviews of 30 such MWRA were completed. Female respondents were selected because they were the major recipients of reproductive healthcare services. The major indicators of health and family-planning were: (a) awareness about services available from FWAs; (b) frequency of contacts with FWAs; (c) number of desired children; (d) unmet contraceptive need; (e) accessibility to H&FWCs and SCs; and (f) use of contraceptive methods. Design effect was used for establishing that 210 children (i.e. 30 clusters with 7 children per cluster) are necessary for a survey. In this study, the required sample was doubled to avoid the design effect.The qualitative methods were used for assessing the routine activities of 66 FWAs. The routine activities observed included: (a) administration of injectables at the door-step and (b) record-keeping. Two research officers made three days' observations on the activities of each FWA in a year during their home- visits. A structured observation checklist was used. At the facility level, three categories of meetings were observed, namely:(i) fortnightly meetings of FWAs and their immediate supervisor and paramedics at H&FWC to review the performance of the previous month and current stock of contraceptives;(ii) monthly mid-level supervisory meetings and local managers to review the union-wise monthly performance, discuss the field problems, and made decision to solve those problems; and(iii) monthly salary-day meetings of field and union-level service providers, supervisors, and local managers to review the MCH-FP-related performance of field workers and paramedics. A structured observation checklist was used for collecting information on 34 meeting proceedings. Content analysis of meeting minutes was done, and reports from observers of meetings were analyzed manually.Univariate analysis was conducted using SPSS (version 10) to determine different indicators of health and family-planning use. Chi-square test was employed to observe any significant differences in proportions between the first cluster survey (referent) and the second cluster survey.In absence of division-wise selected indicators, we used the national survey data of BDHS 1996\u20131997 to compare the selected indicators of health and family planning service use with the cluster survey or rapid assessment survey.Data of 1995 and 1996 showed a consistent pattern of adherence to the recommended protocol for administration of injectables . Other than salary day meetings, formalities in terms of the recording of the agenda and post-discussion resolutions of issues after discussion were maintained in the majority of the meetings. The monthly performance of maternal child health and family planning indicators were reviewed in the majority (70%) of the meetings.Table The remarkable improvement in programme performance as reported in the present study is attributable to two major factors: first, a series of on-the-job-training activities were conducted on the record keeping system, screening checklists of family planning methods, administering injectable contraceptive, management of side-effects of contraceptive methods, supervision and monitoring, etc, that updated the existing knowledge and facilitated close interaction between the trainers and the trainees. Maintenance of the active learning process, use of feedback mechanisms, and job related hands-on training were instrumental. The FWAs almost universally maintained the recommended protocol for administering injectables even after the withdrawal of the interventions. The high coverage of routine activities of the FWAs, such as record-keeping and screening of contraceptive methods, was also sustained after the withdrawal of the interventions.Second, conducting regular performance review meetings was very powerful. The feedback system in those meetings was ensured to evolve close interaction between field workers and supervisors. The local manager had the opportunity to identify any problems and explore appropriate solutions. This led to efficient management of the programme and advance planning. In the meetings, high-performing workers were praised, and poor-performing workers were offered assistance. This process was found to be useful for monitoring individual performance and aggregated outputs at the union levels, which finally created positive attitude and improved motivation for the entire team. Thus, overall improvement of the programme performance took place. Another influential factor was the independent local survey, which was indicator-based and that ultimately motivated the programme managers to fix the target, organize field activities, and generally improve. The FWAs who provided services at the door step motivated their clients to avail of better-quality services at the fixed site centres. The higher use of SC and H&FWC services was an indicator of improved field activities.The in-built review system was crucial. The district and local managers reviewed the results of the rapid assessment survey. These reviews assisted the sub-district managers and front-line supervisors in identifying the weakness of the programme and develop field operational strategies. The local managers then instructed the front-line supervisors to strengthen their monitoring and supervision activities (to improve the work of field-level workers), which were reflected in the survey results. This was an effect of the managers' motivation and positive efforts towards the improvement of the programme.In a review paper on performance monitoring for family planning, experiences of different countries have been highlighted . IndonesThe present study succeeded in using a package of strong MIS systems, performance review meetings having feedback mechanism, in-service training, and ad-hoc rapid assessment surveys to improve the performance of the programme, particularly in the low-performing areas of Bangladesh."}
+{"text": "Conflict and war have long been recognized as determinants of infectious disease risk. Re-emergence of epidemic sleeping sickness in sub-Saharan Africa since the 1970s has coincided with extensive civil conflict in affected regions. Sleeping sickness incidence has placed increasing pressure on the health resources of countries already burdened by malaria, HIV/AIDS, and tuberculosis. In areas of Sudan, the Democratic Republic of the Congo, and Angola, sleeping sickness occurs in epidemic proportions, and is the first or second greatest cause of mortality in some areas, ahead of HIV/AIDS. In Uganda, there is evidence of increasing spread and establishment of new foci in central districts. Conflict is an important determinant of sleeping sickness outbreaks, and has contributed to disease resurgence. This paper presents a review and characterization of the processes by which conflict has contributed to the occurrence of sleeping sickness in Africa. Conflict contributes to disease risk by affecting the transmission potential of sleeping sickness via economic impacts, degradation of health systems and services, internal displacement of populations, regional insecurity, and reduced access for humanitarian support. Particular focus is given to the case of sleeping sickness in south-eastern Uganda, where incidence increase is expected to continue. Disease intervention is constrained in regions with high insecurity; in these areas, political stabilization, localized deployment of health resources, increased administrative integration and national capacity are required to mitigate incidence. Conflict-related variables should be explicitly integrated into risk mapping and prioritization of targeted sleeping sickness research and mitigation initiatives. Sleeping sickness re-emerged in Uganda in the 1970s, and continues to pose a public health and economic burden . SimilarTrypanosoma spp.), a protozoan parasitic disease affecting humans, livestock, and a large number of sylvatic species in much of sub-Saharan Africa , trypanosomiasis represents an important public health and economic burden in sub-Saharan Africa  is a public health problem in places where a research infrastructure can hardly exist\"  p. 147].7.14,61] Prioritization of high-risk areas for sleeping sickness and trypanosomiasis control should explicitly integrate the occurrence of conflict and its impacts on transmission risk. The occurrence of conflict and presence of large number of internally displaced people can be integrated into current risk maps in addition to land cover, tsetse habitat, and livestock distributions. An understanding of areas where conflict may contribute to increased disease risk can guide prioritization of continent-wide as well as national mitigation programs.Conflict is an important determinant of sleeping sickness outbreaks in sub-Saharan Africa. In Uganda, the two sub-species of sleeping sickness can be expected to merge in the absence of immediate and targeted intervention in central districts; the presence of both diseases in one region will dramatically increase burden of disease as well as the complexity and difficultly of subsequent control initiatives. Control and prevention of sleeping sickness by national and international authorities should explicitly integrate consideration of conflict and its impacts into mapping and targeting of regions for priority intervention. Prevention and control campaigns should be assessed and evaluated against the ability of the initiative to address, mitigate, or alleviate the conflict-related drivers of disease risk. The occurrence of sleeping sickness in conflict-affected areas will severely constrain the success and cost-benefit evaluations of continent-wide tsetse eradication campaigns. Prevention of sleeping sickness risk in affected sub-Saharan African countries requires increased international focus on development of administrative policy, capacity, integration, and infrastructure to implement localized control strategies.HIV/AIDS Human Immuno-deficiency Virus/Acquired Immuno-deficiency VirusDRC Democratic Republic of the CongoWHO World Health OrganizationIDP Internally Displaced PersonsThe author(s) declare that they have no competing interests.LBF conceived, designed, researched, and prepared the manuscript."}
+{"text": "Detailed data and statistics per each morphological site of various digestive neoplasms were obtained for the period 1976-87 from the Vaud Cancer Registry datafile, a population-based cancer registration scheme covering about 530,000 inhabitants from the French-speaking part of Switzerland. Tabulations presented include absolute number of cases , percent distributions, age-standardised rates, sex ratios and 5-year survival. The report has essentially a descriptive value, and should be viewed as a contribution towards quantification, in a well surveilled population of the West-central part of Europe, of the proportional distribution of digestive neoplasms by morphological type, and corresponding incidence and survival rates. Among the points deserving specific attention, there are the elevated frequency of upper digestive tract cancers, the very high male-to-female ratios for squamous cell carcinomas, adenocarcinomas of the oesophagus and hepatocellular carcinomas of the liver, the female excesses in infiltrating carcinoids of the colon, transitional and squamous cell carcinomas of the rectum and adenocarcinomas of the gallbladder, and the crossover in male-to-female ratio in squamous cell carcinoma along the digestive tract (i.e. from 6.0 at the level of the mouth/pharynx to 0.5 in the rectum). As concerns survival, rates were higher for lymphomas and sarcomas than for carcinomas in oral cavity and stomach, similar for carcinoids and carcinomas in the small bowel (about 35% at 5 years), as well as for colon (34%) and rectal (37%) cancers. Some of the findings, such as the higher survival of carcinomas arising from polyps in the colon and rectum, or the higher proportion of cholangiocellular and combined cholangio- and hepatocellular carcinomas in females than in males find plausible prognostic or aetiologic correlates, but others, such as the large proportions of squamous and transitional cell cancers of the rectum in females are more difficult to explain. These and several other indications emerging from careful examination of the data herein presented underline the interest of morphological analyses of digestive tract cancers."}
+{"text": "EHP. Korach is director of the Environmental Diseases and Medicine Program, chief of the Laboratory of Reproductive and Developmental Toxicology, and chief of the Receptor Biology Section at the NIEHS. He received his PhD in endocrinology from the Medical College of Georgia in 1974. Korach\u2019s areas of research include the basic mechanisms of estrogen hormone action in reproductive tract and bone tissues, with an application toward understanding how hormonally active environmental estrogens influence physiological processes. He is the past editor-in-chief of Endocrinology, the flagship journal of the American Endocrine Society. Korach will guide EHP until a permanent editor-in-chief is selected.With this issue, Kenneth S. Korach becomes interim editor-in-chief of"}
+{"text": "The behavioral and social sciences offer insights into the comprehensive understanding of human health, including disease etiology and treatment, and the promotion of health and well-being. To encourage the investigation of the impact of social and behavioral factors on health and disease, the participating institutes and centers invite qualified researchers to submit research grant applications on methodology and measurement in the behavioral and social sciences. Methodology and measurement encompass research design, data collection techniques, measurement, and data analysis techniques. The goal is to encourage research that will improve the quality and scientific power of data collected in the behavioral and social sciences, relevant to the missions of the NIH Institutes and Centers (ICs). Research that addresses methodology and measurement issues in diverse populations, issues in studying sensitive behaviors, issues of ethics in research, issues related to confidential data and the protection of research subjects, and issues in developing interdisciplinary, multimethod, and multilevel approaches to behavioral and social science research are particularly encouraged, as are approaches that integrate behavioral and social science research with biomedical, physical, or computational science research or engineering. Applicants are encouraged to contact the Program Contact for Scientific/Research issues (see \u201cAgency Contacts\u201d) of the IC that most closely matches their research focus to determine the IC\u2019s interest in the research topic.This Funding Opportunity Announcement (FOA) encourages applications addressing four general areas of methodology and measurement research in the social and behavioral sciences. These areas include research design, data collection techniques, measurement, and data analysis. Within the broad spectrum of research defined by these areas, applicants are encouraged (but are not required) to consider studies that address one or more of the following key issues: 1) methodology and measurement issues in developing innovative interdisciplinary, multimethod, and multilevel research designs for use in behavioral and social science research, with emphasis on developing new technologies and addressing the analytical complexities associated with the integration of behavioral, social, and biological data; 2) methodology and measurement issues in research relating to diverse populations, e.g., populations that are distinctive by virtue of age, gender, sexual orientation, ethnicity, culture, including culture-specific medical systems, socioeconomic status, literacy, language, or disability; 3) methodology and measurement issues in studying how dramatic changes in economic, social, environmental, physical, or political context affect human health and well-being, including developing new methods if older ones are no longer valid in the face of significant changes in populations and societies over the last several decades; 4) methodology and measurement issues in studying potentially sensitive behaviors, such as sexual behavior and abortion, and covert or illegal behaviors such as drug use, abuse, and violence; 5) methodology and measurement issues concerning ethics in research, with emphasis on the topics of informed consent, assessment of risk and benefit, and selection and retention of subjects, and ensuring subjects\u2019 confidentiality.Multidisciplinary and interdisciplinary approaches are strongly encouraged. Potential applicants are urged to explore the ideas and methods developed in social science and behavioral fields other than their own and to consider the development and integration of behavioral and social science measures with those of the biomedical, physical, or computational sciences or engineering. Consulting relevant literature and collaborating with colleagues from other disciplines may provide important opportunities for cross-fertilization in developing improved methodology and measurement.Research design determines how well a research plan can accomplish stated purposes and test hypotheses. Research design encompasses many decisions including the sampling plan; selection of appropriate study designs, methods, procedures and measures; and assuring confidence in the study\u2019s internal and external validity. An innovative sample design or sampling frame can be the centerpiece of a research design. Examples of topics within research design include the following: 1) conceptual design strategies appropriate for the study of culture in the context of health; culture may include ethnic group, professional affiliation , culturally specific medical system, or interaction of multiple subcultures within a health-related context; 2) designs to improve causal inference from nonexperimental and quasi-experimental research and natural experiments; 3) research to improve the efficacy of multilevel designs; 4) methods for improving the design and evaluation of community-based research and intervention trials ; 5) conceptual, methodological, and ethical issues in designing studies that use different sources of information; e.g., studies comparing self- and third-party reports ; 6) designs to improve and compare various approaches to economic analysis, including cost analysis, cost-effectiveness, cost\u2013benefit, and conjoint analysis for improving decision-making in health policy and health care systems; 7) designs to improve the inclusion of underrepresented groups in research, e.g., women; children; the elderly; ethnic and racial minorities; sexual minority groups; geographically isolated groups; mentally or physically impaired or disabled populations; immigrants and refugees; and language minority populations; 8) designs that allow for the meaningful integration of biological, behavioral, and social science data ; 9) ethical considerations in research design including issues of informed consent, assessment of risk and benefit, confidentiality, and selection and retention of subjects; 10) methods for archiving and disseminating complex data sets, especially longitudinal data sets, data sets including social network data or geographic identifiers so the identities of study participants are protected and so the data sets can be used by other investigators; 11) alternatives to randomized, controlled trials, including studies to investigate the feasibility, validity, and benefit of incorporating subject  preference in intervention design and outcomes assessment; issues regarding blinding; and design of placebo and other control groups; 12) methods to improve the design of clinical research for enhancing quality of patient care ; 13) designs that allow assessment of the active components of multilevel interventions; 14) methodology to ensure the integrity and consistency of data obtained in multisite studies.Developing and validating research instruments and questions are vitally important for collecting reliable information, and have obvious impact on data validity and reliability. For example, health care practitioners must collect reliable reports of symptoms from their patients to accurately diagnose disease. In addition, data collection instruments and questions developed for a particular age, gender, or cultural group may not be valid for other groups. For example, a dietary history questionnaire developed for Americans of European descent may not contain the foods commonly eaten by Americans of African, Asian, or Hispanic descent. Specific consideration of the processes underlying potential bias in self-report data collection remains a measurement issue: perceptual, cognitive, cultural, demographic, motivational, and affective influences on self-report data. Finally, continued improvement and innovation in developing and validating data collection instruments are important for all types of research settings, ranging from the clinical interview and observational study to the survey. Examples of measurement issues include: 1) development and refinement of measures, instruments, or surveys used in behavioral and social science research that fill a gap in research needs, with an eye toward developing and validating core sets of items to reduce redundancy across research projects; 2) instrument design, calibration, and refinement; instrument design issues in studying age, gender, and culture, including methods of studying culture and self-identification of race/ethnicity, as well as the psychometric properties underlying data collection instruments; 3) measurement issues in using technology such as computer-assisted data collection, web-based technology and personal digital assistants; 4) direct and indirect measurement of attitudes, values, self-esteem, and other psychological variables; this includes examination of economic values, including willingness-to-pay, as a means of evaluating benefits; 5) development of instruments that assess degree of change, and rate and variable direction of change; 6) development of instruments or technologies that measure behavior objectively or reduce self-report burden; 7) development of objective measures of components of the built environment that ffect health and of measures for assessing interactions between people and the built environment; 8) methodology to objectively measure the cultural and social environment, including aspects of the community environment that influence health; 9) methodology for validating geographic information system (GIS) data obtained from different sources; 10) methodology to measure fidelity to behavioral interventions, including the development or adaptation of behavioral and interpersonal measures to better assess the fidelity of community-based and multisite behavioral interventions; 11) development of measures of self-management of chronic illness and disability and of family management of chronic illness and disability among children; 12) development of behavioral and social science measures that can be used for efficient data collection in clinical practice\u2013based research networks; 13) methodology to capture the behaviors of health care providers in clinical settings; 14) methods that incorporate relevant biological, physical, or computational measures into behavioral and social science research; 15) development of measures for evaluating quality of life near the end of life in a variety of populations, and refinement of existing measures through longitudinal studies and across various disease states.Data collection techniques are the tools and procedures scientists use for implementing research designs and obtaining measurements. Methods for collecting research data have an important impact on data validity and reliability. For example, studies have suggested that use of self-administered instruments can facilitate the reporting of sensitive or illegal behaviors. Innovative methodologies can also open the door to the collection of new or more complex types of data by behavioral scientists. For example, recent developments in computer-assisted interviewing have permitted more complex question sequences in survey research and the development of hand-held \u201cbeepers\u201d programmed for data entry have permitted the collection of time-specific data on activities such as cigarette smoking. In addition, implicit measures have allowed researchers to examine processes of which people themselves have been unaware. Continued improvement and innovation in data collection methods are important for all types of research settings, including clinical interviews, observational studies, participatory action research, and surveys. In addition, more research is needed to understand how various methods work in diverse populations, and how they can be modified to address the specific needs of populations. Potential topics within data collection techniques include, but are not limited to the following: 1) methods to improve data collection in surveys and epidemiologic self-report studies, ethnographic and other qualitative studies, participatory action research methods, and multimethod studies; this may include new approaches to instrument design and manipulation of method and mode of data collection, length, setting, and interpersonal factors in data collection exchanges; 2) methods to develop innovative gold standards to assess and improve the accuracy of self-reports, in the absence of health record checks ; 3) new methods for qualitative research; methods for validating narrative or text-based analyses; techniques for validating and replicating findings from qualitative research, including collection strategies, development of coding protocols, and techniques that facilitate the integration and validation of qualitative and quantitative measurement; 4) methods to reduce sampling, survey, and item nonresponse bias in research studies, including techniques to improve the coverage of relevant populations in household surveys, to increase the voluntary participation of eligible subjects, to reduce attrition in longitudinal studies and clinical trials, and to improve response rates on sensitive items; 5) techniques for collecting contextual data  and for operationalizing the boundaries of particular social, economic, physical, and cultural contexts; 6) improved technologies for data collection, including automated collection and reporting technologies, such as computer-based data collection and computer adaptive methodology, and research on how the method/mode used to collect data affects the quality of the data in a variety of populations and substantive areas; 7) data collection techniques that address the needs of special populations  and that address how these methods affect data quality and completeness across diverse populations; 8) issues surrounding the collection of self-report data from different settings , different collection methods , from different parties , and the use of implicit and explicit measures; 9) development of better data collection techniques for studies that involve populations which are small or difficult to access, such as the terminally ill.Analytic methods encompass the concepts and techniques used in analyzing data and interpreting and reporting results, to improve estimation, hypothesis testing, and causal modeling based on scientific data. Challenges include developing techniques that distinguish underlying regularities from the noise created by variability and imprecise measurement; developing causal inferences from nonexperimental data; improving both the internal validity and external validity  of measures and studies; and developing appropriate analytic techniques for use with new kinds of data and new approaches to behavioral and social science research, and meaningful integration of behavioral and social science data with those obtained from the biological, physical, computational sciences, or engineering. Examples of topics within analytic methods include: 1) research to improve the analysis of longitudinal data, in particular, the analysis of correlated data, the modeling of different sources of error, and techniques for dealing with missing data at various levels of aggregation; 2) methods for improving the analysis of multicultural; community-based multilevel intervention trials ; 3) methodological research to improve the analysis of complex survey data, including the statistical modeling of nonresponse and other survey errors; 4) analytic issues in innovative techniques for improving causal inference from nonexperimental research; 5) analytic methods for integrating evidence from qualitative and quantitative research, such as research examining the complex relationships among multiple sources of information on a single construct ; 6) analytic methods that appropriately model social structures, social processes, and spatial relationships such as social networks, social influence, diffusion, and contextual effects; 7) statistical procedures for accurately estimating multilevel models; 8) development of novel mathematical and computational techniques for analyzing and modeling behavioral and social processes; 9) methods for improving the analysis of nonindependent data, such as data examining processes in interactions between couples, families, or other groups; 10) developing sophisticated analytic methods that take into account complex probability designs used in epidemiological research; 11) analytical methods to incorporate geographic and built environment measures into behavioral and social science research; 12) expanding current psychometric methodologies to handle the types of data collected in behavioral and social science research, e.g., multidimensional data, shorter scales, nonnormal score distributions, mixed response format, and complex survey structure; 13) methods for the detection and analysis of nonlinear or discontinuous changes in response to treatment.http://www.nichd.nih.gov/publications/pubs/diverse_voices.htm).Potential applicants specifically concerned with research regarding the inclusion of language minorities should see the 2001 report on the conference \u201cDiverse Voices\u2014The Inclusion of Language-Minority Populations in National Studies: Challenges and Opportunities,\u201d sponsored by National Institute on Aging, the National Institute of Child Health and Human Development, and the National Center on Minority Health and Health Disparities (see http://grants.nih.gov/grants/guide/pa-files/PA-05-029.html). However, the research agenda also included detailed recommendations relating to needed methodological research related to the social and cultural dimensions of health. Potential applicants are encouraged to consult this report (see http://obssr.od.nih.gov/Conf_Wkshp/higherlevel/conference.html).In June 2000 the Office of Behavioral and Social Sciences Research held a conference \u201cToward Higher Levels of Analysis: Progress and Promise in Research on Social and Cultural Dimensions of Health.\u201d After the conference, a panel of scientists developed an ambitious research agenda on the social and cultural dimensions of health. A program announcement based on the panel\u2019s recommendations for substantive research has been issued by OBSSR  encouragement of research intended to develop methodological, evaluative, and analytic tools for studying stigma and its consequences with respect to health, and 2) development, evaluation, and optimization of interventions to prevent or mitigate the negative effects of stigma and discrimination on health. In both areas the social and cultural dimensions of stigma and its manifestations should be included. Applicants are encouraged to refer to the stigma conference website: In addition, the following reports may be useful as general references on behavioral and social sciences research as it relates to health:http://www.nap.edu/catalog/10002.html).New Horizons in Health: An Integrative Approach (2001) .Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences (2001) .From Neurons to Neighborhoods: The Science of Early Childhood Development (2000) .Bridging Disciplines in the Brain, Behavioral, and Clinical Sciences (2000) . Frank Kessel, Patricia Rosenfield and Norman Anderson, Editors. New York:Oxford University Press.http://www.nap.edu/books/030907259X/html/).Rebuilding the Unity of Health and the Environment (2001) (http://www.nap.edu/books/0309071992/html/).Cells and Surveys: Should Biological Measures be Included in Social Science Research? (2001) .Qualitative Methods in Health Research: Opportunities and Considerations in Application and Review (2001) .Applicants may also wish to consult the following report on the protection of human subjects in behavioral and social sciences research: Protecting Participants and Facilitating Social and Behavioral Sciences Research (2003) (http://grants.nih.gov/grants/funding/modular/modular.htm).This FOA will use the NIH Research Project Grant (R01) award mechanism. The applicant will be solely responsible for planning, directing, and executing the proposed project. This FOA uses \u201cJust-in-Time\u201d information concepts. It also uses the modular as well as the nonmodular budget formats , use the PHS398 Modular Budget component provided in the SF424 (R&R) Application Package and SF424 (R&R) Application Guide .U.S. applicants requesting more than $250,000 in annual direct costs and all foreign applicants must complete and submit budget requests using the Research & Related Budget component found in the application package for this FOA. See NOT-OD-06-096 23 August 2006. Applicants must download the SF424 (R&R) application forms and the SF424 (R&R) Application Guide for this FOA through Grants.gov/Apply.Note: Only the forms package directly attached to a specific FOA can be used. You will not be able to use any other SF424 (R&R) forms , although some of the \u201cAttachment\u201d files may be useable for more than one FOA.GrantsInfo@nih.gov.For further assistance, contact GrantsInfo: 301-435-0714, (telecommunications for the hearing impaired: TTY 301-451-0088), or by e-mail:http://grants.nih.gov/grants/funding/sub-missionschedule.htm. The complete version of this PA is available at http://grants.nih.gov/grants/guide/pa-files/PA-07-060.html.The application submission dates for this PA are available at http://grants.nih.gov/grants/guide/pa-files/PA-07-060.html.Contacts: The complete list of agency contacts is available at Reference: PA-07-060."}
+{"text": "This paper investigates the wealth of medicinal plants used by the Apatani tribe of Arunachal Pradesh. Apatani have traditionally settled in seven villages in the Ziro valley of Lower Subansiri district of Arunachal Pradesh in the Eastern Himalayan region of India. The present study has resulted in the documentation of 158 medicinal plant species used by the Apatani group of villages. These medicinal plant species were distributed across 73 families and 124 genera. Asteraceae was the most dominant family  of medicinal plants, followed by Zingiberaceae, Solanaceae, Lamiaceae and Araceae. For curing ailments, the use of aboveground plant parts was higher (80%) than the belowground plant parts in the Apatani group of villages. Of the aboveground plant parts, leaf was used in the majority of cases (56 species), followed by fruit. Different belowground plant forms such as root, tuber, rhizome, bulb and pseudo-bulb were used by Apatani as a medicine. About 52 types of ailments were cured by using these 158 medicinal plant species. The results of this study are further discussed in the changing socio-economic contexts. Tribal communities are mainly the forest dwellers who have accumulated a rich knowledge on the uses of various forests and forest products over the centuries. India possesses a total of 427 tribal communities, of these more than 130 major tribal communities live in North East India, which is comprised of the 8 states Meghalaya, Mizoram, Manipur, Tripura, Sikkim, Assam, Nagaland and Arunachal Pradesh. The major tribal communities of the North East India have been categorized into sub-tribes and if these sub-tribes are taken into account the total number of tribal groups reaches up to 300. In general, the tribes of North East India have been categorized into two broad ethnic communities, such as the Khasi and the Jaintia tribe of Meghalaya, who belong to 'Monkhemar' culture of Austoic dialect, and the rest of the tribal groups are basically Mongoloid, who belongs to Tibeto-Burman subfamily of Tibeto-Chinese group  was used as medicine. These 158 medicinal plant species were used in curing about 52 types of ailments, of which the highest numbers of plant species (40 species) were used for the treatment of gastrointestinal disorders such as indigestion and constipation. About 19 medicinal plant species were used in curing cough and cold, and 15 medicinal plant species were used for healing cuts and wounds  than the belowground plant parts. Of the aboveground plant parts, leaf was used in the majority of cases 56 species), followed by fruits. Different belowground plant forms such as root, tuber, rhizome, bulb and pseudo-bulb were also used by the Apatani as a source of curing ailments Table . The who6 speciesPrevious studies carried out in North East India have reported 41 medicinal plant species used by the Apatani of Arunachal Pradesh . However"}
+{"text": "Electrodiagnostic medicine is a specific branch of medicine used by specialist physicians in the field of physical medicine and rehabilitation and/or neurology to diagnose, prognosticate and plan treatment options of peripheral nerve lesions. This meeting was hold to discuss multidisciplinary approaches to this common and important topic in the medical field.The Department of Physical Medicine, Rehabilitation and Electrodiagnosis of Shaheed Beheshti Medical University in collaboration with the Iranian Society of Physical Medicine and Rehabilitation (ISPMR) held the 1 Electrodiagnostic medicine is a specific branch of medicine used by specialist physicians in the field of physical medicine and rehabilitation and/or neurology to diagnose, prognosticate and plan treatment options of peripheral nerve lesions. This meeting was hold to discuss multidisciplinary approaches to this common and important topic in the medical field.The 1st Congress of Electrodiagnostic Medicine in Peripheral Nerve Lesions was held in Tehran,Iran organized by the Department of Physical Medicine, Rehabilitation and Electrodiagnosis of Shaheed Beheshti Medical University in collaboration with the Iranian Society of Physical Medicine and Rehabilitation  and rehabilitation measures of peripheral nerve lesions. Twenty leaders in the field of peripheral nerve including: physiatrists, neurosurgeons, neurologists, orthopedists, hand surgeons, vascular surgeons, and plastic and reconstructive surgeons were invited as key lecturers to present the updates about peripheral nerves in upper and lower limbs. In addition to oral presentations, 2 panel discussions, \"Carpal Tunnel Syndrome\" and \"Thoracic Outlet Syndrome,\" were organized to discuss these challenging topics. About 160 participitants from diverse disciplines including physiatry, orthopedics, neurosurgery, hand surgery, neurology, physiotherapy, occupational therapy and also general practitioners participated in the congress. Seyed Mansoor Rayegani, M.D., associate professor of PM&R, was responsible as the secretary of the congress.The additional files contain the slides from the invited lectures and panel discussions [see additional file Slides from the invited lectures and panel discussions. Compressed PDFs of 15 presentations and 2 panel discussions during the conference.Click here for file"}
+{"text": "Guide to Community Preventive Services. Initial foci for the Cancer Prevention and Control Research Network's research work groups include projects to increase screening for breast, cervical, and colorectal cancers; to promote informed decision making for prostate cancer screening; and to validate educational materials developed for low-literacy populations.The Cancer Prevention and Control Research Network is a national network recently established to focus on developing new interventions and disseminating and translating proven interventions into practice to reduce cancer burden and disparities, especially among minority and medically underserved populations. Jointly funded by the Centers for Disease Control and Prevention and the National Cancer Institute, the Cancer Prevention and Control Research Network consists of sites administered through Prevention Research Centers funded by the Centers for Disease Control and Prevention. The five sites are located in Kentucky, Massachusetts, South Carolina, Texas, Washington State, and West Virginia. The Cancer Prevention and Control Research Network's intervention areas include primary prevention of cancer through healthy eating, physical activity, sun avoidance, tobacco control, and early detection of cancer through screening. The Cancer Prevention and Control Research Network uses the methods of community-based participatory research and seeks to build on the cancer-relevant systematic reviews of the  The Cancer Prevention and Control Research Network (CPCRN) is a federally funded, national network of academic, public health, and community partnerships that work together to reduce the burden of cancer, especially among those disproportionately affected. The CPCRN was initiated in October 2002, with funding from the Centers for Disease Control and Prevention (CDC) and the National Cancer Institute (NCI) as part of their effort to more effectively translate research into practice. The five CPCRN sites were selected through a competition among the CDC-funded Prevention Research Centers (PRCs). Three sites are operated by individual universities: the Universities of South Carolina, Texas-Houston, and Washington. Two sites are operated jointly by pairs of universities: Boston and Harvard Universities; and the University of Kentucky and West Virginia University. This paper introduces the CPCRN; outlines the context for its creation, along with its goals, structure, and operations; and summarizes progress to date.Guide to Community Preventive Services (Community Guide)  , suggesty Guide) , with itThe creation of the CPCRN is, in part, a response to the growing magnitude of and persistent disparities in cancer burden. Cancer is the second leading cause of death in the United States as well as a leading cause of morbidity. Cancer accounts for one of every four deaths , and, inDisparities in cancer incidence and mortality persist. For example, the incidence of cervical cancer is four times as high among Vietnamese women as it is among other Asian American and Pacific Islander women . OverallThose disparities are the result of a complex array of economic, social, and cultural factors, and these factors are also reflected in disparities in preventive behaviors. For example, smoking prevalence is now highest among American Indian 38.6%) and Alaska Native (27.4%) men and women 8.6% and . ScreeniThe CPCRN embraces the principles of CBPR  as core The need for the CPCRN is highlighted by recent reports of both progress against cancer and remaining challenges in disseminating and translating knowledge gained from efficacy and effectiveness research. During the late 1990s, death rates from the four leading cancers \u2014 lung, colorectal, breast, and prostate \u2014 declined nationally and in most states . Two impBoth the NCI and the CDC have given high priority to bridging the dissemination gap. The NCI's Translating Research into Improved Outcomes program has identified the dearth of dissemination research as a key impediment to the adoption of evidence-based cancer control intervention. The program has also identified the need to expand research/practice partnerships as critical to both the adoption and evaluation of evidence-based interventions in public health and clinical practice settings .Community Guide, developed under the aegis of an independent, nonfederal Task Force on Community Preventive Services and maintained at the CDC, has provided a partial summary of the state of the art of community-based cancer prevention and control. Based on a systematic review of the literature, the Community Guide currently recommends 14 interventions aimed at increasing physical activity, reducing exposure to and use of tobacco, and reducing exposure to ultraviolet light (The et light  10-13).-13.CommuThe CDC has a ready dissemination outlet for proven intervention strategies through its state-based cancer prevention and control programs: the National Breast and Cervical Cancer Early Detection Program and the Comprehensive Cancer Control Program.The prior investment of the CDC in its PRC program facilitated the creation of the CPCRN by providing a well-established administrative home for each of the five sites. In 1984, Congress created the PRC program at the CDC by authorizing the funding of academic health centers for innovative research and demonstration projects to prevent chronic disease. In 1986, the CDC established three PRCs for two years. Since then, the funding period has increased to five years, and the number of centers has grown to 28, which are located in 25 states.Three aspects of the PRC program strengthen the ability of the participating CPCRN sites to design, implement, and evaluate cancer prevention research with immediate application to public health practice. First, the PRC peer-review mechanism involves researchers experienced with CBPR. The peer review process provides assurance that applications are scientifically sound and that the research conducted is of practical use to communities. Second, the program's focus on CBPR enhances the likelihood that the PRCs will evaluate acceptable and sustainable community-based interventions. Partnerships and collaborations of PRCs with various entities  increase the likelihood that PRCs will produce evaluations of interventions that are likely to be translated and sustained. Third, research conducted among the most disadvantaged and underserved populations in the nation provides the PRCs with the opportunity to evaluate the external validity of interventions among diverse populations, including the rural poor of Appalachia, African Americans in South Carolina, public housing residents in Boston, residents of the U.S.-Mexico border, and loggers and pulp-mill workers in Washington State.The overall goal for the CPCRN is to conduct community-based cancer prevention and control intervention and dissemination research that extends the knowledge base, addresses critical gaps, and leads to adoption, replication, implementation, and dissemination of successful programs in communities.Community Guide by conducting site-specific and multisite intervention and dissemination research. The four specific research areas include 1) research on the effectiveness of community-based interventions for which evidence is insufficient to justify a Community Guide recommendation; 2) research replicating Community Guide-recommended interventions in populations and settings where they have not been adequately evaluated; 3) research on how to disseminate and implement Community Guide-recommended interventions into communities by public health and community-based organizations; and 4) evaluation of community programs to determine their effectiveness.The CPCRN addresses gaps and builds on recommendations in the The initial funding of the CPCRN for a two-year period supported the development of both local network centers and the larger national network of the CPCRN sites. At both levels, expected outcomes are evidence of the networks' existence and viability, including mission and vision statements, short- and long-term objectives, and active working groups. Of special emphasis in the research arena are efforts to develop strong partnerships with communities bearing the greatest burden from cancer, where community-based participatory research projects are likely to contribute to the reduction and/or the elimination of disparities in cancer burden.The CPCRN is a national network of five sites, each of which is a local network of academic, community, and other organizations with an interest in cancer prevention and research. The work of the CPCRN is led by a Coordinating Center that organizes, among other things, cross-site work groups on research topics of mutual interest to the sites, the CDC, and the NCI. The six sections that follow describe the work of the Coordinating Center and of each of the five local sites.The University of Kentucky and West Virginia University share the coordinating center role for the CPCRN. The Coordinating Center guides discussions on developing research tools for community interventions in cancer prevention and control, organizes collaborative activities with CPCRN members and their partners, fosters relationships among CPCRN members and national/state/local partners to ensure that CPCRN objectives are being achieved, and provides leadership in developing and managing the CPCRN operational structure.Specific activities include 1) developing and implementing a plan and system for effective communication among CPCRN centers; 2) implementing a collaborative planning process resulting in a seven-year plan for CPCRN research, dissemination, and evaluation; 3) implementing processes and procedures for encouraging PRCs to develop collaborative cancer prevention and control research projects; and 4) ensuring that external evaluation is conducted and is focused on the Coordinating Center's performance.The site based at the University of Washington is the Alliance for Reducing Cancer, Northwest . The mission of the ARC NW is to increase primary-preventive and early-detection behaviors to prevent and control cancer in the Puget Sound region, Washington State, and the Pacific Northwest. ARC NW is a collaborative effort among the University of Washington PRC, the American Cancer Society Great West Division; Fred Hutchinson Cancer Research Center; Group Health Cooperative of Puget Sound, a health maintenance organization; Public Health Seattle and King County, a local health department; the Puget Sound Neighborhood Health Centers, an organization of several community health centers in the region; Qualis Health, the Medicare quality improvement organization for Alaska, Idaho, and Washington State; the Washington State Department of Health; and the Weyerhaeuser Company, a large timber products company.Data from the Washington State Behavioral Risk Factor Surveillance System reveal underuse of primary-preventive and early-detection behaviors. In 2002, 21% of Washingtonians aged 18 or older smoked, 15% were physically inactive during leisure time, 76% ate inadequate quantities of fruits and vegetables, and 60% were overweight or obese. Also in 2002, among appropriate age groups, 45% had never received a flexible sigmoidoscopy or colonoscopy, 40% had never received a fecal occult blood test, 26% had not received a mammogram within two years, and 13% had not received a Papanicolaou (Pap) test within three years . Employers of all sizes nationwide reported in the same survey the following health insurance offerings: 80% covered mammograms, 79% covered Pap smears, 68% covered colorectal cancer screening, and 10% covered smoking cessation treatment that included both prescription medications and counseling.The ARC NW focuses on employed populations and on underserved communities. Five current activities include 1) a pilot test, involving the Weyerhaeuser Company, of a policy intervention to promote primary prevention and early detection via the worksite and employment-based health insurance; 2) development of a work site-based, team-oriented intervention to promote primary prevention and early detection of cancer; 3) a pilot test of a tool to increase informed decision making regarding prostate cancer screening; 4) assistance to the Washington State Department of Health in designing and evaluating its colorectal and prostate cancer screening programs; and 5) a review of the literature regarding the quality of life after treatment of prostate cancer.The site based at the University of Kentucky and West Virginia University is the Appalachian Cancer Research Consortium (ACRC). The target population of the ACRC includes the poor, medically underserved, and primarily rural residents of West Virginia and the 51 counties in Appalachian Kentucky. The two universities have a long history of collaboration, with extensive experience in working with communities throughout Appalachia on critical health issues.The U.S. Department of Health and Human Services considers the rural residents of Appalachia a \"special population\" . These rAs a result, West Virginia and the Appalachian regions of Kentucky have higher total cancer mortality rates than the national average ,19. BothThe ACRC focuses its efforts primarily on four cancer sites \u2014 lung, cervix, colorectal, and breast \u2014 with high disease burden, high behavioral risks, and high importance to community members in the region. Current activities of the ACRC include 1) developing a standardized assessment tool to evaluate readability, format, illustrations, and content of cancer prevention and control materials; 2) developing a protocol for colorectal cancer intervention for men and women aged 50 and older; and 3) conducting work site focus groups to identify barriers to colorectal screening for public employees aged 50 and older.The site based at the University of Texas (UT) is Latinos in a Network for Cancer Control . The mission of the LINCC is to reduce cancer-related health disparities among Hispanics/Latinos through community-based intervention, replication, and dissemination research. LINCC is a collaboration among 1) academic researchers at the UT School of Public Health, the UT M.D. Anderson Cancer Center, and the Baylor College of Medicine; 2) cancer control organizations, including the American Cancer Society, Cancer Information Service, Sanchez Cancer Center, Texas Cancer Council, Texas Comprehensive Cancer Coalition, and the Texas Department of Health; and 3) community-based organizations, including the Center for Border Health Research, Hispanic Health Coalition, Migrant Health Promotion, the National Center for Farmworker Health, and the Racial and Ethnic Approaches to Community Health coalition.colonias, unincorporated areas where environmental pollution, inadequate wastewater systems, and inadequate access to public drinking water compound socioeconomic influences on health behavior.Hispanics/Latinos in Texas account for approximately 25% of the total U.S. Hispanic population and 32% of the total Texas population . Along tHispanics in the United States experience higher incidence rates of cervical cancer per 100,000 (16.3) compared with non-Hispanics (7.8) and higher rates of mortality per 100,000 (3.7 compared with 2.6) . Along tpromotora-) based interventions for increasing cancer screening; and 4) research on the effectiveness of small media interventions to increase cancer screening. Another major focus of LINNC is to identify important factors and effective strategies for replicating and disseminating effective cancer control interventions in Hispanic communities. To this end, LINCC is conducting research on the replication and dissemination of an evidence-based, effective breast and cervical cancer screening intervention for Hispanic women: Cultivando la Salud  (Current LINCC activities include 1) new research on factors influencing colorectal cancer screening among Hispanics and the development of a community-based intervention to increase this screening; 2) research on informed decision making for prostate and colorectal cancer screening; 3) an evidence review and new research on lay health-worker-  .The site based at Boston and Harvard Universities is the Massachusetts Cancer Prevention Community Research Network (MCPCRN). The MCPCRN's mission is to foster a network of partnerships among cancer prevention researchers and community collaborators to support CBPR and to reduce social disparities in cancer risk. The MCPCRN is a collaboration of the Dana-Farber/Harvard Cancer Center Risk Reduction Program, the Harvard Prevention Research Center (HPRC), and the Boston University Prevention Research Center, with participation from the American Cancer Society's New England Division and the Massachusetts Cancer Control Coalition.Massachusetts has 6.5 million residents, 82% of whom are non-Hispanic white . In BostTo reduce these risks, the MCPCRN is approaching four priority community sectors: 1) schools and youth, 2) work sites and labor unions, 3) health care providers, 4) and low-income housing. Among schools and youth, the HPRC faculty direct a range of school and community-based research to improve youth nutrition and physical activity. Work sites and union partners include the Massachusetts AFL-CIO , the Massachusetts Coalition on Occupational Safety and Health, and individual local unions. Approximately 50 community health centers, many with strong ties to MCPCRN partners, facilitate access to health care providers in Massachusetts. The cost of housing in Massachusetts ranks third nationally; MCPCRN collaborators have identified more than 100 housing developments in Boston, Cambridge, and Somerville as potential partners.The MCPCRN's current objectives are to strengthen ties with communities and to conduct pilot and developmental studies as a foundation for future research. An upcoming conference on CBPR will emphasize engaging community organizations in cancer prevention research opportunities. Collaborative community efforts support Health Ambassadors for African American and African immigrant women in Boston and train tobacco advocates in housing developments. Developmental research includes a work site protocol to increase informed decision making for prostate cancer screening; materials to promote timely follow-up for abnormal mammograms among low-income, ethnic minority women; and methods to improve decision making on colorectal cancer screening. Pilot studies include an intervention aimed at weight reduction and increased physical activity through the Young Men's Christian Association and data collection in low-income housing developments.The site based at the University of South Carolina is the South Carolina Cancer Prevention and Control Research Network (SCCRN). The SCCRN was created to address the large and growing cancer burden among African Americans living in South Carolina. Its aim is to serve the entire state, with a population of just more than 4 million people, comprising an area of 31,000 square miles, and ranging from a long, broad coastal plain to the Piedmont region of southern Appalachia. The SCCRN builds on a strong network of existing programs that have coalesced recently in the South Carolina Cancer Alliance (SCCA), which consists of more than 750 institutional and individual members. The constituent bodies of the SCCA include the South Carolina Department of Health and Environmental Control and numerous grassroots organizations in addition to all academic, clinical care, and nongovernmental organizations with cancer-related missions.South Carolina is a relatively rural state, with very high >40%) African American representation in rural areas. It is also a poor state, where the average personal income is about 81% of the national average . Cancer 0% AfricaResearch at the SCCRN focuses on investigating ways to implement programs that complement existing cancer prevention and control infrastructure and through which we can anticipate risk reduction based on changes in individual and organizational behavior. The SCCRN focuses on breast, cervix, colorectal, oropharyngeal, prostate, and thoracic cancers. Ongoing projects include 1) investigation of small media approaches to increase breast and cervical cancer screening in low-income, rural women at highest risk of aggressive forms of these cancers, 2) research on informed decision making for prostate cancer screening and treatment, and 3) identification of geographical determinants of prostate cancer. Formative work includes 1) exploration of a community-based, statewide program of research in oral cancer precancerous lesions, 2) development of a mammography registry to understand patterns of use in low-income, predominantly African American populations, and 3) a church-based participatory intervention of lay health advocate-delivered cancer education and referral.In its first year of operation, the CPCRN has focused on a strategic planning process. From the beginning, community partners from each of the five sites have played strong and active roles in these processes. The strategic planning process produced vision and mission statements; a set of operating structures, principles, and plans; and four research work groups (see below).Communities and researchers working together to reduce the burden of cancer, especially among those disproportionately affected.The mission of the CPCRN is to conduct cancer prevention and control research that extends the knowledge base, addresses critical gaps, and leads to adoption, replication, implementation, diffusion, and evaluation of successful programs in communities.The CPCRN has developed a governing structure with a steering committee, guiding principles, and a seven-year strategic plan. Further information on each of these documents is available from: URL: http://ukprc.uky.edu/CPCRN/home.htm.The strategic planning process also suggested the development of work groups to initiate and carry out CPCRN research. The CPCRN currently has work groups focusing on 1) screening for breast and cervical cancers; 2) screening for colorectal cancer; 3) informed decision making and quality-of-life issues for prostate cancer screening and treatment; and 4) validating low-literacy educational and media materials. The work groups involve cross-site collaboration among scientists from the network centers and have established research goals .Community Guide. Finally, the location of the CPCRN within the CDC's PRC program enables its research findings to be easily translated, both nationally and locally, through long-existing partnerships with other prevention organizations.The CPCRN represents a new and innovative approach for addressing the challenge of identifying effective interventions and promoting dissemination and adoption of these interventions into communities. The CPCRN sites are geographically distributed across the nation, enhancing opportunities to develop community partnerships and to conduct community-based assessments, evaluation, and research with populations that represent nearly all types of medically underserved racial and ethnic groups in the continental United States. A strong commitment to CBPR increases the likelihood that CPCRN research will benefit the underserved communities in greatest need. The CPCRN also provides an opportunity for the sites to collaborate in addressing research gaps, including dissemination research and research translation, and to build on recommendations provided in the Fostering the optimal results from the CPCRN will require that its members maintain a delicate balance between coordinated, centralized efforts and retaining and enhancing the critical, locally responsive nature of its individual members. Within the tension between centralization and decentralization lies the exciting opportunity to create new strategies for successfully reducing the burden of cancer, especially among those disproportionately affected."}
+{"text": "This article is derived from a broad, twenty-year study of ethnobotany and folk medicine among pastoral nomads in the Middle East which took place from 1984 to 2004. The article presents examples of different treatments of diseases and disorders of the urinary tract carried out by healer herbalists. The preparation of remedies includes boiling infusions, extraction of dry or fresh leaves, flowers, seeds or whole plants. Some of these plants were used both as food and as medicine, by ingesting different parts of the plants, such as leaves, flowers, fruits, and so on, either while soft, cooked or dried. Data were collected by using unstructured interviews and by observation. These plants were identified by healers, patients, and university botanists. This paper identified eighty-five plant species, which belong to thirty-six families. The most representative families are: Asteraceae (8), Brassicaceae (6), Poaceae (6), Umbelliferae (6). Hadith) of the Prophet Muhammad on health and illness were systemized and became known as The Medicine of the Prophet  [Bayt al-hikmah , where scholars worked to translate them into Arabic [People have been using traditional medicine including ethno-botany for several thousand years. Ancient Arabic medicine was influenced by the ancient medicinal practices of Mesopotamia, Greece, Rome, Persia and India. The Greco-Roman system of medicine was developed based primarily on the writings of Hippocrates 460-360 B.C.), Dioscorides (circa 54 to 68 AD) and Galen 130\u2013201 AD). A combination of political and religious factors caused many Greek and Syriac-speaking scholars to move eastward to Persia and to establish centers of learning there. The city of Gundishapur in southwest Iran also became a center of learning, with a well-known medical school, in the sixth century AD [30\u2013201 AD60 B.C., The Canon of Medicine , the epitome of Islamic medicine. This work is the culmination and masterpiece of the Arab systematization of medical science, and includes many descriptions of the uses of medicinal plants [The Comprehensive Book on Medicine . The material written by al-Hawi is arranged under headings of different diseases, with separate sections on pharmacological topics. Ibn Sina's and al-Razi's works were later translated into Latin, and continued to influence medical science well into the nineteenth century [Within a century, Muslim physicians and scientists were writing original contributions to medical and botanical knowledge. One of the greatest and most famous Islamic doctors was Ibn Sina Avicenna 980\u20131037), author of l plants . Other A80\u20131037, The Compendium of Simple Drugs and Food , in which he described more than 1400 medicinal drugs, 300 of which had not previously been described, recording them alphabetically and discussing them with great clarity and detail. The work specified the names of herbs and remedies in various languages, thus providing a first class tool for the comparative research of medicinal plants. Other well-known physicians who wrote on plant uses were: Ibn Juljul, al-Ghafiqi, Ibn Bajjah, Ibn Samajun, and Abu'l-Hassan al-Andalusi [In the western part of the Islamic empire, the Umayyads of Andalus (Islamic Spain) made their capital at Cordoba. Areas of Cordoba and Granada became centers of learning. The richness and diversity of the flora of Spain were major contributing factors to the development of medical botany. The majority of physicians were herbalists and vice versa. The physician Ibn al-Baytar 1197\u20131248), authored Andalusi ,7. Tradi\u20131248, aujinns, and the negative effects of sorcery and/or witchcraft. The pastoral nomadic tribes depend on their local healers and traditional medicine as recorded in Table 1 . The paper is based on interviews with healers and patients. All the material was recorded in field logs, and some was tape-recorded. Unstructured interviews and the observation of participants were carried out in the informants' homes (120 men and 120 women), as well as in the homes of traditional healers (15 men and 10 women). Most of the healers were in the age range of forty to eighty. All the informants were married and over thirty. There were five males from each desert, and four female healers from the Negev, three from Sinai and three from Jordan. The informants were divided into two groups of forty men and forty women from each desert. The collected information was used to construct a list of the indigenous ethnobotanic medicine. Samples from all the plants were collected and identified by healers, patients and university botanists.This paper describes the treatment of diseases and disorders of the urinary tract by traditional herbalists among the pastoral nomadic Bedouin tribes in the Middle East. In this study, we identified eighty-five plant species, which belong to thirty-six families.The use of traditional medicine by the pastoral nomads, and the appeal to traditional healers over the course of many centuries established a psychological-therapeutic dependence of the pastoral nomadic tribes upon these healers. The rich variety of approaches employed by pastoral nomadic healers to treat disorders and diseases of the urinary tract is indicative of the depth and breadth of indigenous medicine practiced among the pastoral nomads in the twentieth century. The analysis of my collected data, together with the information extracted from the literature on herbal and ethnobotanic medicine of countries in the Middle East ,15,21,18Table 1 presents information on which parts of the plants are used and in what manner. It should be noted that for some plants, the uses in different countries of the Middle East are similar ,16. HoweThe many medicinal substances which we were able to identify as used in traditional medicine included various plants species. The analysis of the findings shows that the three deserts where I conducted my research served as the geographic origin of the medicinal substances. These plants were available because they grew as wild and cultivated plants and were part of the natural flora of these deserts. The pastoral nomads used these plants as food and as medicine, by eating different parts of the plants including the following: leaves, flowers, barks, stems, stalks, roots, rhizomes, bulbs, pith, fruit, corms, inflorescenes, shells, berries, seeds, stones/pits (in fruit), soft seed pods, buds, and shoots.It should be noted that wild desert plants also contain a host of other biologically active compounds besides nutrients. The physiological effects of these other compounds in relation to plant nutrients are not well known, but could affect nutrient and medical utilization or other functions. These topics are of relevance for future research in terms of improving our understanding of human nutritional and medical requirements of the pastoral nomads in the Middle East.Table 1: Urinary Diseases and Ethnobotany among Pastoral Nomads in the middle EastClick here for file"}
+{"text": "Perceptual decision-making tasks usually require subjects to recognize stimulus categories and select between different response alternatives. For example, in Go/No-go tasks, one has to respond to target stimuli and withhold responding to non-target stimuli. Accomplishing even just a single trial of such a task needs a complex sequence of functions (most of them executive) consisting, for example, in motor readiness, sustained attention, sensory processing, inhibitory control, conflict monitoring, stimulus-response mapping, context updating and, if any, error detection and awareness. In this context, the motor response reflects the behavioral outcome of the fast and proper interaction of the above-mentioned processes, and the response consistency (or variability) is often adopted as index of executive functioning.an inconsistent response is one of the most striking consequences of lesions to the cerebral cortex.\u201d More recently, consistent literature indicated response variability as an indirect index of top down control (Tamm et al., Nowadays, one challenge of the cognitive neuroscience is to understand how executive functions allow to make decisions. In fact, understanding decisional processes, and reasons of decision failure, would be helpful to clarify the executive dysfunctions of clinical conditions such as obsessive compulsive disorders, impulsivity, and addictions (typically intended as a failure of inhibition; Chamberlain et al., Even though it is evident the relationship between executive functioning and performance variability at group level (e.g., in the comparison between high- and low-level athletes in sport; Vestberg et al., Identification of neurophysiological correlates of executive functioning requires to investigate different cognitive abilities, which in part depend on the experimental paradigm: for example, in Stroop or sustained attention tasks (Demeter and Woldorff, When performing a decision-making task, the contribution of the PFC executive functions is manifested mainly through cognitive processes like top-down attentional control, maintenance of information in the short-term memory, ability to ignore distractors and focus on relevant features, and inhibition of the wrong schema and selection of the appropriate one. Since even one of these processes would be able to affect the inter- and intra-individual variability of the performance, they should be dissociated and investigated separately.Recent ERP studies described different pre-movement activities within the frontal cortex emerging both before and after the stimulus appearance in decisional tasks: as reviewed by Di Russo et al. , there iConcluding, there is a growing literature revealing the utility of the ERPs in the study of the executive functions of the prefrontal cortex. In fact, even if with a less spatial resolution of neuroimaging scans, recent ERP literature has proven to be able in overcoming some concerns such as the source localization and the presence of artifacts in the anterior sites, that in the past may have limited the EEG investigation of the frontal executive functioning. At the opposite, the background reviewed here on the functional roles and generators of prefrontal ERPs suggest the latter as a promising tool to foster a new-way approach in the neurocognitive study of the executive functions. In fact, the extensive review of Di Russo et al.  revealedRP: conception and writing of the work; FD: contribution to writing and conception of the work, critical revision of the text; RP and FD: approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Xenopus, the progressive determination of the head is an extremely complex process involving the activation and localized antagonism of a number of interdependent intracellular signaling pathways including the Wingless/Int-1 (Wnt), bone morphogenetic protein (BMP), and nodal-related pathways. The sequence of events that specify the head are: dorsal-ventral polarization and head organizer specification in the blastula; gastrulation; neural induction; and patterning of the anterior-posterior and dorsal-ventral neuraxes. Wnt signaling is required for the specification of the dorsal side initially but is then inhibited within the organizer once it has formed. Similarly, Wnt signaling is required along the length of the neural tube, but must be suppressed at its rostral end for normal brain development. Nodal signaling is also necessary for induction of the mesendoderm, but is subsequently suppressed in its dorsal-anterior extreme to specify head organizer. BMP signaling is required for ventral mesoderm and non-neural ectoderm, and must also be suppressed in the head organizer region and for the differentiation of the ventral midline of the neural tube. Thus, development of the head, and indeed the body plan in general, requires precisely timed and spatially restricted activation and repression of these signaling pathways.The head represents the most dorsal and anterior extent of the body axis. In"}
+{"text": "The degree to which comorbidities affect the diagnosis of prostate cancer is not clear. The purpose of this study was to determine how comorbidities affect the stage at which prostate cancer is diagnosed in elderly white and black men. We obtained data from the Surveillance, Epidemiology, and End Results program of the National Cancer Institute merged with Medicare claims data. For each patient, we estimated associations between stage of disease at diagnosis and each of the 27 comorbidities. The sample included 2,489 black and 2,587 white men with staged prostate cancer. Coronary artery disease, benign hypertension, and dyslipidemia reduced the odds of late-stage prostate cancer. A prior diagnosis of peripheral vascular disease, severe renal disease, or substance abuse increased the odds of being diagnosed with late-stage disease. The study shows some effect modification by race, particularly among white men with substance abuse, cardiac conduction disorders, and other neurologic conditions. The strongest predictors of late-stage prostate cancer diagnosis for both white and black men were age at diagnosis of at least 80 years and lack of PSA screening. Comorbidities do affect stage at diagnosis, although in different ways. Four hypotheses are discussed to explain these findings."}
+{"text": "To increase the timeliness of detection of human cases of the new variant ofCreutzfeldt-Jakob disease (vCJD) and to reduce the risk of transmission, theBrazilian Ministry of Health has established and standardized rules and controlmeasures. These include the definition of criteria for suspect cases, reporting,monitoring, and control measures for illness prevention and transmission.Guidelines to be used by the team of health care staff were published anddistributed to health workers. A detailed proposal for a simplified system ofsurveillance for prion diseases was developed and mandatory reportingintroduced. Additional effort is necessary to increase vCJD case detection, thusmaking it necessary to establish a partnership with health care services forbest identification of suspected cases and dissemination of information to allinvolved in the service dealing with vCJD investigation. Materials derived from ruminants are used as components inthe production of medicines, cosmetics and other health related products.3In view of the recent emergence of the new variant of Creutzfeldt-Jakob Disease (vCJD) inhumans, along with its social and economic repercussions, the Brazilian Ministry ofHealth devised specific activities directed toward prevention of CJD in 2001, bycommissioning a Task Force with the following purposes: to produce a report on CJD, tostandardize the criteria for suspect cases, to standardize notification and monitoring,to suggest measures to reduce the risk of disease transmission within the countrythrough health related products and procedure adopted by health care services, and toprovide useful information for the institutions concerned, as well as for thecommunity.3Examples of health related products made from materials of animal origin include:heparin, glycerine, griseofulvin, insulin, magnesium stearate, stearin and polysorbate.For import of such products, ANVISA  hasestablished several legal requirements based on the potential degree of infectivity ofanimal tissue being imported and the risk attributed to the country of origin, definedby the number of infected cases identified in the region.http://www.gov.br/vacalouca/index.htm.ANVISA has published two resolutions: RDC 3O5, of November 14, 2002 and RDC 68 datedMarch 28, 2003.4 The latter establishes conditions for importing, trading, and exposureto consumption of these products while the second measure clarifies rules and proceduresconcerning the proper processing of materials used in patients with clinical suspicionof CJD or vCJD; biosafety procedures for handling of patients, samples and othermaterials potentially contaminated with CJD or vCJD agent; procedures for the handlingof corpses; relative infectivity of the tissues and the body fluids of animals, as wellas definitions for those areas running a geographic risk of transmission. Information onthese measures is available at: In this same period, a few possible suspect CJD cases were reported to the HealthSurveillance Secretariat/Ministry of Health (SVS/MS). At this time however, there was nosurveillance protocol in place. Therefore, in December 2004, the Technical AdvisoryGroup for Prion Diseases (GTA \u2013 Prions) \u2013 was commissioned comprising members of the\u201cNational Health Regulatory Agency\u201d (ANVISA), and the Brazilian association ofneurologists (Academia Brasileira de Neurologia). GTA-Prions developed a detailedproposal for the establishment of the \u201cSimplified System for the Surveillance of PrionDiseases\u201d. The implementation of the system is currently directed towards the timelydiscovery of possible cases of Creutzfeldt-Jakob (CJD) Disease and its variant (vCJD);aiming to reduce under-reporting of prion diseases in Brazil; to better understand theepidemiological profile of this illness throughout the country; to enableepidemiological, clinical and laboratory investigation of reported cases; to adoptindividual and collective protective measures upon detection of new cases of suchdiseases; and to deploy possible prevention and control measures in the event of casesbeing identified within Brazilian territory.At the beginning of 2005, the Technical Advisory Group for Human Prion Diseases(GTA-Prions) put forward the following components of the surveillance system: anotification form with case definitions of the clinical categories of prion diseases; aprotocol for epidemiological, clinical and laboratory investigation of notified cases;the description of epidemiological, clinical and laboratorial information flows withinthe system; the definition of the reference clinics where the system will beimplemented, and the identification of laboratories that are equipped to carry out thetests proposed in the protocol.The National Seminar on Human Prion Diseases was held on June 8, 2005, with theparticipation of members of the Ministry of Agriculture, proposed surveillance actionsfor the Bovine Spongiform Encephalopathies, (BSE) and had the main objective ofsubmitting the surveillance system proposal to neurologists practicing at state leveland to the states\u2019 epidemiological surveillance units. In August the same year, ameeting was held by the GTA-Prion (TAG) to incorporate suggestions presented at theseminar.5 The inclusion of the disease onto thelists of diseases for which suspect cases must be notified to health surveillanceservices to allow further mandatory investigation, raised awareness of the disease tohealth authorities who then began reporting cases in many Brazilian states.On July 07, 2005, the Ministry of Health classified CJD as a disease requiring mandatorynotification through Regulation No. 33/2005, making the Simplified System ofEpidemiological Surveillance of Human Prion Diseases in Brazil official.From August 2005 through December 2006, 30 suspected cases of CJD were reported toSVS/MS, in 12 Brazilian states.5The complexity of some of the required procedures (including biosafety rules), andconsequently the difficulty in establishing a steady flow of samples can delaydefinitive diagnosis, and compromise the outcome of epidemiological investigations.The system still has some limitations, mainly concerning laboratory diagnosis and thevery nature of Human Prion Diseases.Despite the difficulties outlined, the state surveillance services have successfullyadapted their routines during investigations of suspected cases of prion disease andhave managed, with the assistance of reference laboratories and neurology servicesinvolved, to notify a number several of cases given the rareness of the disease andunprecedented nature of the proposal.With regard to laboratory surveillance, collaboration amongst research centers has beenpursued, to devise possible, often highly complex, methodologies. In this context,detection of the 14-3-3 protein achieved by the Laboratory of Hospital dasCl\u00ednicas/School of Medicine of S\u00e3o Paulo University (HCFMUSP), has greatlyaided diagnosis of the sporadic form of the disease, currently representing the soleparametric parameter included in the criteria for probable diagnosis of vCJD, andpresents greater than or equal sensitivity and specificity than typicalelectroencephalogram. In spite of current advances in diagnosing the disease, it isrecommended that other tests available for detection should be used in conjunction.Sc) with thedisease. Two PrPSc strains have also been reported, namely Types 1 and 2, along withthree possible genotypes at codon 129 (Methione homozygous (MM), valine homozygous (VV)and heterozygous], responsible for 6 sub-types of the disease. The majority ofsporadic CJD cases are MM1 or MV1.Molecular diagnosis is being carried out by the Ludwig Institute, through purification ofthe DNA obtained after leukocyte separation. Direct sequencing is performed using HighResolution Liquid Chromatography (DHPLC). Polymorphism studies and mutation research inthe human prion gene (PRNP) can be used as an aid to diagnose CJD, whereby researchershave associated the occurrence of polymorphisms at codon 129 and protease resistantchemical-physical properties of cerebral prion protein (PrPConcerning histopathological diagnoses, sending of material to Rio de Janeiro FederalUniversity laboratory is in place, where macroscopic studies of the brain, frontal lobefragments, basal ganglia, temporal lobe, occipital lobe, mesencephalon, bridge, bulb andcerebellum are being carried out. The diagnosis is considered positive for CJD when thefollowing 3 pathognomic characteristics of the disease are identified: Spongiosis,neuronal loss and gliosis. The microscopic aspect reveals spongiosis of the cortex dueto reactive astrocytic gliosis, in proportion to the degree of neuronal loss.Constant improvements in surveillance activities are aimed primarily at increasing thesensitivity of the system for early detection of vCJD cases, in view of the burden theseplace on the Brazilian health system. The decision to include other prion disease in thesystem stems from the syndromic features displayed by these pathologies, particularly intheir initial stages, which make the devising of a notification form exclusively forsuspected cases of the new variant unrealistic. Thus, all prion diseases are reported.At a later stage, cases not meeting the criteria for vCJD are excluded and may or maynot call for control responses, in addition to the natural interest for clinical andepidemiological research.The epidemiological notification form and flow of delivery of samples to the laboratoryare shown below."}
+{"text": "Cigarette smoke exposure is well known to cause cardiovascular and airway diseases, both of which are leading causes of death and disability in the world. However, the molecular mechanisms that link cigarette smoke to cardiovascular and airway diseases are not fully understood. Vascular and airway hyper-reactivity plays an important role in the pathogenesis of cardiovascular and airway diseases. Recent studies have demonstrated that endothelin receptor up-regulation mediates vascular and airway hyper-reactivity in response to endothelin-1  in cardiovascular and airway diseases. In the vasculature and airways, the main functional consequences of up-regulated endothelin receptors by cigarette smoke exposure are enhanced contraction and proliferation of the smooth muscle cells, which subsequently result in abnormal contraction (spasm) and adverse proliferation (remodeling) of the vasculature and airways. The structural alteration by adverse remodeling involves changes in cell growth, cell death, cell migration, and production or degradation of the extracellular matrix. This review focuses on cigarette smoke exposure that induces activation of intracellular mitogen-activated protein kinase (MAPK) and subsequently results in the up-regulation of endothelin receptors in the vasculature and airways, which mediates vascular and airway hyper-reactivity, one of the important pathogenic characteristics of cardiovascular and airway diseases. Understanding the molecular mechanisms of how cigarette smoke causes up-regulation of endothelin receptors in the vasculature and airways may provide new strategies for the treatment of cigarette smoke\u2014associated cardiovascular and lung diseases."}
+{"text": "The pneumonia team at the Bill & Melinda Gates Foundation congratulates the Pneumonia Etiology Research for Child Health (PERCH) study on delivering on their grant to collect high-quality data from thousands of children with World Health Organization\u2013defined severe and very severe pneumonia and from controls in 9 diverse sites in 7 low- and middle-income countries. This supplement sets the foundation to understanding this complex study by providing an in-depth description of the study methodology, including discussion of key aspects such as antibiotic pretreatment, chest radiograph interpretation, utility of induced sputum in children, measurement of pathogen density, and use of C-reactive protein, and how these affect pneumonia etiology. Haemophilus influenzae type b (Hib) vaccine and pneumococcal conjugate vaccine (PCV) in the poorest countries, it remains the leading killer of children <5 years of age, with an estimated 900000 deaths per year in 2013 [The premise under which the Pneumonia Etiology Research for Child Health (PERCH) study was funded by the Bill & Melinda Gates Foundation deserves consideration . In 2008A large part of the funding premise was that obtaining a comprehensive set of specimens from cases and controls, applying state-of-the art laboratory tests, including use of a new, multiplex real-time polymerase chain reaction assay targeting an extensive array of >30 potential pathogens, and standardizing methodologies across a range of epidemiologic and geographic settings in low- and low- to middle-income countries, would update our understanding of pneumonia etiology and mortality , 4.Many of these tests, particularly the molecular technologies, were not available to a previous large study conducted 30 years ago . The US H. influenzae) post-PCV rollout remains to be determined. The use of a serotype-specific pneumococcal assay in children, like the one used to evaluate vaccine impact on pneumonia in adults [We have made enormous progress and are getting closer to determining the etiology of pneumonia, but there are still many unknowns. Future studies based on patterns of gene expression by these bacteria may be of interest, but unfortunately RNA was not collected as part of the study. The role in nonbacteremic pneumonia of non-vaccine-type pneumococci  definition of standardized alveolar consolidation pneumonia , 12 alloA great strength of PERCH is the storage of specimens from cases and controls that may be useful for evaluation of newly discovered pathogens, and also the evaluation of biomarkers. The biobank repository that PERCH has created may yet hold more answers for future technologies to unravel further the etiology of childhood pneumonia.The detection of bacterial pneumonia remains crucial to understanding bacterial pneumonia burden and to improving treatment algorithms. Transcriptional profiling of host genes has been recently shown to be superior to the more established biomarker, procalcitonin, in adults , althougPreliminary data from the South African PCV efficacy trial suggest that, at least in an urban cohort of children, pneumonia mortality in infants is predicted by a low oxygen saturation in arterial blood together with indicators of undernutrition such as low weight for age and refusal of feeds. This Respiratory Index of Severity in Children (RISC) score  has beenDespite the reduction in pneumonia\u2014related childhood deaths in infants <5 years of age, less impact has been seen on pneumonia- and sepsis-related mortality among neonates , 3. PERCIn view of the challenges, ascertaining the etiology of pneumonia, especially for commonly carried bacterial pathogens in children, is a daunting task. PERCH has approached this task with a thoughtful study design and state-of-the-art diagnostics. This study has achieved many important milestones including the standardization of methods in a complex multicountry study; the study paid careful attention to quality control; it delivered diagnostics through technology transfer to local laboratories; and it pulled together a unique collaboration of multiple investigators and collaborators. With the foundation set by the articles in this supplement, we look forward to the analysis of PERCH data in the future and its contribution to our understanding of both bacterial and viral etiologies of pneumonia."}
+{"text": "The Ebola outbreak in West Africa underlined the urgent need for integration of public health systems, including the establishment of national laboratory networks, surveillance systems, and health research institutions at all levels of service delivery. The integration schema presented here would assist in driving the immediate steps needed for integration of public health systems, particularly laboratory networks, in support of the implementation of International Health Regulations and the Global Health Security Agenda in the African region. Increased funding, political willingness from countries, and coordination through enhanced technical assistance from international partners, are critical in achieving this objective. These concerns and challenges are not limited to the three countries that experienced the recent crisis. In general, challenges faced by public health systems in Africa, especially at the primary care level, include: (1) lack of laboratory facilities integrated across diseases and services; (2) poor funding and uptake of new rapid diagnostic technologies; (3) overemphasis on resourcing vertical disease-control programmes; (4) patient and health system delays; and (5) lack of fully-integrated electronic disease surveillance systems.The recent Ebola virus disease crisis in three West African countries \u2013 Guinea, Liberia and Sierra Leone \u2013 highlighted several concerns with respect to the functioning of public health systems in the resource-constrained settings of Africa.4 Donors and partners in several countries promote \u2018parallel\u2019, disease-specific laboratories, especially for the major diseases of poverty , as governments fail to address deficiencies. In a few countries, government-run centres-of-excellence were developed as public health research institutes with support from international partners.5 In some countries, environmental health protection and food safety services, as well as national drug testing laboratories, are also administered under public health services.Laboratories play a critical role in the prompt diagnosis of diseases and treatment monitoring. The specific administrative structures of public health laboratories within Ministries of Health differ among countries in Africa. In the majority of countries in the African region, laboratories fall under a directorate, department or unit for national laboratory services, which are housed within the Ministry of Health. Difficulties in coordination of laboratory services with disease control programmes have been observed in such conventional administrative structures. District and below district-level hospital laboratories act as the default \u2018integrated\u2019 laboratories, due to inadequate staff levels, skill sets and infrastructure. Intermediate-level laboratories are practically district-level laboratories and act as regional laboratories, but without the necessary functional dichotomy. Primary health centre laboratories are poorly equipped for rapid diagnosis or rapid response; and national-level laboratories are not fully networked with district-level laboratories for the functional management of laboratory networks.6 This has resulted in disparate and loosely-organised skill deployment, resource wastage and redundancies within the system. Laboratory workers with the cross-cutting skills to effect integrated services have been systematically under-utilised, as they are increasingly engaged in services for single-disease programmes.7The lack of adequate resources, both financial and technical, has contributed to undue prioritisation of key diseases, which has in turn resulted in vertical disease control programmes and laboratories . The absence of the integration of policy formulation, strategy and budgeting have been compounded by competing disease funding priorities and has created disjointed laboratory services in several developing countries.9 include: (1) under-resourced infrastructure, including equipment; (2) poor laboratory linkages to clinical services, resulting in low test demand and suboptimal utilisation of modern diagnostics for clinical decisions; (3) poor laboratory quality control and assurance systems; (4) a paucity of leadership to provide adequate policy intervention, technical guidance and supportive supervision; and (5) inadequate or absent national laboratory networks. These issues impact staff motivation and the overall credibility of laboratory services.Some of the key issues plaguing public health laboratoriesIn spite of the functional challenges in the delivery of services, there is an urgent need to integrate already-existing public health technical capacity within countries in the African region. Effective linkages between public health institutes and laboratories, in addition to optimisation of services, would facilitate early detection of emerging antibiotic resistance, cancers and other non-communicable diseases, as well as periodic epidemiological disease surveys, which would inform policy changes.10 works to facilitate the collaboration and strengthening of public health research institutes affiliated to the Network of African National Public Health Institutes in Africa.11 Present membership of the network comprises 16 institutions, including the Kenya Medical Research Institute, the Uganda Viral Research Institute, and the South African National Institute for Communicable Diseases. In addition, in some countries in Africa, private-sector clinical pathology laboratories, either corporate chains, or individual stand-alone laboratories, offer services to people who can afford quality care for a premium . Systematically engaging African national public health research institutions and centres of excellence, as well as private-sector laboratories, with national laboratory systems and integrated surveillances systems would enhance utilisation of available laboratory and research capacities, and management of resources.The Network of African National Public Health Institutes12 The Integrated Disease Surveillance and Response (IDSR) programme, a comprehensive regional framework for strengthening national public health surveillance and response systems in Africa, was initiated in 1998. In 2006, WHO Regional Office for Africa (WHO AFRO) Member States recommended that IHR 2005 be implemented using the IDSR framework. The IDSR strategy is aimed at integrating the collection, analysis, and reporting of data on 40 priority diseases and conditions at different levels of the health system, including relevant laboratory data. Over the past decade, the IDSR strategy has successfully reduced parallel disease-specific surveillance programmes, increased the capacity of central laboratories, and unified disease reporting matrices among implementing countries in the African region. It has enhanced adherence to IHR by encouraging and establishing early disease warning and real-time event management systems at the national level, including prompt reporting to the WHO through national IDSR focal point.In 2005, the IHR mandated countries to detect, assess and respond to all events that may constitute public health emergencies of international concern, and report the events to the WHO.14 In hindsight, such shortcomings may have contributed to the state of unpreparedness within the West African sub-region that increased vulnerability to the recent Ebola virus disease outbreaks.IHR core capacity target dates have been revised twice, first to 2014 and then to 2019 after the Ebola virus disease outbreak in West Africa. As of 2014, two-thirds of countries had not met their core capacity requirements and 48 countries had not responded to WHO queries with respect to their state of readiness.15 Provision of this level of coordination for active surveillance, timely analyses and response, especially for events of public health significance, are anticipated through the establishment of the Centres for Disease Control and Prevention in Africa.16Recent successes in efforts to strengthen African laboratory networks, laboratory infrastructure, rapid diagnostic technologies, and quality management systems need to be comprehensively integrated into the core functions of the IDSR through new regional structures or coordination mechanisms. Furthermore, enhanced research and development support through already-existing public health research institutes and centres of excellence would not only provide inter-disciplinary technical skills and capacity to staff for quality services and accurate diagnosis, but also assist in the systematic introduction of new and rapid diagnostic technologies and the provision of periodic epidemiological research surveys that will inform efficient planning for health services. Surveillance mechanisms need high-level coordination at the sub-regional and national levels, with frequent modification.17 To effect coordination, 11 action packages were designed and entrusted to contributing countries for enlisting political leadership and action. Action packages are bound by a Prevent\u2013Detect\u2013Respond framework. There is a need to develop in-country mechanisms and responsibilities to address the GHSA. Integration of health systems across diseases and structures would provide a path for this. It is envisaged that the capacity to respond to the objectives of the GHSA would depend on maximising detection and surveillance capabilities through integrated laboratory frameworks within target countries.The Global Health Security Agenda (GHSA), formed in 2014 in response to the Ebola virus disease crisis and supported by high-level international collaboration, is a multi-country concerted effort toward creating a world safe and secure from infectious disease threats.18Integration envisages a process whereby regional and country-level governmental services, including multi-dimensional functions such as health financing, human resources, strategic planning, and others, along with international developmental partners and donors, work closely to promptly reach and sustain the goal of health security for all. In the resource-limited settings of Africa, integrating and coordinating laboratory services and different service components of national health structures would lead to efficient use of resources and building of laboratory networks, as well as ensuring that laboratories contribute to national disease surveillance and control at all levels of health services .18In principle, integration of laboratory services should be achieved first at the country level, followed by the sub-regional level, as integration aims to best utilise the available resources in an unbiased fashion. The Ebola virus disease crisis has reinforced the need to act decisively on a new regional and global structure, as well as the necessity for integrating in-country and regional health systems under one unified, rapid service delivery mechanism, with early warning, detection and response capabilities. Political will and fiscal and administrative commitments are urgently required from governments to ensure that cross-cutting integration of health systems happens and that the IHR core requirements and the GHSA are met."}
+{"text": "Cerebral palsy (CP) is the most common cause of chronic disability that restricts participation in areas of occupations for children. The main aim of rehabilitation is enhancement of their clients for participation in occupations. The aim of this study was to overview of the factors influencing the participations of children with CP in Iran. A systematic, evidence-based process (Duffy 2005) was used. For data gathering electronic databases including Google scholar and Iranian and foreigner famous journals in the fields of pediatrics, were used. The main key words for search were Activity of Daily Living (ADL), Instrumental Activity of Daily Living (IADL), play, leisure, work, rest/sleep, social participation, and education. All the papers of this study were about the factors influencing the participation of Iranian CP children during 2000-2016. Totally, 156 articles were found eligible as for Iranian CP children study, of which 100 articles were discarded. Because of repetitive and duplicability of some articles, 17 articles were removed as well.The most studies about Iranian CP children participations in life areas were in the ADL area of participation (N=12), and the lowest articles were in the area in the field of: Work (N=2), play (N=2), and sleep/rest (N=2). Most of the occupational therapists do not focus on the all life areas.In Iran, many researchers do not pay attention to the participation of CP children. Many articles just paid attention to the sensory, motor or cognitive components of their clients. Cerebral palsy (CP) is a general term used to describe motor function disorders, beginning early in life. This disability is the result of injury or dysfunction of the brain . This unCP causes or its risk factors are divided into several categories as pregnancy age under 20 years, birth weight below 2500 gr, the risk factors related to mother, factors related to pregnancy  and fetal factors  are common causes of CP disorder . According to the high prevalence of CP and disorders associated with that and eventually needs to follow disorders occur in people, knowing about their needs and try to decreasing their needs seems necessary. Knowing and understanding their demands, especially their expectation in the field of rehabilitation  is very important . Among tActivity Daily of Living (ADL): Activities oriented toward taking care of one\u2019s own body. These activities are fundamental to living in a social world; they enable basic survival and well-being : Activities to support daily life within the home and community that often require more com\u00acplex interactions than those used in ADLs  was used . For dat1. Electronic databases: Medlin, PubMed, Google scholar, CINAHL, OVID Medline, CINAHL, Cochrane, ProQuest, Up to Date, Web of Science, OT search, OT direct, Pedro, SID, Magiran, IRAN MEDEX, MEDLIB and Iran doc.2. Iranian and foreigner famous journals in the fields of pediatrics as follows: Iranian Journal of Pediatrics (IJP), Iranian Rehabilitation Journal (IRJ), Iranian Journal of Child Neurology (IJCN), Archive Physical Medicine and Rehabilitation, Developmental Medicine, Child Neurology, Physical and Occupational Therapy in Pediatrics, American Journal of Occupational Therapy. The key words used individually or in combination according to the MESH were as follows: Cerebral palsy (CP), participation, Iranian CP children, Activity of Daily Living(ADL), Instrumental Activity of Daily Living(IADL), play, leisure, work, rest/sleep, social participation, education, quality of life, occupational therapy, OT, physical therapy, rehabilitation, CP participation, OTPF, ICF, participation assessment, participation scale. The inclusion and exclusion criteria are categorized in According to the accessible databases, 156 articles were found in the scope of the study. Because of repetitive and duplicability of some articles, 17 articles were discarded. Thirty-nine articles were included . Some arThe aim of this study was to review the articles about Iranian CP children in different life areas. Participation promoting in different areas of occupations independently is the result and main outcome of rehabilitation services. Rehabilitation intervention in participating in life areas are more important that intervention in cognitive, motor, sensory, perceptual components (30). Furthermore, this systematic review helps to promote the rehabilitation interventions in the participations areas independently in contrast of rehabilitation interventions just on motor, sensory, or cognitive components. In this study, the most studies about Iranian CP children participations in life areas were in the ADL area of participation (N=12), and the lowest articles were in the area in the field of: Work (N=2), play (N=2), and sleep/rest (N=2). These findings can be inferred from the: 1) many of occupational therapist or other rehabilitation members, has not enough information about other life areas, many of them just know about ADL areas of participation; 2) maybe the parents of CP children do not know about the main aim of rehabilitation; 3) many of therapists do not know about occupation based practices; 4) the therapists do not know about the sufficient participation assessment tools. The most effective studies on the participation of Iranian CP children are as follows:1) Field of ADL: The Bobath technique, Conductive Education, and education to parents, high level of GMFCS of CP Children, Occupational Therapy Home Program in the form of workshops and educational pamphlets with telephone follow-up, self-steam and self-confidence education, psychological rehabilitation of children with cerebral palsy, high-level of upper extremity function, physical fitness, enhancement of parents knowledge about how to take care of a child with CP professionally, spasticity reduction, appropriate handling can be mentioned as the facilitators of the participation of Iranian CP children in ADL and factors consisting: poor internal physical modification at home, poor practical training to family members and lack of assistive device can be mentioned as barriers of participation of Iranian cerebral palsy children in ADL (n in ADL -23.2) Field of IADL: Minimizing barriers and providing more facilitators, appropriate handlings, right to access to housing, are the facilitators of the participation of Iranian cerebral palsy children in IADL. Participation diversity and intensity of CP children in the field of IADL are lower than their normal peers are (eers are -26.3) Field of Play: Participation diversity and intensity of CP children in the field of play are lower than their normal peers, and right to accesses to play and sport can promote their participation in the field of play  Field of leisure: The participation enjoyments of CP children in leisure activities are lower than other children, and factors such as: lack of access and benefits of facilities to participate in leisure activities, individual , structural (Accessibility to the public facilities) and socio cultural , are the effective barriers to participation in leisure activities  Field of rest/Sleep: the factors such as: enhancement of parent\u2019s knowledge about how to take care of a child with CP professionally and right to assess and benefits of facilities to participate in sleeping and rest activities of CP children had effective influence on participation of CP children in the field of rest/sleep  Field of Education: The factors such as: poor handling at school because of inappropriate physical structure, poor attention to education and environmental barriers in two groups: 1) policies ; 2) physical and structural , leads to poor education of CP children and minimizing barriers and providing more facilitators to access to education and information improves the participation of education Field of Work: Minimizing barriers and providing more facilitators to access to job leads to work participation  Field of social participation: The participation enjoyments of CP children in the field of social participation activities are lower than other children are. Factors such as: 1) lack of access and benefits of facilities, individual , structural (Accessibility to the public facilities) and socio cultural  barriers; 2) poor handling at society consist of: psychological and religious abuse of CP children, inadequate government\u2019s supports and inadequate civil facilities for CP children; 3) poor attention of rehabilitation members team, and; 4) environmental barriers in two groups: 1) policies ; 2) physical and structural , leads to poor social participation of CP children the factors such as; 5) improvement in gross motor functions of CP children; 6) right to access to medical care and rehabilitation and right to access to places and transportation system; 7) psychological rehabilitation of children with cerebral palsy; 8) high level of upper extremity function; and 9) spasticity reduction leads to improvement of social participation activities of CP children  that all of them are important in enhancement of quality of life of CP children. None of them is preferred over another. According to that for good intervention in participation of CP children, using good and properties assessment tools of participation is important. We achieved that in Iran many researchers did not pay attention to the participation of CP children and many articles just paid attention to the sensory, motor or cognitive components of their clients. Among the life areas of participation the most focuses is on the ADL and social participation areas and the other areas are least important. Therefore, the suggestion of this study is that the researchers pay attention to the other areas of occupations and life areas of Iranian CP children because none of these areas are preferred over another."}
+{"text": "Nanoscience and Nanotechnology became the trend of the 21st century, influencing many areas such as electronics, biology, medicine, aerospace, agriculture, and the engineering of novel materials. Recently a new aspect of nanoscience and nanotechnology appeared and has been rising rapidly ever since: functional nanostructures, intelligent nanostructures for targeted applications. In the present Thematic Series a bright spectrum of such targeted functional nanostructures is presented demonstrating the unique possibilities of engineering at the nanometer scale. The self-organization of nanoparticles, nanowires or nanotubes and the introduction of those structures into various materials made it possible to solve long-standing problems. Examples presented in this Thematic Series are:the problem of treatment of multidrug-resistant tuberculosis, which can be resolved using the invented nano-encapsulated medicines penetrating through the cell membrane of the tuberculosis bacilli ,new applications of graphene-based nanostructures \u20134,smart nanoparticles with antitumor activity ,photonic crystals and flexible membranes \u20137 for viA lot of other unusual applications of functional nanostructures are presented in over 40 articles of this Thematic Series, giving the possibility to gain new knowledge about the rapidly developing area of nanoscience and nanotechnology.The idea to this Thematic Series appeared during the international conference \u201cNANO-2016: Ethical, Ecological and Social Problems of Nanoscience and Nanotechnologies\u201d, which took place in May 2016 in Chisinau, Moldova. It presented new technological approaches for assembling of functional nanostructures and nanomaterials with special properties. As the guest editor of this Thematic Series I would like to thank all colleagues and highly experienced experts who submitted their manuscripts with novel results, new ideas, and technological approaches. I believe that this Thematic Series will attract attention of scientists, technologists, engineers and will find many readers. The professional and friendly editorial support by the Production Team of the Beilstein-Institut is greatly acknowledged.Anatolie SidorenkoChisinau, January 2017"}
+{"text": "In plants, the chloroplast is the organelle that conducts photosynthesis. It has been known that chloroplast is involved in virus infection of plants for approximate 70 years. Recently, the subject of chloroplast-virus interplay is getting more and more attention. In this article we discuss the different aspects of chloroplast-virus interaction into three sections: the effect of virus infection on the structure and function of chloroplast, the role of chloroplast in virus infection cycle, and the function of chloroplast in host defense against viruses. In particular, we focus on the characterization of chloroplast protein-viral protein interactions that underlie the interplay between chloroplast and virus. It can be summarized that chloroplast is a common target of plant viruses for viral pathogenesis or propagation; and conversely, chloroplast and its components also can play active roles in plant defense against viruses. Chloroplast photosynthesis-related genes/proteins (CPRGs/CPRPs) are suggested to play a central role during the complex chloroplast-virus interaction. Plant viruses, as obligate biotrophic pathogens, attack a broad range of plant species utilizing host plants' cellular apparatuses for protein synthesis, genome replication and intercellular and systemic movement in order to support their propagation and proliferation. Virus infection usually causes symptoms resulting in morphological and physiological alterations of the infected plant hosts, which always incurs inferior performance such as the decreased host biomass and crop yield loss.The most common viral symptom is leaf chlorosis, reflecting altered pigmentation and structural change of chloroplasts. Viral influence on chloroplast structures and functions usually leads to depleted photosynthetic activity. Since the first half of the twentieth century, an increasing number of reports on a broad range of plant-virus combinations have revealed that virus infection inhibits host photosynthesis, which is usually associated with viral symptoms  fluctuation of chlorophyll fluorescence and reduced chlorophyll pigmentation , affect chloroplast ultrastructure and symptom development (see below).N. tabacum leaves  have been demonstrated as determinants of symptom phenotypes for a much long period  protein in tobacco plants results in a virus-like chlorosis symptom associated with the abnormal thylakoid stacks Figure , Table 2Studies on the effect of virus infection on expression of chloroplast proteins at the transcriptomic and proteomic levels provide insights into the molecular events during symptom expression. In the susceptible plant response to virus infection, the majority of significantly changed proteins are identified to be located in chloroplasts or associated with chloroplast membranes. Most of them are down-regulated and correlate with the severity of chlorosis Dardick, . During As the biosynthesis of CPRPs is a complicated process with a series of steps Seidler, , plant vflavum strain leads to a total depletion of PS II core complex and OEC, including chloroplast-encoded CPRP PsbA and nuclear-encoded CPRPs LhcB1, LhcB2  and PsbO. However, the PsbA mRNA accumulated to a higher level in the infected leaves  gene transcripts and down-regulates its expression by RNA silencing  with blocked chloroplast development and depletion of chloroplast-encoded proteins  RNA which can disturb chloroplast function and induce disease symptoms  pathway for targeting CPRGs transcripts. The tenuivirus RSV, causing a devastating disease in East Asia countries, hijacks CPRP during infection and perturbs photosynthesis  to fulfill the transport via symplastic routes within plant hosts , a gene involved in the JA signaling pathway, accelerates the development of symptoms caused by co-infection of PVX and PVY, and accumulation of viral titers at early stages of infection  in the chloroplast membranes , and the photosynthetic electron transport chain is responsible for ROS generation Asada, . Superoxs Asada, . The burs Asada, . Chlorops Asada, .N-mediated TMV resistance response. Further, a number of stromules surround nuclei during plant defense response, which is correlated with the accumulation of chloroplast-localized defense protein NRIP1 and H2O2 in the nucleus. In the absence of virus infection, suppression of chloroplast CHUP1 induces stromules and enhances programmed cell death constitutively  protein of potyviruses is required for virus replication and cell-to-cell movement. CI protein from PPV and TVMV interacts with photosystem I PSI-K protein Table , the proL88 with high RNAi suppressor activity , a rhodanese sulfurtransferase which is destined to chloroplast under normal conditions, associates with both the tobacco N receptor and 126 K replicase during TMV infection; its relocation from chloroplast to cytoplasm and nucleus is required for N-mediated resistance to TMV , the National Basic Research Program of China (2014CB138400), the Special Fund for Agro-scientific Research in the Public Interest of China (201303028), and the China Postdoctoral Science Foundation (2014M550049), the Initial Funding of Zhejiang Academy of Agricultural Sciences, and the Cultural Funding for Youth Talent of Zhejiang Academy of Agricultural Sciences (2015R21R08E03).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Many physiological processes fluctuate throughout the day/night and daily fluctuations are observed in brain and peripheral levels of several hormones, neuropeptides and transmitters. In turn, mediators under the \u201ccontrol\u201d of the \u201cmaster biological clock\u201d reciprocally influence its function. Dysregulation in the rhythmicity of hormone release as well as hormone receptor sensitivity and availability in different tissues, is a common risk-factor for multiple clinical conditions, including psychiatric and metabolic disorders. At the same time circadian rhythms remain in a strong, reciprocal interaction with the hypothalamic-pituitary-adrenal (HPA) axis. Recent findings point to a role of circadian disturbances and excessive stress in the development of obesity and related food consumption and metabolism abnormalities, which constitute a major health problem worldwide. Appetite, food intake and energy balance are under the influence of several brain neuropeptides, including the orexigenic agouti-related peptide, neuropeptide Y, orexin, melanin-concentrating hormone and relaxin-3. Importantly, orexigenic neuropeptide neurons remain under the control of the circadian timing system and are highly sensitive to various stressors, therefore the potential neuronal mechanisms through which disturbances in the daily rhythmicity and stress-related mediator levels contribute to food intake abnormalities rely on reciprocal interactions between these elements. Circadian (~24 h) fluctuations of different components of the external environment, in particular light-dark conditions, shape animals' physiology and behavior for the optimal synchronization to the cyclical changes encountered. As a consequence of this influence, biological processes called circadian rhythms developed in most organisms , the anterior lobe of the pituitary gland, and the adrenal cortex. PVN neurons synthesize corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP), which stimulates secretion of adrenocorticotrophic hormone (ACTH) from the anterior pituitary and ACTH controls the release of glucocorticoids (GCs) from the adrenal cortex  of the hypothalamus is a key appetite regulatory center Banks, . It contAcute and chronic icv NPY administration result in hyperphagia, obesity and changes in metabolism    neurons , by statutory funds of the Institute of Pharmacology, Polish Academy of Sciences (GH) and by National Health and Medical Research Council of Australia Project Grant 1067522 and Research Fellowship 1005985 (ALG).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "According to the World Health Organization, high-impact diseases (HID) including cardiovascular diseases, metabolic diseases, and a variety of types of cancer are the top challenge to the entire medical community globally . TherapeRecently, omics technologies including genomics, proteomics, transcriptome, and metabolomics have been developed and improved significantly. This is especially true for RNA sequencing together with the system-based pharmacology, which has overcome the barriers and greatly improved our understanding of the pharmacology of natural products for the prevention and treatments of HID.For example, Shuanglong Formula (SLF) and Qishen granules (QSG) are well-studied natural products for the treatment of cardiovascular diseases. Multiomics including metabolomics and comparative proteomics were performed to investigate the SLF's effects on the regulation of myocardial energy metabolism , 4. Y. WIn addition, new omics approaches are also developed to identify the active indigents and potential targets of natural products. A novel approach for relative and absolute quantitation was established to specifically and comprehensively identify the protein targets of andrographolide (Andro) , and BATRheum palmatum L., Gardenia jasminoides Ellis, and Artemisia annua L., had an improved therapeutic effect on hepatic injury syndrome through regulating dynamic patterns in metabolic biomarkers and target proteins and activating both intrinsic and extrinsic pathways [Due to the diverse components of natural products, systematically integrating the readouts of genomics, transcriptomics, proteomics, and metabolomics will dramatically facilitate our understanding of molecular mechanisms of natural product actions, as well as identifying biomarkers or targets for future research and clinical practice. Recently, an integrated proteomic and metabolomics research demonstrated that a combination of natural products comprising of pathways .Unsurprisingly, more omics studies are currently under way to reveal the molecular mechanisms of treatments using natural products. The current issue is a collection of selected works that use the approaches of genomics, metabolomics, RNA sequencing, and network pharmacology to comprehensively elucidate the natural product pharmacology in the treatments of HID including heart failure, diabetes and its complications, nonalcoholic fatty liver disease, and depression. It is a timely update to our knowledge on both the molecular mechanism and novel drug discovery for HID.Yong WangQin FengPeijian HeLixin ZhuGuoxun Chen"}
+{"text": "Quantitative structure-activity relationship (qSAR) models are used to understand how the structure and activity of chemical compounds relate. In the present study, 37 carboquinone derivatives were evaluated and two different qSAR models were developed using members of the Molecular Descriptors Family (MDF) and the Molecular Descriptors Family on Vertices (MDFV). The usual parameters of regression models and the following estimators were defined and calculated in order to analyze the validity and to compare the models: Akaike?s information criteria (three parameters), Schwarz (or Bayesian) information criterion, Amemiya prediction criterion, Hannan-Quinn criterion, Kubinyi function, Steiger's Z test, and Akaike's weights. The MDF and MDFV models proved to have the same estimation ability of the goodness-of-fit according to Steiger's Z test. The MDFV model proved to be the best model for the considered carboquinone derivatives according to the defined information and prediction criteria, Kubinyi function, and Akaike's weights."}
+{"text": "Endemism is an important concept in biogeography and biodiversity conservation. China is one of the richest countries in biodiversity, with very high levels of plant endemism. In this study, we analysed the distribution patterns of diversity, the degree of differentiation, and the endemicity of Chinese endemic seed plants using the floristic unit as a basic spatial analysis unit and 11 indices. The analysis was based on distribution data of 24,951 native seed plant species (excluding subspecies and varieties) and 12,980 Chinese endemic seed plant species, which were sourced from both specimen records and published references. The distribution patterns of Chinese endemic flora were generally consistent but disproportionate across China for diversity, degree of differentiation and endemicity. The South Hengduan Mountains Subregion had the highest values for all indices. At the regional level, both the Hengduan Mountains and the Central China regions were highest in diversity and degrees of differentiation. However, both the rate of local endemic to native species and the rate of local to Chinese endemic species were highest in the Taiwan Region and the South Taiwan Region. The Hengduan Mountains Region and the Central China Region are two key conservation priority areas for Chinese endemic seed plants. Thus, the regionalization of Chinese flora is also difficult and challenging. Wu was the first researcher to publish a comprehensive regionalization of Chinese flora based on pioneering works that had been published over decades. He classified Chinese flora into 2 kingdoms, 7 subkingdoms and 22 regionsAs described previously, many studies of biodiversity conservation have been conducted across China. However, they primarily used an administrative unit, particularly at the provincial level, as the spatial unit for analysis rather than a natural geographic or floristic unit. It is better to identify conservation priority areas on the basis of a natural geographic or floristic unit because such classifications substantially reduce the influence of and definition by human factors. Therefore, using the floristic unit as the basic unit of spatial analysis, we examined the distribution patterns, diversification and degrees of differentiation of Chinese endemic seed plants and identified conservation priority areas across the country for conservation planning and future effective conservation actions.Based on a previously published list of Chinese endemic seed plant speciesWe digitized the map of floristic regions of ChinaMeasurement of species diversity was based on species richness, i.e., the number of species in each spatial units)g)sf)The degrees of differentiation among endemic flora were represented by differentiation indices, which included a species differentiation index .where Proportions of endemism were calculated to compare the distribution patterns of endemic flora in China. These proportions included the rate of Chinese endemic to native species (RCENS), the rate of local endemic to native species (RLENS) and the rate of local to Chinese endemic species (RLCES).s), the number of genera (Ng), the number of families (Nf), the number of local endemic species (NLES), the degree of species differentiation (Ds), the degree of genus differentiation (Dg), the degree of species\u2013family differentiation (Dsf), weighted endemism (WE), the rate of Chinese endemic to native species (RCENS), the rate of local endemic to native species (RLENS) and the rate of local to Chinese endemic species (RLCES). These 11 indices were standardized by dividing their maxima and then summed to produce a total value. All floristic units were ranked according to their total value, and conservation priority areas for Chinese endemic seed plants were identified according to each unit\u2019s rank. The spatial floristic unit was used to prioritize conservation areas, and the units with the highest total values were the tip-ranked areas because higher values were determined by greater endemic species richness and the degree of differentiation and endemism. In this study, the top eight floristic units were designated conservation priority areas.To summarize, the 11 indices were as follow: the number of species  and the Central Yunnan Plateau Subregion (IIIE13a) contained the most families . These tChinese endemic seed plant species were also unevenly distributed across the country. The South Hengduan Mountains Subregion (IIIE14b) was the richest, with 5177 species of Chinese endemic seed plants, which was followed by the Central Yunnan Plateau Subregion (IIIE13a), with 3688 species . The PamThe distribution patterns of Chinese endemic flora at family, genus and species levels across the country were generally consistent . The patThe degree of differentiation among endemic seed plant species was unevenly distributed across China . The higThe spatial distribution patterns of Chinese endemic plant species, local endemic species and weighted endemism were significantly correlated (P\u2009<\u20090.001) , and allThe endemic rates were also unevenly distributed across the country . The ratThe South Hengduan Mountains Subregion (IIIE14b), the Central Yunnan Plateau Subregion (IIIE13a), the Sanjiang Valley Subregion (IIIE14a) and the North Hengduan Mountains Subregion (IIIE14c) had the highest total values of all floristic units . These sThe degree of species differentiation among Chinese endemic seed plants was unevenly distributed across the country. Although the degree of differentiation was not high in many parts of China, it was particularly high in the Hengduan Mountains12The rate of Chinese endemic to native plant species was highest in the South Hengduan Mountains Subregion (IIIE14b), followed by the North Hengduan Mountains Subregion (IIIE14c). Based on this result, endemicity of flora in the Hengduan Mountains is very high across China. However, the South Hengduan Mountains Subregion and the North Hengduan Mountains Subregion differ in endemicity. The terrain of China from west to east forms a flight of three steps, commonly called the \u201cGeomorphological Three Steps\u201d. The First Step mainly encompasses the Qinghai-Tibet Plateau, north to the Kunlun, Aerhchin, and Qilian mountains and east to Min, Qionglai, Daxue and Hengduan mountains. The Second Step lies between the Hengduan Mountains to the west and the Daxing\u2019anling, Taihang, Funiu, and Xuefeng mountains to the east, primarily including the Inner Mongolian Plateau, Loess Plateau, Qinling Mountains, Sichuan Basin, and Yun-Gui Plateau. The Third Step covers the entire area east from the Second Step, and includes the Northeast China Plain, North China Plain, Middle-lower Yangtze Plain, Jiangnan hills, Nanling Mountains, Guangdong and Guangxi hills, Zhejiang and Fujian hills as well as Taiwan and HainanThe rate of local endemic to native plant species was highest in the Taiwan Region (IVG19) and the South Taiwan Region (IVG20), which indicates that the flora of Taiwan is distinctive. The rate of local to national endemic plant species was the highest in the Taiwan Region (IVG19), the South Taiwan Region (IVG20), the Altai Region (IA2) and the Pamir-Karakoram-Kunlun Subregion (III17c). This result shows that the island of Taiwan, the Altai Region (IA2) and the Pamir-Karakoram-Kunlun Subregion (III17c) have different flora that might be influenced by trans-boundary flora from neighbouring countries.The four top conservation priority areas were identified; the South Hengduan Mountains Subregion IIIE14b), the Central Yunnan Plateau Subregion IIIE13a), the Sanjiang Valley Subregion (IIIE14a) and the North Hengduan Mountains Subregion (IIIE14c). Most of these subregions are in the geographical terrain of the Hengduan Mountains. The Hengduan Mountains are rich in mountainous flora and are thus a key area for studies of the relationships among Laurasian, Gondwanian and Tethyan flora414b, the Ca, the SaThree other top conservation priority areas were identified; the Guizhou Plateau Subregion IIID10d), the Sichuan-Hubei-Hunan Border Subregion (IIID10c) and the Qinling-Bashan Subregion (IIID10a). These three subregions are in the Central China Region. The flora of this region comprises direct and nearly intact descendants of a Tertiary ancient flora0d, the S44112The diversity and degrees of differentiation among Chinese endemic seed plants are unevenly distributed across the country. Both the Hengduan Mountains and Central China regions are diversity centres that also have the highest degrees of differentiation. Moreover, the Hengduan Mountains Region and the Central China Region are two key conservation priority areas for Chinese endemic seed plants based on diversity, degrees of differentiation and endemicity. In addition, the Taiwan Region, the Altai Region and the Pamir-Karakoram-Kunlun Subregion have unique endemic flora, and greater attention should be paid to the flora of these regions or subregions in future conservation planning and actions.How to cite this article: Huang, J. et al. Diversity distribution patterns of Chinese endemic seed plant species and their implications for conservation planning. Sci. Rep. 6, 33913; doi: 10.1038/srep33913 (2016)."}
+{"text": "Paralytic ileus is type of functional obstruction caused by the lack of intestinal peristalsis without any mechanical obstruction. This interference of the flow of intestinal contents often leads to intestinal obstruction. Paralytic ileus may be classified into postoperative, inflammatory, metabolic, neurogenic, and drug-induced . The incIranian traditional medicine is one of the oldest traditional medicines. Avicenna (980\u20131037AD) was a great Iranian clinician and philosopher. He in his famous book, Qanun of Medicine thoroughly has reviewed all of the medical science of ancient Greek and Muslim scholars , 5.Based on Iranian traditional medicine, paralytic ileus, type of functional intestinal obstruction, has been described under title of Gholonj disease. This chapter deals with the physiopathology and management of the gastrointestinal obstructive disorders in Iranian traditional medicine , 7. GholGolonj is classified based on the etiology of obstruction  to six categories . Non-mecExcluding type of mechanical obstruction, the strategy of treatment is based on medical because main pathology is no mechanical obstruction. For example, based on the definition of Gholonj-e-Reehi, Avicenna expresses that there is no any real obstruction agent; and accumulation of gas prevents from intestinal movement and defecation.Medical treatment strategies of Golonj disease are various and includes of procedures, medical herbs, and diet recommendations.Recent studies reveals pathophysiology of paralytic ileus is complex and multifactorial, consisting of neurologic and inflammatory agents. Activation of sympatic system or inflammatory response cells in muscle layers of bowel leads to generalized hypo motility of gastrointestinal tract . In explExcluding some of Avicenna\u2019s viewpoint and his etiology of intestinal obstruction based on humoral theories, most of his definition can be compared with medical current concepts. Increased insight into options mentioned in Qanun can be useful for new study, aiming to manage better of disturbances of gastrointestinal function. However, establishing of this concept requires further research and the generation of scientific evidence."}
+{"text": "The results of numerous studies indicate that fish possess bacterial populations on or in their skin, gills, digestive tract, and light-emitting organs. In addition, the internal organs  of healthy fish may contain bacteria, but there is debate about whether or not muscle is actually sterile. Using traditional culture-dependent techniques, the numbers and taxonomic composition of the bacterial populations generally reflect those of the surrounding water. More modern culture-independent approaches have permitted the recognition of previously uncultured bacteria. The role of the organisms includes the ability to degrade complex molecules , to produce vitamins and polymers, and to be responsible for the emission of light by the light-emitting organs of deep-sea fish. Taxa, including Pseudomonas, may contribute to spoilage by the production of histamines in fish tissue."}
+{"text": "Advancements in next-generation sequencing and other -omics technologies are accelerating the detailed molecular characterization of individual patient tumors, and driving the evolution of precision medicine. Cancer is no longer considered a single disease, but rather, a diverse array of diseases wherein each patient has a unique collection of germline variants and somatic mutations. Molecular profiling of patient-derived samples has led to a data explosion that could help us understand the contributions of environment and germline to risk, therapeutic response, and outcome. To maximize the value of these data, an interdisciplinary approach is paramount. The National Cancer Institute (NCI) has initiated multiple projects to characterize tumor samples using multi-omic approaches. These projects harness the expertise of clinicians, biologists, computer scientists, and software engineers to investigate cancer biology and therapeutic response in multidisciplinary teams. Petabytes of cancer genomic, transcriptomic, epigenomic, proteomic, and imaging data have been generated by these projects. To address the data analysis challenges associated with these large datasets, the NCI has sponsored the development of the Genomic Data Commons (GDC) and three Cloud Resources. The GDC ensures data and metadata quality, ingests and harmonizes genomic data, and securely redistributes the data. During its pilot phase, the Cloud Resources tested multiple cloud-based approaches for enhancing data access, collaboration, computational scalability, resource democratization, and reproducibility. These NCI-led efforts are continuously being refined to better support open data practices and precision oncology, and to serve as building blocks of the NCI Cancer Research Data Commons. Precision medicine has evolved out of the seminal work of the Human Genome Project, advancements in DNA sequencing technology, developments in high throughput and large-scale molecular biology technologies, improvements in the speed and scale of computation, and innovations in biomedical informatics. This progress has resulted in the molecular characterization of individual patient tumors, the identification of actionable genetic alterations, and the development of evidence-based molecular cancer diagnostics and targeted therapies. Although, cancer types have been traditionally classified by organ or cell type, with the aid of genomics, cancer patients are increasingly being treated according to their cancer's unique molecular signature. Cancer is a diverse array of genetically-driven diseases. The identification and validation of actionable genetic alterations including amplifications, rearrangements, and gain-of-function mutations, has spurred the use of genomic data in oncology practices. Targeted gene sequencing panels, for example, offer insight into the genetic drivers of an individual's tumor and inform the diagnosis, prognosis, and targeted treatment of cancer patients. A number of targets for drug development have been outlined previously , Therapeutically Applicable Research to Generate Effective Treatments (TARGET), and Clinical Proteomic Tumor Analysis Consortium (CPTAC) have generated large datasets amassing petabytes of data. These, along with other datasets and resources described in this paper are available to researchers both in the US and internationally Table .In December 2005, TCGA was announced as a new collaboration between the NCI and the National Human Genome Research Institute NIH, . Data tyTARGET was launched in 2006. TARGET's goal is to characterize the genome and transcriptome of hundreds of pediatric acute lymphoblastic leukemia, acute myeloid leukemia, Wilms tumor, clear cell sarcoma of the kidney, rhabdoid tumor, neuroblastoma, and osteosarcoma samples. Through genomic and transcriptomic analyses, researchers are studying the relationships among alterations at the DNA and RNA levels, cancer growth, cancer progression, and pediatric patient survival  characterize the proteomes of tumor and normal tissues; (2) perform proteogenomic analyses of cancer biospecimens; (3) identify potential biomarker candidates through discovery proteomics and develop targeted assays against those candidates; and (4) perform verification tests on those targeted assays. Phase I of CPTAC consisted of technical quality assurance studies  Network has emerged as a tri-agency collaboration to enable oncologists to use their patients' unique proteogenomic profiles to inform precision oncology treatments , a cloud-based infrastructure in support of data sharing, tool development, and compute capacity to democratize big data analysis and to increase collaboration among researchers. NCI has sponsored two recent initiatives that serve as the foundation for the Cancer Research Data Commons\u2014the Genomics Data Commons (GDC), and three Cloud Resources.The GDC, built and managed by the University of Chicago Center for Data Intensive Science, in collaboration with Ontario Institute for Cancer Research, all under an NCI contract with Leidos Biomedical Research, is a unified genomic data repository that hosts authoritative NCI reference datasets such as TCGA and TARGET  Pilots. The purpose of the CGC Pilots was to explore multiple cloud-based approaches for enhancing secure data access, collaboration, computational scalability, resource democratization, and reproducibility. Through this program, the Broad Institute, the Institute for Systems Biology, and Seven Bridges have each developed what are now known as Cloud Resources. Each platform is deployed in a commercial cloud, and has applied a distinct approach to providing access to TCGA and TARGET genomic data in a cloud environment, and integrating proteomic data from CPTAC as well as radiology images and associated metadata from The Cancer Imaging Archive (TCIA). In addition to providing access to these datasets through rich Application Programming Interfaces (APIs) and graphical user interfaces, the Cloud Resources each provide a platform to enable the deployment of analysis, visualization, and other computational tools in the cloud, bypassing the need to bring data to a local infrastructure. The Cloud Resources support tool deployment through the use of Docker containers, which allow users to package their tools along with all associated dependencies. These \u201ccontainerized\u201d tools can be connected and executed as workflows in these cloud environments. End user documentation provides users with guidance on how to query data, install tools, as well as create and run workflows in each environment. All three platforms conform to strict federal information system security requirements and manage access to controlled data through Database of Genotype and Phenotype (dbGaP) authorization. In addition to their fundamental charter of providing secure cancer genomic data access co-localized with analysis pipelines and visualization tools, the Cloud Resources each offer unique capabilities suitable for a range of research needs.The Broad Institute's FireCloud, was built as the next generation of Broad Institute's Firehose data analysis infrastructure developed for the TCGA program Ulrich, . FireCloThe Institute for Systems Biology Cancer Genomics Cloud (ISB-CGC) runs on the Google Cloud Platform and offers an interactive web-based application and hosts Application Programming Interfaces (APIs) such as the Global Alliance for Global Health API. ISB-CGC takes advantage of Google Cloud Platform's built-in resources such as BigQuery, Compute Engine, App Engine, Cloud Datalab, and Google Genomics. Researchers can use BigQuery to explore clinical, biospecimen, level-3 open access TCGA, and CPTAC II data. ISB-CGC hosts numerous genomics tools and has recently added the Trans Proteomic Pipeline analysis suite. Researchers can now access complementary genomic and proteomic data, run multi-omic analyses, and perform BigQuery searches to investigate genetic alterations, copy number, transcript expression, protein expression, and molecular pathways that are involved in cancer biology. ISB-CGC has also made radiology and tissue images from TCIA and the GDC available through Google Cloud Storage. Additional datasets available at ISB-CGC include the Catalog of Somatic Mutations in CancerCurrently, over 1,600 researches from over 40 countries are using the Seven Bridges Cancer Genomics Cloud (SB-CGC) to analyze hosted genomic data, and/or their own dataThe initial versions of The NCI Cloud Resources, the CGC Pilots, were created to maximize the value of cancer -omics data through harnessing multi-disciplinary expertise. Synergizing technologies from the fields of medicine, molecular biology, informatics, and cloud computing, the CGC Pilots have begun to transform how cancer data analysis is conducted. Researchers, both in the US and internationally, have been able to advantage of these cloud-based resources. To ensure the success of this project and to identify areas for improvement, the CGC Pilot and NCI teams established mechanisms to support early adopters' use of these platforms and to collect their feedback.The CGC Pilots teams provided technical support to new users who sought to implement new tools, access data, or create collaborative workspaces. Through the three CGC Pilots, NCI provided cloud compute and storage \u201ccredits\u201d to offset the costs of evaluation of these platforms by cancer researchers. These funds directly impacted the work of researchers such as post-doctoral scholar Dr. Brittany Lasseigne, at the HudsonAlpha Institute for Biotechnology in Huntsville, AL. Dr. Lasseigne used the SB-CGC, to study dosage effects, context dependency, and tissue specificity of tumor suppressors across human cancers in TCGA. These Cloud credits supported the use of the large-scale genomic datasets co-located with computational resources and analysis tools, and increased research efficiency for many early stage researchers like Dr. Lasseigne .To evaluate the CGC Pilots and support on-going NCI-funded cancer research, NCI funded administrative supplements to the active grants of investigators performing genomics-based research. The Funding Opportunity Announcement, Supplements to Support Evaluation of the NCI Cancer Genomics Cloud Pilots (PA-15-305), funded projects to use one or more of the NCI CGC Pilots for ongoing research activities. Funds were awarded to investigators whose projects aimed to install and test the performance of new analysis tools on a CGC Pilot, upload locally-generated genomic data and perform analyses on a CGC Pilot, and/or perform analyses of hosted TCGA data. The researchers reported having a generally positive experience working on the CGC Pilots; however, as expected, some encountered technical hurdles. When those technical issues arose, the vast majority of the groups were able to resolve their problems by working directly with the CGC Pilot support teams. Each research group provided extensive feedback to the CGC Pilots and NCI teams on what elements of the CGC Pilots could be improved. The majority of the administrative supplement awardees reported that they plan to continue to use the CGC Pilots to accelerate their research and that the CGC Pilots have the potential to be a vital resource for the cancer research community. The activities and outcomes of projects funded through these supplements have helped inform NCI's decision to continue supporting this project beyond the pilot phase and to develop a more comprehensive computational infrastructure for -omics and other big data types.Cancer research in the era of big data presents major challenges: computing on large datasets, combining expertise from various disciplines, and developing the infrastructure needed to enhance research efficiency. Recognizing the importance and urgency of these needs, the Beau Biden Cancer Moonshot Blue Ribbon Panel has recommended that the cancer research community aim to, \u201ccollect, share, and interconnect a broad array of large datasets so that researchers, clinicians, and patients will be able to both contribute and analyze data, facilitating discovery that will ultimately improve patient care and outcomes BRP, .\u201d In linThe GDC and Cloud Resources currently support basic and translational research, primarily using genomic and clinical data. These activities serve as the building blocks of the cloud-based NCRDC Figure . The NCRThe era of big data in biomedical research and precision oncology calls for creative strategies borrowed from multiple scientific and technological disciplines. The GDC and Cloud Resources are important steps in supporting the next generation of data-driven cancer research. Looking ahead, the NCRDC represents an interdisciplinary solution to the challenges of big data in cancer research. NCI will continue to lead open science efforts toward the goals of improving prevention strategies, developing targeted diagnostics and therapeutics, and reducing the burden of cancer on patients, their families, and society.IH: Manuscript writing, figure design. TD, JK, AK, and WK: Manuscript and figure revision, approval of final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Hypertensive disorders of pregnancy (HDP), particularly pre-eclampsia and eclampsia, remain one of the leading causes of maternal mortality and are contributory in many foetal/newborn deaths. This editorial discusses a supplement of seven papers which provide the results of the first round of the CLIP (Community Level Interventions for Pre-eclampsia) Feasibility Studies. These studies report a number of enablers and barriers in each setting, which have informed the implementation of a cluster\u2013randomized trial (cRCT) aimed at reducing pre-eclampsia-related, and all-cause, maternal and perinatal mortality and major morbidity using community-based identification and treatment of pre-eclampsia in selected geographies of Nigeria, Mozambique, Pakistan and India. This supplement unpacks the diverse community perspectives on determinants of maternal health, variant health worker knowledge and routine management of HDP, and viability of task sharing for preeclampsia identification and management in select settings. These studies demonstrate the need for strategies to improve health worker knowledge and routine management of HDP and consideration of expanding the role of community health workers to reach the most remote women and families with health education and access to health services. A healthy mother and baby are the desired outcomes of all antenatal and intrapartum care. Hypertensive disorders of pregnancy (HDP), particularly pre-eclampsia and eclampsia, remain one of the leading causes of maternal mortality and are contributory in many foetal/newborn deaths. As a result, an estimated 76,000 maternal and 500,000 foetal/newborn deaths occur each year with more than 10 million pregnancy complications [Improving quality of care for mothers and babies during pregnancy and childbirth has the potential to prevent 2 million deaths each year \u20137. DespiSpecific to HDP, research is now underway through the CLIP (Community Level Interventions for Pre-eclampsia) trials in hopes of reducing the burden of adverse maternal and perinatal outcomes related to pregnancy hypertension through community engagement, mobile technology and task-sharing to community health-care providers . Using aThis editorial discusses a supplement of seven papers which provide the results of the first round of the CLIP Feasibility Studies \u201319. ThesUnderstanding the perspectives of women and their communities offers important insights into the enablers and barriers to accessing health care. More context-specific studies and opportunities for women themselves to be engaged in defining quality of maternal and newborn care are needed. One paper in this supplement specifically focuses on community perspectives on the determinants of maternal health in Mozambique, including women\u2019s perspectives, although literature from other settings is referenced in other papers . In MozaThese studies further elucidate the issues of health worker knowledge and routine pregnancy management related to HDP. For CHWs to effectively educate communities about HDP and serve their communities in identifying and managing cases, the CHWs themselves need to have the knowledge about the etiology, symptoms and treatment options available. Across the different settings of the CLIP Feasibility studies, the knowledge of CHWs regarding pre-eclampsia and eclampsia spanned a broad range: Lady Health Workers (LHWs) in Pakistan and Community Health Extension Workers (CHEWs) in Nigeria were correctly able to identify cases , 14; AccMagnesium sulfate \u2013 the World Health Organization (WHO) recommended medication for the treatment and prevention of seizures related to severe pre-eclampsia  - is ineThese studies further examined the feasibility of task-sharing aspects of care for women with HDP , 18, in The two papers in this supplement on task sharing provide further important evidence on known strategies , 18 inclIn several of these countries, the CHWs are multi-purpose, delivering as many as 23 activities and services including nutrition, newborn care, health promotion and prevention and curative care for children . With thThe authors of the CLIP Feasibility Studies report a number of enablers and barriers in each setting, which have informed the implementation of the currently underway CLIP cRCT. This supplement adds to the knowledge base of HDP by revealing the diverse community perspectives on determinants of maternal health, variant health worker knowledge and routine management on HDP, and viability of task sharing for preeclampsia identification and management in select settings. These studies demonstrate the need for strategies to improve health worker knowledge and routine management of HDP and consideration of expanding the role of CHWs to reach the most remote women and families with health education and access to health services.We hope the readers of Reproductive Health find this supplement to be a rich resource for further understanding how best to improve the quality of maternal and perinatal health care in these settings and beyond."}
+{"text": "In the studied units it isgenerated common waste (52-60%), infectious-sharps (31-42%) and recyclable(5-17%). The average rates of generation are: 0,09kg of total waste/outpatientassistance and 0,09kg of infectious-sharps waste/outpatient procedure. Thecompliance with regulations, initially 26-30%, then reached 30-38% a year later. the tool showed to be easy to use, bypassing the existence of a complex range ofexisting regulatory requirements, allowed to identify non-conformities, pointedout corrective measures and evaluated the performance of waste management. In thissense, it contributes to decision making and management practices relating towaste, tasks usually assigned to nurses. It is recommended that the tool beapplied in similar healthcare units for comparative studies, and implementation ofnecessary adaptations for other medical services. Services provided in healthcare facilities generate considerable amount of solid wastedenominated as a whole, Healthcare Waste (HW). Much of this waste (75-90%) is consideredsimilar to those generated in households (recyclable or not)-The management of HW involves planning, implementation and monitoring of actions thataim to prevent exposure, ensure the safety of users and professionals involved, preventthe occurrence of environmental impacts while minimizing the generation of waste-Although the management of HW is routinely practiced by healthcare facilities, studiesin developing countries* suffered progressive updates, involving the ministries of Health,Environment and Labor, ending with the establishment of the National Policy of SolidWaste in 2010. All these Brazilian regulations and directives, which are aligned andcomplementary, provide that any healthcare facility in the country, regardless of sizeand complexity of the service, is responsible for managing its waste, and must prepare,implement and monitor its Healthcare Waste Management Plan (HWMP).In Brazil, in the last two decades, the legal and regulatory framework geared toHW,-HWMP is the document that describes all internal and external steps for the managementof waste in healthcare services, in order to prevent occupational accidents, to avoidenvironmental impacts and to protect the public healthThe literature indicates that the simple formulation of the HWMP, involving multipleaspects such as sanitary, environmental, health, and safety of the workers, has been amajor challenge for healthcare institutions. Factors such as the lack of economicresources for the purchase of materials or equipment needed and the shortage of humanresources also hamper the subsequent stages of implementation and monitoring plan.In 2005, a study covering 21 hospitals and 48 outpatient public units of the State ofRio Grande do Sul, Brazil,The nursing sector has a key role in the management of waste, considering that isdirectly involved in the generation of HW and is often commissioned to theadministrative management of healthcare units because of the understanding of thecomplexity and the organization of these servicesIn practice, the presence of these qualified professionals has not happened, which isworrying. In the surgery department of an university hospital in Egypt, which provide basichealthcare services that do not require hospitalization  are also called upon to properly manage their waste, according to the rulesin force in the country In December 2015, existed in Brazil 34,951 PHCs in activityIn this context, in order to support the work of healthcare facilities managers on theissue of management of HW, this paper aims to propose a facilitation tool, to supportthe diagnosis, formulation and evaluation of HWMP in PHCs, and present the results ofthe application of this tool in four units of the city of S\u00e3o Paulo. The merit of thisinstrument is the integration of the interdisciplinary among the subject areas involvedand the systematization of current legislation.This is a descriptive study, which used as a research method the multiple case study,applied in four PHCs (identified from PHC-A to PHC-D) in the city of S\u00e3o Paulo, Brazil,during the period from February 2011 to February 2012. The selection criteria of theunits considered all the PHCs that constituted, at the time, the West Project - apartnership for management between the Faculty of Medicine Foundation of the Universityof Sao Paulo (USP) and the Municipality of Sao Paulo Administration. The PHC-D wasanalyzed together with an Emergency Healthcare Unit  because they sharedsome services  and the outsourced cleaning service.This study consisted of three stages: i) design of a facilitation tool for diagnosis,formulation and evaluation of HWMP using as indicators: waste generation and performanceanalysis; ii) application of the tool in four PHCs, resulting in two consecutivediagnoses regarding the management of waste in 2011 and one year after; and iii)comparative evaluation of both diagnoses.The facilitation tool was formulated from the systematization of the existing legal andregulatory framework in the country, in the state and in the city of S\u00e3o Paulo, and theBrazilian technical standards, resulting in five forms identified from F-I to F-V.daily amount of totalgeneration and by group (kg/d and percentage) and two more appropriateindicators to represent the production of waste in services that provide care withouthospitalization: generation rate per outpatient assistance* andgeneration rate per outpatient procedure** performed in criticalareas***. To feed the indicators of generation, weighing was performed ineach PHC for five consecutive days (one working week of operation), recording thegeneration of each source sector , separately bywaste group: A (infectious), D (common: recyclable and non-recyclable) and E(sharps). Radioactive waste (group C) and chemical (group B) were not consideredbecause the former is not generated in the PHC, while the chemicals still presentincipient segregation. For infectious materials it was used the sum (A+E) becausethey are collected and treated jointly in this city. The values jotted down in theform (F-IV) are the average of values found in the five weighing procedures.Additionally, through administrative records in the studied PHCs, it was computed thedaily average of assistances and the daily average ofprocedures performed in critical areas (recorded in form F-I). Therate of total waste generation per assistance is obtained bydividing the daily average of total waste by the daily average of assistances. Therate of infectious and sharps waste generation (A+E) results fromthe ratio of the daily average of waste by the daily average of procedures performedin the sectors that produce such waste .1. Waste generation indicators: in the literature, these indicators are used toassess whether the generating institution adopts measures to reduce waste productionand performs the separation into different groups to give the appropriate destinationto each group. The indicators selected for this study: 2. Indicator of performance: represented by the scores that resulted from theevaluation of compliance with 142 regulatory requirements contained in Form V (F-V).For completing this form, various techniques were used: survey of secondary data,available documentation , interviews with leaders of different sectors, and on-site observationrecorded in a diary. During the application of the tool, the information collected bythe authors, fed the F-V, which resulted in two diagnoses of managerial andoperational situation of the HW of the four PHCs in 2011, and a year later, a perioddeemed as reasonable for the implementation of the HWMP. The evaluation of the HW management performance in each of the PHC under study,resulted from comparing the diagnoses in the two periods considered, before and afterthe implementation of the plan.Regarding the ethical aspects, the research project was approved by the Ethics andResearch Committees of the Public Health School/USP (OF. COEP 210/10), and of theMunicipal Health Department (CEP/SMS 361/10).facilitation tool. Thefive forms (F-I to F-V) that make up this instrument are described briefly in thefollowing.All requirements and applicable legal requirements - for health, environmental andlabor issues - were incorporated into the Information on the generator facility and responsible: itinvolves data on the location, physical and operational structure of theestablishment; registration data in the competent agencies; amount of human resourcesby function; monthly average of assistances and procedures, and liability relating toHW management and security.F-I. Characterization of the internal flow of waste by sourcesector: it involves the relationship of waste generated separately bygroups (A to E) and by source sector. Lends itself to mapping the property incritical and non-critical areas and the determination of the collection flow. Thesedata help in the distribution planning and calculation of the number and capacity ofthe needed containers, regarding the more efficient segregation and reduction ofwaste.F-II. Description of the external flow and measures to mitigategeneration: identifies the destination of waste indicating the collectioncompanies and receiving units of different waste streams. This information becomes important, as the generator islegally co-responsible for external stages of management. In addition, it assists inthe decision of minimizing the generation and optimization of costs.F-III. Records of indicators of generation and waste minimizationgoals: keeps the record of three indicators, fed with the resultsobtained by measurements and information gathered in the unit, regarding the numberof outpatients assistances and procedures performed during the period: i)rate of daily average waste generation by group (A to E) and therespective percentages; ii) rate of total waste generation perassistance (kg/assistance); and iii) rate of infectious andsharps waste generation (A+E) per procedure in critical areas(kg/procedure).F-IV. The use of these indicators enables the evaluation of the institution's performancein relation to minimizing waste both at whole as per sectors, and supports futuredecision-making. The goals outlined in this form may be checked during the period duefor their achievement or at the time of reapplication at a future date.Checklist of regulatory requirements: this form resulted in 142regulatory requirements, divided into 3 blocks: B1- documentation required; B2-preventive actions to avoid health and environmental risks and B3- steps of theinternal management . F-V. Answers to the checklist allow assessing whether relevant measures for the managementof HW are being adopted. Each requirement may take the following forms: S(Compliant), P , N (Not compliant), and NA (Not applicable). Theun-weighted sum of requirements met, generates a score that reflects the performanceof the unit analyzed. The challenge is to reach 100% of positive responses (S). Asthe documentation is provided, equipment is purchased and used, training programs aredeveloped and operational practices are corrected, the score increases, raising theperformance level and stimulating the search for better results. As an illustration,In 2011, all forms of the tool were filled with data at each PHC under study. Waste quantification  indicateIn 2011, there were significant fluctuations in generation rates in the four PHCs.The PHC-C showed the highest values and PHC-D the smallest . Among tIn the second diagnosis, carried out in 2012, the quantification of waste and theconsequent application of the F-IV were affected, considering that management andoperating practices to provide the minimization of waste have not been adopted in anyof the four PHC. Then, the situation one year after, remained virtually the same asthe previous year.The application of F-V was feasible in 2011 and 2012. However, the results showedthat progress in performance management of HW in the PHC under study, was negligible,considering the 142 items to be met .The pro-,Inadequacies in the management of HW and consequent occupational and environmentalsituations of risk are often highlighted in studies conducted in hospitals in developingcountriesIn this study, specifically referring to waste on PHCs, management, operation andinfrastructure failures have been identified, comparable to those mentioned in theliterature. This situation indicates that the legal requirements are not being met,putting at risk the safety of health and cleaning workers as well as users, familycaregivers, workers of the external collection, informal waste pickers and even theenvironment.,In line with previous studies-It is noteworthy that, despite the recommendations set out in studies conducted indifferent countries-,--,-It is also apparent that the most widely used generation indicator in literature - dailyrate per hospital bed (kg of waste/bed.day)generation rate per assistanceand generation rate per procedure in critical areas. It isunderstood that this specificity brings greater reliability to the quantification ofwaste and is more appropriate for outpatient units. The rate of total waste generationper assistance in the four studied PHCs ranged from 0.05 to 0.17kg .This value appears to be higher than the value found in other PHC in Sao PauloIn this study, we proposed two more specific indicators to characterize the generationof waste in outpatient units: In the literature is also remarkable the lack of tools to assess the performance of theHW management. Generation and performance indicators as proposed in the present study,lend themselves both to assess progress in the same unit over time, as well as forcomparison and ranking of PHCs, at any given time.In the PHCs under study, the documented way of exposing the nonconformities served as awarning, however it was not enough to motivate their managers to invest in adapting themanagement of HW. Limiting aspects considered were: the delay in political decision ofthe PHC responsible for the management, and the lack of human and financial resources tomake the needed repairs and improvements.The proposed tool seeks to fill the identified gaps enabling the following procedures:Joint visualization of legal requirements dispersed in different regulatory areasinvolved ; Application by non-experts on the issue, afterbrief training; Identification of structural, operational and behavioral failures in thehealthcare facility; Easy identification of corrective measures to be implemented afteridentification of non-conformities; Setting goals and deadlines; Comparison of resultsin consecutive evaluations, in the same unit, and assessments between different units,evidencing the performance of the HW management; Minimizing the subjectivity of theevaluator; and Achievement of more consistent, reliable and measurable results, formaking decisions.This tool, which organizes all the requirements and legal requirements, may contributeto healthcare management practices, tasks usually attributed to nurses. When fullycompleted, the tool also has the role of documentary record of the healthcare facilitysituation at the completion dates.Because it is an easy-to-handle tool, generating consistent and comparable results, itis recommended to apply this tool in other similar outpatient units, public or privateservices that have size, type of service and of similar HW characteristics.It is also recommended that, for dental, veterinary and even hospitals this tool shouldbe adapted to meet the specific needs of these units. For facilities in othermunicipalities, excluding Sao Paulo should be considered the state and municipalregulations in force."}
+{"text": "The conjunction of this narrow therapeutic index and the considerable inter-individual differences in distribution, metabolism and excretion of these cytotoxic agents in humans, results in increased risks of toxicity and sub-therapeutic dosing in the individual patient [Drug developers recruit and combine principles, procedures and strategies from chemistry, pharmacology, nanotechnology and biotechnology, focusing on the generation of functional vehicles as nano-carriers of drugs for improved stability and enhanced intracellular delivery. By exploring macromolecules such as lipids, polymers and proteins, both biocompatibility and cost-effective fabrication are favored, and a plethora of opportunities for architectonic and functional adaptation of vehicles to particular cargo drugs and therapeutic conditions enlighten the cancer treatment scenario. Molecular vehicles specifically developed as carriers for drugs are usually referred to as drug delivery systems (DDS). The application of nanoscale technologies has resulted in an already vast but still expanding catalogue of drugs and appropriate DDS, whose implementation in therapy is heavily represented in the different phases of drug development, from basic research to clinical trials . DDS, as patient .+ prostate cancer cells are representative examples [This landscape may soon change since many actively targeted nanoparticles for drug delivery are being evaluated in clinical assays . Among texamples . We expeexamples , and Breexamples . Current"}
+{"text": "Editorial on the Research TopicMolecular Dynamics at the Immunological SynapseMartin-Cofreces et al.;  is a specialized cell\u2013cell adhesion that mediates antigen acquisition, lymphocyte activation, and effector function. Seminal studies showed a structure composed of stable central and peripheral supramolecular activation clusters (cSMAC and pSMAC) organized at the interface of interacting helper T lymphocytes and B lymphocytes. The T cell receptor (TCR) and signaling molecules were found accumulated at the cSMAC, whereas the integrin LFA-1 and cytoskeleton components distributed at the pSMAC . Current et al.; , 4]. It  et al.; , 6. The  et al.; \u20139. Much Kapoor-Kaushik et al. provide a piece of original data to discuss how the spatial organization of Lck is regulated in activated T cells. Although the open conformation promotes clustering, signaling downstream the TCR further controls the spatial organization of Lck. Regarding the role of integrins in the triggering of the TCR and T cell activation, Hashimoto-Tane and Saito have recently demonstrated the existence at the IS of adhesion rings of integrins and focal adhesion molecules surrounding TCR-containing microclusters. This so-called microsynapse is proposed to support weak TCR activation via cell\u2013cell local adhesion signals.This research topic (RT) contains 10 articles that cover different aspects of the molecular dynamics at the IS. Data are contributed on the spatial regulation of the signaling molecule Lck, an important molecular requirement for TCR triggering. With the assistance of super-resolution microscopy, Comrie and Burkhardt is how mechanotransduction, the transformation of mechanical forces into biochemical modifications, contributes to the TCR triggering and the intracellular signaling. The authors focus on the role of mechanical forces directed by filamentous actin (F-actin). The review contributed by Hivroz and Saitakis focuses on other mechanical clues that regulate T cell activation, including the effect of membrane protrusions and oscillations, cell mobility and spreading, the TCR engagement itself, or the engagement of LFA-1 during the IS formation.One novel and timely aspect discussed by Ramirez-Munoz et al. propose that a local action of the cofilin activator Slingshot-1 at the IS might mediate an ultrasensitive/bistable response of the cofilin signaling module. This signaling module might then contribute to the specific and sensitive responses of na\u00efve T cells and the more efficient and faster activation of antigen-experienced T cells.Regarding the regulation of F-actin regulators, Benvenuti, who focuses her attention on the role of actin regulators, such as fascin and WASp, among others. The author also discusses about DC polarity and secretion induced by maturation stimuli. For example, the Cdc42-mediated polarization of the MTOC controls the delivery of IL-12 to the DC-T cell IS, a process mediated by VAMP7. Thus, it is envisaged that the activating signal three (inflammatory cytokines) is coupled at the IS to the activating signals one (TCR) and two (costimulation).The relevance of the cytoskeleton remodeling at the dendritic cell (DC) side is discussed by Onnis et al.. The authors revise the different Rab GTPases controlling the recycling routes targeting different receptors, such as the TCR and CXCR4, to the IS. They also highlight the recently noticed role of components of the intraflagellar transport system in controlling the traffic of the TCR to the IS downstream the centrosome polarization. This contribution poses the notion that IS and cilium constitute functional homologs. Important mechanisms of cell\u2013cell communication are also described, including the trogocytosis and the local delivery of exoxomes and microvesicles.The dynamics of the endosomal compartment is discussed in the review by Niedergang et al. remark this parallelism and discuss the organization, mechanism of assembly, and regulation of both structures. They pay attention to immune and phagocytic receptors, the interplay of the actin and tubulin cytoskeleton and the vesicular traffic. Discussion is provided about the role of soluble N-ethylmaleimide-sensitive factor attachment protein receptors and Rab GTPases in polarized vesicular traffic.Spatial organization of the IS also resembles the phagocytic cup, leading to the concept of the phagocytic synapse. Brzostek et al.. They describe the function of CD28 and CTLA4 in the immune response, the regulatory role in the cytoskeleton dynamics and signaling and the distribution to the IS in effector and regulatory T cell.The structure and function of costimulatory and coinhibitory receptors upon the engagement of B7 molecules expressed on APCs are discussed by Rocha-Perugini et al. discuss the role of tetraspanin-enriched microdomains in the local accumulation of receptors, adhesion molecules, and integrins at the IS. Associations are described between IS-located tetraspanins, several signaling molecules, and the actin cytoskeleton.In summary, this RT highlights the fine-tuned molecular dynamics at the IS that allows proper T cell activation and effector functions. Methodological and technical advances in microscopy techniques improving spatial and temporal resolution are helping us to understand how the dynamics of the cytoskeleton and the endosomal compartment reorganizes micro and nanodomains of signaling complexes that, in turn, mediate lymphocyte immune responses. In addition, complementary biophysical approaches as well as the comparison with biological systems mentioned in this collection may provide useful hints to unravel the complexity of ISs.PR-N wrote the first draft of the manuscript and updated the last version. AA and VB corrected and completed the initial draft.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "European Journal of Psychotraumatology focuses on traumatized refugees. It includes three review articles as well as four original articles on the mental health burden, screening instruments and interventions in different groups of refugees. The articles published in this special issue focus on important aspects of better understanding the needs of traumatized refugees, as well as on identifying and offering appropriate mental health care for this population. Future research recommendations are provided in the hope to contribute to improving mental health care strategies of this still underserved population.In the past few years the number of refugees worldwide has increased dramatically. Many of them were traumatized in their homelands due to violent conflict or persecution, as well as during their flight, and are confronted with ongoing stressors in the exile countries. In order to contribute to enhancing the clinical knowledge, this special issue of the  International studies show that refugees suffer from increased rates of short-term and long-term mental health problems: approximately one in three refugees is suffering from PTSD or other trauma-related mental disorder (Bogic, Njoku, & Priebe, European Journal of Psychotraumatology has a strong tradition focusing on global mental health issues and populations forced to migrate (see special issues Hall & Olff, In a systematic review and meta-analysis, an overview of the effectiveness of psychosocial interventions for displaced war-traumatized minors is provided focusing on symptoms of PTSD, depression, anxiety, grief and general distress (Nocon, Eberle-Sejari, Unterhitzensberger, & Rosner, The third review article focuses on the special situation of Syrian refugees, their mental health conditions, and scalable evidence-based interventions. It outlines the newly launched STRENGTHS programme for adapting, scaling up and testing Problem Management interventions (Sijbrandij et al., Very little research has been done on the validity of instruments for refugee populations (Wind, van der Aa, de la Rie, & Knipscheer, This issue continues with the cultural adaptation and evaluation of a CBT programme for Farsi-speaking refugees, that was conducted with male refugees from Afghanistan and Iran (Kananian, Ayoughi, Farugie, Hinton, & Stangier, In the third research article, 76 adult patients at a treatment centre for torture victims and traumatized refugees were surveyed in the context of their regular multidisciplinary psychotherapeutic treatment (Stammel et al., Finally, a group-based multidisciplinary day patient treatment for refugees who experienced multiple traumatic losses was evaluated (de Heus et al., European Journal of Psychotraumatology looks forward to receiving more papers focusing on traumatized refugees, to improve the mental health care strategies of this underserved population.The articles published in this special issue focus on important aspects to better understand the needs of traumatized refugees, as well as on identifying and offering appropriate mental health care for this population. Cultural sensitive psychotraumatology remains a priority (Schnyder et al.,"}
+{"text": "Studies emphasize the training of cognitive functions to decrease losses in the population. Memory training associated with neurotracker was performed by an 80-year-old man with memory complaints. A battery for measuring memory, quality of life and stress was initially applied and showed low scores. The patient underwent a program for stimulating memory and attention comprising 32 sessions (2 weekly sessions of 90 minutes each). The post-test follow-up showed improvements in the process of storage and retrieval of episodic and working memory, greater use of strategies, faster information processing speed, as well as reduction in complaints and positive impact on quality of life. The results suggest that the use of Neurotracker for training cognitive processes is valid for cognitive rehabilitation programs to promote improvements in quality of life in the elderly. In this scenario, cognitive rehabilitation programs for stimulating cognitive functions have become commonplace, proving effective in reducing cognitive deficits.The study by BalardinThe study of Barnes et al.,,In this context, many computerized techniques have proven useful resources for cognitive training.Thus, the present study reports the results of a memory training program incorporating the Neurotracker with pre and post-intervention cognitive assessments.We report the case of S.Z., an 80-year-old, right-handed male, married with four children, holder of a Doctorate in architecture and living with family members in S\u00e3o Paulo. There was no history of alcoholism, smoking or pathologies relevant to this report. The patient sought medical assistance in 2014 after presenting frequent memory complaints. Clinical and functional assessments conducted by a neurologist and neuropsychologists revealed no symptoms of cognitive impairment. This result was obtained based on clinical observations and on the Daily Activities Scale and Mini-Mental State Exam,The patient was undergoing medical and neurological treatment with the following medications: Galvus Met 850 mg, Betaserc 24 mg, Lipitor (Atorvastatin) 20 mg, Puran T4 50 mg, Rivotril (Clonazepam) 1 mg, Nexum 20 mg, Fluoxetine 20 mg, Benicar 20 mg, and Vitamin D, 8 gts.In August 2014, the subject was referred for assessment and brain performance training at the Neuropsychology Unit of the Institute of Psychiatry of the Clinicas Hospital of the University of S\u00e3o Paulo School of Medicine. The initial assessment included direct observation of the patient, determination of intelligence quotient, completion of a brief questionnaire on motivation, expectations and impairment prior to training, application of scales measuring self-conception and self-perceived memory, stress, anxiety, depression and quality of life. Tests of attention, memory, information processing speed and reaction time, simple and entailing selection, were also performed. All participants signed the free and informed consent form.The results of the pre and post-training cognitive assessments are given in both Pre-training and training. Intellectual performance was assessed using two sub-tests from the Wechsler Abbreviated Scale of Intelligence - WASI,The subject exhibited no depressive symptoms ,The Colored Trails TestPerformance on the Memo Checkup (randomized computerized test for assessing accuracy of episodic and working memory), showed medium episodic memory and significantly lower-than-expected working memory for age (Graph 1). NeurotrackerAfter the initial assessment battery, the intervention consisting of individual sessions of 90 minutes, twice per week, was run for a 12-month period. The computer was used for the cognitive training, both to access the Neurotracker software and run the Memory Training sessions. The sessions were devised according to the consciously learned mnemonic strategies which required effort to put into practice. The training employed verbal and visual mnemonic methods (image and rhyming cues), expanded repetition , errorless learning (technique for avoiding errors while learning new information), cue removal , PQRST , association , production (similar to association only sentences must be created for the register) and the categorization process (forming classes of the information to be memorized).At the post-training stage, improvements were evident in self-perceived attention, memory, quality of life and self-confidence on the M&M Scale. A similar result was found for perceived subjective memory on the MAC-Q scale.Greater use of the strategy trained was seen on the episodic memory task, suggesting that cognitive training acts as feedback, rendering visible the improvements and consequently, perceptions in terms of well-being and learning strategies, corroborating the results of other studies.,A reduction in stress symptoms was also observed, in line with studies suggesting that cognitive training serves to help improve stress symptoms.Training proved effective for sustained and alternating attention, with above-average cognitive flexibility on the Colored Trails testResults of the computerized memory test showed changes in score during and after training. The results, despite fluctuating at some points, showed a steadily rising curve for both Accuracy and Processing Speed on the test (Graph 1).Positive results were also obtained on the Neurotracker, the computerized stimuli employed, in the form of a rising curve for scores comparing accuracy, speed and difficulty provided by the software .1,2,8The results indicate that the use of the Neurotracker for training cognitive processes is valid as part of cognitive rehabilitation programs promoting improvements in the quality of life of the elderly, corroborating the results of previous studies.,Political issues regarding costs of pension, welfare and healthcare systems oblige societies to seek ways of improving assistance in the aging process. The psychological universe of older adults, besides the biological spectrum , also encompasses individual potentialities , in addition to influences from the environment and the sociocultural context.Given this scenario, such assistance should include computerized cognitive training programs in private and public institutions for elderly care to improve quality of life and delay the signs of senility during the aging process. Future studies focusing on the development of new techniques and furthering this area should also be encouraged."}
+{"text": "Fibromyalgia syndrome (FMS) is a chronic condition characterized by widespread pain accompanied by symptoms like depression, anxiety, sleep disturbance and fatigue. In addition, affected patients frequently report cognitive disruption such as forgetfulness, concentration difficulties or mental slowness. Though cognitive deficits in FMS have been confirmed in various studies, not much is known about the mechanisms involved in their origin. This study aimed to investigate the contribution of affect-related variables to cognitive impairments in FMS. For this purpose, 67 female FMS patients and 32 healthy control subjects completed a battery of cognitive tests measuring processing speed, attention, visuospatial and verbal memory, cognitive flexibility and planning abilities. In addition, participants completed self-report questionnaires pertaining to positive and negative affect, alexithymia, pain catastrophizing and self-esteem. Clinical characteristics including pain severity, symptoms of depression and anxiety, insomnia and fatigue were also assessed. FMS patients showed markedly poorer performance than healthy controls in all of the cognitive domains assessed, in addition to greater levels of depression, anxiety, negative affect, alexithymia and pain catastrophizing, and lower self-esteem and positive affect. In exploratory correlation analysis in the FMS sample, lower cognitive performance was associated with higher pain severity, depression, anxiety, negative affect, alexithymia and pain catastrophizing, as well as lower self-esteem and positive affect. However, in regression analyses, pain, self-esteem, alexithymia, and pain catastrophizing explained the largest portion of the variance in performance. While interference effects of clinical pain in cognition have been previously described, the present findings suggest that affective factors also substantially contribute to the genesis of cognitive impairments. They support the notion that affective disturbances form a crucial aspect of FMS pathology, whereas strategies aiming to improve emotional regulation may be a beneficial element of psychological therapy in the management of FMS. Fibromyalgia syndrome (FMS) is a chronic disorder characterized by widespread musculoskeletal pain and accompanying symptoms like depression, anxiety, sleep disturbance and fatigue. Its prevalence is estimated at 2\u20134% in the general population, with women being predominantly affected . FMS is Complaints about cognitive disruption, such as forgetfulness, concentration difficulties or mental slowness are also frequent in FMS patients. These impairments, also referred to as \u201cfibro fog,\u201d may significantly affect patients\u2019 everyday life and therefore are perceived to be among the most serious symptoms of the disease . ProblemThough the occurrence of cognitive impairments in FMS has been well-established, not much is known about the mechanism involved in their origin. Interference effects of nociception and pain have been considered a relevant factor, as supported by studies showing positive correlations between the severity of clinical pain and the magnitude of cognitive decline . Pain isWhile most available FMS studies on the implications of affect-related variables in cognitive impairments refer to symptoms of depression and anxiety, mood states  have not yet been specifically addressed. Positive and negative affect are regarded as virtually independent dimensions, where positive affect implies enthusiasm, activity and vitality-energy, while negative affect constitutes a general state of distress including aversive emotions like anger, fear and guilt . There iAffect-related coping styles may also be of interest in the present context. Alexithymia is conceptualized as a personality trait related to deficits in the cognitive processing of emotions that involves a lack of emotional awareness, difficulties in identifying and communicating feelings and an externally oriented thinking style , 2006. SFinally, self-esteem may be another relevant aspect. Self-esteem is a component of self-concept defined as an individual\u2019s set of thoughts and feelings about his or her own worth and importance, resulting in a global positive or negative attitude toward oneself . There iIn sum, affect-related factors, including affective dysbalance, alexithymia, pain catastrophizing and low self-esteem, may contribute to cognitive impairments in FMS, in addition to pain experience and symptoms of emotional disorders. However, knowledge concerning the actual magnitude of their impacts remains scarce. Therefore, the main objective of the present study was to evaluate the relationship between self-report measures of these factors and performance on a comprehensive battery of cognitive tests measuring processing speed, attention, visuospatial and verbal memory, and cognitive flexibility, as well as mental planning and organizational skills. Clinical characteristics including pain severity, symptoms of depression and anxiety, as well as sleep disturbance and fatigue were regarded as additional predictors. Moreover, in order to quantify the magnitude of the cognitive decline in the investigated FMS patients, their test performance was compared with a control group of healthy individuals matched for relevant sociodemographic variables.The following hypotheses were tested in the study: (1) Positive affect is positively, and negative affect is inversely, related with cognitive performance in FMS patients. (2) Higher levels of alexithymia and pain catastrophizing, and reduced self-esteem, predict lower performance. (3) Clinical pain severity, symptoms of depression and anxiety, as well as insomnia and fatigue demonstrate inverse associations with test performance. (4) In addition, FMS patients perform poorer than healthy individuals on the applied cognitive tasks.In total, 67 women with FMS, recruited from the Fibromyalgia Association of Ja\u00e9n (Spain), participated in the study. All of them were examined by a rheumatologist and met the 1990 American College of Rheumatology criteria for FMS . The conRey-Osterrieth Complex Figure Test (ROCF) (The t (ROCF)  was usedVerbal Learning Test (TAVEC) (The  (TAVEC)  was usedZoo Map Task (ZMT) from the Behavioural Assessment of the Dysexecutive Syndrome  was applied as a measure of strategic planning and self-regulation (The gulation . The tasTrail Making Test (TMT) was used to evaluate processing speed, attention and cognitive flexibility. The version of The The patients\u2019 clinical history and demographic data were obtained in a semi-structured interview. The Structured Clinical Interview for Axis I Disorders of the Diagnostic and Statistical Manual for Mental Disorders SCID,  was applMcGill Pain Questionnaire (MPQ) (re (MPQ) . This 73re (MPQ) .State-Trait Anxiety Inventory (STAI) (y (STAI) . This iny (STAI) .Beck Depression Inventory (BDI) (ry (BDI) . This 21Fatigue Severity Scale (FSS) (le (FSS) . This scOviedo Quality of Sleep Questionnaire (COS) (re (COS) . The InsPositive and Negative Affect Scale (PANAS) ( (PANAS) . This quToronto Alexithymia Scale (TAS-20) ((TAS-20) . This inCoping Strategies Questionnaire (CSQ) (re (CSQ) . The 6-iRosenberg Self-esteem scale (SS)  . On thisThe study was conducted in two sessions performed on the same day. During the first session, a clinical psychologist took the patients\u2019 clinical history, recorded sociodemographic data and medication use, and evaluated possible violations of the exclusionary criteria. After that, SCID interviews were conducted and the psychometric questionnaires presented. In the second session, the neuropsychological tests were administered in the following order: ROCF (copy), ZMT, R-SAT, ROCF (reproduction), TAVEC , TMT, and TAVEC . The tests were presented in this order to avoid an interference effect of different cognitive domains, especially between visual and verbal memory. Between each test, participants had a break of 5 min. The study protocol was approved by the Ethics Committee for Human Research of the University of Ja\u00e9n and all participants provided written informed consent.t-tests and \u03c72-tests. Group differences in cognitive performance were analyzed by means of multivariate analysis of variance (MANOVA). Age, years of education and body mass index were entered as covariates in this analysis. Effects of medication use and comorbid depression and anxiety disorders were evaluated by stratified analyses done for the FMS group (MANOVA) that compared patients using and not using each type of medication , and comparing patients suffering and not suffering from depression and anxiety disorders. Effect sizes are indicated by adjusted eta squared . Firstly, at an exploratory level, Pearson correlations were computed. Secondly, multiple regression analyses were performed. Two blocks of variables were used as predictors in the analyses: (1) to control for the effects of age, body mass index and years of education, these variables were entered simultaneously (enter method); (2) to determine psychological predictors of cognitive performance, questionnaire scales that showed significant correlations with neuropsychological parameters in the exploratory analysis were included (stepwise method). SPSS software (version 19.0) was employed for data analysis .Associations between questionnaire scores and neuropsychological test results were evaluated in two steps, both restricted to the FMS group  FMS patients and 10 (45%) healthy participants exhibited TAS-20 values above the cut-off score.F = 3.11, p < 0.0001, Table 2 displays the means and standard deviations of the performance indices, together with the statistics of the univariate group comparisons. The results for most test parameters reflect lower task speed and accuracy in FMS patients than controls. Differences were significant for all speed and accuracy parameters of the ROCF (copy and reproduction conditions) and TAVEC . In the ZMT, group differences were seen in the total number of correct responses, execution time for both versions and mistakes in version 1. On the R-SAT, differences arose for the number of correct responses (short items). Among the parameters of the TMT, execution times for the number sequence, letter sequence, switching and motor speed tasks, as well as set loss and time out mistakes, differed between groups. The covariates of age, years of education and body mass index were non-significant. No differences were found between subgroups of patients taking and not taking antidepressants, anxiolytics, non-opioid analgesics, or opioids, or between patients suffering and not suffering from comorbid depression or anxiety disorders .The MANOVA for the neuropsychological test scores showed a multivariate group effect  on the MPQ correlated negatively with the number of correct marks on both conditions of the ROCF and the correct responses in the recognition task of the TAVEC. This score correlated positively with execution time during the number sequence, letter sequence and motor speed tasks of the TMT, omission errors and false positive responses in the TAVEC recognition task, set loss and time out mistakes on the TMT, and execution time during version 2 of the ZMT. The sensorial and total pain scales correlated negatively with the number of correct responses on the ZMT, and positively with execution time during version 2 of this test. Emotional pain correlated negatively with correct responses on the TAVEC recognition task, and positively with omission errors and false positives. Trait anxiety (STAI) was positively associated with execution time during the copy condition of the ROCF, and with the visual scanning and motor speed tasks of the TMT. State anxiety was inversely associated with the number of correct responses (short items) on the R-SAT, and with the number of correct recognition responses, long-delay recall and the discrimination score of the TAVEC, and positively associated with long item mistakes on the R-SAT, omission errors in the TAVEC recognition task, and execution time during the TMT motor speed task. Depression (BDI) correlated positively with the number of long item mistakes on the R-SAT and set loss mistakes on the TMT, and negatively with correct responses on the R-SAT. Fatigue (FSS) correlated positively with execution time during the motor speed task of the TMS. No significant correlations arose for insomnia (COS).Table 4 includes the correlations of the questionnaire scores for positive and negative affect, alexithymia, pain catastrophizing and self-esteem with the indices of neuropsychological test performance in FMS patients. Positive affect (PANAS) was inversely associated with execution time during version 2 of the ZMT, omission errors and false positives on the TAVEC recognition task, execution time during the visual scanning, number sequence, letter sequence and switching tasks of the TMT, as well as set loss and time out mistakes on the latter instrument. Moreover, positive affect correlated positively with correct responses (short items) on the R-SAT, and recall (List B) and recognition performance on the TAVEC, as well as the discrimination score provided by this test. Negative affect (PANAS) correlated positively with face item mistakes on the R-SAT, false positives on the TAVEC recognition task, execution time during the visual scanning task of the TMT, and sequence and set loss mistakes. Negative affect correlated negatively with execution time during version 1 of the ZMT.Alexithymia (TAS-20) correlated negatively with the number of correct marks in the copy condition of the ROCF, and with correct recognition responses and the discrimination score of the TAVEC, and positively with execution time during the copy and reproduction conditions of the ROCF, the visual scanning, number sequence, latter sequence and switching tasks of the TMT, set loss and time out mistakes on the TMT, as well as omissions and false positives on the TAVEC recognition task.Pain catastrophizing (CSQ) correlated negatively with the number of correct recognition responses on the TAVEC, and positively with execution time during the reproduction condition of the ROCF, the number and letter sequence conditions of the TMT, long item and face item mistakes on the R-SAT, sequence and set loss mistakes on the TMT, as well as omissions errors and false positives in the TAVEC recognition task.Self-esteem (SS) was inversely associated with execution time during the copy and reproduction conditions of the ROCF, both versions of the ZMT, the visual scanning, number sequence, letter sequence, switching and motor speed conditions of the TMT, as well as set loss, sequence and time out mistakes on the TMT, and omissions and false positives in the TAVEC recognition task. Moreover, self-esteem correlated positively with the number of correct marks in the copy condition of the ROCF, correct responses (short items) on the R-SAT, and free recall performance (List B) and the discrimination score of the TAVEC.Table 5. Here, current pain intensity (VAS of MPQ) was inversely related to the number of correct marks in the copy and reproduction conditions of the ROCF and execution time during version 2 of the ZMT; and positively related to execution time during the number and letter sequence tasks of the TMT, and to set loss and time out mistakes on this test. The sensorial pain index was positively associated to mistakes in version 1 of the ZMT; emotional pain was inversely associated with correct responses, and positively with omission errors in the TAVEC recognition task. Depression (BDI) was positively associated with long item mistakes on the R-SAT. State anxiety (STAI) was positively associated with execution time during the motor speed task of the TMT and trait anxiety was positively associated with execution time during the copy condition of the ROCF.Significant results of the multiple regression analyses for the prediction of performance parameters, after controlling for the effects of age, years of education and BMI, are presented in Positive affect (PANAS) was inversely related to execution time during the switching task, and negative affect was positively related to execution time during the visual scanning task of the TMT. Alexithymia (TAS-20) was positively associated with execution time during the reproduction condition of the ROCF and the number sequence, letter sequence and switching tasks of the TMT, and with time out mistakes on this instrument. Pain catastrophizing (CSQ) was positively associated with face item mistakes in the R-SAT, false positive responses in the TAVEC recognition task, and sequence mistakes on the TMT. Self-esteem (SS) was inversely related to execution time during the copy condition of the ROCF, version 2 of the ZMT and the number sequence and motor speed tasks of the TMT. It furthermore was inversely related to false positive responses, omission errors in the TAVEC recognition task and set loss mistakes on the TMT. Self-esteem was positively associated with correct responses (short items) on the R-SAT, correct responses in the free recall (List B) and recognition tasks of the TAVEC, and the discrimination score of the test.This study revealed poorer performance in FMS patients vs. healthy individuals on neuropsychological tests of processing speed, attention, visuospatial and verbal memory, cognitive flexibility, as well as mental planning and organizational skills. According to an exploratory correlation analysis conducted in the patient group, test performance was associated with pain severity, symptoms of depression and anxiety, as well as affect-related variables including positive and negative affect, alexithymia, pain catastrophizing and self-esteem. In subsequent regression analyses, pain, self-esteem, alexithymia, and catastrophizing explained the overall largest portion of test score variance.The cognitive performance reduction in FMS patients confirms previous findings. The longer execution times during the number sequence, letter sequence and switching tasks, and the higher number of set loss and time out mistakes on the TMT, are in line with observations of deficits in attentional functions and processing speed . PatientIn the applied questionnaires FMS patients reported more severe symptoms of depression, anxiety, insomnia and fatigue than controls, which constitute typical bodily and mental symptoms accompanying FMS pain . ElevateAs its main aim, this study investigated the impact of FMS symptoms and affect-related variables on cognitive performance. Among clinical symptoms, pain severity was most closely related to neuropsychological test scores. In correlation analysis, high scores on the MPQ scales were associated with lower speed and accuracy on the attentional and planning tasks (TMT and ZMT), as well as fewer correct responses and more mistakes on both memory tests (ROCF and TAVEC). Similar associations also arose in regression analysis. The associations between MPQ scale scores and cognitive function are in line with previous FMS studies, where they were interpreted as indicative of an interference effect of pain with cognitive processing . DepressThe involvement of affect-related variables in cognitive impairment in FMS represents a novel aspect of this study. Positive affect demonstrated a close association with attentional and verbal memory performance. In correlation analysis, the corresponding PANAS scale score was predictive of faster performance and lower error rates in the visual scanning, number sequence, letter sequence and switching tasks of the TMT. This also applies to almost all TAVEC indices of verbal recall and recognition performance. A weaker association between positive affect and planning abilities is suggested by the negative correlation of the PANAS scale score with execution time during one of the two ZMT tasks, and by the positive correlation with correct responses on the R-SAT. Negative affect was related to more errors on the TMT, TAVEC and R-SAT and slower performance on one of the ZMT tasks. The associations of positive and negative affect with performance speed also arose in regression analysis. Beneficial effects of positive affect on cognition have repeatedly been reported in healthy individuals, for example in terms of facilitation of attentional processing, problem solving and decision making . AdverseAlexithymia also showed a close relationship with attentional and memory performance. The TAS-20 global score was positively related to execution time during the visual scanning, number sequence, letter sequence and switching tasks of the TMT, as well as to error rates in this test. It furthermore correlated negatively with speed and accuracy performance on the ROCF, and all parameters reflecting recognition ability on the TAVEC. The associations with the TMT parameters and reproduction performance on the ROCF were also seen in regression analysis. As a major source of emotional dysregulation, alexithymia has been implicated in somatosensory amplification, pain chronification and the pathogenesis of FMS . In addiSignificant associations with attention, memory and planning also arose for pain catastrophizing. The corresponding CSQ scale score correlated positively with mistakes on the TMT and R-SAT, and with execution time during the number and letter sequence conditions of the TMT and the reproduction condition of the ROCF. Furthermore, higher levels of catastrophizing were associated with fewer correct responses and more mistakes on the TAVEC. Less accurate performance in the TMT, TAVEC and R-SAT in patients with high catastrophizing scores was also reflected in the regression analysis. Pain catastrophizing is recognized as a crucial factor in the development of chronic pain, especially in FMS . CatastrFinally, low levels of self-esteem were related to poorer attentional, memory and planning performance. The SS score correlated negatively with execution time during the visual scanning, number sequence, letter sequence and switching tasks of the TMT, as well as with error rates on this test. Higher values were also associated with faster performance during all conditions of the ROCF and ZMT, and with improved free recall and recognition performance on the TAVEC. A large proportion of these relationships was also seen in regression analysis. The association between self-esteem and cognition may be mediated by motivational factors. Self-esteem is related to self-confidence and self-efficacy expectation . These vOne limitation of the study was the relatively small size of the control group, which may have limited the power of the statistical group comparison. Moreover, caution is required in the interpretation of the results of the exploratory correlation analysis considering the increased risk of alpha errors due to the high number of computed correlations. Regarding the selection of self-report scales, some relevant constructs may not have been taken into account. For example, emotional self-regulation, emotional competence or self-efficacy may be of interest in future studies. Finally, the conclusion of a causal contribution of affective factors to cognitive impairments in FMS cannot be drawn with certainty. By definition, the causal impact of cognitive deficits on affective variables, as well as mutual influences between cognition and emotion, also have to be considered.To conclude, this study confirmed marked deficits in the domains of attention, memory and executive functions in FMS and revealed new knowledge regarding the psychological factors involved in their mediation. Overall, affect-related variables, i.e., positive and negative affect, alexithymia, pain catastrophizing and self-esteem, were as closely associated with neuropsychological test scores as pain severity. Our findings underline the importance of these variables in the genesis of cognitive symptoms in FMS. As an important factor of FMS pathology, emotional aberrances may also be relevant with respect to optimizing psychological therapy of FMS. Techniques addressing affect-related variables may constitute a helpful component of cognitive therapy in the management of FMS . In addiAll authors contributed to the design of the study and to the analysis and interpretation of the data. CG-S conducted the experiment, acquired data, and drafted the first version of the manuscript. GRdP and SD critically revised and completed the manuscript and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer MA and handling Editor declared their shared affiliation."}
+{"text": "The world production of cement has greatly increased in the past 10 years. This trend is the most significant factor affecting technological development and the updating of manufacturing facilities in the cement industry. Existing technology for the production of cement clinker is ecologically damaging; it consumes much energy and natural resources and also emits pollutants. A new approach to the production of blended or high-volume mineral additive (HVMA) cement helps to improve its ecological compatibility. HVMA cement technology is based on the intergrinding of portland cement clinker, gypsum, mineral additives, and a special complex admixture. This new method increases the compressive strength of ordinary cement, improves durability of the cement-based materials, and - at the same time - uses inexpensive natural mineral additives or industrial by-products. This improvement leads to a reduction of energy consumption per unit of the cement produced. Higher strength, better durability, reduction of pollution at the clinker production stage, and decrease of landfill area occupied by industrial by-products, all provide ecological advantages for HVMA cement."}
+{"text": "Aims: This review aims to evaluate the most recent evidence on the pathophysiology of impulse control disorders (ICDs) in Parkinson disease (PD).Methods: Computerised searches of Medline, Embase and PsycInfo, along with manual searches for grey literature, were conducted and resulted in a total of 16 studies suitable for review.Results: Evidence was divided into four categories: medication used in PD management, imaging studies, genetic analysis and subthalamic deep brain stimulation (STN-DBS). Analysis of the literature reveals that both intrinsic and extrinsic factors may play a role in the pathophysiology of ICDs in PD. Dysfunction of the mesocorticolimbic pathway and polymorphisms of the dopamine D3 and D4 receptors may increase an individual's susceptibility to the development of ICDs.Discussion: Dopaminergic medication, particularly dopamine agonists (DAs), increases the risk of developing impulsive behaviours in a PD patient. Further evidence, particularly in the form of prospective studies and randomised controlled trials is required to better establish the pathophysiology of ICDs in PD."}
+{"text": "The Asia-Pacific region is a geographic source for emerging infectious diseases, including multidrug-resistant (MDR) organisms (MDROs) and pathogens with pandemic potential. Risks for emerging infectious diseases in this geographic region are complex and are presumed to include ecological, socioeconomic, and technological processes favorable to microbial transmission dynamics. In resource-limited settings, relative to resource-adequate settings, there continues to be a paucity of data in support of infection prevention and control, and patient safety interventions to ensure that regional, if not national, healthcare systems work effectively to improve infection prevention and control interventions. In addition, several viral pandemics and annual influenza strains have originated in the Asia-Pacific region, which, together, has global implications for population health.The prevention, control, and reporting of MDROs and healthcare-associated infections (HAIs) benefit from effective data dissemination plans and harmonized surveillance systems. HAIs compromise patient safety because they are preventable and serve as a reservoir for MDROs, which are associated with excess length of hospital stay, increased antimicrobial drug exposure, and excess costs . In the Clinical Infectious Diseases focuses on 3 key themes of infection prevention and control in healthcare settings across the Asia-Pacific regions: (1) epidemiology and evidence to support prevention and control interventions, (2) enhancements to infection prevention and control in healthcare settings, and (3) practices associated with the containment of emerging infectious diseases and outbreaks. The epidemiological data and evidence to support prevention and control interventions include 2 national survey studies for best practices and 4 epidemiology studies. A survey from Thailand and Japan relative to the United States compared evidence-based practices for prevention of HAIs and identified a modifiable gap associated with quality improvement for hospitals in these Asian-Pacific countries.This issue of Staphylococcus aureus (MRSA) and MDR Acinetobacter baumannii interventions in Thailand. Higher compliance (>75%) with bundled approaches was associated with reduction in MRSA, where containment of MDR A. baumannii necessitated bundle compliance along with additional infection control interventions. Four other publications describe the complex clinical factors, molecular epidemiology, and transmission dynamic associated with prevalent and emerging MDROs in Singapore and South Korea . Together, these studies provide information on the epidemiology of infection prevention and control and the transmission dynamic of MDROs in Asia-Pacific settings.A second national survey focused on policy, process, and outcomes associated with methicillin-resistant The second theme in this issue on infection prevention and control in the Asia-Pacific region is the innovative use of molecular diagnostics, electronically linked administrative data, and information technology to enhance infection prevention and control. Findings from 4 meta-analyses or network meta-analyses demonstrate the reduction in central catheter\u2013associated bloodstream infection with the use of minocycline-rifampin\u2013impregnated central venous catheters; the effects of antibiotic stewardship on outcomes including antibiotic consumptions, mortality rates, and the reduction in MDROs; infection control\u2013specific interventions associated with control of specific MDR gram-negative pathogens in intensive care units; and the potential role of the enteric microbiome in postoperative complications.Together, these studies also provide strong methodological approaches for the use of network meta-analyses, which permitted assessment of these exposure-response relationships inclusive of potential confounding factors. In addition, a report from Singapore describes the use of an electronic medical record\u2013linked administrative database that included language selectively of specific terms, using text parsing of chest radiographic reports to identify evidence of pneumonia. Use of this electronic medical record\u2013linked data source in a case validation of hospitalized adults with community-acquired pneumonia provides an enhanced method for conducting real-world evidence studies that can include enhanced case detection, diagnostic evaluations, and pathogen-specific treatment patterns in future studies. Finally, the real-life feasibility of using the Xpert MTB/RIF assay (Cepheid) in clinical practice in a tuberculosis-prevalent country was reported from Thailand. Results suggest the potential role of this molecular diagnostic method in the containment of MDR tuberculosis in the Asia-Pacific region.The third theme is practices associated with the containment of emerging infectious diseases and outbreaks in Asia-Pacific countries. Two publications describe successful containment for emerging infectious diseases, inclusive of lessons learned from the 15-year Hong Kong infectious diseases preparedness experience and the experience of zero secondary chain transmission of Middle East respiratory syndrome coronavirus in Thailand. Together, these 2 studies emphasize the key message that control of emerging infectious diseases is feasible and sustainable in these geographic regions.Streptococcus agalactiae infection in Singapore. Findings imply a potential role of regional collaboration to control S. agalactiae, because molecular epidemiological data were linked to the zoonotic spread from farmed freshwater fish. These fish share phylogenomic analysis of ST238, similar to human and fish isolates from Thailand and Hong Kong. A second report confirms a pseudo-outbreak of Bacillus spp. bacteremia linked to contaminated hospital linen, with emphasis on the benefit of good hygienic practice in central supply and sterilization services. These collective efforts complement existing evidence for the advancement of infection prevention science in the Asia-Pacific region.Finally, 2 interesting outbreaks are reported in this issue. The first is a large food-borne outbreak of Healthcare in the Asia-Pacific region has had notable milestones in infection and prevention control. The publications in this issue support future work focused on continued generation of evidence and dissemination of data, ongoing microbial surveillance, and implementation, if not adoption, of effective prevention strategies to contain the spread of MDROs and key emerging infectious diseases in the region. We thank the Infectious Diseases Association of Thailand for its partial sponsorship of this issue and share our hope that the collective experience from the study contributors reporting work in this issue will serve as a 2017 platform for improvement in the science and practice of infection prevention in the Asia-Pacific region and in other resource-limited settings."}
+{"text": "Recent neuroimaging studies have shown altered brain connectivity in patients with schizophrenia, associated with disturbed myelination in different fiber tracts and disruptions of white matter (WM) integrity, including prefrontal WM. We aimed to perform a qualitative and morphometric study of the ultrastructure of oligodendrocytes, myelin-forming cells, in prefrontal WM in schizophrenia and normal controls.WM of the prefrontal cortex (Brodmann\u2019s area 10) was studied by transmission electron microscopy and morphometry. Size, volume density (Vv) and the number (N) of organelles in oligodendrocytes were estimated in 21 patients with schizophrenia and 20 normal matched controls. Pearson correlation analysis was performed to assess possible correlations between the parameters measured and age, post-mortem interval, neuroleptic treatment and duration of the disease. ANCOVA tests were used for group comparisons.Qualitative study showed swelling, vacuolation, paucity of ribosomes and mitochondria and accumulation of lipofuscin granules in oligodendrocytes in schizophrenia as compared to controls. Morphometry detected lowered Vv and N of mitochondria and higher Vv and N of lipofuscin granules and vacuoles in oligodendrocytes in the schizophrenic group as compared to the control group .Altered metabolism of oligodendrocytes, previously reported reduced number of oligodendrocytes, disrupted myelin/axon integrity, damage and progressive degeneration of myelin sheaths in prefrontal WM in schizophrenia may lead to disturbances in myelination, deficiency of nerve impulses propagation and contribute to network dysfunctions in schizophrenia. Oligodendrocyte and myelin abnormalities may be a target to prevent or restore WM abnormalities and dysfunction of neuronal connectivity in schizophrenia."}
+{"text": "The Learning Health System Network clinical data research network includes academic medical centers, health-care systems, public health departments, and health plans, and is designed to facilitate outcomes research, pragmatic trials, comparative effectiveness research, and evaluation of population health interventions.The Learning Health System Network is 1 of 13 clinical data research networks assembled to create, in partnership with 20 patient-powered research networks, a National Patient-Centered Clinical Research Network.Herein, we describe the Learning Health System Network as an emerging resource for translational research, providing details on the governance and organizational structure of the network, the key milestones of the current funding period, and challenges and opportunities for collaborative science leveraging the network. The Patient-Centered Network of Learning Health Systems (LHSNet) Clinical Data Research Network (CDRN) is 1 of 13 CDRNs assembled to create, in partnership with 20 Patient-Powered Research Networks (PPRN) .http://www.lhsnet.org) Web site provides a map illustrating the geographic locations of the participating sites and describes each of the partnering organizations in the network [The LHSNet comprises 9 participating organizations and includes data on nearly 10 million patients. The LHSNet  . As defiThe LHSNet leverages existing infrastructure, health information technologies, and data standards to connect its 9 sites and to build the foundation to facilitate patient-centered outcomes research; support large pragmatic clinical trials, and observational and interventional comparative effectiveness studies embedded within the health-care systems; and enable the dissemination, implementation, and evaluation of clinical and community efforts to improve population health. LHSNet is configured as a distributed data model  wherein The 9 LHSNet partners represent an array of health-care delivery system stakeholders. Members of LHSNet have been collaborating for more than a decade and have strong relationships with patients and communities, academic medical centers, universities, health-care systems, and payers across the United States. Three Clinical and Translational Science Award recipients participate in the LHSNet ; all 3 institutions have a long-standing history of strong research collaboration and community engagement. The Clinical and Translational Science Awards at Mayo Clinic, Ohio State University, and the University of Michigan established processes to expedite Institutional Review Board (IRB) approval for multisite trials by creating IRB reciprocity agreements as part of the Midwest Area Research Consortium for Health, a consortium of upper-Midwest Clinical and Translational Science Awards. This experience formed the basis for the LHSNet-wide expansion of the IRB reliance model.http://midwestresearchnetwork.org/). The Midwest Research Network was founded in 2011 by a core group of research and clinical organizations in the Midwest to support collaborative grant proposals and resource sharing for population health research. The history of collaboration among these groups provides a foundation of trust and cross-institutional knowledge upon which the LHSNet is built.Five of the LHSNet sites such as Allina Health System, Essentia Health, Medica Research Institute, Mayo Clinic, and Olmsted County Public Health Services are also members of the Midwest Research Network (http://www.hcsrn.org/en/). This national collaborative of research departments and health-care systems includes nearly 2000 scientists and research staff with multidisciplinary content and methodological expertise. The extensive experience in multisite research efforts and data sharing of the Health Care Systems Research Network serves as a rich resource for the LHSNet.Essentia Health and Medica Research Institute are also members of the Health Care Systems Research Network , which is a learning network of delivery systems dedicated to data-driven improvement to deliver high-value care. The primary aims of the HVHC, to evaluate, disseminate, and facilitate the adoption of high-value care models in health-care settings, are closely aligned to the goals of LHSNet. Thus, the experience gained by our members in HVHC greatly informs the planning and execution of LHSNet efforts.The LHSNet is also benefited by the experience and expertise of members of the High Value Health Care Collaborative (HVHC). Intermountain Healthcare and Mayo Clinic are both founding members of the HVHC  and with PPRNs  to collaboratively conduct research.The governance structure of the LHSNet is comprised of 3 councils to oversee network processes and functions including the Governance Council, the Workgroup Council, and the Advisory Council . The GovRegulatory Workgroup oversees IRB requirements relevant to the multi-organizational research efforts, including streamlining IRB processes, enabling rapid start-up capabilities, and obtaining IRB approvals. The LHSNet Research Workgroup leads efforts to define clinical cohorts and integrate research into clinical practice. The Data Linkage and Data Governance Workgroup is responsible for enabling EHR and claims data linkages, informing data governance policies, and ensuring data completeness. The PCORnet (Informatics) Workgroup is tasked with the major technical aspects of developing the network including development of the following: the PCORnet CDM, the PCORnet Distributed Research Network Architecture, and basic PCORnet query capability. This workgroup is also responsible for data quality, informatics innovation, development of computable phenotypes, and enhancement of the PCORnet CDM. The Governance and Collaboration Workgroup leads the development of governing policies for research and collaboration. Finally, the Engagement Workgroup is leading efforts to understand existing patient engagement efforts across the network and to establish network-wide patient and stakeholder engagement strategies.Several workgroups have been assembled, including representatives from each participating site, to meet the required deliverables for the network . The RegAs one of the more recently funded CDRNs in PCORnet, the LHSNet is committed to meet an ambitious set of milestones within the 36-month period of performance. Key milestones, many of which have already been achieved, include the following: streamline IRB requirements across sites through development of a central IRB; increase data linkage for EHR and claims data from 1 million to 3 million lives; demonstrate full functionality of data mapping from each site to the PCORnet CDM; establish PopMedNet Node and demonstrate the ability to execute a basic query across sites; develop computable phenotypes for identifying condition-specific cohorts; validate cases for the 3 established disease cohorts ; and participate in a formally designated PCORnet study.Despite successful completion of milestones in the first 6 months of this project, we anticipate organizational, regulatory, and technical challenges as we ready the LHSNet for patient-centered comparative effectiveness research as part of the national PCORnet infrastructure . The LHSAs LHSNet works toward streamlining IRB infrastructure to support multisite research, ethical and regulatory challenges will need to be addressed. Systems will need to comply with the ethical and regulatory requirements of each site and support informed consent and enrollment of patients in an efficient manner across participating sites. Several members of LHSNet bring expertise in clinical research and clinical trials, including centralized IRBs and the identification of eligible patients using EHRs. This expertise will guide our efforts toward a centralized IRB and virtual patient consenting. Currently, members of LHSNet have signed master reliance agreements for Mayo Clinic to serve as the IRB of record. However, by January of 2017, LHSNet will adopt the Streamlined, Multisite, Accelerated Resources for Trials IRB Reliance Platform developed by the National Center for Advancing Translational Science. The National Center for Advancing Translational Science Streamlined, Multisite, Accelerated Resources for Trials IRB reliance model provides flexible resources to LHSNet investigators to harmonize and streamline IRB review through a set of agreements and standard operating procedures that enables each site to cede IRB approval to the institution leading the research effort.Technical challenges regarding observational research and longitudinal data capture, standardization and harmonization must be addressed by each participating site within LHSNet without disrupting the ways in which clinical data are routinely collected. Each site has successfully populated their DataMart as per the requirements of the CDM and is able to return data in response to data queries. However, individual research projects may require ongoing changes to the CDM. Furthermore, data capture must also be nimble enough to accommodate ongoing changes in clinical practice and related routine data collection. Technical challenges are also likely to be encountered in our planned data linkage efforts, as well as in the development and execution of computable phenotypes. Several members of LHSNet have robust expertise with methods and tools for longitudinal health-care data standardization, data linkage, data privacy, natural language processing, and computable phenotyping from EHRs and administrative claims. This expertise will guide our approach to addressing technical challenges as they emerge.The LHSNet is being developed as an LHS, including diverse members across a wide geographic region, to support clinical and translational research. As part of the PCORnet infrastructure, the LHSNet will enjoy the broader reach and potential for impact of the national research network. The PCORnet national data research network is being developed to support participation and data sharing with external investigators who are willing to participate in research studies in conjunction with the PCORI-funded CDRNs. Thus, opportunities for leveraging these networks for clinical and translational science will emerge as the networks mature.The LHSNet federated approach to an LHS has enormous potential to increase the efficiency with which clinical and biomedical knowledge is created, validated, and translated into practice . As a re"}
+{"text": "Experiments in rodents have elucidated some of the molecular mechanisms underlying repetitive transcranial magnetic stimulation (rTMS). These studies may be useful in a translational perspective so that future TMS studies in rodents can closely match human TMS protocols designed for therapeutic purposes. In the present work we will review the effects of rTMS on glutamate neurotransmission which in turn induce persistent changes in synaptic activity. In particular, we will focus on the role of NMDA and non-NMDA transmission and on the permissive role of BDNF-TrKB interaction in the rTMS induced after-effects. Experiments in rodents are indeed valuable in providing information about the molecular mechanisms of action of repetitive transcranial magnetic stimulation (rTMS). From the hitherto published work on TMS/rTMS in rodents of almost two decades, it is possible to formulate a working hypothesis on the mechanism of action of rTMS so that future TMS studies in rodents can closely match human TMS protocols. The effects of rTMS in rodents are greatly dependent on: (1) the frequency and field intensity of the stimulation; (2) the acute and chronic mode of treatment; (3) the total number of pulses; (4) the shape and dimension of coils; and (5) the state, either anesthetized or awake, of the animals. Experimental evidences in rodents indicate that rTMS produces complex neurobiochemical effects such as induction of immediate early genes, changes in modulation of neurotransmitters release, effects on glutamate AMPA receptor/NMDA receptor expression , action on neuroendocrine systems, neuroprotective effects by reducing oxidative stress and inflammation, and a powerful activation of neurotrophic factors (Cirillo et al., ++ ions. Once sufficient numbers of AMPA receptors are activated, the membrane is depolarized from resting to active potential, the magnesium blockade is relieved, and the NMDA receptors are opened (Fleming and England, Having said that rTMS provides sustained effects, how does rTMS induce long lasting changes in cortical excitability? An important upstream regulator of synaptic plasticity is the BDNF-TrkB system. Indeed, we showed that 5-day rTMS enhances BDNF binding affinity for TrkB, BDNF-TrkB signaling, and NMDA receptor\u2013TrkB interaction in rat prefrontal cortex (Wang et al., in vitro model that rTMS may increase the steady state current in the presynaptic compartment independently from NMDA postsynaptic transmission. In this way, it is likely that longer duration rTMS protocol may enhance these presynaptic steady state currents thus prolonging the TMS induced after-effects (Banerjee et al., Despite the role of post-synaptic NMDA transmission on the long lasting effects of rTMS seems very clear, on the other hand there are evidences suggesting the involvement of presynaptic glutamatergic mechanisms (Banerjee et al., TS: study conception, drafting of the ms; MG, HW, and PB: critical revision; EM: critical revision, analysis of animal literature; DR: critical revision, clinical implications; AQ: study conception, drafting of the ms, crafting of the ms.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer DP and handling Editor declared their shared affiliation, and the handling Editor states that the process nevertheless met the standards of a fair and objective review."}
+{"text": "Language disorders can be the first symptom of many neurodegenerative diseases, including Alzheimer's disease (AD) and primary progressive aphasia (PPA). The main variants of PPA are: the non-fluent/agrammatic variant, the semantic variant and the logopenic variant.Several additional variants of PPA, however, have been described and are considered as atypical presentations.We describe the case of a woman presenting a progressive isolated language disturbance, characterized by an early dysprosodia, phonological and semantic paraphasias, agrammatism, impairment in repetition, writing of non-words and sentence comprehension. This clinical picture pointed to an atypical presentation of the non-fluent variety. The frequent symptom overlap between the different variants of PPA, most likely reflecting differences in the topography of the pathological changes, needs to be considered in the definition of diagnostic criteria."}
+{"text": "Neuroscience began with neuroanatomy and neurosurgery in Egypt more than 5000 years ago. Knowledge grew over time and specialized neurosurgery centers were established in north Africa in the eleventh century. However, it was not until the twentieth century that neuroscience research became established in sub-Saharan Africa. In most African countries, clinical research focused on understanding the rationale and improving treatment of epilepsy, infections, nutritional neuropathies, stroke and tumors. Significant advances were made. In the twenty-first century, African knowledge expanded to include all branches of neuroscience, contributing to genetic, biochemical and inflammatory determinants of brain disorders. A major focus of basic neuroscience research has been, and is, investigation of plant extracts, drugs and stress in animal models, providing insight and identifying potential novel therapies. A significant event in the history of African neuroscience was the founding of the Society of Neuroscientists of Africa (SONA) in 1993. The International Brain Research Organization (IBRO) supported SONA conferences, as well as workshops and neuroscience training schools in Africa. Thanks to their investment, as well as that of funding agencies, such as the National Institutes of Health (NIH), International Society for Neurochemistry (ISN), World Federation of Neurosurgical Societies (WFNS), World Federation of Neurology (WFN) and the International League Against Epilepsy (ILAE), neuroscience research is well-established in Africa today. However, in order to continue to develop, African neuroscience needs continued international support and African neuroscientists need to engage in policy and decision-making to persuade governments to fund studies that address the unique regional needs in Africa. The earliest evidence of neuroscience research dates back more than 5000 years. Egyptian embalmers were the first to obtain knowledge of human anatomy through the mummification process. However, they had very little regard for the brain and did not try to preserve it , nutritional neuropathies, stroke, tumors, motor disorders and the adverse effects of snake venom Lambo, . SignifiIt is impossible to do adequate justice to all of the neuroscience research that has been carried out in Africa. This mini-review will therefore trace a few of the major trends based on a PubMed search of neuro-related publications by African neuroscientists in the eight African countries listed as having an H index of 20 or greater, in the SCImago Journal & Country Rank Report 2016)61).In the twentieth and twenty-first centuries, neuroscience research in Tunisia and Algeria involved mostly clinical studies on neurogenetics and movement disorders  an addictive psychostimulant grown in abundance in Kenya and impairment of executive function in children with malaria, to name a few 2016; IdrOver the years, science-based non-profit organizations such as the International Brain Research Organization (IBRO) have supported African neuroscientists and helped to build scientific capacity for sustainable education and research by sponsoring training courses and workshops across Africa. Training programmes in Neurosurgery, Neurology and basic Neuroscience, supported by, the World Federation of Neurosurgical Societies (WFNS), the World Federation of Neurology (WFN), the Society of French Speaking Neurosurgeons (SNCLF) the International League Against Epilepsy (ILAE), the National Institutes of Health (NIH), IBRO and the International Society of Neurochemistry (ISN), amongst others, have led to the production of many generations of neuroscientists in Africa. IBRO and ISN, in particular, have engaged in basic neuroscience with a strong translational approach to brain disorders in Africa. IBRO African Centres for Advanced Training in Neuroscience have been established in Morocco and South Africa. WFNS-recognized Centres of Excellence for training neurosurgeons have been established in Nigeria, Ivory Coast, Senegal, Kenya, Zimbabwe and South Africa  by James Kimani in 1993. IBRO generously supported SONA conferences, as well as several workshops and neuroscience training schools in more than 14 African countries. Thanks to their investment, as well as that of the other funding agencies, neuroscience research is well-established in Africa. However, in order to continue to develop, African neuroscience needs continued international support and African neuroscientists need to engage in policy and decision-making to persuade governments to fund studies of unique regional needs in Africa (Bentivoglio et al., VAR wrote the mini-review.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Based on a great number of literatures, we established the database about the Chinese endemic seed plants and analyzed the compositions, growth form, distribution and angiosperm original families of them within three big natural areas and seven natural regions. The results indicate that the above characters of Chinese endemic plants take on relative rule at the different geographical scales. Among the three big natural areas, Eastern Monsoon area has the highest endemic plants richness, whereas Northwest Dryness area is the lowest. For life forms, herbs dominate. In contrast, the proportion of herbs of Eastern Monsoon area is remarkable under other two areas. Correspondingly the proportions of trees and shrubs are substantially higher than other two. For angiosperm original families, the number is the highest in Eastern Monsoon area, and lowest in Northwest Dryness area. On the other hand, among the seven natural regions, the humid and subtropical zone in Central and Southern China has the highest endemic plants richness, whereas the humid, hemi-humid region and temperate zone in Northeast China has the lowest. For life forms, the proportion of herbs tends to decrease from humid, hemi-humid region and temperate zone in Northeast China to humid and tropical zone in Southern China. Comparably, trees, shrubs and vines or lianas increase with the same directions. This fully represents these characters of Chinese endemic plants vary with latitudinal gradients. Furthermore, as to the number of endemic plants belonging to angiosperm original families, the number is the most in humid and subtropical zone in Center and Southern China, and tropical zone in Southern China in the next place. In contrast, the endemic plant of these two regions relatively is richer than that of The Qinghai-Tibet alpine and cold region. All above results sufficiently reflect that the Chinese endemic plants mainly distribute in Eastern Monsoon area, especially humid and subtropical zone in Center and Southern China and tropical zone in Southern China. Furthermore, the flora of Eastern Monsoon area, in particular humid and subtropical zone in Center and Southern China and tropical zone in Southern China, is more ancient and original than that of Northwest Dryness area and Qinghai-Tibet alpine and cold area. Almost mountain . This clmountain , and makmountain ,6, but amountain ,7.Formation and changes of land and sea, climate change, large-scale mountain or plateau uplift as well as regional ecological complications play different and important roles in speciation and diversification of flora. They all directly or indirectly affect speciation, differentiation, migration, extinction and preservation of flora. The early Paleozoic Caledonian movement makes land lift and Chinese continent disperse. Main mountains in northeast and northwest China and Qinling Mountains formed in later Paleozoic Hercynian tectonic period. In this period, Chinese continent was connected to the Siberian continental platform, and Tianshan Mountain was interlinked with mountains and plateau of central Asia. Tanggula mount, Karakoram and Hengduan mountains were formed during Yanshanian Tectonic Period between Mesozoic Jurassic and before Cenozoic . In the In recently years, China has been developing in the field of biodiversity research including Species Catalogue, biodiversity monitoring, phylodiversity, biodiversity informatics and biodiversity conservation \u201315. EndeMany studies on biodiversity conservation and endemism of Chinese flora have carried out across China \u201327. ChinFlora of China [Flora Reipublicae Popularis Sinicae [According to checklist of Chinese endemic seed plant species , we compof China  and Flor Sinicae , b) locaAccording to map of geographical regions of China , we digiWe analyzed the compositions of both the Chinese endemic plants and local endemic plants , and counted quantitative characteristics of each main group in terms of different growth forms. To detect the distribution pattern of Chinese endemic seed plant species in the entire country, we calculated Chinese endemic plants richness and local endemic plants richness separately. In addition, we compared and analyzed compositional characteristics of original taxa for each geographical region according to checklist of orders and families for original taxa . All calChinese endemic seed plants are very unevenly distributed in natural geographical units. In three geographical areas, the Eastern Monsoon area is highest in number of endemic plants, while the Northwest Dryness area is lowest in that . Ratio oChinese endemic plants are mostly limited to relatively narrow areas . Only 7.Chinese endemic seed plants were divided into four kinds of growth forms: tree, shrub, herb, and liana or vine. Herb is dominant in any geographical region Tables , Fig 3. Halerpestes tricuspis var. heterophylla and Berberis farreri, are present commonly in both the Northwest Dryness area and the Qinghai-Tibet alpine and cold area, but are absent in the Eastern Monsoon area. One thousand three hundred and twenty Chinese endemic plants (accounting for 62.3%) from 18 original families are distributed restrictively within the Eastern Monsoon area. Only 56 Chinese endemic plants (accounting for less than 2.6%) form original families are limited in the Northwest Dryness area. There are 310 Chinese endemic plants (accounting for 14.6%) distributed limitedly within the Qinghai-Tibet alpine and cold area. These endemic plants mainly belong to Ranunculaceae, Papaveraceae, Berberidaceae and Lauraceae.There are 2120 Chinese endemic plants belonging to 19 original families  in ChinaRanunculus furcatifidus and Clematis akebioides, which both belong to Ranunculaceae family, are common endemic plants in seven geographical regions. Four Chinese endemic plants, which all belong to Ranunculaceae family, are common in six geographical regions. Thirty Chinese endemic plants, which are dominant in Ranuculaceae, are common in five geographical regions. Eighty six Chinese endemic plants are common in four geographical regions. These endemic plants belong to Ranunculaceae, Papaveraceae, Berberidaceae. There are 1409 endemic plants (accounting for 66.5%) from original families present in the humid and subtropical zone in Center and Southern China (Geo3). Among of them, 653 plants (accounting for 30.8%) are restricted in this geographical region. There are 744 endemic plants (accounting for 35.1%) from original families present in the humid and tropical zone in Southern China (Geo4). Among of them, 255 plants (accounting for 12.0%) are restricted in this geographical region.Only Chinese endemic seed plant species are very unevenly distributed in three geographical areas and seven geographical regions. The Northwest Dryness area is arid because Qinghai-Tibet Plateau, Qinling Mountains, Taihang Mountain, and Yanshan and Da Hinggan Ling Mountain  prevent The proportions of tree, shrub, and liana or vine in the Eastern Monsoon area are higher than that of in the Northwest Dryness area and in the Qinghai-Tibet alpine and cold area. On the contrary, the proportion of herb in the Eastern Monsoon area is less than that of in the Northwest Dryness area and in the Qinghai-Tibet alpine and cold area. Herb is considered to be more evolutionary group than tree . On thisBoth Chinese endemic plants richness and local endemic plants richness are higher in the humid and subtropical zone in Center and Southern China than that in the Qinghai-Tibet alpine and cold area. This might implicate that endemic flora in the humid and subtropical zone in Center and Southern China is older than that in the Qinghai-Tibet alpine and cold area . ConsideChinese endemic plants take on relative rule at the different geographical scales. The Chinese endemic plants mainly distribute in Eastern Monsoon area, especially humid and subtropical zone in Center and Southern China and tropical zone in Southern China. The flora of Eastern Monsoon area, in particular humid and subtropical zone in Center and Southern China and tropical zone in Southern China, is more ancient and original than that of Northwest Dryness area and Qinghai-Tibet alpine and cold area.S1 Table(DOC)Click here for additional data file.S1 Appendix(XLSX)Click here for additional data file.S2 Appendix(DOC)Click here for additional data file."}
+{"text": "Antimicrobial use in food-producing animals selects for antimicrobial resistance that can be transmitted to humans via food or other transmission routes. The World Health Organization (WHO) in 2005 ranked the medical importance of antimicrobials used in humans. In late 2017, to preserve the effectiveness of medically important antimicrobials for humans, WHO released guidelines on use of antimicrobials in food-producing animals that incorporated the latest WHO rankings.WHO commissioned systematic reviews and literature reviews, and convened a Guideline Development Group (GDG) of external experts free of unacceptable conflicts-of-interest. The GDG assessed the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, and formulated recommendations using a structured evidence-to-decision approach that considered the balance of benefits and harms, feasibility, resource implications, and impact on equity. The resulting guidelines were peer-reviewed by an independent External Review Group and approved by the WHO Guidelines Review Committee.These guidelines recommend reductions in the overall use of medically important antimicrobials in food-producing animals, including complete restriction of use of antimicrobials for growth promotion and for disease prevention . These guidelines also recommend that antimicrobials identified as critically important for humans not be used in food-producing animals for treatment or disease control unless susceptibility testing demonstrates the drug to be the only treatment option.To preserve the effectiveness of medically important antimicrobials, veterinarians, farmers, regulatory agencies, and all other stakeholders are urged to adopt these recommendations and work towards implementation of these guidelines. The increasing prevalence of antimicrobial resistance is a worldwide problem , 2. AntiTo address the growing public health problem of antimicrobial resistance, the 68th World Health Assembly adopted the World Health Organization\u2019s (WHO) Global Action Plan on Antimicrobial Resistance (GAP) in May 2015 . The WHOAntimicrobials are widely used in food-producing animals for therapeutic use , prophylactic use , and growth promotion use (to improve rate of gain or feed efficiency) . Such usWith the ever growing public health threat of antimicrobial resistance and the recognized need to preserve the effectiveness of medically important antimicrobials, particularly those antimicrobials judged to be critically important to human medicine on the WHO CIA List, WHO elected to develop formal, evidence-based, guidelines on use of antimicrobials in food producing animals.WHO Handbook for Guideline Development, three groups were organized [In accordance with the rganized . A WHO SA Guideline Development Group (GDG), comprised of thirteen external experts from five WHO regions with expertise in clinical human medicine, infection prevention and control, evidence-based medicine, tropical medicine, epidemiology, veterinary medicine, microbiology, infectious diseases, public health, antimicrobial resistance, economics and veterinary ethics. The GDG assessed the available evidence and formulated recommendations. One member of the GDG was a Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodologist. GDG members were selected in a way that sought geographic representation and gender balance, and avoided conflicts of interest. An External Review Group (ERG), composed of eleven technical experts and stakeholders with interest in use of antimicrobials in food-producing animals including veterinarians, microbiologists, animal scientists, public health practitioners, food safety experts, public health policy officials, and physicians. The ERG reviewed the final draft of the guidelines to identify errors of fact and commented on the clarity of the language, contextual issues and implications for implementation.http://apps.who.int/iris/bitstream/10665/258970/1/9789241550130-eng.pdf). Following a public solicitation for applications, the WHO Steering Group selected the applications from teams at Bond University  and University of Calgary (Canada). The systematic review teams interacted regularly with the WHO Steering Group but worked independently of each other.WHO commissioned systematic reviews of the published evidence that restrictions in use of antimicrobials in food-producing animals reduced the prevalence of antimicrobial resistance in bacteria isolated from food-producing animals and humans  and March 2017 . The GDG formulated recommendations based upon the summarized evidence and judgments of the overall quality of the evidence. Using the GRADE approach, the GDG also judged the strength of each recommendation by considering the importance of the problem, the quality of evidence, the balance between benefits and harms, the values and preferences of affected populations, resource implications, the impact on equity, human rights, gender and social determinants of health, acceptability, and feasibility [As per WHO regulations, all external experts and contributors disclosed their secondary interests  prior to participating in the WHO guideline development process. When a conflict of interest was identified, WHO followed standard procedures to determine whether or not the expert was permitted to participate in the guideline development process. A biographical sketch of each nominated GDG member was posted online for public comments. The WHO Steering Group reviewed all information gathered before approving final GDG membership.Governments of Japan and The Netherlands provided funding for the guidelines but were not involved with guidelines development. WHO facilitated the development of the WHO Guidelines, in accordance with the WHO guideline development process, and provided additional funding for the guidelines.http://apps.who.int/iris/bitstream/10665/259241/1/WHO-NMH-FOS-FZD-17.2-eng.pdf.The systematic reviews yielded a large number of studies that demonstrated a consistent decrease in the prevalence of antimicrobial resistance in bacteria isolated from food-producing animals or humans following restrictions on use of medically important antimicrobials in food-producing animals. The Bond University systematic review team provided a narrative report of the quality of, and summary of findings from, 93 studies and concluded that limiting the antimicrobial use in food animals is likely to reduce the presence of antimicrobial resistance in food \u2013producing animals and humans. The University of Calgary systematic review team provided a quantitative report from 177 studies that included an assessment of the quality of the primary studies and provided a meta-analysis of the risk differences for reductions in the prevalence in antimicrobial resistance reported with various restrictions on antimicrobial use in food producing animals . The Unihttp://apps.who.int/iris/bitstream/10665/259241/1/WHO-NMH-FOS-FZD-17.2-eng.pdf .Of the three commissioned content specific literature reviews, one review provided evidence from illustrative examples of probable transfer of resistant determinants for streptothricins, glycopeptides and colistin from food-producing animals to humans . The sechttp://apps.who.int/iris/bitstream/10665/259242/1/WHO-NMH-FOS-FZD-17.3-eng.pdf .The evidence presented to the GDG was predominately from observational and ecologic studies. Additionally, the systematic reviews found few studies from middle-income and low-income countries, and few studies included small-scale food-producing animal operations. Despite these limitations, the GDG determined that there was sufficient evidence that use of medically important antimicrobials in food-producing animals selects for antimicrobial resistance in bacteria, and that such antimicrobial resistant bacteria can be transmitted to humans, including in middle-income and low-income countries, and small-scale operations. Summaries of the information used by the GDG to develop best practice statements and recommendations related to the use of medically important antimicrobials in food-producing animals, including evidence profiles, summary of findings tables, and evidence-to-recommendations tables, are available at Any new class of antimicrobials or new antimicrobial combination developed for use in humans will be considered critically important for human medicine unless categorized otherwise by WHO.Medically important antimicrobials which are not currently used in food production should not be used in the future in food production, including in food-producing animals or plants.The GDG developed two best practice statements for classes of antimicrobials not currently used in food-producing animals.The GDG judged that these best practice statements were needed to provide a basis for taking actions to preserve the effectiveness of critically important antimicrobials for humans  that are not currently used in food-producing animals. Furthermore, given the critical need for new classes of antimicrobials for the treatment of some serious and life-threatening infections in humans, the development and eventual marketing of new classes of antimicrobials will likely be antimicrobials required for infections in humans with no or limited treatment options.Since these antimicrobials are not yet used in food-producing animals, direct evidence  is not available. Instead, the best practice statements are supported by considerable indirect evidence, including a large body of evidence from the systematic reviews and from mechanistic studies of antimicrobial resistance , 19.An overall reduction of use of all classes of medically important antimicrobials in food-producing animals is recommended. .Complete restriction of use of all classes of medically important antimicrobials in food-producing animals for growth promotion is recommended. .Complete restriction of use of all classes of medically important antimicrobials in food-producing animals for prevention of infectious diseases that have not yet been clinically diagnosed is recommended. .It is suggested that antimicrobials classified as highest-priority critically important for human medicine should not be used for treatment of food-producing animals with clinically diagnosed infectious disease. It is also suggested that antimicrobials classified as critically important for human medicine should not be used for control of the dissemination of a clinically diagnosed infectious disease identified within a group of food-producing animals. .The GDG developed four recommendations, supported by both direct and indirect evidence, concerning the use of medically important antimicrobials in food-producing animals.The GDG determined that the first three recommendations should be strong despite the low-quality evidence due to the large human health benefits of lowered prevalence of antimicrobial resistance in bacteria isolated from humans and the limited evidence of undesirable consequences of restrictions on antimicrobial use of medically important antimicrobials in food producing animals. Specifically, there was a large amount of consistent evidence from the systematic reviews and the literature reviews that resistant bacteria can spread among food-producing animals, into their environment, and to humans, and that restrictions on use of antimicrobials in food-producing animals reduces the prevalence of antimicrobial resistance in bacteria isolated from food-producing animals that are, and can be, transmitted to humans. The GDG also concluded that for the fourth recommendation, although evidence from the systematic reviews and additional studies indicates it will achieve the human health benefit of lowered antimicrobial resistance in bacteria, this recommendation should be conditional due to the very low quality of available evidence. In order to protect animal health and welfare, the GDG concluded that exceptions to recommendations 4a and 4b can be made when, in the judgement of qualified veterinary professionals, susceptibility results demonstrate that the selected drug is the only treatment option.The GDG also concluded that in order for people in all countries to realize the benefits of continued effectiveness of medically important antimicrobials, the recommendations in these guidelines should be applied in all animal production settings and in all countries.With the recognition of the need to reduce the use of medically important antimicrobials in food-producing animals, the GDG identified the following research areas which can be addressed to help facilitate reduced antimicrobial use:  identifiThe use of antimicrobials in food-producing animals has been a public health concern for decades . In 1997In accordance with the WHO guideline development process , the GRAThe GRADE approach follows a rigorous and transparent process, and is the most widely used approach for evidence appraisal for guideline development. The GRADE approach was initially developed for decision-making in clinical settings, where randomized clinical trials are commonly available. It rates evidence derived from randomized controlled trials as high quality, while evidence from epidemiological studies, surveillance programmes and other sources of observational data, in which confounding cannot be adequately controlled, is rated as \u201clow quality\u201d. In common with many important public health issues, due to ethical and technical complexity, there are no randomized controlled studies that have assessed associations between use of antibiotics in food-producing animals and risks of human exposure to infection by drug-resistant zoonotic pathogens. Most of the supporting scientific evidence, representing the best available evidence, was collected from epidemiological studies, surveillance programmes and observational studies. In addition to the quality of the evidence and the balance of benefits and harms of an intervention, a number of other factors are considered when GDGs formulate recommendations. These factors include the relative value placed on the potential beneficial and harmful outcomes of an intervention, the acceptability and feasibility of the intervention, resource considerations, and effects on equity across subpopulations. A \u201cstrong recommendation\u201d means that after taking all relevant considerations into account, the GDG is reasonably certain that the desirable consequences (benefits) of an intervention outweigh the undesirable consequences (risks or harms), such that the intervention should be implemented in most settings.The GRADE approach has been used successfully in public health settings where only observational studies are available. There are challenges, however, in using the GRADE approach in all settings, especially in the formulation of recommendations on complex interventions in public health settings . AlthougUsing the rigorous and transparent WHO guideline development process, the GDG determined that three of the four recommendations on use of medically important antimicrobials in food-producing animals should be strong recommendations given (1) the large body of evidence from the commissioned systematic reviews using a rigorous and evidence based approach of the strength and consistency of the association between restrictions of antimicrobial use in food-producing animals and antimicrobial resistance in animals and humans, (2) the suggestion of a dose-response relationship with this association, (3) the large potential health benefits, and (4) the evidence of limited unintended consequences. The GDG also recommended implementation of the WHO guidelines worldwide. As with all WHO guidelines related to food safety, implementation relies on the impetus of Member States and other stakeholders, including the FAO/WHO Codex Alimentarius Commission, to translate the recommendations into national and international standards or guidance. In order to reach the overall goal of reducing antimicrobials in food-producing animals, there is a particular need to identify management alternatives for use of antimicrobials for disease prevention. The GDG acknowledged that implementation in lower-income or middle-income countries may require special considerations such as assistance in improvement of hygienic and agricultural practices including improved housing and husbandry. Furthermore, many countries may need technical and laboratory capacity building assistance for conducting the recommended bacterial culture and antimicrobial susceptibility testing. It is important for countries to conduct surveillance and monitoring of antimicrobial usage in food-producing animals to evaluate the effectiveness of any interventions.In conclusion, the WHO guidelines recommend overall reduced use of medically important antimicrobials in food-producing animals, including complete restriction of uses of medically important antimicrobials for growth promotion and for disease prevention. Exceptions for disease prevention can be accepted when based upon the judgement of a veterinary professional and if such judgement is based on recent culture and sensitivity testing results. The WHO Guidelines also suggested that antimicrobials identified as critically important for human medicine not be used in food-producing animals for treatment or disease control unless susceptibility testing demonstrates the drug to be the only treatment option. To preserve the effectiveness of medically important antimicrobials, all stakeholders should implement the recommendations in the WHO guidelines. Such implementation will support the WHO GAP to control antimicrobial resistance by reducing unnecessary use of antimicrobials in food-producing animals."}
+{"text": "Challenges posed by demographic changes and population aging are key priorities for the Horizon 2020 Program of the European Commission. Aligned with the vision of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA), the development, exchange, and large-scale adoption of innovative good practices is a key element of the responses required to ensure all European citizens remain as active and healthy as possible as they age. Urged by the need of developing scalable disruptive innovation across Europe, the European Commission and the EIP on AHA created the Reference Sites; local coalition of partners that develop good practices to support AHA. Ageing@Coimbra is an example of how this can be achieved at a regional level. The consortium comprises over 70 institutions that develop innovative practices to support AHA in Portugal. Ageing@Coimbra partners support a regional network of stakeholders that build a holistic ecosystem in health and social care, taking into consideration the specificities of the territories, living environments and cultural resources . Good practices in reducing the burden of brain diseases that affect cognition and memory impairment in older people and tackling social isolation in urban and rural areas are among the top priorities of Ageing@Coimbra. Profiting from the collaborative work of academia, business companies, civil society, and authorities, the quadruple helix of Ageing@Coimbra supports: early diagnosis of frailty and disease; care and cure; and active, assisted, and independent living. This paper describes, as a Community Case Study, the creation of a Reference Site of the EIP on AHA, Ageing@Coimbra, and its impact in Portugal. This Reference Site can motivate other regions to develop innovative formulas to federate stakeholders and networks, building consortia at regional level. This growing movement, across Europe, is inspired by the quadruple helix concept and by the replication of innovative good practices; creating new Reference Sites for the benefit of Citizens. Europe faces the global challenge of population aging with strong impact in the quality of life of individuals and families, society cohesion, health, and economic resources of citizens and member states. The percentage of people aged 65 or over in the population is expected to grow from 18.4% in 2013 to 28.4% in 2060 for the average of European countries  of 143.9 in 2015 compared to 27 in 1960.Within Portugal, the population living in the Centre Region is particularly old due to the increase in life expectancy, migration of young adults and decrease in birth rate. Within the Centre Region, some areas are already facing the demographic scenarios expected for the European landscape in 2060, e.g., municipalities with Ageing Index above 700.Taking together, the demographic landscape of Europe, with a particularly and striking case in Portugal, urges the need of defining new strategies and implementing actions to deliver innovative and disruptive solutions. These solutions are expected to have impact at the individual, family, labor, societal, and economic dimensions to support individual health and well-being, at all ages, and deliver solutions to support health and social care sustainability. As we will elaborate bellow, the EIP on AHA movement, and the particular case of Ageing@Coimbra (as a Community Case Study), may be inspiring for the required change management processes, delivering solutions for the challenges of aging and opening new opportunities for economic growth.The EIP on AHAThe EIP on AHA grew from recognition that the quality of life of older people is strongly affected by life style habits across the life cycle in all ages. Many older people suffer from multiple chronic conditions that demand continuous support by medical and social care providers and limit functional independence. Ultimately, poor health in later life strongly impacts on health and economic resources, human suffering, human dignity of individuals, and families .The EIP on AHA fosters collaborative work of European partners to support three main strategic pillars of AHA: (1) prevention, screening, and early diagnosis; (2) care and cure; (3) independent living and active aging. EIP on AHA partners are organized in six action groups: A1, adherence to prescription and medical plans; A2, personalized health management and prevention of falls; A3, lifespan health promotion and prevention of age-related frailty and disease; B3, replicating and tutoring integrated care for chronic diseases; C2, development of interoperable independent living solutions; D4, innovation for age-friendly buildings, cities and environments.The main goal is to achieve a triple win for Europe: (1) Health and quality of life of European citizens; (2) Sustainable and efficient care systems; and (3) Growth and expansion of EU industry.EIP on AHA is a wide interdisciplinary and transdisciplinary network that seeks innovative collaborative models, removing silos and developing citizen-centered processes. EIP on AHA partners joint academia, health, and social care providers, citizens and patient associations and several other stakeholder groups with innovators, entrepreneurs, and business partners. The aim is to deliver knowledge and user-based competence into innovative good practices, products, and services. Only disruptive innovation and knowledge-based added value will deliver efficient meaningful large-scale interventions to face the societal challenges, opening, at the same time, new opportunities for entrepreneurs, business activity, and job creation , 4.Reference Sites have been defined by the EIP on AHA as \u201cinspirational ecosystems, delivering creative and workable solutions that improve the lives and health of older people.\u201dReference Sites include regions, cities, integrated hospitals, or care organizations that focus on innovative and holistic approaches to support AHA. Reference Sites show diverse levels of impact and maturity toward the goal standard of regional ecosystems aligning actors across the quadruple helix: academia, authorities, business, and civil society. The impact of the activities of Reference Sites provides evidence of innovative components, and indicators are measurable in line with the Monitoring and Assessment Framework of the EIP on AHA (MAFEIP), under the dimensions \u201cQuality of life,\u201d \u201cSustainability of health-care systems,\u201d and \u201cEconomic growth and jobs.\u201dThe first call for Reference Sites by the European Commission resulted in the award of 32 Reference Sites in 2013. The second call led to a total of 74 Reference Sites in 2016. Recently , the Reference Sites launched a non-profit association based in Brussels to promote synergies and collaborative work \u2014the Reference Site Collaborative Network .The Ageing@Coimbra ConsortiumAgeing@Coimbra is an informal network of 5 founder and 65 associated partners that build a \u201cquadruple helix\u201d, aligning: (1) public institutions , (2) academia , (3) industry partners , and (4) civil society organizations . The consortium was founded under a leadership initiative of the University of Coimbra, the Municipality of Coimbra, the Regional Health Authority, the University of Coimbra Hospital, and the Pedro Nunes Institute . The Administrative Authority of the Centre Region of Portugal  has been a major supporter and driver for the success of Ageing@Coimbra, actively engaging in the implementation of activities, international visibility and ownership of responsibility to include AHA in the key priorities of the Smart Specialization Strategy (RIS3) of the Center Region of Portugal. In 2017, CCDRC launched a regional competition to award three cases of good practices in three clusters: Knowledge, Health, and Life.Ageing@Coimbra was the first EIP on AHA Reference Site in Portugal. The innovative formula and lean governance structure created an inclusive partnership with agility, rapid implementation, and growth potential. Concordantly, other regions in Portugal  and regions in other European countries  embraced Ageing@Coimbra example to replicate the model and launched new reference sites in 2016, or they will do so in a future call expected for 2019. The same example has replication potential in other countries in Europe and globally .As an active member of EIP on AHA Action Groups, Ageing@Coimbra participates in the collaborative activities and delivers success cases of projects and good practices.Multimorbidity and the related prescription of multiple drugs are becoming common problems among older people, frequently associated with poor health outcomes, being inadequate and/or poor adherence to medical plans one of the relevant factors that compromise the success of treatments . TherefoThe collaborative work of Ageing@Coimbra in the A1 Action Group resulted in the successful development of the third Health Program Project SIMPATHY (Stimulating Innovative Management of Polypharmacy and Adherence in the Elderly), a project coordinated by the Scottish Government (Grant Agreement 663082)falls are a major indicator of increasing frailty and loss of independence and mobility in older people.\u201d The main objective of the A2 Action Group has been to deliver EU wide evidence-based, validated and operational programs for the prevention, early identification, and minimization of risk and management of falls in order to reduce falls and the personal, system, and societal consequences of fall-related injuries. In order to reach relevant joint achievements and goals four different areas of collaborative work are being developed: (1) implementation of an integrated and person-centered service pathway for fall prevention and management; (2) data collection for evidence-based interventions on falls; (3) awareness, information, and education, to support the training of the workforce; (4) Governance: innovation, sustainability, and scaling-up, including models for exploitation, business analysis, and strategies for falls prevention technologies take up.The relevance of the topic addressed in the A2 Action Group is supported by the Joint Declaration of the European Stakeholders Alliance for Active Ageing through Falls PreventionThe collaborative work of Ageing@Coimbra in the A2 group resulted in joint activities and collaborative work in the Prevention of Falls Network for Dissemination (ProFouND), an EC funded initiative dedicated to the dissemination and implementation of best practices in falls prevention across Europe.Also, within the scope of the A2 action group, the Project \u201cGood practices to develop physical activity programs at work\u2014FitWork\u201d was developed within the framework of the ERASMUS\u2009+\u2009SPORT program aimed at developing good practices to implement physical activity programs at work attending to specific risks of workplaces . The project is coordinated by Instituto de Biomec\u00e1nica de Valencia and more information can be found at.Reflecting a growing awareness of the need for better care and sustainable and effective health services, the A3 Action Group aims to contribute to AHA with a life-course approach, implementing the shift from reactive disease management to anticipatory care of functional decline through community-based prevention, early diagnosis, and screening programs, and integrated care management systems. This patient-centered approach involving social and health-care systems is based on innovative solutions that support interactions in the areas of nutrition, frailty and functional decline, cognitive decline and physical activity. It also fosters the development of networks strengthening education and training of the health workforce, citizens empowerment through health and ICT literacy, and advancing knowledge on the determinants of frailty and chronic diseases to support early detection and sustainable interventions. The joint effort of A3 partners is the improvement and alignment of services delivered to the needs of older populations and enabling caregivers\u2019 education and empowerment.Frailty Management Optimization through EIPAHA Commitments and Utilization of Stakeholders\u2019 Input) was launched  to monitor and control the symptoms of allergic rhinitis , 10 Fig.The objective of the C2 Action Group is to develop interoperable independent living solutions, including guidelines for business models. This should boost the deployment of open and personalized solutions for active and independent living that are supported by global standards and new evidence on the return of investment. The C2 Action Group provides essential input to the creation of a new market for cost-effective products and services that help older people live a more active and independent life. This reinforces ongoing research and innovation activities in Europe (and elsewhere), supported through public\u2013private partnerships.Within the scope of the C2 Action Group, in 2017, the AAL Forum, the biggest European event in the field of Technologies for AHA was organized in Coimbra, by the Pedro Nunes Institute, in partnership with the Portuguese Foundation for Science and Technology and some of the Ageing@Coimbra core partners. The theme of the Forum was \u201cBridging the gaps between technology solutions and aging well. What can YOU do?\u201d Interoperable solutions were discussed as crucial to assure the value of the digital solutions, for example contributing for the integration between social and health care.An inspirational fresh addition to this year\u2019s AAL Forum exhibition hall was the attendance of over 120 end-users above the age of 65, all eager to give their honest opinion on what they saw. Exhibitors had approximately 7\u2009min to present and sell their AAL solution to the guests, which turned out to be more of a challenge than the majority of exhibitors expected Figure . After vFor the first time in the AAL Forum, the jury responsible for awarding the Exhibition Prize was constituted only by end-users above the age of 65. This activity was supported by Ageing@Coimbra and the Administrative Authority of the Centre Region of Portugal.Another example of the collaborative work of Ageing@Coimbra members within the scope of C2 Action Group is well represented by the project GrowMeUp, funded under the H2020 call PHC-19-2014 \u201cAdvancing active and healthy aging with ICT: service robotics within assisted living environments\u201d; coordinated by the University of Coimbra and including the active partnership with Caritas Coimbra as an end-user organization (Grant Agreement 643647).The D4 Action Group has its main roots on the concept of Age-Friendly Environments, as envisaged by the World Health OrganizationCaritas Coimbra is also a founder member and Vice-President of the European Covenant on Demographic Change, an organization that aims to gather local, regional, and national authorities as well as other stakeholders in order to cooperate and implement evidence-based solutions to support AHA.The collaborative work of Ageing@Coimbra in D4 group includes the leadership of the University of Coimbra in the H2020 project Euro-Healthy  with a key goal to deliver a Population Health Index and a Web Geographic Information System (Web-GIS) addressing health inequity across the EU (Grant Agreement 643398) .15The area of biomarkers for neurodegenerative diseases, particularly concerning Alzheimer\u2019s disease, profits from the solid basis of neuroscience research provided by CNC.IBILI. Fundamental research is transferred from bench to bedside by means of knowledge-based genetics, biochemical, imaging, and neuropsychology biomarkers of cognitive dysfunction.Genetics and biochemical biomarkers currently used to identify risk factors and biomarkers of Alzheimer\u2019s disease include APP, tau, amyloid beta 1-42, genotyping for PSEN1, PSEN2, APP, ApoE .The Faculty of Psychology of the University of Coimbra provides neuropsychology tests to screen for functional and memory competence of older adults including Adults and Older Adults Functional Assessment Inventory (IAIFA), World Health Organization Quality of Life-OLD module, Geriatric Depression Scale (GDS-15), cognitive performance .The early diagnosis pipeline is complemented with robust brain imaging tools to ensure high quality diagnosis of putative neurodegenerative conditions. The Applied Nuclear Sciences Institute (ICNAS) pipeline launches innovative cyclotron-based synthesis methods of radiotracers including PET/FDG, PET/PiB, PET/PK11195, and other radiotracers upgrading the diagnosis tools.This integrated approach, aligning technologies and professionals/resources for a better public service results in relevant assets for Ageing@Coimbra stakeholders, creating the most valuable and reliable integrated health service in Alzheimer\u2019s diseases in Portugal; with recognized impact in the Health Cluster Portugal, the Joint Program in Neurodegenerative Diseases, and the EIT Health Knowledge Innovation Community (KIC).The diagnostics pipeline for early detection of Alzheimer\u2019s disease contributes to better health-care management and also to liaise with patient associations  for better social care and support to patients and care providers.The territory of the Center Region of Portugal offers peculiar conditions as a regional living laboratory. In the region, about 23% of residents are aged 65 or over living in diverse environments, urban versus rural, highly dense versus low-density territories. In inland areas, especially in the mountain area, low-density territories also create geographic barriers to mobility especially of frail people contributing to social isolation. On the other hand, social isolation is also a burden of older persons living alone in urban areas of the Centre Region of Portugal.These particular conditions create a local need to develop integrated care and personalized solutions to support older people living in socially challenging conditions.The majority of municipalities in the Region have been equipped with health mobile units to deliver primary care and social care support to frail older people living in rural isolated areas. The added value of these services is well recognized by users and professionals, showing increase demand in terms of individual requests by the citizens and attracted interest by other municipalities.Portugal launched in 2016 a new coordination structure of the National Network for Integrated Care Units. This network provided complementary health and social care support to populations, being socially isolated frail older people the main beneficiaries. The regional network includes 3 main units for palliative care, 9 units for convalescence care, and more than 62 integrated home care teams. Ageing@Coimbra links with integrated home care teams in close collaboration with the regional health authority, the national insurance office, and municipalities.The social support to isolated frail older people in the region is a key priority for local players, including municipalities. Several important actions support intergeneration activities to tackle social isolation, ICT literacy, polypharmacy, and adherence to therapy strategies, assisted living programs, innovative strategies to engage older citizens with meaningful activities, and an humanitarian approach in health care\u2014both in rural and urban areas.The regional health authority launched a program (\u201cp\u00e3o.come\u201d) to reduce the content of salt in the daily food of Portuguese citizens, in particular the amount of salt in bakery. Traditionally, Portuguese citizens use excess salt in food, specially in bakery. This fact has been associated with high-prevalence of cerebrovascular diseases . InteresA schematic representation of the innovation clusters of Ageing@Coimbra  is depicted in Figure Research on the mechanisms of aging-related diseases is a solid and established research area at the University of Coimbra and at the Center for Neuroscience and Cell Biology of Coimbra. Research in this area delivers high-impact and highly cited publications, international collaborations, advanced training of Ph.D., and postdoctoral students as well as entrepreneurship training and new spin off companies. Highlighting the priority of aging research, in 2016, a new ERA Chair group  was appointed by the Faculty of Medicine of the University of Coimbra to develop a research program, advanced teaching and translational research in cardiovascular aging .16In 2015, three founder members of Ageing@Coimbra, the University of Coimbra, University of Coimbra Hospital and Pedro Nunes Institute, were accepted, as Associated Partners, in the new KIC in Active Living and Healthy Ageing from EIT Health. Together with the pharmaceutical company BIAL, they formed a cluster of Innostars, a legal entity member of EIT Health.EIT Health is a powerful consortium of more than 140 members from academia and industry partners that develop collaborative market-driven projects to tackle societal challenges: (1) promote healthy living; (2) support active aging; (3) improve health care. Projects deliver better training of students, executives, and citizens (Campus); transform innovative ideas into products and services (Innovation Projects); and create and catapult business creation (Accelerator).The University of Coimbra Hospital offers a well-established multidisciplinary geriatric assessment service. The knowledge gathered by the clinical team supported the creation of a new clinical service entirely dedicated to AHA, including daily clinical care, a hospital residence, outpatient consultations and community health-care services. The key pillars of the new unit enclose clinical care of geriatric patients, training of new health-care professionals and research on aging and geriatrics.The clinical unit on AHA establishes strong links with other hospital specialty services for prevalent and multimorbid conditions, including Neurodegenerative and Psychiatric Diseases, Pneumology and Respiratory Diseases, Immunology, Cardiovascular Diseases, Diabetes, Cancer, Musculoskeletal Diseases, among others.Geriatric Medicine profits from the institutional collaboration of the University of Coimbra Hospital and the Rehabilitation Hospital Rovisco Pais and other local Hospital units in the region. Dedicated patient-centered rehabilitation services profiting from holistic approaches and multidisciplinary care are key success factors to prevent and treat geriatric frailty, particularly ortogeriatric frailty. Long-term care and palliative care multidisciplinary services in the region offer support to patients and families affected by long-term functional dependence and end-of life care for older patients and their families, including a hospital palliative care team offering support across clinical services at the University of Coimbra Hospital and two inpatient palliative care units, at the Portuguese Cancer Institute\u2014Coimbra and Cantanhede Hospital . Reinforcing this strategic area, the Calouste Gulbenkian Foundation supports a \u201cProfessorship in Palliative Care\u201d at the Faculty of Medicine of the University of Coimbra to strengthen research and education in Palliative Care in the Centre Region.The training of formal caregivers (working in institutions for older people), or informal caregivers (providing non-remunerated care for older people) is extremely important, especially when taking into account the growing older population that depends on care for chronic and degenerative diseases.The University of Coimbra, together with Ageing@Coimbra, knowing the demand for specialized caregivers\u2019 training and the need to reach an audience with time limitations and geographically dispersed, concluded that a distance learning modality (e-learning course) was among the most appropriate responses. The Distance Learning Course, \u201cActive and Healthy Ageing,\u201d which is a method of active learning providing training in the basic care areas of older people, was created by a team of lecturers of the Faculty of Medicine.Health literacy in aging is also a priority topic in postgraduate training. The Faculty of Medicine offers a masters degree in geriatrics and gerontology, where medical doctors can learn and upgrade their knowledge in age and age-related chronic diseases. Geriatrics in Coimbra is supported by advanced teaching, clinical health care and professional training. Advanced teaching at the Faculty of Medicine of the University of Coimbra includes the Ph.D. program in health sciences, the Ph.D. program in aging and chronic diseases, the masters in geriatrics and undergraduate training in geriatrics under the scope of the masters course in medicine. Postgraduate training of health-care professionals also includes the annual course on Ageing and Geriatrics .Nursing School of Coimbra promotes the implementation of the comprehensive geriatric assessment at a national level. The activities include cultural adaptation and validation of tools for use in the field of geriatrics and participation in the development of national and international web platforms to support National and European strategy to intervene on older adults\u2019 frailty and to involve stakeholders in this process. The measurable impact of work of Nursing School of Coimbra is also observable in prevention of cognitive decline in advanced age by promoting the implementation of cognitive stimulation-based practice in different health-care contexts and by enabling multidisciplinary teams to implement autonomously this practice in different regions of Portugal. In addition, Nursing School of Coimbra is also training health professionals at a national level by enabling them to achieve critical reasoning, questioning of the ongoing practices and seeking and evaluating information to support Evidence-Based Practice. Nursing School of Coimbra is also offering postgraduate programs in Geriatric Health and Ageing, Health, and Citizenship.Ageing@Coimbra profits from the engagement of several institutional partners that promote the social inclusion and participation of seniors in meaningful social activities and long-life learning. These institutions include Third Age Universities, Citizenship Associations, Science Centers, Museums, among others. Together, these institutions mobilize thousands of older citizens and their families in a number of activities involving the society: including heart and cardiovascular diseases awareness; Diabetes; Brain Awareness Week; International Day of the Older Person; European Scientists Night; among others.In 2017, the Regional Authority of Centre Region, in a partnership with Ageing@Coimbra, launched a call to award good practices supporting AHA and age-friendly territories in the 100 Municipalities of the Region. This initiative contributes to (1) identify innovative good practices; (2) publicly recognize individual and institutional stakeholders; (3) disseminate knowledge to support adoption and scaling-up in other territories. The call awarded, in 2017, three categories: (1) Life+ (\u201cVida+\u201d), to support healthy life styles; (2) Health+ (\u201cSa\u00fade+\u201d), supporting innovative health care for older people; and (3) knowledge+ (Conhecimento+), to support research and technology applied to AHA.We received 128 valid applications from diverse thematic and geographic origins, including 74 applications for the category \u201cLife,\u201d 38 for \u201cHealth,\u201d and 16 applications for \u201cKnowledge,\u201d from a total of 118 institutions. These institutions included 34 municipalities, 12 social care providers, and several citizenship associations and universities, from a total of 49 municipalities Figure .\u201cLife\u201d projects include programs for physical activity, with or without assessment of health parameters, multidimensional evaluation , intergenerational dialog, therapy by arts, creation, and development of informatics platforms. The winner \u201cNovas Primaveras,\u201d submitted by the Arts and Music Association of Pousos village, describes a program focused on therapy for older people through arts. This good practice was launched in 2004 and involves (currently) 12,711 direct and 84 indirect users from 30 Institutions, engaging users in music, dancing, theater, poetry, and other artistic expressions.\u201cHealth\u201d projects enclosed areas related with new mobile health units to support home care, implementation of new methodologies of health care , prevention of frailty in older people, screening and diagnosis of disease, physical and cognitive stimulation and rehabilitation, monitoring of chronic diseases using ICT\u2019s, support of patients in hospital and care residence settings , health literacy, and health promotion. The winner good practice described specialized care for dementia patients  submitted by the network of care providers \u201cUni\u00e3o das Miseric\u00f3rdias Portuguesas\u2014Unidade de Cuidados Continuados Bento XVI (F\u00e1tima)\u201d. This dementia care residence is a pilot unit established in 2013, including environmental, professional, therapeutics competences, recognized as a reference model for the care of patients with cognitive impairment and dementia. It includes 20 beds for mid-term care and rehabilitation (up to 90\u2009days) and 30 beds for long-term care and maintenance (up to 180\u2009days).\u201cKnowledge\u201d projects include: research and application of programs and new models; application of ICT solutions; collaborative models using telehealth and teleassistance; intergenerational approaches; infrastructures; equipment and access to knowledge; multimorbidity research and care; AHA and longevity, databases and population profiling. The winner was a project submitted by the Faculty of Medicine of the University of Coimbra and the Center for Neuroscience and Cell Biology: \u201cNoMicro Technologies.\u201d This project describes the development of a technology to support healing of chronic wounds and prevention of infection by pathogens. NoMicro Technologies is currently in a phase of preclinical proof of concept.In conclusion, the number and quality of the applications received in the call exceeded the best expectations of the organizing committee, reflecting the growing involvement and awareness of stakeholders of the Centre Region to support AHA of citizens.Standing on the big societal challenges created by the impact of population aging in individual\u2019s health, but also for efficiency and sustainability of the health and social care systems, the movement created by EIP on AHA addresses the individual\u2019s and societal hurdles, under a positive perspective of stimulating the economic growth and job creation.The collaborative work developed by EIP on AHA partners, under the scope of the six active action groups or under the scope of the quadruple helix-based Reference Sites, has delivered an impressive number of ground-transforming good practices, innovation schemes, and change management process, with big societal impact and economic potential.EIP on AHA Reference Sites like Ageing@Coimbra have shown to be instrumental bodies for helping the European Commission in the implementation of policies, including the \u201cBlueprint for Digital Transformation on Health and Care in an Ageing Society\u201dThe impact of Reference Sites in the European landscape is also revealed by the collaborative work under the twinning collaborative scheme, involving delivery of good practices by innovator regions/actor and adoption by twin Reference Sites. The example of the twinning project lead by MACVIA and adopted/replicated by Ageing@Coimbra, and many other Reference Sites is a good example of a successful twinning project with impact in the society (see text footnote 20).The challenges imposed to societies by population aging and demographic changes are of paramount complexity. Innovative formulas to deliver practices and services and organization models, like those embedded in EIP on AHA Reference Sites and Ageing@Coimbra, might prove to be key elements of the change management schemes needed to deliver quality of life to citizens and sustainability of health and care systems, starting from pilot twinning schemes to large scale-up replication across Europe and Globally.In conclusion, the innovative and successful example of Ageing@Coimbra as a Reference Site of EIP on AHA supports the adoption of bottom-up, inclusive, and holistic approaches to create regional networks and partnerships with the aim of supporting the creation and replication of good practices for Active and Healthy Ageing. This methodology has proven to be successful in Coimbra/Centro de Portugal and other regions of Portugal, as well as in other European countries. Other examples of innovative regions embracing this model may follow and reinforce the change management objectives pursued by the EIP on AHA and the European Commission. However, important hurdles related with poor commitment of partners, oversimplification of processes in lean management structures are also difficulties that need to be constantly monitored and overcome.Ageing@Coimbra is a growing consortium, consolidating its unique position as an aging network in the Centre Region of Portugal, with strong collaborations with other Reference Sites and international networks. Ageing@Coimbra will support the replication of good practices emerging from its stakeholder members and will twin with other European partners to foster the adoption of innovative practices and technologies for the benefit of Centre Region and European citizens.JM: concept design, writing the text, editing figures, and manuscript correction. AA: concept design, manuscript correction. AR: concept design, writing the text, editing figures, and manuscript correction. AM-P: writing the text and manuscript correction. AFC: concept design; writing the text; and manuscript correction. AT: concept design; writing the text; and manuscript correction. AT-B: editing figures and manuscript correction. AD: concept design and manuscript correction. AFA: manuscript correction. ALC: concept design; writing the text; and manuscript correction. CD: concept design; writing the text; editing figures; and manuscript correction. BG: writing the text and manuscript correction. CA: concept design; writing the text; and manuscript correction. IS: manuscript correction. JB: editing figures and manuscript correction. JA: concept design; writing the text; and manuscript correction. LS: concept design; writing the text; and manuscript correction. LA: concept design and manuscript correction. MI: writing the text; manuscript correction. RV: manuscript correction. VR: concept design and manuscript correction. MV: concept design; writing the text; editing figures; and manuscript correction.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The risk for cardiovascular disease (CVD) is higher for individuals with a first-degree relative who developed premature CVD . However, little is known about the effect that each unit increase or decrease of maternal or paternal age of onset of CVD has on offspring age of onset of CVD. We hypothesized that there is an association between maternal and paternal age of onset of CVD and offspring age of onset of CVD.We used the Framingham Heart Study database and performed conditional imputation for CVD-censored parental age (i.e. parents that didn\u2019t experience onset of CVD) and Cox proportional regression analysis, with offspring\u2019s age of onset of CVD as the dependent variable and parental age of onset of CVD as the primary predictor. Modifiable risk factors in offspring, such as cigarette smoking, body mass index (BMI), diabetes mellitus, systolic blood pressure (SBP), high-density lipoprotein (HDL) level, and low-density lipoprotein (LDL) level, were controlled for. Separate analyses were performed for the association between maternal age of onset of CVD and offspring age of onset of CVD and the association between paternal age of onset of CVD and offspring age of onset of CVD.Parental age of onset of CVD was predictive of offspring age of onset of CVD for maternal age of onset of CVD  and for paternal age of onset of CVD . A negative estimate of the coefficient of interest signifies that late onset of cardiovascular events in parents is protective of onset of CVD in offspring. Cigarette smoking and HDL level were important associated confounders.Offspring age of onset of cardiovascular disease is significantly associated with both maternal and paternal age of onset CVD. The incorporation of the parameters, maternal or paternal age of onset of CVD, into risk estimate calculators may improve accuracy of identification of high-risk patients in clinical settings. Cardiovascular disease (CVD), defined as coronary death, myocardial infarction, coronary insufficiency, angina, ischemic stroke, hemorrhagic stroke, transient ischemic attack, peripheral artery disease, and heart failure, is the leading global cause of death, accounting for over 30 percent of all deaths worldwide\u2013 17.3 million deaths per year. In the United States, someone dies from cardiovascular diseases every 39 seconds , yet 72%Associations have long been established between CVD and a wide variety of risk factors, including non-modifiable variables such as age, sex, and family history, and modifiable atherosclerotic risk factors, such as cigarette smoking, alcohol intake, increased BMI, systolic blood pressure (SBP), diabetes mellitus, high-density lipoprotein (HDL) level, and hypercholesterolemia \u201310. HighDespite this evidence that recognizes that both parental history and genetic factors are modifiers of MI risk, neither element is routinely used in the clinical determination of CVD risk. Currently, few analyses delineate the association between parental history of CVD and manifestations of CVD other than MI . Furthermore, measuring parental history as a binary variable (\u201cyes\u201d or \u201cno\u201d) is an oversimplification that fails to recognize the effects of several variables within the parental history, including the relatives\u2019 age of onset of disease, patient\u2019s relation to relative, and quantity of relatives affected with cardiovascular disease, all of which have been shown to impact CVD risk \u201317.The Framingham Heart Study has published multivariate models for estimation of the 10-year absolute risk of developing CVD ,19, and While the effect of parental history of premature cardiac events  and the effects of advanced age on CVD risk is well-studied ,27, no rn = 3261) and the FHSO Exam 1 . There was a total of 2622 linked parent-offspring pairs. The age of onset of CVD is the age at which either parent or offspring was diagnosed with CVD, including coronary death, myocardial infarction, coronary insufficiency, angina, ischemic stroke, hemorrhagic stroke, transient ischemic attack, peripheral artery disease, and heart failure, by a medically trained professional. This \u2018time-to-event\u2019 data was collected based on follow up data of both the original and offspring cohorts. Baseline values of the covariates of interest, collected at first clinical visit, were used in data analysis. Participants were included if they had not yet developed overt symptoms of cardiovascular disease or suffered a heart attack or stroke, and subjects were excluded if they had missing data.The study was approved by University of Texas Health Science Center in Houston Institutional Review Board and Biologic Specimen and Data Repository Information (BioLINCC). For this study we used The Framingham Heart Study (FHS) database. The data comes from a well-known, longitudinal prospective cohort study that is a premier database for study of cardiovascular diseases and other terminal disease. The FHS Original Cohort was launched at Exam 1 in 1948 and has continued with biennial examinations to the present. The FHS Original Cohort consists of 5,209 respondents  aged 28\u201362 years residing in Framingham, Massachusetts, between 1948 and 1951. Nearly all subjects were Caucasians. The Offspring Cohort (FHSO) was launched at Exam 1 in 1971 and has on average been examined every 3 to 4 years since enrollment. The FHSO dataset consists of a sample of 3514 biological descendants of the Original Cohort, 1576 of their spouses and 34 adopted offspring for a total sample of 5124 subjects . This analysis used values collected during the FHS Original Cohort Exam 12  was used for statistical analysis. The proportional hazard regression calibration approach employed in this paper for analyzing the time to event outcome and censored predictor is similar to the proportional hazards regression model for survival data with measurement error ,30. ThisUnlike binary thresholding approaches that have shown increased risk of CVD if a first-degree blood relative has had coronary heart disease or a stroke before the age of 55 years  or 65 years , we can compute a hazard ratio for each unit increase or decrease of parent age of onset. The conditional imputation approach employed in this paper combined the non-modifiable risk factors, age of onset of CVD in mother or father and parental history, by defining parental onset of CVD as the instantaneous risk of cardiovascular event, given that the event has not previously occurred. This leads to a relatively stable estimate and avoids bias estimates as the thresholding approach shown by Rigobon & Stocker  and AustThe age of onset of CVD is defined as the age at which either parent or offspring was diagnosed with CVD by a medically trained professional. The dependent variable, age of onset of CVD in offspring, is potentially right-censored. That is, offspring that truly had CVD but were not diagnosed with CVD by a medical professional during this study are considered censored. Similarly, for the primary predictor variable, age of onset of CVD in parents, those that truly had CVD but were not diagnosed with CVD are considered censored. In order to consider`censored parents in the Cox model for age of onset of CVD in offspring, we employed the conditional mean imputation technique ,38.Our primary variable of interest is parental age of onset of CVD, which is potentially right-censored. We controlled for the following confounders: offspring smoking status, offspring diabetes status, offspring BMI, offspring SBP, offspring HDL, and offspring LDL Tables  and 4. TSeparate analyses were performed for each parent, and the data was separated into two groups. There were 2622 linked parent-offspring pairs in total, with 1401 mother-offspring pairs and 1221 father-offspring pairs. The median age of onset of CVD was 68 years and 64 years for mothers and fathers, respectively . The oveThe baseline characteristics for the separate analysis with the primary predictors, maternal age of onset of CVD and paternal age of onset of CVD, are shown in The Cox proportional hazard (Cox PH) models were used to analyze the relationship between offspring age of onset of CVD and parental age of onset of CVD. We presented a separate analysis for the association between offspring age of onset of CVD and maternal age of onset of CVD and offspring age of onset of CVD and paternal age of onset of CVD Tables  and 4. TWe fit a Cox model for the association of age of onset of CVD in parents and offspring. The Schoenfeld residuals  against age of onset CVD in offspring with a smooth line (cubic spline) are fit to the points . These sMaternal age of onset of CVD is statistically significantly related to age of onset of CVD in offspring with a hazard ratio of 0.959, while paternal age of onset has a hazard ratio of 0.973. Our analysis describes hazard ratios based on unit increase or decrease of maternal and paternal age of onset of cardiovascular events. Although several papers have evaluated the link between CVD in parents and CVD risk in offspring, they have categorized parental history of CVD as a dichotomous variable using a thresholding approach ,39 or inThis is the first study to link parental age of onset to offspring age of onset of CVD using continuous variables in survival data. Currently, multivariate models for estimation of the 10-year absolute risk of developing CVD, including the Framingham calculator and the European SCORE calculator, can underestimate subclinical atherosclerosis ,24. NeitSeveral studies have suggested that a maternal transmission of CVD is more important for the development of CVD than paternal transmission \u201344. SomeThe Framingham data comes from a well-known prospective cohort study. Advantages of using the Framingham Heart Study data include access to near-complete data on the development of selected cardiovascular diseases due to their careful longitudinal follow-up of subjects. The Framingham Study was the first large scale cohort study of its kind that compare one generation to the next using a wide variety of data parameters. However, practitioner error may lead to a CVD sensitivity and specificity of less than 100%. That is, some subjects with CVD may be diagnosed an indefinite period of time after time of actual CVD onset or not at all, introducing information bias into the study. As technologies for detection of CVD  have improved dramatically, CVD can be detected more definitively at an earlier time in the disease course and subsequent cohorts (offspring) may have experienced different sensitivity and specificity of diagnosis. Furthermore, nearly all subjects enlisted in the study in 1948 were White. The homogeneity of the cohorts may limit generalizability to a more diverse population, and future studies should include subjects from a variety of ethnic backgrounds to improve the ability to apply findings to the general population.Lastly, the statistical interpretation of this study can be confusing; both independent and dependent variables are potentially right-censored so they may not have clean interpretations. However, based on the sign of the coefficient (negative) it can be determined that the increasing parental age of onset of CVD is protective of early CVD in offspring.rd and 4th generation of this cohort study. More comprehensive understanding of cardiovascular risk factors will allow practitioners to more accurately identify patients at high risk for CVD who would not otherwise be identified by traditional risk calculators.Further research on the role of family history of CVD, including age of onset, number of family members affected, and differential effect of sex of family members affected, and its implications for CVD risk should be explored. The Framingham data is an excellent body of data for use in analyses of this nature, and future research should focus on risk factor studies in the 3"}
+{"text": "Scientific Reports5: Article number: 10198; 10.1038/srep10198 published online: 05142015; updated: 05312017.The Acknowledgements section in this Article is incomplete.\u201cWe would like to express our gratitude to all the participants of the study, management of both King Fahad Medical Research Center (KFMRC) and Arabian centers, and all the students who volunteered to help us in recruiting the subjects. We thank all the support staff of department of Pharmacology, King Abdulaziz University Hospital, Al-Salaam mall and Mall of Arabia. We are particularly grateful to both Iuliana Denetiu and Mohammed Ali Majrashi for their help in collection, input and validation of data. We express our appreciation towards Hussain Ahmad for his help towards database development. We acknowledge the Stratified Medicine Graduate Training Programme in Systems Medicine and Spectroscopic Profiling (STRATiGRAD) for funding of Torben Kimhofer. The authors declare that there are no conflicts of interest.\u201dshould read:\u201cThis project was funded by the Deanship of Scientific Research (DSR) at King Abdulaziz University, Jeddah, under grant no. 2-141-35-HiCi. The authors, therefore, acknowledge with thanks DSR for technical and financial support. We would like to express our gratitude to all the participants of the study, management of both King Fahad Medical Research Center (KFMRC) and Arabian centers, and all the students who volunteered to help us in recruiting the subjects. We thank all the support staff of department of Pharmacology, King Abdulaziz University Hospital, Al-Salaam mall and Mall of Arabia. We are particularly grateful to both Iuliana Denetiu and Mohammed Ali Majrashi for their help in collection, input and validation of data. We express our appreciation towards Hussain Ahmad for his help towards database development. We acknowledge the Stratified Medicine Graduate Training Programme in Systems Medicine and Spectroscopic Profiling (STRATiGRAD) for funding of Torben Kimhofer. The authors declare that there are no conflicts of interest.\u201d"}
+{"text": "Nowadays, most of the research in the field of gerontology is focused on the effects of the grape polyphenols. In particular, resveratrol has been shown to increase life expectancy of various living organisms, including mammals. Resveratrol also plays an important role in cancer prevention and decreases the risk of developing cardiovascular disease. In our research, we proposed the development of the therapeutic product from Cabernet Sauvignon grapes that would exhibit the beneficial properties of polyphenols. Standard operating procedures were developed in our laboratories to collect alcohol free concentrate of polyphenols from the Kazakhstan Cabernet Sauvignon collection of grapes. The purpose of the study was to investigate the composition, biological safety, and potential therapeutic effects of the polyphenol concentrate.The total polyphenol amount was determined using the Enology Analyzer Y15 . HPLC analysis of the polyphenol composition was performed using Agilent 1290 chromatograph. The polyphenol concentrate was analyzed for the microbiological purity and the presence of the toxic elements. The cytoprotective effect of the polyphenol concentrate was studied in experimental models of diabetes, toxic hepatitis, doxorubicin cardiomyopathy, and acute radiation sickness.The total polyphenol amount in one sample was 12,819 mg/l. Polyphenol composition analysis showed presence of the following polyphenols: catechin, epicatechin, gallic acid, quercetin, miricetin, 3-glucosylkaempferol, epicatechin gallate, 3--2-propenoic acid, catechin gallate, pitseid, kaempferol, n-hydroxy-cinnamic acid, resveratrol and chlorogenic acid. The concentrate was proven to be biologically safe and acceptable for use as a dietary supplement. The polyphenol concentrate demonstrated high antioxidant activity against ABTS and DPPH radicals in vitro. It also showed the following impacts on the various experimental models in vivo: reduction of sugar levels in diabetes; regeneration of the structure and function of the heart tissue in cardiomyopathy; regeneration of the nephron structure and function in nephropathy; regeneration of liver in toxic hepatitis; recovery of the antioxidant status in oxidative stress; and recovery of the hematopoiesis in acute radiation sickness.The polyphenol concentrate from Kazakhstan Cabernet Sauvignon collection of grapes was proved to be biologically safe and acceptable for use as a dietary supplement. The concentrate showed high antioxidant, antiradiation activity, and regenerative effect in diabetes, cardiomyopathy, nephropathy, and hepatitis in the corresponding organs."}
+{"text": "A number of major, minor, and trace elements function as important nutrients in foodstuffs of crop and animal origin. These elements occur in a broad range of concentrations in an exceedingly vast array of foods available commercially and home-prepared. In disciplines such as regulatory compliance, product development, quality and safety, and research, reasonably reliable analytical information is mandatory for conclusions and decisions of impact. Although analytical scientists recognize the need for valid data, solid analytical information is at times elusive not only in the area of determination of chemical elements at low (trace) levels \u20135 but alOf the many analytical techniques available for determination of inorganic nutrient constituents in biological matrices, those based on atomic spectrometry (AAS) are convenient and widely applied. The thrust of current research is to define impacts of a number of parameters on the performance of flame AAS (FAAS)-based methods of analysis of soil and biological materials to lead to reference methods for the measurement of major, minor and trace levels of elements of nutritional and toxicological pertinence. Some of these parameters as well as the excellent performance possible with well-applied versions of FAAS procedures are discussed.In spite of wide acceptance of the technique and the proliferation of published articles on its application, very few AAS-based methods have reached official method or reference method status , Require3/HClO4 with further separate treatment of insoluble siliceous residues with HF for measurement of total concentrations of Na, K, Mg, Ca, Mn, Fe, Cu and Zn. Flame atomic absorption measurements were performed under optimized standard operating conditions. Measurement techniques were based on either bracketting of sample with appropriate standard solutions or second order calibration curves incorporating appropriate standard and procedural reagent blanks. Two types of working standard solutions were prepared with one set (regular standard) containing the eight analytes at concentrations required for analysis. The second set (matrix-matched) contained the analytes at approximate concentrations occurring in the plant materials being analyzed and, in addition, contained three other major constituents, Al, S and P present in the samples to match the analytes and matrices of the analytical samples, The scheme of analysis is depicted in Experiments were conducted with four plant Standard Reference Materials as test materials, SRM 1570 Spinach, SRM 1571 Orchard Leaves, SRM 1573 Tomato Leaves, and SRM 1572 Citrus Leaves, from the National Bureau of Standards with the last product uncertified at the time of the study. Samples were dissolved with HNODevelopment and application of a high reliability version of an analytical procedure requires familiarity with all factors having a possible bearing on the precision and systematic errors of the overall procedure. The effect of calibration expressed as differences in elemental concentrations measured using regular and matrix-matched standard solutions is a function of element and sample type. Differences in concentrations ranged from 0.2% to 10.2% depending on element and matrix, indicating that for measurements of the highest reliability, systematic error arising from calibration can be reduced by using reasonable close matrix-matched standard solutions , EffectsThat meticulous attention to detail can lead to a high precision and high accuracy procedure is demonstrated by information in"}
+{"text": "Dear Editor-in-ChiefMyxoid tumors of the oral cavity encompass a broad spectrum of lesions, primarily neoplastic . SignifiThis classification is based on the predominance of the areas of myxoid degeneration in histopathology of the tumors of oral cavity. This classification includes adipose, neural, fibroblastic, chondroblastic, muscle, odontogenic and miscellaneous tumors. This classification wouldprovide a better insight into the histopathology of myxoid tumors of oral cavity and wouldbe useful for oral pathologists and cytopathologists."}
+{"text": "The implementation in China is warranted, since the leading Chinese research institutes as well as the most important local stakeholders, e.g. water suppliers, are involved.The Taihu (Tai lake) region is one of the most economically prospering areas of China. Due to its location within this district of high anthropogenic activities, Taihu represents a drastic example of water pollution with nutrients , organic contaminants and heavy metals. High nutrient levels combined with very shallow water create large eutrophication problems, threatening the drinking water supply of the surrounding cities. Within the international research project SIGN (SinoGerman Water Supply Network,  Water is essential for all forms of life. However, in many parts of the world, water quality is threatened by multiple pollution sources. In the last few decades, China has undergone rapid industrial and economic growth. Especially in densely populated areas, the need for clean water is constantly increasing . At the 2 ).Responsible: IGB Leibniz-Institute of Freshwater Ecology and Inland Fisheries, TZW Water Technology Center.Chinese partners: Chinese Research Academy of Environmental Sciences (CRAES), Nanjing Institute of Geography & Limnology, Chinese Academy of Sciences (NIGLAS), Tongji University.Biodegradation of organic pollutants and nitrogen-containing compounds  as beneficial ecosystem services is investigated by using modern PCR-techniques , 20 as wOnset and duration of cyanobacteria blooms are controlled by the nutrient content  as well Responsible: bbe Moldaenke GmbH, FZJ Forschungszentrum J\u00fclich GmbH, inge GmbH.Chinese partners: Suzhou Water Group Co. Ltd., Tongji University, Hua Yan Water Group.Algae are measured within the lake itself in order to monitor their growth under different environmental conditions. Online analyses at the inlet of the drinking water treatment reveal changes in raw water quality. Further measurements at the different steps of drinking water treatment allow the assessment of the removal efficiencies for the algae themselves, their toxins as well as algae-released drinking-water-relevant taste & odour (T and O) compounds/precursors. New measuring tools are developed in order to assess the integrity status of algae cells and thus the risk of toxin release.Due to the impaired raw water quality, efficient solutions for drinking water treatment of algae contaminated water are needed. Ultrafiltration membranes are employed to efficiently remove algal cells and/or algal compounds. This reduces the formation of disinfection by-products and/or T and O compounds/precursors in subsequent oxidation steps within the drinking water treatment plant. The membrane itself is improved regarding material and geometry. Additionally, the operating modes are optimized with respect to energy-efficiency and maximum performance, supported by the data obtained from an algae-online analyser.Precursors of T and O compounds are identified by in-depth analysis of raw water and water from different treatment steps. Formation of T and O compounds is investigated by mechanistic laboratory studies in order to optimize advanced oxidation processes. Improved elimination of drinking-water-relevant substances by technological process optimization using the above-mentioned ultrafiltration and advanced oxidation techniques is evaluated for practical application within drinking water treatment plants in China.Responsible: F.A.S.T. GmbH, TZW Water Technology Center.Chinese partners: Suzhou Water Group Co. Ltd., Tongji University, Hua Yan Water Group.Drinking water leaving the waterworks in Suzhou has good and stable quality. However, water discoloration and problems with T and O compounds reoccur during transport through the drinking water pipes. In order to remove deposits and thus increase drinking water quality at the consumer\u2019s tap, an innovative optimized flushing strategy is adapted and tested in a model region of the distribution network in Suzhou. Based on the deposit accumulation velocity, the needed flushing intervals are defined in order to allow deposit-free maintenance of the distribution network in the future.Tools for the automatic acoustic detection of leakages within the drinking water pipes are adapted and tested for a model region of the distribution network in Suzhou. The measuring data of the noise loggers are collected via wireless transmission, accessible via internet and evaluated with a specialized software tool. The gained knowledge about the occurring water losses helps the water suppliers to reduce the water losses from their water distribution networks to a minimum being obligatory for technical, hygienic as well as economic reasons.Responsible: UFZ Helmholtz-Zentrum f\u00fcr Umweltforschung GmbH.Chinese partners: Chinese Research Academy of Environmental Sciences (CRAES), Tongji University.Achieving a sustainable urban environmental water cycle is not only a technical challenge. Feasibility, adequacy and performance of technical concepts are highly dependent on the socio-economic and institutional settings. Thus, recommendations for sustainable water policy and administration that consider the particular framework conditions in China are deduced. Further initiatives for effective participatory processes and awareness-raising campaigns are suggested.Responsible: TZW Water Technology Center.www.water-sign.de, with publications and with presentations at local and international conferences.All results obtained are actively shared with the scientific community as well as with the concerned Chinese stakeholders e.g. via the website German best practice examples of pollution elimination and improvement of water resource quality are analysed in view of appropriateness for the Taihu region. Based on the existing Chinese standards and guidelines as well as on the raw water situation of Taihu, the most important parameters for drinking water quality are selected in order to facilitate future monitoring and control."}
+{"text": "Non-mainstream scholarly journals are struggling to maintain a healthy flow of the best submissions, influence science growth locally and internationally, and become indexed in prestigious bibliographic databases. There are financial and non-financial factors confounding editing and publishing practices across low-resource countries. Publishers in these countries often face difficulties with involving experienced reviewers and editors in the processing of submissions to their journal. As a result, non-mainstream scholarly journals are at risk of publishing unchecked, poorly edited, erroneous, and unethical papers. They face challenges of inappropriate authorship, non-disclosure of conflicts of interests, plagiarism, and other forms of scientific misconduct. Journals\u2019 applications to global indexing abstract and citation databases are often declined due to the lack of transparent and ethical editorial strategies, inappropriate scope of interest, low level of evidence, and low citation rates. A hhandful of the indexed regional journals are aggressively targeted by unethical authors and brokering editing agencies, exploiting the deficiencies in the editorial strategies and thus further damaging the reputation of the journals. To curb the problems with editing and publishing, journal editors from non-mainstream science countries are encouraged to upgrade their strategies of ethical editing and research reporting in accordance with the updated recommendations of editorial associations, such as the International Committee of Medical Journal Editors (ICMJE), the Committee on Publication Ethics (COPE), and the Council of Science Editors (CSE). Academic institutions and professional societies from these countries are called to provide guidance for researchers and science editors and allocate resources for improving editing and publishing practices.Croatian Medical Journal and other MEDLINE-indexed journals. As the main problems with editing regional journals were highlighted, the decision was made to draft this Declaration. Journal editors from non-mainstream science countries are called to upgrade and enforce their instructions for authors in accordance with the listed points on integrity and visibility.How to address the problems with journal publishing in non-mainstream science countries was discussed at the First Mediterranean Seminar on Science Writing, Editing and Publishing, which was organized by the Academy of Medical Sciences of Bosnia and Herzegovina in Sarajevo, December 2-3, 2016. The idea of organizing such a meeting and drafting an instructive document for editors and publishers struggling with poor quality and visibility of their journals was proposed by numerous regional experts. They voiced their concerns and suggested to act jointly. The Seminar attracted more than 100 researchers, experienced journal editors, and publishers from Balkan and Mediterranean countries, who shared their experience with writing, reviewing, editing, and publishing. Updates to the recommendations of the most influential editorial associations, such as the ICMJE, COPE, and CSE, were presented to incorporate in the regional journal instructions. Participants had a unique opportunity to receive hands-on training on editing from the flagship regional journals, such as the The Sarajevo Declaration is aimed at upgrading standards of editing and publishing scholarly journals across Balkan and Mediterranean countries. Journal editors from regional and other non-mainstream science countries are encouraged to familiarize themselves with the statements and amend their instructions accordingly.The endorsement and enforcement of the Sarajevo Declaration may help avoid \u2018wasteful\u2019 or unethical publishing practices and improve visibility, scientific prestige, and indexability of the adherent scholarly publications.Transparency of in-house editorial procedures and external editing supportSupport of professional editorial teamsFocus on regional and local scientific research problems defined in the journal aims and scopePromotion of ethical research and reviewsScholarly publications are essential for research productivity, academic promotion, sharing professional information, and networking among scientists worldwide. Authors, reviewers, and editors are required to ensure the trustworthiness and ethical soundness of what they write, edit, and publish. To maintain the quality and ensure the impact of their publications, all stakeholders in science communication should make effort to ensure the integrity and promote innovative and evidence-based sources of information.1. Scholarly papers are final products of collective efforts of all stakeholders in science communication. It is increasingly important to promote these papers post-publication by indexing and archiving on relevant global digital platforms. Responsible editors and publishers alike are in the position to contribute to the post-publication communication. To improve visibility of their publications, authors can rely on reliable social media, sharing platforms, and individual and institutional repositories.2. Authors, reviewers, and editorial board members can increase visibility of their scholarly activities by registering with the Open Researcher and Contributor ID (ORCID) and providing information on their own authoring, reviewing, and publishing activities via their permanent accounts. Publishers of scholarly journals can maintain the integrity of pre- and post-publication communication by joining the ORCID global initiative.3. Erroneous publications are common, and take place because of the authors\u2019, editors\u2019, and publishers\u2019 oversights. Authors, reviewers, editors, and readers have the responsibility to notify publishers about any instances of known research misconduct and erroneous publications, necessitating corrections or retractions.4. Effective functioning of scholarly journals is dependent on skilled individuals involved in the processing of manuscripts. Publishers encountering problems with erroneous and poorly written publications should expand their editorial teams by inviting experienced editors responsible for statistics, publication ethics, language, and design.5. Continuing professional development (CPD) should be complemented by publications in scholarly journals that serve as platforms for distributing professional information of interest to both novice and seasoned authors. To achieve this goal, publishers may create journal sections for students, researchers, and specialists seeking CPD credits. Efforts should be made by publishers to acknowledge their contributors and obtain CPD credits for publishing and reviewing activities.6. Professional societies can take the lead and contribute to the promotion of scholarly journals by taking responsibility for healthy flow of journal submissions from their memberships, quality checks, and publishing established and start-up periodicals and awarding the contributors with academic credits.7. Science editors should adhere to the most recent recommendations of global editorial associations and incorporate relevant sections in their journal\u2019s instructions to improve the quality of pre- and post-publication communication.8. Websites and editorial management platforms of scholarly journals should contain transparent information on the editorial management, peer review, open access or subscription models, and acceptable editing practices. Commercial editing services, which are offered by publishers and other organizations, may help improve the quality of journal submissions. However, all these services require transparency and acknowledgment in accordance with the recommendations of global editorial associations.9. Traditional and alternative impact indicators are instrumental for assessing the scholarly journals in terms of distributing information, attracting readership, and facilitating science growth. Combined quantitative and qualitative approach to citations, downloads, and distributions of individual papers through social networking channels can reveal interest of readers toward certain topics and types of publication, but not necessarily the quality of scholarly journals. Editors and publishers can increase the impact of their journals by improving the functionality of their journal websites and online content, ensuring the completeness of meta-data in the published papers.10."}
+{"text": "They are released outside of the cells immediately after synthesis, and exert their actions by binding to a G-protein coupled rhodopsin-type receptor on the surface of target cells. There are eight types of the prostanoid receptors conserved in mammals from mouse to human. They are the PGD receptor (DP), four subtypes of the PGE receptor , the PGF receptor (FP), PGI receptor (IP), and TXA receptor (TP). Recently, mice deficient in each of these prostanoid receptors were generated and subjected to various experimental models of disease. These studies have revealed the roles of PG receptor signaling in various pathological conditions, and suggest that selective manipulation of the prostanoid receptors may be beneficial in treatment of the pathological conditions. Here we review these recent findings of roles of prostanoid receptor signaling and their therapeutic implications.Prostanoids, consisting of the prostaglandins (PGs) and the thromboxanes (TXs), are a group of lipid mediators formed in response to various stimuli. They include PGD"}
+{"text": "This study aimed to investigate the effectiveness of cognitive-behavioral therapy on relieving migraine headaches in migraine sufferers.In this quasi-experimental study with pre-test and post-test method, the samples were outpatients of public hospitals in Ilam City, southwestern Iran since May-Jul 2010. They were selected based on inclusion and exclusion criteria, and divided into experimental and control groups. The data were analyzed using SPSS ver. 16 and via multivariate covariance method.P<0.05). Cognitive-behavioral therapy affected on reducing the duration of symptoms of migraine in sufferers (Cognitive behavioral therapy effects on reducing the time duration of symptoms of migraine headaches. Thistherapeutic method increases the level of individual, familial, social and occupational activities by reducing the time duration of symptoms and this method helps the individuals to resume their activities and regain their previous control instead of founding themselves incapable and helpless due to the pain they suffer from.  Prevalence of migraine is different in various cultures, but it affects approximately 12% of general population and it is more effective on women. In various populations, the prevalence of migraine is about 6% in men and 18%of women aged between 15-45 yr old. Lifetime prevalence of migraine, is 8%-13% in women and 25%-33% in men  in IlamCity, southwestern Iran were examined since 2010. Out of 635 patients who were willing to cooperate, 30 migraine sufferers were selected regarding several factors: no pregnancy, lack of heart disease, minimum literacy and older than 15 yr old. These participants were divided into two experimental and control groups. The participants of experimental group received both drug and cognitive-behavioral therapy, and the participants of control group only received drug. The pre-test was conducted for both groups. The number of migraine attacks, duration of attacks, severity and the number of taking pain relief pills were controlled by phone within 4 wk. Eleven cognitive-behavioral therapy sessions were held for experimental group.The study was approved by Ethics Committee of the university and informed consent was taken the patients.The key issues trained in form of therapy sessions by the researcher included: Cognitive Restructuring (learning how to recognize the cognitive errors and replacing the positive and efficient thinking with negative and inefficient thinking), training the relaxation methods , doing tasks and activities progressively regarding the time duration based on the resting/activity periods (without doing excessive activities ), assigning the home works in order to reduce the activities and resuming an active and effective life style.Two participants of control group and one participant of experimental group discontinued the research processes. After the implementation of the independent variable, headache indicators  were measured within 8 wk. The results were analyzed using SPSS software  and multivariate analysis of covariance.Various descriptive indicators such as mean, standard deviation, and the Kolmogorov-Smirnov normality test results showed that the distribution of various scores tends to a normal distribution  To examine the effectiveness of cognitive-behavioral therapy on reducing the number of attacks, severity and duration of migraine headaches and the degree of taking drugs in migraine sufferers, Wilkes Lambda test was used, but at first, the precondition for the equality of variances using Lyon test was investigated in P<0.05). According to Eta squared (0.401), the difference wasin moderate. Totally, Eta squared value (0.401) showed that there was an approximately strong relationship between cognitive-behavioral therapy and reducing the symptoms of migraine headaches  and F value (3.013) and degree of freedom of 18 & 4, there weresignificant difference between the mean of post-test scores in 4 variables  in both control and experimental groups (eadaches .P<0.05). In respect of duration of headache symptoms, Eta squared value (0.174) showed an approximate weak relationship between cognitive-behavioral therapy and the duration of migraine headache symptoms  showed that there wasno significant difference between the mean of post-test scores of control and experimental groups. However, there wasa significant difference between the mean of post-test scores of duration of headache symptoms in control and experimental groups (symptoms . In respect of the results of this research, cognitive-behavioral therapy effects on reducing the duration of headache symptoms in migraine sufferers. The results of this study are in consistent with another study. AnotherTherefore, long duration of migraine attacks have detrimental effects on the quality of individual and family life and career of the migraine sufferers as well.It affects on the ability and competence of people to perform social tasks because migraine sufferers have to rest somewhere dark and quiet to relieve headache pain . MoreoveThere were some limitations in this study such as refusing the patients to get involved in different stages of screening and researcher\u2019s follow-up, age control, gender, and education level of patients and making limitations for generalizing the results and not increasing the number of samples due to the high cost of visiting neurologists. In Conclusion, all centers for counseling and psychotherapy, welfare, medical science, physicians, psychologists, consultants, psychotherapists, and neurologists should access to the results of the present study in order to provide better services, and reduce side effects in patients with migraine and tension headaches, and also prepare a therapist and patient handbook and deliver to the rated centers."}
+{"text": "It is with my deepest sorrow that I announce the untimely death of the passing of Dr Dimitri Tassiopoulos.Dr Dimitri Tassiopoulos was a Chief Research Manager with Social Aspects of HIV/AIDS Research Alliance (SAHARA) within the HIV/AIDS, STIs and TB (HAST) research programme of the HSRC. He held a BA (Hons.) degree in Political Science from the University of Stellenbosch, and obtained an MBA and PhD in Management and Administration from the University of Stellenbosch Business School in South Africa.Before joining the HSRC in May 2011, he was an Associate Director at the School of Tourism and Hospitality at the Walter Sisulu University (WSU) in East London, South Africa. He spent the majority of his academic career as a head of a School or as a Departmental Chairperson. After 1993, he was involved in various national and international tourism research projects, of a multidisciplinary and multi-institutional nature, concerning agritourism, event, cultural and wine tourism, amongst others. In 2004 he was appointed as a member of the South African Qualifications Authority\u2019s Standards Generating Body (SGB) for Travel, Tourism and Events, and was appointed as its chairperson. He was the vice president of the Tourism and Hospitality Education Providers of South Africa (THEPSA). This Federation represents further (FET) and higher education (HET) institutions offering the spectrum of qualifications related with the management of the tourism industry. He was also the chairperson of the Tourism and Events Educators Chamber of South Africa (TEECSA), an association representing higher education travel, tourism and events related programme providers.Dr Tassiopoulos successfully supervised post-graduate mini-theses/theses/dissertations and served as an external examiner for post-graduate theses at various universities in South Africa. Dr Tassiopoulos was a board member of a number international peer-reviewed research journals. The evidence of Dr Tassiopoulos\u2019s work is reflected in his publication record that spans the authoring and co-authoring of more than 16 presentations, at local, regional and international conferences, and, nine scientific publications in peer-reviewed journals. He was awarded six grants for research, published six books, published 33 chapters in books, has been involved in seven commissioned research projects. He has been rated a C3 researcher by the National Research Foundation. He served as a book reviewer for a number of publishers and as a proposal reviewer for the National Research Foundation.Tourism Today: published annually by the College of Tourism and Hotel Management, Nicosia, Cyprus (ISSN 1450-0906) (http://www.cothm.ac.cy/research.htm), and European Journal of Tourism Research: an academic refereed journal published bi-annually by International University College, Bulgaria (ISSN: 1994-76580) (http://ejtr.vumk.eu/). He was a regular reviewer of articles submitted to the prestigious Tourism Management Journal for publication.Dr Tassiopoulos was involved as an International Reviewer for the European Council on Hotel, Restaurant and Institutional Education (EuroCHRIE), Dubai 2008 Conference. He was involved as a session chair for the 2008 International Council for Small Business (ICSB) Conference, Halifax, NS, Canada; and, the 7th International Conference for Consumer Behaviour and Retailing Research (CIRCLE), Estoril Higher Institute for Tourism and Hotel Studies (ESHTE), Estoril, Portugal. He served on the following journal editorial boards as a board member of a number international peer-reviewed research journals. In particular, SAHARA-J: Journal of Social Aspects of HIV/AIDS (SAHARAJ). He successfully, while working closely together with Prof. Phaswana-Mafuya, managed to bring the journal under the Taylor & Francis Online stable with Routledge Press. SAHARAJ\u2019s impact factor has risen during his leadership. Dr Tassiopoulos also managed the SAHARA Conference.Among some of his achievements since joining HSRC Dr Tassiopoulos served as Managing Editor of Dr Tassiopoulos was involved in collaborating in cross-disciplinary research projects. He was involved in researching the effects of HIV and AIDS within higher education and the management of this syndrome that is afflicting the higher education population. More recently, he was involved in co-editing and publishing a book entitled non-communicable diseases in developing countries. Most recently, he led both international and South African research in the field of HIV and the World of Work Initiatives.Dr Dimitri Tassiopoulos made a significant contribution to South Africa\u2019s social science capital and his bright mind, dedication and passion will be missed. I take this opportunity again to convey my condolences to all of you who have known and worked with Dr Dimitri Tassiopoulos."}
+{"text": "Over the last two decades, important contributions were made at national, European and international levels to foster collaboration into rare diseases research. The European Union (EU) has put much effort into funding rare diseases research, encouraging national funding organizations to collaborate together in the E-Rare program, setting up European Reference Networks for rare diseases and complex conditions, and initiating the International Rare Diseases Research Consortium (IRDiRC) together with the National Institutes of Health in the USA. Co-ordination of the activities of funding agencies, academic researchers, companies, regulatory bodies, and patient advocacy organizations and partnerships with, for example, the European Research Infrastructures maximizes the collective impact of global investments in rare diseases research. This contributes to accelerating progress, for example, in faster diagnosis through enhanced discovery of causative genes, better understanding of natural history of rare diseases through creation of common registries and databases and boosting of innovative therapeutic approaches. Several examples of funded pre-clinical and clinical gene therapy projects show that integration of multinational and multidisciplinary expertize generates new knowledge and can result in multicentre gene therapy trials. International collaboration in rare diseases research is key to improve the life of people living with a rare disease. In Japan, the legal definition of a RD is one that affects fewer than 50\u2009000 patients in Japan, or ~1 in 2500 people.3 However, while individually these diseases may be considered rare, collectively they are not. It is estimated that 8% of people have one of the 6000\u20138000 RDs, and ~36 million Europeans are affected by one or will be. Eighty per cent of RDs are genetic in origin and often result from a dysfunction of a particular pathway (such as a defective gene or protein). Thus, understanding the impact of a single defect can yield insights into more complex pathways and, as result, RDs can serve as models for more common conditions, in particular in the context of precision medicine.A rare disease (RD) is defined as such by the fact that it affects a small percentage of the population. However, there is no internationally recognized definition of a RD. In the European Union (EU), a disease is defined as rare when it is life-threatening or chronically debilitating and when no more than 1 in 2000 people has it.4 setting out an overall Community strategy to support Member States in diagnosing, treating and caring for EU citizens with RDs. Three main areas were identified: improving recognition and visibility of RDs, supporting national plans for RDs in the EU Member States, and strengthening co-operation and co-ordination for RDs research at the European level. Indeed, RDs are a challenge too big for any one country or world region to tackle alone due to their low prevalence. Research on RDs is not only limited, but also scattered across laboratories and clinics throughout the world. This scarcity of expertize and practice translates into delayed diagnosis, few medicinal products and difficult access to care. That is why the field of RD research is a prime example of a research area that substantially benefits from co-ordination on a European and international scale, as co-operation can bring forth the development of new diagnostics and treatments. By increasing the number of patients available for each study and bringing together the scattered specialists with complementary expertize, the development of new diagnostics and treatments can be notably accelerated. This paper focuses on the efforts in the RDs field in Europe with some additional insights into international activities through the perspective of the International Rare Diseases Research Consortium (IRDiRC).In 2008, the European Commission (EC) adopted a communication5 The EU continues to offer funding opportunities for RD pre-clinical and clinical research and to strengthen international collaboration, in particular, in view of supporting the development of new therapies for RD and the diagnostic characterization of RD thus to develop better and faster means of high quality and clinical utility for the correct diagnosis of undiagnosed RD.The EU has been funding cross-border research on RD for more than two decades through its Framework Programmes for Research and Technological Development (FP) with complementary projects and actions. Since 1998, more than \u20ac1 billion has been invested in over 270 projects on RD , bringin6 European Reference Networks (ERNs) are virtual networks bringing together medical specialists across Europe to tackle rare or complex diseases and conditions that require highly specialized healthcare and a concentration of knowledge and resources. For the first time, a formal structure of voluntary collaboration between healthcare providers across the EU has been created for the direct benefit of the patient. The first 24 thematic networks include over 900 highly specialized healthcare units located in more than 300 hospitals of 25 EU countries plus Norway, and cover a wide range of disease groups including bone disorders, hematological diseases, pediatric cancers and immunodeficiencies; these ERNs will become operational over the course of 2017.7Set-up under the 2011 Directive on Patient Rights in Cross-Border Healthcare,Healthcare providers who are members of ERNs will be connected through a dedicated IT platform and, using a variety of telemedicine tools, offer access to expertize and knowledge of multidisciplinary teams, enabling patients suffering from such conditions to receive the best advice for treatment and diagnosis. A fundamental principle of the ERNs is the stipulation that knowledge should travel rather than patients (with the exception of few cases where patients may be referred for treatment in another country).Research will be a key element of the ERNs providing a structured framework for joining research efforts across countries, thereby creating a knowledge hub, facilitating translational research and the development of good practice guidelines for diagnosis and care, and supporting cross-border registries. By gathering and analyzing a large pool of patient cases, ERNs should contribute to observational studies and clinical trials, leading to new insights into RD and new drug therapies with potentially far-reaching benefits for patients.n=468), in FP7 (n=704) and\u2014until January 2017 (n=322)\u2014in Horizon 2020. The EC, together with European Member States, have been working on ways to support international collaboration in RD research. Statistics of Framework Programme 6 (FP6), Framework Programme 7 (FP7) and Horizon 2020 provide insight into how various aspects of the international collaboration were supported by EU-level public funding. First, the diversity of types of organizations supported by the EU throughout the Framework Programmes: Second, a landscape of the countries that were most frequently participating in FP7 and active in RD research emphasizes how important it is to promote international collaboration . ThroughIn Finally, funded projects foster a variety of medical domains and therapeutic areas. Within FP6, the 59 projects addressing RD covered essentially the following research themes: cardiovascular diseases, diabetes, diagnostics, diseases of the nervous system and cancer. Within FP7, 118 projects addressed neurodegenerative and neuromuscular disorders, pediatric and adult cancers, immunological disorders and immune deficiencies, respiratory disorders and metabolic disorders. In Horizon 2020, the therapeutic areas cover certain infectious diseases in addition to the ones covered in FP7.n=7), number of new patent applications (n=43) and number of publications (n=1989). Of interest, a vast majority of finished projects (76%) prepared peer-reviewed publications, with many publications in high quality journals such as Nature, Nature Genetics, Nature Immunology, Nature Medicine, Cell, New England Journal of Medicine, EMBO Molecular Medicine and Journal of the American Medical Association.The impact of EU funding and how international collaboration has been fruitful is highlighted by the preliminary outcomes of FP7 based on the first 66 projects completed: there are clear benefits in terms of number of spin-off companies  included 15 countries and annual calls for proposals. During this time, the focus was on deepening the co-operation and co-ordination among the E-Rare partners by enabling the systematic exchange of information on national programs and by implementing strategic activities aimed at sustainable development and extension of the network of RD research funders.8 Through its easy-to-access transnational calls, E-Rare has provided a successful platform for entities interested in collaborative transnational research funding. The participation of national funding agencies in E-Rare Joint Transnational Calls (JTCs) is an effective tool to increase interoperability of funding practices and programs. Continuous co-operation of funding organizations, particularly for the implementation of JTCs, influences the alignment of processes, funding procedures and timelines of JTCs in addition to the gained common knowledge. The high number of proposals received in response to the JTCs of E-Rare highlights the great potential and diversity of the European RD research community and the need for funding of collaborative projects. Special consideration is given to avoid duplication with Horizon 2020 calls in the area of RD.Currently, E-Rare-3 is composed of 26 public bodies, ministries and research funding organizations from 18 countries: Member States , three Associated Countries  and two Third Countries (Canada and Japan).In addition to the annual transnational calls, the collaborative approaches now extend to the relevant European Research Infrastructures with the aim to customize their services to the demand of RD researchers. The long-established collaboration with EURORDIS-Rare Diseases Europe has been further strengthened by the development of new funding models and the involvement of patient organizations in research. In 2012, E-Rare also became a member of the International Rare Diseases Research Consortium (IRDiRC) and strongly contributes to its ambitious objectives (see below).Since 2006, E-Rare has launched eight JTCs for projects, investing over \u20ac92 million in research on RD. Exceptionally, in 2015, the EC contributed to funding of research projects. The competitive nature of the JTCs has resulted in the funding of high quality projects. A large proportion of submitting researchers have outstanding track records with publications in high impact journals. 498 scientific teams compose 106 funded consortia. The multinational projects involve a range of three (mandatory) to ten research groups. Interestingly, the collaborations follow geographical, historical and linguistic proximity . In ordeThe transnational collaboration within projects is reflected at different levels. One of the most important aspects is the training and exchange of personnel. The analysis of 37 projects completed since 2007 showed that, in total, 83 MSc students and 108 PhD were trained. In addition, at least half of the projects reported an exchange of students, PhD and post-docs, in either short- or long-stays . A surveThe topics of E-Rare calls are broad and cover the whole range of medical domains. In all calls, the projects have to involve a group of RDs or a single RD following the European definition, that is, a disease affecting not more than five in 10\u2009000 persons in the European Community, EU-associated states and Canada. In all calls (except for the JTC 2016), interventional clinical trials were excluded due to budget limitations of national funding agencies. Furthermore, research concerning rare infectious diseases, rare cancers and rare adverse drug events in treatments of common diseases were also excluded in the past joint calls. When necessary, and based on the consultation of RD research community, the so-called \u2018focused\u2019 calls are implemented. As a result, in 2012, E-Rare launched a call dedicated specifically to young investigators. In 2014, the call focused on new therapeutic approaches and, in 2016, the goal was to finance clinical trials using repurposed molecules to treat RD.All medical domains are represented in projects submitted and financed . The bigOne of the most important goals of E-Rare funding schemes is to allow transnational collaborations that foster pooling of scarce resources, access to patients and knowledge. The ex-post analysis of 37 projects financed between 2007 and 2011 showed that all of them were able to achieve critical mass of resources necessary to complete their goals. In addition, 26 of the consortia demonstrated intensive exchange of samples as well as creation of databases (17 projects), biobanks (14 projects) or registries  and Patient Organizations (POs) are part of this strategy.9 These infrastructures refer to major equipment, resources  or e-infrastructures . This consolidation of knowledge and resources lying in different countries would enable the progression of high-caliber science and technology and facilitate knowledge sharing and innovation.The European Strategy Forum on Research Infrastructures was established and mandated by the EU Council in 2002 with the aim of supporting a strategic approach to the development of pan-European RIs to meet the long-term needs of the research communities across all scientific areas.10 Out of them, 11 are particularly relevant for biological and medical sciences and seven were chosen by E-Rare as most pertinent for RD research: (i) Biobanking and BioMolecular Resources Research Infrastructure (BBMRI), (ii) European Advanced Translational Research Infrastructure in Medicine, (iii) European Clinical Research Infrastructure Network (ECRIN), (iv) Distributed Infrastructure for Life-science Information (ELIXIR), (v) European Infrastructure of Open Screening Platforms for Chemical Biology (EU-OPENSCREEN), (vi) Integrated Structural Biology Infrastructure (INSTRUCT) and (vii) European Research Infrastructure for the Generation, Phenotyping, Archiving and Distribution of Mouse Disease Models (INFRAFRONTIER).At present, 14 European RIs dedicated to health & food domains are operational.The analysis of collaborative research projects submitted and financed by E-Rare revealed that 98% of them use services/infrastructures like biobanks, data repositories, imaging, high throughput sequencing or screening and animal model facilities. This was also confirmed by the outcomes of funded projects where creation or use of existing data and registries together with extensive exchange of samples and animal models were reported regularly. However, only a few projects indicated use of the European RIs, putting in question the origin of applied standards as well as sustainability of generated results. Based on these inputs and corresponding feedback from the E-Rare funding bodies, it was agreed that close collaboration with the European RIs should both mitigate the problem of discrepancies in practiced standards, and ensure the dissemination and sustainability of outcomes especially biobanks, registries, databases or models.http://erare.eu/infrastructures). Moreover, since 2015, E-Rare encourages the use of European RIs within its calls for transnational projects. In 2016, an explicit pilot action was implemented in collaboration with ECRIN where applicants using ECRIN services could benefit from so-called \u2018ECRIN on board\u2019: free-of-charge assistance in the preparation of their proposal to the E-Rare call. Among 30 projects submitted, 11 included collaboration with ECRIN, eight passed the pre-selection stage and four of them were eventually granted (out of eight recommended for funding) ensuring 36.4% success rate (in comparison with 22% success rate of projects not using ECRIN). In this specific case, the added value of using the European Research Infrastructure reflected, as expected, the quality and knowledge of the management of transnational clinical trials that is particularly complex. Thus, the alliance of dedicated institutions from different countries gathered into one infrastructure can directly target the issues and bring added value to the transnational consortium of researchers.In order to facilitate the access of RD research community to those initiatives, a comprehensive list and dedicated thematic pages were created on the E-Rare website  expressed their interest in participating actively in E-Rare and a strong willingness to collaborate with researchers, including providing logistical and financial support. Since some of the E-Rare funding organizations already had experience co-funding research with POs, it was agreed that, with the support of EURORDIS-Rare Diseases Europe, a new model of collaboration between funders and POs would be established. The goal was to engage patients, in a transparent manner, at all levels of research funding: from definition of topics, through evaluation of projects, to budgetary investment . In addi15 It is co-financed by Member States and the EU. It comprises 40 countries in which Orphanet experts collect, annotate and classify (according to the Orphanet nomenclature) information on RD. This includes data on expert centers, patient organizations, diagnostic laboratories, research projects, clinical trials, registries, databases and infrastructures for research.Orphanet is the most comprehensive source of information, in terms of geographical and domain coverage, specific for RD worldwide.The classification of research projects is performed according to their main objectives, and those qualifiers can be grouped in the following categories: basic research, pre-clinical research and observational/epidemiological/natural history studies. In addition, information on the origin of the projects , related source of funding (funding bodies), as well as starting and end dates are collected.Data on 3052 research projects started or ongoing from 2010 on was collected. Importantly, 14% of them are international collaborations funded mainly funded by the EU and/or through the E-Rare mechanism. This confirms that, at present, EU and E-Rare schemes ensure major support of RD transnational research projects in Europe although 86% of RDs research funding remains national. Interestingly, the comparison of national and international projects revealed that the latter focus on pre-clinical research  while national projects cover mostly basic research approaches (67%).Gene therapy development represents a substantial part (22\u201324%) of pre-clinical research studies, and this proportion does not differ between national and transnational studies. The three main medical domains in which these projects focus on are neurology, immunology and metabolic diseases. Transnational pre-clinical gene therapy projects are devoted to rare immune diseases (24%) followed by neurological diseases (20%) and inborn errors of metabolism (12%), whereas rare neurological diseases predominate in national gene therapy projects (36%) followed by metabolic diseases (16%) and immune diseases (7%).17) involving 42 participants from 14 countries. Its role was to foster interaction between all stakeholders\u2014regulators, pre-clinical and clinical investigators, scientists, companies and patient representatives\u2014in order to streamline integration of multidisciplinary expertize and generate new knowledge; to establish the quality, safety, efficacy and ethically acceptable standards for clinical gene transfer products; and to identify and accelerate the \u2018critical path\u2019 from pre-clinical to clinical phase. One particular feature of this network, organized into seven technology platforms, was the possibility to fund its own internal collaborative and exchange program that could target specific bottlenecks such as establishment of improved producer cells, development of validated production and purification protocols for viral and non-viral vectors, address the ethical, legal and regulatory component and facilitation of clinical trials for rare or common diseases . The main results of CliniGene were: integration of EU-wide research and facilities in the field of gene therapy; overcoming of most scientific bottlenecks identified and targeted by the seven technology platforms; publication of more than 745 papers; financial support to over 90 projects targeting novelty and international collaborations between 45 laboratories and companies; creation of new improved producer cells; development of highly efficient production and purification for most important viral and non-viral vectors; implementation of a reliable and validated vector biosafety platform addressing safety and efficiency in vitro and in vivo; contribution to the ethical, legal and regulatory components of these new therapies to the European Medicines Agency and facilitation of clinical trials performance; training as well as technology transfer to industry.The EU had supported during FP6 a \u20ac12 million European network of excellence for the advancement of clinical gene transfer and therapy (CliniGene18 (10 partners from five countries) aims to restore dystrophin production in a subset of Duchenne muscular dystrophy boys by administration of a drug, which \u2018skips\u2019 the mutations causing Duchenne muscular dystrophy. The presence of the US-based Sarepta Therapeutics in the consortium led to the expansion of the initial clinical trial and provided expertize in bringing an oligonucleotide to the market.19 The project is a follow-up to previous EU projects on neuromuscular dystrophies. In addition, the partners also co-ordinate the worldwide endeavors of several laboratories developing standardized methods of dystrophin quantification, which could be used as an outcome measure in clinical trials involving Duchenne muscular dystrophy patients.During the FP7, several clinical trials for RD were supported by the European funds. As example, the Skip-NMD project20 (12 partners from six EU countries) deals with multi-center lentiviral-based gene therapy trials for severe combined immunodeficiency diseases: adenosine deaminase severe combined immunodeficiency, Artemis and SCID-X1, and also derives from previous successful collaborative EU grants. Importantly, for adenosine deaminase severe combined immunodeficiency, the planned clinical trial should lead to marketing authorization of the gene therapy product as a licensed medicine.Amongst the ongoing Horizon 2020 projects, the SCIDNET consortiumhttp://www.erare.eu/all-funded-projects).. In the project CAV-4-MPS, intracranial administration of helper dependent canine adenovirus type 2 vector coding for the missing enzyme in mucopolysaccharidosis VII resulted in short and long-term expression of the therapeutic enzyme in an mucopolysaccharidosis VII mouse and an MPSVII dog model, resulting in global biochemical correction in the brain. In the project Theralymph, several therapeutic approaches for treatment of hereditary lymphedema are investigated: pharmacological and tissue engineering next to gene therapeutic approaches.The IRDiRC was created in 2011 to facilitate co-operation and collaboration on a global scale among the many stakeholders active in RD research, to maximize the output of RD research efforts around the world.21 As such, membership of IRDiRC was expanded to include those constituents.IRDiRC was originally conceived in 2009 by the Directorate General of Research and Innovation for the EC and the Director of the US National Institutes of Health (NIH), who envisioned speeding progress in RD research by coordinating their RD research funding. Over the course of the first preparatory workshop in Reykjav\u00edk, Iceland in 2010, it became clear that the success of the initiative would be dependent on the integration of the activities of not just funding agencies, but also academic researchers, companies, regulatory agencies and patient advocacy organizations.IRDiRC aims to facilitate the achievement of two overarching objectives by the year 2020: to contribute to the development of 200 new therapies and the means to diagnose most RDs. The crucial outcome of this work will be improved health through better diagnostic capabilities and novel therapies for people living with RDs throughout the world.Organizationally, IRDiRC is comprised of a Consortium Assembly, an Operating Committee, three Constituent Committees , three Scientific Committees , Task Forces and the Scientific Secretariat . Represe22IRDiRC focuses on strengthening international co-operation to bring about rapid progress in the field of RD research. Co-ordination of efforts that address common roadblocks is key to maximizing the collective impact of global investments in RD research and accelerating progress. To guide its work, IRDiRC developed a set of Policies and Guidelines, which are the principles that IRDiRC members agree to follow, focused on the following areas: data sharing and standards, ontologies, diagnostics, biomarkers, patient registries, biobanks, natural history, therapeutics, models, publication and intellectual property, and communications about the Consortium.23 The International Consortium of Human Phenotype Task Force developed standards for interoperability among databases which has enabled the linkage of a variety of RD phenotype and genotype databases. The Patient\u2014Centered Outcome Measures Task Force and Small Population Clinical Trials Task Force investigated aspects of RD clinical studies and produced recommendations to, respectively, (1) enable the development of clear outcome measures that benefit patients,24 and (2) advance discussions on optimizing efficient and innovative trial designs relevant to small populations.25 Similarly, the Data Mining and Repurposing Task Force made recommendations on strategies for optimizing the capture, sharing and integration of research and patient data to further research and development investments and realize the full potential of data mining and drug repurposing approaches (draft in review). Another joint IRDiRC-GA4GH effort was the Automatable Discovery and Access (ADA) Task Force that developed an ADA matrix which provides a standardized way to represent consent and other conditions of clinical data use, making the information computer-readable and available for automated search and sharing activities .26 The Privacy-Preserving Record Linkage Task Force, also a joint effort with GA4GH, is developing guidelines on the ethical, legal and technical requirements of participant identifiers in RD research. In addition, they are investigating a technical solution for a system to de-duplicate and link data sets for use by researchers without knowledge of participants\u2019 identity, and to enable the potential re-identification of participants for clinical purposes. Among the additional Task Forces due to commence shortly are those addressing approaches for investigating diagnostic cases unsolved via current technologies, addressing bottlenecks in data sharing including making policy recommendations around clinical data sharing, and developing best practices for patient engagement in RD research.The members of IRDiRC support research projects that contribute to the Consortium objectives and goals. A number of Task Forces have been created by the Scientific and Constituent Committees to identify limitations to efficiency and effectiveness in global RD research, suggest and/or create solutions including standards and tools, and publish recommendations. One of the earliest Task Forces initiated was a collaboration with the Global Alliance for Genomics and Health (GA4GH) and others to create Matchmaker Exchange, which enables RD gene discovery through a federated network of genotype and rare phenotype databases.27 To receive this designation, resources must undergo a peer-review process by IRDiRC Scientific Committee members and external experts in the field. To date, the label has been given to 13 resources: three guidelines, four platforms, two reference databases, two standards, and an advisory committee  highlight to funders the most pressing areas that necessitate support and (2) emphasize the importance of issues like data sharing and harmonization to researchers. The involvement of patients as main actors and crucial stakeholders completes this picture.All these efforts led to the creation of a favorable ecosystem promoting the development of both new and more sustainable collaborations, connecting researchers from internationally dispersed laboratories. The outcomes of these collaborations are tangible: faster diagnosis of RD patients through enhanced discovery of causative genes and production of relevant clinical practice guidelines; better understanding of natural history of diseases through creation of common registries and databases; accelerated creation of animal and cellular models laying the basis for research on disease mechanisms and treatment options and boosting of innovative therapeutic approaches and clinical trials for new and more suitable treatment options.28 Thus, more efforts focused on shortening the translational pipeline and closing the gap between research and care are needed. In February 2017, at the 3rd IRDiRC Conference in Paris, France, stakeholders of RD research from around the globe gathered to discuss global progress to date, transformative new approaches to RD research, and challenging goals to be set for the next decade. What is clear after the 2-day conference: the international RD research community is eager to share knowledge and experience, work collaboratively across borders and address common roadblocks to maximize the impact of investments in order to bring diagnoses and therapies to RD patients. It is time to build new bridges and raise the bar for RD research worldwide.Notwithstanding, these encouraging results also illuminate new challenges that have yet to be overcome as too many RD patients continue to remain without adequate diagnosis and treatment. It is clear that many challenges still remain: (i) better understanding of RD mechanisms and faster translation of this knowledge into new diagnostics and treatments; (ii) development of novel approaches to clinical trial methodologies in small populations to facilitate the demonstration of the safety and efficacy of orphan drug candidates; (iii) improvement of health technology assessment methodologies that can be applied to the RD field and support best practices; (iv) investment in RD research databases and patient registries that are less fragmented and encourage data sharing and re-use via linking to other international platforms. In the EU Member States, ensuring and improving the equitable provision of health care on RD is also very challenging."}
+{"text": "Editorial on the Research TopicCancer Metabolism: Molecular Targeting and Implications for Therapysensu stricto, refers to rewiring of metabolic circuitry, which in turn involves alteration of multiple energy producing pathways , metastasizing cancer cells (peroxide-driven ATP production), tumor cells under stromal influence , and late-stage cancers (hypoxia).\u201d Finally, the review emphasizes on the prospects of therapeutic targeting of cancer metabolism and the necessity to consider a combinatorial approach to overcome any potential challenges.Eidelman et al.) present a detailed overview of the metabolic characteristics of prostate cancer. In addition to the distinguishing feature of citric acid metabolism between the benign and malignant prostate tumors, the review focuses on other energy-producing pathways as well. Noteworthy, the diagnostic potential and implications of versatile techniques involving metabolomics have also been discussed. In the words of Siddiqui and colleagues, \u201cthere is still a great deal of research to be done, as many of the mechanisms of cellular cancer metabolisms are not well understood,\u201d and the review provides a summary of current knowledge on the cancer metabolism of prostate cancer.Although metabolic alteration is common and frequent among cancers, variations do exist in the type of metabolic change between benign and malignant neoplasms. By using prostate cancer as a prototype, Siddiqui and colleagues  have delineated the functional link between metabolic reprogramming and its epigenetic regulation in cancer. With a focus on the chromatin remodeling enzyme, Brg1, the review describes in detail the molecular intricacies involved in metabolic reprogramming, especially the lipid metabolism. The biochemical and functional significance of Brg1-dependent transcriptional regulation of key lipogenic enzymes in breast cancer has been discussed in detail with reference to reprogramming of cancer-related fatty acid metabolism. Notably, the review also emphasizes on one of the emerging areas of research, the \u201cmetaboloepigenetics.\u201dIt is well known that oncogenic events regulate cancer metabolism either directly or indirectly, through signaling mechanisms. In the review, Nickerson and colleagues  exquisitely present the functional association between TME and cancer metabolism. Besides cancer cells, the review also discusses the mechanistic insights on the role of TME and its components on cancer-associated immune cells, adipocytes, endothelial cells, and fibroblasts. Dwarakanath and colleagues appropriately state that advances in the complete understanding of metabolic reprogramming and TME may provide an opportunity to develop effective anticancer therapies.Multiple lines of evidence demonstrate that the immediate vicinity of tumor, commonly referred as the tumor microenvironment (TME) impacts the metabolic phenotype of cancer. In an extensive review, Dwarakanath and colleagues (Ganapathy-Kanniappan) discusses the contributions of tumor glycolysis in escaping immune surveillance and the therapeutic opportunities of its deregulation. Recent data demonstrate that cellular and/or metabolic stress augments the sensitivity of cancer cells to natural killer (NK) cell-mediated cytotoxicity  discuss the molecular and biochemical correlations of aldo-keto reductases in breast cancer and prostate cancer. More importantly, the review deliberates on the catalytic function-dependent and function-independent roles of one of the isoforms of aldo-keto reductase as well. The review focuses on the opportunities and therapeutic potential of targeting aldo-keto reductases with small molecule inhibitors and emphasizes on the need for further research.Among several metabolic enzymes, aldo-keto reductases have been known to play an indispensable role in intermediary metabolism, macromolecular biosynthesis, and the detoxification of free radicals. Recent research has shed light on the association between aldo-keto reductases and cancer growth and therapeutic resistance. In the comprehensive review, Yang and colleagues  discusses the effect of disruption of arachidonic acid metabolism by COX inhibition in prostate cancer. By using the example of NSAID, aspirin, the authors discuss the mechanism underlying its anticancer effects in prostate cancer. Although aspirin-dependent antimetastatic effects have been reported, controversies exist in the mechanism that is implicated for such anticancer effects. With the availability of substantial epidemiological data, the authors underscore al beit with caution the need for further investigation of aspirin-dependent biochemical or metabolic alterations in prostate cancer to verify any beneficial outcomes of aspirin in prostate cancer.Arachidonic acid metabolism has only recently been implicated in prostate cancer, and the review by Abou-Kheir and colleagues , and the natural product compounds, i.e., AG36  and Curcumin . These articles advance our understanding of the antiproliferative effects of miR-150, AG36, and Curcumin in leukemia (miR-150) and breast cancer .The next three research articles are related to the anticancer effect of microRNA, i.e., miR-150 (Overall, the collections of reviews and research articles presented under the research topic will enable us to advance our knowledge on cancer metabolism and stimulate critical evaluation of therapeutic targeting of metabolism in cancer.The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The purpose of this study was to estimate the degree of seasonality and prevalence of winter- and summer-type seasonal affective disorder (SAD) in African immigrant college students in comparison with African American peers. A convenience sample of 246 African immigrants and 599 African Americans studying in Washington, D.C. completed the Seasonal Pattern Assessment Questionnaire (SPAQ), which was used to calculate a global seasonality score (GSS) and to estimate the prevalence of winter- and summer-type SAD. Degree of seasonality was related to a complex interaction between having general awareness of SAD, ethnicity, and gender. A greater percentage of African students reported experiencing a problem with seasonal changes relative to African American students, and had summer SAD, but the groups did not differ on GSS and winter SAD. African students reported more difficulties with seasonal changes than their African American peers, which could represent a manifestation of incomplete acclimatization to a higher latitude and temperate climate. As Africans also had a greater rate of summer SAD, this argues against acclimatization to heat."}
+{"text": "Recommendations on antenatal care for a positive pregnancy experience,As governments are developing schemes for universal health coverage (UHC) and progressing towards the sustainable development goals (SDGs), they need relevant and context-sensitive evidence to support different policies and interventions. Decision-makers are increasingly using qualitative evidence to understand various socioeconomic contexts, health systems and communities. This type of evidence is useful to assess the needs, values, perceptions and experiences of stakeholders, including policymakers, providers, communities and patients, and is thus crucial for complex health decision-making. For instance, during the development of the World Health Organization (WHO) Qualitative evidence syntheses, which combine and analyse evidence from individual qualitative studies, have emerged as a key approach to inform guideline development and address implementation considerations in diverse country settings and complex health systems.Beyond global guidance, qualitative evidence is invaluable for national and local decision-makers and practitioners to understand factors influencing the implementation and scale-up of health policies and programmes. For instance, policy-makers require evidence on factors that influence vaccination coverage, satisfaction and retention of health-care workers or quality of care in health facilities. Qualitative data have proven essential in planning, developing and implementing health policies and interventions, including in low- and middle-income countries, for example to prevent and treat malaria during pregnancy,Yet, despite the relevance of findings from qualitative evidence syntheses, there is limited guidance on how to assess and use this evidence in policy and practice. To address this need, the Alliance for Health Policy and Systems Research and the WHO Department of Reproductive Health and Research have supported the development of a new approach called GRADE-CERQual . The GRADE-CERQual approach is used to describe how much confidence decision-makers and other users can place in findings from qualitative evidence syntheses by transparently assessing methodological limitations, coherence, adequacy and relevance.New guidance on how to apply the GRADE-CERQual approach is now available as a special series of articles to support stakeholders conducting reviews of qualitative research and using their findings to inform decision-making.,The GRADE-CERQual approach was developed as a global public good to advance research methods and promote the uptake of qualitative findings in decision-making within and beyond the health sector. This guidance is also aligned with a global movement towards the generation and use of a wide array of evidence in policy-making."}
+{"text": "Brain injuries are too common. Most people are unaware of the incidence of and horrendous consequences of traumatic brain injury (TBI) and mild traumatic brain injury (MTBI). Research and the advent of sophisticated imaging have led to progression in the understanding of brain pathophysiology following TBI. Seminal evidence from animal and human experiments demonstrate links between TBI and the subsequent onset of premature, psychiatric syndromes and neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Objectives of this summary are, therefore, to instill appreciation regarding the importance of brain injury prevention, diagnosis, and treatment, and to increase awareness regarding the long-term delayed consequences following TBI."}
+{"text": "The objective of the Balearic Islands Palliative Care (PC) Program is to improve the quality of PC through a shared model consisting of primary health care professionals, home-based PC teams, and PC units in hospitals. According to the World Health Organization (WHO), patients with advanced cancer and other terminal diseases benefit from early identification and proactive PC. We will evaluate the effectiveness of an intervention in which a PC leader is established in the primary health care center, and assess the effect of this intervention on the early identification of patients in need of PC, the efficient use of health care services, and direct health care costs.Design: A two-arm cluster randomized clinical trial of 30 Primary Health Care Centers (PHCC) in Mallorca (Spain), in which each center was randomized to an intervention arm or a usual care arm. We expect that the number of patients identified as suitable for PC  is at least 5% greater in the intervention arm.Sample size: A total of 4640 deceased patients. Outcomes will be assessed by a blinded external review of the electronic records.Interventions: General practitioners (GPs) and nurse leaders in PC for each PHCC will be appointed. These leaders will help promote PC training of colleagues, improve symptom management and psychological support of patients, and evaluate the complexity of individual cases so that these cases receive assistance from PC home-based teams.Measurements: Early identification (>90\u00a0days before death), evaluation of case complexity, level of case complexity , use and cost of hospital and primary care services, and quality of life during the last month of life .PC leaders in primary care teams will improve the early identification of patients eligible for PC. This initiative could improve the quality of end-of-life care and utilization of hospital resources.ISRCTN92479122. Retrospectively registered on 28 February 2017.ISRCTN Registry identifier:  The populations of European countries are getting older, and this is leading to major increases in the number of patients needing palliative care (PC) because of chronic incurable diseases or advanced stages of terminal diseases . The 201PC was initially proposed for cancer patients , but wasearly identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual\u201d , an, an22],"}
+{"text": "To alleviate and repair this damage, plants have developed a complex antioxidant system to maintain homeostasis through non-enzymatic  and enzymatic antioxidants . To this end, the exogenous application of Si has been found to induce stress tolerance by regulating the generation of ROS, reducing electrolytic leakage, and malondialdehyde (MDA) contents, and immobilizing and reducing the uptake of toxic ions like Na, under stressful conditions. However, the interaction of Si and plant antioxidant enzyme system remains poorly understood, and further in-depth analyses at the transcriptomic level are needed to understand the mechanisms responsible for the Si-mediated regulation of stress responses.Silicon (Si) is the second most abundant element in soil, where its availability to plants can exhilarate to 10% of total dry weight of the plant. Si accumulation/transport occurs in the upward direction, and has been identified in several crop plants. Si application has been known to ameliorate plant growth and development during normal and stressful conditions over past two-decades. During abiotic  stress, one of the immediate responses by plant is the generation of reactive oxygen species (ROS), such as singlet oxygen ( Following this several Si transport genes have been characterized in other corps such as barley  and maize  has a strong affinity with oxygen; therefore, it usually exists as silica , superoxide (2O2), or hydroxyl radicals (OH) in cells , such as singlet oxygen , and lipophilic metabolites  or indirectly through the regeneration of the two major redox molecules (ascorbate and glutathione) in the cells Figure . AccumulAnethum graveolens plants. Same pattern of SOD, GPX, APX, GR, and CAT activities was observed by Al-aghabary et al. , and found that the activities of SOD, APX and GPX were increased and contrarily that of CAT was decreased  stress may also disturb the balance between ROS and antioxidants activity. Soundararajan et al.  treated ed Table . Liu et ed Table  observeded Table . Almost Normally, natural wounding stress is caused by herbivory or lodging and these events could increase hydrogen peroxide level inside plant tissues  and decreasing MDA activity.During abiotic stress conditions, the Si application shows varying response to ROS scavenging by activating the defense system plants. In doing so, the activity of antioxidant arsenals  may also oscillate depending upon the intensity of stress and plant type. Si supplemented plants showed resistance to abiotic stress through, lowering ROS production by (i) enhancing CAT and APX activities as both are involved in conversion of HYK wrote the manuscript; MW and AK contributed in drafting and revising manuscript; IL draw the figure and revised the manuscript.This work was supported by Korea Institute of Planning and Evaluation for Technology in Food, Agriculture, Forestry and Fisheries (IPET) through Agriculture, Food and Rural Affairs Research Center Support Program, funded by Ministry of Agriculture, Food and Rural Affairs (MAFRA) (716001-7)The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The discovery of prostate-specific antigen (PSA) as a biomarker represented a major discovery in the early diagnosis and monitoring of prostate cancer. However, the use of PSA is limited by the lack of specificity and an inability to differentiate indolent from life-threatening disease reliably at the time of diagnosis. A multitude of studies have aimed to improve the performance of PSA as well as identify additional biomarkers. The purpose of this study is to review available data on prostate cancer biomarkers for prostate cancer screening and prognostication, including prostatic acid phosphatase, PSA, PSA derivatives , PCA3, GSTP1, AMACR, and other newly emerging molecular and genetic markers."}
+{"text": "The lack of proper water and sanitation infrastructures and poor hygiene practices in health-care facilities reduces facilities\u2019 preparedness and response to disease outbreaks and decreases the communities\u2019 trust in the health services provided.To improve water and sanitation infrastructures and hygiene practices, the Liberian health ministry held multistakeholder meetings to develop a national water, sanitation and hygiene and environmental health package. A national train-the-trainer course was held for county environmental health technicians, which included infection prevention and control focal persons; the focal persons acted as change agents.In Liberia, only 45% of 701 surveyed health-care facilities had an improved water source in 2015, and only 27% of these health-care facilities had proper disposal for infectious waste.Local ownership, through engagement of local health workers, was introduced to ensure development and refinement of the package. In-county collaborations between health-care facilities, along with multisectoral collaboration, informed national level direction, which led to increased focus on water and sanitation infrastructures and uptake of hygiene practices to improve the overall quality of service delivery.National level leadership was important to identify a vision and create an enabling environment for changing the perception of water, sanitation and hygiene in health-care provision. The involvement of health workers was central to address basic infrastructure and hygiene practices in health-care facilities and they also worked as stimulators for sustainable change. Further, developing a long-term implementation plan for national level initiatives is important to ensure sustainability. Water, sanitation and hygiene in health-care facilities are preconditions for providing health care of good quality. Despite this knowledge, a 2015 report revealed that 38% of the 66\u2009101 health-care facilities assessed in low- and middle-income countries had no source of water.In Liberia, a low-income country in western Africa, only 45% of 701 surveyed health-care facilities had an improved water source in 2015, and only 27% of health-care facilities had proper disposal for infectious waste . The 2013\u20132016 Ebola virus disease outbreak in the country emphasized the importance of cleanliness, sanitation and regular hand washing. During the outbreak, the majority of patients were fearful of seeking care within health-care facilities due to risk of contracting the virus. The poor compliance with infection prevention and control measures and poor water and sanitation infrastructures and hygiene practices within the facilities further contributed to the fear. Between August and December 2014, outpatient visits were 61% lower and antenatal care visits 40% lower than the same timeframe in 2013.Here we describe the efforts made to improve the quality of health services in Liberia, focusing on the development and implementation of a package to improve water and sanitation infrastructures and hygiene practices during and after the epidemic.A survey of 701 of the 727 health-care facilities in Liberia showed that the majority of them are public (62%), followed by private for-profit (31%) and private not-for-profit facilities (7%). Most of the facilities are clinics (88%), while health centres account for 7% and hospitals 5% .During the epidemic, the Liberian health ministry introduced an infection prevention and control focal person into each of the 15 county\u2019s health management team. In some resource-constrained counties, the focal person also serves as the environmental health officer working on water, sanitation and hygiene. The focal person oversees the delivery of routine infection prevention and control measures and water, sanitation and hygiene health-care interventions at health-care facilities, in collaboration with the facility-based infection prevention and control focal person. The focal person is also responsible for county outbreak preparedness and response efforts related to water, sanitation and hygiene and infection prevention and control.To inform the development of a package of interventions to improve and monitor water, sanitation and hygiene, the health ministry, with support from the World Health Organization (WHO), first conducted a situational assessment in 63 health-care facilities. The assessment revealed challenges in water treatment, testing of water quality and health-care waste management, including segregation, handling, treatment and final disposal of waste, a lack of ash and placenta pits and lack of protective fencing in waste management areas. In addition, environmental management was shown to be poor.In 2015, the health ministry, with support from WHO and the United Nations Children\u2019s Fund launched the package, using a systematic and multisectoral approach, involving health and water, sanitation and hygiene sectors. The overall aim of the implementation was to have complete country coverage on components for water, sanitation and hygiene as well as measures of infection prevention and control. The implementation involved county health teams, since these teams are critical as a first line of defence against potential future outbreaks and overall health systems strengthening.A national train-the-trainer course was held for focal persons, medical directors, community health department directors, community health social administrators, coordinators for water, sanitation and hygiene, coordinators for infection prevention and control, and environmental health technicians. The objective of the course was to teach the trainer to train health workers in their county and to support the roll-out of the package. The course involved four sessions each lasting four or five days, and a total of 94 people were trained between November 2015 and February 2016. The training curriculum was both theoretical and practical, including techniques, such as hand washing. The trainees visited a facility to conduct an assessment and used the results to identify areas for improvement and suggested actions. The course was conducted in close collaboration with infection prevention and control efforts, which provided focal persons with sufficient technical knowledge to improve and monitor water and sanitation infrastructures and hygiene practices, including safe management and treatment of health-care waste. Participants received a certificate upon completion of the course. To ensure trainers\u2019 involvement in future district and health-care facility level training, a database of certified county trainers was created and made available to all water, sanitation and hygiene partners. To catalyse institutional change, the health ministry launched in-county collaborations between health-care facilities, so-called twinning exchange, which included workshops and facility visits.The development of the package was informed by a global risk-based management toolFurther, the national minimum standards for infection prevention and control include water, sanitation and hygiene components. To ensure compliance with the minimum standards, the health ministry, along with WHO and relevant partners, conduct monthly facility assessments using the Liberia Health System Minimum Standards Tool.Key changes introduced in the health system included placing a strong emphasis on training of health workers at the facility level to deliver health services of good quality and to be prepared for future outbreaks. Local ownership, through engagement of local health workers, ensured development and refinement of the package. To improve effectiveness, accountability and efficiency of health programmes, multisectoral collaboration between environmental health; water, sanitation and hygiene; and health colleagues was put in place when developing the package. This exchange informed national level direction, which led to increased uptake of water sanitation and hygiene and infection prevention and control practices. Finally, the monthly facility assessments, which focused attention on functional infrastructures for water, sanitation and hygiene, were an important support for change. Also, the focus on accountability led to facility-based quality improvement processes to facilitate further improvements.The changes have led to high engagement on improving water and sanitation infrastructures and hygiene practices from all health workers involved, including the package\u2019s inclusion in programmes for infection prevention and control training. The engagement has also contributed to broader efforts to improve drinking-water quality and its management through development of national guidelines and a national quality strategy. Similarly, to address identified problems on infection prevention and control and water, sanitation and hygiene standards, the health ministry, in collaboration with partners, launched training for health workers known as Keep Safe \u2013 Keep ServingIt is important to highlight that during this time of the outbreak, very little was being measured due to increased attention on containing and stopping the outbreak in Liberia.After the epidemic, the government wanted to ensure that improvements made during the outbreak were sustained; the government has identified health-service delivery of high quality as a key investment area,Challenges encountered during the implementation of the package included poor water and sanitation infrastructures and poor infection prevention and control measures, specifically hand hygiene practices, at health-care facilities. The lack of a long-term roll-out plan, despite national training-of-trainers undertaken, has resulted in incomplete national implementation of the package. Nonetheless, package components are being implemented in a wider effort to improve the quality of health services. The findings from further implementation of the package, combined with service delivery tools\u2019 implementation, will inform future national direction for quality planning, control and improvement of health services.The main lessons learnt are summarized in Box\u00a01National leadership was important to identify a vision and to create an enabling environment for changing the perception of water, sanitation and hygiene in health-care provision.The involvement of health workers was central to address basic infrastructure and hygiene practices in health-care facilities.Improvements in water and sanitation infrastructures, hygiene and infection prevention and control practices helped re-establish trust between health-care providers and communities and increased the use of health-care services.This paper provides some insights on how water, sanitation and hygiene can be embedded into health service provision. The efforts made during the epidemic to improve water, sanitation and hygiene were used as a catalyst by the government for improvement of the quality of health service provision. The progress includes improving infection prevention and control practices; increasing staff performance; improving outbreak preparedness; and enhancing community engagement. The strategies presented here could be adopted and adapted for low-resourced health settings facing similar challenges."}
+{"text": "The epidermis of amniotes forms a protective barrier against the environment and the differentiation program of keratinocytes, the main cell type in the epidermis, has undergone specific alterations in the course of adaptation of amniotes to a broad variety of environments and lifestyles. The epidermal differentiation complex (EDC) is a cluster of genes expressed at late stages of keratinocyte differentiation in both sauropsids and mammals. In the present study, we identified and analyzed the crocodilian equivalent of the EDC. The gene complement of the EDC of both the American alligator and the saltwater crocodile were determined by comparative genomics, de novo gene prediction and identification of EDC transcripts in published transcriptome data. We found that crocodilians have an organization of the EDC similar to that of their closest living relatives, the birds, with which they form the clade Archosauria. Notable differences include the specific expansion of a subfamily of EDC genes in crocodilians and the loss of distinct ancestral EDC genes in birds. Identification and comparative analysis of crocodilian orthologs of avian feather proteins suggest that the latter evolved by cooption and sequence modification of ancestral EDC genes, and that the amplification of an internal highly cysteine-enriched amino acid sequence motif gave rise to the feather component epidermal differentiation cysteine-rich protein in the avian lineage. Thus, sequence diversification of EDC genes contributed to the evolutionary divergence of the crocodilian and avian integuments. The phylogenetically closest extant relatives of crocodilians are the birds. These two groups constitute the clade Archosauria and their last common ancestor lived 219\u2013255 Ma  in mammals is shared, with clade-specific modifications, among all amniotes investigated so far. The organization of the EDC has been previously defined for birds, lizards, snakes, and turtles , 2017. ELOR) in lizard scales (SCFN) in avian claws and feathers (EDCRP) in feathers (EDMTFH) in feathers  and the saltwater crocodile (Crocodylus porosus). Accession numbers of genome sequence scaffolds corresponding to the EDC can be found in Gallus gallus) and turtle (Chrysemys picta bellii), already identified in previous studies (S100A12 and S100A11) bordering the EDC in the investigated species. Genes coding for functional proteins were included in comparative studies whereas pseudogenes belonging to EDC gene families with functional members in the same species were not investigated further. In case of EDC regions with seemingly low gene density, the nucleotide sequence of the region in question was translated in silico and additional open reading frames of candidate EDC genes were identified by our already published protocol  information about exon coverage by RNA-seq reads was consulted to check for transcribed regions in the EDC of A. mississippiensis. Nucleotide sequences of transcribed regions were translated in all reading frames and the possible translation products were compared with known EDC proteins of other amniotes. To test for expression of predicted crocodilian EDC genes, we performed tBLASTn searches in the transcriptome of A. mississippiensis  was kept at the Vienna Zoo, Vienna, Austria as part of an international breeding program. Skin tissue was sampled through a biopsy at the flank of a 3-year-old female Morelet\u2019s crocodile in agreement with the national laws regulating animal welfare and the guidelines of Good Veterinary Practice. For histological investigation, the sample was fixed with 7.5% formaldehyde, embedded in paraffin, thin-sectioned and stained with hematoxylin and eosin according to a published protocol  and the saltwater crocodile (Crocodylus porosus), sequences of EDC-encoded proteins of chicken and turtle (Chrysemys picta bellii) were used as queries in tBLASTn searches of the crocodilian genomes , we found that some EDC genes were correctly annotated, whereas others were missed by the automatic algorithms and some gene annotations included splice sites and reading frames that were not plausible A. AppareCRNN and SCFN) are present close to one end of the EDC, and SEDC genes form the main part of the EDC in crocodilians. Comparative analysis suggests that a cluster of crocodilian CBP (beta-keratin) genes is syntenic with CBPs in the EDC of other sauropsids  and also with that of the EDC in turtles . Only 2 uropsids . Two EDCodilians , suggest mammals , 2017 , EDPE, and EDQA , serine (S), proline (P), lysine (K), cysteine (C), and glutamine (Q) . In manyMany EDC proteins of crocodilians exhibit sequence repeats rich in the above-mentioned amino acids  online. C. moreletii) (C. porosus) and 21 (A. mississippiensis) having an intact and complete open reading frame , which have a unique organization with an amino-terminal domain rich in cysteine and histidine residues and a carboxy-terminal domain rich in cysteine and proline residues A, were preletii)  online. ng frame  online wng frame B, it appEDPQ  genes were found in the EDCs of the saltwater crocodile and the American alligator, respectively. In a previous study, two EDPQ genes were also identified in the turtle C. picta  , EDMTFH EDAA clusters of turtles and crocodilians    indicategeticus) , and disgeticus)  which wageticus) . As the geticus) , furthervice versa. However, there are also important differences which have likely contributed to the divergent evolution of skin phenotypes in crocodilians and birds. In fact, the epidermal stratum corneum of crocodilians evolved into a particularly mechano-resistant and water-proof component of the skin, and the beak and particularly the feathers of birds represent unique evolutionary innovations that depended on modifications of the epidermal differentiation process.Comparison of alligator and crocodile versus chicken shows that there is a high degree of conservation of EDC genes in archosaurs. Only few SEDC genes of crocodilians lack an ortholog in birds and Our data suggest that the EDC underwent only few changes in gene composition and arrangement in the crocodilian lineage after its split from the avian lineage. These changes were inferred from our comparison of the EDCs of crocodilians with the EDC of birds and turtles. Both the saltwater crocodile and the American alligator have at least 4 times as many EDCH genes as birds, suggesting that the EDCH gene cluster expanded in the stem lineage of crocodilians . Other aEDCRP, we identified orthologs in crocodilians , and a precursor of EDCRP. The cooption of epidermal structural proteins may be a common theme in the evolution of feathers and hair . It remaodilians , whereasodilians . The chaodilians . The croodilians , 2015. Todilians , a layerodilians . This leIn conclusion, the results of the present comparative genomic analysis of the EDC in archosaurs provide a basis for studying the specific roles of genes involved in epidermal differentiation in crocodilians and allow to further delineate the evolutionary divergence between the crocodilian and avian skin.Genome Biology and Evolution online.The authors declare no competing financial interests.Supplementary Figures and TablesClick here for additional data file."}
+{"text": "The Community Assessment of Psychic Experiences (CAPE) is a self-report questionnaire that has been developed to measure the dimensions of psychosis in the general population. The cross-national equivalence of a questionnaire allows the comparability of a scale across different populations in different countries, i.e., using different versions of the scale according to the considered language. In this study, our aim was to investigate the equivalence of the CAPE across different countries.Data were drawn from the European Union Gene-Environment Interaction (EU-GEI) study. Participants  were recruited across in six countries: United Kingdom, the Netherlands, Italy, Spain, Brazil and France. To analyse the cross-national equivalence of the dichotomised version of the CAPE, we used the multigroup categorical confirmatory factory analysis (MCCFA). The cross-national equivalence can be stated after the establishment of three invariances characterised by increased constraints: the configural invariance, the metric invariance and the scalar invariance across the multiples groups.The configural invariance model fits well, providing evidence for identical factor structure across countries. The assumption that factor loadings are identical across countries is granted based on the negligible change in the fit indices in the metric invariance model. Moreover, the fit indices suggest that the CAPE shows scalar invariance across countries.These findings suggest that comparisons across countries of factor and observed means of the CAPE are possible. Thus, differences observed in scores between samples from different countries can be considered as different levels of psychosis."}
+{"text": "Prior to the Ebola virus disease outbreak in Liberia, the laboratory system was duplicative, fragmented and minimally coordinated. The National Reference Laboratory was conceptualised to address the existing challenges by promoting the implementation of effective and sustainable laboratory services in Liberia. However, in a resource-limited environment such as Liberia, progress regarding the rebuilding of the health system can be relatively slow, while efforts to sustain the transient gains remain a key challenge for the Ministry of Health. In this paper, we describe the pre-Ebola virus disease laboratory system in Liberia and its prevailing efforts to address future emerging infectious diseases, as well as current Infectious diseases, all of which are exacerbated by poverty. We conclude that laboratory and diagnostic services in Liberia have encountered numerous challenges regarding its efforts to strengthen the healthcare delivery system. These challenges include limited trained human resource capacity, inadequate infrastructure, and a lack of coordination. As with most countries in sub-Saharan Africa, when comparing urban and rural settings, diagnostic and clinical services are generally skewed toward urban health facilities and private, faith-based health facilities. We recommend that structured policy be directed at these challenges for national institutions to develop guidelines to improve, strengthen and sustain diagnostic and curative laboratory services to effectively address current infectious diseases and prepare for future emerging and re-emerging infectious diseases. Kennedy Memorial Hospital, a tertiary referral hospital in Monrovia. With prevailing viral infectious diseases as its initial core, its primary laboratory diagnostic capacity was limited to measles, rubella and yellow fever. At the time, samples for Lassa fever were collected, packaged and transported for diagnosis at the Lassa Fever Laboratory in Kenema, Sierra Leone. With support from international partners, basic equipment and human resource development aimed at expanding the capacity of the NRL were secured, and the laboratory was subsequently relocated in 2009 to the compound of the Liberia Institute for Biomedical Research in Charlesville, Lower Margibi County. Afterward, a programme known as the National Diagnostic Unit (NDU) was established.The primary focus regarding the implementation of effective and sustainable laboratory services in Liberia was accentuated with the conceptualisation of the National Reference Laboratory (NRL) in 2008.2 and subsequently culminated with a drastic brain drain as the result of the migration of trained Liberians to politically-stable countries. In a resource-limited environment such as Liberia, progress regarding the rebuilding of the health system has been relatively slow and sustaining the gains from transient spikes in improved health indicators remain a major challenge.Liberia has gradually been rebuilding its healthcare delivery system after 16 years of devastating civil conflicts which erupted in December 1989, destroyed the country\u2019s health infrastructure3 of the Ministry of Health that established the minimum threshold for trained human resources development, laboratory infrastructure, disease surveillance and laboratory diagnostic capacities at each level of the healthcare delivery system in the country.Accordingly, laboratory-based service delivery in Liberia has been basically defined in several key policy documents3 The National level comprises the NRL and NDU; the County level involves the referral hospitals in the political subdivisions of the country; and the Peripheral level accounts for the district and community health facilities. With the development of the Country\u2019s National Decentralization Policy4 for the regionalisation of services within the country, geared toward the improvement of services in the disenfranchised rural areas, a fourth level of the laboratory system was incorporated; thereby, allowing for (1) National; (2) Regional; (3) County; and (4) Peripheral levels. Accordingly, the NRL and NDU are strategically situated within the National level. The regional tier consists of five regional laboratories based on the decentralisation of the country, namely: (1) Southeast A; (2) Southeast B; (3) North central; (4) South central; and (5) Western. The county and peripheral tiered systems are basically the same levels as in the prior three-tiered approach.Liberia\u2019s laboratory system was initially classified into a three-tiered health system structure consisting of the: (1) National; (2) County ; and (3) Peripheral  levels.In general, there are two main categories of laboratory services in Liberia. The first is the clinical laboratory services designated for clinical specimen testing for diagnostic purposes and the second is public health laboratory services directed at disease surveillance.According to its mandate, the NRL has a four-fold responsibility: (1) perform diagnostic testing services on specimens for diseases with epidemic potential that are under surveillance, especially those that are immediately notifiable to the World Health Organization, now inclusive of Ebola virus disease (EVD), as required by the International Health Regulations; (2) oversee the network of public laboratory structures within the country and the provision of services through quality assurance, training, monitoring and supportive supervision; (3) assess new and available technologies; and (4) provide technical advice to the Ministry of Health.Similar to the NRL, the NDU conducts quality assurance, monitoring and evaluation, and training. Furthermore, it coordinates procurement processes for the distribution of laboratory commodities for special programmes supported by the Global Funds, such as HIV, AIDS, malaria and tuberculosis programmes. When constructed, the regional laboratories will support the NRL in its surveillance testing , as well as the county-level coordination of the activities of the laboratory system. In addition, they will lend diagnostic support to the laboratories at the county hospitals.These structures are responsible solely for clinical specimen testing for diagnostic purposes. Test categories include, among others, chemistry, haematology and parasitology. Apart from the traditional structures indicated for service delivery, certain programs of the Ministry of Health are also involved in cross-cutting testing activities . These programmes include: (1) the National AIDS Control Program; (2) the National Malaria Control Program; (3) the National Tuberculosis & Leprosy Control Program; and (4) the National Blood Safety Program.Laboratory equipment, reagents and supplies for the operations of the various laboratory structures are either procured by the Ministry of Health or donated by international partners. The operation of the procurement activities is performed by two organisations: (1) the National Drug Service; and (2) the Global Fund, which supports the HIV, tuberculosis and malaria programmes. Both of these key operational processes (procurement and donations) for the effective functionality of the laboratory system in Liberia exist without defined \u2018Maintenance and/or Service Contracts\u2019.There are two accredited faith-based and one publicly-owned laboratory training institutions in Liberia. These are: (1) the Mother Patern College of Health Sciences in Monrovia, Montserrado County; (2) the Phebe School of Nursing in Suacoco, Bong County; and (3) the Tubman National Institute of Medical Arts in Monrovia. The qualifications offered by these training institutions, based on a duration of training that ranges from 2\u20134 years, includes Diploma in Laboratory Science ; Associate of Science and Bachelor of Science in Laboratory Technology by the Mother Patern College of Health Sciences.6 Poor health infrastructure, lack of logistics during the beginning of the outbreak, and an inadequate number of trained staff in public health disease surveillance and laboratory diagnostic response in emergency situations, were key factors leading to the delay in response to the outbreak. These pre-EVD laboratory challenges, among others, included:The status of the existing laboratory structure and service delivery system in Liberia is characterised by numerous challenges, which were uncovered during the EVD outbreak in Liberia that became a major public health problem in the country and the sub-region.Lack of integration between public health surveillance and laboratory diagnostic services, resulting in fragmented service delivery.Lack of a well-defined organisational structure with clearly-defined objectives, including existing duplications of roles and responsibilities within the tiered laboratory systems to support an effective leadership and management system.Lack of adequate financial resources for infrastructure support and operational costs.Inadequately trained laboratory workforce, including inadequate deployment across the country.Unavailability of maintenance and service contracts for procured and/or donated laboratory equipment and supplies to sustain the effective operation of the laboratory infrastructure.Lack of adequate biomedical equipment technicians to maintain and repair laboratory equipment.Unstable electric power supply and inadequate water supply for laboratory service utilisation.Lack of effective Laboratory Information Management System for coordination, operations, and the efficient functionality of the various tiered systems.7 It was aimed at addressing the challenges associated with limited diagnostic services, which subject patients to inappropriate treatment, chronic illnesses, high out-of-pocket expenditures on healthcare, loss of income and, ultimately, loss of confidence in health services. To mitigate the challenges, the proposed policies targeted the following areas:Despite these challenges, efforts were directed at the development of a National Laboratory Policy to prioritise the delivery of laboratory services within the health system.Organisation: Strengthen the legal and regulatory framework, as well as the technical and administrative organisational structures, for the delivery of laboratory services nationwide.Test selection and referral linkage: Ensure that appropriate tests are performed at the appropriate facility level in a decentralised network and the provision of oversight to establish appropriate communication structure and processes in order to create a referral linkage or network between facilities.Human resources: Ensure the presence of certified laboratory personnel in all public and private laboratories, regulate through periodic certification and develop curriculum standards to support training institutions.Quality assurance: Ensure that laboratories are certified according to defined standards with established systems for independent certification.Infrastructure: Provide safe and adequate infrastructure standards for all public and private laboratories at each level of care and ensure, through certification, that laboratories have standard operating procedures and required infrastructure for laboratory safety and operation.Equipment: Ensure that all laboratories have properly working equipment with both preventative and curative maintenance, and enforce standardisation such that all equipment and supplies meet national specifications and are maintained according to manufacture guidance.Supply chain management: Support an uninterrupted distribution of reagents and supplies to all laboratories, and ensure that an effective system is in place to select, quantify, procure, transport, store, distribute and keep records of all equipment, reagents, and supplies.National blood safety: Ensure a safe supply of blood for transfusions and promote voluntary blood donations.Biosafety: Provide a safe environment and ensure laboratory personnel adhere to safety protocols and quality assurance standards, including laboratory safety for protection of professional staff, public and the environment.Financial resources: Allocate resources to sustain quality laboratory services.Research and development: Identify major laboratory research priorities and promote the culture for operational research, and evaluate and introduce new innovative technologies into the laboratory system.Collaboration: Improve laboratory services through public and private partnerships, as well as support for national and international collaborations.Ethics: Ensure a professional code of conduct and client confidentiality.Information system: Design a laboratory information system that is fully integrated for information flow between laboratories within a referral network.Policy implementation: Monitor and evaluate the efficiency and effectiveness of the laboratory system, as well as its sustainability.Policy regulation: Ensure that laboratory guidelines are updated regularly and in compliance with internationally-accepted standards.We recommend that a joint public\u2013private partnership team be established to conduct a comprehensive technical assessment of the laboratory system within the country and provide appropriate recommendations to combat emerging infectious diseases. Enhancing the laboratories\u2019 capacity for research requires: the availability of essential equipment and appliances; development of relevant and sustained human capacity through continuing education, on-the-job training and mentorship; formulation and adherence to guidelines and standard operating procedures, and compliance with Good  Laboratory Practice and other international standards, such as ISO 15189.The EVD outbreak in Liberia has necessitated improved laboratory capacity to respond to an epidemic of emerging infectious pathogens as well as support for the development of a suitable research platform during such public health emergencies. Accordingly, we propose a framework to strengthen the laboratory system of the country based on a preparedness strategy to mitigate future outbreaks of emerging and re-emerging infectious diseases See .Laboratory and diagnostic services in Liberia have encountered numerous challenges regarding their contributions toward the strengthening of the healthcare delivery system in Liberia. These challenges are a consequence of limited trained human resource capacity, inadequate infrastructure, and lack of coordination among the four tiers. Diagnostic services are skewed in urban health facilities as compared to those in rural communities, and also skewed in favour of private and faith-based health facilities when compared to public health facilities. These disparities are markedly observed throughout the country and significantly impact patient care and emergency situations. The lack of in-country diagnostic laboratories for the diagnosis of viral haemorrhagic fevers, such as Lassa fever and EVD, prior to the EVD outbreak, confirmed the limitations and challenges the country faced with regard to diagnostics services. Prior to the EVD outbreak, suspected Lassa fever specimens were transported to Sierra Leone for diagnostic confirmation, which significantly increased the duration of the reporting and turnaround time for case confirmation, especially in a Lassa fever-endemic country, such as Liberia. Limited training of laboratory personnel in molecular diagnostic techniques, and laboratory response in a health emergency, were also a major challenge.Disease surveillance on the national level has been limited to a paper-based system. Protracted turnaround time and delay in reporting has been a key diagnostic and service delivery challenge in most areas, predominantly in rural settings. Surveillance of diseases has been limited to those in humans and not in animals. In the recent EVD outbreak, active case findings were primarily based on the assumptions of humans as the portals for sporadic outbreaks or re-emerging infections. EVD being a zoonotic disease, its surveillance in animals such as bats, monkeys and other primates should also receive adequate attention from the laboratory diagnostic and public health surveillance systems. Furthermore, hunting communities should also be considered as sources of information gathering and active case findings.8 Religious practices such as bathing the dead, wake-keeping for the deceased, gathering in groups and rituals for worship, and secret societies for men and women regarding cultural initiation, also predispose communities by creating favourable portals and suitable enabling environments for the transmission of emerging infectious diseases. For these reasons, the development and availability of diagnostic platforms remain paramount for rapid detection and control of emerging and re-emerging diseases.As with our West African neighbours and other countries in sub-Saharan Africa, Liberians have close cultural ties and extended families across the porous borders. Cultural practices, such as eating bush meat , are common cultural norms which could expose communities to zoonotic-associated diseases, such as EVD."}
+{"text": "The Polio Eradication and Endgame Strategic Plan (PEESP) established a target that at least 50% of the time of personnel receiving funding from the Global Polio Eradication Initiative (GPEI) for polio eradication activities  should be dedicated to the strengthening of immunization systems. This article describes the self-reported profile of how GPEI-funded personnel allocate their time toward immunization goals and activities beyond those associated with polio, the training they have received to conduct tasks to strengthen routine immunization systems, and the type of tasks they have conducted.A survey of approximately 1000 field managers of frontline GPEI-funded personnel was conducted by Boston Consulting Group in the 10 focus countries of the PEESP during 2 phases, in 2013 and 2014, to determine time allocation among frontline staff. Country-specific reports on the training of GPEI-funded personnel were reviewed, and an analysis of the types of tasks that were reported was conducted.A total of 467 managers responded to the survey. Forty-seven percent of the time  of GPEI-funded personnel was dedicated to tasks related to strengthening immunization programs, other than polio eradication. Less time was spent on polio-associated activities in countries that had already interrupted wild poliovirus (WPV) transmission, compared with findings for WPV-endemic countries. All countries conducted periodic trainings of the GPEI-funded personnel. The types of non\u2013polio-related tasks performed by GPEI-funded personnel varied among countries and included surveillance, microplanning, newborn registration and defaulter tracing, monitoring of routine immunization activities, and support of district immunization task teams, as well as promotion of health behaviors, such as clean-water use and good hygiene and sanitation practices.In all countries, GPEI-funded personnel perform critical tasks in the strengthening of routine immunization programs and the control of measles and rubella. In certain countries with very weak immunization systems, GPEI-funded personnel provide critical support for the immunization programs, and sudden discontinuation of their employment would potentially disrupt the immunization programs in their countries and create a setback in capacity and effectiveness that would put children at higher risk for vaccine-preventable diseases. The Polio Eradication and Endgame Strategic Plan (PEESP) defined its second objective around the strengthening of immunization systems and established a target that at least 50% of the time of field personnel funded by international partners of the Global Polio Eradication Initiative  should be dedicated to the strengthening of immunization systems; additional components of the second objective involve increasing coverage with the third-dose of diphtheria, tetanus, and pertussis containing vaccine DTP3) in districts where the risk of polio is high, introducing inactivated poliovirus vaccine, and withdrawing oral polio vaccines following certification of eradication of the wild type virus . This is in distrBecause wild poliovirus has been endemic until recently in many countries with very weak health systems, significant investments have been made by GPEI to increase human-resources capacity at national levels and in high-risk polio districts to achieve the eradication goal. In 2012, close to 28 000 GPEI-funded personnel were active in the 10 focus countries of the PEESP  These peIn their assessment of the impact of polio eradication activities on RI programs, Closser et al , 5 concl6\u2013Until recently, there had not been a formal assessment on the amount of time that GPEI-funded personnel spent on broader immunization and mother-and-child-health goals. This article describes the self-reported profile of how GPEI-funded personnel allocate their time toward immunization goals and activities beyond those associated with polio eradication, the training they have received to conduct tasks to strengthen RI systems, and the type of tasks they have conducted. A survey was conducted among about 1000 managers of GPEI-funded personnel involved in frontline polio eradication activities, to develop a quantitative view of the proportion of time frontline staff spend on polio eradication, RI, and other health and development priorities. The survey collected information on broader issues, such as the criticality of polio eradication programs to other health priorities, the impact of these programs on broader immunization goals, and the capabilities that could be at risk if polio funding and support for personnel was reduced .Haemophilus influenza type B, and hepatitis B), pneumococcal conjugate vaccine, and rotavirus vaccine; the second dose of measles vaccine; development of proposals for new-vaccine introduction; and support provide to governments with respect to readiness assessment and planning, development of operational guidelines, postintroduction evaluations, and surveillance. The fifth  targeted activities related to creating awareness around issues of child health, including advocacy with political, administrative, religious, and community leaders; assistance with health education; provision of basic health services to children; and implementation of child health days. The sixth category included activities related to improving sanitation and hygiene, such as social mobilization to sensitize communities on importance of sanitation and hygiene, supporting water quality assessment and data gathering, assistance with education on waste disposal and infection control, and supporting installation of toilets in schools. The seventh focused on activities to counsel and educate pregnant women and their families, including communication on exclusive breast feeding and importance of institutional delivery; assistance with policy development, program evaluation, and high-level advocacy; supporting distribution of vitamins; and monitoring of nutritional support for malnourished children. The eighth targeted activities related to improving overall healthcare systems and infrastructure, such as provision of data to governments to improve services; assistance with development of government strategy and long-term planning; supporting the overall supply chain; strengthening partnerships among donors, nongovernmental organizations, and governments; and surveillance for other diseases. The ninth comprised activities related to the response to disease outbreaks and other crises and disasters, such as floods, landslides, earthquakes, and humanitarian crises. The tenth was composed of other diseases or program areas that were not included in the first 9 categories.Respondents were asked to approximate the amount of time spent activities across 10 categories . The first category (polio eradication activities) addressed support for the following polio eradication efforts: policy and strategy development, planning, management and oversight, implementation and service delivery, communications and community engagement, disease surveillance and data analysis, and partnership and coordination. The second (RI) targeted activities related to strengthening local RI systems, such as Expanded Program on Immunization (EPI) capacity building, monitoring and supervision of immunization sessions, data management and analysis, and design and implementation of communication strategies for RI. The third (measles and rubella) focused on activities related to targeted measles and rubella prevention and elimination, including vaccination campaign support and case surveillance. The fourth category (new vaccine introduction) consisted of activities related to facilitating the introduction of new and underutilized vaccines, such as pentavalent vaccine , the United Nations Children\u2019s Fund (UNICEF), the Centers for Disease Control and Prevention, and Rotary International were tasked with distributing the survey link via email to their respective country program leaders across the 10 countries, who then identified the managers of frontline staff. The managers completed the survey on behalf of their teams. The number of surveys to managers of frontline workers distributed is presented in Alongside the survey, Boston Consulting Group conducted interviews with country-level leadership not only to validate insight from the survey, but to better understand reasons for success or failure in supporting other health priorities, particularly with regard to meeting or exceeding targets for RI support. The interviews were free-flowing discussions and played an important part in contextualizing the situation and options for moving forward in each country.From the 10 priority countries, responses from 467 GPEI-funded personnel were included in the analysis . GPEI-fuThe time spent on RI activities, by country, ranged from 15% to 32% . WHO and UNICEF personnel allocated a similar proportion of time to RI . The program area with the next-highest time allocation was measles and rubella control , with values of 3% in Afghanistan, 5% in Pakistan, 7% in Nigeria, 7% in Chad, 11% in Somalia, 11% in India, 13% in Angola, 14% in the DRC, 14% in South Sudan, and 21% in Ethiopia.There was variation in time allocation across countries. Countries in the WHO Eastern Mediterranean Region (EMR) countries\u2014particularly the polio-endemic countries of Afghanistan and Pakistan\u2014spend substantially more time on polio eradication activities  and comparatively less time supporting other health priorities . CountriGPEI-funded staff were asked to rank their views of the most important influences of the polio eradication program on non\u2013polio-related health and development programs and goals. The top 5 program activities selected (in rank order) were communication and social mobilization, capacity building, monitoring and supervision, strengthening RI, and support for control of other diseases, such as measles and rubella .P < .025). The same relationship holds true for RI-related activities , compared with the number of frontline workers (close to 29 000), making it logistically feasible under the challenging circumstances of conducting this field survey to achieve a response rate that is high and representative of the universe of frontline workers. Second, some frontline staff may not be able to reliably access an online survey or may not read English (the only language the survey was coded in), which could therefore reduce the response rate and data confidence.The exact number of surveys distributed was reported for 6 of 10 countries. In the 4 remaining countries, the survey was distributed to about 200 managers.Some country and agency data are more robust than others. In particular, the number of responses and yield associated with UNICEF personnel managers for South Sudan and Pakistan are quite low, despite reminders sent to the managers. In these 2 instances in particular, we caution drawing broad implications from the survey results, given the sample size and yield.GPEI-funded personnel spent substantial time on broader immunization and mother and child health program activities. While the amount of time varied by country, GPEI-funded personnel were being used to improve RI program activities and strengthen systems, control measles and rubella, conduct surveillance activities, and support broader maternal, newborn, and child health programs. This is particularly true in countries where wild poliovirus circulation had been interrupted and the number of campaigns was reduced. This finding is in line with findings reported by Closser et al .Analysis of the type of activities conducted in RI reveals that, across regions, GPEI-funded personnel were most frequently engaged in advocacy, communications, and community engagement, followed by research, which included activities related to learning and refining RI approaches in the field, and special studies. Notably, training and capacity building was a top activity in India and less so in the other regions. Personnel terms of reference included RI as per survey data, demonstrating the increasing formal role of GPEI-funded staff in RI activities. However, RI training rates are quite variable\u2014in Chad, all GPEI-funded personnel (100%) have been trained in RI. In contrast, only 56% of surveyed personnel in the EMR countries  have received RI training. In Chad, the revitalization of the RI programs depend largely on GPEI-funded staff both at national level and decentralized levels.GPEI-funded assets have helped raise awareness of the importance of RI for polio and other vaccine-preventable diseases, yield data and surveillance information that allow countries to develop evidence informed RI planning and implementation, facilitate systematic RI microplanning, provide RI services to deprived communities, such as nomads, migrants, rural remote populations . Sudden While self-reported data by GPEI frontline managers may introduce some bias, it is clear that the polio eradication program has been successful in increasing capacity at the local level in countries and places where systems are weakest\u2014districts where the risk of polio is high. Decentralizing support to RI microplanning, and conducting district taskforce meetings to analyze data for action are promising approaches to improve the program, as shown in India. In Nigeria and India, GPEI has shifted its social mobilization efforts from being externally driven to local agents, often women, who promote immunization, child health, and birth registration in their own communities, with tangible results and impacts.Although a direct causal relationship between national RI improvements and GPEI-funded personnel\u2019s\u2019 time spent on non\u2013polio eradication activities is challenging to establish, in 6 of 10 focus countries , DTP3 coverage improved between 2013 and 2015; in 2 , no progress was reported; and in 2 (Angola and South Sudan), coverage regressed between 2013 and 2015, based on WHO and UNICEF estimates for immunization coverage ["}
+{"text": "A 69-year-old man, native of metlaoui in Tunisia, presented to the Department of Rheumatology at our institution with 10 years of non-inflammatory rachialgia with polyarthralgia. On examination, the patient had no fever or joint swelling, his teeth had brown strains and rough, there was diffuse tenderness at the cervical and lumbar spine and neurological examination was normal. Standard radiographs revealed diffuse bone condensation involving all vertebrae of the cervical, dorsal (A) and lumbar (B) spine, the skull (C), the pelvis (D) and the limbs. The origin of the patient, the brownish color of the teeth and the radiological appearance led to suspicion of fluoride poisoning, which was confirmed by the very high blood fluoride and urine dosage. Skeletal fluorosis is a rare toxic osteopathy characterized by massive bone fixation of fluoride. Its origin is dominated in the countries of North Africa by hydro-telluric poisoning. Its severity lies in the development of skeletal deformities and neurological complications. Management of fluorosis generally focuses on symptom treatment."}
+{"text": "Amine oxidases (AOs) are ubiquitous enzymes involved in the metabolism of biogenic amines. Copper AOs (Cu-AOs) catalyze the oxidative deamination of primary amine groups of several biogenic amines, such as putrescine, cadaverine, and histamine. In the present review, the effects of a plant amine oxidase  purified from pea seedlings in the modulation of IgE-mediated allergic reactions, and in the prevention of cardiac and splachnic postischemic reperfusion damage are reported."}
+{"text": "In the Author Contributions section, Omri Tal (OT) should also be listed under Wrote the paper, Wrote the Appendix and performed and analyzed the simulations, and Revision of manuscript.The legend of"}
+{"text": "A global initiative on sharing avian flu data\u2019 (GISAID) [Ten years ago, a correspondence ,2, signe(GISAID) , leading(GISAID) . Its conIn 2006, the reluctance of data sharing, in particular of avian H5N1 influenza viruses, created an emergency bringing into focus certain limitations and inequities, such that the World Health Organization (WHO)\u2019s Global Influenza Surveillance Network  . This daA unique collaboration ensued, involving, in addition to members of WHO\u2019s GISRS and OIE/FAO reference laboratories, the wider influenza research community along with officials in governmental institutions and non-governmental organisations. Facilitated by a well-connected broadcast executive with background in licensing of intellectual property, an agreement was drawn up on the sharing of genetic data to meet emergency situations, without infringing intellectual property rights - the GISAID Database Access Agreement (DAA). The DAA governs each individual\u2019s access to and their use of data in GISAID\u2019s EpiFlu database . It was The essential features of the DAA encourage sharing of data by securing the provider\u2019s ownership of the data, requiring acknowledgement of those providing the samples and producing the data, while placing no restriction on the use of the data by registered users adhering to the DAA. It essentially defines a code of conduct between providers and users of data, cementing mutual respect for their respective complementary contributions, and upholding the collaborative ethos of WHO\u2019s GISRS, initially established 65 years ago this year [Launched in 2008, the EpiFlu database was of key importance in the response to the 2009 influenza A(H1N1) pandemic, allowing countries to readily follow the evolution of the new virus as it spread globally . AcceptaGISAID provides the data-sharing platform particularly used by GISRS, through which sequence data considered by the WHO CCs in selecting viruses recommended for inclusion in seasonal and pre-pandemic vaccines are shared openly and on which research scientists, public and animal health officials and the pharmaceutical industry depend. Such openness of the most up-to-date data assists in an understanding of and enhances the credibility of the WHO recommendations for the composition of these seasonal and potential-pandemic vaccines.Furthermore, in promoting the prompt sharing of data from potential pandemic zoonotic virus infections, as well as from seasonal influenza viruses, GISAID ensures a key tenet of the WHO Pandemic Influenza Preparedness (PIP) Framework , highligTraditional public-domain archives such as GenBank, where sharing and use of data takes place anonymously, fulfil a need for an archive of largely published data; however, that conventional method of data exchange notably has not been successful in encouraging rapid sharing of important data in epidemic or  pandemic situations, such as those caused by Middle East respiratory syndrome coronavirus (MERS-CoV) and Ebola viruses. While the GISAID EpiFlu database is hosted and its sustainability ensured through the commitment of the Federal Republic of Germany , the estThat GISAID has become accepted as a pragmatic means of meeting the needs of the influenza community in part reflects the particular characteristics of influenza and the continual need for year-round monitoring of the viruses circulating worldwide, essential for the biannual vaccine recommendations and assessment of the risk posed by frequent zoonotic infections by animal influenza viruses . In the Given the crucial importance of genetic data in improving our understanding of the progress of an emergent, potentially devastating epidemic, the effectiveness of GISAID in influenza pandemic preparedness is self-evident and provides important lessons for future pandemic threats. While the genetic makeup and the necessary associated data of the different viruses are distinct requiring separate databases/compartments for unambiguous analysis, the modi operandi for sharing genetic data are generic and the GISAID mechanism could be applied to other emerging pathogens. Indeed, the wider implementation of such a data sharing mechanism should be key in concerted efforts to contain spread of disease in animals and threats to human health, in realising the concept of One Health."}
+{"text": "Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition for which pharmacological therapy is not always solvable. Various treatments have been suggested and deep brain stimulation (DBS) is currently under investigation for patients affected by PTSD. We review the neurocircuitry and up-to-date clinical concepts which are behind the use of DBS in posttraumatic stress disorder (PTSD). The role of DBS in treatment-refractory PTSD patients has been investigated relying on both preclinical and clinical studies. DBS for PTSD is in its preliminary phases and likely to provide hope for patients with medical refractory PTSD following the results of randomized controlled studies. In the Diagnostic and Statistical Manual of Mental Disorder\u2013V (DSM-V) post-traumatic stress disorder (PTSD) is described not only as a feeling of fear and helplessness, as it was classified in the DSM-III, but also as a disorder including negative cognitions, negative emotional states, and reactivity symptoms . VictimsThe anatomical structures involved in the neurocircuitry of fear conditioning are amygdala, prefrontal cortex, and hippocampus. Basolateral complex (BLA) of amygdala, consisting of the lateral nucleus (LA), the basal nucleus (BA), and the accessory basal nucleus, is the main receiver of the sensory afferences coming from two sources: the thalamus sensory nuclei and the primary sensory areas of the cerebral cortex. For many types of emotions, and especially for fear, the amygdala is of great importance, and valuable information retransmitted through this path reaches the amygdala more rapidly than sensory information retransmitted by the cortex. For example, lesions of the basolateral complex abolish classic fear conditioning . Other nPharmacotherapy, based on paroxetine, sertraline, fluoxetine, risperidone, topiramate, and venlafaxine, associated with psychotherapy can be effective in PTSD ; howeverLangevin et al. demonstrated a therapeutic response and a decrease of amygdala hyperactivity after DBS stimulation of the BLA complex in PTSD model rats using 4 h/die stimulation with 160 Hz, 120 \u03bcs and 2.5 Volts in monopolar configuration ,26. DeveThe effects of ventral striatum (VS) DBS  have been tested in a rodent PTSD model. DBS of the VS (the VC/VS homolog in rats) during extinction training allowed reduction of fear expression and strength of extinction memory; stimulation of dorso-medial VS, just above the anterior commissure, allowed facilitation of extinction while stimulation of more ventro-lateral sites in VS impaired extinction .Disruptions of fear extinction-related potentiation of synaptic efficacy in the connection between the hippocampus (HPC) and the medial prefrontal cortex (mPFC) have been shown to impair the recall of memory extinction in rats. Moreover, low-frequency hippocampal stimulation delivered after extinction impaired the extinction learning and the development of hippocampal-PFC plasticity . Medial Treatment-resistant PTSD is an important mental health issue in terms of the number of people affected and morbidity and functional impairment associated with the disorder.Neuroimaging studies in humans support the hypothesis of the involvement of limbic regions in the pathophysiology of the disorder. The application of DBS for PTSD is still strictly investigational and animal models suggest that stimulation of the amygdala, ventral striatum, hippocampus, and prefrontal cortex may be effective in fear extinction and anxiety-like behavior. The limited data from humans support the potential safety and effectiveness of high frequency DBS of the basolateral amygdala (BLA) in treating PTSD.Optimal targets and stimulation parameters, greater knowledge of the action mechanisms, and established criteria of inclusion/exclusion need to be characterized prior to the launch of multidisciplinary larger scale studies, always keeping in mind the risks associated with the surgical procedure and long-term neurostimulation."}
+{"text": "A 35-year-old man of Tunisian origin complained of inflammatory arthralgia and he had noticed a progressive enlargement of his hands and feet as well as facial furrowing. On examination, he had thickening of the skin of the head and distal extremities and deep folds and furrows of the skin of the forehead (A), digital clubbing of fingers (B) and toes (C), spadelike enlargement of the hands and feet, hyperhidrosis of the hands and feet and seborrhea. Inflammation tests were disturbed. Radiographs showed periostosis of the long bones (D) and sacro-iliac osteosclerosis. After excluding secondary causes, primary hypertrophic osteoarthropathy also called pachydermoperiostosis (PDP) was established. This disease is characterised by thickening of the skin of the head and distal extremities, deep folds and furrows of the skin of the forehead, cheeks, and scalp, seborrhea; hyperhidrosis; periostosis of the long bones and digital clubbing. The treatment consisted in our case of analgesics and NSAIDs."}
+{"text": "A 45-year-old man presented with low back pain evolving since 8 years associated sometimes with a radicular radiation. The clinical examination found a patient in good general condition, a loss of the lumbar lordosis, an exaggeration of the dorsal kyphosis with stiffness of the lumbar spine. The cutaneous-mucosal examination showed a brownish appearance of the ears, conjunctiva, and lower eyelids. In biology there was neither inflammatory syndrome nor perturbation of the phosphocalcic balance. The standard radiographs of the lumbar spine (A) and dorsal spine (B) revealed multiple disc calcifications associated with large staggered disc clumps and discal empty images. Due to mucocutaneous signs, normality of biology and the radiological aspect, the diagnosis of ochronosis was suspected and confirmed by the test of blackening of the urine to the ambient air, the results of the cutaneous biopsy showed pigmented deposits yellow ocher and brownish in the dermis and the dosage of alkaptonuria. Symptomatic treatment resulted in moderate improvement. The family survey did not reveal any similar cases. Ochronosis or alkaptonuria is a rare autosomal recessive disorder of tyrosine metabolism. Deficiency of homogentisate 1,2 dioxygenase results in accumulation of oxidized homogentisic acid in the connective tissues of the skin, eyes and ears, musculoskeletal system, and cardiac valves, and in urolithiasis. Ochronosis is of late onset, responsible for the rachis of extended disc calcifications with maximum spinal fusion. It is the cause of degenerative arthropathy. Early diagnosis and screening of this disease are then of great interest, especially for genetic counseling."}
+{"text": "Based oDiagnostic laboratories in Senegal operate within a three-tiered laboratory system: (1) district and peripheral health centre level laboratories; (2) regional level laboratories; and (3) central and hospital level laboratories . The orgThe Laboratory of Bacteriology and Virology (LBV) at Cheikh Anta Diop University (CADU), which is located at Le Dantec Hospital in the capital city, has been recognised by health authorities as the HIV National Reference laboratory since 1986. In partnership with the Ministry of Health and the National AIDS programme, LBV/CADU is responsible for evaluating and validating diagnostic testing technologies, and technologies for CD4 count, viral load and EID. Additionally, LBV/CADU ensures the supervision of other laboratories through a national external quality assessment (EQA) programme, through distribution of regular proficiency testing panels, collection of data for analysis, and follow-up and corrective actions in partnership with the Ministry of Health, the National Committee for the Control of AIDS and the Division for the Control of AIDS and Sexually Transmitted Diseases.At the central and reference laboratory level, the HIV viral load, EID, CD4-count monitoring and HIV-diagnosis capabilities of LBV/CADU are described in 7 and proficiency testing is one of the major components of a quality assurance programme. In Senegal, laboratory infrastructure is relatively well developed at the national and regional levels. However, issues such as inadequate infrastructure, shortage of qualified staff, lack of equipment, limited quality assurance and control procedures are frequently seen among district and peripheral health centre laboratories.Quality assurance is the backbone of quality laboratory performance9 LBV/CADU has been working recently with the US Centers for Disease Control and Prevention to strengthen laboratory systems in Africa and Senegal though the implementation of quality management systems. The LBV/CADU-hosted AFRIQUALAB has been created for that purpose. AFRIQUALAB aims to improve laboratory quality in Africa through regular organisation and distribution of proficiency testing panels across the African continent, including in francophone countries. AFRIQUALAB works in partnership with the US Centers for Disease Control and Prevention, Westat and One World Accuracy, a private Canadian-based organisation specialising in EQA. During 2015, there were 174 participating laboratories from 28 countries, of which eight laboratories were from Senegal. The proficiency testing organized by AFRIQUALAB is mostly free and focused on HIV-related proficiency testing panels, including HIV serology and flow cytometry. Through technology transfer from the US Centers for Disease Control and Prevention, the programme is also offering free EQA for EID using dried-blood specimens and for HIV viral load using dried-tube specimens. Currently, more than 60 laboratories are participating in this EQA sub-programme for EID using dried-blood specimens and for HIV viral load using dried-tube specimens in Africa, including eight laboratories in Senegal.The maintenance of a quality management system, including quality assurance, is crucial for having and providing good and reliable laboratory services.Additionally, AFRIQUALAB is also involved in an EQA programme focusing only on CD4 count technologies within Senegal, with the support of the National AIDS programme and the Public Health Agency of Canada, an international programme for quality assessment and standardisation for immunological measures relevant to HIV. AFRIQUALAB also offers other panels, such as haematology, biochemistry, hepatitis B and C and mycobacteria, to participating labs using a fee-based service structure. LBV/CADU has made major improvements to its own quality management system and has recently achieved International Organization for Standardization 15189 accreditation of its medical laboratories.Additionally, within Senegal and at the national level, the Ministry of Health has recently released a national strategic plan that will guide the quality management system across the medical laboratory services and system in the country.Laboratories participating in the EQA programme for HIV rapid testing and CD4 (including POC) received feedback and, based on their results, have implemented corrective actions, as needed, to improve the quality of services, and were encouraged to participate in a laboratory network for continuous improvement. These outcomes are positive steps toward the implementation of quality management systems.The feedback received from the EQA programme has been used as an opportunity for participating laboratories to be more vigilant in many aspects of their work; for example, with respect to the expiration date for reagents, implementation of corrective actions, and on-site training for staff. The quality assurance programme and the external quality control activities must be followed up by systems-strengthening activities, such as staff training at all levels. We found that there is a need for more communication between the National Reference Laboratories and the Bureau of Laboratories, located at the Ministry of Health, regarding the type of corrective actions and support to be provided from the central/national level to regional and peripheral laboratories. There is also a need to provide incentives such as certificates of participation or achievement to successfully performing labs.Currently, all 24 sites in-country with POC diagnostic technologies, including POC for CD4, are participating in an EQA programme organised by LBV. Since 2004, LBV, with the support of the national AIDS programme, has provided voluntary, free-of-charge EQA of HIV rapid testing to assess the performance of laboratories conducting HIV diagnostics in Dakar and other regions. Currently, the EQA programme for HIV rapid testing uses dried-tube specimens. The proficiency testing panels consist of four specimens  distributed at ambient temperature to participants. The results from the participants are sent to the national reference laboratory via email or cell-phone text messaging.With regard to the 90-90-90 goals, the affordability of viral load testing and CD4 count measures is a key factor in plans to expand HIV laboratory services and scaling antiretroviral therapy across Senegal. The country will need to put in place an affordable and sustainable strategy to reinforce the capacity of the public laboratories as well as to advocate for a strong political commitment from the Ministry of Health and sponsors. In partnership with the National AIDS programme, LBV/CADU is planning to estimate the costing and to undertake a cost-effectiveness study of implementing a nationwide HIV POC testing system, for CD4 count and viral load testing. The costing for, and cost-effectiveness of, a related quality assurance programme will be also taken into account. A model of costing for HIV POC testing, including quality assurance activities is currently under review with the International Diagnostics Centre of the London School of Hygiene and Tropical Medicine."}
+{"text": "Xishan Hao, CAE academician from NCRCC and Prof. Raju Kucherlapati, member of the National Academy of Science of the United States (US) from Harvard Medical School. As the conference chair, Prof. Hao, together with co-chair Prof. Kucherlapati, delivered a warm welcome speech. More than 300 people from all over the world attended this conference and 23 talks were presented at this meeting, focused on precision medicine in China. Then Prof. Ping Wang, President of Tianjin Medical University Cancer Institute and Hospital, and Zhaofeng Zhang, Director, Division of Biotechnology and Medicine, Department of Science and Technology for Social Development, Ministry of Science and Technology of China, also gave their brief remarks for welcome. The conference was preceded by a next-generation sequencing (NGS) and bioinformatics analysis workshop on Sept 22, covering topics from DNA/RNA extraction to sequencing data analysis. In this report, we provided a short introduction on the talks and briefly recapitulated each one of them referring to related publications whenever possible. At the end, we summarize this report with a few comments on the success of IConCPM.Cancer, as a global health issue, has been attracting increasing attention from scientists, medical professionals, as well as the general population. During the past several decades, many therapeutic approaches, including surgery, chemotherapy, radiotherapy and immunotherapy, have come into play for cancer treatment. Nonetheless, many of these treatments are not personalized according to the specific situation or genetic context of a particular patient. Nowadays, precision medicine, defined by President Obama as \u201cdelivering the right treatments at the right time\u2014every time\u2014to the right person\u201d, opens a new era of cancer research with the hope to provide personalized treatment for different patients. To foster the knowledge share and promote potential collaboration on cancer precision medicine domestically and internationally, the first International Conference on Cancer Precision Medicine (IConCPM) took place on September 22\u201324, 2016 in Tianjin, China. The conference was hosted by the National Clinical Research Center for Cancer (NCRCC), Chinese Anti-Cancer Association (CACA), China Medicinal Biotechnology Association (CMBA), Medical and Health Engineering Division of Chinese Academy of Engineering (CAE), Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, as well as the National Foundation of Cancer Research (NFCR). IConCPM was initiated by Prof. Hao overviewed the current status of cancer care and precision medicine projects in China, touching global burden of cancer, status of cancer prevention and control, precision medicine and clinical applications in cancer precision medicine. NCRCC, under his leadership, has been committed to establishing precision medicine research platform which includes cancer tissue bank, clinical trial unit, cancer molecular diagnosis, and bioinformatics core. This platform will offer risk prediction, early diagnosis, target therapy, prognosis evaluation, and drug development to help realize the power of precision medicine. Next, Prof. Webster Cavenee from the Ludwig Institute for Cancer Research emphasized in his talk the necessity of international cooperation in cancer clinical trials for precision medicine. One single traditional clinical trial would need hundreds to thousands of patients, but it may turn out impossible to recruit enough patients for certain diseases. Take the US as an example, there are simply not enough patients, say for glioblastoma (GBM), in the entire country to do more than an extremely small number of clinical trials, not even to mention stratification on the basis of ethnicity or other factors. In this context, GBM-AGILE  was born to address these issues, which has to accrue needed numbers of patients for combination trials. The goals of GBM-AGILE are rapid and efficient testing of therapeutic agents and their combinations, as well as developing databases of clinical trials, biomarkers, and molecular data. This global platform will bring frontline trials to a consortium of countries, providing sufficient patients to stratify and test drug combinations. Afterward, Prof. Yixin Zeng from the Beijing Hospital focused his talk on molecular classification and personalized medicine. How does molecular classification lead to precision medicine? The answer is to find the right patients, give the right drug at the right timing. Prof. Zeng took the example of nasal pharyngeal cancer (NPC) to illustrate the importance of personalized prevention strategy and molecular classification, which mainly refers to immune markers including immune cell sub-typing, cytokines, major histocompatibility complex (MHC) I and II molecules, B7 family and immune-related inhibitors. He concluded that precision medicine, on the basis of molecular classification, will lead to future development of clinical practice and make modern medicine more cost-effective. In the following talk, Prof. Qimin Zhan from the Peking University Health Science Center introduced his research on genomic alterations of esophageal squamous cell carcinoma (ESCC) Zhan and his group identified 8 significantly-mutated genes in ESCC and mutations in the gene encoding family with sequence similarity 135 member B (FAM135B) are correlated with clinical characteristics. They also found miR-548k, a microRNA (miRNA) that was amplified and overexpressed in ESCC, possesses oncogenic characteristics in vivo and in vitro. In addition, genetic alterations are also revealed in genes encoding components of multiple pathways including Wnt pathway, Notch pathway, RTK-Ras, and Akt pathways. Their findings support the notion that cancer is now considered fundamentally as a disease of genomic alteration. After the four presentations, there was a panel discussion \u2013 Roles of technology, data and analytics in precision medicine. Dr. Lynda Chin from Institute for Health Transformation, University of Texas System and Dr. Peter Bahrs from IBM Watson Health Implementations Team co-chaired this section and discussed the roles of technology, cognitive analytics, and public\u2013private partnerships in precision medicine.In the morning session on Sept 23, three academicians from CAE or Chinese Academy of Sciences (CAS), China, and one member of the National Academy of Science, US, presented their work on precision medicine. Prof. Kucherlapati summarized the Precision Medicine Initiative of the US, featured by disease prevention, detection, and treatment through the precise manner. He also introduced the Moon Shots Program with the ultimate goal to end the threats of cancer. This program was launched by M. D. Anderson Cancer Center in 2012. On January 12, 2016, President Obama announced a Cancer Moonshot\u00a0initiative to accelerate cancer research, which aimed to make more therapies available to more patients and improve our ability to prevent cancer and detect it at an early stage. Next Qing Li, Director, Science and Development Centre, the National Health and Family Planning Commission of China, introduced the reform of science and technology program management system and the foundation of the several national-level projects. And in the end, he shared his view on the China Precision Medicine Initiative. Then Prof. Daniel Sulivan from the Moffitt Cancer Center presented their practice of the precision medicine in the Oncology Research Information Exchange Network (ORIEN), which is a network of several major cancer centers in the US, with ultimate goals to provide evidence for decision-making and clinical care. Following these talks was the immunotherapy and chimeric antigen receptor T-cell (CAR-T) session. First, Prof. Steven Burakoff from Mount Sinai School of Medicine presented their work of identifying hematopoietic progenitor kinase 1 (HPK1) as a novel immunotherapy target Renier J. Brentjens from the Memorial Sloan Kettering Cancer Center, who leads one of the first teams conducting CAR-T therapy in the world, introduced their latest clinical trials on several cancers with diverse modifications of the therapeutic cells Cheng Qian from the Third Military Medical University shared their clinical practice with modified dendritic cells (DCs) and CAR-T on several cancer types. Then Prof. Chunrong Tong from the Lu Daopei Hematology Oncology Center introduced their experience on utilization of anti-CD19 CAR-T cells for refractory/relapsed b acute lymphoblastic leukemia. Next as a collaborator of Prof. Tong, Prof. Hongsheng Zhang from the Tongji University School of Medicine presented their translational research and clinical application of CAR-T therapy. Prof. Weidong Han from the Chinese PLA General Hospital then summarized their clinical practice of CAR-T cell therapy on both hematologic cancer and solid tumor Zhong Li from the Second Military Medical University talked about his perspective on cancer immunotherapy. At last, Prof. Xiubao Ren from the Tianjin Medical University Cancer Institute and Hospital summarized the overall clinical progress of CAR-T cells in cancer treatment.In the afternoon session on the first day (Sept 23), 11 speakers were invited to share their insightful opinions or brilliant work. Prof. Ying Wang, Secretary General of CACA, and Dr. Michael Wang from NFCR both introduced the contribution of academic societies in precision medicine. In her presentation, Dr. Wang introduced CACA, the role of CACA in cancer prevention and control, as well as the role of CACA in cancer precision medicine. Then Prof. Bruce Johnson from the Harvard Medical School and Dana Farber Cancer Institute gave his presentation about the impact of genomic changes on precision medicine for lung cancer BRAF, are the most common genomic changes in lung cancer. The Lung Cancer Mutation Consortium (LCMC) is planning analyses on these genomic changes and will establish a virtual database that may help doctors and researchers determine the frequency of certain mutations and explore opportunities for clinical trial enrollment. Prof. Toshifumi Wakai from Niigata University next introduced the genomic sequencing for optimal cancer treatment in gastrointestinal cancer. He and his group demonstrated concordance of CancerPlex with whole-exome sequencing from the TCGA in identifying hypermutated samples and microsatellite instability in multiple cancer types, such as colorectal and gastric cancers. They also highlighted the clinical utility of CancerPlex in guiding treatment strategies with targeted therapy in solid tumors, thus demonstrating how to harness the power of NGS in actualizing precision medicine. Prof. Mu-Sheng Zeng from Sun Yat-sen University presented his work on advances of basic and translational study of NPC. They found that expression of B lymphoma Moloney murine leukemia virus insertion region 1 homolog (Bmi-1) or human telomerase reverse transcriptase (hTERT), and knockdown of p16 enabled immortalization of nasopharyngeal epithelial cells (NPECs). Sphere-like culture of Bmi-1 immortalized cells supported high efficiency of cell-free infection of Epstein\u2013Barr virus (EBV), an oncovirus for NPC. They also demonstrated that RNA binding motif protein 24 (RBM24) played a role in NPC by modulating the stability of miRNAs and long non-coding RNAs. In the next talk, Prof. Andreas Keller from Saarland University focused on miRNAs and cancer. They found that blood-borne miRNAs were stable and powerful biomarkers for early diagnosis and companion diagnostics in cancer that are currently pushed from research to clinics. He also cautioned the biases present when measuring microRNA expression from different sources or using different platforms. These issues should be well appreciated and taken into account for translation into clinical practice. After the talk, there was a panel discussion co-chaired by Prof. Qiang Li from Tianjin Medical University Cancer Institute and Hospital and Prof. Xiaoming Zou from EOC Pharma, discussing the target therapies and drug development in the era of precision medicine.In the morning of Sept 24, Dr. Tuan Ha-Ngoc from KEW and Tom Miller from Greybird Ventures, respectively. In the following session chaired by Prof. Keller and myself, Zhimin Yang from Center for Drug Evaluation, China Food and Drug Administration, talked about issues that should be considered for development and evaluation of oncology products in the perspective of precision medicine. She illustrated her viewpoint on the model evolution of oncology product development, precision medicine, development of clinical innovation products, as well as the considerations for development and evaluation under the new model for precision medicine. Prof. Yi Zhao from Institute of Precision Medicine, CAS reported his work on big data platform construction under the China Precision Medicine Initiative, aimed to build the most complete genetic library of the Chinese population. The conference ended with a panel discussion co-chaired by Prof. Hao and Prof. Kucherlapati. Featuring the future of precision medicine in China, participants provided their comments to questions including (1) what technologies are for precision medicine; (2) how these technologies can impact the patient treatment today; (3) how to identify the right patients for new trials; (4) who are going to pay; and (5) what China can benefit from the lessons learnt in precision medicine projects in the US.In the afternoon session on the second day (Sept 24), the meeting started with two panel discussions about genetic testing for cancer and investments in precision medicine in China which were chaired by The conference ended successfully and has received numerous positive feedbacks from the participants. The conference provided a perfect chance for overseas and domestic scientists and physicians to communicate and share their understanding and practice of the Precision Medicine. Meanwhile the conference provided a productive platform for elite from the related fields to collaborate from decision making to drug development and investment. Other than the informative talks and insightful discussion, the conference organizers also made kind arrangements in having slides in both English and Chinese simultaneously with the live interpretation, making sure smooth communication.Given the emerging need of precision medicine in China, the conference introduced overseas system and practice of precision medicine into China as examples. Involvement of people with diverse roles in precision medicine from doctors, researchers, policy makers, industrialists to investors altogether would help to find answers or address specific concerns for China as raised during the conference, and hopefully result in a wider and deeper collaboration among different parties along the whole process of precision medicine for cancer clinical care."}
+{"text": "There are two key features in nanoparticle-based probes which are seldom found in traditional imaging probes: multimodality and multifunctionality. The use of, at least, two complementary imaging techniques  like PET/MRI or MRI/Fluorescence and the possibility of incorporating several vectors on the surface and/or drugs  expand the use of these probes. Furthermore, the properties of some nanoparticles can be used to create new imaging techniques, for example, the superparamagnetism of iron oxide nanoparticles for magnetic particle imaging.The combination of the size-dependent properties of nanomaterials with the noninvasive characterisation in molecular imaging is a powerful combination that is being successfully applied across disciplines. In the past ten years, we have witnessed the development of, literally, hundreds of nanoparticle-based probes for molecular imaging. All major imaging techniques have been enhanced by the use of nanoparticles, particularly magnetic resonance imaging (MRI), positron emission tomography (PET), and optical imaging. The use of iron oxide nanoparticles for TIn this issue, we have aimed to provide a platform for high-quality contributions on nanoparticles application to molecular imaging. Original papers and review articles focusing on the latest application of nanoparticle-based imaging probes were submitted. The topics treated include the application of iron oxides for MRI, for PET/MRI, and for drug delivery; new synthesis approaches to obtain magnetic nanoparticles-based contrast agents; polymeric nanoparticles for ultrasound imaging; new computed tomography (CT) contrast agents; and quantum dots for multiplex optical imaging. We received a total of 16 submissions, and after two rounds of rigorous review, 9 papers were accepted for publications in this special issue."}
+{"text": "This mini-review covers the newly developed biosensoristic and chemosensoristic devices described in recent literature for detection of contaminants in both environmental and food real matrices. Current needs in environmental and food surveillance of contaminants require new simplified, sensitive systems, which are portable and allow for rapid and on-site monitoring and diagnostics. Here, we focus on optical and electrochemical bio/chemosensoristic devices as promising tools with interesting analytical features that can be potentially exploited for innovative on-site and real-time applications for diagnostics and monitoring of environmental and food matrices . In near future, suitably developed and implemented bio/chemosensoristic devices will be a new and modern technological solution for the identification of new quality and safety marker indexes as well as for a more proper and complete characterization of abovementioned environmental and food matrices. Integrated bio/chemosensoristic devices can also allow an \u201cholistic approach\u201d that may prove to be more suitable for diagnostics of environmental and food real matrices, where the copresence of more bioactive substances is frequent. Therefore, this approach can be focused on the determination of net effect (mixture effect) of bioactive substances present in real matrices. Over the last few years, the abiotic contaminants levels in the environmental compartments and food increased to the point where they can cause potential human health effects due to exposure to chemical toxic substances. In particular, the interactions between environment and food supply chain that mainly occur at primary production level  can cause serious both short- and long-term detrimental effects on human health.Environmental and food safety remains a major global challenge, in particular in developing countries, where socioeconomic status predisposes a large share of the population to a direct environmental-origin contamination and/or consumption of contaminated food products.To minimize the negative and dramatic impacts  of chemical toxic substances of anthropic origin on environmental and human health, several focused actions are needed. For instance, promoting a sustainable use of chemicals and agrochemicals ; the development of toxicovigilance practices and systems  and moreAgainst this background, such critical issues have produced a great demand for simplified, sensitive, and rapid screening methods , 3, withOn-site, cost-effective sensoristic devices capable of routine, sensitive, and selective detection of a range of targeted contaminants present in the environment and foods can be employed, for instance, to overcome time limitations and to reduce costs of sample collection and transport to laboratories, thus providing benefits for a rapid diagnostics and early corrective actions.For on-site diagnostics and environmental/food monitoring purposes, the application of standard and traditional analytical techniques  is in contrast with the current need of rapid, cheap, easy-to-use, and portable devices .For these purposes, chemosensoristic and biosensoristic devices (herein collectively referred to as bio/chemosensoristic devices) are promising tools with interesting analytical features, which can be potentially exploited for on-site real-time applications, diagnostics, and screening for both environmental and food matrices. Such devices could be employed, e.g., to overcome existing limitations in measurements currently used in environmental and agro-food fields. While those measurements are mainly focused on the independent analyses of various parameters and analytes, complexity of environmental and food matrices requires a new holistic-like approach .For instance, regarding nutritional and toxicology characterization of foods, a broader modern vision based on the concept of \u201cwhole food\u201d is taking off , 5. Enviwww.alert2015.it), aims at developing the BEST prototype for industrial-scale production. Another new interesting approach for innovative monitoring and diagnostics of the environment and the agro-food supply chain is provided by a recent patented physicochemical sensing device called SNOOP  \u201cas a whole,\u201d integrated analyses of physical, chemical, and biological parameters through sensoristic devices could be more suitable. The multichannel platform BEST  is a HACed SNOOP . SNOOP ian integrated receptor\u2013transducer device, which is capable of providing selective quantitative or semiquantitative analytical information using a biological recognition element) . In particular, biosensors or biosensoristic devices (element)  hold proaminants , 11.A recent review on key research interests in the development of biosensors in South Africa has highlight a particular interest on the development of electrochemical  biosensor due to low fabrication and analytical equipment costs, in particular, for pesticides and heavy metals detection. Other research areas include nanotechnology, identification and validation of biomarkers, and development of biorecognition agents (antibodies and aptamers) and new biosensor design approaches  .In recent literature, enzymes \u201315 and wRegarding electrochemical devices, they possess unique features to address the challenges of field and on-site analytical chemistry: possibility of miniaturization and portability, sensitivity, selectivity, a wide linear range of detection, minimal power requirement, and cost-effective instrumentation. Voltammetry is one of the most widely used electroanalytical techniques for electrochemical detection in bio/chemosensoric devices . In fact, various voltammetric techniques possess intrinsic analytical advantages and features and included excellent sensitivity, rapid analysis times, and possibility of simultaneous determination of different analytes. In voltammetric pulse techniques, through different modulation of the applied potential, a higher speed of measurement and sensitivity (useful for determination of species at trace levels) can be achieved. In particular, differential pulse voltammetry and square-wave voltammetry have been extensively described in the recent literature for detection of various chemical contaminants in environmental samples , 30\u201335. The recent interest in optical biosensoristic devices for food analysis, with fluorescent, bioluminescent or chemiluminescent labels for detection, as well as the direct (label-free) detection  , 55, is Actually, biosensoristic devices based on SPR are ideal platforms for the label-free detection of molecular monolayers as they allow for qualitative and quantitative multiplexing measurements of biomolecular interactions in real-time without requiring a labeling procedure in the framework of food safety , 58.Indeed, by using SPR-based immunosensors, one can obtain robust and quantitative results with narrow- or broad-spectrum specificity in relatively short time. In the case of milk, SPR circumvents the issues related to turbidity and protein fouling  by measuring the refractive index modulation on the reverse side of the metal film where the biological selective element is immobilized , 59.Since late 90s, SPR biosensoristic devices have become the main tool for the study of biomolecular interactions in life science, with successful applications in the field of food safety .Although there are great advantages of the SPR technology, some disadvantages are evident: high cost of the readout instrumentation and a still high cost of the consumables (sensing chip and reagents) and large instrumentation footprint.In recent years, nanoplasmonics  has shown a great potential in overcoming the technological/commercial limits of SPR  and for The development of advanced photonic biosensoristic devices has to be brought beyond the state of the art of the point-of-care-diagnostic systems by the synergetic integration of the different technological building blocks with consequent improvement of the single-component outputs. Moreover, the introduction of outperforming light-excitation/detection scheme allows for unraveling the potentiality of the sensor in terms for disposability, reliability, miniaturization, and multiplexing while providing laboratory quality analysis .Within the current point-of-care diagnostic market, there is a limited number of systems that operate without the requirement for a dedicated desktop reader, and there are no quantitative, portable diagnostic platforms with multiple detection methods. The components from existing laboratory equipment are too bulky, fragile, and expensive and require too much mechanical integration to be consolidated into a point-of-care device .Miniaturization (from microelectrodes/nanosensors to microfluidic platforms) is an increasing trend as a response to these needs to develop new miniature and portable analytical devices for environmental and food monitoring and diagnostics.In this scenario, LOC devices have shown themselves to be highly effective for laboratory-based research, where their superior analytical performance has established them as efficient tools for complex tasks and a promising tools for a number of environmental monitoring applications, i.e., continuous surveillance of selected parameters and contaminant concentrations  and for However, to date, they have not been well suited to point-of-care or in-the-field applications: although the chips themselves are cheap and small, they must generally be used in conjunction with bulky optical detectors, which are needed to identify or quantify the analytes or reagents present. Furthermore, most existing detectors are limited to analysis of a single analyte at a predetermined location on the chip. The lack of an integrated, multiplexing, and fast detection scheme  is a major obstacle to the deployment of diagnostic devices in the field. This issue has prevented the development of more complex tests where rapid, kinetic, or multipoint analysis is required.Development of improved electrochemical and optical bio/chemosensoristic devices represents a technological challenge to broaden boundaries of field diagnostics and monitoring environmental and food samples. In particular, specific improved features of integration, portability , cheapness, simplification of experimental protocols (less time- and labor-demanding protocols), and development of efficient high-throughput approaches are required. Concerning LOC devices, fast detection scheme and the ability to monitor at multiple locations on the chip could ensure a high selectivity and sensitivity for the analyte of interest. All these devices could be employed for the identification of new quality and safety marker indexes in real matrices as well as for the determination of mixture effects of bioactive substances.All authors have made equal contributions in the writing and revising of this mini-review.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The blood-brain barrier (BBB) is a complex network of microvasculature, comprised primarily of brain microvascular endothelial cells (BMECs), astrocytes, and pericytes, which regulates cellular, macromolecule, and metabolite passage between the peripheral circulation and the central nervous system (CNS). Damage to the BBB has been linked to neurocognitive deficits sustained in multiple diseases, including stroke, Alzheimer's Disease, and numerous infections, including human immunodeficiency virus type 1 (HIV-1)  have not yet been reported in detail.Numerous in vitro and in vivo -7-(t-butyl)-pyrazolopyrimidine (PP2) in rats subjected to ischemic insult resulted in the rescue of ischemic BBB leakage  exposed to vascular endothelial growth factor , and a C-terminus bearing the inhibiting tyrosine site (Y529)  and thus generates nitric oxide (NO). This leads to an induction of the S-nitrosylation of c-Src, which then promotes the auto-phosphorylation of c-Src at the activating tyrosine (Y416), which further phosphorylates the NR2A subunit of NMDAR  alter the repair of the BBB and whether the regulation of c-Src is at the center of this question is an open area of significant research to understanding the mechanisms that underlie HIV-1 neuropathogenesis and HAND , the National Institute of Drug Abuse , National Institute of Mental Health , Comprehensive NeuroAIDS Center (CNAC) , and under the Ruth L. Kirschstein National Research Service Award T32 MH079785 . The contents of the paper are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. MN was also supported by faculty development funds provided by the Department of Microbiology and Immunology and the Institute for Molecular Medicine and Infectious Disease.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "This study targets the lesser-known ingredients of smokeless tobacco products, i.e., the toxic metals, in Indian brands. The metals selected in the study included lead (Pb), cadmium (Cd), arsenic (As), copper (Cu), mercury (Hg), and selenium (Se). The differential pulse anodic stripping voltammetry (DPASV) technique was used for estimating the metals Pb, Cd, and Cu; square wave voltammetry for As; and the cold vapor atomic absorption technique for Hg. The resulting levels of the metals were compared to the daily consumption of the smokeless tobacco products. It was observed that almost 30% of gutkha brand samples exceeded the permissible levels of metals Pb and Cu, when compared to the provisional tolerable intake limits determined by the FAO/WHO. The reliability of data was assured by analyzing standard reference materials."}
+{"text": "Intrinsically Disordered Proteins (IDPs) lack a stable, three-dimensional structure under physiological conditions, yet they exhibitnumerous biological activities. Protean segments (ProSs) are the functional regions of intrinsically disordered proteins that undergodisorder-to-order transitions upon binding to their partners. Example ProSs collected from the intrinsically disordered proteins withextensive annotations and literature (IDEAL) database. The interface of protean segments (ProSs) is classified into core, rim, and support,and analyzed their secondary structure elements (SSEs) based on the relative accessible surface area (rASA). The amino acid compositionsand the relative solvent accessible surface areas (rASAs) of ProS secondary structural elements (SSEs) at the interface, core and rim werecompared to those of heterodimers. The average number of contacts of alpha helices and irregular residues was calculated for each ProSand heterodimer. Furthermore, the ProSs were classified into high and low efficient based on their average number of contacts at theinterface. The results indicate that the irregular structures of ProSs and heterodimers are significantly different. The rASA of irregularstructures in the monomeric state (rASAm) is large, leads to the formation of larger \u0394rASA and many contacts in ProSs. An intrinsically disordered protein (IDP) is a protein that isdisordered (as a whole or in part) in the unbound state andundergoes a disorder-to-order transition upon binding to theirpartners ,2,3. TheProtean segments (ProSs) are the functional regions of intrinsicallydisordered proteins that undergo disorder-to-order transitionsupon binding to their partners ,11,12. The goal of this work is to investigate the properties of secondarystructure elements (SSEs) at the interface of ProSs relative to thoseof heterodimers. The interfaces of ProSs and heterodimers were classified into the core, rim, and support based on their relativesolvent accessible surface area (rASA) . The aveAll ProSs (210) in 70 protein sequences were collected from theIDEAL database (as of August 2013) ,12. If mA non-redundant dataset of 276 heterodimers was selected from theProtein Data Bank (PDB) , using tThe program DSSP  was usedThe propensities of amino acids are represented as the Chou\u2013Fasman parameters , CF  were discarded from this classification. Several propertieswere analyzed for each high and low efficient ProSs (See Resultsand Discussion). The datasets contain 11 and 14 ProSs for high andlow efficient, respectively . The radWilcoxon rank-sum test was performed by RStudio  to calcuThe secondary structure assignments for each of the ProS andheterodimer interface were determined by the DSSP program .This anThe amino acid propensities of the different secondary structureelements (SSEs)  for ProSs vs.heterodimers were examined. The Chou\u2013Fasman parameters for alphThe core residues at the interface are the hydrophobic residues,generally in the central region of the interface, and play animportant role in the interaction. The rim residues are the polarresidues, located on the outer edges of the interface. The supportresidues represent the intersection between the interior and theinterface .Previous studies have been indicated that the ProS interface can bein contact with a larger number of residues of the interactionpartners compared with the heterodimer interface ,29. ToeOur previous study showed that the average \u0394rASA correlates wellwith the average number of contacts in ProSs . \u0394rASA oBased on the average number of contacts at the interface, the ProSswere classified into high and low efficient ProSs (See Methods). Toexamine the properties of high efficient ProSs, several factors, suchas average rASAm, average rASAc, average \u0394rASA, rate of theinterface, rate of the core, rate of the rim, radius of gyration (Rg), and length of the ProSs for each high and low efficient ProS wereanalyzed. Boxplots of the distributions of high and low efficientProSs are shown in The radius of gyration is used to describe the compactness of aprotein, as well as the folding process from the denatured state tothe native state ,31. The The properties of secondary structure elements (SSEs) at theinterface, core, and rim of ProSs were analyzed relative to those ofheterodimers. The results demonstrate that irregular structures ofProSs and heterodimers are significantly different. Irregularstructures have a larger rASA in the monomeric state (rASAm) thatleads to the formation of many contacts in ProSs."}
+{"text": "As tick-borne diseases are on the rise, an international effort resulted in the sequence and assembly of the first genome of a tick vector. This result promotes research on comparative, functional and evolutionary genomics and the study of tick-host-pathogen interactions to improve human, animal and ecosystem health on a global scale. Ticks are obligate blood-feeding arthropod ectoparasites that are distributed worldwide and one of the most important vectors of pathogens affecting humans and animals   and funded by the National Institute of Allergy and Infectious Diseases, National Institutes of Health. Annotation for this assembly was produced in a joint effort between JCVI and VectorBase (https://www.vectorbase.org/) with support from The Broad Institute (Gulia-Nuss et al., More recently, a global consortium of 93 scientists described the 2.1 Gbp nuclear genome of the black-legged tick, I. scapularis project proved challenging due to the large size and high repeat content of the genome. However, the results show the assembly and description of features associated with ~57% of the genome. As the only assembly available for a tick, the I. scapularis genome constitutes an invaluable reference for comparative genomic analyses, including resolution of phylogenetic relationships within the diverse phylum Arthropoda. Analysis of the I. scapularis genome revealed new features that may be unique to this organism and with important implications for future research. Highlights include the identification of two new repeat elements, a large-scale gene duplication event that likely occurred ~40 MYA coinciding with tick radiation, gene exon-intron structures more closely resembling that of an ancient protostome/deuterostome ancestor than of extant arthropods examined to date, an expansion of Kunitz domain proteins and other proteins implicated in tick blood feeding, possible remnants of a heme synthesis pathway contrasting with an expansion of heme carrier and storage proteins. Also identified were orthologs for at least 39 invertebrate neuropeptides and neuropeptide receptor genes that are believed or known to regulate tick diuresis, ecdysis, cuticle synthesis, blood feeding and reproduction. The genome contains one of the largest expansions of cytochrome P450 genes known for sequenced arthropods, suggesting potential for rapid development of acaricide resistance in ticks, and it will be important to explore the families of candidate acaricide targets uncovered by genome analyses, the de-orphanisation of which is underway.The I. scapularis genome sequence and annotation also contributed to the characterization of the transcriptome in related tick species such as I. ricinus (Genomic Resources Development Consortium et al., I. scapularis and other tick species, and extend genome analyses were described based on the publication of the I. scapularis genome sequence (e.g., Cabezas-Cruz et al., I. scapularis genome also provides a key reference for comparative genomics with other Parasitiformes like the western orchard predatory mite (Hoy et al., The first genome-wide population genomics study suggested genetic variation between ticks from Lyme prevalent northern and mid-western states compared with southern states in the U.S., paving the way for identification of genes tied to vector competence (Gulia-Nuss et al., I. scapularis genome sequence and assembly on these studies (Figure Anaplasma phagocytophilum, the causative agent of HGA (Ayll\u00f3n et al., A. phagocytophilum and the encephalitis-causing Langat virus (Grabowski et al., Recent results on the characterization of tick-host and tick-pathogen interactions highlighted the impact of s Figure . TranscrI. scapularis genome provide insights into parasitic processes unique to ticks, including host \u201cquesting,\u201d prolonged feeding, cuticle synthesis, blood meal concentration, novel methods of hemoglobin digestion, heme detoxification, vitellogenesis, reproduction, oviposition, prolonged off-host survival and host-tick-pathogen interactions. The I. scapularis gene models will advance research on comparative and functional genomics, while the assembly and physical map will underpin much needed studies of tick genetics. Recent efforts addressed the need for additional tick genomic resources by focusing on tick species relevant for human and animal health (Guerrero et al., The features discovered in the All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.I. scapularis genome.The National Institutes of Health, the National Institute of Allergy and Infectious Diseases and the U.S. Department of Health and Human Services provided principle funding for the sequence and assembly of the The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The interdisciplinary studies between neuroscience and computer science have greatly promoted the development of these two fields. The achievements of these studies can help humans understand the essence of biological systems; provide computational platforms and intelligent methods for biological experiments; and improve the intelligence and performance of the algorithms in computer science.We present 10 papers in this research topic, which are mainly focused on neural mechanisms underlying the perception of vision, motor and pain; computational modeling of visual processing; bio-inspired visual models; and novel machine learning algorithms to reliably predict pain.As our dominant sense, the ultimate purpose of visual processing is to support us in perception, cognition, learning, and activities.Perry et al.) gives a brief review of alterations in visual processing near hand, which supports the hypothesis that there exist parallel, and separate, effector-based attentional systems. Whereas the oculomotor system enhances visual responses through gain modulation, and near-hand attention system sharpens features (such as orientation) relevant to reaching and grasping. This article provides a potential structure for visual-motor interaction modeling in bio-inspired imitation learning.One article  on visual processing near hand. The authors analyzed the functions of neurons in VisNet model through a biologically plausible process of unsupervised competitive learning and self-organization both with realistic and natural images. The experiments showed that individual output cells of the network could develop single, localized, hand-centered receptive fields which are invariant to retinal location. Eguchi et al. modified VisNet to model the neural representation of object shape in the primate ventral visual system. By unsupervised visually-guided learning, the individual neurons show similar firing properties with V4 and TEO. The neurons in the higher layer of the network could learn to respond to localized boundary contour elements and show translation invariance across different retinal locations through the use of a trace learning rule.The work of Both of these two computational modeling methods simulate the principles and mechanisms of the visual pathway, and may inspire the future work in bio-inspired visual modeling for image processing applications.Li et al. proposed an enhanced HMAX model for image categorization. By mimicking the attention modulation, memory processing and feature encoding mechanisms of visual cognition, a bottom-up saliency map, an unsupervised iterative clustering method and multi-feature fusion method are introduced to the HMAX model. The enhanced bio-inspired model with small memory size showed better accuracy than other unsupervised feature learning methods in Caltech101 dataset. Fu et al. proposed an CNN model for feature construction in text analysis. By modifying the CNN model to adapt to the text inputs, introducing similarity of asker-answer information as attention modulation, and bringing in reputation information to imitate memory, the improved CNN model showed better performance in answer recommendation task.Galeazzi et al.; Eguchi et al.), these two bio-inspired visual models had excellent performance in public datasets focusing on computer science application, which shows that biological research can promote the development of computer science.Different from the computational modeling of visual processing . In addition, Li et al. investigated the effects of placebo analgesia on spontaneous brain oscillations during tonic muscle pain. They observed that placebo-induced decreases in the subjective pain perception significantly correlated with the increases of the amplitude of alpha oscillations, which suggested that alpha oscillations in frontal-central region could serve as the cortical indicator of placebo effect on tonic muscle pain . Finally, Peng and Tang provided a comprehensive summary of the functional properties of pain-induced modulations of ongoing cortical oscillations. In addition to the traditional methods, they proposed that novel approaches should be adopted to comprehensively explore the dynamics of oscillatory activities associated with pain perception and behavior. Based on these understandings, Peng and Tang pointed out the potential clinical applications of neurostimuation techniques  and transcranial alternating current stimulation (tACS)) based on the modulation of pain-related cortical oscillations, which could help promote the establishment of rational therapeutic strategy in the framework of intelligent systems.Three articles provide recent advances to better understand the neural mechanism related to the central processing of pain perception. Bai et al. observed that pain-evoked EEG responses were significantly correlated with spontaneous EEG activities at interindividual level, and proposed a normalization approach to reduce the interindividual variability of pain-evoked EEG responses based on the spontaneous EEG activities for each subject. In addition, Bai et al. found that the relationship between pain-evoked EEG responses and pain perception was nonlinear, which inspired them to develop a novel two-stage pain prediction strategy, a binary classification of low-pain and high-pain trials followed by a continuous prediction of high-pain trials to significantly improve the prediction accuracy . From a different aspect, Tu et al. provided evidences showing that the joint use of both pre-stimulus ongoing and post-stimulus evoked EEG/fMRI activities could significantly improve the performance of pain prediction compared to using just post-stimulus evoked brain responses. Both studies  shed new lights on the development of novel algorithms that could improve the prediction accuracy based on functional neuroimaging signals.Two articles in this Research Topic developed novel techniques to improve the performance of pain prediction based on non-invasive functional neuroimaging signals. Taken together, this research topic provides a series of work in the interdisciplinary studies of vision, motor and pain. The biological findings and models of the topic could inspired the future studies both in biology and computer science.HQ and LH are the organizers of the research topic \u201cEditorial: Modeling of Visual Cognition, Body Sense, Motor Control and Their Integrations.\u201d For this editorial, we discussed and built the outline together. HQ was in charge of Section 1, 2 and 3 and the figure. LH was in charge of Section 4, 5. Both of the authors commented on the manuscript.HQ was supported by the National Natural Science Foundation of China , the Beijing Municipal Science and Technology Commission , and the Strategic Priority Research Program of the CAS (No. XDB02080003). LH was supported by the National Natural Science Foundation of China  and the Scientific Foundation project of Institute of Psychology, Chinese Academy of Sciences (No. Y6CX021008). The funders had no role in study design, decision to publish, or preparation of the manuscript. The authors have declared that no competing interests exist.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The environmental sources and behaviors of chlorinated 2- to 5-ring polycyclic aromatic hydrocarbons (ClPAHs). ClPAHs are ubiquitous contaminants found in urban air, vehicle exhaust gas, snow, tap water, and sediments. The concentrations of ClPAHs in each of these environments are generally higher than those of dioxins but markedly lower than the concentrations of the parent compounds, PAHs. Environmental data and emission sources analysis for ClPAHs reveal that the dominant process of generation is by reaction of PAHs with chlorine in pyrosynthesis. This secondary reaction process also occurs in aquatic environments. Certain ClPAHs show greater toxicity, such as mutagenicity and aryl hydrocarbon receptor activity, than their corresponding parent PAHs. Investigation of the sources and environmental behavior of ClPAHs is of great importance in the assessment of human health risks."}
+{"text": "Overall Abstract: Alastair Campbell, talking from personal and family experience, and based on years of campaigning and study, urges a rethink of how we view mental health and mental illness."}
+{"text": "In recent years, the incidence of severe infectious diseases has increased, and the number of emerging infectious diseases continues to increase. The Chinese government and military forces have paid a great deal of attention to infectious disease prevention and control, and using military-civilian cooperation, they have successfully prevented numerous severe epidemic situations, such as severe acute respiratory syndrome (SARS), influenza A (H1N1), avian influenza H5N1 and H7N9, and Ebola hemorrhagic fever, while actively maintained public health, economic development, and national construction. This paper focuses on the mechanisms of the military-cooperative emergency response to infectious diseases--the joint working mechanism, the information-sharing mechanism, the research collaboration mechanism, and the joint disposal mechanism--and presents a sorted summary of the practices and experiences of cooperative emergency responses to infectious diseases. In the future, the Chinese military and the civilian sector will further strengthen the cooperative joint command system and emergency rescue force and will reinforce their collaborative information-sharing platform and technical equipment system to further improve military-civilian collaborative emergency infectious diseases disposal, advance the level of infectious disease prevention and control, and maintain public health. In recent years, the prevalence of severe infectious disease has increased, and the number of emerging infectious diseases continues to increase . The ChiThe military-civilian collaborative emergency response to infectious diseases refers to the integration of military and government strengths and resources during a certain time period and range, according to the principles of unified command, resource sharing, and close cooperation, in order to solve and jointly respond to epidemic outbreaks of infectious diseases, minimize harm to human health, and maintain social stability .In 2004, the Chinese government disseminated \u201cthe Law of the PRC on the Prevention and Treatment of Infectious Diseases,\u201d which clearly defined many aspects of infectious diseases, such as epidemic reports, epidemic situation control, medical rescue, supervision and management, guarantee measures, and legal liability, among others; this law provides a legal basis for effectively preventing and eliminating infectious disease occurrence and prevalence and guarantees the health and hygienic safety of the public. The general principle of this law clearly stipulates that military prevention and control of infectious diseases should be consistent with the law and relevant national provisions . MoreoveUnder the unified leadership and overall deployment of the nation and the military, the collaborative emergency response mechanism of military-civilian integration and efficient linkage has been established, and it develops a pattern of complementary advantages and efficient collaboration as well as rapidly improves national and military infectious disease prevention and control \u201316. For The nation has established a joint working mechanism among different departments, and this mechanism indicates that each department is responsibility for itself, coordinates with the other departments, and jointly implements the prevention measures under central unified leadership. The military joint prevention and control came into effect by the unified leading, joint supervision, persevering management, and workforce formation of medical treatment, health, publicity, and rear service among multiple departments. The military and the civilian sector cooperated often and closely, establishing the joint working mechanism; for example, military experts were appointed to participate in leading expert groups for joint prevention and controlled response to emergency events and in the formulation of relevant policies, regulations, and professional documents. Meanwhile, the military\u2019s working progress was reflected over time, and the military-civilian coordination and communication mechanism was constructed.An epidemic information report and sharing mechanism has been established. Multiple tasks, such as information report development, joint notification and report release, and joint research on case diagnoses and epidemic announcements, are undertaken daily. The epidemic data from local disease control and prevention institutions are shared nationwide in a timely manner using similar procedures and the epidemic report channel, which establishes the collaborative surveillance and forewarning mechanism that discovers early epidemic outbreaks and provides strong technical support so that prompt and effective military-civilian control measures can be taken.Once an epidemic situation has occurred, the military immediately initiates the emergency research mechanism, sets up rapid research channels, and deploys emergency research tasks to scientific research institutions. In the meantime, the national and military disease control and prevention systems immediately integrate scientific research, organize scientific problem-solving measures, collaboratively establish research and development engineering projects, and jointly develop detection reagents and drug-resistant vaccines in response to outbreaks and the prevalence of infectious diseases. These actions can prevent and control epidemic situations.According to the national statement on epidemic information and the national strategy for prevention and control, epidemic prevention and control are jointly deployed at all military-civilian levels, the infection source and close contacts are traced over time, medical quarantine is carefully carried out, and personnel screening and medical observation are put into practice. Military experts and military disease control and prevention institutions at all levels, who are obligated to execute these plans due to national requirements, should actively participate, following the laboratory test index, outbreak investigation program, and clinical treatment standards. In addition, the military is also required to participate in the emergent disposal of local epidemic outbreaks; successful past experiences that resulted in preferable public effects can be attributed to the army.The government and the military have always attached great importance to infectious disease prevention and control. After the SARS epidemic, the country rapidly intensified construction of its public health system, effectively controlled the spread of several severe epidemic situations, and showed the strong capability of the military-civilian collaborative emergency response, relying heavily on the national military system. This was especially evident when the Ebola epidemic outbreaks occurred in West Africa in 2014; China was the first to lend a helping hand, sending approximately 1,200 military-civilian medical and health personnel to carry out laboratory tests, make diagnoses, provide treatment and public health training, and build a biological safety laboratory for the affected countries. This is the largest healthcare foreign-aid action of a military-civilian collaborative emergency response since the founding of new China . The maiThe primary principles of the military-civilian collaborative emergency response are unified command, graded responsibilities, and resident management. By establishing a unified national and military command organization, the comprehensive coordinative command of the military, police, and people was implemented; scientific and effective emergency decisions were made; institutional and functional orientations at all levels were defined; emergency power from all fields was motivated and coordinated for joint participation; unblocked government decree was ensured; and an advantageous configuration of resource integration was achieved.To effectively address severe epidemics, the government and military formulated several laws, regulations, policies, strategic development plans, joint action programs, emergency safety measures, and various types of operable emergency predetermined plans; clearly defined the division of duties and transactions; established an assessment mechanism for military-civilian joint epidemic situations and a docking mechanism for military-civilian relevant departments; and jointly improved the ability to respond to infectious disease emergencies.By using network and communication technologies, an information-sharing mechanism was established and characterized by directional coverage and frequent communication, and a military-civilian collaborative management platform for emergency rescue that can acquire real-time epidemic information, quick responses, and integrated linkage of emergency epidemic situations was built. After the Wenchuan earthquake in 2008, an epidemic reporting system was established based on the mobile network, which greatly improved the capability of the military-civilian collaborative emergency response.Military emergency prevention and control provides important support for not only the military itself but also national missions, such as emergency disposal during public health emergency events, major activity security, and major domestic and overseas disaster rescue. Since 2009, the Military Emergency Medical Rescue Team, the Emergency Epidemic Prevention Team, the anti-Nuclear, Chemical, and Biological (anti-NBC) Medical Field Rescue Team; and the Veterinary Health, Prevention and Control Team have all been included in the national emergency system, which can greatly enhance the capacities of military-civilian collaborative emergency rescue, prevention, and control.In recent years, the national health department has taken the lead and constructed multi-department cooperation, including a health emergency work mode for joint prevention and control that involves the military and coordinates the linkage and efficient decision-making across departments and regions . A serieAlthough the Chinese military-civilian emergency collaboration has accomplished certain achievements regarding prevention and control of infectious diseases, there are still many problems with the collaborative organization and command, professional power construction, equipment performance level, and emergency theory research, which can be solved by establishing a deep civil-military integration mechanism . ChineseThis paper focuses on the mechanisms of the military-cooperative emergency response to infectious diseases--the joint working mechanism, the information-sharing mechanism, the research collaboration mechanism, and the joint disposal mechanism--and presents a sorted summary of the practice and experience of the cooperative emergency response to infectious diseases. The Chinese military and the civilian sector will further strengthen the military-civilian collaborative joint command system and emergency rescue, reinforce the military-civilian collaborative information-sharing platform and technical equipment system, develop theoretical research on the military-civilian collaborative emergency response, enhance the training and modular exercises of the emergency teams, and strengthen the measures for epidemic information sharing, technical cooperation, disposal linkage, and integral prevention and control, which may further improve military-civilian collaborative emergency disposal, promote infectious disease prevention and control, and maintain public health."}
+{"text": "This paper reviews the current research on the speciation and determination of mercury by various analytical techniques, including the atomic absorption spectrometry (AAS), voltammetry, inductively coupled plasma optical emission spectrometry (ICP-OES), ICP-mass spectrometry (MS), atomic fluorescence spectrometry (AFS), spectrophotometry, spectrofluorometry, and high performance liquid chromatography (HPLC). Approximately 96 research papers on the speciation and determination of mercury by various analytical instruments published in international journals since 2015 were reviewed. All analytical parameters, including the limits of detection, linearity range, quality assurance and control, applicability, and interfering ions, evaluated in the reviewed articles were tabulated. In this review, we found a lack of information in speciation studies of mercury in recent years. Another important conclusion from this review was that there were few studies regarding the concentration of mercury in the atmosphere. Mercury is the only metal that exists in a liquid state among the elements in our modern periodic table. Determination and speciation studies of mercury attract researchers because of the toxicity of mercury to humans, as well as to other animals in the food web. The difference between the toxicity of mercury and that of other metals is that mercury easily accumulates in organisms. A few studies have reported bioaccumulation of mercury in various aquatic animals, such as fishes, pelagic seabirds, and earthworms \u20139.This section describes the sources and fate of mercury in the environment and its toxicity.Mercury can enter the environment from natural and/or anthropogenic sources. Natural sources of mercury include volcanoes, forest fires, cinnabar (ore), and fossil fuels, such as coal and petroleum. Anthropogenic sources are numerous; a large number of human activities are responsible for mercury deposition in the environment. Anthropogenic sources of mercury are landfills, dental preparations, and combustion processes, such as coal-fired power generation, medicinal waste incinerators, and municipal waste combustion. Manufacture of metals, alkali, and cement also releases mercury into the environment . AnthropXu et al.  revealedResearchers determine the concentration of mercury in environmental segments because of its toxic nature. Numerous journal articles have been published regarding the toxicity of mercury and its different forms. Yoshida et al.  reportedPlants are exposed to mercury compounds through the administration of antifungal agents. The toxicity of mercury affects seed germination, growth, and development in higher plants. It also causes the breakdown of photosynthesis by affecting chlorophyll and magnesium molecules . MercuryIn this present study, we reviewed speciation and determination studies of mercury in different environmental samples using various analytical techniques, including the atomic absorption spectrometry (AAS), voltammetry, inductively coupled plasma optical emission spectrometry (ICP-OES), ICP-mass spectrometry (MS), atomic fluorescence spectrometry (AFS), spectrophotometry, spectrofluorometry, and high performance liquid chromatography (HPLC). Over 96 research papers published since 2015 in reputable international journals were reviewed. This review clearly summarizes the current research on speciation and determination studies of mercury from locations worldwide.The toxic nature of mercury and its different species encourage researchers to determine their concentrations in different environmental samples. Recently, a number of reviews were published concerning the determination of mercury, which described various factors regarding the concentrations of mercury in the environment. This section summarizes recent reviews of the determination of mercury.Hanna et al.  reviewedColorimetric and visual assay determination of Hg(II) based on gold nanoparticles, fluorescent gold nanoparticles, gold nanorods, gold nanoflowers, and gold nanostars was reviewed by Chansuvarn et al. . They reJagtap and Maher  reviewedIn recent years, a large number of research articles were published regarding the determination and speciation of mercury using various analytical techniques. We have divided this section into four parts based on the analytical techniques used in the determination of type and levels of mercury. They are (i) spectrometric techniques , (ii) electrochemical techniques (voltammetry and potentiometry), and (iii) miscellaneous techniques.The determination and speciation of mercury using spectrometric techniques, such as AAS, AFS, ICP-OES, ICP-MS, spectrophotometry, and spectrofluorometry are presented in Regarding the usage of analytical techniques in the determination studies of mercury, as presented in The analytical variables of merit, such as limits of detection and linearity, quality control and assurance studies, applicability to natural samples, and interference, are indicative of the validity of the method. Detection limit indicates the lowest level of analyte that can be detected using the method. A few studies \u201351 reporTwo very important analytical parameters, in the determination of mercury, are quality assurance (QA) and quality control (QC). The validity and reliability of the data produced by the researchers depend on the quantification of these variables. Quality assurance studies can be performed by testing the accuracy of the data obtained against standard reference materials (SRMs) provided by the National Institute of Standards and Technology  or certified reference materials (CRMs) provided by various reputable institutes or organizations. Quality control can be determined by measuring the precision of the data (repeatability and sensitivity) obtained by each method. The precision of the data can be obtained in many ways, such as the analysis of replicates, interlab comparison of data, and relative standard deviation (RSD) of blank or standard material analysis . RegardiThe validity of analytical methods can be enhanced by applicability to natural samples. Regarding the analysis of natural samples, most of the reviewed papers analyzed water samples, such as those from rivers, lakes, seas, groundwater, and spiked water and wastewater. Following water samples, the most frequently analyzed material for mercury was seafood samples, such as fish, shrimp, and seaweed. A few studies reported the determination of mercury in various environmental samples, such as petroleum hydrocarbons , human hAnother important aspect of analytical parameters of the methods is interference. Interference of other ions in the determination of mercury levels is very important, particularly when those methods are applied to the analysis of natural samples. Natural samples are typically a complex of different ions; the selectivity of the method is very important in the determination of mercury in environmental samples. In this respect, electrochemical methods had a higher degree of selectivity and did not suffer from interference from other ions. Determination of the level of interference was not performed by a large number of authors , 102\u2013106Toxicity of mercury depends upon its chemical form. For example, methylmercury is more toxic than inorganic mercury. Speciation studies revealed the exact toxicity of mercury in environmental samples. However, very few authors , 92, 107The present study reviewed research articles published in recent years (2015-2016) involving determination and speciation of mercury using various analytical instruments. Approximately 100 research papers were reviewed and all the analytical parameters established in their studies were tabulated. Our study concluded that most of researchers used spectrometric instruments for the determination of mercury in different environmental samples. We addressed the quality of the data based on reported QA and QC data by the authors. Another important finding from this review was that most researchers measured inorganic mercury or total mercury, whereas only a few reported speciation of mercury. Speciation studies are very important in the accurate prediction of the toxicity of the mercury in the environment because mercury toxicity depends on its chemical form. Because of the difficulty in sampling and analysis, most researchers did not report the concentrations of mercury in the atmosphere. We conclude by stating that speciation studies and the determination of mercury in the atmosphere should receive greater attention in the future."}
+{"text": "Crocus sativus L.) is a crop species cultivated for its flowers and, more specifically, for its red stigmas. The flower of crocus is bisexual and sterile, since crocus is a triploid species. Its perianth consists of six petaloid tepals: three tepals in whorl 1  and three tepals in whorl 2 . The androecium consists of three distinct stamens and the gynoecium consists of a single compound pistil with three carpels, a single three-branched style, and an inferior ovary. The dry form of the stigmas constitutes the commercial saffron used as a food additive, in the coloring industry, and in medicine. In order to uncover and understand the molecular mechanisms controlling flower development in cultivated crocus and its relative wild progenitor species, and characterize a number of crocus flower mutants, we have cloned and characterized different, full-length, cDNA sequences encoding MADS-box transcription factor proteins involved in flower formation.Crocus  and its modification named familyRCA-RACE (famRCA-RACE). Furthermore, the characteristics of the protein structure and their common and specific domains for each type of MADS-box transcription factors in this lower nongrass monocot belonging to the Iridaceae family are described. Finally, a phylogenetic tree of all the MADS-box sequences available in our lab is presented and discussed in relation to other data from studies of species of the Iridaceae group and closely related families from an evolutionary perspective. The structural and phylogenetic analyses are based on both published and unpublished data."}
+{"text": "Disturbances in cognitive function, particularly memory, are a common complaint of patients with epilepsy. Factors contributing to cognitive dysfunction are the type of epilepsy, type and frequency of seizures, anti-epileptic drugs and the location of underlying brain lesions. Whilst a great deal of attention has been paid to permanent cognitive impairment, the nature and underlying mechanisms of ictal and peri-ictal cognitive changes are poorly understood. In-depth investigation of seizure related cognitive dysfunction is of great clinical relevance, as these changes are potentially reversible and treatable, thus reducing the cumulative effect of frequent seizures Greater knowledge of peri-ictal and ictal cognitive dysfunction would improve seizure prediction, localization of seizure focus and assessment of treatment effectiveness, greatly reducing distress and disability. This paper will review current understanding of peri-ictal and ictal cognitive dysfunction and discuss future directions for research."}
+{"text": "In the elderly, fear of falling (FoF) can lead to activity restriction and affect quality of life (QoL). Our aim was to identify the characteristics of FoF in Parkinson's disease and assess its impact on QoL. We assessed FoF in 130 patients with Parkinson\u2019s disease (PD) on scales measuring perceived self-efficacy in performing a range of activities (FES), perceived consequences of falling (CoF), and activity avoidance (SAFFE). A significant difference was found in FoF between PD patients who had previously fallen and those who had not and between frequent and infrequent fallers. Patient-rated disability significantly influenced FoF. Difficulty in rising from a chair, difficulty turning, start hesitation, festination, loss of balance, and shuffling were the specific mobility problems which were associated with greater FoF in PD. Disability was the main predictor of FoF, additionally depression predicted perceived consequences of falling, while anxiety predicted activity avoidance. The FoF measures explained 65% of the variance of QoL in PD, highlighting the clinical importance of FoF. These results have implications for the clinical management of FoF in PD."}
+{"text": "Editorial on the Research TopicSecond Line Treatment of Non-Small Cell Lung Cancer: Clinical, Pathological and Molecular Aspects of Novel Promising DrugsLazzari et al.; Sullivan and Planchard; Tran and Klempner; K\u00f6hler). In addition, the introduction of immunotherapy, with anti PD-1 Pembrolizumab, in first-line treatment of NSCLC represents the best choice for EGFR, ALK, and ROS1 wild-type patients expressing PD-L1 on \u226550% of neoplastic cells . Despite the survival improvement achieved with these new therapeutic options in first-line treatment, about 30% of patients do not obtain a tumor response . Moreover, those patients, initially sensitive to these treatments, acquire resistance and develop tumor progression. Approximately 60% of the patients progressing from first-line therapy receiving further systemic treatment in the second-line setting  Also in second line, the armamentarium for the treatment of patients with NSCLC, includes a pletora of new drugs, such as immune checkpoint inhibitors  , third generation tyrosine kinase inhibitors (Osimertinib) , and anti-angiogenic agents (Nintedanib and Ramucirumab) .The advent of precision medicine and predictive molecular pathology led to a revolution in clinical management of patients with non-small cell lung cancer. The discovery of oncogene addiction allowed the development of targeted therapies that represent newer therapeutic options reserved to those patients harboring specific gene alterations, such as EGFR mutations, ALK, and ROS1 translocations . Probably the right way is to give all the available opportunities to patients, but challenges and pitfalls should be carefully debated.This exciting therapeutic scenario for NSCLC patients still has unsolved questions and challenging issues, in particular regarding the optimal selection of the patient population through the individualization of the correct methodology and biological source of material (tissues vs liquid biopsy) for clinical relevant biomarkers assessment (Taken together, the papers published in Research Topic \u201cSecond Line Treatment of Non-Small Cell Lung Cancer: Clinical, Pathological and Molecular Aspects of Novel Promising Drugs\u201d represent a critical discussion focused on the older therapies and the historical development of second line, putting into perspective the new agents available in clinical practice, defining their importance from a clinical point of view, but also to consider and exploit the complex molecular mechanisms responsible of their efficacy or of the subsequently observed resistance phenomena, to support the oncologist to design the best therapeutic strategies for NSCLC patients.UM and PP contributed equally to this paper.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Glioblastoma multiforme (GBM) is an aggressive, malignant, and lethal brain tumor, resistant to all current forms of treatment. The rapidly emerging focus on cancer stem cells embodies a paradigm shift in our understanding of tumor pathogenesis, while the development of powerful genome-wide screening techniques has provided cause for optimism related to the development of more reliable therapies primarily targeting GBM stem cells (GBMSCs). There are promising mounting data on providing new molecular targets and predictive markers of response, leading to more effective therapies of GBM, guided by patient-specific genetic and epigenetic profiling. However, the achievement of efficient GBMSC targeting also requires an adequate understanding of the unique microenvironment, and the relationship with the immune system in the central nervous system (CNS) and CNS tumors. The endogenous immune regulation is likely to limit or abrogate the efficacy of the host's immune response, as well as the developed immunotherapeutic strategies at present. Therefore, a comprehensive understanding of the mechanisms underlying the GBM-induced immunosuppression is indispensable. This review presents a summary of the present knowledge both on GBMSCs and the GBM, and/or GBMSC-related mechanisms of developing both local and systemic immunosuppression, of which an understanding may lead to the development of the novel and effective therapeutic strategies."}
+{"text": "Ubiquitin (UB) is a small inactive peptide which dramatically changes the fate of ubiquitinated proteins when enzymatically activated and covalently attached to proteins in the process known as ubiquitination  has been defined as a multifaceted network of cellular pathways that are activated after DNA damage . The group of Simone Sabbioneda  discussed how UB and SUMO control DNA damage tolerance, the last line of defense that allows completion of DNA replication in the presence of an unrepaired template. They focused on post-replication repair, the mechanism cells use to bypass highly distorted templates caused by damaged bases . Jacqueline Jacobs (Netherlands Cancer Institute) and her group demonstrated that UB and SUMO play an essential role in both telomere maintenance and protection, but are also key contributors for the cellular response to dysfunctional telomeres . Besides the physiological role of the UB and SUMO pathways in DNA replication and telomere function, this issue also covers the majority of DNA repair pathways. Thus, Coleman and Huang (New York University School of Medicine) nicely summarized how SUMOylation plays a major role in fine-tuning of the Fanconi-Anemia Pathway, the main pathway for repairing DNA interstrand crosslinks. The group of Hanspeter Naegeli (University of Zurich) highlighted the essential importance of ubiquitination, SUMOylation but also Neddylation in the regulation of nucleotide excision repair, the main mechanism that protects us from UV-light . Smeenk and Mailand (University of Copenhagen) gave us comprehensive overview of UB and SUMO in the repair of DNA double strand break (DSB) repair, the most cytotoxic DNA lesion. Their work clearly demonstrates how ubiquitination and SUMOylation are highly sophisticated and complex PTMs in the DDR. Harding and Greenberg (University of Pennsylvania) presented an additional perspective on DSB repair, with a special focus on nuclear architecture, chromatin dynamics and chromatin organization in DSB repair and how UB and SUMO control and connect these processes. Himmels and Sartori (University of Zurich) went even deeper in the understanding of DSB repair and described how UB and SUMO regulate DNA-end resection, the initial step in DSB repair. Interestingly, they concluded that the UB pathway in DNA-end resection is mostly linked to protein degradation processes, where SUMO acts as an intermolecular \u201cglue\u201d in modulating protein-protein or protein-DNA interactions required for homologous recombination rather than specifically affecting the activity of individual proteins. Dantuma and Pfeiffer  discussed how the E3-UB and E3-SUMO ligases are recruited to sites of DNA damage and the importance of the spatiotemporal relationship among different DNA repair proteins and PTMs. Pellegrino and Altmeyer (University of Zurich) nicely explained how the crosstalk between ubiqutination, SUMOylation and PARylation, another PTM that also forms a chain signal (PAR), regulate genome stability. Pinto-Fernandez and Kessler (University of Oxford) demonstrated the importance of inactivation of the ubiquitin signal in the DDR in their summary of how deubiquitinating enzymes counteract DDR-related ubiquitination. Beside the essential role of UB, SUMO and PAR in the spatiotemporal recruitment of different DNA replication and repair proteins at sites of DNA damage, the group of Thorsten Hoppe (University of Cologne) discussed how protein disassembly is equally as important as protein recruitment for genome stability . The disassembly of proteins from chromatin is mostly orchestrated by the ubiquitin-dependent AAA+ATPase p97/Cdc48, also known as VCP in humans, that serves as the unfoldase and segregase to remove ubiquitinated proteins  described the involvement of the DDR in the G2/M-checkpoint and mitosis and how these two processes are regulated by PTMs. In addition to molecular mechanisms of UB and SUMO in DDR and genome stability, this issue also contains one technical article, which helps us to better understand how to quantitatively investigate UB and SUMO pathways in DDR. Heidelberger et al.  described mass spectrometry-based approaches for quantitative analyses of site-specific protein ubiqutination in the context of the DDR.Helle Ulrich (Institute of Molecular Biology - Mainz) and her group highlighted that ubiquitination and SUMOylation control all aspects of DNA replication, from its initiation, elongation and termination, and not only translesion DNA synthesis as was initially proposed (By reading these outstanding articles one can easily conclude that all authors strongly emphasize the promising therapeutic potential that targeting two PTMs- ubiquitination and SUMOylation- as well as other components of the DDR, has for cancer therapy (Hoeller and Dikic, All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer PB declared a past co-authorship with one of the authors ID to the handling Editor."}
+{"text": "Regarding American Psychiatric Association, Attention-Deficit/Hyperactivity Disorder (ADHD) is one of the most common neurodevelopmental disorders in early childhood. The symptoms of ADHD include inattention, impulsivity, and hyperactivity. Such disorders lead to disruption in the educational, social and individual relationships areas and in other life aspects. Studies have highlighted the side effects of medications in the rehabilitation of individuals with ADHD and supported that many of children with ADHD despite pharmacological treatments experience cognitive dysfunctions ,2. In reThe goals of mHealth apps as one of the main subsets of e-health, are behavior change, education and diagnostic evaluations, collecting and reporting data, direct recording of health status, providing electronic decision supports, facilitating communication, planning and scheduling, alleviating the economic burden of diseases, enhancing the quality of health research and generally improving the effectiveness of healthcare services and health outcomes . mHealthThe interactive nature of mHealth apps along with their capability to be adapted and customized based on individuals\u2019 needs, leads in improving care, promoting rehabilitation and enhancing the quality of life."}
+{"text": "Substance-using women who exchange sex for money, drugs or shelter as a means of basic subsistence  have remained largely at the periphery of HIV and harm reduction policies and services across Canadian cities. This is notwithstanding global evidence of the multiple harms faced by this population, including high rates of violence and poverty, and enhanced vulnerabilities to HIV transmission among women who smoke or inject drugs. In response, a participatory-action research project was developed in partnership with a local sex work agency to examine the HIV-related vulnerabilities, barriers to accessing care, and impact of current prevention and harm reduction strategies among women in survival sex work. This paper provides a brief background of the health and drug-related harms among substance-using women in survival sex work, and outlines the development and methodology of a community-based HIV prevention research project partnership. In doing so, we discuss some of the strengths and challenges of community-based HIV prevention research, as well as some key ethical considerations, in the context of street-level sex work in an urban setting. Substance-using women working in open street-level sex work markets face a myriad of health risks, including pervasive violence and assault, high rates of poverty and homelessness, drug-related harms, stigma, and social isolation -3. MortaOf particular concern, women who exchange sex for money, drugs, shelter, or other commodities as a means of basic subsistence  have been shown to face an elevated risk of HIV transmission , increasIn Vancouver, Canada, a city drug policy response, known as the Four Pillars strategy, and several innovative harm reduction efforts have been shown to be highly successful in reducing the harms of drug users, including primary and secondary prevention, extensive fixed and mobile syringe exchange programs, a heroin maintenance trial and two supervised injection facilities ,25. Yet In an effort to respond to existing gaps in prevention and policy, a community-based HIV prevention research project was developed to investigate the health-related harms, service barriers, and impact of current harm reduction and prevention strategies among women working in survival sex work in Vancouver, Canada. This paper outlines the development and methodology of the Maka Project Partnership, and discusses some of the strengths and challenges of community-based HIV prevention research, as well as ethical considerations, in the context of survival sex work in an urban setting.An initial gap in service access, HIV prevention and harm reduction for survival sex workers was identified as a key issue through informal conversations between health providers, staff, and sex workers at an inner city drop-in centre. In operation since 1987, Women's Information Safe Haven (WISH) Drop-In Centre Society connects with an estimated 200 women engaged in survival sex work per night. While the mandate is not exclusive to Aboriginal women, over half of the women that come through its doors are of First Nations, Metis and Inuit ancestry. The project works closely with WISH's well-established Aboriginal Health and Safety Project for Women in the Sex Trade (AHIP), as well as other key Aboriginal and sex work collaborators.In 2004, researchers were approached to collaborate on an initial needs assessment of women attending the drop-in. The results led to the conception and design of both a research and a service arm . The serA key component of the project is capacity-building among a team of women in survival sex work, supported by an open Community Advisory Board (CAB), that inform all stages of the project. Initial CAB tasks were to identify the working role of the CAB and develop a hiring process for peer team of women. The hiring process aimed to ensure a transparent process, including extensive and flexible options for informing and inviting women to contact the project  and the creation of a community-peer hiring panel (CAB members). Through this process, a team of women with a lived experience of survival sex work were hired, trained and support to play an active role in guiding, developing and conducting the research. These positions are low-threshold employment positions that work from a harm reduction perspective, similar to models of other sex work and drug-user groups. There is considerable focus on capacity building and training, as well as ongoing support and referral for addictions counselling, drug treatment, supportive housing, and child care. Extensive training modules were conducted in collaboration with local community agencies and sex work groups, including sex work specific training created and conducted by PACE Society on lateral oppression, vicarious trauma, debriefing and conflict resolution; participatory-action research principles, methodologies, ethics, and informed consent; and health, HIV/HCV prevention, and harm reduction conducted by community health providers, sex work groups, and Aboriginal agencies.In keeping with community-based research principles, this project adopts multiple research methodologies, including ongoing qualitative focus group discussions, social mapping, and a prospective cohort (6 monthly interview questionnaires and HIV screening) over a three-year period. All focus group discussions are facilitated or co-facilitated by a member of the peer team and inform the 'lived experiences' of survival sex work and barriers to and facilitators for prevention and harm reduction efforts. Individual informed consent is obtained prior to the discussion group and verbal rather than written consent is provided at the time of the interview, due to participant concerns of confidentiality. Discussion groups last approximately two hours and all participants receive Can$25 compensation for their expertise and time.A particularly novel component of the project is the social mapping, a participatory-action research tool that facilitates community access to hidden populations and highlights local expertise. Initial piloting of the maps with over 60 women facilitated by the Maka peer team has informed subsequent recruitment and outreach efforts for both research and service arms of this project. In particular, women are provided with a map of Vancouver's Downtown Eastside and surrounding communities and asked to mark 1) strolls where they work and live; 2) current working conditions ; 3) high and low risk areas for violence and bad dates; 4) working areas impacted by police presence and harassment; 5) areas of health and syringe availability and disposal.Given the difficulty in accessing a representative sample of sex workers due to the illegal and clandestine nature of sex work and unknown boundaries of this population , mappingThrough time-space sampling, a total of 205 women were initially invited and agreed to participate in a baseline visit over a six month period in 2006 (response rate of 93%), with ongoing 6 monthly follow-up visits scheduled to continue through 2008. Baseline and follow-up include detailed interview questionnaires administered by the peer interviewers and HIV screening by the project nurse, supported by extensive pre and post-test counselling. Women 14 years of age and older who have used illicit substances (not including marijuana) within the last month and are actively engaged in street-level sex work are eligible to participate. Semi-structured interview questionnaires elicit responses related to current and past experiences of sex work, violence and trauma, health and addition service access, working conditions, and sexual and drug-related harms. HIV screening is completed by the project nurse using the INSTI rapid HIV test , and new reactive tests are confirmed by western blot. A pre-test counseling questionnaire is completed by the project nurse on detailed questions relating to overall health, experiences with HIV and Hepatitic C testing, and current and past abuse experiences in order to facilitate counselling and referral to support services. Participants receive Can$25 compensation at baseline and each follow-up visit.Sex work researchers have described some of the key ethical issues and challenges in conducting non-exploitative research in this population both in Canada and internationally ,35,38-40The concern of ensuring privacy and confidentiality of participants requires particular consideration in the sex work context, in addition to raising some key ethical issues related to HIV prevention research. Given the historically oppressive nature of research of sex work, significant concern from the onset by both the community partner and sex work activists was that the research did not further stigmatize a highly marginalized population of women, or falsely precipitate sex workers as \"vectors of disease\". A concern similarly voiced in other settings across the globe ,41. As sTwo key ethical issues emerged of important relevance in HIV related research with sex work populations. First, while HIV is a reportable illness using the standard ELISA test, the new rapid point of care test provides women with the opportunity to receive anonymous HIV screening. Women are advised during extensive pre-test counselling that the INSTI test is not a diagnostic test, and a reactive test needs to be confirmed by a western blot, as per standard of care. Women have the choice of being referred to a physician for follow-up testing, or completing the follow-up testing at the Maka Project office. Early findings suggest increased acceptability and utilization of point of care testing among a highly marginalised population of women, with 96% of women agreeing to HIV screening at first visit. Within this context, the role of HIV reportability and disclosure in survival sex work needs to be explored , particuSecondly, reporting of violence experienced by youth less than 18 years of age is a major limitation to research with legal minors , and hasConsistent with recent literature on public health partnerships , the CBRHowever, a particular challenge to the CBR process in this community has been the balancing of interests of academic and community partners, as well as survival sex workers themselves. Three sets of partners are represented in the research: a service agency for sex workers, survival sex workers, and the researchers. Emerging discussions in community-based HIV prevention research have focused on the challenges of defining a \"community\" in the CBR process . In healIn addition to the many strengths of ensuring active involvement of those currently involved in survival sex work for both sex workers and researchers ,39,49, tHigh rates of health and drug-related harms, including violence and victimization, persist among women in open street-level sex worker markets in cities across Canada, and globally ,28,50,51KS conceptualized the manuscript, wrote the original draft, and incorporated suggestions from authors into the final version of the manuscript. VB, SA, DA, KG and MWT were involved in conception of the methodology and provided critical feedback on content and revisions to the original draft. All authors read and approved the final version of the manuscript."}
+{"text": "Work-hour limitations have been implemented by the Accreditation Council for Graduate Medical Education (ACGME) in July 2003 in order to minimize fatigue related medical adverse events. The effects of this regulation are still under intense debate. In this literature review, data of effects of limited work-hours on the quality of life, surgical education, and patient care was summarized, focusing on surgical subspecialities.Studies that assessed the effects of the work-hour regulation published following the implementation of ACGME guidelines (2003) were searched using PubMed database. The following search modules were selected: work-hours, 80-hour work week, quality of life, work satisfaction, surgical education, residency training, patient care, continuity of care. Publications were included if they were completed in the United States and covered the subject of our review. Manuscrips were analysed to identify authors, year of publication, type of study, number of participants, and the main outcomes.Twenty-one articles met the inclusion criteria. Studies demonstrate that the residents quality of life has improved. The effects on surgical education are still unclear due to inconsistency in studies. Furthermore, according to several objective studies there were no changes in mortality and morbidity following the implementation.Further studies are necessary addressing the effects of surgical education and studying the objective methods to assess the technical skill and procedural competence of surgeons. In addition, patient surveys analysing their satisfaction and concerns can contribute to recent discussion, as well. Resident work-hour restrictions have been implemented nationwide under the guidelines established by the Accreditation Council for Graduate Medical Education (ACGME) in July 2003 . The maiwork-hours, 80-hour work week, quality of life, work satisfaction, surgical education, residency training, patient care, continuity of care. Synonyms were used to find further relevant literature. In addition, we reviewed the references from the resulting publications to identify further potential articles to be included in our study.To identify the relevant publications, a Medline database search of articles published following the implementation of ACGME guidelines  through PubMed was performed. Relevant studies were retrieved using the following sequences of key words: Studies were included that assessed the effects of work-hour limitations on residents quality of life, surgical education, and the quality and continuity of patient care, respectively. Publications were selected if they covered at least one subject of our review and were completed in United States. Review articles, textbook chapters, poster presentations, and abstracts were exluded from this study. Studies were eligible if they were prospective, retrospective, or descriptive.A total of twenty-one articles satisfied the inclusion and exclusion criteria for this analysis. We reviewed and summarized the findings published in the studies. Variables of interest included authors, year of publication, type of study, number of participants, and the main outcomes.Resident work hour regulations have been implemented in the State of New York during the 1980s . It was One publication reports emotional exhaustion and depersonalisation among most residents before and after introduction of work-hour reduction, whereas, important clinical activities such time spent in the operating room, clinic, and making rounds did not changes as well .In summary, almost all investigations have reported improved quality of life and work-related satisfaction in surgical residents. However, most authors agree that the working conditions cannot be improved by reducing work-hours only. It is concluded that due to limited work time, the work load should be distributed to colleagues or auxiliary staff (physician extenders).Surgery is a procedure \u2013 based specialty requiring the acquisition of technical skills and procedural competence. This experience depends on the variety of cases and case load during the residency. Several surveys have demonstrated improvements in theoretical surgical education with a significant increase of American Board of Surgery In-Training Examination (ABSITE) scores as a consequence of additional time for reading, more time for self preparation, and for conferences ,14,19,20Many clinicians argue that such work hour limitations adversely affect the training experience and report reduced quantity of operations, reduced consultations seen, and reduced conference attendance ,27,28. TIn summary, it is still controversial whether the restricted work hours negatively influence the surgical education and training. The new regulation reduces the duration of stay in the hospital and may lead to fewer opportunities to participate in operative cases. Thus, less experience may ensue for the surgeon in training. Further observations and objective evaluations of the surgical education can indicate whether the ACGME work-hour policy has adversely affected the clinical experience. Certainly, the estimation of ABSITE scores is an objective method to analyze the theoretical education of surgical residents. Unfortunately, the degree of surgical experience, procedural competence, and technical skills are difficult to assess. Therefore, it has been tried to use analyses of surgical adverse events, mortality, and morbidity to assess operative skills ,31-33.The ACGME work-hour regulation caused the development of shift models with multiple residents being responsible for a given patient . Thus, iAccording to several surveys, surgical residents are concerned about the negative impacts on patient continuity and quality of care. Otherwise, objective studies have demonstrated that the quality of care  of surgical patients rather did not change following the implementation of the ACGME work-hour reform. Certainly, particularly the patient-resident relationship and previous patient focused attitude in treatment may suffer under the new regulation. Whether these changes also have an impact on patient satisfaction has yet to be determined. Surveys among patients are missing to date.To comply with the guidelines of the work-hour regulation, residency programs have to reduce or distribute the work-load that would have been completed by residents. Several benefits were reported after the incorporation of physician extenders (nurse practitioners or physician assistants) into the surgical service -45. StudOur review appears to support the following main findings: The new work-hour regulation improves the quality of life and work-related satisfaction especially in junior residents. In contrast, senior residents were less satisfied with the new reform. The effects on surgical education remain unclear due to inconsistency in studies, problems in assessment of the quality of the education and the quality of the surgeon's performance. Also, there appears to be no evidence whether the reduction of work-hours and the expected decrease of fatigue increased patient safety. Moreover, objective studies demonstrate no changes in mortality and morbidity following the implementation, although, residents perceptions regarding the quality of patient care were mostly negative. Finally, we observed a lack of patient surveys analysing patient satisfaction, quality and changes of care. This data could contribute to the recents debate. Moreover, further studies are necessary to analyse the effects on scientific research in teaching hospitals, to evaluate the changes of medical error and complication, and to assess the development of costs.The authors declare that they have no competing interests.All authors were involved in the research project and preparation of the manuscript. PHC: He made a substantial contribution to conception and design, and gave a critical and final approval. PR: He has collected the data and made an analysis and interpretation of these data. He also made a draft of the manuscript and revisions. All authors read and approved the final version of the manuscript."}
+{"text": "Previous cross-sectional data suggest a positive association between serum cholesterol and brain neoplasms, but the results of cohort studies are inconclusive. There is evidence that in women the growth of meningiomas and astrocytomas depends on the hormonal status. The present investigation comprised data on serum cholesterol and beta-lipoprotein concentration among 229 participants in a health survey with subsequently diagnosed central nervous system (CNS) tumours. Data analyses included comparison of mean serum cholesterol and beta-lipoprotein level between cases and randomly selected controls--five for each case, matched for sex, age at screening and time of examination. The results showed a positive relation between the beta-lipoprotein level and the development of a CNS tumour  in women under 50 years of age, and a negative association in those of older age with development of malignant tumours, which implies a possible influence of the menopausal status. Repeating the computations after excluding cases diagnosed within 5 years from screening revealed significant associations also between the serum cholesterol concentration and the development of a malignant CNS tumour, with a pattern similar to that of beta-lipoprotein. In conclusion, in women, irregular variation in the beta-lipoprotein level, which is involved in the synthesis of progesterone in the CNS, may enhance oncogenic transformation of astrocytes and meningeal cells; however, transformation of the latter is restricted to younger women."}
+{"text": "Microarray data are often used for patient classification and gene selection. An appropriate tool for end users and biomedical researchers should combine user friendliness with statistical rigor, including carefully avoiding selection biases and allowing analysis of multiple solutions, together with access to additional functional information of selected genes. Methodologically, such a tool would be of greater use if it incorporates state-of-the-art computational approaches and makes source code available.. All source code is available from Bioinformatics.org or The Launchpad. The R package is also available from CRAN.We have developed GeneSrF, a web-based tool, and varSelRF, an R package, that implement, in the context of patient classification, a validated method for selecting very small sets of genes while preserving classification accuracy. Computation is parallelized, allowing to take advantage of multicore CPUs and clusters of workstations. Output includes bootstrapped estimates of prediction error rate, and assessments of the stability of the solutions. Clickable tables link to additional information for each gene , and output can be sent to PaLS for examination of PubMed references, GO terms, KEGG and and Reactome pathways characteristic of sets of genes selected for class prediction. The full source code is available, allowing to extend the software. The web-based application is available from varSelRF and GeneSrF implement a validated method for gene selection including bootstrap estimates of classification error rate. They are valuable tools for applied biomedical researchers, specially for exploratory work with microarray data. Because of the underlying technology used  they are also of methodological interest to bioinformaticians and biostatisticians. Patient classification and gene selection related to classification are common uses of microarray data , but stFrom a users' perspective, an ideal tool should also be user friendly and provide additional resources to ease the interpretation of results . Web-basFinally, a tool that fulfills the above requirements is of much greater relevance if it makes its source code available under an open-source license. Source code availability allows the research community to experiment with, and improve upon, the method and fix bugs, encourages reproducible research, allows to verify claims by method developers, makes the international research community the owner of the tools needed to carry out its work and, thus, creates the conditions for swift progress upon previous work, concerns of particular importance in bioinformatics ,16.We have developed GeneSrF and varSelRF , that satisfy the above requirements. The only available web-based tools with similar scope are M@CBETH  and PropThe core statistical functionality is provided by the varSelRF package for R . This paThe input for the web-based application are either plain text files, or files that come from other tools of the Asterias suite . GeneSrFThe parallelization has been implemented over bootstrap resamples. The speedups achieved by parallelizing are shown in Figure The scaling of user wall time of the R code (varSelRFBoot) with number of arrays and number of genes is shown in Figure The run time for the web-based application for a wide range of data sets is shown Figure Scripts for timing experiments are included with the source code (directory \"Benchmarks\").Our procedure is explicitly targeted to select very small sets of genes, and has been shown  to have To avoid underestimating the error rate of the classification procedure, we use the bootstrap (the 0.632+ approach of ). As in Since we obtain 200 resamples in the process of bootstrapping (see above) there is little added computational cost to providing analysis of stability and multiplicity of solutions. We report the number of genes selected and the identity of the individual genes selected in the original sample and the 200 bootstrap runs, including frequencies of every gene selected in the solutions. Moreover, the biological interpretation of the results is enhanced by the access to additional information. If the input file contains gene identifiers for either human, mouse, or rat genomes , for each gene in the results, the web-based application provides a link to IDClight , which aFinally, GeneSrF is one of the very few tools for the analysis of gene expression data that uses parallelization and, as far as we know, the only web-based tool to use parallelization for gene selection and classification. This is an important methodological novelty, as we can no longer expect that increases in single-CPU speed will allow us to analyze larger data sets in shorter time: the rate of increase in CPU speed has slowed down considerably in the last five years but, in contrast, increasing numbers of CPU cores  are becoming much more affordable ,14. ThusFuture work focuses on extending the software to use random forest-related techniques applicable to heterogeneous types of variables such as addition of categorical data  and othevarSelRF and GeneSrF implement a validated method for gene selection and provide bootstrap estimates of classification error rate, take advantage of computing clusters and multicore processors, and encourage careful examination of the multiplicity of solutions problems. Thus, these are both useful tools for applied biomedical researchers using microarray and gene expression data, and represent unique methodological developments in the area of web-based gene expression analysis tools.For GeneSrF:Project name: GeneSrFProject home page: Operating system: Platform independent (web-based application)Programming language: R, PythonOther requirements: A web browser.License: None for usage. Web-based code: Affero GPL (open source).Any restrictions to use by non-academics: None.For varSelRF:Project name: varSelRFProject home page: Operating system: Linux, UnixProgramming language: R, PythonOther requirements: LAM/MPILicense: GNU GPLAny restrictions to use by non-academics: NoneCGI, Common Gateway Interface; GO, Gene Ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes; LAM, Local Area Multicomputer; MPI, Message Passing Interface."}
+{"text": "The experimental data providing evidence for the above roles of tryptase are summarized in the present review, as well as the effects of tryptase inhibition in animal asthma models. The potential strategies for the development of anti-asthmatic agents based on the inhibition of tryptase are discussed.Recent physiological and pharmacological studies have indicated the potential importance of tryptase, the major protein component in mast cells, in inflammatory diseases . Being released at inflammatory sites after the activation of mast cells, tryptase is capable of causing bronchohyperresponsiveness and infiltration of eosinophils, neutrophils, etc. in animal airways. The mechanisms by which tryptase causes bronchoconstriction involve probably the potentiation of other chemical mediators such as histamine, production of bradykinin via the hydrolysis of kininogen, and cleavage of the bronchodilating peptides VIP  and PHM (peptide histidine-methionine). Tryptase has also been found to be a potent mitogen"}
+{"text": "Manjeet Singh, the immediate Past President and Executive Member of the Indian Pharmacological Society passed away on 30th April 1946, Dr. Singh obtained BPharm, MSc (Pharmacology) and PhD from Punjab University, Chandigarh. He started his career in 1973 in the Department of Pharmaceutical Sciences  at the University. He established a cardiovascular sciences laboratory in the department and was known for original basic research in ischemia reperfusion injury and oxidative stress. Dr. Singh joined Punjab University, Patiala in 1994, as Professor and Dean and established the Department of Pharmaceutical Sciences and Drug Research. During his stay, Dr Singh and his team of PhD students described the concept of resident mast cell in heart and its role in ischemia reperfusion injury. They also identified several other molecular targets for new drug development for cardio-protection. This research was very well recognized and a large number of awards were conferred on him such as: Fellow of International Academy of Cardiovascular Science, KG Nair Oration, Dr. OD Gulati Award, Achari Oration, PP Surya Kumari Award, Univas Prize, Achari Prize, NS Dhalla Oration and many more.Born in a small town of Punjab on 18Prof Singh's latest achievement was the establishment of a model private college of pharmacy (Indo-Soviet Friendship College of Pharmacy) at Moga, Punjab. This college has a unique establishment with \u201cstate-of-the-art\u201d research facilities not only in pharmacology but also other disciplines of pharmacy. Although this institute is in a small remote town in Punjab, it attracted a large number of experts as devoted faculty. In November 2008, a high profile scientific conference was also organized under his leadership.Our Society has lost a dynamic and enthusiastic member; the pharmacy community has lost an affectionate and popular teacher, the pharmacology especially cardiovascular fraternity has lost a proud researcher and prolific writer, who made significant and original contributions in the field of basic cardiovascular physiology and pharmacology."}
+{"text": "Tumour-associated prostaglandin-like material, assessed by bioassay, has been examined in 37 patients with primary and metastatic squamous carcinomas of the head and neck, previously treated by radiotherapy and chemotherapy followed by radical surgery. High amounts of prostaglandin-like material were extracted from tumours excised within 3 months of radiotherapy and chemotherapy. These amounts correlated with necrosis, inflammation and fibrosis, but not with tumour site, size or degree of differentiation. Most of the prostaglandins formed by these treated tumours thus seem to be associated with host stromal and inflammatory cells, rather than the neoplastic cells. The possible roles of prostaglandins in facilitating the spread of squamous carcinomas are discussed."}
+{"text": "The diagnosis of bronchus cardiacus accessorius dexter (BCAD) has occurred in 25 casesduring the bronchoscopic investigations of 30,000 adult patients of the authors. In most of thecases, this bronchial anomaly has been revealed as an accessory phenomenon, nevertheless, inone of the patients, it was the source of a considerable hemorrhage. In another case reportedhere in detail, it occurred together with multiple developmental anomalies, such astracheobronchomegaly, mitral valve prolapse, pectus excavatum, hypoplasy of sinus frontalison the right side, inguinal hernia on the left side and hyperlipidemia type IV. Familyanalysis did not confirm the presence of any chromosomal disorders or accumulation ofsimilar developmental anomalies. The forms and frequency of associations of the anomaliesare surveyed on the basis of literary data. The recognition of BCAD is of diagnosticimportance, since it may explain the persistence of some bronchopulmonary symptoms;furthermore, the exploration of the associated abnormal vascular branches may be very usefulin case of an eventual thoracic surgical intervention."}
+{"text": "Africa is confronted by a heavy burden of communicable and non-communicable diseases. Cost-effective interventions that can prevent the disease burden exist but coverage is too low due to health systems weaknesses. This editorial reviews the challenges related to leadership and governance; health workforce; medical products, vaccines and technologies; information; financing; and services delivery. It also provides an overview of the orientations provided by the WHO Regional Committee for Africa for overcoming those challenges. It cautions that it might not be possible to adequately implement those orientations without a concerted fight against corruption, sustained domestic and external investment in social sectors, and enabling macroeconomic and political  environment. Out of 58.03 million people who died globally in 2005, 10.9 million (18.8%) were from the WHO African Region [Firstly, there are serious leadership and governance challenges that include weak public health leadership and management ; inadequSecondly, extreme shortages of health workers exist in 57 countries of which 36 are in Africa . The criThirdly, there is rampant corruption in medical products and technologies procurement systems, unreliable supply systems, unaffordable prices, irrational use, wide variance in quality and safety . This haFourthly, there is a dearth of information and communications technology (ICT) and mass Internet connectivity, compounded by a paucity of ICT-related knowledge and skills limiting capacities of national health management information systems (HMIS) to generate, analyze and disseminate information for use in decision-making .Fifthly, health financing in the Region is characterized by low investment in health, lack of comprehensive health financing policies and strategic plans, extensive out-of-pocket payments, lack of social safety nets to protect the poor, weak financial management, inefficient resource use, and weak mechanisms for coordinating partner support .Finally, in terms of service delivery, the lack of effective organisation and management of health services combined with the above indicated challenges have in tandem led to the current situation where 47% of the population have no access to quality health services, 59% of pregnant women deliver babies without the assistance of skilled health personnel. In relation to water and sanitation which contribute to reducing burden of communicable diseases, 64% of the population lack sustainable access to improved sanitation facilities, and 42% lack sustainable access to an improved water source [Cognizant of the abovementioned challenges, the 46 Ministers of Health from the African Region adopted and signed the Ouagadougou Declaration  that proSubsequently, the fifty-eighth WHO Regional Committee for Africa endorsed a framework for implementing the Ouagadougou Declaration . The fraFirstly, regarding leadership and governance, it proposes updating of national health policy and strategic plan; updating and enforcing public health laws; and strengthening mechanisms for transparency and accountability and intersectoral collaboration .Secondly, concerning HRH, it recommends generation and use of evidence in HRH policy development, planning and management; reinforcing health training institutions capacity; strengthening HRH leadership and management capacities; implementing HRH retention strategies; and increasing fiscal space for HRH development .Thirdly, with regard to medical products and technologies, it proposes development of formulae for determining the requirements and forecasting for medicines, commodities, essential technologies and infrastructure; and creation of a transparent and accountable procurement system .Fourthly, relating to health information and research, the Declaration on Primary Health Care and Health Systems suggests development and implementation of a comprehensive HMIS policy and strategic plan; and establishment of a functional national HMIS by leveraging ICT . In addiFifthly, pertaining to health financing, it recommends development of a comprehensive health financing policy and a strategic plan; institutionalization of national health accounts and efficiency monitoring; strengthening of financial management skills at all levels; allocation of at least 15% of the national budget to health development; implementation of the Paris Declaration on aid effectiveness; and develop social protection mechanisms .Finally, as regards service delivery, the Declaration proposes building on the elements of essential health services, mode of delivery and costs; development of norms, standards and procedures for service provision and health infrastructure construction and maintenance; formulation of integrated service delivery model at all levels including the referral system; development of mechanisms to involve all private health providers in provision of essential health services; development and implementation of multi-sectoral health promotion policies and strategies to optimize community involvement in health development .Effective public health interventions are available to curb the heavy disease burden in Africa. Unfortunately, health systems are too weak to efficiently and equitably deliver those interventions to people who need them, when and where needed. Fortunately, the health policy-makers know what actions ought to be implemented to strengthen health systems. However, it might not be possible to adequately implement those actions without a concerted and coordinated fight against corruption, sustained domestic and external investment in social sectors , and enabling macroeconomic and political  environment.HMIS: Health management information systems; HRH: Human resources for health; ICT: Information and communications technology; PHC: Primary health care; WHO: World Health OrganizationThe authors declare that they have no competing interests.JMK and SPB contributed equally in drafting the editorial. All authors read and approved the final manuscript."}
+{"text": "Diarrhoea was estimated to account for 18% of the estimated 10.6 million deaths of children aged less than five years annually in 2003. Two\u2014Africa and South-East Asia\u2014of the six regions of the World Health Organization accounted for approximately 40% and 31% of these deaths respectively, or almost three-quarters of the global annual deaths of children aged less than five years attributable to diarrhoea. Much of the effort to roll out low-osmolarity oral rehydration solution (ORS) and supplementation of zinc for the management of diarrhoea accordingly is being devoted to sub-Saharan Africa and to South and South-East Asia. A number of significant differences exist in diarrhoea-treatment behaviours and challenges of the public-health systems between Africa and Asia. The differences in rates of ORS use are the most common indicator of treatment of diarrhoea and vary dramatically by and within region and may significantly influence the roll-out strategy for zinc and low-osmolarity ORS. The prevalence of HIV/AIDS and the endemi-city of malaria also differ greatly between regions; both the diseases consume the attention and financial commitment of public-health programmes in regions where rates are high. This paper examined how these differences could affect the context for the introduction of zinc and low-osmolarity ORS at various levels, including the process of policy dialogue with local decision-makers, questions to be addressed in formative research, implementation approaches, and strategies for behaviour-change communication and training of health workers. Over a quarter-century has passed since the introduction of oral rehydration therapy (ORT) for diarrhoea in 1978 , while rIn May 2004, the WHO and United Nations Children's Fund (UNICEF) issued new recommendations for the management of all episodes of childhood diarrhoea, including new low-osmolarity oral rehydration salts (ORS) and supplementation of zinc for 10\u201314 days . When prZinc is an effective treatment for diarrhoea and resembles a modern pharmaceutical (tablets or syrup); therefore, zinc has the potential to reduce inappropriate use of antimicrobials for childhood diarrhoea through a replacement effect. Results of a community-based trial in Bangladesh showed that, in areas where zinc was introduced into the management of diarrhoea, inappropriate use of antibio-tics was significantly less than in control areas without zinc treatment . PrelimiThere are now calls for a sustained effort to roll-out zinc and the new formulation of ORS and to ensure that it is in the hands of low-income and marginalized populations who most need it ,15. SuchRates of ORS use for the management of diarrhoea vary greatly throughout sub-Saharan Africa and South Asia, reflecting regional variations in promotion and acceptance of ORS. High rates of incidence of HIV and malaria represent an added burden to already struggling health systems. This paper focuses on how these three factors\u2014(a) current childhood diarrhoea-management practices, (b) prevalence of HIV, and (c) endemicity of malaria\u2014affect the context of introduction of low-osmolarity ORS and supplementation of zinc at various levels: national policy, health programmes, health facilities, and households. We demonstrate that current rates of ORS use, HIV/AIDS, and malaria might affect the process of policy dialogue with local decision-makers, dictate questions to be addressed through formative research, and influence strategies for behaviour-change communication and training of health workers.For the purpose of this paper, countries in these two regions have been classified by rates of ORS use and rates of prevalence of HIV/AIDS and malaria Table . These cCountries in this first category are primarily francophone, in the Sahel region of West Africa, and have among the highest levels of under-five mortality in the entire world , low rates of ORS use (10\u201320%), high levels of malaria-related morbidity and morta-lity, relatively low but increasing prevalence of HIV, and relatively poor access to government health facilities. The 2003 Lancet child-survival series describes five profiles or patterns of under-five mortality in countries with high rates or contributing large numbers of under-five deaths . These cThis setting includes countries of southern Africa characterized by high ORS use, lower but still considerable under-five mortality , overall high prevalence of HIV (over 20%), and highly seasonal and focal transmission of malaria, resulting in a relatively low burden of malaria-related disease. These countries were assigned to Profile 5 in the 2003 Lancet series .Countries in this setting include nations of eastern and southern Africa, falling in Profile 4 of the 2003 Lancet series , with meThis category includes countries of South Asia corresponding to Profile 1 in the Lancet series , with meThe final setting is represented by parts of South Asia with lower but still considerable under-five mortality , high ORS use (over 60%), and a relatively small burden of disease attributable to HIV/AIDS and malaria ,17.ORS and ORT have been recommended for the treatment and prevention of dehydration since the late 1970s , while the highest levels were observed in Bangladesh, Viet Nam, The Philippines, and the smaller Indian States, such as Kerala, Manipur, and Goa. Factors contributing to lower levels of ORS-use in parts of South Asia include low levels of knowledge and awareness of ORS among some groups  and poorWhere rates of ORS use are high, ORS sachets are generally widely available, affordable, or free of charge  and theiThe availability of and access to ORS sachets vary greatly between regions and can have a significant impact on use-rates. In many Asian countries, ORS sachets are available through various channels, such as health facilities, general stores, and medicine shops , and popAcross southern Africa, ORS sachets tend to be readily available through both public and private channels, whereas in West Africa, ORS sachets are frequently available only at health facilities and pharmacies. These are few in number, making it difficult for people to access ORS, particularly in the rainy season. With the introduction of zinc and new ORS, strong advocacy should be carried out for policies which promote the increased access and availability of these products through private and community distribution channels. African countries also tend to not have as many local manufacturers of ORS as Asian countries do, therefore may only have one public-sector supplier and no private-sector ORS market. The adoption of the new formulation of ORS may be dependent upon the rate at which exporters of ORS adapt to the new formulation. In some cases, suppliers of ORS are producing both original and low-osmolarity ORS, but are only providing the new formulation when requested, thus leaving the choice of which formulation up to the procuring body.The epidemiology of malaria and HIV/AIDS differs greatly across the five settings, with rates of childhood malaria highest in Setting 1 and 3 and HIV/AIDS taking the greatest toll in Setting 2 and 3. The presence of these diseases can affect the receptiveness of a given setting to introduction of zinc and low-osmolarity ORS and the feasibility of attaining an adequate coverage with these interventions  control programmes. Categorical programmes can weaken health systems by hiring already scarce personnel away from existing services into new categorical programmes, or offering specific courses, meetings, and other activities that take away from general patient care , althougComplex clinical presentations of diarrhoea among HIV-positive young children require greater skills to manage appropriately. Acute diarrhoea occurs more often in HIV-infected children, and episodes tend to be more severe and persistent ,36 and aAlthough there is little scientific evidence supporting biological interaction of malaria and diarrhoea -40, the Household structure: Thus far, pilot interventions introducing supplementation of zinc and low-osmolarity ORS have relied upon community education on management of diarrhoea to increase treatment-seeking from public and private sources and, hence, improve management of diarrhoea. In countries where prevalence rates of HIV are high, severe illness and death among young adults have led to an enormous increase in the number of households headed by parents incapacitated by illness, elderly caregivers, or older children  the policy environment and policy-makers, (b) the supply chain for medications and other health-related commodities, (c) the availability of human resources in the health sector, (d) the quality of case management by health workers, and (e) home management of diarrhoea by parents Table .Considering only rates of ORS use, endemicity of malaria, and rates of prevalence of HIV, the most favourable context for the accelerated introduction of zinc and low-osmolarity ORS will be where current rates of ORS use are high, and the burden of disease attributable to HIV/AIDS and malaria is low. This situation is represented by Setting 5 in Table Setting 1 and 4, where rates of ORS use are the lowest, may present the greatest challenges to introduction of these new treatments. If the lowest rates are due to ORS being unavailable, efforts may be needed to both promote local manufacturing of zinc and ORS and ensure that these products are available through multiple public and private distribution channels. Although the burden of disease attributable to HIV is currently lower compared to other countries, these regions have difficulties in achieving high coverage with other critical public-health interventions. Thus, achieving coverage of zinc and low-osmolarity ORS may require additional technical assistance to overcome challenges. The francophone countries in Setting 1 are characterized by high levels of under-five mortality, weak health services, poor transport, and limited ability of governments to implement policies and provide services . Under tIn Setting 2 and 3, considerable progress has been made in strengthening health systems, and this is reflected in the high rates of ORS use and lower levels of under-five mortality compared to many other parts of Africa. HIV/AIDS threatens to reverse many of these gains and is a constant concern in the minds of policy-makers, health workers, and communities. In Setting 3, the challenge of HIV/AIDS is overlaid on the persistent high malaria-related burden of disease. In Setting 2 and 3, strong advocacy before policy-makers for investments to improve case management of diarrhoea is required. At the household and community levels, promotion of appropriate management of diarrhoea should be complemented by adequate care and support for orphans and other vulnerable children. As with Setting 1 and 4, we need to seek new ways of integrating ongoing efforts of new diarrhoea-management guidelines directed at HIV/AIDS and malaria through better training and supervision of health workers and other measures to improve quality of care.It is widely appreciated that national strategies to introduce zinc for the management of diarrhoea and new low-osmolarity formulation of ORS must be adapted through formative research to take into account local understandings of diarrhoea and home-management practices. What is less well-appreciated is the enormous impact the other public-health problems, such as malaria and HIV/AIDS, can have on the environment for the introduction of these new treatments, as summarized in Table This paper was written with support from the Zinc Task Force with funding from the Bill and Melinda Gates Foundation and support from the Office of Health, Infectious Diseases and Nutrition, Global Health Bureau, United States Agency for International Development (Award No. HRN-A-00-96-90006-00)."}
+{"text": "Blood-transfusion services are vital to maternal health because haemorrhage and anaemia are major causes of maternal death in South Asia. Unfortunately, due to continued governmental negligence, blood-transfusion services in India are a highly-fragmented mix of competing independent and hospital-based blood-banks, serving the needs of urban populations. This paper aims to understand the existing systems of blood-transfusion services in India focusing on Maharashtra and Gujarat states. A mix of methodologies, including literature review (including government documents), analysis of management information system data, and interviews with key officials was used. Results of analysis showed that there are many managerial challenges in blood-transfusion services, which calls for strengthening the planning and monitoring of these services. Maharashtra provides a good model for improvement. Unless this is done, access to blood in rural areas may remain poor. Blood is a vital healthcare resource used in a broad range of hospital procedures, viz. accidents, emergency obstetric services, and other surgeries. It is also a potential vector for harmful, and sometimes fatal, infectious diseases, such as HIV, hepatitis B and C. Every year, millions of people are exposed to avoidable, life-threatening risks through the transfusion of unsafe blood. As per a global database, 6 million of 81 million units of blood collected annually in 178 countries are not screened for transfusion-transmissible infections  ,4. AccesResults of a study of the circumstances for maternal deaths in Indonesia indicate that the lack of blood supplies and inability of some healthcare professionals to administer a transfusion contributed to deaths due to haemorrhage . SimilarIn India alone, according to a review of the Sample Registration Survey 1997-2003), postpartum haemorrhage accounts for nearly 38% of all maternal deaths 97-2003, , they arThis global scenario is evidenced from a statement by Director General of the World Health Organization made on the World Health Day 2000. He said, \u201cDespite all the technological marvels that humani-ty is experiencing, a reliable and safe blood supply is still out of the reach for untold millions of people around the world\u201d.To achieve Millennium Development Goal 5, access to effective EmOC, along with provision of professional care at birth, has been identified as vital for reduction in maternal mortality . In IndiThe primary responsibility for blood supply for blood-storage centres at the FRUs lies with the government/national health authority. Regional Blood Transfusion Centres (RBTCs), identified based on the amount of blood collected , carries out this responsibility. Licensing and monitoring of the blood-banks in India is the responsibility of the Drug Controller of India. The National Blood Transfusion Council (NBTC), established in accordance with the agreed national blood policy and within a legislative framework, has the major advisory role in the formulation of policy on safe blood-transfusion services in India. The National AIDS Control Society is responsible for collection of safe blood while providing financial assistance  and State AIDS Control Societies (SACSs) in Maharashtra and Gujarat. The policy guidelines of the National AIDS Control Organization (NACO) have also been reviewed to understand the role of NACO vis-\u00e0-vis NBTC. We have compared blood-banking management in India with the framework proposed by the World Health Organization (WHO) . StatistThe Blood Safety Programme in India began to take shape in 1987 with the establishment of the NACO, a government organization to oversee. In 1992, the Drug Controller General, India, was vested with the power of Central License Approving Authority to approve licensing of notified drugs, viz. blood and blood products. During the same year, under the National AIDS Control Programme I , the NACO launched a scheme to modernize blood-banks by providing assistance to states to upgrade and provide minimum facilities to blood-banks in the public sector and those run by charitable organizations, such as Indian Red Cross Society. Under the NACP I, the NACO modernized 815 blood-banks (282 major blood-banks and 533 district-level blood-banks) and also set up 40 blood component separation facilities to promote the rational use of blood. . Nearly 90% of the blood-banks modernized through this scheme were in the government sector. Meanwhile, in 1996, as a result of a case\u2014Common Cause vs Union of India and others\u2014the Supreme Court of India passed an order directing the Government to improve blood-transfusion services. Consequently, the NBTC and SBTCs were created to develop policies and programmes for improving blood-transfusion services in India.The Blood Safety Programme initiated in the NACP I was considerably strengthened in the NACP II (1999-2004) with modernizing more blood-banks, establishing model blood-banks, and setting up blood-storage centres in rural areas. The Government of India adopted the National Blood Policy in 2002 which aimed at ensuring easy accessibility to and adequate supply of safe and quality blood and blood components collected from voluntary and non-remunerated blood donors. In India, different organizations play different roles in licensing, controlling, and regulating blood-banks. While the Drug Controller General is the licensing authority, the NACO and SACSs aim at preventing the transmission of HIV and ensure 100% screening of all collected blood units, providing training and financial assistance to blood-banks for technical modernization for ensuring the quality of blood-banks. The NBTC and SBTCs aim at ensuring safe and quality blood for transfusion services, promote voluntary and non-remunerated blood donors, follow up quality-control assurance programmes in blood-banks, and conduct training programmes. The Council collects funds by 100% tax-free donations.Despite a directive of the Supreme Court regarding formation and functioning of SBTCs, all SBTCs  are functioning under the SACSs. Since the SACSs have many other responsibilities relating to AIDS control , blood sOver the years, a fragmented mix of competing independent and hospital-based blood-banks of different levels of sophistication, serving different types of hospitals and patients, have emerged. Besides the government blood-banks, there are blood-banks run by charitable trusts, independent commercially-oriented private organizations, and specific non-government health organizations, such as the Indian Red Cross Societies (IRCSs). The piecemeal evolution of blood-banking is linked to the burgeoning population and the expanding and poorly-regulated private healthcare market. Most blood-banks in public hospitals often operate with minimal infrastructure, lack of leadership, and resources; this has resulted in an inadequate/irregular supply of blood in the public system. .Blood-bank activities include recruitment and retention of donors; collection, testing, processing, and storage of blood; and clinical use of blood and blood components and training . Review Following the Supreme Court intervention, the State Government of Maharashtra established its Blood Transfusion Council in 1996 as an independent entity separate from the Maharashtra SACS. The SBTC has a full-time professional of the rank of Assistant Director, supported by a research officer, statistical assistant, and MIS (management information system) staff. It has an objective to coordinate the fragmented blood-supply system while providing adequate, safe, and affordable blood units and components. Given its autonomous status and administrative staff, the SBTC maintains good coordination with other blood-safety units in Maharashtra, such as SACS and international development agencies. It involves the entire health infrastructure, primary hospitals to tertiary hospitals, in blood-donation campaigns as each health facility is given an annual target for blood-donation camps.The organizational structure of the Maharashtra SBTC extends to the regional and district levels. Maharashtra has eight regional blood-transfusion officers and 34 district blood-transfusion officers. The Council has also established the following committees to improve various aspects of blood transfusion in the state: (a) Technical Committee, (b) Voluntary Blood-donation Committee, (c) Thalassaemia Committee, (d) Post-graduation Committee, and (e) Project Formulation Committee.Many other state governments, including Gujarat, established its SBTC as a part of SACS and appointed the Additional Director of SACS as head of SBTC. Thus, the SBTC is not an independent unit and works under the head of SACS. In Gujarat, the SBTC does not have any full-time professional and administrative staff. The Council is mainly composed of honourary members and is headed by the health secretary. As the members and chairperson have many other responsibilities, the meetings of the Council are not held regularly. Compared to Maharashtra, Gujarat lacks systematic organization of the blood-transfusion council.In India, there are 2,063 licensed blood-banks. A significant portion of blood-banking activity is carried out by voluntary (n=257) and private blood-banks (n=980). The total recorded blood collection in India is four million units, which meet only 40% of need against a least requirement of 10 million units  . TherefGiven the overall negligence to blood-banking in India, it is not surprising that its quality control has not been seen as an essential part. A lack of quality-assurance measures, including manuals of standard operating procedures, appropriate training and competency certification programmes, and continuous assessment systems, often hinders the implementation of good laboratory and manufacturing practices. For example, in Gujarat, some stakeholders reported that different blood-banks use different testing procedures and testing standards which hinders the exchange of blood between blood-banks. This may lead to more wastage of blood.Under the Blood Bank Modernization scheme of NACO, till November 2006, the Government of India has provided support to modernize 883 district-level blood-banks and 255 major blood-banks and established 82 blood-component separation units in the country. Ten state-of-the-art blood-banks were also established . The MahMaharashtra conducts regular training programmes on various issues to strengthen the capacities of professionals engaged in blood-banking services. The training programmes cover the following:\u2022Modular training for all blood-bank personnel\u2022Training on hepatitis C, ELISA Reader maintenance and repair, biosafety measures for all zonal BTC Blood Transfusion Officers and Technicians\u2022Component preparation for Blood Transfusion Officers and Technicians\u2022Blood group serology for Blood Transfusion Officers and Technician at the Indian Council of Medical Research\u2022Genetic blood disorder detection for Blood Transfusion Officers and Technicians\u2022Training for Drug Inspectors\u2022Quality-management training\u2014Blood Transfusion Officers\u2022Transfusion and transplantation science\u2022Key Blood Transfusion Officers from medical colleges trained as key trainers to undertake training for technicians of the FRU.In Gujarat, training programmes for blood-bank personnel are offered for updating their skills and knowledge. The training programmes, usually offered once in three months in various regions of the State, usually address topics on necessity of safe blood, the rational use of blood, and clinical procedures.Recently, the Medical Council of India  has approved a postgraduate course in blood-banking and immunology haematology/immunology haematology and blood transfusion. Presently, five medical colleges offer this postgraduate course in the states of Gujarat, Jammu and Kashmir, Maharashtra, Tamil Nadu, and Uttar Pradesh .th of every month, and feedback is given to the regional health officers by the 15th of every month. At the start of each year, monthly analysis of blood collection of the previous year is done to formulate strategies to compensate for the deficit in blood collection in a particular month. Maharashtra has also developed an excellent system of web-based monitoring of storage and availability of blood units and components of each blood group in every blood-bank in the state. This allows hospitals and blood-banks to request blood from neighbouring blood-banks where the needed group may be available. This ensures the most efficient use of available blood and minimizes wastage.Maharashtra maintains a reasonably good computerized management information system (MIS). Reports are compiled at the state level by the 5Gujarat, unfortunately, does not have a similar system. Hence, in the case of need, either blood-bank managers have to call the other blood-banks to check the availability or the relatives of the patient have to visit more than one blood-bank to procure required type of blood. For monitoring the blood-banks, the state maintains a regular database for all the reporting blood-banks. However, feedback is only occasionally provided to blood-banks by the GSACS.Blood is urgently required for saving women's lives in the case of massive postpartum or antepartum haemorrhage or severe anaemia. As the majority of blood-banks are located in urban areas, the availability of blood in rural areas is difficult. To address this lack of availability of blood in rural areas, the policy was changed in 2001, allowing the establishment of blood-storage units in rural regions. However, nothing much happened on this front as it was given low priority in the states. In 2005, the National Rural Health Mission dedicated a part of its funds for the establishment of blood-storage units at the FRUs. These blood-storage units will be attached to large regional blood-banks in urban areas for blood supply.In Maharashtra, 44 blood-storage centres are currently functional in the FRUs. By the end of March 2009, the target is to open 171 blood-storage units. By 2012, 400 blood-storage units will be functional in rural hospitals. Under a recent amendment (2006) of the Nursing Home Registration Act of Maharashtra, all nursing homes, clinics, and private hospitals should be affiliated with a licensed blood-bank for procurement of blood for patients admitted to their hospitals. Along with this, the state also requires blood-bank or storage facility within five km of any registered private abortion facility to ensure the availability of safe blood for transfusion services, if required . All regAll blood-banks and blood-storage centres have to maintain a record on blood collection and distribution in Maharashtra. All regional blood-banks supplying blood units to blood-storage centres record the information on the number of blood units supplied, blood group of the supplied blood units, and dates of issue and expiry. The storage centres and private hospitals/clinics also maintain information on similar indicators to avoid wastage of blood units, as unused blood units can be returned to the regional blood-bank before the date of expiry. However, it has been observed that the government centres discard units after the expiry as there is not much accountability relating to this. The institutions also maintain the records of distribution of blood units, with the name of the patient and hospital, blood group of the patient, and units of blood given. However, this information is not analyzed for management purpose in Maharashtra.The below poverty-line (BPL) population is entitled to receive blood and blood products free of charge from any government blood-bank or storage centre in Maharashtra. Individuals affected by thalassaemia, haemophilia, and sickle-cell anaemia also receive blood free of charge on their identity card. Approximately 40,000 units of blood are given to thalassaemia patients every year in Maharashtra. All voluntary donors of blood are also entitled to one free unit of blood on production of the voluntary blood donor card.The Gujarat State AIDS Control Society arranged a meeting to discuss the \u201cReorganization of blood-transfusion services and developing blood-storage centres at the FRUs\u201d at the end of 2005 to make safe blood available. Recent data on blood-storage units by the Government of Gujarat showed that 26 of the 39 functional blood-storage units in Gujarat are attached to the FRUs required in the state. The blood-storage units are located in the FRUs attached to charitable hospitals, community health centres, and district hospitals. All blood-storage centres are linked to the RBTCs for blood supply. The Government of Gujarat is also planning to recognize more blood-banks as RBTCs to strengthen blood supply in rural areas. Recently, the Gujarat State AIDS Control Society has initiated a free blood scheme for thalassaemia, haemophilia, and sickle-cell patients.By law, there is no charge for blood but blood-processing and testing cost is generally allowed. The charge for blood-transfusion service in the government blood-banks is only Rs 425 to any patient (approximately US$ 9.4). The cost in private blood-banks varies from centre to centre and is generally higher.While the Indian health sector has made some noteworthy achievements over the last 50 years, it has not responded satisfactorily enough to meet the national goals on blood-transfusion services as is witnessed by the substantial negligence to blood-banking services in the country. In India, blood transfusion relies on very fragmented blood-supply systems, where control is exercised by different layers of the Government, making it difficult to assure the quality of blood and blood products. Two parallel systems are in place to monitor the blood-safety programme in India\u2014NBTC/SBTC and NACO/SACS.Given the fact that there are a large number of Charitable Trusts and independent commercial and private blood-banks, the control of quality and coordination of all blood-banks to ensure easy access to blood and minimize wastage are a challenging task. This requires much more managerial capacity, skills, and resources within the State Blood Transfusion Councils. The promotion of postgraduate courses in blood-transfusion services will help in getting the trained and skilled human resource in the field of blood-banking. Given the lack of government resources in blood-transfusion services, there has been poor quality of service and periodic shortages of blood. Many blood-banks depend on philanthropic funding for their basic operations. The Government needs to increase its commitment towards improvement of blood-banking services and ensure that all needy patients get blood on time and free of charge for the BPL population.The existing MIS for blood-banking seems weak although it has been improved in Maharashtra. There is a lack of proper records on the use of blood in India. Due to this, it is not possible to estimate the need, supply, and unmet need for blood in obstetric emergency. Besides, the monitoring of the clinical use of blood and blood products is weak. No systematic analysis is done to measure adverse reactions following blood transfusion. Blood-banks also lack registering or monitoring of the total demand for blood and blood products (requests received) for each blood group that could not be met due to the non-availability of blood or blood products. They only record blood collected and used. They also do not report systematically the proportion of stored blood that expired due to non-use. Thus, substantial improvement in the MIS is needed.We find that, although the overall availability of blood is almost the same in both the states, the organization of blood-transfusion services is much better in Maharashtra as the Maharashtra Blood Transfusion Council is an independent unit with full-time staff under active leadership. Learning from this experience of Maharashtra, we recommend all the states to have independent and well-staffed blood councils. In Gujarat, the NGOs and the Indian Red Cross Societies are actively promoting voluntary donation of blood and, hence, per-capita collection in Gujarat is slightly better than in Maharashtra. Learning from Gujarat indicates the possibility of the dynamic role being played by the NGOs and IRCS in blood-banking.Ensuring a safe supply of blood and blood products and the appropriate and rational clinical use of blood are important public-health responsibilities of every national and state government, especially for saving lives of mothers who need comprehensive EmOC services because of pregnancy-related haemorrhage, severe anaemia, or abortions. The mechanism of availability of blood in rural areas is quite frail. There is a need for networking between urban blood-banks and rural blood-storage units. And as there is no special provision for timely blood supply for maternal emergencies in rural areas, it may not be possible to reduce maternal mortality due to haemorrhage, anaemia, and abortions. The use of blood components, at least in urban areas where facilities exist for storage of components, will also enhance supply of whole blood for rural areas.The authors acknowledge the International Centre for Diarrhoeal Disease Research, Bangladesh, Department of International Development (DFID), United Kingdom, and GSACS for partial funding for the study. They are also thankful to the Maharashtra State Blood Transfusion Council and the Gujarat State AIDS Control Society for their valuable contributions and whole-hearted cooperation in carrying out this study.Its content are solely the responsibility of the authors and do not necessarily represent the official views of the DFID."}
+{"text": "Adjustable rate mortgages and the downturn in the California housing market caused a 300% increase in notices of delinquency in Bakersfield, Kern County. This led to large numbers of neglected swimming pools, which were associated with a 276% increase in the number of human West Nile virus cases during the summer of 2007. Flaviviridae, genus Flavivirus) has remained epidemic in California since its arrival in 2003   because of decreased rainfall, snow pack, and water allotments to agriculture. The Kern River, which flows through Bakersfield, remained mostly dry during spring and summer; key bird species decreased in abundance because of the drought  and the previous negative effect of WNV infection; and surviving birds in key species had high herd immunity to WNV  acquired during previous seasons.An outbreak with 140 laboratory-confirmed human cases of WNV was centered in the Bakersfield area of Kern County, California, during 2007 . This case cluster formed the WNV epicenter for California during 2007, was the largest mosquito-borne encephalitis virus outbreak in Kern County since the 1952 epidemic of western equine encephalitis virus  and an aerial survey of Bakersfield showed an extensive number of green or neglected pools, most of which were producing mosquitoes. The likely reasons for neglected pools are the adjustable rate mortgage and associated housing crises in Kern County and throughout California, which have led to increased house sales, notices of delinquency of payment, declarations of bankruptcy and home abandonment. Kern County was especially affected , with a Cx. p. quinquefasciatus were now occupied by Cx. tarsalis, a more competent vector of WNV than Cx. p. quinquefasciatus  occurred during June 2007.Number of swimming pools treated by mosquito control personnel per month in Bakersfield, California, 2005-2007. KMVCD, Kern Mosquito and Vector Control District."}
+{"text": "We conducted a preliminary survey on 3064 patients who underwent upper gastrointestinal endoscopy at the Al-Thawra Hospital in Sana'a, Republic of Yemen, between January and December 1991. The age/sex distribution, demographic features and social habits with respect to cigarette and water-pipe smoking and Qat chewing were compared for patients with oesophageal and gastric cancers (n = 183). A preponderance of women with carcinoma of the mid-oesophageal was noted, previously only recorded in areas of high prevalence. Unlike Western populations, smoking and alcohol consumption were not significant risk factors. A high frequency of Qat chewing and water-pipe smoking was found for both men and women and for a group with tumours of the gastro-oesophageal junction or cardia . Numbers were insufficient to identify independent effects of each factor individually. Dietary habits alone were insufficient to account for the excess of affected females. A case-control study is now underway to investigate further the role of dietary factors, social habits, demographic features and Helicobacter pylori infection on the development of upper gastrointestinal cancer in the Yemen."}
+{"text": "This paper describes an integrated flow injection (FI) system for the determination of ammonia, sulphate and Fe(II)/Fe(III) which can work unattended for long periods. The system was designed for the determination of individual analytes in long series of samples. Each batch of samples requires manual selection of parameters and units, such as wavelength for monitoring, preconcentration column, loops and switching of three valves to select the carrier, reagents and eluent. The system then works automatically."}
+{"text": "Fear of falling and avoidance of activity are common in old age and are suggested to be (public) health problems of equal importance to falls. Earlier studies of correlates of fear of falling and avoidance of activity did hardly differentiate between severe and mild levels of fear of falling and avoidance of activity which may be relevant from clinical point of view. Furthermore, most studies focused only on socio-demographics and/or health-related variables and hardly incorporated an extensive range of potential correlates of fear of falling including psychosocial variables. This study analyzes the univariate and multivariate associations between five socio-demographic, seven health-related and six psychosocial variables and levels of fear of falling and avoidance of activity in older persons who avoid activity due to fear of falling.Cross-sectional study in 540 community-living older people aged \u2265 70 years with at least mild fear of falling and avoidance of activity. Chi-squares, t-tests and logistics regression analyses were performed to study the associations between the selected correlates and both outcomes.Old age, female sex, limitations in activity of daily living, impaired vision, poor perceived health, chronic morbidity, falls, low general self-efficacy, low mastery, loneliness, feelings of anxiety and symptoms of depression were identified as univariate correlates of severe fear of falling and avoidance of activity. Female sex, limitations in activity of daily living and one or more falls in the previous six months correlated independently with severe fear of falling. Higher age and limitations in activity of daily living correlated independently with severe avoidance of activity.Psychosocial variables did not contribute independently to the difference between mild and severe fear of falling and to the difference between mild and severe avoidance of activity due to fear of falling. Although knowledge about the unique associations of specific variables with levels of severe fear of falling and avoidance of activity is of interest for theoretical reasons, knowledge of univariate association may also help to specify the concepts for developing interventions and programmes to reduce fear of falling and avoidance of activity in old age, particularly in their early stages of development. Fear of falling and avoidance of activity due to fear of falling are common in older people. Prevalence rates for fear of falling in community-living older persons range from 20 to above 60% -8 and foPrevious research has shown that fear of falling and/or avoidance of activity were associated with sociodemographic factors , health-related variables  and psychosocial variables  -8,13-18.severe and mild levels of fear of falling and avoidance of activity which might be relevant from clinical point of view. Knowledge of these factors may facilitate identification of those older persons who are suffering from severe levels of fear of falling and avoidance of activity, and thereby offer routes to effective intervention.Zijlstra and colleagues , in reviThe present cross-sectional study was performed in a sample of community-living older people in the Netherlands who reported at least some fear of falling and associated avoidance of activity. The objective was to examine the relationship between severe levels of fear of falling and avoidance of activity on the one hand, and an extensive range of potential correlates on the other, including socio-demographic, health-related and psychosocial variables.The study was of cross-sectional design and used the baseline data of a trial evaluating the effects of a cognitive behavioral group intervention to reduce fear of falling and fear-related activity avoidance among community-living older persons .Between November 2002 and July 2003, local municipal registry offices of two cities in the south of the Netherlands selected a random sample of 7,431 community-living people aged 70 years and over. They received a short screening questionnaire , which 4Fear of falling was assessed by asking \"Are you afraid of falling?\", and avoidance of activity due to fear of falling was measured by asking \"Do you avoid certain activities due to fear of falling?\" Possible answers to these questions were: \"never\", \"almost never\", \"sometimes\", \"often\", or \"very often\". For the mentioned trial we included only participants who reported either \"sometimes\", \"often\" or \"very often\" on both questions. The answer option \"sometimes\" was denoted as mild fear of falling and avoidance of activity due to this fear. The answer options \"often\" and \"very often\" was denoted as severe fear of falling and avoidance of activity due to this fear.Three groups of correlates were assessed: 1) socio-demographic, 2) health-related and 3) psychosocial correlates.First, we assessed the following socio-demographic variables: age, sex, educational level and living arrangements. Educational level was based on all schooling and professional courses completed in the course of life (lower versus middle/high) and living arrangement was assessed as living alone or living with one or more others.Second, the health-related variables we assessed were limitations in activities of daily living, impaired vision and hearing, perceived general health, number of chronic conditions, cognitive functioning and falls history. Limitations in activities of daily living were assessed with the 11-item subscale of the Groningen Activity Restriction Scale  . ImpaireLastly, the psychosocial variables assessed were general self-efficacy, mastery, social support interactions, feelings of loneliness, and feelings of anxiety and symptoms of depression. General self-efficacy was assessed with a 16-item general self-efficacy questionnaire (score range 16\u201380) . MasteryChronic medical conditions, TICS, GARS and impaired vision and hearing were assessed by telephone interviews. All other data were collected by means of self-administered questionnaires. The study was approved by the medical ethics committee of Maastricht University/Academic Hospital in Maastricht, the Netherlands.First, descriptive analyses were performed for all selected variables. Second, we performed chi squares and independent t-tests to study univariate associations between the socio-demographic, health-related and psychosocial variables on the one hand and the two levels of fear of falling (mild and severe) on the other. We then repeated the same analyses for avoidance of activity. Finally, we conducted logistic regression analyses for each of the two dependent variables: fear of falling and avoidance of activity. Only the socio-demographic, health-related or psychosocial variables that showed a univariate association of p < .05 were included simultaneously in these analyses. We estimated odds ratios (ORs) and corresponding 95% confidence intervals (CIs). Analyses were conducted using SPSS for Windows version 14.0 . A significance level of less than .05 was considered statistically significant.Table Table The outcomes of the logistic regression analyses are presented in Table Our objective was to study the impact of an extensive range of socio-demographic, health-related and psychosocial variables on levels of fear of falling and avoidance of activity in older persons who avoid activity due to fear of falling. The results clearly show that due to the interrelationship between socio-demographic, health-related and psychosocial variables in older people, only a few of them correlated independently with either severe fear of falling and avoidance of activity due to this fear. Although we identified four socio-demographic, five health-related and five psychosocial factors significant univariate correlates of fear of falling, the independent correlation of only female sex, limitations in activity of daily living and falls history remained when covariates were taken into account. With respect to avoidance of activity due to fear of falling, we identified two socio-demographic, five health-related and five psychosocial significant univariate correlates; this pattern is consistent with fear of falling except for low education and living alone status being non-significant. When all significant univariate correlates were taken into account, only higher age and limitations in activity of daily living correlated independently with severe avoidance of activity. The correspondence between correlates for fear of falling and avoidance of activity may partly be explained by the interrelation of both outcomes. In effect, we were trying to determine what influences avoidance of activity in addition to fear of falling.severe fear of falling. However, in our final multivariate model where we took all significant univariate associations into account, only the impact of age, limitations in activity of daily living and falls history remained significant in the model. This latter finding indicates that none of the psychosocial factors we studied can differentiate between severe and mild levels of fear of falling.In a recent review Scheffer and colleagues  identificlinical point of view particularly older people with sever fear of falling and avoidance of activity due to fear of falling are relevant for interventions. Therefore it is important to identify the factors associated with severe levels of fear of falling and related avoidance behavior. Such knowledge may help to specify the contents, approach and length of interventions for these persons. So from clinical point of view it is relevant and important to distinguish between mild and severe levels of fear of falling.Our study has several limitations. First, all measures were self-reported and performance-based measures were not included in the current study. Future studies should include objective measures of balance, gait, muscle strength, vision, etc. to establish a further understanding of the complex construct of fear of falling. Second, our study was cross-sectional so we may not take causal inferences from our data . Future research may identify which correlates can be considered as predictors and which as consequences of severe fear of falling and related avoidance of activity. Third, we included community-living older persons which can be considered as a heterogeneous sample. Future studies could focus on whether different patterns of correlates exist between more frail and less frail older persons. Finally, we included only persons who reported at least mild fear of falling and avoidance of activity. Also having people without fear of falling in our study would have enabled us to say whether, for example, women are more likely to develop any level of fear of falling or only severe fear of falling. However, our interest was not in the development of fear of falling, but rather in those factors that differentiate between mild and severe levels of fear and related avoidance behavior. From severe levels of fear of falling and avoidance of activity. We identified old age, female sex, limitations in activity of daily living, impaired vision, poor perceived health, chronic morbidity, falls, low general self-efficacy, low mastery, loneliness, feelings of anxiety and symptoms of depression as significant correlates of severe fear of falling and avoidance of activity. Although the knowledge about the unique associations of specific variables with levels of fear of falling is of interest for theoretical and scientific reasons, the awareness of the above univariate associations may help to specify the concepts for developing interventions and programmes to reduce severe levels fear of falling in old age, particularly in their early stages of development. A further strength of our study was the attempt to separate fear of falling and the resultant avoidance of activity as outcomes; particularly the latter is under researched in previous studies. This is important, as while fear of falling in itself may be an unwelcome anxiety for an older person, it is the related avoidance of activity that is arguably more significant in terms of its effect on social engagement, functional decline, quality of life, and further falls, particularly when this avoidance is severe. Our work suggests that avoidance of activity in older people with severe levels of fear of falling may be particularly high in those of advanced age and with limitations in activities of daily living, people for whom continued independence may be especially fragile and who will need rapid intervention to maintain that independence.The strength of our study is that in contrast to previous studies we focused on secondary prevention) but also to specify the concepts for developing interventions and programmes to reduce fear of falling and avoidance of activity in old age, particularly in their early stages of development (tertiary prevention).We conclude that female sex, limitations in activity of daily living and one or more falls in the previous six months correlate independently with severe fear of falling. Higher age and limitations in activity of daily living correlate independently with severe avoidance of activity. Psychosocial variables did not contribute independently to the difference between mild and severe fear of falling and to the difference between mild and severe avoidance of activity due to fear of falling. However, old age, female sex, limitations in activity of daily living, impaired vision, poor perceived health, chronic morbidity, falls, low general self-efficacy, low mastery, loneliness, feelings of anxiety and symptoms of depression were identified as univariate correlates of severe fear of falling and avoidance of activity. Although the knowledge about the unique associations of specific variables with levels of severe fear of falling and avoidance of activity is of interest for theoretical reasons, the knowledge of univariate association may also help to identify older people at risk for severe levels of fear of falling and avoidance of activity (The authors declare that they have no competing interests.GIJMK designed the study as a part of a randomized controlled trial. GARZ and JCMvH collected the data. GIJMK analyzed the data and drafted the manuscript with contributions of KJM, KD, JCMvH and GARZ. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:"}
+{"text": "Liza haematocheila (syn. Mugil soiuy), native to the Western North Pacific, provides opportunities to examine the changes of its parasite fauna after its translocation to the Sea of Azov and subsequent establishment in the Black Sea. However, the information on macroparasites of this host in both ranges of its current distribution comes from isolated studies published in difficult-to-access literature sources.The mugilid fish Data from 53 publications, predominantly in Chinese, Russian and Ukrainian, were compiled from an extensive search of the literature and the Host-Parasite Database maintained up to 2005 at the Natural History Museum, London.L. haematocheila throughout its distributional range comprises summarised information for 69 nominal species of helminth and ectoparasitic crustacean parasites, from 45 genera and 27 families  and includes the name of the parasite species, the area/locality of the host capture, and the author and date of the published record. The taxonomy is updated and the validity of the records and synonymies are critically evaluated. A comparison of the parasite faunas based on the records in the native and introduced/invasive range of L. haematocheila suggests that a large number of parasite species was 'lost' in the new distributional range whereas an even greater number was 'gained'.The complete checklist of the metazoan parasites of L. haematocheila in its natural and introduced/invasive ranges cannot be dealt with the current data because of unreliability associated with the large number of non-documented and questionable records. This stresses the importance of data quality analysis in using host-parasite database and checklist data.Although the present checklist provides information that will facilitate future studies, the interesting question of macroparasite faunal diversity in  Liza haematocheila  , nativeisheries ; its expKazanski  predicteet al.  parasitise fish-eating birds  as adults. Unfortunately, the above picture is associated with a large number of non-documented records in the introduced/invasive range  of Gusev  may depart from the real situation in the region and should be treated with caution .The systematics of the species of . Shigin ; Niewiad. Shigin ). Furtheercariae -53. Any ercariae . TherefoL. haematocheila in its native and introduced/invasive range based on the records in the present checklist [L. haematocheila (1978 through 1984) attempted in the Azov Sea basin involved both fry and fish of different ages caught in the Amur and Ussuriisk bays of the Sea of Japan [i.e. Gyrodactylus mugili, G. zhukovi, Ligophorus kaohsiangsieni, L. llewellyni and L. pilengas) transferred to the new distributional areas of the host [A comparison of the parasite faunas of hecklist ,47,54-77the host ,22,35,42L. haematocheila in the Western North Pacific probably do not exist in the new areas (e.g. the absence of the mollusc intermediate host). Further support to the 'supply-side' ecology of parasite transmission provides the 'gain' of the large suite of larval parasite stages (16 species utilising fish as second intermediate and fish-eating birds as definitive hosts). Although this may reflect both high bird and mullet abundance in the areas studied , all Ramsar wetlands of international importance supporting hundred thousands migrating and overwintering birds, I consider these records questionable since none is documented .The replacement of the adult forms (notably the haploporid and haplosplanchnid digeneans) by 'alternative' species of the same families  can be considered a change related to the feeding habits of the host. This process appears to reflect biogeographical differences in the 'supply' since opportunities for transmission of the digenean species infecting L. haematocheila in its natural and introduced/invasive ranges cannot be dealt with the current data because of unreliability associated with the large number of non-documented and questionable records. This stresses the importance of data quality analysis in using host-parasite database and checklist data.Although the present checklist provides information that will facilitate future studies, the interesting question of macroparasite faunal diversity in The author declares that they have no competing interests.Liza haematocheila. Checklist of helminth and crustacean parasites of Liza haematocheila with documented (*) and questionable (?) records marked. Abbreviations: MS, Mugil soiuy; LH, L. haematocheila.Checklist of macroparasites of Click here for file"}
+{"text": "Rickettsial diseases, important causes of illness and death worldwide, exist primarily in endemic and enzootic foci that occasionally give rise to sporadic or seasonal outbreaks. Rickettsial pathogens are highly specialized for obligate intracellular survival in both the vertebrate host and the invertebrate vector. While studies often focus primarily on the vertebrate host, the arthropod vector is often more important in the natural maintenance of the pathogen. Consequently, coevolution of rickettsiae with arthropods is responsible for many features of the host-pathogen relationship that are unique among arthropod-borne diseases, including efficient pathogen replication, long-term maintenance of infection, and transstadial and transovarial transmission. This article examines the common features of the host-pathogen relationship and of the arthropod vectors of the typhus and spotted fever group rickettsiae."}
+{"text": "Meta-regression models were fitted considering linear and non-linear effects of alcohol intake. The effects of characteristics of the studies, of selected covariates (tobacco) and of the gender of individuals included in the studies, were also investigated as putative sources of heterogeneity of the estimates. A total of 235 studies including over 117\u2008000 cases were considered. Strong trends in risk were observed for cancers of the oral cavity and pharynx, oesophagus and larynx. Less strong direct relations were observed for cancers of the stomach, colon and rectum, liver, breast and ovary. For all these diseases, significant increased risks were found also for ethanol intake of 25\u2008g per day. No significant nor consistent relation was observed for cancers of the pancreas, lung, prostate or bladder. Allowance for tobacco appreciably modified the relations with laryngeal, lung and bladder cancers, but not those with oral, oesophageal or colorectal cancers. This meta-analysis showed no evidence of a threshold effect for most alcohol-related neoplasms. The inference is limited by absence of distinction between lifelong abstainers and former drinkers in several studies, and the possible selective inclusion of relevant sites only in cohort studies. \u00a9 2001 Cancer Research Campaign"}
+{"text": "The Receptor for Advanced Glycation Endproducts [RAGE] is an evolutionarily recent member of the immunoglobulin super-family, encoded in the Class III region of the major histocompatability complex. RAGE is highly expressed only in the lung at readily measurable levels but increases quickly at sites of inflammation, largely on inflammatory and epithelial cells. It is found either as a membrane-bound or soluble protein that is markedly upregulated by stress in epithelial cells, thereby regulating their metabolism and enhancing their central barrier functionality. Activation and upregulation of RAGE by its ligands leads to enhanced survival. Perpetual signaling through RAGE-induced survival pathways in the setting of limited nutrients or oxygenation results in enhanced autophagy, diminished apoptosis, and (with ATP depletion) necrosis. This results in chronic inflammation and in many instances is the setting in which epithelial malignancies arise. RAGE and its isoforms sit in a pivotal role, regulating metabolism, inflammation, and epithelial survival in the setting of stress. Understanding the molecular structure and function of it and its ligands in the setting of inflammation is critically important in understanding the role of this receptor in tumor biology. The Receptor for Advanced Glycation Endproducts [RAGE] is a member of the immunoglobulin superfamily, encoded in the Class III region of the major histocompatability complex -4. This RAGE is expressed as both full-length, membrane-bound forms  and various soluble forms lacking the transmembrane domain. Soluble RAGE is produced by both proteolytic cleavage of fl-RAGE and alternative mRNA splicing. The soluble isoforms include the extracellular domains but lack the transmembrane and cytoplasmic domains -15. Soluin vivo is are fl-RAGE, sRAGE, and esRAGE , Matthew Albert , W. Herve Fridman and Catherine Sautes , and David Chou  served as mentors in this program.LJS, DT, RK, HJZ, AAA, and MTL are part of a coalition of laboratories known as the DAMP Lab. It was formed in 2006 at University of Pittsburgh to focus on the role of Damage Associated Molecular Pattern Molecules [DAMPs] released or secreted by damaged or injured cells or the inflammatory cells responding to the \"danger\". Along with Dr. Michael E. de Vera and Dr. Xiaoyan Liang, they focus on the critical role of DAMPs in the initiation of chronic inflammation and the disease that often eventuates as a consequence, cancer."}
+{"text": "This is a report of a meeting sponsored by MundiPharma International to identify ways to exploit the cerebrospinal fluid system pharmacologically, for more effective management and prevention of primary and metastatic CNS tumors. The Science of Prevention: New Insights into the Importance of Intra-CSF Prophylaxis', was organized around several provocative theses to stimulate discussion of novel ways to treat, and even prevent, brain and meningeal tumors.Thirty investigators from numerous cancer research centers in the United States and Europe were convened by conference organizer, Michael Glantz (University of Utah School of Medicine \u2013 Huntsman Cancer Institute), to brainstorm the understanding of novel mechanisms, and the development of new paradigms involving the cerebrospinal fluid (CSF) system, for thwarting the spread and improving the treatment of nervous system cancers. This retreat brought oncologists and clinical neuroscientists to St. Thomas, Virgin Islands on February 22\u201324, 2007. The conference, entitled 'Pathophysiogically and pharmacologically, the CSF is an important circulatory system in the brain and spinal cord that, on the one hand disseminates malignant cells, but on the other hand might be harnessed to distribute corrective chemotherapeutic drugs. As knowledge of the CSF system increases, so do the opportunities for managing brain cancer. Successful CSF prophylaxis for medulloblastoma and acute leukemia could well serve as a paradigm for more effective treatment of lymphomas. Conference introductory keynotes by Ching-Hon Pui  and Eckhard Thiel (Charite University Medicine Berlin) provided historical perspective and state-of-the-art reviews on acute leukemia and non-Hodgkin's lymphoma. Michael Glantz then addressed the feasibility of a randomized, controlled trial of CSF prophylaxis in patients with high-risk non-Hodgkin's lymphoma. The treatment-refractory glioblastoma multiforme, in dire need of a new therapeutic model, was addressed by Lawrence Recht  who analyzed gliomagenesis in the context of growth factor effects on cancer stem cells in the subventricular zone. Utilizing new basic science information, Glantz then proposed a phase II trial incorporating intra-CSF chemotherapy into the initial treatment of patients with newly diagnosed glioblastoma multiforme.Three decades of experience with neoplastic meningitis (NM) has afforded many clinical insights on treatment, but cures remain exceedingly rare, and controversy persists regarding the most basic tenets. Marc Chamberlain (Fred Hutchinson Cancer Center) reviewed prognostic variables within subgroups of patients with solid tumor neoplastic meningitis, and urged tumor-specific strategies for CSF-directed therapy. However, the whole concept of intrathecal chemotherapy as a treatment for solid tumor NM was questioned by Willem Boogerd (Netherlands Cancer Institute) who emphasized the urgent need for a randomized clinical trial to address this issue, and presented such a proposal on behalf of the European Organisation for Research and Treatment of Cancer (EORTC). The rationale and techniques for treating malignant cells in CSF were discussed by William Shapiro , while the expectations for significantly improving survival in solid-tumor patients were outlined by Stuart Grossman . Conrad Johanson  introduced the potential role of pharmacologically modifying choroid plexus function to treat or prevent cancer spread along the ventriculo-subarachnoid CSF system. Recognizing the limitations of CSF cytology and magnetic resonance scanning, Glantz outlined the need for more sensitive techniques to diagnose CSF malignancies and evaluate treatment outcomes. The importance of novel markers for diagnosing and monitoring responses in NM and lymphomatous meningitis was extensively treated by Morris Groves (M.D. Anderson Cancer Center) and Wyndham Wilson .The final session of the conference was both practical and visionary. Clinical trials, both newly completed and projected, were discussed. New insights for protecting against brain metastases (including lung and breast cancer) were delineated by Wallace Akerley (University of Utah School of Medicine \u2013 Huntsman Cancer Institute), Frankie Holmes (Baylor College of Medicine) and Ricardo Soffietti (University of Turin). Gudrun Fleischhack  introduced opportunities for pediatric primary brain tumor initiatives, while Ulrich Herrlinger (University of Bonn) discussed primary central nervous system lymphoma. Randy Jensen (University of Utah School of Medicine \u2013 Huntsman Cancer Institute) reviewed the evidence in favor of post-neurosurgical prophylaxis. Finally, Jennifer Smith (Geron Corp) treated statistical issues in designing critical trials, including identifying predictive and prognostic markers. She also offered advice on clinical trial proposals developed during the conference.Science of Prevention conference was the first of its kind to focus on the CSF as a medium around which to marshall research and clinical strategies for preventing and treating brain cancer. Brain tumor development or spread, from both the pathologic and the pharmacologic point of view, is critically dependent upon functional relationships between CSF dynamics and brain metabolism. Considerably more information is needed about CSF-bordering cells  in order to more effectively thwart dissemination of cancer cells throughout the CSF and interstitial fluid compartments. Also, analysis of primary brain tumor development in the subventricular zone deserves more attention as a site for modulating (by growth factors and antagonists) stem cell oncogenicity. The efficacy of intrathecal versus combined intrathecal and systemic administration of chemotherapeutic drugs also merits more attention. Clearly new CSF markers and diagnostic techniques are essential for improving disease identification and monitoring response to therapy in a class of diseases which continues to challenge oncologists, neurologists, neurosurgeons, basic scientists, and, most especially, patients. As a result of this conference, the rationale for expanding the intra-CSF prophylaxis approach to brain and meningeal tumors has now been more sharply defined.This The author(s) declare that they have no competing interests.Both authors contributed equally to this report and have read and approved the final version of the manuscript."}
+{"text": "In this manuscript, the information available on the molecular epidemiology of HBV in India has been reviewed and the results of studies among the eastern Indian population have been summarised.Hepatitis B virus (HBV) is one of the major global public health problems. In India, HBsAg prevalence among general population ranges from 2% to 8%, placing India in intermediate HBV endemicity zone and the number of HBV carriers is estimated to be 50 million, forming the second largest global pool of chronic HBV infections. India is a vast country, comprised of multiracial communities with wide variations in ethnicity and cultural patterns, which is attributable to its geographical location, gene influx due to invasion and/or anthropological migrations in the past. Moreover, recent increase in trade, trafficking and use of illicit drugs has also considerably influenced the epidemiology of HBV, specifically in the eastern and north eastern parts of India. However, data on the molecular epidemiology of HBV in India is scanty. HBV genotypes A and D have been well documented from different parts of mainland India. Interestingly, in addition to genotypes A and D, genotype C having high nucleotide similarity with south East Asian subgenotype Cs/C1 strain, have been detected exclusively from eastern Indian HBV carriers, suggesting a recent introduction. Thus, compared to other parts of India, the molecular epidemiology of HBV is naturally distinct in eastern India. Very recently, taking the advantage of circulation of three distinct HBV genotypes within the population of eastern India, different aspects of HBV molecular epidemiology was studied that revealed very interesting results. In this study, the clinical significance of HBV genotypes, core promoter and precore mutations, possible routes of introduction of HBV genotype C in eastern India, the clinical implications of  About 30 percent of the world's population has serological evidence of current or past infection with HBV. Of these, an estimated 350 million are chronically infected with HBV and approximately 1 million persons die annually from HBV-related chronic liver diseases, including severe complications such as liver cirrhosis (LC) and HCC .In conclusion, the results of this thesis sheds light on many important aspects of HBV molecular epidemiology that are very much important for identifying the population at risk of acquiring HBV and developing severe disease, and also pose a risk of transmission through different modes. This information are essential for determining the risk factors associated with HBV infections, to formulate necessary preventive measures to lessen the burden of new infections and spread of newly introduced genotype to other parts, from eastern India. Moreover, considering the higher pathogenic potentials associated with certain HBV genotypes, the results of the thesis work will be helpful in prognosis and better management of HBV infected subjects.Emergence of new genotypes/subgenotypes, clinically important mutations have immense importance in determining the clinical outcome, efficacy of vaccination and therefore strict surveillance of these variants are extremely important. Hope that the present study will advance the understanding of changing molecular epidemiology of HBV, and will also help in formulation of effective preventive measures. Last but most important, the results of this thesis work, demonstrating compartment specific high prevalence of HBV DNA associated with vaccine/immune escape mutation in the PBL of HBsAg negative subjects have extremely important implications in the field of transfusion medicine, organ transplantation, and in vaccination strategies, and thus need further investigations. Finally, together with contributing unique data on molecular epidemiology of HBV in India, this thesis work also open new avenues for further studying the molecular virology of HBV.The author declares that they have no competing interests.The author studied Zoology at the Bachelor and Master Degree level and later joined the Indian Council of Medical Research Virus Unit, for doctoral research. He specializes in the fields of molecular diagnostics, epidemiology, evolution and genomics of viruses.Molecular Epidemiology of Hepatitis B virus in Eastern India: Role of Genotypes, X gene Variability and Disease Outcome\", which has been approved by the doctoral committee of Jadavpur University, for the award of PhD degree.The author compiled the above information for writing the background section of his doctoral thesis entitled \""}
+{"text": "Integrated vector management (IVM) is defined as \"a rational decision-making process for the optimal use of resources for vector control\" and includes five key elements: 1) evidence-based decision-making, 2) integrated approaches 3), collaboration within the health sector and with other sectors, 4) advocacy, social mobilization, and legislation, and 5) capacity-building. In 2004, the WHO adopted IVM globally for the control of all vector-borne diseases. Important recent progress has been made in developing and promoting IVM for national malaria control programmes in Africa at a time when successful malaria control programmes are scaling-up with insecticide-treated nets (ITN) and/or indoor residual spraying (IRS) coverage. While interventions using only ITNs and/or IRS successfully reduce transmission intensity and the burden of malaria in many situations, it is not clear if these interventions alone will achieve those critical low levels that result in malaria elimination. Despite the successful employment of comprehensive integrated malaria control programmes, further strengthening of vector control components through IVM is relevant, especially during the \"end-game\" where control is successful and further efforts are required to go from low transmission situations to sustained local and country-wide malaria elimination. To meet this need and to ensure sustainability of control efforts, malaria control programmes should strengthen their capacity to use data for decision-making with respect to evaluation of current vector control programmes, employment of additional vector control tools in conjunction with ITN/IRS tactics, case-detection and treatment strategies, and determine how much and what types of vector control and interdisciplinary input are required to achieve malaria elimination. Similarly, on a global scale, there is a need for continued research to identify and evaluate new tools for vector control that can be integrated with existing biomedical strategies within national malaria control programmes. This review provides an overview of how IVM programmes are being implemented, and provides recommendations for further development of IVM to meet the goals of national malaria control programmes in Africa. Malaria and other vector-borne diseases contribute substantially to the global burden of diseases and disproportionately affect poor and under-served populations living in tropical and sub-tropical regions [The control of vector-borne diseases represents one of the greatest global public health challenges of the 21 regions . In the Integrated vector management (IVM) is not a new concept and the basic principles of IVM have been used over the past century in the U.S.A. and elsewhere for mosquito control. An example includes the vast network of Mosquito Abatement Districts throughout the U.S.A. -9. TheseAll the tactics of standard vector control are included in the IVM approach. IVM goes beyond the integration of traditional control measures to emphasize strategies to make vector control programmes compatible with national health systems. IVM also incorporates decision-making based on human and institutional resources, and engages communities to promote sustainability. IVM encourages integrative, multi-disease approaches and promotes the systematic application of different interventions in combination and in synergy with each other. The framework for implementation strategies extends beyond the health sector and involves multiple stake-holders. To promote success, IVM requires continual monitoring, evaluation and legislation, linked with a strong commitment and concerted action by governments and international organizations .In 2004, the global strategic framework for IVM was prepared establishing new, broad principles and approaches to vector control that are applicable to all vector-borne diseases . IVM wasmost programme managers are unaware of this possibility that an integrated approach can, in principle, be introduced without additional resources\"; 2) over-sophistication of integrated control: \"in short, for many mosquito species enough is already known ....to base the introduction of integrated control\"; 3) insufficient conviction of the advantages of integrated control; 4) misconceptions about the use of pesticides in integrated control: \"project managers need to be assured that integrated control does not, nor cannot, mean exclusion of pesticides, but their more rational and correct use.\"; and 5) insufficient consciousness of comparative costs, effectiveness, benefits and risks: \"application of pesticides, especially via indoor residual spraying (IRS), frequently becomes a routine practice, regardless of the need or the results obtained\" [Historically, the implementation of integrated approaches to vector control has been a slow and complicated process. In the 1970's, WHO listed five reasons for the slow uptake of integrated vector control: 1) over-estimation of the requirements of integrated control: \"btained\" . Additioeffective IVM requires the establishment of principles, decision-making criteria and procedures, together with time-frames and targets\" [Like traditional approaches to vector control, IVM relies on an understanding of how environmental factors affect the distribution and densities of different species of vectors, and how effectively control measures reduce vector-human contact, vector survival and the overall intensity of pathogen transmission. IVM expands on traditional approaches to vector control in that collaboration with local communities, other stakeholders , and public health regulatory and legislative frameworks support the evolution of vector control. Programmes seeking to implement IVM must appreciate that \"targets\" ,16. ThesFigure Advocacy, social mobilization and legislation. Promotion and embedding of IVM principles in the development policies of all relevant agencies, organizations and civil society; establishment or strengthening of regulatory and legislative controls for public health and pesticide management; empowerment of communities.\u2022 Collaboration within the health sector and with other sectors. Consideration of all options for collaboration within and between public and private sectors; strengthening channels of communication among policymakers, vector-borne disease control programme managers and other IVM partners.\u2022 Integrated approach. Ensure rational use of available resources through a multi-disease control approach, integration of non-chemical and chemical vector control methods, and integration with other disease control measures, such as active and passive case detection and treatment.\u2022 Evidence-based decision-making. Adaptation of strategies and interventions to local vector ecology, epidemiology and resources, guided by operational research and subject to routine monitoring and evaluation.\u2022 Capacity-building. Development of essential physical infrastructure, financial resources and adequate human resources at local and national levels to manage IVM programmes based on needs assessments.\u2022 Are malaria vector control approaches involving ITNs and IRS sufficient? Where and when are they effective? What else is needed to eliminate the remaining low-levels of transmission? There is also a strong case for implementing larval control to target immature stages of anopheline mosquitoes to reduce malaria transmission [Plasmodium falciparum and Plasmodium vivax malaria will take at least another 50 years [Throughout Africa, National Malaria Control Programmes have recently embarked on emphasizing vector control as an essential component ,17. Mostsmission -27, but smission . Even wi50 years .In developing countries, Ministries of Health are normally charged with mosquito control as part of their overall public health programme, although lines of responsibility and organizational networks vary according to different countries. National guidelines are often developed with input from international organizations, such as the WHO and the CDC; these guidelines influence the strategies and tools employed for control programmes that are carried out by decentralized units of the government. However, there are many reasons why vector-borne diseases remain a major public health problem: 1) entomologists and vector-control specialists often fail to convince decision-makers of the importance of sound vector control; 2) intersectoral collaboration has been recommended as a method to improve mosquito control, but in practice, this type of collaboration has proved difficult; 3) modeling and adaptive management have not been used effectively to quantify the effect of disease and vector control interventions on the economic and social development of communities and nations; 4) failed management of insecticides has created a conflict of \"to spray or not to spray\"; 5) there has been a failure to connect the true disease burden with other societal burdens to establish the public health importance of vector-borne diseases in low-transmission settings; 6) the interaction between proper utilization of law enforcement and health education has not been explored in sufficient detail; 7) economics plays a central role in mosquito-borne disease control but has not been fully integrated in the evaluation of disease control programmes; 8) entomologists and public health specialists have failed to convince decision-makers that they have an ethical duty to control mosquitoes and the pathogens they transmit; and 9) biomedical strategies, such as active and passive case-detection and treatment, are often used instead of preventative vector control measures, as a result of international donor requirements.A comparative evaluation of vector-control programmes in five countries  suggestsProgress in implementing IVM continues to be slow. In an Institute of Medicine review of Vector Borne Diseases, David Morens cites five fundamental deficiencies that inhibit our ability to find realistic solutions for vector-borne disease problems: deterioration of public health infrastructure, lack of adequate funding, lack of adequate training and training models, over-specialization in the biomedical sciences, driven by emerging technology and emphasis on the basic sciences, and bureaucratization . If IVM A recent report by Chanda et al.  describeWhile much remains unknown about the impact of fully developed IVM programmes on malaria transmission -36, the Castro and colleagues  describeOne of the largest integrated disease control schemes developed in the 1980's was the Blue Nile Health Project . The 10-Sri Lanka has long linked vector control with agricultural development. In the 1970s and 1980s, the Mahaweli River hydroelectric and irrigation development project caused new foci of malaria transmission to emerge around Kandi. The hydrological changes and the relocation of people between malaria endemic and non-endemic areas as a result of resettlement due to the dam reservoirs, contributed to an upsurge in malaria  and JapaEritrea uses national-level ITN distribution strategies, larval habitat management in malarious areas, and indoor residual spraying in areas with the appropriate eco-epidemiological characteristics. Although Eritrea has seen a marked drop in malaria parasite prevalence and disease, no rigorous evaluation of the IVM activities linked to health outcomes has been done. Among the reasons why impact evaluation exercises have not been done are cost and time. In many instances, not enough resources are allocated for the proper evaluation of an intervention programme, forcing the use of a less rigorous study designs for establishing causal inference.IVM should be seen as a framework and a strategy rather than a circumscribed, tactical intervention. As such there are a large number of African national malaria control programmes that incorporate some, but possibly not at the present time, all of the IVM elements. \"Community-based\" IVM programmes incorporating larval source management have recently been implemented in two different settings: in Rusinga Island, Western Kenya , and in The implementation of IVM requires a needs assessment of vector control capability through:Policy needs: reform and adjustment of the policy framework which provides the enabling environment for vector control;\u2022 Institution building needs: the strengthening of existing institutions and the arrangements between them that aim at facilitating vector control;\u2022 Managerial development needs: the establishment of clear criteria and decision-making procedures to manage the vector control programme;\u2022 Technical strengthening: development of the technical facilities to support vector control programmes;\u2022 Human-resource development needs: the formation and in-service training of personnel in the relevant disciplines and skills.\u2022 Community participation; this will ensure the sustainability of control approaches.\u2022 Needs assessments of vector control capability must identify approaches that will assure that the elements from Table IVM in the Africa region was launched at a regional workshop of policy makers and vector control specialists in Harare in February 2001. From that workshop a strategic plan was further developed to initiate the implementation of IVM in Africa.Subsequently, a series of regional IVM training workshops were organized in Nairobi, Kenya in 2002 and 2004, and in Accra, Ghana in 2003. A total of 31 participants from 23 countries, including entomologists and vector control specialists working with Ministry of Health disease control programmes and Ministries of the Environment, attended the workshops .National plans of action were prepared and implementation of IVM was started in 16 countries. Vector-control needs assessments and the organization of national consensus workshops on IVM have been conducted in nine countries. In order to support all these efforts, the \"Partnership for IVM in Africa\", called \"IVM Africa,\" was founded in Harare with six organizations initially: WHO, UNEP, ICIPE, the USAID Environmental Health Project (EHP), The Hashimoto Initiative, and the Panel of Experts on Environmental Management (PEEM) .There is a rapidly increasing number of programmes incorporating ITNs with IRS . For exaThe Global Malaria Business Plan and a recent technical review of Global Malaria Control and Elimination  recognizThere is a need to show that IVM approaches are being implemented and that they are making an impact. In addition to the basic requirements for implementing IVM at the national level for malaria control, further coordinated national and international efforts and financial support are needed to achieve the following:\u2022 Strengthen capacity-building for IVM at national level, improve the scope and quality of regional IVM training initiatives, and support post-graduate education.\u2022 Further promote interdisciplinary integration and inter-sectoral cooperation by engaging appropriate stake-holders at the national level, including community groups and NGOs, and engaging experts from outside traditional entomological and public health frameworks for vector-borne disease control.\u2022 Promote the incorporation of emerging technologies in database management, information systems, and communication into the IVM strategy for better national and regional level operations.\u2022 Develop novel training models that also have interaction components among entomologists in the field, health-care workers in the clinics and decision-makers in national and local government offices.\u2022 Support research that further elaborates approaches and tactics needed to combat malaria, especially for low-transmission settings where national programmes have successfully reduced levels of transmission and are now pursuing or moving toward country-wide elimination.\u2022 Support research in options for improving strategic management and decision-making to more comprehensively integrate IVM strategies into national malaria control programmes.\u2022 Support international research to develop new tools for malaria vector control, including new generation insecticides, new biological control strategies, new trapping methods, and innovative methods that target mosquitoes at different points in their life history cycles .\u2022 Identify and support activities that establish long-term partnerships between national malaria control programmes and international experts and institutions to strengthen capacity building and operational research components of IVM programmes.\u2022 Establish and fund IVM demonstration projects across different malaria-endemic environments to illustrate the importance of integrated IVM approaches for vector-borne disease control.\u2022 Increase research on the financial and economic costs of IVM including projected estimates of IVM, real-world cost-effectiveness calculations of IVM programmes from demonstration projects, and financial and economic models related to scaling-up IVM in Africa.IVM: Integrated Vector Management; ITNs: Insecticide-treated bednets; IRS: Indoor Residual spraying; WHO: World Health Organization; CDC: Centers for Disease Control; FAO: Food and Agriculture Organization; NGOs: Non-governmental organizations; UNEP: United Nations Environment Programme; ICIPE: International Centre of Insect Physiology and Ecology; USAID: United States Agency for International Development; LLINs: Long-lasting insecticide-treated bednets; NMCPs: National Malaria Control Programmes.The authors declare that they have no competing interests.JCB conceived the review concept, organized the draft sections, co-wrote sections of the draft and edited the overall manuscript. JK participated in the conception, helped organize the draft sections, co-wrote sections of the draft and helped in editing the overall manuscript. JIG participated in the conception and helped in editing the overall manuscript. MBM participated in the conception, co-wrote sections of the draft, and helped in editing the overall manuscript. DEI co-wrote and edited sections of the manuscript and formatted the draft for submission. RJN participated in the conception, provided specific IVM information, co-wrote sections of the manuscript and helped in editing the overall manuscript."}
+{"text": "An automated apparatus to assist in the development of analyticalcontinuous flow methods is described. The system is capable ofcontrolling and monitoring a variety of pumps, valves, anddetectors through an IBM PC-AT compatible computer. Systemcomponents consist of two types of peristaltic pumps (including amultiple pump unit), syringe pumps, electrically and pneumaticallyactuated valves, and an assortment of spectrophotometric andelectrochemical detectors. Details of the interface circuitry are givenwhere appropriate. To demonstrate the utility of the system, anautomatically generated response surface is presented for the flowinjection determination of iron(II) by its reaction with1,10-phenanthroline."}
+{"text": "Transposable elements are the most abundant components of all characterized genomes of higher eukaryotes. It has been documented that these elements not only contribute to the shaping and reshaping of their host genomes, but also play significant roles in regulating gene expression, altering gene function, and creating new genes. Thus, complete identification of transposable elements in sequenced genomes and construction of comprehensive transposable element databases are essential for accurate annotation of genes and other genomic components, for investigation of potential functional interaction between transposable elements and genes, and for study of genome evolution. The recent availability of the soybean genome sequence has provided an unprecedented opportunity for discovery, and structural and functional characterization of transposable elements in this economically important legume crop.Using a combination of structure-based and homology-based approaches, a total of 32,552 retrotransposons (Class I) and 6,029 DNA transposons (Class II) with clear boundaries and insertion sites were structurally annotated and clearly categorized, and a soybean transposable element database, SoyTEdb, was established. These transposable elements have been anchored in and integrated with the soybean physical map and genetic map, and are browsable and visualizable at any scale along the 20 soybean chromosomes, along with predicted genes and other sequence annotations. BLAST search and other infrastracture tools were implemented to facilitate annotation of transposable elements or fragments from soybean and other related legume species. The majority (> 95%) of these elements (particularly a few hundred low-copy-number families) are first described in this study.SoyTEdb provides resources and information related to transposable elements in the soybean genome, representing the most comprehensive and the largest manually curated transposable element database for any individual plant genome completely sequenced to date. Transposable elements previously identified in legumes, the third largest family of flowering plants, are relatively scarce. Thus this database will facilitate structural, evolutionary, functional, and epigenetic analyses of transposable elements in soybean and other legume species. Transposable elements (TEs) are the most abundant genomic components in flowering plants. For example, approximately 40% of the rice genome  and 80% Pack-MULEs in rice . In addition, genes captured by TEs and TEs that carry gene fragments in soybean and these relatives will be identified, classified and integrated into the database in the context of the comparative genome maps of multiple species.Future SoyTEdb development includes the integration of TE data from http://www.soytedb.org, which is publicly accessible. These data are freely available without any restrictions to use by non-academics.All TEs or subsets of TEs can be downloaded from the SoyTEdb website LINE: Long interspersed repetitive element; LTR: Long terminal repeat; SoyTEdb: Soybean Transposable Element Database; TE: Transposable element; TSD: Target site duplication; WGS: whole genome shotgun sequencing.JD, ZT and LZ identified transposable elements. DG and RTN constructed the web-based database and helped to draft the manuscript. RCS and JM conceived of the study, participated in its design and corordination, and drafted the manuscript, and served as principle investigators of the project. All authors read and approved the final manuscript."}
+{"text": "TGF-beta is the prototype of a large family of multifunctional regulatory proteins. The principal sources of the peptide, platelets and bone, suggest that it plays a role in healing and remodeling processes. In vitro, TGF-beta is chemotactic for monocytes and fibroblasts and can greatly enhance accumulation of extracellular matrix components by fibroblasts. Its ability to stimulate the formation of granulation tissue locally and the demonstration of specific time- and tissue-dependent expression in embryogenesis suggest that similar mechanisms are operative in vivo. By analogy to its effects in wound healing and embryogenesis, it is proposed that TGF-beta, secreted by tumour cells, can augment tumour growth indirectly by effects on the stromal elements. These effects include suppression of the immune response, and enhancement of both angiogenesis and formation of connective tissue. Many tumour cells have escaped from direct growth inhibitory effects of TGF-beta by a variety of mechanisms including inability to activate the latent form of the peptide, loss of cellular receptors for TGF-beta, and loss of functional intracellular signal transduction pathways."}
+{"text": "Central and northern Europe are now at risk from bluetongue virus. Keywords: Bluetongue, BTV-8, epidemiology, cattle, sheep, Europe, disease perspectives, vectorial capacity, vector competence, vaccination, perspective Bluetongue (BT) is a reportable disease of considerable socioeconomic concern and of major importance in the international trade of animals and animal products. Before 1998, BT was considered an exotic disease in Europe. From 1998 through 2005, at least 6 BT virus strains belonging to 5 serotypes  were continuously present in the Mediterranean Basin. Since August 2006, BTV-8 has caused a severe epizootic of BT in northern Europe. The widespread recrudescence and extension of BTV-8 infections in northern Europe during 2007 suggest that requirements for BTV establishment may now be fulfilled in this area. In addition, the radial extension of BTV-8 across Europe increases the risk for an encounter between this serotype and others, particularly those that occur in the Mediterranean Basin, where vector activity continues for more of the year. This condition increases the risk for reassortment of individual BTV gene segments. Bluetongue virus (BTV). The virus belongs to the family Reoviridae, genus Orbivirus; there are 24 serotypes (Bluetongue (BT) is an infectious but noncontagious viral disease caused by BT is a World Organization for Animal Health reportable disease and is of considerable socioeconomic concern and of major importance in the international trade of animals and animal products  since BTV\u2019s introduction in 1998. To this effect, we provide a short overview of the epidemiologic situation in Europe, followed by a brief description of the susceptible species, a discussion of the vectorial capacity and competence of the Culicoides imicola (Kieffer), which is an Afro-Asiatic species of biting midge  have been continuously present in parts of the Mediterranean Basin, including several member states of the EU   (C. obsoletus (Meigen) and C. scoticus (Downes and Kettle), collected in central Italy (C. pulicaris (Linnaeus) in Sicily  (C. dewulfi (Goetghebuer) in the Netherlands were positive by PCR for BTV  were also PCR positive for BTV   (19). In for BTV . AlthougCulicoides spp. were captured in animal housing during the winter period   .Culicoides biting midge  and a few deer species   conditions. Vector capacity can be defined as the number of infective bites that an infected vector causes during its lifetime  or inanimate  means; through the active flight of infected vector Culicoides spp. ; and through passive flight of infected vector Culicoides spp. on the wind (responsible for long-distance dissemination).Introduction of BTV from 1 area into another can occur in 4 ways: through animal movement (domestic and wild ruminants) or animal product transport ; by infected vector Culicoides spp. becoming infected by feeding upon local viremic hosts, surviving long enough to ensure completion of the intrinsic incubation period , and transmitting the virus by bite to new hosts . In addition, the radial extension of BTV-8 across Europe (including the jump across the English Channel)    (39) incChannel)  .C. imicola, the Afro-Asiatic vector of BTV, occurs in addition to the C. obsoletus complex. As the population abundance of C. imicola peaks later in the year than the Obsoletus complex, this means that virus may be transmitted for a much greater portion of the year.Furthermore, in the southern epidemiologic system, With regard to prophylaxis, possibly the best strategic option for control of clinical BT outbreaks in the European endemic areas is vaccination of susceptible animals with inactivated vaccines to protect against disease and to exclude the possibility of reversion to virulence of the vaccine viruses and reassortment between vaccine and field strains of the virus ("}
+{"text": "Risks of being thin and stunted were higher if girls had general morbidity in the last fortnight and foul-smelling vaginal discharge than their peers. Consumptions of non-staple good-quality food items in the last week were less frequent and correlated well positively with the household asset quintile. Girls of the highest asset quintile ate fish/meat 2.1 (55%) days more and egg/milk two (91%) days more than the girls in the lowest asset quintile. The overall dietary knowledge was low. More than half could not name the main food sources of energy and protein, and 36% were not aware of the importance of taking extra nutrients during adolescence for growth spurt. The use of iron supplement was 21% in nutrition-intervention areas compared to 8% in non-intervention areas. Factors associated with the increased use of iron supplements were related to awareness of the girls about extra nutrients and their access to mass media and education. Community-based adolescent-friendly health and nutrition education and services and economic development may improve the overall health and nutritional knowledge and status of adolescents.This study estimated the levels and differentials in nutritional status and dietary intake and relevant knowledge of adolescent girls in rural Bangladesh using data from the Baseline Survey 2004 of the National Nutrition Programme. A stratified two-stage random cluster-sampling was used for selecting 4,993 unmarried adolescent girls aged 13\u201318 years in 708 rural clusters. Female interviewers visited girls at home to record their education, occupation, dietary knowledge, seven-day food-frequency, intake of iron and folic acid, morbidity, weight, and height. They inquired mothers about age of their daughters and possessions of durable assets to divide households into asset quintiles. Results revealed that 26% of the girls were thin, with body mass index (BMI)-for-age <15 Childhood undernutrition, highly prevalent in South Asia , continuAdolescence is a unique intervention point in the life-cycle for a number of reasons . Early aIn developing countries, factors associated with undernutrition of adolescents are: poor household economic condition, periodic food-shortage, child-labour (marker of household income-poverty), burden of disease, poor knowledge about long-term consequences of undernutrition of adolescents, quantity and quality of food, and access to health and nutrition services . In BangDietary knowledge and access to resources are critical to improve health and nutrition in a sustainable way. Adolescence is the time to learn and adopt healthy habits to avoid many health and nutritional problems later in life . AdolescTo combat the high prevalence of micronutrient deficiencies, the Government of Bangladesh recommends supplementation of micronutrients , 13. TheNutrition promoters need information on levels and differentials in undernutrition of adolescents, burden of disease, dietary knowledge, and intake and coverage of iron supplement to meet the needs of those who need them most. The objectives of this study were to provide them with such information that would assist in planning for remedial actions to address health and nutrition needs of adolescent girls in Bangladesh.This study used data from the Baseline Survey 2004 of the National Nutrition Programme (NNP) conducted in rural areas of Bangladesh. The NNP is the successor to the Bangladesh Integrated Nutrition Project (BINP), which was launched in 1994. The BINP expanded its activities in phases and continued up to 2003. The community-based nutrition centres run by female community nutrition promoters (CNPs) were the focus of the BINP activities. The CNPs imparted health and nutrition education to mothers of children aged less than two years (under-two children), adolescent girls, and pregnant women; monitored growth of under-two children; and provided food supplements to severely-underweight and growth-faltered under-two children and to undernourished pregnant women (BINP implementation plan 1994). They organized never-married adolescent (out-of-school and schoolgoing) girls of the community to form Adolescent Girls Forum and to hold its meeting monthly to discuss their health, nutrition and social safety issues and distributed iron and folic acid tablets to the participants of the meeting.A stratified two-stage random cluster-sampling was used for selecting 5,028 never-married adolescent girls aged 13\u201318 years from 708 clusters in 113 upazilas (subdistricts) spread in all six administrative divisions (strata) of Bangladesh. The first stage was the random selection of clusters from cluster lists in programme and non-programme upazilas where each cluster contains about 300 households. The second stage was the random selection of nine unmarried adolescent girls from each cluster of the NNP and comparison upazilas and six unmarried adolescent girls from each cluster of the BINP upazilas for interview. Upazilas were grouped into BINP upazilas, NNP upazilas (where NNP activities were yet to start), and comparison upazilas (selected to assess the effects of NNP interventions later). Analysis included 4,993 never-married adolescent girls aged 13\u201318 years (excluded were 35 girls with flagged BMI-for-age or height-for-age z-score).Female interviewers, trained by social scientists and nutritionists, visited adolescent girls at their homes with a structured questionnaire to obtain consent of parents and to collect data on health and nutrition status of the adolescent girls. Field supervisors checked work of the field interviewers daily to ensure the quality of data collected in the field. Interviewers inquired girls about their education, occupation, and access to electronic and print media. Education was measured with grade passed and categorized as: up to primary (passed grade 5 or less) and secondary or above (passed grade 6 or more). Access to media was considered high if she had listened to radio or watched television at least weekly or read a newspaper or magazine (no matter how frequent it was); otherwise, it was considered low.To assess their dietary knowledge, a checklist of food items  was used. Girls were asked to name the check-listed foods that provide mainly energy, protein, vitamin, and minerals. They were asked if they were aware of the importance of taking extra nutrients during adolescence and use of iron supplements to assess their dietary knowledge and intake. Despite the possibility of recall bias, the girls were asked about the seven-day food-frequency questions to assess eating patterns of energy, protein, fat, and vitamin- and mineral-rich food items. A checklist was used for recording general morbidity symptoms they had experienced in the preceding two weeks. The checklist included fever, cough/cold, diarrhoea/dysentery, stomachache, respiratory problems, ear and eye problems, skin problems, and others. The girls were asked privately about menstrual irregularities, avoidance of any food during last menstruation, and passage of white discharge with foul smell. Self-reported morbidity symptoms were taken at face value.th percentile value of the WHO growth reference for girls refers to severely thin and BMI-for-age in between the 5th and the 15th percentile value refers to moderately thin. BMI-for-age below the 15th percentile value and height-for-age z-score <-2SD were used in measuring the prevalence of thinness and stunting respectively.Weight, height, and mid-upper arm circumference (MUAC) of the girls were measured by Uniscales, locally-made height scales and TALC (Teaching Aid at Low Cost) tape respectively. Weight and height were used for computing BMI and height-for-age z-score using the WHO growth reference for school-age children and girls , 15. BMIMothers were inquired about age or date of birth of their daughters and household possessions of durable items. A local calendar was used for determining age or date of birth accurately. Misreporting, particularly under-reporting of age, is likely and so are the underestimation of the prevalence of stunting and thinness. Household durables included bed-stand, chair, table, cupboard, radio, television, bike (including motor bike), land owned, wall material of the main dwelling unit , and type of toilet used. The principal components analysis of household durable assets retained one factor and assigned factor score to each household . The higBivariate and logistic regression techniques were used for estimating the differentials in nutrition status, dietary consumption, and knowledge and intake of iron supplement. The differentials included age, education, morbidity, access to mass media, household asset quintile, and type of upazila (proxy for exposure to the community-based nutrition education project). Bivariate differentials are shown in terms of prevalence (in %) and mean of seven-day food intake. Logistic regression  was used in estimating the differentials, controlling simultaneously for others and expressed as odds ratios.The sampled girls were mostly young because some older ones got married and did not fit the inclusion criteria . A very The burden of disease measured with self-reported morbidity was quit high; 33% of the girls had one or more morbidity symptoms in the last two weeks . Morbidith percentile value of BMI-for-age for girls), 16% moderately thin , and 0.3% obese   . The ageStunting (measured with height-for-age z-score <2SD) was prevalent among 32% of the girls, and its prevalence increased with increase in age. Girls with symptomatic RTI and lower education were more likely to be stunted than their counterparts. Knowledge of girls about the need for extra nutrients in adolescence, exposure to mass media, and household asset quintile were not associated with the prevalence of stunting.dal (lentils), fruits, and leafy vegetables, were not frequent in rural areas  in the last seven days was universal with no difference between the asset quintiles (data not shown). Consumptions of non-staple food items, such as meat, eggs, al areas . Half ofTo estimate the economic differentials in consumptions of protein- and fat-rich foods, we grouped together fish and meat  and egg and milk . The mean frequencies of eating fish/meat and egg/milk were 4.7 and 3.3 days respectively . The houdal (lentils) (21%), meat (32%), and fish (43%). Knowledge on vitamin- and mineral-rich foods was common; 75% mentioned vegetables, and 51% mentioned fruits as vitamin- and mineral-rich foods.Knowledge of adolescents on common food sources of energy and protein was limited. When asked to name main food sources of energy, 31% mentioned rice and 12% mentioned wheat, and these are correct responses (data not shown). Less than half correctly named high-protein foods: Two-thirds (64%) of the girls were aware of the need to take extra nutrients during adolescence to attain growth spurt . FactorsThe results of the study revealed that, in rural Bangladesh, the prevalence of thinness and stunting among the adolescent girls aged 13\u201318 years was widespread and persistent. Severe thinness was 9%\u2014lower than 16% found in schoolgirls aged 10\u201316 years in Dhaka city in 1995 , the preAlthough education was not associated with the risk of being thin, girls with higher education were less likely to be stunted than girls with lower education . Household economic condition (measured by the asset quintile) was not associated with the risk of being thin or stunted. This could happen for a number of reasons. The seven-day food-frequency data showed no difference in the intake of rice/wheat (staple diet) among economic groups. Selectivity can be another possible reason; healthier girls looked mature and belonged to wealthier households and got married at a higher rate at earlier age than girls of poor households. Some like to look slim to improve body image and may have lowered the economic differential in thinness and stunting. Last but not the least is the frailty; girls of the poor households died off at a higher rate leaving behind the healthy ones and underestimating the economic differentials in the cross-sectional survey. Only a longitudinal study can resolve the frailty issue.We explored the dietary patterns among rural girls in relation to household economic condition (measured with asset quintile). Food items, such as fish, meat, eggs, and milk, are the major sources of animal-protein, calcium, and vitamin A. Half of them could not have meat, eggs, or milk in a week. Girls of the households in the highest asset quintile did consume fish/meat 2.1 (55%) days more, and eggs/milk two (91%) days more than the girls of the households in the lowest asset quintile. The difference in intake of quality food between income-groups was reported for schoolgirls in Dhaka city . The larIron deficiency is common among adolescent girls in Bangladesh , 6, as lWidespread undernutrition, micronutrient deficiency, low dietary knowledge, and low coverage of iron supplement among adolescents are concerns for public-health nutrition in Bangladesh. Adolescents are not the sole decision-makers. Parents, particularly mothers, often make decisions on their behalf, and they need to be sensitized about diet and nutritional needs in adolescence and adverse effects of undernutrition of adolescents to change their mindset. The CNPs, with appropriate communication materials, can do the job effectively. Dietary education in schools, communities, and health facilities in a coherent manner can bring larger effects than stand-alone interventions. Schools can incorporate dietary education and nutritional needs at this age into family-life education or health education.The school education programme cannot reach out-of-school girls who account for 34% or more in Bangladesh . An effeThe study used the data from the Baseline Survey 2004 of the National Nutrition Programme (NNP) implemented by a collaborative effort of ICDDR,B, Institute of Public Health Nutrition, and National Institute of Population Research and Training. The NNP, World Bank, and Canadian International Development Agency provided guidance and financial assistance to the baseline survey. The study was funded by ICDDR,B and its donors which provide unrestricted support to the Centre for its operation and research. Current donors providing unrestricted support include: Australian Agency for International Development (AusAID), Government of the People's Republic of Bangladesh, Canadian International Development Agency (CIDA), Embassy of the Kingdom of the Netherlands (EKN), Swedish International Development Cooperative Agency (Sida), Swiss Agency for Development and Cooperation (SDC), and Department for International Development (DFID), UK. The authors gratefully acknowledge these donors for their support and commitment to the Centre's research efforts."}
+{"text": "Lyme disease is the most commonly transmitted vector-borne disease in the United States, with many regions of the country at risk. Like other spirochete-borne infections, Lyme disease progresses in stages, making diagnosis in the early stages of the illness and prompt treatment important for cure. An early diagnosis is made difficult by the less-than-ideal serologic tests and the varied clinical presentations of the disease. Although Lyme disease has been reported in pregnancy, the transmission rate to the fetus and potential harmful effects are largely unknown. This review discusses the diagnosis, clinical course, and treatment of Lyme disease with an emphasis on the pregnant patient."}
+{"text": "The full set of symposium articles, including recommendations for future research, appear in Archives of Physical Medicine and Rehabilitation.The Rehabilitation Research and Training Center on Measuring Rehabilitation Outcomes and Effectiveness along with academic, professional, provider, accreditor and other organizations, sponsored a 2-day State-of-the-Science of Post-Acute Rehabilitation Symposium in February 2007. The aim of this symposium was to serve as a catalyst for expanded research on postacute care (PAC) rehabilitation so that health policy is founded on a solid evidence base. The goals were to: (1) describe the state of our knowledge regarding utilization, organization and outcomes of postacute rehabilitation settings, (2) identify methodologic and measurement challenges to conducting research, (3) foster the exchange of ideas among researchers, policymakers, industry representatives, funding agency staff, consumers and advocacy groups, and (4) identify critical questions related to setting, delivery, payment and effectiveness of rehabilitation services. Plenary presentation and state-of-the-science summaries were organized around four themes: (1) the need for improved  The growing population of older adults who sustain strokes, hip fractures, joint replacements, and other conditions, Centers for Medicare & Medicaid Services' (CMS) inpatient prospective payment system (PPS), and technical advances in medical and surgical care have led to increasing demand for medical rehabilitation services. Medical rehabilitation provides crucial services that help people with chronic illness and disability learn to live as independently as possible. In inpatient rehabilitation facilities, physician coordinated, multidisciplinary teams focus on reducing impairments, enhancing independence in daily activities and quality of life, and minimizing caregiver burden. As documented in a recent Medicare Payment Advisory Commission (MedPAC) report , the heaOver the past 20 years the cost of postacute services, including postacute rehabilitation services, have grown much faster than overall inflation, reflecting an increased demand for services and growth in number of providers. The U.S. Congress passed a series of laws  intended to reduce Medicare's PAC expenditures by establishing and refining PPSs for rehabilitation hospitals, nursing homes, long-term care hospitals (LTCHs), and home health (HHAs).Changes in payment mechanisms alters providers' incentives and indirectly the organization and availability of PAC. The consequences of payment changes on Medicare beneficiaries' access to high-quality rehabilitation services, independence, and quality of life are unknown. Research on access to, organization of, and the effectiveness of rehabilitation services is needed in order to understand the consequences of new payment mechanisms.Rehabilitation-focused health services research has concentrated on patients' natural recovery in single types of rehabilitation settings \u2013 rehabilitation hospitals and units, SNFs, LTCHs, and HHAs. It is often too expensive and unfeasible to evaluate costs and benefits of rehabilitation across sites of care, let alone specific paths of care, such as from hospitals to nursing homes to home. We know that most patients' functional independence improves during rehabilitation, but we know little about the \"active ingredients\" of rehabilitation and which types of patients are best suited for which setting so that optimal outcomes are achieved at a reasonable cost.Comparing outcomes across postacute settings has been hampered by the lack of a common outcome assessment instrument across settings, or a cross-walk between the instruments used by rehabilitation hospitals, SNFs, LTCHs, and home health agencies (HHAs). Imagine if Maryland's weights and measures differed from California's and Illinois's and Texas's \u2013 and we had no way to convert their measures. With only a bit of hyperbole, this is the situation Medicare finds itself in when trying to evaluate the relative effectiveness and cost effectiveness of rehabilitation hospitals, nursing homes, LTCHs, and HHAs.In the absence of scientific evidence and a way to compare outcomes across settings, Medicare has promulgated rules that limit access to IRFs. The so-called \"75% rule\" and Medicare fiscal intermediaries' \"local coverage determinations\" are based on expert opinion and on a dearth of scientific evidence. In developing these regulations, Medicare was dependent on anecdotal information. While the 75% rule was written to distinguish rehabilitation hospitals and units from acute care hospitals, Medicare revised inpatient rehabilitation facility (IRF) regulations to require explicit documentation of medical necessity and adopted the 75% rule to limit the types of patients admitted. Beneficiaries' access to rehabilitation services could suffer if the truism that \"the absence of evidence of effectiveness does not imply evidence of absence of effectiveness\" is not recognized.The need for expanded rehabilitation-focused health services research was addressed during a workshop in 2005 that was sponsored by the National Center for Medical Rehabilitation and Research (NCMRR) within the National Institute of Child Health and Human Development (NICHD) and the CMS [The Rehabilitation Research and Training Center on Measuring Rehabilitation Outcomes and Effectiveness, funded by the National Institute on Disability and Rehabilitation Research (NIDRR), was asked to lead the planning for what became the Symposium on Post-Acute Rehabilitation. The symposium was guided by a planning committee (see Acknowledgments) with representatives from the American Academy of Physical Medicine and Rehabilitation, the American Congress of Rehabilitation Medicine, the Association of Academic Physiatrists, the Foundation for Physical Medicine and Rehabilitation, the American Hospital Association, and the Federation for American Hospitals. The same organizations provided financial support. Major financial and staff support was provided by the American Medical Rehabilitation Providers Association (AMRPA). Additional sponsors included the American Physiatric Education Council, CARF International (formerly the Commission on Accreditation of Rehabilitation Facilities), Casa Colina Centers for Rehabilitation, eRehabData, Fowler Healthcare Associates, HealthSouth Corporation, IT Health Track, Johns Hopkins University Department of Physical Medicine and Rehabilitation, Kessler Institute for Rehabilitation, Moss Rehabilitation Hospital, MetroHealth Rehabilitation Institute of Ohio, the Rehabilitation Institute of Chicago, and UDSMR.The goal for the symposium was to serve as a catalyst for expanded research efforts on PAC rehabilitation so that relevant research can be used as the basis for policy and funding decisions. The planning committee sought to develop an agenda for research that supports an evidence base for PAC rehabilitation, including issues related to measurement and research design, access to PAC rehabilitation services, organization of rehabilitation services, and outcomes attained for beneficiaries of Medicare and other insurers. The objectives were to: (1) describe the current state of our knowledge regarding utilization, organization and outcomes of postacute rehabilitation settings; (2) identify methodologic and measurement challenges to conducting research in this area; (3) foster the exchange of ideas among researchers, policy-makers, industry representatives, funding agency staff, consumers, and members of advocacy groups; and (4) identify critical questions related to setting, delivery, payment, and effectiveness of rehabilitation services that are of the highest priority for investigation.The activities of the symposium were designed to help formulate a research and policy agenda and to stimulate policy discussions, to engage stakeholders who are involved in policy decisions, and to provide emphasis for the need for an evidence base for rational policymaking. Symposium organizers sought balance in perspectives of key stakeholders, including Congress, the CMS and private insurers, providers of rehabilitation services, patients and their advocates, and health service researchers.The planning committee invited research and policy leaders to present plenary and track-specific state-of-the-science summary speakers, and rehabilitation researchers to provide reports on contemporary work funded by AMRPA, the Rehabilitation Research and Training Center and other agencies. The planning committee invited 3 keynote speakers, former Senator Robert Dole; Laurence Wilson, director, Chronic Care Policy Group, CMS; and Steven Tingus, director, NIDRR. Four plenary speakers were invited to address each of the track themes. Articles by Pamela Duncan and Craig Velozo  and discussion leaders  summarized the recommendations which appear as the final report in the series. The remainder of this summary encapsulates key points from the plenary and state-of-the-science presentations followed by the track-specific research recommendations.Patient assessment data are collected in 3 of the 4 PAC settings. SNFs use an instrument called the Minimum Data Set 2.0, HHAs use the Outcome and Assessment Information Set, and IRFs use the Inpatient Rehabilitation Facility Patient Assessment Instrument, which includes the FIM instrument. LTCHs do not have a mandate to use an assessment instrument. Although these instruments include similar items, the item definitions and assessment periods are different. Further, for the functional assessment domain, all 3 instruments were designed with a fixed set of items, regardless of relevance. In their plenary session, Duncan and Velozo  called fResearch priorities suggested by the measurement and methodology track participants included: develop validated measures of rehabilitation treatments; develop stronger cognitive and psychosocial outcome measures; develop long-term outcomes measures; develop robust severity and selection adjusters across the PAC rehabilitation patient population; assess the role of environmental factors on patient outcomes; and continue development of evidence-based treatment guidelines.Buntin  identifiResearch priorities related to access include projecting the PAC needs of the population and determining the range and geographic distribution of existing PAC entities. Research should be directed to understand better how access is influenced by attitudes about family dynamics, social support, and cultural differences, as well as assumptions about the value of improvement for a patient who will not achieve complete independence.Kaplan  describeChan  describeParticipants in the processes of care track suggested that future research include randomized trials that test individual components of PAC care to determine optimal intensity, duration, and frequency of interventions. To overcome the current barriers of conducting research across provider types, the experiences of other health care systems such as the Veteran's Administration and Kaiser Permanente should be examined.Kane  discusseParticipants in the effectiveness group suggested that future research should focus on what kind of treatment, or combination of services, is most effective in achieving specific outcomes for whom across the continuum of care. In addition, better measures of PAC rehabilitation treatments are needed so that key contents or treatments are identified and can be studied systematically and compared across the continuum of PAC. Participants expressed a strong need for a strategic research plan that is shared by payers, providers, research funders, and researchers; a common measurement time period; and collaboration between CMS, National Institutes of Health, the NIDRR, and the research community to provide flexibility within rigorously designed research protocols, because the PPS itself is a primary obstacle to treatment innovation.uSPEQ: Giving Quality a Voice, CARF International's customer feedback service. Keith began his affiliation with Casa Colina in the 1950s. He began volunteering as a clinical psychologist and soon developed a special interest in rehabilitation services, which eventually led him to develop Casa Colina's Research Department. He became a pioneer in the study of rehabilitation outcomes, published extensively, and helped contribute to the development of the industry standard method of assessing functional status. Our accomplishments are a reflection of their dedication and inspiration.Two colleagues who made major contributions to research and policy discussions on rehabilitation outcomes were very much with symposium participants in spirit, though their recent passing leaves us with a major loss. Deborah Wilkerson and Robert Allen Keith made enormous contributions to rehabilitation research. Wilkerson was a researcher, administrator, and national leader on outcomes measurement, rehabilitation services quality, postacute payment policy, and independent living issues. She led the outcomes measurement and performance indicator programs at CARF and spearheaded the research and development for Postacute rehabilitation care is a key component of the health care delivery system, yet we know little about the active ingredients of the rehabilitation process that produce the best outcomes. Well-designed research is needed to develop better measures for case-mix adjustment and outcomes of care. To advance rehabilitation effectiveness research and support the development of evidence-based policies, we must invest in developing new and improve existing measures of patient characteristics, treatment contents, and long-term outcomes. Critical research needs include (1) developing validated measures of rehabilitation interventions and case mix; (2) standardizing PAC measures and timing of routine measurement for payment and quality assurance purposes across sites of care; (3) examining differences in content and processes of care both within facilities of the same type and across types of facilities; (4) identifying patient characteristics that vary by region such as rural and urban mix, cultural characteristics, and provider referral patterns; and (4) implementing a \"strategic plan for effectiveness research\" that is characterized by collaboration between CMS, federal research funders, researchers, and care sites.The organizers and sponsors of this symposium trust that our goal of catalyzing expanded research on PAC rehabilitation is furthered by the publication of this set of articles. Our nation's health policy requires a solid base founded on compelling evidence. We look forward to the benefits of greater research attention to improved measurement and research design, access to PAC rehabilitation services, organization of rehabilitation services, and outcomes attained for patients, taxpayers, and Medicare and other insurers.Archives of Physical Medicine and Rehabilitation .Supported by the National Institute on Disability and Rehabilitation Research through a Rehabilitation Research and Training Center on Measuring Rehabilitation Outcomes and Effectiveness (grant no. H133B040032).No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the author or upon any organization with which the author is associated."}
+{"text": "The establishment and characterisation  of six cell lines from primary human colorectal adenocarcinomas is described. These lines were established from surgical specimens, from 49 unselected patients, without the use of 'feeder' cells, 'conditioned' medium or passage of cells in nude mice. The six cell lines exhibit considerable variation in morphology, CEA secretion and tumourigenicity in nude mice. At least two of the lines retain some of the differentiated characteristics of colorectal epithelium."}
+{"text": "The HomB encoded outer membrane protein was shown to contribute to the proinflammatory properties of H. pylori and also to be involved in bacterial adherence.The homB and homA genes in 455 H. pylori strains from East Asian and Western countries, and carried out sequence comparison and phylogenetic analyses.This study investigated the distribution of homB and homA genes were heterogeneously distributed worldwide, with a marked difference between East Asian and Western strains.Both homB and homA sequences revealed diversity regarding the number of copies and their genomic localization, with East Asian and Western strains presenting different genotypes. Moreover, homB and homA sequence analysis suggests regulation by phase variation. It also indicates possible recombination events, leading to gene duplication or homB/homA conversion which may as well be implicated in the regulation of these genes. Phylogenetic reconstruction of homB and homA revealed clustering according to the geographic origin of strains. Allelic diversity in the middle region of the genes was observed for both homB and homA, although there was no correlation between any allele and disease. For each gene, a dominant worldwide allele was detected, suggesting that homB/homA allelic variants were independent of the geographical origin of the strain. Moreover, all alleles were demonstrated to be expressed in vivo.Analysis of homB and homA genes are good candidates to be part of the pool of H. pylori OMPs implicated in host-bacteria interface and also contributing to the generation of antigenic variability, and thus involved in H. pylori persistence.Overall, these results suggest that  H. pylori infection is implicated in the development of several gastroduodenal diseases, ranging from chronic active gastritis and dyspepsia to peptic ulcer disease (PUD), and associated with an increased risk for gastric cancer .The sequences used in this study are under the GenBank accession numbers [GenBanK: (PUD): Peptic ulcer disease; (NUD): non-ulcer dyspepsia; (OMP): outer membrane protein; (ORF): open reading frame; (Ks): synonymous substitutions; (Ka): non-synonymous substitutions.MO carried out experimental design of the study, phylogenetic analysis and co-drafted the manuscript; RC carried out bacterial cultures, PCR and phylogenetic analysis; AM co-drafted the manuscript; YY and DQ carried out bacterial cultures and PCR; FM and LM supervised the study. All authors have read and approved the final version of the manuscript."}
+{"text": "The epidemiology of foodborne disease is changing. New pathogens have emerged, and some have spread worldwide. Many, including Salmonella, Escherichia coli O157:H7, Campylobacter, and Yersinia enterocolitica, have reservoirs in healthy food animals, from which they spread to an increasing variety of foods. These pathogens cause millions of cases of sporadic illness and chronic complications, as well as large and challenging outbreaks over many states and nations. Improved surveillance that combines rapid subtyping methods, cluster identification, and collaborative epidemiologic investigation can identify and halt large, dispersed outbreaks. Outbreak investigations and case-control studies of sporadic cases can identify sources of infection and guide the development of specific prevention strategies. Better understanding of how pathogens persist in animal reservoirs is also critical to successful long-term prevention. In the past, the central challenge of foodborne disease lay in preventing the contamination of human food with sewage or animal manure. In the future, prevention of foodborne disease will increasingly depend on controlling contamination of feed and water consumed by the animals themselves."}
+{"text": "The relationship between food intake and cancer of the large bowel was assessed by calculating the average intakes of foods, nutrients and dietary fibre in the different regions of Great Britain and relating these to the regional pattern of death from colon and rectal cancers between 1969 and 1973. No significant associations were found with the consumption of fat, animal protein or beer, nor with current estimates of total dietary fibre intake. Average intakes of the pentose fraction of total dietary fibres, and of vegetables other than potatoes, were negatively correlated with the truncated age- and sex-standardized death rates from colon cancer (r = -0.960 and -0.940). Specific components of dietary fibre may therefore inhibit colon carcinogenesis."}
+{"text": "Tourism has been an instrument of social, cultural, religious, and economic phenomena throughout the globe since ancient time. Progress in opportunities of travel, stay, and information and communication technology has further facilitated people moving from one place to another for leisure, business, education, or medical purpose. A booming economy has far-reaching consequences on all sectors of human development including health. This is true for countries in transition especially India.International tourist arrival throughout the globe was 922 million and India\u2019s share of foreign tourist arrivals (FTAs) stood at 5.4 million during 2008 whereas it was 2.38 million in 2002. Though tThe International Passenger Survey (2003) estimates that about 2.2% of the foreign travelers and 10% of the non-resident Indians (NRIs) visited India with the objective of health care and treatment. India trMedical tourism (MT) involves traveling to an advanced facility in another country for receiving requisite medical/surgical treatment at a much lower cost that is often linked with using the savings to opt for and enjoy a holiday during recovery. However, this is largely true for ambulatory/elective interventions. Some of the favored destinations for MT across the globe include Cuba, Costa Rica, Hungary, Israel, Jordon, Lithuania, Belgium, South Africa, Singapore, Thailand, Philippines, Malaysia, India, and South Korea. MT is noDue to aggressive promotion from stakeholders, Indian private hospitals are increasingly finding a mention in the travel itineraries of foreigners. MT is witnessing an upward trend because India has large number of world heritage monuments, archeological and religious sites, and diverse cultural festivals at one end to state-of-the-art infrastructure and skilled medical manpower that is using innovative technology; quality care of service with high success rate/outcome; compassionate nursing care, English-speaking staff, no waiting time for surgeries; and the most critical element of service delivery at a very affordable cost in comparison to well-developed nations. The indicative cost is shown in On the similar front, outsourcing of diagnostics, promotion of research and development (R&D), rapid growth of research institutes, well-established pharmaceutical industries, initiation of large number of clinical trials, development of newer concepts like surrogate mothers, preservation of cord blood/stem cells, milk banks, and successful use of telemedicine at various settings are some of the catalyzing factors ensuring high visibility and prominence of the Indian health sector in the global news. The rise of Sports Medicine as a subspecialty and successful culmination of Commonwealth Games in New Delhi during the latter half of 2010 will further propagate the phenomenon of MT by leaps and bounds. In addition to above, other value-added service offered in India includes a bouquet of preventive check-ups, wellness therapies, yoga, meditation/spiritual enlightenment, hydrotherapy, mud-therapy, and ayurvedic healing, thus enlarging the scope from \u201cmedical\u201d to \u201chealth\u201d tourism.Tourism is overwhelmingly an industry of private sector although public sector has a significant role to play at different levels including the promotion of public private partnership (PPP). Government of India (GoI) has recognized the economic potential of MT and is promoting this underexplored arena through its market development assistance (MDA) scheme especially for accredited institutions to strengthen the Indian health care brand overseas. Under this, hospital groups will be provided financial assistance for publicity through printed materials, travel and stay expenses for sales-cum-study tours, and participation fees for trade fairs and exhibitions. Calendars of international health events are being planned and the events are being held annually. Efforts are being made for introducing uniform pricing band through various consultative processes by stimulating stakeholders for the formation of common platform/consortium. GoI has introduced medical visa for patients desirous of undergoing treatment in India.On the regulation of human resource for health, Planning Commission (GoI) is encouraging all State Councils to shift to a system of periodical renewal of registration of medical personnel. In the field of paramedical education including physiotherapy and occupational therapy, priority is being given to the establishment of National Paramedical Council as an apex body to determine standards of education/training and to ensure uniform enforcement on the lines of Medical Council of India (MCI) for MBBS/higher courses. In the rTo enhance visibility and scalability and attract more clients, health institutions in India will require intensive efforts on the establishment and compliance of rigorous quality standards, implementation of international best practices, and communication thereof. Health services are increasingly coming under independent evaluation by accreditation agencies in many countries. Accreditation is a voluntary process by which an authorized agency/organization evaluates and accredits health service according to a set of standards describing the structure and processes that contribute to desirable patient outcomes. The patients get services by credential medical staff. Rights of patients are respected/protected and regularly evaluated through patient satisfaction and simultaneously there is an element for professional growth/enrichment.Accredited institutions are potential winners in attracting and retaining foreign clients. Some private health institutions in India have taken up accreditation from JCI and stilIn spite of very optimistic, supportive, and economically driven environment being garnered for MT, some of the issues and concerns could be incentives, concessions and taxation, follow-up services, limited presence of global health insurers, exodus of specialists from public health system to private sector, malpractices by patients/attendants, litigation, legal stay, and import of exogenous infection(s). However, taking a clue from the current scenario, it would be apt to conclude that MT has a huge potential in times to come as more and more foreign travelers will be visiting India for their health needs and keeping an eye on future will lead to quantitative and qualitative gains for both international and national clients."}
+{"text": "The characteristics of sites of intramural cancer spread were examined by comparing theintraductal ultrasonography (IDUS) and wall thickening findings at sites of intramural cancerspread and non-spread, in patients with malignant bile duct stenosis who had undergonepercutaneous transhepatic biliary drainage (PTBD).The subjects were ten patients with extrahepatic bile duct cancer, two with pancreaticcancer, one with cancer of the gallbladder, and one with cancer of the papilla of Vater whounderwent preoperative IDUS. From these patients, 50 IDUS slices were examined with acongruent relationship with the histologic section of resected tissue. The maximumthickening, minimum thickening, maximum/minimum thickening ratio, and form factor of themedial and lateral margins of the medial hypoechoic layer were determined using diagnosticimaging, and the results were compared at sites of cancer spread and non-spread.Twelve slices were obtained from the site of stenosis, 14 from sites of cancer spread, and 24from non-spread sites. The maximum thickening, minimum thickening, and maximum/minimumthickening ratio differed significantly between the sites of spread and the non-spread.The absolute values for wall thickening are useful for diagnosing the presence of intramuralspread in patients with malignant biliary duct stenosis."}
+{"text": "N-deacetylated derivative chitosan, have been identified as versatile biopolymers for a broad range of applications in medicine, agriculture and the food industry. Two of the main reasons for this are firstly the unique chemical, physicochemical and biological properties of chitin and chitosan, and secondly the unlimited supply of raw materials for their production. These polymers exhibit widely differing physicochemical properties depending on the chitin source and the conditions of chitosan production. The presence of reactive functional groups as well as the polysaccharide nature of these biopolymers enables them to undergo diverse chemical modifications. A complete chemical and physicochemical characterization of chitin, chitosan and their derivatives is not possible without using spectroscopic techniques. This review focuses on the application of spectroscopic methods for the structural analysis of these compounds.Chitin, the second most important natural polymer in the world, and its  For HPLC separation a different type of column is used, and the mobile phase often consists of acetonitrile or water with added formic acid + and [M + H]+, respectively  . This haversus right-handed polarized light that arise due to structural asymmetry [et al. [N-acetylation of low-molecular-weight chitosan (LMWC) prepared from pectolytic hydrolysates of chitosan. Circular dichroism spectra showed a decrease in the segment of N-acetylated glucosamine units in LMWC.CD spectroscopy measures differences in the absorption of left-handed polarized light symmetry . A CD sp [et al.  used CD In general spectroscopic techniques are very useful and important in the structural analysis of chitin, chitosan and their derivatives, although we need to mention that there are many other non-spectroscopic analytical methods that are routinely used in such studies: viscosity measurements, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), isothermal titration calorimetry (ITC), cyclic voltamperometry, high-performance liquid chromatography (HPLC) and size exclusion chromatography (SEC).N-acetylation, pattern of N-acetylation, degree of polymerization, molecular weight, crystallinity, the sequence or degree of substitution, as well as in monitoring reactions, controlling the purity of these compounds and in characterizing their intra- and intermolecular interactions, is discussed. It should also be mentioned that the structural analysis of chitin/chitosan and their derivatives is based on the application of at least a few different types of spectroscopic methods during the same study. The main reason for this is the possibility of obtaining different but compatible and complete information about the structure and physicochemical properties of these compounds, which is impossible using only one spectroscopic technique. Continuous improvements in sampling techniques, analysis software and instrumentation hardware, mean that spectroscopic methods have revolutionized the chemical and physicochemical characterization of chitin/chitosan samples, and are now routinely used by scientists working in the chitin/chitosan field.Chitin and chitosan are natural aminopolysaccharides with unique structures and interesting properties such as biocompatibility and biodegradability; they are non-toxic, have a wide range of applications, and the raw material sources for their production are unlimited. Chemical modification of these polymers results in improved solubility in water or organic solvents, which enhances their biological activities and favors the continuous development of their applications as new functional biomaterials with excellent potential in various fields. In order to acquire a deeper understanding of the mechanism of these properties, it is necessary for chitin/chitosan and their derivatives to be structurally and physicochemically well characterized. Knowledge of the microstructure of these compounds is essential for an understanding of structure\u2013property\u2013activity relationships. Although spectroscopic methods are of great use to scientists working in the chitin/chitosan field, many researchers lack specialist knowledge of these techniques. This paper focuses on the practical aspects of using the five spectroscopic methods most often applied \u2013 X-ray spectroscopy, infrared (IR) and UV-Vis-spectroscopy, mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (NMR-spectroscopy) \u2013 in the structural investigation and physicochemical characterization of chitin, chitosan and their derivatives. The application of other spectroscopic methods is also discussed. This paper provides hands-on information about these valuable research tools, emphasizing practical aspects such as sample preparation or typical measurement conditions, their limitations and advantages, and interpretation of results. The usefulness of these methods in establishing and confirming molecular structures, determining physicochemical parameters such as the degree of"}
+{"text": "In contrast to most other forms of cancer, data from some developing and developed countries show surprisingly similar survival rates for ovarian cancer. We aimed to compare ovarian cancer survival in Philippine residents, Filipino-Americans and Caucasians living in the US, using a high resolution approach, taking potential differences in prognostic factors into account.Using databases from the SEER 13 and from the Manila and Rizal Cancer Registries, age-adjusted five-year absolute and relative survival estimates were computed using the period analysis method and compared between Filipino-American ovarian cancer patients with cancer patients from the Philippines and Caucasians in the US. Cox proportional hazards modelling was used to determine factors affecting survival differences.Despite more favorable distribution of age and cancer morphology and similar stage distribution, 5-year absolute and relative survival were lower in Philippine residents  than in Filipino-Americans . After adjustment for these and additional covariates, strong excess risk of death for Philippine residents was found . In contrast, no significant differences were found between Filipino-Americans and Caucasians living in the US.Multivariate analyses disclosed strong survival disadvantages of Philippine residents compared to Filipino-American patients, for which differences in access to health care might have played an important role. Survival is no worse among Filipino-Americans than among Caucasians living in the US. Ovarian cancer is the second most common gynaecological cancer worldwide and the sixth most common cancer in women overall ,2. The mComparisons in ovarian cancer survival between developed and developing nations, as well as between ethnic groups within countries, are few -7, but aIn this paper, we take a \"high resolution\" approach -10 to elUsing the Surveillance, Epidemiology and End Results (SEER) 13 database , ovarianPatient information for residents of the National Capital Region (NCR) of the Philippines was abstracted from the Philippine Cancer Society-Manila Cancer Registry (PCS-MCR) and the Department of Health-Rizal Cancer Registry (DOH-RCR). The registries are regarded as among the high-quality registries from developing countries and have consistently been included in the \"Cancer Incidence in Five Continents\" series -15. TheyUsing the same inclusion and exclusion criteria as for the SEER databases, a list of 2,898 ovarian cancer cases diagnosed between 1998 and 2002 was generated, from which sub samples of 200 cases diagnosed in each calendar year of interest were randomly drawn using the .sample command in STATA version 6 . PatientThe project proposal was approved by the Ethics Review Board of the National Institutes of Health of the University of the Philippines Manila. The information obtained strictly conformed to the code of conduct stipulated by the Guidelines on Confidentiality for Population-based Cancer Registries .To derive survival estimates, cohort-based analyses such as the conventional life-table  method or the Kaplan-Meier method ,19 have As commonly practiced in population-based cancer survival analysis, both absolute and relative survival rates were calculated. The relative survival probabilities are estimated as ratios of the observed survival of cancer patients and the expected survival of a group of people with the same age and sex distribution from the general population, and reflect the survival experience of cancer patients in the absence of competing causes of death ,27. UsinTo enable comparison of ovarian cancer survival estimates between different cancer populations, age adjustment was done. Age-specific period survival estimates (absolute and relative), using age groups 15-39, 40-49, 50-59, 60-69 and 70 and above, were first obtained from the Philippine resident, the Filipino-American and the Caucasian populations. The age-specific estimates were then weighted and summed for each population group, using weights from the World Standard Cancer Patient Population (WSCPP) .The differences between survival estimates for the three cancer patient populations were tested for statistical significance using a novel modelling approach for period analysis . First, To explain possible survival differences and identify factors affecting survival, both within and between the three cancer patient populations, the Cox Proportional Hazards model was used. For each population group, bivariate associations of age, stage at diagnosis, histology, and receipt of surgery and of radiotherapy with survival were determined using individual Cox models. A multivariate model was then built jointly for all three groups to compare survival probabilities between populations. Relative hazards were calculated using Filipino-Americans as the reference group, while controlling for the effects of age, stage, histology, surgery and radiotherapy, first individually and then simultaneously. Those with missing information were excluded in the multivariate analysis. The assumption of proportional hazards for Cox models was checked by plotting the log of the negative log of the survival density functions vs the log of survival time. The plotted lines were roughly parallel over time and no violations of the proportional hazards assumption were found.Age at diagnosis was categorized into the age adjustment groupings mentioned earlier. Stage categories were based on the Federation of Gynecology and Obstetrics (FIGO) stages I, II III and IV . HistoloAll analyses were done with the SAS Statistical Analysis Software. Special macros were used for standard and modelled period survival analysis as previously described ,34.A total of 463 Filipino-American and 22,290 Caucasian ovarian cancer patients were included in the analysis, after exclusion of around 1% of cases who are coded in situ and those who were identified by death certificates only (DCO). From the 2,000 randomly sampled patients from the Philippine databases, 1,475 ovarian cancer patients (73.8%) were included after 220 (11%) and 305 (15.2%) patients were removed due to invalid data, such as incorrect age, sex and primary site, and due to the absence of any survival time information, respectively. Of the included patients not known to be dead, complete 5-year follow-up information was obtained for 33.8%, while at least some follow-up could be ascertained for another 41.3%.The distribution of cases by age groups, stage at diagnosis, histology, surgery and radiotherapy are shown for each population in Table Age adjusted and age-specific estimates of absolute and relative 5-year survival are shown in table As shown in table In bivariate comparative survival analysis between population groups table , substanIn this \"high resolution\" study comparing ovarian cancer survival in the Philippine resident and Filipino-American patients, sharing the same ethnicity, and in Filipino-American and Caucasian patients in the US, sharing the same health care system, overall survival differences were found to be relatively small. However, Philippine resident patients showed a more favorable distribution with respect to major prognostic factors, such as age, stage and morphology, and major excess mortality in this patient group was disclosed after control for these factors in age specific and multivariate analysis. By contrast, an apparent survival disadvantage of Caucasian patients compared to Filipino-American patients essentially disappeared after controlling for these factors. Taken together, these results point to the relevance of health care related factors for explaining survival differences.Disadvantages in absolute and relative survival of Philippine residents compared to Filipino-Americans were particularly large for age groups 50-59 and 60-69, which can be explained to some extent by more unfavorable stage distributions. The proportions of patients presenting with advanced stages in age groups 50-59 and 60-69 were much lower in Filipino-Americans  than among Philippine residents .In the absence of effective screening methods, only a small proportion of ovarian cancer cases are diagnosed in early stages, where surgery alone will be effective ,35,36. MIn developed countries, survival rates have improved in the recent decades -40, mainIn the NCR, Philippines, adjuvant chemotherapy has been shown to improve survival . HoweverCompounding the problem among Philippine residents is the persistent disbelief in chances to be cured from cancer . In spitWhile much of the differences are likely to be explained by health care access, dissimilar distributions by age, stage and histology suggest a possible role of biological factors. The differences in tumor biology between populations might be reflective of the heterogeneous nature of ovarian cancer, and should be investigated in more detail, given that previous studies have shown significant variation of survival by histologic subtypes ,47-49.Between Filipino-Americans and Caucasians, slightly higher absolute and relative survival rates were observed for the former group. The distributions by age and stage at diagnosis vary between the groups, with Filipino-Americans having more favorable characteristics. The Cox model showed that the higher proportion of Caucasian women with older age and advanced disease explains most of the apparent survival difference. After adjustment for these variables, as well as morphology and treatment, the residual excess risk was small (15%) and not significant. Sensitivity analyses regarding difference in survival estimates between Caucasian population with and without Hispanics did not show a significant difference.Our study is limited to variables that were available and comparable in the databases, and not all possible factors that could affect survival were considered. Information on chemotherapy is not included in the SEER public use database whereas some tumor characteristics such as grade, size and heterogeneity were not available from the Philippine database. In addition, socio-economic status, family history of ovarian cancer and lifestyle factors, like contraceptive use and hormone intake, were also not studied. Similarly, more detailed information on health care access, particularly on access to and availability of various treatment regimens, as well as application of treatment guidelines, protocols used, specialization and expertise of treating physicians, were not obtainable.Patients with invalid data and those who do not have follow-up time were excluded from the study, but it is unlikely that they have higher survival than those who were included. Most such patients have incomplete records and were not traced to other hospitals in the NCR, indicating that they might not have consulted physicians after the initial diagnosis, or have had limited consultations afterwards. They most probably have not received any form of treatment as the availability of cancer treatment is limited outside the NCR. The survival rates presented might therefore overestimate true survival of Philippine residents to some extent.In conclusion, the results of the multivariate analyses disclosed strong survival disadvantages of Philippine residents compared to Filipino-American patients, despite similar overall survival rates observed in the presence of more favorable distributions of major prognostic factors. The survival disadvantage of Philippine resident patients most likely reflects differences in access to and affordability of effective health care and treatment, such as chemotherapy. Emphasis should therefore be given on improving access to and affordability of effective treatment regimens. Prognosis is no worse among Filipino-Americans than among Caucasians living in the US.cancer registry-based study on survival and care of cancer patients; FIGO: Federation of Gynecology and Obstetrics; RR: Relative risk; IACR: International Association of Cancer Registries; IARC: International Agency for Research on Cancer; ICD-O: International Classification of Diseases for Oncology; NCR: National Capital Region; PCS-MCR: Philippine Cancer Society-Manila Cancer Registry; RS: Relative survival; SE: Standard error; SEER: Surveillance, Epidemiology and End Results; WSCPP: World Standard Cancer Patient Population; US: United StatesAPI: Asian and Pacific Islanders; AS: Absolute survival; DCO: Death certificates only; DOH-RCR: Department of Health-Rizal Cancer Registry; EUROCARE: European The authors declare that they have no competing interests.The contributions of the authors are as follows: MTR contributed in the planning of the study, supervised data collection, performed the analysis and wrote the manuscript; AL, MRL, GU, JT and DB planned and supervised data collection, reviewed and edited registry abstracts, and performed data management; AG assisted in the analysis; HB contributed in the planning of the study and supervised data analysis and writing of the manuscript. All authors have read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/9/340/prepub"}
+{"text": "The carcinogenic effects of dimethylnitrosamine (DMN) and nitrosomethylurea (NMU) injected subcutaneously at 3 different dose levels in European hamsters were studied. DMN induced malignant haemangioendotheliomata of the liver and kidney, hepatocellular carcinomata and, in one animal, a cholangiocellular carcinoma. The effect of NMU was localized at the site of administration and resulted in subcutaneous fibrosarcomata, carcinosarcomata or epidermal carcinomata."}
+{"text": "There is no national joint replacement registry in the country of Asia and reports of national outcomes of joint replacement in Asia as yet. Therefore, this study was then to report a national data of the number of hip replacements, incidence rate, demographic characteristics of hip replacement patients, and short-time survival rate after hip replacement of Han Chinese in Taiwan.We analyzed 105,688 cases of hip replacements  from National Health Insurance research database between 1996 and 2004. The survival rate of primary hip replacement was estimated for each disease by the Kaplan-Meier method.Average annual number of primary partial hip replacement and primary total hip replacement were 4,257 and 6,206 cases, respectively. The most two common diagnosis of primary partial hip replacement were femoral neck fractures  and avascular necrosis . In primary total hip replacements, the most two common diagnosis were avascular necrosis  and osteoarthrosis . Both the number of primary partial hip replacements and primary total hip replacements increased steadily between 1996 and 2004. The cumulative survival of primary partial hip replacements and primary total hip replacements in all patients were 93.97% and 79.47% in 9 years follow-up, respectively.Avascular necrosis is the main disease in total hip replacement in Taiwan. The epidemiology of hip diseases was different between Han Chinese (in Taiwan) and Caucasian and the number of hip replacements increased substantially in Taiwan between 1996 and 2004. National joint replacement registry is a good solution to record and publish the information for the orthopaedic community on the outcome of joint replacement surgery. Norway in 1987) [987 [1] aSince the implementation of the National Health Insurance (NHI) in Taiwan in 1995, we have accumulated a huge database of clinical cases greater than 96% of the total population in Taiwan. People have received medical health care coverage from this universal national health care system. There were greater than 95% of all the hospitals contained in the NHI databases in Taiwan . InformaThe purpose of this study was then to report a data of the number of hip replacements, incidence rate, demographic characteristics of hip replacement patients, and short-time survival rate after primary hip replacement in Taiwan.The National Health Insurance program has implemented since March 1995, and the development of the Taiwan's health economy has really taken off. It provides several measures to protect the unemployed, the poor, and the victims of natural and manmade disasters. Moreover, by safeguarding the right of the weak to have access to medical care, the program maintains social order and provides security during this time of economic recession. Until June 2006, there were 22.3 million individuals enrolled in the NHI with a coverage rate of 99% populations (22.7 million) and 18,289 healthcare providers contracted with NHI, representing 91.45% of all providers in Taiwan.In order to survey the results of hip replacement surgery, we analyzed 105,688 cases of registry for contracted medical facilities and inpatient expenditures by admissions from NHI research database between 1996 and 2004, on the basis of the International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) code for THR (81.51), partial hip replacement (PHR) (81.52) and revision of hip replacement (including PHR and THR) (81.53) listed as the major operation. These cases included 38,349 cases of primary THR, 55,884 cases of primary PHR and 11,455 cases of revision of hip replacement. We excluded 51 cases (26 cases of primary THR and 25 cases of primary PHR) which aged less than 16 years old. The insurance data was registered by physicians before operation. The data of inpatient expenditures contained six categories including personal information, date of inpatient, diagnosis, operation, expenditures, and hospital information. The items including patient identity, date of operation, birthday, gender, diagnosis, and treatment were used in this study. We compared the patient identity between primary operation (PHR and THR) and revision of hip replacement, and found there were 1,201 and 1,905 cases of revision from the failure of primary PHR and THR originally enrolled in the database, respectively. Survival of primary hip replacement was estimated for each disease by the Kaplan-Meier method .The reports of primary THR in Taiwan, Norwegian ,13 and SIt is worth to be taken notice of the difference that the mean age of OA patients in Taiwan (60 years) were younger than Norwegian and Swedish (70 years) as shown in Table This study reported statistical data of primary PHR and THR in Taiwan and showed the difference in epidemiology of hip diseases between Han Chinese and Caucasian. AVN is the main disease in primary THR in Taiwan and it is very different form Caucasian in age and gender. Moreover, mechanical complication of hip prosthesis is the main reason for revision. We should be careful with the generalizing results from western countries to other ethnic groups.The authors declare that they have no competing interests.YS wrote the initial manuscript drafts. HW ensured the accuracy of analysis and revised the initial manuscript drafts. YS and HW participated in the design of the study and performed the statistical analysis. YS and CK conceived of the study, and participated in its design and coordination. All authors read and approved the final manuscript."}
+{"text": "In a series of patients drawn from the Birmingham Regional Cancer Registry (England) with tumours of the salivary glands, a significant excess of second primary tumours was observed. For females, the excess was found mainly in breast and bronchus and, for males, in prostate and skin. In a parallel series of female breast-cancer patients, the observed number of second primary tumours in salivary glands significantly exceeded expectation. These results support the reported association between salivary gland and breast cancer, and suggest that other hormone-dependent sites are also at risk."}
+{"text": "East African countries have in the recent past experienced a tremendous increase in the volume of antiretroviral drugs. Capacity to manage these medicines in the region remains limited. Makerere University, with technical assistance from the USAID supported Rational Pharmaceutical Management Plus (RPM Plus) Program of Management Sciences for Health (MSH) established a network of academic institutions to build capacity for pharmaceutical management in the East African region. The initiative includes institutions from Uganda, Tanzania, Kenya and Rwanda and aims to improve access to safe, effective and quality-assured medicines for the treatment of HIV/AIDS, TB and Malaria through spearheading in-country capacity. The initiative conducted a regional assessment to determine the existing capacity for the management of antiretroviral drugs and related commodities.Heads and implementing workers of fifty HIV/AIDS programs and institutions accredited to offer antiretroviral services in Uganda, Kenya, Tanzania and Rwanda were key informants in face-to-face interviews guided by structured questionnaires. The assessment explored categories of health workers involved in the management of ARVs, their knowledge and practices in selection, quantification, distribution and use of ARVs, nature of existing training programs, training preferences and resources for capacity building.Inadequate human resource capacity including, inability to select, quantify and distribute ARVs and related commodities, and irrational prescribing and dispensing were some of the problems identified. A competence gap existed in all the four countries with a variety of healthcare professionals involved in the supply and distribution of ARVs. Training opportunities and resources for capacity development were limited particularly for workers in remote facilities. On-the-job training and short courses were the preferred modes of training.There is inadequate capacity for managing medicines and related commodities in East Africa. There is an urgent need for training in aspects of pharmaceutical management to different categories of health workers. Skills building activities that do not take healthcare workers from their places of work are preferred. Over the past few years, East African countries have experienced a tremendous increase in the volume of antiretroviral drugs. This is a direct result of the commendable global initiatives towards improving access to effective treatment of HIV/AIDS ,2. Lack To build in-country and regional capacity in pharmaceutical management, Uganda's Makerere University, with technical assistance from the USAID supported Rational Pharmaceutical Management Plus (RPM Plus) Program of Management Sciences for Health (MSH) established the Regional Technical Resource Collaboration (RTRC), a network of academic institutions to build capacity for pharmaceutical management. The initiative , which iA cross-sectional survey of fifty governmental and non-governmental institutions accredited to provide ART services in the four countries was conducted in the months of February and March 2005. One researcher from Makerere University and one in-country collaborator carried out the assessment. The assessment used a qualitative research methodology that included interviewing key informants, in-depth interviews of health care workers, and a survey of health facilities and programs.The survey covered both urban and rural areas and looked at different facets of healthcare provision including, public, private-for-profit, and private not-for-profit sectors. By convenience sampling, a minimum of 10 facilities were targeted in each country and at least three healthcare workers from each facility were interviewed.The assessment was standardized across the participating countries through a planning workshop, which brought together collaborators from Makerere University, Harvard Centre for International health, Management Sciences for Health, and two representatives of the AIDS Control Program from each of the four countries. The workshop reviewed the data collection tools, discussed the assessment logistics and process and agreed on time lines. Data collection tools were piloted at three health facilities and two programs in Uganda and their validity and reliability ascertained. These were later excluded from the main study. Permission to carry out the survey was obtained from the national HIV/AIDS control programs of the respective countries. Appointments with heads of the facilities and respondents were made by personnel from the national AIDS control program in each country.The heads of the National AIDS Control Programs, Ministry of Health Pharmacy Services, and HIV treatment programs were identified as key informants. Using the data collection tool information on; the general features of the country's ARV supply system , qualification and training of health care workers involved in supply management of ARVs and related commodities, and the training needs for the supply management of pharmaceuticals was sought in a face to face interview.The heads of the facilities providing ART services in the four countries were the key informants at the program level. The survey looked at the types of HIV/AIDS services provided, the existence of guidelines for management of ARVs and related commodities, the qualification of healthcare workers managing the supply of pharmaceuticals, existence of any ongoing skills building activities, and areas covered in ongoing training programs.Structured in-depth interviews of healthcare providers were held with physicians, pharmacists, pharmacy assistants, nurses and clinical officers. Information was sought on training background, knowledge of ARV supply management systems and the quality of the service provided.At the end of each survey, questionnaires were checked for completeness, accuracy and consistency. At the end of each assessment, analysis of the data involved discussion with various in-country stakeholders for more in-depth interpretation of perceptions and opinion on possible interventions to address identified problems. Quantitative data were analyzed using EPI INFO Version 3.3, while qualitative data were coded and manually analyzed. No statistical comparisons were made as this was a situational analysis survey without sufficient power for such analysis.National AIDS Control Programs were responsible for the development and implementation of HIV/AIDS treatment policies in all four countries. Public, private-not-for profit and private-for-profit institutions were involved in HIV/AIDS treatment and care in all the four countries. In the public institutions HIV/AIDS treatment was limited to district level facilities or higher at the time of the assessment.A total of 54 facilities involved in ART services were surveyed in the four countries, comprising of 27 public, 18 private not-for-profit, 5 private-for-profit, and 4 academic institutions  were delivering a series of training courses on managing procurement and logistics of HIV/AIDS drugs and related supplies . The tarEven though retail pharmacy outlets dispensed ARVs in Kenya, Uganda and Tanzania, clinical training programs on ART seldom included them. Future training initiative should include private pharmacies. In Kenya, policy makers believe that professional bodies such as the Kenya Pharmaceutical Society could contribute significantly to the training of community pharmacists providing ART services.Capacity for ARVs supply management in Uganda, Kenya, Tanzania, and Rwanda were found to be limited due many problems. These problems included poor human resource with inadequate skills and capacity to select, quantify and distribute the drugs, with irrational prescribing and dispensing. This calls for There is thus need to provide training in drug supply management in all four countries. Training processes that include local institutions are more sustainable and likely to cover wider geographical areas. The preferred modes of training are on-the-job training and short courses that do not draw participants away from their workplaces.The authors declare that they have no competing interests.PJW: Participated in designing the study, planning, data collection, data analysis and manuscript writing. ROA: Participated in designing the study, planning, data collection, data analysis and manuscript writing. CO: Participated in designing the study, planning, data collection, and manuscript writing. EO: Participated in designing the study, planning and data collection. WT: Participated in designing the study, planning and data collection. JO: Participated in designing the study, planning and data collection. WWA: Participated in designing the study, planning and data collection. LM: Participated in organizing funding, data analysis and manuscript writing. OA: Participated in applying for funding, designing the study, data collection, data analysis and manuscript writing."}
+{"text": "To the Editor: The global increase of antimicrobial-drug resistance, including resistance to the new and most potent antimicrobial agents, is a major public health concern. In low-resource countries, where bacterial infections are still among the major causes of death, especially for children, it is of particular concern (www.unifi.it/infdis/antres/default.htm). In 2002, the baseline ANTRES study showed a high rate of fecal carriage of Escherichia coli with acquired resistance to several antimicrobial drugs, especially older drugs , in preschool children from 4 urban settings in Bolivia and Peru  is a research project on antimicrobial-drug use and resistance in low-resource countries of Latin America  and 2 in Peru . The study design, sampling and inclusion criteria, methods, and ethical issues were the same as those of the baseline study . StatistE. coli population in both surveys. The most relevant finding of the 2005 survey was the remarkable increase since 2002 in the resistance rates to fluoroquinolones and expanded-spectrum cephalosporins . The increased prevalence of resistant E. coli strains in preschool children most likely reflects increased exposure within a contaminated household setting, in the food chain, or both (,,Increasing resistance to fluoroquinolones and expanded-spectrum cephalosporins among E. coli, to evaluate the effects of these important reservoirs of resistance genes distributed in the community, to investigate the epidemiologic relationship with clinical isolates, and to define the role of the food supply. Investigation into whether carriage of resistant strains in adults correlates with data on antimicrobial-drug use in hospitals and in the community would also be of interest.Our findings support the need to continue monitoring the evolution of resistance in commensal"}
+{"text": "Symposium: A Practical Approach to Evidence-Based OrthopaedicsThe process of scientific discovery is, in effect, a continual flight from wonder.Albert EinsteinJournal of Bone and Joint Surgery adopted EBM and levels of evidence grading for all clinical papers. Since then, all major North American orthopedic meetings and journals have adopted evidence-based orthopedic teachings in some format or another.Evidence-based medicine (EBM) was recently noted as one of the top 15 medical discoveries over the past 160 years. The term EBM has become so commonplace in the practice of medicine that it seems hard to believe that the term, itself, was only coined in 1990 at McMaster University (Canada). The popularity of EBM has only recently expanded to evidence-based orthopedics. In 2003, the Evidence-based orthopedics requires an understanding of a new language and principle in the evaluation of clinical research and its impact on patient decision-making. While the concepts may not be entirely intuitive, they are an absolute prerequisite to any surgeon who wishes to practice in the era of EBM. Educational efforts have largely focused on medicine with little focus on the unique educational needs of surgeons. The unique features of surgical research and the associated challenges have often been minimized by researchers and practitioners promoting double randomized controlled drug trials as the gold standard.The current symposium has been developed to cover practical concepts of evidence-based orthopedics including its history, definitions, quality of the literature, checklists for surgeons to evaluate orthopedic literature and communication with patients.The core articles were developed by researchers at McMaster University in collaboration with experts from Boston (Massachussetts), Toronto (Ontario), Greenville (South Carolina), Zurich (Switzerland), Kiel (Germany), New Delhi (India) and Pune (India)."}
+{"text": "Concerns about the impact of the oceans on human health can be traced to ancient times. Jewish law prohibited the consumption of shellfish, probably reflecting the fact that filter-feeding bivalves can accumulate pathogens and toxins. The Portuguese explorer Pedro Fernandes de Queir\u00f3s described symptoms associated with ciguatera fish poisoning after eating Caribbean sea bream in 1606, and several of British explorer James Cook's crew experienced similar symptoms after eating fish off the coast of Vanuatu in 1774 [ impacts . A tsuna impacts . LookingDespite concerns about biological, physical and chemical risks, and the possible long-term effects of global warming, the oceans remain a resource of immense value to mankind. Many marine fish and shellfish, for example, are excellent sources of protein, selenium, and omega-3 polyunsaturated fatty acids. Around the globe, the coastal ocean is a recreational destination for a substantial percentage of the human population as well as a venue of intensive commercial activity. In 1999, the National Research Council (NRC) published From Monsoons to Microbes: Understanding the Oceans Role in Human Health , a seminRecognizing the growing need for interdisciplinary basic and applied research addressing the linkages between human health and the oceans, in 2004 the National Science Foundation (NSF) and the National Institute of Environmental Health Science (NIEHS) jointly funded grants establishing four Centers for Oceans and Human Health (COHH). These centers are: (i) the Oceans and Human Health Center at the University of Miami, (ii) the Pacific Research Center for Marine Biomedicine at the University of Hawaii, (iii) the Pacific Northwest Center for Human Health and Ocean Studies at the University of Washington, and (iv) the Woods Hole Center for Oceans and Human Health at the Woods Hole Oceanographic Institution, the Marine Biological Laboratory, and Massachusetts Institute of Technology. Through an internal competitive process, the National Oceanic and Atmospheric Administration (NOAA) in the same year designated three NOAA centers of excellence in oceans and human health under their Oceans and Human Health Initiative (OHHI): (i) the West Coast Center for Oceans and Human Health at the Northwest Fisheries Science Center in Seattle, Washington, (ii) the NOAA Center of Excellence in Oceans and Human Health at the Hollings Marine Laboratory in Charleston, South Carolina, and (iii) the NOAA Center of Excellence for Great Lakes and Human Health at the Great Lakes Environmental Research Laboratory in Ann Arbor, Michigan. The NOAA initiative also includes external competitive grant, distinguished scholar, and traineeship programs.V. vulnificus wound infections have a death rate of some 50% [Vibrio bacteria and Noroviruses) as a result of the consumption of raw and even cooked molluscan shellfish remain a concern [In the United States, one of the motivations for OHH research arises from the fact that some 62 million Americans swim in the coastal waters of the United States and spend 800 million person-days at beaches annually . Wound, some 50% . Public  concern ,15. The  concern .Oceans and Human Health is a growing integration of several disciplines, from physical oceanography to molecular biology to epidemiology, emerging largely from the recognition that ocean processes have important implications for public health, and human activities can influence these processes. Details on approaches to this new area of concern may be found in the Interagency Oceans and Human Health Research Implementation Plan . The fivThe primary concern regarding microbial pathogens is human exposure associated with the recreational and commercial use of coastal waters containing either indigenous or introduced pathogens. The primary route of transmission is the consumption of seafood, but can occur also by contact with seawater or exposure to marine aerosols and zoonoses. Almost all major bacterial lineages that contain human pathogens have also been detected in samples from ocean environments or organisms. Yet forStaphyllococcus aureus, Naegleri fowleri and Legionella pneumophila). Recent epidemiological studies conducted at recreational beaches impacted by non-point source pollution have revealed no statistically significant correlation between FIB concentrations and morbidity [For years, the standard strategy for monitoring introduced pathogens has been measuring the concentration of so-called fecal indicator bacteria (FIB). There are acknowledged and serious problems associated with the use of FIB for this purpose . These iorbidity . These iorbidity ,19; and orbidity .Vibrio cholerae at natural concentrations in New England estuarine water, suggesting that microarrays may be applicable to broad environmental monitoring of co-occurring pathogens [Polymerase chain reaction methods for example, are being used to rapidly and specifically target microbes of public health concern, including those not examined previously because of an inability to culture them. New molecular assays have been introduced for detection of FIB, bacterial pathogens, viral pathogens, and protistan (protozoan) parasites. And recent methodological improvements are allowing simultaneous detection of multiple targets in a single assay. Scientists from MIT in the Woods Hole Center, in collaboration with colleagues from Northwestern University, have recently developed a protocol involving DNA microarrays that enables accurate identification of specific bacterial sequences in natural samples. Applied to environmental samples, the microarrays are able to detect athogens . OHH resathogens .The acronym \"HAB\" is somewhat misleading since some HAB-designated problems , though caused by algae, are not associated with blooms in any conventional sense of the word, and others are caused by cyanobacteria, which are prokaryotic and, strictly speaking, not algae. Regardless, there are a variety of human health problems associated with HABs. The most common is acute  intoxication resulting from the consumption of shellfish or finfish that contain neurotoxins produced by HABs . Other pKarenia brevis blooms off the west coast of Florida by scientists at the University of Miami COHH in collaboration with NOAA OHH researchers [Alexandrium fundyense blooms in the Gulf of Maine by the Woods Hole COHH [In some cases remote sensing has been very successful in detecting HABs (and warning the public). A good example is detection of earchers . Scientiearchers . In Pugeearchers . As withole COHH ,21,23.Pseudo-nitzschia [Vibrio cholerae, for example acquires the cholera toxin gene via phage transduction [A concern with modeling and forecasting is the growing awareness that the abundance and, in particular, the toxicity of HAB species may not be explainable solely in terms of the physics and chemistry of the environment. Interactions with bacteria and/or viruses, for example, may play an important role in toxin production. Interactions with bacteria appear to play a role in the production of the neurotoxin, domoic acid, by the diatom, itzschia . The impsduction ,Another emerging issue has been the discovery by scientists at the Hawaii COHH and others that the neurotoxin, \u03b2-N-methylamino-L-alanine (BMAA), is produced by all known groups of cyanobacteria . BMAA ha2 emissions, fertilization of large areas of the ocean with iron, could also stimulate HABs. Field studies of the impact of iron fertilization by researchers at the Hawaii OHH Center have indicated that pennate diatoms are the primary beneficiaries of iron fertilization; Pseudo-nitzschia, the genus containing a number of species associated with the production of the neurotoxin domoic acid and amnesiac shellfish poisoning, is particularly responsive [In terms of human health effects worldwide, a very important yet poorly understood issue emerging in OHH is the potential impact of climate change on the ecology of pathogens and harmful algal species. Among the eukaryotic microalgae, dinoflagellates are expected to benefit from a warmer climate and more thermally stratified water column . Most HAsponsive .Various agencies, in part through the Centers, are helping to train a new generation of scientists in the interdisciplinary aspects of OHH through the participation of students and post-docs in OHH research projects and related activities, including the NSF-funded OHH research experience for undergraduates (REU) program and a new NOAA-funded OHH Traineeship Program.. Synergistic and collaborative contributions to the ongoing work of the Interagency Working Group on Harmful Algal Blooms, Hypoxia and Human Health have played an important role in the success of the Working Group in producing the first comprehensive assessment of the status of OHH research and opportunities for advancement in this new field [Collaborations among the various OHH centers and other OHH researchers have: (i) produced a noteworthy multi-center and interdisciplinary microbiological study of New Orleans and Lake Pontchartrain following Hurricane Katrina ; (ii) prew field . HopefulThe authors declare that they have no competing interests."}
+{"text": "The objective of this paper was to analyze the data supporting the possible role of melatonin on bone metabolism and its repercussion in the etiology and treatment of bone pathologies such as the osteoporosis and the adolescent idiopathic scoliosis (AIS). Melatonin may prevent bone degradation and promote bone formation through mechanisms involving both melatonin receptor-mediated and receptor-independent actions. The three principal mechanisms of melatonin effects on bone function could be: (a) the promotion of the osteoblast differentiation and activity; (b) an increase in the osteoprotegerin expression by osteoblasts, thereby preventing the differentiation of osteoclasts; (c) scavenging of free radicals generated by osteoclast activity and responsible for bone resorption. A variety of in vitro and in vivo experimental studies, although with some controversial results, point toward a possible role of melatonin deficits in the etiology of osteoporosis and AIS and open a new field related to the possible therapeutic use of melatonin in these bone diseases. Bones are structures under a continuous process of remodelating by the coupled activity of cells with resorptive functions (osteoclasts) and cells responsible for the formation of new bone (osteoblasts). The balance between the activities of both cell types is under the control of systemic hormones including parathyroid hormone (PTH), estradiol E2), and growth hormone as well as of cytokines and growth factors produced in the bone marrow . A major, and groMelatonin is an indoleamine secreted primarily by the pineal gland but also synthesized in other organs such as retina, gastrointestinal tract, and bone marrow. Melatonin plays a regulatory role in many physiological processes including bone physiology \u201310. NoctThe objectives of the current paper are (a) to review the data supporting the possible role of the age-dependent decrease of melatonin in the development of osteoporosis and the therapeutic value of melatonin as a treatment for this disease, and (b) to analyze the evidence related to the role of melatonin in the etiology and treatment of the AIS. Before doing so, we will describe the effects of melatonin on bone physiology, as the basis to understand the participation of this indoleamine in bone pathology.\u03b2-adrenoceptor blockers, serum concentrations of calcium dropped [The effects of melatonin on bone physiology were reviewed in an excellent article by Cardinali et al. . The pos dropped  an effec3) were also described. These results led the authors to conclude that lighting conditions influence bone metabolism in rats, and that melatonin likely plays an important role in these photoperiodic effects. Secondary changes in daily IGF-I and T3 oscillations, caused by short- and long-day conditions, also result in altered rhythmicity of daily bone resorption [More recently, Ostrowska et al.  re-examisorption . This exsorption . de novo [One interesting finding potentially related to melatonin and bone health is the demonstration of high concentrations of melatonin in bone marrow cells from mice and humans , 33, witde novo . The prede novo , 35. A variety of in vitro studies support the hypothesis of stimulatory effects of melatonin on both osteoblast differentiation and activity. Preosteoblasts cultured in the presence of melatonin underwent early cell differentiation and a major expression of bone marker proteins compared to control cells incubated without melatonin . These e\u03bcM range), (a) stimulates the proliferation and alkaline phosphatase activity of these cells; (b) promotes the expression of type I collagen, osteopontin, bone sialoprotein, and osteocalcin; (c) stimulates the formation of mineralized matrix. The signaling mechanisms mediating the melatonin actions on osteoblasts are still unknown although the role of the MAPK pathway seems relevant [In cultures of human osteoblasts , 40, melrelevant .\u03baB (RANK) on the surface of the osteoclast activating bone resorption [The activity of osteoclasts is under the control of paracrine factors produced by the osteoblasts. PTH and 1,25-dihydroxycholecalcipherol stimulate the expression of an osteoclast differentiating factor (ODF) by the marrow stromal cells and osteoblasts. ODF binds to the receptor activator of nuclear factor-sorption , 41. In sorption . Via thiOne important component of the osteoclasts activity is the generation of free radicals which contribute to the process of bone degradation and resorption . MelatonThere are, however, data contrary to the hypothesis of the effect of melatonin on bone-forming osteoblasts. Ostrowska et al.  found, i\u03b1 in MCF-7 cells by mechanisms involving calmodulin [An interesting question is the interaction of melatonin with estrogens at the level of the osteoblast. Estrogens have a positive impact on bone growth. Melatonin, according to the studies summarized above, has similar effects. Under many other circumstances, however, estrogens and melatonin usually have opposing effects. Thus, it is well known that estradiol modulates the function of the melatonin receptors in rat ovary  and Chinlmodulin \u201353. A stlmodulin ; howeverlmodulin . The natOsteoporosis is a prolonged structural deterioration of the skeletal system, usually associated with age, and with a major prevalence in women. Antiosteoporosis therapies include the use bisphosphonates, estrogen, and calcitonin to inhibit bone-resorbing osteoclasts preventing further bone breakdown. However, these therapies are insufficient in cases of individuals suffering from severe osteoporosis. Drugs that stimulate bone-forming osteoblasts  are expensive and with important associated side effects . These fAt present, no clinical trials have focused on the possible therapeutic value of melatonin in the treatment of osteoporosis. Some epidemiologic studies re-enforce the possible etiologic role of melatonin in osteoporosis. This is the case from a recent study of Feskanich et al. . This grExperimental studies carried out mostly in ovariectomized rats (as a model of menopause) suggest, in general, a protective role of melatonin in preventing bone degradation and promoting bone formation most probably through an action that involves melatonin receptors , 5. AmonAlthough the etiology of the AIS is unclear, histomorphometric data on iliac crest biopsies and vertebrae of scoliosis patients showed an impaired function of both osteoblasts and osteoclasts , 65. TheThe neuroendocrine hypothesis involving a melatonin deficiency as the source for AIS has generated great interest and controversy. This hypothesis, represented in In bipedal pinealectomized rats a reduction in melatonin, as a consequence of the pineal ablation, was found to cause scoliosis . RecentlNot all data support the hypothesis of the reduction of melatonin as the cause of scoliosis. Melatonin therapy after pinealectomy in young chickens had no effect on the development or progression of scoliosis , and cutBipedal ambulation in mammals is required, associated to low levels of melatonin, to generate scoliosis , 86. TheIn humans, the question of the possible role of melatonin in scoliosis has been addressed using different analytical approaches  Melatonin seems to promote bone formation and prevent bone resorption via several mechanisms which include the increase in the osteoblastic activity and differentiation, as well as the reduction in osteoclastic differentiation and activity, and by increasing osteoprotegerin expression and scavenging the free radicals responsible of bone resorption. (b) Melatonin may be an etiologic factor in the postmenopausal osteoporosis, and a therapeutic tool for this pathology, as an adjuvant with conventional treatments such as the administration of estrogens. (c) The recent data concerning the association of melatonin and AIS point toward their possible usefulness as both a diagnostic and therapeutic tool. (d) The experimental evidence on animal models suggests the value of clinical trials to assess the therapeutic possibilities of melatonin in bone diseases."}
+{"text": "Molecular pathology, a rapidly expanding discipline connecting pathology and molecular biology, is providing a deeper insight and understanding of the molecular basis of the aetiology and pathogenesis of human disease. This well-laid-out book covers the basic principles of molecular pathology, explains the most important molecular diagnostic techniques in user-friendly language, and describes their applications across a broad range of human diseases and problems, including cancer, hereditary disorders, identity testing, and infectious diseases. The book is divided into 11 comprehensive yet concise chapters, each providing extensive bibliographic references to the primary literature for those wanting to delve deeper into the subject.In the first four chapters the reader is introduced to basic concepts of gene structure and function, epigenetics, Mendellian and non-Mendellian patterns of inheritance, population genetics, types of mutations and chromosomal abnormalities, and modern molecular diagnostic techniques. In chapter five, common inherited diseases such as cystic fibrosis and Huntington's disease are discussed as examples of molecular screening for specific mutated genes or linked DNA polymorphisms now commonplace in clinical laboratories. The material covered in this chapter also includes testing for common mitochondrial and metabolic disorders, and the implementation of newborn and carrier screening programmes. In chapters six, seven and eight, basic concepts of tumour biology are covered, including oncogenes and tumour suppressor genes, programmed cell death (apoptosis) and telomere maintenance, and are reviewed in the context of molecular detection of gene rearrangements, tissue-specific gene transcription and oncogene activation in selected sporadic cancers, haematological malignancies, and familial cancer syndromes. Chapter nine provides a useful introduction to the field of pharmacogenetics and includes examples of genes demonstrating pharmacokinetic and pharmacodynamic variation together with their phenotyping. Chapter ten describes the differentiation of individuals from one another by \u2018DNA fingerprinting\u2019 for purposes of paternity testing, forensic sample identification, and bone marrow engraftment monitoring. The final chapter discusses the diagnosis and monitoring of human immunodeficiency virus and hepatitis C virus infections as examples of how DNA probes for viruses, bacteria, and parasites promise to revolutionise the practice of medical microbiology.Overall the book provides an excellent overview of the ongoing molecular revolution that is now transforming pathology and the practice of laboratory medicine. As well as providing a basic reference text for staff in clinical molecular diagnostic laboratories, it also forms a good basis for tutorials and exam preparations. I would highly recommend this book to scientists and health-care professionals working in the field of pathology, including pathology residents, clinicians, and medical students."}
+{"text": "Although the first case of fibrolamellar hepatocellularcarcinoma (FI-HCC) was described by Edmondson in 1956, and later confirmed in fivepatients by Peters, the majority of reports followed those of Berman A case of FI-HCC, which is rarely diagnosed in Mediterranean countries including Turkey,is presented in the following report."}
+{"text": "Seasonal variation has been described in the presentation and growth of several malignant tumours, including cancers of the breast, uterus, uterine cervix, urinary bladder, liver, lymphatic system and skin, although the mechanisms are not known. We herein describe a circannual rhythm for thyroid cancer , with significantly more cases presenting during the late autumn and winter. In a subset of these cases (127 papillary carcinomas), significant seasonal variations with highest values in autumn-winter were found for tumour diameter and proliferation indicators (S- and G2M-phase fractions). These results indicate the likelihood of a seasonal factor (or factors) of importance for the regulation and modification of tumour cell proliferation. When further clarified, this might be of relevance for the planning of diagnostic and therapeutic strategies."}
+{"text": "Geographical correlations between standardized, mortality ratios (SMRs) of cancers and consumption of different types of alcoholic beverages , of cigarettes, and urbanization were examined for all 46 prefectures in Japan. Suggestive correlations were observed between cancer of the oesophagus in males and both shochu and whisky (r = 0.27 and 0.22 respectively), between cancer of the rectum in males and wine (r = 0.45), and between cancer of the prostate and shochu (r = 0.50). These correlations were also confirmed in the partial correlations between SMRs of cancers and consumption of alcoholic beverages, controlling for the two variables urbanization and consumption of cigarettes. Alhtough cancers of other sites were also correlated with certain types of alcoholic beverages, their associations seemed to be secondary to other factors. The validity of higher-order partial correlations and the problems of correlation study are also referred to."}
+{"text": "Nasopharyngeal cancer (NPC) is a unique disease with increasing interest for many physicians due to its unusual etiology, histology, and epidemiology. The recent era of fiberoptic endoscopy now provides the clinician with better tools for the screening, diagnosis, staging, and follow-up of NPC. Theuse of high resolution flexible and rigid nasopharyngoscopy gives the physician an opportunity fora more sensitive examination in a higher proportion of patients. Ultimately, this will allow for earlierdiagnosis of NPC, and improved prognosis and better quality of life for the patients with this disease.Also, by allowing the clinician to perform directed biopsies of the nasopharynx under localanesthesia, fiberoptic nasopharyngoscopy allows a less morbid and more cost-effective approach towardsthis disease, including screening protocols in certain high risk regions of the world."}
+{"text": "Founded in 1969, the Organisation of the Islamic Conference (OIC) is comprised of 57 nations that together represent the second largest international organization after the United Nations The information in Schistosoma haematobiumS. haematobium infection is associated with reductions in child growth and development similar to those caused by the intestinal helminths Schistosomiasis is also a common NTD in the Islamic world. Almost one-half of the world's schistosome infections occur in OIC member states, especially in Nigeria, Mozambique, Burkina Faso, Mali, and Cote d'Ivoire Ascaris lumbricoides are capable of withstanding the cold and dry conditions that can occur in these countries. Ascariasis and other intestinal parasitic infections are also highly prevalent among children living in the Gaza strip Indeed, several conflict and post-conflict countries in the OIC stand out for their high prevalence rates of NTDs. In Sudan, the high endemicity of trachoma, hookworm and other intestinal helminth infections, and schistosomiasis were already mentioned. In addition, dracunculiasis (guinea worm) is still prevalent, and more cases of guinea worm occur there relative to any other country The health and socioeconomic effects of the NTDs, including their poverty-promoting and conflict-promoting features, should provide strong incentives to try and control or eliminate these infections in the poorest countries of the OIC. Indeed, through mass drug administration with either low-cost generic drugs or drugs donated by multinational pharmaceutical companies, most of the NTDs listed in Through private donations from the Bill & Melinda Gates Foundation and other foundations, the United States government, the British Department for International Development, and the World Health Organization are working together with public\u2013private partnerships aligned through the Global Network for Neglected Tropical Diseases and several non-governmental organizations, including the Carter Center, to implement and integrate mass drug administration for the most common NTDs in more than one dozen endemic countries The impressive establishment of new and distinguished universities in Saudi Arabia, UAE, Qatar, and elsewhere"}
+{"text": "Cryptosporidium parvum.Since the genomic DNA sequence encodes all of the heritable information responsible fordevelopment, disease pathogenesis, virulence, species permissiveness and immune resistance,a comprehensive knowledge of the C. parvum genome will provide the necessaryinformation required for cost-effective and targeted research into disease prevention andtreatment. With the recent advances in high-throughput automated DNA sequencingcapabilities, large-scale genomic sequencing has become a cost-effective and time-efficientapproach to understanding the biology of an organism. In addition, the continueddevelopment and implementation of new software tools that can scan raw sequences forsigns of genes and then identify clues as to potential functions, has provided the finalrealization of the potential rewards of genome sequencing. To further our understanding ofC. parvum biology, we have initiated a random shotgun sequencing approach to obtain thecomplete sequence of the IOWA isolate of C. parvum. Our progress to date hasdemonstrated that sequencing of the C. parvum genome will be an efficient and costeffectivemethod for gene discovery of this important eukaryotic pathogen. This will allowfor the identification of key metabolic and immunological features of the organism that willprovide the basis for future development of safe and effective strategies for prevention andtreatment of disease in AIDS patients, as well as immunocompetent hosts. Moreover, byobtaining the complete sequence of the C. parvum genome, effective methods forsubspecific differentiation (strain typing) and epidemiologic surveillance (strain tracking)of this pathogen can be developed.A lack of basic understanding of parasite biology has been a limiting factor in designingeffective means of treating and preventing disease caused by"}
+{"text": "World Health Organization cites among the main challenges of populational aging the dual disease burden: the greater risk of disability, and the need for care. In this sense, the most frequent chronic diseases during old age worldwide are high blood pressure, type 2 diabetes mellitus, cancer, arthritis, osteoporosis, depression, and dementia. Chronic disease-associated dependency represents an onerous sanitary and financial burden for the older adult, the family, and the health care system. Thus, it is necessary to propose community-level models for chronic disease prevention and control in old age. The aim of the present work is to show our experience in the development and implementation of a model for chronic disease prevention and control in old age at the community level under the active aging paradigm.A longitudinal study will be carried out in a sample of 400 elderly urban and rural-dwelling individuals residing in Hidalgo State, Mexico during five years. All participants will be enrolled in the model active aging. This establishes the formation of 40 gerontological promoters (GPs) from among the older adults themselves. The GPs function as mutual-help group coordinators  and establish self-care and self-promotion actions for elderly well-being and social development. It will be conformed a big-net of social network of 40 mutual-help groups of ten elderly adults each one, in which self-care is a daily practice for chronic disease prevention and control, as well as for achieving maximal well-being and life quality in old age. Indicators of the model's impact will be (i) therapeutic adherence; (ii) the incidence of the main chronic diseases in old age; (iii) life expectancy without chronic diseases at 60 years of age; (iv) disability adjusted life years lost; (v) years of life lost due to premature mortality, and (vi) years lived with disability.We propose that the implementation of the model active aging framework will permits the empowerment of older adults, which constitutes basic social capital for chronic disease prevention and control in old age. The challenges of populational aging involve everyone. In this regard, the United Nations reported that in 2007 there were 700 million persons aged 60 years and over on the planet, which represents 11% of the entire world population. Likewise, it is projected that this percentage will increase to 15% by the year 2025 and to 22% by 2050 [On the other hand, the World Health Organization (WHO) cites among the main challenges of populational aging the dual disease burden: the greater risk of disability, and the need for care .The most frequent chronic diseases during old age worldwide are high blood pressure, type 2 diabetes mellitus, cancer, arthritis, osteoporosis, depression, and dementia ,4, In thWe observed the principal repercussions of chronic diseases in old age in terms of physical, mental, and social functionality, affecting basic, instrumental, and advanced activities of daily life. Chronic disease-associated dependency represents an onerous sanitary and financial burden for the older adult, the family, and the health care system ,8.In the Second World Assembly on Ageing held in Madrid in 2002, the relevance of active aging was highlighted as a key strategy for achieving the maximum health, well-being, and quality of life (QOL) of older adults, defining this as \"the process of optimizing opportunities for health, participation and security in order to enhance quality of life as people age\" .Active aging refers to the empowerment of older persons in biological, psychological, and social areas, understanding empowerment as the individual's self-promotion, independence, and self-confidence, as well as his/her right to a dignified way of life according to self-imposed values, the ability to stand up for one's own rights, and to be free . Active Social networks refer to the personal, community, and institutional contacts by means of which the individual maintains his/her social identity and receive material, instrumental, emotional, and informative support Figure . In thesThe type of social support that social networks can afford are the material, instrumental, affective, and informative provisions, real or perceived, provided by family, friends, the community, and formal institutions -11.Our research group developed an active aging model for chronic disease prevention and control in old age at the community level, comprising a big-net of social networks of mutual-help of elders in which self-care is a daily practice ,13.Thus, it is necessary to propose community-level models for chronic disease prevention and control in old age. The aim of the development and implementation of a model active aging is reach the empowerment of elderly-dwelling individuals for chronic disease prevention and control in old age at the community through self-care, self-help and self-promotion.A longitudinal study will be carried out in a sample of 400 elderly urban and rural-dwelling individuals residing in Hidalgo State, Mexico during five years, with a significance level of 0.05, a power of 80% and an expected difference in chronic diseases incidence of 50%  between The subjects agreed to participate in the study after giving their informed consent. The Ethics Committee of the Universidad Nacional Aut\u00f3noma de M\u00e9xico (UNAM) Zaragoza Campus approved the research protocol for this study.All participants will be enrolled in the model active aging. This establishes the formation of 40 gerontological promoters (GPs) from among the older adults themselves. The GPs function as mutual-help group coordinators  and establish self-care and self-promotion actions for elderly well-being and social development. It will be conformed a big-net of social network of 40 mutual-help groups of ten elderly adults each one, which will be established actions of self-care as daily practice for chronic disease prevention and control, as well as for achieving maximal well-being and life quality in old age.As a key element, the model establishes the training of gerontological promoters (GPs) from among the older adults themselves. The GPs function as mutual-help group coordinators  and establish self-care and self-promotion actions for elderly well-being and social development.Self-care at the gerontological level refers to the reasoned theoretically based behavior of the individual that allows the elderly adult to decide and act upon the prevention, diagnosis, and treatment of his/her disease, as well as the maintenance of health and maximum enjoyment of QOL, according to his/her sociocultural context, utilizing formal and informal social networks in optimal fashion during aging. Similarly, the mutual-help including reasoned solidarity-oriented behavior that is adopted by a group of elderly individuals who share like problems and whose members are aware of the advantages and commitments acquired on accepting voluntarily to form part of the group. Concerning self-promotion, this involves the actions that an older adult or a self-help group carries out autonomously, in advance, and in optimal form and considers elements and mechanisms of formal and informal social support networks.The model contemplates a Primary Gerontological Health Care Unit (PGHCU), whose purpose is to coordinate the big-net of social networks of mutual-help groups of elderly adults, in which self-care is a daily practice for chronic disease prevention and control, as well as for achieving maximal well-being and QOL in old age Figure .Mature individuals learn only what they want to learn; (ii)Mature individuals learn only what they are capable of learning; (iii) Mature individuals learn mainly what they teach themselves, and (iv)Mature individuals learn mainly in terms of their experience.The PGHCU linked with Institutions of Higher Education in Gerontology will be responsible for the training of gerontological promoters (GP) following the formal academic structure of a workshop Table  and consThe requirements for participating in training courses for GPs are as follows: (i) interest in participating in an intensive training program focused on holistic gerontological development; (ii) 60-74 years of age; (iii) literate; (iv) absence of handicapping illnesses or serious visual or auditory disabilities, and (v) leadership attributes and the ability to coordinate small groups.We will implement a 60-hour workshop that integrated both theoretical and practical aspects (14 weekly sessions). An introductory textbook entitled \"Community Gerontology\" was designed specifically for this aim .Topics for the workshop were selected and approved by a panel of four Gerontologists and took into consideration their basic knowledge on Community Gerontology and age-related changes in the following: biological; psychological, and social aspects; prevention of chronic diseases; healthy lifestyle in the aging period; empowerment, and social networks Table , accordiThe pillars of the model are as follows: gerontological health care; gerontological orientation for families, and gerontological social development.The fundamental objective of GHC is to prevent and detect the diseases of greatest prevalence in the elderly, such as high blood pressure, diabetes mellitus, depression, osteoarthrosis, cognitive deterioration, and osteoporosis, as well as establishing actions of healthy aging for the maintenance, prolongation, and recuperation of physical, mental, and social functionality Figure . The actGPs should possess sufficient knowledge for orienting and training family members to provide basic care for the healthy and ill elderly adult in the home, with the purpose of preventing diseases and/or their complications, in addition to promoting healthy lifestyles for the maintenance, prolongation and recuperation of physical, mental, and social functionality.Among its goals, the model contemplates maximum enjoyment by older adults of their situation of being old. Thus, implantation is recommended of programs of recreation, adaptation, and psychosocial and occupational excelling within an anthropological focus, according to the elderly individual's interests, age, schooling, gender, health state, and socioeconomic situation.The model established flexible general guidelines framed within an active aging paradigm. Therefore, actions for GSD should be adopted by the population in which the model is implemented , as well as by older adult groups of different sociocultural and economic conditions.In 2007, an agreement was signed between the National Autonomous University of Mexico (UNAM) and the Institute for Care of the Elderly in the State of Hidalgo (Mexico) with the objective of implementing a State Active Aging Program according to the model developed at the UNAM (Zaragoza Campus).Among actions implemented within the agreement's framework, we are able to highlight the following: (i) the training of professional personnel of the Institute on the active aging paradigm; (ii) training of gerontological promoters; (iii) the editing of a text on Community Gerontology direct toward elderly adults, and (iv) in 2008, the Institute adopted the Active Aging paradigm as public and strategic policy for care of the elderly.Indicators of the model's impact will be the following: (i) empowerment; (ii) therapeutic adherence; (iii) the incidence of the main chronic diseases in old age; (iv) life expectancy without chronic diseases at 60 years of age; (v) disability adjusted life years lost (DALYs); (vi) years of life lost due to premature mortality (YLL), and (vii) years lived with disability (YLD).Walter (2006) proposes the following seven principles that allow for delineating the components of active aging: (i) participation should contribute to the well-being of the older adult; (ii) it should have a preventive focus; (iii) it should be within the reach of the entire population of elderly individuals, including those who are frailty and dependent, with the degree of participation according to the physical, psychological, and social conditions of the older adult; (iv) it should propitiate the maintenance and strengthening of intergenerational solidarity; (v) it should take into consideration the person's rights and obligations; (vi) it should be participative with empowerment, and (vii) it should contemplate national, local elements and cultural diversity .The following are the pillars of active aging are health, participation, and security: (i) the prevention and control of chronic diseases, as well as maintaining, prolonging, and recuperating physical, mental, and social functionality according to the older adult's age and specific sociocultural context should be considered as fundamental elements with regard to health; (ii) concerning participation, opportunities should be provided that permit older adults to have productive social participation in remunerated and unremunerated activities, in programs linked with social development, work, education, health, cultural and spiritual development, etc., according to elderly persons' rights, capabilities, needs, and preferences; (iii) concerning security, policies should be established that guarantee permanent access to health, alimentation, housing, and well-being for functional older adults, as well as for those requiring instrumental care.On the other hand, active aging as a policy framework constitutes a feasible alternative for substituting the current model, which visualizes the elderly adult as a sickly being and one in decadence, without the possibility of economic and social development. Therefore, the elderly are frequently considered a social and economic burden.The development of community care models within the framework of active aging is a call and a challenge to which we should devote ourselves in all countries. In this regard, we should confront the present hegemonic view of aging within the framework of a structured dependency, which has propitiated a marketing focus in parallel fashion on covering hospital and care needs, developing in parallel great industries of technical, care, and drug industries for aging, which indirectly has negative repercussions on physical, mental, and social functionality . This foOn the other hand, there is an ever greater demand for health care for older adults, outpacing in some cases the resources allocated for this purpose. Thus, there is a need to propose alternative care models that exert a significant impact on cost-benefit and on the QOL of the elderly . In thisIn different studies, the social capital has been recognized of the group of young-old individuals (aged 60-74 years) for active aging, because >80% of this age group are functional and can potentially provide material, instrumental, affective, and informative support to other older adults -24 Figu.We propose that the implementation of the model active aging will permit us to reach the empowerment of older adults for self-care, and consequently prevent and control the diseases chronic, besides its complications.The authors declare that they have no competing interests.VMMN conceived and designed the study, drafted the manuscript. MLMM participated in the design of the study and interviews of the participants. ECM participated in the design of the study and interviews of the participants. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:"}
+{"text": "In the spring of 1999 in rural Newfoundland, abortions in goats were associated with illness in goat workers. An epidemiologic investigation and a serologic survey were conducted in April 1999 to determine the number of infections, nature of illness, and risk factors for infection. Thirty-seven percent of the outbreak cohort had antibody titers to phase II Coxiella burnetii antigen >1:64, suggesting recent infection. The predominant clinical manifestation of Q fever was an acute febrile illness. Independent risk factors for infection included contact with goat placenta, smoking tobacco, and eating cheese made from pasteurized goat milk. This outbreak raises questions about management of such outbreaks, interprovincial sale and movement of domestic ungulates, and the need for discussion between public health practitioners and the dairy industry on control of this highly infectious organism."}
+{"text": "The Second International Conference of the African-Caribbean Cancer Consortium (AC3) was held on May 12\u201313, 2008 at the Wyndham Miami Airport Hotel & Executive Meeting Center in Miami, FL, USA. The conference was organized by the University of Pittsburgh, Graduate School of Public Health and the University of Pittsburgh Cancer Institute.) was established in 2006 for the study of viral, genetic, environmental, and lifestyle risk factors for cancer in populations of African descent [The AC3 . Session I continued with five additional short presentations of research findings by AC3 members -6.The second general session was chaired by Dr. Camille Ragin from the University of Pittsburgh, US and Dr. Norma McFarlane-Anderson from the University of the West Indies, Jamaica. The keynote address was given by Dr. Raleigh Butler from the University of the West Indies, The Bahamas and was entitled: \"Fact, Frictions and Fractions, HPV the Bahamian Experience\". Dr. Butler presented an overview of the Epidemiology of HPV and related cancers and described the current status of this disease among Caribbean populations. Cervical cancer is the second cause of cancer deaths in the Bahamas, and annual cervical screening is performed in less than 10% of this at risk population. Session II continued with four additional presentations of human papillomavirus (HPV) related studies conducted in Caribbean populations -10.Day one of this conference concluded with two Special Topics sessions. The first, \"Sample Collection, Data Sharing and Confidentiality\" was facilitated by Dr. Emanuela Taioli from the University of Pittsburgh. The participants defined appropriate protocols for collection and storage of data and samples as well discussed the importance of standardization in multi-centered collaborative studies. The second Special Topic, \"Building Infrastructure for Multi-Center Studies\" was facilitated by Dr. Judith Jacobson from Columbia University. During this session the participants discussed decisions and steps necessary for obtaining funding and implementing a collaborative study.The day ended with a dynamic poster session and networking dinner reception, where the participants continued their discussions about their research projects and reconnected with their colleagues and met new ones.This session was chaired by Dr. Michael Okobia, from the University of Benin, Nigeria and Dr. Emanuela Taioli from the University of Pittsburgh, US. Dr. Taioli launched the session as the keynote speaker where she presented the descriptive Epidemiology of Breast cancer among individuals of African ancestry; discussed risk factors for this disease and identified the gaps in research for minority populations. Dr. Taioli also presented some of her current research findings from her studies of African American populations. The session ended with three additional research presentations by AC3 investigators -13.Dr. Elizabeth Quamina Cancer Registry in Trinidad and Tobago and Dr. Wallis Best-Plummer representing the Guyana Cancer Registry in Guyana. The presenters provided data from their corresponding cancer registry and were later joined by Dr. Michael Okobia, from the University of Benin, Nigeria for a panel discussion about the establishment process of cancer registries and the challenges surrounding cancer registration in developing countries.The breast cancer session was followed by a Special Topic discussion on Cancer Registration. There were presentations of cancer statistics by Ms. Veronica Roach from The conference concluded with concurrent breakout sessions where AC3 investigators divided into cancer-specific working groups . During these sessions, AC3 investigators discussed the status of the ongoing collaborative studies and defined future studies.All participants were asked to complete evaluation forms for both meeting dates and 95% of the forms were returned. The majority of the participants (65%) reported that, based on their prior knowledge, they learned more after attending the cancer registration session. In general, participants reported that the conference fulfilled their reason for attending (73%). Eight-five percent were satisfied with the conference content, organization (81%), and overall conference experience (85%).The authors declare that they have no competing interests."}
+{"text": "The results of two 5-year studies, for 1974-78 and 1984-88, of cutaneous malignant melanoma (CMM) in Northern Ireland show changes in the presentation of the disease. Although there is some evidence of earlier diagnosis, the rise in incidence has produced an overall increase in the number of cases with advanced disease."}
+{"text": "The conference was sponsored by the following units of the University of Illinois at Urbana-Champaign: Center for Zoonoses Research; Department of Pathobiology; Environmental Council; Host-Microbe Systems Theme of the Institute for Genomic Biology; Office of International Programs and Studies; Program in Arms Control, Disarmament, and International Security; and Conservation Medicine Center of Chicago. Proceedings are available at Jonathan Patz, University of Wisconsin-Madison, opened the conference with a presentation about the effects of deforestation and climate on infectious diseases in the northern region of the Peruvian Amazon. Concomitant with new deforestation, the area experienced a sharp (50-fold) rise in malaria incidence during 1987\u20131997, coupled with an invasion by Anopheles darlingi, the most important vector of malaria in South America. A strong relationship has been found between the extent of deforestation, larval sites of A. darlingi, and abundance of adult mosquitoes. The need for a broad-based policy approach to ecology-disease relationships was highlighted.Paul Gibbs, University of Florida-Gainesville, discussed emerging infectious disease trends. The potential overshadowing of recent, naturally occurring emerging diseases and epidemics  by a succession of disasters, both natural and manmade, was examined. Dr. Gibbs presented the global factors that have led to the increased emergence of these diseases, a summary of lessons learned, and a broad agenda for action.Alison Weiss, University of Cincinnati, addressed the reemergence of Bordetella pertussis as a notable health threat despite active vaccination programs. She discussed the increased cases of pertussis during the past 25 years and the shift from a whole-cell vaccine to acellular pertussis vaccines, which failed to reverse this increase. Bactericidal immunity, if achievable, was presented as an option for preventing the disease (whooping cough) and transmission of the agent (B. pertussis).Steven Blanke, University of Illinois at Urbana-Champaign, discussed persistence mechanisms of Helicobacter pylori and explored the hypothesis that phase variation results in altered forms of H. pylori that can withstand the gastric environment. Phase variants of a single gene have been found to demonstrate remarkably distinct properties in terms of stress resistance and virulence factor expression.R. Mark Buller, Saint Louis University, presented evidence that human monkeypox is a poxvirus zoonotic disease. The first US outbreak of monkeypox virus infection in 2003, unlike previous outbreaks in Africa, resulted in no deaths and no documented human-to-human transmission. Evidence supports the existence of monkeypox virus strains that differ in virulence and transmissibility for humans.Ricardo Gurtler, University of Buenos Aires, outlined a longitudinal study of the transmission dynamics and control of Trypanosoma cruzi, the causative agent of Chagas disease, in 3 rural villages in northwestern Argentina. Regular monitoring of insect infestations and parasite infections of triatomine bugs was accompanied by demographic assessments of prevalence and infection in humans and dogs before and after the establishment of community-based surveillance in 1992.May Berenbaum, University of Illinois at Urbana-Champaign, discussed biological invasions that resulted in establishment of nonindigenous species, their role in contemporary global change, and their subsequent economic and ecologic costs. Effects on health are disproportionately large, in part because invasive species often owe their success to unique chemical defense mechanisms and because, without coevolved enemies of their own, they can serve as extraordinarily effective disease vectors.Nina Marano, Centers for Disease Control and Prevention, addressed the need for multidisciplinary public policy responses to emerging zoonoses. In particular, she examined the case of highly pathogenic avian influenza in Southeast Asia and presented recommendations for integrated research approaches.A panel consisting of the conference speakers and local experts explored differences between molecular and ecologic studies, between animal and human studies, and between science and public policy. The panel examined strategies for bridging these gaps. Recommendations from this session will appear in a forthcoming Center for Zoonoses Research white paper."}
+{"text": "The effects of combinations of dipyridamole, an effective blocker of the salvage pathway of DNA synthesis, and 8 types of anti-cancer drugs on the growth of human T, B and myeloid leukaemia/lymphoma cell lines in vitro were examined. In combinations, dipyridamole and vincristine (VCR), and dipyridamole and vindesine had synergistic inhibitory effects. Dipyridamole reduced the efflux of VCR from cells and enhanced their VCR accumulation in a dose-dependent manner at concentrations of up to 10 microM in the lymphoid cell lines, MOLT-3 and BL-TH, and of up to at least 20 microM in the myeloid cell line, ML-1. Dipyridamole also enhanced the accumulation of VCR in PHA-stimulated and un-stimulated lymphocytes of normal donors, but efflux of VCR was more rapid from normal lymphocytes than from cultured cell lines. It is proposed that combination therapy with dipyridamole plus VCR should be effective in the treatment of leukaemia and lymphoma."}
+{"text": "This paper describes an integrated approach to the computerizationof all major disciplines of laboratory medicine and pathology.Installed in the Department of Pathology, Singapore GeneralHospital (SGH), the computer system discussed comprises aRISC-based Data General Aviion 6200 computer and MeditechMAGIC software. The system has been interfaced with thehospital host IBM computer and supports patient informationtransfer, result reporting, phlebotomy management, and compilationof laboratory and financial management reports. The mainfunctions of the system include: on-line and off-line acquisition ofpatient information and test data; preparation of single/combined/cumulative reports; transmission of reports within and betweenlaboratories; instantaneous provision of data in response totelephone enquiries; calculations of quality control/workload/productivity statistics and indices; and generation of billing lists.The computer enables reports to be provided on patient tests resultsin individual wards, at various specialist out-patient clinics, and inthe Accident and Emergency Department of the SGH through theIBM mainframe, as well as to remote printers installed at severalother major hospitals.The use of the MAGIC integrated laboratory informationsystem has resulted in a significant increase in laboratory efficiencyand productivity."}
+{"text": "The first-ever National Summit on Neglected Infections of Poverty in the United Stateswas held October 27, 2009, in Washington, DC, bringing together key leaders in publichealth, public policy, and government. Organized by the Eisenhower Institute, the GeorgeWashington University, the Adler School, the American Public Health Association, and theCenters for Disease Control and Prevention, the goal of the summit was to raiseawareness about neglected infections of poverty in the United States and identifyresources and actions to address them.Neglected infections of poverty are a group of chronic and debilitating parasitic andother infections  that disproportionately affect peopleliving in poverty. Major neglected infections of poverty in the United States includetoxocariasis, trichomoniasis, toxoplasmosis, cysticercosis, Chagas disease, andcongenital cytomegalovirus infection  improve understanding of theimpact and geographic distribution of neglected infections of poverty; 2) enhanceunderstanding of modes of transmission and human ecology of infections of poverty; 3)enhance prevention and promote research and development; and 4) disseminate informationto multiple audiences. Through a wide-ranging and rich dialogue, summit participantsdeveloped 4 priority areas for follow-up. These areas will be pursued by working groupsconvening in early 2010.Outreach and mobilizationData and surveillance needsEconomic impact of neglected infections of povertyResearch and development needshttp://inside.gwumc.edu/niops/ or contactneglectedinfectionsofpoverty@cdc.govFor further information see"}
+{"text": "The conference centered on chronic intracranial hypertension (IH) including the latest research and clinical information. It was sponsored by the Intracranial Hypertension Research Foundation and held at the University of Texas Medical School, Houston, on June 21\u201322 The Intracranial Hypertension Research Foundation (IHRF) in Vancouver, Washington, promotes research into the pathophysiological basis of chronic IH and the evolution of better treatment and, ultimately, a cure. IHRF is a multi-functional organization. It not only encourages research, but also facilitates understanding and management of chronic primary and secondary IH, through research, training and education programs worldwide.IHRF sponsors programs for researchers and clinicians, as well as educational conferences for patients and families. The Houston conference was attended by 108 patients and family members who heard presentations by nine clinicians and researchers.Patients asked many questions during extensive panel sessions. The conference also allowed patients to speak about personal experiences with the disorder. IHRF held the first conference on chronic IH in 2006 at the Oregon Health & Science University (OHSU). A wide variety of subjects were presented to enhance patient knowledge and awareness. Patient education importantly improves patient insight about the disorder. It also facilitates active cooperation with their physicians. Understanding limitations of accepted medical and surgical treatment leads to realistic goals in management.Additionally, patient education is vital in controlling health care costs.The opening presentation by Conrad Johanson, Professor of Clinical Neuroscience at Brown University dealt with CSF production in the choroid plexus and its possible role in IH. Covered in the lecture was the structure of the choroid plexus, the dynamic turnover of ions and water in CSF production by the choroidal epithelium, the transport of CSF solute for the brain, and homeostasis of CNS extracellular fluid. A discussion of translational research goals involving the choroid plexus and CSF and possible directions for research in IH concluded the presentation.John McGregor, Associate Professor of Neurosurgery at Ohio State University, spoke on \"Neural Hydrodynamics Disorders: Hydrocephalus, Intracranial Hypertension and the Chiari Malformation. Relationships, Similarities and Differences\" which was followed by two lectures covering CSF shunt and valve technology. The latter two presentations discussed in depth the available technology with details of the features of each device.The conclusion was that despite the numerous designs, the overall success rate for the various shunts and valve equipment are similar. Better designed shunts are greatly needed.The next lecture by Conrad Johanson: \"Current Theories on Causation and Reduction of Elevated CSF Pressures: Implications for Intracranial Hypertension\", began with a discussion of CSF fluid dynamics centering on CSF reabsorption including the controversial arachnoid and CSF lymphatic drainage. The role of neuropeptides such as atrial natriuretic peptide (ANP) in CSF production and the role of growth factors like basic fibroblast growth factor (FGF2) in CSF reabsorption, were identified. The intriguing possibility of peptides as pharmacological agents in controlling intracranial pressure (ICP) was thought provoking and stimulating, especially since no specific drug is available to control production and egress of CSF.Steven Katz, neuro-ophthalmologist and Associate Professor of Ophthalmology at Ohio State University, lectured on the symptoms and signs in idiopathic intracranial hypertension (IIH) and the medical management options. He discussed approaches that work best in his practice. Steven Katz had previously demonstrated the somatostatin receptors 1 and 2 in normal human choroid plexus and arachnoid granulations and thus surmised that somatostatin is involved in CSF production and egress. His preliminary clinical use of octreotide, a peptide that mimics somatostatin, was discussed, including the potential complications of somatosatin analogs to control IH. Steven Katz described his techniques for optic nerve sheath decompression and demonstrated findings from many of his procedures. He attributed excellent outcomes to reduced surgery duration, i.e. especially the time of optic nerve stretching. He emphasized that short exposure and optimal surgical approach lead to minimal diplopia, ptosis and most importantly, minimal vision loss.Marc Criden, neuro-ophthalmologist and Assistant Professor of Ophthalmology at the University of Texas, Houston, presented an updated overview of pediatric IH. In children under 10 years, gender and weight are not the factors they are in adults. He pointed out that many physicians consider IH in children under 10 to be a different disorder because of these characteristic differences. Headaches associated with IH and how best to manage them were discussed by neurologist and neuro-ophthalmologist, Leonard Hershkowitz of Baylor University. He indicated his management techniques that worked well for him.A reception followed in which patients again communicated with the speakers.The 2nd conference day opened with a discussion of the mission and goals of IHRF and a review of IHRF-sponsored research by Emanuel Tanne, Clinical Assistant Professor of Ophthalmology, OHSU and president of IHRF. He pointed out that IHRF works to remove significant obstacles to research: under-funding, under-coordination of effort, incomplete recognition of the life-altering effects of IIH, and low recruitment of researchers in this area. IHRF funded animal model development projects at the University of Chicago and the University of Arkansas. Under investigation is a knockout mouse that develops IH shortly after weaning. Other research areas included joint testing at the University of Utah of a NASA-developed, non-invasive, closed loop ultrasound device to measure ICP in microgravity and an investigation of vitamin A receptors in arachnoid granulations at Ohio State University. IHRF also partners with the Casey EyeInstitute, in regard to the Intracranial Hypertension Registry at the Oregon Health & Science University, Portland. The IH Registry is a relational database management system designed for medical research. Emanuel Tanne discussed ongoing Registry research, including studies in genetics, economics, weight gain and pregnancy. Jessica Tanne, IHRF Director, Communications & Development, discussed raising community awareness, fundraising and the importance of becoming an IH ambassador. Illustrating and discussing their fundraising creativity were Dori Clements and Jacque Tate, both parents of IH children.Clark Sitton, Assistant Professor of Radiology, University of Texas, Houston, discussed types of imaging studies and the goals of imaging in IH. He presented an extensive collection of studies demonstrating pathological findings associated with IH.Bariatric surgery as a possible option in the management of IH was presented by Erik Wilson, Assistant Professor of Surgery, University of Texas, Houston, who covered risks and benefits of bariatric surgery, using his extensive experience as a guide. He also discussed types of procedures available and his personal approach to follow-up and long term goals for patients. Marc Criden presented a new hypothesis to consider for clinical management of chronic IH: establishing target pressures for each patient with IH. The hypothesis arose out of his and Steven Katz's experience with patients at the last IHRF patient conference, where they were impressed by the variety of symptoms and patient reports contradictory to current teaching. They hypothesized that chronically elevated ICP is neurologically damaging, even in patients without significant visual dysfunction or intractable headache. They are presently investigating and evaluating this hypothesis. The final speaker, Kapil Kapoor, resident in ophthalmology at the University of Texas, Galveston, presented his research on hyposmia and IH. He found that patients with elevated ICP have a decreased sense of smell and concluded that other nerves such as the olfactory nerve may be functionally compromised in the setting of IH by a mechanism similar to that of optic nerve compression. Therefore, it may be appropriate to consider IH as a more global neuroanatomic insult of augmented CSF pressure than previously considered.While the intent of educating patients was admirably accomplished by this conference, the conference served as a unique experience for researchers and clinicians to hear from a large group of patients about the nature of their disorders. Therefore, not only did physicians from a variety of sub-specialties have an opportunity to exchange ideas and explore future collaborative projects they also left with a different perspective of chronic IH and a new appreciation of patient-centered conferences as a mechanism to expedite translational CSF research.The author declares he has no competing interests.I am the sole author and have read and approved the final version of this paper."}
+{"text": "The well-known association between vte modern molecular techniques vte trials of cancer therapy have defined additional risk factors that compound the thrombotic risk The burden of venous thromboembolism (vte has been associated with a high risk of recurrent thrombosis and of bleeding complications vte are at increased risk of mortality vte prevention and treatment in cancer patients, and sets the stage for future directions in this important domain The treatment of cancer patients for The inherent properties of blood vessels, endothelial cells, adhesion receptors, and soluble plasma coagulation proteins render these structures and molecules important in the propagation of coagulation and the regulation of cancer-cell growth. Perturbation of these components by cancer treatment interventions such as surgery, chemotherapy, and supportive care can further exacerbate prothrombotic properties.vte, as are certain cancer types, including pancreatic, stomach, brain, lung, and hematologic malignancies. In cancer patients, vte is not only a frequent cause of death, it also identifies a patient population with poor prognosis, and it is both clinically challenging and financially costly to treat. As cancer treatment modalities evolve, differences in the added thrombogenic risk for patients also emerge\u2014for example, the addition of anti-angiogenic therapy is associated with one of the highest risks of thrombotic complications.Advanced cancer is more often associated with vte, how should thromboprophylaxis for cancer patients be optimized?Given the strong association of cancer and Current Oncology, patients undergoing cancer surgery and those hospitalized for investigations and treatment of cancer are good candidates for appropriate thromboprophylaxis vte should be considered for long-term low molecular weight heparin therapy, given the more favourable clinical outcomes seen as compared with the outcomes seen with traditional oral anticoagulant therapy.Clearly, as recently reviewed in vte, and participation in good clinical trials evaluating cancer and coagulation should routinely be part of our comprehensive care of cancer patients.The recent guidelines from the American Society of Clinical Oncology underline the importance of optimizing anticoagulation management of cancer patients. The practice of appropriate thromboprophylaxis, up-to-date anticoagulation of cancer-associated"}
+{"text": "It was launched on July 2 The specific objectives of i-FAB are to:(i) Increase the profile of foot and ankle biomechanics research within academic, clinical and industry communities(ii) Promote the value of foot and ankle biomechanics research to research users (iii) Develop a coordinated approach to addressing the challenges of experimental and computational biomechanics of the foot and ankle(iv) Enable better coordination of multidisciplinary research(v) Enable more effective coordination of foot and ankle biomechanics research between groups in different countriesA Steering Group has been formed to guide the initial development of the i-FAB community and its activities. The Steering Group seeks to construct a framework for developing i-FAB to meet the needs of the foot and ankle biomechanics community and welcomes input and direction from members.In September 2008, we had our first congress at Istituto Ortopedico Rizzoli, Bologna, Italy, chaired by Dr. Alberto Leardini. A mix of 150 lectures, posters and workshops were presented to 170 delegates from 30 different countries. Highlights included a live operation of a total ankle replacement by Professor Sandro Giannini, hands-on multi-segment foot kinematics demonstration by Professor Maria Grazia Benedetti, and keynotes lectures by Professor Harold Kitaoka , Professor George Arangio (Sailing charted seas: biomechanics and the orthopaedic surgeon), Dr. Mario Lafortune (The role of research in the development of athletic footwear), Professor Peter Cavanagh (Foot complications of diabetes), Dr. Sorin Siegler (Advances in image-based biomechanics of the human ankle) and Dr. Marco Viceconti .in vivo axes of the subtalar and talocrural joints using functional MRI during foot plantarflexion and dorsiflexion [Journal of Foot and Ankle Research [The Best Paper of the Congress was awarded to Dr. Frances Sheehan from the Physical Disabilities Branch of the National Institutes of Health, Bethesda, MD, USA for her paper 'Direct in vivo quantification of the 3D talocrural and subtalar finite helical axes' about a revolutionary non-invasive technique for quantifying the 3D iflexion . Dr. SheResearch  and can th to 18th 2010. We anticipate an outstanding program covering both basic and clinical aspects of foot and ankle biomechanics together with a social program that will exploit the resources of the Pacific Northwest.Planning for three i-FAB activities is presently underway: website, 2010 congress, and e-communications. The website and e-communications are the start of a global \"collaborative workspace\" in which all members of the foot and ankle biomechanics community can engage. This collaborative workspace will harness the most recent IT developments for supporting the organisation and coordination of activities across traditional disciplinary boundaries and between groups who are geographically distributed. We are pleased to announce that the 2010 i-FAB congress will be at The University of Washington in Seattle between September 16One exciting goal of i-FAB is to promote and advance research in the field of foot and ankle biomechanics by providing up-to-date consensus based standards for the study and description of foot and ankle kinematics. We have assembled a committee to provide standardised quantitative morphological databases and periodic reviews of the state-of-the-art in foot and ankle kinematic research.i-FAB welcomes members from every community related to foot and ankle biomechanics, from academics, physicians, podiatrists, surgeons, and health professionals, to members of the footwear, orthosis, surgery and related industries. i-FAB has an open philosophy and connecting people across traditional disciplinary boundaries is one of its key objectives. Membership is presently free. Further details regarding i-FAB can be found on our website ."}
+{"text": "We examined the liver of adult polar bears, arctic foxes, and rats by gold chloride staining, fluorescence microscopy for the detection of autofluorescence of vitamin A, hematoxylin-eosin staining, staining with Masson's trichrome, Ishii and Ishii's silver impregnation, and transmission electron microscopical morphometry. The liver lobules of the arctic animals showed a zonal gradient in the storage of vitamin A. The density  of hepatic stellate cells was essentially the same among the zones. These results indicate that the hepatic stellate cells of the polar bears and arctic foxes possess heterogeneity of vitamin A-storing capacity in their liver lobules. Hepatic stellate cells  are located in the perisinusoidal space of Disse and extend their thin fibrillar processes into this space ,2. UnderAlopex lagopus) during the period from August 1996 to September 2001. Three polar bears (Ursus maritimus) were shot in self-defense in February and August 1998. We examined the liver of these animals by gold chloride staining, fluorescence microscopy for the detection of autofluorescence of vitamin A, hematoxylin-eosin staining, staining with Masson's trichrome, Ishii and Ishii's silver impregnation, and transmission electron microscopical morphometry using a division map of liver lobule for a zonal analysis (Figure After having obtained permission to hunt animals from the District Governor of Svalbard, we caught 11 arctic foxes (The liver lobules of the arctic animals showed a zonal gradient in the storage of vitamin A Figure . The graResults of this study indicate that arctic animals possess the intralobular heterogeneity of vitamin A-storage capacity in the hepatic stellate cells.In earlier studies, a specific zonality for intralobular vitamin A-storage was reported. Although our results agree with other reports as to the presence of the heterogeneity of vitamin A-storing lipid droplets in the hepatic stellate cells in the liver lobule ,5, the lThe existence of the intralobular heterogeneity of vitamin A storage would relate to the number of hepatic stellate cells within the each zone or the maturation of hepatic stellate cells itself . HoweverHence, we speculate that the intralobular distribution of CRBP in the liver of polar bears and arctic foxes may also show similar heterogeneity to that in the rats, and have effects on the intralobular heterogeneity of storing vitamin A in the livers."}
+{"text": "The search for the infectious agents responsible for cat-scratch disease, bacillary angiomatosis, and related syndromes has a long and often circuitous history. Recognition of the etiologic agents and a new understanding of the fundamental features of the epidemiology and natural history of modern day Bartonella -associated diseases culminate a multipartite story that combines clinical medicine, traditional microbiology, and novel technological approaches to solve a long-standing enigma."}
+{"text": "The study group included 684 cases: 258 patients with breast carcinoma, 113 males with lung cancer, 42 patients with rectal tumours, 42 patients with stomach tumours, 59 patients with fibroadenomatosis, and 170 healthy subjects of varying age . A relatively high blood triglyceride level was found in patients with breast, lung, rectal , and stomach  tumours. The blood concentration of high-density lipoprotein-cholesterol in patients with breast, lung, and stomach  tumours was relatively low. The elimination of tumour (breast carcinoma) did not lead to significant changes in lipid metabolism. There was no correlation between degree of lipidaemia and stage of tumour progression except in the cases of rectal cancer. Preliminary results are presented on the tentative classification of hyperlipoproteinaemia in tumour patients, using the lipid concentration threshold values advocated by Carlson et al. (1977); an increased frequency of Type IV hyperlipoproteinaemia proved to be the most characteristic feature of tumour patients. The results are discussed in terms of the concept of the importance of lipid metabolic disturbances, primarily those due to ageing, in the genesis of the syndrome of \"cancerophilia\" (predisposition to cancer)."}
+{"text": "British Journal of Cancer (2002) 86, 1528\u20131528. DOI: 10.1038/sj/bjc/6600300www.bjcancer.comCancer Research UK\u00a9 2002  E Edmund Kim and David J Yang. Publishers: Springer-Verlag, 2001. ISBN 0-387-95028-1. \u00a3120.50, $169.00.As the foreword to this book states, our passage into the new millennium gives the opportunity to use the medical achievements of the past 1000 years to develop treatment strategies for the future. It describes and explains the roles that imaging plays in the emergence of new diagnostic and therapeutic procedures.Increased knowledge regarding the genetics and the molecular biology of tumour development offers the potential of new targets of therapy. However, devising methods with which to determine the existence, and the evaluation, of novel diagnostic and therapeutic strategies in cancer remains a challenge. Improved imaging techniques and the radiolabelling of tracers and drugs are making non-invasive imaging of molecular targets possible, thereby facilitating the translation of these scientific breakthroughs into clinical practice.This book provides an excellent review of imaging technologies and their role within oncological treatment strategies. It begins with a basic science chapter giving a very structured and readable background to the molecular genetics of cancer, cancer cell immunology, biochemistry and pathology. This chapter explains DNA replication and the genetic mutations that give rise to the activation of oncogenes and the inactivation of tumour suppressor genes in neoplasia. It discusses the role of cellular immunology, including T-cell and B-cell immunity and cytokine interactions, providing an insight into active and passive immunotherapy in the treatment of cancer. This gives the reader a good platform from which to proceed with the subject of molecular targeting.The following chapters cover the principles of each of the imaging technologies available, and include the techniques of ultrasound, computerised tomography (CT), magnetic resonance imaging (MRI) and spectroscopy (MRS), single positron emission tomography (SPECT) and positron emission tomography (PET). Each chapter addresses the difficult topic of technique methodology and the authors manage to describe this in a surprisingly straightforward manner. Obviously, some chapters are slightly more complicated than others, but in general the points are made clearly and simply.Having set the scene and discussed the various advantages and disadvantages of each imaging method, the second part of the book gives examples of the ways in which they can be used to image molecular targets utilising, for instance, radiolabelled antibodies and radiopharmaceuticals. Chapter 5 provides an overview of some of the radiopharmaceuticals that target tumours, concentrating on the rationale and the results of these studies.The radiolabelled antibody chapter, Chapter 6, is particularly interesting. It covers the production of monoclonal antibodies from hybridomas, made from the fusion of myeloma cells and B-lymphocytes, through to current phage library techniques. The importance of optimising antibody selection for tumour targeting, in particular the kinetics according to fragment size, is highlighted. Finally, the radioisotopes available for antibody radiolabelling are discussed. The following chapter expands upon this theme by demonstrating the possibility of radioimmunodetection of different tumour-marker expressing cancers using commercially available monoclonal antibody conjugates, such as ProstaScint (Cytogen) for prostate carcinoma, CEA-Scan (Immunomedics) for colorectal cancer and OncoScint (Cytogen) for colorectal and ovarian cancer.The potential value of polymer-drug conjugates and macromolecular contrast media imaged with MRI are described, together with the use of paramagnetic radionuclides to label monoclonal antibodies, and newer contrast agents, to aid in specifically targeting these for magnetic resonance imaging. This, thereby, expands the use from gadolinium-based interstitial agents to agents tailored to specific clinical applications.99mtechnetium-sestamibi scans in SPECT and fluorine-18 fluorodeoxyglucose scanning in PET. The main thrust of these chapters is to describe those radiotracers with established roles in oncology, with suggestions of those requiring further investigation.Dynamic PET images have been likened to displaying \u2018slices of life\u2019, however the expense of performing these scans generally confines their use to academic and teaching medical centres. On the other hand, SPECT is more accessible. Both techniques provide 3-dimensional images of the distribution of radiotracers and the chapters regarding targeted SPECT and PET provide data and images of gallium-67, thallium-201, The final third of the book expands upon the roles of the different techniques for imaging the processes important in tumour development and survival, in particular angiogenesis, hypoxia, apoptosis and signal transduction. The potential for imaging anti-cancer drugs themselves, including anti-sense oligonucleotides, gene delivery and expression, is also discussed. Illustrations are shown and the images and results are discussed providing a vast array of potential and future applications for targeting imaging.Overall, this is a very informative, readable book. The chapter sizes are easily digestible and there is a clear progression through the book presenting a succinct and balanced picture of the methodologies available. The black and white images of the techniques and the targets help to enlighten the reader visually regarding the text. I thoroughly enjoyed reading the book and learning from it. I would recommend it to both the reader with some knowledge wishing to explore the topic further as well as to those wanting a basic introduction and background to the subject."}
+{"text": "Acute aortic dissection can occur at the time of intense physical exertion in strength-trained athletes like weightlifters, bodybuilders, throwers, and wrestlers.Rapid rise in blood pressure and history of hypertension are the most common causes of aortic dissection in athletes. It is a very tragic event because of its high mortality rate of about 32% in young patients. We report a case of aortic dissection in a young weightlifter with an extensive intimal tear of the aorta, from the sinus of Valsalva to the abdominal aorta. Acute aortic dissection results from a tear in the intima and media of the aortic wall, with the subsequent creation of a false lumen in the outer half of the media and elongation of this channel by pulsatile blood flow. Dissection of the aorta is associated with a high degree of morbidity and mortality despite continuing improvements in diagnostic and surgical techniques , and hypA 37-year-old Iranian man with a history of hypertension and long history of weightlifting was admitted to our hospital complaining of knifelike retrosternal chest pain, which was abrupt while lifting weight, accompanied by severe sweating and palpitation. Distal pulses were weakly palpable. Electrocardiography showed non-sinus arrhythmia, Wolf-Parkinson-White (WPW) syndrome, and Q in lead III and avf. Echocardiography findings were normal left ventricular size with concentric left ventricular hypertrophy (LVH), left ventricular ejection fraction (LVEF) of about 55%, dilated ascending aorta of about 56 mm, and mild mitral regurgitation. In addition, the intimal flap in the ascending aorta was seen collapsed. The diagnosis was obtained by computed tomography (CT) angiography, which showed a typical aspect of type A of Stanford classification of aortic dissection  fig . The intThe cardiovascular system adapts to exercise. Top-level training is often associated with morphological changes in the heart including increases in the left ventricular chamber size, wall thickness, and mass. The increase in the left ventricular mass as a result of training is called\" athletes' heart\" . MorganrWe strongly advise that athletes with one of the predisposing factors for aortic dissection eschew intense physical exertion. Unfortunately, survival after such dissections is extremely unanticipated because of the lengthy extension of the intimal tear, massive hemorrhage, and organ dysfunction. WPW: Wolf-Parkinson-White; CT: Computed tomography;  LVH: Left ventricular hypertrophy; LVEF: Left ventricular ejection fraction; ICU: Intensive care unit; CPR: Cardiopulmonary resuscitation; CPB: Cardiopulmonary bypass.The authors declare that they have no competing interests.AK carried out the surgery and was directly involved in the conception, design and drafting of the manuscript. SS participated in the diagnosis and treatment; also gave critical comments on the results. PY collaborated in the design of the study and was directly involved in drafting and revising the manuscript. All the authors read and approved the final manuscript.Written informed consent was obtained from the patient's family for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal."}
+{"text": "The study of cell behavior is of crucial importance in drug anddisease research. The fields of bioinformatics and biotechnologyrely on the collection, processing, and analysis of huge numbersof biocellular images, including cell features such as cell size,shape, and motility. However manual methods of inferring thesevalues are so onerous that automated methods of cell tracking andsegmentation are in high demand. In this paper, a novelmodel-based cell tracker is designed to locate and trackindividual cells. The proposed cell tracker has been successfullyapplied to track hematopoietic stem cells (HSCs) based onidentified cell locations and probabilistic data association."}
+{"text": "The main aims of the Society are the organization of an annual scientific meeting and the fostering of Bioinformatics in Italy. The 4th Annual BITS Meeting, , was held in Naples, Italy, on April 26-28 2007, in the \u201cFederico II\u201d Congress Center, in view of the entire gulf of Naples, the Vesuvio, Castel dell'Ovo, the island of Capri and the city seashore. Over 130 scientists actively working in the field or strongly interested in its development met and discussed their work, state of the art and future perspectives. A total of 149 abstracts were accepted and presented in the poster session and 31 of them were selected for oral presentation.The Italian Society of Bioinformatics  Structural and functional analysis of genomes; ii) Novel methodologies, algorithms and tools; iii) Molecular evolution and novel algorithms; iv) Biomedical Informatics; v) Large scale analysis of experimental data; vi) Gene expression and system biology and vii) Structural biology and drug design.BMC Bioinformatics supplement. We adopted a stringent reviewing procedure, based on selected Associate Editors handling the process according to their recognized knowledge in specific subjects of Bioinformatics and following a peer review procedure.From these conference sessions, 21 papers were submitted for publication in this After this process, 14 papers were accepted. They cover different aspects of theoretical and applied Bioinformatics, including: i) useful algorithms and tools for sequence analysis aimed at the prediction and characterization of functional motifs in nucleotide and protein sequences, of SNPs affecting protein stability, and of protein interaction networks and protein complexes; ii) curated databases of expression data and of conserved non coding sequences; iii) system biology models and iv) interesting technological breakthroughs for data management and for speeding up large-scale database searches.Whether this will help in encouraging scientists involved in biological and/or medical researches in our country to plan, merge and spread their knowledge by means of Bioinformatics is left to the future and to the availability of national grants specifically devoted to this.In this presentation, we gratefully acknowledge the patience and help of our colleagues around the world who helped in the process of reviewing as Associate Editors:Bert AbbotGill BejeranoAxel BrennickeIdelfonso CasesGino CingolaniLarry CroftManolis DermitzakisChristiane GebhardJerzy JurkaPeter KarpReinhard LabenbacherRoman LaskowskiArthur LeskRodrigo LopezJohn MattickSayan MukerjeeAnnalisa PastoreFrancis QuetierPeter RiceMarie-France SagotMarco SalvettiYves van de Peer and at .The next Annual meeting of the Italian Society of Bioinformatics will be held in Cagliari, September 22\u201326, 2008, in conjunction with ECCB08, the 2008 European Conference of Computational Biology. Further information about BITS2008 will be available on our web site at the address"}
+{"text": "The Second Meeting of the British Society for Immunology Tumour Immunology Affinity Group (TIAG) took place at King's College  on 17-18 June 1997 and brought together over 100 tumour immunologists from the UK and abroad. In contrast to previous meetings the focus of the meeting was on the role of adhesion in immunosurveillance and tumour dissemination. In addition, recent achievements in the areas of chemokines, cytotoxic T-lymphocyte (CTL) and natural killer (NK) cells, co-stimulation, gene and adoptive immunotherapy were also addressed. The purpose of this report is to outline current trends in tumour immunology."}
+{"text": "Sir,In his letter, Dr. Al-Hajoj proposesBCG vaccination of infants was confirmed to have significant protective efficacy against disseminated childhood tuberculosis and tuberculous meningitis. A meta-analysis of 5 randomized control trials and 8 case-control studies showed an average protection of 80% among children vaccinated in infancy. The impaCurrently, BCG vaccine is not given routinely in USA, Canada and parts of western Europe, because of the low disease incidence in these countries . In Saudi Arabia, the incidence of the disease remains moderate , and there is a high influx of foreign workers (including housemaids) from countries with high prevalence of tuberculosis. In these circumstances, exposure of children to the disease is likely to be significant; and therefore, prevention of serious childhood tuberculosis should remain a priority. This emphasizes the need to continue with the current policy of compulsory BCG vaccination of infants in Saudi Arabia. A revision of this policy is justified when the disease incidence declines to low levels."}
+{"text": "In a restricted sense, the resource curse is a theory that explains the inverse relationship classically seen between dependence on natural resources and economic growth. It defines a peculiar economic and political environment, epitomised by oil extraction in sub-Saharan Africa.Based on secondary research and illustrations from four oil-rich geographical areas , I propose a framework for analysing the effects of the resource curse on the structure of health systems at sub-national levels. Qualitative attributes are emphasised. The role of the corporate sector, the influence of conflicts, and the value of classical mitigation measures  are further examined.Health systems in a resource curse environment are classically fractured into tripartite components, including governmental health agencies, non-profit non-governmental organisations, and the corporate extractive sector. The three components entertain a range of contractual relationships generally based on operational considerations which are withdrawn from social or community values. Characterisation of agencies in this system should also include: values, operating principles, legitimacy and operational spaces. From this approach, it appears that community health is at the same time marginalised and instrumentalised toward economic and corporate interests in resource curse settings.From a public health point of view, the resource curse represents a fundamental failure of dominant development theories, rather than a delay in creating the proper economy and governance environment for social progress. The scope of research on the resource curse should be broadened to include more accurate or comprehensive indicators of destitution  and more open perspectives on causal mechanisms. Considering the extreme and deepening subjection of industrialised nations toward fossil energy, this economic approach to the resource curse would thus explain- as a first approximation \u2013 why the case is today nowhere better illustrated than in sub-Saharan Africa, the fastest growing oil-producing region worldwide [et al. [economic mechanisms have been examined as possible explanatory arguments. These explanations classically encompass processes such as: (i) the loss of economic diversification, following the appreciation of the domestic exchange rate caused by exports of natural resources (the 'Dutch disease'), and (ii) the volatility of the price of fossil fuels. Second, resource curse countries are characterised by high corruption levels. The theoretical framework behind this observation relies on the concept of 'rentier state', whereby governments in a capacity to rule in the absence of a functioning tax system are less accountable for misallocation of resources and poor governance. Third, states that rely heavily on oil exports are more likely to adopt authoritarian modes of governance. Fourth, the presence of natural resources increases the risk of civil wars. While this set of findings focusing on politico-economic mechanisms provides essential pieces to the overall picture describing resource curse environments, causal mechanisms and exact interactions are incompletely understood. The initial econometric definition of the 'curse of natural resources' is a useful framework to approach the counter-intuitive observation that economic growth is hampered by the availability of domestic mineral resources. However, this angle of analysis is clearly reductionist, for at least two reasons. First, much of the macro-economic framework (comparing growth performance between countries) is oblivious of sub-national or local differences within countries, and conceals deeper adverse effects for the very populations residing in mineral rich areas. Second, the focus on economic growth to describe the nature of the resource curse assumes that other dimensions  are subsidiary to economic factors. Fortunately, some scholars have examined the effect of extractive industries from a broader perspective and used more comprehensive indicators of deprivation than purely economic ones. For example, Gylfason [a and that 'oil dependence is also associated with high rates of child malnutrition; low spending levels on health care; low enrolment rates in primary and secondary schools; and low rates of adult literacy'. More recently, Ross [The soils of most of African countries are rich in mineral, oil or gas resources , and couorldwide . As a coorldwide ,11, Rossorldwide , Karl [1orldwide , and Hum [et al.   does not provide so far any comprehensive description of health systems in specific resource curse environments. As a first approach to fill this gap, I carried out secondary (desk) research to identify existing data about health outcomes/impacts and about components of health systems in oil-producing countries located in sub-Saharan Africa. These countries are listed in reference . I extenBased on this compilation of country data and on a review of the resource curse literature, I first propose a possible generic analytical framework Figure  to definThe definition of health systems is open to interpretation and, depending on individual points of view or values, it can encompass increasing circles of inclusiveness among activities that define a society  , as well as the overlapping category of traditional health practitioners. The latter two categories are popular and probably important in terms of numbers of providers b [The current definition endorsed by WHO  draws frviders b , but theviders b  and theiAlthough the three core categories considered in the framework provide services based on 'western' paradigms of healthcare and operate within the same geographical boundaries, they are clearly different in their underlying values, operating principles and self-defined legitimacy, as illustrated by examples in Table et al. [While government agencies are well defined by national policies and laws, the category of NPNGO providing health services is heterogeneous, and includes faith-based and humanitarian organisations, both further categorised as national or international agencies. Their defining values are generally altruism  or solidet al.  have shoIt has become popular for the corporate sector to be engaged in a number of health actions covering a range of public health endeavours, such as: supporting global or regional health initiatives, sponsoring biomedical research, sponsoring non-governmental organisations or, more directly, financing local health projects. As an example, the case of Exxon Mobil illustrates the diversity of such contributions through its involvement in malaria control . Obviousc, resulting in some confusion over its scope [d  is a distinct and rather recent operating principle originating from the commercial sector. Definitions of CSR are loose ts scope ,29. CSR ts scope , but CSRts scope . It is ud Figure . This raRelated, but distinct from CSR is the concept of 'social license to operate' (SLO), which is the main operational objective of CSR at community level, giving the corporate industry its share of informal legitimacy and additional operational space Table . How the\"Social investments in local health (...), skills and infrastructure improve the capacity to absorb positive spillovers from and enhance linkages with businesses. The concept of absorptive capacity plays an important and positive role in the theory of FDI and development...At the same time, businesses also have an incentive to make social investments through partnerships over and above the developmental needs of the local people. Such investments will improve local skills, motivation and health of the local workforce, and thus create more efficient labour inputs and higher quality local suppliers on which business become increasingly dependent. Efficient labour inputs and the quality of local suppliers improve business efficiency, while the consent of the local communities provides a 'social license to operate\"' .Lee and Bialous  advocateself-regulated norms, and resource curse environments are characterised by poor state governance or deficits in the rule of law. It is therefore important to examine if any international convention would cover norms regulating health systems governance in this context. Article 12 of the International Covenant on Economic, Social and Cultural Rights addresses a number of issues directly relevant to health in resource curse environments. These are specified in General Comment No. 14 issued by the UN Economic and Social Council under 'the right to the highest attainable standard of health' [et al. [A last point to consider here is the nature of health governance regimes under which the corporate sector operates in resource curse environments. By essence CSR entails  health' , notably [et al.  for inteThe three core categories of agencies introduced so far in the analytical framework Figure  entertaiFirst, GOV and NPNGO interact classically through informal trust-based relationships or relational contracts. However, multilateral development agencies are currently promoting more binding relationships through contracting-out of health services, as indicated in the case of Southern Sudan. The benefits of this experimental approach are still disputed ,38. For Second, CES and GOV partnerships in the health sector can be biased by political agendas, at the expense of social achievements. Frynas  and Le BThird, the relationship between CES and NPNGO has some underlying complexity. For example, oil companies are unable and unwilling to undertake comprehensive development projects and they are clearly looking for partnerships and joint initiatives to achieve their corporate social responsibilities ,43. For With the notable exception of international humanitarian organisations, the 'tri-sector partnership model' promoted by the corporate sector and multilateral development agencies thus draws from the same categories of actors that define the core elements of the formal health sector in a resource curse environment.Whether implemented under the umbrella of bilateral or multilateral development agencies, the place of ODA-financed health programmes in this context is ambivalent. They dwell upon the core categories of the tripartite health system model illustrated in Figure e [The tripartite health system framework described in previous sections is a dynamic model and it is naturally bound to evolve. Demographic pressure and urbanisation are obvious motors of change for local communities  impacted by the resource curse, either through in site infrastructure developments or, more commonly, through migration toward booming urban areas. To different extents, the four areas examined in this paper are undergoing rapid demographic changes, which result in increased and mostly unregulated urbanisation. This is obvious for Luanda, the capital of Angola, and for Port Harcourt, the capital city of Rivers State, Nigeria. In the Doba basin of southern Chad, the oil extraction area of Kom\u00e9 has doubled its population since 1993 . In Soute . Even fre  acknowleHarpham and Molyneux  have revf and/or to the weapons industry. Sudan [The association between oil extraction and armed violence is well established, and it is classically considered one of the root causes of the resource curse. First, interstate conflicts are a recurrent theme in the history of oil extraction  (p. 9.8\u2013y. Sudan  (p. 18) y. Sudan  (p. 10) y. Sudan   addresses an important development issue. However, the theory has been criticised by independent evaluators for its 'lack of appropriate conceptual and empirical framework' g [Using econometric analyses, Collier and colleagues ,60 have ework' g  and its ework' g ,63,64. Rework' g ,65,66 prework' g , none ofework' g  have shoHaving reviewed the evidence for armed violence as a leitmotiv in the landscape of oil extraction, the key question is: to what extent does violence contribute to adverse health effects in a resource curse environment? Coupland  has clarThere are at least three processes through which adverse health effects of industrial development projects can be mitigated at community level, and which would apply directly to oil extraction. These are: health impact assessments, consultations with local communities, and long term monitoring. A Health Impact Assessment (HIA) is an essential part of the broader Environmental Impact Assessment (EIA) process that is now considered standard practice for project proposals submitted to international development agencies . Lee et If one considers that the 'Chad Cameroon Petroleum Development and Pipeline Project' (CCPDPP: see Appendix 1) is a model of environmental and health impact mitigation in oil extraction (due to the oversight of the World Bank Group), the weight given to public health concerns and to HIA as a guarantee of best practices is at best disappointing. While the preliminary HIA had arguably induced some improvements in specific health outcomes , broader systemic health issues raised by the international panel of experts appointed by the World Bank were ignored or dismissed by the Consortium of corporate stakeholders . One of Finally, longitudinal monitoring of health outcomes and impacts of projects such as oil extraction should be standard procedures. Taking again the CCPDPP as an alleged model, there is much scope for improvement in practice, with a need for systematic baseline studies and pre-established public health surveillance mechanisms.primary intent criteria would formally exclude the corporate component (CES) of the core agencies depicted in Figure The presence of extractive industries in oil-rich areas affects directly the health of local populations. Examples of adverse health outcomes and impacts include: direct effects of environmental degradation, increase in road traffic accidents, acceleration of the spread of HIV and of other sexually transmitted infections. In addition, in oil-dependent countries complex systemic effects interact to determine broader consequences on health, such as: higher rates of child mortality, lower life expectancy, higher malnutrition rates or lower spending levels on health care . SimilarAside from direct health effects of oil extraction, Figure marginalised and instrumentalised, not only in the concrete contexts in which extractive industries operate, but also in mainstream development discourses proposing remediation to resource curse situations. Marginalisation of health has been exposed throughout this paper: (i) by the dominance of econometric parameters to define the resource curse, (ii) by the lack of a longer-term analysis taking into account the health consequences of urbanisation and (iii) by the poor weight that HIA and other health mitigation measures carry in the face of economic interests. Instrumentalisation of health appears in: (i) the nature of the operational concept of 'license to operate', (ii) the corporate perspective on HIA as an instrument to secure licenses to operate and (iii) the type of contractual partnerships promoted by multilateral development agencies, including tri-sector partnerships.I argue that health  has been h co-authored by Jeffrey Sachs. This is still more troubling as one remembers that the same author has prominently been leading research and political agendas valuing health as a major determinant of economic growth [One might wonder why, with few exceptions, health and other social parameters of well-being have not received more attention in the resource curse literature until recently. Reasons might be historical or methodological, but also ideological. For example, the possibility of health as an explanatory variable is conspicuously absent from a recent authoritative textbook  on 'Escac growth .As mentioned in the introduction, initial econometric findings on the resource curse are reductionist in their scope (countries vs. affected communities) and in their perspective . The theoretical foundations of this reductionist perspective obviously reflect mainstream development theories and macro-economic policies supported by international financial institutions. Perpetuating an exclusively economic and political research agenda would carry the risk to see ideologically biased solutions prescribed prematurely, while ignoring other important and neglected dimensions of the resource curse phenomenon. Remediation measures to armed conflict proposed by some analysts of the resource curse are indeed biased toward macro-economic interventions. Bannon and Collier  . The country gained independence in 1960 and started oil exploitation in 1958, essentially in the Niger Delta region, where four states  account for most of the national production. In spite of such wealth, this is a region where the GNP per capita and educational levels remain below national average, and 70 percent of its 20 million people are living below the poverty line j ,90. The j ,90-92. Dj  add to tj ,63. Thisj . Politicj  and massj . The Nigk [As shown by Human Rights Watch  in the Rk , and in k ,98. Howek ,32,43 ask .With huge reserves of mostly offshore oil and a population of 12.4 million, Angola is one of the richest countries in Africa. Yet, it ranks poorly in terms of social development and it has the highest level of inequality among oil and gas producers. At least one third of Angola's population resides in shantytowns  with verThe ruling elite of Angola is opaque and largely unaccountable about national oil revenues amounting to several billion US$ per year. The country is still very much dependent on foreign aid for the vital sectors of health, food relief and emergency assistance. The transition from humanitarian relief to reconstruction has been slow, partly due to obstructions to the work of aid agencies by the Angolan government. The role of oil companies in the social sector is troubling, and Le Billon  could coCompared to the Niger delta, Angola thus offers a more straightforward example of the resource curse, devoid of major local and environmental dimensions, while the country at large is still relying heavily on foreign aid and relief agencies for the provision of basic services. For example, excluding landmines action, Angola has appealed for a total of US$ 17,468,992 in foreign emergency assistance in 2007 .l [With the assistance of the World Bank Group (WBG), oil fields have been exploited since 2004 in the Doba basin of southern Chad, through an impressive and elaborate public-private partnership between a consortium of transnational companies, and the governments of Chad and Cameroon. The project includes the development of three oil fields in southern Chad, a 1000-km underground pipeline running through Cameroon, an offshore export terminal, and the construction or rehabilitation of a large number of ancillary infrastructures alongside . The 'Chl ,102,104.l ) is thatth and 9th statutory missions) has repeatedly noted the absence of baseline studies and delays in setting up monitoring mechanisms, in particular with respect to HIV/AIDS prevalence in the project areas. Health impacts of the project will therefore be difficult to determine.The health sector is poorly developed in Chad, due to a lack of qualified medical staff, a lack of management skills at all levels, and a concentration of health services in urban areas . The quem [A glance at a concession map  reveals m . As an im  has submm  (p. 122)m . The exam  .g. Acemoglu D, quoted in Banerjee .h. In the book , health i. The following references and considerations about Botswana were kindly suggested to me by one of the reviewers.j. Niger Delta Development Commission (NDDC), 2004: quoted by Idemudia and Ite ; see alsk. For an historical overview, see 'Capital and community: a case study' in Watts .l. For a comprehensive analysis of the CCPDPP, see Gary and Karl . For an m. Letter of Sector Development Policy by Dr. Theophilus Ochang Lotti, Minister of Health. Annex 12, In: Government of Southern Sudan .CCPDPP: Chad Cameroon Petroleum Development and Pipeline Project; CES: Corporate Extractive Sector; CPA: Comprehensive Peace Agreement (Sudan); CSR: Corporate Social Responsibility; EIA: Environmental Impact Assessment; FDI: Foreign Direct Investment; GDP: Gross Domestic Product; GNU: Government of National Unity (Sudan); GOS: Government of Sudan; GOSS: Government of Southern Sudan; GPI: Genuine Progress Indicator; GOV: Governmental health agencies; HDI: Human Development Index; HIA: Health Impact Assessment; LGC: Local Government Council (Nigeria); MPLA: Movimento Popular de Liberta\u00e7\u00e3o de Angola; NPNGO: Non-Profit Non-Governmental Organisations; ODA: Official Development Assistance; SLO: Social License to Operate; SPLM: Sudan People's Liberation Movement; SSA: Sub-Saharan Africa; UNITA: Uni\u00e3o Nacional para a Independ\u00eancao Total de Angola; WBG: World Bank Group.The author declares that he has no competing interests.Table 2. Some key features about selected oil-producing countries.Click here for file"}
+{"text": "The theme of the conference was \u201cAdvanced Technology of Radiation Medicine and Medical Physics Practice\u201d. About 650 delegates from India and abroad, including 120 radiological / medical physics students from different universities of India participated in the conference. ICMP-2008 was inaugurated by Dr. Anil Kakodkar, Chairman, Atomic Energy Commission and Secretary to the Government of India, Department of Atomic Energy (DAE). While delivering the inaugural address, Dr. Anil Kakodkar summarized the importance of ionizing radiation in daily life, and the contributions of DAE / BARC toward the cancer control program of the country. He also stated that a sufficient number of trained technical manpower for safe medical applications of ionizing radiation is available in the country. However, there is a need to take the advanced technology equipment to the rural sector, improve the working conditions at rural medical institutions and remunerate the technically trained people adequately. In addition, he emphasised the need to restructure the training modules so that the trained manpower could efficiently use the advanced technology equipment for its intended applications. Shri S. K. Sharma, Chairman, Atomic Energy Regulatory Board (AERB) presided over the inaugural function and released the Souvenir and Book of Abstracts. In the presidential address, Shri S. K. Sharma highlighted the role of AERB in ensuring the safety and security of radiation sources. He also stated that though the radiation safety record in medical applications of ionizing radiation is very good we must be cautious while using advanced technology equipment for radiodiagnosis and treatment. Prof. Bhudatt Paliwal, Director of Medical Physics, Department of Human Oncology and Medical Physics, University of Wisconsin, Madison, USA, presented the keynote address where he described in detail the dosimetry problems associated with organ movements during intensity modulated radiotherapy (IMRT). The keynote address highlighted the feasibility of real-time motion tracking methodology during the delivery of IMRT. Dr. Anil Kakodkar felicitated five Ex-BARC scientists for their contribution to AMPI (See Annexure-1 for their brief bio-data).The International Conference on Medical Physics (ICMP-2008) and the 29One hundred eighty five papers, including the AMPI Ramaiah Naidu Memorial Oration, 29 invited, 35 oral and 120 poster papers were presented during the conference. Shri P. S. Viswantahan, Former Head, Department of Medical Physics, Tata Memorial Hospital, Mumbai, delivered the seventeenth AMPI Ramaiah Naidu Memorial Oration (RNMO). The RNMO award is bestowed on an eminent personality who has a long working experience in the field of medical physics with a good track record of academics, research, and clinical practice. The title of his deliberation was \u201cMedical Physics in India: History, Development, and Activities\u201d. During his talk he described in detail the early days (1943) and the current medical physics activities in the country, including commercially available technology and indigenous developments. He also listed the future directions to deal with hi-tech equipment and emphasized the need for harmonization in medical physics training modules. The key feature of ICMP-2008 was the AMPI-AROI (Association of Radiation Oncologists of India) joint scientific meeting on November 28, 2008, at Nehru Centre, Worli, Mumbai. The joint meeting was the first of its kind, which could be assumed to be the defining moment in the history of medical applications of ionizing radiation in India. Both the clinical and physical aspects of recent radiation oncology, such as, IMRT, IGRT, precision radiotherapy by Cyber Knife, adapted Telecobalt machines and Proton accelerators, Image guided brachytherapy, and indigenous development of radiotherapy technology were presented during the joint meeting. The joint meeting was useful for radiation oncologists, for improving their understanding of medical physics and the technological aspects of recent radiotherapy, while it was equally beneficial for medical physicists to understand the clinical requirements and associated complexities when implementing hi-tech radiotherapy. Panel discussion on \u201cNewer Technologies: Promises and Pitfalls\u201d witnessed the active participation of a large number of medical physicists and radiation oncologists. It was concluded during the discussion that technology is available for high precision radiotherapy and dose escalation, but it should be used discriminately as a majority of cancers require palliative treatment by conventional techniques.The scientific deliberations of ICMP-2008 covered the whole spectrum of medical radiation physics: Radiation Therapy Physics and Devices; Medical Imaging Physics and Devices; Radiation Dosimetry and Standards; Radiation Physics; Radiation Biology; Time Dose Models; Commissioning, Quality Assurance, and Audits; Clinical Aspects of Radiation Oncology; Clinical Aspects of Medical Imaging; Computational Tools in Medical Physics; Education and Training in Medical Physics; and Radiation Protection and Safety. Presentations on recent developments in the technology of radiation medicine and methodology of imaging and radiation therapy were the special attractions. The oral and poster presentations were evaluated for the best Oral and Poster articles. At the end of the conference \u201cImprovement of ImatriXX in terms of spatial resolution and large field acquisition for patient specific IMRT verification\u201d by Arun S. Oinam, Lakhwant Singh, Pradeep Goswami, Anup Bhardwaj, B. S. Rana, S. C. Sharma, from the Radiotherapy Department, Postgraduate Institute of Medical Education and Research, Chandigarh, India, and \u201cDosimetry of in-house designed circular cone for stereotactic treatment using MVCBCT\u201d by Kamlesh Kumar Gupta, V. K. Sathiyanarayanan, Janhavi R. Bhangle, R. Vaitheeswaran, from the Department of Radiation Oncology, Ruby Hall Clinic, Pune, India were declared the best Oral and Poster papers respectively.The overwhelming participation of trades dealing with medical radiation equipment, dosimetry systems, phantoms, computerized treatment planning systems, and treatment accessories was the other attraction of ICMP-2008. A number of recent technological equipments  and dosimetry systems (2-D array with high resolution), phantoms (Dynamic phantoms to simulate organ movements), patient immobilization devices (SBRT immobilization systems), and other related products were demonstrated in 32 stalls arranged near the conference venue.In summary, the conference deliberations were useful for radiation scientists, medical physicists, radiation oncologists, radiologists, radiobiologists, dosimetrists, and radiation technologists."}
+{"text": "Utilizing data from the California Health Interview Survey (CHIS) 2009, we examine caregiving activities among foreign born and US born Latinos, and US born Non-Hispanic whites ages 18 to 80 who are caring for an adult age 60 or older. Utilizing OLS regression, we first examine the relationship between race, ethnicity, nativity, and age and the amount of caregiving, types of caregiving, and use of long-term care (LTC) services among the population. Next we examine the health, mental health, and economic status of the three caregiver populations. The results find that middle aged and younger foreign born Latinos provide the greatest amount of care and also present with the greatest amount of economic challenges. US born middle- aged Latino caregivers also provide relatively high levels of care and also are more likely than other caregivers to experience health challenges including diabetes, obesity, depression and social isolation."}
+{"text": "Bartlett pioneered the use of Extra-Corporeal Membrane Oxygenation (ECMO) for prolonged cardio-respiratory support in critical patients in the 1970's . Early cBurke and McMullan contribute a very extensive and precise review of their experience with Extra-Corporeal Life Support (ECLS) for pediatric heart failure, including the utilization as peri-operative support as bridge to heart transplant. Very appropriately, they present the extracorporeal cardio-pulmonary resuscitation as one of the most significant advancements in the field of ECLS (Burke and McMullan). In addition to a clear list of contraindications, a very detailed list of the potential complications was given, including hemorragic episodes, central nervous system injuries, pericardial tamponade, pneumothorax, metabolic acidosis, seizures, infections, renal failure, failure of the oxygenator, and limb ischemia (Burke and McMullan).Di Nardo et al. contribute review of ECLS, with particular attention to current indications, pre-operative stabilization, peri-operative support and use beyond the peri-operative period .. An important contribution was given with a list of special indications for ECLS: intractable arrhythmias, extracorporeal cardio-pulmonary resuscitation, and use in the presence of \u201cfunctionally\u201d uni-ventricular type of circulation .The contraindications, as well as the details to facilitate the cannulation in neonate and small patients are reviewed .Their very strong message was that every attempt should be done to start ECLS \u201curgently\u201d rather than \u201cemergently,\u201d before the presence of dysfunction of end organs or circulatory collapse Harvey contributed a useful and practical review on cannulation, based on his very extensive clinical experience. Pure cannulation considerations about the design of the available cannulas and the type of required support are discussed (Harvey). For the Veno-Arterial (V-A) support suggestions were given for difficult cannulation, with special considerations particularly for neonates, and for the central cannulation for V-A support. For the Veno-Venous (V-V) support a list of potential complications was presented, with suggestion about their prevention and treatment (Harvey). A separate part was dedicated to the surgical cannulation of the femoral vessels for larger size patients, with attention to the distal limb perfusion, as well as to the vessel sparing cannulation (Harvey). Finally, all aspects related to the need of left heart venting were presented, for both situations of open and closed chest left heart venting (Harvey).Broman and Frenckner contribute an interesting article on the transportation of critical patients on ECMO. After an accurate report of the background, they gave a carefully detailed description of the logistics of the transport, including the requirements for the transport vehicle, the equipment and the personnel (Broman and Frenckner). Special situations were also taken in consideration, such as international transportations, environmental and climate issues, and working environment (Broman and Frenckner).Ryerson and Lequier contribute a review of one of the most important and difficult issues of the ECLS: the management and monitoring of the anticoagulation. They very appropriately started by specifying than anticoagulation per se is more complex in neonates and infants, and anticoagulation on ECLS provides an additional layer of complexity (Ryerson and Lequier). Furthermore, heparin is only an indirect anticoagulant, and the standard monitoring is hugely imperfect. Then they analyzed the role of activated clotting time, activated partial thromboplastin time, anti-Xa assay, viscoelastic testing, and antithrombin replacement (Ryerson and Lequier). Alternative options of anticoagulation were considered, such as direct thrombin inhibitors, new oral anticoagulants, and factor XIIa inhibitors. They provide an useful review on the prevention and management of bleeding and thrombotic complications during ECLS: definition and criteria of significant bleeding, role of antifibrinolytic therapy, activated factor VII, thrombotic complications in the patient and in the circuit, heparin-induced thrombocytopenia, and finally the optimal blood products replacement (Ryerson and Lequier).(Nair and Oishi). After an extensive introduction and explanation of the role of the ECLS in the presence of respiratory issues, they focused on ECLS in patients with \u201cfunctionally\u201d uni-ventricular hearts, discussing the role of V-V vs. V-A support. Special considerations were proposed for patients with \u201cfunctionally\u201d uni-ventricular hearts requiring V-V support because of ARDS: in particular (a) timing of cannulation, (b) type and positioning of the cannula, (c) bleeding, thrombosis and anticoagulation, (d) ECLS flow in these patients, (e) lung rest settings, and finally (f) weaning from ECLS.In the last article of this Research Topic Nair and Oishi report their experience with the management of patients with single-ventricle pathophysiology and acute respiratory distress syndrome (ARDS), with V-V ECLS We strongly believe that this collection of articles on ECMO will be very useful to all people involved in the care of pediatric patients requiring cardiac and/or respiratory support.AFC and TK edited this Research Topic and this editorial was written by AFC.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The use of video-games, either online or offline, has significantly increased, and almost homogeneously, around the globe over the last decades , the USA , Norway , Italy , Greece, Cyprus, and Australia . Online gender specific  and face to face data collection procedures  were applied, in conjunction with a number of different models and analytical methodologies ranging from Confirmatory Factor Analysis , Mokken analysis , Rash analysis , Classical Test Theory , Complex Regressions , and the PRISMA guidelines for systematic literature reviews (Costa and Kuss). Disordered gaming scales were assessed comparatively , across genders , while the differential functioning of disordered gaming criteria was examined .In this context, the goal of the present special topic-issue is to contribute to the ongoing discussions concerning this phenomenon. The studies included utilized culturally and developmentally diverse, normative samples from Iran  Cultural values of independence, competitiveness and hierarchy  have been suggested to confound the assessment of the experienced level of absorbance by the gaming activity ; (c) the need of particular emphasis on female gamers and their specialized assessment was emphasized ; (d) a considerable delay in the employment of consistent measurements/ assessment in studies of clinically diagnosed disordered gamers was illustrated (Costa and Kuss); and (e) analogies with the emergence of gambling behaviors among younger individuals became clearer in the context of the broader literature .The findings of this special topic contribute to the extant literature by shedding light to much debated, yet important, aspects of the assessment and measurement of disordered gaming behaviors. Indicatively: (a) the inclusion of gaming motivation as an inherent part of the assessment of disordered gaming behaviors has been supported by Costa and Kuss), while the number of measurement invariance studies, targeting in particular issues of scalar invariance (whether the same scores indicate the same severity) across populations of different genders, cultures, and developmental stages  are rare (Stavropoulos et al., assessment and measurement discipline in regards to the officially introduced definitions of DSM-5 (American Psychiatric Association, However, challenges in the field of disordered gaming assessment still remain. Scholars continue to disagree about the nature of the behavior (Kardefelt-Winther et al., All procedures performed in the study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors. Informed consent was obtained from all individual participants included in the study.VS and RG contributed to the literature review, the structure, and sequence of theoretical arguments. FM-S contributed to the theoretical consolidation of the current work, revised, and edited the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Social status - the standing of a person or group in the social hierarchy - is part and parcel of social life and a significant determinant of cognition and behavior. Status hierarchies are basis of virtually all human and primate societies and assign different roles and privileges to its members. However, the dynamic nature of social status and the underlying mechanisms in old age are not well understood. Therefore, this symposium addresses questions of how social status is influenced by aging-related changes in roles, life events, self-concept, and images of aging and how social status shapes in response personality, subjective age, prosocial behavior, performance, and well-being in old age. Bellingtier and colleagues examined objective and subjective social status and their connections to subjective age, attitudes towards aging, and awareness of age-related changes. Zhang shows paradoxical association between aging stereotypes and prosocial behaviors toward older adults. Barber and Hamel investigated how stereotypes of reduced physical competence in old age affect the gait performance on easy and difficult tasks. Weiss and colleagues take a cross-cultural perspective on the different sources of social status in China, Germany, and the US showing that generations in contrast to age groups represent a source of high social status in later life. Finally, Kornadt investigates the dynamic interplay of changes in social roles and personality in old age. Together, these presentations enlarge our understanding of the dynamics of social status in old age."}
+{"text": "During the workshop, experts discussed the state of the science. The U.S. Food and Drug Administration (FDA) has approved several medications to prevent osteoporotic fractures. These include bisphosphonates (BPs), denosumab, teriparatide, estrogens, and selective estrogen-receptor modulators. BPs are a first line of pharmacologic treatment for most women and men who have osteoporosis. Despite the efficacy of short-term use of BPs and other osteoporosis medications, treatment rates are low and appear to be decreasing. This talk would describe the problem/epidemiology of fracture prevention in the United States; the importance of drug therapy and their effectiveness; the limited evidence regarding long-term use of drug therapies; the questions surrounding the application of drug holidays; and the complex physician and patient factors that impact the use of and adherence to osteoporotic drugs."}
+{"text": "The northern coast of Central Java Province, Indonesia, is considered as the critical area of flooding. The area always suffers from flooding because of heavy rainfall and/or sea level rise. Flooding brings a lot of consequences, including people\u2019s suffering, property damage and property loss. A number of efforts have been carried out to manage flood problems, yet the achievement is incomplete without stakeholder involvement. Stakeholders have a very important role in flood risk reduction. A common understanding on the existence and role of stakeholders is important in achieving community resilience. The aim of this article was to analyse interest and cooperation among stakeholders in flood risk reduction. In-depth interviews were conducted to identify and analyse interest and influence of stakeholders in relation to flood risk reduction. MIC-MAC (Cross-impact Matrix Multiplication Applied to Classification) and MACTOR  methods were employed to analyse collected data. The results of this study indicated that restoration and humanity are the key objectives with major influence in lowering flood risk. The objectives are critical for the success of flood risk reduction efforts. The Disaster Management Agency is identified as the main stakeholder with the most important role in reducing flood risk in Central Java Province. The Indonesia Disaster Data and Information shows a long-term upward trend in the number of floods in Indonesia, in which 5233 occurrences or approximately 38.99% of the total number of natural disasters occurred between 1815 and 2015. From 2011 to 2015, 368 cases of flooding in the Central Java Province, Indonesia, were reported, and the number has been continuously rising ever since  and MACTOR .Cross-impact Matrix Multiplication Applied to Classification is an analytical tool used to analyse the drive power and dependence power of factors and various objectives of stakeholders. The Cross-impact Matrix Multiplication Applied to Classification principle is based on the multiplication properties of matrices. Analysis using MIC-MAC is performed to identify the key factors that drive the system in various categories. Based on their drive power and dependence power, the factors have been classified into four categories which are autonomous factors, linkage factors, dependent factors and independent factors  of stakeholders . This quadrant includes objectives that have a weak influence and dependence. The objective is less related to flood risk reduction and may have few relationships that will be eliminated from the objectives of stakeholders in flood risk reduction.Quadrant 2 is dependent factors (weak influence \u2013 strongly dependent). It includes objectives that have weak influence and strong dependence. The objectives in this quadrant are non-independent ones.Quadrant 3 is a linkage factor (strong influence \u2013 strongly dependent). It includes objectives that have a strong influence and strong dependence. They should be determined meticulously as the relationship between goals is unstable.Quadrant 4 is an independent factor (strong influence \u2013 weak dependent). This quadrant includes objectives that have strong strength and weak dependence. The objectives are the key factors in flood risk reduction.The objectives in the upper-left quadrant (restoration and humanity) imply the high influence and low dependence of other variables in flood risk reduction. These objectives have major influence in reducing flood risk. They, thus, become the key objectives that are critical in the success of flood risk reduction efforts. Restoration enables stakeholders to undertake the development, maintenance and improvement of natural resources and/or infrastructures, such as rivers, embankments and floodgates, which have been proven to lower the risk of flooding, while humanity raises awareness and empathy to others. These two objectives have the greatest impact in reducing flood risk.The second most important quadrant is the upper-right quadrant. The two objectives included in this quadrant are main duty and safety. The objective of carrying out the main duty is important for government agencies because it is their main activity as well as a major indicator of the performance of their agencies. The objective of promoting people\u2019s safety is also an important goal for an individual or group or organisation in reducing flood risk.The lower-right quadrant is dependent on weak driver and strongly dependent variables. The objective of this quadrant is the element of awareness, which is a non-independent factor. Image, income, relocation and incentives are also classified in this quadrant. They are the objectives of several stakeholders in conducting flood risk reduction activities.Stakeholders involved in the activities of flood risk reduction have different influences and interests (objectives). Based on the identification and analysis of stakeholders, flood risk reduction activities in the northern coastal area of Central Java Province, Indonesia, were conducted by the Provincial Disaster Management Agency (Badan Penanggulangan Bencana Daerah [BPBD] Jateng), Semarang City Disaster Management Agency (Badan Penanggulangan Bencana Daerah [BPBD] Semarang), Pati Regional Disaster Management Agency (Badan Penanggulangan Bencana Daerah [BPBD] Pati), Pekalongan Regional Disaster Management Agency , Regional Development Planning Agency (Badan Perencanaan Pembangunan Daerah[APPEDA]), Public Health Office (Dinas Kesehatan), Public Works Service (Dinas Pekerjaan Umum), Environmental Services (Dinas Lingkungan Hidup), businessmen, village heads, Search and Rescue (SAR) Team (Tim SAR), Indonesian Military and Indonesian Police , Indonesian Red Cross, farmers, volunteers, fisherman, village community leaders, local community (Masyarakat), Non-government Organisation (NGO) (community), Universities (university), business actors and journalists.Stakeholders in flood risk reduction can be categorised into three groups , Disaster Management Agency of Pati Regency (BPBD Pati) and Disaster Management Agency of Pekalongan Regency  are the institutions responsible for disaster risk reduction at regional level and have the highest impact. It means that these institutions have an important role in reducing flood risk in Central Java Province. The BPBD Central Java Province ranks second, followed by community leaders as stakeholders who have a high competitiveness in reducing flood risk in the Central Java Province.The other major findings of stakeholder analysis are convergence and divergence , Semarang City Disaster Management Agency (BPBD Semarang), Pati Regional Disaster Management Agency (BPBD Pati), Pekalongan Regional Disaster Management Agency , Regional Development Planning Agency (BAPPEDA), Public Health Office, Public Works Service (DPU), environmental services, businessmen, village heads, SAR Team, TNI and POLRI, Indonesian Red Cross (PMI), village community leaders, Community, NGO, universities and business actors . StakehoBased on the actor\u2019s preference in objectives and competitiveness, the actors involved in reducing flood risk groups are grouped into four major groups. The first group consists of BPBD Central Java Province, BPBDs at regional level, Health Office, Public Works Service (DPU), environmental services, village heads, SAR and Indonesian Red Cross. The second group consists of universities, farmers, communities, fishermen, community leaders and NGOs (community). The third group includes the business actors and journalists, and the fourth group is the TNI-POLRI.The next finding is divergence. The results of MACTOR analysis show that stakeholders with a high potential of divergence are BPBD, farmers, fishermen and businessmen. The result indicates that these stakeholders have a relatively high probability of conflict or goal difference. On the contrary, university, TNI-POLRI, PMI and SAR have a low probability of conflict. In fact, their position is neutral because they have indirect interests in flood risk reduction activities.Not all actors involved in flood management have an important role in reducing flood risk. Each stakeholder has different objectives in conducting flood risk reduction activities; they are restoration, humanity, safety, income, image, main duty, incentive and relocation. Restoration and humanity are two objectives that have a major influence in lowering flood risk. These key objectives are critical in supporting the success of flood risk reduction. Restoration encourages stakeholders to undertake the development, maintenance and improvement of natural resources and/or infrastructure, such as rivers, embankments and floodgates, which may lower the risk of flooding. Meanwhile, humanity raises the awareness and empathy to others. In general, stakeholders in flood risk reduction can be grouped into three, namely beneficiaries, intermediaries and policy-makers. The Disaster Management Agency (BPBD) as the institution of policy-makers for disaster risk reduction at the regional level appears to have the highest role. The Disaster Management Agency (BPBD) has an important role in reducing flood risk in Central Java Province."}
+{"text": "Therapies originating from traditional medical systems are widely used bypatients in both India and the United States. The first India-US Workshop onTraditional Medicine was held in New Delhi, India, on March 3 and 4, 2016, as acollaboration between the Ministry of Ayurveda, Yoga and Naturopathy, Unani,Siddha, and Homoeopathy (AYUSH) of the Government of India, the US NationalCancer Institute (NCI), National Institutes of Health, and the Office of GlobalAffairs, US Department of Health and Human Services. It was attended by Indianand US policymakers, scientists, academics, and medical practitioners fromvarious disciplines. The workshop provided an opportunity to open a dialoguebetween AYUSH and NCI to identify promising research results and potentialtopics for Indo-US collaboration. Recommendations that emerged from the workshopunderlined the importance of applying rational and scientific approaches fordrug development; standardizing traditional medicine products and procedures toensure reliability and reproducibility; promotion of collaboration betweenIndian traditional medicine practitioners and researchers and US researchers;greater integration of evidence-based traditional medicine practices withmainstream medical practices in India; and development of training programsbetween AYUSH and NCI to facilitate crosstraining. Several positive developmentstook place after the thought-provoking deliberations. This makes India one among 12mega\u2013biodiverse countries of the world.Upgrade the educational standards in Indian Systems of Medicines andHomoeopathy colleges in the country,Strengthen existing research institutions and ensure a time-bound researchprogram on identified diseases for which these systems have an effectivetreatment,Draw up schemes for promotion, cultivation, and regeneration of medicinalplants used in these systems, and5Evolve pharmacopeial standards for Indian Systems of Medicine and Homoeopathydrugs.6 Of the threepharmacopeia committees for Ayurvedic, Siddha, and Unani drugs, the PharmacopoeialLaboratory for Indian Medicines, Ghaziabad, has thus far published standards on1,082 single drugs and 302 compound formulations.7 The Ministry of AYUSH has also set up a research portal,managed by the National Institute of Indian Medical Heritage, for disseminatingknowledge regarding AYUSH systems and research updates for academicpurposes.8 The TraditionalKnowledge Digital Library was initiated in 2001 as a collaborative project betweenthe Indian Council of Scientific and Industrial Research, the Ministry of Scienceand Technology, and the then\u2013Department of AYUSH. Managed by the Council ofScientific and Industrial Research, the Traditional Knowledge Digital Librarydatabase contains 34 million pages of formatted information on over 0.29 millionmedicinal formulations of Ayurveda, Unani, Siddha, and asanas of yoga in fiveinternational languages . Access hasbeen provided to 10 international patent offices under a nondisclosure agreement tocheck for prior art while granting patents.9As part of the 12th Five-Year Plan (2012 to 2017), the Government of India launchedthe National AYUSH Mission, which envisages better access to AYUSH services throughan increase in the number of AYUSH hospitals and dispensaries; mainstreaming ofAYUSH through colocation of AYUSH facilities at primary health centers, communityhealth centers, and district hospitals; and ensuring availability of AYUSH drugs andtrained manpower. The plan also aims to improve the quality of AYUSH educationthrough enhancement of the number of upgraded educational institutions, sustainedavailability of quality raw materials, and promoting medicinal plantconservation.10According to the 2012 US National Health Interview Survey, one in three adults in theUnited States used complementary and alternative medicine (CAM) approaches, withnatural dietary supplement products and yoga being the most commonly used CAMmodalities. It has been estimated that in 2006, Americans spent 33.9 billion USdollars out of pocket on CAM products and services.11 For dietary supplements, the FDA\u2019s Center for FoodSafety and Applied Nutrition is responsible for the agency's oversight of theseproducts, and premarket approval is not required for many ingredients that havehistorically been in the marketplace. However, new dietary ingredients do requirepremarket notification with the Center for Food Safety and Applied Nutrition, withsupporting information that the ingredient will reasonably be expected to be safeunder the conditions of use recommended or suggested in the labeling.Several arms of the US Department of Health and Human Services (HHS) address aspectsof TM. Natural products from herbal sources  are oftensold as dietary supplements and are readily available to consumers in the US.Because dietary supplements are not intended to treat, diagnose, cure, or alleviatethe effects of diseases, they do not undergo the drug approval process with the USFood and Drug Administration (FDA).12 The NIH Office of Dietary Supplements was created tostrengthen knowledge and understanding of dietary supplements by evaluatingscientific information, stimulating and supporting research, disseminating researchresults, and educating the public to foster an enhanced quality of life and healthfor the US population.13 AnotherNIH institute, the National Cancer Institute (NCI), has at least two programs thatspecifically address traditional medicines. NCI\u2019s Developmental TherapeuticsProgram has empowered its Natural Products Branch to acquire plants, microbes, andmarine organisms through collection contracts encompassing over 25 tropical andsubtropical countries worldwide. The NCI Natural Products Repository, which isconsidered a national resource, includes approximately 80,000 plant samples, 20,000marine invertebrates and algae, and 16,000 microbes.14 The NCI Office of Cancer Complementary andAlternative Medicine is responsible for NCI\u2019s research agenda in CAM as itrelates to cancer prevention, diagnosis, treatment, and symptommanagement.15The US National Institutes of Health (NIH), part of the HHS, comprises 27 differentinstitutes and centers that support biomedical research, including research on manyaspects of CAM. The National Center for Complementary and Integrative Health,formerly the National Center for Complementary and Alternative Medicine, is the NIHagency with a mission to define, through rigorous scientific investigation, theusefulness and safety of complementary and integrative health interventions andtheir roles in improving health and health care.16 State and local governments areresponsible for deciding what credentials practitioners must have to work in theirjurisdiction.In the United States, there is currently no standardized, national system forcredentialing complementary health practitioners, and the credentials varysignificantly from state to state and discipline to discipline.17In April 2015, the Secretary and Joint Secretary of the Ministry of AYUSH, alongwith other associates, visited the HHS and NIH to explore the potential forcollaboration. As an outcome of this visit, AYUSH and NCI proposed a follow-upmeeting as an opportunity for additional discussions. In September 2015, the JointSecretary of the Ministry of AYUSH participated in the First US-India HealthDialogue in Washington DC,18 whereboth sides agreed that they would collaborate on various aspects of TM, includingregulatory assessment and research capacity building. Specifically, the HHS Officeof Global Affairs, NCI, and the Ministry of AYUSH agreed to hold a workshop on TM inearly 2016 to create a roadmap for AYUSH collaborations between India and the UnitedStates and to contribute to health, wellness, and people-centered health care inboth nations.In this context, President Barack Obama and Prime Minister Narendra Modi, in theirIndia-US Joint Statement of January 2015, pledged to encourage dialogue between theUnited States and India on TM.The first India-US Workshop on Traditional Medicine (ayushworkshop.in) was held atthe National Agricultural Science Complex, New Delhi, India, on March 3 and 4, 2016.The workshop\u2019s inaugural session started with a welcome address by JointSecretary Jitendra Sharma (Ministry of AYUSH) and was followed by keynote addressesby Ambassador Jimmy Kolker , H.K. Pande, and Ajit Mohan Sharan ; a special address was providedby US Ambassador to India, Richard Verma, and an address was presented by Shripad Y.Naik . The speakersnoted that the goal of this workshop was to discuss the importance of applyingrigorous scientific methodologies to the study of traditional Indian medicalsystems, using evidence derived from such studies to inform both traditional medicalpractices, appropriately integrating evidence-based traditional practices withmodern (Western) medical practices, and making use of the particular strengths thatIndia and the United States can bring to this endeavor.The workshop was attended by Indian and US policymakers, scientists, academicians,and medical practitioners from various disciplines, including but not limited tonatural product chemistry, pharmacology, biochemistry, cancer biology, immunology,cancer prevention, cancer control and population sciences, medical oncology,radiation oncology, integrative oncology, yoga, Ayurveda, Unani, and homeopathy.The program included specific themes divided into four sessions: (1) TraditionalMedicine in the National Cancer Institute, (2) Traditional Medicine in India(introduced by the Ministry of AYUSH), (3) Strength of AYUSH and Promising AYUSHInterventions for Cancer and Other Areas (presented by AYUSH scientists), and (4)Research Presentations on Alternate Systems and Cancer (presented by US scientists).The second day of the workshop was devoted to group discussions on (1) NaturalProducts Research, (2) AYUSH Systems of Medicine in Cancer: What Holds Promise, and(3) Generating Evidence Toward Market Access for AYUSH Products and Practice.The remainder of this article summarizes the workshop proceedings; recommendationsfrom the first India-US Workshop on Traditional Medicine, including areas thatdeserve additional development in cancer research and management; and possibleresearch areas for Indo-US collaboration. The article also highlights developmentsin the bilateral collaboration since the workshop.19 O\u2019Keefedescribed the work of NCI\u2019s Natural Products Branch and Molecular TargetsLaboratory. The NCI Natural Products Repository is one of the largest and mostdiverse collections of natural products, housing more than 230,000 extracts. Thegrowth inhibitory effects of these extracts and their fractions are tested in theNCI-60 Human Tumor Cell Line Screen, as well as against discrete cancer-relatedmolecular targets. O\u2019Keefe described how the active components in extractsare isolated, identified, and assessed for their mechanism of action. He discussedthe use of analytical techniques, such as liquid chromatography massspectroscopy\u2013mass spectroscopy to help upgrade the Ayurveda, Siddha, andUnani pharmacopeia and bring it on a par with the US Pharmacopeia.The presenters in this session were Jeffrey D. White, MD , Barry R. O\u2019Keefe, PhD , and Ikhlas Khan, PhD . White presented anoverview of CAM use and research in the United States, with an emphasis on cancer.In fiscal year 2014 , NCI supported 212grants for which some component of the research was relevant to CAM . More th Khan explained the US government\u2019s approach to regulating botanical productsas either dietary supplements or drugs. Important issues in the regulatoryassessments of these products are safety, quality, and efficacy. Several aspects ofproduct quality were examined, including standardization, selection of markercompounds, adulteration, and misidentification. Finally, Khan introduced the Indo-USCenter for Research in Indian Systems of Medicine at the University of Mississippi,which has as its mission the facilitation of scientific validation and disseminationof information on Indian systems of medicine through collaborative research.On behalf of the Ministry of AYUSH, Sharma presented a brief overview of AYUSH andAYUSH research programs, including current collaborations with US institutions.Presentations of promising AYUSH interventions for treating cancer included acollaborative study with the Tata Memorial Centre-Advanced Centre for TreatmentResearch and Education in Cancer, Mumbai, which has identified nine medicinal plantswith potential cytotoxic or cytostatic effects against different types of cancers,including cancers of the oral cavity, lung, ovary, colon, and prostate. In addition,a former patient with cancer shared his experience with treatment through the use ofmeditation, yoga, and Ayurvedic medicines, along with a vegetarian diet and simpleliving.The main thrust of this session was that AYUSH interventions/therapies have thepotential to be used for regression of the disease process in cancer, managing itssymptoms and complications, reducing the adverse effects from chemotherapeuticdrugs, improving quality of life, increasing the survival period, and preventingrecurrences and complications. 20Similarly, a presentation by Subhash Padhye, PhD , demonstrated the potential anticancertherapeutic effects of a Unani intervention, black cumin seeds (Nigella sativa). Themajor active component of black cumin is thymoquinone, which demonstrates cytotoxicactivity against pancreatic cancer cell lines by targeting the prolactinreceptor.Chitra Mandal, PhD , discussed a newmolecule, CM-5, a carbazole alkaloid derived from the plant Murraya koenigii(Rutaceae), commonly known as curry leaf or kari patta, which has shown tumoricidalactivity and also increased the efficacy of known cancer drugs in an animal model ofvarious types of cancers at doses that did not cause serious systemic toxicity. CM-5has also been shown to exhibit antiproliferative activity against several pancreaticcancer cells through apoptosis.The utility of yoga in improving the quality of life in patients with cancer washighlighted through two presentations. R. Nagarathna, MBBS, MD, Medical Director,S-VYASA Deemed University, Bengaluru, and Raghavendra Rao, PhD, Senior Scientist andHead, CAM Program, Health Care Global Enterprises, gave a presentation on theintegration of Ayurveda and yoga with conventional Western medicine to relieve thesymptoms of cancer, notably, nausea, vomiting, fatigability, alopecia, diarrhea,insomnia, pain, and the adverse effects of chemotherapy, radiation, and surgery.Ramesh Bijlani, MBBS, MD, Emeritus Professor of Physiology, All India Institute ofMedical Sciences, highlighted the use of yoga as a potential cancer preventionstrategy. G. Geetha Krishnan, BAMS, MD (Ayurveda), Senior Consultant & Head ofthe Department of Integrative Medicine, Medanta Hospital, discussed his work on theuse of yoga and Ayurvedic therapies, such as Panchakarma, to prevent adverse effectsof radiotherapy and chemotherapy, including nausea, vomiting, and insomnia.A pilot study in which metal-based formulations from Ayurveda were used to treatacute promyelocytic leukemia was presented by Vaidya Balendu Prakash of the VaidyaChandra Prakash Cancer Research Foundation in Dehradun. The study, which wasconducted in collaboration with the Central Council for Research in AyurvedicSciences, the Ministry of AYUSH, and the All India Institute of Medical Sciences,provided some evidence for consistent and sustained antileukemic effects.A preclinical study of the anticancer effect of a homeopathic preparation of Thujaoccidentalis was presented by Gaurisankar Sa, PhD, Division of Molecular Medicine,Bose Institute, Kolkata. Results from this study suggested that homeopathicmedicines prepared from Thuja sulfur and Calcarea carbonica in dynamic or potentizeddoses may be able to induce apoptosis in cancer cells through a p53-dependentpathway in various cell lines studied. Jayesh V. Sanghvi, MD (Homeopathy), Director,Nature Clinic Super Specialty Center in Chennai, proposed homeopathy as a singletherapy or as an add-on therapy for relieving pain and other symptoms and adverseeffects of radiotherapy, chemotherapy, and surgery. N. Deepa, M.Pharm, PhD, Vice Principal, College of Pharmacy, Chennai, discussedSiddha interventions derived from aqueous extracts of two plants that showedanticancer properties in preclinical studies. These extracts were shown to becytotoxic to a cancer cell line, apparently through DNA damaging effects. 21Arvind Kulkarni, MD, Director, Radiation Oncology Department, Lady Ratan Tata MedicalCenter, spoke about integrative oncology and highlighted the functioning of theAyurveda Centre in the Integrated Cancer Hospital, which has been established inPune and declared a Centre of Excellence by Ministry of AYUSH. The Centre has donework in evaluating the efficacy of combinations of Ayurvedic drugs in alleviatingdrug toxicity and improving the quality of life in patients with cancer treated withchemotherapy.This session provided examples of relevant US research projects and programs. NagiKumar, PhD, RD, Director, Cancer Chemoprevention, Moffitt Cancer Center, presentedon chemoprevention and treatment of cancers with botanicals. She provided a detaileddescription of the process of drug development with reference to botanicals anddiscussed current challenges for targeted therapies in cancer, as well as theadvantage of a multitargeted approach through botanicals. Limitations of the presentbiomarker-based approaches were also described, along with ways to overcome theselimitations to facilitate botanical drug development.Hasan Mukhtar, PhD, Helfaer Professor of Cancer Research, Director and Vice Chair forResearch, Department of Dermatology, Wisconsin Medical Sciences Center, presented onnatural products for cancer chemoprevention on the basis of lessons learned fromanimal experiments. Studies exploring potentially effective approaches for cancercontrol in humans were discussed. Encouraging findings from these prevention studiesindicate the need for additional investigations of these and other naturalproducts.Guido Pauli, Pharm D, PhD, Professor and University Scholar at the University ofIllinois at Chicago College of Pharmacy, presented on advancing the holisticapproach to traditional plant-based medicine. He elaborated on the need to studynatural products both qualitatively and quantitatively, and presented approaches fora more holistic analysis that captures the complex constitution of natural healthproducts. Although marker compounds for natural products are used widely andglobally, they should be thoroughly investigated and defined with caution.Validation methodology for chemotaxonomic and bioactive markers as well as potentialleads for active pharmaceutical ingredients should be congruent.Day 2 of the workshop began with discussions to identify research areas for Indo-UScollaboration and to summarize the meeting outcomes. The workshop attendees weredivided into three discussion groups: (1) Natural Products Research; (2) AYUSHSystems of Medicine in Cancer: What Holds Promise; and (3) Generating EvidenceToward Market Access for AYUSH Products and Practices.The natural products research group discussed research methods, training needs,prerequisites for material transfer agreements with US NCI and Indianperspectives, intellectual property rights, and National Biodiversity Authorityperspectives on benefit sharing and commercialization.Several recommendations emerged from these discussions:The need to add capacity for conducting research in natural products,including both single herbs and mixtures. Suggestions included buildinga central repository for cell lines, extracts, and fractions, as well asdeveloping infrastructure for translation of validated research intoclinical practice, including incubation of start-up companies.The need for harmonization of pharmacopeias from India and Westernnations, including the United States. Important for such harmonizationis the creation of a centralized laboratory for analytical methodologydevoted to standardized quality control for Ayurvedic preparations. Sucha facility would lead to the development of standard operatingprocedures (SOPs) for herbal and herbomineral preparations.The proposed enhancement of quality control and standardization inAyurvedic preparations would better ensure the reproducibility ofresults among disparate laboratories to increase transferability betweeninstitutes and countries. To support such reproducibility studies, thegroup recommended that the Ministry of AYUSH encourage multicenterclinical studies on interventions for the most prevalent cancers inIndia and the United States. These studies should use a standard formatfor data collection, analyses, and management. Open dissemination of theresults of such clinical trials and evaluation of their power andreproducibility are critical.Additional recommendations included focusing on the strengths oftraditional medical systems such as rasayanas  and the development of specialized expertise inintellectual property rights.The overall goal of this group was to identify research gaps and ultimatelydevelop steps for generating evidence and moving research to practice. The groupdiscussed research methods, training needs, and next steps. The focus was onepidemiology studies, palliative care, and support studies. The discussion ledto the following recommendations:Evidence to translate research to practice should be obtained in aculture of collaboration, ensuring communication and cooperation amongall stakeholders, including AYUSH, extramural scientists, clinicians,and pharmaceutical/biotechnology companies. AYUSH activities should bewell integrated, involving both basic scientists and clinical teams.Basic research is needed to generate robust supporting data for claimsregarding the integrity, safety, and efficacy of botanicals that arewell founded , to inform the development andimplementation of clinical trials.There is a critical need to develop guidelines and standard operatingprocedures to ensure product integrity ,including a clear understanding of biology, molecular targets, safety,and indications for use of AYUSH products.Clinical trials should be performed with scientific rigor and includesafety and clinical efficacy studies. Focus areas should includeadjuvant therapy and remission therapy by AYUSH modalities, benefitsfrom such approaches in the form of personalized medicine, andimprovement in quality of life.Mechanisms should be established that encourage the articulation ofresults of TM observations in scientific meetings and their publicationin peer-reviewed journals.With regard to the training and education of the next generation of TMpractitioners, the group felt that joint Indo-US training programs wouldbe mutually beneficial. One particular recommendation was the jointdevelopment of protocols for clinical and basic research. Such protocolsshould consider quantitative clinical parameters.Finally, the formation of US-India activity groups was recommended tocontinue discussions of relevant topics.The overall goals of this group were to identify gaps, define the key role ofresearch, discuss approaches to implementing validation studies, consider therole of rigorous clinical trials, and identify areas for collaboration thatwould ultimately lead to generating sufficient evidence to move research resultsinto clinical practice. Recommendations from this group included thefollowing:Recognize the need to advance basic sciences in AYUSH by establishingcollaborations among basic, clinical, and population science researchteams as well as the private sector and industry.Establish guidelines and standards for product integrity in terms ofbiology, targets, and rigor/reproducibility, including developing SOPsfor product development, validation, batch-to-batch consistency,preclinical models, and clinical trials.Build centralized Good Manufacturing Practice laboratories, usingestablished manufacturing practices for product development and create ahub for making this information, including cost of production ofproducts, available to all users.Establish a regulatory structure to address consistency in standards ofresearch conduct and compliance.Articulate and publish findings of studies conducted using rigorousscientific methodology.Create cross-disciplinary exchange and scholarships, including a platformfor joint India-US conferences and/or symposia, providing trainingopportunities across and within disciplines.After the workshop, the participating agencies agreed to adopt a multidisciplinaryapproach for moving ahead in the intersection of Indian TM and cancer research.Several meetings have been held with representatives of NCI, HHS, National Instituteof Cancer Prevention and Research (NICPR)/Indian Council of Medical Research, theAll India Institute of Ayurveda and the Ministry of AYUSH. All India Institute ofAyurveda has been declared the nodal center to coordinate AYUSH cancer research inIndia. Under the aegis of an MoU signed with NICPR\u2013Indian Council of MedicalResearch, a Centre for Integrative Oncology has been set up in Noida at NICPR whereofficers from each AYUSH system are stationed to collate all information related tocancer research done in AYUSH systems. This center will also coordinateinternational activities, including with the NCI and HHS. The Ministry of AYUSH hasalso signed memoranda of understanding (MoUs) with the United States PharmacopeiaConvention and Pharmacopeia Commission of Indian Medicine and Homoeopathy;Homoeopathic Pharmacopeia Convention of United States and Central Council forResearch in Homeopathy and Pharmacopeia Commission of Indian Medicine andHomoeopathy. This will help in the development and harmonization of pharmacopeiasfor the traditional systems of medicine. The Ministry of AYUSH is also deputingofficers to the National Centre for Natural Products Research, University ofMississippi, for postdoctoral training. A draft MoU between HHS and the Ministry ofAYUSH is in the process of finalization, with the aim of facilitating capacitybuilding and joint academic and research collaborations. These progressivedevelopments will help take forward the shared commitments of the two countries inthe field of TM.In conclusion, the workshop served as an important initial engagement for theMinistry of AYUSH, HHS\u2013Office of Global Affairs, and NCI to discusscooperative activities in areas including research training and research programs.These discussions highlighted the opportunities to develop rigorous scientificportfolios and collaboration, while integrating existing knowledge, clinical bestpractices, and considering regulatory issues that govern the process of bringingscientific results to the benefit of public health.The workshop provided a comprehensive understanding of existing gaps, such asinclusion of rational and scientific approaches for drug development; policies andprocedures that can help develop milestones/expected outcomes; promotion ofcollaborative research; implementation of regulatory structures to ensure productreproducibility; and development of procedures and principles for productvalidation. The workshop also provided the opportunity for NCI and AYUSH researchersto begin engagement that continues as agreements and priorities are formalized.Several important recommendations emerged from the workshop, such as the need forbasic sciences in deepening the understanding of TM; creation of cross disciplineexchange/scholarships; development of centers of excellence; centralizedlaboratories; a platform for joint India-U.S. conferences and symposia to share andacquire knowledge; a hub of standardized information; regulatory structure andcompliance; and development of Good Manufacturing Practice facilities. It would seemhighly beneficial to link together some of the well-established centers in India forbasic, translational, and clinical research with joint projects. Such projectsshould emphasize product supply and encourage industries to participate in productdevelopment. Development of plant biotechnology was another area of interest.Implementing data and procedure optimization via development of SOPs and validationprocedures was highly recommended. Development of training programs for TMscientists and medical practitioners, as well as crosstraining opportunities acrossall relevant disciplines, was also prominent among the recommendations.The first bilateral workshop provided a strong foundation for AYUSH, NCI, and theirpartners to work together on implementing the recommendations for better developmentand promotion of the growth of traditional Indian medicine research, advancing itsevidence-based practice, and defining its role in the care of patients with cancerin an integrated fashion with conventional biomedicine. A Centre for IntegrativeOncology is in place to coordinate interactions on cancer-related research at thenational and international levels. One of the premium institutes of Ayurveda hasbeen designated as a nodal institute for cancer research. Efforts are under way toformalize the collaboration between HHS and AYUSH to advance the research andregulatory capacity of TM."}
+{"text": "Adult protective services (APS) and other community-based agencies respond to hundreds of thousands of elder abuse cases each year in the United States; however, little is known about what constitutes success in the context of elder abuse response intervention. This study explored the meaning of elder abuse intervention success from the perspective of victims themselves toward the development of a victim-centric taxonomy of outcomes. Guided by a phenomenological qualitative methodology, this study conducted in-person, semi-structured interviews with a sample of elder abuse victims (n = 30) recruited from APS in the states of Maine, New York, and California, as well as a community-based elder abuse social service program in New York City. To enhance trustworthiness, two researchers independently analyzed transcript data to identify key transcript statements into themes. Outcomes of success were identified across broad domains related to the victim, perpetrator, victim-perpetrator relationship, family system, and home environment. Specifically, common themes represented outcomes related to victim safety, autonomy, social support, and state of mind; perpetrator independence and accountability; and victim-perpetrator separation. For decades, the field of elder abuse has struggled to understand how to define success in the context of community-based intervention from a client-centered perspective. The taxonomy developed in this study provides a comprehensive and conceptually organized range of successful outcomes to serve as infrastructure for the development of meaningful intervention outcome measures. This study represents one of the largest efforts to understand and integrate the perspectives and needs of victims into elder abuse intervention practice/research to date."}
+{"text": "Despite the wide recognition of the multifactorial nature of Alzheimer\u2019s disease (AD), mechanisms of the collective influence of genetic and environmental factors on AD remain poorly understood. We used the Cardiovascular Health Study (CHS) and Framingham Heart Study (FHS) data to investigate the effects of genetic and gene-environment interactions on AD prevalence in the association analysis using logistic regression. Based on results of this analysis, we developed several new measures of integrated effects of SNPs, including for specific gene or group of genes, by constructing SNP-specific Interaction Polygenic Risk Scores (SIPRSs), Gene-specific Interaction Polygenic Risk Scores (GIPRS), and Trait-specific Interaction Polygenic Risk Scores (TIPRS), and tested them in the above data. We found strong interaction effects on AD among the SNPs in NRG3 gene and smoking, and among the SNPs in ATM and creatinine. In summary, we developed a new approach to measuring the collective impact of SNPs on complex traits, and discovered significant effects of the newly constructed SIPRS, GIPRS, and TIPRS on AD prevalence. The results of this study open a new opportunity of investigating the joint impacts of genetic and environmental factors on AD and other phenotypes of aging and health."}
+{"text": "Following publication of the original article , the autCenter for Disease Control and Prevention, Kisumu, KenyaOriginally the affiliation for Felix Humwa and Vallarie Opollo has been published as:Kenya Medical Research Institute (KEMRI), Kisumu, KenyaThe correct affiliation is:The corrected list of affiliations is included in this Correction."}
+{"text": "We demonstrate how application of analytic approaches developed in demography, biodemography, epidemiology, and population studies to Medicare and Medicare-linked data allows to identify causes and mechanisms of disparities in AD/ADRD. Our studies i) confirmed geographic disparities in AD mortality  but did not detect them in Medicare data, ii) confirmed racial disparities in AD/ADRD incidence and survival  and demonstrated that they can be partly explained by heterogeneity in diagnosis severity and partly by genetic factors, iii) detected unexpectedly strong effects of systemic hypotension, chronic kidney and liver diseases on the risk of AD/ADRD. We concluded that further progress in understanding of mechanisms and causes of the disparities in AD/ADRD is possible by clarifying the role of cause-of-death coding, the effects of comorbidity and their treatment, dynamics in cognition scores before AD/ADRD diagnosis, and genetic factors."}
+{"text": "Microbes and Environments, the nitrogen cycle is one of the most important and commonly researched topics in the field of environmental microbiology.If a story was written entitled the \u201cKingdom of Microbial Ecology\u201d, how would the characters and plot be decided? Many microbiologists will agree with the following: the primary story setting involves a magnificent castle (a habitat) in fertile land with bright sunlight (the energy source), and the king and queen are the carbon and nitrogen cycles, respectively. Although this is an unusual way to begin a research highlight article in Nitrogen is among 6 major essential elements of CHNOPS for life and composes the building blocks and intact molecules for metabolism (amino acids and proteins), heredity (nucleotides and nucleic acids), and other important biological functions. Among the essential elements, circulating volumes of biologically available nitrogen and phosphorus are slightly limited in many biospheres of the planet, and, thus, as a whole, the biological demand for nitrogen and phosphorus and their circulation speeds are markedly greater and faster than those for carbon . Further2) and  reactive nitrogen   processes, nitrogen fixation and denitrification  (2 to reactive nitrogens (such as NO) always occurs with lightning, which provides reactive nitrogens to the land and ocean , nitric oxide (NO) and nitrous oxide (N2O), has been recognized in many scientific and social contexts. Nitrification, denitrification, dissimilatory nitrate reduction to ammonium (DNRA), assimilatory ammonication, and anaerobic ammonium oxidation (Anammox) each through the transformation of these intermediate nitrogen metabolites and intermediates in natural microbial communities may be multi-directionally transformed by the complex nitrogen metabolism of various populations in response to intra- and extracellular physicochemical conditions and reaction dynamics through interspecies interactions  in coastal eelgrass sediments and suggested that sulfur-oxidizing Gammaproteobacteria and Bacteroidetes populations contribute to N2O removal in eelgrass sediment microbiomes. Siqueira et al. respond to the physicochemical conditions of habitats . Although nitrous oxide reduction (with and without nosZ) is not key for denitrification, the abundance of nitrate reduction (the expression of napA) may be more important. Jang et al.(Bradyrhizobium nitroreducens from rice paddy soil that hosted and co-expressed two types of nitrite reductase genes (nirK and nirS), and the majority of denitrifiers are known to possess and use each of the two types of nitrite reductases. These are also excellent examples of the complexity of the nitrogen cycle in natural microbial communities.In catabolic and anabolic metabolic pathways, the significance of intermediate nitrogen metabolites, such as nitrite ; however, the enzymatic entity that catalyzes the oxidation of hydroxylamine to nitrite, corresponding to hydroxylamine dehydrogenase (Hao) in the case of ammonia-oxidizing bacteria (AOB), remains unclear   and alsoet al.  demonstra et al.  and Nuno (et al.  reported unclear . AOA are unclear . Using ti et al.  confirmei et al. ; howeverMicrobes and Environments in the last two years have been awarded to studies on the nitrogen cycle. Therefore, the large, fast, and complex nitrogen cycle has attracted the attention of many environmental microbiologists worldwide, and Microbes and Environments has significantly contributed to lifting the veil of secrecy surrounding \u201cthe Queen of the Kingdom of Microbial Ecology\u201d.The MVPs in"}
+{"text": "Allopurinol (xanthine oxidase inhibitor) is indicated for the treatment of symptomatic hyperuricemia, the treatment of gout and the treatment and prevention of uric and calcium lithiasis. It is one of the leading drugs for severe toxic dermal reactions, such as Lyell Syndrome (NET), Stevens-Johnson Syndrome (SJS) and Dress Syndrome (Drug reaction with eosinophilia and systemic symptoms). We report the case of a 45-year-old woman who was hospitalized for bullous skin rashes, without pathological history, the patient had generalized erythematous and bullous rash  one week after taking allopurinol, prescribed by his rheumatologist for a gout. The diagnosis of bullous Cutaneous reaction due to allopurinol was retained, allopurinol was discontinued and the course was favorable with the disappearance of cutaneous lesions."}
+{"text": "The goal of this review is to confer recent advances in our understanding of the brain ISS, including its structure, function, and the various processes mediating or disrupting ISF drainage in physiological and pathological conditions. The brain ISF in the deep brain regions has recently been demonstrated to drain in a compartmentalized ISS instead of a highly connected system, together with the drainage of ISF into the cerebrospinal fluid (CSF) at the surface of the cerebral cortex and the transportation from CSF into cervical lymph nodes. Besides, accumulation of tau in the brain ISS in conditions such as Alzheimer\u2019s disease and its link to the sleep-wake cycle and sleep deprivation, clearance of ISF in a deep sleep via increased CSF flow, novel approaches to remove beta-amyloid from the brain ISS, and obstruction to the ISF drainage in neurological conditions are deliberated. Moreover, the role of ISS in the passage of extracellular vesicles (EVs) released from neural cells and the rapid targeting of therapeutic EVs into neural cells in the entire brain following an intranasal administration, and the promise and limitations of ISS based drug delivery approaches are discussedThe brain interstitial fluid (ISF) and the cerebrospinal fluid (CSF) cushion and support the brain cells. The ISF occupies the brain interstitial system (ISS), whereas the CSF fills the brain ventricles and the subarachnoid space. The brain ISS is an asymmetrical, tortuous, and exceptionally confined space between neural cells and the brain microvasculature. Recently, with a newly developed  The brain is made up of neural cells such as neurons, astrocytes, oligodendrocytes, and microglia, the vasculature comprising arteries, arterioles, capillaries, venules and veins, and the interstitial system (ISS) The brain cells are cushioned and supported by two forms of brain-specific fluids, the brain interstitial fluid (ISF) and the cerebrospinal fluid (CSF) , 2 The IThe ISS is circumscribed by the plasma membrane of neurons or glia and the wall of blood vessels  Fig. 1)Fig. 1). +/K+-ATPase enzymes in the cell membrane [The constituents of the ISS comprise ISF, ECM, and diffusely distributed interstitial matrix (ISM)  Fig. 1)Fig. 1). membrane , 27.The ECM, an abundantly hydrated net-like assembly produced by cells and disintegrated by enzymes, comprises collagen, elastin, glycosaminoglycans, proteoglycans, and glycoproteins such as tenascin, reelin, laminin, and fibronectin , 28-30 . Besidesin vivo using single-photon emission computed tomography (SPECT)/positron emission tomography (SPECT/PET), and magnetic resonance imaging (MRI) will be needed to validate the above possibility.The cerebrospinal fluid (CSF) resides in the subarachnoid space covering the entire surface of the brain and the brain ventricles. The CSF serves as a reservoir for the ISF, and an extensive communiqu\u00e9 between the ISF and CSF helps in the removal of waste products from the brain ISF , 45 Fig. Such anSome exchange of substances also occurs between the ISF and the cytoplasm of neural cells as the plasma membrane of neurons and glia is selectively permeable to specific ions and molecules -55 Fig.. MoreoveThe ISS of the brain is dynamic, which provides a route for cross-talk between elements of the vascular system and neural cells. The role of ISS includes the facilitation of communication between neural cells, processing and integration of information, and coordinated response to changes in the brain environment , 62-66. The ISS also facilitates the passage of neural cell derived EVs into local and distant sites in the brain and to the bloodstream. EVs are broadly classified as microvesicles (MVs) having a size of 100-1000 nm and exosomes (EXs) ranging in size from 30-150 nm. Microvesicles directly bud-off from the plasma membrane of cells , 77 wherThe biophysical and biochemical balance between CSF and ISF is crucial for the metabolism of brain cells and drugs, and hence, continuous exchanges between CSF and ISF are critical . Three pKiviniemi and associates, using ultra-fast MRI techniques have demonstrated that three discrete pulsation processes in the human glymphatic system facilitate the exchange between ISF and CSF . The swiIn conditions such as hydrocephalus, increased ventricular pressure causes high ependymal permeability and enhances the flow from CSF to ISF, which leads to interstitial edema of white matter . HoweverThe pathological changes in conditions such as glioma or stroke can alter multiple aspects of the ISS, which may include changes in geometry, ECM and its components, the constituents of the ISF, and the transport of substances in the ISS , 101. InIn ischemic stroke, studies have shown decreased ISS volume as a result of cytotoxic edema , and incThe failure rate of CNS drugs in both preclinical and clinical studies is much higher than non-CNS drugs , 122. InNonetheless, further refinements are necessary for CED to be translated successfully to the clinic. Notably, a device that avoids the backflow or reflux of injection and mechanical damage to the brain tissue is needed -131. FurMany exciting advances occurred in the past decade regarding our understanding of brain ISS. The new developments in the field include identification of differential ISF drainage in distinct functional segments of the brain, and several routes and mechanisms underlying the drainage of ISF into ventricles and the subarachnoid space. Interestingly, tau accumulation in the brain ISS and sleep deprivation augmenting that process have been identified as one of the factors that facilitate the spread of tau in AD. Additional studies have also shown the promise of the removal of beta-amyloid from the brain ISF for improving cognitive function in AD. On the other hand, ISS-based drug delivery, though promising, needs further development and refinement for a successful clinical application of this approach."}
+{"text": "Family members often serve as informal caregivers for the first line of care. The complexity of family caregiving suggests the need to examine the personal and environmental resources that contribute to caregivers\u2019 psychosocial well-being. Informed by the life course perspective, this study investigates the impacts of providing care to a family member on global and daily psychosocial well-being, and the moderating influences of age, gender, marital status, and social support. The sample consists of 1449  participants from Midlife in the United States (MIDUS-II: Main and Diary) survey. Regression and multilevel models results indicated greater global negative affect and daily stressors in caregivers as compared to non-caregivers. In line with the positive correlates of caregiving, caregivers reported greater daily positive events. Age, gender, and marital status significantly moderated the associations between caregiving and well-being. Findings showed that services aimed at family caregivers should take into account of personal resources."}
+{"text": "Antimicrobial resistance is projected to become the leading cause of death worldwide, claiming an estimated 10 million lives a year by 2050, primarily in low- and middle-income countries.,Antimicrobial resistance develops in, and is maintained and transmitted across humans, animals and the natural environment. Resistance is an ancient and naturally occurring phenomenon, but anthropogenic antibiotic use since the 1930s has been linked to the increasing occurrence of antimicrobial-resistant microorganisms, particularly bacteria.One of the key guiding principles of the national plans is to use a One Health approach and multisectoral coordination. This principle gives the various collaborating organizations equal status and emphasizes a sense of ownership of the plan.We analysed the 18 national action plans published in English between 2015 and October 2017  to deterBox\u00a01United Republic of Tanzania (2017)Barbados (2017) and Canada (2017)Oman (2017)Denmark (2017) and Sweden (2016)Bangladesh (2017), India (2017), Indonesia (2017), Maldives (2017), Nepal (2016), Sri Lanka (2017), Thailand (2016) and Timor-Leste (2017)China (2016), Japan (2016), Mongolia (2017) and New Zealand (2017),Ten out of 18 action plans followed the World Health Organization (WHO) guidelines and identified five objectives in line with the global action plan on antimicrobial resistance: (i)\u00a0improve awareness and understanding of antimicrobial resistance through effective communication, education and training; (ii)\u00a0strengthen the knowledge and evidence base through surveillance and research; (iii)\u00a0reduce the incidence of infection through effective sanitation, hygiene and infection prevention measures; (iv)\u00a0optimize the use of antimicrobial medicines in human and animal health; and (v)\u00a0develop the economic case for sustainable investment that takes account of the needs of all countries, and increase investment in new medicines, diagnostic tools, vaccines and other interventions.The most frequent term across all action plans  was that,Although most plans have been drafted by multisectoral coordination teams who acknowledge that One Health guides their approach, the predominance of topics around human-animal health and the scarcity of topics around the natural environment suggests that there are more representatives of human-animal health in the coordination teams. The reason for this could be twofold. First, we have an increasing understanding of resistance mechanisms in human-animal systems, alongside better developed surveillance methods, and longer-term collaborations among key agencies, such as WHO, the Food and Agriculture Organization of the United Nations (FAO) and the World Organisation for Animal Health (OIE).Antimicrobial resistance is a complex multisectoral challenge. Some progress is being made towards embedding a One Health approach in national action plans on antimicrobial resistance. For example, the national plan of Sri Lanka provides an example of a cross-sectoral approach including expertise from rural economy, fisheries, aquatic sciences, veterinarians and public health, and the national plan of India includes an objective on reducing the environmental spread of antimicrobial resistance. However, our analysis suggests that the first set of national action plans have not been wholly successful in incorporating a One Health approach. The plans have prompted the establishment of multisectoral committees and, in some cases, governance. Yet, while human and animal health feature prominently, the natural environment has yet to be fully integrated into these plans. Since the natural environment is a key source and driver of antimicrobial resistance, as highlighted by the WHO/OIE/FAO Tripartite and by the global action plan on antimicrobial resistance,"}
+{"text": "Chronic venous disorders are common vascular pathology of great medical and socioeconomic impact, characterized by a wide spectrum of clinical manifestations occurring with symptoms and/or signs that vary in type and severity. The predominant pathophysiological mechanisms of chronic venous disease start from the development of venous hypertension from shear stress and reflux, leading to endothelial dysfunction and venous wall dilatation. The altered hemodynamic transduces physical signals into harmful bio-molecular pathways, creating a vicious cycle among shear stress, proteolytic remodeling, and inflammatory processes. This intricate network is further exacerbated by the degradation of protective endothelial glycocalyx. In this special issue, at least three main aspects of these interactions are highlighted: the dangerous, the good, and the diverse, which may help to focus attention on the biomolecular mechanisms and the possible targeted therapy of chronic venous disorders (CVeD). Chronic venous disorders (CVeD) are common lower extremity vascular pathologies of great medical and socioeconomic impact , affecting a large part of the population worldwide  and significantly decreasing the quality of life of affected patients ..4].The enhanced production, secretion, and activation of several enzymes   induced The properties and functions of glycosaminoglycan (GAG) layer, forming a protective barrier in endothelial cells, are critical for the maintenance of water, ions, and protein balance between the intra- and extra-vascular compartments . The cheThe highly negatively charged, unbranched polysaccharide family of GAGs  may mediate chemokine mobilization, modulating the recruitment of leukocytes and neutrophils, a vital process in inflammation . InteresIn vitro and in vivo studies have highlighted that the GAGs of endothelial glycocalyx have a profound influence on the vascular wall physiology through: (1) the transmission of shear stress, as mechano-transducer of some hemodynamic stimuli; (2) the maintenance of a selective permeability barrier and a low hydraulic conductivity, like a protective layer for the endothelial cells, both in arteries and veins; and (3) the modulation of blood leukocytes, lymphocytes, and platelets adhesion, limiting extravasation of reactive cells capable of inducing inflammation and proteolysis in blood vessel microenvironment. So, endothelial glycocalyx (and its GAG constituents) represents the good but fragile barrier of both vein and artery wall .The major constituents of the endothelial glycocalyx may be degraded from the endothelial surface under various acute and chronic clinical conditions; a plethora of proteolytic enzymes may have a wide array of potentially destructive capability against vessel GAGs. In fact, other than the well-known matrix metalloproteases, also heparinases, hyaluronidase, and serine proteases , as well as cathepsins, may lead to loss or destruction of GAG from the endothelial surface layer . All theIn this respect, pharmacological agents   may dispThe glycosaminoglycans physiologically present as a protective layer and a significant barrier for all endothelial cells , as wellSeveral studies provided evidence that the integrity of GAG compounds of endothelial glycocalyx plays crucial roles and protective functions in several vascular diseases. The loss and/or degradation of glycocalyx prone the vessel wall to the development of inflammatory and proteolytic damages \u201copening the door\u201d for: (a) the mechano-transduction of acute and chronic stimuli; (b) the increased permeability barrier; (c) enhancing harmful adhesion of blood leukocytes, lymphocytes, and platelets; and (d) favoring extravasation of the reactive blood cells capable of induce inflammation and proteolysis in blood vessel microenvironment ,3,14.On the other hand, studies on the GAG-based drugs have demonstrated its \u201cJanus Bifrons\u201d vascular protective properties , throughSeveral veno-active drugs  may counteract the hemodynamic, inflammatory, and proteolytic pathologic mechanisms of venous diseases, including all stages of CVeD ,17 but aThe potential of these veno-active and veno-protective drugs is mainly focused to limit the initiation/progression of early stages of CVeD, accelerating also the wound closure in the late stages of CVI, suggesting then a potential utility of GAG-based drugs in endothelial dysfunctions as a promising therapeutic approach for patients suffering of both deep-vein thrombosis and pulmonary embolism, serious and complicated pathologies with significant clinical and epidemiological impact in the elderly reviewed in .An updated consensus highlighted all the clinically complex aspects included in the terminology Chronic Venous Disorders (CVeD), including early clinical pictures which cannot be called simply \u201cdisease\u201d  compared to the late stages CVI mainly due to insufficient venous drainage, edema, skin damage, and leg ulcers . This clIt is noteworthy that for resolving CVeD we need to take into account different approaches: on one hand, the ability of pharmacological therapy to target the dangerous biochemical events, on the other hand the positive role of the physical \u201canti-stasis\u201d effects of both compression and/or surgical reflux ablation.The first endothelial alterations induce and guide the subsequent harmful inflammatory and proteolytic cascades, mainly evidenced by the classic hemodynamic CVeD symptomatology .Starting from the primum movens, the complicated network of the CVeD is further exacerbated by the vicious cycle, giving life, over time, to progressive pictures of varying severity, from telangiectasia to varicose veins , to edema and cutaneous trophic lesions up-to venous ulcers (characteristics of CVI), including also venous thromboembolism ,8. It isAn understanding of the hemodynamic-inflammatory-proteolytic biomolecular mechanisms and events may help to orientate the treatment in a more targeted way to the needs of the individual patient suffering of CVeD ,17. The Finally, GAG-based drugs represent the good and the diverse to counteract the dangerous network among hemodynamic, inflammatory, and proteolytic processes occurring from the early stages of symptomatic varicose veins to severe steps of ulcers including the post-thrombotic patients, stigmatizing the fundamental role of the biomolecular mechanisms of endothelium in the management of vascular diseases."}
+{"text": "HIV/AIDS continues to be one of the most challenging individual and public health concerns of our days. According to the latest UNAIDS data, in 2018, roughly 37.9 million individuals were infected with HIV globally, while around 770,000 people died of AIDS-related illness . Gene thStill, different challenges remain in anti-HIV drug therapy/prophylaxis, and these include the following, among others: (i) the onset of severe adverse effects leading to the discontinuation or interruption of therapy or even prophylaxis ,9; (ii) This Special Issue presents an exciting series of reviews and original research articles from eminent scientists in academia and different nonprofit organizations involved in the development of antiretroviral drug products, focusing mainly on novel strategies for the formulation and delivery of anti-HIV compounds. Innovative approaches towards improved gene therapy and immunotherapy are also addressed. The presented reports provide not only interesting overviews and opinion on recent developments in the broad field of antiretroviral therapy/prophylaxis and drug delivery, but also describe the development of new products that are currently tracked for clinical testing.The Special Issue starts with an interesting review by Tsukamoto at Kindai University, Japan, on strategies explored for curing HIV infection using a combination of gene therapy and host immunization . In partIn the first original research study included in the Special Issue, the group of Veiga at the Complutense University of Madrid, Spain, provides details on the development of mucoadhesive tablets for the vaginal delivery of tenofovir, in the context of topical PrEP . The comStill in the area of prophylaxis, the team led by Banga at Mercer University and CONRAD, USA, propose a new transdermal delivery system for tenofovir alafenamide, a nucleotide reverse transcriptase inhibitor . The silco-glycolic acid)-based nanoparticles were developed as carriers for the co-delivery of griffithsin and dapivirine, two potent candidate microbicide compounds. Studies in vitro showed that the proposed formulation not only featured interesting technological properties (including biphasic drug release), but also allowed a synergistic antiretroviral effect to be obtained. In another paper pertaining to the application of nanotechnology against HIV infection, Grande et al.  reviewed the literature for nanocarriers of reverse transcriptase inhibitors [Rohan and colleagues at the University of Pittsburgh, Magee-Womens Research Institute, University of Louisville and International Partnership for Microbicides, USA, contributed an interesting study that further endorses the potential of nanotechnology-based microbicides . In theihibitors . In thisPharmaceutics possible.I hope that researchers involved in the fields of antiretroviral drug delivery and anti-HIV therapy/prophylaxis may find useful and stimulating information here that can be translated into their own ongoing and future work. A final word of appreciation is due to all the contributing authors, anonymous reviewers, and editorial staff at MDPI for making the publication of this Special Issue of"}
+{"text": "Food insecurity or insufficiency, among other factors, is triggered by structural inequalities. Food insecurity is an inflexible problematic situation in South Africa. The country has a custom of evidence-based decision making, stocked in the findings of generalized national household surveys. Conversely, the deep insights from the heterogeneity of the sub-national analysis remain a principally unexploited means of understanding of the contextual experience of food insecurity or insufficiency in South Africa. The data present the food insufficiency status with special focus on adult and children. The data also reveal the adult and children food insufficiency status across the provinces in South Africa. The data contains socioeconomic and demographic characteristics as well the living condition and food security status of the households. A questionnaire was administered to a household to elicit information on household members. The survey covers all legally recognized household members  of households in the nine provinces  of South Africa. The survey does not cover collective living quarters such as student hostels, old-age homes, hospitals, prisons, and military barracks but specifically on households. The General Household Survey (GHS) collects data on education, health and social development, housing, access to services and facilities, food security, and agriculture.The data in In In the same vein, the data in 2The dataset employed is the General Household Survey (GHS), 2016. The dataset was compiled based on stratified two-stage design, and a total of rural and urban 21,218 households were interviewed containing 72,604 respondents. The dataset were coded in SPSS software 22 version which the descriptive part of the research such as mean, frequency, standard deviation were carried out. In addition, the inferencial statistics were carried out on STATA package 13 using the FGT index to classify the respondents into food secured or otherwise. The dataset was robust and representative enough to generalize on the household food sufficiency status of South Africa.Acknowledgements"}
+{"text": "Adults aged 70 and older have the highest suicide rates in most countries across the globe . Prevalence may increase as the Baby Boomers transition into older adulthood . Disease and disability increase risk for late-life suicide, thus identifying opportunities to intervene within the network of services utilized by older adults with illness and disability could reduce suicide risk. This symposium will explore the impact of disease and disability on late-life suicide risk, and present novel ideas for intervention and prevention. Emphasizing the conference theme, we will discuss prevention points spanning networks of care, including mental health and social services, and long-term care. Dr. Bower will frame the scope of the problem by presenting findings of age-stratified associations between physical illness and suicide attempt among older veterans using secondary data from a retrospective case-control study of veterans. Ms. Lutz will present findings on the relationship between disability and suicidal thoughts from a clinical trial of problem-solving therapy. Dr. Lane will discuss management and identification of suicide risk factors during the transition from independent living to long-term care through the lens of a case-series. Dr. Fullen will present preliminary findings from a novel, randomized controlled trial of a community-based suicide prevention training program for nutrition service volunteers. Dr. Yeates Conwell, Co-Director of the Center for the Study and Prevention of Suicide and Director of the Geriatric Psychiatry Program at the University of Rochester Medical Center, will serve as the discussant."}
+{"text": "Cushing\u2019s syndrome (CS) is a set of clinical symptoms which occur as a result of hypercortisolemia. Endogenous ACTH-dependent CS related to an ectopic ACTH-secreting tumour constitutes 12%\u201317% of CS cases and is one of the most common causes of paraneoplastic syndromes. This study presents a case of a 31 year-old man with diabetes, hypertension, rosacea, purple stretch marks and hypokalemia. Findings of diagnostic procedures include high concentrations of cortisol and ACTH, pituitary microadenoma and a tumour in the anterior mediastinum. Dynamic hormone tests determined the source of excess hormone secretion and ectopic ACTH-dependent CS was diagnosed. Due to increasing symptoms of superior vena cava syndrome, an emergency resection of almost the whole tumour was performed, with only a small part of the upper pole left because of the proximity of large vessels and a risk of damaging them. On the basis of histopathological tests, an atypical carcinoid tumour of the thymus was identified. Immediately after the surgical procedure, there was a significant reduction of clinical and laboratory traits of hypercortisolemia, yet, during the 46 weeks of postoperative observation, despite chemotherapy, the progression of residual masses of the tumour occurred with metastases and increased hormone indices. The presented case shows and discusses the differentiation of ACTH-dependent hypercortisolemia and its causes, difficulties in surgical therapy and chemotherapy, as well as prognosis for atypical carcinoid of the thymus, which is a rare disease. Cushing\u2019s syndrome (CS) is a set of clinical symptoms which occur as a result of hypercortisolemia. An excessive concentration of cortisol in the body can have either exogenous or endogenous aetiology. In most cases, its origin is iatrogenic. The incidence of this rare disease is 0.7\u20132.4 cases in a million of the population in a year ,2. ThereA smoking 31-year-old man with 1.5-year history of poorly controlled hypertension treated with angiotensin inhibitor and calcium channel blockers and a 6-month history of diabetes with metabolic imbalance treated with intensive functional insulin therapy and with metformin was admitted to the Clinic of Endocrinology, Diabetology and Internal Medicine of the Regional Specialist Hospital in Olsztyn. The patient was admitted as he manifested clinical and laboratory features of hypercortisolemia and body weight loss of about 18 kg in 6 months, swelling of lower limbs, decreased muscular strength/power, mood changes and lower back pain.2, WHR 0.86, conjunctival hyperaemia, oedema, erythema and lividity of the skin on the neck and face, dilated neck veins, spread papulopustular rosacea, purple stretch marks on the hips and thighs, amyotrophy of proximal limb muscles  . After fThe first descriptions of CS concerning ACTH-secreting tumours not located in the pituitary gland come from 1928 . The terThe patient was diagnosed with ACTH-dependent CS on the basis of hormone tests: high concentrations of ACTH and cortisol with a rigid circadian rhythm and no suppression of cortisol secretion in 2 mg dexamethasone suppression test. Imaging tests showed both a tumour of the anterior lobe of the pituitary gland as well as a massive tumour in the mediastinum. Both lesions could have led to hypercortisolemia, thus, differentiation of ectopic and pituitary overproduction of ACTH was made. Both very high concentrations of ACTH as well as no response in the CRH test unambiguously confirmed ectopic ACTH secretion. Moreover, a significantly increased concentration of chromogranin A suggested neuroendocrine nature of the tumour in the mediastinum, which was confirmed in the histopathological tests of postoperative material, in which traits of an atypical carcinoid of the thymus were found. The ACTH ectopy was ultimately confirmed by normalization of its concentration on the second day after the operation. A neurogenic tumour of the thymus is a rare malignant primary carcinoma of the thymus  which taA CT scan of the chest with contrast is a test of choice in the case of neuroendocrine tumours of the thymus. It reveals a large irregular or patchy mass in the anterior mediastinum, with a heterogenous contrast enhancement and foci of necrosis in the central section of the tumour, at times with microcalcifications. Histological differentiation of neuroendocrine tumours of the thymus includes three categories: low grade of malignancy (well differentiated G1 neoplasms), intermediate grade of malignancy (moderately differentiated G2 neoplasms), and high grade of malignancy (poorly differentiated G3 neoplasms). The majority of thymic tumours belong to the group of well differentiated neoplasms . ImmunohUntil 2016, the total number of cases of neuroendocrine tumours of the thymus was about 400 , while aThe treatment of choice in cases like the one presented here is early total operative resection  which, iACTH-dependent hypercortisolemia requires deep diagnostics to know the real aetiology of the disease. When diagnosing ectopic ACTH secretion syndrome, it should be remembered that its cause may be very rarely occurring atypical carcinoid tumour of the thymus\u2014a neoplasma with extremely poor prognosis. The procedure of choice is complete surgery, which is only possible in some cases. Adjuvant treatment is chemotherapy, radiotherapy, and in the case of expression of somatostatin receptors, SST receptor analogues. The grade of histological malignancy, the size of the tumour, non-complete resection, no expression of SST receptors, distant metastases, progression of residual mass of the tumour and concentrations of particular hormones can be additional very unfavourable prognostic factors, as in the presented case."}
+{"text": "The first speaker is Dr. Thomas Ferris the Center Director of the NSF Center for Health Organization Transformation (CHOT). Dr. Ferris will provide a high-level overview of CHOT and provide the audience with a greater understanding of its history, funding, partners, and accomplishments. In this section, the mission, annual research model, and the I/UCRC planning integration framework will be reviewed and discussed. The NSF CHOT is the only Industry-University Cooperative Research Center (I/UCRC) focused on innovations in healthcare delivery in the nation. CHOT researchers work alongside the Industry Advisory Board (IAB) to conduct research that supports the implementation of evidence-based transformational strategies within the healthcare sector. During this symposium, Dr. Ferris will discuss some of the challenges and opportunities that can arise from these partnerships. More importantly, in this section will speak to how value is created through these collaborative efforts and how ultimately this can improve health outcomes."}
+{"text": "West J Emerg Med. 2019 March;20(2):409\u2013419Best Practices for Evaluation and Treatment of Agitated Children and Adolescents (BETA) in the Emergency Department: Consensus Statement of the American Association for Emergency PsychiatryGerson R, Malas N, Feuer V, Silver GH, Prasad R, Mroczkowski MMErratum inWest J Emerg Med. 2019 May;20(3):537. Pediatric BETA Consensus Guideline Working Group members should not be included in full author list. The author list has now been corrected on this erratum.AbstractIntroduction: Agitation in children and adolescents in the emergency department (ED) can be dangerous and distressing for patients, family and staff. We present consensus guidelines for management of agitation among pediatric patients in the ED, including non-pharmacologic methods and the use of immediate and as-needed medications.Methods: Using the Delphi method of consensus, a workgroup comprised of 17 experts in emergency child and adolescent psychiatry and psychopharmacology from the the American Association for Emergency Psychiatry and the American Academy of Child and Adolescent Psychiatry Emergency Child Psychiatry Committee sought to create consensus guidelines for the management of acute agitation in children and adolescents in the ED.Results: Consensus found that there should be a multimodal approach to managing agitation in the ED, and that etiology of agitation should drive choice of treatment. We describe general and specific recommendations for medication use.Conclusion: These guidelines describing child and adolescent psychiatry expert consensus for the management of agitation in the ED may be of use to pediatricians and emergency physicians who are without immediate access to psychiatry consultation.PMCID: PMC6404720 [PubMed - indexed for MEDLINE]"}
+{"text": "Despite an established positive link between social wealth, health, and social capability among older adults, the effect and mechanisms among these factors are understudied. This paper uses the WHO Study on Global Ageing and Adult Health (SAGE) data and a mediation analysis method, combing social capital theory and a social capabilities approach, to provide new evidence on the effects of financial resource, physical function, and cognitive function on the social capabilities of older adults (aged 55 and above) in China and the possible mediating role of social network in this relationship. The descriptive analysis results show that urban older adults , on average, had lower freedom of expression, lower sense of living safety, and less frequent community participation, while having better self-perceived health, higher physical and cognitive functions, more household income, and higher educational background than their rural peers . The Baron and Kenny\u2019s mediation analysis results show that social networks accounted for a substantial proportion of the effects of wealth and health on social capabilities, but wealth and health still had strong, positive direct effects of its own. Higher mediating effects of social networks were found in the association between functions and social capabilities of freedom of expression (9.46%) and sense of safety (36.33%) among rural older adults. Results of this study urge for further social policies and intervention programs to enhance older adults\u2019 social capabilities, including social cohesion, sense of trust and safety, physical and mental functioning, and subjective well-being."}
+{"text": "Understanding the immune system is of paramount importance for the prevention and treatment of disease as well as the development of novel immunotherapies and immunodiagnostics in the framework of precision immunology and medicine. Recently, the advent of high-throughput biological methods has provided unprecedented insight into the molecular mechanisms underlying immune cell dynamics. The immense complexity of innate and adaptive immunity spanning several orders of spatial and temporal scales may, however, only be grasped by a systems computational immunology approach\u2014specifically, by developing powerful computational approaches, which process, model, and integrate these big immunological data.Original Research , 5 Methods , 5 Technology Reports , 4 Reviews , 1 Hypothesis and Theory (Cohen and Efroni), and 1 Perspective .This Research Topic was designed to give a comprehensive overview of current methods and applications of computational immunology for the dissection of mammalian immunity. Twenty-nine articles are included in this Research Topic, and are categorized into the following types: 13 Davidsen and Matsen;Schramm and Douek;Yermanos et al.), study the inference of immunoglobulin germline genes and polymorphisms , shed light on immunoglobulin light chain characteristics , compare immune repertoires in aging and disease , and improve and/or develop novel computational tools for clustering immune receptor sequences , immune repertoire benchmarking and error correction . Furthermore, storage and standardization of immune receptor data were advanced by the development of a webserver for immunoglobulin analysis pipelines , a new database of epitope-specific B-cell and T-cell receptors , and guidelines for immune receptor data format standardization . The antigen targets of immune receptor repertoires were investigated in works on B-cell epitope prediction  and antigen presentation (Gfeller and Bassani-Sternberg).These papers address a broad range of conceptual challenges in computational immunology. The majority of papers focus on the development and application of computational tools for immune repertoire analysis. Specifically, they elucidate B-cell receptor phylogenetics and somatic hypermutation , plasma cell ontogeny , and regulatory T-cell proliferation . Immune cell signaling was investigated for cytokines , the immune synapse , and macrophage function .In addition to immune receptor biology, the dynamics of immune cells were explored for germinal center B cells (Cohen and Efroni).Finally, a conceptual paper summarized the similarities between the mammalian immune system and supervised machine learning (We would like to express our deepest gratitude and appreciation to all the authors who contributed papers, and to the reviewers and editors without whose invaluable work the publication of this Research Topic would not have been possible.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "This collection focuses on innovative approaches and analytical advancement in drugs of abuse testing and monitoring. Substance abuse negatively impacts all facets of society. Drug testing programs have been developed in many jurisdictions to service law enforcement agencies for drug intelligence, criminal justice systems for prosecution of drug-related crimes, and the health industry for harm minimization.Klingberg et al. investigated the mass fragmentation during the collision-induced dissociation process of a series of synthetic opioids including fentanyl derivatives, AH series opioids, U series opioids, W series opioids and MT-45, and identified a number of common fragments that can potentially be used as markers to indicate the presence of a particular synthetic opioid class of compounds within a sample.One significant challenge in drugs of abuse testing is the continuous emergence of new psychoactive substances (NPS) in the illicit drug market. Routine methods of analysis are no longer effective in screening NPS due to the lack of structural information and commercial reference materials which are needed for performing targeted analysis of these NPS. Scientists are developing non-targeted approaches to overcome this difficulty. In this regard, the use of high-resolution mass spectrometry (HRMS) operated in data dependent acquisition (DDA) mode or more often data independent acquisition (DIA) mode has drawn a wide interest among forensic toxicologists and chemists to advance the non-targeted approach for NPS detection  based on interactions of the compounds with CBSteuer et al. reviewed the recent development of metabolomics approaches for drugs of abuse testing based on the monitoring of changes in small endogenous molecules in response to drugs of abuse consumption and to specimen manipulation. Based on the limited number of studies reported in the literature, the authors conclude that metabolomic approaches possess potential for detection of biomarkers indicating drug consumption. More studies, including more sensitive targeted analyses, multi-variant statistical models or deep-learning approaches are needed to fully explore the potential of omics science in drugs of abuse testing, especially in testing consumption of unknown NPS.Xu et al. studied the metabolism of AMB-FUBINACA, another indazole-3-carboxamide-type SCRA, using both human liver microsomes and zebra fish systems, and discovered a number of unique metabolites to be used as potential poisoning markers for drug monitoring purpose. Diao and Huestis reviewed the advantages and disadvantages of multiple metabolic approaches for investigating SCRA metabolism, including the human hepatocyte incubation model, human liver microsomes incubation, in silico prediction, rat in vivo, zebrafish, and fungus Cunninghamella elegans models and recommended the use of the human hepatocyte model when possible.Adding to the challenge of detecting the use of a large number of NPS available in the illicit drug market is the limited understanding of their biotransformation following consumption. Many NPS such as SCRAs undergo extensive metabolic transformation in the body and drug monitoring needs to target not only the parent drugs but also their metabolites. Studying the metabolism of these compounds is also important to better understand the toxicity of NPS as many NPS metabolites are also pharmacologically active and contribute to the overall toxicity of the parent drugs. Chen et al. reported the development and validation of a simple, rapid, and sensitive LC-MS/MS method for chiral analysis of selegiline and its metabolites desmethylselegiline, R/S-methamphetamine, and R/S-amphetamine in dried urine spots. Busard\u00f2 et al. developed a comprehensive LC-MS/MS method for quantifying fentanyl and 22 analogs and metabolites in whole blood, urine, and hair.Another important aspect of the collection covers the development of sensitive analytical test methods for the detection of drugs of abuse in a variety of biological matrices. In summary, this collection covers Research Topics representative of a number of important research focuses in the area of drugs of abuse testing. Speedy, sensitive and accurate detection of drugs of abuse, including NPS, is part of the crucial steps in the fight against substance misuse and its associated crimes and harms.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.SE was employed by company Elliott Forensic Consulting. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Microorganisms are the prominent sources of valuable products ranging from large  to small molecules . Most of these small molecules termed as \u201csecondary metabolites (SM)s\u201d are inessential to the producer for their growth and development. However, these SMs have significant applications in human and animal health Demain, . BesidesPham et al. have summarized the biological activities and applications of a variety of small molecular medicines and biologics. The manuscript has reviewed the diverse microbial systems used for the production of these biomolecules along with the versatile engineering strategies of such microbial platforms. Generally, each of the microbial strains can produce multiple compounds, but it can produce only subsets of these compounds under specific growth conditions. Therefore, variations in cultivation parameters can elicit the production and discovery of new SMs. For example, by changing cultivation parameters such as temperature, salinity, aeration, and even by altering the shape of the flasks, the production profile from a microbial platform can be altered  approach. They have presented the role of variation in medium, cultivation conditions, use of epigenetic modifiers, and co-cultivation in the discovery of novel secondary metabolites from diverse microbial sources utilizing OSMAC approach .Escherichia coli is reported as the most common cell factory for the production of both small molecules and biologics. The clear understanding of its physiological and genetic characteristics, fast-growth even in minimal salts medium, and availability of easy genetic manipulation techniques has established it as first-choice production host . The metabolic engineering approach utilizing gene over-expression cassette for enhanced production of nucleotide diphosphate (NDP)-sugars was utilized for generating the salicylate glucoside and other glycosylated variants . Similarly, the gene-silencing approach was employed for enriching the titer of 3\u2032-phosphoadenosine-5\u2032-phosphosulfate (PAPS), which is donor substrate for sulfation of natural product (NP) precursors. Hence, by inhibiting the degradation of PAPS mediated by repression of PAPS reductase (cysH) and optimization of different sulfate donors significantly enhanced the production titer of naringenin-7-sulfate . Ribosomally synthesized and post-translationally modified peptides (RiPPs) are special class of NPs with diverse structures and bioactivities, and thus possess a complex biosynthetic mechanism. Different aspects for heterologous expression of RiPPs in E. coli have been reviewed by Zhang et al.E. coli, some of the non-lethal Gram-positive bacteria including the native producer strains such as actinobacteria or heterologous hosts [generally recognized as safe (GRAS)] such as Bacillus and Corynebacterium are used as excellent cell factories in industries. Actinobacteria are characterized as the most prominent producers of thousands of bioactive molecules, particularly small molecular medicines such as commercially available antibiotics and anticancer-drugs  by modulation by a number of global positive and negative regulatory genes, and genes encoding drug efflux pumps. Further the optimized strain was used for production of NPs of diverse nature such as actinorhodin, murayaquinone, hybrubins, piericidin A1, dehydrorabelomycin, and actinomycin D. Generally, the production of SMs in Streptomyces is controlled by a complex regulatory network that involves pathway-specific, pleiotropic, and global regulators, which tune the expression level of biosynthetic genes in response to a variation in diverse physiological and environmental conditions  and its associated protein (Cas9) has enabled the multiplexed genome engineering of actinomycetes including Streptomyces. Tao et al. have reviewed the application of CRISPR/Cas9 based genome editing in Streptomyces for discovery, characterization, and production of NPs. The recent advances in heterologous expression of RiPPs in Streptomyces have been presented by Zhang et al.Due to the presence of endotoxins in products obtained from Gram negative bacteria as Bacillus species has an ability to adapt to varying environmental conditions and capacity for high production yield , hence they are crucial industrial microorganisms. Further, the application of recent advances in metabolic engineering, enzyme/pathway engineering along with the synthetic biological tools have contributed to ameliorate the production titer from these microorganisms. Yang et al. utilized enzyme engineering of homogentisate dioxygenase for production of enhanced production of melanin. Similarly, a metabolic engineering approach was utilized for enhanced heterologous production of 2-deoxy-scyllo-inosose in Bacillus subtilis. Unlike E.coli and Bacillus, Corynebacterium has significant ability to utilize a variety of carbon sources  has great prospects for simulating the connection between the genomics and metabolomics to generate the intelligence in these super hosts, so that they can sense the environment condition, and respond rationally.Taken together, all these papers illustrate the applicability of engineering of microbial platforms for the production of small molecular medicines to complex biologics. However, in case of all of these microbial cell factories  the industrial scale titer, yield, and productivity is generally difficult to achieve. The major constraint is unavailability of abundant information about their metabolic behavior, unavailability of appropriate genetic engineering tools, or complication in redesigning appropriate flux balance for diverting primary metabolites to target molecules (Bhan et al., DD wrote the manuscript. E-SK and MK revised and corrected the manuscript. The final draft of the manuscript was finalized and approved for publication by all the authors.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In 2013, the outbreak of wild poliovirus (WPV) in the Horn of Africa (HOA) triggered an aggressive, coordinated national and regional response to interrupt continued transmission. Kenya, Somalia, Ethiopia, South Sudan, and other HOA countries share a range of complex factors that enabled the outbreak: porous and sparsely populated borders, insecurity due to armed conflicts, and weak health systems with persistently under-resourced health facilities resulting in low-quality care and low levels of immunization coverage in mobile populations. Consequently, the continued risk of WPV importation demanded cross-border and intersectoral collaboration. Assessing and addressing persistent communication gaps at the subnational levels were necessary to gain traction for improved immunization coverage and surveillance activities. This article describes a systematic approach to institutionalizing processes of dialogue and facilitation that can provide for a sustainable and effective joint cross-border health platform between Kenya and Somalia. It examines an operational model called the Cross-Border Health Initiative (CBHI) to support joint intercountry collaboration and coordination efforts. To evaluate progress of the CBHI, the authors used data from population coverage surveys for routine immunization and supplemental immunization activities (for polio), from acute flaccid paralysis (AFP) surveillance, and from plans developed by border districts and border health facilities. The project-trained community health volunteers have been a critical link between the hard-to-reach communities and the health facilities as well as an excellent resource to support understaffed health facilities. The authors conclude that the CBHI has been effective in bolstering immunization coverage, disease surveillance, and rapid outbreak response in border areas. The CBHI has the potential to address other public health threats that transcend borders. In 2010, the first WPV importation into the European region since the region was declared polio-free in 2002 resulted in 476 confirmed cases: 458 in Tajikistan, 14 in Russia, three in Turkmenistan, and one in Kazakhstan. In Africa and Asia, 11 new importations into six countries were observed in 2010; 30 WPV importations during 2008\u20132009 resulted in 215 WPV cases in 15 African countries during 2009\u20132013. Across six African and Asian countries, 11 new importations were recorded in 2009\u20132010.3For more than three decades, humankind has pursued the possibility of a \u201cpolio-free world.\u201d4 In Somalia, the first importation occurred during 2005\u20132007, resulting in more than 200 cases of paralytic polio.5 Likewise, in Kenya, two cases in Garissa County were reported in 2006, 19 cases in Turkana County in 2009, and one case in Rongo district in 2011. Somalia experienced a polio-free period from 2007 to 2013.5 This period of calm was upset when an outbreak of WPV type 1 (WPV1) rattled the Horn of Africa (HOA).6 In May 2013, the Somalia Ministry of Health (MOH) and the WHO reported a confirmed WPV1 case in a child from Mogadishu (Banadir region). Subsequently, in May 2013, eight additional WPV1 cases were confirmed in Somalia: seven in the Banadir region and one in the Bay region.7 Just 3 weeks after the initial polio cases were detected in May 2013 in Somalia, Kenya reported its first case across the border in the Dadaab refugee camp. As a result, five people were paralyzed by polio, including young adults, in the northeastern part of Kenya.8 Polio quickly spread from Somalia to its neighboring countries of Ethiopia and Kenya. By April 2013, the case count stood at 223: 199 cases in Somalia, 14 in Kenya, and 10 in Ethiopia. All the Somalia polio cases belonged to cluster N5A,Kenya and Somalia have not been spared from the impact of WPV importation.9 At the same time, the Global Polio Eradication Initiative entered a new phase, with a significant reduction in cases in endemic countries and a heightened recognition of the risk for the international spread of the virus.10 To combat the threat of an international outbreak, the WHO declared polio a public health emergency of international concern in May 2014 and issued recommendations requiring proof of polio vaccination for travel to and from countries experiencing polio cases.10 Frequent cross-border movement of the high-risk mobile populations between Kenya and Somalia and the low level of population immunity in the region continue to be major contributing factors to the spread of poliovirus and the risk of ongoing transmission.11The 2013 HOA outbreak vividly confirmed that \u201cAll countries will continue to have some level of risk for WPV outbreaks as long as endemic circulation continues in Afghanistan, Nigeria, and Pakistan.\u201d12In 2014, Kenya\u2019s MOH requested the United States Agency for International Development (USAID)-funded CORE Group Polio Project (CGPP) Kenya and Somalia HOA Secretariat based in Nairobi, Kenya, to initiate polio eradication activities in five counties along the Kenya\u2013Somalia border deemed at high risk for poliovirus importation. It was clear that effective immunization activities across borders and migration pathways were essential to improve immunization rates. Under the leadership of the respective MOHs of Kenya and Somalia and in collaboration with the WHO, the CGPP began holding cross-border meetings in October 2014\u2014a significant and instrumental move that would shape a systematic, unified, and well-coordinated response in the form of the Cross-Border Health Initiative (CBHI).Objectives arising from the 2015 cross-border meetings targeted improving collaboration between the health and administrative authorities of border regions through enhancing acute flaccid paralysis (AFP) surveillance sensitivity, increasing coverage of supplemental immunization activities (SIAs), and improving coverage and access to quality routine immunization services in the HOA border regions. Before the formation of the CBHI, cross-border committee meetings were first initiated by the WHO in collaboration with the Intergovernmental Authority on Development (IGAD) under the \u201cHealth for Peace Initiative\u201d in 1996. However, these cross-border committees were formed in only a few selected sites and the meetings were ad hoc, resulting in limited capacity for implementation, monitoring, accountability, resource allocation, and sustainability of cross-border polio eradication activities. To address these gaps yet keeping and reaffirming the same set of valuable original objectives, the CGPP Kenya and Somalia HOA Secretariat over a 1-year period transformed the ad hoc cross-border meetings into a full CBHI in October 2015. The secretariat subsequently established more CBHI committees in Kenya and Somalia. The work of the committees funded by the CGPP set the course for the eventual full implementation of the CBHI.13 Cross-border coordination bridges the disease surveillance gaps by forming partnerships among institutions, agencies, and communities in cross-border areas. Specifically, the CBHI works to ensure the vaccination of all cross-border populations, to support the detection of cases of AFP, to conduct joint case investigations of transborder AFP and WPV cases, and to synchronize all polio SIAs.The overarching goal of the CBHI is to reach every child with polio vaccine.In October 2015, the CGPP established a total of seven CBHI committees in five polio high-risk countiesIn Kenya, the government-led committees consisted of representatives from the five counties and subcounties. At the county level, the representatives included the director for health, the disease surveillance coordinator, the Expanded Program on Immunization (EPI) coordinator, the health records and information officer, and the community health strategy focal person. At the subcounty level, representation included subcounty coordinators and disease surveillance or EPI officers. In addition, the CGPP implementing partner officers, WHO and United Nations Children\u2019s Fund (UNICEF) county coordinators, and officers from border administration, immigration, and security completed the committee membership.In Somalia, the committees consisted of regional and district medical officers and a regional EPI coordinator. Similar to the Kenya committees, representation included the CGPP implementing partner officers, WHO regional and district coordinators, UNICEF field staff, and officers from border administration, immigration, and security.To reach high-risk mobile populations, the CGPP, in collaboration with the local authorities and CBHI, identified and profiled both formal and informal crossing points and communities at borders, transit hubs, and migratory routes. This exercise was beneficial; after developing detailed micro-planning to identify and document all border towns, villages, and settlements and their inhabitants, it was possible to estimate the number of children in the catchment areas. Moreover, the major transit points in the area provided pertinent information about population movement patterns, whereas joint mapping of border crossing points and border communities served to improve micro-planning for country-specific and joint country cross-border activities. The CGPP\u2019s non-governmental organization (NGO) implementing partners and local health authorities mapped 11 border health facilities, 161 formal/informal border crossing points, and 372 villages along the border as shown in To guide the CBHI committee members, the CGPP Secretariat in coordination with the MOH wrote a terms-of-reference document to structure regular meetings and outline roles for reporting and for the implementation of action plans. This document defined how to develop the agenda, meeting reports with outcomes, and implementation of activities arising from the meeting. Cross-Border Health Initiative committees followed activity work plan templates to ensure monitoring and accountability through joint supportive health facility visits. The project trained and provided the committees with selection criteria for recruiting community health volunteers (CHVs), whose primary focus was to ensure efficient and sustainable community-based surveillance, and with secondary responsibilities of supporting the committee and health facilities to conduct community mobilization for routine immunization and polio campaigns. In turn, the committees provided training materials for border health facility staff and border CHVs, including reporting forms based on the Integrated Disease Surveillance Response Framework to identify key diseases.The government-led high-level, intercountry cross-border forums and CBHI committee meetings funded by the CGPP and other partners have served as critical communication and community engagement platforms to raise issues of the risk of polio importation in the HOA. The respective local health authorities have owned the CBHI and provided the leadership in its implementation. As a result, the CBHI has led to improved immunization coverage and increased AFP detection among high-risk mobile populations, limiting the importation of WPV across borders.14 who serve as a link between the hard-to-reach nomadic communities and the health facilities. The committees, with funds from the CGPP, trained the CHVs to conduct social mobilization, perform community-based surveillance on vaccine-preventable diseases, report suspected AFP cases from the community, promote routine immunizations, and track immunization defaulters. Community health volunteers reported all suspected AFP cases from conflict-prone and insecure areas inaccessible to trained health workers. A key success of the committee\u2019s work has been the recruitment of CHVsThe risk of persistent threat of WPV importation demands cross-border collaboration and coordinated interventions. In response, the CGPP, in collaboration with the respective country\u2019s MOH and WHO, supported more than 70 local and international cross-border meetings in the HOA to highlight this risk see . These mThe CBHI has expanded access to polio vaccination for high-risk mobile populations in under-resourced areas. The strategic and systematic collaboration of the cross-border health committees has improved access to vaccination for children on the move at formal and informal border crossing points, enhanced tracking of nomadic pastoralist communities, and improved reporting of suspected AFP cases. 15Major obstacles to polio eradication efforts in the HOA and specifically at the security-compromised border areas have been inadequate health infrastructure, limited funding, poor health workforce management, and low-quality skills of health workers. There are inadequate government services in the border areas as the presence of government and NGO workers is restricted because of security risks, especially kidnappings. Polio funding has been critical to supporting the expansion of other health services.The government EPI and surveillance officers carry out their activities through direct, personal contact on a regular basis to guide, support, and assist designated health-care facility staff to become more competent in their immunization and disease surveillance services. In coordination with the National Vaccine and Immunization Program and the Disease Surveillance and Response Unit of the respective government, the CGPP mentored the immunization and surveillance managers on a monthly and quarterly basis to conduct on-the-job training of the service providers, which had a positive impact on the immunization program indicators and on the provision of all services in general. In the border areas of the HOA, the CGPP has provided technical and logistic support for district/subcounty training on the Reach Every District strategy, local micro-planning, data quality self-audits, and supportive supervision of routine immunization at health facilities and outreach sites.Cross-border coordination and scaled-up efforts of community-based surveillance activities to combat polio have contributed to positive AFP surveillance indicator trends; improvements are particularly significant in the hard-to-reach border areas . The geoThe second row of maps shown in Multiple challenges have compromised the AFP surveillance efforts. A strike by health workers in Kenya in 2017 affected service delivery, particularly in the border counties of Turkana and Marsabit. The protracted conflict in South Sudan created an influx of refugees across the border in Kenya, further complicating surveillance efforts. The maintenance of biological specimens  is referred to as the reverse cold chain. Maintenance of the reverse cold chain remains a significant barrier. Although stool sample collection rates are high, transportation of quality samples is still a problem due to poor infrastructure and impassable roads. Other operational challenges faced by the project were the high cost of programming due to the difficult terrain (poor roads and insecurity) and the occasional border closures hampering the cross-border work. However, some of these challenges were overcome by working closely with community leaders, building the capacity of the community through the CHVs to conduct the cross-border work, integrating the polio interventions with other cross-border activities undertaken by NGOs, and leveraging their presence and expertise. These partnerships created synergy and reduced the cost of programming. The CGPP closely coordinated with the IGAD, the regional intergovernmental body, and the respective immigration departments to address challenges with border access.17 The CGPP in the HOA has focused on improving access to vaccination services in high-risk mobile populations that straddle common borders. The CBHI in Kenya and Somalia has contributed to improved population immunity among cross-border communities, and it has created and maintained an active AFP surveillance system in these vulnerable regions that includes a community-based surveillance component. The CBHI has supported the collaboration of countries and border districts to develop early warning and response systems as well as the harmonization of cross-border vaccination and surveillance activities.3The CGPP has demonstrated the value of an institutionalized approach that is collaborative and coordinated. This important strategy is adaptable to address other communicable diseases that transcend borders.The communities that straddle the border of Kenya and Somalia are homogenous, sharing a common language and culture that allow for easier collaboration for teams on both sides of the border.The contribution of communities through participation in the cross-border health committees and the community-based surveillance by CHVs has magnified the CGPP\u2019s credibility and ownership among border communities.The cross-border forums have heightened sensitization and advocacy for cross-border issues, leading to high-level political commitment and support from the respective government health authorities and renewed interest and support from the United Nations partners.Frequent cross-border committee meetings  have improved opportunities for communication, stronger partnerships, joint regional advocacy, effective management of challenges, and the facilitation and implementation of collective outbreak response activities.Cross-border meetings have proven to be crucial at the local level, providing a forum to exchange information and carry out synchronized action for health service activities, including disease-control and eradication activities.The CBHI has become vital for closely monitoring vaccination status to reduce the risk of WPV importation by those crossing the border. Effective communication among the cross-border committees and border authorities, coordinated immunization activities, and sharing of AFP surveillance data have led to an improved, in-depth understanding of the dynamics of cross-border threats of WPV importations.18The diverse committee representation of the stakeholders has ensured wide sharing of information across the borders.Implementation of the CBHI in Kenya and Somalia has strengthened information flow through monitoring and evaluation of joint action plans.19The border health facilities have conducted mapping and profiling of cross-border populations for routine immunization and SIA micro-planning in hard-to-reach border villages and in high-risk populations that include those residing in \u201cno-man\u2019s land\u201d villages, immigrants and pastoralists, and nomadic populations.online supplement). The guide promotes internal and cross-border partnerships between border health operational units to identify and address the health issues of border populations, identify and document transit routes and hubs, and monitor population movements between borders which can affect cross-border transmission of communicable diseases, including polio.20The capacity built through these committees, although specific to polio eradication, can serve other health initiatives, including the identification of emerging infectious disease threats with epidemic or even pandemic potential and other diseases that continue to challenge fragile health systems. This knowledge has been captured in the CBHI Operational Guide  management. In Mandera County, the health committee worked together on a cholera outbreak in 2016. In addition, the Kenyan counties that border Somalia have merged their county development integrated plans with cross-border county action plans and widened the role of their CBHI committees to address other diseases. The CBHI is now an integral part of the operational health plans of border health units and the annual work plans of the participating county departments of health, thus ensuring sustainability of the CBHI after the end of the project. A manual that is used to guide the work of the CBHI is available as an online supplement to this article.As a testament to the power of collaboration, the CBHI\u2019s domain has expanded to integrate the control of other infectious diseases.The CBHI has improved access to health services, particularly for the immunization of nomadic pastoralists. In partnership with other government departments and NGOs that provide nomadic communities with livestock, education, drought management, and internal security, the CBHI has successfully tracked the movement of the nomadic populations to vaccinate missed children\u2014something that was unheard of before the CBHI. Even with the CBHI in the HOA, the long border between Kenya and Somalia remains porous and dangerous. The limited health infrastructure on the border there poses a significant challenge to effective cross-border collaboration. The CGPP will continue to build on the lessons of the CBHI to combat importation of WPV across the borders and will continue its search for new and innovative solutions.19 the CBHI is an important step for \u201cplanning for the end of all polio.\u201d21 The CBHI demonstrates the coherent impact of CBHI committees to engage across borders and across sectors (such as veterinary services and surveillance for zoonotic diseases) to capitalize on already existing synergies. The work of the committees as part of the CBHI could be adapted for other health interventions that require strong partnerships to achieve similar goals.In an acknowledgment that \u201cPolio will not end everywhere until everywhere ends it,\u201d22 The CBHI has been critical in reaching underserved, high-risk mobile populations with oral polio immunizations and other health services. Building on the success of the CBHI in Kenya and Somalia, this article highlights the value of the systemic process of institutionalizing the intervention so that it will continue beyond the eradication of polio. Integration of the CBHI committees into the country-driven County Integrated Development Plans has given particular attention to the often marginalized, security-compromised, and neglected border areas, raising coverage and potentially reducing inequities in immunization services. This integration has enhanced accountability and commitment through resource allocation and sustainability of the CBHI, leading to a gradual improvement in AFP surveillance and in routine immunization uptake in border areas. The CBHI has provided an in-depth understanding of the threat of disease importation, and it has built a cross-border framework for tackling cross-border challenges.Poliovirus circulation is most persistent in high-risk areas deprived of essential health services.23 hence the need for political commitment under the premise of the cross-border governance framework of the IGAD that could institutionalize the CBHI and standardize regional surveillance reporting tools.20 Effective, robust cross-border coordination of polio eradication activities requires a high level of political commitment, solid coordination, and mobilization of cross-border communities and their leaders.24 The potential of strong cross-border collaboration for health that the CGPP\u2019s CBHI has initiated holds great promise not only for contributing to the final eradication of polio but also for addressing other public health priorities.It is essential, however, to acknowledge the everyday challenges faced by HOA countries. The frequent movement of mobile populations in geographic areas that are unsafe for immunization workers makes the achievement of high levels of immunization coverage difficult and increases the threat of re-importation of the WPV and other communicable diseases,Supplemental materials"}
+{"text": "Osteotomies are the established surgical procedure for the deformity of the lower limb induced by osteoarthritis (OA) of the knee and ankle. Closed-wedge (CW) and open-wedge (OW) high tibial osteotomy (HTO) are extra-articular surgery, which aim to shift the mechanical axis from medial to slightly lateral and reduce the overload in the medial compartment of the varus deformed knee by extra-articular correction. However, varus deformity of the knee with the teeter effect, which could be accompanied with subluxation and thrust due to the medial-lateral soft tissue imbalance, is not resolved only by the shift of mechanical axis. The depression of the medial tibia plateau, so-called pagoda deformity, is the intra-articular deformity, which could potentially cause the teeter effect and involves intra-articular incongruency. In such case, the osteotomy with novel concept should be developed to overcome the issues, both the imbalance of soft tissue and intra-articular deformity. Tibial condylar valgus osteotomy (TCVO) is an intra-articular osteotomy, which improves the joint congruency of the medial-compartment knee OA with subluxation and/or intra-articular deformity and also provides better joint stability. A similar argument is raised in the treatment of the ankle OA. Low tibial osteotomy (LTO) is an extra-articular surgery to correct malalignment of lower leg. Distal tibial oblique osteotomy (DTOO) is a novel surgery to improve the bony congruency of the ankle OA. In DTOO, the distal tibia is cut obliquely from the proximal medial to the distal lateral in the coronal plane and towards the center of the tibiofibular joint to improve the bony congruency of the ankle joint. Tibial condylar valgus osteotomy (TCVO) and distal tibial oblique osteotomy (DTOO) can correct intra-articular deformity of knee and ankle, respectively. The rationale and indication of TCVO and DTOO for the treatment of the lower limb by reconstructing the joint congruency are discussed. Deformity of the lower limb induced by osteoarthritis of the knee or ankle causes the adverse effect on daily living due to gait disturbance, which could cause abnormal posture, as well as local problem such as pain. Various surgical procedures have been performed such as femoral, tibial osteotomies, and hip and knee arthroplasties to overcome these issues. Osteotomies are the established surgical options for the treatment of lower limb.Osteoarthritis of the knee is a representative disease, which involves malalignment of the lower limb with the joint degeneration. Arthroplasty of the knee, involving total knee arthroplasty (TKA), unicompartmental knee arthroplasty (UKA), is established as surgical procedures with good clinical results \u20133. ArounThe concept of traditional HTO has been the extra-articular correction of the alignment, aiming at the reduction of the overload in the medial compartment of the varus deformed knee by shifting the mechanical axis from medial to slightly lateral. On the other hand, deformities of the lower limb are affected by several factors. The bony deformity and soft tissue balance are the different issues relating to the malalignment. Varus deformity in OA of the knee without excessed medial loosening of soft tissue could be corrected by usual HTO, which is the extra-articular correction with transfer of the mechanical axis. However, the varus deformity of the knee with the teeter effect, which is the medial-lateral soft tissue imbalance, is not resolved only by the shift of mechanical axis to lateral. The depression of the medial tibia plateau, so-called pagoda deformity, is the intra-articular deformity, which could cause intra-articular incongruency and the teeter effect. In such case, the osteotomy with novel concept should be developed to overcome the issues, both the imbalance of soft tissue and intra-articular deformity; otherwise the relief of the pain and disability would not be achieved.For the treatment of osteoarthritis of ankle joint, the same argument exists as the correction of the varus knee. Low tibial osteotomy (LTO) for osteoarthritis of ankle joint has been performed to change the load distribution on the ankle joint by changing the extra-articular alignment , 10. HowConsidering the correction of lower limb alignment, regardless of cause of mal-alignment, such as post-traumatic, degenerative, or congenital, we need to consider two kinds of deformities: extra-articular and intra-articular deformity. Extra-articular deformity can be discussed under static loading condition, and intra-articular deformity should be discussed under dynamic loading condition.Extra-articular deformity in frontal plane is evaluated by the measurement of the standing long-leg AP view. Theoretically, there are 728 kinds of extra-articular deformity, and these deformities can be accurately corrected by using hexapod system. Evaluation of intra-articular deformity should be evaluated by dynamic motion of the contours of the bone facing in the joint. Tibial condylar valgus osteotomy (TCVO) and distal tibial oblique osteotomy (DTOO) can correct intra-articular deformity of knee and ankle, respectively.Traditionally the degree of extra-articular deformity of the frontal plane has been expressed as the degree of deviation from the mechanical axis of the lower extremity  Figure . The mecThe frontal plane knee joint orientation line of the distal femur is drawn as a line tangential to the most distal point on the convexity of the two femoral condyles. The frontal plane knee joint line of the proximal tibia is drawn across the subchondral line of the two tibial plateaus. The angle formed between joint orientation lines on opposite sides of the same joint is called the joint line convergence angle (JLCA) . The ankThe deviation from the normal of the lower extremity alignment can be evaluated by the joint orientation angles, such as MPTA, LDFA, LPDA, etc. measured with the full leg standing frontal X-ray image of the lower limb  Figure . MalaligAngular deformity has four types: varus/valgus deformity at the frontal plane and procurvatum/recurvatum deformity at the sagittal plane. Similarly, there are four kinds of deformities in translation  and axial  deformities. Consequently, there are 728 patterns of extra-articular deformities.The angular deformity correction of lower limb can be achieved using hinges set on center of rotation of angulation (CORA) of the connecting rods by Ilizarov technique . CurrentIntra-articular deformity means joint congruency. Joint congruency is defined as the fittings of two opposing joint surfaces as they relate to one another considering the spatial contour of each bone at their interface.In theory, joint congruency can be mainly explained by three factors: contours of bone, functions of ligament, and integrity of articular cartilage and meniscus. Incongruency of the joint immediately causes joint instability or abnormal joint kinematics resulting in the secondary osteoarthritis in the future. For example, mal-union of tibial plateau fracture and/or knee ligament injury such as anterior cruciate ligament and/or collateral ligaments causes easily knee instability and secondary osteoarthritis of the involved knee with joint incongruency .Two primary biomechanical purposes of the articular cartilage are lubrication and shock absorption. The articular cartilage provides a smooth lubricated surface for low friction articulation and acts as a remarkably efficient shock absorber , 20.From the view point of joint congruency, it is considered that the effect of articular cartilage as the shock absorber is not large because the thickness of articular cartilage is thin as 1 \u2013 4\u2009mm. Rather in the cartilaginous element, the menisci may be more important because they have a large effect of filling the gap of the joint . HoweverHigh tibial osteotomy (HTO) is intended to transfer the mechanical axis from medial to slightly lateral to the midline of the knee to decrease the load and subsequently delay osteoarthritis (OA) \u201324. TherOn the other hand, tibial condylar valgus osteotomy (TCVO) developed by Chiba G et al. in 1989 and published in 1994 is an operation that corrects intra-articular deformity , 33 Fig and 7. TThe same argument holds for distal tibial oblique osteotomy (DTOO) and low tibial osteotomy (LTO) for osteoarthritis of ankle joint. LTO is an operation of an attempt to change the load distribution on the ankle joint by changing the extra-articular alignment. However, if instability of the talo-tibial joint exists , improveOn the other hand, DTOO developed by Teramoto in 1994 is an operation to improve the bony congruency of the ankle joint . DTOO coAlthough osteotomies are effective in managing malalignment of knee and ankle arthrosis, determination regarding the type of osteotomy should be based on the pathology in each patient. The cause of deformity of the knee varies, which involves intra- and extra-articular or the combination of them. Center of the deformity may also vary. Soft tissue balance should be another critical issue for the selection of optimal osteotomy type. Traditional HTO should be an optimal strategy to overcome the malalignment in OA of the knee; however, the excessed medial-lateral soft tissue imbalance and intra-articular deformity are not solved by this surgical procedure. Tibial condylar valgus osteotomy (TCVO) should be an optimal option to overcome these issues that improves intra-articular deformity followed by acquisition of medial-lateral stability of the knee, not lower limb alignment. Although LTO is the good treatment for the deformity in OA of ankle by the extra-articular correction of alignment, treatment for incongruency and instability for OA in ankle is the remaining issue of this surgical technique. Distal tibial oblique osteotomy improves the bony congruency of the ankle joint by the oblique osteotomy.Tibial condylar valgus osteotomy and DTOO that correct intra-articular deformity of knee and ankle are the optimal osteotomies for OA with intra-articular deformity and instability."}
+{"text": "Evidence-based programs (EBPs) offer proven ways to promote health and prevent disease among older adults in their communities. EBPs are based on rigorous study of the effects of specific interventions or model programs, demonstrate consistently positive changes in important health-related and functional measures, and have tools in place to maintain program access, quality, and efficiency across diverse settings. The University of North Carolina at Chapel Hill\u2019s Center for Health Promotion and Disease Prevention (UNC HPDP), in partnership with the Evidence-Based Leadership Collaborative (EBLC), has established a review process and Review Council to identify new community programs that meet the evidence-based program criteria established by the Administration for Community Living (ACL), one of the chief U.S. federal agencies responsible for aging programs. Approved programs are then eligible for Older Americans Act Title III-D and other discretionary funding to support organizations that deliver EBPs to improve older adult health. The review process assesses the effectiveness, outcomes, and evaluation of the program, information about program implementation, training, and other key elements for successful program dissemination. The Review Council consists of national leaders with expertise in program research, evaluation, and implementation. The review process is supported by the ACL-funded National Chronic Disease Self-Management Education and Falls Prevention Resource Centers. This session will describe the ACL evidence-based health promotion program criteria that must be met for approval; an overview of the review process; and how researchers can submit their programs for review. Time will be allowed for questions, discussion, and research to practice implications."}
+{"text": "Participation in active transportation by older persons has been associated with higher quality of life and longevity. Efforts across the United States to increase active transportation  by older adults have lacked meaningful input by older adults, are non-theoretical and have had inconclusive results. This paper describes the findings from Phase 1 of the Safe Routes to Age in Place project, a collaboration between Age-Friendly Franklin County, The Ohio State University (OSU) and the University of Texas-Arlington (UT-A), funded by the Ohio Department of Transportation. The aim of the study is to increase the options and safe utilization of active transportation by older persons in three pilot neighborhoods in Franklin County, Ohio utilizing community-based participatory action research strategies with a customized data collection app, MyAmble. The purpose of Phase 1 was to engage city and regional planning students, government officials and older adults to identify \u201chot spots\u201d in the three pilot neighborhoods. Heat mapping of community data including locations of densely-populated vulnerable older adults, fixed transportation routes, bus stop signage and benches, shared bike stations, bike routes, paratransit routes and pedestrian crash data was completed. Maps were used to identify areas of focus and discussions with municipal leaders and older adult residents further refined target areas to be used in the second phase of the study. Older residents completed walk audits using the MyAmble app and identified issues with sidewalks, crosswalk timers and bus stops. Implications related to age-friendly communities and active transportation are offered."}
+{"text": "Non Western therapies have played a vital role in dealing with a variety of crisis such as physical, emotional and existential over the last few centuries . Since the introduction of Western medicine in India as early as the eighteenth century, the two systems of medicine have coexisted and influenced each other. Mutual recognition of the therapeutic values of the two systems was further bolstered when American medicine recognized the role of alternative therapies as viable option for healing in the early eighties. The purpose of this paper is to examine the roles two kinds of healers (western and non- western) play in the Asian Indian Hindu context. For this qualitative study, 30 physicians (trained in Western medicine) and 5 sadhus (holy men) were interviewed in the city of Allahabad, during the Kumbh Mela. Open ended questions ranged from: a) field of practice (physicians), sadhus (mystics), b) years of practice, c) number of patients/followers, d) treatment offered (physician \u2013surgery or medications), sadhus , e) adverse reactions. In-depth interviews were recorded and transcribed by two researchers from Hindi to English and coded into themes. Results indicate that about a quarter of Western trained physicians not only sought assistance from the sadhus for their emotional/spiritual issues, but also referred patients with terminal disease. Besides individual consults, the mystics conduct lectures on climate change, on holistic diet, meditation, yoga practices, and healing. Social workers need to assess the value Hindu immigrant families in United States attach to Non-Western therapies."}
+{"text": "Healthcare providers (HCPs) are recognized as one of the cornerstones and drivers of health interventions. Roles such as documentation of patient care, data management, analysing, interpreting and appropriate use of data are key to ending vaccine-preventable diseases (VPDs). However, there is a great deal of uncertainty and concerns about HCPs\u2019 skills and competencies regarding immunization data handling and the importance of data use for improving service delivery in low- and middle-income countries (LMICs). Questions about the suitability and relevance of the contents of training curriculum, appropriateness of platforms through which training is delivered and the impact of such training on immunization data handling competencies and service delivery remain a source of concern. This review identified and assessed published studies that report on pre- and in-service training with a focus on HCPs\u2019 competencies and skills to manage immunization data in LMICs.An electronic search of six online databases was performed, in addition to websites of the WHO, Global Alliance for Vaccines and Immunization (GAVI), Oxfam International, Save the Children, Community Health Workers Central , UNAIDS and UNICEF. Using appropriate keywords, MeSH terms and selection procedure, 12 articles published between January 1980 and May 2019 on pre- and in-service training of HCPs, interventions geared towards standardized data collection procedures, data documentation and management of immunization data in LMICs, including curriculum reviews, were considered for analysis.Of the 2705 identified references, only 12 studies met the inclusion criteria. The review provides evidence that shows that combined and multifaceted training interventions could help improve HCPs\u2019 knowledge, skills and competency on immunization data management. It further suggests that offering the right training to HCPs and sustaining standard immunization data management is hampered in LMICs by limited or/lack of training resources.Pre-service training is fundamental in the skills\u2019 acquisition of HCPs; however, they require additional in-service training and supportive supervision to function effectively in managing immunization data tasks. Continuous capacity development in immunization data-management competencies such as data collection, analysis, interpretation, synthesis and data use should be strengthened at all levels of the health system. Furthermore, there is a need for periodic review of the immunization-training curriculum in health training institutions, capacity development and retraining tutors on the current trends in immunization data management. Human resources for health, also known as the health workforce, is one of the building blocks proposed by the World Health Organization (WHO) Health Systems Framework and is central to achieving universal health coverage (UHC) and enhancing the achievement of the Sustainable Development Goals (SDGs) , 2. HoweHigh-quality vaccine coverage and vaccine-preventable disease (VPD) surveillance data are needed to monitor the performance and impact of the Expanded Programme on Immunization (EPI), which aims to reduce infant and child mortality and morbidity. However, inconsistent and inaccurate recording and reporting of these data limit the ability to accurately monitor EPI coverage and remain a source of concern particularly in LMICs. Due to poor and sub-standard measurement and errors in vaccination records, reliability and validity of reported data on immunization coverage are highly questionable. Additionally, incomplete and incorrect data entry and poor documentation of coverage, as well as double entries by HCPs, have decreased the reporting quality \u20137. CapacAttempts to bridge the gaps associated with poor data quality, which are often attributed to insufficient technology rather than the people who drive the system, have led to the implementation of complex health information systems (HIS), including web-based solutions. Nevertheless, these still require human capacity and capability. Persistent challenges identified with these systems include inadequate human resources, insufficient capacity of HIS staff at all levels of the health system, high staff-attrition rates, inadequate training, unstandardized job descriptions, limited HIS development planning and lack of established HIS career path and accredited training programmes .Competency can be defined as a combination of knowledge, skills and abilities needed to perform a specific task in a given context , which cThere is a great deal of uncertainty and concerns about HCPs\u2019 skills and competencies regarding immunization data handling and the importance of data use for improving service delivery. It is unclear whether HCPs\u2019 training curriculum and modalities are appropriate and optimal for improved skills and competencies in data collection procedures and management . QuestioThis scoping review seeks to identify and assess published studies that report on pre- and in-service training with a focus on healthcare providers\u2019 competencies and skills to manage immunization data in LMICs. For the purpose of this study, we assessed available interventions (on improving immunization data documentation and reporting), pre- and in-service training and compared reports on which modality best informs good-quality immunization data collection and management in LMICs.We conducted an exploratory research and systematically mapped available literature on specific topics relating to HCPs\u2019 competencies in immunization data management. Key concepts of pre- and in-service training were identified, and sources of evidence and gaps in the research were also highlighted . This apAll categories of health personnel qualified as healthcare providers (HCPs) involved with immunization data management, such as doctors, pharmacists, nurses, midwives as well as community HCPs were included.In addition, studies on interventions that include any training or capacity-building activities related to standardized data collection procedures and management of immunization data, including curriculum reviews, were considered. As the purpose of this study was to assess and compare pre- and in-service training of HCPs on standardized data collection procedures in immunization services, we assessed interventions that were measured and evaluated. Hence, the study design and outcomes of included studies were left intentionally broad, and a meta-analysis was not appropriate at this stage.Published articles on pre- and in-service trainings of HCPs, healthcare professional curriculum, on-going training and interventions geared towards standardized data collection, correctness, consistency, data reporting and recording and management of immunization data were included. We also included all studies assessing the effect of pre- and in-service training of HCPs in data management improvement, including data collection, entry, completeness, accuracy and timeliness, as well as training on standardized data collection and maintenance in immunization services, interventions on capacity building, improving skills and competencies in data collection and management in immunization services. All studies evaluating educational curriculum, pre- and in-service trainings of HCPs; capacity development on immunization data competencies in data recording and reporting, data analysis, interpretation, synthesis and presentation of immunization data; and interventions and on-going capacity development on standardized data collection and management in immunization services in LMICs were included.In addition, studies on HCPs\u2019 responsive training programmes on immunization data and district-level data improvement programmes conducted in LMICs according to the World Bank Group 2012 classification  were incComprehensive search terms and strategy based on the \u2018Population\u2013Concept\u2013Context (PCC)\u2019 framework for scoping reviews  were devThe search terms included keywords and Medical Subject Headings (MeSH) together with corresponding synonyms and associated terms, which are summarized in Table Articles were considered relevant if they were about healthcare providers\u2019 capacity development on data collection and quality in immunization programmes in LMICs. All citations were imported into Thomson Reuter EndNote X7 software, and duplicate citations were removed manually. A two-stage screening process for eligibility was conducted, and articles that met the inclusion criteria were selected. In the first stage of screening, two authors (Eunice Turawa (ET) and Edward Nicol (EN)) independently reviewed titles and abstracts of the citations to identify relevant articles. These results were then compared, and discrepancies resolved. As part of the second-stage screening for review, the full text of all potential eligible studies were retrieved, and two authors (ET and EN) independently reviewed the articles for eligibility for inclusion in the review; discrepancies were resolved through discussion, and when consensus was not reached, the third author (George Bonsu (GB)) intervened. Studies that did not meet the eligibility criteria were excluded at this stage. Articles that could not be obtained through online databases were also excluded from the final analysis. A data extraction form was developed according to pre-specified eligibility criteria. To ensure the reliability and consistency of the extraction form, two authors (EN) and (ET) independently piloted the extraction form using the first 20 articles. Results were compared, and the extraction form amended accordingly. At every stage of study selection and data extraction, discrepancies were resolved through discussion and contribution from the third author (GB).Using a pre-designed data-charting form, key and relevant information was identified and systematically extracted from each article that met the inclusion criteria. Following the transfer of the data into an excel spreadsheet, two authors (EN and ET) reviewed the extracted information and selected key focus areas for this review and categorized the information according to the training modules, method of assessment and outcome assessed. The two review authors grouped the outcomes into thematic heading, using the following categories: type of training, authors and titles, study setting, population, method of training and outcome of training (comments/relevant findings). Other useful available information in each article was extracted for clear and deeper understanding of the study.Data were summarized according to key components and definitions used for categorizing data. For each study, we categorized training or interventions evaluated and the outcomes into four levels  based on the Kirkpatrick model .As shown in Fig. Key concepts of all studies that met the inclusion criteria were systematically summarized to provide a comprehensive but concise descriptive map of the nature and breadth of research on pre- and in-service training of HCPs\u2019 competence on immunization data handling and to identify obvious research gaps. The research objectives were used to identify and evaluate the evidence gaps. All 12 included studies were from LMICs; four studies were from sub-Saharan Africa, one from Asia and five were multi-country studies including Angola, Bolivia, Chad, the Democratic Republic of Congo, Ethiopia, Cameroon, Ghana, Lesotho, Madagascar, Malawi, Mali, Mexico, Niger, Nigeria, Senegal, South Sudan, Tanzania, Uganda, Zambia, Zimbabwe and the Philippines Table . The parOne third (33%) of the included studies , 24, 32 Sub-standard or lack of knowledge on supervision and monitoring is a major problem among the tutors. While basic knowledge on the principles of immunization is above average, student clinical practice was poorly supervised due to clinical supervisors\u2019 lack of skill and knowledge. One of the studies showed that only three of the seven medical training colleges in Kenya have the updated WHO EPI prototype curriculum , and thaNine of the 12 identified studies were on in-service training , 26\u201332. One of the major problems in HCP training is the lack of appropriate equipment and teaching aids  and updated reference manuals and curriculum . Evidence shows that the majority (75%) of the pre-service training institutions lacked the necessary equipment and tools needed for practical demonstrations and knowledge of current EPI theory and practice .This review found that the curriculum, especially in pre-service institutions, is not responsive to current needs and is often outdated and usually only updated every 5 years , 30, 32.Although Hussein et al.  reportedHealth information systems (HISs) are recognized as a useful tool in improving data management and access to essential data from multiple sources, but lack of the required skills to operate HIS and convey data information to the target audience has been a major bottleneck among immunization HCPs . Ward etAlthough routine follow-up and accountability are still a challenge, monitoring and evaluation of HCPs\u2019 activities, supportive supervision and development of specific, measurable, achievable, realistic and time-bound targets are essential for improving health providers\u2019 knowledge and competencies.Supervision can also lead to more efficient and effective data handling by HCPs. Effective supervision is difficult to achieve because there is no clarity on the most effective approach to supervision activities and the design and implementation of supervision. There is also no comparative intervention strategy that establishes a clear standard for performance, quality assessment and improvement in immunization data management , 30. EveRowe et al.  also ideGood-quality immunization data are crucial for effective policies on vaccine-preventable disease, and in particular the reduction and prevention of under-five morbidity and mortality. However, the task of collecting and managing these data in LMICs rests mostly on HCPs who often lack the necessary skills and competencies to effectively function in these roles . CapacitFindings from this scoping review provide evidence that shows both pre- and in-service trainings are essential for the development of HCPs\u2019 competence in immunization data management, and analysis at all levels of the health system. The evidence shows that although pre-service training is fundamental, it does not adequately prepare HCPs, especially clinicians, with the necessary skills and competencies to collect, analyse and use data. This is due to a number of reasons, which include the inadequacies of the training curricula, which are not responsive to current needs, such as the changing trends in technology and preventive healthcare services, since the training curricula are often outdated , 30, 32.More importantly, the training institutions are not adequately equipped to train HCPs on data skills as the majority of the tutors and clinical instructors at pre-service training institutes lack sufficient skills and knowledge to enable adequate translation of knowledge . ContinuWard et al.  highlighIn the systematic review by Vasan et al. , which lThese findings are consistent with the study by Whittaker et al. , which lThe strength of this review lies on the comprehensive nature of the search strategies used to identify the studies, which involves a range of methodologies that support exploratory review. The review extracted studies on HCPs\u2019 capacity development on data collection and quality in immunization programmes in LMICs. However, the restrictions placed as a result of the selection criteria could potentially bias the findings. Our search terms were restricted to low- and middle-income countries and specifically on the expanded programme immunization (EPI), and the review relied only on open access articles or those accessible through the electronic database and search engines, and those articles published in English, thereby possibly omitting some useful articles on the subject.This scoping review has highlighted the challenges faced by HCPs in terms of competencies and skills to perform immunization data management tasks, which have been attributed to insufficient pre-service training. Even though pre-service training is fundamental in the skills acquisition of HCPs, they often require additional in-service training and supportive supervision to effectively function in immunization data management tasks.Other issues around poor data management also stem from errors in processing data, limited use of already generated data, poor standardization of immunization data collection tools and processes such as registers, as well as ill-defined target population. These will require progressive implementation and uptake.Immunization is one of the most cost-effective ways to save lives, improve health and ensure long-term prosperity. Achievement of the aim of the Astana Declaration on primary health care to meet all people\u2019s health needs across the life course through comprehensive preventive and promotive care will require strong immunization programmes with well-trained and motivated workforce.Continuous capacity development in immunization data management competencies such as data collection, analysis, interpretation, synthesis and data use, and efforts to improve data quality should be strengthened at all levels of the health system using the minimum health information competencies framework. Additionally, all new hires require orientation by employers in data management before they commence work.Furthermore, there is a need for periodic review of the immunization-training curriculum in health training institutions, capacity development and retraining of tutors on the current trends in immunization data management such as the use of mobile technologies. The web district health information system (DHIS2) and tool like the WHO Immunization Information System (WIISE) are useful tools in improving immunization data management and use; however, these also require skilled workforce."}
+{"text": "Here, we will review the recent literature regarding the interactions between columnar epithelial cells and neutrophils, with an emphasis on intestinal epithelial cells, structural aspects of neutrophil transepithelial migration, molecular determinants of neutrophil-epithelial cell interactions, as well as modulation of these pathways. These recent studies highlight the dynamic nature of these pathways and lend insight into the complexity of treating mucosal inflammation.Inflammatory diseases of mucosal organs as diverse as the lung, kidney, and intestine, inevitably require the intimate interactions of neutrophils with columnar epithelia. The physiologic consequences of such interactions often determine endpoint organ function, and for this reason, much recent interest has developed in identifying mechanisms and novel targets for the treatment of mucosal inflammation. Elegant"}
+{"text": "To investigate the rule of kidney-tonifying method in Chinese medicine for the treatment of bone marrow suppression (BMS), in order to provide evidence and references for the clinical application of herbs and formulae. Collecting and sorting the information about the treatment of BMS related to kidney-tonifying (Bushen) method in Chinese medicine literatures on databases including Chinese National Knowledge Infrastructure (CNKI), and Chinese Biomedical Literature Database (CBM), establishing a database of BMS treating formulae after radiotherapy and chemotherapy with traditional Chinese medicine (TCM) kidney-tonifying method, and finally applying the relevant theories and techniques of data mining to analyze the medication rules of it. A total of 239 formulae and 202 herbs were included in this database, in which the herbs occurred 2,602 times in general. The high frequency herbs included Astragali Radix (Huangqi), Atractylodis Macrocephalae Rhizoma (Baizhu), and Ligustri Lucidi Fructus (Nvzhenzi). The main herb categories were deficiency-tonifying herbs, blood-activating herbs, dampness-draining diuretic herbs, heat-clearing herbs, and digestant herbs. Deficiency-tonifying herbs accounted for 64.60% of the total number. A total of 8 clustering formulae are summarized according to cluster analysis and 26 herb suits association rules are identified by Apriori algorithm. The treatment of BMS is mainly based on the method of invigorating the spleen and tonifying the kidney and liver to strengthen healthy qi, supplementing with blood-activating herbs, and dampness-draining diuretic herbs to eliminate pathogenic factors. BMS is one of the major side effect that is produced during the treatment of cancer patients with radiation, chemotherapy and drugs, which affect seriously patients' radio- and chemotherapical process and even led to treatment failure, which has become a major and difficult problem in clinical practice , 2. Acco kidney-tonifying, 239 related formulae were retrieved, upon which a database of BMS formulae was established and was standardized and classified according to the standard name and Chinese medicine classification of People's Republic of China Pharmacopoeia (2015 Edition) [ Chinese Medicine Dictionary [By collecting and collating the literatures on the databases including CNKI, CBM, VIP database, and WANFANG database about the treatment of BMS after radiotherapy and chemotherapy in Chinese medicine and inputting them to the NoteExpress literature management software and eliminating the literatures which do not meet the requirements, such as reviews, thin sample or not representative cases, and proven reports and animal experiments, this study established a data information collection form and entered the filtered prescription information into it. When the data was collected and sorted, a total of 621 effective formulae were gained to build a database of Chinese medicine treatment of BMS. By inputting the keywordEdition)  and Chinctionary .A database of BMS treatment with kidney-tonifying formulae was established with the application of Excel 2013 and was converted into the format required by the data mining software. Programming and modelling the data with R language are done according to the data characteristics of Chinese medicine medication rules, within which the core herbs were clustered by Hierarchical clustering algorithm. For example, Vania M. Youroukova et al. analyzed the phenotype of severe bronchial asthma by using cluster analysis and obtained four clusters that provided reference for clinical treatment . The AprAmong the 239 formulae included in the analysis, there were 202 herbs of Chinese medicine included, and their occurrence frequency was 2, 602 times. Of the highest frequency was the herb Astragali Radix (Huangqi), which occurs 184 times, with a frequency rate of 7.07%. The second was Atractylodis Macrocephalae Rhizoma (Baizhu), whose frequency was 129 times (4.96%); the Ligustri Lucidi Fructus (Nvzhenzi) ranked the third with 125 times and (4.80%). And the top-nine herbs, respectively, are Astragali Radix (Huangqi), Atractylodis Macrocephalae Rhizoma (Baizhu), Lucidi Fructus (Nvzhenzi), Angelicae Sinensis Radix(Danggui), Lycii Frucyus(Gouqizi), Codonopsis Radix (Dangshen), Poria(Fuling), Rehmanniae Radix Praepapata (Shudihuang), and Spatholobi Caulis (Jixueteng), whose frequencies all exceed 95 times, with their frequency rate higher than 3.65%, and their cumulative frequency reached 41.12%. Herbs with a frequency more than 18 times are shown in One hundred and eight high-frequency herbs with a frequency of 9 or more were categorized in this study. The details of herb categories and frequency are shown in Thirty-eight core herbs mentioned above were clustered by Hierarchical clustering algorithm in R language and were divided into 4-10 classes by system clustering. Considering Chinese medicine theory, 8 categories are more appropriate in this study, and they were named as cluster one to eight subsequently. The clustering details are shown in In this study, the R language data mining software was applied for modeling, and the Apriori algorithm was used to analyze the association rules of the core herbs above. The parameters were set as support degree \u226520% and confidence level \u226585% , upon wh(1) The method of strengthening the spleen and tonifying the kidney is the most common method for treating BMS in kidney-tonifying method. The herbs used in the tonifying kidney are mainly sweet, bitter, and pungent, rather than salty which is the corresponding flavor of the kidney in Chinese medicine theory and is different from the general idea that herbs salt in flavor are mainly used in kidney-reinforcing therapies and is more practical for clinical use . The herThe top nine frequent herbs are all deficiency-tonifying herbs apart from Poria (Fuling), the dampness-draining diuretic herb and Spatholobi Caulis (Jixueteng), the blood-activating herb. Although the two herbs are not classified as deficiency-tonifying herbs, they are often used in combination with deficiency-tonifying herbs to prevent the stagnation caused by deficiency-tonifying herbs. A former study shows that alfalfa polysaccharides and their derivatives have the effects of anticancer, anti-inflammatory, antioxidant, and antiviral activity biological activities and are good for health . In in vAccording to the relevant techniques and theories of data mining and the analysis of medication rules of applying kidney-tonifying method in treating BMS after chemoradiotherapy, it is revealed that this kind of treatment is based on the method of strengthening spleen and tonifying kidney, replenishing liver and kidney and combined with invigorating healthy qi, and also applied methods include dampness-draining and blood-activating to eliminate pathogenic factors. With the help of data mining techniques and theories, this study has summarized the medication rules of kidney-tonifying method in treating BMS after radiotherapy and chemotherapy, which can facilitate TCM diagnosis, treatment, and experimental research, and would be helpful for BMS patients."}
+{"text": "According to the recent report of the World Health Organization (WHO), the global burden of non-communicable diseases (NCDs) has been rising over the last century, with the leading causes of disability being depression, diabetes, cardiovascular diseases (CVDs), and certain cancers . BesidesNumerous epidemiological studies have demonstrated the association between oxidative stress and NCDs. Oxidative stress is commonly known as an imbalance in the production of reactive oxygen species (ROS) and the biological antioxidant defense system. Over the last years, exogenous antioxidants have received great attention because of their potential beneficial effects toward human health. Contained in foods commonly consumed in all populations worldwide, antioxidants represent an attractive explanation of their beneficial effects. However, antioxidants are contained not only of fruits and vegetables, which are characteristic components of healthy dietary patterns, but also in other plant-derived foods, such as tea, coffee, and cocoa. Therefore, the evaluation of dietary habits of a population, and in particular the intake of antioxidants and adherence to healthy dietary patterns is crucial. Indeed, several studies explored the dietary intake of antioxidants and antioxidant-rich foods in a Mediterranean area, as well as their association with fluid and beverage intake ,5,6, demMoringa oleifera leaves [Accumulating epidemiological evidence have demonstrated the association between both antioxidants and antioxidant-rich foods intake and human health. For instance, recent meta-analysis and cohort studies showed that high consumption of antioxidants and antioxidant-rich foods is associated with decreased risk of overall and CVD-related mortality , certaina leaves , coffee a leaves , mulberra leaves , and broa leaves .Nevertheless, nowadays studies exploring the possible effects of antioxidants toward human health, should take into consideration the differences in dietary intake of polyphenols in various populations, differences in food processing (loss of phenolic content), absorption, bioavailability, and metabolism of polyphenols. The study by Khairallah et al. focused on the antioxidant effect of phenolic extracts from polyphenol-rich potato, demonstrating that the colonic microbial digestion of potato-based polyphenols could lead to improved colonic health, as this process generates phenolic metabolites with significant antioxidant potential .Several molecular mechanisms may account for the beneficial effects of polyphenols. The antioxidant effects of dietary polyphenols can be attributed to the regulation of redox enzymes through reducing reactive oxygen species (ROS) production and modulation of the II-phase enzymes responsible for the cellular oxidative response. Indeed, the study by Marmouzi et al. showed that antioxidant compounds from hybrid oat lines prevent against hyperglycemia-induced oxidative stress via the modulation of expression of key II-phase enzymes . AdditioFurther evidence from both epidemiological and experimental studies is needed in order to better characterize antioxidants that may exert beneficial effects toward the prevention of chronic diseases associated with oxidative stress and inflammation."}
+{"text": "In the last decades the study of older people and social networks has been at the core of gerontology research. The literature underlines the positive health effects of traditional and online social connections and also the social networks\u2019s positive impact on cognitive performance, mental health and quality of life. Aging in a Networked Society is a randomized controlled study aimed at investigating causal impact of traditional face-to-face social networks and online social networks  on older people\u2019 health, cognitive functions and well-being. A social experiment, based on a pre-existing longitudinal study (InveCe - Brain Aging in Abbiategrasso) has involved 180 older people born from 1935 to 1939 living in Abbiategrasso, a municipality near Milan. We analyse effects on health and well-being of smartphones and Facebook use , exploiting the research potential of past waves of InveCe study, which collected information concerning physical, cognitive and mental health using international validate scale, blood samples, genetic markers and information on social networks and socio-demographic characteristics of all participants. Results of statistical analysis show that poor social relations and high level of perceived loneliness  affect negatively physical and mental outcomes. We also found that gender and marital status mediate the relationship between loneliness and mental wellbeing, while education has not significant effect. Moreover, trial results underline the causal impact of ICT use  on self-perceived loneliness and cognitive and physical health."}
+{"text": "This descriptive paper aims to describe the design and implementation of a community engaged primary healthcare strategy in rural Australia, the Primary Healthcare Registered Nurse: Schools-Based strategy. This strategy seeks to address the health, education and social inequities confronting children and adolescents through community engaged service provision and nursing practice.There have been increasing calls for primary healthcare approaches to address rural health inequities, including contextualised healthcare, enhanced healthcare access, community engagement in needs and solutions identification and local-level collaborations. However, rural healthcare can be poorly aligned to community contexts and needs and be firmly entrenched in health systems, marginalising community participation.This strategy has been designed to enhance nursing service and practice responsiveness to the rural context, primary healthcare principles, and community experiences and expectations of healthcare. The strategy is underpinned by a cross-sector collaboration between a local health district, school education and a university department of rural health. A research framework is being developed to explore strategy impacts for service recipients, cross-sector systems, and the establishment and maintenance of a primary healthcare nursing workforce.Although in the early stages of implementation, key learnings have been acquired and strategic, relationship, resource and workforce gains achieved. This strategy seeks to address the health, education, and social inequities confronting rural children and adolescents through community engaged primary healthcare service design and implementation. This strategy aligns nursing services and practice to the unique rural context, the principles of primary healthcare [World Health Organization (WHO), et al., The PHCRN:SB strategy, whilst sharing some similarities with contemporary school nursing services  an exploration of evidence and theory; (2) the identification of the right health professional with the right scope of practice to provide services to address these findings; and (3) the design and implementation of a potential solution, the PHCRN:SB strategy.Guided by these findings, an exploration of the literature focused on the principles associated with primary healthcare and integrated care and the theories of family-centred care (FCC) and trauma-informed care. Primary healthcare principles include community participation in promoting health and addressing health inequities and cross-sectorial collaborations. Within primary healthcare, resources and actions are directed towards populations that experience the greatest levels of inequities WHO, , in thiset al., et al., et al., FCC locates \u2018the needs of the child, in the context of their family and community\u2019 through the development of collaborative and dynamic models of care  service recipient impacts and outcomes; (2) cross-sector systems impacts and; (3) implications for the establishment and maintenance of a rural Australian primary healthcare nursing workforce. Each of these streams has a number of key focus areas. Stream 1 will explore education, health and social impacts for service recipients . Stream 2 will explore strategic, policy, funding and practice impacts on cross-sector systems. Stream 3 will explore impacts for the PHCRNs, the influence of the nursing model of care on nursing practice and pre-registration student experiences within the strategy. Each stream has cross-sector research leaders with responsibility to convene research sub-groups, develop research protocols and collectively contribute to the overarching research agenda.Governance structures play a critical role in promoting the effectiveness and success of healthcare innovations. Governance involves \u2018ensuring strategic policy frameworks exist and are combined with effective oversight, coalition building, regulation, attention to system design and accountability\u2019 WHO, : 86. A cA number of conceptual, cross-sector, health, professional, financial and research learning points have been gained. Conceptually, it became evident early in community consultations that the title \u2018school nurse\u2019 was not considered sufficient in describing the role and scope of nursing practice. Whilst synergies exist between contemporary school nursing practices, strategy aims, and the role of the PHCRNs, significant differences were identified . The title, PHCRN:SB, was adopted to: clarify the role and scope of nursing practice; respond to community perceptions and feedback; and provide a contemporary interpretation of nursing care and practice within a rural Australian and school-based settings.et al., Key cross-sector learning points included the requirement for significant time investments to establish a consensus-orientated (Johnston Despite wide spread support for the strategy, concerns were raised in relation to the potential for the PHCRNs to contribute to service fragmentation, increased referrals and workloads for other services. In contrast, the literature consistently identified the role of PHCRNs in promoting care coordination and integration. Cross-sector stakeholders acknowledge that tensions can be created when new health strategies have the potential to disrupt existing status quos and healthcare arrangements (North West Joint Improvement Partnership, Professionally, challenges have been experienced in attracting suitably qualified registered nurses to the positions. Additional investments have been required to support the appointed PHCRNs in transitioning from hospital-centric and acute care practice to schools-based and primary healthcare practice. Substantial resource, time and education investments have been directed towards nurse preparation for primary healthcare practice, including the enrolment of all nurses in post-graduate primary healthcare coursework.The uniqueness of the opportunity to co-design and contextualise nursing care and practice has been described by nursing executives and academics. Financially, the need to secure sustainable funding to appoint the PHCRNs has been a focus of the collaboration. This focus has been informed by previous experiences of short-term funding, lack of sustainability of new initiatives in rural contexts and levels of community cynicism towards poorly resourced healthcare innovations.Although in the early stages of implementation, strategic, relationship, resource and workforce gains have already been achieved. Strategically, a cross-sector governance committee has been established and convened to provide guidance and executive level endorsement of strategy aims, nursing care and practice approaches. Strategic documents have been developed and endorsed by this committee, including strategy proposal, communication strategy, comprehensive literature reviews, an initial evaluation and research framework, and a new model of nursing care. Relationships across sectors at the executive, senior management and service levels have been established or consolidated with relationship consistency being promoted through structured and routine multi-level committee, management and service meetings. New and sustained resources to fund the five PHCRN positions have been secured through the local health district, contributing to service continuity, consistency and sustainability. All five nursing positions have now been appointed to.et al., et al., Evidence indicates that to effectively address the challenges confronting disadvantaged children and adolescents we need to build supportive services that coordinate care across agencies in the same community, specifically those engaging with the same families. Increasing our understanding of the health needs of children and adolescents, and the application of this knowledge in the development of responsive primary healthcare policies and practices is necessary in establishing safe, health promoting environments and improved health outcomes (Viner et al., As the complexity of health, educational and social needs of rural school students increases, there are calls for greater levels of innovation in the design and implementation of alternative healthcare models that enhance service accessibility, acceptability and sustainability. Social innovations, those that have the capacity to transform the lives of individuals and communities, are required to resolve complex health inequities (Phills"}
+{"text": "RECOTOX is a cross-cutting initiative promoting an integrated research to respond to the challenges of monitoring, understanding, and mitigating environmental and health impacts of pesticides in agroecosystems. The added value of RECOTOX is to develop a common culture around spatial ecotoxicology including the whole chain of pressure-exposure-impact, while strengthening an integrated network of in natura specifically equipped sites. In particular, it promotes transversal approaches at relevant socioecological system scales, to capitalize knowledge, expertise, and ongoing research in ecotoxicology and, to a lesser extent, environmental toxicology. Thus, it will open existing research infrastructures in environmental sciences to research programs in ecotoxicology of pesticides. One of the greatest challenges for ecosystem sustainability and human health is currently the ever-increasing pollution of all environmental compartments by chemicals of various types and properties. For many years, the scientific community has emphasized the lack of long-term field- and landscape-scale monitoring of the fate of chemicals in water, soil, air, and biota, and of their negative effects on living organisms. AllEnvi, Aviesan, and Athena, the French alliances that combine the national research potential and coordinate the scientific strategy, created the French initiative on toxicology, ecotoxicology, epidemiology, and social sciences, that underlined these points in 2013 AllEnvi , they liAgricultural systems, subject to frequent and diverse pesticide inputs, have been treated for more than 70 years with pesticides and other biocides to increase crop production and quality  and the variable characteristics of the hydroagroecosystems  where they are applied require the implementation of interdisciplinary research to address the complex issues of ecotoxicology and environmental toxicology of pesticides at the landscape or territorial scale.https://www.anses.fr/en/content/phytopharmacovigilance).Institutional and professional organizations request integrated methods and models to improve monitoring, assessment, management, and mitigation of both environmental and human health risks associated with pesticides. Indeed, assessing the impacts of these substances on ecosystems, and their possible consequences on human health, in a context of global change and of exposure to multiple stressors, remains a priority issue for policy makers. Under the French legislation, the \u201cphytopharmacovigilance\u201d concept has been erected in order to monitor the adverse effects of pesticides used in agriculture in relation with the granting of their marketing authorizations  is a cross-cutting initiative to promote integrated research to respond to the scientific challenges of monitoring, understanding, and mitigating the environmental and health impacts of pesticides and biocides in agricultural landscapes, in agreement with the \u201cEco Health\u201d approach. Here, we describe the scientific and operational objectives of RECOTOX, based on its experimental site network.In that context, RECOTOX  that promotes a common culture of spatial ecotoxicology of pesticides that considers the whole chain pressure-exposure-impact. RECOTOX accounts for a wide range of agropedoclimatical situations, in terms of soil-bedrock, agronomic, and climatic-hydrologic characteristics, influencing pesticide sources or biotransformation (retention-degradation) and transfer processes. RECOTOX, therefore, explores the panel of responses to provide systemic and generic outcomes.RECOTOX aims to (i) determine pesticide transfers and mitigation in soil/water/atmosphere, (ii) analyze the effects of pesticides on biodiversity and resilience processes, (iii) understand how farmer practices in interaction with the environmental affect pesticides transfers, and (iv) examine socioeconomic processes such as acceptability of changing practices, costs, or expectations of civil society. Consequently, the scientific community embedded within RECOTOX comprises environmental chemists, hydrogeologists and hydrologists of the critical zone, ecotoxicologists, microbiologists, ecologists and toxicologists, agricultural scientists, and scientists of human, economic, and social sciences. The added value of RECOTOX in terms of skill, knowledge, and tool capitalization in the field of ecotoxicology could be transposed to toxicology, and then promote interdisciplinary and federative research projects, e.g., in the field of phytopharmacovigilance.Promoting an integrated research in ecotoxicology. The first and main action of RECOTOX is to incubate research projects, involving the wide range of scientific and technological expertise of its partners, and making use of the complementarity of their observatories and skills. As a consequence, RECOTOX aims to create general knowledge, synthesis of information, and facilitate the emergence of integrated research in spatial ecotoxicology among its sites. It will also rely on the homogenization of reference documents and integration of existing metadata in a common open information system. RECOTOX will strengthen in selected sites\u2019 existing measurements of practices and uses, transfers, exposure, or impacts in the different compartments , and at the relevant spatial and temporal scales, establish an integrated approach of the pressure-exposure-impact chain. This integrated approach will benefit from ongoing research programs conducted at the concerned research sites, and/or more comprehensive projects to share methods and models previously developed for different sites of the network.Upscaling approaches in ecotoxicology from plot to landscape. One current challenge is to include ecological realism into ecotoxicological studies. A major step is to understand the relationships between chemical releases and mitigation, exposure patterns, and population spatiotemporal dynamics in heterogeneous landscapes, in response to agricultural practices at various spatial and temporal scales. More, there is a lack of more realistic biological indicators in the case of moderate and chronic environmental degradation by pesticides, in particular indicators based on networks of interactions between organisms under the influence of the physicochemical conditions of the environment. Ecotoxicologists, as well as risk assessors, express increasing interest in learning more about both exposure to and effects of chemicals at the landscape scales. RECOTOX will also evaluate the effect of remediation solutions  on the measured or expected impacts at the relevant management scales. Here, observation, experimentation, and modeling will be combined.From ecotoxicology to toxicology. RECOTOX aims at developing, in some cases, observational studies to improve the characterization of human exposure and exposome, by collecting environmental samples, data, and information on daily environments of volunteers. Actions may include (i) the identification of pesticide sources; (ii) the selection of sentinel populations, highest-exposed individuals, activities, and behaviors that yield exposures; (iii) the evaluation of the magnitude and frequency of exposure; and (iv) the examination of the exposure\u2013response relationships. Such data are particularly necessary to improve performance of epidemiologic studies and reduce uncertainties in risk assessment. These studies will also enable to share experience with epidemiologists. RECOTOX will also fact to integrate both environmental and human exposure assessments  implies organizing the network to develop interoperability of data, metrics, datasets, and methods. An appropriate information system will be devoted to data management from new experiments and also to ensure identification and valorization of acquired data currently managed by different and distributed information systems within each observatory.Communication, exploitation, and dissemination of results. RECOTOX aims at structuring the scientific community in ecotoxicology and developing interactions with toxicologists. RECOTOX will favor interdisciplinary research programs and promote facilities for an integrated approach, and thus contribute to increase the research potential on continental ecosystems. The wide range of scientific and technological expertise of RECOTOX partners may also serve as an educational support for training in the fields of toxicological risks ecosystems (ecotoxicology) and human  health.RECOTOX develops cross-cutting actions, presented hereafter, within a current network of 10 sites.http://www.lter-europe.net/lter-europe/infrastructure/networks/national-networks#lter-france), five of which  being involved in RECOTOX, will provide a very strong basis for landscape-scale analyses of pesticide distribution within ecosystems, as well as excellent connections with society and stakeholders in general. The Research Infrastructure OZCAR \u201cNetwork of Critical Zone Observatories\u201d (http://www.ozcar-ri.org/) is a network of sites of continental surfaces  with instrumentation on soil, subsurface, water, and ice dedicated to continuous measurement in support of knowledge and modeling of water, carbon, and associated elemental cycling, and comprises two sites of RECOTOX. Then, RECOTOX can also benefit from the Research Infrastructure \u201cAnalysis and Experimentation on Ecosystems - France\u201d . AnaEE-France is an integrated network of the major French experimental, analytical, and modeling platforms dedicated to the biological study of continental ecosystems . This infrastructure aims at understanding and predicting ecosystem dynamics under global change. AnaEE-France comprises complementary nodes offering access to the best experimental facilities and associated biological resources and data: the Research Infractructure Ecotrons, and semi-natural experimental platforms to manipulate terrestrial and aquatic ecosystems. AnaEE-France also provides shared instruments and analytical platforms dedicated to environmental (micro-) biology, as well as databases and modeling tools designed to represent ecosystem dynamics in coupling ecological, agronomic, and evolutionary approaches. AnaEE-France is already open to the community of scientists in the field of continental ecotoxicology . Indeed, this infrastructure brings together networks of Biological Resource Centers (BRC) maintaining genetic, genomic, and biological resources produced and characterized by research on domestic animals, crops and model plant species, wild relatives of domestic species, microorganisms relevant for agriculture and macrofauna of the environment, and environmental samples. RECOTOX can particularly benefit from its capacity to maintain a large diversity of well-documented resources, to collect novel resources, to contribute to their characterization, to distribute them, and to manage the related data. RARe can also help the sites of the network in strengthening and organizing their ability to store and secure collected samples and their related data in the long-term.In addition, RECOTOX would benefit from the Research Infrastructure \u201cAgronomic Resources for Research\u201d (AgroBRC-RARe), and its pillar \u201cenvironmental resources\u201d . Indeed, ECOTOX has three main objectives: (i) to encourage scientific thinking within the community of ecotoxicologists, whether they are dealing with aquatic or terrestrial ecosystems; (ii) to contribute to defining a national research strategy in this field; and (iii) to favor scientific production , the international network on Microbial Ecotoxicology  which includes sites centered on the design of agricultural systems, allowing reduced agricultural pressure (including pesticides) for the characterization of the determinants and effects of agricultural practices at the local scale,The catchment, landscape, or territory scale, which allows the observation, experimentation, and modeling of various agricultural practices, pollutant dissipation/retention/transformation schemes in both cultivated or non-cultivated landscape components, or various exposures and impacts on continental terrestrial and aquatic ecosystems,The global  scale, where it is intended to organize and cross observations and experimentation results obtained on a similar way in several complementary sites.RECOTOX focuses its activities in a network of instrumented sites mostly belonging to recognized Research Infrastructures , managed by research institutes and universities. The sites cover a variety of soil, agronomic, climatic, and socioeconomic situations, which are reflected in the diversity of agricultural practices, land uses, and landscapes, as well as hydrological and biogeochemical conditions. Their main characteristics are presented in Table http://www.zaplainevaldesevre.fr/, Bretagnolle et al. 2, including the forest of Chiz\u00e9, and is a typical rural area with a temperate Atlantic oceanic climate. It includes around 450 farms with high diversity of agricultural strategies with organic farming, conservation farming, and conventional farming. Since 2003, half of the area is designated as a Special Protection Area (NATURA 2000 network) for conservation of remarkable or endangered bird species such as the little Bustard Tetrax tetrax or harriers Circus spp. From 1994 onwards, biodiversity surveys have been carried out every year in 120 to 200 farmers\u2019 fields. Monitoring started with birds and small mammals in 1994, ground-dwelling arthropods since 1995 and then other arthropods , plants since 2005, and soil organisms since 2016. In addition to biodiversity monitoring, farming practices have been monitored by means of farmer interviews (about 150 fields per year) which allow to quantify pesticide uses and analyze the relationships between this use and biodiversity. The ZAPVS also hosts the ECOBEE platform   comprises the observatory ORACLE/BVRE Orgeval (http://gisoracle.irstea.fr). Located 70 km east of Paris, the Orgeval catchment supports research on understanding the processes and developing integrative modeling of the hydrological functioning of its small upstream catchment. Started in 1962, the Orgeval catchment is managed by Irstea. This site belongs to the ORACLE observatory (1800 km2) which is composed of the Grand Morin and Petit Morin catchments. The ORACLE observatory gathers many national and international research units in the GIS ORACLE (Group of Scientific Interest) created in 2011. The Orgeval catchment is also part of the \u201cZone Atelier Seine\u201d thanks to the Interdisciplinary Research Program in Environment on the Seine basin (Piren Seine) and it is also part of the IR OZCAR. The ORACLE observatory is dedicated to the improvement of the knowledge on the hydrological and biogeochemical functioning of sedimentary basins in rural anthropized systems. Its objective is the observation and modeling of streamflow and of water and pollutant transfer processes at various scales. It also works on the optimization of data acquisition methods. ORACLE, with its set of nested subbasins and its perennial long-term observations (more than 50 years), allows to address the scaling and global change issues. The Orgeval catchment area covers 104 km2. It is mostly constituted of drained fields and devoted to field crops. It has a direct influence, in terms of quantity and quality, on the flows going from the Marne to the Seine Rivers until the Paris conurbation. On the Orgeval catchment, chronicles of streamflow and water quality data are available since 1962 and 1978, respectively, and the monitoring of pesticides started in 2008, in the context of two projects: Phyt\u2019ORACLE (EC2CO) and PIREN Seine  is an environmental research platform created in 2000 and located in the Grand Est region. Currently, the ZAM gathers a Lorraine scientific community  around the protection of water resource of the Moselle River. The ZAM covers 15,400 km2 in France and presents a highly contrasted occupation of the territory combined with specific anthropic pressures. The upper part of the basin is dominated by the Vosges Mountains, sitting on acidic soils . The middle and lower parts of the French basin correspond to a succession of cuestas characterized by limestone plateaus with permeable soils and plains with a dominant clay soil. Agriculture, especially mixed farming and livestock farming, is present on the middle part of the basin, which receives regular agricultural inputs . The downstream part of the basin is characterized by increasing urbanization  and by the heritage of Lorraine\u2019s industrial past (iron mining and steel industry). Still, throughout its journey, the Moselle River contributes to maintain wetlands areas with a rich biodiversity . The ZAM research actions are structured around five main disruptions linked to geomorphology, land use, and human activities: the acidification of streams and rivers in the Vosges mountains; pesticides and their residues, mainly linked to agricultural activities  (http://www.zabr.org/) comprises the Ardi\u00e8res-Morcille experimental site (https://saam.irstea.fr/), which studies the impacts of anthropization, especially wine growing, on river water quality and aquatic ecosystem functioning in order to highlight the key involved processes, biological adaptations, and remediation trajectories. The Ardi\u00e8res-Morcille experimental site belongs to the Rh\u00f4ne Basin Long-term Environmental Research Observatory (ZABR) which comprises a set of observatories and experimental sites  devoted to a better understanding and management of the Rh\u00f4ne River basin. The Ardi\u00e8res-Morcille experimental site was set up in 1987 by the Cemagref, the regional service for water use and supply and the Beaujolais Development Committee. It moved in 2007 to the ZABR (which has been labeled SOERE ZA in 2001). Among the other experimental sites and observatories of the ZABR, the Ardi\u00e8res-Morcille experimental site was chosen in priority to be part of the RECOTOX network because of the anteriority and history of the research devoted to the fate and effects of pesticides used in agriculture, and because of the interdisciplinary approach developed along the fate-exposure-impact chain. Researches on the Ardi\u00e8res-Morcille experimental site also contribute to providing operational tools to better understand and implement buffer zones in catchments so as to limit the diffuse agricultural pollutions of rivers . The Ardi\u00e8res-Morcille experimental site consists of two nested catchments: the Morcille catchment (8 km2) and the Ardi\u00e8res catchment (150 km2). Located northwest of Lyon in continental climate, the Ardi\u00e8res-Morcille experimental site is characterized by intensive wine growing. It is representative of the agricultural, soil, and climatic conditions of the central and northern Beaujolais. The first studies (since 1987) started on the Morcille subcatchment which is now equipped with long-term hydrometeorological stations and experimental subsites. The recent studies on the Ardi\u00e8res catchment (since 2011) enable both to address the question of hydrological processes and modeling scaling up and to strengthen the involvement of the economic and social sciences. Four research themes are crossed on the Ardi\u00e8res-Morcille site: observation and modeling of hydric transfers of pesticides; characterization of the chemical  contamination of the river; development of knowledge and indicators of the in situ impacts of pesticides on aquatic ecosystems and their recovery capacity (resilience); development of methods and tools to help public decision-makers to understand and use the research results  (http://zaaj.univ-fcomte.fr/) is an area of 13,500 km2 that covers a large part of the Jura medium mountains in Bourgogne-Franche-Comt\u00e9 and Rh\u00f4ne-Alpes regions, eastern France. It is composed of grasslands exploited for cheese production, karst and rivers, forests, peatlands and wetlands, and urban areas. ZAAJ observatories are designed to promote long-term interdisciplinary research on the dynamics of the socioecosystems of this territory. They contribute to capitalize on field data and to analyze and promote the results from long-term observation schemes at the interface between ecology, environment, and society. The main researches questioned the impacts of human activities, including those due to environmental contaminants, and their implications in terms of ecosystems health, social economic issues, and biodiversity conservation. They aim to assess the vulnerability of ecosystems and population at risk and to provide predictive and management tools to help maintain ecosystem services and protect population and ecosystems\u2019 health. Among questions related to RECOTOX, we can cite for instance vole outbreak management in grassland agrosystems and side effects on wildlife  (http://www.obs-omere.org) is composed of two cultivated headwater Mediterranean catchments: the Roujan catchment (0.91km2) located in France (Languedoc region) and the Kamech catchment (2.63 km2) located in Tunisia (Cap Bon Peninsula). The OMERE observatory was set up in 2002 to understand the impact of agricultural and land management on mass fluxes in typical farmed headwater catchments of the Mediterranean region. Within this main objective, the OMERE aims at studying the natural and anthropogenic drivers of pesticide contamination of soil and water across scales from plot to catchment scales. The observatory helps to address the effect on pesticide transfer of highly variable hydroclimatic conditions characterizing Mediterranean regions , as well of soil type, crop treatment, and land management. The two catchments are similar with respect to environmental and climatic conditions. They differ according to the change in land use and human activities they are submitted to. In the Kamech catchment, cereals, legumes, and irrigated market gardening are mainly cultivated and a progressive intensification of agriculture occurs with a full use of the area available for agriculture and an increasing application of fertilizers and pesticides. In the Roujan catchment characterized by wine growing, intensification of agriculture has already been operated for a few decades and has led to the creation of a network of ditches and human-made slopes. So far, the dynamics of pesticides, mainly herbicides, has been studied in Roujan catchment. Pesticides have been monitored in soil, runoff water, groundwater, and rainfall. In surface waters, the monitoring is performed from plot to catchment scale using a nested network of hydrometric stations. The monitoring design is based on the knowledge of the applied treatments that are also recorded.The agro-hydrological observatory OMERE  is an observatory of agricultural pollution in the French West Indies  composed of two equipped catchments: one in Guadeloupe and the other one in Martinique. It is dedicated to the study of the fate of pesticides (including chlordecone) in the environment according to agricultural practices. The OPALE observatory  in Capesterre-Belle-Eau in Guadeloupe, and the Galion catchment (40 km2) in Martinique. Previously called OPA-C, the OPALE observatory was accepted in the frame of the call for projects of the Chlordecone National Action Plan\u2014catchment (PNAC-BV) in May 2012. This project, lasting from 2012 to 2014 enabled the implementation of equipment in the two catchments thanks to a partnership between the BRGM, CIRAD, IRD, and INRA. The P\u00e9rou-P\u00e8res River catchment in Guadeloupe is located on the edge of the volcano la Souffri\u00e8re. It is composed of ashy soil on a recent geological formation. The Galion catchment in Martinique is located on well-developed soils with old geological formation. Those two sites are typical of tropical conditions with the leaching of soils with a high organic matter content. They enable to cover the main crops specifically of the French West Indies: sugar cane and banana. Therefore, those two sites have been affected by a heavy use of chlordecone between 1972 and 1993. The OPALE observatory aims at monitoring the agricultural practices and surface or groundwater contamination on a small agricultural area  is an agroenvironmental observatory on the Vesle catchment. It aims to guide territory stakeholders in the coconstruction of a collective knowledge management device about agricultural practices, in order to help the implementation of actions to improve the water resource quality. OBSERVOX is a territorial observatory of agricultural practices  on the Vesle catchment up to the Couraux water catchment area, which covers 700 km2. It was created in 2007 in the frame of the AQUAL objective contract. OBSERVOX consists of five subcatchments. It is carried by the SIABAVE  and the scientific part is led by the CReSTIC (Research Center in Sciences and Technology of Information and Communication \u2013 Universit\u00e9 Reims Champagne Ardennes) and the ASTER unity of INRA of Mirecourt. The Seine Normandie Water Agency and the FEDER take part in the cofinancing of the project. In OBSERVOX, two sites are part of the RECOTOX network: the site of Cernay-les-Reims and the site of Sommevesle. The first one covers 37 ha of vineyards localized on the Reims and Berru mountain slope. Approximately 50 farmers work on this site. The second one covers 830 ha of croplands. Those two sites are characterized by a temperate continental climate tending towards oceanic and chalk soils of the Champagne region. This territory is typical of the Champagne region. The OBSERVOX observatory aims to increase knowledge in partnership with territory stakeholders on water resource quality and changing agricultural and wine-making practices, as well as on the factors affecting molecule transfers towards water resource. It has three objectives: access the change in pesticide pressures linked to their use in vineyards and croplands; explain this evolution; link this evolution to analyzed pesticides and metabolites in waters from the Couraux water catchment area. Benefiting from a 10-year monitoring in the Champagne region, the OBSERVOX site is also located in an agricultural area where there is a heavy use of pesticides. Therefore, this site is particularly relevant to study the impact of pesticide use on water resources.The observatory OBSERVOX  enables the quantitative evaluation of matter transfer processes  in relation to hydrological and agronomic forcing and human activities in vineyards in order to understand, quantify, and predict the hydrological and biogeochemical functioning of an agrosystem in perennial culture. Located 15 km southwest of the town of Colmar in Alsace, the site is one of the observatories of the Laboratory of Hydrology and Geochemistry of Strasbourg . A 43-ha vineyard catchment was equipped in 2003 for the monitoring of pesticides, and then in 2009 for the monitoring of flows and cycles of solutes, including pesticides and metals  and integrating an artificial wet buffer zone at the outlet of the 43-ha catchment. The Hohrain\u2019s catchment team is composed of researchers of the LHyGeS and lecturers of ENGEES  and EPLEFPA (College for winegrowers), as well as the city of Rouffach and winegrowers in the catchment area. The monitoring of the Hohrain-Rouffach catchment has been developed in the framework of the LIFE Environment project ArtWET (2006\u20132011), the INTERREG IV PhytoRET (2011\u20132014), and the PACOV project , coordinated by the LHyGeS. The Hohrain-Rouffach site is representative of agriculture, soil , and continental climatic conditions of the Alsatian Piedmont. The site is equipped to quantify solute flows at the catchment scale and the vineyard plot (two 1341-m2 plots equipped). The artificial stormwater wetland zone (320 m2 and 1500 m3) located at the catchment\u2019s outlet is studied since 2009 in terms of reactive transport of pesticides and metals at the water/plant/sediment interface. For 10 years, the catchment has served to collect information on water and chemical flows as well as land use data. A specificity of the catchment is that it enables to investigate the plot\u2013catchment\u2013wetland buffer zone continuum  is an observatory devoted to the study of diffuse contamination of crop fields by mycotoxins, trace elements, and pesticide residues. It is an agronomic tool created in 2010 in the frame of the Combined Technology Network (CNT) in order to focus on the thematic field of sanitary quality of major agricultural products. Quasaprove is a network of plots whose agropedogeochemical conditions are well known. It enables to perform full-scale tests on hypotheses and models about the sanitary quality of crops in pre- and post-harvest . The Quasaprove network is spread on the whole French territory. It is located in seven INRA sites, two Terres Inovia stations, four ITAB stations, 11 agricultural secondary schools sites, and one Arvalis site in Boigneville. The seven involved INRA sites are as follows: UE Domaine exp\u00e9rimental de la Motte au Vicomte de Rennes, UE 0802 d\u2019Agronomie de Toulouse, UE 1246 Grandes Cultures Versailles-Grignon, UE 1373 Fourrages Environnement Ruminants de Lusignan, UMR EMMAH Domaine St Paul Avignon, UE d\u2019Epoisses, UE Grandes Cultures Innovation Environnement \u2013 Picardie. Quasaprove is led by ACTA and INRA. In the Quasaprove network, seven sites belong to the RECOTOX network. Located in Auzeville in Haute-Garonne, Lusignan in the Vienne, Epoisses in C\u00f4te-d\u2019Or, Le Rheu in Ile et Vilaine, Versailles in the Yvelines, Estr\u00e9es-Mons in the Somme, and Avignon in the Vaucluse; those sites cover a wide range of soil  agricultural practices and climate conditions all over the French territory. Conventional and organic croplands  are prevailing in the studied sites. These focus on diffuse agricultural contamination in different compartments  and try to understand the sources and accumulation pathway of pollutants. The CNT Quasaprove activities deal with scientific and technical questions in relation with the source, fate, and management of contaminants  and non-desirable organisms which jeopardize the sanitary quality at every stage of the food chain. The objectives of the CNT Quasaprove are to assess the contamination levels of crops and agricultural soils; quantify the plot trace elements flow and assess the impact of practices on soil contamination; test characterization tools of the trace element availability, test at a field scale the hypotheses and predictive models of the crop contamination risk; keep a sample bank for further analysis on contaminants not yet studied. The Quasaprove network benefits from a chronicle of the exogenous intakes (fertilizers and pesticides). The multicontamination approach is studied in priority. One of its originality is also to take simultaneously into account the soil and plant compartments with the subsequent difficulty to analyze and model transfers.The QUASAPROVE network  its quasi monoculture of vines and its relatively homogeneous soils make it possible to select comparative measurement stations; (ii) agricultural practices, moderate to high slopes, and climate characteristics are favorable to pesticide transfer to surface water; and (iii) the wide range of pesticide substances  used for vine protection allows exploration of different physicochemical properties and associated pesticide fate. The tested chemical tools were passive samplers as, for example, Silicone Rods (SR) dedicated to hydrophobic to moderately hydrophilic compounds. In total, 28 pesticides  were analyzed as well as potential confusing parameters s, nutrients, temperature). In parallel, the biological approach consisted in an in situ study of a range of selected impacts on microbial and invertebrate communities. As an example, the following were measured: (i) leaf litter decomposition, which is mediated by the combined action of natural microbial and invertebrate communities; (ii) fungal biomass within leaf-associated natural microbial communities; (iii) alimentation and acetylcholine esterase inhibition in standardized caged Gammares (Gammarus fossarum). The tools have been applied during June 2014 and June 2015 (corresponding to a period of pesticide application on vineyard) in the Ardi\u00e8res River at three measurement stations from upstream to downstream. The results . Landscape organization can modulate the resistance and resilience of ecosystems to the impacts of anthropogenic disturbances such as soil pollution, particularly by pesticides. Moreover, landscape elements influence the distribution of contaminants, exposure of living organisms, ecological processes related to ecosystem services, and therefore agroecosystem functioning. For instance, the presence of hedges may limit pesticide transfer or a high percentage of organic farming or grassland in a landscape may buffer the negative effect of pesticides. Unraveling the respective influence of landscape organization and pesticide inputs can thus provide recommendations for risk assessors and suggest spatial arrangement that best support multifunctional and resilient agricultural landscapes. However, assessing the pesticide transfer and risk at landscape scale is challenging and requires dedicated infrastructures. The extensive knowledge of land use in the LTSER Zone Atelier Plaine & Val de S\u00e8vre (ZA PVS) as well as available data on farming practices in the area allows investigating how local farming practices and landscape organization affect biodiversity, ecosystem functions, and pesticide transfer. Three projects address this issue in the LTSER ZA PVS: BIOSERV , funded by INRA metaprogram ECOSERV, test this hypothesis that the flows of goods and services that organic farming will benefit crop production and farmers profitability both in organic farming and conventional farming fields through higher regulation services; RESCAPE  funded by French Biodiversity Agency on \u201cResistance and Pesticides\u201d research call, with the fees for diffuse pollution coming from the Ecophyto Plan; and PING  funded by Metaprogramme SMaCH of INRA aims to assess the impact of landscape features (composition and configuration) and agricultural practices  on pesticide transfers in soils and living organisms. All projects use an integrated and interdisciplinary approach. BIOSERV analyzes the effect of landscape composition  and their spatial arrangement  on biodiversity, key ecosystem services , and farmers\u2019 incomes. RESCAPE and PING establish quantitative links between agricultural management, the spatial distribution of pesticides and the effects of pesticides. The PING project also investigates the link between ecotoxicology and socioeconomy by analyzing the farmers\u2019 decision to use glyphosate and how, based on scientific results , their perception and use of glyphosate may change. In the three projects, several measurements are performed in arable fields (120 fields) and semi-natural elements  such as soil sampling for physicochemical characterization and pesticide concentrations, biodiversity monitoring , and ecological functions . In RESCAPE and PING, the spatial distribution of pesticides in soils is also studied through the development of analytical methods (Daniele et al. Several sites already host research projects in the context of the chain pressure-exposure-impact applied to pesticides. The RECOTOX network offers the perspective to extend them and to address new issues. Examples of projects are presented hereafter:The initiative RECOTOX federates in natura sites that develop a common culture in spatial ecotoxicology in the context of the whole chain pressure-exposure-impact applied to pesticides. RECOTOX will provide an added value to existing research infrastructures for environmental research by launching transversal approaches at relevant socioecological system scales, by capitalizing their knowledge and expertise, and seeking complementarity in the fields of ecotoxicology, and to a lesser extent, in environmental toxicology. RECOTOX will generate proposal and partnership that can serve as a framework for project preparation addressed to funding agencies. Finally, RECOTOX is positioned as the French part of a European network to develop for the research on ecotoxicological effects of pesticides."}
+{"text": "Pancreatic cancer is one of the most aggressive malignancies, accounting for more than 45,750 deaths annually in the U.S. alone. The aggressive nature and late diagnosis of pancreatic cancer, coupled with the limitations of existing chemotherapy, present the pressing need for the development of novel therapeutic strategies. Recent reports have demonstrated a critical role of microRNAs (miRNAs) in the initiation, progression, and metastasis of cancer. Furthermore, aberrant expressions of miRNAs have often been associated with the cause and consequence of pancreatic cancer, emphasizing the possible use of miRNAs in the effective management of pancreatic cancer patients. In this review, we provide a brief overview of miRNA biogenesis and its role in fundamental cellular process and miRNA studies in pancreatic cancer patients and animal models. Subsequent sections narrate the role of miRNA in, (i) cell cycle and proliferation; (ii) apoptosis; (iii) invasions and metastasis; and (iv) various cellular signaling pathways. We also describe the role of miRNA\u2019s in pancreatic cancer; (i) diagnosis; (ii) prognosis and (iii) therapeutic intervention. Conclusion section describes the gist of review with future directions. Pancreatic cancer impinges profoundly on mankind and, is one of the most aggressive and fatal malignancies. Pancreatic cancer is the third leading cause of cancer-related deaths in the USA and is anticipated to take the second spot by 2020 ,2. In 20Despite enormous progress in the field of cancer research and treatment, the biomarkers for initiation and progression of pancreatic cancer are still not well-defined. Micro RNA (miRNA) might help to establish a better diagnostic tool for pancreatic cancer. Altered and aberrant expression of miRNA is a hallmark of several human malignancies . Recent In this review, we provide a brief account of the biogenesis of miRNA and its effects on cellular functions and miRNA related studies in pancreatic cancer patients and animal models. We also review existing literature on the role of miRNA in cell cycle and cell proliferation, apoptosis, invasion, metastasis, and cellular signaling pathways. We also explore the use of miRNA as diagnostic, prognostic and therapeutic targets in pancreatic cancer. Caenorhabditis elegans . Re. Re87]. Given the decisive role of miRNAs in various stages of pancreatic cancer, starting from its initiation to progression to metastasis; miRNAs are potential targets for the therapeutic interventions . miRNA-bA separate approach comprises of miRNA antagonists. These are single-stranded antisense oligonucleotides corresponding to target miRNA, synthesized chemically with specific modification to provide high stability, binding affinity, and protection from nucleases ,156. TheThe association of miRNAs with cancer and using these miRNAs as therapeutic targets provides new hope for the effective diagnosis and treatment of fatal pancreatic cancer. Novel data about the biogenesis, regulation, and functions of miRNAs is increasing at an exponential rate. The cardinal regulatory role of miRNAs in key biological processes such as cell survival and proliferation, invasion and metastasis, apoptosis, and drug responsiveness, highlights their potential as diagnostic, prognostic and therapeutic targets. Also, little is known about inter-cellular communication mediated by miRNAs in pancreatic cancer. Moreover, a single miRNA target several genes and a single gene may be targeted by multiple miRNAs resulting in the additive action of miRNAs in the course of the disease. The aberrant expression of miRNAs is strongly correlated with pancreatic cancer, and in at least some cases appears to play a causative role in the establishment and progression of the disease. Restoration of down-regulated tumor suppressor miRNAs and inhibition of up-regulated oncogenic miRNAs holds the enormous prospect for the development of novel effective anticancer therapies or diagnostics. While there has been tremendous progress in the field with ample ongoing progress, there remain some limitations that need to be addressed before employing miRNAs as a therapeutic target. One of the most serious limitations is the potential for off-target effects and levels of toxicity of these chemically modified miRNAs on the healthy cells of the patients. The specific delivery of therapeutics into the pancreatic cancer cells is another consideration. Nonetheless, the recently developed intravenous injections and nanoparticle associated delivery system have shown great promise. Thus far, the progress in the field of miRNAs is impressive, but there is a long way to go. Pancreatic cancer remains a leading cause of mortality but the new body of work on the function of miRNA in cancer provides hope for miRNA-based strategies for early diagnosis, improved prognosis, and better management of clinical systems."}
+{"text": "The natriuretic peptides (NPs) family includes a class of hormones and their receptors needed for the physiological control of cardiovascular functions. The discovery of NPs provided a fundamental contribution into our understanding of the physiological regulation of blood pressure, and of heart and kidney functions. NPs have also been implicated in the pathogenesis of several cardiovascular diseases (CVDs), including hypertension, atherosclerosis, heart failure, and stroke. A fine comprehension of the molecular mechanisms dependent from NPs and underlying the promotion of cardiovascular damage has contributed to improve our understanding of the molecular basis of all major CVDs. Finally, the opportunity to target NPs in order to develop new therapeutic tools for a better treatment of CVDs has been developed over the years. The current Special Issue of the Journal covers all major aspects of the molecular implications of NPs in physiology and pathology of the cardiovascular system, including NP-based therapeutic approaches. The natriuretic peptides (NPs) family includes a class of hormones  and their receptors  needed for the physiological control of cardiovascular functions. First, the discovery of NPs provided a fundamental contribution for the understanding of the physiological regulation of blood pressure (BP) and of cardiovascular and renal functions . SubsequAs a matter of fact, the NPs system has provided over time a continuous, attractive source of new knowledge and discoveries regarding the pathogenesis, diagnosis, prognosis, and therapy of CVDs. In particular, the opportunity to target NPs in order to design new therapeutic tools for a more effective treatment of CVDs has been developed, ultimately culminating in the introduction of a new class of drugs for the management of HF, the angiotensin receptor neprilysin inhibitor (ARNi) ,6. The continuous interest in this field of biomedical research is documented by accumulating data produced from several expert scientific groups. This issue of the Journal collects some original and review articles on the molecular and biomedical aspects concerning NPs, with a discussion of their current clinical and therapeutic applications. Nppa) or NPRA gene (Npr-1) led to hypertension and marked cardiac hypertrophy, the latter being independent from high blood pressure levels [Npr-1 led to salt-sensitive increases in BP whereas Npr-1 gene duplication lowered BP and protected against high dietary salt concentrations [Nppa, BNP gene (Nppb), and Npr-1 with cardiovascular disorders in humans [The cellular effects of NPs include the regulation of cell proliferation, angiogenesis, apoptosis, fibrosis, and inflammation . Their ae levels . In parte levels , the gentrations . The fintrations ,8. In fan humans ,8,9. Interestingly, NPs control the lipid metabolism through an anti-lipolytic effect . Of noteNppa, Nppb, CNP gene (Nppc), Npr-1, NPRC gene (Nprc), Corin, and Proprotein convertase subtilisin/kexin type 6 gene (PCSK6) are known contributors to hypertension development in experimental models as well as in humans through a decreased function of the system and of its impact on BP regulation [Nppa , that is frequently encountered in the general population , has shown functional deleterious properties that completely diverge from those of the wild type form, which makes this molecular variant a significant contributor to cardiovascular acute events such as stroke and myocardial infarction [Nppa variant (rs5068) is able to reduce the cardiometabolic risk by increasing the circulating ANP level and its beneficial cardiovascular and metabolic properties [Nppa variant (rs5063) was associated to reduced left ventricular mass in hypertension [Nppa support the existence of genetic predictors of cardiovascular risk that contribute to the individual risk profile (as part of the emerging field of predictive medicine).Both the hemodynamic and cellular effects of NPs explain the pathogenetic involvement of NPs in hypertension and related target organ damage. In particular, as discussed in this issue of the Journal, the comprehension of the fine molecular mechanisms underlying hypertension has been largely improved through the dissection of the molecular genetics of the NPs system . Nowadaygulation . Furtherfarction . On the operties . Furtherrtension . OverallNPs represent today well established and useful diagnostic biomarkers in HF, being of particular help for the differential diagnosis of dyspnea in the emergency room . The incHF is often associated to atrial fibrillation (AF), a condition that on its own presents with higher BNP levels ,33. ThisIn the context of HF, a renal dysfunction often develops . As reviewed in this issue by Okamoto R. et al. , BNP is The strength of the relevance of NPs in HF is reinforced by an interesting review article of this Special issue. Specifically, the article by Cao Z. et al. focuses on the role of NT-proBNP/BNP as valuable diagnostic biomarkers of cardiac dysfunction in deceased individuals . This orAn important component of the NPs system is represented by CNP, which acts through either the NPRB or NPRC receptors. CNP is mainly synthetized by endothelial cells and also by cardiomyocytes and fibroblasts. It circulates in the blood at very low amounts, offering a clear example of an autocrine/paracrine mediator within the cardiovascular system . The mosAmong the recent discoveries regarding the NPs system, the one that deserves particular attention is the potential involvement of NPRC signaling in the pathogenesis of pulmonary arterial hypertension . The artThe main therapeutic approaches to treat CVDs involving the NPs system are based on either the development of peptide analogs or the blockade of peptides catabolism ,4. In thAn overview of the strategies aimed at blocking the NPs catabolism through a NPRC blockade, and particularly through NEP inhibition, is presented by Volpe M. et al. . The appOverall, the comprehension of the multiple functional roles of NPs, gained over the last 35 years, makes this hormonal system an essential contributor to the maintenance of the cardiovascular health. On the other hand, a deeper understanding of the complex molecular mechanisms underlying the functionality of NPs has opened a new way to relevant therapeutic innovations. Future years, through the continuous efforts of several research groups, will certainly reveal more insights on this multifaceted cardiovascular hormonal system."}
+{"text": "An emerging component of mHealth is the use of tailored mobile applications (app) to facilitate self-management of chronic illnesses, including the mapping of social networks to assist adults living with chronic illnesses to help them be able to identify sources of social support. The purpose of this study is to describe a prototype app to support persons living with dementia (PLWD) in the community and their informal caregivers to map social networks and identify sources of emotional, instrumental, informational, and appraisal of social support. Adapting the Network Canvas open-source software and drawing upon a previously-developed mobile application for adults to self-manage chronic illnesses, we share the key specifications, including health care provider output, preliminary end user feedback, and the pilot protocol designed to test the feasibility. Findings illustrate the importance of leveraging social network data in novel ways to enhance self-management and well-being among PLWD and their caregivers"}
+{"text": "Diagnosis, that is, characterization of building materials and assessment of building materials' decay, as well as assessment of environmental loads;Assessment of compatibility and performance of conservation/restoration materials and interventions, both in lab and in situ on building scale;Monitoring of the structure after the application of the most appropriate materials and interventions, to assure sustainability.Protection of built heritage passes through three distinguished steps that involve the following:Scanning microscopy techniques are among the techniques that are used throughout the investigation of the aforementioned processes, and their applicability is increasingly gaining ground. In this framework, the input aspects of the scanning microscopy techniques in the field of built heritage protection are of high importance. The enhancement of our knowledge on the physicochemical and microstructural characteristics of historic and modern building materials and their degradation processes, as well as on the properties of the conservation and repair materials that we need to design in terms of compatibility and sustainability, is vital, and scanning microscopy techniques are key tools towards this direction, with technological advances further increasing their effectiveness.A. Moropoulou et al. review the literature for the use of scanning microscopy techniques in the fields of building materials and cultural heritage, comparing these techniques with other analytical techniques widely used in these fields, regarding acquired information, sample requirements, and major limitations. They also summarize the main advantages and limitations of the most commonly used scanning microscopy techniques in the field of built cultural heritage through numerically comparing the research papers that report their use and findings in bibliography and demonstrate that scanning electron microscopy with energy-dispersive X-ray spectroscopy analysis (SEM-EDX) can be regarded now as a routine and a key role technique, whereas transmission electron microscopy (TEM) is progressively utilized. Distinctive results of SEM-EDX are presented regarding building material characterization, such as stone and mortars; mortar production technology; stone decay diagnosis, as far as it concerns the impact of pollution, salt crystallisation, and biodeterioration; and assessment of cleaning, consolidation, and protection treatments. Furthermore, characteristic TEM results are displayed, revealing the presence of nanostructures in historical mortars, shedding light on their properties and their specific production technology. The use of TEM in the evaluation of the development of advanced nanomaterials, designed in particular for conservation treatments, such as consolidation and antifouling action, is also recorded.M. Stefanidou and E. Pavlidou investigated the role of SEM-EDX in the characterization of historical mortars, not only in relation to their main components  but also in relation to their microstructure. It is demonstrated that important information about production technology of mortars and their preservation state can be acquired by SEM utilization. Furthermore, new repair mortars are to be designed with corresponding and compatible properties to the historical ones. In such cases, SEM results about raw material suitability, effectiveness evaluation of nanoparticle addition, and self-healing processes of special mortar additives are presented.In the two following works of L. Ferrazza et al. and A. Gil-Torrano et al., the numerous ways that SEM-EDX can be coupled with several other techniques, in order to ensure the protection of built heritage, are demonstrated.In particular, L. Ferrazza et al. focus on the conservation study of the facade of the Arciprestal Church of Santa Mar\u00eda de Morella in Spain. A vast array of techniques such as ground penetration radar (GPR), X-ray fluorescence (XRF), optical microscopy (OM), X-ray diffraction (XRD), SEM-EDX, and Fourier transform infrared spectroscopy (FTIR) are used for building material characterization and decay diagnosis, while assessment of cleaning and consolidation treatments on architectural surfaces of both stones and polychromes is included. The multidisciplinary character of this work and the importance of SEM-EDX in investigating crusts, patina, and especially pigments and their substrates are highlighted.rd to 4th century AD) and the Caliphal era (10th to 11th century AD). The similarities and variances between the employed materials and technologies of the different eras' wall paintings are investigated through the combined use of OM, SEM-EDX, XRD and \u03bc-XRD, wavelength-dispersive X-ray fluorescence (WD-XRF), and FTIR. The secco technique is used for the manufacturing of both wall paintings under investigation, while the wall paintings of the Roman era present more preparatory layers in comparison to the Arabic ones. Furthermore, red earth and calcite are detected as red and white pigments in the case of Roman paintings, whereas red ochre and calcite are identified as red and white pigments in the case of Arabic paintings.Correspondingly, A. Gil-Torrano et al. investigate the archaeological site of Cercadilla in Cordoba, Spain, regarding the preservation state of wall paintings of the Roman era  and heat resistance, whereas microstructure characteristics are examined by SEM-EDS.Last but not least, S. Nicolopoulos et al. demonstrate a combination of ADT and ASTAR orientation/phase mapping techniques in TEM to investigate various materials with emphasis on pigments used in different artefacts, such as amphoriskos, glass tesserae, and Mayan mural paintings. Nanocrystalline mapping of pigments is achieved using the abovementioned TEM electron crystallography techniques. Ancient composite materials are thus thoroughly investigated, since chemical and structural information is acquired at nanoscale. Through this work, multiple scaled impacts are evident regarding the ways of how technological evolution can significantly enhance our knowledge in several areas of interest for the protection of cultural heritage.The protection of built heritage is a vast and fascinating research field where many questions still have to be answered regarding the properties of building materials, as well as the weathering processes that govern their life cycle. Answering these questions will inspire scientists to pioneer in designing novel conservation/restoration and repair materials that will ensure structures' protection and sustainability.In this context, scanning microscopy techniques play a key role in establishing methodologies and protocols towards revealing the past and planning the future. Technological advances further evolve the capabilities and the applicability of scanning microscopy techniques contributing to the sustainable protection of built heritage.Antonia MoropoulouElisabetta ZendriPilar OrtizGeorge Fourlaris"}
+{"text": "The Health Resources and Services Administration recently announced a notice of funding opportunity (NOFO) for the Geriatrics Academic Career Award Program (GACA). The purpose of the GACA program is to support the career development of individual junior faculty in geriatrics as academic geriatrics specialists and to provide clinical training in geriatrics, including the training of interprofessional teams of health care professionals. The GACA program is a mentorship model where the awardee is guided through a faculty career development plan, with required project deliverables, over the course of four years. The GACA supported 222 junior faculty members between 1998 and 2006, when it was discontinued. This initial NOFO provides funding for up to 26 awardees in the schools of allopathic medicine, osteopathic medicine, nursing, social work, psychology, dentistry, pharmacy, and allied health. This presentation will provide an up-to-date overview of the program with awardee demographics and project deliverables."}
+{"text": "Cancer on the African continent is quickly becoming an overt public health crisis due to an aging population and changes in lifestyle. The World Health Organization (WHO) states that a national cancer-control programme should aim to reduce cancer incidence and mortality and improve quality of life of cancer patients, through a national cancer-control plan (NCCP) that is systematic, equitable and evidence-based. Despite this, only 11 countries in Africa have a current NCCP. Participants in a US National Cancer Institute-supported, multi-year, technical assistance programme for cancer-control planning noted three main opportunities to improve how plans are created and implemented: 1) mobilisation of resources and partners for plan implementation; 2) accurate surveillance data to promote better resourcing of NCCPs; and, 3) sustainable and innovative partnership models to strengthen capacity to implement NCCPs. Most countries in the region face similar challenges in the development and implementation of an NCCP, including inadequate human, technical, and financial resources. Collaborative partnerships increase access to evidence-based cancer-control planning tools, mentoring and technical assistance, and have the potential to bridge the capacity gap and catalyse better implementation of NCCPs. Challenges can be overcome by better leveraging these opportunities to address the gaps that inhibit cancer control in Africa. Cancer on the African continent is quickly becoming an overt public health crisis due to an aging population and changes in lifestyle, including increased tobacco and alcohol use, rising obesity and physical inactivity. Unchecked, the burden of cancer in low- and middle-income countries will increase by more than 60% by 2030 , plaguinThe World Health Organization (WHO) states that a national cancer-control programme should aim to reduce cancer incidence and mortality and improve quality of life of cancer patients, through a national cancer-control plan (NCCP) that is systematic, equitable and evidence-based . A comprEven with multiple calls for strengthened national cancer-control planning measures, a 2018 analysis of the International Cancer Control Partnership (ICCP) portal shows that a total of only 11 countries (20.1%) in the Africa region have a current NCCP . Given tBuilding on the US government\u2019s domestic engagement in comprehensive cancer-control planning , the US In order to understand the challenges and priorities in cancer-control planning for curriculum development purposes, CGH administered baseline surveys to participants of the 2017 ICCLF (response rate 73%) and 2018 ECHO (response rate 77%), prior to each programme's launch, via Google Forms. The most-often identified challenges and priorities can be seen in Participants identified resource and partner mobilisation for NCCP implementation as two of the leading challenges they face . DespiteAn additional barrier is the organisation of national cancer programmes within ministries of health (MoH). In most African countries, the structure is inconsistent, creating an obstacle to mobilise resources and partners for NCCP implementation. National cancer programmes are, at times, part of the NCD programme under the coordination of a cancer-control officer or an NCD programme officer , a standalone cancer-control programme, or one divided across MoH units .Unlike the global HIV/AIDS response, a centralised pool of financial and technical resources does not exist for cancer and other NCDs. Therefore, MoH technical officers must mobilise resources and engage non-governmental implementing partners as a crucial step for successful NCCP implementation. The suboptimal level of coordination of cancer prevention and control within most ministries of health in Africa means that agreement on priorities, which is necessary for partner and stakeholder engagement, is less efficient and thus, impacts funding for the NCCP.Opportunities to make progress in this critical area are emerging. The increasing number of health economists now working on NCDs can support governments in assessing the cost  and affordability of interventions to prevent and control cancer and other NCDs . The WHOCancer Incidence in Five Continents (Volume XI), only seven population-based cancer registries from six African countries had sufficient data quality and capture [The collection of data to inform NCCP efforts was the top challenge identified by 2017 ICCLF participants . Robust  capture  for inclGovernments across Africa have an opportunity to prioritise and resource population-based cancer registries to enable ministries of health to develop, cost, resource, implement and evaluate NCCPs in a way that truly benefits populations. Nigeria is an example of where sustainable and long-standing cancer registries, coordinated under the Federal MoH, have provided national estimates of the increasing cancer burden which allowed decision-makers to subsequently inform policies and most recently, the National Cancer Control Strategy (2018\u20132022). The ability to prioritise which cancers to address will allow for strategic partner engagement toward effective implementation .A primary challenge for cancer-control planning in Africa, and perhaps the most commonly identified in the literature, is the lack of essential health system capacity and infrastructure needed to prevent, detect and treat cancer , 21. HumThere is growing momentum among medical schools and universities in Africa to develop specialised oncology-related diploma courses and fellowships , 23. WhiCancer-care-focused partnerships such as the Academic Model Providing Access to Healthcare in Eldoret, Kenya, Partners in Health in Butaro, Rwanda, and the Fred Hutchinson Cancer Research Center Partnership with the Uganda Cancer Institute, show how a long-standing commitment to collaboration and partnership , 28 can Lancet Oncology analysis of national cancer-control plans, led by the ICCP, WHO, and Union for International Cancer Control, reveals that the number of plans worldwide has increased and the focus is now on successful plan implementation. The authors cite examples from Africa where planning has led to action, both in cervical cancer screening and in population-based cancer registries [Finally, while this paper is focused on challenges specific to cancer-control in Africa, there are lessons to be learnt globally from similar challenges and solutions in other regions, where building research networks with a focus on implementation science questions to inform effective programming have propelled the effective implementation of national cancer-control plans . Additiogistries . These eReduction in mortality and morbidity from cancer are keys to the attainment of the WHO voluntary global target of 25% reduction in premature mortality from NCDs by 2025 as well as the Sustainable Development Goal target of a one-third reduction in premature mortality from NCDs by 2030. In order to achieve cancer-related global targets, a well-organised and resourced NCCP, guided by accurate data on the burden of cancer and related risk factors, is necessary. Most countries in the region face similar challenges in the development and implementation of an NCCP, including inadequate human, technical and financial resources. Collaborative partnerships increase access to evidence-based cancer-control planning tools, mentoring and technical assistance, and have the potential to bridge the capacity gap and catalyse better implementation of NCCPs. There is tremendous opportunity in the continued support of these kinds of partnerships for cancer-control programmes in Africa.The authors have no conflicts of interest to disclose.This project has been funded in whole or in part with US federal funds from the US National Cancer Institute, National Institutes of Health, and under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services or National Institutes of Health, nor does mention of trade names, commercial products, or organisations imply endorsement by the US government.KD wrote or co-wrote the introduction, background and methods, challenges, and opportunities sections, edited and revised the paper. MKC co-wrote the background and methods, challenges, opportunities, edited and revised the paper. PB wrote or co-wrote the conclusion and background, edited, and revised the paper. ELT edited and revised the paper."}
+{"text": "The linkages between ecosystem services and poverty alleviation, however, are complex and poorly understood. In many cases, gains in well-being have gone hand-in-hand with rising inequalities and increasing vulnerability of the more marginalised to environmental shocks and stresses. The Ecosystem Services for Poverty Alleviation  interdisciplinary research programme aimed to work towards the Sustainable Development Goals2 by giving decision-makers and natural resource users the evidence they need to address the challenges of combining sustainable ecosystem management with poverty reduction. ESPA set out to:The 2005 Millennium Ecosystem Assessmentbuild a strong evidence base on how human use interacts with ecosystem services, and their dynamics and management;develop innovative, interdisciplinary research and methodologies, so decision-makers may predict socio-ecological responses to complex social and economic trends;get research into practice, by engaging with policymakers, practitioners and decision-makers;use international research partnerships to build research capacity around the global South.The scope of ESPA\u2019s research into different dimensions of ecosystem services, and the social and ecological implications of their management, are summarised in This collection highlights a series of ESPA-funded projects contributing original, interdisciplinary datasets and analytical approaches on social-ecological systems in Asia, Africa and Latin America. They cover ecosystems ranging from montane headwater catchments, through arid and semi-arid rangelands, mesic farmlands and wetlands, to coastal deltas, mangrove and island forests. This collection makes available to a wider scientific audience a set of rigorously compiled and carefully curated interdisciplinary datasets characterising interactions in these social-ecological systems. Each dataset offers considerable potential for further analysis both in its own right and in conjunction with new data, not least as baselines for future studies of the impacts of environmental change and interventions. The data descriptor papers presented here fall into two categories. The first focuses on drivers and outcomes of variability and change in the biophysical dimensions of key social-ecological systems, while the second documents the social implications of these changes.et al.3 addresses measurement of the biophysical features underpinning social-ecological systems, in order to inform land use planning and evaluate the impacts of environmental interventions. This paper presents hydrological measurements from multiple paired catchments, encompassing a wide range of ecosystem types and management systems across three major biomes of the Andean montane region  and three countries . By comparing intervention and control sites, the study was able to attribute observed effects to particular land use changes, restoration or water harvesting interventions. Datasets document rainfall, streamflow, and catchment shape, drainage, elevation, topography, soils, land cover and land use, including derived indices of change, under different management approaches, in water yield, water balance, streamflow magnitude, timing and flashiness; and ratio of baseflow to total flow. These data can be used to analyse the impact of human activities on watersheds, and to guide decision-making and governance aimed at reducing poverty.Decision-making and resource-use planning need data on changes in environment, resource availability and use, and on the drivers of those changes. The first paper by Ochoa-Tocachi 4, and free prior informed consent procedures adapted to prevailing literacy and local sensitivities.Beyond documenting the spatial and biophysical underpinnings of social-ecological systems, ESPA set out to establish an evidence base on how different groups of people  are impacted by and respond to changes in their environment. The second, larger group of papers in this collection deals primarily with datasets reporting the lives, livelihoods and wellbeing of local communities in the face of environmental change or intervention. Stakeholder participation is an essential ingredient of this set of papers. All involve in-depth, two-way participation, with local users shaping the ways research questions are formulated and research undertaken, as well as volunteering the information recorded, and validating those data through their feedback. All employ ethics scrutiny of processes for working with local respondentset al.5 use an initial spatial land cover classification, comprising seven dominant production systems in the Ganges-Meghna-Brahmaputra delta: rainfed or irrigated farming, freshwater prawn or saltwater shrimp farming, and riverine, mangrove or offshore systems. Their household survey datasets then form the basis for analysis of multidimensional wellbeing associated with particular farming, fishing or other livelihoods and social-ecological systems.The different studies illustrate a range of approaches in terms of how to conceptualise relationships between local users and ecosystem services, in terms of research design, and in terms of practical purpose. Adams et al.6 apply a classic formal agricultural research experimental design to allow causal attribution. An initially purposive sample design to choose intervention and matching control sites is followed by random sampling stratified by location and involvement in the subsidy programme, drawing on formal lists of farmers. Where formal lists are not available, projects have to undertake baseline surveys to establish sample frames. These baseline datasets are themselves a rich source of possible investigation. For example, the data collected by Bluwstein et al.7 allow for analysis of the change in wealth rank through time for 13578 Tanzanian households, potentially contributing to our understanding of changing prosperity in rural Tanzania. Subsequent in-depth survey sample datasets include a couple of thousand households.In the other papers, household survey datasets are used to evaluate implications of specific ecosystem services interventions, including conservation agriculture and wildlife management areas, and are structured accordingly. In their study of subsidy payments in Malawi, Bell 7 or asset indices); natural resource use practices; livelihoods and income; perceptions of wellbeing and of its change, both through time and with respect to specific interventions; and in one case5 biomedical status ; perceptions of the interventions and of the benefits (or disadvantages) of involvement. Each of these papers represents a useful baseline dataset against which the implications of future environmental change in general and of current environmental interventions in particular can be measured.Different studies all follow similar principles of questionnaire, survey and interview design, building on mixed methods and using qualitative approaches to establish context, identify key issues and variables to be evaluated. Local language issues are addressed in different ways according to circumstances, but all rely on extensive discussion, training and role play to ensure data collectors share the same in-depth grasp of underlying principles, general thrust and specific meaning of individual terms used and questions asked. All consider quality control issues, with built in checks at various stages. The different studies capture different but overlapping sets of key variables according to their research question. All record household demographic composition and socioeconomic status .Publisher\u2019s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations."}
+{"text": "Given a growing body of evidence for the developmental relevance of the perceived experience of aging and for the presence of interindividual variability in the way people experience aging, this symposium examines the determinants and outcomes of various subjective aging constructs. This session will explore the role of various psychological variables in explaining variability in subjective aging experiences. Consequences of various subjective aging concepts on cognitive functioning, emotional and physical well-being will also be discussed. The first two presentations examine Attitudes Toward Own Aging (ATOA). Kornadt, Siebert and Wahl will address the developmental co-dynamics of personality and ATOA across the second half of life. Siebert and Wahl will examine the associations of ATOA with subjective and objective cognitive functioning. The last two presentations focus on awareness of age-related change (AARC). Sabatini, Silarova, Collins, Martyr, Ballard, Anstey, Kim & Clare will present findings from a systematic-review and meta-analysis synthesizing and quantifying associations of awareness of age-related change (AARC) with emotional and physical well-being and cognitive functioning. Finally, Rothermund and de Paula Couto will show how both the experience of positive and/or negative changes (gains and losses) and the presence of positive and/or negative age stereotypes predict individual\u2019s attributions of change to age. This last presentation will also examine how together the presence of change and attribution of change to age predict developmental outcomes. The symposium will conclude with summarizing remarks from the discussant who suggests possible directions for future research on determinants and outcomes of perceived experience of aging."}
+{"text": "This narrative review aimed to identify and categorize the barriers and facilitators to the provision of brief intervention and behavioral change programs that target several risk behaviors among the Indigenous populations of Australia, Canada, and New Zealand.A systematic database search was conducted of six databases including PubMeD, Embase, CINAHL, HealthStar, PsycINFO, and Web of Science. Thematic analysis was utilized to analyze qualitative data extracted from the included studies, and a narrative approach was employed to synthesize the common themes that\u00a0emerged. The quality of studies was assessed in accordance with the Joanna Briggs Institute\u2019s guidelines and using the software SUMARI \u2013 The System for the Unified Management, Assessment and Review of Information.Nine studies were included. The studies were classified at three intervention levels: (1) individual-based brief interventions, (2) family-based interventions, and (3) community-based-interventions. Across the studies, selection of the intervention level was associated with Indigenous priorities and preferences, and approaches with Indigenous collaboration were supported. Barriers and facilitators were grouped under four major categories representing the common themes: (1) characteristics of design, development, and delivery, (2) patient/provider relationship, (3) environmental factors, and (4) organizational capacity and workplace-related factors. Several sub-themes also emerged under the above-mentioned categories including level of intervention, Indigenous leadership and participation, cultural appropriateness, social and economic barriers, and design elements.To improve the effectiveness of multiple health behavior change interventions among Indigenous populations, collaborative approaches that target different intervention levels are beneficial. Further research to bridge the knowledge gap in this topic will help to improve the quality of preventive health strategies to achieve better outcomes at all levels, and will improve intervention implementation from development and delivery fidelity, to acceptability and sustainability. Historical commonalities in colonization, assimilation, and ongoing socio-economic disadvantages have made the Indigenous populations of Australia, Canada, and New Zealand more vulnerable compared to their non-Indigenous counterparts, and they experience higher rates of chronic disease risk factors , 2. FromOf significance, the clustering of such determinants tends to be more prominent in socioeconomically-disadvantaged groups, such as Indigenous populations, and the synergistic interaction of such risk factors has been shown to be responsible for detrimental health outcomes including elevated morbidity and mortality among these population groups , 9. As sThere is, indeed, growing evidence highlighting the effectiveness of multiple health behavior change (MHBC) interventions . Among tTherefore, identifying the barriers and enablers to the successful implementation of these beneficial preventive strategies in the three countries, sharing similarities in Indigenous history, health system governance, constitutional agreements, and recognition from the state or provincial governments , 15, shoThe primary objective of this narrative review was to identify the barriers and facilitators to implementing brief intervention and behavioral change programs that target several risk behaviors among the Indigenous populations of Australia, Canada, and New Zealand, and to portray the current state of knowledge on this topic In addition to the highlighted importance of such lifestyle behaviors in the prevention of chronic disease development, the major focus of this review on lifestyle risk factors was in line with the objective of the Queensland Health Aboriginal and Torres Strait Islander Brief Intervention Training Program (B.strong), developed by Menzies School of Health Research . B.stronPreferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines.The review was undertaken in accordance with the With the assistance of a librarian, six electronic databases were searched: PubMed, Embase, CINAHL, HealthStar, PsycINFO, and Web of Science. The search consisted of keywords and subject headings, the details of which are included in an Additional\u00a0file\u00a0Conduct of the search across the six databases retrieved a total of 741 citations.n\u2009=\u20092). Studies were included if (1) they were published in peer-reviewed journals from 2007 to 2018; (2) they discussed at least one facilitator or barrier in terms of brief intervention implementations that addressed SNP risk behaviours; and (3) they included Indigenous peoples in Australia, Canada, or New Zealand. To ensure rigor and relevance, the selection of interventions was guided by the definition of brief intervention by Nilsen et al. where \u2018brief intervention\u2019 encompasses any preventive, patient-focused, and motivational counselling that is performed by healthcare professionals in short timespans, aimed at changing behavioral risk behaviours [A total of 75 peer-reviewed journal articles was selected following the initial abstract and title screening. An additional hand search of bibliographies of articles retrieved from the search was carried out to identify other relevant publications on the subject  the study population was not exclusive to Indigenous peoples of any of the three countries; or (2) they did not present MHBC programs .The search identified a large gap in brief intervention studies in Canada and New Zealand, although the same definition of brief intervention is used in these countries. Following consultation with Indigenous health researchers in both Canada and New Zealand, two common explanatory themes emerged based on their expert opinion and on our thorough thematic analysis of the selected studies: (1) although many similar programs may run across countries with Indigenous peoples, there is a large gap in academia in terms of research and publication of peer-reviewed evaluations of such interventions; (2) brief intervention programs in Canada appear to be mostly focused on substance abuse and alcohol management programs.Thus, to include relevant findings from those countries, and to address the scarcity of such programs in terms of the type of intervention in Canada and New Zealand, the search also included studies that focused on community-based and/or family-based interventions that met the same inclusion criteria, if the components of the programs were similar to those for brief interventions. Importantly, this decision drew upon the findings of a study highlighting the effectiveness of community-level strategies in targeting SNP risk factors in comparison with individual-level programs among Indigenous populations .Overall, 22 articles met the criteria for full text review. A sensitive and comprehensive review was conducted of these articles by the authors to ensure their rigor and relevance in meeting our review criteria, and this yielded nine articles for the review Fig.\u00a0. StudiesThe quality of studies was appraised in accordance with the Joanna Briggs Institute (JBI) guidelines, and by utilizing the JBI System for the Unified Management, Assessment and Review of Information (SUMARI) .Thematic analysis was used to synthesize findings and a narrative approach was used to present findings in accordance with the JBI guidelines . To enhaTable\u00a0Studies were categorized by the intervention level reported on in the study. Based on the characteristics of the included studies, the three intervention levels were identified as (1) individually-based brief interventions, (2) family-based, and (3) community-based behavioral interventions which targeted more than one of the chronic disease risk factors of smoking, nutrition, and physical activity. The priorities and preferences of Indigenous populations with regard to MHBC strategies were also presented in a separate category as they could be applied to all three intervention levels while also providing insights into the analysis of the barriers and enablers.One study used a mixed-methods approach to evaluate the performance and organizational capacity of health services in delivering brief interventions on smoking, nutrition, alcohol, and physical activity (SNAP) risk factors across four Aboriginal and Torres Strait Islander medical services in Queensland . Study mThis study found significant inconsistencies and poor quality in the recording of SNAP risk factors and their assessment measures in medical charts . In addiAnother study reviewed brief intervention resource kits targeting SNAP risk factors for Indigenous Australians to assess the content and quality of such resources . The stuCanadian research found that family-based collaboration models were effective in improving the health of an individual within a group (a family) . This isIn New Zealand, a health promotion program called REPLACE was developed to improve healthy lifestyles of Maori populations. Hamerton et al. , presentThe approach recognized the large role small lifestyle changes could play in people\u2019s quality of life over time. Process and short-term outcome evaluation of the intervention showed successful changes at individual, family, and community levels. The evaluation method fostered a face-to-face approach among participants, stakeholders, and project coordinators, and qualitative data were collected over a two-year period by means of participant observation, surveys and interviews, holding focus groups, and monthly staff meeting reports . The majThe Vanguard study was a pilot study of a cohort of 160 Maori participants in the New Zealand Maori Community Health Worker (MCHW) intervention, Data collection was conducted both prior to and during the MCHW intervention. The major study was aimed at improving lifestyle risk factors for diabetes . The intn\u2009=\u2009160) showed a significant weight reduction for participants over the course of the intervention (189\u2009days), compared with baseline data. Several facilitators contributed to the high acceptability of this program among the Indigenous population. First, the intervention was promoted through media, cultural events, and by the majority of the community members. The major focus in intervention delivery was on building trust and respecting family and community relationships. The core of the intervention was based on the key \u2018message\u2019 approach - created to set small success points to further improve perceived control over multiple lifestyle changes. Also, the design of the study included determining barriers and solutions to facilitate such changes. The promotion of preferred types of physical activities (identified by the community) was another enabler for the observed success rates of the program. However, conflicts existed in terms of participants\u2019 dietary preferences (higher fat and protein than recommended in guidelines) and their macronutrient components  [The results of the pilot study conducted on the initial study participants (hydrate) .Ngati and Healthy intervention in New Zealand was a community-led diabetes prevention healthy lifestyle intervention program aimed at modifying high risk behavioral factors in areas of physical activity and nutrition: promoting weight loss, increasing exercise and adoption of healthy eating habits over a period of 2\u2009years . The majA Canadian study evaluated the effectiveness of a school-based intervention (Actions Schools! BC) targeting physical activity and nutrition among Indigenous children and youth in three remote Indigenous communities of British Columbia (Canada) . EmployiHealthy Foods North (HFN) was a community-based, multi-institutional intervention to promote healthy lifestyles among the Indigenous populations of the Canadian Arctic (four interventions and two comparison groups in Nunavut and Northwest Territories) . This prA recent Australian cross-sectional study was conducted to identify the determinants of acceptance of MHBC programs for an Indigenous population in Australia. The study had three main objectives: (1) assessing readiness towards high risk lifestyle changes; (2) acceptability of types of MHBC models: synchronously, in a sequence, or separately; (3) preferences for types of support programs, and the socioeconomic determinants responsible for the preferred choices . A totalSurvey results showed that on the client\u2019s readiness to change their lifestyle health behaviors across all risk factors, smoking was the participants\u2019 number one choice for behavior change . Also, tThose who indicated willingness to change at least a single high-risk behavior had a preference for receiving healthcare practitioner help over other types of support, and, in particular, for improving nutrition and physical activity . ReceiviOverall, the findings presented from the reviewed studies highlight the major facilitators and barriers to the implementation of brief interventions that address more than one modifiable risk behavior for chronic disease. Following a thorough thematic analysis, and due to the presence of varying outcome measures for both the quantitative and qualitative data extracted from the studies, the synthesized findings were grouped into four major categories based on the common themes that emerged: (1) characteristics of design, development, and delivery; (2) patient/provider relationship; (3) environmental factors; and (4) organizational capacity and workplace-related factors. To ensure consistency and relevance, the discussion of each theme and sub-theme is supported by data synthesized from the primary studies and their corresponding interventions.To date, in targeting multiple lifestyle modifications, evidence has supported the superiority of behavioral and cognitive methods along with lifestyle counselling over other types of interventions . Some rePriorities and preferences of Indigenous peoples must also be taken into account when considering the target level for a health behavior change intervention. For example, a cross-sectional study that assessed priorities and preferences of Indigenous populations on multiple behavior change found that when Indigenous clients were surveyed about their preferences over the level of support, the majority preferred individual-level supports for SNP health behaviors over family or community level approaches .To analyze the evaluations of design and developmental characteristics of SNAP behavioral interventions among the Indigenous Australian communities, and to assess the interventions\u2019 effectiveness in improving such risk factors, Clifford et al. , conductInvolving communities in the design and planning as pre-implementation steps in developing interventions is a critical factor in ensuring successful delivery and uptake of health promotion programs among Indigenous populations . More spThe Ngati and Healthy intervention, a community-led project which was based on a community development approach and on the collaboration of community health workers and researchers, relied heavily on Indigenous participation and leadership in all phases of the project, including the design and development phase, delivery and implementation . The autHealth promotion programs that are designed and implemented based on Indigenous cultural values have demonstrated higher perceived value among these population groups in targeting behavior change . In addiIn the Vanguard study, the development of intervention constructs based on Maori cultural values, both from the past and the present, was a major contributing factor to the high rate of program acceptability by Maori individuals . FurtherThe quality of design components plays a critical role in enhancing successful implementation . Based oAllocating enough time in primary care visits for health staff to build a relationship with clients can facilitate the delivery of lifestyle brief interventions, and can enhance the assessment of chronic disease risk factors . Both reIn the review of five Canadian community-based interventions for Aboriginal populations including First Nations, Inuits, and Metis, there was no evidence of improved healthy weight outcomes . AlthougIn the HFN project, the results of the study showed that the intervention had a higher impact on healthy eating and behaviors in higher socioeconomic status populations compared with their lower socioeconomic status counterparts . The autIn assessing the organizational capacity of health services to deliver brief interventions for chronic disease risk factors to Indigenous Australians, Panaretto et al. identified several enablers and barriers to the successful delivery of health messages . EnablerOverall, these authors suggest that the barriers could be addressed to a reasonable extent through the development of assessment tools for modifiable risk factors, specifically nutrition and physical activity, along with appropriate training of staff in the delivery of the most recent state of knowledge that is evidence-based on SNAP risk factors, and by adding Adult Health Checks into the routine delivery of care.A process evaluation found that barriers to the implementation of Actions schools! BC included high staff turnover, limited staff knowledge of healthy lifestyle behaviors, and minimal variation in choices. However, the ease of implementation and participant support were potential facilitators of such programs .Despite employing a thorough and systematically-based method in searching databases, it is possible that this review may not have located all relevant Indigenous health promotion brief interventions from Australia, Canada, and New Zealand. The main purpose of this review was to identify the barriers and facilitators to the implementation of brief interventions that target MHBC in areas of smoking, nutrition, and physical activity among the Indigenous populations of Australia, Canada, and New Zealand. Unfortunately, varying outcome measures in behavioral interventions across the different countries limited any higher level or meta-comparison of such interventions. The level of the intervention also varied across different studies, largely due to the inclusion of community- and family-based interventions in addition to behavioral brief interventions.We note that the specific inclusion criteria employed in this review made the limited pool of studies narrower. Firstly, there was a gap in the literature with regards to Indigenous-specific behavioral interventions. Secondly, the fact that the review looked for interventions that targeted multiple risk factors contributed significantly to the narrow body of literature. Thirdly, no brief intervention study targeting nutrition and physical activity was identified in either Canada or New Zealand (to the knowledge of the authors and the experts contacted). All retrieved brief intervention studies in Canada and New Zealand related to addressing substance abuse and addiction . Lastly, the exclusion of grey literature may have significantly limited the retrieved results since many evaluations of health promotion programs and projects are not published in the peer-reviewed literature. This was a common theme suggested by Indigenous health experts contacted throughout the review.In conducting this research, we found a significant gap in the literature for systematic reviews analyzing multiple health behavior change interventions among vulnerable populations. The findings of this review make a contribution to the evidence relating to Indigenous populations in Australia, New Zealand and Canada. Further research is required to evaluate the effectiveness of brief and behavioral interventions for multiple health behavior change for Indigenous populations at different intervention levels. Findings of such research will assist in the development of recommendations and guidelines to inform policy changes and program funding support, and should facilitate the process of effective brief intervention program design, implementation, delivery, and evaluation.This review aimed to identify the enablers and barriers to the implementation of MHBC interventions among Indigenous populations drawing upon evidence from three countries. The high prevalence of chronic disease risk behaviors among the Indigenous populations has stemmed from the interplay of numerous underlying causes including the unique histories of population groups and the range of ecological, cultural and social determinants of health with different levels of impact. These underlying factors can also directly and indirectly hinder the effectiveness of MHBC interventions. Thus, understanding the interrelationships of barriers and facilitators along with their myriad drivers is essential in developing successful preventive health programs. Also, it is important to recognize that, to target successful and sustainable behavior changes in chronic disease risk factors, single-level approaches and interventions are not sufficient. Importantly, based on the findings from this systematically conducted narrative review, MHBC interventions targeting different intervention levels should be optimized by promoting authentic and effective collaboration of different health and educational sectors, organizations, and community members, with a strong emphasis on Indigenous participation and leadership at all stages of program development and implementation. Adding community-based interventions to target chronic disease risk behaviors could improve the outcome and complement the use of individual-based MHBC brief interventions among Indigenous Australian populations . Lastly,Additional file 1. Search Subject Headings and Term Harvesting Table.Additional file 2. PRISMA 2009 Checklist."}
+{"text": "In its 2017 report on the status of tuberculosis in the world, the World Health Organization (WHO) estimated that tuberculosis causes about 1.7 million deaths each year, making it the single leading infectious cause of death [A core mandate of WHO is the development of evidence-based policy for public health interventions . The latClinical Infectious Diseases features a series of papers prompted by the scientific debate in the 2017 WHO expert consultation. The authors explore critical issues of uncertainty in tuberculosis therapeutics, some of them of long-standing. Most of the papers refer to findings from hollow fibre infection models (HFIM), which are increasingly employed to investigate the anti-tuberculosis properties of substances at the preclinical stage to complement the more-conventional tools applied to determine drug/regimen efficacy and safety [WHO convened a technical consultation in Geneva in April 2017 to review the latest data on the pharmacology of those tuberculosis medicines used in MDR-TB regimens . The disThis Supplement includes a set of articles coordinated by the University Medical Center Groningen that review the literature on PK/PD data for mainstay components of second-line MDR-TB regimens. These systematic reviews formed part of the preparation for the WHO consultation in 2017, and provide a useful update on the PK/PD parameters that are best correlated with the performance of amikacin, linezolid, and cycloserine .The other papers analyze data from new or completed studies, often employing novel approaches. In 2 separate articles, Deshpande et al  and SrivThe exciting new findings in tuberculosis pharmacology and the novel investigative techniques reported in this Supplement are relevant to the continued development of new medicines, both in pre-clinical and clinical studies. Artificial intelligence could help identify complementary medicinal combinations and dosages to optimize the composition of candidate regimens ahead of the start of trials. In clinical practice, PK/PD knowledge is likely to bring the prospect of precision medicine in public health within closer reach of more patients worldwide, especially if linked to drug discoveries and concurrent advances in diagnostics, therapeutics, and digital technologies. The optimization of drug dosages and treatment schedules for drug-resistant tuberculosis require more scientific debate, along with fresh data of better quality from patients receiving treatment. Therapeutic drug monitoring (TDM) may be relevant to MDR-TB care, due to the narrow therapeutic index and inter-patient variation in PK/PD of fluoroquinolones, injectable agents, linezolid, and other second-line tuberculosis medicines. TDM may become more feasible in resource-limited settings with the addition of advancements in specimen transportation and analytic methods based on mass spectrometry. However, the added value of different TDM strategies on clinical outcomes still needs to be confirmed and quantified.The conclusions made in the papers of this Supplement do not represent WHO recommendations on the use of the medicines, or an endorsement of experimental medicines, regimens, dosages, or new methods of diagnosis. Nevertheless, in the absence of a more robust evidence base from trials and other studies, these PK/PD updates may help researchers to optimize their efforts and inform health care practitioners to assist them in making better decisions in the clinical management of tuberculosis. This information also serves as a valuable background to the ongoing updates being made by WHO to its MDR/RR-TB treatment policies ."}
+{"text": "Background: The expert panel that conducted the Assessing Surgical Site Infection Surveillance Technologies (ASSIST) project elaborates on the key findings of the health technologies assessment (HTA) report in a series of articles addressing topics from workflow challenges to implementation strategies to new big data analytics tailored to incorporate serial patient-generated health data (PGHD).Conclusion: By reporting on the methodology, with an emphasis on stakeholder engagement, the ASSIST investigators provide the basis for a future deep dive into the next phase of PGHD integration into surgical site infection (SSI) surveillance. Star Trek are now second nature to digital natives, who bring their own devices to healthcare with the expectation that providers will review patient-generated health data (PGHD) and engage via new communication channels. It is now possible to offer expanded, personalized care to patients after surgery, using new data streams and data types via mobile devices to facilitate remote patient monitoring. One of the most compelling use cases for post-operative mobile health  tracking is the triage of surgical sites for evidence of surgical site infection (SSI) through review of serial incision photography and symptom reporting.The adoption of smartphones, texting, and patient portals for post-operative care coordination present both challenges and opportunities to the surgeon. Real-time communications that were once the fantasy of Dick Tracy and Although the current standard of care for SSI diagnosis requires in-person physical examination of the surgical site, patient-generated photographs are increasingly submitted to and reviewed by surgical providers via e-mail, text messaging, and electronic health record-based patient portals. Although the current use of telemedicine for post-discharge surgical care has been reviewed systematically, the specific use of mHealth for SSI surveillance and the process of work associated with this activity is highly variable and generally unacknowledged in the medical literature. In September 2017, the Safety and Healthcare Epidemiology Prevention Research Development (SHEPheRD) program [www.cirg.washington.edu/assistPSAGreport [In year one, the ASSIST investigators completed a literature review and a landscape analysis of apps directed specifically at post-operative incision monitoring. Through this initial work, the group also developed a network of stakeholders  and conducted key informant interviews to gain additional perspective on real-world use. In May 2018, the group hosted a one-day Patient-Generated Health Data Stakeholder Advisory Group workshop to seek feedback from key opinion leaders on the findings from the HTA process. A report from this workshop is available online at AGreport .Surgical Infections, the expert panel that conducted the ASSIST project elaborates on the key findings of the HTA report in a series of articles addressing topics from workflow challenges to implementation strategies to new big data analytics tailored to incorporate serial PGHD. Acknowledging the rapid development cycle used in design and deployment of mHealth apps, the ASSIST investigators concede that any report from a defined period of time can best be regarded as a biopsy, as the field continues to grow unabated. Even since the conclusion of the project, new clinical trials of mHealth apps for post-operative care have been presented [In this special issue of resented  and publresented , and a cresented .The number of mHealth apps increases exponentially each year, and as new apps emerge, older ones may mature and expand or regress into the past with little usage or impact on patient care. Furthermore, some of the apps reviewed may never advance to commercialization, remaining research endeavors for their whole lifespan. But these orphan apps have value, in that the process of development, the features contained, and the implementation trials all frame lessons for future app design, integration and dissemination. Additionally, the data collected can serve as fuel to drive innovation in analytic methods and to incorporate PGHD, especially incision images, into the clinical and surveillance definition standards for SSI. Finally, by reporting on the methodology, with an emphasis on stakeholder engagement, the ASSIST investigators provide the basis for a future deep dive into the next phase of PGHD integration into SSI surveillance.Heather Evans, Medical University of South Carolina; William Lober, University of Washington; Danielle Lavallee, University of Washington; Sheri Chernetsky Tejedor, Emory University, Centers for Disease Control; E. Patchen Dellinger, University of Washington; Traci Hedrick, University of Virginia, Shuai Huang, University of Washington; Dan Pollock, Centers for Disease Control and Prevention; Aven Samareh, University of Washington; Robert G. Sawyer, Western Michigan University; John Semple, University of Toranto; Jyotirmay Sharma, Emory University; Elizabeth Wick, University of California San Francisco; Jenney Lee, University of Washington; Sarah Lawrence, University of Washington."}
+{"text": "Elder mistreatment (EM) and the magnitude of its relationship to anxiety may vary depending on definitional criteria. We leveraged data from the PINE Study, a study of 3,157 Chinese older adults in Chicago. EM was measured by 56 items on psychological, physical and sexual mistreatment, caregiver neglect and financial exploitation subtypes. Least restrictive, moderately restrictive, and most restrictive definitions of EM were constructed. Symptoms of anxiety were measured by the Hospital Anxiety and Depression Scale. Least restrictive , moderately restrictive , and most restrictive  definitions of EM were all significantly associated with the likelihood of experiencing any anxiety symptoms. The magnitude of associations between EM and anxiety symptoms vary based on strictness of the EM definition. Future research should explore the potential causal relationships between EM and anxiety through longitudinal data."}
+{"text": "Cystic echinococcosis (CE) is endemic in many regions of Central Asia putting up almost 58% of population at risk including areas of Mongolia, Kazakhstan, Kyrgyzstan, Tajikistan, Turkmenistan, Uzbekistan, Afghanistan, Iran, Pakistan and western China . PakistaCystic Echinococcosis (CE) is responsible for over US$ 3 billion in expenses globally every year , and theIn Pakistan, lack of research data at molecular and epidemiological level of CE necessitates more focus on this area of research. To best of our knowledge, published data to date show 1611 CE cases in humans from different cities of Pakistan. These published reports are mostly based on data obtained from different areas of the country . There iLimited epidemiological data on CE impedes in devising effective management strategies for its control. Recently a useful ultra-sound-based study of latent CE and AE cases in rural parts of Romania, Bulgaria, and Turkey  was reported which adds to the knowledge of global epidemiology of these diseases  consisting of 13 countries was established in Chengdu, China in 2017 , but unfMost of the population in Pakistan lives in rural area with unhygienic life styles. If such increasing burden of the disease is left un-checked, it would pose greater threat to animal and public health. The international research cooperation is a needed act of time to combat and root out this silently evolving neglected tropical disease. The seriousness of issue needs to be addressed by international community to make a point for effective control strategies on regional and global level."}
+{"text": "Non-invasive detection of urothelial cancer through the analysis of driver gene mutations and aneuploidy. Published 20, March 2018The affiliation of Luis A Diaz was incorrect. The correct affiliation is: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States. In addition, Luis Diaz would like to declare the following for his competing interests statement:Luis A Diaz (LAD) is a member of the board of directors of Personal Genome Diagnostics (PGDx) and Jounce Therapeutics. LAD holds equity in PapGene, Personal Genome Diagnostics (PGDx) and Phoremost. He is a paid consultant for Merck, PGDx and Phoremost. LAD is an inventor of licensed intellectual property related to technology for ctDNA analyses and mismatch repair deficiency for diagnosis and therapy from Johns Hopkins University. These licenses and relationships are associated with equity or royalty payments to LAD. The terms of all these arrangements are being managed by Johns Hopkins and Memorial Sloan Kettering in accordance with their conflict of interest policies. In addition, in the past 5 years, LAD has participated as a paid consultant for one-time engagements with Caris, Lyndra, Genocea Biosciences, Illumina and Cell Design Labs.The article has been corrected accordingly."}
+{"text": "For more than 40 years, under the leadership of four editors and two publishers, The International Journal of Aging and Human Development (IJAHD) has featured multidisciplinary scholarship related to aging processes and older adults. With the publication of eight issues a year, with over 800 pages of scientific content, the IJAHD places emphasis upon psychological and social studies of aging and the aged. However, the Journal also publishes research that integrates observations from other disciplines that illuminate the \"human\" side of gerontology. A more recent focus includes midlife development, as well. About half (47%) of the publications in the IJAHD are from international colleagues. This presentation will discuss tips for both international and US-based scholars for ensuring timely reviews and positive decisions for manuscript submissions, including such areas as key words, suggesting unbiased reviewers, formatting, writing mechanics, clearly-articulated methods, and a sound theoretical basis."}
+{"text": "Furthermore, populations of African ancestry are substantially under-represented in global research of neuropsychiatric genetics.10 Training events, online courses, and workshops have provided unprecedented learning strategies for medical, bioinformatics, and public health education in LMICs. However, most of the existing training components are often developed without input from prospective trainees, not specifically focused on neuropsychiatric genomics, and convened over a restricted time period. Therefore, a tailored approach, wherein researchers from the targeted populations continuously participate in defining neuropsychiatric training needs, might add value to the established methods through ensuring ownership and effectiveness of research training programmes.To date, advancements in neuropsychiatric genetics research in sub-Saharan Africa have been limited by low capacity\u2014funding availability, appropriate infrastructure, and qualified researchers are under-represented in African institutions compared with counterparts in high-income countries (HICs). To improve representation of African institutions in neuropsychiatric genetics research, researchers and funding bodies should prioritise projects involving collaborations between institutions in HICs and LMICs that contain a capacity-building component. Initiatives such as Human Hereditary and Health in Africa (H3Africa), the International Brain Research Organization (IBRO), and the Wellcome Trust Developing Excellence in Leadership, Training, and Science Initiative (DELTAS) programme have been invaluable in building these collaborations and in providing genomics-related research training opportunities for researchers from African institutions.The Global Initiative for Neuropsychiatric Genetics Education in Research (GINGER) programme seeks to address these limitations. GINGER is a collaboration between the Stanley Center for Psychiatric Research at the Broad Institute of Massachusetts Institute of Technology and the Harvard T H Chan School of Public Health, and several academic institutions in sub-Saharan Africa . Comprising 17 investigators from these countries, GINGER aims to enhance the capacity of neuropsychiatric genetics research in Africa by training early-career researchers in genetics analysis, psychiatric phenotyping, epidemiology, bioinformatics, biostatistics, ethics, and manuscript and grant writing.A unique feature of the 2 year GINGER programme is the active participation of the fellows and African mentors in selection of programme topics on the basis of the individual and collective needs of the fellows and their host institutions. Intra-African networking and collaborations are strongly encouraged to expand the training and capacity-building of the first GINGER cohort and to contribute to innovative research driven by African investigators. Furthermore, the initiative seeks to increase the awareness of key stakeholders and policy makers about the burden of neuropsychiatric disorders in sub-Saharan Africa.The first cohort of GINGER fellows aims to establish an interdisciplinary group of African researchers, with the potential for sustainability beyond GINGER. Through continued conversations, skills building, and collaborative efforts between African institutions, this group will be equipped to produce first-class research equal to that produced in HICs. This Comment, therefore, serves as a call to action to develop and reaffirm the relationships needed to study neuropsychiatric genetics research in Africa. Improved characterisation of the prevalence and molecular causes of neuropsychiatric disorders in Africa might lead to development of population-specific and individual-specific treatment methods. These discoveries might ultimately improve global health-care strategies."}
+{"text": "As America ages, an increased interest has been placed on understanding the development and maintenance of autonomy in later life. This is of particular importance given the impact of autonomy on vitality, well-being, and mood within older adults . However, the research examining which aspects of autonomy directly impact successful aging remains underexplored. As such, the current study utilizes the Functional Autonomy Measurement System (SMAF) to better understand which facets of autonomy promote life satisfaction in older adults. Data included assessments of the Functional Autonomy Measurement System and data was derived from the Survey of Midlife in the US Database (MIDUS 3). Participants were primarily White/Caucasian (88.7%) and female (54.0%); with a mean age of 63.64 years (SD=11.35). A series of hierarchical multiple linear regressions revealed that higher levels of Mental Functions predicted increased life satisfaction scores in models adjusted for age, sex, race, marital status, and education  and that higher levels of Communication , Activities of Daily Living , Mobility , and Instrumental Activities of Daily Living  also predicted increases in life satisfaction scores but to a lesser extent. The present findings suggest that higher levels of autonomy, both physically and mentally, result in higher satisfaction with life; with perceptions of cognitive independence producing the highest levels. Implications of the current findings include increased understanding of the multifaceted nature of autonomy, and provision of recommendations which could increase autonomous behavior in later life, thus increase life satisfaction and promote successful aging."}
+{"text": "Researchers, practitioners and policymakers are daily confronted with multiple and competing situations regarding vulnerable older adults and the complex issues that they face in all aspects of their lives. Challenges can arise in the provision of social services, dispensing justice, conducting research, or addressing legal issues. The purpose of this symposium is to discuss dilemmas that vulnerable older adults and concerned others face by elucidating current and future challenges facing this population, particularly in the realms of compromised health (cognitive impairment); effective status (gender); care arrangements (home and community-based services); and abuse, neglect, and exploitation. Teaster and Anetzberger discuss relevant ethical theories and principles as well as a definition of vulnerability. Santos and Nichols-Hadeed report on ethical issues embedded in vulnerable elders\u2019 cognitive status. Bowland and Halaas highlight the intersection of ethics, gender and vulnerable elders. Niles-Yokum and Beaumaster discuss the nexus of ethics and the provision of home and community based services for vulnerable older adults. Heisler considers vulnerabilities of older adults and ethical challenges when addressing elder abuse. Throughout the papers, we weave the ethical principles of autonomy, beneficence, nonmaleficence, and justice."}
+{"text": "Countries in East Asia have the largest aging population in the world. The consequences of aging largely depend on whether it is accompanied by a healthy, active, and high-quality life. This symposium aims to gain a better understanding of aging support and determinants of health in the contexts of two major East Asian countries - China and Japan. We will present new research using data from the Fukui Longitudinal Caregiver Study (FLCS) in Japan, and two most important aging surveys in China \u2013 the China Health and Retirement Longitudinal Study (CHARLS) and the Chinese Longitudinal Healthy Longevity Survey (CLHLS), addressing critical topics including retirement, family care, social mobility, and mortality. Song and Smith investigate the impact of hukou change on mental health in later life. Zang examines the effect of a man\u2019s retirement on his wife\u2019s mental and physical health in China. Zhang et al. explore the determinants of mortality in China by conducting a comprehensive analysis of life-course conditions, community characteristics, biological and physical functioning, and disease burden. Zeng et al. compare demographic, socioeconomic, behavioral characteristics and health phenotypes of centenarians in China and Italy. Wakui et al. focus on the emergence of compound caregiving and the relationship of caregiving status to burden, depression, and social support in Japan. The cross-national comparisons will be informative regarding aging in various contexts. We will discuss the potential for further investigations using population-based aging data from different countries."}
+{"text": "This thematic issue on advanced simulation tools applied to materials development and design predictions gathers selected extended papers related to power generation systems, presented at the XIX International Colloquium on Mechanical Fatigue of Metals (ICMFM XIX) organized at University of Porto, Portugal, in 2018. Guest editors express special thanks to all contributors for the success of this special issue\u2014authors, reviewers, and journal staff. Fatigue damage represents one of the most important degradation phenomena which structural materials are subjected to in normal industrial operation, which may finally result in a sudden and unexpected failure/fracture. Since metal alloys are still the most used materials for the design of the majority of components and structures intended to carry out the highest service loads, the study of the different aspects of metals fatigue still attracts the permanent attention of scientists, engineers, and designers.The first International Colloquium on Mechanical Fatigue of Metals (ICMFM) was organized in Brno, Czech Republic in 1968. Afterwards, regular Colloquia on Mechanical Fatigue of Metals started in 1972 also in Brno and were originally limited to participants from the countries of the former \u201cEastern Block\u201d. They continued until the 12th Colloquium in 1994 at Miskolc, Hungary, every two years. After a break twelve years long, the Colloquia restarted in 2006 at Ternopil, Ukraine, followed by the ones in 2008 , 2010 , 2012 , 2014  ,4. The XThis special issue approaches the thematic about the limits of the current generation of materials, which are continuously being reached according to the frontier of hostile environments, whether in the aerospace, nuclear, or petrochemistry industry, or in the design of gas turbines where efficiency of energy production and transformation demands increased temperatures and pressures . At the -Environmental assisted fatigue;-Multi-damage/degradation;-Multi-scale modeling and simulation;-Micromechanics of fracture;-Material defects evolution;-Interactions of extreme environments;-Microstructure-based modeling and simulation;-Fracture in extreme environments;-Probabilistic physics of failure modeling and simulation;-Probabilistic optimization;-Advanced testing and simulation;-Life prediction and extension;-Stochastic degradation modeling and analysis;-Low- and high-cycle fatigue;-Artificial intelligence methods.This issue collects selected papers from ICMFM XIX  related This section addresses in brief the scientific papers published in this thematic issue on advanced analytical and numerical simulation approaches applied to materials development and design predictions about power generation systems.Zhang\u2019s group from the Harbin University of Science and Technology, Fudan University and Northwestern Polytechnical University (China) developed a fuzzy multi-extremum response surface method (FMERSM) for the comprehensive probabilistic optimization of multi-failure/multi-component structures, where the probabilistic fatigue/creep coupling optimization of turbine bladed disks was implemented\u2014the rotor speed, temperature, and density as optimization parameters, and the creep stress, creep strain, fatigue damage, and creep damage as optimization objectives .Duda, Pach, and Lesiuk  presenteKotch et al.  from theLiu et al.  suggesteOther study related to the influence of thermal\u2013structural coupling on the blisk low-cycle fatigue life reliability analysis was introduced by Zhang et al. , where tNormally, fatigue crack growth relations are usually presented by using a linear-elastic stress intensity factor range, \u0394K. Lesiuk , from th2O, and PF5 adsorbed on Cu(111) and the geometric parameters of the admolecules were confirmed after structure optimization [Chen et al. group from the Changsha University of Science and Technology and Guangxi University (China) presented a scientific work entitled by first-principles study on the adsorption and dissociation of Impurities on Copper Current Collector in Electrolyte for Lithium-Ion Batteries, where the stable configurations of HF, Hmization .Luo et al. research team applied an innovative surface technology, laser shock peening (LSP), to the dual-phase TC11 titanium alloy to fabricate an amorphous and nanocrystalline surface layer at room temperature, for the ultrahigh strain-rate plastic deformation .Xie et al.  have preFinally, a Polish\u2013Portuguese team  presenteGuest Editors for this thematic issue are pleased with the final result of the published papers and hope that these scientific works can be useful to researchers, engineers, designers, and other colleagues involved in different thematic aspects of the advanced analytical and numerical simulation approaches applied to materials development and design predictions about power generation systems.Additionally, the Guest Editors would like to express gratitude to all authors for their contributions and to all reviewers for their generous work that is fundamental in the dissemination of the scientific finding.Finally, the Guest Editors would also like to express special thanks to the Editorial Board of Materials international journal for help, support, and patience and for their exceptional contributions during this time."}
+{"text": "The NIA/NCI ASPREE (ASPirin in Reducing Events in the Elderly) Study was a landmark RCT of 19,114 healthy adults aged 70 (whites) and 65 (US minorities) in Australia and the US that demonstrated lack of effect of low dose aspirin (LDA:100 mg/d) on the novel primary end point of Disability- Free Survival (life free of disability and dementia) over a mean treatment of 4.7 years. Surprisingly, LDA was associated with a trend toward increased all cause mortality, driven by cancer deaths (results published NEJM September 2018). After the LDA intervention was halted in June 2017, ASPREE was extended as an observational cohort follow-on study, ASPREE-XT, to measure potential delayed LDA effects on ASPREE outcomes. The ASPREE study primary results will be summarized, and the rationale for and performance of the novel DFS geriatric outcome discussed. New results of the analysis of dementia as a secondary outcome will also be presented . We will also examine the unexpected increased all-cause mortality attributed to cancer deaths, despite no significant difference between groups for all incident cancer, and effects of LDA on incident metastatic disease. The important implications of the ASPREE results for prescribing LDA for primary prevention in health elderly will be discussed, and the ASPREE-XT study design and progress described. Lastly, the breadth of the ASPREE sub-studies including the Biobank, Brain Imaging studies and Genomics, and opportunities to access the rich ASPREE data and collaborate with ASPREE investigators will be reviewed."}
+{"text": "Clock gene.Investigators from Children\u2019s National Medical Center, Wenzhou Medical University, Virginia Tech, University of Colorado, University of Virginia, Georgetown University, University of Maryland, and Brown University performed transcriptome analysis on human epileptogenic tissue and extended the investigation by creating and testing mouse lines with targeted genetic deletions of the  Clock gene.Investigators from Children\u2019s National Medical Center, Wenzhou Medical University, Virginia Tech, University of Colorado, University of Virginia, Georgetown University, University of Maryland, and Brown University performed transcriptome analysis on human epileptogenic tissue and extended the investigation by creating and testing mouse lines with targeted genetic deletions of the Bmal1) had been previously shown to alter seizure threshold in mice, the authors of this article evaluated the expression of the Clock gene  in brain tissue from patients with intractable epilepsy. They found decreased CLOCK protein in epileptogenic tissue as compared to control tissue. Next, they generated mouse lines with deletion of Clock in cortical excitatory neurons  and found that these mice showed diminished seizure threshold and their excitatory neurons exhibited spontaneous epileptiform discharges. The authors also noticed that flox/floxEmx-Cre;Clock mice have defects in dendritic spines similar to spine defects seen in human epileptogenic tissue and that neurons from both the mutant mice and human tissue show decreased spontaneous inhibitory post-synaptic currents.Because one of the genes that make up the molecular mechanism of the circadian clock .If the loss of The author(s) have declared that no competing interests exist."}
+{"text": "PageBreak11th European Congress of Entomology. Maurizio Biondi  and Michael Schmitt  co-organised the Naples meeting and worked together with Caroline S. Chaboo  in the editorial committee for RoC8.Volume 8 of Research on Chrysomelidae (RoC8) presents again examples of the attractiveness and the diversity of Chrysomelidae (sensu lato) as subjects of scientific research. The seven papers included here cover taxonomy, ecology, faunistics as well as phylogenetics. Four of these papers  are extended versions of talks presented to the Third European Symposium on the Chrysomelidae, held on 5 July, 2018, in Naples, Italy within the frame of the As with the previous RoC volumes, the team at Pensoft Publishers , especially Yordanka Banalieva, did a wonderful job and made the co-operation of editors and publishers a relaxed and rewarding experience. The editors thank our counterparts at Pensoft for this harmonious collaboration. The editors also thank all authors who submitted their high-quality manuscripts and so made this volume another important contribution towards the science of leaf and seed beetles.th International Symposium in Helsinki (Finland) in 2020 and the 4th European Symposium on Crete (Greece) in 2022. The proceedings of these symposia along with submitted papers on Chrysomelidae sensu lato will be published in subsequent volumes of Research on Chrysomelidae, as special issues of ZooKeys.The series of symposia on Chrysomelidae will continue with the 10Michael Schmitt, Caroline S. Chaboo, Maurizio Biondi"}
+{"text": "The number of males diagnosed with prostate cancer (PCa) is increasing all over the world . Most paGenerally, well-differentiated PCa cells are androgen-dependent, i.e., androgen receptor (AR) signaling regulates cell cycle and differentiation. Loss of AR signaling after ADT triggers androgen-independent outgrowth, generating poorly differentiated, uncontrollable PCa cells . Once PCDepartments of Nephro-Urologic Surgery and Andrology (Professor Emeritus Yoshiki Sugimura) and Oncologic Pathology (Professor Emeritus Taizo Shiraishi), Mie University Graduate School of Medicine, organized the semi-closed symposium on Biology of Prostate Gland Ise-Shima. This symposium was started in 2002 and was held every four years in 2006, 2010, 2014, and 2018 without any financial support from pharmaceutical companies and chemical industries. Each year, the symposium was attended by 40\u201350 Japanese investigators with expertise and interest in biology of the prostate gland and PCa. The goal of this symposium was to discuss the biological mechanism of the development and progression of prostatic proliferative diseases such as benign prostatic hyperplasia (BPH) and PCa. Several major topic areas were discussed, e.g., the pathophysiology of BPH, the tumor microenvironment of PCa, AR signaling in PCa progression, and the development of PCa detection and diagnosis. This Special Issue includes the major topics discussed at the symposium in 2018.In this Special Issue, we focused on cytobiology of human PCa cells and its clinical applications to develop a major step towards personalized medicine matched to the individual needs of patients with early-stage and advanced PCa and CRPC. We hope that this Special Issue attracts a lot of attention for readers with expertise and interest in the cytobiology of human PCa cells and its clinical applications."}
+{"text": "With the life expectancy in China continuing to increase, age-dependent chronic diseases are also likely to increase, as is the number of people with long-term care needs. This study evaluated the Long Term Care (LTC) needs of the Chinese older population and introduced related policy priorities. Using the 2014 and 2016 \u201cChina Longitudinal Aging Social Survey\u201d, this study assessed the physical functions of older adults by measuring their ability to perform Activities of Daily Living independently, compared changes within the two years, and explored other related indicators including, Instrumental Activities of Daily Living, major chronic disease, and mental health conditions. The study also discussed the development of long-term care policies in China and highlighted the priorities of these policies."}
+{"text": "Journal of Ovarian Research [Pursuant to a decree of the Tribunal of Catania, First Civil Section, LJ Pharma SRL obtained an ex Parte order. The Judge orders BioMed Central Ltd, in the person of the legal representative pro tempore to implement the remedy of the retraction notice on the study, signed by Isabella and Raffone, \u201cDoes Ovary need d-chiro-inositol?\u201d, published in 2012 in the specialized journal"}
+{"text": "Healthcare Technology Letters (HTL) journal dedicated to the joint edition of the 8th Medical Imaging and Augmented Reality (MIAR), the Augmented Environments for Computer-Assisted Interventions (AE-CAI), and the 6th Computer Assisted and Robotic Endoscopy (CARE) workshops. We are pleased to present the proceedings of this exciting scientific gathering held in conjunction with the Medical Image Computing and Computer-Assisted Interventions (MICCAI) conference on October 13th, 2019 at in Shenzhen, China.Welcome to this Special Issue of the IET's Over the past several years, the satellite workshops and tutorials at MICCAI have experienced increased popularity. This year's workshop brings together three communities that joined forces back in February 2019 in light of our common interests in image guidance, navigation and visualization for computer-assisted interventions. MIAR / AE-CAI / CARE 2019 is a joint venture between the prestigious Medical Imaging and Augmented Reality (MIAR) workshop series founded in 2002, the series of MICCAI-affiliated workshops on Augmented Environments for Computer-Assisted Interventions (AE-CAI) founded in 2006 and featured annually ever since, and the Computer Assisted and Robotic Endoscopy (CARE) workshop series, now on its 6th edition. This year's edition of the workshop received 30 submissions and reached over 60 registrants, not including the members of the organizing and program committees, making MIAR/AE-CAI/CARE one of the best received and best attended workshops with more than a decade-long standing tradition at MICCAI 2019.Computer-Assisted Interventions (CAI) is a field of research and practice, where medical interventions are supported by computer-based tools and methodologies. CAI systems enable more precise, safer, and less invasive interventional treatments by providing enhanced planning, real-time visualization, instrument guidance and navigation, as well as situation awareness and cognition. These research domains have been motivated by the development of medical imaging and its evolution from being primarily a diagnostic modality towards its use as a therapeutic and interventional aid, driven by the need to streamline the diagnostic and therapeutic processes via minimally invasive visualization and therapy. To promote this field of research, our workshop seeks to showcase papers that disseminate novel theoretical algorithms, technical implementations, and development and validation of integrated hardware and software systems in the context of their dedicated clinical applications.The objective of the joint workshop has been to attract scientific contributions that offer solutions to the technical problems in the area of augmented and virtual environments for computer-assisted and robotic interventions to provide a venue for dissemination of papers describing both complete systems and clinical applications. The workshop attracts researchers in computer science, biomedical engineering, computer vision, robotics, and medical imaging.The workshop featured a single track that consisted of long and short oral presentations showcasing original research engaged in the development of virtual and augmented environments for medical image visualization and image-guided interventions. To foster networking and discussion, we also provided all authors with the opportunity to present their work as a poster in addition to their oral presentation slot.Healthcare Technology Letters journal. This year's joint workshop received 30 manuscripts spanning a strong geographic representation from Europe, North America and Asia. The review process was rigorous and involved evaluation of each manuscript by three to five external reviewers. Following the first stage of review, sixteen manuscripts were further considered for major or minor revision, and resubmission. Authors were required to submit a response to reviewers and resubmit a revised manuscript that addressed all reviewers\u2019 critiques.All manuscripts submitted to the joint MIAR / AE-CAI / CARE 2019 were held up to journal standards, as the ultimate objective was to publish accepted work in this Special Issue of the IET's Once revised, all resubmitted manuscripts entered a second round of review conducted by the Program Committee, Workshop Chairs, as well as the HTL Managing Editor and Editor-in-Chief to ensure that all reviewers\u2019 critiques were properly addressed in the revised manuscripts and that the quality of the manuscript was appropriate for journal publication. All manuscript were then accepted for publication and forwarded to the journal for production and publication.In addition to the contributed papers, we were pleased to welcome Dr. Kensaku Mori \u2013 Professor in the Graduate School of Informatics and Director of the Information Technology Center at Nagoya University \u2013 who spoke on the development and use of artificial intelligence for endoscopic procedures.On behalf of the MIAR, AE-CAI and CARE 2019 Program and Organizing Committee, we would like to extend our sincere gratitude to all authors, presenters, and attendees for their scientific contribution, enthusiasm, and support. We also extend special thanks to all reviewers for providing detailed and timely critiques of the submitted manuscripts. We also acknowledge the support we received from the MICCAI 2019 Workshop Committee, and the HTL Editorial Office for their dedication to maintaining the high quality of the workshops, and for selecting outstanding manuscripts that fostered exciting discussions at the meeting.Northern Digital Inc. (NDI) for their continued support over the years, and we also welcome and thank Intuitive Surgical as a new sponsor for our workshop. Our sponsors\u2019 generous contributions have enabled us to recognize our authors for their much deserved dedication and scientific enthusiasm through several paper awards. A big thank you on behalf of all awardees and once again, sincere congratulations to all award winners! The award-winning papers appearing in this Special Issue are listed below!et al. Development and Face Validation of Ultrasound-Guided Renal Biopsy Virtual TrainerAndinet Enquobahrie et al. A Marker-less Real Time Intra-Operative Camera and Hand-Eye Calibration Procedure for Surgical Augmented RealityMegha Kalia et al. Determining blood flow direction from short neurovascular surgical microscope videosReid Vassallo et al. An Augmented Reality Mastectomy Surgical Planning Prototype using the HoloLensSara M. S. Amini et al. Learning colon centerline from optical colonoscopy, a new way to generate a map of the internal colon surfaceMohammad Ali Armin et al. A deep learning approach for automatic out-of-plane needle localization for semiautomatic ultrasound probe calibrationLeah Groves Last but not least, we acknowledge our generous sponsors. We thank We hope that you will enjoy reading this Special Issue and we look forward to your continuing support and participation in future editions of the MIAR, AE-CAI & CARE workshops. Their continued success demands our ongoing commitment.Cristian A. Linte, Rochester Institute of Technology, United StatesXiongbiao Luo, Xiamen Medical University, ChinaJonathan McLeod, Intuitive Surgical, United StatesZiv Yaniv, National Institutes of Health and TAJ Technologies, United StatesElvis C. S. Chen, Western University, CanadaMarta Kersten-Oertel, Concordia University, CanadaHongen Liao, Tsinghua University, ChinaYuan Zhang, University of Jinan"}
+{"text": "With an ever-increasing human population size, increasing human impacts on the natural environment, and a growing scarcity of freshwater resources, the study of freshwater systems has become one of the most critical areas of focus for environmental scientists. Never before has there been such a need for an integrated understanding of lakes, wetlands, and flowing waters. This understanding must cross the boundaries of traditional disciplines, reach a wide international audience, and strongly facilitate the linkage between scientific discovery and its real-world application."}
+{"text": "Journal of the Belgian Society of Radiology (JBSR), issued for the annual symposium of the BSR, again honors our PhD grant recipients. These highly graduated individuals present themselves and summarize their long-standing work and academic careers. In this article the summaries of their doctoral theses are available on the site of the JBSR: https://www.jbsr.be/.In 2017\u20132018, the Belgian Society of Radiology (BSR) continued its efforts to close the gaps of knowledge and disseminate new concepts in radiology. This year\u2019s special number of the Rodrigo Salgado was born on December 8, 1971, in Independencia (Santiago), Chile. After secondary school, he graduated in 1993 with a degree in computer engineering. That same year, he started his medical studies at the University of Antwerp, graduating in 2000 (cum laude). From 2000 to 2005 he fulfilled his radiology residency under supervision of Prof. Dr. A. De Schepper and Prof. Dr. P.M. Parizel at the Antwerp University Hospital.After his residency, he achieved a staff position in 2005 at the radiology department of the University Hospital Antwerp, chaired by Prof. Dr. P.M. Parizel. During the following decade, and continuing through the present, he specialized in non-invasive cardiovascular imaging using CT and MR. Currently, he\u2019s a consultant radiologist at the Antwerp University Hospital and a staff member at Heilig Hart Hospital Lier.Insights into Imaging and the International Journal of Cardiovascular Imaging. In the past, he has been a member of both the executive and scientific board of the BSR. He is the editor of the ESR publication on the International Day of Radiology 2018 (Cardiac Imaging), and congress president of the ESCR 2019 Congress which will be held in Antwerp, 24\u201326 October 2019. Dr Salgado presented and defended an original PhD thesis in 2017 at the Antwerp University entitled, \u2018Non-invasive Imaging for Cardiovascular Interventions: An Evolving Paradigm\u2019.Dr. Salgado is an active member of the Belgian Society of Radiology (BSR), the European Society of Radiology (ESR), and the European Society of Cardiovascular Radiology (ESCR). He is currently the elected president of the non-invasive cardiovascular imaging section of the BSR and member of the executive board of the ESCR, in which he is also chair of the Communication and New Media committee. He is member of the European Congress of Radiology (ECR) 2018, 2019, and 2020 scientific subcommittees for cardiac imaging, and serves on the scientific editorial board of Radiology, Investigative Radiology, European Radiology, European Heart Journal, JACC Cardiovascular Imaging, and the International Journal of Cardiovascular Imaging. He won the Young Investigator Award (YIA) at the Society of Cardiovascular Computed Tomography (SCCT) 2016 conference, Orlando, Florida (2016), with a presentation entitled \u2018CCTA Reproducibility of Coronary Plaque Volume: Sample Size Implications for Clinical Trials\u2019. He has been awarded an NIH and Research Foundation Flanders (FWO) grant for his research. The goal of his research is to use state-of-the-art cardiovascular magnetic resonance (CMR) and emerging cardiovascular computed tomography (CCT) technology to elucidate the relationship between epicardial coronary flow, microvascular dysfunction, clinical risk factors, and adverse left ventricular (LV) remodeling in patients with coronary artery disease (CAD). The unique tissue characterization capabilities of CMR allow for a non-invasive assessment of microvascular obstruction (MVO) and intramyocardial hemorrhage (IMH), two markers of microvascular damage. These CMR markers could be used to improve the short- and long-term prognostication of patients after myocardial infarction. Second, emerging spectral dual-energy and photon-counting CCT technology may allow for a more detailed and reproducible assessment of both epicardial blood flow and myocardial perfusion due to a substantial improvement in tissue characterization capabilities, lower image noise, and higher spatial resolution.Rolf Symons completed his medical degree at the KU Leuven in 2013 (highest distinction and felicitations of the jury). During his residency in radiology, he completed his PhD in 2018 in a joint project between the University Hospitals Leuven and the National Institutes of Health (NIH)/Johns Hopkins University (JHU) for a dissertation entitled \u2018The Role Of State-of-the-Art and Emerging Non-Invasive Imaging Techniques in Improving Risk Stratification in Patients with Coronary Artery Disease\u2019 with promotor Jan Bogaert, MD, PhD, and David A. Bluemke, MD, PhD. He authored 28 publications in international peer-reviewed journals and two book chapters with more than 30 presentations at international conferences, including RSNA 2016, 2017, and 2018. He is an active member of the Radiological Society of North America (RSNA), Society of Cardiovascular Computed Tomography (SCCT), and Belgian Society of Radiology (BSR) and a reviewer for numerous journals including"}
+{"text": "The Biological Resource Centre for the Environment BRC4Env is a network of Biological Resource Centres (BRCs) and collections whose leading objectives are to improve the visibility of genetic and biological resources maintained by its BRCs and collections and to facilitate their use by a large research community, from agriculture research to life sciences and environmental sciences. Its added value relies on sharing skills, harmonizing practices, triggering projects in comparative biology, and ultimately proposing a single-entry portal to facilitate access to documented samples, taking into account the partnership policies of research institutions as well as the legal frame which varies with the biological nature of resources. BRC4Env currently includes three BRCs: the Centre for Soil Genetic Resources of the platform GenoSol, in partnership with the European Conservatory of Soil Samples; the Egg Parasitoids Collection (EP-Coll); and the collection of ichthyological samples, Colisa. BRC4Env is also associated to several biological collections: microbial consortia , terrestrial arthropods, nematodes , and small mammals. The BRCs and collections of BRC4Env are involved in partnership with academic scientists, as well as private companies, in the fields of medicinal mining, biocontrol, sustainable agriculture, and additional sectors. Moreover, the staff of the BRCs is involved in many training courses for students from French licence degree to Ph.D, engineers, as well as ongoing training. The BRCs of AgroBRC-RARe are grouped in five pillars according to the origin of their resources: animal/crop/forestry/micro-organisms/environment. AgroBRC-RARe is registered on the French national roadmap for Research Infrastructures.Conserving and ensuring the availability of genetic and biological resources, particularly for the purposes of research, conservation of biodiversity, education, and economic valorization, are today major societal and scientific challenges, mainly faced by Biological Resource Centres (BRCs). In that context, AgroBRC  is a network of BRCs and collections hosted by several French research institutions INRA , IRD (Institut de Recherche et D\u00e9veloppement), CIRAD , and CNRS , as well as associated to technical and higher education institutions. The leading objective of BRC4Env is to improve the French and European visibility of biological resources maintained by its BRCs and to facilitate their use by a large research community, from agriculture research to life sciences and environmental sciences. Its added value relies on sharing skills, harmonizing practices, triggering projects in comparative biology, and ultimately proposing a single-entry portal to facilitate access to documented samples, taking into account the partnership policies of research institutions as well as the legal frame which varies with the biological nature of resources .Since late 2015, the pillar \u201cBiological Resource Centre for the Environment\u201d BRC4Env . Currently, BRC4Env includes three BRCs: the Centre for Soil Genetic Resources of the platform GenoSol in partnership with the European Conservatory of Soils Samples, the Egg Parasitoids Collection EP-Coll, and the collection of ichthyological samples, Colisa. BRC4Env also comprises other biological collections including microbial consortia , terrestrial arthropods (insects and mites), nematodes , and small mammals Table . These Bhttps://www.brc4env.fr/Associated-platforms) in biochemistry: Biochem-Env in Versailles .The network develops interactions with analytical platforms for the characterization of samples  of the platform GenoSol provides a national BRC for soils unique in Europe for the storage and conservation of genetic resources (DNA) and making them available to the scientific community. Most of the stored soil samples come from soil survey networks , environmental research observatories , long-term experimental sites (within French and European networks), and networks of farms. All these sites are involved in scientific questions concerning the environmental assessment of soil uses and management, as well as the impact of global changes. The platform GenoSol is a strategic tool to supply these sites in the long term and monitor soil biodiversity.The Centre for Soil Genetic Resources  with the possibility to store soils from non-European countries granted by a quarantine agreement. The GenoSol platform has all the laboratory facilities needed for molecular biology studies in the service \u201cLaboratory of Molecular Analysis and Development.\u201d Indeed, the CSGR will provide DNA extracted from soil sample rather than soil itself, as soil quantity is limited (ca 50\u00a0g per sample). In consequence, the CSGR of GenoSol needs to routinize and automatize DNA extraction from sample in order to provide good-quality DNA.https://www.brc4env.fr/BRCs-and-collections/Environmental-matrices/CEES) hosted by the US1106 InfoSol in Orleans, in the frame of the French Network of Measurement of Soil Quality . The CEES stores an archive of French soils collected within the national soil survey and monitoring programs coordinated by the French Soils Scientific Interest Group (GIS Sol). This collective infrastructure is also supporting French and European research programs and Research Infrastructures such as ICOS, with inputs in expertise and support on sampling strategies and methods, sample collection, preparation and archiving, supply of samples to research programs, and partner analysis laboratories. The first sampling campaign of RMQS occurred from 2000 to 2009 and corresponded to 20,000 samples from 2200 sites. The second sampling campaign began in 2016 and will finish in 2027.GenoSol performs its activities in partnership with the European Conservatory of Soils Samples  or restricted storage (access restricted to the soil owner).https://www.brc4env.fr/BRCs-and-collections/Invertebrates/Arthropods/EP-Coll) aims to collect, characterize, maintain, investigate, and share egg parasitoids\u2019 strains, these organisms being useful for biological control, applied entomology, and evolutionary ecology.The Egg Parasitoids Collection  the conservation of living collections and (ii) the management of strains\u2019 transfers, the activities of the BRC are (iii) the collection of new strains (species and/or populations); (iv) the characterization of these individuals using morphological, molecular, phenotypic, and ecological criteria; (v) the optimization of sampling, rearing, and management methods; and (vi) the optimization of phenotyping methods.https://www6.paca.inra.fr/institut-sophia-agrobiotech/Infrastructure-PlantBIOs)), with greenhouses and controlled environment chambers for carrying out in vitro and in situ experiments, with official agreement for the manipulation of quarantine insects and nematodes, and all the laboratory needed for morphological and molecular biology studies.The BRC is deposited at the UMR1355 Institut Sophia AgroBiotech (ISA) in Sophia Antipolis, France. ISA is a research laboratory which benefits of an original collective scientific infrastructure PlantBIOs , and thermal biology including the development of a prototype for the evaluation of some key parameters.https://www.brc4env.fr/BRCs-and-collections/Vertebrates/Colisa) results from the merging of historical samples collected by three INRA units  and by FBA  as part of the AFB-INRA Pole \u201cGest\u2019aqua.\u201d These samples come from long-term monitoring and research activities conducted by these units and from a national catch declaration scheme .The historical collection of fish scales and tissues  that have occurred.http://golo.cirad.fr). The network BRC4Env, the CSGR of GenoSol, EP-Coll, and Colisa have been labelled as BRCs by the French organism IBiSA.The network BRC4Env and its BRCs and collections implement a quality management according to the INRA Quality Framework v2 for optimized functioning, continual improvement, and stakeholder satisfaction. They plan to move to national (NF S 96-900) or international (ISO 9001:2015) certification in the next 2\u00a0years. Numerous BRCs and collections ensure the traceability and planning of their animation activities using the software AQ-tools developed by CIRAD , by providing temporal set of samples to scientists  holds more than 900 strains . Microalgae and especially Diatoms are known to be excellent indicators of aquatic ecosystem pollution Rimet . This coTrichogramma pour la protection des cultures: Pang\u00e9nomique, Traits d\u2019histoire de vIe et Capacit\u00e9s d\u2019\u00e9tablissement) aims at characterizing the inter- and intra-specific diversity of the Trichogramma species at several levels of investigation .Trichograms of the BRC EP-Coll are relevant biological models for eco-evolutionary investigations and constitute a reservoir of candidate strains (species/populations/genotypes) for biocontrol  of the INRA metaprogram SMaCH  relies on a part of this Arthropods Collection: sequenced specimens, studied morphologically, preserved with their DNA for traceability purposes The samples of the collection Colisa, carrying DNA, allow genetic characterization of wild fish individuals or population. Via microchemistry, these samples allow to characterize the trophic status and the environmental conditions of life of these animals The Plant-parasitic Nematodes Collection of BRC4Env has been the support of various collaborative European research programs. For example, the pinewood nematode collection has been instrumental in the achievement of some objectives of the FP7/EU-project REPHRAME . Together with additional field sampling, these biological resources have been used to characterize the genetic diversity of nematode populations from both the native and the invaded areas, and to infer the worldwide routes of invasion of the parasite Haemonchus contortus populations, one of the most deadly livestock parasitic nematodes . The molt of this collection towards a more formal BRC has been recently initiated.The collection of animal parasitic nematodes has been established 30\u00a0years ago. It has originally been dedicated to ruminant trichostrongylid to delineate the genetic basis of anthelmintic resistance (Silvestre and Humbert 8)Leptospira, Tatard et al. Trypanosoma, Diagne et al. The CBGP Small Mammal Collection, including specimens (skins and/or skulls) and their corresponding samples , and the Small Mammal Database gathering all the associated information have been the support of a number of studies over the last years. Among others, we may cite the description of the invasion of Senegal by the house mouse , BRCs and collections of BRC4Env will determine the legal status of their accessions and consequences for their introduction and distribution, regarding the Access and Benefit Sharing as well as French and European policies. A case study based on soil samples will be developed during the project, because these resources are not well characterized at the time of sampling in terms of taxonomy.The main objective of BRC4Env is to develop the Information System of the network, currently constituted by shared tools and distributed services among BRCs, by making these tools interoperable and relevant regarding the Nagoya policy. A specificity of BRC4Env is the hosting of living collections of invertebrates. The Information System must provide and share information concerning sampling, rearing, phenotyping and molecular data, and barcoding. Here, we plan to set the following requirements: (i) centralization and standardization of metadata concerning the resources, (ii) secure storage and confidentiality by controlled access, (iii) tools to perform queries (in partnership with applications to be developed by AgroBRC-RARe). A common database for registering the projects hosted by the BRCs of the network will be developed.The Information System of BRC4Env will offer shared information dedicated to the resources hosted by its BRCs. It will also promote and contribute to make easier the access, storage, archiving of datasets, and their subsequent valorization, and provide to end-users access to the productions of the network  by subscription to News and RSS feed. Experience gained in other pillars of AgroBRC-RARe in these fields will be used in order to optimize the functional specificities of our IS and to select the most relevant technical solution.Internal practice harmonization. Considering the diversity of BRCs and collections, the network will encourage practice harmonization for improved management and enhanced traceability of its activities within its BRCs and make available a comprehensive set of harmonized procedures. One main objective is the introduction (if necessary), the development, and the support for a common process-based quality management system for continual improvement and stakeholder satisfaction. Taken together, these actions will facilitate the sharing of experience and the identification of best practices within the BRCs and collections of the network. Sharing experience will then make possible to define a common policy for BRC and collections functioning, charters for sample and data access, relationships between BRCs and private partners\u2026Valorization of the activities of the BRCs. The network will produce scientific and perspective papers , illustrating the research questions that a better and beneficial coordination between BRCs can help to tackle, as well as the scientific and technical support they can provide to end-users. The network promotes also the production by the BRCs and collections of technical papers valorizing their expertise and know-how. It will also produce and support an action plan for attending national and relevant international conferences and workshops to increase its national and international visibility.BRC4Env shares two main other objectives in the next future.BRC4Enc is a network structuring the BRCs dedicated to environmental resources in France. It is currently seeking for similar networks of BRCs in Europe and worldwide to be a French component of international networks. Today, environmental resources are mainly taken into account in environmental specimen banking. BRC4Env can offer a frame to host samples and collections specifically addressing ecotoxicological issues."}
+{"text": "The European Board & College of Obstetrics and Gynaecology has initiated improvement of the European standards of training in Obstetrics and Gynaecology through the project called \u2018EBCOG-PACT\u2019. In this project, a pan-European curriculum for postgraduate training in Obstetrics and Gynaecology has been developed. The curriculum is societally responsive, and based on the latest medical educational methodology. It consists of the description of outcomes of training for the common Core Curriculum and Electives, the General competencies and soft skills to be trained, and strategies for training of obstetrical skills, gynaecological skills, ultrasound skills and bio-psychosocial and communicative skills. Also, the curriculum provides strategies for assessment through entrustment, a model for portfolio as well as strategies for faculty development and quality management of training. The implementation of the European curriculum in Obstetrics and Gynaecology will provide opportunities for national scientific and professional societies and ministries of health or education to consider modernisation of national or local OBGYN training programs. In the ever more internationalising world of today, with increasing mobility of both patients and doctors, training of the gynaecologist of the future requires high quality curricula that allow for continuous improvement and modernisation. Therefore, the European Board & College of Obstetrics and Gynaecology (EBCOG) has taken up the task to initiate improvement of the European standards of training in Obstetrics and Gynaecology (OBGYN) through the project called \u2018EBCOG-PACT\u2019 (Project for Achieving Consensus in Training). In this project, a pan-European curriculum for postgraduate training in OBGYN has been developed, which is societally responsive, and based on the latest medical educational methodology.Three main reasons clarify why development of a pan-European curriculum in OBGYN, and therefore European harmonisation of training, is needed . PrimariThe PACT project has been executed in close collaboration between European gynaecologists, trainees, educationalists, change managers, midwives, specialized nurses, hospital board members, and last but not least, patient representatives. It was recognised as a valuable strategic partnership for improvement of European higher education by the European Commission, and therefore was awarded an \u2018Erasmusplus\u2019 grant. Partners in this project represented four highly-renowned medical institutions from Denmark, Italy, Czech Republic, Belgium and the Netherlands, as well as organisations representing the societal stakeholders.The project ran between September 2015 and September 2018 and has resulted in several outcomes. The curriculum consists of the description of outcomes of training for the common Core Curriculum and Electives, both developed through a (Delphi) consensus procedure amongst European gynaecologists and trainees . BesidesThe curriculum has been translated and is currently available in seven different languages  with two additional languages soon to follow . Also, several national scientific societies have initiated translation of the curriculum in their national language .https://www.uems.eu/areas-of-expertise/postgraduate-training/european-standards-in-medical-training). We are convinced that the implementation of the European curriculum in OBGYN will provide opportunities for national scientific and professional societies or ministries of health and education to consider modernisation of national or local OBGYN training programs.The UEMS council has officially adopted the curriculum as the European Training Requirements (ETR) in the field of Obstetrics and Gynaecology ("}
+{"text": "A meeting and course supported by the Vice-Presidency for International Affairs of the Spanish National Research Council (CSIC) and the National Agricultural Research Organization of Uganda (NARO) were held at the National Livestock Resources Research Institute (NaLIRRI) in Nakyesasa, Wakiso, Uganda on September 2\u20139, 2019. The activities were conducted within the collaboration program between the Institute of Game and Wildlife Research  and NARO for the development of vaccines and other interventions for the control of cattle ticks in Uganda. Theileria parva), babesiosis (caused by Babesia bigemina), anaplasmosis , and heartwater (caused by Ehrlichia ruminantium), that affect cattle production in Uganda [Tick-borne diseases (TBDs), such as East Coast fever , in coordination with the Government of Uganda and stakeholders , proposeRhipicephalus microplus BM86 or BM95 recombinant antigens and registered in Cuba and Australia in the early 1990s [Antitick vaccines constitute an environmentally sound intervention with demonstrated efficacy for the control of cattle ticks and TBDs ,14. The ly 1990s ,15. Thesly 1990s ,14,15. Ily 1990s . Despitely 1990s . The collaboration between the Institute of Game and Wildlife Research (IREC) and the National Agricultural Research Organization of Uganda (NARO) for the development of vaccines to control cattle tick infestations began with P. D. Kasaija\u2019s arrival at our laboratory at SaBio, IREC to enroll in the Ph.D. program at the University of Castilla, La Mancha in Spain and during the visit of NARO executives to IREC in September 2018 -based vaccine for the control of cattle tick infestations in Uganda. As stated in the letter by the General Director of NARO, Ambrose Agona, the objectives were (i) understanding the institutional framework that supports successful vaccine production, (ii) identifying the best practices in livestock vaccine production, (iii) identifying infrastructural and human resources requirements for vaccine production, and (iv) establishing a lasting partnership and linkages between NARO and IREC for the development, registration, and production in Uganda of a cattle tick vaccine. Bos indicus and crossbred cattle in Uganda, Rhipicephalus appendiculatus, Rhipicephalus decoloratus, and Amblyomma variegatum. Vaccination trials with systemic and oral vaccine formulations are currently ongoing at NaLIRRI with the participation of the Ph.D. student enrolled in the Ph.D. program at the University of Castilla, La Mancha in Spain. This is the first time that vaccines based on SUB antigens are being tried to successfully control multiple cattle tick species. A second meeting between NARO management and IREC representatives was conducted at NaLIRRI in September 5, 2019 to discuss preliminary results of ongoing vaccination trials and future strategies for the control of tick-borne and other diseases affecting cattle health and production in Uganda  was discovered in 2002 , and sinAs part of the project, a course was prepared to address the objective of developing the infrastructure and human resources required for the control of ticks and TBDs and vaccine production. The course was intended to build scientific capacity at the NaLIRRI in Uganda at both theoretical and laboratory practical levels and to implement a multidisciplinary approach for the control of infectious diseases affecting humans and animals in Uganda . A speciTick infestation and tick-borne diseases such as anaplasmosis and piroplasmosis are ranked high among the most important cattle diseases for poverty reduction and global trade. However, the list is much longer, including other relevant shared infections such as foot-and-mouth disease (FMD), Rift Valley fever (RVF), brucellosis, and tuberculosis (TB). Often, these shared infections are regarded as \u201cdouble-burden diseases\u201d, the control of which would benefit both human and animal health and livestock production and trade .Mycobacterium bovis and other closely related members of the Mycobacterium tuberculosis complex (MTC). It is a typical multihost shared infection present worldwide in a wide range of domestic  and wild  maintenance hosts [Syncerus caffer) and the widespread warthog (Phacochoerus africanus) [One of these priority double-burden diseases is animal TB, caused by ce hosts . It is kce hosts . Howeverce hosts . Regardice hosts , and 14%ce hosts . In Uganricanus) . TherefoM. bovis as an immunostimulant in oral vaccination against ticks [The ongoing trials of cattle tick vaccines might provide an opportunity for animal TB control in Uganda. Cattle enrolled in field trials could be tested for TB, possibly using alternatives to the traditional skin test, such as serology, in order to enable single-sampling protocols and facilitate diagnosis in remote regions . Other lst ticks . Given the key role of cattle in Africa as a safety net and a ladder out of poverty, it is important to maximize the contribution of research activities on livestock disease control to global health, wealth, equity, and sustainability .In Uganda, several arthropods are vectors of pathogens of medical and/or veterinary relevance, with mosquitoes and tsetse flies ranking highest as vectors for human pathogens and ticks having a massive impact on livestock production. R. decoloratus being less plastic than the three-host ticks A. variegatum and R. appendiculatus. However, all three species of ticks of relevance for cattle in Uganda can parasitize wild mammals, such as wild bovids, suids, lagomorphs, hedgehogs, carnivores, and small rodents, and a high number of wild bird species [Tick species differ in their host selection plasticity, with highly specialized one-host ticks such as  species ,29, as w species . Despite species ,32. Oura et al.  highlighConsequently, Uganda faces a potentially increasing wildlife\u2013human conflict to preserve the biodiversity that attracts tourists and supports the services sector of the country, which accounts for 50% of the GDP. Fighting ticks of cattle with acaricides and antitick vaccines would aid but not solve the conflict, which could only be solved by increasing scientific knowledge with a One Health approach that includes humans, livestock, wildlife, and ecosystems together to understand the ecology of ticks and tick-borne pathogens. This would allow designing effective and environmentally friendly prevention and control strategies in the future to control tick infestations and TBDs of cattle in Uganda. This was one of the main topics of the course at NaLIRRI, which was intended to build scientific capacity and increase concern about wildlife as relevant in the life cycle of ticks and tick-borne pathogens in Uganda.Exposure to cattle ticks or acaricides such as organophosphates account for pediatric poisonings in rural Uganda  and toxiThe uncontrolled use of this acaricide may lead to environmental damage in aquatic ecosystems, acaricide resistance in ticks, and a possible exacerbation of TBDs . AlthougTherefore, the correct use and application of the most appropriate and effective acaricides, which was recently proposed as one of the key measures to prevent economic losses caused by ticks and TBDs in the cattle industry in Uganda , should The control of ticks and TBDs constitutes a priority for the Government of Uganda to promote economic growth in the country. This challenge requires a multidisciplinary approach to combine different control measures that range from cattle management and the rational use of acaricides to antitick vaccine development and application. Collaboration between research institutions leading research in these areas with those located in the most affected countries is necessary to achieve these goals. The ongoing collaboration project between IREC and NARO is focused on developing and implementing the production and application of SUB-based vaccines for the control of cattle tick infestations in combination with other control interventions. Controlled pen vaccination trials are currently ongoing. Future directions will include (i) characterization of protective immune response in cattle and vaccine antigen design, (ii) development and evaluation of oral vaccine formulations, (iii) building of vaccine production facilities at NARO, (iv) field trials with effective antitick vaccine formation, (v) characterization of animal TB epidemiology and future control options, (vi) study of the ecology and epidemiology of vector-borne diseases for effective control and prevention, and (vii) application of veterinary toxicology approaches to reduce the detrimental effects of acaricides and other compounds on human and animal health and cattle production."}
+{"text": "These processes include investigation of bioavailability to assess to what degree and how fast compounds are absorbed after drug administration, elucidation of metabolic pathways, and elimination routes and their kinetics, as well as the interactions of HMPs with synthetically derived drug products. Due to the complex chemical composition of HMPs, the absorption, distribution, metabolism, and excretion characteristics of the bioactive or toxic HMPs remain to be further explored. The difficulty lies primarily in the selection of appropriate biomarkers for detection, quantification of trace constituents, identification of potential drug-drug interactions, and the discovery of active constituents based on metabolic results.Herbal medicinal products (HMPs) are expected to be safe and effective. Nevertheless, evidence-based verification of the safety and efficacy of HMPs is still lacking. Understanding the metabolic profile and In this special issue, investigators contribute original research articles and review articles that would facilitate the understanding of the basic mechanisms as well as the development of new and promising complementary and alternative strategies for the metabolic profiling and pharmacokinetics of HMPs.Integrating pharmacokinetics is a crucial tool to identify the therapeutic agent. The research article by C. Zhang et al. elucidated the pharmacokinetic profiles and disposition kinetics of the administered and generated stereoisomers in the brain and cerebrospinal fluid (CSF) after oral administration of Isorhynchophylline (IRN) and Rhynchophylline (RN). The results demonstrated that, after oral administration, RN showed significantly higher systemic exposure and disposition in the brain and CSF than IRN, indicating that RN would be more appropriate to be developed as a potential therapeutic agent for the treatment of AD.In technology, ultrahigh-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) is still the most popular tool for the pharmacokinetics study of HMPs. The research article by Y. Fu et al. established a simple, sensitive, and reliable UPLC-MS/MS method for quantifying pinosylvin in rat plasma, urine, feces, and various tissues. Nine metabolites of pinosylvin were found in plasma, and glucuronidation, hydroxylation, and methylation proved to be its main metabolic pathways. Sophora flavescens extract with cytochrome P450 (CYP) isoforms in human liver microsomes. The result showed that S. flavescens and its prenylated flavonoids caused significant herb-drug interactions when coadministered or incubated with substrates of CYP2B6, CYP2C8, CYP2C9, and CYP3A4. The research article by N. Temyingyong et al. determined the effect of short-course oral ciprofloxacin on isoflavone pharmacokinetics in healthy postmenopausal women. The results showed that ciprofloxacin administration significantly reduced the absorption of the aglycones of genistein and daidzein.There are many factors affecting the pharmacokinetics of HMPs, among which herb-drug interaction has been frequently studied. The research article by D. Yim et al. examined the selective interaction ofDrug formulation and administration route also significantly affect the pharmacokinetics of HMPs. The research article by P. Smyk et al. elucidated the influence of propolis on ion channels, channels location in cell membrane, and electrical resistance of skin. In this work, a model skin of Ussing chamber proved to be useful for studying the effect of chemicals on transepidermal ion transport.Finally, in addition to herb-drug interaction, the review article by S. Sun et al. summarized other important factors that affect the clinical practice of HMPs, such as herb pretreatment, herb-herb interactions, pathological status, gender, age of patients, and chemical and physical modification of certain ingredients. in vitro and in vivo studies as well as the literature review related to the objective of this special issue.Thus, this special issue included different aspects related to the recent advances in metabolic profiling and pharmacokinetics of HMPs, based on various"}
+{"text": "Skin pigmentation represents one of the most peculiar traits of human beings and its alteration as a consequence of pathological conditions has a dramatic impact on the wellness of individuals and their social relationships. Therefore, the possibility of controlling pigmentation by intervention at the different stages of the melanogenic process has represented over the years a most important research target, with many implications for the dermatological and cosmetic fields. One way of reaching such a goal is an in-depth knowledge of the genetics of pigmentation, the mechanism of activation of the melanocortin receptor 1 (MC1R) and the signaling cascade, and finally the expression and trafficking of melanogenic enzymes. In this regard, it is timely that Del Bino et al. [Most of the papers and review articles appeared in this issue provide a contribution along two main lines, that is, a) unraveling hitherto unappreciated aspects of the complex melanogenesis machinery, or b) identifying new compounds or natural extracts with the ability to suppress or stimulate melanogenesis and elucidating their mechanism of action. N-glycosylation occupancy, incorporating the two metal ions and acting on two different steps of melanogenesis, that is, Cu(II) to acquire 5,6-dihydroxyindole-2-carboxylic acid (DHICA) oxidase activity, or Zn(II) to acquire tautomerase activity. Of particular interest is the review paper by Solano , which rN-acetyltransferase 10, so far considered as a valuable target for cancer and laminopathies, was shown to play a role also in melanogenesis and melanoma growth through regulation of microphthalmia-associated transcription factor (MITF) [In Oh et al., r (MITF) . The evor (MITF) . The posr (MITF) . In Campr (MITF) . Oroxylum indicum seeds) [Polygonum tinctorium flower extract [A series of compounds exhibiting a broad structural diversity have also been investigated for their antimelanogenic activity by much different mechanisms of action, ranging from direct inhibition of tyrosinase, as reported for thiazolyl resorcinols  or lipoym seeds) , Bamboo m seeds) ), conditm seeds) , or syntm seeds) , phenylhm seeds) ). It shom seeds)  used humm seeds) , Polygon extract ).New strategies for melanogenesis stimulation are presented based on the use of low frequency  or pulseThe case of rhododendrol, a skin-whitening ingredient that was reported to induce leukoderma, was reviewed by Ito and Wakamatsu . This prFinally, the opportunities opened by knowledge of the different chemical reactivity of the two major indole intermediates of melanogenesis, 5,6-dihydroxyindole (DHI) and DHICA, for cosmetic purposes were illustrated through examples in the field of hair dyeing and photoprotection . A uniquIn conclusion, the research contributions presented in this issue clearly illustrate how investigation of the basic facets of the melanogenetic process and insight into the mechanism of action of natural and synthetic compounds may offer a valuable tool for the design of efficient and selective strategies for the control of hyperpigmentary disorders or melanin stimulation as required in vitiligo. In this regard, the current status of clinical and molecular aspects of vitiligo treatments is discussed by Bishnoi and Parsad ."}
+{"text": "These include accelerated literature searches, analysis and prediction of physical and quantum chemical properties, transition states, chemical structures, chemical reactions, and also new catalysts and drug candidates. The generalization of scalability to larger chemical problems, rather than specialization, is now the main principle for transforming chemical tasks in multiple fronts, for which systematic and cost-effective solutions have benefited from ML approaches, including those based on deep learning . The latter class of ML algorithms is capable of combining raw input into layers of intermediate features, enabling bench-to-bytes designs with the potential to transform several chemical domains. In this review, the most exciting developments concerning the use of ML in a range of different chemical scenarios are described. A range of different chemical problems and respective rationalization, that have hitherto been inaccessible due to the lack of suitable analysis tools, is thus detailed, evidencing the breadth of potential applications of these emerging multidimensional approaches. Focus is given to the models, algorithms and methods proposed to facilitate research on compound design and synthesis, materials design, prediction of binding, molecular activity, and soft matter behavior. The information produced by pairing Chemistry and ML, through data-driven analyses, neural network predictions and monitoring of chemical systems, allows (i) prompting the ability to understand the complexity of chemical data, (ii) streamlining and designing experiments, (ii) discovering new molecular targets and materials, and also (iv) planning or rethinking forthcoming chemical challenges. In fact, optimization engulfs all these tasks directly.Computational Chemistry is currently a synergistic assembly between  Patterns are ubiquitous in Chemistry. From the crystalline structures of solid forms to the branched chains of lipids, or the complex combinations of functional groups, chemical patterns determine the underlying properties of molecules and materials, essential to address important issues of societal concern. Artificial Intelligence (AI), and machine learning (ML) in particular, are committed to recognizing and learn from these patterns  understanding and controlling chemical systems and related behavior  approaches can also be particularly useful to solving a variety of chemical problems, including compound identification and classification, and description of soft matter behavior  are critical challenges, that may, however, facilitate the routine implementation of data mining in chemistry and expedite new discoveries.The amount and quality of chemical data generated by experiments and simulations have been the mainstay of the new data-driven paradigm, that establishes the bridge between theory, experiment, computation, and simulation.This review describes, in a critical and comprehensive way, relevant contributions carried out recently and involving the development of chemistry ML approaches. An exhaustive account of the theoretical foundations and applications published in the early years of AI and ML in Chemistry falls beyond the scope of this review. The reader is referred to Lecun et al. , CoveneyUntil 10 years ago, only a few 100 studies on the use of ML in Chemistry were published, resulting from the contributions made over four decades. In 2018, ca. 8,000 articles in the Web of Science database included these keywords, corresponding to an increase in ca. 35% for just one decade. In this review, there is room to mention only a small fraction of these applications.Despite the increasing number of works on the topic, the models proposed and practices carried out by chemists are entailing serious concerns  to be able to quickly identify areas that have benefited most from the development and implementation of ML approaches, and those that still lack of such an optimization, as evidenced by the type of outcome, (ii) to identify the most relevant ML outcomes in each sub-field, and (iii) to assess the dynamics of ML outcomes over the 2008\u20132019 period and how these are related, giving rise to relevant research trends.machine learning, type of outcome and the sub-field in which they co-occur . A total of 5,279 contributions  on ML in Chemistry, with 81,248 citations, and published between 2008 and June 30, 2019, are found in the worldwide Web of Science database, corresponding to a 4-fold increase over the previous four decades. Considering the compiled data and the selected Chemistry fields , nine different ML outcomes embracing the most frequent chemical challenges are defined, including (i) text mining and system description, (ii) quantitative structure-activity/property relationships, (iii) DFT functionals and interatomic potentials, (iv) generative models and inverse molecular design, (v) molecular screening, (vi) synthesis/characterization of new compounds and materials, (vii) catalytic technologies, (viii) analytical techniques, and (ix) quantum models, algorithms, and quantum sensing. Note how these have a strong relation with the seven overall applications presented above (i\u2013vii).An extensive literature search on ML contributions in 30 Chemistry sub-fields is carried out, using a global set of 270 co-occurring keywords, each composed of three main terms, The heatmap represented in The natural clusters generated from the most important co-occurring relationships are also identified. Considering the dendrogram for the Chemistry sub-fields, it can be observed that these are organized in two main groups, which discriminates, in general, classical Chemistry sub-fields  from analytical and biochemical sub-fields. This structure suggests a significant similarity in the type of ML outcomes within each group. Group 1 have benefitted from a significant production on catalytic technologies, DFT functionals and interatomic potentials, quantum models and quantum sensing. The most representative ML outcomes in group 2 are associated to text mining, analytical techniques, generative models and inverse design, molecular screening, structure activity relationships, and synthesis of new compounds and materials. Examination of the similarity between the type of ML outcomes reveals that there are three main groups, corresponding to (i) text mining, analytical techniques, generative modes and inverse design, and molecular screening (group 1), (ii) structure-activity relationships and synthesis of new compounds and materials (group 2), and (iii) catalytic technologies, DFT functionals and interatomic potentials, and quantum models and quantum sensing (group 3).ab initio approaches. However, the computational cost inherent to these classical approximations have limited the size, flexibility, and extensibility of the studies. Larger searches on relevant chemical patterns, have been successfully conducted since several research groups have developed ML models and algorithms to predict chemical properties using training data generated by DFT, which have also contributed to the increase of public collections of molecules coupled with vibrational, thermodynamic and DFT computed electronic properties  , shown in Other strong correlations are found between generative models & inverse design and the two abovementioned ML applications, molecular screening (0.95) and text mining (0.93). This can be explained by the fact that many researchers have proposed machine learning frameworks based on a variety of generative models for modeling molecules, which differ in the respective model structure and in the selected input features , and between generative models and inverse design and analytical techniques (0.85). The former relation evidences the significant effort that has been made on applying ML models, in particular those based on accurate DL architectures, to find and select lead molecules , displaying desired properties  molecular screening and (0.84), (ii) synthesis/characterization of new compounds and materials (0.78), and (iii) generative models and inverse design (0.75), DFT functionals and interatomic potentials with quantum models and quantum sensing (0.83), and synthesis/characterization of new compounds and materials with analytical techniques (0.79).Both generative models and analytical techniques have been extensively used in the qualitative/quantitative search of patterns underlying chemical systems  optimization of reaction parameters and process conditions, e.g., changing the type of reagents, catalysts, and solvents, and also varying systematically, concentration, addition rate, time, temperature, or solvent polarity, (ii) suggestion of new reactions based on critical functional groups, (iii) prediction of reaction/catalyst design, and optimization of heterogeneous/homogeneous catalytic reactions, (iv) acceleration and discovery of new process strategies for batch reactions, (v) establishment of trade-offs in the reaction rate and yield of organic compounds, (vi) description and maximization of the production rate and conversion efficiency of chemical reactions, (vii) prediction of the potential toxicity of different compounds, and also the (viii) rational design of target molecules and guided exploration of chemical space   , obtained from automatic and accurate electronic structure calculations Behler, .However, the intricate nature of the configuration space and its exponential dependence on system size and composition, have hampered the screening of the entire set of candidate structures directly by electronic structure calculations Behler, .Despite the usefulness of ML approaches being indisputable, with the promise to modernize molecular simulations, synthesis, materials science, and drug discovery, the respective endorsement and practical aspects in some chemical sub-fields is far from consensual  pitfalls of some practices using ML. It has been argued that ML algorithms may lead to overestimated performances and deficient model generalizations, due to their sensitivity to the presence of maze-like variables and experimental artifacts  from each molecule with random (Gaussian distributed) numeric strings. It was shown that the predictions were similar to the original ones. Chuang and Keiser  have alsThe original assumptions regarding the significance and validity of the random-forest  model to describe important and general chemical features were also confirmed , lack of standardization of chemical data, expertise and familiarity with ML and DL in chemistry sectors, and also lack of collaboration opportunities)  which confer the ability of DLNs to learn from highly complex data and perform correlation and reduction. This means that the algorithm discovers correlated data, while discarding irrelevant information. Each layer combines information collected from the previous layer, and subsequently infers on the respective significance and send the relevant information to the next layer. The hidden term is used to represent layers that are not direct neighbors of the input or output layers.The process allows constructing increasingly complex and abstract features, by adding layers and/or increasing the number of neurons per layer. However, the use of more than a single hidden layer requires determining error attributions and corrections to the respective weights. This is carried out via a backpropagation, i.e., a backward process starting from the predicted output, and back through the neural network  and ML methods in the search for novel molecular components, have also been implemented , contributing to increase knowledge on the interactions within quantum many-body systems and efficiency of DFT-based quantum mechanical modeling methods  algorithm has been conducted , can be represented and predicted by ML methods  of hybrid DFT per each atomization energy into milliseconds using ML. Cross-validation over more than seven thousand organic molecules yielded a mean absolute error below 10 kcal/mol. The authors have trained the ML algorithm on a set of compounds in a database, comparing the respective matrices to determine differences between molecules, so as to develop a landscape of such differences. Based on the atomic composition and configuration, the unknown molecule can be positioned in the landscape and the respective atomization energy can be estimated by the contributions (weights) obtained from the differences between the unknown and all known molecules , random-forest, kernel ridge regression, and neural networks (graph convolutions and gated graph networks) were tested. It was concluded that out-of-sample errors were strongly affected by the molecular properties, and by the type of representation and regression method. Molecular graphs and graph convolutions displayed better performances for electronic properties, while kernel ridge regression and histograms of dihedrals were suitable for describing energy-related properties [see Faber et al.  for detaIn terms of drug development Brockherde et al.  have devSpecifically, the algorithm was created and trained on the basis of a small sample set of the molecule under study, and applied to simulate the intricate chemical behavior within selected molecules, including malonaldehyde. A directed learning of the density-potential and energy-density maps was conducted, as illustrated in In more detail, one of the key tasks in atomistic modeling is the prompt and automated analysis of the simulation results, in order to provide a comprehensive understanding of the behavior of individual atoms and target collective properties. The main supervised and unsupervised machine-learning methods directed at classifying and coarse-graining of molecular simulations were recently summarized and discussed in Ceriotti . A schemab initio MD  level of accuracy and produced converged MD simulations with fully quantized electrons and nuclei  the free-energy and mean force with respect to translation of the molecule, (ii) the free-energy and variance of the mean force associated to molecular rotation, and considering (iii) the mean force being a conservative force field generated by the free-energy, and (iv) a prior energy for preventing deviations of the simulations with coarse-grained neural networks into unphysical state space regions, i.e., states displaying overstretched bonds or clashing atoms, which are captured out of the training data.The proposed strategy also outperformed classical coarse-graining approaches, which generally failed to capture relevant features of the free-energy surface, providing the all-atom explicit-solvent free-energy surfaces estimated with models including just a few coarse-grained beads, in the absence of solvent , and a predictor, which estimates chemical properties from the latent continuous vector representation of the molecule. These representations allowed generating new chemical structures automatically by employing simple operations in the latent space , and applying gradient-based optimization for a oriented-search of functional molecules  for ensuring region/chemo/stereo selectivity and obtaining the highest yields, estimating the precise rate, yield and time for the reaction, predicting major/minor product, and also evaluating similarity between reactions   modeling, and based on ML techniques, has been proposed for predicting the pre-discharge chemical profiles of ammunition components from the components of the respective post-discharge gunshot residue (Gallidabino et al., The integration of ML-based algorithms in a chemosensor has also pointed out the future of ML and the artificial internet of things applicability, i.e., optimized sensors, linked to a central data analysis unit via wireless (Mayer and Baeumner, Additionally, researchers have used ML to develop tools for predicting catalytic components and dynamics. For instance, the identification and prediction of ligands for metal-catalyzed coupling reaction have been conducted for designing a synthetic economic and ecological route, with the potential to be expanded into a system of pharmaceutical interest (Durand and Fey, Different case studies covering the application of these descriptors, including maps and models and DFT calculations, have been discussed, demonstrating the usefulness of descriptor-oriented studies of catalysis for guiding experiments and successfully evaluate and compare the proposed models (Durand and Fey, Li and Eastgate  have desDesigning catalysts using computational approaches is also a major challenge in chemistry. Conventional approaches have been restricted to calculate properties for a complex and large number of potential catalysts. More recently, innovative approaches for inverse design have emerged, for finding the desired property and optimizing the respective chemical structure. The chemical space has been explored by combining gradient-based optimization, alchemical transformations, and ML. These efforts have been duly reviewed in the context of inverse design and relevance to developing catalytic technologies (Freeze et al., One possible approach to inverse design is to use the synthetic accessibility score, commonly used for drug molecules, in the scoring functions of inverse design for ensuring synthetic feasibility. For that purpose, empirical parameters can be used to describe molecules without the cost of using 3D coordinates for an entire structure and without using a model to describe the complex interactions from geometries.The major progress on inverse design relies on optimization algorithms, which govern the process for exploring a specific space, improving identification rates of parameters that allows optimizing the value of the scoring function. For example, the Classical Optimal Control Optimization algorithm, used for global energy minimization, is based on the diffeomorphic modulation under the observable-response-preserving homotopy algorithm, and lead the classical dynamics of a probe particle, driven by an external field for reaching the optimal value of a multidimensional function, by adjusting iteratively field control parameters over the gradient of the scoring function related to the controls. However, the respective use for scoring functions in inverse design applications still remain a challenge (Freeze et al., The application of autoencoders have allowed transforming SMILES representations of compounds into a continuous latent space in order to optimize chemical properties, including synthetic accessibility score and Quantitative Estimation of Drug Likeness. Additionally, by resorting to gradient-based methods the latent space can be intersected to predict new candidate structures for being synthesized and tested.The integration of inverse design, gradient-based optimization and ML is a very promising strategy to shorten the long path toward catalyst discovery (Freeze et al., This review has sought to provide a sample of ML approaches that support the major research trends in Chemistry, especially in computational chemistry, focusing on DLNs. Such an approaches have offered the possibility of solving chemical problems that cannot be described and explained via conventional methods. In the last few years, the application of ML to the optimization and prediction of molecular properties has become very popular, since more researchers are trained and acquired technical skills to develop and use such methods. ML applications are area-dependent and follow, in fact, a more or less obvious pattern. For instance, medicinal chemistry excels in structure-activity relationships. In other words, each sub-field is progressing essentially in activities that belong to its core subjects. It seems that these fields are evolving naturally, and we cannot identify significant disruptive trends.Despite the historical route of ML methods involving the implementation of clustering or dimensionality reduction approaches, to provide a simple, low dimensional, or coarse-grained representations of structural and dynamical patterns of complex chemical systems, the interplay between innovative ML-driven predictions and molecular simulations can be combined to make time-consuming electronic calculations feasible, obtain accurate interatomic potentials on complex systems, and provide a rational design of molecules and materials. However, the convergence between different ML algorithms is a major challenge to achieve a definite progress in the chemistry fields.Unsupervised learning may also contribute to elucidate the operating aspects of supervised algorithms, while supervised approaches may contribute to the formulation of objective metrics to evaluate the performance of unsupervised approaches.In Chemistry DL is still at an incipient stage, particularly in computational chemistry, although the pace of contributions has been increasing very recently. One of the major challenges is the disparity, quality and interpretability of the generated outcomes. Paired with the sophistication and ability of GPU-accelerated computing for training DLNs and the massive growth of chemical information used for training DLNs, it is anticipated that DL algorithms will be an invaluable engine for computational chemistry. DL uses a hierarchical cascade of non-linear functions allowing to learn representations and capture the required features from raw chemical data, necessary for predicting target physicochemical properties.Considering the recent effort on the topic, DL models have been implemented in various Chemistry sub-fields, including quantum-chemistry, compound and materials design, with superior performances to conventional ML algorithms. There is still tremendous room for improved model accuracy and interpretability. While industrial sectors will continue driving many advances, academia will continue playing a critical role in supplying innovative technical and practical contributions, as well as in fostering cross-disciplinary cooperation.TC performed the bibliometrics analysis, collected the relevant studies in the context of the review, structured, and wrote the paper. AP directed the work, contributed to the interpretation of the data, and to the structure of the review. Both authors reviewed the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Professor Christian Weber studied medicine at the Ludwig Maximilians \u2013 University (LMU) of Munich, Germany, the University Hospital Galway, Ireland and Princess Alexandra Hospital, Australia. After receiving his medical degree in 1994, he joined the Center for Blood Research (T. Springer), Harvard Medical School for a postdoctoral research fellowship. Coming back to Germany, he was awarded as junior research group leader in Vascular Medicine at the Ludwig-Maximilians-University and later was appointed as full-time professor and head of Molecular Cardiology at the University Hospital of the RWTH Aachen. As founding Director of the Institute for Molecular Cardiovascular Research in Aachen, he became a prominent and well-known figure in cardiovascular field, launching well-funded hypothesis and opening novel visions on therapeutic strategies for cardiovascular diseases. In 2010, he was appointed as Chair in Vascular Medicine and Director of the Institute for Cardiovascular Prevention, the Ludwig - Maximilians - University of Munich, as well as Chair of the August-Lenz-Foundation.During his career, he published more than 400 scientific articles, with a cumulative impact factor of over 3100 and more than 20 000 citations, achieving the h-index of 74. His activity was recognized and awarded by the German Society of Atherosclerosis Research (W.H. Hauss-Prize), the European Society of Cardiology (Outstanding Achievement Award 2008), the American Heart Association  and the Netherlands Organization for Scientific Research (VICI Award). He is the Chief Editor, Editorial Board Member and/or Referee of many prestigious scientific journals, as well as the president and/or important organizer of several scientific meetings. At last, but not at least, he is an appreciated model and mentor for many ambitioned and motivated young scientists.dolor, calor, rubor, tumor and function laesa. Basically, these symptoms can be explained by high production of pro-inflammatory mediators, recruitment of leukocyte subsets and increased vascular permeability. The role of inflammation in cardiovascular disease is immense. For instance, atherogenesis and plaque growth are driven by imbalanced lipid metabolism and chronic inflammatory processes involving the innate and adaptive immune system1. Therefore, studying inflammation is fundamental to understand the complex pathogenesis of cardiovascular disease and to develop novel biomarker panels together with more effective therapeutics.Inflammation is a protective or adaptive response of the immune system against pathogens or tissue damage. The clinical signs of acute inflammation are 2. The research on platelets, chemokine-receptor pairs and heterophilic chemokine interactions during inflammation is intensively developing as well in the recent past3.Before, the central role of monocytes, macrophages and innate versus adaptive immunity in cardiovascular disease have been extensively discussed. Recently, new aspects on monocyte and macrophage heterogeneity with differential subset-specific recruitment and hitherto less appreciated cellular players such as neutrophils, dendritic, mast and regulatory T-cells become more evident4. However, just a fractional amount of the comprehensive experimental  data shows indeed relevance in clinical setting. The exact risk-benefit prediction is often obscure and associated with adverse side effects. The versatile experimental animal models are similar but largely not identical to men and the development of new therapeutics takes a long time with numerous clinical phases until approval.The translation of basic research into clinic is a huge challenge with several pitfalls and very heavy responsibility. Unraveling the molecular mechanisms of inflammation could catalyze the development of innovative cardiovascular therapeutics5.The atherosclerosis field is so vast that attempting to comprehensively cover all aspects will be futile. It will be rather crucial for the future to identify key determinants that lead to chronic inflammation in atherosclerosis, to dissect the intriguing diversity of lipid-related pro-inflammatory versus homeostatic and atheroprotective pathways, to review and validate genetic variants contributing to cardiovascular disease and to discuss promising clinical applications of selectively and local targeting inflammation depending on disease stageScience is a cruel mistress, so do not take shortcuts and be prepared for frustration. It will always be \u201cper aspera ad astra\u201d. But on your way, look out for the right mentor. That will help."}
+{"text": "Surface properties of biomaterials, such as chemistry and morphology, have a major role in modulating cellular behavior and therefore impact on the development of high-performance devices for biomedical applications, such as scaffolds for tissue engineering and systems for drug delivery. Opportunely-designed micro- and nanostructures provides a unique way of controlling cell-biomaterial interaction. This mini-review discusses the current research on the use of electrospinning (extrusion of polymer nanofibers upon the application of an electric field) as effective technique to fabricate patterns of micro- and nano-scale resolution, and the corresponding biological studies. The focus is on the effect of morphological cues, including fiber alignment, porosity and surface roughness of electrospun mats, to direct cell migration and to influence cell adhesion, differentiation and proliferation. Experimental studies are combined with computational models that predict and correlate the surface composition of a biomaterial with the response of cells in contact with it. The use of predictive models can facilitate the rational design of new bio-interfaces. The natural regeneration process of human tissues is strongly regulated by the interaction of cells with the extracellular matrix (ECM)  for controlling adhesion, differentiation, and migration of different cells lines. The mini review is divided in two main sections: the first one will focus on experimental studies on electrospun fibers that provide physical cues for cell growth and differentiation; the second section will discuss computational models to predict cell behavior on micropatterns. Although mathematical models that simulate cell behavior on electrospun fibers are not currently available, the computational approaches here discussed can be adapted, in the future, to electrospun scaffolds and used to elucidate the underlying mechanisms responsible for cell-fiber interaction.Multiple studies have demonstrated that the morphology and roughness of fibers produced by electrospinning influence cell adhesion, proliferation, and orientation    (PCL) fibers influences the recruitment of MSCs In vitro tests on human bone marrow MSCs (hBMSCs) revealed that fiber anisotropy modified cells' morphology: polygonal, round-shaped cells without alignment were detected in the random, mineralized regions of the scaffold; while elongated spindle-shaped cells aligned along the fiber direction were visible in the aligned region. Moreover, the aligned fibers significantly up-regulated tendon-specific and tendon-related markers  and therefore guided tenogenic phenotypes of hBMSCs; while, the regions with random, mineralized fibers determined the expression of bone-specific markers  and consequently hBMSCs osteogenic phenotypes. Although the authors have not elucidated the underlying cell signaling mechanisms, this work demonstrates that electrospun scaffolds with engineered fiber anisotropy are advantageous to achieve region-specific distribution of tendon- and bone-related genes and find potential application in ligament repair and regeneration of bone-ligament connections.Another study has investigated how electrospun PCL scaffolds with a novel random-aligned-random structure can be used to mimic bone-ligament connections and native ligaments  by mediating the production of signaling molecules including Wnt3a, and to promote dentinogenesis. Osteogenesis of MSCs has been reported also on random Poly-L-lactic acid (PLLA) fibers, due to cytoskeletal rearrangements and tensions, which in turn influence intracellular mechanotransductive pathways , there is a clear gap in the field which has great potential if correctly pursued. This will open even more possibilities to design and create novel fibrous scaffolds with engineered surface structures (Ziebert and Aranson, Electrospun nanofibers have become vital structures for a plethora of different applications, with the field of biomedical engineering being, arguably, one of the most important. Thanks to the versatility of electrospinning, nanofibrous scaffolds can be tailored and modified to improve their biocompatibility for applications such as tissue engineering, drug delivery and wound dressings. For example, electrospun mats have been used in clinical studies for the treatment of arterial occlusive disease, skin cancer and diabetic foot Table . As discAD and EM contributed to the conception and design of the study. AD and EM wrote the first draft of the manuscript. DT wrote sections of the manuscript. All authors contributed to manuscript revision, read and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The Geriatric Interprofessional Team Transformation in Primary Care (GITT-PC) model improves delivery of healthcare to older adults in primary care by training healthcare professionals in team functioning, rapid cycle QI, and evidence based geriatric practice. The program capitalizes on the role of nursing and other healthcare disciplines. To maximize sustainability, it focuses on Medicare-reimbursable visits. This program will focus on the implementation of the Annual Wellness Visit (AWV) through a collaboration between Dartmouth and 3 GWEPs: University of Florida, University of Louisville and the University of Wyoming. The model\u2019s standardized approach to implementation begins with practice assessments and two trainings. The first training focuses on team functioning & rapid cycle QI and the second is a deep dive training focused on the implementation of the AWV. After the training, practices participate in a data-driven, virtual learning collaborative with monthly data collection and learning sessions. Since 2015, the AWV, through the GITT-PC model has been implemented in 14 sites in northern New England, 10 sites in upstate New York, and nationally through five other GWEP awardees across the country."}
+{"text": "This article describes the data associated with the research paper entitled \u201cSubjective life satisfaction in public housing in urban areas of Ogun State\u201d by\u00a0Ibem and Amole (2013). A multistage sampling technique and questionnaire were used to extract data from occupants in 517 dwelling units in ten selected government mass housing schemes located in five urban centers in Ogun State, Nigeria. The dataset has 57 different variables describing households\u2019 demographics, dwelling units\u2019 features, supply of basic services, and neighbourhood environment in the residential estates. In addition, it also contains variables used to assess residential satisfaction and satisfaction with life. The Statistical Package of the Social Sciences (SPSS) file, descriptive statistics for all the variables and questionnaire used to derive the data are provided in this article. The dataset will enhance understanding of the main research findings and conclusions. Specifications tableValue of the data\u2022The dataset is valuable as it provides insight into the housing situations of occupants in government mass housing projects in five urban centers of Ogun State southwest, Nigeria.\u2022The data also have value in understanding the standard of living of occupants in selected mass housing schemes developed by the government in Ogun State.\u2022Housing researchers can use the dataset to compare the housing situations of occupants in other government residential mass housing estates and types of urban housing environment.\u2022The dataset can be used to assess the performance of government constructed mass housing schemes in meeting the needs and expectations of end-users.\u2022The data and questionnaire instrument can be valuable in similar studies in the future.1The dataset described in this article was extracted from 517 residents in the (i) Workers Housing Estate, Laderin (ii) Ogun State Housing Corporation Estate, Ajebo (iii) Obasanjo Hill-Top (GRA) Estate (iv) Kemta Extension Housing Estate, Olokota (v) Media Village, Ajebo; and (vi) Otunba Gbenga Daniel Housing Estate, Asero in Abeokuta. Others are the Ogun State Housing Corporation, Idiroko Road, Ota; Otunba Gbenga Daniel-Sparklight housing estate, Ibafo; Ogun State Property Investment Corporation (OPIC) Estate, Agbara and Otunba Gbenga Daniel Housing Estate, Itanrin, Ijebu-Ode in Ogun State, southwest Nigeria The dataset comprises nominal, interval and ordinal data and contains nine demographics variables  and 16 objective housing characteristics, including the number of bedrooms, type of residence, location and use of kitchen, type of walling and ceiling materials, window and door types, wall and floor finishes, type of roofing materials, mode of acquisition of residence and state of repair of the buildings, and modes of water supply, main source of power supply, domestics waste disposal arrangement. It also has 31 subjective variables drawn from dwelling units\u2019 characteristics, sources of water and electricity in the dwelling units; physical, social and economic characteristics of the neighbourhood environments as well as management practices in the residential estates, used to investigate residential satisfaction Detailed descriptions of each of these variables can be found in the sample copy of questionnaire instrument, the SPSS file, and residents\u2019 responses to the questionnaire included in the supplementary files and made available in this article.2Very Dissatisfied and ending with \u20185\u2019 for Very Satisfied was used. Similar studies have used this scale of measurement as seen in the previous works by The dataset was sourced from ten mass housing estates constructed between 2003 and 2010 by the Government of Ogun State using the Core housing, Shell, Public-Private Partnerships (PPPs) and Turnkey strategies in Abeokuta, Ota, Ijebu- Ode, Ifo and Agbara. Based on the research by Ibem and Amole A cross-sectional survey involving the administration of pre-tested questionnaire was used to gather the data from residents in the selected estates. This is in line with the approach adopted by previous authors in similar studies In the survey, each of the 15 and 30 housing units occupied in the residential estates developed through Shell and PPPs strategies, respectively, was given a questionnaire to fill, however, while in the residential estates developed using the Core housing and Turnkey strategies, random sampling method was applied in selecting dwelling units for the administration of questionnaire to the occupants. The questionnaire was administered by hand to household heads or their representatives in each of the dwelling units selected in the morning and evening hours of week days and daytime at weekends between December 2009 and February 2010. Although 670 questionnaires were distributed in all the ten estates, 517 questionnaires retrieved were found to have been correctly filled by the respondents. The SPSS software package was used to analyse the data and the responses are presented using tables and figures as shown in the supplementary files."}
+{"text": "This initiative, partially supported by public Spanish government funds, was also the promoter of the Spanish Network on Ion Channels (RECI), a multidisciplinary network that includes more than 50 Spanish groups interested on ion channels (www.reci-ionchannel.org). In the present Special Issue, some SICI members, as well as RECI colleagues, wanted to contribute with the most update knowledge of representative ion channel research in Spain for the last 10 years.The Spanish Ion Channel Initiative consortium  the composition, structure and role of signaling channel complexes (channelosomes) in health and disease; (ii) the atomic structure of the pore forming subunits, of channel complexes and their dynamics; (iii) the molecular and cellular mechanisms underlying channelopathy phenotypes, as well as the implication of ion channels in the etiology of other human diseases; and, (iv) the discovery of therapeutically useful channel modulators for drug development. SICI has addressed these questions by establishing an integrative and inter-disciplinary ion channel program that brought together complementary skills. SICI pursued innovation through integration by assembling a multidisciplinary team composed of physiologists, biochemists, biophysicists, structural biologists, chemists, and pharmacologists. The major outcome of SICI has been the generation of innovative knowledge in the ion channel arena that has resulted in: (i) ground-breaking, transferable technology; (ii) original ion channel therapeutics for the treatment of human disorders; and, (iii) an integrated educational program on ion channels for graduated and postgraduate students. The integration of ion channel research via the multidisciplinary teamwork has proven to be very productive, as reflected by almost 500 scientific articles produced by the research groups that participate in SICI. In this special issue the reader may find interesting contributions from structure-function studies to cell biology, pharmacology, or physiology of ion channels.Keeping all this in mind, we, the editors of this special issue, thank the contributors for their effort and whish that the lecture of these selected contributions will be enjoyable. These reviews and research papers bona fide reflect the outstanding level of the last 10 years research on ion channels performed by SICI and RECI members."}
+{"text": "To assess the impact of scientific and technical training on midwives' abilities in collecting and recording the key performance indicators for fetal growth chart development in limited-resource settings. A descriptive design was used to describe midwives' abilities in timely collecting and recording the minimum data required to estimate fetal weight and develop fetal growth chart. The study was conducted among 19 urban and rural midwives in South Kalimantan, Indonesia, between April 2016 and October 2017. The training provided access to antenatal care information on 4,946 women (retrospective cohort study) and 381 women (prospective cohort study). The average amount of recorded antenatal care data on the key performance indicators of fetal growth assessment has been significantly improved  through scientific and technical training. Scientific knowledge and technical abilities have enabled midwives to timely record routine data of the key performance indicators for fetal growth surveillance. Access to this information is vital during different stages of pregnancy. The information can be utilised as evidence-based guidelines to assess fetal risks through fetal weight estimation and to develop fetal growth chart that is currently not available in Indonesian primary healthcare systems. Fetal growth assessment during antenatal care (ANC) is fundamental in preventing potentially adverse pregnancy outcomes. It has been well documented that one of the main objectives of ANC services is to detect the risk of intergrowth abnormalities , 2. The Access to, adequate use of, and systematic analysis of fetal growth information is crucial for monitoring, detecting, and assessing risks linked to neonatal mortality. The access to reliable, complete, and timely information on pregnancy-related outcomes and interventions remains challenging in Indonesia. Thus, leading to non-evidence-based decisions for program planning and allocating resources , 7.Access to the results of fetal growth assessment during routine ANC examinations is essential , 8\u201310. TImprovement of the data availability, consistency, and quality has become one of the world's priority actions in increasing life survival and reducing the burden of care costs for life-threatening situations and disability for newborns , 15\u201317. Midwives are primary practitioners over 87%) in providing ANC service to pregnant women, detecting potential complications and abnormalities through pregnancy to delivery, and providing timely interventions and referrals \u201321. They7% in proAccess to national and local data on individual maternal, fetal, and neonatal health information during ANC remains insufficient, particularly in developing countries. In Indonesia, the difficulty in collecting the data hampered the development of both standard fetal and newborn growth charts . UnrecorThe aim of this study was to assess the impact of scientific and technical training on midwives' abilities in documenting the minimum data required for fetal weight estimation and fetal growth chart development.This research is the continuation of the previously published study, and the details have been provided in Anggraini et al. . The priA descriptive design using quantitative methods was used to achieve the research aim. Midwives' abilities in collecting and recording the minimum data required for fetal weight estimation , 26 and This study used fetal growth assessment tools which are listed in the first column of Descriptive statistics used to assess the performance of routine ANC data collection, particularly in documenting the key performance indicators of fetal growth assessment , are theAs a part of doctoral degree research, this study has obtained research permissions from the Indonesian national, provincial, and local governments and two ethics' clearances from the Medical Research Ethics Committee, University of Lambung Mangkurat (ULM), Indonesia (reference: 018/KEPK-FK UNLAM/EC/III/2016) and the College Human Ethics Advisory Network (CHEAN), RMIT University, Australia (reference: ASEHAPP 19-16/RM no. 19974). Information about the confidential nature of the project and a consent form (written in both Bahasa Indonesia and English) for recruitment to the study were given to the selected midwives and pregnant women (prospective study), who all agreed to participate.The results discussed below are based on information obtained from the participating midwives, who have the average age of 41 years (ranged between 29 and 56 years) and the average working experience of 19 years (ranged between 6 and 36 years). Further details on participants' characteristics are provided in Anggraini et al. .Scientific and technical training has significantly improved the average amount of recorded ANC data on the key performance indicators of fetal growth assessment suggested in In Indonesia, Johnson-Toshach model  is natioBefore training, midwives' unawareness on the importance of recording FH is clearly indicated in However, after training, the responsiveness to those data documentation was significantly improved , particuGardosi et al.  recommenFigures As with the main database performance, there was significant improvement of midwives' competencies across PHC facilities in documenting the optional databases for individual fetal growth chart development Figures . This waThe awareness by Indonesian midwives, particularly in rural areas, of the importance of documenting FH and FS at a given GA to estimate fetal weight using the current formula has significantly improved after the training . However, the databases' adequacy remained below 70%. A similar trend of low recording of FH (range 36-76%) was also found in rural Australia .Routine and reliable measurement of FH and its documentation at a given GA throughout pregnancy are essential. Although many factors influence the wellbeing of the fetus, FH remains one of the most recommended and accessible predictors to estimate fetal weight  and moniThe measurement of FH is a simple and cost-effective clinical activity. It remains an important first-level screening tool, widely used during routine ANC in both high- and low-income settings, particularly in rural areas where ultrasound machines and skilled personnel are not always available , 41. WheBefore training, access to the recommended minimum databases to develop individual fetal growth chart  based onThe adoption of the international standard of fetal and newborn growth references , 46, 47 The current utilisation of global reference in Indonesia  has deplThe provision of the fetal growth chart during pregnancy is important to assess the viability of the fetus at different stages of pregnancy and to ensure neonatal survival and wellbeing. The chart can be an effective screening tool to assist midwives in analysing and detecting the risks of fetal growth abnormalities such as prematurity and LBW, as part of their role to improve ANC service . Consequth highest for preterm births in the world [Maternal, neonatal, and child health programmes have been initiated and implemented to reduce the mortality rate in Indonesia, particularly due to prematurity and LBW , 52, 53.he world , 55. Thehe world , 13, 56.To the best of our knowledge, the scientific and technical training has, for the first time, equipped the urban and rural Indonesian midwives with the updated scientific knowledge and technology regarding fetal growth assessment during pregnancy. The training has also increased the midwives' awareness on the importance of timely documentation of the key data on characteristics of mother and fetus in the current manual pregnancy registers . In relaScientific and technical training has significantly improved the average amount of recorded ANC data on the key performance indicators of fetal growth assessment during pregnancy. The training has equipped midwives with scientific knowledge and technical abilities to electronically record maternal, fetal, and neonatal health information during pregnancy and delivery. Provision and adequate use of this information during different stages of pregnancy enables fetal weight estimation and promotes the development of fetal growth chart that is currently not available in Indonesian ANC practices, particularly in rural areas. The fetal growth chart is an effective surveillance tool that can assist midwives in capturing, reviewing, and assessing fetal risk factors to end preventable mortality."}
+{"text": "Currently, the GHS has three panels consisting of 5000 households of the GHS collecting additional data on agricultural activities, other household income activities, and household expenditure and consumption, among others. This is to improve data from the agricultural sector and the linkage to other facets of households\u2019 characteristics and outcomes. The LSMS data-set, questionnaire, and basic information document are freely available online at:  Specifications TableValue of the data\u2022LSMS-ISA data is an integration of longitudinal panel survey into GHS that makes it possible to produce a more comprehensive analysis of poverty indicators on socio-economic characteristics for rural households3\u2022LSMS-ISA data helps in building capacity and the development of sustainable systems for the production of accurate and timely information on agricultural households\u2022LSMS-ISA helps the development of an innovating model for collecting agricultural data\u2022LSMS generates high-quality data, improving survey methods, and building capacity. The goal of the LSMS is to facilitate the use of household survey data for evidence-based policymaking.1The rural households\u2019 survey is important source of development data, but in low- and middle-income countries, the capacity to conduct and analyse them widely differs. The LSMS-ISA helps address these issues with respect to agricultural data The Living Standards Measurement Study-Integrated Surveys on Agriculture (LSMS-ISA), General Household Survey (GHS) Panel is part of a larger, regional project in Sub-Saharan Africa (SSA) to improve agricultural data for analysis. Ethiopia, Mali, Malawi, Niger, Nigeria, Tanzania and Uganda are the seven countries being supported by the World Bank through funding from the Bill and Melinda Gates Foundation (BMGF), to strengthen the production of household-level data on agriculture. This regional project, the LSMS-ISA has the aim of enhancing people\u05f3s understanding of agriculture in SSA, specifically, its role on household welfare, access to agricultural land and poverty reduction 2The survey instruments for this data set is based on LSMS-ISA for the Household Survey Panel sample which comprises of 5000 households  were considered to be characteristics at the zonal and national levels which is made up of both the urban and rural areas.Wave 3 GHS-Panel comprises three questionnaires2.1The Household Questionnaire gives data on socioeconomics; instruction; wellbeing (counting anthropometric estimation for kids and kid vaccination); work and work information accumulation alternatives; nourishment and non-sustenance use; family unit nonfarm pay producing exercises; nourishment security and stuns; security nets; lodging conditions; resources; data and correspondence innovation; and different wellsprings of family unit salary.2.2The Agriculture Questionnaire solicits information on the ownership of land and its uses such as farm labour; inputs use; GPS measuring area of land and management of household farmland; machinery used for farming; irrigation; harvesting and crop utilisation; animal holdings and fishing , Table 2"}
+{"text": "Dear Editor,Fibroepithelioma of Pinkus (FEP), also known as fibroepithelial basal cell carcinoma, is a rare cutaneous neoplasm. It has a frequency that ranges from 0.2% to 1.4% in a series of basal cell carcinomas.The patient was 69 years old, male, white, and with a history of bone tumor in the left femur at the age of 17 years. He had undergone a surgical intervention and adjuvant radiotherapy. Years later, he noticed the appearance of red-brown, asymptomatic, slowly evolving papules, restricted to the skin adjacent to the surgical scar, in the area previously subjected to radiotherapy. In 2016, the patient sought dermatological treatment. He exhibited discreetly raised translucent erythematous plaques with pigmented inferior borders, located on the upper lateral aspect of the left thigh. He also exhibited some translucent erythematous papules, located near the surgical scar . The hisFEP affects non-photoexposed areas, commonly in the inguinal and lumbosacral regions.The etiopathogenesis of FEP is controversial.5The histopathological features are fundamental for diagnosis. They are described as peculiar and unmistakable, evidencing thin anastomosing strands of basaloid cells, surrounded by abundant stroma, which form a uniform border with the underlying dermis, resembling a honeycomb.The evolution of FEP is slow. It exhibits low local aggression and little risk of metastasis.In the presented case, the patient had multiple FEP lesions excised and is attending regular follow-up appointments at the dermatology service.This case is reported to emphasize the possibility of other etiologies of basal cell carcinomas, such as previous radiotherapy.None declared.Bruna Anjos Badar\u00f3: Conception and planning of the study; elaboration and writing of the manuscript; obtaining, analyzing and interpreting the data; critical review of the literature; critical review of the manuscript.Lucia Martins Diniz: Approval of the final version of the manuscript; conception and planning of the study; effective participation in research orientation; intellectual participation in propaedeutic and/or therapeutic conduct of the cases studied; critical review of the literature; critical review of the manuscript.Ernesto Negris Neto: Obtaining, analyzing and interpreting the data; intellectual participation in propaedeutic and/or therapeutic conduct of the cases studied.Elton Almeida Lucas: Obtaining, analyzing and interpreting the data; effective participation in research orientation; intellectual participation in propaedeutic and/or therapeutic conduct of the cases studied.None declared."}
+{"text": "The human brain is the most complex organ in the human body. It comprises billions of neurons and supporting cells in a complex network, managing everything from physical functions to thoughts and feelings of humans. Dysfunctions of the complex network caused by both genetic and environmental factors result in many brain disorders. Several large brain projects have been launched, aiming to understand how the brain works in health and disease, including the Human Brain Project of the European Union, the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative of the United States, and the Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MIND) project of Japan. These projects gather, organize, and disseminate data describing the brain and related diseases, in the meantime develop brain-inspired computing and data analytics. As an example, the Human Connectome project (HCP) uses cutting-edge brain imaging technologies to map the circuitry of the healthy adult human brain in order to track their susceptibility to change during aging and disorder occurrence. In addition, the HCP will collect DNA samples, demographic information and behavioral data from the subject to investigate the effect on human brain by both genetics and environment. By analyzing the functional magnetic resonance imaging (fMRI) mappings to detect the factors determining face recognition, the code for facial identity comprised of 205 neurons in primate brain was discovered China Brain Project (CBP) has recently been initiated to promote major advances in the basic understanding of brain and address some urgent societal needs on human health ., for the first time, systematically explored the cellular and molecular mechanisms involved in the formation of prefrontal lobes in the development of the human prefrontal cortex (PFC) by single-cell RNA sequencing (scRNA-seq) Technologies for single-cell amplification and sequencing are maturing, which will be applied by more researchers as a routine tool to assess the genome, transcriptome, proteome, and epigenome of single cells to gain biological insights, particularly in brain science. To date, single-cell transcriptome is the most widely used single-cell sequencing technology, especially in model organism mice The underlying causes of neurological and psychiatric disorders, such as Alzheimer\u2019s disease (AD), Parkinson\u2019s disease (PD), and major depression, are as important as the principles of how the brain works in normal state. Genome-wide association study (GWAS) has been the primary method to explore the genetic risk of common genetic diseases, like PD. Recently the subpopulations of dopaminergic neurons that are linked to PD in the mouse brain at embryonic and early postnatal time points were characterized by scRNA-seq Brain science has entered a new era of big data with the development of single-cell sequencing technologies, the development of new tools for mapping neuronal connections, the increasing resolution of imaging technologies, and the explosion of nanoscience. Many large brain projects and individual studies have accumulated a huge amount of data related to brain function. Taking the HCP as an example, it released high quality image data from 1100 subjects plus out-of-scanner, behavior-only data from 100 subjects, which have an unprecedented spatial resolution of 1.25\u202fmm and very low structured temporal noise We are facing a real big challenge with the increasingly complex datasets in brain science. First, for each type of data, there is a lack of standard specification for their generation, storage, processing, and utilization, which hampers the comparison and integration of data or results from different research groups. Moreover, most of the data are unstructured, heterogeneous, and generated from different sources. Developing efficient tools to transform them into structured and normalized format is of critical importance. Second, how to integrate all different types of data including medical information, omics data, morphology, and connectivity images to gain a deep understanding of the brain\u2019s role is a bottleneck. In addition, the technologies of the internet, artificial intelligence, augmented reality (AR), and virtual reality (VR) will be gradually applied to the study of brain science. Improved statistical models are needed for reliable inference from these data. Computational strategies are becoming central to virtually everything we do now. Third, storage and processing of such large datasets with high efficiency remain difficult. The rapid rate of data generation requires powerful storage and processing ability. New processing and computing methods as well as storage devices are needed to bridge the increasing gap between data growth and processing power. Advances in neuroimaging, genomics, computational neuroscience, and engineering have ushered us to another great era of brain science, when we are bound to make extraordinary discoveries regarding normal brain activity, disorders of the brain, and our very sense of self.In the era of big data, brain science is a fast-developing field. This special issue provides a glimpse of advances in the field of brain science, mainly focused on genomics and neuroimaging.de novo mutations in developmental disorders with special emphasis on isoform-specific mutations Genomics is at present one of the main workhorses for brain science. We specifically highlight the application of genomics tools to the investigation of brain disorders, including causal mutations, diagnostic biomarkers, and actionable targets. Built upon previous high-throughput sequencing studies, Ludwig et al. derived a model based on microRNAs to detect AD using peripheral blood In the meantime, neuroimaging is increasingly utilized in the investigation of brain function and dysfunction. Liu et al. investigated cognitive dysfunction in type 2 diabetes using functional neural network Through these snapshots, we hope the readers can achieve better understanding of the current status in brain science, especially the challenges we are facing and the road ahead of us.The authors have declared no competing interests."}
+{"text": "Gender equality in access to higher education is an important factor in building a sustainable world. Although a good number of countries across the globe have achieved parity in primary education between boys and girls, the target is yet to be widely attained at tertiary level of education. In this data article, empirical data on yearly admissions into accredited tertiary institutions in Nigeria are extensively explored to reveal the existence of gender gaps in the national admission process. Details on the number of candidates admitted into all accredited universities, polytechnics, and colleges of education between 2010 and 2015 were obtained directly from the Joint Admissions and Matriculation Board (JAMB). Gender distributions of admitted candidates are analyzed across the thirty-six (36) states of the federation, the Federal Capital Territory (FCT), and the international students\u2019 category. Gender disparity in admissions into Nigerian tertiary institutions are explored using relevant descriptive statistics, box plots, bar charts, line graphs, and pie charts. In addition, Analysis of Variance (ANOVA) is carried out on the historical data to find out if there are significant differences in the arithmetic means of females and males admitted over the six-year period. Furthermore, multiple comparison post-hoc test results are presented in tables to understand the extent of variations (if any) in gender distribution over the years. The robust data exploration reported in this data article will help national regulatory bodies and relevant stakeholders in policy formulation and decision making towards ensuring equal access to higher education in Nigeria. Specifications tableValue of the data\u2022Thorough evaluation, correct interpretation, and contextual discussion of the data analyses provided in this data article may speed up the achievement of Goals 4 and 5 of the global Sustainable Development Goals (SDGs) in Nigeria.\u2022Various research efforts aimed at achieving SDGs 1, 3, 7, 10, and 11, will be intensified if access is granted to more females into Higher Education Institutions, particularly into Science, Technology, Engineering, and Mathematics (STEM) programs.\u2022The data exploration provided in this data article will call the attention of national regulatory bodies, executives, administrators, and relevant stakeholders to the need for strategic advocacy and promotion of equal access to higher education among all women and men in Nigeria.\u2022Robust data exploration presented in this data article will help the United Nations (UN) to objectively assess the level of gender disparity in access to higher education in Nigeria.\u2022The contribution of this data article will further widen the coverage of evidence-based and reproducible research on gender disparity in higher education. In addition, the utility of the data may open doors for new research collaborations on the trends and patterns of enrollment by gender in higher institutions in sub-Saharan Africa.1Elimination of gender disparity at all levels of education is one of the major global goals in the pursuit of sustainable development across the globe The basic features of the quantitative data on yearly admissions into all accredited Nigerian universities, polytechnics, and colleges of education between 2010 and 2015 were described using eleven (11) different statistical parameters namely: mean, median, mode, standard deviation, variance, kurtosis, Skewness, range, minimum value, maximum value, and the sum. The descriptive statistics of the number of candidates admitted are computed for two gender category  and the results obtained are presented in Also, the gender distributions of admitted candidates were analyzed across the thirty-six (36) states of the federation, the Federal Capital Territory (FCT), and the international students\u2019 category. The distributions of enrollment in higher education for the period of six years (2010\u20132015) are shown in The proportions of females and males in admissions into Nigerian tertiary institutions are depicted using pie charts shown in 2Details on the number of candidates admitted into all accredited universities, polytechnics, and colleges of education between 2010 and 2015 were obtained directly from the Joint Admissions and Matriculation Board (JAMB). Gender distributions of admitted candidates are analyzed across the thirty-six (36) states of the federation, the Federal Capital Territory (FCT), and the international students\u2019 category. Gender disparity in admissions into Nigerian tertiary institutions are explored using relevant descriptive statistics, box plots, bar charts, line graphs, and pie charts."}
+{"text": "Population aging and longevity in an era of immense environmental instability raises concerns about the precarity of aging and insecurity in later life. From home- and neighborhood-level insecurities to uncertainties generated by climate change or broad economic and sociopolitical upheaval across the globe, the factors contributing to instabilities relevant to older populations are heterogeneous in scale and cause. This symposium focuses on understanding older people\u2019s needs and experiences in the context of unstable social, economic, political, and natural environments. The first paper investigates effects of socio-environmental disruption on the well-being, recovery, and resilience of older adults in Louisiana and Mississippi deeply affected by Hurricane Katrina. The second paper explores the confinement, exclusion, and loss of autonomy, as well as the creative negotiation and sociopolitical reclamation of space, among disabled older adults experiencing houselessness. The third paper discusses filmmaking with formerly homeless older adults as a method to engage marginalized individuals in community-based participatory research and better understand nuanced meanings of \u2018home\u2019. The fourth paper explores how transportation and technology can serve as both facilitators and barriers to accessibility and social connectivity among ethnically diverse low-income older adults. Altogether, the papers critically discuss novel scholarship and applied research in environmental gerontology from the micro to macro scale. The symposium inspires methodological innovation and critical research directions, and informs place-based policymaking to address diverse contexts of aging in place."}
+{"text": "International Journal of Telerehabilitation (IJT) is a biannual journal dedicated to advancing telerehabilitation by disseminating information about current research and practices. The journal is PubMed indexed, and was recently accepted into Scopus, with indexing to follow.The International Journal of Telerehabilitation (IJT) explores five diverse topics that fall under the unifying umbrella of telerehabilitation: telehealth privacy and security; the usability of an immersive augmented reality based system with haptics for synchronous remote musculoskeletal examination; parent perspectives of occupational therapy delivered through telehealth; the use of telehealth in early intervention in Colorado; and the use of telerehabilitation as an effective platform to help manage Low-Back Pain (LBP). We thank our authors and are honored to publish their work.The current issue of the multi-disciplinary We are grateful for the generous efforts of the IJT reviewers, many of whom have reviewed prospective IJT articles for over a decade. Sections Editor, William E. Janes, OTD, MSCI, OTR/L has been a very impactful reviewer and support to authors.Thanks also to the publisher of IJT, the University Library System, University of Pittsburgh. IJT is currently sponsored by the Rehabilitation Engineering Research Center on Information and Communication Technology Access at the University of Pittsburgh. The RERC is funded by the National Institute on Disability, Independent Living, and Rehabilitation Research (NIDILRR). Volumes 1\u20137 were sponsored by the Rehabilitation Engineering Research Center (RERC) on Telerehabilitation at the University of Pittsburgh.We cordially invite submissions to the Fall 2019 issue by mid-September 2019. IJT accepts original research, case studies, viewpoints, technology reviews, book reviews, and country reports that detail the status of telerehabilitation.Sincerely,Ellen R. Cohn, PhD, CCC-SLP, ASHA-FIJT EditorJana Cason, DHSc, OTR/L, FAOTASenior Associate Editor"}
+{"text": "In Practice, and The World Allergy Organization Journal and chaired by Mariana Castells, MD, PhD, and Pascal Demoly, MD, PhD.This article is one of a series of international consensus documents developed from the International Drug Allergy Symposium held at the Joint Congress of the American Academy of Allergy, Asthma & Immunology/World Allergy Organization on March 1, 2018, in Orlando, Florida, USA. The symposium was sponsored by The Journal of Allergy and Clinical Immunology, The Journal of Allergy and Clinical Immunology:  The prevalence of self-reported drug allergy has been reported up to 8% in the general population  and thatDHRs have a significant impact on clinical practice, socio-economy, drug development, and public health. Although tremendous progress has been made over the past two decades in the understanding of the mechanisms of drug allergy and hypersensitivity and their management, several unmet needs remain. Several task forces with representatives from the key stakeholders  have identified the critical data gaps and opportunities and made recommendations on how to overcome some of the barriers to DHRs research and address research needs , 6, 7. WEpidemiologic risk factors for DHRs are not well characterized and may be influenced by regional/national differences in drug prescriptions. All drugs can induce DHRs, but the incidence and risk factors for individual drugs have been poorly defined. The development of a network that can increase the population size from which to capture data on DHRs would be a major advance. The establishment of such a network would need the concomitant development of unique DHR databases collecting standardised data, the nature of which would have to be defined on the basis of expert consensus. The development of such a database would have huge benefits in validating diagnostic procedures and defining the risk factors associated with DHRs. It would permit personalized analysis at the individual level and the country level , and would allow longitudinal assessment of the safety of new drugs. It would overcome the major limitation of spontaneous reporting, i.e. under-reporting, by engaging interested clinicians involved in the network. It would assess the socio-economic impact of DHRs, drug allergy pathways, and allow follow-up studies .One of the major reason why we are still lacking reliable in vitro tests is due to a lag in the understanding of the mechanisms of most DHRs. Drugs are capable of inducing all the types of immunological reactions described by Gell and Coombs, with the most common being IgE and T-cell mediated reactions . Drugs c(1) identifying the differences in standard management in the field, (2) providing evidence-based data supporting the different approaches, (3) developing potential expert opinion regarding best practices, and (4) designing future pragmatic research and clinical studies to evaluate outcomes. In order to guide and standardize the approach, we asked them to summarize the current knowledge on their topic in terms of (1) what we knew  and what we have (most recently) learned, (2) what is (still) controversial and/or done differently in different institutions or geographical areas , (3) what consensus recommendations can be made now? , and (4) list the unmet needs . The individual controversy and consensus statements are being concurrently published [With the above in mind, the editors of The Journal of Allergy and Clinical Immunology, The Journal of Allergy and Clinical Immunology: In Practice, and The World Allergy Organization Journal sponsored the International Drug Allergy Symposium. This symposium, which was held March 1, 2018 during the American Academy of Allergy, Asthma and Immunology (AAAAI)/World Allergy Organization (WAO) Joint Congress in Orlando, Florida, aimed at developing a series of international consensus documents. The controversies were grouped into five categories: 1) Penicillin and cephalosporin testing, 2) Radiographic contrast media, 3) In vitro testing, 4) Testing for delayed reactions, and 5) Drug allergy pathways. The information was presented by team leaders and discussed thoroughly in person and then evaluated by an expanded group of more than fifty experts around the world. Experts were asked to focus on ublished \u201313. ThisThe group on penicillin and cephalosporin testing  identifiThe group on radiographic contrast media (RCM) testing  classifiThe group on in vitro testing  reviewedThe group on testing for delayed reactions  identifiThe group on drug allergy pathways  identifi"}
+{"text": "Despite the well-documented clinical and public health impacts of palliative care on older patients\u2019 end of life experiences, racial and ethnic disparities in palliative care use still remain. However, empirical evidence on the sources of disparities is lacking, particularly for Asian Americans. Given the rapid growth and increasing cultural diversity of the older Asian population in the United States, a systematic review was conducted to provide a comprehensive overview of the best available evidence on the barriers to palliative care use among Asian Americans. Search was conducted using six electronic databases , and all procedures of the study have been guided by Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P). A total of 23 studies published in the U.S. since 1998 were included. Individual level barriers to palliative care service use among Asian Americans identified by the study included lack of palliative care knowledge, lack of insurance, cultural beliefs, language barrier, attitude toward death, family centered decision-making. Provider level barriers included lack of training and experience about palliative care, patient-provider discordance in language and culture, and absence of policy or guidance for providers. Although racial disparities in palliative care for Asian Americans were evident, Asian Americans were underrepresented in palliative research. Future research effort should be directed toward the development of culturally sensitive palliative care services and policies that reduce racial and ethnic specific barriers."}
+{"text": "The evolution of the various hearing adaptations is connected to major structural changes in nearly all groups of vertebrates. Besides hearing, the detection of acceleration and orientation in space are key functions of this mechanosensory system.The symposium \u201cshow me your ear \u2013 the inner and middle ear in vertebrates\u201d held at the 11th International Congress of Vertebrate Morphology (ICVM) 2016 in Washington, DC (USA) intended to present current research addressing adaptation and evolution of the vertebrate otic region, auditory ossicles, vestibular system, and hearing physiology. The symposium aimed at an audience with interest in hearing research focusing on morphological, functional, and comparative studies. The presented talks and posters lead to the contributions of this virtual issue highlighting recent advances in the vertebrate balance and hearing system. This article serves as an introduction to the virtual issue contributions and intends to give a short overview of research papers focusing on vertebrate labyrinth and middle ear related structures in past and recent years. With the increasing application of high resolution and noninvasive computer tomography since the 1980s, 3D visualization and their respective analyses became essential for anatomical studies of the middle and inner ear.The vertebrate ear combines two main functions: balance and hearing. The vestibular part of the inner ear is the organ of equilibrium detecting head and body movements during locomotion . The semicircular canals (SCs)  of the vestibular system detect angular acceleration, while utricule and saccule detect linear acceleration  of elasmobranchs  of the lateral line receptors and the labyrinth  differs anatomically from the derived amniote ear  in showing large and bulky stapedial bones (relative to braincase size) capable of the detection of substrate\u2010borne vibrations  is the tympanum (tympanic membrane) overlying an air\u2010filled middle ear cavity with ossicles transmitting the sound to the oval window of the inner ear  are able to close their external acoustic meatus with a meatal muscle, possibly for protection against mechanical damage or their own sound  of nonmammalian amniotes, sounds bouncing off the skin surface are transmitted to the cochlear duct Manley, .In the 19th century, Georges Cuvier  describeDiarthrognathus), which possess both functional jaw joints (primary and secondary) at the same time , incus (anvil), and stapes (stirrup) is laterally restricted by the ectotympanic ring and completely detached from the mandible Allin, . Complexe Allin, . The sege Allin, . Even ife Allin, , 1973. De Allin,  conductee Allin,  and Fleie Allin, .1.2The inner ear (labyrinth) of vertebrates comprises two main functions: (a) balancing of the individual using the ampullae of the three SCs and the sensory field of utriculus and sacculus, and (b) hearing ability with the sensory hair cells of basilar papilla of the lagena of nonmammalian amniotes . The inner ear is composed of a membranous system (membranous labyrinth) filled with endolymphatic fluid enclosed inside a bony endocast (bony labyrinth), filled with perilymphatic fluid. Both fluids differ in their concentration of potassium and sodium  and early tetrapods, which remains unossified during embryogenesis (Clack, In jawless vertebrates, the number of SCs varies Retzius, . The vess Clack, . The rous Clack, , which es Clack, .In the 16th century, Bartholomeus Eustachius discovered the cochlear part of the ear, which was denoted by Gabriel Falloppio as \u201ccochlea\u201d in 1561 Gitter, . PolitzeEven though Hyrtl  doubted The shape and number of coils of the mammalian cochlea is known to have a strong phylogenetic signal Ekdale, . MonotreThe evolution of the amphibian inner ear on its way to amniotes is controversially discussed Lombard, , 1976. T1.3Since the expanding availability of noninvasive microcomputed tomography anatomical investigations of the middle and inner ear region of extant and extinct vertebrates are of still growing interest to the scientific community addressing complex questions. For example, the evolution of the huge diversity of the membranous inner ear labyrinth morphology, the function of the vestibular system for detecting acceleration and deceleration of the head and related transmission of sensory signals, the evolution of the mammalian coiled cochlea for enhanced hearing capability, and many more. Recently conducted studies focus on phylogenetic signals to contribute to the tree of life and reveal ecological adaptations. The goal of the symposium held at the 11th ICVM was to exchange newly acquired insights, new technical approaches, and exchange of information addressing anatomical meaning of the bony structure of inner and middle ear related structures in the system of vertebrates.There are no Conflict of interests.All authors drafted the manuscript, and gave final approval for publication."}
+{"text": "To assess the public health risk to Singapore posed by the emergence of artemisinin-resistant (ART-R) malaria in the Greater Mekong Subregion (GMS).We assessed the likelihood of importation of drug-resistant malaria into Singapore and the impact on public health of its subsequent secondary spread in Singapore. Literature on the epidemiology and contextual factors associated with ART-R malaria was reviewed. The epidemiology of malaria cases in Singapore was analysed. The vulnerability and receptivity of Singapore were examined, including the connectivity with countries reporting ART-R malaria, as well as the preparedness of Singaporean health authorities. Sources of information include international journals, World Health Organization guidelines, data from the Singapore Ministry of Health and National Public Health Laboratory of the National Centre for Infectious Diseases, and the International Air Transport Association.The importation of ART-R malaria into Singapore is possible given the close proximity and significant travel volume between Singapore and the GMS countries reporting artemisinin resistance. Singapore\u2019s vulnerability is further enhanced by the presence of foreign workers from neighbouring endemic countries. Nonetheless, the overall likelihood of such an event is low based on the rarity and decreasing trend of imported malaria incidence.Anopheles vectors in Singapore, imported cases of drug-resistant malaria could cause secondary transmission. Nevertheless, the risk of sustained spread is likely to be mitigated by the comprehensive surveillance and control system in place for both infected vectors and human cases.With the presence of This risk assessment highlights the need for a continued high degree of vigilance of ART-R malaria locally and globally to minimize the risk and public health impact of drug-resistant malaria in Singapore. Plasmodium falciparum, P. vivax and P. malariae. , which comprises Cambodia, the Lao People's Democratic Republic, Myanmar, Thailand, Viet Nam and Yunnan Province of China, has long been the epicentre of antimalarial drug resistance.  since 1982, Singapore is at risk of importation of emerging diseases including artemisinin-resistant (ART-R) malaria. In view of the emergence of resistance across the GMS and the spread beyond its borders, we carried out an analysis to assess the risk of importation and secondary spread of ART-R malaria infection in Singapore.The risk of importation of drug-resistant malaria into Singapore and the public health impact of its subsequent secondary spread in Singapore were assessed following WHO guidance on the risk assessment of acute public health events.  gene was performed by the Malaria Reference Centre from the National Public Health Laboratory (MRC-NPHL) by polymerase chain reaction (PCR) amplification and sequencing according to the protocol of Ariey et al.  followed by P. falciparum (22%).Among the 290 cases of malaria reported in Singapore between 2013 and 2017, 289 (99.7%) were imported cases, of whom 141 (49%) were work-permit or employment pass holders. The majority of imported cases were from South-East Asia (16%), Africa (16%) and India (62%). Among the cases imported from South-East Asia, most were from Indonesia and Malaysia, which accounted for 8% and 4% of cases, respectively. Most of the cases of malaria reported in Singapore between 2013 and 2017 were caused by P. falciparum cases tested had mutations possibly associated with artemisinin resistance  Among cities outside the GMS, Singapore receives the highest number of travellers from the GMS , which was endorsed by all GMS countries. (To prevent global spread of artemisinin resistance, containment efforts have been initiated in the GMS. In 2015, WHO launched the The risk imposed to Singapore by the emergence of ART-R malaria was characterized using the information collected; key factors were considered to assess the likelihood of importation of cases into Singapore and the impact on public health (The risk characterization of likely based on the likelihood of importation and the according minimal consequence suggest that the overall risk of ART-R malaria to Singapore is low. The importation of a case of ART-R malaria into Singapore is possible given the close proximity and significant travel volume between Singapore and the GMS countries reporting artemisinin resistance. Singapore\u2019s vulnerability is further enhanced by the presence of foreign workers from neighbouring endemic countries. Nonetheless, the overall likelihood of importation is considered low based on the rarity and the decreasing trend of imported malaria incidence over the past few years.Anopheles vectors in Singapore, imported cases of ART-R malaria can cause secondary transmission. The risk of sustained spread is likely to be mitigated by the comprehensive surveillance and control system in place for both infected vectors and human cases as observed in the past local outbreaks of malaria initiated by imported cases.With the presence of P. falciparum cases in Singapore, 5.8% had genetic mutations that may confer resistance to artemisinin. The presence of competent local vectors, the high volume of travel from regions with ART-R malaria, and the presence of foreign workers from neighbouring endemic countries make it possible that drug-resistant malaria could be imported and introduced to Singapore. To reduce the risk of Singapore residents acquiring malaria infections overseas, pre-travel health education, particularly by travel agents, the media and health-care providers, can increase awareness of the risk of contracting malaria overseas so that personal preventive measures can be taken.Singapore is the top destination for travellers from the GMS. Among the imported Secondary spread following an imported case is also possible. However, any spread is not likely to be sustained. Malaria has not re-established itself as an endemic disease in Singapore despite local outbreaks since it was declared malaria-free in 1982. The Singapore health ministry and NEA have implemented comprehensive malaria surveillance and control programmes to detect cases and curb the transmission of local outbreaks.The risk assessment has some limitations. The assessment is based on limited data as the number of imported cases of malaria in Singapore is small. As the risk characterization was defined by the epidemiological and contextual knowledge available currently, conclusions could change as new information emerges. Ongoing studies on genetic mutations, particularly their underlying molecular and cellular mechanisms and their phenotypic manifestations in resistance, could provide a better understanding of an epidemic and facilitate the design of surveillance and control measures. Identification of new molecular markers and improvements in laboratory capability continues to impact disease surveillance as illustrated by the significant progress in global surveillance of artemisinin resistance expedited by the discovery of the molecular marker K13. (In conclusion, in view of the emergence of ART-R malaria in the GMS and its geographical expansion, this risk assessment highlights the need for a high degree of vigilance over the local and global situation to be maintained to minimize the risk and severity of the public health threat of ART-R malaria to Singapore."}
+{"text": "Quantifying the impact of climate change and human activities on grassland dynamics is an essential step for developing sustainable grassland ecosystem management strategies. However, the direction and magnitude of climate change and human activities in driving alpine grassland dynamic over the Tibetan Plateau remain under debates. Here, we systematically reviewed the relevant studies on the methods, main conclusions, and causes for the inconsistency in distinguishing the respective contribution of climatic and anthropogenic forces to alpine grassland dynamic. Both manipulative experiments and traditional statistical analysis show that climate warming increase biomass in alpine meadows and decrease in alpine steppes, while both alpine steppes and meadows benefit from an increase in precipitation or soil moisture. Overgrazing is a major factor for the degradation of alpine grassland in local areas with high level of human activity intensity. However, across the entire Tibetan Plateau and its subregions, four views characterize the remaining controversies: alpine grassland changes are primarily due to (1) climatic force, (2) nonclimatic force, (3) combination of anthropogenic and climatic force, or (4) alternation of anthropogenic and climatic force. Furthermore, these views also show spatial inconsistencies. Differences on the source and quality of remote sensing products, the structure and parameter of models, and overlooking the spatiotemporal heterogeneity of human activity intensity contribute to current disagreements. In this review, we highlight the necessity for taking the spatiotemporal heterogeneity of human activity intensity into account in the models of attribution assessment, and the importance for accurate validation of climatic and anthropogenic contribution to alpine grassland variation at multiple scales for future studies. Finally, the relative contribution of climatic and anthropogenic factors to alpine grassland changes can be identified by comparing the trends of NPPH and NPPP , and Aqua  climatic force, (2) nonclimatic force, (3) combination of anthropogenic and climatic force, or (4) alternation of anthropogenic and climatic force. These views also show spatial inconsistencies and lack validation. The current challenges in distinguishing climatic and anthropogenic contributions to alpine grassland variation on Tibetan Plateau mainly include the uncertainties in quality of remote sensing products, uncertainties in the accuracy of models, especially for simulating the potential vegetation growth, and overlooking spatiotemporal heterogeneity of human activity intensity. Thus, it is necessary to evaluate the differences among the multiple remote sensing datasets before inputting some of them into the models of attribution assessment, to take the spatiotemporal heterogeneity of human activity intensity into account in the models, and further to improve the accuracy of models. We also proposed a framework for accurate validation of anthropogenic and climatic contribution to alpine grassland variation at multiple scales for future studies.None declared.Zhang Y. and Liu L. designed the study, and Li L. wrote most of the first draft. Wu J., Li S., and Zhang H. contributed to the analysis and interpretation of the results. Zhang B., Ding M., Wang Z., and Paudel B. contributed to revise the manuscript and provided conceptual advice. All authors contributed to final approval for publication.\u00a0Click here for additional data file."}
+{"text": "Axial sesamoiditis or osteitis of the proximal sesamoid bones (PSBs) in the horse is described as a rare condition. The cause remains unknown and speculative, with vascular, infectious and traumatic aetiologies implicated. It is specifically associated with injury of the palmar or plantar ligament (PL), also known as the intersesamoidean ligament. Imaging findings are generally rewarding, and radiological changes are typical, if not pathognomonic, for the condition. Lesions consist of bone lysis at the apical to mid-body axial margins of the PSBs, with variable degrees of joint effusion. Radiographic technique warrants careful attention to make a diagnosis, and exposure factors may need to be adjusted. Perineural, intra-articular and intra-thecal anaesthesia does not seem to provide consistent improvement of lameness in these cases, with literature reporting inconsistent findings. Ultrasonographic findings include digital flexor sheath effusion, loss of the normal fibre structure of the PL at its attachment to the PSBs, abnormal echogenicity or change in thickness of the PL, and irregular hyperechoic cortical margins of the axial margins of the PSBs. Scintigraphy, computed tomography and magnetic resonance imaging, although not necessary to make a diagnosis, may add valuable information regarding the location and extent of lesions. The prognosis remains guarded to poor for return to athletic function. The focus of this article is a comprehensive review of the proposed aetiopathogenesis of the condition, the prognosis and a summary of the literature findings with focus on the notable diagnostic imaging features, including radiography, ultrasonography, scintigraphy, computed tomography and magnetic resonance imaging. The PL is a thick collagenous structure firmly attached to the PSBs by a layer of fibrocartilage, creating a firm union between the two bones  in the horse is described as a rare condition, with approximately 56 cases reported in the literature, with 32 of these cases described in the past 5 years , may be intermittent and is often of variable duration prior to presentation, with reports ranging from a few days to several months , intra-articular and intra-thecal (DFTS) anaesthesia do not seem to provide consistent improvement of lameness in these cases, with literature reporting inconsistent findings , lateromedial (LM), and two oblique views \u2013 dorsomedial-palmaro lateral oblique (DM-PaLO) and dorsolateral-palmaromedial oblique (DL-PaMO)  uptake in the bone phase of the study of most lesions, with the exception of very small or inactive lesions  findings have shown abnormal increased signal intensity within the ligament, and/or high signal intensity within the axial aspects of the sesamoid bones on short-Tau-inversion recovery (STIR) or proton density sequences, consistent with inflammation, necrosis or scar formation , infectious (degenerative neutrophilic fluid) and even normal findings described (Wisner et al. Arthroscopy of the palmar MCPJ or plantar MTPJ joint pouch reveals PL damage, consisting of fraying, discolouration and separation from the PSBs, and osteomalacia and osteochondral fragmentation of the axial borders of the PSBs (Dabareiner et al. Histopathological changes of the PL may range from acute to chronic, which is consistent with the duration of clinical signs (Wisner et al. Post-mortem findings usually consist of hyperaemia and defects or fissuring of the PL gliding surface and brown discolouration of the collagenous substance of the ligament (Wisner et al. Debate exists on the long-term outcome and prognosis of axial sesamoiditis. Evaluation of outcome was hampered in the past by several horses undergoing euthanasia without any treatment (Wisner et al. Septic forms generally carry a poor prognosis, and the general consensus appears to be that of a poor to guarded prognosis (Dunkerley et al. The Friesian breed has also been reported to carry an especially poor prognosis (Brommer et al. Axial sesamoiditis is a clinical entity in which the imaging findings are well documented and rewarding, but treatment and long-term outcome are often disappointing, and a poor prognosis can be expected in the majority of cases."}
+{"text": "Healthcare Technology Letters (HTL) journal dedicated to the 12th edition of the Joint International Workshop on Augmented Environments for Computer-Assisted Interventions (AE-CAI) and Cerebral Visualization (CereVis). We are pleased to present the proceedings of this exciting scientific gathering held in conjunction with the Medical Image Computing and Computer-Assisted Interventions (MICCAI) conference on September 16th, 2018 in Granada, Spain.Welcome to this Special Issue of the IET's The AE-CAI workshop series dates as far back as MICCAI 2006 in Denmark and has evolved as a forum to discuss the latest developments in Computer-Assisted Interventions (CAI). CAI is a field of research and practice, where medical interventions are supported by computer-based tools and methodologies. CAI systems enable more precise, safer, and less invasive interventional treatments by providing enhanced planning, real-time visualization, instrument guidance and navigation, as well as situation awareness and cognition. These research domains have been motivated by the development of medical imaging and its evolution from being primarily a diagnostic modality towards its use as a therapeutic and interventional aid, driven by the need to streamline the diagnostic and therapeutic processes via minimally invasive visualization and therapy.To promote this field of research, the AE-CAI workshop series seeks to showcase papers that disseminate novel theoretical algorithms, technical implementations, and development and validation of integrated hardware and software systems in the context of their dedicated clinical applications. This year's workshop is a joint effort between two communities \u2013 the AE-CAI community and the CereVis community. We joined forces back in June 2018 in light of our common interests in neuro-navigation and visualization for image-guided neuro-interventions.The objective of the AE-CAI & CereVis workshop has been to attract scientific contributions that offer solutions to the technical problems in the area of augmented and virtual environments for computer-assisted interventions, with CereVis contributions focusing on neuro-navigation and neuro-interventions, and to provide a venue for dissemination of papers describing both complete systems and clinical applications. The workshop attracts researchers in computer science, biomedical engineering, computer vision, robotics, and medical imaging.The workshop featured a single track that consisted of long and short oral presentations showcasing original research engaged in the development of virtual and augmented environments for medical image visualization and image-guided interventions. To foster networking and discussion, we also provided all authors with the opportunity to present their work as a poster in addition to their oral presentation slot.In addition to the contributed papers, we were pleased to welcome two keynote speakers: Dr. Klaus Engel and Dr. Terry Peters. Dr. Engel is an expert in visualization from Siemens Healthineers in Erlangen, Germany and spoke on cinematic rendering from medical imaging. Dr. Terry Peters is a pioneer in image-guided interventions from Robarts Research Institute at Western University in London, Ontario, Canada and spoke on current and future trends in mixed, augmented and virtual reality visualization in medicine.Healthcare Technology Letters journal. This year AE-CAI & CereVis received 20 manuscripts spanning a strong geographic representation from Europe, North America and Asia. The review process was rigorous and involved evaluation of each manuscript by three to five external reviewers. Following the first stage of review, sixteen manuscripts were further considered for major or minor revision, and resubmission. Authors were required to submit a response to reviewers and resubmit a revised manuscript that addressed all reviewers\u2019 critiques.All manuscripts submitted to the joint AE-CAI & CereVis 2018 were held up to journal standards, as the ultimate objective was to publish accepted work in this Special Issue of the IET's Once revised, all resubmitted manuscripts entered a second round of review conducted by the AE-CAI Program Committee, Workshop Chairs, as well as the HTL Managing Editor and Editor-in-Chief to ensure that all reviewers\u2019 critiques were properly addressed in the revised manuscripts and that the quality of the manuscript was appropriate for journal publication. All manuscript were then accepted for publication and forwarded to the journal for production and publication.On behalf of the AE-CAI & CereVis 2018 Program and Organizing Committee, we would like to extend our sincere gratitude to all authors, presenters, and attendees for their scientific contribution, enthusiasm, and support. We also extend special thanks to all reviewers for providing detailed and timely critiques of the submitted manuscripts. We also acknowledge the support we received from the MICCAI 2018 Workshop Committee, and the HTL Editorial Office for their dedication to maintaining the high quality of AE-CAI and CereVis workshops, and for selecting outstanding manuscripts that fostered exciting discussions at the meeting.Northern Digital Inc. (NDI) for their continued support over the years that has enabled us to recognize AE-CAI authors for their much deserved dedication and scientific enthusiasm through several paper awards. We also thank BrainLab for their generous sponsorship of the top papers presented as part of the neuro-imaging/navigation/visualization track encompassed by the CereVis workshop. A big thank you on behalf of all awardees and once again, sincere congratulations to all award winners!Last but not least, we acknowledge our generous sponsors. We thank CereVis Award Papers:by David ShattuckA Multiuser Virtual Reality Environment for Visualizing Neuroimaging Data, by Taylor Frantz; Bart Jansen; Johnny Duerinck; Jef VandemeulebrouckeAugmenting Microsoft's HoloLens with Vuforia Tracking for Neuronavigation, by Reid Vassallo; Hidetoshi Kasuya; Benjamin Lo; Terry Peters; Yiming XiaoAugmented reality guidance in cerebrovascular surgery using microscopic video enhancement, AE-CAI Award Papers:by Gavin Wheeler; Shujie Deng; Nicolas Toussaint; Kuberan Pushparajah; Julia Schnabel; John Simpson; Alberto Gomez HerreroVirtual Interaction and Visualisation of 3D Medical Imaging Data with VTK and Unity, by Long Qian; Anton Deguet; Peter KazanzidesARssist: Augmented Reality on a Head-Mounted Display for the First Assistant in Robotic Surgery, by Ehsan Azimi; Tianyu Song; Chenglin Yang; Omid DianatEndodontic Guided Treatment Using Augmented Reality on a Head-Mounted Display System, by Andrew Speers; Burton Ma; William Jarnagin; Sharifa Himidan; Amber Simpson; Richard WildesFast and accurate vision-based stereo reconstruction and motion estimation for image-guided liver surgery, We hope that you will enjoy reading this Special Issue and we look forward to your continuing support and participation in future editions of the AE-CAI & CereVis workshops. Their continued success demands our ongoing commitment.Cristian A. Linte, Rochester Institute of Technology, USAMarta Kersten-Oertel, Concordia University, CanadaZiv Yaniv, National Institutes of Health and TAJ Technologies, USAYiming Xiao, Western University, CanadaCaroline Essert, University of Strasbourg, FrancePierre Jannin, University of Rennes IJonathan Lau, Western University, CanadaPhilip Pratt, Imperial College London, UKIngerid Reinertsen, SINTEF, NorwayHassan Rivaz, Concordia University, Canada"}
+{"text": "The findings of recent research on drinking patterns and problems among African-Americans can be summarized as follows: (1) African-Americans report higher abstention rates than do whites; (2) African-Americans and whites report similar levels of frequent heavy drinking; (3) rates of heavy drinking have not declined at the same rate among African-American men and women as among white men; and (4) variables such as age, social class, church attendance, drinking norms, and avoidance coping may be important in understanding differences in drinking and drinking problem rates among African-Americans and whites. Limitations of the research are described and suggestions are made for possible directions for future research. Alcohol studies on African-Americans make up a small but growing body of research. The limited research that does exist has focused on a number of issues, including patterns and determinants of drinking and drinking problems. This article reviews recent studies examining the drinking patterns and problems of adult African-Americans. Studies of African-Americans have, for the most part, involved comparisons of drinking patterns and drinking problems among African-American and white populations. This review therefore focuses primarily on studies of that type. After discussing drinking patterns and problems among African-Americans, the article describes some of the possible determinants of drinking patterns in that population.The term \u201cdrinking patterns\u201d refers to various styles of drinking, such as abstention or heavy drinking. Categories of drinking patterns frequently are based on indexes of quantity and frequency or on assessments of the volume of alcohol consumed by a person in a given period of time. Unless otherwise noted, terms describing drinking patterns are based on the definitions used in the studies being discussed.National surveys examining the prevalence of drinking in African-American populations indicate that African-Americans report lower rates of alcohol use than whites. In 1997, according to the National Household Survey on Drug Abuse, 53 percent of African-Americans and 68 percent of whites reported drinking in the past year . The difHeavy drinking increases the risk of drinking problems; researchers therefore often focus on heavy drinking when comparing African-American and white drinkers. Data from the National Alcohol Survey  show thaPanel studiesTwo of the most widely studied indicators of drinking problems include drinking consequences and alcohol dependence symptoms. Drinking consequences are concrete problems that arise in different areas of a person\u2019s life because of drinking . Alcohol dependence symptoms refer to a set of behaviors and experiences associated with alcoholism or addiction, such as withdrawal and blackouts . Some stLongitudinal surveys have focused on changes in drinking-problem indicators and alcohol-related mortality among African-Americans and whites. Rates of alcohol dependence symptoms and drinking consequences remained stable from 1984 to 1995 among African-American and white men and women  see tab, p. 262.Some of the most promising studies on drinking problems have examined the relationships between race, social class, and drinking problems. Studies in this area have focused on two central hypotheses. The first hypothesis is that adjusting for social class may eliminate racial and ethnic differences in drinking problem rates. To summarize, studies comparing self-reported drinking problems in African-American and white populations have yielded mixed results. Some studies have shown that African-Americans report more drinking problems than do whites, whereas other studies have reported no significant differences between the two groups. Higher social class appears to be a protective factor for African-Americans against the effects of race on drinking problems. Continuing research is needed to understand the effects of social class status on drinking problems among African-Americans.For the most part, research on drinking patterns and drinking problems in African-American populations has not been based on theory. Nevertheless, etiological studies of drinking patterns and drinking problems in African-American populations have focused on a wide range of demographic, biological, environmental, and behavioral variables.Sex, age, income, education, and employment status have been shown to be related to drinking patterns and drinking problems in both African-American and white populations a, 1997. In addition to demographic variables, studies also have examined whether a family history of alcohol problems contributes to drinking problems. Two of the studies reviewed for this article reported\u2014and many researchers agree\u2014that a family history of drinking problems is an important correlate of drinking behavior . People Studies have examined the influence of stress, parental and peer attitudes about drinking, drinking norms, and drinking contexts  on drinking patterns and problems among African-Americans. To see how stress influenced drinking, Studies have consistently found a positive relationship between drinking and drinking problems\u2014that is, as drinking increases, drinking-related problems increase . IncreasResearch regarding drinking patterns and drinking problems in African-Americans can be summarized as follows:African-Americans report higher abstention rates than do whites.African-Americans and whites report similar levels of frequent heavy drinking.Rates of heavy drinking have not declined at the same rate among African-American men and women as among white men.Variables such as age, social class, church attendance, drinking norms, and coping behaviors may be important in understanding differences in drinking and drinking problem rates among African-Americans and whites.Studies examining the determinants of drinking patterns and problems suggest that demographic and psychological variables may be important in understanding the differences in drinking patterns and drinking problems among African-American and white men and women. Despite the wide range of variables that have been studied, however, notable gaps exist in the research. None of the studies reviewed examined the effects of illicit drugs and tobacco use, the concentration of stores selling alcohol in a given area , or exposure to alcohol through the mass media on drinking patterns and drinking problems. The scant research on alcohol outlet density and media exposure is surprising, given the large number of alcohol outlets in many African-American inner cities and efforts by the alcohol industry to target African-Americans . Future studies should focus on those variables. In addition, few studies have included other ethnic populations, such as Asians and American Indians; those studies are needed to investigate the reasons behind the different trends in heavy drinking patterns for different ethnic groups.Continuing research is needed on the drinking patterns and drinking problems of African-Americans to address current gaps in knowledge. To ensure that interventions and policies to reduce drinking problems in African-American populations are guided by sound research, future studies will need to be theory based; use a wide range of study designs and variables; and include comparisons with other ethnic groups, such as Hispanics, Asians, and Native Americans. Panel studies also are needed to better understand changes in drinking patterns of African-Americans over time."}
+{"text": "Wilting disorder is an abnormal condition characterized by weakness and paralysis of the upper and lower extremities. Pathogenesis and treatment target of the disorder are unclear; hence, allopathic treatment is generally used to relieve the symptoms. To investigate the treatment mechanism and effect of Traditional Korean Medicine (TKM) in patients with wilting disorder, we reviewed in vivo studies that focused on the effect of TKM on the main symptoms of wilting disorder and treatment of the diseases that can cause these symptoms. We electronically searched the PubMed, Cochrane, and CNKI  databases using the following search terms: (weakness OR motor function disorder)  AND . We selected 11 studies that demonstrated the effect of TKM treatment on the main symptoms of wilting disorder. In these studies, inducted models of amyotrophic lateral sclerosis, myasthenia gravis, Duchenne muscular atrophy, polymyositis, and Guillain-Barre syndrome were used. With regard to treatment, herbal medicine was used in five studies, and acupuncture and bee-venom pharmacoacupuncture were used in three studies each. Future research is needed to determine the effectiveness of TKM treatment in patients with diseases that can cause the main symptoms of wilting disorder. Wilting disorder, also called \u201cWei-syndrome\u201d in Traditional Korean Medicine (TKM), is defined as an abnormal condition characterized by weakness and paralysis of the upper and lower extremities in the Korean Standard Classification of Disease and Cause of Death (KCD classification). The main symptoms of Wilting disorder are loss of muscle tone in the weakened or paralyzed parts, decrease in muscle strength, and decrease or disappearance of reflexes. In the TKM, the cause of wilting disorder is divided into the factors outside of the body and the factors inside of the body. The external factors include the traumatic events or overwork that can damage bones, joints, and soft tissues, fever causing neurologic dysfunction, and disease which have long morbidity period. The internal factors include energy reduction caused by wrong lifestyle or diseases and malfunctioning of viscera such as liver, heart, spleen, lung, and kidney , 2.There have been arguments between TKM doctors about the TKM treatment of wilting disorder, but the mechanisms and treatment effects of each treatment have remained unclear, despite many modern studies on wilting disorder in TKM , 2.The purpose of this study was to review clinical studies focusing on the treatment mechanisms and effects of TKM treatments on wilting disease. A modern study focusing on wilting disorder suggested that diseases such as myasthenia gravis, Guillain-Barre syndrome, amyotrophic lateral sclerosis, paralysis, polymyositis, and muscular dystrophy could manifest clinical signs similar to those of wilting disorder, such as weakness, paralysis, and loss of motion .So we tried to investigate the treatment mechanisms and effects of TKM treatments in these diseases. This study aimed to investigate the research trends of TKM treatment for diseases that can cause wilting disorder through utilizing various databases and analyze the results. This process will provide information and evidences of TKM treatment to treat wilting disorder in clinical practice and designing a clinical research about TKM treatments.We searched the PubMed, Cochrane, and CNKI databases from inception through April 2018. No language limitation was applied. Key search terms were  AND (weakness OR motor function disorder) AND .The data were extracted and grouped using a data extraction form that included the animal , the disease model type , the type of intervention, and the outcome measures . The data were extracted primarily by one author and checked by all other authors.We extracted 159 studies by using our key terms and read their titles and abstracts. Out of these 159 articles, 89 records remained after the duplicates were removed. Of these 89 articles, six articles were systematic review or review of literature, and 23 articles were case reports. There were 29 articles not satisfying intervention criteria; and 11 articles were not research studies on the treatment effect. Nine articles were excluded because of improper group-setting. After screening, we selected 11 animal model studies for analysis . We analWilting disorder can occur because of the abnormality of the muscle, neuromuscular junction, peripheral nerve, and lower and upper motor neuron.The main symptoms of wilting disorder include flaccid palsy, muscle atrophy, loss of reflex, muscular fasciculation, muscular contracture, and reaction of degeneration. Diseases that could cause this condition include myasthenia gravis, Guillain-Barre syndrome, amyotrophic lateral sclerosis, multiple sclerosis, paralysis, polymyositis, and muscular dystrophy.Myasthenia gravis is an autoimmune disease that results from abnormality of the neuromuscular junction. The pathogenesis involves the action of antibodies to block or destroy nicotinic acetylcholine receptors at the neuromuscular junction between the nerve and muscles and eventually prevent nerve impulses from triggering muscle contractions. The main symptoms of myasthenia gravis are painless weakness of specific muscles. The weakness becomes progressively worse during physical activity and improves at rest. Several in vivo studies have reported the effectiveness of TKM treatment with curative intent in patients with this autoimmune synaptopathy . In an aThe area and the integrated optical density of the immunoreactivity for the acetylcholine receptor at the neuromuscular junction of the phrenic nerve were significantly increased following acupuncture treatment .Another study investigated the protective role of herbal medicine, Sizunzi decoction, in the neuromuscular junction. Intervention with Sizunzi decoction resulted in the findings of close to normal NMJ structure and significantly increased expression of the acetylcholine receptor and agrin .Amyotrophic lateral sclerosis (ALS) is a disease characterized by abnormal function of the voluntary muscles. This malfunction results from death of the neurons which control voluntary muscles . ALS is Most of the studies have focused on bee venom pharmacoacupuncture at the Zusanli (ST36) acupoint. An animal study investigating the effect of bee venom pharmacoacupuncture on the central nervous system and muscle in an animal model of ALS showed that bee venom treatment at the Zusanli acupoint significantly enhanced motor function and decreased motor neuron death in the spinal cord compared to the control group. Furthermore, this treatment eliminated downstream signaling of inflammatory proteins, such as TLR4, in the spinal cord, and reduced levels of TNF-alpha and Bcl-2 expression in the ALS animal model .In another similar animal study, bee venom treated animals reported decreased expression levels of microglia marker and phospho-p38 MAPK in the spinal cord and brainstem; moreover, treatment with bee venom improved motor activity in animals with symptomatic ALS .Another study explored the effect of electroacupuncture treatment at the Zusanli acupoint. This study reported that ALS animal models treated with electroacupuncture showed a decrease in microglial cell activity and TNF-alpha expression in the spinal cord and brain stem. In addition, the treatment significantly improved motor activity compared to that in the control group and reduced neuronal cell loss in the ALS model .In a study investigating the effect of an herbal medicine, Wen-Pi-Tang, on the ALS animal model showed that the Wen-Pi-Tang treatment inhibited neuronal loss in the lumbar segment of the spinal cord of mice. In addition, astrocytes and CD11b positive microglial cell in the spinal cord that increase prior to neuronal loss were significantly reduced in the Wen-Pi-Tang treated group .Multiple sclerosis is a demyelinating disease with three main characteristics: plaque formation, inflammation, and destruction of the myelin sheaths of neurons. The insulating covers of nerve cells in the brain and spinal cord are damaged and this disrupts the ability of parts of the nervous system to communicate, resulting in muscle weakness and motor dysfunction . Apart fIn a study investigating the effect of bee venom in suppression of motor neuron loss and microglial cell activation, bee venom was injected at the Zusanli (ST36) acupoint in the experimental group. As a result, the symptoms of clinical disorder, pathologic changes, inflammatory cell infiltration, demyelination in the central nervous system, and levels of TNF-alfa, and serum nitrates were decreased in the multiple sclerosis model .Another study investigated whether Hyung bangpaedok-san (HBPDS), a traditional herbal medicine, has a beneficial effect in the multiple sclerosis model in rats. Onset-treatment with HBPDS alleviated neurological signs, reduced demyelination and the infiltration of microglia and macrophages, and reduced the mRNA expression of proinflammatory cytokines and chemokines in the spinal cord .Guillain-Barre syndrome is a rapid-onset muscle weakness caused by immune system-mediated damage to the peripheral nerve system. The muscle weakness begins in the feet and hands. This often spreads to the arms and upper body with bilateral involvement. The cause and mechanism of this disease is unknown .A study investigated the mechanism of electro acupuncture at the Shu-points of the five zang-organs for treatment of Guillain-Barre syndrome. In this study, electroacupuncture treatment increased the sciatic nerve movement conduction velocity and decreased the abnormal F wave incidence rate of the sciatic nerve in the Guillain-Barre syndrome model group .Duchenne muscular dystrophy is a severe type of muscular dystrophy caused by X-linked recessive gene. The muscular weakness is associated with muscle wasting of the voluntary muscles. The hips, pelvic area, thighs, shoulders, and calves are the first to be affected; subsequently, muscle weakness occurs in the arms, neck, and other areas .A study accessed the effects of herbal medicine on Duchenne muscular dystrophy. This study showed that the Liu-Wei-Di-Huang-Wan (LDW) and San-Lin-Pai-Tsu-San (SPS) can facilitate locomotor activity with the parameters of horizontal activity, total distance, number of movements, movement time, vertical activity, number of vertical movements, and vertical movement time .Polymyositis is a chronic inflammation of muscles related to dermatomyositis and inclusion body myositis. The hallmark of this disease is weakness and loss of muscle mass in the proximal musculature, as well as flexion of the neck and torso .A study investigated the therapeutic effects of Radix Bupleuri and Ramulus Cinnamomi on the polymyositis model. The herbal medicine treatment significantly increased expression of MyoD and myogenin and the function of myosin heavy chain and activated the Akt/mTOR pathway. In addition, the treatment suppressed the TNF-alpha activation .Due to lack of understanding of the cause and mechanism of wilting disorder, allopathic treatment is generally used to relive the patients' symptoms of pain and weakness. We reviewed the in vitro studies focusing on diseases that can cause the symptoms of wilting disorder and reported our results. Our results indicated that TKM was effective in improving the electrophysiological status, histological and biochemical measurement values, and motor function value index, especially in animal models of myasthenia gravis, amyotrophic lateral sclerosis, and multiple sclerosis. However, there was lack of evidence for the TKM treatment effect in the Guillain-Barre syndrome, Duchenne muscular atrophy, and polymyositis models.This study has some limitations. First, the use of limited search strategies returned a small number of studies. However, very few studies have been reported on the effect of TKM on wilting disease. Second, it was difficult to follow a strictly standardized method of analysis because of limited access to complete data from the studies. Future research is required to fully evaluate the effectiveness of TKM treatment in animal models."}
+{"text": "Renal cell carcinoma (RCC) is the most common tumor of the kidney. After diagnosis, 20\u201330% of patients will relapse, with a high probability of death from cancer-related causes. The development of non-invasive biomarkers will allow the identification of patients with a high risk of recurrence after radical or partial nephrectomy and will improve the assessment of tumor response to targeted therapy or immunotherapy. The search for non-invasive diagnostic techniques represents one of the most difficult challenges for cancer researchers. The contemporary scenario includes a variety of strategies that share the aim of maximally reducing the impact of the diagnosis on patients' quality of life (QoL). In this context, liquid biopsy offers a promising perspective for cancer diagnosis and monitoring, with several advantages compared to traditional diagnostic procedures . Indeed,The liquid biopsy of circulating tumor cells (CTCs), which belong to the larger family of circulating rare cells (CRC), has been validated and approved by the US Food and Drug Administration (FDA) as a useful prognostic tool in a variety of cancer types . This isIn the last decade, several studies have investigated the clinical and pathological significance of CTC numbers and characteristics in patients with urogenital cancers , 7. In vVon Hippel\u2013Lindau (VHL) gene and include LOH at 3p and epigenetic silencing. VHL inactivation is a crucial event in the majority of clear cell RCC and represents the only ubiquitous event, in contrast from the other genetic and/or epigenetic aberrations reported which are just subclonal  \u201319 and tThe collection, identification, enrichment, and analysis of CTC require the use of different methods, including the following: (1) Epithelial or non-epithelial marker-dependent isolation; (2) RT-PCR-based methods; (3) and morphological- and cell size-based detection .The first method consists of the detection of CTCs through epithelial markers, such as the epithelial cell adhesion molecule EpCAM, . EpCAM iCAIX, VHL and Cadherin-6 (CDH-6)  . VHL genof cases . On the  samples .The third method is built upon size-based blood filtration combined with morphological and genetic analyses. The need to associate different techniques derives from the evidence that cytomorphological classification alone is not sufficient to detect CTCs in RCC patients . InteresThe survival mechanisms underlying the circulation and migration of CTCs depend on multiple factors. Their biological characteristics, genetic alterations, epithelial mesenchymal transition, and cancer stem cell properties are internal factors that influence their survival. Great importance is now also being attributed to the external factors in the bloodstream microenvironment, consisting of platelets, immune cells, cytokines, and circulating tumor microemboli (CTM) .ex vivo expanded CTC lines, administration of digitoxin significantly inhibited the capacity of CTC clusters to generate metastases  are being developed to better characterize CTCs. With this method, independent of cell size variation, and free of hypotonic damage as well as anti-EpCAM perturbing, it is possible to karyotype chromosome ploidy of CTCs and phenotype multi-protein expression. Among different cancers, an aneuploid chromosome 8 (tetraploid or polyploid) identified a positive CTC  combined with immunostaining-fluorescence tive CTC \u201344. Thistive CTC , 46.A novel straight microfluidic chip technology to focus and capture CTCs has been applied in head and neck cancer patients. The microchip is designed based on inertial migration of cells in a straight microchannel and allow to isolate single CTCs, CTCs clusters, and CTM by a size-based method, with high recovery efficiencies and low background cell contamination , 48.In future years, technical advances should aim to isolate a greater number of CTCs in metastatic patients than in patients with localized disease and to find the same mutations present in the correspondent histologic sample or, especially, in the metastatic cohort. In our opinion, this could be realized by improving the connection between cytomorphological and genetic analyses, thus overcoming the limits of present techniques, which can be challenging and time-consuming. Indeed, the specificity of CAIX and CDH-6 for CTCs in RCC patients is poor and could be increased only by the design of studies focused on comparing CTCs isolated from patients with clear cell and from patients with benign kidney diseases or healthy volunteers.We hope that in future years whole genome, transcriptome, and proteome analyses of single cells could lead to an increase in our knowledge of tumor heterogeneity and acquired drug resistance. In the localized RCC setting, CTCs could have potential as a surveillance biomarker for disease recurrence. Earlier detection of metastatic RCC, prior to the onset of symptoms, may lead to improved clinical outcomes. In patients with metastatic disease, CTC analysis could be used to select patients for biomarker-guided clinical trials. As in colorectal cancers, the mutational profile of metastatic RCC could evolve after treatment progression, developing an acquired resistance to therapy potentially investigable in a non-invasive way with CTCs. Moreover, the introduction of data on CTCs within the TNM classification represents another step forward on the route of personalized medicine for RCC patients.RCC may benefit from the development of non-invasive and reliable biomarkers, enabling early and timely personalized treatment changes. The introduction of CTC analysis within daily clinical practice for patients with RCC seems still far at the moment. However, the advances obtained in the last 5 years in isolating and analyzing CTCs bring optimism about the future therapeutic landscape in RCC patients.RM and MSc: conception and design; MSa, AC, and FM: drafting the manuscript; NB and ABG: review of the literature; LC, SB, and AL-B: critical revision of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Health systems face increasingly complex challenges, such as the growing burden of chronic noncommunicable diseases, multisource pollution, new epidemics and antimicrobial resistance. These challenges have prompted an important shift in focus from curative care to health promotion and disease prevention, as well as the development of new models of service delivery, financing and governance for primary health care.Global health stakeholders are pushing for renewed commitments to enhance primary health care in the 21st century, in light of the 2018 Declaration of Astana.Achieving the health-related sustainable development goals (SDGs), including universal health coverage (UHC), will not be possible without stronger primary health care.\u2013Most people not covered by essential health services belong to disadvantaged groups. Primary health care can address this issue because it enhances equity and is the most feasible approach to reach people.However, in many low- and middle-income countries, primary health-care systems are weak and do not provide sufficient high-quality, comprehensive, people-centred and integrated care. In addition, the core principles of empowering people and strengthening health systems are often overshadowed by short-term interventions, with countries attempting to meet an overwhelming number of programme-specific targets that are dependent on donor priorities and funding. This situation highlights the need to strengthen comprehensive primary health-care systems based on local priorities, needs and contexts. These systems should be co-developed by people who are engaged in their own health.Implementation and systems reforms of primary health care are also challenged by the lack of contextualized knowledge and scarcity of research on effective and acceptable approaches to strengthen primary health care, especially in low- and middle-income countries. Primary health-care research that is applicable to different health systems settings is needed.Bulletin of the World Health Organization will publish a theme issue on advancing the science and practice of primary health care as a foundation for UHC. The theme issue aims at providing a forward-looking view of the innovations, challenges and shared responsibilities in driving primary health care, and at filling gaps and fostering discussions around what is needed to implement a primary health-care vision towards UHC. To tackle these challenges, the We welcome manuscripts that capture learnings and experience in the implementation of primary health-care policies and interventions as well as the strengthening of primary health-care systems. The ability of countries to fulfil the commitments made in the Declaration of Astana depends on the active engagement of various stakeholders of primary health care. We therefore encourage analysis of challenges, contextualized research, good practices and innovations in enhancing primary health care at the national or sub-national level, with a strong focus on stakeholder engagement and impact on population health and equity. Papers could focus on, for example, multisectoral action for primary health care and equity, implementation research and analysis of health systems reforms, bridging the gaps in workforce, digital health, quality improvement and the contribution of primary health care in advancing UHC and the SDGs.Documenting good practices on effective approaches to engage and empower people, communities, youth and other stakeholders will also be useful to support efforts enhancing the responsiveness and people-centeredness of primary health care. The theme issue will focus on cross-cutting themes and challenges of primary health care affecting all countries, but we also encourage submission of experiences from low- and middle-income countries and conflict-affected and humanitarian settings, as well as comparative cross-country analyses.Bulletin\u2019s guidelines for contributors (available at: http://www.who.int/bulletin/volumes/96/1/18-990118/en/) and the cover letter should mention this call for papers.The deadline for submission is 30 November 2019. Manuscripts should be submitted in accordance with the This theme issue will be launched at the Global Symposium on Health Systems Research in Dubai in 2020."}
+{"text": "Long-distance caregiving (LDC) is a growing phenomenon and common experience for caregivers of frail older adults. In fact, 11% of family caregivers in the US live more than two hours distance from the care recipient (CR). Unfortunately, there is a paucity of research on unique experiences of LDCs and the impact of LDC on the mental health of LDCs. This symposium presents findings from the NIA funded Fordham Long-Distance Caregiving Study (R21AG050018) analyzing data of 304 long-distance caregivers (LDCs). The overall study goal was to better understand how LDCs deal with the structural constraint of distance, and to examine LDC consequences and resources. First, Horowitz presents the study background, characteristics of the sample, and provides a description of the unique experiences of LDCs. Next, Cimarolli concentrates on the Sociocultural Stress Process Model applied to LDC. Her study tested the impact of LDC on mental health and investigated resources  which could mediate the association between caregiving stressors and mental health outcomes. The third paper  presents data related to satisfaction with formal service providers for four subgroups of LDCs based on CR residence and dementia status. Finally, Jimenez focuses on the characteristics of LDCs\u2019 network of other informal caregivers (IC) providing assistance to the CR and factors are associated with more help received from other ICs. Dr. Pruchno, an expert in caregiving research, will discuss study findings. The symposium provides insights into unique experiences of LDCs, the impact of LDC on mental health, and resource use among LDCs."}
+{"text": "Drosophila melanogaster are derived from the imaginal discs, epithelial sac-like structures specified in the embryo that grow and pattern during larva development. In the last decades, genetic and developmental studies in the fruit fly have provided extensive knowledge regarding the mechanisms that direct the formation of the appendages. Importantly, many of the signaling pathways and patterning genes identified and characterized in Drosophila have similar functions during vertebrate appendage development. In this review, we will summarize the genetic and molecular mechanisms that lead to the specification of appendage primordia in the embryo and their posterior patterning during imaginal disc development. The identification of the regulatory logic underlying appendage specification in Drosophila suggests that the evolutionary origin of the insect wing is, in part, related to the development of ventral appendages.Appendages are external projections of the body that serve the animal for locomotion, feeding, or environment exploration. The appendages of the fruit fly  Molecular and genetic studies in the fruit fly, Drosophila melanogaster, have provided the basis of appendage development and served for comparative analysis with other arthropods . ,19. 8,19lication ,21. The lication ,22,23,24lication ). Thereflication ,22,23.snail (sna) and vg  genes, while the VP expresses Distal-less (Dll) and the Sp family members Sp1 and buttonhead (btd) . TDll gene . At the Dll gene ,67  in posterior cells. Compartment boundaries are the source of signaling molecules that organize the pattern and growth of the imaginal disc [After the specification stage in the embryonic ectoderm, each imaginal primordium follows a developmental program in which the same signaling pathways and an increasing number of transcription factors cooperate to pattern the growing epithelium. In this process the size of each disc increases by cell proliferation, and the epithelium is progressively divided into domains of gene expression that confer each territory with particular cell identities. A common aspect of all thoracic discs is their division in A and P compartments conferred by the expression of nal disc . In thisAntp is the selector Hox gene for leg identity that is expressed in the leg imaginal disc but not in the antenna disc. As expected for its selector function, Antp mutant legs are transformed into antenna and Antp ectopic expression in the antenna converts it into leg [hedgehog (hh) which acts as a short-range signal that activates the expression of dpp and wg in the anterior dorsal and ventral halves of the disc, respectively [H15 and midline (mid) and the repression of dorsal genes such as Doc and optomotor blind (omb) [wg mutants all the ventral structures are lost and replaced by a mirror duplication of dorsal ones and the reverse phenotypes are observed for dpp mutants [The third instar leg imaginal disc is roughly circular in shape with the distal-most region of the leg located in the center of the disc, and the most proximal leg segments and the pleura arising from the periphery of the disc. into leg . The legectively . Dpp andectively ,78,79,80nd (omb) ,81. Ther mutants ,78,80,82Dll [dachshund (dac) in the medial domain of the leg disc, whereas high levels of Wg and Dpp represses its expression in the distal tip [Dll and dac expression is maintained in part by autoregulatory mechanisms [hth is restricted to the periphery of the disc by a Wg and Dpp dependent repression mechanism [elbow (el) and no ocelli (noc) genes that act in the leg and the wing discs to repress hth expression, and therefore body wall fates [hth, dac, and Dll, respectively , Bar (B), and rotund (rn) among others [Delta (Dl) and Serrate (Ser) [btd and Sp1 are co-opted later during imaginal development to control the growth and pattern of the leg, in part through the regulation of Ser expression and therefore Notch signaling [dysfusion (dysf), proximal joints such as the odd-skipped gen family of for all joints like dAp-2 , that regulates the expression in a distal to proximal manner of g others ,96 . Beste (Ser) ,100. Notte (Ser) ,102,103 ignaling ,104,105.e dAp-2  and vg [nub and vg is accompanied by the repression of the body wall genes teashirt (tsh) and hth (hth/tsh (notum and hinge) and vg (wing blade) is analogous to the leg disc, where hth/tsh are also restricted to the proximal domain to promote body wall structures  that subdivide the thorax and the wing field in dorsal (D) and ventral (V) compartments [vg expression and wing outgrowth [vg in the cells that will become the wing blade [hth and vg subdivide the wing field in the pouch and the hinge [Iroquois-complex (Iro-C) that are repressed in the wing field by Dpp secreted in the A-P boundary  and vg . The act and hth  [114,115ructures C. It haserritory ,114,116.artments ,117,118.utgrowth . Ap regung blade ,121,122.he hinge ,114,121.boundary  [123,124al fates .en expression subdivides the wing disc in two populations of cells, the A and P compartments. The A-P boundary acts a source of positional information where Hh secreted from the posterior compartment activates the expression of dpp in A cells. Dpp and Hh are both required to pattern the wing blade along the A-P axis (brinker (brk) to the lateral domain of the wing [omb and the spalt genes  in nested domains [As in the leg disc, A-P axis . Dpp difthe wing ,129,130. domains ,132).hth, spineless (ss), and Antp that converts every antenna part to its corresponding leg segment [The eye-antennal disc (EAD) is formed by different populations of cells located in the cephalic segments that coalesce together . The EAD segment ,134  and sine oculis (so)  [distal antenna (dan) and distal antenna related (danr) genes, responsible for the specification of distal antenna identity [Early on larval development (L1) the EAD shows no sign of regional specification and presents uniform expression of several transcription factors including lis (so) A [135,13lis (so) A. Accordo)   ,147. Ss identity ,149.Drosophila melanogaster has provided a detailed picture of the molecular mechanisms that lead to the specification and patterning of the adult appendages. Importantly, many of the signaling pathways and transcription factors identified in the fly have similar functions during vertebrate limb development. However, many important questions remain unsolved. First, the target genes and the regulatory networks controlled by the transcription factors that subdivide the appendages along the different axes are still largely unknown. This includes the analysis of the molecular interactions between patterning genes and signaling pathways. Second, further investigation would be required to unravel how the patterning information is translated into cellular behaviors , which are ultimately responsible for the characteristic shape and size of the different appendages of the fly. The use of whole genome techniques such as ChIP (Chromatin Immunoprecipitation) or ATAC (assay for transposase accessible chromatin) assays, coupled with whole genome sequencing is essential to identify the target genes and the regulatory landscapes governed by the patterning transcription factors. In addition, live imaging techniques would provide novel information of the morphogenetic processes and dynamics during appendage specification and formation.In this review, we have discussed how the study of"}
+{"text": "Many Latino older adults delay seeking help for symptoms of Alzheimer\u2019s Disease or Related Dementia (ADRD) due to substantial barriers to services. Community-based Natural helpers (NHs) can increase health-related knowledge and can serve as full partners in health education and promotion. This paper presents the process and product of the first phase of a community-based participatory research study to develop a culturally-tailored intervention increasing knowledge about ADRD and services in East Harlem, NY. We describe the results of the initial survey and development of El Barrio SHARE, an intervention that recruits and trains community residents to provide information and referrals about dementia, tapping into natural community networks of people  who interact with and have longstanding relationships with older adults in the course of their work. NHs are well-positioned to observe and detect problems, and can link elders to relevant, culturally-sensitive resources, accessible support, and treatment."}
+{"text": "Marked erosion with punched-out resorptive lesion and dilatation of joint cleft, on the distal interphalangeal joint, were seen.In addition, bone erosion and narrowing of the joint cleft were seen on carpometacarpal joint."}
+{"text": "Somatic embryogenesis (SE) and organogenesis have become leading biotechnologies for forest tree improvement and the implementation of multi-varietal forestry. Despite major advances in clonal propagation using these technologies, many forest tree species, such as conifers, show a low regeneration capacity. Developmental factors such as genotype, the type and age of the explant or tissue, and the age and maturity of the mother tree are limiting factors for the success of propagation programs. This review summarizes recent research on the molecular pathways involved in the regulation of key steps in SE and organogenesis of forest tree species, mainly conifers. The interaction between auxin and stress conditions, the induction of cell identity regulators and the role of cell wall remodeling are reviewed. This information is essential to develop tools and strategies to improve clonal propagation programs for forest tree species. Recalcitrance to somatic embryogenesis (SE), adventitious rooting (AR) from stem cuttings or adventitious shoot (AS) formation is a major limitation for the clonal propagation/micropropagation of elite trees in many woody species, especially forest tree species. Several reviews on the state-of-the-art of the application of these techniques as well as the impacts of recalcitrance and tree domestication on forestry have been published . There aThis review summarizes the results of recent studies on the molecular and cellular mechanisms involved in the regeneration capacity of forest tree species by SE, AR, or AS formation, with special focus on conifers. The interaction between auxin and stress conditions, the induction of cell identity regulators and the role of cell wall remodeling are mainly reviewed. We have focused on the early stages of regeneration, when the transition from a somatic to an embryonic or meristematic cell occurs, in an attempt to highlight factors or common pathways that may be relevant for the control of the recalcitrance.The induction of SE, AR, or AS formation is a multi-factorial developmental process that includes the effects of hormones and chemical and physical factors. Such factors include the composition of media, growth conditions, stress associated with wounding (excision) or the culture environment, and other stress factors . It has The conditions and requirements for the induction of SE, AR, or AS formation vary within and among forest tree species; however, some common pathways can be identified. The most obvious is the absolute requirement for auxin and polar auxin transport during the initiation stage. Plant growth regulators play a central role in both the initiation of pro-embryogenic masses (PEMs) and the differentiation and maturation of somatic embryos. In forest tree species, initiation and proliferation of embryogenic masses (EMs) are induced in the presence of auxin and cytokinin. Withdrawal of these plant growth regulators results in the differentiation of somatic embryos from PEMs. Embryos are subsequently transferred to medium supplemented with abscisic acid (ABA) to induce somatic embryo maturation.Abies alba  has been shown to negatively affect embryogenesis initiation and development. This indicates that high levels of endogenous IAA and polar auxin transport are required for resuming proliferation and activating the embryogenic program during cell reprogramming leading to SE. Similar results have been described during SE from adult leaf tissues of Quercus alba  have been shown to reduce the level and distribution of auxin in rooting cells 3 and PIN7 was only marginally influenced by time after induction, physiological age, or auxin treatments. However, the expression of AUXIN RESPONSE FACTOR (ARF)6 and ARF8, which promote AR in model species, increased only in rooting-competent parenchyma cells. In addition, expression of ARF17, which inhibits rooting, decreased concomitantly with the increase in ARF6 and ARF8 expression. Auxin was required for localizing changes in gene expression. Recalcitrant mature cuttings showed a diffuse and uniform mRNA signal among all tissue types. The authors concluded that recalcitrance of black walnut to AR resulted from the failure of rooting-competent cells to perceive molecular signals initiated by auxin in mature cuttings. This confirmed the results of earlier studies on AR in conifers, demonstrating that auxin acts as an unspecific signal of preset cell reaction patterns -related homeobox gene family of transcription factors whose expression is associated with specifying apical cell identity during the earliest stages of Arabidopsis embryogenesis , a novel NF-YB subunit of the CCAAT-binding transcription factor that functions as a master regulator of embryogenesis , encoding an AP2/ERF responsive transcription factor involved in promoting cell proliferation and morphogenesis during embryogenesis 3 gene, encoding a B3-domain transcription factor involved in ABA signaling , indicating that it may be involved in cell division and could not be used as a marker of EMs like in white spruce 1-2 and WOX13 genes, the former encoding a LRR receptor-like kinase involved in the induction of SE competence in culture . The large number of differentially expressed genes encoding cell cycle regulators, PCD-related proteins, and BBM and WOX transcription factors suggested that these proteins may play crucial roles in PEMs establishment and development in larch , PrSCR, and SCARECROW-LIKE (SCL) 6, PrSCL6, were significantly reduced or non-existent in adult tissues that had lost the capacity to form adventitious roots, but were maintained or induced after the reprogramming of adult cells in rooting-competent tissues. GRAS gene expression associated with the maturation-related decrease in adventitious root formation in chestnut. Other studies have reported asymmetrical increases in the transcript levels of other members of the GRAS gene family, PrSCL1  were upregulated in embryogenic tissues compared with non-embryogenic ones. This finding indicated that cell wall signaling and intercellular communication play important roles in the acquisition of embryogenic competence and the initiation of SE in this species. Early work on SE in Norway spruce described the importance of the interactions among cells, and the roles of cell wall signaling and chitinase-cleaved forms of AGPs for induction of SE (Abies hybrid cell line, compared with low embryogenic lines. The AGPs progressively accumulated within the extracellular surface matrix network, a structure covering embryogenic cells, during the early stages of embryo development (To understand the molecular mechanisms regulating the role of the cell wall in the initiation of SE, on of SE . An increlopment . They wein vitro protocols, and have similar early embryogenic markers in Q. suber (Q. alba (Cell wall remodeling by increasing pectin esterification and an increase in endogenous auxin occur concomitantly at the early stages of two embryogenesis pathways: microspore embryogenesis; and embryogenesis from immature zygotic embryos. These pathways can be induced by different Q. suber . Similar(Q. alba .Microtubules and microfilaments are involved in cell polarity and the orientation of the cell division plane, cell wall development, intracellular transport processes, the mechanical properties of the plant cell and tissues, and how these tissues interact with the plasma membrane and the cell wall. Therefore, along with the cell wall, these structures may play important roles in the organization of new structures during regeneration. Microtubules and F-actin were both found to be important for embryogenesis in Norway spruce . CytochaEucalyptus (Eucalyptus. The relevance of microtubule remodeling in the maturation-related decline of AR has been demonstrated using microtubule-disrupting drugs, which increased the rooting capacity of adult cuttings of Eucalyptus grandis (Several studies have identified components of the molecular pathways underlying cell wall and cytoskeleton remodeling which are associated with adventitious root formation and the maturation-related decline in AR in pine and calyptus . These a grandis .Flexibility of the interactions between the cell wall, plasma membrane, and cytoskeleton is required to establish new cell polarity, reorient cell division planes, modify growth direction and induce a new morphogenic program. The components involved in these pathways are regulated by auxin, stress or cell identity regulators during induction of SE or organogenesis. In addition, modifications in the cell wall and cytoskeleton result in changes in cell polarity and the polarization of auxin transporters and auxin gradients.SERK was induced by auxin and stress conditions (PpWOX13-like genes were found to be involved in the control of cell wall loosening to facilitate stem cell formation in Physcomitrella patens (Arabidopsis (de novo regeneration. Molecular dissection of the mechanisms underlying regeneration capacity and identification of the genes expressed in common interrelated pathways regulating competence for SE and organogenesis would allow identification of an expressional signature characterizing specific levels of regulation, developmental stages, age, position, timing, type of tissues, clones or genetic traits associated with competence for SE or organogenesis. Cutting-edge technologies for analyzing multigene expression profiling may provide additional prognostic information for competence. Furthermore, the identification of rechanneling and master genes may provide additional tools for the modification of competence. Moving forward in the same direction, a more precise characterization of tissues used in operational programs will allow individualized management after diagnosis.Several interrelated pathways are involved in the plasticity of plant cells for SE or organogenesis in forest tree species Figure . Stress,nditions . Interesa patens . Crosstabidopsis ,b. All tCD-S conceived the idea, gathered data, and wrote the manuscript.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In response to the urgent need to scale up access to antiretroviral therapy, the Global Nursing Education Partnership Initiative (GNCBP), a PEPFAR program administered by the U.S. Department of Health Resources and Services Administration (HRSA), was implemented from 2011 to 2018 by ICAP at Columbia University. Working closely together, HRSA and ICAP partnered with local nursing leaders and ministries of health to strengthen the nursing and midwifery workforce across 11 countries. This multi-country project, developed to address critical gaps in nursing education and training worked across six building blocks of health workforce strengthening: infrastructure improvement, curricula revision, clinical skills development, in-service training, faculty development and building partnerships for policy and regulation to increase the quality and quantity of the nursing and midwifery workforce. As a result, 13,387 nursing and midwifery students graduated from schools supported under GNCBP. A total of 5,554 nurses received critical in-service training and 4,886 faculty, clinical mentors and preceptors received training in key clinical care areas and modern teaching methodologies. ICAP completed 43 infrastructure enhancements to ensure environments conducive to learning and strengthened nursing leaders as best evidenced by the election and formation of Mozambique\u2019s first national nursing council and the NEPI Network. Going forward, efforts to strengthen nursing and midwifery can build on the results of the GNCBP project. Going forward, a new group of African nursing leaders are being supported to advocate for high quality patient-care led through inter-professional collaboration and participation in international efforts championing the critical role of nurses in achieving universal health coverage. To achieve the UNAIDS  90-90-90In response, the Global Nursing Education Partnership Initiative (GNCBP), a PEPFAR program administered by the U.S. Department of Health Resources and Services Administration (HRSA), was implemented by ICAP at Columbia University. Working closely together, HRSA and ICAP have partnered with local leaders to strengthen the nursing and midwifery workforce. This multi-country project, developed to address critical gaps in nursing education and training, was launched in 2011, with the field work completed in September 2017. The GNCBP spanned 11 countries and included two subprojects; the Nursing Education Partnership Initiative (NEPI) and General Nursing (GN). The GNCBP supported local projects, institutions, and networks to expand, enhance, and sustain the nursing and midwifery workforce through NEPI and GN . The purpose of NEPI was to strengthen both the quality and quantity of the nursing and midwifery workforce through strengthened nursing and midwifery education. The NEPI project had five broad objectives: 1) strengthen teaching/learning infrastructure; 2) improve quality and relevance of teaching and learning; 3) improve the capacity of nursing and midwifery faculty; 4) build governance, leadership and administrative capacity within education institutions; and 5) enhance partnerships and networks. With the release in 2014 of PEPFAR 3.0 \u2013 Across the six countries supported by NEPI, a total of twenty-two schools of nursing participated Table . SchoolsA brief description of nursing and midwifery strengthening efforts within each building block is provided below.Faculty development focused on improving the ability of faculty to lead quality education programs and in later years to provide greater support and attention to nursing and midwifery education locally and regionally. Support was provided for a wide array of educational opportunities, including but not limited to, in-service training initiatives, such as nurse initiated and managed ART (NIMART), training in the set-up and use of simulation-based education and training, development of competency-based curricula, the nursing process, as well as tuition support for those nurses pursuing Master\u2019s and PhD degrees. In the final year of NEPI, a leadership webinar series was undertaken, as well as an in-person nursing and midwifery leadership development workshop.Robust nursing education and leadership networks were developed across NEPI-supported institutions and active links to regional and international nursing bodies have been formed through local technical working groups, the \u2018NEPI network\u2019, and through supporting local, regional and international conference attendance.Prior to the NEPI program, nursing schools lacked the basic equipment and supplies including textbooks, journals and lecture halls able to accommodate an increased number of students. WHO, in the 2006 World Health Report, recognized the importance of increasing the size of the health workforce but at the same time improving educational infrastructure . \u201cInsuffNursing and midwifery curricula needed to be updated to reflect nurses and midwives current scope of practice and \u2018real world demands\u2019. We used the backward design to curriculum development was employed throughout the network of schools . EducatoWithin the NEPI project, ensuring that nursing students were both competent and confident was prioritized. Competency-based curricula were coupled with improved clinical skills training through both simulations and supervised clinical practice. The development of simulation-based education (SBE) included the procurement, set-up and training on use of SBE. Training was provided by both the equipment supplier, as well as regional faculty trained in SBE. High, medium and low fidelity equipment were acquired to ensure students had the ability to learn core skills in a controlled practice environment. Mannequins able to simulate routine nursing functions, such as venipuncture and intravenous infusion were complemented with higher fidelity mannequins that could simulate life-threatening conditions, such as emergency obstetric complications. Faculty were trained in the use of a wide range of equipment, including computer aided simulation which allowed dynamic manipulation of the \u2018patients\u2019 condition. Such features enable students to acquire experience and skills to be able to more competently deal with rare events, such as post-partum haemorrhage, as well as allowing faculty to assess student\u2019s competence for real world challenges. In addition to SBE, NEPI country programs strengthened clinical training through preceptor education and training, improved access to rural practice settings, and allowed for the development and use of model wards.Continuing professional development (CPD) included increasing faculty access to HIV competency-based e-learning, with a pilot of Option B+ e-learning at NEPI supported schools in Lesotho, Zambia and Malawi and NIMART in-service training. Local, regional and international nursing conference participation and abstract submission was encouraged. Over the life of the project, NEPI attended and presented as such conferences as ECSACON , Sigma Theta Tau Honor Society of Nursing, the International Council of Nurses (ICN) and the Association of Nurses in AIDS Care (ANAC). With the PEPFAR Pivot, CPD courses and abstracts focused on HIV priority areas.We present results across the six building blocks is presented here. Table  The PEPFNursing Now Campaign, which builds on the Triple Impact report championing the critical role of nurses in achieving universal health coverage [By supporting the education and training of over 13,000 new nurses and midwives, the NEPI program has made a significant contribution by increasing both the quality and the quantity of the health-care workforce in sub-Saharan Africa and strengthening the health care workforce\u2019s ability to respond to HIV . In addicoverage .Nurses provide the majority of HIV services in Africa. Epidemic control will not be achieved without a strong nursing and midwifery workforce at the front lines of primary health care. The NEPI project is the first large-scale systematic multi-country investment in Africa to strengthen nursing and midwifery education reflective of clinical practice. NEPI leaders now drive education and practice change at 22 schools of nursing in Africa, equipped with the basic building blocks for quality education. Recent inter-professional collaboration efforts are building partnerships across professions to drive improvement in education, research and service delivery. Yet, much work remains to ensure nursing and midwifery strengthening is sustained and shared with the thousands of nursing and midwifery schools that lack the basic building blocks of high quality education. The critical role of nurses in HIV must continue to be met with substantive investment in nursing and midwifery education."}
+{"text": "Equitable access to essential psychotropic medicines at primary level is fundamental to universal health coverage for mental health. It relies upon rational selection, affordable pricing, financial protection and consistent supply systems. Which medicines are selected as essential impacts patient care and the economic sustainability of the health system. Rational selection uses the best available evidence for efficacy, safety and acceptability, and requires the assurance of affordability, obtainability and appropriate usage of the medicines. The process should be reliable, transparent and consultative.The aim of this study is to describe the process of rational selection of essential psychotropic medicines at primary health care (PHC) level, using SSRIs as an example.Population, intervention, comparison and outcome (PICO) questions were developed for a rapid review of SSRIs for depression and anxiety. PubMed, Trip Database and Cochrane Library were searched for evidence, which was critically appraised (graded as per SORT criteria) and synthesised. Good governance principles were maintained using a consensus decision-making process within the constraints of the PHC Expert Review Committee\u2019s terms of reference, confidentiality and conflict of interest policies. Evidence-based medicine principles were used, considering social values of equity, acceptability, comparative cost and relative budget impact analysis.The PubMed search for meta-analyses yielded 588 articles, of which 13 met inclusion criteria. An additional 4 meta-analyses were retrieved from the Cochrane Library and 4 from additional reference lists. A second search specifying an HIV population retrieved 43 articles, of which 3 were included. The evidence for efficacy and harm of 24 papers was critically appraised by the committee. Conflicts of interest were declared, and there was appropriate recusal from the final decision-making, which took place in July 2018.Rapid reviews using an evidence-based medicine framework contributed to the selection of SSRIs for the PHC essential medicine list. This approach is intensive in terms of resources and capacity, requiring adaptation to the South African setting. Important limitations include time pressure and the use of a single reviewer, with possible incomplete database searches and reviewer bias. Nevertheless, the process allows for thorough, consistent and transparent decision-making, and improved capacity is recommended."}
+{"text": "While family caregiving of the elderly has long been part of the cultural life of most OECD countries, longer life expectancy combined with low fertility rates has increased the share of the population dependent on current workers and minimized the available population of informal caregivers. The demand for expanded public provision of long-term care (LTC) resulting from this demographic shift prompted reforms in many OECD countries in the 1990s and 2000s. Differences in these reforms provide an opportunity to examine how individual choices between formal and informal care types are shaped by the policy context. I use longitudinal data on elders in three OECD countries, Sweden, Germany, and Japan, to examine LTC decisions under three varied approaches to population aging. The direction of LTC reforms in each country has been shaped by the existing model of care provision and financial constraints. In response to cost pressures, Sweden introduced need-based provision, financial devolution, and market-based approaches to its universal care model. Germany and Japan, in contrast, widely expanded restricted LTC coverage through public LTC insurance models. I use three multinomial logistic models of the LTC decision to test how differing policy schemes influence choices between formal and informal care. Using longitudinal Global Gateway to Aging data for each country, I model the LTC decision in each country as a factor of demographic and need characteristics of the elder experiencing limitations, characteristics of their family, and eligibility for publicly-provided LTC."}
+{"text": "For more than a decade, the United States has performed environmental monitoring by collecting and analyzing air samples for a handful of biological threat agents (BTAs) in order to detect a possible biological attack. This effort has faced numerous technical challenges including timeliness, sampling efficiency, sensitivity, specificity, and robustness. The cost of city-wide environmental monitoring using conventional technology has also been a challenge. A large group of scientists with expertise in bioterrorism defense met to assess the objectives and current efficacy of environmental monitoring and to identify operational and technological changes that could enhance its efficacy and cost-effectiveness, thus enhancing its value. The highest priority operational change that was identified was to abandon the current concept of city-wide environmental monitoring because the operational costs were too high and its value was compromised by low detection sensitivity and other environmental factors. Instead, it was suggested that the focus should primarily be on indoor monitoring and secondarily on special-event monitoring because objectives are tractable and these operational settings are aligned with likelihood and risk assessments. The highest priority technological change identified was the development of a reagent-less, real-time sensor that can identify a potential airborne release and trigger secondary tests of greater sensitivity and specificity for occasional samples of interest. This technological change could be transformative with the potential to greatly reduce operational costs and thereby create the opportunity to expand the scope and effectiveness of environmental monitoring. The release of a BTA as an aerosol has the potential to kill thousands of individuals Riedel, . The iniSurveillance for a biological attack currently relies on a combination of public health/clinical surveillance and environmental monitoring. Public health/clinical surveillance involves a combination of syndromic disease surveillance  met to discuss the current state-of-the-art technology for 9 h over three consecutive days during a conference on chemical and biological terrorism defense. The participants included past and present DHS program managers tasked with Research and Development to support the Biowatch program, experts who have contributed in various ways to environmental monitoring of BTAs over the entire history of the Biowatch program, and members of other U.S. Government agencies that have participated in prior assessments of the Biowatch program. State government end-users of the Biowatch program did not attend the scientific conference from which this discussion group was assembled. The discussion group was tasked with providing recommendations to address three specific challenges: value and benefit to public health, cost and sustainability, and probability of detection. The consensus recommendations from the discussion group include operational and technological changes that range from incremental to transformative. Implementing these recommendations could lead to a more robust and cost-effective environmental monitoring program.detect-to-warn and detect-to-treat. The two operational modes were originally defined in the context of warning systems for U.S. military personnel . In the detect-to-warn mode, the early cases of illness diagnosed through conventional public health channels provide confirmation of an exposure event. The early cases can also provide additional characterization of the event and the identification of the potential exposure zone that can be used to trigger a larger public health response for soon-to-emerge cases. Detect-to-warn is the easiest mode to implement. Current environmental monitoring for airborne BTAs operates in the detect-to-warn mode (using the definition provided here) but lacks some of the critical elements needed to support a rapid response, namely adequate data or demonstrated approaches to gather supplemental data that can engender widespread confidence among public health officials.The detect-to-warn mode simply alerts public health officials of a high-confidence exposure event and can trigger population-level distribution of MCMs for post exposure prophylaxis if the scale and geographic scope of the attack is reasonably understood. In this mode, the presence of an air borne biological agent of interest must be established with high confidence because MCMs  cannot be delivered to a population based on inconclusive or false positive results. Population-level treatment for an unconfirmed threat is too costly in logistics, materials, and possible adverse health events. Adverse health events  can occur as a result of potential side-effects or adverse interactions with other medications in a large, physiologically heterogeneous civilian population in which an unknown number may also have varying degrees of immune-suppression.The detect-to-treat mode alerts public health providers of a Bacillus anthracis or Francisella tularensis) or genetic near neighbors that are indistinguishable from the agent of interest by the assays employed. For example, the microorganisms that cause anthrax and tularemia are endemic in the U. S. and can be found in environmental matrices such as soil and water, respectively, that can serve as sources of low numbers of airborne organisms. However, the airborne concentrations or the viability of these naturally occurring agents are likely insufficient to cause human disease as suggested by the absence of reported cases of inhalation anthrax and pneumonic tularemia in areas where Biowatch is deployed. This is particularly significant with F. tularensis because the infectious dose may be <10 organisms  may occasionally be found on air collection filters and detected by current assays resulting in false positive results. The Biowatch program reported 149 false positives from 2003 to 2012  in the performance of environmental monitoring is a significant challenge. Like any clinical diagnostic device, the end-to-end performance of an environmental monitoring system must be thoroughly validated under relevant conditions and the benefit must be unambiguous  and their likelihood of detection.detect-to-warn mode, but it is essential for surveillance in the detect-to-treat mode. Viability confirms that a BTA of interest was detected that can potentially cause infection. It also enables antibiotic susceptibility testing to confirm the appropriate antibiotic(s) for prophylaxis. An integrated system does not currently exist for routine surveillance of air borne organisms or toxins of interest and simultaneous confirmation of agent viability or toxicity. In currently existing environmental monitoring systems, for example, a 24-h period of collection results in cell desiccation and possibly additional stresses such as denaturation of proteins that pose substantial challenges for the recovery of viable organisms and active toxins. Given that surveillance in detect-to-treat mode can reduce morbidity and mortality to a much greater degree than in detect-to-warn mode, developing an effective approach to reduce the loss of viable pathogens and toxins during aerosol sampling would be a valuable investment.Confirming the viability of an aerosolized pathogen is unnecessary for environmental monitoring in the Any approach to recovering and documenting viable, non-sporulating biological agents and active toxins of interest must address two major problems: (a) desiccation-related loss of viability or stability; and, (b) ability to rapidly distinguish a viable BTA of interest from other viable cells that may be present in a sample.Although desiccation resulting in cellular destruction or protein denaturation is commonly believed to be the cause of cell death and loss of toxin activity in aerosol samples, dehydration is a common method used for long-term preservation of microbial cells or toxins. In aerosol samples, cell death may occur from the rapid re-hydration of cells during assays for viability  increasing the probability that one or more detectors are close to the point source where the released agent concentrations are highest, and (ii) increasing the probability that at least one detector will capture an event despite changing air-flow patterns. A denser network would also improve the likelihood that multiple detectors document an event, which can facilitate the characterization of the magnitude and spatial coverage of an event. However, the cost of denser networks is expected to make outdoor environmental surveillance prohibitive. Consequently, the panel recommended abandoning outdoor monitoring because, as currently practiced, outdoor environmental monitoring seems unlikely to achieve its operational goal  have been suggested as potential technologies for a reagent-less bioagent sensor (National Research Council, Raman spectroscopy has been evaluated as a potential technology platform for a reagent-less environmental monitoring system (Ronningen and Bartko, Our recommendations are consistent with those from prior expert panels that evaluated environmental surveillance for biodefense (National Research Council, Kevin Anderson, Department of Homeland Security; Tamilselvam Batcha, University of Illinois; Thomas Blake, Centers for Disease Control and Prevention; Steven Blanke, University of Illinois; Catherine Branda, Sandia National Laboratory; Katrina Campbell, Queen's University Belfast; Stephen Casalnuovo, Sandia National Laboratory; Rodrigo Castillo-Garza, United Technologies Research Center; Douglas Cerasoli, U.S. Army Medical Research Institute of Chemical Defense; Jean Challacombe, Los Alamos National Laboratory; James Dillman, US Army Medical Research Institute of Chemical Defense; John Dunbar, Los Alamos National Laboratory; David Franz, NGI; Mark Geisberg, Silver Lake Research Corporation; David Hodge, Department of Homeland Security; Robin Holland, University of Illinois at Urbana Champaign; Hayden Huang, Government Accountability Office; Molly Hughes, University of Virginia; Janine Hutchison, Pacific Northwest National Laboratory; Morten Jensen, Gate Scientific; Justin Kita, Federal Bureau of Investigation; Luther Lindler, Department of Homeland Security; Ronald Manginell, Sandia National Labs; Patrick Martin, Takara Bio USA; Patrick McNutt, U.S. Army Medical Research Institute of Chemical Defense; Eric Merkley, Pacific Northwest National Laboratory; Stephen Morse, Centers for Disease Control and Prevention; William Nelson, Tetracore; Tom O'Brien, Tetracore; Timothy Persons, Government Accountability Office; Segaran Pillai, HHS Food and Drug Administration; Kristian Scaboo, Gate Scientific; Shashi Sharma, HHS Food and Drug Administration; Sushil Sharma, Government Accountability Office; Patrick Stayton, University of Washington; Nicole Steinmetz, Case Western Reserve University; Jane Tang, Department of Homeland Security; Bernhard Weigl, Global Good; David Wunschel, Pacific Northwest National Laboratory.These participants were attending a conference on Chemical and Bioterrorism Defense and were invited as subject matter experts to the independently organized discussions from which this perspectives article arose.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The INTERGROWTH-21st standards, it is essential to assess the feasibility and acceptability of their implementation and their effect on clinical decision-making in a low-resource clinical setting.To scale up the INTERGROWTH-21This study protocol describes a pre-post, quasi-experimental implementation study of the standards at Jacaranda Health, a maternity hospital in peri-urban Nairobi, Kenya. All women with viable fetuses receiving antenatal and delivery services, their resulting newborns, and the clinicians caring for them from March 2016 to March 2018 are included. The study comprises a 12-month preimplementation phase, a 12-month implementation phase, and a 5-month post-implementation phase to be completed in August 2018. Quantitative clinical and qualitative data collected during the preimplementation and implementation phases will be assessed. A clinician survey was administered eight months into the implementation phase, month 20 of the study. Implementation outcomes include quantitative and qualitative analyses of feasibility, acceptability, adoption, appropriateness, fidelity, and penetration of the standards. Clinical outcomes include appropriateness of referral and effect of the standards on clinical care and decision-making. Descriptive analyses will be conducted, and comparisons will be made between pre- and postimplementation outcomes. Qualitative data will be analyzed using thematic coding and compared across time. The study was approved by the Amref Ethics and Scientific Review Committee (Kenya) and the Harvard University Institutional Review Board. Study results will be shared with stakeholders through conferences, seminars, publications, and knowledge management platforms.st training: gestational dating ultrasound, fetal growth monitoring ultrasound, and neonatal anthropometry standards. Following the training, implementation and evaluation of the standards in Jacaranda Health\u2019s clinical workflow will take place from March 2017 through March 5, 2018. Data analysis will be finalized, and results will be shared by August 2018.From October 2016 to February 2017, over 90% of all full-time Jacaranda clinicians (26/28) received at least one of the three aspects of the INTERGROWTH-21st standards and on the process of scaling up global standards in general, particularly in limited-resource settings.The findings of this study will have major implications on the national and global scale up of the INTERGROWTH-21RR1-10.2196/10293 The neonatal period (first 28 days of life) is the most vulnerable time for an infant\u2019s survival. In 2016, 2.6 million neonates died globally representing 46% of all under-five deaths . There aTo make sound clinical decisions and provide quality maternal and neonatal care, clinicians require measurement standards for accurate pregnancy dating, monitoring of fetal growth, and assessment of newborn size and growth . Such stThe date of the maternal last menstrual period (LMP) can be used for pregnancy dating but is often inaccurate or unknown; in these cases, ultrasound is the most accurate method for determining gestational age ,18-20. Ust Project completed a five-year, global, prospective study of growth, health, nutrition, and neurodevelopment. The study followed women and their infants longitudinally from less than 14 weeks gestation until two years postnatal. The project enrolled populations at low risk of adverse outcome in Brazil, Italy, Oman, UK, USA, China, India, and Kenya [st data were compiled to develop new prospective standards to be used to assess pregnancy dating in the first trimester [In 2014, the INTERGROWTH-21nd Kenya ,29. INTErimester  and secorimester , fetal grimester  (includirimester  and ultrrimester ), and nerimester ,17. WithTo scale these standards and affect preterm birth and its complications, including neonatal mortality, it is essential to assess the feasibility and acceptability of implementing these standards and their effect on clinical decision-making, particularly in low-resource clinical settings.st standards over a one-year period at Jacaranda Health, a private, social enterprise maternity hospital in peri-urban Nairobi, Kenya. To our knowledge, this is the first facility-based implementation study of the INTERGROWTH-21st standards in a limited-resource setting. The research design considers stakeholder inputs, the physical and institutional environment, and the health system structure.We aim to assess the feasibility and acceptability of implementing the INTERGROWTH-21st standards in other settings and to inform the translation of guidelines and tools into routine clinical practice.The ultimate aim of the project is to use the results of the study to inform the implementation and scale up of the INTERGROWTH-21st standards at Jacaranda Health. The specific components of the primary objective are to assess the introduction of the INTERGROWTH-21st standards and the training of clinicians at Jacaranda Health, the effect of the implementation of the INTERGROWTH-21st standards on clinical practices at Jacaranda Health, clinicians\u2019 experiences and satisfaction with the INTERGROWTH-21st standards, clinicians\u2019 perceived effect of the standards on the clinical care they provide, and patient experiences and satisfaction with the care they received at Jacaranda Health during implementation of the INTERGROWTH-21st standards.The primary objective is to determine the facilitators and barriers to implementing the INTERGROWTH-21st standards on clinicians\u2019 decision-making and patient outcomes, including the processes for determining gestational age and estimated due date, internal referral to Jacaranda Health clinicians providing high-risk consultations, tertiary-center referral of high-risk pregnant women, and indications for and rates of labor inductions and caesarean sections.The secondary objective of this study is to assess the effect of implementing the INTERGROWTH-21st standards on clinical decision-making and management at Jacaranda Health. Study activities consisted of a 12-month preimplementation phase which included a baseline facility assessment, changes to facility protocols and charting forms, planning work flow adaptations to facilitate implementation of the standards, equipment procurement, training of clinicians, and baseline data collection; a 12-month implementation phase which included the implementation of the INTERGROWTH-21st clinical standards, revised facility protocols and charting forms into routine clinical practice, and data collection; and a five-month post-implementation phase which includes analysis and dissemination.This is a pre-post, quasi-experimental implementation study using quantitative clinical data, focus group discussions (FGDs), in-depth interviews (IDIs), and a short clinician survey. The study describes the feasibility, acceptability, and the effect of implementing the INTERGROWTH-21st researchers at Oxford University and researchers at the Harvard T.H. Chan School of Public Health.This study design was based on a conceptual model created by INTERGROWTH-21st standards and capturing factors that facilitate and challenge that process. Jacaranda Health patients come from densely-populated, peri-urban neighborhoods in northeastern Nairobi, including Kiambu, Thika, Gatundu, and Embakasi districts. These areas are served by many facilities that range from small pharmacies and outpatient care clinics to private and public sector secondary and tertiary hospitals with maternity wards; the services and prices vary substantially across these facilities.This implementation study is currently being carried out at Jacaranda Health, a social enterprise, 18-bed maternity hospital that provides women in peri-urban Nairobi with affordable, safe, and respectful ANC, standard vaginal and cesarean delivery, and postnatal care (PNC) services. Women in preterm labor and newborns with LBW and/or complications are not managed at this facility and are referred to tertiary-level facilities for specialized care. With a model that emphasizes quality and affordable care provided primarily by nurse-midwives , Jacaranda Health provides an ideal venue for evaluating the implementation of the INTERGROWTH-21Pregnant women with a viable fetus presenting for ANC and/or delivery at Jacaranda Health were eligible for the following three elements of the intervention: (1) gestational dating standards for women who present for their initial ANC visit in the first or second trimester ; (2) fetal growth monitoring standards for women who present for an ANC visit in the third trimester (after 26 weeks gestation) and are identified as high-risk based on factors related to their surgical, medical, or obstetric history or current pregnancy; and (3) newborn size at birth standards for all newborns born at Jacaranda Health. We excluded pregnant women with a nonviable fetus in both quantitative and qualitative data collection, women who present for their initial ANC visit in the third trimester (after 26 weeks gestation) for gestational dating standards, and parents of stillborn infants in qualitative data collection. All eligible pregnant women and mothers of newborns described above were eligible to participate in FGDs and IDIs.st training sessions are eligible to participate in FGDs, IDIs, and a short clinician survey. Clinicians who only work in child wellness clinics and not in prenatal or intrapartum care units were excluded.All clinicians delivering ANC and newborn anthropometry who attended INTERGROWTH-21st standards at Jacaranda Health to assess their acceptability and inform their further scale up. The results of the study will be disseminated to providers at Jacaranda Health by study staff at the end of the study.The development of the study design, research questions, and outcome measures did not formally involve patient and public opinions and contributions. However, the study assesses patient and provider perceptions and experiences of the implementation of the INTERGROWTH-21st standards, we conducted a baseline assessment of current facility practices as they relate to our study objectives. Focus was placed on policies and practices related to ANC provision, pregnancy dating, identification and referral of high-risk pregnancies to high-risk care within Jacaranda Health and to tertiary facilities, fetal growth monitoring, newborn size measurement, and indications for and rates of cesarean section and labor induction.Before implementing the INTERGROWTH-21The baseline assessment was conducted through clinic observations; a desk review of written policies; IDIs with Jacaranda Health\u2019s director of clinical operations, clinical programs manager, and clinical educator; a chart review to understand clinician practices and indications for and rates of cesarean sections and labor inductions; an equipment and supply inventory with a focus on ultrasound and newborn anthropometry; and a human resource inventory to understand existing personnel and clinician roles and responsibilities related to clinic flow, pregnancy dating, fetal growth monitoring, and patient counseling. We then adapted ANC protocols to align with the 2002 WHO ANC model . This wost standards. In partnership with Oxford University, we created a computerized calculator to calculate gestational age and fetal growth percentiles: clinicians use the ultrasound machine to measure the required biometrics for gestational dating or fetal growth, input the measurements into the calculator, and then record the resulting gestational age or fetal growth percentiles in the patient\u2019s chart. Additionally, neonatal scales, measuring tapes, and infantometers, chosen in consultation with the INTERGROWTH-21st Oxford team and adjusted based on local availability and resource constraints, were sourced and integrated into clinical practice.A key element of preimplementation activities was ensuring that the hospital\u2019s equipment, protocols, and procedures were updated and adapted for the implementation of the INTERGROWTH-21st standards.We updated Jacaranda Health clinical protocols for standard ANC, high-risk pregnancy classification and subsequent internal and tertiary-center referral, gestational dating, fetal growth monitoring, and newborn anthropometry, in addition to corresponding patient charting forms, to support the implementation and evaluation of the INTERGROWTH-21Clinician job aids were created to facilitate the implementation of the standards and related decision-making algorithms. We also altered clinic flow processes to accommodate the introduction of ultrasound services; a separate room was designated exclusively for gestational dating ultrasounds. In the context of adapting clinical definitions of high-risk pregnancy criteria and processes for both internal and tertiary-center referrals, we trained clinicians to only do activities (like ultrasound) within their scope of practice as determined by the Nursing Council of Kenya.st standards. This was done in collaboration with the original INTERGROWTH-21st Project study team based at Oxford University and Aga Khan University Hospital (AKUH) in Nairobi, Kenya [A main aim of implementation was training Jacaranda Health staff how to use the INTERGROWTH-21i, Kenya -37.st gestational dating ultrasound, fetal growth monitoring ultrasound, and neonatal anthropometry standards. Emphasis was placed on including assessment, identification, and referral of high-risk patients as part of the study design to evaluate operational system capacity to support the implementation of the standards and their clinical implications.From October 2016 to February 2017, we conducted training of Jacaranda Health clinical and management staff on the purpose and use of the INTERGROWTH-21st standards and accompanying adaptations to charting practices and clinical protocols. Of the 23 participants in the training, 22 were nurse-midwives and one was a clinical officer; these staff provide the majority of ANC and PNC at Jacaranda Health.An obstetrician-led half-day training included essential components of ANC, basic obstetric ultrasound skills, and the INTERGROWTH-21st anthropometry trainer from AKUH provided a half-day anthropometry training which included theory, equipment, and techniques needed to perform accurate newborn length, weight, and head circumference measurements. The anthropometry trainer certified clinicians in neonatal anthropometry after they performed length, weight, and head circumference measurements accurately on newborns. One group of 24 clinicians, 23 nurse-midwives and one clinical officer, attended this training. Nearly 90% (24/28) of all full-time and part-time Jacaranda Health clinicians attended these initial trainings.An obstetrician and an INTERGROWTH-21st ultrasound measurements for the first, second, and third trimesters over the course of two weeks. At the end of the two weeks, the sonographer demonstrated proficiency in performing INTERGROWTH-21st measurements as determined by a senior radiologist at AKUH. The Jacaranda Health sonographer then trained a group of six Jacaranda Health nurse-midwives with prior experience in basic obstetric ultrasound during a half-day training on gestational dating ultrasounds. Three of the six nurse-midwives were certified to perform gestational dating ultrasounds after proving competence in performing measurements and calculating estimated delivery date accurately three consecutive times in the presence of the sonographer. This group of three nurse-midwives constitutes over 10% (3/28) of all clinicians.AKUH trained Jacaranda Health\u2019s primary sonographer in INTERGROWTH-21st standards, revised facility protocols, and adapted patient charting forms were introduced into routine clinical practice in March 2017. The clinic work flow adaptations were implemented to facilitate the identification of pregnant women eligible for ultrasound using the new standards and ensure that pregnant women were seen by the appropriate clinician. Work flow adaptations were not needed to implement the newborn size at birth standards since newborn anthropometry was an established part of routine practice.After training was completed and equipment was put into place, the INTERGROWTH-21st standards, three quality monitoring processes were utilized: expert ultrasound image review, weekly clinic stakeholder meetings, and targeted refresher training. Our protocol includes sending copies of de-identified gestational dating and fetal growth ultrasound images to the quality assurance team at Oxford University. The team reviews the images, assesses the quality of each image based on INTERGROWTH-21st guidelines, and provides guidance to Jacaranda Health staff on how to improve ultrasound quality, if needed. Images were sent to Oxford for review every two months via a double password-protected Dropbox folder. The program management team at Jacaranda Health then shared feedback from the Oxford team with the ultrasound providers to strengthen sonography skills and processes. Reinforcement training was provided by Oxford University clinical researchers specializing in sonography midway through implementation to further improve the quality of the ultrasound procedures. Challenges in clinical implementation were discussed by the clinical staff during weekly meetings, which enabled staff to quickly resolve any problems. Lastly, through chart review and observation, the clinical and project management teams had the discretion to identify clinicians who required targeted refresher training and to provide that training at any point during the study. Important project notifications and reminders were administered to all staff at weekly clinical meetings by clinic managers and project management.To ensure the quality of the implementation of the INTERGROWTH-21st standards and (2) uptake of gestational dating ultrasounds, fetal growth monitoring by ultrasound, and newborn anthropometry. These outcomes were explored through the following dimensions: feasibility, acceptability, appropriateness, adoption, fidelity and penetration [The primary study outcomes are (1) clinicians\u2019 and patients\u2019 perception of facilitators and barriers to the implementation of the INTERGROWTH-21etration .The secondary outcomes used to evaluate clinical decision-making include (1) proportion of ANC clients whose gestational age and estimated due date were correctly calculated and documented, (2) proportion of high-risk pregnant women who were referred internally to a high-risk clinician or to a tertiary care facility, (3) proportion of pregnant women receiving gestational dating scans who were induced for labor due to a prolonged pregnancy, and (4) proportion of pregnant women receiving gestational dating scans who delivered via cesarean section.During the preimplementation phase, baseline data were collected for 12 consecutive months (months 1-12) prior to the start of the implementation phase. Data were also collected for 12 consecutive months during the implementation phase (months 13-24). These preimplementation and implementation phase quantitative data come from patient charting forms completed in the two-year period. Qualitative data were also collected during the preimplementation phase (month eight) and the implementation phase (month 16 and month 24). Additionally, a one-time short provider survey was administered during the implementation phase at month 20 to assess clinicians\u2019 attitudes and acceptability of the standards. .We collected outcome data from patient charts and from a clinic log of external referrals for pregnancies and deliveries one year before and one year after the start of implementation.We conducted FGDs and IDIs with participants sampled from two population groups using purposeful and convenience sampling: (1) patients who received ANC and/or delivery care at Jacaranda Health and (2) clinicians who work directly with patients  including nurse-midwives, hospital managers, ultrasonographers, and physicians.FGDs and IDIs with patients and clinicians were conducted in the preimplementation phase and twice during the implementation phase. Patients were interviewed to evaluate their perceptions, attitudes, and experiences of receiving an ultrasound for gestational dating and fetal growth, their newborn receiving a growth assessment, and their interactions with clinicians implementing this care. Clinicians were interviewed to evaluate their perceptions, attitudes, and experiences of the introduction and implementation of the new standards as part of their routine clinical practice.The research team developed semistructured discussion guides for both FGDs and IDIs, which were piloted with Jacaranda Health staff and patients. Research assistants conducted all interviews in a private and secure location and took great care to protect the identity and confidentiality of all participants. To encourage patient participation in qualitative interviews, we offered reimbursement for transportation to the facility and free refreshments after the completion of the interviews. All FGDs and IDIs were audio-recorded and transcribed verbatim by an external transcriber; in the instances that participants spoke a language other than English, the transcriber translated the recording to English for the transcript. Hand-written notes taken by the research assistant provided the context for the interviews.st standards, the ease of integration into their workflow, and their perceptions of the effect of the standards on the quality of care they provided.Additionally, a survey (10 questions) was administered by a research assistant to all clinicians during the implementation phase at month 20 via Survey Monkey on an Android tablet. Clinicians were asked to grade their comfort  with the INTERGROWTH-21We used a census of clinicians and patients for this implementation study based on the inclusion and exclusion criteria described prior. According to clinic estimates and projections of ANC and delivery care utilization, data for up to 5,000 pregnant women and newborns will be recorded. The total number included in the final analysis will be based on the number of patients who meet eligibility criteria as confirmed at the time of data entry based on indicators in patient charting forms.In each time period, the sample will be stratified into the following three categories: (1) pregnant women who attended ANC at Jacaranda Health and delivered there, allowing analysis of longitudinal ANC and delivery data; (2) pregnant women who attended ANC at Jacaranda Health but did not deliver there, providing ANC data only; and (3) women who did not attend ANC but who delivered at Jacaranda Health, capturing delivery and newborn data only. All clinic managers, physicians, and nurse-midwives who met the criteria are included. Clinician attrition will be documented.Data from patient charts and referral logs were double-entered and managed in REDCap , a securMost implementation and process indicators will be measured and presented using descriptive statistics. We will analyze changes in quantitative outcomes where relevant, by evaluating the difference in response to the indicators between pre- and postimplementation. Measurements of differences in continuous data will be assessed using t-tests for data that is normally distributed; otherwise, a non-parametric test will be performed. Categorical data will be compared using a chi-squared test. Quantitative data will be analyzed using Stata 15 . All datFor each cycle of qualitative data transcription, the transcriber completed transcription of one initial data file and sent it to the qualitative data manager at Jacaranda Health for quality control prior to transcribing the rest of the data files.Qualitative data collected at each stage are being analyzed independently by two investigators using thematic coding in NVivo  and compResults of the study will be shared with key stakeholders both in Kenya and globally through a national dissemination meeting, global conferences, an online knowledge management platform, and publications.The Amref Ethics and Scientific Review Committee of Kenya and the Harvard University Institutional Review Board approved all study activities, protocols, and standards prior to the commencement of study activities.Facility-level informed consent was obtained from the Jacaranda Health hospital manager, acting as the facility\u2019s representative, prior to the collection of any implementation data. The facility informed consent emphasized that no patient-identifiable health data would be shared or disseminated beyond the Jacaranda Health team. All FGD, IDI, and survey participants\u2014patients and clinicians\u2014provided written informed consent prior to any interview. Participants were informed that they could withdraw their consent at any time and be removed from the sample.st training: gestational dating ultrasound, fetal growth monitoring ultrasound, and neonatal anthropometry standards. Following the training, the implementation and study of the INTERGROWTH-21st standards as part of Jacaranda\u2019s clinical workflow took place from March 2017 through March 5, 2018. Data analysis will be finalized, and results are expected in August 2018.From October 2016 to February 2017, over 90% of all Jacaranda Health clinicians  received at least one of the three aspects of the INTERGROWTH-21st standards and on the process of scaling up global standards in general, particularly in limited-resource settings. The ability to implement a standard methodology of gestational dating, fetal growth monitoring, and assessment of newborn size at birth will result in better data to enable clinicians, researchers, and policy makers to more accurately identify and quantify high-risk pregnancies, preterm birth, and fetal and neonatal growth disturbances. In turn, standardized data that is comparable across global populations empowers researchers and policy makers to better understand and act on distributions of high-risk pregnancies, restricted growth, and prematurity. Lastly, based on this data, clinical practice and resources can be modified to meet the needs of pregnant women and their fetuses and newborns to decrease the incidence and morbidities associated with poor fetal and newborn growth and prematurity.The findings of this study will have major implications on the national and global scale up of the INTERGROWTH-21While Jacaranda Health provides the right environment for this study, the generalizability of our findings needs to be carefully considered when applying lessons learned to other clinical settings. Given that clinic protocols were amended to meet the 2002 WHO ANC guidelines, which affected the criteria for high-risk referral, this change may confound the outcome of the percentage of women who are referred to high-risk care. The study is also limited in its ability to assess the long-term health outcomes of these standards, yet it will inform future research designed to assess them.st clinical standards into a low-resource setting. Due to the dearth of innovative gestational dating tools and burden of preterm birth in low-resource settings, it is particularly important to study the implementation of these standards in this setting. The results of our evaluation will provide useful insights and recommendations for further implementation in similar clinical settings in Kenya and beyond.This will be the first study to assess the feasibility and acceptability of introducing the new INTERGROWTH-21st standards and the resulting impact on short-term clinical decision-making. Lastly, Jacaranda Health is dedicated to health facility quality improvement in peri-urban Nairobi, which makes it an excellent venue for evaluating the implementation of the INTERGROWTH-21st standards and for capturing factors that facilitate and challenge that process.Additionally, the mixed-methods approach used in this study will yield unique insights into the barriers, facilitators, and process of implementing the INTERGROWTH-21"}
+{"text": "Dear Editor,In 1923, Masson initially described a process, at that time neoplastic, which consisted of vascular lumen obliteration due to papillary endothelial hyperplasia associated with degenerative changes.None declared.Sergio Emerson Sasso: Approval of the final version of the manuscript; conception and planning of the study; elaboration and writing of the manuscript; obtaining, analyzing and interpreting the data; effective participation in research orientation; intellectual participation in propaedeutic and/or therapeutic conduct of the cases studied; critical review of the literature; critical review of the manuscript.Ana Paula Naspolini: Approval of the final version of the manuscript; elaboration and writing of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the cases studied; critical review of the manuscript.Tassiana De Boit Milanez: Obtaining, analyzing and interpreting the data.Guilherme Suchard: Obtaining, analyzing and interpreting the data.None declared."}
+{"text": "The Mediterranean climate is characterized by hot dry summers and frequent droughts. Mediterranean crops are frequently subjected to high evapotranspiration demands, soil water deficits, high temperatures, and photo-oxidative stress. These conditions will become more severe due to global warming which poses major challenges to the sustainability of the agricultural sector in Mediterranean countries. Selection of crop varieties adapted to future climatic conditions and more tolerant to extreme climatic events is urgently required. Plant phenotyping is a crucial approach to address these challenges. High-throughput plant phenotyping (HTPP) helps to monitor the performance of improved genotypes and is one of the most effective strategies to improve the sustainability of agricultural production. In spite of the remarkable progress in basic knowledge and technology of plant phenotyping, there are still several practical, financial, and political constraints to implement HTPP approaches in field and controlled conditions across the Mediterranean. The European panorama of phenotyping is heterogeneous and integration of phenotyping data across different scales and translation of \u201cphytotron research\u201d to the field, and from model species to crops, remain major challenges. Moreover, solutions specifically tailored to Mediterranean agriculture  are in high demand, as the region is vulnerable to climate change and to desertification processes. The specific phenotyping requirements of Mediterranean crops have not yet been fully identified. The high cost of HTPP infrastructures is a major limiting factor, though the limited availability of skilled personnel may also impair its implementation in Mediterranean countries. We propose that the lack of suitable phenotyping infrastructures is hindering the development of new Mediterranean agricultural varieties and will negatively affect future competitiveness of the agricultural sector. We provide an overview of the heterogeneous panorama of phenotyping within Mediterranean countries, describing the state of the art of agricultural production, breeding initiatives, and phenotyping capabilities in five countries: Italy, Greece, Portugal, Spain, and Turkey. We characterize some of the main impediments for development of plant phenotyping in those countries and identify strategies to overcome barriers and maximize the benefits of phenotyping and modeling approaches to Mediterranean agriculture and related sustainability. Mediterranean countries are important producers of vegetables, legumes, cereals, fruits, olives and olive oil, grapes, and wine. Vegetable production accounts for 13.7% of the EU\u2019s agricultural output with 63.9 million tons of vegetables grown in 2016 . Spain aTotal cereal production (rice included) in the EU reached 309 million tons in 2017, representing 12% of global production . AccordiOutside the EU, Turkey is a major contributor to European and global agricultural production. In 2017, Turkey accounted for approximately 70% (12.6 million tons) of EU tomato production . MoreoveForestry is another economically crucial sector for Europe, in addition to providing environmental sustainability and key ecosystem services. European forests can also help to mitigate the impact of climate change and enable adaptation policies. Indeed, EU forests absorb the equivalent of about 10% of the total annual greenhouse gas emissions from the EU . Forest The Mediterranean region typically experiences long periods of drought and abrupt rainstorms and floods that negatively impact on crop performance as well as the available water and soil resources. The region has typical dry periods combined with high temperatures and a marked inter-annual weather variability, which results in a large and a highly variable demand for irrigation and in higher incidence of pests and diseases . Spain, A more comprehensive understanding of the specific agricultural environment found in the Mediterranean region is required to support rural development and to meet the goals of the EU-Common Agriculture Program of CAP 2014-2020 . More prDigitization of agriculture and expansion of precision farming can reduce costs and minimize the environmental impact of agriculture . For exaPlant phenotyping, based on non-destructive image analysis, data management, and modeling, has emerged as a cutting-edge technology playing an important role in plant and agronomic sciences, namely, to design new crops, characterize the responses of genetic resources to the environment, and improve the breeding and management of crops . Therefore, implementation of such technologies is crucial for sustainable agro-food operations, while optimizing the use of natural resources such as water and soil.https://eppn2020.plant-phenotyping.eu/EPPN2020_installations#/). These high-throughput platforms are generating considerable volumes of data that provide valuable insights for plant/agronomic sciences and plant/crop breeding as evidenced by the increasing number of publications derived from these phenotyping facilities  is most commonly used in high-throughput screening, with structural phenotyping  and functional phenotyping  being investigated in both model species and crops . Top-dowPhenotyping requires networks and interactions of sensor and data bases  with biological and agricultural sciences . Phenotyping is also increasingly linked to modeling studies. Phenotyping should ideally be conducted at maximal throughput (number of units processed per unit time), resolution , and dimensionality (number of captured traits). However, in practice, a trade-off between these three phenotyping descriptors must occur due to economic, technological, time, and personnel constraints . The intTo support and accelerate plant improvement, plant phenotyping must be based on more cost-effective technologies and sensors . In thisvs. greenhouse crops, traits of interest) (see www.phenome-fppn.fr/) congregated nine phenotyping platforms, including controlled conditions (two units), semi-controlled conditions (two units), field conditions (three units), and molecular platforms (two units). This panorama contrasts with other Southern Mediterranean countries  see . Yet, duest) see . In 2018http://www.plant-phenotyping-network.eu/eppn). The EPPN established a pan-European infrastructure that includes the whole phenotyping pipeline (involving sensors and imaging techniques), data analysis, and interpretation in a biological context and meta-analyses of experiments carried out on different organs and at different scales of plant organization. The EPPN currently operates in 10 countries providing access to 36 different plant-phenotyping facilities to the users. Furthermore, the European Strategic Forum for Research Infrastructure (ESFRI) has recognized plant phenotyping as a priority for the European research area to achieve food security in a changing climate context. Consequently, EMPHASIS  was included in the ESFRI Roadmap 2016 (https://www.esfri.eu/roadmap-2016) as a project to develop and implement pan-European plant phenotyping facilities available to the user community. EMPHASIS aims at increasing the integration of major players and users involved in data acquisition, management, storage, and sharing, to provide a more practical use of the available phenotyping data to analyze genotype performance in diverse environments (The quest for tolerant varieties\u2014phenotyping at plant and cellular level) has further contributed to improve networking by facilitating the exchange of researchers, knowledge, skills, and training across countries, thus leveraging the absence of phenotyping facilities within some EU countries.Improved integration of phenotyping and genetic and genomic platforms and resources should facilitate increased understanding of crop performance for the development of more effective breeding strategies and also guarantee improved big data management . To accoronments . EMPHASIronments Figure 2To further enhance the sustainability of agriculture in Mediterranean countries, the establishment of phenotyping facilities remains a timely and indispensable issue. In the following section, we provide a short overview of the major characteristics of the existing phenotyping infrastructure and the knowledge and networks available in Southern Mediterranean countries.Greece and Portugal share rather similar constraints in terms of agricultural production, related to climate change vulnerability and limited investments in innovation and technology. The recent economic crisis had a marked impact on the development and use of modern technologies in the agriculture and agri-food sectors. Therefore, the panorama for plant/crop phenotyping is closely identical in the two countries and will be discussed in parallel.a (chl a) fluorescence, nutrient deficiencies, and infections have most commonly been assessed  . In graia fluorescence induction transients  open-field facilities to study the eco-physiological dynamics of plant species and specific crops in their natural environment ;(2) semi-controlled climate conditions within modern glasshouse facilities equipped with both contact and remote-sensing phenotyping tools to assess crop physiological performance;(3) fully controlled climate conditions (climate chamber facilities) for molecular phenotyping ; these facilities would complement the existing EPPN network, thus increasing the number of European facilities with fully controlled environmental conditions .Vitis phenotyping . For both Portugal and Greece, low-cost phenotyping approaches (and/or platforms) would be the most feasible way to move forward on the short to medium term, considering current financial constraints.For Greece and Portugal, the exploitation of current plant phenomics and crop-phenotyping technologies and strategies could provide valuable data for improved management of biodiversity resources, fostering crop/cultivar adaptability to climate and resistance against pests and diseases. However, field-phenotyping infrastructures are still unviable due to high costs. Some initiatives have been instigated to implement the use of phenotyping strategies in crop management, particularly using thermal and multispectral imaging alongside ground-based and aerial approaches (e.g. see projects INTERPHENO https://europa.eu/european-union/topics/agriculture_en).Spanish agriculture is highly competitive at both the European and global levels. The country is a major exporter of both fresh and processed agricultural and horticultural goods/products . Nevertha fluorescence, UV induced-multicolor fluorescence , and thermography  using low-throughput imaging sensors for chl mography . Some grmography .Plant and ecosystem functions are also evaluated by mean of proximal and remote sensing, as well as diverse ecophysiological measurements . This reThe relationship between photosynthesis and production under drought conditions in Mediterranean crops is of special interest. The production of high-quality wines in Protected Designation of Origin Areas under a full range of climate conditions is particularly important in Spain . In grapXylella fastidiosa is a quarantine pathogen in the EU, and it has been detected in Spain, Italy, France, and Germany (https://www.eppo.int/ACTIVITIES/plant_quarantine/shortnotes_qps/shortnotes_xylella). X. fastidiosa is a threat to multiple crops  across the whole Mediterranean  analyses  was established in 2017 to coordinate and develop plant-phenotyping research within Italy. The PHEN-ITALY network consists of 13 research organizations, universities, and regional agencies led by the National Research Council of Italy (CNR) and Agenzia Lucana di Sviluppo e di Innovazione in Agricoltura (ALSIA) where a large HTPP infrastructure is operating. CNR is a partner within the EMPHASIS-PREP. PHEN-ITALY aims to become the Italian infrastructural node of EMPHASIS. PHEN-ITALY also participates in the EPPN and the activities and projects of the International Plant Phenotyping Network (IPPN). Following the main principles of plant phenotyping (non-invasive and high-throughput measurements), the PHEN-ITALY infrastructure is based on optical systems  that include a conveyor system, two imaging stations , and three computer stations to study: (i) the phenotypic background of genetically characterized crops of interest in Italy , (ii) the root to shoot architecture of plants, and (iii) the VOCs emitted by plants as markers of biodiversity and stress. For example, 3D scanning and chlorophyll fluorescence technology have been used to non-destructively assess the physiological and molecular responses to drought of tomato sprayed with a commercial mixture of amino acids and nutrients  was grown around Sanliurfa between 10,000 and 12,000 years ago  is crucial to understand crop/plant responses to the environment, but such integrated information remains comparatively limited. Moreover, we must identify which traits to phenotype, and at which moment of the plant\u2019s life cycle this should be done in a fast but robust way. These major questions must be addressed along with more specific issues during any investigation. The lack of integrated phenotyping data is a general drawback in plant phenotyping but is of particular importance in the Mediterranean region and related agriculture due to the structural complexity of field cropping systems . The use of non-invasive methods facilitates more objective and repeatable measurements of traits such as plant architecture, fruit quality, and/or the impact of biotic or abiotic stress under field conditions. Moreover, improvements in phenotyping imaging technology are resolving limitations associated with variable backgrounds and light conditions . To effehttps://emphasis.plant-phenotyping.eu/modelling). HTPP platforms and tools offer a new avenue in the parameterization of models to scale up data from molecular and morphological levels to breeding. Integration of phenotyping data with crop growth models can provide the means to evaluate and quantify the usefulness of agronomic practices  to optimize resource use, as well as generate genotypes for different environmental contexts such as resilience to climate change. To this end, different classes of G2P (genotype-to-phenotype) models have been shown to help predict complex phenotypic traits as functions of GxExM interaction  demand improved selection criteria and phenotyping strategies for both field and greenhouse conditions. To achieve this, we must: (1) define selection criteria for crop and phenotyping traits, according to the specific breeding needs of each country/region; (2) optimize the practical implementation of phenotyping efforts, as a function of the specific conditions of each country; (3) raise financial support among public and private stakeholders, and (4) include HTPP in national research policies for agriculture.Increasing integration of information across HTPP facilities  or different biological levels  to bring together farmers, the agro-industry, government, and consumers to identify the most adequate strategies to face the adversities associated with climate change in Mediterranean countries . The rolThe rapid (and expensive) development of phenotyping technologies can partly explain the heterogeneous panorama of phenotyping infrastructure within Europe. Indeed, differences in the establishment of infrastructure, budget, knowledge, and technological capacities are apparent when comparing Northern and Southern European countries. There are further differences amongst Mediterranean countries as well. The major ones are apparent in the available infrastructure, availability of qualified labor, dimension of the companies , and priorities of national and international networks. Solutions to the lack of financial resources, a problem common to Mediterranean countries  are needed. Public\u2013private partnerships could assist in resolving this lack of investment and foster political will. This public\u2013private approach is already being implemented in some countries through the close cooperation of academic research institutes and commercial-breeding companies.2, etc.). In this way, it will be possible to properly assist breeding and selection of genotypes/phenotypes better suited to the prevailing and forthcoming climatic conditions in the Mediterranean. In parallel, the development of image processing, analysis, and modeling is also crucial to ensure relevant outputs. Interdisciplinary education of young researchers and technicians, from both public and private sectors, will also benefit from the establishment of phenotyping infrastructures.The establishment of phenotyping and phenomics facilities and infrastructures in Southern EU member states is crucial to meet the EU 2020 targets of smart specialization, sustainable growth, and the development of an inclusive and circular economy. Particularly in light of the budget limitations, commonly experienced by Southern European countries, phenotyping infrastructures should rely on simple, lower cost, and rapid methods, which are user-friendly, reliable, and robust. Improved phenotyping approaches will enhance our understanding of crop responses to Mediterranean climate conditions  should be encouraged to implement phenotyping technologies in agricultural and climate change scenarios and to further incorporate genetic and molecular approaches to improve crop productivity.All authors wrote the paper and read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The United States and Mexico differ greatly in the organization and financing of their old-age welfare states. They also differ politically and organizationally in government response at all levels to the needs of low-income and frail citizens. While both countries are aging rapidly, Mexico faces more serious challenges in old-age support that arise from a less developed old-age welfare state and economy. For Mexico, financial support and medical care for older low-income citizens are universal rights, however, limited fiscal resources for a large low-income population create inevitable competition among the old and the young alike. Although the United States has a more developed economy and well-developed Social Security and health care financing systems for the elderly, older Mexican-origin individuals in the U.S. do not necessarily benefit fully from these programs. These institutional and financial problems to aging are compounded in both countries by longer life spans, smaller families, as well as changing gender roles and cultural norms. In this interdisciplinary panel, the authors of five papers deal with the following topics: (1) an analysis of old age health and dependency conditions, the supply of aging and disability services, and related norms and policies, including the role of the government and the private sector; (2) a binational comparison of federal safety net programs for low-income elderly in U.S. and Mexico; (3) when strangers become family: the role of civil society in addressing the needs of aging populations; and (4) unmet needs for dementia care for Latinos in the Hispanic-EPESE."}
+{"text": "Methopolophium dirhodum Walk.) is a major pest of maize (Zea mays L.), but little is known about the biochemical interactions between M. dirhodum and its host plant. Thiol compounds and glutathione S-transferase (GST) play a crucial role in the defense responses of maize to biotic stress factors, including aphids. The purpose of this research was to evaluate the impact of M. dirhodum herbivory on the total thiol (TT), protein bound thiol (PT), reduced glutathione (GSH) and oxidized glutathione (GSSG) contents as well as the activity of GST in three varieties of Z. mays , that were classified as aphid-susceptible, aphid-relatively resistant and aphid-resistant, respectively. The earliest and strongest aphid-triggered alterations in the levels of TT, PT and GSH, and the greatest induction of GST activity, were recorded in the resistant P\u0142omyk seedlings in relation to the relatively resistant Ambrozja and the susceptible Z\u0142ota Kar\u0142owa.The rose-grass aphid ( Zea mays L.) is one of the most important crops worldwide and its economic importance is growing \u201378M. dire plants .M. dirhodum attacks are based on the metabolism of thiol compounds, which is evidenced by alterations in the level of total thiols, protein-bound thiols and GSH, as well as by the activity of GST. The fluctuations in thiol content and GST activity were dependent on the maize variety, the number of aphids and the duration of M. dirhodum feeding. The strongest modulation of the antioxidant system related to sulfhydryl compounds was noted in the resistant variety, P\u0142omyk, which highlights the role of thiols in the resistance of maize genotypes to aphids.In conclusion, our experimental results indicate, that the defense mechanisms of maize plants against"}
+{"text": "Scientific Reports 10.1038/s41598-017-10365-3, published online 30 August 2017Retraction of: This Article is being retracted at the request of the corresponding author, because the authors did not obtain relevant permissions from the Liver Cancer Laboratory at Xiangya Hospital, Central South University, who is the owner of some of the clinical specimens and related data for the use of these materials in the study.Xiong Lei, Shuai Xiao, and Taiyuan Li agreed to the retraction. The other authors could not be reached."}
+{"text": "The International Federation of Pigment Cell Societies (IFPCS) held its XXIII triennial International Pigment Cell Conference (IPCC) in Denver, Colorado in August 2017. The goal of the summit was to provide a venue promoting a vibrant interchange among leading basic and clinical researchers working on leading-edge aspects of melanocyte biology and disease. The philosophy of the meeting, entitled Breakthroughs in Pigment Cell and Melanoma Research, was to deliver a comprehensive program in an inclusive environment fostering scientific exchange and building new academic bridges. This document provides an outlook on the history, accomplishments, and sustainability of the pigment cell and melanoma research community. Shared progress in the understanding of cellular homeostasis of pigment cells but also clinical successes and hurdles in the treatment of melanoma and dermatological disorders continue to drive future research activities. A sustainable direction of the societies creates an international forum identifying key areas of imminent needs in laboratory research and clinical care and ensures the future of this vibrant, diverse and unique research community at the same time. Important advances showcase wealth and breadth of the field in melanocyte and melanoma research and include emerging frontiers in melanoma immunotherapy, medical and surgical oncology, dermatology, vitiligo, albinism, genomics and systems biology, precision bench-to-bedside approaches, epidemiology, pigment biophysics and chemistry, and evolution. This report recapitulates highlights of the federate meeting agenda designed to advance clinical and basic research frontiers from melanoma and dermatological sciences followed by a historical perspective of the associated societies and conferences. The XXIII IPCC encompassed a series of opening and award lectures, including the IFPCS Presidential lecture and honorary lectures by the recipients of the Fitzpatrick, Lerner, and Seiji Awards. These awards are bestowed by regional pigment cell societies to leading international scientists who have made extraordinary contributions to pigment cell research. There were 8 plenary sessions and 32 concurrent sessions accomplishing a balance between clinical and basic melanoma and dermatology research.In addition to opening lectures, the first day included a plenary session on the evolution of pigmentary systems across the animal kingdom and three concurrent sessions on advances in vitiligo, melanocyte, and melanoma biology as well as disease management. On the second day, two plenary sessions covered fascinating advances in the genetics of coloration in various animal species and in UV light responses and DNA repair. The fourth day included two plenary sessions and four concurrent sessions that emphasized basic biology of melanoma and the latest developments in translational melanoma therapies and resistance. Day five was headlined by a plenary session with keynote speakers on the impact of regenerative medicine on pigmentary diseases and a plenary session on the immunologic control of melanocytes and melanoma. General sessions covered evolutionary biology of pigmentation, developmental biology, genetics, genomic profiling, neuroscience and pigmentation, melanocyte stem cells and regenerative medicine, hair biology, mouse and non-mouse models of pigmentation, melanosome biogenesis and transfer, melanin function and chemistry, and UV signaling in the melanocyte. The program also included three lunchtime poster sessions with presentation of about 200 posters. Importantly, sessions were specifically dedicated to provide mentoring and career opportunities for young scientists, women in science, and underrepresented minorities in science.The basic and clinical melanoma research sessions presented a state-of-the-art picture of immunotherapy, precision medicine, and genomic profiling of skin cutaneous, uveal, mucosal, and acral melanoma . KeynoteMC1R) variants. Dr. Nicolas Hayward delivered analysis of whole-genome sequences from cutaneous, acral and mucosal subtypes of melanoma. In contrast to frequently occurring coding and non-coding mutations in cutaneous melanoma, the Australian consortium resolved structural changes and novel signatures of mutagenesis in acral and mucosal melanomas, not previously identified in melanoma [Highlights included updates on precision dermatology, bench-to-bedside approaches, genome-wide association studies, genetic diversity of pigmentation, and progress in immunotherapy . Dr. Ianmelanoma .A number of presentations also explored the genetic diversity of pigmentation in non-human and non-mouse systems. Dr. Cheng-Ming Chuong presented a novel foray into the world of feather pigment pattern formation, where color patterns important for animal behavior and speciation is modulated by the presence, arrangement, or differentiation of melanocytes . Among mThe International Pigment Cell Conference has emerged as the sole international scientific convention devoted to the study of the normal pigment cell and the advancement of basic, translational, and clinical research on diseases involving pigment cells. The first meeting was held in New York in 1946 and reconvenes on a triennial basis  was developed first as the International Pigment Cell Society and then formalized as IFPCS in 1990. With the IFPCS formally acting as a means to provide interaction between the independently formed sister societies, the IPCC meeting was chartered as a main function of IFPCS. The Japanese Society for Pigment Cell Research (JSPCR) was founded in 1984, the European Society for Pigment Cell Research (ESPCR) in 1985, the Pan-American Society for Pigment Cell Research (PASPCR) in 1988, and the Asian Society for Pigment Cell Research (ASPCR) in 2004, each becoming members of IFPCS at that time. Thus, the mission of the IFPCS is to disseminate cutting edge research via the publication of the federation\u2019s journal, The XXIII IPCC, representing the four member Pigment Cell Societies of the International Federation, was hosted by the Pan-American Society for Pigment Cell Research in Denver, Colorado, on 26\u201330 August 2017. 540 registrants from 28 countries participated in the 8 plenary and 32 concurrent sessions. 8 keynote speakers led the program, along with 21 plenary session speakers and 80 invited speakers. A further 103 speakers were chosen from submitted abstracts. The main program was complemented by four pre-conference satellite symposia and four pharmaceutical company sponsored symposia. The annual meeting of the Melanoma Prevention Working Group (MPWG) was hosted for the first time at the IPCC meeting. The MPWG functions under the umbrella of the Southwest Oncology Group (SWOG) and the Eastern Cooperative Oncology Group (ECOG). The MPWG meeting promoted clinically relevant research focused on key aspects of melanoma prevention and discussed innovative paths forward into clinical trials of chemoprevention agents for high-risk melanoma patients . The comA major program highlight was a dedicated session on advances in basic and clinical research on albinism. Albinism is a rare genetically inherited condition affecting approximately one in twenty thousand people in most world populations. Albinism occurs at relatively high frequency in sub-Saharan Africa. People with albinism experience visual deficits, hypopigmentation, and sun-sensitivity. In less advanced societies, people with albinism may not have access to healthcare specialists, sunscreen, or protective clothes. Moreover, in sub-Saharan Africa, a humanitarian crisis is presently underway affecting patients with this disease . The dedBreakthroughs in Pigment Cell and Melanoma Research. In essence, IPCC 2017 was at once an outreach to all members of the community and a call to stand unified in facing potential funding challenges as a field.IPCC 2017 was planned for late summer, 26\u201330 August 2017 in downtown Denver, Colorado. The strategy for designing and marketing of IPCC 2017 was informed by multiple lines of reasoning. First, with new melanoma therapies providing improvements in medical care, the field has progressed in an increasingly clinical direction, in some ways diminishing the focus on the basic research that has given rise to successful treatment strategies. Inevitably, new strategies will be needed to further advance the treatment of melanoma patients, and without a strong basic research base, these advances will not be possible. Moreover, successes in the translational arena of melanoma need to be duplicated in other key areas of pigment cell research, including vitiligo, melasma, and other pigmentary diseases. Providing a strong conference venue to support basic research in pigmentary diseases and melanoma in essence embraced the true mission of the IPCC meeting and of the IFPCS organization. A second influencing factor in designing IPCC 2017 was the recognition that with the World Melanoma Congress (WMC) associated with the Society for Melanoma Research (SMR) being scheduled for Brisbane in October, the IPCC would be the only major melanoma meeting to be held in the Northern Hemisphere in 2017. Thus a strong focus on melanoma would allow North American clinicians and researchers proximal access to the latest advances in the field. The third factor embraces all who are interested in pigment cell biology and disease by providing a comprehensive format for promoting interchange between such diverse groups of researchers. Thus, the theme of IPCC 2017 was strategically chosen as Initially, a dual focus on pigmentary disease and melanoma seemed to allow maximal opportunity for industry based meeting support. With strong support from the melanoma committee, major pharmaceutical company support was obtained to support the melanoma program. However, it proved more challenging to raise support from companies with an interest in pigment cell function and disease. This was compensated for by outstanding institutional support from groups within the University of Colorado system affiliated with the local organizing committee. Consequently, the meeting was supported by the melanoma related pharmaceutical industry, the University of Colorado, by conference registration fees and even through generous support from speakers, session chairs and attendees.The IFPCS is a vital global umbrella organization for the regional pigment cell societies. Over more than seven decades, the triennial IPCC has been an opportunity for scientist across the globe to gather to discuss recent findings, progress, and ongoing research. Consistently, the federation and local societies have provided the international research community with essential resources on all aspects of pigment cells including development, cell and molecular biology, genetics, diseases of pigment cells including melanoma.Melanoma to Vitilio: The Melanocyte in Biology and Medicine at Glendan Beach, OR commencing on October 17\u201322, 2018. The IPCC 2020 will be hosted in Yamagata, Japan from 18\u201321 July 2020. The title and focus of the XXIV triennial IPCC will be Integration of Basic Science and Clinical Practice in Pigment Cell Biology.In 2018, the Montagna Symposium on the Biology of the Skin and the Annual meeting of the Pan-American Society for Pigment Cell Research will host a joint conference entitled"}
+{"text": "With the rise of older adults and the number of chronic health issues in this population, comes the need for greater collaboration across organizations and health care settings. Age-friendly health systems offer the benefits of providing the best care possible to individuals and families, connect people to specific community resources, and optimize the best access to services and programs. The Gateway Geriatric Workforce Enhancement Program (GWEP) has combined the efforts of Saint Louis University and a rural, critical access hospital to establish a care network across Missouri. Together, this partnership has created a number of services, initiatives, and projects to help older adults maintain independence and offer families ways to take of their loved ones in more effective ways. In this symposium, presenters from Social Work, Marriage and Family Therapy, Geriatric Medicine, Psychology and Nursing disciplines will introduce several areas of this age-friendly network. The four abstracts for this symposium include: 1.) Assessing At-Risk Older Adults through the Rapid Geriatric Assessment, 2.) Cognitive Stimulation Therapy for Individuals with Memory Loss, 3.) Predictors of Falls in Older Adults Across Partner Settings, and 4.) Development of program initiatives such as the Rapid Geriatric Assessment screening, Cognitive Stimulation Therapy, Falls Assessment in Seniors, and Care for Persons with Dementia in their Environments will be covered in detail. At the end of the four presentations, the presenters will highlight the importance of this collaborative network and ways for audience members to consider building an age-friendly network in their community."}
+{"text": "The identification and development of cancer biomarkers and targets have greatly accelerated progress towards precision medicine in oncology. Studies of tumor biology have not only provided insights into the mechanisms underlying carcinogenesis, but have also led to discovery of molecules that have been developed into cancer biomarkers and targets. Multi-platforms for molecular characterization of tumors and blood-based biopsies have greatly expanded the portfolio of potential biomarkers and targets. These cancer biomarkers have been developed for diagnosis, early detection, prognosis, and prediction of treatment response. The molecular targets have been exploited for anti-cancer therapy with proven benefits in improving treatment response and survival. However, plenty of research opportunity exists for discovering, developing, and validating cancer biomarkers and targets for improving the clinical outcomes of patients with malignant diseases, particularly those in the digestive system.Pancreatic-hepato-biliary and gastrointestinal carcinoma are among the most lethal human malignant diseases . With thBiomedicines comprises a variety of articles about recent advances in the discovery, characterization, translation, and clinical application of cancer biomarkers and targets in the digestive system. These articles include original research, reviews, case studies, and conference papers. At the Multi-Disciplinary Patient Care in Gastrointestinal Oncology conference in Hershey, Pennsylvania, the new frontiers in various aspects of digestive organ cancers were presented [This Special Issue of resented . In thisresented . The bioresented . In thisresented . MoreoveA number of articles in this Special Issue examine the biomarkers and targets with a focus on cancer in individual organs, including liver. While liver transplantation is a potentially curative treatment of hepatocellular carcinoma, liver graft injury has been identified as an acute phase event that leads to post-transplant tumor recurrence. Lee et al. examined this acute phase event at the molecular level by transcriptomic analysis of liver grafts from recipients with or without tumor recurrence following liver transplantation . This stBesides hepatocellular carcinoma, several articles focus on cancer biomarkers and targets in the gastrointestinal tract. Fonkoua and Yee present a critical review of the molecular characterization of gastric carcinoma by the Cancer Genome Atlas Research Network, the Asian Cancer Research Group, and tumor molecular profiling through expression analysis and genomic sequencing of tumor DNA . These mDespite advances in developing clinically useful biomarkers and targets in gastrointestinal cancers, relatively little progress has been made for patients with pancreatic carcinoma. While early detection of pancreatic carcinoma is critical for improving patient survival, agents that selectively target pancreatic tumor are expected to enhance therapeutic efficacy. In this Special Issue, Matters and Harms present a detailed review of G protein-coupled receptors, which are key target proteins for drug discovery. They further discuss the potential of GPCRs as biomarkers for tumor imaging and targeted treatment of pancreatic carcinoma .Research on discovery and development of cancer biomarkers and targets has been steadily progressing. Rigorous investigation for identification and validation of biomarkers and targets in both preclinical models and clinical studies are expected to generate new opportunities for making a positive impact on survival and quality of life in the patients. The articles in this Special Issue provide an update on the frontiers in gastrointestinal oncology, with a focus on biomarkers and targets in cancers of the digestive system. We hope this Special Issue will help stimulate research collaboration on developing strategies for prevention, early detection, diagnosis, and screening of cancers in digestive organs, as well as improving treatment outcomes and psychosocial support in patients with these malignant diseases. In particular, liquid biopsy for cancer biomarkers and targets has been a major focus of research with translation into clinical applications.Recent advances in plasma-derived extracellular vesicles (EVs) have demonstrated the potential of making a clinically meaningful impact in the field of cancer biomarkers and targets. Analysis of EV-derived molecular markers is complementary to the conventional diagnostic modalities. By application of nano-, micro-, digital-, and microarray-based technologies, multiplex analysis of disease-specific markers is expected to improve the sensitivity and specificity of bodily fluid-based biopsies for diagnosis of cancer. These minimally invasive diagnostic tools that utilize ultra-low sample volume may prove to be economically cost effective for screening of cancer in the high-risk population and even in the general population. In addition to this, increasing evidence has indicated the potential value of blood-based biopsies in combination with tumor molecular profiling for developing predictive biomarkers of treatment response, as well as personalized targets of therapy. Further development, optimization, and clinical validation of these cancer biomarkers and targets will hopefully enable us to attain the goal of precision medicine in cancer of digestive organs."}
+{"text": "Click chemistry has great potential for use in binding between nucleic acids, lipids, proteins, and other molecules, and has been used in many research fields because of its beneficial characteristics, including high yield, high specificity, and simplicity. The recent development of copper-free and less cytotoxic click chemistry reactions has allowed for the application of click chemistry to the field of medicine. Moreover, metabolic glycoengineering allows for the direct modification of living cells with substrates for click chemistry either in vitro or in vivo. As such, click chemistry has become a powerful tool for cell transplantation and drug delivery. In this review, we describe some applications of click chemistry for cell engineering in cell transplantation and for drug delivery in the diagnosis and treatment of diseases. The iEDDA reaction has been used for the visualization of both antibodies and tumor tissues by PET imaging. Rossin et al. applied the iEDDA reaction for the selective cleavage of tumor-bound ADCs for cancer therapy [Since the iEDDA reaction has the fastest reaction rate of the bioorthogonal reactions , its app quality . They syon doses ,97. Theson doses . They sy therapy . First, In this review, we discussed the application of copper-free click chemistry for cell engineering in cell transplantation and drug delivery. Although certain factors remain unclear, including the safety of utilizing copper-free click chemistry and metabolic glycoengineering, these reports suggest that copper-free click chemistry is a powerful tool for cell engineering and drug delivery. As such, high biocompatible and fast copper-free click chemistry and its application in the biological and medical fields can be expected to develop further in the near future."}
+{"text": "Recent evidence has suggested that polyphenol-rich foods intake may be associated with decreased risk of chronic diseases. The Special Issue \u201cEffects of Polyphenol-Rich Foods on Human Health\u201d comprised 64 peer-reviewed papers on the most recent evidence regarding the dietary intake of polyphenols and polyphenol-rich foods, as well as their effect toward the prevention and treatment of non-communicable diseases. Original contributions and literature reviews demonstrated the potential protective effects of polyphenol-rich foods and their extracts toward cardiovascular diseases, certain cancers, and neurodegenerative diseases, mostly through anti-oxidant and chemo-preventive properties. Over the last years, polyphenol-rich foods and polyphenols have received great attention due to their potential beneficial effects toward human health. Contained not only in fruits and vegetables, but also in whole-grains, nuts, olive oil and beverages such as coffee and tea, they are characteristic components of healthy dietary patterns . Recent This Special Issue \u201cEffects of Polyphenol-Rich Foods on Human Health\u201d comprises 64 peer-reviewed papers, including 43 original research papers ,48,49,50The Special Issue included systematic reviews and meta-analysis summarizing the level of evidence on both polyphenols and polyphenol-rich foods. In particular, published articles demonstrated that a moderate intake of coffee is inversely associated with the risk of hypertension , and canEpidemiological and clinical studies reported the following associations of polyphenols and polyphenol food extracts: silibinin and non-alcoholic fatty liver disease ,39, resvImportantly, numerous reviews summarized the evidence regarding polyphenols and polyphenol-rich foods and their association with NCDs related to oxidative stress and inflammation, including CVDs, diabetes, hypertension, obesity, certain cancers and neurodegenerative diseases ,69,70,71Several contributions investigated polyphenol metabolism and transformation into bioavailable molecules and underlined the importance of the clarification of the metabolic fate of polyphenols and their bioavailability in order to fully understand the molecular forms responsible for the preventive actions of polyphenols ,35,36,43Polyphenols have been demonstrated to be responsible for the anti-inflammatory and antioxidant properties of potentially functional foods. Numerous studies explored in detail the molecular mechanisms underlying the protective effects of polyphenols, including antioxidant capacity, that can be attributed to the regulation of redox enzymes through reducing reactive oxygen species (ROS) production and modulation of the II-phase enzymes responsible for the cellular oxidative response; other studies explored the chemo-preventive effects of polyphenols, including the elimination of carcinogenic agents, the modulation of pathways responsible for cancer cell signaling and cell cycle progression, and in the promotion of apoptosis ,48,49,50Nutrients for their professional help in the completion of this Special Issue.As a guest editor, I would like to acknowledge all the authors for their valuable contributions and the reviewers for their constructive remarks. Special thanks to the publishing team of the journal"}
+{"text": "An ad hoc committee of the National Academies of Sciences, Engineering, and Medicine examined the potential for integrating services addressing social needs and the social determinants of health into the delivery of health care to achieve better health outcomes and to address major challenges facing the U.S. health care system. These challenges, include persisting disparities in health outcomes among vulnerable subpopulations, often defined by a number of factors including age. Presenters will discuss and provide recommendations in the following areas: 1. evidence of impact of social needs care on patient and caregiver/family health and wellbeing, patient activation, health care utilization, cost savings, and patient and provider satisfaction; 2. opportunities and barriers to expanding historical roles and leadership of social workers in providing health-related social needs care and evidence-based care models that incorporate social workers and/or other social needs care providers in interprofessional care teams across the care continuum  and in delivery system reform efforts ; and 3. realized and potential contributions of social needs care to make health care delivery systems more community based, person- and family/caregiver-centered, and responsive to social and structural determinants of health, particularly for vulnerable populations and communities, such as older adults and low-income families. Examples for each of the three areas will also be presented."}
+{"text": "Otala lactea snails during estivation  arrest of transcriptional and translational activity, (ii) depression of metabolic rate, (iii) re-wiring of energy metabolism pathways toward fermentative rather than oxidative routes, (iv) activation of mechanisms involved in both macromolecular repair and detoxification of cellular-derived oxidants  toward a reduced state, favoring the production of superoxide radicals , followed by up to 40\u201360% reductions (from 7 to 21 days) , and GPX activities by 53 and 100%, respectively, upon severe hypoxia  further understand the molecular mechanisms controlling the hormetic POS phenomena, for example providing evidence for the role of kinases/phosphatases in the improvement of the antioxidant response in hypoxic tolerant species, and (ii) keep searching for the POS-response in nature (Moreira et al., MO, DM, and MH-L worked on the concept of hormesis and its application on the POS theory. DM, TF, and MG contributed with key examples of POS-related studies. MO and MH-L drafted the manuscript, which was reviewed and approved by all authors.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "This systematic review aimed to examine the associations between health-related outcomes and the built environment (BE) characteristics of compact metropolitan cities in Korea using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework. Searching the three Korean academic databases and PubMed, two independent reviewers identified 27 empirical articles published between 2011 and 2016. Data extracted for review included the study characteristics, the variables and measurement methods related to the BE and health-related outcomes, and the findings on the associations between the BE characteristics and health-related outcomes. Vote counting was used to assess the consistency of associations and the direction of associations between the BE characteristics and health-related outcomes. All of the reviewed studies used cross-sectional designs. The objective BE qualities were commonly examined. The BE characteristics associated with health-related outcomes in the reviewed articles included land use, street environment, transportation infrastructure, green and open spaces, and neighborhood facilities. Street environment, transportation infrastructure, and green and open spaces had consistent positive associations with physical health. Mixed land use and neighborhood facilities, however, had inconsistent associations with physical health. Generally, insufficient findings were reported in the association between the BE characteristics and mental and social health. The accessibility of the BE in a compact urban environment was the prominent attribute related to health promotion, health challenges, and health equity. An international comparative analysis of compact cities with different urban contexts and scale is required. Interdisciplinary urban health strategies are recommended based on the associations between the BE characteristics and health-related outcomes.  As health promotion strategies targeting policy, system, and environment changes become more important, the built environment (BE) is becoming a key element of interventions . The BE In the Global Report on Urban Health, the World Health Organization (WHO) indicated the influence BE conditions have on public health, notably in the urban context . This iswhat aspects of and how the BE in metropolitan cities affects public health. The impact of BE on public health is a topic that has been studied extensively around the world. Existing literature suggests that mixed land use, street connectivity, public transportation, and green space are positively related to physical activity and weight loss ,7. Furth2, (2) an independent budget management system, (3) public transit infrastructure (subway and bus), and (4) an urban master plan for compact urban design [The Organisation for Economic Co-operation and Development (OECD) recommends that metropolitan cities adopt a compact urban design to solve urban problems caused by high population density and inefficient land use . Metropon design . AccordiThe health status of residents in Korean metropolitan cities is complicated. The following indicators were better than the WHO average in 2016: Life expectancy at birth was 82.7 years, prevalence of insufficient physical activity was 35.4%, prevalence of depressive disorders was 3.0%, and the prevalence of obesity was 26.0% ,14. On tAlthough Korean studies on the BE and health have been conducted since 1978, there have been scare attempts to integrate the results of BE characteristics that affect the health of urban populations. These studies have focused on different BE and health-related variables, and have used different methods and measurement criteria . They alThis study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework for conducting and reporting systematic reviews . The rev-Studies conducted in Korean metropolitan cities.-Studies that objectively  or subjectively  measured the BE reported as independent variables.-Studies that objectively  or subjectively measured health-related outcomes  .-Peer-reviewed and fully published articles.-Published articles written in Korean or English.Studies were selected by applying the eligibility criteria of settings, study design, methods, and outcome measures. Inclusion criteria were: -Studies that objectively or subjectively measured indoor facilities and working facilities reported as independent variables.-Studies that objectively or subjectively measured the natural environment  reported as independent variables.-Systematic reviews.-Qualitative studies.-Studies conducted to develop the BE measuring instrument that does not analyze the correlation with health.-Descriptive studies with only bivariate analysis.Exclusion criteria were:Between February and June 2017, we conducted literature searches in three Korean academic databases  and PubMed. The search terms were identified from previous related reviews  and the Data extracted included the characteristics , the BE variables and measurement methods, health-related variables and measurement methods, and significant and non-significant findings on the correlation between the BE characteristics and health-related outcomes.To include all the BE variables across studies, we listed and categorized each variable and construct of the BE characteristics  . The BE Vote counting was conducted to summarize the number of studies reporting significant and non-significant findings and the direction of the associations between the BE characteristics and health-related outcomes. The Cochrane handbook indicates that vote counting may be useful when statistical meta-analysis cannot be applied due to the heterogeneity of measured outcomes .\u201cConsistent association\u201d was defined as 75% to 100% of the significant findings reporting the same direction within the BE characteristics (c.f. <75%: \u201cinconsistent association\u201d) [In order to clarify the direction of association, we classified the findings as positive  or negative  as a result of the direction of health promotion. The consistency of associations between the BE characteristics and health-related outcomes was determined by five studies or more that reported significant findings to sufficiently indicate consensus   .In the first PRISMA stage, 1077 articles were selected . Of thesThe number of publications has increased in recent years. Researchers represented 12 fields of study, primarily urban planning and design (39%). Some studies (14%) involved researchers from two disciplines. Only three studies were conducted by public health researchers (11%). Overall, Korean studies tended toward a mono-disciplinary approach from the perspective of urban planning rather than public health.All studies used a cross-sectional design. The research setting was as follows: 67% in the capital city, 22% in the metropolitan cities, and 11% in both. More than half the studies (56%) had participants of specific age groups, including adolescents (15%), adults (22%), and the elderly (19%), and 44% had participants of all ages. One study  used comHealth-related variables were classified according to the physical, mental, and social health domain. Most studies (81%) used physical health-related variables to examine the relationship between the BE and health, including health-related behaviors, illness or death, and perceived health status. The health-related behaviors included moderate or high intensity physical activity, walking, sedentary behavior, and dietary behavior, with walking being the most common ,41,45,46About one-fifth (19%) of the studies examined the relationship between the BE and mental and social health. The mental health-related variables included prevalence of mental illness and levels of depression, stress, and self-esteem. Of these, depression was used in four studies as a measure of mental health ,28,30,37We investigated the associations between the BE characteristics and health-related outcomes. As noted earlier in Mixed land use had an inconsistent association with physical health ; five ouNon-consistent associations were found between mixed land use, mental health, and social health ,43. MixePedestrian-friendly environments had a positively consistent association with physical health . The higher density and shorter distance of welfare centers were correlated with reduced depression . PerceivThis systematic review has clarified the association between the BE and health in compact metropolitan cities. Empirical research on the BE and health in Korean metropolitan scale cities has been conducted primarily in the fields of urban planning and urban design. All studies reviewed were cross-sectional. Among the studies using secondary data, none conducted detailed spatial unit analyses at the community level, which Lee  considerThe BE characteristics that affected health were land use, street environment, transportation infrastructure, green and open spaces, and neighborhood facilities, which aligns with previous studies . The BE The health-related outcomes in the included studies focused on physical health, with few studies including the mental and social health domains. This result supports previous findings suggesting associations between the BE and health lacked an integrated view of health and multi-domain considerations . To overIn previous studies, mixed land use has been reported to be a key strategy for compact city policies that contribute to reduced obesity and promote physical activity ,58. HowePedestrian-friendly environments promote walking and social activities of urban residents. In particular, safety and accessibility were important attributes of the pedestrian-friendly environment ,41,43,49Safety and accessibility can serve as factors for cities to stay active for 24-h, but they can lead to negative health outcomes. Koo et al.  pointed In our study, transportation infrastructure has been found to be associated with the promotion of physical and social health through public transportation and bicycle use; whereas, automobile use has a negative impact on physical activity and community safety. These findings support the health promotion effect of active transportation that restrains the use of vehicles and promote the use of bicycle and public transportation ,63. In aWe found that the proportion of parks and green spaces was associated with physical and mental health. However, if the green area of the city is excessively large, it would interfere with spatial connectivity and have a negative effect on physical, social, and mental health. This supports the hypothesis that open spaces only promote walking up to a certain size threshold . Some stWhen neighborhood living facilities are safe, close and convenient to use, outdoor activities are frequently performed, opportunities for social relationships increase, and depression decreases. In terms of equitable utilization of community assets, physical and economic accessibility and the spatial distribution of neighborhood facilities are related to health equity. This suggests that the strategic utilization of neighborhood facilities as a daily life condition for local residents can lead to the social participation of vulnerable groups and physical health promotion . In our Overall, we found that BE characteristics in compact metropolitan cities associated to health-related outcomes had accessibility as a common attribute. The accessibility of the BE contributed to health promotion in terms of resource availability. Urban planning and policies for compact cities positively affected walking for travel and physical activity, and promoted social interactions and networks ,48,49,50However, the accessibility of the BE produced some health challenges: 24-h facilities near the residential area increased fatigue and the obesity rate of residents by increasing their nighttime activity and chances of eating later in the evening ,35. MixeThe accessibility of the BE is an important health equity issue. Areas with a low density of public transport and neighborhood facilities tended to worsen the physical, mental, and social health of the residents. In urban areas with low access to the BE, physical activity and walking decreased, obesity increased, and residents had difficulty maintaining and forming social relationships ,42,43. TThe association between the BE and health studied in the Korean metropolitan cities with a compact urban environment was mostly consistent with that found in urban health research conducted at other urban scales. However, there were differences for some health-related outcomes, the criteria for spatial accessibility, and the BE variable of density. These differences were attributed to the dense and complex urban structure of Korean metropolitan cities and the manner in which the decision-making of health behavior interacts with the perceived environment. Therefore, health promotion strategies aimed at environmental change should consider the environmental specificity and the attributes of the perceived environment related to health behaviors.Because this study only examined studies published in peer-reviewed journals, high-quality research published outside of peer-reviewed journals was included in the results. This review was limited to studies published from 2011 to 2016, and some studies might have been left out of the review because of the limitations of the search terms, search criteria, and search databases used. Additionally, quality assessment was not conducted, and all the included studies used cross-sectional designs. The causal assumption and true effects are difficult to determine by synthesizing results from cross-sectional studies.Despite these limitations, due to a systematic review by following PRISMA, the consistency and direction of findings across studies reviewed were rigorously examined. We also identified the BE variables and measurement methods, and health-related variables and measurement methods. These results strengthen the existing evidence for the associations between the BE and health and provide research design and methodological implications for future research on the BE and health.This study systematically examined the associations between the BE characteristics and health-related outcomes in compact metropolitan cities in Korea and identified the health benefits and risks of the particular BE characteristics in such cities. All of the reviewed studies were cross-sectional, the study methods and measurement tools varied, and there was insufficient evidence for the associations between the BE characteristics and social and mental health. Future research is called for to focus on the impact of BE characteristics on mental health and social health in a compact urban context, and to use theoretically sound longitudinal designs.Interdisciplinary urban health strategies are required based on the associations between the BE characteristics, health-related outcomes, and the environmental context. Evidence for the associations between the BE characteristics and health-related outcomes in compact metropolitan cities may provide a greater understanding of the health effects and health behaviors of urban development for compact cities in other countries. A comparative analysis with international studies would contribute to further planning for rational urban development."}
+{"text": "Keywords: trauma; intimate partner violence; mental disturbance; torture; corrigendumAt a community-wide level, in the case of torture survivors, the focus should be on violence prevention by way of early identification and support for men at risk; provision of timely work, educational, and financial assistance; and programs aimed at harmonizing the re-entry of the male survivor back into the family and broader community.The references Pease & Flood, 2008 and Vichealth, 2014 were mistakenly added following the paragraph:"}
+{"text": "Chitin and chitosan are very abundant natural polymers with distinctive properties, such as bioactivity, biocompatibility and biodegradability, that have inspired a number of basic and applied studies, mostly in biotechnology, medicine, food preservation and agriculture. The interest in these polysaccharides is still quite high and lot of scientists are currently devoting their efforts to improve the knowledge in this field, gather in various scientific societies spread all over the world and organise specific conferences. The same broad interest in chitin and chitosan has been devoted to the various enzymes involved in their hydrolysis and the corresponding enzyme-producing organisms, in particular bacteria and fungi.Research on chitin, chitosan, and related enzymes has led to many basic and applied studies carried out in order to: explore the potential of these natural polymers , investigate the action and perspectives of the various enzymes and to directly apply the chitinolytic organisms. Although the field had been widely investigated, there is still room for interesting research novelties. This Special Issue aimed to provide a platform for the dissemination of the most advanced studies in this field and main topics were: the physics, chemistry, and biochemistry of chitin and chitosan; chitin, chitosan, and chitin-derivatives production; applications of chitin, chitosan, and their derivatives; and the bio-synthesis and bio-degradation of chitin and chitosan.Various scientists participated in this issue dealing with these various topics, and the Editorial Committee sought to accept only peculiar and/or particularly innovative papers, including review papers, covering the various aspects of the issue as follows:Synthesis and Characterization of Glutamic-Chitosan Hydrogel for Copper and Nickel Removal from Wastewater [. Chitosan preparations were treated with various concentrations of glutamic acid resulting in different types of glutamic-chitosan hydrogels that were tested for the removal of copper(II) and nickel(II) from wastewater. The increase of glutamic acid concentration led to a decrease of metal removal efficiency, probably due to a decrease in the pore size of the hydrogels.stewater . ChitosaInhibition of Listeria monocytogenes in Fresh Cheese Using Chitosan-Grafted Lactic Acid Packaging [. Chitosan was grafted with d,l-lactic acid in aqueous media using p-toluensulfonic acid as catalyst to obtain a non-toxic, biodegradable packaging material that was characterized using scanning electron microscopy and other techniques. The grafting in chitosan with d,l-lactic acid produced films with improved mechanical properties. This material successfully extended the shelf life of fresh cheese and inhibited the growth of Listeria monocytogenes during 14 days at 4 \u00b0C and 22% relative humidity. The results were compared to control samples and commercial low-density polyethylene packaging demonstrating that the use of non-toxic chitosan-g-LA for packaging of fresh cheese offers a valid alternative for the preservation and conservation of this product and inhibited the growth of Listeria monocytogenes.ackaging . ChitosaChitosan Nanoparticles as Carriers for the Delivery of \u03a6KAZ14 Bacteriophage for Oral Biological Control of Colibacillosis in Chickens . The useSorption of Cu(II) Ions on Chitosan-Zeolite X Composites: Impact of Gelling and Drying Conditions [. Different typologies of chitosan-zeolite Na-X composite beads were prepared by encapsulation and analysed by a series of methods  in order to investigate Cu(II) sorption. The drying method used for the storage of the adsorbent severely affected both the structural properties of the composite and the copper sorption effectiveness. Textural and Cu(II) sorption data indicated that whereas a chitosan coating impaired the accessibility of the microporosity of the zeolite; presence of zeolite improved the stability of chitosan dispersion upon supercritical drying and increased the affinity of the composites for Cu(II) cations.nditions . DiffereThe Psychrotolerant Antarctic Fungus Lecanicillium muscarium CCFEE 5003: A Powerful Producer of Cold-Tolerant Chitinolytic Enzymes [Chitosan and Its Derivatives as Highly Efficient Polymer Ligands [. This review paper covers results of the last decade. Chitosan has a polyfunctional nature permitting its application as a polymer ligand not only for the recovery, separation, and concentration of metal ions, but also for the fabrication of various functional materials. Although unmodified chitosan itself is the unique cationic polysaccharide with very good complexing properties toward numerous metal ions, its sorption capacity and selectivity can be sufficiently increased and turned via chemical modification to meet requirements of the specific applications. The main information supplied by this paper was aimed to demonstrate how different strategies of chemical chitosan modification effect metal ions binding, and to underline the mechanisms involved in ions binding by chitosan derivatives. Ligands . This reAll the published manuscripts have contributed to provide an image of the current and future trends in the development of chitin, chitosan and related enzyme research. The Editorial Committee expects that this Special Issue may help to understand the great potential of this specific research field and encourage further research on this matter."}
+{"text": "Typhoid fever is a continuing public health problem in many low- and middle-income countries; however, routine vaccination as a recommended control strategy has not been implemented in the past in most countries. Greater understanding of the typhoid fever burden, the increasing threat of antimicrobial resistance, and licensure of a new generation of typhoid conjugate vaccines (TCVs) were instrumental in paving the way for the World Health Organization (WHO) to issue a revised global policy on typhoid vaccines in March 2018. The new policy follows evidence-based recommendations by the WHO Strategic Advisory Group of Experts on immunization for routine and catch-up vaccination with TCVs and highlights considerations for universal, risk-based, or phased vaccination strategies in different settings. Further, the first WHO-prequalified TCV and Gavi funding for eligible countries make vaccination a realistic control strategy for many affected countries, especially if combined with improved water and sanitation services, strengthened surveillance systems, and appropriate antimicrobial treatment. Salmonella enterica serovar Typhi, include access to safe water, adequate sanitation, personal and food hygiene, health education, appropriate antimicrobial treatment, and vaccination. While water, sanitation, and hygiene (WASH) strategies are powerful tools for typhoid control, the major financial investments required for infrastructure development and maintenance limit WASH solutions in the short to medium term in most typhoid-endemic countries [An estimated 11 to 21 million cases and more than 128 000 deaths from typhoid fever occur annually across many low- and middle-income countries, primarily in South and Southeast Asia and sub-Saharan Africa . Effectiountries , 5. WeigWHO is mandated to provide global vaccine policy recommendations based on a transparent and systematic evidence review process by the Strategic Advisory Group of Experts (SAGE) on Immunization, an independent advisory committee that advises the WHO on the development of policy related to vaccines and immunization , 7. WHO In 2008, WHO updated its policy on the parenteral unconjugated Vi polysaccharide and oral live attenuated Ty21a typhoid vaccines and emphasized their programmatic use to control endemic and epidemic typhoid fever where the disease remained a significant public health problem. Public health use of the Vi polysaccharide vaccine in 2 large demonstration projects in Asia, in 2003\u20132004 and 2010\u20132012, provided evidence of vaccine effectiveness and safety, feasibility of community- and school-based delivery strategies, and acceptability of the vaccine in the target populations , 10. HowSeveral key developments over the last decade refocused attention on the potential for routine vaccine use as a critical public health tool, especially when integrated with WASH and other strategies, for the control of typhoid fever. Crucially, data from the Typhoid Surveillance in Africa Program showed moderate to high disease incidence in some sub-Saharan Africa countries, rivalling rates previously described in parts of Asia . These gSalmonella Typhi, including spread of the H58 haplotype, which has been responsible for much of the recent and current spread of resistant strains [Salmonella Typhi H58 strain with resistance to the traditional first-line antibiotics of ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole, as well as additional resistance to fluoroquinolones and ceftriaxone, in an ongoing outbreak in Pakistan [Second, there has been a growing body of evidence about the threat of antimicrobial-resistant strains of  strains  and emer strains . ConcernPakistan .Third, the long-anticipated availability of a newer generation of typhoid conjugate vaccines (TCVs) moved closer to reality with licensure in India of 2 Vi-tetanus toxoid conjugate vaccine products in 2008 and 2013. An earlier Vi-rEPA conjugate vaccine had provided extensive clinical trial data that demonstrated safety, immunogenicity, and clinical efficacy of 89.0%  over 46 months follow-up in Vietnamese children aged 2\u20135 years . HoweverFocus on typhoid conjugate vaccines necessitated a review of the (hitherto limited evidence on) age-specific burden in infants and children aged <2 years and the key considerations for the optimum schedule and delivery strategies for that age group. Revision of the typhoid vaccine policy followed the standard SAGE process for the development of vaccine recommendations, which incorporates review of the best available evidence on the clinical and epidemiologic characteristics of the targeted disease in different settings; vaccine characteristics and performance; and immunization, economic, health-system, legal, and ethical considerations, as well as social values and preferences regarding the target vaccine. This evidence review is combined with assessment of the quality of evidence on critical policy questions and, where needed, expert interpretation and judgment on specific programmatic questions to guide the resulting public health decision-making . As withThe new WHO policy recommendations reemphasize programmatic use of typhoid vaccines for the control of typhoid fever and specify that among the available typhoid vaccines, TCV is preferred at all ages in view of its improved immunological properties, suitability for use in younger children, and expected longer duration of protection. Recommendations for routine and catch-up vaccination as well as the specific considerations for national decisions on the preferred vaccination strategy  are laid out in the WHO position paper .With the first WHO prequalification of a TCV  and a de"}
+{"text": "Herbal medicines have been used in traditional medical practices for centuries. While practitioners of herbal medicines are often comfortable with the application of such medicines and are also largely convinced by the results they experience with patients, the scientific validity of herbal medicines in research and development is still often questioned. This is partly due to the lack of quality control, identification, and standardization of chemical compounds and drug formulations, as well as the challenges of applying the same methodologies across dissimilar medicinal products. The development of herbal medicine within the framework of evidence-based medicine is relatively new. Applying the methodologies of Western-based pharmaceutical sciences to herbal medicines presents the research community with a complex set of challenges. However, it is essential that herbal medicine research design and conduct be scientifically and ethically sound, while also taking into account the medical philosophies and practices that accompany the use of traditional herbal medicine.Our special issue is focused on the application of modern technologies and methodologies in herbal medicine research and development using the accepted Western scientific and ethical standards. In the last decades, there has been significant progress in advancing traditional herbal medicine research and development, particularly in Asia, where there is an abundance of medicinal plants. As this issue will illustrate, the application of modern technologies and methodologies can have a significant impact on the scientific validity, quality improvement, and standardization of herbal medicines. et al., the extraction of the bioactive ingredient glycyrrhizic acid from Glycyrrhiza glabra was successfully optimized using a mathematical modeling approach. The plant is one of the most widely used traditional medicines in China, mainly for invigorating the spleen, replenishing qi, and clearing away heat and toxic substances to treat diseases such as the weakness of the spleen and stomach, coughs, and phlegm. The authors demonstrated that the combinational method of genetic algorithm and artificial neural networks provides a reliable and accurate strategy for designing and optimizing glycyrrhizic acid extraction from Glycyrrhiza glabra.In the study of L. Yu et al. investigated the association between the proangiogenic mechanisms of Long-Zhi Decoction (LZD) medicated serum on cellular autophagy. The promotional effect of LZD on angiogenesis was examined in vitro using human umbilical vein endothelial cells (HUVECs). Proliferation, migration, and tube formation were assessed in a cell-based assay. A transmission electron microscope was used in the measurement of autophagosomes to determine the extent of autophagy. Immunofluorescence and Western blot were used to determine the autophagy-related proteins of LC3-ll and Beclin-1. The results showed that the LZD-medicated serum increased autophagosomes and the autophagic protein expressions of LC3-ll and Beclin-1. The LZD-medicated serum also promoted the proliferation, tube formation, and invasion of HUVECs. This may suggest that LZD promotes angiogenesis by increasing cellular autophagy.Q. He et al. conducted a preliminary study in a transgenic strain of mice with adenocarcinoma of the mouse prostate (TRAMP) to evaluate the efficacy of the Deep Immune\u00ae (DI) as a prevention strategy to control the progression of prostate cancer. DI is a commercial natural health product consisting of a mixture of eight medicinal herbs. It was shown to stimulate phagocytosis and expression of a panel of inflammatory mediators  in cultured macrophages in vitro. In addition, it also increases the tumor-killing ability of both macrophages and TRAMP mouse splenocytes. Daily intake of this herbal product significantly prevented prostate cancer progression, suggesting the possible effectiveness of the immunostimulant herbal products in the prevention of the progression of prostate cancer.P. Liang Candida albicans. Based on the microbiological test, the concentration of 0.05% of thyme essential oil in the oleogel mixture was shown to exhibit an antifungal activity against Candida albicans.G. Kasparaviciene et al. successfully formulated oleogel with thyme essential oil, designed its optimal formulation, and investigated the influence of ingredients on texture parameters of the preparation while also testing for its antimicrobial activity. The formulation optimization of oleogel was designed by means of a response surface model using Design-Expert 6 program, accompanied by texture analysis. The characterization and quantification of components of essential oils and oleogels were performed by GC-FID. The antimicrobial activity of oleogels with essential thyme oil was determined against Gynostemma pentaphyllum (GP) extract on NAFLD. The in vivo results showed that GP extract alleviated fatty degeneration and haptic fibrosis in NAFLD mice. Through a network pharmacology approach and biomedical assay, the potential active components of GP and their intracellular targets for hepatoprotective activity were identified as acyl-CoA oxidase (ACO) and carnitine palmitoyltransferase-1 (CPT-1).Nonalcoholic fatty liver disease (NAFLD) is the most common type of liver disease in developed countries. M. Hong et al. conducted a study to explore the potential protective effects and mechanisms of action of et al. performed a systematic review and meta-analysis of the effects of Panax ginseng on obesity in animal models. Sixteen studies were included in the review. The meta-analysis indicated that oral administration of P. ginseng is effective against weight gain particularly in the obesity model induced by high-fat diet. The review showed that while P. ginseng improved serum lipid profile in animal obesity model, its processing method may affect treatment outcomes.H.-S. ParkJ. Zhong et al. performed another systematic review to evaluate the efficacy and safety of Ma-Huang-Fu-Zi-Xi-Xin decoction (MHFZXXD) in patients with allergic rhinitis (AR). The review included six randomized control trials (RCTs) in 576 patients. Despite its long use and recommendation in a clinical guideline for the alleviation of symptoms of AR, this systematic review concluded that there is insufficient evidence to support the use of MHFZXXD alone for routine treatment of AR. Several scientific issues were identified in the included RCTs, indicating that there were various types of biases in each study, including selection, performance, attrition, and reporting bias. In addition, the sample size of each trial was shown to be too small to provide conclusive results.In conclusion, significant progress is seen in the application of Western research methodologies to the evidence-based evaluation of, and further development of, traditional herbal medicines. The research presented in this special issue demonstrates advances in the technologies and scientific strategies for an evidence-based approach to herbal medicines. This offers promise for a more solid and uniformly accepted basis for the confirmation or rejection of the continued use of specific traditional herbal medicines. The employment of these research methodologies also opens new vistas for discovering new chemical compounds and formulations that may support the development of traditional herbal medicine formulations into Western pharmaceuticals. This special issue further provides evidence that modern techniques and methodologies, including mathematical modeling, are not limited in their application to any stage of herbal medicine research and development, assisting both traditional practitioners and Western scientists in addressing challenges to the scientific validity of specific herbal medicines as well as to help further develop these medicines for uses outside their traditional practices and contexts."}
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+{"text": "Interleukin-1\u03b2 in hypothalamic paraventricular nucleus mediates excitatory renal reflex the central pathways of a sympathetic excitatory reflex, which is triggered by renal afferent nerve fibers. The authors had already described this reflex in more detail before: a direct infusion of capsaicin into the renal interstitium resulting in an increase of sympathetic nerve activity to the kidneys. In their recent work addressing central nervous mechanisms, the authors focused on the paraventricular nucleus of the hypothalamus, which plays an important role in the processing of various peripheral afferent information, which in turn participate in the generation of central sympathetic outflow. With regard to their specific question, the authors convincingly demonstrated that sympathetic activation following administration of capsaicin directly into the renal interstitium is mediated via IL-1\u03b2 in the paraventricular nucleus of the hypothalamus.Fen Zheng and his co-authors investigated in their article The investigation of neurophysiological structures like the paraventricular nucleus of the hypothalamus is important because the central pathways integrating afferent and efferent renal nerve activity are not well understood. Clinical studies suggest an important role of renal sensory afferent innervation in the regulation of efferent sympathetic tone. In patients with hypertension and end-stage kidney disease, peripheral sympathetic activity remained increased after renal transplantation. Peripheral sympathetic tone decreased only in patients who had additionally undergone bilateral nephrectomies of the failing kidneys .At first glance, it may seem surprising why an interleukin-like IL-1\u03b2 should play such a prominent role in processing afferent neuronal input for the generation of central sympathetic outflow. However, one should bear in mind that the immune system and many visceral organs are autonomously innervated quite densely . The infIf capsaicin was not injected into the renal tissue but directly into the organ via the renal arteries, a long lasting sympathetic depression  and no sMore extensive research will be needed to clarify these last mentioned open points. The fact that there will be no quick and easy explanations in this context is not least due to the observation that afferent nerve fibers always have both mechano- and chemosensitive properties, whereby they express a large number of different receptors, quite a few of them with significant involvement in immunological responses."}
+{"text": "Flaviviruses are enveloped single-stranded RNA viruses and major human pathogens. They are responsible for causing outbreaks and therefore they represent a serious health issue worldwide . BecauseAedes aegypti mosquitoes and recent studies have begun to examine vector-virus relationships and transmission dynamics of this virus pathogen (Ae. aegypti mosquitoes infected with ZIKV activate the RNA interference (RNAi) mechanism by upregulating several virus-produced short interfering RNAs (siRNAs), piwi-interacting RNAs and microRNAs. Many of the latter are also regulated by DENV and WNVs, but not by the alphavirus Chikungunya, indicating conservation in the mosquito response to flavivirus infection  pathway  limits ZIKV infection by maintaining midgut homeostasis through modulation of reactive oxygen species in the midgut as well as microbiota growth and stem cell proliferation  gene, which is involved in brain development and has been previously implicated in hereditary microcephaly, in flies overexpressing ZIKV NS4A abolishes these defects. These results provide proof that ZIKV NS4A interacts physically with the ANKLE2 protein and causes microcephaly in an ANKLE2-dependent manner  reduces flavivirus infection in adult flies demonstrating the power of Drosophila for the discovery of novel host molecules with anti-flavivirus activity , the use of ral host . This apSH wrote the original draft of the manuscript and IE revised and edited the paper. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Point-of-care ultrasound (POCUS) education during medical school develops physicians who are properly prepared for the next generation of medicine. The authors present the case of a first-year medical student who self-diagnosed appendicitis using POCUS.A 25-year-old, first-year medical student presented to the emergency department with lower abdominal pain. What seemed like a straightforward appendicitis presentation came with a twist; the student brought self-performed ultrasound imaging of his appendix.The student\u2019s ultrasound skill set reflects favorably on the rapid evolution of ultrasound teaching in medical education. Point-of-care ultrasound (POCUS), the acquisition and interpretation of ultrasound images at the bedside, is an essential skill for the next generation of physicians. The integration of POCUS into undergraduate medical education (UGME) curricula is occurring at an accelerated rate. This no doubt reflects on the recognition that POCUS promotes patient safety, clinical efficiency, and elevates the level of care physicians can offer their patients. One benefit of early medical school integration is that students develop ultrasound skills in parallel with learning human anatomy \u2013 a critical element that accelerates sonographic learning. It cannot be overstated that the development of an early sonographic skill set is meant to augment the patient interview and clinical exam, not replace them. Each is an essential competency developed and ingrained early in medical school although through different educational pathways. Today\u2019s medical students benefit from the ability to develop their sonographic skill set in parallel with learning the traditional pillars of medicine: inspection, palpation, percussion, and auscultation.POCUS has become commonplace in many medical specialties and is evolving in others. The ability to evaluate and diagnose patients with emergent conditions using ultrasound is best illustrated in emergency medicine (EM). Diagnosing acute conditions such as appendicitis are well within the capabilities of ultrasound-trained clinicians. EM-trained physicians using POCUS to evaluate for appendicitis have been shown to have comparable operating characteristics  to comprehensive ultrasounds interpreted by radiologists.A 25-year-old first-year medical student arrived in the emergency department (ED) with 24 hours of lower abdominal pain. The pain was worse with cough, yard work, and eventually with walking. The clinical exam demonstrated right lower quadrant tenderness without peritoneal signs. His vital signs were normal except for mild tachycardia. Lab work, including urinalysis, was unremarkable.Although the clinical presentation in this case was typical of appendicitis, in many institutions the next step is to obtain a computed tomography (CT) to confirm the diagnosis. The use of CT to diagnose appendicitis approaches 90% in some centers.3In this case, what seemed like an otherwise straightforward appendicitis presentation came with a twist; the student brought self-performed ultrasound imaging of his appendix. Prior to his ED visit, the student went to our ultrasound teaching lab and was able to identify his inflamed appendix (without a proctor). He printed his ultrasound images and presented them to the ED attending physician. The images demonstrated an enlarged appendix (approximately 1 centimeter) with appendicolith .The emergency physician also used POCUS to reaffirm the sonographic diagnosis of appendicitis .CPC-EM CapsuleWhat do we already know about this clinical entity?Diagnosing appendicitis using ultrasound is accurate and efficient. It is an advanced skill that can challenge even experienced sonographers.What makes this presentation of disease reportable?This is the first report in the literature of a medical student extrapolating a basic ultrasound skill set to self-diagnose appendicitis.What is the major learning point?The self-diagnosis of appendicitis by a 1st-year medical student demonstrates the rapid ultrasound skill development by future physicians.How might this improve emergency medicine practice?Point-of-care ultrasound taught by emergency physicians elevates the clinical skill set of future physicians.The patient was taken to the operating room without further imaging and had an uneventful appendectomy. Appendicitis was confirmed upon pathologic review of the specimen.It is clear that basic patient evaluation skills taught early in medical school become the framework students rely on during their clinical years and beyond. It is our goal to integrate the use of sonography as a standard part of a student\u2019s history and physical exam. An integrated UGME ultrasound program helps students develop symbiotic clinical and sonographic skill sets. Students at our medical school Eastern Virginia Medical School (EVMS) have an ultrasound transducer in their hands as early as the orientation week of their first year.The framework of sonographic teaching at our institution is structured around 10 core ultrasound skills that every student should graduate with. These core skills range from echocardiography to procedural guidance .Abdominal ultrasound education at our institution is focused primarily on common hepatobiliary and renal disorders. Although we do not formally train students to specifically image the appendix, the ultrasound skill set they develop during the first few months of training makes this an achievable endeavor.POCUS is becoming the standard of care in many areas of clinical medicine. The early integration of POCUS into UGME curricula is the key to arming the next generation of physicians with the tools necessary to elevate the current standard of patient care.5Although anecdotal, this report of the self-diagnosis of acute appendicitis by a medical student is evidence of a novice learner\u2019s ability to rapidly extrapolate basic sonographic concepts into more advanced skills.The medical student\u2019s ultrasound skills reflect favorably on the rapid evolution of ultrasound teaching in undergraduate medical education. As the use of ultrasound in the clinical setting expands for both diagnostic and procedural indications, it is important for medical schools to properly prepare future physicians."}
+{"text": "We then evaluate in detail the role of soluble innate inhibitors including surfactant protein D and antimicrobial peptides that have a potential dual capacity for down-regulating viral replication and also inhibiting excessive inflammatory responses and how these innate host factors could possibly be harnessed to treat IAV infection. Where appropriate we draw comparisons and contrasts the SARS-CoV viruses and IAV in an effort to point out where the extensive knowledge existing regarding severe IAV infection could help guide research into severe COVID 19 illness or vice versa.There is abundant evidence that the innate immune response to influenza A virus (IAV) is highly complex and plays a key role in protection against IAV induced infection and illness. Unfortunately it also clear that aspects of innate immunity can lead to severe morbidity or mortality from IAV, including inflammatory lung injury, bacterial superinfection, and exacerbation of reactive airways disease. We review broadly the virus and host factors that result in adverse outcomes from IAV and show evidence that inflammatory responses can become damaging even apart from changes in viral replication  There is a vast, and still growing, literature on the pathogenesis of severe IAV infection. A major concern has been adaptation of avian viral strains  to human to human transmission. There is a strong system of surveillance for human infection with such avian strains that has been effective in containing outbreaks in domestic animals to lower the risk for human transmission. The last IAV pandemic (2009) was not caused by a virus bearing a novel HA but the re-emergence from a porcine source of an H1N1 strain similar to the 1918 pandemic IAV. The current catastrophic SARS-CoV2 pandemic (and related SARS-CoV1 and MERS outbreaks) emerged from different sources altogether. This does not lessen the need for avian and porcine IAV surveillance. However, it is reasonable to consider what we know about severe IAV pathogenesis for lessens applicable to other severe respiratory virus infections, like COVID 19, to seek common points that could be used to guide treatments. In both cases it appears that innate immunity plays a central role in early protection but also in the most adverse outcomes.Based on the high degree of variability of IAV strains from year to year through antigenic drift and the potential for reshuffling of whole genome segments through reassortment, adaptive immune responses generated against prior strains (or prior vaccines) can be of limited or possibly no effectiveness vs. a new strain. Coronaviruses may not have as high a propensity to variation and do not have a multi-segmented genome as does IAV. However, there are many strains of coronavirus in animal reservoirs so that novel infections with these strains are a major risk. Whereas, seasonal IAV tends to be somewhat attenuated due to adaptations made for sustained maintenance in humans and due to partial immunity against them, highly pathogenic coronavirus infections resemble more closely novel pandemic IAV strains in that humans are immunologically largely na\u00efve to them. These factors leave innate immunity with a key role in bridging the gap between initial infection and onset of cell and antibody mediated immunity for both IAV and novel coronaviruses.The overall topic of innate immunity to IAV is quite vast we will not be able to review it in great depth but rather will refer to recent reviews for more detail. We will summarize viral and host factors established to be involved in the development of severe IAV infection. We will then explore in more depth evidence for a role for myeloid cells in host defense and damaging inflammation during IAV infection. We will then summarize the work of our and other labs on the role of key soluble innate inhibitors including surfactant protein D (SP-D) and antimicrobial peptides (defensins and LL-37) in host defense and potential treatment of IAV infection. Where appropriate draw comparisons or contrasts to COVID-19, since knowledge of severe IAV pathogenesis may allow a more rapid discovery of aspects of pathogenesis of severe COVID 19 and conversely treatments being tested for COVID-19 may prove beneficial for severe IAV as well see .There is an extensive literature on the extraordinary innate immune response to IAV which plays a key role as a bridge between initial infection and onset of adaptive immunity . Of interest some soluble factors like the collectins , LL-37 and also alveolar macrophages appear to limit viral replication while also inhibiting inflammation . If viral infection does reach the lung profound illness can occur and can be associated with severe outcomes. Of note, SARS-CoV2 appears to have greater potential to achieve lung infection (perhaps due to greater binding affinity for ACE2 receptors present in the lung), whereas IAV has highest affinity for upper airway epithelia which contain alpha-2,6 linked sialic acids needed for hemagglutinin (HA) binding , and very young age. Malnutrition and co-infection with TB or malaria have also been noted as risk factors  7 and 9, interferon induced transmembrane protein (IFTIM3), complement component 1q binding protein and IL-1 among others  play fundamental roles in host defense against IAV and other viruses, as evidenced by the evolution of viral proteins (like the IAV NS1 and similar proteins for SARS-CoV1)  have recently been intensely studied in relation to their positive or negative roles in various infections of inflammatory states  could be adverse but the net effect of SP-D or LL-37 in vivo is to reduce inflammation during IAV or other infections in vivo  of SP-D with that of MBL or bovine conglutinin both of which have intrinsically stronger viral binding and inhibition capacity than human SP-Ds NCRD. These created as full length molecules and indeed had increased viral neutralizing activity for seasonal IAV strains and were able to restore the host defense function of SP-D when over-expressed in SP-D knockout mice  we showed that a modified version of LL-37 had increased IAV neutralizing activity and was able to inhibit pandemic IAV (Tripathi et al., There are many similarities in manifestations of severe IAV and severe SAR-CoV infection, including profound, uncontrolled inflammatory response, massive cytokine release, diffuse alveolar damage, and lung infiltration with neutrophils . It is lIt appears likely that myeloid cells will be found to contribute to inflammatory damage in COVID-19 as they appear to do in severe IAV infection. Studies similar to those of Brandes et al. using targeted reduction of myeloid or neutrophil activity can be evaluated in animal models of COVID-19 as well (Brandes et al., in vitro (Michelow et al., Like the HA of IAV and gp140 of HIV, the coronavirus spike protein is heavily glycosylated (Vankadari and Wilce, in vitro. Other strategies like increasing endogenous production of LL-37 with Vitamin D or HDAC inhibitors can be considered as well. A challenge for treatment with SP-D or peptides will be how to achieve adequate lung concentrations to inhibit the virus and possibly down-regulate inflammatory responses.It is very likely also that antimicrobial peptides including LL-37 or defensins modified to reduce proteolysis and increase antiviral activity will have activity against SARS-CoV2. Hence, it will be important to test modified versions of these There is a vast literature on the pathogenesis of severe IAV infection and how it relates to innate immunity for better or worse. Remarkably, there is likely still a lot to learn and important new findings continue to appear regularly. The focus of this review is predominantly on the role of myeloid cells and soluble inhibitors of IAV including collectins like SP-D and antimicrobial peptides since these are the areas of our greatest expertise. Unfortunately it is very likely that IAV both in seasonal epidemic and in pandemic form will continue to be a major threat to human health and one can hope lesions learned from the COVID-19 pandemic will inform future responses to IAV infection as well. Methods of blocking inflammasome activation or neutrophil infiltration are being considered for COVID-19 and severe IAV, but as summarized above the literature suggests down-modulation rather than total blockade may be most beneficial. In general it will be important to balance the host defense role of elements of the innate response vs. both virus and potential superinfecting bacteria against their damaging effects. Timing of interventions may also be key as evidenced by the likely beneficial role of early IFN and neutrophil responses vs. their damaging effects when in excess at later times during the course of illness.KH conceived and wrote the whole article but the work also summarizes results of a wide range of collaborators and that of other laboratories.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Mitochondrial DNA (mtDNA) molecules are packaged into compact nucleo-protein structures called mitochondrial nucleoids (mt-nucleoids). Their compaction is mediated in part by high-mobility group (HMG)-box containing proteins (mtHMG proteins), whose additional roles include the protection of mtDNA against damage, the regulation of gene expression and the segregation of mtDNA into daughter organelles. The molecular mechanisms underlying these functions have been identified through extensive biochemical, genetic, and structural studies, particularly on yeast (Abf2) and mammalian mitochondrial transcription factor A (TFAM) mtHMG proteins. The aim of this paper is to provide a comprehensive overview of the biochemical properties of mtHMG proteins, the structural basis of their interaction with DNA, their roles in various mtDNA transactions, and the evolutionary trajectories leading to their rapid diversification. We also describe how defects in the maintenance of mtDNA in cells with dysfunctional mtHMG proteins lead to different pathologies at the cellular and organismal level. According to the widely accepted endosymbiotic theory ,2, mitocSaccharomyces cerevisiae cells contain on average about 50 copies of a 75\u201386 kbp long mtDNA molecule . F. F130]. ese mice .Overexpression of TFAM increases the mtDNA copy number  and alsoThe variability in mtDNA copy number among different cancers was reviewed recently by Yuan et al.  and is sTFAM expression does not have the same effect on the prognosis of all types of TFAM-associated cancers. Expression of TFAM at higher levels was associated with longer overall survival time in cases of diffusely infiltrating astrocytomas . Convers\u2192A in 5\u2032-UTR exon 1 and the Ala105Thr missense mutation of TFAM were shown to be involved in the pathogenesis of cardiac hypertrophy [\u2192G) SNP upstream and rs1937 (G\u2192C) SNP in exon 1 of TFAM were associated with diffuse-type gastric cancer [Mycobacterium leprae, causing leprosy, and affect the risk of infection [In addition to pathological states caused by altered levels of wild-type TFAM, there are several examples of dysfunctional mitochondria associated with single-nucleotide substitutions within both the coding and noncoding regions of the TFAM-encoding gene . For exaertrophy  and varic cancer . Geneticnfection ,307. Pronfection . Manifesnfection . Possiblnfection . In a human prostate cancer cell line and in tissue samples of ovarian cancer, TFAM was detected not only in the mitochondria, but also in nuclear chromatin, where it could regulate the expression of nuclear genes in addition to those in the mitochondria ,308. ThiIn addition to serving as a prognostic marker, TFAM might also be employed as a candidate therapeutic agent. Mitochondrial dysfunction has been reported in various forms of heart failure and TFAM overexpression showed an increased mtDNA copy number and cardioprotective effects against ROS-mediated mitochondrial oxidative stress in transgenic mice ,309. A pThe overexpression of TFAM also has a potentially synergistic effect with exercise training in enhancing mitochondrial function in order to prevent skeletal muscle atrophy . TFAM ovA TFAM-mediated \u201cProtoFection\u201d was employed to deliver mtDNA into the mitochondria of cells representing a model of Parkinson\u2019s disease and resulted in the restoration of mtDNA levels accompanied by the activation of mitochondrial biogenesis . SimilarSince some cellular pathologies are caused by an increased level of mitochondrial biogenesis, some interventions are aimed at decreasing the level of TFAM. For example, antisense oligonucleotides were used to decrease the expression of TFAM in injured rat carotid arteries  and knocThe symbiosis that gave rise to modern eukaryotic organisms required fine-tuning the coordination between the genomes of the original host and the endosymbiont. This led to an apparatus for maintaining the mtDNA able to protect, replicate, and express its genetic information in response to intra- and extracellular stimuli. The principal players in the mitochondrial genome maintenance are mtHMG proteins that mediate the compaction of mtDNA molecules into mt-nucleoids. The properties and regulators of mtHMG proteins have been adapted for the unique characteristics of the mitochondrial genomes and are pivotal in these transactions. This review provides a comprehensive analysis of mtHMG proteins highlighting the following key points: (1) The mechanism of DNA compaction by mtHMG proteins is relatively conserved and is primarily mediated by the bending of DNA by tandemly arranged HMG-boxes; (2) with the exception of the HMG-boxes, the amino-acid sequences of the mtHMG proteins exhibit faster evolutionary diversification than the other mt-nucleoid protein components; (3) the activity of the mtHMG proteins  is regulated at all levels of gene expression, including transcription activation/repression, alternative splicing, regulation by miRNAs, posttranslational modifications, and proteolytic cleavage; (4) in many (even strictly aerobic) microorganisms, the deletion of a gene for a mtHMG protein is in part compensated for by employing other molecular means of mtDNA compaction; and (5) compromising the functions of the mammalian mtHMG protein TFAM results in a variety of pathological states whose nature depends on the particular mutation and the affected tissue. Although research on mtHMG proteins during the last four decades has provided substantial insight into their functions and evolution, there are still important questions that need to be addressed. For example, how does the metabolic state of a cell or modifications to the mtDNA affect the DNA-mtHMG protein interactions? Which additional posttranslational modifications affect mtHMG proteins? What are the effects of these modifications on the structure and stability of mtHMG proteins? Can combining different posttranslational modifications provide the means for producing a heterogeneous intramitochondrial population of mtHMG proteins with distinct DNA- or protein-binding properties? What are the mechanisms of co-evolution of the conserved protein components of the mt-nucleoid and the rapidly evolving mtHMG proteins? How is mtDNA compacted in cells lacking mtHMG proteins? Are there other possibilities for using TFAM as a prognostic tool or a therapeutic target for pharmacological interventions in human diseases with aberrant mtDNA maintenance? Answering these and other related questions will be instrumental for understanding the molecular bases of pathologies linked to the dysfunction of mtHMG proteins and to mitochondria in general."}
+{"text": "Research into the advanced imaging appearance of Thoroughbred racehorse fetlocks is receiving increased attention in an effort to better understand and potentially reduce the occurrence of catastrophic fracture in these horses. Studies in this area commonly use cadaver equine limbs from racehorses and a freeze-thaw process prior to imaging. The low-field magnetic resonance imaging (MRI) appearance of the bones of the fetlock joint is of particular interest in the diagnosis of impending fracture in this location. However, little is known about the effect of the freeze-thaw process on the appearance of certain signal changes (\u201cSTIR hyperintensity\u201d) seen commonly in racehorses. This study compares the low-field MRI appearance of short tau inversion recovery (STIR) hyperintensity in the bones of cadaver fetlocks from Thoroughbreds in race training, before and after a freeze-thaw protocol. Fifteen cadaver fetlocks with abnormal bone signal were included in the study. Blinded and unblinded statistical comparisons were made. No overall clinical or statistical difference was detected in intensity and distribution of the STIR signal before and after freeze-thaw. This indicates that the MRI appearance of STIR hyperintensity in freeze-thawed cadaver fetlocks can be considered representative of the appearance of pathology in the recently euthanized horse. This is important information to further advance research in the area of Thoroughbred racing fatality reduction.Equine advanced imaging research involving racehorse fetlock pathology commonly uses cadaver limbs and a freeze-thaw process. The presence of short tau inversion recovery (STIR) signal intensity in the distal third metacarpal/metatarsal bone is of particular interest and may be clinically relevant in the diagnosis of horses at risk of fracture. However, little is known about the effect of the freeze-thaw process on the MRI appearance of STIR hyperintensity in these bones. This study compares the low-field MRI appearance of the distal third metacarpal/metatarsal bone from cadaver limbs of Thoroughbreds in race training before and after a freeze-thaw protocol. Blinded and unblinded comparisons were made using objective SNR values and subjective grading. Fifteen cadaver limbs with STIR hyperintensity in the distal third metacarpal/metatarsal bone were included. No overall clinical or statistical significance was detected in STIR signal intensity and distribution after freeze-thaw. Three limbs from one horse had individual changes in STIR hyperintensity that were hypothesized to be attributable to ante-mortem haemodynamic abnormalities caused by anaesthesia. These results indicate that the distribution and intensity of STIR hyperintensity in freeze-thawed cadaver fetlocks can be considered representative of the appearance of pathology in the recently euthanized horse. However, care should be taken with horse selection and handling of the cadaver limbs to ensure reliable appearance of STIR signal after freeze-thaw. Research into the advanced imaging appearance of racehorse limbs is essential to better understand the pathophysiology and aetiology of bone fatigue and stress-related injury and so reduce the incidence of catastrophic fracture and associated racing fatality. The fetlock region is an anatomical area of interest as it is the most common location of musculoskeletal injury and breakdown in racehorses. Many advanced imaging fetlock studies use cadaver distal limbs from Thoroughbred racehorses and implement a freeze-thaw process prior to imaging the cadaver limbs ,2,3. TheLow-field magnetic resonance imaging (MRI) is one of the advanced imaging modalities being investigated to aid in diagnosis of pathology in the distal limbs of racehorses. It is a relatively widely available, non-invasive modality that can be performed in sedated standing horses, especially in cases with suspected fetlock pathology. A specific MRI sequence, short tau inversion recovery (STIR), suppresses fat signal in tissue, allowing other signal such as fluid to be visualized, and is a common sequence included in a standard fetlock MRI examination. The presence of STIR signal hyperintensity in the distal third metacarpal/metatarsal bone is of particular interest and may be clinically relevant for the diagnosis of horses with stress fracture and for prevention of subsequent catastrophic bone failure .Despite the frequency of equine imaging studies using a freeze-thaw protocol, much is unknown about the effects of the freeze-thaw process on the MRI appearance of STIR hyperintensity in bone in the equine fetlock region. Whilst it has been shown that temperature and handling, among other freeze-thaw process variables, can affect the MRI appearance of equine cadaver limbs ,6,7,8, tPrevious research has found that the process of freezing and thawing can affect bone parameters and material properties. One study found a small but significant reduction 12%) in bovine tendon T2*-weighted signal intensity after the first freeze-thaw cycle but not after successive cycles . A spect% in boviThere remains a paucity of data regarding the reliability of MRI interpretation after freeze-thawing cadaveric limbs with regards to the appearance of STIR signal in bone. Although STIR hyperintensity was originally referred to as \u201cbone oedema\u201d, subsequent studies have shown this signal change can represent a number of different osseous changes including haemorrhage, oedema, fibrosis and osteonecrosis ,14. The This study aims to investigate the effect of a freeze-thaw protocol on the low-field MRI appearance of STIR hyperintensity in the distal equine metacarpus/metatarsus. We hypothesize that freezing and thawing of a cadaver equine fetlock does not change the distribution or the intensity of STIR hyperintensity in the distal aspect of the third metacarpal/metatarsal bone.Distal limbs from racing Thoroughbreds in work, euthanized in South-East Queensland, were collected. Limbs were included in the study if they (1) were available for MRI examination within 12 h of death and (2) showed evidence of STIR hyperintensity in the distal third metacarpal/metatarsal bone. Distal limbs with a catastrophic fracture in the fetlock region were excluded. Horse data pertaining to age, signalment and date euthanized was collected. This research received ethics approval from the University of Queensland Animal Ethics Committee (SVS/ANRFA/041/18) and informed consent for collection of the cadaver limbs.Limbs were secured in a weight bearing position within a low field 0.27T magnet , and a standard fetlock coil was placed at the level of the fetlock. T1W gradient recalled echo (GRE) and STIR fast spin echo (FSE) sequences of the distal metacarpus/metatarsus were acquired in transverse, frontal and sagittal planes, aligned parallel and perpendicular to the long axis of the third metacarpal/metatarsal bone . The inv2 were imported into each study. The ROIs were positioned in predetermined locations for each plane of the STIR sequences (Images were viewed by a veterinary radiologist experienced with the interpretation of low-field equine fetlock MRI examinations (AY). MRI studies were viewed in \u201cdigital imaging and communications in medicine\u201d (DICOM) format on an interactive DICOM viewer workstation (Osirix MD). Standardised regions of interest (ROIs) of 2 cmequences  then copThe first part of the experiment was performed objectively by one veterinary radiologist (AY) blinded to the identity and fresh/thawed status of the limbs. Blinding was performed by another investigator (GJ) by randomizing the order of the studies and then removing all identifying details. SNR values were compared between fresh and thawed MRI images at standardised, predetermined locations in the distal third metacarpal/metatarsal bone. These predetermined locations were chosen as those likely to have STIR hyperintensity present and included the distal palmar/plantar region of the lateral and medial condyles and axial physeal region. Each MRI study was assessed in a frontal, transverse and sagittal plane with efforts made to standardize the image chosen for ROI measurement.The frontal plane image slice immediately dorsal to the corticomedullary junction of the palmar/plantar cortex of the third metacarpal/metatarsal bone was used to obtain ROI measurements at the distal palmar/plantar aspect of the lateral and medial condyles as well as the axial physis . CondylaThe transverse image located two slices distal to the level of the physeal vasculature was chosen for the transverse plane measurements . Three RThe sagittal plane measurements required three different images for ROI placement; parasagittal slices through the centre of the lateral and medial condyles of the third metacarpal/metatarsal bone  as well The ROI measurements on the fresh limbs were performed three times by the same blinded veterinary radiologist (AY) across both STIR FSE and T1W GRE sequences to assess intra-observer reliability. Repeated grading of each limb was performed with an interval of at least one week between image interpretations.The second part of the experiment was designed to compare and assess the appearance of STIR signal in fresh and thawed limbs in a clinical setting. The same veterinary radiologist (AY) objectively measured SNR and subjectively graded the same limbs using STIR FSE images from co-registered fresh and thawed limbs examined side by side . Window The location of each fresh limb STIR FSE ROI was copied across to the corresponding thawed image and manually adjusted to match the location on the fresh image as closely as possible. Some images could not be matched exactly due to differences in slice location between the fresh and thawed limbs. SNR was calculated for each maximum and minimum STIR location. Minimum and maximum locations of STIR hyperintensity were used in order to ensure the study assessed many different intensities of STIR signal. The minimum and maximum STIR hyperintensity was subjectively graded as 0\u20133 for each plane in both fresh and thawed images . The overall similarity of the fresh and thawed images was subjectively assessed and graded for similarity of distribution  and signal intensity  of STIR hyperintensity.www.ncss.com, accessed on 15 August 2020). Input assumptions included alpha (0.05), and beta . These input parameter levels are standard for bioequivalence analyses. Summary statistics for mean SNR values and standard deviation were derived for mild, moderate and severe STIR hyperintensity and were used to produce estimates of a coefficient of variation (CoV). Running sample size estimates in PASS for different input CoV values (holding other inputs constant) produced required sample sizes ranging from four to fifteen limbs. These findings suggested that the proposed sample size of n = 15 was likely to detect a change in STIR grade and produce results that were statistically meaningful. Descriptive statistics were used to summarize SNR values for the blinded and unblinded data. An investigator (GJ) not blinded to the identity of the studies collated all the blinded data for statistical comparison between fresh and thawed measurements on the same limb. A Shapiro\u2013Wilks test for normality was performed. For normally distributed data, independent t-tests were performed to assess statistical difference between fresh and thawed data. For comparison of non-normally distributed fresh and thawed data, Mann\u2013Whitney U tests (Wilcoxon rank sum test) were conducted to assess statistical difference. Statistically significant difference was set at 95% (p < 0.05).Sample estimates were based on preliminary SNR data for mild, moderate and severe STIR hyperintensity. Sample size estimates were conducted using a custom commercial software package designed for power analysis and sample size  as a measure of intra-observer reliability for the blinded fresh data . A 95% cFifteen cadaver distal limbs from five different horses met the inclusion criteria for this study. Of the fifteen limbs, nine were forelimbs and six were hindlimbs. The horses were all Thoroughbred racehorses in active training and aged 3 to 4 years old (mean 3.4 years). Three were geldings and two were fillies. Causes of mortality were sudden death while racing (3/5) or euthanasia due to catastrophic fracture (2/5). Of the horses that were euthanized, one horse had catastrophic fracture in recovery immediately following general anaesthesia for an elective arthroscopy and the other fractured while racing.The limbs were frozen for 24 to 205 days (mean 75 days). The mean internal temperature of the limbs was 19.7 \u00b0C (range 19.5\u201320.3) in the fresh limbs and 19.9 \u00b0C (range 19.8\u201320.1) in the thawed limbs. The quality of fat suppression on STIR images was subjectively graded good to excellent in all limbs, both fresh and thawed.Blinded and unblinded data were collected from MRI images of all fifteen cadaver distal third metacarpal/metatarsal bones in the sagittal, transverse and frontal planes both before and after the freeze-thaw process . There wNo statistically significant differences were found between fresh and thawed SNR values for all assessed sequences, planes and locations .The intra-observer reliability for blinded fresh SNR values was variable for different sequences, planes and locations . The oveNo statistically significant differences were found between fresh and thawed SNR values nor the subjectively applied grades for any STIR sequence plane . The maxSubjectively, twelve of the 15 limbs had good overall similarity with the distribution and relative intensities of the STIR hyperintense regions considered almost identical between the fresh and thawed studies. Two limbs of one horse were graded as good for similarity in STIR signal intensity but moderate for similarity in signal distribution between the fresh and thawed studies. In these two limbs, a mild increase in STIR hyperintensity was visible after the freeze-thaw process at the periphery of the previously identified regions of STIR hyperintensity. A third limb of this same horse was graded as moderate for similarity in STIR signal distribution and poor for similarity in STIR signal intensity due to a marked decrease in STIR hyperintensity following the freeze-thaw process.This study assessed the effects of a freeze-thaw process on the appearance of STIR hyperintensity in the distal third metacarpal/metatarsal bone of cadaver equine fetlocks. There was no statistical difference in low field MRI appearance of STIR hyperintensity between images acquired from fresh cadaver limbs compared to following a freeze-thaw process. Subjectively, similarity in distribution and intensity of STIR hyperintensity before and after the freeze-thaw process was overall high.There are a number of variables that may affect the appearance of intraosseous STIR signal intensity in cadaver limbs, including the interval between death and image acquisition, the interval between death and freezing as well as the specific conditions of the freezing and thawing process  ,20,21,22The collection of blinded randomised data in this study enabled objective comparison of the SNR values between fresh and thawed images for each limb, sequence and imaging plane. There were no statistically significant differences between any of the SNR measurements. However, intra-observer reliability, although considered good for T1W images, was lower than expected for the STIR images. The lower intra-observer reliability for STIR sequences in the blinded portion of the study were attributed mostly to the slight differences encountered in slice location between the fresh and thawed studies with subsequent differences in ROI location and therefore variations from the effect on volume averaging and the appearance of the vessels.Although positioning was standardised as much as possible for the blinded measurements, mild variations in image location and placement of the ROIs also likely produced some variability in SNR results. This was particularly evident when the ROIs included physeal vasculature or condylar margins. Vascular channels are markedly STIR hyperintense and large variations in SNR values were observed as the ROI was placed slightly proximally or distally in the most axial location possible. In contrast, the axial SNR measurements of the corresponding T1W images were much more consistent. The small areas of hypointensity associated with these same vascular channels on the T1W GRE sequences were presumed to have had a lesser effect on the corresponding SNR measurements. In contrast to this, condylar SNR measurements obtained in the transverse plane were more consistent on STIR images than the corresponding T1W images. This was likely attributable to the volume averaging present in the palmar condyles, with both hypointense subchondral bone and hyperintense medullary bone included in both the lateral and medial distal palmar/plantar condylar ROI. The corresponding STIR images were more uniformly hypointense in the absence of intraosseous pathology resulting in more consistent SNR measurements from fresh to thawed images in the transverse plane.Repeatability of manual ROI drawing has previously been found to be good, however repeatability for STIR sequences was not separated from the other MRI sequences in that study . In thisUnlike the blinded comparison, the unblinded portion of the study allowed direct side-by-side objective and subjective comparison of the fresh and thawed images of each limb. This allowed us to select areas of STIR hyperintensity as we would in the clinical setting rather than have the location of each measurement predetermined as in the blinded portion of the study. The direct comparison of co-registered fresh and thawed STIR sequences enabled more consistent ROI placement both with respect to image selection and specific ROI placement. This likely minimized variations in ROI positioning and subsequently the effect of volume averaging and blood vessel inclusion.In the unblinded portion of the study, STIR hyperintensity was commonly identified in the axial physis, distal palmar/plantar aspect of the lateral and medial condyles, dorsal sagittal ridge and distal dorsal diaphysis; areas commonly associated with racing related bone injury. A maximum and minimum STIR hyperintensity were subjectively graded for each image plane so that a range of STIR hyperintensities were assessed  and so that data was not solely related to areas with marked intraosseous STIR hyperintensity. There was no statistically significant difference found in the subjective grade of the fresh images compared to the thawed images regardless of the severity of STIR hyperintensity.Subjective and objective comparison of fresh and thawed limbs found no statistical difference in the appearance of STIR hyperintensity, and clinically, there was overall a high similarity between the intensity and distribution of the STIR hyperintensity of fresh and thawed limbs. However, in three of the 15 limbs, there were visible changes in STIR hyperintensity following the freeze-thaw process. Two limbs had a subjective increase in signal at the periphery of the area of STIR hyperintensity when the thawed limbs were compared to the fresh. Another limb from the same horse had a marked reduction in STIR signal intensity with an altered distribution of signal following the freeze-thaw process. Considering these three limbs were collected from the same horse, we hypothesize that the changes in STIR hyperintensity may have been attributable to horse-specific conditions. The horse had been under general anaesthesia in lateral recumbency immediately prior to fracture and subsequent euthanasia. It is possible that this affected the haemodynamics in the distal limbs and predisposed the limbs to fluid changes during the freeze-thaw process. This suggests that limbs from horses euthanized closely following or under general anaesthesia should not be included in cadaver limb MRI research.This study has some intrinsic limitations. All images were obtained from cadaver fetlocks. Although these results decrease the need to image only \u201cfresh\u201d cadaver limbs when studying the appearance of intraosseous STIR hyperintensity in the fetlock region, we cannot assume this appearance is perfectly representative of the antemortem specimen. Transient causes of intraosseous STIR hyperintensity such as oedema, haemorrhage and inflammatory infiltrate may change rapidly post-euthanasia and could have altered the appearance of STIR hyperintensity in these limbs. However, the locations and distribution of STIR hyperintensity identified in this population were consistent with those seen commonly in our clinical racehorse population.Previous freeze-thaw studies have used high-field MRI, whereas this study used a 0.27 T low-field magnet. This may have reduced our ability to detect mild changes between fresh and thawed limbs. However, standing low-field MRI is the most commonly used MRI modality for racing Thoroughbreds, and so it is clinically relevant for research with cadaver racehorse fetlocks.The images of some sequences could not be perfectly co-registered for slice and angle between fresh and thawed MRI acquisitions due to slight differences in limb and image positioning at the time of acquisition. This likely contributed to reduce the similarity between fresh and thawed SNR data and appearance of STIR hyperintensity. There was a small variability in quality of fat suppression between studies. Fat suppression was graded as good to excellent in all image series, however small differences in fat suppression between fresh and thawed limbs may also have affected the appearance of STIR hyperintensity and the SNR values.No overall clinical or statistically significant alterations in the low field MRI appearance of STIR hyperintensity were identified in the distal third metacarpal/metatarsal bone of cadaver equine fetlocks following a freeze-thaw protocol. These results indicate that the distribution and intensity of STIR hyperintensity in thawed cadaver fetlocks can be considered representative of the appearance of pathology in the recently euthanized horse. However, it is recommended that cadaver limbs from recently anaesthetized horses are not used in equine MRI research with freeze-thaw protocols. Given the ongoing interest in STIR hyperintensity in equine fetlocks and the use of cadaver limbs in research, further study is required into the effects of handling and environmental conditions on the MRI appearance following freeze-thaw. This information is important to advance further cadaver research into Thoroughbred racing fatality reduction."}
+{"text": "Gnathostoma spp., acquired through the consumption of raw or undercooked contaminated aquatic animals.The disease is endemic in Southeast Asia and Central America. Two male patients, both middle-aged, presented with single itchy erythemato-edematous plaques on the anterior thorax and left flank. Both had consumed raw fish in the Amazon region. The clinical and epidemiological examinations suggested gnathostomiasis, and treatment with albendazole caused total regression of the lesions. Health teams should be familiar with the disease to provide correct diagnosis. The control strategy should be based on health education for the population.Gnathostomiasis is a parasitic zoonosis caused by the helminth  Gnathostoma spp., acquired by the consumption of raw or undercooked aquatic animals contaminated with larvae of Gnasthostoma in the third stage of development (AL3). The larvae will never become adult worms in a human host-.Gnathostomiasis is a parasitic zoonosis caused by the helminth nematode -The disease is endemic in Southeast Asia and Central and South America. Humans are occasional hosts due to the ingestion of the larvae, which cross the digestive tract and enter the subcutaneous tissue or other solid organs . Cutaneous gnathostomiasis occurs three to four weeks after larvae ingestion and a migratory skin lesion ranging from a nodule to an infiltrated ill-defined mass appears. Peripheral eosinophilia and a dense eosinophilic infiltrate of the dermis and subcutaneous are suggestive of the disease, but the definitive diagnosis is made by identifying the parasite. Treatment with albendazole or ivermectin is effective, but some patients may experience recurrence even after therapy-Regarding the cutaneous form (the most common), a migratory skin lesion ranging from a nodule to an infiltrated ill-defined mass usually appears three to four weeks after larvae ingestion. Another presentation of the disease is the pseudo-furuncular type, which happens spontaneously or a few days after therapy and can provoke a large nodular or ill-defined infiltrated area to a tiny papule or even a pustuletucunar\u00e9s or peacock bass marinated in lemon juice (ceviche) from the Telles Pires River, on a group fishery in the Amazon region  approximately 15 days before the exam.Patient 1: A middle- aged male presented with ill-defined itchy single erythemato-edematous plaques on the anterior thorax  with anttucunar\u00e9s ceviche from the Juruena River, in the same region, three weeks before the exam.Patient 2: A middle- aged male presented with ill-defined itchy single erythemato-edematous plaques on the left flank  without The patients were not on the same fishing expedition and were examined about two months apart.Once the clinical and epidemiological diagnoses of gnathostomiasis were made, biopsies were performed and the histopathological examinations in both patients showed a diffuse eosinophilic infiltrate reaching the dermis and subcutaneous tissue and edema of the upper dermis , which itucunar\u00e9s or peacock bass (Cichla sp. - -,Both patients had consumed the meat of"}
+{"text": "A consequence of the strict visitor restrictions implemented by many Long-term Care Facilities (LTCFs), during the COVID-19 pandemic, was the exacerbation of loneliness and social isolation felt by older adult residents. While there had been a shift by some persons to utilize digital solutions to mitigate the effects of the imposed social isolation, many facilities did not have sufficient information regarding available solutions to implement institutional strategies to support social connectedness through digital solutions. To support our partners in evidence-based policy-making we conducted a scoping review to identify existing virtual technology solutions, apps, and platforms feasible to promote social connectedness among persons residing in a long-term care facility context during times of lockdown such as experienced during the COVID-19 pandemic. Initial identification of relevant literature involved a combination of keywords and subject headings searches within 5 databases . DistillerSR was used to screen, chart and summarize the data. There is growth in the availability of technologies focused on promoting health and well-being in later life for persons in long-term care facilities however a gap remains in widespread uptake. We will describe the breadth of technologies identified in this review and discuss how they vary in utility in smaller scale facilities common in rural areas. Of the technologies that can be used to mitigate the impacts of social isolation felt by long-term care residents, many \u201csolutions\u201d depend on stable highspeed internet, which remains a challenge in rural and northern areas."}
+{"text": "Although the present review is narrative in nature, systematic literature analysis has been performed, allowing a concise overview of this emerging research direction till the point of writing. While a number of excellent studies have been published, future studies will need to clearly highlight the safety and added value of MOFs compared to established materials for clinical TERM applications. The scope of the present review is clearly delimited from the general \u2018biomedical application\u2019 of MOFs that focuses mainly on drug delivery or diagnostic applications not involving aspects of tissue healing or better implant integration.The synthesis of Metal-organic Frameworks (MOFs) and their evaluation for various applications is one of the largest research areas within materials sciences and chemistry. Here, the use of MOFs in biomaterials and implants is summarized as narrative review addressing primarely the Tissue Engineering and Regenerative Medicine (TERM) community. Focus is given on MOFs as bioactive component to aid tissue engineering and to augment clinically established or future therapies in regenerative medicine. A summary of synthesis methods suitable for TERM laboratories and key properties of MOFs relevant to biomaterials is provided. The use of MOFs is categorized according to their targeted organ  and whether the MOFs are used as intrinsically bioactive material or as drug delivery vehicle. Further distinction between  MOFs are new synthetic materials that emerged over the past three decades . MOFs coA systematic literature analysis was performed using Clarivate Analytics Web of Science database in combination with a structured key word search. In brief, a comprehensive list of works on MOFs was generated and those interfacing with biomaterials, tissue engineering, regenerative medicine or MOFs interfacing with neuronal repair were identified. Works solely focusing on drug-delivery or cancer treatment were excluded if not reporting aspect of tissue healing, integration or improvement of the foreign body response.In addition to the drug loading capacity, the present review aims to highlight that MOFs may also have intrinsic bioactivity through delivering specific metal ions , ligandsThe concept of MOFs originates from natural minerals, which have a substantial track record in TERM applications. Calcium phosphate has intrinsic osteogenic effect  and its Another naturally occurring mineral is zinc oxide (ZnO), a non-porous solid devoid of any drug loading capacity, that has long been used to treat cutaneous wounds and pathological skin conditions . In contZIF-8 is easily synthesized through simple precipitation reactions facilitated by mixing the ligand (2-methylimidazole) and zinc salt solution at room temperature . ZIF-8 cMOFs may also be synthesized mechanochemically  by mixinDuring solvo-thermal synthesis, two precursor solutions of organic ligands and metal ions are mixed and heated in a micro-autoclave beyond the boiling point of the solvent . Copper is typicElectro-deposition of MOFs  may be uMost reports on use of MOFs in TERM applications focus on the improvement of structural bone implants. Indeed, a small but significant fraction of clinical implants fail due to an unfavorable, non-healing wound environment that may be aggravated by bacterial infection .In vitrostudies showed significantly improved corrosion resistance of magnesium alloys upon coating with bio-MOF-1, comprising of zinc ions and adenine as well as interconnections of 4,4-biphenyldicarboxylate linkers  scaffolds coated with copper loaded ZIF-8 promoted osteogenic differentiation as compared to pure PLLA scaffolds while preventing bacterial infection in the presence of Zn2+ and Cu2+ ions  requiring intervention . TraditiIn vitro: Cu-BTC was established to be an efficient catalyst for the conversion of blood borne s-nitroso-cysteine to nitric oxide and cysteine  poly(\u03b5\u2212caprolactone) composite was investigated as material for metal free stents, using the MOF as mechanical re-enforcement, sustained drug release vehicle and Magnetic Resonance Imaging (MRI) contrast agent . FurtherIn vivo, Cu-BTC was shown effective as cardiovascular stent surface modification through coating together with polydopamine  with low cytotoxicity on PC12 neuron cells and high drug loading due to electrostatic accumulation  MOF in a mixed linker approach with 5-methylisophthalic acid and 1,3-bispropane propane . This MOA very inspiring study used MIL-100 (Fe) as a drug carrier for siSOX9 and retinoic acid in combination with co-encapsulated ceria based nanozymes to reduce oxidative stress . This coin vitro and in vivo works have highlighted a clear potential of MOFs to treat neurological disorders. Very few macroscopic biomaterials have been developed along this thought and future studies should include evaluating the opportunity to improve implant-nervous tissue interfaces with these materials.These inspiring in vitro and in vivo data are impressive in terms of the strong biological response that MOFs elicit toward a positive healing outcome in various tissues and applications. However, more efforts are required to understand the basic dose dependent response of individual cell types and tissues to different MOFs. In addition, concerns about the safety of some organic linkers of MOFs need to be eliminated or alternative linkers considered save for clinical applications must be shown effective in yielding MOFs with similar properties. This is essential before MOF based biomaterials for TERM applications will commence improving healing outcomes in the treatment of human patients.The presented MS reviewed literature related to orthopedic implants and cutaneous wound care and designed the figures. JR reviewed literature related to neuronal TERM applications. XL reviewed literature related to nitric oxide producing biomaterials. JM reviewed literature related to MOF & polymer composite materials. AB and SB wrote the manuscript. SB guided the review process. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "AVRT is a reentry tachycardia and, when the atrial exit site of the arrhythmia circuit was mapped in this case, it appeared to have a focal centrifugal activation pattern as depicted by coherent mapping.Here, we discuss mapping of an atrioventricular reciprocating tachycardia (AVRT) using color-coding and a coherence module of the CARTO Accessory pathway\u2013 mediated tachycardia is a reentrant arrhythmia and the utility of electroanatomic mapping (EAM) using an activation map with color-coding is limited during the mapping and ablation of such a tachycardia.. The tachycardia was induced easily with an eccentric retrograde atrial activation pattern . Finally, the diagnosis of left-side lateral atrioventricular reciprocating tachycardia (AVRT) was made using various maneuvers described previously.2A 27-year-old male with a history of recurrent palpitations was evaluated in the electrophysiology clinic. He had a documented episode of narrow complex tachycardia on a cardiac monitor. The patient was offered an electrophysiology study (EPS) and underwent EPS and catheter ablation in the postabsorptive state, under general anesthesia. Surface electrocardiography (ECG) and bipolar electrograms were continuously monitored using the CardioLab\u2122 Electrophysiology Recording System , sampled at 1 kHz and bandpass-filtered at 30 to 300 Hz. A multielectrode mapping catheter  and a 3.5-mm open-irrigated-tip ablation catheter  were placed through sheaths into the atrial chamber of interest. Then, the 3D fast anatomical map of the cardiac structures was acquired. The catheters were advanced and placed in the right atrium, His bundle, right ventricle, and coronary sinus. During the EP study, the retrograde conduction was eccentric AVRT was induced with programmed stimulation from the proximal and distal coronary sinuses. After inducing sustained AVRT, 3D EAM was performed. A transseptal puncture under intracardiac echocardiography (ICE) guidance was performed to access the left atrium and intravenous heparin was administered to maintain an activated clotting time of between 300 and 350 seconds. Activation mapping was performed after inducing (AVRT) and during RV pacing.. This focal appearing exit site with centrifugal spread was ablated using a 3.5-mm irrigated-tip force-sense catheter in a power-controlled mode using 35 W of power, with immediate loss of retrograde conduction through an accessory pathway . The ablation was delivered for one minute initially, followed by 30 seconds of insurance burn. Ventricular pacing performed postablation revealed the loss of retrograde conduction. The procedure was performed without the use of any fluoroscopy.Coherent mapping was used and the atrial exit site was mapped during ventricular pacing and during AVRT. Upon acquisition of a coherent activation map, the earliest atrial exit site showed a point source and centrifugal activation appearing as a focal tachycardia mechanism Accurate identification of the atrial exit site of concealed accessory pathway conduction during AVRT can be difficult using conventional electrogram annotation. EAM using an activation map has been extensively used for both focal and reentrant arrhythmias. By estimating delays between adjacent sites relative to the fiducial point, activation map computation can be completed.\u00ae 3 system  that improves the representation of electric-wave propagation over the chamber being mapped by means of coloring and direction vectors, focusing on the displayed path of cyclic arrhythmia propagation. This algorithm uses the local activation time values of all the points in a map and performs an iterative calculation to discern a global best-fit solution in these arrhythmias, analogous to calculating a regression line to show how scattered points indicate a global trend.3 The mechanism of the AVRT is reentry and mapping only one limb of the tachycardia circuit would yield a centrifugal pattern of activation and may help to precisely locate the target for ablation. There is also a potential for demonstrating the pathway with a slant by mapping other (ventricular) sites as well.The role of activation maps using color-coding and EAM is limited during ablation of the accessory pathway. Coherent mapping is a feature of the CARTO4 terminate complex atrial arrhythmias following atrial fibrillation ablation. Thus, coherence mapping has the potential to reduce procedural times and the risk of complications.Although the new coherent mapping supports the mapping and ablation of complex micro- and macro-reentry circuits, we present its utility in less complex arrhythmias with normal cardiac tissue. By integrating vector and velocity information with coherent mapping, such not only provides the direction of activation but also helps to identify the critical isthmus. This may be particularly helpful in minimizing the amount of ablation that is needed to successfully and safelyThe assumption was that the atrial exit wavefront from the atrial insertion site of the accessory pathway would behave as a focal source and exhibit a centrifugal spread from a point source in the case of an orthodromic reciprocating tachycardia. Coherent mapping may therefore facilitate precise localization for ablation in a zero-fluoroscopy environment. In addition, in situations where retrograde conduction over an accessory pathway is lost because of mechanical damage, pathway bump, or incomplete ablation, the coherent map has the potential to allow for the ablation of the previously acquired and color-coded earliest activation point of the atrial exit. By precisely locating the targets, coherent mapping may hold a role in the ablation of sites close to the atrioventricular node. By accurately localizing the area of interest and providing information about the directionality of the activation, this mapping approach may help to ensure safe and effective ablation.Coherent mapping can accurately identify and localize the atrial exit of orthodromic reentrant tachycardia for precision-guided ablation in a zero-fluoroscopy environment."}
+{"text": "This study highlights changing disagreement between census and death record information in the reporting of the education of the deceased and shows how these reporting differences influence a range of mortality inequality estimates.This study uses a census-linked mortality data set for Estonia for the periods 2000\u20132003 and 2012\u20132015. The information on the education of the deceased was drawn from both the censuses and death records. Range-type, Gini-type and regression-based measures were applied to measure absolute and relative mortality inequality according to the two types of data on the education of the deceased.The study found a small effect of the numerator\u2013denominator bias on unlinked mortality estimates for the period 2000\u20132003. The effect of this bias became sizeable in the period 2012\u20132015: in high education group, mortality was overestimated by 23\u201328%, whereas the middle education group showed notable underestimation of mortality. The same effect was small for the lowest education group. These biases led to substantial distortions in range-type inequality measures, whereas unlinked and linked Gini-type measures showed somewhat closer agreement.The changing distortions in the unlinked estimates reported in this study warn that this type of evidence cannot be readily used for monitoring changes in mortality inequalities. Such data covering entire populations are still missing for many developed countries. A widely used alternative in these cases is relying on cross-sectional unlinked data based on separate tabulations of deaths and population exposures by socio-economic groups. The major problem with unlinked data is the disagreement between the sources of information on death and census records.6 The socio-demographic information provided on death certificates is considered as lower quality due to a higher probability of misreporting by proxy informants.7 8 The mismatch in the sources of information establishing numerators and denominators of death rates may lead to distortions of aggregated mortality and inequality estimates. Matching studies checking the validity of socio-demographic information on death records are scarce.13 To our knowledge, the only evidence on the importance of numerator\u2013denominator bias in Eastern Europe comes from two studies on Lithuania.10 13 These studies found a substantial misreporting of education and ethnicity on death records leading to biases in group-specific mortality and failing to report the gradient of inequality correctly.Monitoring socioeconomic inequalities in mortality is a crucial component for designing appropriate policies promoting more sustainable health development.This study extends prior evidence about the numerator\u2013denominator bias in unlinked data by providing new evidence based on the data for Estonia with a special focus on the change in the size of the bias in time. In addition, the current study broadens the scope of previous analyses by performing systematic sensitivity testing of a wider range of inequality measures.This study uses an aggregated census-linked mortality dataset provided by Statistics Estonia. These data were compiled from longitudinal mortality follow-up studies based on the 2000 and 2011 censuses. All permanent residents of Estonia taking part in both censuses were followed from the census dates (31 March 2000 and 31 December 2011) until the date of death or end of the follow-up period . Of all death records, 95\u201398% were successfully linked to the preceding censuses. For the analyses, the data were organised into two periods (2000\u20132003 and 2012\u20132015). The age-specific population exposures by education used to calculate both census-linked and unlinked mortality estimates were estimated by aggregating person-years lived by individuals during the period of observation . Meanwhile, deaths were grouped according to the exact age at death.low education combining primary and lower secondary education (ISCED11 categories 0\u20132); (2) middle education combining upper secondary and post-secondary non-tertiary education (ISCED11 categories 3\u20135); (3) high education referring to tertiary education (ISCED11 categories 6\u20138). For a better match with death records, ISCED11 category 5 was combined with middle education. The per cent of missing education was very low for both the census and death record information (0\u20130.8%) with the exception of unlinked deaths for the period 2012\u20132015 . For this period, deaths and person-years of exposure with unknown education were redistributed using a conservative approach assuming a proportional distribution across the three educational categories 11 categories: (1) tegories . In all 10.1136/jech-2020-214487.supp1Supplementary data14 15 Regression-based inequality measures  and Relative Index of Inequality (RII)) were calculated using common algorithm described by Anand et al.14 The public health impact of inequality was estimated using population-attributable fractions (PAFs).14Education-specific mortality for males and females was measured by age-standardised death rates (SDRs) using the WHO European Population (1976) as a standard. Relative mortality differences were assessed using age-adjusted Poisson regression mortality rate ratios (MRRs). More advanced numerically calculated inequality measures (average intergroup difference (AID) and Gini coefficient)) were applied to account for the total amount of inequality across all educational groups and group-specific weights in the population .14 15 ReThe observed biases in education-specific unlinked mortality estimates predetermined substantial distortions in the corresponding range-type measures of mortality inequality . For botWe found that using numerically calculated inequality measures (AID and Gini) accounting for mortality rates and population weights for each educational group may lead to a somewhat closer agreement between the linked and unlinked inequality measures. The biggest difference was detected comparing AID and Gini coefficients for females aged 30\u201364\u00a0years. In this case, underestimation of total mortality variation by education using unlinked data was about 20%. The corresponding disagreement was much lower for males in the same age group and both sexes at ages 30+ and 65+. Interestingly, similar regression-based inequality measures (SII and RII) show more pronounced discrepancies. Our final comparison examining PAFs warns that population-based mortality burden due to educational inequalities estimated according to unlinked data was vastly undercounted in the second period.The study found that the growing effect of misreporting of education on death records in Estonia had a substantial impact on the decreasing quality of education-specific mortality estimates based on unlinked data. This bias was also responsible for distortions in the magnitude and even direction of change in mortality inequalities. This finding is a warning sign against using unlinked estimates for monitoring changes in mortality inequality. A slightly better agreement was achieved using more advanced numerically calculated Gini-type measures of inequality . The advantage of the AID and Gini coefficient is probably related to a very good agreement between the unlinked and linked SDRs for the lowest educational group showing larger population weights.10 As in other countries, census questions in Estonia were more detailed and better suited to classify own education within different educational systems functioning during various historical periods. This design contrasts to less detailed questions available on death records. Differently from death records, the census records also specify the entry-level for each educational level. Studies suggest that reported information on death records may depend on the socio-demographic characteristics of proxy informants and the deceased.5 10 For example, the Lithuanian study shows that misreporting of education increases with age and is more frequent among those dying from alcohol-related or external causes of death and non-married individuals and Russian, Polish and other ethnic groups.10 Although self-reported education in the census is also prone to reporting errors, using the same source of information for both the deceased and population exposures allows to avoid the well-known numerator\u2013denominator bias.6The observed distortions in education-specific mortality estimates derived from the unlinked data using death record-based information about education can be attributed to a variety of changeable factors. First, notable discrepancies may occur due to differences in the design and wording of questions on education in both the census and death records.One of the main reasons for the changing bias in the unlinked mortality data for Estonia can be related to the spread of post-secondary non-higher education. It is possible that a substantial share of third-party informants assumed this category being a part of the tertiary (high) education. This misclassification would explain a notable overestimation of mortality in the high education group, as reflected by the unlinked data. Finally, the rise in the proportion of the unknown category from almost 0% to 13\u201314% in the period 2012\u20132015 suggests the decreasing quality of filling this information on death records. Applying a simple proportional redistribution of unlinked deaths across the three educational groups is a limitation of the study. However, sensitivity analyses have shown that applying such an assumption leads to more plausible results if compared to the alternative solution based on assigning all deaths with unknown education to the lowest educational category. We were not able to test more sophisticated multiple imputation methods requiring access to the individual-level data. Finally, this study used education to rank socio-economic groups and did not provide any insights into the causal impact of education on mortality.10 Therefore, the finding suggesting that more advanced Gini-type measures are less prone to the numerator\u2013denominator bias may reflect the Estonian specifics and do not apply to other countries. Scientific and policy efforts should be reinforced by informing policy-makers about the risks of using unlinked data and highlight the need for more reliable evidence based on the registry- or census-linked data.The results of this study have important implications for interpreting past and emerging evidence on mortality differentials based on unlinked data. Our findings warn that small numerator\u2013denominator bias observed at some point in time cannot guaranty the sustainability of such a pattern in the future. The misreporting of education seems to be country-specific, indicating that the numerator\u2013denominator bias can take different forms in various contexts. This conclusion is supported by completely different evidence from Lithuania for the period 2001\u20132004, revealing a very important effect of the numerator\u2013denominator bias on education-specific mortality estimates based on unlinked data.The numerator\u2013denominator bias leads to notable distortions in education-specific mortality.The misreporting patterns and magnitude of the bias in the unlinked data vary across countries.Matching studies checking the validity of socio-demographic information on death records are scarce.The numerator\u2013denominator bias in the unlinked mortality data may change in time, suggesting that such evidence cannot be readily used for monitoring mortality inequalities.Conventional range-type measures of inequality are particularly sensitive to the bias.High and middle education groups in Estonia were particularly affected by misreporting on death records."}
+{"text": "Until about 30 years ago, lipids were thought to only play a structural role in cell membranes. Over time they have acquired a new face and today represent a new frontier research aimed at studying them as biologically active molecules essential for cell fate, especially in the central nervous system (CNS).This special issue includes nine papers, five reviews, and four research articles, covering some of the more recent and exciting findings about the role in the brain physiopathology.Corraliza-Gomez et al. \u201cLipid-Binding Proteins in Brain Health and Disease\u201d that summarizes a systematic literature search to identify lipid interacting proteins and the biological processes in which they are involved related to nervous system function and dysfunction. Lipid-binding scaffolding proteins, membrane transporters and receptors, and transcription regulators contribute to blood brain barrier crossing and maintenance, control of oxidative stress and inflammation, organelle function, vesicle trafficking, myelin management, and amyloid dynamics. When altered, they may become therapeutic options.The first paper of the special issue is a review written by Torres et al. \u201cMitochondrial Cholesterol in Alzheimer's Disease and Niemann\u2013Pick Type C Disease\u201d illustrates the case of the aberrant accumulation of cholesterol in mitochondria as a common pathological event in Alzheimer disease (AD) and Niemann Pick type C. Mitochondrial cholesterol accumulation alters membrane physical properties and impairs the transport of glutathione into this organelle disrupting the antioxidant defense. The potential role of the up- regulation of a family of lipid transporting proteins containing StAR-related lipid transfer domains (StARD), by different mechanisms in the two diseases, is discussed.The minireview by Isacson et al. \u201cNovel Results and Concepts Emerging From Lipid Cell Biology Relevant to Degenerative Brain Aging and Disease\u201d describes biochemical and clinical evidence of an interdependence of lipids and proteinpathy in neurodegenerative diseases (NDD). The authors illustrate that Parkinson's disease (PD) can be triggered by lipid disturbances caused by lysosomal genetic or similar age-induced enzymatic loss of function. The lipid-carrying apolipoprotein E4 variant is associated with increased risk for dementias and \u03b1-synuclein may even have a cooperative role with apolipoproteins and lipid transport.The minireview of Azizkhanian et al. in \u201cPlasma Lipid Profiling Identifies Biomarkers of Cerebral Microvascular Disease\u201d investigate the biomarker value of plasma sphingolipids as a non-invasive marker of chronic subclinical cerebral small vessel disease. To this end they quantify the association of plasma sphingolipid (SphLs) levels with white matter hyperintensity volumes on brain magnetic resonance imaging, the current imaging gold-standard for cerebral small vessel disease. They find that levels of certain plasma SphLs are highly associated with white matter hyperintensities.Given the biological links between sphingolipids and brain injury, Wai Kin Wong et al., in \u201cComparison of Single Phase and Biphasic Extraction Protocols for Lipidomic Studies Using Human Plasma\u201d compare the efficacy of different lipid extraction protocols for lipidomic studies. Using human plasma from normolipidomic adult volunteers they show that the recently developed single phase Alshehry method, which also has the advantage of avoiding the use of chloroform, is more effective than established biphasic methods particularly in the extraction of polar lipids.As the relevance of lipid alterations is confirmed for the pathology of numerous brain diseases the use of lipid levels as diagnostic tool gains interest. Kalinichenko et al. in \u201cEnhanced Alcohol Preference and Anxiolytic Alcohol Effects in Niemann-Pick Disease Model in Mice\u201d use acid sphingomyelin-knockout mice to show that forced alcohol consumption decreases anxiety while increasing depression in these models.The following paper spans the association between lipid dysmetabolism with complex psychiatric symptomatology. Taking an innovative approach to the study of acid sphingomyelinase pathways in comorbid psychiatric symptoms of depression-alcoholism, Martin-Segura et al. in \u201cAging Increases Hippocampal DUSP2 by a Membrane Cholesterol Loss-Mediated RTK/p38MAPK Activation Mechanism\u201d study a mechanism that would link age-associated cholesterol changes to the chronic sterile inflammation when homeostatic control of kinases is lost. The authors provide compelling findings on the involvement of p38MAPK activity and its downstream targets in the hippocampus of old mice. The work presented builds on this to show that age-dependent loss of membrane cholesterol takes part in a negative-feedback loop that keeps p38MAPK activity levels within physiological range.Yang et al. provide information on the role of Yin-Yang mechanism in the release of arachidonic acid and docosahexaenoic acid due to different phospholipases A2 and in the regulation on their lipid peroxidation. The products of lipid peroxidation may be detected in body organs and fluids and may confer cytotoxic or protective effects depending on the conditions for production. The review reports in detail the involvement of these lipids in neurological and inflammatory pain, cerebral ischemia and brain injury, several neurodegenerative and neuropsychiatric disorders.The next review \u201cYin-Yang Mechanisms Regulating Lipid Peroxidation of Docosahexaenoic Acid and Arachidonic Acid in the Central Nervous System\u201d by Alessenko and Albi provides evidence of participation of SphLs in the pathogenesis of AD, Parkinson's disease (PD) and, Amyotrophic Lateral Sclerosis (ALS). Recent studies have shown that SphLs play a decisive role in the neuronal function due to regulation of cell growth, differentiation, and death in the CNS. The review discusses results obtained in vitro and in vivo, such as brain tissue from both animals in which diseases were induced and humans in autopsy samples, liquor, and blood. It was highlighted that SphL species might be diagnostic markers and/or new targets for innovative therapeutic strategies.The review \u201cExploring Sphingolipid Implications in Neurodegeneration\u201d by Thus, the special issue gives an overview about the current knowledge and highlight interesting new insights into the roles of the complex world of lipids in the brain and on its involvement in NDD.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The purpose of this study was to determine if Puerto Rican bats had previous exposure to rabies virus based on viral neutralizing antibodies. Our results demonstrate that 6.5% of the bats in this study had some exposure to rabies virus. The route of exposure is unknown but may have occurred following interaction with a rabid terrestrial animal or an unidentified bat rabies virus. Puerto Rico is home to 13 diverse species of bats, none of which is currently considered rabies vector species, but their capacity to become a vector is unknown . AdditioBrachyphylla cavernarum). Two hundred eighteen healthy Antillean fruit-eating bats, a common non-migratory species of bat found throughout Puerto Rico and the Lesser Antilles, were captured from Cueva Bonita Cave in north-central Puerto Rico from 2012 to 2014  in Antillean fruit-eating bats  of rabid animal to which bats may be exposed. This results in a conundrum for public health practices; should humans and domestic animals with direct contact with a bat be evaluated for post-exposure rabies treatment? Additional research to determine the route by which bats are exposed to rabies and the prevalence of rVNA in other bat colonies in Puerto Rico would be valuable in shaping public health policy.Click here for additional data file."}
+{"text": "The huge amount of information and data available in histopathology images, and ease of their digitization has rapidly advanced the field of computational pathology. The effectiveness of computational pathology, coupled with impressive recent advances in the fields of deep learning and computer vision, provide an ideal setting to revolutionize established clinical workflows.The goal of this Research Topic is to publish the latest research advances and bring together scientific researchers, medical experts, and industry partners working in the field of computational pathology for clinical outcome analysis.Whole Slide Imaging and Its Applications to Histopathological Studies of Liver Disorders,\u201d by Melo et al. This article presents the review of current knowledge on the application of WSI to histopathological analyses of liver disorders as well as to understand liver biology. This article also addresses how WSI may improve the assessment and quantification of multiple histological parameters in the liver, and help diagnose several hepatic conditions with important clinical implications.Emerging technologies such as whole slide imaging (WSI), have increasingly been used to improve the assessment of histological features with several advantages such as easy image accessibility and storage, portability, sharing, annotation, qualitative and quantitative image analysis, and use for diagnostic purposes, including routine diagnosis of liver specimens. The first highlight of this Research Topic is an article entitled \u201cDeep Learning for Whole Slide Image Analysis: An Overview,\u201d by Dimitriou et al. Building deep learning models capable of understanding WSIs presents novel challenges to the field. This article presents a review work on the interdisciplinary attempt of training deep neural networks using whole slide images, and highlights the different ideas underlying these methodologies.The technical limitations of the WSI have further been investigated in the article \u201cOpen Practices and Resources for Collaborative Digital Pathology,\u201d by Mar\u00e9e. This article describes open practices and open resources in the field of digital pathology with specific focus on approaches that ease collaboration in research and education settings. This review includes open access journals and open peer review, open-source software , and open access collections.Another highlight of this edition is an article entitled \u201cStrategies to Reduce the Expert Supervision Required for Deep Learning-Based Segmentation of Histopathological Images,\u201d by Van Eycke et al.. The article presents a study to review strategies that could help provide the very large number of annotated images needed to automate the segmentation of histological images using deep learning. This review identifies and describes four different approaches: the use of immunohistochemical markers as labels, realistic data augmentation, Generative Adversarial Networks (GAN), and transfer learning.Deep learning algorithms have demonstrated their effectiveness for the segmentation of numerous histological objects . However, obtaining annotations for these algorithms is a tedious and potentially biased task. A further highlight of this Research Topic is an article entitled \u201cClinical Application of a Real-Time Telepathology System for Frozen Section Diagnosis in Comparison With Optical Microscope,\u201d by Huang et al.. This article compares the effectiveness of NED to that of optical microscope (OM) in the process of intra-operatory histological diagnosis.The imbalance between the increasing demand of highly specialized service and the reduction of specialists able to release this service is a global challenge for pathology. The use of e-pathology devices, such as remote-control microscopes, offers a possible solution to this imbalance. Nano-Eye Device (NED) is a classical microscope integrated by a computer system warranting all the numerous possibilities of an electronic device, including the live control by a distant position. Due to this last characteristic it represents a possible solution for the management of intra-operatory diagnosis in hospitals performing surgical procedures but lacking on-site pathology service. Another highlight of this Research Topic, an article entitled \u201cA High-Performance System for Robust Stain Normalization of Whole-Slide Images in Histopathology,\u201d by Anghel et al.. This article addresses two aspects related to the stain normalization pre-processing that is part of modern ML-based pipelines in histopathology. (1) Stain normalization, which can significantly impact the latency of such pipelines especially when dealing with large-size and high-resolution whole-slide images; (2) Poor-quality images can decrease the decision accuracy of the ML pipelines. This article demonstrates that the stain normalization output can be seriously affected when the input image contains artifacts.Stain normalization is an important processing task for computer-aided diagnosis (CAD) systems in modern digital pathology. A further highlight of this Research Topic is an article entitled \u201cMulti-Organ Gland Segmentation Using Deep Learning,\u201d by Binder et al.. This article investigates the idea of cross-domain (organ type) gland segmentation strategy that aims at reducing the need for organ-specific annotations. The ability of neural networks based on convolutional layers to isolate and locate this tissue would greatly benefit any specialist aiming to measure gland morphologies within the cancer grading workflow.Analysis of glandular morphology in H&E stained histopathology slides is among the primary factors in cancer staging and thereby selecting the treatment procedure. So far, deep learning techniques have produced promising results on a few organ-specific gland segmentation tasks, however, the demand for organ-specific gland annotations hinder the extensibility of these techniques to other organs. The last highlight of this edition is an article entitled \u201cAll the papers published in this Research Topic underwent peer-review process involving a minimum of two reviewers. We thank the authors for agreeing to publish their papers in this Research Topic, and the reviewers involved in the publishing process of these papers.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Borderline Personality Disorder (BPD) significantly impairs functioning. Fortunately, effective treatments are available for borderline symptoms but their effect on functioning should be assessed. The objective of this meta-analysis is to assess the effect of specifically-designed versus non-specifically designed psychotherapies on function in adult patients with BPD. The reference list of Cristea et al. 2017 was used to identify the randomized controlled trials (RCTs) assessing the BPD-specifically-designed psychotherapy versus non-specific psychotherapies in adult BPD patients. Among those, RCTs assessing post-treatment functioning using the Global Assessment of Functioning, Social Adjustment Scale\u2013Self-Report and Inventory of Interpersonal Problems were included. Ten trials (880 participants) were included. Summary effect size was calculated using the measured Hedge\u2019s g. The results indicate the BPD patients in the intervention group had a significantly higher  level of psychosocial functioning after receiving the specifically-designed psychotherapies in comparison with BPD patients in control groups after receiving non-specific psychotherapies. Specifically-designed psychotherapies can improve psychosocial functioning although improvement in measurement of function  and improvement in psychotherapies  will be helpful. Borderline Personality Disorder (BPD) significantly impairs psychosocial functioning and this is regardless of individuals\u2019 gender  or settiBPD is common and almost 6 people out of 100 will have BPD in the course of their lives . The proEffective treatments exist to improve BPD related problems and symptoms  but the The list of included studies in the Cristea et al. (2017)  meta-anaCristea et al. (2017) used borderline personality keywords to search for randomized control trials in PubMed, PsycINFO, EMBASE, and the Cochrane Central Register (from the date of creation of the database to November 2015). They included RCTs which compared specifically-designed psychotherapies for BPD versus non-specifically-designed psychotherapies in adult populations. This inclusion was regardless of participants\u2019 status of using medication.Cristea et al. 2017)  assessed  assesseTypically, publication bias is assessed using funnel plot techniques, Begg\u2019s rank test and Egger\u2019s regression test (see page 5 for a discussion of publication bias in the current study).The study articles were used to extract post-treatment outcome data. These data include the number of treated participants, the mean score results of psychosocial measurement tools, and Standard Deviation (SD) or Standard Error of the Mean (SEM). Comprehensive Meta-Analysis Software (CMA) was used to calculate the effect size and Hedge\u2019s g. In order to calculate the effect size, we used the random-effect model. The same software, CMA, was also used to create forest plots as well as calculate heterogeneity.The full text articles of 33 RCTs which were previously included in Cristea et al. (2017)  were exaIn the ten included RCTs, 880 intention-to-treat participants were recruited from adult individuals who were diagnosed with Borderline Personality Disorder (BPD) Structured Clinical Interview for DSM (SCID) except for Farrell et al. (2009) who used Diagnostic Interview for Borderline Personality Disorders-Revised (DIBP-R) and Borderline Syndrome Index (BSI). Recruitment took place mostly in outpatient and inpatient psychiatric units as well as community mental health care settings.Treatments in intervention groups are demonstrated in The outcome measurement tools used are Global Assessment of Functioning (GAF), Social Adjustment Scale-Self-Report (SAS-SR), and Inventory of Interpersonal Problems (IIP) shown in The results indicate the BPD patients in the intervention group had a higher  level of psychosocial functioning after receiving the specifically-designed psychotherapies in comparison with BPD patients in control groups who received non-specifically-designed psychotherapies. Hedge\u2019s g for the individual studies is presented in In calculation of heterogeneity, there is much uncertainty when a small number of studies are included in a meta-analysis, like ours. Although there is no specific number of studies as the cutoff point in this regard, it seems that I-squared is less affected by the small number of studies included although it should be considered that I-squared is rather a more descriptive statistic than point estimate . In our In our study, funnel plot or more advanced regression-based assessments were not calculated to examine the publication bias and the reason is that the number of trials included in our study was limited which could cause unreliable results.The results of this meta-analysis show psychotherapies specifically designed for BPD can improve psychosocial functioning. The results indicate the BPD patients in the intervention group had a significantly higher  level of psychosocial functioning after receiving the specifically-designed psychotherapies in comparison with BPD patients in control groups after receiving non-specific psychotherapies. Specifically-designed psychotherapies can improve psychosocial functioning although improvement in measurement of function  and improvement in psychotherapies  will be helpful in future intervention studies. The importance of this improvement will be even more apparent when considering that long term follow up studies indicated poor functioning continues  while syIt is important to point out a few limitations of the research: (I) considerable variability is seen in the results of the functioning assessments; (II) many different measurement tools are used to assess functioning and more universally accepted tools are needed; for example GAF was the most commonly used measure along with the Inventory of Interpersonal Problems ; however, the GAF combines both symptoms and function and has been criticised as measure of function ; (III) mThe meta-analysis result shows a higher level of functioning in the treatment group. This can challenge the impression that BPD psychotherapies may not impact patients\u2019 functioning.Although the results show the specific therapies lead to improvement in functioning, the following points about tools and interventions should be considered. Firstly, considerable variability is seen when the results of the three different functioning assessment tools are compared. This indicates the potential need for an agreed upon measurement tool. A more universal tool will make it easier to compare different studies and also will create a more common language among clinicians and researchers. Developing such a consensus will make it more practical to consider psychosocial functioning in clinical assessments, treatment and research. Secondly, the current measurement tools are self-reported which can be a source of bias indicating the need for more objective and multiple methods of assessment.Lastly, interventions are mostly focused on BPD symptoms. Until further empirical evidence is established, the study may suggest approaches to clinical care for patients with BPD. Clinicians are well advised to have their patients focus on life outside of treatment and particularly to develop goals that foster productive vocational activities. When medications are prescribed, clinicians should look for evidence that the psychopharmacological intervention has an impact on measurable functional improvement. Interventions should focus more on work function and function in spousal and interpersonal relations to improve global functioning in BPD patients, as well as the barriers  to improving functioning. Additionally, the interplay between such barriers and BPD symptoms also merits further research.To that end, Level of Personality Functioning Scale (LPFS) is a promising psychosocial functioning measurement method which evaluates the global level of impairment in personality functioning. Several measures of function have been developed and validated based on the alternative DSM-5 model for personality disorders that hopefully will be useful in clinical trials .Stepped care is a useful and known method of treatment in mental health disorders which is particularly useful for BPD. Adding steps in BPD treatments to specifically focus on spousal and interpersonal relations and work functioning could help to enhance the beneficial impacts of BPD treatments."}
+{"text": "With the seminal discovery of somatic cell reprogramming with defined genetic factors, it is now a routine laboratory procedure to reprogram somatic cells to generate patient-specific induced pluripotent stem cells (iPSCs) [1] Patient-specific iPSCs can be differentiated to generate mature neurons as well as three-dimensional brain organoids that show appropriate functional activity in electrophysiological studies . However, there is a significant gap in the thoughtful incorporation of patient-derived neuronal cells in clinical studies addressing disease risk. With the seminal discovery of somatic cell reprogramming with defined genetic factors, it is now a routine laboratory procedure to reprogram somatic cells to generate patient-specific induced pluripotent stem cells (iPSCs)  Patient-Recently, we have seen the implementation of well-designed clinical studies aimed at delineating biological and psychosocial risk factors for psychiatric disorders. One such example is the Identifying Depression in Adolescence, a multisite global study spanning four continents that has developed an empirically derived stratification tool for the identification of adolescents at high and low risk for developing depression . These sThe ability to generate specific neuronal and glial cell types as well as three-dimensional brain organoids with disease-specific genetic backgrounds provides new opportunities for targeted biological studies . For insHuman neuronal cells with disease-specific genetic backgrounds provide novel ways to explore disease biology . We can in vitro experiments to identify mechanisms underlying differential response to treatment. Identification of cellular features that correlate with treatment response not only provides face validity to the mechanistic basis for the disease biology, but it will also aid in the development of predictive and precision medicine methods. With the identification of a robust and reliable treatment-response signature, one can evaluate effects of potential medications in neurons from individual patients before making an educated decision to pick the medication that shows the most robust response in the in vitro assays for that particular patient.There are subgroups of patients in the disease categories that respond to specific treatments while others do not. The differential treatment response is hypothesized to be due to different underlying biology in these subgroups . It woulWe are at an opportune juncture for the application of cutting-edge stem cell approaches to study psychiatric disease biology. In order to successfully bring these new technologies to the service of psychiatric research, we need a more engaged collaboration between clinical researchers and basic scientists. It will also require funding agencies and academic journals to view this rich area of potential research with new lenses and involve translational researchers who understand the new technologies and at the same time can appreciate the intricacies involved in their application to the complex issues involved in clinical psychiatry research."}
+{"text": "The COVID-19 pandemic has had a significant impact on the operation of donor human milk banks in various countries such as China, Italy and India. It is understandable that this impact on operations of donor human milk might hamper the capability of these milk banks to provide sufficient pasteurized donor milk to neonates who need it. Contrary to developed world, predominant donors in developing nations are mothers of hospitalised neonates who have a relatively long period of hospital stay. This longer maternal hospital stay enhances the feasibility of milk donation by providing mothers with access to breast pumps to express their milk. Any excess milk a mother expresses which is above the needs of their own infant can be voluntarily donated. This physical proximity of milk banks to donors may help continuation of human milk donation in developing nations during the pandemic. Nevertheless, protocols need to be implemented to i) ensure the microbiological quality of the milk collected and ii) consider steps to mitigate potential consequences related to the possibility of the donor being an asymptomatic carrier of COVID-19. We present the procedural modifications implemented at the Comprehensive Lactation Management Centre at\u00a0Lady Hardinge Medical College in India to promote breastfeeding and human milk donation during the pandemic which comply with International and National guidelines. This commentary provides a perspective from a milk bank in India which might differ from the perspective of the international donor human milk banking societies. The novelty of the causative agent for COVID-19, the SARS-CoV-2 virus means that various aspects of the disease including its epidemiology, pathophysiology, clinical manifestations and management remain largely unknown. Clinical manifestations reported in COVID-19 patients include the full spectrum from asymptomatic carriers, to mild pneumonia-like symptoms, to severe respiratory distress or having a fatal outcome [Pregnant women are immune suppressed and were reported to be more susceptible to respiratory infections including SARS-CoV and MERS-CoV , 3. AdveBenefits of breastfeeding and human milk feeding for neonates have been well documented. The World Health Organization recommends observing necessary precautions for IPC  and continuing breastfeeding when a mother has, or is suspected of, COVID-19 infection . Table\u00a01Davanzo , Chen 66 and FavThe WHO scientific brief based on a systematic review including data prior to 15 May 2020, comprising of 46 mother baby dyads acknowledged lack of sufficient data but a low risk of SARS-CoV-2 transmission through breast milk culminating in the recommendation to initiate and continue direct breastfeeding for infants born to COVID-19 suspect/confirmed mothers , KritsmeBreast milk possesses numerous bioactive components including immunoglobulins, lactoferrin, lysozymes, oligosaccharides and microRNA. The presence of protective antibodies against SARS-CoV and specifically against receptor-binding domain of spike protein of SARS-CoV-2 has been reported in various studies \u201334 althoCOVID-19 suspicion or positivity in a mother, her isolation to a COVID ward and surrounding uncertainties during parturition have unfortunately resulted in mothers being separated from their infants. Under such circumstances, direct breastfeeding and expressing breast milk may not be possible, donor human milk has been considered as the best alternative. An initial guideline also suggests the consideration of donor human milk . HoweverJournal of Human Lactation, Marinelli explores the challenges faced by the international donor human milk banking community [In the recent commentary regarding an international perspective on donor human milk banking during COVID-19 pandemic in the ommunity . It highMoro et al. from Italy shares the negative impact of COVID-19 on donor human milk bank systems . In a neIn India, human milk banks are established as Lactation Management Centres (LMC) at three levels such as, Lactation Support Units (LSU) at delivery points, Lactation Management Units (LMU) at district levels with functional Special Newborn Care Units (SNCU) and Comprehensive Lactation Management Centres (CLMC) at a tertiary level Fig.\u00a0. India nThe donation of milk is a non-incentivised process and remains a completely voluntary activity. The guidelines condemn the usage of donated human milk for commercial purposes. The protocol for screening of donors is stringent and concurs with the donation policies of other human milk banking associations . The proThe predominant way of expressing milk for an infant who cannot breastfeed directly in LMIC is hand expression. In accordance with the interim guidelines for breastfeeding during COVID-19, maintaining proper hand hygiene is strictly enforced . The expAt our centre, a CLMC, the milk expressed using breast pumps under lactation counsellor\u2019s supervision is usually sent back to the NICU to feed mother\u2019s own milk to her own baby. The electric breast pumps are currently stationed in CLMC due to space and cost constraints. The mother comes to CLMC to express her milk through pumping. A mother\u2019s milk is donated only if it is in excess of her own infant\u2019s need and the mother is willing to donate. This presents a unique opportunity for human milk banks to play a quintessential role in ensuring the adherence to recommendations of hand hygiene and measures under IPC while expressing the milk. This also relieves the NICU staff of additional burden of expression and taking care of pumps and safeguards that the benefits of mother\u2019s own milk are passed onto the neonate.Before entering, a mother is verbally screened for symptoms of flu-like illness by a health care professional. If the mother is symptomatic, she is referred to the COVID-19 screening facility at the hospital and is only allowed to express if reported negative for COVID-19.Adherence of mothers and milk bank staff to social distancing during expression of milk and while practicing hand hygiene.A limited number of mothers and health care professionals are allowed in the expression room.Milk Bank staff who can work from home have been relieved and only called on duty, if necessary. Our centre is fully functional at its maximum capacity with the minimum number of necessary staff.Face masks are worn by health care professionals and mothers at all times.Lactation counsellors are provided with personal protective equipment (PPE) for assisting a Covid-19 suspect or positive mother during pumping to avoid unnecessary contact with surface. Autoclaved closed containers are supplied to the milk bank from the NICU and mothers carry their expressed milk in those closed containers to the NICU.The general hygienic practices implemented at LMUs and CLMCs ensure cleanliness and prevent cross contamination. In addition, during this pandemic a few experts emphasised practices for mothers to follow at our centre including:Reportedly, amidst the ongoing COVID-19 pandemic, the international donor human milk banking community is impacted by COVID-19preventative measures \u201344. The In India and many other LMICs, predominant donors to human milk banks at tertiary care hospitals are mothers who have given birth to infants requiring NICU admissions . These dAs a precautionary step, questions about possible travel history, history of contact with a COVID-19 positive person, residence in a containment area or belonging to a hotspot zone along with presence of flu-like illness have been added to the existing donor registration form. These are similar to the questions asked for non-donor mothers who visit the centre to express with breast pumps.The process of handling milk in a milk bank requires good manufacturing practices and the use of PPE to protect the personnel and donated human milk from unnecessary exposure. Donor screening and microbiological profiling of raw donor human milk and pasteurization ensures the safety of the PDHM. As elaborated by the European Milk Banking Association (EMBA) in its statement, the process of pasteurization could potentially help destroy SARS-CoV-2, if present . The staHygiene helpers are responsible for cleaning plasticware in CLMCs. In view of the fact that mothers visiting the facility could potentially be asymptomatic carriers of SARS-CoV-2, appropriate protective gear like face shields, N-95 masks, gowns and gloves are donned by the hygiene helpers while handling the plasticware utilized for mothers during milk expression.Human milk banks should maintain impeccable hygiene standards at all times. With the well debated issue surrounding the handling of human milk containers as being potential sources of SARS-CoV-2 transmission, Marinelli et al. suggested using \u201chigh level of disinfection\u201d bleach to clean plasticwares in milk banks . AlternaWhat is interesting to note is that the temperature stability study reports complete inactivation of SARS-CoV-2 virus after 5\u2009min of exposure at 70 degrees Celsius . The proThe ongoing pandemic has impacted the functioning of human milk banks throughout the world. Attempts should be made to minimise the impact on the health and well-being of the vulnerable infants. Breast milk has notable benefits for the neonate including the potential for transfer of bioactive agents such as anti-infective antibodies along with other established long-term benefits. The core belief of human milk banking across the globe is to promote and strengthen breastfeeding.Human milk banks in developing nations have a pivotal role during these unpropitious circumstances to facilitate the use of breast milk and ensure provision of donor milk as gap support to the most vulnerable preterm infants (<\u20091500\u2009g and\u2009<\u200932\u2009weeks gestation) if mother\u2019s own milk is not available."}
+{"text": "Lone and colleagues used a national cohort to examine the association between living in a socioeconomically deprived area and critical care using timely data linkage Socioeconomic inequalities in health are pervasive and have been demonstrated across health outcomes and throughout the world. It is perhaps unsurprising that socioeconomic disadvantage is linked to higher risk of SARS-CoV-2 infection Lone and colleagues provide novel insight into the capacity of critical care units during the first wave of the pandemic in Scotland. Hospitals serving areas of higher deprivation saw greater use of critical care beds compared to hospitals serving areas of lesser deprivation. These findings demonstrate the continued relevance of Tudor Hart's Inverse Care Law, which describes an inverse relationship between the need for healthcare and its availability Lone et\u00a0al's recent contribution justifies the adoption of such an approach to the resourcing of critical care during the second wave of the pandemic, where additional staff and beds should be prioritised for areas with higher levels of deprivation to meet the greater critical care demand in these areas, whilst ensuring all areas have adequate resource to manage individuals requiring critical care.Understanding the socioeconomic gradient in demand for critical care beds is vital for policymakers if they are to mitigate the socioeconomic inequalities in COVID-19 outcomes, as we face a second wave of COVID-19 disease. Proportionate universalism has been advocated in addressing health inequalities, where universal provision of services are combined with targeting distribution to those most in need Although this research examined the association between COVID-19 outcomes and socioeconomic deprivation in the context of critical illness and intensive care admission, there is growing evidence of a socioeconomic gradient in COVID-19 prognosis across the spectrum of COVID-19 disease severity. Individuals living in more socioeconomically deprived areas are at increased risk of acquiring infection, complications and mortality . UnderstThe imminent introduction of effective COVID-19 vaccinations brings hope of controlling the infection and reducing harm. However, the burden of post-acute COVID-19 or \u2018Long COVID\u2019 will likely persist as the pandemic resolves. Given the higher incidence of COVID-19 disease in more socioeconomically deprived population, a greater incidence of Long COVID would be anticipated in this group. The inequity in clinical outcomes of COVID-19 disease across the socioeconomic gradient will be compounded by the unequal distribution of the indirect consequences of the pandemic and its impact on individuals\u2019 future health Lone and colleagues consider the association of socioeconomic deprivation and COVID-19 outcomes, other inequalities were omitted. The high proportion of missing ethnicity data in this cohort exemplifies the challenge of using healthcare records to explore ethnicity, because of their often incomplete or unreliable recording Whilst Inequalities do not exist in isolation and individuals will often experience multiple dimensions of social disadvantage, which will combine to produce their resultant health outcomes. As a result, the importance of applying the lens of intersectionality when examining health inequalities has been increasingly acknowledged in recent years. As an example, the intersection of ethnicity/race and occupation on COVID-19 risk has been demonstrated, where non-White healthcare and essential workers experienced higher infection risks compared to equivalent White workers ,9. WhilsScotland has a universal healthcare system which is free at the point of use and prioritises minimising barriers to access. Finding inequalities in this context suggests similar or larger health inequalities will occur elsewhere. Further international research which ideally takes a comparative perspective would be informative, allowing the assessment of if and how inequalities differ across different health systems SVK is co-chair of Scottish Government's Expert Reference Group on ethnicity and COVID-19. Except for the funding acknowledged above, we declare no other conflicts of interest."}
+{"text": "This study examines the relationship between social support profiles and cognitive functioning by race, ethnicity and nativity in older adults using cross-sectional data drawn from the Health and Retirement Study (2010 and 2012). We employed a hierarchical clustering routine to generate nine support profiles that differentiated three sources of support: children, wider family relationships and friendships. Cognitive functioning was measured as the score on the Telephone Interview for Cognitive Status (TICS-m), a 27 point scale of cognitive function. Our approach explicitly acknowledges the ambivalence and multidimensionality of close relationships and the resources embedded within them. Descriptive analyses revealed significant differences in access to support across demographic groups. White respondents are over-represented in profiles that are characterized by support from friends, and under-represented in family support profiles. The reverse is found among Foreign-born Hispanic respondents who are over-represented in the profiles characterized by high family support and under-represented in those with high friend support. Native-born Hispanic respondents and Black respondents have less clear support patterns, although both are more likely to receive support from family and children compared to friends. Findings from the poisson regression suggest that the relationship between familial support and cognitive decline is stronger among Hispanic respondents, particularly those who are foreign born. These findings are supported even with the inclusion of other relationship quality indicators including negative support and frequency of contact."}
+{"text": "From the onset of the Health Resources and Services Administration\u2019s Geriatrics Workforce Enhancement Program (GWEP), project initiatives have been developed to collaborate with Area Agencies on Aging and other community-based organizations (CBOs) serving the older adult community to improve health outcomes. The current GWEP funding cycle includes an initiative to further the principles of Age-Friendly Health Systems. Having built relationships within the aging services community, GWEPs are well positioned to deliver educational interventions framed around the 4M pillars of age-friendly healthcare. Three GWEPs are working with CBOs to implement and test interventions that address the interactive 4Ms. One GWEP has created an Age Friendly Community Education series in conjunction with their CBO partners in a low-income urban setting. Another GWEP has secured age friendly designation for its teams and worked with a coalition of CBOs to obtain both age and dementia-friendly designations for its home city of Springfield, MA. A third GWEP is implementing age-friendly practice workflows in programs that connect primary care and community-based organizations to address specific needs of an underserved older population. By integrating CBOs within the age-friendly health system framework, we can better create sustainable partnerships with health systems to improve health outcomes for our elders."}
+{"text": "Macaca fascicularis). We found soft and liquid feces, and vomiting in all treated groups with inorganic and organic arsenics. The monkeys in inorganic arsenic-treated group showed a significant increase in vomiting frequency compared with those in three organic arsenics-treated groups. These results suggest that inorganic arsenic might be more toxic than three other organic arsenics tested. The monkeys in inorganic arsenic-treated group showed a decrease in platelet and an increase in monocyte on day 4 and the monkeys in arsenocholine-treated group showed an increase in reticulocyte percentage on day 8. The monkeys in inorganic-treated group also showed decreases in AST and ALT values and the monkeys in arsenobetaine-treated group showed a decrease in AST value and an increase in T-CHO value. However, these hematological and biochemical changes were within the physiological ranges, showing that the single dose of inorganic and organic arsenics did not affect at least hematological and serum biochemical parameters. The present study of toxicity with single dose of arsenics provides valuable indicators for longer term study of toxicity of repeated doses of arsenics in primates.A screening study of the acute toxicity of organic arsenics such as arsenobetaine and arsenocholine, a product of arsenic methylation metabolite, and inorganic arsenic was carried out to examine hematological and serum biochemical parameters in cynomolgus monkeys ("}
+{"text": "Research has pointed to sense of purpose in life as an important individual difference that promotes successful aging, predicting greater psychological wellbeing, physical functioning, and cognitive health in older adulthood. Despite such benefits, it is unclear how major life challenges such as the onset of cognitive impairment may impact the sense of purpose of older adults. Building on this, the present study examined long-term change in sense of purpose in a longitudinal sample of older adults who would later develop dementia. Data were from 341 participants without dementia at study intake who were subsequently diagnosed with dementia during the follow-up period . Participants completed annual assessments of purpose in life up to 17 years prior to dementia diagnosis (M = 6.99 assessments prior to diagnosis). Piecewise growth modeling examined change in sense of purpose in life with time structured as years to diagnosis. Results suggested a period of accelerated decline distinct from normative age-related change beginning around 5.60 years prior to dementia onset. Discussion will focus on two potential explanations: that perceiving declines in cognition may lead to diminished sense of purpose in life or that underlying changes in the brain may impact both cognition and sense of purpose resulting in concurrent decline over time."}
+{"text": "The Arkansas Geriatric Education Collaborative (AGEC)\u2019s Geriatric Workforce Enhancement Program is partnering with a plethora of community based organizations (CBO) and with ARcare, an Arkansas federally qualified healthcare clinic network, to implement the 4Ms of age-friendly care in rural clinics. Baseline clinical data related to the Age-Friendly 4M Framework has been gathered and quality improvement projects initiated to improve the outcomes. Initiatives to improve depression and cognitive screenings are addressing Mentation; fall prevention screens and the offering of fall prevention programs have been added for Mobility; high risk medication screens and chronic pain educational programs are being implemented to address Medications; and finally, Medicare Annual Wellness Visits is the cornerstone to improve what Matters to older adults. A campaign that involves partnered CBOs to address health literacy and increase involvement in evidence-based programs is also helping to drive improvements in age-friendly care in rural Arkansas."}
+{"text": "Human cytomegalovirus (HCMV) is a beta herpesvirus that persists for life in the majority of the world's population. The persistence of HCMV in the human population is due to the exquisite ability of herpesviruses to establish a latent infection that evades elimination by the host immune response. How the virus moves into and out of the latent state has been an intense area of research focus and debate. The prevailing paradigm is that the major immediate early promoter (MIEP), which drives robust expression of the major immediate early (MIE) transactivators, is epigenetically silenced during the establishment of latency, and must be reactivated for the virus to exit latency and re-enter productive replication. While it is clear that the MIEP is silenced by the association of repressive chromatin remodeling factors and histone marks, the mechanisms by which HCMV de-represses MIE gene expression for reactivation are less well understood. We have identified alternative promoter elements within the MIE locus that drive a second or delayed phase of MIE gene expression during productive infection. In the context of reactivation in THP-1 macrophages and primary CD34+ human progenitor cells, MIE transcripts are predominantly derived from initiation at these alternative promoters. Here we review the mechanisms by which alternative viral promoters might tailor the control of viral gene expression and the corresponding pattern of infection to specific cell types. Alternative promoter control of the HCMV MIE locus increases versatility in the system and allows the virus to tightly repress viral gene expression for latency but retain the ability to sense and respond to cell type-specific host cues for reactivation of replication. Human cytomegalovirus (HCMV) is one of nine herpesviruses infecting humans. Primary HCMV infection is typically asymptomatic. Like all herpesviruses, HCMV evades immune clearance and establishes a life-long latent persistence Goodrum, . The latHCMV infects a diverse array of human cell types. While the biology of HCMV infection has been most thoroughly characterized in the context of robust productive replication in fibroblasts, other patterns of infection are unique to other cell types. For example, replication in epithelial cells and endothelial cells results in a chronic or low-level smoldering infection  response upregulates PML-associated host factors and reversibly blocks IE gene expression to drive latency in MCMV-infected endothelial cells (Dag et al., SAMHD1 is a restriction factor that depletes the pool of available dNTPs to suppress DNA polymerase processivity and has recently been shown to restrict MIE gene expression and replication by impeding NFkB activation in myeloid cells (Kim et al., While much remains to be understood about the signaling events and coordination of repressive activities to repress viral gene expression for latency, much less is known about how these layers of control are unraveled for reactivation. Reactivation necessarily depends on counteracting the strong, layered epigenetic silencing associated with latency. The reactivation of CMV from latency has been intimately linked to changes in signaling and hematopoietic differentiation (Soderberg-Naucler et al., Reactivation is associated with changes in the levels or binding of host transcriptional activators to the MIE region that stimulates reactivation (Bain et al., Because the MIEP is strongly repressed during latency and chromatin modifications in the MIE region correlate with cellular differentiation and the permissive state, it has been presumed that de-repression of the MIEP is a prerequisite to re-expression of IE genes upon reactivation . Recent + HPCs and CD14+ cells (Shelbourn et al., in vitro, MIE transcripts are also predominantly derived from the intronic promoters, and mutant viruses wherein the intronic promoters are disrupted reactivate poorly following stimulation in infected THP-1 or CD34+ HPCs.While MIE gene expression from the intronic promoters is not required for virus replication in fibroblasts, the presence of these alternative MIE promoters offers exciting possibilities with regard to the control of MIE gene expression in the context of latency and reactivation. This is particularly true in light of findings that MIEP activity is weak in cells that support HCMV latency, including CD34+ monocytes treated with phorbol ester (Mason et al., + or CD14+ cells and in CD14+-derived macrophages stimulated with IL-1b and M-CSF, MIE transcripts were predominantly derived from the MIEP. These findings raise the possibility that regulation of the MIE locus, including the usage of various transcription factor binding sites and distinct promoters, is cell type-specific. This level of complexity would allow the virus to respond to multiple reactivation stimuli using different signaling pathways. In support, the transcription factors CREB and NF-\u03baB, which bind the MIE enhancer region upstream of the MIEP transcription start site, were shown to play a cooperative role in re-initiating MIE gene expression in NT2 cells treated with phorbol ester (Liu et al., These findings suggest a model whereby the MIEP is silenced upon the establishment of latency and re-expression of MIE genes and reactivation of the replicative cycle requires switching to the intronic promoters to drive MIE gene expression . At leas+ HPCs, demonstrating a role for FOXO transcription factors in reactivation. This is intriguing, as FOXO3a localizes to the nucleus or is induced in myeloid progenitor cells in response to cellular stresses and differentiation (Paik et al., Providing insight into the regulation of the intronic promoters, intron A sequences contain consensus binding sites for the forkhead family transcription factors. The MIE intronic promoters can be activated by both FOXO1 and FOXO3a members; however, FOXO3a appears to be the transcription factor critical for reactivation (Hale et al., Transcripts with alternative 5\u2032 ends may be driven by promiscuous initiation of transcription or alternative promoter usage. Either mechanism serves to provide additional, context-dependent regulation of gene expression or to expand the limited coding potential within a viral genome. The ~240 base pair HCMV genome is estimated to encode >165 ORFs (Davison et al., UL136 is encoded on a polycistronic locus spanning UL133-UL138 that encodes multiple proteins important to viral latency and reactivation. UL136 protein is not synthesized from longer transcripts encoding UL133 or UL135 (Grainger et al., UL136 transcripts have unique 5\u2032 ends that give rise to a series of unique proteins, each with a successive truncation amino terminal end compared to the full-length UL136 protein (Caviness et al., UL136 promoter has not been mapped and it is not yet clear if UL136 transcripts arise from multiple promoters or initiation of transcript or how they might be differentially regulated in different contexts of infection. However, mutant viruses lacking single or combinations of the UL136 variants have revealed important roles for each in either stimulating or suppressing virus replication in endothelial cells and for the establishment of latency or reactivation from latency in CD34+ HPCs and humanized mice (Caviness et al., Alternative promoters play key roles in tailoring gene expression for cell lineages, tissue types, developmental stages, stress and differentiation (Davuluri et al., FG wrote manuscript. DC-M and NM contributed data supporting manuscript and revised manuscript. JK contributed data supporting manuscript, revised manuscript, and contributed to figure. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Macular telangiectasia type 2 (MacTel) is a bilateral retinal disease that seems to be limited to the juxtafoveal region of the macula. We herein report an unusual presentation of MacTel with a large pigment deposit at the macula. Fundus of the right eye showed a large pigment deposit at the macula and right-angled venule. The left eye fundus showed a grayish discoloration due to subretinal fibrosis, dark pigment clumps and right-angled venule in the macula. Lesions were highlighted on multicolor imaging and blue reflectance imaging. Spectral domain optical coherence tomography (SD-OCT) of both eyes showed hyperreflectivity on the inner aspect of the retina corresponding to the area of pigment clumping. Macular telangiectasia type 2 (MacTel) is a bilateral retinal disease that seems to be limited to the juxtafoveal region of the macula . It is uA 65-year-old female patient came to our hospital with the complaint of diminution of vision in both eyes. Best corrected visual acuity was counting fingers at 2 meters in the right eye, and 20/30 in the left eye. The patient gave a history of diabetes and hypertension for 10 years. Fundus examination of the right eye showed a large pigmented lesion and right-angled venule in the macula  in the parafoveolar area may be the first ophthalmoscopically visible change in patients with MacTel, which is seen as an area of increased reflectance on confocal BR imaging. Paracentral vertically oriented slightly dilated right-angled venules are seen draining the telangiectatic area. These right-angled venules typically develop temporally. It has been suggested that a retinal Muller glial dysfunction or cell death may contribute to the formation of these venules . Due to Optical coherence tomography angiography (OCTA) is a novel technique that visualizes vascular tissue using flow characteristics. Volume-rendered OCTA allows clear visualization of retinal vasculature at all depths. Subretinal neovascularization can occur in MacTel. RPE abnormalities may provide a conduit for abnormal vessels in the subretinal space to proliferate into the sub-RPE compartment . In OCT-Extensive pigmentation can often be seen in patients treated with focal laser or photodynamic therapy. In our case, there was no previous history of laser treatment. Interestingly we found an unusual large dark pigment deposit at the macula which has not yet been described in the literature. However, these pigmented lesions should be differentiated from tumors of the RPE that include solitary congenital hypertrophy of the RPE (CHRPE), congenital hamartoma of the RPE, combined hamartoma of retina and RPE (CHRRPE) and adenoma of RPE. The differentiation between these conditions is primarily done clinically. CHRPE is a peripheral or mid-peripheral fundus lesion that is well-demarcated, flat or slightly elevated, and can either be black homogeneous with typical depigmented lacunae or completely depigmented . Most soThis case report highlights an unusual presentation of a large pigment clump in a case of MacTel which has not been previously reported.The authors declare that they have no competing interests."}
+{"text": "Ageism, a multidimensional construct, is also understood as a relational process whereby perceptions and behaviors toward older individuals by younger individuals not only damage the self-esteem of elders, but also create a hostile environment for their own future social interactions and their own future self-development as elders. Anti-ageism interventions have the hefty task of improving attitudes and behaviors toward aging within all of these contexts. This presentation will discuss findings from two different anti-ageism interventions both designed to mitigate the negative impacts of ageism. Results from a study on an intergenerational arts-based program found that after participation students demonstrated a positive change in their attitudes toward older adults. Findings from a video-based ageism intervention among a sample of 265 staff members in 15 senior living communities demonstrated decreased internalized aging anxiety as well as decreased ageist behaviors directly after the training and at three month post follow-up. Given the complex and systemic nature of ageism, diversity is necessary in scope and type of intervention in order to reach the broadest audience."}
+{"text": "In recent years, there have been outstanding achievements in stroke diagnosis and care ,2. Our bThis Special Issue of the Journal of Clinical Medicine features articles presenting considerations and improvements in acute stroke treatment, emerging neurosonology applications and novel predictors of stroke outcome.Intravenous thrombolysis (IVT) in patients with a low National Institutes of Health Stroke Scale (NIHSS) score of 0\u20135 remains controversial. The Potential of rtPA for Ischemic Strokes with Mild Symptoms (PRISMS) trial was a phase 3, randomized, double-blind clinical trial that aimed to test the safety and efficacy of intravenous thrombolysis, with tissue plasminogen activator (tPA) administered within 3 h of symptom onset in acute ischemic stroke (AIS) patients with mild, non-disabling neurological deficits  score equal to or less than 5) . The stuMerlino et al. tested the hypothesis that the utility of intravenous tPA in patients with mild stroke symptoms may depend on their level of functional dependence at hospital admission . AuthorsRandomized controlled clinical trials have provided robust evidence on the benefit of both intravenous tissue tPA and EVT for improving the outcomes of acute ischemic stroke patients . HoweverRapid EVT delivery for acute ischemic stroke caused by large vessel occlusion leads to improved outcomes . OptimizThe underlying pathomechanism of a large vessel occlusion has been suggested to be associated with effectiveness of the EVT procedure and the outcomes of patients . In a reAlthough paroxysmal atrial fibrillation (AF) has been suggested to be present in at least a third of patients with cryptogenic stroke or transient ischemic attack (TIA) , currentLiantinioti et al. sought to identify whether cardiac arrhythmia detection in spectral waveform analysis during neurosonology examinations with Carotid Duplex and Transcranial Doppler ultrasound may be associated with a higher likelihood of paroxysmal AF detection . They ev2DS2-VASc score [Park et al. investigated the association between total carotid plaque number and long-term prognosis in ischemic stroke patients with AF . Total pSc score . AlthougSc score . The finCT perfusion imaging is used to guide systematic and endovascular stroke treatments for patients presenting in the extended time windows ,5,6. UltMost physicians use their own clinical experience in predicting their patients\u2019 outcomes after a stroke, as accurate prognostic models and tests of functional recovery in stroke patients are lacking to date .Min et al. performed a prospective cohort study to evaluate the usefulness of interhemispheric functional connectivity as a predictor of motor recovery in stroke patients with unilateral severe upper-limb paresis . FunctioAnkle-brachial blood pressure index (ABI) is calculated by the ratio of the systolic blood pressure of an ipsilateral ankle divided by the higher systolic blood pressure of the two arms . Low ABIThe impact of hemoglobin status and red blood cell transfusions (RBC) on acute ischemic stroke outcomes is controversial. Kim et al. aimed to investigate whether RBC transfusions and hemoglobin variability affects the outcome of patients after an acute ischemic stroke . The autAlthough platelet activation and aggregation has been suggested to play an important role in the pathogenesis of ischemic stroke, the association between platelet reactivity and ischemic lesions is still debatable. Ischemic stroke patients with high on-treatment platelet reactivity have previously been reported to be at increased risk of recurrent cerebrovascular ischemic events . WisniewIn a subsequent publication in the same issue of the Journal of Clinical Medicine, Wisniewski et al. assessed the relationship of platelet reactivity with early and late prognosis after an acute ischemic stroke, according to the stroke etiology . PerformEndothelial progenitor cells are considered to be a marker of both endothelial damage and endothelium regeneration ability . In a thAlthough real-world evidence confirms the beneficial effect of reperfusion therapies in the real-world setting, as well as the temporal improvements in stroke treatment delivery over the last few years, several research areas are still pending further investigation. The utility of intravenous tPA in patients with non-disabling stroke syndromes, the use of ultrasound cerebral perfusion imaging in the pre-hospital setting and the optimal in-hospital route for acute ischemic stroke patients with suspected large vessel occlusion are topics in acute stroke care that need to be further investigated. Ongoing research also needs to focus on the development of reliable radiologic, clinical and biomarkers predictors of stroke outcome."}
+{"text": "Management of coronary artery fistula (CAF) is based on obliterating the fistula communication between the cardiac arteries and other thoracic vessels.We describe the presentation of an 85-year-old female with progressive exertional dyspnea on a background of a long standing left anterior descending diagonal to pulmonary artery fistula. We utilized neuro-interventional techniques to perform coil embolization via use of a Scepter XC dual lumen micro catheter.Dual lumen balloon catheters allow for super-selective artery interrogation, stability of balloon positioning, with less trauma to vessel architecture and accurate embolization. There were no complications and the patient reported improvement of symptoms on review. Coronary artery fistulae (CAF) were first described by Krause in 1865 Krause . The majThe treatment of dural arteriovenous fistulae and cerebral aneurysms with liquid embolic agents or coil embolization, are well established in the neuro-interventional literature  was inserted. Diagnostic angiography was performed using an 8 French Judkins catheter  Fig.\u00a0 with supThe patient was well at 1 month clinical review with improvement in symptoms and no further delayed complications.The first percutaneous transluminal closure of a coronary artery fistula was described in 1989 (Nguyen et al. Balloon assisted embolisation is a common neuro-interventional procedure, first described in 1997 (Moret et al. Jagadeesan et al. (Jagadeesan et al. The use of detachable neurovascular coils allows for controlled placement and assessment of flow in non-target vessels prior to deployment. The enhanced potential for navigation of the microwire allows for super-selective interrogation of small feeder vessels which may otherwise be missed due to competitive arterial flow. Therefore the Scepter XC is useful for super-selective interrogation that is useful in tortuous cardiac vessels as in our case.The compliance of the Scepter XC balloon has previously been documented in the treatment of cerebral vasospasm, where radial expansion of the balloon conforms to the course of the vessel, which allows for balloon inflation that is less traumatic to the vascular architecture to prevent arterial injury and vessel rupture (Heit et al. Furthermore, the balloon and microwire lumens are separate in the Scepter XC micro catheter, which allows for retraction, exchange or reposition of the microwire without losing position of the catheter. This is not possible in a single lumen catheter due to subsequent retrograde blood flow into the balloon that can hamper inflation and deflation of the balloon (Wallace et al. A potential shortfall of using the Scepter XC catheter, however, is that the 5\u2009mm nose distal to the balloon can make positioning of the catheter difficult in areas of vessel bifurcation or tortuosity (Heit et al. The patient was well at six-month clinical review with improvement in symptoms and no delayed complications.The management of CAF is based on obliterating the fistula communication between cardiac arteries and other vessels. Dual lumen balloon catheters allow for super-selective artery interrogation and more accurate embolization, while reducing flow into a shunting lesion. Our approach took advantage of the Scepter XC balloon\u2019s compliance which provided greater stability in balloon positioning and can reduce trauma to vessel architecture."}
+{"text": "A routine of regular aerobic exercise has been shown to have non-pharmacological benefits for the prevention and treatment of many potential side effects from chemotherapy. This includes the whole spectrum of cancer care from diagnosis through treatment and long-term survivorship. The case report by Korn et al that accompanies this editorial describes an adolescent leukemia survivor with anthracycline-induced cardiomyopathy who was able to train and compete in a triathlon. This is an important contribution that demonstrates to an extreme the physical capabilities of cancer survivors.The role of exercise in the prevention and treatment of anthracycline cardiotoxicity remains controversial. In animal models, beneficial effects of exercise include preservation of left ventricular systolic and diastolic function by modulating heart rate and contractility through (a) an increase in antioxidant activity with reduction of reactive oxygen species release and increase in heat shock proteins; (b) a decrease in proapoptotic signaling; (c) a decrease in myocyte turnover through suppression of proapoptotic protein synthesis; and (d) changes in energy metabolism . In humaIn the patient not exposed to potentially cardiotoxic chemotherapy, long-term excessive endurance exercise may induce pathologic structural remodeling of the heart \u2013 training and participation in \u201cextreme\u201d activities  can increase pre-load and induce atrial and ventricular volume overload with liberation of cardiac troponins, and with continued training, may induce structural changes -- patchy areas of myocardial fibrosis, LV dilatation/hypertrophy and increase in myocardial mass .This leads to a word of caution related to the intensity of exercise described in this case report. Vigorous activity with potential acute increases in catecholamines and increased energy demands can increase the risk of sudden death and acute myocardial infarction, especially in patients with underlying structural heart disease . PatientRisk of sudden cardiac death has also been described in cancer survivors with cancer therapy-related cardiac dysfunction. In the general population, sudden cardiac death in young athletes <35\u00a0years of age is typically due to inherited conditions  and in older athletes >35\u00a0years of age is typically due to coronary artery disease (CAD) . In piloThe lack of consensus in the guidelines for exercise intensity among cancer survivors at high risk of cardiovascular late effects reflects the paucity of clinical studies in this area. The International Late Effects of Childhood Cancer Guideline Harmonization Group recommends cardiology consultation for cancer survivors with known therapy-related cardiomyopathy and for cancer survivors at high risk of cardiomyopathy prior to initiation of high-intensity exercise . The AmeThorough screening history and physical exam that includes a current assessment of cardiac structure and function (echocardiogram and possibly cardiopulmonary exercise testing);Education about possible warning \u201cred-flag\u201d symptoms;Prescription for graded training with avoidance of high-risk activities, especially in the absence of adequate pre-training;General recommendations about healthy lifestyle;Regular supervision and follow-up with medical personnelWhat is the answer? Maintaining balance and moderation is critical. A \u201clittle exercise\u201d is good; \u201cexcessive exercise\u201d may be detrimental. Therefore, our practice is to discourage extreme levels of exercise but recommend low-intensity endurance training and activities. Before prescribing a vigorous exercise program in patients previously exposed to anthracycline-based chemotherapy or radiation therapy to the left chest, patients should have:"}
+{"text": "Compton scatter photons are generally considered problematic in nuclear medicine imaging. Therefore, efforts are being made to minimize the involvement of these photons by employing some special strategies in daily practice. Basically, photons scattering at a small angle and traveling in the proper direction stand a chance of getting recorded and thereby participate in the image formation. These photons may create artifactual hot spots in the vicinity of a region with high concentration of radioactivity. The present study focuses on the negative impact of such photons during routine imaging in clinical setting, through an artifact detected in technetium-99m-IDA hepatobiliary scintigraphy, with the purpose of highlighting this issue to the nuclear medicine practitioners."}
+{"text": "Shellfish constitute an important protein source but may be contaminated by viruses from various origins. A study performed on clams collected in Cameroon showed a high prevalence of norovirus and hepatitis A virus. After sequencing, the hepatitis A virus showed similarities with the genotype V simian strains. The need for a one-health approach to protect humans from emerging diseases is evident by the high number of microbial pathogens that become zoonotic following insect bites or consumption of contaminated meat. This is particularly well documented for infectious disease transmission from non-human primates to human  were collected on the Sanaga river , between February 2018 and March 2019 from two sampling points (eight from site B and six from site M). Clams were immediately frozen and shipped to the Ifremer laboratory where they were dissected and the digestive tissues (DT) recovered. Viruses were eluted from clam DT and nucleic acids were extracted using the reference method . The sequence of the VP3-VP1 cleavage site of KZN_Irr-20130530 suggested a simian origin for this strain (Rachida et al. Finding this virus in a food raises several concerns. If the strain originates from simian hosts, the risk of host jump to humans is enhanced by the high frequency of positive samples, the close relation between human and non-human primates, and the high stability of HAV. Indeed, some HAV strains appear highly resistant to heat and cooked coquina clams have been implicated in outbreaks (Pinto et al."}
+{"text": "A 35-year-old male smoker presented with reduced vision in OD for the previous two years. He reported a further drop in the vision for the previous two weeks after he underwent focal laser elsewhere. Clinical examination and multimodal imaging confirmed a giant tear of the retinal pigment epithelium (RPE) and a focal leak of CSCR. He was managed with the focal laser to the active leak and lifestyle modification. The ocular condition remained stable. RPE rips in CSCR have been reported to occur spontaneously or with an intervention like exogenous use of steroids, or photodynamic therapy (PDT). This case highlighted the fact that focal laser can precipitate RPE rip in a case of CSCR with tense bullous PED. The physician should keep this fact in mind while counselling the patient before a laser procedure and suspect an RPE rip in a patient with CSCR who presents with an acute onset of vision loss. The incidence and reporting of RPE rip has increased further with the extensive use of anti-VEGF injections [2]. RPE rips associated with central serous chorioretinopathy (CSCR) are uncommon, yet bullous variant of CSCR can present with RPE rip [3]. RPE tears associated with CNVM are caused by contraction of CNVM at the edge of PED; on the contrary, increased hydrostatic pressure in the PED is implicated for the blowout of RPE in CSCR [1]. The incidence of CNVM related RPE tear is reported to be 20% [2]. In an isolated case report, PDT has been associated with RPE tear in a case of CSCR [4]. Moreover, the continued use of steroids can worsen the PED in CSCR, leading to RPE tear [5]. RPE tears or rips are commonly associated with choroidal neovascular membrane (CNVM) and pigment epithelial detachment (PED) in patients with age-related macular degeneration . The prognosis of CSCR related RPE tear is considered better than CNVM related RPE tear [7]. The vision loss depends on the location and extent of the RPE tear. The RPE tear involving the fovea can cause substantial vision loss. The healing takes by either scarring or migration of RPE cells [8]. It is crucial to identify those cases that have the risk of RPE tear like a bullous variant of CSCR [3]. Patients should be counselled regarding the risk of RPE tear following laser, especially in high-risk cases. Utmost care should be taken for laser delivery, as the RPE is tense and high energy with small spot size can tear the RPE.No definitive treatment guidelines exist for the management of RPE tear. In our patient, we found an active focal leak in FFA and so decided to treat with focal laser because the focal leak would have further compromised RPE with fluid overload. Specific predictive markers have been described for RPE rip formation like the PED height, change in reflectance based on autofluorescence, subretinal cleft formation and duration of PED [This report highlighted a rare case of RPE tear in CSCR induced by focal laser. A high index of suspicion of RPE tear should be kept in mind in a case of CSCR if the patient presents with a sudden reduction of vision after the laser procedure. Multimodal imaging helps in early diagnosis and regular follow-up of the patient. Proper patient counselling before focal laser, especially in high-risk cases with a tense PED, must be done.Conflict of interestThe authors declare no conflict of interest. Financial DisclosureNil financial disclosures.No public private support."}
+{"text": "Amber can thus check AST, PAST, as well as their negations for a large class of polynomial probabilistic programs, while carrying out the termination reasoning fully with polynomial witnesses. Experimental results show the merits of our generalized proof rules and demonstrate that Amber can handle probabilistic programs that are out of reach for other state-of-the-art tools.The termination behavior of probabilistic programs depends on the outcomes of random assignments. Almost sure termination (AST) is concerned with the question whether a program terminates with probability one on all possible inputs. Positive almost sure termination (PAST) focuses on termination in a finite expected number of steps. This paper presents a fully automated approach to the termination analysis of probabilistic while-programs whose guards and expressions are polynomial expressions. As proving (positive) AST is undecidable in general, existing proof rules typically provide sufficient conditions. These conditions mostly involve constraints on supermartingales. We consider four proof rules from the literature and extend these with generalizations of existing proof rules for (P)AST. We automate the resulting set of proof rules by effectively computing asymptotic bounds on polynomials over the program variables. These bounds are used to decide the sufficient conditions \u2013 including the constraints on supermartingales \u2013 of a proof rule. Our software tool"}
+{"text": "The emergence of COVID-19 has recently dominated public discourse given its serious impact on vulnerable patient groups. Advice in relation to reducing risk of contamination has justifiably been circulated widely during the COVID-19 crisis. Contamination fear is a common obsessional theme in patients with obsessive\u2013compulsive disorder (OCD), and there is a need for increased research on how infectious disease epidemics affect patients with OCD. We present the case of a lady in her 30s with a history of well-controlled contamination OCD who presented acutely with a significant exacerbation of OCD symptoms precipitated by media reports of COVID-19. The case highlights the potential psychological impacts of infectious disease epidemics on individuals with mental illness. We also highlight some of the risks posed to such patients in response to epidemics such as the COVID-19 crisis. These functional limitations represented a significant deterioration from baseline and had emerged over a 3-week period. Furthermore, the patient\u2019s worsening OCD symptoms were associated with significant psychological distress including panic symptoms and passive death wish. AB exhibited good insight into the nature of her OCD symptoms and spoke of her difficulty in cognitively re-appraising her intrusive thoughts in light of the public discourse surrounding COVID-19.AB is single, unemployed and lives alone in rental accommodation. She reported a history of child sexual abuse (CSA), significant childhood separation anxiety, emetophobia (fear of vomiting) and depressive episodes throughout her 20s. She reported that her OCD symptoms had emerged in her early 20s and had fluctuated at this time. Fear of contamination was the predominant obsession and excessive hand washing the predominant compulsion; however, preoccupation with symmetry and pathological doubt with associated checking behaviours was also present to a lesser extent. She was treated as an outpatient for OCD approximately 10 years prior to the current presentation with Sertraline 150 mg daily and Cognitive Behavioural Therapy (CBT), with significant effect. The Sertraline was subsequently self-discontinued secondary to side effects. AB had also attended counselling for trauma related to previous CSA.AB satisfied ICD-10 criteria for a diagnosis of OCD. She did not meet ICD-10 criteria for current co-morbid depressive or other anxiety disorders. Following the initial emergency assessment, AB was commenced on Mirtazapine 15 mg nocte and was prescribed a short course of Alprazolam 250 mcg as required to treat her acute distress. At a subsequent psychiatric assessment, the mirtazapine was titrated to 30 mg, and an urgent referral for psychological assessment was made with a view to commencing CBT targeting OCD symptoms. At outpatient follow-up 2 weeks later, AB reported some initial improvement; however, news reports of the emergence of COVID-19 cases within Europe had briefly triggered a deterioration in her mental state with intensification of compulsive rituals, avoidance behaviours and psychological distress. AB described a reduction in the emotional reactivity to her obsessional thoughts, however reported that her compulsive acts continued. Augmentation with oral Risperidone was offered; however, the patient declined same, instead opting for dose titration of Mirtazapine to 45 mg nocte. Her mental state improved with this initial medication input, and she also reported feeling more assured as increased public health measures were implemented in Ireland to address the emerging COVID-19 crisis.This case describes the role of an infectious disease epidemic in precipitating a significant deterioration in a patient with OCD with predominant contamination obsessions and associated compulsions. Of note, the deterioration in mental state occurred prior to the arrival of COVID-19 in Europe, suggesting that it was predominantly increased media reporting of COVID-19 which precipitated her relapse in symptoms. The case raises several important points warranting further consideration.et al., In response to the COVID-19 pandemic, public health authorities have implemented public health measures and sought to increase public awareness around the importance of frequent hand washing and the observation of appropriate social-distancing measures. In this context, it is important to distinguish between the rational adaptive behavioural modifications undertaken by individuals in response to the pandemic, which are vital from a public health perspective, and the obsessional, irrational thoughts and compulsive acts exhibited during relapse of OCD. The presence of significant psychological distress in response to obsessional thoughts is a key feature of OCD and may predispose this patient cohort to a variety of risks. Some of the risks identified based on the current case include increasing isolation beyond the public health need for self-isolation; avoiding certain food types or restricting food intake to avoid contamination; the emergence of co-morbid conditions such as depression, anxiety or panic symptoms and the risk of misadventure by engaging in irrational acts to counter perceived risk of contamination. Of note, figures published recently by the United States Centre for Disease Control (CDC) show a significant spike in unintentional poisonings with household sanitising agents in recent months and there have been several media reports documenting cases of physical injury and death caused by overzealous or inappropriate use of cleaning products , may need to be substituted with approaches that encourage the client to imagine exposure to the feared stimulus. It has been suggested that the imaginal approach to exposure and response prevention provides less potent disconfirmation than that achieved by an In the current case, antidepressant pharmacotherapy was the principal initial treatment strategy employed which resulted in gradual stabilisation of symptoms, reduction in levels of distress and improvement of the patient\u2019s functional capacity over time. The initial stabilisation in mental state will allow improved chance for engagement with psychological therapies once COVID-19 restrictions are lifted.This case report outlines a possible clinical effect related to the onset of an infectious pandemic and the associated media reporting. Further research is needed to determine other potential mental health effects of the recent COVID-19 pandemic, and these effects should become more apparent in the coming months. In the meantime, it is important that clinicians and policymakers are aware of the potential increased risk of relapse among those with an underlying OCD diagnosis during infectious disease pandemics and that proactive efforts are made to provide necessary supports to this vulnerable population."}
+{"text": "We introduce our techniques using concrete example modules that have all been verified using the Coq proof assistant and combine to fully linked verified programs using a novel, abstraction-respecting component composition rule for Verifiable C.Modularity - the partitioning of software into units of functionality that interact with each other via interfaces - has been the mainstay of software development for half a century. In case of the C language, the main mechanism for modularity is the compilation unit / header file abstraction. This paper complements programmatic modularity for C with modularity idioms for specification and verification in the context of Verifiable C, an expressive separation logic for CompCert Clight. Technical innovations include (i)"}
+{"text": "A 56-year-old man was referred to our institution for cardiac ablation because of several episodes of palpitations and thoracic pain with an electrocardiogram suggestive for left atrial tachycardia (160 bpm). He was affected by arrhythmogenic right ventricular cardiomyopathy (ARVC) with left ventricular involvement and a plakophillin-2 gene mutation. A cardiac magnetic resonance imaging scan showed biventricular fibro-fatty infiltration with matching late gadolinium enhancement.. However, we could not exclude a macro-reentrant  tachycardia  with a slow-conduction isthmus inside the vein of Marshall with its fibrous and muscular component  as supported by the presence of fragmented potential along the line of block.An electrophysiological study was performed in combination with electroanatomic mapping (EnSite Precision\u2122). An activation map of the left atrium during tachycardia was created with the Advisor\u2122 HD Grid Mapping Catheter, Sensor Enabled\u2122. The region of earliest activation was identified at the base of the left atrial appendage (LAA), confirmed also by the EnSite\u2122 LiveView Dynamic Display. The activation wavefront was suggestive for a focal-origin tachycardia from the LAA with an uncommon line of block between the LAA and left superior pulmonary vein along the left atrial roof Ablation with 25 W  at the earliest activation site terminated the tachycardia within three seconds. At six months of follow-up, no recurrence of the arrhythmia was observed."}
+{"text": "Sustainable energy and chemical/material transformation constrained by limited greenhouse gas generation impose a grand challenge and posit outstanding opportunities to electrochemical material devices. Dramatic advancements in experimental and computational methodologies have captured detailed insights into the working of these material devices at a molecular scale and have brought to light some fundamental constraints that impose bounds on efficiency. We propose that the coupling of molecular events in the material device gives rise to contra-varying or co-varying properties and efficiency improving partial decoupling of such properties can be achieved via introducing engineered heterogeneities. A specific class of engineered heterogeneity is in the form of isomaterial heterostructures comprised of non-native and native polymorphs. The non-native polymorph differs from their native/ground state bulk polymorph in terms of its discrete translational symmetry and we anticipate specific symmetry relationships exist between non-native and native structures that enable the formation of interfaces that enhance efficiency. We present circumstantial evidence and provide speculative mechanisms for such an approach with the hope that a more comprehensive delineation of proposed material design will be undertaken. Improving the stability of the photoelectrodes via conformal coatings with optimal transparency and catalytic properties  and the third contra varying property has implications on this front. Many approaches toward improving optical absorption cross-section like incorporating substitutional dopants, surface grafted-dyes, plasmonic nanoparticles  of such devices as opposed to other solid-state devices like solar-cells and microprocessors, which have stability ~20 years. The issues of stability are severe in PEC-OER. Typically, most stable materials (like TiOThe main contra-varying property in EC-OER is that the more (less) active OER electrocatalyst are less (more) stable which is due to molecular reasons behind instability involving over-oxidation of cations leading to dissolution into the solutions  does not readily give information about the thermodynamic stability and hence, we have adopted the notation like NN2, NN1, and N, where the energetic stability is in the order NN2 < NN1 < N  from electrochemical processes (via electrolyzer), allowing for better optimization of the two material components separately. Coupling of physicochemical events impose fundamental bounds on efficiencies and may give rise to contra varying  or co-varying relationships (Activation barriers in a multi-electron transfer step) that makes engineering processes at a molecular scale challenging.We propose that decoupling can be implemented via engineering heterogeneity in the material in the form of isomaterially heterostructured interfaces comprised of non-native and native crystallographic structures. A variety of non-native structures have been synthesized and well-characterized by modulating the surface and bulk energies. Such interfaces will be related via group-subgroup relationship within space-group theory due to which there is a higher chance of having interfaces bound coherently without broken interfacial bonds, which in turn aid in the efficiency of material devices. Much of the important details of such an approach remains to be worked out and corroborated via experiments and we hope that this article will aid in further exploration along this direction.The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In the skill acquisition and rehabilitation literature substantial attention is placed on the central and peripheral action systems\u2014the efferent and motor performance side of the behavior. However, there is a quiet but steady interest being expressed in the role of sensation\u2014and the perception of sensation\u2014in improving performance. There is also growing recognition that the primary function of different sensory systems can be trained in clinical populations to improve detection, discrimination, and spatial/object recognition. Moreover, the more hidden function of perception of sensations can improve motor performance by improving feedback and feedforward.We are delighted that the following selection of 12 papers explores these topics conceptually and empirically in humans. They include a systematic review, randomized controlled trials, pilot reports, imaging, and mechanistic studies; in clinical and non-clinical populations.Zerr et al. have explored multi-sensory processing\u2014in particular the temporal binding window\u2014whereby we build up composite and coherent perception. Their pilot randomized controlled trial (RCT) demonstrates this window of time for binding multiple sensory input is both modifiable with training AND can influence function\u2014in this example fluency of speech. Further, Matsugi et al. elaborate on the role of the cerebellum in modulating specifically vestibulo-spinal function using either transcranial magnetic (repetitive cerebellar) or galvanic (noisy) stimulation. Both authors invite readers to consider future clinical applications.Several authors have investigated aspects of sensory function in healthy populations. Yasuda et al. and Zhang et al. both considered the sensory aspects of walking in healthy populations. Yasuda investigated augmenting feedback (vibrotactile) to the feet during gait practice whilst Zhang tested a system that simulates the usual tactile pressures experienced on the soles of the feet during walking. Lopez-Rosado et al. explored these ideas in a pilot clinical trial with people with stroke\u2014finding that increasing tactile input to the affected foot (using a sock that passively stimulates) could improve gait speed.Serrada et al.) have reported a systematic review and meta-analyses of RCTs investigating the effect of sensory-based interventions on function after stroke. They confirmed that the literature still supports the effectiveness of more passive modalities\u2014stimulating body parts with afferent (sub-motor-level) devices\u2014with the strongest evidence. There is also emerging evidence for the active retraining of sensory appreciation and its effect on both sensory appreciation and motor performance, however more research in larger, stronger studies is still needed.Other papers also investigated the role of sensory training in people with stroke. To provide an overview of the current literature  improved both postural control and sensory integration in their RCT. Allowing the participants to have a voice in their RCT, Turville et al. reported that people post-stroke found their somato-sensory retraining program (SENSe) to be both challenging and rewarding\u2014believing it helped them to increase their sensation and to improve the way they used their stroke-affected arm. Adding to the quest for robust methodology in sensory training research, Carey et al. validated an objective measure of haptic object identification for researchers and clinicians to use to evaluate change in stroke survivors before and after the same form of somatosensory retraining.Other studies investigated specific modalities for sensory-based intervention post-stroke. Cai et al. concluded that people with stroke can consistently and accurately perceive force production (torque or effort) at either their affected or less affected elbow if tested unilaterally, but not simultaneously. This confirms we need to further consider the role of cognition and attention in sensory rehabilitation.The final stroke-related paper investigated a different form of somato-sensory appreciation. Cuppone et al. investigated the idea that people with visual impairments may also have spatial perceptual issues. They used an intact sense (auditory) coupled with movement to improve proprioceptive spatial perception in this group. This furthers our understanding of the way we can use complementary senses to substitute in situations of severe impairment.The remaining paper leads us back to considering multiple sensory input. We hope you find these studies of interest\u2014we are particularly pleased that the research spans different sensory modalities from vision and audition to somatosensory and vestibular. We look forward to ongoing interest in the training of sensation (and perception) for improvement of skilled performance in non-clinical and clinical populations.All authors contributed to the editorial and approved the final version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The prevailing practices adopted during the coronavirus disease 2019 (COVID-19) pandemic pertaining to hygiene, personal protection strategies, and quarantine measures have opened up unforeseen possibilities of these basic measures being one of the key factors that could reduce exacerbation rates in asthma and COPD. This pandemic may just provide the right framework for these comprehensive guidelines to be revisited to review their present recommendations.Global Initiative for Chronic Obstructive Lung Diseases (GOLD)6. Several theories have been proposed to explain this paradox. These range from protective effects of inhaled corticosteroids, a different immune response in patients with COPD, under diagnosis of chronic respiratory diseases (CRDs), and possible benefits of hygiene and isolation measures6.During the COVID-19 pandemic, there has been a lot of focus on its impact on those with comorbidities in whom the outcome, in terms of hospitalizations and mortality, has been higher. However, surprisingly and contrary to the general perception, overall prevalence of COPD and bronchial asthma patients affected by COVID-19 has been quite low as compared to the global burden of these diseases8. This intriguing association of CRDs in those with mild COVID compared to those with severe illness is not clearly understood.By contrast, the disease severity and overall outcome in COVID-19 patients with CRD has been more severe. Reports from across the globe state CRDs as among the most frequent comorbidities associated with severe COVID illnesses requiring intensive care unit admissions, need for mechanical ventilation, and deathsA common clinical observation shared by physicians worldwide has been a significant reduction of acute exacerbation of COPD (AECB) and asthma in the last quarter of 2020. The impact of the pandemic has resulted in appreciably better air quality. These are likely due to reduced pollution and extreme measures practiced globally to avoid respiratory transmission of infections. Concerns about access to health care and awareness among patients that optimized treatment of their lung disease lowers their risk of COVID-19 complications probably are factors leading to good adherence to prescribed medications. It is plausible that an interplay of these factors may have resulted in reduced AECB and exacerbation of asthma, although this causal relationship needs to be confirmed.9. Such studies could also encourage better adherence to the use of face masks and respirators in public and health-care settings. Robust randomized trials are, however, needed to gauge and substantiate the evidence for these interventions. Systematic appraisal of currently available evidence might pave the way for interim guidance on effectiveness of these basic and common interventions in combating the immediate threat of COVID-19 infections9.Data emerging from systematic review and meta-analysis have demonstrated lower risk of infection for physical distancing of 1\u2009m as was with the use of face masks. Added benefits are likely with physical distances of \u22652\u2009m based on modeling by meta-regression analysisThe landmark guidelines GOLD and GINA have been surprisingly silent on basic sanitary and respiratory hygiene measures and have overlooked the role of masks in certain specific settings. Recommending the use of masks for stratified high-risk group of CRD patients in certain settings such as mass gathering may be a judicious and far-sighted move. Weighing the scientific uncertainty and the contextual considerations, there is a need for a more nuanced view by members of the task force formulating the guidelines. It would only be prudent to include these basic lifestyle modifications and preventive measures among the non-pharmacological interventions for COPD and asthma in the guidelines. GOLD and GINA should also consider updating their guidelines with practical recommendations for personal protection equipment and other hygiene measures for safe spirometry procedures. Presently, this phenomenon is largely based on non-scientific observations from the real-world clinical practice. Data from randomized controlled trials and other scientific studies are needed to validate these preliminary observations.Exacerbations are the primary factors that modify the long-term disease progression in these CRDs. Therefore, these above-mentioned basic but feasible and universally adaptable measures have a promising role along with pharmacotherapy in potentially reducing exacerbation. As a result, these measures could modify the overall disease outcome in CRDs."}
+{"text": "In December 2019, a new virus causing pneumonia called Severe Acute Respiratory Syndrom Coronavirus 2 (SARS-COV 2) appeared in the city of Wuhan in China . TransmiEarly diagnosis based on cases definition, isolation and supportive therapy in severe forms were adopted . In the Infection control and prevention of transmission, therefore, become a permanent challenge in the dental care and require additional resources especially in resources constraints setting such as sub-Saharan Africa. The following measures has been proposed to reduce the risk of transmission for dental health care worker: reorganization of the reception system with systematic temperature-taking of patients; a questionnaire (in order to stratify patients according to their risk of being infected) asking for the general health status, a history of travel to an epidemic zone in the previous 14 days and a close contact with an infected or suspected positive SRAS-COV 2 individual . FurtherWhile business support plans have been developed and include dental professionals in developed countries, in sub-Saharan Africa few efforts in this direction have been undertaken . There iThe COVID-19 pandemic in sub-Saharan Africa brings up a big challenge to the continuity of oral health care provision. Adaptation and reshaping seem necessary to reduce the contamination\u2019s risk for staff and patients. It would be important to support these professionals to maintain their activity while ensuring safety for patients and the community.The author declares no competing interests."}
+{"text": "Background: Glioblastoma multiforme is a malignant intracranial neoplasm that constitutes a therapeutic challenge because of the associated high morbidity and mortality given the lack of effective approved medication and aggressive nature of the tumor. However, there has been extensive research recently to address the reasons implicated in the resistant nature of the tumor to pharmaceutical compounds, which have resulted in several clinical trials investigating promising treatment approaches. Methods: We reviewed literature published since 2010 from PUBMED and several annual meeting abstracts through 15 September 2020. Selected articles included those relevant to topics of glioblastoma tumor biology, original basic research, clinical trials, seminal reviews, and meta-analyses. We provide a discussion based on the collected evidence regarding the challenging factors encountered during treatment, and we highlighted the relevant trials of novel therapies including immunotherapy and targeted medication. Results: Selected literature revealed four main factors implicated in the low efficacy encountered with investigational treatments which included: (1) blood-brain barrier; (2) immunosuppressive microenvironment; (3) genetic heterogeneity; (4) external factors related to previous systemic treatment that can modulate tumor microenvironment. Investigational therapies discussed in this review were classified as immunotherapy and targeted therapy. Immunotherapy included: (1) immune checkpoint inhibitors; (2) adoptive cell transfer therapy; (3) therapeutic vaccines; (4) oncolytic virus therapy. Targeted therapy included tyrosine kinase inhibitors and other receptor inhibitors. Finally, we provide our perspective on future directions in treatment of glioblastoma. Conclusion: Despite the limited success in development of effective therapeutics in glioblastoma, many treatment approaches hold potential promise including immunotherapy and novel combinational drugs. Addressing the molecular landscape and resistant immunosuppressive nature of glioblastoma are imperative in further development of effective treatments. Glioblastoma multiforme is the most aggressive intracranial tumor; histologically considered as a malignant glioma arising from an astrocytic lineage (WHO classification: astrocytoma grade IV), and it represents the most common malignant primary brain tumor in adults ,2. DespiIn this review, we discuss the distinct factors that are essential in understanding the challenges in the treatment of glioblastoma. Second, we offer a review of potential novel treatments including (immunotherapy and targeted therapy), and the rationale behind their use. Finally, we present our prospective on future directions in the pursuit of novel effective treatments for glioblastoma.Perhaps the most consequential discovery that has shifted the paradigm of cancer treatment and substantially led to improved outcomes in multiple cancer types is the discovery of the immune system role in preventing tumor growth and killing cancer cells which has coined the term \u201canti-tumor immunity\u201d . For exaThe blood-brain barrier (BBB) forms a dynamic interaction of endothelial cells, pericytes, microglia, astrocytes, and is responsible for the integrity of the central nervous system . BBB plaOf importance to immunotherapy, BBB plays an essential role in regulating immunosurveillance and restricting immune cell passage into the central nervous system (CNS), which could limit the efficacy of many novel drugs that work by recruiting the immune system to attack cancer cells. However, the insight gained from other CNS diseases on the ability of immune cells to cross BBB in certain autoimmune and inflammatory diseases, could help further research on exploiting this vulnerability in the administration of novel immunotherapies in glioblastoma ,42,43.To circumvent these challenges, several methods are under ongoing investigation to overcome the BBB and BBTB and achieve sufficient delivery of therapeutic compounds inside glioblastoma. One promising method is the delivery of drugs through nanoparticles which allow for the individual units loaded with drug to be carried to glioblastoma cells . For exaConvection-enhanced delivery (CED) is another promising method that has shown to encourage preclinical and clinical results . This meMoreover, it is important to note that some drugs can have an effect on glioblastoma despite not being able to penetrate BBB into the tumor. For example, bevacizumab, which is a VEGF inhibitor that has shown improved PFS and quality of life in glioblastoma patients, prevents angiogenesis within the vasculature compartment without the need of being present inside the tumor cells ,11,12. AThe long-standing historical notion of the CNS being considered an immune desert because it is devoid of effective resident immune cells has been challenged by rigorous research which demonstrated that the CNS has specific lymphatic system and is occupied by immune cells with unique characteristics compared to its counterparts in other organs .The paramount advances in cancer treatment with the introduction of ICI as well as other immunotherapies have drastically shifted the focus in cancer treatment on exploiting pathways involved in host immune defense mechanisms to fight cancer cells \u201canti-tumor immunity.\u201dAlthough immunotherapies have shown significantly improved outcomes in different solid and hematological malignancies, the outcomes in glioblastoma have been mild to moderate at best. This stems from the fact that TME of glioblastoma employs an immunosuppressive effect despite the abundance of a variety of immune cell subsets ,51. For Additionally, tumor-associated macrophages (TAM) and microglia are essential subtypes of immune cells that constitute the majority of cellular mass in glioblastoma (30\u201350%) . These cThe other important factor that is associated with an immunosuppressive microenvironment in glioblastoma is the increased expression of checkpoint receptors such as PD-L1, IDO, TIM3 on T-cells and TAMs ,68,69,70For the abovementioned reasons, the negative impact of glioblastoma on the immune microenvironment which favors the presence of dysfunctional and deregulated immune cell subpopulations, constitute a major challenge on the implementation of effective immunotherapies in the treatment of glioblastoma. Therefore, efforts are focused on exploiting existing vulnerabilities in the TME of glioblastoma to reactivate the immune system against tumor cells. For example, TAMs display plasticity which refers to their ability of switching their phenotypic features leading to a change in their function. As such, this plasticity could be exploited to selectively express a phenotype that favors macrophage type-1 (M1) which is a pro-inflammatory cell that can boost host immunity versus macrophage type-2 (M2) which is considered pro-tumorigenic . SimilarThe common definition of glioblastoma by World Health Organization classification as a high-grade glioma-IV offers limited insight into the genetic heterogeneity of glioblastoma. Genomic characterization by The Cancer Genome Atlas (TCGA) research group and the comprehensive molecular analysis helped delineate three distinct tumor-intrinsic transcriptional glioblastoma subtypes including proneural, mesenchymal, and classical ,75. ThisThe genetic heterogeneity appears to reflect distinct glioblastoma immune subsets based on the molecular signature . For exaFurthermore, tumor mutation burden (TMB) status that estimates the frequency of mutations that are present per megabase of malignant cell DNA correlates with response observed in several solid malignancies during treatment with ICI. This is the result of increased neoantigen formation and presence of new mutant proteins that are immunogenic and can induce anti-tumor response . As suchTherefore, further characterization of immune abundance based on gene expression of glioblastoma can prove to be helpful in identifying selected patients as immunotherapy continues to assume a critical role in the treatment of cancer. The correlation between glioblastoma genetic subtypes and tumor response to immunotherapy is an open area for research as deeper understanding is required to evaluate the effect of molecular variations on tumor cell survival and sensitivity or resistance to immunotherapy.Several iatrogenic factors can affect and lead to alteration of glioblastoma on the genomic level as well as TME. As mentioned in the previous section, treatment with TMZ can increase hypermutated status, which is associated with higher neoantigen formation ,88,89,90Additionally, bevacizumab which is used in the treatment of primary and recurrent glioblastoma can lead to diminished infiltrative immune suppressive cells, low PD-1/PD-L1 expression and increased cytotoxic T cells which can alter the efficacy of immunotherapies . To thisImmunotherapy entails several pharmaceutical compounds that have different mechanism of action and can be categorized into: (1) Monoclonal antibodies (ICI) that target checkpoint protein receptors ; (2) adoptive transfer of bioengineered immune cells which are designed to destroy malignant cells such as CAR-T cell therapy and CAR-natural killer therapy (CAR-NK); (3) cancer vaccines that use mutant tumor peptides or immune cell-based components to induce anti-tumor immunity; and (4) oncolytic viruses that preferentially destroy malignant cells through direct and indirect mechanisms by engaging effector immune cells against cancer cells.p = 0.0343) [Immune checkpoint inhibitors (ICIs) have revolutionized the management of cancer in the last decade since the approval of CTLA-4 inhibitor (ipilimumab) in 2011, which was followed by approval of other ICI (PD-1/PD-L1 inhibitors). As mentioned previously, ICI can reinvigorate anti-tumor immune response by blocking checkpoint receptor molecules which are responsible for an immune-inhibitory effect that leads to immune evasion of cancer cells. The clinical efficacy of this class of medication has been echoed by durable improved outcomes including prolonged OS and PFS in several solid tumors including melanoma, lung, urothelial, breast, and liver cancers. Following the successful implementation of ICI in several solid malignancies, further research was conducted to evaluate their efficacy in other tumor types including glioblastoma. As the main target of ICI is the checkpoint receptor in TME, the presence of these receptors appears to be essential to enhance the ability of these drugs to interrupt checkpoint protein interaction with the respective ligand receptor which eventually lead to reactivation of anti-tumor response . This wa 0.0343) . Similar 0.0343) ,102,103.The enthusiasm to carry out the outstanding results achieved in cancer management with ICI, has not been as successful as anticipated in glioblastoma trials. This was demonstrated in a pivotal phase III randomized controlled trial (CheckMate-143), which compared the safety and efficacy of nivolumab (PD-1 inhibitor) versus bevacizumab in patients with recurrent glioblastoma who were previously treated with TMZ and radiotherapy at initial diagnosis . This stOne of the factors that is proposed to contribute to the decreased response of ICI is its inability to reach tumor cells. This is of importance as the BBB allows passage of limited small size compounds less than 400 Da, whereas nivolumab and pembrolizumab have a molecular weight of 146 kDA and 149 kDa respectively ,108,109.Another factor that appears to be fundamental for the efficacy of ICI in treatment of glioblastoma is the timing of administration. Most of the trials to date have examined efficacy of ICI either in the recurrent setting or in first line setting in combination with concurrent chemoradiation after surgical resection of the tumor. Therefore, it was tempting to evaluate the use of ICI prior to surgery as they have demonstrated improved outcomes in the neo-adjuvant setting in different tumors such as breast cancer and melanoma . SeveralFurthermore, the potential role of ICI in the treatment of glioblastoma appears to be significant in specific subpopulations. For example, tumor mutation burden (TMB) and mismatch repair deficiency (MRD) reflect a state in which a tumor is loaded with a high number of mutated proteins and neoantigens given the defective DNA repair mechanisms. This can convert the tumor into a hotspot as a target for anti-tumor immunity mediated by ICI as higher number of immunogenic antigens are expected to elicit a strong immune response ,115. DesCurrent efforts are focused on combining ICI with different treatment modalities in glioblastoma such as the novel checkpoint inhibitors of LAG3 and TIM3 ,120. IntAdoptive cell therapy in cancer treatment relies on redirecting immune cells to engage with specific tumor antigens based on bioengineered chimeric antigen receptors expressed in autologous T cells . By targTherapeutic cancer vaccination relies on the method of inducing an anti-tumor immune response by selecting tumor-associated antigens or mutated peptides that are specific for cancer cells and are not universally expressed in healthy tissue. These candidate antigens are then either enhanced ex vivo or incubated in specific immune cells like dendritic cells and then reintroduced into the patient. By doing so, immunogenic tumor-associated antigens are hypothesized to initiate a tumor-specific immune response that can contribute to regression of malignant cells . The plaVaccine-based therapies using EGFRvIII have generated a lot of enthusiasm as extracellular mutations of EGFRvIII are commonly expressed in glioblastoma (approximately 20%) and are responsible for constitutive EGFR pathway activation . Early pWhile vaccines against EGFRvIII and IDH1 R132H target specifically malignant cells that express the mutant protein, vaccination using heat shock protein family can leverage a broader response targeting a variety of tumor antigens in glioblastoma which could mitigate the heterogeneous nature of the tumor as a resistance mechanism. This is hypothesized to be the result of the function of heat shock protein family in post translational protein processes and presentation of antigens on MHC class I . SeveralThe rationale of using DC vaccines stems from their unique characteristics as highly potent cells that have the capacity to present antigens. The presentation of antigens by DC leads to sensitization of na\u00efve T cells and priming of an anti-tumor immune response. The potential benefit of dendritic cell vaccination in newly diagnosed and recurrent glioblastoma has been illustrated in a systematic review that included a total of 403 patients and showed improved OS in patients with glioblastoma who received DC vaccines compared to historical average survival . A randoFinally, personalized vaccines using newly detected neoantigens is another promising avenue in glioblastoma research. This personalized vaccine approach is based on the fact that neoantigens are composed of immunogenic-mutated peptides that are the product of genomic disruption in glioblastoma cells and when expressed in the TME can lead to an anti-tumor response . For exaKey challenges remain when developing therapeutic glioblastoma vaccines including heterogeneity of glioblastoma as well as the immunosuppressive environment, which constitute a major hurdle given their direct dependency on antigen-specific derived immune response. The ongoing work evaluating variable vaccines in glioblastoma treatment should offer further insight.Oncolytic viral therapy in glioblastoma involves the intratumoral administration of genetically modified viruses that usually have neural tropism and an ability to selectively replicate inside malignant infected cells. The amplified replication of lytic viruses leads to the destruction of the target cell and further propagation of viral progeny in addition to intracellular molecules, which can induce and augment anti-tumor immune response ,151. SomThe advent of molecular targeted therapy has revamped cancer treatment since their introduction in early 2000. Their efficacy relies on targeting specific molecular alterations or their protein products which govern malignant cell growth and enhance the invasive nature of the tumor. Most of the targeted therapies are tyrosine kinase inhibitors (TKIs) that can prevent kinase phosphorylation which are implicated in cancer cell proliferation and angiogenesis . ConversFrequency of EGFR amplification is estimated to reach 40%, and in-frame deletions (EGFRvIII) in approximately 25% . The altThe presence of FGFR gene fusion was investigated as a target for therapy despite its low frequency (3.5%) in glioblastoma which is exclusive to IDH1/2 wild-type tumors . In the V600E mutation in glioblastoma (up to 3%), some subtypes of glioblastoma such as epithelioid glioblastoma show high frequency reaching 50% [V600E in melanoma, several anecdotal reports described rapid and durable anti-tumor response using inhibitors of this pathways such as BRAF and MEK inhibitors [Targeting the PI3K-AKT-mTOR pathway which is universally altered in glioblastoma has also been unsuccessful and showed no improved outcomes in both newly diagnosed and recurrent glioblastoma using PI3K inhibitors and mTOR inhibitors ,171,172.hing 50% ,174. Bashibitors ,176. A shibitors . NeverthFinally, other study groups attempted targeting receptors in the TME of glioblastoma which are not necessarily expressed on tumor cells such as VEGF and integrins. The trials using the anti-VEGF (bevacizumab) later led to its approval in the treatment of glioblastoma as described earlier in the introduction. Several trials evaluated the efficacy of several integrin inhibitors but failed to show any benefit of the addition of these targeted therapies and have been summarized in detail by Le Rhun et al. .Collectively, the failure of most targeted therapy trials to date in treatment of glioblastoma has resulted in the decline in the interest of targeted molecular therapy with the exception of novel molecular targets that are under active research . SupplemDespite the increased armamentarium of effective cancer therapeutics across multiple tumor types, management of glioblastoma continues to prove the unmet need for further research to develop new effective medication, which is echoed by the high number of clinical trials that are under way . Phase 3 randomized clinical trials are crucial for evaluating the role of novel therapies in glioblastoma despite the promising results of early phase clinical trials.Addressing the immunological landscape and the crosstalk between intracranial glioblastoma and the extracranial immune components appear to be of a high priority given that most of the concentration revolves around exploiting the immune system against glioblastoma. Achieving clarity on the utility of immunotherapy (ICI) up-front in the neo-adjuvant setting is promising but requires further validation in large prospective randomized trials. In addition, several proposed approaches have been suggested to overcome the immunosuppressive TME in glioblastoma and are currently under investigation  inhibitors which induces synthetic lethality and leads to overload with defective DNA repair mechanisms appears to be promising. Preclinical studies suggest that PARP inhibition with drugs such as olaparib can increase neoantigen formation, lead to PD-L1 upregulation, boost type I Interferon signaling, and reprogram TME to facilitate anti-tumor response when using ICI . In addiUltimately, as immunotherapy continues to dominate the research arena in glioblastoma therapeutic development, it would be important to stratify patients based on their previous glucocorticoid use as most of the patients require to be on steroids which is implicated in suppression of the immune system and can counteract the effect of drugs targeting the immune system.The lack of drug approvals for the treatment of glioblastoma and the mild to modest improvement in survival in the past decade represent a growing need for well-designed research to develop effective therapeutics. The ongoing effort should consider the factors that are implicated in the resistance observed with these novel investigational therapeutics to further leverage our understanding and optimize our treatment approach. Immunotherapy holds a promise in glioblastoma despite the immunosuppressive nature of the tumor. Combination immunotherapy with other treatment modalities, investigational novel compounds, and innovative delivery modalities such as antibody\u2013drug conjugates, convection-enhanced delivery, and nanoparticles are currently under ongoing research which will address their safety and efficacy in glioblastoma. Further characterization of patients\u2019 tumor molecular profiles can help identify subpopulations who could derive a benefit from currently available treatments."}
+{"text": "Viruses have evolved to efficiently express their genes in host cells, which makes them ideally suited as gene delivery vectors for gene and immunotherapies. Replication competent (RC) viral vectors encoding foreign or self-proteins induce strong T-cell responses that can be used for the development of effective cancer treatments. Replication-defective (RD) viral vectors encoding self-proteins are non-immunogenic when introduced in a host na\u00efve for the cognate virus. RD viral vectors can be used to develop gene replacement therapies for genetic disorders and tolerization therapies for autoimmune diseases and allergies. Degenerative/inflammatory diseases are associated with chronic inflammation and immune responses that damage the tissues involved. These diseases therefore strongly resemble autoimmune diseases. This review deals with the use of RC and RD viral vectors for unraveling the pathogenesis of immune-related diseases and their application to the development of the next generation prophylactics and therapeutics for todays\u2019 major diseases. The inflammation stops and homeostasis is restored when all necroptotic and proinflammatory cellular components including the PAMPs or DAMPs are removed by cells of the innate immune system.Our immune system ensures homeostasis by protecting us from infection, malignant cell growth and by playing an important role in wound and tissue repair. Today\u2019s major human diseases coincide with aberrant immune responses: cancer patients lack effective immune responses to malignant cells, patients with autoimmune diseases have excessive immune responses to cells of a specific tissue or organ and allergies result from having undesired and exaggerated immune responses to harmless antigens. Innate immunity, involving macrophages, dendritic cells and granulocytes, is the first line of active immunity. Cells of the innate immune system are activated by pathogen-associated molecular patterns (PAMPs) released from infected cells or damage-associated molecular patterns (DAMPs) released from malignant or wounded cells. Additionally, DAMPs are released from damaged body cells as the result of ongoing metabolic and mechanical activity. When PAMPs or DAMPs are registered by innate immunity cells, inflammasomes assemble in the cytoplasm and a local inflammatory response is initiated.2 The lymphocyte population consists of clones, in which each clone bears a different receptor that recognizes a specific MHC-bound epitope. During homeostasis, lymphocytes are in tolerance mode. Peripheral immune tolerance is actively maintained by homeostatic interactions between our body cells, innate immunity cells and lymphocytes, wherein immune responses to self and foreign antigens are actively suppressed. Lymphocytes actively migrate to inflamed areas, locally break the immune tolerance in an antigen-specific manner and start to destroy infected, malignant or damaged cells. The destroyed and thus necroptotic cells further enhance innate and adaptive immune responses and speed-up the tissue repair process.3 After removal of the necroptotic cells by innate (and adaptive) immune cells, the inflammation stops and the immune tolerance toward self-antigens is restored. In addition, the tissue is repaired by a system of replenishment with new cells under the control of tissue-resident stem cells. These stem cells divide asymmetrically upon cell damage or hormonal signals, giving rise to new stem cells that maintain the capacity to divide and form progenitor cells programmed for terminal differentiation. The progenitor cells have the capacity to divide several times before they differentiate into mature terminal tissue cells that lack the capacity to further proliferate.4 Aging of body cells, including those of the immune system, increases the risk of aberrant immune responses that may result in the development of immune-related diseases. This occurs especially in individuals that carry mutations in genes associated with immunity, e.g. in individuals that are genetically predisposed to developing immune-related diseases.6When an infection is too widespread, the malignancy grows too fast or the wound is too big, the innate immunity cells recruit and activate a second line of immunity: the adaptive immune system. The adaptive immune system consists of two different sets of lymphocytes circulating in the blood and lymphatic system. B lymphocytes (B cells) secrete antibodies and are responsible for humoral immunity, whereas T lymphocytes (T cells) are capable of directly destroying damaged, malignant or infected cells and are responsible for cellular immunity. In contrast to the innate immune system that responds to PAMPs and DAMPs, lymphocytes respond to antigenic peptides (epitopes) derived from self or foreign proteins (antigens), bound to major histocompatibility complex (MHC) molecules in the presence of co-inhibitory or co-stimulatory molecules on the cellular membranes of all body cells.7 Wound healing is a beneficial process, but chronic self-sustaining wound healing is detrimental to the affected tissue and may result in the development of an autoimmune disease. In this process the primary targets of the chronically or repeatedly stimulated T cells, e.g. the primary self-antigens (pSAgs) are driving the pathogenesis and thus disease progression. Relatively late in the disease process when the affected tissue is chronically inflamed, secondary self-antigens presented in a proinflammatory context also become targeted by activated T cells. The gradual increase in the number of targeted self-antigens is named epitope spreading.8 In contrast to pSAgs that are produced exclusively in the tissue/organ affected by the autoimmune disease, secondary self-antigens usually are produced throughout the body. Degenerative/inflammatory diseases resemble autoimmune diseases in which a tissue/organ is damaged by sustained or flaring T cell responses directed to tissue-specific pSAgs. Autoimmune diseases are caused by either rare genetically determined cellular defects  or much more frequently by environmental responses (the sporadic or idiopathic cases) in those genetically predisposed to the disease.8 The list of autoimmune diseases is rapidly growing beyond the established \u2018classic\u2019 autoimmune diseases such as diabetes mellitus type 1 (DM1), arthritis and multiple sclerosis (MS) to encompass other even more important diseases. These diseases include neurodegenerative diseases such as Alzheimer\u2019s dementia (AD) and Parkinson disease (PD), psychiatric diseases such as schizophrenia, and depression, and certain metabolic diseases such as obesity and diabetes mellitus type 2 (DM2), chronic obstructive pulmonary disease (COPD), inflammatory bowel diseases (IBD), atherosclerotic cardiovascular disease (ACD) and many more.8\u201314In the case that a repair response remains active because the immune tolerance is not restored in a timely manner, the process becomes self-sustaining and chronic.16To date, autoimmune diseases have no approved cures and for most of them symptomatic or disease masking treatments are the only therapies available. Disease-specific inhibition of the destructive immune response would be the ultimate solution for this group of diseases as it leaves the patient\u2019s immune system intact. This can be achieved by tolerization, in which the immune response to the pSAg of the disease is reversed into a pSAg-specific immune tolerance response. Restoration of the immune tolerance to the pSAgs of autoimmune diseases will stop the tissue destruction by the antigen specific T cells and halt disease progression. This has been attempted by administration of purified disease-specific pSAgs or derived peptide fragments to patients. However, naked proteins or peptides are rapidly degraded in the body. Linkage of peptides to nanoparticles to improve their stability results in a transient therapeutic effect with a narrow spectrum of activity. It remains questionable whether this therapeutic activity in mice can be repeated in clinical settings.8 In patients with an autoimmune disease it is almost impossible to identify the pSAgs of the disease, since the characteristic disease symptoms resulting from the tissue damage manifest often years after the onset of the sustained destructive immune responses. Furthermore, it is difficult if not impossible for most of the diseases to obtain samples of the chronically inflamed tissue needed to characterize the immune responses, this is especially the case for neurodegenerative diseases for which, in most cases, accurate diagnosis can only be confirmed post mortem. For these reasons, most efforts to identify the pSAg of an autoimmune disease have been dedicated to characterizing antibody responses in patients with the disease.17 These studies have revealed the presence of a plethora of auto-antibodies in the serum of patients that, with a few exceptions, bind to intracellular components including enzymes that are released in the blood after cell destruction. The extracellular enzymatic activity may result in the accumulation of modified and immunogenic protein deposits in the inflamed tissues, providing a new source of antibody antigens.18 Because the studies are performed with blood or tissue samples from patients that have had the disease for a long time, most of the identified antibody targets represent secondary self-antigens, which severely challenges our ability to uncover the pSAg of the disease.In order to develop effective antigen-specific treatments for autoimmune diseases we need to know the disease specific pSAgs. Our knowledge on the immunology of most of the newly identified autoimmune diseases is fragmented and for most autoimmune diseases only candidate pSAgs are known.20 However, intramuscular pSAg expression from expression plasmids does not result in the development of disease symptoms for most of the autoimmune diseases. To develop effective treatments for autoimmune diseases, more detailed knowledge is needed of the pathogenesis of specific diseases followed by identification of the pSAgs. These objectives can only be met by studying pathogenic processes using animal models of autoimmune diseases. Since most of the autoimmune diseases are sporadic, inducible animal disease models are preferred above wild type or monogenetic animal models.The role of humoral responses in the development of autoimmunity has remained unclear. For most if not all autoimmune diseases the pathogenesis is driven by T cell responses to pSAgs. The causal relationship between chronic T cell activation directed to the pSAg of a disease and the disease symptoms has been demonstrated in experimentally induced animal models. Studies using these inducible animal models revealed that the pSAg of an autoimmune disease is predominantly or exclusively expressed in the affected tissue and that all patients have a T cell response to it. In addition, induction of a T cell response to the pSAg in an animal by vaccination results in the development of the disease. To date, the vaccination-based autoimmune disease models rely on subcutaneous or intramuscular administration of animals with purified self-antigen or peptides derived together with a complete Freund\u2019s adjuvant (CFA). This method is expensive, labor-intensive and the life-long presence of CFA in the body of the injected animals complicates the subsequent testing of interventions to the disease in the symptomatic animals. Some autoimmune diseases can be induced in mice by intramuscular administration of an expression plasmid encoding the pSAg of the disease.21 TLR activation (before replication) usually results in the induction of B cell-mediated antibody responses to viral antigens. For this reason vaccines consisting of non-replicating adjuvated viral structural proteins are able to transiently protect vaccinated individuals from infection by the cognate virus. Vaccination with empty viral capsids or purified viral structural proteins lacking an adjuvant usually are non-immunogenic in vivo. Fully RD viral gene delivery vectors are considered to be harmless components by the immune system and are therefore non-immunogenic when injected in hosts that are na\u00efve for the cognate virus. RLR activation (after replication) is a much stronger proinflammatory signal and results in the induction of predominantly T cell responses to viral antigens. This is the reason why RC attenuated virus strains are extensively used as prophylactic vaccines to provide usually life-long protection to reinfection by the homologous wildtype virus.22Since viruses evolved to deliver and express their genetic information in host target cells, viral vectors are by far the most effective gene delivery vehicles to express self or foreign proteins in vivo see . Hosts oex vivo gene replacement therapy to treat blood-related genetic disorders and cancer .22 The genomes of AAV vectors remain as stable episomes in the nuclei of transduced target cells and AAV vectors are mainly used for in vivo gene therapies. Similar to LV vectors the first AAV-based gene therapies have now reached the market.23 The preclinical studies using animal models of genetic disorders revealed that AAV-mediated transgene expression in the muscle is associated with immunity to the transgene protein, whereas that in the liver of animals results in the induction of immune tolerance to the transgene protein.25 The tolerogenic potential of RD AAV vectors in animals na\u00efve for the cognate virus is crucial for establishing stable and long term transgene expression in the liver.26 For the best-studied autoimmune disease animal models  it has been shown that RD viral vector-mediated expression of the pSAg of the disease in the liver both protects and cures the treated animals from the autoimmune disease.27\u201329 The preclinical AAV-based gene replacement and tolerization studies in animals demonstrated that RD viral vector-mediated tolerization has an enormous potential for effectively treating patients with autoimmune diseases.30 However, nobody at that time realized that the animal species used in the AAV studies, such as mouse, rat and dog are immunologically na\u00efve for AAV, which is a primarily human virus that co-replicates with adenoviruses: the causal agents of the common cold. Almost the entire human population has been exposed to AAV and developed a strong immune memory for the viral capsid proteins.32 Numerous clinical studies using recombinant AAV vectors indeed confirmed that administration of vector particles elicits innate and adaptive immune responses against the viral and transgene-encoded proteins in the majority of treated patients. The immune responses lead to elimination of the transduced cells from the body and decreasing expression levels of the therapeutic transgenes over time, compromising re-administration of the vector.33 AAV\u2019s immunogenicity in humans, and as a result its clinical inefficacy, will remain the major challenge for the development and approval of new AAV vector-based interventions. Furthermore, the immunogenicity of AAV vectors in humans is the main reason why tolerization using an RD viral vector has not been tested in the clinic so far. Overall, in order to develop effective in vivo gene replacement therapies and to efficiently restore immune tolerance in patients with an autoimmune disease, a new non-immunogenic viral gene delivery vector is needed.Among the RD viral vector systems currently used for gene therapy, lentiviral (LV) vectors derived from the human immunodeficiency virus type 1 and adeno-associated viral (AAV) vectors derived from adeno-associated virus are the most popular. For both vectors it has been shown that they are non-immunogenic or tolerogenic in hosts that are na\u00efve to the cognate virus. LV vectors permanently modify transduced target cells by integrating their viral genomes randomly into the host genome. LV vectors are mainly used for 35 Because humans can be considered naive to SV40, it is expected that RD SV40 vectors are non-immunogenic or tolerogenic when applied in humans. The lack of immunogenicity in humans and capacity to induce immune tolerance to transgene proteins render SV40 vectors highly attractive for use in gene replacement and tolerization therapies to treat genetic disorders and autoimmune diseases.36RD simian virus 40 (SV40) vectors are an attractive alternative to AAV vectors for clinical gene therapy. SV40 is a polyomavirus that strictly replicates in its natural host, macaques, where it causes chronic asymptomatic infections. SV40 has a 5.25kb long circular double-stranded DNA genome that encodes two genes. The early gene encodes two non-structural replication-associated proteins Small T antigen (STag) and Large T antigen (LTag). The late gene codes for the structural viral proteins VP1, VP2 and VP3. RD SV40 vectors have thus far been generated by deleting the coding region of the early gene. SV40 particles enter infected cells via the caveolar-endosomal route, but in contrast to other viral vectors are able to avoid lysosomal degradation, thereby evading exposure to the host immune system.37 Such derailed or malignant cells secrete DAMPs that activate innate immunity cells. The activated innate immunity cells destroy the malignant cells, eventually with help from activated T cells that target self-antigens specific for the malignant cells, named primary tumor-associated antigens (TAAs), present on the cellular membranes of the tumor cells.38 TAAs are usually encoded by genes expressed early during embryogenesis, in differentiated tissue cells or by genes overexpressed in the tumor.39 Malignant cells that are capable of escaping from this stringent immune surveillance further proliferate and undergo genetic and epigenetic changes that result in the expression of a range of secondary tumor-associated neo-antigens (TANAs).40 Under the pressure of this immune selection, the malignancies induce strong immune tolerance responses to the TAAs and TANAs and rapidly evolve into immune-tolerated tumors. Under the same selection pressure, genetic and epigenetic changes are responsible for tumors to become resistant to cancer treatments.41 Immune-tolerated (and treatment-resistant) tumors have the capacity to expand and metastasize, eventually becoming lethal to the patient.42 In patients with autoimmune diseases or chronic virus infections the risk is increased that immune-tolerated tumors emerge in the chronically inflamed tissues/organs compared to that in healthy individuals.43 This phenomenon adds to the worldwide growing incidence of immune-related diseases over the last decades.During tissue repair, mutations occur in the genome of dividing (stem and progenitor) cells. Most of these somatic mutations are silent and do not affect cellular functionality. These mutant cells are tolerated by the immune system. However, cells with mutations in oncogenes or tumor suppressor genes that inhibit cell death or cell cycle arrest gain the capacity to divide in an uncontrolled manner.44\u201346To date many cancers are effectively treated by surgical removal combined with radio and/or chemotherapy to clear the body of all tumor cells. Chemotherapeutics act relatively non- specifically by targeting rapidly dividing cells and their systemic use is therefore associated with severe side effects. Therapeutic antibodies binding TAAs or immune tolerance promoting (co-inhibitory) molecules on the surface of tumor cells represent a remarkable breakthrough in cancer medicine. However, these immunotherapies are effective in only certain subsets of patients and many patients who initially respond eventually relapse via antigenic escape via antigenic escape.48For many rapidly metastasizing cancers, effective treatments have not become available creating a strong unmet medical need. Because of its potential safety, specificity, and long-lasting response, therapeutic cancer vaccination is an attractive method to completely clear the body of all tumor cells. Effective vaccines need to break the immune tolerance to the TAAs or TANAs. Therefore, strong PAMPs and/or DAMPs named adjuvants, co-stimulation and repeated vaccination schedules have been used to amplify the activation and expansion of tumor antigen-reactive T cells. Cancer vaccines consisting of TAA- or TANA-derived peptides supplemented with strong adjuvants or DNA/RNA molecules expressing tumor antigens have shown limited efficacy in clinical studies, just as cellular vaccines consisting of living or inactivated tumor cells, dendritic cells loaded with TAAs or microorganisms expressing TAAs. Apparently, these vaccines are not potent enough to break the immune tolerance to tumor antigens.49 However, several limitations prevent the use of most naturally occurring viruses for oncolytic virotherapy. Many of them are immunogenic and usually rapidly inactivated/removed from the body by the patients\u2019 immune system. Moreover, oncolytic viruses have a limited capacity to induce tumor-directed T cell responses. In order to generate oncolytic viral strains with superior clinical efficacy oncolytic RC viral vectors were generated that encode immune-stimulatory proteins or proteins that lure the immune response to tumors instead of the vector.50 Despite such enhancements, the induced T cell responses are generally not strong enough to break the immune tolerance to the tumor-antigens.Many viruses have a preference for infecting rapidly dividing cells. Oncolytic viruses are oncotropic nonpathogenic viral strains that preferentially kill (rapidly dividing) malignant cells. Adeno-, herpes-, reo-, retro-, picorna-, rhabdo-, paramyxo-, parvo-, poxviral strains have been extensively tested for their capacity to selectively destroy tumor cells.51 LV vector-based T cell therapies targeting self-proteins may therefore cause autoimmune diseases. This problem can be solved by using RD viral vectors that do not integrate in the genome but remain in the nuclei of transduced T cells as stable episomes. It is expected that after a number of cell divisions the tumor cells have been removed, whereas the CAR-T-expressing vector molecules will dilute-out and the development of autoimmune disease symptoms will be prevented .LV vectors expressing tumor-specific T cell receptors (TCRs) or chimeric antigen receptors (CARs) that combine the properties of T cell receptors with the specificity of antibodies are used to transduce T cells isolated from the blood of cancer patients. The transduced T cells are re-infused in the blood stream of the autologous patients, where they bind and subsequently destroy cancer cells. To date, CAR T cell therapies specific for B cell surface molecules have reached the market for the treatment of B cell leukemias and lymphomas. Although highly successful, a major disadvantage of using LV vectors for T cell therapies is that the CAR-positive T cells remain permanently in the bloodstream of treated patients, continuously removing body cells that express tumor antigens at their surface.52 These experiments clearly demonstrate that TRP-2 is a relevant melanoma TAA and the pSAg of vitiligo, implying that anti-tumor immune responses and autoimmune responses are identical processes.53 RC viral vectors encoding a tumor antigen effectively break the immune tolerance to the antigen and thereby induce tumor destruction by activated T cells, whereas those encoding a pSAg of an autoimmune disease effectively induce autoimmune disease symptoms. Vaccines based on RC and thus self-adjuvating viral vectors have been shown to be highly effective in inducing cellular immune responses in vaccinated animals.54 The best studied tumor antigen-encoding RC viral vectors for use as cancer vaccines are derived from adeno-, herpes- and poxviruses. These viruses have large double-stranded DNA genomes and their RC vector derivatives encoding tumor antigens express many viral proteins in transduced cells. As a consequence, a major part of the induced T cell responses is directed to viral proteins and not to the tumor antigens. Upon introduction in a host the vectors are rapidly inactivated by T cells and repeat vaccination will not enhance the anti-tumor antigen immune response.55 To overcome this limitation, prime-boost vaccination schemes have been used where a tumor antigen is delivered with one RC viral vector first, followed by a boost with the same tumor antigen delivered by a different viral vector or other therapeutic . Unfortunately, to date cancer vaccines involving RC adeno-, herpes- and poxviral vectors are not powerful enough to break the immune tolerance to tumor cells.56\u201358It has been reported that RC viral vectors encoding tyrosinase TRP-2, one of the melanoma TAA\u2019s is capable of breaking the immune tolerance to the TAA, thereby inducing melanoma destruction in mice. Simultaneously, the induced T cell response to TRP-2, but not those to other melanoma TAA\u2019s, induces the development of vitiligo, an autoimmune skin depigmentation disease.59 SFV- or VEEV-based Alphaviral vector particles encoding TAAs including the human papillomavirus E6,7 non-structural protein, the prostate specific membrane antigen PSMA or HER2/neu have been tested in clinical studies. These studies revealed that RC Alphaviral vector vaccines induce cellular cytotoxicity against tumor cells coinciding with longer overall survival of the treated patients.60\u201362 To further enhance the therapeutic potential of RC Alphaviral vector vaccines, prime boost vaccination schemes combining different Alphaviral vectors  encoding the same tumor antigen could be applied.RC vectors derived from RNA viruses, in particular those which lack the coding capacity for the viral structural proteins are attractive alternative cancer vaccine carriers to prevent anti-vector immunity. In this respect Alphaviruses, including Semliki Forest virus (SFV), Sindbis virus (SINV) and Venezuelan equine encephalitis virus (VEEV), meet these prerequisites. Alphaviruses have single stranded RNA genomes harboring two coding domains or cistrons. The first cistron is translated from the genomic RNA and encodes the non-structural proteins involved in viral RNA replication and transcription. The second downstream cistron is translated from a sub-genomic RNA that is transcribed from a sub-genomic promoter by the viral non-structural proteins and encodes the structural proteins. Expression plasmids have been generated that encode RC Alphaviral RNAs in which the second cistron is replaced by a gene-of-interest. Intradermal or intramuscular administration in animals with plasmid-based RC Alphaviral vectors results in the induction of strong T cell responses to the transgene proteins, while anti-vector immune responses are limited. Vaccination studies with plasmid-based Alphaviral vectors encoding TAAs have successfully demonstrated tumor regression and protection against challenges with tumor cells in animal tumor models.Besides being highly promising cancer vaccine carriers, RC Alphaviral vectors are well suited to identify pSAgs of autoimmune diseases and to develop reliable inducible animal models for this group of diseases. The coding sequences of these proteins can be inserted in RC Alphaviral vector plasmids an can be directly administered with the recombinant plasmid DNA into mice. This fast and convenient method to induce autoimmune disease symptoms in mice will lay the foundation to increase our knowledge of the pathogenesis of autoimmune diseases and will serve as the starting point for developing effective therapeutic interventions.The major diseases of our time, including cancer, autoimmune diseases and allergies are caused by aberrant immune responses to self or non-self components. With our rapidly increasing knowledge of gene therapy, vaccinology, virology and immunology we now have RC and RD viral vector tools available to effectively address immune-related diseases. These vector systems are perfectly suited to unraveling the pathogenesis of immune-related diseases and developing the next generation of prophylactics and therapeutics to combat this cluster of diseases with a high impact on our society.In the next few years further research using RC Alphaviral vectors that effectively break the immune tolerance to self-antigens of autoimmune diseases will result in the development of inducible animal models for human autoimmune diseases. Such animal models will be highly useful for studying the disease pathogenesis and testing novel prophylactics and therapeutics. Moreover, RC Alphaviral vectors expressing TAAs or TANAs have the potential to serve as effective cancer vaccines. Within five years from now it is expected that new Alphaviral vector-based cancer vaccination approaches will be tested for safety and efficacy in clinical settings. Because of their lack of immunogenicity and capacity to induce immune tolerance to transgene proteins in humans, RD SV40 vectors are well positioned to become the viral vector system of choice for developing effective gene replacement and immunotherapies to treat genetic disorders, autoimmune diseases and allergies. To date, SV40 vectors have not been tested in clinical studies. Considering the potential of this vector system a clinical study of an SV40-based therapeutic is highly desired to demonstrate the safety and efficacy of this vector system in humans.63 In order to keep the health care expenditure sustainable, we desperately need effective and preferably curative treatments for the main chronic age- and immune-related diseases including cancer and autoimmune diseases. Recent developments in gene therapy and vaccinology have opened the way to develop effective treatments for this seemingly incurable group of diseases. Powerful viral gene delivery vectors have recently become available that have the potential to generate the platforms of a whole new generation of medicines based on their high efficacy to induce or suppress immune responses against self and foreign proteins. RC Alphaviral vectors can be used to develop effective immunotherapies for cancer, whereas RD SV40 vectors can be employed in tolerization therapies for autoimmune diseases including neurodegenerative & psychiatric diseases, ACD, obesity, diabetes mellitus, arthritis, COPD and many other inflammatory diseases. As an important first step in the development of effective tolerization strategies the pSAgs of individual autoimmune indications need to be identified. Together, Alphaviral and SV40 vector platforms have the potential to develop effective interventions for immune-related disease. Interventions that will contribute significantly to the healthy aging concept and dramatically improve the life expectancy and quality of life of individual patients.It is predicted that with our aging population, health care costs will rise dramatically in the decades to come."}
+{"text": "The lung is the vital target organ of coronavirus disease 2019 (COVID-19) caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In the majority of patients the most active virus replication seems to be found in the upper respiratory tract, severe cases however suffer from SARS-like disease associated with virus replication in lung tissues. Due to the current lack of suitable anti-viral drugs the induction of protective immunity such as neutralizing antibodies in the lung is the key aim of the only alternative approach\u2014the development and application of SARS-CoV-2 vaccines. However, past experience from experimental animals, livestock, and humans showed that induction of immunity in the lung is limited following application of vaccines at peripheral sides such as skin or muscles. Based on several considerations we therefore propose here to consider the application of a Modified Vaccinia virus Ankara (MVA)-based vaccine to mucosal surfaces of the respiratory tract as a favorable approach to combat COVID-19. Like skin and intestinal tract the lung stays in close contact with the living environment and is therefore potentially exposed to air-borne pathogens including SARS-CoV-2. However, in contrast to skin and intestine that harbor large amounts of effector immune cells and lymphoid tissues, the non-inflamed lung is largely devoid of both components rendering this organ particularly vulnerable for airborne infections.Several subsets of immune cells populate the skin. Antigen-presenting Langerhans cells reside in the epidermis while dendritic cells, macrophages, and various populations of T cells occupy the dermis . LikewisLungs of healthy adults however are largely devoid of lymphoid structures and immune cells are sparsely found in the mucosal layers lining the trachea and the bronchial tree, in the alveolar space but not in the alveolar interstitium. Adaptive immune responses of the lung are primarily initiated and maintained in bronchial and mediastinal lymph nodes that drain the lung but usually not within the lung tissue . FurtherInterestingly, children and adolescents\u2014but not healthy adults\u2014frequently harbor tertiary lymphoid tissue structures within the lung . These aMVA is a highly attenuated orthopoxvirus that was growth adapted to avian cells and lost its ability to replicate in mammalian hosts. Historically, it had been safety tested in more than 100,000 persons during the smallpox eradication campaign in Germany in the 1970s. Today, MVA serves as basis for licensed vaccines against smallpox and monkeypox in Europe, Canada and the United States  . Recent During the last decade we studied extensively the ability of MVA to induce BALT and subsequent immune responses in mice. The single intranasal application of MVA in mice induced long lasting formation of BALT within 6\u20138 days. Extensive immunological characterization, including two-photon microscopy, revealed that MVA-induced BALT acts as a general priming site for T cells against antigens that reach the lower respiratory tract. Furthermore, following intranasal but not intramuscular application, MVA led to the accumulation of activated CD8 effector T cells in the lung . Due to + plasma cells per mm2 tissue section this value increased 87-fold to 34.7 IgA+ plasma cells/mm2 in MVA-treated mice (Arguably, the induction of plasma cells secreting neutralizing antibodies of the IgA isotype would be most suited to prevent air-borne lung infections. We therefore studied to what degree intranasal application of MVA led to induction of IgA plasma cells in the lung. To that end mice received a single dose of MVA or were left untreated. Twelve days later lungs were analyzed by histology for the presence of BALT as well as plasma cells. While untreated mice carried on average 0.4 IgAted mice . AlthougThese findings are in agreement with observations of others identifying ovalbumin-specific IgA antibodies in the bronchoalveolar lavage fluid in mice intranasally immunized with MVA expressing ovalbumin . Others The profound production of lymphoid tissue that acts as a priming side for immune responses in the lung including induction of T cells as well as IgA-secreting plasma cells renders the local application of MVA encoding the SARS-CoV-2 spike protein a promising approach for preclinical and clinical studies aiming at the prevention of COVID-19.All datasets generated for this study are included in the article/supplementary material.This animal study was reviewed and approved by Nieders\u00e4chsisches Landesamt f\u00fcr Verbraucherschutz und Lebensmittelsicherheit, LAVES.HF conducted the research. RF conceived the study and analyzed the data. RF and GS wrote the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "COVID-19 is a new disease of pandemic proportions. Since the announcement of the first confirmed case of COVID-19 in Cameroon early this year, there has been an increasing number of circulating videos and messages from families about the poor management of their loved ones in clinical care settings. This correspondence highlights the challenges posed by COVID-19 and its impact on clinical care of patients in Cameroon. Since the announcement of the first confirmed case of COVID-19 in Cameroon early this year, there has been an increasing number of circulating videos and messages from families about the poor management of their loved ones in clinical care settings around the country. This has brought about untold suffering to both patients and their families. Patients leave their homes for the hospital generally under very uncomfortable circumstances. This can be due to an acute, sub-acute or chronic condition. When these patients approach a clinician or medical facility, they expect medical treatment and care given with all the knowledge and skill that will bring relief to their problem. The relationship takes the shape of a tacit contract based on good faith retaining the essential elements of tort . CamerooMany health facilities providing clinical care in Cameroon are challenged with insufficient availability of basic protective materials for health personnel and the human resource capacity to adequately tackle COVID-19. The lack of essential personal protective equipment such as the N95 or surgical facemasks, fluid resistant long-sleeve gowns, goggles recommended for clinicians are rarely available even in referral hospitals. The lack of specialist clinicians, technological and infrastructural resources to support health care providers during this period especially on issues of COVID-19 is challenging. Many health facilities lack the proper management systems to aid clinicians conduct proper triage and manage suspected cases effectively. This is further compounded by the lack of willingness and or potential to provide adequate trainings to aid in the process. Also, many health facilities in Cameroon are faced with serious challenges of setting up conducive pre-isolation and isolation centres making quarantine of suspected and confirmed cases respectively difficult with very poor compliance and poor outcomes for severe cases. It is generally accepted in clinical medicine that early intervention reduces complications and cost. Suspected COVID-19 cases should be validated by a laboratory test. Currently in Cameroon the nucleic acid amplification test (NAAT): the real time-polymerase chain reaction (RT-PCR) test is being used alongside the recent introduction of the rapid diagnostic test (RDT). Despite the accuracy/specificity of the former, it is quite labour-intensive requiring experts with a long turnaround time from sample collection to test result availability at the point of care . RT-PCR Clinicians and patients suffer the consequences of the aforementioned challenges. While clinicians are obligatorily expected to constantly be protected from becoming infected , there is increasing fear amongst them of contracting COVID-19 in clinical settings. Clinicians are afraid of being exposed for long periods in taking histories and examining patients who present with symptoms suggestive of COVID-19 and following these suspects in pre-isolation units because of the lack of the necessary personal protective equipment for themselves. The long diagnostic delays of COVID-19 infection equally heighten these fears among clinicians providing care during this period. The consequences of the present situation also affect the majority of patients using clinical facilities during this period in one way or the other. With a growing paranoid attitude among clinicians, patients presenting with episodes of cough and/or fever are easily over suspected as having Covid- 19 without a proper clinical examination. Patients are not well interrogated and examined before a diagnosis is suspected or made given the non-specific aspect of the clinical features of COVID-19. As such patients presenting with other well-known common pulmonary diseases  are not diagnosed correctly. Development of complications and even fatal outcomes for non COVID-19 cases is on the rise. Over diagnosis of Coivid-19 suspects also leads to some problems. Many are kept for long periods in the pre-isolation unit while awaiting results of the diagnostic tests; a situation which can lead to profound psychological stress for these suspects. Mixing of potentially real COVID-19 cases and non-cases in these units which are generally poorly constructed and overcrowded  for prolonged periods can also lead to the spread of the disease to non Covid- 19 cases. Delays in establishing COVID-19 diagnosis also slow down interventions to trace potential contacts for isolation and quarantine measures; this can lead to the further spread of the disease. The management of such cases is often sub optimal until a confirmatory test result is available. Some of these conditions in combination with or without other existing co-morbidities may deteriorate very rapidly leading to respiratory failure with possible fatal outcomes. In the area of clinical case management of those with severe COVID-19 disease, a majority of the health facilities lack intensive care units (ICUs) and those that have, do not have adequate equipment and materials to cater for those who present with severe respiratory distress. Last but not the least, rehabilitation professionals are not mobilized to address the rehabilitation needs of the survivors of this disease. This may result in an increase in disabilities among the survivors of the disease.It is a well acknowledged fact that providing adequate health care globally during this period of the COVID-19 pandemic especially in developing countries is daunting. Several interrelated factors make it even more complex for the health personnel to arrive at an informed decision timely for optimal care of patients with or without COVID-19. Despite these challenges, clinicians are obliged to provide the best available care without compromise to all patients. It is imperative to acknowledge these challenges and consequences so as to develop strategies to improve on care in clinical settings during this period."}
+{"text": "Viral dissemination is a key mechanism responsible for persistence and disease following human cytomegalovirus (HCMV) infection. Monocytes play a pivotal role in viral dissemination to organ tissue during primary infection and following reactivation from latency. For example, during primary infection, infected monocytes migrate into tissues and differentiate into macrophages, which then become a source of viral replication. In addition, because differentiated macrophages can survive for months to years, they provide a potential persistent infection source in various organ systems. We broadly note that there are three phases to infection and differentiation of HCMV-infected monocytes: (1) Virus enters and traffics to the nucleus through a virus receptor ligand engagement event that activates a unique signalsome that initiates the monocyte-to-macrophage differentiation process. (2) Following initial infection, HCMV undergoes a \u201cquiescence-like state\u201d in monocytes lasting for several weeks and promotes monocyte differentiation into macrophages. While, the initial event is triggered by the receptor-ligand engagement, the long-term cellular activation is maintained by chronic viral-mediated signaling events. (3) Once HCMV infected monocytes differentiate into macrophages, the expression of immediate early viral (IE) genes is detectable, followed by viral replication and long term infectious viral particles release. Herein, we review the detailed mechanisms of each phase during infection and differentiation into macrophages and discuss the biological significance of the differentiation of monocytes in the pathogenesis of HCMV. HCMV is a global infectious pathogen with 56\u201394% seroprevalence in adults worldwide , the virus establishes a latent infection K and other signaling pathways  independent manner  such as Toll-like receptors (TLRs) or the various intracellular biosensors such as Retinoic Acid Inducible Gene I (RIG-I), cyclic GMP-AMP synthase (cGAS), and Stimulator of Interferon Gene (STING) - like molecule, that is homologous to CD229, the signaling lymphocyte-activation molecule (SLAM) which is involved in leukocyte activation (MacManiman et al., in vitro primary infected monocytes expressed CD68 and HLA-DR (Smith et al., The replication of HCMV in primary infected myeloid cells is closely related to their differentiation status (Chan et al., in vivo, we need to define how HCMV controls specific points of differentiation using ex vivo or equivalent systems in order to better define mechanism involved and what the ideal virally infected long-term macrophage really \u201clooks like.\u201d Even though these questions are difficult to answer, these results would provide a new point for discussion of HCMV pathogenesis during primary infection and reactivation and the information would help promote the development of new drug targets that could be used to alleviate disease in immunocompromised patients.A distinct combination of viral and cellular mechanisms orchestrates the differentiation of HCMV-infected myeloid cells. This differentiation of monocytes into tissue macrophages is a required step both in primary infection and in reactivating virus in monocytes. Since previous studies elucidated some of the responsible factors for the differentiation using advanced techniques and diverse models, we now need to focus on the specific factors driving the molecular and biological processes with an attention toward identifying the steps that could be blocked to mitigate disease. We also need to better characterize the differentiated macrophage in order to understand how HCMV manipulates the immune system of the host. Since monocytes differentiate into a diverse array of macrophages via various environmental factors All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "N-methyl-D-aspartate receptors (NMDAR) play a key role in brain development and function, including contributing to the pathogenesis of many neurological disorders. Immunization against the GluN1 subunit of the NMDAR and the production of GluN1 antibodies is associated with neuroprotective and seizure-protective effects in rodent models of stroke and epilepsy, respectively. Whilst these data suggest the potential for the development of GluN1 antibody therapy, paradoxically GluN1 autoantibodies in humans are associated with the pathogenesis of the autoimmune disease anti-NMDA receptor encephalitis. This review discusses possible reasons for the differential effects of GluN1 antibodies on NMDAR physiology that could contribute to these phenotypes. Antibody-based immunotherapies form a key component of the pharmacological arsenal for treatment of cancer , and infThe potential of antibodies to modulate the function of other molecular targets in the central nervous system (CNS) for therapeutic benefit has not been extensively investigated. In this review, I will provide an overview of our studies and those of others exploring the possibility of an immunoprotective approach for neurological diseases including stroke and epilepsy involving antibody-mediated targeting of the N-methyl-D-aspartate (NMDAR) subclass of glutamate receptor.The NMDAR plays a pivotal role in brain development, neuronal survival, and synaptic plasticity associated with learning and memory. The receptor is a hetero-tetramer composed of two obligatory GluN1 subunits of which there are eight distinct splice variants, and two variable subunits from the GluN2 (GluN2A-2D) or GluN3 (GluN3A-3B) subunit families. The combination of GluN1 with different GluN2/3 family members provides for the creation of diverse NMDAR subtypes varying in their regional distribution and functional properties. The majority of native NMDAR are triheteromeric, with GluN1/GluN2A/GluN2B receptors being the most common subtype in forebrain excitatory neurons .The subunits are transmembrane-spanning and arranged to form an ion channel pore that is gated in a ligand- and voltage-dependent manner. The extracellular regions of the receptor resembling two clamshell structures with binding sites for glutamate on the GluN2 subunit and sites for glycine binding on the GluN1 subunit. The interaction between the distal amino terminal domain (ATD) of the receptor and other proteins regulate subtype-specific receptor assembly and receptor trafficking and sites for allosteric modulation of NMDAR function are also found in the ATD. The cytoplasmic C-terminus domain engages in interactions with scaffold proteins and intracellular messenger systems in the postsynaptic density.The importance of NMDAR in the maintenance of physiological brain function is underpinned by observations that NMDAR-mediated hypofunction caused by either receptor loss, or altered distribution at synapses, is implicated in neurodevelopmental (autism spectrum disorders)  and neurWe previously described an immunotherapeutic approach for stroke and epilepsy involving targeted vaccination against the GluN1 subunit of the NMDAR . Rats geOur studies suggest that a GluN1 immunotherapy could have broad utility for a range of neurodegenerative disorders but further mechanistic characterization is required to assess the feasibility and safety of such an approach. This is of critical importance as within the last decade, NMDAR autoantibodies targeting the GluN1 subunit have been linked to the pathogenesis of the autoimmune disease NMDAR encephalitis.Anti-NMDAR encephalitis is a devastating autoimmune condition characterized by the onset of psychiatric manifestations including psychosis, rapid memory loss and seizures and the presence of high-titer CSF autoantibodies of the IgG class against the GluN1 subunit \u201321. The Whilst the role of GluN1 autoantibodies in disease pathogenesis has been the key focus, more recently a mouse model of NMDAR encephalitis involving active immunization with intact native-like NMDAR GluN1/GluN2B tetramers embedded in a liposome scaffold has been described that recapitulates a broader range of features reminiscent of that found in the human disease . ImmunizThe pathogenic effects induced by patient antibodies contrast sharply to the protective benefit achieved in our studies in rodent models. Single amino acid substitutions at key residues within the extracellular regions of the GluN1 subunit can significantly affect channel permeability , so it iIn contrast, NMDAR patient autoantibodies recognize conformational epitopes at the GluN-ATD . ScreeniConversely, neuroprotection in mouse models of stroke and experimental autoimmune encephalitis can be produced using GluN1 antibodies that target the interaction site of the serine protease tissue plasminogen activator (tPA) at the ATD \u201337. GluNAltogether, these data suggest that NMDA receptor location, and function, can be differentially modulated by GluN1 antibodies in a target-dependent manner with GluN1 immunotherapeutic benefit made feasible through strategic targeting to defined sites. What are the challenges for applying such an approach, for example, as a preventative treatment against stroke-induced damage in humans?In preclinical studies, GluN1 antibodies generated following immunization of na\u00efve animals are presumed to be able to freely interact with their target site following passage into the brain. How the therapies would perform in humans with preexisting serum antibodies directed against the NMDAR that could directly compete for the same epitope targets (if present in sufficient quantities), is unknown. Serum GluN1 autoantibodies are found in healthy older adults and there is increased seroprevalence (>20%) in individuals affected by a wide-range of diseases including stroke, neuropsychiatric illnesses, and dementia \u201345, withGluN1 autoantibodies in stroke have been associated with larger  as well There are many outstanding questions. Whether a GluN1 immunotherapy could counteract or override any possible pathogenic effects produced by GluN1 autoantibodies or help boost the neuroprotective capability of endogenous antibodies at multiple levels including modulating NMDAR signaling at neurons, maintaining BBB health, and function remains to be determined.Another key challenge is whether sufficient amounts of antibody as one of the key drawbacks of immunotherapies for CNS disorders is the low efficiency of delivery into the brain. The BBB strictly regulates the entry of molecules including therapeutics, immune cells, and immune mediators from the systemic circulation into and out of the brain. Osmotic or chemical disruption of BBB integrity can facilitate delivery of therapeutics into the brain but the lack of specificity for the therapeutic biologic agent is problematic. Alternative methodologies have exploited the properties of endogenous BBB receptor-mediated transporters responsible for the passage of endogenous large molecules such as insulin, transferrin, insulin-like growth factor, and leptin into the brain. These circulating proteins bind to their cognate receptors on the luminal surface of the endothelial cells lining the BBB. Upon binding, the receptor\u2013ligand complex is internalized into the endothelial cell by receptor-mediated endocytosis where the ligand molecule is transported across the abluminal membrane of the endothelial cell into the brain. Molecular Trojan horses that are engineered to carry peptides or proteins ligands that target receptor mediated transport systems  or monoclonal antibodies that specifically target transferrin and insulin receptors have been shown to be effective in facilitating delivery of various therapeutic proteins into the brain , 51. ProDY wrote the paper and conceived this work.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Research on traditional cardiac telemetry demonstrates that excessive alarms are related to lead failures and noise-related interruptions. Patch-based continuous cardiac rhythm monitoring (CCRM) has emerged in outpatient ambulatory monitoring situations as a means to improve recording fidelity. In this study, patients hospitalized but not in the intensive care unit were simultaneously monitored via telemetry in parallel with the use of the Vital Signs Patch\u2122 (VSP) CCRM system , applying standardized monitoring and notifications provided by an off-site central monitoring unit (CMU). Among 11 patients , there were 42 CMU detections and 98 VSP detections. The VSP device was successfully applied by nursing with connectivity established in all 11 patients (100%). There were no VSP device\u2013related adverse events or skin eruptions during the study. The CMU agreed with 59 (60%) of 98 VSP detections. Among those detections marked by disagreement 30 (77%) of 39 VSP detections were related to clinically meaningful arrhythmias  undetected by VSP due to noise. In two patients (18%), there were four clinically meaningful atrial fibrillation detections not recorded by the CMU. In conclusion, patch-based CCRM requires further development and review to replace traditional cardiac telemetry monitoring but could evolve into an appropriate method to detect clinically meaningful events missed by traditional methods if noise issues can be mitigated. The fidelity of electrode connections has been identified as a major contributor to telemetry disruptions in previous studies.5 Patch-based continuous cardiac rhythm monitoring (CCRM) has emerged in the outpatient setting as a useful clinical tool for the quantification and surveillance of bradyarrhythmias and tachyarrhythmias.7 These patch-based CCRM devices have been studied in the outpatient setting as an alternative to traditional Holter monitoring and have emerged as feasible and patient-friendly options for the detection of clinically meaningful arrhythmias.9 The present study sought to evaluate the feasibility and usability of the Vital Signs Patch\u2122 (VSP) CCRM system  in non-ICU\u2013hospitalized patients against the outcomes achieved with the current standard of conventional telemetry monitoring. The primary goal of this research was to elucidate early feasibility and usability characteristics of the aforementioned VSP device (including any skin-related adverse events) and to investigate its capacity to detect clinically meaningful arrhythmias while potentially decreasing the number of alarms due to telemetry interruptions by way of its novel skin fixation mechanism.Several hospital-based studies to date have demonstrated that routine electrocardiographic telemetry monitoring results in a high volume of alarms without immediate clinical relevance.4 The CMU is referred to as \u201csecondary\u201d monitoring because it does not replace \u201cprimary\u201d monitoring alarms in the form of audible alerts occurring at the nursing station, but rather aims to ensure that clinically important alarms are not missed by bedside nursing personnel. Pediatric patients, pregnant individuals, patients with internal or external defibrillators, patients with extensive skin damage or fresh surgical incisions on the chest, and patients in critical care areas were excluded from participation in this study. The present investigation followed the relevant institutional review board policies, and written informed consent was obtained from all patients. The initial single-center study plan called for a minimum of 10 patients receiving telemetry monitoring for the early feasibility and usability assessment, followed by a larger enrollment of 25 patients; however, this latter initiative was discontinued when the manufacturer discontinued the product as a result of evolving business considerations.Between August 2015 and December 2015, 11 non-ICU\u2013hospitalized patients underwent CCRM simultaneously with use of the VSP device and traditional telemetry systems in parallel, applying standardized monitoring criteria and notifications provided by a monitoring technician located at an off-site CMU to bedside nursing personnel using a previously published protocol.. The data from the VSP CCRM system were stored on the manufacturer\u2019s secure server on the premises of the Cleveland Clinic and under its firewall in compliance with institutional data security policies. After the end of the study, the raw data underwent technical review for report generation and were made available to the investigators for review. The report included the specifics of arrhythmia detection and raw ECG waveforms for every instance of detection by the VSP CCRM system. The investigators compared data from the CMU flow sheet, which contained the specifics of conventional telemetry detections and included raw ECG waveforms of every detection.The VSP device considered in this study was a United States Food and Drug Administration\u2013approved multichannel [three-lead electrocardiogram (ECG)] patch-based CCRM system. It is also designed to monitor and record blood saturation, body temperature, respiration, and blood pressure, but these parameters were not assessed in the present research 4 Each triggered event was either assigned a rhythm interpretation or designated as uninterpretable in the event of unacceptable noise or as a loss of ECG signal. A board-certified cardiac electrophysiologist was then provided blinded rhythm strips for final approval. Adjudicated interpretations of the VSP data and CMU interpretations were subsequently evaluated for agreement.The data from the VSP CCRM and the CMU using traditional telemetry were first aligned according to their timestamps and comparisons triggered by events detected on either platform were performed. For each triggered event, the rhythm strip was reviewed on both the triggered platform and the corresponding platform at the precise timestamp. The real-time CMU interpretation assigned by a monitoring technician utilized for clinical care was captured in the electronic medical record. An unblinded internal medicine resident physician acting as an investigator provided initial rhythm interpretation reads of the VSP detections as well as over-reads of the CMU detections, applying institutional standards.Table 1 shows the baseline clinical characteristics of the study cohort. The VSP device was successfully applied by nursing staff, with connectivity established in all 11 patients (100%). There were no VSP-related adverse events or skin eruptions that occurred during the period of the study. There were 42 triggered CMU detections and 98 triggered VSP detections . In all 42 CMU detections, the real-time interpretation assigned by the monitoring technician agreed with the over-read interpretation assigned by the resident physician investigator as well as the blinded electrophysiologist over-read.Eleven patients were monitored simultaneously via the VSP CCRM system and conventional cardiac telemetry monitoring using notifications provided by the CMU. . The overwhelming majority of those disagreements were related to VSP noise artifacts, while the on-site telemetry was recording interpretable waveform data  . Accordingly, the telemetry captured normal sinus rhythm (13%), atrial arrhythmia (23%), ventricular arrhythmia (18%), and sinus bradycardia (36%) during VSP noise . Significantly, none of the above telemetry detections resulted in a CMU detection and notification. The CMU essentially learned to ignore baseline rhythm abnormalities with the help of feedback from the nursing staff. However, in 10% (four detections) of the discordance, the VSP recorded atrial arrhythmias that were not also detected by the CMU due to lead failure at the time of arrhythmia detection.Out of the 98 VSP detections, agreements were established between the VSP and the CMU in 59 (60%) of the detections. The CMU did not agree with 39 (40%) of the VSP detections . Most of the instances of discordance  were related to the availability of interpretable CMU waveform data during VSP noise . The CMU detected ventricular arrhythmia , sinus bradycardia , and pause  during VSP noise. The one remaining instance of CMU\u2013VSP discordance (8%) was related with a VSP recording of sinus rhythm during a loss of signal in the CMU as a result of lead failure.Out of the 42 CMU detections, there was discordance between the VSP and the CMU in the case of 13 (31%) 3 Furthermore, we determined that most of the discordance (90% of VSP discordance and 92% of CMU discordance) occurred because of VSP noise resulting in the loss of raw ECG data. Unfortunately, our study hypothesis was that the use of a patch-based skin fixation mechanism for ECG recording would improve the fidelity of waveform recording, not worsen it. However, the status quo of traditional telemetry monitoring again demonstrated a potential for improvement. In 10% of the VSP-triggered discordance, VSP-recorded atrial arrhythmias were missed by the CMU because of lead failure. Furthermore, in 8% of the CMU-triggered discordance, the VSP recorded normal sinus rhythm during lead failure. Thus, these preliminary findings suggest that a better patch monitor could potentially detect arrhythmia events missed by the status quo and also have recorded interpretable ECG data during the interruption of traditional telemetry detection.In this study, we sought to prospectively examine the feasibility and usability of the VSP CCRM system in non-ICU telemetry\u2013monitored hospitalized patients, which is a group largely composed of patients with established heart rhythm disturbances who had just undergone an ablation procedure or who were electively admitted for monitored initiation of antiarrhythmic drug therapy to assess safety and efficacy. At a high level, the use of a novel patch-based monitor was successfully applied by nursing in all cases with relatively easy adaptation into their workflow and without any patch-related adverse events such as skin eruptions. Such is encouraging for the potential of patch-based hospital monitoring given widespread adoption in outpatient ambulatory ECG monitoring. However, the number of VSP detections (n = 98) was more than twice the number of CMU detections (n = 42), which is relevant in the era of heightened patient safety concerns regarding alarm fatigue.8 comparing a 14-day monitoring protocol with the Zio patch  and conventional 24-hour Holter monitoring in the outpatient setting, the former detected 57% more clinically significant events but was found to be less sensitive in the detection of events during the first 24 hours of dual monitoring, when the multilead Holter connections were still very robust. In our study, the number of VSP detections was higher than the number of CMU detections because the VSP detected baseline rhythm abnormalities that were not generally clinically meaningful. Meanwhile, the CMU employed reprogrammed patient-specific alarm thresholds as determined by the nursing staff to mitigate the number of unactionable alarms, which is a routine care protocol in our institution. For example, one of the study patients experienced an elevated burden of premature ventricular contractions (PVCs) at baseline that did not require clinical action. Communication between the nursing and the CMU had resulted in a higher patient-specific threshold of 20 PVCs/minute or more for the alarm, which resulted in a marked alarm reduction for the CMU as compared with the VSP system for that patient, which used its nominal settings. It should be noted that this reflects the standard workflow of the CMU and could perhaps be judged to be unfair to the VSP given the locked-in nature of its nominal settings. A similar patient-specific alarm parameter detection method could be applied to future-state patch monitors in the instance of live patient monitoring. Thus, this barrier could be easily overcome.To our knowledge, this is the first study to evaluate patch-based monitors in the inpatient setting. In a study by Barrett et al.Our study has several limitations that are important to bring up. The first limitation was the feasibility sample size. This study could be completed only in 11 patients instead of the proposed 25 patients because the VSP device was withdrawn from the market by the manufacturer. The second limitation is that the study was conducted in a single center, which limits the generalizability of its findings.The principal aim of assessing the early feasibility and usability of patch-based monitoring for non-ICU patients receiving telemetry monitoring was achieved, but the overall results were quite disappointing. The authors continue to see opportunities to challenge the gold standard of conventional cardiac telemetry monitoring. However, it is abundantly clear that patch-based CCRM requires further development and refinement to replace traditional cardiac telemetry monitoring, with a focus on better fidelity of ECG recording. Still, the technology could one day evolve to detect clinically meaningful events missed by traditional methods if noise issues are mitigated. With the ongoing novel advances in both the areas of hardware and software in wireless cardiac monitoring technology, we believe that an opportunity to improve the existing telemetry infrastructure exists. An ideal patch monitor should have a high degree of recording fidelity, allow for real-time analysis of ECG waveforms, and be patient- and nursing-friendly. As patch monitoring\u2013based technology continues to evolve, more large-scale trials are required to validate device safety, efficacy, and cost-effectiveness in relation to conventional monitoring."}
+{"text": "The Geriatric Anxiety Inventory (GAI) is a widely used self-report measure of anxiety symptoms in older adults. Although much research has been conducted on the psychometric properties of the GAI, previous reviews have examined only a small proportion of studies and have not evaluated the methodological quality of this work. In view of this, we conducted a systematic review of the psychometric properties of the GAI and it\u2019s short form (GAI-SF). Relevant studies (N = 31) were retrieved through a search of electronic databases  and a hand search. The methodological quality of the included studies was assessed by two independent reviewers using the \u2018\u2018COnsensus-based Standards for the selection of health status Measurement INstruments\u2019\u2019 (COSMIN) checklist. Based on the COSMIN checklist, internal consistency and test reliability were mostly rated as poorly assessed  and quality of studies examining structural validity was mostly fair (60% of studies). Both the GAI and GAI-SF showed adequate internal consistency and test-retest reliability. Convergent validity indices were highest with measures of generalized anxiety and lowest with instruments that include somatic symptoms. Substantial overlap with measures of depression was reported. While there is no consensus on the factorial structure of the GAI, the short version was found to be unidimensional. Our review therefore suggests that the GAI and GAI-SF have satisfactory psychometric properties while indicating that future efforts should aim to achieve a higher degree of methodological quality."}
+{"text": "Drug delivery systems have shown tremendous promise to improve the diagnostic and therapeutic effects of drugs due to their special property. Targeting tissue damage, tumors, or drugs with limited toxicity at the site of infection is the goal of successful pharmaceuticals. Targeted drug delivery has become significantly important in enhancing the pharmaceutical effects of drugs and reducing their side effects of therapeutics in the treatment of various disease conditions. Unfortunately, clinical translation of these targeted drug delivery system mechanisms faces many challenges. At present, only a few targeted drug delivery systems can achieve high targeting efficiency after intravenous injection, even though numerous surface markers and targeting approaches have been developed. Thus, cell-mediated drug-delivery targeting systems have received considerable attention for their enhanced therapeutic specificity and efficacy in the treatment of the disease. This review highlights the recent advances in the design of the different types of cells that have been explored for cell-mediated drug delivery and targeting mechanisms. A better understanding of cell biology orientation and a new generation of delivery strategies that utilize these endogenous approaches are expected to provide better solutions for specific site delivery and further facilitate clinical translation. About 2 million new RBCs are continuously produced per second in the human body  directly and indirectly, the therapeutic agents can be attached to the RBCs surface  bearing mice  are slightly altered compared to encapsulation by red blood cells  is generally shorter than the lifespan of RBCs, their special functions make them attractive as drug delivery vehicles because leukocytes are involved in various immune responses, cellular interactions, and cell adhesion  that contain distinctive cytoplasmic granules, are the most abundant immune cell population in the human peripheral blood and are generated from the bone marrow  Neutrophils are the first cell type to arrive at the sites of infection or inflammation, producing cytokines to recruit other cells, and are cleared after a few days  on the surface of T-cells   reliable and reproducible, (ii) purified target cells are simpler, (iii) the selectivity and specificity of ligand-receptor attachment can be exploited by active nanoparticle targeting strategies, and (iv) in the case of specific ligand-receptors can be converted into The current CD44-hyaluronic acid interaction has been used in a variety of cell types, mainly to mediate the attachment of cell backpacks to various leukocyte surfaces  through specific antibody\u2013antigen recognition on the cell membrane interface  on the cell surface, the cell vaccine can be quickly distributed to the liver and spleen since it does not require additional pretreatment to achieve opsinization  ester group is used as the cross-linking agent to modify the primary amine by carbodiimide reaction. Current research uses methods to modify particles and cells to provide covalent bonds, which are stronger than adsorption or ligand-induced binding.The sulfhydryl group in the cysteine-containing membrane protein can be coupled through maleimide-sulfhydryl conjugation. The maleimide group can be covalently conjugated to the surface of thiol-rich T cells by reacting to the maleimide group on the liposome. Using this strategy, each cell can bind up to 100 nanoparticles without causing toxicity or affecting cell function , it has been a major challenge in recent years. CTC can automatically leave the primary tumor and sow metastases in the distance. More interestingly, studies have shown that tumor cells interact with leukocytes and endothelial cells through adhesion molecules, which provides a platform for targeting CTCs through leukocytes. Inspired by the rolling of selectin-dependent blood vessels, the study describes a method for targeting leukocytes in blood by directly targeting the apoptosis-inducing ligand TRAIL and the adhesion receptor E-selectin in the blood under shear flow, thereby effectively killing tumors  surface painted RBCs could be in one step converted into targeted entities that efficiently and specifically bind to CD45 positive leukocytes and CD19+/CD20+/CD45+ human lymphoma cells Another method is to use an external magnetic field to enhance the accumulation of cellular carriers in the target. Tumor targeting with magnetic carriers induced by an applied external magnetic field (MF) relies on physical forces to enhance tumor accumulation of therapeutic agents. Magnetic nanomaterials can enable remote control of the location of drug vehicles including circulating cells by an external magnetic field and therefore could be applicable to a wide range of solid tumors.in\u00a0vivo and ex vivo imaging data evidenced the highly efficient MF-induced tumor homing of those RBCs, further reducing the RES aggregation , obtaining a DOX@RBC-IONP-Ce6-PEG structure with a long blood-circulation time and strong responses to an external MF. Both The combination of molecular binding and cell-mediated drug delivery is a new and emerging field. The techniques in cellular engineering and biomaterial modifications offer significant opportunities for targeted drug and nanoparticle delivery.5.There are many potential biomedical applications of cell-based drug delivery systems that open up new perspectives on the possibility of using our cells for therapeutic purposes. Compared with traditional targeted drug delivery and nano-drug strategies, cell-mediated drug delivery must consider additional factors. Drugs/particles must not be toxic to the cell carrier and should prevent cell changes after the drug is loaded  and the release of pathological mediators including cytokines, ROS, etc., it may cause inflammation or aggravate inflammation.Although cell-mediated drug delivery systems have made great progress in improving diagnostic and therapeutic effects, there are still many challenges to the safety of clinical practice. First, the main challenge in the process of isolating cells Whatever these challenges, cell-mediated drug delivery has enormous potential to revolutionize current diagnostics and medical techniques. Advances in biomaterials may open up the new doors for DDS design. Combining living circulating cells and nanotechnology will become a new direction for controlling drug delivery while providing a powerful technology that can improve overall diagnosis and therapeutic outcomes. Thus, under a variety of pathophysiological conditions, studies of endogenous targeting are gaining momentum. Through the innovation of new technologies, the goal of improving and controlling drug delivery is achieved."}
+{"text": "Congenital Cytomegalovirus (cCMV) is a serious global public health issue that can cause irreversible fetal and neonatal congenital defects in symptomatic or asymptomatic newborns at birth. In absence of universal cCMV screening, the retrospective diagnosis of cCMV infection in children is only possible by examining Dried Blood Spot (DBS) samples routinely collected at birth and stored for different time spans depending on the newborn screening regulations in force in different countries. In this article, we summarize the arguments in favor of long-term DBS sample storage for detecting cCMV infection.CMV infection is the most common cause of congenital infection resulting in severe defects and anomalies that can be apparent at birth or develop in early childhood. Sensorineural hearing loss is the most frequent consequence of cCMV infection and may have a late onset and progress in the first years of life. The virological diagnosis of cCMV is essential for clinical research and public health practices. In fact, in order to assess the natural history of CMV infection and distinguish between congenital or acquired infection, children should be diagnosed early by analyzing biological samples collected in the first weeks of life , which, unfortunately, are not always available for asymptomatic or mildly symptomatic children. It now seems possible to overcome this problem since the CMV-DNA present in the blood of congenitally infected newborns can be easily retrieved from the DBS samples on the Guthrie cards routinely collected and stored within 3\u00a0days from birth in the neonatal screening program for genetic and congenital diseases. Early collection and long-term storage are inexpensive methods for long-term bio-banking and are the key points of DBS testing for the detection of cCMV.DBS sampling is a reliable and inexpensive method for long-term bio-banking, which enables to diagnose known infectious diseases - including cCMV - as well as diseases not jet recognized, therefore their storage sites and long-term storage conditions and durations should be the subject of political decision-making. Dried blood spot (DBS) sampling was first introduced in the early 1960s by Dr. Robert Guthrie who used few microliters of blood obtained by pricking the heel or finger and then blotted and dried onto filter paper in order to detect phenylketonuria in newborns .The most important application of DBS testing is the retrospective diagnosis of congenital Cytomegalovirus (cCMV) infection; since CMV is the most common cause of sensorineural hearing loss (SNHL), CMV diagnosis should be recommended when children fail newborn hearing screening and should be carried out within the first weeks of life . AlthougcCMV infection is a serious global health issue affecting 0.2\u20132.2% of newborns in all populations . It caus. cCMV infection is often insidious as it is most often asymptomatic or poorly symptomatic at birth while it can result in defects that appear during infancy from birth up until six years of age, in at least 13.5% of congenitally infected children [The virological diagnosis of cCMV infection by detecting either the virus or its components is essential for clinical, research and public health purposeschildren , a percechildren . In factchildren .A solution to these issues was offered by the fact that CMV-DNA present in the blood of congenitally infected newborns can be easily identified in DBS samples, obtained from heel or finger pricks and spotted onto filter paper (Guthrie cards), which are routinely collected within 3\u00a0days from birth in most countries under the neonatal screening for genetic and congenital diseases framework .The standard DBS collection methods, transfer of blood onto the paper and the storage and transportation of DBS samples have been described in detail . In brieThe universality of early collection and long-term storage at regional screening centres represent an inexpensive method for long-term bio-banking , 12 and Prospective and retrospective studies have demonstrated that the detection of CMV via DBS sample testing by viral DNA extraction and amplification using PCR methods proved to be as sensitive (64\u2013100%) and specific (99\u2013100%) in diagnosing the congenital infection as the gold standard technique of saliva or urine PCR-testing . HoweverSensitivity to detect CMV in DBS samples compared to saliva and urine is variable across studies mainly due to the DNA extraction method including in-house protocol and commercial kit \u201318 and cIn order to prevent the onset or the progression of SNHL and other CMV-associated disabilities in both asymptomatic and symptomatic newborns and to evaluate the role of cCMV in children with severe neurological sequelae, it is essential to carry out a universal or targeted CMV screening in the framework of the neonatal hearing screening (NHS) program. In this scenario, in the past decade, an ever-increasing number of studies has demonstrated that urine and saliva  are speunpublished data). The impossibility of diagnosing cCMV due to the disposal of residual DBS specimens is frustrating.Moreover, the sensitivity of DBS for the retrospective diagnosis of cCMV has been clearly proved in children developing the related-illness in the first few years of life , 32 and DBS storage times and its\u00a0purpose\u00a0made of residual newborn screening DBS specimens depends on the newborn screening programs implemented in different countries, federal states or regions in the same country , 12. WanThe choice of short-term storage (<\u20093\u2009years) of DBS in screening centres may be due to the fact that several social and ethical issues have arisen over the potential uses of residual specimens and patient privacy. However, short-term storage can hinder the cCMV diagnosis after the first few years of life, thus making the diagnosis of CMV-related sequelae an unaddressed issue. The main issue is to find a balance between the need for privacy and the possible public health research uses and benefits. The right DBS long-term storage might be to raise public awareness and parental knowledge on the usefulness of DBS samples (like the cCMV issue), through patient education and counselling and educational programs. In this way, parents might be asked to donate the residual specimens and parents can request that a part of the donated sample is stored for future use. Moreover, collecting paired DBS specimens and giving one to the child\u2019s parents could solve the DBS sample storage issue.Concluding, we state that DBS long-life storage is essential! Since DBS samples can be a helpful and inexpensive diagnostic tools for long-term bio-banking that enable diagnosis of leading infectious diseases - including cCMV- as well as further disease not jet recognized. Long-term DBS storage and usage should be subject to political decision-making."}
+{"text": "Life expectancy has increased over previous decades, but several countries are seeing widening inequalities in disability-free life expectancy (DFLE) by socioeconomic position (SEP). In this symposium we address three unanswered questions.1. Do DFLE trends differ for SEP groups, and which of the underlying transitions  explains the differences?2. Do DFLE trends by SEP depend on when in the life-course SEP is measured ?3. How much does multi-morbidity contribute to differing trends in DFLE by SEP, since multi-morbidity is more prevalent in low SEP groups? To answer these questions, we use unique longitudinal studies of older people across different generations in two countries: the UK (Cognitive Function and Ageing Studies \u2013 CFAS I and II) and Australia . The first presentation sets the scene with findings from a systematic review of worldwide trends in life and healthy life expectancy by SEP. Presentations two and three examine the first question using DFLE at age65 by SEP defined by late-life disadvantage in CFAS (1991-2011), followed by HILDA (2001-2017). The fourth presentation investigates the effect of different life-course measures of SEP using HILDA. The final presentation from CFAS examines the third question. This symposium increases our understanding of how and why inequalities in DFLE by SEP are changing with the goal of achieving healthy ageing for all."}
+{"text": "Vaccination is an effective means to prevent infectious diseases including tick-borne encephalitis (TBE), an emerging Flavivirus infection. There is, however, only limited knowledge about risk of vaccination failure, the disease course and the challenges for work-up and care. Of note, there is evidence that patients with breakthrough disease experience a more severe disease course. We report the case of a previously healthy 49-year-old woman who developed severe myeloradiculitis caused by the TBE virus despite receiving a complete cycle of primary immunization and booster vaccinations within the recommended timeframe. The disease course was characterized by progressive tetraparesis, pain and bladder dysfunction and necessitated intensive care unit admission (ICU) and the escalation of pain management. This case raises awareness for the recognition of breakthrough disease in younger patients and reinforces the need to develop measures to identify patients with insufficient protection. Tick-borne encephalitis (TBE) is an emerging Flavivirus infection with 10,000-12,000 cases reported in Europe each year . These iVaccination is an effective measure to prevent morbidity and mortality associated with infectious diseases. This is also the case for TBE where no specific therapy is approved and treatment is supportive only . TBE is We report the case of a previously healthy 49-year-old woman who developed severe myeloradiculitis caused by the TBE virus despite receiving a complete cycle of a primary vaccination and booster vaccinations within the recommended timeframe.A 49-year-old afebrile woman sought treatment at our department due to intractable lower back pain and a mild paresis of the right leg. The symptoms had increased over the course of four days; there was no prodromal phase. Her medical history included an early localized borrelia infection nine years earlier, which was treated with a full course of third generation cephalosporins. She did not take regular medication but had received analgesics  from her general practitioner. Living in an endemic region and being at risk of disease exposure as a part-time farmer, she had been immunized for TBEV with a 3-dose standard scheme in childhood and received booster vaccinations according to the national recommendations for individuals at higher risk since then (every three years).A T2-weighted MRI of the spinal cord revealed hyperintense signals in the central and anterior plane of the cervical to the midthoracic cord . Patchy Additional serological tests were directed towards exclusion of neuromyelitis spectrum disorders (aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) antibodies), other neurotropic viruses (West-Nile Virus (WNV)) and CNS manifestations of systemic autoimmune disorders which included serological tests of autoimmune and paraneoplastic antibodies, dermatological and rheumatological consultation and additional imaging.Three days later, she developed voiding dysfunction, paresis of the left arm and paraplegia of the lower extremities. The rapid progression of motor symptoms necessitated a temporary transfer to the intensive care unit (ICU) but eventually ventilation was not required. The treatment of pain was further escalated with gabapentin, piritramide and fentanyl.There was no evidence for the aforementioned conditions as a cause of longitudinally extensive transverse myelitis (LETM) and repeat CSF examination revealed a further increase of the cell count , elevation of CSF protein (174 mg/dL) and IgG synthesis (48%). We thus extended the work-up towards TBE with the possibility of vaccination failure in mind. Serological tests were reactive for TBEV  and corroborated the diagnosis of myeloradiculitis due to the TBEV despite active immunization and regular booster vaccinations. The neurological deficits improved at the time of relocation to a specialized rehabilitation facility and she was able to manage the transfer by herself.On clinical examination two years later, a mild lower extremity paraparesis persisted whereas the function of the upper extremity, urinary dysfunction and pain had fully recovered. A brain MRI performed twice over a period of 2 years showed neither new or expanding lesions nor contrast enhancement.Vaccination failure for the TBEV has been characterized in-depth only recently. Thus, there is no consensus for the criteria for vaccine failure but the definition of \u201cA clinical case of TBE with debut of symptoms after at least two doses of vaccine. The last dose of vaccine received within (i) >4 weeks and <12 weeks if two vaccine doses, (ii) <36 months if three vaccine doses and (iii) <60 months if four or more vaccine doses\u201d could be used as guidance . Our patUsing the aforementioned criteria, a recent Swedish study evaluated a total of 1004 TBE cases and defined 53 of them (5%) as vaccine failures . These dOur finding of extensive intrathecal IgG-synthesis and detection of OCB in combination brain lesions within the white matter and in vicinity to the corpus callosum led to additional diagnostic considerations. Yet, LETM is a rarity in MS and a tractopathy is not reported in MS. Thus, autoimmune conditions as a cause of LETM and viruses leading to anterior horn tractopathy including WNV and Herpes viruses needed to be excluded ,17. A siOur patient had a monophasic course. This is a typical feature of patients with vaccination failure, as reported in 77% of patients in the Swedish cohort, which is more frequent in vaccinated patients . The autThis case illustrates a typical presentation of anterior horn involvement and radiculitis related to TBE, as well as the hazards for the diagnostic work-up and interdisciplinary management in a relatively young patient despite the appropriate vaccination. Moreover, our report reinforces the need to better understand vaccination failure in TBE and develop measures to identify patients which have insufficient protection."}
+{"text": "B\u00e1lint et al. global forebrain ischemia and later reperfusion were induced by the bilateral occlusion and later release of both common carotid arteries in young and aged Sprague-Dawley rats. Spreading depolarizations were elicited repeatedly with topical 1 M KCl. Pial vascular density was measured in green intrinsic optical signal images of the brain surface, while the density and resting diameter of the cortical penetrating vasculature was estimated with micro-computed tomography of paraformaldehyde-fixed cortical samples. Pial arteriolar dilation was found to be reduced in the old rat brain in response to spreading depolarization or ischemia induction. Spreading depolarization was recognized as a potent pathophysiological contributor to ischemic lesion expansion, in part because of the insufficiency of the associated cerebral blood flow response. The age-related impairment of cerebral vasoreactivity as shown by B\u00e1lint et al. is suggested to contribute to the age-related acceleration of ischemic lesion development.In our special issue the different aspects of cerebrovascular aging have been discussed. In the original article authored by Gresita et al. hypothesized that restoring the balance within the neurovascular unit may lead to an improved neurorestoration after focal ischemia. A novel, innovative technology was used for reprogramming of reactive glia into neuroblasts and mature neurons by a retroviral delivery system encoding the transcription factor Ngn2 alone or in combination with the antiapoptotic factor Bcl-2 to target proliferating astrocytes in the neocortex in young and aged mice after cerebral ischemia. The conversion efficacy of proliferating astrocytes into neurons after cerebral ischemia was however, disappointingly low. The authors hypothesized that therapeutic vectors carrying the conversion gene were engulfed by phagocytes shortly after intracortical administration. Gresita et al. suggested to use other viral vectors and combinations of transcription factors to improve the efficacy of glia-to-neuron conversion after stroke in young and aged rodents.After cerebral ischemia, the ratio between astroglial cells and neurons in the neurovascular unit is disrupted in the perilesional area. Miller et al. described a clinical study on the measurement of the effect of advanced age on cerebrovascular reactivity. Young and older healthy, physically active adults with low vascular risk participated in the study. Cerebrovascular reactivity was measured in response to hypercapnia using 4D flow MRI, which allows for simultaneous angiographic and quantitative blood flow measurements in the intracranial arteries . As it was shown older adults had lower global cerebrovascular reactivity and reduced reactivity was also shown individually in multiple intracranial arteries compared with young adults. In addition, the MCA dilated significantly in response to hypercapnia in young, but not older adults, which is a marker or predictor of future risk of cerebrovascular disease. These results demonstrated using 4D flow MRI, that normal aging is associated with lower cerebrovascular reactivity in healthy adults and also demonstrated that the state-of-the-art technology of 4D flow MRI may provide a promising new alternative to measure cerebrovascular physiology without the limitations of commonly used techniques.Zhao et al. three groups of aged patients were compared. The first group has a severe small vessel disease, the second has a low severity small vessel disease and the third was an aged \u2013matched healthy group. A cognitive behavioral test was performed to evaluate the possible cognitive deficit of the patients. The digital clock drawing test (dCDT) has been proved to be a more useful assessment tool for cognitive disorders compared to traditional clock drawing test DT (tCDT). Zhao et al. aimed to check whether this tool worked well in capturing some specific aspects of cognitive performance in aged patients with small-vessel disease. The dCDT and a series of neuropsychological assessments were performed to evaluate the cognitive function of participants. Severe-small vessel diseased patients showed higher air-time percentage and lower mean handwriting/drawing pressure on surface during drawing compared with low-severity and healthy subjects. The data indicated that some early manifestations of cognitive deficits in aged patients with small vessel disease could be detected using the dCDT with a brand-new perspective different from the tCDT.In another clinical study performed by Egimendia et al. described a resting state fMRI study on different groups of C57Bl6 mice of varying age between 2 and 13 months without any therapeutic or surgical intervention. Dedicated data analysis resulted in an inverse U-shape curve of functional connectivity strength in both the sensorimotor and default mode network. This inverse U-shape pattern presented a maximum of functional connectivity strength at 8\u20139 months of age, followed by a continuous decrease during later aging phases. At progressed aging at 13 months, the reduction of connectivity strength was ~50%. The authors concluded that these substantial age dependent changes in functional connectivity strength must be considered in future longitudinal studies.Resting state fMRI is increasingly used to unravel the functional neuronal networks in health and disease. In particular, this technique of simultaneously probing the whole brain has found high interest in monitoring brain wide effects of cerebral disease and in evaluating therapeutic strategies. Such studies, applied in preclinical experimental mouse models, often require long-term observations. These long periods of following the functional deficits during disease evolution as well as the functional recoveries during therapeutic interventions represent a substantial fraction of the life span of the experimental animals. Based on this observation Erdo and Krajcsi is focusing on the role of efflux transporters at the blood-brain barrier in age-related brain pathologies and also in healthy aging.During the last decade several research article reported a relationship between advanced age and changes in the integrity of the blood-brain barrier. These alterations manifested not only in the morphology and structure of the cerebral microvessels but also in the expression and functionality of the transporter proteins in the apical and basolateral surface of the capillary endothelial cells. Age-associated downregulation of the efflux pumps (ABC transporters) resulted in increased permeability and greater brain exposure to different xenobiotics enhancing the risk of drug-induced toxicity. In age-related neurodegenerative pathologies like Alzheimer's disease the amyloid beta clearance decreased due to P-glycoprotein dysfunction leading to higher brain exposure. In contrast, in stroke an enhanced P-glycoprotein function was reported in the cerebral capillaries making even more difficult to perform effective neuroprotective therapy in the infarcted brain area. The mini-review of In summary, this special issue presents a wide spectrum of original research studies from animal experiments to clinical investigations focusing on different aspects of cerebrovascular aging. Some innovative methodological and evaluation-related approaches are nicely discussed.The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The aim of this paper is to assess the extent of the potential bias introduced by the exclusion of the Medicare Advantage (MA) population\u2013 an increasingly sizeable  subset of the Medicare population which does not provide claims data to the Centers for Medicare and Medicaid Services\u2013 from Medicare-based health outcomes and epidemiologic analyses. Using self-reported data from the Health and Retirement Study together with monthly information on Medicare enrollment, we compared MA enrollees with individuals enrolled in traditional Medicare (TM) on 42 variables representing demographic, socioeconomic, adverse health behavior and health status-related characteristics over the 1991-2015 period. We used both univariate analysis (t-tests and standardized differences) and multivariate logistic regression to compare the two groups. We found that apart from differences in economic (higher in TM group) and education status (lower in MA group) \u2013 which have been increasing in magnitude over the 1991-2015 period\u2013 the MA subset was highly comparable with the traditional Medicare (TM) population. Even though the TM population was characterized by slightly higher levels of morbidity, the resulting crude prevalence rates for common age-related diseases in the TM/MA groups were within each other\u2019s 95% confidence intervals and did not represent a major source of bias. MA membership was not associated with increased mortality at any point over the 1991-2015 period. We conclude that exclusion of the MA population will not lead to notable bias in health outcome analyses apart from those for which income and education are important explanatory factors."}
+{"text": "It is recognised that surgical conservatism is the most effective way of managing the axilla in breast cancer patients undergoing primary breast conserving surgery. The extended clinical scenarios in which a less aggressive approach can be safely adopted warrant consideration\u2014including a group of patients who potentially could bypass surgical staging of the axilla altogether. The application of omission of further surgical management and axillary radiotherapy in the primary surgical and neoadjuvant chemotherapy settings are considered. Surgical axillary nodal status remains relevant for the determination of adjuvant systemic therapies in breast cancer. Modern breast cancer care is based upon multimodal management and has since evolved several diagnostic and therapeutic techniques that allow for a more nuanced approach with the aim of avoiding complete axillary node clearance (ANC) where possible. This includes genomic assessments, such as MammaPrint , OncotypFor patients presenting with primary invasive breast cancer, current practice with regards to the axilla includes a clinical and radiological assessment (most commonly ultrasound) at the time of work up . The cliANC was once a one-size-fits-all tool to enable locoregional control. The subsequent development of sentinel node biopsy (SNB) meant that the pathological status of some axillary nodes could be assessed prior to the completion of ANC. An important further step forward came from the results of the NSABP B-32  and IBCSThe landmark ACOSOG Z011  trial deRadiotherapy itself also has adverse side effects\u2014including lymphoedema\u2014and should be avoided where safely possible. In patients with early breast cancer and favourable biomarkers (using the composite IHC4+C score), the PRIMETIME  trial wiThe Z11 trial did not use axillary ultrasound to stratify patients prior to sentinel node biopsy. Since axillary ultrasound is routinely used is in clinical practice, the relevance of it on quantification of axillary burden is an important consideration.In the case of a positive pre-operative AUS, the current standard is to either proceed with ANC or to commence upon PST to downstage the axilla. The practice of \u2018fast-tracking\u2019 positive AUS patients to ANC based on the assumption that, owing to its relatively low sensitivity , a positThe current standard of practice consists of SNB being performed to confirm the node-negative status of the axilla\u2014in the clinically and radiologically negative axilla. However, despite AUS\u2019s relatively low specificity, its sensitivity is far more robust. Indeed, a pooled meta-analysis showed that among 5,139 patients with a negative axillary clinical and ultrasound examination pre-operatively, the negative predictive value of AUS was 95.1% for low nodal burden . This suTraditionally, patients undergoing mastectomy\u2014regardless of their axillary node status\u2014have been considered as a separate group in terms of the management of the axilla, owing to the omission of adjuvant radiotherapy in certain patients. Current indications for post-mastectomy radiotherapy (PMRT) include tumour size greater than 5 cm, T4 disease, 4 or more positive axillary lymph nodes and positive or close surgical margins . All of The use of neo-adjuvant chemotherapy (NACT) in breast cancer is successfully deployed in downsizing the primary tumour to permit breast conserving surgery, thus avoiding mastectomy. Long term survival outcomes in NACT versus adjuvant chemotherapy have been comparable . In termThree clinical trials have examined the false-negative rate (FNR) of SNB following NACT as previous retrospective series had demonstrated highly variable rates\u2014some so high as to nullify the utility of the procedure in this setting . ACOSOG et al [In patients with node-positive disease prior to NACT, a biopsy can be performed to confirm pathological status of the node, and a radiological clip placed in the node. This is useful as the pathological response to NACT of the clipped node is used as a surrogate for the overall nodal status of the axilla. Indeed, a further finding from the Z1071 trial was that FNR of SNB in the 203 patients with a radiologically clipped node was 6.8% when the clipped node was in the SNB specimen . So-callet al  in 191 pet al  procedurThese techniques seek to optimise the diagnostic and therapeutic value of an augmented sentinel node biopsy procedure to enable the minimum amount of surgical intervention in the axilla post-NACT. Removing the clipped node, and at least three nodes as a part of SNB is evidence-supported to provide good oncological control while avoiding ANC. If, at TAD, residual disease is found in the biopsy-proven node, then further axillary management is needed\u2014current standard of practice would be to perform completion ANC. However, those with low axillary burden are likely being overtreated with this approach. These patients require assessment in future trials of no further management \u2014in the context of breast conserving surgery post-NACT receiving whole breast radiotherapy\u2014and also axillary radiotherapy. The ongoing Alliance A11202 trial  will assThe evidence-supported direction of axillary surgical management is of decreasing intervention to the axilla. This is supported in both the primary breast surgery and systemically-treated settings. The future refinements of surgery will be based upon the selection of omission of surgical staging, enhancing the bespoke nature of targeted axillary dissection, determination of the significance of residual disease\u2014after PST\u2014and further assessing what truly represents the threshold for low axillary burden. This will herald an exciting era of reduced morbidity for patients.The authors have no disclosures to make concerning financial or personal relationships that could inappropriately influence their work.No funding was received for this study."}
+{"text": "Interstitial Lung Disease (ILD) represents one of the most severe complications of Rheumatoid Arthritis (RA). Preliminary data from the RA Greek cohort show a prevalence of 5.3%. Due to scarcity of data, little is known regarding the epidemiological and clinical features of Greek patients with RA-ILD. Moreover, use of pulmonary function tests for prognostic purposes in patients with RA-ILD is still not sufficiently studied. Interestingly, the treatment approach of patients with RA-ILD remains controversial due to high risk of infection, possible drug-related pulmonary toxicity, and scarce evidence regarding the efficacy of medications used in these patients. The aim of this research protocol is to collect data from patients with RA-ILD followed in multiple centres across Greece in order to identify the clinical and epidemiological features of these patients. The second part of the study focuses on the prospective data collection regarding the progression of ILD, the response to different treatment modalities and the incidence of adverse events attributed either to the disease itself or to its treatment in patients with RA-ILD. This study may provide useful evidence in exploring both the natural history and the risk factors contributing to the development of ILD, as well as the efficacy and the adverse events attributed to the medications used in Greek patients with RA-ILD; thus ameliorating the therapeutic approach of RA-ILD patients in daily clinical practice. ILD prevalence in RA patients from a multicentre study involving 15 European countries was reported at 4.5%,2 and preliminary data from the RA Greek cohort show a prevalence of 5.3%. Interestingly, a recent large multicentre UK study reported that in 83% of RA patients arthritis preceded the diagnosis of ILD while in the remaining 17% of patients arthritis appeared synchronously (7%) or metachronously (10%) of the ILD diagnosis.3 Importantly, mortality risk is 3 times higher in RA patients with ILD compared with RA patients without ILD while mean survival since the diagnosis of symptomatic ILD ranges from 2\u20136 years. Overall, ILD confers 13% of the increased mortality risk noted in RA patients compared to the general population.1Interstitial Lung Disease (ILD) represents one of the most severe complications of Rheumatoid Arthritis (RA). Epidemiological data from Mayo Clinic reveal that ILD development in RA patients has a hazard ratio (HR) of 8.96 which is further heightened in patients with increased age, male gender, smokers and with high disease burden .5 To our knowledge, no study so far exploring the prevalence of the different HRCT patterns in Greek RA patients has been published.Recent data highlight the crucial prognostic role of the ILD HRCT pattern. Thus, the Usual Interstitial Pneumonia (UIP) pattern is discovered with increased frequency in RA patients and is associated with significantly worse survival compared to other HRCT patterns .6 Reduction of FVC and/or DLCO levels below of 70% of predicted values is significantly associated both with ILD progression and ILD-related mortality in systemic sclerosis patients. Similar data regarding RA-ILD patients are scarce.7 Consequently, use of such PFTs parameters in the assessment and management of RA-ILD patients in clinical practice is not evidence-based.Moreover, studies in Systemic Sclerosis demonstrate that pulmonary function tests play a crucial prognostic role in assessing both the severity as well as the progression of ILD in these patients.10 Observational studies in RA-ILD patients have also established the increased risk for infections (both common and opportunistic) due to the use of immunomodulatory/immunosuppressive medications.12 Further increasing the uncertainty regarding management decisions in RAILD patients, the effectiveness of DMARDs in treating or at least halting the progression of ILD is supported by weak evidence mainly by non-randomized small sample sized studies13 or case series.15Whilst all other extra-articular manifestations of RA show decreasing frequency over the years mainly due to the use of highly-effective DMARDs, RA-ILD frequency is rising; demonstrating that its management remains highly controversial. Available DMARDs used in RA management  have been invariably associated with de novo detection or deterioration of pre-existing ILD as well as other pulmonary manifestations.16 with and without ILD who are referred and followed at the participating hospitals will be collected (both in hardcopy datasheets and electronic database). For each patient the initial dataset includes:Detailed data of RA patients (fulfilling the 2010 ACR/EULAR criteria)Demographical data ;Comorbidities ;Clinical and Laboratory data regarding RA ;Past and current medications use (relative to RA); andVaccinations.Chest HRCT will be adopted for establishing the diagnosis of ILD. Additional data regarding ILD will be collected including date of ILD diagnosis, presenting symptoms as well as the subjective respiratory functional status (as per MRC), HRCT pattern of ILD  and the results of PFTs .At the follow-up visits taking place every 3 months  the following data will be collected:Data regarding RADisease activity assessment  and functional status (HAQ);Treatment and eventual treatment/dose modifications ; andAdverse events such as infections, hospitalizations or other events attributed either to the disease itself or to its treatment.Data regarding ILDPatient\u2019s respiratory functional status (as per MRC);Results of PFTs ; andHRCT report.The first part consists of a cross-sectional study between patients with RA-ILD and RA-non ILD (gender- and age-matched control group) in order to identify independent risk factors associated with ILD and the relative risk attributed to each one of these risk factors.The second part of the study focuses on the prospective data collection regarding RA-ILD patients aiming at the determination of the following outcomes:Prevalence of the different HRCT patterns;Severity assessment of ILD in the initial and successive follow-up visits;Response to different treatment modalities; andIncidence of adverse events attributed either to the disease itself or to its treatment.Our goal is to collect data from at least 100 RA-ILD patients for this study to be sufficiently powered. Moreover, we aim to complete both data collection and statistical analysis by July 2019 in order to publish the results in the forthcoming 2019 ACR Congress and to peer-reviewed international journals.All analyses will be performed with the use of Microsoft Excel 2013 and IBM SPSS Statistics v.20 software. At first, data will be analysed by descriptive statistics. Continuous variables will be presented by mean and median values and standard deviations. Categorical variables will be presented by percentages. Multivariate analysis will be performed in order for independent risk factors to be assessed.This is the first study aiming to collect data from RA-ILD patients followed in multiple hospital centres in Greece in order to assess both the natural history and the risk factors contributing to the development of ILD. Exploring both the efficacy and the adverse events attributed to the medications used in patients with RA-ILD will provide useful evidence leading to the amelioration of the therapeutic approach to RA-ILD patients in daily clinical practice. An additional benefit of this study will be the generation of a biobank of serum and nucleic acids for future biomarker studies."}
+{"text": "Neoadjuvant therapy improves long-term survival by providing locoregional disease control and reducing the risk of long-term recurrence. The most important prognostic factor of survival after neoadjuvant therapy followed by surgery is the burden of lymph node involvement. Several trials have demonstrated improved long-term survival with neoadjuvant therapy; however, there are little data evaluating adenocarcinoma and squamous cell carcinoma (SCC) and difference in outcomes for similar pathological stage with and without neoadjuvant treatment. This studyThese results corroborate what has been found in other recent studiesThis study reinforces the understanding that post-neoadjuvant stage influences prognosis. While some may advocate \u2018complete\u2019 restaging prior to progressing to surgery, induction therapy is known to potentially impact on the reliability of staging modalities. It may also be important to consider the post-neoadjuvant stage when deciding on the merit of adjuvant treatment. There has been some suggestion that adjuvant treatment may confer some benefit in node-positive patients with adenocarcinoma who received neoadjuvant chemoradiotherapy, and it already forms part of the standard of treatment in patients receiving MAGIC protocol chemotherapy."}
+{"text": "It has been brought to our attention that the first sentence of the Conclusion in the original publication [1] is incorrect. We have removed this sentence and the correct version can be found in this Erratum.Conclusion:Urethral strictures are common and management of long-segment strictures present a ongoing challenging surgical problem primarily because of stricture recurrence following urethrotomy or urethral dilatation This is an area where much more research is needed and we would conclude that it is an area of unmet clinical need where users of tissue engineering in the future need to carry out a rigorous basic science programme and need to be cautious in drawing conclusions based on initial experience and report on long-term clinical results.Chapple C (2019) Tissue engineering of the urethra: where are we in 2019? World J Urol. 10.1007/s00345-019-02826-3.Reference:The original article has been corrected."}
+{"text": "Identification of prognostic factors for swallowing recovery in patients with post-stroke dysphagia is crucial for determining therapeutic strategies. We aimed at exploring hyoid kinematic features of poor swallowing prognosis in patients with post-stroke dysphagia. Of 122 patients who experienced dysphagia following ischemic stroke, 18 with poor prognosis, and 18 age- and sex-matched patients with good prognosis were selected and retrospectively reviewed. Positional data of the hyoid bone during swallowing were obtained from the initial videofluoroscopic swallowing study after stroke onset. Normalized hyoid profiles of displacement/velocity and direction angle were analyzed using functional regression analysis, and maximal or mean values were compared between the good and poor prognosis patient groups. Kinematic analysis showed that maximal horizontal displacement (P\u2009=\u20090.031) and velocity (P\u2009=\u20090.034) in forward hyoid motions were significantly reduced in patients with poor prognosis compared to those with good prognosis. Mean direction angle for the initial swallowing phase was significantly lower in patients with poor prognosis than in those with good prognosis (P\u2009=\u20090.0498). Our study revealed that reduced horizontal forward and altered initial backward motions of the hyoid bone during swallowing can be novel kinematic features indicating poor swallowing prognosis in patients with post-stroke dysphagia. Post-stroke dysphagia is a common complication following stroke2. It can induce malnutrition, dehydration, and aspiration pneumonia, which can potentially increase mortality or the duration of hospitalization, and can interfere with the recovery of the neurological and functional status of patients5. Although most patients with post-stroke dysphagia follow a benign clinical course, 13\u201318% can show severe dysphagia that can persist for more than 6\u00a0months7. Identification of prognostic factors for poor swallowing recovery in patients with post-stroke dysphagia is crucial for determining therapeutic strategies and counseling patients and their relatives.Stroke is one of leading causes of death and disabilities worldwide11. In particular, the hyoid bone, which is a \u2018U\u2019-shaped structure located in anterior neck12, has been utilized as a target structure in previous kinematic studies, since hyoid motions are the main physiological events that occur during pharyngeal swallowing15, and the hyoid bone can be well-visualized in fluoroscopic images16. It moves anteriorly and superiorly in normal swallowing, actively opening the upper esophageal sphincter and leading to an epiglottic tilt; this is the principal protection mechanism of pulmonary aspiration18. It is known that forward movements of the hyoid bone are substantially decreased in patients with post-stroke dysphagia, which is one of the distinctions compared with healthy individuals19. However, there have been rare studies that have investigated hyoid kinematic features associated with swallowing recovery in patients with post-stroke dysphagia.Kinematic analysis of videofluoroscopic swallowing study (VFSS) has contributed to the exploration of novel swallowing characteristics by investigating motions of swallowing-related structures. Numerous studies have reported that the pharyngeal swallowing motions were disorganized in dysphagia patients with varying etiologies20. It is used to analyze the functional data that are converted from discrete observations in the form of a time series. This is done by using basis function expansion and smoothing methods, thus enabling the quantitative analysis of time-series data for group comparison showing regression coefficient functions and differential time interval21. Previous swallowing kinematic studies have analyzed swallowing motions by observing discrete variables such as maximum or mean displacement, or velocity rather than the entire profile of movements over time11. However, this traditional approach may be limited in exploring novel kinematic features of pathologic swallowing because it does not consider pointwise differences in hyoid trajectories over time. In this regard, FLR allows the collection of time-series data of the hyoid bone during the swallowing process to be represented in new ways than the previously described ones; these data can be beneficial for analyzing group differences in a quantitative manner22.Functional linear regression analysis (FLR) is a version of linear regression analysis where dependent or independent variables are functionalAlthough the prognostic features of post-stroke dysphagia should receive attention in clinical practice, hyoid kinematic features for swallowing prognosis have not been fully elucidated. FLR can be a beneficial method to compare time-series motion data. In this study, we used FLR and aimed to investigate novel hyoid kinematic features for poor swallowing prognosis in patients with post-stroke dysphagia.23. The exclusion criteria were as follows: concomitant neurologic diseases associated with dysphagia, age less than 19\u00a0years, tracheostomy, unconsciousness, history of dysphagia, no swallowing reflex on VFSS, VFSS images of poor quality, and no records of brain magnetic resonance imaging. After exclusion, a total of 122 patients with post-stroke dysphagia were included in the kinematic analysis of VFSS. Among these candidates, 24 (17.5%) patients showed poor swallowing recovery until 6\u00a0months after stroke onset. Age- matching and sex-matching were performed between patients with good and poor prognosis for swallowing function because age and sex may affect the kinematic parameters of the hyoid bone during swallowing24. Finally, 18 patients with poor prognosis of swallowing function (no recovery to pre-stroke status at 6\u00a0months) and 18 age- and sex-matched patients with good prognosis of swallowing function (recovery to pre-stroke status at 6\u00a0months) were selected for this study.Clinical and VFSS data of consecutive patients who experienced an acute ischemic stroke and were referred for VFSS due to dysphagia between January 1, 2014, and June 31, 2018 were retrospectively obtained25, stroke location, vascular territory of the brainstem27 stroke laterality, multifocal lesions, bilateral lesions at the corona radiata, basal ganglia and/or internal capsule, severity of white matter hyperintensity in terms of the Fazekas rating scale  in terms of the National Institute of Health Stroke Scale upon admissionAll patients in this study were referred to physiatrists for swallowing assessments and were scheduled to undergo VFSS if post-stroke dysphagia was suspected. VFSS was performed by physiatrists to assess swallowing function and establish feeding strategies. Two-dimensional X-ray images were obtained from patients with post-stroke dysphagia by using VFSS to assess hyoid motions during swallowing in the lateral view Fig.\u00a0. During https://github.com/cmookj/stamps) was used in the present study30. The positional data of the second cervical vertebrae (C2) and the fourth cervical vertebrae (C4), and a coin with a diameter of 23.5\u00a0mm as a reference object were additionally obtained to adjust neck movements during swallowing and to normalize the length of displacement. A local coordinate system was applied for each VFSS image in which the origin and the vertical axis were defined as the anteroinferior vertex of the C4 and the line connecting the origin and the anteroinferior vertex of the C2. The starting point of the hyoid bone was set as the origin of the coordinate axes for comparison of trajectories. Previously published researches have provided detailed information about methods for determining the relative position and time lapse in the motion of the hyoid bone during swallowing30.All VFSS images were acquired from the patients included in this study. To extract positional data of the hyoid bone from these images, the swallowing motion analysis software called the spatio-temporal analyzer for motion and physiologic study  with the FDA package. The two-dimensional hyoid trajectories were illustrated using MATLAB R2019a .Positional data of the hyoid bone were converted to functional data after adjustment for neck movements and normalization. Discrete observations in the t-test for continuous variables, and the chi-square test or Fisher\u2019s exact test for categorical variables. The maximal values of hyoid displacement (HD) and velocity (HV) and mean values of direction angle for the 5th\u201320th percentile durations were compared between the age- and sex-matched stroke patients, using an independent-sample The clinical information was compared between patients with post-stroke dysphagia who showed good and poor swallowing prognosis using an independent-sample Table Figure\u00a0The mean HVs in the horizontal and vertical planes for the age- and sex-matched stroke patients with good and poor prognosis for swallowing function are shown in Fig.\u00a0The mean trajectories for the hyoid direction angles in the age- and sex-matched stroke patients with good and poor prognosis for swallowing function are illustrated in Fig.\u00a0Table The current study aimed to investigate the characteristic kinematic parameters of the hyoid bone, which are associated with poor swallowing prognosis in patients with post-stroke dysphagia. Pointwise differences in swallowing motion over time were analyzed between patients with good and poor swallowing prognosis by using FLR and analyzing maximal or mean values of hyoid kinematic parameters. The results showed that HD and HV of the horizontal plane during the forward motions were significantly reduced in patients with poor swallowing prognosis compared with those with good swallowing prognosis, though the values of the vertical plane were not significantly different. Decreased direction angle of the hyoid bone during the early phase of swallowing was also evident in patients with poor swallowing prognosis.19, were consistently decreased in stroke patients with poor swallowing prognosis compared to those with good swallowing prognosis in the current study. Horizontal HV increased and then decreased rapidly in stroke patients with good prognosis compared to those with poor prognosis according to the results of FLR analyses. A substantial decrease in horizontal HD and HV at the early phase of stroke may reflect initial severity of dysphagia which has been previously reported to be associated with the hindrance of swallowing recovery36. Since the contraction sequence of the\u00a0hyoid-adjacent muscles is constant during the pharyngeal phase of swallowing37, damage to the swallowing-related neural systems that control the hyoid-adjacent muscles can cause the deterioration of this sequence39. Decreased forward motion of the hyoid bone caused by impairment of the swallowing-related neural systems can result in poor relaxation of the upper esophageal sphincter, accumulation of the residue in the pyriform sinus, and an increase in aspiration risk18. In addition, hyoid motions during the late phase of swallowing are involved in returning to the initial position before swallowing and can be essentially affected by the hyoid trajectories in the early phase of swallowing. Thus, hyoid trajectories during the late phase of swallowing can be an indirect result of weakness of the hyoid-adjacent muscles after stroke and clinical emphasis should be placed on the early phase of swallowing rather than on the late phase.This study suggests that a decrease in horizontal HD and HV indicates poor swallowing prognosis in post-stroke dysphagia. HD and HV, which were discrepant in comparison between stroke patients and healthy controls in a previous study40. The decreased direction angle can be explained by weakness of the hyoid-adjacent muscles to pull the hyoid bone posteriorly, including the stylohyoid muscle and posterior digastric muscle37. The capacity to generate strong forces in the forward direction by lengthening the suprahyoid muscles can be deteriorated in the vertical direction of backward force vectors during the early phase of swallowing in patients with poor prognosis of swallowing function11. Additionally, the observation of preserved vertical motions during swallowing was in concordance with the findings of a\u00a0previous research which showed that maximal HV was preserved in the vertical plane, but decreased significantly in the horizontal plane in stroke patients with aspiration, compared with healthy participants19. In this previous study, maximal HD was preserved in the vertical plane unlike that in the horizontal plane, even though the difference between the two groups was not significant. Another study comparing healthy younger and older participants also indicated that vertical HD was greater in older participants than in younger participants8. Effortful swallowing is a plausible compensatory mechanism to explain the following disjunction: HD and HV in the horizontal plane are less affected by effortful swallowing than the HD and HV in the vertical plane41. To offset the weakness of the pharyngeal musculature for swallowing difficulty, patients with more severe dysphagia may show forceful swallowing as a natural compensation42.The direction angle, which is the angle of the vectors, was adopted in this study as a kinematic parameter to reflect the dominant direction of the hyoid motions in the early phase of swallowing. Figure\u00a011. The present study showed a reduced direction angle in the early phase of swallowing, which was identified using FLR by analyzing time-series data for the hyoid bone during swallowing. This finding supports the relative preservation of hyoid motions in the vertical plane, contrary to hyoid motions in the horizontal plane. In fact, previous studies investigating the effects of therapeutic interventions on swallowing outcomes in patients with post-stroke dysphagia usually did not adopt kinematic parameters to determine patient inclusion43. This is possibly because of the technical difficulty in conducting image processing of VFSS data and analyzing kinematic parameters related to swallowing in clinical studies. The methods used to quantitatively analyze swallowing kinematics in this study can be potentially useful for reducing or correcting a potential selection bias in further comparative studies  on post-stroke dysphagia.In this study, FLR was used as the main statistical method to identify pointwise differences in swallowing trajectories over time between stroke patients with good and poor prognosis for swallowing function. This method was previously used to explore novel kinematic features related to swallowing by quantitatively analyzing hyoid trajectories in patients with Parkinson\u2019s diseaseThis study has several limitations. First, the sample size of the current study was small. To analyze the differences between good and poor swallowing prognosis groups, age- and sex-matching were used; many patients with good swallowing prognosis were not included in the analysis. It was difficult to conduct subgroup analyses to identify subtle between-group differences in clinical and radiologic variables. This is the first study to explore swallowing kinematic features of stroke patients with poor prognosis and future studies involving a larger sample size may be necessary to generalize the results of this study. Second, hyoid motions for only the specific liquid volume were analyzed to ensure comparability in this study. Previous studies have indicated that viscosity and volume of the ingested liquid can affect the hyoid kinematic features considerably. Hyoid kinematic analyses for diverse viscosity or volume of liquid can be helpful to explore novel kinematic features indicating poor swallowing prognosis of post-stroke dysphagia in further studies. Third, potential confounding factors such as sarcopenia and nutritional status, which can affect swallowing function, were not measured in this study and should be considered in prospective comparative studies for swallowing interventions.In conclusion, the swallowing kinematic analysis based on FLR indicated reduced horizontal HD and HV and decreased direction angle for the early phase of swallowing in patients with post-stroke dysphagia showing poor swallowing prognosis. Altered initial backward motions and reduced horizontal forward motions of the hyoid bone during swallowing may be novel kinematic features for poor prognosis of post-stroke dysphagia. FLR can potentially provide new insights in understanding swallowing kinematics and physiology in pathologic swallowing in further studies."}
+{"text": "In vector borne diseases the human hosts' epidemiology often acts on a much slower timescales than the one of the mosquitos which transmit the disease as a vector from human tohuman, due to their vastly different life cycles. We investigate in a model withsusceptible (S), infected (I) and recovered (R) humans and susceptible (U) and infected(V) mosquitoes in how far the fast time scale of the mosquito epidemiology can be slavedby the slower human epidemiology, so that for the understanding of human disease datamainly the dynamics of the human time scale is essential and only slightly perturbed bythe mosquito dynamics. This analysis of the SIRUV model is qualitatively in agreement witha previously investigated simpler SISUV model, hence a feature of vector-borne diseases ingeneral."}
+{"text": "First Person is a series of interviews with the first authors of a selection of papers published in Biology Open, helping early-career researchers promote themselves alongside their papers. Bishal Basak is first author on \u2018 Bishal BasakWhat is your scientific background and the general focus of your lab?I joined Prof. Padinjat's lab as an Integrated MSc-PhD student soon after receiving my Bachelor's degree in Microbiology from St. Xavier's College, Kolkata, India.I have always been intrigued with the concept of how cells communicate using simple molecules like lipids, proteins and other effectors. Such communication is essential to support physiology starting from a unicellular bacterium to the most complex eukaryotic organism. Prof. Padinjat's lab looks at the role of a specific group of lipids termed phosphoinositides in maintaining membrane trafficking, sub-cellular organization, in addition to understanding how they regulate human brain development and function. The lab provided me with an ideal platform to study how lipid mediated signalling is key to driving multiple cellular processes.\u201cI have always been intrigued with the concept of how cells communicate using simple molecules\u2026\u201dHow would you explain the main findings of your paper to non-scientific family and friends?My article deciphers how the interactions of each subunit of a complex protein is essential to provide vision in insects such as the fruit fly.What are the potential implications of these results for your field of research?Drosophila photoreceptors is one of the few studies which deduces the importance of regulated lipid transfer at ER-PM interface from an in vivo cell biological perspective.Since the initial discovery of Phosphatidylinositol (PI) transfer proteins (PITPs) in 1974, a long-standing question has been why some PITPs have multiple domains as opposed to few others which just harbor only a singular PI transfer domain. Our results not only address how each domain in a multidomain PITP is important to the protein per se, but also sheds light on how loss of these domains disrupt cellular homeostasis. Our detailed study on RDGB function in What has surprised you the most while conducting your research?I have been amazed by how different domains of a protein, each with distinct role, also interact with each other to regulate neuronal structure and function.What, in your opinion, are some of the greatest achievements in your field and how has this influenced your research?Drosophila serve as an unique and powerful model system to study the in vivo effects of lipid transfer at membrane contact sites, not many of which are known in the field, have been extremely influential for our study.Some of the initial discoveries which showed that blocking traditional vesicular trafficking pathways do not affect transport of certain lipids paved the path for identifying and studying non-conventional modes of trafficking within cells. Additionally, discoveries involving how photoreceptors of What changes do you think could improve the professional lives of early-career scientists?I believe there should be more opportunities for early-career scientists to present their work out in the scientific community. This should include more workshops, symposiums and conferences at both national and international level dedicated for people at such career stages. In conferences there should be more student talks than faculty, online streaming/poster sessions (even after in-person conferences resume) should be made mandatory benefitting those who cannot afford the expenditures of attending an international conference. Also, symposiums dedicated particularly for career guidance will greatly impact the lives of many early-career scientists who may wish to transition from academia.\u201c\u2026online streaming/poster sessions (even after in-person conferences resume) should be made mandatory\u2026\u201dWhat's next for you?I am currently working on getting another manuscript out for publication. I am also looking forward to starting working as a post-doctoral fellow soon."}
+{"text": "N-methyl-D-aspartate receptor (NMDAR) response magnitudes result in synaptic potentiation or depression. We asked whether NMDAR response magnitude also affects\u00a0the transformation of temporal information into directional spatial maps. We quantified retinotectal axon branch dynamics in Xenopus optic tectum in response to temporal sequences of visual stimulation. Reducing NMDAR responses by 50% inverts the spatial distribution of branch dynamics along the rostrocaudal axis in response to temporal patterns of input, suggesting that the magnitude of NMDAR signaling encodes the temporal sequence of inputs and translates the temporal code into a directional spatial map using structural plasticity-based branch dynamics. We discuss how this NMDAR-dependent decoding mechanism retrieves spatial information from sequential afferent activity.Spatial representations of the sensory world are important for brain function. Timing is an essential component of sensory information. Many brain circuits transform the temporal sequence of input activity into spatial maps; however, the mechanisms underlying this transformation are unclear. Different   \u2022NMDAR response magnitude encodes the temporal sequence of inputs\u2022NMDAR mechanism decodes spatial information from sequential input activity\u2022NMDAR attenuation inverts the temporal to spatial transformation\u2022NMDAR activity alters the spatial distribution of dynamic and stable branches Developmental Neuroscience; Sensory Neuroscience ; Techniques in Neuroscience Timing is an essential component of information in the brain. Many brain circuits transform the temporal sequence of input activity into spatial maps of inputs as seen in sensory circuits and circuits for cognition, such as entorhinal cortex  and cereXenopus optic tectum provides an excellent system to analyze how temporal information is transformed into spatial information. The visuotopic map in the tadpole tectum is continually updated by visual input activity to accommodate developmental changes in the size of the tectum and the size and position of the eyes (Experience-dependent plasticity of the visuotopic map in the eyes . With fothe eyes . FurtherN-methyl-D-aspartate receptors (NMDARs) are highly conserved voltage-dependent calcium-permeable ionotropic glutamate receptors that function in diverse plasticity mechanisms across species  positioned to stimulate both eyes sequentially with a 15-ms interval between the left and right eyes at 11\u00a0Hz. We choose the 15-ms interval because sequential stimuli with a 15- to 20-ms interval induced the most consistent branch tip shifts in our previous study  to produce a graded decrease in the amplitude of NMDAR currents. We stimulated the optic nerve A measureChanges in branch dynamics and stability contribute to experience-dependent structural plasticity in sensory inputs during map refinement. Correlated convergent input activity stabilizes axon branches, whereas inputs that are not correlated are destabilized . Data inTo address this question, we analyzed the branch dynamics in axons imaged in the experiment described above. Dynamic branches were categorized as added, transient, and lost, as shown in Axon arbors have many branch points, each of which gives rise to two sub-arbors A. A spatThe inverted branch tip shift in 5\u00a0\u03bcM APV indicates that the amplitude of the NMDAR current is sufficient to control the direction of branch tip shift. This suggests that information required for the temporal to spatial transformation is encoded by the amplitude of NMDAR response in a manner such that a larger response drives a rostral shift in branches. Alternatively, the spatial information may not be mediated directly by the amplitude of the NMDAR signal and the NMDAR signal could modulate other signaling pathways that mediate the structural plasticity. To distinguish these alternatives, we tested whether decreasing of the strength of NMDAR activity in one of the convergent retinotectal pathways would produce a shift in the distribution of axon branches when both input pathways are stimulated simultaneously. To attenuate NMDAR responses in one of the two retinotectal pathways, we employed the use-dependent NMDAR antagonist MK801 . We treaXenopus optic tectum to analyze the transformation of the temporal sequence of RGC activity into the spatial order of axons in the tectum. Our results show that NMDAR activity translates the temporal sequence of afferent activity into the spatial representation of retinotectal axon arbors. NMDARs are recognized to play essential roles in several forms of plasticity operating over different timescales .For correspondence or materials, contact Hollis Cline , \u201cSTS transformation-2\u201d, Mendeley Data, V1, All methods can be found in the accompanying"}
+{"text": "A coring technique is an effective strategy to overcome short linear segmental chronic occlusions in subclavian veins caused by previously implanted leads. We present the case of an 82-year-old male who was transferred from a primary care center for consideration for implantable cardioverter-defibrillator placement following an episode of sustained monomorphic ventricular tachycardia and hemodynamic compromise that required direct-current cardioversion. A coring technique was successfully used in this patient. The patient was noted to be right-handed and functionally active; he reported preferring to keep the device on his left side. Following discussion about the potential options, such as lead extraction and reimplantation and coring recanalization, the patient opted for the latter. Therefore, we proceeded with the device upgrade on the left side using a coring recanalization technique.An 82-year-old male was transferred from a primary care center for consideration for implantable cardioverter-defibrillator (ICD) placement after experiencing an instance of sustained monomorphic ventricular tachycardia (MVT) and hemodynamic compromise that required direct-current cardioversion. He was known to have ischemic cardiomyopathy and triple vessel coronary artery disease, having undergone coronary bypass grafting in 1993. His electrocardiogram showed left bundle branch block morphology. The patient had undergone dual-chamber permanent pacemaker implantation 10 years prior for high-grade atrioventricular block and was pacing-dependent. His most recent echocardiogram had shown severe left ventricular systolic dysfunction with an ejection fraction of < 30%. He was on optimum heart failure therapy with New York Heart Association class I symptoms and was not clinically fluid-overloaded. Based on the current American College of Cardiology/American Heart Association (ACC/AHA) and Heart Rhythm Society (HRS) guidelines, the patient was deemed to meet the criteria to receive a cardiac resynchronization therapy defibrillator (CRT-D) upgrade. A preprocedure venogram of the left subclavian vein showed a totally occluded vessel with collaterals filling antegradely . This maneuver was delicately repeated until the guidewire passed into the vessel lumen proximal to the stenosis. The Asahi Grand Slam guidewire (Abbott Laboratories) was confirmed on fluoroscopy as passing into the inferior vena cava and thus remaining intraluminal. The beveled needle was withdrawn and sequential short sheath dilators starting with the smallest caliber available [5-French (Fr)] were then used to dilate through the stenosis. Eventually, a 7-Fr splittable sheath  was admitted over the guidewire through the stenosis and a single-coil Durata\u2122 lead  was subsequently successfully implanted into the apical septum of the right ventricle . A further attempt to implant a left ventricular lead was not technically feasible; therefore, the CRT-D implantation was ultimately abandoned. The overall procedure time was two hours using 30 mL of contrast, with a fluoroscopy time of 21 minutes. The patient was discharged on optimum medical therapy and was stable at six months after the operation.The procedure was performed with a surgical backup while the surgeons were on-site. A beveled edge needle  was advanced under fluoroscopic guidance into the subclavian/axillary vein intersection over the first rib using the stored cine venogram as a scout image. A contrast mixture  was injected into the vessel through a side arm port to confirm a coaxial location with the lumen of the vein, and the tip of the puncture needle was then advanced into the occlusion. A high-support, nonhydrophilic (to avoid stripping of the coating) angioplasty guidewire  was used as a battering ram for advancement judiciously into the organized thrombus and was then pulled back into the needle. The needle was subsequently telescoped over the guidewire, following the course plotted by the guidewire, and was kept parallel to the existing leads A coring technique is an effective strategy to overcome short linear segmental chronic occlusions in subclavian veins caused by previously implanted leads. This method avoids accessing the contralateral side and removes the need for using subcutaneously implanted ICD systems when vascular access is difficult or unattainable. Balloon angioplasty of these chronic occlusions may be suboptimal as the site of occlusion is prone to recoil. By \u201ccoring\u201d through the organized thrombus, a microchannel remains present to allow for the admission of an extra support wire."}
+{"text": "Increment in the levels of D-dimer, Fibrin Degradation Product (FDP) and decrement in antithrombin (AT) has been seen in patients with COVID-19. Changes in D-dimer and FDP were prominent in severe disease as compared to the mild group. Thrombin time has been detected as shorter in critical patients compared to controls.Our hypothesis is that probable mechanisms for the increased D-dimer in COVID-19 may be related to virus life cycle. The apoptotic processes target the endothelial cells of the vascular structure resulting in triggered coagulopathy and the ultimate result of increased D-dimer.1113 However, it can\u2019t always be explained simply because different viruses interfere with apoptotic pathways in different ways. It is our opinion that increased D-dimer may be the result of apoptotic endothelial cell induced coagulopathy. If apoptotic endothelial injury has a substantial role in pathogenesis, then we have to be concerned about the fate of large endothelial surface in the alveolar vascular bed of lungs. Uncontrolled apoptosis of alveolar endothelial cells can destroy oxygenation in different ways such as micro vascular apoptosis induced thrombi in the alveolar vascular bed and vascular fluid leaks to the lung tissue.Apoptosis is a programmed cell death and has a critical role in the life cycle of viruses. Viruses can\u2019t live without a host cell and after entering the host cell, they use its organelles to produce structures of virus. To keep alive the host cell, it is important for the virus replication phase after finishing this process, to kill a host cell. This gives an advantage to the virus which can leave the host cell and spread to microenvironments. It is probable that during infection, not only the virus interferes with the apoptotic pathway but also the immune system starts to interact with the apoptotic pathways. Killing infected cells during the replication phase is important.14 Li et al studied infectious bronchitis virus (IBV) which is another coronavirus that showed that IBV induces apoptosis at late stages of infection.15 Some studies investigated the virus induced apoptosis of endothelial cells. Sumikoshi et al demonstrated that human influenza virus can infect and induce apoptosis in the human umbilical vein endothelial cells (HUVECs).16 It is an important finding for apoptosis in human vascular endothelial cells, which may lead to other studies for COVID-19. Another interesting study performed by Anfasa et al showed that Zika virus (ZIKV) infected HUVEC demonstrated increased apoptosis, induction in tissue factor concentration and shortened thrombin generation tests.17 Increased levels of D-dimer and thrombosis were also clinically demonstrated in patients with ZIKV and Chikungunya.18 These all show us that viruses can infect the endothelium and trigger the secondary hemostasis.Swine acute diarrhea syndrome coronavirus (SADS-CoV) is a coronavirus that causes severe acute diarrhea. Zhang et al investigated the effects of pan-caspase inhibitors on SADS-CoV infected cells to see the role of apoptosis. They observed decreased SADS-CoV-induced apoptosis and reduced virus replication in SADS-CoV infected cells after the pan-caspase inhibitor.19 They reported that these apoptotic findings may help to understand the pathogenesis of acute lung injury in viral pneumonias.Armstrong et al studies infected human lung microvascular endothelium with human influenza virus. These lung cells underwent apoptosis and caused in an increase in vascular permeability. Inhibition of caspases decreased the influenza-induced endothelial leak.20 This finding brings us to whether or not to use angiotensin or AT2 receptor blockers which may help to prevent or recover from COVID-19 because SARS-CoV-2 uses ACE2 for entering to the targeted cells.21Another inspiring study showed that angiotensin-II-induced apoptosis in primary pulmonary endothelial cells uses AT2 receptor. This study found the results on the activation of intrinsic pathway of apoptotic pathway due to an increased release of cytochrome c from mitochondria and activation of caspase 9. Ongoing apoptosis was blocked by an inhibitor of apoptotic protein Bax.22There is a probability that after entering the cell, SARS-CoV-2 may start the apoptotic processes in the lung microvascular bed endothelium or coronary endothelium or tissue cells which carry ACE2 receptors. We feel that the microvascular pathology can explain this virus\u2019s different clinical pictures due to tissue damage caused from vascular damage. There is also a risk for other tissue cells that carry ACE2 receptor for apoptotic damages and organ failures. There are supportive histological clues in humans on the results of ongoing apoptosis in endothelial cells. Varga et al showed apoptotic changes in endothelial cells, histologically in COVID-19.We believe that the relationship between COVID-19 and apoptotic pathways contributes to the observed focal pathogenesis in the lungs and is involved in the progression of severity of the observed acute respiratory distress syndrome. Drugs with anti-apoptotic properties may therefore be helpful in the management of these patients and merit further investigations."}
+{"text": "Chronic exposure to ethanol induces cumulative damage to the liver starting from fatty infiltration to cirrhosis depending on the dose and duration of exposure. The whole process leading to the development of alcoholic liver disease is very complex and the mechanisms involved are not fully understood. Among many experimental animal models, Lieber-DeCarli liquid diet provides moderate to severe pathophysiological outcome depending on the compositional changes. In the present study, we investigated the temporal changes in the early phase hepatic disease in rats fed with standard Lieber-DeCarli diet. Male Wistar rats were fed with Lieber-Decarli ethanol diet for 6 weeks and the liver samples were obtained after 2, 4 and 6 weeks. Mild fatty infiltration was observed in 2 weeks of feeding and it became evident in 4 and 6 week samples. The level of hepatic triglyceride showed a good agreement with the data obtained in the pathological analysis. Feeding mice with ethanol diet resulted in the maturation and translocation of SREBP-1 to nucleus in the liver. Western blot analysis of the pooled liver sample of control and ethanol fed animals showed a clear-cut time-dependent increase in the expression of nSREBP-1. These data provide important information for selecting proper time point in experimental intervention study in the field of drug development for alcoholic liver disease."}
+{"text": "An otherwise healthy 49-year-old man presented to the emergency department with complaint of a 3-day history of abdominal bulging  in the sHerpes zoster is characterized by clustered maculopapular and vesicular lesions along a dermatome as a result of reactivation of varicella zoster virus in the dorsal root ganglia of peripheral nerves. An infrequent complication is postherpetic pseudohernia which arises when the anterior root ganglia is involved, thus provoking muscular paralysis . Differe"}
+{"text": "Smartphones affect everyday life of people across the lifespan with increasing relevance in later life. Although half of older adults in Germany (65+) use smartphones and the numbers of users are growing, only few studies address the integration of older adult\u2019s smartphone use in everyday life as well as its potential effects on social context and wellbeing, which is been done in this study. Data are drawn from surveying the devices of 35 older adults , allowing to objectively monitor real time smartphone use over the course of a regular week. In addition a semi-standardized ambulatory assessment procedure is administered four times a day to capture the everyday situation of smartphone use as well as aspects of user experience, affect and social context. Preliminary findings show inter- and intra-individual differences in everyday smartphone use in relation to individual differences in social context and wellbeing."}
+{"text": "By emphasising the internal-external security nexus inherent in democratic security, the US could aspire again to lead through the example of its democracy\u2019s resilience and ability to self-correct."}
+{"text": "Racial/ethnic disparities have been well documented in long-term care literature. Culture change is a movement to transition nursing homes to more home-like environments to improve the quality of care for all residents. The purpose of this study was to examine how the involvement of culture change initiatives among high Medicaid facilities was associated with nursing home quality. The study relied on both survey and secondary nursing home data for the years 2017-2018. The sample included high Medicaid facilities. The final model consisted of an ordinal logistic regression. High-Medicaid nursing homes with six or more years in culture change initiatives had higher odds of having a higher star rating, while facilities with one year or less had significantly lower odds of having a higher star rating. Culture change initiatives may require some time to effectively implement, but these initiatives are potential mechanisms to improve quality in high Medicaid nursing homes."}
+{"text": "Deirdre Harrington and Michelle O'Reilly discuss the article \"Effectiveness and cost-effectiveness of the GoActive intervention to increase physical activity among UK adolescents: A cluster randomised controlled trial\" by Kirsten Corder and colleagues. The coronavirus disease 2019 (COVID-19) pandemic has illuminated the chasm of societal inequality and vulnerability within the United Kingdom concurrently highlighted by the February 2020 Marmot Review , and, ofResearchers also recognise the attractiveness of the school setting for applying research-driven solutions to childhood physical inactivity because the majority of young people can be easily reached. Evaluation of school-based physical activity programmes using the rigid cluster randomised controlled trial (RCT) design aim to contribute high-quality evidence on approaches to tackling physical inactivity. The National Institute for Health Research (NIHR) in the UK is one funder that has invested significant funds in large school-based cluster RCTs . These trials overcame methodological weaknesses identified in previous systematic reviews  by havinPLOS Medicine special issue [The Corder and colleagues paper in this al issue  is the lal issue , issues Despite the methodological quality of this and previous trials, effectiveness (through the narrow definition of positively affecting the primary outcome) has been limited. Little new knowledge of what works, or clear results that have led to policy or provision change, has been produced from these trials. It is clear that doing more of the same will not lead to the creation of new knowledge relevant to stakeholders. This is particularly pertinent because the Corder publication coincides with the crest of the COVID-19 pandemic\u2014a global issue that means researchers and funders are likely to be forced to reassess their priorities and approach.The general area of \u2018health, sport and physical education\u2019 in schools is commonly used as a vehicle to address public health or societal \u2018problems\u2019 . UK PrimThe research world has quickly mobilised and repurposed studies to tackle the COVID-19 pandemic including research on how health behaviours and outcomes, such as physical activity, have changed. School-based physical activity research too will likely change. The need for social distancing and enhanced personal hygiene practices would pose practical challenges if we imagine planning the GoActive study methods in the COVID-19 era.The Corder trial employed a cluster RCT design that required large amounts of data collected during a narrow time frame to fit in with the academic calendar . This is done by teams of research staff travelling together, sharing equipment, and co-operating in settings the researchers often have little control over. Collection of outcome data such as waist circumference requires close proximity between research staff and participants. The rapid deployment, use, and collection of body-worn physical activity measurement devices would require careful hygiene procedures. Research staff would facilitate large groups of pupil participants completing extensive questionnaire booklets in packed classrooms. The willingness to engage in these data collection methods will largely be down to the researchers\u2019 own personal assessments of risk and that of the school.As the world still reels from the effect of the COVID-19 pandemic, there is an impending threat of triple inertia: that funders may stop funding school-based physical activity research, that academics may flounder under the weight of evidence lacking effectiveness, and that stakeholders will have new priorities resulting in limited physical activity research opportunities with schools.The stark and transparent light of COVID-19 provides the UK government a real chance to tackle health inequality and to reinstate local government public health and education funding that schools rely on. This would provide schools with adequate financial and human resources to develop bespoke physical activity programmes. These practice-driven programmes are more likely to suit the needs and preferences of the school\u2019s own pupils and account for and listen to adolescents\u2019 perspectives as well as other key stakeholders. This would open up the opportunity for pragmatic and flexible evaluation of these practice-led programmes in schools allowing researchers to move away from RCTs and towards more realist  methodol"}
+{"text": "Diabetes can elicit direct deleterious effects on the myocardium, independent of coronary artery disease or hypertension. These cardiac disturbances are termed diabetic cardiomyopathy showing increased risk of heart failure with or without reduced ejection fraction. Presently, there is no specific treatment for this type of cardiomyopathy and in the case of type I diabetes, it may start in early childhood independent of glycemic control. We hypothesized that alterations in isolated myocyte contractility and cardiac function are present in the early stages of experimental diabetes in rats before overt changes in myocardium structure occur. Diabetes was induced by single-dose injection of streptozotocin (STZ) in rats with data collected from control and diabetic animals 3 weeks after injection. Left ventricle myocyte contractility was measured by single-cell length variation under electrical stimulation. Cardiac function and morphology were studied by high-resolution echocardiography with pulsed-wave tissue Doppler imaging (TDI) measurements and three-lead surface electrocardiogram. Triglycerides, cholesterol and liver enzyme levels were measured from plasma samples obtained from both groups. Myocardial collagen content and perivascular fibrosis of atria and ventricle were studied by histological analysis after picrosirius red staining. Diabetes resulted in altered contractility of isolated cardiac myocytes with increased contraction and relaxation time intervals. Echocardiography showed left atrium dilation, increased end-diastolic LV and posterior wall thickness, with reduced longitudinal systolic peak velocity (S\u2019) of the septum mitral annulus at the apical four-chamber view obtained by TDI. Triglycerides, aspartate aminotransferase and alkaline phosphatase were elevated in diabetic animals. Intertitial collagen content was higher in atria of both groups and did not differ among control and diabetic animals. Perivascular intramyocardial arterioles collagen did not differ between groups. These results suggest that alterations in cardiac function are present in the early phase in this model of diabetes type 1 and occur before overt changes in myocardium structure appear as evaluated by intersticial collagen deposition and perivascular fibrosis of intramyocardial arterioles. The incpression . The profunction .In vivo cardiac function was assessed in diabetic and control animals by ECG and high-resolution echocardiographic imaging. Echocardiographic findings showed reduced systolic peak velocity (S\u2019) pointing to reduced segmental longitudinal systolic function accompanied by changes in cardiac morphology, with increased LA dimension in diabetic compared to control rats. Increase in LA diameter may be related to increased LV stiffness and end-diastolic pressure.Alterations in atrial conduction with prolonged action potential were first observed in electrically stimulated isolated atria after 1 week of STZ injection in rats . IncreasIt is of note that the wider P-wave observed in our study in diabetic animals was concomitant to an increase LA dimension . FurtherIn our study diabetic rats showed an increase in plasma levels of hepatic aspartate aminotransferase and alkaline phosphatase, which may suggest hepatic damage induced by diabetes .We found increased levels of plasma triglycerides  in diabeWe observed no differences in collagen content in the interstitium and in the perivascular area of diabetic animals when compared to controls. This suggests that, at such an early stage, the observed changes in contractility may not involve increase in wall stiffness from collagen deposition, as is usually reported in later periods of this animal model of T1DM. The presence of interstitial fibrosis and perivascular myocardial fibrosis is a common finding after 8 weeks of STZ injection and it is usually considered an important factor in the reduced contractility seen in the later stages .al. [In one of the few studies that address early stages of the T1DM STZ-model, Becher et al.  found reWe found significant decreases in both contractile and relaxation parameters in the isolated cardiomyocytes from diabetic animals, which are the most relevant functional alterations observed at this stage. Impairment of electrical conductivity from changes in interstitial collagen are not likely a relevant event at this stage as well. However, the observed increase in left atrial dimension may be associated to the appearance of other electrical disturbances.One limitation of this experimental model, especially if results are to be applied to therapeutic strategies, is the short duration of the diabetic state which is substantially different than the slowly and accumulating damage of diabetes in humans. T1DM is a chronic disease that develops over years even with strict glycemic control and insulin therapy. Another relevant limitation is the lack of comparison with other time-points in the same animals, which would further corroborate our findings.In conclusion, the present study demonstrates reduced systolic function with impaired myocyte contractility in early-stage type-1 diabetic rats, which is attributed to the effects of diabetes at the cardiomyocyte level. The data suggest that alterations in longitudinal systolic heart function observed in diabetic animals are associated to the prolonged time course of shortening and relaxation of isolated ventricular myocyte. The changes observed in isolated myocytes may represent the initial cellular substrate for diabetic cardiomyopathy, already manifested in an early phase of DM in this experimental model. We found early functional changes, including contraction abnormalities in isolated cells, systolic alterations in vivo and changes in duration and variability of P wave in ECG, occurring before signs of interstitial and ventricular perivascular fibrosis. This may indicate that the present STZ model may be suitable to investigate the initial phase of DCM, the pathophysiological mechanisms involved and possible effects of drug interventions."}
+{"text": "Discoveries of adaptive gene knockouts and widespread losses of complete genes have in recent years led to a major rethink of the early view that loss-of-function alleles are almost always deleterious. Today, surveys of population genomic diversity are revealing extensive loss-of-function and gene content variation, yet the adaptive significance of much of this variation remains unknown. Here we examine the evolutionary dynamics of adaptive loss of function through the lens of population genomics and consider the challenges and opportunities of studying adaptive loss-of-function alleles using population genetics models. We discuss how the theoretically expected existence of allelic heterogeneity, defined as multiple functionally analogous mutations at the same locus, has proven consistent with empirical evidence and why this impedes both the detection of selection and causal relationships with phenotypes. We then review technical progress towards new functionally explicit population genomic tools and genotype-phenotype methods to overcome these limitations. More broadly, we discuss how the challenges of studying adaptive loss of function highlight the value of classifying genomic variation in a way consistent with the functional concept of an allele from classical population genetics. Views on loss-of-function mutations\u2014those abolishing a gene\u2019s biomolecular activity\u2014have changed considerably over the last half century. Early theories of molecular evolution that emerged during the 1960\u2019s and 1970\u2019s saw little potential for loss-of-function mutations to contribute to adaptation , mutation rate of an adaptive allele (u), and selection coefficient on that adaptive allele (s), the expected number of mutationally independent alleles of the locus that will be observed in a population at the moment of allele fixation (k), a unit of allelic heterogeneity, is predicted  per generation (Muller \u22128 to 10\u221210 mutations (change in sequence) per site per generation   from related species rather than polymorphic (Pn) within the study species. When genes putatively experiencing adaptive loss of function are investigated, they are often found to have high NI values  scans in natural populations have become a popular alternative to conventional mapping in an experimental population derived from a bi-parental cross. GWA is normally implemented by testing for associations between individual DNA sequence variants in a population and the phenotype  of interest. This statistical framework can fail to detect causal loci in the presence of allelic heterogeneity because none of the individual variants are linked to a single causal variant\u2014an assumption of single-locus two-allele population genetic models (Korte and Farlow A. thaliana identified cases of likely loss-of-function differences between genotypes, a conventional GWA looking for loci explaining variation in plant height failed to detect the GA-20 oxidase locus in A. thaliana (Barboza et al. The case of the GA-20 oxidase gene in plants provides a useful illustration of these challenges. This well-studied gene is involved in gibberellin biosynthesis and loss of function produces semi-dwarf phenotypes in wild plants and crop varieties of the Green Revolution Fig.  Spielme. While fSLC30A8 was found to be strongly associated with decreased risk of type 2 diabetes when all loss-of-function variants were collapsed into a single allele state (Flannick et al. To date, such a framework has been primarily used in the study of rare variants (Wu et al. A functionally explicit GWA framework may have value beyond scanning genomes for causal loss-of-function alleles. More broadly, it reflects a step toward representing genetic diversity as a matrix of functionally relevant genetic alleles rather than a matrix of DNA sequence variants. While loss of function is currently the easiest allele state to classify, we anticipate that more nuanced and precise allele categories can be identified through analyses of population genomic diversity with advances in sequence annotation. Ideally, these categories would specify the activity of an allele along a scale that reflects Muller\u2019s original categories of amorphic, hypomorphic, hypermorphic, antimorphic, and neomorphic states Muller . In addiLoss-of-function alleles were once often held up as a paragon of deleterious genetic variation. Today a more nuanced appreciation for their potential role in adaptation has emerged. This new paradigm inspires investigations into deeper questions about the causes and consequences of adaptation by genetic loss of function. For example: Do species or populations differ in their capacity to adapt via loss of function, and if so, why? Does the high effective mutation rate of loss-of-function alleles lead to bias in the probabilities of different evolutionary outcomes? What is the contribution of adaptive loss of function to the phenomena of antagonistic pleiotropy and reproductive isolation? How does adaptation by loss of function affect long term evolutionary trajectories of populations and future evolvability? Ongoing technical breakthroughs promise to scale up the study of loss-of-function alleles experiencing positive selection for population genomic research to address these questions. More broadly, these lines of research provide paths toward advancing tools and concepts that facilitate a continued synthesis between functional molecular genomics and classic population genetic theory."}
+{"text": "Blood vessel sprouting from pre-existing vessels or angiogenesis plays a significant role in tumour progression. Development of novel biomolecules from marine natural sources has a promising role in drug discovery specifically in the area of antiangiogenic chemotherapeutics. Symbiotic actinomycetes from marine origin proved to be potent and valuable sources of antiangiogenic compounds. Zebrafish represent a well-established model for small molecular screening and employed to study tumour angiogenesis over the last decade. Use of zebrafish has increased in the laboratory due to its various advantages like rapid embryo development, optically transparent embryos, large clutch size of embryos and most importantly high genetic conservation comparable to humans. Zebrafish also shares similar physiopathology of tumour angiogenesis with humans and with these advantages, zebrafish has become a popular model in the past decade to study on angiogenesis related disorders like diabetic retinopathy and cancer. This review focuses on the importance of antiangiogenic compounds from marine actinomycetes and utility of zebrafish in cancer angiogenesis research. Danio rerio; Angiogenesis; Actinomycetes; Bioactive molecules; Transgenic model; Xenograft model; Biotechnology; Genetics; Proteins; Pharmaceutical science; Biomedical engineering; Molecular biology; Cancer research; Developmental biology; Toxicology In t2Marine sources are rich in secondary metabolites and there are many compounds reported to possess anticancer properties. In a recent review, it has been elucidated that more than 45 compounds from marine origin are shown to have antiangiogenic potential and 10 of them have already entered clinical trials at different phases for cancer therapy . These cActinomycetes are filamentous Gram-positive bacteria which belongs to the phylum Actinobateria, are considered to be the largest group in the bacterial domain . Bioacti3Zebrafish model is widely used in angiogenesis study as the circulation starts after 24 hours post-fertilization (hpf), and the vascular system bears a strong similarity to that of humans. In the early embryonic development, blood vessels and organ formation can be easily visualized in the transparent embryos and larvae of both wildtype and transgenic species making it a viable model for angiogenesis research . Therefo3.1in vivo imaging capabilities of zebrafish larvae and embryos. A dissecting microscope is sufficient to visualize the blood flow and vessel development in early embryos and larvae, yet tissue specific expression of fluorescent proteins is required to study the vasculature in detail  - INSPIRE [DST/INSPIRE/04/2018/003392] and DST- Science & Engineering Research Board (SERB) - National Postdoctoral Fellowship [File Number: PDF/2016/003879].This work was supported by No data was used for the research described in the article.The authors declare no conflict of interest.No additional information is available for this paper."}
+{"text": "The image of modern aging had changed. While before ageing was associated with degenerative processes, today more older adults become active and meaningful members of the society. Still more knowledge is needed to help the majority of older adults to age in active and positive way. Solid body of research shows that in ageing the value of subjective factors dramatically increases. Gerotranscendence that suggests important positive personality changes to occur in aging, could be one of such mechanisms. The aim of the present study was to investigate which psychological characteristics were important for development of gerotranscendence and which positive outcomes it might cause. Participants were 200 older adults aged 60-89 . Methods: Gerotranscendence scale (Strizhitskaya), self-actualization test (Shostrom), Self-acceptance test (Pantileev), Psychological well-being scale (Ryff), Scale of social activity (Strizhitskaya). Our results confirmed in consistence with literature that higher scores on self-acceptance and self-actualization favored development of gerotranscendence. We also found that developed gerotranscendence positively affected psychological well-being. New in our research was that we showed that people who demonstrated higher scores on gerotranscendence were more interested in maintaining social activities; they were interested in participation in social life of their community and were trying to continue active and meaningful social participation. The final model fitted the original data . Thus gerotranscendence had positive effects on older adult\u2019s functioning and social participation."}
+{"text": "Resident glial cells can be reprogrammed into neuronal progenitors and mature neurons in the CNS of adult mammals. In this review article, we briefly summarize the current knowledge on innate adult neurogenesis under pathological conditions and then focus on induced neurogenesis through cell fate reprogramming. We discuss how the reprogramming process can be regulated and raise critical issues requiring careful considerations to move the field forward. With emerging evidence, we envision that fate reprogramming-based regenerative medicine will have a great potential for treating neurological conditions such as brain injury, spinal cord injury (SCI), Alzheimer\u2019s disease (AD), Parkinson\u2019s disease (PD), and retinopathy.The adult mammalian central nervous system (CNS) has very limited regenerative capacity upon neural injuries or under degenerative conditions. In recent years, however, significant progress has been made on  A functional central nervous system (CNS) consists of both neurons and glial cells. While neurons are responsible for generating and communicating electrical and chemical signals essential for neural networks, their activities are supported and modulated by surrounding glial cells Rasband, . Both neNew neurons can be generated in the adult mammalian brain through a process of neurogenesis, which is positively or negatively regulated by pathological conditions  of the lateral ventricle and the subgranular zone (SGZ) of the hippocampal dentate gyrus  triggers rapid cell death predominantly in the cerebral cortex followed by secondary tissue loss in the hippocampus. TBI-induced changes in adult neurogenesis are well observed in rodents  and four microRNAs , the stem cell factor SOX2 was identified to be sufficient to reprogram resident astrocytes into functional neurons in the adult mouse striatum , cells resembling induced pluripotent stem cells (iPSCs) could be induced from reactive glial cells in the injured cortex  was shown to be sufficient to reprogram mouse fibroblasts and astrocytes into dopaminergic neurons in culture  was delivered into the ipsilateral striatum  and in combination with electromagnetic gold nanoparticles (AuNPs) and the presence of specific electromagnetic fields, Yoo et al. , striatal astrocytes were reported to be directly converted into dopaminergic neurons when a cocktail of four transcription factors  lead to the disruption of neural circuits and the loss of propriospinal neurons. The addition of new neurons may well serve as relays that could form neural circuits for functional improvements. Ectopic expression of Ascl1 in young transgenic mice renders MGs to generate retinal neurons including amacrine and bipolar cells and photoreceptors after injury  are the major glial cells in the retina, an integral part of the mammalian CNS that lacks any neurogenesis under both physiological and pathological conditions. Ectopic Otx2, Crx, and Nrl in these activated MGs allows them to produce rod photoreceptors, which are capable of restoring visual responses in a mouse model of congenital blindness , cell signaling, and apoptosis , the attached sequences (such as GFP vs. reprogramming factors) can significantly affect cell specificity, consistent with a previous report in transgenic mice (Su et al., The cell origin for the induced neurons requires thorough investigation and confirmation. Unlike in vivo reprogramming process. The neurogenic factor Ascl1 and the nuclear receptor Tlx are found to be essential mediators of SOX2-dependent reprogramming of astrocytes in the adult brain (Niu et al., in vivo screens, the p53-p21 pathway was identified to function as a critical checkpoint for glial reprogramming in the adult mouse spinal cord (Wang L. L. et al., Neurog2-mediated direct neuronal reprogramming can be remarkably promoted by a cocktail of growth factors or coexpression of Bcl-2 and anti-oxidative treatments in the adult brain (Grande et al., Neurod1 is accompanied by changes in the epigenetic landscape, which gradually leads to loss of microglial traits and acquisition of neuronal identity (Matsuda et al., Ascl1 to convert adult MGs into neurons in the injured retina (Jorstad et al., in vivo conditions. For example, both mouse fibroblasts and astrocytes can be efficiently reprogrammed into dopaminergic neurons in culture (Addis et al., Emerging evidence indicates that multiple pathways regulate the Neurog2 and Nurr1 reprograms adult astrocytes into diverse neuronal subtypes with cortical layer-specificity and precise long-distance axonal projections (Mattugini et al., Neurod1 in the adult cortex with or without prior injury (Chen et al., Neurod1 can efficiently reprogram both astrocytes and microglia into mature striatal neurons (Matsuda et al., Ptbp1 (Weinberg et al., Neurod1? Since most, if not all, of the developmental cues for axon guidance, are diminished in the adult CNS, how do these newly reprogrammed neurons make precise axonal projections especially after neural injuries? Answers to these questions will provide critical insights into the cellular mechanisms for neural reprogramming in vivo.Intriguingly, various glial cells can be efficiently reprogrammed by diverse factors into brain region-specific neuronal subtypes. For example, a combination of In vivo neural reprogramming has shown promising biological functions for stroke-induced brain injury (Chen et al., In vivo neural reprogramming has achieved impressive progress, ranging from generation of diverse glia-converted neurons in multiple CNS regions to functional improvements for certain neurological conditions. Such a reprogramming-based approach may kill two birds with one stone: regeneration of functional neurons and modulation of pathological microenvironment. Nonetheless, efforts should be taken to vigorously validate the cell origin for the claimed new neurons and to tease out the molecular and cellular mechanisms underlying the reprogramming progress. The results of these efforts will lay a solid scientific foundation to move in vivo cell fate reprogramming towards neural repair.WT and C-LZ wrote the manuscript and X-MX commented on the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The ability to extinguish fear memories when threats are no longer present is critical for adaptive behavior. Fear extinction represents a new learning process that eventually leads to the formation of extinction memories. Understanding the neural basis of fear extinction has considerable clinical significance as deficits in extinction learning are the hallmark of human anxiety disorders. In recent years, the dopamine (DA) system has emerged as one of the key regulators of fear extinction. In this review article, we highlight recent advances that have demonstrated the crucial role DA plays in mediating different phases of fear extinction. Emerging concepts and outstanding questions for future research are also discussed. Learning to associate stimuli and situations with danger or safety is critical for survival and adaptive behavior. In the laboratory, these forms of learning are typically studied using Pavlovian fear conditioning and extinction. Fear conditioning is an example of associative learning in which an initially neutral stimulus such as a tone  comes to elicit fear responses after being paired in time with an aversive outcome such as a foot shock . Once the CS-US association is learned, subsequently repeated presentations of the CS in the absence of the aversive US result in a gradual decrease in conditioned fear responses, a process known as fear extinction. In the last decades, fear extinction has attracted much interest in part because deficits in extinction learning are thought to underlie human anxiety disorders, such as post-traumatic stress disorder (PTSD) and phobias  system has also emerged as an important mediator of fear extinction. DA is a neurotransmitter critically involved in a wide range of functions including reward learning, motivation, motor control, and cognitive functioning. DA neurons that are mainly located in the ventral tegmental area (VTA) and substantia nigra (SN) in the midbrain. DA receptors are metabotropic receptors that can be classified into two main types with the DA D1-type receptors (Gs-coupled) comprised of D1 and D5 and the DA D2-type receptors (Gi-coupled) comprised of D2, D3, and D4 subtypes  could be conceptualized as an appetitive or reward-like prediction error. Thus, fear extinction may be mediated by the reward learning system , the main DA output region in the rodent ventral striatum, form the canonical reward circuitry Wise, , NAc conThe amygdala is a key structure underlying the acquisition and expression of fear extinction memories. Specifically, two subregions within the amygdala microcircuitry, the basolateral amygdala (BLA) and the intercalated cell masses (ITCs) are critically involved in fear extinction , which are a network of interconnected GABAergic cell groups located in the external and intermediate capsules surrounding the BLA. Notably, the ITCs located within the intermediate capsule are comprised of the dorsomedial (dmITCs) and ventromedial (vmITCs) clusters where dmITCs exert a unidirectional inhibitory control over vmITCs  subregion of mPFC, is crucial for the consolidation of fear extinction memories  during extinction learning are reactivated shortly after extinction during memory consolidation and the number of these reactivations predicts extinction memory strength when tested the next day. Importantly, systemic administration of L-DOPA enhances vmPFC reactivations in parallel to improving extinction memory (Gerlicher et al., While the studies summarized above highlight the crucial role DA plays in extinction memories, the source of DA release in the mPFC during fear extinction has not yet been identified. Anatomical studies demonstrate that the mPFC-projecting DA neurons are mainly located in the VTA (Lammel et al., Considerable progress has been made towards understanding the role DA plays in fear extinction. The studies reviewed above provide insights into how DA mediates different phases of extinction through its actions in the distinct components of the neural circuitry underlying fear extinction. The main conclusions and outstanding questions permitted from these studies are summarized in XS-H and SD wrote the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In this invited review Dr. Chung from Australia presented a good revision on Penile Prosthesis Implant (PPI) pointing to important technical aspects about this therapeutic option considering special populations.The author conducted a critical review of all relevant publications from Medline and Embase databases and included a brief review of surgical challenges and a practical action-based set of recommendations on surgical options.The risk of infection is still a matter and in diabetics it is more frequent and serious. Dr. Chung presented controversial numbers on ideal cut off value on HbA1c level and the lack of an evidence-based guideline published that precludes surgery above a certain value for HbA1c. He also stressed on the protective effect of antibiotic-impregnated implants . PostopeOther important special group is the one formed by spinal cord injury (SCI) men. Besides the fact that literature on the clinical outcomes of PPI surgery among neurogenic men is limited, Dr. Chung presented the question of which would be the best option for SCI patients: inflatable three-piece or the malleable or semi-rigid prosthesis, since they are often physically handicapped with poor hand dexterity, limited range of mobility, and muscle fatigue. On the other hand, the lack of sensation among SCI men may predispose those with a malleable implant to have a delayed identification and presentation of prosthetic complications . DiscussThe author also approached corporal fibrosis , and salvage PPI surgery, since those cases can pose a substantial technical challenge in terms of corporal dilation and they do have a greater risk of prosthetic complications, especially device infection and erosion."}
+{"text": "The main challenge for a positive long-term outcome in lung transplantation is the lack of early detection for chronic lung allograft dysfunction (CLAD). With advancements in technology, an increasing number of studies demonstrate that cell-free DNA (cfDNA) in body fluids could be used as a marker for disease diagnosis, prognosis or monitoring response to treatment. A previous report from this journal found the joint assessment of cfDNA and CXCL10 from brochoalveolar lavage (BAL) could determine the subphenotypes of CLAD and predict lung transplant survival. This is an exciting attempt in monitoring the progress for lung transplant recipients. More studies and better understanding of cfDNA are needed to develop an accessible and reliable biomarker to monitor the progress of CLAD to improve the long-term survival for lung transplant recipients.  Lung transplantation is the treatment option for patients with end-stage lung diseases . CompareThere are many risk factors for developing CLAD after lung transplant, such as acute cellular rejection, lymphocytic bronchiolitis and antibody-mediated rejection . CLAD isFor the liquid biopsies of lung transplant, BAL from the lung transplant recipient would offer direct sampling of the cellular and molecular events from the anatomic site of lung allograft rejection. Attempts were made to identify markers from BAL fluid to detect allograft rejection ; howeverThe findings in this study are important as they offer new ways to establish biomarkers to monitor lung transplant recipients for developing CLAD. The survival rate in lung transplantation is about 6 years, which is behind other solid organ transplantations, and CLAD is the major impediment of survival . HoweverIn this study, cfDNA was measured by an ELISA-like kit . With th"}
+{"text": "Diagnosing and treating low back pain (LBP) is a worldwide major primary care challenge in which a differential diagnosis between non-specific LBP and conditions with a known pathology is essential for choosing the optimal treatment strategy. The time required for the diagnosis of a condition such as ankylosing spondylitis (AS) was previously found too long. However, a recently published paper by Bashir et al. found that distinct episodes of axial pain separated by more than 6 months seem more predictive than currently applied characteristics in reaching an early diagnosis of AS. With a global one-month point prevalence of 23.2%, low back pain (LBP) is a major health challenge across cultures . LBP is Clinical diagnosis of LBP based on the patients\u2019 history and clinical examinations is the key initial assessment by the first-line assessor of LBP\u2014often the general practitioner (GP). This triage determines the subsequent diagnostic workup and informs the future treatment plan for the patient, including involvements of allied health care providers and medical specialist referrals . The purAnkylosing Spondylitis (AS) is considered a relatively rare diagnosis in general practice . HoweverAmong the large group of patients with non-specific LBP, recent studies have found fear avoidance and other psychosocial factors predictive of worse outcomes when experiencing LBP , 18. WhiGood early predictors for AS have previously been difficult to identify . HoweverA newly published paper found that two distinct periods of axial pain is predictive of receiving an AS diagnosis. This can support clinicians in reaching earlier diagnoses of AS among patients with non-specific pain, and this finding is important to inform future research into the differential diagnosis of patients with fluctuating non-specific LBP."}
+{"text": "Synergistic associations between infection and nutrition are well known. Impact of nutrition interventions on the outcomes have been scientifically assessed and reported. The role of nutrition in limiting the infection related morbidity and mortality does not appear to be a debatable question but nutrition interventions do not appear to be an essential part of current COVID-19 management strategies. Given the nature of pandemic and lack of organism-specific evidence, variability in nutrition interventions and lack of nutrition interventions is not unexpected. However, delay in realization of the crucial need of nutrition interventions to limit the immediate and long term outcomes at personal and community level may aggravate health related issues that can have long term impact on quality of life and economy. Due to existing undernutrition and lack of nutrition related awareness and competence, need for timely and appropriate interventions is much more critical for developing countries. This manuscript highlights the need and feasibility of various nutrition interventions to assure optimum quality of life during and after COVID-19 pandemic. Available evidence provides enough guidance for nutrition interventions that are safe and promise to accrue various degrees of benefits with almost no likelihood of harm. Nutrition interventions suggested by author are: 1) population level efforts for promoting better use of existing resources; 2) quicker augmentation of nutrition status of high risk people and non-hospitalized cases by use of supplement and individualized guidance and 3) nutritional support of sever case by timely and adequate enteral and parenteral feeding. COVID-19 is a highly infectious disease caused by infection with a new strain of coronavirus identified in late 2019. Absence of vaccination and evidence-based treatment regimes, rapid escalation in cases; and need for hospitalization and mechanical ventilation of severe cases has made its management extraordinarily challenging.2The main strategy suggested by experts to deal with the pandemic to flatten the curve by slowing down the rate of transmission, specially to people at high risk of severe impact. Personal hygiene, voluntary social distancing and mandatory restrictions to distance people are the measures being stressed to reduce the rate of transmission.This manuscript highlights the available evidence to identify nutrition interventions that have potential to alleviate the negative impact of COVID-19 pandemic on developing countries like Pakistan.To explore the potential of nutrition interventions in supporting the management of COVID-19 available evidence regarding mechanism of COVID-19 infection and its clinical course sequel was retrieved form \u201cPubMed\u201d. All the evidence, and guidelines by professional association and expert\u2019s opinions about role of nutrition in managing COVID-19 was also studied. Evidence about role of nutrition in managing similar viral infections and similar pathophysiology was also reviewed. Search terms used included: \u201cCOVID-19 AND Nutrition\u201d, \u201cCOVID-19 AND food\u201d \u201cCOVID-19 AND Pakistan\u201d; \u201cViral Infections AND Nutrition\u201d \u201cViral Infections AND food\u201d.For estimating the feasibility and effectiveness of possible nutrition intervention in Pakistan information was retrieved from research databases and publications of international agencies and government of Pakistan. Search terms used included: \u201cViral Infections AND Pakistan\u201d \u201cNUTRTIONAL STATUS AND Pakistan\u201d \u201cDiet quality and Pakistan\u201d \u201cNutrition AND Pakistan\u201d.Evidence overwhelmingly supports the notion that nutrition can influence any person\u2019s ability to fight off viral infection.Development of vaccine to prevent COVID-19 could take more than year and even when developed its availability to all is not guaranteed. Recent reports of re-occurrence of infection in infected patients diminish hope for assured natural immunity. The high rates of morbidity and mortality highlight the need for additional public level strategies to support the immune system, so that the impact of the infection can be reduced.Impact of nutrition on immunity has been acknowledged for decades and mechanism of actions have been presented by many researchers. One simple presentation is quoted in Fig.112Moderate-quality evidence exists from both human intervention and observational studies to suggest that diet and individual nutrients can influence systemic markers of immune function and inflammation;6Lack of national and population level data about food and nutrient intake limits the opportunities for accurate assessment of micronutrient status of Pakistani population. Evidence available from small studies and food balance sheets leaves no doubts about presence of multiple micronutrient deficiencies in a large section of the population.18\u201cStay home, wash hands and strengthen your immunity by healthy diet, exercise and relaxation\u201d; \u201cno matter how healthy you are, for stopping entry of the virus you need to stay at home and wash hands; but once the virus enters your body, the strength of body\u2019s defense system decides the outcome and by eating healthy we can strengthen our immune system\u201d. Descriptions of healthy diet can be given in more detailed messages.In Pakistan, Micronutrient status of a high proportion of people can be improved simply by modifying food choices, food preparation methods, meal planning and within household food distribution. A brief list of required modifications is given in Mobile-health-interventions are observed to be effective in promoting behaviours change in many health and nutrition related behaviors in lower income groups in other countries.22For optimizing immune status, Calder et al on the basis of recent review recommend a multivitamin and mineral supplement that supplies the basic micronutrient requirements (e.g. RDA) for vitamins and minerals in addition to the consumption of a well-balanced diet. They allow supplementation above the RDA, but within recommended upper safety limits, for specific nutrients such as vitamins C and D and intake of 250 mg EPA + DHA per day.In addition to consumption of a healthy diet, provision of nutrition support by concentrated food sources and supplements to confirmed or suspected cases of COVID-19 can help in reducing hospital visits and hospitalizations. Use of hydration solutions, concentrated forms of high-energy, high-protein, micro-nutrient rich diet and use of nutrition supplements may be needed for symptomatic non-hospitalized patients.\u201cNutrition intervention and therapy needs to be considered as an integral part of the approach to patients victim of SARS-CoV-2 infection in the ICU setting, internal medicine ward setting as well as in general healthcare.\u201d because \u201cOptimal outcome can be improved implementing adherence to recommendations to ensure survival of this life-threatening disease as well as better and shorter recovery\u201d. ASPEN recommends nutrition screening of all high-risk patients of CVOID-19 and patients found to be malnourished should seek diet counselling form expert professionals, sufficient supplementation with vitamins and minerals, oral nutritional supplements (ONS), early enteral feeding and parenteral nutrition where provision of adequate amount of required feeds is not feasible via enteral nutrition.Regarding nutrition care of COVID-19 in health care facilities ASPEN states: This paper has reviewed available evidence that could assist in estimating the potential of nutrition in reducing the impact of COVID-19 infection. The findings strongly support the role of nutrition in reducing COVID-19 related morbidity and mortality in any population but opportunities for utilization the potential of nutrition are much greater in malnourished people.As low resource countries have very limited ability to manage critically ill cases of COVID-19, there is a dire need for improving the immunity of people by all available approaches including nutrition. Integration of nutrition interventions in COVID-19 pandemic-response strategies in urgently required in developing countries like Pakistan.Nutrition interventions suggested by author are: 1) population level efforts for promoting better use of existing resources; 2) prompt improvement of nutritional status of high risk people and non-hospitalized patients by use of supplements and individualized guidance and 3) nutritional support of severely ill patients through timely and adequate enteral and parenteral feeding.Similar concerns and suggestion have been shared by other nutrition experts from relatively more developed countries.26"}
+{"text": "These scientific advances associated with the use of developmental manipulations in the immature brain of animal models are the basic preclinical systems that will allow the future translatability of timely interventions into clinical applications for neurodevelopmental disorders such as intellectual disability, autism spectrum disorders (ASD) and schizophrenia.Critical periods of brain development are epochs of heightened plasticity driven by environmental influence necessary for normal brain function. Recent studies are beginning to shed light on the possibility that timely interventions during critical periods hold potential to reorient abnormal developmental trajectories in animal models of neurological and neuropsychiatric disorders. In this review, we re-examine the criteria defining critical periods, highlighting the recently discovered mechanisms of developmental plasticity in health and disease. In addition, we touch upon technological improvements for modeling critical periods in human-derived neural networks  Normal brain function results from a conserved sequence of developmental processes of cell division, migration, network formation and maturation, directed by intrinsic genetic programs as well as by environmental and systemic cues, extrinsic to the nervous system. Within this sequence, appropriate stimuli induce events of heightened plasticity that are required to develop a given function. This capacity of the brain to reorganize during unique developmental time windows in adaptation to the environment has been termed \u201ccritical period.\u201dFmr1 knock out model of Fragile X syndrome .In the form of electrical activity, experience during development drives the structural and functional organization of neural connectivity 13.5, the ability of apical progenitors to revert to an earlier neurogenic competence and to generate early-born Cajal-Retzius cells, instead of deep-layer pyramidal neurons  could have a different impact on the dimensionality of neural responses than changes in connectivity patterns . Currently, it is unclear how programmed cell death of postnatal neurons precisely influences information processing in the cerebral cortex. However, initial studies performed in mice demonstrate that manipulating the number of excitatory pyramidal neurons in the cerebral cortex results in permanent consequences for brain function and behavior. Glutamatergic neuron overproduction as well as increased glutamatergic neuron apoptosis result in altered motor learning, hyperactivity or phenotypes reminiscent of autism-like traits  and Bcl2 antagonist/killer (Bak) render specific cell populations susceptible to undergo cell death during brain development  displaying abnormal GABA polarity in the hippocampus (excitatory GABA instead of inhibitory), until very late in brain development . These efforts normalized somatosensory whisker-evoked responses and GABA polarity in the mouse hippocampus of the FXS mouse model  brain organoids, derived from human induced pluripotent stem cells (iPSCs), resolved the long-standing limitations of a 2D approach and provide unprecedented opportunity to understand neurobiological mechanisms of human brain development in health and disease. Currently, 3D brain organoids have a demonstrated validity to model basic features of the human embryonic neural tissue and critical steps of early brain development such as neurogenesis, neuronal migration and neuroanatomical features\u2014upper and deep layer neurons\u2014specific of brain tissue . ALI-COs have been useful in the generation of brain organoids with specific features more reminiscent of in vitro brain organoid systems to model critical periods require further systematic efforts to reliable model the emergence of network activity patterns and new approaches that mimic environmental influences together with techniques tailored to measure their long-term consequences in organoid culture conditions. So far, brain organoid preparations display spontaneous neural activity  in a dish faces many technical challenges and will probably require of brain assembloid technology. Brain organoid preparations containing photoreceptor-like cells and forebrain-like structures, display neural activity in response to light stimuli (Quadrato et al., Critical periods hold potential to reinstate brain function. We provide a perspective on how the different aspects of critical period research paves the way for potential disease-modifying therapeutic strategies in neurodevelopmental disorders. Timely interventions during specific developmental windows restore network activity or behavior in animal models, thus reinforcing the notion that critical episodes of developmental plasticity can be used as unique windows of therapeutic opportunity to reorient pathophysiological states towards a \u201cnormal\u201d developmental path Mar\u00edn, . CriticaA key challenge to further understand the time-course of vulnerable periods during brain formation is the study of sex-specific differences. A wealth of data demonstrates that the critical period of sexual differentiation in the brain starts in the embryonic brain (from E16 to P4 in mice and second trimester in human; McCarthy et al., Finally, careful classification of vulnerable periods as \u201ccritical\u201d or \u201csensitive\u201d has implications beyond basic research. Policymakers, psychosocial therapies and educational aid programs for early childhood adversity should be guided by the scientific advances in critical period research (see recent review Nelson and Gabard-Durnam, ND and ID contributed equally.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "To examine how food insecurity is related to emerging adults\u2019 food behaviours and experiences of neighbourhood safety and discrimination and to identify resources needed to support their health during the COVID-19 outbreak.Rapid response online survey. Participants completed the six-item US Household Food Security Survey Module, a brief measure of food insufficiency, and measures of food behaviours, neighbourhood safety and discrimination. Open-ended questions were used to assess changes in eating behaviours during COVID-19 and needed resources.C-EAT (COVID-19 Eating and Activity over Time) study invitations were sent by email and text message to a longitudinal cohort.sd 2\u00b70) years, 70\u00b72 % female) completed a survey in April\u2013May 2020 during a stay-at-home order in Minnesota.A total of 218 emerging adults (mean age = 24\u00b76 (The past year prevalence of food insecurity was 28\u00b74 %. Among food-insecure respondents, 41\u00b70 % reported both eating less and experiencing hunger due to lack of money in the past month. Food-insecure respondents were less likely than those who were food secure to have fruits/vegetables at home and more likely to have frequent fast-food restaurant meals, feel unsafe in their neighbourhood and experience discrimination during the stay-at-home order. Food-insecure adults reported changes including eating more food prepared at home, eating more take-out restaurant meals and purchasing more energy-dense snacks as a result of events related to COVID-19. Resources most needed to support their health included eligibility for more food assistance and relief funds.Food-insecure emerging adults experience many barriers to maintaining healthful eating patterns during COVID-19. Federal and local policies and programmes that support equitable access to adequate food are critical to ensuring the health of populations and especially vulnerable groups impacted by public health emergencies such as the COVID-19 pandemic. The life course transition from adolescence to adulthood is a period of particular vulnerability for experiencing food insecurity and its impacts on health,9.Having a safe and dignified manner to access adequate food is a basic human right. The condition of food insecurity  is associated with poorer health behaviours and compromised physical and mental well-being. The subgroups of emerging adults who reported unemployment, living with children of their own and an ethnic/racial identity of African American, Black or Native American were most likely to have experienced food insufficiency. These observed disparities among the emerging adults who were invited to participate in the present study are in line with disparities identified by national surveillance data for the overall US population. The disparities highlight the need for more attention to structural and racial barriers to health and their influence on susceptibility to food insecurity,12. Only a small number of studies have investigated linkages between neighbourhood safety, exposure to racism and experiencing food insecurity; however, the available evidence suggests that unsafe neighbourhood conditions and multiple forms of experiencing discrimination are likely to have substantial negative impacts on one\u2019s ability to access adequate food\u201316.A 2018 survey of the EAT 2010\u20132018 (Eating and Activity over Time) study cohort from Minneapolis\u2013St. Paul, Minnesota found that about one in four emerging adults (18\u201326 years) had experienced food insufficiency in the past year. National survey data indicate that the prevalence of food insecurity has recently doubled in the overall population and tripled among households with children as a result of many businesses and schools being forced to shut. The stay-at-home orders that were implemented as part of efforts to protect public health have led to increasing unemployment and new barriers to food access\u201321. Several recent changes in the operation of food assistance programmes (e.g. grocery deliveries by food shelves) and supportive policies (e.g. Families First Coronavirus Response Act) have been enacted to respond to the crisis. There is however little known about home food availability and food shopping and eating behaviours during COVID-19 with specific concern for households that have experienced food insecurity at one or more times in the past year. In order to guide policy decisions about food assistance programmes and supportive services, and the design of effective health promotion messaging for public health emergencies, it will be important to build understanding of the food behaviours and discrimination experiences of those who are faced with food insecurity.The US outbreak of COVID-19 has intensified challenges and disparities in food access among vulnerable populations and led to an epidemic of food insecurity,23\u201325, the present study was specifically designed to help inform the development of policies and services for emerging adults. The three aims focus on food insecurity and intersecting problems. The first aim is to describe how past year experiences of food insecurity are related to emerging adults\u2019 experiences of food insufficiency, food shopping behaviours, home food availability, eating behaviours and experiences of neighbourhood safety and discrimination during COVID-19. Secondly, the study examines how food shopping, food preparation and eating behaviours have been influenced by events related to COVID-19 for emerging adults who were food insecure at one or more times in the past year. The third aim is to identify the resources that are most needed by food-insecure emerging adults to help them gain access to healthy foods and maintain their overall health during a public health emergency.As one of the first US studies to examine food insecurity and related factors during COVID-19,26. Invitations to participate in the online C-EAT survey were sent to cohort members by email and text message in April 2020. A reminder message was similarly sent to a subset of non-responders who had provided both forms of contact information. Responses to the survey had been received from 218 young people (21 % of those who could be contacted) at the time that COVID-19 emergency stay-at-home orders were lifted in Minnesota on 18 May. All participants were mailed a financial incentive of $25 following survey completion. The University of Minnesota Institutional Review Board Human Subjects Committee approved all protocols.Participants in the C-EAT (COVID-19 Eating and Activity over Time) study were members of the EAT 2010\u20132018 longitudinal study cohort and invited to complete a follow-up online survey in the spring of 2020 during the initial months of the US outbreak of COVID-19. The EAT 2010\u20132018 study is a population-based investigation of weight-related health behaviours and associated factors among 1568 young people who were attending secondary school in Minneapolis\u2013St. Paul, Minnesota in 2009\u20132010sd 2\u00b70) years in 2020. Although C-EAT survey participants were less likely than 2018 survey participants to identify as male, identify their race as African American or Black and have a parent of lower SES, C-EAT participants were of diverse backgrounds. The distribution of ethnic/racial backgrounds reported by C-EAT participants was similar but more diverse than the overall population in Minneapolis\u2013St. Paul, Minnesota with 36\u00b74 % White, 19\u00b74 % Asian American, 19\u00b73 % Hispanic, 14\u00b73 % African American or Black and 10\u00b76 % mixed or other. The distribution across categories of parental SES based primarily on baseline educational attainment was: 30\u00b73 % low, 16\u00b71 % low-middle, 18\u00b73 % middle, 21\u00b71 % upper-middle and 14\u00b72 % high. Most participants (87 %) were living in Minnesota at the time they completed the C-EAT survey.The C-EAT survey sample included 153 females, 62 males and 3 participants indicating another sex identity. The sample had a mean age of 24\u00b76  and ethnicity/race (test\u2013retest agreement range: 98\u2013100 %) were assessed on the original school-based survey in 2009\u20132010,31,32.The C-EAT survey was based on prior EAT surveys with modifications made to focus recall on the past month of events related to the COVID-19 outbreak\u03c72 tests were initially examined to assess the prevalence of food insecurity in the past year and food insufficiency in the past month across sociodemographic characteristics of emerging adults in the sample. The first study aim was accomplished by focusing on the more common experience of being food insecure at any point over the past year; regression models were used to produce least square mean estimates for measures of food shopping behaviours, home food availability, eating behaviours and neighbourhood safety and discrimination experiences among food-secure and food-insecure emerging adults. Generalised binomial models were used to examine statistical associations of each measure with food security status , and the inverse linked scale option was used to estimate the adjusted prevalence for the measures of interest. Regression models were examined without adjustment and also adjusted for emerging adult sex, ethnicity/race, employment status, household receipt of public assistance and living situation given these variables were identified as correlates of food security in the present analysis or prior research,33,34. A third set of models were additionally adjusted for parental SES to build understanding of how the experience of food insecurity may be distinct from the experience of having limited financial resources. As both sets of adjusted models produced similar results and the former is most relevant to intervention design, the model adjusting for SES is not described in detail below. A 95 % confidence level was used to interpret the statistical significance of all probability tests. Analyses were conducted using the Statistical Analysis System .Frequencies, percentages and n 1 participant was food insufficient in the past month but not food insecure in the past year) were qualitatively coded in order to address the second and third aims of the study regarding how events related to COVID-19 had influenced eating behaviours and what resources were needed. A content analysis was conducted in three stages. The initial stage of coding involved review of all responses by the first author (N.L.) and the generation of several topic areas by which the diverse comments could be categorised. Next, the third author (T.A.) reviewed all comments using the schema developed in the initial coding and assigned each comment to relevant topic categories. Third, there were five coding discrepancies (<1 % of coding decisions) that were identified between the second coder and the initial coder; each of these discrepancies was discussed to resolution. All names in quotes were either removed or changed to protect participant confidentiality.Open-ended survey responses from sixty-two respondents who were food insecure in the past year or food insufficient in the past month (n 61) of emerging adults and, among this group of food-insecure participants, 41\u00b70 % (n 25) reported food insufficiency in the past month . Some food-insecure emerging adults reported eating less, whereas others reported eating more than usual due to anxiety, other emotions or boredom. It was also common for food-insecure emerging adults to report eating fewer meals and/or more snacks (n 14).Among the comments regarding the influence of COVID-19 on eating behaviours . Some food-insecure emerging adults reported eating more healthy foods for reasons such as boosting their immunity; however, most who mentioned this topic reported shifts towards eating less fresh food, more frozen and non-perishable foods, and more sugary snacks and junk food.Changes in the eat more food prepared at home (n 11) and for some to also have more meals that were prepared for sharing as a household. In correspondence with eating more food prepared at home, a number of emerging adults reported changing patterns of food shopping (n 18). Food shopping frequency was reported by some emerging adults to increase; however, there was much variability with others reporting they changed how they shop to reduce their number of trips to the store. While shortages at grocery stores made it more difficult to purchase desired quantities of food, a few emerging adults reported purchasing more non-perishables when possible.Events related to COVID-19 led a number of food-insecure emerging adults to changing the frequency of eating food from restaurants (n 16). Fears about getting sick at the grocery store led some food-insecure emerging adults to eat more take-out food from restaurants, whereas others had concerns about the safety of restaurant food. Among emerging adults who reported eating out, traditional fast-food restaurants were perceived by some to be the safest option.There was variability in the comments of emerging adults regarding n 18) and the overall sample of food-insecure young people  focused on a desire to receive food assistance benefits, including needs for a larger amount of benefits, having food delivery or pick-up options, and access to food at food pantries . Emerging adults experienced challenges with these resources due to limited eligibility for benefits as well as troubles with accessing food  that would serve the needs of their culturally diverse families.When asked about resources needed to help in getting enough healthy food for yourself and your family Table , most ofRelief funds and money  were also among the most common responses from food-insecure emerging adults with regard to needed resources. Emerging adults mentioned stimulus checks, relief funds, unemployment benefits, inadequate household income and the cost associated with healthy food. Eligibility for financial resources was particularly challenging for emerging adults who were single and did not have children of their own.accessing food at retail stores . Food-insecure emerging adults raised concerns relating to store policies that did not allow children to enter, out-of-stock items, inadequate cleaning procedures and lack of opportunities for ordering food online. In alignment with the quantitative findings, one participant specifically mentioned discrimination (i.e. fearing to go out because of their race) and another described worries about having to go to the store to purchase food with food assistance benefits.Resources were needed by emerging adults to address challenges with safely n 31) made by food-insecure emerging adults again focused on needs for money (n 11), food assistance (n 8) and challenges with food access (n 6). In particular, several participants mentioned the need for financial assistance to pay for rent. Health care was also a challenge for food-insecure emerging adults with comments (n 6) made regarding the cost, need for more mental health resources and the desire to have universal care and virtual care  options.When asked more generally about resources needed to support their overall health and the health of their family Table , most of,23\u201325. Results of the present study align with and extend prior research in finding that food insecurity is a prevalent problem among diverse emerging adults and common needs during the outbreak for resources such as support for food delivery costs, improved stocking of food in retail stores and increased food assistance benefits,23,25. As structural racism has resulted in a disproportionate burden of COVID-19 for Black, Indigenous and people of colour\u201337, the present study also included a novel focus on the co-occurrence of food insecurity with neighbourhood safety concerns and exposure to interpersonal forms of discrimination that may further limit access to healthy food. The findings indicate that emerging adults who were food insecure in the past year had poorer access to healthy foods at home, more frequent fast-food restaurant meals and more experiences of discrimination and feeling unsafe during the initial months of the COVID-19 outbreak when compared with emerging adults who were food secure. While the influence of COVID-19 on eating behaviour resulted in some health promoting shifts (e.g. preparing more food at home), most of the changes described by food-insecure emerging adults are likely to have negative health consequences. The results regarding unhealthy changes in food purchasing and eating are in line with other recent studies and emphasise the unique challenges faced by emerging adults during a public health emergency.This study is one of the first to our knowledge to examine food insecurity and intersecting barriers to health during the US outbreak of COVID-19 and was specifically designed to help inform the development of policies and services for emerging adults. The existing literature on food insecurity during the outbreak has focused on the high prevalence and disparities among population-based samples of adults, households with children and university students. Prior research has demonstrated there may be discomfort around making online purchases of nutrient-dense food items that are perishable , and thus strategies may also be needed for optimally using online options to purchase these foods.Results of the present study indicate that a majority of emerging adults have not recently made use of food shopping practices that could help them to more easily manage their resources for food and safety when shopping. Although the use of most food shopping practices was unrelated to food security status, practices such as planning meals before shopping and deciding on a set amount of money to spend could be particularly helpful for young people to manage their food needs and limit the time they need to spend in retail food stores. The practice of buying groceries online could also benefit emerging adults when store policies do not allow them to enter with children or they have a concern about potentially being exposed to COVID-19 while shopping. At the time of the C-EAT survey, only a small percentage of emerging adults reported buying groceries online; however, most Minnesota retailers did not yet have available the option for food assistance benefits to be used for purchasing groceries online. The recent expansion of the Supplemental Nutrition Assistance Program Online Purchasing Pilot in Minnesota and other states may lead to changes in the prevalence of this practice among food-insecure emerging adults if they are made aware of the new option and strategies for planning needed purchases around available time windows for pick-up and deliveryAnother unique contribution of the present study relates to building understanding of how food shopping, food preparation and eating behaviours of food-insecure emerging adults have been influenced by the COVID-19 outbreak. The findings may provide valuable guidance to organisations working to provide food assistance and health education during the current outbreak and future public health emergencies. Many emerging adults reported worries about becoming infected with COVID-19, but, in alignment with the state of confusion about health recommendations at the start of the outbreak, their worries led to different types of shifts in eating behaviour. Preparing more food at home and purchasing more non-perishable foods were common responses to worries about COVID-19. It was also common for emerging adults to report eating take-out food from restaurants and a shift to purchasing more often from traditional fast-food restaurants that provide drive-thru services. While some emerging adult respondents had fears about getting infected with COVID-19 as a result of poor food safety practices in fast-food restaurants, others were more concerned with getting infected as a result of being around other people in a crowded restaurant or grocery store. Findings from the present study suggest there is a need for clear and consistent messaging with a broad reach to inform young people about how to safely manage the purchasing of healthy food and meal planning during an infectious disease pandemic. For example, it may be helpful for agencies involved in providing food assistance to also have a role in educating young people on safety practices such as wearing a mask inside stores and restaurants, washing fruits and vegetables and thorough hand washing. Government programmes that focus on providing nutrition education to low-income populations  may be particularly well positioned to provide this vital information.,14. For example, research involving Latinx and Black/African American mothers of young children in Philadelphia found that experiences of discrimination from police, courts and in workplaces were associated with a greater likelihood of being food insecure. Discrimination in workplaces, schools and courts as examined by existing studies might plausibly be linked to greater food insecurity by pathways involving higher rates of incarceration, lower wages, lower rates of promotion and poorer job security. The emerging adult participants who reported experiencing racism in the month prior to the C-EAT survey were not asked about the specific settings in which people said mean or rude things to them because of their race or ethnic group, but many of the same pathways are likely to hamper access to healthy food for these young people and members of their household. Although most participants in the present study were not financially responsible for children of their own and 40 % were not independently responsible for housing expenses, it is likely that experiences of racism had a significant impact on the wages and job security of emerging adult participants and thus the adequacy of their household income. Additional research is needed to explore whether experiences of interpersonal racism in grocery stores and restaurants may play a role in food access and possibly compound the consequences of structural racism on access to large grocery stores and supermarkets.The findings of the present study build on what is known about linkages between experiences of interpersonal racism and food insecurity among ethnically/racially diverse emerging adults. The small number of prior investigations regarding this relationship have focused on households with children\u201343. Also, because the measures of food shopping behaviours and experiences of neighbourhood safety and discrimination were not included in the 2018 survey and the 2018 survey included only a two-item measure of experiencing food insufficiency in the past year, the study design was not ideal for examining changes from before to after the US outbreak of COVID-19. The measure of SES was validated by parental report at baseline of the study and incorporated information on parental education, parental employment and receipt of public assistance in order to help prevent misclassification of resources. Despite the established nature of the measure, it is important to acknowledge that SES may improve or decline as young people transition from adolescence to adulthood. The small size of the sample and variability of individual experiences also led to low numbers for some of the qualitative themes identified by the analysis and thus make the results more challenging to interpret.Study weaknesses to be taken into account in interpreting the findings include the limited generalisability of responses primarily coming from a convenience sample of emerging adults in one Midwestern state and the brevity of survey measures. It is a limitation that participants completed only the short form of the US Household Food Security Survey Module; although this tool is validated and ideal for limiting participant burden during a stressful time, it does not allow for assessing the most severe levels of food insecurity or conditions of children in the household. Participants completed measures of unsafe neighbourhood conditions and exposure to discrimination that were adapted from established tools, but the measures were very brief (e.g. captured only discrimination that involved having someone say mean or rude things about you). The C-EAT survey did not address all possible forms of discrimination and safety concerns and did not specifically assess the ways that these problems might influence one\u2019s ability to access healthy foodStrengths of the present study include the combined use of quantitative and qualitative data, breadth of food behaviours examined and the sociodemographic diversity of emerging adult participants. The timely collection of surveys from young people impacted by emergency stay-at-home orders will help to fill an urgent need for data to inform health protection policies and services. In particular, the analysis of open-ended comments provides important context for understanding the challenges faced by emerging adults who responded to survey measures in a manner indicative of experiencing food insecurity. It will be important for additional studies to examine the impact of stay-at-home orders on food insecurity in other population-based samples of emerging adults; however, the present study provided valuable insights into the experiences of ethnically/racially diverse young people and was inclusive of persons living alone, persons living with their parents and others who were living with families of their own.. The much higher prevalence of 12 % of emerging adults reporting food insufficiency in the past 30 d during the COVID-19 outbreak is of great concern. Research building on the present study is needed to guide the ongoing response to food insecurity in areas impacted by COVID-19 outbreaks and as part of future public health emergencies. It will be important for follow-up studies to evaluate how the needs of emerging adults may change as communities continue to cope with COVID-19 and what challenges are encountered after stay-at-home orders are lifted. The role of racism in food insecurity is complex. The results reported here suggest it would be worthwhile to further use more in-depth measures to assess exposure to racism and explore the perceptions of emerging adults regarding how various forms of racism influence their shopping habits and ability to obtain healthy food. It could likewise be informative to comprehensively investigate experiences of racism within settings such as schools, food pantries and sites that administer nutrition assistance programmes and how they might influence food access for emerging adults. Efforts to simplify the process of accessing food assistance for emerging adult populations should be evaluated along with messages about potentially beneficial food purchasing practices .In conclusion, the results described here demonstrate that emerging adults are experiencing many barriers to accessing food and maintaining healthful eating patterns during the US outbreak of COVID-19. The national prevalence of food insecurity in the past 30 d was 5\u00b75 %, and 2\u00b73 % of US households experienced very low food security in December 2019 prior to the outbreak of COVID-19. Access to adequate benefits through federal programmes has been a particular challenge that needs to be monitored for emerging adults who do not have a spouse or children and may be living alone or with other adults who are employed. Additionally, the results strongly suggest the need for public health efforts to reduce barriers to the safe purchasing of healthy foods and ensure local nutrition programmes provide culturally acceptable food options for all community members in need. The option to use food assistance benefits to purchase food online and have the food delivered or available for pick-up outside the store was identified as very desirable, and thus it will be important for nutrition professionals to support, help to evaluate and help to educate emerging adults about the Supplemental Nutrition Assistance Program Online Purchasing Pilot. Findings of the present study further emphasised the need for nutrition professionals to take an active role in addressing racism and neighbourhood safety given the strong relationships between these public health problems and food insecurity. Safety with regard to avoiding exposure to COVID-19 when purchasing food and meal planning are yet more challenges that can be addressed by the work of nutrition professionals in providing guidance on how to safely manage the purchasing and preparation of healthy food. The diversity of experiences reported by young people as part of this study further suggest that nutrition professionals will need to be responsive to unique challenges and should take time to ask about and listen to how their clients are coping with the health risks and food access barriers posed by COVID-19.Despite the need for additional research, the results of the present study emphasise the importance and urgency of supporting ongoing efforts to expand food assistance benefits, benefit flexibilities and relief funds in order to provide emerging adults with the tools they need to maintain their health in times of public health emergencies. The response of the US Department of Agriculture Food and Nutrition Service to COVID-19 has begun to address many of the challenges that were raised by emerging adults as part of this study, and nutrition professionals will have an important role in ensuring that programme changes are communicated broadly and evaluated"}
+{"text": "Parkinsonism is a commonly seen movement disorder syndrome with neurodegenerative and non-neurodegenerative causes. Presynaptic dopamine transporter (DaT) single\u2010photon emission computed tomography (SPECT) imaging is the most commonly used imaging technique in clinical practice to differentiate degenerative Parkinson\u2019s disease (PD) and PD plus syndromes from other causes such as essential tremor and drug-induced parkinsonism. This can help identify the patients who would benefit from medical therapy due to underlying pre-synaptic dopaminergic deficits. We report a case of unilateral parkinsonism caused by ipsilateral substantia nigra micro-haemorrhage resulting in disruption of the nigrostriatal pathway. This is an unusual case of a 55-year-old male patient who presented with unilateral Parkinsonism a decade after significant head trauma where MRI plays a critical and complementary role in diagnosing complete interruption of the nigrostriatal pathway due to cerebral micro-haemorrhage. The case also beautifully demonstrates the anatomy of the nigrostriatal pathway where a small lesion in the substantia nigra caused complete loss of radioligand uptake in the ipsilateral corpus striatum. Physicians should be aware of the importance of structural imaging in atypical movement disorder cases and, in particular, the routine use of susceptibility-weighted sequences (SWI). MRI of the brain is a helpful first-line imaging tool to differentiate neurodegenerative parkinsonian disorders from parkinsonism caused by lesions involving the nigrostriatal pathway such as infarcts, mass lesions, and demyelination.3 Presynaptic dopamine transporter (DaT) single\u2010photon emission CT (SPECT) uses a radioactive pharmaceutical which binds to the presynaptic membranes of the terminals of dopaminergic projections. DaT is contemplated as an indicator of dopamine terminal integrity from the substantia nigra in the midbrain to the striatum in the basal ganglia (caudate nucleus and putamen).4 An abnormal DaT scan can help differentiate conditions associated with pre-synaptic dopaminergic dysfunction, such as neurodegenerative parkinsonism and vascular Parkinson\u2019s, from essential tremor and drug-induced Parkinson\u2019s.Parkinsonism is a movement disorder defined by the presence of bradykinesia in addition to rest tremor or rigidity.5\u20137 have been described. To our knowledge, this is the first case of hemi-parkinsonism caused by ipsilateral substantia nigra micro-haemorrhage resulting in disruption of the nigrostriatal pathway. This emphasises the importance of susceptibility-weighted sequences in imaging patients with parkinsonism especially in the presence of unilateral abnormal DaT scan and normal head CT or structural MRI scans.There are many case reports in the literature describing focal lesions within the substantia nigra affecting the nigrostriatal pathway DaT uptake and causing contralateral hemi-parkinsonism. The causes ranging from lacunar infarcts to Japanese encephalitisWe present a 55-year-old male patient who sustained a head injury in a road traffic accident about 13 years ago. CT scan of his head at that time showed multiple brain parenchymal haemorrhagic contusions involving the corpus callosum, bilateral frontal, and temporal lobes. He suffered right-sided hemiparesis since then. Seven years later he started to develop gradual worsening of the unilateral hemiparesis along with new onset of rigidity and hyperreflexia, symptoms which are indicative of extrapyramidal syndrome and had worsened along the course of 2 years. He was thus investigated for the possibility of idiopathic Parkinson\u2019s disease. MRI of his head was done and showed encephalomalacia changes involving bilateral superior frontal gyri. The lesion within the left frontal lobe involves the supplementary motor cortex (area 6) which explains the post-traumatic right-sided hemiparesis that he had suffered from for years. No abnormality was seen within the basal ganglia or midbrain to explain the extrapyramidal symptoms. No susceptibility-weighted imaging was obtained at that time. The DaT scan showed complete absence of the radioligand uptake within the right striatum with normal uptake on the left . Whilst 8 However, few studies have discussed the SWI importance in evaluating unilateral parkinsonism apart from that.Structural imaging is performed in the presence of abnormal DaT scan uptake to rule out focal abnormalities involving the nigrostriatal pathway. This is of particular importance in patients not presenting with the typical clinical picture of degenerative PD. SWI should always be included in the MRI sequencesto evaluate for the presence of iron accumulation and focal haemorrhages.Our patient presented with symptoms of unilateral parkinsonism with ipsilateral absent radioligand uptake on DaT scan within the right striatum. The cause of which was found to be right substantia nigra haemorrhage from a previous head injury. Susceptibility-weighted imaging has long been used in imaging of Parkinson\u2019s disease but was always used to detect iron accumulation in the substantia nigra. An area of particular importance is the dorsolateral substantia nigra called Nigrosome one which typically shows hyperintense signal on SWI, the so-called swallow-tail sign. Several studies have proved that the loss of the swallow-tail sign was both sensitive and specific for Parkinson\u2019s disease.The connection between the presence of a substantia nigra lesion and unilateral parkinsonism is well recognised.9 Thus, any lesion along the pathway will cause symptoms on the contralateral side-of the body.The substantia nigra is connected to the ipsilateral motor cortex via connections with the caudate and putamen in the process of movement regulation.10 Furthermore, the radioligand uptake on DaT scan was significantly reduced in the putamen on the symptomatic side. Whereas the putamen uptake contralateral to the symptomatic side was only slightly reduced or normal. This was attributed to being due to hand dominance. This is in concordance with other studies which support the hypothesis that motor symptoms in unilateral parkinsonism are usually on the hand dominant side.11Additionally, a case report published in 1978 described a case with right-sided parkinsonism due to a right substantia nigra infarct confirmed at autopsy.12 Further studies are needed to justify the occurrence of clinical symptoms ipsilateral to the substantia nigra abnormalities.DaT scan can evaluate the integrity of the nigrostriatal pathway from the substantia nigra in the midbrain to the caudate and putamen in the basal ganglia. Nonetheless, most of the information in the literature discusses the contra laterality of the clinical symptoms in relation to the substantia nigra lesion. However, one study in evaluating patients with early-stage unilateral Parkinson\u2019s disease found that changes in the substantia nigra correlated with clinical symptoms on the ipsilateral side-of the body.To our knowledge, this is the first case of substantia nigra haemorrhage causing unilateral absent uptake in the right striatum. Moreover, the ipsilateral symptomatology of our patient adds to the uniqueness of our case.Substantia nigra micro-haemorrhage is a rare cause for unilateral parkinsonism.The importance of utilizing structural imaging along with nuclear scans in diagnosing movement disorders.The use of susceptibility-weighted imaging in unilateral parkinsonism."}
+{"text": "Hartmut Porst and Andrea Burri pointed the actual situation of Premature Ejaculation (PE) arguing that there is a gap between what doctors are prescribing and what patients expect from treatment.The only so far officially approved medication \u2013 dapoxetine - is characterized by high discontinuation rates of up to 90%, mostly because of high side effects, cost issues, efficacy below expectations, and the need for scheduling sexual intercourse.The authors discussed advantages and disadvantages of currently available off-label and officially approved treatment options and presented the dose-metered lidocaine-prilocaine spray (Fortacin\u2122), the first topical treatment to be officially approved in Europe for the treatment of primary PE in adult men.The use of drugs that selectively reduce penile sensitization or which modify the afferent-efferent reflex could provide effective therapy for PE, as has been shown with the off-label use of topical desensitizing creams    that reThere are many studies   , 3  demFortacin \u2122 was officially approved for use in the European Union in 2013 and finally launched in the United Kingdom in November 2016. This lidocaine-prilocaine spray, with all pharmacological advantages and well conducted trials, has not yet reached a significant first-line therapy status both for the physicians and the patients in PE. There are no comments from the authors to contradict or explain this fact."}
+{"text": "Cancer metastasis is still the main cause of death for most cancer types  or protein levels in cells with identical genomes. While there are different uses of the term \u201cnoise\u201d across the fields of biology, we define noise here as in physics and engineering disciplines besides biology: as a general stochastic process that does not exclude heritability. Indeed, the existence of noise with various spectra  in nature implies that there can be various short- and long-term components of randomness.forward  investigation  investigation ] characterizes how far molecule numbers can deviate from the mean. Noise amplitudes can range from slight (CV < 20%) to dramatic (CV > 200%), giving rise to vastly different cellular phenotypes  interdependence. Typically, this relationship holds for various bursting regimes  different gene circuits to express the same gene with different noise-vs.-mean dependencies (Blake et al., As an illustrative classification inspired by studies examining how mean and noise affect drug resistance (Blake et al., Protein mean- and noise-dependent crossings of various thresholds in synthetic and natural scenarios can also be explored visually as landscapes . SynthetExperimental evidence for how gene expression mean and noise independently affect metastasis threshold crossing is relatively lacking, but synthetic biology is already shedding light on drug resistance (Farquhar et al., MG, YW, and GB conceived and wrote the manuscript. SL surveyed the literature and added the references. DY and MR contributed some critical concepts and feedback on the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Racial/ethnic disparities have been well documented in long-term care literature. As the population ages and becomes more diverse over time, it is essential to identify mechanisms that may eliminate or mitigate racial/ethnic disparities. Culture change is a movement to transition nursing homes to more home-like environments. The literature on culture change initiatives and quality has been mixed, with little to no literature on the use of culture change initiatives in high Medicaid nursing homes and quality. The purpose of this study was to examine how the involvement of culture change initiatives among high Medicaid facilities was associated with nursing home quality. The study relied on both survey and secondary nursing home data for the years 2017-2018. The sample included high Medicaid (85% or higher) nursing homes. The outcome of interest was the overall nursing home star rating obtained from the Nursing Home Compare Five-Star Quality Rating System. The primary independent variable of interest was the years of involvement in culture change initiatives among nursing homes, which was obtained from the nursing home administrator survey. The final model consisted of an ordinal logistic regression with state-level fixed effects. High-Medicaid nursing homes with six or more years in culture change initiatives had higher odds of having a higher star rating, while facilities with one year or less had significantly lower odds of having a higher star rating. Culture change initiatives may require some time to effectively implement, but these initiatives are potential mechanisms to improve quality in high Medicaid nursing homes."}
+{"text": "Anemia remains a challenge for most cancer patients treated with therapies that include chemotherapy to current immunotherapy or chemo-immunotherapy treatments. Multiple myeloma (MM) is a plasma cell neoplasm marked by the clonal proliferation of malignant plasma cells. Preceding stage in MM includes asymptomatic stages including monoclonal gammopathy of undetermined significance or MGUS before the disease progression to clinical MM. One of the clinical features of MM at diagnosis includes anemia, presenting in a majority of MM patients. Pathological changes in bone marrow microenvironment in monoclonal gammopathy/MGUS and MM contribute to the pathological imbalance in erythroid cell production, leading to lowered downstream mature erythroid cells. Molecular events and pathways that contribute to this pathological remodeling of erythroid pathway-elements remain unclear and need further investigations.Regulator of Hemoglobinization and Erythroid cell eXpansion or RHEX in the erythropoietin (EPO)/EPO receptor (EPOR) pathway that play key roles in erythroid cell maturation and development exclusively in humans were recently reported - Cereblon (CRBN) E3 ligase complex mediated proteasomal degradation of downstream targets (Immunomodulatory (IMiD) agents like pomalidomide have recently been reported to induce increased patients . These s targets . These C targets . Specifi targets .R based) as reported by Dulmovits et al. (It is to be noted that monoclonal gammopathy-associated PRCA might be a paraprotein-related phenomenon. It can be further speculated that there could be a functional relationship between altered plasma cell and erythroid precursor, with a possible causal relationship between M-protein response and hematological response including PRCA reversal in the PRCA bone marrow after treatment with pomalidomide or IMiDs . A numbes et al. .Detailed molecular mechanisms describing the additional targets of IMiD action remain an active area of research  and thesR drive the erythroid recovery in this pathology but independent of currently known molecular pathways that exclusively drive the action of these drugs on myeloma cells and potentially some immune cell subsets. Absence of RTK mutations further makes a strong case for an alternative mechanistic active in the progenitor cells under the action of novel agents like pomalidomide or lenalidomide for erythroid recovery in MM. Recent discovery of novel regulators like RHEX implicated in the human erythroid cell maturation combined with the findings of Dulmovits et al. proposes further investigations of erythroid maturation pathways in MM and Monoclonal gammopathy or MGUS associated PRCA to uncover the underlying molecular mechanism. With the progress of cell therapies like the BCMA targeting CAR-T cells for late stage or relapsed/refractory MM (Monoclonal gammopathy-associated PRCA illustrates an open ended clinical challenge to describe the underlying possible pathogenetic mechanisms by future mechanistic studies . Anti-myctory MM , these iRV prepared and wrote the manuscript.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In order to elucidate this, we first experimentally demonstrate an interferometric weak value amplification concept by generating nearly destructive interference of two paths of an interferometer having slightly rotated linear polarization states of light. The weak value amplification of polarization rotation effect is manifested as dramatic changes in the polarization state of light, which acts as the pointer. We go on to demonstrate that the manifestation of natural interferometric weak value amplification is an important contributing factor to the observed giant Faraday rotation and ellipticity in waveguided magneto-plasmonic crystals exhibiting prominent Fano resonance. The natural weak value interpretation of the enhanced Faraday rotation in hybrid magneto-plasmonic systems enriches the existing understanding on its origin. This opens up a new paradigm of natural weak measurement for gaining fundamental insights and ensuing practical applications on various weak interaction effects in rich variety of wave phenomena that originate from fine interference effects.The extraordinary concept of weak value amplification can be formulated within the realm of wave interference as nearly destructive interference between the eigenstates of the measuring observable. Here we report on a phenomenon of interferometric weak value amplification of small polarization rotation in Fano resonance that evolves completely  The outcome, the so-called weak value may lie far outside the eigenvalue spectrum of an observable and can also assume complex values. These strange characteristics have allowed a wide range of applicability of weak values in both classical and quantum contexts15. The weak value amplification (WVA) has turned out to be a useful tool for addressing foundational questions in quantum mechanics13 and for resolving quantum paradoxes15. WVA is also finding widespread metrological applications11, to quantify small physical parameters, e.g., for precision measurements of angular rotation6, phase shift8, temporal shift9, frequency shift10, detection of ultra-sensitive beam deflections11, and so forth.The weak measurement concept, introduced by Aharonov, Albert, and Vaidman11. In most of the optical weak measurements, Gaussian spatial modes of laser beams or Gaussian temporal pulse are employed as external pointer and associated polarization state of light is used as a pre-post selection mechanism, with tiny polarization dependent optical effects providing the weak coupling between the pointer and the measuring observable10. The enigmatic concept of WVA can also be interpreted as near destructive interference between the eigenstates of the measuring observable as a consequence of nearly mutually orthogonal pre and post selections of the system states3. Here, we demonstrate that due to the common interferometric origin, weak value amplification of an appropriate weak interaction parameter can naturally evolve in a universal wave interference phenomenon, namely, Fano resonance20. Fano resonance exhibits a characteristic asymmetric spectral line shape which emerges due to the interference of a discrete excited state with continuum of states16. Investigations on Fano resonances in wide range of micro and nano scale optical systems have attracted particular attention due to their numerous potential application such as in sensing, switching, lasing, filters, color display, nonlinear and slow-light devices and in invisibility cloaking etc27. The waveguided plasmonic crystal is one such nano-optical system that exhibit prominent Fano resonances and has already shown a number of interesting fundamental optical effects and demonstrated promising applications27. Taking example of Fano resonance in such a waveguided magneto-plasmonic crystal system31, we show that spectral domain interference between a continuum mode and a narrow resonance mode having slightly different polarization response can indeed provide a natural interferometric WVA of weak polarization rotation effect. In order to prove this concept, we first develop and experimentally demonstrate an intuitive interferometric WVA concept that uses near destructive interference of two paths of an interferometer having slightly rotated linear polarization states of light (playing the role of weak interaction). Unlike conventional optical weak measurements, here, near destructive interference between two paths are used to mimic the near orthogonal pre and post-selections of states  narrow quasiguided mode and a polarization isotropic photon continuum or broad surface plasmon mode in waveguided magneto-plasmonic crystal28. Using a theoretical model of interferometric weak value amplification and by employing finite element method (FEM) simulation33 in magneto-plasmonic crystal, we demonstrate that natural interferometric WVA plays an important role in the observed giant Faraday rotation in such systems that exhibit prominent Fano resonance features28. This is the first demonstration of weak value amplification that occurs completely naturally.Even though WVA is a quantum mechanical concept, it can be understood using the wave interference phenomena and can therefore be realized in classical optical setting alsoWe consider near destructive interference of two paths of an interferometer having slightly rotated  on top of a dielectric waveguiding layer20. The coupling of the surface plasmons in the metallic nanostructures or the photon continuum with the narrow quasi-guided photonic modes in the waveguiding layer leads to Fano resonance28. It is pertinent to note that for excitation with transverse electric (TE) polarized light, the surface plasmons are not directly excited in such system as the electric field is parallel to the metal grating  polarization on the other hand, Fano type resonance appears due to the interference of the broad surface plasmon mode in the metal nanostructures and the quasi-guided photonic mode in the waveguiding layer27. As opposed to the usual plasmonic crystal systems, in waveguided magneto-plasmonic crystal, the waveguiding layer is made of magneto optical materials that additionally exhibit Faraday rotation and ellipticity32, which acts as the desirable weak interaction parameter in this weak measurement scenario of Fano resonance. We demonstrate below that the in-built near destructive spectral domain Fano interference in the neighborhood the Fano spectral dip in such systems provides the near orthogonal pre-post selection of states leading to natural interferometric WVA of small Faraday rotation and ellipticity. We also show that this natural interferometric WVA of Fano resonance is an important contributing factor to the recently observed giant enhancement of small Faraday rotation in such system28. We used finite element method (FEM)33 for simulating the Fano resonance in the transmitted light from magneto-plasmonic crystal system  polarization excitation. Figure\u00a028. Before we proceed to the main findings of this study on natural interferometric WVA in Fano resonance, it is worth noting that the waveguide modes in the magneto-plasmonic crystal system are leaky as they couple to light through momentum matching enabled by the presence of the gold (Au) grating on top of the waveguide layer (Y-BIG film)20. The overall damping and the lossy nature of such quasiguided photonic modes are accordingly reflected in the comparatively large line width 37. Now, turning to the results on the natural interferometric WVA, significant enhancement of the Faraday rotation . This is being investigated in details.We now demonstrate this concept in a realistic Fano resonant system, namely, the waveguided magneto-plasmonic crystalsence Eq.\u00a0. Note th31. In such scenario, the natural WVA phenomenon does not take place and the enhancement of magneto optical effects can be primarily attributed to the other known mechanisms38. We also emphasize that the presented framework of natural WVA in spectral interference of Fano resonance is a generic one, which is applicable to a broad range of Fano resonant systems  in the presence of an appropriate weak interaction parameter . As evident, the ratio of the amplitudes of the narrow resonance mode and the continuum mode 18 are only important in the weak value formalism. Since these two parameters are directly related to the coupling strength or the resulting Fano asymmetry parameter In general, it is exclusively in the case of prominent Fano resonance that the near destructive spectral domain interference between a continuum and a narrow resonance mode having slightly different polarization response mimics the unique phenomenon of natural interferometric WVA, which cannot be produced by any arbitrary interference effects. Caution must therefore be exercised in interpreting enhancements of magneto-optical effects in many other plasmonic systems which do not exhibit prominent Fano type spectral interferenceweak polarization anisotropy effect in one of the interfering modes. The results of these studies provide new insights on the vital role of natural WVA in the giant enhancement of Faraday rotation and ellipticity in Fano resonant magneto-plasmonic systems. In general, these results are quite remarkable as the weak value amplification procedure usually demands careful state preparation (pre-selection), a weak coupling between the pointer and the measuring observable and post-selection on a final state. Whereas these results clearly show that the entire process of WVA may naturally evolve in the spectral domain Fano interference in the presence of a weak polarization anisotropy effect. It is envisaged that in presence of an appropriate weak interaction parameter such natural interferometric WVA can be realized in diverse other non-trivial phenomena also that originate due to fine interference effects41.\u00a0This opens up a new regime for the study of natural weak measurements on fundamentally important weak interactions associated with a rich variety of interference related effects for their enhanced probing and for enhancing related metrological applications in the optical domain and beyond.In summary, we have developed and experimentally validated a fundamentally interesting concept of interferometric WVA to amplify small polarization anisotropy effect. Unlike conventional optical WVA schemes, in this approach, near destructive interference between two paths of an interferometer is used to mimic the near orthogonal pre and post-selections of states, small polarization anisotropy effects act as the weak interaction, and polarization Stokes parameters are used as pointer. It is shown that such interferometric WVA naturally arises in Fano resonance due to the spectral domain interference between a continuum mode and a narrow resonance mode having slightly different polarization response which arises due to the presence of a 32 across the interference fringe. In order to realize the real WVA scheme, the relative intensities (or amplitude ratio a) of light in the two interfering paths were varied using a variable neutral density filter\u00a0ND. The polarization vector orientation angle (a). For probing the imaginary WVA, on the other hand, the intensities of the two paths were kept equal and the recorded We employed a conventional Mach\u2013Zehnder interferometric arrangement to demonstrate the interferometric WVA concept Fig.\u00a0a Supplementary information"}
+{"text": "We investigated a clinical case of variant Creutzfeldt-Jakob Disease in a person heterozygous for methionine/valine at codon 129 of the prion protein gene and identified the same strain properties in variant Creutzfeldt-Jakob disease in methionine homozygous persons and in bovine spongiform encephalopathy. These results indicate no adaptation of the agent in a different genetic background. PRNP 129MV) was reported in the United Kingdom  in a person heterozygous for methionine/valine (MV) at codon 129 of the prion protein gene . Results from magnetic resonance imaging (MRI) of the patient\u2019s brain were suggestive of sCJD on diffusion-weighted imaging (DWI) sequences, although the single coronal fluid-attenuated inversion recovery (FLAIR) sequence in this case was not diagnostic because of movement artifact. Results of cerebrospinal fluid (CSF) real-time quaking-induced conversion assay analysis and the direct detection assay for vCJD infection in the blood were negative. However, at autopsy, neuropathological examination revealed florid plaques, and biochemical analysis of prion protein (PrP) from the brain confirmed a type 2B profile, both characteristic of vCJD . This finding is within the range of previous transmission studies for UK vCJD in this mouse line (mean incubation 306\u2013387 dpi) and similar to those for BSE (mean incubation 316\u2013335 dpi). Clinical signs with individual incubation periods ranging from 300 to 392 days postinfection (dpi) were apparent in the mice. The major clinical signs were a loss of body weight and body condition with eye winking and gait abnormalities. Toward the end of the clinical phase, a wet genital area could also be observed. Pathologically confirmed disease developed in 14 of 16 mice  vacuolation profile from clinically affected RIII mice and compared it with profiles from UK vCJD and BSE transmissions . We obseWe conducted an immunohistochemical analysis, which showed abnormal PrP deposition throughout the brain of both a granular and punctate nature (res). We identified a similar type 2B\u2013like pattern and glycosylation profile in the RIII mice. This profile is characterized by a predominance of the diglycosylated form of PrPres at \u224830 kDa, a monoglycosylated form at \u224827kDa, and an unglycosylated band at \u224819kDa (res. Biochemical analysis of the MV isolate confirmed the presence of protease-resistant PrP (PrPt \u224819kDa  Figure. This transmission study in RIII mice provides evidence that the prion strain isolated from this confirmed case of vCJD in a 129MV person is the same as that identified in typical 129MM vCJD and BSE cases. Further characterization in a range of mouse models is ongoing. However, transmission to RIII mice in previous studies has led to definitive identification of several strains, vCJD and BSE in particular (PRNP codon 129 genotype has been shown to be a major factor influencing disease characteristics of Creutzfeldt-Jakob disease (PRNP background and investigations including CSF protein misfolding cyclic amplification (The clinical diagnosis in the MV case we report was uncertain while the patient was alive, and it was only at autopsy that neuropathology and biochemistry confirmed vCJD. The neurologic features alone cannot be used to discriminate between sCJD and vCJD, and the MRI findings on DWI imaging favored a diagnosis of sCJD. However, the high sensitivity and specificity of MRI for vCJD were determined by analyzing FLAIR images primarily (The identification of vCJD in a 129MV person may indicate the start of a second wave of vCJD in association with the 129MV genotype which is present in around 45% of the UK population (Additional information for study showing no adaption of the prion strain in a heterozygous case of variant Creutzfeldt-Jakob disease."}
+{"text": "While the COVID-19 pandemic posits a significant challenge to all societies around the world, it also reveals in the most dramatic manner the many abysmal differences between so-called advanced economies and the developing world."}
+{"text": "Stroke is one of the leading causes of death resulting in long term disability worldwide . OutcomeDecreased Aix and elder age are associated with higher in-hospital mortality in patients with acute ischemic stroke. Further studies are needed in order to clarify the paradoxical effect of arterial stiffness to patient's outcome after acute ischemic stroke.The authors declare no competing interests."}
+{"text": "Diabetic kidney disease (DKD) affects approximately one-third of patients with diabetes and taking into consideration the high cardiovascular risk burden associated to this condition a multifactorial therapeutic approach is traditionally recommended, in which glucose and blood pressure control play a central role. The inhibition of renin\u2013angiotensin\u2013aldosterone RAAS system represent traditionally the cornerstone of DKD. Clinical outcome trials have demonstrated clinical significant benefit in slowing nephropathy progression mainly in the presence of albuminuria. Thus, international guidelines mandate their use in such patients. Given the central role of RAAS activity in the pathogenesis and progression of renal and cardiovascular damage, a more profound inhibition of the system by the use of multiple agents has been proposed in the past, especially in the presence of proteinuria, however clinical trials have failed to confirm the usefulness of this therapeutic approach. Furthermore, whether strict blood pressure control and pharmacologic RAAS inhibition entails a favorable renal outcome in non-albuminuric patients is at present unclear. This aspect is becoming an important issue in the management of DKD since nonalbuminuric DKD is currently the prevailing presenting phenotype. For these reasons it would be advisable that blood pressure management should be tailored in each subject on the basis of the renal phenotype as well as related comorbidities. This article reviews the current literature and discusses potentials and limitation of targeting the RAAS in order to provide the greatest renal protection in DKD. Throughout their lifetime, approximately one-third of patients with diabetes will eventually develop diabetic kidney disease (DKD) . FurtherIn the context of this rather complex and clinically challenging scenario a multifactorial therapeutic approach has traditionally been recommended. As a matter of fact, more than a decade ago, in the Steno-2 study an intensified multifactorial intervention with tight glucose control, the use of renin\u2013angiotensin-aldosterone system (RAAS) blockers, aspirin, and lipid-lowering agents on top of behavior modification had been proved to effectively reduce CV morbidity and mortality over a long-term follow-up in patients with persistent microalbuminuria . NowadayHypertension is a common condition in patients with diabetes and its prevalence in subjects with DKD is significantly higher than in general population and increases gradually according to glomerular filtration rate (GFR) decline, reaching the 90% in ESKD subjects . TherefoAlbuminuria is a known marker of renal damage and has been shown to have a strong cardiovascular and renal predictive power. Furthermore, modifications of urinary albumin excretion under pharmacological treatment might impact CV and renal prognosis independent of blood pressure reduction \u201311. In tMore recent studies, however, have shown that DKD in both type 1 and type 2 diabetes has an heterogeneous histologic phenotype, with various involvement of glomeruli and the interstitium . On the DCRecent International Guidelines  suggest DKD is a complex disease, wherein various pathological changes including glomerular hypertrophy with progressive mesangial expansion and tubulointerstitial fibrosis are associated with multiple pathophysiological abnormalities such as inappropriate activation of the RAAS at the systemic and tissue level , 23. HypMain clinical trials that have evaluated renal protective effect of RAAS blockade across the renal continuum in DKD are reported in Table\u00a0Patients with normal albuminuria In diabetic patients without microalbuminuria RAAS blockade has been studied to evaluate the effect on the transition from normoalbuminuria to microalbuminuria. Trials conducted on type 1 diabetic patients, such as Renin-Angiotensin System Study (RASS) [y (RASS)  and Diaby (RASS)  failed ty (RASS) , while iy (RASS)  the 2 ary (RASS)  the use Patients with moderately increased albuminuria As for the transition from microalbuminuria to overt proteinuria in the IRMA-2 (Effect of Irbesartan in the Development of Diabetic Nephropathy in Patients With T2DM) trial [M) trial  irbesartPatients with severely increased albuminuria More solid data support the use of RAAS inhibitors in DKD with overt albuminuria. The Collaborative study group evaluated the impact of captopril versus placebo on CKD progression in patients with type 1 diabetes and proteinuria [teinuria . Despiteteinuria  and IDNTteinuria  trials cTherefore, the use of RAAS blockers has been considered for many years the gold standard therapy to reduce cardiovascular risk and to slow the progression of diabetic nephropathy and previous guidelines recommended the use of RAAS blockers in all patients with diabetes without distinction . HoweverAccordingly, more recently, guidelines do not recommend routine use of RAAS blockers in diabetic subjects unless in the presence of nephropathy with an urinary albumin-to-creatinine ratio greater than 30\u00a0mg/g creatinine in order to reduce the risk of progressive kidney disease , 36, 37.Several studies have explored the potential benefit of maximal inhibition of the RAAS by means of high doses monotherapy or combination drug. Dual RAAS blockade is based on the pathophysiological rationale of a more profound inhibition of the RAAS cascade which may counteract the well known \u201caldosterone escape\u201d phenomenon observed in patients treated with a single agent. However, disappointing results from several mega trials with hard endpoints have subsided the initial enthusiasm on the promising effects of dual RAAS blockade on surrogate outcomes. In fact, the combination of two RAAS blocking drugs did not provide considerable benefit in terms of long term renal protection and was accompanied by higher incidence of acute kidney injury and hyperkaliemia as compared to single-drug therapy \u201340. It iFinally, mineralocorticoid receptor inhibitors (MRI) such as spironolactone or eplerenone might offer an additional opportunity for RAAS intervention by counteracting the \u201caldosterone breakthrough\u201d that occurs in a subset of patients on RAAS-inhibiting therapy. Aldosterone is known to affect volume status by the regulating renal sodium reabsorption and exert profibrotic effects through increased production of TGF-beta, reactive oxygen, species, PAI-1 and increased collagen gene expression and synthesis , 42 and,Multiple trials have demonstrated that the use of RAAS blocking drugs can slow progression to ESKD in patients with diabetic nephropathy and proteinuria\u2009>\u2009300\u00a0mg/day, however single agent RAAS blockade is not sufficient in slowering progression in many patients. In fact, significant residual risk remains in patients with DN and many patients progress to ESKD despite standard recommended care, including optimal control of blood pressure, glycemia and lipids and the use of RAAS blockade , 50. FurGiven the steady increase in the prevalence of diabetes worldwide and the soaring costs related to its management, prevention and treatment of DKD remains an unmet clinical need. Within this context, recently developed therapeutic agents such as sodium-glucose co-transporter-2 inhibitors and glucagone like peptide-1 receptor agonist have shown promising therapeutic potential not only to reduce CV risk but also to slow the progression of kidney disease with beneficial effect on albuminuria as well as on GFR \u201355. As aBecause of their remarkable antiproteinuric and renoprotective activity, confirmed in many large trials, SGLT2i may soon become, in association with RAASi, the standard of care to prevent DKD and retard its progression.Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease and represent a significant cause of morbidity and mortality worldwide due to the related cardiovascular risk burden.The standard of care for management of DKD over the last three decades has been the control of cardiovascular risk factors and the pharmacologic inhibition of renin\u2013angiotensin\u2013aldosterone system (RAAS).Nowadays, non-albuminuric DKD is the prevailing phenotype. The nephroprotective role of intensive blood pressure control and the use of RAAS inhibitor in these patients is at present unclear.Recent evidence supports a renal protective effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors independent of their hypoglycemic properties.We suggest that co-treatment with RAAS and SGLT2 inhibitors may represent the new era of therapeutic options for DKD."}
+{"text": "The COVID-19 pandemic has triggered an unprecedented economic crisis. This article analyses the impact of mandatory social distancing imposed by lockdown policies and voluntary social distancing triggered by COVID-19 fatality rates on GDP growth in the first three quarters of 2020 for a sample of 42 countries. OLS and IV results indicate an important role for the fatality rate, while panel regressions show that lockdown stringency is the more important driver of growth. When including lagged variables, more restrictive measures lead to lower GDP growth in the same quarter but are associated with a positive, catching-up effect in the following quarter."}
+{"text": "The current coronavirus disease 2019 (COVID-19) pandemic has global significance. From a neurological point of view, COVID-19 patients frequently present with neurological symptoms .We here analyzed current data of all inpatient PD patients in Germany as coded in the German Diagnosis-Related Groups (G-DRG) system which is relevant for reimbursement of inpatient treatment cost. For the year 2018, we extracted the data of PD patients to determine the presence of comorbidities with known high risk for a severe course of COVID-19  such as We found a strikingly high prevalence of these risk comorbidities in the PD cohort, especially in the patient subgroup without presence of motor fluctuations. This specifically supports the hypothesis that PD patients in general and some subgroups could be at a higher risk for a severe course of COVID-19. Moreover, we found a high level of care dependency of PD patients which makes it impossible to completely limit contacts to other people or self-isolate because of their need for care staff (Table\u00a0We additionally analyzed the inpatient prevalence of non-aspiration and aspiration pneumonia in which PD was coded only as secondary diagnosis to differentiate pneumonia subtypes . InteresIn summary, this nationalwide data from Germany points out several clinical characteristics of inpatient PD patients that are risk factors for a more severe course of COVID-19. Apart from the increased occurrence of pulmonary infections, strict social distancing is often difficult due to care dependency. We do not consider PD itself to represent a risk factor for COVID-19 and a diagnosis of PD should not lead to any difference in decisions making to treat COVID-19 in these patients. The frequent comorbidities with PD rather highlight the importance of preventive strategies such as telemedicine consultations and preventive testing of care staff. Neurologists and movement disorders specialists should consider a very careful attitude in the treatment of Parkinson\u2019s patients with prudent prevention of infections in these challenging times."}
+{"text": "Mediterranean Journal of Rheumatology. In the next pages, you will find interesting papers covering a wide spectrum of topics including education in Rheumatology, recent data for targeted synthetic disease-modifying antirheumatic drugs in psoriatic arthritis, metabolic bone disease, physical therapy, pathogenetic pathways of fibrosis in systemic inflammatory disorders as well as useful clinical cases with implications for daily clinical practice.On behalf of the Editorial Board, I welcome you to the December 2017 issue of the 1 Given the ongoing argument in Greece and other countries regarding changes and reorganization of training for Rheumatology trainees, this topical editorial can promote discussion and considerably contribute to the development of a fair and transparent system in favour of the national health system, rheumatology service delivery and physicians themselves.Andrew Hassell from Keele University UK gives a - very well-considered, given his enormous experience - personal view on the Rheumatology training process in the UK, highlighting the positive and negative aspects of key developments in terms of selection, supervision, assessment and quality assurance of training that have taken place over the last 2 decades.2 provide novel insights regarding the role of the canonical Wnt signaling pathway in the regulation of fibrotic process. It is known that Dickkopf-1 (Dkk-1) - an endogenous Wtn signaling pathway inhibitor - is involved in joint remodeling and represents a crucial player in the balance between joint destruction and new bone formation in rheumatoid arthritis and ankylosing spondylitis respectively, as well as in osteoporosis. Recent data indicate Wtn signaling as a mediator of transforming growth factor-beta (TGF-\u03b2) induced fibrosis suggesting that inhibition of this pathway via Dkk-1 may be an attractive therapeutic approach for halting fibrosis in several conditions.Klavdianou et al.3 review the utility of various types of physical therapy; such as electrical therapy, hydrotherapy, thermotherapy and therapeutic exercise in autoinflammatory diseases underlying for one more time the role of non-pharmacological therapeutic strategies in the overall management of systemic diseases and the necessity for an individualized treatment approach.Gurcay and Akinci4 describe the process of translating into Maltese language scoring algorithms for lupus individuals and how the questionnaires were validated by the patients. This has implications for many assessment tools if they are to be used in different languages.Apart from strictly clinical measurements, the modern management of lupus patients necessitates the assessment of parameters such as fatigue, sleep quality and overall health status. In an interesting article, Magro et al.5 She discusses the new trends in treatment strategies of rheumatic diseases, the development of a three-tier standardized system for the management of these conditions including amongst others treatment protocols, rehabilitation and patient education programs. Of note, T2T protocols for rheumatoid arthritis in Russia are based on the initiation of high doses subcutaneous methotrexate with considerably good outcomes. There are obvious opportunities for learning from each other\u2019s experience in different countries and health systems, and for research and practice evaluation collaborations in the future, activities that MJR wants very much to support and facilitate.The challenges of rheumatology care and research in modern Russia are presented by Elena Tchetina.6 This mini review concludes with some valuable points weighing up sun exposure as a source of Vitamin-D and risk factor for skin cancer from a dermatology perspective.Dr Clifopoulos discusses the effect of Vitamin-D levels on vascular morbidity and skin cancer risk concluding that there are no robust data supporting any direct and causal relationship between these conditions.7Prof Sakkas comments on emerging data from double-blind controlled studies published a couple of months ago suggesting that tofacitinib - an oral Janus kinase inhibitor- may represent an alternative treatment option for either biologic na\u00efve or TNF-a inhibitor exposed patients with psoriatic arthritis who are unresponsive to methotrexate.8 difficulties in treating complicated patients with biologic drugs and how to overcome these problems9 as well as clinical images from a lupus patient with significant cardiac involvement.10In this issue, you can also find a couple of interesting cases discussing common clinical problems; such as diagnostic uncertainties in anti-synthetase syndrome,th century proposed by French physician Landr\u00e9-Beau-vais.11Last but not least, we are very happy to host in this issue a nice historical note by Tsoucalas and Sgantzos who remind the very first \u2013 almost forgotten and underappreciated - description of rheumatoid arthritis back in early 19MJR in 2017.Finally, we would like to express our sincere gratitude to the reviewers \u2013 listed in the current issue - who provided their judgment concerning the quality of the submitted papers and have enormously contributed to the progress of the"}
+{"text": "Neurotrophin signaling via receptor tyrosine kinases is essential for the development and function of the nervous system in vertebrates. TrkB activation and signaling show substantial differences to other receptor tyrosine kinases of the Trk family that mediate the responses to nerve growth factor and neurotrophin-3. Growing evidence suggests that TrkB cell surface expression is highly regulated and determines the sensitivity of neurons to brain-derived neurotrophic factor (BDNF). This translocation of TrkB depends on co-factors and modulators of cAMP levels, N-glycosylation, and receptor transactivation. This process can occur in very short time periods and the resulting rapid modulation of target cell sensitivity to BDNF could represent a mechanism for fine-tuning\u00a0of synaptic plasticity and communication in complex neuronal networks. This review focuses on those modulatory mechanisms in neurons that regulate responsiveness to BDNF via control of TrkB surface expression. Nerve growth factor (NGF) was the first member of the neurotrophin family that was discovered as a survival factor for distinct populations of neurons during a critical period of development. When brain-derived neurotrophic factor (BDNF) and the other members of the neurotrophin family were identified, it became apparent that the responsiveness of BDNF-sensitive neurons was also qualitatively different from NGF-dependent neurons. These differences can be explained by differential target cell responsiveness to BDNF rather than differential expression of the corresponding TrkB receptor. In the present article, we aim to provide an overview about some historic aspects that first pointed to differences between NGF and BDNF, and recent findings on molecular mechanisms how target cell sensitivity to BDNF signaling is regulated by TrkB cell surface expression. These mechanisms could explain differential responsiveness of developing neurons to NGF and BDNF.Work by Viktor Hamburger and others has shown that many types of neurons are generated in excess in the embryonic nervous system of vertebrates and that only subpopulations that are supported by neurotrophic factors are maintained (reviewed by Purves and Lichtman 2A-R) depend on the presence of TrkB  and spinal motoneurons . First, neuronal activity triggers Ca2+ entry via AMPA and NMDA receptors (a). Ca2+ stimulates adenylyl cyclase activity, thus causing an elevation of cAMP levels which trigger PKA and PI3K activity (b). This leads to the mobilization of a rapidly available intracellular reserve pool of TrkB (c). TrkB containing vesicles are transported in a microtubule-dependent manner to distinct sites at the cell surface where they integrate, such as dendritic spines. In the dendritic target area, TrkB is transported in an actin-dependent manner via Myosin Va and associates with PSD-95 for guided integration into the PSD (d). TrkB is then able to bind BDNF and gets activated via autophosphorylation at C-terminal tyrosine residues (e).In summary, these studies provide evidence that cAMP-mediated TrkB surface translocation in dendritic spines but also axon terminals involves several critical steps Fig.\u00a0. First, Elevated levels of cAMP play a central role in the translocation of TrkB to distinct cell surface regions within neurons. Thus, it is not surprising that G protein\u2013coupled receptors (GPCRs) were proposed as key activators and potential central physiological regulators for the effects observed in cultured neurons after cAMP treatment , phospholipase C (PLC), or L- and N-type Ca2+ channels  via stimulation of phospholipase C-beta (PLC-\u03b2) activity    constitute the largest and most diverse family of transmembrane receptors , or mannose (Man) modifies the core oligosaccharide (Moremen et al. Glycan structures on newly synthesized glycoproteins are crucial for protein secretion. N-glycosylation is the most frequent form of posttranslational modification in the ER (Moremen et al. An unconventional secretory pathway from the ER to the cell surface that is independent of the Golgi apparatus has recently been described (Hanus et al. Taken together, N-glycosylation appears as a modulatory mechanism for retention or export of Trk receptors from the ER. While TrkA and insulin receptors require N-glycosylation for surface export, the same condition retains TrkB in the ER, leading to the conclusion that N-glycosylation has individual effects on distinct Trk receptors. Notably, TrkB export from the ER after EGF-mediated transactivation is a very fast process and occurs within seconds. For this reason, it appears unlikely that this mechanism involves processing in the ERGIC and Golgi. This observation rather favors the idea of a direct ER export to the cell surface (Puehringer et al. The development and function of neuronal networks, especially correct communication and adequate responses to incoming synaptic signals, crucially depend on neurotrophin signaling. TrkB and TrkA differ in the way how they induce cell death in the absence of corresponding ligands (Nikoletopoulou et al. The regulation of TrkB cell surface expression has many advantages for the function of BDNF/TrkB signaling in the context of synaptic plasticity. Changes in subcellular cAMP could act in a highly local manner and thus fine-tune individual synapses (Maiellaro et al. So far, it remains elusive whether the simultaneous activity of different afferents is required to induce BDNF-/TrkB-mediated LTP in such circuits. LTP then would be induced in a spatio-temporal manner only when both afferents are active. On the other side, such a scenario also would require a highly precise mechanism for removal of TrkB from the cell surface, and it is not clear whether this occurs only after ligand-induced endocytosis or also by other mechanisms. Alterations of such control mechanisms could cause aberrant synaptic plasticity and network communication and thus might be involved in numerous neuropsychiatric diseases."}
+{"text": "Tumour growth is not solely driven by tumour cell-intrinsic mechanisms, but also depends on paracrine signals provided by the tumour micro-environment. These signals comprise cytokines and growth factors that are synthesized as trans-membrane proteins and need to be liberated by limited proteolysis also termed ectodomain shedding. Members of the family of A disintegrin and metalloproteases (ADAM) are major mediators of ectodomain shedding and therefore initiators of paracrine signal transduction. In this review, we summarize the current knowledge on how ADAM proteases on tumour cells but also on cells of the tumour micro-environment contribute to the formation of gastrointestinal tumours, and discuss how these processes can be exploited pharmacologically. Gastrointestinal organs are composed of highly complex tissue and most of these tissues are constantly replenished by the proliferation and differentiation of multi-potent tissue stem cells. These processes are regulated by paracrine signals provided by cells of the stem cell niche. Moreover, signals emitted from inflammatory cells recruited to damaged or infected tissue contribute to the mobilisation of tissue stem cells, regeneration and remodelling of the damaged tissue. Several paracrine signal proteins are synthesized as membrane-bound proteins and need to be proteolytically processed to give rise to soluble factors that then can act in a paracrine or even an endocrine fashion. Additionally, receptor molecules and proteins of the extracellular matrix are subject to proteolytic remodelling. Members of the A disintegrin and metalloprotease (ADAM) family are involved in all these processes. Aberrant activation of paracrine signal transduction is key to the development of gastrointestinal tumours and it is therefore not surprising that ADAM proteases play a decisive role in gastrointestinal tumorigenesis. Here, we give an overview of ADAM protease biology and the current knowledge regarding their tumour-promoting role in gastrointestinal malignancies. We further discuss how ADAM proteases can be therapeutically targeted for the treatment of gastrointestinal cancers.Limited ectodomain proteolysis is a regulatory mechanism mediated by proteases that converts membrane-bound proteins irreversibly into their soluble isoforms. The family of A disintegrin and metalloproteases (ADAMs) consists of 21 members  with 13 Proteolytic activity of ADAM proteases can either be constitutive or activated by signal transduction pathways. Regulation of ADAM protease activity is best described for the family members ADAM10 and ADAM17. Members of the membrane multi-pass families inactive rhomboids (iRhoms) ,10 and tThe rhomboid family comprises several transmembrane proteins that are evolutionarily conserved. The inactive rhomboid members lack the amino-acid residues that are indispensable for catalytic activity.rhomboid family member (RHBDF) 2 gene. iRhom2 is localized in the ER and shuttles ADAM17 from the ER to the Golgi apparatus . PDGFR\u03b2 was previously shown to induce ADAM17 activation . . 111]. I+ breast cancer, large B-cell non-Hodgkin lymphoma . . 129]. FThere is now a growing body of evidence that members of the ADAM protease family are over-expressed on tumour cells and are correlated with tumour formation and the progression of gastrointestinal tumours (summarized in Given the fact that ADAM proteases generate paracrine signals, the role of ADAM proteases in the tumour microenvironment needs more attention. Cell type-specific gene targeting in mouse models of cancer combined with unbiased proteomic substrate identification will improve our understanding of how ADAM proteases shape the tumour microenvironment and promote tumour metastasis. This will also help to design tissue-specific ADAM protease inhibitors or to target ADAM-mediated novel tumour cell vulnerabilities, with the aim to reduce the severe side effects encountered with current ADAM protease inhibitors."}
+{"text": "Phosphorus is a macromineral with numerous important biologic functions. Metabolites with a phosphorus moiety include structural lipids of the cell membrane (phospholipids) and nucleic acid molecules. Phosphorus metabolites also play an important role in metabolic activity and energy metabolism, processes that inherently depend on the capacity to phosphorylate intermediate metabolites and to store energy released during oxidative phosphorylation in high-energy phosphate bonds such as ATP or phosphocreatine. In skeletal muscle, phosphorus metabolites are essential for providing high-energy phosphates for contractile activity and structural integrity of the sarcolemma membrane and intracellular organelles including the sarcoplasmic and mitochondrial reticulum.31P-MRS) is a valuable tool to assess in vivo phosphorus metabolites and has been used to further understand skeletal muscle aging. While the phosphocreatine peak is most prominent in the spectra, several additional peaks  1 and 2, putative readouts of membrane damage) can be quantified by obtaining the fully relaxed spectrum over a longer (12 minute) acquisition time to improve spectral resolution. This is important, as recent work has shown that resting levels of phosphocreatine and PDE in skeletal muscle appear be linked with whole-body and skeletal muscle metabolism including insulin sensitivity, glucose homeostasis, and mitochondrial content [in vivo phosphocreatine content was associated with lower muscle volume and knee extensor peak power, while an elevated PDE2 peak was negatively related to these variables. We further validated these findings in a second group of well-phenotyped older adults classified as non-sarcopenic or sarcopenic based on the European Working Group on Sarcopenia in Older People (EWGSOP) definition and observed that phosphocreatine was lower in muscle from sarcopenic adults while PDE2 was higher.The age-related loss of skeletal muscle mass and function (sarcopenia) is a significant healthcare problem for older adults and an unmet medical need. The use of 31-phosphorus magnetic resonance spectroscopy  . In skelCellular membranes consist primarily of phospholipids, including phosphatidylcholine (PC) and phosphatidylethanolamine (PE). Along with maintaining structure, the phospholipid composition of cellular membranes can impact several biological functions important to skeletal muscle health, including controlling intracellular calcium levels and mitochondrial energetics . Given tIn order to successfully develop effective therapeutics to halt the progression of sarcopenia it is important to understand the underlying etiology to identify potential therapeutic targets. Our results suggest phosphorus metabolites involved in energy metabolism (phosphocreatine) and cellular membrane integrity (PDE and phospholipids) are distinct in sarcopenia and are related to lower muscle mass and function in older adults . This ad"}
+{"text": "This paper presents a lightweight, infrastructureless head-worn interface for robust and real-time robot control in Cartesian space using head- and eye-gaze. The interface comes at a total weight of just 162 g. It combines a state-of-the-art visual simultaneous localization and mapping algorithm (ORB-SLAM 2) for RGB-D cameras with a Magnetic Angular rate Gravity (MARG)-sensor filter. The data fusion process is designed to dynamically switch between magnetic, inertial and visual heading sources to enable robust orientation estimation under various disturbances, e.g., magnetic disturbances or degraded visual sensor data. The interface furthermore delivers accurate eye- and head-gaze vectors to enable precise robot end effector (EFF) positioning and employs a head motion mapping technique to effectively control the robots end effector orientation. An experimental proof of concept demonstrates that the proposed interface and its data fusion process generate reliable and robust pose estimation. The three-dimensional head- and eye-gaze position estimation pipeline delivers a mean Euclidean error of  Direct human robot collaboration demands robust interfaces to interact with or control a robotic system in a human safe manner. Especially in situations where the hands of a person are either occupied (industry 4.0) or not usable, e.g., people with severe physical disabilities, a safe, reliable and intuitive communication source that enables a direct interaction with the robotic system should be provided. In the context of assistive robotics, most of these interfaces have been designed hands-free ,2,3.A robust hands-free interface provides the opportunity for people suffering from physical motor impairments the opportunity to be (re)integrated into working life, e.g., for pick and place tasks in a library workplace designed for people with tetraplegia . The queThis paper presents a lightweight, infrastructureless head-worn interface for robust and real-time robot control with a total weight of just 162 g, see Recent Interfaces focus on the use of head motion or eye tracking data to allow for continuous robot control and deliver a low-cost and intuitive control mechanism ,11.Head motion based interfaces usually employ low-cost sensors, i.e., Magnetic AngularRate Gravity (MARG)-sensors, to estimate orientation without a need for static infrastructure, e.g., markers, that would limit the useable motion range and environment . The oriEye-gaze based robot control utilizes the natural eye motion of a human. A recent approach utilizes 2D gaze points and gaze gestures to control the pose of a robotic arm in three-dimensional space . The useTostado et al.  proposedScalera et al.  present Dezmien et al.  developeA recent approach delivers a potential interface for a full eye-gaze based control of a robotic arm by combining eye tracking, head tracking and depth information . This inThe HoloLens 1 is a commercially available interface that is capable of delivering accurate three-dimensional head-gaze but lacks the ability to track eye positions and deliver eye-gaze. The HoloLens one is weighing 579 g in total . The cenWith the recent technological advantages in camera miniaturization, mobile eye tracking and computer vision this work aims to fill the gap and propose an infrastructureless and lightweight solution for accurate head- and eye-gaze based six DoF robot control in Cartesian space to facilitate hands free and multi-modal human robot collaboration. It enables head motion, head-gaze and eye-gaze based robot teleoperation in six degrees of freedom. The interface combines a binocular head-worn eye tracker, a low-cost RGB-D world camera and a low-cost custom MARG-sensor board to calculate the users head pose and gaze point in three-dimensional space with respect to a user defined world coordinate system. The proposed system does not rely on stationary cameras and is therefore infrastructureless and mobile regarding potential operational environments and usable motion space. The interface utilizes a state of the art and completely open source visual SLAM  approach, namely ORB-SLAM 2  and fuseWithin this work an interface for six dimensional robot teleoperation in Cartesian space, with three dimensions for orientation and three dimensions for position control, respectively, is proposed. This interface is capable of head- or eye-gaze based point-to-point position teleoperation of a robotic arm as well as head motion based EFF orientation control. This is achieved by combining an active infrared stereo camera and a custom MARG-sensor in a 3D printed case that is mounted on top of a mobile binocular eye tracker. The interface is independent of external infrastructure and therefore usable within most indoor environments.The Interface consists of three main hardware parts. The infrared stereo camera, a custom MARG-sensor board and a binocular mobile eye tracker with a USB-C world camera connector. This hardware setup tackles various software tasks which rely on each other and enable the robot teleoperation. We divide these tasks into the following categories and explain them in detail in the subsections below: (A) 3D head pose estimation through visual and inertial data fusion, (B) 3D gaze estimation with respect to the robot coordinate frame and (C) the application interface for the robot control. To align all coordinate frames the head pose estimation block also features an input for any absolute pose measurement system . All software components besides the MARG-filter framework are written in C++ and embedded in the Robot Operating System (ROS) . ROS ena\u00ae RealSense\u2122 [In this work we use an active infrared stereo camera, namely the d435 from IntelalSense\u2122 . This caalSense\u2122 . One of alSense\u2122 . The d43The head pose estimation block A) from The proposed data fusion addresses the environmental challenges which arise from the teleoperation task and is not reliably solvable using only a single sensing technology. For example, the orientation estimation from MARG-sensors is based on the numerical integration of angular rate measured through the gyroscope. These low-cost consumer grade MEMS based gyroscopes suffer from DC-offsets, known as gyroscope bias. This bias leads to a drift in the integrated angles. This drift is typically compensated by using global references, i.e., direction of gravity and geomagnetic field of the earth measured by the accelerometer and magnetometer, in the data fusion process. However, the measurements are subject to external disturbances effecting the measured direction of the reference vectors and therefore leading to orientation estimation errors. This is especially the case for the measurement of the geomagnetic field vector used to correct heading estimation errors. Indoor scenarios and the presence of ferromagnetic and permanent magnetic materials  will lead to varying magnetic field vectors which degrade the effect from the geomagnetic vector measurement on the heading correction. Within this work we use visual odometry data in the data fusion process of the MARG-sensor to apply heading correction and improve absolute orientation estimation in indoor scenarios. On the other hand, the sole use of visual odometry is not robust related to the proposed scenario. Using vision based techniques only  would also result in accumulations of errors since the visual scenery will be exposed to a lot of relative motion from the robotic system. Robust visual odometry is based on the dominance of static feature points over moving objects and therefore degrades in the presence of moving objects, in this case the moving robot system.To address these issues this work utilizes a visual SLAM approach to (a) create an accurate map of the working area to relocalize within the map based on the detected and matched features in order to increase accuracy and robustness and (b) fuse the measurements with MARG-sensor data to reduce the impact of relative motion in front of the cameras visual scene on the orientation estimation and (c) to be able to reset to a known orientation based on the discrete MARG-sensor estimations. The head pose estimation block fuses visual and inertial sensor readings to form a robust pose estimation of a users head without the need for external marker placement, i.e., fiducial markers. Due to the recent technology and research efforts in camera technologies, depth camera sensors have become small, fast, reliable and affordable when it comes to everyday use. Using a depth camera over a regular monocular 2D image sensor adds a complete new dimension and has major advantages when it comes to pose estimation in general. We therefore use a stereo depth camera as the input measurement for a visual SLAM approach and combine the orientation measurement with a MARG-sensors orientation estimation to generate reliable and robust orientation even under complete loss of visual information. The visual position estimation is used as true head position since MARG-sensors are known for accumulating errors upon estimating translation from double integration of acceleration and might therefore lead to wrong position estimation.The visual SLAM framework is part of block A, the head pose estimation pipeline in We use the RGB-D based implementation of ORB-SLAM 2 but instead of supplying the RGB image, we use the infrared image of the first infrared camera sensor from the stereo infrared module of the RealSense\u2122 d435 camera . This image is the basis for the depth image alignment. This avoids the need for an alignment step between RGB and depth image. Furthermore, the RGB camera is rolling shutter whereas the infrared cameras have global shutter and will therefore contain less motion blur. The infrared cameras also features a wider field of view (FOV) compared to the RGB camera (H \u00d7 V \u00d7 D-Infrared: \u00d741\u2218\u00d772\u2218 ). Using This algorithm is capable of generating reliable position and orientation data while visual frames are available. If a sufficient large map has been created (>50 keyframes) we enable the localization only mode to reduce computational costs and reduce pose estimation errors from relative motion in the visual scenery. To further enhance robustness, we disable the visual odometry constant velocity motion model within the localization mode. This ensures that the pose estimation does rely on matched feature points in the map only and does not interpolate between unmatched features using the velocity model. On the one hand this procedure ensures that the visual pose estimation is less error-prone to relative motion in the scene. On the other hand the overall tracking robustness of ORB-SLAM is reduced which will result in localization failures during strong dynamic motion. If ORB-SLAM fails to localize in the scene the mapping mode is enabled again. The visual SLAM framework passes the visual orientation data to the MARG-filter for data fusion purposes described in The second algorithm to robust pose estimation utilizes MARG-sensor measurements fused with visual heading information from the V-SLAM approach. The fusion of data are used to calculate an orientation estimation. The following section first explains the MARG filter framework and secondly introduces the data fusion between visual heading information and MARG-sensor orientation estimation in more detail. The data fusion process consists out of a dual stage filter that incorporates a gradient descent filter stage (GDA), calculating a correction quaternion based on reference sensors (accelerometer and magnetometer) and fuses it with a gyroscope based prediction quaternion inside a linear Kalman filter (KF). The complete filter derivation is given in . The firThe solution proposed by Madgwick et al.  is basedThe MARG-filter framework transfers the iteratively updated quaternion, calculated at the onboard MCU of the MARG-sensor, to the visual SLAM algorithm. The quaternion is split into a roll and pitch quaternion as well as a yaw quaternion. The roll and pitch quaternion is directly used as robust input for orientation information, whereas the yaw quaternion is corrected within the visual SLAM framework using the V-SLAM based heading vector. This is because the yaw quaternion is subject to drift originating from the gyroscope offset, which dynamically changes over time due to temperature and mechanical packaging conditions. Within this work the gyroscope offset drift in heading direction is corrected by applying a set of equations to calculate the visual heading vector within the RGB-D odometry framework. In our previous work we proposed the prior mentioned set of equations to calculate an IMU heading vector and apply it to a GDA based filter while magnetic disturbance is present . The IMUThe quaternion The heading part of the transformed visual quaternion is extracted using the following processSecondly a roll and pitch quaternion is calculated based on the iteratively updated orientation estimation from the MARG-sensor by conjugate quaternion multiplication of the heading quaternion from the MARG-sensor and the current output quaternion, to get rid of the heading rotationA new quaternion is formed that represents the complete visual heading quaternion by quaternion multiplication from the visual heading and the roll and pitch quaternionThis quaternion is now used to directly transform an x-axis unit vector into the visual heading vector by quaternion multiplicationThe visual heading vector The proposed mechanism of calculating a substitute for the GDA heading vector is not limited to the visual heading vector substitute presented here. In the case of degraded data from the RGB-D odometry framework, e.g., visual occlusion, the procedure enables the use of IMU or magnetometer data for the calculation of the heading vector. Switching in between the three heading vector modes based on visual, magnetic and inertial data, respectively, allows robust heading estimation based on the current availability and reliability of the different sensor measurements. In the following inertial and magnetic heading vector calculation is presented in more detail.The method for calculating the heading vector Equation  with thequations \u20137). The. TheBN\u2192Iquations  which alThe magnetic heading is calculated based on cross product between the measured gravity and magnetic field vectors from the MARG-sensor. More details are given in reference .Regardless of whether the heading vector is calculated based on visual, IMU or magnetic data it represents redundant information perpendicular to the plane defined by the pitch and roll component. However, in the case of disturbance of any data source the other sensors are used to calculate the heading vector. The result is a robust and complete orientation estimation under various disturbances.The filter switches between the heading sources based on vector scalar product of the heading vector based on visual, IMU or magnetic data and the current output of the Kalman filter heading estimateThe filter selects the most reliable heading source from the relative deviations 11) descrlity see .The presented fusion approach allows for robust orientation estimation even if visual feedback is lost or magnetic disturbance is present and therefore enables robust head pose estimation which is key for mobile and accurate gaze based robot control.The estimated head pose in the MARG-sensor navigation frame is transformed into the robots coordinate system to allow for direct orientation and position estimation in the applications Cartesian space.The proposed interface is designed to generate two different gaze signals: eye-gaze and head-gaze, respectively. First eye-gaze mapping is described followed by gaze transformation, see Obtaining accurate eye-gaze data strongly depends on the eye to world camera calibration. Three-dimensional eye-gaze estimation from binocular gaze ray intersection are heavily dependent on the eye model and calibration accuracy . InsteadIn this work a lightweight binocular eye tracker with an USB-C mount from Pupil Labs is used. We use the pupil labs open source software pupil service . The pupUsing the pinhole camera model without lens distortion see a, a 3D pLeaving out the perspective transformation, assuming the camera coordinate is the origin, we can rewrite it to the following:Z from the depth image stream which is aligned to the infrared image stream. Having Z we can rearrange and reduce the equation to get the X and Y coordinatesSince we get the pixel coordinates Head pose estimate and gaze mapper outputs are the input variables for the 3D gaze transformer, see The 3D vector Substituting the rotation matrix from the perspective transformation by two-sided quaternion multiplication results in the following formula for 3D world gaze estimationUsing the above mentioned setup allows for accurate 3D eye-gaze estimation in a working area, that is restricted by the RGB-D cameras depth resolution. The gaze mapping method will only correspond to the pixel value chosen.Z from vector B). This results in the following set of equations to calculate the projected depth x and y-axis displacement of the laser pointer,N), respectively. The laser pointers\u2019 pixel position is calculated based on Equation 16). SincEquation  where thThere are various strategies for control of a robot in 3D space by head motions. In this work we use two control strategies to precisely control the robots EFF in Cartesian space in all 6 DoF\u2019s. The first control strategy uses head- or eye-gaze to control the robots EFF\u2019s position in 3D Cartesian space, while the orientation stays fixed. The second mode utilizes head motion to control the robots EFF\u2019s orientation. This strategy employs a motion mapping between the 3 DoF of the humans head rotation onto the robots EFF orientation. This is based on the work from Rudigkeit et al. ,6. The uIn position control the 3D gaze point  the long term heading drift reduction through the proposed visual and inertial data fusion, in contrast to inertial or visual data only orientation estimation, and (b) the short term orientation estimation stability if visual data are not available and (c) proof of functionality of the interface for real world gaze based robot control.The accuracy of the pose estimation with the proposed interface is benchmarked against an infrared based marker system from Qualisys . TherefoFor eye-gaze accuracy tests a single calibration marker (AprilTag ) is presThe same setup is used to investigate head-gaze accuracy. The laser diode is turned on to give the user feedback of the current head-gaze point. Likewise, to the eye-gaze experiment the user starts focusing targets with the laser dot for around The data streams of the proposed interface  and the ground truth motion capture data  are synchronized via timestamp based filtering from a custom ROS-node. The recording node ensures that maximum latency between the data streams is about 3 ms in total between the data streams. The data streams are synchronized at a 100 Hz rate.The proof of concept for the full gaze based control pipeline is tested on a real robotic system. The user randomly gazes at five different target points inside a robots working area for 20 min in total. The user blinks with the left eye to send the gaze point to the robot control pipeline upon which the robot moves to this point. The user sits in front of a dual arm robotic system and is in control of one arm, see The presented data fusion approach from the combination of the MARG-filter and RGB-D SLAM framework\u2019s is evaluated based on the accuracy of the orientation and position estimation and presented in Furthermore this work presents an eye-gaze or head-gaze based modality to move the robot to a desired point in three-dimensional space. Accuracy of the 3D gaze point estimation is also benchmarked against the Qualisys system in Head- and eye-gaze accuracy are calculated from 15 trials for each gaze vector method, respectively. The data was accumulated for three male participants in the age of 29\u201335. Two individuals wear glasses.Lastly the results for gaze based robot control in a real world scenario with a robotic system are reported in The orientation estimation accuracy is calculated as the mean of the RMSE values (root mean squared error) between ground truth Qualisys data, the visual-inertial and inertial only orientation estimations for all 30 trials. RMSE values for visual only data is not calculated since the RMSE will change with respect to the number of visual data losses and the magnitude of error compared to ground truth during these losses. Furthermore, the ORB SLAM framework is resetted if relocalization fails within a time frame of five seconds and will be aligned with the MARG-sensors orientation estimation, compare The results are presented as Euler angles in degrees, compare The proposed visual inertial orientation estimation pipeline reduces the gyro based drift accumulation for the yaw angle estimate to a minimum compared to the inertial only orientation estimation. During all trials the proposed fusion approach maintains the orientation and results in a mean RMSE drift of tion see . Pitch aThe proposed visual inertial orientation estimation pipeline significantly reduces accumulation of drift in the heading estimate in magnetically disturbed environments and enables full quaternion based orientation calculation, even if the visual heading vector is not available, compare x, y, z) in total.Trajectory estimation accuracy is calculated as the mean of the RMSE values of the visual position estimation and the ground truth Qualisys data and is presented in meters. The mean Euclidean position estimation error for the total of 30 trials is z-axis for a short duration of The trajectory estimation relies on visual position estimation from the ORB SLAM framework and transformation into the correct coordinate frame based on the visual and inertial based orientation estimation. This setup allows for accurate position estimation while visual pose estimation is available. If visual information vanishes, the last known position is held until visual position estimation is available again. If the local map from ORB-SLAM is sufficient, a relocalization and recovery is possible which will result in a small error in the position estimation. Relocalization is effective for example at minute Gaze point accuracy is divided into two subsections, head- and eye-gaze accuracy, respectively. The accuracy for either method is calculated based on mean error values between ground truth values of the target points from Qualisys measurements and the estimated head or eye-gaze point on the target. A mean gaze point is calculated for each of the 24 targets. A total of 30 trials was recorded, 15 for either head and eye-gaze target positions.The head-gaze error is increasing with distance between the participant and the target. Target points at the more distant end of the table have a higher standard deviation and larger mean error compared to the targets in the front of the table see b. This iBesides head-gaze the interface and data fusion process presented here also enable three-dimensional eye-gaze position estimation.Eye-gaze point estimation is less accurate when compared to head-gaze estimation, see This subsection presents a proof of functionality of the head-gaze based control pipeline in a real world robot control application. The mean Euclidean RMSE for head-gaze based position control results in This work presents a mobile head-worn interface that enables a user to accurately control a robotic arm in 3D Cartesian space via head or eye-gaze. Furthermore, it enables to control the orientation of the end effector of a robotic arm by using accurate 3D head motion angles. The exclusive use of a camera with V-SLAM method or the exclusive use of MARG-sensors for robust estimation of the heading angle shows different intrinsic features in the time domain. While purely visual data from the V-SLAM method have the disadvantage at higher dynamics, i.e., at strong relative movement of the robot arm in the scene, the IMU-sensors show a drift of the heading angle at very slow movements of the head. This work estimates a robust heading angle by fusion of data from a V-SLAM camera with a MARG-sensor. Even though other interfaces exist, these might be obstructive or to heavy for people with severe physical disabilities, e.g., people suffering from paraplegia. The proposed interface is lightweight and mobile and can be used without the need for external reference markers or static cameras.The data fusion process generates robust and accurate orientation and position estimation of a users head with respect to a dedicated workspace in indoor environments and is capable of switching between visual-inertial, inertial only and inertial-magnetic orientation estimation, based on reliability of sensor data. The presented data fusion is infrastructureless and therefore not dependent on any external references, e.g., fiducial markers, stationary camera equipment and so on. The data fusion process is capable of delivering robust orientation and position even while subject to significant relative motion from the robotic system.The head or eye-gaze control enables an intuitive communication channel for robot collaboration that facilitates natural gaze based task interaction. Depending on the desired accuracy and size of the workspace, head or eye-gaze could be used interchangeable. For example, the 3D eye-gaze point could be used to quickly determine a ROI for the robot and switch towards head-gaze for accurate control of the end effector position. If the eye-gaze experiences an offset due to slippage from the eye-tracker framer a user can switch towards head-gaze mode and thus maintain control and safety. To further enhance robot end effector positioning precision a mixed control strategy could be used. The head or eye-gaze could be used to determine an ROI for the robots TCP and afterwards switch to use head motion mapping for precise end effector position. This can be achieved by simply using the head motion mapping approach bypassing the PID controller into the jogger node to move the arm in Cartesian position space. The presented interface allows for a multitude of new interaction strategies which will be elaborated in future work.The interface enables a variety of new control and teleoperation mechanisms for human robot collaboration. For example, the eye-gaze position estimation and head motion measurement could be used in direct combination to translate and rotate the robots EFF at the same time without switching motion states, i.e., fixating a target object with the eyes and directly rotating the head in the desired orientation.Furthermore, future research will focus on utilizing the Cartesian gaze point estimation for semi autonomous object grasping. The three-dimensional gaze position output could be used to set a Cartesian region of interest (ROI) for a robotic arm that is equipped with a wrist camera. The estimation of the ROI of the object enables the wrist camera on the robotic arm to accurately localize and grab the object. This procedure could lead to a more natural way of human robot collaboration by just gazing at an object of interest therefore effectively reducing the number of control inputs or motion groups needed.The proposed interface could also be used in various human robot applications. For example, in robotic painting. The presented interface could be used directly on top of the canvas at any location inside the robots workspace and without the need for a dedicated computer screen. This could represent a more natural way of drawing since the head- or eye-gaze point is directly reflected by the robots TCP motion on the same plane. A further example is assembly of small parts. We are planning on using the interface in an assembly task that utilizes the humans vision and decision-making skills to control a robotic arm in order to separate and grab parts from bulk containers. After separation, the parts are placed inside a magazine that is used by a second robotic arm to autonomously assemble the full assembly-module."}
+{"text": "The healthy aging model of the World Health Organization (2015) highlights the value of assessing and monitoring everyday activities in understanding health in old age. This symposium includes four studies that used the Electronically Activated Recorder (EAR), a portable recording device that periodically collects sound snippets in everyday life, to assess various real-life cognitive activities in the context of healthy aging. The four studies collected over 100,000 sound snippets (30-seconds long) over a few days from young and older adults in the US and Switzerland. Participants\u2019 speech in the sound snippets were transcribed and coded for different cognitive activity information. Specifically, Haas and Kliegel have investigated the \u201cprospective memory paradox\u201d by examining the commonality and differences in utterances about retrospective and prospective memory failure in young and older adults\u2019 everyday conversations. Demiray and colleagues investigated the relation between autobiographical memory functions and conversation types in young and older adults in relation to well-being. Luo and colleagues have identified the compensatory function of real-world contexts in cognitive aging: Their study showed that older adults benefited from talking with their spouse in producing complex grammatical structures. Finally, Polsinelli and colleagues found robust associations between language markers  and executive functions, highlighting the potential use of spontaneous speech in predicting cognitive status in healthy older adults. Finally, Prof. Matthew Grilli will serve as a discussant and provide an integrative discussion of the papers, informed by his extensive work on clinical and cognitive neuroscience of memory in relation to real-life contexts."}
+{"text": "Whether to don face masks or facial coverings to prevent community spread of coronavirus disease 2019 (COVID-19) has perhaps been one of the most argued and divisive issues, initially between East Asia and the West and later within western countries. Even the World Health Organization (WHO) had prevaricated on the issue during the initial months of the pandemic until it advised governments to \u2018encourage the general public to wear masks in specific situations and settings as part of a comprehensive approach to suppress COVID-19 transmission\u2019 in guidance issued in June 2020 [To assess the appropriateness of masks as an intervention measure, it is important to first understand the aerobiology and modes of transmission of COVID-19. There is general agreement that transmission risk is increased with prolonged close contact. The question concerning longer-range aerosol transmission remains a subject of strong debate. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA detection in aerosols has been reported in some retrospective case reviews  and viabWidespread use of face masks may reduce community transmission in two ways. First, through source control, since masks worn by persons who are infected and contagious can effectively reduce viral dissemination into the environment ,10. ThisWhile there is mechanistic support for the effectiveness of face masks from laboratory-based studies, evidence from real-life studies can confirm whether mask policies could have an impact on community transmission. The highest quality of scientific evidence on the real-life efficacy or effectiveness of an intervention is provided by randomised controlled trials. A number of randomised trials of face masks have been done to prevent transmission of respiratory virus infections. For example, the 2019 WHO guidance on non-pharmaceutical interventions cited evidence from 14 randomised controlled trials that did not support a statistically significant effect on transmission of laboratory-confirmed influenza . HoweverEurosurveillance, Brainard et al. reviewed 12 randomised trials and 21 observational studies of the effectiveness of face mask use against respiratory virus transmission [In this issue of smission . The metsmission -21 and psmission -37, namesmission . While rIt should be noted that widespread use of face masks in an epidemic will have greater community benefit through reducing contagiousness of infected persons in addition to protecting susceptible wearers. One recent study from Germany reports a 45% reduction in transmission through face mask use , althougWhile most face mask trials have aimed to prevent influenza virus or any respiratory virus transmission, the Danish Study to Assess Face Masks for the Protection Against COVID-19 Infection (DANMASK-19) trial has just reported on the efficacy of masks to prevent COVID-19 transmission . In thisIn comparison to randomised trials, observational studies provide relatively less reliable information on the effects of interventions, particularly for an intervention such as face masks that are often combined with other protective measures or changes in behaviours. A recent meta-analysis of observational studies found that face mask use by those exposed to infected individuals in non-healthcare observational settings was associated with a 44% risk reduction of infection with severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003 . HoweverThere are clear evidential gaps in the science of modes of COVID-19 transmission. Nevertheless, there is compelling evidence that masks can contribute to the control of COVID-19. Given that face masks are inexpensive in comparison to the other public health measures being used to control COVID-19, even a limited effect on transmission would justify their widespread use. In addition to recommending that people wear face masks in poorly ventilated, crowded settings or when community prevalence is high, some health authorities might even consider to recommend the practice in all settings when in company. The only caveat relates to potential diversion of scarce supplies for healthcare settings, in which case alternative forms of facial coverings that are made of appropriate materials should be considered ["}
+{"text": "MFsim is an open Java all-in-one rich-client computing environment for mesoscopic simulation with Jdpd as its default simulation kernel for Molecular Fragment (Dissipative Particle) Dynamics. The new environment comprises the complete preparation-simulation\u2013evaluation triad of a mesoscopic simulation task and especially enables biomolecular simulation tasks with peptides and proteins. Productive highlights are a SPICES molecular structure editor, a PDB-to-SPICES parser for particle-based peptide/protein representations, a support of polymer definitions, a compartment editor for complex simulation box start configurations, interactive and flexible simulation box views including analytics, simulation movie generation or animated diagrams. As an open project, MFsim allows for customized extensions for different fields of research.  A molecular simulation workflow comprises three successive steps: The definition of a simulation job with all necessary input information (preparation step), the approximate numerical integration of the equations of motion  and the analysis of the simulation record with all calculated results . A computational all-in-one rich-client environment aims at supporting this triad in a unified and comprehensive manner to allow for productive applicability with minimum effort, minimized training periods and usability without programming skills. An additional goal is the prevention of common problems like inadequate or ill-defined parameter settings by extensively safeguarding simulation job definitions and operations. In general, these desirable features require a highly integrated monolithic architecture: Its pre-defined optimized workflows are comfortable and fast but inflexible in comparison with scripting or pipelining-workflow approaches. For the latter the implementation of a new feature may be achieved within minutes whereas its rich-client realization may involve days and weeks of complex software development. Thus, the different approaches have their intrinsic strengths and weaknesses.Particle-based mesoscopic simulation investigates supramolecular phenomena at the nanometer length and microsecond time scale for large interacting physical ensembles representing millions of atoms. Dissipative Particle Dynamics (DPD) is a mesoscopic simulation technique for isothermal complex fluids and soft matter systems which satisfies Galilean invariance and isotropy, conserves mass and momentum and achieves a rigorous sampling of the canonical NVT ensemble due to soft particle pair potentials that diminish molecular entanglements or caging effects. DPD is expected to show correct hydrodynamic behavior and to obey the Navier\u2013Stokes equations. DPD particle trajectories are guided by Newton\u2019s equation of motion where the total force on a particle exerted by other particles consists of a conservative, a dissipative  and a random part. The opposing dissipative and random forces depend on each other and act as a thermostat conserving the total momentum and introducing Brownian motion into the system. The conservative forces comprise soft DPD particle repulsions as well as possible harmonic springs between bonded and electrostatic interactions between charged particles \u20135. DPD pThe new MFsim project provides (to our knowledge) the first open Java all-in-one rich-client mesoscopic simulation environment and complements the few available commercial systems , 14 withUsage of MFsim does not require programming skills and supports the complete preparation-simulation\u2013evaluation triad of a mesoscopic simulation task. It comprises features like a SPICES line notation , 26 basegui packages control, dialog and main). The controllers communicate with a layer of Molecular Fragment Cheminformatics (MFC) models  that provide all core functions where the MFC layer itself controls the particle simulation kernel (Jdpd as a default).The object-oriented Java architecture see Fig.\u00a0 follows Design, job Execution and job Results evaluation that operate on a defined workspace directory of the file system  and a JobResults folder (with subfolders corresponding to Job Result instances). During job execution a temporary directory is used for file storage which may be located on an fast hardware/memory device for maximum performance. All specific GUI functions are provided by successive levels of modal dialogs that can be opened above the basic GUI frame.The basic GUI frame is organized by three management tabs for simulation job see Fig.\u00a0: This woHelp/MFsim log/Browse of the basic GUI frame.MFsim automatically logs internal problems to support the detection of possibly subtle errors which are likely to occur in complex architectures with hundred thousands of code lines. The log file entries may be viewed via menu entry Details about internal data objects, preferences and convenient re-usable settings are comprised in Appendix Parallel computing provides options for fine-tuning of concurrent operations. As an example the number of parallel calculation threads for force calculations of the (default Jdpd) particle simulation engine may be specified in combination with the number of concurrent jobs in simulation to achieve an adequate workload of an octa-core processor with 2 concurrent simulations and 4 force calculation threads each\u2014whereas for a maximum single-job performance the number of force calculation threads could be increased to 8 with the number of parallel simulations decreased to 1. Additional parallel computing options address the number of concurrent particle position writers for output file creation, the minimum number of simulation box cells and particle\u2013particle bonds for parallelization  and the number of concurrent graphical simulation box slice and diagram generators (abbreviated slicers \u2013 their number should at best correspond to the number of available processor threads including Hyper-Threading).MFsim supports concurrent calculations to exploit the capabilities of multi-core processors for performance improvements that  linearly scale with the number of available processor cores . To arrive at an overall optimum balance the global preference section SpicesPool of package model.particleStructure) and PDB file related protein definitions (class PdbToDpdPool of package model.peptide) are kept in memory to speed-up chemical structure related operations by avoidance of expensive reevaluations during calculations. The size of the SPICES and protein cache may be inspected via menu entry Application/Cache/Show of the basic GUI frame. In-memory caching also improves the performance of simulation box slice image related operations: Preference/Simulation box/Slicer graphics/Image storage in the global preferences dialog may be used to activate the Memory uncompressed\u00a0(fastest) or compressed  image cache, otherwise slice images are stored as image files which is comparably slow.Another performance related feature is global caching: SPICES line notations  and supports the automated update of a Job Input definition for a new particle set.Since there is no unique particle set for mesoscopic simulation, a specific field of research requires a specific particle set\u2014a situation that is similar to Molecular Mechanics/Dynamics with different force fields and specific atom types. All mandatory particle information and particle\u2013particle interactions must be provided by a particle set text file where particle definitions are to be described in mandatory section  data in  with resLast but not least\u2014as an open project itself, MFsim uses several other open libraries: Apache Commons IO  /Lang 3 /RNG 3535, BioJaThe MFsim simulation system aims at supporting the complete preparation-simulation\u2013evaluation triad in form of an integrated all-in-one workflow which is sketched step-by-step in the following paragraphs.Design tab of the basic GUI frame manages all Job Input related operations. It comprises an optionally filtered list of all available Job Input definitions of the specified workspace where a single Job Input definition may be viewed, edited, re-used (as a start for a new definition), removed, imported from an archive file or itself archived to a file (e.g. for exchange purposes). For a new Job Input definition, a corresponding modal dialog is opened above the basic GUI frame.The simulation Job Input definition is already a complete and valid simulation job definition with a single particle type (the water particle). The Job Input features have to be defined in a top-down manner where a change in a higher-level feature leads to an immediate update of subordinate features in an adequate manner\u2014e.g. a change in the number of particles via the Quantity feature automatically changes the subordinate Box size feature to be consistent with the new higher-level Quantity settings according to the even higher DPD density setting. These successive top-down updates  whereas an activated Error tab signals a severe problem which has to be resolved . Since the list of Job Input features should exploit the range of capabilities of the underlying particle simulation kernel the current MFsim Job Input feature set especially addresses the default Jdpd simulation kernel . For other particle simulation kernels the feature set would have to be customized accordingly  that is afterwards converted to a SPICES line notation in the structure editor . A pH value may be set with the modal pH dialog to charge corresponding particles. The modal Property dialog offers a number of settings for the amino acids of all chains: Protein backbone particles may be replaced by probe particles with identical physical properties but different labels for e.g. selective display of specific amino acids of a chain. In addition, a status and a segment may be defined for each amino acid backbone particle which can be used for intra-protein force assignments in order to achieve specific control concerning the flexibility or stiffness of the protein backbone . The complete protein information is encapsulated in a PdbToDpd object (package model.peptide) which is globally stored in the protein cache for inexpensive reuse in protein related calculations. A PdbToDpd object also comprises an automated mapping of the 3D protein structure to the relative positions of its DPD backbone particles which supports realistic 3D protein start geometries in the simulation box.For biomolecular simulations MFsim provides a PDB-to-SPICES parser which is available via the see Fig.\u00a0. An openMonomer definition) and the SPICES structure editor (feature Molecule definition) for polymer construction from monomers.The SPICES related polymer construction exploits the syntax characteristics of the SPICES definition  and is rSimulation box subsection of the Chemical system description . The generated default molecular simulation box configuration consists of randomly-oriented spatial SPICES 3D tubes . The editor also supports a correct a priori DPD density of particles inside a compartment (which may be arbitrarily changed).The ribed in ) at randMovement sub-subsection of the Simulation box subsection address molecule movement control capabilities of the Jdpd simulation kernel: Molecules may be spatially fixed (Molecule fixation) or their movement restricted to virtual cages surrounded by \u201creflective walls\u201d within the simulation box (Molecule boundary). On the other hand, molecules may possess a fixed velocity (Molecule fixed velocity) or may be kicked with a specified frequency (Molecule acceleration).The settings of the final Property calculation subsection of the Chemical system description offers several calculation options during simulations like particle-pair radial distribution functions (RDF) and distances, particle-based molecular radii of gyration or a detailed particle/molecule nearest-neighbor analysis to monitor changing particle/molecule vicinities with temporal evolution of the simulated ensemble.The final Interaction description as the third main Job Input section addresses the fundamental physics of the DPD particle\u2013particle interactions like the Temperature setting, Random DPD force magnitude, electrostatic interactions of charged particles, gravitational acceleration or the characteristics of bonds between particles and their neighbor particles within molecules. Since mesoscopic DPD simulations are based on isotropic particle\u2013particle repulsions (editable via feature Particle interactions with the default repulsion parameters taken from the selected particle set) it may be necessary to impose preferential molecular conformations, e.g. to stabilize the 3D backbone structure of proteins by adequate spring forces between backbone particles to prevent a structural collapse. Thus, additional particle\u2013particle spring forces may be specifically defined between indexed particles in SPICES line notations (Molecule backbone forces), the amino acid backbone particles of peptides and proteins (Protein backbone forces) and the backbone particles of peptides and proteins within assigned chain segments (Protein distance forces).Simulation description section completes the Job Input settings with definitions for control of the simulation itself. The number of Simulation steps defines the temporal physical period to be simulated by integration of the equations of motion with a defined Time step length and a specific Integration type. Output frequency controls the intermediate output (e.g. the creation of particle position files for specific simulation steps) for later evaluation of the simulation record. Initial minimization steps may be defined to improve the initial simulation box start configuration with Minimization step output as a control setting for later inspection. Remaining definitions address Periodic boundaries along the box axes, the use of a DPD unit mass, possible Initial velocity scaling steps for temperature control and the choice of the Random number generator for the random DPD force.The final main Apply button of the modal Job Input dialog) with an automated addition to the list of available Job Input definitions of the current workspace.A completely defined job may be finally saved (Execution tab of the basic GUI frame manages the simulation of defined (error-free) Job Input definitions and a restart of already simulated Job Result instances : After addition to the Job Execution Queue jobs may be executed in parallel according to the global settings defined in Preferences/Parallel computing. For job execution MFsim must convert a Job Input definition to a Jdpd command file with corresponding particle position files . Job execution is always performed in background so it does not interfere with the concurrent usage of any other MFsim function . For every job in simulation its progress in percent and the estimated remaining simulation period is displayed and constantly updated. The Job Execution Queue may be altered in an arbitrary manner after execution start where a job in simulation cannot be immediately killed but only stopped with a delay to guarantee a valid Job Result. All Job Result evaluation functions are also available for jobs in execution which allows for a detailed inspection and analysis of simulation progress.The Job Result restart feature offers the possibility of successive simulation pipelines since underlying Job Input definitions may be changed before a restart. As an example, a possible molecule fixation or caging defined in the Movement sub-subsection (see above) could be removed before a restart of an initial relaxation simulation to allow for new modes of interaction between the molecular species. Changes of the molecular composition or the spatial configuration are not possible since they would affect the overall physical state of a simulation.The Results tab of the basic GUI frame comprises a list of all Job Result instances of the current workspace where a Job Result may be viewed, removed, imported from or exported to an archive file.The View of a Job Result opens a modal dialog that consists of a feature tree which offers substantial simulation related evaluations  to allow for a combined display. If specific property calculations throughout the simulation were defined in the Property calculation subsection of the underlying Job Input definition the corresponding result evaluations appear as additional sections in the Job Result feature tree, e.g. the Nearest neighbor section in Fig.\u00a0Distribution movie section  simulation box views of all (output) steps of the simulation process including the a priori minimization steps (if defined in the Job Input definition) and the generation of simulation movies for defined simulation periods uses the graphical Jmol capabilities designed for atom-based molecule representations to display particle structures whereas the Simulation box slicer generates successive slice images of the simulation box using Java2D. Moreover, the Simulation box slicer provides extensive box analysis features like through-space measurements,  particle selections or the definition of zoom volumes with a corresponding particle/molecule frequency analysis  may be used to contribute to the movie generation in an additive manner: A simulation movie may start with a spinning box, then show the minimization steps, again stop with a spinning box after minimization, exclude specific particles/molecules, zoom-in, then show a defined part of the simulation process within the zoomed box volume etc. All slicer functions produce sequences of images which may finally be merged into a MP4 movie clip with the open FFmpeg software (automated integration of FFmpeg is currently only available for the Windows OS).Job Input section just shows all features of the underlying Job Input definition.Last but not least the final The new MFsim environment may be beneficial for different fields of research. Theoretical physicists and chemists that contribute to the foundations of mesoscopic simulation with new methods/models/applications or improved/extended particle parameter sets may choose the open environment for an exemplification of their work so that their new insights and developments can be more easily adapted and utilized by a wider scientific community where especially scientific end-user communities appreciate availability within a rich-client system.Chemo- and bioinformaticians may likewise be interested in the extended possibilities to popularize their new and improved algorithmic solutions by offering a versatile usage in a convenient environment with only comparatively small additional development efforts.Simulation of a DMPC bilayer membrane model [Cyclotide-membrane sandwich interaction model [2020 Cyclotide-membrane interaction study) which demonstrate an especially attractive feature for visual communication of research findings .As an open all-in-one rich-client system with (modest) hardware requirements that are commonly available in scientific institutions, MFsim especially targets scientific end-users without programming skills. Presumed, a theoretically sound simulation model is available, specific alterations and extensions can be performed by end-users themselves. Tutorials ne model , 49 and on model , 51 illuIn summary, MFsim may broaden the applicability of mesoscopic approaches  and stimulate the collaboration between the different disciplines from theory over computing to end-user application.With the MFsim project an open simulation environment for mesoscopic simulation is provided with the default Jdpd simulation kernel for Dissipative Particle Dynamics. MFsim supports polymer and especially biomolecular simulations containing peptides and proteins aiming at pushing the mesoscopic simulation frontiers towards these areas of research which often require the study of large systems on the microsecond scale. As an open rich-client all-in-one approach MFsim targets theoretical, computational as well as end-user scientists (without programming skills) thus it contributes to making computational tools more widespread in the scientific community. For the chemo- or bioinformatician the project may serve as a starting point for specific customizations where the reusable functionality may outweigh the initial training hurdle.MFsim is publicly available as open source published under the GNU General Public License version 3 . The MFs"}
+{"text": "The spatial and temporal regulation of gene expression in neurons is an important step in creating functional and structural neuronal networks. The complexity of neurons require differential expression of various proteins in different compartments. Highly polarised cells, such as neurons, respond rapidly to different external stimuli by changing their local protein abundance and composition. Neurons can have extensions up to a meter away from their cell body in humans, so it is easy to envisage why they need to manage the synthesis of new proteins locally and on-demand. Recent research has demonstrated that neurons can control the expression of different proteins by localising translationally silent mRNAs, followed by subsequent translation. Neurons use mRNA localization and local translation to achieve different purposes during their life cycle. While developing neurons rely on mRNA localization for axon guidance and synaptogenesis, mature neurons can use mRNA localization for maintenance of essential physiological processes. mRNA localization also plays a role in response to neuron injury to regenerate and restore neuronal connections. Recent microscopic imaging techniques such as live imaging of fluorescently tagged molecules combined with genetic and biochemical studies in neurons have illustrated evolutionarily conserved mechanisms for targeting mRNAs into their correct compartments. This review provides an overview of mRNA localization and local translation in vertebrate and invertebrate neurons and discusses the mechanism by which mRNAs are trafficked into axons. Furthermore, the role of mRNA localization in synaptic activation, as well as axonal injury is explored. The positioning of proteins to different regions of the neuron can determine their function. The common depiction in the central dogma of molecular biology that mRNAs are simply transcript molecules for transferring nuclear information in the DNA to the protein synthesis machinery in the cytoplasm has changed. Local control over the expression of genes can be achieved by trafficking mRNA molecules to different subcellular compartments, where they are translated to their protein products. Thus, mRNAs can have active roles in regulating protein expression through their subcellular localization and local translation. However, mRNA trafficking and protein trafficking are not mutually exclusive mechanisms for subcellular localization of cargoes in the cytoplasm. mRNA localization can work in parallel to the protein sorting machinery, ensuring efficient targeting of proteins to their site of action.Styela plicata about four decades ago. In situ hybridization using a DNA probe showed that actin mRNA was asymmetrically distributed in different regions of the cytoplasm of the ascidian embryo, with the highest concentration in the myoplasm and the lowest concentration in the endoplasm Saccharomyces cerevisiae, migrating fibroblasts, Caenorhabditis elegans, Drosophila melanogaster, Xenopus laevis, epithelial cells, neuroblasts, and nerve cells can localize mRNAs The first evidence for asymmetric mRNA localization in the cytoplasm was found in an ascidian, 2.Data from deep sequencing and high-resolution imaging of rat hippocampal neurons led to the conclusion that approximately half of neuronally expressed mRNAs are enriched in dendrites compared to the soma Calcium/calmodulin-dependent kinase-2\u03b1 (CamKII\u03b1) co-localizes in vivo with the RNA localization factor Staufen in dendrites of hippocampal neurons upon depolarisation with potassium chloride (KCl), and the RNA has a stronger enrichment in dendrites upon neuronal stimulation \u03b2-actin mRNA and its associated proteins can localize in dendritic spines upon neuronal stimulation. Live imaging of a GFP-tagged version of the \u03b2-actin mRNA binding protein ZBP1 showed that proteins redistributed from the cell bodies to the base and spines of dendrites of hippocampal neurons upon depolarisation with KCl ZBP1 was abolished after treatment of neurons with antagonists of NMDA receptors \u03b2-actin mRNA granules in dendrites Localization of mRNA and subsequent translation can be regulated by neuronal activity . CalciumCamKII\u03b1 granules can be explained by a study that showed cytoplasmic polyadenylation element binding protein (CPEB) interacts with CamKII\u03b1 3\u2032 UTR and can be co-immunoprecipitated with both Dynein and Kinesin-1 Bidirectional movement of mRNAs in both anterograde and retrograde can occur in dendrites by simultaneous association of mRNAs with both Dynein and Kinesin. Bidirectional transport of DrosophilaDrosophilaARC mRNA molecules have been observed at the base of dendritic spines Molecular motors play a significant role in active localization of mRNAs. The RNA binding protein (RBP) fragile X mental retardation protein (FMRP), which is present in ribonucleoprotein particle (RNP) granules 3.Coupled with local translation, mRNA localization can provide several advantages compared to protein trafficking. Asymmetric distribution of mRNAs in the cytoplasm can provide neurons with both temporal and spatial resolution over the expression of proteins in different regions of cytoplasm, as translation of pre-localized messages can be triggered on demand. The ability to rapidly respond to different stimuli and regulate the expression level of the corresponding proteins can be crucial in highly polarised cells, such as neurons. Another potential advantage of targeting proteins by prelocalizing their RNAs is that proteins that are newly synthesized from localized mRNAs can have different functions compared to the existing repertoire of proteins in the cell, due to differences in their post-translational modifications (PTMs) UTR) of mRNAs does not require any changes in the coding sequence of transcripts In addition, direct transportation of some proteins, especially those that have a high binding affinity to cytoskeletal elements and other cytoplasmic factors, can pose logistically challenging for cells. In such cases, cells can take advantage of localizing translationally silenced mRNAs to their target sites, followed by triggering of translation at the destination. For example, Map2 and Tau proteins bind to microtubules and cannot readily be trafficked to the distal regions of the neurons; therefore, they are localized as precursor mRNAs to dendrites and axons, respectively before they are translated 4.in vitro and in vivo demonstrated that ribosomes were present in mammalian axons in vivoFormation of a functional neuronal network requires precise positioning of axons in the CNS. Early studies failed to identify ribosomes in mature vertebrates' axons, leading to a notion that all axons do not have the capacity for local translation, and thus shifting the focus to dendritic mRNA trafficking Xenopus retinal ganglion cells axons demonstrated that receptor-ribosome coupling is used by guidance cues where guidance cues can induce dissociation of ribosomes followed by specific mRNA translation A study by Tcherkezian et al. Lymnea stagnalis) do not have conventional RER and Golgi, injection of exogenous mRNAs into axons isolated from the soma resulted in the translation of fully functional transmembrane proteins For many years it was unclear whether vertebrate axons have the machinery to fold and process the locally synthesised proteins as various electron microscopy attempts failed to identify rough endoplasmic reticulum (RER) and the Golgi apparatus in axons It is still unknown whether newly synthesized proteins in axons require specific post-translation modification compared to the proteins present in the soma, which might be achieved by the presence of RER and Golgi with a special function.In vitro data from cultured neurons have shown that isolated axons require axonal protein synthesis and degradation to respond to chemotropic factors or to regenerate after an induced injury (axon-severing) Extrinsic signals can affect growth, pathfinding, and synaptogenesis of developing axons . Mature Xenopus retinal axon pathfinding Navigating axons can also grow in the absence of soma. The removal of the cell body did not affect in situ hybridization (FISH) showed that more than 300 mRNAs encoding various components of the translational machinery, cargo transportation, cytoskeleton and mitochondria are enriched in axons of the CNS and peripheral nervous system (PNS) of mammalian neurons Microarray analysis combined with fluorescent \u03b2-actin and translation induction, thereby promoting growth cone turning Axonal branching in the vertebrate CNS is linked closely to local protein synthesis. Guidance cues such as Netrin-1, BDNF, Sema3A, and Slit2 trigger local protein synthesis in the responsive neuron Xenopus in vivo, and move to the distal tip of stable branches \u03b2-actin translation disrupted branch formation, thereby demonstrating the importance of mRNA localization and local protein synthesis in arbour formation and stabilisation In cultured dorsal root ganglion (DRG) neurons, mRNAs encoding the components of the actin-nucleating Arp2/3 complex are localized to branch points and promote branch formation in response to nerve growth factor (NGF) Deep sequencing of ribosome-bound mRNAs showed that many presynaptic proteins are translated locally in mouse retinal axons during branch formation \u03b2-actin, growth-associated protein 43 (GAP43) and neuritin/cpg15 mRNAs in motor neurons Defective assembly of RNPs has been implicated in the pathogenesis of neurological diseases that affect axons such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) 5.in vitro studies of cultured neurons have provided very useful information on mRNA localisation and local translation, we still do not have a clear understanding of the detailed molecular mechanisms underlying axonal mRNA localisation. This is particularly the case in vivo, where neurons are present in their physiological environment. Further studies are required to decipher the role of neuronal activity in mRNA localization during formation of neuronal network.Localization of mRNA and subsequent translation can provide intricate network of the neurons with a delicate control over gene expression in different compartments at different times. Various studies have demonstrated the functional importance of mRNA localization in axon and dendrites. While molecular mechanism of mRNA localization is conserved in neurons from invertebrates to vertebrates, the role of different factors and regulators in trafficking and translation of mRNAs remains to be discovered. Although"}
+{"text": "The SARS-CoV-2 pandemic represents one of the greatest infectious challenges to humanity in recent history. One of the striking features of infection is the heterogeneous clinical response with worse outcomes observed in older patients and those with underlying health conditions. To date the potential impact of previous infection history has been poorly\u00a0investigated as a potential determinant of risk. Cytomegalovirus (CMV), a persistent herpesvirus infection whose prevalence increases with age, is a major modulator of immune function and several observations suggest that infection might act to influence clinical outcome following SARS-CoV-2 infection. In particular, CMV is associated with the acceleration of immune senescence and has been linked to a range of cardiovascular and metabolic disorders. This review addresses mechanisms by which cytomegalovirus infection may act to worsen the clinical outcome of SARS-CoV-2 infection, discusses how these potential links could be investigated, and assesses the potential significance of any findings that emerge. The SARS-CoV-2 pandemic, which is believed to have originated in Wuhan in 2019, has already led to the deaths of over 340,000 people, a number that is rising steadily at this time [The herpesvirus family is one of the best characterized and largest group of persistent viral infections . These eCytomegalovirus is one of the most common persistent infections within the human population and it is likely that over 4 billion people are infected at the current time . InfectiOne of the characteristic and unique features of cytomegalovirus infection is its influence on the immune response. The virus acts as a hugely important influence on the maturation and long term composition of the immune repertoire , 10. ThiWikby and colleagues first identified CMV as component of the \u2018immune risk phenotype\u2019 associated with increased mortality in elderly individuals in 2002 . This seSomewhat surprisingly, CMV seropositive status has actually being shown to boost vaccine responses in younger people  and thisAs such, the profound correlation between risk of mortality from SARS-CoV-2 infection and increasing age might be explained partly by the negative impact of CMV on immune function in older people\u00a0Fig. . This efA characteristic feature of COVID-19 has been the significantly increased risk of mortality in patients with established cardiovascular disorders . This inThese immunological findings underlie epidemiological studies which show a clear association between CMV serostatus and vascular disorders. This was noted in early studies within US populations , 30 and These observations suggest that the intimate relationship between CMV infection and the vascular system may also act as a potential mechanism to enhance pathophysiological consequences of SARS infection.Finally, a somewhat surprising observation from the SARS-CoV-2 pandemic has been the significant increased clinical risk for patients with diabetes mellitus . DysreguNot surprisingly, research into SARS-CoV-2 infection is currently the major priority for science communities worldwide. If persistent infection with viruses such as CMV do indeed impact on clinical outcome it will be important to consider what steps may be needed to investigate this.-The first, and most definitive assessment, would be to determine the relative clinical outcome from SARS-CoV-2 infection in matched populations assessed by CMV serostatus. Such analysis would be straightforward and inexpensive and the only limitation is access to adequate numbers of serum samples from well-characterised clinical cohorts. These are now becoming available in many settings.-Notwithstanding the outcome of this primary analysis, it would also be of interest to look at the titre of CMV-specific antibodies within CMV seropositive patients. It has been observed in many studies that patients with high titres of antibody display a range of impaired clinical outcomes although it is not clear if this is a \u2018cause or effect\u2019 in relation to secondary health conditions . Indeed,-If such serological studies do suggest an association between CMV infection and Covid-19 outcome then further analysis should be undertaken to assess how cytomegalovirus may act to modify SARS-CoV-2 viral load after infection or modulate the magnitude or functional profile of the SARS-CoV-2-specific immune response. In parallel, it will also be of interest to assess whether CMV reactivation is observed in patients with Covid-19. Indeed, other viruses may also be at play and some of the features of severe infection resemble hemophagocytic syndrome, itself commonly triggered by the herpesvirus Epstein-Barr Virus.If laboratory studies do confirm an interaction between CMV serostatus and the clinical outcome of Covid-19 infection it is important to reflect on how this might be utilised to modify the severity of the current pandemic. CMV-specific drugs could be used to suppress viral load if this were indeed elevated in severely ill patients. However, these would not reverse the immunomodulatory effects of CMV infection over the short term. CMV-specific memory cells have a half-life of many months  and antiHomo sapiens is much greater than simply eukaryotic cells. The microbiome has taken centre stage in recent years and is certainly an important determinant of human health. The virome has received somewhat less attention although its impact may be no less considerable. At a time of global challenge from a new emerging virus it is timely to think how this may be modulated by carriage of an ancient and highly complex virus that has taken many millions of years to adapt to co-existence with primates. The control of SARS-CoV-2 infection cannot wait that long.It is now clearly established that the complexity of SARS-CoV-2 infection is associated with much higher rates of mortality in older people and those with coexisting health disorders. The underlying basis for this is not certain.Cytomegalovirus is a common and persistent herpesvirus infection and the proportion of people that are infected increases with age.Older people who are infected with cytomegalovirus have been shown to display accelerated immune senescence and increased death rates from vascular disease.Cytomegalovirus may act as a negative risk factor for clinical outcome following SARS-CoV-2 infection and this could be of importance in relation to clinical management and optimisation of epidemiological control strategy."}
+{"text": "We report on a case of an asymptomatic splenic artery aneurysm (SAA) with a large neck in a 53-year-old female with an extreme vessel tortuosity which was treated with a Double Microcatheter Technique. This endovascular procedure consists of embolization of the aneurysm using detachable coils with no application of any glue, stent or balloon.At the end of procedure, no complications occurred. At the three-month follow-up an MRI showed the aneurysm\u2019s complete exclusion and patency of the splenic artery. Splenic artery aneurysms (SAAs) are the third most frequent aneurysms in the abdomen after aneurysms of the aorta and iliac arteries and are the most frequent visceral aneurysms with a reported prevalence of 0.8% on arteriography and 0.04\u20130.10% at autopsy Rupture remains the most feared complication with incidence ranging from 2.3% to 18% and a mortality rate ranging from 20 to 100% Size is the first indication for treatment of asymptomatic SAA considering that a diameter greater than 20 mm is related to a high risk of rupture In this report we present the case of a saccular SAA successfully treated with coil embolization using the double-microcatheter technique; a further endovascular approach in treating SAAs in patients with tortuous vessel anatomy.A 53-year-old mother of two children with a family history of lung carcinoma and affected with hypertension, dyslipidemia and sideropenic anemia, underwent a duplex scan to investigate a chronic biliary micro-lithiasis. The exam detected an abdominal lesion suspected of adrenal adenoma. The patient was submitted to a CT-scan that revealed a saccular aneurysm  in the medium-distal part of the splenic artery which also presented an extremely tortuous course . Given tUnder local anesthesia a 7 Fr vascular sheath was positioned in the right common femoral artery. A 5-Fr Simmons 1 catheter (Glidecath) was advanced through the celiac artery on a standard guidewire  and selective catheterization of the splenic artery was carried out.The following angiographic control confirmed the extreme tortuosity of the splenic artery and the saccular dilatation in its medium-distal part . The SimIt was decided to perform the double microcatheter technique to avoid coil migration and therefore 2 microcatheters were inserted through the guiding-catheter and positioned up to the proximal and distal part of the neck of the aneurysm, respectively. .Coil packing was performed using detachable coils, alternately released through the 2 microcatheters to obtain a safe and accurate placement. Four coils  were used overall. The last angiogram showed complete aneurysm exclusion and patency of the splenic artery . The patAfter three months an MRI was given showing good coil positioning with complete exclusion of the aneurysm, total splenic artery patency and no evidence of splenic ischemic lesions or infarctions . The patVisceral artery aneurysms represent a rare entity but are a serious and potentially lethal condition when rupture occurs. Treatment options include standard surgery and endovascular embolization with either coils or glue or both or aneurysm exclusion with a covered stent.The surgical approach has shown excellent long-term results but is still burdened by higher rates of periprocedural morbidity and mortality, longer operative times and length of stay The endovascular treatment was initially reserved for high risk patients or in emergency conditions when rupture occurs but nowadays this approach is first choice in many centers due to technical success and lower mortality comparable with traditional open repair procedure. Furthermore, the endovascular technique is less invasive and associated with a shorter length of stay with a mean hospital stay of 3.8 vs 12 days The two most common endovascular techniques are transcatheter embolization and covered stenting. Transcatheter embolization is currently considered a first choice for saccular aneurysms The use of covered stenting for SAAs exclusion is widely consolidated offering the potential benefit of maintaining splenic perfusion and eliminating risk of rupture however it has been reported to not work 30% of the time as it requires a favorable anatomy for a correct positioning Recently the use of stent-assisted coil embolization or multilayer flow modulator stents has extended endovascular treatment to multiple types of complex aneurysms Failures may be related to technical difficulties in catheterizing the aneurysm neck resulting in intra-procedural dissection or rupture and may more frequently occur in treatment of larger aneurysms, a large neck size and flow turbulence which can lead to unstable coils and incomplete sac packing The extreme tortuosity of the splenic artery which was the main feature in our case led us to perform the SAAs exclusion using the double microcatheter technique which could be considered an evolution on the standard transcatheter embolization. This technique is widely used for wide-necked and irregular-shaped intracranial aneurysms A limit to this approach consists of the angiographic acquisitions which could be difficult through a 4Fr\u20135Fr guiding sheath because of the smaller internal space due to the use of microcatheters. To avoid this problem we used a 7Fr guiding sheath.A recent report We chose to follow up the patient with a contrast enhanced MRI because of its reported usefulness in post-treated intracranial aneurysms and pulmonary arteriovenous malformations. Kawai et al. reported that the advantages of MRI compared to contrast-enhanced and/or unenhanced CTs were: 1) less susceptibility to metallic artefacts from platinum coils, 2) detectability of dynamic blood flow at a high temporal resolution, and 3) no radiation exposure"}
+{"text": "This study investigated the fitting accuracy of titanium alloy fixed dental prostheses (FDP) after sequential CAD/CAM (Computer Aided Design/Computer Aided Manufacturing) fabrication. A three-unit FDP model connecting mandibular second premolars and molars was prepared and scanned to fabricate titanium FDPs by CAD/CAM milling. A total of six FDPs were sequentially milled in one titanium alloy disk using a new set of burs every time (n = 4). The fitting accuracy of FDPs was mesiodistally evaluated by a silicone replica technique and the measurement was triplicated at four different locations: MO , MG , AG , and OG . Data were statistically analyzed using ANOVA and Tukey\u2019s HSD test. The fitting accuracy of PMMA (polymethyl methacrylate) FDPs milled using the worn or new bur were evaluated by the same procedure (n = 6). The mean dimensions of titanium FDP for all measuring positions, except for AG, were significantly increased from the third milling. However, no difference was noted between the first FDP and the second FDP milled with the same set of burs. Severe edge chippings were observed in all milling burs. Detrimental effects of the worn burs on the fitting accuracy were demonstrated in the CAD/CAM-milled PMMA FDP. The results recommend proper changing frequency of cutting burs to achieve the quality of fit and predictable outcomes for dental CAD/CAM prostheses. Dental CAD/CAM (Computer Aided Design/Computer Aided Manufacturing) systems have become mainstream in the fabrication of most dental fixed prostheses, even for metal restorations that have conventionally been fabricated by casting with the lost-wax technique ,2,3. In The degree of marginal and internal accuracy of fixed dental prostheses (FDPs) is of great importance to evaluate the clinical performance of a newly developed fabrication system. Although the fit of metal restoration fabricated by conventional lost-wax casting is better than that of milled restoration, the marginal fit of titanium copings fabricated by the milling technique with CAD/CAM is currently comparable to that of the conventional casting technique with or without manual refinement ,6. LaserTitanium and titanium alloys have many advantages as fixed and removable prosthetic materials in terms of physical properties and corrosion resistance . HoweverThere have been concerns about the durability of milling tools (tungsten carbide burs) for dental CAD/CAM machines . HoweverA standardized three-unit posterior FDP model connecting mandibular second premolars and molars was manufactured with stainless steel cylinders. Two abutment teeth were circumferentially prepared with a 12\u00b0 total occlusal convergence and 0.8-mm chamfer margin using a 6\u00b0 tungsten carbide burs  and lab milling machine . A central fossa with a 1-mm depth was prepared in the center of the occlusal surface to simulate occlusal form of natural teeth, and the sharp edges were intentionally beveled to reduce possible needs for internal refinement [\u03a698 \u00d7 12 mm, Doowon ID). A total of six three-unit FDPs were sequentially milled in one Titanium disk using a new set of milling burs  to fabricate the bridges using Titanium alloy CAD/CAM disk blocks  for CAD/CAM fabrication were milled with the new set or the used set of burs for six Ti FDPs. The marginal opening and gap dimensions of the PMMA FDPs fabricated using the worn or new bur were evaluated by the same procedure (n = 6). Scanning electron microscopy  observations were conducted to examine the cutting surface of milling burs before and after use. The surface topographies of milled Ti FDPs were compared with SEM  observations.The silicon replicas were examined at 125\u00d7 magnification using a metallurgical microscope  and image analysis software . The dimensions at each of four gap locations were determined by averaging data from the left and right sides of the premolar and second molar. All measurements were performed in triplicate with new silicon replicas to compensate for the limited number of specimens in this study . To examp < 0.05.Data were statistically analyzed using the IBM SPSS Statistics program . The Levene test was used to test the homogeneity of variances between milling sequences for each measuring location. Mean data were compared by one-way ANOVA and a post hoc test (Tukey HSD) at the level of significance of The marginal opening and gap dimensions at four measuring points, according to the milling sequence, are presented with a box-and-whisker plot in The fitting accuracy of titanium three-unit fixed dental prostheses fabricated by a 5-axis dental CAD/CAM system was significantly affected by the milling sequence. The marginal opening and gap dimensions at all measuring positions, except for AG, severely deteriorate from the third milling with the same set of burs. No significant difference in the adaption accuracy of FDP was noted between the first and second millings. The overall results of this study rejected the null hypothesis, suggesting no significant differences in the fit accuracy of the three-unit FDP milled using the new or used burs. The declines in the internal fit accuracy of the titanium FDP during sequential milling could be attributed to damage or wear of the milling burs due to extended use over the limitation of the bur lifetime. The significant increase in the marginal opening and gap dimensions of the titanium FDP can be directly shown by the results of the PMMA three-unit temporary FDP between milled using as-received new burs and worn burs after the sixth milling of Ti prosthesis . The resThe detailed reproduction of the crown intaglio surface by milling can be affected by the smallest bur diameter among the set of cutting tools, which must be considered in abutment preparation ,24. FurtThe occlusal gap (OG) dimension was generally higher than those of the other measurement positions in most CAD/CAM-fabricated fixed dental prostheses as reported in this and other studies ,6,19. InThe results of this study recommend changing milling burs at a proper frequency to maintain the accuracy of fit for CAD/CAM fabrication of dental metal prostheses. Periodic changes in milling burs were required to achieve the quality of fit and predictable outcomes for dental CAD/CAM prostheses. Moreover, an improved durability of cutting edges in milling burs will reduce the fabrication costs for dental CAD/CAM prostheses with low machinable materials. A drill compensation program for bur wearing can be incorporated into dental CAD software to reduce the inaccuracy of dental prosthesis milling. The limitations of this study are that the fitting accuracy of sequential milling was evaluated with only one dental alloy and milling system. Further studies should evaluate the relation of the machinability of various dental alloys with the fitting accuracy for different dental CAD/CAM systems.Within the limitations of this study, the marginal opening and gap dimensions of CAD/CAM-fabricated titanium three-unit FDP were significantly affected by the milling sequence or the conditions of milling burs. The results of this study recommend changing milling burs at a proper frequency to achieve the quality of fit and predictable outcomes for dental CAD/CAM prostheses."}
+{"text": "A novel coronavirus disease COVID-19) was initially reported in December 2019 in China and was rapidly declared a pandemic by World Health Organization challenging healthcare systems at a global level. Many elective surgeries were postponed worldwide in an effort to minimize spread of disease as well as to conserve resources. With the ongoing need for emergency and elective colorectal cancer surgery several issues and concerns raise from this situation while management of those patients globally including Greece has changed [9 was iniBased on the Italian experience, within colorectal emergency surgery, only life-threatening emergencies should be treated , in order to spare crucial resources for the management of the pandemic and an open approach is recommended . Yu et aCOVID-19 pandemic is seriously affecting the structure of healthcare systems globally. Many interventions will be needed to deal with the new scenario after the crisis has been controlled. Colorectal cancer surgery is arguably life-threatening if not conducted within a \u201creasonable\u201d time-frame and there is an urgent need to re-group and rethink the way the surgical care is being offered in this subgroup of patients during the COVID-19 pandemic.The author declares no competing interests."}
+{"text": "Myelin is a dynamic membrane that is important for coordinating the fast propagation of action potentials along small or large caliber axons (0.1\u201310 \u03bcm) some of which extend the entire length of the spinal cord. Due to the heterogeneity of electrical and energy demands of the variable neuronal populations, the axo-myelinic and axo-glial interactions that regulate the biophysical properties of myelinated axons also vary in terms of molecular interactions at the membrane interfaces. An important topic of debate in neuroscience is how myelin is maintained and modified under neuronal control and how disruption of this control (due to disease or injury) can initiate and/or propagate neurodegeneration. One of the key molecular signaling cascades that have been investigated in the context of neural injury over the past two decades involves the myelin-associated inhibitory factors (MAIFs) that interact with Nogo receptor 1 (NgR1). Chief among the MAIF superfamily of molecules is a reticulon family protein, Nogo-A, that is established as a potent inhibitor of neurite sprouting and axon regeneration. However, an understated role for NgR1 is its ability to control axo-myelin interactions and Nogo-A specific ligand binding. These interactions may occur at axo-dendritic and axo-glial synapses regulating their functional and dynamic membrane domains. The current review provides a comprehensive analysis of how neuronal NgR1 can regulate myelin thickness and plasticity under normal and disease conditions. Specifically, we discuss how NgR1 plays an important role in regulating paranodal and juxtaparanodal domains through specific signal transduction cascades that are important for microdomain molecular architecture and action potential propagation. Potential therapeutics designed to target NgR1-dependent signaling during disease are being developed in animal models since interference with the involvement of the receptor may facilitate neurological recovery. Hence, the regulatory role played by NgR1 in the axo-myelinic interface is an important research field of clinical significance that requires comprehensive investigation. Central nervous system (CNS) myelination is a developmentally regulated process governed by key molecular events that integrate dynamic changes at axonal and oligodendroglial cell membranes. Myelination ensures efficient propagation of action potentials along axons. CNS myelin-forming oligodendrocytes initially contact axons that they subsequently may ensheath depending on their electrical activity  or astroglial-derived chondroitin sulfate proteoglycans  exhibit abnormal formation of CNS nodes, since Caspr regulates the binding of NF155 to contactin 1 through direct interaction and processing for its membrane localization  close to and encroaching into the nodal gap  mutant mice that although display normal myelination but exhibit disrupted paranodal septate-like junctions, resulting in reduced axonal conduction velocity (CV). Therefore, it is plausible that in the presence of axonal degeneration without prominent demyelination observed in some MS lesions , and their hind paws more externally rotated (wider absolute paw angles) than na\u00efve wild-type mice , a measure of how rapidly the animal decelerates during the braking phase. These observations need to be further investigated to elucidate the precise neurophysiological role/s of NgR1 in gait regulation, and further dissect how changes in axon and myelin properties observed in the ngr1\u2212/\u2212 mice can potentiate such neurobehavioral outcomes.Our gait analysis of na\u00efve wildtype and ype mice . These o\u2212/\u2212ngr1 mice shows an altered adhesion of paranodal myelin with the axolemma that corresponds with a preserved expression of Kv1.2 ion channels but distributed (or the diffusion of) contactin-related protein throughout the node and internode regions  are reduced in both spinal cord dorsal white matter tracts and optic nerves of these mice , that the segregation of sodium and potassium channels that is necessary for the propagation of action potentials at nodes of Ranvier  and axonopathy that can differentiate the role of NgR1 in myelin turnover during remyelination compared to the axonal degeneration occurring in MOG-induced models. Elucidating the precise coupling of NgR1-dependent neuronal activity with the molecular restructuring of the node of Ranvier and paranodal myelin is a critical line of investigation in neuroscience that will drive the development of future regenerative therapeutic interventions that target the Nogo-A/NgR1 cell signaling mechanism during neurodegenerative diseases governed by the sequelae of inflammation.How NgR1 regulates the distribution of Caspr in a tightly orchestrated paranodal interaction with its glial membrane proteins that are integral to the synchrony of axonal myelin physiology is an important question. Future research should involve investigations into CNS remyelination in adult The AMREP Animal Ethics Committee (AEC nos. E/1532/2015/M and E/1602/2015/M) reviewed and approved the use of these animals for experimentation in this study, in accordance with the guidelines and regulations set out by the National Health and Medical Research Council of Australia. All animal experiments are governed by the Australian Code for the care and use of animals for scientific purposes (2013) and comply with the Victorian Cruelty to Animals Act 1986. All frozen human deep-cortical white matter tissues used for this study were acquired from the Victorian Brain Bank Network (VBBN) under the National Health and Medical Research Council guidelines and the Monash University Human Research Ethics Committee approval number CF13/1646-2013000831.SP wrote the manuscript. PT, MK, MA and JL edited the manuscript and generated data.JL is currently employed by the company ToolGen Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase with key roles in the regulation of cell adhesion migration, proliferation and survival. In cancer FAK is a major driver of invasion and metastasis and its upregulation is associated with poor patient prognosis. FAK is autoinhibited in the cytosol, but activated upon localisation into a protein complex, known as focal adhesion complex. This complex forms upon cell adhesion to the extracellular matrix (ECM) at the cytoplasmic side of the plasma membrane at sites of ECM attachment. FAK is anchored to the complex via multiple sites, including direct interactions with specific membrane lipids and connector proteins that attach focal adhesions to the actin cytoskeleton. In migrating cells, the contraction of actomyosin stress fibres attached to the focal adhesion complex apply a force to the complex, which is likely transmitted to the FAK protein, causing stretching of the FAK molecule. In this review we discuss the current knowledge of the FAK structure and how specific structural features are involved in the regulation of FAK signalling. We focus on two major regulatory mechanisms known to contribute to FAK activation, namely interactions with membrane lipids and stretching forces applied to FAK, and discuss how they might induce structural changes that facilitate FAK activation. Focal adhesion kinase (FAK) was discovered almost three decades ago as a kinase that is highly phosphorylated in response to cell adhesion and localisation into the focal adhesion complex ,2. Its iFAK is today recognised as a hub in the interactome of focal adhesions ,20,21, aSuper-resolution optical microscopy has defined a layered focal adhesion architecture with a signalling layer closest to the plasma membrane, a central force transduction layer and an actin regulatory layer, the site of actin attachment to the focal adhesion complex . In addiFAK contains an N-terminal FERM  domain a central kinase domain followed by a 220-residue proline-rich low-complexity region and a C-terminal focal adhesion targeting (FAT) domain a. IndiviThe FERM domain (residues 33\u2013361) of FAK adopts a three lobed structure , with the three lobes arranged in a clover-leaf shaped assembly  Figure b. The F1Crystallised FERM domains contain most of the linker residues following the FERM domain . This lThe FAK kinase domain adopts a typical two lobed fold seen in all protein kinases with the ATP binding site sandwiched between the two lobes c. Within712PKP) interacts with the SH3 domain of p130Cas [874PKKPP) with the SH3 domains of the small GTPase activating proteins GRAF and ASAP [The region C-terminal to the kinase (residues 686\u2013917) is proline rich and predicted to be unstructured. It contains two PxxP motives, site I  FATIn addition to FERM-kinase rupture, there are additional features in the structure of FAK that are compatible with force induced structural changes. As mentioned in Another intriguing thought is how force might affect the structure and function of the FAT domain. As discussed in High resolution structures of FAK regions, including all portions predicted to adopt globular domains, have provided important insights into the architecture and function of FAK at atomic level. These structures have defined the mechanism of FAK autoinhibition in the cytosol  and idenOn the other hand, studying the FAK structure in the context of the focal adhesion ultrastructure in cells by cryo-electron tomography will also entail major challenges. A past study has identified donut shaped structures in focal adhesions . However"}
+{"text": "Agrawal et al.  characteUnfortunately, these important data are often greeted in the medical oncology or radiation therapy communities with a tacit acceptance that adverse health outcomes are part of the \u201ccost\u201d of a reliable cure of metastatic cancer and that most late effects occur \u201cout of sight and out of mind,\u201d often after care transition from the GCT care providers complicates awareness and interventions.Consider survivorship in GCTs as an inverted funnel where patients enter at the time of diagnosis with or without subsequent chemotherapy, extensive surgery, or radiation therapy. In the United States and Canada, approximately 11\u2009000 patients are diagnosed with GCTs annually. After a few years of either observation or definitive treatment, about 10\u2009500 of these patients will enter the large and expanding portion of the funnel where they will remain for the rest of their lives. An estimated quarter million survivors of testicular cancer and its management live in North America with a per-patient additional life-years added of 40\u201350\u2009years postdiagnosis\u2014not a small challenge by any means.Let\u2019s think about the large proportion of patients who are posttreatment, which is the same group addressed by the Agrawal study . CurrentLittle recent attention with respect to survivorship has been paid at the narrow end of the inverted funnel . The recent history of academic GCT oncology has not concentrated on delivering similar high cure rates with less chemotherapy, less radiation, or less imaging, all of which are fundamental drivers of short-term and late effects and patient bother. Current practice and clinical investigations have often been pointed to more toxic approaches; combined approaches; and exuberant, unnecessary imaging .Successful delivery of newly diagnosed patients to the other side of survivorship should entail meaningful reduction in the number of cycles of chemotherapy delivered, elimination of prophylactic and therapeutic radiation therapy, and a marked reduction in imaging. Two emerging themes in GCT clinical research oncology offer hope of achieving this goal: precision medicine and centralized and collaborative clinical decision support and triaging complex care to high-volume centers.The most exciting development in precision medicine in GCTs comes from two recent, large prospective studies with serial measurement of serum or plasma microRNA 371 . These sPrimary retroperitoneal lymph node dissection (RPLND) is somewhat limited in large part because of the insensitivity of current imaging and classic marker-based determination of relapse . Since the 1970s, primary RPLND alone in the common setting of small-volume, marker negative stage II nonseminoma is known to be remarkably effective without the need for adjuvant chemotherapy (relapse free rate of approximately 75%). Several centers in the United States and Europe are testing an identical approach in small-volume stage II seminoma with similar preliminary results seen when classic, open primary RPLND is applied .If clinical trials using miR371-guided and expert surgical management of early stage GCT demonstrate equivalent therapeutic outcome with reduction or elimination of the use of radiation-based, chemotherapy-based approaches and computed tomography\u2013based imaging, nearly 85% of patients presenting with any stage of GCT will enjoy those subsequent 40\u2009years with nearly zero risk of severe late effects of treatment or frequent imaging. These innovations along with increased focus directed at chemotherapy-sparing and imaging-sparing approaches will likely further reduce the number of GCT patients at risk for consequential late effects of treatment. No small victory by any means."}
+{"text": "Elastic \u201ctethers\u201d connect separating anaphase chromosomes in most  animal cells. We tested whether tethers are involved in coordinating movements of separating anaphase chromosomes in crane-fly spermatocytes. In these cells the coupled movements of separating chromosomes become uncoupled after the tethers are severed by laser microbeam irradiation of the interzone region between the chromosomes . While t This article deals with possible functions of \u201ctethers,\u201d elastic connections between anaphase chromosomes. Tethers extend between the telomeres of all pairs of separating anaphase chromosomes in all (or most) animal cell spindles . One canTethers are universally present in animal cells, connecting all separating chromosome pairs . They alDo tethers coordinate the movements of separating anaphase chromosomes? Evidence that movements of separating chromosomes in crane-fly spermatocytes are coordinated  derives from non-laser ultraviolet-light (UV) microbeam irradiations of individual kinetochore spindle fibres. Those studies used as UV source a high-pressure mercury-arc lamp that emits a broad spectrum of wavelengths restricted by a monochromator to a peak wavelength  at a given setting . IrradiaWhen irradiation of one kinetochore fibre stopped the anaphase movement of the associated chromosome, the partner chromosome moving to the opposite pole also stopped moving ; the othcan use visible-light laser irradiations to test the possible role of tethers. That phenomenon is the continued movements of anaphase chromosomes after their kinetochore microtubules are severed. In crane-fly spermatocytes, anaphase chromosome movement is not altered when kinetochore fibre microtubules are severed by visible-light laser irradiations  reared in the laboratory using methods described elsewhere  files; the resultant bmp images were converted to avi files using VirtualDub2 freeware. Graphs of distance versus time were obtained from the avi files using an in-house program  that mean = 8 and each spermatocyte has three bivalent and two univalent chromosomes. At anaphase the bivalents disjoin and move to the stationary poles but the univalent sex-chromosomes (X and Y) remain at the equator  for between 20 and 100 s, and then returned to a slower speed, comparable to the starting speed, as illustrated graphically in After cutting kinetochore fibres the acceleration period lasted on average \u223c41 s before the chromosomes slowed down to near their original speeds . The aveA main conclusion from our experiments is that tethers coordinate the movements of separating anaphase chromosomes in crane-fly spermatocytes. Anaphase chromosomes with normal tethers do not speed up when their kinetochore spindle fibres are severed but chromosomes with cut tethers do . To exclHow might tethers coordinate the separating chromosomes? One possibility is that the tension on chromosome arms [stretching them by about 10% ] is tranAnother possibility is that tensegral interactions might influence the movements of chromosome partners. Tensegrity involves stabilised interactions between networks of tension-producing components and networks of load-bearing components (struts). Tensegrity has been considered a major foundation of the structure of living cells: many changes in cell function and structure, both overall and local, including position-specific mechanical-transduction, can be explained assuming that cell structure is based on tensegrity, i.e., that cells contain an interacting system of tensile elements and struts , 2003a,bDo our experiments unequivocally prove that tethers coordinate chromosome movements or could there be alternate interpretations of our data? Our irradiations unavoidably included spindle regions immediately adjacent to chromosome arms so we cannot rule out the possibility that other spindle components were damaged by the laser. However, any alternative interpretation must satisfy several conditions. One is that the component responsible for coordinating the movements must be in the interzone, between the arms of separating chromosome: this is because chromosome movements become uncoupled when that region is cut with the laser . A seconChromosomes accelerate after first tethers and then kinetochore fibres are severed ; later tOenothera meiosis are a series of reciprocal translocations  in the absence of kinetochore microtubules  disrupts the coordination between separating chromosomes in crane-fly spermatocytes. These data strongly argue that regulation of the speeds of separating anaphase chromosomes in crane-fly spermatocytes is due to the tethers that connect them.The datasets generated for this study are available on request to the corresponding author.AF did most of the experimentation, which took place in the laboratory of MB. Both authors contributed to writing the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Research has suggested that growth in Black and Hispanic older adults\u2019 nursing home (NH) use may be the result of disparities in options for long-term services and supports (LTSS). To investigate this issue, we aimed to determine whether there were no differences in the functional needs of racial and ethnic groups who received care in NHs versus the community. We identified respondents aged \u226565 years in the 2016 Health and Retirement Study who reported requiring caregiving help. We compared the site of care for Black and Hispanic older adults (minority group) to White older adults (comparison group). We performed unadjusted analyses to assess the association of functional need with community vs. NH care. Functional need was operationalized using a functional-limitations score and six individual activities of daily living (ADL). There were 186 minority older adults  and 357 White older adults . Across settings, minority older adults did not differ in age, marital status, and income, but a greater percentage of men were in NHs . The functional-limitations score was higher in NHs than in the community for both groups. Functional needs for the minority group were similar across the two settings in 2/6 ADLs , while White older adults in NHs were more impaired in all ADLs. Functional need for minority older adults primarily differed by setting while demographics did not. These are important factors to consider when implementing programs to keep older adults out of NHs and in the community."}
+{"text": "Polio has become the major vaccine-preventable disease that has received the much-needed support for its complete eradication following the eradication of smallpox. Currently, the incidence of the disease has been reduced by 99% owing to the intensive efforts of the Global Polio Eradication Initiative (GPEI), which was instituted in 1988 to achieve complete eradication  which isThe value of Qualitative Evidence Synthesis (QES) methodology in improving complex health interventions, particularly in low- and middle-income countries, is increasingly being recognised. This methodology uniquely identifies factors from qualitative research papers that can inform the improvement of health care interventions . ExpertsThe review used a best-fit framework of themes from Pakistan , which mIt is important to note that the new themes of vaccine hesitancy and insecurity in high-risk polio areas are the current major barriers faced by polio-endemic countries of Nigeria, Pakistan and Afghanistan . TherefoInsecurity impacts on vaccination activities either resulting in the mass movement of children leading to missing vaccination, inaccessibility or polio workers being targeted by insurgents. A recent report condemned the killing of a dedicated polio worker in Pakistan while undertaking polio vaccination activities . A suggeFurther evidence demonstrates the use of community mobilisation using indigenous community members in conflict settings. This was a cluster randomised control trial that was carried out in conflict areas of Pakistan . The finAnother important community factor relates to vaccine resistance with underpinning factors as shown in Nigeria is an important case study when it comes to addressing vaccine hesitance as remarkable success was achieved through the innovative use of Voluntary Community Mobilisers (VCM) . These vImmunisation is key to universal health coverage and that immunisation coverage is a valuable indicator of the strength of services delivered by any health system . Since v"}
+{"text": "Dystonia is a movement disorder characterised by involuntary muscle contractions resulting in abnormal movements, postures and tremor. The pathophysiology of dystonia is not fully understood but loss of neuronal inhibition, excessive sensorimotor plasticity and defective sensory processing are thought to contribute to network dysfunction underlying the disorder. Neurophysiology studies have been important in furthering our understanding of dystonia and have provided insights into the mechanism of effective dystonia treatment with pallidal deep brain stimulation. In this article we review neurophysiology studies in dystonia and its treatment with Deep Brain Stimulation, including Transcranial magnetic stimulation studies, studies of reflexes and sensory processing, and oscillatory activity recordings including local field potentials, micro-recordings, EEG and evoked potentials. Dystonia is defined by \u201csustained or intermittent muscle contractions that lead to abnormal movements, postures, or both\u201d Fahn . The mosAlthough the pathophysiology of dystonia is not fully understood, the loss of intracortical inhibition, increased cortical plasticity and abnormal sensorimotor integration are known to be involved in dystonia.Deep brain stimulation of the globus pallidus interna (GPi-DBS) is considered effective and safe in refractory dystonia  and long-term depression (LTD). Low-frequency rTMS (repetitive TMS) around 1\u00a0Hz leads to sustained decreases in motor cortex excitability  which allows topographically restricted increase in motor cortex excitability that can be blocked by NMDA antagonists suggesting LTP-like mechanisms  demonstrated co-contraction of agonist and antagonist muscles in a task-specific manner during handwriting in patients with writer\u2019s cramp  can provide some insight into the pathophysiology of dystonia, in particular through the pattern of activity of the basal ganglia-thalamo-cortical pathways. It can also inform us on the mechanisms of action of DBS. Single-cell recordings have been collected during DBS surgery, as part of the process of target localisation, and give us information at unicellular level. Cortical electrical activity recorded through EEG, electrocorticography (EcoG) or magnetic encephalography (MEG) allows to record activity at another point of the basal ganglia-thalamo-cortical circuitry. This activity has often been recorded in conjunction with basal ganglia LFP. Finally evoked potentials (EP) from the DBS pulse within the GPi have been recorded on the cortex.In Parkinson\u2019s disease (PD) many studies have reported increased activity not only in the beta band in the STN but also in GPi  and was functionally coupled across the GPi, GPe, and the motor cortex. In patients with tonic dystonia, delta oscillatory activities (2\u20134\u00a0Hz) were measured in the GPi with delta GPi\u2013GPe functional coupling  from the DBS pulses within the GPi have been recorded on the cortex and contribute to our understanding of the mechanism of action of GPi DBS. The studies have demonstrated a peak in the central regions, likely to be the primary motor cortex, around 20\u201330\u00a0ms (Tisch et al. In summary dystonia severity appears related to GPi low frequency activity. One the mechanisms of action of DBS is probably through reducing this activity. This might be used as biomarker for adaptive DBS in the future. Nevertheless, the role of activities in other frequency bands and the effect of DBS on those activities need to be explored further. In addition, we do not know how these findings differ according to the type of dystonia. Microrecordings have confirmed that the low frequency activity recorded with LFP comes from the pallidal neurons and is relevant for the expression of the symptoms including real-time modulation of dystonic contractions by effective sensory tricks. Evoked potentials and recordings of cortical activity also support the role of an inhibition of the motor cortex mediated by the pallido-thalamo-cortical pathway. Finally, adaptive DBS approaches may differ for thalamic targets owing to added complexity of thalamic reorganisation in dystonia (Lenz et al. Dystonia pathophysiology as elucidated by neurophysiology shows wide ranging abnormalities some of which normalise after clinically effective GPi DBS. The keys facts are summarised Table"}
+{"text": "Recent advancements in research on control beliefs have enabled the assessment of inter-individual differences in its intra-individual variability via a measure of control diversity. However, past research has focused on control diversity in relation to daily stressors. Among a sample of prosocial exemplars, this experience sampling study investigates control diversity across general daily activities and explores its relationship with subjective well-being. Participants indicated the activity they were primarily involved in, the extent to which they felt in control over the situation, and levels of positive and negative affect each time they were signaled; satisfaction with life was measured using a one-time survey at the end of the study. Results from multilevel structural equation modeling suggested that control diversity did not significantly predict positive or negative affect, or satisfaction with life. The study points toward the lack of association between control diversity and subjective well-being and highlights future directions for research."}
+{"text": "Xanthophylls are coloured isoprenoid metabolites synthesized in many organisms with a variety of functions from the attraction of animals for impollination to absorption of light energy for photosynthesis to photoprotection against photooxidative stress. The finding by Proctor and co-workers makes a new addition to the last type of functions by showing that zeaxanthin is instrumental in coordinating chlorophyll biosynthesis with the insertion of pigment-binding proteins into the photosynthetic membrane by glueing the protein components catalyzing these functions into a supercomplex and regulating its activity. Commentary on: Xanthophyll carotenoids stabilise the association of cyanobacterial chlorophyll synthase with the LHC-like protein HliDBy Matthew S. Proctor and co-workers2 to yield singlet oxygen, a ROS (reactive oxygen species) which causes photodamage and photoinhibition. Chlorophyll, however, is the most abundant pigment on Earth, reaching \u223c0.1\u2005M in thylakoids. How each and all these innumerable potentially harmful molecules can possibly be prevented from producing ROS and destroying the photosynthetic systems they are aimed to serve is a rich chapter of biological studies. Among other examples is the peculiar folding mechanism of light-harvesting complex (LHC) pigment-proteins, binding most of the chlorophyll on earth: these chlorophyll\u2013protein complexes can only fold by incorporating a set of xanthophylls (oxygenated carotenoids) [The early definition of carotenoids as \u2018accessory pigments\u2019 in photosynthesis is misleading. These isoprenoid pigments are essential for both light harvesting and photoprotection. Indeed, chlorophylls, essential components for both light harvesting and charge separation reactions in all photosynthetic systems, have a major problem with oxygen: their triplet states react with Otenoids) , a functtenoids)  respect tenoids) . Despitezeaxanthin is located at the interface between protein subunits or binds to allosteric sites to induce protein\u2013protein interactions, via conformational change.The way authors have traced this new function of xanthophyll is reverse genetic. Based on the observation that Synechocystis 6803 produces zeaxanthin while no know function makes explicitly use of this xanthophylls, they did produce a zeaxanthin-less strain. Previous work from members of the team had shown that TAG-ChlG formed a complex with HliD (a photoprotective protein quenching Chl fluorescence) and Ycf39 (an insertase carrying the precursor polypeptide for thylakoid insertion) in a pull-down assay. This complex was dissociated in the zeaxanthin-less strain but could be reconstituted by fusing zeaxanthin repleted membranes with the depleted ones. Re-association of the HliD and ChlD enhanced the catalyting activity of ChlD to release the accumulation of the ChlG substrate monovinyl (MV)-Chlide and resume Chl a biosynthesis. This is a brilliant experimental work. Authors discuss the glue-like activity of Zea on the basis of its rigid structure due to the extension of the conjugated double bond of the polyene to both b-ionone rings. This part of the work requires further research to clarify whether the complex-stabilizing function of Zea is a case of a general function for Zea in mediating protein\u2013protein interactions or is specifically taylored for HliD and ChlD complex. The HliD\u2013Ycf39 complex was maintained in the Zea-less mutant, supporting the latter hypothesis. Indeed, evidence from higher plants yielded several reports of changes in the aggregation state of proteic supercomplexes depending of the synthesis of Zea or structurally similar xanthophylls. To list a few examples, Zea synthesis in high light was needed for the dissociation of supercomplexes within the Photosystem II antenna system . This wo"}
+{"text": "The purpose of this study was to determine how an interprofessional education (IPE) intervention with Communication Sciences and Disorders (CSAD) and Nursing students can affect their ability to communicate effectively with older adults who have hearing loss. As the older adult demographic increases, healthcare professionals must provide competent care, which includes effectively managing hearing-related communication difficulties in an increasingly diverse population. Faculty received IRB approval to conduct a descriptive mixed-methods study to determine knowledge and satisfaction of students completing an IPE activity. Students were divided into teams of CSAD and Nursing students. Students listened to a brief presentation on IPE before they were introduced to a complex case study of an 84-year-old male with age-related hearing loss. We administered a knowledge assessment questionnaire (KAQ) we created regarding communication with older adults before and after the activity. A total of 92 participants in the two programs  completed the KAQ before and after the activity and an evaluation with a Likert-type scale and open-ended questions. CSAD students scored significantly higher than Nursing students on the KAQ at baseline  and KAQ scores increased significantly  among both groups from pretest to posttest. The evaluation data indicated students were able to learn other perspectives and found the experience valuable. Based on the improvement in scores on the KAQ and evaluation data, this IPE activity increased knowledge related to communication with older adults with hearing loss and awareness of the roles of other professions."}
+{"text": "Influenza (flu) infection is a leading cause of morbidity and mortality in older adults. Although vaccination is the best strategy to combat the effects of flu infection, there is a marked decline in vaccine efficacy in older adults. We hypothesized that an increased level of basal inflammation, a hallmark of the aging, plays a role in this decreased vaccine efficacy and that a vaccination strategy designed to augment the aged response to flu would be beneficial. Adjuvanted vaccination with a conserved influenza protein enhanced viral clearance, antibody production, and protected against weight loss in both young and aged mice. Vaccination also decreased levels of inflammation brought about by leukocyte infiltration and induced a strong type 2 cytokine environment in the lung. Additionally, vaccination reduced the proportion of flu-specific FoxP3+ T regulatory cells (Tregs) and decreased levels of TGF-\u03b2 in aged lungs following infection. Accumulation of senescent cells, another hallmark of aging, can contribute to the inflammatory environment via their senescent associated secretory phenotype (SASP). Supporting a role for senescent cells in exacerbating age-related deficits in the response to vaccination, treatment of aged mice with the senolytic drugs Dasatinib and Quercetin also decreased levels of Tregs and TGF-\u03b2 in the lungs following flu infection. These findings give insight to how vaccination responses can be ameliorated in older adults by targeting both inflammatory and regulatory signals and how accumulation of senescent cells could influence the dysregulation of the immune response with age."}
+{"text": "We report a case of a 29-year-old male referred to our hospital for endovascular treatment of a left-sided painful varicocele. Standard retrograde embolization via the left renal vein was not possible because of the presence of a left circum-aortic renal vein making the catheterization of the testicular vein not feasible. The patient was successfully treated via ultrasound-guided percutaneous antegrade access of the testicular vein at the inguinal level with subsequent cyanoacrylate glue embolization as a minimally invasive alternative to surgical therapy. This is a new approach to varicocele embolization when the left renal vein does not feed the varicocele."}
+{"text": "The visual word form area (VWFA) in the left ventral occipito-temporal (vOT) cortex is key to fluent reading in children and adults. Diminished VWFA activation during print processing tasks is a common finding in subjects with severe reading problems. Here, we report fMRI data from a multicentre study with 140 children in primary school . All performed a semantic task on visually presented words and a matched control task on symbol strings. With this large group of children, including the entire spectrum from severely impaired to highly fluent readers, we aimed to clarify the association of reading fluency and left vOT activation during visual word processing. The results of this study confirm reduced word-sensitive activation within the left vOT in children with dyslexia. Interestingly, the association of reading skills and left vOT activation was especially strong and spatially extended in children with dyslexia. Thus, deficits in basic visual word form processing increase with the severity of reading disability but seem only weakly associated with fluency within the typical reading range suggesting a linear dependence of reading scores with VFWA activation only in the poorest readers. The poorest 5\u201310% of the children with insufficient mastery of reading are considered as presenting with developmental dyslexia2. While phonological deficits have been suggested to play a central role for the impairments seen in dyslexia3, processing visual words for meaning remains the central task in reading. Thus, understanding how poor readers and especially children with dyslexia process visual words in the context of a semantic task is essential, and functional neuroimaging studies offer insight into the neural mechanisms involved.Reading words correctly and fluently is a prerequisite for understanding written text. Like other scholastic skills, reading shows a normal distribution within the population15 and consequently in reading for meaning. Especially an area within the left mid-fusiform gyrus, often referred to as the visual word form area (VWFA) typically shows a preference in responding to words or orthographic stimuli as compared to visual control stimuli such as checkerboard patterns7 even though this region is also involved in other processes17. Subsequent studies extended the notion of a VWFA to an entire visual word form system (VWFS) in the inferior occipito-temporal cortex that is progressively tuned to orthographic regularities with more anterior locations22 and a slightly more posterior region to encode letters (letter form area: LFA23). Even more fine grained functional divisions of the complex left vOT system along the posterior-anterior and lateral-medial dimensions were detected in more recent studies: Functional and microarchitectonic properties divide the larger visual word form system into a posterior perceptual word form area responsible for feature extraction and a more anterior lexical integration site corresponding approximately to the location of the classic VWFA24. Lately, Bouhali and colleagues suggested an additional lateral to medial functional segregation of the vOT, whereby multiletter sublexical graphemes are processed in medial regions in comparison to the lexico-semantic encoding in more lateral sites25.It is undisputed that the left ventral occipito-temporal cortex (vOT) has a prominent role in processing print33 and that it is initiated by grapheme-phoneme correspondence training in children34 and adults36. The location of the emerging print-sensitive area within the vOT seems constrained by its established connectivity to language regions long before children learn to read at school37 and develops in cortical patches with only weak specialization29. The exact location of the VWFA within the left vOT is subject to individual variations38. Importantly, the strength of the print sensitive response in the VWFA is modulated by the expertise level of reading in children and adults33. It is for this reason that the VWFA has also been referred to as reading skill zone40. Meta-analyses on children and adults with reading impairments revealed some of the most robust and consistent functional alterations in left vOT areas when tasks involve reading. Poor readers such as those with dyslexia activate this region less than typical readers43. This deficient activation in poor readers seems convergent for shallow and deep alphabetic languages45 and even generalizes to different writings systems46. Disruption of the activation in the VWFS through stimulation or through acquired brain lesions47 results in impaired reading48, again emphasizing its critical role for fluent reading.Developmental studies indicate that the print-sensitive response of the VWFA shows a rapid development in the first few months and years of learning to read49. The visual word processing system in the left vOT is sensitive to the perceptual and lexical properties of words31 and sublexical units25. This system is, however at the same time strongly influenced by top-down input from higher level phonological and semantic language areas50 and the dorsal attention network51. Therefore, also task demands modulate the differences seen between typical readers and subjects with dyslexia in the left vOT. Several studies reporting reduced left vOT activation in dyslexia for example employed tasks that put strong demands on phonological processing, such as reading pseudowords55, reading pseudohomophones54, or reading words having orthographic-phonological conflicts56. Studies employing explicit or implicit reading tasks with regular words typically reported less robust underactivation in left vOT in dyslexia , although deviant left vOT activation could still be detected in more focal ROI analyses60 or when comparing basic word processing and not print-sensitivity contrasts among groups30. While these studies emphasize that reading impairments are strongly associated with hypoactivation in inferior occipito-temporal regions under certain task conditions, it is less clear to what extent such deviations occur in more natural reading situations when readers focus on the meaning of words.Taken together, recent evidence points to a pivotal role of the VWFA for reading and reading acquisition64. Thus, the goal of the current study was to investigate word reading in a large sample of children at varying reading skills in a primarily dimensional approach using a task that emphasizes semantic processing, i.e. reading for meaning. The use of our large sample allowed us to use reading fluency as a continuous regressor in the analyses instead of examining just categorical differences.Some ambiguity in the dyslexia results might also stem from the typically small samples and the often-used categorical approaches in neuroimaging studies. Large-scale imaging studies on reading are still rare, and so far often examined tasks challenging the phonological system65]. Data analyses focussed on the modulation of print-sensitivity through reading skills across the entire multi-center sample while controlling for differences between sites.In order to obtain a large sample of subjects we developed a short controlled reading task in a multi-center study (NEURODYS). This task not only included visual words in the context of a semantic task, but also a low-level visual control task (cross-hatches and stars), where subjects had to decide whether all characters were the same or not  and meta-analyses42. A recent meta-analysis specifically addressing word processing in shallow and deep orthographies indicated that this overactivation is especially prominent in shallow orthographies44. Accordingly, the hyperactivation observed in our sample of children with reading difficulties may have been especially pronounced because of using simple and short words in our task, which can be read easily and automatically by typical but not by children with reading difficulties. The precentral regions are known to be involved in the articulatory network97, speech production98 and silent articulation99. An overlap of frontal regions usually showing hyperactivation in individuals with reading disorder with regions supporting articulation has been demonstrated in a recent quantitative meta-analysis and thereby supports the notion that such hyperactivation reflects compensatory processing to access the meaning of print96. Thus, poor reading children may use these regions to support reading by employing letter-by-letter decoding or covert articulation processes30. As an alternative explanation the hyperactivation in the precentral gyri could also reflect greater difficulties with and increased resources necessary for covert articulation or general processing of words in children with dyslexia. In either case these explanations converge with less efficient processing as indicated by slower reaction times to semantic decisions on words (and not symbols strings) in our task.The strong group difference of increased (rather than decreased) print-sensitive activation in children with dyslexia in left and right precentral regions is well in line with previous findings. Such overactivation has been reported consistently across studies [e.g.101 orthographic complexity (Dutch and German). This merging of three different groups may be seen as a limitation of this study. To address this potential limitation, our linear mixed models included site and age as covariates to regress out potential confounds. This suggests that the critical effects in this study were not affected by the different conditions across the three\u00a0sites or by the differences in age among the children, and thus generalize across involved languages and educational systems. Further one needs to keep in mind, that the present study design does not allow to finally conclude on whether the hypoactivation of the VWFA and the hyperactivation in the precentral gyri to print reflect specific dyslexia effects or whether these differences may rather be explained by differences in print exposure or reading level between children with dyslexia and typical reading skills. However, a study comparing adolescents with dyslexia to age- and reading-level matched control groups, suggested that the hypoactivation in the left parietal and fusiform gyri indeed reflect atypical brain function in dyslexic individuals, while the frontal hyperactivation is more likely related to the current reading skills independent of dyslexia102.In order to achieve a large sample size, we collected data across three different sites, including two different languages with similar semi-transparentTaken together, this large-scale neuroimaging study on the influence of word reading fluency on brain activation emphasizes the important role of the left vOT for reading skills and highlights its functional impairment in poor reading children. It extends the insight of previous large-scale studies specifically challenging phonological processing and using more liberal criteria for defining dyslexia by focussing on reading for meaning. Thus, the present study represents one of the largest datasets (n\u00a0=\u00a0140) on functional activation in children with severe dyslexia compared to typical readers and clearly corroborates previous notions that the print-sensitive activation in the left vOT represents a critical limiting factor of reading for meaning especially at the lower end of the reading fluency spectrum. Given that the most robust underactivation in children with dyslexia occurred in this region, the left vOT function appears to be a prime target for supportive interventions in those needing it most.Supplementary Information."}
+{"text": "We present the case of a young male with high clinical suspicion of a penile fracture found to have dorsal vein rupture by emergency department point-of-care ultrasound. This false form of penile fracture was subsequently confirmed intraoperatively.Penile fracture is a rare clinical entity that may be separated into true vs false penile fracture, with only true fracture requiring surgery. The images submitted here add to the sparse literature evidence that point-of-care ultrasound can be used to differentiate between these two clinical entities. Additionally, this case report highlights an opportunity for further research into and application of point-of-care ultrasound to the evaluation of suspected penile fractures. A 26-year-old man presented to the emergency department with penile pain and bruising after accidental trauma during intercourse one hour prior to arrival. He reported immediate pain and bruising with detumescence within minutes. Exam was revealing for eggplant deformity of the penis with soft dorsal ecchymosis and mass felt extending into the scrotum .This patient\u2019s ultrasound images showed hematoma external to Buck\u2019s fascia and intact tunica albuginea, suggestive of dorsal penile vessel injury  and 3. TSurgical exploration confirmed a dorsal vein rupture with subsequent drainage of a large hematoma involving the dorsal vein and dartos layer dorsally. There were no acute complications. On follow-up the patient reported recovery of sexual function without curvature, but with mild residual pain to the incision site at six-week postoperative follow-up.What do we already know about this clinical entity?Penile fracture is a rare clinical entity encountered following trauma to the erect penis and is typically managed surgically.What is the major impact of the image(s)?This image increases awareness of false penile fracture and the utility of ultrasound in evaluation for possible penile fracture.How might this improve emergency medicine practice?Increased use of point-of-care ultrasound may allow for improved accuracy in differentiating between true and false penile fracture and reduce the need for surgery."}
+{"text": "In December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) firstly presented in a group of patients suffering from symptoms of pneumonia in Wuhan, China .Triaging women based on their symptoms  by phone call carried out by a medical intern prior to the scheduled visit to the ART center. For the new patients first seen in the center, triage is performed before access to the clinic for consultation by a medical intern wearing the appropriate personal protective equipment (PPE).Ensuring proper social distancing through proper respect of the time of scheduled visits with spacing out the appointment intervals between patients to minimize the crowding in the waiting area. Additionally, preventing any relative to the couple to enter the IVF center, especially children or adults over the age of 60\u2009years.Laboratory evaluation of all patients before initiating the IVF cycle treatment through complete blood picture, C-reactive protein, erythrocyte sedimentation rate, and serum ferritin . Those wPatients under immune suppression therapy and those who have medical disorders affecting the immune system are advised to postpone the IVF cycle treatment as the risk of acquiring the COVID-19 complications is high.Patients sign a written consent before starting the IVF cycle treatment, including the freeze-all embryos policy and deferring the transfer after the pandemic ends. Otherwise, if the couple insisted on fresh embryo transfer, we inform them that the available data on the effect of COVID-19 on pregnancy is limited .Using the fixed GnRH antagonist protocol and GnRH agonist triggering for all patients at risk of ovarian hyperstimulation syndrome (OHSS).Minimizing the monitoring visits by using the long-acting GnRH agonist drugs and long-acting gonadotropin stimulation drugs like corifollitropin alfa prefilled pin . AdditioThe use of effective preoperative analgesia in patients requiring office hysteroscopy prior to IVF , and thePatients who get pregnancy tested for B-HCG through providing a home blood sample by a laboratory technician and repeat it after 48 h to confirm doubling. Using Telehealth-based care through the Whatsapp messenger, follow-up of their condition and revising the medications in the first eight weeks at home is instituted.In Egypt, in vitro fertilization (IVF) is a client-paid service with no medical insurance, the cost of IVF cycles is high relative to the average yearly income of Egyptians, and private centers mainly offer assisted reproduction services. Therefore, pragmatic solutions should be established to amend the recent guidelines to suit the local requirements in the context of the golden rule of \u201cdo no harm.\u201d These solutions should be in conjunction with the latest guidelines to continue the proper management of patients while ensuring adequate resource allocation in response to COVID-19. We proposed the following measures adopted by an Egyptian IVF clinic to support the best practice and face the highly dynamic situation on day to day basis. This could provide guidance for low-resource countries that must cope with the pandemic for an extended period.As it is unclear how long the COVID-19 pandemic will continue, we are hoping that those measures could help the ART centers to provide their services for patients in developing countries, especially with low COVID-19 infection rates like Egypt. Moreover, the provided measures could be initially recommended in the centers located in countries with high infection rates such as the European Union and the USA after eradication of the COVID-19 pandemic."}
+{"text": "A lockdown is a social distancing intervention that aims to minimise physical contact between individuals and groups in order to reduce transmission of a communicable disease . Social The lack of any effective pharmaceutical interventions for COVID-19 or vaccine against SARS-CoV-2 and the resulting failure to contain the virus has led to widespread adoption of physical distancing measures . For exaA number of governments have been provided anonymous aggregated mobile phone GPS data allowing monitoring of compliance with physical distancing at the population level  . In contA number of other technology companies  are also sharing GPS data with academic institutions, governments and health providers  . RecentlSimilarly, Unacast has repurposed location and movement data that they collect via mobile phones to create a daily updated interactive scoreboard for \u201csocial distancing activity\u201d for the United States that gives data at national, state and county levels . For example, the Inter-American Development Bank and IDB Invest have developed a public COVID-19 dashboard for Latin American and Caribbean countries including traffic data supplied by the navigation apps, Waze & Moovit (COVID-19 has resulted in the introduction of lockdowns on an unprecedented scale in an attempt to modify the course of the pandemic and mitigate its effects. Measuring compliance with physical distancing is crucial to inform modelling deliberations and enable evidence-based policy making. We have summarised three key approaches that are currently being used to help estimate compliance with lockdowns in the context of the COVID-19 pandemic. Although currently used in a small minority of countries, there is substantial opportunity to scale up use of these approaches globally."}
+{"text": "Although effective mobility is the end result of the functional capacity of multiple systems, some adults appear resilient and maintain higher mobility later in life. Epidemiological studies suggest up to 20% of adults aged 65 and older maintain fast walking speed in the presence of multi-system impairments. What could be the reason for such mobility resilience? In this symposium, we focus on the brain dopaminergic signaling as a potential driver of mobility resilience. We examine the genetic val158met polymorphism of catechol-O-methyltransferase (COMT), an enzyme regulating dopaminergic signaling in the brain. The Met allele results in higher tonic dopamine levels; the Val allele results in lower tonic dopamine levels. The influence of COMT polymorphism on mobility is known for Parkinson\u2019s disease (PD) and neurodegenerative conditions, but it not clear for asymptomatic adults aged 65 living in the community. We present data from the Cardiovascular Health Study, the Health Aging Body Composition Study, and several neuropharmachological studies with extensive information on PD ascertainment, medications, and health characteristics. We test the hypothesis that the Met allele of the COMT gene is associated with a) lower fall risk (Rosso), b) slower decline in gait reserve (Sprague), c) less gait slowing due to frailty (Mannon), d) more favorable response to pharmacotherapy in older adults without PD (Bohnen). Our results suggest a unique modulatory capacity of dopaminergic-related genes that may favor mobility resilience and predict better response to therapy. Our data provide clues for novel targeted interventions to delay physical disability in older adults."}
+{"text": "Using thymidine analogues and retrovirus-mediated cell labeling, we show that synaptic integration and subsequent survival of newborn neurons is decreased in NIPP1*-expressing mice, suggesting that newborn neurons compete with preexisting granule cells for stable integration. The data presented here provides experimental evidence for a long-standing hypothesis and suggest cellular competition as a key mechanism regulating the integration and survival of newborn granule cells in the adult mammalian hippocampus.Dentate granule cells are born throughout life in the mammalian hippocampus. The integration of newborn neurons into the dentate circuit is activity-dependent, and structural data characterizing synapse formation suggested that the survival of adult-born granule cells is regulated by competition for synaptic partners. Here we tested this hypothesis by using a mouse model with genetically enhanced plasticity of mature granule cells through temporally controlled expression of a nuclear inhibitor of protein phosphatase  Neural stem/progenitor cells (NSPCs) generate the vast majority of neurons in the brain during embryonic development. However, the neurogenic capacity of NSPCs does not end with birth as new neurons are born across the entire life-span in discrete areas of the mammalian brain . One of Neural stem/progenitor cells (NSPCs) generate the vast majority of neurons in the brain during embryonic development. However, the neurogenic capacity of NSPCs does not end with birth as new neurons are born across the entire life-span in discrete areas of the mammalian brain . One of We investigate the survival and morphology of newborn granule cells in the adult dentate gyrus in a model of enhanced plasticity of mature neurons to test the hypothesis that a mechanism of competition governs integration into the neuronal circuits.1 (NIPP1*)  ..1* mice,1* in mature granule cells and found that enhancing plasticity of the mature granule cell circuit . Wi. Wi22].  circuit  25] imp imp1* insurvival  18] [19 [191* insurvival . This unsurvival  38] [39 [391* inWe used a single mouse model of enhanced plasticity with wildtype littermate controls. While, we interpret our data as a strong suggestion of a competitive mechanism at work, additional studies using different models and approaches are needed to prove that the effects observed are not specific to the model. In our model, the transgene is expressed under the control of the CaMKII\u03b1 promoter, which is active in all forebrain neurons. It is possible that, next to the effect of the immediate environment, other changes inherent to the transgene also affect neuronal integration and morphology. One immediate effect on newborn granule cells may be altered input by medial entorhinal cortex cells, the primary input of the hippocampus.Suppl. Fig."}
+{"text": "Dear Editor,The coronavirus disease 2019 (COVID-19) pandemic has caused an immense surge in the use of personal protective equipment (PPE) in healthcare settings. The use of goggles is an integral part of the PPE used by healthcare professionals involved in direct patient care . This caCommercial anti-fogging agents commonly used by scuba divers can be used when donning goggles and have been found to be effective. Procuring sufficient amounts of commercially available anti-fogging agents can be difficult in the current situation. Some tricks used by professional scuba divers can be applied in emergency settings. Many scuba divers spit on the inner surface of their eyewear and wipe the sputum to prevent fogging . We haveThe author declares that he has no competing interests."}
+{"text": "Diet plays a major role in cardiovascular disease (CVD) risk.To determine the effectiveness of a Mediterranean-style diet for the primary and secondary prevention of CVD.We searched for randomised controlled trials (RCTs) of Mediterranean-style diets in healthy adults and those at increased risk of CVD (primary prevention) and with established CVD (secondary prevention).Thirty RCTs were included, 22 in primary prevention and eight in secondary prevention. Clinical endpoints were reported in two trials where there was moderate quality evidence for a reduction in strokes for primary prevention, and low quality evidence for a reduction in total and CVD mortality in secondary prevention. We found moderate quality evidence of improvement in CVD risk factors for primary prevention and low quality evidence of little or no effect in secondary prevention.There is still some uncertainty regarding the effects of a Mediterranean-style diet in CVD prevention. Cardiovascular disease (CVD) is currently the leading cause of mortality worldwide, causing one-third of deaths globally . PreventThe Seven Countries study from the 1960s demonstrated the potential beneficial effects of a Mediterranean dietary pattern . Systema4567810Studies also differ in their definition of a Mediterranean diet. The original description reflects the common dietary pattern of communities in countries of the Mediterranean region in the early 1960s , which w131415There is evidence supporting potential mechanisms to explain the beneficial effect of the Mediterranean diet on cardiovascular health . Favoura1819202122101124252627We included RCTs with follow-up periods of three months or more, examining the effects of a Mediterranean-style diet in adults (18 years or more) without established CVD and in those with established CVD to determine the effects of the intervention on primary and secondary prevention respectively. To reach our definition of a Mediterranean-style diet the intervention needed to include at least the following two components: a high monounsaturated/saturated fat ratio ; and high intake of plant-based foods, including fruits, vegetables and legumes. This definition was based on recent work showing that the protective effects of the diet appear to be most attributable to olive oil, fruits, vegetables and legumes 30. We coClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (ICTRP) for ongoing trials. We applied no date or language restrictions. We contacted authors where necessary for further information.We identified trials through systematic searches of the following bibliographic databases (from inception to 26 September 2018): Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and Web of Science Core Collection. We adapted the preliminary search strategy for MEDLINE (Ovid) for use in the other databases (Appendix 1). In addition, we checked reference lists of reviews for additional studies. We searched Two review authors  independently screened titles and abstracts for inclusion of all the potential studies identified as a result of the searches and coded them as \u2018retrieve\u2019  or \u2018do not retrieve\u2019. We combined the responses from each of the two review authors and retrieved the full-text study reports/publications. Two review authors  independently screened the full text and identified studies for inclusion and exclusion using the pre-specified inclusion criteria. In the case of any disagreements, a third author arbitrated (KR).We used a data collection form for study characteristics and outcome data, which we had piloted. Two review authors  extracted study characteristics and outcome data from included studies. Disagreements were resolved by consensus or by involving a third person (KR). One review author (KR) transferred data into the Review Manager software . We doubTwo review authors  independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions . We resoWe processed data in accordance with the Cochrane Handbook for Systematic Reviews of Interventions . We expr2 statistic to measure heterogeneity among the trials in each analysis. We used the five GRADE considerations  to assess the quality of a body of evidence as it relates to the studies that contribute data to the meta-analyses for the prespecified outcomes. In the main analysis we did not combine primary and secondary prevention studies and different comparator groups as this would have made interpretation of the results difficult due to heterogeneity; instead we conducted four main analyses: Mediterranean dietary intervention versus no intervention or minimal intervention for primary prevention; Mediterranean dietary intervention versus another dietary intervention for primary prevention; Mediterranean dietary intervention versus usual care for secondary prevention; Mediterranean dietary intervention versus another dietary intervention for secondary prevention.We summarised and analysed all eligible studies in Review Manager 5. We undertook meta-analyses only where this was meaningful, i.e. if the treatments, participants and the underlying clinical question were similar enough for pooling to make sense. We used a random-effects model as we could not assume that all studies in the meta-analysis are estimating the same intervention effect, but rather are estimating intervention effects that follow a distribution across studies. We used the ISearching for this updated Cochrane review yielded 9483 records after duplicates were removed. Following screening of titles and abstracts 9296 were excluded and 187 full text papers were assessed for eligibility. Twenty one completed and seven ongoing trials were included from the new search. Six studies were included from the previous review and rescreening the original database identified three further trials, so a total of 30 completed studies and seven ongoing trials were included in this review  presented in Table None of the nine included studies reported on clinical events.The PREDIMED trial was the only trial reporting clinical events for this comparison . This trThe Lyon Diet Heart Study examined the effect of advice to follow a Mediterranean diet and supplemental canola margarine compared to usual care in 605 CHD patients over 46 months and there was low-quality evidence of a reduction in adjusted estimates for CVD mortality  and total mortality  with the intervention .Three studies reported clinical endpoints for this comparison group 5459, and54535463We assessed the overall quality of evidence using the five GRADE considerations  presented in Table For CVD risk factors for comparison one, there was low-quality evidence for a possible small reduction in total cholesterol  and moderate-quality evidence for a reduction in systolic (\u20132.99 mmHg (95% CI \u20133.45 to \u20132.53) and diastolic blood pressure , with low or very low-quality evidence of little or no effect on LDL or HDL cholesterol or triglycerides.For comparison 2 there was moderate-quality evidence of a possible small reduction in LDL cholesterol  and triglycerides  with moderate or low-quality evidence of little or no effect on total or HDL cholesterol or blood pressure.For comparison three there was low-quality evidence of little or no effect of a Mediterranean-style diet on lipid levels and very low-quality evidence for blood pressure.For comparison four where only two trials contributed to the analyses there was low or very low-quality evidence of little or no effect of the intervention on lipid levels or blood pressure.In this substantive review update, 30 RCTs (49 papers) and seven ongoing trials met our inclusion criteria. Four pre-specified comparison groups were used to analyse the data to address both heterogeneity between participants and comparison groups and aid interpretation of findings. Clinical endpoints were measured in only one large primary prevention trial (PREDIMED) , where f535463There were a large number of included trials , but few reported on clinical endpoints, our primary outcome, and the majority of trials reported on CVD risk factors for primary prevention. Due to the breadth of the review question, heterogeneity in terms of participants, interventions and comparators was high and we have attempted to reduce this by conducting the main analyses in four comparison groups for primary and secondary prevention and different comparators. Two studies were excluded from all main analyses in sensitivity analyses due to published concerns regarding the reliability of the data 546364. O5463We conducted a comprehensive search across major databases for interventions involving the Mediterranean diet. Two review authors independently selected and assessed trials for inclusion using pre-specified criteria, extracted data and assessed the quality of trials to minimise potential biases in the review processes. Our decision to restrict this review to interventions that only focused on the effectiveness of a Mediterranean-style diet per se avoided the potential confounding effects of other behavioural interventions on our outcomes, for example, those involving increased exercise in the context of trials examining multifactorial interventions. Our decision to exclude trials in people with diabetes who are at increased risk of CVD also missed relevant studies, but people with diabetes represent a distinct group and interventions for the management of diabetes are covered by another review group, the Cochrane Metabolic and Endocrine Disorders Group.Definitions of the Mediterranean diet differed across studies. We used a classification system in our definition in an attempt to address the heterogeneity. The components required to meet our definition of a Mediterranean-style diet were based on previous definitions 14151617,1415165Several recent systematic reviews and overviews of reviews have reported on the effects of the Mediterranean diet on cardiovascular health. A recent narrative overview of both prospective observational studies and RCTs concluded that the Mediterranean diet has some beneficial effects for CVD prevention but the effects were inconsistent between studies with few studies reported in meta-analyses and the overview authors called for more high-quality trials to address the inconsistencies . This isA recent systematic review included both primary and secondary prevention trials and pooled clinical endpoints for these showing beneficial effects for major vascular events (risk ratio (RR) 0.69, 95% CI 0.55 to 0.86) and stroke  . Other s10Despite the large number of trials included in the review there is still uncertainty regarding the effects of a Mediterranean-style diet on clinical endpoints and cardiovascular disease (CVD) risk factors for both primary and secondary prevention from current clinical trial evidence. Two trials reporting clinical endpoints for secondary prevention were excluded because of concerns regarding the reliability of the data, so the available evidence is restricted to one large trial and a small trial reporting unadjusted estimates of effect. Evidence for primary prevention on clinical endpoints is limited to one large trial with methodological issues . Further adequately powered primary prevention trials are needed to confirm findings on clinical endpoints to date. Many trials reported on CVD risk factors, particularly in primary prevention, but heterogeneity precluded meta-analyses for some outcomes. Several ongoing trials have been identified which will add to the evidence base.The additional file for this article can be found as follows:10.5334/gh.853.s1Appendix 1.Medline search strategy (Ovid)."}
+{"text": "In this paper, a novel approach is presented to the measurement of marine icing phenomena under the presence of a two-phase condition. We have developed a sensor consisting of an electrostatic array and a signal processing based on a decision tree method. A three-element electrostatic array is employed to derive signals having linearly decoupled characteristics from which two key parameters, ice and water accretion layer dimension, can be determined for the purpose of environmental monitoring. The quantified characteristics revealed a correlation with the ice layer thickness in spite of the strong influence from the top water phase layer. The decision tree model established a relationship between the signal characteristics and the two accretion thickness parameters of water and ice layer. Through experimental verification, it has been observed that our sensor array in combination with the decision tree model based signal processing provides a simple practical solution to the challenging field of a two phase composition measurement such as in the marine icing considered in this study. Marine Icing is an adverse phenomena affecting offshore vessels and other structures like wind farms  or oil aGraz Technical University  applied Combitech IceMonitor  measuresThe Goodrich 0871LH1 ice detectors  use an aHoloOptics T42  employs The Ice Meister Model 9734-SYSTEM industrial ice detector [IDS-20 system  measuresJeung Sang Go with Xiang Zhi  employedWe have developed a sensor array that allows a flexibility to be applied on curved surfaces such as wind turbine wings. Our earlier work described in  utilizedPreviously we processed the array signals by a multidimensional least squares method  and in aMachine learning algorithms are being used in many applications ranging from flood prediction , solar rThe ice can take different formations described in , howeverOur research into sensing and detecting the marine icing as a two phase phenomena has been initially founded on the principles of linearly decoupled array of electrostatic sensors of variable electrode gap spacing. The experimental verification confirmed our hypothesis of dissimilar gap spacing being capable to encode the stray electrostatic field above the sensor plane in a unique and linearly independent way. This phenomena was utilized in discriminating each individual phase, ice and water. Our team developed a multi-dimensional least-squares-method  to map tconstant gap spacing, variable insulator height), (2) at the signal pick up circuitry , (3) at the signal processing algorithm level (decision tree method) and (4) at the spacial adaptation to curved surfaces . Our earlier setup resulted in a large variation of capacitance range which required a custom build circuitry for capacitance to frequency conversion. In this work, we adapted an off-the-shelf signal detection board FDC2214EVM from Texas Instruments [In this paper, we modified our earlier methods in four ways, (1) at the transducer array level  using Ansys Maxwell software . The solAny traditional insulation material that is not permeable to water will provide the function of eliminating the conductance  from the impedance measurement. PET sheets were readily available to us and their dielectric constant is similar to the epoxy resin used in the past. The critical part in obtaining the linearly independent characteristics across the array is in a different number of stacked layers of PET sheets above each array element.We have conducted a series of ice layer deposition experiments in a similar way described in  using a The Decision tree model is constructed from the main root branches consisting of the interior nodes and the final nodes also called the decision nodes . The treWe have split the acquired signal data and the corresponding ice and water accretion estimate into the training data set and the test data set. The training data is used to derive the decision tree parameters during the training phase. Our decision tree implementation is based on the Entropy rule described in . In compWe implemented a twelve level deep decision tree processes the measured data based on entropy value where a low entropy value leads to the best leaf node in terms of purity. Applying the trained decision tree model to the test data results in the ice accretion estimate depicted in The Precision, Recall, F-Measure and Accuracy are commonly used for evaluating classification methods in Machine learning . PrecisiTP) is a classification method outcome where the decision tree method generates a correct positive class layer. Likewise, True Negative (TN) is a classification method outcome where the decision tree method generates a correct negative class layer. False Positive (FP) and False Negative (FP) are a classification method outcome where the decision tree method generates incorrect positive and negative class, respectively.True Positive (The Confusion-matrix yields the most ideal suite of metrics for evaluating the performance of a classification algorithm. Gupta  providesThe conventional method of using the least squares method to our experimental data as reported in  is preseA novel sensor array has been developed to measure the marine icing accretion and to allow flexibility in deployment over curved surfaces. A new signal processing method based on a decision tree method has been applied to the array data. A theoretical analysis confirmed linearly decoupled signal characteristics that are critical in discriminating the water phase influence on the ice accretion measurement. An experimental analysis validated the high relevance of employing the decision tree method for signal processing. The ice accretion estimate obtained through the decision tree method demonstrates a significant improvement over the conventional least square method and a similar characteristic with the Neural Network method, however of a lesser computational overhead and a smaller footprint. Our three element capacitive array is easy to fabricate with off-the-shelf components and the 4 ch 28 bit signal processing interface circuit from TI is also aligned with a very low cost characteristics. The nature of our non-contact based design without any moving parts and the low cost characteristics promises a robust solution towards the marine icing measurement under the harsh environmental conditions."}
+{"text": "Phylogenetic analyses were crucial to elucidate the origin and spread of the pandemic human immunodeficiency virus type 1 (HIV-1) group M virus, both during the pre-epidemic period of cryptic dissemination in human populations as well as during the epidemic phase of spread. The use of phylogenetics and phylodynamics approaches has provided important insights to track the founder events that resulted in the spread of HIV-1 strains across vast geographic areas, specific countries and within geographically restricted communities. In the recent years, the use of phylogenetic analysis combined with the huge availability of HIV sequences has become an increasingly important approach to reconstruct HIV transmission networks and understand transmission dynamics in concentrated and generalised epidemics. Significant efforts to obtain viral sequences from newly HIV-infected individuals could certainly contribute to detect rapidly expanding HIV-1 lineages, identify key populations at high-risk and understand what public health interventions should be prioritised in different scenarios. Phylogenetics and the pre-epidemic phase of HIV-1 spreadPan troglodytes) and gorillas (Gorilla gorilla) to humans.,Pan troglodytes troglodytes and Gorilla gorilla gorilla, endemic from Cameroon, were pointed as the sources of the zoonotic transmissions to humans, originating the groups M and N, and O and P, respectively [,The human immunodeficiency virus type 1 (HIV-1) has been spreading in human populations over the last 100 years and is responsible for most of the global HIV/AIDS pandemic. Phylogenetic analyses of simian immunodeficiency viruses (SIV) sequences from different species of non-human primates and of HIV-1 sequences from Central African countries were decisive to elucidate the origin of this pandemic human virus. Those analyses revealed that the four HIV-1 phylogenetic clades termed groups  have resulted from different cross-species transmission events of SIV from chimpanzees  and of the non-pandemic subtype B variants prevalent in the Caribbean region (BCAR).,FSU clade resulted from exportation of a subtype A lineage from the DRC to Ukraine in the 1980s, where it initially spread via heterosexual transmission for about a decade before its explosive dissemination among intravenous drug users (IDU). Cabello et al.CAR epidemic resulted from early viral transmissions from Hispaniola to Trinidad and Tobago and to Jamaica between the late 1960s and the early 1970s and from Hispaniola and Trinidad and Tobago to other Lesser Antilles islands at later times.Phylodynamics could provide important epidemiological insights about HIV-1 epidemics affecting a vast geographic area. This approach, for example, was used to resolve the spatiotemporal dynamics of the HIV-1 subtype A variant that dominates the epidemic in the former Soviet Union  and Central (CRF45_cpx) Africa.Phylodynamics analyses also helped to elucidate the origin and populations\u2019 dynamics of HIV-1 lineages spreading within small communities. One example was the characterisation of an HIV outbreak in children from a Libyan hospital that occurred in 1998, suspected to have originated from the malicious intervention of foreign medical staff.Phylodynamics analyses combined with birth-death models could be a useful tool to elucidate the impact of preventive or therapeutic strategies on localised HIV epidemics. A recent study dated back the origin of a Belgian HIV-1 subtype F1 epidemic among men having sex with men (MSM) to the early 2000s and suggested that its extensive growth was controlled about 10 years later, most likely due to highly active antiretroviral therapy (ART) as prevention.Phylogenetics and the study of HIV-1 transmission networksThe absence of proofreading activity of the viral reverse transcriptase and fast replication rate make mutations to accumulate in HIV genomes in an epidemiological timescale.In an attempt to reconstruct the HIV transmission events in a population, the better the sampling coverage, the closer to reality is the inferred network. In this sense, most of the studies in this field have used databases compiled by national services for screening of drug-resistance mutations (genotyping), which generate HIV partial genome sequences for virtually every individual entering/failing therapy. Focusing on highly supported phylogenetic clusters mostly compose by local (from a single country) individuals, Hu\u00e9 et al.+ T cell counts, not on ART and not aware about the HIV serostatus were found, underscoring the importance of acute phase of infection in the HIV transmission dynamics. Despite the high HIV transmissibility during acute phase, Volz et al.To identify current and still active transmission networks, many studies apply a genetic cut-off to define clusters.When a dense body of clinical and demographic data from patients is available, the source attribution methods could be used to find potential transmission pairs and resolve the timing and direction of the infection. Ratmann et al.,While phylogenetics has been increasingly deployed to study HIV transmission dynamics in developed countries with concentrated epidemics, where viral sequences are routinely sampled, few studies were able to apply these tools in resource-limited locations, where the epidemic is generalised and HIV has the greatest burden. The main limitation is the lack of a good sampling coverage of these locations, for example, African countries has more than 60% of the HIV infection cases in the world, but less than 30% of the public available sequences. Yet, cohort studies like the HIV Incidence Provincial Surveillance System (HIPSS) and the Rakai Community Cohort Study (RCCS) has enlighten important features of HIV dissemination in geographic settings with huge epidemics like South Africa and Uganda, respectively.Phylogenetics analysis has been successful in identifying and analysing HIV-1 transmission networks, especially when sampling covers a great proportion of the infected population and when combined with detailed epidemiological and clinical data. Consequently, most studies describe transmission dynamics in developed countries, while significant sequencing efforts are still needed to phylogenetic methods be able to capture HIV transmission networks where the epidemic is worst. In an intermediate position, middle income countries might find in the phylogenetic approach a way to design better public health campaigns to halt HIV dissemination. Brazil, for instance, has one of the biggest public health systems in the world and access to ART is free and universal, with genotyping service deployed for those who fail therapy. This could be a good source of data to investigate HIV transmission dynamics in the country and complement the scarce literature on this topic."}
+{"text": "Activity-dependent protein synthesis plays an important role during neuronal development by fine-tuning the formation and function of neuronal circuits. Recent studies have shown that miRNAs are integral to this regulation because of their ability to control protein synthesis in a rapid, specific and potentially reversible manner. miRNA mediated regulation is a multistep process that involves inhibition of translation before degradation of targeted mRNA, which provides the possibility to store and reverse the inhibition at multiple stages. This flexibility is primarily thought to be derived from the composition of miRNA induced silencing complex (miRISC). AGO2 is likely the only obligatory component of miRISC, while multiple RBPs are shown to be associated with this core miRISC to form diverse miRISC complexes. The formation of these heterogeneous miRISC complexes is intricately regulated by various extracellular signals and cell-specific contexts. In this review, we discuss the composition of miRISC and its functions during neuronal development. Neurodevelopment is guided by both internal programs and external cues. Neuronal activity and external signals play an important role in the formation and refining of the neuronal network. miRISC composition and diversity have a critical role at distinct stages of neurodevelopment. Even though there is a good amount of literature available on the role of miRNAs mediated regulation of neuronal development, surprisingly the role of miRISC composition and its functional dynamics in neuronal development is not much discussed. In this article, we review the available literature on the heterogeneity of the neuronal miRISC composition and how this may influence translation regulation in the context of neuronal development. MicroRNAs (miRNAs) are among the most studied and discussed regulators of gene expression in the last two decades. The reason they have attracted so much attention is because of their specificity in targeting and versatility in their function. These small RNAs (~22 nt long) recognize their targets through a \u201cseed sequence\u201d (forming 5\u20138 base pair match on target mRNA) and lead to a rapid decrease in the corresponding protein level by translation repression and/or degradation of mRNA , miRNA mediated translation repression is a multistep process. Several studies have indicated a clear correlation between decreased protein levels and the degradation of mRNAs targeted by miRNAs  associates with miRNAs and load them on to their cognate target mRNAs to form the core of the miRISC . Now theIn addition to miRNA mediated post-transcriptional gene silencing, AGO proteins are reported to perform various moonlighting functions in other subcellular compartments. Nuclear localized AGO proteins regulate transcriptional silencing, epigenetic modulation, alternative splicing, and DNA repair  interacts with FMRP and AGO to regulate dendritic elaboration in larval sensory neurons (Barbee et al., Another correlative evidence suggesting miRISC as a regulator of dendrite morphogenesis is that various miRISC proteins show peak expression or activity during an intensive period of dendritogenesis. The decapping activator DCP1a shows development associated changes in its phosphorylation status (Blumenthal et al., As the axonal and dendritic processes meet their respective partners, further they mature to form pre- and post-synaptic compartments, respectively . NeuronaStudies have demonstrated the presence of entire protein synthesis machinery along with ribosomes at developing and mature synapses (Steward et al., Synaptic plasticity is the mechanism by which specific patterns of synaptic activity results in changes in synaptic strength . DifferemiRISC components have been shown to form heterogeneous and dynamic granules in neurons (Cougot et al., Compositionally distinct miRISC complexes have been shown to form in response to synaptic stimulation. These complexes play a crucial role in regulating the translation of specific mRNA downstream of synaptic activity. Drosophila miRISC protein AGO1, dFMR1, and Me31B were shown to interact with Ataxin-2 to regulate long term olfactory habituation and translation of CaMKII mRNA (McCann et al., Work from Gary Bassell's lab established FMRP phosphorylation as a reversible switch in regulation miRISC mediated repression of specific target mRNAs (Muddashetty et al., 2+ results in a reduction of PICK-AGO2 interaction, leading to AGO2 dissociation from endosomes. This led to a subsequent increase in AGO2 mediated repression by dendritically localized miRNAs like miR-134 and miR-138 (Rajgor et al., Modulating the phosphorylation of AGO2 is shown to be a mechanism employed for regulating NMDAR mediated translation response and spine dynamics (Antoniou et al., Different miRISC components are degraded downstream of neuronal activity to mediate synaptic plasticity. For example, long term memory formation in drosophila NMJ is regulated by activity mediated rapid degradation of miRISC protein Armitage (Ashraf et al., The work we discussed in this review highlight the importance of dynamic miRISC in normal neuronal development. Several miRISC proteins are shown to have a significant role during distinct stages of neuronal development as summarized in Finally, it is important to highlight the role of the dynamic composition of miRISC in normal neuronal development as well as its potential implication in disorders of neuronal development. Indeed, defective translational regulation is a common feature of multiple neurodevelopmental and neuropsychiatric disorders (Kapur et al., Recent SFARI study has identified missense mutations in miRISC proteins AGO1, TNRC6B, and CNOT3 among patients diagnosed with Autism Spectrum Disorders (Chen et al., BN, SR, and RM reviewed the literature, conceptualized, and wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Robustness, compactness, and portability of tensegrity robots make them suitable candidates for locomotion on unknown terrains. Despite these advantages, challenges remain relating to ease of fabrication, shape morphing (packing-unpacking), and locomotion capabilities. The paper introduces a design methodology for fabricating tensegrity robots of varying morphologies with modular components. The design methodology utilizes perforated links, coplanar (2D) alignment of components and individual cable tensioning to achieve a 3D tensegrity structure. These techniques are utilized to fabricate prism (three-link) tensegrity structures, followed by tensegrity robots in icosahedron (six-link), and shpericon (curved two-link) formation. The methodology is used to explore different robot morphologies that attempt to minimize structural complexity (number of elements) while facilitating smooth locomotion (impact between robot and surface). Locomotion strategies for such robots involve altering the position of center-of-mass  to induce \u201ctip-over.\u201d As an example, a sphericon formation comprising of two orthogonally placed circular arcs with conincident center illustrates smooth locomotion along a line (one degree of freedom). The design of curved links of tensegrity mechanisms facilitates continuous change of the point of contact  that results from the tip-over. This contrasts to the sudden and piece-wise continuous change for the case of robots with traditional straight links which generate impulse reaction forces during locomotion. The two resulting robots\u2014the Icosahedron and the Sphericon Tensegrity Robots\u2014display shape morphing (packing-unpacking) capabilities and achieve locomotion through internal mass-shifting. The presented static equilibrium analysis of sphericon with mass is the first step in the direction of dynamic locomotion control of these curved link robots. Tensegrity structures are comprised of disconnected rigid compressive elements (links) suspended by a network of pre-stressed tensile elements (cables). The redundant links impart robust and fault tolerance, the strategic prestressed cable-link combination provides them with compliance and shape morphing ability (packing-unpacking)  but do not move during assembly. Cables are intentionally cut past their tuned free length so that routing to distant holes does not require stretching cables or forcing links into position. With sufficiently oversized cable lengths, all connections may even be made on a flat surface, eliminating the need for jigs . FinallyThe proposed methodology provides the benefits of rapid prototyping and hassle-free assembly, and cable manipulation capability. The components are quickly produced, applicable to a range of designs, and simple to assemble. Cutting a link by laser takes around 2 min, while printing the same link through an FDM process takes 45 min (machine preparation times are approximately the same). Only five tools are used: fabric shears to cut cables, a BOSS LS-1416 laser cutter for the links, a wrench and hex key to modify the clamping force of the nut-bolts and forceps to grab difficult-to-grasp cables when tuning. Additionally, individual cables may be passively and independently clamped and removed without pretensioning. Icosahedron, as illustrated in The three-link prism  and the Tensegrity mechanisms adapted to mobile robots conventionally achieve locomotion through rolling about their body. Intuitively, morphologies resembling spheres facilitate smooth rolling which can be defined as continuous change in the point of contact along the body as the robot moves. Traditional straight link robots are limited in their ability to approximate a spheres curvature and achieve smooth rolling motion. Closer approximations to a sphere require increases in structural complexity, i.e., more links, cables and connections. For example, as shown in Another approach to achieving smooth rolling locomotion is by directly introducing curvature to the compressive rigid links. Here, the curvature introduces additional bending moment to links (straining the definition of tensegrity). Smooth uniaxial rolling locomotion has been achieved using tensegrity mechanism comprising of two curved links\u2014a morphology that resembles a condensed spehricon, rather than a sphere   and Sphericon (curved two-link) Tensergrity Robots.The three orthogonal links were modified to incorporate mass-shifting systems and the electronics payload was distributed over two additional links as highlighted in This morphology overcomes challenges faced by the previous case and incorporates mass-shifting systems into both curved links while the control payload was bundled and suspended in the center of the robot as illustrated in This tensegrity robot can be modeled as a sphericon mechanism . They arI coordinate system be fixed in the inertial reference frame with origin at a point on a planar surface and orthonormal basis vectors B coordinate system be fixed on the body reference frame, origin at the center of the sphericon and orthonormal basis vectors {\u00eax, \u00eay, \u00eaz}. The rotation matrix defining the relationship between the two coordinate systems can be written as . Thereafter, it is rotated by \u2212\u03b3 about the z-axis of the intermediate coordinate system (\u00ea3) as illustrated in B and inertial I coordinate systems arewhere the mechanism is rotated 45\u00b0 about the y-axis of the inertial coordinate system Consequently, the velocity of these points can be calculated asThe potential energy of the system is equivalent toThe static equilibrium positions of the mechanism can be obtained through the Lagrange's equations where the kinetic energy is zero and the generalized coordinate is \u03b3The paper presents a design methodology for fabricating tensegrity robots of varying morphologies with modular components that facilitates rapid prototyping and hassle-free assembly, and capabilities to manipulate cable positions and tensions during assembly. Exploration of desirable morphologies for locomotion is critical to the design of tensegrity robots and includes investigation of their shapes (straight versus curved links), their placement (location of center of link arcs), number of links and even non-structural elements. The resulting two autonomous shape morphing tensegrity robots\u2014the straight link Icosahedron and curved link Sphericon morphology\u2014achieve locomotion through internal mass-shifting utilizing the presented mass-shifting mechanism. The curve link tensegrity robot demonstrates smooth locomotion and packing behavior with folding-deployment orientations.All datasets generated for this study are included in the article/TR fabricated all the tensegrity morphologies, designed the mechatronics, programming logic of the robots and contributed to the writing the draft. CG assisted TR with fabrication, writing and performed the mathematical analysis. VV supervised the research and oversaw all the activities.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Sudden cardiac death caused by ventricular arrhythmias is among the leading causes of mortality, with approximately half of all deaths attributed to heart disease worldwide. Periodic repolarization dynamics (PRD) is a novel marker of repolarization instability and strong predictor of death in patients post-myocardial infarction that is believed to occur in association with low-frequency oscillations in sympathetic nerve activity. However, this hypothesis is based on associations of PRD with indices of sympathetic activity that are not directly linked to cardiac function, such as muscle vasoconstrictor activity and the variability of cardiovascular autospectra. In this review article, we critically evaluate existing scientific evidence obtained primarily in experimental animal models, with the aim of identifying the neuronal networks responsible for the generation of low-frequency sympathetic rhythms along the neurocardiac axis. We discuss the functional significance of rhythmic sympathetic activity on neurotransmission efficacy and explore its role in the pathogenesis of ventricular repolarization instability. Most importantly, we discuss important gaps in our knowledge that require further investigation in order to confirm the hypothesis that low frequency cardiac sympathetic oscillations play a causative role in the generation of PRD. Sudden cardiac death caused by ventricular arrhythmias is a leading cause of mortality globally, resulting in approximately 50% of all cardiovascular-related deaths each year . Excessiin vitro and in whole animal preparations in vivo that prove that sympathetic neuronal networks most likely involved in the control of cardiac function can exhibit LF oscillatory activity under some experimental conditions. We then discuss the mechanisms involved in the generation of rhythmic sympathetic discharges and explore the physiological role of patterned activity in the sympathetic system and its impact on neurotransmission efficacy. In doing so, we identify important gaps in our knowledge that need to be addressed in future studies.This article aims to review the available evidence in support of the hypothesis that rhythmic sympathetic nerve traffic to the myocardium underlies the origin of PRD. We first focus on how excessive adrenergic signaling affects myocardial repolarization. We then present a comprehensive review of published data obtained in rodent brain tissue Cardiomyocyte repolarization represents a complex sequence of electrical events that occur during phases 1 to 3 of the action potential in which the net outward current exceeds the net inward current, causing the return of the membrane potential to its baseline resting state prior to the next depolarization. Cardiac ventricular repolarization is a significant determinant of the QT interval, represented on the surface ECG by the interval between the start of the QRS complex and the end of the T wave .There is general agreement that the T wave is the result of voltage gradients that exist within the ventricular myocardium during cardiac repolarization although the precise mechanism appears to differ depending on the species studied and the experimental preparation used. Using arterially perfused canine right ventricular wedge preparations, Antzelevitch found three layers of electrically and functionally distinct cell types of the ventricular myocardium: the epicardial cells, the M cells and the endocardial cells . These sIn addition to the transmural electrical gradient, there is also evidence of electrical heterogeneity between the apex to base  and left2+ current which leads to an increase in APD but this is counterbalanced by the concomitant increase in outwards K+ currents via the rapidly (IKr) and slowly (IKs) activating delayed rectifier potassium channels (Sympathoexcitation leads to norepinephrine release which activates \u03b2-adrenoceptors (\u03b2-AR) to modulate myocardial repolarization and contractility. \u03b2-AR stimulation increases L-type Cachannels . Sympathchannels . This efchannels .2+ channels, ryanodine receptors (RyR) and phospholamban, with concomitant increase in sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA) activity  and membrane depolarizations during phase 4 of the action potential. This process is also known as delayed after depolarizations (DADs)  dependent phosphorylation of proteins involved in excitation\u2013contraction coupling which includes L-type Caactivity . This res (DADs)  and paths (DADs)  and by p via RyR  and a de current . At the  current . Electri current . DADs oc current . Adverse current . On a ma current . Finally current . As a re current .In summary, sympathoexcitation leads to both an increase in triggered activity, and dispersion of repolarization. This leads to abnormalities in activation and propagation of electrical activity in the ventricular myocardium that have been shown in experimental and clinical studies to be pro-arrhythmic .An area of intense clinical research has been the search for a reliable biomarker of increased susceptibility to potentially fatal ventricular arrhythmia which would help direct clinical intervention such as prophylactic implantation of an implantable cardioverter defibrillator device (ICD). Various non-invasive methods have been studied, including assessments of increased/altered sympathetic tone [heart rate variability  and baroX-, Y-, and Z-. Low frequency (\u22640.1 Hz) periodic changes of the T wave vector provide an index to measure both sympathetic activity and its effects on ventricular repolarization. In a cohort of 908 patients, increased PRD predicted total and cardiovascular mortality in survivors of MI and was independent of underlying heart rate and respiratory activity. Furthermore, in multivariate analysis PRD provided incremental prognostic value in addition to established risk markers such as LV ejection fraction and measure of T wave alternans  enhance the magnitude of PRD whilst pharmacological blockade of \u03b2-adrenergic antagonists have the opposite effect . The perOne of the most remarkable characteristics of sympathetic neuronal discharges is their rhythmic nature. Autonomic neuroscientists have applied power spectral analysis methods based on fast Fourier transform (FFT) algorithms to detect rhythmic patterns in sympathetic neurons and peripheral nerves both in experimental laboratory animals and in human subjects .Rhythmic sympathetic oscillations occur over a wide spectrum of distinct frequencies, ranging from 0.1 to 10 Hz, depending on the sympathetic outflow being measured . In humaLow-frequency oscillations in sympathetic outflows appear to be less ubiquitous than cardiac-related (2\u20136 Hz) and respiratory-related (1\u20133 Hz) rhythms. Nevertheless, numerous studies have found that LF rhythms are a robust feature of sympathetic neuronal networks involved in the control of cardiac function. Although none of the studies discussed in the following sections have investigated rhythmic sympathetic oscillations in the context of ventricular repolarization instability, the mechanisms described herein are likely to contribute, at least in part, to the origin, regulation and synchronization of PRD.Sympathetic activity originates in a lower brainstem region known as the rostral ventrolateral medulla (RVLM). The RVLM contains a group of C1 catecholaminergic neurons and a group of non-catecholaminergic neurons believed to produce glutamate . RVLM neLow-frequency oscillatory patterns have been identified in single RVLM neurons in experiments conducted in unanesthetized, decerebrated, vagotomised and artificially ventilated cats with denervated baroreceptors , 1996 anin vitro studies have demonstrated that RVLM neurons have the capability of displaying intrinsic pacemaker activity in conditions of reduced synaptic activity, which suggests that synaptic inputs are only involved in the modulation of rhythmic patterns , nucleus intermediolateralis thoracolumbalis pars funicularis, intercalated nucleus (IN), and central autonomic area (CA). The axon from the spns exit the spinal cord through the ventral root to make synaptic contact with cardiac sympathetic ganglia via white rami communicans. Anatomical tracing studies in guinea pigs  and catsin vivo studies conducted in whole animal preparations. Neuronal recordings from thoracic preganglionic axons in anesthetized cats with high spinal transection at the C1 level showed neuronal discharge variability in the range of 0.1 Hz that were temporally synchronized with the oscillations in systemic arterial pressure  are significantly increased in patients after MI . HoweverTo our best knowledge, there are no studies in experimental animals models of MI that have investigated changes in the power of the LF component in the variability of neuronal discharges of bulbospinal RVLM neurons, spns in the IML and postganglionic sympathetic neurons of the CSN. Electrophysiological studies conducted to investigate the neuronal response properties to MI in anesthetized cats have shown that interruption of the left coronary artery blood flow produced a substantial increase in the discharge of afferent sympathetic fibers that supply the ventricular myocardium and this effect was mimicked by intracoronary administration of bradykinin . FunctioMi triggers a cardio-cardiac reflex which results in increased activity of preganglionic fibers of the third thoracic white ramus communicans and these responses were found to be preserved in animals with spinal cord transection . ExperimA recent study using a porcine model of MI revealed that the spontaneous LF rhythmic firing rate of intracardiac GP neurons in the left ventricle are preserved at the same level following a MI, however, with a significant reduction in the detection of afferent inputs. These functional changes were associated with a significant increase in intracardiac neuron cell size and an upregulation in the expression of the sympathetic neuronal marker Tyrosine Hydroxylase . Future The physiological meaning of sympathetic oscillatory activity remains unclear. Many studies support the notion that rhythmic activity promotes the coordination of neuronal firing of individual sympathetic neurons which may lead to a highly coordinated and more efficient release of neurotransmitter at the nerve terminal . Also, rin vitro studies conducted in fully innervated isolated rabbit hearts have shown that electrical stimulation of CSN (with a stimulation frequency of 15 Hz for 50 s) changed the spatial dispersion of repolarization (DOR) from apex toward the base to base toward the apex within 15 s following the start of the stimulation (At present, the physiological mechanisms underlying the genesis of PRD are unknown. In this review article we worked under the unverified assumption that recurrent periods of ventricular repolarization instability follow the LF rhythm of cardiac sympathetic postganglionic activity. In support of this hypothesis, mulation . When symulation , 2016, tmulation . FurtherSince The discovery of PRD as a novel marker of CSN traffic and strong predictor of death has recently reignited the interest in the phenomenon of sympathetic rhythmicity. The experimental evidence reviewed here identified sympathetic circuitries contained in the brainstem and in the spinal cord which may have direct connections with the ventricular myocardium and that are capable of generating LF oscillatory activity. However, the hypothesis that PRD is directly driven by sympathetic neuronal oscillations , 2016 isNM designed the review and drafted the manuscript. RA contributed to the writing of the final version of the manuscript. Percentage contributions are NM 70% and RA 30%. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "This series of 12 articles, consisting of 9 original articles and 3 reviews, is presented by international leaders in translational cancer research. This series highlights the various efforts to establish valuable panels of patient-derived xenograft (PDX) models from various cancer types and relevant tools to apply translational research. We are especially pleased to also have reports in this series which focus on important new developments to serve as alternative patient-specific model systems. Patient-directed  medicine is an attractive concept that is embraced by clinicians to improve therapeutic success. PDXs are considered to retain the unique genetic characteristics of the patient tumor, therewith enabling the prediction of patient-specific tumor responses. This Special Issue includes three reviews describing the potential translational power of current PDXs for head and neck squamous cell carcinoma , pancreaThe original papers by Meneceur et al.  and OshiThe importance of the tumor niche on drug response was also investigated in PDX models of acute myeloid leukemia described in the contribution by Schueler et al. . They deConsiderations regarding the fitness of traditional PDXs as tools for response prediction especially also relate to their use as platforms to evaluate the efficacy of immunotherapies. Liu et al.  describeThis series also includes four original papers describing the use of alternative PDX-based systems for therapy response prediction. One interesting application of PDX xenografted tumors is the use of thin-cut tissue slice cultures (TSC). TSC has the advantage of relatively fast and standardized culture procedures with maintenance of the original 3D architecture and essential cell interactions. Suckert et al.  describeAnother interesting alternative PDX platform to mouse-based PDX models that has been pursued intensely for various cancer types over the last 15 years is the zebrafish (ZF) xenotransplantation model. Like PDXs in immune-compromised mice, patient-derived xenografted tumor tissues in zebrafish embryos have been suggested as attractive models  to facilitate co-clinical trials and implement personalized medicine. In this special series, we have two papers that address highly relevant issues related to the utility and translational power of these PDX systems. The paper by Usai et al.  offers aFinally, another alternative PDX platform is provided in the contribution by Winter et al.  using thTo finish, this collection on PDX models is completed by the report by O\u2019Farrell et al. , who offThis series of articles demonstrates the wide use of PDX models in a broad and diverse field of research. It contains detailed descriptions for the development of PDXs for a specific cancer type, while others report on more generally applicable issues regarding the utility of PDX models. Besides the use of the immune-compromised mouse as a host for PDXs, several papers highlight alternative systems for patient-specific tissue engraftment. Collectively, these articles are a valuable asset to the field of PDX research, with the overall goal to aid patient-directed  medicine and to improve therapeutic success."}
+{"text": "Since the implementation of deep-brain stimulation as a therapy for movement disorders, there has been little progress in the clinical application of novel alternative treatments. Movement disorders are a group of neurological conditions, which are characterised with impairment of voluntary movement and share similar anatomical loci across the basal ganglia. The focus of the current review is on Parkinson\u2019s disease and Huntington\u2019s disease as they are the most investigated hypokinetic and hyperkinetic movement disorders, respectively. The last decade has seen enormous advances in the development of laboratory techniques that control neuronal activity. The two major ways to genetically control the neuronal function are: 1) expression of light-sensitive proteins that allow for the optogenetic control of the neuronal spiking and 2) expression or suppression of genes that control the transcription and translation of proteins. However, the translation of these methodologies from the laboratories into the clinics still faces significant challenges. The article summarizes the latest developments in optogenetics and gene therapy. Here, I compare the physiological mechanisms of established electrical deep brain stimulation to the experimental optogenetical deep brain stimulation. I compare also the advantages of DNA- and RNA-based techniques for gene therapy of familial movement disorders. I highlight the benefits and the major issues of each technique and I discuss the translational potential and clinical feasibility of optogenetic stimulation and gene expression control. The review emphasises recent technical breakthroughs that could initiate a notable leap in the treatment of movement disorders. If a PD patient overcomes the initial freeze, a movement towards a particular goal could be successfully achieved. Similarly, the therapies for movement disorders face difficulty with the translation of novel solutions from basic neuroscience level, but once translated clinically, their implementation is usually efficient and lasting. The major steps of the fundamental PD research so far were triggered by levodopa pharmacological application, apomorphine infusion pumps and deep-brain stimulation (DBS). Since then the translational advance of PD therapy has stalled in a gait freeze with little development. Now, this is about to change and recent research advances might soon revolutionize the treatment for some neurological diseases. PD is just one representative of the movement disorders, which are a large group of hypokinetic and hyperkinetic conditions with different genesis, symptoms and progression. However, the majority of them share the functional principles of motor execution, their physiology undergoes similar neuromodulatory control and the anatomy of their neuronal circuits generally overlaps. Therefore, novel research findings and treatment innovations for a particular dysfunction would have a noteworthy impact on the therapy for the rest of the movement disorders. The review focuses particularly on the therapeutic approaches designed to control the neuronal function. Other \u2018non-neuronal\u2019 therapeutic directions such as immunotherapy and infusion therapy are outside the scope of this review. Immunotherapy uses antibodies and inhibitors that bind to the neurotoxic antigens. Infusion therapies involve continuous application of pharmacological agents such as levodopa and dopamine agonists. Immuno- and infusion therapies are highly-beneficial and may further exert a significant therapeutic impact. The extensive literature about their translation requires a separate review. Here, I will address how the genetic control of neuronal function can be utilized for the treatment of movement disorders. I will review the development of optogenetic DBS and the progress of DNA- and RNA-based gene therapy. The review encompasses the innovative research in the fields of DBS, optogenetics and gene therapy and examines the proximity of the novel methodologies to clinical translation.2The last prominent therapeutic innovation of movement disorders was achieved in the 1980\u00a0s DBS is a technique that delivers electric current to basal ganglia regions such as globus pallidus internus, globus pallidus externus or subthalamic nucleus. The neuronal stimulation through electric current is already outdated in the majority of laboratories conducting fundamental neuroscience research. Current-induced stimulation is now widely replaced by light-induced stimulation, a technique which is known as optogenetics The three main advantages of light-induced neuronal stimulation that position it as the preferred lab stimulation technique are: 1) physiological depolarization, 2) neurotransmission specificity and 3) neuronal selectivity. The physiological depolarization relies on threshold-dependent depolarization of the axonal hillock followed by axonal action potential with orthodromic spike propagation. This is compromised in electrically-evoked depolarization where the electric field depolarizes simultaneously different segments of the neurons, leading to antidromic spike propagation. This disadvantage of electrical stimulation leads to possible recruitment of distant neurons through direct axonal stimulation 3Currently, the most effective treatment for advanced PD is the electrical DBS with electrodes implanted in the subthalamic nucleus or internal globus pallidus, and with frequency of the electrical current in the range of 120\u2013130\u00a0Hz, delivered continuously. It is not fully understood what makes this stimulation protocol so efficient. The efficiency of DBS is a matter of controversy The classical model predicts that deactivation of subthalamic nucleus (STN) halts the dysfunctional excitatory subthalamic activity, which is abnormally increased in hypokinetic- (PD) and abnormally decreased for hyperkinetic movement disorders (HD and dystonia) The translational implication arising from these studies is that optogenetic stimulation must target different neuronal types and pathways to address the full spectrum of symptoms in patients with movement disorders. The optogenetic DBS may need to target more than one cell population for the parallel treatment of motor, postural and gait symptoms. The cognitive and speech symptoms observed in movement disorders will require the targeting of additional brain networks and their treatment unlikely will be addressed by the first translated generation of optogenetics DBS. Whether the optogenetic physiological stimulation will translate into better therapeutic treatment of movement disorders remains an open question. The translation of optogenetic methodology requires: 1) identification of the most suitable neuronal population or pathway that can mediate the therapeutic effect of DBS, 2) identification of the most efficient stimulation or inhibition frequency. While for some movement disorders, such as PD, the neuronal groups and stimulation protocol for DBS have been identified, for others, such as HD, it will take substantial pre-clinical experimental work before clinical trials are initiated.4The translational future of optogenetic DBS became even brighter after another technical development: the brain-computer interface (BCI). Closed-loop BCI interface allows the patterns of neuronal recordings to control the external stimulation Desynchronizing feedback stimulation approach is suggested to be effective closed-loop technique for the control of abnormally-synchronized neuronal populations observed in movement disorders Despite the promising start of adaptive DBS, this approach has been restricted to limited clinical trials and further technical development is needed for the approval of closed-loop DBS as a validated treatment option. The translation of closed-loop BCI adaptive DBS will require: 1) improvement of the signal detection algorithms, 2) development of electrophysiological biomarkers for the detection of dysfunctional neuronal activity across different movement disorders. The resolution of these issues will take several years and large number of clinical trials for the optimization of this methodology. The combination of DBS and BCI can advance the therapy of movement disorders, while the combination of optogenetics and BCI may lead to ground-breaking patient-centred therapy 5Adeno-associated virus (AAV), which is the most common virus used in optogenetics, is safe for use in rodents The European Medicines Agency (EMA) approved AAV-based product alipogene tiparvovec (Glybera by uniQuire) 6The translation of optogenetics to humans faces other technical challenges such as limitation in the cell specificity for non-transgenic species and variability of opsin expression. Currently, the optogenetic modulation of neural activity in non-transgenic animals and primates is successful only for a few promoters 12 particles per mL showed that 52\u00a0\u00b1\u00a08% of neurons that expressed TH also expressed YFP in one lab The success rate of opsin expression is another major consideration for the clinical translation of optogenetics. The variability of opsin expression depends on different factors such as the animal species, brain volume, targeted cell types and even technical skills. In transgenic mouse line, expressing cre-recombinase under the choline acetyltransferase (ChAT) promoter, 91.3\u00a0\u00b1\u00a01.3% of neurons that expressed yellow fluorescent protein  also stained for the ChAT antibody and 93.5\u00a0\u00b1\u00a02.8% of neurons that stained for the ChAT antibody also expressed YFP 7333 in the tissue of a macaque brain The optogenetics must also resolve the technical issue of continuous light delivery in large brains. Rodents are much easier target due to their small brain volumes and light can be delivered in the structure of interest by a single optic fiber. The level of penetration of the light within the neuronal tissue shown as a function of distance from the fiber tip in brain tissue 8The Nobel Prize for Chemistry in 2020 was awarded to Emmanuelle Charpentier and Jennifer Doudna for the development of genome editing methodology. Their finding introduced a new conceptual approach for genetic control of dysfunctional neurons. While the concept of optogenetics is to stimulate populations of neurons, which are physiologically impaired due to advanced neurodegeneration, the concept of genome editing is to genetically reduce or slow down the process of neurodegeneration itself. Instead of injecting the brain with AAV viral vector that carries the gene for opsin expression as it is with optogenetics, gene therapy uses AAV viral vector to edit the mutant genes responsible for neurodegeneration . The DNAClustered regularly interspaced short palindromic repeats (CRISPR) and the accompanying CRISPR-associated system (Cas) genome editing constructs is a technique in which guide RNAs direct the nuclease Cas9\u00a0to selected sequences of genomic DNA. The enzyme Cas9 is recruited as molecular scissors to cuts both strands at a precise location and repair or remove the mutation. The genomic DNA is restored by non-homologous end joining or homology-directed repair; for current variants of CRISPR-Cas9 see reviews Another technique for DNA gene therapy is the zinc finger proteins (ZFPs). ZFPs are characterized with zinc finger array that targets selected DNA sequence and each individual finger relates to three bases. ZFPs include zinc finger nucleases known to cleave DNA and zinc finger transcription factors that can regulate gene expression Overall, the successful translation of gene therapy will be able to halt the process of neurodegeneration. This achievement will be able to affect not only the motor symptoms of movement disorders  but also other symptoms due to dysfunctional brain circuits . The translation of DNA gene therapy requires additional pre-clinical tests regarding: 1) aversive immunological and inflammatory responses, 2) non-specific gene editing. It is a matter of time that these issues will be resolved but the safety concerns make the forthcoming initiation of this methodology uncertain. While the adverse effects of DNA gene editing can lead to unwanted permanent mutations of the genome, RNA gene therapy, by contrast, allows the researchers to make only temporary regulations of the gene expression. If the RNA-based suppression of mutant genes results in accidental adverse effect it can be easily discontinued. Because the neurons will rapidly degrade the RNA nucleotides, any errors evoked by the RNA-based treatment would be soon washed out. If we are searching for the imminent next step of the gene therapy in patients with movement disorders, we may have to look at RNA technique.9In 2006 Andrew Fire and Craig Mello were awarded with the Nobel Prize for their finding that RNA interference (RNAi) methodology can silence targeted gene expression. Their study demonstrated how RNAi suppresses gene translation, by neutralizing targeted mRNA molecules Preclinical tests showed enormous potential of the RNAi methodology for the therapy of movement disorders This is not the case with shRNA, which is easily delivered by AAV. The shRNA technique uses a transcribed RNA that is enzymatically cleaved of hairpin by Dicer . The adv10ASO are synthetic single-stranded nucleotides, with approximate length of 12\u201322 bases that complementary bind messenger RNA (mRNA) to supress mutant protein expression The pathogenesis of Parkinson\u2019s disease involves dominantly-inherited genetic causes. One of the most frequent loci of mutation is the leucine-rich repeat kinase 2 (LRRK2) and genetic errors or variations within the LRRK2 gene result in enhanced formation of abnormal protein, \u03b1-synuclein (aSyn). The neurotoxic aSyn accumulates intracellularly and leads to widespread neuronal degeneration. Recently-developed model for gene therapy of PD involves the administration of ASO to supress the post-transcriptional LRRK2 gene expression. Targeted delivery of ASO in mice brains inhibits local gene expression by directly binding to target mRNA and supressing the synthesis of aSyn ASO has been proposed as a suitable treatment strategy for monogenic hyperkinetic movement disorders such as Huntington\u2019s disease. Fundamental preclinical research showed that ASO robustly lowers the htt protein levels and ameliorates disease-associated symptoms and reverses disease phenotype in rodent models of HD 11Movement disorders encompass hypokinetic and hyperkinetic neurological conditions, requiring differential treatment approaches. In order to choose the most appropriate potential therapies we must consider their major methodological disadvantages . A largeMarian Tsanov: Conceptualization, Visualization, Writing - original draft, Writing - review & editing.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."}
+{"text": "Acute coronary syndrome (ACS) is caused by reduced perfusion of the myocardium and characterized by chest pain. The primary goals of treatment for ACS are to restore blood flow through occluded coronary arteries and prevent recurrent coronary events. Antiplatelet and anticoagulant therapies play a crucial role in the treatment of ACS by interrupting the thrombotic process.To characterize the pathophysiology of ACS and to describe the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for reperfusion therapy in patients with ST-segment elevation myocardial infarction (STEMI); the use of antiplatelet and anticoagulant therapies for the treatment of STEMI, non-ST-segment elevation myocardial infarction (NSTEMI), and unstable angina (UA), including patients who undergo percutaneous coronary intervention (PCI); and long-term antiplatelet therapy after an ACS episode.The preferred reperfusion strategy in patients with STEMI is PCI if it can be performed within 90 minutes after arrival at the hospital. Patients with NSTEMI or UA also may undergo PCI. Thrombolysis is an alternative method of reperfusion for patients with STEMI but not for patients with NSTEMI or UA. Dual antiplatelet therapy with aspirin and the thienopyridine clopidogrel is recommended by the ACC/AHA for 12 months in patients with STEMI, NSTEMI, or UA, including patients with coronary stents. Platelet glycoprotein (GP) IIb/IIIa inhibitors are routinely used during PCI in patients with STEMI and NSTEMI. These agents should be used in addition to aspirin and clopidogrel in patients with NSTEMI and elevated troponin levels who undergo coronary intervention. Unfractionated heparin (UFH) or the low-molecular-weight heparin enoxaparin may be used in patients with STEMI undergoing reperfusion with thrombolytic agents or PCI and patients with NSTEMI or UA. There are substantial data on enoxaparin in the ACS arena, but UFH is preferred for patients who undergo coronary intervention because of greater ease of therapeutic monitoring and reversal of anticoagulant effects if bleeding complications arise. The pentasaccharide fondaparinux may become an alternative to UFH and enoxaparin for patients with STEMI and some patients with NSTEMI or UA. Fondaparinux is preferred for patients with NSTEMI or UA who are at increased risk for bleeding when a conservative approach is chosen, but it is not recommended for patients when an early invasive approach is chosen because of the risk of catheter-related thrombi. The direct thrombin inhibitor bivalirudin may be used for anticoagulation in patients with NSTEMI who undergo early invasive procedures, and GP IIb/IIIa inhibitor use may be avoided in some patients; however, upstream antiplatelet therapy with clopidogrel is also needed if these patients undergo PCI. Patients undergoing coronary stenting must receive dual antiplatelet therapy.Antiplatelet and anticoagulant therapies for patients with ACS are complex. Evidence-based guidelines facilitate the therapeutic decision-making process for these therapies in patients with ACS."}
+{"text": "The available high-throughput omics data, such as genomics, transcriptomics, proteomics and metabolomics, provide us unprecedented opportunity and challenge to decipher the corresponding global molecular profiles in cells. The need of data integration is urgent by developing integrative bioinformatics methods . The bulMEMO: mass spectrometry-based sample vectorization to explore chemodiverse datasets\u201d Gaudry et al. proposed an approach called Memo for integrating mass spectrometry data. Memo captures the spectral diversity of complex samples to implement an efficient comparison of large amounts of samples without the need of a feature pre-alignment step. The efficiency of Memo was demonstrated on experiments about a large and chemodiverse sample clustering. Memo also demonstrates its superiority in computational time and other performance metrics.This Research Topic aims to provide a Research Topic of integatve bioinformatics techniques for biomedical data integration. In \u201cApplication of network pharmacology in the study of mechanism of Chinese medicine in the treatment of ulcerative colitis: A review\u201d Zheng et al. proposed a summary of the applications of tranditional Chinese medicine (TCM) for the treatment of ulcerative colitis. They summarized the multiple TCM databases available for ulcerative colitis. The multiple datasets were organized via a network pharmacology framework. The TCM resources presented here will benefit for the monotherapy and compound therapy of ulcerative colitis.In \u201cAlgorithms to anonymize structured medical and healthcare data: A systematic review\u201d Sepas et al. proposed a systematic review of algorithms to anonymize structured medical and healthcare data (SMHD). The paper summarized and categorized different anonymization approaches for different types of SMHD, such as demographics, diagnosis codes and genomic data with sufficient levels of protection and utility. Further research is expected to build more efficient algorithms for the anonymization of SMHD in the biomedical big data era.In \u201cEnhancer/gene relationships: Need for more reliable genome-wide reference sets\u201d Hoellinger et al. proposed a comparision study of the major methods available to detect the relationships between enhancer and gene. The identificaiton of enhancer-gene links will provide deep understanding of the cooperation between regulatory elements playing key roles in gene expression. In this work, the authors benchmarked three methods in the category of functional link methods. They concluded that it is urgent to propose new reliable and genome-wide reference data as well as the new bioinformatics methods for functional link identification between enhancer and gene.In \u201cThese interesting papers shed lens for the integrative bioinformatics methods in diverse scenarios such as in genomics, proteomics, clinical and TCM data. These diverse applications indicates the integrative bioinformsitcs methods are important in multi-omics data analytics. These papers also demonstrate that we need proposed case-intensive and flexible data integration strategy and method for the available multi-omics data according to particular research purpose."}
+{"text": "The area of interventional nanotheranostics combines the use of interventional procedures with nanotechnology for the detection and treatment of physiological disorders. Using catheters or endoscopes, for example, interventional techniques make use of minimally invasive approaches to diagnose and treat medical disorders. It is feasible to increase the precision of these approaches and potency by integrating nanotechnology. To visualize and target various parts of the body, such as tumors or obstructed blood veins, one can utilize nanoscale probes or therapeutic delivery systems. Interventional nanotheranostics offers targeted, minimally invasive therapies that can reduce side effects and enhance patient outcomes, and it has the potential to alter the way that many medical illnesses are handled. Clinical enrollment and implementation of such laboratory scale theranostics approach in medical practice is promising for the patients where the user can benefit by tracking its physiological state. This review aims to introduce the most recent advancements in the field of clinical imaging and diagnostic techniques as well as newly developed on-body wearable devices to deliver therapeutics and monitor its due alleviation in the biological milieu. The scope of various therapeutic approaches towards physiological ailments has widened in recent times in vivo imaging system have overcome the challenges of autofluorescence, low resolution, and closed-circuit camera by improving the penetration depth of the incident laser, that has resulted in non-invasive imaging modalities Bioimaging has proved to be an accurate and reliable diagnostic method owing to the visual aid in observing damaged tissue or organ Historically, the application of imaging techniques, that were originally developed for space applications, began in 1960s where researchers explored the possibilities of optical imaging, X-ray imaging and computed tomography (CT), magnetic resonance imaging (MRI) for inspecting food and agricultural products. Further advancements by assembling optical cameras, appropriate illumination and developing computer software began the era of bioimaging that opened a new research area. Currently acceptable clinical imaging techniques such as Positron emission tomography (PET), CT-scan, MRI, ultrasound imaging, or photoacoustic imaging have their own advantages and limitations.18F-fluorodeoxyglucose (FDG) is prepared by selectively replacing the oxygen atom by 18F, which is further metabolized by the cells revealing the metabolic processes following the Warburg effect. Similarly, 11C-L-methionine amino acid is used to identify cancer in the biological environment 64Cu labelled nanoparticles have been reported as an efficient alternative demonstrating shorter half-life and biocompatibility than the conventional probes 64Cu2+ is still a challenge, its doping with other metals prevents aggregation of the probe while extending circulation times and easy excretion. A recent report on the use of 89Zr conjugated Doxil as a nanotheranostic agent was used to assist in imaging the tumor recession and monitor the efficacy of the drugs in PET PET is one the most sensitive imaging tools that can reveal functional images at the molecular level with high resolution. Owing to its sensitivity, PET has been employed for various ailments such as cancer, neurodegenerative diseases, coronary artery and assessing myocardial variability. The operation of PET relies on the detection of the gamma rays originating from the annihilation of the positrons emitted from the radioactive molecule introduced in the patient. Among the most popular radioactive molecules, The clinical challenges associated with PET scan such as exposure to radioactive materials and biocompatibility are slightly resolved in computed tomography (CT) scans which are derived from X-ray imaging. Compared to the use of radioactive probes in PET, CT scans functions by collecting and analyzing the cross-sectional X-ray signals that are retrieved from the contrast agents injected in the patient several hours before the test. To obtain high-resolution images, the scan time is longer which necessitates the longer retention and circulation time of the contrast agents. The renal clearance of the contrast agents and prolonged circulation are achieved by controlled size of the contrast agents (larger than the glomerular filtration barrier) and partial diffusion in the blood. The success of the CT scan is justified by its ability to differentiate between soft tissues, water, and bones. Apart from barium sulfate, several different contrast agents based on iodine 99mTechnetium, which requires single photon emission computed tomography (SPECT-CT) and a tedious standard operating procedure While PET and CT scans require ionizing radiation for biological imaging, causing serious side effects on human health, magnetic resonance imaging has overcome some inherent problems associated with observing the skeletal and neuronal tissues While these imaging modalities are currently used in clinical practice, the demand for efficient and biofriendly contrast agents with ease of handling is growing. Due to the rise in electronic health and precision therapy, theranostics tools capable of monitoring physiological conditions are gaining popularity. Several innovative researches have brought diagnosis and therapy together with patient-controlled delivery of therapeutic agents, thereby facilitating personalized medication. The following section shows the advancements in the direction of theranostics and patient compliance.As highlighted above, the clinical application of probe-based imaging tools poses a health risk due to their radioactivity and biocompatibility. On the contrary, light and sound waves are relatively much safer alternatives to gather information from biological system. The spectrum of light encompassing UV, Vis, NIR, IR, are known to penetrate under the skin and reach deeper tissues and organs Figure A 33. Sou2 and Zr-MOFs are excellent sonosensitizers; their efficiency has been improved by introducing other transition metal groups like Fe3O4 to form Janus nanostructure 2 is popularly known as a sonosensitizer; however, it suffers from low transduction efficiency due to the rapid recombination of the electron-hole pairs. Owing to its biocompatibility, improving the sonodynamic transduction efficiency to produce ROS will be promising for cancer therapy and theranostics applications. The coating by Fe3O2 on TiO2 improves the transduction efficiency by narrowing the bandgap of TiO2, thereby reducing the recombination rate. Similarly, ZrO2-deficient nanoparticles showed higher efficiency in producing ROS under the US due to the more significant separation of the electron-hole pairs. The biocompatibility of ZrO2-x nanoparticles was improved by capping with amine-polyethylene glycol with high absorption in the NIR-II window. It is seen that the NIR-II irradiation also triggers ROS generation in the biological tissue, which is an intriguing approach to employing NIR-II-based therapeutic activation and imaging. Despite the ease of operability of ultrasound imaging in observing SDT activity Various sonosensitizers producing reactive oxygen species in an aqueous environment have been employed to treat cancer Molecular imaging is another upgrade in medical imaging providing information about the biochemical processes in the biological milieu. The resulting images overcome the limitations of poor spatial resolution and radiolabeling in other imaging tools. Based on its sensitivity towards nanocontrast agents, photoacoustic imaging has been employed in molecular imaging for several applications. J-aggregates of organic dyes are known to exhibit emission in longer wavelengths that further translate to photoacoustic imaging contrast agents. Indocyanine green (ICG) are also shown as a potential contrast agent due to its stable J-aggregates which are encapsulated in a liposome for high sensitivity and estimating saturated oxygen in blood vessels The success of photoacoustic imaging for diagnosis still relies largely on the efficiency contrast agents. However, the need for high intensity laser light to facilitate skin penetration may lead to low resolution due to optical attenuation. Other factors such as targeted tissue localization and ultrasound obstruction through gas cavities or lung tissues affect the resolution of the image Light based imaging modalities based on fluorescent nanomaterials are another approach to visualize biological processes and structures in living cells and tissues 2O2 catalyzed separation of the prodrug causes tumor cell death, resulting in highly efficient therapy. Conjugating fluorescent probe on similar designs could facilitate a theranostics solution to monitor the treatment progress of the tumor.Fluorescent nanomaterials have been at the forefront of the bioimaging-based tracking of biological tissues. Various functional groups have been reported to facilitate the functionalization of nanomaterials, acting as a probe for a visual aid of the targeted tissue. Targeting adipose tissues is a significant challenge due to their widespread availability as a protective layer surrounding vital organs and metabolic activity. Brown adipose tissue, among the other types, viz. Beige and White adipose tissue, actively metabolize fatty acids when subjected to low temperatures. Owing to the inherent fatty acid composition, the adipose tissue is non-responsive to alternate detection methods such as electrical signals, thus, leaving an optical or ultrasound-based approach Using optogenetics, researchers have developed methods to release therapeutic genes using visible light from smartphone as a convenient source to activate the release process, with the goal of making treatment more patient friendly. A recent study by Mansouri et al in situ, photo instability of the probes, long duration of the imaging, photon scattering and tissue absorption at the visible or near infrared region of the spectrum with poor spatiotemporal resolution Current fluorescence-based bioimaging modalities employing nanomaterials as contrast agents suffer from certain limitations such as altered physicochemical properties post-interaction with the biological entities Wearable devices are being developed for the therapeutic treatment of various organs and systems in the body. For example, wearable devices are being used to deliver insulin to patients with diabetes 2O2 are associated with the healing stages 2O2 is significantly high in the hemostasis and inflammation stage while gradually reducing through the proliferation and remodeling stages. Owing to its dynamic localized concentrations, H2O2 has attracted the development of smart composite dressings that can exhibit functional properties in the form of fluorescence or electrical signals. Wu et al developed europium coordinated polymers loaded into polyacrylonitrile nanofiber mats which can absorb the wound exudate and exhibit varying fluorescence intensity after interaction with localized H2O2 concentration  and nuclear medicine, are particularly high in radiation dose, and care must be taken to ensure that the benefits of the examination outweigh the risks For cancer theranostics and obesity, it is now shown that the Brown adipose tissue is closely related to cancer progression and overcoming hypoxia-based treatment hindrance in the tissue. BODIPY-based fluorescent nanoprobe have been shown to target the adipose tissue, primarily the brown adipose tissue, that opens new avenues towards cancer theranostics. Nanomaterials with properties of targeting the adipose tissue and exhibiting fluorescent response upon excitation under NIR-II laser could be a new direction to tackle cancer. Photoacoustic imaging is another promising tool to observe and narrow down the field of vision to blood cells and single cells. Coupled with ultrasound imaging or electrical impedance, such methods can be useful for monitoring the treatment progress. Interventional nanotheranostics encompassing both therapeutics and diagnosis/monitoring of the treatment progress is a promising and enticing approach that would aim at patient compliant and patient friendly treatment."}
+{"text": "Since first described, sickle cell disease (SCD) has represented a therapeutic challenge for clinicians trying to help patients enduring the ramifications of this dreadful condition. This life-long disease from the first crisis begins with processes that will change the physiological milieu of patients. These processes in the setting of chronic anemia can translate into potentially worsening neurological symptomatology and organ damage that characterize those patients having frequent and recurrent vaso-occlusive crises. Thus, it is readily apparent that reducing the negative effects caused by levels of hemoglobin S does represent the best approach to ameliorate the long-term outlook of patients. The main therapeutic is to provide chronic transfusion support of patients with SCD. However, many patients are unable to tolerate the known adverse events of concomitant chelation therapy needed to reduce the iron load caused by a long transfusion issue, we introduce a variety of SCD-related topics describing concepts and advances in the treatment of this disease.Gargot et al.). Importantly, even though these data show that the risk of ischemic stroke was low at 3.1%, this risk than doubled by the time patients reached teenage years. These data emphasizes that therapeutic approaches for SCD patients should focus on targeted interventions early in childhood to decrease complications. For diagnosis and testing, this issue also revisits both erythrocyte and reticulocyte counts of SCD patients as predictors of vasoocclusive crises . Authors of this study recommend the use of reticulocyte parameters obtained with a complete blood count. Specifically, a higher reticulocyte count in conjunction with higher medium reticulocyte fluorescence have the highest sensitivity and specificity (81% and 88% respectively) for predicting a looming crisis.Most SCD patients manifest symptoms and complications of the disease from childhood. With this in mind, this issue includes a large study from French Guiana describing the incidence and type of complications of pediatric patients over time, and determining the incidence of complications such as acute chest syndrome and ischemic stroke . This study indicates that a proportion of SCD patients continued to experience symptoms requiring additional intense chronic transfusion support with no reduction in acute SCD-related complications despite receiving hydroxycarbamide. Furthermore, this study exemplifies one of the known complications of transfusion therapy in SCD and that is alloimmunization, which occurred in 8.5% of patients despite matching for Rh and Kell antigens. The authors argue that differences between red blood cell donors and patients explain the high alloimmunization rates seen in SCD patients . The risk of iron overload, a major complication of chronic transfusions in SCD is being mitigated by performing exchanges instead of regular red cell transfusion. But despite good patient compliance, chronic red cell exchanges did not extend the life expectancy of patients with marked iron overload . Moreover, an article in this Research Topic will review the role that systemic hypertension plays in SCD patients in Cameroon by outlining a deep analysis of blood pressure variables that affect renal function over time .Among the known complications of SCD, avascular necrosis of the hip and shoulder are often requiring surgical interventions in this patient population, as symptomatology of the affected joint(s) worsen and crises accumulate. In this Research Topic the use of intense hyperbaric oxygen therapy will be introduced and discussed for SCD patients with avascular necrosis of hip and/or shoulder, that can lead to resolution of the necrosis . Matched-related and haploidentical hematopoitic stem cell transplant (HSCT) with modified conditioning regimens will be compared to and contrasted to new gene therapies entering clinical trials in the same review. Understanding that adverse events to biologicals can also occur, an article proposes how to triage patients presenting with reactions to crizanlizumab while still being beneficial to the patient's treatment outcome [Alshurafa and Yassin (a)]. One of the studies in this Research Topic reviews L-glutamine's role in reducing oxidative stress in SCD over an extended follow-up period  and confirms the medication's safety while it reduces hospitalizations, need for transfusions and organ damage. Similarly, this issue also describes the high effectiveness of voxelotor in SCD patients with significant kidney disease [Alshurafa and Yassin (b)].Lastly, the current issue includes a comprehensive review of most SCD disease-modifying therapies including hydroxyurea, L-glutamine, voxelotor, and crizanlizumab known to reduce pain crises . Despite the potential for allogeneic HSC transplantation, use of new gene-editing tools such as Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and gene transfer technologies to correct the genetic cause of the disease are gaining momentum. CRISPR-associated protein currently represents an opportunity to treat or even cure patients with SCD by targeting either B-cell lymphoma/leukemia 11A gene (BCL11A) and the promoter regions of gamma globin genes (HBG1/2), both of which have been identified to significantly increase HbF protein expression. This issue presents a meta-analysis of the most recent work showing that of these two genes, HBG1/2 has the greater effect on HbF induction . This Research Topic also contains a novel study using the Townes SCD mouse model that shows the extent by which the microRNA29B can induce HbF production in vivo . This report demonstrates that this induction occurs by silencing the MYB gene product. Along these lines another article in this issue outlines challenges facing scientists trying to find new HbF-inducing agents and will discuss recently completed or ongoing clinical trials testing some of these agents . Additionally, a review in this issue will describe the effects of homology-directed repair of the HBB gene, and disruption of cisregulatory elements of BCL11A or leukemia/lymphoma related factor binding sites in the \u03b3-globin gene promoters that result in enhancement of HbF expression . Finally, an article in this Research Topic will describe how inhibition of BACH1 transcription factor using a novel small molecular inhibitor can increase the concentration of HbF and even enhance the effectiveness of hydroxyurea in the setting of drug resistance using in vitro and in vivo models .As mentioned above, allogeneic HSCT is a potentially curative, therapy is limited since finding suitable HLA compatible donors is the first challenge that needs to be overcome. This type of transplantation and graft manipulation including T cell depletion, presents with high infection risks secondary to transplantation conditioning regimens, as well as risks of graft vs. host disease (In conclusion, approaches to treat and cure SCD are rapidly developing. This is a period of great excitement and hope. Contributors to this Research Topic and the editors of this special topic encourage readers to appreciate this collection as an attempt to provide up to date information while introducing a variety of research areas in the field. Clinical advances including current clinical trials will be covered with focus on all recent developments in the field.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
+{"text": "Nature,1 Hsueh et al. developed a non-invasive optogenetic approach to control heart rate in freely moving mice. Optically induced tachycardia elicited an anxiety-like state in risky contexts, with the posterior insular cortex mediating the apprehensive behaviours arising from cardiac pacing  the delivery of exogenous opsins by safe and sustainable AAV gene transfer strategies (2); phototoxicity and dysfunctional cellular reactions, especially during long-term stimulations; and (3) the development of implantable light devices that can adapt to cardiac movement while maintaining sufficient energy supply. Importantly, differences in organ dimension will require innovation of powerful, yet safe light emitters to achieve homogeneous and sufficient stimulation of cardiac tissue in humans. While gene and light delivery to the human heart comprise different constraints as compared to the eye, a promising clinical case of partial vision restoration after AAV-mediated optogenetic therapy was reported in 2021.A second implication derived from the work of Hsueh et al. is the possibility to modulate affective states by controlling bodily signals. Could heart rate be tuned in a specific manner to attenuate the pathological impact of psychiatric disorders such as anxiety or depression? By optogenetically stimulating cardiomyocytes Hsueh and colleagues could impose strong tachycardia, which caused enhanced anxiety-like behaviour. The opposite effect would be desirable to potentially treat emotional disorders associated with high sympathetic tone via downregulation of heart function and resulting interoception. In the long run, this could be achieved via specific optogenetic cardio-inhibitory approaches but in order to do so, we need a better understanding of how the heart conveys signals to the brain, and vice versa. Induction of tachycardia via stimulation of myocardial syncytium is a rather coarse manipulation of cardiac function and more specific stimulation approaches are required to fine-tune cardiac dynamics without interfering with the physiological beating function of the heart. This will open up new possibilities to explore the role of the heart-brain axis in psychiatric disorders. Hsueh et al. have achieved an important milestone for peripheral optogenetics in basic research, but have also paved the way for future clinical approaches targeting the peripheral nervous system for treatment of systems disorders."}
+{"text": "There exists a body of research regarding ethnic differences in perinatal health whereas this is not the case concerning the role of migration status and acculturation in attenuating these differences. This study aims to investigate determinants of health during pregnancy up to one-year postpartum by migration status.The study utilises data collected by the Born in Bradford cohort. The focus of analysis was migration status groupings, based on self-reported country of birth of participants and their parents and grandparents. Chi-Square, one-way ANOVA and correlation coefficients examined relationships between variables.Migrant women were less likely to smoke  or to be obese  compared to native women. Migrants were less physically active at 6 months (Mean (SD) minutes/week: native 265 (245), 1st generation 113 (162), 2nd generation 147 (182)) with larger increases in BMI over time compared to native women. Migrant women were more likely to be suffering psychological distress at baseline and 6 months postpartum and migrant families were more likely to live in areas of high socio-economic deprivation, despite higher levels of educational attainment.This study ethnicity and migration identifies some important differences between ethnic groups with different migration histories, therefore indicating that healthcare professionals should consider eliciting full migration histories to improve care. The impact of these differences on perinatal outcomes is a priority for future research. What is Already Known on this Subject? There is substantial ethnic variation in health inequalities and health-related behaviours during pregnancy. Women of non-white ethnic origin are less likely to engage in harmful behaviours such as smoking or binge drinking in the UK, yet often have poorer pregnancy outcomes.What does this Study Add? This study adds the dimension of migration status to the investigation of ethnicity and perinatal health. The study considers differences between first-and-second-generation migrant women and native women with no family migration history. The results show that, among women of South Asian ethnicity, women\u2019s own country of birth and that of their parents makes a difference to patterns of health-related behaviours. This new information is important in directing health promotion activities effectively. There is evidence to suggest that migrants of South Asian origin living in Europe are at increased risk of acquiring non-communicable diseases such as diabetes compared to populations in their country of origin. In pregnant populations, Jenum et al.  reportedIn the maternity population, a study of lifestyle related risk factors in the Born in Bradford cohort has established significant differences between ethnic groups  is a prospective cohort study recruiting participants during pregnancy in the Northern English city of Bradford. Women were invited to participate in the Born in Bradford study when attending an oral glucose tolerance test at 26\u201328 weeks\u2019 gestation or when attending other antenatal appointments. Informed consent was obtained, and women were asked to complete a baseline questionnaire providing data on maternal characteristics. Women also provided venous blood and urine samples and umbilical cord blood samples at birth. Recruitment took place between March 2007 and December 2010, and over 80% of women eligible in this period agreed to take part, which represents approximately 64% of the births occurring in Bradford during this period  due to small numbers, precluding further stratified analysis. Women in the native group were those who reported that they themselves, their parents and their grandparents were all born in the UK, regardless of self-reported ethnicity. While women\u2019s ethnicity did not have a bearing on group allocation, the analysis explores the impact of ethnicity as an independent variable.The current study focuses on exploring differences between groups based on migration status in individual variables that impact on maternal and infant health and wellbeing. The study utilises the most relevant variables from each of the three questionnaire data sets, with changes over time examined where adequate comparable data were available. For first-generation migrants this includes length of stay in the UK at baseline. The variables included in the study from the baseline questionnaire were Body mass index (BMI); smoking history; smoking during pregnancy; second-hand smoke exposure; use of vitamins and supplements and General Health Questionnaire-28 (GHQ-28) score. Variables included from the BIB 1000 six-month postpartum questionnaire were BMI; current smoking; smoke exposure; fruit and vegetable consumption; GHQ-28 score; breastfeeding initiation and physical activity. Variables included from the BIB 1000 twelve-month postpartum questionnaire were BMI; and Kessler Scale-6 (KS6) score.2). For comparison of BMI categories, international cut off values published by the World Health Organisation were used  and one-way ANOVA (for continuous data); categorical variables are presented as percentages and continuous variables as means and standard deviations.For first-generation migrants, the analysis calculated length of stay in the UK from the woman\u2019s self-reported age of arrival in the UK and her age at the time of delivery. Analysis of the impact of length of stay in this group used correlations between length of stay and BMI and GHQ score and reported as a correlation coefficient (R) and its associate P value.The demographic characteristics of the sample vary considerably between groups. Native women have the highest proportion of pregnancies among teenagers while the rate of pregnancies in those aged over 35 is highest among first-generation migrants. First-generation migrants had substantially higher parity, with 19% having parity of three or more compared to 15.5% of second-generation migrants and 7.2% of natives. Both first- and second-generation migrants were much more likely to be married and less likely to be single parent compared to native women.Both the mothers and fathers of children born to migrant women had a higher level of educational attainment compared to natives. Only 9% of native women had never had a paid job at baseline compared to over half of first-generation migrant women who had never done paid work outside of the home. The differences in employment patterns among fathers were less striking. There was a higher rate of unemployment (including students) among native men compared to both migrant groups and higher levels of self-employment among migrants. Despite higher levels of education, migration status appears to be linked to higher levels of deprivation according to index of multiple deprivation (IMD). IMD is the official measure of relative deprivation for small areas in England and combines information from seven domains of deprivation  to give a deprivation score . Mean BMI increase was higher among migrant women from baseline to 6 and 12 months postpartum compared to the native women  and score difference from baseline to 6 months postpartum . This relationship was not apparent however in the total score at six months postpartum which showed a slight negative correlation, although this wasn\u2019t statistically significant . Figure\u00a0Maternal physical activity data were only collected at 6 months postpartum. There were significant differences between groups in mean total minutes of physical activity per week with native women reporting more than double the number of active minutes compared to first-generation migrants, as shown in Fig.\u00a0The current study aimed to investigate the basic characteristics, lifestyle and health related behaviours of a large, diverse cohort of women during pregnancy and up to a year postpartum with a focus on maternal migration status. The self-reported country of birth of the mother and of her parents and grandparents informed migration status groups. While ethnicity was not the focus of this study the majority of women in both the first-generation migrant and second-generation migrant groups were of South Asian ethnicity with the majority of these women\u2019s heritage being in Pakistan.The exploration of the demographic characteristics of the sample showed substantial differences in age and parity for first-generation migrants compared to native women, suggesting different care needs. Higher levels of maternal education and yet lower rates of employment and higher IMD as an indicator of area deprivation among migrant women is also of interest and warrants further in-depth exploration.The native women were more likely to become mothers during adolescence whereas a higher proportion of migrant women were continuing to have children at older ages. Higher rates of teenage pregnancy in the native communities as opposed to migrant populations is of interest. A higher rate of women being a single parent or living without a partner in native women is also of concern, meriting in depth explorations.Other positive health related behaviours in migrant women included lower rates of smoking and higher rates of breastfeeding. This is particularly of interest as the results suggest a trend towards rates seen in the native population in second- generation migrants. These findings potentially add evidence to the theory of acculturation and adapting the host country behaviours albeit with potential health and social complications. These findings relate to the concept of the \u2018Healthy Migrant Effect\u2019, where migrant populations have better health outcomes relative to native populations. This concept has come under scrutiny, particularly in the UK, as self-reported ethnicity is often assumed as a proxy due to a lack of data relating to migration status and country of origin in health datasets. Mortality rates in the 2011 census show a slight advantage in terms of life expectancy at birth among first-generation migrants. The authors concluded that improving recording of ethnicity, country of origin and migration status in health records is of paramount importance in effectively studying the patterns of health and disease in migrant and ethnic minority populations. The ability in this study to assess migration status in addition to ethnicity is therefore important; however further work is needed to understand how these observations might translate into differences in perinatal outcomes.While overweight and obesity are higher in non-migrant populations, migrant women had higher BMI increases perinatally may suggest some impact of acculturation on eating habits. The correlation between length of stay in the UK and BMI for first-generation migrants in our study appears to support this. While there has been some debate regarding amending BMI classifications based on ethnicity, particularly for Asian populations, this study uses the international classifications outlined by the World Health Organisation. This approach was recommended by a WHO expert consultation published in the Lancet (WHO Expert Consultation, The results also suggested a higher likelihood of psychological distress and mental health problems in migrant groups. Our study also shows that this may worsen as length of stay in the UK increases, assessed by the positive correlation of length of stay with increasing GHQ-28 score and a higher proportion of women scoring over the 75th percentile for the sample in the second-generation migrant group. A review of ethnic minority women\u2019s experiences of perinatal mental health conditions and services in Europe found that women reported significant barriers to recognising and seeking help for mental health problems (Watson et al., There have been criticisms of the concept of acculturation, particularly in its application to health research. (Fox et al., This study presents valuable new information regarding the determinants of perinatal and child health for different migrant groups. There is evidence to suggest that basic characteristics and health related behaviours are more positive in first-generation migrants and that there is some acculturation affect bringing second-generation migrant women closer to native women in terms of health behaviours. This study also presents evidence of higher levels of psychological distress in migrant women which is not reflected in formal diagnoses of mental health conditions. This highlights an area of work which warrants urgent attention. Further work to explore the interplay between health behaviours, maternal ethnicity and migration status and their effect on pregnancy and birth outcomes is critical to establish where targeted interventions might benefit communities."}
+{"text": "In this abstract, we review current approaches to the management of uncomplicated urinary tract infection (UTI) and begin to explore alternative approaches to antibiotic prescribing. We review clinical guidelines on the use of nitrofurantoin internationally to capture the level of variation in evidence-based guidance. We find that the evidence base has been interpreted in very different ways. UK guidelines from NICE and the Scottish Intercollegiate Guidelines Network (SIGN) are unusual in promoting short (3 day) courses of nitrofurantoin. We find little direct evidence to support this, and that this guidance has been extrapolated from studies based on other agents. \u2018Short\u2019 courses of antibiotics aim to provide optimum balance between providing effective treatment whilst reducing selective pressure driving resistance amongst colonizing microbial flora. Three days of nitrofurantoin may indeed be a useful intervention in a large group of patients. Longer courses of nitrofurantoin still demonstrate considerable rates of treatment failure. The concept of a course length in itself is limited. The variation between recommendations internationally reflects both the uncertain foundations upon which evidence-based guidelines are written, and the limits of what can be safely concluded from evidence. We join others in pointing out there may be ways of customizing duration of therapy to the patient\u2019s response in primary care settings. There is a need for a more patient-focused approach to uncomplicated UTI, including better safety-netting and (currently lacking) guidance on best practice in the common clinical scenario of treatment failure."}
+{"text": "Subsequently, both the test and control group students attended another conventional pulpotomy simulation session where the quality of their access outline and pulp chamber deroofing steps were evaluated on plastic teeth. After the control group students also experienced the HVRS, all study participants completed a perception questionnaire on their experience. No significant differences were found between the study and control group students for the quantitative parameters assessed. Although the students regarded HVRS to be a useful adjunct to support their pre-clinical training, an overwhelming majority of the students did not consider HVRS to be a replacement for conventional pre-clinical simulation training.Simulation training for invasive dental procedures is a core component of the pre-clinical dental curriculum. Besides conventional mannequin-based simulators, dental schools are now incorporating haptic virtual reality simulation (HVRS) devices to facilitate the transition of students from the simulated dental learning environment to the clinical settings. This study aimed to assess student performance and perceptions of HVRS training as a pedagogical tool in pre-clinical paediatric dentistry. After practicing the primary molar pulpotomy procedure on plastic teeth, participants were randomized into test and control groups. Test group students performed the same procedure on a HVRS device, namely the SIMtoCARE Dente Undergraduate dental education requires students to demonstrate pre-clinical competence in a variety of irreversible operative procedures prior to their clinical placement. Dental education programs are time- and place-bound which adds pressure on educators to assist students to achieve the requisite fine motor skills before they perform invasive clinical procedures on patients. Traditionally, dental schools have relied on pre-clinical simulation training using plastic teeth mounted on mannequins to optimise students\u2019 practical skills and hand-eye-foot co-ordination. However, practicing dental procedures on virgin plastic teeth does not accurately simulate patient cases encountered in clinical practice and poses some limitations on the translational value of pre-clinical training. Moreover, plastic teeth do not replicate enamel and dentine hardness and it is difficult for students to receive realistic tactile feedback. The risk of injury associated with the use of sharp instruments during these sessions mandates close supervision which further restricts and reduces the number of pre-clinical simulated sessions that can be offered to students. With dental students required to show competency in increasingly complex procedures, conventional standalone mannequin simulators do not offer an ideal solution and technological advances are required to address their limitations .Dental schools around the world are now increasingly incorporating virtual reality simulators into pre-clinical training to facilitate the transition of students from the simulated dental learning environment into clinical settings. The experience of using virtual reality simulators has been reported to be more pleasurable and enjoyable by early year dental students . These tSeveral questions remain concerning the role and place HVRS should be given in pre-clinical dental education courses. Studies indicate that HVRS introduced in the early stages of undergraduate dental education has greater potential of predicting subsequent clinical performance scores compared to mannequin-based typodont models and also facilitates psychomotor skill acquisition ,10. HowePre-clinical training on operative skillsets in simulated dental learning environments is a fundamental educational strategy to ensure dental students demonstrate appropriate clinical procedural skills before they undertake invasive procedures in real patients. Training in simulated settings offers a safe environment to develop and consolidate core skills without the risk of harming patients. Management of paediatric dental patients poses additional challenges due to the anxiety within dental care settings often observed in young patients. Dental students often need additional time to calm children and establish a rapport with them using appropriate behaviour management techniques . Dental There is clearly a need for more studies to evaluate the effectiveness and student perceptions of training with the HVRS compared to the conventional mannequin simulator for pre-clinical operative procedures in paediatric dentistry. Therefore, the aim of the study was to assess whether augmenting the conventional simulation environment (CSE) with HVRS is likely to affect student performance and experiences for performing the primary molar pulpotomy procedure. The research objectives of the study include: (i) to evaluate if augmenting the CSE pre-clinical training with HVRS for a primary molar pulpotomy can improve student performance scores and reduce procedural time in comparison to pre-clinical training only in the CSE; and (ii) gauging student perceptions of HVRS training for the pre-clinical primary molar pulpotomy procedure.The conceptual framework of the study was built on the theory of deliberate practice which emphasizes embedding a self-reflective feedback loop in the development of skills rather than simply performing a task repetitively to achieve mastery . StudentThe study protocol and participant consent forms were approved by the Institutional Review Board of Qatar University (Reference number: QU-IRB 1652-EA/22). Prior to the study, full disclosure of the study and participants rights were given verbally and written informed consent was obtained. Students were clearly informed that participation in the study is optional and would in no way affect their training or assessment.Qatar University College of Dental Medicine.Interventional randomised controlled pilot study.The entire batch of Year 4 undergraduate dental students at the Qatar University College of Dental Medicine consented to participate in the study. The total number of students who participated in the study was 14, the mean age of the students was 22.4 years, and the female/male proportion was 12:2. Prior to the study, the students had received three credit hours of paediatric dentistry training that included attending didactic lectures and completing pre-clinical preventive and restorative exercises in primary teeth. All the participants had previous experience of using the HVRS and the mannequin simulator for pre-clinical restorative and endodontic procedures in permanent teeth.\u00ae  was the HVRS device used in the study  feedback via a physical handpiece with a virtual tip and a dental mirror handle. These physical instruments are graphically modelled on a display monitor along with the realistic images of the teeth and the jaws. Handpiece speed is controlled by a real foot pedal and the handpiece is connected to a force feedback robotic arm giving haptic tactile sensations of real tooth preparations and aerator sound renderings. This system creates a representative and virtual dental environment allowing users to feel tactile sensations experienced when drilling with the dental bur for procedures such as removal of caries or cavity/crown preparations. The SIMtoCARE Dente\u00ae is equipped with bespoke \u2018Courseware\u2019 software  that includes a ranges of manual dexterity exercises and dental operative procedures of varying complexity. For this study, the pulpotomy exercise on a carious primary molar (tooth #85) was chosen from the Courseware package. The SIMtoCARE Dentehe study . SIMtoCAThe conventional simulator used in this study was a mannequin head with rubber cheeks that was fitted with replaceable plastic jaws . This simulator setup uses actual dental instruments including high- and low-speed handpieces and suction devices . For thi\u00ae simulator. All the students then practiced the pulpotomy procedure on the plastic primary molar over a 90-min session under instructor supervision. The students were then randomly assigned to test (HVRS + CSE) and control groups (CSE) using an online research randomizer tool (www.randomizer.org (accessed on 20 October 2022)). Following this, the test group students practiced the access outline and pulp chamber deroofing steps on the SIMtoCARE Dente\u00ae over a single 60-min session. There were no limits placed on the number of attempts the test group students could practice using the pulpotomy procedural steps on the HVRS device during this session. All students participating in the study received a 60-min didactic lecture on pulpotomy in primary teeth. The students also attended two practical demonstrations of how to perform the pulpotomy procedure on a plastic primary tooth mounted on the mannequin simulator and on a virtual carious primary tooth in the SIMtoCARE Dente\u00ae simulator similar to their test group counterparts. The following week, both the test and control group students attended another conventional pulpotomy simulation session and the quality of their access outline and pulp chamber deroofing steps were independently assessed by two examiners who were blinded to the group the students belonged to, based on a defined rubric . Four-poOnce all students completed training in both simulation environments, they were invited to participate in a survey questionnaire recording their experiences and perceptions . Ten Likt-tests were used to compare the mean differences in performance scores between the test and control groups. All statistical tests were two-tailed and a p < 0.05 was set as the cut-off point to control for alpha error. The statistical analyses were performed using SPSS ver.23 .Normal distribution of data was confirmed using the Shapiro\u2013Wilk test and the equality of variances checked with the two-tailed F-test. Independent sample All 14 students in Year 4 participated in the study yielding a 100% response rate. Performance scores for the access outline and pulp chamber deroofing steps did not show any significant differences between the study and control groups. Time taken to complete the procedural steps and number of instructor prompts requested by students also showed no differences between the groups . Figure n = 14) once the control group students completed their HVRS session. The student responses to the questionnaire are presented in \u00ae simulator. A significant majority of the students (79%) also suggested that deroofing the pulp chamber felt different in the two simulation environments. Approximately, 64% of the students agreed or strongly agreed that training on the HVRS device improved their psychomotor skills and confidence in performing the pulpotomy procedure. Nevertheless, an overwhelming majority of students (86%) disagreed or strongly disagreed with the statement that HVRS training can replace conventional pre-clinical training on typodont teeth for the pulpotomy procedure, with most suggesting that HVRS may be used as an adjunct to the conventional simulation training. Just over half the students (57.1%) expressed interest for more HVRS sessions for paediatric pre-clinical pulp therapy procedures.A questionnaire  to assesStudent responses to the open-ended questions suggested that the main benefits of training on the HVRS device was that it allowed more repetitions for practice and provided better visualization of pulp chamber and root orifices. Among the HVRS limitations was the lack of finger rests and the lag in navigating through the displayed images while performing the procedure. Most of the students also preferred to experience the HVRS training after the conventional simulation training. Student recommendations for improving pre-clinical training for the primary molar pulpotomy procedure included providing them an opportunity to practice the procedure on extracted primary teeth and scheduling extra pre-clinical sessions.Procedure-based dental specialties like paediatric dentistry require students to demonstrate high levels of psychomotor skills before they start treating patients in clinics. Consequently, acquisition of psychomotor skills is fundamental to developing competency in operative procedures during pre-clinical training for undergraduate dental students. While mannequin-based simulation training using typodont teeth has conventionally been the standard pedagogical tool used in the pre-clinical teaching curriculum, dental schools have also been investing in virtual reality simulators to further enhance fine motor skills of their students. However, the impact of these digital methods of pre-clinical training on students\u2019 learning experiences in paediatric dentistry needs further investigation. Previous studies from around the world have reported low confidence among undergraduate dental students in performing pulp treatment in children and reiterated the need to improve pre-clinical training ,25,26,27A plausible reason why no performance score differences were found in this study could be attributed to the fact that study participants had previously experienced both the simulation environments for other pre-clinical tasks in the earlier years of their training. Additionally, the plastic teeth used in this study were customized for the pulpotomy procedure with wax inserts in the pulp chamber, allowing students to \u2018feel\u2019 the pulp in both the simulation environments. In this study, study group students were exposed to approximately 60 min of haptic pulpotomy exercises prior to the combined performance evaluation with the control group students on plastic teeth. Whether a longer time for practice on the HVRS device could have significantly improved student performance scores needs further investigation. Qualitative data on student perceptions about pre-clinical HVRS training for the primary molar pulpotomy procedure was also collected in this study. The vast majority of the study participants did not consider HVRS training to be an adequate replacement for conventional simulation training and instead preferred the HVRS be used as an adjunct along with conventional mannequin simulators. This is in agreement with the findings reported by Zafar et al. in a similar pre-clinical paediatric dentistry training study of Australian dental students . DespiteThe willingness of a large proportion of the students to engage in more HVRS sessions for pre-clinical paediatric dental procedures is of interest. This apparent incongruity could be explained by the fact that the HVRS allows students\u2019 multiple practice attempts with less time pressures as indicated in the student responses to the open-ended questions of the survey. Furthermore, HVRS training allows the students to receive multi-source feedback, that includes not just instructor- and computer-generated feedback, but also the opportunity and time for self-reflective feedback.Recreating a clinical experience in a simulated environment is challenging and complex, but it remains the core component of the pre-clinical dental curriculum. This makes it important to explore the benefits of different simulation training environments from the students\u2019 perspective and their relevance to actual clinical practice of different dental procedures. To the best of our knowledge, this is the first study to assess both students\u2019 performance scores and perceptions for a pre-clinical pediatric dental procedure in two simulation environments. The randomisation of students and blinding of assessors in this study improve and reduce selection and detection/performance bias, respectively. Despite recruiting 100% of students attending the paediatric dental pre-clinical training, the low number of participants in this pilot study coupled with the use of a single operative procedure might have affected the results of this study. Another limitation of the study was that the unidimensional Likert scales used to assess student perceptions may not have fully captured the entire gamut of student perceptions. This was partly overcome by including four open-ended questions in the questionnaire to obtain a wider range of student opinions. While the study results should not be over generalized, the study does provide preliminary data for dental faculty considering the use of HVRS as a pedagogical tool for pre-clinical paediatric dentistry training. A multi-center assessment of the effect of HVRS as an adjunct to CSE on a larger cohort of students with different operative procedures such as conventional stainless steel crown preparation and restorative techniques such Class II cavity preparation on primary molars could help further investigate the true benefits of augmenting the conventional simulation with HVRS.Despite the current generation of students being more comfortable with digital technologies, the initial findings of this pilot study suggest that HVRS should augment rather than replace conventional pre-clinical paediatric dentistry training. Similar evidence has been reported for other pre-clinical procedures, suggesting that students see HVRS as providing a more diverse learning environment, serving as a bridge between the conventional pre-clinical training and the clinics. Well-designed and adequately powered long-term prospective studies exploring matters of student performance, learning outcomes, and cost-effectiveness are warranted."}
+{"text": "In this paper, we investigate the electromagnetic response of metasurfaces due to excitation of the toroidal moment. A toroidal curved metasurface analyzad using a novel theoretical solution based on the Fourier analysis to evaluate the localized fields. Analyzing localized near-field interactions are crucial in investigating the excited trapped modes and enables us to optimize the reflection properties of the proposed metasurface. Optimization is accomplished using graphene layer and resulted a hybrid dielectric-graphene structure with near-zero reflection properties. According to a recent study3, Greta Otto\u2019s wings have asymmetrically dispersed nanostructures in the transparent areas Fig. 4. This observation motivates us to investigate analytical approaches of non-periodic nano-structures.A zero-reflection structure is required to achieve transparency. This characteristic is present in the wings of the remarkable species of butterfly known as Greta oto Fig. 5. A toroidal dipole is the third member of localized electromagnetic excitations which is created by a current circulating on the surface of a torus and has been observed in solid-state physics6. The toroidal response of metasurfaces was experimentally observed in microwave regime7 and then theoretically scaled to the THz regime8. The performances of these metasurfaces are usually limited by radiative and nonradiative losses where nonradiative losses can by reduced by employing materials of low loss such as dielectric10 likewise the solution employed in nontoroidal metasurfaces11.The electromagnetic response of metasurfaces can be related to traditional electric and magnetic dipoles or their complex combinations known as multipoles12. Trapped modes that excited in such asymmetrical structures are included in the the concept of bound states in the continuum (BIC)13. A strong link between the toroidal dipole resonance and the BIC was defined in the context of all-dielectric metasurfaces14. To construct a trapped mode supporting metasurface, we utilize a set of identical subwavelength unit cells with two asymmetric high-refractive index Silicon particles made in the form of modified nanodisks.Radiative losses can be regulated by designing the asymmetric all-dielectric unit cells to excite a high-quality factor resonant response known as Fano resonance in which the radiative damping can be efficiently suppressed by trapped mode and leads to the reduction of radiative lossesTrapped modes lead to a strong near-field enhancement where the located electromagnetic fields becomes notable. We utilize a novel theoretical approach to analytically evaluate localized electromagnetic fields near the all-dielectric unit cells of trapped mode supporting metasurface.16. To accomplish a comprehensive solution, we consider a cylindrical surface where any arbitrary surface can be fitted on a cylindrical surface with a defined cross-section.This evaluation provides the capability of manipulating the reflection coefficient for the surface. Our investigations should support every possible surface shape in the practical applications of such metasurfaces as sensingSince all-dielectric curved metasurfaces are composed of multi subwavelength cells, their optical properties are related to resonant features of each constitutive unit cell resonator and its mutual interaction with the other cells, trapped mode excitation does not merely satisfy the high-Q and zero-reflection properties which necessitates computing the localized electromagnetic fields to optimize such curved multi-cell metasurfaces.The sampled curved metasurface was selected as entclass1pt{minimaGraphene is selected to optimize the obtained reflectivity from evaluated electromagnetic fields. Optimization can be implemented by varying the graphene chemical potential when the graphene layer is integrated with the proposed dielectric structure.6. c indicates the speed of light in free space. Equation  do not merely provide the high quality properties for proposed curved structure and accentuates our introduced novel approach for determining localized electromagnetic fields. Consequently, any practical surface with random and arbitrary curve can be optimized by utilizing the near-field responses. To figure out the functionality of the procedure, a reasonable segment of the designed Silicon metasurface is optimized using graphene ribbons and strip lines which results near-zero reflectivity properties for the structure. To bias graphene sheets empirically, one can apply an external voltage to the sheets using a voltage source or bias tee. Graphene can be indirectly stimulated by applying thin gold electrodes on the side borders of the structure and mounting the graphene layers onto them. By applying stimulation to the metal electrodes, the graphene layers can be activated or manipulated to achieve the desired conductivity or impedance properties. It is important to note that the exact procedure for mounting and stimulating graphene layers may depend on the specific experimental setup and conditions, and may require careful calibration and optimization to achieve the desired results"}
+{"text": "If we can deepen our understanding of the molecular and cellular events taking place during preimplantation embryo development, we will be closer to identifying new potential molecular markers of embryo viability, which may one day be used to increase the success of Oh et al. report deriving lineage specific embryonic cell lines from porcine blastocysts to assess gene expression.Much of what is known about human embryo development at the cell and molecular level was discovered in mouse embryos or other animal models. Therefore, understanding the similarities and differences between human embryo development and other animal models is essential in clarifying the molecular steps taking place during human embryo development  from the trophectoderm , as these mutations may predict poor IVF outcomes. If specific poor-IVF-outcome-gene-mutations can be identified, then a future step could be finding ways to alter/fix these mutations in the preimplantation embryo. Yaghoobi et al. propose a strategy to take the molecular knowledge we have regarding embryo implantation to alter gene expression in the trophoblast layer of the developing blastocyst via CRISPR/dCas9 exosome system.Having a more thorough understanding of the changes taking place in this stage of development may allow for better use and interpretation of biomarkers of embryo viability, therefore increasing IVF success rates."}
+{"text": "The authors read the article with great enthusiasm: \u201cChanges in the neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios before and after percutaneous coronary intervention and their impact on the prognosis of patients with acute coronary syndrome\u201d, which aimed to evaluate Neutrophil/Lymphocyte (NLR) and Platelet/Lymphocyte (PLR) ratios before and after percutaneous coronary intervention (PCI) to estimate major adverse cardiac events (MACE).,It is known that NLR has been a special marker of interest due to its role in the prognosis after Acute Coronary Syndrome (ACS), Systemic Arterial Hypertension (SAH), Chronic Kidney Disease (CKD), Diabetes Mellitus (DM), Heart Failure (HF), cerebrovascular disease and arterial disease. The plausible pathophysiological mechanism for this relationship is the role of neutrophils in mediating the inflammatory response to acute myocardial injury, causing further tissue damage.The present study demonstrated an increase in the proportion of neutrophils and NLR in patients with acute coronary syndrome (ACS) after PCI, accompanied by a reduction in the count and proportion of lymphocytes, as well as presenting a greater predictive value for the incidence of the main MACE compared to the PLR after 24\u00a0h.,,On the other hand, recent studies indicate that PLR can be a useful biomarker in the evaluation of patients with ACS, since a higher PLR ratio seems to be associated with worse cardiovascular outcomes and greater disease severity, as well as being associated with a greater extent of the coronary lesion in patients with ACS.The authors declare no conflicts of interest."}
+{"text": "Restricted visitations of family members of persons with mental illness in psychiatric hospitals which may occur during times of public health crises such as the COVID-19 pandemic can have potential adverse consequences on the family members and on their ability to fulfill the caregiving role. Therefore, mental health professionals may encounter difficulties implementing a family centered-care model during such periods.Due to the limited knowledge about the effects of the restrictions during the pandemic a study was conducted in Israel. It examined the difficulties which family members experienced as a result of the restricted visitations and the effects of the restrictions on advancing a family-centered care model,A semi-structured questionnaire was distributed via digital means to 75 family members who had a family member who was hospitalized in psychiatric hospitals during the pandemic.The findings indicate that family members had limited opportunities in the following areas during the COVID-19 area: Developing relationships with the professional staff, being involved in the therapeutic process during the hospitalization, communicating with the hospitalized family member, and receiving help for themselves.Mental health professionals in psychiatric hospitals should adapt family-centric procedures to circumvent restrictions on physical presence and maintain the involvement of family members during psychiatric hospitalization.None Declared"}
+{"text": "Teaching Point: Leakage of fluid or intra-articular contrast from the subacromial bursa through the acromioclavicular joint, also known as the \u2018geyser sign\u2019, is an uncommon presentation of chronic rotator cuff injury and acromioclavicular joint degeneration. A 62-year-old man known with chronic rotator cuff pathology underwent a magnetic resonance (MR) arthrogram to assess the condition of the rotator cuff. The examination showed a full-thickness tear in the anterior segment of the supraspinatus tendon with leakage of intra-articular contrast to the subacromial bursa as well as chronic degeneration of the acromioclavicular joint . The conRotator cuff injury and acromioclavicular joint degeneration are common pathologies encountered in daily practice. The prevalence increases with age. The geyser sign is an uncommon presentation of chronic rotator cuff and acromioclavicular. It was first described in 1984 by Craig and can be observed on ultrasound (as a type 2 acromioclavicular cyst), arthrography and magnetic resonance imaging (MRI). Due to chronic degeneration of the rotator cuff and the acromioclavicular joint, the inferior capsule of the acromioclavicular joint can disrupt and allow extension of fluid from the bursa subacromialis-subdeltoidea to \u2018erupt\u2019 above the acromioclavicular joint ["}
+{"text": "Editorial on the Research TopicAdvances in non-union diagnostics, therapy and the understanding of its pathogenesis: current concepts from bench to bedsideDespite years of dedicated research and advances across a variety of associated medical fields failed fracture healing resulting in non-union remains a frequent and persistently challenging clinical problem . TreatmeTang et al.). Interestingly, despite its pro-inflammatory function on immune cells, recent studies showed that IFN-y signaling serves an anabolic function when focusing on osseous biology . In particular, IFN-y signalling leads to a osteoblastic activation via Runx2 and further upregulation of osteogenic factors  . On the other hand, IFN-y inhibits osteoclastogenesis by down regulating c-Fms in monocyte-derived osteoclast precursors to reduce RANK and the subsequent RANK-induced osteoclast differentiation . When focusing on the direct effects of IFN-y on bone biology, studies showed that presence of IFN-y seems to be vital to maintain normal bone mass. However, in-vivo a dichotomous function for substituted IFN-y suggested an highly individual patient dependent manner of IFN-y effects, which is further corroborated by studies showing that IFN-y gamma treatment is effective in preventing bone loss during rheumatoid arthritis as well as during estrogen deficiency . Taken together this review highlights the importance of INF-y signaling on bone biology and how its understanding has direct implications to preserve bone mass and how to potentially counteract changes during pathological conditions. Emerging technologies allowed researcher to take the findings made on a broader cellular or systemic level one step further towards a single cell level. A recent single cell RNA sequencing study confirmed the importance of osteoimmunology by revealing a comprehensive intercellular interaction landscape between local immune cells and osteoblastic lineage cells (OBCs) . Amongst others, the authors found that crosstalk between immune cells and OBCs resulted in a ligand receptor reaction of Jagged1 and Notch2 leading to an enhanced BMP-2 induced osteoblastic differentiation. Hereby, the authors highlighted that despite lessons learned on a systemic or macro level single cell studies are important to further understand crosstalk between immune and osseous cells . When focusing on musculoskeletal trauma a corroborating study indicated a potentially crucial role for a dysregulated systemic immune response resulting in poor outcomes following trauma . In particular, myeloid-derived suppressor cells (MSDCs) were identified as a potential target in restoring systemic immune homeostasis. Furthermore, targeted depletion of those cells resulted in a normalization of bone healing further supporting the importance of osteoimmunology in the context if bone healing.Although the inflammatory response marks the beginning of the fracture healing cascade  an unresMulica et al.). However, previously no diagnostic modality existed that allowed immediate and reliable evaluation of the patency of the vascular pedicle. In the current research topic Mulica et al., presented compelling data regarding the benefits of using an indocyanine green fluorescence (ICG) angiography intraoperatively. The authors were able to reliably detect patency of the vascular pedicles in all patients and furthermore document sufficient perfusion of the bone graft itself and in some cases even of the cancellous bone . Clinically despite the complex nature of the included cases no additional treatment was to achieve bony union, and the authors concluded that ICG angiography is a promising diagnostic tool in treating complicated cases of recalcitrant scaphoid non-unions.Although a variety of materials  exist that are suitable for bone grafting as part of non-union treatment, the most challenging graft requiring not only substantial expertise of the surgeon but also a highly advanced infrastructure remains vascularized bone grafts having a vascular pedicle . In scapFailed fracture healing remains a severe and debilitating complication of an already traumatic event in the life of affected patients. Although the underlying pathophysiological mechanisms remain complex ongoing research efforts provide data contributing towards a better understanding of the contributing factors both on a locally or systemically level. The current research topic highlights the importance of the immune system during bone healing and while studies over the years indicated that the immune system is neither friend no foe when it comes to bone healing moderation and modulation of immunological factors involved might help to make the immune system at least our lasting ally. Finally, while surgical techniques are improving intraoperative decision making is based on the experience of the surgeon but also on objective diagnostical tools that are readily available. The current topic introduces such a diagnostic modality and by publishing these results we hope to encourage surgeons to evaluate and potentially incorporate these diagnostical tools into their surgical and clinical routine."}
+{"text": "The primary cilium is an antenna-like structure of the plasma membrane. Primary cilia contain receptors and channels that detect extracellular signals and transduce them into the cells to regulate physiological functions such as cell proliferation, differentiation, and migration. The formation of primary cilia is dynamically regulated depending on the context. Dysregulation in the signaling and formation of primary cilia can lead to various diseases. The physiological and pathophysiological mechanisms underlying the regulation of primary cilia have been extensively investigated. These studies have revealed many aspects of primary cilia which can be considered as therapeutic targets. The scope of this Research Topic is to integrate the current knowledge and opinions of primary cilia in relation to their potential as therapeutic targets.Toriyama et al. analyzed the primary cilia of human dendritic cells (DCs) and Langerhans cells (LCs). They revealed that primary cilia mediated the signaling of granulocyte-macrophage colony-stimulating factor, a Th2 cytokine, to stimulate the proliferation of DCs and that the formation of primary cilia is halted in mature DCs. They also found that the primary cilia of LCs and keratinocytes from patients with atopic dermatitis were aberrantly ciliated in immature and proliferating states. They proposed a vicious cycle in atopic dermatitis in which ciliated immature DCs strongly recognized antigens and secreted GM-CSF to stimulate the proliferation in autocrine and paracrine fashions. This situation might be the same as some groups of medulloblastoma where primary cilia aberrantly mediate oncogenic signaling  in a canine model. MAP9 is thought to stabilize the ciliary microtubule-axoneme of photoreceptors and to regulate motor-protein-mediated ciliary trafficking (Takahashi et al. studied the homozygous 22\u00a0kb deletion in canine MAP9 which causes only a slight amino acid difference from wild-type MAP9 due to a duplication. They demonstrated that mutant MAP9 exacerbated the photoreceptor degeneration in RPGRIP1 mutants both functionally and structurally. They identified that MAP9 is prominently localized in the basal body of primary cilia suggesting an important role in maintaining the structure of ciliary microtubule axoneme. Their findings highlighted the role of MAP9 as a modifier and that the RPGRIP1 complex may be a therapeutic target in the cilia-related retinal degeneration.fficking . TakahasDeMars et al. provide a comprehensive review of neuronal primary cilia regulating metabolic homeostasis in these inter-neuronal connectivity. These studies may pave the way for novel anti-obesity therapies by correcting the abnormal signaling related to primary cilia.Obesity is caused by various factors, including adipogenesis in response to high-fat diet and the dysregulation of metabolic homeostasis. Primary cilia are involved in both the peripheral adipogenesis and the central control of metabolism associated with obesity . For exaKimura et al.elegantly review the association between cholesterol and ciliary signaling such as Sonic hedgehog and Wingless/INT pathways, suggesting that enzymes involved in cholesterol synthesis such as hydroxymethylglutaryl-CoA reductase and hydroxysteroid 11-\u03b2 dehydrogenase 2 can be therapeutic targets against cancer. Hart provides an interesting hypothesis that increased dietary polyunsaturated fat may suppress ciliogenesis which could be the cause of preeclampsia, a complication of pregnancy characterized by hypertension, protein urea, and other signs of organ damage. Cholesterol and lipid rafts have been considered important therapeutic targets in various diseases (The relationship between primary cilia and the signaling modulated by cholesterol and lipid rafts has attracted increasing attention in areas of research, especially those focusing on cancer . Kimura diseases . ExaminiSaito et al. summarize recent advances in the understanding of cilia mechanisms and their applications as therapeutic targets, especially focusing on ciliary receptors, ciliogenesis, intracellular trafficking pathway to primary cilia, and animal models and clinical trials in inherited retinal diseases. These studies suggest that dysregulation of primary cilia associated with diseases may be treated by genetic and/or pharmacological therapies targeting genes and their protein products as well as signal transductions related to the primary cilia. We may change the functions of primary cilia in a specific cell type to modulate other cellular components dysregulated in diseases."}
+{"text": "The social defeat hypothesis (SDH) suggests that a chronic experience of social defeat increases the likelihood of the development of psychosis. The SDH indicates that a negative experience of exclusion leads to an increase in the baseline activity of the mesolimbic dopamine system (MDS), which in turn leads to the onset of psychosis. Social defeat models have previously been produced using animal models and preclinical literature; however, these theories have not fully been tested in human clinical samples. There have been studies implying changes in brain structure due to social defeat interactions; however, research evidence is varied.This study aims to uncover whether exposure to SoDe has an impact on brain structure. Furthermore, we hope to understand if these changes are relevant to other mental health disorders.698  participants between the ages of 15-41 were recruited from the PRONIA-FP7 study. SoDe was measured from the self-reported questionnaires\u2019 Bullying Scale\u2019 and \u2018The Everyday Discrimination Scale\u2019. T1-weighted structural MRI data were processed; five 2 sample t-test analyses were carried out to compare the GMV differences in the entire sample and between the four groups.The VBM analysis showed significant group interactions in the right thalamus proper when comparing participants who had experience SoDe to participants who had not experienced SoDe including all 4 groups along with left cerebral white matter differences. In the ROP subgroup, significant group interactions in the left cerebellum white matter were found along with right cerebral white matter, left cerebral white matter and right Thalamus proper.The findings suggest that there are significant group interactions in thalamus and cerebral white matter. This is in keeping with some previous research suggesting volumetric changes in the thalamus due to stress and psychosis. Similarly for white matter there is some evidence suggesting differences due to SoDe and psychosis. However, there is a scarcity of research in this area with different research suggesting distinctive findings and therefore the evidence is inconclusive. In the ROP group analysis significant group interactions were present in the cerebellum due to SoDe experience. There is research suggesting the cerebellum\u2019s role in multiple different aspects like social interaction, higher-order cognition, working memory, cognitive flexibility, and psychotic symptoms, with every research suggesting multiple different things the role of the cerebellum in SoDe in the ROP population is in question. Nonetheless this large-scale research presents some interesting novel finding and leads the way to a new area of research. Further analysis will explore the relationship between groups on markers of stress (CRP) and neuroinflammation as potential mediation of the environmental effects of SoDe.None Declared"}
+{"text": "Staphylococcus aureus (MRSA), but Vancomycin resistance (VRSA) as well. They then demonstrated successful decolonization and long-term maintenance of animals free of these critical organisms, improving the health/welfare of the animals and staff safety .Preclinical macaque models of viral diseases are among the most translatable animal models to human patients \u20133. TheseDross et\u00a0al.). They demonstrated the safety of this approach and, whereas they were unable to demonstrate significant efficacy, the results mirrored those seen in the clinic demonstrating that the macaque model offers a highly translatable method to evaluate the immunology, safety and virological outcomes for CAR T cell therapies prior to use in patients. The second article evaluated the use of a CD20 depleting antibody prior to administration of SIV-specific CD4-MBL-CAR T cells expressing the follicular homing receptor CXCR5, resulting in increased follicular homing of the CAR T cells . Sampling of key lymphoid sites demonstrated reduced efficacy of the CD20 depletion in lymph nodes compared to blood as well as the increased homing of the CAR T cells to this location in CD20 depleted animals. However, despite the increased number of CAR T cells the animals failed to control the SIVmac239 infection upon ART withdrawal and the depleted animals demonstrated Cytokine Release Syndrome (CRS) with elevated levels of IL-6 that required treatment with anti-IL-6 antibodies to prevent mortality; an important safety consideration for potential translation of these therapies to the clinic.Two additional manuscripts also evaluated transplant models related to prevention/elimination of HIV in relevant macaque models. These manuscripts evaluated autologous transplantation of two different Chimeric Antigen Receptor (CAR) T cells aimed at preventing or eliminating SIV or Simian-Human Immunodeficiency Virus (SHIV) in macaque models of acquisition and/or ART suppressed infection. The first article looked at the use of a conserved elements vaccine and with exvivo expansion and autologous transplantation to increase the number of polyfunctional SHIV specific T cells present at the time of SHIV challenge . Looking at the Fc\u03b3III functions, which play a significant role in antibody mediated effector function, they demonstrated important differences between humans and macaques that further our understanding of how to interpret results of macaque studies used to evaluate vaccines and antibody-based therapeutics that involve or depend on Fc-effector functions. The final article looked at a macaque model of Zika virus infection . Pregnant macaques were inoculated during the first trimester of pregnancy and half demonstrated clearance of the virus from the maternal circulation by 7 days post infection (DPI). The other half took longer to eliminate viral RNA from the maternal plasma and had higher levels of vRNA at the maternal-fetal interface at the time of delivery. Outcomes were determined in the first 7 DPI with higher antibody titers associated with worse outcomes indicating that antibodies were not associated with maternal control and could be a potential biomarker for worse outcomes.Another accepted article evaluated similarities and differences in the fragment crystallizable (Fc) mediated functions of antibodies between rhesus macaques and humans (These articles demonstrate the potential macaques represent as powerful translatable infectious disease models permitting interrogation of key questions involving pathogen-host interactions as well as evaluating the efficacy of vaccines, therapeutics and other interventions and how further improvements in the models and the background health of the animals will allow for improved sampling, improved animal care and welfare, improved human health and safety, and elimination of critical sources of variability leading to even more rigorous and reproducible experiments.JS: Writing \u2013 original draft."}
+{"text": "Evidence is growing for the bio-immuno-metabolic model of pathogenesis in anorexia nervosa (AN), an eating disorder with a chronic and relapsing nature. The role of the gut microbiome in this process is also receiving intense research interest. The gut microbiome and the use of probiotics and prebiotics have been extensively studied in gastrointestinal (GI) disorders such as inflammatory bowel disease (IBD) and functional GI disorders (FGIDs). Exploring links between AN and these GI disorders may open new avenues of treatment such as the use of probiotics and prebiotics in AN.This review explores: i) GI presentation in AN and its relationship with the gut microbiome ii) factors influencing the gut microbiome presentation in AN including dietary patterns iii) whether the gut microbiome may be involved in the pathogenesis and maintenance of AN iv) gut microbiome presentation in GI disorders and commonalities with AN v) evidence for the potential use of probiotics and prebiotics as adjunct treatment in AN.GI symptomatology and gut microbiome presentation in AN were examined through literature searches. Gut microbiome changes related to common dietary patterns in AN were explored. Microbiome changes that may influence development or maintenance of AN were considered. Microbiome alterations seen in relevant GI disorders were explored and commonalities considered between these and alterations in the microbiome in AN. Literature searches were performed for the use of probiotics and prebiotics in AN and relevant GI disorders.GI symptoms occur commonly in AN with evidence suggesting some symptoms continuing beyond weight restoration. Significant disruption of the gut microbiome has been associated with AN with some changes related to typical dietary patterns seen during AN development. Additionally, similarities exist between microbiome alterations in AN and those seen in IBD and FGIDs indicating factors apart from the diet, such as a pro-inflammatory milieu, in play. These changes may not only influence GI presentation in AN but may also have a role in maintenance of the disorder. Some evidence suggests that the pre-morbid gut microbiome may influence risk for AN development. Preliminary evidence of the use of probiotics in AN indicates a positive influence on immune modulation although no evidence exists as yet of their influence on AN symptomatology. There has been extensive research into the use of probiotics and prebiotics in IBD and FGIDs with some evidence for reduction in disease parameters and symptomatology with the use of multi-strain probiotics.Some theoretical, mechanistic and clinical evidence exists for the use of probiotics in ameliorating GI symptoms in AN. However, further research is needed into the context of the gut microbiome changes in AN, the specifics of efficacy and the effects that probiotics and prebiotics may have in AN.None Declared"}
+{"text": "Background: The CDC\u2019s new Public Health Strategies to Prevent the Spread of Novel and Targeted Multidrug-Resistant Organisms (MDROs) were informed by mathematical models that assessed the impact of implementing preventive strategies directed at a subset of healthcare facilities characterized as influential or highly connected based on their predicted role in the regional spread of MDROs. We developed an interactive tool to communicate mathematical modeling results and visualize the regional patient transfer network for public health departments and healthcare facilities to assist in planning and implementing prevention strategies. Methods: An interactive RShiny application is currently hosted in the CDC network and is accessible to external partners through the Secure Access Management Services (SAMS). Patient transfer volumes  were estimated from the CMS fee-for-service claims data from 2019. The spread of a carbapenem-resistant Enterobacterales (CRE)\u2013like MDROs within a US state was simulated using a deterministic model with susceptible and infectious compartments in the community and healthcare facilities interconnected through patient transfers. Individuals determined to be infectious through admission screening, point-prevalence surveys (PPSs), or notified from interfacility communication were assigned lower transmissibility if enhanced infection prevention and control practices were in place at a facility. Results: The application consists of 4 interactive tabs. Users can visualize the statewide patient-sharing network for any US state and select territories in the first tab . A feature allows users to highlight a facility of interest and display downstream or upstream facilities that received or sent transfers from the facility of interest, respectively. A second tab lists influential facilities to aid in prioritizing screening and prevention activities. A third tab lists all facilities in the state in descending order of their dispersal rate , which can help identify highly connected facilities. In the fourth tab, an interactive graph displays the predicted reduction of MDRO prevalence given a range of intervention scenarios . Conclusions: Our RShiny application, which can be accessed by public health partners, can assist healthcare facilities and public health departments in planning and tailoring MDRO prevention activity bundles.Disclosures: None"}
+{"text": "Cell type-specific differential gene expression analyses based on single-cell transcriptome datasets are sensitive to the presence of cell-free mRNA in the droplets containing single cells. This so-called ambient RNA contamination may differ between samples obtained from patients and healthy controls. Current ambient RNA correction methods were not developed specifically for single-cell differential gene expression (sc-DGE) analyses and might therefore not sufficiently correct for ambient RNA-derived signals. Here, we show that ambient RNA levels are highly sample-specific. We found that without ambient RNA correction, sc-DGE analyses erroneously identify transcripts originating from ambient RNA as cell type-specific disease-associated genes. We therefore developed a computationally lean and intuitive correction method, Fast Correction for Ambient RNA (FastCAR), optimized for sc-DGE analysis of scRNA-Seq datasets generated by droplet-based methods including the 10XGenomics Chromium platform. FastCAR uses the profile of transcripts observed in libraries that likely represent empty droplets to determine the level of ambient RNA in each individual sample, and then corrects for these ambient RNA gene expression values. FastCAR can be applied as part of the data pre-processing and QC in sc-DGE workflows comparing scRNA-Seq data in a health versus disease experimental design. We compared FastCAR with two methods previously developed to remove ambient RNA, SoupX and CellBender. All three methods identified additional genes in sc-DGE analyses that were not identified in the absence of ambient RNA correction. However, we show that FastCAR performs better at correcting gene expression values attributed to ambient RNA, resulting in a lower frequency of false-positive observations. Moreover, the use of FastCAR in a sc-DGE workflow increases the cell-type specificity of sc-DGE analyses across disease conditions.The online version contains supplementary material available at 10.1186/s12864-023-09822-3. Single cell RNA sequencing (scRNA-Seq) is revolutionizing basic and translational biomedical research. The ability to quantify RNA expression in individual cells with high throughput enables quantification of cell type composition of complex tissue samples and characterization of their transcriptional phenotypes, or cell states, in great detail . The useWe previously published a comparison of the cellular landscape in airway wall samples between healthy controls and patients with asthma . While cAmbient RNA is cell-free mRNA that is released during preparation of single-cell suspensions for scRNA-Seq analysis and is one of the features that limits sc-DGE analyses, next to sparsity of data and the presence of doublets , 6. Sc-DThe composition of ambient RNA depends on the cell type composition and processing of the tissue, and is therefore highly sample-specific. When comparing gene expression profiles across cell types within a single sample, transcripts of ambient RNA will be shared and will not be identified as differentially expressed genes. In contrast, when comparing gene expression profiles in a cell-type specific fashion between different samples belonging to an experimental or disease condition, the ambient RNA composition might be different across the contrast used in the DGE analysis. In such a case, transcripts identified as differentially expressed genes may be derived from either cellular RNA or from contaminating ambient RNA, leading to false-positive results in the latter case. Therefore, a new, stringent method for ambient RNA correction that allows sc-DGE studies comparing healthy to diseased tissue samples is urgently needed.Here, we characterized the contamination by ambient RNA in sc-DGE analyses and present a novel method \u2018FastCAR\u2019 (Fast Correction for Ambient RNA) to quickly identify and correct for ambient RNA in droplet-based scRNA-Seq data. We provide a rationale for selection of the genes that should be corrected on the basis of the data retained within the gene expression matrix, without the need for prior knowledge on the expected cell-type specific gene expression patterns. Furthermore we compare its performance to the other ambient RNA correction methods SoupX and CellBender-remove-background which were either not thorough enough or computationally prohibitive . The useTo test FastCAR, we used our previously published  scRNA-SeAs another disease/control dataset we used PBMCs from seven healthy donors and seven hospital admitted COVID-19 patients  platformTo perform the differential expression analyses we used R package EdgeR  using thautoest function of the original tutorial starting from the count matrices. The cell selection step was not applied as we used only the libraries that were selected as live, high-quality cells in our previous publication [We applied SoupX using the suggested settings by the lication . For theTo perform the ambient RNA correction using CellBender remove background we used the default recommended settings . The cell selection was not applied as we used only the libraries that were selected as live, high-quality cells in our previous publication .SCGB3A1, expressed in secretory cells [IGKC from B cells [HBB, originating from erythrocytes [In order to develop a method that can be used to correct for ambient RNA in a sc-DGE analysis, we took advantage of a previously reported data set in which we reported the changes in the cellular landscape of the airway wall in patients with asthma compared to healthy controls . After ury cells , 14, IGK B cells , 16 and hrocytes  which whThis ambient RNA is sample-specific which leads to samples where the total ambient RNA (summed UMI in libraries with =\u2009<\u2009100 UMI) of a gene is higher to also have relatively higher presence of that gene in non-expressing cells compared to other samples , every library (j) with that number of UMIs or fewer is used to generate the ambient RNA profile. For every gene (g), the fraction of these selected libraries containing any UMIs of that gene (frC) is determined, as well as the highest number of UMIs of that gene occurring in a single library (gMax). If frC exceeds the user provided allowable fraction of ambient affected cells (frAA), the UMI counts for that gene in each cell is reduced by gMax. If this results in negative counts, the number of counts of that gene in the cell is set to 0.FastCAR determines the ambient RNA profile to correct the cell expression for on a gene by gene basis. The user provides a threshold for the number of Unique Molecular Identifiers (UMI) per sequencing library . Secondly, the maximum UMI-per-library threshold at which libraries are considered to only contain ambient RNA(thE).As stated earlier, there are two variables to consider when running FastCAR. Firstly, the minimum allowable fraction of libraries that contains ambient RNA of each gene.  will not be identified in the sc-DGE method, and therefore do not need to be corrected for. The default setting for this contamination chance parameter is 0.005; any genes present in less than 5 out of each 1000 ambient RNA libraries are ignored. This limits the total profile of ambient RNA that needs to be corrected for quite significantly.8. We have established a workflow  IGKC level in the non-expressing libraries will be mostly corrected for while expression levels of IGKC in the B cells remains high , a computational method that provides an unbiased way to identify and correct for the ambient RNA likely to affect DGE analyses on a per-sample basis that is intuitive and easy-to-use. FastCAR identifies the genes in the ambient RNA and applies a threshold for filtering that can be adapted to the settings of the DGE analyses, effectively removing the ambient RNA from the DE gene results. We show that this method effectively removes ambient RNA, but still retains a large proportion (~\u200992%) of the DE genes observed prior to ambient RNA removal.IGKC and SCGB1A1, we could show that the performance for ambient RNA removal of these genes with FastCAR is superior compared to CellBender and SoupX. Other genes that FastCAR identifies and corrects for are also more thoroughly corrected for meaning that applying the other methods would still result on falsely identifying genes as differentially expressed that result from ambient RNA.When comparing the results of DGE analysis before and after ambient RNA correction using FastCAR to the other methods we tested, there is a striking difference in the number of genes affected by correction procedures. Because FastCAR is made to only adjust for the expression of genes likely to affect DGE analyses, it corrects only a small subset of genes which leaves most results are identical to the uncorrected results. Both SoupX and CellBender adjust for the expression of many genes which results in large differences in the number and identity of the differentially expressed genes before and after ambient RNA correction. While both CellBender and FastCAR apply linear transformation of the data during correction, SoupX also applies a normalization that might interfere with certain downstream analyses. In the absence of a gold standard to compare the results of the DGE analyses and the low sample numbers in the dataset we used for testing, it is not possible now to determine with certainty which of these methods is optimal for the identification of DE genes that reflect the biological truth. However, using well-established cell type-specific genes like DGE analyses between healthy and control or other experimental groups in specific sub-populations of cells is a promising use of single cell data that may have large impact on our understanding of how the in-situ behaviour of cells of the same type differs between groups. Correcting for the presence of ambient RNA will be vital to finding meaningful results in these analyses and FastCAR is an effective method to do so. We developed FastCAR as part of a workflow for sc-DGE analysis, and therefore propose to use FastCAR for this specific application. We did not compare performance of FastCAR or any of the other ambient RNA correction methods for any other downstream applications.FastCAR can be run on a per-sample basis as part of the pre-processing pipeline used for scRNA-seq data and does not require a specific computational infrastructure.FastCAR can also be used to merely report the mRNA profile of the ambient RNA fraction on a per-samples basis, which can then be used to interpret results from the sc-DGE analysis performed without ambient RNA correction.Because of the large variability in cells and processing there is no perfect threshold to use to profile the ambient RNA, or a method to determine with certainty what this threshold should be for a specific sample. This necessitates the use of arbitrary thresholds or user-defined thresholds. The FastCAR R package includes functions that help the user set these thresholds and allows for profiling the ambient RNA without performing the correction to facilitate choosing these thresholds.A reasonable concern is whether removing the highest expression found in the ambient RNA is not too strict. We analysed the cell-type specific gene expression compared to the ambient expression levels and found these to be an order of magnitude higher. Consequently, the cell-type specific expression levels are well retained even for the genes that are highly expressed in the ambient RNA. Moreover, the FastCAR correction does not strongly affect clustering of the cells. This is not unexpected as the ambient RNA is a low and ubiquitous signal that has an equal chance of affecting each cell in a sample.The correction method works under the assumption that cell containing libraries are equally likely to contain ambient RNA and that mRNA from lysed cells is the only meaningful source of transcripts that are not expressed in the measured cell. Other possible sources of such transcripts are barcode switching, where spontaneous errors in the cell barcodes cause transcripts to be assigned to the wrong cell. This may also be partially responsible for some of the signal . FastCARWhile there are datasets of mixed human/murine cells that can be used to benchmark ambient RNA correction methods that strive for precise removal for ambient RNA, these datasets don\u2019t have test/control groups with possible effects on ambient RNA and resulting DEGs. In conclusion, to perform cell type-specific DGE analyses between groups there needs to be some correction to account for the sample-specific ambient RNA. FastCAR is a resource efficient method of thoroughly correcting the expression of genes most likely to be affected by ambient RNA. While other tools are available for general ambient RNA correction, FastCAR is more thorough in its correction than the other tested methods for genes it identifies as likely to affect sc-DGE.Below is the link to the electronic supplementary material.Supplementary Material 1: Tables of all differential gene expression results between conditions with no correction, and the tested ambient RNA correction methods appliedSupplementary Material 2: Supplementary Figure 1: FastCAR correction does not strongly affect clustering. A) Effect of FastCAR on the UMAP and clustering in the same cells from bronchial biopsies. B) Jaccard index of the overlap of the cell contained in the clusters between corrected and non-corrected bronchial biopsies. The same cells cluster together even if the clusters get split differently along a gradient. Supplementary Figure 2: Comparison of applying different ambient RNA correction methods between asthma and control in selected cell types in bronchial biopsies. A) IGKC levels in selected expressing and non-expressing cell types without correction and after applying other correction methods. B) SCGB3A1 levels in selected expressing and non-expressing cell types without correction and after applying other correction methods"}
+{"text": "Reactive ion etching (RIE) is the dominating technology for micromachining semiconductors with a high aspect ratio (HAR). It has long been recognized as a powerful manufacturing tool and has been widely applied across different research fields and industrial sectors. The semiconductor industry is continuously pushing to shrink lateral dimensions and to increase the aspect ratio of features while maintaining a cost advantage. This is driving new challenges in RIE processes to meet the demands of control feature-size variation and fabrication of HAR features in high-volume manufacturing. Recent developments in RIE methods and equipment have enabled considerably deeper etches and higher aspect ratios compared to traditional RIE methods and have revolutionized bulk micromachining technologies. The most widely known of these technologies is called inductively coupled plasma (ICP) deep reactive ion etching (DRIE), and this has become a mainstay for the development and production of silicon-based micro- and nano-machined devices. In the ICP DRIE systems, the plasma is generated with an RF-powered magnetic field, and a separate RF generator directs an electrical field to steer the reactants toward the substrate and obtain a highly anisotropic etch result . ICP hasOn one side, several papers address typical problems of pattern transfer, such as the mask effect on the lateral undercut  and etch"}
+{"text": "Traumatic brain injury (TBI) remains a significant medical and socioeconomic challenge of our times. The age-adjusted incidence across all TBI severities from population-based studies 2015\u20132020 ranged between 476/100,000 in South Korea to 787/100,000 in the US with temporal trends and variations still confounded by methodological diversity including inconsistent definitions, variations in data capture and interpretation [The work presented by Gunning and colleagues is highly supportive of this endeavour in suggesting variability in injury severity coding to be one of the main drivers for still existing differences in reported mortality after severe TBI across international trauma centers . The autAnother key perspective of the novel TBI databank is the critical validation of current practice and the adherence to existing guidelines when managing TBI patients on a larger and more comprehensive scale. An electronic survey conducted by Lagares and the BRAINI investigators among 200 physicians from 131 hospitals in four southern European countries confirmed large variations in guideline adherence, in particular when it came to CT imaging after clinical mild TBI . AnotherOne key element of the novel TBI databank TR-DGU is outcome assessment by using the GOSE-E at 6 and 12\u00a0months with potential expansion of observation periods to later time points in the future. The focus in this respect may then clearly be directed toward the impact of rehabilitation for the overall outcome after TBI. Once broadly established and running, it is also anticipated that the novel databank will be open for the inclusion of additional laboratory datapoints and biomarkers. In the present issue, the meta-analysis by Yunlong Pei and colleagues once more confirmed the diagnostic  and prognostic value  of GFAP, in particular during early TBI .The novel TBI databank TR-DGU, as first presented in this focus issue of the EJTES, will open up future perspectives for TBI research both on the national and international scale. Along with a series of other successful initiatives such as the pan-European CENTER-TBI project including sister projects in India and China, but also the North-American TRACK TBI initiative, it will provide not only qualitative data but also quantitative data sufficient enough to aim for future big data analysis introducing novel and innovative technologies. Large-scale international collaboration is key to overcome the still-existing gaps and hurdles in the care for the severely injured TBI patient. The first step, however, remains local motivation and active participation."}
+{"text": "Gene sets are being increasingly leveraged to make high-level biological inferences from transcriptomic data; however, existing gene set analysis methods rely on overly conservative, heuristic approaches for quantifying the statistical significance of gene set enrichment. We created Nonparametric analytical-Rank-based Enrichment Analysis (NaRnEA) to facilitate accurate and robust gene set analysis with an optimal null model derived using the information theoretic Principle of Maximum Entropy. By measuring the differential activity of ~2500 transcriptional regulatory proteins based on the differential expression of each protein\u2019s transcriptional targets between primary tumors and normal tissue samples in three cohorts from The Cancer Genome Atlas (TCGA), we demonstrate that NaRnEA critically improves in two widely used gene set analysis methods: Gene Set Enrichment Analysis (GSEA) and analytical-Rank-based Enrichment Analysis (aREA). We show that the NaRnEA-inferred differential protein activity is significantly correlated with differential protein abundance inferred from independent, phenotype-matched mass spectrometry data in the Clinical Proteomic Tumor Analysis Consortium (CPTAC), confirming the statistical and biological accuracy of our approach. Additionally, our analysis crucially demonstrates that the sample-shuffling empirical null models leveraged by GSEA and aREA for gene set analysis are overly conservative, a shortcoming that is avoided by the newly developed Maximum Entropy analytical null model employed by NaRnEA. Next-generation sequencing technologies and highly accurate annotations for prokaryotic and eukaryotic genomes have transformed biology into a data-rich scientific discipline . ConsequWhile existing gene set analysis methods employ distinct mathematical approaches for calculating the test statistic associated with a gene set\u2019s enrichment, the field of gene set analysis is uniquely dominated by the question of how to accurately evaluate the statistical significance of gene set enrichment. The origins of this debate are alluded to by Mootha et al.  in theirp-value) of the OXPHOS gene set enrichment.Mootha et al. used a two-sample Kolmogorov\u2013Smirnov test to compare the SNR values for genes associated with oxidative phosphorylation (OXPHOS) with the SNR values for all other genes. Rather than calculating the statistical significance of this enrichment score using the existing analytical null model for the two-sample Kolmogorov\u2013Smirnov test, Mootha et al. chose to approximate the null model for their gene set enrichment score using an empirical phenotype-based permutation test procedure. In this procedure, Mootha et al. shuffled the phenotype label of each DM2 sample and NGT sample to produce two new groups: a null test phenotype and a null reference phenotype. Each of these null phenotypes consisted of samples from both the original test phenotype  and the original reference phenotype . They recomputed a null SNR for each gene based on its expression in the null test samples and the null reference samples, producing a null differential gene expression signature; the same two-sample Kolmogorov\u2013Smirnov test statistic was then calculated as the null enrichment score for the OXPHOS gene set in this null differential gene expression signature. Mootha et al. repeated this procedure of permuting phenotype labels, calculating a null differential gene expression signature and computing a null enrichment score 1000 times, allowing them to estimate the statistical significance  of the [GSEA enrichment score] by using an empirical phenotype-based permutation test procedure that preserves the complex correlation structure of the gene expression data. Specifically, we permute the phenotype labels and recompute the [GSEA enrichment score] of the gene set for the permuted data, which generates a null distribution for the [GSEA enrichment score]. The empirical, nominal P value of the observed [GSEA enrichment score] is then calculated relative to this null distribution. Importantly, the permutation of class labels preserves gene-gene correlations and, thus, provides a more biologically reasonable assessment of significance than would be obtained by permuting genes\u201d.The logic of this empirical phenotype-based permutation null model for GSEA was more clearly described by Subramanian et al.  in their\u201cWe show, in agreement with earlier observations, that the gene independence assumption is not realistic because gene correlations are non-trivial and produce a substantial amount of variance inflation in the global statistic that in turn produces a large number of false positive results\u201d.This justification for the empirical phenotype-based permutation null model of GSEA was defended by Tamayo et al.  when theWe can more clearly state the central claim underlying this procedure with symbolic logic as follows:A \u2192 BA: Genes in a gene set are correlated when the gene setis not enriched in the gene expression signature.B: A gene set analysis method that assumes independence betweengenes will not control the Type I error rate of gene set analysis.Tamayo et al. sought to prove their primary claim  by showing that SEA produced a large number of false positives in their benchmark analyses . Unfortunately, such a verification would only be valid if the converse of the statement  were true in general, and the converse of a statement and the statement itself are not logically equivalent in general. However, the statement (A \u2192 B) does prove useful through its contrapositive, which may be stated as follows:\u00acB \u2192 \u00acA\u00acB: A gene set analysis method that assumes independence betweengenes adequately controls the Type I error rate of gene set analysis.\u00acA: Genes in a gene set are not correlated when the gene setis not enriched in the gene expression signature.\u201cFor each dataset in the benchmark, we randomized the phenotype labels 1000 times and ran both algorithms \u2026 The p values are computed using the areas under the empirical null histograms from GSEA and areas under the normal distribution for SEA\u201d.Since the contrapositive of a statement and the statement itself are always logically equivalent, we find that the primary claim underlying the validity of the empirical phenotype-based permutation null model for GSEA can be falsified if we are able to create a gene set analysis method that assumes that genes in a gene set are independent when the gene set is not enriched in a gene expression signature and subsequently show that this method adequately controls the Type I error rate of gene set analysis. Additionally, we note that the approach undertaken by Tamayo et al. as an attempt to defend GSEA and falsify SEA is fundamentally flawed because the method that Tamayo et al. used to evaluate the specificity of GSEA and SEA is the same empirical phenotype-based permutation procedure that GSEA relies on to estimate the null model for gene set enrichment. Tamayo et al. describe their benchmarking procedure as follows:We see this is the same description provided by Subramanian et al.  for the This discussion also serves to highlight the challenges intrinsic to accurately benchmarking gene set analysis methods using experimental data; in particular, gene sets that are frequently analyzed are often derived from the literature for biological processes or other gene ontologies that are not amenable to systematic, experimental validation. However, recent work in the field of cancer systems biology has shown that gene set analysis methods can be used to measure the differential activity of transcriptional regulatory proteins ,11; in tIn this manuscript, we derive and benchmark Nonparametric analytical-Rank-based Enrichment Analysis (NaRnEA), a novel gene set analysis method that leverages a fully analytical null model for gene set enrichment created using the information theoretic Principle of Maximum Entropy . By virtFurthermore, we demonstrate that NaRnEA is highly sensitive, identifying far more statistically significantly enriched regulon gene sets in these TCGA cohorts than either GSEA or analytical-Rank-based Enrichment Analysis (aREA), the gene set analysis method originally developed as the computational engine of VIPER that also employs an empirical phenotype-based permutation null model. Using independent proteomic data from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) for LUAD, COAD, and HNSC cancer types, we demonstrate that the differential activity of transcriptional regulatory proteins measured by NaRnEA in TCGA is significantly correlated with the differential abundance of the same transcriptional regulatory proteins in CPTAC. Given that the abundance and the activity of transcriptional regulatory proteins differ due to a number of biochemical processes , this agreement provides substantial biological support for NaRnEA-inferred differential protein activity. Crucially, this comparative analysis is not possible in a large-scale, systematic fashion for literature-curated gene sets since the corresponding gene ontologies are infrequently amenable to independent, experimental validation.https://github.com/califano-lab/NaRnEA (accessed on 3 March 2023)).These findings demonstrate that NaRnEA is statistically robust, having greater sensitivity than either GSEA or aREA without loss of specificity, and produces biologically meaningful inferences. We also interrogated the statistical properties of the empirical phenotype-based permutation procedure leveraged by GSEA and aREA and determined that the resulting null gene expression signatures exhibit substantial correlation with the true gene expression signature, thus providing a rigorous explanation for the reduced sensitivity of any gene set analysis method that relies on this procedure to approximate the null model for gene set enrichment. Finally, we identify systematic flaws in both GSEA and aREA when these methods are applied using alternative null models for gene set analysis while further highlighting the excellent performance of NaRnEA. NaRnEA and ARACNe3, along with all the code necessary to reproduce these analyses, are freely available for research use on GitHub ):rth regulator, where As a result of the nonparametric transformation in Equation (2), we can instead consider the discrete joint sampling distribution for the gene set members where the domain of each marginal is rth regulator corresponds with a greater increase in probability mass at the extremes of the nonparametric differential gene expression signature and therefore a more substantial reduction in the joint Shannon entropy of the discrete joint probability distribution. It follows from this line of reasoning that when the magnitude of the difference in the activity of the rth regulator between the test phenotype . Thus, to falsify this claim, it will be sufficient to demonstrate that NaRnEA is capable of adequately controlling the Type I error rate of gene set analysis.rth regulator is enriched in the nonparametric differential gene expression signature computed between the test phenotype  for which the Association Weight and Association Mode parameters are sufficiently well balanced; this ensures that the variance of the summand is not dominated by the variance of any element of the summand under the null hypothesis.Thus, the vector that consists of the Normalized Directed Enrichment Score and the Normalized Undirected Enrichment Score is a bivariate normal random vector under the null hypothesis of gene set analysis; furthermore, the mean of each marginal is equal to zero, and the variance of equal marginal is equal to one. We can also compute the covariance of this bivariate normal random vector under the null hypothesis of gene set analysis as follows (Equation (14)):rth regulator under each version of the alternative hypothesis. Since each gene in the regulon gene set for the rth regulator with a positive Association Mode will have a positive differential gene expression signature value under the positive alternative hypothesis, and each gene in the regulon gene set for the rth regulator with a negative Association Mode will have a negative differential gene expression signature value under the positive alternative hypothesis, it follows that both the Normalized Directed Enrichment Score and the Normalized Undirected Enrichment Score will be positive under the positive alternative hypothesis. Based on this rationale, we can combine the Normalized Directed Enrichment Score with the Normalized Undirected Enrichment Score to produce a single test statistic that will be strongly positive under the positive alternative hypothesis, which we refer to as the positive Normalized Enrichment Score (Equation (15)):To determine how we should interpret the bivariate vector consisting of the Normalized Directed Enrichment Score and the Normalized Undirected Enrichment Score as providing evidence for either positive or negative gene set enrichment in the nonparametric differential gene expression signature, we return to our previous discussion regarding the differential gene expression signature values for the members of the regulon gene set for the rth regulator with a positive Association Mode will have a negative differential gene expression signature value under the negative alternative hypothesis, and each gene in the regulon gene set for the rth regulator with a negative Association Mode will have a positive differential gene expression signature value under the negative alternative hypothesis, it follows that the Normalized Directed Enrichment Score will be negative under the negative alternative hypothesis while the Normalized Undirected Enrichment Score will be positive under the negative alternative hypothesis. Based on this rationale, we can combine the Normalized Directed Enrichment Score with the Normalized Undirected Enrichment Score to produce a single test statistic that will be strongly negative under the negative alternative hypothesis, which we refer to as the negative Normalized Enrichment Score (Equation (16)):Since each gene in the regulon gene set for the This biologically motivated change of variables is mathematically equivalent to an affine transformation of the original bivariate vector lculated . More foWe find that p-values can be interpreted in a one-tailed manner as providing evidence against the null hypothesis in favor of the positive or negative version of the alternative hypothesis, respectively. Under the frequentist paradigm of null hypothesis significance testing, a sufficiently small ):In order to control the overall Type I error rate of NaRnEA, we recognize that selecting the most likely form of the alternative hypothesis based on the minimum of these one-tailed It follows from the Data Processing Inequality Theorem  that ):We have already shown that, as a result of the affine transformation that produced the positive Normalized Enrichment Score and the negative Normalized Enrichment Score, the Pearson product moment correlation between these test statistics is equal to zero under the null hypothesis of gene set analysis. Thus, it immediately follows that the mutual information between the positive Normalized Enrichment Score and the negative Normalized Enrichment Score is equal to zero under the null hypothesis of gene set analysis. As a result,  and is approximately normally distributed under the null hypothesis of the Wilcoxon signed-rank test. If the T-statistic is divided by its maximum possible value , the resulting effect size is known as the rank\u2013biserial correlation; it has a maximum value of (1) and minimum value of (\u22121). We can leverage a similar approach to calculate the NaRnEA Proportional Enrichment Score (PES), which serves as the effect size for the enrichment of the rth regulon in the nonparametric differential gene expression signature computed between the test phenotype  and greater than or equal to (\u22121).The Proportional Enrichment Score for the regulon gene set of the rth regulator is equal to (0) when the regulon gene set of the rth regulator is not enriched in the nonparametric differential gene expression signature computed between the test phenotype . Thus, the Proportional Enrichment Score can be interpreted as type of nonparametric correlation coefficient. A confidence interval for the NaRnEA Proportional Enrichment Score can be estimated by applying the Fisher z-transformation to achieve approximate normality of this effect size under the alternative hypothesis; the associated standard error of the Fisher z-transformed NaRnEA Proportional Enrichment Score can be estimated by applying a suitable resampling procedure such as bootstrapping members of the gene set [The effect size for NaRnEA  is calculated from the test statistic for NaRnEA  in the same way that the effect size for the Wilcoxon signed-rank test  is calculated from the test statistic for the Wilcoxon signed-rank test  and the reference phenotype (B). Thus, we can calculate the statistical significance of this Leading Edge Score for the gth gene with respect to the rth regulator using the Maximum Entropy null model for gene set analysis as follows (Equation (26)):p-values may be adjusted for multiple hypothesis testing to identify those gene set members that contribute most significantly to the gene set enrichment. Importantly, the Leading Edge Score does not depend on the Association Weight of the gth gene with respect to the rth regulator; this ensures that the selection of genes that belong to the leading edge of the gene set a posteriori is not biased by any measure of gene set member importance that has been determined a priori.If either the positive alternative hypothesis or the negative alternative hypothesis is true, we would expect the ARACNe3 is an updated implementation of the Algorithm for the Reconstruction of Accurate Cellular Networks. The goal of ARACNe3 is to reverse-engineer a context-specific transcriptional regulatory network that consists of bivariate interactions between a set of predefined, putative transcriptional regulators and potential transcriptional targets.ARACNe3 accepts properly normalized gene expression profiles that correspond to independent samples from a single biological phenotype. Like previous versions of the algorithm, ARACNe3 recommends that users reverse-engineer multiple estimates of the transcriptional regulatory network topology and integrate these to form a consensus network. Previously, ARACNe-AP recommended that the estimates of the transcriptional regulatory network topology should be reverse-engineered in a decorrelated manner by sampling from the original set of gene expression profiles with replacement . While this approach is commonly employed in the field of ensemble machine learning , we finTo avoid these pitfalls, ARACNe3 generates decorrelated individual networks by sampling  a prespecified maximum number of individual networks have been reverse-engineered, or (2) each putative transcriptional regulator has been assigned a prespecified minimum number of unique targets. The individual networks are then integrated to form an ARACNe3-inferred consensus transcriptional regulatory network. The mutual information and Spearman correlation for each putative transcriptional regulatory interaction in the ensemble network are estimated a final time using all gene expression profiles for greater accuracy.rth transcriptional regulator is constructed by extracting all putative transcriptional regulatory interactions for the rth transcriptional regulator from the ARACNe3-inferred consensus transcriptional regulatory network. The Association Weight values are calculated by sorting all putative target genes based on (1) the number of individual networks in which they appeared as targets of the rth transcriptional regulator and (2) the final estimated mutual information between the rth transcriptional regulator and target gene. A copula transformation is then applied to the Association Weight values to ensure that the ARACNe3-inferred regulon gene sets are sufficiently well balanced to meet Lindeberg\u2019s condition and guarantee the asymptotic standard normality of the NaRnEA Normalized Enrichment Score under the null hypothesis of gene set analysis. The Association Mode values are taken to be the Spearman correlation coefficient between the rth transcriptional regulator and each regulon gene set member as estimated from all gene expression profiles.The ARACNe3-inferred regulon gene set for the The lung adenocarcinoma (LUAD) context-specific transcriptional regulatory network was reverse-engineered with ARACNe3 from 476 unpaired primary tumor gene expression profiles from TCGA using 2491 putative transcriptional regulators. Gene expression profiles were downloaded using the TCGAbiolinks R package from Bioconductor  and normThe colon adenocarcinoma (COAD) context-specific transcriptional regulatory network was reverse-engineered with ARACNe3 from 437 unpaired primary tumor gene expression profiles from TCGA using 2491 putative transcriptional regulators. Gene expression profiles were downloaded using the TCGAbiolinks R package from Bioconductor and normalized for sequencing depth prior to network reverse engineering . The first round of individual network pruning was carried out with a threshold for mutual information calculated to control the FDR at 5%. Individual networks were reverse-engineered until each putative transcriptional regulator had at least 50 unique transcriptional targets; this was achieved after seven iterations. The final consensus ARACNe3-inferred transcriptional regulatory network for COAD consists of 2491 regulators, 19,350 targets, and 675,373 regulatory interactions.The head and neck squamous cell carcinoma (HNSC) context-specific transcriptional regulatory network was reverse-engineered with ARACNe3 from 457 unpaired primary tumor gene expression profiles from TCGA using 2491 putative transcriptional regulators. Gene expression profiles were downloaded using the TCGAbiolinks R package from Bioconductor and normalized for sequencing depth prior to network reverse engineering . The first round of individual network pruning was carried out with a threshold for mutual information calculated to control the FDR at 5%. Individual networks were reverse-engineered until each putative transcriptional regulator had at least 50 unique putative transcriptional targets; this was achieved after 12 iterations. The final consensus ARACNe3-inferred transcriptional regulatory network for HNSC consists of 2491 regulators, 19,350 targets, and 812,199 regulatory interactions.GSEA accepts properly normalized gene expression profiles from samples representing a test phenotype and a reference phenotype; the differential expression of each gene is then estimated using the Signal-to-Noise Ratio (SNR). The enrichment of a gene set in this gene expression signature is calculated with a weighted Kolmogorov\u2013Smirnov-like statistic . Subramanian et al.  recommenhttp://www.gsea-msigdb.org/gsea/downloads.jsp (accessed on 1 October 2020)). The GSEA null model was estimated using 1000 sample-shuffling permutations. Empirical two-sided p-values returned by GSEA were corrected to a minimum of (1/1001), the smallest possible two-sided p-value for an empirical null model constructed from 1000 sample-shuffling permutations [Paired gene expression profiles from primary tumors and phenotype-matched normal tissue samples from TCGA were normalized using a blinded DESeq2  varianceutations .t-test [aREA accepts properly normalized gene expression profiles from samples representing a test phenotype and a reference phenotype; the differential expression of each gene is then estimated using Welch\u2019s unpaired t-test . The enrt-test  recommenp-values returned by aREA were corrected to a minimum of (1/1001), the smallest possible two-sided p-value for an empirical null model constructed from 1000 sample-shuffling permutations.Paired gene expression profiles from primary tumors and phenotype-matched normal tissue samples from TCGA were normalized using a blinded DESeq2 variance-stabilizing transformation prior to analysis with aREA. The VIPER R package from Bioconductor was used to run aREA, as described previously by Alvarez et al. . The aREhttp://linkedomics.org (accessed on 1 October 2020)) [Log-ratio normalized protein abundance data for primary tumors and phenotype-matched normal tissue samples were downloaded from CPTAC for the LUAD, COAD, and HNSC cancer types (r 2020)) . Data wer 2020)) . Gene nar 2020)) .All figures were created in R using the ggplot2 R package from CRAN .p-values were corrected for multiple hypothesis testing to control the FDR according to the methodology of Benjamini and Hochberg or to control the FWER according to the methodology of Bonferroni [nferroni . The 95%nferroni .We evaluated NaRnEA by performing gene set analysis using gene expression data from The Cancer Genome Atlas (TCGA) for lung adenocarcinoma (LUAD), colon adenocarcinoma (COAD), and head and neck squamous cell carcinoma (HNSC); these cancer types were selected because of (1) the availability of phenotype-matched primary tumor and normal tissue RNA-Seq gene expression profiles in TCGA and (2) the availability of phenotype-matched primary tumor and normal tissue mass spectrometry protein abundance profiles in the Clinical Proteomic Tumor Analysis Consortium (CPTAC). Crucially, the differential protein abundance inferred from mass spectrometry data in CPTAC provides orthogonal validation for the differential protein activity inferred from gene expression data in TCGA. For each TCGA cohort, we separated the primary tumor gene expression profiles into two groups based on whether each primary tumor was submitted with or without an associated adjacent normal tissue sample; we refer to these as paired and unpaired primary tumor gene expression profiles, respectively. From the unpaired primary tumor gene expression profiles, we reverse-engineered a context-specific transcriptional regulatory network for each cancer type with ARACNe3 for 2491 putative transcriptional regulatory proteins  [p-values based on the control of the False-Positive Rate (FPR < 0.05), False Discovery Rate (FDR < 0.05), or Family-Wise Error Rate (FWER < 0.05).Subsequently, we created an identical number of null model (NM) regulons by swapping out the members of each TS regulon with an equal number of genes selected at random from the complement of the corresponding TS regulon gene set. By virtue of their construction, the NM regulons are biologically meaningless and therefore will not be enriched in any differential gene expression signature. We used the gene expression profiles from 57 LUAD, 41 COAD, and 43 HNSC patient-matched primary tumor  and adjacent normal tissue  samples from TCGA to estimate cohort-specific differential gene expression signatures. We then used NaRnEA to test for the enrichment of the NM regulons in the corresponding differential gene expression signatures. The number of statistically significantly enriched NM regulons was determined from the NaRnEA two-sided This analysis demonstrates that after correcting for multiple hypothesis testing, NaRnEA did not find any of the NM regulons to be statistically significantly enriched in the differential gene expression signatures computed between primary tumor and adjacent normal tissue samples from TCGA . CrucialHaving established the specificity of NaRnEA using the NM regulons, we subsequently evaluated the sensitivity of NaRnEA using the TS regulons. Given the substantial differences in gene expression between malignant and benign phenotypes, we expected that at least some fraction of the 2491 transcriptional regulatory proteins to which these TS regulons correspond would exhibit differential activity between the primary tumor and adjacent normal tissue samples from TCGA. However, we did not know a priori which subset of transcriptional regulatory proteins would exhibit differential activity, since no experimental methodology exists to measure the activity of transcriptional regulatory proteins in a systematic, high-throughput manner in vivo. Instead, we used NaRnEA to test for the enrichment of the TS regulons in the corresponding differential gene expression signatures computed between the primary tumor and adjacent normal tissue samples from TCGA; then, we used independent mass spectrometry data from CPTAC to determine whether the differential activity of the transcriptional regulatory proteins, inferred from TCGA gene expression data using NaRnEA, was correlated with the differential abundance of the transcriptional regulatory proteins, inferred from CPTAC proteomic data using a Mann\u2013Whitney U (MWU) test.rth regulator between the test phenotype ): Theorem  that thep-values based on the control of the False-Positive Rate (FPR < 0.05), False Discovery Rate (FDR < 0.05), or Family-Wise Error Rate (FWER < 0.05).The number of TS regulons that were statistically significantly enriched in the differential gene expression signatures computed between primary tumor and adjacent normal tissue samples in each of the cancer types from TCGA was determined from the NaRnEA two-sided tumor = 110, 97, 109) and phenotype-matched normal tissue  samples in the LUAD, COAD, and HNSC cohorts from CPTAC, respectively. For each cancer type, we restricted our analysis to the transcriptional regulatory proteins for which a TS regulon and mass spectrometry data were available. We corrected the MWU test two-sided p-values from CPTAC for multiple hypothesis testing and classified each transcriptional regulatory protein as upregulated , downregulated , or not statistically significantly differentially abundant . Similarly, we also corrected the NaRnEA two-sided p-values from TCGA for multiple hypothesis testing and classified each transcriptional regulatory protein as activated , deactivated , or not statistically significantly differentially activated . We tested for an association between NaRnEA-inferred differential protein activity from TCGA- and MWU-inferred differential protein abundance from CPTAC using a three-by-three contingency table for LUAD , COAD , and HNSC  cancer types. These results offer biological validity for the NaRnEA-inferred differential protein activity, further reinforcing that NaRnEA is a highly sensitive gene set analysis method. The NaRnEA-inferred differential protein activity for all putative transcriptional regulatory proteins can be visualized en masse by plotting the absolute value of the Normalized Enrichment Score vs. the Proportional Enrichment Score for each TS regulon using a modified version of a volcano plot [This analysis revealed that the NaRnEA-inferred differential protein activity from TCGA was statistically significantly positively correlated with the MWU-inferred differential protein abundance from CPTAC for the LUAD . Since there was no overlap between the gene expression profiles that were used by ARACNe3 to reverse-engineer the context-specific transcriptional regulatory networks and the gene expression profiles that were used to estimate the differential gene expression signatures for these cancer types, the NaRnEA Leading Edge p-values and the ARACNe3-inferred Association Weight values would be independent under the null hypothesis that the NaRnEA Leading Edge analysis cannot identify the gene set members that contribute most significantly to the gene set enrichment. In support of the NaRnEA Leading Edge analysis, this analysis revealed that the ARACNe3-inferred Association Weight values and the NaRnEA-inferred post hoc Leading Edge p-values exhibited a statistically significantly negative Spearman correlation (FWER < 0.05) for the vast majority of TS regulons in TCGA LUAD (91.75%), TCGA COAD (90.56%), and TCGA HNSC (88.33%). This analysis was restricted to those TS regulons that NaRnEA inferred were statistically significantly enriched in the differential gene expression signatures computed between the corresponding primary tumor and adjacent normal tissue samples from TCGA (FWER < 0.05) since post hoc Leading Edge analysis is only interpretable for these gene sets.To demonstrate the utility of the NaRnEA Leading Edge analysis, we calculated the post hoc Leading Edge p-values; statistical significance was established based on the control of the False-Positive Rate (FPR < 0.05), False Discovery Rate (FDR < 0.05), or Family-Wise Error Rate (FWER < 0.05).To compare NaRnEA with GSEA and aREA, we first applied these alternative gene set analysis methods to test for the enrichment of the NM regulons in the gene expression data from TCGA for LUAD, COAD, and HNSC. The number of statistically significantly enriched NM regulons was determined for GSEA  and aREAp-values; statistical significance was established based on the control of the False-Positive Rate (FPR < 0.05), False Discovery Rate (FDR < 0.05), or Family-Wise Error Rate (FWER < 0.05).This analysis demonstrates that, after correcting for multiple hypothesis testing, neither GSEA nor aREA found any of the NM regulons to be statistically significantly enriched in the differential gene expression signatures computed between primary tumor and adjacent normal tissue samples from TCGA; thus, we conclude that both methods adequately control the Type I error rate of gene set analysis. We subsequently applied GSEA and aREA to test for the enrichment of the TS regulons in the gene expression data from TCGA for LUAD, COAD, and HNSC. The number of statistically significantly enriched TS regulons was determined for GSEA  and aREAThis analysis demonstrates that, after correcting for multiple hypothesis testing, neither GSEA nor aREA found any of the TS regulons to be statistically significantly enriched in the differential gene expression signatures computed between primary tumor and adjacent normal tissue samples from TCGA. Given that the NaRnEA-inferred differential protein activity from TCGA was significantly correlated with MWU-inferred differential protein abundance from CPTAC, we conclude that NaRnEA is significantly more sensitive than both GSEA and aREA; furthermore, the fact that NaRnEA did not identify any statistically significantly enriched NM regulons after correcting for multiple hypothesis testing demonstrates that this gain in sensitivity is achieved without loss of specificity.The low sensitivity of GSEA and aREA, as evidenced by their inability to identify statistically significantly enriched TS regulons after correcting for multiple hypothesis testing, can be attributed directly to their reliance on the empirical phenotype-based permutation null model, which we have shown to be unnecessary for achieving adequate control of the gene set analysis Type I error rate. In order to determine why the use of the empirical phenotype-based permutation null model decreases the sensitivity of these methods, we applied this procedure to the gene expression data from TCGA while determining how many primary tumor and adjacent normal tissue samples were distributed to the null test phenotype and null reference phenotype during each permutation. Then, for each of the sample-shuffling permutations, we estimated a null differential gene expression signature between the null test phenotype samples and the null reference phenotype samples using an MWU test; we repeated this process 1000 times for each cancer type. We then tested for the enrichment of the ARACNe3-inferred TS regulons in each of these null differential gene expression signatures with NaRnEA.p-values for multiple hypothesis testing (FWER < 0.05), we found that some of the TS regulons were statistically significantly enriched in each of the null differential gene expression signatures computed from TCGA LUAD , TCGA COAD , and TCGA HNSC . Since we established that NaRnEA adequately controls the Type I error rate of gene set analysis, we can conclude that the enrichment of the TS regulons was not an artifact; rather, this finding suggests that each of the null differential gene expression signatures exhibited some degree of correlation with the original differential gene expression signature.After correcting the resulting NaRnEA two-sided p-values for multiple hypothesis testing (FWER < 0.05), we found that nearly all of the null differential gene expression signatures from TCGA LUAD (94.7%), TCGA COAD (95%), and TCGA HNSC (93.2%) were statistically significantly correlated with the original differential gene expression signature from the same cancer type. Furthermore, we found that this correlation between each null differential gene expression signature and the original differential gene expression signature was strongly associated with the degree of imbalance between the corresponding null phenotypes; for example, when the null test phenotype contained a greater number of primary tumor samples than adjacent normal tissue samples, the resulting null differential gene expression signature was more likely to be positively correlated with the original differential gene expression signature n et al.  attemptep-value was greater than 0.50. Thus, these TN regulons consisted solely of genes that were not enriched at the extremes of the corresponding differential gene expression signature; therefore, an accurate gene set analysis method should not identify any statistically significant enrichment for these gene sets. We used NaRnEA , False Discovery Rate (FDR < 0.05), or Family-Wise Error Rate (FWER < 0.05).We constructed a new group of gene sets, which we refer to as totally null (TN) regulons, by replacing the members of each TS regulon with genes drawn at random from the set of genes for which the MWU differential gene expression two-sided d NaRnEA  and GSEAd NaRnEA  to test We determined that, after correcting for multiple hypothesis testing to control the False Discovery Rate, GSEA found 100% of the TN regulons to be statistically significantly enriched in the differential gene expression signatures computed between primary tumor and adjacent normal tissue samples from TCGA. In contrast, even without correcting for multiple hypothesis testing, NaRnEA did not find any of the TN regulons to be statistically significantly enriched in the differential gene expression signatures. These results falsify the secondary claim made by Subramanian et al.  and Tama\u201c\u2026 the statistical significance for the enrichment score is estimated by comparison to a null model generated by permuting the samples uniformly at random or by an analytic approach equivalent to shuffle the genes in the signatures uniformly at random \u2026 Gene shuffling can be approximated analytically as follows: according to the central limit theorem, the mean of a sufficiently large number of independent random variables will be approximately normally distributed. The enrichment score of our null hypothesis fulfill this condition, and we ensure a mean of zero and variance equal to one for the enrichment score under the null hypothesis by applying a quantile transformation based on the normal distribution to the rank-transformed gene expression signature before computing the enrichment score\u201d.We also examined the alternative null model for aREA, which is described by Alvarez et al.  as folloAlvarez et al.  invoked p-values for multiple hypothesis testing (FWER < 0.05), we rejected the null hypothesis that the aREA test statistics were normally distributed with a mean of zero and a variance of one under the null hypothesis of gene set analysis for 100% of the TS regulons in TCGA LUAD, TCGA COAD, and TCGA HNSC. This analysis demonstrates that the alternative null model provided for aREA does not behave in the manner described by Alvarez et al. [We found that, after correcting the resulting z et al. ; unfortuhttps://github.com/califano-lab/NaRnEA (accessed on 3 March 2023)).It is widely appreciated that the rigor and reproducibility of scientific research depends on the use of computational and experimental methods that are sufficiently sensitive to make meaningful inferences while maintaining adequate control of the Type I error rate to reduce spurious findings . Gene se"}
+{"text": "Technology advancement has allowed more frequent monitoring of biomarkers. The resulting data structure entails more frequent follow-ups compared to traditional longitudinal studies where the number of follow-up is often small. Such data allow explorations of the role of intra-person variability in understanding disease etiology and characterizing disease processes. A specific example was to characterize pathogenesis of bacterial vaginosis (BV) using weekly vaginal microbiota Nugent assay scores collected over 2 years in post-menarcheeal women from Rakai, Uganda, and to identify risk factors for each vaginal microbiota pattern to inform epidemiological and etiological understanding of the pathogenesis of BV.We use a fully data-driven approach to characterize the longitudinal patters of vaginal microbiota by considering the densely sampled Nugent scores to be random functions over time and performing dimension reduction by functional principal components. Extending a current functional data clustering method, we use a hierarchical functional clustering framework considering multiple data features to help identify clinically meaningful patterns of vaginal microbiota fluctuations. Additionally, multinomial logistic regression was used to identify risk factors for each vaginal microbiota pattern to inform epidemiological and etiological understanding of the pathogenesis of BV.Using weekly Nugent scores over 2 years of 211 sexually active and post-menarcheal women in Rakai, four patterns of vaginal microbiota variation were identified: persistent with a BV state (high Nugent scores), persistent with normal ranged Nugent scores, large fluctuation of Nugent scores which however are predominantly in the BV state; large fluctuation of Nugent scores but predominantly the scores are in the normal state. Higher Nugent score at the start of an interval, younger age group of less than 20 years, unprotected source for bathing water, a woman\u2019s partner\u2019s being not circumcised, use of injectable/Norplant hormonal contraceptives for family planning were associated with higher odds of persistent BV in women.The hierarchical functional data clustering method can be used for fully data driven unsupervised clustering of densely sampled longitudinal data to identify clinically informative clusters and risk-factors associated with each cluster. Technology advancement has allowed more frequent monitoring of biomarkers to evaluate diseases or health conditions. For example, weekly measurements of grip strength collected during a 6-months period have been used to study how trajectories of muscle weakness served as a marker for adverse health outcomes in older adults . AnotherTraditional longitudinal data analysis methods such as mixed effects models or generalized estimating equation models focus on modeling the cross-sectional mean values and thus do not apply when the scientific goal is to explore and characterize the patterns of intra-person longitudinal changes. To analyze the frequently sampled data in the aforementioned BV dataset, we resorted to functional data analysis framework and developed a hierarchical functional clustering framework utilizing a set of data features by applying the functional non-parametric clustering method by Ferraty and Vieu (2006) .BV is a common form of vaginitis in women and is related to various adverse health outcomes , 6. BV csymptoms , 8, and mentclasspt{minimasymptoms  developeHere we use a fully data-driven approach to characterize the longitudinal patterns of vaginal microbiota. The approach uses the original numerical values of Nugent scores and utilizes the intra-person variability to characterize the longitudinal patterns. More specifically, we applied functional data analysis (FDA) \u201317 basedThe remaining of the paper is structured as below: the \u201cIn the rural Rakai Region of Uganda, 312 consenting females between the ages of 13 and 39 participated in a two-year cohort study between 2001 and 2003. For up to two years, participants underwent weekly home-based self-collection of vaginal swabs for assessment of the vaginal microbiota and vaginal pH level. The self-collected vaginal swabs were placed on slides and allowed to air dry before being stained with Gram stain and scored using the Nugent quantitative morphologic categorization for vaginal microbiota, which yields integer scores ranging from 0  to 10 (BV). Detailed questionnaires on sexual risk behaviors and general health were administered at baseline and every 6 months. Every 6 months, a serologic sample was examined for the presence of HIV using HIV enzyme immunosorbent assays, with any discrepant findings being validated by Western blot.The women who were sexually active, post-menarcheal, and who continued in the research for at least 18 months of observation were the focus of this analysis  extends the methods of multivariate statistics which concern n spaces . In partn spaces .v corresponding to eigenvalues j-th FPC of Let q terms q-dimensional linear projection of q FPC, According to the Karhunen\u2013Lo\u00e8ve expansion, it holds that cument}\u03c7 . Thus thcument}\u03c7 .i index a study subject and i and at recording times K is the number of time recordings for each i  in Rakai) for family planning increased the odds of persistent BV in women . Some studies summarized the longitudinal data into cross-sectional proportions of each category. This provided a summary measure of BV disease burden but prohibited the exploration of biological knowledge embedded in the intra-person variability in the Nugent scores and vaginal microbiota , 10. AnoPrior epidemiological studies of BV primarily relied on measurements of samples collected at one or a few time points every a few months apart , 31. SevFrequently sampled longitudinal data have become increasingly available in recent years. Such data greatly expand the information from a single or a few time points of measurements of biomarkers and allow researchers to explore the clinical utility of the whole process of fluctuations of biomarkers in reflecting a disease or health condition. We applied FDA methods to identify vaginal microbiota patterns using the Nugent scores. Compared to traditional longitudinal data methods, FDA is known to perform better in higher dimensions  and can The original Ferraty & Vieu\u2019s method uses the small ball proportions to cluster the functional data. Considering that the proportions have removed information of the values themselves of the functional data, we extended Ferraty & Vieu\u2019s algorithm by further clustering the functional data using other data features, such as the estimated first FPC itself for each subject. The extended algorithm provides a flexible framework of unsupervised learning of frequently sampled longitudinal data to identify biologically or clinically meaningful patterns. The data features to be used in the extended algorithm are chosen by the user, and the number of features to consider should depend on the problem at hand. Using a large number of data features for clustering may not be accepted by the splitting score criterion, or the resulting clusters may not be clinically or biologically interpretable. Our extended algorithm uses a one-feature-at-a-time hierarchical approach instead of clustering using a set of features simultaneously. The latter may be over fitting the data and results in spurious clusters in the presence of many features. With the hierarchical approach, the extended clustering algorithm checks one feature at a time and determines whether the feature is informative for the clustering before proceeding to the next one. This allows informative features to be used in clustering and also allows users\u2019 control of data features to ensure that the non-supervised learning of data can generate scientifically interpretable subpopulations. For example, if the frequently sampled longitudinal biomarker measurements pertain to a degenerative process, then the data feature may include a measure of the rate of decline of the biomarker measurements to inform the clustering process.The clustering methods may also be adapted to characterize disease processes using multivariate frequently sampled longitudinal data. For example, it may be applied to frequenly sampled vaginal microbiota data obtained from higher resolution tools using 16S rRNA gene amplicon sequencing to explore species-specific longitudinal patterns, which may allow identifications of specific pathogenic vaginal organisms with persistent or fluctuating patterns. The original and extended clustering methods are model-free and do not require parametric distribution assumptions. Thus they can be applied to a wide variety of high dimensional time series obtained from other subject areas to study whether intra-person variability and other data features in longitudinal trajectories can identify different biologic or clinical sub-populations.When it is of interest to explore clinical patterns using densely sampled longitudinal data, the hierarchical functional data clustering method can be used for fully data driven unsupervised clustering. The method was applied to the frequently sampled longitudinal Nugent scores to identify different patterns in the natural history of BV in a cohort of Ugandan women. Further risk factor analysis identified demographic and behavioral risk factors associated with persistent BV burden in women. The hierarchical functional data clustering method provides an exploratory data analysis approach for frequent longitudinal data."}
+{"text": "SRXN1 downregulation was accompanied by changes in the DNA methylation level of its promoter and, if so, whether it was correlated with the redox properties of catechins. The impact on DNA methylation profile in HT29 cells treated with different concentrations of five catechins, varying in chemical structures and standard reduction potentials as well as susceptibility to oxidation, was monitored by a methylation-sensitive high-resolution melting technique employing the SRXN1 promoter region as a model target. We demonstrated that catechins, indeed, are able to modulate DNA methylation of the SRXN1 gene in a redox-related manner. The nonlinear method in the statistical analysis made it possible to fish out two parameters (charge transfer in oxidation process oxQ and time of electron transfer t), whose strong interactions correlated with observed modulation of DNA methylation by catechins. Based on these findings, we present a proof-of-concept that DNA methylation, which limits SRXN1 expression and thus restricts the multidirectional antioxidant action of SRXN1, may represent a mechanism protecting cells against reductive stress caused by particularly fast-reacting reductants such as EGC and (\u2212)-epicatechin gallate (ECG) in our study.The role of catechins in the epigenetic regulation of gene expression has been widely studied; however, if and how this phenomenon relates to the redox properties of these polyphenols remains unknown. Our earlier study demonstrated that exposure of the human colon adenocarcinoma HT29 cell line to these antioxidants affects the expression of redox-related genes. In particular, treatment with (\u2212)-epigallocatechin (EGC) downregulated transcription of gene encoding sulfiredoxin-1 (SRXN1), the peroxidase involved in the protection of cells against hydrogen peroxide-induced oxidative stress. The aim of this study was to investigate whether the observed  Plant-borne foods and beverages constitute a rich source of antioxidant phytochemicals such as polyphenols, whose consumption has been documented to bring beneficial effects for human health . Dietaryin vitro and in vivo . Ind. IndE0, ly on E0 . Due to promoter , and maySRXN1 by DNA methylation of its promoter seems a particularly powerful mechanism as this enzyme is necessary for the restoration of activity of one of the most important classes of antioxidant enzymes\u2014peroxiredoxins as well as the reduction of other numerous S-sulfinylated proteins [Altogether, our results that compare redox properties of studied catechins with their impact on DNA methylation summarized graphically in the heatmap included in proteins . Our stuSRXN1 promoter might have been driven by the postulated redox-sensitive cellular response. The demonstrated increased DNA methylation of SRXN1 promoter region by EGC and ECG sheds new light on the epigenetic potential of catechins, which so far has been mainly associated with the impaired maintenance of global DNA methylation patterns as a result of DNMT1 activity inhibition. Our results revealed unexpected interrelations between otherwise seemingly independent phenomena (electrochemistry and epigenetics), indicating that novel, interdisciplinary research approaches are needed to define the cause-and-effect relationship for bioactive food components before their usefulness in epigenetic-based cancer chemoprevention becomes predictable.In conclusion, our study demonstrated that the downregulation of SRXN1 gene transcription by some catechins might be a result of increased DNA methylation level within its promoter. This effect seems to depend neither on the standard reduction potentials of these antioxidants nor on their chemical structures as decisive features but rather on the kinetics of redox reaction. A comprehensive electrochemical characterization of catechins and more advanced dedicated experiments are needed to fully understand whether the changes in DNA methylation level in the"}
+{"text": "The success of the global polio eradication initiative is threatened by the genetic instability of the oral polio vaccine, which can result in the emergence of pathogenic vaccine-derived polioviruses following prolonged replication in the guts of individuals with primary immune deficiencies or in communities with low vaccination coverage. Through environmental surveillance, circulating vaccine-derived poliovirus type 2 was detected in Uganda in the absence of detection by acute flaccid paralysis (AFP) surveillance. This underscores the sensitivity of environmental surveillance and emphasizes its usefulness in supplementing AFP surveillance for poliovirus infections in the race towards global polio eradication. Enterovirus in the family Picornaviridae , wi, wi18], The increasing spread and continued evolution of cVDPVs in countries previously declared polio-free is a concern, raising the question of whether the risk mitigation strategies implemented prior to the \u2018switch\u2019 were sufficiently effective. Detection of polioviruses (cVDPVs) in environmental specimens only is a growing trend and has recently been reported in Ghana  and the"}
+{"text": "Editorial on the Research TopicNovel methodologies in structural interventional cardiology: Case reportsStructural interventional cardiology has rapidly evolved since the innovation of coronary balloon angioplasty in 1977. Having initially been dominated by coronary intervention the field has grown to provide minimally invasive alternatives to traditional surgical procedures for the treatment of a range of cardiovascular diseases. The continuous advances in technology, new devices, procedural strategies, and imaging techniques that have emerged in the field has led to improved patient outcomes, reduced procedural complications, and expanded indications for interventional treatments. Many inoperable patients are now eligible for the correction of structural cardiac defects with benefits in terms of functional capacity and quality of life. At the forefront of innovation are procedures such as insertion of left atrial appendage occlusion (LAAO) devices, transcatheter aortic valve implantation (TAVI) as well as advancements in imaging techniques, such as multidetector computed tomography (MDCT) and three-dimensional (3D) reconstruction . In thisCase Report: Severe Aortic Valve Regurgitation and Pseudoaneurysm in Aortic Valve-Sparing Operation: The usefulness of Multimodality imaging in a Complex Clinical Scenario, by Leonardo Varotto et al. perfectly illustrates this point. The authors presented a case of a patient presenting with two potentially disastrous complications of aortic valve sparing surgery in that of severe aortic insufficiency and aortic arch pseudoaneurysm. They showed how the use of contrast-enhanced computed tomography and its translation into a 3D printed model was able to provide an accurate representation of the complex anatomy of the aortic root aneurysm and aortic root geometry. This enabled the team, with the aid of transoesophageal 3D ultrasound, to efficaciously treat the patient percutaneously with a combination of transcatheter occluder device plus microcoil embolization and transfemoral valve implantation. The use of multimodal imaging and formation of a 3D printed model in this complex case highlights how these techniques can aid in preoperational planning hopefully leading to the reduction of intra- and post-operative complications.A key adjunct to structural interventional advances is the parallel evolution of cardiac imaging techniques and use of novel technologies such as 3D reconstruction. Catheter-Based Closure of a Post-infective Aortic Paravalvular Pseudoaneurysm Fistula with Severe Regurgitation After Two Valve Replacement Surgeries: A Case Report\u201d by Eustaquio Maria Onorato et al. continues the above theme of combining novel interventional and imaging techniques to tackle complex pathologies in patients at prohibitive surgical risk. Here, the authors report a case of a paravalvular pseudoaneurysm fistula (PPF) with severe paravalvular leak (PVL) after infective endocarditis of a bioprosthetic valve causing severe heart failure in a 72 year old female with multiple comorbidities. Again a 3D model is printed this time based on a MDCT reconstruction in order to better understand PPF anatomy and its relationship with the surrounding structures. This allowed for planning of \u201cex vivo\u201d transcatheter implantation of the most appropriate occluding device to limit residual leak and prevent serious complications. Successful implantation of an Occlutech paravalvular leak device was achieved without any intra or postoperative complications perhaps indicating that catheter-based closure of PPF may be a feasible and safe alternative to surgical repair.\u201cTao Chen et al. in their study entitled \u201cOcclusion of Bilobulated Left Atrial Appendage Using the Dual-Watchman Technique: A Long Term Follow-Up Study\u201d provides a good example of this, describing how the heterogeneous anatomy of the left atrial appendage has to date proved an obstacle for LAAO in a certain subset of cases. The authors conducted a retrospective analysis of 330 patients undergoing LAAO with watchman devices and found 7 cases where large bilobulated LAA's were successfully closed with dual watchman devices using one-stop implantation technology. Although a retrospective study with a small sample size, it provides an indicator that a dual device approach is feasible in a patient population with challenging anatomy where single device closure has been ruled out.As shown in the previous cases advanced imaging modalities and 3D reconstruction can be a powerful adjunct to the structural interventional cardiologist. Despite this, complex anatomy can often be prohibitive to traditional interventional methodologies and thus a search for novel techniques is ever ongoing. Case Report: Sapien 3 Transcatheter Heart Valve Embolization: Cause, Management, and Redo\u201d by Mi Chen et al. highlights a rare and challenging complication of TAVI in that of transcatheter heart valve (THV) embolization. The authors go on to describe the subsequent repositioning and successful navigation of the Sapien 3 THV through the aortic arch using a buddy balloon and performing a pullback manoeuvre into the descending aorta on the shoulder of the inflated deployment balloon. A second THV is then implanted with careful post-implantation evaluation.With the ongoing evolution of structural interventional techniques, such as those mentioned in the case reports thus far, the risk of complications inevitably rises. As such novel methodologies to mitigate these complications are as important to highlight in the literature. \u201cXiangfei Haung et al. entitled \u201cDifferential Diagnosis of Fulminant Myocarditis and Acute Coronary Syndromes in the Case of Failure of Coronary Angiography: A Case Report\u201d. The authors present the readers with a case of 34 year old male with fulminant myocarditis whose presentation is complicated by a coronary artery malformation resulting in failure of coronary angiography and thus initial delay in the true diagnosis. As a result of a comprehensive approach including careful history taking, adjunct imaging and supportive measures such as intra-aortic balloon pump insertion and vein-artery extracorporeal membrane oxygenation (ECMO) the patient was successfully treated and discharged home after 27 days in hospital.Finally we finish with a case report by"}
+{"text": "The expected economic burden on the healthcare system because of quarantining patients with monkeypox virusAlshahrani determines the expected economic cost for healthcare systems due to quarantine in the case of the monkeypox virus. A systematic literature review of studies on similar virus outbreaks was performed. The findings affirm that quarantine effectively mitigates the spread of a virus outbreak, but it has high direct and indirect costs that can only be justifiable for a dangerous virus with high mortality. The monkeypox virus presents moderate risk, unlike high-risk diseases for which quarantine is mandatory. The study recommends the introduction of mass vaccination programs and public awareness and sensitization forums to inform the population about the best behavioral practices to curb the spread of monkeypox virus.see page 231 A retrospective study in a city in the Southeastern region of TurkeyCOVID-19 infection during pregnancy. Akg\u00fcl et al evaluate maternal and fetal clinical outcomes in SARS-CoV-2 infected pregnant women during the whole period of the pandemic in a single province in the southeast of Turkey. They concluded that in the 3rd trimester of pregnancy, obesity and hypothyroidism were found to be risk factors for severe-critical cases of COVID-19 infection, and the clinical course was more severe with a higher rate of mortality in the recent period of the pandemic.see page 268A cross-sectional study in Saudi populationSelf-care practices among heart failure patients. Aljohani describes self-care practices among Saudi heart failure (HF) patients and identify sociodemographic characteristics contributing to self-care practices. He concluded that Self-care practices in this study showed higher scores than those reported in international studies. Further studies are warranted to explore everyday self-care needs and challenges among HF patients.see page 277Patellar height changes after treatment of tibia plateau fractures. A radiological analysisDo\u011fan et al determine the impact of tibial plateau fractures on patellar height and the factors affecting this impact in in a retrospective prognostic study. They concluded that Long-term functions of tibial plateau fractures should be evaluated not only with a painless range of motion but also with patellar height. It should be noted that the Luo classification, which evaluates the plateau 3-dimensionally, may be associated with changes in postoperative patellar height valuessee page 306"}
+{"text": "The foundation for long-term functional outcomes of the burn patient is laid in the Burn ICU. Nursing plays a vital role in the Rehabilitation Plan of Care for patients with burn injuries. As the member of the critical care team who is most present with the patient around the clock, the burn nurse is essential for carrying over and following through with interventions initiated by Occupational Therapy, Physiotherapy and Speech & Language Pathology. Without cohesion and partnership on the interdisciplinary burn team, the Rehabilitation Plan Care cannot succeed. In the midst of the COVID-19 pandemic, burn nursing turnover rates are higher than pre-pandemic rates. Burn Centers are relying on travel nursing contracts or novice nurses fresh out of school to provide specialized burn care. Our center developed a didactic and \u201chands on\u201d learning initiative to improve collaboration between the Burn Nursing and Burn Physical Medicine departments in order to equip the critical care burn nurses to actively participate in the Rehabilitation Plan of Care. \u2022 Collaboration between Burn Nursing leadership and Burn Physical Medicine leadership to examine ABA nursing competencies pertaining to the Rehabilitation Plan of Care \u2022 Team of PTs/OTs identified to develop curriculum based off these competencies \u2022 Learning objectives set \u2022 Hands on training program developed \u2022 8 small group training sessions completed \u2022 Competency assessments completed \u2022 7 question pre- & post-testing completed to assess learning \u2022 Opportunity for input from participants for quality improvement104 Burn ICU nurses participated in the classes. 99% passed competency assessment.Improvements between Pre- and Post- Test scores demonstrate learning of desired knowledge and skills.Feedback assessment from RNs regarding value of course participation & ongoing need for collaborative training (most common was related to positioning & compression)104 burn ICU nurses participated in hands-on, didactic training related to nursing competencies related to the Rehabilitation Plan of Care. Data is now being collected regarding follow through of knowledge and skills implementation.This project showed the improvement that can be made in regards to the cooperation of burn ICU nurses with the rehabilitation plan of care."}
+{"text": "Electronic health record (EHR)\u2013integrated digital personal health records (PHRs) via Fast Healthcare Interoperability Resources (FHIR) are promising digital health tools to support care coordination (CC) for children and youth with special health care needs but remain widely unadopted; as their adoption grows, mixed methods and implementation research could guide real-world implementation and evaluation.This study (1) evaluates the feasibility of an FHIR-enabled digital PHR app for CC for children and youth with special health care needs, (2) characterizes determinants of implementation, and (3) explores associations between adoption and patient- or family-reported outcomes.This nonrandomized, single-arm, prospective feasibility trial will test an FHIR-enabled digital PHR app\u2019s use among families of children and youth with special health care needs in primary care settings. Key app features are FHIR-enabled access to structured data from the child\u2019s medical record, families\u2019 abilities to longitudinally track patient- or family-centered care goals, and sharing progress toward care goals with the child\u2019s primary care provider via a clinician dashboard. We shall enroll 40 parents or caregivers of children and youth with special health care needs to use the app for 6 months. Inclusion criteria for children and youth with special health care needs are age 0-16 years; primary care at a participating site; complex needs benefiting from CC; high hospitalization risk in the next 6 months; English speaking; having requisite technology at home ; and an active web-based EHR patient portal account to which a parent or caregiver has full proxy access. Digital prescriptions will be used to disseminate study recruitment materials directly to eligible participants via their existing EHR patient portal accounts. We will apply an intervention mixed methods design to link quantitative and qualitative  data and characterize implementation determinants. Two CC frameworks  and 2 evaluation frameworks  provide theoretical foundations for this study.Participant recruitment began in fall 2022, before which we identified >300 potentially eligible patients in EHR data. A family engagement panel in fall 2021 generated formative feedback from family partners. Integrated analysis of pretrial quantitative and qualitative data informed family-centered enhancements to study procedures.Our findings will inform how to integrate an FHIR-enabled digital PHR app for children and youth with special health care needs into clinical care. Mixed methods and implementation research will help strengthen implementation in diverse clinical settings. The study is positioned to advance knowledge of how to use digital health innovations for improving care and outcomes for children and youth with special health care needs and their families.ClinicalTrials.gov NCT05513235; https://clinicaltrials.gov/study/NCT05513235DERR1-10.2196/46847 Care coordination (CC) is an essential intervention for children and youth with special health care needs that involves clinicians and patients or families collaborating to coordinate numerous health and related services across multiple service sectors within the \u201ccomplex care ecosystem\u201d of each child and youth with special health care needs . ChildreTo fill CC gaps, some families of children and youth with special health care needs have developed strategies to organize details of their child\u2019s lifelong health records  ,12; howeDespite their potential as digital health innovations and the clinical need for solutions for children and youth with special health care needs, FHIR-enabled digital PHRs have not yet been broadly adopted due to logistical and research challenges. Key logistical challenges include technical barriers, funding and infrastructure support, and lack of end user engagement in co-design . In the The objectives of this study are to (1) evaluate the feasibility of a digital PHR mobile app with FHIR-enabled EHR integration to coordinate care for children and youth with special health care needs, (2) identify and describe barriers and facilitators (determinants) of mobile app implementation, and (3) explore associations between mobile app adoption and patient or family-reported outcomes.This study protocol describes a nonrandomized, single arm, prospective feasibility trial of a FHIR-enabled digital PHR mobile app used as a CC tool by families of children and youth with special health care needs in primary care settings for a 6-month period. We will apply an intervention MMR study design  within tThe intervention under evaluation in this study is a FHIR-enabled digital PHR mobile app (Caremap). The app is a digital health innovation designed to facilitate family-centered CC for children and youth with special health care needs through several key features. One key CC feature of the app is FHIR-enabled access to structured data elements from the child\u2019s EHR chart , thereby allowing families to view health information as seen by their child\u2019s primary care provider (PCP) in the EHR , left. ACore app features were developed to maintain the locus of control for the child\u2019s health information with their families; development of the clinician dashboard involved input from practicing clinicians. After initial app development was completed, parents of children and youth with special health care needs with established pediatric specialty care within our health system and a sample of parents of children and youth with special health care needs with care external to our health system tested an early app prototype . These eThis study will be conducted at a large health system in the southern United States that includes a tertiary care children\u2019s hospital and multiple primary care pediatric practices using an enterprise-wide EHR system (Epic). The study will recruit adult parents or guardians of children and youth with special health care needs aged 0-16 years old with primary care established within a network of pediatric primary care sites that are academically affiliated with our institution.PCPs will be recruited as study participants in order to include clinician perspectives on the feasibility of a dashboard as a companion to the mobile app. The clinician dashboard is accessible from within the EHR and includes a summary of information recorded by families on their personal device and synchronized with the EHR, thereby providing PCPs with view-only access to family-reported longitudinal health insights at the point-of-care during clinical visits.Eligibility criteria for study participation will include (1) patient age of 0-16 years, (2) primary care attribution to a participating site, (3) PCP clinical determination that the child has complex needs that can benefit from additional CC support, (4) child is at high-risk for hospitalization in the next 6 months defined using a novel EHR-based machine learning clinical predictive model , (5) EngA 3-step process  will be The second step in recruitment\u2014assessment of clinical eligibility\u2014will be an assessment by each potentially eligible child\u2019s PCP to determine whether the child has complex needs that can benefit from additional CC support. If the PCP determines that more CC support would be beneficial, the study will be introduced to parents of children and youth with special health care needs during an upcoming PCP office visit or via a mailed recruitment letter.The third, final step of recruitment will be direct delivery of detailed study materials  as a digital prescription . The digGuiding this study are 2 categories of extant theoretical frameworks focused on CC and evaluation . The 2 CTo complement these 2 CC frameworks, in this study we are also applying 2 theoretical frameworks focused on evaluation: the Technology Acceptance Model (TAM) and the Consolidated Framework for Implementation Research (CFIR). The TAM is a theoretical model widely applied in digital health research to explain adoption and use of new technologies by end users ; the TAMDespite potential for integration of CFIR with the TAM within digital health research , we are Selection of primary and secondary study outcome measures was guided by operationalizing the TAM-3 and CFIR theoretical frameworks as a study-specific logic model of hypothesized associations between mobile app use and process, proximal, and distal outcomes . Our stuA summary of quantitative measures is shown in Qualitative measures, data collection, and analytical procedures are summarized in A second source of qualitative data will be family engagement panels (FEP) with a group of parents of children and youth with special health care needs purposively sampled to reflect a diversity of lived experiences. FEPs are modeled after Community Engagement Panels, a consultative model that engages patients, families, and other community stakeholders for project-specific input . Rooted To address the study aim of identification and description of implementation determinants, we will use the MMR data integration method of embedding to link quantitative and qualitative data collection and analysis at multiple points within the intervention MMR study design  ConsisteThe study protocol has been reviewed and approved by our institutional review board Duke Health (Pro00109514). Informed consent for eligible parents or caregivers will occur on their personal device. Eligible participants will review and sign the written electronic informed consent form prior to beginning the study. Participant confidentiality will be protected by collecting only information needed to assess study outcomes, and study data used for final summative quantitative analyses will be deidentified. All qualitative interviews will be conducted by a trained interviewer from the study team on the telephone, via video call (Zoom), or in-person. Interviews will be video-recorded or audio-recorded and transcribed; if an interviewee wishes to not be recorded, detailed notes will be taken instead. Parent or caregiver participants will receive US $50 compensation for completion of surveys ; participants who complete an interview will receive an additional US $50 compensation.Participant recruitment began in October 2022. We expect that data analyses will be completed by early 2024. We anticipate that quantitative and qualitative findings will address primary and secondary outcomes outlined in Analyses of pretrial quantitative and qualitative data gathered to-date have informed study procedures and design. A pretrial FEP was conducted in fall 2021 with 4 parents of children and youth with special health care needs. Formative qualitative feedback gathered during this first FEP informed changes to app design and user-facing materials, monetary incentives for study participation, and recruitment procedures. An initial EHR data analysis was conducted in January 2022 to estimate the size of the eligible population for the study. From a population of >40,000 children with primary care attributed to the 3 participating PCP sites, our preliminary analysis identified 317 patients who met all inclusion criteria based on available EHR data; it is expected that this sample will be of sufficient size to enroll the goal of 40 study participants to use the mobile app.We have used these preliminary quantitative and qualitative findings to refine study recruitment procedures. Specifically, based on feedback from parents of children and youth with special health care needs during the first FEP, recruitment procedures were revised to introduce the study to eligible patients directly during a PCP office visit instead of via automated web-based patient portal electronic messaging. Additionally, detailed patient-facing videos and written tutorials were developed in response to family requests for user-friendly onboarding materials. Quantitative estimate of the potentially eligible patient population led to procedural revisions so that PCPs will be familiar with study aims (to facilitate introduction of the study during office visits) and study materials can be delivered via digital prescription in order to better align with real-world clinical workflows.Findings from this study will characterize the feasibility and implementation barriers and facilitators (determinants) for a digital PHR mobile app used by parents of children and youth with special health care needs for CC in primary care settings. Novel study procedures that can contribute to the digital health literature include the protocol\u2019s use of digital prescriptions for participant recruitment. Additionally, application of MMR and implementation research methods offers a novel methodological approach that could address recent calls for innovative and pragmatic evaluation of digital health solutions .This study protocol describes a pragmatic approach for integrating theory into digital health study design by combining the established CFIR and TAM-3 frameworks ,32,33,38Similar to implementation science, methodological approaches from the MMR field that systematically integrate quantitative and qualitative data ,22 can gIn addition to integrating MMR and implementation science methods into digital health research, there are opportunities to streamline study procedures. For this protocol in particular, the use of digital prescriptions will be used to facilitate dissemination of study materials directly to eligible participants via existing web-based patient portal accounts. This approach may help improve study workflow efficiency and mitigate infectious risk in the face of the ongoing COVID-19 pandemic by reducing study personnel\u2019s reliance on in-person recruitment. Digital prescriptions are also positioned for future studies where they could facilitate scaled recruitment via automated delivery of study materials to large numbers of eligible patients identified by EHR data. Although a digital prescription-based approach is promising for study recruitment, caution should be exercised. More efforts are needed to close the digital divide , mitigatThis study has several limitations that should be acknowledged, including the study\u2019s single center design and limited size and scope. Smaller scope is necessary at this early stage to focus on feasibility and to gather in-depth feedback from participants that can inform subsequent app improvements. Additionally, our inclusion criteria that study participants have existing internet access, a digital device, and an active web-based patient portal account may introduce barriers to research participation. Factors that could mitigate these barriers include national-level data that demonstrated that 81% of US adults own a smartphone  and dataDigital health tools have the potential to improve care and outcomes for children and youth with special health care needs; however, the evidence base is early in development. The methodological rigor of early phase digital health studies could be enhanced by incorporating novel study procedures and methods from research fields outside of traditional pediatric clinical trials. By doing so, strengthened conclusions from early phase digital health studies will be positioned to serve as foundations for future multisite prospective trials that measure effectiveness for health and implementation outcomes. Ultimately, these future directions can serve to accelerate the pace of investigation so that clinicians and families of children and youth with special health care needs will have the evidence base needed to determine the impact of new digital health tools on patient and family-centered outcomes.This study will evaluate the feasibility of integrating a FHIR-enabled digital PHR mobile app as a CC tool for children and youth with special health care needs into clinical care. Application of MMR and implementation science methods is anticipated to facilitate understanding of implementation determinants in primary care settings. The findings of this study are positioned to inform future pragmatic trials that can further advance knowledge of how to use digital health innovations for improving care and outcomes for children and youth with special health care needs."}
+{"text": "Editorial on the Research Topic[Application of stem cells in the treatment of myocardial infarction]Chen et al. with a follow-up period up to five months has demonstrated a significantly larger reduction in infarct size as well as better preservation of left ventricular function in animals having received left intracoronary arterial administration of human bone marrow-derived mesenchymal stem cells 90\u2005min after infarct induction compared to those without stem cell treatment, thereby paving the way for further clinical trials.Myocardial infarction remains one of the top killers in the developed world. In contrast to conventional coronary intervention in the treatment of ischemic heart disease, the use of stem cells has unleashed the therapeutic potential of a novel biological approach. Taking into account the similarity in cardiac anatomy and function between pigs and humans, a preclinical study using a porcine balloon-induced myocardial infarction model by Lai et al. identified functional maturation of stem cells and the application of biomaterials as potential hotspots in this research area, further highlighting the mutual positive influences between tissue engineering development and the clinical application of stem cells.Moreover, given that the goal of cardiovascular tissue engineering is to establish functional scaffolds with biologically compatible materials to provide a cellular environment for restoring the functions of damaged tissues or organs, the therapeutic potential of stem cells against myocardial infarction and ischemic cardiomyopathy has triggered the development in this discipline. A bibliometric analysis of 2,273 documents in the field of cardiovascular tissue engineering published in recent three decades conducted by Kawamura et al., which reported three patients with severely compromised cardiac function, revealed an improvement in heart failure symptoms without accompanying transplanted cell-related adverse events after one-year follow-up. Intriguingly, the authors also noted improved left ventricular contractility as well as myocardial blood flow in the three patients following three-month immunosuppressant administration. The results, therefore, support the safety of iPSC use in patients with severely compromised heart functions although further clinical studies are warranted to reinforce their findings.Besides, the clinical applicability of stem cell therapy is underscored by its ubiquity. In addition to common sources such as adipose tissue, blood, and bone marrow, induced pluripotent stem cells (iPSCs) generated directly from somatic cells have sparked a keen interest in research because of the promising implication of an unlimited supply of stem cells. Nevertheless, there have been concerns over the safety of iPSCs due to their malignant potential. To address this issue, a human clinical trial examined the feasibility of allogeneic induced pluripotent stem cell (iPSC)-derived cardiomyocyte patch in the treatment of ischemic cardiomyopathy. That study by Saito et al. attempted to test the feasibility of non-invasive in vivo tracking of transplanted cardiomyocytes derived from human iPSCs using the technique of nuclear medicine imaging. Human iPCSs, after being transduced with sodium/iodide symporter (NIS), were subcutaneously implanted into the animals. The resulting teratomas were successfully detected with single photon emission computed tomography (SPECT/CT) after six weeks, thereby reinforcing the applicability of this technique in tracing the implanted stem cells. Nevertheless, further studies are required to assess the effect of symporter transduction on stem cell function as well as the safety of radioactive tracer use.Another question regarding the use of iPSCs is their fate after administration. Utilizing an immunodeficient rat model, Luo et al. investigated the role of \u03b3\u03b4T cells  in the process. The authors reported that IL-17A, which is the core cytokine of \u03b3\u03b4T-mediated immune response, could be protective against cardiac ischemia-reperfusion insult. The finding is of potential clinical interest as it bears significant immunological implications that may guide the direction of the development of appropriate stem cell strategies for treating myocardial infarction as well as the subsequent ischemia-reperfusion injuries that adversely impact the prognosis of this patient population. The intricate immunological network underlying cellular protection against myocardial ischemic diseases warrants further explorations. One further step that needs to be taken to complete the jigsaw puzzle is a deeper understanding of the biological mechanisms underpinning the observed stem cell therapeutic efficacy. Ischemia-reperfusion injury, the severity of which is proportional to the duration of ischemia of an organ followed by a restoration of blood flow, is known to involve the activation and release of inflammatory mediators and is common in patients experiencing myocardial infarction. In addition to the ischemic injuries from the initial myocardial infarction, ischemia-reperfusion contributes to further myocardial damage after resuming the patency of the obstructed coronary artery. To elucidate the underlying immunological mechanism, In conclusion, as evidence accumulates regarding the biomolecular mechanisms involved in the therapeutic effects of stem cells against ischemic heart disease, it is foreseeable that stem cell therapy will have a significant part to play in the treatment of myocardial infarction either alone or in combination with other interventional strategies. Notwithstanding the apparently encouraging outcomes from previous studies, further large-scale clinical trials are needed to consolidate the role of stem cell therapy as a routine evidence-based clinical practice."}
+{"text": "Pmmn borophene for incident infrared photons at room temperature. This work highlights the potential of two-dimensional tilted Dirac cone materials as a platform for tunable broadband optovalleytronic applications.Quasiparticles emerging in crystalline materials can possess a binary flavor known as the valley quantum number which can be used as a basis to encode information in an emerging class of valleytronic devices. Here we show that two-dimensional semimetals with tilted Dirac cones in the electronic band structure exhibit spatial separation of carriers belonging to different valleys under illumination. In stark contrast to gapped Dirac materials this optovalleytronic phenomenon occurs in systems with intact inversion and time-reversal symmetry that host gapless Dirac cones in the band structure, thereby retaining the exceptional graphene-like transport properties. We thus demonstrate that optical valley separation is possible at arbitrarily low photon frequencies including the deep infrared and terahertz regimes with full gate tunability via Pauli blocking. As a specific example of our theory, we predict tunable valley separation in the proposed two-dimensional tilted Dirac cone semimetal 8- The most celebrated example are electrons in graphene which behave as massless relativistic quasiparticles described by two inequivalent Dirac cones in the electronic band structure  typically suffer from low electron mobility that hampers the efficiency of information transport across the device and ii) due to the presence of the gap it is inherently impossible to obtain optical control at low photon frequencies.The pseudo-relativistic nature of electrons bestows graphene with exceptional transport properties in the form of high electron mobility stemming from the suppression of back-scattering resulting from the Klein tunneling phenomenon15. As this mechanism of optical valley control is enabled by asymmetry in the band structure, the exciting light need not be polarized. Furthermore, the degree of valley polarization can be controlled via Pauli blocking which in 2D semimetals is readily tuned with a back gate. The spatial separation of photoexcited carriers belonging to different valleys results in an unequal valley population at opposite sides of the illuminating light spot. It is possible to reverse the sign of the valley polarization at a given side of the light spot by moving the Fermi energy from above to below the Dirac point; this can be practically achieved by tuning a back-gate voltage. We suggest that this effect can be detected by measuring the degree of circular polarization of the edge luminescence in a nearby gapped material16, which ideally could be the same material with locally broken inversion symmetry.In this work we provide a solution to these problems: demonstrating the spatial separation of photoexcited carriers at arbitrarily low photon energy belonging to different valleys in two-dimensional (2D) semimetals hosting tilted gapless Dirac cones in the electronic band structure see Fig.\u00a0. In starPmmn borophene19, an organic salt 20 and many more31. As a case study of our work we demonstrate tunable valley separation in the candidate type-I Dirac cone material 8-Pmmn borophene upon illumination of infrared photons at room temperature. In type-II Dirac cone materials, the super-critically tilted band structure results in the perfect spatial separation of valley carriers for a broad frequency range of unpolarized photons for arbitrary Fermi energies. As an extension to our theory we show that type-III Dirac cones will display enhanced spatial separation of valley carriers and emission of highly polarized terahertz photons via hot luminescence aided by the inclusion of carrier scattering.Tilted Dirac cones can be classified in to one of three varieties defined by the degree of tilt: sub-critically tilted (type-I) with closed elliptical isoenergy contours, critically tilted (type-III) with open parabolic isoenergy contours and super-critically tilted (type-II) with open hyperbolic isoenergy contours. Two-dimensional materials hosting tilted Dirac cones are an ever growing family with candidate materials including 8-q the radial wavevector and 32.We consider a 2D Dirac semimetal with tilted Dirac cones in the electronic band structure described by the Bloch Hamiltoniani) Initial and final states with wavevector ii) The transition rate describes the likelihood of an absorption event occurring at a given wavevector. For linearly polarized photons the transition rate is proportional to the absolute value squared of the expectation value of the velocity operator projected along the axis of polarization . We can now derive the squared velocity matrix element yielding37. The velocity matrix element is equivalent to that of non-tilted cones and hence is independent of both valley (iii) For an absorption event to occur we must ensure that the initial state is occupied and the final state is empty to avoid Pauli blocking. We define these conditions with the Fermi-Dirac distributions e) and holes (h) with Boltzmann constant T. Crucially, the regions of Pauli blocking are valley . This discovery sparked a desire for valleytronic components that in conjunction with the valley Hall effect could lead to valley-sensitive logic gates for classical and quantum computing applications7. In our work we demonstrate the spatial separation of valley carriers away from the light spot in gapless Dirac materials with tilted Dirac cones. Our discovery paves the way to the realization of novel valleytronic devices benefiting from the superior transport properties of massless Dirac fermions.The realization of the valley-polarized currents via the valley Hall effect provided the elementary building block for valleytronic devices in gapped Dirac cone materials (see review articles44. Combining these transport techniques with the optical spatial separation of valley carriers proposed in our work could enable the design of valleytronic components such as valley filters and switches in gapless materials. It may also be possible to further direct the propagation of valley carriers across graphene-based interconnects based on electrostatic waveguides46, quantum wire leads47 or gated junctions in externally applied fields48. Furthermore, the spatial separation of valley carriers in gapless tilted Dirac cone materials could be combined with valley-sensitive components of gapped Dirac cone materials such as valley transistors49 or decoding the valley index via emission of circularly polarized light16. This would require a detailed understanding of the transport phenomena occurring at the interface between gapless and gapped Dirac cone materials. It is well-known that placing graphene on a hexagonal boron nitride substrate induces a superlattice structure inducing local regions with pseudo-gaps52\u2014a similar technique for tilted Dirac materials should enable the seamless transport of valley carriers between gapless and gapped regions in the spectrum allowing valley index measurement. Whilst we suggest the use of a gapped region of the material to decode the valley index, before measurement, information transfer across the device will benefit from the superior transport properties of massless Dirac fermions as well as gate-tunable optical valley control. Lastly, the theoretical and computational predictions of two-dimensional materials hosting massless tilted Dirac cones are rapidly growing in number31. The experimental efforts aiming at realizing these materials are catching up55. We hope that the prospect of optovalleytronics put forward in our work will stimulate further research into massless tilted Dirac cone materials.With the recent burst of interest in massless tilted Dirac cone materials there have been several theoretical works investigating the valley-dependent transport of carriers traversing gated junctions, waveguides and external fieldsSupplementary Information."}
+{"text": "Diagnostics require precision and predictive ability to be clinically useful. Integration of multi-omic with clinical data is crucial to our understanding of disease pathogenesis and diagnosis. However, interpretation of overwhelming amounts of information at the individual level requires sophisticated computational tools for extraction of clinically meaningful outputs. Moreover, evolution of technical and analytical methods often outpaces standardisation strategies. RNA is the most dynamic component of all -omics technologies carrying an abundance of regulatory information that is least harnessed for use in clinical diagnostics. Gene expression-based tests capture genetic and non-genetic heterogeneity and have been implemented in certain diseases. For example patients with early breast cancer are spared toxic unnecessary treatments with scores based on the expression of a set of genes . The ability of transcriptomics to portray the transcriptional status at a moment in time has also been used in diagnosis of dynamic diseases such as sepsis. Gene expression profiles identify endotypes in sepsis patients with prognostic value and a potential to discriminate between viral and bacterial infection. The application of transcriptomics for patient stratification in clinical environments and clinical trials thus holds promise. In this review, we discuss the current clinical application in the fields of cancer and infection. We use these paradigms to highlight the impediments in identifying useful diagnostic and prognostic biomarkers and propose approaches to overcome them and aid efforts towards clinical implementation. Precision diagnosis recognises the individuality among patients in their clinical pathway by the simultaneous analysis of multimodal data with artificial intelligence . PrecisiThere is an unprecedented abundance of heterogenous data available at the clinical  and molecular (-omic databases) level, but occasionally phenotypic information is incomplete to assist interpretation of high through-put data . The intIn the era of precision medicine, misdiagnosis is still common in clinical practice. In a US national epidemiologic study, serious diagnostic errors resulting in significant harm were higher for certain conditions such as spinal abscess, aortic aneurysm and dissection and lung cancer  . A gold This narrative review attempts to summarise the potential benefits and challenges of implementation of transcriptomic-based technologies into clinical settings. Cancer (in particular breast cancer) and sepsis are the two areas where gene expression tests have been developed from bulk RNA exploration. We use these paradigms to highlight the impediments in identifying useful diagnostic and prognostic biomarkers and propose ways to circumvent difficulties in the translational pathway.The transcriptome is the total set of expressed RNA in a cell or population of cells at a specific time point. Mature messenger RNA (mRNA), which is the interim carrier of information between the genome and protein, is transcribed from a very small fraction (less than 2% to 3%) of cellular DNA . MultiplRNA is the most dynamic cellular component regulating gene expression through complex processes including transcription, maturation and degradation . TranscrTechnological advancements have enhanced our understanding of the transcriptome. Reverse transcriptase polymerase chain reaction (RT-PCR) is considered a gold standard for detecting qualitatively and quantitatively a limited number of transcripts . MicroarGene expression profiling provides an enormous amount of high-resolution data from a single experiment. The size of the human transcriptome remains debatable with the majority of it referred to as \u201cdark matter\u201d because its function is unknown . RNA-seqOver 100 genetic tests for 30 conditions in the field of oncology, haematology, genetic disorders and pharmacogenetics, have received FDA approval to date. Less than ten tests are based on RNA measurement and only four utilise gene expression profiles with more than two RNA targets .in vivo variability within a condition at a particular time-point and among patients. The hallmark of acute lymphoblastic leukaemia (ALL), for instance, is numerous genetic aberrations stratifying patients into prognostic and therapeutic groups . However, multiple mutations identified at the genome level may not be contributing to the disease. Transcriptome sequencing characterises clinically relevant genomic alterations and variants in real time with higher sensitivity compared to whole-genome sequencing and it has been crucial in the discovery of novel subtypes and therapy tailoring . Gene expression studies identified the Philadelphia chromosome-like ALL subtype and the downstream involvement of kinases guiding the use of tyrosine kinase inhibitors (TKI) .Molecular diagnostics focusing on the genome suffer from a limited ability to reflect accurately the Transcriptomics is explored as a complementary method to genomic testing for precision-based treatments in cancer patients . The WorLiquid biopsy of extracellular RNA (exRNA) has been embraced as a promising tool for screening and disease monitoring purposes and as an alternative to invasive methods of diagnosis such as tissue biopsy . AlthougIn breast cancer, patient stratification based on expression of tumour markers  has guided treatment strategies for over 30\u00a0years  laying tCommercially available assays, such as Oncotype DX , MammaPrint (Agendia), EndoPredict (Myriad Genetics) and Prosigna (Nanostring Technologies) are endorsed by the UK National Institute for Health and Care Excellence (NICE) and international guidelines . ExpressThe development of Oncotype DX was a gradual process involving the use of data from large clinical studies and diligent address of issues . Due to Oncotype DX and the Decipher Genomic Classifier  have been shown to be cost-effective approaches for guidance of treatment decisions . This reFollowing on from the success of the oncotype Dx for early breast cancer, the Oncotype DX Genomic Prostate Score has been developed on the same principles and similar processes . It aimsDisease heterogeneity is a major caveat in the design of diagnostic biomarkers. Inter-assay comparisons revealed discordance in prognostic performance of gene expression-based tests for stratification of patients with early breast cancer . These dHeterogeneity at the tissue level is multi-layered and not confined to the oncogenic cells. Neoplastic cancer cells are nurtured by neighbouring stromal cells comprising the tumour microenvironment (TME). A diverse community of tumour infiltrating immune cells is a major component of the stromal microenvironment exerting both beneficial and detrimental effects . Growingin silico deconvolution ; and\u2022 \u2022 gene set enrichment analysis  .By contrast, gene expression profiling coupled with computational algorithms can characterise cell composition of complex tissues . Many toDeconvolution is based on a linear model of the expression of a gene in the different cell types. Digital dissection of the tumour into the relative fractions of cell types is estimated against a library of cell-specific expression signatures (reference signature or matrix). The matrix appears rigid considering the diversity of infiltrating immune cells  among tissues and cancer stages . Refinem+ tumour infiltrating lymphocytes is well established in melanoma, renal and non-small cell lung cancer and it has guided the use of immune check point inhibitors (ICIs)  CD8s (ICIs) . Tumour-s (ICIs) .Immune response to infection is initiated by a \u201cgenomic storm\u201d of both pro-inflammatory and anti-inflammatory cytokines expressed concomitantly . In sepsTo address individual variation in the response to sepsis, a multi-layered approach, including at the molecular level, for stratification in treatment subgroups is required. As a proof-of-concept, machine learning algorithms which classify patients based on routine clinical data have been shown to accurately predict clinical outcomes and sepsis onset . MachineTranscriptomic-based real-time subclassification of patients has been developed and validated in individual studies . The KniThe Molecular Diagnosis and Risk Stratification of Sepsis (MARS) project identified four endotypes (Mars1\u20134) in patients with sepsis admitted to ICU in the Netherlands . BiomarkPaediatric patients with septic shock were categorised into three groups based on a 100-gene set microarray-derived signature . Two A . The autn = 1,300) identified three clusters which were descriptive of underlying molecular pathways, the Inflammopathic, the Adaptive and the Coagulopathic  and the transfer of transcriptomics knowledge to routine clinical care may be seen in the near future  and complex mathematical algorithms resulting in computational chaos. Hence, findings require vigorous confirmation with the use of conventional methods to monitor  processes or validate results technically and clinically. To this point, study design is paramount. Discovery studies should aim to address specific and clinically relevant questions with patient stratification into prognostic and/or treatment groups through novel diagnostic tools which outperform standard practice. Validation should be driven by large prospective randomised clinical trials and population-based studies. Our increasing knowledge of the properties of the transcriptome and its regulators is our ally in all steps of the journey of developing improved diagnostic tools . Breast"}
+{"text": "Imaging in the freely moving animal gives unparalleled access to circuit activity as the animal interacts with its environment in a self-guided way. Over the past few years, new imaging technologies have enabled the interrogation of neuronal populations located at any depth of the cortex in freely moving mice while preserving the animal\u2019s behavioral repertoire. This commentary gives an updated overview of the recent advances that have enabled the link between behavior and the underlying neuronal activity to be explored. This is an important constraint and requires not only that the total weight of the microscope is well below 10% of the animals\u2019 weight but also that head-motion is not restricted. To achieve this a key challenge in the design of head-mounted microscopes is the management of cable-bundle flexibility.,,\u2013,Recent advances in remote focusing mechanisms for head-mounted microscopes have enabled changes in the imaging plane depth during free behavior,iber tip . This wo,Head-mounted microscopes allow for long-term recording from hundreds of cortical neurons over multiple days, and they can sample from neuronal populations spread throughout the cortical depth during a wide range of complex behaviors. Although specific distortion issues of miniature optics and scanners have been recently addressed,"}
+{"text": "Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality in developed countries  and encoIn the Research Topic\u2014\u201dThe Role of Circulating Immune Mediators in the Crosstalk Between Cells of the Immune System and Cardiovascular System in CVDs\u201d, we provided a platform for exposing the main advancements in the ongoing CVD research. Six papers including both reviews and original articles are published in the volume.Li et\u00a0al. described the role of the endothelial glycocalyx (eGCX) in lung diseases mainly focusing on the hepatopulmonary syndrome (HPS). The eGCX is a carbohydrate-rich layer lining the vascular endothelium. It is formed by soluble plasma components, bound together either directly or via soluble proteoglycans and/or glycosaminoglycans. The composition of eGCX is dynamic due to enzymatic degradation, de novo biosynthesis of new molecules and recruitments of soluble molecules from the bloodstream  in a large cohort of ASCVD individuals. Of note, the SII combines the neutrophil/lymphocyte and platelet/lymphocyte ratios thus taking into account both immune and non-immune cells involved in the pathogenesis of atherosclerosis  causes postoperative atrial fibrillation (POAF) via two parallel mechanisms. They previously reported that IL-6 predisposes to atrial fibrosis and fibrillation by inducing cardiac fibroblast activation  release TF enriched EMVs (TF-EMVs) that target monocytes and induce their differentiation into EC-like cells (A new frontier of inflammation-correlated circulating factors is represented by the release of extracellular microvesicles (EMVs). EMVs could be characterized by the presence of tissue factor (TF) on their external surface that is able to guide them to specific target tissues. ke cells . With thThis Research Topic highlighted the complexity of the interaction between circulating inflammatory mediators and CVDs. Interestingly, the papers published in the current volume cover the study of this interaction in distinct pathological conditions that affect eventually the cardiovascular system. Even though the overall big picture leads to a common take home message that focus the attention on inflammatory mediators as putative prognostic and pathogenic co-factors, the extension to new direct and undirect mechanisms played by distinct cytokines point out to the necessity of further studies.AA, VB and AR wrote and edited the manuscript. All authors contributed to the article and approved the submitted version."}
+{"text": "A COVID-19 vaccine awareness campaign conducted by Sudanese doctors helped to mitigate vaccine hesitancy among Sudanese diaspora groups in the United Kingdom. Diaspora health care professionals can assist in mitigating COVID-19 vaccine hesitancy for members of their respective diaspora communities who share similar ethnocultural characteristics and societal environments.The campaign\u2019s diversification of speakers, methods, and educational platforms coupled with constant reinforcement of positive messages were critical to harnessing motivation among diaspora minorities with an engendered feeling of mistrust in the vaccine development and deployment process.The unmediated interaction and crossover of false information between groups of the same ethnic and cultural backgrounds living abroad and those living in their home countries impacts global vaccine uptake and requires attention.The use of health care professionals from the same societal and cultural background to alleviate vaccine hesitancy among ethnic minorities should receive more support and investigation. People from ethnic minority groups are at risk of adverse sequelae of COVID-19, but their vaccine acceptance and enrollment rates remain suboptimal. Diaspora communities are unique in that they continue to engage in epistemic networks related to vaccination with dwellers in their country of origin. We describe the COVID-19 vaccine awareness campaign we conducted from January 2021 to November 2021 for Sudanese diaspora groups in the United Kingdom and the various techniques and methods used by health care professionals from the same ethnocultural background to address vaccine reluctance among this cohort. We explore the impact of our joint efforts with local authorities in Sudan to overcome the initial barriers to the national vaccination program in Sudan. The influence of the intercommunication between the diaspora and their relatives at home regarding COVID-19 vaccine misinformation is also discussed. Finally, we highlight these observations as key areas for future research to improve the global impact of vaccine deployment in pandemic situations. While the literature generally refers to groups reluctant to receive the COVID-19 vaccine as \u201chesitant,\u201d emerging evidence suggests that those who are \u201ccompletely resistant\u201d constitute a distinct group from the hesitant or indecisive cohort.Understanding the complex continuum of vaccine hesitancy is essential to appreciate why awareness campaigns may not always lead to vaccine acceptance.Evidence emerged from previous experiences indicating that immigrant populations may experience higher rates of non-COVID-19 vaccine hesitancy. For instance, the uptake rate of the measles-mumps-rubella vaccine among the Romanian diaspora in the United Kingdom was low due to cultural differences as well as convenience barriers such as difficulty in registering with general practitioners.Since the COVID-19 vaccination campaign started, significant emphasis has been placed on strategies focused on appropriate community engagement and culturally tailored communication to help mitigate possible vaccine concerns.The Sudanese community in the United Kingdom is considered the oldest and among the largest Sudanese diaspora groups in the Global North and includes, according to the last UK census, about 24,000 Sudanese-born residents.BOX 1Methods and Platforms Used to Raise Awareness and Debunk COVID-19 Vaccine MisinformationLive-streamed interactive sessions using the various social media platforms.Illustrative posters with infographics using simple language with the native dialect.Short, easily distributable videos addressing misconceptions/misinformation.Provision of technical and policymaking support to Sudan\u2019s national COVID-19 vaccine program.Joint update sessions with representatives of Sudan\u2019s Ministry of Health and the World Health Organization Sudan\u2019s Office.,The content of the awareness campaign was produced by expert UK-based Sudanese doctors specialized in infectious diseases, virology, and public health. Involving health care professionals from the same cultural background enables the implementation of educational programs that can conceivably diminish feelings of cultural conspiracy among vulnerable diaspora communities. In scenarios such as global vaccination campaign rollouts, trust involves 2 components: (1) the relationship between individuals and (2) the relationship between individuals and a system. The latter is linked to a long history of structural racism and medical abuses against Black populations,,To promote engagement with the targeted audience, the campaign occasionally adopted an approach of embedding positive vaccination messages within a broad health awareness session, beginning with the provision of general health and well-being advice before moving on to the subject of COVID-19 . This apBOX 2Principles and Concepts Adopted in the COVID-19 Vaccine Educational CampaignDiversifying the methods of delivering the educational campaign.Addressing the influence of Sudanese diaspora communities on their families and friends living in their native country (and vice versa) and the crossover of misinformation between the 2 groups.Ensuring responsiveness, adaptability, and readiness to tackle constantly emerging misconceptions and false information.Embedding COVID-19 vaccination awareness messages as part of general health awareness sessions to prevent immediate rejection by the audience.Conducting ongoing debates and discussions among Sudanese health care professionals, particularly those who may be hesitant themselves.Liaising and combining efforts with community champions and refugee organizations.Targeting hesitancy among specific groups (children and pregnant women).One of the most challenging aspects of the vaccination awareness campaign was the dynamic evolution of misinterpretations and constant emergence of data regarding the safety and efficacy of vaccines. Such developments demanded close monitoring and a swift response to address false material being promulgated in the media, as well as a high degree of adaptability and fluidity within our awareness campaign for the Sudanese community. We made an additional, peculiar observation\u2014the intercommunication and interactions of diaspora communities with people in their native countries through readily accessible social media platforms meant that any anxieties or misinformation about the vaccines would propagate momentously and spill over from 1 group to the other, despite geographical distances. The similarity in risk perception of COVID-19 among the African diaspora in high-income countries and those living in Africa was documented in earlier studies, raising the possibility that this may also apply to COVID-19 hesitancy.Diaspora communities may retain their vaccine-related misbeliefs and concerns from before they immigrated or continue to be influenced by anti-vaccine campaigns in their native country.Our doctors\u2019 union was notably involved in supporting the COVID-19 vaccination campaign in Sudan in its initial phase and providing guidance to local health authorities since the arrival of the first batch of COVID-19 vaccines in the country.Although it was challenging to evaluate the outcomes or gauge the specific impact metrics of our vaccination campaign, pre/post questionnaires during the live-streaming sessions revealed an increase in knowledge about the vaccine and improved readiness to enroll in the vaccination program. Moreover, the social media videos were viewed by a total of over 42,000 viewers. We also observed that the reach of these sessions extended to Sudanese diaspora groups from other European countries. Locally, our conjoined endeavors with the national vaccine program in Sudan led to the successful and timely distribution of the first batch of vaccines allocated to Sudan through the World Health Organization\u2019s COVID-19 Vaccines Global Access initiative, with 98% of the 828,000 initial doses administered before the set deadline. This enabled the country to benefit from further funding and vaccine allocations.Addressing COVID-19 vaccine hesitancy among diaspora and ethnic minority groups can be complex and should involve vigilant consideration of the unmediated interaction and sharing of misinformation between groups of the same ethnic and cultural backgrounds living abroad and those living in their home countries. The global impact of this synergy and interaction on vaccine uptake deserves careful attention and systematic examination. The influence of networking between similar diaspora groups in distinct geographical areas on vaccine hesitancy also merits investigation. Finally, the role of health care professionals from the same ethnocultural and societal environments in alleviating vaccine hesitancy among ethnic minorities is vital and should receive more support."}
+{"text": "The authors regret the omission of a funding acknowledgement in the original article. This acknowledgement is given below.Venkata Ram Gannavarapu would like to acknowledge support from the Institut Curie 3-i PhD Program under the Marie Sk\u0142odowska-Curie Grant Agreement No. 666003.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "Cataglyphis desert ants possess excellent navigational skills. After far-ranging foraging excursions, the ants return to their inconspicuous nest entrance using celestial and panoramic cues. This review focuses on the question about how na\u00efve ants acquire the necessary spatial information and adjust their visual compass systems. Na\u00efve ants perform structured learning walks during their transition from the dark nest interior to foraging under bright sunlight. During initial learning walks, the ants perform rotational movements with nest-directed views using the earth\u2019s magnetic field as an earthbound compass reference. Experimental manipulations demonstrate that specific sky compass cues trigger structural neuronal plasticity in visual circuits to integration centers in the central complex and mushroom bodies. During learning walks, rotation of the sky-polarization pattern is required for an increase in volume and synaptic complexes in both integration centers. In contrast, passive light exposure triggers light-spectrum  dependent changes in synaptic complexes upstream of the central complex. We discuss a multisensory circuit model in the ant brain for pathways mediating structural neuroplasticity at different levels following passive light exposure and multisensory experience during the performance of learning walks.Efficient spatial orientation in the natural environment is crucial for the survival of most animal species.  Cataglyphis are excellent experimental models to study the mechanisms underlying insect navigation . Desert ants of the genus n Wehner , 2020. TOcymyrmex or Melophorus and non-desert ant species like Myrmecia bull ants and Formica wood ants  in visual circuits of the ant\u2019s brain triggered by multisensory experience during learning walks that are performed during a sensitive period before the onset of foraging behavior. Most studies on neuroplasticity have been done in Cataglyphis ants. We complement these by looking at select neuroanatomical, neurophysiological, and behavioral studies on multisensory pathways in the brain of other insects. This synthesis aims at understanding the neuronal circuits mediating multisensory experience during learning walks and at stimulating future studies to unravel the neuronal mechanisms underlying the striking flexibility of navigational systems in the brain of these remarkable navigators.In the present review, we integrate results from studies on learning walks with a special focus on Cataglyphis foragers use path integration to return to their nest on the shortest distance possible by integrating directional (compass) and distance information. The resulting home vector leads the ants back to their nest entrance along an almost straight path  that na\u00efve ants perform before they head out on their first foraging excursions  systematically acquire and memorize nest-directed panoramic views around the nest entrance  learning walks, at a time when the celestial compass has not yet been calibrated? To ask whether na\u00efve ants nevertheless use the sun as a compass for path integration during their short learning walks, different filter settings above the nest entrance were used to manipulate relevant skylight cues   and the central complex (CX)  memories, whereas path integration information expresses a faster memory decay. This early discovery was already highly suggestive of two distinct channels for visual information transfer  and proceeds via the lamina, medulla, and lobula along the anterior optic tract (AOT) to the anterior optic tubercle  active zones (synaptic contacts) connected to numerous dendrites of postsynaptic Kenyon cells (the MB intrinsic neurons) forming microglomerular synaptic complexes  without any further relay to the visual compartments (collar) of the MB and was termed MB pathway  of the JO in the antenna of Before we draw further conclusions on the role of multisensory convergences in these neuropils in the ant\u2019s central brain, the next chapter reviews the results from experimental manipulations of sensory input during the performance of learning walks in the natural habitat, particularly their consequences for neuroplastic changes along the two visual pathways described above.Recent studies have applied various manipulations of sensory input during learning walks in the natural habitat and subsequently screened the brains of the experimental ants for neuroplastic changes in visual circuits along the CX and MB pathways  and learning-related visual experience during learning walks . Na\u00efve ants experience light for the first time when they reach a point in their natural ontogeny where they approach the nest entrance for the first time from the inside of the nest and when ants, for example during nest-building activities, perform so-called short digging walks to expel material from the interior of the nest to the outside  of the central body in the CX are GABAergic  during learning walks  panoramic cues. Previous studies have shown that a minimum requirement of time (at least 2\u00a0days) and space (at least 0.5\u00a0m distance from the nest entrance) are required to learn the panoramic scenery around the nest  function of the solar ephemeris to the internal clock Wehner . NeuronsCataglyphis brain  suggests a prominent role of this part of the CX in multisensory integration and modulation of spatial orientation.Like in other Hymenoptera, olfactory information in Cataglyphis, projections in the posterior slope are in very close apposition with input from ocellar interneurons  from the JO, and, although still speculative, potentially magnetosensory information from the JO (Fleischmann et al. Cataglyphis it is still an open question how information from the posterior slope and ventrolateral neuropils might be relayed to the CX, several pathways shown in Drosophila provide potential candidates. For example, connections of auditory circuits from the JO to the CX (Lai et al. Drosophila revealed connections between the CX and lateral accessory lobe with the posterior slope and other neuropils in the central brain (Hadeln et al. Cataglyphis might be relevant for plasticity in CX neuropils observed during the active performance of learning walks under a rotating sky-polarization pattern, while the ants use the earth\u2019s magnetic field as a compass reference (Fleischmann et al. Cataglyphis brain atlas will be a helpful tool for such experiments (Habenstein et al. Cataglyphis brain (Habenstein et al. Where does information from the JO converge with visual information and how could it be relayed to the CX? Interestingly, in both the honeybee and Cataglyphis ants. Clearly, future tracing studies are necessary to characterize these pathways. However, as the CX circuitry appears to be highly conserved across insect taxa (Strausfeld Cataglyphis ants represent a most exciting field for multidisciplinary neuroethological research aimed at elucidating the ontogeny of spatial orientation in a highly skilled insect navigator.The connections between the output from the CX and MBs to premotor centers have not yet been investigated in"}
+{"text": "Spatially Fractionated Radiation Therapy (SFRT) is a form of radiotherapy that delivers a single large dose of radiation within the target volume in a heterogeneous pattern with regions of peak dosage and regions of under dosage. SFRT types can be defined by how the heterogeneous pattern of radiation is obtained. Immune checkpoint inhibitors (ICIs) have been approved for various malignant tumors and are widely used to treat patients with metastatic cancer. The efficacy of ICI monotherapy is limited due to the \u201ccold\u201d tumor microenvironment. Fractionated radiotherapy can achieve higher doses per fraction to the target tumor, and induce immune activation (immodulate tumor immunogenicity and microenvironment). Therefore, coupling ICI therapy and fractionated radiation therapy could significantly improve the outcome of metastatic cancer. This review focuses on both preclinical and clinical studies that use a combination of radiotherapy and ICI therapy in cancer. Spatially Fractionated Radiation Therapy (SFRT) is a form of radiotherapy that delivers a single large dose of radiation within the target volume in a heterogeneous pattern with regions of peak dosage and regions of under dosageunderdosing. SFRT types can be defined by how the heterogeneous pattern of radiation is obtained. There are many ways to deliver heterogeneous radiation based on this concept. GRID therapy is the oldest form of SFRT and was introduced by Kohler in 1909 The 3D LATTICE radiotherapy (LRT) Microplanar beam radiation therapy is another form of spatially fractionated radiotherapy. In Microbeam Radiation Therapy (MRT) Microbeam Radiotherapy is another Novel Therapeutic Approach that has been investigated to Overcome Radioresistance and Enhance Anti-Tumour Response in Melanoma Abscopal effect refers to disappearance or reduction of tumor lesions outside of the field of irradiation A novel SBRT-based PArtial Tumor irradiation of HYpoxic clonogenic cells (SBRT-PATHY) has been developed to enhance the radiotherapy therapeutic ratio of advanced bulky tumors by sparing the peritumoral immune microenvironment and regional circulating lymphocytes. It has been shown SBRT-PATHY can mediate the bystander (BE) and abscopal effects (AE).Hence, SBRT PATHY is another novel form of SFT that has been pioneered by Tubin et al in recent years SCART is another novel approach for induction of tumor immunogenicity that has been pioneered by Radiobiological effects: Radiobiological mechanisms of SFRT radiation action proceed through a number of processes with non-linear dose\u2013response curves at low doses. These can be broadly classified as Non-immune and Immune effects:Non-immune effects: Dose-volume effects: At its simplest, this is the relationship between the radiation doses that cause the same probability of a certain acute or late normal tissue damage and the irradiated proportion or the irradiated volume of the investigated tissue or organ DNA damage: The primary method of cell killing and damage done by radiation is based on the ability of ionizing radiation to damage DNA. This DNA damage can create irreparable base pair mismatches within the nucleus of the cell. There are two main methods in which DNA is damaged by ionizing radiation, direct and indirect damage. Direct damage occurs when the radiation interacts directly with the DNA strand. Indirect damage occurs when the radiation first interacts with the water in the nucleus of the cell creating a free radical. That free radical can then go forward and damage DNA. Indirect damage is more common in low linear energy transfer (LET) forms of radiation like photons or x-rays. Oxygen plays a role in the ability of a cell to repair DNA damage. When DNA damage occurs, Oxygen has the ability to react with the DNA strand at the location of the damage preventing the repair, one of the many cellular responses to DNA damage. While this occurrence in healthy tissue is an unfortunate reality, it plays a large role in the effectiveness of radiation therapy in tumor cells. The oxygen enhancement ratio or (OER) is a concept that proves the importance of oxygen concentration in cell kill with radiation. Microvascular alterations: Vascular, transvascular, and interstitial transport are affected by fractionated radiation, but that modulation is not consistent. Total doses above 45\u00a0Gy can damage tumor microvessels, while doses up to 40\u00a0Gy tend to have inconsistent effects on microvasculature. Immune effects: Findings from several preclinical studies using various animal models have suggested that the highly heterogeneous dose deposition achieved with SFRT is associated with a superior immunological response in tumor tissue as compared to homogenous radiation doses Local effects: Radiation-induced bystander effects: the phenomenon in which non irradiated cells exhibit effects as a result of cell communication Radiation therapy causes a type of sterile tissue injury, and radiation-induced inflammation is regulated by complex interactions among a variety of immune mediators which can durably reshape the immune response Radiation can modify the response of the immune system by immune stimulation or immunosuppression Abscopal effects and bystander effects are hypothesized Immune suppressive effects: Radiation therapy can induce various immune suppressive effects.Immune stimulatory effects: Radiation therapy can also evoke immune stimulatory effects Distant effect: The \u2018RadScopal\u2019 effect arises as a consequence of radiation directed to part of the primary tumor, and may be accompanied by low-dose RT towards secondary lesions. It has been proposed that this double form of radiation, combined with ICIs, might be able to modulate the TME of both primary and secondary tumors, maximizing the anti-tumor immune responses Anti-Tumor Immunity Elicited by SFRT in Pre-clinical Studies: The radiation scheme of SFRT results in the administration of ablative- and low-dose irradiation in different regions. In conventional radiation therapy the combination of a single, high ablative dose followed by subsequent lower doses can convert the immunosuppressive microenvironment to a more immunogenic one with increased infiltration of immune effector cells and a downregulation of regulatory T cells Microbeam radiation therapy (MRT) has been compared against broad beam radiation therapy (BBRT) in murine mammary carcinoma models. MRT treated mice had a general decrease in tumor-associated-macrophages (TAMs) while the BBRT group had increased TAMs relative to the un-irradiated controlsAthymic nude mice injected with F98 glioma cells into their right cerebral hemisphere were exposed to pencil beam or microbeam irradiation and showed significant abscopal effects in their bladders The Radiation Induced Abscopal Effect (RIAE) might be due to modulation of the tumor immune environment, or through triggering systemic immune responses. Single-fraction spatially fractionated radiation therapy (SFRT) significantly delayed unirradiated distant tumor growth in a mice Xenograft lung tumor model. LRT induced increased secretion of inflammatory cytokines in mice serum. Interestingly, infiltration of CD3\u00a0+\u00a0T cells increased significantly in the right-sided unirradiated tumor after irradiation with LRT to 50\u00a0% tumor volume in the left-sided leg tumor. This finding suggested that cellular immunity might play a role in LRT-triggered AR. Furthermore, What is more interesting was that high-dose partial volume irradiation with LRT resulted in increased CD3 T-cell infiltration in the unirradiated tumor, compared with whole tumor volume irradiation. Thus, partial tumor irradiation might activate the host immune system in a different manner compared with whole tumor volume irradiation Fractionated but not single-dose radiotherapy has been shown to induce an immune-mediated abscopal effect when combined with anti-CTLA-4 antibodies in TSA mouse breast carcinoma and MCA38 mouse colon carcinoma models Anti-Tumor Immunity Elicited by SFRT in Clinical Studies: Hypofractionated radiotherapy (HFRT) can raise inflammatory cytokine levels more than compared to conventional fractionated radiotherapy Mohiuddin et al. Formenti and Demaria In SFRT using microbeam therapy, GRID or LATTICE in animal models, a strong bystander effect has been shown in unirradiated tumor cells adjacent to cells exposed to high dose radiation Since the immune system plays an important role as the mediator/effector of RIBEs/RIAEs, SBRT-PATHY planning considers peritumoral immune microenvironment and the circulating regional lymphocytes as the new organ at risk that should be spared by radiation and \u2018protected\u2019 by its own dose constraints. In this published study, the bulky tumor control rate (RIBE response rate) among patients with unresectable NSCLC treated exclusively with SBRT-PATHY was 95\u00a0%. RIAEs were seen in 45\u00a0% of patients. The authors reported on possible relationship between RIBE and RIAE, stating that a significantly higher AR rate has been seen in patients in which more intense RIBE occurred . SBRT-PATHY concept implied that for successful therapeutic immune modulation, the entire tumor volume may not need to be irradiated. This should initiate more optimal antigen shedding, increase effector T-cell activation, and lead to favorable alterations in radiation-spared peritumoral immune microenvironment. Recently, an Italian group also confirmed the efficacy of SBRT-PATHY in their initial experience. Results from preclinical mouse models from Memorial Sloan Kettering Cancer Center also support the hypothesis behind SBRT-PATHY. The authors investigated tumor response to partial irradiation in 67 NR murine orthotopic breast tumors in both immunocompetent and nude mice. Partial tumor irradiation with a single dose of 10\u00a0Gy delivered to half of the tumor led to reproducibly inducible antitumor immune responses that eliminates the entire tumor in immunocompetent mice, but not in nude mice. In addition, a significant RIAE was observed after partial irradiation with a single dose of 10\u00a0Gy. The results of this study were comparable to those previously achieved in the clinic by using SBRT-PATHY The studies highlighted in this section show that spatially fractionated radiation renews or enhances an immunological response: The timing for combining radiotherapy and immune checkpoint inhibition therapy could also affect the response from of the combination therapy. Preclinical studies on this are not conclusive about the optimal timing from with studies that suggesting concurrent therapy is better SFRT and Immunomodulation/Immunotherapy in Clinical Studies: Conventional radiotherapy and fractionated radiotherapy by itself can function as an immunomodulator We have presented evidence in the previous sections for immune activation with high dose radiation and for preclinical studies where various SFRT is combined with immunotherapy. Other reviews Summary: SFRT has the potential to overcome tumor radio resistance and modulate the local immune response, which could lead to significant improvement in tumor control locally, regionally, and distantly while preserving healthy tissues. Combining this with immune checkpoint inhibitors is a promising strategy for treating metastatic cancers and can trigger abscopal effects. We have discussed here the anti-tumor immunity elicited by fractionated radiotherapy and its role in immunomodulation. Wide acceptance of this combinatorial treatment will require further research to optimize the fractional radiotherapy and immune checkpoint therapy parameters that would allow for maximizing an immune response while still reducing the adverse effects of radiotherapy. It is reasonable to hypothesize that radiation could modulate immune functions in its applications such as dose, fractionation size, tumor site and size, and location of nearby organs at risk.peri-tumor microenvironment.If the hypothesis is proved, radiomics and genomics studies would be valuable to elucidate the effect of radiation in human body in a systematic manner. On occasions, it is difficult or impractical to deliver the higher dose per fraction ideal for eliciting an anti-tumor immune response due to tumor size or location. Under these circumstances, RT may be delivered by irradiating a fractional tumor volume. Spatially fractionated radiation therapy (SFRT) is a way to deliver radiation to a whole or partial tumor with inhomogeneous radiation dose. We suspect that anti-PD-1/anti-PD-L1 combination with SFRT will be translated into meaningful Phase II and Phase III trials and lead to improvement in outcomes for metastatic patients. Knowledge of radiotherapy causing increased antigen shedding and increased expression of neoantigens paved the pathway for combination approaches with anti-CTLA-4. Similarly, advances in checkpoint agonists and cytokines may also provide additional avenues of combination trials with radiotherapy. Future trials should incorporate these immunotherapy agents with modern radiotherapy and use a more biologically targeted, organs at risk sparing approach, which may include the The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."}
+{"text": "Pituitary adenomas are benign neoplasms of the pituitary. The most prevalent are prolactinomas and non-functioning pituitary adenomas, followed by growth hormone- and ACTH-secreting adenomas. Most pituitary adenomas seem to be sporadic and their persistent growth is very atypical. No molecular markers predict their behavior. The occurrence of pituitary adenomas and malignancies in the same patient can be either pure coincidence or caused by shared underlying genetic susceptibility involved in tumorigenesis. Detailed family history on cancers/tumors in the first, second and third generation of family members on each side of the family has been reported in a few studies. They found an association of pituitary tumors with positive family history for breast, lung and colorectal cancer. We have reported that in about 50% of patients with pituitary adenomas, an association with positive family history for cancer has been found independent of secretory phenotype . We also found earlier onset of pituitary tumors (younger age at diagnosis of pituitary tumors) in patients with a strong family history of cancer. In our recent unpublished series of 1300 patients with pituitary adenomas, 6.8% of patients were diagnosed with malignancy. The latency period between the diagnosis of pituitary adenoma and cancer was variable, and in 33% of patients, it was longer than 5 years. Besides the inherited trophic mechanisms (shared underlying genetic variants), the potential influence of shared complex epigenetic influences  is discussed. Further studies are needed to better understand if patients with pituitary adenomas are at increased risk for cancer. Pituitary adenomas are usually benign neoplasms arising from anterior pituitary cells, grow slowly and usually change little in size over many years. The autopsy and MRI studies showed that 10\u201315% of patients with no history of pituitary disease had previously undiagnosed pituitary tumors, incidentalomas and clinically relevant pituitary tumors . EpidemiSDHA, SDHB, SDHC, SDHD, MAX, TMEM 127) and other conditions . In this review, we will not discuss these hereditary syndromes.The number of genetic factors linked to pituitary tumors is very small. Usually, pituitary tumors may be diagnosed as a part of hereditary endocrine neoplasia, such as multiple endocrine neoplasia types 1 and 4, familial isolated pituitary adenomas, succinate dehydrogenase mutations /insulin-like growth factor 1 (IGF-1) axis and cancer risk is complex. Experimental studies showed that GH and IGFs have pro-mitogenic and anti-apoptotic properties and have an important role in growth, metabolism, control of cell cycle and chemoresistance . ExperimMany studies showed that high-normal serum IGF-1 levels may be associated with an increased risk of malignancy in the general population  overexpression , but it is associated with age and family history of cancer  had non-functioning pituitary adenoma. Clinical characteristics and type of malignancy in these patients are presented in n\u2009\u2009= 2795) have an increased overall risk of developing malignancies (only men) and increased incidence of neoplasms of the brain, skin and melanoma /breast cancer gene 2 (BRCA2) mutation and was positive.There are 21 reported cases and series in the literature on metastasis of malignancy to a pituitary non-secreting-gonadotroph adenoma, reminding us of the coexistence of two diagnoses and the need for the correct solution of the relationship     and the other female patient had congenital hypopituitarism and both were diagnosed with a pituitary tumor (prolactinoma) in adulthood  and a female patient with congenital hypopituitarism (combined pituitary hormone deficiency - CPHD) due to PROP1 (pituitary homeobox protein prophet of the Pit 1 gene mutation) who both developed in adulthood well-differentiated pituitary adenoma \u2013 prolactinoma. The latency period before the diagnosis of prolactinoma for the male patient with KS was 25 years, while for the female patient with PROP1 mutation was 10 years..These authors state that it is unclear how the PIT-1\u03b2 mutation is associated with the development of prolactinoma and that there is no clear explanation regarding the possible mechanism for the association between developmental hypothalamic\u2013pituitary disorders with the development of pituitary tumors. Are they separated and potentially unrelated disease processes that may occur concomitantly or not is to be shown in further studies We should not dismiss reports that mutations in early developmental transcription factor such as SOX2 are associated with slowly progressing hypothalamo\u2013pituitary tumor  compared to other tumors and another study showed that all functional pituitary tumors demonstrated higher variability in copy number profiles  cancer-testis antigen (CTAG2) involved in cellular movement, highly expressed also in invasive breast cancer; (3) creatine transporter (SLC6A8) involved in creatine metabolism  will overtake smoking and alcohol as modifiable cancer risk factors. \u2018Insulin resistance\u2019 (observed in obesity and type 2 diabetes mellitus) does not apply equally to all of insulin\u2019s actions. Adverse trophic actions of the high insulin concentration in insulin resistance required to maintain euglycemia have been reported. These trophic actions of increased insulin actions in different tissues are in particular observed in ovaries in patients with polycystic ovary syndrome (AIP gene (Aryl hydrocarbon receptor-interacting protein) originated from the discoveries that inactivating germline AIP mutations are associated with occurrence of pituitary adenomas . This suggests different or additional mechanisms in the case of AIP  and pituitary tumorigenesis is the AIP\u2013AhR pathway. Scientific interest for the nature and function of AhR-AIP pathway since AhR signaling was recently observed to be involved in the lung leukocyte proinflammatory cytokine response to cadmium  is a monomer of plastics and epoxy resins widely used in the dentistry and food packaging industry, persistently present in the environment due to its long biological half-life. BPA exposure was identified to present a potential risk factor for breast cancer .Polychlorinated biphenyls (PCBs) are persistent pollutants and pro-tumorigenic in the liver. Although non-dioxin like, these substances were also observed to affect the pituitary AhR pathway. Data on the capacity of PCBs to modulate cell proliferation at the pituitary level signal a potential tumor-promoting role of this pollutant  are low-concentration pollutants from various sources capable of mimicking hormonal actions or affecting endocrine pathways, by interfering with the synthesis, metabolism, binding or cellular responses of natural hormones .Data show that dual diagnoses do arise: common (cancers) and uncommon tumors (pituitary tumors) in the same patient. Following the Occam razor principle, we believe that strong family history of malignancy (inherited trophic mechanisms) in our patients in the context of unfavorable environment is the underlying risk factors for the development of cancer and pituitary tumorigenesis.The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.This study was supported by a grant from the Ministry of Science of Republic of Serbia (Project 175033).S P, M S and V P wrote the paper."}
+{"text": "Resistant to treatment depression (RTD) is a prevalent disease that implies functional impairment and high resources consumption. Theta Burst Transcranial Magnetic Stimulation (TBS) in dorsolateral prefrontal cortex (DLPFC) is a novel therapy that has shown experimental efficacy and as an adjuvant strategy in RTD. The implementation of TBS in the Public National Health Service requires cost-effective protocols that achieve earlier responses and higher rates of effectiveness, and whose design is based on biomarkers of response so as to adequately select candidate patients.To assess the efficacy and safety of novel bilateral and unilateral intensive/spaced protocols of TBS in outpatients with unipolar/bipolar RTD compared with sham stimulation. Specific objectives: I) Comparison of mood change at the end of TBS protocol in the groups and maintenance of its effect at 3 months; II) Characterization of cerebral connectivity and metabolism patterns related to the effects of TBS; III) Analysis of the interaction between clinical and neuroimaging predictors so as to determine a RTD profile of patient that can benefit from TBS.A two-year randomized double-blind clinical trial with 96 outpatients with TRD will be carried out. Participants will be randomized in three groups  to receive 22 active/sham sessions of continuous TBS (right DLPFC) and intermittent TBS (left DLPFC) during 6 weeks . Assessments of mood and side-effects will be carried out weekly. Functional neuroimaging will be a a simultaneous PET/MR acquisition previous and at the end of TBS treatment. Between-group comparisons of efficacy in terms of Hamilton Depression Rating Scale (HDRS-17) from basal to 6th week will be performed using controlled mixed regression models. Between-group comparisons will be made at baseline and after treatment, studying the imaging biomarkers obtained. Clinical and neuroimaging predictors of response will be integrated in machine learning models.The expected results of the project are summarized in the following hypotheses: 1) The intensive and spaced protocols of TBS as an adjuvant antidepressant treatment will have greater efficacy than sham stimulation in patients with TRD. 2) Both protocols will be safe, with mild side effects. 3) Unilateral and bilateral TBS protocols will involve changes in connectivity and cerebral metabolic consumption mainly in regions of the fronto-cingulo-temporal circuitry. 4) PET/MR imaging biomarkers will allow us to differentiate whether patients have responded to treatment with TBS.This project may help to improve resistant to treatment depression management by personalizing TMS treatment with the use of neuroimaging biomarkers.None Declared"}
+{"text": "In 2011, the Agency for Health Care Research and Quality (AHRQ) published a systematic review on the comparative effectiveness of disease-modifying anti-rheumatic drugs (DMARDs) used to treat adults with rheumatoid arthritis (RA). The publication was an update to a 2007 report. A total of 258 published articles were used in the AHRQ review to compare the effectiveness of corticosteroids, and oral and biologic DMARDs in the treatment of RA. Head-to-head studies and prospective cohort trials were used to compare one drug to another in determining efficacy and effectiveness. AHRQ compiled this report in an attempt to summarize and integrate the available data for clinicians to make evidence based practice decisions for their patients since there is limited consensus among the medical community regarding the comparative effectiveness of drugs used to treat RA. The report reveals there is still much research to bedone concerning the side effects of these agents and their influence in different patient subgroups.To: (a) utilize review findings to make diagnostic and treatment management decisions in clinical practice, (b) inform clinicians on thefindings from the updated AHRQ\u2019s 2011 comparative effectiveness reviewon drug therapy for RA in adults, and (c) identify shortcomings in the current research and future directions revealed by the report.Rheumatoid arthritis is a major public health burden. The 2011 updated AHRQ report includes several new medications approved by the FDA since 2007. The review includes 31 head-to-head randomized clinical trials (RCTs), 1 head-to-head nonrandomized controlled trial, 44 placebo controlled trials, 28 meta-analyses or systematic reviews, and 107 observational studies. Most of the studies used for the comparative analysis are of fair quality with an insufficient to moderate strength of evidence assigned to the findings (Table 1). A mixed treatment comparisons (MTC)meta-analysis from the AHRQ report found that the biologic etanercept hasa higher probability of improvement in disease activity compared with other biologic DMARDs, but the MTC findings have a low strength of evidence and caution is recommended in the interpretation of this weak evidence. For patients with early RA, limited evidence precludes conclusions about the superiority of one combination therapy versus another.The data are also inconclusive for comparisons of therapeutic similarity among oral DMARDs including the limitation created by differences in methotrexate (MTX) dosing across trials. Extensive clinical experience overthe years support the preferred use of MTX in most patients versus other oral DMARDs as well as its use in multidrug regimens, whereas there is little data on the use of oral DMARDs in combination with biologic agents.The review does not support a specific biologic DMARD over another due to the lack of head-to-head trials comparing these agents using validated RA outcome measures. The data show that the majority of biologics have approximately the same efficacy except for anakinra, which was found tobe less effective.The biologic and oral DMARDs are similar in overall tolerability, but several studies suggest that adverse events are more common with biologic DMARDs versus oral DMARDs. Based on limited evidence, the oralD MARDs do not appear to have an increased risk of severe adverse events including cardiovascular events and cancer. Although most studies also found no increased risk of cardiovascular events or cancer with the biologic DMARDs, cohort studies show an increased risk of heart failure with adalimumab, etanercept, and infliximab compared with oral DMARDs.The updated AHRQ review synthesizes the current literature on therapies used for the treatment of RA in adults. The investigators are also able to identify pertinent research gaps in the literature that can be addressed with future research."}
+{"text": "Early cancer detection is key to improving patient survival and quality of life and reducing cancer treatments\u2019 financial burden. The past several decades have seen the evolution of technologies for detecting signatures in cancer diagnosis, therapy, and prognosis. Although targeting multiple cancers based on common molecular mechanisms is convenient and cost-effective, the specialization of technologies to individual cancer types is indispensable due to differences in the developmental mechanisms of each cancer that exist in distinct organ with physically diverse characteristics. Operating from these two aspects and targeting single- and multi-cancer treatment, this Special Issue introduces current paradigms and recent advances or challenges in this field.C. elegans), which can report the risk of at least 15 types of cancer from a small volume of urine samples taken from customers [The first topic concerns the methods of multi-cancer screening and therapy. Although increasing the cancer screening rate affects early detection and reduces cancer-specific mortality, the rate remains low in the population, especially in Japan. New technologies for non-invasive cancer detection related to \u201cliquid biopsy\u201d have recently been developed with high sensitivity and reasonable cost-effectiveness. Some new technologies have already been launched into business and are available as a new service. The advent of such new products provides a glimmer of hope that we may improve the situation of the low screening rate. The review by di Luccio et al. focuses on the latest technology based on the scent detection of nematode  remains challenging due to the blood\u2013brain barrier (BBB). This is despite recognizing the importance of prognostic chemotherapy for CNS diseases and brain cancer to reducing the risk of recurrence. Tashima introduced current trends in Japan in drug delivery systems based on receptor-mediated transcytosis using monoclonal antibody conjugates . To cros"}
+{"text": "Analog quantum simulators rely on programmable and scalable quantum devices to emulate Hamiltonians describing various physical phenomenon. Photonic coupled cavity arrays are a promising alternative platform for realizing such simulators, due to their potential for scalability, small size, and high-temperature operability. However, programmability and nonlinearity in photonic cavities remain outstanding challenges. Here, using a silicon photonic coupled cavity array made up of  The authors demonstrate a programmable and mappable silicon photonic coupled cavity array capable of implementing a wide range of tight-binding Hamiltonians. This work is useful for realizing integrated photonic analog quantum simulators. Due to their inherent driven-dissipative nature, photonic systems are a promising platform for non-equilibrium quantum simulation2. An archetypal photonic quantum simulator consists of an array of programmable non-linear nodes with access to the entire quantized eigenenergy spectra of the Hamiltonians being simulated. While there have been numerous works on analog quantum simulation with microwave photons7, optical photons with their extremely weak interaction with the environment, can provide several additional advantages. The higher energy of optical photons allows for the preservation of quantum states even at room temperature, enabling operability at much higher temperatures8, which significantly simplifies the experiments and lowers the resources needed to scale the simulator. Additionally, availability of single photon detectors in the optical domain allows direct measurement of multiparticle correlations10 which are a key set of measurements for characterizing the quantum-ness of realized states. Building on recent advancements in nanofabrication, quantum optical systems have shifted from bulky tabletop systems prone to misalignments to fully integrated on chip photonic circuits. These large scale photonic integrated circuits owing to their small size and high speed of operation present opportunities for unprecedented scalability to practical quantum advantage11.Achieving analog quantum simulation necessitates the realization of programmable quantum devices12 where coupling between cavities provides a potential map for photons to move around, and strong spatial confinement of light for long durations allows access to onsite non-linearity via coupling with various excitonic materials. For photonic CCAs to be used as quantum simulators, four broad requirements need to be satisfied, namely, (i) scalability: there must exist pathways to scale to a large number of sites; (ii) measurability: there is a need for protocols to perform Hamiltonian tomography with restricted access and have CCAs with addressability to all the eigenstates of the system; (iii) controllability: control over all the terms describing the Hamiltonian is required; and finally (iv) optical non-linearity: need to realize photon-photon interaction to simulate many-body Hamiltonians. The last demand as a precondition, necessitates using high-quality factor (Q) cavities with small mode volumes as constituents of the CCA. Such high-Q cavities are also necessary to probe the entire quantized eigenenergy spectra. Though several experiments showing various physical phenomena using optical CCAs have been previously reported15, none of these CCAs are programmable and have access to the entire quantized eigenenergy spectra of the Hamiltonian. While careful selection of the operation regime can lead to pathways that allow scalability to multiple sites using photonics16, in the optical regime achieving programmability and measurability of the eigen-spectrum, is very challenging owing to the extremely small physical dimensions involved.One solution to engineer such quantum systems in optics is via photonic coupled cavity arrays (CCA)Qs up to In this work, we tackle these problems by engineering a silicon photonic CCA made of high-Q  minimizing the additional optical loss incurred when introducing the heaters and (ii) reducing the thermal crosstalk between heaters, which need to be placed in close proximity owing to the small device footprint necessary to obtain small mode volumes for each cavity and ensure strong coupling between the cavities while maintaining large free spectral rangesers Fig.\u00a0. In suchWe characterize the realized CCA by applying a linearly increasing voltage across each heater one at a time and recording the respective transmission spectra. The eigenenergies are then extracted from the recorded spectra and combined with our knowledge of We next model the CCA to accurately predict the eigenenergies of the system on application of a voltage profile [Note that, we assume that We visualize this process in Fig.\u00a0These predicted eigenenergies are then used to fit for The probability distribution of the fitting error normalized to the mean hopping-rate 12, we engineered special TO islands heaters, which reduced the effects of thermal crosstalk by almost 23 and allowed Q-factors up to 13 and the Su\u2013Schrieffer\u2013Heeger (SSH) model24. One potential disadvantage of using TO heaters is that our dynamic modulation rates are limited to the 21 which rules out the possibility to implement models like the Haldane quantum Hall effect25 requiring modulation of onsite potentials at rates comparable to the mean hopping rate  to reach the regime of interacting photons and allow access to the full quantized eigen-spectrumAnsys Lumerical FDTD, MODE and HEAT were used to simulate and optimize the device parameters.Pt layers were then defined using a A silicon on insulator wafer (SOITEC) with The spectrum of the fabricated device was measured via a fiber coupled setup in which the input light was provided by a tunable continuous-wave laser (Santec TSL-510) and a low-noise power meter (Keysight 81634B) was used to collect the output light from the grating couplers. A DAQ (MCC USB 3114) was used to apply the electrical potential profile across the device.Supplementary InformationPeer review file"}
+{"text": "Plasma cell leukemia is a rare yet aggressive form of multiple myeloma characterized by high levels of plasma cells circulating in the peripheral blood. We recently experienced a case of plasma cell leukemia that had been in stringent complete remission for nine years after autologous stem cell transplantations with subsequent courses of lenalidomide maintenance therapy, and then relapsed as an extramedullary plasmacytoma in the central nervous system. Assessment of the bone marrow did not prove proliferation of plasma cells at relapse, but imbalanced elevation of serum levels of free light chains was observed without changes in other clinical biomarkers including immunoglobulin levels. Salvage chemotherapy with isatuximab, pomalidomide, and dexamethasone (IsaPD) was promptly initiated. After two courses of IsaPD, significant remission was achieved and the neuronal symptoms completely resolved. When excessive serum levels of clonotypic free light chains are noted, their significance should be carefully assessed even when plasma cell propagation in the bone marrow is not observed. In such cases, hematologists should search for extramedullary proliferation of plasma cells, including in the immune-privileged central nervous system. Plasma cell leukemia is a rare but aggressive entity of plasma cell dyscrasia. Plasma cell leukemia is defined by the presence of five percent or more circulating plasma cells in the peripheral blood smears in patients otherwise diagnosed with symptomatic multiple myeloma . Approxi18F-fluorodeoxyglucose Positron Emission Tomography (FDG-PET) and the 11C methionine Positron Emission Tomography (MET-PET) scans, which are the two most powerful methods to detect a minimal residual disease (MRD) in patients with plasma cell malignancies  and the urinary analysis (TP/Creatinine (Cr) 77.9\u00a0mg/g x Cr) were insignificant, except for the imbalanced elevation of the serum free light chain levels . As shown in the Fig.\u00a0A 68-year-old Japanese female was referred to our hospital for gradually worsening intracranial neuronal symptoms of confusion and expressive aphasia for the past two weeks. The patient had originally been diagnosed as monoclonal gammopathy of undetermined significance (MGUS) 18\u00a0years ago, and progressed to the plasma cell leukemia nine years ago. The patient had undergone induction chemotherapy with bortezomib and dexamethasone, followed by two autologous stem cell transplantations. During courses of the lenalidomide maintenance therapy, the patient had been in a stringent complete remission with the normal serum levels of free light chains. The systemic imaging studies resulted negative with the gnancies . Nine yeImmunoglobulins are composed of heavy and light chains. Plasma cells make a small amount of extra light chains that do not bind with heavy chains, and these are called free light chains. In patients with plasma cell neoplasms, the multi-clonal production of light chains is overwhelmed by the monoclonal production by the transformed plasma cells, which subsequently affects the kappa to lambda ratio of the free light chains. Since the concept was originally introduced by Dr. Henry Bence Jones in 1847, the analysis of serum levels of the free light chains is now a standard as well as an essential examination in the diagnosis and management of plasma cell neoplasms . AlthougReviewing the past literatures resulted only five cases of plasma cell leukemia that had relapsed in the central nervous systems after the initial treatment Table . NotablyIn summary, we have experienced a case of plasma cell leukemia that had been in a stringent complete remission for nine years after autologous stem cell transplantations with courses of lenalidomide maintenance therapy, and then relapsed as an extramedullary plasmacytoma in the central nervous system. Imbalanced elevation of serum levels of the free light chains could be the initial and the only clinical manifestation at the time of relapse, and thus systemic work-up including the central nervous systems would be necessary to examine the presence of extramedullary lesions especially when the bone marrow assessment resulted negative for the aberrant propagation of plasma cells."}
+{"text": "The term \u201cmetastatic cascade\u201d defines a process whereby few tumor cells complete a sequence of steps to leave the primary tumor to reach one or more sites elsewhere in the body, usually through the bloodstream to develop one or several metastases. Due to the nature and plasticity of cancer, unfortunately no specific and functional anti-metastatic drugs are available. In this Commentary, we are highlighting how four essential factors are able to induce adhesion-to-suspension transition (herein referred to as AST) in human cancer cells and how this process may play a key role in tumor metastasis. We further underlined the potential role of hematopoietic transcriptional regulators in reprogramming anchorage dependency of cells, supporting the possible targeting of AST factors as promising therapeutic strategy to overcome metastasis in solid tumor cells. The ability of cancer cells to break off from the primary tumor and generate metastases is still one of the main determinants of unsuccessful outcomes of cancer treatment. Although important results in terms of outcome and life expectancy have been achieved in the last two decades with the development of intense multimodal treatment approaches, better tumor characterization and the development of translational interdisciplinary research require urgent attention. Although the macro-events leading to the multi-step metastatic cascade have been fully elucidated, several questions are still unanswered. Molecular and genetic factors that determine the spatio-temporal control of cancer cells detachment from primary tumor site still remain elusive. Understanding the biogenesis of circulating tumor cells (CTCs), that are precursors of metastases, is fundamental to \u2018clip the wings\u2019 of the most invasive and deadly cancer types. During the last decades, transcriptional programs that are able to shape cell commitment and differentiation (i.e. Yamanaka factors) have been identified as well as the pleiotropic epithelial-to-mesenchymal transition (EMT) process that orchestrates cell polarity and intercellular communications , 2. Up tWhat regulates the loss of anchorage of tumor cells from their original mass? How do CTCs re-acquire their adhesive properties once they reach their target sites? Are there targetable transcriptional programs regulating CTCs interactions with the extracellular environment in the bloodstream?A very recent study from Huh et al. elegantly demonstrates how a cocktail of four essential factors is able to induce adhesion-to-suspension transition (herein referred to as AST) in human cells both in vitro and in vivo . The autHuh and colleagues analyzed a plethora of adherent and suspension cell types looking for differential expression of genes regulating their different morphological state. By gene expression analyses, they isolated four genes that are sufficient to induce anchorage-independent growth when ectopically expressed in human adherent cell lines: IKZF1 (IKAROS Family Zinc Finger 1), NFE2 (Nuclear Factor Erythroid 2), BTG2 (BTG Anti-Proliferation Factor 2) and IRF8 (Interferon Regulatory Factor 8). Those factors are normally expressed in blood cells regulating hematopoiesis of blood precursor cells, whereas they are epigenetically suppressed in adherent cells. Transient expression of those hematopoietic factors results in cell rounding and clustering without triggering cell differentiation  that ultimately induce anoikis, a form of programmed cell death that occurs in cells detached from the surrounding ECM. Resistance to anoikis is a \u201cde novo metastatic breast cancer patients. By means of scRNA-seq analyses, they found that CTCs isolated from whole blood exhibit high expression of AST factors, that is instead barely undetectable in primary tumor samples. Moreover, studies on orthotopic murine models of both metastatic breast and melanoma cancers have shown a marked raise of AST factors expression in CTCs. Upregulation of AST factors correlates with low YAP/TEAD signaling and low expression of genes related to ECM organization in CTCs. Strikingly, the expression of AST factors was turned off at metastatic sites (lung nodules for melanoma), thus corroborating the plasticity of AST phenomenon observed in vitro. These data demonstrate, for the first time, that the dynamic expression of four hematopoietic factors governs the formation of CTCs, their dissemination into the bloodstream and their colonization of the target tissue  that are known to induce the degradation of IKZF1, one of the four AST factors. IMiDs, such as Lenalidomide and Pomalidomide, facilitate the Cereblon (CRBN)-mediated degradation of Ikaros family proteins (such as IKZF1) and have already been approved for the treatment of hematological malignancies such as multiple myeloma and lymphoma. Treatment with both Lenalidomide and Pomalidomide reverts AST in vitro and specifically inhibits lung colonization in vivo without reducing primary breast masses. The authors propose IMiDs repositioning as a specific anti-metastatic therapeutic strategy for solid tumors. Since IMiDs are known to stimulate immune cells (such as T and NK lymphocytes), their anti-metastatic efficacy could also be potentiated by enhanced anti-tumor immunity. However, repositioning of these drugs for solid tumors deserves deeper studies.It is very well documented that CTC clusters are more aggressive than single CTCs . Indeed,The four AST factors are known to exert multiple functions such as determinants of blood cell lineage development or oncosuppressive factors in hematological malignancies. Their implication in cancer biology is mainly restricted to their different roles in the control of cancer immunosurveillance in various tumor types. Very little is known about their role in solid tumors. Their expression is mostly suppressed in these cancers, where they were reported to act as modulators of immune cells infiltration (IRF8 and IKZF1) or as cell stress responsive factors (BTG2 and NFE2). For example, IRF8 enhances CD8-T cell population in the tumor microenvironment as previously demonstrated in murine melanoma models  and in bIn summary, these findings underscored an important early regulation of how cancer cells spread and highlighted novel targets for a specific anti-metastatic therapy. Understanding how AST factors/dependent genetic changes dynamically adapt to the different environments, is important to gain a wide view of this fascinating process. Furthermore, these observations are now opening a new and not still explored scenario for the role of AST process and its impact in other physiological events such as development, organ morphogenesis or immune cell development."}
+{"text": "This review highlights some of the recent advances in modelling thrombus formation Microfluidic devices and the availability of commercial chips in addition to enhanced accessibility of 3D printing has facilitated a rapid surge in the development of novel in-vitro thrombosis models. These include progression towards more sophisticated, \u2018vessel on a chip\u2019 models which incorporate vascular endothelial cells and smooth muscle cells. Other approaches include the addition of branches to the traditional single channel to yield an occlusive model; and developments in the adhesive coating of microfluidic chambers to better mimic the thrombogenic surface exposed following plaque rupture. Future developments in the drive to create more biologically relevant chambers could see a move towards the use of human placental vessels, perfused ex-vivo. However, further work is required to determine the feasibility and validity of this approach.Recent advances in thrombus formation models have significantly improved the pathophysiological relevance of in-vitro flow chambers to better reflect the in-vivo environment and provide a more translational platform to test novel antithrombotics. The use of experimental in-vivo and in-vitro thrombosis models has been fundamental in furthering our knowledge of arterial thrombosis, from understanding the mechanisms governing thrombosis through to the screening of novel antiplatelet drugs. The most common in-vivo models of arterial thrombosis are murine models where the vascular endothelium is damaged using laser ablation or chemically damaged using ferric chloride . The sizIn-vitro thrombosis models have been around since the 1930s with one of the earliest models being the capillary thrombometer , which wType I collagen is the most thrombogenic extracellular matrix protein found in the blood vessel wall  and is eIn-vitro thrombus formation assays have proved pivotal in characterizing the mechanism by which VWF and the GPIb-IX-V complex facilitates the initial platelet tethering to collagen ,18, the Secondly, the linear kinetics of thrombus growth observed in flow chambers is different to the dynamic thrombus assembly observed in mouse models, where disaggregation and embolization occur prior to thrombus stabilization ,28. It iFinally, the single channel flow models are relatively low throughput impeding their uptake commercially to screen for novel antithrombotic compounds, and clinically to assess thrombus formation on a range of adhesive ligands. In this review we discuss the most important recent advances and approaches, which address many of the limitations of the traditional in-vitro thrombosis model.Microfluidic chambers enable investigations demonstrating the influence of whole blood rheology on platelet activity and thrombus formation, as they often use smaller amounts of blood, increasing accessibility . AdditioThe early development of in-vitro models consisted of whole blood perfused over Type I Horm collagen, sometimes in combination with tissue factor , to inveAn alternative approach which has also enhanced the throughput of in-vitro flow experiments is microspotting pioneered by Cosemans and Heemskerk \u201340. Precet al., overcame some of these limitations by culturing HUVECs to confluency on collagen coated coverslips and using a scalpel to create a scratch exposing the collagen, in addition to acute activation of the cells with histamine. The study demonstrated enhanced platelet adhesion evoked by histamine induced VWF release and also provided proof of principal that the model could be used to assess antithrombotic drugs which target the endothelium [\u25aa\u25aa].The use of plaque material within in-vitro thrombosis models provides a trigger for arterial thrombosis much more akin to the in-vivo scenario; however, these advances are still limited by the lack of vascular cells, in particular endothelial cells, and their important contributions to arterial thrombus formation. Indeed, endothelial cells are key regulators of platelets ormation ,54. Seven . Berry et al.[\u25aa\u25aa] created a custom-made pressure relief PDMS-based model to generate occlusive clot formation on a patch coating of Type I Horm collagen and tissue factor, enabling measurement of time to occlusion following treatment with antiplatelet drugs. The model was successful in occluding chambers due to the incorporation of a branching design, with blood flow able to divert following a build-up of fluid pressure. However, off-site coagulation occurring downstream of the patch was observed and required downstream infusion of ethylenediaminetetraacetic acid (EDTA) [\u25aa\u25aa], potentially due to the absence of endothelial cell regulation in the model.Historically, in-vitro thrombosis models are largely nonocclusive, due to the dislodgement of large thrombi in chambers caused by the build-up in pressure and the lack of co-lateral vessels providing an alternative route of less resistance. Recently, however a series of adaptations to the standard flow chamber model has enabled an occlusive model of thrombosis to be established \u25aa\u25aa. Berryry et al.\u25aa\u25aa created (EDTA) \u25aa\u25aa, potenex vivo. Human placental tissue represents a continuous and easily accessible source of human blood vessels, with arteries and veins ranging in size from large conduit vessels to small resistance vessels [ex vivo studies, with most Universities associated with hospitals or located in proximity. Experimental studies have previously demonstrated perfusion of placental vessels for up to 6\u200ah after delivery [Future advances in the development of in-vitro thrombosis models have the potential to move towards using human blood vessels perfused with human blood  vessels  Fig. 2)ex vivo.  vessels  and mostdelivery \u201368 with delivery , and enddelivery .in vivo (e.g. laser injury or ferric chloride), offering the prospect of a bona fide human thrombosis model with the potential to replace animal experiments. The availability of numerous arteries and veins from the same placenta also allows simultaneous haemostasis assays to be performed in place of murine tail bleeding assays. Puncture wounds of a set diameter can be initiated using specific gauge needles [The accessibility of chorionic plate placental vessels Fig.  faciliti needles  and the et al., unpublished data). As with most in-vivo models, the vessels will also be devoid of cardiovascular disease. However, there is the prospect of utilising placental vessels from pregnancies complicated by hypertension or diabetes to better model disease or using inflammatory mediators to evoke endothelial dysfunction. A benefit over in-vivo models however is the ability to treat or manipulate different components of the model in isolation. This is an exciting and revolutionary area of research, which requires future investigations to reveal the full potential of using human placental vessels ex vivo, as a robust, reproducible, and standardized method for investigating thrombosis and haemostasis.As with any model, there are limitations with using placental vessels, these include immaturity in cell phenotype as the placental vessels are foetal origin. Our own work however has demonstrated that placental endothelial cells express similar levels of platelet regulators eNOS, COX1 and CD39 to HCAECs and protect against platelet thrombus formation to a similar extent when compared in microfluidic chambers  and a Biotechnology and Biological Sciences Research Council/ National Centre for the Replacement, Refinement and Reduction of Animals in Research project grant (NC/X002292/1).Funding: BHF/NC3Rs joint studentship (NC/S001662/1); BBSRC/NC3Rs joint project grant (NC/X002292/1).There are no conflicts of interest."}
+{"text": "We express our gratitude to the concerns raised by Hsieh et al. regarding to our investigation on the anatomical and visual outcomes of fovea-sparing internal limiting membrane (ILM) peeling with or without the inverted flap technique for myopic foveoschisis (MF).In our study, we incline to interpret the case mentioned by Hsieh et al. as an occurrence of postoperative full-thickness macular hole (FTMH) formation. FTMH is characterized by an interruption of all neural retinal layers from the ILM to the retinal pigment epithelium (RPE) . We concPrevious studies have reported the incidence of FTMH development subsequent to fovea-sparing ILM peeling in myopic traction maculopathy ranging from 5.6 to 9.7%. The presence of preoperative lamellar macular hole (LMH) is also associated with an increased risk of postoperative FTMH formation , 3. We aThe inverted ILM flap technique has been commonly used for FTMH. A flap of ILM covering the surface of macular hole promotes the proliferation of glial cells and contributed to the restoration of foveal architecture as a scaffold . The flaThe satisfactory success rate of the operation has been shown in our study. That only one eye in each group of the inverted and non-inverted flaps experienced a delayed onset of postoperative FTMH. Our findings were based on the statistical analyses from the retrospective clinical case observation. Further prospective controlled trials with larger sample size are warranted to evaluate the advantages of the inverted ILM flap technique for MF comprehensively."}
+{"text": "Over the past few years, multiparametric MRI (mpMRI) of the prostate has emerged as the most successful radiologic imaging study for detecting prostate cancer. The PI-RADS system and the MRI pathway have paved the way for a widespread usage of this imaging test in daily clinical practice . Prostat"}
+{"text": "Background: The FIRST Trial is a 5-year study funded by the Agency for Healthcare Research and Quality. Our investigation is situated within a more extensive study to restrict fluoroquinolone antibiotics by requiring providers to obtain authorization from an infectious disease physician before prescribing fluoroquinolones. Our research team is performing a systematic evaluation to identify organizational characteristics and influencers of the fluoroquinolone preprescription authorization implementation process to understand variables that may facilitate or hinder implementation success. Methods: To address this critical gap, we present a qualitative analysis from our ongoing, multisite research project aimed at systematically assessing the adoption of an antimicrobial stewardship intervention in the form of an EHR-integrated best-practice alert (BPA) at each site to identify work system factors that impact uptake and variability in the implementation of the BPA at each location. The evaluation provides a detailed explanation of activities through the implementation process  to assess how an organization effectively negotiates the phases and transitions, ultimately influencing the impact of the intervention. We have used a contextual determinant framework (CFIR) that has enabled us to perform a systematic and comprehensive exploration and identification of potential explanatory themes or variables to shed light on the complex social phenomenon of implementation. Results: Participants who will be a part of our poster presentation will learn about implementing a BPA, the potential barriers to implementation, and strategies for overcoming these barriers. Stakeholders within our study include site coordinators, medical doctors, nurses, pharmacists, and clinical informaticists. Our analysis synthesizes their experiences implementing and sustaining this evidence-based antimicrobial stewardship intervention. It includes (1) a detailed description of the process of change, (2) work-system factors  that they believe influenced the success of the intervention, (3) barriers and facilitators  within the implementation process; and (4) description of how these could have influenced the outcomes of interest . Conclusions: Our research is expected to advance patient safety research and initiatives by providing a more robust approach to performing systematic intervention evaluations. By outlining stakeholders\u2019 experiences within our study, implementation leaders within healthcare systems will utilize our findings to aid them in their design and implementation process when designing and implementing similar types of healthcare interventions.Disclosures: None"}
+{"text": "Climate change disproportionately harms people of color and low-income communities. Despite their unprecedented numbers, being constantly on the move, and suffering extreme social vulnerability, almost nothing is known about the impact of climate change on the health of refugees. This study uses state-of-the-art mixed methods to examine the differential susceptibility of climate-sensitive exposures and environmental exposures among refugees and their links to perceived health after resettlement.Arabic-speaking refugees (N=67) from Iraq and Syria previously diagnosed with hypertension who resettled in California were recruited from a community center. Semi-structured interviews were conducted to explore participant\u2019s understanding of the impact of climate on health. Survey data were collected to inquire regarding participant\u2019s refugee journeys prior to resettlement in the US. Survey data on climate-related disasters was retrospectively geo-referenced through the Emergency Events Database (EM-DAT). Qualitative data was analyzed using inductive thematic analysis.All participants stayed in at least one temporary resettlement country during their migration journey and 12% has stayed in refugee camps. The most popular resettlement sites were Turkey (most disaster-prone in the region due to frequent floods and earthquakes) and Jordan . Participants reported harsh weather conditions during their migratory journeys including extreme cold in Turkey and extreme heat in Jordan. Many participants noted their exposure to dust throughout their travels, and an inability to deal with harsh weather conditions due to financial insecurity. Participants did not link their diagnosis of hypertension to their experience of extreme weather and would only link it to their exposure to stress from war. Participants did note poorer mental health due to poor weather conditions and a challenge adjusting to the climate conditions in different countries. Few participants reported residing in a refugee camp and described it as ill-equipped for the challenges of climate hazards.This study reveals the links between structural drivers of climate change and health inequities for refugee populations. Refugees are highly vulnerable to climate-sensitive exposures but remain not fully aware of the potential links between these exposures and health. Learnings from this study will inform clinical and public health interventions, and policies to close the climate gap without leaving this vulnerable population behind. Refugees are among the population groups least equipped to protect themselves from environmental hazards due to a combination of factors and geographical trajectories. These can include insecure living conditions, such as living in overcrowded refugee camps, a lack of economic resources, the experience of conflict and persecution in their place of origin, and often extremely perilous journeys. Previous research shows that refugees have a greater prevalence of poor physical3 and mental health4 as compared to the general population, including chronic conditions such as hypertension3, which are shown to be aggravated by exposure to extreme climate events5. Yet little is known about the implications of the climate crisis on refugees\u2019 health, mainly due to the difficulty of studying displaced populations as well as their previous exposures to climate-related disasters. Understanding and documenting such refugees\u2019 cumulative exposure to various environmental exposures can be particularly helpful to better understand differential susceptibility regarding the role of climate-sensitive exposures and ambient environmental exposures once resettled in the United States (US) or elsewhere.The climate crisis poses multiple threats to human healthIn this study, we demonstrate how some of these gaps in the literature can be addressed through a mixed-methods approach applied to a small sample of Syrian and Iraqi refugees. Semi-structured interviews were conducted with 67 adult refugees residing in San Diego, California \u2013 a major resettlement city for refugees from the Middle East and North Africa (MENA) in the US. The sociodemographic characteristics of interviewed refugees are presented in Table S1. These data were analyzed through inductive thematic analysis alongside geo-referenced data on climate-related disasters retrieved from the Emergency Events Database (EM-DAT) (see supplementary information). Participants were asked about their refugee journeys prior to resettlement in the United States, which span from 1992 to 2018, including the experience of climate-related hazards and perceived health implications.6. At the same time, this region is warming significantly faster than other regions and incurs some of the highest rates of human losses from the climate crisis due to its poor adaptive capacity7.The MENA region is important to study since it has been badly affected by conflicts and is a major contributor to the global refugee crisis, with more than 12 million people currently displaced in the regionMost of the surveyed individuals stayed in at least at one temporary resettlement site in the MENA region during their migratory journey, primarily in Turkey and Jordan ,1G. Besi8. Both dust and extreme ambient temperatures can aggravate hypertension, which was a chronic condition among all survey participants. While some related their hypertension to the experience of war and violence, no direct links were made between the experience of extreme weather during the migratory journey and poor physical health. However, some refugees reported poor mental health due to poor environmental conditions. Overall, participants reported difficulties adjusting to a climate that was different from their home countries.Surveyed participants reported experiencing harsh weather conditions, including extreme heat in in Jordan and extremely cold temperatures in Turkey. Access to heating during cold winters was noted as a problem due to a lack of financial resources. Almost all participants mentioned being exposed to dust throughout their resettlement journey. Such dust storms are becoming more common in the Middle East due to the climate crisis9 in extremely precarious living conditions10.A few survey participants reported staying in a refugee camp in Jordan  and geneThe impact of environmental disasters on refugees\u2019 health is an immensely understudied field of research. Applying a mixed-methods approach, we propose a framework to study such links and highlight specific health risks faced by refugees in the MENA region where violent conflict has displaced millions of people against the backdrop of an intensifying climate crisis. As climate change is expected to displace an ever-growing number of people in the next decades, there is an urgent need to develop actionable interventions to improve the quality of life and health of this highly vulnerable group."}
+{"text": "The application of a second layer between the neourethra and skin was a major contribution, which has improved the outcome of hypospadias repair. Here, we report our experience of revisiting the original Smith technique using a de-epithelialized overlap flap to support the urethroplasty in staged hypospadias repair.The study included primary cases of proximal hypospadias with significant chordee who underwent two-stage repair during the period 2016 through 2021. The ventral curvature was corrected at first stage by excision of the urethral plate, followed by covering the ventral shaft by skin flaps or inner preputial graft. The second stage (Thiersch -Duplay urethroplasty) was performed six months later. The de-epithelialized overlap flap (double breasting) technique was used to cover the neo-urethra in all cases, which was combined with a dartos scrotal flap to cover the proximal neourethra when indicated.The study included 17 boys with proximal hypospadias who underwent two-stage repair. Follow up period after the second stage ranged between 6 and 30 months . Post-operative complications were detected in 7 cases (41%). Most complications were related to distal/glanular disruptions whether partial or complete (5 cases). One case developed a penoscrotal fistula that was closed surgically. Another case  presented 21 months after the second stage with urethral stricture .Applying the de-epithelialized double-breasting skin closure can offer alternative second layer coverage for the neourethra along the penile shaft in staged repair of proximal hypospadias. While surgery for distal hypospadias is considered an aesthetic procedure, surgery for proximal hypospadias aims to improve function . Two maiWe can all agree that adding a second layer between the neourethra and skin had a significant impact on the success of the hypospadias correction . This deHere, we report our experience of revisiting the original Smith technique using a de-epithelialized overlap flap to support the urethroplasty in staged repair of proximal hypospadias.We retrospectively analysed the data of primary cases of proximal hypospadias with significant chordee who underwent two-stage repair during the period 2016 through 2021. Only cases who applied the de-epithelialized double breasting skin closure at second stage of repair were included in this study.The first stage starts by degloving of the penile skin. Ventral dissection is extended down to the scrotum exposing the bulbar urethra. The position of the hypospadiac meatus as well as the site of bifurcation of the corpus spongiosum is defined after complete degloving reflecting the degree of severity of hypospadias. In presence of significant ventral curvature (chordee\u2009>\u200930\u00b0), the decision is made to sacrifice the urethral plate. The urethral plate together with all subjacent dysplastic tissue are meticulously excised to straighten the penile shaft. This will relatively shift the meatus to a more proximal position. Either skin flaps Fig.\u00a0 or innerDuring the second stage, a Thiersch-Duplay urethroplasty is applied to reconstruct the anterior urethra transferring the urinary meatus distally to the glans. The urethroplasty is performed using polyglactin 6\u2009\u2212\u20090 continuous (full thickness) suturing technique; a second layer of interrupted sutures are applied at wide intervals to support the underlying continuous suture line of the urethroplasty. Before skin closure, a rectangular area is de-epithelialized along the free edge of the penile skin on one side as shown in Fig.\u00a0The study included 17 boys with proximal hypospadias who underwent two-stage repair. In all cases, the de-epithelialized overlap flap (double breasting) technique was used to cover the neo-urethra, which was combined with a dartos scrotal flap to cover the proximal neourethra when indicated. Their age at first stage ranged between 6 and 66 months . The meatus position was penoscrotal in eight, scrotal in seven, and perineal in two. In all cases, the ventral curvature was corrected at first stage by careful dissection and excision of the urethral plate with all subjacent dysplastic tissues on the penile ventrum . Dorsal skin flaps were used to substitute the urethral plate in 10 cases, while inner preputial graft was used in the rest (7 cases). No complications were detected after the first stage in this case series. The second stage (Thiersch -Duplay urethroplasty) was performed at least six months after the first stage.Follow up period after the second stage ranged between 6 and 30 months . Post-operative complications were detected in 7 cases 41%); six of them required a third intervention  was found, which may be quite expected in such group of severe hypospadias , 17. WheWith the trend back to two-stage repairs for proximal hypospadias, applying the de-epithelialized double-breasting skin closure is an alternative way to provide second layer coverage for the neourethra along the penile shaft."}
+{"text": "Cotton leaf curl virus (CLCuV) causes devastating losses to fiber production in Central Asia. Viral spread across Asia in the last decade is causing concern that the virus will spread further before resistant varieties can be bred. Current development depends on screening each generation under disease pressure in a country where the disease is endemic. We utilized quantitative trait loci (QTL) mapping in four crosses with different sources of resistance to identify single nucleotide polymorphism (SNP) markers associated with the resistance trait to allow development of varieties without the need for field screening every generation. To assist in the analysis of multiple populations, a new publicly available R/Shiny App was developed to streamline genetic mapping using SNP arrays and to also provide an easy method to convert and deposit genetic data into the CottonGen database. Results identified several QTL from each cross, indicating possible multiple modes of resistance. Multiple sources of resistance would provide several genetic routes to combat the virus as it evolves over time. Kompetitive allele specific PCR (KASP) markers were developed and validated for a subset of QTL, which can be used in further development of CLCuV-resistant cotton lines. Gossypium hirsutum, is an allotetraploid crop that accounts for much of the fiber used in natural textiles. In addition to its uses in clothing and other textile products, cotton is used in the production of American currency  for high DNA concentrations. The few samples that had lower concentrations were standardized to 10 [ng/\u00b5L]. F1 samples were created in the lab by mixing DNA from both parents. The testing panel was replicated in 96-well sections of each quadrant of three 384-well plates, with all unfilled wells acting as non-template controls with water  and performed the first genetic analyses on these materials. The identification of multiple QTL in different locations on the genome suggests there are multiple resistance genes present in geographically diverse cotton germplasm. Identification of these sources provides the basis for more durable resistance via the stacking of these resistance QTL. We have developed a R/Shiny App, iCottonQTL, which streamlines the process to QTL mapping from cotton genotyping arrays and subsequent deposit of data to the CottonGen database."}
+{"text": "This review discusses picosecond ultrasonics experiments using ultrashort hard x-ray probe pulses to extract the transient strain response of laser-excited nanoscopic structures from Bragg-peak shifts. This method provides direct, layer-specific, and quantitative information on the picosecond strain response for structures down to few-nm thickness. We model the transient strain using the elastic wave equation and express the driving stress using Gr\u00fcneisen parameters stating that the laser-induced stress is proportional to energy density changes in the microscopic subsystems of the solid, i.e., electrons, phonons and spins. The laser-driven strain response can thus serve as an ultrafast proxy for local energy-density and temperature changes, but we emphasize the importance of the nanoscale morphology for an accurate interpretation due to the Poisson effect. The presented experimental use cases encompass ultrathin and opaque metal-heterostructures, continuous and granular nanolayers as well as negative thermal expansion materials, that each pose a challenge to established all-optical techniques.  In the most straight-forward experiments, strain induced changes of the reflectivity witness the arrival of a strain pulse in the layer and the timing can be used to infer layer thicknesses or elastic properties In ultrafast x-ray diffraction (UXRD) experiments the optical probe pulses are replaced by ultrashort hard x-ray pulses that are diffracted from the crystal structure in motion X-rays from laser-based plasma sources, in contrast, are sufficient to support the conceptually simple picosecond ultrasonics experiments that investigate Bragg peak shifts In this article, we highlight the conceptual advantages of picosecond ultrasonics with x-rays (PUX) experiments that observe shifts of Bragg peaks of layered heterostructures. Each crystalline material scatters at a characteristic Bragg diffraction angle, and hence, the signal is often a layer-specific measure of the lattice distortions caused by the strain pulse propagation and heat flow. In other words, for each pump-probe delay, x-ray probe pulses can project the Bragg peak of each layer onto the detector with a peak shift that is proportional to the instantaneous strain averaged over one layer. The four central advantages of x-ray probing in picosecond ultrasonics are: (i) Diffraction yields quantitative strain values (ii) with layer specific information for (iii) strain pulses and quasi static strain. (iv) The x-ray probe penetrates metals and insulators irrespective of their optical properties. This permits a very flexible exploitation of dedicated strain-sensing layers that can be placed within the heterostructure and often naturally exist as buffer, contact or electrode layers. We elaborate and illustrate concepts for the analysis of PUX experiments that have emerged to utilize the quantitative access to the strain response for tracking the energy flow in laser-excited heterostructures in the sequence of events sketched in We structured the manuscript as follows: In Section In Section In Section Section The 2A typical picosecond ultrasonics experiment is schematically depicted in In applications using optical probe pulses, the main results of such experiments are often the echo time for thickness determination In the remainder of this section, we discuss a representative PUX experiment on metallic heterostructures composed of Pt, Cu and Ni to exemplify the measurement principle and data evaluation. This example demonstrates the advantages of PUX experiments on a sample structure that is frequently used to study the effect of hot-electron pulses that are launched in a Pt layer and propagate through an opaque Cu stack towards a buried functional detection layer The integration of the RSM along  see Eq. . FollowiThe resulting strain response of the Pt transducer, the Cu propagation layer, and the Ni detection layer are compared in Here, we highlight the suppression of the crucial electronic energy transport from Pt to Ni, if the additional MgO interlayer is introduced The deformation of the solid is described by the strain In general, the strain response of an elastic solid to a time- and space-dependent stress is found as a solution of the elastic wave equation, i.e., the equation of motion for the displacement field (5)In this publication, we limit our discussion to longitudinal laser-induced stresses Here, the negative sign in front of the external stress is chosen such that a positive longitudinal stress (6)The anisotropic linear expansion coefficient When the driven strain pulses and their reflections have propagated out of the volume of interest, the elastic and the Poisson stress contributions fully compensate the external stress and the vanishing total stress marks a quasi-static state.(7)This temperature increase originates from an optically deposited energy density The parametrization of The advantage of using the Gr\u00fcneisen concept is that the ratios of the intrinsically temperature-dependent quantities 3.2In most picosecond ultrasound experiments the footprint of the excitation laser pulse (sub-mm) is much larger than both the thickness of the transducer \u03b13uhin film , because Eq. The one-dimensional nature of the picosecond strain response of continuous thin films was already considered implicitly by the seminal work by Thomsen et al.  see Eq.  that exiFinally, the simple formulation of the wave equation given in Eq. 3.3The elastic wave equation Under this assumption the shape of both the driven picosecond strain pulses and the spatio-temporal distribution of the remaining quasi-static expansion However, for most of the materials assuming a single temperature, i.e., quasi-instantaneous equilibration of the electrons, phonons or any other energy reservoirs in the solid is a strong oversimplification. In typical metals such as Au, Cu and Pt the laser excitation leads to a sudden increase of the energy density in the electron system, which is subsequently transferred to phonons within few picoseconds. This coupling of the subsystems on a timescale comparable to the relaxation of the lattice may be crucial for the induced stress and the driven picosecond strain pulses as experimentally demonstrated for Al (17)In addition to the energy distribution among different degrees of freedom, a one-temperature model also oversimplifies spatial heat transport within metal heterostructures because it disregards non-equilibrium transport phenomena like ballistic Such a diffusive 2TM not only includes the coupling between the two subsystems  transition metal elements  in the high excitation fluence regime observe a distinct fluence and temperature dependence of the electron\u2013phonon coupling timescale 3.4The prevailing paradigms in picosecond ultrasonics are thermoelastic stresses that drive the observed picosecond strain response according to the elastic wave equation This energy density initially deposited to electronic excitations is subsequently distributed within the sample structure and also locally transferred to other degrees of freedom as already discussed in Section It depends on the properties of the material under investigation, which degrees of freedom have to be considered separately to account for the total spatio-temporal external stress. In general, the individual treatment of different degrees of freedom is only necessary for describing the picosecond strain response if the subsystem-specific Gr\u00fcneisen parameters differ. Conversely, the strain measurement only provides access to ultrafast microscopic processes if the involved quasi-particle excitations contribute differently to the total external stress. The separation of subsystem contributions to the strain response of the atomic lattice is schematically visualized in The quasi-instantaneous electronic stress contribution is captured by an electronic Gr\u00fcneisen parameter In laser-excited magnetically ordered metals, the laser-induced spin disorder provides an additional magnetic stress contribution in addition to the electron and phonon stresses. For a Heisenberg exchange interaction the respective Gr\u00fcneisen parameter can be expressed as In total, the Gr\u00fcneisen approach provides a separation of the laser-induced stress into distinct degrees of freedom, which is linear in the contributing energy densities, and can be used even if these subsystems are out-of-equilibrium with each other for many picoseconds 3.5udkm1DsimMatlabModeling the time-dependent strain response allows us to obtain the spatio-temporal stress profile udkm1Dsim code In the following, we display and discuss the modeled laser-driven strain response for a generic sample structure that consists of an opaque transducer with thickness The color maps and selected profiles in Modeling the laser-driven strain response via the elastic wave equation is independent of experimental probing technique e.g. optical probe pulses or x-ray diffraction. A direct comparison between experimental data with the model, however, requires a weighting of the modeled spatio-temporal strain map 4This section is dedicated to the presentation of PUX experiments that illustrate the theoretical concepts discussed in the previous section by utilizing the capabilities of hard x-ray diffraction as a quantitative, material specific probing technique.In Section 4.1Observing the timing, shape and amplitude of picosecond strain pulses is central to picosecond ultrasonics experiments. Here, we showcase the ability of PUX to track the propagation of strain pulses within an opaque heterostructure consisting of a thick transducer on a thin detection layer In particular, we discuss the strain response of heterostructures that consist of a few hundred nm thick TbFeThe femtosecond laser pump-pulse deposits energy into the near surface region inducing an expansion of the Adding an additional transparent SiOWe modeled the strain response of the TbFeOverall, we find that the observation of the strain pulses in a thin crystalline detection layer is advantageous compared to the analysis of the strain response of a thick transducer layer. The separation of the detection layer from the laser-excitation region separates the strain signatures of sound and heat in the time domain which can be exploited for the detection of strain pulses with an unconventional shape, as shown in Section 4.2Here, we compare the qualitative and quantitative picosecond strain response of thin films for various in-plane expansion constraints that are shown to affect the out-of-plane strain response. Different sample morphologies change the nature of the ultrafast strain response from one-dimensional in the case of a homogeneous film to three-dimensional in the case of nanograins even if they are attached to a substrate. Describing the ultrafast strain response of granular morphologies requires a model for the three-dimensional elastic response in accordance with Eq. Specifically, we discuss the picosecond strain response of three xis \u03b13\u22480 under neThe schematic depictions  phase at The entrance of the leading compression into the unexcited Nb layer leads to a negative average strain in Nb, while the exit of the compression and the entrance of the tensile part of the strain pulse cause an expansion (The excitation of Dy in its AFM or FM state below The solid lines in (21)with the Poisson stress contribution arising from the expansion within the hexagonal plane Utilizing the anisotropic expansion of Dy Finally, the extracted Gr\u00fcneisen parameters are used to model the laser-induced strain response of Dy and Nb shown in The magnetic degrees of freedom are locally excited by energy transfer from the electron and phonon subsystem on two timescales with a sub-picosecond contribution and a slower This complex interplay of a saturable magnetic stress and a non-saturable phonon stress results in a spatially non-monotonic total stress within the inhomogeneously excited Dy transducer at In summary, this use case demonstrates the unambiguous detection of NTE on picosecond timescales via PUX and exemplifies the extraction of the subsystem-specific stress contributions utilizing subsystem-specific Gr\u00fcneisen constants extracted from thermal expansion in equilibrium. In heavy rare-earth elements NTE arises from magnetostrictive stresses. However, several other mechanisms for NTE and Invar behavior exist e.g. dominant transverse phonon contributions at low temperature and repulsive deformation potential contributions 5We have presented an overview of the capabilities and concepts of PUX, where hard x-ray probe pulses detect laser-induced transient material strain via Bragg peak shifts. Layered heterostructures provide excellent use cases, because the strain propagation and reflections connect the signals from different layers, which \u2013 thanks to the large penetration depth of x-rays \u2013 are accessible even beneath thick metal layers. PUX experiments often provide an intuitive picture of both the strain pulses and the quasistatic strain from the local increase in the energy density as these effects can be separated in the time-domain due to their different propagation speeds.Motivated by the quantitative access to the strain response, we have revisited continuum elasticity theory, to connect the established formulation of picosecond ultrasonics in homogeneously excited continuous thin films via the thermal expansion coefficient to a formulation that incorporates NTE and is able to reveal the Poisson effect on ultrafast timescales.We have shown that PUX experiments may serve as an ultrafast probe of the local energy content in nanoscopic layers. The observed strain is driven by a stress, which is in many scenarios directly proportional to the energy densities in different subsystems. The proportionality constants are the sub-system specific Gr\u00fcneisen parameters for electrons, phonons and magnetic excitations which enable a simplified expression for the driving stress in the inhomogeneous elastic wave equation.The selected examples of PUX experiments illustrate scenarios where x-ray probing is advantageous compared to established and versatile all-optical experiments. Strain pulse detection in buried layers that allows us to separate propagating strain pulses and quasi-static strain in the time-domain is one of the key advantages of PUX experiments as demonstrated for a thin Nb layer buried below an opaque TbFeThe presented experiments work in the symmetric diffraction of rather dim and poorly collimated x-rays from a laser-driven plasma source Large scale facilities from synchrotron radiation sources to FELs provide many additional opportunities beyond the basic PUX experiments discussed here. The excellent collimation and energy resolution of the x-ray beam supports grazing-incidence measurements The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."}
+{"text": "Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related mortality worldwide. Spontaneous regression of HCC is rare with few documented cases in literature. The mechanism of this phenomenon is unknown, but tumor hypoxia and systemic inflammatory response have been suggested as possible etiologies. This article aims to shed more light on this rare phenomenon and provides an opportunity to review the proposed pathophysiology of spontaneous HCC regression. In this case report, we describe\u00a0an interesting case of a 39-year-old male with HCC who underwent spontaneous regression. Hepatocellular carcinoma (HCC) is a primary liver tumor that usually occurs in the setting of cirrhosis. It is the third leading cause of cancer-related deaths in the world, according to the World Health Organization GLOBOCAN database, and the most rapidly growing cause of cancer deaths in the United States ,2. The tA 39-year-old male with alcohol-associated cirrhosis  23) underwent evaluation of abdominal pain in the emergency room with computed tomography (CT) with contrast. The CT revealed cirrhotic morphology of the liver with a 4 cm hyper-enhancing mass in the right hepatic lobe. Triple-phase CT done for further evaluation of the hepatic mass noted on the single-phase study showed an arterially enhancing mass in segment VIII, which measured at least 3.6 cm in axial dimension and washes out on delayed phase CT; this was classified as LI-RADS 5 lesion (imaging features consistent with HCC, Figures Staphylococcus aureus sepsis at which time her imaging demonstrated near-complete resolution of her HCC [Spontaneous regression of HCC is a rare phenomenon, and there have been a few documented cases of spontaneous HCC regression in the United States . Spontan her HCC . The tru her HCC . The mecTumor hypoxia as a mechanism is inherently appealing as it simulates the conditions created by certain established treatment modalities such as TACE and sorafenib. There are some documented cases of spontaneous regression where patients were noted to have direct ischemic insult either through thrombosis of the hepatic artery or portal vein or profound systemic hypoperfusion from massive variceal hemorrhage -9. TACE There have been some reports of spontaneous regression of metastatic disease which suggests a systemic process may possibly be involved in spontaneous regression -14. AbstThe characteristics of the HCC in this present case were large multifocal lesions in a young adult with significant alcohol intake. The exact mechanism for the spontaneous regression observed here is unclear but it is possibly related to his abstinence from alcohol and/or a spontaneous venous or arterial thrombosis that went undiagnosed when the patient was lost to follow-up.With regard to our patient, alcohol cessation, which has been shown to induce a form of systemic inflammatory response, might have contributed to the spontaneous regression of his HCC. The data reviewed here shows that tumor hypoxia and systemic inflammatory response are important components of spontaneous regression. The true mechanism of spontaneous HCC is likely complex and multifactorial. It is entirely plausible that these two factors described likely have a synergistic effect on spontaneous regression. Analysis of the immunological reactions involved in the spontaneous regression of HCC has serious implications for the development of newer forms of immune-based therapies. It is, therefore, clear that the accumulation of more literature on the spontaneous regression of HCC is necessary in this active area of research."}
+{"text": "Despite activities of daily living being frequently performed simultaneously with a cognitive task, motor function is often investigated in isolation, which can hinder the applicability of findings. This brief review presents evidence that 1) performing a cognitive challenge simultaneously with a motor task can negatively impact force steadiness and fatigability of limb muscles during a static contraction, 2) the negative impact on old adults (>65\u00a0years old), particularly older women is greater than young when a cognitive challenge is simultaneously performed with a static motor task, 3) age-related mechanisms potentially explain impairments in motor performance in the presence of a cognitive challenge, and 4) the mechanisms for the age-related decrements in motor performance can be distinct between men and women. These observations are highly relevant to the older adults, given the increased risk of accidents and injury when a motor task is performed with a high cognitive-demand task, especially in light of the expanding reliance on an aging workforce. Motor function differs between the sexes and declines with age . Two impIn the laboratory setting, experimental models have mimicked these stressful conditions found in daily activities or sport events by imposing a cognitive task before or during the motor task of interest . The cogMotor and cognitive function diminishes with aging with more rapid declines after 65\u00a0years , with imThis brief review will highlight the impact of increased cortical input via imposing a challenging cognitive task during fatiguing and non-fatiguing static contractions in young and older men and women. We focus on force steadiness and time to task failure of limb muscles. The evidence summarized in this review suggests that imposing a cognitive challenge during a motor task can expose sex and age differences in motor performance that are subclinical and not typically observed in the absence of cognitive challenge. Exposing these sex and age-related differences in motor function when simultaneously performing cognitive and a motor tasks, and understanding the physiological mechanisms involved are relevant for designing interventions to improve performance during similar work-related tasks.Fatigue is a disabling symptom in which physical and cognitive function are limited by interactions between performance fatigability and perceived fatigability . QuantifSome work-related tasks and activities of daily living are performed for prolonged periods in the presence of cognitive demand and stress. To understand the effects of cognitive demand and stress on motor fatigability, the time-to-task failure of sustained static and intermittent contractions was determined while individuals simultaneously solved a challenging mental math designed to increases the perceived stress   with disAlthough not fully understood, there are some insights on the potential physiological mechanisms that might explain the sex differences in young adults and limb dependency on the reduction in time-to-task failure in the presence of a high-cognitive challenge . The increased cardiovascular response in the presence of the high-cognitive challenge was not associated with the magnitude of the reduction in time-to-task failure, regardless of the limb assessed . HoweverLimb differences in maximal strength may also explain the minimal reduction of time-to-task failure in presence of high-cognitive challenge  for the low extremity muscles but not upper extremity muscles. Specifically, the initial maximal force obtained on the upper extremity muscles  was larger than lower extremity muscles  and the magnitude of sex differences in strength was also larger for the upper extremity compared with the lower extremity . CombineAge-related decrements in maximal force  and the In the lower limb experiments, however, a key component of the age-related decrements in motor performance was exposed. The high-cognitive challenge  increased the between-subject variability in performance fatigability of the lower extremity muscles for older adults compared with young individuals. This was seen as a much larger reductions of the time-to-task failure in the presence of a high-cognitive challenge for some older individuals but not others, with the group average not changing . The greIn the laboratory setting, force steadiness during static tasks can be quantified with the fluctuations in force output normalized by the average of target force [Coefficient of variation (CV)] . During The magnitude of impairment in force steadiness in the presence of the cognitive challenge  was larger at very low force levels, such as 5% of maximum than at moderate levels of contraction  . Age andThe mechanisms for the force fluctuations during a static contraction involve variability in the signals from the central nervous system to the skeletal muscle. Experiments without a cognitive challenge using recent advances in non-invasive technology, such as the ability to quantify motor unit behavior using high-definition electrodes , observeFactors influencing the increased variability of common synaptic input to motor units and impaired force steadiness, particularly at very low force levels, with the imposition of a high-cognitive challenge potentially involve disruptions in cortical mechanisms that are yet to be fully understood. The high-cognitive challenge can alter the oscillations in the effective neural drive to motor neuron pool, as observed by increased oscillatory activity between cortex and muscle  when a difficult mental math was imposed during very low intensity contractions of the hand muscles in older but not young individuals . FurtherAdditionally, the magnitude of influence of the Trail Making Test results on the impaired force steadiness with high-cognitive challenge was larger in older men compared with older women , indicatThe force steadiness obtained with laboratory-based tests using static contractions during control conditions is frequently associated with dynamic functional tasks of the upper and lower extremities that resemble activities of daily living . RegardlImposing a cognitive challenge during very low and moderate intensity static contractions can further increase the differences in motor performance between young and older men and women. A difficult cognitive challenge executed simultaneously with a motor task can amplify age-related decrements in motor function including brief time-to-task failure and reduction in force steadiness especially in women. Emerging evidence indicates that cortical mechanisms are involved with the loss of force steadiness with the imposition of cognitive challenge and include more variable common synaptic input to motor units. Peripheral mechanisms associated with strength, however, are predictive of the brief time-to-task failure during static contractions in presence of a cognitive challenge. These findings have potential implications for an aging workforce considering that accident proneness and injuries from work-related tasks are associated with the magnitude of cognitive stress."}
+{"text": "In order to enhance and promote tissue repair and healing processes, current exploratory and investigative research lines in medical and dental treatments are focusing on the use of bioactive materials that are able to induce and trigger a specific targeted biological activity to stimulate the suitable response from the host tissue.-\u00ae  and BiominF\u00ae  are examples of two developed toothpastes containing BAGs (with or without Fluor) for enamel remineralisation and dental hypersensitivity/tooth sensitivity [In oral hygiene: Novaminsitivity .-In endodontics: BAG-based pulp capping materials could stimulate pulp cells\u2019 secretory potential, increase the sealing ability, decrease bacterial infiltration, and preserve pulp vitality.-In restorative dentistry: BAGs can be potentially added to dental adhesives and composites. BAG-based restorative materials are expected to possess remineralizing potential or at least to provide a certain degree of anti-enzymatic/bacterial activity with sustained durability over time.-\u00ae -Perioglas\u00ae ) or implant coatings to improve osteointegration. Current research lines are focused on the development of BAG-based bone scaffolds to promote bone regeneration through in vivo tissue engineering [In bone healing: Some products containing BAG particles are already available in the market such as bone filling materials  could be classified as \u201cbioactive materials\u201d because of their ability to interact with biological tissues through formation of a hydroxyapatite-rich layer at the BAG\u2013tissue interfaces, and encourage tissue remineralization, regeneration and integration. One of the potential interactions is the formation of a chemical bond with bone, or at least, promoting its self-healing potential through cell stimulation. Since the introduction of BAGs in 1969 by Professor Larry Hench, the development of BAG-based materials has continued to rise for diverse clinical indications for minimally invasive and biologically based therapies [Although the majority of BAG-based dental materials are still in the experimental phase, this Special Issue aims to explore and elucidate the current status and future perspectives related to BAG use in dental biomaterials and highlight the rationale and benefits behind their applications in the medical as well as dental fields."}
+{"text": "Incidental testicular irradiation during prostate cancer radiotherapy is rarely documented in literature and the long-term impact on gonadal function largely underreported. Here we present an overview of available data on incidental testicular irradiation and radiation-induced hypogonadism during prostate cancer radiotherapy and discuss future technical developments to minimize testis irradiation. The long-term impact of androgen suppression has largely been demonstrated in prostate cancer (PCa) patients, with a wide range of hormone-induced side effects, including an increased risk of cardiac events, osteoporosis, metabolic syndrome, and impaired sexual function et al. estimated a 9% decrease rate in testosterone levels 3\u00a0months after irradiation, but failed to demonstrate a clear correlation between testicular doses and a potential hypogonadal effect et al.The existence of a dose\u2013response relationship between the incidental testicular irradiation and the decrease of the testosterone levels following curative external beam radiotherapy (EBRT) for PCa is far to be well established . In patiet al., despite the testosterone levels 19\u00a0months after SBRT returned to baseline and EPIC hormonal scores remained stable, patients showed a 10.9 point decline in the EPIC sexual scores at the 19- to 24-month time period, suggesting a more complex etiology of sexual dysfunction in patients treated with curative radiotherapy Although the impact of incidental testicular irradiation on gonadal function is determined, the further repercussion on sexual function remains to date speculative. As demonstrated by Yuan et al.The relationship between the incidental testicular dose and the recovery time of testosterone to normal levels has been studied by Pickles et al. were unable to demonstrate a significant change in testosterone levels, even if the subgroup of patients with normal pre-treatment gonadal function was the only one to experience a significant decrease in the testosterone levels at all time periods (approximately 20%) As far as the radiotherapy techniques are concerned, some points merit special considerations. First, while the widespread use of stereotactic body radiation therapy (SBRT) has the potential to decrease the integral dose to the testis compared to standard fractionated regimens, caution to avoid beams directly traversing the testicles and to limit the scattered dose is required when non-coplanar robotic arm devices are used In summary, in the wide spectrum of radiation-induced toxicities, hypogonadism induced by incidental testicular irradiation constitutes an often neglected and underestimated side effect observed in men with PCa treated with curative radiotherapy. Although the relationship with the sexual function and disease control remains to be elucidated, approaches in planning optimization and image guidance trying to limit testes doses are therefore highly encouraged when irradiating curatively PCa patients.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."}
+{"text": "Digital interventions for common mental disorders are coming of age. The uptake of evidence-based self-guided and guided (a-synchronic in time) cognitive behavioural digital interventions for depression and anxiety in routine care is however low. Blended treatment formats appear an attractive alternative for routine care settings as these combine face-to-face sessions with digital ones in integrated treatment protocols. Yet little is known about the clinical and cost-effectiveness of blended CBT (bCBT). In this presentation I will touch upon the current state of the art of digital interventions for depression and anxiety disorders, including blended formats in routine care and I will go beyond that state by addressing new developments. I will illustrate these new developments by virtue of several studies (RCT\u2019s) we conducted on the clinical and cost-effectiveness of blended CBT interventions (and their implementation) in routine care settings. A specific focus will be put on blending digital phenotyping in CBT treatment which includes mobile ecological momentary assessment tools and AI algorithms.While digital mental health for depression and anxiety in routine care was boosted through the Covid-19 pandemic, the question remains whether the current knowledge base will leveraging digital mental health research and services to the next level. Implications for future research on blended treatments and clinical applications in routine care will be discussed.None Declared"}
+{"text": "Ironically, the correlation between systemic pathologies and caries/ periodontal diseases is commonly accepted by the scientific and medical community, but the fact that severe mental illnesses may affect one\u2019s physical health, and thus lead to poor oral health is less well-known.This clinical case report\u2019s aim is to raise awareness among medical staff about the relevance of appropriate management of patients with severe mental illnesses in terms of dental care.Illustration of integrative management through the description of the oral rehabilitation of a 63-year-old female whose bipolar disorder had been diagnosed 20 years ago. This patient came in May 2020 to the Cliniques Universitaires Saint-Luc  for painless mobility of the lower central incisors. Her diagnosis later revealed more than 20 advanced carious lesions as well as chronic severe periodontitis. Since then, despite numerous dental treatments and regular follow-up appointments, an important degradation of her oral health could be noted over time, characterized by a recurrent carious phenomenon  and a failure in the stabilization of her periodontitis.The literature review revealed that bipolarity was a major risk factor leading to tooth decay and aggravation of periodontal disease; when bipolar disorders\u2019 inherent symptoms are coupled with medication\u2019s side effects, they work in synergy towards a deterioration of oral health. Following the results obtained after this etiological research, the management of this patient was pursued in accordance with specific recommendations proposed in the literature. A stabilization of her oral condition was then observed at the 3-6-9-12 month check-ups, without the appearance of any new lesion.Image:Image 2:The positive effect obtained on this patient\u2019s oral health following the implementation of bipolar disorders specific measures opens the discussion on the relevance of integrating individual strategies within the therapeutic management of patients with severe mental illnesses.None Declared"}
+{"text": "Editorial on the Research TopicInsights in Anti-doping Sciences: 2021The year 2021 may represent a turning point in anti-doping with the enforcement of a new World Anti-Doping Code after a thorough revision of the 2015 edition  that came in force in 2021 and from a theoretical perspective, Petr\u00f3czi & Boardley address \u201cregulative, normative, and cognitive components of clean sport if we are to maximise its legitimacy\u201d Krumm et al. underlines major confounders as a starting point towards selection and validation of new approaches to rapidly reinforce the ABP. Krumm et al. interestingly highlight that research including the administration of doping substances result systematically in more atypical passport findings (ATPFs) in comparison to interventions including for example exercise training of hypoxic exposures while ATPFs are not excluded in the latter. Putting more weight on confounders to better target tests or interpret biological profile is therefore paramount.From a more practical point of view, the concept of the indirect detection of doping by monitoring hematological and steroidal variations in athletes longitudinally  still represents a useful strategy in the anti-doping toolbox. Recent research and discussion among anti-doping stakeholders in various workshop and conferences push towards testing and implementing new biomarkers for the ABP. However, hemoglobin concentration [(Hb)] as a primary biomarker for the hematological module of the ABP are influenced by plasma volume shifts. The perspective article presenting the future opportunities for the ABP Saugy et al. reported that mean effects of rhEPO on blood parameters were greater than those induced by hypoxic exposure [1.7 times higher for (Hb) and reticulocytes percentage and 4 times higher for hemoglobin mass]. The interpretation of ABP profiles is hence facilitated by this identification of \u201ctemporal and quantitative evolution of blood parameters in connection with different hypoxic exposure doses, as well as different rhEPOs doses\u201d.Further, the comparative impact of either altitude exposure or recombinant human erythropoietin (rhEPO) injections on ABP parameters is evaluated. In their review, Donati et al. minimize false negatives by expanding the antigen panel, selecting more accurately the gating area of the red blood cells and optimizing instrumental protocols. Their experimental approach was thus successful in samples simulating HBT between two compatible subjects.With the evidence that the detection window and methods for EPO have improved, athletes regained interest in blood transfusions as an effective method to illegally boost their muscle oxygen convective transport. Homologous blood transfusion (HBT), i.e., with blood from a compatible donor, was widely used before it was forbidden in 1985 and athletes began to use rhEPO. Detecting autologous (reinjecting your own blood) however remains challenging with no internationally recognized method for its detection. In that context, an original research proposed a strategy to reduce false-negative results by improving the current antigen method The objective of this Research Topic is to provide well-documented insights by experts in the field to address the current challenges faced in the anti-doping efforts.The body of evidence provided in this Research Topic supports the application of the updated 2021 World Anti-Doping Code as a robust basis to define priorities and strategies to tackle athletes trying to cheat. The included articles reflect research in this niche field ranging from perspectives to reviews with original research needing to answer pragmatically questions that arise in the daily implementation of the Code.This Research Topic ultimately allows to collect and discuss existing evidence with practical proposals and empirical findings to strengthen the fight against doping."}
+{"text": "Exercise is a powerful physiological modulator of metabolism that represents a cornerstone in the prevention and treatment of various metabolic diseases . The protective effect of exercise on metabolic abnormalities involves multiple tissues, of which skeletal muscle is highly important because it is a major determinant of resting energy expenditure  that may2max) and muscle growth after aerobic and resistance exercise training are also known to exist  and fitness level associate with inter-individual differences in local and systemic aspects of metabolic efficacy during exercise. They propose that the ACE-D allele influences differences in acute exercise-induced aerobic metabolic processes at the level of skeletal muscle and lung tissue in different fitness states. They further argue that in aerobically fit subjects, dependence on mitochondrial function in working muscle is relatively more important for increased power output in D-allele carriers than in non-carriers.In this Research Topic, Fortino et al. subjected young male and female individuals to eccentric contraction exercise in order to evaluate gender differences in the myogenic and inflammatory response. It has long been known that eccentric exercise increases satellite cell expression and inflammatory responses in human muscle  is identified as a myokine released from contracting muscle that enhances glucose uptake in cultured myotubes. This suggests that LIF plays a role in autocrine regulation of muscle glucose metabolism during exercise.In order to identify factors that regulate the inter-individual metabolic differences occurring following exercise, it is also important to develop unique experimental models that allow control of external and internal factors affecting the metabolic responses. By the use of omics analyses, Janzen et al. seek to explore the molecular mechanisms that regulate intramuscular glucose utilization during exercise. Janzen et al. identify that AMPK DKI mice have decreased exercise endurance and maximal running capacity likely due to higher and lower glucose and fat oxidation during exercise, respectively. Although the knock-in mutation in the glycogen-binding region of AMPK \u03b2 does not affect glycogen content in rested and exercised muscle, findings presented by Janzen et al. suggest that the binding of AMPK \u03b2 to glycogen is necessary to preserve exercise endurance and maximal running capacity by securing proper substrate utilization during exercise.AMPK \u03b2 is regarded as the glycogen-binding subunit of the AMPK heterotrimeric complex as it contains a carbohydrate-binding module . Introduvia unique physiological and biological approaches. Such findings are ultimately important for establishing effective, efficient, and personalized exercise programs for all individuals in order to secure a healthy lifestyle and prevent development of metabolic diseases.In summary, this Research Topic has advanced our understanding of the mechanisms regulating whole-body and skeletal muscle metabolism in response to various forms of exercise. Specifically, the series of articles have addressed some of the factors that cause inter-individual differences in metabolic changes following exercise. Moreover, new regulatory mechanisms of energy metabolism at rest and during exercise have been elucidated Exercise adaptations are controlled by numerous regulatory and interacting protein networks of which many still need to be fully described. In addition, non-protein molecules such as lipids and metabolites are presumably also mediators of exercise adaptive responses but have not been adequately studied in detail. Mechanistic investigations of these molecular determinants will provide the basis for new hypotheses and ideas about the mechanisms responsible for the exercise-induced adaptations in skeletal muscle. This will contribute to our understanding of the health beneficial and therapeutic effect of regular exercise that may be exploited for pharmacotherapies to combat various lifestyle and chronic diseases."}
+{"text": "Face and neck burns bring unique complications and often require specific training and experience for the burn physical rehabilitation professional. The COVID-19 Pandemic created a need for virtual learning during a time when in-person learning was not possible. While this format can meet some needs, it does not allow for practice and interaction with instructors. There are limited education and training opportunities for burn therapists which include such extensive practical opportunities. This unique didactic training program provided mentorship and tangible skills of a complex and specialized area of burn rehabilitation. \u2022 Learning Objectives were determined using the Burn Therapist Competency Tool-Version 2 \u2022 Developed curriculum for each facial/neck regions as well as various scar management techniques throughout the continuum of care \u2022 Individual modules were developed by Occupational Therapists, Physical Therapist and Speech and Language Pathologist with experience in the field \u2022 The in-person course consisted of 4 hours of lecture and 8 hours of hands-on splinting and scar management training \u2022 Instructors provided interactive and collaborative feedback for every participant Pre & Post testing completed to assess learning \u2022 Feedback from participants was assessed for quality improvement \u2022 Follow up questionnaire was provided to assess implementation into clinical practice and self-perceived level of experience related to rehabilitation of face/neck burns24 Occupational, Physical and Speech Therapists participated in the 2-day course. Results of the post-test indicate increased knowledge pertaining to the learning objectives. 21 participants remained for the second day of the hands-on splinting and scar management portions and demonstrated learned knowledge of these intervention techniques. Post-course assessments attest to increased comfort with new skills. Participant follow up gaged overall effectiveness of clinical practice improvements.Participant feedback provided valuable insight into the ongoing need for training and mentoring of burn therapists. This is vital in developing additional training resources, including step-by-step explanation and video content for repetition and learning. Ultimately, implementation of these new skills into each participant\u2019s clinical practice was the desired outcome of this course.This project highlighted the gap in knowledge for burn therapists when it came to face and neck burns."}
+{"text": "In the Author Summary, there is an error in the second sentence. The correct sentence is: In places where injectable treatment is not available, the World Health Organization (WHO) malaria guidelines recommend that children below 6 years of age be administered a single dose of rectal artesunate (RAS) before being referred to a higher-level health facility for parenteral treatment completed with a full course of artemisinin-based combination therapy (ACT)."}
+{"text": "Prediction modelling increasingly becomes an important risk assessment tool in perioperative systems approaches, e.g. in complex patients with open abdomen treatment for peritonitis. In this population, combining predictors from multiple medical domains  outperforms the prediction capabilities of single-domain prediction models. However, the benefit of these prediction models for clinical decision-making remains to be investigated. We therefore examined the clinical utility of mortality prediction models in patients suffering from peritonitis with a decision curve analysis.In this secondary analysis of a large dataset, a traditional logistic regression approach, three machine learning methods and a stacked ensemble were employed to examine the predictive capability of demographic, physiological and surgical variables in predicting mortality under open abdomen treatment for peritonitis. Calibration was examined with calibration belts and predictive performance was assessed with the area both under the receiver operating characteristic curve (AUROC) and under the precision recall curve (AUPRC) and with the Brier Score. Clinical utility of the prediction models was examined by means of a decision curve analysis (DCA) within a treatment threshold range of interest of 0\u201330%, where threshold probabilities are traditionally defined as the minimum probability of disease at which further intervention would be warranted.Machine learning methods supported available evidence of a higher prediction performance of a multi- versus single-domain prediction models. Interestingly, their prediction performance was similar to a logistic regression model. The DCA demonstrated that the overall net benefit is largest for a multi-domain prediction model and that this benefit is larger compared to the default \u201ctreat all\u201d strategy only for treatment threshold probabilities above about 10%. Importantly, the net benefit for low threshold probabilities is dominated by physiological predictors: surgical and demographics predictors provide only secondary decision-analytic benefit.DCA provides a valuable tool to compare single-domain and multi-domain prediction models and demonstrates overall higher decision-analytic value of the latter. Importantly, DCA provides a means to clinically differentiate the risks associated with each of these domains in more depth than with traditional performance metrics and highlighted the importance of physiological predictors for conservative intervention strategies for low treatment thresholds. Further, machine learning methods did not add significant benefit either in prediction performance or decision-analytic utility compared to logistic regression in these data.The online version contains supplementary material available at 10.1186/s12911-023-02156-w. Advanced statistical methods such as those summarized under the term machine learning are becoming ever more important in the analysis of medical data as illustrated by the rapid and exponential increase in the number of machine learning papers . Such memodel evaluation, the important issue of calibration has traditionally received only little attention relative to the issue of model performance [However, several issues in terms of building, evaluating and using such clinical prediction models and questions regarding the added benefit of advanced machine learning methods over traditional statistical methods have been noted recently: First and in terms of formance . Calibraformance . Modern formance .model performance, the discrimination capacity of these prediction models is traditionally evaluated by means of the area under the receiver operating characteristic curve (AUROC) [Second and in terms of  (AUROC) . Predict (AUROC) , the AUR (AUROC) . In such (AUROC) . In addi (AUROC) .clinical utility, it has been noted that the question how and if such prediction models can improve care delivery and disease management cannot be determined by solely inspecting model discrimination or model calibration [Third and in terms of ibration , 17. Intibration . DCA cenibration . Overallibration . DCA hasibration , oncologibration  and manyibration , 24.machine learning for prediction modelling, a systematic reviews showed no benefit in terms of performance gain by more advanced statistical machine learning algorithms over the traditional method of logistic regression [Fourth and in terms of gression . To levegression . Stackedgression , the risgression , the COVgression  and the gression .In this study, we aim at applying these methods holistically to a clinical prediction model for a previously defined cohort of patients with open abdomen treatment for peritonitis, a clinically challenging cohort deserving optimal resource allocation at the time of admission to intensive care. While the performance benefit of using predictors from multiple medical domains could be recently demonstrated , the benThe aim, therefore, is to examine if single- and multi-domain prediction models provide a higher net benefit than the default intervention strategy of \u201ctreat all\u201d (where the intervention consists of the broad interventions mentioned above). In addition, we employ several base machine learners and a stacked ensemble to examine the potential benefit of modern machine learning methods compared to regular and penalized logistic regression both in terms of model performance and in terms of clinical utility by means of a decision curve analysis.This is a secondary analysis of a study performed in adherence to the principles in the Declaration of Helsinki and which was approved by the Hamburg Medical Association (#WF072/20). In brief, the initial study described a cohort of 1,351 consecutive adult patients surgically treated for peritonitis over a decade (January 1998 to December 2018) at the Department of General and Visceral Surgery of the Asklepios Hospital Altona, Hamburg, Germany, with survival  as primary outcome measure [Categorical variables were summarized by counts and percentages and compared by means of a chi-square test. Numerical variables were summarized with median and interquartile range and compared by means of an unpaired two-sample Wilcoxon test.The study follows the network \u201cEnhancing the QUAlity and Transparency Of health Research\u201d (EQUATOR)\u2019s guideline for transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD) .As recommended in the literature , Fig.\u00a01 alpha  and lambda (shrinkage parameter) for Elastic Net; mtry (number of variables to possibly split at in each node), splitrule (splitting rule), min.node.size  for Random Forest and n.trees , interaction.depth (maximum depth of each tree), shrinkage (shrinkage parameter) and n.minobsinnode  for Gradient Boosting Machine. The hyperparameters with the largest AUROC value were chosen as the optimal hyperparameters.In terms of model training for each method, a repeated random stratified sampling with respect to the outcome variable was performed where 66% of the available data was assigned to a training set and the remaining 34% to a test set. Fifteen hyperparameter settings for each tunable hyperparameter were randomly sampled for each round of a 5-times repeated 5-fold cross-validation. The following hyperparameters were available for tuning: Calibration of the prediction models was assessed by means of calibration belts  and assoDecision curves are computed based on the model predicted probabilities for the test dataset of each random split-sample, allowing to illustrate both the median and 95%-confidence interval of the net benefit for a given treatment threshold. The decision curves were computed for each base learner and the stacked learner and separately for each medical domain within the treatment threshold range of interest (0-30%). To aid the interpretation of the decision curve, we note that the maximum net benefit is equal to the mortality prevalence , 39, whiThe original dataset contained several systematically missing data not at random  as discucaret package [dcurves package [In terms of statistical software, the prediction models were computed with the  package  decision package . All com package .Patients\u2019 characteristics are summarized in Table\u00a0The calibration in both single- and multi-domain models for different types of statistical approaches is shown in Fig.\u00a0Similar to the primary study which only used logistic regression, Fig.\u00a0An overview of the performance metrics of the various prediction models is shown in Table\u00a0Figure\u00a0Another result is that the decision-related net benefit of the prediction models is limited to threshold probabilities above about 10%: for lower thresholds, the net benefit is equal to the default intervention strategy of \u201ctreat all\u201d and thus provides no added decision-related value. For threshold ranges between 10 and 20%, the decision-related added benefit from the prediction models derives predominately from physiological factors . As the stacked learner is based on the cross-validated predicted probabilities of the individual base learners, it shares many calibration features of the individual base learners: For example, the stacked demographic prediction model features the same miscalibration as the demographic prediction model based on the random forest. However, the multi-domain prediction model of the stacked learner is well calibrated (p\u2009=\u20090.24). The performance metrics of the stacked ensemble are similar to the individual base learners Fig.\u00a0B. AdditiWe assessed the benefit of machine learning methods both in the terms of predictive performance and clinical decision-related benefit in a large cohort of patients with open abdomen treatment for peritonitis. Similar to the primary analysis , the mulThe fact that more advanced machine learning prediction models demonstrate similar performance metrics as regular and penalized logistic regression is likely related to the sample size and the limited number of predictors: in these cases , a simulation study recently demonstrated that conventional logistic regression features good prediction performance compared to machine learning methods . The facAgainst the current questions regarding the added benefit of machine learning methods in clinical prediction modelling for binary outcomes across medical domains  or in paIn terms of clinical importance, our decision curve analyses reveal different net benefits in terms of modelling clinical consequences in a suite of prediction models that are based on predictors from individual medical domains. Importantly, the framework of this study allows to assess the degree of risk aversion, for example in conservative risk-avoid strategy, for different medical domains and thus provides a much more nuanced perspective on risk modelling of patient with open abdomen treatment for peritonitis than the examination of traditional performance metrics. We focused on low threshold probabilities in the clinically-motivated range between 0 and 30% representing a conservative risk approach as we are more much more concerned about the patients\u2019 possible death than about unnecessary interventions for surviving patients. We adopted a broad, general perspective on the possible interventions based on the predicted mortality risks by the models, i.e. possible interventions could constitute running additional diagnostic tests and laboratory measurements or modifications of the existing treatment plan.Of clinical interest is that the decision curve framework revealed that the decision-related benefit of the prediction models is limited to threshold probabilities above around 10%: for lower threshold probabilities, the models\u2019 benefit is equal to the default \u201ctreat all\u201d intervention strategy. A further clinically important finding is that physiological predictors represent the domain with the largest decision-related benefit in the threshold range of interest of this study. The surgical predictors offer only secondary benefits which are limited to threshold ranges above 20%. Demographic predictors offer only marginal benefit. Importantly, these results are robust in terms of choice of the type of prediction model (i.e. logistic regression or a more advanced machine learning method).Since this study demonstrated that different domain-specific prediction model differ (i) in the magnitude of net benefit and (ii) in the threshold range when they actually do provide a benefit , we conclude that the decision curve analysis framework provides a valuable tool to compare single-domain and multi-domain prediction models. While outcome prediction traditionally relies on clinical experience and single scores, these dimensions remain very basic and more sophisticated approaches such as the one described here are warranted. Additionally, a clinically-relevant consequence of the result that that the routinely collected variables that were available for this cohort of patients with open abdomen treatment for peritonitis did not provide additional decision-related benefit for threshold probabilities below 10% is that variables from further domains (i.e. laboratory measurements) should be examined for their benefit in this low treatment threshold range.This study features inherent limitations. First, the dataset features a large degree of missing data not at random. A sensitivity analysis in the Supplementary Material using a single imputation approach to the missing data confirmed the conclusions from the complete case analysis. Second, the performance and decision-related aspects of the prediction models was evaluated only by means of internal validation and not by external validation, which is essential in terms of generalizing our results beyond the cohort of this secondary analysis . Third, Overall, we emphasize that the results and conclusions stated above apply to the clinical prediction setting of this cohort of patients with open abdomen treatment for peritonitis and the chosen threshold range (0\u201330%). Depending of the clinical setting, different threshold ranges may be required which might result in different interpretations regarding the decision-related benefit of single-domain and multi-domain prediction models.In summary, in this cohort of patients with open abdomen treatment for peritonitis we found that machine learning methods did not add significant benefit either in prediction performance or decision-analytic utility compared to logistic regression within a treatment threshold range of interest of 0\u201330%. The decision curve analysis framework provides an invaluable tool to compare single-domain and multi-domain prediction model and demonstrates overall higher decision-analytic value of the latter and highlights different net benefits for demographic, physiological and surgical predictors of as a function of threshold probability. Thus, DCA provides the means to clinically differentiate the risks associated with each of these domains in more depth than with traditional performance metrics.Below is the link to the electronic supplementary material.Supplementary Material 1Supplementary Material 2"}
+{"text": "Primary intrinsic brain tumors and brain metastases are among the most lethal of all human malignancies despite decades of scientific advances. The intersecting fields of cancer epigenetics and metabolism lie at the core of our current conceptual framework for the pathophysiology of these diseases , 2. WhilMcCornack et\u00a0al. discuss mechanisms by which histone methyltransferases and acetyltransferases mediate these diverse processes including reviewing downstream signaling elements and therapeutic targeting opportunities. Valproic acid is a commonly used anti-epileptic with anti-tumor effects through its histone deacetylase (HDAC) activity; however, in this Research Topic, Barciszewska et\u00a0al. define a new epigenetic role for valproic acid in the induction of global hypermethylation. This study provides a rationale for the combination of valproic acid with temozolomide for enhancing DNA damage and oxidative stress in glioblastoma tissues. Although extrachromosomal circular DNA (eccDNA) had been originally observed nearly six decades ago , and lipophagy (a lipid specific form of autophagy). Autophagy is a finely tuned cellular process that enables cancer cell survival in nutrient- and energy-poor settings that define the tumor microenvironment, but can also be exploited for anti-cancer therapies . These studies highlight the important metabolic adaptations utilized by primary brain tumors to survive in the intracranial setting and suggest a new approach to undermining these key dependencies.Tumor metabolism impinges on multiple key oncogenic processes through the coordination of signaling cascades, bioenergetics, and structural components both in a cell-intrinsic manner and in the coordination of cellular interactions within the brain tumor microenvironment. herapies . InductiZhang et\u00a0al. identify that the blood-brain barriers of patients with advanced lung cancers are more permeable than those of patients with early-stage lung cancers or healthy controls, suggesting that primary lung cancers may act at a distance to disrupt the blood-brain barrier and set the stage for future metastases. Further understanding of the processes underlying blood-brain barrier disruption may yield strategies to protect the brain from metastatic colonization. Meningiomas are among the most common primary brain tumors with widely variable prognoses based on molecular classification and morphologic features. Jiang et\u00a0al. utilize imaging characteristics from MRI studies to improve the identification of the extent of tumor invasion to facilitate improved extent of resection. This study further identifies imaging features that serve as independent risk factors for predicting WHO tumor grades through deeper scrutiny of interactions within the brain-tumor interface.Epigenetic and metabolic pathways further support tumor cell invasion. The blood-brain barrier preserves the integrity of the central nervous system and shields against toxins from the central circulation and from invading cancer cells. Breaching the blood-brain barrier is a critical step in the metastatic cascade responsible for the generation of brain metastases . Zhang eBai and Zhou investigate the role of bevacizumab in patients with lung or colon brain metastases, showing differential effectiveness based on the tumor of origin. The prognosis for patients with brain metastases from non-small cell lung cancer remains dismal, particularly when patients are not candidates for surgical resection due to a variety of patient or tumor characteristics. Yang et\u00a0al. study the use of an alternative radiation therapy delivery modality, 125-Iodide brachytherapy, compared to external beam radiotherapy (EBRT) and find improved 6-month survival and similar 12-month survival for the 125-iodide group compared to the EBRT group. This study provides further evidence for an additional modality for the treatment of brain metastases.This Research Topic further touches on therapeutics in the intracranial setting. Vasogenic edema is a major source of morbidity and mortality in intracranial malignancies with limited treatment options . While sJohanssen et\u00a0al. describe the current state of basic and translational research as it applies to glioblastoma with a discussion of the importance of understanding brain tumors through the lens of intratumoral heterogeneity and within the context of their tumor microenvironments. They suggest the use of both rationally designed and hypothesis-generating unbiased combinatorial screening approaches that incorporate heterogeneous tumor models as well as important microenvironmental features to identify compounds and combination therapies with the greatest clinical utility. Taken together, this Research Topic highlights some of the latest advances in the fields of brain tumor biology, specifically focused on the intersection between cancer epigenetics and metabolism and touching on key elements of the tumor microenvironment, with an eye towards improving outcomes for patients with primary and metastatic brain tumors.In a prescient and well-timed review, RG: Writing \u2013 original draft, Writing \u2013 review & editing. BP: Writing \u2013 original draft, Writing \u2013 review & editing. QX: Writing \u2013 original draft, Writing \u2013 review & editing."}
+{"text": "To compare the effect of statin use in relation to castration-resistant prostate cancer (CRPC) treatment, we assessed the risk of ADT-treated PCa-patients to initiate CRPC treatment by statin use and the outcomes of CRPC treatment by statin use. Our study cohort consisted of 1169 men who participated in the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC) and initiated androgen deprivation therapy (ADT) during the follow-up (1996\u20132017). Statin use was associated with slightly decreased risk of initiating CRPC treatment  with a 5.7 years\u2019 median follow-up until CRPC for non-users and 7.5 years for statin users. The risk of discontinuation of first or second line CRPC treatment due to inefficacy was not modified by statin use and the results remained similar in subgroup analysis assessing separately patients treated with taxans or androgen receptor signaling inhibitors. We observed an inverse association between statin use and the risk of initiation of the CRPC treatment. No beneficial risk modification by statin use during CRPC treatment was observed. These results suggest that statins might be beneficial during hormone-sensitive phase but not in the later phases of prostate cancer treatment. The beneficial effect of statins seems, however, not to be limited to cardiovascular prevention. Several studies have found statins to be linked to either improved prostate cancer mortality or progression-free survival6. However, results on statins\u2019 effect on prostate cancer mortality or risk of biochemical recurrence have been partly conflicting. Hence, it is still unclear if the possible benefit of statins is limited to a subgroup of cancer patients e.g. those receiving specific cancer treatment9. Especially, prostate cancer patients on androgen deprivation therapy have been consistently reported to benefit from concurrent statin use13.Statins lower blood cholesterol levels and decrease morbidity and mortality in cardiovascular diseases, especially in secondary prevention12. Raittinen et al.14 compared atorvastatin to placebo and reported atorvastatin to induce adrenal androgen downshift possibly providing a novel pathway reducing androgen concentration in prostate cancer patients. Hu et al.15 found that statins have synergistic effect with abiraterone on neuroblastoma progression in vitro and in vivo. Our previous report showed an additive inhibitory effect of statins on prostate cancer cells in combination with enzalutamide16. Some studies have also demonstrated growth inhibition or induction of apoptosis in prostate cancer cells for statins in combination with docetaxel20.In vitro studies have proposed possible mechanisms that may explain potential additive effects of statin use in combination with androgen deprivation therapy, chemotherapy or androgen receptor signaling inhibitors. Harshman et al. showed statins to competitively reduce uptake of dehydroepiandrosterone sulfate (DHEAS) by prostate cancer cells suggesting a plausible mechanism to reduce supply of DHEAS and act in synergism with ADT21. However, the possible modifying effect of statin use on prognosis of castration-resistant prostate cancer patients treated with docetaxel, enzalutamide or abiraterone still needs further evaluation. Some studies have shown an additive effect of statins combined with either abiraterone or abiraterone/enzalutamide24, but studies assessing statins\u2019 effect on PCa patients treated with docetaxel are scarce.Several epidemiological studies and at least one meta-analysis have reported improved overall and cancer-specific survival in prostate cancer patients treated with statins plus androgen deprivation therapyWe assessed the risk of developing castration-resistant prostate cancer (CRPC), risk of initiation of first- or second-line CRPC treatment and discontinuation of CRPC treatment due to inefficacy in a population-based cohort of men receiving androgen deprivation therapy for prostate cancer.The Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC) is a randomized population-based trial assessing the effect of systematic screening with prostate-specific antigen on prostate cancer mortality. The trial population consisted of all men aged 55, 59, 63 or 67 at baseline residing in Helsinki and Tampere metropolitan areas in Finland. We identified all participants of FinRSPC from Tampere metropolitan area diagnosed with prostate cancer and initiating androgen deprivation therapy during 1996\u20132017. Those 1169 men formed the study cohort for the present study. The follow-up started at the initiation of androgen deprivation therapy and continued until death, emigration from Finland or 31 December 2017, whichever occurred first.Statistics Finland registers all deaths in Finland. Patients with prostate cancer (ICD-10 C61) as a primary cause of death were defined as prostate cancer deaths. In addition, all other causes of deaths were acquired from the database. Statistics Finland gave permission for using the cause of death data (TK/3536/07.03.00/2021).25. The Finnish Institute for Health and Welfare has approved this study protocol and all methods were carried out in accordance to relevant guidelines.The FinRSPC study protocol  has been described comprehensively previously and informed consent was obtained from all FinRSPC participants2. Information on the amount, dosage, generic name, and purchase dates was obtained for all statin purchases. In analyses utilizing \u2018any statin use\u2019 each year with recorded statin purchases was considered as a year of usage. The mg amount of different statins was standardized by dividing the total mg amount of statins with the amount corresponding to a Defined Daily Dose (DDD) defined by the World Health Organization26. Intensity of statin use (average DDDs/year) was calculated by dividing cumulative DDDs with number of years with statin usage. Statin use status was allowed to change on a yearly basis. Dichotomous statin use variables (any/none) and intensity variables were updated for each follow-up year based on recorded purchases. After first reimbursed drug purchase, status remained as ever user even when purchases stopped, to limit bias related to the tendency to discontinue statins during the final stages of cancer. Statin exposure in different analyses is illustrated in Fig.\u00a0The study cohort was linked to the National Prescription Database maintained by Social Insurance Institute of Finland (SII) to obtain information on statin purchases. SII provides reimbursements for purchases of physician-prescribed medications in Finland and registers nearly all drug purchases (over-the-counter purchases not included). The reimbursement system has been described in detail previouslyThe cohort was also linked to the database of Care Register for Health Care (Hilmo) maintained by the National Institute for Health and Welfare to obtain diagnoses from inpatient and outpatient hospital contacts during the follow-up. By using hospital episode diagnoses until year 2000, we calculated a modified Charlson comorbidity index, which was utilized as surrogate for overall comorbidity and short-term risk of dying.The information on CRPC treatment was obtained from electronic patient record system of Tampere University Hospital and included all initiation and ending dates during 2001 to 2020, type of treatment and cause of discontinuation of treatment.Risk of three different outcomes were examined by statin use: the risk of initiating the first-line treatment for CRPC, the risk of initiating second- or third-line treatment for CRPC and the risk for a given CRPC treatment to end due to inefficacy.Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for the risk of initiation of CRPC treatment Table . Statin Logistic regression was used to estimate the odds ratios for the risk of second- and third-line CRPC treatment by statin use status after the initiation of previous CRPC treatment line Table . The folThe risk of a given CRPC treatment to discontinue due to inefficacy was estimated using Cox proportional hazards regression Table . Statin We used adjustment for age at diagnosis, EAU risk group and Charlson comorbidity index in analyses. Statin use was considered as a time-dependent variable in analysis assessing risk of initiating CRPC treatment and as a fixed variable (statin use on initiation year of CRPC treatment) in all other analyses (risk of initiation of CRPC treatment and risk of treatment to end due to inefficacy). When statins\u2019 effect on risk of next CRPC treatment line initiation and discontinuation of current CRPC treatment line due to inefficacy was examined, patients were divided as statin users and nonusers at the year of initiation of CRPC treatment and status was updated for each treatment line separately.Of the 1,169 men, who received androgen deprivation therapy, 615 (52.6%) had used statins during the follow-up. During the median follow-up of 7.5 and 5.7 years, there were 99 prostate cancer deaths among statin users and 150 among non-users. In comparison, there were 289 (47.0%) and 340 (61.4%) overall deaths among statin users and non-users. Use of co-medications, i.e., antidiabetics, antihypertensive drugs, NSAIDs and aspirin was clearly more common among statin users .The median duration from ADT initiation to first-line CRPC treatment was 4.1 years for statin non-users (111/68.9%) and 6.0 years for statin users 50/31.1%), respectively. Statin use was associated with a decreased risk of initiation of CRPC treatment   or third-line  CRPC treatment was observed. In subgroup analyses stratified by median amount of DDDs used at the initiation year of CRPC treatment line, risk modification was not observed, either Table .Table 4RWe did not observe any meaningful differences by statin use in the risk of discontinuation of CRPC treatment due to inefficacy Table . Hazard The duration of first-line CRPC treatment was not affected by statin use status  Fig.\u00a0.Figure 2Statin use among men receiving ADT for PCa was associated with a lower risk of initiating CRPC treatment. This is consistent with previous findings suggesting that statin use may enhance the therapeutic effect of ADT. In contrast, statin use was not associated with risk of initiating second- or third-line CRPC treatment or treatment discontinuation for inefficacy. Contrary to our initial hypothesis, statin users were statistically significantly more likely to have shorter duration of second-line CRPC treatment than non-users.27. Two of those studies also found statins to be linked with better prostate cancer-specific survival21. Especially, the statin use after initiation of ADT has provided most consistent results showing statins to improve prognosis in patients with advanced PCa. In our analysis, the follow-up started at the initiation of ADT and only statin use occurring at the year or after the initiation of ADT was taken into account with time-dependent statin use variables that were allowed to change on a yearly basis. This enabled us to manage immortal time bias which is known to potentially cause results favoring medication users in pharmacoepidemiologic studies28.Three recent meta-analyses have shown statins to be associated with improved overall survival in prostate cancer patients treated with ADT20. To our knowledge, there are no published epidemiological studies assessing specifically the effect of docetaxel or other taxans in combination with statins on prostate cancer prognosis. Our study cohort consisted of men whose primary CRPC treatment was mostly (41.6%) docetaxel reflecting the treatment guidance and reimbursement practice in the beginning of twenty-first century and thus we were able to analyze statins\u2019 potential benefit in combination with docetaxel. In subgroup analyses, we did not observe statistically significant difference in the risk of first or second line taxan treatment line to discontinue as ineffective between statin users and non-users.A couple of previous in vitro studies have found statins to have additive inhibitory effect on prostate cancer cell growth in combination with docetaxel24. However, at least one study showing no benefit from statins in combination with abiraterone exists29. In our cohort, we did not observe differences by statin use status in the risk of enzalutamide or abiraterone treatment to discontinue due to inefficacy. However, our cohort size in regard of subgroup analyses was relatively small and minute differences between groups were not detectable in this analysis. Nonetheless, in our analysis of duration of second line CRPC treatment which consisted mainly of abiraterone or enzalutamide, we observed statistically significantly longer second treatment line duration in men not treated with concurrent statins. This finding that is not in line with previous results might be explained by increased risk of side effects or poorer toleration of treatment among statin users due to e.g. comorbidities or poor performance status which are known to be linked both to statin use status and treatment-associated adverse effects31. Additionally, our analysis examining the risk of treatment line to end due to inefficacy differs from previous studies by outcome measure as survival, per se, was not in scope.Previously, some epidemiological studies have found statins to improve prognosis in castration-resistant prostate cancer treated with enzalutamide or abirateroneThe durations of treatment lines for CRPC were relatively short and therefore we were forced to use mostly fixed statin use variables in these analyses predisposing us to healthy-user bias as discontinuation of statins becomes more likely with shorter life-expectancy. As no statistically significant differences despite this potential source of bias favoring statin users were observed, this is suggestive that statins do not have marked benefit in this late phase of prostate cancer treatment. In addition, healthy user bias would probably not pose a major problem in this situation because PCa patients initiating treatment for CRPC still may have years of life remaining and therefore discontinuation of statin use is unlikely to happen that early. Considering the current evidence, we suppose the optimal timing of statin use in relation to prostate cancer treatment to be concurrently with androgen deprivation therapy.32. The participants of FinRSPC study were followed-up during 1996\u20132017 which represents the era when androgen receptor signaling inhibitors (ARSI) were initiated less frequently and mostly for the second line treatment of CRPC. Due to that fact the number of patients treated with ARSIs remains relatively low limiting detection of possible differences in subgroup analysis.The drug reimbursement practice in Finland has changed since the start of follow-up as at that time enzalutamide or abiraterone purchases were reimbursed only for patients previously treated with docetaxel. The current treatment guidance by European Association of Urology recommends the initiation of abiraterone or enzalutamide increasingly in the earlier phase of disease limiting the generalizability of these results for the presentWe were able to analyze the association between statin use and the risk of developing castration resistant prostate cancer and the outcomes of CRPC treatment by statin use in our population-based cohort of 1,169 men initiating ADT during the follow-up. The comprehensive and reliable data provided by national databases and electronic patient records enabled us to conduct a multi-variable analysis assessing the risk of ending to CRPC by using time-dependent statin use variables and adjustment for patient age, EAU risk group and Charlson comorbidity index. The precise information on the durations of CRPC treatment lines allowed us to compare the outcomes of first and second line CRPC treatment by statin use status at the initiation of each treatment lines. However, we did not have information on behavioral factors such as smoking, diet, use of health services and physical activity which might represent potential confounding factors.Based on the results of this study and previous studies, we believe statins to be of most benefit for the treatment of hormone-sensitive prostate cancer in combination with ADT. It can be assumed that statin-induced decrease in circulating cholesterol, which is a precursor for steroid hormone synthesis, eventually leads to decrease in androgen biosynthesis. Therefore, of medications currently on the market for the treatment of prostate cancer, statins\u2019 anticancer effects probably resemble most abiraterone which reduces androgen production by blocking enzyme CYP17. Similarly to abiraterone, statin use may provide survival benefit especially when used in the hormone-sensitive phase.Our results support previous epidemiological studies showing statin use may improve survival in concurrent use with ADT and suggest better PCa-specific survival among statin users to be explained by longer time to development of castration-resistant prostate cancer. Considering the main results of this study and the results of previous studies assessing the prognosis of PCa patients by statin use, we suggest the optimal time window for statin use to be concurrently with androgen deprivation therapy. Therefore, future trials assessing the benefit of statin use in PCa prognosis should focus especially on that period when plenty of quality life years can still be saved.In our population-based cohort consisting of 1,169 men initiating ADT during the follow-up, inverse association between statin use and the risk of developing CRPC was observed. This finding is in line with previous studies detecting statins might be linked to improved prostate cancer prognosis among ADT treated patients. In our cohort, we did not observe statistically significant improvement by statin use in survival of CRPC patients. These results are suggestive that optimal timing of repurposing statins on prostate cancer treatment is concurrently with androgen deprivation therapy."}
+{"text": "The kinetics of myosin controls the speed and power of muscle contraction. Mammalian skeletal muscles express twelve kinetically different myosin heavy chain (MyHC) genes which provides a wide range of muscle speeds to meet different functional demands. Myogenic progenitors from diverse craniofacial and somitic mesoderm specify muscle allotypes with different repertoires for MyHC expression. This review provides a brief synopsis on the historical and current views on how cell lineage, neural impulse patterns, and thyroid hormone influence MyHC gene expression in muscles of the limb allotype during development and in adult life and the molecular mechanisms thereof. During somitic myogenesis, embryonic and foetal myoblast lineages form slow and fast primary and secondary myotube ontotypes which respond differently to postnatal neural and thyroidal influences to generate fully differentiated fibre phenotypes. Fibres of a given phenotype may arise from myotubes of different ontotypes which retain their capacity to respond differently to neural and thyroidal influences during postnatal life. This gives muscles physiological plasticity to adapt to fluctuations in thyroid hormone levels and patterns of use. The kinetics of MyHC isoforms vary inversely with animal body mass. Fast 2b fibres are specifically absent in muscles involved in elastic energy saving in hopping marsupials and generally absent in large eutherian mammals. Changes in MyHC expression are viewed in the context of the physiology of the whole animal. The roles of myoblast lineage and thyroid hormone in regulating MyHC gene expression are phylogenetically the most ancient while that of neural impulse patterns the most recent. Myosin is the motor protein in muscle cells which generates force and movement of muscle fibres by hydrolysing ATP. Structurally, it is a hexamer consisting of a pair of heavy chains (MyHC) and two pairs of light chains (MLC1 and MLC2) which together form a two-headed molecule with an elongated rod-like tail. The C-terminal halves of the heavy chains are \u03b1-helical and wrap around each other to form the tail, while the N-terminal halves form the globular heads, each of which contains an ATPase site and an actin binding site. Each head is attached to the rod by a lever arm domain to which the essential light chain (MLC1) and the regulatory light chain (MLC2) are attached. In striated muscles, myosin molecules assemble into thick filaments with the heads on their surface. During muscle contraction, myosin heads act as cross-bridges that cyclically interact with actin molecules of the thin filaments, hydrolysing ATP and generating force and movement. During the chemo-mechanical coupling, small conformational change in the catalytic domain of the head gets amplified by the lever arm Squire . This cyMyosin controls the kinetics of energy transduction from ATP, and through it, the kinetic properties of muscles. The speed of contraction of a muscle is generally proportional to the ATPase activity of its myosin Barany . As the Prior to 1960, it was known that all mammalian limb muscles were slow at birth, the differentiation into the fast and slow types occurred during the first few weeks after birth  (MYH10) which is only expressed in extraocular muscle   as well as that of the atrial (MLC1A) myosin  and the possible enhancement of the basal level of phosphorylation of MLC2 in small animals could significantly contribute to their higher basal metabolic rate.The release of myosin heads from SRX following phosphorylation of MLC2 has an impact on resting metabolism of the animal. Measurement of single nucleotide turnover rate of relaxed, skinned rabbit psoas muscle fibres revealed two lifetimes for nucleotide release, a fast component similar in kinetics to that of purified myosin, and a slow component that is more than 10 times slower. The slow component is attributable to the helically ordered cross-bridges in thick filaments in the SRX state while the fast component is due to cross-bridges released from the thick filament by the phosphorylation of MLC2  also has an influence of myosin kinetics. This myofibrillar protein exists in\u00a0four known isoforms: fast skeletal (fMyBP-C), slow skeletal, masticatory (m-MyBP-C) and cardiac (cMyBP-C). Much of the work on the function of MyBP-C  that simulates the pattern of nerve impulses delivered by the nerve to slow muscle rapidly induces a 2B\u21922X\u21922A MyHC transition , enabling it to enter the nucleus to interact with myocyte enhancer factor 2 (MEF-2C) to induce \u03b2-slow MyHC expression , causing it to exit the nucleus, thereby disinhibiting MEF-2C to induce \u03b2-slow MyHC expression   \u22120.25 25 Stahl  and the This review has highlighted the fact that the pattern of expression of MyHCs in mammals is principally influenced by the complex interplay of cell lineages, neural impulse pattern, thyroid hormone, body mass and functional demand. Even before myogenesis, myoblast progenitors of craniofacial and somitic muscles from different regions of the mesoderm are channelled into specific lineages of progenitor myoblasts and satellite cells that give rise to the various muscle allotypes with different repertoires for MyHC expression during subsequent myogenesis. During somitic muscle myogenesis, myoblast progenitors that give rise to embryonic and foetal myoblast lineages emerge and form slow and fast primary and secondary myotube ontotypes which give rise to slow and various fast muscle fibre types. These ontotypes determine the topographic distribution of the fibre types within the muscle and their specific modes of response to neural and hormonal influences.During early postnatal life, the emerging myotubes simultaneously come under the influences of a surge of thyroid hormone and the different impulse patterns of fast and slow motoneurons. The surge of thyroid hormone stimulates the expression of fast MyHCs in fast muscles to enhance speed and power. Simultaneously, high frequency neural impulses from fast motoneurons modulate the expression of different fast MyHC isoforms to give rise to the various fast fibre types. In slow muscles, the slow motoneurons and the neonate\u2019s encounter with gravity generate tonic low frequency neural impulses which induce \u03b2-slow MyHC in postural muscle fibres.The postnatal surge of thyroid hormone enhances cellular metabolism Hulbert  to suppo0.75 and physiological cycles should scale to (body mass)\u22120.25 \u22120.25  McMahon . Experim25 Stahl , in acco25 Stahl  and\u00a0smal25 Stahl  but \u03b2-sl25 Stahl  and dogs25 Stahl  and EO M25 Stahl  while in25 Stahl  and babo25 Stahl  laryngeaThe functional demands on different types of muscle across the species varies considerably. Somitic muscles must deal with the postural, locomotory and energetic demands of living in a gravitational environment. The four types of fibres offer a wide range of speeds and fatiguability to satisfy these needs. They consume a very large proportion of the organism\u2019s total energy expenditure, so that minimization of energy expenditure is very important. Hence, the deployment of slow fibres of low tension cost in postural muscles and the availability of three fast MyHCs with a wide range of speed, power and fatiguability for locomotion at different speeds and other motor needs. The physiological plasticity of fibre types allows them to adapt to the pattern of use and to hormonal changes. Energy expenditure during locomotion is minimized by elastic energy saving Biewener , most liThe effects of functional demand on MyHC expression are more complex in craniofacial muscles. For EOMs, the functional demands are extremely complex, requiring a panel of twelve MyHCs Hoh . HoweverOf the mechanisms regulating MyHC gene expression in mammals, the roles of myoblast lineage and of thyroid hormone are phylogenetically the most ancient while the role of neural impulse patterns is the most recent. Distinct lineages of progenitor myoblasts giving rise to slow and fast muscle fibres have also been found in zebrafish  activity (Little and Seebacher In sharp contrast to the thyroid regulation of skeletal muscle MyHCs during early vertebrate phylogeny, there is no evidence for thyroid regulation of cardiac MyHC expression in amphibians (Gauthier et al. The capacity of motor nerves in regulating muscle MyHC gene expression in mature animals is uniquely mammalian. Neural regulation confers physiological plasticity to muscle fibre types in mammals, enabling their muscles to adapt to the pattern of use during the lifetime of the animal rather than through intergenerational change via phylogenetic plasticity. Neural influence does play some role in regulating MyHC expression in developing but not in mature avian muscles. During avian development, neonatal myosin is first replaced by adult myosin at the endplate zone, the change progressively moves towards the fibre ends, the reverse occurring following denervation, suggesting that trophic factors emanating from the motor endplate may be involved in myosin regulation (Rosser et al. The ability of androgens to influence MyHC expression is found in laryngeal muscles of the Xenopus laevis, which are sexually dimorphic: all male laryngeal muscle fibres express a laryngeal specific MyHC while female laryngeal muscle expresses predominantly slow MyHC. Androgen exposure stimulates laryngeal specific MyHC in female\u00a0Xenopus laryngeal muscles (Catz et al. Although the pattern of MyHC expression in muscles of different allotypes and the regulation of MyHCs by neural and hormonal mechanisms are established in outline, a considerable amount of work has yet to be done in the future to enhance our knowledge of the molecular mechanisms in this area. Suggestions for future work on specific topics of interest have been made passim in this review. The network of transcription factors in fibres of various ontotypes that determine their different adaptive ranges in MyHC expression needs to be determined. Craniofacial muscles show considerable species variations in MyHC gene expression. Much work also needs to be done to elucidate the transcription factors and cis-regulatory regions of the various MyHC genes in different species that underlie their expression in muscles of different allotypes. It would also be interesting to compare the molecular mechanisms of MyHC regulation by androgens in muscles of different allotypes."}
+{"text": "A 51-year-old man with a history of hypertension and dyslipidemia presented with stable angina and underwent successful percutaneous coronary intervention with stent implantation to the left anterior descending. To evaluate angiographically moderate lesions in the right coronary artery (RCA) (Fig.\u00a0The mechanisms of the initiation and development of NC/CNs were not fully understood. Based on detailed histological characterizations of CNs at autopsy, CNs are hypothesized to be formed from a breakdown of calcified necrotic cores and develop between flanking areas of stable fibrocalcific plaques in coronary arteries in which hinge motion, or excessive torsion is observed, namely in the proximal to midportions of tortuous RCA . In line"}
+{"text": "Dysregulated immune responses correlate closely with CNS aging and neurodegenerative pathology. However, the heterogeneous nature of microglia and peripheral immune cells has impeded the characterization of their role and crosstalk in these processes. A comprehensive understanding of how peripheral immune cells act in concert with microglia to regulate the aging process and neurodegenerative diseases will advance the understanding of immunoregulation of neurological disorders and provide novel insights in the development of next-generation immunotherapies for various age-related neurodegenerative diseases.In contrast to the long-withheld concept that neurodegenerative diseases are \u201cneuron-centric\u201d disorders, emerging evidence from recent years has shifted this notion into a more \u201cimmune-centric \u201cview highlighting the contribution of dysregulated immune responses to disease progression . MicroglIn this Research Topic, we present a Research Topic of five articles describing different aspects of microglial and peripheral immune response in various age-related neurodegenerative diseases, including Alzheimer\u2019s disease (AD), Parkinson\u2019s disease (PD) and age-related macular degeneration (AMD). The two original research articles provide evidence of the contribution of microglial and peripheral proinflammatory responses to the neuropathology of AD and PD, respectively. Whereas the three review articles describe a general picture of brain and peripheral innate immune system in regulating neurodegenerative diseases affecting the brain and retina.Li et al. described that Acteoside (ACT), a neuroprotective compound, played a beneficial role in AD by suppressing microglial polarization towards a pro-inflammatory phenotype. Mechanistic analyses integrating multi-omics database have revealed that ACT regulates microglial polarization though oppositely modulating NF-\u03baB and AMPK pathways. These findings suggest ACT as a potential therapeutic agent for neurodegenerative disease associated with neuroinflammation. In addition to neuroinflammation, peripheral proinflammatory response may be implicated in the pathogenesis of neurodegenerative diseases as well. Fu et al. reported an elevated level of IL-6 and TNF-\u03b1 production in the sera of PD patients and the level correlates strongly with clinical symptoms. Noteworthy, activated microglia also produce IL-6 and TNF-\u03b1 under pathologic conditions  is not only conventionally expressed by peripheral immune cells but also expressed by microglia exclusively in the CNS and plays an essential role in neuroinflammation . Li et aBrian et al. extensively reviewed the role of peripheral innate immune cells in AMD, highlighting the potential dysregulated crosstalk between immune cells residing in the retina and periphery. This review also discussed recent developments in single-cell transcriptomics that advance the understanding of developing therapeutic interventions for AMD targeting immune dysregulation.As a part of CNS, the retina contains resident innate immune cells (microglia) and may also be populated with innate components from the periphery under pathological conditions. Dysregulated immune responses have been linked to retinal degenerative disorders, including AMD. A recent study provides an unparalleled depth of insight into key inflammatory pathways residing in microglia that promote neuroinflammation in AMD . MoreoveIn summary, the collection of articles in this Research Topic provides a snapshot of a newly rising multidisciplinary research field deciphering neurological diseases from the immunology perspective. These articles expand our understanding of central and peripheral immune responses in neurodegenerative diseases and shed light on developing therapeutic strategies targeting novel immunological targets. However, some questions which have gained increasing interest in this field remain to be further addressed. For example, as age is a main risk factor of many neurodegenerative diseases, is age-related dysregulation of microglial and peripheral immune response causally related to the onset or progression of neurodegenerative diseases? Whether and how microglia dialogue with peripheral immune cells and how such interaction affects disease progression? More importantly, the extreme heterogeneity of immune cells greatly impedes the accurate definition of their contribution to disease progression. Identification and characterization of distinct disease-associated immune cell subsets will surely favor the discovery of novel, effective therapeutic targets. We hope that the articles in this Research Topic will be insightful to a broad range of researchers working in the immune response to neurodegenerative diseases and will enlighten future research to decipher the role and molecular mechanisms at play between central and peripheral immune cells to regulate neurodegenerative diseases in both preclinical and clinical settings."}
+{"text": "Insomnia in depression is common and difficult to resolve. Music is commonly used as a sleep aid, and clinical trials pointing to positive effects of music as a sleep aid are increasing adding to the evidence base. There is little knowledge on the effectiveness of music for depression related insomnia.A recent RCT study conducted in psychiatry at Aalborg University Hospital examined effects of a music intervention for insomnia in depression. The intervention group listened to music at bedtime for four weeks, controls were offered music intervention post-test. Primary outcome measure was Pittsburgh Sleep Quality Index (PSQI). Secondary outcomes included Actigraphy, The Hamilton depression Rating Scale (HAMD-17) and World Health Organisation well-being questionnaires .A two-armed randomized controlled trial (n=112) and a qualitative interview study (n=4)The RCT study showed signficant improvements for the music intervention group in sleep quality and quality of life at four weeks according to global PSQI scores  and WHO-5 scores . Actigraphy measures showed no changes and changes in depression symptoms (HAMD-17) were not detected.The interview study unfolded examples of the influences of music on sleep and relaxation. Music distracted, affected mood and arousal positively and supported formation of sleep habits.Results from the trial are discussed and merged with findings from the interview study. The results from the trial suggested moderate effects of music listening for the population while findings from the interview study showed examples of individual and highly varying outcomes.Music is suggested as a low-cost, side-effect free and safe intervention in supplement to existing treatments improving sleep in depression.None Declared"}
+{"text": "The purpose of the study is to examine higher moment connectedness among 12 cryptocurrencies using data sampled at the 1-minute high-frequency interval. We use methods that demonstrate the heterogeneity of agents from their distinct investing horizons. This includes wavelet multiple cross-correlations, CEEMDAN-based Diebold-Yilmaz (DY) connectedness index and the Barunik-Krehlik (BK) frequency connectedness index. First, our results show that higher moment multiple correlations among the sampled cryptocurrencies are higher at all time scales and the relationship strengthens at lower frequencies. Second, the wavelet cross-correlations show different cryptocurrencies with the potential to lead and lag in the transmission of higher moment shocks to the whole system at different frequencies. Again, the multiple wavelet cross-correlations increase with increasing time scales. The results from the CEEMDAN-based DY connectedness index as well as the BK framework also reveal cyclical connectedness and differences in connectedness across different frequencies. The results show more connectedness of higher moments than the connectedness empirically reported for returns and volatility. Cryptocurrency connectedness has mostly been examined using the first two moments. We extend this line of literature by examining the third and fourth moments, which might be more useful for risk management purposes. Traditional asset pricing models like the Capital Asset Pricing Model of Sharpe  and LintThe majority of the studies that have investigated the interconnectedness of cryptocurrencies have\u00a0mainly focussed on the first two moments, namely, returns  and second (variance) moments quantify the location and dispersion of a distribution respectively. The third (skewness) and fourth (kurtosis) moments are used to identify the shape of a particular distribution. The skewness verifies the symmetry of distribution around the mean where a zero value implies symmetry while positive (negative) values imply asymmetry. A tendency toward positive skewness is a reflection of investors\u2019 penchant for lottery-like assets  increases with scale and peaks at close to 1 at the lowest frequency. The findings from the local CEEMDAN-based DY framework reveal that the higher moment connectedness among the cryptocurrencies is cyclical, albeit aperiodical at higher frequencies and smoothens at lower frequencies. Using the CEEMDAN-based DY framework and BK framework, we also establish that higher moment connectedness is especially high at lower frequencies.The study proceeds as follows: in the next section, we look at the methodology used to examine the connectedness of cryptocurrencies, followed by a presentation of the results and the discussion thereof. The study ends with a conclusion that wraps up the study and provides potential areas for future studies.https://www.cryptodatadownload.com/data/. According to Alexander and Dakos (We include data gathered at 1-minute granularity for twelve cryptocurrencies namely Bitcoin (BTC), Binance (BNB), Cardano (ADA), Ethereum Classic (ETC), Ethereum (ETH), Chainlink (LINK), Litecoin (LTC), Neo (NEO), Tron (TRX), Stellar (XLM), XRP (XRP), Zcash (ZEC). The 1-minute data are collected from the Binance exchange and downloaded from nd Dakos , using rnd Dakos . The samThe N = 1440. The opening log price on day t is Pt,0 and the closing log price on day t is Pt,1.Where P is the price of the cryptocurrency and In line with Amaya et al. , we defiRealised daily kurtosis is defined following Amaya et al.  again asThe scaling of Though our ultimate objective is to demonstrate the spillover of higher moment return shocks using the seminal spillover indexes, we first establish the multiple correlations among the cryptocurrencies using wavelets. Simultaneous inclusion of methods based on wavelets and spillover indexes provides robustness in trying to understand the connectedness among variables and this approach has been used in recent studies  of Fern\u00e1ndez-Macho . In compWhere:To identify a potential leader that can influence other cryptocurrencies within a system, we utilise the Wavelet Multiple Cross-Correlation (WMCC). WMCC can be used to identify potential leaders and followers in a set of time series data. This can be particularly useful in financial and economic applications where identifying the leader-follower relationships between different assets or indicators can provide insights into portfolio management and risk assessments. By applying WMCC to a set of time series data, we can analyse the strength and direction of the cross-correlations between different time series at different frequencies or scales. By allowing lag Where:To examine the higher-order connectedness of the cryptocurrencies, we also depend on the seminal Diebold and Yilmaz  spilloveThe computation procedure of the CEEMDAN is guided by Torres et al.  and is iThe second step involves the deployment of the Empirical Mode Decomposition (EMD) to decompose Eq.\u00a0 to obtaiThis is followed by the computation of the remainder of the signal components The Finally, the The total number of IMFs of a time series signal including the residual is given as After decomposing the realised skewness and realised kurtosis values for all the cryptocurrencies, we then deploy the DY framework to examine the connectedness of the cryptocurrencies across time and different investing horizons (represented by the various IMFs). The DF framework utilises the generalised forecast error variance decomposition (GFEVD) in a VAR framework in place of utilising Cholesky factorisation. Using the DY (2012) framework, a covariance stationary Where The DY (2012) framework depends on the GFEVD framework which was formalised by Koop et al.  and PesaWith To measure the frequency dynamics of higher moment connectedness among sampled cryptocurrencies resulting from heterogeneous frequency responses to shocks in each of the cryptocurrencies, we also use the Barun\u00edk and K\u0159ehl\u00edk \u2019s framewThe band Where generalised forecast error variance decomposition (FEVD) on different frequency bands In this section, we report the findings of the connectedness among cryptocurrencies using the different econometric models adopted. We first report the descriptive statistics displayed in Table\u00a0As shown in Fig.\u00a0The results in Fig.\u00a0The results for the two moments visualised in Fig.\u00a0Figure\u00a0In Table\u00a0The same pattern that is depicted in the descriptive statistics in Table\u00a0In further robustness checks, we report the time-frequency higher-order connectedness of the cryptocurrencies using the BK frequency connectedness framework, results which are visualised in Fig. The results in Fig.\u00a0The results from wavelet multiple correlations, the CEEMDAN-based DY framework and the BK framework unanimously point to higher moment connectedness among the sampled cryptocurrencies, with the connectedness amplified at lower frequencies. This means that there are higher chances of cryptocurrencies crashing together and also experiencing extreme returns (both positive and negative returns) together. This provides evidence of the existence of herding behaviour in the crypto markets as documented by Vidal-Tom\u00e1s et al., . The finCryptocurrency has become an important asset class in the past few years. A lot of research has been done to untangle different facets of this growing asset class. The majority of the research has however mostly concentrated on the first two moments (return and volatility) of cryptocurrencies and has left the higher moment properties of the cryptocurrencies at the peripherals. We particularly investigate the higher moment  connectedness of 12 cryptocurrencies sampled at high frequency  in a time-frequency domain. We apply methods robust in the presence of nonlinearities, deviation from Gaussian distributions and several stylised facts of financial variables. Our results show high moment connectedness of cryptocurrencies which is mostly amplified at lower frequencies. These results have important implications for policymakers and investors. For policymakers, the findings suggest that they need to consider the higher moment connectedness when developing regulatory frameworks for the cryptocurrency market. This may involve developing new risk management strategies that specifically target higher-moment shocks to the system, as well as improving the monitoring and surveillance of the market to better detect and respond to such shocks. For investors, the findings suggest that they need to be aware of the potential for higher moment shocks in the cryptocurrency market and should consider incorporating this information into their investment strategies. This may involve using more sophisticated risk management techniques that take into account the higher moment correlations between different cryptocurrencies, as well as carefully monitoring the leading and lagging indicators identified in the study."}
+{"text": "One of the holy grails of neuroscience is to record the activity of every neuron in the brain while an animal moves freely and performs complex behavioral tasks. While important steps forward have been taken recently in large-scale neural recording in rodent models, single neuron resolution across the entire mammalian brain remains elusive. In contrast the larval zebrafish offers great promise in this regard. Zebrafish are a vertebrate model with substantial homology to the mammalian brain, but their transparency allows whole-brain recordings of genetically-encoded fluorescent indicators at single-neuron resolution using optical microscopy techniques. Furthermore zebrafish begin to show a complex repertoire of natural behavior from an early age, including hunting small, fast-moving prey using visual cues. Until recently work to address the neural bases of these behaviors mostly relied on assays where the fish was immobilized under the microscope objective, and stimuli such as prey were presented virtually. However significant progress has recently been made in developing brain imaging techniques for zebrafish which are not immobilized. Here we discuss recent advances, focusing particularly on techniques based on light-field microscopy. We also draw attention to several important outstanding issues which remain to be addressed to increase the ecological validity of the results obtained. To fully understand how neural circuits process sensory input and generate complex behaviors it is critical to be able to record simultaneously from large numbers of neurons while the animal is behaving as naturally as possible. Larval zebrafish are transparent and, uniquely amongst vertebrate model organisms used in neuroscience, allow the potential for neural activity in all ~100,000 neurons in the brain to be optically imaged simultaneously. Zebrafish have a strong genetic and physiological homology to mammals, and they have analogous social and cognitive behavioral processes to those seen in rodents and humans . Bouts can be grouped into 7\u201313 different classes  and hunting sequences (eyes converged). Eye convergence creates a small binocular zone about 0.5 mm directly in front of the fish that is likely useful for calibrating the final strike  with specific selectivity  and its UAS system (TrpR/tUAS), and the QF transcription factor (adopted from fungus Neurospora crassa) and its UAS system (QF/QUAS). All these systems were developed to create a binary expression system where the fluorescence reporter protein expression is regulated by cell-type specific promoters  and Gal4 upstream activating sequence (gUAS) system , the tryptophan repressor (utilizing tryptophan biogenesis in nacre zebrafish (which carry mutations that affect pigment cells) are transparent at larval stages, making them ideal for volumetric optical imaging of brain activity   decreases since the depth of focus is inversely proportional to NA and the overall FoV of the system is not affected. Higher NA also increases the imaging speed as the light gathering capability of the system increases  deconvolution algorithm applied to LFM reconstructs the 3D volume by maximizing the Poisson likelihood of the light-field image given an estimate of the 3D volume  due to their powerful non-linear fitting capacity. The PSF measurement information here is optional as long as the methods can implicitly learn the underlying physical process New developments in recent years have combined LFM with various types of illumination and conventional optical microscopy systems. These novel hybrid systems aim to improve the performance of the system by offering better spatial resolution, signal to noise ratio, and contrast. Here we focus on methods that have been applied to zebrafish.m3 over a cylindrical imaging volume of 800 \u03bcm diameter and 200 \u03bcm height. Moreover, this system eliminated the reconstruction artifacts near the focal plane presented in the conventional LFM  are based on 1-photon imaging, which stimulates the fish's visual system and thus potentially interferes with the fish's ability to respond to visual stimuli such as prey items. This could be addressed by developing faster 2-photon volumetric imaging methods.Although current techniques approximate single-neuron resolution, this resolution is still significantly lower than that achieved by more conventional imaging techniques for head-fixed animals.In their natural environment zebrafish larvae make use of vertical movements through the water column, and in particular prefer to strike at prey items from below (Bolton et al., The techniques of Cong et al.  and Kim All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
+{"text": "Editorial on the Research TopicCase reports in pediatric infectious diseases 2022Case reports of patients with unusual findings have been a source of inspiration for researchers and have contributed to improved clinical practice in the past . EspeciaThe editors of this special issue feel that in general, the scientific community, and more specifically, boards of universities deciding on promotion of staff tend to undervalue the contribution that case reports make to the advancement of new knowledge and to science as such. Pioneers in medicine were great supporters of documenting each unusual presentation of patients and sharing with a wide range of physicians, the findings and outcomes of such cases .Writing a good case report is not easy though. Authors may get lost in less relevant details or present a textbook chapter in the introduction of the report, discouraging the target audience from finishing the reading of the report. A concise focused summary of literature can highlight why the particular case is so special and needs to be shared with as many doctors seeing similar patients as possible.Another problem encountered is the lack of proper documentation of proper findings to exclude alternative diagnoses or contributing factors to the outcome of the patients. In order to write a good case report, the clinician should plan ahead and get all relevant investigations properly documented, of course with the permission of the patients or their guardian.Editors of other journals have suggested that it may be a good idea to incorporate more training for physicians, not only during the undergraduate years but also in continuing medical education to ensure the skills of writing a good report are readily available in most doctors seeing a wide variety of cases.Guidelines for reporting cases reports are available in literature , even thIt has been the great pleasure of the editors of this special issue to select and compile nine very relevant case reports in paediatric infectious diseases. In 4 reports, comprehensive pathogen analysis was useful for rapid diagnosis in pediatric infectious diseases, and it is desirable to examine its utilization in this area in the future. Other reports describe rare complications or unexpected diagnoses in patients with infectious diseases.Below a concise critical review of each of the articles is presented.Huang et al. present a case of a 10-year-old immunocompetent boy presenting with a 5-day history of intermittent, left-sided chest pain, having a left lung nodule caused by Streptococcus intermedius. The nodule was identified by chest radiography. The cultures of aspirates of the nodule were negative but the germ was identified by metagenomic next-generation sequencing. He was given proper antibiotics and did not require a surgical intervention. The authors highlight the rarity of the case and the importance of metagenomic next-generation sequencing in the diagnostic process.Zhuang et al. reported a case of Congenital tuberculosis in a neonate following in vitro fertilization-embryo transfer. They performed pathogenic microorganism metagenomic analysis and isolated the Mycobacterium tuberculosis complex in a preterm infant poorly responding to treatment. Subsequently, maternal pelvic tuberculosis was confirmed. Since, in vitro fertilization (IVF) treatment and pregnancy can exacerbate latent tuberculosis, identifying maternal tuberculosis during IVF treatment using metagenomic approach can be a useful option.Rodriguez et al. reported a case of an unusual pneumonia pathogen, detected by plasma cell free next-generation sequencing in an immunocompetent adolescent with acute respiratory distress syndrome. This case details a rapid diagnosis of legionella pneumonia causing severe acute respiratory distress syndrome (ARDS) in an otherwise healthy adolescent through plasma microbial cell-free DNA next generation sequencing (mcfDNA-NGS). Diagnosis by mcfDNA-NGS of this unexpected pathogen led to narrowing of antimicrobials and this novel technology can be a useful tool for paediatric infectious disease diagnosis.Liao et al. reported a case of Respiratory tract infection of fatal severe human bocavirus 1 in a 13-month-old child. They reported the case of a 13-month-old boy who presented with a cough, shortness of breath, and wheezing, and who eventually died of severe pneumonia and acute respiratory distress syndrome (ARDS). They confirmed that HBoV1 was the only detected pathogen by Metagenomics next-generation sequencing (mNGS).Zhang and Yu reported a rare case of severe and fulminant paediatric Mycoplasma pneumoniae in an immuno-competent child. There were severe lung lesions associated with pleural effusion, coagulopathy, diffuse alveolar haemorrhage and severe respiratory distress, requiring ventilator and intravenous extracorporeal membrane oxygenation (VV-ECMO) support. The authors want to highlight that early recognition and prompt institution of advanced life support measures the treatment can be successful.Zhang et al. reported another rare complication of Mycoplasma pneumoniae: multiple cardiac thrombi and pulmonary embolism. They successfully treated the case with thrombolytic and anticoagulant therapy. While other thromboembolic complications of Mycoplasma pneumoniae have been reported, this may be the first report of cardiac thrombi as a complication of infection by this organism.Han et al. reported a case of pleural empyema and necrotizing pneumonia related to methicillin resistant Staphylococcus aureus (MRSA) secondary infection in a teenager who initially presented with Influenza A virus infection. They describe the clinical symptoms and treatment and they highlight the importance of early recognition and application of thoracoscopy for this potentially fatal pleural empyema caused by MRSA and influenza A co-infection. The authors hope that this article will raise awareness regarding rarely occurring severe respiratory infections by MRSA in a child with normal immune function after influenza A virus infection.Feussner et al. reported a lethal case of mastoiditis and cerebral herniation as a complication of otitis media in a 13 year old patient with Arnold Chiari Malformation. This case demonstrates a very rare lethal complication of acute otitis media on the basis of a cerebral malformation and emphasizes the need to stay alert when patients complain of symptoms after assumed resolution.Chang et al. reported an adolescent immune-compromised patient with histoplasmosis, coming from a non-endemic area. The patient presented with nonspecific symptoms and was successfully treated with amphotericin B and itraconazole. The authors encourage a high index of suspicion for this pathogen in immune-compromised patients, even in non-endemic areas.In conclusion, the cases reported in this issue are likely to contribute to a better clinical practice and it is hoped that they are a source of inspiration for clinicians to keep sharing their special cases in excellent case reports."}
+{"text": "At the dawn of this millennium, the Human Genome Project (HGP) prospected the most detailed description of the genetic and epigenetic regulatory pathways . HoweverSuch milestones have proven to be catalytic in advancing the technological barriers. An exciting example could be the invention of molecular 3D structure prediction methods like, AlphaFold  and RoseScientific milestones usually result in attracting research groups who would design their work-plan around that exciting discovery. Although quite natural, it often leads to a very pertinent question that does the designed project consider the complex nature of biological systems by assessing the inherent flexibility of the molecular system being studied. The aforementioned examples demonstrate the caveats of neglecting the inherent flexibility of the genomes and proteomes. This flexibility makes the biological systems complex to study and understand. Therefore, it is important that we assert a similar flexibility in our approaches to broaden our understanding of life.Chandra et al. investigated the disordered region of the antitoxin from the toxin-antitoxin (TA) pair in the pathogen M. tuberculosis. This bacterium has nine MazEF family toxin-antitoxin systems, which have a significant impact on the persistence and survival of Mycobacterium tuberculosis within their host. Using charged residue (Asp) scanning mutagenesis at the intrinsically disordered regions, they showed a TA interaction module unique to MazEF6 system. They established that N-terminus of the antitoxin (MazE) that is usually expected to be involved in DNA binding could bind to the toxin (MazF) instead. These counter-expected results highlight that structure prediction built on evolution may not work for predicting correct binding mode in MazEF6 TA pair. Thus, pointing out the specificity of individual antitoxins towards their partner toxins that is likely to provide selective evolutionary advantage to the organism.This Research Topic was therefore aimed at compiling original research that could impart flexibility to our understanding of complex biomolecular systems. For example, two groups studied protein disorders in two very different systems and concluded the role of inherent flexibility towards their adaptive advantage. Chauhan and Sowdhamini performed an in-depth analysis of LIM domains of the Cysteine and Glycine-rich Protein 3 (CSRP3), a key protein implicated in dilated and hypertrophic cardiomyopathies. CSRP3 is structurally characterized by two LIM domains (each containing two Zinc fingers) connected by a disordered region. Zinc fingers are well characterised as DNA binding domains and are highly conserved. However, comparing  sequences of LIM domain across the tree of life, authors observe a trimodal distribution for their length variations which they attributed to the varying length of the disordered linker. Using MD simulation experiments, they have asserted the role of the disordered region in facilitating the LIM domain interactions which can vary among different species. An interesting finding from the phylogeny of CSRP3 was the identification of a homolog in freshwater microspecies which are not known to have a circulatory network, thus, scratching a curious gateway into the origins of CSRP3 gene.Yu et al.) are interested in understanding the function of X-derived retrogenes that are known to contribute towards genetic diversity during evolution. These genes are usually expressed in the testes and perform important functions during spermatogenesis. Phylogenetic analysis showed that a retrogene and an X-linked maintenance gene are subject to purifying selection and hence may have evolutionarily conserved functions. However, they have no functional role in spermatogenesis as shown by mice experiments. This study has provided direct evidence that some autosomal X-derived retrogenes may be non-functional in spermatogenesis, thus, challenging our understanding that flexibility imparts adaptive advantage.Yu and collaborators  establishes two important biomarkers, the C-reactive protein (CRP) and D-dimer in 228 Bangladeshi COVID-19 patients. They observed a significant association between the severity of COVID-19 and the two biomarkers within the population. Such studies are aimed at making the diagnostics precise by considering ethnic populations and their varied immune responses against a disease.Finally, a brief research report by Sultana and collaborators (Overall, this research topic explores the role of flexibility by studying various systems that range from retrogenes to multi-protein complexes to disordered systems while providing insight into each system and their selective advantage imparted by their inherent flexibility."}
+{"text": "The role of the basal ganglia in somatosensory-motor interactions: evidence from neurophysiology and behavior II,\u201d seven articles have been published. All seven contributions consisted of original work. Interestingly, each article used a unique approach  to invasive micro-electrode recordings . This heterogeneity of approaches is in line with the approaches described in its predecessor  in the thalamus , could have made use of the currently available fully-implantable devices that have also been able to record LFP activity in the thalamus . Although 3 years seems a short period, as we know after the pandemic, a lot can happen. One important development in studying the basal ganglia over the last 3 years is the availability of commercially available DBS devices by at least three companies that can record local field potentials (LFP's) from fully implanted devices  and Pinky et al. studied the role of the caudate as modulator in the recovery of TBI. These insights show how studying basal-ganglia functions beyond movement disorders can help in developing neuro-modulation strategies and the development of (image-based) biomarkers. The development of biomarkers is also relevant for the prodromal stages of Parkinson's disease (PD) such as in patients with rapid eye movement sleep behavior disorder (RBD), which are at a higher risk for developing PD. By identifying these patients using advanced imaging approaches, such as described by Chen et al., patients may benefit in the future from disease- modifying therapies before the onset of motor symptoms  pain syndromes and traumatic brain injury (TBI) as respectively described by Sengupta et al. show the nature of response disinhibition in PD during natural movement performance whilst  were able to distinguish neural patterns of self-initiated vs externally cued response in the STN. With the dawn of DBS stimulation paradigms that influence decision making processes  processing actually leads to disturbed basal-ganglia function. In their contribution All authors contributed to the editorial and have seen all revisions, including the final revision."}
+{"text": "Gastrointestinal (GI) cancers are malignancies that develop within the digestive system and account for one in four cancer cases according to WHO data . EsophagThe application of liquid biopsy in these types of cancers and more specifically in colorectal cancer (CRC) and gastro-esophageal cancer is the focus of this Special Issue. Four original articles on the use of EVs and cell-free DNA (cfDNA)\u2014including diagnostic plasma variants as predictive markers of these tumors and one review on the use of circulating tumor DNA (ctDNA) in the assessment of minimal residual disease (MRD) in CRC\u2014are included. The technical aspects and challenges behind the clinical application of liquid biopsy are especially underlined. The detection of disseminated and residual disease before and after surgical resection, respectively, are important clinical issues faced by surgeons and medical oncologists treating digestive tumors. The term MRD is used to describe the very few cancer cells which remain in the patient\u2019s body during or after cancer treatment, which are below detectable levels after oncological treatment using routine laboratory methods . MRD wasThe study of Wallander et al.  describeOn a more technical note, Kalm\u00e1r et al. , describIn CRC patients, metastasis prediction is also a major issue as many patients progress after treatment for localized disease . The stuPatient stratification via the detection of MRD after a curative-intent resection has been a challenge in CRC over the last years . In thisThe research study of Hofste et al. is focused on patients with locally advanced esophageal cancer and represents a well-designed and executed study for the use of ctDNA detection to predict residual disease during treatment . EsophagLiquid biopsy has emerged in clinical oncology as an important tool for patient management, and is on the verge of being implemented into the clinical practice , as the The prognosis of CRC has improved significantly in recent years due to liquid biopsy-based early detection strategies, such as the fecal occult blood test or fecal immunochemical test ,22. Howe"}
+{"text": "A patient presented to clinic with atopic dermatitis that had been previously unresponsive to multiple topical and systemic therapies. They were successfully treated with a combination of tralokinumab and upadacitinib, showing significant improvement after 3 weeks and near-resolution after 6 months. We present a case of atopic dermatitis treated successfully with a combination of tralokinumab and upadacitinib.Biologic therapies and Janus kinase inhibitors have both been successfully used in the management of patients with atopic dermatitis.A 42-year-old male patient with atopic dermatitis (AD) had attempted multiple systemic therapies , topicalThe multifaceted pathophysiology of AD makes combination therapy an intriguing avenue in the management of the condition. The efficacy and tolerability seen in our patient, along with the lack of response to multiple previous monotherapies, encourages the possibility of treating unresponsive AD with biologic therapies and JAK inhibitors simultaneously."}
+{"text": "Sickle cell disease is a common condition in the eastern part of India and can often present with pain crisis, vasculo-occlusive crisis and anemia. These patients seldom have coexisting rheumatological illnesses like rheumatoid arthritis that are camouflaged with the pain crisis of sickle cell disease, leading to a delay in the diagnosis and a delay in initiating the treatment which leads to a poorer quality of life. Herein we discuss a case of sickle cell disease presenting concomitantly with the features of rheumatoid arthritis and the challenges faced in the diagnosis and treatment. Sickle cell disease is caused by a point mutation in the beta-globin gene leading to the replacement of glutamic acid to valine in the sixth position of the beta chain of hemoglobin. Rheumatoid arthritis is an autoimmune chronic inflammatory disease that often presents with early morning stiffness and symmetrical small joint pains. Patients with rheumatoid arthritis may have cartilage and bone destruction that leads to permanent disability and reduced quality of life. The joint pains in rheumatoid arthritis are sometimes masked by the pain crisis of sickle cell disease which leads to a diagnostic dilemma. Besides, there is a contrast in the treatment of rheumatoid arthritis and sickle cell disease that also leads to a treatment dilemma .A 36-year-old female patient presented to us with multiple joint pains and weakness for a duration of seven days. The patient had a confirmed history of sickle cell disease spanning over the course of 11 years. On this occasion, the patient presented with complaints similar to those experienced in the past. Previous episodes had been managed by administering analgesics to alleviate the pain crisis. Upon further inquiry into her symptoms, she disclosed a medical history involving stiffness during the early morning hours and symmetrically distributed joint pain affecting the small joints of her hands. On general examination, her vitals were stable. She had tender and swollen proximal interphalangeal joints and metacarpophalangeal joints in both hands. She also had boutonniere deformity which was quite evident on examination  and C-reactive protein (CRP). Her anti-cyclic citrullinated peptide, antinuclear antibodies and human leukocyte antigen B27 (HLA-B27) were negative. Her hemoglobin levels were 6.4 gm% which was microcytic hypochromic type. Her Disease Activity Score (DAS-28) was 5.1. She was transfused three units of packed red blood cells (RBC). She was treated with a short course of non-steroidal anti-inflammatory drugs (NSAIDs), methotrexate and hydroxychloroquine sulphate and showed improvement in her pains in about seven days and was discharged. She is being followed up regularly to monitor her blood picture and to titrate the dose of disease-modifying antirheumatic drugs (DMARDs).The diagnosis of rheumatoid arthritis in a patient with sickle cell disease poses a challenge due to the similarities in their presentation. Rheumatoid arthritis is a chronic inflammatory disease that is characterised by cartilage damage, synovitis and juxta-articular bone destruction . HemogloOnce the diagnostic dilemma is overcome, the next barrier a clinician faces is the treatment dilemma. The use of steroids in rheumatoid arthritis is for transient pain relief before the action of DMARDs sets in. However, steroids if used in rheumatoid arthritis with sickle cell disease can lead to vasculo-occlusive crisis and bone infarcts. Hydroxyurea can reduce the white blood cell and reticulocyte counts and can lead to opportunistic infections . The useThe musculoskeletal features of sickle cell disease can mask the clinical features of rheumatoid arthritis, leading to diagnostic challenges and once diagnosed can present with challenges in the treatment. Steroids if used in rheumatoid arthritis with sickle cell disease should be used with caution. Regular monitoring of the hemoglobin, platelets, liver and renal function is required with using DMARDs in rheumatoid arthritis and sickle cell disease. The diagnosis of rheumatoid arthritis is rarely considered and overlooked because of the musculoskeletal symptoms of sickle cell crises. Underlying inflammatory mechanisms of both sickle cell disease and rheumatoid arthritis may mask the clinical manifestation of each. Prompt use of DMARDs improves the quality of life and prevents further damage.\u00a0Long-term research to study the quality of life and clinical course is needed in detection of rheumatoid arthritis in sickle cell disease."}
+{"text": "Some researchers hypothesize that PTLDS might be related to a persistent but difficult to detect infection. The authors wish to improve the clarity of a statement in the background section of the summary. The updated background section is presented below:SummaryBackground Post-treatment Lyme disease syndrome (PTLDS) is used to describe Lyme disease patients who have completed antibiotic therapy but then experience persisting symptoms of pain, fatigue, or cognitive impairment."}
+{"text": "Digital tools may improve chronic obstructive pulmonary disease (COPD) management, but further evidence of significant, persisting benefits are required. The RECEIVER trial was devised to evaluate the Lenus COPD support service by determining if people with severe COPD would continue to utilize the co-designed patient web application throughout study follow-up and to explore the impact of this digital service on clinical outcomes with its adoption alongside routine care.The prospective observational cohort hybrid implementation-effectiveness study began in September 2019 and included 83 participants. Recruitment stopped in March 2020 due to COVID-19, but follow-up continued as planned. A contemporary matched control cohort was identified to compare participant clinical outcomes with and minimize biases associated with wider COVID-19 impacts. Utilization was determined by daily COPD assessment test (CAT) completion through the application. Survival metrics and post-index date changes in annual hospitalizations were compared between the RECEIVER and control cohorts. Longitudinal quality of life and symptom burden data and community-managed exacerbation events were also captured through the application.High and sustained application utilization was noted across the RECEIVER cohort with a mean follow-up of 78 weeks (64/83 participants completed at least one CAT entry on \u226550% of possible follow-up weeks). Subgroup analysis of participants resident in more socioeconomically deprived postcode areas revealed equivalent utilization. Median time to death or a COPD or respiratory-related admission was higher in the RECEIVER cohort compared to control (335 days vs 155 days). Mean reduction in annual occupied bed days was 8.12 days vs 3.38 days in the control cohort. Quality of life and symptom burden remained stable despite the progressive nature of COPD.The sustained utilization of the co-designed patient application and improvements in participant outcomes observed in the RECEIVER trial support scale-up implementation with continued evaluation of this digital service. COPD accounts for many hospital admissions and deaths and is expensive to manage.Digital tools could improve COPD management but more evidence is needed that people with COPD continue to use them and that they have a positive impact on clinical outcomes.The goal of this study was to record usage of a digital COPD self-management and remote monitoring service by people with severe COPD over a long-term period, and to explore the impact of introducing this service on participant\u2019s outcomes.Why was this Study Done?The majority of trial participants frequently used the service across the time period that they were in the study (12\u201324 months).Those registered with the service had a greater reduction in hospital admissions related to their COPD than a comparator cohort with severe COPD over the same period.Participants reported consistent quality of life across the study, despite COPD being a progressive disease.What Did the Researchers Do/Find?People with severe COPD continue to use the service regularly.Adoption of the service was associated with improved clinical outcomes.What Do these Results Mean?Chronic obstructive pulmonary disease (COPD) is a leading cause of global mortality, morbidity, and disability,7Interventions that support self-management of COPD have been shown to reduce length and frequency of hospital admissions,21In parallel, emerging innovations such as smart inhalers, remotely monitored home non-invasive ventilation (NIV) machines, wearable physiology monitors, and predictive AI-models offer potential COPD care-quality improvements. The projected benefits are based on these digitally enabled tools providing actionable insight to clinical care teams in real-time outside of traditional care settings.25https://support.nhscopd.scot.Given the above context, a digital health technology catalyst project was commenced to further the evidence base for digital self-management and remote monitoring interventions in the management of COPD, and to establish a test-bed infrastructure for additional innovations. To address these aims, a patient and clinician co-designed COPD digital support service (Lenus COPD) was developed and evaluated. This digital COPD support service consists of a patient application, a clinician application/dashboard, and a support website. Additional information on the digital service is available at: The RECEIVER  trial was commenced in September 2019 in NHS Greater Glasgow and Clyde (NHS GG&C). The aim of the trial was to determine the acceptability, feasibility, and utility of deploying the co-developed COPD digital service alongside routine clinical care for people with severe COPD. An implementation-effectiveness observational cohort design was applied to facilitate adaptations to the intervention and the implementation strategy if required. The primary objective of the study was to determine service utilization by people with severe COPD, with additional clinical and non-clinical secondary objectives outlined in the published protocol.At the first UK COVID-19 lockdown (March 2020), recruitment for the trial was stopped. However, based on positive interim evaluations, follow-up of the 83 already recruited participants was continued. Based on these same evaluations, provision of the COPD digital service was scaled up to a wider cohort of vulnerable people with COPD resident in NHS GG&C outside of the trial, to mitigate care disruptions for these individuals. The service evaluation analyses from this cohort will be reported separately. Additionally, a location and time-period matched control cohort with severe COPD was identified from an approved de-identified dataset from the NHS GG&C Safe Haven.Having reached the follow-up censor date for the RECEIVER trial, the primary and core secondary outcomes of the study can now be reported on. These include measures evaluating patient application usage, clinical outcome measures compared to the matched control cohort, characterization of trends in quality of life and symptom burden following service onboarding, and determining community-managed exacerbation count amongst the participants. Results from exploratory analysis to identify potential factors determining utilization and analysis to establish the extent of utilization amongst a subpopulation of participants resident in more deprived postcode areas are also reported on.The RECEIVER trial is a prospective observational cohort hybrid implementation-effectiveness study, performed according to the UK Policy Framework for Health and Social Care Research.26People with COPD attending secondary care in NHS GG&C were screened for eligibility to be included in the RECEIVER cohort.At least 18 years of age at onboardingConfirmed diagnosis of COPD (GOLD 2019 criteria)A COPD exacerbation requiring hospitalization in the previous 12 months and/or chronic hypercapnic respiratory failure or sleep-disordered breathing meeting established criteria for home NIV/continuous positive airway pressure (CPAP) treatmentDaily access to a smartphone, tablet, or desktop computer with internet access either personally or through a close contactRECEIVER cohort inclusion criteria:Lack of capacity to give informed consent or having a communication barrier precluding the use of the serviceRECEIVER cohort exclusion criteria:A patient web application accessible via smartphone, tablet, or computer where patient-reported outcomes (PROs) can be entered, and standardized self-management advice can be accessedA clinician dashboard where structured data from electronic health records (EHRs), PROs, wearables, and home NIV machines are displayedAn asynchronous messaging facility accessible via the patient application and clinician dashboard which facilitates out of hospital, non-urgent patient-clinician contactA support website providing further self-management resourcesThe service consists of:Screen capture views of the intervention components are shown in Supplementary Methods.The clinician dashboard was utilized to maximize information available and support clinician decision-making following participant-initiated contact through the messaging service or during routine clinical contact . Participants were made aware that their symptom data would not be routinely reviewed or monitored outside of this context and that they should seek medical advice through usual care channels if they felt unwell. Further details of the intervention components and how they were used, as well as details on data processing and data storage are available in the Semi-structured interviews with people living with COPD in NHS GG&C were undertaken as part of the design of the Lenus COPD digital tools to understand the experience of people living with COPD and to allow for iterative co-design of the COPD digital service. The digital service and the RECEIVER study design were informed by these interactions, alongside published data on the priorities of people with COPD.Study follow-up took place from the 3rd of September 2019 to the 31st of August 2021. Recruitment ceased for the RECEIVER cohort in March 2020 due to UK COVID-19 restrictions. PRO data was collected via the patient application, and baseline demographic and physiology data were obtained from EHRs, with all data aggregated into the clinician dashboard. Where available, summary home NIV (ResMed Lumis 150 ST-A) and wearable data (Fitbit Charge 3) were also included in the clinician dashboard. However, analysis of this physiology and therapy data is outside of the scope of this paper.The control cohort was established from a linked and deidentified dataset produced by the NHS GG&C Safe HavenHad a COPD or respiratory-related admission in the seven-days up to the onboarding date of the RECEIVER participantAlive at the onboarding date of the RECEIVER participantSame sex as the RECEIVER participantNot already matched to another RECEIVER participantNot a user of the intervention These matching criteria were as follows:Due to data availability and constraints within the Safe Haven deidentified dataset, it was not possible for additional disease-related criteria to be matched for . Each RECEIVER participant was matched with five controls to mitigate any biases resulting from the lack of complete data for the control cohort. Alternative time windows of up to 12 months for the preceding COPD/respiratory-related admission for control subjects were considered. As this would have potentially introduced additional biases , and as evaluation would combine 12-month pre-post index event and survival data, a 7-day window was considered to be most appropriate.The primary outcome measure for the trial was the proportion of trial participants utilizing the patient application as determined by completion of daily COPD assessment test (CAT)Supplementary Methods. Supplementary Table 1 details the outcomes that are reported in this paper, as well as the data that were collected throughout the RECEIVER trial that are not included in the analyses presented in this paper but will be reported on subsequently.Clinical secondary outcomes were directly compared between the RECEIVER and control cohorts with the index date for both the RECEIVER participants and their matched controls set as the RECEIVER participant\u2019s onboarding date. Survival metrics and changes in annual COPD or respiratory-related admissions and occupied bed days were compared between the cohorts. Other secondary outcomes included analysis of changes in health-related quality of life Utilization at each timepoint was calculated from the participants who were alive and onboarded at that time. Survival analyses were conducted comparing time to admission, death, and admission or death between the RECEIVER, and control cohorts using Kaplan\u2013Meier survival analysis with a Log rank test. Survival between cohorts was compared with median time to event metrics and unadjusted hazard ratios. Wilcoxon signed-rank test effect sizes were used to compare the change in annual admission and occupied bed day (OBD) counts between the cohorts. Kruskal\u2013Wallis tests and chi-squared tests were used as appropriate to explore differences in baseline characteristics and admission events over the first year of follow-up between groups of participants with different levels of application utilization. All statistical analyses were performed using R version 4.0.5.The RECEIVER participant flow diagram details the recruitment strategies for the trial participants . The conRECEIVER participant and control cohort characteristics are summarized in Supplementary Table 2).Around 58% of the RECEIVER and 63% of the control cohort were resident in postcodes in the most socioeconomically deprived quintile of the Scottish Index of Multiple Deprivation (SIMD),Supplementary Figure 1).The percentage of participants completing at least one CAT entry per week was \u2265 68.1% each week over the first year of follow-up (mean weekly completion 79.8%), with consistent usage noted beyond this . Around Supplementary Tables 3 and 4).Analysis characterizing utilization in more depth was also conducted by stratifying the cohort into four quartiles based on the mean number of entries completed in the previous seven days at each possible point over the first year of follow-up (seven-day rolling average completion) and conducting stratified analyses. A heatmap visualization displaying CAT completion over the first year of follow-up with the trial participants grouped into these quartiles is shown in Median time to first COPD or respiratory-related admission or death was increased in the RECEIVER cohort compared to the control cohort (335 days vs 155 days) . The difSupplementary Table 5).The effect size of the reduction in annual COPD or respiratory-related admissions  and occuHealth-related quality of life and symptom burden data were obtained throughout the study period through the once four-weekly EQ-5D-visual analogue scale (EQ-VAS) and the once daily COPD assessment test (CAT) entries, respectively. Changes in the distribution of reported values for these metrics over four equal time windows in the trial relative to onboarding were investigated. Health-related quality of life  and sympSupplementary Figure 2).RECEIVER participants reported a median of 2 community-managed exacerbations per year in the 12-months post-index . A higheThe objectives of this study were to determine the acceptability, feasibility, and utility of deploying the co-developed COPD digital service alongside routine clinical care for people with severe COPD, as well as to further develop the evidence base for digital self-management and remote monitoring interventions in the management of COPD. Focus was placed on determining service utilization over a prolonged period, and evaluating the impact of service adoption on clinical outcomes. Sustained and high levels of interaction with the patient application were illustrated in the trial, including in participants resident in postcode areas in the most socioeconomically deprived quintile of the SIMD. Improved survival metrics and admission reductions were also noted amongst the participants in comparison to a location and time-period matched control cohort with a comparable admissions profile in the year prior to study index date, as well as an equivalent age and sex distribution. These outcomes were obtained with a median of 2 community-managed exacerbations recorded per participant per year, and broadly stable quality of life and disease impact metrics recorded across the study follow-up period, despite the progressive nature of COPD.Some major strengths of the study were the detailed characterization of patient application usage and incorporating study follow-up beyond one year. It was very encouraging that most participants continued to complete at least one CAT entry per week across follow-up and that even participants with interrupted usage generally resumed interactions at a later point. The average completion of four CAT entries per participant per week throughout the study period was also very encouraging, with a notable proportion of participants sustaining daily usage. Within the RECEIVER trial, participant symptom data was reviewed only on an as required basis . This detailed symptom trend and insight data were available to enrich these reviews, reducing patient-clinician time spent on information gathering, without increasing clinical team workload by mandating regular reviews of the PRO data. It will be valuable to explore in subsequent service evaluations which components of the digital service are most useful to patients and clinicians in different scenarios.In addition to providing the clinical team with granular data for clinical decision support, this data will be highly valuable for ongoing machine learning analysis to generate predictive models that could potentially improve COPD management further. Exploratory analysis to determine if any demographic factors, factors related to disease severity, comorbidities, additional therapies or admission rate over follow-up were associated with utilization, did not identify any significant differences in these metrics between participants with different application utilization frequencies. The difficulty in identifying discrete characteristics associated with utilization of digital interventions has been widely reported elsewhere.Out of a potential 283 RECEIVER participants, only 41 lacked technology access. This was lower than anticipated and is an improvement when compared to previous reports.37Supplementary Material for a breakdown of the RECEIVER and control cohorts by SIMD quintile).COPD prevalence is disproportionately high in more deprived communities and deprivation is independently associated with increased risk of COPD hospitalization and mortality.The improvements in survival metrics and admission reductions compared to the control cohort provide reassurance about the safety of digital co-management of COPD, when it is co-designed and deployed as part of transformation of routine care. Analysis of qualitative data on the patient-perceived benefits of the COPD digital service is in progress, and this should provide insight into the potential mechanisms by which the benefits observed here have been realized. It is our anticipation that the digital tools help support guideline-based care including COPD self-management. The improved participant outcomes seen in the RECEIVER cohort compared to the control cohort are in line with those seen in participants who were successfully taught self-management in a previous trial undertaken in our organization, supporting this view.39Interpretation of these clinical outcomes should be measured: this was an observational study with risk of multiple biases which can only be partly mitigated by the use of a location and time-period matched routine clinical dataset derived control cohort. It is notable that reduced hospital admission rates were seen in the control cohort in the year following study index. This effect has been widely reported over the period overlapping with COVID-19 restrictions and is attributed to a reduction in community transmission of respiratory infections that can trigger COPD exacerbations.With all of this noted, the observed improved outcomes amongst RECEIVER participants are encouraging both at an individual and population level. In addition to improving outcomes for people with COPD, the observed reductions in COPD or respiratory-related occupied bed days observed amongst the RECEIVER participants could have wider benefits to health-care systems, such as cost savings resulting from avoided hospitalizations and alleviating strains on hospital capacity. Additionally, reductions in admissions reduce the environmental impact of COPD management per individual per year, with hospital admissions accounting for a considerable proportion of NHS emissions.41The findings in the study are consistent with several previous studies on telehealth, remote-monitoring, and supported self-management-based COPD digital services that showed improved clinical outcomes.Supplementary Figure 3). Some of the next steps include analysis of patient application utilization and clinical outcomes amongst the individuals who were onboarded as part of the COVID response, as well as analysis of RECEIVER participant physiology and therapy data from wearables and home NIV machines. Implementation of AI-based actionable insights is in development, with ongoing work to operationalize machine-learning models trained and validated using data collected during the RECEIVER trial and Safe Haven data.Based on these evaluations, scale up of the digital support service to other health boards has progressed and some of the key results of the trial have been summarized in a plain language flyer to encourage additional individuals with COPD within the NHS GG&C health board to sign up to the support service (The primary objective of the RECEIVER trial has been successfully delivered, with sustained participant usage of the co-designed digital service confirmed. An improvement in clinical outcomes in the trial participants compared to a matched control cohort derived from routine clinical data was also observed. Based on these positive findings, scale up of service provision to support end-end proactive and preventative COPD care is in progress. The rich user experience and structured datasets collated in the RECEIVER trial will support the development and deployment of future digital innovations, including the use of AI derived insights, to further enhance care and continue the drive to improve outcomes for people living with COPD."}
+{"text": "This article provides an overview of the principles and techniques of oncoplastic and reconstructive breast surgery for patients with early-stage breast cancer. Oncoplastic breast surgery (OPBS) with partial breast reconstruction is a natural evolution in the application of breast conserving surgery and permits wide surgical resection of tumours that might otherwise mandate mastectomy and whole breast reconstruction. These reconstructive techniques must be optimally selected and integrated with ablative breast surgery together with non-surgical treatments such as radiotherapy and chemotherapy that may be variably sequenced with each other. A multidisciplinary approach with shared decision-making is essential to ensure optimal clinical and patient-reported outcomes that address oncological, aesthetic, functional and psychosocial domains. Future practice of OPBS must incorporate routine audit and comprehensive evaluation of outcomes. Breast cancer remains the most common malignancy worldwide with recent lifetime estimates of 1 in 7 in the United Kingdom (UK) . Within Those countries that historically had moderate or low rates of breast cancer based on income levels are now experiencing rapid rate increases with an inexorable rise in the incidence of breast cancer in China and India and a doubling of rates in Japan over the past 50 years. The high incidence rates in Western industrial nations have been attributed to lifestyle factors that now have relevance to increasing rates amongst emerging economies. These include changes in reproductive behaviour, altered dietary habits with increased consumption of polyunsaturated fats and alcohol together with a more sedentary lifestyle and physical inactivity \u201310. ThesMortality rates for breast cancer have fallen over the past 30 years despite a continued rise in incidence. This testifies to the success of interventional strategies such as screening and adjuvant systemic therapies that permit diagnosis of breast cancer prior to formation of micrometastatic disease or obliteration of established foci of disease at distant sites. Survival rates at 10 years for breast cancer in the UK are currently 80.4% compared with approximately 55% in the final quarter of the last century . Survivaen bloc the breast, pectoral musculature, and the axillary lymph nodes (up to level III). This operation was rapidly implemented as routine surgical practice for breast cancer patients in the first half of the twentieth century irrespective of clinical features (assuming the tumour was operable). A fundamental concept of this so-called Halstedian paradigm was that maximal efforts at local control would prolong survival; breast cancer was considered to originate as a localised disease, and it was surmised that cure rates could be improved by a more meticulous and comprehensive surgical approach. Local recurrence was considered to be the cause of distant metastases and the aim was to minimise rates of local relapse. Halsted observed that many patients developed local recurrence before they succumbed from distant metastatic disease. His operation of radical mastectomy reduced rates of local recurrence from 60% to 6% but had no impact on overall survival \u2013 so this mutilating operation did not provide patients with any additional years of life. There was a problem with the existing paradigm; hence an alternative hypothesis was proposed by the eminent surgeon Bernard Fisher (1918-2019) whose brother Edward (\u2018Ed\u201d) was a pathologist. This paradigm was known as biological pre-determinism and contended that breast cancer is a local manifestation of a systemic disease with complex interactions between the host, the primary tumour and distant micrometastases  lymph nodes. It followed that surgery could only achieve local control of disease and some form of systemic treatment was necessary to improve overall survival  published the first formal description of an operation for breast cancer based on a series of patients treated at the Johns Hopkins Hospital in Baltimore, USA . He post52-1922 pher 1918-19 whose survival  by Bernasurvival . Hence psurvival . Nonethesurvival .Halstedian paradigm and more aggressive tumours (triple negative and HER2 positive cancers) disseminating early on \u2013 consistent with the Fisherian paradigm  behaving according to the paradigm . MoleculThe modified radical mastectomy removed breast and axillary tissue in continuity but preserved the pectoralis major muscle and much reduced the morbidity of the traditional radical operation. This operation was championed by David Patey of the Middlesex Hospital in London but was never widely adopted outside the UK . With thAxillary surgery is an integral component of breast cancer surgery and has undergone a revolutionary change with progressive de-escalation of nodal resection. The operations of both radical and modified radical mastectomy implied concomitant axillary lymph node dissection (ALND). However, with the advent of sentinel lymph node (SLN) biopsy, formal ALND is now much less commonly performed (as either a primary or a secondary procedure); a notable change has been omission of completion ALND in selected sentinel node positive cases with reliance on adjuvant non-surgical treatment modalities for eradication of low burden axillary disease in non-sentinel lymph nodes . The majThe development of oncoplastic surgery and partial breast reconstruction is a natural evolution in the application of BCS to management of breast cancer. Most patients who are considered eligible for BCS have a favourable tumour to breast size ratio and are suitable for conventional forms of wide local excision with local glandular readjustment but no formal remodelling of the breast. Even when re-excision of margins is required (in up to one-quarter of cases), an optimal cosmetic outcome should be attainable in the long term after irradiation of the breast. There is a \u2018grey area\u2019 where the limits of BCS are being approached and the patient may be better served with a skin/nipple-sparing mastectomy and immediate breast reconstruction at the outset. It becomes progressively more difficult to achieve a good cosmetic outcome as the proportion of breast tissue removed increases. When more than 10%-20% of breast tissue is removed, there is a risk of an unsatisfactory result, but relatively modest losses of 5%-10% of breast volume from tumours in cosmetically sensitive areas  can adversely affect cosmesis . OncoplaThe \u2018coming of age\u2019 of OPBS  has alloA patient\u2019s expectations of the final cosmetic result will be determined by any relevant prior knowledge and influenced by information derived from family, friends, other patients, the media and increasingly the internet. Any misperceptions must be corrected, and fully informed consent obtained before proceeding with any form of breast reconstruction. Levels of patient satisfaction are often more related to adequate information and a robust shared decision-making process than an aesthetically pleasing cosmetic result.There must be alignment between the aims of the surgeon and the patient \u2013 the latter takes comfort and reassurance from a surgeon\u2019s knowledge and skills. Establishment of a good rapport will encourage shared decision-making and lead to optimal outcomes. Patients must be given sufficient time to assimilate all information and reach a decision that feels right for them; sometimes they will change their mind, and this must be accommodated. Surgeon preference should not dominate discussions and patients should be offered a full repertoire of reconstructive options and not compelled to accept a reconstructive option that is especially favoured by her surgeon (for whatever reason). Surveys have revealed that patients who chose reconstruction are motivated by body image rather than reasons relating to sexuality or femininity . By contIncreasingly breast units around the world are employing specialist breast care nurses as well as dedicated breast reconstruction nurses. These individuals exercise a valuable role in clarifying and processing information for patients. They can sometimes help frame relevant questions ahead of any consultation with the surgeon and this will facilitate shared decision-making. Introduction of separate oncoplastic multidisciplinary team meetings combines the expertise of breast surgeons, plastic surgeons, radiologists, and medical/radiation oncologists. It is important that these potentially problematic OPBS cases are discussed jointly between breast surgeons, plastic surgeons and oncologists to determine optimal management. Treatments are increasingly tailored to individual patients and based on tumor phenotype. Most triple negative and HER2 positive tumors >2cm will be managed with primary chemotherapy and in the latter case anti-HER2 therapy. Complete pathological response rates often exceed 50% and concentric shrinkage of tumors will facilitate subsequent surgery with breast conservation being an option instead of mastectomy (with or without whole breast reconstruction). Individual cases can be discussed in depth with access to clinical notes, radiological images and medical photography. Oncoplastic multidisciplinary team meetings are being widely adopted and used to aid in surgical decision making and providing options for patients. These meetings are also an excellent forum for trainees.The range of OPBS options in the modern era is considerable and the potential choice of options available to a woman with a newly diagnosed breast cancer can be overwhelming. Extreme oncoplastic breast conserving surgery (EOBCS) refers to the use of oncoplastic breast conservation techniques in patients with multifocal, multicentric or locally advanced breast cancer (>5cm) which would be conventionally treated with mastectomy (+/- reconstruction). EOBCS has evolved with the improvements in systemic therapies, radiotherapy techniques and increased awareness of the psychological and quality-of-life benefits of breast conservation. In 2015 Silverstein et\u00a0al. reported 66 cases of EOBCS in patients who were advised mastectomy and declined. There is a lack of long-term data on the impact on recurrence, overall survival and distant metastases in patients opting for EOBCS , 49. TheHistorically there has been a dearth of high quality research in OPBS with minimal level I evidence derived from randomised controlled trials \u2013 the latter are arguably more challenging to undertake in this field. This often relates to issues of patient and surgeon preference in terms of specific operative procedures that can undermine surgical equipoise and dissuade patients from accepting treatment options determined by a process of randomisation. A more pragmatic trial design for evaluation of clinical and patient reported outcomes is prospective observational studies whereby patients can chose a particular surgical option and different groups of patients will then be compared in terms of specific outcome measures. This type of design is subject to confounding from unmeasured bias but otherwise represents a way of encouraging trial participation and relatively rigorous evaluation of outcomes whilst allowing patients to chose their surgery . Failure of trials to randomise OPBS patients provides valuable insights into how future clinical trials in this field should be designed .There has been a flurry of public interest in genetic testing and risk reduction strategies following revelations that the actress Angelina Jolie had chosen to undergo bilateral prophylactic mastectomy due to carriage of a BRCA-1 gene mutation. In addition to increased demand for genetic testing amongst breast cancer patients, the number of contralateral prophylactic mastectomy (CPM) cases have increased three-fold since this story appeared in the New York Times in 2013 . GeneticGenetic testing in the UK can take up to 12 weeks before results become available and management of younger women with primary chemotherapy (triple negative/HER2 positive breast cancer) provides a convenient surgical pause allowing genetic test results to be available when planning definitive surgical treatment. Some younger women without a documented pathogenic variant but a strong family history of breast/ovarian cancer may opt for risk-reducing surgery.The second part of this article will address the different types of techniques available for OPBS and criteria for selection of patients for appropriate options. The latter must ensure optimal oncological, and patient reported outcomes whilst minimising complications and delays in commencement of adjuvant treatments.The challenge of oncoplastic surgery is to reconcile oncological and aesthetic outcomes and maximise levels of patient satisfaction. There are broadly three primary aims that need to be addressed for each patient:1) Optimal oncological outcome \u2013 performing an extirpative procedure that minimises the chance of recurrence by removing the tumour with a clear margin of normal surrounding breast tissue as part of either a partial or complete mastectomy.2) Optimal cosmetic outcome \u2013 reconstituting the breast with either partial or whole breast reconstruction to provide optimal symmetry and shape in relation to the native breast.3) Minimal delays in commencement of adjuvant treatments \u2013 prevention of post-operative complications such as infection, wound dehiscence, haematoma, seroma, or fat necrosis that interfere with delivery of adjuvant treatment such as radiotherapy and chemotherapy.Volume rearrangement involves the use of local tissues to optimize the shape after wide local excision. It incorporates careful incision planning, appropriate undermining of the breast skin, meticulous closure of the dead space and mobilization of the local tissues. Volume replacement imports additional tissue with a flap to compensate for loss of volume from surgical ablation. By contrast, volume displacement rearranges the remaining breast tissue using methods of glandular advancement/rotation/transposition that serve to redistribute parenchyma and minimize the cosmetic impact of tumour excision. This is also referred to as \u2018therapeutic mammoplasty\u2019. In effect, the volume loss is absorbed over a wider area with concomitant re-shaping of the breast. Volume displacement surgery is less complex than autologous tissue transfer methods and avoids associated donor site morbidity. The reconstructed breast is notably of smaller volume and plastic surgery on the contralateral side is often required for symmetrization, which (more often than not) is an integral part of therapeutic mammoplasty. This applies especially to therapeutic mammoplasty where tumour excision is incorporated into standard/modified reduction procedure or breast lift. Volume displacement represents the simplest option for partial breast reconstruction and is usually preferred over techniques for volume replacement that involve more extensive surgery with harvesting of a myocutaneous or subcutaneous perforator flap. Volume displacement techniques are preferably used in patients with medium to large breasts with a significant degree of ptosis that render these patients well suited to these techniques. By contrast, volume replacement techniques are indicated in small breasted women  encompasses volume rearrangement, volume displacement and volume replacement techniques. ed women , 49, 55.Techniques for OPBS were formally classified by Krishna Clough in 2010  and diviLevel 1 OPBS techniques - these involve resection of at least 20% of total breast volume that require relatively straightforward volume displacement techniques to achieve an acceptable cosmetic result with reshaping of the breast through advancement, rotation or transposition of existing parenchyma and skin with a resultant decrease in overall breast volume.Level 2 OPBS techniques \u2013 these involve resection of between 20% and 50% of total breast volume with restoration using methods for either displacement or replacement of breast tissue that may be combined with skin reduction or transfer.When up to 20% of breast volume is resected without any attempt to mobilize and re-model adjacent glandular tissue, then a significant defect in breast contour, shape and size may ensue. Resection of breast tissue in the upper outer or lower outer quadrants is less likely to result in a noticeable defect compared with resections in more cosmetically sensitive areas such as the upper inner quadrant. The cosmetic outcome after removal of a relatively small volume of tissue can be enhanced by simple mobilization of breast tissue adjacent to the surgical cavity. The extent of mobilization required will depend on the size of the defect and may involve undermining the whole breast plate. Extensive mobilization of breast tissue can sometimes threaten the blood supply to both the glandular tissue and skin. This can lead to post-operative necrosis and secondary infection with a poor aesthetic outcome and impaired quality-of-life . TherefoVolume displacement techniques \u2013 these can be employed to adjust for loss of larger breast volumes (20 \u2013 50%) and usually involve some form of mammoplasty that includes a variety of techniques such as Wise pattern, batwing, Grisotti, Benelli, Round block and vertical mammoplasty (LeJour) pattern.These various mammoplasty techniques involve resecting the tumour and a pre-determined volume of tissue and skin with rearrangement of the glandular tissue to re-form the breast. The re-fashioned breast is often smaller and less ptotic than the native breast and contralateral breast surgery is frequently indicated for symmetrization  \u2013 Volume replacement techniques \u2013 these have previously been reliant on use of the latissimus dorsi (LD) flap harvested as either a myocutaneous flap in the form of a standard LD flap or the mini-LD muscle flap, the latter popularized by Rainsbury .Other methods for enhancing breast volume include lipo-modelling that has recently had a renaissance in the context of breast cancer surgery. This is especially useful as an adjunctive technique to \u2018plump up\u2019 mastectomy skin flap thickness around implants , 64. MorA wide range of OPBS techniques are now available and selection of the optimal method for any individual patient is dependent on breast size, degree of ptosis, tumour location (quadrant), the surgeon\u2019s expertise and patient preference. In terms of patient satisfaction, it is important that expectations are realistic, and patients understand that their overall breast size many be smaller following oncoplastic breast surgery and scarring can be more extensive than anticipated for some level II OPBS techniques. The choice of OPBS technique will also be influenced by the surgeon\u2019s skills set.Careful planning of skin incisions and appropriate orientation of the nipple-areola complex pedicle is essential when performing more complex volume displacement techniques that demand detailed knowledge of the blood supply of the breast and appreciation of plastic surgery principles. This applies particularly to transposition of glandular tissue when there has been extensive undermining from both chest wall and skin and secondary pedicles have been created during a classical Wise-pattern (therapeutic) mammoplasty to address complex/extensive defects and avoid a mastectomy . In the UK, breast surgeons are routinely trained in techniques of whole breast reconstruction that are implant-based with or without adjuvant material (matrix/mesh). NICE guidelines state that patients should be offered reconstruction unless existing co-morbidities pose a contraindication .Breast reconstruction can be performed at the time of mastectomy (immediate breast reconstruction [IBR]) or at any time after mastectomy (delayed breast reconstruction [DBR]). In recent years, IBR has gained wider acceptance with improved cosmetic results and reassuring evidence that reconstruction does not mask detection of recurrent disease \u201372.Furthermore, there are documented psychological benefits from IBR \u201376 and pFor some patients, mastectomy is mandated for breast cancer treatment based on factors such as the tumour: breast ratio, multifocal/centric cancers, or perhaps failed attempts at breast conserving surgery. A decision for mastectomy may also relate to age, genetic predisposition, and availability of IBR. Not all patients seek IBR and this may be contraindicated for some patients based on cancer type (inflammatory cancers), co-morbidities, BMI and smoking history. When proceeding with IBR, one of the most important early decisions is whether the nipple-areola complex should be preserved, and this will be determined on grounds of oncological safety, aesthetic benefit, surgical feasibility, and patient wishes. If pre-operative imaging reveals no direct involvement of the nipple by tumour and there is sufficient distance to the nipple, then nipple preservation is usually feasible, and several studies have confirmed the safety of NSM in terms of local recurrence , 81. NonMany breast units have strict selection criteria for IBR with smoking status and BMI being of paramount importance. A BMI in excess of 30 is associated with a 4-fold increase in major complications following IBR \u201384 but mSkin incisions for skin- and nipple sparing mastectomy should be discussed between surgeon and patient as these are associated with different rates of complications but a peri-areolar incision  and infra-mammary fold (IMF) incision respectively are conventionally used and preferred by the majority of surgeons  flap and deep inferior epigastric artery perforator flap (DIEP) and the superficial inferior epigastric flap (SIEA). The upper back flaps based on the thoracodorsal vessels are the standard latissimus dorsi (LD) flap and the totally autologous LD flap. Other potential flap donor sites for breast reconstruction include the thighs  buttocks  posterior trunk (LAP flap) and iliac region (Ruben\u2019s peri-iliac flap). Interestingly the use of the LD flap in conjunction with an implant (implant-assisted LD flap) for breast reconstruction has dramatically fallen in recent years with the advent of acellular dermal matrices that provide alternative coverage and support for an implant , 87. SimThe lower abdominal pannus provides generous tissue bulk for reconstruction purposes and therefore supplementation with an implant is unnecessary. These abdominal flap-based reconstructions have pedicle and free-flap variants and are more technically challenging with a greater risk of complications than implant only methods and may entail a microvascular anastomosis. Training in these autologous flap techniques is often protracted and involves specific microsurgical training (e.g. one year fellowship) and therefore these procedures are performed exclusively by plastic surgeons. The free-TRAM flap necessitates harvesting a variable amount of the ipsilateral rectus abdominis muscle (Nahabedian types 1-4) with consequent associated morbidity. The DIEP flap involves dissection and isolation of vascular perforators that pass from the inferior epigastric artery through to the rectus muscle fibres to supply the overlying skin and fat. The muscle therefore remains intact without compromise of abdominal wall integrity but retaining a large infra-umbilical pannus of skin and subcutaneous tissue with which to reconstruct the breast. The evolution of the free-TRAM into the DIEP flap has helped reduce donor site morbidity but there remains a finite risk of complete flap failure. This is generally between 3% and 5% and surgeon-specific rates should be made available to patients who may then chose not to embark on these higher risk reconstructive procedures. Rates of flap failure as low as 3% are achievable in units with high volume throughput and dedicated plastic surgeons with a predominant interest in breast reconstruction. Pre-operative CT angiography has helped predict the chance of success with a DIEP flap reconstruction by identifying candidate perforators and conversely indicating those patients who are technically unsuitable for this procedure. The biggest advantage of CT angiography in breast reconstruction has been to speed up the surgery  as it prImplant-based procedures are the most commonly performed type of reconstruction worldwide and constitute about 70% of breast reconstructions in the UK (and a progressively increasing proportion of cases in the United States). This represents a simpler reconstructive option and has a more acceptable risk profile for many patients than autogenous forms of breast reconstruction. A particular advantage of implant-based IBR is a more rapid return to work and daily activities including familial and other commitments. Most women prefer to retain the same breast size but bilateral mastectomy and implant reconstruction provides the option for either downsizing or upsizing. This can also be possible with abdominal flap reconstruction depending on the relative sizes of the breasts and lower abdomen , anatomical site , shape  and implant size and to a lesser extent projection. More recently whether to use a smooth or textured surface prostheses has become important in the light of the causative association of implant surface texturing with ALCL.in situ rotation can have serious consequences for the cosmetic appearance by producing weird breast shapes. Fortunately, anatomical implants only come with textured surfaces which reduce malrotation, malposition and flicking over.Round implants provide uniform projection all around and especially in the upper pole. Rotation of such implants has minimal consequence in terms of cosmetic appearance. By contrast, anatomical/bi-dimensional implants are tear drop in shape and more closely mimic the natural anatomical shape of the breast. Their via a port that is tunnelled subcutaneously. This can be minimally filled initially to relieve any pressure effects on the mastectomy flaps and wound during healing and can then be slowly expanded. Expanders can be temporary or permanent and ports can be removed separately if required .Fixed volume implants are exactly as their name implies and have an immutable size and volume compared with expander implants whose volume is adjustable Fixed volume implants and tissue expanders can be placed in a sub-muscular location with complete muscle coverage . Today prostheses are generally placed in the subpectoral position with partial coverage in a dual plane setting with a combination of pectoralis major muscle and a piece of ADM that is sutured between the lateral border of pectoralis major and the chest wall (IMF) to complete the implant pocket. Increasingly, the implant is placed in a pre-pectoral  location without disruption of the pectoralis major muscle. In consequence there is no muscle animation, less post-operative pain and possibly evidence of less capsular contracture . A potenth) of implants are composed of material that is unlikely to cause an issue with longevity and necessitate routine replacement. Capsular contracture is an individual response of the host and exacerbated by exposure to irradiation which may require further surgery with capsulotomy and implant exchange. Breast implant associated anaplastic large cell lymphoma (BIA-ALCL) and breast implant-related illness are well publicized conditions which remain poorly understand but explanation of associated risks are part of the standard consent process. The risk of BIA-ALCL is commonly quoted as 1 in 28,000 but figures vary widely. This rare form of lymphoma arises in an effusion or scar capsule and patients are warned that any sudden breast swelling occurring more than 8-10 years from original surgery should be investigated to exclude BIA-ALCL. Fluid aspirated from around the implant can be tested for CD30 and the disease-specific marker ALK (anaplastic lymphoma kinase), reflecting a translocation in the tyrosine kinase receptor gene. Treatment in most cases is local and involves excision of the capsule and removal of the implant with later stages sometimes requiring systemic treatment with chemotherapy that is more effective for ALK positive cases (The current generation (5ve cases .Radiotherapy has a major impact on aesthetic outcomes following irradiation of skin and remaining breast parenchyma after OPBS and in the context of post-mastectomy radiotherapy (PMRT) with whole breast implant-based reconstruction. Although all cases of breast conservation will require radiotherapy, often a final decision on PMRT is made post-operatively when results of definitive histopathology are available. Nonetheless, PMRT may be anticipated, and this will be factored into the decision-making process in terms of surgical approach. Reports to-date suggest that ADM offers some protection from radiotherapy effects and pre-pThe Dindo classification of surgical complications introduced in 2004 is widely employed in breast surgery and permits objective comparison of outcomes between different studies.Complications relating to breast surgery patients are generally of mild to moderate severity and lie somewhere between grade 1 and grade 3b, grade 1 being a deviation from normal surgical course without the need for any type of intervention; grade 2 being a complication that requires pharmacological intervention or blood transfusion; grade 3a requiring surgical or radiological intervention without general anaesthetic . Nonethein vivo determination of tumor sensitivity, eradication of micrometastatic disease with improved overall survival and downstaging of axillary nodes to de-escalate definitive surgery and minimize upper limb morbidity. Some patients have dramatic clinical response to standard pre-operative chemotherapy regimens and for patients with HER2 positive disease and triple negative cancers, complete pathological response rates can be as high as 70%. Those patients with a complete pathological response (pCR) in both the breast and axilla have improved longer term survival , surgeon-related factors (including preference and skills set) and healthcare resources (including availability of theatre/capacity).Patients should be encouraged to engage in a shared decision-making process and will derive information from discussion with surgeons and breast care nurses often supplemented with online resources. They must be given sufficient time to absorb and process information before reaching a final decision on surgical management. Some studies have reported that only one-third of patients recalled being adequately informed about surgical options upon being questioned 3 months following surgery , 105. ThMore objective patient-related factors that influence suitability for an oncoplastic or reconstructive procedure include tumour: breast ratio, breast size and shape (degree of ptosis), body habitus, BMI, co-morbidities, anticipated adjuvant treatments, smoking habits, anatomical factors determining available tissue volume for breast reconstruction/replacement and previous radiotherapy.Patient factors and co-morbidities that influence healing, recovery, and tolerance of surgical/adjuvant treatments (chemotherapy and radiotherapy) include factors such as: smoking, diabetes, high BMI, vasculopathy, connective tissue diseases. Other factors to consider are patient expectations and understanding of their disease and treatment together with the need for any psychological evaluation and support.Breast cancer treatment involves a variety of modalities with possible side effects, which can be difficult for patients to understand and accept. One patient compared her journey through chemotherapy, surgery, and radiotherapy to being \"poisoned, slashed, and burnt.\" She revealed that she was unprepared for the whirlwind experience and its considerable impact. From a holistic perspective, breast cancer treatment affects patients' families, relationships, work, sexuality, confidence, independence, and mortality perception. With deadlines looming, patients must overcome obstacles and make decisions, even though they recognize that their choices may affect their survival. It is not unreasonable for patients to question the consequences of failure.As we have all seen once patients cross that initial phase of treatment and suddenly their chemotherapy and radiotherapy has finished, they are left with the one visible reminder of their journey; the breast. It can be a conflicting entity, a symbol of their sexuality, motherhood, cancer, and mortality. Many studies have confirmed that better aesthetic outcomes improve quality-of-life. The aforementioned catalogue of oncoplastic and reconstructive procedures provide breast cancer patients with a variety of options that can maintain or improve overall well-being and quality-of-life.Future directions of oncoplastic and reconstructive breast cancer surgery includes the sharing of information on a national and international level to identify trends and learn from good practice. BCCT.core software can help breast surgeons evaluate cosmetic outcomes of OPBS more objectively and 3D imaging for reconstruction can help with the consent and planning process . As we cOther patient-related factors that impact wound healing, post-operative recovery and how well patients tolerate adjuvant treatments include diabetes (types I and II), vasculopathy and connective tissue disorders. These latter conditions can affect viability of mastectomy flaps and transposed glandular tissue of the breast and some connective tissue diseases are a relative contraindication to radiotherapy.The diagnostic and treatment pathway for breast cancer patients is a difficult journey psychologically and it is important to gauge patients\u2019 understanding of their disease and in particular expectations from breast reconstructive surgery. Patients should not undergo simultaneous contralateral prophylactic mastectomy without formal psychological assessment. There is a relatively restricted timeline once a tissue diagnosis of breast cancer has been made and this may prove challenging and overwhelming for some patients who need more time to adjust to the diagnosis and accept a management plan that is likely to involve multi-modality treatment. Patients must cope with the mutilating effects of surgery and adverse side-effects of radiotherapy and systemic treatments . A breast cancer diagnosis has wider implications for a patient\u2019s family and relationships be this work-related or more intimate. Apart from negatively affecting body image, self-confidence and sense of femininity, breast cancer is a potentially life-threatening disease and can abruptly remind a patient of their own mortality. Survivorship has come to the forefront in recent years with more attention to quality-of-life and minimising the sequelae of breast cancer treatments \u2013 especially surgery and radiotherapy. Patients should have not only an acceptable cosmetic result, but also optimal functional outcomes without chronic symptoms of niggling discomfort or more overt pain symptoms. Nonetheless, the majority of women are successfully treated and will live for many years following breast cancer treatment.PW and JRB wrote the article. JRB edited article. CMM edited second part of the article, contributed photography and diagrams. All authors contributed to the article and approved the submitted version."}
+{"text": "This paper presents a hybrid and unsupervised approach to flame front detection for low signal-to-noise planar laser-induced fluorescence (PLIF) images. The algorithm combines segmentation and edge detection techniques to achieve low-cost and accurate flame front detection in the presence of noise and variability in the flame structure. The method first uses an adaptive contrast enhancement scheme to improve the quality of the image prior to segmentation. The general shape of the flame front is then highlighted using segmentation, while the edge detection method is used to refine the results and highlight the flame front more accurately. The performance of the algorithm is tested on a dataset of high-speed PLIF images and is shown to achieve high accuracy in finely wrinkled turbulent hydrogen-enriched flames with order of magnitude improvements in computation speed. This new algorithm has potential applications in the experimental study of turbulent flames subject to intense wrinkling and low signal-to-noise ratios.The online version contains supplementary material available at 10.1007/s00348-023-03651-6. Identifying the instantaneous position of the flame front and its representative geometric features is one of the most common tasks in the post-processing of optical images of turbulent flames. Indeed, accurate flame front detection gives access to an array of quantities such as curvature and flame surface density which are essential to relating turbulence and reaction rates. A common definition of the flame front is the location of peak heat release  and are presented in Table Flames in this burner were imaged using a high-speed (10 kHz acquisition rate) OH-PLIF imaging system. This system has been described extensively in previous papers  and a background (unburnt gases). Given an arbitrary intensity threshold mentclass2pt{minimi\u2217) Otsu . The proDespite its low cost and lack of supervision, Otsu segmentation tends to be less accurate as the flame fronts obtained are usually shifted from the location of peak gradients, as has been observed in Sweeney and Hochgreb . As willEdge detection is a common alternative to segmentation in flame front detection tasks. The aim is to locate the steepest gradients of OH intensity in PLIF images, which makes it a more accurate tracer of the position of the flame front. It is also a more attractive approach when the PLIF signal varies across the image, as gradients tend to be more reliable and resilient to noise than raw intensity values. Basic edge detection relies on computing a two-dimensional gradient map of the image, then using gradient magnitudes and their direction to trace a flame front and its relevant geometric features  is smoothed by convolution : The gradient map is thinned to produce an image T consisting of edges of single pixel width. This is typically done by placing a Hysteresis thresholding:  This step aims at eliminating low gradient edges due to noise and non-uniformities. Two hysteresis (gradient) thresholds, T with gradient magnitudes F is obtained. The algorithm Fig.\u00a0 can be bAt this stage, it is important to mention that the Canny algorithm, unlike Otsu segmentation, is supervised and requires that three operating parameters  and on the other hand an accurate but supervised algorithm (Canny edge detection) which can only run unsupervised at the cost of precious computation time. In light of this, it is clear that a hybrid method combining both approaches would be of interest. The goal would be to use the approximate location of the flame front obtained using segmentation to guide the edge detection algorithm and eliminate the need for supervision. This involves finding a way around the problematic hysteresis thresholding stage which is the major point of supervision in the Canny algorithm. This idea is further explored in Sect.\u00a0A second motivation for a segmentation and edge detection hybrid stems from the thermodiffusive nature of lean hydrogen-air flames which causes the concentration of the OH radical to vary with the local curvature of the flame front. As can be seen in Fig.\u00a0Prior to flame front detection, it is common practice to pre-process images using a suitable combination of filters and contrast enhancement techniques. The goal is to improve the quality of the raw images and reduce some of the experimental noise to render any further processing possible. Filtering the image also helps produce smoother flame fronts unpolluted by high-frequency noise and undesirable zigzag effects. Here, we briefly highlight the importance of ensuring compatibility between flame front detection and pre-processing techniques, which is often overlooked in combustion literature.N is varied to cover a reasonable range of low, moderate, and high filtering settings. The flame fronts obtained using segmentation (s1-6) are strikingly sensitive to filtering and indicate significantly different flame surface geometries depending on filtering intensity. In the first image, the thin corridors separating the isolated product pockets and the main flame front appear to shrink with increasing N which is likely due to the blurring effect of filtering. Notice how the flame surface in (s3) is almost unrecognizable from its original shape in the raw OH-PLIF image, as the two product pockets are absent and the algorithm detects two erroneous small reactant pockets downstream. Similar observations can be made about the second image, where the small reactant pockets shrink gradually with filtering until they disappear completely when N reaches 100. Conversely, flame fronts computed using Canny edge detection (e1-6) are remarkably resilient to filtering and become smoother as N is increased. They also seem to benefit from edge-preserving filtering in the second snapshot as the algorithm is able to detect the isolated reactant pockets with greater ease. This is an additional testament to the excellent compatibility between edge-preserving filtering and gradient-based flame front detectors. Hence, if edge-preserving filters are to be used jointly with segmentation as has been done in a handful past investigations  to more sophisticated non-linear, edge-preserving, filters   where the SNR is typically very low   is defined by measuring the distance across the flame front. The two-dimensional curvature can then be estimated using the formula:s are estimated at each point by fitting a second-order polynomial using the nearest 20 adjacent points (10 on either side)  is used to adjust the contrast in the image. This is done by dividing the image into 64 equal tiles (8-by-8 grid) then applying histogram equalization to each one. About In the pre-processing stage, MATLAB\u00ae  matrix product, denoted using the circled dot symbol \u201cA preliminary flame front is first obtained using the Enhanced Otsu algorithm, then used to construct a binary mentclass2pt{minimHochgreb , with moThe performance of the Filtered Canny algorithm is evaluated against the ground-truth Augmented Canny algorithm based on accuracy  and computation time using the metrics introduced in Sect.\u00a0Localization errors are evaluated using precision and recall. Both quantities are measured on an image-by-image basis, so reliable statistics can be computed. The results are provided in Table Probability density functions (pdf) of two-dimensional curvature are computed for both the Filtered and Augmented Canny algorithms and are presented in Fig.\u00a0We conclude that accurate mapping of turbulent flame fronts can be achieved using the proposed hybrid scheme. The algorithm is able to detect flame edge points with comparable accuracy to its sophisticated high-performance alternative and identifies the global shape of complex and highly convoluted flame fronts faithfully.\u00ae (R2021b) which is commonly used for post-processing tasks in experimental combustion. The same implementation and settings of the Augmented algorithm presented in Sweeney and Hochgreb  in record time, estimated at 2\u00a0h approximately. The reported runtimes include the edge detection stage only. Therefore, any further processing  will most likely increase the total computation time. Thus, it is evident the proposed hybrid algorithm, in addition to being just as accurate, is quicker and more time-efficient than the high-performance Augmented algorithm. This facilitates the processing of larger data sets of turbulent and highly wrinkled flame fronts within reasonable computation times.Finally, the execution times of both the Filtered and Augmented Canny algorithms are recorded for each experimental condition on an image-by-image basis. Both algorithms are implemented in MATLABHochgreb  are usedThe paper presents a hybrid and unsupervised approach to flame front detection in noisy PLIF images combining Otsu segmentation and Canny edge detection: the Filtered Canny algorithm. An adaptive contrast enhancement method, CLAHE, is proposed to improve the accuracy of segmentation with little increase in computational overhead. The contours obtained using segmentation can then be used to filter two-dimensional gradient maps in the Canny edge detection algorithm, which suppresses the need for hysteresis thresholding and hence supervision. The proposed hybrid Filtered Canny algorithm is evaluated against a high-performance alternative, the Augmented Canny algorithm (Sweeney and Hochgreb Supplementary file 1 (mp4 12053 KB)Below is the link to the electronic supplementary material."}
+{"text": "In individuals with first episode psychosis (FEP) and cannabis use disorder (CUD), reducing cannabis use is associated with improved clinical outcomes. Access to evidence-based psychological interventions to decrease cannabis use in FEP clinics is highly variable; E-mental health interventions may help to address this gap. Development of E-interventions for CUD in individuals with FEP is in its incipient phases.To assess preferences for online psychological interventions aiming at decreasing or stopping cannabis use in young adults with psychosis and CUD.Individuals aged 18 to 35 years old with psychosis and CUD were recruited from seven FEP intervention programs in Canada and responded to an electronic survey between January 2020-July 2022. We used the Case 2 Best Worst Scaling methodology that is grounded in the trade-off utility concept to collect and analyse data. Participants selected the best or worst option for each of the nine questions corresponding to three distinct domains. For each domain we used conditional logistic regression and marginal models  to estimate preferences for attributes  and attribute levels .Participants (N=104) showed higher preferences for the following attributes: duration of online sessions; mode of receiving the intervention; method of feedback delivery and the frequency of feedback from clinicians (Table 1). Attribute-level analyses showed higher preferences for participating once a week in short (15 minutes) online interventions . Participants valued the autonomy offered by online interventions which aligns with their preference for completing the intervention outside the clinic and only require assistance once a week . Participants\u2019 preferences were higher for receiving feedback related to cannabis consumption both from the application and clinicians at a frequency of once a week from clinicians .Image:Image 2:Image 3:Using advanced methodologies to assess preferences, our results can inform the development of highly acceptable E-Mental health interventions for decreasing cannabis use in individuals with CUD and FEP.None Declared"}
+{"text": "We then examined the association between different bonding styles, illness course and severity, and global functioning over a 10-year follow-up. Participants who perceived that their fathers had a more caring and less controlling parenting style showed better functioning at follow-up. However, in contrast to previous research, participants who reported having been subject to uncaring and controlling parenting styles were not found to have a notably worse course of illness or symptom severity over the follow-up period. These results indicate that more optimal parental bonding styles may be associated with better overall functioning in individuals with psychosis but not with other measures of illness outcome.A parenting style with high amounts of control combined with low caring or nurturing behaviour has been reported in association with mental disorders including schizophrenia. However, the association of parenting style with illness severity in individuals with schizophrenia has never been evaluated retrospectively or over a longitudinal time course. In a subset ( Studies that have operationalised parental bonding show there are two main concepts that contribute to the parental bonding relationship: warmth and affection over coldness and neglect, and excessive control, defined by strict rules and intrusiveness . An \u2018optimal\u2019 parental bonding style as defined by Bowlby (1977) consists of adequate care and nurture, but involves the promotion of independence.Sub-optimal, affectionless-control, styles of parental bonding have been found to be more prevalent in individuals diagnosed schizophrenia than in unaffected individuals . Nottingham participants showed lower symptom severity at baseline compared to London participants .Illness course over 10 years was assessed retrospectively. Information was collated from clinical records and, where possible, from follow-up interviews with participants and treating clinicians using an extended version of the World Health Organization (WHO) Life Chart  scale with symptom (GAF-s) and disability (GAF-d) subscales Hall .Illness severity at baseline was calculated using a sum of the dimension scores from the Item Group Checklist (ICG) of the SCAN to compare between the full AESOP sample and those included in this analysis.t-test. Regression analyses were performed to evaluate the relationship between parental bonding and contribution of multiple covariates  on global functioning scores.Differences in PBI risk scores between participants with different illness courses and severity were estimated using ANOVA or independent Socio-demographic and clinical characteristics of the sample are presented in Table No differences were seen in paternal or maternal PBI risk scores between participants with a remitting or non-remitting course of illness or between participants with different illness severity . Age, gender and baseline diagnosis were included as covariates. Symptom severity was not included as a covariate as it was not associated with either GAF or PBI scores. Paternal PBI risk scores  were a significant predictor of GAF-s scores at follow-up (R2 = 0.34).A multiple regression analysis was carried out to investigate the association between PBI scores and global functioning. Only paternal PBI risk scores were included in the analysis as these were significantly correlated with GAF scores (GAF-s: Here we have evaluated, for the first time, the relationship between perceived parental bonding at the time of the first episode of psychosis and illness course and level of functioning over the first 10 years of illness. Our data show that the perception of sub-optimal paternal parenting at illness onset is associated with lower level of functioning 10 years later, but not with other clinical outcomes.A perceived high care and low protection style of parenting by fathers as indicated by a lower paternal PBI risk score was associated with higher GAF scores at follow-up. Our results suggest that parental bonding styles may be associated with broad psychosocial functioning following a first episode of psychosis. This result indirectly supports findings from previous cross-sectional studies of individuals with a diagnosis of schizophrenia showing that this optimal parenting style is associated with a milder course of illness (Parker et al. We did not find sub-optimal parental bonding style to be associated with specific measures of illness severity in individuals experiencing a first episode of psychosis. This result is in contrast with previous findings that individuals with a diagnosis of schizophrenia who report unfavourable parenting styles are more likely to experience a more severe course of illness (Parker et al. This study has some methodological limitations to be considered. We have a relatively smaller sample size which reduced the statistical power of our study. We included participants from just one study site, which had a lower average severity of illness at baseline. This might bias our results and restrict the generalisability of the findings.While this study has its limitations, it gives a unique opportunity to consider the role of the perception of parental bonding early in the development of a psychotic illness and its impact on patient outcomes over an extended period.To our knowledge, this is the first study evaluating the impact of perceived parental bonding styles on functional and illness outcomes in individuals with psychosis after 10 years of illness. We found an association between \u2018optimal\u2019 paternal bonding styles and better long-term functioning in this sample. The observational nature of these data prevents any conclusion on a causal relationship between parental bonding styles and psychosis outcomes. Still, the results provide a basis for future studies on the role of parental bonding styles in individuals living with psychosis, with a view to improve familial support for these individuals and therefore improve functional and clinical outcomes."}
+{"text": "Thyroglossal duct (TGD) remnants in the form of cysts or fistulas usually present as midline neck masses and they are removed along with the central body of the hyoid bone (Sistrunk\u2019s procedure). For other pathologies associated with the TGD tract, the latter operation might be not necessary. In the present report, a case of a TGD lipoma is presented and a systematic review of the pertinent literature was performed. We present the case of a 57-year-old woman with a pathologically confirmed TGD lipoma who underwent transcervical excision without resecting the hyoid bone. Recurrence was not observed after six months of follow-up. The literature search revealed only one other case of TGD lipoma and controversies are addressed. TGD lipoma is an exceedingly rare entity whose management might avoid hyoid bone excision."}
+{"text": "Advanced computer vision mechanisms have been inspired by neuroscientific findings. However, with the focus on improving benchmark achievements, technical solutions have been shaped by application and engineering constraints. This includes the training of neural networks which led to the development of feature detectors optimally suited to the application domain. However, the limitations of such approaches motivate the need to identify computational principles, or motifs, in biological vision that can enable further foundational advances in machine vision. We propose to utilize structural and functional principles of neural systems that have been largely overlooked. They potentially provide new inspirations for computer vision mechanisms and models. Recurrent feedforward, lateral, and feedback interactions characterize general principles underlying processing in mammals. We derive a formal specification of core computational motifs that utilize these principles. These are combined to define model mechanisms for visual shape and motion processing. We demonstrate how such a framework can be adopted to run on neuromorphic brain-inspired hardware platforms and can be extended to automatically adapt to environment statistics. We argue that the identified principles and their formalization inspires sophisticated computational mechanisms with improved explanatory scope. These and other elaborated, biologically inspired models can be employed to design computer vision solutions for different tasks and they can be used to advance neural network architectures of learning. ImageNet challenge. This started the era of deep learning, in which progress on many computer vision tasks was made by training deep convolutional neural networks (CNNs). While neural networks are clearly inspired by biology (hence the name), most recent breakthroughs are attributed to technical improvements to network components, architectures, and training procedures  natural scene statistics.But do the learned feature detectors tell us anything about neuroscience mechanisms?The apparent ease and robustness by which biological organisms operate and solve visual tasks motivates taking such functionality as inspiration for computer vision. In recent neural network models, complex detectors are trained end-to-end to generate feature representations at different hierarchical levels. Such deep learning architectures are inspired by the neural architecture of the mammalian visual system. These systems consist of processing stages with increasingly complex response characteristics and feature selectivity (Yamins and DiCarlo What) and spatial (Where) characteristics of the input, respectively  stages of the visual system in primates  how to compare model frameworks that were developed in different domain contexts and (ii) how to define a particular task in which computational mechanisms from biology and machine vision are considered.The opportunity to cross-fertilize between the fields of computer vision and in computational cognitive neuroscience is self-evident. The core question is, Middlebury datasets  that can mimic biological plausibility depends on statistical properties of the training data. For example, the ImageNet database is biased toward object categories as they are indexed by the WordNet hierarchy  cells interact laterally over larger intra-areal spatial distances  and (ii) they receive input from cells in areas higher up in the processing hierarchy (via feedback). Thus top-down signals are re-entered at representations of lower stages  and red Masland .For each of the above-mentioned principles we provide some example investigations into various tasks of visual information processing. All are based on a small set of key neural processing principles. They demonstrate their capabilities to yield high efficiency through brain-like processing.The canonical principles that we focus on are summarized in the following. We subsequently provide examples of different modeling investigations and how such principles lead to computational solutions for different visual tasks. These mechanisms provide a basis set of elemental operations with inputs from different feature domains. Different latent representations will be generated for individual tasks and their solutions. The canonical principles considered are the following:Neural network models can be described at different levels of detail, ranging from molecules over membrane channels, synapses, neurons and networks up to large-scale components interacting at the neural systems level  of an already existing cell activation. The activation will have been generated by driving input. Consequently, modulating input by itself cannot generate an output activation of a target cell. The compartmentalized structure of pyramidal cells implements such functionality through a net multiplicative effect for coincident basal and apical cell activation  input filtering specific to the level in the architecture and recurrent lateral integration of activities generated by neighboring nodes, (ii) the top-down modulation utilizing the mechanism in eq.\u00a0r integrates the input (right hand side) that is defined by a leak current  that is again defined by a leak current (first term) and the weighted integration of E-state activations over a neighborhood in the space-feature domain (second term). In addition, a tonic input level and a self-inhibitory term are optional components . The finally calculated output activation is determined by the E-state which is passed through a firing rate function g. Indexes i and v (or k and f in the weighted activity integration) represent spatial locations and quantified feature values, respectively. Different P. Here, filtered bottom-up input, intra-layer activity and top-down signals converge at individual sites as depicted in Fig.\u00a0The dynamics of the resulting E-I node is formally described by a pair of ordinary differential equationsr is given in eq.\u00a0The output calculation of E-I model nodes is more complex than simple filter models used in computer vision or in convolutional neural networks (CNN). Filtering is here part of the response calculation. The activity entclass1pt{minimaP in eq.\u00a0The response calculation for model units here is more complex and integrates filtering with lateral and feedback mechanisms. At each stage of a hierarchical processing architecture, bottom-up peripheral sensory data streams (filter outputs) are now combined with contextual information. Such contextual information is provided (i) at the same level of the perceptual representations through lateral interaction and (ii) by representations higher up in the hierarchy through top-down feedback signals. In the modeling framework outlined here, the feedback is modulatory and thus amplifies the resulting activations generated by the filtering and the lateral integration  and two variants have the feedback connections between two stages eliminated while the other stays intact. This results in two further versions, namely one with the V4Using the proposed model architecture, we investigated which network connections contribute most to the desired functionality. To evaluate the strength of contrast selectivity, we defined a metric that compares activations in model area V4, which is selective to texture segregation . The results demonstrate that computer vision tasks can be solved by such neural mechanisms. They could be further improved by adopting task-specific requirements defined for a given application domain  is guided by a coherence or homogeneity property that region elements share. As already highlighted above, Nothdurft\u2019s experiments suggest that such homogeneity properties should include first-order contrast information between feature items as well  representations at the stage of motion integration in model area MT recurrently interact with motion integration in model MSTl and the local spatiotemporal frequency detection in area V1. This integrates unambiguous feature responses, e.g., at line ends, with ambiguous motion estimates at outlines. The resolution of uncertainty is achieved iteratively and it therefore takes time to disambiguate local estimates starting at localized features. The motion integration robustly combines translatory and rotational motion.biological inspiration and characterization of computational properties to be incorporated in computer vision models:In addition, we demonstrate how such models of motion detection and integration can be implemented on neuromorphic hardware. We show how event-based input from a neuromorphic camera leads to the representation of event clouds (without discrete frames) to be processed by a bank of oriented spatiotemporally sensitive filters. Such a scheme can be executed on a neuromorphic chip to operate in real-time. Additional stages of normalization and the integration in a two-layer bidirectionally coupled network (outlined in the first example) can also be made operational to build neuromorphic schemes of motion analysis. Again, both example cases characterize some canonical principles summarized in Sect.\u00a0The computational functions are supported by structural and functional motifs from visual neuroscience and can be employed in computer vision tasks.Local motion seen through an aperture allows measuring normal flow only, leading to the aperture problem. In Pack and Born  it is deWe proposed a multi-layer hierarchical model architecture of processing along the dorsal pathway with similar components as the model for shape processing in the ventral stream. The model is composed of three layers, which correspond to cortical areas V1, MT, and MSTl. The areas are represented by layers of mutually coupled excitatory and inhibitory cells. In the first layer, we utilize oriented filters with contrast sensitive spatial weighting functions. Their response characteristics are selective to spatiotemporal shifts to the left or to the right of the axis of orientation. Filter responses are inhibited by activity of a pool of cells over a spatial neighborhood, different contrast orientations and spatiotemporal motion selectivities. Like in the model architectures described in the previous sections, the inhibition has a divisive, or shunting, effect. The resulting output responses are integrated by velocity selective cells in the next layer, corresponding to area MT. Cells tuned to different directions integrate input activations from model V1 cells at locations corresponding to the individual speed selectivity of model MT cells. Again, cell responses are normalized by integrated pool activities over a space-velocity neighborhood. Output responses feed forward to a layer of direction sensitive cells, corresponding to area MSTl. They integrate MT output over a large spatial neighborhood and different speed selectivities. Cell responses undergo mutual competition to normalize their activities. All outputs generated at the different model layers also generate modulatory feedback to cells at topographically corresponding positions in the previous layers. The recipient locations are shifted corresponding to the linear forward predictions by motion selective cells. The motion selective cells are able to make these predictions due to their direction as well as speed selectivity. The modulatory enhancement again follows the mechanism specified in eqs.\u00a0Simulation results of the model are shown in Fig.\u00a0Regularized motion integration schemes in computer vision often employ a data term that minimizes the IOC error of the velocity estimates Hildreth . In addiThe influence of the modulating top-down feedback at different levels of the model architecture is demonstrated in Fig.\u00a0To illustrate the contributions of modulatory feedback for motion integration and the consequences of their elimination, we show two examples generated by using an intact model architecture and MTier Fig.\u00a0. The offion Fig.\u00a0.MT feedback activity generates a perceptual hysteresis effect for prolonged input motion statistics Fig.\u00a0c. An inpmultiple object motions in the scene? We briefly summarize some of our investigations that extend the introduced model framework to handle more complex motions that are generated by multiple shapes or patterns and their occlusions.The local cooperative-competition mechanisms described above support building representations of shapes moving in the image plane. So far, we discussed how coherent motion interpretations of such objects could be inferred. What about intrinsic termination feature belongs to an object or surface, while an extrinsic feature belongs to an occluder. The visual system seemingly re-weights the influence of such features to integrate those that belong to a coherent shape and to segregate the occluding segments apart  each pixel asynchronously generates a response if the intensity sensed at a pixel position changes significantlyA family of image sensors have been developed that generate address-event representations (AER) instead of recording full-frame images . For example, in the waterfall illusion the adapting stimulus is defined by water flowing in one direction . Figure\u00a0w denotes the scalar weight that is subject to dynamic adaptation (at a rate s(t) is the temporal input signal generated by presynaptic nodes. The constant The model makes the prediction that the different observed adaptation time-scales are due to adaptive synaptic efficacy in the feedforward and the feedback streams. In order to assess this prediction, different model variants have been specified, which employ adaptive synapses with slow or fast adapting time-scales. One model architecture extinguishes the feedback connections to test a feedforward model with fast and slow synaptic adaptation (model 1 and 2). The full recurrent model architecture employs adapting synapses either in the forward path  or in the backward path . Finally, both pathways use adapting synaptic connections with fast feedforward and slow feedback adaptation (model 5). The temporal dynamics of the synaptic efficacy, or weight scaling function, is defined byboth feedforward and feedback pathways responded within the psychophysical range of human performance. The different icons in Fig.\u00a0The different models generate predictions for the psychometric PSE using parameter settings (The authors incorporated adaptive synapses in the cortical model architecture of feedforward and feedback motion detection and integration. This specifies a powerful extension that enables the visual representations adapt to the temporal statistics of the input. For computational vision systems, such function defines a candidate mechanism habituating to unforeseen distortions of an imaging sensor. The multiple rates of adaptation in the feedforward and the feedback path, respectively, systematically change the properties of sensing natural environments. The exposure to skewed natural stimuli induces an adaptation in motion perception by changing the weight coefficients in the spatiotemporal kernels.In this paper, we have reviewed canonical principles of computation found in biological vision systems that can be utilized to potentially advance computer vision algorithms. These principles of computation were distilled from physiological, anatomical, and behavioral findings. The resulting survey of computational approaches is not exhaustive. Rather, its aim is to distill a conceptual narrative from studies in neuroscience and perception. We do not claim that the principles considered in this work form a complete taxonomy of structural and functional evidence. At the beginning of such a proposal stands the question what computer vision can learn from neuroscience and how the different domains can be compared. Based on our own previous work, we advocate a task perspective on the development and comparison of biologically inspired vision mechanisms.The primary focus is the integrated processing along feedforward, lateral and feedback streams. Growing evidence supports the view that the recurrent interaction of signal flows determines the flexibility and adaptability of processing at different sub-cortical and cortical stages. Different theoretical frameworks have been developed over the last four decades that predict different computational roles for the feedback recurrence in biological information processing Fig.\u00a0. Some ofWe emphasized the theme of recurrent feedforward and feedback interaction of information streams. This theme is combined with other computational principles, such as normalization, integration and segregation of responses, and competitive-cooperative mechanisms. We describe an emerging computational motif that is composed of a few core mechanisms to transform an input to an output activity. Crucially, bottom-up signals drive the activity, while top-down signals modulate the activations - in accordance with experimental evidence. The model structure is modular in the sense that it defines a template that can be parameterized. It has then been instantiated at different stages in the processing hierarchy and in the different pathways of form and motion processing. Based on the task perspective we identify and characterize biological computational principles. We define a potential candidate mechanism that is able to solve the considered task and its constraints. We specify only a few characteristic neural computational principles and demonstrate how these operate in a particular task domain. In particular, we specify the basic neural mechanisms for processing shape and form, specifically to demonstrate the binding of local feature characteristics. This leads to the formation of object boundaries and to the segregation of textured regions in cluttered scenes. The same set of mechanisms is subsequently used to investigate the local detection and integration of motion in images. These mechanisms support the disambiguation of local evidences to form coherent representations of object motion. The neural mechanisms robustly handle different types of motion, namely translatory and rotational motion. Together with complementary form information, they can generate early decisions to segregate motion information and assign it to distinct mutually occluding objects in the scene. Cases of illusory motion perception that are predicted by the model are investigated to reveal the detailed computations and properties underlying motion integration.The computational template can be easily extended to process different representations and to incorporate further functionality. We present examples of adapting the model to process sensor data in an address-event format utilizing neuromorphic computing principles, resulting in efficient, low-redundancy computation with brain-like principles. In addition, we extended the basic model architecture of motion processing to incorporate temporal adaptation mechanisms. These mechanisms adjust the sensitivity of the computational elements when the environmental conditions change. Together, these examples with the specified mechanisms and their example computational demonstrations are further contributions of this paper.We motivated the investigation of biologically inspired computer vision mechanisms and their properties. We set the focus on mechanisms of mid-level vision that operate in the ventral and the dorsal cortical pathway in primates. We emphasized several computational principles, such as recurrent processing, normalization, and gain control, which can be used to explain computational mechanisms of feature binding for grouping and selection based on cooperative-competitive response integration. Assembling them to utilize the complementary characteristics of form and motion, we can realize perceptual decision-making in discrimination tasks and employ coding principles and representation to achieve sparseness, coherence, and high temporal precision. Augmenting the kernel functions with temporal adaptation characteristics incorporates short-term response adaptation to changing environmental properties.A key behavioral task of vision systems, biological or technical, is object recognition. In DiCarlo et\u00a0al.  an attemThis paper discussed modeling examples that were investigated in previous work by our group. As mentioned above, we did not fully elaborate the description relating the selected modeling results to other state-of-the-art neural modeling investigations. The work cited regarding comparable or competing model investigations is selective and certainly incomplete. The research cited served as motivation for the developments shown here, some of which are using similar principles. None of the other models employ the full set of basic mechanisms which, according to our proposal, form a set of canonical principles. The combination of these mechanisms forms a template, which can be adapted to many computer vision tasks. The mechanisms, which define the basic computational motif, were originally utilized to explain or predict data observed in neuroscience or behavioral experiments. However, the models demonstrate their applicability also in processing data from real-world scenarios. The identified canonical principles of neural computation serve as candidate mechanisms for computational vision algorithms and can directly be adapted to recent neuromorphic architectures of brain-like computation.The focus of our paper was on the specification of neural processes of mid-level vision and their spatio-temporal dynamics. This focus was motivated through a task-level perspective of vision and the assumption of a structure-function relation to understand key neural computational principles. The principles of canonical circuit computation have identified recurrent feedforward and feedback interaction as a main principle of information processing that is employed in the brain. Their closed loop interaction allows biasing the forward sweep of sensory-driven input by contextual information and by decisions made at higher stages in the processing hierarchy. Such interactive processing combines sensory with contextual information and with local mechanisms of competitive processing. These support activity normalization over a specified region in space-feature representations. Together with the canonical feedforward and feedback processes, the mechanisms achieve local decision-making and the assignment of perceptual value to neural activations at a specific stage in the neural hierarchy.learning,incremental grouping, andattention and active perception.The network functions discussed in this work did not consider any learning mechanisms in order to build the necessary filters or feature detectors to form neural representations or adapting them to the input statistics. Major lines of previous investigations capitalize on how neural principles may establish internal neural representations. One such theme investigates how representations self-organize through local correlated activation of coupled neurons and their kernels of local connection weights (Grossberg Necessarily, our focus in the discussion leaves out other topics. The following items list major functions in neural architecture that were not considered here, namelyincremental grouping operations which act serially (Ullman The mechanisms of perceptual grouping considered here process the local feature maps in parallel and automatically. They aim at binding relatable visual items to build coherent representations of boundaries and relatable items as inputs for higher-level processing. Such processing is realized by base grouping operations, which operate by evaluating hard-wired associations in primary feature dimensions. However, evaluating more specific feature elements in the visual input is based on y Ullman . The seaattention. Attentive selection enables an observer to actively pick relevant information from the wealth of input streams while at the same time discarding or filtering other information (Tsotsos et\u00a0al. The serial processing of features and their binding incrementally builds neural representations for task-driven recognition and decision-making. It requires additional mechanisms to schedule and execute processes sequentially (Tsotsos and Kruijne All such processes and mechanisms discussed in the paragraphs above, define possible routes to further investigate the presented canonical circuit mechanisms of brain computations and their employment in approaches to computer vision. Tasks related to these functionalities define challenges for investigations to utilize the discussed network functions and how they might be integrated in new more elaborated principles of computation and learning. We suggest that these are candidates to provide an enriched repertoire of brain-inspired mechanisms, that define computational motifs to develop future systems level computer vision mechanisms."}
+{"text": "There is increasing evidence from human and animal studies that cortical spreading depression (CSD) is the neurophysiological correlate of migraine aura and a trigger of migraine pain mechanisms. The mechanisms of initiation of CSD in the brain of migraineurs remain unknown, and the mechanisms of initiation of experimentally induced CSD in normally metabolizing brain tissue remain incompletely understood and controversial. Here, we investigated the mechanisms of CSD initiation by focal application of KCl in mouse cerebral cortex slices.2+ (CaV) channels. If the drug blocked CSD, stimuli up to 12\u201315 times the threshold were applied.High KCl puffs of increasing duration up to the threshold duration eliciting a CSD were applied on layer 2/3 whilst the membrane potential of a pyramidal neuron located very close to the site of KCl application and the intrinsic optic signal were simultaneously recorded. This was done before and after the application of a specific blocker of either NMDA or AMPA glutamate receptors  or voltage-gated CaV channels with Ni2+ completely inhibited CSD initiation by both CSD threshold and largely suprathreshold KCl stimuli. Inhibiting AMPARs with NBQX was without effect on the CSD threshold and velocity. Analysis of the CSD subthreshold and threshold neuronal depolarizations in control conditions and in the presence of MK-801 or Ni2+ revealed that the mechanism underlying ignition of CSD by a threshold stimulus (and not by a just subthreshold stimulus) is the CaV-dependent activation of a threshold level of NMDARs (and/or of channels whose opening depends on the latter). The delay of several seconds with which this occurs underlies the delay of CSD initiation relative to the rapid neuronal depolarization produced by KCl.Blocking either NMDARs with MK-801 or CaV channels are necessary for CSD initiation, which is not determined by the extracellular K+ or neuronal depolarization levels per se, but requires the CaV-dependent activation of a threshold level of NMDARs. This occurs with a delay of several seconds relative to the rapid depolarization produced by the KCl stimulus. Our data give insights into potential mechanisms of CSD initiation in migraine.Both NMDARs and Ca Cortical spreading depression (CSD) is a slowly propagating self-sustaining wave of nearly complete depolarization of a sizable population of brain cells that lasts about one minute and silences brain electrical activity for several minutes (hence the name spreading depression) \u20133. Theree [e and/or extracellular glutamate above critical threshold values are key initiating events for CSD ignition. The idea that an uncontrolled rise of [K]e and of spilled glutamate can cooperate in the generation of CSD is also supported by modeling studies aimed to define the minimal biophysical machinery capable of initiating CSD [In vivo measurements of [K]e  and, onle  at the Cting CSD , 11. Accting CSD , 11.e) and that they are highly expressed in the apical dendrites of pyramidal cells, which appear preferentially involved in CSD initiation in-dependent and their opening occurs above a certain [Ca2+]in, or presynaptic, as e.g. could be the case if the opening of the cationic channels depends on sufficient CaV-dependent neurotransmitter release. The lack of effect of NBQX and the little effect of MK-801 on the second peak depolarization exclude that these cationic channels are glutamate receptors.The kinetics of development of the Canecessary for initiation of CSD. The finding that blocking either NMDARs or CaV channels prevents initiation of CSD by even very intense, largely suprathreshold stimuli (up to 12\u201315 times the threshold stimulation) shows that both CaV channels and NMDARs are necessary for initiation of CSD . Near the site of application of the suprathreshold stimuli, neurons are completely depolarized but, in the presence of MK-801 or Ni2+, the depolarization  does not propagate (and hence is not a CSD). This provides strong evidence that it is not the level of extracellular K+ and of the neuronal depolarization per se that determines the initiation of CSD. Consistent with and supporting this conclusion is also the finding that the early depolarization produced by threshold stimulation was quite different in different experiments and was similar to that produced by a just subthreshold stimulation.Our study provides novel insights into the ion channels that are Based on the finding that the early depolarization recorded in pyramidal cells located far (>\u2009200\u00a0\u03bcm) from the KCl puffer was not affected by the selective block of NMDARs in the recorded individual neurons (by either intracellular MK-801 or genetic ablation of GluN1), Mei et al.  concludee diminished and in some cases completely returned to baseline by the time CSD developed.How general are our conclusions regarding the CSD initiation mechanisms if we consider other methods of CSD induction in normally metabolizing brain tissue? They appear valid for optogenetic CSD induced by focal light stimulation to depolarize pyramidal cells expressing channelorodopsin2 in anesthetized  or awake+/K+ ATPase [2+ completely inhibited the glutamate rise preceding CSD initiation by veratridine in FHM2 mice, thus showing its dependence on CaV-initiated release, and prevented CSD initiation by threshold stimulation in most FHM2 mice [2+ did not prevent CSD initiation by suprathreshold stimulation, suggesting that, in contrast with KCl-induced CSD, CaV channels and CaV-dependent glutamate release are not necessary for initiation of CSD by high concentrations of veratridine, which likely activates other processes contributing to CSD ignition [Our conclusions appear also in large part valid for CSD initiation by veratridine in awake head-fixed mice . CSD ini+ ATPase ), despit+ ATPase , in agre+ ATPase , 32, 39.+ ATPase ) compareHM2 mice . Howeverignition .V channels and NMDARs do not appear necessary for initiation of this cerebral cortex-specific optogenetic CSD, since initiation of CSD induced by likely suprathreshold light stimuli was not prevented by the block of CaV channels or NMDARs . However, the inhibition of CaV channels or NMDARs delayed CSD initiation, suggesting that both CaV channels and NMDARs likely contribute to the initiation of CSD (and it remains to be seen whether their inhibition would prevent it at threshold stimulation).Our conclusions do not appear valid for CSD induced in cortical slices by focal light stimulation to depolarize GABAergic interneurons expressing channelorhodopsin2 . CaV chaV channels activation and CaV-dependent glutamate (and possibly other neurotransmitters) release as well as impaired handling of glutamate release, which result in threshold levels of extracellular glutamate and glutamatergic plumes and cooperative activation of (synaptic and extrasynaptic) NMDARs on the apical dendrites of pyramidal cells above a threshold level. Increased susceptibility to CSD in both FHM1 and FHM2 knockin mice is due to the fact that these threshold levels are reached with stimuli of lower intensity.Overall, the data on the mechanisms underlying the initiation of CSD by a threshold focal stimulus  in wild-type mice as well as the data on the mechanisms underlying the facilitation of CSD initiation in FHM1 and FHM2 knockin mice , 27, 32 V-dependent glutamate release and clearance of glutamate at cortical excitatory synapses, which might be created by enhanced CaV2.1-dependent glutamate release (as in FHM1) [Shedding light on the CSD initiation process in normally metabolizing brain tissue, our data give insights into potential mechanisms of CSD initiation in the brain of migraineurs. In particular, they suggest that initiation of a \u201cspontaneous\u201d CSD may be favored by conditions leading to excessive activation  of synaptic and extrasynaptic NMDARs in the apical dendrites of cortical pyramidal cells, due to excessive synaptic excitation and local elevation of glutamate above a critical threshold level. This may occur as a consequence of an imbalance between Cain FHM1) , 26, 41 in FHM1) , 27 or oin FHM1) . This miin FHM1) .Vs and NMDARs both of which do not seem necessary for initiation of spreading depolarizations [V-dependent NMDAR activation  as a mechanism for the increased frequency of peri-infarct spreading depolarizations in the FHM1 mice and with prolonged activation of NMDARs and calcium influx during the spreading depolarizations as cellular mechanisms of neuronal injury [Peri-infarct and post-trauma recurrent spreading depolarizations are frequently observed in infarct and brain trauma, and they affect the disease outcome \u201347. Accoizations . Nonetheizations \u201350. In fizations , 50. Intizations . This isl injury .V channels are necessary for CSD initiation, which is not determined by the level of extracellular K+ or neuronal depolarization per se, but requires the CaV-dependent activation of a threshold level of NMDARs. This occurs with a delay of several seconds relative to the rapid depolarization produced by the KCl stimulus. We hypothesize that this delay might reflect the time necessary to reach threshold levels of extracellular glutamate-glutamatergic plumes consequent to impairment of glutamate clearance. Our data give insights into potential mechanisms of initiation of \u201cspontaneous\u201d CSDs in the brain and hence into the unknown mechanisms which make the brain of migraineurs susceptible to CSD, the neurophysiological correlate of migraine aura and a trigger of the migraine pain mechanisms.Our investigation of the mechanisms underlying CSD initiation by focal application of high KCl in acute cerebral cortex slices shows that both NMDARs and Ca"}
+{"text": "Although differentiated service delivery (DSD) for HIV treatment was endorsed by the WHO in its landmark 2016 guidelines to lessen patients\u2019 need to frequently visit clinics and hence to reduce unnecessary burdens on health systems, uptake has been uneven globally. This paper is prompted by the HIV Policy Lab\u2019s annual report of 2022 which reveals substantial variations in programmatic uptake of differentiated HIV treatment services across the globe. We use Uganda as a case study of an \u2018early adopter\u2019 to explore the drivers of programmatic uptake of novel differentiated HIV treatment services.n\u2009=\u200918), district health team members (n\u2009=\u200924), HIV clinic managers (n\u2009=\u200936) and five focus groups with recipients of HIV care (60 participants) supplemented with documentary reviews. Our thematic analysis of the qualitative data was guided by the Consolidated Framework for Implementation Research (CFIR)\u2019s five domains .We conducted a qualitative case-study in Uganda. In-depth interviews were held with national-level HIV program managers  and implementation strategies  for promoting programmatic adoption.Our analysis suggests early adoption derives from Uganda\u2019s decades-old HIV intervention implementation experience, the imperative of having a high HIV burden which prompted innovations in HIV treatment delivery as well as outer context factors such as receiving substantial external assistance in policy uptake. Our case study of Uganda offers implementation research lessons on pragmatic strategies for promoting programmatic uptake of differentiated treatment HIV services in other countries with a high HIV burden. Sub-Saharan Africa (SSA) has the highest HIV burden in the world. Of the 37 million people living with HIV in the world, 20.6 Million  come from this region alone .Within SSA, Eastern and Southern Africa has the highest HIV prevalence . Four coThe majority of countries in SSA have generalized HIV epidemics with significant numbers of their people living with HIV (PLHIV) on ART. South Africa alone has nearly five million people on ART . As a coTo ease pressure on over-burdened health systems and to help meet the escalating demand for ART, the World Health Organization (WHO) and major donors such as the President\u2019s Emergency Plan for AIDS Relief (PEPFAR) and the Global Fund to Fight AIDS, Malaria and Tuberculosis  have endorsed \u2018differentiated service delivery\u2019 (DSD), which is a novel adaptation to traditional HIV service delivery. DSD contrasts with the traditional HIV care \u2018one-size-fits-all\u2019 approach, that is, undifferentiated to the needs of individual patients. Traditional HIV treatment services are clinic-based, physician-centered and entail fixed monthly visits to clinics regardless of clinical need. For instance, Uganda is currently implementing four DSD models which include; i) Fast Track Drug Refill (FTDR) that entails receiving 3\u20136 monthly medication refills freed from clinical review, ii) Community Client-Led ART Delivery (CCLAD) where voluntary groups of 6\u201312 patients rotate in picking up medication refills from facilities iii) Community Drug Distribution Points (CDDPs) where outreach sites within communities are designated for medication pick-ups and iv) Facility Based Group (FBG) where patients form adherence support clubs. Select providers in Uganda such as The AIDS Support Organization (TASO) piloted the FTDR model prior to WHO\u2019s formal endorsement in 2016 which enhanced uptake by RoC when these models were formally approved in 2017 in Uganda.Differentiated HIV treatment services entail a reduction in the intensity of contact by patients with the health system from monthly to quarterly or even six-monthly visits, particularly for those who are clinically stable \u20139. The WDSD holds multiple advantages for the health system such as reducing health worker workloads due to greater appointment spacing afforded to patients stable on ART. From the perspective of patients, DSD entails savings in time and transport through reduced frequency of visits to clinics \u20139. DurinSeveral countries in SSA have been implementing DSD since the WHO\u2019s landmark 2016 guidelines were published, and previous studies have focused on implementation barriers to DSD roll-out , 7 and pThis study is partly prompted by findings from the HIV Policy Lab\u2019s global report of March 2022  which reWe utilize an implementation research lens  to underWe adopted a qualitative case study research design \u201323. As YUganda was purposively selected because it adopted WHO\u2019s 2016 landmark international guidelines on differentiated HIV treatment services in its national HIV treatment guidelines the same year they were released . SecondlUganda\u2019s resource-constrained setting is similar to that in other countries in SSA and the implementation research \u2018lessons learned\u2019 approach is likely to have relevance beyond Uganda. Gilson and colleagues  have higintervention characteristics ; (2) outer setting ; (3) inner setting ; (4) characteristics of individuals  and; (5) process . The five CFIR-derived domains guided this study in multiple ways; it was used to categorize our study participants, it provided a structure for our interview topic guides, it guided our data analysis and in the overall interpretation and synthesis of study findings.This study was underpinned by the Consolidated Framework for Implementation Research (CFIR) framework . The CFIIn line with the adopted analytical framework , we purpBetween June and September 2020, we conducted sixteen in-depth interviews (IDIs) with national-level HIV program managers at the Ministry of Health headquarters and five district health officers (DHOs) in Eastern Uganda. We held four IDIs with representatives of PEPFAR implementing organizations. We interviewed twelve HIV clinicians to understand provider-level perspectives on facilitators and barriers to uptake of differentiated HIV treatment models. Table We aimed to understand the perspectives of RoC around trends in the uptake of either community-based or less-intensive facility-based models of care. We sought the collective experiences of RoC as a group rather than as individuals. To this end, we conducted focus group discussions seeking to understand the \u2018demand-side\u2019 dimension  of the uWe included RoCs who were eighteen years of age or older. We enrolled RoCs who had been in differentiated HIV treatment models for at least twelve months and had substantial experiences in these models. We conducted five FGDs ensuring that we conducted at least one focus group with patients in each of the five differentiated HIV treatment models currently in implementation in Uganda. We had twelve participants in each of our five focus groups (sixty participants). The focus groups were conducted by the first author who was assisted by two research assistants who took notes during the proceedings and operated the recorder. The focus groups were mostly conducted in English but also in Lusoga, the local language spoken at participating facilities in East-central Uganda depending on participants\u2019 fluency in either language. We purposively sampled ROC from East-Central Uganda because it was one of the first regions in Uganda to roll-out DSD models at routine points-of-care. ROC in this part of Uganda were deemed to have substantial experience of HIV care under the varied DSD models models. East-central Uganda is a largely rural and the majority depend on subsistence agriculture for their livelihoods. We selected ROC from Jinja Regional Referral Hospital. The HIV clinic is a stand-alone unit within the larger hospital complex. Jinja is 87\u00a0km East of the Ugandan capital of Kampala. The majority of ROC hail from neighboring rural districts and derive a livelihood from subsistence agriculture.An established strength of case studies is the reliance on multiple data collection approaches \u201323. To tProcess of implementation, characteristics of the intervention, Inner setting, Outer setting, Individuals). Hence, we used a hybrid model of inductive and deductive theme development National-level informants were emphatic in relaying the notion that Uganda was an \u2018early adopter\u2019 of DSD. To demonstrate this point, national-level HIV program managers reported that Uganda adopted WHO\u2019s 2016 global guidelines on DSD in the same year they were released. In 2016, a Technical Working Group (TWG) on DSD was constituted at the Ministry of Health headquarters with a broad membership that co-opted civil society groups representing patient interests. The brief of the TWG was to scrutinize WHO\u2019s global guidelines and develop national DSD guidelines that were context-specific to Uganda and defined which DSD models were feasible to implement given the operational context in the country. Uganda updated its overall national ART treatment guidelines in 2016 to incorporate differentiated HIV services.In 2017, with external support from PEPFAR, national DSD implementation guidelines were unveiled to guide roll out at 474 pilot high-volume HIV clinics in 2018, with countrywide roll-out through 2019. These implementation guidelines provided for two community-based models and three facility-based models. The implementation guidelines also provided a detailed \u2018roadmap\u2019 for adopting differentiated HIV treatment services and delivery mechanisms, including patient \u2018differentiation\u2019 clarifying which patients were eligible for which models and the formation of facility-level DSD committees.\u2018One of the facilitators of adoption of evidence on DSD was about engaging with recipients of HIV care and their leaders. We have tried to engage patients all the way from policy to program implementation. Patients were represented on the Technical Working Group which domesticated WHO\u2019s 2016 guidelines to our context. Stakeholder engagement has been key. Patients through their leaders give us feedback as the Ministry of Health. How can we do this better? What are the voices of the people (patients)? They actually tell us\u2019. [National-level HIV program manager]A salient feature of DSD adoption and implementation in Uganda was the protracted involvement of recipients of HIV care in the design and roll-out of Uganda\u2019s five DSD models which enhanced client uptake of these innovations in HIV treatment delivery. Patients were involved right from the inception with their representation on the national DSD Technical Working Group at the Ministry of Health in 2016, in the development of national implementation guidelines in June 2017, and their involvement in on-site evaluations of the quality of DSD services offered at pilot sites in Uganda.\u2018We have disseminated these (DSD) guidelines at different levels from the national, regional, up to the facility levels and I know that one or two people received those guidelines at each of the levels\u2019 [National-level HIV program manager]Beyond development of national DSD implementation guidelines, national-level HIV program managers indicated that dissemination of the approved guidelines was fundamental in moving from policy to routine practice. With funding from PEPFAR they were able to conduct multiple planning meetings for national roll-out of DSD between 2017 and 2018 at the national-level with HIV services managers of public and private providers. At the sub-national level, regionally-based PEPFAR implementing organizations were mandated to spearhead roll out at the level of districts given Uganda\u2019s decentralized health system set up whereby overall responsibility for social services provision has been devolved to sub-national units.Recipients of HIV care were involved in providing feedback on pilot DSD services. Patient leaders have been engaged in support supervision of DSD at the facility-level to ensure that quality is offered and implementation is aligned with policy and intervention design [National-level HIV program manager]Between 2017 and 2019, Uganda embarked on an ambitious programme of health worker (HW) training in DSD delivery. These trainings were mainly conducted at sub-national level where regional trainings were convened, and facility-level HIV clinicians were invited. At these meetings clinicians were sensitized on national DSD implementation guidelines of 2017 such as selecting a DSD focal person at each facility and offered practical trainings in aspects such as patient differentiation selecting patients who were stable on treatment and assigning them to less-intensive models such those who could access their refills in the community. In addition, on-site supervisions were conducted as part of the evaluations of differentiated HIV treatment services.\u2018We have one of the oldest HIV treatment programmes in Africa. We have been doing HIV programming since 2004. Uganda is one of the countries I think that is at the forefront of implementing DSD and I would like to say that several countries are flying into Uganda to see how Uganda is doing DSD. We were one of the first countries to implement this and we are learning by doing.\u2019 [National-level HIV program manager]Our analysis reveals that country context is relevant in understanding early policy adoption of evidence on DSD. Uganda has a generalized HIV epidemic and has one of the greatest HIV burdens in Eastern and Southern Africa . Uganda\u2019\u2018We were already doing differentiated HIV care in Uganda even before the term was coined as DSD but as a country, we did not have a systematic way of implementing these innovations in HIV care. What made policy adoption of DSD easier in Uganda is that we were already implementing these innovations such as appointment spacing long before they were baptized as such. The fact is that DSD is not new, and what is new is the nomenclature. Uganda is one of the countries that is a leader in implementing DSD and I would like to say that several countries are flying into Uganda to see how Uganda is doing DSD. We have tried to engage all the way from policy development to implementation\u2019 [National-level HIV program manager].Our interviews with national-level HIV program managers revealed that an important enabler of policy transfer between international and national levels of DSD for HIV treatment in Uganda was the country\u2019s long-standing experience of implementing innovations in HIV treatment services due to its high HIV burden, the associated challenges of overcrowding at routine points of care within an overburdened health system. Participants frequently mentioned that Uganda had a head start in implementing adaptations to traditional HIV service delivery models given its decades-old experience of attempts at mitigating health system constraints in the face of escalating demand for HIV treatment.\u2018In Uganda we were already doing longer appointment spacing for stable patients many years ago. In fact, some of the evidence underpinning DSD came from Uganda. Some providers like TASO piloted these models for many years before WHO endorsed them in 2016. For us as TASO, it has been a walk over because before the DSD models started we had already started implementing them. So it has just been a revision. Already our clients are well versed and they know what to do and also our health workers are fully trained\u2019 It emerged that some of the evidence underpinning WHO\u2019s global guidelines on differentiated HIV treatment services derived from Uganda\u2019s experience as a facilitator of programmatic uptake. Some private providers in Uganda such as The AIDS Support Organization (TASO) were already implementing innovations such as community drug distribution points (CDDP) and Fast Track Drug Refills (FTDR) before the models were formally endorsed by the WHO in 2016. Participants revealed that uptake of DSD was enhanced by Uganda\u2019s participation in pilot studies assessing patient outcomes on less-intensive HIV care models for the clinically stable.In March 2020, Uganda announced Covid-19 \u2018lockdown\u2019 measures that included a ban on public and private transport. This effectively impeded facility-based access to drug refills for the 1.4 million Ugandans enrolled on HIV treatment across the country. In response, the Ministry of Health swiftly announced emergency policy guidelines for enabling access to HIV medication refills during lockdown restrictions. The policy measures entailed an aggressive expansion of decentralized medication refill deliveries at outreach sites within the community . The gui\u2018CDDP was a model that was especially helpful during Covid-19 lockdown. What made life simple for us in TASO is that we had started DSD models much earlier and it made life easy for clients because the health workers meet clients at the community distribution points (CDDP) venue; where they were picking their drugs. At TASO, we have been doing multi month dispensing for stable clients. We have now drugs to give them for six months for stable clients and three months for unstable clientsOn their part, a range of providers such as TASO leveraged existing community-based models of service delivery such as the CDDP model, which was scaled-up to maintain continuity in access to refills.\u2018Covid-19 came in as an advantage. We would do home-to-home drug delivery so we took the drugs to their homes. For those we were unable access in their homes we could make an arrangement for them to be in a nearby place in their community. .There was accelerated implementation of home-based HIV medication refills delivery. Not-for-profit providers such as TASO mobilized vehicle fleets for distribution of refills on patients\u2019 homes deep within quite remote rural communities.\u2018We engaged our regional implementing partner (RHITES- E) and they were kind enough to offer some vehicles and we used them to reach people in their communities where they were stuck due to bans on public and private transport. We took medicine to about 2,000 people to some designated outreach points in the community by bolstering and strengthening our CDDP (community drug distribution points) model. We did this with the aid of a mobile brigade of health workers\u2019 .At sub-national level, district health teams sourced funding from regionally-based PEPFAR implementing organizations in Eastern Uganda for mobilizing vehicle fleets and fuel for distributing medication refills at designated points in the community.In several PEPFAR \u2018focus countries\u2019, including Uganda, PEPFAR seconded Technical Advisors to Ministry of Health headquarters to spearhead country wide roll-out of DSD. PEPFAR typically provides salary support to key officials at the Ministry of Health headquarters with governance mandates for HIV epidemic control and for whom PEPFAR targets such as domesticating DSD evidence in national policies is key programmatic target . Hence, \u2018PEPFAR has been consistent in prioritizing the uptake of differentiated HIV services in Uganda. PEPFAR has provided millions of dollars in annual HIV programming budgets for Uganda for more than five years. PEPFAR strongly believes in the potential of DSD in reducing burdens on overwhelmed health systems and in improving the quality of HIV care\u2019 .In-depth interviews with national-level HIV program managers in Uganda revealed the nature of donor support they received from PEPFAR for policy adoption of differentiated HIV care besides annual program budgets and targets described in the PEPFAR Country Operational Plans (COP) from 2018\u20132021.Participants reported that PEPFAR provided program funding for convening Technical Working Groups at the Uganda Ministry of Health headquarters with the aim of scrutinizing WHO\u2019s 2016 landmark global HIV treatment guidelines with a view to domesticating them in Uganda\u2019s national ART treatment guidelines. National-level HIV program managers reported that they assessed the WHO\u2019S 2016 guidelines on DSD roll-out and teased out components that were contextually relevant and feasible to implement in Uganda. At sub-national level, PEPFAR provided multi-year funding and programmatic targets to its regionally-based implementing organizations to spear head DSD roll out at district level \u201351.Documentary evidence further revealed that besides PEPFAR support, Uganda benefited from substantial philanthropic aid from the Bill & Melinda Gates Foundation for policy adoption of DSD through Columbia University\u2019 CQUIN  entailing a multi-country \u2018community of practice\u2019 of more than eleven countries in Eastern and Southern Africa . ThroughGates Foundation support also included tracking progress on programmatic adoption of DSD through specified metrics for assessing progress on programmatic uptake of DSD evidence via a \u2018dashboard\u2019 for measuring progress on DSD implementation. The dashboard assesses the maturity of national DSD programs and overall uptake based on thirteen domains that included presence of a scale-up plan, policies in place, community engagement and training of health workers .\u2018First of all, I fear rumor-mongering amongst members in these patient groups. I imagine going back in my neighborhood and finding my group member gossiping about me in the village and telling everyone about how I am HIV positive. It was not easy for me to join a (CCLAD) group because I don\u2019t want people to gossip about me in the village\u2019 .Overall, patients indicated a preference for facility-based DSD models due to a desire for privacy and avoidance of inadvertent HIV sero-status disclosure. In the focus groups, patients appreciated the convenience that accrues from some models such as Fast Track Drug Refill (FTDR) which entails visits to facilities that are freed from clinical reviews for stable patients. In addition, patients extoled the benefits that accrue from regular visits to facilities such as comprehensive medical care in the event of opportunistic infections which they perceived as difficult to track when one is enrolled in less-intensive HIV care models. Patients indicated that HIV-related stigma was a fundamental barrier to enrollment in community-based models.\u2018We have some community-based models that are expensive such as community drug distribution points (CDDPs) because we have transport costs borne by the facility. I think that the most practical DSD models remain the facility \u2013based ones. It is not sustainable going to these communities. You are able to deliver these medicines in communities now just because there is external donor funding but time is going to come when there is no funding\u2019 .At the provider-level, HIV clinicians offered explanatory insights into understanding the variable uptake of DSD models in Uganda, particularly the lag in adoption of community-based models despite a heightened interest during Covid-19 lockdown restrictions. It emerged that select community-based ART delivery models such CDDPs were perceived as relatively expensive to operate in terms of the required operational expenses such as with regard to the needed vehicle fleets and fuel for transporting medication refills to outreach sites deep inside rural communities , 28. Thi\u2018I wish to highlight the issue of HIV-related stigma, I think that as we plan on implementing community -based models of care, it is incumbent upon us to regard stigma as a key challenge which still exists in our communities. The few on-site support supervisions that I have conducted around the uptake of DSD is we found that clients actually prefer facility-based HIV care. The do not like community models because of stigma\u2019 .National-level HIV program managers in Uganda also revealed that HIV-related stigma is a fundamental impediment in the roll-out of community-based HIV treatment models which could provide further contextual insight into understanding the relatively low uptake of community models.\u2018WHO goes through a series of processes and one of them is looking at evidence. Evidence was collected from different countries such as South Africa, Malawi and Zambia. By the time it is put into a global treatment guideline it implied that WHO was confident that DSD was evidence-based. You know it is backed by science. So already there has been demonstration that these models actually work and which is why we selected certain models that work well in our setting\u2019 [ National-level HIV program manager].There was broad consensus across participants that differentiated HIV treatment models were evidence-based which they regarded as a facilitator of acceptance among providers. Uganda\u2019s participation in the clinical trials and the broader evidence that underpinned WHO\u2019s 2016 global treatment guidelines was frequently cited as an enabler of programmatic uptake. WHO\u2019s formal endorsement of DSD was perceived by national-level HIV program managers as affirmation that the endorsement was informed by rigorous processes.Representatives of providers, such as from TASO, indicated that they had piloted some community-based models including the community drug distribution model prior its policy adoption in global and national treatment guidelines. Other not-for-profit providers indicated that they had experimented with models, particularly that of appointment spacing even before it was formally adapted by the WHO in 2016 and that from their operational experience, patient outcomes were not inferior to standard care.\u2018Basically, I was overburdened by the heavy expenditure on transport to come to the(HIV) clinic every month and the long distance from my home. I often came late to the clinic and it was always overcrowded. When they said we could form patient groups (CCLAD), I got six of my colleagues and we formed a group. We now share transport costs and alternate in picking our medication refills so that we don\u2019t get tired of coming to clinic\u2019 .Right from the outset, the design of DSD models was meant to be tailored to the preferences of individual patients and this was identified as an enabler of model uptake in Uganda. Recipients of HIV care in rural settings expressed satisfaction and preference for less-intensive HIV treatment models that resulted in savings in transport and time off work. The demand for community-based models was particularly strong for PLHIV who are based in rural settings who would otherwise have to make monthly trips to urban centres to collect medication refills.\u2018Patients are aware of community models but the majority have internalized stigma. They fear they think their colleagues will gossip about them in their neighborhoods so some people decide not to join the groups. Personally I prefer to come to the facility and pick my drugs. I spend less than ten minutes yet I used to spend the whole day. Now I have ample time to go and man my business\u2019 .On the other hand, patients in urban settings revealed preference for facility-based models particularly the Fast Track Drug Refill (FTDR) model which offered them better privacy and convenience.Utilizing the CFIR framework\u2019s five domains, we explore factors contributing to early adoption of evidence on differentiated HIV treatment services in Uganda. These include a decades-old HIV intervention implementation experience, having a high HIV burden which prompted innovations in HIV treatment delivery, receiving substantial external aid and technical support for policy uptake, protracted engagement of patients in policy planning and program implementation, accelerated uptake of community-based models owing to Covid-19 \u2018lockdown\u2019 restrictions and the perceived effectiveness of DSD models due to participation in the clinical trials that underpin WHO guidance on DSD.Although a few of the emergent factors are context-specific to Uganda, such as its long HIV programming experience, our findings provide valuable implementation research lessons on the processes involved in policy adoption of DSD especially in countries with a high HIV burden. These lessons include the key role of Technical Working Groups in domesticating global guidelines and fleshing out national DSD implementation guidelines, and implementation strategies including high-level health ministry buy-in, protracted patient engagement to enhance model uptake, and devising metrics for measuring DSD uptake progress in programmatic adoption. Our findings provide empirical insight into understanding variations in programmatic uptake of WHO guidelines on differentiated HIV treatment services which have been identified by multiple studies , 6, 9 anhow and why substantial variations in DSD uptake across the globe persist despite the wide dissemination of WHO\u2019s landmark 2016 guidelines on how to domesticate this evidence in the national policies of member countries [Previous studies have identified implementation barriers in the national scale-up of differentiated HIV services in countries that include South Africa , Uganda Our case study sheds light on the impact of the Covid-19 pandemic on the accelerated uptake of differentiated HIV care models, and their adaptation in light of \u2018lockdown\u2019 measures. Grimsrud and colleagues have highlighted the imperative of the Covid-19 in the accelerated adoption of especially community-based ART delivery models , 14. StuIn this case study we highlight the role of international assistance in the early adoption of DSD in Uganda. Although a previous analysis by Carbaugh and colleagues  found thSeveral studies have already reported patient preferences for facility-based HIV care over community based platforms \u201359. A raThe CFIR framework was helpful in unraveling, especially, the outer setting and inner context drivers of Uganda\u2019s early adoption of differentiated HIV treatment services which afforded us a well-rounded perspective on programmatic uptake of DSD from a multi-level analysis lens; at the different levels of the Ugandan health system such as at the meso or national level, at the sub-national level, at the meso or provider level and at the individual level of patients. In our assessment, some identified drivers, such as Covid-19 lockdown imperatives for accelerated uptake of community models in Uganda, was an attribute that cut across two CFIR \u2018domains\u2019 of both inner and outer contexts and that there appeared to be some dynamic interactions in the five CFIR domains such as in the latter case . RelatedThis study had limitations which we wish to acknowledge. We conducted a cross-sectional study where we collected data at one-time point. Perhaps, a longitudinal case study could have been more insightful. Additionally, we did not interview PEPFAR officials at the global level who set donor funding policy for PEPFAR-supported countries across the world which would have yielded a global lens on PEPFAR\u2019s push for policy adoption of DSD in high burden countries. This study has some strengths. These include multi-stakeholder perspectives at different levels of the Ugandan health system such as national-level HIV program managers, sub-national level health system actors, representatives of external donors and community engagement component entailing patient voices. We contribute a country case study that helps in understanding the uneven uptake of these novel HIV service delivery approaches across the globe by identifying the drivers of programmatic uptake from the CFIR lens of \u2018inner context\u2019 and \u2018outer context\u2019.Using the CFIR, we have identified facilitators of early adoption of DSD arising from inner context and outer setting factors in Uganda. Our case study of Uganda contributes implementation research lessons on pragmatic strategies for promoting programmatic uptake of differentiated treatment HIV services in other countries with a high HIV burden particularly those in resource-limited settings."}
+{"text": "Meta-analyses can be a powerful tool but need to calibrate potential unrepresentativeness of the included trials to a target population. Estimating target population average treatment effects (TATE) in meta-analyses is important to understand how treatments perform in well-defined target populations. This study estimated TATE of paliperidone palmitate in patients with schizophrenia using meta-analysis with individual patient trial data and target population data.We conducted a meta-analysis with data from four randomized clinical trials and target population data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study. Efficacy was measured using the Positive and Negative Syndrome Scale (PANSS). Weights to equate the trial participants and target population were calculated by comparing baseline characteristics between the trials and CATIE. A calibrated weighted meta-analysis with random effects was performed to estimate the TATE of paliperidone compared to placebo.A total of 1,738 patients were included in the meta-analysis along with 1,458 patients in CATIE. After weighting, the covariate distributions of the trial participants and target population were similar. Compared to placebo, paliperidone palmitate was associated with a significant reduction of the PANSS total score under both unweighted  and calibrated weighted  meta-analysis.The effect of paliperidone palmitate compared with placebo is slightly smaller in the target population than that estimated directly from the unweighted meta-analysis. Representativeness of samples of trials included in a meta-analysis to a target population should be assessed and incorporated properly to obtain the most reliable evidence of treatment effects in target populations.The online version contains supplementary material available at 10.1186/s12874-023-01958-w. Randomized controlled trials (RCTs) and meta-analyses based on these RCTs are the cornerstone of evidence-based clinical practice. While attention to internal validity of this evidence is critical, there is growing concern regarding a lack of external validity due to significant differences between the composition of participants of RCTs and the target populations \u20137. Concetarget population average treatment effect (TATE) [Disseminating and implementing findings of RCTs to a target population for routine care is important for clinical practice guidelines, cost-effectiveness research, and health-policy decision making. This population-based inference requires understanding generalizability of RCTs and correct estimation of an average treatment effect in the target population, denoted by t (TATE) , 13. HowMeta-analysis is often viewed as a way to approach the \u201ctrue\u201d effect of a treatment of interest because it combines information from multiple studies . HoweverWith the growing trend in availability and use of individual-participant data (IPD) and availability of administrative data on target patient populations in usual care settings, it is now possible to take the composition of RCT samples into account and to adjust for their deviation from the target population. The estimates of TATEs in meta-analyses using IPD can be made more generalizable by strategically utilizing external target population data and assessing and adjusting the level of representativeness of RCTs , 23. In In this paper, we conducted such a calibrated meta-analysis using IPD from four paliperidone RCTs and with a external data source on a well-characterized target population sample. These RCTs studied the efficacy of paliperidone palmitate , a long-For the meta-analysis, eligible studies were phase III double-blind RCTs that studied the efficacy of paliperidone palmitate compared to placebo for treatment of schizophrenia and in which IPD were available. We searched trials in the Yale University Open Data Access (YODA) Project  and identarget population as adults suffering from schizophrenia in usual care settings in the United States. To obtain data on the target population  we used patients in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study [We defined the E) study . CATIE wSchizophrenia symptoms were measured based on the Positive and Negative Syndrome Scale (PANSS) total score, the sum of 30 items of which each ranges from 1 (absent) to 7 (extreme psychopathology) to assess various symptoms of schizophrenia . The PANWe considered a total of 6 baseline covariates that were reported in the 4 RCTs and CATIE and could be potential effect modifiers: sex, race , age in years  between each RCT and the target population. Unmeasured effect moderators may lead to unreliable TATE estimates.To obtain accurate TATE estimates, two key assumptions are required . First, We also carried out a random-effects meta-analysis using unweighted outcomes and compared the results. In addition, we conducted a subgroup analysis including only RCT patients from North America as a sensitive analysis. All analyses were executed using R version 3.6.3 .A total of 1,738 patients were included in the meta-analysis  along with 1,458 patients in CATIE. Table Figure\u00a0Figure\u00a0Table SGeneralizing results from meta-analysis of RCTs to a target population is not guaranteed without thorough assessment of the representativeness of RCTs included in the meta-analysis followed by proper calibration of the RCT samples. We introduced a calibrated meta-analysis approach to estimate target population average treatment effects and applied it to a meta-analysis of RCTs comparing paliperidone palmitate and placebo for treating patients with schizophrenia. By weighting patients in the RCTs, we made the weighted RCT samples more similar to the target population, represented by the CATIE sample. Our results showed that paliperidone palmitate was significantly more effective in reducing the PANSS total score than placebo under both unweighted and calibrated meta-analyses. However, the estimated TATE of paliperidone palmitate in calibrated analysis was smaller than the effect estimated from the unweighted meta-analysis, though the 95% confidence intervals overlapped, yielding unchanged conclusions regarding the treatment efficacy.Our results reproduced the results from recently published two meta-analyses , 21. KisOur findings support that RCT samples and a target population may differ substantially on covariates , which may result in the effect estimates from an unweighted meta-analysis to deviate from what would be seen in the population. That is, treatment effects in RCTs samples and the target population may differ when the distributions of effect moderators differ between the samples. If there is no effect heterogeneity (no effect moderation) then RCTs and meta-analyses of RCTs will yield accurate inferences about population effects, though this rarely happens in practice \u201344. The Current practice guidelines for treatment of mental disorders, such as the recent practice guidelines for treatment of schizophrenia published by the American Psychiatric Association  are baseThe standardized mean difference between each RCT and the target population was used to assess representativeness of the RCTs after weighting. The imbalance between RCTs and CATIE samples was improved dramatically for most baseline features except PANSS and patient weight\u2014likely because the RCT participants tended to have more severe symptoms than those in CATIE. The imbalance in weight may be related to national differences in average weight\u2014the CATIE sample was drawn only from the United States; whereas the paliperidone RCTs also included participants from countries in Europe and Asia. Although the distributions of PANSS and weight between RCTs and CATIE were not perfectly similar in unweighted comparisons, there was considerable overlap in the distributions between the RCTs and CATIE, which meant that weighting could successfully improve the covariate balance. If there is no or little overlap of the distributions of effect moderators between the RCTs and target population , statistical approaches may not estimate population treatment effects well because of the inherent extrapolation that will be required. The positivity violation cannot be formally tested, but it can be assessed by comparing distributions of baseline characteristics between RCTs and CATIE.The weighting method used in the calibrated meta-analysis resulted in more similar samples between CATIE and RCTs, though it did not achieve fully equivalent samples. This may be due to some of the exclusion criteria applied to RCTs , and statistical analyses cannot solve fundamentally large differences between groups\u2014if the trials really do not represent the target population then statistical methods cannot fully help. That said, the weighting approach helps make the combination of trials as similar to the population as possible, and so even though the distributions are not fully similar to CATIE the calibrated meta-analysis results do better reflect what we expect the TATE would be in the CATIE population.This analysis has several limitations. First, we chose CATIE to represent the target population because it was among the best sources for providing data on the target population of patients receiving treatment for schizophrenia in a wide range of usual care settings in the United States. Furthermore, CATIE collected a broad range of demographic and clinical data from a large sample of diverse participants. However, target populations for future studies may be drawn from administrative data sources such as electronic health records or claims data and the results may differ by the choice of target population. This is a challenge of the calibrated meta-analysis as it depends on availability of truly representative target population samples along with individual patient RCT data\u2014and consistent measurement of baseline characteristics between the two. Note that we had to use the coarsest category for age, age at onset, and weight variables in our analysis because several RCTs included in our meta-analysis did not have consistent continuous measures for those variables. Even when such data do exist, gaining access to the data remains a challenge. We hope that the current emerging movement of data sharing and data harmonization can resolve this challenge , 50.Second, the participation scores and weights help balance the paliperidone RCTs and CATIE with respect to the observed covariates, but are not able to adjust for potential unobserved moderators. This is related to our results about the outstanding differences in treatment effect estimates between the unweighted and weighted analyses in NCT00590577. Knowing that the difference between NCT00590577 and CATIE is comparable with the differences between other RCTs and CATIE, this finding might be due to unobserved covariates that should have been adjusted for. When estimating TATEs is of primary interest, it is important to understand potential effect moderators in advance and collect the relevant information systematically and consistently across RCTs and target population data sources. In addition, further methodological research is required to handle unobserved effect moderators in calibrated meta-analysis.In this study, we sought relatively large RCTs of a single medication treatment of schizophrenia conducted about the same time and using the same outcome measure (PANSS) as the CATIE trial (which represents the target population of interest). The identified paliperidone RCTs were conducted within a 5-year window (2003\u20132008), a time window that overlapped with CATIE\u2019s timeframe (2000\u20132004). Focusing on a single medication and restricted time period reduces variations in outcomes and changes in population composition due to these factors. In addition, the methods examined could easily be used in other application areas \u2013 we are using the schizophrenia context here as a motivating example. Our methods can be used to examine generalizability for other disease conditions and treatments as well.This paper focuses on how the TATE results are interpreted and implemented in clinical practice using a simple but widely-accepted method. However, multiple weighting methods are available, including flexible models such as generalized boosted model  and, BayRepresentativeness of samples of trials included in a meta-analysis to a target population should be assessed and incorporated properly to obtain the most reliable evidence of treatment effects in target populations. Calibrated meta-analysis, which integrates RCTs and population data, can be a powerful technique to estimate target population average treatment effects and draw population-level inferences. We recommend that when external data from target populations are available, these data be used to calibrate RCT samples and that future IPD meta-analyses be based on these calibrated RCT data.Additional file 1:\u00a0Table S1. Key eligibility criteria and references for included studies.\u00a0Table S2.\u00a0Absolute Standardized mean differences of baseline covariates between each RCT and CATIE before weighting and after weighting in parentheses.\u00a0Table S3.\u00a0Mean difference of change in PANSS total score between paliperidone palmitate and placebo and 95% confidence intervals from all meta-analyses including secondary and sensitivity ones."}
+{"text": "Tubulinopathies are a wide family of neurological disorders caused by mutations in genes encoding tubulins, the structural units of microtubules. They represent a growing class of pathologies for which no therapies are currently available.More than 255 tubulin mutations have been reported so far  and with malformations of cortical development (MCDs)  as well as post translational modifications (PTMs) of tubulins in normal and pathological conditions .Hoff et al. highlight how deepening our knowledge on the interaction between tubulins, microtubules and MAPs can better predict the effects of tubulin mutations. The authors offer a description of tubulin structural dynamics and MAPs, and explain how microtubules and MAPs regulate critical steps of neurodevelopment. They further discuss how tubulin mutations can cause tubulinopathies by altering interactions between microtubules and their regulators or by impairing microtubule dynamics. M\u00fcller, Ringer et al. demonstrate that the balance of tyrosinated and detyrosinated microtubules finely regulates cell shape and adhesion in both D2 epithelial cell cultures and D3 intestinal organoids. The authors also propose that TTL has a central role in regulating the assembly of focal adhesion since its depletion prolonged the persistence of vinculin at these sites and its binding efficiency to different focal adhesion adapters.By modulating the expression of tubulin tyrosine ligase (TTL), the enzyme that catalyzes the post-translational addition of tyrosine to the detyrosinated end of \u03b1-tubulin, M\u00fcller, Gorek et al.). Dysregulation of tubulin PTMs occur in a wide range of brain disorders  of patients affected by Spastin (SPAST)-associated hereditary spastic paraplegia (HSP), exhibit reduced levels of acetylated \u03b1-tubulin, thus reflecting the pathological reduction of acetylated \u03b1-tubulin previously observed in patient-derived neuronal cells (Wali et al., in vitro treatment and in mouse brain following in vivo administration. The authors thus propose that PBMCs of SPAST-related HSP patients may represent a suitable in vitro model to study the pathology and the measurement of acetylated tubulin a tool to quantify the treatment effects of noscapine. A schematic representation of microtubule complexity and microtubule related diseases is shown in We hope that this Research Topic will help to better understand the complex network of microtubule functions and regulations, to understand how the latter act at the cellular and sub-cellular levels, and how they are differentially affected by tubulin mutations.In addition, we hope that the Research Topic will foster further functional and genetic studies on microtubule function and dysfunction in neurons to expand the mutational and phenotypic spectrum of tubulinopathies. These efforts will be key to design innovative microtubule-based interventions for the treatment of tubulinopathies.AS: Writing\u2014original draft. EB: Writing\u2014review and editing. GH: Writing\u2014review and editing."}
+{"text": "Soon after, the approved labeling was adjusted to direct treatment to mild cognitive impairment (MCI) due to Alzheimer\u2019s disease (AD) and mild AD dementia reflecting the severity of cognitive impairment among participants in the clinical trials that led to the approval  if they participate in an approved insurance plan. Most people pay a monthly fee for this benefit. When a new agent becomes available it may be subject to a National Coverage Determination (NCD) to ascertain if CMS will pay for the drug and under what circumstances. CMS covers drugs that are considered \u201creasonable and necessary\u201d for the treatment of an illness. The covered treatment must be shown to meaningfully improve health outcomes. The NCD process can lead to approval of coverage, denial for coverage, or limited coverage .https://www.cms.gov/medicare-coverage-database/search.aspx).On January 11, 2022, Medicare Issued its draft NCD on Coverage with Evidence Development (CED) for aducanumab which limits coverage to patients participating in CMS-approved randomized controlled clinical trials supported by the US National Institutes of Health (NIH) . This deAducanumab is an anti-amyloid IgG1 monoclonal antibody (mAb) directed to the N-terminus of the amyloid beta peptide (A\u00df) occurring in aggregates . NonclinThe first clinical trial of aducanumab was the PRIME study, a Phase 1B dose-finding trial . ParticiOn the basis of the PRIME observations, two identical Phase 3 trials --- ENGAGE and EMERGE --- with 1643 planned participants each were launched . ParticiThe 22% slowing on the primary outcome has been challenged as inappropriately small to warrant the treatment. Slowing by this amount translates to approximately one additional year in the typical 5-year period in the MCI stage of AD prior to entering the terminal dementia phase of the illness; patients should be empowered to decide if this degree of slowing is desirable for them.ARIA of the effusion type (ARIA-E) and of the hemorrhagic type (ARIA-H) were observed in trials of aducanumab , 7. In pThe irregular aspects of the trials of aducanumab with premature termination suggest caution in interpreting the results. The consistent pharmacodynamic relationships among dose, duration, amyloid lowering, and slowing of clinical decline (as seen on the CDR-SB) support the efficacy of aducanumab. The effect on \u201cdownstream\u201d biomarkers  associated with cognitive decline in many studies is additional evidence of the impact of aducanumab on the biology of AD and disease modification . An effiAducanumab was approved by the FDA using the regulatory mechanism of accelerated approval. This approval pathway was used for 14 of 50 (28%) approvals by the FDA in 2021 and is commonly used for cancer therapies . AccelerReduction of amyloid plaques as shown on amyloid PET is the biomarker on which accelerated approval was based. Plaque reduction is not a fully validated surrogate and there is a lack of consensus on the predictive value of plaque removal. There have been many failures of anti-amyloid therapies suggesting that approval based on anti-amyloid effects does not have an adequate scientific rationale . Nearly Accelerated approval is intended to make drugs available to patients with life-threatening diseases such as AD while additional evidence to confirm efficacy and safety is generated. The decision of CMS to limit aducanumab to clinical trials is at variance with the purpose of this approach and inconsistent with the intent of the FDA to provide a mechanism for accelerated access to aducanumab for appropriate patients.In their draft determination, CMS proposed to cover FDA approved mAbs directed against plaque amyloid for the treatment of AD under a Coverage with Evidence Development (CED) approach limiting coverage of mAbs to patients participating in CMS-approved randomized controlled trials supported by the NIH . All triThis approach is not patient-centered and will greatly delay access to treatment for individuals with early AD. This proposed determination is predicted to reduce interest in treatment development when the increasing population of those with and at risk for AD requires innovative solutions for their cognitive and functional impairment.Requiring that aducanumab be studied in clinical trials conducted in a hospital setting greatly limits the number of patients with early AD who could receive treatment with coverage. Proposed trials are likely to be placebo-controlled . In placebo-controlled trials, patients seeking treatment must agree to be randomized to drug or placebo to have a chance of receiving therapy. Severely limiting access to an approved therapy in this way is coercive.Requiring that the trial be funded by NIH attaches additional limits to the availability of treatment. NIH funding is directed mostly to trial sites associated with academic medical centers restricting access to therapy to those living in nearby areas. Academic trials sites are rarely in minority neighborhoods and are not situated to allow recruitment of rural populations . NIH funding for trials is less than that invested by pharmaceutical companies and recruiting an adequate number of participants to adequately power a trial to demonstrate benefit may be difficult if not impossible. Funding by NIH is subject to extensive peer review on scheduled review cycles. Trials as proposed by CMS would require 1\u20132 years to secure funding plus 3\u20135 years to conduct and analyze, delaying the availability of an approved treatment that could be available NOW. NIH funding has been instrumental in supporting Phase 2 proof-of-concept and dose-finding studies; it has rarely been used for trials of the type proposed by CMS that more closely resemble Phase 3 trials .CMS requires that approved trials must determine if treatment with an anti-amyloid mAb results in a statistically significant and meaningful reduction in decline in cognition and function. CMS chose the CDR-SB to exemplify what constitutes a clinically meaningful improvement as a primary outcome. To define minimal clinically important differences they suggest a 1\u20132 point increase in CDR-SB, plus a 1\u20133 point decrease in MMSE and 3\u20135 point increase in Functional Activities Questionnaire (FAQ) . The popThe CMS proposal does not state how many trials with meaningful results are required to support coverage although the proposed decision memo refers to \u201ctrials.\u201d The expected relationship of results from different trials or the required consistency of outcomes is not discussed.Noting the lack of diversity in previous trials, the higher prevalence of AD in Black and non-White Americans, and the directives in Executive Order 13985, Advancing Racial Equity and Support for Underserved Communities through the Federal Government, CMS proposes requiring that the patients included in each trial be representative of the national population diagnosed with AD. This is a noble aspiration. It is also an unrealistic expectation given the known challenges in recruiting underrepresented and underserved populations to trials. We must improve inclusion of diverse populations in trials; this is a long-term goal requiring trial infrastructure not currently available and trust that has not been built. Requiring a representative sample in the CMS trial will delay the trial and limit the availability of drug treatment to both minority and majority culture patients. The mandate ignores other underserved populations such as those dwelling in rural areas who have essentially no opportunity to reach trial sites and treatment in a trial.Aducanumab is approved and can be purchased through self-pay mechanisms independent of coverage by CMS. Limitation of treatment coverage to those in trials means that persons in limited financial circumstances will have limited access to therapy while those with financial means will have access to treatment. CMS requirements will increase the lack of equity in AD care in the US.Unlike participating in an industry-sponsored trial where experimental therapy is provided without cost, CMS typically does not cover the full costs of drugs and a substantial co-payment may be leveraged for aducanumab trial participants. Up to 50 percent of patients in a trial (depending on the use of a placebo and the randomization ratio) may be paying for placebo. These circumstances will further disincentivize trial participation.Together these observations argue against the requirement for a CED comprised of clinical trials to provide coverage for mAbs.CMS expresses concerns about harms to patients that would be treated outside the context of the safety monitoring of a controlled trial. Clinicians agree that the occurrence of ARIA can have serious consequences and must be monitored. In the EMERGE and ENGAGE trials, most ARIA events 72.3%) occurred within the period of the first eight doses (7 months) and vigilance early in the course of therapy is key to safe introduction of aducanumab. Seventy-four percent of those with MRI-proven ARIA had no symptoms. Of the 26 percent who exhibited symptoms, most had headache with fewer having confusion, dizziness, or nausea  findings suggesting the patient may not be a good candidate for aducanumab, provide guidance for optimal timing of MRI to detect ARIA, and discuss ARIA management strategies when the MRI changes of ARIA are detected . As realMonoclonal antibodies directed at amyloid plaques are the first agents to show an effect on the underlying biology of AD and to qualify as disease-modifying therapies. These agents have succeeded where many non-plaque-directed anti-amyloid therapies have failed . They prNot all anti-amyloid mAbs are plaque-lowering. Solanezumab is directed at the monomeric form of A\u00df. It does not lower plaque burden. A Phase 3 trial in mild AD dementia did not meet its primary outcome; it is uncertain if limited efficacy was shown . This mADrug development for AD is a costly and lengthy enterprise requiring extensive financial and time investment . Pharmachttps://www.cms.gov/medicare-coverage-database/search.aspx).CMS concludes the proposed decision memo by stating that the proposal strikes an appropriate balance of providing patient access while also ensuring both protections for patients from harms and the appropriate data collection and analysis to determine whether CMS should undertake an NCD reconsideration . The rec"}
+{"text": "One such example is mediated by Nitric Oxide (NO) in principal neurons of the Medial Nucleus of the Trapezoid Body (MNTB) in the auditory brainstem. These act as relay neurons, receiving excitatory input and transmitting inhibitory signals to the auditory nuclei involved in sound localisation. NO is released here in an activity-dependent manner and switches the basis of action potential (AP) repolarisation from Kt trains . We havev2 conductance leads to improved post-synaptic transmission at high frequencies, while also decreasing the metabolic efficiency of an action potential. The location of Kv2 channels adjacent to Nav channels at the axon initial segment (AIS), as opposed to Kv3, which is located at the soma, is found to be crucial in determining how it affects metabolic efficiency. Figure v conductances [It is observed that increasing Kuctances ."}
+{"text": "Dog-bites and rabies are under-reported in developing countries such as Pakistan and there is a poor understanding of the disease burden. We prospectively collected data utilizing mobile phones for dog-bite and rabies surveillance across nine emergency rooms (ER) in Pakistan, recording patient health-seeking behaviors, access to care and analyzed spatial distribution of cases from Karachi.A total of 6212 dog-bite cases were identified over two years starting in February 2009 with largest number reported from Karachi (59.7%), followed by Peshawar (13.1%) and Hyderabad (11.4%). Severity of dog-bites was assessed using the WHO classification. Forty percent of patients had Category I (least severe) bites, 28.1% had Category II bites and 31.9% had Category III (most severe bites). Patients visiting a large public hospital ER in Karachi were least likely to seek immediate healthcare at non-medical facilities , and had shorter mean travel time to emergency rooms, adjusted for age and gender  than patients visiting hospitals in smaller cities. Spatial analysis of dog-bites in Karachi suggested clustering of cases , and increased risk of exposure in particular around Korangi and Malir that are adjacent to the city's largest abattoir in Landhi. The direct cost of operating the mHealth surveillance system was USD 7.15 per dog-bite case reported, or approximately USD 44,408 over two years.Our findings suggest significant differences in access to care and health-seeking behaviors in Pakistan following dog-bites. The distribution of cases in Karachi was suggestive of clustering of cases that could guide targeted disease-control efforts in the city. Mobile phone technologies for health  allowed for the operation of a national-level disease reporting and surveillance system at a low cost. Resource constraints prevent adequate surveillance of neglected infectious diseases such as rabies in developing countries leading to a poor understanding of the disease burden and limited evidence with which to design effective control measures. We utilized a low cost mobile-phone based system to carry out the first prospective surveillance of dog-bites and rabies in Pakistan by screening all patients presenting to nine emergency rooms in eight cities over a two-year period. We found a large number of dog-bite cases  with substantial geographical variability in time to presentation as well as health-seeking behavior following dog-bites across the reporting sites. Spatial analyses of collected data from Karachi, Pakistan's largest city identified areas with increased risk of dog-bite exposure, which has implications for the design of necessary control measures such as dog vaccination. While mobile phone based technologies have the potential to address limitations in disease surveillance in developing countries, the cost-effectiveness of large scale implementations of such strategies need to be explored and further evaluated where appropriate. Infectious disease surveillance continues to remain challenging in developing countries with resource constraints, weak health systems and poor reporting mechanisms Rabies is a notifiable disease in most developed countries; however, cases are generally underreported in countries like Pakistan and there is a poor understanding of the disease burden The aims of this study were to: 1) estimate the burden of dog-bites in Pakistan; 2) describe the frequency, age and gender distributions and severity of dog-bite cases across the reporting sites; 3) assess differences in patient health-seeking behavior and patient access to care amongst the reporting sites; 4) identify high-risk neighborhoods for dog-bite exposure in Karachi, Pakistan's most populous city; 5) describe implementation costs of the mHealth surveillance system from a health services perspective.Surveillance was carried out from February 2009 to February 2011. Cases were defined as all patients presenting with dog-bites to emergency rooms at enlisted centers and patients with dog-bites referred from other facilities. If dog-bite victims did not seek healthcare, or sought care with traditional healthcare providers and alternative medical centers from where referrals were not made to an enlisted center, those cases would not be reported through our system. In addition, information on some cases was not captured because of refusals to take part in the questionnaire and could not be included.Lay persons with at least 12 years of education were recruited on recommendation of local hospital administrators, and were provided training for the role of \u201cscreener\u201d to implement the study protocols regarding informed consent procedures and phone-based screening. The training emphasized basic research ethics and the necessity of voluntary informed consent. Training was provided onsite for data entry and storage using the mobile phone and included role-play to enable screeners to familiarize themselves with the study tools. The administrative heads of ERs were involved in supervision of screeners and in providing local logistical support. Screeners were provided a monthly stipend of approximately USD 80 per month.Dog-bite cases were approached immediately after initial treatment, introduced to the study and its objectives and consent was requested for an interview. A standardized questionnaire using a mobile phone based application was completed for all consenting patients. The questionnaire was created using the openXdata software package for low-cost mobile devices. OpenXdata is an open source software for service providers and researchers to design and manage forms for data collection using mobile devices and remotely monitor data collection activity in the field. OpenXdata has two components, a web-based server application and openXdata mobile which is installed on low cost phones. We provided a GPS-enabled Nokia 6220 mobile phone (costing USD 250 each) to screeners at each site programmed with forms to collect patient demographics, details about the nature of the bite and geographic location of the incident. A patient's attendants provided history of exposure and treatment in cases where rabies was suspected and the patient was incapable of responding. The use of openXdata allowed for predefined validation checks as data was being entered into the phone, and eliminated the use of paper forms other than for consent. Date and time stamps were automatically recorded along with GPS coordinates each morning immediately outside the site to monitor the screeners attendance at the hospital. All data entered via mobile phones was uploaded on to the centralized openXdata server, using a GPRS connection.Ethical approval for the study was obtained from the Institutional Review Board (IRB) at Interactive Research & Development (IRD) which is registered with the U.S. Department of Health and Human Services (DHHS), Office for Human Research Protections (IRB # 00005148). Informed consent was obtained from patients or from guardians in the case of children, through signatures or thumbprints (for illiterate patients) onto paper consent forms, each of which was bar-coded with the patient ID to enable linking with electronic forms. Approval for the use of thumb ink prints in patients unable to provide signed consent as well as for guardians in the case of children was provided by the IRB. An IRB exemption was subsequently obtained for retrospective analysis of surveillance data following closure of the study and data collection activities.Statistical analysis was carried out using Stata version 12.1 . We calculated summary statistics by center for total number of cases, patient demographics and severity of bites based on the WHO classification Spatial analyses were limited to the city of Karachi as it had the highest number of cases and administrative boundaries for the city (as distinct town units) were easily available to permit geocoding of addresses. In addition, an insufficient number of addresses in other cities were deemed appropriately detailed for inclusion in spatial analysis, or were outside city limits. Due to the presence of a large stray dog population and wide variations in social determinants of health such as poverty and homelessness we hypothesized a non-uniform distribution of dog-bite incidence in the city The costs of the mHealth surveillance system have been described in US Dollars and International US Dollars (I$), a conceptual currency which adjusts costs for purchasing power parities between countries. The costs have been calculated from a health services perspective and do not include patient related variables such as lost productivity.A total of 6,470 cases of animal-bites were reported during the 24 months of surveillance, of which 96%  were due to dog-bites. The largest number of cases was reported at the public tertiary care hospital in Karachi (48.26%), as shown in A previous study from a major public-sector tertiary care hospital in Karachi estimated that 25\u201335% of cases in the city visited its facility for management of dog-bites, Overall, a greater proportion of cases sought immediate healthcare at a non-medical facility or administered self-treatment (52.29%) . The medOverall 13 cases died due to rabies at an Emergency Room, 8 of which took place in Mansehra. Only one case was confirmed using the Fluorescent Antibody Test (FAT) on post-mortem examination, with the remaining diagnoses based on clinical symptoms.As described in The high costs associated with establishing and maintaining infectious disease surveillance systems makes poor countries such as Pakistan vulnerable to outbreaks and hinders control of endemic diseases. In the case of rabies, whose transmission is primarily mediated through a canine reservoir, understanding and mitigating the risk of exposure to dog-bites provides an opportunity to control a universally fatal disease No prior studies from Pakistan have attempted to quantify the burden of dog-bites and rabies in the country as multi-center surveillance was absent in the country. Published studies from the region have focused largely on clinical evaluations of dog-bite cases and wound-management practices. In addition, such studies have relied upon retrospective data or historical recall to ascertain bite-exposure with inherent limitations of such approaches, in particular with missing patient data for risk-factors and outcomes. Our mHealth system permitted electronic data capture at large public and private facilities, and allowed for the prospective assessment for a range of risk factors related to dog-bites and documentation of patient mortality. Through this study we highlight a large, previously undocumented burden of dog-bites in Pakistan. Given the challenges in setting up such surveillance mechanisms, the absence of well-documented evidence of this disease burden has prevented adequate control mechanisms to take root in the country, even though such initiatives began several decades earlier This study identified large variations in patient access to care and health-seeking behaviors across different reporting sites that may serve as indicators of risk for developing rabies. Cases presenting to urban centers such as Karachi and Hyderabad were least likely to visit non-medical facilities first or administer self-treatment and unsurprisingly had shorter travel times compared to centers serving more rural populations. An exception to this was Abbottabad where cases were less likely to seek care at a non-medical facility compared to other centers, although the median travel time to the ER in Abbottabad was significantly longer than in Karachi and Hyderabad. This likely reflects a more educated and affluent peri-urban and rural population accessing the ER at Abbottabad than at some of the other reporting sites. Similarly, the large catchment population served by the private hospital in Karachi that includes many rural fishering communities could have accounted for the differences in health-seeking behavior seen between the two reporting ERs in the city. A disproportionately high number of deaths were reported at the ER in Mansehra, which serves as a referral center for remote, rural mountainous communities. This center reported the longest adjusted travel times and it is likely that these cases presented when symptoms had already developed. In addition, the absence of cell-culture vaccines at this center may have also contributed to the higher mortality.A far greater proportion of males presented to ERs as compared to females, likely a reflection of total time spent outdoors, and possibly associated reduced risk of exposure, but this could also reflect limited access to health facilities for females. Women in Pakistan are less frequently outdoors, particularly in urban areas and non-agricultural rural communities and are also likely to have less access to healthcare compared to males. Although children were frequently victims of dog-bites, the age distribution of cases was not necessarily suggestive of increased risk given the young age of the Pakistani population. We found that at most centers, there were substantially more patients with severe dog-bite wounds (Category III). Possibly, less severe bites were being treated at lower levels of care, including using non-allopathic providers or self-care.Several public health initiatives will be required through evidence generated from this study. Foremost, advocacy efforts for rabies control need to be greatly strengthened and supported. It is important to emphasize that appropriate management of dog-bites and control of rabies is not neglected by policy-makers, public officials and hospitals given the focus on other key infectious diseases programs such as polio eradication, measles elimination and tuberculosis control. Significant investments will need to be made to improve public awareness about appropriate care following dog-bite exposure particularly in rural areas. Services for post-exposure prophylaxis need to be greatly expanded beyond urban centers. This may involve setting-up dog-bite care clinics within the publicly administered Basic Healthcare Units system or increasing the availability of reduced costs rabies vaccines in the private sector to promote its uptake in less developed regions of the country. Pre-exposure vaccination for low-income workers outside of more formalized animal farming settings such as abattoirs also needs to be considered by the government. Larger public facilities, especially those in more remote areas could benefit from intra-dermal injections of cell-cultured vaccines that are less costly and requires less vaccine therefore reducing the possibilities for potential stock-outs.Limited efforts under the banner of rabies control currently exist in most cities of Pakistan. In Karachi, measures largely include shooting of stray-dogs and depositing large numbers on an uninhabited island in order to help control their population. Spatial analyses can help direct more effective rabies control initiatives such as canine vaccination in low-resource settings by identifying high-risk populations. The presence of a large abattoir on the eastern border of Landhi, may have attracted large stray dog-populations in the area and contributed to the high incidence of reported cases from the immediately adjacent and more densely populated, low-income towns of Korangi and Malir. Our experience of establishing public health services and community cohorts in these towns spanning the past several years supports the premise of a large stray dog population concentrated in the area though their numbers are as yet not quantified. Based on the findings from the spatial analysis, we have approached veterinary-physicians in the military  as well as officials in the city municipal offices to establish canine vaccination efforts focused around the eastern parts of the city highlighted within the maps as well as in Gadap Town, a large urban sprawl towards the north-east. Such programs would need to involve close coordination between administrative authorities of each town and can be supported in data monitoring and evaluation by academic organizations. Investigation of urban canine habitat and migration patterns will be required that can further help narrow areas with high risk of exposure and these activities can also be supported through the use of mobile-phone technologies. In addition, a more detailed understanding of dog-ownership and proportion of stray-dogs in high risk areas will be required. Findings from these investigations can help determine resource requirements and allow for targeted immunization campaigns.A major limitation of the system was the small number of centers that were enrolled in the study relative to all facilities where dog-bite cases might access care. This may lead to selection bias while making inferences about population characteristics. It is difficult to quantify the extent of missing data since dog-bite victims could visit any one of a number of public or private healthcare facilities, including non-allopathic providers across the country or may not seek any treatment at all. Resource constraints required selection of a limited number of high-volume tertiary care facilities that were also regional referral centers for dog-bites. Our estimates of the total number of dog-bites cases in the country are therefore likely to be conservative since fewer number of notifications may have taken place from rural centers with wider catchment areas as well as notifications from outside our reporting sites. For patient health access and health-seeking behaviors including centers within the regression models may have helped account for area-level indicators such as land use and transportation. However, socio-economic indicators from patients were not collected as part of the questionnaire and could therefore not be included. Patient travel time to ER was therefore used to approximate access to care.The spatial analysis included population estimates that were extrapolated from census data that were more than a decade old. A uniform population growth rate for this entire period and across all of Karachi's administrative units may not accurately reflect higher population growth in recent years and increases due to migration which may be more concentrated in certain areas. The accuracy of incidence rates for dog-bites is likely to be most sensitive to this variation in population; however, identification of clustering may be less affected since it is more dependent on the distribution of cases. Other well-known risk factors for dog-bites such as poverty, homelessness and dog population densities were unavailable or not generalizable, and prevented a more robust analysis. Investigating covariates that might account for some of the observed spatial dependence could identify potential risk factors for dog-bites and can further aid in the decision-making process. Since only two centers were enrolled in Karachi reporting bias may have contributed towards the observed clustering of cases around Korangi, a major limitation of the spatial analysis. Increasing the number of surveillance sites would have accounted for this. Employing case-control methodologies with mapping of point-pattern data in order to more appropriately quantify differences in risk could help enhance inferences regarding the spatial distribution of dog-bites.Scale-up and sustainability are major limitations that prevent this system from being more effective. Whilst short, on-site trainings provided sufficient familiarity for screeners to utilize the software for reporting, the data-collection process itself was occasionally perceived as disruptive to patient-care. This suggests that any integration of innovative technologies within a health system needs to take into account the broader environment in which it will operate. Health administration in South-Asia, particularly in the public sector is frequently hierarchical and scaling-up such initiatives is challenging without support from senior officials, as was the case at two sites we had approached. Data collected via the system may be integrated within wider reporting systems. OXD stores data as a relational database that allows data export in CSV formats for data integration provided other systems support such formats. For non-supportive systems programs would be required to appropriately transform the data. Technological challenges in scale-up of the system infrastructure were largely related to data-storage capacity of servers. Mobile internet connectivity was not an issue at our reporting sites largely due to rapid advances in telecommunications coverage over the past decade. However, it may be a challenge to extend this system to more remote settings with poor connectivity. Newer technologies such as 3G and O3B (Other 3 Billion) that are under development in the country may help improve connectivity and speed of data-transfer. Limitations in the software mobile-application utilized for the surveillance system included the absence of SMS reminders for vaccinations. Phone calls attempted by screeners to follow-up were not logged in the database, and hence did not generate automatic alerts for patients potentially defaulting their vaccine schedule.Assessing the cost-effectiveness of this system is challenging in the absence of any mechanisms for surveillance of dog-bites and rabies in Pakistan. Our cost estimate of USD 7.15 per dog-bite case identified is higher compared to other mHealth surveillance evaluations in resource-limited settings Sustainability of such surveillance systems are generally linked to funding commitments from governments or donor agencies. Through this study we attempted to first highlight the need for dog-bites and rabies surveillance and secondly demonstrate the ability of mHealth technologies to deliver such a system. However, the type of analyses carried out in this study may well be beyond the scope of screeners or even public health administrators to carry-out on a routine basis, thus limiting its appeal. Enhancements to the software therefore need to include elements of product design utilized by commercial technology companies that involve sophisticated yet user-friendly server front-end applications for easier data-visualization (e.g. GIS) and presentation of complicated data analyses . Costs associated with such software development was not feasible within the project funding. An alternative sustainability strategy may therefore be to seek investor funding that helps further develop the software with a commercial intent and for it to be delivered as a package to provincial or national governments. The business model could involve recovering costs by charging for each case registered and tracked via the system, rather than seeking upfront costs for project implementation which may be met with greater resistance.We identified a high burden of severe  dog-bites and substantial variation in patient health-seeking behavior and access to care across different regions of Pakistan. Spatial analyses were suggestive of clustering of dog-bite cases in Karachi and can facilitate preventive efforts. Low-cost mobile phone technologies have the potential to address gaps in surveillance systems in low-resource settings. Further cost-effectiveness studies are required of large-scale implementations of mHealth based infectious diseases surveillance systems in developing countries to generate evidence for necessary resources for scale-up and sustainability."}
+{"text": "Chest X-ray is routinely performed to check the position of the central venous catheter (CVC) inserted through the internal jugular or subclavian vein, while the further evaluation of CVC malfunction is usually performed by contrast venography. In patients with superior vena cava obstruction, the tip of the catheter is often seen in collateral mediastinal venous pathways, rather than in the superior vena cava. In such cases detailed knowledge of thoracic vessel anatomy is necessary to identify the exact location of the catheter.We report a case of 32-year-old female patient with relapsing mediastinal lymphoma and previous superior vena cava obstruction with collateral azygos-hemiazygos venous pathways. The patient had CVC inserted through the left subclavian vein and its position was detected by CT to be in the dilated left superior intercostal vein and accessory hemiazygos vein. Considering that dilated accessory hemiazygos vein can tolerate infusion, the CVC was left in place and the patient had no complaints related to CVC position. Furthermore, we present anatomical and radiological observations on the azygos-hemiazygos venous system with the special emphasis on the left superior intercostal vein.Non-contrast CT scans can be a valuable imaging tool in the detection of the CVC position, especially in patients with renal insufficiency and contrast media hypersensitivity. Chest X-ray is routinely performed to ascertain the position of the central venous catheter (CVC). The catheter should be placed in a large-calibre vein with a sufficient flow to tolerate infusion which is usually the subclavian vein, brachiocephalic vein or superior vena cava.3Radiographic and venographic features of CVC malposition in the left superior intercostal vein were previously described.A 32-year-old woman presented to our hospital with relapsing bulky mediastinal non-Hodgkin lymphoma and previous superior vena cava obstruction. A single-lumen CVC was uneventfully inserted through the left subclavian vein without imaging guidance. Aspirated blood was venous. Routine chest X-ray was obtained to ascertain the position of the catheter  and was Since hemodynamic parameters were consistent with a venous localization of the catheter, it was left in place and three hours later a non-contrast thoracic CT scan  was performed in order to clarify its position . It showMalposition occurs in about one-third of CVC insertions if imaging guidance is not used, while it happens less frequently under sonographic or fluoroscopic guidance.The left superior intercostal vein and azygos arch present a major venous loop connecting the posteriorly located azygos-hemiazygos system with the anteriorly located superior vena cava and left brachiocephalic vein.1The left superior intercostal vein can be identified on upright posteroanterior chest radiograph in 1.4%\u20139.5% of healthy people as a small \u201cnipple\u201d lateral to the aortic arch.1The non-dilated left superior intercostal vein is usually too narrow for the insertion of a CVC. The insertion of the CVC tip into the narrow left superior intercostal vein irritates the vessel wall leading to catheter-related infection and thrombosis. Our patient had prior superior vena cava syndrome and thrombosis, and consequently developed collateral venous pathways, including the enlargement of the left superior intercostal vein. Enlarged collateral veins can occasionally be the site of CVC malposition. The CVC was left in place in the left superior intercostal and accessory hemiazygos vein because developed collateral venous pathways usually have a sufficient flow to tolerate infusion. The deliberate placement of CVC into the azygos-hemiazygos system with the effective long-term venous access in the patient with superior vena caval occlusion was previously reported.12When oncologic patients undergo follow-up CT examinations of their underlying disease processCT can be a valuable tool in evaluation of the CVC position, especially in patients in whom diagnostic contrast venography is contraindicated due to renal failure or contrast media hypersensitivity. If the CVC tip is detected to be in the dilated left superior intercostal vein or accessory hemiazygos vein in patients with superior vena caval syndrome, the vein can usually tolerate infusion and the catheter can be left in place. Detailed knowledge of normal and anomalous venous anatomy is required for the optimal interpretation of the CVC position."}
+{"text": "Background. Transoral robotic surgery (TORS) is an emerging treatment option for the treatment of head and neck malignancies, particularly for oropharyngeal squamous cell carcinoma (OPSCC). Preliminary studies have demonstrated excellent oncologic and functional outcomes that have led to a resurgence of interest in the primary surgical management of OPSCC. The aim of the present study was to review the evidence base supporting the use of TORS in OPSCC. Methods. Studies evaluating the application of TORS in the treatment of head and neck squamous cell carcinoma (HNSCC), and more specifically OPSCC, were identified for review. Further searches were made of reference lists for complete evaluation of minimally invasive surgery (MIS) in treating OPSCC. Results. Seventeen results relating to the application of TORS in treatment of OPSCC were identified. Further results relating to the role of transoral laser microsurgery (TLM) in OPSCC were included for review. Feasibility, oncologic, and functional data is summarized and discussed. Discussion. Management strategies for patients with OPSCC continue to evolve. Minimally invasive surgical techniques including TORS and TLM offer impressive functional and oncologic outcomes particularly for patients with early T-classification and low-volume regional metastatic disease. Potential exists for treatment deintensification, particularly in patients who are HPV positive. Approximately 500,000 new cases of head and neck squamous cell carcinoma (HNSCC) are diagnosed each year making HNSCC the 6th most common cancer worldwide . The ratThese trends, which have seen rates of OPSCC as much as double over the last three decades in some countries, have been associated with a shift in demographics to a younger population that is typically high functioning with lower rates of comorbid illness . CombineThese new developments in the pathogenesis of HNSCC, and in particular OPSCC, are occurring in the context of large-scale paradigm shifts over the past two decades towards organ preservation treatment protocols. The Veterans Affairs laryngeal cancer study published in 1991 began the era of organ preservation and led to the application of primary radiation approaches to other subsites such as the oropharynx . AlthougMinimally invasive surgery (MIS) for HNSCC continues to be extensively reported within the head and neck literature, driven by the desire to offer a less morbid alternative to chemoradiation. These techniques have included transoral laser microsurgery (TLM) and more recently, transoral robotic surgery (TORS). TORS was first introduced into the literature by Weinstein et al. in 2005 with their case report of a supraglottic laryngectomy performed in a canine model . The adaSince this early report, the development of TORS in its various human applications has been steadily progressing with feasibility studies confirming the safety and usability of this technology in live human patients , 6. GiveVarious reports of the use of TORS in benign disease processes have been published in the literature \u201310, howeThe aim of the current review is to provide an evaluation of the existing literature with regards to the oncologic and functional outcomes following treatment of OPSCC with minimally invasive surgery and in particular, TORS.A literature search was conducted using PUBMED and MEDLINE with search parameters including  OR robot[All Fields] OR telerobot[All Fields] OR (\u201crobotics\u201d[MeSH Terms] OR \u201crobotics\u201d[All Fields] OR \u201ctelerobotics\u201d[All Fields]) OR robot-assisted[Title])) OR TORS[Title].The references of the identified studies were reviewed further for completeness. In addition, studies relating to the use of TLM were identified to facilitate a complete evaluation of the evidence base for the current role of MIS in the management of OPSCC.Only those studies dealing specifically with the management of patients with HNSCC were included, with descriptions of TORS for benign disease, nonmucosal malignancies of the upper aerodigestive tract, novel applications of TORS and descriptions of cadaveric studies all being excluded. Specifically, data relating to the evaluation of quality of life, oncologic and functional outcomes in the identified studies was reviewed.Sixty-nine results were identified for review of which the references were further evaluated for potential inclusion in the analysis. Of particular note, studies related to the use of transoral laser microsurgery were included for complete review of minimally invasive surgery in the treatment of OPSCC.Sixteen studies were excluded as they were not related to the application of TORS in patients with HNSCC. Forty studies addressed the role of TORS in treatment of head and neck tumors and in particular, 17 studies commented directly on the use of TORS in patients with OPSCC. Six studies were identified that investigated quality of life and functional outcomes following TORS for treatment of HNSCC/OPSCC with a further seven discussing feasibility aspects including setup and operative times .The initiation of new TORS programs, generally established in conjunction with robotic programs in other surgical specialties, has repeatedly demonstrated success in establishing safe and efficient robotic services for head and neck oncology units \u201319. OperFor patients who require free flap reconstruction of the ablative defect, feasibility studies and initial case series detailing free tissue transfers via minimally invasive surgical approaches and robotic-assisted microanastomotic techniques have also demonstrated reliable perioperative outcomes , 20\u201325.In excess of 500 patients receiving TORS to manage OPSCC have been reported across 17 studies. A summary of the TORS literature relating to the oncologic outcomes in patients with OPSCC is presented in Nonetheless, preliminary data relating to local control, disease-specific survival, and overall survival using upfront TORS is encouraging, with early overall survival rates at 1 year exceeding 90% with emerging 2-year survival data between 80% and 90% , 28, 29.These oncologic outcomes with TORS largely mirror the experience reported in the TLM literature with patient populations again largely demonstrating early T-classification, deintensified adjuvant treatment recommendations based on pathological staging, and impressive oncologic control . SteinerThis potential to deintensify treatment based on successful surgical control of the primary tumor burden has led to retrospective analysis of the experience in some centers with single modality treatment of OPSCC. Grant et al. reported in 2009 their experience with 69 patients with select mostly early T-stage OPSCC who did not receive adjuvant therapy (64% not indicated and 36% offered but declined) . The 5-yIt remains unclear whether a subset of patients with OPSCC can be treated with primary surgery in order to achieve superior functional results with deintensification of adjuvant treatment. Following on from Steiner's early work the use of TLM has repeatedly demonstrated impressive functional outcomes with low rates of gastrostomy dependency, decannulation and high quality of life scores on questionnaire assessment. These results are summarized in Tables Early TORS data supports these impressive functional outcomes with most series reporting 1-year gastrostomy-tube rates under 10% and long-term rates of 0% for patients treated with upfront surgery , 28, 33 A further confounder in the management of OPSCC is the role of HPV in disease pathogenesis and significance as a prognostic factor, apparently irrespective of treatment modality , 34\u201336. Weinstein et al. also reported on 50 patients treated for OPSCC with an HPV-positive rate of 74% (37/50). In this series of patients treated with upfront TORS, the disease-specific survival of patients with HPV-positive OPSCC at 1-year and 2-years was 97% and 90%, respectively. However, the HPV-negative cohort in this primary surgical series demonstrated equal oncologic control with disease-specific survival rates at both 1-year and 2-years of 100%.The management of patients with OPSCC continues to evolve with both advances in therapeutic regimens and evolution of our understanding of the underlying disease pathophysiology. Early surgery-based treatment paradigms have been largely abandoned with the general adoption of nonsurgical regimens supported by an evidence base demonstrating superior functional outcomes whilst retaining comparable survival results \u201341.Paralleling the improvements in surgical technique, the natural evolution of radiotherapy has resulted in a decrease in treatment-related morbidity. Refinement of targeted 3D conformal radiotherapy methods such as intensity-modulated radiotherapy (IMRT) has allowed increased precision in delivery of radiotherapy to patients with HNSCC with associated decreases in adverse sequelae . TemperiAs the etiologic factors involved in the development of OPSCC continue to be elucidated one variable that has proven immensely significant is the role of human papillomavirus (HPV). This HPV epidemic has interestingly occurred during the same period as the widespread adoption of chemoradiotherapy as standard of care treatment for advanced stage OPSCC. This has managed to blur the lines somewhat with respect to whether these improved outcomes are secondary to treatment modifications or reflective of a naturally improved survival rate in patients with HPV-positive disease. Furthermore, the HPV-positive OPSCC patient has been defined as typically younger with lower rates of significant medical comorbidities . CombineOncologic outcomes in patients with HPV-positive OPSCC remain similar regardless of treatment approach. Therefore, an appreciation of functional outcomes represents a significant and fundamental consideration when formulating management recommendations. Transfacial and transmandibular surgical approaches to the oropharynx carry potential morbidity and have been demonstrated on retrospective analysis to be associated with poor functional outcomes when compared to radiotherapy \u201341. BothComparisons of outcomes after TORS versus chemoradiotherapy across studies are hampered by differences in baseline patient populations, selection, and treatment technique. Nonetheless, rates of gastrostomy tube dependency after chemoradiotherapy have typically been reported as between 9% to 39% in patients treated with chemoradiotherapy \u201359. CritThe promising impact of TORS on the quality of life and survival outcomes of OPSCC patients remains an important clinical question that requires higher levels of supporting evidence. A recent surgical consensus statement (the \u201cIDEAL\u201d guidelines) suggests that randomized comparisons be carried out wherever possible, once adequate pretrial data are available . ThroughUltimately, ORATOR aims to assist in the identification of OPSCC patients who might be best served by upfront surgery. Adapting data from other head and neck subsites we understand that in a select group of \u201csurgical responders\u201d chemoradiotherapy represents a suboptimal treatment approach due to either lack of response in locoregional disease control or excessive treatment-related side effects and morbidity. Further, defining the \u201csurgical responder\u201d in patients with OPSCC is perhaps even more important than other subsites such as the larynx given the relative lack of success with surgical salvage. Combined with the work of others, ORATOR can hopefully work to identify the ideal OPSCC patients for upfront TORS, with the realization that chemoradiotherapy will still represent an excellent treatment option for the \u201cnonsurgical responder.\u201dUltimately, providing truly accurate risk assessment will require a clearer understanding of the underlying molecular genetics of HNSCC. Only then can patients be risk stratified with relative certainty utilizing both clinical and genetic evidence to guide treatment plans. Recent high-throughput genetic sequencing publications in science by Agrawal and Stransky provide exciting insights into a future that promises genetically guided management to optimize survival and minimize treatment-related morbidity , 62. FurThe continued development of minimally invasive surgical techniques such as TORS offers a significant opportunity to impact positively on patient quality of life and posttreatment function whilst retaining satisfactory oncologic control. Initial feasibility and case series reports are encouraging but require further validation through well-designed randomized control trials prior to widespread shifts in accepted treatment paradigms."}
+{"text": "Plants and pathogens evolve in response to each other. This co-evolutionary arms race is fueled by genetic variation underlying the recognition of pathogen proteins by the host and the defeat of host defenses by the pathogen. Together with new mutations, genetic diversity in populations of both the host and pathogen represent a pool of possible variants to maintain adaptation via natural selection.Drastic changes in genetic diversity in crop species have occurred as a consequence of domestication. Whether changes in the genetic composition of these host populations also have affected genetic diversity in pathogen species is, so far, poorly understood. Advances in comparative genomics and population genomic approaches open new avenues to study adaptive processes in plant pathogens and to infer the impact of agro-ecosystems on the evolution of pathogen populations. Here we summarize new insights gained from comparative genome studies and population genomics in host-pathogen systems.In the process of domestication, crop species have undergone striking changes in both morphology and physiology. At the genetic level, these phenotypic changes have been brought by strong directional selection on a few genes Phythophthora infestansMagnaporthe oryzaePuccinia striiformisAgro-ecosystems brought by domestication have favored the emergence and specialization of new pathogen species by providing a new ecological niche. High densities of host individuals, genetic homogeneity of host populations, and recently the facilitated long distance dispersal of propagules by anthropogenic activities are factors that are greatly conducive for the propagation of pathogens in agro-ecosystems Comparative genomics and population genomic analyses have provided new insights into genome evolution, speciation, and the origin of pathogenicity traits. A main conclusion from these studies is that fungal pathogens can exhibit very high levels of genome plasticity and plasticity itself may be instrumental in enabling the emergence of new virulence traits Verticillium dahliae a population genomics analysis was used to identify a determinant of race specificity V. dahliae led to the identification of a 50 kb fragment only present in race 1 isolates. Subsequent RNAseq data revealed only a single highly expressed ORF in this region. Experimental analyses confirmed the determining role of this gene as a virulence factor in race 1 strains of the pathogen. V. dahliae is a predominantly asexual pathogen and the acquisition of this virulence factor, possibly through a horizontal gene transfer event, underlines the importance of genome plasticity in adaptive evolution of fungal pathogens.In the plant pathogen Zymoseptoria pseudotritici revealed a particular evolutionary history for this species Z. pseudotritici harbors a mosaic of long fragments without any polymorphisms interspersed with fragments exhibiting two distinct haplotypes. This pattern is consistent with a recent interspecific mating of just two genotypes resulting in a successful new species formation via hybrid speciation. The underlying molecular traits responsible for pathogenicity in the hybrid still remain to be identified. However, the broad distribution of Z. pseudotritici at its center of origin demonstrates how new genomic combinations mediated through interspecific hybridization can lead to the successful emergence of new pathogens.In addition to horizontal gene transfer, new pathogenicity traits may emerge from the crossing of genetically rather distant individuals. Population genomic analysis of the grass pathogen N and PS) furthermore measures the direct effect of natural selection removing slightly deleterious non-synonymous variants in coding sequences (purifying selection). Most genes are expected to evolve under purifying selection , however a local increase in PN/PS may reveal those few genes where new non-synonymous variants are favored by natural selection (positive selection). If genomic data from one or more related species are available, rates of non-synonymous (dN) and synonymous (dS) substitutions can be assessed to contrast within and between species patterns of variation  were analyzed jointly with rates of branch-specific estimates of substitutions (Nd and Sd) to assess the effect of natural selection on coding sequences. A significant finding was that the transition to an agro-ecosystem did not entail an evolutionary \u201ccost\u201d in M. graminicola. Evolution in M. graminicola is instead characterized by the efficient fixation of new beneficial mutations enabling the pathogen to adapt to its new host and environment as reflected by currents ratios of PN/PS in the three species and branch-specific rates of dN and dS. Sexual recombination in the pathogen has likely also played a significant role in the purging of deleterious mutations.A population genomics approach was also used to study patterns of adaptive evolution in the wheat pathogen The above-mentioned studies exemplify the broad potential of population genomic analyses in evolutionary studies of plant pathogens including the identification of strongly selected genes, estimates of evolutionary potential, and inferences of past demographic histories and current levels of adaptive evolution.Population genomics studies will boost our understanding of adaptive evolution of plant pathogens in agro-ecosystems. The first studies on fungal pathogens have so far shown that fungal pathogens readily adapt to the agricultural environment and have revealed strong footprints of natural selection on their genome-wide diversity. Several studies have documented unexpectedly high levels of genome plasticity in fungal pathogens, allowing the acquisition of new genetic material and the presence of supernumerary chromosomes. We still need to understand the drivers of genome plasticity and their importance for adaptation. An equally important endeavor will be to understand further how the evolutionary potential of pathogen populations is maintained in spite of strong directional selection within homogenous host environments.In light of the increasing need to control plant pathogens, we consider the close integration of evolutionary genomics with experimental studies will be essential to describe and predict the emergence, establishment, and adaptation of plant pathogens in agro-ecosystems. A combination of evolutionary analyses of genome-wide patterns of genetic diversity in crops and pathogens combined with targeted experiments, including functional studies and experimental evolution on pathogens, will be important to guide the much-needed design of novel and sustainable strategies to slow down the emergence and spread of pathogens"}
+{"text": "To test this hypothesis, we incorporated a novel active learning (AL) algorithm into FARSIGHT image analysis software that aids the expert by seeking out informative examples for the operator to label. The resulting FARSIGHT-AL system identified EC with specificity and sensitivity consistently greater than 0.9 and outperformed traditional supervised classification algorithms. The system modeled individual operator preferences and generated reproducible results. Using the results of EC classification, we also quantified proliferation (Ki67) and activity in important signal transduction pathways  in immunostained human clear cell renal cell carcinoma and other tumors. FARSIGHT-AL enables characterization of EC in conventionally preserved human tumors in a more automated process suitable for testing and validating in clinical trials. The results of our study support a unique opportunity for quantifying angiogenesis in a manner that can now be tested for its ability to identify novel predictive and response biomarkers.Currently, no available pathological or molecular measures of tumor angiogenesis predict response to antiangiogenic therapies used in clinical practice. Recognizing that tumor endothelial cells (EC) and EC activation and survival signaling are the direct targets of these therapies, we sought to develop an automated platform for quantifying activity of critical signaling pathways and other biological events in EC of patient tumors by histopathology. Computer image analysis of EC in highly heterogeneous human tumors by a statistical classifier trained using examples selected by human experts performed poorly due to subjectivity and selection bias. We hypothesized that the analysis can be optimized by a more  Cancers are a complex community of different cell types with the transformed tumor cell population usually receiving primary attention. Cells of the tumor stroma, often considered secondary, provide essential support for tumor cells and are increasingly recognized for their contributions to the malignant behavior of cancers Based on prior studies in mouse tumor models active learning algorithm developed originally for Unexploded Ordnance Cleanup Performing comprehensive, cytometric analysis of EC from tumor images is predicated on the identification of individual cells present in the tumor and their classification into cell types of interest. We developed a hybrid nuclear segmentation algorithm  Section The fundamental idea behind active learning (AL) is that not all training examples are equally useful for classification. Based on what we know about the cells by observing the labels for a few training examples, labels of certain examples are more useful than others. By focusing on these examples iteratively, the algorithm can learn the problem more quickly and classify the data more accurately. AL algorithms sequentially select the most informative cells from the large unlabeled pool and query the user for their labels. Based on how the notion of information is defined, several active learning methods have been proposed. One of the most popular frameworks is the Uncertainty Sampling where the algorithm queries for examples that it is most uncertain about. It is commonly used with margin based classifiers like SVM Traditionally, supervised classification algorithms also require the users to select the best set of features that will help differentiate between different cells of interest. The more discriminative the set of features selected, the better the classification accuracy. However, most feature selection algorithms require a representative training set apropri to select the best set of features for classification. Other feature reduction methods involve exploiting the information in the eigenstructure of the data and project the original data into a latent space where the new features are linear/non-linear combination of original features. Although effective, the transparency of features is lost when latent space methods are used and additional effort is required to interpret these results. Most feature selection algorithms require the user to perform offline analysis. To select the important features on the fly and obviate the offline feature selection process, we improved the active learning algorithm to automatically select the important features for classification also, thereby freeing the user from expending additional effort for deciding the relevant features for different cell classification problems. The complex mathematics of the proposed algorithm . We previously developed FARSIGHT to analyze images and classify carcinoma cells based on morphometric characteristics and association with epithelial cytokeratin or other biomarker staining To teach FARSIGHT-AL to classify EC in a set of tumor images, the trainer provides one initial example of EC and non-EC nuclei. The system then displays a list of cell features that can be utilized for the current classification task. Since the algorithm automatically selects the important features, we initially performed a \u201cblind\u201d analysis where all the computed features  were proWe created a set of 20 images of stained ccRCC tumors from five different patients (ccRCC20 image set) with which to train and test the program .Although the performance of the algorithm in auto-select mode met expectations in all the datasets, we wanted to compare its classification performance in manual-select mode. To test this approach, the trainer selected the features to be used for EC classification  and allowed the algorithm to select only the informative training examples for which the user provided the labels. When compared with the auto-select mode, the algorithm with manual feature selection achieved a comparable specificity value (0.998) and PPV (0.99) but the performance degraded slightly with respect to sensitivity (0.93) and NPV (0.988). .Aware that human experts disagree frequently on which cells are EC in images, we evaluated how machine EC classification depended on its training. Two additional experts trained FARSIGHT-AL (in auto-select mode) to classify EC using the ccRCC20 image set and also personally classified EC in these images. Venn diagrams  show theWith FARSIGHT-AL trained to classify EC in ccRCC tumors, we tested its ability to classify EC in other tumor types that had been similarly stained. Since the cell-type identifications of the three pathologists agreed reasonably, we used the classification models obtained by training against trainer 2's interpretations only. We compared models where features were auto-selected or manual-selected with human EC classification. EC were classified in 22 images containing a total of 13,585 cells taken from seven RCC tumors that were subtyped as non-clear cell (non-ccRCC image set) and included papillary type I and type II and chromophobe RCC. Comparison of the two models  with humAccurate classification of EC in tumors using FARSIGHT-AL sets the stage for obtaining biologically meaningful information on these cells. Our interest in and the potential clinical significance of the biological activity of EC in tumors led us to train FARSIGHT-AL to determine their cell proliferative and signal transduction activities as reflected in EC expression of Ki67 and activated signaling intermediates, p-ERK and p-STAT3. The characteristic subcellular distribution and staining intensity of these analytes in immunostained ccRCC tumors dictated how EC were assessed for their presence: Ki67 and p-STAT3 are nuclear, and their expression was assessed by quantifying staining within nuclear boundaries drawn during segmentation; p-ERK is found in the nucleus, cytoplasm or both and was assessed by quantifying staining within a perimeter of two pixels (0.5 micron in images taken at 400X magnification) beyond nuclear boundaries. These factors and other distinctive characteristics of analyte immunostaining see  led us tAn issue with quantifying analyte expression is the variability in analyte background signal (DAB staining) among different tumors and even among images from different regions of the same tumor. Selecting a threshold to classify analyte-positive cells without compensating for the background can result in many cells being incorrectly classified as analyte-positive. We observed this effect in Ki67 and p-STAT3 analyte channels with the p-ERK channel being relatively free of background staining effects. Therefore, both Ki67 and p-STAT3 channels were processed with a background subtraction algorithm that computes the average background signal (pixel intensity) and subtracts this value from the pixel intensities of the image. After performing background subtraction, cells classified as analyte-positive were the ones with analyte expression greater than the specified threshold. Trainer 2 manually classified every cell in the ccRCC20 image set as analyte- positive or negative and, treating this labeled set as ground truth, we validated the thresholding method against it. The method yielded excellent specificity and sensitivity . We present a software system with a sophisticated machine learning algorithm that is scalable and enables rapid, reproducible and accurate classification of cells with selective quantification of molecular analytes over subpopulations. It is responsive and searches features of hundreds of thousands of cells in a matter of seconds to present the user with the most informative cells for labeling. A critical requirement of any algorithm when dealing with human tumors is to adapt to the inherent variability present in the tissue samples, and our results on ccRCC tumors indicate that the algorithm performs very well in this regard. Moreover, the classifier model generated to identify EC in ccRCC performed similarly on data from different tumors from different species. Since cancer histopathology studies often examine similar cells in different tumor tissues, FARSIGHT-AL may save researcher time and effort in cell classification by creating representative cell type classification models that are broadly applicable and yield accurate results when the imaging protocols are similar. Our studies with multiple experts indicate that FARSIGHT-AL is malleable and learns the nuances of trainer interpretations. The algorithm is consistent and, as long as the initial examples and the labels provided by the trainer are the same, the algorithm queries for the same cells and yields the same final EC classification result; this contrasts with human EC classification, which often shows differences from occasion to occasion (data not shown).www.farsight-toolkit.org).An attractive feature of our system is the complete flexibility it provides to the user in terms of automation and robustness to user-selected settings. The auto-select mode requires minimal supervision from the user; this ability of the algorithm may be especially useful in cases where cell types of interest have not been stained with a specific marker and training relies heavily on morphological features that might not be easily specified. The system can be integrated in clinical workflow and used by researchers easily as it works without the need for careful parameter adjustments or specialized training. The auto-select mode allows development of accurate classification models when only images with the labeled cells are available. The pathologist labeling the cells need not be an expert in software, the software operator need not be expert in histopathology, and the two only have to communicate and grade results. All the algorithms and software have been integrated into the open-source FARSIGHT toolkit , information was unavailable about how tumors were handled prior to fixation and embedding. As quantitative analysis of biologically important antigens in patient cancers becomes feasible, it highlights the need for quality control and standards in the handling of clinical specimens to limit preanalytic variables.Management of advanced RCC has been transformed by the advent of therapeutic agents that target components of the VEGF and other important EC signaling pathways The Institutional Review Board of the University of Pennsylvania approved this study of renal cell carcinoma tumor samples previously collected by the Eastern Cooperative Oncology Group (ECOG) in their multi-institutional study protocol ECOG2804. Patients enrolled in ECOG2804 provided written informed consent for ECOG to collect tumor tissue previously removed.Human renal cell carcinoma specimens were obtained from the University of Pennsylvania's Department of Pathology & Laboratory Medicine's clinical paraffin archive and the Eastern Cooperative Oncology Group (ECOG) pathology core lab  under IRB approval.5 micron sections of formalin-fixed, paraffin embedded tumor tissues were deparaffinized and treated with citric acid monohydrate buffer (pH 6) at 75\u00b0C for 11 minutes prior to staining. The antibodies used for immunostaining included rabbit monoclonal anti-phospho-extracellular-signal-regulated-kinase (p-ERK), rabbit monoclonal anti-phospho-signal transducer and activator of transcription 3 (p-STAT3), mouse monoclonal anti-human Ki67 , rabbit monoclonal anti-CD34 , mouse monoclonal anti-carbonic anhydrase 9 (CA IX) Multiplex staining protocols were developed to stain slides with combinations of the above antibodies and chemicals to reveal cellular compartments and antigens that report on cell type and molecular analytes. A frequently used combination included staining for a molecular analyte with DAB, CD34 with Alexa Fluor 488, CA IX with Alexa Fluor 647, SMA with Cy3, and nuclei labeled in hematoxylin .Multispectral images were captured using a Vectra\u00ae multispectral microscope and camera  at 400X magnification (8 bits/pixel depth) from 420 nm-720 nm at 20 nm wavelength intervals (brightfield mode) or 10 nm wavelength intervals (fluorescence mode). Nuance\u00ae software  was used to spectrally unmix the image cubes into individual channels corresponding to hematoxylin, DAB, and the fluorochromes . Unmixing was based on the pure spectra of the respective chromogens and fluorochromes.The spectral unmixing procedure results in multiple non-overlapping channels including a nuclear channel. We employed a hybrid segmentation algorithm that combines the algorithms proposed by Al-Kofahi et al th cell. Considering a binary classification problem, the labels of the cells are denoted by Each cell is denoted by a vector of cell measurements - (1); i.e.,Where actively based on the Fisher information matrix and this approach is called active learning. We denote the Fisher information matrix by In the proposed method, training examples are selected 1-regularized logistic regression 1 norm and 1- norm, we use the eps-L1 approximation to maximize the log-likelihood function. Finally, the Fisher Information matrix in auto-select mode is given by \u22129).The selection of training examples proceeds in a sequential fashion where examples that maximize the determinant of the Fisher information criterion are queried for their labels; i.e., the algorithm queries the user for labls of those examples that maximize, in every iteration, the value of the expression oP as the observed proportion of classification calls that are the same between two raters and eP as the proportion of classification calls that would be the same by chance given the observed data, then Cohen's Kappa (\u03ba) oP will equal eP and \u03ba will be zero. Although in general the interpretation of \u03ba depends on the prevalence of a positive rating and the bias (the difference between raters in the proportion of positive ratings), a \u03ba value of 0.6 or greater between raters is generally regarded as substantial agreement.The numerator in this expression represents the proportion of observed agreement minus the agreement expected by chance assuming the fractions of observed positive ratings in the two classifiers, and the denominator represents the highest possible agreement minus the agreement expected by chance. If the raters agree as well as if they simply flipped coins i.e., completely randomly, Multispectral microscopy was performed in the Tumor Tissue and Biosample Bank (TTAB) facility, which is supported by the Department of Pathology & Laboratory Medicine and Abramson Cancer Center (P30 CA16520). We thank Jaromir Pastorek  for M75 anti-CA IX antibody Figure S1Multispectral image of a multiplex-stained ccRCC tumor with results of spectral unmixing. A clear cell renal cell carcinoma (ccRCC) slide was stained for an analyte (Ki67) and nuclei using chromogens DAB (brown) and hematoxylin (blue), respectively, and for antigens that mark different cells types  using different fluorochromes. After spectral unmixing, the brightfield image (A) yielded hematoxylin (B) and DAB (C) chromogen channels, which were used for nuclear segmentation and analyte determination, respectively. After spectral unmixing, the fluorescent image (D) yielded the Alexa Fluor 488 (E), Cy3 (F) and Alexa Fluor 647 (G) channels, which were used to stain CD34 , SMA (pericyte) and CA IX (tumor cell) antigens, respectively.(TIF)Click here for additional data file.Figure S2Comparison of FARSIGHT-AL performance with other feature selection algorithms for UCI machine learning breast cancer datasets. Mean classification accuracy of 25 independent simulations plotted as a function of number of training examples for different automated feature selection algorithms including FARSIGHT AL (blue lines) on the UCI Breast Cancer Datasets. FARSIGHT-AL selected 50 training examples sequentially based on the increase in information gain whereas logistic regression was used to classify examples after feature selection by PCA (green), T-Test (purple), MRMR (Orange). Standard Logistic regression (red) with no feature selection performs poorly compared to other algorithms. The bars indicate standard error of the mean of classification accuracy.(TIF)Click here for additional data file.Figure S3Subcellular distribution of different analytes. The diversity in the staining patterns of different analytes is illustrated in the above figure. The nuclear stain appears blue in color whereas the analyte stain appears brown. Ki67 (A) and pSTAT3 (B) are predominantly nuclear bound whereas pERK (C) IS found in both the cytoplasmic and nuclear regions.(TIF)Click here for additional data file.Figure S4Comparison of ccRCC and non-ccRCC tumors for hypervascularity. The whisker plot shows the proportion of EC as a percentage of total number of cells in 22 ccRCC tumors (left) and 6 non-ccRCC tumors (right). In both the panels, the dot and the whiskers follow standard notation i.e., the dot indicates the median value of the proportion of cells and the top and bottom whiskers indicate the 25th and 75th percentile. Visual inspection of these plots suggests that the proportion of EC is higher in the ccRCC case. Comparison of the median values from each group using the Wilcoxon rank sum test revealed statistically significant differences between the groups with a p-value of 0.0015.(TIF)Click here for additional data file.File S1File containing Tables S1\u2013S4.(DOC)Click here for additional data file."}
+{"text": "Visual attention mechanisms allow the visual cortex to direct cortical processing to salient locations within a visual scene, at the expense of diminished processing of stimuli at other locations. The deployment of attention to a given location is known as spatial attention. Attention may also be applied to a known feature in a visual scene, such as a colour or shape, enhancing its occurrences across the visual field. In , a modelWe present here a neural dynamical model of feature-based attention that directs attention to salient locations in a multi-object scene through interaction of stimulus driven and cue driven neural activation. This interaction is managed by a disinhibition circuit gating output to a retinotopic neural region of the dorsal stream, the lateral intraparietal area (LIP). When visual stimuli are presented to primary visual cortex (V1), neural activation spreads into higher ventral stream areas through increasing neural receptive fields between layers. Stimulus driven neurons activate excitatory output and inhibitory interneuron populations in the disinhbition circuit. When a salient feature is cued by activation of its associated anterior inferotemporal (AIT) neuronal population, neural activity propagates to lower visual areas across all locations of the visual field. Activity in this top-down flow inhibits the inhibitory interneuron population allowing excitatory output from the disinhibition circuit to LIP in a retinotopic manner where activity is correlated in the stimulus and cue driven pathways. In areas where the two pathways do not match, local inhibition in the disinhibition layer prevents neighbouring circuits' excitatory populations from outputting to LIP.The model exhibits effects of feature-based attention, such as the feature similarity gain principle and biased competition through interactions of stimulus and cue initiated neural activity. The dynamical nature of the model as neural populations of Wilson-Cowan differential equations allows the time-course of neural activity to be investigated.Although originally designed as a model for binding, the model replicates the experimental correlates of feature-based attention, which strongly suggests its functional role is actually binding An important prediction of the model is that local non-matches between cue and stimulus are the most important information projected from the ventral to the dorsal stream and that this interaction is highly non-linear. We present candidates for neural circuits implementing this interaction."}
+{"text": "In oncology, there is increasing interest in studying combinations of drugs to improve treatment efficacy and/or reduce harmful side-effects. Dual-agent Phase I clinical trials are primarily concerned with drug safety, with the aim to discover a maximum tolerated combination dose via dose-escalation; small cohorts of patients are given set doses of both drugs and monitored to see if any particular toxic reactions occur. Whether to escalate, de-escalate or maintain the current dose for either drug for subsequent cohorts is based on the number and severity of observed toxic reactions, and a decision rule.We propose a novel Bayesian phase I trial design for the study of two chemotherapeutic agents in combination based on a penalized D-optimality criterion. Patients are allocated to dose combinations that provide the most information about the two agents in combination and their interactive behaviour, subject to a penalty function that doses patients at combinations with a probability of toxicity close to some desired target level. Such a criterion compromises between population gain (maximizing information) and patient gain .We show how the design can be applied to a dual-agent Phase I dose-escalation study of Paclitaxel and an Aurora Kinase Inhibitor in combination. Our simulation studies show that the method provides accurate and tolerable recommendations for further clinical testing and has the ability to outperform other proposed methods."}
+{"text": "Here we: The trial recruits men with locally advanced or metastatic prostate cancer starting standard long-term hormone therapy. There are 5 research arms and 1 control arm. The trial has a pilot stage assessing safety and feasibility, 3 intermediate \u201cactivity\u201d stages (I-III) where the outcome measure is failure-free survival (FFS) and one final \u201cefficacy\u201d stage (IV) with overall survival as primary outcome measure. At the end of each stage, each research arm is formally compared pairwise to the control arm. Accrual of further patients is discontinued early for any research arm either not showing sufficient evidence of activity or with adverse safety considerations; accrual continues to arms showing activity with acceptable safety. The stopping guideline compares the treatment effect against a pre-defined cut-off value using the hazard ratio when the hazards are proportional and restricted-mean survival time otherwise. This interim hurdle becomes increasingly stringent stage-by-stage. The addition of new research arm(s) can be actively considered when sufficiently interesting agents emerge. New research arms are compared only to contemporaneously-recruited control arm patients using the same intermediate guidelines in a time-delayed manner. The addition of new research arms is independent of any of the original research arms stopping accrual early subject to adequate recruitment to support the overall trial aims.(1) After the second intermediate activity analysis (March-2011), the IDMC recommended and the Trial Steering Committee ratified discontinuation of recruitment to two research arms for lack-of-sufficient activity. Nearly 100 recruiting centres in UK and Switzerland had to promptly implement the changes. Detailed advanced preparation meant that activation was swift and recruitment continued seamlessly into Activity Stage III; MHRA and REC approval was not required because this was already included in the trial design. (2) An application to add a new research arm has been successfully approved by the CRUK\u2019s CTAAC funding committee and accepted by the relevant industry partner. Details on the methodological and practical issues and implementation of these changes will be presented.The STAMPEDE experiences shows that recruitment to MAMS trial is achievable and that mid-flow changes to trial design are practicable with good planning."}
+{"text": "Molecular Fragment Dynamics (MFD) is a mesoscopic simulation technique based on dissipative particle dynamics. The method has been shown to successfully describe the phase behaviour and interfacial tensions of large chemical systems in good agreement with experimental results . Unlike The current MFD fragment definition is based on a SMILES like one-dimensional line notation which is visualized with the Structure Diagram Generator of the Chemistry Development Kit (CDK) . For an This work provides an editor for the construction of peptides and proteins from molecular fragments. It includes building blocks for all 20 proteinogenic amino acids, their charged species and disulfide bonds. A flexible input of one-letter and three-letter amino acid codes is supported. Additionally, the editor has the capability to set charges of side chains manually or automatically."}
+{"text": "The enhanced levels of Hsp90 were detected in the serum of SLE patients. The elevated level of Hsp90 in SLE has also been correlated with increased levels of IL-6 and presence of autoantibodies to Hsp90. This suggests that Hsp90 may contribute to the inflammation and disease progression and that targeting of Hsp 90 expression may be a potential treatment of SLE. The pharmacologic inhibition of Hsp90 was successfully applied in mouse models of autoimmune encephalomyelitis and SLE\u2014like autoimmune diseases. Thus targeting Hsp90 may be an effective treatment for SLE, especially if combined with other targeted therapeutic approaches.Heat shock proteins (HSP) are a family of ubiquitous and phylogenically highly conserved proteins which play an essential role as molecular chaperones in protein folding and transport. Heat Shock Protein 90 (Hsp90) is not mandatory for the biogenesis of most proteins, rather it participate in structural maturation and conformational regulation of a number of signaling molecules and transcription factors. Hsp90 has been shown to play an important role in antigen presentation, activation of lymphocytes, macrophages, maturation of dendritic cells, and in the enhanceosome mediated induction of inflammation. Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease with complex immunological and clinical manifestations. Dysregulated expression of Type I interferon  Heat shock proteins (HSPs) are a family of ubiquitous and phylogenically highly conserved proteins and play an essential role as molecular chaperones in protein folding and transport within the cell . These p\u03b1 and HSP90-\u03b2), but the functional differences between these isoforms are not well understood [In vertebrates, two distinct genes encode inducible and constitutively expressed isoforms of the protein , which are generated as part of the heat shock response (HSR), to maintain cellular homeostasis and to develop cell survival functions. The heat-shock factors (HSFs) bind to the heat-shock element (HSE) in the promoters of the genes encoding hsps. Four heat shock factors (HSFs) have been identified and well characterized and their roles clearly elucidated. The functional role of HSF1 and HSF3 has been linked to regulating Hsps in response to thermal stress whereas HSF2 and HSF4 are involved in Hsp regulation in unstressed cells and have been linked to a wide variety of biological processes such as immune activation and cellular differentiation . The strInfection is a stressful process for both the pathogen and the host and therefore inevitably results in increased production of molecular chaperones by the pathogen as well as by the host. The conservation of HSPs through prokaryotes and eukaryotes, together with the increased production of host and microbial HSPs at the site of infection, suggests that cross-reactivity between host and pathogen HSPs might be responsible for a variety of autoreactive disorders that are associated with high frequency recognition of HSPs . In thisvia the TLR2- and 4-signal transduction pathways [Autoimmune diseases remain among the most poorly understood and recognized categories of illnesses in the world. Many autoimmune diseases are much more common in women than in men, and estrogens exacerbate systemic lupus erythematosus in murine models of the disease by altering the B-cell repertoire in the absence of inflammation . In addipathways . Chaperones function as stimulators of the innate immune system; HSPs have been also shown to play a role in generating antigen-specific T-cell responses . The proMisdirected immune responses target self-antigens and induce severe inflammatory responses, which is a typical sign of autoimmune diseases and sometimes cause death. In addition to numerous components in autoimmune responses, heat shock proteins (HSPs) have been also implicated in autoimmune and inflammatory diseases , 30. BecSystemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease with complex immunological and clinical manifestations. Reduced immune tolerance and abnormal activation of T and B cells lead to autoantibody production mainly against protein-nucleic acid complexes, such as chromatin, and small ribonucleoprotein particles . These aAutoreactivity to HSP is often associated with autoimmune pathology. The investigations have demonstrated the presence of autoantibodies to the HSP90 in a significant proportion of patients with systemic lupus. Anti-HSP90 autoantibodies of the IgG class were detected in approximately 50%  and 26% HSP90 is abundant in normal tissues and the relative increase found is difficult to explain the deposits. With these considerations, the results of the present study are in support of the hypothesis that anti-HSP90 autoreactivity is involved specifically in the renal pathology associated with SLE. IgG autoantibodies to HSP90 from SLE patients are found to be less idiotypically regulated within the normal IgG repertoire than natural anti-HSP90 antibodies. These results were supported by the demonstration of an antiidiotypic inhibition of natural anti-HSP90 autoantibodies by IgG antibodies which were more pronounced in normal than in SLE IgG. Thus, the complete IgG repertoire present therein seems to be beneficial in experimental SLE and primary antiphospholipid syndrome . FurtherAlthough lupus-like diseases can be caused by defects in many pathways of the immune system, studies suggest that one of the mechanisms for SLE is the defect in peripheral B- or T-cell tolerance as a result of chronic stimulation and activation of APCs. For example, chronic activation of Langerhans cells by ectopic CD40 ligand expression in the murine epidermis led to not only chronic skin inflammations but also systemic autoimmunity, including immune complex-mediated glomerular nephritis . ActivatHeat shock proteins have been implicated as endogenous activators for dendritic cells (DCs). Chronic expression of heat shock protein gp96 on cell surfaces induces significant DC activations and systemic-lupus-erythematosus- (SLE)-like phenotypes in mice . HoweverHSP90 has also been reported to play important roles in antigen presentation, activation of lymphocytes and macrophages, and activation and maturation of dendritic cells, indicating a potential treatment target for inflammatory diseases, including autoimmune diseases . This in"}
+{"text": "Chaos should occur often in gene regulatory networks (GRNs) which have been widely described by nonlinear coupled ordinary differential equations, if their dimensions are no less than 3. It is therefore puzzling that chaos has never been reported in GRNs in nature and is also extremely rare in models of GRNs. On the other hand, the topic of motifs has attracted great attention in studying biological networks, and network motifs are suggested to be elementary building blocks that carry out some key functions in the network. In this paper, chaotic motifs (subnetworks with chaos) in GRNs are systematically investigated. The conclusion is that: (i) chaos can only appear through competitions between different oscillatory modes with rivaling intensities. Conditions required for chaotic GRNs are found to be very strict, which make chaotic GRNs extremely rare. (ii) Chaotic motifs are explored as the simplest few-node structures capable of producing chaos, and serve as the intrinsic source of chaos of random few-node GRNs. Several optimal motifs causing chaos with atypically high probability are figured out. (iii) Moreover, we discovered that a number of special oscillators can never produce chaos. These structures bring some advantages on rhythmic functions and may help us understand the robustness of diverse biological rhythms. (iv) The methods of dominant phase-advanced driving (DPAD) and DPAD time fraction are proposed to quantitatively identify chaotic motifs and to explain the origin of chaotic behaviors in GRNs. In systems biology, gene regulatory networks (GRNs), a kind of biochemical regulatory networks, are widely described by coupled differential equations (ODEs) According to our understanding on the theory of nonlinear dynamical systems, strongly coupled high dimensional ODEs are very likely to show chaotic behaviors. Especially, chaos has been found in some chemical reactions both in experiments and simulations, such as the Peroxidase-Oxidase reaction Recently, the topic of motifs has attracted great interest in studying biological networks Dynamical motifs  have been presented as a new approach to the study of the dynamics in networks In this paper, we concentrate on chaotic behaviors of autonomous GRNs and address the above issues by answering the following questions: considering the crucial conditions for chaos in GRNs, why chaos is so rare; and are there some simple patterns namely chaotic motifs in complex GRNs serve as the basic building blocks for chaotic motions. We extensively search for chaos in low-dimensional GRNs  Some period-It can be inferred from We analyze the chaotic behaviors of some chaotic samples in Similar concept can be also defined for 4-node GRNs. In to chaos  and persto chaos . These oIt is of special importance to investigate what kinds of GRNs can serve as chaotic motifs. We define chaotic motifs as those irreducible chaotic subnetworks which have the fewest feedback loops and the least cross interactions  All these motifs have two feedback loops (the fewest feedback loops for chaotic motifs); (ii) At least one of the two loops is NFL. We exhaustively search all 3-node and 4-node GRNs with minimal (irreducible) interactions satisfying the above two conditions, and eventually find 19 distinct 3-node and 86 distinct 4-node candidates of chaotic motifs. With all the With further investigation on the network structures of the chaotic motifs in Extensive numerical simulations with these The reason for condition (iii) can be intuitively understood based on the the competition between different oscillatory modes. It is known that NFLs can support self-sustained oscillations while PFLs alone can not All 3-node and 4-node TLSs which satisfy conditions (i) and (ii) while violate condition (iii) are listed in The mechanism underlying condition (iv) is not yet clear. Competition between the two loops of chaotic motifs is essentially determined by the dynamics of the dual-input nodes  It is remarkable that all the chaotic motifs discovered in In Besides, it is also interesting to study some distinct differences between simple periodic oscillations and chaotic motions by applying the method of   in  in  and domiIn the above discussion, chaotic motifs are defined as the minimal and irreducible building blocks for chaotic motions in GRNs. By analyzing the structures of the chaotic GRNs in n\u22654.For any given GRN, we can find all the TLSs embedded in it. An example of such computation is shown in By the above definition, we can get different There are usually many feedback loops (far more than two loops) in chaotic GRNs, and the competitions among these loops to produce chaos turn out to be very complicated. The significant motifs effectively producing chaos shown in  are remaIt is remarkable that among all the TLSs with In conclusion, we studied chaotic behaviors in genomic regulatory systems, and found rich chaotic states in few-node GRNs and TLSs. The rareness of chaos in GRNs is due to the fact that chaos can appear only through competitions among different oscillatory modes under a number of strict conditions. Usually, GRNs do not construct effective oscillatory feedback loops, or build only single strong feedback loops dominating their dynamics Chaotic motifs are explored as the minimal and irreducible building blocks satisfying some conditions for chaotic motions (three necessary conditions (i)\u2212(iii) and sufficient conditions (i)\u2212(iv) on the structures of cross interactions) and serve as the intrinsic source of chaos of random few-node GRNs. Some motifs show atypically high probabilities of chaos. Methods of DPAD and Chaotic GRNs usually have very complex structures and contain various regulatory circuits much more than TLSs. It is our future work to recognize the few dominant oscillatory modes essentially determining the chaotic motions from probably large numbers of topological feedback loops in GRNs. DPAD and We find a large set of chaotic TLSs (chaotic motifs) and the topological conditions for chaos in GRNs by simulations. It is interesting whether these indeed make sense in real GRNs. For example, the P53 system, a crucial complex GRNs for regulating cell cycle and suppressing tumor, has many feedback loops. The core regulative structure of P53 system has been pointed out by a recent study We hope that the findings in the present work may give some impacts on the investigation of extremely rich behaviors of nonlinear dynamics and pattern formation in various biochemical systems, and contribute to exploring mystery biological functions and effects caused by chaotic regulatory networks.j activates gene i, In this paper, we discuss the chaotic dynamics of few-node autonomous GRNs by using a model of ODEs. The main conclusions of this article do not depend on the detail of the model, and can be extended to a class of models with monotonic regulatory functions. We use the following simplified genomic regulatory model where  isSearching for chaos: (i) In The idea to make the DPAD analysis is that any single node of a GRN  They have two feedback loops (the fewest feedback loops); (ii) At least one of the two loops is NFL. We exhaustively search all 3-node and 4-node two-loop structures satisfying the above two conditions. Figure S1The  Complete set of distinctive 3-node and 4-node TLSs satisfying conditions (i) and (ii), serve as possible candidates of chaotic motifs. All the 105 TLSs are listed (4-node (1)\u2212(86) and 3-node (87)\u2212(105)) with the corresponding indexes used in the text and other figures.(EPS)Click here for additional data file."}
+{"text": "Ohtahara syndrome is the earliest appearing age-related epileptic encephalopathy with seizures first presenting as early as the neonatal period and is diagnosed with a characteristic burst-suppression pattern on EEG   and Munc13, and indeed neurotransmitter release is completely abolished in STXBP1-deficient cells (Verhage et al., The formation of the SNARE fusion complex in vivo would cause very little side-effects. Another key consideration is the fact that the syntaxin1a-SNAP25 interaction also occurs in the functional SNARE fusion core complex and its structural elements appear largely indistinguishable in nature form its non-productive counterpart (Margittai et al., The findings of Ma et al. were most intriguing as it suggested a novel role for STXBP1 in the disassembly of non-productive SNARE complexes and the resulting generation of a productive STXBP1-syntaxin1a sub-complex starting point of SNARE fusion complex assembly. Indeed, due to their stability, the disassembly of the non-productive SNARE complexes may represent a slow rate-limiting step in the pathway toward productive fusion complex assembly. Thus in situations where the number of functional STXBP1 molecules is reduced, such as occurs in STXBP1 haploinsufficieny, progress through the neurotransmitter release pathway is likely to be severely compromised. It may be possible however that increasing the incidence of disassembled syntaxin1a monomers in the presynaptic plasma membrane would counterbalance situations where there is a reduced amount of STXBP1 molecules so that the balance of syntaxin1a-STXBP1 complex formation is restored (Figure Targeting protein-protein interfaces of multiprotein complexes has become a significant focus in drug discovery (Higueruelo et al., in vivo. Thus with the combination of clinical genetics, cell biology, and structural biology knowledge at hand, and the potential offered by PPI inhibitors in targeted drug design, we could be on the way to developing a targeted anticonvulsant therapy for the treatment of a particularly devastating class of epileptic disorder.Thus several examples of the successful development of alpha-helical PPI inhibitors have been previously described and the interested reader is referred to previous excellent reviews (Cummings and Hamilton, It is perhaps also noteworthy that in stxbp1-null mice, although neurotransmitter release was completely abolished, neural differentiation and brain assembly occurred normally. But apoptosis in mature neural cells then caused neurodegeneration throughout the brain resulting in death of the null-mice. This may be consistent with the observation that anatomical brain abnormalities can be observed in Ohtahara syndrome patients and less frequently in West syndrome patients (Barcia et al.,"}
+{"text": "The purpose of this paper is to show that graph theory provides a mathematical tool to develop theory-driven biomarkers of pro-cognitive drug effects, and also to discuss how these approaches can contribute to the understanding of the role of cholinergic and noradrenergic modulation in the human brain. Finally we discuss the \u201cglobal workspace\u201d theory as a theoretical framework of pro-cognitive drug effects and argue that pro-cognitive effects of cholinergic and noradrenergic drugs might be related to higher network integration.Previous studies document that cholinergic and noradrenergic drugs improve attention, memory and cognitive control in healthy subjects and patients with neuropsychiatric disorders. In humans neural mechanisms of cholinergic and noradrenergic modulation have mainly been analyzed by investigating drug-induced changes of task-related neural activity measured with functional magnetic resonance imaging (fMRI). Endogenous neural activity has often been neglected. Further, although drugs affect the coupling between neurons, only a few human studies have explicitly addressed how drugs modulate the functional connectome, i.e., the functional neural interactions within the brain. These studies have mainly focused on synchronization or correlation of brain activations. Recently, there are some drug studies using graph theory and other new mathematical approaches to model the brain as a complex network of interconnected processing nodes. Using such measures it is possible to detect not only focal, but also subtle, widely distributed drug effects on functional network topology. Most important, graph theoretical measures also quantify whether drug-induced changes in topology or network organization facilitate or hinder information processing. Several studies could show that functional brain integration is highly correlated with behavioral performance suggesting that cholinergic and noradrenergic drugs which improve measures of cognitive performance should increase functional  In the recent years there has been an intensive debate on how to take advantage of brain imaging techniques, in particular functional magnetic resonance imaging (fMRI) to investigate the role of neurotransmitter systems in the human brain. fMRI measurements basically capture blood oxygenation within brain regions via the so-called blood oxygen level dependent (BOLD) contrast which was shown to be related to the processing of neuronal activity within brain regions  x n correlation matrix is computed to estimate the adjacency between nodes. In many studies, the adjacency matrix is thresholded to exclude edges which reflect noise and to receive binary entries representing the presence or absence of an edge between two nodes.Characterize the network topology: Based on these binary adjacency matrices the network graphs are visualized and graph-theoretical measures which describe the topology of the brain network are computed and compared between different groups or conditions.The basic principles of graph theory have been described elsewhere  a modular or cliquish structure that consists of highly connected sub-networks and (2) small shortest-path-lengths with few edges between nodes (Watts and Strogatz, There is strong empirical evidence that variation in network integration and network efficiency correlates with cognitive performance. This correlation has been shown, for example, for higher IQ (Hampson et al., The reported empirical correlations between functional brain network topology and behavioral performance fit with contemporary network theories of information processing in the brain, like the \u201cbrainweb\u201d (Varela et al., Only a few studies have used complex network analyses to investigate drug effects. We will thus mention also studies outside the cholinergic and noradrenergic system to underline the feasibility of graph analytical approaches in understanding drug effects. Complex network analyses have been previously used to partition functional brain networks into communities of densely interconnected nodes after drug challenge (Schwarz et al., Even though different drugs or other experimental conditions might have similar effects on network topology on the global, whole brain level, the underlying mechanisms might be quite different. For example, Achard and Bullmore  showed tLong-lasting endogenous brain states interact with task-related processing (Li et al., specific and a task-unspecific effect on functional resting state topology. Within the placebo condition the performance of both tasks have similar effects on the following resting state periods. However, within the drug condition only the effect of task 1 on the following resting state topology is affected.To investigate drug effects on endogenous and task processing we suggest to measure both processes during different time periods (see Figure Functional connectivity analyses have to deal with indirect or mediated correlations: a correlation between the time series of brain regions X1 and X2 can be mediated by a second common source X3 without any direct correlation between X1 and X2 (Erhardt et al., In healthy individuals as well as in many patient groups the effects of pro-cognitive drugs have been described to be modest (Husain and Mehta, On behavioral level, there is the first evidence that long-term nicotine treatment improves cognitive performance in patients with mild cognitive impairment (Newhouse et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In Africa and western Eurasia, occurrences of burials and utilized ocher fragments during the late Middle and early Late Pleistocene are often considered evidence for the emergence of symbolically-mediated behavior. Perhaps less controversial for the study of human cognitive evolution are finds of marine shell beads and complex designs on organic and mineral artifacts in early modern human (EMH) assemblages conservatively dated to \u2248100\u201360 kilo-years (ka) ago. Here we show that, in France, Neanderthals used skeletal parts of large diurnal raptors presumably for symbolic purposes at Combe-Grenal in a layer dated to marine isotope stage (MIS) 5b (\u224890 ka) and at Les Fieux in stratigraphic units dated to the early/middle phase of MIS 3 (60\u201340 ka). The presence of similar objects in other Middle Paleolithic contexts in France and Italy suggest that raptors were used as means of symbolic expression by Neanderthals in these regions. Nassarius specimens) and fragments of ocher pigments in Israel, the Maghreb and South Africa indicate that late Middle and early Late Pleistocene EMHs were capable of symbolically-mediated behavior In recent years, several studies have argued that early (\u2248100\u201370 ka) occurrences of marine shell beads  and large-sized raptors . Although cutmarks were also observed on non-raptorial species , the over-representation of raptors in the cutmark sample and the anatomical distribution of these marks\u2014all are found on wing and foot bones\u2014suggest a symbolic, rather than alimentary, use of bird parts by Neanderthals In Europe and southwest Asia, marks of human activity are rare on bird bones before the Upper Paleolithic, which suggests that this class of prey species was seldom eaten or utilized All the unidentified and taxonomically identified bird specimens from Combe Grenal and Les Fieux were inspected for cutmarks using a stereomicroscope at low magnification. The cutmarks that we identified are unambiguous and fall well within the range of those documented in ungulate taxa Equus ferus caballus), roe deer (Capreolus capreolus) and red deer (Cervus elaphus) Combe Grenal is a Middle Paleolithic site in the Dordogne region of France with a remarkably long (13 m) sequence comprising sixty-five stratigraphic layers n\u200a=\u200a7) of bird bones, all but one assigned to small indeterminate species. The only taxonomically identified bird remain in this sample is a terminal phalanx of a golden eagle (Aquila chrysaetos). This well-preserved specimen bears on its proximo-dorsal side two incisions produced by a stone tool. These incisions closely coincide with the proximal margin of the keratinous sheath overlying the terminal phalanx of the digit, which suggests removal of the claw sheath , one from stratigraphic unit Jbase and the other from the possibly coeval unit I/J . Moreover, tool marks on ground-feeding (Phasianidae) and water-adapted  birds are poorly represented in the French-Italian cutmark sample (1/21 or 4.8%). These taxa, which became economically important during the Upper Paleolithic 2\u200a=\u200a28.1, p<.0001). Together, these patterns attest to a non-subsistence oriented use of diurnal raptors by Neanderthals during the Middle Paleolithic of France and Italy.The selective use of raptors by at least some Neandertal groups is confirmed by taxonomic data. According to ca. 20 ka) at Meged Rockshelter in Israel Because claws are inedible, the specimens presented here are not compatible with human consumption. This means that the tool-marked terminal phalanges found at Combe-Grenal, Les Fieux, Pech de l'Az\u00e9 IV, and Grotta di Fumane were likely used as tools and/or as items of symbolic expression. Although the sample size is small, the fact that all the terminal phalanges that show cutmarks are from eagles argues against their utilization in strictly non-symbolic contexts. This last pattern is noteworthy because eagles are among the rarest birds in the environment, a pattern explained by their high trophic position in the food web These results do not exclude occasional consumption by archaic humans of large diurnal raptors. Two previously unpublished Mousterian specimens  present cutmarks on meat-bearing portions . AlthougThese results cast additional light on Neandertal behavioral adaptation by suggesting the rise in this population of complex cognitive abilities similar to those of coeval EMH. Moreover, the use of raptor terminal phalanges during several temporal phases of the French Mousterian may indicate continuity in behavior in this region, although the possibility of simple convergence cannot be excluded. More research on bird remains will be required to fully assess the implications of these patterns."}
+{"text": "In primary health-care (PHC) settings, less than 10% of hazardous and harmful drinkers are identified, and less than 5% of those who could benefit are offered brief interventions (BIs). Delivery of BI adds up to 15 minutes to the primary consultation, constituting a significant barrier to implementation by PHC professionals. A review of trials of computer-based interventions (on- and off-line) for college drinkers found them to be more effective than no treatment and as effective as alternative treatment approaches. The recent large-scale trial of the online Down Your Drink (DYD) intervention found potentially significant reductions in alcohol consumption and risky drinking behavior, but there was evidence that users of the DYD website made only relatively limited use of it . Facilitated access by professionals in PHC settings could not only increase patient engagement but also address the \"know/do\u201d gap in PHC by removing the need for providers to deliver a time-consuming face-to-face intervention. The University College of London eHealth team has undertaken an exploratory qualitative study using interviews and participant observation of facilitated access to DYD at PHC practices in two London localities (Kingston and Islington) to assess acceptability and uptake. Preliminary results suggest good levels of acceptability and uptake of facilitated access to DYD. Findings are presented together with proposals for a noninferiority international randomized controlled trial to determine whether there is similarity in outcomes in patients identified as risky drinkers who receive facilitated access to an alcohol reduction website and those who receive conventional face-to-face BIs. Research is needed to determine whether PHC-based facilitated access to alcohol reduction websites can reduce the \"know/do\" gap in primary-care alcohol screening and intervention."}
+{"text": "The exercise pressor reflex (EPR) is a neural control mechanism responsible for the cardiovascular responses to exercise. As exercise is initiated, thin fiber muscle afferent nerves are activated by mechanical and metabolic stimuli arising in the contracting muscles. This leads to reflex increases in arterial blood pressure (BP) and heart rate primarily through activation of sympathetic nerve activity (SNA). Studies of humans and animals have indicated that the EPR is exaggerated in a number of cardiovascular diseases. For the last several years, studies have specifically employed a rodent model to examine the mechanisms at receptor and cellular levels by which responses of SNA and BP to static exercise are heightened in peripheral artery disease (PAD), one of the most common cardiovascular disorders. A rat model of this disease has well been established. Specifically, femoral artery occlusion is used to study intermittent claudication that is observed in human PAD. The receptors on thin fiber muscle afferents that are engaged in this disease include transient receptor potential vanilloid type 1 (TRPV1), purinergic P2X, and acid sensing ion channel (ASIC). The role played by nerve growth factor in regulating those sensory receptors in the processing of amplified EPR was also investigated. The purpose of this review is to focus on a theme namely that PAD accentuates autonomic reflex responses to exercise and further address regulatory mechanisms leading to abnormal sympathetic responsiveness. This review will present some of recent results in regard with several receptors in muscle sensory neurons in contribution to augmented autonomic reflex responses in PAD. Review of the findings from recent studies would lead to a better understanding in integrated processing of sympathetic nervous system in PAD. During exercise, sympathetic nervous activity (SNA) increases and this leads to rises in blood pressure (BP) and heart rate (HR), myocardial contractility, and peripheral vasoconstriction  in the hindlimb muscles and dorsal root ganglion (DRG) neurons of rats  protein expression of TRPV1, P2X3, and ASIC3 receptors in DRG and their responses with stimulation of those receptors are increased after femoral artery ligation and (2) NGF contributes to augmented reflex SNA and BP responses evoked by stimulation of metabolically sensitive muscle afferent nerves via enhancement of metabolic receptors expression such as ASIC3 in thin C-fiber afferent neurons.A number of studies have been performed to examine how the muscle reflex mediated-SNA is engaged via sensory receptors mechanism. This review will focus on the roles of TRPV1, P2X, and ASICs receptors on muscle sensory nerves in mediating the exaggerated sympathetic response in hindlimb muscle ischemia seen in PAD patients. Note that those receptors to be studied appear at the peripheral terminals and the cell body of the sensory afferent neurons-DRG Figure . Especiain vitro and in vivo  and inflammatory mediators themselves  have been identified as potential endogenous ligands for the C-fiber \u201ccapsaicin\u201d receptor. Hydrogen ions (H+) in general and lactic acid in particular have been shown to activate C-fiber afferents similar to the effect seen with capsaicin  to vanilloid receptors, a finding that was attributed to competition for the same binding site  in the muscle interstitium. It has been reported that TRPV1 and ASIC play a coordinated role in the processing of muscle sensory signals  contributes to regulation of discharges of vagal lung thin afferent fiber nerves  receptors are engaged in processing chronic ischemia of the hindlimb muscles , depend on GDNF for survival during postnatal development, and are relatively \u201cpeptide poor\u201d but express a surface carbohydrate group that binds IB4  are distinct as IB4-positive, and -negative DRG neurons (Xing et al., 4-negative DRG neurons but not in IB4-positive DRG neurons. These findings suggest that NGF plays a role in augmented TRPV1 responses in the processing of muscle ischemia or vascular insufficiency induced by the femoral artery occlusion (Xing et al., The data show that arterial occlusion augments responses with activation of metabolite sensitive TRPV1 receptors in IBFurthermore, infusion of NGF into the hindlimb of healthy rats through a micro-osmotic pump induces 1.39-fold increases in P2X3 protein of the DRGs of the infused leg as compared to the control leg (Liu et al., Finally, the role of NGF in regulating the enhanced sympathetic responsiveness during stimulation of primary muscle afferent nerves was examined as the blood flow directed to hindlimb muscles is insufficient following femoral artery ligation. In the first set of experiments, NGF-Ab was previously injected into the hindlimb muscles to block effects of NGF that were induced by femoral occlusion. Then, mechano- and/or metabo-sensitive afferents nerves were activated by three interventions, namely muscle contraction, tendon stretch, and stimulation of ASICs using lactic acid. The data demonstrate that NGF neutralization significantly attenuates femoral occlusion-augmented reflex sympathetic and BP responses evoked by static contraction and lactic acid, but not by muscle stretch. Given that administration of NGF-Ab into the hindlimb muscles significantly attenuates occlusion-enhanced protein levels of ASIC3 in DRG tissues, these results suggest that NGF that is increased in sensory nerves of occluded limbs contributes to augmented reflex SNA and BP responses to stimulation of chemically, but not mechanically sensitive muscle afferent nerves. Also, this study has examined whether NGF is engaged in the role of sensory nerves\u2019 ASIC3 in augmented responses evoked by the hindlimb vascular insufficiency. In the second set of experiments, effects of NGF on expression of ASIC3 in DRG neurons that project thin C-fiber and A-fiber were examined. NGF infused into the hindlimb muscles significantly increases the protein levels of ASIC3 in DRG and selectively increase expression of ASIC3 in DRG neurons that project C-fiber afferents. Thus, these data support the hypothesis that NGF plays a role in exaggeration of the muscle metaboreflex via enhancement of ASIC3 expression in thin C-fiber afferent neurons.Peripheral artery disease affects life styles in 20% of adults who are older than 65\u2009years. The narrowing of blood vessels of the lower limbs, mainly due to atherosclerotic vascular disease, is a main cause of PAD. Intermittent claudication is the most common symptom of this disease and it regularly occurs during exercise/physical activity but is relieved promptly by rest. It is well known that the sympathetic nerve system plays an important role in regulating blood flow directed to skeletal muscle tissues during exercise. Thus, the goal of those studies was to examine the role of metabolite sensitive receptors on muscle afferent neurons in the responses of SNA after limiting blood flow to hindlimb muscle, as seen in PAD. Currently, several studies using a rat model of femoral artery ligation show that sympathetic responses of the EPR engagement are exaggerated as seen in PAD patients. Findings of the completed studies also suggest that enhanced protein levels of TRPV1, P2X3, and ASIC3 in muscle afferent nerves and amplified responses of those receptors contributes to the exaggerated reflex sympathetic and pressor responses to their individual receptor stimulus (Figure The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The United States has the world's highest prison population, and an estimated one in seven HIV-positive persons in the USA passes through a correctional facility annually. Given this, it is critical to develop innovative and effective approaches to support HIV treatment and retention in care among HIV-positive individuals involved in the criminal justice (CJ) system. Information and communication technologies (ICTs), including mobile health  interventions, may offer one component of a successful strategy for linkage/retention in care. We describe CARE+ Corrections, a randomized controlled trial (RCT) study now underway in Washington, that will evaluate the combined effect of computerized motivational interview counseling and postrelease short message service (SMS) text message reminders to increase antiretroviral therapy (ART) adherence and linkage and retention in care among HIV-infected persons involved in the criminal justice system. In this report, we describe the development of this ICT/mHealth intervention, outline the study procedures used to evaluate this intervention, and summarize the implications for the mHealth knowledge base. The criminal justice system in the USA comprised prisons, jails, and community supervision programs including probation and parole and incarcerates more persons than any other nation in the world which disproportionately affects persons of color, the economically disadvantaged, and those who suffer from mental illness , 2. In 2It has been estimated that one in seven HIV-infected persons in the USA passes through correctional facilities in a given year , and forThe Washington, DC Department of Corrections (DOC) Central Detention Facility (CDF) has conducted routine opt-out HIV testing since 2006. The HIV prevalence among the Washington, DC DOC population has been estimated to be between 5-6% and among those completing HIV testing upon entrance, close to 1% test positive and among those, 60% represent new HIV diagnoses . These dWe took a user-centered design  approachn = 12) and Washington DC (n = 12) among HIV positive persons with a history of recent incarceration. Participants were asked about their perceptions of the acceptability, usability, and ideas for best practices regarding ICT/mHealth tools including (1) the computer-based counseling intervention; (2) cell phone technology; and (3) text messaging. The returning citizens in this qualitative study reported positive experiences when testing an older version of the CARE+ computerized counseling platform and provided favorable feedback regarding the use of technology-based tools to facilitate linkage to HIV care in the community and adherence to HV medications. Participants with little to no experience using a computer reported feeling comfortable using the tool and felt that the tool would provide more confidentiality than a live counselor. In addition, participants identified additional content that would be relevant for the criminal justice population, including substance use and housing support. To inform the development of the CARE+ corrections intervention, we conducted formative research with individuals released from either jail or prison  in the District of Columbia and Rhode Island to determine perceptions of using technology-based tools designed to facilitate linkage to community-based care and viral suppression for HIV-positive jail detainees on ART being released to the community. A complete description of this formative research is reported separately , but briTo develop the SMS text message component of the intervention, we reviewed published and unpublished mHealth resources to develop a library of relevant text messages  a counseling session delivered on the CARE platform prior to jail release or soon after release in the community and (2) the SMS text messaging intervention delivered in the community after release. The computerized counseling session on the CARE platform will consist of a one-time, interactive session delivered on a standalone basis on a tablet computer with a touch screen. The session is audio-narrated and 30\u201340 minutes in length during which participants provide responses to questions about demographic characteristics, sexual risk behaviors and attitudes, substance use, mental health, and HIV treatment and adherence. Based on this assessment, the tool provides tailored feedback messages, displays skill-building videos  for participants to view to support the delivered feedback, and allows users to make a postrelease health promotion plan to support ART adherence and linkage to community care. Finally, a printout provides a referral list that is customized to meet their identified needs . The couThe cell phone text messaging component of the intervention will be delivered in the community after release from jail. Participants will receive a study cell phone or use an existing personal cell phone for delivery of the text messages to support the participant's linkage plan. Text messages are divided into four distinct categories addressing specific issues related to linkage to care: (1) appointment reminders; (2) medication adherence, (3) HIV secondary prevention, and (4) barriers to care . ParticiThe effectiveness of the combined intervention with respect to improving linkage to community HIV care after release and maintaining viral suppression on ART after jail release is being evaluated in a randomized controlled trial among 320 HIV-positive persons in Washington, DC. One-half of the study participants will be randomized to the combined CARE+ Corrections intervention. To achieve a level of intervention equity among study participants, those in the control arm will also view an educational video related to the prevention of overdose following release. All study participants will also receive standard discharge planning services. We will follow all participants for 24 weeks after release for those recruited in the DOC or from the time of study entry for those recruited from the community during which we will conduct follow-up assessments at 12-week and 24-week appointments to determine if linkage to care and adherence to HIV medications were higher in the intervention arm. Monthly check-in phone calls and/or in-person meetings will be used to update locator information and to adjust the content and frequency of text messaging. The main outcome of the trial is the overall proportion of participants in each arm with suppressed HIV viral load; secondary outcomes include attendance at community-based HIV care appointments and self-reported ART adherence. The cost effectiveness of the intervention to support linkage and engagement in care also will be assessed. Using the outcomes as observed within the trial, these analyses will examine the costs per outcome measure from both the correctional system and the community or societal perspective. Because the proposed trial is limited in the duration of observation yet induced benefits or costs may extend beyond the time horizon of the study; we will project future implications of the observed trial outcomes on health and on costs using Markov or simulation models.The study protocol was approved by the George Washington University IRB (primary), the Miriam Hospital IRB, and the Office of Human Subjects Research Protection (OHRP).We will test whether our combined ICT intervention consisting of an interactive tablet-based counseling tool delivered in jail before release or immediately after release combined with an SMS text messaging intervention delivered in the community can support this highly vulnerable group of returning citizens who are living with HIV. These returning citizens often are struggling with active substance use and facing challenges related to poverty, unemployment, and unstable housing all of which create barriers to being retained in continuous HIV care . We hypo"}
+{"text": "Organized infection control (IC) programs have been successful in reducing the hospital-acquired infections (HAI). However, in India well organized IC programmes are confined to few corporate hospitals in urban areas. Rural community hospitals, although contributing significantly to the health care system, have none or inadequate IC programmes.We here report the successful implementation of infection control program to a rural hospital for the first time in India.As a part of novel imitative to provide IC program to a 50 bed rural community hospital, infectious disease physician from the urban hospital visited the hospital periodically & through tele-conferences assessed baseline status & implemented the infection control program.At baseline (October 2012) there was only two member infection control committee on paper without regular meetings, hand hygiene faculties were at the end of each ward with soap and water facility and compliance rate of 10%, no education program regarding infection control & prevention was conducted, and no HAI surveillance was done and finally no antibiotic stewardship program was present in the hospital. In the next 6 months (March 2013) with the infection control implementation the IC team expanded to include nurse, infectious disease physician and housekeeping staff with regular monthly meetings. Alcohol hand rub was introduced at each bed side of patient with subsequent improvement in the hand hygiene compliance to 50%. Regular infection control education to both physicians and staff were started in person and through tele-medicine. HAI surveillance for catheter associated urinary tract infection and surgical site infection was initiated. Antibiotic stewardship in the form of removing irrational combinations from the pharmacy and single dose surgical peri-operative antibiotic prophylaxis was initiated.With trained personnel & technology the Implementation of infection control program to rural community hospital is reality in India. The IC program implementation improves the IC knowledge, hand hygiene compliance and antibiotic prescriptions in the rural settings. In the future this model should be replicated to other smaller rural hospitals in India.None declared"}
+{"text": "It has been 50 years since Anfinsen first showed that the native structure of protein molecules is determined solely by their amino acid sequence, with the folded state representing a unique and kinetically accessible minimum of the free energy . This fiBMC Biology in 2007 is an extension of the TASSER algorithm for iterative structure assembly and refinement of protein molecules [The I-TASSER (Iterative Threading ASSEmbly Refinement) method that we published in olecules . The ideolecules , which molecules ) is showolecules ). Nevertolecules .ab initio protein folding [The idea of model assembly iterations driven by structure alignments has recently found promising uses in both atomic-level structure refinement and  folding ,8. Start folding , a metho folding , where aab initio folding as the probe to detect new templates. Since the probe models were constructed from scratch, any reasonable match of the ab initio models with real experimental proteins is significant and often indicates correct folding template identifications. Figure th CASP  experiment, a community-wide experiment designed to assess computational methods with all modeling predictions generated before the experimental structures are released [ab initio protein folding algorithm that assembles structural models from random conformations as guided by a composite physics- and knowledge-based force field [As the success of structure assembly iterations relies on the new structural information introduced in the simulations, more efficient structural improvements were achieved when using the models built by released . In thesce field . Based oab initio modeling in both fold-recognition and structure refinement procedures, the development of efficient ab initio folding algorithms will remain a major theme in the field and should have important impacts on all aspects of protein structure predictions.The major goal of protein structure prediction is to help understand the biological roles of protein molecules in living cells. Since the launch, at the beginning of this century, of structural genomics projects that aim to solve experimentally the structure of a set of proteins covering all representative structural types in nature , the genhttp://www.biomedcentral.com/bmcbiol/series/tenthanniversary.This article is part of the BMC Biology tenth anniversary series. Other articles in this series can be found at"}
+{"text": "A 2011 report from the National Lung Screening Trial indicates that three annual low-dose computed tomography (LDCT) screenings for lung cancer reduced lung cancer mortality by 20% compared to chest X-ray among older individuals at high risk for lung cancer. Discussion has shifted from clinical proof to financial feasibility. The goal of this study was to determine whether LDCT screening for lung cancer in a commercially-insured population (aged 50\u201364) at high risk for lung cancer is cost-effective and to quantify the additional benefits of incorporating smoking cessation interventions in a lung cancer screening program.The current study builds upon a previous simulation model to estimate the cost-utility of annual, repeated LDCT screenings over 15 years in a high risk hypothetical cohort of 18 million adults between age 50 and 64 with 30+ pack-years of smoking history. In the base case, the lung cancer screening intervention cost $27.8 billion over 15 years and yielded 985,284 quality-adjusted life years (QALYs) gained for a cost-utility ratio of $28,240 per QALY gained. Adding smoking cessation to these annual screenings resulted in increases in both the costs and QALYs saved, reflected in cost-utility ratios ranging from $16,198 per QALY gained to $23,185 per QALY gained. Annual LDCT lung cancer screening in this high risk population remained cost-effective across all sensitivity analyses.The findings of this study indicate that repeat annual lung cancer screening in a high risk cohort of adults aged 50\u201364 is highly cost-effective. Offering smoking cessation interventions with the annual screening program improved the cost-effectiveness of lung cancer screening between 20% and 45%. The cost-utility ratios estimated in this study were in line with other accepted cancer screening interventions and support inclusion of annual LDCT screening for lung cancer in a high risk population in clinical recommendations. Despite reductions in cigarette consumption and adult smoking prevalence in the years following publication of the 1964 Surgeon General's Report This study is the third in a series that applied actuarial mortality and payer cost analytics to the feasibility of early lung cancer detection and treatment. The first study explored the huge mortality differences between early stage and late stage lung cancer that emerge from national cancer registry data Since our first study was published, a large randomized controlled trial, the National Lung Screening Trial (NLST), was stopped early when data showed a 20% reduction in lung cancer mortality in the LDCT screening arm compared to the chest x-ray (CXR) arm after a baseline and two follow-up scans, with no significant adverse effects of the screening program Despite the large population-based studies and randomized controlled trials of LDCT screening for lung cancer, there continues to be debate on recommending screening at the population level. A 2012 systematic review of LDCT screening for lung cancer by Bach et al. concluded that screening may benefit individuals at high risk of lung cancer, though the bulk of the conclusions focused on the potential harms of screening due to follow-up investigations, biopsies, and surgical procedures in patients with benign lesions Given the tremendous potential for improved diagnosis, treatment and survival from lung cancer screening, several studies have been conducted to examine the cost-effectiveness of these programs. Two studies from 2001 simulated the effect of LDCT compared to no screening in a hypothetical cohort aged 60\u201374 at high risk of lung cancer over a five-year time horizon; both used data from the Early Lung Cancer Action Project (ELCAP) cohort study An important distinction in comparing lung cancer screening to other cancer screening is the concentration of lung cancer risk among former or current smokers. Among adults with lung cancer, 21% report being current smokers, 61% former smokers and 18% never smokers The current study builds upon our two previous studies Details on the previous model have been published elsewhere The current study expands the previous model by estimating the QALYs saved by lung cancer screening and treatment, incorporating the impact of smoking cessation interventions on costs, health care costs saved, and QALYs saved, and addressing the impact of lung cancer screening on economic output. As with the earlier model, a 2-year lead time was assumed for all screening-detected cancer and we used the New York ELCAP data to inform our base case. In this model, we estimate the incremental effect of screening or screening plus cessation treatment over no screening. We used a previous published The previous model used data from the New York ELCAP for probability of detecting lung cancers at Stages A, B, and C using LDCT The hypothetical cohort in this study was comprised of individuals with a 30 pack-year history of smoking, and the probability of survival for those without lung cancer accounted for gender, age and smoking status (current or former), which were estimated using results from a 1997 paper by Schoenbaum Quality adjusted life years were estimated by multiplying the probability that an individual survives to each future year by a utility weight related to age, sex and stage of lung cancer. Utility weights for the general population of males and females aged 50\u201359 and 60\u201369 were obtained from a study using the SF-6D and standard gamble technique in a nationally-representative sample Treating Tobacco Use and DependenceIn the previous model Input parameters on the costs and effectiveness of the smoking cessation interventions are presented in We conducted a range of sensitivity analyses to the test the robustness of our findings, including using NLST rather than ELCAP data on stage-shift as a result of LDCT screening for lung cancer, varying the utility weights used in estimating QALYs by ten percent, and increasing the cost of screening to 125% and 150%. We also present results for four types of smoking cessation interventions in two categories: light and intensive. Further, we examine the inclusion of health care costs incurred among quitters in the cost of the cessation program, as well as a ten percent change in the participation and quit rates of each program and the ex-smoker mortality rate. Because the medical cost component of the CPI tends to understate medical inflation we produced a sensitivity scenario by trending dollar values of other preventive health interventions to 2012 USD at twice the medical CPI.Assuming annual LDCT screenings are given over 15 years to a cohort of high risk adults aged 50\u201364, the projected cost of lung cancer screening and treatment in the base case averaged $1.8 billion per year  and yielded 985,284 QALYs over the 15-year period. The resulting cost-utility ratio comparing 100% participation in repeat annual LDCT screenings to no screening was $28,240 per QALY gained . The ligSensitivity analyses examined the robustness of the results to variations in model parameters. We compared the cost per QALY saved of the current LDCT screening protocol to studies of the cost-effectiveness of lung cancer screening and other preventive health interventions, including colon cancer screening By reducing deaths of individuals during productive years, lung cancer screening is also likely to increase economic output. To provide insight into this issue, we estimated the incremental annual wages due to screening, and the resulting taxes and total economic impact associated with those wages for people under age 65, assuming the current portion of workers by age and gender Building on our two other studies The range of costs per QALY saved in our study  is approximately 50% lower than some previous estimates Even at older ages, the risk of lung cancer mortality among current smokers is substantially reduced by smoking cessation Our findings emphasize the unprecedented public health potential of lung cancer screening as a medical home for smokers and ex-smokers to motivate cessation and other health behavior change. For example, the addition of coronary artery calcium scores (CACS) measured by LDCT scan to an existing risk prediction model has been shown to improve risk classifications for coronary heart disease Our model likely overestimates the cost per QALY saved by lung cancer screening in several ways. First, we used 2012 cost levels throughout our work. Our cost projection is a retrospective model, in that we examine results for 2012 if screening had started 15 years ago. Since medical inflation has been much higher than either general inflation or risk free interest  rates, had we applied a present value calculation to lower historical costs, our cost per QALY saved would be significantly lower. From a forecast perspective, our assumption is consistent with the view that healthcare spending maintains its current, high portion of GDP and does not further increase or decline. Similarly, estimates of the QALYs gained per quit in our model used a 3% discount rate Our sensitivity analyses included increasing the price of lung cancer screening by 50% of our estimated cost and using stage-shift data from both the I-ELCAP and NLST studies. Lung cancer screening remained cost-effective in all scenarios. NLST shows a smaller stage shift than the New York ELCAP figures we utilized in our base case and resulted in a lower mortality reduction. The smaller stage shift can be understood by the limits of NLST\u2014only three annual screens and inclusion of older, four-slice LDCT technology. By default, NLST used community standard practice and not a protocol for follow-up (as used in the I-ELCAP), which may account for the lower observed mortality reduction. However, both I-ELCAP and NLST are voluntary programs and could reflect unknown biases. If future recommendations for lung cancer screening would include a protocol for follow-up, the base case of our cost-utility analysis using New York-ELCAP data may better reflect the effectiveness and cost-effectiveness of LDCT screening at the broader population level.Results from our simulation model indicate that repeat annual LDCT lung cancer screening for adults aged 50\u201364 with 30+ pack-years of smoking history is highly cost-effective from a commercial payer perspective. Lung cancer screening becomes even more cost-effective when linked with smoking cessation interventions and this study presents cost-utility ratios across a range of programs consisting of a single counseling session up to a full course of combined behavioral and pharmacological treatment. Annual LDCT lung cancer screening in this high risk population remained cost-effective across all sensitivity analyses and we would expect this screening to become more favorable over time with increased identification of early stage cancers in the routine screening pool. The cost-utility ratios estimated in this study were in line with other cancer screening interventions endorsed by the USPSTF and support inclusion of annual LDCT screening for lung cancer in future USPSTF recommendations.File S1(DOCX)Click here for additional data file."}
+{"text": "Turning Turing's logic on its head, we used widespread letter-based Turing Tests found on the internet (CAPTCHAs) to shed light on human cognition. We examined the basis of the human ability to solve CAPTCHAs, where machines fail. We asked whether this is due to our use of slow-acting inferential processes that would not be available to machines, or whether fast-acting automatic orthographic processing in humans has superior robustness to shape variations. A masked priming lexical decision experiment revealed efficient processing of CAPTCHA words in conditions that rule out the use of slow inferential processing. This shows that the human superiority in solving CAPTCHAs builds on a high degree of invariance to location and continuous transforms, which is achieved during the very early stages of visual word recognition in skilled readers. While browsing the Internet one is regularly annoyed by requests to demonstrate that one is not a robot. The most familiar of these CAPTCHAs - Completely Automated Public Turing test to tell Computers and Humans Apart CAPTCHAs are telling us something about the way humans represent and process strings of letters - what we will call orthographic processing Human superiority in solving CAPTCHAs could be due to at least two factors. One, favoured by our subjective experience, could involve slow inferential processes to make explicit guesses on letter identities in the face of ambiguous bottom-up information, perhaps not unlike letter-by-letter reading. Another possibility however is that our extensive reading experience, often in difficult conditions , could have helped us develop an automatic system for orthographic processing that is highly tolerant to noise and shape variations in the input. Here we eliminated the possible use of slow inferential processes by presenting CAPTCHAs as prime stimuli in a masked priming experiment. Prime stimuli are presented very briefly and immediately before a clearly visible target stimulus  that participants must classify as being a word or not 2\u00d72 repeated-measures ANOVAs with relatedness  and prime type  as factors were run separately on mean correct RTs and error rates, for word and nonword targets . An inverse transformation was applied to the RT data to reduce the influence of skewness and outliers Our results show that without rising to the level of normal printed words, word CAPTCHAs are remarkably efficient primes that generate a quite large and significant facilitation both in reaction times and in error rates see . Given tThe flip-side of these findings is to hint at what might be valuable strategies for automatic text processing algorithms and cognitive models of reading alike, suggesting that a neuromorphic system should not emphasize slow computations (for instance direct searches in the lexicon) but rather might want to be primarily constrained by the very rapid resolution of subsets of letters under a variety of continuous transforms and rotations. This could possibly be achieved by combining both the letter-based and the bigram-pruning strategies proposed in 24 participants recruited from the undergraduate and postgraduate populations at Aix-Marseille University took part in the study. All were native French speakers and reported normal or corrected-to-normal vision.A repeated-measures design was employed in which the three independent variables were Lexicality (words and nonwords), Prime Type (CAPTCHA and printed) and Relatedness (related and unrelated). Mean response time to correct responses and response accuracy in the lexical decision task were measured. Prime stimuli comprised 160 CAPTCHA and their equivalent 160 printed letter strings, half of which spelled familiar French words (5\u201310 letters long) and the other half readable nonwords (5\u20139 letters long). First, CAPTCHA stimuli were drawn from the reCAPTCHA website A masked priming lexical decision task was used. Participants were run individually in a sound-attenuated room. Each participant sat 82 cm in front of a 20\u2033 monitor. The trial sequence of the experiment is illustrated in"}
+{"text": "The intestinal microbiota plays an important role in immune development and homeostasis. A disturbed microbiota during early infancy is associated with an increased risk of developing inflammatory and allergic diseases later in life. The mechanisms underlying these effects are poorly understood but are likely to involve alterations in microbial production of fermentation-derived metabolites, which have potent immune modulating properties and are required for maintenance of healthy mucosal immune responses. Probiotics are beneficial bacteria that have the capacity to alter the composition of bacterial species in the intestine that can in turn influence the production of fermentation-derived metabolites. Principal among these metabolites are the short-chain fatty acids butyrate and acetate that have potent anti-inflammatory activities important in regulating immune function at the intestinal mucosal surface. Therefore strategies aimed at restoring the microbiota profile may be effective in the prevention or treatment of allergic and inflammatory diseases.Probiotic bacteria have diverse effects including altering microbiota composition, regulating epithelial cell barrier function and modulating of immune responses. The precise molecular mechanisms mediating these probiotic effects are not well understood. Short-chain fatty acids such as butyrate are a class of histone deacetylase inhibitors important in the epigenetic control of host cell responses. It is hypothesized that the biological function of probiotics may be a result of epigenetic modifications that may explain the wide range of effects observed. Studies delineating the effects of probiotics on short-chain fatty acid production and the epigenetic actions of short-chain fatty acids will assist in understanding the association between microbiota and allergic or autoimmune disorders.in vivo conditions would offer the ideal conditions to examine the microbiological, immunological and epigenetic mechanisms of action. Advances in epigenetic technology now allow investigators to better understand the complex biological properties of probiotics and their metabolites.We propose that treatment with specific probiotic bacteria under Determining the precise mechanisms of probiotic action will lead to more specific and efficacious therapeutic strategies in the prevention or treatment of chronic inflammatory conditions. Bifidobacteria species and increased numbers of pathogenic Clostridia and Staphylococci compared to non-allergic infants [The intestinal microbiota plays a critical role in the establishment and maintenance of healthy immune responses. Delayed colonisation of the infant gut with commensal bacteria or alterations in the microbiota profile are suggested to be strong risk factors for the development of immune-mediated chronic disorders such as allergic and autoimmune diseases. Mice raised in a germ- free environment fail to develop oral tolerance and have persistent Th2-dependent immune responses . This im infants . Moreovein vitro or in vivo effects that are relevant to the clinical context they will be applied to. Lactobacillus and Bifidobacteria species have been studied in greatest detail and are the most commonly used in research studies [Lactobacillus rhamnosus GG (LGG) was found to reduce the development of atopic dermatitis in high-risk infants by 2 years of age [Probiotics mediate their activity by a variety of mechanisms including altering the microbiota composition, maintaining epithelial barrier function and modulating mucosal and systemic immune responses . Importa studies . In part studies -9. Prenas of age . Howevers of age .L. casei and L. rhamnosus revealed upregulation of several key mucosal immune response genes encoding IFN-\u03b3 production and TLR3/9 expression while L. acidophilus was found to upregulate immunoregulatory genes including IL-17B, IRAK2 as well as several chemokines and cellular adhesion molecules in duodenal biopsies using a novel transcriptome analysis [Treatment with probiotics induces a variety of immunological effects on epithelial function, dendritic cells, Treg and T-helper responses. Examples of these effects include 1) enhanced epithelial barrier function via interactions with Toll-like receptors (TLRs) and modulation of epithelial cell signal transduction pathways that regulate cytokine production to promote anti-inflammatory responses -13; 2) ianalysis .An important role for commensal (including probiotic) bacteria is the fermentation of dietary compounds leading to production of short-chain fatty acid (SCFA) metabolites. Several SCFAs are known to be produced such as butyrate, acetate and propionate. Levels of SCFA have been demonstrated to be reduced in inflammatory diseases, possibly as a result of an altered gut microbiota. These SCFAs have an important protective function in the intestine and exert anti-inflammatory effects in a number of animal models. Intestinal epithelial cells of germ-free mice had reduced SCFA receptor expression which was normalized following reconstitution with normal gut bacteria . The SCF+ coupled monocarboxylate transporter Slc5a8 [Probiotic metabolites such as butyrate are therefore an important class of therapeutic compounds. These SCFAs are also a well-known class of epigenetic drugs known as histone deacetylase inhibitors (HDACi) that have a central role as anti-cancer agents with strong anti-proliferative effects on tumour cells ,29. Thisr Slc5a8 .Faecalibacterium prausnitzii, is a novel probiotic used for the treatment of inflammatory bowel disease (IBD) [F. prausnitzii led to a shift in microbiota composition, reduced inflammatory cytokine levels such as IL-2, increased the anti-inflammatory cytokine IL-10 and reduced colitis and mortality, suggesting that butyrate and other related metabolites may be critical in host protection [Propionibacterium freudenreichii, which was found to shift the extracellular pH from 7.5 to 5.5 in the colon and was related to levels of the SCFAs, acetate and propionate [Given the role of bacterial species in the production of SCFAs, probiotics may be considered as an alternative approach for the prevention or treatment of chronic inflammatory diseases. Evidence in support of this effect by probiotics is limited. The butyric acid-producing anaerobic bacterium, se (IBD) . The levotection . The antopionate . It is pProbiotics mediate pleiotropic effects however the precise mechanism(s) have yet to be fully elucidated. The 'epigenome targeting' hypothesis contends that the activity of probiotics and their metabolites are associated with chromatin remodeling as a function of intrinsic histone deacetylase inhibition. Modulation of gene transcription is an essential component of many biological processes. The onset of pathological conditions such as cancer and chronic inflammation often result from aberrant gene transcription. Integral to this process are epigenetic factors involving two critical enzymes, histone acetylases (HATs) and histone deacetylases (HDACs). These produce post-translational modifications of histone proteins and result in changes to chromatin structure and function ,37. WhilThe recent advances in understanding epigenetic processes in the maintenance of health allows us to investigate more precisely the mechanisms of action of novel therapies such as probiotics in defined clinical contexts. Critical transcriptional regulators of inflammation such as NF-\u03baB and Foxp3 can now be studied closely to determine the impact of dietary/probiotic supplementation. The evidence presented above and our hypothesis provide for the first time a direct link between the anti-inflammatory and immunoregulatory properties observed for probiotics in terms of Treg induction, DC maturation and cytokine/chemokine secretion and the molecular events involved at the epigenetic level. We believe that the biological activity of probiotics are mediated through complex epigenetic changes that regulate the activation status of key transcription factors involved in host immunity.in vivo system such as the mouse, or preferably in humans using a randomized, double-blind, placebo-controlled study design. Probiotic bacteria or placebo should be given prenatally and/or post-natally to infants at high-risk of developing allergic disease. Clinical effects of the probiotic should be assessed by doctor-diagnosed allergy using defined criteria, skin prick test positivity, and SCORAD analysis of eczema severity. Immunological outcomes can be assessed by enumerating Treg and DC populations and the profile of cytokine secretion by cultured cord and peripheral blood mononuclear cells in response to SCFA metabolites. Levels of SCFA can be measured in stool or blood. Correlation between immunological and epigenetic changes could be assessed in the first instance by simple immunoblot analysis for histone hyperacetylation as well as real-time PCR for specific immune gene regulation in relevant cells. Genome-wide sequencing techniques such as mRNA-Seq (gene expression) and ChIP-Seq (specific epigenetic modifications including acetylation) will further our understanding of the critical biological functions of probiotics.Testing this hypothesis should be undertaken in an Interest in probiotics has intensified in recent years due to their potential health benefits and as treatments for a wide range of inflammatory and immunological conditions. Probiotic bacteria have been demonstrated to modulate a variety of microbiological and immunological parameters although the precise mechanisms for these effects are yet to be fully elucidated. The ability of probiotics to alter intestinal microbiota composition and diversity suggest an important role for SCFAs such as butyrate. The demonstration of beneficial probiotic effects through as yet unidentified epigenetic mechanisms will have significant implications in the prevention and/or treatment of allergy and other chronic inflammatory diseases.PVL, SSW and TCK declare that they have no competing interests. MLKT is a member of the medical advisory board of Nestle Nutrition Institute and has delivered speaker presentations for Wyeth/Pfizer.PVL conceived and wrote the paper, SSW contributed to the manuscript, MLKT and TCK contributed to and critically appraised the manuscript. All authors read and approved the final manuscript."}
+{"text": "The objectives of this study were to examine relationships between neighbourhood-level and individual-level characteristics and physical activity in deprived London neighbourhoods.In 40 of the most deprived neighbourhoods in London (ranked in top 11% in London by Index of Multiple Deprivation) a cross-sectional survey (n\u200a=\u200a4107 adults aged >\u200a=\u200a16 years), neighbourhood audit tool, GIS measures and routine data measured neighbourhood and individual-level characteristics.The binary outcome was meeting the minimum recommended  5\u00d730 mins moderate physical activity per week. Multilevel modelling was used to examine associations between physical activity and individual and neighbourhood-level characteristics.Respondents living more than 300 m away from accessible greenspace had lower odds of achieving recommended physical activity levels than those who lived within 300 m; from 301\u2013600 m  and from 601\u2013900 m . There was substantial residual between-neighbourhood variance in physical activity (median odds ratio\u200a=\u200a1.7). Other objectively measured neighbourhood-level characteristics were not associated with physical activity levels.Distance to nearest greenspace is associated with meeting recommended physical activity levels in deprived London neighbourhoods. Despite residual variance in physical activity levels between neighbourhoods, we found little evidence for the influence of other measured neighbourhood-level characteristics. Regular physical activity is effective in reducing the risk of premature death and in preventing the development of many chronic diseases The majority of research on factors associated with physical activity has focused on individual-level factors The vast majority of this research has been published outside the UK  and there is evidence to suggest that the findings of these studies may not be generalizable between countries Research question 1: Are individual and neighbourhood-level characteristics of deprived neighbourhoods in London associated with individual-level physical activity?Research Question 2: How much variation in physical activity levels is there between neighbourhoods?This study utilises an observational design based on a cross-sectional survey. The survey was conducted at baseline within the Well London programme cluster randomised controlled trial, which includes twenty pairs of control and intervention neighbourhoods across twenty boroughs The setting for this study was 40 of the most deprived neighbourhoods in London (2 in each of 20 London boroughs). Neighbourhoods were defined as census lower super-output areas (LSOA) selected for inclusion in the Well London trial because they are ranked within the top 11% for deprivation in London as measured by the English indices of deprivation Interviewer-administered surveys were conducted in 2008 by trained fieldworkers in households selected at random from the Post Office Address Files for each of the 40 neighbourhoods. At addresses that responded to visits from fieldworkers, every eligible adult (aged 16 years and over) providing written, informed consent was interviewed separately from other participants. Households were classified as non-responding only after fieldworkers had attempted visits on at least five separate days, at varying times of the day.The household survey included the short form of the International Physical Activity Questionnaire (IPAQ-SF) The household survey collected self-reported measures of sociodemographic characteristics, positive mental wellbeing . Publicly accessible and useable greenspaces in close proximity to each of the neighbourhoods were identified visually using aerial images from Google Earth and then the access points to the greenspaces were geocoded using Arc GIS. Only greenspaces larger than 2 hectares were geocoded as areas smaller than this were considered to be of inadequate size for adults to use to be physically active The English Indices of Deprivation core accessibility measures were used as indicators of the neighbourhood average walking distances to the nearest available food store and town centre Missing data were accounted for using multiple imputation models. The user-written ice commands Analyses were conducted using Stata v11.2 . For the individual-level factors, logistic regression models were used to adjust associations between the household survey items  and physical activity levels for age, sex, ethnicity and LSOA. Logistic regression analyses were also conducted for level-one variables including LSOA as a random effect, but the fixed effects approach was preferred in order to account for potential endogeneity in level-one variables Larsen and colleagues Ethical approval for all procedures was granted by the University of East London ethics committee in line with the declaration of Helsinki. Written, informed consent was granted by all participants. For participants aged 16 or 17, written, informed consent from both the participant and a parent or guardian was obtained prior to participation (these consent forms were signed by both participants and parents/guardians).The household survey was completed by 4,107 adults. Further information about the study sample is presented elsewhere Data from the IPAQ-SF indicated that 64.8% of respondents achieved the CMO's minimum recommended physical activity levels After adjusting for age, gender and ethnicity, the Median Odds Ratio was 1.7 . The odds of meeting the CMO's recommended levels of physical activity were higher for respondents reporting higher levels of positive mental wellbeing  had nearly twice the odds of achieving the minimum recommended physical activity levels when compared to those living 600\u2013900 m from the nearest greenspace. In addition to this measure of distance to nearest greenspace, we also examined the presence of large parks or greenspaces within neighbourhoods. These variables were not associated with meeting recommended physical activity levels.The evidence base for a relationship between greenspace and physical activity is equivocal, with approximately two thirds of previous studies examining associations between proximity to greenspace and physical activity reporting some evidence of a relationship We found evidence of considerable between-neighbourhood variation in the propensity to meet the minimum recommended physical activity levels. However, the measures of neighbourhood-level characteristics used in this study were not associated with the propensity to meet these physical activity levels, and did not explain a substantial amount of the variation in physical activity levels between neighbourhoods.Limitations of this study include the cross-sectional design which prevents us from making inferences about the direction or existence of a causal link. The use of LSOAs to represent the neighbourhood unit has facilitated the collation of information about neighbourhood characteristics, but the use of census tract areas to define \u2018neighbourhoods\u2019 has several limitations The physical activity levels reported by respondents to the Well London survey were considerably higher than the national average National surveys have shown that low-income groups are less physically active than higher-income groups There is however, substantial variance in physical activity levels between these deprived neighbourhoods. Multilevel social-ecological studies of physical activity have rarely reported information regarding the magnitude of variance in physical activity that can be attributed to variation between neighbourhoods or other geographical areas. The use of the median odds ratio to quantify between-neighbourhood variation in the physical activity outcome provides important information that is seldom reported in multilevel studies of physical activity. This median odds ratio is directly comparable to the odds ratios for individual-level characteristics, suggesting that the median difference in propensity to meet recommended physical activity levels between these 40 neighbourhoods may be similar in magnitude to the differences in propensity between men and women or differences between individuals aged 16\u201324 and individuals over 55 years old.The substantial between-neighbourhood variation in physical activity was not explained by the neighbourhood-level variables in this study. This may indicate that neighbourhood-level factors not measured in this study are important determinants of physical activity or that the operationalisation of neighbourhood characteristics in this study was not able to capture the features of the neighbourhoods that are important in determining physical activity levels in this deprived population. The methods used in previous studies to operationalise neighbourhood characteristics have been wide ranging and have seldom focused on deprived neighbourhoods. This may be important in explaining the varying findings in the literature A further potential explanation of our findings is that neighbourhood characteristics influence physical activity through complex and contingent causal pathways that have not been captured in the models presented in this study. Further research is needed to examine such pathways. This research may take the form of analyses that include potential mediating and moderating variables Our observations suggest that in this deprived population, characteristics measured at the individual-level are stronger determinants of physical activity than the neighbourhood-level characteristics examined in this study. However, limited variability in the neighbourhood environments may have restricted the potential to detect neighbourhood-level associations. Variation in the measured neighbourhood characteristics between the deprived neighbourhoods examined in this study and other less deprived neighbourhoods is likely to be greater than the variation between the deprived neighbourhoods alone. Therefore, examination of more heterogeneous neighbourhoods may have yielded different results.Table S1Associations Between Individual-Level Characteristics and Physical Activity in Adult Residents of Deprived London Neighbourhoods in 2008.(DOC)Click here for additional data file.Table S2Associations Between Neighbourhood-Level Characteristics and Physical Activity in Adult Residents of Deprived London Neighbourhoods in 2008.(DOC)Click here for additional data file.Text S1Details of the Specification of the Multiple Imputation Models.(DOC)Click here for additional data file."}
+{"text": "Results of extensive experiments on different genome-scale metabolic networks show that optGpSampler is up to 40 times faster than gpSampler. Application of existing convergence diagnostics on small network reconstructions indicate that optGpSampler converges roughly ten times faster than gpSampler towards similar sampling distributions. For networks of higher dimension (i.e. containing more than 500 reactions), we observed significantly better convergence of optGpSampler and a large deviation between the samples generated by the two algorithms. Availability:optGpSampler for Matlab and Python is available for non-commercial use at: http://cs.ru.nl/~wmegchel/optGpSampler/.Constraint-based models of metabolic networks are typically underdetermined, because they contain more reactions than metabolites. Therefore the solutions to this system do not consist of unique flux rates for each reaction, but rather a space of possible flux rates. By uniformly sampling this space, an estimated probability distribution for each reaction\u2019s flux in the network can be obtained. However, sampling a high dimensional network is time-consuming. Furthermore, the constraints imposed on the network give rise to an irregularly shaped solution space. Therefore more tailored, efficient sampling methods are needed. We propose an efficient sampling algorithm (called  Modelling metabolic networks helps to unravel the complex machinery of metabolism within the cell. A classic approach is to model the reaction pathways in a dynamic fashion, using detailed kinetic data. For genome-scale models, often involving hundreds or thousands of reactions and metabolites, it is experimentally prohibitive to obtain the kinetic parameters involved. A constraint-based approach has successfully been applied to model and address a wide range of biological questions in the absence of detailed kinetic data where Many constraint-based methods have been proposed to find flux distributions that are of biological interest. A successful approach is Flux Balance Analysis (FBA) hit-and-run (HR) gpSampler is often used to sample metabolic networks and implemented in the COnstrained Based Reconstruction and Analysis (COBRA) Toolbox In order to obtain an estimated probability distribution of attainable flux values for each reaction in the network, methods based on uniform sampling are used. A fast algorithm for this task is called gpSampler; (2) we propose a new measure to quantify the deviation between samples obtained from two independent sampling runs; (3) we perform a thorough analysis on five metabolic network models.Therefore in this paper we investigate uniform random sampling in the context of metabolic networks. Our contributions are threefold: (1) we introduce an efficient and effective random sampling algorithm which combines the advantages of ACHR and rejection sampling technique One of the first attempts to sample the flux states in a metabolic network used a hit-and-run (HR) algorithm The In general, the constraints in metabolic network models lead to a convex space of irregular shape which is elongated for reactions whose flux rates are loosely constrained, and is narrow for tightly constrained fluxes. A consequence of this phenomenon is that many sample points are close to the boundary of the solution space. Since HR chooses a direction warm-up phase an arbitrary initial point sampling phase starts from warm-up and the main sampling phase of ACHR.ACHR The sequence of ACHR iterates is not a Markov chain, due to the dependence of directions on prior iterates. Thus the sequence of iterates is not guaranteed to converge to a uniform distribution gpSamplergpSampler works. The highly irregular shape of the solution space of metabolic networks makes a uniform direction choice on gpSampler\u2019s warm-up phase uses linear programming in a two parts procedure. In part (1) gpSampler uses a linear transformation to \u2018pull\u2019 the warm-up points more into the interior of the solution space. Then, each moved warm-up point is used in the main sampling phase to generate step count parameter ACHR is at the core of gpSampler and ACHR. The resulting algorithm is called optGpSampler  and inequality (2) often lead to the same or a similar optimal solution. This could bias the starting points and directions choice of our sampler.We propose to combine a part of the warm-up phase of optGpSampler is similar to that of ACHR , producing For each reaction Compute the mean chain of the Our assumption is that chains generated by sampler Our choice to use a mean deviation over the standard deviation is motivated by the fact that the mean deviation is more efficient than the standard deviation in the realistic situation where some of the measurements are in error, and more efficient for distributions other than perfect normal xy-deviation over Then the xy-deviation indicate convergence of gpSampler implementation in the COBRA Toolbox. Results of extensive experiments are given in supplementary material. Tables S1\u2013S5 in We used the gpSampler and optGpSampler were executed in parallel mode on an AMD desktop computer using optGpSampler is roughly 6 to 40 times faster than gpSampler.We sampled all networks four times using To asses the quality of the results, we performed four independent runs with each sampler. Each run collected gpSampler and optGpSampler was assessed by applying the Wilcoxon signed-rank test to the corresponding vectors. The results for the Gelman and Rubin test indicated convergence for all experiments, in disagreement with results of the Geweke and HW tests.We ran all convergence diagnostics with the default settings in the CODA package. The convergence tests results were averaged over the four runs. A univariate test for a sampler outputs a vector of length The obtained chains were also used to compute the E. coli central metabolism network, the Geweke test returned relatively low z-values for both gpSampler and optGpSampler . We compared the runtimes with those of gpSampler, and showed its superior efficiency. We investigated empirical convergence using different diagnostics and showed faster convergence of optGpSampler on the two smaller networks studied. Moreover, by using the here introduced optGpSampler using a small step count are close to those obtained with a high step count by both optGpSampler and gpSampler.We proposed a new algorithm for uniform sampling of the steady-state solution space of metabolic networks. Our algorithm also implements ACHR, but in a different manner than the state-of-the-art sampling method for metabolic networks Click here for additional data file."}
+{"text": "Esophageal impedance monitoring and high-resolution manometry (HRM) are useful tools in the diagnostic work-up of patients with upper gastrointestinal complaints. Impedance monitoring increases the diagnostic yield for gastroesophageal reflux disease in adults and children and has become the gold standard in the diagnostic work-up of reflux symptoms. Its role in the work-up for belching disorders and rumination seems promising. HRM is superior to other diagnostic tools for the evaluation of achalasia and contributes to a more specific classification of esophageal disorders in patients with non-obstructive dysphagia. The role of HRM in patients with dysphagia after laparoscopic placement of an adjustable gastric band seems promising. Future studies will further determine the clinical implications of the new insights which have been acquired with these techniques. This review aims to describe the clinical applications of impedance monitoring and HRM. Esophageal manometry is being performed in humans since the early 1950s . HoweverJohnson and deMeester introduced ambulatory pH-monitoring for the detection of reflux episodes in 1975 . EsophagThe concept of a simultaneous measurement of reflux episodes and pressure dates back to the late 1950s when it was described by Tuttle and Grossman . More reThis review aims to describe the clinical applications of esophageal impedance monitoring and HRM. Furthermore, we aim to stipulate novel insights which have emerged from using the application of techniques.When HRM was introduced in clinical practice, the Spechler and Castell classification of esophageal disorders was the gold standard for assessing manometric data . HoweverWith HRM several new features were added to the analysis of esophageal pressure data. The integrated relaxation pressure (IRP) is a more complex measurement of deglutitive esophagogastric junction (EGJ) relaxation than the end-expiratory nadir pressure  Fig.\u00a01b1b. ConceAbnormalities of the force of the distal esophageal contraction can be classified as hypotensive, absent or hypertensive peristalsis. Hypotensive or absent peristalsis can be easily recognized using the isobaric contour lines Fig.\u00a0. The thrThe first feature which is used to determine the transmission of peristalsis is the contractile front velocity (CFV) Fig.\u00a0. ConceptA recent study by Pandolfino et al. aimed to apply the CFV and distal latency to refine the diagnosis of distal esophageal spasm . These aThe novel manometric criteria defined by the Chicago Classification could potentially result in a decreased reproducibility. However, Bogte et al. found that these novel HRM criteria yield reproducible results . FurtherBelow, we will discuss new insights gained with high-resolution manometry.Fox et al. described that the close spacing of pressure sensors at the HRM catheter allows the clinician to identify isolated hypotensive segments in the peristaltic contraction . These iThe close spacing of pressure sensors at the HRM catheter also allows one to differentiate between the pressure generated by the lower esophageal sphincter (LES) and the crural diaphragm if a hiatal hernia is present. This spatial separation of the LES and the crural diaphragm in patients with a hiatal hernia is observed as a double high-pressure zone compared to a single high-pressure zone in subjects without a hiatal hernia . SchererThe diagnostic work-up for non-obstructive dysphagia can be troublesome due to the lack of agreement between objective measurements of esophageal function and the lack of bolus transit assessment as measured by conventional manometry and subjective perception of bolus passage \u2022. This sGhosh et al. described that with the use of HRM substantial shortening of the esophagus can be observed in achalasia patients . If convFurthermore, HRM has prompted the recognition of three different subtypes of achalasia which are achalasia with minimal esophageal pressurization , achalasia with esophageal compression (type II) and achalasia with spasm (type III) . HoweverWith the use of intraluminal ultrasonography a longitudinal muscle contraction of the distal esophagus was recently identified as the cause of pan-esophageal pressurization in type II achalasia . FurtherThe clinical relevance of identifying the achalasia subtype was demonstrated by a recent study by Pratap et al. who demonstrated that patients with type II achalasia respond best to treatment followed by type I and type III .Laparoscopic placement of an adjustable gastric band (LAGB) is a widely performed treatment for obesity. However, dysphagia, vomiting, and regurgitation are common side effects of gastric banding. Several studies have aimed to assess esophageal motility and clearance in symptomatic LAGB patients using high resolution manometry , 26. By A recent study by Roman et al. evaluated the use of HRM in 48 patients with eosinophilic esophagitis . Using hBy far the largest application of esophageal impedance monitoring in clinical practice is in the diagnostic work-up of patients with GERD symptoms. Impedance monitoring detects retrograde flow in the esophagus whereas pH monitoring detects reflux events as a drop in the pH-level Fig.\u00a0. CompareHemmink et al. assessed whether cessation of PPI could further increase the diagnostic yield in patients with GERD . These aAnti-reflux surgery, also known as surgical fundoplication, is a widely performed intervention for GERD. Besides decreasing the number of acid reflux episodes, anti-reflux surgery also reduces the number of weakly acidic reflux episodes . TherefoDespite the fact that reflux monitoring is a valuable diagnostic tool, evidence for the use of pH-metry as a preoperative predictor of surgical outcome has shown conflicting evidence . FurtherBetween reflux episodes and swallows, the esophageal lumen is collapsed and the resulting baseline impedance level is determined by the esophageal wall. Several studies hypothesized that impedance baseline measurements could also be used to evaluate changes in esophageal mucosa integrity , 36, 37\u2022Whereas the detection of reflux episodes with pH-metry can be easily detected as a pH-drop <4, the detection of reflux episodes with impedance monitoring can be somewhat more troublesome. Several studies have assessed inter-observer variability for the detection of reflux episodes with impedance monitoring in the same center, however, a multi-center study has not yet been performed in adults. A recent multi-center study by Loots et al. assessed inter observer variability in impedance tracings of children and found only moderate agreement between the observers . A diffeDuring the work-up of reflux symptoms in children pH-impedance monitoring is increasingly being performed. Studies revealed that a significant proportion of all reflux episodes is weakly acidic and weakly acidic reflux episodes are more prevalent than acid reflux episodes in infants with symptoms , 47\u2022. ThA recent study by Rosen et al. aimed to determine predictors of fundoplication outcome in children using pH-impedance monitoring . These aGastric belching is a physiological mechanism which enables venting of gas from the stomach to the esophagus in order to prevent accumulation of excess gas in the stomach or duodenum , 41. WitThe clinical relevance of this differentiation between supragastric belches and gastric belches was demonstrated in patients with excessive belching as their main symptom . BredenoBelching is a common symptom in GERD patients with an incidence of 40% to 49%. Hemmink et al. showed that supragastric belching can also occur in patients with GERD . MoreoveAerophagia is a disorder which is characterized by abdominal bloating and abdominal distension due to an excessive volume of intestinal gas . With thWith the use of impedance monitoring the clinician can differentiate between supragastric belching, aerophagia and gastric belching in patients with gas related symptoms such as belching and abdominal bloating. This results in a more accurate diagnosis and could possibly result in a more specific treatment for selected patients.The rumination syndrome is a functional gastroduodenal disorder of unknown etiology characterized by persistent or recurrent regurgitation of recently ingested food into the mouth. Diagnosis of rumination is currently based on clinical features as defined by the Rome III criteria . The patCombined manometry-impedance can be used to identify esophageal function abnormalities in patients with non-obstructive dysphagia . The advA recent study by Burgess et al. applied this technique of combined HRM-impedance monitoring and described that little further information was gained compared to HRM alone . HoweverThe application of HRM has improved our understanding of the esophagus and increases the diagnostic yield of manometry. Furthermore, the design of the manometry assembly and the presentation of the acquired data are easier to perform in clinical practice and easier learned by the clinician.The technique of HRM, the interpretation of the acquired data and the classification of disease is constantly being improved. Recently, 3D-HRM was developed which measures pressure with several radial pressure sensors at the location of the EGJ . 3D-HRM pH-impedance monitoring has proven to be a diagnostic tool which is superior to pH-metry in the diagnostic work-up of adult and pediatric patients with GERD symptoms. Furthermore, the application of pH-impedance monitoring with regard to belching complaints has already lead to more specific treatment targets. Currently, evolving concepts regarding the use of baseline impedance levels and the role of supragastric belching in patients with GERD are being assessed. The outcomes of these studies will determine the clinical relevance of these novel concepts and could expand the clinical applications of impedance monitoring.HRM and pH-impedance monitoring have lead to an improvement in diagnostics and classification of esophageal disorders. Future studies will further determine the clinical implications of the new insights which have been acquired with these techniques."}
+{"text": "Delirium is a common and serious condition, which affects many of our older hospitalised patients. It is an indicator of severe underlying illness and requires early diagnosis and prompt treatment, associated with poor survival, functional outcomes with increased risk of institutionalisation following the delirium episode in the acute care setting. We describe a new model of delirium care in the acute care setting, titled Geriatric Monitoring Unit (GMU) where the important concepts of delirium prevention and management are integrated. We hypothesize that patients with delirium admitted to the GMU would have better clinical outcomes with less need for physical and psychotropic restraints compared to usual care.GMU models after the Delirium Room with adoption of core interventions from Hospital Elder Life Program and use of evening bright light therapy to consolidate circadian rhythm and improve sleep in the elderly patients. The novelty of this approach lies in the amalgamation of these interventions in a multi-faceted approach in acute delirium management. GMU development thus consists of key considerations for room design and resource planning, program specific interventions and daily core interventions. Assessments undertaken include baseline demographics, comorbidity scoring, duration and severity of delirium, cognitive, functional measures at baseline, 6 months and 12 months later. Additionally we also analysed the pre and post-GMU implementation knowledge and attitude on delirium care among staff members in the geriatric wards  and undertook satisfaction surveys for caregivers of patients treated in GMU.This study protocol describes the conceptualization and implementation of a specialized unit for delirium management. We hypothesize that such a model of care will not only result in better clinical outcomes for the elderly patient with delirium compared to usual geriatric care, but also improved staff knowledge and satisfaction. The model may then be transposed across various locations and disciplines in the acute hospital where delirious patients could be sited.ISRCTN52323811Current Controlled Trials  Delirium is a common and serious condition, which affects many of our older hospitalised patients. The prevalence in hospitalised elderly patients is shown to be as high as 50%, with the diagnosis in 11-24% of older patients upon admission and another 5-35% of them developing delirium during admission . ComplicThe importance of delirium is highlighted by its inclusion as a marker for quality of care and patient safety by the National Quality Measures Clearinghouse of the Agency for Healthcare Research and Quality, as higher delirium rates would be expected to correlate with lower quality of hospital care after adjustment for casemix. Moreover, the Assessing Care of Vulnerable Elders Project has ranked delirium among the top 3 conditions for which the quality of care needs to be improved ,11. OtheThe Asian state of Singapore has one of the fastest ageing populations in the Asia-Pacific region with 15-20% of total population consisting of persons aged 65 and above by the year 2030. A random point survey in our geriatric medicine department demonstrated a delirium prevalence rate of 15%. This potentially translates to 3,600 patients per year or 10 patients per day. The survey also showed that elderly inpatients with delirium had a longer average length of stay (ALOS)(15 days) than that of a normal geriatric inpatient (ALOS = 11 days). In addition, 50% of falls in the geriatric wards were related to delirium, resulting in an even longer ALOS of 23.9 days, thus strengthening the case for improved delirium care (data available upon request).Studies have looked at interventions for delirium prevention in hospitalised geriatric patients , yet othIn improving delirium care in the acute hospitalised elderly, the establishment of a specific unit for acute delirium care represents a significant step towards the systematic delivery of good geriatric care for the delirious elderly. For the current study, we describe the development of the Geriatric Monitoring Unit (GMU)- a specialised 5-bedded unit which incorporates specific room design for an elder-friendly environment, lower staff-patient ratio, coupled with structured core, program interventions and bright light therapy to reside delirious patients, supported by 24-hour intensive nursing care.The primary aim of this study is to compare delirious patients admitted to the Geriatric Monitoring Unit (GMU), compared to usual geriatric care in general ward setting on the following primary measures: (1) Duration of delirium and severity of delirium, (2) Use of physical and chemical restraints, (3) Falls rate, (4) Physical injury rate due to agitated behavior, (5) Functional outcomes/gains in the elderly geriatric patients, (6) Morbidity ; (7) Patient and family satisfaction score in elderly persons with delirium. We postulate better outcomes in patients admitted to GMU versus usual geriatric care. Our secondary aims include looking at which specific aspects of the interventions would yield the greatest benefit for future translation on a larger scale; the effects of the multicomponent intervention and bright light therapy on sleep of these patients as well as their effect on antipsychotic and sedative-hypnotic use.The GMU concept was developed via an evidence-based approach using specific interventions that have been found to be beneficial for delirium care. GMU incorporated specific measures from the following programs: (i) Delirium Room which provides comprehensive medical care with multidisciplinary team meetings, initial behavioural and appropriate non-pharmacological methods being first line management in these patients  (ii) ConThe development of the GMU program included key considerations for room design and resource planning, program specific interventions and daily core interventions.Room design incorporated the aggregation of patients with delirium and difficult to control behaviours in a single 5-bedded cubicle. In Singapore, a multi-bedded system is common and hence would not cause additional concerns to patients and caregivers. Specific elder-friendly considerations include: 1) card access door; 2) low hospital beds; 3) individual night light; 4) falls modification in the toilet with movement-activated sensor lighting; 5) large wall clock; 6) calendars and 7) headboards indicating sensory impairments (if present), patient's favourite hobbies or activities to aid in individualised activity sessions. Other features of the GMU room include adequate lighting, panic button to ensure staff safety (in event of unpredictable combative patient behaviour) and a central space for group activities.We aimed to provide higher nursing ratio of 1 trained nursing staff to 2.5 patients. The trained nurses, without distraction from other nursing and patient issues, are able to devote full attention to monitor the conditions of the 5 patients in the GMU and thereby able to initiate early interventions should they detect any deterioration in condition. This form of set up will ensure the reduction of the likelihood of injuries, falls and also allow active and early intervention to prevent functional decline and deterioration of the condition.The following program interventions were implemented by the multi-disciplinary team:(1) Family orientation upon patients entering the GMU . Family members are encouraged to visit patients daily to encourage communication and social support to the patients (Daily Visitor program).(2) Geriatric nursing assessment and interventions .(3) The nurses involved in this program underwent a series of in-service training sessions with regards to the interventions including training on administration of cognitive screening tests and delirium scales; non-pharmacological and pharmacological management of delirium; delirium care and one-on-one interactions; communication skills in counseling concerned family members; psychogeriatrician teaching stress management skills; with support from the geriatric ward level nursing managers as well as cognition nurse clinicians who will counsel and aid in on-site difficult-to-manage behaviours. A pre- and post-implementation questionnaire of delirium knowledge was administered table .(4) Reference resources and practical reminders were made available for the staff in GMU.(5) A continuing education program for care providers was implemented where the staff  involved in the GMU has regular training to increase awareness and knowledge in diagnosis and management of delirious patients.(6) Nursing leaders helped support the trained nurses during the implementation stage.(7) Daily geriatrician input with regards to these patients with daily documentation of mental status /Chinese Mini Mental State Examination (CMMSE)) ,38, Conf(8) Twice-weekly multidisciplinary rounds .(9) Monthly meetings with the multidisciplinary staff members to evaluate the ongoing program, refine, voice out problems(10) Early involvement of care co-ordinator or medical social worker (where appropriate) in discharge planning.GMU core interventions are performed daily . The aim of bright light therapy is to establish healthy sleep-wake cycle with appropriate timing set to a desired phase. Since sleep deprivation is one of the contributing factors to worsening delirium, it will be beneficial to place such patients in this room to modulate their sleep-wake cycle. The peaceful environment, free from the movement and noises from other patients will allow better and uninterrupted period of sleep.The admission criteria for GMU included patients above age of 65 years old assessed to have delirium  who were admitted to the geriatric medicine department. Patients were excluded if they had medical illnesses which require special monitoring ; were deemed to be dangerously ill, in coma or had terminal illness; uncommunicative patients or patients with severe aphasia; severely combative behaviour with high risk of harm; and patients with mania or other severe eye disorders and other contraindications to bright light therapy (such as patients on photosensitising medications). Finally we also excluded patients with respiratory or contact precautions, or there was verbal refusal of GMU stay by family/patient/physician-in-charge.The GMU will have a dynamic system for transfers (akin to an intensive care unit) whereby patient flow is effected once they are assessed to have met entry or discharge criteria. This will be based upon both subjective and objective approach when the medical team deems the patients to have easy to manage behaviour/minimal or stable behavioural medications and objectively supported by decreased severity of delirium, based on DRS and CAM-severity scores.Our study consist of a pre/post GMU implementation as well as concurrent GMU patients versus patients with delirium managed in the geriatric ward as controls. We will collect available data for patients with delirium admitted to the geriatric department one month prior to GMU implementation. We will give a one-month run-in period after establishment of GMU to smoothen out the initial teething issues and operational issues. The study recruitment commenced in November 2011. We will subsequently identify patients with delirium who meet the inclusion and exclusion criteria for GMU. Using Zelen's method of randomization ,42, we wTable The primary outcome measures we will look at include: (i) Clinical data with regards to duration and severity of delirium; frequency of use of physical restraints, use of pharmacological agents/sedative hypnotics, physical injuries or monthly falls rates; and nosocomial infection rates (ii) Functional outcomes by way of modified Barthel Index score and (iii) Patient/family satisfaction score; all adjusted for baseline demographics and comorbidities. We aim to look at the outcomes measures of patients with delirium admitted to GMU versus those managed under usual care (control group) group . We based our calculations on a two-sample comparison of means for the GMU and control group using non-repeated measures. Using mean Barthel Index score difference of 10 with standard deviation of 14 with ratio between groups of 1, a sample size of 45 patients in each group will be adequately powered to detect a 10-point mean Barthel Index group differences, with 90% power. Assuming that 10% of patients are lost to follow-up at 1 year, we project a final sample size of 50 (rounded up). Level of significance was set at 5%. Sample size calculation was performed in PS Power and Sample Size Calculations V2.1.30. Statistical analysis will be performed using appropriate statistical methods  for between group comparisons. Appropriate statistical methods will be used for the longitudinal outcome analyses and statistical significance is set at 5%.Informed consent for data collection will be obtained from the legal guardians of patients with delirium. Ethics approval has been obtained from National Healthcare Group Domain Specific Review Board (NHG DSRB).We describe the rationale and concepts for GMU, a specialized 5- bedded unit dedicated to delirium care. Studies have shown that good leadership and effective management play a key role in bringing about a successful change to a positive workplace culture through innovative programs and research projects. Organisational investment can improve outcomes for staff stability and productivity, care quality and budgets, and better prepare those involved in the care of the elderly. The above provided the rationale for our development of a specialised delirium unit. The unit uses evidence-based practices of Delirium Room, HELP program and bright light therapy as its ground model.The Delirium Room described by Flaherty et al is a specialized 4-bed unit that provides 24-hour intensive nursing care with a restraint-free concept . This DeWhile Delirium Room has been shown in literature to improve delirium care, the HELP program is primarily a multi-component intervention developed to prevent delirium in hospitalized older patients ,27. It hWhile the GMU model has been developed for delirium care as a limited 5-bedded unit, it is unclear currently whether the benefits would be best seen in the hypoactive, mixed or hyperactive delirium. We had excluded combative hyperactive delirium patients who might cause the most caregiver/staff distress and who might require the most care time. However, this is done taking into account staff safety as well as safety of other patients. Also the combative delirious patient might least benefit from the core interventions as he/she might not be able to co-operate with the respective strategies applied. In order to look at the subtype of delirium patients who might best benefit from the GMU, we will further review their delirium and functional outcomes post-GMU admission to refine and improve our model in the future. We hope that the development of GMU will improve both short and long-term outcomes of hospitalized patients with delirium compared to usual care. This model of care in future may also be translated in a trans-disciplinary manner across other medical and surgical wards (akin to ACE unit model) where delirious patients could be sited.The authors declare that they have no competing interests.CMS, MC participated in the design of the GMU and writing up of manuscript. JK and HHC participated in the design of GMU, design and administration of satisfaction questionnaire and design of structured GMU nursing protocol. DYY and TTL participated in design of GMU and inputs into the manuscript. All the authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2318/11/41/prepub"}
+{"text": "Systemic properties of living cells are the result of molecular dynamics governed by so-called genetic regulatory networks (GRN). These networks capture all possible features of cells and are responsible for the immense levels of adaptation characteristic to living systems. At any point in time only small subsets of these networks are active. Any active subset of the GRN leads to the expression of particular sets of molecules (expression modes). The subsets of active networks change over time, leading to the observed complex dynamics of expression patterns. Understanding of these dynamics becomes increasingly important in systems biology and medicine. While the importance of transcription rates and catalytic interactions has been widely recognized in modeling genetic regulatory systems, the understanding of the role of degradation of biochemical agents  in regulatory dynamics remains limited. Recent experimental data suggests that there exists a functional relation between mRNA and protein decay rates and expression modes. In this paper we propose a model for the dynamics of successions of sequences of active subnetworks of the GRN. The model is able to reproduce key characteristics of molecular dynamics, including homeostasis, multi-stability, periodic dynamics, alternating activity, differentiability, and self-organized critical dynamics. Moreover the model allows to naturally understand the mechanism behind the relation between decay rates and expression modes. The model explains recent experimental observations that decay-rates (or turnovers) vary between differentiated tissue-classes at a general systemic level and highlights the role of intracellular decay rate control mechanisms in cell differentiation. GRN coordinate regulatory dynamics on all levels from cell-fate up- or down-regulation of the production of one agent by another agent. It has been recognized that quantitative information is required to understand the complex dynamical properties of regulatory interactions in living cells adequately reproduce GRN dynamics and sufficiently exhibit systemic properties of the GRN, including (i) homeostasis, (ii) multi-stability, (iii) periodic dynamics, (iv) alternating activity, (v) self-organized critical dynamics (SOC) and (vi) differentiability.Understanding living cells at a systemic level is an increasingly important challenge in biology and medicine Homeostatic dynamics regulates the equilibrium concentration levels of agents, e.g. multi-stability shows switching between multiple steady states periodic dynamics are e.g. the cell-cycle alternating activity, i.e. their concentrations alternate between being detectable (on) and below detection threshold (off), see e.g. Self-organized critical (SOC) dynamics corresponds to details of regulatory dynamics ensuring (approximate) stability within a fluctuating environment through various mechanisms of adaptation. Finally the property of differentiability means that cells of multicellular organisms can differentiate into various cell-types. The differentiated cells possess identical GRN but express distinguishable patterns of regulatory activity. The same GRN therefore can be expressed in different modes so that some agents become expressed in one mode but not in another compartments which usually are not resolved in models of experimental data. Besides active degradation of effector molecules also transport-mechanisms between different cell-compartments, e.g. between the nucleus and the cytosol, can change the concentration of effector molecules (e.g. transcription factor) in the compartment containing their target molecules (e.g. promoter). Thus transport phenomena may also emulate the effect of local production or decay rates.Recently it has been reported that both regulation of transcription and mRNA decay rates (i.e. the mRNA turnover) are necessary to understand experimentally observed expression values active regulatory network at time active agent set at time expression modes of a specific cell-type and its general state. Expression modes themselves can be modified, either locally as a reaction to an external signal, or fundamentally through further cell differentiation. Active sets of molecules are transient and what is observed in experiments is a superposition of subsequent active sets, which we call the expressed set of agents. The regulatory interactions between the expressed agents we call the expressed regulatory network. To find the property of differentiability in a regulatory network model therefore requires that one network is capable of producing different expression modes while perturbations  only modify active sets locally and the particular expression mode can be restored.Variable decay rates however and the property of differentiability are hardly ever considered in GRN models where decay rates of effector molecules (agents) are usually kept constant. Understanding the effects of changes of decay rates of agents therefore is a crucial step towards a deeper understanding of GRN dynamics and the role decay rates play in cell-differentiation. The GRN is the set of all possible interactions of molecular reactions and bindings. The GRN captures all possible features of cells and are responsible for the immense levels of adaptation characteristic to living systems. What happens when different cell-types express the same GRN in alternative ways? At any point in time only small subsets of the GRN are active. Any active subset of the GRN leads to the expression of particular sets of molecules (expression modes). The The six dynamical properties we have listed above have been addressed with a variety of conceptually different models. The essence of all these models is that they try to capture the dynamics induced by positive and negative feed back loops within the GRN. The choice of model depends largely on the type and resolution (coarse graining) of experimental data. At the single cell level cellular activity can be modeled by nonlinear (stochastic) differential equations Differential equation models can be approximated by cellular automata, Boolean or piecewise-linear models. The property of SOC dynamics, or dynamics at the \u201cedge of chaos\u201d regulatory domains  consider Given that the interaction matrix all desired GRN properties.Not all models approximating nonlinear differential equation descriptions of GRN are equally suited to capture all GRN properties discussed above simultaneously depending on whether discrete  or smooth  features dominate the model. However there exists a surprisingly simple class of models which exhibits Here we present such a simple model that captures all of the above dynamical properties. We find that the alternating dynamics plays a key role for the stability of regulatory systems and for the formation of SOC dynamics in particular expressed genetic regulatory network, and (b) these differences can be controlled via decay rates of intracellular agents. In other words typical expression modes  can be altered and switched by controlling decay rates.We show that experimental facts, linking variations of decay rates observed between different cell-types of an organism to variations of the abundance of intra-cellular biochemical agents in these cell-types, correspond to (a) differences in the Setting active at time inactive, if Equation (2) generalizes this class of models to systems allowing to explicitly model linear regulatory interactions active set of agents. The remaining agents have zero concentration, and therefore do not actively influence the concentrations of any of the non-vanishing agents. There exist active networks and denote them by effective fixed point sequentially linear systems. The attractiveness of this description arises through the fact that it becomes possible to understand the dynamics by considering the sequences of active networksThe positivity constraint Eq. (4) implies the following consequences. At any point in time there will be a sub-set of agents with non-vanishing concentrations which we call the ces  see . This moattractors of the dynamics . Which attractor is \u201cfound\u201d depends on the initial condition. Sequentially linear systems can possess multiple distinct limit cycles and fixed points. Perturbations  may push a system from one to another attractor. The question of how many different attractors a sequentially linear system possesses goes beyond the scope of this paper and will be discussed elsewhere.The dynamics of nonlinear systems in general and sequentially linear system in particular converges to different In the picture of sequentially linear dynamics it becomes possible to identify operational modes of a cell as a particular sequence of active networks. Cell types in ordinary operational modes may be classified by specific sequences of active networks. Two distinct possibilities for such sequences exist. One possibility is that, after some initial switching events, a system ends up in a stationary state associated with a particular active network of the system see . The othperiodic sequence As a hypothetical example a liver cell under typical conditions might be characterized by a As an example for sequentially linear dynamics we consider a system with see also . In thishomeostasis, and multi-stability. This has been demonstrated for a wide range of system size Periodic dynamics, and self-organized critical dynamics have been noted in Some details of the dynamics, like the existence of multiple stable fixed-points, the periodicity of bounded attractors and temporal self-organization, can be mathematically fully understood. In The temporal balance condition states that the time-average over the real parts of the leading eigenvalues accessible however, meaning that the trajectory on the way toward the fixed point hits a boundary  are absorbed into switching events, where the dynamics of one linear system switches to another one. In this view different cell types correspond to different sequences of active sub-networks over time.These sequentially linear models allow not only for the first time to describe all the relevant dynamical features of the GNR , but also offers the handle to understand the role of molecular decay rates. The fact that sequentially linear dynamics properly models homeostasis, multi-stability and periodic behavior was shown in Applying the sequentially linear model to the problem of cell-differentiation we demonstrate that different levels of decay rates are one to one related with transitions from one active sub-network sequence (cell type) to another. This might be a key ingredient to understand a series of recent experimental facts reported on the role of decay-rate regulation systems and the role of noise in cell differentiation The eigenvalues stable and perturbations of concentrations vanish if accessible if inaccessible otherwise. Stationary solutions of a sequentially linear system therefore require fixed points that are both stable and accessible.Let Stable and accessible fixed points can be fully understood. Suppose agents We have seen that attractors either are fixed points or periodic. The longer periodic sequence of While eigenvalues tell us something about the stability of a fixed point the Lyaponov exponent Here we derive a simple approximation of the Lyapunov exponent of sequentially linear dynamics which explains temporal self-organization quantitatively. This is necessary for understanding why switching in general happens between active networks with stable and unstable dynamics and not from one stable stable (unstable) to another stable (unstable) active network.Temporal balance and refocusing are two aspects of the temporal self-organizing principle manipulating switching times.Qualitative analysis of bounded attractors of sequentially linear dynamics has shown that the attractor is periodic and the Lyapunov exponent"}
+{"text": "In the past decade, a high incidence of somatic mitochondrial DNA (mtDNA) mutations has been observed, mostly based on a fraction of the molecule, in various cancerous tissues; nevertheless, some of them were queried due to problems in data quality. Obviously, without a comprehensive understanding of mtDNA mutational profile in the cancerous tissue of a specific patient, it is unlikely to disclose the genuine relationship between somatic mtDNA mutations and tumorigenesis. To achieve this objective, the most straightforward way is to directly compare the whole mtDNA genome variation among three tissues  from the same patient. Considering the fact that most of the previous studies on the role of mtDNA in colorectal tumor focused merely on the D-loop or partial segment of the molecule, in the current study we have collected three tissues  respectively recruited from 20 patients with colorectal tumor and completely sequenced the mitochondrial genome of each tissue. Our results reveal a relatively lower incidence of somatic mutations in these patients; intriguingly, all somatic mutations are in heteroplasmic status. Surprisingly, the observed somatic mutations are not restricted to cancer tissues, for the para-cancer tissues and distant normal tissues also harbor somatic mtDNA mutations with a lower frequency than cancerous tissues but higher than that observed in the general population. Our results suggest that somatic mtDNA mutations in cancerous tissues could not be simply explained as a consequence of tumorigenesis; meanwhile, the somatic mtDNA mutations in normal tissues might reflect an altered physiological environment in cancer patients. In the past decade, the role of mitochondrial DNA (mtDNA) mutation in tumorigenesis has received much attention. A high incidence of somatic mtDNA mutations, mostly in homoplastic, has been identified in nearly all types of cancerous tissues In the present study, we performed the whole mitochondrial genome screening for somatic mutation in paired cancerous and non-cancerous tissues from 20 patients with colorectal cancer. By using the same quality control measures as adopted in our previous studies in complete mtDNA sequencing http://www.ncbi.nlm.nih.gov/Genbank/) with accession numbers GU392048\u2013GU392106. All the mtDNA variable sites of each tissue have been displayed on a schematic tree  under study do not harbor any mtDNA somatic mutation in their cancerous tissues, one explanation could be that it is the modification in nuclear genome which has contributed to the tumorigenesis in the samples without involving any mtDNA changes. The frequency of mtDNA somatic mutations  observed in our current study, which is comparable to our previous results on breast cancer , corresponding para-cancerous normal tissues (CP1\u2013CP10) and distant normal tissues (CN1\u2013CN10), which were taken from 20 Chinese patients with colorectal cancer during surgery with informed consent. The cancerous tissue was confirmed by HE-stained slides of the frozen section after surgery, whereas the para-cancerous normal tissue was obtained from the normal tissue surrounding the cancer, and the distant normal tissue is at least 5 cm away from the edge of the cancer tissue. All the patients were clinically diagnosed with stage I  colorectal cancer according to the clinical standard for the category of the cancer Total genomic DNA was respectively extracted from the para-cancerous tissue, primary cancerous tissue and distant normal tissue by using the standard phenol/chloroform method. The entire mtDNA genomes were amplified and sequenced as fully described in our previous studies To avoid potential problems and errors observed in the published mtDNA disease studies For the observed heteroplasmic mutation during the direct DNA sequencing, we further confirmed it by denaturing high-performance liquid chromatography (DHPLC) .Table S1Somatic mtDNA mutations identified in 20 colorectal patients(DOC)Click here for additional data file.Table S2Comparison of the frequency of individuals harboring heteroplasmic mtDNA mutations in normal population and in cancer patients.(DOC)Click here for additional data file."}
+{"text": "Currently, investigations into disease onset and progression in mouse models of these conditions depend on somewhat unreliable tests that only measure a few motor functions. Now, Mandillo et al. validate an automated home-cage wheel-running system for the measurement of early motor deficits in mouse disease models. By undertaking studies at two centres, the researchers show that the system consistently detects differences in performance among four inbred strains of mice. They also report that the system allows the detection of very early motor function deficits in mutant mouse models of two progressive neurodegenerative diseases and in a mouse strain with subtle gait abnormalities. This new test therefore provides a reliable method for detecting motor deficits at pre-symptomatic stages in mouse disease models that should be useful in longitudinal investigations of potential therapeutic agents."}
+{"text": "Evidence supporting the essential role of brain-derived ethanol metabolites in the excitation of dopamine (DA) midbrain neurons has multiplied in the last 10\u201315 years. The pioneer and influential behavioral studies by CM Aragon and colleagues   (Hip\u00f3lito et al., Collectively, the data reviewed suggest that Sal could be the responsible for the activation of the VTA DA neurons after ethanol administration. However, to definitively link Sal to ethanol-derived excitation of DA mesolimbic system after ethanol consumption, it is compulsory resolving, at least, two important interrogations. First, it is crucial to demonstrate the existence of an increase of VTA Sal levels after acute local or systemic ethanol administration. Second, it would be also decisive to establish a clear correlation between changes in VTA Sal levels and excitation of VTA DA neurons after ethanol administration. Future experiments on these crucial issues may be pivotal to unambiguously probe the involvement of Sal in the excitation of DA mesolimbic neurons after ethanol administration."}
+{"text": "Rationale: Dense array EEG (dEEG) evenly covers the whole head surface with over 100 channels contributing to more accurate electrical source imaging due to the higher spatial and temporal resolution. Several studies have shown the clinical utility of dEEG in presurgical clinical evaluation of epilepsy. However validation studies measuring the accuracy of dEEG source imaging are still needed. This can be achieved through simultaneously recording both scalp dEEG with intracranial electrodes (icEEG), which is considered as the true measure of cortical activity at the source. The purpose of this study is to evaluate the accuracy of 256-channel dEEG electrical source estimation for interictal spikes.Methods: Four patients with medically refractory neocortical epilepsy, all surgical candidates, underwent subdural electrode implantation to determine ictal onset and define functional areas. One patient showed a lesion on the magnetic resonance imaging in the right parietal lobe. The patient underwent simultaneous recording of interictal spikes by both scalp 256-channelsvdEEG and icEEG. The dEEG was used to non-invasively estimate the source of the interictal spikes detected by the 256-channel dEEG array, which was then compared to the activity measured directly at the source by the icEEG.Results: From the four patients, a total of 287 interictal spikes were measured with the icEEG. One hundred fifty-five of the 287 spikes (54%) were visually detected by the dEEG upon examination of the 256 channel head surface array. The spike amplitudes detected by the 256-channel dEEG correlated with icEEG spike amplitudes (p\u2009<\u20090.01). All spikes detected in dEEG were localized to the same lobe correctly.Conclusion: Our study demonstrates that 256-channel dEEG can reliably detect interictal spikes and localize them with reasonable accuracy. Two hundred fifty-six-channel dEEG may be clinically useful in the presurgical workup for epilepsy and also reduce the need for invasive EEG evaluation. For patients with intractable epilepsy, surgical therapy is an important treatment option. Although the propagation of seizures may involve complex cerebral networks, surgical resection of the cortical zone of seizure onset may be effective, if this zone can be identified and delineated from surrounding tissue. The first stage of diagnostic tests is typically non-invasive, with the goal being to characterize the epileptogenic zone as comprehensively as possible in order to guide the next stage of invasive testing with intracranial electrodes that confirms the decision on resective surgery.Magnetoencephalography (MEG) and electroencephalography (EEG) have both been used as non-invasive methods in the electrophysiological evaluation of the epileptogenic zone. A number of studies has shown that multi-channel MEG is useful for dipole localization of interictal spike events, especially in neocortical epilepsy, where the sources may be more superficial (closer to the skull) compared to epilepsy with deeper sources, such as mesial temporal lobe epilepsy  and CT (for skull conductivity), the conventional 21-channel scalp EEG does not have high enough spatial resolution to allow for accurate source localization in most cases -single-photon emission tomography (SPECT), 18-F fluorodeoxyglucose (FDG)-Positron emission tomography (PET), and neuropsychological testing. Clinical information for these patients is summarized in Table We received approval for this study from Seirei Hamamatsu General Hospital Human Subject Committee and informed consent was obtained from all patients.Subdural strip and grid electrodes  were implanted for each patient in order to delineate the epileptogenic zone for cortical excision, and to separate it from functional areas. All electrode contacts were platinum, and interelectrode distance was 10\u2009mm. The location and types of subdural electrodes used for each patient are shown in Table The dEEG was recorded with the 256-channel Geodesic Sensor Net , providing 257 electrodes (including vertex reference) covering the face and neck as well as cranium, with 20\u201325\u2009mm interelectrode distances. The coverage of the face and neck is important for measuring the downward projection of electrical potentials from basal brain regions.We conducted simultaneous icEEG recording with NicoletOne  and dEEG with Net Amp300  at 1\u2009kHz sampling with bandpass filter 0.1 and 400\u2009Hz for approximately 30\u201340\u2009min. A digital pulse from the icEEG system was provided to the dEEG acquisition system for synchronization. Prior to the simultaneous icEEG-dEEG recording, each patient recovered from the intracranial placement for at least 3\u2009days, allowing surgical wounds to heal to avoid infection risk during simultaneous scalp recording. There were no complications due to any of the simultaneous recordings.Frequent epileptiform discharges were selected during artifact free periods in the simultaneous dEEG and icEEG recordings. Interictal spikes seen in icEEG were visually identified by a certified EEG technologist (MY) and confirmed by a board-certified clinical epileptologist (AF). As expected, many of the icEEG spikes were not detectible by inspection of the dEEG. We calculated the spike detection rate of 256-channel dEEG (with the icEEG detection as the criterion), and we measured the average maximum amplitude for both the icEEG detected spikes and the smaller subset of dEEG detected spikes.Electrical source localization was conducted at the rising phase for the dEEG detected spikes with a linear inverse method (LAURA) using the GeoSource 1.0 software packageA total of 287 spikes were recorded in icEEG with four patients during recordings of approximately 30\u201340\u2009min each. One hundred fifty-five of these spikes (54%) were also clearly distinguishable from background activity in the simultaneously recorded dEEG. The dEEG detection rate for the spikes verified by icEEG for each patient is summarized in Table p\u2009<\u20090.01) than that of dEEG undetectable spikes . The average maximal icEEG amplitude of mesial temporal spikes that were also detectable by the scalp dEEG was 1112\u2009\u03bcV (standard deviation of 197\u2009\u03bcV), significantly higher (p\u2009<\u20090.01) than that of dEEG undetectable spikes .The average maximal icEEG amplitude of neocortical interictal spikes that were also detectable by the scalp dEEG was 968\u2009\u03bcV (standard deviation of 139\u2009\u03bcV), significantly higher , IId (case 1), and IIIa (case 2) within the post-operative follow-up period 23\u201335\u2009months at this time .Simultaneous recording of non-invasive dEEG with icEEG allowed a direct comparison of the sensitivity of dEEG to epileptiform events (spikes) that were confirmed by intracranial recordings. In these four patients with neocortical  epilepsy, the non-invasive dEEG localization of spikes predicted not only the intracranial location of the spikes, but also the cortical location of seizure onset Figure .Clearly there were many spikes visible in the icEEG that were not detected through visual inspection of the dEEG. For the neocortical spikes identified by icEEG in the present study, the dEEG spike detection rate was 56%. As would be expected, the dEEG detected spikes were consistently larger in amplitude than the dEEG undetected spikes in each patient. For the mesial temporal spikes examined in our previous studies with simultaneous icEEG and dEEG , requires precise accuracy because the epileptogenic zones are often located adjacent to critical functional areas of cortex (Otsubo et al., There were several important technical limitations of this study that should be addressed in future research. We used standard 3D sensor positions, rather than the precise 3D locations of the 256-channels for each individual net application, such as can be obtained with photogrammetry (Russell et al., Simultaneous recording of dEEG and icEEG allows direct examination of the accuracy of localizing cortical electrical sources from non-invasive dEEG recordings. In four patients with neocortical epilepsy examined with 256-channel dEEG, we observed good prediction of both the interictal spikes and seizure onset as verified by icEEG. Careful non-invasive analysis of the patient\u2019s typical interictal events with dEEG may be an important first step in the neurosurgical planning for resection of the seizure onset zone.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Using a zebrafish line in which neutrophils are labelled by GFP expression, the team screened a library of fungi-derived compounds and pinpointed a mycotoxin and a natural antibiotic with specific inhibitory effects on neutrophil migration. An in vivo imaging assay showed that the antibiotic acts independently of commonly implicated signalling pathways, suggesting an unanticipated mechanism of action. This work demonstrates that zebrafish can be used as a robust in vivo platform for high-throughput drug discovery. Page 163Neutrophils are key cells of the innate immune system, the first line of defense against infection. However, neutrophils can drive a chronic inflammatory response that underlies the pathogenesis of many common diseases, including chronic obstructive pulmonary disease and inflammatory bowel disease. Despite the prominence of neutrophil-mediated inflammation in disease, there are no suitable neutrophil-targeted treatments currently available. A new report from the laboratories of Stephen Renshaw and Philip Ingham describes a novel approach for the rapid identification of compounds that can inhibit neutrophil recruitment in response to tissue injury"}
+{"text": "The high sample rate provides an attractive approach for karyotype analysis (flow karyotyping) and the purification of chromosomes in large numbers. In characterizing the chromosome complement of an organism, the high number that can be studied using flow cytometry allows for a statistically accurate analysis. Chromosome sorting plays a particularly important role in the analysis of nuclear genome structure and the analysis of particular and aberrant chromosomes. Other attractive but not well-explored features include the analysis of chromosomal proteins, chromosome ultrastructure, and high-resolution mapping using FISH. Recent results demonstrate that chromosome flow sorting can be coupled seamlessly with DNA array and next-generation sequencing technologies for high-throughput analyses. The main advantages are targeting the analysis to a genome region of interest and a significant reduction in sample complexity. As flow sorters can also sort single copies of chromosomes, shotgun sequencing DNA amplified from them enables the production of haplotype-resolved genome sequences. This review explains the principles of flow cytometric chromosome analysis and sorting (flow cytogenetics), discusses the major uses of this technology in genome analysis, and outlines future directions.Nuclear genomes of human, animals, and plants are organized into subunits called chromosomes. When isolated into aqueous suspension, mitotic chromosomes can be classified using flow cytometry according to light scatter and fluorescence parameters. Chromosomes of interest can be purified by flow sorting if they can be resolved from other chromosomes in a karyotype. The analysis and sorting are carried out at rates of 10 With some rare exceptions  were analyzed in a short time and the position of peaks in flow karyotypes corresponded with the expected distribution of chromosomal DNA content. Microscopic analysis of particles sorted onto microscope slides from each peak showed less than 20\u00a0% contamination with other chromosomes. Subsequent flow measurement of chromosomes from two Chinese hamster cell lines indicated a potential to detect chromosome rearrangements such as translocations . Initial et al. . This apl et al. , karyolol et al. , and notl et al. , 1989 sul et al. . The merl et al. .Plant mitotic chromosomes were initially released by lyzing synchronized cells into a hypotonic buffer after the enzymatic removal of their walls  are analyzed in a short time to generate univariate or bivariate flow karyotypes. This provides an accurate measurement of the frequency of different chromosome types. For instance, trisomy 21 appears as a 50-% increase in the volume of peak representing chromosome 21 as compared with other chromosome types . A successful attempt to label animal and human chromosomes in suspension was reported by Brind\u2019Amour and Lansdorp  and have been a key breakthrough in genome sequencing projects. The flow-sorted chromosome-based analysis of the wheat and barley genomes has simplified positional gene cloning especially in wheat because it is a polyploid genome, almost four times larger than that of human.Construction of physical maps and positional gene cloning requires large-insert DNA libraries. Although their construction requires large amounts of high molecular weight DNA, numerous libraries were constructed successfully from partially digested chromosomal DNA by cloning into cosmid . Production of chromosome painting probes revolutionized clinical and research cytogenetics and provided an instrument to study structural chromosome changes accompanying genome evolution in human and many lineages of animals. Dissecting large and complex genomes of some crops to smaller, chromosome-based parts has facilitated the construction of physical maps, positional gene cloning, and genome sequencing. Coupling flow cytogenetics with high-resolution DNA arrays and mass parallel sequencing has led to new applications with enormous potential for genome analysis and suggests that technology will continue to play a significant role in many areas of genetic and genomic research.Flow cytometric chromosome analysis and sorting (flow cytogenetics) is a unique technology which requires specialized equipment and thus has never been mastered by many research teams. This contrasts with the enormous impact the technology has made during the past 35\u00a0years in many areas of basic and applied research in human and many animal and plant species. Success was possible also due to the fact that molecular chromosome resources could be distributed worldwide from a few specialized laboratories. This mode of work stimulates international collaborations in which several laboratories work in parallel on different chromosomes. For example, the availability of chromosome-specific DNA libraries greatly facilitated the initial phases of the human genome sequencing project. In wheat, the production and distribution of chromosome arm-specific BAC libraries has underpinned the current international effort to sequence the huge genome (Feuillet and Eversole"}
+{"text": "The shift in marine resource management from a compartmentalized approach of dealing with resources on a species basis to an approach based on management of spatially defined ecosystems requires an accurate accounting of energy flow. The flow of energy from primary production through the food web will ultimately limit upper trophic-level fishery yields. In this work, we examine the relationship between yield and several metrics including net primary production, chlorophyll concentration, particle-export ratio, and the ratio of secondary to primary production. We also evaluate the relationship between yield and two additional rate measures that describe the export of energy from the pelagic food web, particle export flux and mesozooplankton productivity. We found primary production is a poor predictor of global fishery yields for a sample of 52 large marine ecosystems. However, chlorophyll concentration, particle-export ratio, and the ratio of secondary to primary production were positively associated with yields. The latter two measures provide greater mechanistic insight into factors controlling fishery production than chlorophyll concentration alone. Particle export flux and mesozooplankton productivity were also significantly related to yield on a global basis. Collectively, our analyses suggest that factors related to the export of energy from pelagic food webs are critical to defining patterns of fishery yields. Such trophic patterns are associated with temperature and latitude and hence greater yields are associated with colder, high latitude ecosystems. Resident fish yield in the Northeast Pacific for eleven different fishing areas was strongly and linearly correlated (r2\u200a=\u200a0.87) with the mean chlorophyll a concentration, which provided an adequate proxy of primary production in this system a and fisheries yield (r2\u200a=\u200a0.69) was found across nine coastal areas in the Northwest Atlantic 2\u200a=\u200a0.73) and for all fish species (r2\u200a=\u200a0.64) 2\u200a=\u200a0.96), but the analysis included only 10 sites and excluded upwelling regions and areas with strong tidal mixing. In the regional analyses for marine ecosystems, where yield and some measure of primary production have been examined, the linear relationship is generally positive; however, this relationship is not consistent when global patterns are examined.Regional-scale analyses, those that have analyzed a subset of world ocean basins or some portion of a basin, have used both measured and proxy estimates of primary production as a predictor of the associated fish yield. One often-used proxy of primary production is chlorophyll \u22122 y\u22121) Robust relationships between estimates of primary production and fisheries yield at global scales have been difficult to discern. In an analysis of global fishery yields disaggregated by 64 globally-distributed Large Marine Ecosystems (LMEs), total yields were found to scale with rates of net primary production  sensor. We used the monthly level-3 processed data averaged over each LME for the period 1998\u20132009 to compute an annual mean concentration (mg m\u22123) (http://oceancolor.gsfc.nasa.gov). Chlorophyll concentrations were fourth root transformed for the Pearson product-moment correlation analysis.Chlorophyll http://www.science.oregonstate.edu/ocean.productivity). The Vertically Generalized Production Model (VGPM) estimates NPP using photosynthetically available radiation, chlorophyll, an estimate of the euphotic zone depth, and a temperature-dependent estimate of the maximum photosynthetic rate th order polynomial to describe the relationship between the maximum photosynthetic rate and temperature which was derived from a North Atlantic dataset and exhibits a peak near 20\u00b0C. The Eppley-VGPM replaces the 6th-order polynomial with a monotonically increasing exponential relationship supported by global compilations of phytoplankton growth rate data There are a large number of algorithms used to estimate NPP from remote sensing data. The remote sensing community has conducted a series of reviews titled \u201cprimary production algorithm round robins\u201d (PPARR) that evaluated NPP models using a range of performance statistics and differing calibration datasets Eppley-VGPM had root mean square difference (RMSD) errors that were lower than the VGPM model in 9 of 10 study sites , decreasing pe-ratios with increasing euphotic zone depth (attributed to extended time in the euphotic zone before export), and increasing pe-ratios with increasing primary productivity . We used the multi-linear regression fit provided in Dunne et al. pe-ratio, which is given as:eu is the euphotic zone depth, estimated from surface chlorophyll using the relationships of Morel and Berthon tot is the total pigment or total chlorophyll a content within the euphotic layer, which is scaled non-linearly with chlorophyll concentration in the surface layer of the ocean, Csur.pe-ratio based on Eppley-VGPM was log-normally distributed so a log-transformed was used for the Pearson product-moment correlation analysis. The product of pe-ratio and NPP yields an estimate of particle export flux, pe-flux, which unlike the scalar of pe-ratio represents a system flux rate. This flux was log transformed for the Pearson product-moment correlation analysis.There are a number of published models to estimate the ratio between rapidly sinking particulate matter from the euphotic zone and primary production, or the particle export ratio (z-ratio) for each LME from the model estimates provided in Stock and Dunne z-ratio estimates derived from in situ measurements of primary production, mesozooplankton biomass, and empirically-derived estimates of mesozooplankton growth rates z-ratio estimates obtained from the mesozooplankton biomass estimates from the COPEPOD database z-ratios, but is characterized by considerable small-scale variability from fluctuations in mesozooplankton biomass. The model indicates a pronounced increase in the z-ratio as primary productivity increases, with the transition to high z-ratios occurring at lower NPP in cold water  Total monthly fisheries yield is correlated to annual mean SST and LME centroid latitude in a complementary fashion: greater yield is associated with lower mean SST and positively correlated with higher latitudes . The pria concentration  with chlorophyll ntration  for bothntration . All thentration .Eppley-VGPM NPP resulted in a bivariate distribution with respect to total fisheries yield with no detectable correlation using either the untransformed or transformed data  in both untransformed and transformed data treatments  and phytoplankton biomass . Both of these interpretations have serious limitations at global scales. The assignment of high chlorophyll concentration in an environment as a proxy for phytoplankton biomass can be problematic. Chlorophyll concentration can indicate the potential of substantial net primary production, but also the capacity of the phytoplankton assemblage to outgrow and/or inhibit predation activity The concentration of chlorophyll a, particle export flux and the ratio of mesozooplankton production to primary production are highly correlated with fishery yields on a global basis. The former is directly related to measures of the ratio of new primary production to total production (the sum of new and recycled production). New primary production is directly available to mesozooplankton which in turn supports production of upper trophic levels. The ratio of mesozooplankton production to primary production reflects transfer efficiencies between two critical components of the food web affecting fishery productivity. These metrics provide more detailed insights to fishery production throughout the world ocean than chlorophyll concentration alone. The additional mechanistic detail, coupled with their ability to explore different pathways and respond to more explicitly known processes offsets the less than straightforward calculations needed to obtain such measures as compared to chlorophyll a estimates. Although all three measures are associated with global fisheries yields, the rationale for why one would want to use these rate measures beyond the easier to measure and obtain chlorophyll a estimates reside in the purpose of exploring such relationships; simple and cursory predictions may imply chlorophyll would be fine in some circumstances, whereas more nuanced considerations and explorations would likely merit use of the rate measures we describe here.While the detection of chlorophyll is more directly indicative of the dynamics of the lower trophic level of a region than is latitude or SST, a more complete understanding of the mechanisms underlying the global scale relationship of chlorophyll and fisheries yield is needed. Like chlorophyll pe- and z-ratios with increasing NPP, and second, SST is negatively correlated with both ratios for the vast majority of NPP values. These two patterns correlate to the observed high fishery yields in moderate to highly productive ecosystems in temperate and sub-polar regions, producing improved correlations relative to primary production.Particle export flux and mesozooplankton production are both estimates of the export of energy from the planktonic foodweb to forms more readily available to fisheries  and offer deeper mechanistic understanding still of fishery production processes. Such a connection can be used to understand differences in yield among regions. Two major patterns are apparent in the particle flux and mesozooplankton production indices: first , there is a non-linear transition from low to high pe-/z-ratios and particle export fluxes/mesozooplankton production to high values with increasing NPP (z-ratio because ingestion rates become large relative to basal metabolic costs in more productive ecosystems. These explanatory mechanisms are consistent with Ryther's theoretical arguments for the relationship between primary production and fish production A major driver of the shift from low sing NPP  is the tpe- and z-ratio in a number of ways to create the negative correlation with SST. First, faster remineralization rates in warmer temperatures decrease pe-ratios in warm water ecosystems z-ratio, simultaneous increases in phytoplankton growth rates and zooplankton ingestion rates with increasing temperature stabilizes the biomass at which small phytoplankton growth nears its maximum and large phytoplankton becomes prevalent. The small phytoplankton growth rate at this transition point, however, is higher at higher temperatures z-ratio estimates derived from a combination of in-situ data and empirical models Temperature acts on the There was no strong evidence in the analysis that pelagic and demersal fisheries respond differently to primary production and rates related to trophic transfer. In particular, estimated particle export flux and mesozooplankton production performed similarly well as predictors of both pelagic and demersal fish, though the former flux is thought to primarily fuel benthic production and the later pelagic. This in part reflects the similarity of emergent trends in both quantities that arises for the common linkage of these quantities to changes in planktonic foodweb structure. It may also reflect the prevalence of fish that interact with both the demersal and pelagic foodwebs, supporting the interpretation that many functional groups assumed to feed in a particular sector of the water column likely feed in multiple sectors. As has been noted, many of these fishes show clear feeding tendencies, but even appropriation into feeding guilds still exhibits high dietary overlaps across guilds pe- and z-ratios represent low-frequency broad-scale changes that underlie significant unresolved spatial and temporal variations. In the case of the z-ratio, the modeled transition to high z-ratio state is delayed relative to independent z-ratio estimates. Analysis against region-specific data and further improvement of these models is needed. A second consideration is the potential impact of uncertainties in satellite-based NPP measurements; as model validation improves with improving global calibration data, NPP estimates should be re-evaluated. Thirdly, NPP temporal variability has recently been associated with catch trophic level and yield leading to the suggestion that lower yields are associated with less variable ecosystems and higher yield associated with greater variability There are a number of limitations of the analyses herein that will be addressed in future work. First, the observed patterns in pe-ratio also suggests that ecosystem models not only need to account for lower trophic level linkages, but should also explicitly model the vertical distribution of organic carbon. It would seem the dimensional distribution of particulate carbon energy may be important to movement of energy up the food chain and that reduction of energy distribution from three to two dimension plays a role. It would be useful to explore other measures of energy movement beyond pe-ratio which is tied to rates of primary production. It may be useful to consider rates independent of phytoplankton production or rates related to plankton biomass. Furthermore, it would be useful to explore regional and time series data to see if relationships could be developed to estimate yield potential based on the spatial aspects of the trophic transfer of primary production.Accounting for variations in the dynamics of planktonic ecosystems in the context of NPP and temperature change remains an essential step for understanding upper trophic level yields. Understanding these trophic linkages should guide more parsimonious ecosystem model development, especially as it relates to linked ecosystem models that may be applied to fishery and marine spatial planning problems. The prominence of the association between yield and"}
+{"text": "The studies suggest a complex interaction between cannabis and Nrg1: the neuro-behavioral effects of cannabinoids were different in Nrg1 mutant and control mice and depended on exposure time, sex, and age of test animals. This research provides the first evidence of complex cannabis-Nrg1 interactions suggesting Nrg1 as a prime target for future clinical investigations. Furthermore, it highlights that animal model research can broaden our understanding of the complex multi-factorial etiology of schizophrenia. Finally, the findings are important to preventive psychiatry: if the genes that confer genetic vulnerability to cannabis-induced psychosis were identified patients at-high risk could be forewarned of the potential dangers of cannabis abuse.The link between cannabis and psychosis has been debated although there is substantial epidemiological evidence showing that cannabis increases the risk of psychosis. It has been hypothesized that schizophrenia patients carrying particular risk genes might be more sensitive to the psychosis-inducing effects of cannabis than other patients and healthy test subjects. Here we review the effects of cannabinoids on a mutant mouse model for the schizophrenia candidate gene  Neuregulin 1 (NRG1) is one of the more promising schizophrenia candidate genes as associations with schizophrenia have been found in several studies  was implicated in conferring vulnerability to cannabis-induced psychosis  during adolescence and exhibited a greater behavioral sensitivity to the long-term effects of THC , which is devoid of psychoactive properties and has been reported to block or reverse effects of THC and have antipsychotic properties  has shown compelling face, construct, and partial predictive validity for schizophrenia research  receptors . Surprisingly, the mutants also showed improved sensorimotor gating following THC challenge as measured by prepulse inhibition of the startle response (PPI) . In summary, these animal studies provided the very first evidence for an interaction between the schizophrenia risk gene Nrg1 and cannabis and implied that stress and gender may also influence these interactions.The increased behavioral susceptibility of male Nrg1 mutants to long-term cannabinoid exposure. Nrg1 mutant and control mice were treated chronically with the synthetic CB1 receptor agonist CP 55,940 . Mutant mice showed a selective increase in CP 55,940-induced FosB/\u0394FosB expression in the LSV, which is a marker for long-term neuroadaptive changes. These findings suggest that Nrg1 is not only involved in the acute neuro-behavioral response to cannabinoids but also modulates neuroadaptive responses to long-term cannabinoid challenge. Furthermore, it confirms the LSV as an important brain region for Nrg1\u2013cannabinoid interactions. This could be related to the fact that the lateral septum shares reciprocal projections with the hypothalamus and the amygdala and receives cognitive input from the hippocampus and the prefrontal cortex . Interestingly, ErbB4 is localized in dopaminergic neurons in the substantia nigra  at baseline. Furthermore, chronic CBD also increased GABAA receptor binding in the granular retrosplenial cortex of mutant mice suggesting that Nrg1 may not only modulate neuro-behavioral actions of THC but also of CBD in a task- and brain region-specific manner. Further research using a variety of CBD doses thereby considering dose and age-effects will address the issue of varying or even opposing effects of different cannabinoids more comprehensively.The Nrg1 mouse model has enabled the detailed analysis of acute vs. chronic effects of cannabinoids at different stages of brain development. Nrg1 modulated the behavioral sensitivity of mice to cannabinoids differentially during adolescence and adulthood providing evidence for a role of Nrg1-cannabis interactions in schizophrenia. Furthermore, insights into the molecular and neurobiological mechanisms of Nrg1-cannabinoid interactions  would not have been possible without utilizing these mouse mutants. Future research will extend on our initial findings and address sex specificity and the opposite effects of CB1 stimulation in adolescence (Nrg1 mutant less susceptible) and adulthood (Nrg1 mutants more susceptible) in greater detail. Finally, models of cannabinoid addiction should be considered given the significant comorbidity of schizophrenia and drug dependence.In summary, the transmembrane domain The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Head movements can greatly affect swallowing accelerometry signals. In this paper, we implement a spline-based approach to remove low frequency components associated with these motions. Our approach was tested using both synthetic and real data. Synthetic signals were used to perform a comparative analysis of the spline-based approach with other similar techniques. Real data, obtained data from 408 healthy participants during various swallowing tasks, was used to analyze the processing accuracy with and without the spline-based head motions removal scheme. Specifically, we analyzed the segmentation accuracy and the effects of the scheme on statistical properties of these signals, as measured by the scaling analysis. The results of the numerical analysis showed that the spline-based technique achieves a superior performance in comparison to other existing techniques. Additionally, when applied to real data, we improved the accuracy of the segmentation process by achieving a 27% drop in the number of false negatives and a 30% drop in the number of false positives. Furthermore, the anthropometric trends in the statistical properties of these signals remained unaltered as shown by the scaling analysis, but the strength of statistical persistence was significantly reduced. These results clearly indicate that any future medical devices based on swallowing accelerometry signals should remove head motions from these signals in order to increase segmentation accuracy. Patients living with the effects of stroke or neurodegenerative conditions commonly encounter swallowing difficulties (dysphagia) Previous contributions have observed that swallowing accelerometry signals contain low frequency components associated with head motions e.g., . ExtensiIn this paper, we analyzed the data collected in previous studies of swallowing accelerometry First, each participant was cued to perform 5 saliva swallows. Subsequently, the participant completed 5 water swallows by cup with their chin in the natural position  and 5 water swallows in the chin-tucked position , while schemes based on higher order polynomials take longer time to execute Our data analysis was a three-part process. The first two parts involved the analysis of the proposed approach using synthetic signals, while the third part involved the analysis of real dual-axis swallowing accelerometry signals that were acquired as described in Section \u201cData collection\u201d.In the first part, we simulated swallowing signals to analyze the effects of varying signal-to-noise ratio (SNR) on the value of Using these simulated signals, our goal was to investigate the optimal value of In the second part of the analysis we compared performances of our approach against well known approaches based on empirical mode decomposition (EMD) The third part of our experiment involved the analysis of real swallowing signals as described in Section \u201cData collection\u201d. Specifically, we examined the effect of removing low frequency components associated with head movements on segmentation accuracy and statistical persistence observed in these signals. To investigate the effects on the segmentation accuracy, we initially segmented recordings containing head movements using the procedure described in In order to establish statistical significance of our results, a non-parametric inferential statistical method known as the Mann-Whitney test was used The results for the last part of our analysis are summarized in We should mention that removing low frequency components associated with head motions did introduce any previously unreported trends In this paper, an approach for the removal of low frequency components associated with head movements was proposed for dual-axis swallowing accelerometry signals. The scheme is based on spline least square approximations of the signal and is well-suited for long signals. First, we carried out a comparative analysis of our spline-based scheme against well-known approaches using synthetic signals. We found that the spline-basesd scheme provided more accurate segmentation results. Then, dual-axis swallowing accelerometry signals collected during 3 swallowing tasks completed by 408 healthy participants were processed using the spline approach. In particular, we found that by removing low frequency components associated with head movements we increased the accuracy of the segmentation process. Nevertheless, we observed a significant decrease in the strength of statistical persistence suggesting that any accelerometry-based decision support tools should remove these low-frequency components since they could confound the decision support process."}
+{"text": "The increased risk of coronary artery disease in human immunodeficiency virus (HIV) positive patients is collectively contributed to by the human immunodeficiency virus and antiretroviral-associated dyslipidaemia. In this study, we investigate the characterisation of the plasma lipid profiles of treated HIV patients and the relationship of 316 plasma lipid species across multiple lipid classes with the risk of future cardiovascular events in HIV- positive patients.In a retrospective case-control study, we analysed plasma lipid profiles of 113 subjects. Cases (n\u200a=\u200a23) were HIV-positive individuals with a stored blood sample available 12 months prior to their diagnosis of coronary artery disease (CAD). They were age and sex matched to HIV-positive individuals without a diagnosis of CAD (n\u200a=\u200a45) and with healthy HIV-negative volunteers (n\u200a=\u200a45).Association of plasma lipid species and classes with HIV infection and cardiovascular risk in HIV were determined. In multiple logistic regression, we identified 83 lipids species and 7 lipid classes significantly associated with HIV infection and a further identified 74 lipid species and 8 lipid classes significantly associated with future cardiovascular events in HIV-positive subjects. Risk prediction models incorporating lipid species attained an area under the receiver operator characteristic curve (AUC) of 0.78 ) and outperformed all other tested markers and risk scores in the identification of HIV-positive subjects with increased risk of cardiovascular events.Our results demonstrate that HIV-positive patients have significant differences in their plasma lipid profiles compared with healthy HIV-negative controls and that numerous lipid species were significantly associated with elevated cardiovascular risk. This suggests a potential novel application for plasma lipids in cardiovascular risk screening of HIV-positive patients. With advances in antiretroviral therapy (ART) and the management of HIV disease there have been substantial improvements in disease-free survival for individuals with HIV Disequilibrium in lipid metabolism is key to the formation and rupture of the atherosclerotic plaques which underpin coronary artery disease (CAD). ART-induced dyslipidaemia is classically characterised by elevated triglycerides, total cholesterol and low-density lipoprotein cholesterol (LDL-C), with reduced high-density lipoprotein cholesterol (HDL-C) Attempts to rectify this by incorporating HIV factors such as the duration of exposure to specific antiretrovirals into traditional risk scores have to date not contributed significantly to the overall accuracy of risk predication models This study aims to describe the differences in plasma lipid profiles between HIV-positive patients with and without CAD and healthy participants so as to develop and cross-validate a predictive model for future cardiovascular events in HIV-positive patients.Participants provided written informed consent for the original study and for their samples to be stored and used for future research. This project received ethics approval from the Alfred Hospital Research and Ethics Committee (Project number 205/09).This study was based on a subset of patients drawn from a retrospective case- control study on HIV-positive patients who were seen at the Alfred Hospital, Melbourne, Australia from January 1996 to December 2009. The aim of original study was to determine risk factors for the development of CAD in the Australian context. A detailed description of the methods and results have been described elsewhere Stored specimens were retrieved from The Victorian HIV Blood and Tissue Storage Bank (VHBTSB) . From the original study, 23 HIV cases had stored plasma samples available. The 23 cases were frequency-matched for age, sex, body mass index (BMI) and systolic blood pressure to 45 HIV controls for lipidomic profiling. Samples from 45 HIV-negative healthy subjects with no prior history of cardiovascular disease  were drawn from the Baker IDI Heart and Diabetes Institute biobank and also frequency- matched to the HIV controls for age, sex, BMI, systolic blood pressure and date of sample collection.Lipidomic analysis of 316 lipid species from 24 lipid classes was performed as previously described Multiple binary logistic regression was applied to examine the association of plasma lipid species with HIV infection independent of cardiovascular risk. This analysis was based on the HIV control group and the healthy control group adjusting for significant non-lipid related characteristics  between the groups. To examine the association of plasma lipid species with cardiovascular risk in HIV subjects we applied multiple binary logistic regression adjusting for significant non-lipid related characteristics (current statin treatment) between the HIV case and HIV control groups. The odds ratios obtained in these analyses represent a change in the risk of being associated with an outcome (either being HIV-positive or having a future cardiovascular event if HIV-positive) corresponding to an interquartile range increase in lipid species measurement. The p-values were corrected for multiple comparisons using the Benjamini-Hochberg method Models were developed to predict future cardiovascular events in HIV-positive subjects through the application of statistical machine learning approaches similar to that applied in previous related work Participant characteristics for each group are described in There were six lipid classes  that were negatively associated with HIV while diacylglycerol was positively associated . Not allWithin the HIV groups, diacylglycerol showed a further positive association with cardiovascular events and this was accompanied by positive associations in seven other lipid classes  . There wThe performance of all predictive models for future cardiovascular events is presented in Dyslipidemia is well described and common in patients with HIV infection on ART. In our study, we describe the significant differences in plasma lipid profiles between HIV-positive patients and healthy HIV-negative volunteers, whilst also identifying lipid species significantly associated with future cardiovascular events in HIV-positive patients.Increased de novo lipogenesis, the process by which acetyl-CoA is converted to fatty acids, has previously been observed in HIV Interestingly, several lipid classes were found to be negatively associated with HIV infection, these included monohexosylceramide, dihexosylceramide, GM3 ganglioside and sphingomyelin all of which are metabolites of ceramide and suggest a possible dysregulation of sphingolipid metabolism in HIV infection , albeit Oxidative stress in HIV disease has previously been characterised in Pace et al. The observed positive association of diacylglycerol with both HIV infection and future cardiovascular events and triacylglycerol with future cardiovascular events appear to be consistent with previous findings The alterations of fatty acid metabolism leading to elevated free fatty acid and subsequently elevated diacylglycerol and triacylglycerol appear to be exacerbated in individuals who progress to the development of CAD and subsequent cardiovascular events. This also appears to affect other lipid metabolic pathways; while we observed a decrease in several ceramide metabolites associated with HIV infection, in those individuals who subsequently experienced a cardiovascular event we observe a positive association with ceramide itself that may be driven by a dual effect of increased free fatty acid leading to an increased ceramide production and a down regulation of ceramide conversion into downstream metabolites. Further effect of free fatty acids driving the production of phosphatidylethanolamine, phosphatidylglycerol and phosphatidylinositol were also observed . We haveAntiretroviral (ARV) therapy including the use of protease inhibitors (PIs), nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and fusion inhibitors are known to have different effects on the plasma lipid profile We postulate that a patient's lipidomic response to HIV infection and HIV therapy can vary based on a number of currently unidentified factors and that patients who develop a more significant elevation of diacylglycerols and dysregulation of other related metabolic pathways are at higher risk of future cardiovascular events.Risk prediction models based on existing cardiovascular risk scores demonstrated limited performance in predicting cardiovascular events in the HIV-positive participants included in this study. The D:A:D (CHD 10 year) risk score which takes into account exposure to specific antiretroviral therapies in addition to traditional CAD risk factors, the Framingham (CHD 10 year) score and the Reynolds (CHD 10 year) scores were comparable in performance  and did not perform as well as predictive models based on conventional lipid predictors . The conventional lipid model performed well  and an accuracy \u200a=\u200a74.5% ) in reflecting the more severe dyslipidemia in HIV-positive subjects who experienced future cardiovascular events in this study. However, the lipid species model performed best with an AUC of 0.78  and an accuracy of 79%  as it exploits more specific markers of the dyslipidemia at the individual species level.In conclusion, HIV-positive patients demonstrate significant abnormalities in their plasma lipid profiles compared with healthy volunteers. The degree of these changes appears to relate to the risk of future cardiovascular events. Predictive models of future cardiovascular events based on plasma lipid profiles demonstrate the potential to outperform traditional risk equations in HIV populations which, if confirmed in larger trials, may allow for the accurate, targeted utilisation of primary preventative strategies. The strongest markers associated with elevated cardiovascular risk in HIV-positive patients were identified to be diacylglycerol and triacylglycerol species where individual species outperform the clinical measure of triglycerides. This suggests the possible dysregulation of the triacylglycerol biosynthetic pathway and/or VLDL metabolism where individuals at greater risk display a more severe elevation in particular triacylglycerol species. This observation may have therapeutic implications and warrants further investigation into the effect of treatment of hypertriglyceridemia in HIV-positive subjects on diacylgylcerol and triacylglycerol levels. An extended study looking at the impact of individual antiretroviral regimens on plasma lipidome may further advance our understanding of the pathogenesis of ART-associated cardiovascular risk and allow for individualised treatment decisions in those at high risk.Statistical power is limited in this study due to its small sample size. Most HIV-positive participants in this study were treatment-experienced, but as these proportions were matched between the HIV cases and controls and we cannot comment on the individual contributions of HIV infection and ART to changes in lipid species. The study group were mostly male (91%) and so further studies are required to validate these findings in females. While the associations identified in the analysis are expected to hold in larger population-based studies, the predictive model for future cardiovascular events is proof-of-concept and does not represent a final model for clinical utility. The model does however demonstrate the potential gain in predictive performance that may be achieved through the use of plasma lipid species as novel biomarkers of cardiovascular risk over the use of conventional clinical lipids and existing cardiovascular risk scores.File S1This supplementary material contains Protocol S1 and Table S1. Experimental Protocol. Sample preparation and lipid extraction. High performance liquid chromatography-mass spectrometry analysis. Assay performance. Table S1. Association of lipid species and lipid classes with future cardiovascular events in HIV positive individuals and HIV infection.(DOCX)Click here for additional data file."}
+{"text": "Various neurons exhibit membrane potential (or subthreshold) resonance , a peak h) and persistent sodium (INap). This model is based on measurements for stellate cells (SCs) in layer II of the medial entorhinal cortex [h/INap model describes the cell's subthreshold dynamics and the onset of spikes [In this work, we investigate the firing frequency patterns generated in response to both current and conductance sinusoidal inputs in a biophysical (conductance-based) neuron model that includes two ionic currents: h- (Il cortex  and captl cortex . The Ih/f spikes . Spikes f spikes ).h/INap model to both current and conductance sinusoidal inputs for a wide range of frequencies and input amplitudes (Ain). The resulting patterns for current and conductance input are qualitatively different. For current inputs, the firing frequency  patterns show up to three prominent peaks with heights that differ only slightly. The number of peaks increases with increasing values of Ain. For small values of Ain, the peak input frequency coincides with the subthreshold resonant frequency. The voltage traces (voltage vs. time) corresponding different peaks for the same value of Ain have roughly the same number of spikes , and differ in the number of subthreshold oscillations interspersed in between two consecutive spikes. For conductance (excitatory) inputs, the firing rate patterns show multiple peaks with different heights. As Ain increases, the highest peak moves to the right. For input frequencies above 60 Hz, the firing rate and gain of the highest peak significantly increases relative to other peaks for the same value of Ain. This prominent peak reflects the fast time scale present in the model that has been shown to underlie hyper-excitable firing in SCs [We computed the firing rate and signal gain responses of the IWe use dynamical systems tools to explain the mechanism that govern the generation of the firing frequency patterns described above. We show that the nonlinearities present in the model and the time scale separation between voltage and the h-current gating variables play an important role in determining these patterns."}
+{"text": "Molecular mechanisms in the brain are assumed to cause the symptoms and severity of neuropsychiatric disorders. This review concerns the elusive nature of relationships between the severity of depressive disorders and neuromolecular processes studied by positron emission tomography (PET). Recent PET studies of human depression have focused on serotonergic, dopaminergic, muscarinic, nicotinic, and GABAergic receptors, as well as central processes dependent on monoamine oxidase, phosphodiesterase type 4, amyloid plaques, neurofibrillar tangles, and P-glycoprotein. We find that reliable causal links between neuromolecular mechanisms and relief from depressive disorders have yet to be convincingly demonstrated. This situation may contribute to the currently limited use of PET for exploring the neuropathways that are currently viewed as being responsible for beneficial effects of antidepressant treatment regimes. Depressive disorders continue to attract much attention due to their detrimental impact on individuals and societies  and binding potentials (phenotypes). As a result, the findings cannot indicate whether there were any reliable differences between properties of serotonin transporters in depressed versus non-depressed subjects. Special procedures, most of which are unfamiliar to the present authors, were used in the data analysis to adjust for multiple correlated comparisons. Binding potentials of [11C]DASB by serotonin transporters in thalamus and insula were associated with one genetic variant of serotonin type 2A receptors (rs7333412). Laje and coworkers proposed that genetic variation in serotonin type 2A receptors and either functional aspects of serotonin transporters or central serotonergic transmission affect the therapeutic response to drug-induced inhibition of serotonin transport in major depression, although their findings provided no direct empirical evidence for such claims.Laje et al.  also use11C]WAY-100635 by serotonin type 1A receptors differs between healthy subjects, depressed patients, and depressive patients in remission. Their previous work had shown an increase in serotonin type 1A receptor binding in depressed patients G promoter polymorphisms. Similarly, estimates of binding potentials by a reference region method provided no reliable difference between bipolar depressed patients and never-depressed subjects.Sullivan and coworkers studied binding of [11C]WAY-100635 to examine possible sources of discrepancies in previous studies concerning whether regional binding potentials of serotonin type 1A receptors are higher or lower in major depressive disorders than in non-depressed subjects. As noted above , whereas no such differences were noted for [18F]FP-TZTP binding between healthy subjects and subjects with unipolar depressive disorder. Cannon and coworkers interpreted their finding of relatively low [18F]FP-TZTP binding in bipolar disorder in relation to the nucleotide sequence coding for the muscarinic type 2 receptor. In our view, that is a truly bold hypothesis on the basis of a single study.Cholinergic neurotransmission has a widespread distribution in the brain and the parasympathetic nervous system -rolipram for PET to probe the cAMP second messenger system in healthy subjects and depressed patients -rolipram binding was reliably lower throughout the brain of depressed patients than in healthy subjects, with no reliable correlations between radioligand binding and the severity of depressive symptoms.Fujita and coworkers used [18F]DDNP to see whether amyloid plaques and neurofibrillar tangles are also present in the brain of middle-aged and older subjects with mild-to-moderate depressive disorders, with and without mild cognitive impairment. None of the subjects had required antidepressant drug treatment. Depressive symptoms in subjects with mild cognitive impairment were associated with increased binding of [18F]DDNP in lateral temporal regions, whereas symptoms of depression in subjects without mild cognitive impairment were associated with increased binding of [18F]DDNP in medial temporal regions. Thus, amyloid plaques and neurofibrillar tangles were identified by PET in elderly, mildly depressed subjects, regardless of their cognitive condition.Pathological changes in the brain consisting of amyloid plaques and neurofibrillar tangles typically herald cognitive disturbances in Alzheimer disease (Vardy et al., 18F]DDNP for PET to explore possible links between depressive disorders and amyloid plaques and neurofibrillar tangles (Kumar et al., 18F]DDNP in several cortical brain regions was higher in the group with late-life depression than in the age-matched, non-depressed group.Kumar and coworkers also used [11C]verapamil for PET brain imaging in a group of severely depressed subjects receiving various antidepressant drugs and in a group of non-depressed, unmedicated subjects. The binding of [11C]verapamil in the whole brain failed to differ reliably between groups, while regional data analysis indicated that levels of [11C]verapamil were lower in prefrontal cortex and temporal lobes of depressed subjects than in healthy controls. de Klerk and coworkers interpreted their finding in relation to the possible impact of long-term usage of antidepressant drugs and/or treatment-resistant depression on the P-glycoprotein pump.The blood-brain barrier limits the bi-directional passage of molecules, while the removal of certain molecules from the brain is enhanced by the P-glycoprotein efflux pump. Verapamil is a calcium channel blocker that is removed from the brain by the P-glycoprotein pump, and the drug can be radiolabeled with a positron-emitting nuclide and used to study the P-glycoprotein pump (Bartels et al., 18F]DDNP was used in two recent studies that found an association between binding by amyloid plaques and neurofibrillar tangles in temporal lobes of elderly subjects with mild-to-moderate depression. That finding concurs with reports on neuropathology in temporal cortex of depressed subjects (Saylam et al., 18F]FP-TZTP and [18F]FA-85380 between healthy subjects and subjects with depressive disorders. With regard to GABAergic neurotransmission, much evidence implicates disturbances of function in depression as well as other neuropsychiatric disorders (Rudolph and Knoflach, 11C]flumazenil are of interest in that respect (Klumpers et al., The diversity of recent PET studies on non-monoaminergic mechanisms in depressive disorders precludes general statements concerning the findings. [The search continues for PET radioligands that can disclose causal links between the binding properties of central neuromolecular processes and the clinical condition of people suffering from depressive disorders. Our account of PET findings presented in this review is both critical and harsh, based on our serious concern regarding the current lack of clear-cut relationships between neuromolecular processes as measured by PET and changes in the severity of depression. In particular, beneficial effects of potent antidepressant treatments have typically failed to affect neuroreceptor binding of PET radioligands in subjects who were depressed at the start of the study, but who experienced clear-cut reductions in symptom severity. We are aware that lack of effect of beneficial antidepressant treatment on receptor binding in depressed subjects can be said to reflect a so-called \u201ctrait variable,\u201d but we fail to see the value of that notion since it has no impact on treatment strategy. What is more, the notion of a \u201ctrait variable\u201d as a stable, neuromolecular abnormality fails to take into account the possibility that the foreign experience of being constrained in a PET scanner and having a radioactive substance injected into a vein may affect brain function differently in depressed subjects than in healthy volunteers. If that were to occur, then the PET findings would reflect a so-called \u201cstate variable\u201d rather than a \u201ctrait variable.\u201dThe failure of changes in the clinical condition of depressed subjects to be reliably linked with changes in binding of PET radioligands in the living brain adds to the disappointment that currently surrounds the field (Jones and Rabiner, The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Early investigations of cerebellar function focused on motor learning, in particular on eyeblink conditioning and adaptation of the vestibulo-ocular reflex, and led to the general view that cerebellar long-term depression (LTD) at parallel fiber (PF)\u2013Purkinje cell (PC) synapses is the neural correlate of cerebellar motor learning. Thereafter, while the full complexity of cerebellar plasticities was being unraveled, cerebellar involvement in more cognitive tasks\u2014including spatial navigation\u2014was further investigated. However, cerebellar implication in spatial navigation remains a matter of debate because motor deficits frequently associated with cerebellar damage often prevent the dissociation between its role in spatial cognition from its implication in motor function. Here, we review recent findings from behavioral and electrophysiological analyses of cerebellar mutant mouse models, which show that the cerebellum might participate in the construction of hippocampal spatial representation map  and thereby in goal-directed navigation. These recent advances in cerebellar research point toward a model in which computation from the cerebellum could be required for spatial representation and would involve the integration of multi-source self-motion information to: (1) transform the reference frame of vestibular signals and (2) distinguish between self- and externally-generated vestibular signals. We eventually present herein anatomical and functional connectivity data supporting a cerebello-hippocampal interaction. Whilst a direct cerebello-hippocampal projection has been suggested, recent investigations rather favor a multi-synaptic pathway involving posterior parietal and retrosplenial cortices, two regions critically involved in spatial navigation. Whilst the cerebellum has long been exclusively associated with motor function, its role in cognitive processes has, in the last decades, progressively become apparent. This review will first focus on the original work leading to the major hypothesis that long-term depression (LTD) at parallel fiber (PF)\u2013Purkinje cell (PC) synapses underlies cerebellar motor learning. We then provide an overview of the arguments suggesting that cerebellar processing is also required in cognitive function such as spatial navigation and that it contributes to both hippocampal spatial map formation and optimal goal-directed navigation. The potential computation undertaken by the cerebellum for building hippocampal spatial representation is also discussed. Finally, the possible anatomical pathways involved in this cerebello-hippocampal association are explored.LTD refers to an activity-dependent long lasting decrease in synaptic efficacy. This anti-hebbian form of synaptic plasticity was initially discovered in and thought to be unique to the cerebellum Contribution of the cerebellum to cognitive functions such as navigation remains a controversial subject. Indeed, whilst an extensive range of cerebellar functions has been pointed out as early as 1950 Snider, .It can however be acknowledged that the view of the cerebellum in cognitive function has evolved with reports describing dysfunction of non-motor processes in patients with cerebellar pathology as well as findings from neuroimaging studies in normal adults  which displays a postnatal specific degeneration of virtually all cerebellar PCs  and the mossy fiber\u2013granule cells\u2013PF input. Rondi-Reig et al.  tested rRecent use of the L7-PKCI transgenic model, in which the PKC dependent LTD that occurs at PF\u2013PC synapses is altered, brought new insight regarding the process performed by the cerebellum \u2014one synapse downstream the PCs\u2014that has been shown to encode motion in body coordinates  are selectively active during passively applied movements   is a multi-modal cortical area integrating self-motion and visuo-spatial information (Snyder et al., The retrosplenial cortex is also thought to be involved in the allocentric-to-egocentric transformation process (Vann et al., Therefore, the cerebellum may contribute to two major circuits crucial for the representation of space in the hippocampal system Figure : one comRecent converging evidence demonstrates the importance of the cerebellum in spatial navigation. Such implication in the navigation system at the hippocampal level or in forebrain navigation areas has been elucidated using electrophysiological, anatomical, and behavioral analyses in both human and animal models. Although the cerebellar network does not encode a spatial map of the environment, it does participate in map formation in the forebrain navigation areas by specifically encoding and computing self-motion information from different sources required to build the representation of the body in space. PF\u2013PC LTD is implicated in this process, and other as yet to be determined modes of cerebellar plasticity may participate as well. The recent development of tetrodes multi-unit recordings in rat's cerebellum (de Solages et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Brain-computer interfaces (BCIs) are systems that use real-time analysis of neuroimaging data to determine the mental state of their user for purposes such as providing neurofeedback. Here, we investigate the feasibility of a BCI based on speech perception. Multivariate pattern classification methods were applied to single-trial EEG data collected during speech perception by native and non-native speakers. Two principal questions were asked: 1) Can differences in the perceived categories of pairs of phonemes be decoded at the single-trial level? 2) Can these same categorical differences be decoded across participants, within or between native-language groups? Results indicated that classification performance progressively increased with respect to the categorical status  of the stimulus contrast, and was also influenced by the native language of individual participants. Classifier performance showed strong relationships with traditional event-related potential measures and behavioral responses. The results of the cross-participant analysis indicated an overall increase in average classifier performance when trained on data from all participants (native and non-native). A second cross-participant classifier trained only on data from native speakers led to an overall improvement in performance for native speakers, but a reduction in performance for non-native speakers. We also found that the native language of a given participant could be decoded on the basis of EEG data with accuracy above 80%. These results indicate that electrophysiological responses underlying speech perception can be decoded at the single-trial level, and that decoding performance systematically reflects graded changes in the responses related to the phonological status of the stimuli. This approach could be used in extensions of the BCI paradigm to support perceptual learning during second language acquisition. Learning foreign languages is difficult, in part because they often make use of sounds which are unfamiliar. Moreover, foreign speech sounds can be difficult to discriminate from one another, depending on the types of phonemes used in one\u2019s native language. Studies of human language perception have made use of EEG measurements to reveal differences in the processing of speech sounds by the brains of native and non-native listeners. The results of these studies are typically based on the analysis of event-related potentials collected over hundreds of trials and using many individual participants. This is done because the signals of interest are much smaller in amplitude than the ongoing brain activity measured during single-trials To this end, a study was conducted using a multivariate analysis of EEG data collected during passive auditory perception of English language phonemes by native and non-native speakers of English. It investigated whether such methods are sensitive to the different electrophysiological response patterns elicited when native and non-native listeners are presented with pairs of stimuli from a continuum of phonemes representing either within- or across-category contrasts. Additionally, the study used the same methods in conjunction with two cross-participant data sets to address questions regarding the consistency of the functional brain organization underlying speech perception across individuals both within and between language groups.Previous research using auditory event-related potentials (ERPs) has revealed consistent differences between native and non-native speakers in the brain responses underlying the perception of phonetic contrasts The MMN has been observed in response to both changes in acoustic features of phonemes typical of within-category variation While MMN responses to artificial tone stimuli are consistently reported in the N1 interval While the neurophysiology of speech perception has been examined extensively using traditional ERP methodologies, there has recently been an increasing interest in the use of multivariate pattern classification methods to address questions regarding the functional organization of cognitive processes using data collected at the single-trial level Several BCI studies have used multivariate methods to detect different classes of auditory ERPs elicited by target and non-target stimuli in an active task. Such tasks are know to elicit a P3 response Multivariate approaches have also been used in several studies to investigate auditory perception of speech and music at the single-trial level. In the music domain, it has been shown that decoding perceived music from EEG data at the single trial level is possible, and that decoding using cross-participant data sets leads to similar overall performance as compared to within-participant analyses Here, we aim to extend these findings by examining whether the perception of phonetic contrasts representing within- or across-category contrasts can be decoded using single-trial EEG data. This is accomplished using a dataset from a recently published study on within- and between-group differences in the perception of a phonetic continuum by native (English) and non-native (native-Dutch) speakers All participants provided written informed consent prior to their participation in the experiment. The experiment was performed in accordance with the guidelines of and was approved by the ethics committee of the Faculty of Social Sciences, Radboud University Nijmegen.The present study was a reanalysis of the data collected in Four consonant-vowel (CV) syllables representing an English language stop consonant continuum were used as stimuli during the EEG measurements. A recording of the CV syllable/pa/spoken by a male native-English speaker with a Voice Onset Time (VOT) of 85 ms was used to create the other three stimuli by removing successive 22 ms portions of the aspirated portion of the original recording prior to voice onset. Thus, the VOTs of these stimuli were 63 ms, 41 ms and 19 ms. The duration of these stimuli were preserved by inserting additional periods of voicing in the voiced portion of the recording. Waveforms of the four stimuli are presented in The purpose of this manipulation was to produce a continuum which sounded progressively more like/ba/to native speakers of English. In the English language, voiced and voiceless stop consonants  are primarily distinguished from one another on the basis of VOT, while in the Dutch language the voiced and voiceless stop consonants are primarily distinguished by the presence of pre-voicing During EEG measurements, these stimuli were presented in pseudorandom oddball sequences containing a standard stimulus  and one of three deviant stimuli  analysis. Typically used for problems in the domain of signal detection theory, ROC analyses are often used to analyze both the performance of classifiers Individual participant\u2019s single-trial EEG data (64 channels\u00d790 samples per epoch) were used to train a set of quadratically regularized linear logistic regression classifiers A series of within-participants analyses were carried out to determine whether differences in the perceived categories of pairs of phonemes influenced single-trial decoding performance. To this end, a separate analysis was performed using data collected in each of the three stimulus conditions: \u201863 ms VOT deviant\u2019, \u201841 ms VOT deviant\u2019 and \u201819 ms VOT deviant\u2019. These names will be used subsequently to refer to each of the within participant analyses. All of the within-participant analyses investigated a binary comparison of single-trial EEG data collected during standard trials  and deviant trials in a given measurement condition. A fourth analysis was performed which included all of the data collected across conditions for each individual participant. The results of this analysis were used to compare mean decoding performance for each of the four stimuli with the individual behavioral identification scores collected in In each analysis, an equal number of epochs of data recorded during the presentation of a deviant stimulus and the standard stimulus immediately preceding it represented the two classes in a binary classification problem. On average, 202.5 consecutively recorded trials (St. Dev.\u200a=\u200a42.2) were available for each of these classification analyses. All of the within-participant analyses utilized a ten-fold cross validation procedure, in which subsets of the available data were used for training and testing  the classifier in each of the folds.A subsequent analysis of the classifier decisions obtained at the single-trial level was performed in order to determine the performance benefits of using multiple trials. For this, we made use of the classifier decisions obtained for all available data epochs in the test folds of the within-participant analyses conducted for the 19 ms VOT deviant condition. Each decision represents a continuous probability Where, Noting that for Logistic regression Another aim of the present study was to investigate whether the decoding of categorical speech perception is possible across different individuals, both within and between native-language groups. Two additional classifiers were trained on cross-participant datasets collected in the 19 ms VOT deviant condition . This stimulus contrast was chosen because it represented a clear categorical distinction for both native-English and native-Dutch listeners. The first classifier was trained using data from 10 of the 11 native speakers whose within-participant classification results were significantly above chance level (see below for details), and will be referred to with the name \u2018Cross-PP Native\u2019. The second made use of all 22 participants\u2019 data, and will be referred to with the name \u2018Cross-PP All\u2019.Both cross-participant classifiers were trained using a double-nested cross-validation procedure in order to account for the additional inter-subject variability introduced by these datasets. Such a procedure provides a means for selecting an optimal hyperparameter for a given classification problem whilst estimating generalization performance. In each main fold of the data, one participant\u2019s data served as a test set , while the remaining participants\u2019 data formed the classifier training set. An additional set of nested folds repeated this procedure in order to estimate the regularization parameter, with the participant whose data was used for the test set being excluded from the nested analyses.A final series of classification analyses were conducted that aimed to decode the native language (English or Dutch) of a given participant using either EEG or behavioral data. In the previous analyses, the labels assigned to the data used for training and testing the classifiers indicated whether an individual epoch was collected on a standard or deviant trial. Here, the labels indicated whether the data belonged to a native-English or native-Dutch speaker. The classifier performance levels obtained in such an analysis indicate the extent to which the response patterns  obtained from the two native-language groups generalize within-group, and how well these response patterns can be distinguished from one another at the group level.Four separate analyses were performed with each of the following data sets: concatenated single-trial data from all three measurement conditions , concatenated grand average data from all three measurement conditions, concatenated grand average data measured from the 63 ms and 41 ms VOT deviant stimuli  Is it possible to decode stimulus categories from single-trial EEG data elicited using different speech sound contrasts for native-English and native-Dutch speakers? 2) Is it possible to decode these same stimulus categories across individual participants, either within or between native-langauge groups?The results of the within-participant analyses demonstrate that single-trial EEG measurements of brain responses to phonemes contain sufficient information to decode speech sound categorization, and that the performance of such analyses improved across conditions representing increasingly salient phonetic contrasts. As such, the results confirm that the within-participants trends previously observed in analyses of grand-averaged ERP data are also present at the single-trial level A marginally significant effect of native language was also observed, suggesting an overall difference in decoding performance across the two groups. In general, decoding rates were higher for the native-English speakers as compared with the native-Dutch speakers, with this difference reaching significance for the 63 ms VOT condition. When looking at the AUC scores presented in A modest correlation was observed when investigating the relationship between individual decoding results and individual mean MMN amplitudes measured in the original analysis in A much stronger correlation was found when examining the relationship between the individual behavioral data collected in Within-participant single-trial classification rates were comparable with the average rates reported in It was also shown that this performance could be improved through the inclusion of additional trials. Performance increased on average with each additional trial that was included, reaching above 95% correct for some participants when 7 trials were included in the classifier\u2019s decision. However, the relative benefit in classification performance which was achieved through the use of additional trials was also a function of individual participant\u2019s single-trial classification rates. While individuals with relatively good single-trial classification rates tended to show the most improvement across trials, participants with low single-trial classification rates did not show much benefit when including additional trials, with performance sometimes being even lower than the single-trial rates. This would seem to point to a general lack of discriminative information in the single-trial EEG data for some participants. Previous multivariate pattern classification analyses of EEG-data collected in an auditory paradigm and using multiple-trials have also shown similar results One of the goals of the present analysis was to determine the amount of individual overlap in the functional brain organization underlying the perception of the phonemes used during EEG measurements, both within and across native-language groups. When using a classifier trained on data from 10 of the 11 native-English participants collected in the 19 ms VOT condition (\u2018Cross-PP Native\u2019), a difference in the classifier\u2019s performance was observed for the two language groups. While performance improved for native-English speakers relative to the within-participant analysis (64% vs 72% correct), performance decreased for native-Dutch speakers (61% vs 59%). In contrast, when using a classifier trained using data collected in the same condition from all 22 participants (\u2018Cross-PP All\u2019), a significant overall improvement was observed for all participants relative to the within-participant analysis. Here the performance benefit for native-English speakers was slightly less as compared with the benefit seen when using a classifier trained using only data from native-English speakers. This seems to indicate a discrepancy in the extent to which features present in the single-trial data of native-English speakers are utilized by the two cross-participant classifiers, and that features present in the single-trial data of the native-Dutch speakers do not completely overlap with those of the native-English speakers.Previous work using fMRI to investigate differences in the functional neuroanatomy of language processing between native and non-native speakers suggests that, while both groups rely on the same cortical network, non-native speakers show enhanced activation in some regions relative to native speakers This study also presented the results of a set of cross-participant classification analyses that focused on the native language of participants. Analyses that made use of single-trial ERP data were less successful at determining the native language of a given participant than those which made use of individual behavioral data. However, analyses which made use of individual grand-averaged ERPs showed better native-language classification than the analysis using behavioral data, with the best overall performance obtained when using ERPs measured in response to the 63 ms VOT and 41 ms VOT deviant stimuli. These were the two conditions which showed a significant between-groups difference in MMN response amplitude in the original study The use of multivariate pattern classification methods to identify differences in the characteristic brain responses generated by individual members of groups with differing perceptual profiles could have potential applications in both education and clinical settings. A new class of BCIs has recently been described, called passive BCIs, which combine cognitive monitoring with the real-time decoding methods typical of BCIs The present results also suggest that BCIs which directly support language learning through neurofeedback have potential. Neurofeedback provides real-time information about brain activity as measured using EEG or fMRI, providing users with a mechanism to modulate activity related to specific brain structures or cognitive states This type of induced perceptual learning may also be possible using decoded-EEG neurofeedback based on the evoked responses underlying speech perception. Such a system would, in principle, provide users with real-time information regarding their brain\u2019s ongoing responses to unfamiliar foreign speech sound contrasts, as reflected in the MMN and other components of the auditory evoked response. Research on the time course of language learning and associated changes in brain responses has shown that the MMN response develops prior to changes in behavioral responses associated with the successful discrimination of foreign phoneme contrasts The present study has shown that both within- and cross-participant decoding of evoked responses measured during speech perception is possible, with the results being a function of both the relative size of the contrasts employed as well as the phonological status of the contrast for a given listener. Moreover, the results indicate that, while the functional brain organization underlying speech perception may involve the same fundamental networks in native and non-native speakers, differences in the relative distribution of activation patterns influence the outcomes of the multivariate analyses for native and non-native speakers. On the basis of these results, we suggest that these methods can be used for developing novel BCI applications related to second language learning."}
+{"text": "In the primary visual cortex of primates and carnivores, functional architecture can be characterized by maps of various stimulus features such as orientation preference (OP), ocular dominance (OD), and spatial frequency. It is a long-standing question in theoretical neuroscience whether the observed maps should be interpreted as optima of a specific energy functional that summarizes the design principles of cortical functional architecture. A rigorous evaluation of this optimization hypothesis is particularly demanded by recent evidence that the functional architecture of orientation columns precisely follows species invariant quantitative laws. Because it would be desirable to infer the form of such an optimization principle from the biological data, the optimization approach to explain cortical functional architecture raises the following questions: i) What are the genuine ground states of candidate energy functionals and how can they be calculated with precision and rigor? ii) How do differences in candidate optimization principles impact on the predicted map structure and conversely what can be learned about a hypothetical underlying optimization principle from observations on map structure? iii) Is there a way to analyze the coordinated organization of cortical maps predicted by optimization principles in general? To answer these questions we developed a general dynamical systems approach to the combined optimization of visual cortical maps of OP and another scalar feature such as OD or spatial frequency preference. From basic symmetry assumptions we obtain a comprehensive phenomenological classification of possible inter-map coupling energies and examine representative examples. We show that each individual coupling energy leads to a different class of OP solutions with different correlations among the maps such that inferences about the optimization principle from map layout appear viable. We systematically assess whether quantitative laws resembling experimental observations can result from the coordinated optimization of orientation columns with other feature maps. Neurons in the visual cortex form spatial representations or maps of several stimulus features. How are different spatial representations of visual information coordinated in the brain? In this paper, we study the hypothesis that the coordinated organization of several visual cortical maps can be explained by joint optimization. Previous attempts to explain the spatial layout of functional maps in the visual cortex proposed specific optimization principles ad hoc. Here, we systematically analyze how optimization principles in a general class of models impact on the spatial layout of visual cortical maps. For each considered optimization principle we identify the corresponding optima and analyze their spatial layout. This directly demonstrates that by studying map layout and geometric inter-map correlations one can substantially constrain the underlying optimization principle. In particular, we study whether such optimization principles can lead to spatially complex patterns and to geometric correlations among cortical maps as observed in imaging experiments. Neurons in the primary visual cortex are selective to a multidimensional set of visual stimulus features, including visual field position, contour orientation, ocular dominance, direction of motion, and spatial frequency Visual cortical maps are often spatially complex patterns that contain defect structures such as point singularities (pinwheels) Minima of a given energy functional can be found by gradient descent which is naturally represented by a dynamical system describing a formal time evolution of the maps. Response properties in visual cortical maps are arranged in repetitive modules of a typical spatial length called hypercolumn. Optimization models that reproduce this typical length scale are therefore effectively pattern forming systems with a so-called \u2018cellular\u2019 or finite wavelength instability, see A recent study found strong evidence for a common design in the functional architecture of orientation columns The presentation of our results is organized as follows. First we introduce a formalism to model the coordinated optimization of complex and real valued scalar fields. Complex valued fields can represent for instance orientation preference (OP) or direction preference maps Second we apply the derived formalism by calculating optima of two representative low order examples of coordinated optimization models and examine how they impact on the resulting map layout. Two higher order optimization models are analyzed in We model the response properties of neuronal populations in the visual cortex by two-dimensional scalar order parameter fields which are either complex valued or real valued pinwheels, regions in which columns preferring all possible orientations are organized around a common center in a radial fashion. The centers of pinwheels are point discontinuities of the field OP maps are characterized by so-called OD maps can be described by a real valued two-dimensional field In this article, we view visual cortical maps as optima of some energy functional critical circleAll visual cortical maps are arranged in repetitive patterns of a typical wavelength The coupled dynamics we considered is of the formHow many inter-map coupling energies These higher order terms contain combinations of terms in Numerical simulations of the dynamics We studied At second order in tion see , we get OP rhombic solutions compared to the stripe solutions. Finally, inter-map coupling can lead to the stabilization of new PWC solutions.For the low order interaction terms the amplitude equations are given by We first studied the impact of the low order product-type coupling energy. Here, the constant In the case of OD stripes, see In addition to the OP stripe patterns there exist rhombic OP solutions, see In the case the OD map is a constant, The stability of the orientation scotoma solutions. The phase relations ensure that OD borders that run parallel to the OP stripes are located at the OP maxima and minima i.e. in the center of the orientation scotoma stripes. With increasing inter-map coupling, this orientation scotoma pattern is suppressed until finally all amplitudes are zero and only the homogeneous solution is stable. In case of OP rhombs inter-map coupling makes the rhombic pattern more stripe-like by reducing the amplitude For increasing inter-map coupling strength the amplitudes of the OP solutions are shown in The parameter dependence of OP solutions when interacting with OD hexagons is shown in To summarize, stripe solutions were deformed but no pinwheels were created for this solution. The rhombic solutions were energetically not preferred for low inter-map coupling whereas for intermediate inter-map coupling these solutions lose pinwheels and became stripe solutions. Instead, additional pinwheel rich solutions with a crystal layout became stable for intermediate inter-map coupling. For large inter-map coupling orientation selectivity was completely suppressed.The phase diagram as a function of the OD bias Ipsi-center pinwheel crystal. The iso-orientation lines intersect the OD borders (gray) exactly with a right angle. The intersection angles are, within the stability range of OD hexagons, independent of the bias The uniform solution To summarize, the low order product-type inter-map coupling leads in case of OD hexagons to a transition from pinwheel free stripe solutions towards pinwheel crystals. The design of the PWC is an example of an orientation hypercolumn dominated by one pinwheel. With increasing inter-map coupling the PWC solution is suppressed until only the homogeneous solution is stable. In case of OD stripes or the constant solution the OP solutions are pinwheel free stripe pattern.When using a gradient-type inter-map coupling energy the interaction terms are independent of the OD shift A coupling to OD stripes is easy to analyze in the case of a gradient-type inter-map coupling. The energetically preferred solutions are OP stripes with the direction perpendicular to the OD stripes for which In the case the OD map is a constant, In the case of OD hexagons the amplitude equations readThe course of the stationary amplitudes when interacting with OD hexagons is shown in The phase diagram of this coupling energy is shown in Braitenberg pinwheel crystal.The uniform solution The iso-orientation lines are again perfectly perpendicular to OD borders and this is independent of the bias Overall this OP map is dominated by uniform regions around hyperbolic points. In contrast to the ipsi center PWC all pinwheels in this OP map organize a roughly similar fraction of the cortical surface.In this study we presented a symmetry-based analysis of models formalizing that visual cortical architecture is shaped by the coordinated optimization of different functional maps. In particular, we focused on the question of whether and how different optimization principles specifically impact on the spatial layout of functional columns in the primary visual cortex. We identified different representative candidate optimization principles. We developed a dynamical systems approach for analyzing the simultaneous optimization of interacting maps and examined how their layout is influenced by coordinated optimization. In particular, we found that inter-map coupling can stabilize pinwheel-rich layouts even if pinwheels are intrinsically unstable in the weak coupling limit. We calculated and analyzed the stability properties of solutions forming spatially regular layouts with pinwheels arranged in a crystalline array. We analyzed the structure of these pinwheel crystals in terms of their stability properties, spatial layout, and geometric inter-map relationships. For all models, we calculated phase diagrams showing the stability of the pinwheel crystals depending on the OD bias and the inter-map coupling strength. Although differing in detail and exhibiting distinct pinwheel crystal phases for strong coupling, the phase diagrams exhibited many commonalities in their structure. These include the general fact that the hexagonal PWC phase is preceded by a phase of rhombic PWCs and that the range of OD biases over which pinwheel crystallization occurs is confined to the stability region of OD patch solutions.Our analytical calculations of attractor and ground states close a fundamental gap in the theory of visual cortical architecture and its development. They rigorously establish that models of interacting OP and OD maps in principle offer a solution to the problem of pinwheel stability Independent of its predictions, our study clarifies the general mathematical structure of interaction dominated optimization models. To the best of our knowledge our study for the first time describes an analytical approach for examining the solutions of coordinated optimization models for OP and OD maps. Our symmetry-based phenomenological analysis of conceivable coupling terms provides a general classification and parametrization of biologically plausible coupling terms. To achieve this we mapped the optimization problem to a dynamical systems problem which allows for a perturbation expansion of fixed points, local minima, and optima. Using weakly nonlinear analysis, we derived amplitude equations as an approximate description near the symmetry breaking transition. We identified a limit in which inter-map coupling becomes effectively unidirectional enabling the use of the uncoupled OD patterns. We studied fixed points and calculated their stability properties for different types of inter-map coupling energies. This analysis revealed a fundamental difference between high and low order coupling energies. For the low order versions of these energies, a strong inter-map coupling typically leads to OP map suppression, causing the orientation selectivity of all neurons to vanish. In contrast, the higher order variants of the coupling energies do generally not cause map suppression but only influence pattern selection, see Our results indicate that a patchy layout of a second visual map interacting with the OP map is important for the effectiveness of pinwheel stabilization by inter-map coupling. Such a patchy layout can be easily induced by an asymmetry in the representation of the corresponding stimulus feature such as eye dominance or spatial frequency preference. In spatial frequency maps, for instance, low spatial frequency patches tend to form islands in a sea of high spatial frequency preference Several lines of biological evidence appear to support the picture of interaction induced pinwheel stabilization. Supporting the notion that pinwheels might be stabilized by the interaction with patchy OD columns, visual cortex is indeed dominated by one eye in early postnatal development and has a pronounced patchy layout of OD domains One important general observation from our results is that map organization was often not inferable by simple qualitative considerations on the energy functional. The organization of interaction induced hexagonal pinwheel crystals reveals that the relation between coupling energy and resulting map structure is quite complex and often counter intuitive. We analyzed the stationary patterns with respect to intersection angles and pinwheel positions. In all models, intersection angles of iso-orientation lines and OD borders have a tendency towards perpendicular angles whether the energy term mathematically depends on this angle, as for the gradient-type energies, or not, as for the product-type energies. Intersection angle statistics thus are not a very sensitive indicator of the type of interaction optimized. Mathematically, these phenomena result from the complex interplay between the single map energies and the interaction energies. In case of the low order gradient-type inter-map coupling energy all pinwheels are located at OD extrema, as expected from the used coupling energy. For other analyzed coupling energies, however, the remaining pinwheels are located either at OD saddle-points (low order product-type energy) or near OD borders (higher order gradient-type energy), in contrast to the expection that OD extrema should be energetically preferred. Remarkably, such correlations, which are expected from the gradient-type coupling energies, occur also in the case of the product-type energies. Remarkably, in case of product type energies pinwheels are located at OD saddle-points. which is not expected per se and presumably result from the periodic layout of OP and OD maps. Correlations between pinwheels and OD saddle-points have not yet been studied quantitatively in experiments and may thus provide valuable information on the principles shaping cortical functional architecture.Our results demonstrate that, although distinct types of coupling energies can leave distinguishing signatures in the structure of maps shaped by interaction (as the OP map in our example), drawing precise conclusions about the coordinated optimization principle from observed map structures is not possible for the analyzed models. In the past numerous studies have attempted to identify signatures of coordinated optimization in the layout of visual cortical maps and to infer the validity of specific optimization models from aspects of their coordinated geometry We examined the impact of different interaction energies on the structure of local minima and ground states of models for the coordinated optimization of a complex and a real scalar feature map such as OP and OD maps. The models were constructed such that in the absence of interactions, the maps reorganized into simple stripe or blob pattern. In particular, the complex scalar map without interactions would form a periodic stripe pattern without any phase singularity. In all models, increasing the strength of interactions could eventually stabilize qualitatively different, more complex, and biologically more realistic patterns containing pinwheels that can become the energetic ground states for strong enough inter-map interactions. The way in which this happens provides fundamental insights into the relationships between map structure and energy functionals in optimization models for visual cortical functional architecture.Our results demonstrate that the structure of maps shaped by inter-map interactions is in principle informative about the type of coupling energy. The organization of the complex scalar map that optimizes the joined energy functional was in general different for all different types of coupling terms examined. We identified a class of hPWC solutions which become stable for large inter-map coupling. This class depends on a single parameter which is specific to the used inter-map coupling energy. Furthermore, as shown in In the case of the product-type coupling energies, the resulting phase diagrams are relatively complex as stationary solutions and stability borders depend on the magnitude of the OD bias. Here, even quantitative values of model parameters can in principle be constrained by analysis of the map layout. In contrast, for the gradient-type coupling energies, the bias dependence can be absorbed into the coupling strength and only selects the stationary OD pattern. This leads to relatively simple phase diagrams. For these models map layout is thus uninformative of quantitative model parameters. We identified several biologically very implausible OP patterns. In the case of the product-type energies, we found orientation scotoma solutions which are selective to only two preferred orientations. In the case of the low order gradient-type energy, we found OP patterns containing pinwheels with a topological charge of 1 which have not yet been observed in experiments. If the relevant terms in the coupling energy could be determined by other means, the parameter regions in which these patterns occur could be used to constrain model parameters by theoretical bounds.The information provided by map structure overall appears qualitative rather than quantitative. In both low order inter-map coupling energies  lines: stable (unstable) solutions. A,B OD stripes, C,D OD hexagons, A,C Transition from OP stripe solutions, B,D Transition from OP rhombic solutions. E Potential, F Potential, (TIF)Click here for additional data file.Figure S2A Phase diagram with coupling energy , . Vertical black lines: stability range of OD stripes, hexagons, and constant solutions. Magenta (orange) line: Stability border of orientation scotoma stripes. Green solid line: Stability border of rhombic solutions. Red solid line: Stability border of PWC solutions, red dashed line: B Course of C Stability border between A).(TIF)Click here for additional data file.Figure S3Bias dependent pinwheel crystals, ABCD. OP map, superimposed are the OD borders (gray), 90% ipsilateral eye dominance (black), and 90% contralateral eye dominance (white), E,F Distribution of orientation preference. G Intersection angles between iso-orientation lines and OD borders.(TIF)Click here for additional data file.Figure S4Stationary amplitudes with coupling energyA Solid (dashed) lines: Stable (unstable) solutions. Blue: rPWC, green: distorted rPWC, red: hPWC. Black lines: stripe-like solutions. B Potential, (TIF)Click here for additional data file.Figure S5Phase diagram with coupling energy. Vertical lines: stability range of OD hexagons, green line: transition from rPWC to distorted rPWC, red line: stability border of hPWC, blue line: stability border of distorted rPWC. Above orange line: hPWC corresponds to ground state of energy.(TIF)Click here for additional data file.Figure S6Rhombic pinwheel crystals.A OP map with superimposed OD borders (gray), 90% ipsilateral eye dominance (black), and 90% contralateral eye dominance (white), B Selectivity (TIF)Click here for additional data file.Figure S7Contra-center pinwheel crystals.A,B OP map, superimposed are the OD borders (gray), 90% ipsilateral eye dominance (black), and 90% contralateral eye dominance (white), ABC Distribution of orientation preference. D OP map with superimposed OD map for three different values (E Selectivity F Distribution of intersection angles.(TIF)Click here for additional data file.Figure S8Inter-map coupling strength dependent pinwheel positions. OD map, superimposed pinwheel positions (points) for different inter-map coupling strengths, ABD Positions of rPWCs move continuously .(TIF)Click here for additional data file.Text S1Derivation of higher order amplitude equations and the analysis of optima for the higher order gradient-type and product-type inter-map coupling energies.(PDF)Click here for additional data file.Text S2Amplitude equations for the OP dynamics in case of the high order inter-map coupling energies  and .(PDF)Click here for additional data file.Text S3Stability matrices for the low order inter-map coupling energies.(PDF)Click here for additional data file."}
+{"text": "Newer antidepressants are needed for the many individuals with major depressive disorder (MDD) that do not respond adequately to treatment and because of a delay of weeks before the emergence of therapeutic effects. Recent evidence from clinical trials shows that the NMDA antagonist ketamine is a revolutionary novel antidepressant because it acts rapidly and is effective for treatment-resistant patients. A single infusion of ketamine alleviates depressive symptoms in treatment-resistant depressed patients within hours and these effects may be sustained for up to 2 weeks. Although the discovery of ketamine's effects has reshaped drug discovery for antidepressants, the psychotomimetic properties of this compound limit the use of this therapy to the most severely ill patients. In order to develop additional antidepressants like ketamine, adequate preclinical behavioral screening paradigms for fast-acting antidepressants need to be established and used to identify the underlying neural mechanisms. This review examines the preclinical literature attempting to model the antidepressant-like effects of ketamine. Acute administration of ketamine has produced effects in behavioral screens for antidepressants like the forced swim test, novelty suppression of feeding and in rodent models for depression. Protracted behavioral effects of ketamine have been reported to appear after a single treatment that last for days. This temporal pattern is similar to its clinical effects and may serve as a new animal paradigm for rapid antidepressant effects in humans. In addition, protracted changes in molecules mediating synaptic plasticity have been implicated in mediating the antidepressant-like behavioral effects of ketamine. Current preclinical studies are examining compounds with more specific pharmacological effects at glutamate receptors and synapses in order to develop additional rapidly acting antidepressants without the hallucinogenic side effects or abuse potential of ketamine. Major depressive disorder (MDD) is a serious public health problem and one of the most common psychiatric disorders, with a lifetime prevalence of 17% in the United States  administered intravenously over a 40 min period  tests, the latency to feed is increased and the amount of food consumption is reduced in a novel environment. These tests, based on a similar principle, differ in methodology; NSF requires acute food deprivation 24 h prior to testing whereas the NIH utilizes an 8\u201310-day training period without deprivation. These tests have considerable face validity, although interpretation of results with the NSF may be limited by the use of food deprivation. Hyponeophagia is one of the few anxiety-related tests that are reliably attenuated following chronic, but not acute, administration of antidepressant drugs  reversed the decrease in sucrose consumption in rats exposed to chronic stress. Although it should be noted that this dosing regimen with ketamine also increased sweet food consumption in both stressed and non-stressed rats , rats displayed hyperactivity in spontaneous activity  and long-term depression (LTD). These processes involve significant alterations in pre and post-synaptic scaffolding proteins and glutamate receptors, primarily the glutamatergic receptor, \u03b1-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA). The AMPA receptor containing the subunits GluR1, GluR4, and GluR2 are involved in LTP, whereas GluR2, GluR3, and GluR4 are required for the AMPA receptor internalization needed to facilitate LTD  at concentrations of 2\u201350 \u03bcm. The subsequent suppression of tonic glutamate input to GABAergic interneurons, results in disinhibition of glutamate signaling. This disinhibition and increase in glutamate neurotransmission is mediated by a decrease in GABAergic inhibitory feedback of the pyramidal neurons in layer V of the PFC, a region widely implicated in the development of psychiatric disorders quinoxaline-2, 3-dione (NBQX), reversing the antidepressant effects of ketamine in the LH paradigm   all increase mTORC1 levels  in the BDNF gene has been proposed as a potential impediment to the antidepressant response to ketamine in TRD patients. Val/Val carriers are more sensitive to the antidepressant-effects of ketamine compared to the Val/Met carriers  are capable of mediating protracted antidepressant like effects in the FST lasting up to 6 days following the infusion  is universally used in ketamine preparations both for clinical and preclinical use. Although present in low concentrations, BCl can act synergistically with ketamine to inhibit muscarinic and \u03b17-nicotinic acetylcholine receptors (Durieux and Nietgen, The mechanisms underlying ketamine's effects, the simultaneous blockade of NMDA receptors and activation of AMPA receptors, are integral for the induction of the antidepressant response. The long-term consequences of these molecular alterations are likely to mediate ketamine's protracted antidepressant-like effects mediated via increased synaptic plasticity, neuronal survival and maturation. These changes occur within hours of ketamine administration and occur in parallel with both the rapid and protracted behavioral effects in animal models of depression. The rapid modulation of mTOR, its downstream mediators, such as Akt and ERK, and BDNF represent markers of the molecular correlates of the antidepressant effects of ketamine and its ability to modify synaptic plasticity. Novel therapeutics for TRD are likely to modulate these markers in a similar temporal pattern to that of ketamine and can be used to identify better pharmaceutical agents to treat TRD.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The central actions of the hormone leptin in regulating energy homeostasis via the hypothalamus are well documented. However, evidence is growing that this hormone can also modify the structure and function of synapses throughout the CNS. The hippocampus is a region of the forebrain that plays a crucial role in associative learning and memory and is an area also highly vulnerable to neurodegenerative processes. Recent studies indicate that leptin is a potential cognitive enhancer as it modulates the cellular processes underlying hippocampal-dependent learning and memory including dendritic morphology, glutamate receptor trafficking and activity-dependent synaptic plasticity. Here, we review the recent evidence implicating the hormone leptin as a key regulator of hippocampal synaptic function and discuss the role of leptin receptor-driven lipid signaling pathways involved in this process. The endocrine hormone, leptin is a 167 amino acid protein that is mainly produced by adipocytes and circulates in the plasma at levels closely correlated with body fat content  and alternative splicing of this gene generates six leptin receptor isoforms (ObRa-f) with identical N-terminal domains but vary in the length of their C-terminal region. All the isoforms, except ObRe, have a membrane spanning region consisting of 34 amino acids. ObRe is thought to buffer free circulating leptin levels in the plasma. The membrane spanning ObRs all contain an intracellular proline-rich box which enables association with janus tyrosine kinases, in particular JAK2. However, only the long leptin receptor isoform (ObRb) contains additional intracellular signaling motifs necessary for full JAK-STAT  signaling. Following leptin binding to ObRb and JAK2 activation, JAK2 associates with and promotes phosphorylation of tyrosine residues within the C-terminal domain. The phosphorylated tyrosine residues enable recruitment and activation of various downstream signaling pathways including the STAT  family of transcription factors, phosphoinositide 3-kinase as well as adaptor proteins associated with the Ras-Raf-MAPK (mitogen activated protein kinase) pathway. Leptin is capable of activating all of these ObR-driven signaling in central neurons  and long-term depression (LTD) are key cellular events underlying learning, memory and habituation  in LFS-induced depotentiation  rats results in a transient and readily reversible depression of excitatory synaptic transmission P3, is not only an integral part of neuronal leptin receptor-driven signaling but it is also critical for trafficking AMPA receptors to hippocampal synapses during LTP P3 levels were blocked by selective PI 3-kinase inhibitors. However, PtdInsP3 levels are also controlled by PTEN, a phosphatase that promotes conversion of PtdInsP3 to PtdInsP2, and thus antagonizes PI 3-kinase activity. In support of a role for PTEN, the leptin-driven increase in GluA1 surface expression is combined with an elevation in P366-PTEN staining in hippocampal cultures. Moreover, application of leptin to hippocampal slices resulted in a robust increase in the phosphorylation of PTEN P3 levels, it is likely that alterations in the levels of this inositol lipid are crucial for modifying AMPA receptor trafficking processes. Recent evidence supports this possibility as the availability of PtdInsP3 is reported to maintain AMPA receptor clustering and synaptic function at hippocampal synapses P3 influences AMPA receptor trafficking by either altering actin cytoskeletal dynamics  in neurons or pharmacological inhibition of PTEN with the phosphatase inhibitor bisperoxovanadium (Bpv) mirror and occlude the effects of leptin on GluA1 trafficking and hippocampal synaptic function  channels by leptin  mice have identified significant alterations in the density of both excitatory and inhibitory synapses compared to wild type mice  channels but channel activation by both hormones involves a PI 3-kinase-dependent process  channels by leptin and insulin . Moreover, as evidence is growing that IL-6 is a potent regulator of hippocampal synaptic function (Tancredi et al., It is well established that the endocrine hormone leptin regulates many central processes including energy homeostasis. However, evidence is growing that the structure and function of hippocampal CA1 synapses is also markedly influenced by leptin. Recent studies indicate that leptin has cognitive enhancing properties as it rapidly alters glutamate receptor trafficking, dendritic morphology and different forms of activity-dependent hippocampal synaptic plasticity. Regulation of NMDA receptor activity by leptin appears to be key for its ability to influence multiple aspects of hippocampal synaptic function, although it is not entirely clear how leptin-driven activation of NMDARs leads to such opposing effects on hippocampal synaptic function. However, emerging studies indicate not only that distinct NMDA receptor subunits are pivotal for leptin's effects on excitatory synaptic transmission, but also that distinct signaling pathways couple leptin receptors to molecularly distinct NMDA receptors at different developmental stages. Although it is established that leptin plays a pivotal role in normal brain function, disruption of the leptin system is also linked to neurodegenerative disorders, like Alzheimer's disease. Thus, the ability of leptin to regulate neuronal morphology and synaptic efficacy is likely to have important implications not only in health but also in diseases associated with leptin dysfunction.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "This is achieved by injecting tumor cell aggregates derived from fresh ovarian tumor biopsy tissues  i.p. into NSG mice. Tumor progression in these mice closely parallels many of the events that are observed in ovarian cancer patients. Tumors establish in the omentum, ovaries, liver, spleen, uterus, and pancreas. Tumor growth is initially very slow and progressive within the peritoneal cavity with an ultimate development of tumor ascites, spontaneous metastasis to the lung, increasing serum and ascites levels of CA125, and the retention of tumor-associated human fibroblasts and lymphocytes that remain functional and responsive to cytokines for prolonged periods. With this model one will be able to determine how fibroblasts and lymphocytes within the tumor microenvironment may contribute to tumor growth and metastasis, and will make it possible to evaluate the efficacy of therapies that are designed to target these cells in the tumor stroma.Ovarian cancer is the most common cause of death from gynecological cancer. Understanding the biology of this disease, particularly how tumor-associated lymphocytes and fibroblasts contribute to the progression and metastasis of the tumor, has been impeded by the lack of a suitable tumor xenograft model. We report a simple and reproducible system in which the tumor and tumor stroma are successfully engrafted into NOD-scid IL2R\u03b3 The first successful engraftment of human cells into these C.B-17 scid mice was reported over 20 years ago scid mice lacked functional B and T cells, these mice had an intact innate immune response that was responsible for the complex cellular and molecular HVG response. The intensity of this HVG response varied considerably from mouse to mouse and with the histological type of tumor used for engraftment scidIL-2rgtm1WjlPrkdc, abbreviated NSG. Immunodeficient mice lacking the IL-2 receptor \u03b3 chain have been found to support the prolonged engraftment of human hematopoietic cells and peripheral blood mononuclear cells Both normal and neoplastic human tissues have been successfully engrafted into T cell and B cell-deficient in vivo would provide an opportunity to determine how human immunocompetent cells and tumor cells influence each other. The findings could potentially be used to evaluate immunotherapeutic approaches to cancer. Further, in view of the increasing awareness that nonmalignant stromal cells including fibroblasts, epithelial cells and other leukocytes interact with and have an impact upon tumor growth and metastases A xenograft model in which human tumors and autologous tumor-associated T and B cells could be co-engrafted and their interactions studied in situ tumor progression. Moreover, the model provides the potential to evaluate the efficacy of single, as well as combination, therapeutic approaches to ovarian cancer.A tumor xenograft model has been developed and is reported here in which human epithelial ovarian tumor xenografts are established orthotopically, and the pattern of tumor growth and metastasis reflects that which is observed in ovarian cancer patients. Tumor-associated T and B lymphocytes and fibroblasts co-engraft within tumor nodules and the T cells remain functional and responsive to exogenously administered cytokine. CA125 is present in the sera and ascites of CA125+ tumor-bearing mice and provides an opportunity to monitor the presence and progress of tumor xenografts periodically. It is expected that this model will make it possible to study the ability of human tumor-associated leukocytes and tumor stroma to modulate It was established previously that the subcutaneous implantation of solid pieces of fresh human tumor tissues into NSG mice resulted in the establishment of tumor microenvironments We report here a method of engraftment, in which ovarian tumors can be successfully established as xenografts orthotopically in the ovary and other organ sites of recipient mice. The tumor growth reflects the pattern and progression observed in ovarian cancer patients. This has been accomplished by injecting a suspension of cell aggregates (that is derived from a mild disruption of solid ovarian tumors) i.p. into NSG mice see  section.Nodules detected grossly within the peritoneal cavity of mice injected with tumor-derived cell aggregates were confirmed histologically to be tumors . The tumThe frequency of tumors observed histologically in different organ sites varied from tumor to tumor and from mouse to mouse for each tumor-derived cell aggregate implanted. In a typical example of the organ distribution in 15 mice, 116 days after the i.p. injection of cell aggregates derived from solid ovarian tumors  were present in juxtaposition with tumor cells (see arrowhead) . ImmunohA trichrome stain of the tumor nodules showed that in addition to the inflammatory cells, fibroblasts were present within the microenvironment of the tumor xenografts (see arrow) . The fibWe conclude that the histological architecture and cellular composition including the tumor cells, inflammatory leukocytes and fibroblasts of the original tumor tissue are maintained for prolonged periods (up to 177 days post-engraftment) in the tumor xenograft, and that tumor cells continue to proliferate within the tumor nodules present in the peritoneal cavity.Ovarian cancer patients typically develop a tumor ascites in the later stages of their disease CA125 is a high molecular weight glycoprotein that is elevated in the serum of approximately 90% of patients with advanced epithelial ovarian cancer The intra-abdominal spreading that we observed following the i.p. inoculation of ovarian tumor-derived cell aggregates into NSG mice, and the generation of tumor ascites fluid are consistent with what is seen in Stage IIIc ovarian cancer patients Stage IV disease patients present with evidence of extra-abdominal spreading of the tumor and this may involve the pleural space with metastasis into the lung parenchyma Our collective findings indicate that the slow and progressive pattern of tumor growth and metastasis of ovarian tumors in NSG mice following the i.p. inoculation of fresh human ovarian tumor-derived cell aggregates closely reflects that seen in patients who develop into Stages IIIc and IV of disease which accounts for over 70% of the ovarian cancer patients seen in the clinic in vivo were investigated.Lymphocytes including effector memory CD4+ T cells We have previously established that T cells in the tumor microenvironment have an attenuated TCR driven activation signal, but remain viable and respond to stimulation with IL-12 by producing IFN-\u03b3 The viability and function of B cells and plasma cells in the tumor bearing mice were addressed by assaying the sera for the presence of human Ig. We consistently observed high levels of human Ig in the sera of tumor bearing mice . In one in situ.The presence of both functional tumor-associated T and B cells in the tumor xenograft bearing mice for >100 days provides an opportunity to investigate the possible role that these lymphocytes  play in the survival and metastasis of the tumor, and to determine whether it is possible to manipulate these lymphocytes so that they mount an effective anti-tumor response Since the first report on the successful engraftment of human cells in C.B-17-scid mice We report here a humanized model that more closely parallels the patterns of tumor progression that are observed in ovarian cancer patients than does any other previously described model. Our model captures several important features of human ovarian cancer not seen in previous models. The intra-abdominal spreading along with the development of ascites is strikingly similar to what is observed in patients. The co-engraftment of tumor-associated fibroblasts and T and B lymphocytes that remain viable and functional for prolonged periods provides an opportunity to investigate the possible contribution of these non-malignant cells, and the biologically active factors they produce, to the growth and spread of the tumor cells.in vivo the interaction between lymphocytes and the tumor, lymphocytes and tumor-associated fibroblasts and fibroblasts and the tumor. It has previously been established that tumor stroma is critical for preventing or permitting the immunological destruction of cancer cells et al. showed that fibroblasts derived from human invasive breast carcinomas significantly enhanced tumor growth in xenograft models The orthotopic engraftment and dissemination of the tumor and co-engraftment of tumor-associated immunocompetent cells with tumor stroma in this new humanized mouse model make it possible to study Ovarian cancer is most often asymptomatic in its early stages as most patients have widespread disease at the time of diagnosis in vivo therapeutic effects in our humanized mouse model.Thus, while CA125 levels are a reliable indicator of the presence and expansion of ovarian tumors in patients and in our humanized mouse model, it is not suitable for early tumor detection in either patients or in mice inoculated with the tumor-derived cell aggregates. However, serum levels of CA125 are currently used effectively to monitor ovarian cancer patients' response to chemotherapy and surgery The enhanced ability of small aggregates of tumor and non-malignant tumor cells to establish, grow and spread within the peritoneal cavity (compared to solid non-disrupted pieces of tumor tissue) may depend upon the ability of small cell clusters to survive initially until a sufficient vascular supply is established to permit tumor expansion. The success of the engraftment of tumor-derived cell aggregates may also depend in part upon the contribution of biologically active factors produced by the non-malignant cells in the cell aggregates that produce tumor growth factors and stimulants to angiogenesis. Tumor masses most often occur first in the cranial areas of the peritoneal cavity near and within the omentum. The position of the tumor nodules as well as the enhanced growth of the cell aggregates and slow progression of the tumors to other organs may result from the initial attachment of the tumor cell aggregates to highly vascularized areas within the omentum called milky spots. These discrete areas were first recognized by Ranvier in situ strategy of cancer vaccination has already been demonstrated to be efficacious in several mouse tumor models The results presented here suggest that our humanized NSG mouse ovarian transplant model has the potential to serve as a useful preclinical tool with which to test the efficacy of chemotherapeutic strategies, immunotherapeutic strategies or combinations of both. One of the attractions of this model is that it makes it possible to test strategies that target tumor-associated T cells and thereby initiate an anti-tumor response. One possible use of the model would be to test the ability of a cytokine such as IL-12 to initiate systemic anti-tumor responses. While the single treatment of tumor bearing mice 21 days post tumor inoculation did not result in a significant inhibition of tumor progression, future studies will assess the effect of multiple treatments with IL-12 or IL-12 in combination with other cytokines and chemotherapy. This type of an The humanized mouse model described here has focused solely upon the engraftment of epithelial ovarian cancer tissues. Whether or not this approach could be used effectively to engraft and study other tumors that originate in the peritoneal cavity is currently being investigated. Other orthotopic xenograft models of intraperitoneal tumors have been reported A key factor in the success of the engraftment and long-term survival of human tumor xenografts has been the use of the NSG mice Tumor tissues were obtained with an IRB-approved protocol covered under Human Subject Assurance Number 00008824 assigned through the UB Health Sciences Institutional Review Board accredited by the Association for the Accreditation of Human Research Protection Programs. All animal work was conducted with an Institutional Animal Care and Use Committee (IACUC) approval covered under Animal Welfare Assurance Number A3354-01 accredited through the Association for Assessment and Accreditation of Laboratory Animal Care.The Roswell Park Cancer Institute Tissue Procurement Facility provided the human primary and metastatic ovarian solid tumor tissue and ovarian ascites fluid. All samples were provided under sterile conditions using Institute Review Board approved protocols.Tumor tissue was mechanically disrupted using a Teflon policeman to generate clusters or aggregates of cells that passed through a size 50 stainless steel wire mesh. The resulting tumor-derived cell aggregates were washed once in RPMI 1640 and resuspended in PBS, pH 7.2. Aggregates of cells in size from approximately 200\u2013300 \u00b5m in diameter and included tumor cells, fibroblasts, endothelial cells and lymphocytes.et al.Large multilamellar liposomes were prepared by rehydrating the lipid film of appropriate molar ratios of distearoyl phosphatidylcholine (DSPC), dimyristoyl phosphatidylglycerol (DMPG) and cholesterol (CHOL)  with phosphate buffer containing recombinant human IL-12 at 45\u00b0C. The spontaneous loading of a large complex molecule such as IL-12 is accomplished by a mild denaturation of IL-12 to partially and reversibly unfold the protein to expose hydrophobic domains resulting in the intercalation of the cytokine within or between the lipid bilayers of the liposomes Suspensions of tumor-derived cell aggregates were injected i.p. into NSG mice. All NSG mice raised in a high barrier research colony at The Jackson Laboratory, were housed in specific pathogen-free conditions at SUNY at Buffalo. Each mouse received between 100 to 300 mg of the cell aggregates in a volume of 1.0 ml. All animal experiments were approved by the Institute Animal Care and Use Committee at SUNY at Buffalo.Wyeth Laboratory provided the recombinant human IL-12 that was incorporated into liposomes as described above. Mice bearing the human ovarian tumor xenograft were randomly divided into control and treatment groups. Mice were treated with a) empty liposomes, b) IL-12 containing liposomes (50 \u00b5g/mouse) \u2013 once or multiple times or c) left untreated. The dose of IL-12 was determined based upon the calculated loading efficiency for each liposome preparation. All of the cytokine was associated with the liposome as the free IL-12 was removed from the liposome preparations prior to injection.Blood samples were collected via a retro-orbital sinus bleed. Clotted blood was centrifuged at 1000\u00d7g for 20 minutes and sera harvested and stored at \u221220\u00b0C until use.450\u2013540 and analyzed by comparison with a recombinant IFN-\u03b3 standard using SigmaPlot software.A sandwich ELISA for the detection of human IFN-\u03b3 in mouse serum was performed as previously described 450\u2013540 and analyzed with a human Ig standard  using Sigma Plot software.The ELISA for the detection of human Ig (huIg) in mouse serum was reported previously Levels of CA 125 were determined by analysis with the Bayer Immuno ITM CA-125 II assay .H&E staining was performed by the SUNY at Buffalo Histology Service Laboratory where fresh surgical sections of the original tumor, xenografts and mouse tissues were fixed in 10% neutral-buffered formalin and processed for paraffin embedding. Anti-human specific antibodies to the following markers were used for immunohistochemical staining of the xenografts and mouse tissues: anti-CD3 (Dako), anti huHLA-A Class I (Santa Cruz), anti-huCD45 (R&D Systems), anti-hu 138 (Dako) and anti-hu CD20 (ab Cam). Staining was performed as previously reported"}
+{"text": "We show that 25 minutes of transcranial electrical stimulation, as predicted, reduced the decay of SWO in the remainder of the night. Anatomically accurate simulations of the field intensities on human cortex precisely matched the effect size in different EEG electrodes. Together these results suggest a mechanistic link between electrical stimulation and accelerated synaptic homeostasis in human sleep.The sleeping brain exhibits characteristic slow-wave activity which decays over the course of the night. This decay is thought to result from homeostatic synaptic downscaling. Transcranial electrical stimulation can entrain slow-wave oscillations (SWO) in the human electro-encephalogram (EEG). A computational model of the underlying mechanism predicts that firing rates are predominantly increased during stimulation. Assuming that synaptic homeostasis is driven by average firing rates, we expected an acceleration of synaptic downscaling  Sleep pressure is reflected in the power of slow-wave activity: it is high after extended wakefulness and gradually decays in the course of the night. Transcranial stimulation with slow-oscillating currents can entrain electro-encephalographic slow-wave oscillations (SWO) and transiently increase their power. Motivated by the results from a multi-scale computational model, we tested in humans whether 25 minutes of transcranial stimulation attenuates the decay of SWO in the remainder of the night. A Finite-Element Model (FEM) is used to estimate the current flow in the brain and a network model of spiking neurons determines the resultant effect on SWO. This multi-scale model predicted increased neuronal firing rates leading to accelerated synaptic downscaling. As a consequence, the decay of SWO power and spatial coherence after stimulation is reduced. In addition to reduced decay rate, the model was also able to successfully predict, in the human experiments, the spatial distribution of the effect across EEG electrodes. These combined experimental and modeling results suggest a mechanism by which electrical stimulation can accelerate synaptic homeostasis and thereby influence a putative process of sleep regulation. The ability to accelerate the homeostatic function of sleep may have important practical implications. Human sleep is characterized by distinct sleep stages which can be readily identified in the electroencephalogram (EEG). Of particular interest is the activity in the 0.5\u20134 Hz frequency band known as slow-wave activity (SWA). The power of SWA increases following extended waking and decreases in power and spatial coherence throughout the night Homeostatic plasticity refers to a physiological feedback mechanism that regulates average firing rates by altering synaptic strength: high firing rates lead to synaptic depression and low firing rates to potentiation Here we consider slow-wave oscillations  in the human EEG as a marker for sleep homeostasis and its modulation by transcranial electrical stimulation. We found that a relatively short 25 minutes of stimulation in humans during slow-wave sleep at the beginning of the night had a lasting effect on homeostatic decay of SWO in the hours following stimulation.The effects of transcranial electrical stimulation on brain activity have been the subject of intense investigation in the last decade We hypothesized that stimulation during slow-wave sleep alters neuronal firing rates, which would modulate homeostatic synaptic downscaling and thus alter the homeostatic decay of SWO. A multi-scale computational model makes this hypothesis explicit by linking the macroscopic domains of current flow in the entire head with the microscopic cellular effects of polarization. The model shows that network dynamics of SWA can rectify bi-directional polarization leading to an unidirectional increase of firing rates and synaptic downscaling. A number of predicted effects of stimulation on SWO are subsequently confirmed by the present human EEG sleep data. Specifically, the data confirmed the prediction of diminished SWO decay in the hours after stimulation, and the multi-scale model accurately predicted the effect sizes across multiple scalp electrodes.The ability to accelerate sleep homeostasis may have important practical implications given that SWA is widely considered to be a marker of the restorative power of sleep.In a study on memory consolidation during sleep Our hypothesis on homeostatic plasticity predicted that the decay of SWO should be altered by the transcranial slow-oscillating stimulation administered to participants for 25 minutes  in the minute preceding the stimulation period did not differ between sham and stimulation conditions  for two representative subjects.Example traces of the analysis performed on the EEG data. The decay of slow-wave oscillations was estimated by fitting  power and spatial coherence after the stimulation see . A\u2013B: De(TIFF)Click here for additional data file.Figure S2A: Coherence  between model LFP and applied slow-oscillating field as a function of field intensity and fractions of neuron polarized in either direction. B.1: Relative change of the duration of the DOWN state in the case of cathodal (blue) or anodal (red) stimulation (0.31 V/m). B.2: Relative change of the duration of the UP state in the case of cathodal (blue) or anodal (red) stimulation (0.31 V/m). C.1: Entrainment of slow-wave oscillations immediately after the stimulation in the human EEG data (shown here for Pz electrode). The dark gray bar indicate the 10 s interval (delimited by the dashed magenta line) where the distribution of phases of the oscillations across trials and subjects is significantly different from being uniform. The same analysis performed on the following 10 s does not produce results statistically different from a uniform distribution . C.2: Distribution of phases relative to figure C.1 considering all the trials and all the subjects. The 5 stimulation periods for all the subjects were aligned and the exponential decay from the AC-coupled amplifier was removed. The residual was fit to as sinusoid in frequency, phase and amplitude. Entrainment phase was only analyzed for the Pz electrode as this was the electrode with the smallest stimulation artifact. Note that the EEG recording equipment was AC-coupled resulting in a constant phase delay. Thus absolute value of phase is not relevant here. Nevertheless, a consistent phase across subjects despite anatomical differences is indicative of the predicted entrainment to a preferred phase.Entrainment of slow oscillatory activity by applying weak electrical stimulation. (TIFF)Click here for additional data file."}
+{"text": "Journal of Cardiovascular Magnetic Resonance (JCMR) in 2010, which is a 34% increase in the number of articles since 2009. The quality of the submissions continues to increase, and the editors were delighted with the recent announcement of the JCMR Impact Factor of 4.33 which showed a 90% increase since last year. Our acceptance rate is approximately 30%, but has been falling as the number of articles being submitted has been increasing. In accordance with Open-Access publishing, the JCMR articles go on-line as they are accepted with no collating of the articles into sections or special thematic issues. Last year for the first time, the Editors summarized the papers for the readership into broad areas of interest or theme, which we felt would be useful to practitioners of cardiovascular magnetic resonance (CMR) so that you could review areas of interest from the previous year in a single article in relation to each other and other recent JCMR articles [There were 75 articles published in the  The definition of normal values for CMR is reasonably mature, although values for special groups are still being defined, but a nuMaceira et al published a comprehensive analysis of normal values for left atrial dimensions and volumes using steady state free precession cine imaging which is categorized by age decile, gender and body surface area. This fo2 = 0.74, p < 0.001), and as LV end-diastolic volume (EDV) increased, RVEDV increased in the same order of magnitude in both males and females . The authors conclude that total heart volume is a strong, independent predictor of maximal work capacity for both males and females, and that long term endurance training is associated with a physiologically enlarged heart with a balance between the left and right ventricular dimensions in both genders.Steding et al describe a study of 113 subjects of whom 71 were athletes of both genders, to test the hypothesis that total heart volume is an independent predictor of peak oxygen uptake, which is known to increase with long term endurance training and relate to left ventricular mass. MultivaThe syndrome of heart failure still raises questions, including the genesis of exercise intolerance and symptoms. EngblomCondreanu et al used high resolution CMR to detect new details of LV systolic and diastolic function, to explain the twisting and longitudinal movements of the left ventricle. The autMendoza et al examined the relation between the severity of echocardiography derived diastolic dysfunction and volumetric filling by automated processing of routine cine CMR. AutomatBollache et al aimed to develop a robust process to automatically estimate velocity and flow rate-related diastolic parameters from PC-CMR data and to test the consistency of these parameters against echocardiography as well as their ability to characterize left ventricular (LV) diastolic dysfunction. The MR Leyva has been a pioneer of the application of CMR to guide cardiac resynchronization therapy, and relate the CMR findings to hard cardiac outcomes. Previous work published in JCMR includes the visualisation of the coronary venous anatomy to guide wire placement, and CMR A number of influences on cardiac function and the electrocardiogram have been reported in JCMR, including obesity, and athlThe unique capability of CMR to measure cardiovascular flow is important in the armamentarium of techniques that contribute to the versatility of CMR. This has greatest application in valve disease,20 but iThe ability to measure the volumes of forward and regurgitant flow through planes transecting the aorta and pulmonary trunk is a unique and clinically valuable capability of CMR. However, these derived measurements of volumetric flow are sensitive to errors caused by small offsets of the measured velocities, and this has been reported previously in JCMR. This muThis paper addressed the related subject of post-acquisition phantom correction of CMR phase contrast flow velocity acquisitions on a General Electric 1.5 Tesla system, as used for aortic, pulmonary and shunt flow measurements in 149 patients in a clinical congenital CMR program. PhantomThe acquisition, analysis and display of multidirectional time resolved 3D or 7D flow has been well developed in JCMR. ErikssoThe presence or absence of gadolinium contrast agent in the blood had no demonstrable effect on phase contrast measurements of aortic flow in this study. TherefoThe treatment of patients with aortic regurgitation (AR) or mitral regurgitation (MR) relies on the assessment of the severity of the regurgitation as well as its effect on LV size and function. This study set out to determine relations between regurgitant volume, measured by phase contrast velocity mapping, LV volumes and LV dimensions in patients with isolated AR or MR and preserved LV function. It is uDirect anatomical imaging of the valves by CMR, including valve morphometry, and reguBicuspid aortic valve (BAV) is a common congenital malformation which, besides its tendency to develop stenosis or regurgitation, predisposes to aortic dilatation and dissection. Compared to healthy controls, this study reports the aortic dilatation found in the group of 18 young BAV patients studied and the increased angle measured between the direction of the left ventricular outflow stream and the axis of aortic root channel. These tPre-procedure assessment of maximal and minimal atrial septal defect (ASD) dimensions and atrial septal margins was performed by both CMR and transesophageal echocardiography (TOE) in this study. CMR acqIn patients with pulmonary hypertension, fractional transverse dimensional shortening, measured from the mid septal region to the free wall of the RV in a four-chamber cine, was found to correlate better with RV ejection fraction than the fractional shortening of the long axis of the RV in this CMR study. The traContrast-enhanced magnetic resonance angiography (CE-MRA) was found to be a useful diagnostic tool for the preoperative evaluation of the morphology of pulmonary arteries and blood supply in this retrospective study of 15 neonates with pulmonary atresia. In mostCMR findings in an unusual case of a 28 year-old female patient with unrepaired truncus arteriosus and also interruption of the aortic arch were illustrated and described in this report.The use of CMR in cardiomyopathy has exploded in the last 5 years and many CMR centres now find cardiomyopathy patients form the largest proportion of the workload. The synergy of CMR with cardiovascular genetics has become clear, as has the need for CMR physicians to work closely with electrophysiology colleagues in assessing arrhythmic and suddCardiac resynchronization therapy (CRT) has been shown to improve clinical outcomes in patients with heart-failure. However, 30-40% of patients who receive CRT therapy do not show significant clinical improvement. There is much interest in refining our recognition of the latter group. In this study, Han et al sought to examine circumferential patterns in patients with LBBB and systolic dysfunction by applying tagged CMR. Septal HCM is typically due to a sarcomeric gene mutation with an autosomal dominant pattern of inheritance. As such, early recognition of functional changes to either recognise gene carriers or as a putative target for therapy would be advantageous. In this study, Germans et al used CMR to assess global LA and LV volumes and regional intramural myocardial function in carriers with normal wall thickness. The asyDuchenne Muscular Dystrophy (DMD) is associated with a skeletal and cardiac myopathy, the latter of which is coming under increasing scrutiny, in humans and animals, as a cauThe presence and amount of fibrosis in HCM appears to portend an adverse prognosis. An important practical challenge however has been defining and quantifying the presence of myocardial fibrosis by the late enhancement technique. Several methods based on a standard deviation or a full-width half maximum method have been proposed. Whilst these are highly reproducible in an infarct setting, in HCM where the fibrosis is more patchy and often diffuse, there is often the challenge of distinguishing true fibrosis from noise. In this study, Donato Aquaro and colleagues describe the merits of a cut-off derived from a Rayleigh curve as being potentially more accurate than using a fixed cut-off using a standard deviation algorithm. FurtherBeta-thalassemia major (TM) is a severe hereditary anemia requiring lifelong transfusions. There is a consequent iron overload, predominantly affecting the heart, liver and endocrine organs. Iron overload cardiomyopathy remains a major cause of death and therefore early detection of iron-induced cardiac toxicity is important, following by iron chelation treatment tailored to the heart. In addiThe first question raised by this title must be -'so what is Miyoshi myopathy'? Miyoshi Myopathy (MM) is a distinct form of muscular dystrophy caused by mutations within the dysferlin (DYSF) gene resulting in severe to complete deficiency of dysferlin expression. Clinically, these dysferlinopathies start in young adulthood with progressive muscle weakness and atrophy that advances to severe disability in older adulthood. While the profound effect of dysferlin deficiency in skeletal muscle has been the subject of much investigation, the effect of dysferlin deficiency in cardiac muscle have not been studied yet. In this study, Choi et al, demonstrated a reduction in longitudinal strain and the presence of replacement fibrosis in a subset of affected patients. This waIt is generally acknowledged that exercise is a good thing. Yet debate persists about the true health benefits of ultra-endurance forms exercise - particularly marathon running where a troponin rise is seen - often to the same levels as an acute myocardial infarction. In this study, O'Hanlon and colleagues examined if there were detectable tissue changes on CMR in a cohort of volunteers scanned following a marathon. A baselThe role of epicardial adipose tissue (EAT) and its contribution to the development of cardiac pathology is quite ambiguous. There is growing evidence of a close functional and anatomical relationship between the adipose tissue and muscular components of the heart. Its close proximity to the myocardium suggests that EAT is a metabolically active organ and a source of several bioactive molecules may influence cardiac morphology and function. In this study, Doesch et al demonstrate that in patients with CHF and severely reduced impaired LV-EF (LV-EF < 35%), EAT is significantly reduced compared to healthy controls. The redEnd stage liver disease (ELD) is associated with major alterations in the regulation of the cardiovascular system. Portal hypertension and/or hormonal changes in ELD induce a hyperdynamic circulatory state characterized by arterial hypotension and tachycardia and are often accompanied by ascites and electrolyte disturbances. Recent data also emphasizes the impact of liver function on renal  and pulmonary (hepatopulmonary and portopulmonary syndrome) circulation. Whilst there is much focus on the causes and treatment of renal and pulmonary manifestations, relatively little is understood about the myocardial changes as a result of ELD. In this study, Lossnitzer et al show that myocardial alterations have a high prevalence among ELD patients. This isIn the evaluation of myocarditis, CMR has now frequently replaced the more traditional method of endomyocardial biopsies (EMB) to confirm the diagnosis. As well as being invasive and with a tangible risk of severe morbidity or mortality, EMB has frequently suffered from sampling bias resulting in a low sensitivity. In an animal model, the extent of LGE correlated to the histological severity of myocarditis and to serum-levels of troponin T on day 21. Areas oDesmin is the main intermediate filament protein expressed in skeletal, cardiac, and smooth muscle. It interacts with other proteins to form a continuous cytoskeletal network that maintains a spatial relationship between the contractile apparatus and other structural elements of the cell, thus providing maintenance of cellular integrity, force transmission, and mechano-chemical signalling. Primary desminopathies are caused by mutations in the desmin gene. This disease is characterized by an intracellular accumulation of insoluble protein aggregates eventually leading to cell death and replacement fibrosis. In this case report, fibrosis was detected by LGE in the absence of global or focal systolic wall motion abnormalities. LGE mayMany experts consider that CMR will play an increasing role in characterisation of the atherosclerotic arterial wall, with a fThis is an interesting study that attempts to examine atherosclerosis progression and regression in multiple vascular beds  of 28 patients using black blood CMR over a one year period. LuminalThis is an observational, cross-sectional study of aortic dimensions within a large, unselected cohort of adult patients with Turner's syndrome (TS). As suchThis small ex vivo study examines the feasibility of detecting carotid plaque calcification using an ultra-short TE (UTE) technique. FourteeThe authors quantitatively compare three different approaches for aortic pulse wave velocity measurements at 3 T including transit time, flow area measurements and the cross correlation method. Fifty hThis is an interesting case report on the natural history and evolution of spontaneous intramural haematoma (IMH) in a patient with good quality images and literature review. The IMHThe authors describe the association between atheromatous plaque eccentricity with morphology and composition in the superficial artery assessed by multicontrast weighted-CMR. The stuThis study describing a phantom and mouse set of experiments validating the transit time method by MR phase velocity encoding for measuring pulse wave velocity using 17.6 T scanner. The autCMR Black blood coronary wall imaging was used in 223 elderly patients without known history of cardiovascular disease to evaluate coronary wall CMR in an asymptomatic older cohort. Image qPerfusion CMR continues to grow, and new steps in optimisation have been published including accelerated acquisition, high field CMR, and improved analysis including quantification. In many centres, perfusion CMR is making inroads into established referral patterns for nuclear based techniques. Progress in perfusion CMR in children and women in particular has occurred in a desire to lower radiation burden in these sensitive individuals. HoweverKelle et al performed perfusion CMR on 38 patients after coronary bypass grafting (CBG) without coronary obstruction and compared the results with 20 patients with no obstructive coronary disease at coronary angiography to determine whether differences in epicardial wash-in kinetics were present. In areaHamon et al performed a meta-analysis of the performance of perfusion CMR summarising 35 original articles fitting pre-specified inclusion criteria including 1.5 T imaging and comparison with coronary angiography. From thRaman et al performed an unusual and interesting perfusion CMR study, using treadmill stress and real-time CMR in a cohort of 43 patients referred for perfusion SPECT. Using aChih et al performed an important study examining the interstudy reproducibility (test-retest repeatability) of adenosine stress perfusion CMR in 20 patients (10 with coronary disease and 10 at low risk for coronary disease). The CoVKim et al explored the use of radial data acquisition at 3 T for quantification of perfusion CMR. Using aJerosch-Herold has pioneered many aspects of perfusion CMR, and in this authoritative review he summarises the quantification of myocardial perfusion using first pass techniques. The potNguyen et al studied whether obstructive sleep apnoea (OSA) as a risk factor for coronary artery disease, by measuring myocardial perfusion and brachial artery reactivity in a randomised controlled study of 35 OSA patients randomised to 3 months of nasal continuous positive airway pressure (nCPAP) or sham nCPAP. PatientKaramitsos et al studied the use of high-dose adenosine for perfusion CMR in patients who showed no haemodynamic response to adenosine at the normal dose of 140 ug/kg/minute. In a stIncreased research in acute coronary syndromes has been driven by the ability of CMR to look at a number of phenomena that are difficult or impossible to image by other in-vivo techniques. This includes microvascular obstruction, myocardial edema, myocardial salvage and relation of findings to wall motion. There iTroponin biomarkers are very sensitive of myocardial infarction but patients sometimes present with an elevated troponin in the setting of inconclusive symptoms and ECG-changes. Confirmation of acute coronary syndrome (ACS) or accurate non-ACS diagnosis is of paramount importance to avoid unnecessary invasive procedures and to guide therapy. Steen et al reported on the role of CMR in 29 such patients with elevated troponin yet low-intermediate probability of IHD. A comprThe use of CMR for identification of myocardium at risk (MaR), the myocardium supplied by the occluded vessel that is subject to ischemia has received considerable recent attention. Ubachs et al compared short-axis triple inversion turbo spin echo T2w imaging with LGE for assessment of MaR in 37 patients with early reperfused first-time ST segment elevation myocardial infarction (STEMI) within a week of percutaneous coronary intervention. T2w MaRIn another ACS study, Sorensson et al studied MaR derived from the contrast enhanced cine steady-state-free precession (SSFP) CMR compared with single photon emission computer tomography (SPECT) as the gold standard. SixteenMather et al applied LGE CMR to examine the impact of dysglycemia on acute myocardial infarction (AMI) size in 93 patients presenting with their first AMI. PatientKirschner et al used a novel CMR contrast agent gadolinium, Gd (ABE-DTTA), to differentiate acute vs. chronic (one month old) myocardial infarction in a dual infarction canine model. Gd ABE-Since the seminal clinical publication by Kim et al over a decade ago, LGE CMR plus normal segments. Receiver operator characteristic analysis demonstrated that at least 10 viable plus normal segments best predicted an LVEF improvement of \u2265 3%.Pegg et al extended this work by examining whether viable or the sum of viable plus normal segments best predicted recovery of global LVEF in 33 patients undergoing coronary artery bypass grafting (CABG). OverallNovel insights into the mechanism of ventricular remodelling to betablocker and mechanical revascularization were reported by Kaandorp et al who studied 32 patients with chronic IHD before and 8 months after assignment to betablocker or revascularization therapy. In bothCMR has been used to monitor the success of stem cell treatment in animals, but humaA highlight of the 2010 JCMR publications was an comprehensive review of dobutamine stress CMR by Charoenpanichkit and Hundley, a pioneer and ongoing leader in the field. The revFluechter et al investigated the role of myocardial fibrosis detected by late gadolinium-enhancement (LGE) CMR as a potential arrhythmogenic substrate in 76 consecutive patients with HCM. Of thes\u00ae) and a custom-built, CMR-compatible delivery device for the Medtronic CoreValve\u00ae prosthesis as an initial step towards real-time CMR-guided TAVI[\u00ae prosthesis was well visualized with good visualization during catheter movement and valve deployment on real-time TrueFISP imaging. Reliable flow measurements could be performed for both stent-valves after deployment using phase-contrast sequences. The authors conclude that the novel prosthesis is potentially suited for real-time CMR-guided placement in vivo after suggested design modifications of the delivery system.Cardiovascular magnetic resonance (CMR) is attractive for real-time device placement and intervention, but soluided TAVI. The devex vivo animal hearts proved very popular[The editors of JCMR continue to support publication of new CMR techniques and the recent review on diffusion spectral imaging (DSI) with application to tractography of y popular. The newin vivo by 3D tagging during systole were validated by comparison with more conventional analysis and measurements of myocardial strain.Myocardial tagging still presents technical challenges in implementation and analysis,110. ThiThe paper describes a means of estimating the full 3D strain tensor from a slice displacement encoded in three orthogonal directions, and including assumptions about the through-plane shear components and compressibility of the tissue. The anaThis paper demonstrates initial results of an approach providing real-time CMR, the data from which can be retrospectively reconstructed to provide high resolution. The metThe huge increase in the development of transgenic mouse models has made mouse phenotyping an increasingly important topic, and basic issues such as sedation and anaesthesia can affect these tiny hearts. In thisThis article by Schuster et al is of significant interest to the CMR community. While pThis paper describes a novel approach to detect stress-induced myocardial ischemic reaction using CMR T2* at 3 T in patients with suspected or known coronary artery disease (CAD). With quThis manuscript represents a useful review of the application of 3 T CMR and how this differs from 1.5 T. It is wIn this paper, the authors present an investigational study on a potential application of MR-Elastography (MRE) in cardiology, and the This paper describes the use of the acoustic sensing approach to gating CMR data acquisitions. The metThis manuscript is of interest to the CMR community, since many advanced CMR sites are currently moving to quantitative techniques for the assessment of myocardial injury. The autThis is an excellent introduction into the basic physics relating to cardiovascular magnetic resonance. It reviFor busy practitioners of CMR, there is a well recognised source of referrals which is simply put as unusual pathology, or cases where other imaging has failed to yield a definitive diagnosis, or where a research technique might have clinical application. These include pericardial disease,,125 tumoAs myocardial oxygenation may serve as a marker for ischemia and microvascular dysfunction, it could be clinically useful to have a non-invasive measure of changes in myocardial oxygenation, however the impact of induced blood flow changes on oxygenation is not well understood. Vohringer et al used oxygenation-sensitive CMR to assess the relation between myocardial oxygenation, coronary sinus blood oxygen saturation (SvO2) and coronary blood flow in a dog model in which hyperemia was induced by intracoronary administration of vasodilators. During McCommis et al assessed the feasibility of new CMR methods to quantify global and/or regional myocardial oxygen consumption rate (MVO2) at rest and during pharmacologically induced vasodilation in 6 normal volunteers. A breatWinter et al review the growing field of CMR molecular imaging, which aims to identify and map the expression of important biomarkers on a cellular scale utilizing contrast agents that are specifically targeted to the biochemical signatures of disease and are capable of generating sufficient image contrast. ExampleTomasian et al report a beautifully illustrated case of left atrial paraganglioma with striking PET-CT and CMR images.AR: aortic regurgitation; ASD: atrial septal defect; CMR: Cardiovascular magnetic resonance; DMD: Duchenne muscular dystrophy; EAT: epicardial adipose tissue; EF: ejection fraction; EDV: end diastolic volume; ESV: end systolic volume; HCM: hypertrophic cardiomyopathy; JCMR: Journal of cardiovascular magnetic resonance; LGE: Late gadolinium enhancement; LV: Left ventricle; MAR: myocardium at risk; MR: mitral regurgitation; MVO2: myocardial oxygen consumption rate; OEF: oxygen extraction fraction; PC: phase contrast; RV: right ventricle; TM: thalassemia major.The authors declare that they have no competing interests.All authors contributed to the writing of this review article."}
+{"text": "Understanding the neural mechanisms of action potential generation is critical to establish the way neural circuits generate and coordinate activity. Accordingly, we investigated the dynamics of action potential initiation in the GABAergic thalamic reticular nucleus (TRN) using in vivo intracellular recordings in cats in order to preserve anatomically-intact axo-dendritic distributions and naturally-occurring spatiotemporal patterns of synaptic activity in this structure that regulates the thalamic relay to neocortex. We found a wide operational range of voltage thresholds for action potentials, mostly due to intrinsic voltage-gated conductances and not synaptic activity driven by network oscillations. Varying levels of synchronous synaptic inputs produced fast rates of membrane potential depolarization preceding the action potential onset that were associated with lower thresholds and increased excitability, consistent with TRN neurons performing as coincidence detectors. On the other hand the presence of action potentials preceding any given spike was associated with more depolarized thresholds. The phase-plane trajectory of the action potential showed somato-dendritic propagation, but no obvious axon initial segment component, prominent in other neuronal classes and allegedly responsible for the high onset speed. Overall, our results suggest that TRN neurons could flexibly integrate synaptic inputs to discharge action potentials over wide voltage ranges, and perform as coincidence detectors and temporal integrators, supported by a dynamic action potential threshold. Brain activity is structured by the dynamic encoding and processing of information in neuronal circuits. The cellular components of neural circuits continuously transform varying spatiotemporal patterns of synaptic inputs into trains of action potentials that support network operations and communication An important component of the temporal sensitivity of cortical neurons derives from the voltage-gated conductances that underlie the action potential Not much information is available about action potential initiation in the thalamus, where neuronal populations exhibit distinct activity patterns, anatomical structure and connectivity We report a wide operational spike threshold range, rapid onset and steep initiation of action potentials, and the unexpected voltage-dependent onset speed of action potentials in TRN neurons in vivo, a phenomenon that seemingly depends on the effective density of sodium channels. We previously found that TRN neurons can operate as temporal integrators, due to a long voltage-dependent membrane time constant in the cortically evoked synaptic responses TRN neurons (n\u200a=\u200a27) were intracellularly recorded and electrophysiologically identified by their characteristic low-threshold spikes, high-frequency burst discharge and accelerando-decelerando firing pattern The standard deviation of each voltage threshold distribution provides a measure of spike threshold variation The fact that the wide range of the spike thresholds found in TRN neurons was similar under two distinct network conditions suggested that it could be the result of intrinsic membrane mechanisms. To establish if that was the case, we compared in the same cells the distribution of action potential thresholds in response to depolarizing currents steps at various intensities (0.5\u20131.5 nA) to the onset range measured from the spontaneously active periods during network oscillations; that is, activated epochs during slow oscillations (in recordings with ketamine-xylazine anesthesia) or spindle oscillations (in recordings with barbiturate anesthesia) . The varSeveral causes underlie the variation in action potential threshold. Previous studies have found in cortical neurons that the rate of change of the membrane potential preceding the action potential affects the action potential initiation In the population of analysed tonic spikes, we found results similar to previous studies in cortical cells The increase in the spike threshold could be related to a decrease in the availability of sodium channels due to inactivation Previous modelling studies have suggested that for short intervals, the inter-spike interval (ISI) could influence the occurrence of subsequent spikes nth previous ISI. In fact, the action potential threshold of any given spike was partially correlated with multiple previous ISIs. In addition, the number of significantly correlated previous ISIs was linearly correlated with the mean ISI for any given cell .So far we have characterised the onset range of action potential voltage thresholds. Next, we set out to analyse the onset speed of action potentials. The dynamics of action potential initiation in TRN neurons was characterized by a very rapid onset and a steep slope in membrane potential , similar\u22121ms\u22121) was statistically significant . Furthermore, reducing the effective density of available sodium channels by QX-314 application in the recording pipette .Previous modelling studies have predicted that the steepness of the action potential onset in cortical neurons is independent of the spike threshold  pipette  decrease pipette  and freq pipette , as expeThese results indicate that the onset speed of action potentials is voltage-dependent in TRN neurons, a phenomenon that also depends on the effective density of sodium channels, as it becomes more apparent when sodium channels are blocked by the lidocaine derivative QX-314.We have studied the dynamics of initiation of action potentials in the GABAergic TRN neurons in vivo. We found that TRN neurons are sensitive to synchronous synaptic inputs that result in rapid changes in the membrane potential preceding the onset of action potentials, suggesting a dynamic mechanism for synaptic coincidence detection. In addition, we have previously shown that TRN neurons can perform as good rate-coding integrators Our results demonstrate that TRN neurons do not perform only as enhanced temporal integrators that discharge an action potential once the voltage threshold is reached. Instead, spike threshold varies over a wide operational range of membrane potentials and is sensitive to the rate of membrane potential depolarization. So that the spike threshold is lowest when the membrane potential depolarizes rapidly and highest when TRN neurons are depolarized and discharging at high rates. This indicates that the mechanism of spike generation dynamically regulates the neuronal output as a function of the magnitude and time course of the membrane potential depolarization Despite the fact that the TRN nucleus is entirely constituted by GABAergic cells, it is still able to generate and propagate patterned synaptic activity, both locally and globally Our results show that TRN neurons exhibit one of the most dynamic spike voltage thresholds reported so far; a fact suggesting that these neurons can flexibly integrate synaptic inputs to discharge action potentials over wide voltage ranges. The GABAergic nature of TRN neurons does not explain the large spike voltage thresholds variability reported here, as previous studies have found narrow dynamic ranges for GABAergic neurons in the neocortex B-receptor mediated IPSPs onto target thalamocortical cells that overcome GABAA-receptor mediated inhibitory potentials A-receptor mediated inhibitory currents The large variability of voltage thresholds is unlikely to be relevant for the precise timing of burst discharges, as they activate large GABADuring wakefulness, when most sensory information is encoded and relayed to the cortex, TRN neurons operate mostly, if not exclusively, under the tonic regime. Under such conditions, the dynamic range of spike thresholds could be highly relevant for setting the precise timing of inhibition on thalamocortical cells, gating the flow of information between the thalamus and the cortex. During sleep stages, when large territories are highly synchronized and organized by spindle oscillations and slow waves, thalamocortical neurons and corticothalamic intrinsically bursting neurons preferentially discharge high-frequency bursts (>200 Hz), impinging onto TRN neurons and driving their activity Recordings from pyramidal neurons have shown a biphasic rate of rise during early phases of the action potential Previous studies have provided experimental and modelling evidence for the steepness of the action potential onset in cortical neurons as independent of the spike threshold Finally, the TRN is not the first structure proposed to combine the seemingly antagonistic functions of temporal integration and coincidence detection. Indeed, recent work in vitro has shown that neurons in slices of the subthalamic nucleus exhibit a balance between active and passive conductances that gives them an effectively zero membrane conductance (and an effectively infinite membrane time constant) over a wide voltage range 2 concentration at 3.5%. Body temperature was maintained at 36\u201338\u00b0C. The depth of anesthesia was continuously monitored by EEG, and additional doses of anaesthetic were administered at the slightest tendency toward low-voltage and fast EEG rhythms. At the end of experiments, animals were given a lethal dose of pentobarbital (50 mg/kg).All experiments were carried out in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Protocols  were approved by Comit\u00e9 de protection des animaux de l'Universit\u00e9 Laval, Vice-rectorat \u00e0 la recherche et \u00e0 la cr\u00e9ation . All surgery was performed under deep anesthesia, and all efforts were made to minimize suffering. Experiments were conducted on adult cats (2.5\u20134.5 kg) from either gender, anesthetized with pentobarbital sodium  or a mixture of ketamine HCl or xylazine HCl . When cats showed the signs of deep anesthesia, they were paralysed with gallamine triethiodide  and artificially ventilated with control of the end-tidal COCurrent-clamp intracellular recordings from the rostral and rostrolateral sector of the TRN were performed using sharp electrodes, glass micropipettes . To avoid breaking of recording micropipettes, the cortex and white matter overlying the head of the caudate nucleus were removed by suction. Pipettes were then descended 3 mm through the caudate nucleus to reach the TRN nucleus. Pipettes were generally filled with a solution of K-acetate (3 M) and, in some experiments, the lidocaine derivative N-ethyl lidocaine  was added. The stability of intracellular recordings was ensured by cisternal drainage, bilateral pneumothorax, hip suspension, and by filling the hole over the thalamus with 4% agar solution. A high-impedance amplifier with active bridge circuitry  was used to record and inject current inside the cells. Input resistance and intrinsic firing patterns were assessed by using square wave current pulses (range \u22122 to +2 nA). Electrophysiological signals were digitized at a rate of 20 KHz and stored for off-line analysis.Electrical stimulation of corticothalamic fibers was performed by descending one or two bipolar stimulating electrodes  to the internal capsule  and applying extracellular current pulses .The software package Neuromatic  was used for most analyses. Neuromatic runs in Igor Pro 6.0 . For some analyses we also used MatLab . The aim of the analysis was to measure the voltage threshold of each action potential in each cell and to determine the threshold range and onset speed of action potentials and their relation to several parameters of cellular activity. Only cells with large action potentials (that reached 0 mV) that did not decrease in amplitude (>10 mV) during sustained depolarization were included To measure the action potential threshold we used two different methods. In the first method, voltage threshold was defined as the voltage at the onset of each action potential that generated the maximum curvature with a fitting Boltzmann function  the action potential was plotted against the voltage threshold of the action potential and correlated by adjusting a linear fit as previously reported for pyramidal cells To obtain an estimation of the degree of inactivation during spiking in vivo  we calcuSome portions of raw data (intracellular voltage recordings) from several of the cells presented here (n\u200a=\u200a11 of 27) have been used in previous publications (cell in Unless stated, all tabulated data are presented as the mean \u00b1 SD. Exact Mann Whitney U-test was used for statistical comparisons between populations and the two-tailed t test distribution was used to assess significance of linear correlations. Significant differences were accepted at p<0.05.In order to compare the means from small samples  we used"}
+{"text": "An error occurred in the \"Scaling issues and analysis\" sub-section of the Methods section, in which certain characters were changed to question marks. Please see the corrected paragraph here:"}
+{"text": "Models of cortical dynamics usually either cover small cortical circuits in detail, or represent large patches in a highly simplified manner, for instance using a few differential equations for each area. This is due partly to limited computational resources, and partly to sparsity of large-scale structural connectivity data. These two barriers are now being lifted. Recent developments in the simulation technology NEST  and the Making use of these developments, we construct a model comprising the 32 areas of the macaque cortex associated with visual processing, where the individual areas are based on our recent layered cortical microcircuit model  and anatCombining a simple neuron model with complex connectivity enables us to study the influence of the structural connectivity itself on cortical dynamics. We present preliminary results on basic dynamical features like area- and population-specific firing rates and degrees of irregularity. In addition, we examine the influence of the cortico-cortical connections by comparing dynamical features like power spectra of the isolated primary visual cortex (V1) with Poisson input to its dynamics when embedded in the global network. This model bridges the gap between abstract large-scale models and small-scale microcircuit models. It therefore provides a link between global activity patterns and local spiking activity."}
+{"text": "During the last years accumulating evidence demonstrated that the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) regulates the expression of renin gene and thus the overall renin production. This review summarizes the current knowledge of the transcriptional control of the renin gene by PPARgamma received from variety of models ranging from cell culture to transgenic animals. The molecular mechanisms of the PPARgamma action on renin are particularly interesting because they are featured by two newly described characteristics: one of them is the recently identified PPARgamma target sequence Pal3 which is specific for the human renin gene and mediates exceptionally high sensitivity to transactivation; the other is the potentiating effect of PPARgamma on the cAMP signaling in the renin-producing cells. Furthermore, I discuss the need for generating of additional transgenic animal models which are more appropriate with regard to the role of the PPARgamma-dependent regulation of the renin gene expression in human diseases such as arterial hypertension and metabolic syndrome. The renin promoter has two evolutionary conserved regulatory regions: the proximal promoter which lies immediately upstream of the transcription starting site and the distal (or kidney) enhancer which consists of approximately 240\u2009bp located at around \u22122.6\u2009kb in the mouse and \u221212\u2009kb in the human renin gene [Renin is aspartyl protease produced by the juxtaglomerular (JG) cells in the afferent arterioles of the kidney. It is the limiting enzyme in renin-angiotensin system (RAS), which plays crucial role in the control of blood pressure and salt excretion. The renin production is tightly regulated at the transcriptional level. Although the active renin is released into the circulation through regulated exocytosis, chronic (patho)physiological cues influencing the renin production  always induce parallel changes in the plasma renin concentration (PRC) and the renin mRNA levels in the JG cells . TherefoThe transcription factors driving the renin gene could be divided into two groups based on their functional role and their promoter interaction site . The firPPARgamma belongs to a family of nuclear receptors which also includes PPARalpha and PPARdelta/beta. The PPARs are class I ligand-activated nuclear receptors (termed NR1C1 to C3 according to the unified nuclear receptor nomenclature) and are generally induced by fatty acids. They bind to DNA as heterodimers with RXR to a core recognition sequence known as PPRE (PPAR response element) or DR1 since it represents a direct repeat with 1\u2009bp spacer of the consensus nuclear receptor binding site 5\u2032-A(G)GGTCA-3\u2032 (termed hormone response element (HRE)). Although the PPARs were originally described to regulate the lipid metabolism, it is now known that they are ubiquitously expressed and involved in multiple aspects of the control of whole body homeostasis , 17. PPARgamma was originally identified to stimulate the renin production during screening of the effect of free fatty acids on renin in an attempt to identify mechanisms responsible for the development of arterial hypertension during obesity . It was We also found that the combination of the dual binding pattern of PPARgamma with the promiscuous heterodimerization of RXR with nuclear receptors at other HRE-binding sites could contribute to the preserved binding of PPARgamma homodimers to Pal3 at low cellular expression of PPARgamma . This prNext to the classical ligand-dependent activation, posttranslational modification by the small ubiquitin-like modifier (SUMO) was found to modulate the PPARgamma function . NotewoThe mouse orthologue of the human renin Pal3 turned out to be functionally silent in spite of the high sequence similarity. Consequently a quest for the PPARgamma-binding site in the mouse renin gene started. Such sequence proved to be the direct repeat HRE element in the kidney enhancer which had already been reported to mediate the upregulation of the renin expression by vitamin A , 20. Thi3 receptor (VDR) heterodimerizes with CREB bound to the renin enhancer CRE (cAMP response element) to repress the renin transcription [A large board of data from cell culture and in vivo studies unequivocally demonstrates that the cAMP/PKA/CREB pathway is central for the control of the renin gene transcription and the overall renin production (reviewed in ). cAMP mcription . Furthercription . PPARgamcription . The potcription .In summary, PPARgamma appeared to stimulate the renin expression via a dual mechanism: directly, through the PPARgamma-binding sequences in the renin promoter; and indirectly, by amplifying the agonist-induced cAMP production through increased AC6 transcription .PPARgamma is considered as the key molecule in the pathogenesis of MetS. This syndrome includes obesity accompanied by hyperlipidemia, insulin resistance/diabetes mellitus type 2, and arterial hypertension . AccordiThe plasma renin concentration is increased in obesity and contributes significantly to cardiovascular and renal complications  . Since P"}
+{"text": "The aim of this case report is to present the additional value provided by CT virtual endoscopy and 3D stereoscopic visualisation when compared with 2D visualisations in the assessment of coronary stenting. A 64-year old patient was treated with left coronary stenting 8 years ago and recently followed up with multidetector row CT angiography. An in-stent restenosis of the left coronary artery was suspected based on 2D axial and multiplanar reformatted images. 3D virtual endoscopy was generated to demonstrate the smooth intraluminal surface of coronary artery wall, and there was no evidence of restenosis or intraluminal irregularity. Virtual fly-through of the coronary artery was produced to examine the entire length of the coronary artery with the aim of demonstrating the intraluminal changes following placement of the coronary stent. In addition, stereoscopic views were generated to show the relationship between coronary artery branches and the coronary stent. In comparison with traditional 2D visualisations, virtual endoscopy was useful for assessment of the intraluminal appearance of the coronary artery wall following coronary stent implantation, while stereoscopic visualisation improved observers\u2019 understanding of the complex cardiac structures. Thus, both methods could be used as a complementary tool in cardiac imaging. In recent years, coronary artery disease has been increasingly treated by coronary stent placement. Although stent implantation has been shown to greatly reduce restenosis after balloon angioplasty , 2, in-sCurrently multi-detector row computed tomography (MDCT) is increasingly used for non-invasive imaging of coronary artery disease and has been reported to have a high diagnostic accuracy in the detection of coronary artery stenosis and in-stent restenosis, especially with the development of the latest 64-detector row CT scanners -7. NearlIn this case report, we presented our experience of using virtual endoscopy and 3D stereoscopic views for visualisation of the coronary artery and coronary stent in a patient treated with coronary stenting. The aim of the case report was to identify the potential value of these 3D visualisations in demonstration of complicated cardiac structures when compared to conventional 2D visualisations.A 64-year old man presented with exertional angina in 1998 and was investigated with an exercise ECG, which showed weakly positive results. Thallium scans were negative for differential differences in left ventricular coronary artery flow. Persistent angina was further investigated in 1999 with coronary angiography and showed a 70% stenosis at the origin of the left main coronary artery. This was treated with a Left Internal Mammary Artery (LIMA) bypass to the descending and long saphenous Vein Bypass (LSV) to the circumflex coronary arteries. Angina persisted and repeated angiography in 2000 showed that the LIMA bypass was not patent and the stenosis had progressed. The origin of the left main coronary artery was treated with a bare stent and dilated to 4 mm. In 2008 further investigation was requested for travel insurance and the CT angiography was performed to avoid invasive investigation.Coronary CT angiography was performed using a 64-detector row CT scanner  with a section thickness of 0.625 mm and reconstruction interval of 0.4 mm. Curved multiplanar reformatted images were generated at the CT scanner workstation. The original DICOM  data was transferred to a separate workstation equipped with Analyze V 7.0  for generation of virtual endoscopic and stereoscopic images. Generation of virtual endoscopic images was performed with a CT thresholding technique, which has been described before . IntraluIn addition to the static virtual endoscopy visualisations, we also produced dynamic fly-through of the coronary arteries with the aim of demonstrating the entire coronary arteries. This was performed by setting a number of virtual cameras along the path of the coronary arteries. A fly-through of the left coronary artery including left anterior descending and left circumflex branch confirmed the findings of static virtual endoscopic visualisations, which showed the smooth appearance of coronary lumen.A stereoscopic pair of images consists of two projections of the same 3D object acquired from two slightly different viewing angles. The pair of stereoscopic images is displayed so that only the left eye sees the left projection and only the right eye sees the right projection. As a result, the observer is able to reconstruct and appreciate the 3D object mentally including the depth dimension. In our study, the reviewers used red/blue glasses for the stereoscopic display of the cardiac anatomic structures as shown in MDCT has been increasingly used for the diagnosis of coronary artery disease and follow-up of coronary stenting due to its improved spatial and temporal resolution, especially with the advancement of 64-detector row scanners -7. In adOur results in this case study demonstrated the superiority of virtual endoscopy with intraluminal views over conventional extraluminal visualisations. This is manifested by visualisation of the smooth intraluminal surface in both stented and normal coronary artery lumen. In this case, virtual endoscopy excludes the presence of coronary in-stent re-stenosis or any stent-related changes in the coronary artery wall.We also included stereoscopic visualisation in this case and our results showed that it offers better understanding of the complex cardiac structures. Our previous study confirmed that stereoscopic viewing provides additional information regarding any distortions of the fenestrated stents compared with conventional 2D visualisations . Thus, sDrug-eluting stents are increasingly being used in clinical practice with the aim of preventing in-stent restenosis, and research has shown the decreased incidence of stent re-stenosis when compared to bare metal stents , 14. HowFollow-up of coronary stenting  with regard to the appearance of intraluminal wall with the aim of identifying the artery wall changes by use of virtual endoscopy;Confirmation of suspected in-stent re-stenosis in any section of the coronary artery branch with aid of virtual endoscopy;Enhancement of endovascular specialists\u2019 understanding of the relationship between coronary stents and coronary arteries and appreciation of complex anatomic structures with the aid of 3D stereoscopic visualisation."}
+{"text": "Mycobacterium tuberculosis (MTB), survives inside macrophages by blocking phagosome maturation and establishes chronic infection characterized by the formation of granulomas. Trehalose-6,6-dimycolate (TDM), the mycobacterial cord factor, is the most abundant cell wall lipid of virulent mycobacteria, is sufficient to cause granuloma formation, and has long been known to be a major virulence factor of MTB. Recently, TDM has been shown to activate the Syk-Card9 signaling pathway in macrophages through binding to the C-type lectin receptor Mincle. The Mincle-Card9 pathway is required for activation of macrophages by TDM in vitro and for granuloma formation in vivo following injection of TDM. Whether this pathway is also exploited by MTB to reprogram the macrophage into a comfortable niche has not been explored yet. Several recent studies have investigated the phenotype of Mincle-deficient mice in mycobacterial infection, yielding divergent results in terms of a role for Mincle in host resistance. Here, we review these studies, discuss possible reasons for discrepant results and highlight open questions in the role of Mincle and other C-type lectin receptors in the infection biology of MTB.The world's most successful intracellular bacterial pathogen,  In Geisel et al. . The increased mycobacterial numbers in the Mincle\u2212/\u2212 mice were paralleled by a stronger expression of inflammatory genes in the lungs. Given the expression and function of Mincle in granulocytes described in the same paper, it would be interesting to know whether neutrophil accumulation, integrin expression and cytokine production in the lungs is particularly affected in the mice infected in the Lee et al. study. The higher expression of inflammatory genes in Mincle\u2212/\u2212 lungs is difficult to interpret because it could be entirely due to the increased mycobacterial load generating more PAMPs for activation of receptors other than Mincle. One can only speculate at which time after infection Mincle\u2212/\u2212 mice start to have higher MTB burden in the lung; one possibility is that a lack of recruitment and proper activation of neutrophils early after infection gives MTB the ability to survive and grow better than in WT mice.The second study reporting on the phenotype of MincleM. bovis BCG in intratracheal and intravenous infection models  or employed the vaccine strain M. bovis BCG . Although all these strains have abundant TDM in the cell wall, they may differ in the length of mycolic acid chains, modifications and the mixture of other glycolipids present in the cell wall, which may account for the difference in the requirement for Mincle. Of interest, in vitro infection experiments of macrophages showed a stronger dependence of the NO production and of G-CSF secretion on Mincle when BCG was used compared to MTB H37Rv  in an Ag85A-dependent manner (Matsunaga et al., In principle, another variable can be introduced by changes in the culture conditions used to grow the mycobacteria before infection. For example, the commonly used inclusion of detergents like Tween in the mycobacterial broth to prevent clumping has been shown to drastically modify the presence of a polysaccharide capsular structure (Sani et al., Finally, the hygiene status of mouse colonies can be expected to alter the basal levels of innate immune activation in general and of Mincle expression levels on phagocytes in particular through effects of TLR- and CLR-dependent PAMPs.\u2212/\u2212 mice develop high mycobacterial burden in the lungs and die within 4\u20136 weeks. Card9\u2212/\u2212 macrophages normally phagocytosed and killed MTB in vitro, but were impaired in the production of inflammatory cytokines and chemokines. In vivo, Card9\u2212/\u2212 mice had a striking increase in neutrophil infiltration in the lung that was linked to tissue destruction and death of the mice by depletion experiments (Dorhoi et al., The adapter protein Card9 is expressed in myeloid cells and was initially identified as crucial for transducing the signal of the C-type lectin receptor Dectin-1 to NFkB activation (Gross et al., M. bovis BCG or MTB (Yadav and Schorey, M. abscessus and impaired ROS production was reported when Dectin-1 was blocked in mouse macrophages (Shin et al., in vivo, Brown and colleagues challenged Dectin-1 KO mice with virulent MTB. The mycobacterial load in the lungs was unexpectedly slightly reduced in Dectin-1 KO mice, but there were no significant differences in lung pathology or adaptive immune responses (Marakalala et al., Dectin-1 has been implicated by several labs in the response to mycobacteria, but the nature of the ligand has remained unknown to date. Blocking Dectin-1 with antibodies or laminarin reduced cytokine responses to via induction of IL-10 production (Geijtenbeek et al., \u2212/\u2212 mice was seen in the spleen. SIGNR3 binding of ManLAM and whole mycobacteria induces production of proinflammatory cytokines through activation of Syk and the kinase Raf1 (Tanne et al., \u2212/\u2212 mice in tuberculosis, although it appears to be essential for anti-mycobacterial resistance only during the early innate phase of infection.The human C-type lectin DC-SIGN has received considerable attention in the mycobacterial immunity field when it was discovered that binding of mycobacterial Man-LAM to DC-SIGN on human macrophages down-regulates costimulatory molecules and inflammatory responses, presumably Given the large number of CLR that can be expressed in myeloid cells, additional players must be expected to contribute to recognition of mycobacterial ligands and to macrophage activation and anti-mycobacterial defense via Card9-dependent mechanisms. Another interesting candidate to look at is Dectin-2; of note a Dectin-2-Fc fusion protein binds to the surface of mycobacteria (McGreal et al., The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "XMRV is a gammaretrovirus associated in some studies with human prostate cancer and chronic fatigue syndrome. Central to the hypothesis of XMRV as a human pathogen is the description of integration sites in DNA from prostate tumour tissues. Here we demonstrate that 2 of 14 patient-derived sites are identical to sites cloned in the same laboratory from experimentally infected DU145 cells. Identical integration sites have never previously been described in any retrovirus infection. We propose that the patient-derived sites are the result of PCR contamination. This observation further undermines the notion that XMRV is a genuine human pathogen. XMRV was originally described in 2006 in the tumour tissue of patients with a familial form of prostate cancer associated with mutations that impair the function of the antiviral defence protein RNase L . Three iin situ-hybridisation and serological studies have also been inconsistent in their findings. Some studies  [EU981808 and GenBank: EU981810], obtained from two different patients, were identical to XMRV integration sites [GenBank: GU816103 and GenBank: EU981678] respectively, which were cloned from the experimentally infected human tumour cell line, DU145 [The only research group describing patient-derived XMRV integration sites provides sequence data from 14 XMRV integration sites cloned from the prostatic tumour tissues of 9 patients [GenBank: U981813] ,8. Nuclein vivo and an experimentally infected cell line in vitro, on two separate occasions.Current knowledge based on the analysis of several thousand retroviral integration sites suggests that target site selection is not primarily sequence-specific, although different classes of retrovirus exhibit distinct genome location biases . HIV-1 fWe consider PCR based contamination to be the most likely explanation for the identification of identical integration sites from the patients' prostate tumour tissues and from the DU145 cells experimentally infected with XMRV. It is noteworthy that the prostate tumour tissue sites and the DU145 cell sites were cloned by the same research group in the same laboratories -9 and thWhilst it is conceivable that the other 12 integration sites apparently derived from prostatic tumour tissues ,8 are geCFS: chronic fatigue syndrome; FISH: fluorescence in situ hybridization; HIV-1: human immunodeficiency virus type 1; HPLC: high performance liquid chromatography; LTR: long terminal repeat; MLV: murine leukaemia virus; PCR: polymerase chain reaction; XMRV: Xenotropic murine leukaemia virus-related virus.The authors declare that they have no competing interests.JAG conceived the study and performed the research. JAG, GJT and PK interpreted the data and wrote the paper. All authors read and approved the final manuscript."}
+{"text": "To explore the molecular function of Osteopontin (OPN) in the pathogenesis of human OA, we compared the expression levels of OPN in synovial fluid with clinical parameters such as arthroscopic observation of cartilage damage and joint pain after joint injury.Synovial fluid was obtained from patients who underwent anterior cruciate ligament (ACL) reconstruction surgery from 2009 through 2011 in our university hospital. The amounts of intact OPN (OPN Full) and it\u2019s N-terminal fragment  in synovial fluid from each patient were quantified by ELISA and compared with clinical parameters such as severity of articular cartilage damage (TMDU cartilage score) and severity of joint pain .Within a month after ACL rupture, both OPN Full and N-half levels in patient synovial fluid were positively correlated with the severity of joint pain. In contrast, patients with ACL injuries greater than one month ago felt less pain if they had higher amounts of OPN N-half in synovial fluid. OPN Full levels were positively correlated with articular cartilage damage in lateral tibial plateau.Our data suggest that OPN Full and N-half have distinct functions in articular cartilage homeostasis and in human joint pain. Osteoarthritis (OA) is a group of diseases and mechanical abnormalities involving degradation of articular cartilage and subchondral bone. Clinical manifestations of OA may include joint pain, tenderness, stiffness, creaking, locking of joints, and local inflammation Currently, the major therapeutic strategy for OA is based on conservative treatments, such as muscle exercise with medications, to relieve joint inflammation and pain OPN is an O-glycosylated phosphoprotein produced by a variety of tissues and cells including osteoblasts, chondrocytes, synoviocytes, and T cells Since OPN contains cryptic binding sequences for several different receptors, fragmented OPN proteins are considered to have different functions in distinct pathological conditions Studies utilizing OPN knockout mice have reported that aging-associated and instability-induced OA were accelerated in the absence of OPN Since OPN is considered as a proinflammatory cytokine, we hypothesized that OPN levels in the synovial fluid were correlated with joint inflammation and pain. In this study, to examine our hypothesis and to further explore the distinct roles of OPN Full and N-half in joint homeostasis, we analyzed OPN Full and N-half levels in synovial fluid after joint injury and performed correlation analyses with various clinical parameters. Here we report that OPN Full and OPN N-half levels are associated with the severity of joint pain and articular cartilage damage in humans. We consider the two most important subjects in OA research to be the elucidation of the mechanism of joint pain and the mechanism of articular cartilage degradation in humans, both of which are quite difficult to answer using animal models.This study was approved by the Ethics Committee of Tokyo Medical and Dental University. All patients included in this study gave their full written, informed consent for participation prior to the operative procedure. For minors/children, we obtained informed written consent from their parents or guardians. In this study, we regarded ACL reconstruction patients as a high risk OA group as it was reported that more than 30% of ACL reconstruction patients develop radiographic OA on an average of 7.8 years after surgery, with most patients having no evidence of OA at the time of rupture Since OPN is shown to process by thrombin in an inflammatory environment The severity of articular cartilage damage was scored during ACL reconstruction surgery according to the classification protocol described by Asano et al with modification VAS was collected in the examination room before consultation (one day before ACL reconstruction surgery). Lysholm scores were collected by expert joint surgeons in our university hospital during consultation. Details are shown in P<0.05 were considered significant.All the analyses were performed by a double-blind method. Mann-Whitney\u2019s U-test or Kruskal\u2013Wallis test followed by Steel\u2013Dwass multiple comparison tests were employed to analyze the differences between groups. Pearson\u2019s correlation coefficient test was employed for correlation analyses. Values of As shown in Matsui et al reported that the development of aging-associated and instability-induced osteoarthritis was accelerated in OPN deficient mice Since local inflammation is considered to be a major contributor for joint pain, we next examined if synovial fluid OPN levels are correlated with the severity of systemic and local inflammation. As shown in OPN is a phosphorylated acidic glycoprotein with diverse functions including cell adhesion, chemoattraction, immunomodulation, and cell differentiation In the present study we demonstrated that kinetics of OPN Full and N-half levels were different in synovial fluid. Both OPN Full and N-half levels surged almost 10-fold by 4 days after ACL reconstruction surgery. This result is comparable with previous reports indicating that OPN is an early response gene against various stress signals With regard to the correlation of OPN levels and articular cartilage damage, we found that OPN Full levels are positively correlated with the severity of articular cartilage damage in lateral tibial plateau . LateralThe most interesting finding of this study was the correlation of OPN levels with the severity of joint pain. We observed that OPN Full and N-half levels are positively correlated with the severity of joint pain in patients who suffered from ACL rupture within 1 month. Since OPN functions as a proinflammatory cytokine and regulates PTGS2 and iNOS expression In summary, we found that OPN levels were correlated with the severity of articular cartilage damage in lateral tibial plateau and joint pain. These results suggest that OPN may be an important target to relieve OA patients from severe joint pain and cartilage degradation.Table S1Classification of arthroscopic observation of articular cartilage damage. Severity of articular cartilage damage was scored according to the protocol described by Asano et al (DOCX)Click here for additional data file.Table S2Visual Analogue Scale (VAS) for pain. VAS was collected using a questionnaire described in the table.(DOCX)Click here for additional data file.Table S3Lysholm score for pain. Lysholm scores were collected in an examination room by expert joint surgeons in our university hospital. Classification of each score was described in the table.(DOCX)Click here for additional data file."}
+{"text": "PLOS Biology reports that if the target gene contains multiple Brachyury-binding sites it will be activated early in development but if it contains only one site it will be activated later. Genes that contain no binding site can still be activated by Brachyury, but only indirectly by an earlier Brachyury-dependent gene product, so later than the directly activated genes. Thus, this study shows how several genes can interpret the presence of a single factor differently to become active at distinct times in development.How does a fertilized egg decode its own genome to eventually develop into a mature animal? Each developing cell must activate a battery of genes in a timely manner and according to the function it will ultimately perform, but how? During development of the notochord\u2014a structure akin to the vertebrate spine\u2014in a simple marine invertebrate, an essential protein called Brachyury binds to specific sites in its target genes. A study just published in  One or more specific transcription factors bind the CRMs in a target gene and then recruit and/or activate the basal transcription machinery to transcribe the coding sequence of the gene in a particular cell at a precise time The development of a multicellular animal embryo from a single cell begins upon fertilization of the egg: the resulting zygote divides repeatedly to produce variable amounts of diverse early embryonic cells. These cells will go on to differentiate by activating distinct subsets of genes depending on their positions in the embryo and according to their prospective fates Ciona intestinalis and C.savignyi provide simple model systems for chordate development: their larvae have the typical body-plan of animals with backbones, including a notochord\u2014the precursor of the backbone. The ascidian notochord offers the opportunity to study, in a simple system, how the genomic blueprint directs the behavior of cells that form a specific structure during development. In 64-cell stage embryos, four cells start transcribing Ci-Bra, the gene that encodes the DNA-binding transcription factor Brachyury  assays showed direct binding of the endogenous Bra protein to early- and middle-onset CRMs but not to the late-onset CRM in tailbud embryos. Thus, it appears that Bra controls late-onset gene expression indirectly by a \u201crelay\u201d mechanism in which early- and/or middle-onset transcription regulators, such as those recently identified by the Di Gregorio team C. savignyi found only one early- and one middle-onset type CRM containing Bra-binding motifs and these were not systematically or perfectly conserved when compared to those in C. intestinalis. This further indicates that Bra-responsive CRM design is rather flexible and therefore variable even in evolutionarily related species, even though the underlying regulatory code may be conserved. Evolutionary conservation of the enhancer code was demonstrated previously in a comparative analysis of the CRMs controlling expression of the homeobox gene Otx from divergent ascidian species, where CRMs for neural, endodermal, and muscular expression relied on the same motifs  in the two species even though the sequences of the CRMs could not be aligned Further investigation of the structural requirements for early-onset activity of notochord CRMs in response to Bra suggested that the observed synergistic effect between Bra-binding sites depends neither on the orientation, distance, or position of the functional sites relative to each other within the CRM, nor on a precise organization with respect to the promoter. Inspection of the non-coding sequences flanking orthologous notochord genes in the related species Caenorhabditis elegans pharynx, where individual sites of high binding affinity for PHA-4 determine early onset of target gene expression How might multiple Bra-binding sites in a notochord CRM determine early onset of gene expression? One explanation is that the cluster of several sites might increase the overall affinity of the CRM for the transcription factor This threshold\u2013response model also implies that the availability of Bra protein is limiting for activation of middle-onset CRMs in early gastrula versus early neurula embryos. The availability of Bra might be determined by its gene expression, control of its accumulation in the nucleus, how its target DNA is packaged in chromatin, and/or competition with other DNA-binding proteins  Drosophila melanogaster, where the transcription factor Dorsal controls dorso-ventral patterning. Like the Bra target genes, the sensitive Dorsal target gene sog, which is governed by a multi-site CRM sna and vndbra activation, and whether the temporally distinct onsets of notochord gene expression coincide with successive divisions.The threshold\u2013response model of gene activation has been extensively tested during early development of the fruitfly, Drosophila indicate that transcription factor binding is not necessarily sufficient for transcriptional activation: some sites bind their transcription factors early but activate transcription only later when other factors have bound Drosophila visceral mesoderm development illustrates this idea trans-acting factors, whereas the class that bound bin late contained only bin-binding sequences, suggesting that early bin binding requires cooperation with other DNA-binding factors. Comprehensive ChIP and expression studies further substantiated the notion that combinatorial transcription factor binding determines the spatio-temporal pattern of CRM activity in the fly mesoderm Studies in Drosophila ventral mesoderm, however. Whereas the Drosophila mesoderm is a complex population of transient progenitors with diverse developmental outcomes and proliferative potential, the ascidian notochord cells are fate-restricted at the onset of Ci-Bra expression and become post-mitotic after only two divisions. In other words, ascidian notochord cells undergo terminal differentiation following bra expression. As in C. elegans post-mitotic neurons and male tail tip differentiation Ci-Bra, controls most aspects of notochord differentiation in ascidians. However, additional transcription regulators, such as FoxA and Tbx2/3, govern late notochord gene expression and probably also contribute to regulating early- and middle-onset gene expression The control of ascidian notochord development by Bra might be simpler than that of the Drosophila embryo showed that asynchronous expression of the early determinant sna throughout the mesoderm profoundly affects gastrulation The premise that timely activation of notochord genes is essential for the morphogenesis of this structure remains to be tested functionally. Recent work on the early"}
+{"text": "Monotremes (echidna and platypus) are egg-laying mammals. One of their most unique characteristic is that males have venom/crural glands that are seasonally active. Male platypuses produce venom during the breeding season, delivered via spurs, to aid in competition against other males. Echidnas are not able to erect their spurs, but a milky secretion is produced by the gland during the breeding season. The function and molecular composition of echidna venom is as yet unknown. Hence, we compared the deeply sequenced transcriptome of an in-season echidna crural gland to that of a platypus and searched for putative venom genes to provide clues into the function of echidna venom and the evolutionary history of monotreme venom. We found that the echidna venom gland transcriptome was markedly different from the platypus with no correlation between the top 50 most highly expressed genes. Four peptides found in the venom of the platypus were detected in the echidna transcriptome. However, these genes were not highly expressed in echidna, suggesting that they are the remnants of the evolutionary history of the ancestral venom gland. Gene ontology terms associated with the top 100 most highly expressed genes in echidna, showed functional terms associated with steroidal and fatty acid production, suggesting that echidna \u201cvenom\u201d may play a role in scent communication during the breeding season. The loss of the ability to erect the spur and other unknown evolutionary forces acting in the echidna lineage resulted in the gradual decay of venom components and the evolution of a new role for the crural gland. Ornithorhynchus anatinus), the short-beaked echidna (Tachyglossus aculeatus) (shown in Zaglossus sp). It has been long recognised that male platypuses have spurs on their hind legs that are connected to venom glands by venom ducts. The venom glands increase in size during the breeding season Monotremes are egg-laying mammals and include the platypus , mesencephalic astrocyte-derived neurotrophic factor (MANF) and a ribosomal protein (RPL9). The most highly expressed genes in the echidna venom gland are shown in To provide insight into the function of echidna venom, we examine the most highly expressed genes in the echidna venom gland. Quantification of expression levels involved the counting of raw reads that map to assembled scaffolds. The numbers were normalized with respect to the length of the scaffolds. This method allowed us to examine the most highly expressed genes and allowed comparison with similar experiments in platypus. None of the top 50 most highly expressed echidna genes were found in the top 50 of platypus. Similar results were obtained when human protein-coding transcripts instead of platypus ones were used to assemble the contigs. Comparison of the top 200 most abundant transcripts from the two datasets identified three proteins common to both echidna and platypus glands: a mitochondrial phosphate carrier protein (We compared gene ontology (GO) enrichment statistics between the expressed genes (RPKM>10) in the echidna and platypus datasets to examine and infer biological differences between the two species by restricting the analysis to the top 200 most highly expressed genes in both datasets. 182 out of the top 200 echidna genes were associated with 1,537 GO annotations that represented 580 unique terms. Compared to the platypus dataset, we detected five significantly enriched GO terms that included adenyl ribonucleotide binding, adenyl nucleotide binding, ATP binding, post-translational modification and plasma membrane .We also performed functional term analyses on the top 200 most highly expressed genes in both echidna and platypus datasets. No gene ontology terms were found to be significant at p<0.05 after multiple testing correction (FDR) in independent tests for each species.These analyses confirm that the key role of the echidna crural gland is not venom production. The life history of echidnas may point to the likely functional role of this gland. Echidnas are usually solitary, but during the breeding season (June to September) they are believed to use chemical cues to attract mates et al. SCD) \u2013 a protein involved in fatty acid biosynthesis was highly expressed in the echidna transcriptome. Other proteins involved in fatty acid metabolism including acyl-CoA dehydrogenase (ACADVL), acetyl-CoA carboxylase beta (ACACB), acyl-CoA synthetase long-chain family member 1 (ACSL1) as well as lecithin-cholesterol acetyltransferase (LCAT), sortilin-related receptor, L(DLR class) Repeats-containing protein (SORL1) and the Niemann-Pick disease protein (NPC1) are also all involved in sterol metabolic processes and expressed in the echidna crural gland transcriptome. Similar sterols and fatty acids are commonly found in scent gland secretions from other animals and can function to prolong the life of a scent mark (sterol esters) and encode complex informational content (long-chain fatty acids) (reviewed in The recent study by Harris The major components of secretory granules in echidna crural glands are proteins Our results suggest that the primary role of the echidna crural gland is not to produce venom for offensive or defensive purposes. The majority of known platypus toxins were not detected in the transcriptome of the echidna crural gland. 30 echidna scaffolds matched 12 known toxins from a number of venomous species, but these were only lowly expressed in the gland and perhaps provide a remnant of the glands life history. Today the transcriptomes of the echidna and platypus crural glands have distinct expression profiles sharing few similarities in their most highly expressed genes. Should the echidna genome become available a review of the evolutionary remnants of venom genes can be conducted. The echidna gland appears to have evolved to play a role in chemical communication during the breeding season. Although the function of the crural gland has diverged significantly since the last common monotreme ancestor, each lineage continues to use the gland to aid reproduction."}
+{"text": "In Phase II oncology trials, targeted therapies are being constantly evaluated for their efficacy in specific populations of interest. Such trials require designs that allow for stratification based on the participants' biomarker signature. One of the disadvantages of a targeted design (defined as enrichment in biomarker-positive sub-population) is that if the drug has at least some activity in the biomarker-negative subjects, then their effect in the biomarker-negative population may never be known.Jones and Holmgren (JH) have proposed a design to determine whether drug has activity only in target population or the general population. Their design is an enrichment adaptation based on two parallel Simon two-stage designs. Unfortunately, there are several pitfalls in the JH design: the issue of hypothesis testing is not properly addressed and the type I error, power calculations and expected sample size formulae are wrong too.We study the JH design in detail, appropriately control the type I and type II error probabilities that yield novel optimal designs. We also discuss various alternative Family Wise Error Rates (FWER) and the Individual Hypothesis (IH) error rates in the weak sense as well as the strong sense.For each option of the error controls, we search for designs over a 10 trillion search space and obtain optimal designs that minimise the expected sample size. For the particular example trial that JH consider, our optimal design requires 38% fewer subjects in comparison with the two parallel Simon two-stage design thereby offering substantial efficiency in terms of the expected sample size. In conclusion, our rectified design provides a robust framework for adaptive enrichment in biomarker-stratified Phase II trial design."}
+{"text": "The coherence function of integrate-and-fire neurons shows low-pass properties in the most diverse firing regimes . While tNumerical calculation of the mutual information rate is now a commonly adopted practice, but it does not indicate what aspects of the stimulus are best represented by the neuronal response. We developed a numerical procedure to directly calculate a frequency-selective version of the mutual information rate. This can be used to study how different frequency components of a Gaussian stimulus are encoded in neural models without invoking a weak-signal paradigm."}
+{"text": "Quercus species co-occurring in the forests of southern Spain. For this purpose, we considered not only the quantity of dispersed seeds but also the quality of the seed dispersal process. The suitability for recruitment of the microhabitats where the seeds were deposited was evaluated in a multi-stage demographic approach. The highest rates of seed handling and predation occurred in those microhabitats located under shrubs, mostly due to the foraging activity of rodents. However, the probability of a seed being successfully cached was higher in microhabitats located beneath a tree canopy as a result of the feeding behaviour of beetles. Rodents and beetles showed remarkable differences in their effectiveness as local acorn dispersers. Quantitatively, rodents were much more important than beetles because they dispersed the vast majority of acorns. However, they were qualitatively less effective because they consumed a high proportion of them (over 95%), and seeds were mostly dispersed under shrubs, a less suitable microhabitat for short-term recruitment of the two oak species. Our findings demonstrate that certain species of dung beetles (such as Thorectes lusitanicus), despite being quantitatively less important than rodents, can act as effective local seed dispersers of Mediterranean oak species. Changes in the abundance of beetle populations could thus have profound implications for oak recruitment and community dynamics.The process of seed dispersal of many animal-dispersed plants is frequently mediated by a small set of biotic agents. However, the contribution that each of these dispersers makes to the overall recruitment may differ largely, with important ecological and management implications for the population viability and dynamics of the species implied in these interactions. In this paper, we compared the relative contribution of two local guilds of scatter-hoarding animals with contrasting metabolic requirements and foraging behaviours (rodents and dung beetles) to the overall recruitment of two  Plant-animal interactions are key components in the regeneration process of many plant species with strong implications for population viability and community dynamics Recent studies have shown that both the quantity and the quality of seed dispersal are highly context-dependent, highlighting habitat structure as one of the main drivers of the spatiotemporal variation in SDE Apodemus, Mus, Sciurus, etc.) are broadly considered the main guilds of seed dispersers worldwide In most cases, the seed dispersal of animal-dispersed plants is due to a small set of biotic agents In this paper, we compared for the first time the relative contribution of two local guilds of scatter-hoarding animals (rodents and dung beetles) with contrasting foraging behaviours and metabolic requirements  to the overall short-term recruitment of two oak species co-occurring in the forests of southern Spain. Despite the unquestioned role of jays for oak regeneration at large distances et al.We used a multi-stage demographic approach  and followed the framework described by Schupp All necessary permits were obtained for the field studies described herein thanks to J. Manuel Fornell Fern\u00e1ndez, Director of Los Alcornocales Natural Park.Quercus suber) forests mixed with winter-deciduous oaks (Q. canariensis), which are more abundant near streams 2.The study was conducted in La Sauceda forest , located in the mixed-oak forests of the Aljibe Mountains in southern Spain. The climate is subhumid Mediterranean, with mild and wet winters alternating with hot and dry summers. Annual mean temperature ranges from 14.6 to 18.4\u00b0C (mean of 17\u00b0C). Annual mean rainfall varies from 900 to 1800 mm (mean of 1265 mm). Vegetation is dominated by evergreen cork oak  is a flightless, medium-sized species of dung beetle (mean dry body weight of 130\u2013175 mg specimen), endemic to the southern Iberian Peninsula Cervus elaphus, roe deer Capreolus capreolus and free-ranging cattle are abundant in these forests and could act as potential acorn predators.The two dominant oak species show a strong inter-annual variability in seed production Q. suber and Q. canariensis in the study area from several trees (at least ten of each species) to encompass intra-specific variation. We selected healthy medium-sized acorns, discarding those infested by moth or beetle larvae through flotation Q. suber and 5.81\u00b11.52 g for Q. canariensis. Acorns of known weight were further distributed in 54 experimental units (a minimum distance of 25 m relative to one another) and equally separated into three types of microhabitat, which spanned a wide gradient of plant cover and light availability: (i) inside dense shrub and tree overstory; (ii) under oak trees without shrub understory; and (iii) open microsites. In general, these three types of microhabitats appear intermingled in the understory forming a mosaic of different microsites separated among them by similar distances. Open areas tend to suffer events of sporadic soil waterlogging during the wet period due to less interception of rain by the canopy and, in most cases, a higher proportion of clay Pistacia lentiscus, Phillyrea latifolia, Viburnum tinus, Erica arborea and Erica scoparia.We collected acorns of 2 mesh that allowed the entrance of only rodents and beetles. In mid-autumn (November of 2009 and 2010), coinciding with the onset of the acorn-crop, we intermixed each group of 30 acorns and distributed them inside each cage in five equidistant lines of six acorns (three per oak species). We periodically checked all the experimental acorns during a whole reproductive-cycle (from December to October-November of the next year). To avoid interference with beetle foraging during the process of acorn consumption, we visited each of the five lines of six acorns once at different dates. The first line of acorns was checked 10\u201314 days after starting the experiment, coinciding with the peak of maximum beetle activity in situ), noting when possible the identity of the dispersal agent (rodent or beetle). The acorns consumed in situ by rodents were easily identified by signs of gnawing, whereas those handled by beetles usually showed a circular (beetle-sized) hole in the coat. When we did not locate an experimental acorn in its original site, we dug 10\u201315 cm deep within a circle 50 cm in radius to verify evidence of handling by the dung beetle Thorectes lusitanicus. When a buried acorn was found intact, it was assigned to T. lusitanicus handling only when a beetle was also buried together with it.To explore spatiotemporal patterns of seed handling by local dispersers, we individually numbered with a permanent maker groups of 30 acorns (15 per oak species) and randomly placed them on the forest floor in each of the 54 above-mentioned experimental units (18 in each type of microhabitat). Acorns were protected from birds and large herbivores in each experimental unit by wire cages (80\u00d780\u00d725 cm) with 4-cm2 quadrat. These acorns were individually weighed and attached to a metal wire (10 cm long by 0.6 mm wide) by drilling a hole with a needle. We marked both the metal wires and the corners of the quadrats with numbered coloured flags for monitoring acorn fates. We used this method of seed tracking  to avoid the interference of cages with the process of seed dispersal. In mid-autumn (November 2009 and 2010), we randomly distributed 54 additional groups of ten acorns (five per oak species) along the same above-mentioned experimental units to determine acorn fate (seed status and microhabitat destination). In each experimental unit, we placed five acorns (without cupule) per species on the ground, four in the corners and one in the centre of a 0.5-min situ. We searched outwards for the removed acorns in the experimental units in expanding circles to a maximum distance of 30 m. We considered an acorn to be dispersed when it was moved horizontally and/or vertically  from its original point by rodents or beetles. To characterise spatial patterns of seed dispersal and caching, we recorded the distance from the experimental unit and the type of microhabitat where the acorn was dispersed . We also noted whether the relocated acorn remained potentially viable  or not . Those removed acorns that were not further relocated  could not be assigned to any of these two categories and were excluded from statistical analyses. Although we detected some evidence of seed re-dispersal over the sampling periods, we only considered the final fate of experimental acorns  for statistical analyses due to its higher relevance for recruitment.We periodically visited (at the same censuses specified above) all the experimental acorns and also classified them as intact, removed, or consumed We repeated the experiments of seed handling and seed deposition during two consecutive sampling years (2009/2010 and 2010/2011), making a total of 4320 experimental acorns (2160 per oak species) that were individually monitored to explore the spatiotemporal patterns of seed handling and dispersal.Microhabitat suitability for seedling recruitment  was previously assessed by conducting a parallel seed-sowing experiment at the same study site where seed handling and dispersal were evaluated. In December 2003, we randomly placed a total of 1200 acorns (600 per oak species) across 60 experimental units evenly distributed along the same previously mentioned three types of microhabitats. We sowed ten acorns per species in each experimental unit at 1\u20133 cm depth, simulating biotic seed dispersal and burial by European jays versus handled (including both consumed in situ and removed acorns). We assumed a logit link function between this binomial dependent variable and two independent variables (oak species and microhabitat of origin). This analysis was applied separately for the five censuses carried out in each of the two sampling years.We first studied seed handling patterns for rodents and dung beetles using Generalized Linear Models GLMs;  and clasQ. suber or Q. canariensis) and the three microhabitats of origin . Seed mass was also included in the analyses as a continuous co-variable. The microhabitat distribution of dispersed acorns  was also studied using GLMM. In this case, the dependent variable was treated as a multinomial with three categories , using the same explanatory factors described in the previous analyses. Seed dispersal distance (log-transformed) was fitted to a normal distribution and, therefore, the effects of the above-described factors were evaluated using Linear Mixed Models (LMM). In all these analyses, the experimental unit was included as a random factor.Second, we examined seed viability in the experiments on seed deposition and caching using Generalized Linear Mixed Models (GLMM). The dependent variable was fitted to a multinomial distribution with four categories depending on the combination of the dispersal agent (rodents or beetles) and the final seed status (preyed versus undamaged). The explanatory variables in this case were the two sampling years (2009/2010 or 2010/2011), the oak species . The remaining analyses were carried out using Statistica .Quercus grouping the two studied oak species.Seed dispersal effectiveness (SDE) was calculated for each of the two scatter-hoarding animals considered in this study (rodents and beetles) as the proportion of seeds dispersed by each dispersal agent  multiplied by the probability that a dispersed seed becomes established as a third-year seedling  (see a recent review Thorectes lusitanicus), with the highest rates of handled seeds during the first census . Of these handled acorns, animals removed more than 85% and consumed the rest Q. suber acorns, as indicated by the significant effect of this factor in the fitted model  only depended on the microhabitat of origin . Thus, tFinally, seed mass did not affect any of the aspects related to the process of seed dispersal that were considered in this study  and S3.We found significant differences among microhabitats for each of the stage-specific probabilities of recruitment considered in this study. Seed germination and seedling emergence were much lower in open sites than in the other two types of microhabitats  showed remarkable differences in seed dispersal effectiveness (SDE) due to large variations in the quantitative and qualitative components of SDE. Rodents dispersed a large percentage of acorns of the two oak species, especially under shrubs. However, they consumed more than 95% of these dispersed acorns  and only cached a very low proportion of them  without signs of embryo damage, resulting in a very low quality of dispersal . In contQuercus species Quercus species. This fact likely mitigated the inter-specific differences in seed removal promoted by variations in seed mass that were previously detected in the study area Thorectes lusitanicus) only contributed to a low proportion of acorn dispersal, but with potential repercussions for recruitment and population dynamics for the two study oak species.Scatter-hoarding animals (mainly rodents and dung beetles) handled a very large proportion of experimental acorns in the study area (over 98%). This emphasises the seed\u2013seedling transition as a crucial step for the regeneration process of the two oak species studied, as was previously documented for other Mediterranean Spatial patterns of seed dispersal and seedling recruitment were largely explained by the heterogeneity of the forest habitat structure. The microhabitat type where a seed was placed affected both the quantitative component and the two qualitative subcomponents (seed viability and seed deposition) of seed dispersal effectiveness (SDE).T. lusitanicus are more abundant in closed microhabitats compared with open sites The microhabitat of origin strongly determined the quantity of seeds handled and predated by scatter-hoarding animals, highlighting the relevance of habitat structure as mediator of plant-animal interactions in heterogeneous environments Quercus species , likely due to their lower metabolic requirements compared with rodents. Although beetles only displaced acorns a few centimetres around the original point, they buried nearly all the handled acorns into the soil at a depth (10 cm maximum) compatible with seedling establishment. This type of vertical dispersal could have significant benefits for oak recruitment because burial avoids seed desiccation, stimulates germination and reduces pilferage risk by other seed predators Rodents and beetles showed remarkable differences in their effectiveness as local acorn dispersers as a consequence of their distinct foraging behaviours and metabolic requirements. Quantitatively, rodents were much more important than beetles because they dispersed the vast majority of acorns. However, they were qualitatively less effective than beetles for two main reasons. First, they consumed most of the dispersed acorns (over 95%), a common feature of disperser assemblages where the main dispersal agents are also major seed consumers Therefore, the quality of dispersal was the component that better explained the SDE of scatter-hoarding animals in the Mediterranean oak forests studied and was inversely related to the quantitative component. These results are in accordance with a recent study on a Mediterranean fleshy-fruited species x-axis could result in large increases in the SDE provided by these high-quality dispersers  will be most likely less marked Table S1Results from the Generalized Linear Mixed Models testing the different factors  affecting the microhabitat destination of acorns dispersed by rodents. Seed mass was included in the analysis as a counting covariable. Experimental unit was considered as a random factor. The dependent variable was fitted to a multinomial distribution with three possible categories . Significant factors are highlighted with bold letters.(TIF)Click here for additional data file.Table S2Results from the Linear Mixed Models evaluating the factors  affecting the dispersal distance (log-transformed) of those experimental acorns dispersed by rodents. Seed mass was included in the analysis as a counting covariable. Experimental unit was considered as a random factor. Significant factors are highlighted with bold letters.(TIF)Click here for additional data file.Table S3Results from the Generalized Linear Models analysing the effect of different factors  on the final status of experimental acorns . Seed mass was included in the analysis as a counting covariable. Experimental unit was considered as a random factor. The dependent variable was fitted to a multinomial distribution with four possible categories depending on the combination of dispersal agent (rodents or beetles) and the final seed status (preyed upon versus successfully cached). Significant factors are highlighted with bold letters.(TIF)Click here for additional data file."}
+{"text": "G protein-coupled receptors (GPCRs) are a major family of membrane receptors in eukaryotic cells and play a crucial role in various biological processes. They represent a family of protein targets with significant therapeutic value, and accordingly more than 30% of prescription drugs are GPCR ligands .Extending previous attempts to map the pharmacological space solely based on ligand chemical similarity,,3 we in The results of the study aim to contribute to a better understanding of the overlap of GPCRs in chemical space, and to the cross-reactivity observed even among distant biological targets, as defined by their sequence similarities . Releva"}
+{"text": "Three-fold accelerated cine-MRI followed by Compressed Sensing reconstruction has been shown to provide accurate measurement of cardiac functional parameters in normal and chronically infarcted mouse hearts. This study demonstrates that infarct size can also be accurately quantified from the three-fold undersampled cine-data.Compressed Sensing (CS) is becoming more common as an alternative means to speed up the inherently time-consuming data acquisition process in Magnetic Resonance Imaging (MRI). More specifically, global cardiac function (cine) MRI combined with CS has been demonstrated to provide a three-fold reduction in scan time in normal mice and in a murine model of chronic myocardial infarction without compromising the accuracy of cardiac functional parameters . However, this study did not validate the measurement of infarct size, an important parameter that is also obtained from these data and does not require the administration of exogenous contrast agents. We therefore sought to investigate whether or not three-fold undersampled and CS-reconstructed cine-images allow for an accurate determination of infarct size.Mice with permanent ligation of the left coronary artery were scanned on a preclinical 9.4 T MR system with a standard cine-MRI protocol 8 weeks post surgery. The fully acquired cine-data sets were retrospectively undersampled by a factor of three and subjected to the CS reconstruction described in Wech et al (JMRI 2011). Using the method proposed by Takagawa et al (J Appl Physiol 2007), infarct size was subsequently measured in fully and undersampled data by an operator, who was blinded to animal ID and acquisition/reconstruction schemes.Figure Our retrospective analysis demonstrates that an undersampling factor of three does indeed allow for an accurate determination of infarct size. Work is in progress to validate this approach further using a wider range of infarct sizes.This work was funded by the British Heart Foundation and the Elite Network of Bavaria."}
+{"text": "Identification and classification of cancer types and subtypes is a major issue in current cancer research. Whole genome expression profiling of cancer tissues is often the basis for such subtype classifications of tumors and different signatures for individual cancer types have been described. However, the search for best performing discriminatory gene-expression signatures covering more than one cancer type remains a relevant topic in cancer research as such a signature would help understanding the common changes in signaling networks in these disease types. In this work, we explore the idea of a top down approach for sample stratification based on a module-based network of cancer relevant signaling pathways. For assembly of this network, we consider several of the most established cancer pathways. We evaluate our sample stratification approach using expression data of human breast and ovarian cancer signatures. We show that our approach performs equally well to previously reported methods besides providing the advantage to classify different cancer types. Furthermore, it allows to identify common changes in network module activity of those cancer samples. Deregulation of growth regulating signaling pathways contributes to an extensive alteration of cellular physiology and confers excessive proliferation properties to cancer cells  that tend to assign core components as well as components with more general modifying function to the same pathway. The nine major cancer-related signaling pathways that we assembled into a module-based network consist of 719 edges and 592 nodes covering 558 genes , which is, among other functions, a proteolytic activator of PDGFC . Clustering the network module activity of these samples results in separation of one main-cluster containing a mixed population of high and low grade, ER-negative or positive but predominantly HER2-negative samples from all other samples constituting the heterogeneous second main cluster on the right hand side Figure A. This ss Figure E. Similad Figure F. We cond Figure G. For thd Figure H. Taken In the next step of our analysis we wanted to test whether our network-based stratification approach might also be applicable to another cancer type and we therefore performed hierarchical clustering of ovarian cancer samples of a large patient cohort that is well annotated with regard to clinical parameters as provided by Tothill et al. . HierarcINSR-RTK, PDGFR-CoActivator, and PDGF-RTK modules as well as the AP1 and MAPK-Inhibitor modules were identified among the top differentially activated modules. Here, INSR-RTK, AP1, and MAPK-Inhibitor module activities appears to be higher, while PDGFR-RTK and PDGFR-CoActivator module activities as well as PDGFR- and INSR-ADAPTOR modules appear lower activated in LMP versus all other samples.Several network modules appear to show differential activity in the LMP- and co-clustering high grade samples versus all other samples Figure A. Again INSR-RTK, PDGFR-CoActivator, and PDGF-RTK modules as well as the AP1, MAPK-Inhibitor modules show differential activity between LMP and all others samples, a finding that is highly similar to the situation found in the Tothill et al.  and the linear Pearson correlation measures for sample clustering. The Pearson correlation measure lead to a significant sample clustering in case of ER-grade for breast cancer and tumor stage for ovarian cancer, respectively. Currently, we cannot exclude that alternative unsupervised clustering algorithms or correlation measures might lead to more significant findings for additional clinical parameters in the analyzed data sets and further work is needed to test this hypothesis. Furthermore, for assembly of our network, we considered several of the most established cancer pathways, while leaving out other signaling pathways even if they might be of relevance for a distinct group of cancer types or their general contribution to cancer development has yet to be established more firmly. Also, our network, in its current state, does not consider other cellular processes coupled to signaling events such as the DNA damage response or the core cell cycle regulating machinery which are known to be frequently deregulated in cancer  to downstream transcription factor modules including MYC, AP1, GLI, and NICD transcription factors. To compare the composition of ERBB and MAPK pathway modules described in our network to previous pathway annotations we consulted the KEGG , and MSigDB databases . We normalized the individual raw data using the quantile normalization method. We selected only those samples for analysis that are annotated with respect to all individual clinical markers. We then extracted the normalized expression values of all genes contributing to the network modules from those data for further analysis. We assume that a similar cellular phenotype and clinical representation of the analyzed samples might arise not only from deregulation of the exact same gene within a module at the same hierarchical step within the network but also from: (i) deregulation of normally co-expressed and functionally interchangeable proteins within the same network module and/or (ii) deregulation of the same pathway on different levels within the network hierarchy potentially involving CoActivators/CoInhibitor regulatory modules. After determining gene-expression values for all the genes of all modules a \u201cnetwork module activity\u201d was calculated for each module as the median value of all the gene-expression values of the given module. We then tested the feasibility of using these network module activity values to distinguish cancer subtypes within the two distinct breast and ovarian cancer patient cohorts in comparison to all genes in the network (network genes) and previously published discriminatory gene sets as described in detail in the main text.To determine differential module activation between selected sample subclusters we calculated the average of the network module activity for the subcluster of interest and all other samples individually and then computed the differences in average module activity between these sub-groups. To compare the differential activation of network module activity between two data sets we calculated the difference of average network module activity of clusters of interest in each of the data sets individually and then calculated the absolute values of the differences. We then determined the top 15% of differences for each data set individually and selected for further analysis those pathways modules that showed the same trend for higher or lower network module activity within both data sets.k-means clustering as an unsupervised classification method on all patient samples. We tested Spearman and Pearson correlation measures for k-means clustering and found that with regard to the ER-status, the Pearson correlation resulted in sample clustering with more significant p-values. Therefore, we decided to keep Pearson correlation rather than Spearman correlation for further analysis. In addition to the network module activity value, we used the normalized expression values of all network genes or those genes representing known discriminative gene signatures for hierarchical and k-means-based clustering. We determined the optimal number of expected clusters independently of the data labels given by the data sets and found that a cluster number of two is optimal for all four data sets (data not shown). For this cluster stability analysis we used the clValid tool (Brock et al., k-means clusterings we assigned each clustering the p-value from a chi-square test using the respective known annotations. It is therefore possible to compare the quality of the clustering results.We subjected the standardized median network module activity values for complete linkage hierarchical clustering of the patient samples using Pearson correlation as the distance measure. The heatmap-like representation in the hierarchical clustering is achieved through standardization of the data over all samples resulting in a mean gene vector of zero and a standard deviation of one; red and green labels were assigned to values with a higher and lower expression than the mean, respectively. Furthermore, we applied The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.http://www.frontiersin.org/Systems_Biology/10.3389/fphys.2013.00124/abstractThe Supplementary Material for this article can be found online at Click here for additional data file."}
+{"text": "Traumatic brain injury often leads to epileptic seizures. Among other factors, homeostatic synaptic plasticity (HSP) mediates posttraumatic epileptogenesis through unbalanced synaptic scaling, partially compensating for the trauma-incurred loss of neural excitability. HSP is mediated in part by tumor necrosis factor alpha (TNF\u03b1), which is released locally from reactive astrocytes early after trauma in response to chronic neuronal inactivity. During this early period, TNF\u03b1 is likely to be constrained to its glial sources; however, the contribution of glia-mediated spatially localized HSP to post-traumatic epileptogenesis remains poorly understood. We used computational model to investigate the reorganization of collective neural activity early after trauma. Trauma and synaptic scaling transformed asynchronous spiking into paroxysmal discharges. The rate of paroxysms could be reduced by functional segregation of synaptic input into astrocytic microdomains. Thus, we propose that trauma-triggered reactive gliosis could exert both beneficial and deleterious effects on neural activity. Homeostatic plasticity refers to the ability of neurons and neuronal circuitry to adjust their properties in order to maintain physiologically relevant electrical activity notwithstanding perturbations in synaptic input. Synaptic input is often chronically reduced immediately following brain trauma, and previous studies had suggested that homeostatic synaptic plasticity can aid in the dynamical transition of the traumatized network toward epileptic seizures, a condition known as \u201cpost-traumatic epilepsy\u201d. This form of homeostatic plasticity is mediated by glial cells which release regulatory molecules shortly after trauma. In this study we used computational modeling to investigate the mechanisms and the implications of glial mediated plasticity early after trauma. We show that astrocytes  exert both beneficial and deleterious effects on post-traumatic reorganization of neural activity. This suggests that, in the dysfunctional neuronal network, some aspects of glial-neuronal signaling could alleviate the dynamical transition to pathological activity. Post-traumatic epilepsy develops in some but not all head injury cases, depending on the severity of injury and the time elapsed since trauma. Often there is a latent period between the traumatic event and onset of paroxysmal activity Homeostatic synaptic plasticity (HSP) likely operates on several spatial and temporal scales Earlier studies showed that TNF\u03b1 causes a rapid, p55 receptor mediated insertion of neuronal AMPA receptors In our previous studies In the present study, we addressed this question by studying the early effects of TNF\u03b1 mediated HSP hours after trauma. Homeostatic synaptic plasticity restored the average network firing rate to its pre-traumatic level but transformed asynchronous spiking to paroxysmal bursts. Thus, we adopted the rate of paroxysmal burst generation (rather than the network-averaged firing rate) as a measure of network's propensity to exhibit the transition to seizures. Paroxysmal bursts of highly correlated population activity in our model resembled interictal epileptiform discharges (IEDs), which are often considered an important diagnostic feature of epileptic seizures The primary goal of the present study was to explore the impact of spatially localized homeostatic synaptic plasticity (HSP) on the emergence of paroxysmal activity in deafferented post-traumatic cortical network and to identify mechanisms that might operate to suppress this activity in the early post-traumatic window. We have shown previously that the spatial pattern of trauma itself can significantly affect the trauma threshold for paroxysmal burst generation Homeostatic regulation is likely to operate on a localized spatial scale during the early phase of response to trauma, reflecting the local response of glial cells to nearby synaptic activity. Such a change of scale could in principle affect our earlier conclusions regarding the role of trauma pattern in post-traumatic epileptogenesis local HSP model.Here, we assumed that the downregulation of excitatory synaptic conductances in a computational model of a hyperactive pyramidal (PY) neuron was determined by the time-averaged firing rate of the postsynaptic neuron, consistent with postsynaptic synaptic scaling To compare with our previous results focal trauma , and dirk e.g., ). In whaWithin the \u201cearly response\u201d scheme of the HSP based on the activity of presynaptic neurons , the rate of paroxysmal bursts was significantly higher for focal trauma  comparedThe difference between the two HSP models was also reflected in the dynamics of the network-averaged firing rate of the PY neurons, shown in The quantitative differences between the two HSP models, as reflected in the dynamics of the network-averaged firing rate of model pyramidal neurons, were discernible also within the scenario of diffuse trauma . HoweverThus, qualitatively, the strongest effect of HSP localization on the post-traumatic reorganization of electrical activity was observed for relatively small volumes of focal trauma. This is consistent with the results in We next explored the intriguing independence of the paroxysmal burst rate on trauma volume in a model with a local HSP rule. Several mechanisms in the new model of homeostatic plasticity could have been responsible for this observation. It could have been a consequence of normalizing the neuronal firing rates, which was implemented by downregulating postsynaptic component of HSP  between the burst rate and trauma volume was recovered  was clamped at \u223c5 Hz and did not depend on the spatial scale of presynaptic HSP component . Indeed,When the global scale presynaptic scheme was combined with exclusion of the postsynaptic downregulating HSP component, the averaged firing rate of intact PY neurons at the traumatized-intact boundary \u2014 defined as a set of PY neurons located within one synaptic footprint from the boundary deafferented neuron  \u2014 displayed strong dependence on the trauma volume parameter  , the probability of establishing synaptic contacts inversely depended on the number of potential pre-synaptic partners, as determined by the footprint size, in order to keep the average number of synapses to a given neuron the same, regardless of the footprint size. This allowed us to avoid conflating the effects of footprint size with an increase in synaptic connectivity. As he burst .Because burst nucleation in our model required the activity of a certain fraction of intact neurons to be sufficiently correlated (in order to be able to \u201cignite\u201d their deafferented postsynaptic partners) Another possibility is that a reduced rate of burst generation reflects higher heterogeneity in interconnectedness and synaptic weights for synapses formed among neurons on the boundary between intact and deafferented regions. Indeed, distributions of HSP scaling factors at PY-PY synapses in post-traumatic steady state  were chaAssuming that the heterogeneity of synaptic organization at the boundary between traumatized and intact regions is likely to be important in post-traumatic epileptogenesis, we sought to identify the physiological mechanisms that might mediate this effect. Experimental evidence suggests that homeostatic scaling of synaptic conductances might be at least in part mediated by the soluble tumor necrosis factor alpha (TNF\u03b1) that is believed to be released from astrocytes to compensate for low levels of glutamatergic synaptic activity Spatial localization of astrocytic signaling may translate into autonomous regulation of groups of synapses. Since we consider here the early stage of post-traumatic response  such autonomous regulation could increase the heterogeneity of synaptic conductances scaled by glia-mediated HSP. Thus, we hypothesized that functional segregation of synaptic inputs into astrocytic microdomains could help alleviate the rate of paroxysmal discharges in our model networks. To test this hypothesis, for each model PY neuron the set of all Several computational models were developed to describe interactions between astrocytes and synapses The averaged intra-burst firing rates of PY and IN model neurons were higher for stronger segregation of synaptic input into microdomains , as wereThe effect of microdomain partitioning in reducing the rate of paroxysmal bursts was further seen by visual inspection of network activity raster plots . This su larger  .Segregation of synaptic input into microdomains allows a more independent scaling of the inputs from deafferented and intact neurons and thus enhances the correspondence between the firing rate of a given presynaptic neuron and the resulting homeostatic scaling of its downstream synaptic conductance. As a result, in segregated inputs scenario, synaptic conductance from intact neurons is weaker than synaptic conductance from deafferented neurons . On the Results reported in the previous section suggest that functional segregation of homeostatic synaptic scaling by astrocytes has the potential to alleviate the rate of paroxysmal burst discharges in post-traumatic network albeit the reduction in burst rate is relatively small when only a small number of microdomains is considered. Remarkably however, astrocytes in injured cortex also undergo significant rapid morphological remodeling To model the role of astrocytic morphological reorganization in trauma induced epileptic like activity, we used the microdomains scheme  to model the presynaptic component of HSP and further assumed that synaptic input arriving to a specific model PY neuron was subdivided into two microdomains. One microdomain included the synapses exclusively from intact presynaptic neurons, and the other microdomain included synapses exclusively from deafferented presynaptic neurons . We furtIn the focal trauma scenario, the rate of paroxysmal bursts was significantly lower for the scenario of \u201csegregated inputs\u201d (compared to the model with one microdomain), and this difference was observed for a wide range of trauma volumes considered . For comFiring rates of PY neurons varied depending on the neuronal location in the network  and the As expected, the reduction in burst rate was paralleled by an increase in the average number of spikes fired per burst , as wellBased on the computational model of deafferentation-induced cortical trauma presented here, we predict that the functionally segregated organization of synaptic input to a neuron could help alleviate the rate of paroxysmal activity in early post-traumatic period (hours to days). The post-traumatic morphological reorganization of astrocytes could further mitigate paroxysmal activity The increased heterogeneity of synaptic organization, reflected in the higher variability of HSP scaling factors at the boundary between intact and traumatized subnetworks , may undIn our previous studies we showed that the pattern of trauma can itself determine the threshold for post-traumatic paroxysmal activity A simple explanation of these simulation results would be as follows: In focal trauma and spatially local HSP rule, neurons at the boundary between intact and deafferented regions get \u223c50% of their synaptic input from other intact neurons and another \u223c50% from deafferented neurons. Because this breakdown does not depend on the trauma volume, and because paroxysmal bursts are generated at the boundary between intact and deafferented regions We showed earlier It is widely recognized that astrocytes assume a critical role in different kinds of epilepsies In our own models of post-traumatic epileptogenesis The main clinically relevant prediction of our model is that a local homeostatic regulation of synaptic activity by astrocytes can lead to distinct network behavior . This prediction can be tested by targeting glial fibrillary acidic protein (GFAP), which is a common biological marker of trauma-induced morphological transformation of astrocytes and is dramatically increased during reactive gliosis. GFAP helps astrocytes to maintain mechanical strength and thus is instrumental in determining the cell shape and spatial distribution of finer astrocytic processes (microdomains) for synaptic regulation. Thus, our model would predict a higher incidence of seizures in trauma models of GFAP knockout animals. A higher incidence of seizures should occur following failure of astrocytic microdomains to reorganize after trauma. Consistent with this prediction, one experimental study reported that hippocampi of GFAP knockout mice exhibited higher sensitivity to kainate-induced seizures The pathological action of homeostatic synaptic plasticity studied here is only one of the several known mechanisms of epileptogenesis. A common, long-recognized, cause of epileptic seizures is impaired clearance of extra-cellular potassium ions Trauma-induced morphological reorganization of astrocytes, as well as their release of cytokines and gliotransmitters, is part of \u201creactive gliosis\u201d, a complex set of processes whereby astrocytes undergo various molecular and morphological changes Management of post-traumatic epilepsy and related convulsive disorders is often done with a variety of anti-epileptic drugs Synaptic activity can be increased or decreased by molecules released from astrocytes and vice versa. In particular, accumulating evidence indicates that endocannabinoids (eCB) might be involved in compensatory mechanisms to offset the effects of trauma Consistent with this emerging evidence, and based on our modeling results, we propose two opposing roles for reactive astrocytes in early post-traumatic epileptogenesis. Specifically, we propose that the release of TNF\u03b1 promotes the generation of paroxysmal bursts, and that a post-traumatic morphological reorganization of astrocytes acts to suppress bursting activity at the expense of less frequent, but more intense, paroxysmal bursts. In this conceptual model the reorganization of astrocytes might be an adaptive step aimed at reducing the pro-convulsive effects of TNF\u03b1. Interestingly, in the ferrous chloride model of epilepsy, seizure suppressing drugs led to a significant reduction in the extent of seizure-related morphological transformation of astrocytes The core computational model used in the present study was based on the modeling framework that we earlier developed to study the effect of different trauma patterns on the incidence of network bursts in post-traumatic cortex th neuron was inhibitory. Our goal was to understand the general responses of a cortical network to traumatic perturbation and therefore specific features pertaining to specific cortical layers were not included in the model.A cortical network was modeled as a 2D network on square lattice (80\u00d780 neurons) in which each neuron could establish synapses with its peers with probability The dynamics of neurons were modeled with the one compartmental Morris-Lecar model Synaptic transmission was modeled as a deterministic process, during which synaptic conductance rose instantaneously following the spike and relaxed, with the characteristics time The temporal dynamics of the NMDA conductance was modeled as a difference of fast  excitation to a fraction us block , right. us block , right.Recent experimental evidence indicates that TNF\u03b1 is a permissive, rather than instructive, mechanism that allows the synapses to express homeostatic synaptic plasticity This modeling assumption stems from the fact that TNF\u03b1 can only upregulate excitatory synaptic conductance; thus, down regulation of synaptic conductance likely depends on the firing rate of postsynaptic neuron The extent of per synapse homeostatic adjustment was computed as percentage of change in synaptic conductance relative to its value in the corresponding intact model. Taking PY-PY synapse as an example, In some simulations, we investigated the effect that functional segregation of synaptic input into microdomains might have on the post-traumatic reorganization of electrical activity in cortical network. For each model PY neuron, the entire set of Several models of astrocyte-synapse interaction In a separate set of simulations we modeled correlated segregated inputs, whereby the entire set of synapses to each model PY neuron was partitioned into two groups , which are often considered as an important diagnostic feature of epileptic seizures Paroxysmal bursting events were detected as previously described in The large size of our model network  made analysis of the entire network computationally intractable; thus, we sampled the activity of a subset of neurons , using this sample to estimate the rate of paroxysmal bursts in the network. In the case of a diffusely traumatized network , the sampling region was a square block  co-centered with the center of the 2D network because spatially random deafferentation resulted in activity roughly symmetric with respect to the center of the lattice. In the case of a focally traumatized network , the sampling region was composed of 5 parallel adjacent lines  because the activity generally propagated from intact regions into deafferented regions.In our earlier studies we showed that, in the deafferentation model of post-traumatic epileptic activity, the paroxysmal activity is generated by model pyramidal neurons with partially intact connectivity that are located at the boundary between intact and deafferented regions"}
+{"text": "We present here the patient undergoing laparoendoscopic single-site (LESS) retroperitoneal radical nephrectomy while receiving hemodialysis. An 81-year-old man under hemodialysis for 6 years was incidentally discovered to have two left renal masses with acquired cystic disease of the kidney (ACDK). A 4-cm flank incision for GelPort was made. Three trocars were inserted into the retroperitoneum through GelPort. After division of the renal vessels and ureter, the kidney was placed into the extraction bag and was retrieved through flank incision without any extra skin incision. There were no intraoperative and postoperative complications. This procedure offers an effective, minimally invasive therapeutic alternative to the standard laparoscopic technique in high-risk end-stage renal disease patients. The incidence of developing renal cell carcinoma (RCC) has been estimated to be more than 20 times higher in dialysis patients compared to the general population . In patiLaparoscopic radical nephrectomy (LRN) is the most common operation described as minimally invasive surgery with a high success rate and low incidence of complications in RCC patients . Shoma eAn 81-year-old man under hemodialysis for 6 years was incidentally discovered to have two left renal masses with ACDK Figures . FollowiPatients with end-stage renal disease have increased the risk of developing RCC with an estimated incidence of more than 20 times higher compared to the general population . ACDK woSince Clayman's initial description of LRN in 1991 , this prLESS nephrectomy offers some advantages over conventional LRN including decreased pain, quicker convalescence, and improved cosmesis . The maiIn our opinion, LESS retroperitoneal radical nephrectomy has surgical challenge. Although LESS transperitoneal approach seems to be easier in a wide working space and many localizing landmarks, the benefits of retroperitoneal approach are little possibility of intra-abdominal organ injury and ligation of renal vessels prior to dissection of the kidney, in particular, for patients with a history of previous abdominal surgery and adhesions. Indeed, the major disadvantage of retroperitoneal approach is a narrow working space that may render it unsuitable for nephrectomy of large kidneys, but the kidneys in patients with dialysis are typically small and atrophic and are thus well suited for removal by LESS. In addition, preservation of the peritoneum is important for patients with hemodialysis in view of possible conversion to peritoneal dialysis. The main disadvantage is the longer operative time, which decreased as we gained more experience. The safe and successful development of LESS has the potential to become a standard for the treatment of small renal tumors in atrophic kidneys secondary to chronic renal failure in the continuing evolution of minimally invasive surgery."}
+{"text": "While the induction of neutralizing antibodies remains a cornerstone of HIV vaccine development, the success of the Thai trail and evidence from non-human primate (NHP) studies has indicated that non-neutralizing antibodies may provide protection from infection. These non-neutralizing antibodies can act as molecular beacons to recruit innate immune cells to recognize infected CD4T cells or free virus as pathogenic. The ability of an antibody to efficiently recruit innate immune cells depends on complex interactions between the pathogenic target, the antibody, and an effector cell.Here we present a quantitative model of natural killer cell mediated antibody dependent cellular cytotoxicity (ADCC), and examine the impact of core fucosylation, FcgR3a expression/occupancy, serum IgG competition and mutations in the Fc binding domain.The results indicate that FcgR3a site occupancy can predict the percentage of cells killed on an ADCC dose response curve. In addition, it appears ADCC is initiated past a threshold of FgR3a site occupancy on the natural killer cell.This provides key insight into the mechanism of the innate immune response and provides powerful evidence that the effector function of antibodies should be a key consideration in the development of HIV vaccines."}
+{"text": "Now, 57\u00a0years after the first report on the wobbler mouse we summarize the progress made in understanding the disease mechanism and testing various therapeutic approaches and discuss the relevance of these advances for human ALS. The identification of the causative mutation linking the wobbler mutation to a vesicle transport factor and the research focussed on the cellular basis and the therapeutic treatment of the wobbler motor neuron degeneration has shed new light on the molecular pathology of the disease and might contribute to the understanding the complexity of ALS.This review article is focused on the research progress made utilizing the wobbler mouse as animal model for human motor neuron diseases, especially the amyotrophic lateral sclerosis (ALS). The wobbler mouse develops progressive degeneration of upper and lower motor neurons and shows striking similarities to ALS. The cellular effects of the  The wobbler mouse has successfully been used as animal model for human motor neuron diseases, especially ALS in the investigation of both, pathology and therapeutic intervention, as reviewed by  was first described in 1869 by Jean-Martin Charcot and is the most common motor neuron disease (MND) among adults  gene (ALS1 locus), coding for a major antioxidant protein. SOD1 is an enzyme involved in the detoxification of free superoxide radicals and more than 100 different ALS-associated mutations have been described in the SOD1 gene so far . Some ALS patients show increased levels of glutamate in the cerebrospinal fluid (CSF) . Alsin takes part in endosomal fusion and trafficking as well as neurite outgrowth , deep cerebellar nuclei, brain stem (N. vestibularis) and spinal inter neurons, while spinal motor neurons follow around day 15 p.n. . Four splice isoforms of the gene were detected, where the predominant encodes a protein of 977 amino acids  is a component of the Golgi-associated retrograde protein (GARP) complex Fig.\u00a0. The VpsVps54 gene indeed is affected by the wobbler mutation, a transgenic rescue experiment was conducted. A transgene covering the full genomic sequence of wild-type Vps54 including sequences 63\u00a0kb upstream and 18\u00a0kb downstream was used to generate transgenic mice, which were bred into the wobbler strain. This wild-type Vps54 transgene could compensate the wobbler phenotype 2841Ucd, hence termed as Vps54\u03b2-geo, has a \u03b2-geo  cassette inserted between exon 4 and 5, and the non-functional fusion protein product contains the first 152 amino acids of Vps54 fused with \u03b2-geo. The embryonic stem cells were used to generate chimeric mice and among their offspring heterozygous Vps54\u03b2-geo/+ mice were obtained, which generally had a normal phenotype , which causes a gastrulation defect and thus earlier embryonic lethality  and thus might be a more general hallmark of ALS. Transport defects might also explain the mitochondrial dysfunction seen in wobbler cells  or ion channels on the neuronal surface are affected, which would directly affect the electrical properties of the neurons. Recent electrophysiological recordings have demonstrated a hyperexcitability of layer V pyramidal neurons of the wobbler motor cortex already prior to the onset of disease symptoms, due to decreased GABAergic inhibition  and abnormally shaped round-headed sperm cells (globozoospermia) with decreased motility  has little success, because the injected sperm cells fail to activate the oocyte. Since wobbler sperm resembles the human sperm defects and also fail to activate oocytes after ICSI, the wobbler mouse was used as an animal model to test methods for assisted oocyte activation (AOA). After injection of wobbler spermatozoa in mouse oocytes, AOA leads to successful fertilization  and the brain-derived neurotrophic factor (BDNF) hugely delayed motor impairment by directly acting on the survival of the cervical spinal cord motor neurons, and that even the administration of CNTF or BDNF alone was able to slow down symptom progression, even though to at a lesser extent   was tested in wobbler mice by two different approaches. The rationale of these studies was to connect the well-known effect of ALCAR on mitochondrial activity  mRNA expression and mitigation of reactive gliosis  has proven to reproducibly increase, the life span of SOD1G93A mice in a dose-dependent manner  and Hoechst 33258 was used to track human amniotic fluid cells (hAFCs) after transplantation in the lateral ventricles of wobbler- and healthy mice. In vivo and ex vivo approaches have shown that hAFCs rapidly spread to the whole ventricular system, but did not migrate into the brain parenchyma independently from the health status of the individual mouse. The transplanted cells survive for a long time in the ventricles of both wobbler and healthy mice, but had no influence on the survival of mice and did not cause inflammation or pleocytosis (Bigini et al. The phenotype of the wobbler mouse closely resembles human ALS regarding motor neuron degeneration, muscle atrophy, reactive gliosis as well as the cellular effects like ubiquitinated protein aggregation, oxidative stress, cortical hyperexcitability and cellular transport defects. Thus, the wobbler mouse models the complexity of ALS pathology with a number of interdependent cellular defects, the precise contribution of which is currently unclear. The ALS-like wobbler phenotype is caused by a point mutation in Vps54, a component of the GARP vesicle-tethering complex. The point mutation leads to a decreased stability of the GARP complex and thereby to impairments in the retrograde vesicle transport from endosomes to the TGN. These impairments consequently lead to missorting of proteins, accumulation of abnormally enlarged APP-positive endosomal compartments as it is also seen in a subset of human ALS patients. Even though there is no gap-less chain of evidence, it appears plausible that the impairment of the retrograde vesicle traffic leads to disturbance of several cellular processes such axonal protein- and organelle transport and the final consequences could be protein aggregation and mitochondrial dysfunction. The therapeutic interventions tested on wobbler mice have also contributed to the understanding of the complex pathology of ALS. The beneficial effects seen for anti-inflammatory- and antioxidant agents indicate that neuroinflammation and oxidative stress also plays a critical role in the wobbler motor neuron degeneration, while the poor effect of antiglutamatergic compounds might argue that glutamate-associated excitotoxicity plays a minor role. Our recent finding of hyperexcitability due to a reduced number of GABAergic interneurons in wobbler CNS, even prior to the disease onset appears to be more difficult to explain. However, similar cortical hyperexcitability has been reported in human ALS cases, also already prior to the onset of disease symptoms and has been attributed to the degeneration of inhibitory circuits (Vucic et al."}
+{"text": "Birth cohort patterns in mortality are often used to infer long-lasting impacts of early life conditions. One of the most widely accepted examples of a birth cohort effect is that of tuberculosis mortality before the late 1940s. However the evidential basis for claims of cohort-specific declines in tuberculosis mortality is very slight. Reanalysis of original or enhanced versions of datasets used previously to support claims of cohort effects in tuberculosis mortality indicated that: 1. where the initial decline in tuberculosis mortality occurred within the period of observation, onset of decline occurred simultaneously in many age groups, in a pattern indicative of \u2018period\u2019 not cohort-dependent effects. 2. there was little evidence of \u2018proportional hazard\u2019-type cohort patterns in tuberculosis mortality for any female population studied. Therefore any mechanisms proposed to underlie this type of cohort pattern in male mortality must be sex-specific. 3. sex ratios of tuberculosis mortality at older ages peaked in cohorts born around 1900, and resembled cohort sex ratios of lung cancer mortality. This analysis indicates that age-specific patterns in the decline in tuberculosis mortality before 1950 are unlikely to reflect improvements in early life conditions. The patterns observed are generally more consistent with the influence of factors that reduced mortality simultaneously in most age groups. Additional influences, possibly smoking habits, impeded the decline of tuberculosis in older adult males, and produced the sex-specific shifts in age distributions of mortality that were previously interpreted as evidence of cohort-dependent mortality decline. Birth cohort effects in epidemiology can be defined as variations in risk according to year of birth and arising from influences unique to particular birth cohorts, or which affected some birth cohorts more than others (for example because the effect varied with age at exposure) Tuberculosis is a chronic infectious disease with a complex and poorly understood aetiology that provides rich possibilities for life course influences. Disease can arise from primary infection or re-infection, or from re-activation of earlier infections that have persisted in a latent form. The relative contributions of recent and prior infection events to adult disease remain contested, and may vary with transmission rates The Norwegian physician Andvord is usually credited as the first to have recognized cohort patterns in tuberculosis data in the 1920s The type of cohort pattern described by Andvord can be termed a \u2018proportional hazard\u2019 cohort pattern, because the proportional difference in mortality rate for a given cohort compared to other cohorts was the same at all ages. Andvord\u2019s findings were popularized by Frost, who discovered similar proportional hazard type cohort patterns in tuberculosis mortality in the United States and Massachusetts The evidence for proportional hazard-type cohort patterns in historical tuberculosis mortality rests principally on two types of evidence: (1) the regularity of age patterns of tuberculosis mortality by birth cohort, compared with age patterns in period  data; and (2) the progressive shift of the age distribution of tuberculosis mortality to older ages observed in some male populations. In both cases the evidence is circumstantial, and is limited to males, since age patterns were fairly stable by both cohort and period in female populations analysed, implying similar rates of decline at all adult ages In addition to graphical analyses, age-period-cohort models were used to detect period and cohort patterns in three studies recorded historical tuberculosis mortality using the same sources deployed by earlier authors.Close analysis of cohort patterns was precluded in previous studies by the use of occasional years or aggregated series of years of data, which prevented the construction of well-defined birth cohorts and the analysis of continuous series of rates. The present study is the first to use single calendar years of cause-specific age-specific mortality rates for analysis of cohort patterns in tuberculosis mortality in nineteenth century and early twentieth century populations. A sustained comparison of sex differences in tuberculosis mortality is also presented. A graphical approach was employed to provide simple tests for the presence of unambiguous proportional hazard-type cohort patterns. The very considerable problem of misdiagnosis of tuberculosis is ignored, because the purpose of the study was to test the existence of cohort patterns in Annual series of sex-specific age-specific tuberculosis mortality data were obtained as counts of deaths for England and Wales  Contour diagrams were constructed using Lexis 1.1 software Shifts in the age distribution of tuberculosis mortality could be quantified using median age at death. The existence of time trends in median age at death was tested statistically using non-parametric Mann-Kendall tests . The median age at death rose significantly in the male populations of England and Wales, Massachusetts, the USA and Australia, although the rate of rise varied from 0.06 years of age per calendar year  to 0.3 years per year . Although Mann-Kendall tests identified trends in the two of the four female populations tested  the estimated rate of change in median age was slight compared with male trends, and negative in the case of females in England and Wales . ConsistThe constancy of the age pattern of cohort rates compared with period rates constitutes the most compelling evidence for cohort effects in the literature, and has often been interpreted to mean that the age pattern of tuberculosis mortality was biologically determined The argument that susceptibility to tuberculosis was a property of birth cohorts and acquired early in life requires that decline should have occurred first in the youngest age groups, and then proceeded with progressive lags at successively older ages, as cohorts with lower risk progressed through life. In three populations the onset of tuberculosis mortality decline occurred within observation . In eachIn most populations studied the age pattern of period female tuberculosis mortality remained relatively stable until the 1940s, whereas the age distributions for males shifted progressively to the right , 2 and 3Tuberculosis was the \u2018white plague\u2019 of the nineteenth century but declined dramatically in the decades before 1946, before the intervention of effective drug therapy or vaccination. This decline remains poorly understood, and has been variously attributed to increased human resistance due to genetic adaptation see , reducedTuberculosis decline began in most of the populations studied before the development of vital registration systems, and this makes it difficult to establish the existence or otherwise of the kind of lagged age-dependent initiation of mortality decline that Andvord considered diagnostic of cohort patterns. However in three cases where the initial stages of tuberculosis mortality decline occurred within observation the decline appeared to be initiated simultaneously in multiple, if not all, age groups , Table 3The intuitively most compelling aspect of the cohort decline of tuberculosis hypothesis is the observed regularity of cohort age patterns of mortality , which sThe second line of evidence for cohort effects, the progressive shift to the right of the male age distribution of tuberculosis mortality observed in some populations, did not constitute strong evidence of a cohort effect in the absence of evidence for a late onset of decline in these age groups. The absence of this shift in females, despite similar childhood mortality rates, makes it very unlikely that this pattern reflects effects of early life conditions on tuberculosis susceptibility. Rather these patterns arose from the relative slowness, but not lateness, of mortality decline at older ages in males of some populations. The widening of sex differences in tuberculosis risk over the first half of the twentieth century resembles closely the rise in excess male risk in mortality more generally in this period, and in particular the excess risk associated with smoking. Smoking grew rapidly in popularity in the late nineteenth century and in populations such as England and Wales, Australia and the USA its health impact was greatest in male cohorts born in the early twentieth century. Smoking is a risk factor for tuberculosis Previous claims regarding cohort patterns in tuberculosis mortality decline suggested a key role for infection in early childhood in determining lifelong risk, through primary disease in childhood and reactivation in adulthood. In contrast, the evidence presented here has no direct implications for debates regarding the importance of re-infection versus reactivation, or changes in resistance versus exposure, because the patterns reported  could be produced by a wide variety of factors, that could have affected re-infection and reactivation simultaneously, and could have improved resistance and/or exposure at most ages. Nevertheless the finding that tuberculosis mortality decline was not cohort-dependent has important implications for research into the distal causes of tuberculosis mortality decline. In this respect the most important function of this paper is to describe more clearly which patterns need to be explained. In particular any mechanisms proposed to account for declines in tuberculosis mortality should account for the simultaneity of changes in age groups predicted to differ in their history of exposure and immune status.One of the most striking results of the present analysis is the diversity of patterns of historical tuberculosis decline. Tuberculosis mortality fell in most now-developed countries for decades before effective chemotherapy, but the timing of onset, and patterns of decline by age and sex, show marked differences between populations. This diversity presents a rich opportunity to test theories regarding the causes of tuberculosis mortality decline. Comparative modelling exercises should consider age-specific interactions that allow potential influences such as cohort-specific adult smoking habits and historical migration rates to be taken into account. Mason and Smith identified immigration as an important factor in the cohort patterns they discerned in US data, and speculated that mortality decline may have depended in part on a reduction in the proportion of foreign-born in the US population The patterns of decline of recorded tuberculosis mortality before the mid-twentieth century lend support mainly to theories of improvements that were relatively independent of age or prior exposure. The historical decline of tuberculosis therefore offers little evidence of benefits accruing to particular birth cohorts as a consequence of improvements in living conditions in childhood. The evidence for proportional hazard-type cohort patterns in tuberculosis mortality decline rests largely on the visual appeal of graphs showing cohort data for isolated years in males of selected populations with distinctive patterns of mortality. When more complete datasets for a range of populations and both sexes are considered then the evidence for this type of cohort effect appears very weak. Tuberculosis mortality decline is a poor example of a \u2018cohort effect\u2019 and should be dropped from textbooks in favour of other examples of cohort patterns such as lung cancer, where there is both better evidence and a biologically plausible explanation for the pattern. However the pattern of tuberculosis mortality decline is clearly complex and may involve both factors acting with immediate effect and factors with a prolonged or delayed effect on exposed groups that give rise to cohort-type patterns. Older males benefited less than other groups from the general decline in tuberculosis risk, and this probably reflects the contribution of a very well-established cohort pattern, that of smoking history and associated lung damage. Together with patterns of HIV infection, smoking habits may be a major influence on contemporary age distributions of tuberculosis morbidity, that has substantially modified the pattern of excess risk in early adulthood that predominated before 1950. This historical pattern of young adult risk remains poorly understood, but may provide important insights into age-specific aspects of tuberculosis immunity in contemporary populations.Figure S1Annual percentage improvement in age-specific respiratory tuberculosis mortality rates, England and Wales 1848\u20131980. Colours represent the range in percentage annual change indicated by the scale. Diagonal lines represent birth cohorts. Vertical patterns indicate that rates of mortality improvement were similar across age groups in a given year; diagonal patterns indicate that rates of change were more consistent within birth cohorts than by period.(TIF)Click here for additional data file.Figure S2Annual percentage improvement in age-specific respiratory tuberculosis mortality rates, Massachusetts 1880\u20131950. Five year age groups were used for ages 0\u20139, creating a discontinuity with single year of age data at older ages. Colours represent the range in percentage annual change indicated by the scale. Diagonal lines represent birth cohorts. Vertical patterns indicate that rates of mortality improvement were similar across age groups in a given year; diagonal patterns indicate that rates of change were more consistent within birth cohorts than by period.(TIF)Click here for additional data file.Figure S3Annual percentage improvement in age-specific respiratory tuberculosis mortality rates, US death registration states, 1900\u20131980 . Four-year age groups were used for ages 1\u20135, creating a discontinuity with single year of age data at older ages. Colours represent the range in percentage annual change indicated by the scale. Diagonal lines represent birth cohorts. Vertical patterns indicate that rates of mortality improvement were similar across age groups in a given year; diagonal patterns indicate that rates of change were more consistent within birth cohorts than by period.(TIF)Click here for additional data file.Figure S4Annual percentage improvement in age-specific respiratory tuberculosis mortality rates, Australia, 1907\u20131960 . Five year age groups were used for ages 0\u20134, creating a discontinuity with single year of age data at older ages. Colours represent the range in percentage annual change indicated by the scale. Diagonal lines represent birth cohorts. Vertical patterns indicate that rates of mortality improvement were similar across age groups in a given year; diagonal patterns indicate that rates of change were more consistent within birth cohorts than by period.(TIF)Click here for additional data file.Figure S5Quinquennial percentage improvement in age-specific respiratory tuberculosis mortality rates, Norway, 1871\u20131955. Colours represent the range in percentage annual change indicated by the scale. Diagonal lines represent birth cohorts. Vertical patterns indicate that rates of mortality improvement were similar across age groups in a given year; diagonal patterns indicate that rates of change were more consistent within birth cohorts than by period.(TIF)Click here for additional data file.Data S1Deaths registered from tuberculosis in Massachusetts 1880\u20131950, documentation file.(DOCX)Click here for additional data file.Data S2Deaths registered from tuberculosis in Massachusetts 1880\u20131950 by age group and sex. Comma-delimited text file as described in (TXT)Click here for additional data file."}
+{"text": "Ataxia-telangiectasia is a syndrome of chromosome instability (CIN) featured by progressive neurodegeneration affecting the cerebellumin in contrast to other brain areas. Previously, progressive neuronal death in AT was hypothesized to be driven by increased post-zygotic CIN in the cerebellum -3. To asCIN was evaluated by high-resolution single cell (immuno-) FISH techniques in 7 AT and 7 control samples. Bioinformatics analyses of neurodegeneration pathways were done as described earlier .Global aneuploidization affecting 20% of neurons and 80% of glial cells in the prefrontal cortex and cerebellum was observed. CIN in the cerebellum has affected specific chromosomes  similarly the immune system. Paradoxically, dramatic and age-dependent increase in the pathological level of CIN did not result in accelerated neurodegeneration in the brain of patients, but was associated with increased lifespan. Bioinformatics analyses have shown that the SMAD pathway is implicated in neurodegeneration in addition to genome integrity maintenance, somatic V(D)J recombination and DNA damage response in neural cells.To explain paradoxes we hypothesized that progressive neurodegeneration in the cerebellum can be associated with activation of adult neurogenesis in the diseased cerebellum and/or activation and proliferation of microglia - the phagocyte system of the brain. Neurodegeneration pathways in the AT brain are likely to be applicable to disorders exhibiting neurogeneration in specific brain areas."}
+{"text": "The turbulent history of clinical trials in viral gene therapy has taught us important lessons about vector design and safety issues. Much effort was spent on analyzing genotoxicity after somatic integration of therapeutic DNA into the host genome. Based on these findings major improvements in vector design including the development of viral hybrid vectors for somatic integration have been achieved. This review provides a state-of-the-art overview of available hybrid vectors utilizing viruses for high transduction efficiencies in concert with various integration machineries for random and targeted integration patterns. It discusses advantages but also limitations of each vector system. For instance therapies for these genetic diseases would benefit from such tools because they rely on stable production of the defective gene product and subsequent long-term phenotypic correction. Furthermore, these vectors would circumvent repeated vector administration necessary for life-long correction. Moreover, inconveniences for the patient due to repeated drug administration could be avoided.Recombinant viral vectors commonly used for stable gene transfer can be divided by their ability to either integrate foreign DNA into the host genome or by their capability to be maintained as episomal, non-integrative viral vector genomes. However, until now none of the commonly used vector systems for maintenance of therapeutic DNA in dividing cells is optimal: (i) the development of episomally maintained DNA molecules, although without any risk of insertional mutagenesis, remains a challenging task. Limiting features are insufficient retention and replication of the episomal viral  or non-viral (plasmid replicon) DNA molecule during cell division, inefficient delivery of replicating DNA, and the involvement of potential toxic viral coding products which in many cases are prerequisites for DNA retention within the nucleus. (ii) Integrating viral vectors were tested in preclinical and clinical settings and gathered information revealed that integration site preferences may cause genotoxicity by changing the expression profile and properties of the transduced target cell due to insertional mutagenesis. Therefore, one obvious approach to improve stable gene transfer for therapeutic applications is improving target site selection of integrating viral vectors by specifying their integration site preferences. To accomplish this goal, one solution could be the generation of viral hybrid vectors. Viral hybrid vectors are defined as vectors which combine the high transduction rates of viruses with genetic elements for stable maintenance of therapeutic DNA.This article focuses on recombinant viral hybrid vectors with the ability to integrate their therapeutic DNA into the host genome of eukaryotic cells. The principle of integrating viral hybrid vectors is schematically shown in The number of different hybrid vectors which are under development as gene-therapeutic integrating hybrid vectors is steadily increasing . and 2..Integrating hybrid vectors are an attractive choice if stable alterations need to be maintained in dividing cells. Each of these different integrating viral hybrid vectors is characterized by a set of different properties coming from the delivering vector itself and the integration machinery which is used, that make it suitable for some applications in gene therapy and unsuitable for others. Herein, we classified the hybrid vector by its delivery vehicle  and subdivided the respective group depending on the integration machinery employed ..2.Mastadenoviridae. Until now, 53 human adenoviral serotypes were identified which were divided into 6 subgroups (A\u2013F). They display a very diverse and broad cellular tropism after in vivo application making them very attractive for gene transfer studies.Adenoviruses are non-enveloped viruses with an icosahedral capsid. The length of the linear, double-stranded adenoviral DNA genome is 26 to 45 kilobase (kb) in size ).Last but not least, it is important to explore these hybrid vector systems in larger animals, because the toxicity profile may be species dependent. History has taught us that the performance of a viral vector strongly differs between mice, larger animals and humans. At present, it remains an unanswered question whether combining the best of two worlds in viral hybrid vectors will provide a valuable option for therapeutic and experimental gene transfer approaches. Looking into the future, we believe that customized viral hybrid vectors which address the single needs of a certain genetic or acquired disease will play an important role.7.For successful treatment of various genetic diseases genomic insertion of therapeutic DNA is required for achieving long-term therapeutic effects. In this review we provided a state-of-the-art overview of integrating hybrid vectors. We believe that these vector types have a high potential for a variety of clinical applications for which conventional vectors may not be suited, because hybrid vectors may be specifically designed for a certain disease and its individual needs. However, at the time the appropriate answer to the original question raised in the title of this review article  should be that for certain diseases and applications the current versions of integrating viral hybrid may be the better solution but for others they are not.in vivo applications in their current forms. We believe that gene therapy of monogenic diseases like hemophilia B would most likely not benefit from integrating viral hybrid vectors, because non-integrating HDAdV and AAV vectors were already shown to result in long-term expression of the human coagulation factor IX in mice and dogs [For instance, due to the complexity of currently available hybrid vector systems, they may not be suited for and dogs ,146. FurHowever, we think that integrating viral hybrid vectors will be beneficial for the treatment of some diseases originated from rapidly dividing cells like stem cells, keratinocytes or cancer cells. Within these large groups of target cells, hybrid vectors may find an important niche for transduction of those cell types for which MLV and HIV-based are not suited. Furthermore, conventionally used integrating vectors are limited by their packaging capacity. For example retroviral and lentiviral vectors have a limiting packaging capacity of 8\u201310 kb. Therefore, the significantly higher packaging capacity of HDAdV- and HSV-based hybrid vectors will be the only solution for diseases which require stable transduction of cells with large transgenes (> 10 kb)."}
+{"text": "Osteosarcoma, the most common malignant bone tumor of childhood, is a high-grade primary bone sarcoma that occurs mostly in adolescence. Standard treatment consists of surgery in combination with multi-agent chemotherapy regimens. The development and approval of imatinib for Philadelphia chromosome-positive acute lymphoblastic leukemia in children and the fully human monoclonal antibody, anti-GD2, as part of an immune therapy for high-risk neuroblastoma patients have established the precedent for use of targeted inhibitors along with standard chemotherapy backbones. However, few targeted agents tested have achieved traditional clinical endpoints for osteosarcoma. Many biological agents demonstrating anti-tumor responses in preclinical and early-phase clinical testing have failed to reach response thresholds to justify randomized trials with large numbers of patients. The development of targeted therapies for pediatric cancer remains a significant challenge. To aid in the prioritization of new agents for clinical testing, the Pediatric Preclinical Testing Program (PPTP) has developed reliable and robust preclinical pediatric cancer models to rapidly screen agents for activity in multiple childhood cancers and establish pharmacological parameters and effective drug concentrations for clinical trials. In this article, we examine a range of standard and novel agents that have been evaluated by the PPTP, and we discuss the preclinical and clinical development of these for the treatment of osteosarcoma. We further demonstrate that committed resources for hypothesis-driven drug discovery and development are needed to yield clinical successes in the search for new therapies for this pediatric disease. Osteosarcoma (OS), Ewing sarcoma, and rhabdomyosarcoma, are the most common sarcomas in children and adolescents. OS is the most frequent bone cancer occurring mostly in children and adolescents between 10 and 20\u2009years of age  gene . Response criteria for the solid tumor panels are categorized as high, intermediate, or low. Agents inducing objective responses  are considered highly active against the tumor xenograft. A PR is defined as \u226550% tumor volume regression, CR is immeasurable tumor volume and MCR is maintained CR at the end of the experimental study  is an initiative supported by the National Cancer Institute (NCI) made up of a consortium of institutions in the United States and Australia  and non-RTKs that lack transmembrane domains and are found in the cytosol, nucleus, and inner surface of the plasma membrane  pathway is involved in angiogenesis and is crucial for tumor growth and progression. Several agents for anti-angiogenic therapies have been developed that target either VEGF or its cell surface receptors to induce anti-proliferative, anti-angiogenic, and proapoptotic effects. Of the three VEGF receptor isoforms , VEGFR-3 is overexpressed in OS cell lines and correlates with poor survival    is a transmembrane RTK for which selective IGF-1R tyrosine kinase inhibitors have been developed. The binding of insulin-like growth factor-1 and 2 (IGF-1 and IGF-2) to the IGF-1R results in autophosphorylation and subsequent activation of multiple signaling pathways including the Ras/Raf/mitogen-activated protein kinase (MAPK) and PI3K/Akt pathways which both regulate cell growth and development  in two lines and tumor growth inhibition (PD2) in another two of six OS xenografts  in three of five OS xenografts  in xenografts (PD2 in four of six tumors)  which regulates cellular proliferation and mTOR complex-2 (mTORC2) which phosphorylates and activates Akt. Activation of the mTOR pathway is implicated in the development and progression of OS  though specific results in OS are not yet available. Ridaforolimus  is under clinical development for numerous adult cancers but is not FDA approved. A phase II trial of pazopanib and everolimus in patients with PI3K mutations and/or phosphatase and tensin homolog (PTEN) tumor suppressor loss is underway (NCT01430572).Response activity to rapamycin was high in one OS xenograft (CR) and intermediate in five tumors (PD2) . A current COG pediatric phase 1/II study investigating MLN8237 in children with relapsed/refractory solid tumors (NCT00739427) includes a cohort of patients with OS. Dose limiting toxicities of aurora kinase inhibition for neuroblastoma has been demonstrated  is activated by MAPK/ERK kinase (MEK). MEK1 and MEK2 are dual-specificity protein kinases that function in the MAPK signaling cascade to control cell growth and differentiation  binds and inactivates p53 to promote ubiquitination and proteasomal degradation for the p53 growth-suppressive function in unstressed cells. Selective inhibitors have been developed which disrupt binding of p53 and MDM2, to activate the p53 pathway in cancer cells leading to cell cycle arrest and apoptosis. Mutations in p53  is a recent candidate for molecular targeting in cancer. CENP-E is required for correct chromosomal alignment in mitosis. This protein integrates mitotic spindle mechanics with mitotic checkpoint signaling and is overexpressed in a variety of human tumors suggesting a role in tumor cell proliferation. Inhibition of CENP-E in cultured human tumor cells leads to cell cycle arrest in mitosis with bipolar mitotic spindles and misaligned chromosomes and eventual cell death. In the PPTP testing of GSK923295A, two OS xenografts met the criteria for high activity with a CR or MCR  regulate acetylation of histone lysine residues which triggers transcriptional activity promoting cell transformation and proliferation. Deregulation of histone acetylation is associated with disease pathogenesis by promoting alterations in chromatin structure and gene transcription. HDAC inhibitors induce growth arrest and cell death by epigenetic changes in many preclinical and clinical cancer models. Vorinostat is an oral HDAC inhibitor of class I and II HDACs that is in clinical trials for hematologic and solid tumors that metastasize and compromise bone structure. Vorinostat is approved for cutaneous T-cell lymphoma and has advanced to phase III clinical trials for multiple myeloma. It is also in many phase II trials including acute myeloid leukemia, B-cell lymphoma, glioblastoma, myelodysplastic syndromes, and breast cancer.Preclinical studies of vorinostat in the PPTP revealed intermediate activity (PD2) in two of four OS tumors  protein has triggered the development of Smac derivatives and mimetics for use in cancer treatment. During programed cell death, Smac, an endogenous proapoptotic protein of the mitochondria is released and promotes apoptosis via inhibition or proteasomal degradation of the inhibitor of apoptosis (IAP) family of proteins. Included in the IAP family is X-linked IAP protein (XIAP) and cellular-linked IAP protein-1 and -2 (cIAP1 and cIAP2) , angiogenesis (VEGF inhibitors), apoptosis, and DNA cytotoxicity in combination with standard chemotherapy has demonstrated promise in preclinical and early-phase clinical trials for OS. Significantly, these studies also highlight many of the major challenges faced by clinicians and researchers in the development of novel drugs and therapies for this disease. Many signal-transduction pathways activated by binding of growth factors to their receptors are proven \u201cdruggable\u201d targets. However, the responses are variable and the most dramatic benefits seen with biologic agents in ongoing studies are in the adjuvant setting. It is now apparent that successful treatment for this heterogeneous disease will involve combination strategies of new agents or personalized therapies. This integrated approach is anticipated to help realize the true potential of targeted therapies in OS.in vitro and in vivo panels of childhood cancers.The emergence of numerous anti-cancer agents and the small number of OS patients eligible for early-phase clinical trials present another challenge in the clinical testing of novel compounds. Predictive animal model systems for preclinical studies of safety assessment, drug metabolism, and pharmacokinetics may help to inform and prioritize available drugs for clinical development. The systematic preclinical evaluation of new agents in pediatric cancer has received tremendous support by the efforts of the NCI-supported PPTP  which targets the ganglioside GD2, that is expressed on the surface of OS and Ewing sarcoma cells and denosumab which binds and neutralizes the activity of the receptor activator of nuclear factor kappa B ligand (RANK-L) cannot be tested in mice. Canine models recapitulate the primary human disease and provide a useful platform for the development of more effective treatments for both humans and canines. Spontaneous OS is the most common primary bone tumor in dogs with many phenotypic and molecular similarities between dogs and humans (Mueller et al., in vivo models and advanced testing strategies for the evaluation of different targets and therapies. A wealth of preclinical and clinical data of agents with activity in OS now exists which provides support for novel, single-agent therapies currently in clinical development. Future work evaluating these agents in the preclinical models can focus on their utility in novel, multi-agent combinations, to justify future approaches that may result in improved prognosis of pediatric patients. The search for new treatment strategies is ongoing and there remains considerable hope that progressive and continuous research through these preclinical testing programs will fully exploit the potential of targeted therapies in OS to maximize the benefits in this pediatric disease.In summary, the goal to find new targeted therapies for patients with OS has seen the development of suitable The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Highly pathogenic avian influenza virus (HPAI) strain H5N1 has had direct and indirect economic impacts arising from direct mortality and control programmes in over 50 countries reporting poultry outbreaks. HPAI H5N1 is now reported as the most widespread and expensive zoonotic disease recorded and continues to pose a global health threat. The aim of this research was to assess the potential of utilising Hazard Analysis of Critical Control Points (HACCP) assessments in providing a framework for a rapid response to emerging infectious disease outbreaks. This novel approach applies a scientific process, widely used in food production systems, to assess risks related to a specific emerging health threat within a known zoonotic disease hotspot. We conducted a HACCP assessment for HPAI viruses within Vietnam\u2019s domestic poultry trade and relate our findings to the existing literature. Our HACCP assessment identified poultry flock isolation, transportation, slaughter, preparation and consumption as critical control points for Vietnam\u2019s domestic poultry trade. Introduction of the preventative measures highlighted through this HACCP evaluation would reduce the risks posed by HPAI viruses and pressure on the national economy. We conclude that this HACCP assessment provides compelling evidence for the future potential that HACCP analyses could play in initiating a rapid response to emerging infectious diseases. Since 1980, on average one new emerging infectious disease (EID) has appeared in humans every eight months ,3. ReseaSince late 2003, highly pathogenic avian influenza virus (HPAI) strain H5N1 has been responsible for the deaths of millions of animals, primarily poultry taxa but also a range of other avian and mammalian species ,10. HPAIApproximately 80% of the Vietnamese population live in rural areas and almost 80% of these rural households participate in small-scale (backyard) poultry production . The RedHPAI H5N1 spread rapidly from Southeast Asia into Europe and Africa. The main mechanism for HPAI spread is the movement of poultry and their products ,14 howevHere we take a technique, Hazard Analysis of Critical Control Points (HACCP) analysis  and applThe HACCP assessment of Vietnam\u2019s domestic poultry trade followed the first three HACCP principles . A CCP is a point in poultry trade which provides an opportunity to control, prevent or eliminate the risks for HPAI transmission. Each of these first two principles required cross-referencing outputs with existing literature on HPAI virus epidemiology within Vietnam\u2019s poultry trade. We also referred to recent reviews of the scientific literature to identify any risks which the HACCP analysis failed to identify.Critical limits were then set for each of the CCPs identified. These critical limits are thresholds used as preventative measures to control the hazards within the system. Setting the critical limits required prior research of both Vietnam\u2019s domestic poultry trade and consumer behaviour.The stages of the poultry trade chain identified as presenting increased opportunities for HPAI transmission in the HACCP were grouped into four categories, namely: 1. contact within poultry flocks, 2. poultry transportation and sale, 3. poultry purchase and slaughter, and 4. poultry preparation and consumption.1Contact within poultry flocks occurs at multiple stages within the trade. These potential viral \u2018mixing pots\u2019 exist when i) established flocks mix with newly recruited birds purchased by the owner; ii) flocks mix at a market; iii) birds mix at communal HPAI H5N1 vaccinations centres and iv) fighting cock contests bring birds together in one contact arena. Each of these scenarios present high-risk opportunities for poultry to poultry transmission whereas scenarios i), iii) and iv) also present high-risk opportunities for poultry-to-human transmission.2Poultry may experience multiple transportation events across a large spatial scale throughout their lifetime. At all stages of the poultry trade, the transportation and sale of eggs, chicks, adult birds or poultry products, creates opportunities for human-mediated transmission of HPAI viruses. Due to the contact opportunities and volume of birds moved across various spatial scales, the transportation and sale of poultry is considered a high-risk activity for HPAI transmission from both poultry-to-poultry as well as poultry-to-humans.3The purchase and slaughtering of poultry from wet markets primarily occurs in one of two ways; i) purchase from wet markets can involve the consumer buying a live bird which they then take home to slaughter themselves or ii) they can request the poultry seller to slaughter and prepare a chosen bird which the consumer then takes home as joints of raw meat. Both of these modes of purchase are closely linked to the fourth risk category, described further below. Purchase of poultry via mode i) is an HPAI transmission risk to poultry if the consumer has other household poultry and a risk to the consumer themselves when they come to slaughter and prepare the bird at home. The purchase of poultry via mode ii) is an HPAI transmission risk for the poultry seller as they slaughter and prepare the bird at the market and the handling of raw meat is a transmission risk for the consumer.4The preparation of poultry for consumption introduces poultry\u2013to-human HPAI transmission risks in the later stages of the trade chain, primarily through the slaughtering process. In the absence of appropriate hygiene practices, poultry slaughtering and carcass preparation put the slaughterer at substantial risk of exposure to HPAI viruses due to the contact with raw poultry and blood.Poultry consumption  is a high-risk activity for HPAI transmission from poultry-to-humans if the infection is maintained in the raw or under-cooked tissue. Contrastingly, the consumption of well-cooked poultry and poultry products pose low-risks for viral transmission.CCPs were defined for each of the four risk stages identified during the HACCP assessment of Vietnam\u2019s poultry trade. Each CCP is a point in the poultry trade which provides HPAI viruses with an opportunity for transmission between host animals. For each CCP, critical limits have been proposed to limit virus transmission risks from poultry-to-poultry and from poultry-to-humans .The CCPs for limiting transmission through contact within poultry flocks involve the same approach as those for the transportation and sale of poultry; a combination of flock isolation, whereby established poultry flocks are prevented from mixing with other birds; quarantining newly purchased birds, where the newly purchased birds are held in isolation from other birds for a minimum of seven days; and household vaccination programmes .CCPs for the transportation and sale of the poultry begin once they depart from their household of origin. The suggested critical limit for this transmission risk is a total ban on inter-flock mixing of birds throughout poultry transportation and sale.Preparing poultry for human consumption is the first stage of the trade chain when non-farmers are introduced to a high-risk opportunity to contract HPAI viruses. Two key CCPs concern poultry slaughtering and carcass preparation; this refers to the slaughter of poultry both at home and in the wet markets.The associated risks can be reduced through the correct use of protective equipment such as face masks, gloves and sterile utensils to prevent contact with raw and bloody poultry. Further intervention should include the provision of additional education to the population through a range of health promotion mechanisms  as to how to handle potentially infectious meat to hygiene standards imposed as a feature of standard food preparation HACCPs in the retail food industry.Poultry consumption is not a substantial risk for poultry-to-human HPAI transmission provided poultry products are well-cooked, thus the cooking stage is the CCP for poultry consumption with a critical limit of cooking temperature and duration. Consuming raw blood pudding poses some of the highest risks for poultry-to-human transmission of HPAI viruses and controlling this risk is only possible through thorough cooking practices or abstinence.Our HACCP assessment has identified poultry flock isolation as well as the transportation, slaughter, preparation and consumption of poultry as critical control points for HPAI H5N1 transmission in Vietnam\u2019s domestic poultry trade. Critical limits at each of these control points are recommended to control the risks of HPAI transmission from poultry-to-poultry and from poultry-to-humans.The scope of Vietnam\u2019s poultry trade is far-reaching both geographically and across social classes. Rural Vietnamese households typically keep a few backyard poultry and are likely to consume these birds or birds from neighbouring flocks. In urban Vietnamese households, it is less common for poultry to be kept within the household and birds are typically purchased at local markets . TypicalPoultry provides an important source of income as well as a low-cost protein source for many rural Vietnamese households . The HPAIf the management of infectious zoonotic diseases is to be successfully implemented, controlling the transmission chain from infected to uninfected animals is essential . PathogeIncubation periods differ between chickens and ducks with reports of deaths occurring within one to five days for chickens and up to seven days for ducks . As a rePoultry and its products are often transported in considerable numbers across large spatial scales. During transportation, HPAI material may be shed by infected individuals and lead to other poultry coming into contact with viral material. Consultation of published literature has shown that exposure to an environment contaminated with viral material  can also pose a risk for viral transmission \u201323. The The H5N1 virus can survive in poultry carcasses kept at room temperature for several days or longer at cooler temperatures . Human iWithin Vietnamese households it is typical to consume the meat, eggs and organs of both chickens and ducks. The consumption of chicken and chicken products varies from that of ducks with regard to the parts consumed . UncookeExposure to hazards iii) and iv) will depend on the vaccination system employed and the suitability of the birds for cock-fighting. In some communes the Department of Animal Health (DAH) organises door-to-door vaccinations by local veterinarians. In more remote villages, the DAH organises communal vaccination days where households from several villages bring their poultry to one centralised location for vaccination. This latter vaccination system encourages the mixing of poultry flocks from different localities, promoting contact within poultry flocks, and given the time-lag before the HPAI H5N1 vaccine becomes effective, presents a high risk for the transmission of HPAI viruses. Door-to-door vaccinations ensure a lower risk of inter-flock viral transmission and are recommended. Should this approach prove impractical, the isolation of flocks whilst at the communal vaccination centre would limit the chances of inter-flock viral transmission. It is also noted that vaccination programmes are currently lacking any system of coordinated monitoring  which woFighting cock contests may play a role in the transmission of HPAI viruses to humans ,28. FighAlthough not highlighted by this HACCP analysis, the review of existing literature also identified the care of poultry as a risk factor for HPAI H5N1 viral transmission from poultry to humans .Introducing the preventative measures highlighted by this HACCP evaluation should reduce the occurrence of HPAI outbreaks. The parallel findings of our rapid HACCP assessment with the existing literature cited, provides strong evidence for the potential that HACCP analyses may have as a framework for helping local personnel to formulate a rapid response to an emerging health threat. Indeed, because the involvement of local personnel is a critical aspect of the HACCP process, we would argue that the process not only identifies key critical control points and suggests control strategies but provides those local personnel with the knowledge, understanding and ownership to more reliably implement any identified control measures.The HACCP framework enables the identification of risks within a system and the design of control methods. It does not contain the scope for monitoring or ensuring compliance of the control points identified; such control should be applied via other means. Given that EIDs are appearing with increasing frequency, often in countries where they place additional strain on already over-burdened public health and healthcare systems, being able to rapidly identify and design strategies for control has valuable application in responding to emerging health threats such as the Middle East Respiratory Syndrome (MERS) virus which first appeared in Saudi Arabia in late 2012  or the r"}
+{"text": "Candida albicans causes mucosal candidiasis in the rapidly expanding number of immunocompromised patients. Mucosal candidiasis includes oropharyngeal, esophageal, gastrointestinal, and vaginal infections. Vulvovaginal candidiasis (VVC) and antimycotic-refractory recurrent VVC is a frequent problem in healthy childbearing women. Both these mucosal infections can affect the quality of life and finding new therapeutical and preventive approaches is a challenge. A vaccine against candidal infections would be a new important tool to prevent and/or cure mucosal candidiasis and would be of benefit to many patients. Several Candida antigens have been proposed as vaccine candidates including cell wall components and virulence factors. Here we discuss the recent progress and problems associated with vaccination against mucosal candidiasis.The commensal fungus  Candida albicans is a dimorphic fungus that colonizes different areas of the body from the gastrointestinal tract to oral and vaginal mucosa. It is usually a commensal microorganism but in immunocompromised or otherwise debilitated hosts it can cause disseminated and mucosal candidiasis. Systemic candidiasis is the fourth most common hospital-acquired infection in the USA  is a common distressing infection that affects up to 75% of childbearing women worldwide at least once in their life. Up to 7% of these women suffer from frustrating recurrent infection (RVVC) defined as at least three or four episodes of acute VVC in 1\u2009year Fidel, . Two forOverall, the growing impact of fungal diseases has resulted in renewed interest in new approaches for improving their control. Among these new approaches, the generation of fungal vaccines is recognized as a priority. A mucosal vaccine would improve the quality of life of a long list of target populations of women suffering from RVVC. The aim of this review is to discuss the recent progress and problems associated with the development of a protective mucosal vaccine against candidiasis.C. albicans as a commensal on the mucosal surface does not go unnoticed or tolerated by the host \u2013 humoral and cellular factors of the innate and acquired immune response play an important role in limiting the growth of the fungus and neutralizing the activity of the virulence factors  lining the mucosa play an essential role in the defense against C. albicans recognition by TLR4 on monocytes/macrophages results in release of proinflammatory cytokines such as IL-1 and TNF-\u03b1  with fungal cells and re-administering the loaded DCs to the host 3-Fba glycopeptide to tetanus toxoid to render this vaccine entirely compatible with human use, a high degree of antibody-mediated protection was observed . Antibodies have also been generated but their titers did not correlate with protection. The rAls3p-N vaccine is a promising new vaccine candidate for further exploration to prevent systemic and mucosal candidal infections , a very well known enzyme belonging to a family of virulence factors of in vitro the anti-Candida activity as an Id vaccine to elicit Abs. An effective protection that correlated with a significant decrease in vaginal Candida CFU was obtained in Id-vaccinated animals compared with controls. The protection was associated with rising vaginal titers of anti-idiotypic Abs (IdAb), prevalently of the IgA isotype, that were able to passively transfer the protective state to non-immunized animals  was used, neutralizing C. albicans heat shock protein 90\u2009kDa (hsp90-CA). Intradermal priming with recombinant hsp90-CA protein, followed by an intranasal or intradermal booster with recombinant hsp90-CA protein, induced significant increases of specific IgG and IgA antibodies in both serum and vaginal fluid. The specific IgG isotype increased after vaginal Candida infection, suggesting that Candida has the ability to induce a local hsp90-specific antibody (IgG) response during VVC  have been generated by classical \u201cempiric\u201d approaches, including clinical impressions. Now, a large variety of covalently attached proteins has been found in fungal walls and these proteins can rapidly change their expression in response to different environmental conditions. The knowledge of the specific proteome of the fungus in the host is fundamental for the identification of new vaccine candidates (Klis et al., Despite several promising approaches, the achievement of a vaccine against mucosal infections in humans still faces a number of problems and challenges. The major challenge remains the difficulties in translating results from rodents to humans, as rodent models can represent at best only part of the variegate patterns of vaginal n Sobel, . In factn Sobel, . In addiKnowledge of the host mechanisms involved in candidiasis protection, and understanding of the fungal virulence factors, will allow the development of a novel topical mucosal vaccine.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Expectations held by patients and health professionals may affect treatment choices and participation  in therapeutic interventions in contemporary patient-centered healthcare environments. If patients in rehabilitation settings overestimate their discharge health-related quality of life, they may become despondent as their progress falls short of their expectations. On the other hand, underestimating their discharge health-related quality of life may lead to a lack of motivation to participate in therapies if they do not perceive likely benefit. There is a scarcity of empirical evidence evaluating whether patients\u2019 expectations of future health states are accurate. The purpose of this study is to evaluate the accuracy with which older patients admitted for subacute in-hospital rehabilitation can anticipate their discharge health-related quality of life.A prospective longitudinal cohort investigation of agreement between patients\u2019 anticipated discharge health-related quality of life (as reported on the EQ-5D instrument at admission to a rehabilitation unit) and their actual self-reported health-related quality of life at the time of discharge from this unit was undertaken. The mini-mental state examination was used as an indicator of patients\u2019 cognitive ability.Overall, 232(85%) patients had all assessment data completed and were included in analysis. Kappa scores ranged from 0.42-0.68 across the five EQ-5D domains and two patient cognition groups. The percentage of exact correct matches within each domain ranged from 69% to 85% across domains and cognition groups. Overall 40% of participants in each cognition group correctly anticipated all of their self-reported discharge EQ-5D domain responses.Patients admitted for subacute in-hospital rehabilitation were able to anticipate their discharge health-related quality of life on the EQ-5D instrument with a moderate level of accuracy. This finding adds to the foundational empirical work supporting joint treatment decision making and patient-centered models of care during rehabilitation following acute illness or injury. Accurate patient expectations of the impact of treatment (or disease progression) on future health-related related quality of life is likely to allow patients and health professionals to successfully target interventions to priority areas where meaningful gains can be achieved. Expectations held by patients and health professionals may affect treatment choices and participation  in therapeutic interventions in contemporary patient-centered healthcare environments,2. AccurSubacute in-hospital rehabilitation amongst older adults following acute illness or injury is one clinical setting where issues pertaining to health-related quality of life are paramount,8. The nAccurate expectations of the impact of treatment (or disease progression) on future health-related related quality of life is desirable in rehabilitation settings to allow patients and health professionals to target interventions to priority areas where meaningful gains can be achieved. SimilarThis investigation aimed to evaluate the accuracy with which patients admitted for subacute inpatient rehabilitation can anticipate their discharge health-related quality of life as reported on the Euroqol-5D (EQ-5D) instrument.A prospective longitudinal cohort investigation of agreement between patients\u2019 anticipated discharge health-related quality of life and their actual discharge health-related quality of life was undertaken.Two hundred and seventy-two patients (consecutive admissions) from a subacute geriatric assessment and rehabilitation unit at a tertiary hospital participated in this investigation. Patients admitted to this unit for multi-disciplinary rehabilitation had overcome the acute phase of their injury or illness causing hospitalisation, but required further multidisciplinary rehabilitation to maximize their recovery and health-related quality of life on discharge and thereafter. No specific sample size calculation was carried out prior to commencement due to the novel nature of this observational study (sample size of convenience).To evaluate health-related quality of life the EQ-5D instrumeThe Dolan tariff system was applied to these responses to produce a multi-attribute utility score (utility) where death and perfect health are represented by 0 and 1 respectively . The fulThe EQ-5D has a range of empirical evidence supporting its internal, external, concurrent and construct validity across a wide variety of populations and patient groups; including older adults,26,28-33Due to the prevalence of cognitive impairment amongst clinical populations of this nature, agreement between anticipated and actual discharge reports of health-related quality of life was examined for the sample as a whole; as well as by level of cognitive ability indicated by the Mini-Mental State Examination (MMSE) score. The MiniPatients from this clinical group may (or may not) have cognitive impairment. For the purpose of analysis, each patient from the sample was classified into a better cognition group (admission MMSE greater than 23) or a poorer cognition group . This cuPatients completed a standard battery of clinical assessments conducted by their physical therapists on the first weekday of their admission. In this way, all admission assessments were undertaken within 72 hours of admission to the unit. This assessment included physical performance tests as well as an interview administered EQ-5D for patients to report their health-related quality of life. Patients were then given a blank copy of the EQ-5D and the therapist read the words of the EQ-5D aloud (directly from the EQ-5D text). Patients then marked their response on EQ-5D instrument. The EQ-5D was administered as part of routine assessments for all patients. Physical therapists in this unit received in-service training on how to administer the EQ-5D without influencing patients\u2019 responses by reading directly from the text without leading patients with their tone or non-verbal cues. In addition to this standard training, staff conducting assessments included in this research received one to one instruction from a member of the investigative team to ensure that the EQ-5D was administered without bias at each assessment.Immediately following the completion of the standard admission EQ-5D, patients were then given a blank EQ-5D questionnaire and a brief scripted statement was read by the clinician conducting the assessment. This scripted statement was to prepare the patients to report their anticipated discharge health-related quality of life (on the EQ-5D instrument). This included a rudimentary outline of what usually occurs during a rehabilitation admission in this hospital unit to provide patients with a consistent frame reference irrespective of which therapist was conducting the assessment. It is also noteworthy that the study did not aim to investigate patients\u2019 ability to predict their length of stay, but rather their discharge health-related quality of life. Therefore the investigators considered the scripted statement necessary for ensuring that all patients had a foundational understanding of what rehabilitation may involve (such as participating in therapies) and knowing approximately how far ahead they were reporting their anticipated quality of life (approximately 42 days in this case). The clinicians were instructed to read this statement at a slow, steady pace for all participants to provide patients with a standard description of what care to expect.\u201cYou will receive regular therapies and other treatments during your stay to help you get ready for discharge. The average length of stay in this unit is six weeks. Some patients are ready and leave earlier than six weeks. Some patients need to stay longer than six weeks. When you are ready to be discharged from this unit, which of these statements do you think will best describe your health state at that time?\u201d\"\"When completing their anticipated discharge EQ-5D, the assessing clinician was permitted to answer patient questions regarding the nature of the treatment they would receive during their inpatient stay. Clinicians were also permitted to read the question again for the patient (directly from the script and the EQ-5D questions) without leading or assisting the patient to select a particular response. For this reason both the admission and anticipated EQ-5D was considered to have been interview administered rather than self administered and clinical staff were considered to be unblinded to patient assessments.The MMSE was completed by hospital occupational therapists or medical staff for each patient admitted to the unit as part of their routine care. Patients\u2019 admission MMSE assessments were completed within 24 hours of EQ-5D completion. This may have occurred before or after the EQ-5D assessment depending on therapy assessment scheduling within the clinical unit. The MMSE results along with other patient demographic variables were collated from the medical history. Immediately prior to discharge, patients again completed the standardised battery of assessments. This assessment also included an EQ-5D evaluation of their current health state at the time of discharge from the rehabilitation unit.This research investigation was approved by the institutional human ethical review board who waived the need for individual consent (negligible risk and utilising routine assessments); gatekeeper consent for staff participation was attained from the clinical managers in the unit.Conventional descriptive statistics were used to describe the sample. Tests of hypothesis were used to examine difference between the lower and higher cognition groups in age (unpaired t-test) and length of stay (Mann\u2013Whitney U). For the individual EQ-5D domain scores, levels of agreement between the anticipated discharge and actual discharge EQ-5D responses were calculated using weighted kappa with disagreements of only one level ascribed a 0.5 weighting; bias corrected 95% confidence intervals for kappa scores were calculated using bootstrap resampling ,48. The For the summary EQ-5D scores (utility and EQ-VAS), Limits of Agreement (LOA) and intrParticipant flow through for the duration of the study is outlined in FigureFor agreement between anticipated and actual EQ-5D domain scores, kappa statistics and exact matches are reported in TableIn regard to agreement between anticipated and actual discharge summary scores for the EQ-5D (utility and EQ-VAS), intraclass correlation coefficients and limits of agreement are presented in TableFindings from this investigation indicate that patients admitted for inpatient hospital rehabilitation were able to predict their discharge health-related quality of life on the EQ-5D instrument with a moderate level of accuracy in each of the five broad domains. Patients\u2019 health-related quality of life improved in all domains over the duration of their stay. Patients did not systematically overestimate or underestimate their discharge utility score derived from the individual domain responses. However, there was greater variability between anticipated and actual discharge summary scores for the poorer cognition group than the better cognition group. The small observed mean difference in EQ-VAS  is unlikely to represent a clinically meaningful difference-52.There was no clear pattern of difference in predicting individual item responses across the individual health-related quality of life domains between the poorer and better cognition groups. The domain kappa scores and exact matches were comparable across cognition groupings and across domains. This may be attributable in part to the limited response options at discharge; where most respondents utilised only the two higher response options. However, the wider LOA among the lower cognition group for the EQ-5D utility index and EQ-VAS indicated that patients in the better cognition group had a smaller error margin than their peers in the lower cognition category.Comparisons to previous research are difficult given the scarcity of empirical evidence on this topic. This research provides the first empirical evidence indicating that patients undergoing in-hospital rehabilitation have, at worst, moderately accurate expectations of their discharge health-related quality of life. This adds to the weight of foundational evidence supporting joint goal setting and patient centered models of care in rehabilitation contexts for older adults-56. PatiAn important consideration when interpreting implications from this study\u2019s findings is that reports of patients\u2019 anticipated health-related quality of life may act as a self-fulfilling prophecy. Those patients who felt helpless and anticipated poor levels of physical functioning, pain and depression may have been less likely to participate in therapies and other treatments. SimilarIncluding a comparison between health-professional expectations and patient expectations of discharge health-related quality of life may be a worthwhile undertaking as a future research direction. The notion of patient expectations acting as a self-fulfilling prophecy would be supported if patients who anticipated a poorer outcome then their therapists, did actually achieve a poorer outcome in comparison to those where the patient and health professionals were in agreement. However, investigation of the influence of health-professional expectations on their patients\u2019 expectation for discharge health-related quality of life would also be worthy of consideration. It is plausible that health professional expectations may act as a self fulfilling prophecy if patients considered to have greater potential to improve were provided with additional therapies, treatments or other resources.It is also possible that patients in this study anticipated the level of functioning that would be required to be discharged safely back into the community and simply reported how they anticipated their health-related quality of life would be if they were to able to function at that level. They may have taken this heuristic response approach by surmising they would not be discharged until that level of functioning had been achieved. This woAnother factor worthy of consideration is whether patients recalled their anticipated discharge health-related quality of life responses and intentionally repeated the same responses at the discharge assessment. The investigators do not believe this occurred for four primary reasons. First, patients completed a wide range of routine assessments from multiple health professional disciplines during the first 72 hours of their admission to the participating rehabilitation unit. The large number of items assessed in this period offered natural protection against recalling their response to the six specific anticipated EQ-5D items. Second, some level of cognitive impairment is present among many patients in this older clinical group. This is evident in the MMSE scores, which indicated a large proportion of patients (including those in the \u2018better\u2019 cognition group) were likely to have some difficulty with memory and other rudimentary cognitive functions. Third, the long length of time between assessments (median 6 week length of stay) also provided natural protection against recalling responses from the initial assessment. Fourth, prior research has indicated that patients from comparable clinical groups do not give much consideration to health state scales when reporting their health-related quality of life and do not accurately recall responses to health-related quality of life reports completed at earlier assessments,5,60.A number of caveats should be considered when interpreting findings from this investigation. The EQ-5D is a straightforward instrument with limited response options. In this study the 3-level multiple choice EQ-5D was used. This was a logical choice of instrument for this style of investigation where the objective was to examine a patient reported outcome capturing generic health-related quality of life information. Nonetheless correct prediction of the broad response categories did not require a detailed understanding of their discharge health state . This is likely to have contributed to a higher level of agreement than that which may have been observed if a more detailed prediction was required. It is also noteworthy that alternative instruments with different psychometric properties may have resulted in more (or less) accurate predictions depending on the qualities of the instrument .There are several factors limiting the extent to which these findings can be generalized. First, all participants were from a single tertiary hospital. Patients from other hospitals or geographical locations may not have responded in the same way. Second, a single generic health-related quality of life instrument was used. Additionally, patients beginning the subacute rehabilitation phase of their recovery are likely to have already been provided with substantial information and advice about their prognosis. Patients in acute hospital care or community based settings may not have the same level of accuracy in anticipating their future health-related quality of life as the sample in this investigation.A priority for future research following this investigation includes examining patients\u2019 expectations across the continuum of care. This could potentially reveal valuable information regarding the role and timing of health education in joint decision making and patient-centered models of care. The nature of health information and focus of advice is likely to contrast across acute, subacute and community settings. This investigation has also exposed several opportunities for methodological improvement when undertaking future investigations of this nature among older adults. These opportunities include collecting a wider range of patient demographic clinical information that may influence ability to predict future health states. This may include recording patients\u2019 level of education, evaluating patient depression or anxiety levels, determining the amount and content of health education already delivered to patients prior to study commencement and a potential comparison to health professionals accuracy in predicting patients\u2019 future health-related quality of life.On a broader note, it would also be valuable for future investigations to consider how positive or negative findings regarding patients\u2019 preferences and expectations for their recovery should impact models of service delivery and individual treatment choices. There are many complex ethical considerations that could arise from this line of enquiry. For example, how should health-professionals with a duty of care to their patients respond if inaccurate patient expectations of disease progression  result in a declination of evidenced based treatments to pursue an unadvisable course of action? How would this response differ depending on the potential severity of outcome or impact on third party dependents, such as children? Many issues in this sphere may initially seem straight forward in the context of patients being central decision makers in their care. Similarly, additional ethical complexity may be exposed if health-professionals do not have some degree of accuracy in anticipating future health-states. To this end, future research should investigate whether health professionals have the ability to predict patients\u2019 future health-related quality of life in a variety of contexts, given that patients are likely to formulate their own expectations after taking into account the opinion of their treating health professionals. Expectations held by health-professionals are likely to directly influence therapies and other treatment options offered to patients.Patients admitted for subacute in-hospital rehabilitation were able to anticipate their discharge health-related quality of life on the EQ-5D instrument with a moderate level of accuracy. This finding adds to the foundational empirical work supporting joint treatment decision making and patient-centered models of care during rehabilitation following acute illness or injury. Accurate patient expectations of the impact of treatment (or disease progression) on future health-related related quality of life is likely to allow patients and health professionals to successfully target interventions to priority areas where meaningful gains can be achieved. Accurate expectations may also help avoid despondency associated with falling short of unrealistic expectations or a lack of motivation associated with underestimating the potential for improvement in health-related quality of life.The authors declare they have no competing interests.SM contributed to research idea conception, data collection, data analysis and manuscript preparation, as well as manuscript review, appraisal and editing. TH contributed to research idea conception and manuscript review, appraisal and editing. Both authors read and approved the final manuscript."}
+{"text": "Measures of heart rate variability (HRV) and respiratory sinus arrhythmia (RSA), which are the healthy fluctuations in heart rate that reflect autonomic influences on cardiac activity, have been proposed as indicators of physical and psychological health. Previous studies suggest that HRV increases during some meditative states, but it is not clear how autonomic tone is affected either in the short term during meditative states, nor as a long-term result of meditation practice. Here we test two hypotheses: (1) eight weeks of meditation training will improve autonomic tone, in the form of increased overall HRV and decreased low-frequency HRV to high-frequency HRV (LF/HF) ratio; and (2) RSA increases during the meditation state compared to rest.We collected electrocardiogram recordings as part of a larger randomized controlled trial of the effects of an eight-week meditation training intervention on healthy adults without prior meditation experience. Here we report data from eight subjects before and after the \u201cmindful-attention\u201d meditation intervention and the control intervention. The recordings were performed while the subjects were lying supine, at rest (for both groups) and in a meditative state (for the meditation group only). We computed measures of HRV and RSA across a 3-minute epoch using a point-process model of heart beat dynamics.We found a longitudinal increase in HRV and a longitudinal decrease in LF/HF ratio , both consistent with improved autonomic function, in the meditation group but not in the control group. We also found a marked increase in RSA during meditation compared to rest.These preliminary outcomes, although derived from a small sample, support our hypotheses. They suggest that measures of RSA might be useful markers of the meditative state, and encourage further investigation on the efficacy of HRV measures to indicate a general improvement of autonomic health after meditation interventions."}
+{"text": "Polycystic ovary syndrome (PCOS) is the most common female endocrine disorder, affecting 6-18% of women of reproductive age. Irregular periods are a hallmark symptom of PCOS and whilst Chinese herbal medicine (CHM) has historically been used as an effective treatment for irregular periods, this requires further investigation in randomised controlled trials (RCTs). To ensure that the methods used within an RCT reflects Chinese herbal methods used in clinical practice, a study was proposed to establish good practice guidelines in the treatment of PCOS through achieving consensus amongst a group of Chinese medicine herbalists.a priori as a mean Likert scale score of 5 or more. Questionnaire items not reaching consensus were re-distributed to experts for re-consideration via a second and a third and final round of questionnaires where necessary.The Delphi method was used involving in-depth interviews with a purposive sample of 11 expert Chinese medicine herbalists. Interview data was analysed using thematic and framework analysis to formulate Delphi questionnaire items. Experts were then distributed the questionnaire online and asked to rate their agreement with each questionnaire item on a 7-point Likert scale. Consensus was defined Preliminary results suggest that consensus exists amongst experts regarding common diagnostic categories, treatment strategies used, appropriate dosage and appropriate duration of treatment to observe a clinical effect.The preliminary results suggest that consensus can be achieved at least within the core aspects of Chinese herbal medicine treatment for PCOS. This methodology is vital in the development of rigorous RCTs for CHM and the outcome and principles of good practice guidelines for PCOS will be presented at the conference."}
+{"text": "Patient recruitment is one of the main challenges in conducting randomised controlled trials (RCTs). Patients\u2019 treatment preferences are viewed as a barrier to RCT recruitment yet there is little research to understand them. This study explored the expression of preferences by potential trial recruits, the response to them by recruiters, and their influence on trial participation decisions during trial recruitment appointments.We undertook an analysis of audio recordings of consecutive recruitment appointments to a UK multi-centre RCT of three different treatments for prostate cancer (the ProtecT - Prostate cancer testing and Treatment - study) over a three month period. 93/108 appointments with men aged 51-70 years were recorded successfully and analysed using techniques of content and thematic analysis.Most potential participants expressed a desire for a particular treatment early in appointments, with their desires ranging on a continuum from hesitant to well-formed opinions. Recruiters explored these initial treatment views in the context of evidence-based treatment and study information which resulted in many men becoming uncertain about their initial views and open to RCT recruitment, often accepting a different treatment from their original \u2018preference\u2019. Only a quarter of men who initially expressed a wish for a particular treatment sustained or developed a clear treatment preference as the consultation proceeded and ultimately received this treatment. In most of these cases the recruiters established the rationale for the preference then provided specific information that counter-balanced their reasoning by emphasising the position of clinical equipoise, uncertainty of the prognosis and the pros and cons of their desired and non desired treatment. This counter-balancing of information continued until they were sufficiently satisfied that the man was making a fully informed decision.Many potential trial recruits will present initially with a treatment preference at trial recruitment but most of these preferences will dissolve after thorough exploration and targeted evidence-based information enabling trial participation. Only a minority of preferences are upheld after specific counter-balancing of information is tactfully given. The key for future research is to continue developing strategies that sensitively elicit and explore treatment preferences so that the more robust preferences can be distinguished from the ephemeral views to maximise trial recruitment."}
+{"text": "Neural stem cells have been isolated from post-mortem brain of Alzheimer\u2019s patients and neural stem cells generated from biopsies of the olfactory organ of patients is another approach. These \u201colfactory neurosphere-derived\u201d cells demonstrate robust disease-specific phenotypes in patients with schizophrenia and Parkinson\u2019s disease. HCS is already in use to find small molecules for the generation and differentiation of ESCs and iPSCs. The challenges for using stem cells for drug discovery are to develop robust stem cell culture methods that meet the rigorous requirements for repeatable, consistent quantities of defined cell types at the industrial scale necessary for HCS.The concept of drug discovery through stem cell biology is based on technological developments whose genesis is now coincident. The first is automated cell microscopy with concurrent advances in image acquisition and analysis, known as high content screening (HCS). The second is patient-derived stem cells for modeling the cell biology of brain diseases. HCS has developed from the requirements of the pharmaceutical industry for high throughput assays to screen thousands of chemical compounds in the search for new drugs. HCS combines new fluorescent probes with automated microscopy and computational power to quantify the effects of compounds on cell functions. Stem cell biology has advanced greatly since the discovery of genetic reprograming of somatic cells into induced pluripotent stem cells (iPSCs). There is now a rush of papers describing their generation from patients with various diseases of the nervous system. Although the majority of these have been genetic diseases, iPSCs have been generated from patients with complex diseases (schizophrenia and sporadic Parkinson\u2019s disease). Some genetic diseases are also modeled in embryonic stem cells (ESCs) generated from blastocysts rejected during  The last decades have seen development and applications in cellular neuroscience of DNA, RNA, and protein analysis technologies that provide large volumes of information, getting away from the traditional methods that follow the activities of single genes or single cell types. The application of DNA sequencing, RNA microarrays and higher throughput protein mass spectrometry is allowing examination of biological systems in all their complexity. What has been missing for cell biologists is the ability to interrogate cell functions at the same scale and level of complexity. This is being addressed by the developments in automated technologies developed by pharmaceutical companies to screen massive compound libraries for the discovery of new drug leads. Until recently this high throughput screening, with robotic control and automated data capture and analysis of experiments in 96-, 384-, and 1,536-well plates, centered on enzyme and receptor assays but increasingly, interest is turning to cell-based assays that capture the complexity of the environment in which drugs will actually operate. There has been a move to drug screening based on cellular outcomes  rather than predicted mechanism . This led to the concept and development of \u201chigh content screening\u201d (HCS) that combines advances in fluorescence labeling of cells, robotic and automated microscopy, and automated image analysis that brings the analysis of cell functions to the high throughput formats of multiwell plates . For theIn neuroscience, the discovery of the genetic causes of familial diseases has driven understanding of the functions of individual genes and proteins in cell function in the nervous system and the effects of mutations on brain function. Identification of a candidate gene is followed by genetically modified cell and mouse models to identify the functions of the identified gene at cell and systems level. Mouse models have been important for elucidating protein and gene functions but they often do not recapitulate human disease because the mice lack the human genetic background and the introduced human genes are acting in a non-human cellular context. Immortalized human cell lines have a more relevant genetic background but, being derived from tumors, they may not reflect a normal cellular context. Patient-derived primary cells might be a solution for both drawbacks but they cannot usually be maintained for very long in culture and finding an accessible cell type for brain diseases is problematic. Stem cell technologies may have the solution to these drawbacks.There is an emerging interest in using stem cells to understand the cellular bases of human diseases. There is an imperative here, especially for neurological diseases and conditions. Large pharmaceutical companies are withdrawing from investing in neuroscience research because of the failure of the current paradigms to convert findings in animal models to drugs for human disease . There aFigure 1). These high throughput technologies arose from the desire of pharmaceutical companies to test all theoretical chemical compounds (~100 million) against all theoretical human biological targets, estimated from the number genes  or proteins , indicating that as many as 1012 assays would be needed to identify all interactions between chemicals and targets . This allows quantitative analyses of components of cells such as spatio-temporal distributions of individual proteins, cytoskeletal structures, vesicles, and organelles when challenged with chemical compounds. HCS can be used to monitor activation or inhibition of individual proteins and protein\u2013protein interactions as well as allowing analysis of broader changes in biological processes and cell functions. Recent advances in the range of fluorescent probes for biological processes, functions, and cell components have combined with developments in fluorescence microscopy to give the cell biologists many new ways to understand cell functions in health and disease. These cell-centric developments have converged with high throughput concepts and with developments in automated microscopy and image analysis to evolve into the new technological synthesis of high throughput screening in which cell-based assays are conducted in multiwell plate formats. High content technologies are now used to screen chemical libraries for drug discovery as well as genome-wide RNA interference libraries to probe gene functions  evident when the brain functions as a whole.The analysis of gene function through gain- or loss-of-function in cell, fly, and mouse models has been very instructive in elucidating functions of genes and proteins but less successful in providing models that predict drug efficacy in human diseases. An example is the failure of the superoxide dismutase transgenic mouse model for amyotrophic lateral sclerosis that has yielded multiple compounds that are therapeutic in mouse but not humans  with genetic or chromosomal disorders derived from surplus blastocysts during iagnosis . Althougiagnosis . At thisiagnosis . No doubin vitro and reduced glutamate receptor expression  is an autosomal dominant disease affecting the long spinal axons from the motor cortex to the lower motor neurons in the spinal cord. ONS cells from patients with HSP were similar in many basic cell functions to ONS cells from healthy controls despite dysregulation of expression of 60% of the genome, indicating a high level of homeostatic regulation in response to dominant mutations in  protein . Closer  protein . Live-ce protein . Ataxia  protein . Immatur protein . Olfactoutonomia .IKBKAP gene in familial dysautonomia patient-derived ectomesenchymal cells . Both drugs increased acetylated a-tubulin, but with different dose\u2013response curves, and low doses of both drugs (~0.3 nM) restored patient cell acetylated a-tubulin to the control cell level . ONS cells are derived from neural tissue and can obviously show disease-specific phenotypes relevant to the neurological diseases from which the donors suffer. Proof-of-principle analyses have shown that brain diseases \u201cain a dish\u201d can be ameliorated by drug treatment. For example, Parkinson\u2019s patient-derived ONS cell functions were restored to control-derived cell levels by treatment with L-sulforaphane, an agonist of NRF2 . Similaral cells  as it haal cells . HCS wasal cells . HSP patal cells . HCS sholl level .These experiments show that disease-associated dysfunctions in olfactory cells can be ameliorated by candidate chemical compounds acting on targets known to be disrupted in the patient-derived cells compared to controls. The next challenge is to see whether ONS cells are useful for screening libraries of compounds. They have some of the necessary characteristics such as ease of generation, low cost, robust and repeatable growth characteristics and predictable phenotype. These properties make them useful for building up banks of cells that will allow assessment of variability of cell biology across a wider population of patients and controls, to discriminate disease-specific differences from individual differences in complex diseases like Parkinson\u2019s disease and schizophrenia.in vitro. In growth factor-free medium 50% of the cells were \u201castrocytes\u201d [glial fibrillary acidic protein (GFAP)-positive cells], a proportion elevated by ciliary neurotrophic factor . These questions and challenges are all signs of a field at the very beginning of its genesis and many will undoubtedly be resolved in the coming years.The concept of drug discovery through patient-derived stem cell models of brain diseases is attractive but has many other challenges apart from the practical issues of cost and reliable production. Concerns are raised about the epigenetic status of iPSCs and ESCs \u2013 epigenetic status is variably altered by reprograming and by culture methods  hence diOther developments in reprograming will affect this future. It is now possible to generate neurons directly from skin fibroblasts . This maThe author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Trichosurus vulpecula) within the North Island of New Zealand, demonstrating how commonly collected empirical dispersal data can be used to calibrate a cost-surface and associated accumulated-cost dispersal kernel. Our results indicate that considerable improvements could be made to the modelling of the transfer stage of possum dispersal by using a cost-surface and associated accumulated-cost dispersal kernel instead of a more traditional straight-line distance based dispersal kernel. We envisage a variety of ways in which the information from this novel combination of a cost-surface and accumulated-cost dispersal kernel could be gainfully incorporated into existing dispersal models. This would enable more realistic modelling of the direct transfer costs associated with the dispersal process, without requiring existing dispersal models to be abandoned.Dispersal costs need to be quantified from empirical data and incorporated into dispersal models to improve our understanding of the dispersal process. We are interested in quantifying how landscape features affect the immediately incurred direct costs associated with the transfer of an organism from one location to another. We propose that least-cost modelling is one method that can be used to quantify direct transfer costs. By representing the landscape as a cost-surface, which describes the costs associated with traversing different landscape features, least-cost modelling is often applied to measure connectivity between locations in accumulated-cost units that are a combination of both the distance travelled and the costs traversed. However, we take an additional step by defining an accumulated-cost dispersal kernel, which describes the probability of dispersal in accumulated-cost units. This novel combination of cost-surface and accumulated-cost dispersal kernel enables the transfer stage of dispersal to incorporate the effects of landscape features by modifying the direction of dispersal based on the cost-surface and the distance of dispersal based on the accumulated-cost dispersal kernel. We apply this approach to the common brushtail possum ( Dispersal is an important process for ecology and evolution, affecting organisms at the individual, population, and species levels by influencing population dynamics and gene flow. Conceptually, dispersal can be viewed as a combination of three stages: departure, transfer, and settlement. Each stage imposes energy, time, risk, and opportunity-based costs on the disperser that can either be direct and incurred immediately, or indirect and incurred subsequently We are interested in quantifying the direct costs associated with the transfer stage of dispersal, in which an organism moves from one location to another. Traditionally a distance-based dispersal kernel, calibrated from data on straight-line distances between the start and end locations of known dispersal events , is usedLeast-cost modelling is based upon a geographic information system (GIS) raster called a cost-surface . Cost-surfaces are developed using a variety of approaches Given a cost-surface and the same start and end locations of known dispersal events that are typically used to calibrate a distance based dispersal kernel, we can envisage a least-cost modelling approach to quantifying direct transfer dispersal costs. If LCPs are calculated between the start and end locations, then the accumulated-cost of the LCPs could be used to calibrate an accumulated-cost based dispersal kernel. This novel combination of a cost-surface and its associated accumulated-cost dispersal kernel would then enable the transfer stage of dispersal to incorporate the effects of landscape features, by modifying the direction of dispersal based on the cost-surface and the distance of dispersal based on the accumulated-cost dispersal kernel.Therefore, in contrast to the straight-line distance approach to modelling dispersal that assumes that the landscape does not affect dispersal directions or distances, a least-cost modelling approach to quantifying the direct transfer costs of dispersal would enable landscape features to be taken into account. This would help in moving towards a new generation of dispersal models that are more empirically based Trichosurus vulpecula), a nocturnal marsupial, about 70\u201390 cm in length and 2\u20133.5 kg in weight, which has become a notorious invasive species since its introduction to New Zealand from Australia during the late 1800s and early 1900s To demonstrate how the direct transfer costs of dispersal can be quantified using least-cost modelling, we apply our proposed approach to the common brushtail possum  Tree and scrub cover for each area where possum dispersal data were gathered was rasterised from the most contemporary of New Zealand's landcover databases Rivers were differentiated by stream order, assuming that stream order is relative to river characteristics such as channel size and discharge Highway traffic volumes were based on point estimates of annual average daily traffic (AADT) for state All offshore areas and any features from the lagoon and lake entity classes of the national topographic database So that the set of rasters could be combined into a cost-surface, each raster's values were rescaled to between zero and one such that a set of relative inter-feature weights could be applied. This rescaling also provided an opportunity to control the intra-feature weighting of each landscape variable. With limited knowledge regarding how possum dispersal may vary across the range of values associated with each of the features, we assumed a linear function for rescaling the values of elevation, plan curvature, tree and scrub cover, and bridge length between zero and one  A\u2013D.n requires two rivers of order n-1 n was half that of a river of order n+1  from the set of raster landscape features that made up a cost-surface (S) by multiplying each raster (r) by its associated weight (rw). To find a best fitting set of weights for each of these cost-surfaces, we generated a Latin hypercube sample (LHS) To determine the best fitting set of inter-feature weights for each of the 47 cost-surfaces, the computational efficient irregular landscape graph approach wi) to better interpret the relative strength of evidence for each landscape representation r2) from the linear regressions to assess the explanatory power. As well as ranking the 47 cost-surfaces landscape representations, we also included a uniform landscape representation in which connectivity between the possum sampling locations was measured using straight-line distance rather than LCP accumulated-cost. As with the cost-surfaces, an RSS value was also calculated by fitting a linear regression between the rescaled distances and the genetic distances.The 47 best fitting cost-surface landscape representations were then ranked by the corrected small sample AIC (AICc) that was calculated directly from the RSS values wi and r2 values derived from RSS value of each linear regression were reliable, each set of linear regression residuals were examined for signs of spatial autocorrelation. As the residuals were associated with links within a network of neighbouring possum sampling locations, the spatial structure between the residuals was defined as a binary variable representing adjacency of the links within the network. The level and significance of spatial autocorrelation was measured using a randomisation based global Moran's I To ensure the A dispersal kernel was calibrated for each of the landscape representations using the start and end points of dispersal events from 65 (47 \u2642 and 18 \u2640) radio-collared possums across five different studies U-tests were used to check for differences in dispersal connectivity values between sexes, in order to assess whether different kernels were required for each sex. The dispersal kernel for each landscape representation was defined by a lognormal probability distribution fitted to the dispersal connectivity values of the possum dispersal events via maximum-likelihood Dispersal connectivity was calculated between the start and end points of all of the radio-collared possum dispersal events as either straight-line distance for the uniform landscape representation, or as LCPs for the 47 cost-surface landscape representations. Mann-Whitney To compare the differing quantifications of dispersal transfer costs associated with the traditional straight-line distance approach and our proposed least-cost modelling approach, we produced maps that visualised the likely dispersal directions and distances given an arbitrary starting location.wi and r2 values indicating that there was minimal evidence to support this option as it does not explain differences in genetic distance  indicating that the wi and r2 values can be interpreted with confidence. In contrast the uniform landscape representation's residuals had significant positive autocorrelation , indicating that some spatial factor that influences genetic distances is not accounted for \u2013 which we would argue is clearly the effect of landscape features.Analyses of the spatial autocorrelation of the regression residuals support these results. There was only slightly positive and non-significant spatial autocorrelation present for the top ranked cost-surface landscape representations . Therefore, lognormal dispersal kernels were fitted to the dispersal connectivity values derived for each landscape representation with the two sexes combined (There were notable differences for dispersal events when measured using straight-line distance for the uniform landscape representation, or LCPs for the cost-surface landscape representations . The discombined .The fact that the least-cost modelling approach to quantifying direct transfer costs was able to incorporate landscape features into the likely dispersal directions and distances was evident when these costs were visualised . This abThe LCP accumulated-cost connectivity values derived from our cost-surface landscape representations explained about one-third of the variation in genetic differentiation . These oAssuming that our cost-surfaces are a reasonable representation of the actual traversal costs for possums on the North Island of New Zealand, our results are conclusive in demonstrating that a uniform landscape representation in which dispersal can be based upon straight-line distance movement is far too simplistic. We feel confident that this will be the case for other species and locations as previous studies have also shown that least-cost modelling derived accumulated-cost values are better than straight-line distance at explaining ecological patterns that are affected by dispersal If a dispersal event is modelled as a single discrete movement, the probability density function of a dispersal kernel could be used to describe the likelihood of the dispersal event having a specific accumulated-cost value. This could then be used in combination with a cost-surface to randomly select an end point for the dispersal event. This is essentially an equivalent process as that used by the straight-line distance dispersal approach, but with the benefit of recognising landscape structure.It has also been suggested that a dispersing organism is increasingly likely to settle as accumulated transfer costs increase There are a variety of least-cost modelling approaches that aim to identify the area around a point that is likely to be reached With these different applications in mind, it is important to highlight that the landscape genetics approach we used to calibrate our cost-surface landscape representations is not the only or necessarily the best approach. While gene flow and dispersal are generally correlated they are not synonymous, as contemporary genetic structure is affected by other processes such as historical landscape change and population level survival and reproduction rates It is also important to remember that we focussed on the direct costs associated with the transfer stage of dispersal, which is only one part of the broader whole dispersal process that also includes departure and settlement costs To conclude, a new generation of dispersal models is required that better exploits recent empirical advances in understanding the dispersal process"}
+{"text": "Computational Structural Bioinformatics Workshop (CSBW) was held in Philadelphia on October 4, 2012. This issue includes eleven papers selected from the work presented at the CSBW of 2012. In \"Four-body atomic potential for modeling protein-ligand binding affinity: application to enzyme-inhibitor binding energy prediction\", a predictive model of free-energy was built to evaluate the binding between a protein and a ligand. In \"Unbiased, scalable sampling of protein loop conformations from probabilistic priors\", a new Markov chain Monte Carlo algorithm was proposed to generate unbiased conformations of closed protein loops from probabilistic priors. In \"Enhancement of accuracy and efficiency for RNA secondary structure prediction by sequence segmentation and MapReduce\", authors demonstrate an enhanced method by cutting a long RNA sequence into smaller chunks at strategically selected points, and distributing the tasks to multiple processors. In \"A population-based evolutionary search approach to the multiple minima problem in de novo protein structure prediction\", the authors present an evolutionary search algorithm to obtain a discrete representation of the protein energy surface in terms of an ensemble of conformations representing local energy minima. In \"Estimating loop length from Cryo-EM images at medium resolutions\", the authors developed a computational geometry method to simplify the points along the skeleton to measure loop length in 3D images. The paper \"A conservation and rigidity based method for detecting critical protein residues\" presents a method that combines the rigidity and the evolutionary conservation in detection of the critical residues. In \"A conservation and biophysics guided stochastic approach to refining docked multimeric proteins\", the authors introduce a refinement method that accepts complexes consisting of any number of monomeric units. In \"Elucidating the ensemble of functionally-relevant transitions in protein systems with a robotics-inspired method,\" the authors present a robotics-inspired tree-based method to sample energetically-credible conformational pathways connecting diverse functional states in multimodal proteins. The paper \"An aggregate analysis of many predicted structures to reduce errors in protein structure comparison caused by conformational flexibility\" applies protein structure prediction algorithms to enhance the classification of homologous proteins according to their binding preferences. In \"DINC: A new AutoDock-based protocol for docking large ligands\", an enhanced method was demonstrated for docking large ligands. The paper \"Modeling protein conformational transitions by a combination of coarse-grained normal mode analysis and robotics-inspired methods\" presents an efficient approach involving robotics concepts.The rapid accumulation of macromolecular structures presents a unique set of challenges and opportunities in the analysis, comparison, modeling, and prediction of macromolecular structures and interactions. The 6th The authors declare that they have no competing interests."}
+{"text": "Current prognostic clinical and morphological parameters are insufficient to accurately predict metastasis in individual melanoma patients. Several studies have described gene expression signatures to predict survival or metastasis of primary melanoma patients, however the reproducibility among these studies is disappointingly low.We followed extended REMARK/Gould Rothberg criteria to identify gene sets predictive for metastasis in patients with primary cutaneous melanoma. For class comparison, gene expression data from 116 patients with clinical stage I/II (no metastasis) and 72 with III/IV primary melanoma (with metastasis) at time of first diagnosis were used. Significance analysis of microarrays identified the top 50 differentially expressed genes. In an independent data set from a second cohort of 28 primary melanoma patients, these genes were analyzed by multivariate Cox regression analysis and leave-one-out cross validation for association with development of metastatic disease. In a multivariate Cox regression analysis, expression of the genes Ena/vasodilator-stimulated phosphoprotein-like (EVL) and CD24 antigen gave the best predictive value . A multivariate Cox proportional hazards model revealed these genes as a potential independent predictor, which may possibly add (both p\u200a=\u200a0.01) to the predictive value of the most important morphological indicator, Breslow depth.Combination of molecular with morphological information may potentially enable an improved prediction of metastasis in primary melanoma patients. A strength of the gene expression set is the small number of genes, which should allow easy reevaluation in independent data sets and adequately designed clinical trials. Human melanoma is the most malignant skin cancer 2) Although numerous molecular events have been associated with development and progression of melanoma In the last years several attempts have been made to develop individualized prediction of metastasis from a merely morphology-based into a state-of-the-art molecular approach. Within the past decade several gene expression studies have reported molecular predictors for disease outcome in melanoma, may it be survival or development of metastasis, with disappointingly low congruence i.e. metastasis during clinical follow up. The Cox proportional hazards model followed by leave-one-out cross validation (LOOCV) revealed two genes whose expression was associated best with metastasis, namely the genes encoding the Ena/vasodilator-stimulated phosphoprotein-like (EVL) and CD24 antigen (CD24).In this study, we followed the guidelines on statistical analysis and reporting of gene expression data for cancer outcome To identify the gene expression profiles of individual melanoma patients, the cDNA from each tumor was hybridized against a common skin reference as described The top 50 genes identified by class comparison were used in the second independent gene expression dataset of 28 primary melanomas for prediction of metastasis.http://david.abcc.ncifcrf.gov), most of these genes were assigned to immune defense response and regulation of cell proliferation.Affymetrix probe sets matching these 50 genes were determined using the GeneAnnot-database These 43 genes were used as independent variables in a multivariate Cox regression analysis. The two probe sets with the best predictive value comprised the Affymetrix probe set IDs 217838_s_at  and 208651_x_at  matching the genes encoding Ena/vasodilator-stimulated phosphoprotein-like (EVL) and CD24 antigen (CD24), respectively . The expLeave-one-out cross-validation analysis was used on the 28 patient dataset to evaluate the model-based gene set for hypothetical prediction of metastasis for each patient. Here, one sample was withdrawn from the initial 28-sample dataset, leaving a temporary 27-sample training set and one left out-sample. On the training set, the gene set obtained from Cox regression is then used to classify the previously left out-test sample We next asked, whether gene expression could possibly add to the predictive power of the most important morphological parameter, Breslow depth. In a multivariate Cox proportional hazards model we evaluated the combination of Breslow depth either with ulceration, mitotic rate or gene expression for additional effects on prediction of metastasis.While addition of ulceration or mitotic rate did not improve the predictive value of Breslow depth , additioConsistent with the results obtained by the Cox proportional hazards model, there was a low correlation between Breslow depth and the model risk score calculated from the two genes , suggesting the latter as a potential independent predictor for metastasis. In contrast, the morphological parameter mitotic rate correlated significantly with Breslow depth .i.e. lymphotoxin beta, was identified by at least three of these studies Although genomic information has significantly contributed to the understanding of the cell biology and also to the therapy of melanoma, molecular information has failed so far to provide robust information for individualized prediction of the clinical course of patients. This is best exemplified by studies using gene expression microarrays for class prediction such as survival or metastasis. For example, in 7 independent and prominently published studies on class prediction for survival in human melanoma biopsies a total number of around 590 different candidate genes  were proposed as molecular markers In 2007, Dupuy and Simon critically reviewed a number of 90 published microarray studies on cancer outcome and described several issues heavily compromising the validity and the reproducibility of these studies . In view of the many pervasive mistakes and misunderstandings in studies published even in high impact journals, the REMARK/Gould Rothberg criteria were developed for statistical analysis and reporting of microarray studies for clinical outcomes of patients with primary cutaneous melanoma i.e. metastasis).Interestingly, the use of a separate test set for supervised prediction appears to be a gold standard to some authors, but in many studies the use of a separate test set almost invariably brought more confusion than clarity. Instead, the gold standard should rather be a proper validation of the classifier performance and this can be achieved through a cross-validation procedure as well The identified gene sequences encode CD24 and EVL and both have documented established and/or proposed biological functions relevant to cancer cell biology. CD24 is a GPI-anchored mucin-like membrane protein originally identified as a signal-transducing molecule on the surfaces of most human B cells EVL (Ena/VASP-like) is a member of the Ena/VASP (Enabled/vasodilator-stimulated phosphoprotein) family of proteins, which is a key regulator of cytoplasmic actin at sites of actin remodeling such as focal adhesions, the tips of filopodia or cell-matrix and cell-cell junctions Taken together our data show that, in contrast to morphological parameters such as mitotic rate and ulceration, gene expression analysis may potentially add to the predictive value of the most important indicator of primary cutaneous melanoma, Breslow depth. Whether this information is becoming translationally relevant is subject to further evaluation in independent datasets and adequately designed clinical trials.This study was approved by the Local Ethic Committees at the Universities of Cologne, Bonn and Aachen and has fulfilled the Declaration of Helsinki Principles for human research. All patients signed a consent form to participate in this study.Primary melanoma tissue samples were either collected at the Departments of Dermatology at the Universities of Cologne, Bonn or Aachen. Each department performed its histological and immunohistochemical routine procedures. Reference histology for melanoma biopsies was done at the Department of Dermatology of the University of Cologne. Healthy skin control samples were obtained at the Department of Dermatology at the Universities of Bonn or Cologne and re-examined at the Department of Dermatology at the University of Bonn. Primary melanoma lesions were classified at the time of surgery based on a combination of clinicopathological features and the AJCC 2002 staging system Immediately after surgery, skin biopsies were flash-frozen in liquid nitrogen. Total RNA from skin excision biopsies was isolated as described earlier http://www.sagenet.org, with minor modifications. Each SAGE library was obtained from a pool of mRNAs derived from 20 to 22 biopsies of melanomas and normal skin, respectively, to minimize biopsy related variations Serial analyses of the gene expression (SAGE\u2122) analysis of total RNA was performed as previously described The formula by Audic and Claviere All research involving human participants was approved by the institutional review board at the University of Essen and granted an exemption. The study has fulfilled the Declaration of Helsinki Principles. All patients gave written informed consent.Fresh primary cutaneous melanoma biopsies from twenty-eight patients were processed as described GeneArray@ 2500 Scanner (Affymetrix) was used for scanning and the quality of raw microarray profiles assessed as described Cellular RNA was extracted by guanidinium thiocyanate and cesium chloride centrifugation. The purification from the remaining melanin was performed using the Qiagen RNeasy Fibrous Tissue Mini Kit. The preparation of cRNA was carried out according to the GeneChip Expression Analysis Technical Manual (Affymetrix), and hybridized onto HU133A chips (Affymetrix). A Microarray probe intensity data from 28 primary melanoma patients were read from Affymetrix CEL files and processed with the Genespring GX11.5 software . The Robust Multi-Array Average algorithm (RMA) The Cox proportional hazard model i.e. metastasis) of a particular patient was predicted from the patient's risk score as calculated from the Cox model fitted to all other patients. The predicted outcome was compared to the real outcome to estimate the error rate (i.e. the probability of incorrectly classifying a future case) of the predictor on the basis of a suitably chosen decision rule (\u201ccutoff\u201d). The cross-validated risk scores were used as the covariate in another (univariate) Cox regression model. The resulting parameter estimate was used as a shrinkage factor for the -due to the limited number of patients and the forward modeling procedure- expectedly overestimated coefficients of the original Cox model.In a LOOCV we tried to evaluate the predictive capability of the model-based gene set. The outcome  analysis using the binary outcome of documented metastasis or not.The area under the curve (AUC) was calculated by summarizing the relative frequencies of true positive predictions over the relative frequencies of false positive predictions from Cox regression (risk scores), Table S1Top 50 genes differentially expressed between human non-metastatic and metastatic primary melanomas of the class comparison data set.(DOCX)Click here for additional data file."}
+{"text": "Contractile function of striated muscle cells depends crucially on the almost crystalline order of actin and myosin filaments in myofibrils, but the physical mechanisms that lead to myofibril assembly remains ill-defined. Passive diffusive sorting of actin filaments into sarcomeric order is kinetically impossible, suggesting a pivotal role of active processes in sarcomeric pattern formation. Using a one-dimensional computational model of an initially unstriated actin bundle, we show that actin filament treadmilling in the presence of processive plus-end crosslinking provides a simple and robust mechanism for the polarity sorting of actin filaments as well as for the correct localization of myosin filaments. We propose that the coalescence of crosslinked actin clusters could be key for sarcomeric pattern formation. In our simulations, sarcomere spacing is set by filament length prompting tight length control already at early stages of pattern formation. The proposed mechanism could be generic and apply both to premyofibrils and nascent myofibrils in developing muscle cells as well as possibly to striated stress-fibers in non-muscle cells. Muscle contraction driving voluntary movements and the beating of the heart relies on the contraction of highly regular bundles of actin and myosin filaments, which share a periodic, sarcomeric pattern. We know little about the mechanisms by which these \u2018biological crystals\u2019 are assembled and it is a general question how order on a scale of 100 micrometers can emerge from the interactions of micrometer-sized building blocks, such as actin and myosin filaments. In our paper, we consider a computational model for a bundle of actin filaments and discuss physical mechanisms by which periodic order emerges spontaneously. Mutual crosslinking of actin filaments results in the formation and coalescence of growing actin clusters. Active elongation and shrinkage dynamics of actin filaments generates polymerization forces and causes local actin flow that can act like a conveyor belt to sort myosin filaments in place. We employ periodic boundary conditions with a system size nts  for .In the premyofibrils of developing muscle cells as well as in stress fibers of non-muscle cells, the molecular motor myosin II polymerizes into bipolar filaments of a few hundred nanometers length that have numerous myosin heads at either end For sake of illustration, consider an isolated actin cluster that comprises a total number The structure factor is a standard measure used in condensed matter physics to quantify the regularity of periodic order Our computational model primarily serves as a proof of physical principle. The emergence of striated order in the framework of this model is a robust process that is not sensitive to the parameter choices. A sensitivity analysis can be found in the SI in vitro, while filopodia protrusion driven by actin polymerization can be as fast as e.g. in stereocilia.In unstriated stress fibers, actin filament length range from i.e. well below both the stall force of actin polymerization and the buckling force of single actin filaments.Myosin filaments may exert pico Newton forces on actin filament at full activation. Decoration of actin filaments with troponin/tropomyosin reduces myosin walking, which would correspond to lower values for the active myosin force We did not incorporate filament diffusion explicitly in our model, as thermal motion will be small in a dense bundle. Note, however, that dynamic myosin forces with short correlation time can induce stochastic, bidirectional motion of filaments.Several studies pointed out the effect of integrin-mediated anchorage of Z-lines for myofibrillogenesis In our simulations, we consider a minimal, one-dimensional model of a bundle of treadmilling actin filaments. Actin filaments with nearby plus-ends can form a stable crosslink by a complex of molecules  that holds the plus-end of the two actin filaments, but still allows for actin polymerization at the plus-end, see section \u2018The computational model\u2019 and In each actin cluster, the constituent actin filaments polymerize at their plus-ends, thereby pushing against the processive crosslinkers of the Z-band. The growing actin filaments themselves move away from the Z-band in a form of \u2018local retrograde flow\u2019. The polymerization forces exerted by the polymerizing actin filaments on the Z-band are counter-balanced by friction forces that constrain the motion of the actin filaments. Any imbalance in the number of filaments of the two orientations will result in a net polymerization force and thus net motion of the cluster. The collision of two clusters can result in their mutual coalescence and the formation of a larger cluster. If actin filaments slide past each other without any friction, all filaments would eventually coalesce into a small number of very large clusters, see The arrest of actin cluster coalescence due to our proposed inter-filament friction can be understood on qualitative grounds as follows: The active motion of a single actin cluster is driven by an imbalance of polymerization forces acting on the Z body that can arise from an imbalance between the respective numbers of the constituent filaments of the two different filament orientations. This net polymerization force is balanced by the total friction force of the actin cluster . Since this total friction is proportional to the total number of filaments in the actin cluster, whereas the net polymerization force  roughly scales only as the square root of this number, smaller actin clusters move faster than larger clusters. Furthermore, the mutual friction force between two overlapping actin clusters adds a friction term to the force balance that scales as the product of the respective filament numbers and therefore will eventually stall the approach of actin clusters above a certain size. In the more complex case of an actin bundle, the force balance for all actin clusters has to be considered. Friction between sliding actin filaments may be provided by fast, dynamic crosslinking along the entire lengths of the actin filaments by a second set of crosslinkers. Next, we discuss the possibility that myosin filaments serve as such a dynamic actin crosslinker, which mediates an effective repulsion between neighboring actin clusters.We now augment the simple actin bundle model by adding bipolar myosin filaments that can dynamically attach to actin filaments in a polarity-specific way, see To account for a distribution of actin filament lengths, we simulated bundles comprising actin filaments of different lengths. For simplicity, we chose a static polydispersity for the actin length given by a unimodular distribution of fixed mean length de novo polymerization of new actin filaments Actin filament length control and turnover of filaments both depend crucially on the polymerization and depolymerization dynamics of actin filaments. Thus, length control and filament turnover are in principle inseparable. This being said, we nonetheless aimed at isolating the qualitative effect of actin turnover. To this end, we augmented our computational model by including prototypical actin dynamics that differentiates between idealized dynamic regimes of either (i) steady-state treadmilling with constant actin filament length Our simulations suggest that sarcomere spacing is set by the length of actin filaments at early stages of striated ordering. How is actin filament length controlled within a pool of highly dynamic actin filaments? Capping proteins regulate filament polymerization and depolymerization rates. However, on their own, these proteins do not provide a means to tune the average filament length to a set point since they act locally in a manner that is not sensitive to the total length of a filament. Energetically favorable crosslinking or attraction of actin filaments all along their length can result in a unimodular length distribution as this ensures maximal mutual overlap of filaments This simple severing mechanism results in a unimodular length distribution at steady state, see Here, we proposed a simple, generic, and robust mechanism for striated pattern formation in a crosslinked bundle of aligned actin filaments. This physical mechanism of sarcomeric ordering is based on the formation of small actin clusters by the plus-end crosslinking of single actin filaments and the subsequent coalescence of these smaller actin clusters into larger ones, which are reminiscent of the I-Z-I complexes observed during early myofibrillogenesis The assembly of mature myofibrils in striated muscle cells has been proposed to be a multi-step process Experimental visualization of early sarcomeric pattern formation including actin filament length distribution, polymerization dynamics and their associated forces is technically challenging, but may be essential to test theoretical models of sarcomere formation. Little is known about the dynamics of actin filaments at early stages of sarcomeric pattern formation. In mature myofibrils, actin polymerization dynamics has been observed at both the plus- and the minus end In vitro experiments with reconstituted actin stress fibers et al., which showed that sarcomeric pattern formation was impaired in the presence of RNAi against tropomyosin and troponin Myosin filaments walk towards actin plus-ends. Unless counter-acted by other mechanisms, myosin walking would result in a wrong localization of myosin at nascent Z-bodies and thus impair sarcomeric ordering. In our model, actin treadmilling counter-acts myosin walking and transports myosin towards the future M-band, provided active myosin forces are not too strong. It has been suggested that in some species, the early establishment of sarcomeric patterning involves a non-muscle isoform of myosin II, which is later replaced by muscle-specific myosin II in silicio acto-myosin bundles. We acknowledge the possibility that the mechanism presented here is only partial and that other mechanisms also contribute to sarcomeric pattern formation that can be tested experimentally. In particular, details of our computational model can differ from the genesis of sarcomeres in developing muscle cells: Actin filament buckling as observed in reconstituted in vitro systems In conclusion, we put forward a model that includes a minimal number of generic mechanisms that results in sarcomeric polarity sorting in Text S1Supplementary (PDF)Click here for additional data file.Video S1Supplementary Video S1 shows the emergence of sarcomeric order in a simulated, one-dimensional acto-myosin bundle: Single, treadmilling actin filaments are shown in blue and red depending on the direction of their plus-end. At their plus end, actin filaments can become permanently crosslinked by a processive crosslinker that tracks actin plus ends while allowing for plus-end actin polymerization. Additionally, bipolar myosin filaments (magenta) dynamically attach to actin filaments in a polarity-specific manner, thus acting as a second set of active crosslinkers. Different vertical positions of the filaments are indicated solely for visualization purposes. Sarcomeric order in these simulated bundles can be quantified by the structure factor (AVI)Click here for additional data file."}
+{"text": "Based on long-term investigations we have concluded that IS is a compensatory response of the vertebral complex and has several strictly sequential stages:The first stage \u2013 pre-clinical. The usage of physiological kyphosis reserve (kyphosis is being transformed into lordosis).The second stage \u2013 sub-clinical. Elimination of the \u201cexcess\u201d length of osseous vertebra column owing to its torsion around relatively short medulla spinalis: frontal axis of shoulder (thoracic) girdle loses its parallelism relatively to the same axis of pelvis. \u201cOperate\u201d muscles-rotators of caudal zone.The third stage \u2013 clinical. Generated at the second stage stable shoulder (thoracic) girdle torsion is eliminated thanks to contra-lateral muscles-rotators in cranial zone and at the level where the process begins is left the most rotated vertebra that comes to be the top of the functional scoliosis. From that standpoint can be explained the well known fact of increased electro-activity of paravertebral muscles on the convex side of the scoliotic curve.The fourth stage \u2013 vicious circle. Generated at the third stage functional frontal curve disturbs vertebra column biomechanics and creates all conditions for realization of Huter-Volkman\u2019s law. The order of the following actions is evident: asymmetric pressure brings to development of vertebrae bodies wedge-shape, which sequentially, increases the frontal curve, etc. During examination of such patients the physician becomes the witness of typical IS development \u2013 tragedy, where the stage is vertebral complex.This opens up new horizons in treatment of scoliosis."}
+{"text": "Synaptobrevin II (sybII) is a key fusogenic molecule on synaptic vesicles (SVs) therefore the active maintenance of both its conformation and location in sufficient numbers on this organelle is critical in both mediating and sustaining neurotransmitter release. Recently three proteins have been identified having key roles in the presentation, trafficking and retrieval of sybII during the fusion and endocytosis of SVs. The nerve terminal protein \u03b1-synuclein catalyses sybII entry into SNARE complexes, whereas the monomeric adaptor protein AP-180 is required for sybII retrieval during SV endocytosis. Overarching these events is the tetraspan SV protein synaptophysin, which is a major sybII interaction partner on the SV. This review will evaluate recent studies to propose working models for the control of sybII traffic by synaptophysin and other Sybtraps (sybII trafficking partners) and suggest how dysfunction in sybII traffic may contribute to human disease. The regulated fusion of synaptic vesicles (SVs) on action potential invasion of central nerve terminals mediates neurotransmitter release. The subsequent retrieval and recycling of SVs after fusion is essential for the maintenance of neurotransmission. The SV is a highly organized molecular machine; therefore the mechanisms which control the sequestering of SV cargo from the plasma membrane during endocytosis are critical for generating functional organelles that are capable of responding to neuronal activity with high temporal and spatial precision. Cargo clustering and selection occurs at the plasma membrane during SV formation, via the coordinated recruitment of the classical adaptor protein complex AP-2 Synaptobrevin II (sybII) and synaptophysin are the two most abundant SV cargo proteins, with approximately 70 and 30 copies, respectively per SV Crosslinking experiments in neurons revealed that outside of the SNARE complex sybII exists in a combination of monomers and dimers In contrast to sybII, synaptophysin is a protein which until very recently had no defined function in the SV life cycle. It is a tetraspan (four transmembrane domain) SV protein, with cytoplasmic N- and C-termini. It is a glycoprotein, with glycosylation essential for its targeting to SVs on its exit from the Golgi apparatus In addition to being the two most abundant SV proteins, sybII and synaptophysin also form a complex together The functional role of the sybII\u2013synaptophysin complex has been investigated by a number of groups. It was established from an early stage that the interaction of sybII with synaptophysin was mutually exclusive to its interaction with other SNARE proteins per se.The sybII\u2013synaptophysin interaction has also been proposed to mediate targeting of sybII to SVs. Studies in either heterologous expression systems or primary neuronal culture demonstrated that the overexpression of sybII resulted in either its increased expression at the plasma membrane or mislocalization from nerve terminals The fact that synaptophysin can rescue mistargetted exogenous sybII and that it displayed an increased association with sybII following stimulation suggests that synaptophysin may participate in sybII retrieval during SV endocytosis. In agreement, synaptophysin knockout neurons in culture display a de-enrichment of endogenous sybII from their nerve terminals, and a stranding of the genetic reporter sybII-pHluorin on their plasma membrane The profound defect in sybII retrieval in synaptophysin knockout mice suggests that there could be subsidiary consequences for SV recycling. The most obvious would be a perturbation in neurotransmitter release, due to a lack of sybII on SVs. However, original studies in synaptophysin knockout mice found no obvious defects in evoked neurotransmission Ablation of sybII expression at the genomic level results in a slowing in the rate of SV endocytosis Caenorhabditis elegans, where mutants of the AP-180 homolog Unc-11 resulted in increased plasma membrane sybII SybII has no canonical endocytosis motifs to mark it for recognition and internalization via classical adaptor protein complexes such as AP-2. Instead its retrieval is mediated by the monomeric adaptor protein AP-180. This requirement was first suggested in Another recently identified sybII trafficking molecule is the SV-associated protein \u03b1-synuclein. \u03b1-Synuclein is a small nerve terminal-enriched soluble protein with an N-terminus that forms an amphipathic helix when bound to membrane Research over the past few years have therefore identified a number of proteins essential for sybII traffic. Due to their discrete and complementary function in facilitating the movement of this key molecule, we have termed them Sybtraps.The primary role of the Sybtraps is to ensure that sybII is delivered to the exact location in the correct conformation with high temporal precision. These events are likely to be pivotal in ensuring the high fidelity of neurotransmission. There is now sufficient experimental evidence from multiple independent studies to generate a working model that explains the co-ordinated trafficking of sybII by Sybtraps .trans-SNARE complexes by presenting vesicular sybII in the optimal conformation to interact with the plasma membrane SNAP-25/syntaxin1A dimer In resting nerve terminals sybII is complexed with synaptophysin on the SV. It is possible that sybII may also simultaneously bind \u03b1-synuclein, since both synaptophysin and \u03b1-synuclein interact with sybII at independent sites. However, as mentioned above, peptides encompassing the \u03b1-synuclein interaction site displace synaptophysin from sybII cis-SNARE complex in the plasma membrane is disassembled by the combined actions of NEM-sensitive factor and soluble NSF-attachment proteins cis-SNARE complexes, since these complexes are extremely stable with a very low rate of spontaneous dissociation cis-SNARE complexes, allowing t-SNAREs to remain available to receive fusogenic SV-located sybII. Although synaptophysin is displaced from sybII by t-SNARES when in SVs Following SV fusion, the cis-SNARE complexes in the plasma membrane by synaptophysin is that it should maintain monomeric sybII in a preferred conformation for recognition by the endocytosis machinery , which is implicated in Alzheimer's disease pathogenesis, interferes with the synaptophysin-sybII interaction The two most abundant proteins on the SV, sybII and synaptophysin have received divergent degrees of attention over the past 30\u2009years. The key role played by sybII in evoked neurotransmitter release has lead to the intense study of its molecular mode of action. Conversely after initial studies showing little overt phenotype in knockout mice, research into synaptophysin waned for a number of years. The discovery that synaptophysin belonged to a growing class of sybII trafficking partners, the Sybtraps, has revitalized research into its function and in doing so have revealed the critical role sybtraps perform in ensuring sybII always makes it to the correct place, at the correct time and in the correct position."}
+{"text": "The fine control of molecules mediating communication in the nervous system is key to adjusting neuronal signaling during development and in maintaining the stability of established networks in the face of altered sensory input. To prevent the culmination of pathological recurrent network excitation or debilitating periods of quiescence, adaptive alterations occur in the signaling molecules and ion channels that control membrane excitability and synaptic transmission. However, rather than encoding (and thus \u201chardwiring\u201d) modified gene copies, the nervous systems of metazoa have opted for expanding on post-transcriptional pre-mRNA splicing by altering key encoded amino acids using a conserved mechanism of A-to-I RNA editing: the enzymatic deamination of adenosine to inosine. Inosine exhibits similar base-pairing properties to guanosine with respect to tRNA codon recognition, replication by polymerases, and RNA secondary structure . In addition to recoding within the open reading frame, adenosine deamination also occurs with high frequency throughout the non-coding transcriptome, where it affects multiple aspects of RNA metabolism and gene expression. Here, we describe the recoding function of key RNA editing targets in the mammalian central nervous system and their potential to be regulated. We will then discuss how interactions of A-to-I editing with gene expression and alternative splicing could play a wider role in regulating the neuronal transcriptome. Finally, we will highlight the increasing complexity of this multifaceted control hub by summarizing new findings from high-throughput studies. A receptor ion channels modulates agonist potency and receptor gating properties to tune inhibition  is not known. Base changes via RNA editing expand on the central dogma of molecular biology by readjusting the genetic code at the RNA level in order to substitute amino acids . The relatively high inosine content of brain mRNA  is silenced by a sequence element, which is weakened either by RNA editing -specific alternative splicing factor Nova1, reduces its degradation by the proteasome thereby increasing Nova1 protein levels  required for efficient editing activity  following 5-HT2C activation might increase activity of nascent ADAR2 protein and account for some of the feedback onto 5-HT2C receptor editing (Schmauss et al., 6 in neurons are rate-limiting for ADAR2 activity. Post-translational modifications have also been shown to regulate ADAR protein function or abundance, including SUMOylation, phosphorylation-dependent propyl-isomerization and ubiquitination (Desterro et al., The mechanisms underlying editing regulation are currently unclear. These partly involve changes in ADAR levels (Balik et al., The lack of a clear signature for potential editing sites in gene sequence was limiting for the identification of new RNA editing sites (Hoopengardner et al., in vivo more routinely (J\u00e4rver et al., As the discovery of new editing sites continues, so does the need to understand their function, and regulation, in maintaining normal neurophysiology and in mediating adaptability during neuronal plasticity. It is increasingly apparent that the impact of ADARs is widespread, diverse, and under dynamic control, thus the need to dissect the functions of individual editing sites is apparent. Animal models are going some way to achieve this and their contribution to our current understanding have been reviewed (e.g., Rula and Emeson, The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The prospect of eliminating onchocerciasis from Africa by mass treatment with ivermectin has been rejuvenated following recent successes in foci in Mali, Nigeria and Senegal. Elimination prospects depend strongly on local transmission conditions and therefore on pre-control infection levels. Pre-control infection levels in Africa have been mapped largely by means of nodule palpation of adult males, a relatively crude method for detecting infection. We investigated how informative pre-control nodule prevalence data are for estimating the pre-control prevalence of microfilariae (mf) in the skin and discuss implications for assessing elimination prospects.We analyzed published data on pre-control nodule prevalence in males aged \u226520 years and mf prevalence in the population aged \u22655 years from 148 African villages. A meta-analysis was performed by means of Bayesian hierarchical multivariate logistic regression, accounting for measurement error in mf and nodule prevalence, bioclimatic zones, and other geographical variation. There was a strong positive correlation between nodule prevalence in adult males and mf prevalence in the general population. In the forest-savanna mosaic area, the pattern in nodule and mf prevalence differed significantly from that in the savanna or forest areas.We provide a tool to convert pre-control nodule prevalence in adult males to mf prevalence in the general population, allowing historical data to be interpreted in terms of elimination prospects and disease burden of onchocerciasis. Furthermore, we identified significant geographical variation in mf prevalence and nodule prevalence patterns warranting further investigation of geographical differences in transmission patterns of onchocerciasis. Onchocerca volvulus worm in the skin, which can be detected in a skin snip . Because this method is considered invasive, pre-control infection levels in Africa have been mapped mostly by means of palpation of subcutaneous nodules (protuberances under the skin where the adult worms live) in adult males, a relatively crude but non-invasive method of detecting infection. We developed a tool to derive estimates of pre-control mf prevalence from available pre-control nodule prevalence estimates. This tool can help evaluate ongoing control programs, help assess local elimination prospects, and help estimate levels of disease due to onchocerciasis by linking pre-control nodule palpation data to the large body of literature on the association between mf prevalence and disease.Until recently, elimination of onchocerciasis (river blindness) from Africa by mass treatment with ivermectin alone was deemed impossible. However, recent reports of elimination of onchocerciasis from various African foci have stimulated renewed interest. An important determinant of achieving elimination is the pre-control microfilarial (mf) prevalence, i.e. the percentage of people with larval stages of the  In 1995, the World Health Organization launched the African Programme for Onchocerciasis Control (APOC). At that time, APOC aimed to control morbidity due to onchocerciasis (river blindness) in Africa, with a focus on those countries not covered by the previous Onchocerciasis Control Programme in West Africa (OCP). Since 1995, APOC has successfully coordinated mass treatment with ivermectin in sixteen onchocerciasis-endemic African countries Onchocerca volvulus worms in a sample of 30\u201350 males aged \u226520 years in villages selected using a standardized selection procedure Pre-control infection levels are an important predictor of morbidity levels We present a statistical model describing the association between pre-control nodule prevalence in adult males and pre-control mf prevalence in the general population. Quantitative relationships for this association have been previously described, but were based on smaller number of surveys, did not provide estimates of uncertainty around parameter estimates and model predictions, and did not account for geographical variation or the relatively small sample sizes routinely used for the nodule palpation method, resulting in attenuation bias  We analyzed original data on pre-control nodule prevalence in adult males  and mf prevalence in the population aged five years and above  from 148 villages in seven geographical areas including countries in the former OCP area, and foci in Cameroon, Nigeria, and Uganda, which are part of APOC . Most ofThe association between village-level mf prevalence and nodule prevalence was quantified in a meta-analysis by means of hierarchical multivariate logistic regression, i.e. logistic regression where the predicted outcome is a set of correlated binary random variables rather than a single binary random variable. A hierarchical approach was taken to account for unmeasured sources of variation between geographical areas. A multivariate approach was taken to account for measurement error in each measure of infection. This approach prevents regression of model coefficients towards zero (attenuation bias) as we do not have to assume that there is no measurement error in the explanatory variable , an assumption inherent to univariate regression m binary outcomes:m-th binary outcome  among i-th unit (village) and the j-th cluster . The error terms m components) represent the variation (random effects) in infection levels within and between the j geographical areas, respectively. For each village there is a set of observed covariates m predicted binary outcomes there is a set of parameters m components of the error term at each level of analysis. See supplementary We extended the ordinary hierarchical logistic regression model to a multivariate model simultaneously predicting To account for measurement error due to misclassification of nodules , we added parameters to the model for specificity and sensitivity of nodule palpation, allowing these to be estimated from the data. Prior information for parameter values was based on the literature. A wide range of values is reported for specificity (60%\u201399%), based on various definitions Based on the model described above, we estimated the conditional distribution of mf prevalence in a hypothetical village outside the dataset, given an estimate of the \u2018true\u2019 nodule prevalence in adult males (i.e. corrected for misclassification of nodules). We assumed that nodule prevalence estimates were based on a sample of 30 adult males, the minimal sample size used in REMO surveys http://mcmc-jags.sourceforge.net). Simulations in JAGS were set up and analyzed in R (version 2.14.2) rjags  and R2jags . Improvements in model fit by addition of parameters were assessed via the deviance information criterion (DIC), a generalization of Akaike's information criterion for hierarchical models  The model was fitted to the data in a Bayesian framework. Posterior distributions of parameters and predictions were simulated in JAGS , and the median mf prevalence in the population aged five years and above was 74% (4%\u201399%). The median sample size for nodule prevalence in a village was 42 (range: 9\u2013181). The median sample size for mf prevalence in a village was 167 (33\u2013727).Nodule prevalence in adult males was strongly positively correlated with mf prevalence in the general population . There wer areas . After t dataset .Mixed posterior predictive checks showed that the model fitted well to the data . Only thWe investigated the association between pre-control nodule prevalence in adult males (aged \u226520 years) and pre-control mf prevalence in the general population (aged \u22655 years). Our model is the first to examine geographical variation due to bioclime and other unmeasured variables, and to take account of measurement error in nodule prevalence. Our results show that there is a strong positive correlation between nodule and mf prevalence, but also significant variation between geographical regions, which should be taken into consideration when evaluating the prospects of elimination and the burden of disease.Our analysis showed significant geographical variation in patterns of nodule and mf prevalence, though not related to bioclimatic zones according to the classic forest vs. savanna classification of onchocerciasis. In \u2018forest\u2019 areas \u2013 Leki\u00e9, Cameroon (degraded forest) and Kigoyera parish, Uganda (forest) \u2013 the patterns in nodule and mf prevalences did not differ much from the pattern in savanna areas. Yet, we found that mf prevalence levels in the general population were relatively higher in the only forest-savanna mosaic area , while nodule prevalence in adult males levels were not significantly different. There are several possible explanations for this pattern. Most likely, the pattern in Mbam is explained by a different pattern in age-dependent exposure to black flies' bites. Both mf and nodule prevalences in individuals under the age of twenty years were relatively high in Mbam compared to the other areas in Cameroon, especially in villages with relatively low nodule prevalence in adult males (data not shown). This indicates that individuals in Mbam experience relatively high exposure levels at a young age. This might be explained by the presence of dense forest in this region with relatively few narrow open spaces, which is associated with higher dispersal of flies around the breeding sites Our model could be used as a tool for assessing the prospects of elimination of onchocerciasis or the burden of onchocercal disease when pre-control nodule prevalence in adult males is the only measure of infection available (as is the case for most of Africa). With our model, an estimate of pre-control mf prevalence may be derived from pre-control nodule prevalence data. Such an estimate may be helpful for program planning, providing an indication of minimum program duration (with regard to prospects of elimination), and could be helpful in the interpretation of ongoing epidemiological parasitological surveys that rely on the skin snipping method (in terms of progress towards elimination). Prospects of elimination may be evaluated by comparing the model-derived estimate of mf prevalence to known trends of infection levels in other foci with a similar history of mass treatment, or by means of dynamic modeling of the effect of mass treatments with ivermectin using onchocerciasis transmission models such as ONCHOSIM In conclusion, we provide a tool to convert nodule prevalence in adult males to mf prevalence in the general population, which accounts for uncertainty due to measurement error and geographical variation. This tool allows interpretation of a large amount of pre-control data on levels of infection in Africa which may a) be combined with information on coverage of mass treatment to assess the feasibility of elimination of onchocerciasis and b) enable estimation of disease burden. Furthermore, we identified significant geographical variation in mf prevalence and nodule prevalence patterns that warrants further investigation of age-dependent transmission patterns of onchocerciasis.Table S1Weights used to standardize mf prevalences.(DOC)Click here for additional data file.Table S2Parameter estimates of the model, based on Bayesian hierarchical multivariate logistic regression.(DOC)Click here for additional data file.Text S1Detailed description of the statistical model, and the methods used to estimate the model parameters with an explanation of how the model should be applied to data outside the current study, and providing the code that was used to specify the model in JAGS.(PDF)Click here for additional data file."}
+{"text": "In trials of physical and talking therapies or group administered treatments, clustering of patients within care-provider or treatment group has implications for sample size and statistical analysis analogous to those found in cluster randomised trials . BetweenIn trials with treatment related clustering, the cluster size may differ systematically between treatment arms, due to differing number of therapists in each arm or differences in the size of therapy groups between arms. The intra-cluster correlation due to therapist or therapy group may also differ between treatment arms. An extreme case of such heterogeneity is the partially nested design in which the clustering effect is absent in one treatment arm. Where both cluster size and the underlying variance components differ between treatments, failure to correctly model heterogeneity can bias estimates of the intra-cluster correlation coefficient and test size . This coIn a cluster randomised trial, it is generally assumed that each subject belongs to just a single unit of randomisation so that the design is hierarchical. In non-pharmacological therapy trials patients may receive treatment from more than one therapist or in more than one therapy group so the multilevel model is no longer strictly hierarchical. Statistical analysis will therefore require simplifying assumptions regarding the pattern of clustering such as use of a primary therapist or primary group for each patient or the application of a multiple membership model .In conclusion, analysis of trials with treatment related clustering may therefore require more complex methods of analysis than cluster randomised trials."}
+{"text": "Primary small bowel bezoars are rare and cause acute abdomen due to small bowel obstruction (SBO). A 69-year-old Japanese man presented with epigastric pain associated with fullness. Physical examination of the abdomen showed no marked signs of peritoneal irritation. An erect X-ray film of the abdomen showed small bowel obstruction. Computed tomography (CT) showed a dilated small bowel loop proximal to the site of the obstruction. Retrograde double balloon enteroscopy (DBE) was performed and showed yellow, hard bezoars blocking the distal ileum. At surgery, a bezoar was found impacted in the distal ileum, and enterotomy with extraction was performed. After 9 days, the patient was discharged from our hospital in satisfactory condition. DBE also appears to be a safe and useful diagnostic tool in patients with SBO, and the findings of DBE influence the strategy of therapy in patients in whom the cause of SBO could not be determined by conventional radiography. Bezoars are an uncommon cause of small bowel obstruction (SBO) and are usually concretions of foreign material found in the stomach. They most often develop in patients who have undergone gastric surgery . BezoarsIn this case, we could diagnose small bowel obstruction due to bezoars with DBE.3 and C-reactive protein of 8.0\u2009mg/dL. Other chemistry and liver function tests were normal. An erect X-ray film of the abdomen showed small bowel gas. Contrast examination of the ileus tube showed total obstruction of the ileum with the mass  imaging has been reported to be useful for imaging patients with SBO as this modality is very effective for determining the presence or absence of SBO as well as the level and cause of SBO ; howeverIn conclusion, DBE is a feasible method for the management of bezoar-induced intestinal obstruction when performed by a well-trained and experienced surgeon."}
+{"text": "The impairment of immune functions in the elderly (immunosenescence) results in post-vaccination antibody titers that are significantly lower than in young individuals. It is, however, a controversial question whether also the quality of antibodies declines with age. In this study, we have therefore investigated the age-dependence of functional characteristics of antibody responses induced by vaccination with an inactivated flavivirus vaccine against tick-borne encephalitis (TBE). For this purpose, we quantified TBE virus-specific IgG and neutralizing antibody titers in post-vaccination sera from groups of young and elderly healthy adults and determined antibody avidities and NT/ELISA titer ratios . In contrast to the quantitative impairment of antibody production in the elderly, we found no age-related differences in the avidity and functional activity of antibodies induced by vaccination, which also appeared to be independent of the age at primary immunization. There was no correlation between antibody avidity and NT/ELISA ratios suggesting that additional factors affect the quality of polyclonal responses, independent of age. Our work indicates that healthy elderly people are able to produce antibodies in response to vaccination with similar avidity and functional activity as young individuals, albeit at lower titers. The effects of aging on the immune system \u2013 commonly termed \u2018immunosenescence\u2019 \u2013 are multifaceted and impair both innate and adaptive responses TBEV is closely related to yellow fever, dengue, West Nile and Japanese encephalitis virus Despite a strong quantitative impairment of antibody responses in healthy elderly adults our study shows that there is no significant age-dependent difference in the avidities and in the ratios of neutralizing to ELISA-binding activities  of antibodies induced by TBE vaccination. These factors were also not affected by the age at primary immunization. Surprisingly, antibody avidity did not correlate with functional activity in both young and old. This ratio, however, was highly variable from person to person and - at least to a certain extent - appears to be an imprinted individual trait, regardless of age.Two panels of serum samples obtained after vaccination with an inactivated whole-virus vaccine  were used in our study: Panel A was derived from a booster immunization study in young and old healthy adults conducted at the Institute of Biomedical Aging Research, Austrian Academy of Sciences, in Innsbruck and consisted of 79 pre- and post-booster vaccination sera used previously for determining antibody titers In both studies, participants had no clinically significant diseases, acute infections or health conditions known to affect immune responses and were not under immunosuppressive therapy The studies were approved by the ethics committees of the Medical University of Innsbruck and of the Medical University of Vienna, respectively, and the participants gave their written informed consent.TBEV-specific IgG antibodies were analyzed by ELISA using purified formalin-inactivated TBEV as described previously Neutralization tests (NTs) were carried out in baby hamster kidney cells (ATCC BHK-21) as described previously Avidities of TBEV-specific IgG antibodies were analyzed in an ELISA using purified formalin-inactivated TBEV as described previously Statistical analyses were performed with GraphPad Prism 5 (GraphPad Software Inc.). Logarithmic transformation of the data was carried out to obtain approximate normal distribution of antibody concentrations, avidity values and NT/ELISA ratios. A sample size of 17 volunteers in each group provides a power of 80%  to detect a 10% difference in avidities as well as a 20% difference in NT/ELISA ratios following the formula of Dallal for two-sided statistical tests To investigate potential age-dependent differences in the quality and functional activity of antibodies induced by vaccination, we first analyzed a serum panel from a TBE booster vaccination study conducted in young and old adults panel A,  with no Avidity is considered to be a crucial parameter of the quality and functionality of antibodies To assess a possible influence of i) the time period before booster and ii) the age at primary immunization on IgG avidities, elderly subjects (range: 51 to 87 years of age at booster vaccination) were stratified by the interval since the last TBE vaccination (\u22645 and >5years)  as well The key quality of protective antiviral antibodies is their capacity to bind to epitopes involved in virus neutralization. Infection and vaccination, however, can induce substantial amounts of antibodies that are measurable in in vitro binding assays (such as ELISA) but do not contribute to virus neutralization and protection Although age at primary immunization did not appear to influence the quality of antibody responses, we analyzed whether it had an effect on the amount of booster-induced TBEV neutralizing antibodies. As shown in We could not detect differences in the mean IgG avidities and NT/ELISA ratios between the young and elderly, but some degree of variation of both parameters was observed in both age groups  and 2. SThe strong variation of functional antibody activities (NT/ELISA ratios) observed  raised tTo determine whether such a phenomenon can already be detected after primary immunization, we analyzed a second panel of sera from a recent TBE immunization study in which the age-dependence of the immune response after primary vaccination (2 doses) and the first booster vaccination (3rd vaccination) was investigated panel B, . SimilarWith both serum panels, the correlation in the elderly was slightly stronger and \u2013 in contrast to the young \u2013 significant. Since, especially in the primary immunization study , fewer sCentral to our work was the question whether the quality of antibody responses to an inactivated whole virus vaccine is impaired in healthy elderly. The data presented demonstrate that neither the avidity of the polyclonal antibodies present in TBE post-vaccination sera nor their functional activity  displayed any statistically significant differences in healthy young and old individuals. With respect to avidities, all sera from both age groups had low avidities consistent with values characteristic of robust anamnestic immune responses In the case of TBE vaccination, this impairment was already found for the age group of 50 to 60 year old individuals In addition to quantity, however, it is the quality of antibodies that matters and high avidity binding to the pathogen is considered to be essential for antibody effector functions It is a surprising and intriguing finding of our work that there was no correlation between antibody avidity and functional activity of vaccine-induced antibodies, a trait that was characteristic for both the young and the old age groups. Considering the importance of high-avidity for antibody effector functions Although our analyses did not reveal an overall difference in the avidities and functional activities (NT/ELISA ratios) of post-vaccination antibodies in young and old, we observed a remarkable degree of individual variation of the ratios in both age groups. We interpret these findings as evidence for variations in the composition of antibody subsets as well as their specificities and functionalities between different individuals. Most interestingly, the functional quality of antibody responses appears to be imprinted individually, at least to a certain extent, since we found a positive correlation between the NT/ELISA ratios before and after booster vaccination and also between primary immunization and first booster vaccination. This suggests a tendency for maintaining a \u2018specific antibody profile established during initial priming of the immune response. We have recently shown in a related flavivirus model that certain prime-boost regimens can modulate the ratio of post-vaccination antibody specificities and increase the amount of highly functional antibodies Figure S1Mean TBEV-specific IgG units (A) and neutralizing antibody titers (B) of young (<30) and elderly (>50: range 51\u201387 years of age) TBE vaccinees. Dotted bars: values obtained before TBE booster immunization; white bars: values obtained 4 weeks after TBE booster vaccination. IgG antibodies were determined by ELISA and the functional activity by neutralization tests, using 50% virus neutralization as a cut-off (NT50). (TIF)Click here for additional data file.Figure S2Correlation of avidity and NT/ELISA ratio after TBE booster vaccination in young (A) and elderly (B) individuals. The Pearson correlation coefficients r and the P values are indicated.(TIF)Click here for additional data file."}
+{"text": "A diverse range of study designs (e.g. case-control or cohort) are used in the evaluation of adverse effects. We aimed to ascertain whether the risk estimates from meta-analyses of case-control studies differ from that of other study designs.Searches were carried out in 10 databases in addition to reference checking, contacting experts, and handsearching key journals and conference proceedings. Studies were included where a pooled relative measure of an adverse effect (odds ratio or risk ratio) from case-control studies could be directly compared with the pooled estimate for the same adverse effect arising from other types of observational studies.We included 82 meta-analyses. Pooled estimates of harm from the different study designs had 95% confidence intervals that overlapped in 78/82 instances (95%). Of the 23 cases of discrepant findings , 16 (70%) stemmed from significantly elevated pooled estimates from case-control studies. There was associated evidence of funnel plot asymmetry consistent with higher risk estimates from case-control studies. On average, cohort or cross-sectional studies yielded pooled odds ratios 0.94 (95% CI 0.88\u20131.00) times lower than that from case-control studies.Empirical evidence from this overview indicates that meta-analysis of case-control studies tend to give slightly higher estimates of harm as compared to meta-analyses of other observational studies. However it is impossible to rule out potential confounding from differences in drug dose, duration and populations when comparing between study designs. A variety of study designs  are used in the evaluation of adverse effects, and data from these diverse sources may be incorporated into subsequent systematic reviews and meta-analyses The extent of any discrepancy or heterogeneity between the pooled risk estimates from case-control studies and other study designs is a key concern for systematic reviewers. Previous research has tended to focus on differences in beneficial effects To identify studies for inclusion searches were undertaken in 10 key electronic databases to retrieve methodological papers related to any aspect of the incorporation of adverse effects into systematic reviews. These databases were carefully selected to allow the identification of reports, dissertations, and grey literature in addition to journal articles. A list of the databases and other sources searched is given in Due to the difficulty of searching for methodological papers we also undertook handsearching of selected key journals, conference proceedings and web sources, and made contact with other researchers in the field. In particular, one reviewer (SG) undertook a detailed handsearch focusing on the Cochrane Database of Systematic Reviews (CDSR), and Database of Abstracts of Reviews of Effects (DARE) to identify systematic reviews that had evaluated adverse effects as a primary outcome and had a methodological analysis embedded A meta-analysis or methodological evaluation was considered eligible for inclusion in our overview if it included case-control studies and at least one other type of observational study design  in the identification and/or quantification of an adverse effect or effects of a health-care intervention. Any healthcare intervention was deemed to be relevant including pharmaceutical interventions, diagnostic procedures, surgical interventions and medical devices. Relevant articles had to provide pooled estimates of the risk (risk ratio or odds ratio) of adverse effects according to different observational study designs.Articles were independently assessed by two reviewers for potential included studies (S.G. and Y.K.L.). Full copies of the articles which were deemed potentially relevant by either reviewer were obtained. These articles were then reassessed and consensus reached after discussion.Information was extracted on, the primary objective of the meta-analysis or methodological evaluation, included study designs, interventions and adverse effects evaluated. The number of primary studies included in the pooled analysis, number of patients by study design and the number of adverse effects observed in the treatment and control arm or comparator group were also recorded as were the type of summary statistic used in assessing differences between studies. We relied on the categorisation of study design as specified by the author of the meta-analysis or methodological evaluation. For example, if the authors stated that they looked at case-control studies and cohort studies, it was assumed that the studies were indeed case-control studies and cohort studies.The following criteria were used to consider the validity of comparing risk estimates across different study designs;Presence of other factors that may have accounted for variation in results between studies of different designsDiscrepancies between the results obtained from different study designs may arise because of confounding factors other than study design . A record was made of whether the authors of the meta-analysis or methodological evaluation reported that they had checked if the groups of different studies shared similar features in terms of population, interventions, comparators, and measurement of outcomes.Heterogeneity in the pooled estimates2 or I2). An indication of heterogeneity of each set of pooled estimates by study design was assessed using a cut-off point of P<0.10 for Chi2 test results and 50% for I2 results 2 test were given precedence A record was made of whether the authors of the meta-analysis or methodological evaluation explored heterogeneity amongst the primary studies  and checked by a second reviewer (Y.K.L.). All discrepancies were resolved after going back to the original source papers, with full consensus reached after discussion.We checked for potential discrepancy between the pooled odds ratios (OR) from meta-analyses of different study designs by (i) quantitatively and graphically comparing the ratio of the pooled odds ratios from each study design, and (ii) comparing the separate point estimates and overlap in confidence intervals. Because adverse effects are rare, ORs and RRs were treated as equivalent In order to quantitatively describe the extent of discrepancy between study designs, we calculated the ratio of odds ratios (ROR) by taking the pooled OR for the adverse outcome from one study design divided by the pooled OR for the adverse outcome from another study design. If the meta-analysis of one study design for a particular adverse effect yielded exactly the same OR as the meta-analysis of another study design , then the ROR would be 1.0 (and Ln ROR\u200a=\u200a0) The estimated RORs from each \u2018cohort vs. case-control study\u2019 comparison were then combined in a meta-analysis  and OR were calculated from the published 95% CI Funnel plots were constructed to evaluate the distribution of the ROR against estimates of precision (1/SE) We also provide a descriptive summary of the data in terms of confidence interval (CI) overlap between pooled sets of results by study design, and any differences in the direction of effect between study designs. The results were said to agree if both study designs identified a significant increase, a significant decrease or no significant difference in the adverse effects under investigation.6218 unique records were retrieved from the electronic database searches and 86 records from additional sources  . In totaA further 22 articles compared RCTs with observational studies (in some instances using the incidence of adverse effects \u2013 without reporting RR/ORs) We therefore included 29 eligible articles which contained a total of 82 meta-analyses where it was possible to compare the pooled risk estimates from case-control studies against that of cohort or cross-sectional studies. Some articles included more than one meta-analysis, usually for the same adverse effect but with slight variations in the intervention, for example with different drug dosages, exposure times or different drugs within the same class. The 82 meta-analyses included a total of 521 case-control studies, 302 cohort studies, and 38 cross-sectional studies , table 1Only one of the 29 articles was a methodological evaluation with the primary aim to assess the impact of study design Most  focused on adverse effects of pharmacological interventions  Although many of the methodological evaluations acknowledged the potential for confounding factors that might yield discrepant findings between study designs, no adjustment for confounding factors was reported in most instances 2 or I212 reviews measured the heterogeneity of at least one set of the included studies grouped by study design using statistical analysis such as ChiAuthors of four reviews explicitly tested for a difference between the results by study design using p-values The calculated differences between study designs (ROR) for each adverse effect were summarized together in a random effects model to give an average picture of the extent of discrepancy . On averOverall, the pooled ROR of 0.94 (95% CI 0.88\u20131.00) from the study design comparisons shows that on average, meta-analyses of meta-analyses of cohort and cross-sectional designs gave odds ratios that were a relative 6% lower than those from meta-analyses of case-control studies. Although the differences between study designs did not reach conventional threshold of statistical significance, the low to moderate heterogeneity seen overall is an indicator that there may be consistent pattern of variation between study designs.Visual inspection of the Funnel Plot  and resuThe confidence intervals for all the pooled results from case-control studies and cross-sectional studies overlapped, and almost all the confidence intervals (CIs) for the pooled results from case-control studies and cohort studies overlapped  .In most of the reviews the results of the adverse effects estimates agreed between types of study design The tendency for case-control studies to show greater degree of harm is illustrated by the 16 adverse effects where meta-analyses of case-control studies found significantly elevated risk, but meta-analyses of cohort or cross-sectional studies did not confirm this risk. Conversely, there were 7 adverse effects where meta-analyses of cohort or cross-sectional studies demonstrated significantly elevated risk, but meta-analyses of case-control studies did not show significant risk.There was one major discrepancy in one pooled sets of results. Grady et al 1995 There are no adverse effects where two or more separate meta-analyses have used exactly the same primary studies, (i.e. had complete overlap of case-control and cohort studies) to generate the pooled estimates. This reflects the different time periods, varying search strategies and inclusion and exclusion criteria that have been used by authors of these meta-analyses such that even though they were looking at the same adverse effect, they used data from different studies in generating pooled overall estimates.There were three adverse effects that were evaluated in more than one review; venous thromboembolism (VTE), gastrointestinal complications and stroke. In the few instances where adverse effects were described in more than one review, sensitivity analysis limiting it to one review per adverse effect showed similar ROR .We found that on average, meta-analysis of case-control studies tended to give slightly higher estimates of harm as compared to cohort or cross-sectional studies. This finding was reflected in the asymmetrical shape of the funnel plot showing that the direction of the discrepancies (as estimated by the RORs) were more frequently due to relatively higher estimates of harm from case-control studies. Alternatively, this could be interpreted as cohort studies being more susceptible to underestimating the extent of harm. This is illustrated by our finding of 16 adverse effects where case-control studies showed significant harm but cohorts and case-controls did not. Conversely there were seven adverse effects where the opposite was true, with case-control studies showing no increase in risk, whereas the other observational designs found significant likelihood of harm. Given that observational study designs are important data sources on rare adverse effects, we recommend that readers of medical journals, as well as systematic reviewers should evaluate consistency of findings across a broad range of study designs when considering rare harms.An explanation for the tendency for slightly higher estimates of harm from case-control studies is difficult to ascertain. However, there are a number of possible reasons. Firstly, this could be a spurious result as the values for the ROR do not reach statistical significance. Nevertheless, the asymmetrical funnel plot does demonstrate a fairly consistent discrepancy between cohort studies compared to case-control studies. One important factor here may stem from the potentially greater ability of case-control studies to enrol sufficient numbers of patients who are known to have experienced a rare adverse event, thus yielding more statistical power to detect small, but significant risk of harm Equally, discrepancies between study designs could have stemmed from confounding as a result of variation in characteristics of participants, timing and site of study, and definitions of exposure and outcomes. For instance, if one set of studies are carried out on a younger cohort of patients, with a lower drug dosage, or with shorter duration of use, or relied on passive ascertainment of adverse effects data Finally, differences in observed and unobserved patient characteristics may have accounted for discrepancies between designs. The extent of statistical adjustment for potential confounders in observational studies depends somewhat on which variables were measured in the primary dataset. Given the different starting points in data collection between case-control and cohort studies, the effect of unmeasured confounders may afflict either design to dissimilar extents.Our previous work showed that meta-analyses of RCTs versus cohort studies showed little discrepancy ROR 1.02 (95% CI 0.82\u20131.28) whereas meta-analyses of RCTs versus case-controls showed a greater discrepancy with a ROR of 0.84 (95% CI 0.57\u20131.23), thus indicating that case-control studies give higher estimates of harm when compared to RCTs. Given that cohort studies showed similar risk of harm compared to RCTs, it can be indirectly inferred that case-control studies also provide a higher risk of harm when compared to cohorts. Our current analysis would be entirely consistent with the previous findings.Our overview was constrained by information and data contained in the included evaluations as it was not straightforward to source and evaluate the >850 primary studies contained in the meta-analyses. In each instance the authors\u2019 categorisation of the study design was used. However, we note that most of the included reviews had passed DARE criteria or were from peer-reviewed sources i.e. both the primary study and the systematic review had undergone peer-review. Moreover, any misclassification is likely to be non-differential in impact, which should not lead to elevated risk estimates from any particular study designs.Another important limitation to this review is the potentially unrepresentative sample used. Systematic reviews with embedded data comparing different study designs may have been missed. The search strategy used was limited to a literature search to identify methodological papers whose primary aim was to assess the influence of study design and to a sift of systematic reviews of adverse effects identified from the Cochrane Database of Systematic Reviews (CDSR) and Database of Abstracts of Reviews of Effects (DARE). Nevertheless, it should be noted that the CDSR and DARE databases cover a large proportion of all systematic reviews and that systematic reviews in which adverse effects are included as a secondary aim are unlikely to present subgroup analysis by study design for the adverse effects data.There was considerable heterogeneity between the comparisons of different studies, suggesting that any differences could be specific to particular types of interventions or adverse effects. It may be that particular types of adverse effects can be identified more easily via particular types of study designs 85 have already looked at methods of signal generation for detecting new adverse events in 10 observational databases, and extending this approach to signal refinement or hypothesis testing should clearly be feasible.In the light of our findings, we believe that regulatory authorities, as well as interested patients and physicians, who appraise articles on adverse effects, should look carefully at the study designs involved, and be aware of potential differences in whether the particular design may tend to provide relatively higher or lower estimates on risk of harm. The differences between study designs are most apparent when the meta-analysis only has a few studies, thus suggesting that we should be particularly cautious in trusting single studies of rare harms. Further research should evaluate the impact of different study designs across a wide range of adverse effects in multiple databases. As an example, Ryan et al 2012Our overview also has important implications for the conduct of systematic reviews of harm, particularly with regards to selection of a broad range of relevant studies. Although there are strengths and weaknesses to each study design, empirical evidence from this overview indicates that there are slight differences (on average) between estimates on the risk of adverse effects obtained from meta-analyses of different observational study designs. Instead of restricting the adverse effects analysis to certain study designs , it seems preferable for systematic reviewers to evaluate a broad range of studies that can help build a complete picture of any potential harm and improve the generalisability of the review without loss of validity.Appendix S1Search strategy and Data Sources.(DOCX)Click here for additional data file.Appendix S2Characteristics of Included Studies.(DOCX)Click here for additional data file.Appendix S3Excluded Studies and Reasons for Exclusion.(DOCX)Click here for additional data file.Appendix S4Selection of outcomes and handling of duplicate data.(DOCX)Click here for additional data file.Appendix S5Forest Plot: meta-analysis of RORs from cohort/cross-sectional studies versus case-control studies.(DOCX)Click here for additional data file.Appendix S6Funnel plot of distribution of RORs from (i) meta-analyses of cohort studies compared to case-control studies (ii) meta-analyses of cross-sectional studies compared to case-control studies.(DOCX)Click here for additional data file.Appendix S7Sensitivity analysis based on exclusion of meta-analyses covering the same adverse effect where there is some overlap in the included primary studies.(DOCX)Click here for additional data file."}
+{"text": "Classical physiology teaches that vagal post-ganglionic nerves modulate the heart via acetylcholine acting at muscarinic receptors, whilst it is accepted that vagus nerve stimulation (VNS) slows heart rate, atrioventricular conduction and decreases atrial contraction; there is continued controversy as to whether the vagus has any significant direct effect on ventricular performance. Despite this, there is a significant body of evidence from experimental and clinical studies, demonstrating that the vagus nerve has an anti-arrhythmic action, protecting against induced and spontaneously occurring ventricular arrhythmias. Over 100\u00a0years ago Einbrodt first demonstrated that direct cervical VNS significantly increased the threshold for experimentally induced ventricular fibrillation. A large body of evidence has subsequently been collected supporting the existence of an anti-arrhythmic effect of the vagus on the ventricle. The development of prognostic indicators of heart rate variability and baroreceptor reflex sensitivity\u2014measures of parasympathetic tone and reflex activation respectively\u2014and the more recent interest in chronic VNS therapy are a direct consequence of the earlier experimental studies. Despite this, mechanisms underlying the anti-arrhythmic actions of the vagus nerve have not been fully characterised and are not well understood. This review summarises historical and recently published data to highlight the importance of this powerful endogenous protective phenomenon. Sudden cardiac death (SCD) resulting from malignant ventricular arrhythmias including ventricular tachycardia (VT) and ventricular fibrillation (VF) represents a significant unsolved clinical problem with an annual death toll of over 325 000 people in the USA (Heart Rhythm Foundation ) and aroThere is strong evidence that the relationship between impaired neurocardiological control and increased mortality is the result of an increased vulnerability to lethal ventricular arrhythmias . Whilst There is a strong correlation between survival and \u2018markers\u2019 of parasympathetic tone in patients with HF irrespective of \u03b2-blocker therapy \u201313 or foSeveral small- and large-scale clinical trials have demonstrated the predictive value of BRS and HRV in patient populations. An early prospective clinical study reported that a low BRS was significantly associated with greater all-cause mortality , and a sThe dogma of physiology teaching states that vagal post-ganglionic nerves modulate the heart through acetylcholine (ACh) acting on muscarinic receptors (mAChRs) to slow heart rate, increase atrioventricular conduction and inhibit atrial force, with little influence on ventricular performance. The latter reflects historical reports that ventricular parasympathetic (cholinergic) innervation was sparse. This view is, however, outdated because modern histological techniques reveal a dense and intricate network of ACh containing nerves running over the epi- and endo-cardial surfaces of left and right ventricles and a widespread distribution of mAChRs throughout the ventricle . More imThe somata of the parasympathetic efferent pre-ganglionic neurones arise chiefly from the ventral lateral region of the nucleus ambiguous, and a smaller proportion from the dorsal motor nucleus and intermediate zone between these sites . Pre-ganheart brain, reviewed by Armour [There is a complex network of neuronal subtypes within the ganglionated plexuses which can modulate the heart on a beat-by-beat basis that can act independent of peripheral input . The roly Armour , is an ey Armour  and thaty Armour .1\u2013M5) have been described, and 3 subtypes are found within the heart  [2 receptor and is found on cardiomyocytes [2 receptor subtype is predominantly responsible for regulating cardiac function [i-protein mediated direct action on ACh-dependent ion channels such as IKAch and indirect effects on inhibition of adenylate cyclase activity that reduces intracellular cAMP. cAMP is known to stimulate the non-selective cationic current (If) which drives spontaneous depolarisation of pacemaker tissues such as the sinoatrial and atrioventricular nodes and purkinje fibres. The activation of the IKACh results in membrane hyperpolarisation, increasing the cells threshold for firing which contribute to heart rate reduction. M3 and M4 ACh receptors are [Post-ganglionic vagal fibres are primarily cholinergic in nature releasing ACh which act on mAChRs. Five distinct mAChRs subtypes (M and M4) \u201346. The myocytes  and withmyocytes . Evidencfunction  through tors are . It is tTable\u00a0The first report that VNS reduced the susceptibility of the ventricle to experimental arrhythmia was presented by Einbrodt in 1859 , who demA number of studies have shown that VNS prevents arrhythmias as a result of CAO. Myers et al.  investigAn elegant canine model of SCD developed by Peter Schwartz and colleagues has been used extensively to study the protective effect of the vagus in conscious animals aimed at circumventing the confounding influence of anaesthetics , 59, 60.direct anti-arrhythmic effect which is separate from the indirect action concerning antagonism of adrenergic effects (accentuated antagonism), which is evident from single cells studies using pharmacology investigating the effects on individual ionic currents from heart failure preparations [The onset of VF is believed to be associated with the break-up of spiral waves or rotors into multiple wavelets and oscillations in electrical activity . One mecarations .Fig.\u00a02Audirect effects of VNS are not possible. VFT provides a quantifiable and robust measure of arrhythmia susceptibility, allowing that the examination of how physiological, pathophysiological and pharmacological factors can affect electrical stability in addition to effects from nerve stimulation. VFT is widely used for the study of arrhythmia susceptibility and has been shown to predict the increased and decreased susceptibility of the ventricle to arrhythmias in a range of situations [The use of \u2018spontaneous\u2019 and induced methods of arrhythmia occurrence is a contentious issue that warrants discussion. CAO represents one of the most common methodologies to generate arrhythmias which rely on spontaneous arrhythmia generation. Studies utilising CAO often use quantitative measures of arrhythmic events, that is, number of premature ventricular contractions (PVCs), VT and VF or the time course of these events. A disadvantage of this approach is the stochastic nature of arrhythmic event occurrence. The development of the canine model of SCD addressed many of the issues of reproducibility . Howevertuations , 66, 70.tuations . Howevertuations  have demtuations , 56.Data on the use of vagal stimulation in the treatment for arrhythmia secondary to HF are somewhat limited despite the fact that ventricular arrhythmias are responsible for a large proportion of SCDs and that arrhythmic disturbance, that is, ectopic beats or runs of non-sustained ventricular tachycardia, occurs in 50\u201380\u00a0% of all HF patients , 74. TheIn addition to its anti-arrhythmic properties, chronic VNS has been shown to reverse the contractile dysfunction and adverse remodelling associated with experimental HF \u201384 and aVagal stimulation modulates ventricular arrhythmias by a number of direct and indirect actions including activation of muscarinic receptors, antagonism of sympathetic actions, heart rate reduction, prolonged APD and reduced APD dispersion, effects on restitution/refractoriness, and possibly via nitric oxide (NO). Several theories describe how alterations in cardiac electrophysiological parameters may influence the generation and propagation of ventricular arrhythmias. Table\u00a0Interaction between the sympathetic and parasympathetic branches of the autonomic nervous system is complex. Competitive antagonism between autonomic divisions provides an important site of regulation. Samaan  first il3) and M2 receptors on cardiomyocytes to inhibit noradrenaline (NA) release and/or accumulation of intracellular cAMP, respectively [Interaction between the sympathetic and vagal systems occurs via pre- and/or post-junctional mechanisms. ACh binds to mAChRs, on the pre-synaptic sympathetic nerve terminals  versus ventricular (decreased) [3 receptors reduces the occurrence of ischaemia-, aconitine- and ouabain-induced ventricular arrhythmias [3 mAChR gene reduces the occurrence of spontaneous arrhythmias in a mouse model of ischaemia reperfusion [3 receptor in regulating cardiac repolarisation and cell-to-cell communication is particularly relevant to the discussion of ventricular arrhythmia susceptibility. The M3 receptor activation can stimulate the potassium channel IKM3 [3 activation reduces calcium overload in ventricular myocytes, and it has been proposed that this action mediates its protective action in ischaemia-induced arrhythmias [3 receptor appears to regulate the expression of phosphorylated connexin-43 (Cx43), a gap junction channel protein highly expressed in ventricular tissue and reduced in ischaemia and HF. Efferent vagal nerve stimulation may protect the heart form ischaemia-induced arrhythmias by preventing a reduction of phosphorylated Cx43 associated with ischaemia [Since the discovery of a functional Ml et al. , there hcreased) . Pharmachythmias . Furthererfusion . The rolnel IKM3 , which hnel IKM3 . Studieshythmias . In addischaemia . Similarschaemia .3 activation oppose those of the M2 receptor, to enhance contractility and increase heart rate [3 receptor promotes arrhythmias in atrial tissues but suppresses ventricular arrhythmias (a likely result of opposing effects on repolarisation time course), which may indicate difference in the distribution of the mAChRs throughout the myocardium or regional variations in ion channel expression . Importantly, the expression of M3 appears to be increased in hearts from patients with congestive heart failure [3 receptor, its contributions to the action of the vagus nerve remain to be elucidated.Evidence from studies in gene knockout mice suggests that the effects of Mart rate . It is r failure . Whilst f), [An obvious consideration when stimulating the vagus nerve is the resulting bradycardia. Some studies suggest that the anti-arrhythmic influence of the vagus nerve is reduced but not abolished when the heart rate is controlled , 56, 58.f),  though if), .A common finding of clinical trials on HF is a negative correlation between heart rate and patient survival and the ability to increase heart rate in response to exercise . The relThe relative importance of bradycardia as a protective mechanism is unclear and contrasts with our findings that the effects of VNS are preserved during constant ventricular pacing. VNS still has a profound effect on ventricular electrophysiology during constant pacing, reducing susceptibility to VF . StudiesAnother important concept in the generation of ventricular arrhythmias is that of action potential duration dispersion. Spatial repolarisation heterogeneity provides a substrate for the generation of ventricular arrhythmias, and dispersion of APD is a known mechanism underlying circus movement re-entry around refractory regions . AlthougThe biosynthesis and multitude of biological functions of nitric oxide (NO) have been reviewed extensively elsewhere \u2013127. OurIt is widely accepted that NO is involved in both central and peripheral aspects of vagal control, not only in terms of cardiac function but also in other bodily systems such as the GI tract . In the l-Arginine, the NO substrate which competes with L-NA for binding to NOS. This anti-arrhythmic effect of NO is supported by the work of Kumar et al. [After confirming the anti-VF effect of VNS together with an increase in ERP and reduction in the slope of the restitution curve, we perfused the innervated heart preparation with the non-specific nitric oxide synthase (NOS) inhibitor L-NA and investigated the effects of VNS. In the presence of L-NA, the increase in VFT and flattening of electrical restitution slope with VNS were abolished whilst the increase in ERP was preserved  see Fig. The resr et al. , who demr et al. . These dAlthough the aforementioned study provides basis for a working hypothesis for NO in mediating the ventricular effects of the vagus, it provided only indirect evidence of this mechanism. Through the use of the NO-sensitive dye DAF-2 DA, we were able to provide direct evidence of VNS-mediated NO release . NO-depeMore recently, we have extended these findings to show that these effects of the vagus do not occur through activation of mAChR\u2019s since perfusion with atropine at a concentration sufficient to block changes in heart rate and ERP did not influence the vagal effect on DAF-2 fluorescence, the reduction of the slope of the electrical restitution curve or increase in VFT . In addiIt has previously been suggested that vagally released ACh and NO can act through parallel independent signalling pathways . Given oNOS expression is found in endothelial cells, myocytes and neuronal cells, and it regulates a huge range of biological functions in a manner which appears to be dependent upon location \u2013127. TheIt is recognised that direct neurochemical stimulation of decentralised intrinsic cardiac neurones can generate atrial and ventricular arrhythmias  and thatSensory (or afferent) nerve fibres relay information from the myocardium to the brain for processing, and approximately 70 and 80\u00a0% of the vagus nerve consists of these afferent fibres. Therefore, electrical stimulation of the vagus may capture both afferent and the effector efferent nerves, unless selective stimulation protocols, such as anodal block, are used to exclude a specific population of neurones. The contribution of these distinct populations of nerves to the anti-arrhythmic benefits of VNS is currently unknown. Studies conducted in our laboratory with the innervated rabbit heart show that the protective effect of VNS is not dependent upon the brain, but these experiments do not exclude the existence of additional anti-arrhythmic mechanisms in vivo or afferent reflex responses which can occur locally . An earlAnother mechanism by which the parasympathetic nervous system may protect the heart is via an anti-inflammatory action. It has become increasingly evident over the two decades that inflammatory responses can be modulated and feedback into the autonomic nervous system, the so-called inflammatory reflex . LocallyThe role of inflammation in the generation of arrhythmias in HF and following ischaemic injury is not clear, but it is recognised that malignant arrhythmias are more likely in patients with acute and chronic myocarditis , 145. CyThe profound anti-arrhythmic influence of the vagus nerve has provided modern clinical practice with valuable tools for assessing risk in the form of HRV and BRS, and chronic VNS may prove to be a powerful therapy for heart failure. The effects of the vagus nerve on ventricular arrhythmogenesis are multi-faceted involving effects on heart rate, interactions with the sympathetic nervous system, anti-inflammatory influences and a direct effect on ventricular electrophysiology. Our data indicate that the vagus nerve exerts a direct anti-arrhythmic action at the level of the ventricles through the release of NO\u2014a tentative-independent nitrergic neural network regulating cardiac physiology which could potentially offer a novel therapeutic avenue."}
+{"text": "Recently, the RNActive technology has been developed to generate highly active cancer vaccines. The antigen of choice is encoded by a sequence engineered mRNA that increases antigen expression up to 5 orders of magnitude. Immunogenicity of the RNActive vaccines is ensured by a built-in adjuvant function based on complexation of half of the mRNA with protamine that leads to activation of toll-like receptor 7 (TLR7). 5 intradermal administrations of a mRNA vaccine encoding PSA, PSCA, PSMA, and STEAP (CV9103) were tested in phase I/IIa studies in 44 patients with castrate-resistant prostate carcinoma (PCA). The vaccine was well tolerated and induced antigen-specific immunogenicity assessed by ex-vivo assays against all encoded antigens independent of the HLA-profile of patients. The overall immune response rate in evaluable patients was 80 %, close to 60% of these reacted against multiple antigens. In the subgroup of 36 patients with metastatic CRPC a median overall survival of over 30 months was estimated whereas the predicted survival according to the Halabi nomogram was 16.5 months. Patients responding to at least one tumor antigen had a reduced risk to die during the observation period compared to immunological non-responders, although the Halabi-predicted survival of both groups was similar. Responses against multiple antigens seemed to correlate even more strongly with improved survival, with patients reacting against 3 antigens s showing the longest survival. The results of this clinical study demonstrated high immunogenicity paired with a good safety profile for this new prostate cancer vaccine. The apparent correlation of immunogenicity with prolonged survival despite unfavorable patient characteristics according to the Halabi-score suggests a therapeutic effect. CV9104, an advancement of CV9103 encoding two more antigens is currently tested in a randomized, placebo-controlled phase IIb trial with overall survival as primary endpoint. It appears that mRNA based vaccines offer an ideal basis to exploit the potential of nucleotide based cancer vaccines for the benefit of patients. Precise data will be presented at the meeting."}
+{"text": "Anatomic study related to the anterior cruciate ligament (ACL) reconstruction surgery has been developed in accordance with the progress of imaging technology. Advances in imaging techniques, especially the move from two-dimensional (2D) to three-dimensional (3D) image analysis, substantially contribute to anatomic understanding and its application to advanced ACL reconstruction surgery. This paper introduces previous research about image analysis of the ACL anatomy and its application to ACL reconstruction surgery. Crucial bony landmarks for the accurate placement of the ACL graft can be identified by 3D imaging technique. Additionally, 3D-CT analysis of the ACL insertion site anatomy provides better and more consistent evaluation than conventional \u201cclock-face\u201d reference and roentgenologic quadrant method. Since the human anatomy has a complex three-dimensional structure, further anatomic research using three-dimensional imaging analysis and its clinical application by navigation system or other technologies is warranted for the improvement of the ACL reconstruction. Recent progress of the anterior cruciate ligament (ACL) reconstruction procedure and related research largely stems from the increased attention to the restoration of the original anatomy. An accurate evaluation of the native anatomy is critical for achieving anatomic ACL reconstruction. Clinical outcome could be imperfect when the graft placement is not located at an anatomic position , 2. AlsoThe purpose of this paper is to introduce the progression of imaging technology into three-dimensional analysis on various fields of research related to the ACL and to suggest the future direction of ACL-related anatomic studies.Anatomic research investigating the native ACL location has been developed over the last several decades. In 1975, Girgis et al.  investigAs anatomic double bundle ACL reconstruction was introduced in the 2000s, meticulous investigations of bony landmarks were conducted to identify useful landmarks which are available under arthroscopy and can be used for precise graft placements. Three-dimensional 3D) CT images contributed to this decade's progress of anatomic research. Purnell et al.  demonstrD CT imagThe progress of CT imaging technique from two- to three-dimensional has contributed significantly to the anatomic research of the ACL. Similar progress is still warranted for MRI because of its capacity to evaluate soft-tissue structures.Femoral intercondylar notch width has been often discussed as a risk factor for the ACL injury, but it remains unknown if the narrow notch truly leads to ACL injury. Several studies evaluating intercondylar notch width by X-ray or CT reported narrow notch as a risk factor for the ACL injury \u201352. HousThe development of 3D imaging techniques and increased attention to the anatomic procedure are accompanied with the advanced technology of computers and robots, leading to strong motivation for computer-assisted surgery which could provide real-time imaging feedback with the individualized anatomic information to the surgeons during ACL reconstruction.In the early 1980s, computer-assisted ACL reconstruction was first attempted by the technique using stereotaxic frame of CT scan for brain surgery . HoweverNavigation systems can be divided into image-guided  and imagNavigation systems can provide real-time quantitative feedback during arthroscopic procedure and minimize technical error with enhanced reproducibility and reliability , 66. HowResearch on the anatomy of to the ACL has progressed along with the advancement of imaging and navigation technology. Useful bony landmarks for placing the ACL graft at the ideal position can be identified by 3D imaging technique. Also, 3D-CT analysis for the location of the native and reconstructed ACL provides better and more consistent evaluation than conventional \u201cclock-face\u201d reference and roentgenologic quadrant method. Three-dimensional image analysis of the ACL anatomy and its application to the navigation system is becoming more prevalent and reliable for advancing the anatomic studies related to the native ACL and the ACL reconstruction procedure."}
+{"text": "Functional connectivity between brain regions during swallowing tasks is still not well understood. Understanding these complex interactions is of great interest from both a scientific and a clinical perspective. In this study, functional magnetic resonance imaging (fMRI) was utilized to study brain functional networks during voluntary saliva swallowing in twenty-two adult healthy subjects (all females,  Dysphagia  may arise from the entry of foreign matter into respiratory pathways The human brain is considered to be a large-scale robust and interactive biological system with non-trivial topological properties Previous studies on graph theory suggested the possibility of performing network analysis on the human brain Recent neuroimaging studies have consistently demonstrated evidence that swallowing is associated with activation in multiple regions of the human brain The goal of this study is to use graph-theoretic approaches to examine the interaction between brain regions during voluntary saliva swallowing in healthy young adults and compare network properties between and within subjects. To be specific, we aim to determine inter- and intra- hemispherical connections during swallowing tasks. Furthermore, differences between the whole-brain network and various regions of interest (ROIs) on computed network measures will be studied.Twenty-two healthy young-adult subjects, all females  images were acquired using an echo planar imaging sequence in 36 axial slices  software Specifically, the fMRI scans for each subject were first adjusted for time delay between different scans. Second, for each subject the images were realigned to the first slices among all slices using a least squares fitting algorithm and a 6 parameter rigid body transformation After removing the movement interference in fMRI images, the fMRI images further underwent the coregistration step during which the mean fMRI scans were overlayed on a high resolution anatomical image to maximize the mutual information. Therefore, all other functional images were resliced to align with the reference image.Then, to make inter-individual comparisons, normalization was then performed to warp the images to fit a standard MNI  template. Finally, smoothing was applied with Gaussian kernel with a 4-mm full-width at half maximum to suppress noise and effects due to residual differences The choice of nodes and links greatly influences the results of network connectivity analysis Graphs are sets of nodes and links. Nodes are the most basic element in functional network analysis. Links can be used as undirected paths, meaning that it can go both directions. Links can also be directed, meaning a node can traverse the network either forward or backward but never reverse direction Using a graph-theoretical definition, a network is a collection of sets of nodes and links, where a node is considered as the most essential element of the network For binary undirected networks, we use The node degree describes the number of direct connections a node has with the rest of the nodes in the network. The node degree is considered to be the most fundamental network measure. It is also a foundation for most of the network measures in this study. The summation of all the node degrees in a set in the network derives a degree distribution The degree The clustering coefficient The shortest path length The global efficiency of a network, In comparison to the mean path length , the gloFor binary networks, the local efficiency of the Small-world measurements e.g.,  involve A high clustering coefficient and a short characteristic path length suggests the network is described by optimal small-world attributes In addition to small-world attributes, the hierarchy was used to characterize topological properties of the human brain Functional connectivity networks share various significant common ground with anatomical and structural connectivity networks Partial correlation could measure the inter-regional functional connectivity by attenuating the contribution of other sources of covariance The individual partial correlation matrices were thresholded to ensure that each node in the network is not too densely clustered, nor too sparsely connected. In other words, thresholding was used in the study to eliminate the links that were likely to attenuate the effect of important connections To understand the small-world properties of the obtained networks, the value of In our study, we examined hierarchy values derived from both whole-brain functional networks and also swallowing related regions. These two connectivity matrices were constructed by thresholding the correlation matrix such that each node in the resulting network generally had 48 connections. The threshold values ranged from 0 to 1, with an increment of 0.05. In order to calculate hierarchy, the clustering coefficient In our analysis, we compared the network measures calculated for the whole brain and for the previously identified regions activated during swallowing e.g., , which aIn this study, we used an open source Brain Connectivity Toolbox (BCT) To distinguish the difference between swallowing related regions to whole brain metrics we used the non-parametric Mann-Whitney Wilcoxon rank-sum test Binary and weighted functional networks were created for all subjects using the outlined approach. These functional networks were sensitive to threshold values as shown in Our study demonstrated the brain functional networks are characterized by small-world attributes. First of all, the mean network clustering coefficient As we can see in We believe that our study is the first one to use novel graph theoretical approaches to report brain functional connectivity during voluntary saliva swallowing. By utilizing the graph theoretical approaches, we are able to study the alteration of functional connectivity at both the global scale as well as the divisional scale.Our results highlighted that the spatial topological connectivity in swallowing related regions are significantly distinguished compared to whole-brain properties, as can be reflected on various network measurement parameters. Furthermore, our results reported the advantage of applying functional connectivity analysis rather than anatomical connectivity analysis, which is the importance of bilaterally symmetric inter-hemispheric connections. This finding from functional connectivity during swallowing tasks has not been clearly demonstrated by previous studies using anatomical connectivity approaches.Network measures for weighted networks in this study consisted of characteristic path length  Swallowing regions and the whole-brain metrics showed a similar node degree distribution and optimal small-world properties. (2) Swallowing-related areas had distinct inter-regional connectivity patterns. (3) The network properties of large-scale brain connectivity differs significantly between swallowing-related areas and the whole brain. Collectively, these and other findings reported in this study provided new insights into how graph-theoretical approaches can be utilized to describe the brain functional network during swallowing and thus provided new clues for understanding the mechanism of swallowing."}
+{"text": "Drosophila genomes. We illustrate the use of these resources to address three types of evolutionary genomics questions: about fluxes in amino acid composition in proteins, about asymmetries in amino acid substitutions and about patterns of molecular evolution in duplicated genes.Harnessing vast amounts of genomic data in phylogenetic context stemming from massive sequencing of multiple closely related genomes requires new tools and approaches. We present a tool for the genome-wide analysis of frequencies and patterns of amino acid substitutions in multiple alignments of genes\u2019 coding regions, and a database of amino acid substitutions in the phylogeny of 12 Drosophila proteins underwent a significant shift over the last 70 million years encompassed by the studied phylogeny, with less common amino acids  increasing in frequency and more common ones  becoming less frequent. These fluxes are strongly correlated with polarity of source and destination amino acids, resulting in overall systematic decrease of mean polarity of amino acids found in Drosophila proteins. Frequency and radicality of amino acid substitutions are higher in paralogs than in orthologous single-copy genes and are higher in gene families with paralogs than in gene families without surviving duplications. Rate and radicality of substitutions, as expected, are negatively correlated with overall level and uniformity of gene expression. However, these correlations are not observed for substitutions occurring in duplicated genes, indicating a different selective constraint on the evolution of paralogous sequences. Clades resulting from duplications show a marked asymmetry in rate and radicality of amino acid substitutions, possibly a signal of widespread neofunctionalization. These patterns differ among protein families of different functionality, with genes coding for RNA-binding proteins differing from most other functional groups in terms of amino acid substitution patterns in duplicated and single-copy genes.We demonstrate that amino acid composition of We demonstrate that deep phylogenetic analysis of amino acid substitutions can reveal interesting genome-wide patterns. Amino acid composition of drosophilid proteins is shaped by fluxes similar to those previously observed in prokaryotic, yeast and mammalian genomes, indicating globally present patterns. Increased frequency and radicality of amino acid substitutions in duplicated genes and the presence of asymmetry of these parameters between paralogous clades indicate widespread neofunctionalization among paralogs as the mechanism of duplication retention. Drosophila genomes and illustrate its utility by the analysis of the resulting database of amino acid substitutions spanning 70 million years of drosophilid proteins evolution.Until recently, evolutionary genomics questions, including questions about amino acid composition of proteins, patterns of stabilising and positive selection and mechanisms of retention of duplicated genes and new function evolution, were typically answered either by analyzing phylogenies of select gene families ,2 or by Global patterns of amino acid compositions of proteins is thought to not be at a detailed balance, but rather appears to be gradually evolving by consistently adding rare to and removing common amino acids from the amino acid repertoire of protein sequences ,5. ThereDrosophila genomes  detecteThe main purpose of AcidMiner is to extract amino acid substitutions data from multiple alignments and to expand them in the form of relational tables so then standard SQL can be used to perform queries by any combination of criteria and to calculate aggregates. AcidMiner takes raw data in the form of multiple alignments and Newick protein and species trees, processes it to produce derivative data such as parsimony-based polarization of substitutions and stores the result in a relational database structure. The raw data for the analysis reported here was a set of multiple amino acids alignments from 12 completely sequenced Drosophila genomes  and a Duplications table, which includes phylogenetic information about each duplication and the two clades generated it. The database is available for download from AcidMiner website  in the fD. persimulans/D. pseudoobscura), while arginine, a weak loser in the whole phylogeny shows a strong net gain in the shallow branches.Figure Contrary to the prediction based on the effect of intraspecific polymorphism ,9, the oPair-wise asymmetry of amino acid gains and losses had a clear manifestation in terms of average change in amino acid polarity. Amino acid pairs with the largest polarity gain had the highest asymmetry towards net gain of the less polar amino acid Fig. . The degDuplicated genes appeared to accumulate more amino acid changes since duplication (per unit of time measured in units of synonymous substitutions per 4-fold degenerative site) than single copy genes Fig. . AlthougParalogs also evolved by more radical substitutions. Across functional groups of proteins (with the exception of transporter proteins) duplicated portions of phylogenies accumulated amino acid substitutions with greater average absolute change in polarity Fig. , while sAs expected, substitution rates and radicalilty decreased with mean expression rate in the whole fly and increased with the coefficient of variance of expression rate across larval and adult tissues  Fig. 5)5), corroTable Clade asymmetries by molecular function categories are presented on Fig. Several caveats in the data and analysis require attention. Firstly, alignments we used may contain pairs of paralogs, in which one of the copies is undergoing pseudogenization and is nor longer expressed, but has not yet acquired a frameshift, which would allow it to be recognized as a pseudogene. Indeed, there is a significant excess of nonsense mutations (per missense) present in the terminal branches of phylogeny (data not presented), indicating presence of pseudogenes in the alignments. Pairs of paralogs, in which one gene copy is undergoing pseudogenization, will demonstrate clade asymmetry, mimicking the signature of neofunctionalization. However, such paralogs are almost certainly present only in the most terminal branches of Drosophila phylogeny spanning over 70 mln years, because the half-life of duplications, in which one of the copies undergoes pseudogenization, is 2-4 mln years 12; 26). Terminal branches include a minority of duplications in our database and excluding such branches from the analysis does not alter the results . This creates a bias towards less divergent paralogs, reducing our ability to detect elevated rates of evolution in duplicated genes. Relative magnitude of these opposing biases remains unknown.Further, results presented in Table Drosophila genomes corroborates patterns previously observed in a variety of taxonomically diverse triplets of genomes [Systematic loss/gain asymmetry in amino acid composition in 12  genomes . This pa genomes ,9.We also demonstrate that this net loss/gain asymmetry is strongly correlated with source and destination amino acid polarities: substitutions of polar amino acids by non-polar ones have a higher net rate than the reciprocal substitutions. In the past we have demonstrated a similar polarity-related asymmetry in selection coefficients against amino acid substitutions in human proteins ; howeverOne may hypothesise that replacing polar amino acids by any is less disruptive for the protein function because polar amino acids have a lower tendency to be located internally in the tertiary protein structure . If so, A question remains how is it possible that asymmetry in amino acid gains and losses systematically removed polar amino acids more often than non-polar ones Fig. over 70 a/Ks) and through more radical amino acid substitutions  than single copy genes  and to list all possible alternatives for other, ambiguous substitutions. It results in a database, which can be used to answer questions about patterns of amino acids substitutions genome-wide or in particular categories of genes such as molecular functions or duplication status.The analysis of such database of substitutions in 12 Drosophila genomes confirmed previously observed non-equilibrium patterns of net losses and gains of individual amino acids, demonstrated that these patterns do not weaken with the depth of phylogeny and revealed a strong correlation between polarity of amino acid and propensity to display a net loss. We hypothesize that this effect can be explained by relaxed selective constraints on externally located amino acid sites occupied by polar residuals. Evolution of duplicated genes is characterized by both higher relative rate of substitution and more radical nature of these substitutions, as compared to single copy genes. The rate and radicality in paralogs displays a weaker relation with mean expression rate and variance of expression rates across tissues than in single copy genes. This pattern, along with the strong asymmetry between clades resulting from duplication events, indicates widespread neofunctionalization of retained duplications.A new a phylogenetic analysis tool AcidMiner  is used Protein alignments and corresponding phylogenies were acquired from Dfam database at Indiana University ,27. ThesNOTUNG phylogenies reconciling topological incongruence between species trees and proteins trees  were useParalogs were identified as homologs present in the same genome and substitutions were considered to have been acquired by duplicated genes if their most parsimonious placement on the phylogeny is more terminal than the placement of the duplication event. Conversely, substitutions occurring in branches basal to the most ancient surviving duplication in a clade were considered to have occurred in a single-copy gene.Net relative gain (or loss) of amino acids through substitutions (flux) was characterized by the parameter D = (C-R)/(C+R), where C is the number of times each amino acids was created and R \u2013 the number of times the same amino acid has been removed by substitutions . The para/Ks value, obtained in the following manner. Ka was estimated as the ratio of the number of substitutions  to the number of amino acid sites in the alignment. Ks was calculated as the sum of branch lengths of the corresponding section of the tree expressed as the frequency of synonymous substitutions per 4-fold degenerative site [Each gene family was characterized by a KD. melanogaster genes FlyBase IDs [D. melanogaster gene were excluded. Conversely, families with duplicated D. melanogaster genes appeared in these types of analysis with the number of times equal to the number of D. melanogaster paralogs they contained. Gene families were subdivided into the following molecular function categories using FlyBase ontology data [Gene ontology and gene expression data were merged with amino acid substitution data by Base IDs . Therefoogy data : structuogy data .LYY proposed the study methodology, accomplished data analysis and prepared the manuscript. MAB wrote software, generated the dataset and contributed to the manuscript preparation.The authors declare that they have no competing interests.Excel spreadsheet with pair-wise amino acid substitution frequencies mapped to terminal branches of the phylogeny, by species.Click here for fileExcel spreadsheet with pair-wise amino acid substitution frequencies, separately for terminal and non-terminal branches.Click here for fileExcel spreadsheet with data on rates and radicalities of substitutions by gene family.Click here for fileExcel spreadsheet with data on rates and radicalities of substitutions by duplication with separate columns for each of the two clades resulting from each duplication events.Click here for file"}
+{"text": "Micro RNAs (MiRNAs) are small endogenous, regulatory RNAs comprising of about 19\u201325 noncoding nucleotides . PrimaryAcute rejection is the result of an alloimmune response against the allograft and can be caused by either a cellular or humoral response. An acute cellular rejection normally occurs 5 to 7 days after transplant but can occur in an accelerated fashion or any time after transplantation. Chronic rejection is a progressive deterioration in renal dysfunction characterized clinically by a progressive increase in serum creatinine level, and histologically by tubular atrophy, and interstitial fibrosis. It is an almost universal finding that finally happens in all renal transplant recipients and most commonly have an immunological reason. Previously the terminology of chronic allograft nephropathy (CAN) was used to describe these changes The Banff classification system for renal allograft injury has recently adopted the term interstitial fibrosis and tubular atrophy (IFTA) to describe these changes . It usually starts after the first transplantation year and results in a continuous decrease in renal allograft function. In the preliminary publication of miRNA profiling in CAD with IF/TA, 56 differential regulation of miRNAs were studied in tissue samples and urinary cell pellets. Up regulation of: miR-142-3p, miR-32 and down regulation of: miR-204, miR-107, miR-211 were observed in their studied population with IF/TA . All thoIn the context of kidney disease and early noninvasive diagnosis, urine is a specimen of choice. It provides a representative sampling of the entire kidney and an indirect way to visualize intragraft compartment; therefore, it is naturally appealing to nephrologists . The rolThe recent discovery of human microRNAs (miRNA) opens a new horizon to biomedical research Several publications have supported the value of urinary miRNAs for diagnosis renal allograft dysfunction so it could be a useful tool to monitor the status of the kidney allograft function and a feasible biomarker of IF/TA ."}
+{"text": "A new transgenic mouse that enables tissue-specific GFP labeling of cilia creates new opportunities for using live imaging to understand cilium function and to better characterize the many genetic models of ciliopathies.Nearly all cells have cilia, microtubule based projections from the apical cell surface, and nearly all cells use them in essential and unique ways. How mammalian cilia function http://www.ciliajournal.com/content/2/1/8See research article:  For instance, in the kidney, conditional knockout of genes essential for ciliogenesis in adult animals does not result in immediate or uniform kidney cyst formation, raising questions of how cilia detect fluid movement in vivo and how they function in normal epithelial homeostasis [in vivo has largely relied on DIC optics to detect motile cilia in a limited number of organ contexts where cilia can be made accessible, for instance in the isolated embryonic node [in vivo with green fluorescent protein (GFP) promises to open up new opportunities to understand the function of cilia in their normal organ context.The cilium is a multifunctional organelle now known to be a focal point of cell signaling as well as an essential mechanical device that cells use to propel themselves or surrounding fluid. Ciliary dysfunction in \u2018ciliopathies\u2019 leads to a wide range of human disease pathologies . The coneostasis . Much haeostasis . Imagingnic node  or the tnic node . The recin vivo imaging of cilia using fluorescent protein reporter transgenes has been a mainstay of studies using Caenorhabditis elegans for examination of ciliogenesis and ciliary sensory functions. Transgenic GFP fusion proteins have been used to report in vivo rates of ciliary transport  [in vivo ciliary motility [in vivo. For instance, in the embryonic mouse node, two populations of cilia are proposed to co-exist and be essential for the determination of embryonic left-right asymmetry. Motile cilia drive fluid in a leftward direction while non-motile, mechanosensory cilia are proposed to detect this fluid flow and initiate asymmetric signaling on the left side of the embryo [ex vivo lentiviral infection of mouse embryos with GFP targeted to cilia have been reported [GFP mouse harboring a floxed, cilia-targeted GFP transgene integrated in the ROSA locus promises to become the new standard for in vivo visualization of cilia. In their recent report, O\u2019Connor et al. [GFP mouse and show that cilia can be labeled in vivo with a transgene-encoded somatostatin receptor 3-GFP fusion protein (Sstr3::GFP) using ubiquitous and cell-type-specific Cre lines. Live imaging of kidney tubules reveals that fluid flow in the mouse nephron is sufficient to force the cilia to lie flat against the cell surface in the direction of flow, while at reduced heart rate cilia show a pulsatile and coordinated back and forth motion. After years of debate and supposition about how sensory cilia behave in vivo and how they may be linked to disease, the work from O'Connor et al. finally provides empirical measurements of ciliary deflection and movement that will be essential for deducing their in vivo function. How is ciliary deflection transduced as a cellular signal in vivo? Do cilia have a characteristic bending pattern and is this important in mechanotransduction? Or do some kidney cilia move on their own using internal motors (dyneins)? These questions and many others are now within the grasp of researchers. The CiliaGFP mouse will also be useful for studies of the brain where primary cilia in the hippocampus as well as motile cilia on ependymal cells of the ventricles have been shown to be well labeled. The CiliaGFP mouse approach will impact studies of how cerebrospinal fluid movements may affect brain development [Live, rt; IFT) , the delrt; IFT) . More rert; IFT)  and permmotility . A key ae embryo . While ireported , but thir et al.  describeelopment .GFP mouse suggests new approaches, integrating observations on the behavior of cilia with in vivo measurements of cell signaling. Imaging cilia in the CiliaGFP mouse coupled with genetically encoded biosensor transgenics  promise"}
+{"text": "Glucose control in critical care has been shown to improve patient outcome, yet tight glucose control has led to increased hypoglycemia in the clinic. We employed a systems engineering approach to assist clinicians in maintaining blood glucose within a desired target range while avoiding hypoglycemia in the critically ill. The long-term vision is a decision support system that provides recommended insulin and glucose administrations leading to patient-specific achievement of tight glucose control without hypoglycemia.To achieve these goals, we employ a model predictive control (MPC) algorithmic platform using two control inputs: insulin for glucose control and glucose for hypoglycemia. The MPC controller is designed based on a nonlinear dynamic model of glucose-insulin-fatty acid interactions . A movinThe response of the MPC controller to measured deviations in glucose is shown in Figure The algorithm achieves tight glucose control in response to multiple measured and unmeasured disturbances. Furthermore, the MHE scheme updates patient parameters in real time in response to changing patient dynamics. The adaptive MPC algorithm is currently being validated using a retrospective cohort of critically ill patients at the University of Pittsburgh Medical Center."}
+{"text": "Liming has been used extensively in Scandinavia and elsewhere since the 1970s to counteract the negative effects of acidification. Communities in limed lakes usually return to acidified conditions once liming is discontinued, suggesting that liming is unlikely to shift acidified lakes to a state equivalent to pre-acidification conditions that requires no further management intervention. While this suggests a low resilience of limed lakes, attributes that confer resilience have not been assessed, limiting our understanding of the efficiency of costly management programs. In this study, we assessed community metrics , multivariate community structure and the relative resilience of phytoplankton in limed, acidified and circum-neutral lakes from 1997 to 2009, using multivariate time series modeling. We identified dominant temporal frequencies in the data, allowing us to track community change at distinct temporal scales. We assessed two attributes of relative resilience  of the phytoplankton communities, based on the fluctuation frequency patterns identified. We also assessed species with stochastic temporal dynamics. Liming increased phytoplankton diversity and richness; however, multivariate community structure differed in limed relative to acidified and circum-neutral lakes. Cross-scale and within-scale attributes of resilience were similar across all lakes studied but the contribution of those species exhibiting stochastic dynamics was higher in the acidified and limed compared to circum-neutral lakes. From a resilience perspective, our results suggest that limed lakes comprise a particular condition of an acidified lake state. This explains why liming does not move acidified lakes out of a \u201cdegraded\u201d basin of attraction. In addition, our study demonstrates the potential of time series modeling to assess the efficiency of restoration and management outcomes through quantification of the attributes contributing to resilience in ecosystems. The capacity of an ecosystem to tolerate disturbances without changing its original structure, functions and processes has been defined as ecological resilience Clear examples of ecosystems that are trapped in a degraded state are acidified lakes Here, we describe an analysis of the resilience of phytoplankton community structure  and no permission for use of the data is therefore required. It is also confirmed that the field studies did not involve endangered or protected species.All field sampling and laboratory analyses reported in this study are part of either the Swedish National Lake Monitoring Program or the national monitoring program for Integrated Studies of the Effects of Liming of Acidified Waters, both regulated by the Swedish Agency for Marine and Water Management. All data are made freely available to the public via the web by the data host : 1) managed lakes  that were limed to mitigate the effects of anthropogenic acidification; 2) acidified lakes  that were unmanaged; 3) circum-neutral lakes , used as reference lakes with \u201cdesired\u201d ecosystem properties. The study lakes are situated in the same ecoregion , are of similar size  and have been monitored regularly for surface water chemistry and phytoplankton for 13 years (1997\u20132009).For this study, nine lakes representing three different management types were selected from the webpage hosting data from monitoring programs of Swedish inland waters (http://www.swedac.se/en/) at the Department of Aquatic Sciences and Assessment, Swedish University of Agricultural Sciences, following International (ISO) or European (EU) standards when available Phytoplankton and two water chemistry variables that are directly related to liming  were sampled monthly during the ice-free period at a mid-lake station in each lake. Water was collected at 0.5 m depth with a Plexiglas\u00ae sampler and kept cool during transport to the laboratory for further analysis. All physicochemical analyses were done by SWEDAC certified laboratories  were calculated from geometric shapes following protocols developed by Blomqvist and Herlitz Phytoplankton was sampled by taking a water sample from the epilimnion using a 2-m long Plexiglas tube sampler (diameter\u200a=\u200a3 cm). In lakes with a surface area >1 kmPrior to analyses, phytoplankton data were averaged to obtain three values that were spaced nearly equidistantly in time, covering early spring, summer and late autumn each year. We characterized phytoplankton community structure across lakes using common metrics  following recent recommendations by Jost Repeated measures analysis of variance (rm-ANOVA) was carried out in Statistica v.5  to test for significant differences in phytoplankton community metrics between the three categories of lakes. Similar rm-ANOVAs were conducted for pH and calcium concentration, to associate phytoplankton community dynamics with abiotic effects of liming. We tested for the effects of \u201cmanagement type\u201d  (fixed factor), \u201ctime\u201d (random factor) and their interactions. These factors comprised the independent variables while the community metrics comprised the dependent variables in the analysis. All data were log-transformed when necessary prior to analyses to fulfill the requirements of parametric tests. Because assumptions of sphericity were violated, degrees of freedom were corrected following the procedure by Huynh and Feldt These univariate comparisons were complemented with multivariate analyses on phytoplankton communities using permutational multivariate analysis of variance in PERMANOVA version 1.6 et alWe assessed two attributes of relative resilience  of the phytoplankton communities with a time series modeling approach based on redundancy analysis (RDA) R2 values of the canonical axes. The overall temporal structure of the whole community can then be deduced from the number of significant canonical axes in the RDA models. The number of canonical (RDA) axes identified gives insight about the number of temporal scales at which phytoplankton community fluctuations take place and can therefore be used to assess the cross-scale structure attribute of resilience Redundancy analysis (RDA) retains significant AEM variables and these are linearly combined in ways to extract temporal patterns from the Hellinger-transformed species matrices . The RDA identifies species with similar temporal patterns in the species \u00d7 time matrix and uses their temporal pattern to calculate a modeled species group trend for these species based on linearly combined AEMs. The significance of the temporal patterns of all modeled fluctuation patterns of species groups revealed by the RDA is tested by means of permutation tests. The RDA relates each modeled temporal fluctuation pattern with a significant canonical axis. The R software generates linear combination (lc) score plots, which visually present the modeled temporal patterns of species groups that are associated with each canonical axis. Based on the number of significant canonical axes, the number of modeled fluctuation patterns of species groups with independent temporal patterns can be deduced. The ecological relevance of each temporal pattern identified can be quantified, using adjusted All relevant steps in the analyses were carried out with two functions implemented in the R 2.15.2 statistical software package After identifying the cross-scale structure in phytoplankton community dynamics, we evaluated the within-scale attribute of resilience using correlation analysis. Spearman\u2019s rank correlation analysis was used to investigate the relationship between individual phytoplankton species  with the linear combination (lc) scores extracted from significant canonical axes of the time series models for each lake type. With this approach we were able to calculate scale-specific taxon richness. Species that did not correlate with any canonical axes were considered to reflect stochastic dynamics. The number of these stochastic species was evaluated by subtracting the total number of species that correlated with canonical axes from the total number of species used for the time series modeling across lakes P<0.001).Univariate analyses of community metrics  revealedThe results of the repeated measures analysis of variance revealed that management type has an effect on both the pH and the calcium concentration, while the effect of time and the interaction term were not significant . MoreoveTime series modeling revealed significant temporal structure in all lakes studied . The RDAThe relative resilience of limed lakes in terms of the dynamic within- and cross-scale structure of phytoplankton communities was predicted to be lower relative to acidified and circum-neutral lakes. The within-scale component of resilience, expressed as the percentage of species that explained each temporal pattern, was similar across lake types. Also the cross-scale structure differed marginally between managed and unmanaged lakes, although water chemistry accounted for subtle differences in cross-scale structure. All circum-neutral lakes and the least acidified Brunnsj\u00f6n showed six distinct temporal frequency fluctuations, while the most acidified lake H\u00e4rsvatten, that clearly comprises an undesired but stable state, had only four patterns. This pattern is counterintuitive because it suggests a lower resilience of this lake. This highlights that the cross-scale structure analysis, despite characterizing important features of complexity, may not capture the full spectrum of resilience. Our study shows how considering the dynamics of stochastic species can provide a broader picture of resilience. Similarly, despite liming substantially increasing pH and calcium concentration, no significant increase in cross-scale structure was observed, highlighting no pronounced effect of management action on phytoplankton cross-scale attributes of resilience. Although our study hypothesis was rejected, our results provided us with a better understanding how management action, specifically liming, influences resilience.Management and restoration efforts are often directed towards breaking equilibrium conditions of undesired system states, returning them to more desired states and increasing the resilience of these restored or managed states (2) The resilience characteristics observed in acidified lakes characterizes their basin of attraction and thus their resistance to return to desired target conditions The similar within- and cross-scale attributes of resilience in limed and acidified lakes, suggest that liming produces at least a partial management success in terms of increasing species richness and diversity, which has also been observed in other studies In addition to assessing patterns of resilience across managed and unmanaged boreal lakes, our study provides new insight into the consequences of liming for biodiversity and its effects on resilience. Increased resilience has been associated with a higher species richness and diversity in communities We conclude by highlighting that, given the similar within- and cross-scale attributes observed across lakes, an assessment of resilience characteristic of limed lakes would have been inconclusive. Without information of the broader ecological impacts of liming on communities and other ecosystem characteristics that has accumulated in the literature Table S1Summary of geographical positions, morphological characteristics and water chemistry of study lakes. Values represent the inter-annual mean value and standard deviation for the study period 1997\u20132009.(DOCX)Click here for additional data file.Appendix S1Flow chart outlining the steps involved in time series modeling.(DOCX)Click here for additional data file.Appendix S2Non-metric multidimensional scaling (NMDS) ordination showing phytoplankton communities across the different lake types over the study period (1997\u20132009).(DOCX)Click here for additional data file."}
+{"text": "Simulating electronic devices built from flexible organic molecules requires both adequate conformational sampling and a reliable quantum mechanical description of the electronics of the system.The former is best achieved using classical (force field) molecular-dynamics simulations, from which individual geometries (\u201csnapshots\u201d) can be used for subsequent quantum mechanical calculations.As the repeating unit in the classical simulations typically involves thousands of atoms, the quantum mechanical techniques must also be able to handle many thousands of atoms quickly and effectively on modern parallel hardware.The newly developed EMPIRE program has been used in such a scheme to perform simulations on self-assembled-monolayer field-effect transistors (SAMFETs). Calculations of the size needed require novel interpretation and post-processing techniques based on local properties calculated on grids, rather than the more traditional population analyses.The results of simulations using the techniques described above will be presented and the algorithms and parallelization strategies implemented to be able to calculate as many as 100,000 atoms on 1,024 cores."}
+{"text": "The 2012 International Conference on Computational Intelligence and Security (CIS) is the ninth one focusing on all areas of two crucial fields in information processing: computational intelligence (CI) and information security (IS). In particular, the CIS Conference provides a platform to explore the potential applications of CI models, algorithms, and technologies to IS. (i)\u201cAttribute index and uniform design based multiobjective association rule mining with evolutionary algorithm,\u201d (ii)\u201cReliable execution based on CPN and skyline pptimization for web service composition,\u201d (iii)\u201cRobust adaptive control for a class of uncertain nonlinear systems with time-varying delay,\u201d (iv)\u201cBounds of the spectral radius and the Nordhaus-Gaddum type of the graphs,\u201d (v)\u201cThe effects of different representations on static structure analysis of computer malware signatures.\u201dAmong all accepted papers in CIS Conference 2012, five papers were further screened and extended to be included in this special issue. They are the following:The first paper formulates the association rule mining as a multiobjective problem, through which the algorithm of attribute index and uniform design-based multiobjective association rule mining with evolutionary algorithm is presented without the user-specified minimum support and minimum confidence anymore. Experiments on several databases have demonstrated that the proposed algorithm has excellent performance and that it can significantly reduce the number of comparisons and time consumption. The second paper is to employ the transactional properties and nonfunctional quality-of-service (QoS) properties for selecting the web services. Furthermore, the third paper presents an adaptive neural control design for a class of perturbed nonlinear MIMO time-varying delay systems in a block-triangular form. The proposed control guarantees that all closed-loop signals remain bounded, while the output tracking error dynamics converge to a neighborhood of the desired trajectories. The simulation results have demonstrated the effectiveness of the proposed control scheme. The fourth paper is to study the upper bounds for the spectral radius in quantum chemistry. As a result, an upper bound of the Nordhaus-Gaddum type is obtained for the sum of Laplacian spectral radius of a connected graph and its complement. Lastly, the fifth paper is to evaluate a static structure approach to malware modeling using the growing malware signature databases. It has been shown that it is possible to apply standard sequence alignment techniques in bioinformatics to improve accuracy of distinguishing between worm and virus signatures if malware signatures are represented as artificial protein sequences. Moreover, aligned signature sequences can be mined through traditional data mining techniques to extract metasignatures that help distinguish between viral and worm signatures.To sum up, the previously mentioned papers will provide readers and researchers with some useful ideas in the fields of computational intelligence and security.Yiu-ming CheungYiu-ming CheungYuping WangYuping WangHailin LiuHailin LiuXiaodong LiXiaodong Li"}
+{"text": "Cell-based therapies for degenerative diseases of the musculature remain on the verge of feasibility. Myogenic cells are relatively abundant, accessible, and typically harbor significant proliferative potential ex vivo. However, their use for therapeutic intervention is limited due to several critical aspects of their complex biology. Recent insights based on mouse models have advanced our understanding of the molecular mechanisms controlling the function of myogenic progenitors significantly. Moreover, the discovery of atypical myogenic cell types with the ability to cross the blood-muscle barrier has opened exciting new therapeutic avenues. In this paper, we outline the major problems that are currently associated with the manipulation of myogenic cells and discuss promising strategies to overcome these obstacles. Muscles all over the body are heterogeneous, differing in function, cellular composition and biochemical properties Unfortunately, a number of problems are associated with the sole genetic correction of muscle fibers. In healthy young muscle, the turnover of postmitotic muscle fibers is barely detectable Satellite cells, the predominant myogenic cells in skeletal muscle, have a strong dependence on their niche consisting of specialized heparan sulfate rich microenvironment and adhesion molecules on the myofiber plasma membrane The majority of muscle satellite cells spend the most of their lifetime quiescent in their niche  27, 28. It appears that satellite cells also remodel their ECM microenvironment upon activation. While quiescent satellite cells express specific protease inhibitors, proliferating cells express high levels of matrix metalloproteinases (MMP) The importance of the muscle fiber basal-lamina is illustrated by the severe phenotype of mice with mutations in the laminin alpha 2 chain An interesting scenario with respect to the satellite cell niche concept is that non-myogenic cell types could accompany activated satellite cells and contribute to the maintenance of their microenvironment. Fibroblasts which are well known to express high levels of ECM molecules and have no direct myogenic potential, are required for efficient muscle regeneration In 2005, Collins et al. demonstrated that transplantation of single fibers with their niche associated satellite cells leads to an outstandingly efficient engraftment into immunocompromised mdx recipient mice Next to fibroblasts, other non-myogenic cells, including endothelial cells and FAPs, have been implicated in the regulation of myogenesis Taken together, a variety of non-myogenic cell types contribute to the microenvironment of satellite cells and are likely to play a role in the preservation of their stem cell properties. This knowledge has important implications for future cell therapy. The concept of supportive cell types for the maintenance of stemness has long been applied in case of embryonic stem (ES) cells which are routinely cultured on a supportive layer of feeder fibroblasts Apart from the ECM and localized paracrine signals, cell-cell interactions are an important regulatory mechanism in the satellite cell niche. Satellite cells express several genes involved in cell-cell signaling at high levels. Amongst these are cadherins, neural cell adhesion molecule 1 (NCAM-1), vascular cell adhesion protein 1 (Vcam-1), intercellular adhesion molecule 1 (Icam1), claudin 5 (Cldn5), endothelial cell-specific adhesion molecule (Esam) Recent evidence suggests that the elasticity of the niche is crucial for the function of satellite cells Under homeostatic conditions, satellite cells are mostly quiescent remaining in a non-dividing G0 state Taken together, the muscle stem cell niche integrates a plethora of molecular signals that control the maintenance of satellite cells in quiescence and their function upon activation All quiescent satellite cells express the transcription factor paired-box 7 (Pax7) and some myogenic factor 5 (Myf5) The satellite cell pool remains constant over multiple rounds of injury. Consequently, a self-renewing population of stem cells must exist within the myogenic progenitor pool. Early studies revealed that upon injury a subset of myogenic cells undergo immediate fusion into myofibers without preceding cell division while others, with delayed kinetics, enter mitosis A variety of different methodologies has been established to identify satellite cell subpopulations with stem cell character. The gold standard to test the stemness of a given myogenic subpopulation is transplantation into regenerating, eventually irradiated muscle with subsequent analysis of contribution of exogenous cells to the satellite cell compartment. This can be based on quantification of grafted cells in the satellite cell position on muscle sections or by fluorescence-activated cell sorting (FACS). Ideally, in such transplantation experiments, a given subpopulation of satellite cells with superior stemness is compared to the total pool of satellite cells or to the fraction of cells remaining after extraction of the stem population. Despite abundant reports on satellite cell heterogeneity only few studies have compared satellite cell subpopulations in this manner.Based on expression reporter alleles and by immunostaining it has been shown that a fraction of satellite cells in adult muscle do not express Myf5 As described by others In another line of research, Tanaka et al. characterized a subpopulation of satellite cells with characteristics of side population (SP) cells which express Pax7, Sdc3, Sdc4, ATP-binding cassette sub-family G member 2 (ABCG2) and stem cell antigen 1 (Sca1) During regeneration, heterogeneous populations within satellite cells also behave differently in terms of proliferation kinetics. Asymmetric divisions giving rise to more differentiated progeny can be observed at almost every stage; satellite cell lineage progression thus allowing for a small population of satellite cells to retain stem cell characteristics. Based on a GFP live-reporter for Pax7 expression, Rocheteau et al. have shown that undifferentiated satellite cells with high Pax7 expression have the capability to asymmetrically distribute their chromatids when compared to cycling cells which have begun to downregulate Pax7 It remains to be determined to which extent each of the above mentioned label and sorting approaches enrich for the same primitive \u201cstem-like\u201d population present in skeletal muscle and it is hoped that future studies will be able to unequivocally unravel the identity and biology of these satellite stem cells. Unfortunately, up to date no definitive stem cell marker has been established to isolate such satellite cells in species other than the mouse. The availability of a satellite stem cell marker that allows for sorting of living cells from human tissue would be of great use from a therapeutic point of view. It would allow for the selective enrichment of these cells from donor tissue, reduce immunogenicity due to the low number of cells required for transplantation, decrease the number of injections required to obtain a therapeutic effect and it would result in a sustained muscle-wide repopulation of the host stem cell niche by donor cells without loss due to excessive differentiation. Another problem associated with the intramuscular delivery of myogenic cells that could be solved by transplantation of few stem cells is the massive cell death that has been described upon grafting of large amounts of myoblasts into muscle A variety of cells different from satellite cells possess myogenic potential . Some ofSeveral other cell types with varying myogenic potential that could be of therapeutic relevance have been described. (i) A rare population of cells expressing CD133 or Prominin-1 that is present in human skeletal muscle and circulating in adult blood has myogenic potential So far, a wide variety of cells with myogenic potential harboring distinct advantages and disadvantages for therapy have been discovered. In the recent years, basic research has begun to define parameters for experimental cell-based treatments that are likely to be translationally relevant. Desirable characteristics of transplanted cells are a high proliferative capacity without tumorigenicity, a minimal immunogenicity, the ability to cross the blood-muscle barrier and/or a robust migratory capacity within muscle tissue, the ability to sustainably repopulate the satellite cell niche, the ability to return to quiescence, and an unimpaired differentiation potential allowing for an extensive transfer of genetic material into muscle fibers. Apart from isolating sufficient cells with these characteristics, some of the main limitations we are facing now are the lack of ex vivo cultivation methods allowing for genetic correction while preserving satellite cell \u201cstemness\u201d, the lack of definite markers for the enrichment of viable satellite stem cell populations, inefficient delivery methods and a lack of strategies to efficiently control fibrosis and inflammation. At present, the ability to cross the blood-muscle barrier after systemic delivery and the capability to populate the satellite cell niche makes mesoangioblast-like cells/pericytes the most promising candidates for cell-based therapy of muscular dystrophy. Future research will have to advance the feasibility of alternative approaches such as the genetic correction and/or grafting of satellite cells so they can be assessed for their efficiency in a clinical setting.It is now more than 50 years since the satellite cell of skeletal muscle has been discovered"}
+{"text": "A 71 years old Italian man had type 3 gastric cancer of the greater curvature. Total gastrectomy with splenectomy and D2 lymph node dissection were performed. After discharge chemotherapy ELF regimen was administred for 6 months. After 16 months from the operation a local recurrence was discovered by CT scan. Surgical en-bloc resection was performed removing pancreatic tail, splenic colic flexure and a portion of left diaphragm. Histological examination confirmed local recurrence of gastric adenocarcinoma infiltrating pancreas, colon and diaphragm with lymph node metastasis. In Western countries gastric cancer still represents a disabling disease: unfortunately late diagnosis is common and loco-regional recurrence rate after surgery alone is high especially in patients with advanced stage disease at the time of diagnosis . Local recurrence may occur also in those patient which had R0 resection: management of these cases is extremely difficult for the involvement of regional structures resulting in poor surgical chances. Therefore multidisciplinary therapeutic approach is necessary to achieve better results. The aim of this report is to refer about an unusual presentation of local relapse in an old patient submitted to a total gastrectomy in which surgical approach permitted a good control of the disease.th post-operative day after X-ray control with hydro-soluble contrast. Hospital stay was prolonged by left basal pneumonia associated to pleural effusion; discharge occurred after one month. Histological examination demonstrated an adenocarcinoma  extended to all layers of gastric wall and metastasis to greater curvature lymph-nodes (station 4 of JGCA) [th post-operative day; after resolution of this complication patient was discharged. Histological examination resulted in poor differentiated gastric carcinoma infiltrating colic wall and pancreas with metastasis in one of nine peri-colic lymph-nodes examinated.Male, 71 years old; on July 27, 2004, he was submitted to total gastrectomy with splenectomy and lymph-node dissection (D2) for an ulcerated adenocarcinoma of the greater curvature of the upper third of the stomach. Roux-en-Y stapled esofago-jejunoanastomosis was performed and oral food intake resumed in 7Loco-regional recurrence and distant metastases are common events after surgery for gastric adenocarcinoma. Abdominal extraluminal recurrence of gastric cancer is a disarmimg condition because of poor therapeutic chances. Generally it is a matter of peritoneal carcinosis or multiple liver metastasis; in these cases surgery has little opportunities to be useful. Literature reports rare cases of single localization in abdominal cavity that may be resected. Menzel  reportedOur case is unusual in its presentation: an isolated bulk involving neighbouring organs suitable for surgical resection. The result after the en-bloc resection is very amazing. Considering the primary surgical specimen we may suppose the modalities of the local relapse: the spleen and local lymph-nodes were radically removed, but in spite of that, local contamination during the first operation remains the most reasonable interpretation. All risk factors suggested by Yoo and Colleagues  were preThe authors declare that they have no competing interests.BM, CM and RL have studied the patient and performed the surgical operation. FC performed the endoscopic preoperative study of the patient and contributed to the literature review. CT contributed to the discussion of medico-legal issues and to the writing of the paper. BA and CM gave their contribution to the analysis of the data and contributed to the writing of the paper. All the authors read and approved the final manuscript."}
+{"text": "Based on the concept that the tumorogenesis in chronic lymphocytic leukaemia comprises both an initial, inherited mutation and subsequent somatic mutations, the pleiotypic diversity of familial chronic lymphocytic leukaemia and related malignant lymphoproliferative disorders is generally explained by a repertoire of monoallelic polygenes in the initial mutation. Epigenetic genomic imprinting is a likely mechanism behind of the asynchroneous replicating monoallelic polygenes which is discussed in the light of pleiotrophy and birth order effect. Furthermore, it is discussed that one possible mechanism available for the epigenetic transfer of these genes could be the physiological pregnancy-related microchimerism between mother and fetus. It is generally accepted that chronic lymphocytic leukemia (CLL) is a monoclonal B-lymphoproliferative disorder caused by a mutation in the differentiation pathway of the B-lymphocyte and that this mutation causes an arrest in the differentiation with accumulation of the leukemic subset of immature monoclonal B-lymphocytes. Since these B-lymphocytes are genuinely circulating in blood and lymph, the leukemic cells are spread to all part of the body with vessels and accumulated especially in bone marrow, lymph nodes and spleen and sometimes even in lamina propria and in other extra-lymphoid tissues \u20135. RelatThe multistep evolution of LD is based on a paradigm  and 2 coA hereditary mechanism in CLL and LDs is seen from the marked familial clustering with pleiotrophy, which means familial co-expression of CLL and LDs \u201317. The However, to date the gene or genes involved have not been identified. A considerable number of publications on gene-defects in CLL address the subsequent somatic mutations . There iNeither linking studies \u201327 nor gWhether the somatic mutations in the development of LDs  and 2 alOne of the major recent contributions to the discussion on familial CLL is the demonstration of a likely monoallelic polygene model where each monoallelic gene confer a small relative risk which increases when the monoalleleic genes occur in multiplicative and/or additional combinations ,40\u201343.If the interacting monoallelic polygenes arises as a consequence of inherited and initial mutations they mimic an autosomal dominant syndrome in which the individual cells in the mutated clone become homozygous for a recessive neoplasma causing gene \u201343. DuriHowever, in spite of multiple damages some mutated cell lines survive leading to \u201ccancer\u201d. This diversity of surviving, mutated clones caused by multiple monoallelic genes explains most likely the pleiotypic appearance of subsets of diagnoses in families with clustering of CLL and related LDs. Such asynchronous replicating monoallelic genes are often either genomic imprinted genes or genes subjected to X-chromosome inactivation . While aGenomic imprinting is a non-Mendelian gene expression depending upon the parent that transmit it and where the mechanism which silences the maternal or the paternal copy is epigenetic, meaning outside the genes , 46\u201351. The parent\u2019s age and the birth-order effect were originally united parameters in Haldane and Smith\u2019s test from 1947 ,61 basedGenomic imprinting is in favour of adjustment of different maternal resources to her offspring to maximize maternal fitness . Perhaps"}
+{"text": "Transcranial direct current stimulation (tDCS) is a non-invasive technique that is generally assumed to work by increasing the level of brain activity near the anode (positive polarity), while decreasing it near the cathode (negative polarity). However, this is based in part on untested assumptions: the exact (cellular and synaptic) inhibitory or excitatory processes that are targeted preferentially using either polarity is still an open area of research. Furthermore, the relationship between electrode polarity and membrane excitability is highly contingent upon stimulation parameters . Although neuroimaging has been utilized to verify these general effects in the brain, further development is needed to advance our understanding of the mechanisms by which tDCS produces changes across different levels of the nervous system. To date, tDCS has produced reliable changes in neurometabolite concentration using magnetic resonance spectroscopy . We then demonstrate the need for multimodal imaging, with the goal of establishing a more comprehensive examination of both local and global neuroplastic changes due to tDCS. Such a design would enable measurements of brain chemistry and large-scale functional connectivity within the same subject and tDCS session, thus capturing interactions of these measures that may account for significant variability in cognition and behavior.1H-MRS) allows for accurate quantification of certain neurotransmitters within a localized region of the brain. To date, there have been few published MRS-tDCS studies where data were acquired immediately before and after tDCS. For instance, Rango et al.  and NAA (N acetyl aspartate) under the anodal electrode (located near P4), compared to the opposite hemisphere  fMRI have been interpreted as measures of the Other fMRI studies have investigated network connectivity changes induced by tDCS  vary across studies and therefore introduce another layer of complexity when trying to compare and interpret results from multiple studies. These parameters can have complex effects on experimental results\u2014for instance, increasing stimulation intensity can have non-linear effects on motor evoked-potential amplitudes (Batsikadze et al., A recently published study demonstrated the feasibility of combined EEG-fMRI with transcranial magnetic stimulation (Peters et al., In summary, it has been shown that tDCS is well-poised as a novel intervention to alter learning and memory (Clark et al.,"}
+{"text": "The past decade has witnessed dramatic advances in genome sequencing and a substantial shift in the number of genome wide association studies (GWAS). These efforts have expanded considerably our knowledge on the sequential variations in Human DNA and their consequences on the human biology. Nevertheless, complex genetic disorders often involve products of multiple genes acting cooperatively and pinpointing the decisive elements of such disease pathways remains a challenge. Network biology recently proved its use in identifying candidate disease genes based on the simple observation that proteins translated by phenotypically related genes tend to interact, the so called guilt-by-association principle.Here, we present GUILD (Genes Underlying Inheritance Linked Disorders), a network-based candidate disease-gene prioritization framework which reveals the pathways associated with the disorder . We exploit several distinct plausible communication mechanisms of known genes associated with the phenotype emerging from the topology of the interaction network. We used three sources of gene-phenotypic association to specify nodes involved in a disorder (seeds for the methods proposed): Online Mendelian Inheritance in Man (OMIM) database  and two Analysis on multiple human disease phenotypes demonstrate that the methods proposed in GUILD surpass state-of-the-art prioritization methods such as PageRank with priors  and Func"}
+{"text": "The interactions between the insulin signaling pathway (ISP) and juvenile hormone (JH) controlling reproductive trade-offs are well documented in insects. JH and insulin regulate reproductive output in mosquitoes; both hormones are involved in a complex regulatory network, in which they influence each other and in which the mosquito's nutritional status is a crucial determinant of the network's output. Previous studies reported that the insulin-TOR (target of rapamacyn) signaling pathway is involved in the nutritional regulation of JH synthesis in female mosquitoes. The present studies further investigate the regulatory circuitry that controls both JH synthesis and reproductive output in response to nutrient availability.We used a combination of diet restriction, RNA interference (RNAi) and insulin treatments to modify insulin signaling and study the cross-talk between insulin and JH in response to starvation. JH synthesis was analyzed using a newly developed assay utilizing fluorescent tags.corpora allata (CA). Paradoxically, starvation-induced up regulation of insulin receptor transcripts and therefore \u201cprimed\u201d the gland to respond rapidly to increases in insulin levels. During this response to starvation the synthetic potential of the CA remained unaffected, and the gland rapidly and efficiently responded to insulin stimulation by increasing JH synthesis to rates similar to those of CA from non-starved females.Our results reveal that starvation decreased JH synthesis via a decrease in insulin signaling in the  The correct allocation of nutrients between conflicting needs such as reproduction, growth, maturation or flight is a vital component of an insect's life-history strategy Aedes aegypti JH is a key mediator of trade-offs between survival and reproduction during the PVGS and ORS The reproductive cycle of female mosquitoes proceeds through a previtellogenic stage (PVGS), an ovarian resting stage (ORS) and a vitellogenic stage (VGS) corpora allata (CA) synthesize JH A. aegypti mosquito are very dynamic and nutrition-dependent in vitro caused a strong and fast stimulation on JH synthesis; while systemic depletion of TOR by RNAi and rapamycin administration had inhibitory effects on JH synthesis How these two hormonal signaling pathways (ISP and JH) interact to regulate all the physiological functions necessary for egg production is not totally clear. JH titers in female adult mosquitoes are mainly determined by the rate at which the in vivo depletion of INSr and FOXO using RNA interference (RNAi) and insulin treatments were used to modify insulin signaling and study the cross-talk between insulin and JH in response to starvation. Our results reveal that starvation decreased JH synthesis via a decrease in insulin signaling in the CA. Starvation-induced up regulation of the insulin receptor increased CA insulin sensitivity and might \u201cprime\u201d the gland to respond rapidly to increases in insulin levels after feeding resumption. During this response to starvation the synthetic potential of the CA remained unaffected, and the gland rapidly and efficiently responded to insulin stimulation by increasing JH synthesis to rates similar to those of CA from non-starved females.Here diet restriction, Aedes aegypti of the Rockefeller strain were reared at 28\u00b0C and 80% relative humidity under a photoperiod of 16 h light: 8 h dark. Female were offered a cotton pad soaked in 20% sucrose solution for the first 24 h after adult emergence. Afterwards, one day-old females were separated into two experimental groups: starved females were offered water, and sugar-fed females were maintained on a 20% sucrose solution. All experiments were performed with 4-day old virgin females.To test the effect of starvation we used four days old females because our RNAi protocol requires waiting a 4-day period after injection to be effective Lipids were quantified in mosquitoes using a triglyceride quantification kit  as previously described Corpora allata-corpora cardiaca complexes (CA-CC) attached to the head capsule were isolated from adult females as previously described in vitro was quantified using high performance liquid chromatography coupled to a fluorescent detector (HPLC-FD) The amount of JH synthesized by CA-CC complexes Total RNA was isolated using RNA-binding glass powder as previously described Synthesis and microinjections of double-stranded RNA (dsRNA) were performed as described by Perez-Hedo et al. Statistical analyses were performed using the GraphPad Prism Software . The results are expressed as means \u00b1 S.E.M. Significant differences (P<0.05) were determined with a one tailed students t-test performed in a pair wise manner or one-way ANOVA followed by a comparison of means (Tukey's test).To determine the effect of starvation on lipid reserves, the total lipid contents of mosquitoes were quantified in either sugar-fed or starved females. Lipids reserves increased more than 2-fold by feeding 20% sugar for the first 24 h. Lipids continued to increase in sugar-fed females, while starved females gradually lost lipids during the starvation period. There was a 10 fold decrease in total lipid contents of 4 day-old starved females when compared with mosquitoes fed 20% sucrose .Starvation resulted in a significant decrease of JH synthesis . The CA To dissect the transcriptional regulatory circuitry of the insulin signaling cascade in the CA in response to starvation, transcript levels for 4 key genes were analyzed in the CA of 4 days old adult females fed sugar or water .Transcriin vivo depletion of INSr and FOXO. Injection of dsINSr resulted in a significant reduction of INSr mRNA when compared with dsYFP treated in both starved (55%) and sugar-fed adult females (58%), without reducing FOXO's transcript levels . JH synthesis was significantly stimulated by insulin in glands dissected from starved females; while CA dissected from sugar-fed females did not respond to insulin stimulation , with three of them  specifically expressed in brains of adult females corpora cardiaca (CC) or they are received from the circulating hemolymph. Transcript levels for several A. aegypti ILPs show age dependent and diet dependent changes in female mosquitoes On the other hand, lipids reserves increased more than 2-fold by feeding 20% sugar for the first 24 h after emergence, indicating that a sugar meal could rapidly augment lipid stores. It is important for a female mosquito to rapidly and effectively detect these dynamic changes in nutrient reserves and correct nutrient allocations. The interactions between the ISP and JH controlling reproductive trade-offs are well documented in insects in vitro caused a strong and fast stimulation of JH synthesis The TOR and ILP signaling pathways are considered as nutritional sensors at the cellular and systemic level, respectively. We have previously established that application of bovine insulin on the mosquito CA incubated The insulin receptor itself is a target gene for FOXO regulation in Drosophila and mammals Blatella germanicaThere is evidence that the ISP affects JH levels; in Drosophila, a mutation of the INSr resulted in a significant decrease in JH synthesis, reduced reproductive output and extended life-span In vivo knockdown of the mosquito insulin receptor by RNAi delayed but did not fully inhibit trypsin-like gene expression in the midgut, ecdysteroid production by ovaries and vitellogenin expression by the fat body. In contrast, in vivo treatment with double-stranded INSr RNA and rapamycin completely blocked egg production In female adult mosquito, the interactions between JH, insulin, nutrition and oogenesis are diverse depending on the tissue and physiological stage. After adult emergence, JH connects the nutritional status with insulin signaling by inducing the expression of TOR signaling components in the fat body. Thus, through JH action, the fat body becomes competent to respond to insulin and transduce the nutritional signal from a blood meal to activate vitellogenin transcription Manipulations that decrease systemically the activity of nutrient sensing system are often difficult to interpret. Depletion of INSr or FOXO has profound consequences beyond reducing the activity of any of these particular genes. We observed that silencing of FOXO very efficiently reduced both FOXO and INSr mRNAs in starved and sugar-fed adult females. That explains that although starvation clearly increased FOXO transcript levels in the CA with a concomitant decrease in JH synthesis, systemic silencing of FOXO decreased INSr levels, phenocopied starvation and reduced JH synthesis in both sugar-fed and starved females. Interestingly, systemic silencing of the INSr had opposite effects in JH synthesis by CA dissected from sugar-fed and starved females. Insulin stimulates JH synthesis, so a decrease in the biosynthetic activity by the CA of sugar-fed females deficient in INSr is expected. On the other hand, the significant increase in JH synthesis by the CA of starved females deficient in INSr might be explained by a systemic depletion of INSr in tissues such as brain, fat body or ovaries that might affect organismal nutrient sensing and feed back into CA physiology.JHsynthesis by the CA of female mosquitoes displays remarkable dynamic changes. The CA needs to adjust its synthetic activity to generate these dynamic changes In summary our studies are providing new insights into the regulatory circuitry that controls both JH synthesis and reproductive output in response to nutrient availability. The decrease of JH synthesis in response to starvation is primarily caused by a reduction on insulin signaling and therefore can be completely reversed by stimulation with insulin. JH primarily controls nutrient allocation into the ovaries and starvation reduces JH synthesis and redirects resources away from reproduction. The CA of starved females remains fully competent to synthesize JH; starvation triggers the up regulation of INSr mRNA in CA cells, so they became more sensitive to insulin signaling, providing a mechanism to amplify insulin signals by allowing their detection in lower concentrations once nutrients are acquired and JH synthesis needs to be reactivated.Table S1Primers used for amplification, quantification of the genes studied mRNA and to make dsRNA.(DOCX)Click here for additional data file."}
+{"text": "Functional near-infrared spectroscopy (fNIRS) is an established optical neuroimaging method for measuring functional hemodynamic responses to infer neural activation. However, the impact of individual anatomy on the sensitivity of fNIRS measuring hemodynamics within cortical gray matter is still unknown. By means of Monte Carlo simulations and structural MRI of 23 healthy subjects (mean age:  Functional near-infrared spectroscopy (fNIRS) is an optical neuroimaging technique increasingly used to investigate neural processing in healthy subjects and in psychiatric patients NIR-light penetration depth has been shown to depend on the scalp-cortex distance (SCD) using spatial distributions of correlations between hemodynamic responses concurrently measured with fNIRS and functional magnetic resonance imaging (fMRI) The frontal sinus is a fronto-polar air-filled cavity, whose morphology is highly inter-individually variable and may differ among races (mean volume standard deviation (SD):  of a large number of photon packages. MCS have repeatedly been used to describe characteristics of photon scattering and migration using head or tissue layer models Radiation Transport Equation the Beer-Lambert law can be used to calculate the attenuation The MCS implemented in our study considered the following basic principles. The light attenuation between an emitter-detector pair is decribed by The total absorbed energy from photon packages reaching the detector was Slices through three individual channel cubes (subject #20) exemplify the spatial distribution of different tissues and NIR-light absorbing voxels in . Slices The mean SCD over all channels and subjects was Based on the assumption of a rotational ellipsoid traverse of NIR-light through the tissue The parameter el-cubes . The cumel-cubes . We usedHowever, since mere distance from scalp to cortex may not fully explain the variance of nd skull . Previou skull  While NIR-light traverses biological tissues of the head (and is partly absorbed),the average pathway of the light and the average absorption distribution are best described by an elliptical curve Moreover, this study shows that (3) not only penetration depth, but also the simulated These findings are discussed with regard to previous studies and their implications for fNIRS as a functional neuroimaging technique in human neuroscience and clinical research. MCS have repeatedly been used to provide numerical solutions for the forward problem of photon migration in highly scattering biological tissues By comparing the spatial sensitivity profile of simulated NIR-light between a virtual head phantom  and a simplified layered slab model Although biological tissues absorb relatively little of the NIR-light, the exponential attenuation of light intensity along a given pathway explains the differences in tissue-wise absorption  with a mean age of We precisely defined optode locations using a typical 0 system . SpecifiThe head circumference of each subject was measured using the individual Fpz marker point  and inion head surface position. From these two points the head circumference was assessed by a mearsuring tape.Structural MRI images were acquired using a Automatic anatomical tissue segmentation was performed using the SPM8 tool New Segment, that is an extension of the default unfied segmentation However, the segmentation may have been improved by using multi-spectral data, e.g. additonal The purpose of the Monte Carlo simulation (MCS) implemented in this study is to describe the interaction of light within different tissue types in individually segmented human heads. We thereby characterize the spatial distribution of absorbed energy in voxels along NIR-light pathways from emitter to detector. As a guideline for implementation served the MCS by weightThe MCS consecutively and perpendicularly launches photon packages from the emitter into the individual foreheads. For the packages of photons an energy amount referred to as Henyey-Greenstein phase function Because the absorption and scattering coefficient Snell's law (Depending on the difference in refractive indices (Fresnel equations under the assumption of equally distributed polarization directions:The acute incident angle of a photon hitting a surface was calculated by the dot product between the photon direction The step size We simulated the spatial distribution of voxel-wise absorbed energy of NIR-light photon packages reaching the detector within the channel-cubes. Each weight loss Optical properties of each tissue type were described by four coefficients taken from the literature: Absorption coefficient Depending on For To estimate how many photons are required for the MCS to obtain stable absorption distributions, the MCS was conducted for channel #1 and #9 of two subjects with increasing number of emitted photon packages The SCD was individually assessed for each subject and NIRS channel. We calculated the radial distance between the reference point on the head surface and the closest volume per mille of gray matter within a channel cube. The layer thickness of scalp, skull and CSF layers ("}
+{"text": "Alces alces) contribute to landscape patterns in predation by wolves (Canis lupus) in Isle Royale National Park, Lake Superior, USA. We use pattern analysis and kernel density estimates of moose kill sites to demonstrate that moose in senescent condition and moose in prime condition tend to be wolf-killed in different regions of Isle Royale in winter. Predation on senescent moose was clustered in one kill zone in the northeast portion of the island, whereas predation on prime moose was clustered in 13 separate kill zones distributed throughout the full extent of the island. Moreover, the probability of kill occurrence for senescent moose, in comparison to prime moose, increased in high elevation habitat with patches of dense coniferous trees. These differences can be attributed, at least in part, to senescent moose being more vulnerable to predation and making different risk-sensitive habitat decisions than prime moose. Landscape patterns emerging from prey life history dynamics and habitat heterogeneity have been observed in the predation ecology of fish and insects, but this is the first mammalian system for which such observations have been made.The landscape ecology of predation is well studied and known to be influenced by habitat heterogeneity. Little attention has been given to how the influence of habitat heterogeneity on the landscape ecology of predation might be modulated by life history dynamics of prey in mammalian systems. We demonstrate how life history dynamics of moose ( Spatial variation in predation pressure is a fundamental feature of predation ecology. Such variation has been observed across a variety of spatial scales Canis lupus) predation influences the distribution of moose  carcasses where subsequent decomposition increases soil nutrient cycling and corresponding plant growth Recent evidence, derived from examination of predator-killed carcasses in mammalian systems however, suggests otherwise. For instance, wolf (Wolves are highly selective predators that disproportionately kill prey in vulnerable age and condition classes i) Does the pattern of kill sites for moose in senescent condition exhibit greater spatial clustering in specific regions of Isle Royale when compared to the pattern of kill sites for moose in prime condition? ii) Does the predicted probability of kill occurrence for senescent moose increase in inland habitats characterized by patches of conifer tree cover and high elevation when compared to the predicted probability of kill occurrence for prime moose?Variation in habitat features should be an important component of sites where wolves kill moose by life history stage. For instance, ungulates modulate predation risk through fission-fusion herding, long distance migrations, and the selection of habitat features that provide refugia 2) is located in Lake Superior, USA . The island is essentially a single-predator single-prey system Isle Royale National Park  designed to monitor wolf movement across the island. Some additional carcasses were also located during summer ground surveys that involved extensive off-trail searching. Because most carcasses in this sample were located from light fixed-wing aircraft in conjunction with estimating wolf kill rate, few moose that died during each field season were missed i) calves are easier to kill than their mothers, ii) a motherless calf is easy for wolves to kill, and iii) it is rare for wolves on Isle Royale to kill a cow and a calf at the same time. We also assessed two senescent-associated pathologies, osteoarthritis Necropsies included inferring the cause of death from field sign . For carcasses discovered during summer ground surveys, season of death was estimated from field observations including degree of decomposition and the presence of adult ticks which exist only in winter or early spring. We recorded age of the moose at time of death by counting annual cementum lines in teeth We classified moose as being in senescent condition if they exhibited signs of senescent-associated pathologies To determine if the kill sites for senescent moose tended to be more clustered when compared to prime moose we evaluated the pattern in the distribution of wolf-killed carcasses for these different kinds of moose using the Ripley's K function www.cran.r-project.org>, accessed 1 Dec 2010) using least-squares cross-validation If significant clustering in kill sites was apparent, our next objective was to evaluate whether the probability of kill occurrence for senescent moose increased in specific areas of the island when compared to prime moose kill occurrence. To facilitate this comparison, we developed kernel density estimates (KDE) of the kill sites for prime and senescent moose. We coded these KDEs in R . We used the National Elevation Dataset to portray elevation (in meters) and calculate slope (in degrees). We also assessed distance to Lake Superior shore and distance to nearest inland lake (in meters). Habitats close to the Isle Royale shore tend to be characterized by a greater distribution of preferred conifer species for moose forage  were derived from the U.S. Geologic Survey's National Land Cover Database NLCD; , which iTo evaluate whether the probability of kill occurrence for senescent and prime moose was characterized by different habitat features, we built spatially-explicit multiple linear regression models for each type of moose by quantifying habitat in an area around each carcass location of 0.79 ha . This scale corresponds to the spatial extent of daily moose movements  took the form; P<0.01) spatial clustering in prime .Bayesian analysis indicated that the kill zone of the senescent moose KDE corresponded to the top 30% of the distribution . For comg 84 km2 . The prig 84 km2 . Taken tDifferences in the distribution and extent of kill zones for prime and senescent moose were associated with differences in habitat features. As the probability of kill occurrence for prime moose increased, habitat at kill sites was characterized by greater canopy cover (\u03b2\u200a=\u200a2.73) and less conifer cover  are one of the basic mechanisms that can result in a ratio-dependent functional response sensur in the Lotka-Volterra formulation of predation; see also Landscape patterns in predation can also have a destabilizing influence on predation dynamics sensu. This isConversely, spatial heterogeneity across a landscape can have a stabilizing influence on predator-prey dynamics through other potentially relevant mechanisms involving, for example, spatial heterogeneity in density and non-linear responses to density-dependent processes Figure S1Standardized regression coefficients with standard error bars from the multiple linear regression model (with insignificant coefficients removed) describing habitat features at prime and senescent moose kill sites in Isle Royale National Park, Lake Superior, USA, 2000\u20132008. The response variable for this model was the percentile of the kernel density estimate see  at each (JPG)Click here for additional data file."}
+{"text": "Our studies identified a deficiency in the ability to generate mature dendritic cell using CD14+ cells from cancer patients that corresponded with an increased population of monocytes with altered surface marker expression (CD14+HLA-DRlo/neg). Further studies identified systemic immune suppression and increased concentrations of CD14+HLA-DRlo/neg monocytes capable of inhibiting T-cell proliferation and DC maturation. Together, these findings strongly suggest that protocols aimed at immune stimulation via monocytes/dendritic cells, if optimized on normal monocytes or in systems without these suppressive monocytes, are unlikely to engender effective DC maturation in vitro or efficiently trigger DC maturation in vivo. This highlights the importance of developing optimal protocols for stimulating DCs in the context of significantly altered monocyte phenotypes often seen in cancer patients.Dendritic cells are an important target in cancer immunotherapy based on their critical role in antigen presentation and response to tumor development. The capacity of dendritic cells to stimulate anti-tumor immunity has led investigators to use these cells to mediate anti-tumor responses in a number of clinical trials. However, these trials have had mixed results. The typical method for generation of  Increasgnancies .+HLA-DRlo/neg monocytes are detectable systemically in patients with a variety of malignancies and that they are functionally immune suppressive raises important questions regarding their influence in ex vivo DC vaccine preparations. To address this, we have studied the effects of these altered monocytes on mDC generation across several cancer types using an ex vivo culture system. Briefly, CD14+ mononuclear cells were isolated from buffy coats or apheresis leukoreduction system chambers of normal donors using immunomagnetic selection  with the cells in excess cytokines. This deficit likely represents a significant block in the differentiation pathway. This strongly suggests that immune stimulation in vivo, even with precise targeting of the pathways known to convert mature DC, is unlikely to efficiently trigger mDC maturation in patients. Further understanding of the biology of these CD14+HLA-DRlo/neg monocytes is needed; strategies to overcome the effects of these cells can lead to better DC generation and immune reconstitution.Cancer patients showed significant deficits in the ability to generate mDCs independent of the underlying tumor. There is also substantially more variability in the efficiency of DC generation using monocytes from cancer patients Figure B. While e Figure C. Howeveex vivo generation of mature DCs from patient myeloid-derived monocyte precursors by co-culturing with GM-CSF and various cocktails of cytokines and TLR agonists to produce mature DCs. Optimizing DC culture conditions using normal healthy donors will likely not directly translate into the protocols needed for cancer patients. It will be important for those protocols that use CD14+ cells to generate their DC product from primary patient samples to confirm and optimize the manufacturing method and assure that potent DCs are being generated. In our hands, a serum-free method that includes IL-4 is a good starting point. Adequate sampling size of the patient population is needed to determine the range of differentiation efficiency in each specific cancer patient population to inform the design of release criteria for vaccine manufacturing. Our data also have clear implications for other approaches attempting to mediate anti-tumor immune stimulation. Adjuvants known to work in healthy people may not work in cancer patients if their approach is to target the DC or DC differentiation pathways.Most currently active DC-based cancer immunotherapy protocols differ in either the cell source or some of the methods associated with the generation of DC. The most common approach has been the +HLA-DRlo/neg monocytes in promoting immunosuppression, it is imperative that we adjust our clinical practices to ensure effective outcomes for patients using DC-based immunotherapy. This will require continued efforts to develop optimal protocols for generating ex vivo DC vaccine preparations and testing these protocols in individual patients. The complexity of the human immune system and individual tumor micro environments will likely require an element of individualized protocol development to achieve optimal clinical benefit.As we improve our understanding of the importance of CD14The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Hepatoblastoma is a rare early malignant liver neoplasm occurring in infants and children. Some cases of hepatoblastoma are associated with genetic conditions such as trisomies of chromosomes 18, Beckwith-Wiedemann syndrome and familial adenomatous polyposis (FAP). The observed increase in the risk of hepatoblastoma in APC (adenomatous polyposis coli) gene mutation carriers is low, not exceeding 1%, which is associated with APC gene mutation located in the region of codons 459-1309, where most mutations identified in families affected by FAP in Poland are found. Tissues obtained from patients with hepatoblastoma but without the diagnosis of FAP show loss of heterozygocity at the locus of APC or MCC  genes. Hepatoblastoma growth is the result of the sequence of changes in genetic material. However, a major role can be ascribed to the Wnt pathway where somatic mutations have been observed in the genes of Bcathenin , beta 1.88kD) and AXIN1 (Axis inhibitor 1). We present a case of familial hepatoblastoma in a 3-month-old infant with a constitutional mutation in the APC gene."}
+{"text": "Neuronal networks are able to synchronize in phase-locking regimes. Depending on the structural connectivity it is possible to determine the sign of the phase difference between oscillatory nodes. Specially in unidirectionally coupled motifs the relative phase difference is usually positive. However it has been shown that in the presence of dynamical inhibitory loops, unidirectionally coupled neuron models may present both positive or negative phase difference . The unuThese results are important in light of the growing experimental evidence that the synaptic strength between neurons can undergo spike-timing-dependent plasticity (STDP) . In the Considering that in certain situations the relative potentiation in strong synapses is less intense than in weak synapses, but the depression do not show this dependence , we comp"}
+{"text": "Networks are employed to represent many nonlinear complex systems in the real world. The topological aspects and relationships between the structure and function of biological networks have been widely studied in the past few decades. However dynamic and control features of complex networks have not been widely researched, in comparison to topological network features. In this study, we explore the relationship between network controllability, topological parameters, and network medicine (metabolic drug targets). Considering the assumption that targets of approved anticancer metabolic drugs are driver nodes (which control cancer metabolic networks), we have applied topological analysis to genome-scale metabolic models of 15 normal and corresponding cancer cell types. The results show that besides primary network parameters, more complex network metrics such as motifs and clusters may also be appropriate for controlling the systems providing the controllability relationship between topological parameters and drug targets. Consequently, this study reveals the possibilities of following a set of driver nodes in network clusters instead of considering them individually according to their centralities. This outcome suggests considering distributed control systems instead of nodal control for cancer metabolic networks, leading to a new strategy in the field of network medicine. Ever since Otto Warburg discovered the unique characteristics of tumor cell metabolism over 80 years ago Reconstructed human metabolic networks provide a useful tool for the study of diseases and the development of drugs. Several simulations and modeling methods have been developed to address the issues of drug-target prediction Network medicine is a new subject that tries to link topological network properties to biological function and disease. Network medicine explores the molecular complexity of a special disease and relationships between distinct phenotypes which may lead to the identification of disease modules and pathways k is treated as if it were a set of k nodes There have been reactions to Liu's work. Ferrarini Both nodal and edge dynamics frameworks (the approaches mentioned above) have been implied for covering unipartite graphs. In 2013, Nacher et al. introduced a modified version of MDS in order to study the controllability of bipartite networks. The results demonstrated that MDS tends to select high degree nodes and nodes with a high betweenness centrality in bipartite networks. But the author mentioned that this approach may not be possible in some kinds of biological networks such as Protein-Protein Interaction (PPI) and metabolic networks.In this paper, we have tried to explore possible relation between topological analysis, structural controllability, and metabolic networks. We have applied a comprehensive  topological analysis of recently published genome-scale metabolic models of normal and cancer tissue-specific models to assess the controllability relation between topological parameters and drug targets (as driver nodes),with the assumption that the targets of approved anticancer metabolic drugs are driver nodes and therefore control cancer metabolic networks. In addition, the outcomes of metabolic networks controllability could create insights leading to the discovery of novel drug targets. We have shown that besides primary network parameters, more complex network metrics such as motif and clusters may also provide new tools for addressing network controllability in metabolic networks. Characterizing the drug target in enzyme-centric clusters shows that most of the drug targets belong to one specific cluster of an enzyme-centric network. This could provide new insight into considering distributed control systems (DCS) instead of nodal control for cancer metabolic networks Omics data such as transcriptomic data are often noisy. In addition, mRNA expressions are relative to a reference condition and sometimes do not correlate well with enzyme levels http://www.metabolicatlas.com/All original SBML files have been downloaded from The SBML files are bipartite graphs including two types of nodes (metabolites and reactions). Bipartite characteristics of metabolic networks make it difficult to analyse them with structural methods. In addition, metabolite-metabolite (metabolite-centric) and enzyme-enzyme (enzyme-centric) networks can provide extra insights and are therefore relevant for further analysis of the metabolism. It is also necessary to address structural controllability based on nodal dynamics (the approach of this study), and to construct metabolite- and enzyme-centric networks. We have written scripts in MATLAB software (R2012b) in order to construct undirected and directed metabolite-centric, as well as undirected and directed enzyme-centric networks based on SBML files. We have added network construction procedures including the algorithms in the Network Analysis plugin in Cytoscape Primary topological analysis has been carried out on four different networks of normal and cancer cell metabolic networks  using the cytoHubba plugin Centrality analysis has been carried out on the directed enzyme-centric networks of cancer and normal cell types using the Motif finding has been carried out on the directed metabolic and enzyme-centric networks of cancer and normal cell types using the Quatexelero algorithm MCODEClustering analysis has been performed on the directed enzyme-centric networks of cancer and normal cell types using the For finding anticancer metabolic drugs and their targets, we have used the drug bank database k connections to other nodes satisfies the following relation Since metabolic networks satisfy power-law degree distribution, scale-free, and small-world properties Centrality parameters are global properties of a network that rank graph nodes according to their importance in the network. The higher the rank, the more important a node is in the network, indicating that it may play key roles in controlling cellular functions. We have carried out centrality analysis for directed enzyme-centric networks. All enzymes in 15 enzyme-centric networks have been sorted according to 12 different centrality parameters in order to check whether drug targets appears as highly connected nodes. As Network motifs  have served as the building blocks of biological networks from bacteria to mammals, and their function has been experimentally studied in some species such as the transcription network of E. coli MCODE clustering algorithm  through clusters in the enzyme-centric network of cancer cell types. The results shows drug targets gather in a specific cluster of an enzyme-centric network of the cancer cell  contribute to controllability In this study, we have explored the relationships between structural network controllability, topological parameters, and network medicine (metabolic drug targets). We have applied a topological analysis to genome-scale metabolic models of 15 normal and corresponding cancer cell types. First, we have constructed metabolite- and enzyme-centric networks based on the metabolic SBML files. We have performed primary topological analysis to check whether there are any structural differences in the metabolite-centric and enzyme-centric of normal and cancer metabolic networks. The results show all constructed networks satisfy scale-free and small-world properties. But there is not any significant differences between normal and cancer tissues. Next, we have used the MDS concept in metabolic networks since controlling cancer metabolism through internal signals seems more reasonable biologically. Metabolic networks are appropriate choice because they allow us to consider both metabolite-centric  and enzyme-centric  networks separately. Based on an assumption (the targets of approved anticancer metabolic drugs are driver nodes and therefore control cancer metabolic networks), we wanted to explore whether it is possible to explore topological parameters which could specify driver nodes in the metabolic networks. So, we have done two studies based on the MDS controllability concept in the enzyme-centric metabolic networks: 1) to check whether driver nodes tend to be part of centrality indexes such as highly connected nodes (Hubs). 2) to explore topological parameters which could specify driver nodes in the metabolic networks.In performing centrality analysis, the distribution of drug targets among the 100 top of twelve centrality parameters was not significant. It means that drug targets avoid being highly connected enzymes. So, different centralities used in this study could not consider as a driver node for controlling systems. Motifs, as another local property of networks, have also been examined and there was no difference in metabolite-centric networks of cancer and normal cell types, but there were significant discrepancies in the enzyme-centric networks of cancer cells and their corresponding normal cell types. The number of clusters between cancer and corresponding normal cell networks show no significant differences, but characterizing drug targets in enzyme-centric clusters shows that most of the drug targets belong in one specific cluster of an enzyme-centric network. Therefore our results indicate that besides primary network parameters, more complex network metrics such as motifs and clusters may be also appropriate parameters for controlling the metabolic systems. Besides, for metabolic networks, enzyme-centric networks could be more reliable in the context of controllability, although little attention has been paid to such networks in systems controllability. The outcomes of metabolic network controllability could create insights into the discovery of novel drug targets.The results also suggest considering DCS File S1Compare metabolites and reactions between normal and cancer models .(RAR)Click here for additional data file.File S2Lists of metabolites and reactions of cancers models.(XLSX)Click here for additional data file.File S3Lists of metabolites and reactions of normal models.(XLSX)Click here for additional data file.File S4Constructed networks .(RAR)Click here for additional data file.File S5Summary definition of the different parameters.(DOC)Click here for additional data file.File S6Anticancer metabolic drugs and their targets.(XLSX)Click here for additional data file.File S7Metabolic functions of the drug targets.(XLSX)Click here for additional data file.File S8Primary topological parameters for all constructed networks (including metabolite- and enzyme-centric directed and undirected networks).(RAR)Click here for additional data file.File S9Centrality data .(RAR)Click here for additional data file.File S10Motif data .(RAR)Click here for additional data file.File S11Clustering data .(RAR)Click here for additional data file.File S12Power-law plots for every constructed network with fitting results (including metabolite- and enzyme-centric directed and undirected networks).(RAR)Click here for additional data file.File S13Network construction procedures.(DOCX)Click here for additional data file."}
+{"text": "The molecular complexity of genetic diseases requires novel approaches to break it down into coherent biological modules. For this purpose, many disease network models have been created and analyzed. We highlight two of them, \u201cthe human diseases networks\u201d (HDN) and \u201cthe orphan disease networks\u201d (ODN). However, in these models, each single node represents one disease or an ambiguous group of diseases. In these cases, the notion of diseases as unique entities reduces the usefulness of network-based methods. We hypothesize that using the clinical features (pathophenotypes) to define pathophenotypic connections between disease-causing genes improve our understanding of the molecular events originated by genetic disturbances. For this, we have built a pathophenotypic similarity gene network (PSGN) and compared it with the unipartite projections (based on gene-to-gene edges) similar to those used in previous network models (HDN and ODN). Unlike these disease network models, the PSGN uses semantic similarities. This pathophenotypic similarity has been calculated by comparing pathophenotypic annotations of genes  in the \u201cHuman Phenotype Ontology\u201d. The resulting network contains 1075 genes (nodes) and 26197 significant pathophenotypic similarities (edges). A global analysis of this network reveals: unnoticed pairs of genes showing significant pathophenotypic similarity, a biological meaningful re-arrangement of the pathological relationships between genes, correlations of biochemical interactions with higher similarity scores and functional biases in metabolic and essential genes toward the pathophenotypic specificity and the pleiotropy, respectively. Additionally, pathophenotypic similarities and metabolic interactions of genes associated with maple syrup urine disease (MSUD) have been used to merge into a coherent pathological module.Our results indicate that pathophenotypes contribute to identify underlying co-dependencies among disease-causing genes that are useful to describe disease modularity. Phenotypes are the result of the expression of specific genetic backgrounds submitted to the influence of changing environmental conditions th century following Osle\u0155s principles However, current pathognomonic classifications are influenced by the traditional clinical procedures used during the 19In this work, network medicine approaches have been used to study the pathological relationships among genes using semantic similarities (that in this case are pathophenotypic similarities) instead of inferred unipartite edges (gene-to-gene) from bipartite edges (disease-to-gene associations). For instance, a classification of four distinct disease-to-gene associations is proposed  to illusSummarizing, this work provides evidence that a standard phenotypic profiling expands the genetic disease associations using a specific ontology for human abnormalities. These pathologic relationships among genes were not obvious and, consequently, disregarded in previous disease network analyses.http://www.omim.org/). HDN represents a bipartite projection of edges with two types of nodes, genes (MIM genes) and diseases (MIM phenotypes and genes/phenotypes) as described in OMIM. We followed a similar methodology to the one described by Goh et al. In the present study, we worked on an updated version of the \u201cHuman Diseases Network\u201d (HDN) An updated version of the \u201cOrphan Disease Networks\u201d (ODN) Both HDN and ODN were decomposed into four subclasses, based on the classification of the different types of disease-to-gene associations : monogenth percentile that corresponds to the top 2% of significant gene pairs with higher semantic similarity values. To assess this clustering process of PSGN in the top 2% of phenotypic similarity, we plotted a kernel density distribution of probability of the pathophenotypic similarity for gene pairs . Previously, we had to describe the pathophenotypic space for genes as the set of clinical features (HPO terms) associated with each gene. Altogether 4669 diseases and 258 genes have direct annotations of their clinical features in HPO, so these diseases and genes have a list of HPO terms describing their phenotypic space. However, the lack of specific HPO terms regarding phenotypic abnormalities for many disease-causing genes hinders the explanation of their semantic relationships in the ontology. Many genes are annotated in the ontology with the sum of all HPO terms that describe their associated diseases in Morbid Map. In these cases, we used the file \u201cgene_to_phenotype.txt\u201d (available on HPO website) to link HPO terms and genes. This file was generated using Morbid Map associations between genes and diseases. Therefore, clinical features described in OMIM were translated in a standardized vocabulary of HPO terms  that have been used to define a pathophenotypic space. As mentioned above, this pathophenotypic space for a gene can be directly annotated in HPO or indirectly annotated by the diseases associated with the gene in Morbid Map. We used the phenotypic space of genes to calculate their pathophenotypic semantic similarities with other genes. Only HPO terms with maximal information were used in agreement with the ontology properties and distribution of terms . We discarded those branches of the ontology without an explicit description of phenotypic abnormalities such as \u201cmode of inheritance\u201d and \u201conset and clinical course\u201d. We obtained a large pathophenotype gene network based on all semantic similarities between genes sharing HPO terms annotated in the phenotypic abnormality branch of the HPO. Despite an extensive literature review we could not detect a systematic methodology to calculate a cut-off score distinguishing between relevant or non-specific semantic similarities. Previous works used the semantic similarity to validate predictions or to evaluate shared biological features between highly specific subset of genes. However, in this case, we needed an optimal statistical threshold from which the signals, pathophenotypic similarities, should be out of the background noise. The cut-off will predetermine the topology of the network, so it could affect arguments and discussion about the \u201cexpansion\u201d of pathophenotypic relationships respect to current unipartite projections (HDGN and ODGN). If we select a low similarity score we will introduce exponentially nonspecific relationships. In contrast, a very high score will constraint the model to already known pathological relationships. Therefore, we used the subset of known pathophenotypic similarities (gene pairs) in a binary classification system to estimate the optimal statistical threshold . This network of protein-to-protein physical interactions contains 10299 genes (Ensembl gene IDs) and 80922 interactions supported by evidence from at least one experiment Metabolic networks are usually based on different metabolic coupling approaches such as metabolite sharing  th percentile instead of the 98th. Thus we selected the top 0.5% of gene pairs with higher functional similarities . The functional space of a gene is represented by the set of GO annotations about the biological context where the gene is involved. Thanks to these annotations, genes are directly linked to biological processes describing all the functional features direct or indirectly related to genes. Classical semantic similarity measurements were used to calculate functional similarities between genes according to their functional space. In a similar procedure used for PSGN we removed unspecific functional associations in FSGN generated by irrelevant semantic relationships. However, there are great differences in the number of annotations between HPO and the branch of biological processes of GO. In this case, the main concern is that it resulted in huge size of this dataset. Therefore, we preferred to be quite more restrictive for this threshold, by taking as cut-off the 99.5larities .The way to assign terms to objects is to add annotations. In the present case, the objects represent genes and terms corresponding to phenotypes (HPO terms) or biological processes (GO terms). The specificity of the terms associated with genes allows us to calculate the most significant relationships between them, which use to be related to its proximity to the root. The method we have chosen to calculate the semantic similarity between objects annotated is mainly based on the classical Resnik\u2019s measurement For t1 and t2 terms in the ontology, the semantic similarity proposed by Resnik is defined as:Many studies so far have made a comparison between semantic similarity measurements using the Gene Ontology, but it seems that there is not a gold standard for semantic similarity measures between set of GO terms. In this work we use:Human Phenotype Ontology is still a novel tool and there are not many works related to the calculation of semantic similarity for this data structure. We have chosen the method proposed by the HPO creators for the comparisons between phenotypic profiles The previous equation does not provide a symmetric matrix, since the calculated semantic similarity between g1 and g2 will not be the same as semantic similarity between g2 and g1, so Robinson and co-workers http://igraph.sourceforge.net/). Due to the large number of subsequent analysis of all built network, we provided a schematic workflow of all the essential steps followed for this study . In the case of disease-causing gene networks (HDGN and ODGN unipartite projections of diseasomes), the intersection could provide a broad view of the similarity of these networks and the PSGN. Previously, we also calculated the intersection of edges between HDGN and ODGN to assess their mutual similarity. For biomolecular interactomes  the nodal and edge intersection can be useful to explore the underlying molecular events of pathophenotypic similarities. However, biomolecular interactomes require two steps before the intersection analysis. First, we filter networks to ensure that both compared networks have only intersected nodes to minimize their differences in sizes (see schematic diagram of the process in All gene (node) degrees were calculated for each pathological network and biomolecular interactome, using the iGraph software. Subsequently, a non-parametric test was used to study in each subset of genes the distributions of the node (gene) degree, the number of associated pathophenotypes per gene and the mean value of pathophenotypic similarity per gene. More precisely, a Mann-Whitney test was used to assess the significance of these distributions for gene subsets with the distributions of all genes in PSGN and their respective disease-causing gene network. This non-parametric test was run 1000 times for every subset of genes using a different random sample in each test. These random samples conserved the same size (number of genes) as their respective subset in the correspondent network. Subsequently, we calculated the mean p-value of all runs for every subset. Additionally, a Spearman's rank correlation test (\u03b1\u200a=\u200a0.05) was used to analyze the degree of genes in HDGN, ODGN, PIN, MGN and FSGN with respect to the number of pathophenotypic relationships in PSGN.A binary classification system was used to analyze the performance of intersected interactions between different cellular networks  and phenotypic interactions in PSGN. This binary classification is based on signal detection theory, using a receiver operating characteristic (ROC) analysis The projection in networks of the genetic associations data, available in OMIM and Orphanet, shows different patterns of connectivity among diseases and mutated genes . Thus, wThe abundance of genes in each subset indicates how genetic association studies tend to distribute genes with different degrees of specificity for pathologies. In both networks, monotropic genes are found to be the most abundant ones, irrespective of the actual number of genes involved in the diseases . For insThe ratios of diseases per gene agree with a pathological convergence (exclusive associations) and divergence (non exclusive associations) for monotropic and pleiotropic genes respectively . These rFrom the bipartite projections (disease-to-gene) of HDN and ODN, we built their corresponding unipartite projections (gene-to-gene) (as can be seen in HDGN include 749 genes (nodes) and 2654 inferred gene-gene relationships (edges) among them . Howevera priori which indicates strong differences between the two data sources (OMIM and Orphanet).We carried out an analysis of the intersection between both unipartite networks (HDGN and ODGN) to assess an estimation of their similarity. But first we removed all unconnected nodes because they were not considered structural components of these networks. The resulting intersection was 481 genes (intersected nodes) and 662 inferred gene-gene relationships (intersected edges) corresponding to 24% and 10% of edges in HDGN and ODGN respectively . Both neThese results reinforce the hypothesis that the absence of a systematic procedure in the phenotypically characterization of genetic diseases will affect the utility of network medicine methods. In particular, it leads to the isolation of genes and diseases from their real pathological processes, making it practically impossible to identify groups or subgroups of related pathologies. This observed tendency to the exclusiveness  considerably increases the disease-gene association specificity that may be of interest for genetic testing.The exclusiveness mentioned above could affect pathological processes with many disease variants. In the case of these diseases, some genes play a primary role in the progression of the pathology but others modulate the phenotypic variability.To tackle this problem, HPO offers possibilities for a formal study of the pathophenotypic relationships among genes on the bases of their semantic similarities (pathophenotypic similarities). Therefore, we defined the pathophenotypic space of each gene, consisting of the set of HPO terms associated with the gene  with 1075 genes and 26197 gene-to-gene pathophenotypic similarities . DiseaseAlmost all the pathophenotypic gene annotations used in HPO originally come from OMIM and they represent the sum of all clinical features of diseases associated with a gene. Accordingly, the pathophenotypic similarity for a gene is somehow dependent on the number of diseases associated with this gene (see methods section). Hence, we proceed with a comprehensive study to assess whether the pathophenotypic similarity can be used to reinterpret the pathological relationships between genes  was carried out with an analysis of their intersections.The resulting intersections of PSGN with each unipartite projection proved 528 shared nodes and 1055 shared edges for HDGN and 931 and 1669 for ODGN . TherefoWe have also studied how genes in PSGN are distributed in comparison to HDGN and ODGN. Subsequently, we analyzed the degree distribution of genes for each network , as well as for their respective gene subsets . We carried out a Mann-Whitney test to assess the significance of the difference of the degree distribution of each subset in their respective disease-causing gene network and in PSGN . By contThe (apparently) most striking observation is that genes uniquely associated with monogenic diseases (genes in MD-MG and many of MD-PG) are present in PSGN. The vast majority of these genes appeared as unconnected genes in the unipartite projections of HDN and ODN  pathophenotypic relationships.Taking into account that metabolic and essential disease genes represent about 18% and 34% respectively of the total disease-causing genes, we also studied how they are represented in each subset of genes in our classification . The subBiunivocal classes (MD-MG) are markedly enriched in metabolic coding genes with respect to the other classes; on the contrary, PD-MG is underrepresented by metabolic enzymes. On the other hand, the pathophenotypes corresponding to metabolic genes do not differ from those of the whole pathophenome  the progression of the diseases \u2018A network intersection analysis was carried out using the PSGN as reference and the biomolecular interactomes  as queries. Nevertheless, the observed differences in size and density of the studied networks could be the cause that the direct network comparison analysis would provide no useful significance values. Therefore, we decided to standardize the contents of the networks by using the intersection of nodes (see methods section) to minimize differences between the reference (PSGN) and the rest of the networks . This step  provokedThe network comparison results show statistically significant intersections of edges for all biomolecular interactome sub-networks compared to their respective PSGN sub-network . This waMost of the published network biology studies have made use of the degree of a node (number of connections with other nodes) to assess its relevance in a network. In fact, node degree has been extensively used in physical interaction networks To estimate whether the abundance of biological interactions for genes is correlated with the number of phatophenotypic similarities in PSGN, we carried out a Spearman's rank correlation test of gene degrees. This test showed weak, but statistically significant, positive correlations between gene degrees for the whole set of genes  when PIN was compared to PSGN. No significant correlations were found when either MGN or FSGN were compared to PSGN . The valWe analyzed a metabolic disorder named as maple syrup urine disease . MSUD is a genetic disease grouped into aminoacidurias and caused by a decreased activity of the branched-chain alpha-ketoacid dehydrogenase (BCKD) complex. It catalyzes the first steps for the degradation of branched-chain amino acids . This enzymatic complex has three subunits  encoded by four different genes BCKDHA-E1A (Entrez GeneID 593), BCKDHB-E1B (Entrez GeneID 594), DBT-E2 (Entrez GeneID 1629), and DLD-E3 (Entrez GeneID 1738). This inborn error of metabolism is genetically and phenotypically well characterized This metabolic syndrome illustrates the potentials of PSGN. This network provides novel pathological similarities between genes and outlines the pathobiology and functional context of disease-causing genes using metabolic interactions.Finally, given the relevance of the physical interactions, we carried out a manual exploration of the intersection between PIN and PSGN. This is to remove all those gene-to-gene edges in both HDGN and ODGN from the resulting intersection. This resulted in the selection of all the disregarded relationships between genes in unipartite projections of diseasomes that are phenotypically and physically related . TherefoCurrent studies in medical genetics are mainly centered in establishing associations among diseases and genetic variations for personalized medicine. Many of these genetic variations are located in intragenic regions of DNA and they constitute the basic data to build disease-causing gene networks In the future, network integration and standardization of molecular and cellular phenotypes could improve the understanding of the evolutionary mechanisms involved in pathological processes. Further experimental and analytical efforts in this direction are warranted.Figure S1Schematic representation of the workflow of essential steps followed in this study: building network processes, optimal statistical threshold selection, network comparisons, topological analysis and ROC curve construction.(PDF)Click here for additional data file.Figure S2Spearman correlation between the number of pathophenotypes per gene and the average pathophenotypic similarity per gene for PSGN genes.(PDF)Click here for additional data file.Figure S3Graph of the pathophenotypes annotated to maple syrup urine syndrome. Parental nodes are close to the root in the human phenotype ontology and, therefore, with lower specificity. In contrast, child nodes are the most informative and specific pathological phenotypes.(PDF)Click here for additional data file.Table S1Bipartite and unipartite projections of the updated version of the human diseases network.(XLS)Click here for additional data file.Table S2Bipartite and unipartite projections of the updated version of the orphan disease network.(XLS)Click here for additional data file.Table S3Different gene subsets in the human diseases network following proposed classification.(XLS)Click here for additional data file.Table S4Different gene subsets in the orphan diseases network following proposed classification.(XLS)Click here for additional data file.Table S5Different biomolecular interactomes based on physical, metabolic and functional interactions.(XLS)Click here for additional data file.Table S6Biomolecular interactome and PSGN sub-networks after nodal intersections.(XLS)Click here for additional data file.Table S7Pathophenotypic similarity gene network.(XLS)Click here for additional data file.Table S8Spearman correlations between gene degrees in PSGN and HDGN/ODGN.(PDF)Click here for additional data file.Table S9Spearman correlation between gene degrees in PSGN and biomolecular interactomes.(PDF)Click here for additional data file.Table S10Network intersection between PSGN and PIN removing inferred gene-to-gene associations.(XLS)Click here for additional data file.Methods S1(PDF)Click here for additional data file."}
+{"text": "Relative individual information is a measurement that scores the quality of DNA- and RNA-binding sites for biological machines. The development of analytical approaches to increase the power of this scoring method will improve its utility in evaluating the functions of motifs. In this study, the scoring method was applied to potential translation initiation sites in Drosophila to compute Translation Relative Individual Information (TRII) scores. The weight matrix at the core of the scoring method was optimized based on high-confidence translation initiation sites identified by using a progressive partitioning approach. Comparing the distributions of TRII scores for sites of interest with those for high-confidence translation initiation sites and random sequences provides a new methodology for assessing the quality of translation initiation sites. The optimized weight matrices can also be used to describe the consensus at translation initiation sites, providing a quantitative measure of preferred and avoided nucleotides at each position. MEME [Understanding how biological machines work in the context of genomes, transcriptomes, and proteomes requires appropriate languages and representations for successful modeling of their biological processes. Information theory provides one of the foundations for this goal and underlies sequence motif-finding algorithms such as MEME . For exaMEME \u20134. The aIn this study, several analytical approaches are integrated to increase the power of these scoring methods using Drosophila translation initiation sites as a model setting. As an introduction, we describe first the information theoretic basis for these scoring methods. Motifs of functional importance can be quantitatively assessed through their sequence conservation, measured as information content in sets of aligned sequences , 5, 6. TThe summation represents the uncertainty based on the frequencies of occurrence ncreases . relative information  at each nucleotide position It is sometimes important to take into account nonrandom background nucleotide frequencies. For example, the mean frequencies of each nucleotide in Drosophila cDNAs deviate significantly from 0.25 , and thiwhere groups of aligned sequences. The theory can be extended to allow assessment of individual sequences. Measurement of individual information allows scoring of how well an individual sequence conforms to a conserved motif [individual information of The information values defined above are based on ed motif . For exaed motif . Individwhere relative individual information  which is defined as follows: Nonrandom background nucleotide frequencies can be taken into account using where ce sites , backgroMEME [distributions of TRII scores for sets of sequences of interest. By appropriate choices of control test TRII score distributions, this approach allows one to interpret score distributions for sites of interest in a probabilistic manner. Analysis of score distributions provides insights into translation initiation: potential initiation sites with TRII scores that resemble high-confidence start sites can be considered likely initiation sites whereas sites similar to random sequences are likely to be weak or nonfunctional for translation initiation. We also discuss how the methods described in this paper can be applied to the initiation context scoring method of Miyasaka [Relative individual information scoring of individual DNA and RNA sequences has been discussed previously , and forMEME  which arMiyasaka  which haMiyasaka . In contAn initial goal of this analysis was to define sets of high-confidence translation start sites whose TRII score distributions could be used as standards for analysis of TRII score distributions of other test sets. Previous studies have tended to rely on \"curated\" gene sets to define training sets of high-confidence translation initiation sites. Instead, we developed a bioinformatics approach to identify large sets of initiation sites in which we could have high confidence.'UTRs has been associated previously with weak contexts of translation start codons in several organisms [In previous studies , 4, we st Figure . Relativt Figure . Consistrganisms .We hypothesized that the depressed relative information levels at annAUGs associated with upAUGs might be explained by the presence of annAUGs that are weak or nonfunctional translation initiation sites. For example, weak or nonfunctional annAUG sites might be expected if there is translation initiation at upAUGs followed by translation reinitiation \u201316 at an'UTRs contain at least 200 nucleotides  scores were calculated using a reference set 'UTR \u2265 200) with a series of test sets of cDNAs with increasing numbers of upAUGs (and 5'UTR \u2265 200). To represent weak or nonfunctional annAUGs, we generated the set 'UTR background nucleotide frequencies. Figure We compared a control test set of cDNAs with no upAUGs , and a higher-scoring set of likely functional annAUGs (represented by the 0-upAUG set). For the test set with \u226510 upAUGs, a large fraction  of the annAUGs appears to be low scoring and possibly nonfunctional  to modify the weight matrices that underpin the TRII scoring method, and (ii) to provide control test score distributions for assessment of scores. We first discuss optimization of the weight matrix. Up to this point, we have used We observed that using 0-upAUG reference sets gives a greater spread of relative individual information values\u2014a higher \"dynamic range\" of scores\u2014compared to using the set of all annAUGs as a reference set Figure . The entThe use of 0-upAUG reference sets is supported by our testing of the TRII score method in budding yeast  reveals strikingly similar distributions. This is consistent with gold collection cDNAs being viewed as representative of current annotated gene models. The TRII score distributions for the Gold collection and Release 5.9 predicted genes are both similar to the score distribution for the 0-upAUG set of cDNAs (blue curve), except that both have slightly greater frequencies of low-scoring start sites. We partitioned the Gold set cDNAs with 5'UTR \u2265 200 into two test subsets: those with no upAUGs, and those with 1 or more upAUGs. The 300 0-upAUG cDNAs in the Gold set have a distribution of TRII scores that is very similar to the distribution of the scores using Using the improved weight matrices, we assessed the effectiveness of using score distributions of 0-upAUG sets as control test distributions for analysis of TRII scores. Comparisons of 0-upAUG distributions with distributions for sets of translation initiation sites from the Drosophila genome project support the use of 0-upAUG sets as representative of functional initiation sites. The Berkeley Drosophila Genome Project (BDGP) cDNA sequence set was constructed by sequencing high-quality, full-length cDNA libraries. The annotated ORFs and annAUGs were determined by finding the longest ORF encoded by each cDNA. The sequenced cDNAs (copies of mRNAs), which are part of the Drosophila Genome Project, can be compared with the set of annotated genes and their transcripts that has been assembled based initially on gene prediction algorithms. A subset of the cDNA ORFs that matched ORFs of annotated transcripts in the lection\" . Gold coIn this analysis, we noticed a disparity between TRII score distributions for experimentally observed cDNAs not in the Gold collection compared to Gold collection cDNAs that match predicted transcripts. TRII score distributions were compared using chi-square goodness of fit tests  assess upstream AUGs through comparisons with control distributions, and (2) assess nonconserved annAUGs using linear combinations of control curves.'UTRs. We examined the TRII score distribution for the set of first AUGs upstream of the annAUG in gold collection cDNAs containing upAUGs (with 5'UTR \u2265 200). The distribution of TRII scores , this suggests that there may be some selection in favor of C or U at this position to reduce the likelihood of translation initiation at upAUGs. These observations suggest that the random sequence set is an appropriate comparison set to represent weak or nonfunctional AUGs in analysis of TRII score distributions. Nucleotide position \u22123 plays a central role in defining the consensus motif for translation initiation in Drosophila . We observed that 57.6% of the upAUGs have C or U at this position, in contrast to only 7.6% of the annAUGs in the 0-upAUG set. Given that 47.5% of random sequences have C or U at this position . The set of reference sequences Release 5.9 Drosophila melanogaster genome are also provided in Supplementary Material The weight matrix used to calculate the TRII scores is provided in Supplementary Material In Table The significant overlap in the TRII score distributions for random sequences and high-confidence initiation sites makes it necessary to treat intermediate TRII scores probabilistically as discussed above. Even though the distributions overlap, the TRII score measure can contribute to future algorithms for assessment of translation initiation in combination with other classifiers that incorporate properties such as RNA structure prediction  and sequThe methods discussed to optimize TRII scoring\u2014the utilization of high-confidence sets and probabilistic analysis of score distributions\u2014can also be applied to the initiation context scoring method of Miyasaka . The latIn addition to optimizing the TRII scoring method, the 0-upAUG high-confidence sets were used to improve assessment of nucleotide preferences at translation initiation sites. In particular, the optimized high-confidence sets of annotated translation start sites were used to assess sequence conservation at initiation sites and to compare this conservation with previous descriptions of consensus sequences , 24. Figerations . The relThis optimized 0-upAUG set Figure  was useds Figure . The wei'UTRs, the elevation in C at this position is more pronounced  scores, are provided in Supplementary Material The collections of genomic and cDNA sequences were stored in a relational database. The database schema is illustrated in Supplementary Figure As described in the Introduction, relative individual information was calculated using the expression 'UTR background frequencies are used to estimate where the sampling correction eviously , 4 assumminimizes the sum of the differences squared between these values and the values of the actual test set distribution We estimated the fraction r  Table  or  . The interface generates a weight matrix from the aligned sequences so that relative information values and relative individual information scores can be calculated for sequences of interest. The interface can be used to assess potential translation initiation sites, or other kinds of motifs for which sets of aligned sequences with the motif are available. We provide a web interface for performing calculations on sets of inputed aligned sequences (TRII: Translation relative individual information; ORF: Open reading frame; BDGP: Berkeley drosophila genome project; upAUG: Upstream AUG; annAUG: Annotated AUG; UTR: Untranslated region.Saccharomyces cerevisiae. An additional supplemental file provides the set of reference sequences S100-199 used to construct the weight matrix, and score distributions for the 0-upAUG control test set S200 and the random test sets Srand. Another supplemental file provides TRII scores for annAUGs of all predicted transcripts in the Release 5.9 Drosophila melanogaster genome.The Supplemental Materials include descriptions of statistical tests to compare TRII score distributions, individual TRII scores, and weight matrices. Weight matrices computed with various reference sets are provided, as well as a schema for the database used in this study, and a summary of the gene sets used for analysis. The Supplemental Materials close with results from a parallel analysis performed in Click here for fileClick here for fileClick here for file"}
+{"text": "The human heel fat pad (HFP) is an effective shock absorber . A remodTwenty-three healthy elderly corpulent  and nineteen non-corpulent men and women  took part in the experiment. A loading device was used for in vivo testing of the HFP (Figure Thickness variables of corpulent subjects were significantly higher compared to the non-corpulent. The stiffness was found to have a nonlinear behaviour in which corpulent subjects show lower stiffness in the final stage. There was no significant difference in \u03b5.Increased HFP thickness is an adaption process to increased body weight, suggesting that an accumulation of fat cells with good blood supply at micro chamber structure may have occurred. This process protects the macro chamber structure of the HFP against overload that is transferred by micro chambers. Therefore, the micro chamber structure of corpulent elderly may be mechanically more sensitive and damageable than in non-corpulent subjects."}
+{"text": "While there is almost universal agreement amongst researchers that autism is associated with alterations in brain connectivity, the precise nature of these alterations continues to be debated. Theoretical and empirical work is beginning to reveal that autism is associated with a complex functional phenotype characterized by both hypo- and hyper-connectivity of large-scale brain systems. It is not yet understood why such conflicting patterns of brain connectivity are observed across different studies, and the factors contributing to these heterogeneous findings have not been identified. Developmental changes in functional connectivity have received inadequate attention to date. We propose that discrepancies between findings of autism related hypo-connectivity and hyper-connectivity might be reconciled by taking developmental changes into account. We review neuroimaging studies of autism, with an emphasis on functional magnetic resonance imaging studies of intrinsic functional connectivity in children, adolescents and adults. The consistent pattern emerging across several studies is that while intrinsic functional connectivity in adolescents and adults with autism is generally reduced compared with age-matched controls, functional connectivity in younger children with the disorder appears to be increased. We suggest that by placing recent empirical findings within a developmental framework, and explicitly characterizing age and pubertal stage in future work, it may be possible to resolve conflicting findings of hypo- and hyper-connectivity in the extant literature and arrive at a more comprehensive understanding of the neurobiology of autism. Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interaction and communication, repetitive behaviors, and restricted interests. According to the latest reports, ASD affects nearly 1 in 88 children, and the prevalence continues to grow  fMRI signals are thought to arise from signal propagation and dynamical slowing down of fluctuations in anatomically constrained neural networks  has made pre-publication datasets of neuroimaging data collected from individuals between the ages of 6 and 60 available to researchers to facilitate and accelerate the discovery of the functional architecture of the autistic brain  summarize the current status of the field by highlighting key findings from studies using fMRI to examine task-related and intrinsic functional connectivity in individuals with ASD across various age groups, (2) reveal critical gaps in the literature which have led to an inconsistent characterization of functional connectivity in ASD, and (3) argue that a developmental perspective can help reconcile some extant contradictory findings, and is necessary for future progress in the field.Autism is a disorder with early life onset and variable developmental trajectory  children and children with ASD  approach to demonstrate functional hypo-connectivity in anterior\u2013posterior connections in adolescents and adults with ASD . A survey of presentations at recent meetings of the International Meeting for Autism Research (IMFAR) and the Organization for Human Brain Mapping (OHBM) suggests that this may in fact be the case. Deen and colleagues conducted ROI-based analyses on data collected from children aged ~13 with ASD and TD control participants. In a poster presented at IMFAR in 2011, they report: \u201cA number of group differences were found in both directions, with no trend toward more differences in the direction of TD>ASD \u2026 in the ROI analysis, 19 correlations were stronger in the TD group, while 38 were stronger in the ASD group\u201d  and outside (distant) its neighborhood defined as a sphere of 14 mm radius  encompasses a wide range of abilities and levels of functioning. Almost no functional brain imaging data is available from individuals who are considered \u201clow-functioning.\u201d Additionally, because of the 4:1 male:female ratio in diagnosis  with ASD  reviewed the emerging literature on intrinsic functional brain connectivity in ASD, (2) identified results of hypo- and hyper-connectivity as being partially attributable to the age of participants examined, and (3) proposed that longitudinal studies examining pre- and post-pubertal individuals with ASD are sorely needed to resolve current controversies regarding the nature of brain connectivity abnormalities in the disorder. A developmental perspective will contribute greatly to future research efforts in autism neuroimaging.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "X-ray dark-field scatter imaging allows to gain information on the average local direction and anisotropy of micro-structural features in a sample well below the actual detector resolution. For thin samples the morphological interpretation of the signal is straight forward, provided that only one average orientation of sub-pixel features is present in the specimen. For thick samples, however, where the x-ray beam may pass structures of many different orientations and dimensions, this simple assumption in general does not hold and a quantitative description of the resulting directional dark-field signal is required to draw deductions on the morphology. Here we present a description of the signal formation for thick samples with many overlying structures and show its validity in experiment. In contrast to existing experimental work this description follows from theoretical predictions of a numerical study using a Fourier optics approach. One can easily extend this description and perform a quantitative structural analysis of clinical or materials science samples with directional dark-field imaging or even direction-dependent dark-field CT. X-ray grating interferometry is a very promising candidate to improve current imaging techniques in materials science and medicine without the large effort of creating completely new machines The dark-field contrast signal For thin specimens the x-ray beam passes only through a few structures located behind each other. Because of that, almost all structures that contribute to the dark-field signal in each single detector pixel can be assumed to be parallel and it is easy to deduce their direction and anisotropy from the orientations producing the maximum signal. Up to now it is unknown how the recorded directional dark-field signal is formed for thick samples. Here several differently oriented layers of substructures can lie behind each other, each producing its own direction-dependent signal. Knowing the physics behind the signal formation is a fundamental prerequisite for potential future medical diagnostic and materials science applications as well as direction-dependent computed tomography methods.In this study we show how the x-ray directional dark-field signal of the superposition of arbitrarily oriented structure layers is related to the signal created by each component. In contrast to existing experimental work Let us first focus on the theoretical predictions for the superposition of directional dark-field signals drawn from simulations cf. . For thaEach single sample layer on its own produces a signal, which follows an ence see . This isThe signal of both layers together shows the same angular dependence as the two single layers but with varying amplitude and phase depending on the relative orientation and the amplitudes of the signal of each single layer. When the orientations of the structures in both layers are chosen to be parallel, the sum signal only changes in amplitude with respect to the individual signals. For a relative angle of From these findings we derived a physical model predicting the superposition principle of x-ray directional dark-field imaging. The directional dark-field signal of each single layer Here Starting from this we can express the scattering caused by each sample layer with a two-dimensional vector From the plots in This equation describes the directional dark-field superposition principle for two completely anisotropic sample layers passed by an x-ray beam one after each other. An arbitrary number of further layers can be added by applying One immediate consequence of this equation is that the superposition of two orthogonal structures of equal scattering strength results in a constant scattering profile with respect to the rotation angle. In directional dark-field imaging such a sample will appear isotropic. Furthermore every directional dark-field signal will be a superposition of harmonics of the same angular period and consequently be another harmonic with identical period. This kind of superposition in contrast to small-angle x-ray scattering (SAXS) can be regarded coherent.For two arbitrary scattering directions and strengths the logarithmic sum signal can be calculated by simply adding two harmonics. We predicted the results for the superposition signal by multiplying the fit curves of the single sample layers, which is equivalent to that. The expected curves are shown in Generalizing To realize the simulated situation in experiment we chose a specimen composed of two wooden skewers located one behind the other in the x-ray beam. For these samples scattering mainly occurs in directions perpendicular to the skewer axis because of the numerous wooden fibers oriented along this direction. For the experimental demonstration, we utilized a more involved setup than the simplified one used for the simulations above. We used a tube source for illumination, so that we needed to introduce a source grating  and the medial-lateral direction (cube 2). In the first case the superior-inferior direction was pointing upward, while in the second case it was the anterior-posterior direction. This was kept constant for the whole experiment.Both femoral cubes showed a distinct preferred orientation as expected  and a rectangle (dominated by cube 2). A large fraction of the area that is occupied by both cubes in the combined sample shows less if no anisotropy at all. This follows directly from the superposition model we derived above and the perpendicular orientation of the structures between both cubes.In summary we have shown how the directional dark-field signal drawn from x-ray grating interferometry can be calculated for samples that are composed of highly anisotropic layers of differing orientation. Starting from theoretical predictions gained from simulations we developed a model for the superposition of the signals originating in two different sample slices: The harmonic oscillations observed for the single layers can simply be added to retrieve the superposition signal. As a direct consequence, layers with perpendicular orientation and similar scattering strength will show no anisotropy in dark-field imaging. We checked the correctness of this model by means of experimental data and found very good agreement.With this model at hand it is now possible to predict and describe the directional dark-field signal for thick samples containing more than one layer of oriented scatterers. This could for example be applied in materials science (e.g. compounds containing carbon fibers or meshes) and even have a large impact on medical diagnostics for example in the case of trabecular bone as we have pointed out in this study. For instance, diagnosis and treatment monitoring of osteoporosis, which is major public health problem through its association with fragility fractures, may be improved by taking interferometric projection images. Osteoporosis is characterized not only by loss of bone mineral density but also by decreasing bone quality including a deterioration of the trabecular microstructure mucal written by Bandyopadhyay and Segre The simulations described in this article were performed using a Fourier optics The experiments were performed at a laboratory setup at the Technische Universit\u00e4t M\u00fcnchen consisting of a High Power X-Ray tube  at an acceleration voltage of The wooden skewer and femur cube samples were measured in air while mounted on a plexiglass (PMMA) panel, which was fixed inside an Eulerian cradle manufactured by Huber Diffraktionstechnik GmbH & Co. KG, Germany. This goniometer allowed rotation of the samples around the beam axis. The distances between the gratings were Both cubical bone specimens Click here for additional data file."}
+{"text": "Austrominiusmodestus, on a unique art installation located in Liverpool Bay. Population growth and recruitment success were examined by comparing recruitment rates within disturbance clearings of 4 different sizes and by contrasting population development with early recruitment rates over a 10 week period. Disturbed areas were rapidly recolonised and monocultures of Amodestus.  formed within 6 weeks. The size of patch created during disturbance had no effect on the rate of recruitment, while a linear relationship between recruit density and patch size was observed. Density-dependent processes mediated initial high recruitment resulting in population stability after 8-10 weeks, but densities continued to greatly exceed those reported in natural habitats. Given that artificial structures are likely to continue to proliferate in light of climate change projections, free-space is likely to become more available more frequently in the future supporting the expansion of fast-colonising species.Artificial structures can create novel habitat in the marine environment that has been associated with the spread of invasive species. They are often located in areas of high disturbance and can vary significantly in the area of free space provided for settlement of marine organisms. Whilst correlation between the amount of free space available and recruitment success has been shown in populations of several marine benthic organisms, there has been relatively little focus on invasive species, a group with the potential to reproduce in vast numbers and colonise habitats rapidly. Invasion success following different scales of disturbance was examined in the invasive acorn barnacle,  The introduction of novel species into vulnerable habitats can impact upon the balance of species and allocation of resources. Although chance and timing play an important role , invasioThe colonisation of natural habitats by an invasive species following disturbance can be offset by the presence of an established native biota , such thA primary factor in determining which species will colonise an artificial structure is its placement, and specifically the proximity (connectivity) of the structure to a source population (i.e. a rescue effect). Many marine species exhibit a planktonic larval stage , facilitArtificial structures are implicated in the spread of invasive and non-native species by acting as stepping stones to dispersal across areas of unsuitable habitat (i.e. sedimentary substrata) . MorpholAustrominiusmodestus  has become widespread along UK coasts since its introduction in the late 1940s )d Europe  and the ed (e.g. ) and sug"}
+{"text": "After two randomised studies published in 2002 ,2 mild tWhile several prehospital or pre-CPR factors contributing to the patients' outcome are well known and implemented in the BLS and ACLS guidelines, only little is known about the kind and impact of in-hospital contributing factors worsening the chance of surviving the event with good neurological function. After return of spontaneous circulation, major cardiovascular and haemodynamic disorders are widely common and associated with a high rate of deaths within the first 24 hours after CPR. Sufficient post-resuscitation therapy has to include optimal treatment strategies of the cardiovascular and metabolic system, adaequate ventilation support and strategies of neuroprotection . In patiSeveral factors of hospital care are obviously important for survival of post-CA patients. Observational investigations done in Norway and Sweden detected severe differences in outcome of patients admitted to hospital with ROSC after out-of-hospital CA presenting survival rates between 33 to 56% and 14 to 42% respectively [Based on this evidence a prospective observational study was performed in patients admitted to hospital after regaining ROSC and treated using a standardised treatment protocol including instant onset of therapeutic hypothermia, early reperfusion treatment with PCI, and protocol-based early-goal-directed therapy to restore adaequate arterial blood flow in the reperfusion period . The obsDespite the fact that the level of evidence for many of the treatment strategies with the exception of therapeutic hypothermia in post-resuscitation care is weak, the quality of care after admission to the ICU or ED seems to be a somewhat missing link in the chain of survival. The post-resuscitation phase is associated with a sepsis-like syndrome  of unknoMany factors Table  may contIn our hospital an early algorithm for therapeutic hypothermia based on the standards used during the HACA trial  was desiUnfortunately there is only limited access to outcome data of our patients treated before implementation of these SOP protocols, so the data from the CoolBrain Registry are only observational and cannot be compared with a control group before using protocol-driven therapeutic standards. Neurologic outcome was not recorded before implementing therapeutic hypothermia as standard care in 2001; survival rates after OHCA were recorded between 1990 and 2000 as lower than 20%.n = 276) presented a general survival rate of 51% independent of origin, initial rhythm and localisation of the cardiac arrest. Thirty-nine per cent of those patients showed a favourable neurologic outcome (CPC 0.5), 12% severe neurologic disability. In the group of survivors, 69.5% of patients with ventricular fibrillation as the initial rhythm showed an excellent neurologic performance (CPC 1) and 35% of patients presenting with asystole/PEA as well at hospital discharge.Data enrolled from March 2001 to December 2011 (Despite missing a control group before implementing therapeutic hypothermia and standardised treatment protocols for post-resuscitation care, these data show the effect of protocol-based treatment especially on neurologic outcome of those patients. This underlines that more attention has to be focused on optimising and standardising post-resuscitation care to improve survival and neurologic outcome. Treatment of patients with CA does not end with ROSC; despite the fact that there is only weak scientific level of evidence for some singular strategies of post-CA treatment, the combination of an aggressive multifactorial therapeutic approach including temperature management significantly improves outcome. Therefore further clinical trials of other post-resuscitation therapies seem to be essential."}
+{"text": "Genome wide association studies (GWAS) are becoming the approach of choice to identify genetic determinants of complex phenotypes and common diseases. The astonishing amount of generated data and the use of distinct genotyping platforms with variable genomic coverage are still analytical challenges. Imputation algorithms combine directly genotyped markers information with haplotypic structure for the population of interest for the inference of a badly genotyped or missing marker and are considered a near zero cost approach to allow the comparison and combination of data generated in different studies. Several reports stated that imputed markers have an overall acceptable accuracy but no published report has performed a pair wise comparison of imputed and empiric association statistics of a complete set of GWAS markers.P < 10 -5 for type 2 Diabetes Mellitus and compared them with results obtained based on empirical allelic frequencies. Interestingly, despite their overall high correlation, association statistics based on imputed frequencies were discordant in 35 of the 73 (47%) associated markers, considerably inflating the type I error rate of imputed markers. We comprehensively tested several quality thresholds, the haplotypic structure underlying imputed markers and the use of flanking markers as predictors of inaccurate association statistics derived from imputed markers.In this report we identified a total of 73 imputed markers that yielded a nominally statistically significant association at Our results suggest that association statistics from imputed markers showing specific MAF (Minor Allele Frequencies) range, located in weak linkage disequilibrium blocks or strongly deviating from local patterns of association are prone to have inflated false positive association signals. The present study highlights the potential of imputation procedures and proposes simple procedures for selecting the best imputed markers for follow-up genotyping studies. Genome-wide association studies (GWAS) are a promising tool for the identification of genetic markers underlying phenotypes of interest and recently allowed the identification of markers associated with several human complex phenotypes. These sTo overcome these issues, genotyping imputation algorithms were developed. These methods use information provided by high quality markers combined with genome structure information for the population of interest organized in the HapMap database. These procedures can potentially be a nearly zero-cost alternative to increase both power and coverage in individual GWA studies. The imputation procedures allow meta- and pooled analyses of GWAS data generated by distinct genotyping platforms, maximizing their overlap and, consequently, the number of typed individuals. Despite promising, the success of imputation algorithms are relative since they could also amplify non-detected technical errors in genotyped markers, the available HapMap information may not be well consolidated for the population of interest or the applied imputation algorithm may not be well suited for a specific dataset .Here, we present a comprehensive comparative analysis of the data generated by the multipoint imputation algorithm and the data obtained by direct genotyping in a type-II diabetes GWAS dataset. This imputation algorithm uses a Markov chain to infer the allelic frequencies of a marker by the information provided by a large set of flanking markers. The analyzed dataset was generated and organized by the Welcome Trust Case Control Consortium (WTCCC) and is a constituent of a large epidemiological study focused in the determination of genetic markers that could predispose an individual to seven different diseases of interest . In thisThe results discussed herein are based on data available for approximately 2000 individuals accessed by type-II diabetes and 3000 healthy individuals (controls). We limited our evaluation to 387,662 biallelic markers with full information on both observed (genotyped) and imputed genotype frequencies. This set of markers covers all chromosomes, but sex-linked markers, having no major over-representation in any specific chromosome. A detailed list of the examined markers and their respective imputed and empiric frequencies is available upon request. In this report, the term empiric denotes markers whose allelic frequencies were determined by direct genotyping.P-values  assuming a multiplicative (log-additive) model of inheritance applied to empiric and imputed frequencies of markers in the complete and filtered dataset. The analysis of Figure Association studies using empiric or imputed frequencies are very sensitive to low quality markers. Accuracy of the Impute algorithm is significantly reduced in alleles showing small MAFs or low calling posterior probabilities . Initialon a -log0 scale aon a -log0 scale arS = 0.80). However, it is important to note some points. Firstly, the wide dispersion of dots around the upper left side of Figure -5 we observed that inferences based on truly genotyped markers yielded evidence for 38 markers possibly associated with type-II diabetes, whereas this number would be 73 SNPs had the same inference been based on imputed markers solely. Approximately 47% of markers that would be considered associated by imputed allelic frequencies were discordant to the evidence derived from direct genotyping. Table Using the filtered dataset, the examined imputation algorithm, as previously described for allele and genotype imputation, also presents a high overall accuracy when comparing the association statistics generated using genotyped and imputed markers . Our empirical analysis demonstrated that the magnitude of the odds ratio of false-positive associations lies in the range of effects typically found in the GWA setting: median 1.26 ; odds ratios were coined to be \u22651 for consistency. However, false-signals from imputed genotypes suggest more commonly protective effects (n = 47) rather than susceptibility effects (n = 26) for the minor allele variant.Next, we sought to examine characteristics of false-positive associations that could be used as predictors of the quality of association signal derived from imputated markers. An analysis of the characteristics of false-positive signals is of paramount importance to guide investigators in appropriately evaluating P-values and the observed bias between associations statistics were plotted against their relative chromosomal positions  to diabetes in contrast to their empiric frequencies, inflating considerably the number of associated markers. The number of these \"low imputation quality\" markers is limited especially when compared to the immense number of markers analyzed that could, consequently, pass undetected by common diagnostic analysis.It is accepted that some chromosomal regions, due to a higher number of recombination events, have less consolidated frequency panels in markers underlying these regions in human populations . Allelics Figure   thresholds could predict the observed bias between empiric and imputed frequencies. This feature was explored by using more stringent cutoffs for calling rates, Hardy-Weinberg disequilibrium (HWD) and the use of SNPs showing a MAF \u22651%. The number of markers excluded by these quality filters was determined. The minus log transformed association statistics of the remaining imputed or genotyped markers were compared by analyzing their degree of correlation . Initially, we determined markers of our filtered dataset that were also evaluated in the HapMap database. This group is composed of 317,255 polymorphisms and it will be used in our further analysis. For each marker, a haplotypic block was determined using the complete set of markers showing a linkage disequilibrium measure to the specific marker (See methods for further details). Each haplotypic block is composed by a limited set of marker-to-marker r2 statistics. In each block, four different descriptive statistics were evaluated: mean, median, maximum value and variance of the values of the r2 statistic. We plotted separately the four statistics against the observed bias between association statistics of the complete set of markers  would also present a higher chance of also being associated. In this scenario, a considerable proportion of markers flanking an associated SNP should also present significant levels of association for the phenotype under investigation. Imputed SNPs located in the same chromosomal region are inferred with similar accuracy since the same haplotypic structure information was used by the imputation algorithm. In the same hand, it is expected that a totally isolated associated marker within a well-known LD block will likely represent a false positive association. To evaluate the validity of this hypothesis, we developed an algorithm implementing a sliding window procedure that determines and collects minus log corrected association statistics of consecutive imputed markers using three different window sizes  (see methods for further discussion). We determined different sliding windows size centered in the 73 imputed markers considered associated for diabetes II, these sliding windows were separated in two groups of sliding windows based if their central marker was concordant or discordant to empirically measured association statistics and three different summary statistics  were collected.Using box plot graphical representations we evaluated the discriminative values of the different summary statistics of flanking markers as a predictor of imputation accuracy for association statistics. Interestingly, the use of the total sum of association values was very robust to efficiently separate true-positive and false-positive association statistics of imputed markers, independent of the size of the sliding window Figure . Using tIn a complementary way, we used a graphical representation to highlight this feature plotting the corrected association of statistics of sliding windows centered in true-positive and false-positive imputed markers considered associated in human chromosome 10 Figure . In the Genome wide association studies are a promising tool for the determination of genetic signatures that could, when associated with environmental factors, predispose an individual to a phenotype of interest. Quality control of data in a GWAS study has been implicated as an important source of bias and loss of power in both linkage analyses and population-based association studies . ImputatP-values of empiric and imputed allelic frequencies under a log-additive model of inheritance. We used a combined quality criteria of markers showing MAF > 0.01 and calling probability higher than 0,95 and filtered markers showing a considerably higher accuracy between association statistics using imputed and empiric frequencies  would be considered associated based on their empiric (directly genotyped) association statistics . The same pattern was observed when different and more stringent significance thresholds were used (10 -6 and 10 -7).This result suggests that imputation methods are prone to inflate the number of markers considered associated in any of the evaluated thresholds in this report. These results are not a contradiction to the overall high accuracy for predicting genotype status previously described. These few highly deviated markers would be considered associated even when using highly stringent significance thresholds (< 10 -7 or lower) which could considerably jeopardize follow-up studies based only on association statistics of imputed markers. Since imputed markers are indispensable for merging the information generated by different platforms or studies , it's important to identify these badly imputed and hugely biased markers.The association of imputation procedures with low density chips can offer a convenient way to enhance the cost efficiency ratio and statistical power of a GWAS, since more individuals/markers can be typed by the same cost . SeveralIn this report, we comprehensively tested several genotyping and imputation quality criteria, haplotypic information and chromosomal location as predictors of the quality of association statistics derived from imputed markers. As demonstrated in other reports dealing with the accuracy of genotypic determination, when the MAF of imputed markers are close to 50%  imputatiA commonly accepted source of bias is the use of not well consolidated haplotypic information as an input for imputation algorithms. This could lead to imputed allelic frequencies not coherent to the population under study and, consequently strongly biased association tests. To explore this hypothesis we determined haplotypic blocks centered in each marker of the WTCCC dataset that were also present in the HapMap database. The comparison between the observed biases and four different summary statistics, representing haplotypic block consistency, showed a modest success when variance and maximum values were tested as predictors. Interestingly, the comparison between mean and median values of linkage disequilibrium as predictors showed that imputed markers located in regions showing weaker linkage disequilibrium structure are prone to higher bias. Their imputation and subsequent analysis under different genetic models of inheritance should be carefully done especially if the imputed marker is to be considered strongly associated to the phenotype under study. A similar result was suggested by Bakker P. I.W et al, when constructing a guide to the use of imputed information in meta-analysis of genome wide association studies.-5) in the WTCCC hypertension dataset with similar results  - ). All the analyses were conducted on the R statistical environment; the complete set of developed programs can be obtained upon request.Markers typed in a specific chromosome were selected and sorted by their chromosomal position. The association statistics of a marker under a log-additive model of inheritance were collected and using a minus-log transformation plotted (Y-axis) with their position in the sorted vector. Markers in different specific chromosomes were plotted in grey and black, respectively. The bias was determined as the algebraic difference between minus log transformed association statistics derived from direct genotyping and imputation . A haplotypic block was defined as the complete set of rP-values of imputed and directly genotyped markers under a log-addictive model of inheritance was collected and ordered based on chromosomal position. Imputed markers that were considered associated using a pre-defined threshold (10 -5) were determined and classified into concordant and discordant markers in terms of their agreement within the association statistics. A locally developed Perl algorithm constructed sliding windows of different sizes  centered in the imputed markers (concordant or not) and collected the set of minus-log transformed association statistics of the flanking markers. A set of summary statistics, such as mean, median and variance of each sliding window was collected and referenced to the central marker. The complete set of raw results, summary statistics and markers comprised in each window can be obtained upon request.The complete set of minus log transformed MAAA: Conducted the statistical analysis, the implementation of the computational routines and drafted the manuscript; PSOL: Supervised the implementation of computational routines; TVP: conducted data filtering analysis and statistical analysis JEK: helped the concept and design of the study. ACP: conceived the study and drafted the manuscript. All authors read and approved the final manuscript.QQ plots of entire and filtered datasets. A. QQ plot of the entire dataset; B. QQ plot of dataset after standard filtering criteria.Click here for fileComplete set of imputed associated markers. All markers that would be considered associated based on imputed allelic frequencies using a significance treshold of 10-5. A markers determined as concordant (STATUS column) could be considered associated by imputed and empiric allelic frequencies.Click here for fileComparison of the number of considered associated markers by empiric and imputes allelic frequencies in hypertension database. Determination of markers showing concordance and discordance of association statistics based on imputed and empiric allelic frequencies based on information provided by hypertension database of WTCCC.Click here for fileThe effects of the use of different minimum thresholds for calling probabilities. We serially tested a series of different minimum thresholds for empiric and imputed frequencies and analysed the effect of such filtering in the remaining dataset by determining the correlation of association statistics and the outlier percentageClick here for fileThe effects of the use of different minimum thresholds for MAF . We serially tested a series of different minimum thresholds for minor allele frequencies and analysed the effect of such filtering in the remaining dataset by determining the correlation of association statistics and the outlier percentage.Click here for fileDispersion plots and histogram of markers showing extreme MAF conditions. Dispersion plots and histogram of markers showing extreme MAF (Minor Allele Frequency) conditions MAF < = 0,01 or MAF > = 0,49Click here for fileComplete set of comparisons of different size sliding windows. Each box-plot represents the tendency observed in association statistics of markers within different size sliding windows.Click here for fileSliding window algorithm applied in hypertension dataset. Each box-plot represents the tendency observed in association statistics of markers within different size sliding windows applied in hypertension dataset.Click here for file"}
+{"text": "The difficulties in the management of the blunt chest wall trauma patient in the Emergency Department due to the development of late complications are well recognised in the literature. Pre-injury anti-platelet therapy has been previously investigated as a risk factor for poor outcomes following traumatic head injury, but not in the blunt chest wall trauma patient cohort. The aim of this study was to investigate pre-injury anti-platelet therapy as a risk factor for the development of complications in the recovery phase following blunt chest wall trauma.A retrospective study was completed in which the medical notes were analysed of all blunt chest wall trauma patients presenting to a large trauma centre in Wales in 2012 and 2013. Using univariate and multivariable logistic regression analysis, pre-injury platelet therapy was investigated as a risk factor for the development of complications following blunt chest wall trauma. Previously identified risk factors were included in the analysis to address the influence of confounding.A total of 1303 isolated blunt chest wall trauma patients presented to the ED in Morriston Hospital in 2012 and 2013 with complications recorded in 144 patients (11%). On multi-variable analysis, pre-injury anti-platelet therapy was found to be a significant risk factor for the development of complications following isolated blunt chest wall trauma . As in previous studies patient age, number of rib fractures, chronic lung disease and pre-injury anti-coagulant use were also found to be significant risk factors.Pre-injury anti-platelet therapy is being increasingly used as a first line treatment for a number of conditions and there is a concurrent increase in trauma in the elderly population. Pre-injury anti-platelet therapy should be considered as a risk factor for the development of complications by clinicians managing blunt chest wall trauma. The use of anti-platelet therapy has increased over the last decade as a result of research which has reported their effectiveness in preventing cardiovascular events in high risk populations. Blunt chest wall trauma accounts for over 15% of all trauma admissions to Emergency Departments worldwide. A retrospective study design was used in order to examine the medical notes of all blunt chest wall trauma patients who presented to the ED of a large regional trauma centre in South Wales  in 2012 and 2013. Morriston hospital has approximately 90,000 presentations to the ED per year and serves a population of 450,000 people. Those patients coded as \u2018blunt chest trauma\u2019 or \u2018rib fractures\u2019 were identified using the hospital database. Patients with any significant concurrent injuries were excluded to reduce the effect of confounding.We wished to include sufficient patients that we could present the unadjusted and adjusted odds ratios and 95% confidence intervals for the risk factors for the development of complications following blunt chest wall trauma. Peduzzi et al (1995) suggested that the number of patients needed to ensure sufficient power in a retrospective cohort study is equivalent to ten events per variable (EPV) being investigated. The medical notes were reviewed following guidelines suggested in a study by Gilbert et al (1996). The dataset included demographic variables such as age, gender and injury mechanism. The independent variables examined were defined a priori and consisted of the risk factors for mortality and morbidity highlighted previously in the literature. The South West Wales Research and Ethics Committee confirmed that ethical approval was not required for this study and also waived the need to obtain written informed consent from the patients. All patient information was anonymised and de-identified prior to analysis.The patient\u2019s age, chronic lung disease including; chronic obstructive pulmonary disease or bronchiectasis, pre-injury anti-coagulant use , pre-injury anti-platelet use  were all identified from the medical notes. The number of rib fractures was determined by the clinical notes however in the cases where the number of rib fractures could not be determined using the clinical records, then the x-ray report (IMPAX software) was reviewed by the investigators.The development of complications during the recovery phase following blunt chest wall trauma was the composite outcome measure investigated in this study. Data collection for this outcome was completed from the time the patient presented to the ED through to discharge from hospital. Patients were reported to have developed complications if one or more of the following were documented in their medical records; in-hospital mortality, morbidity including all pulmonary complications , ICU admission, an unplanned representation to the ED, or a prolonged length of stay as defined as a total hospital stay of seven or more days.Baseline characteristics were presented as median and interquartile range  for the continuous variables and numbers and percentages for categorical variables. Differences between the baseline characteristics were analysed using Mann Whitney U test (continuous variables) and Fisher\u2019s Exact test . Odds ratios and 95% confidence intervals were presented from the univariable analysis. All significant prognostic variables at 5% significance on the univariable analysis were included in final analysis. Multivariable logistic regression analysis using fractional polynomials (to assess linearity of the continuous variables) was used to identify significant predictors using the Likelihood test statistic. There was less than 2% missing data therefore we used a simple imputation of the mean method to avoid exclusion of patients from the final analysis. A total of 1303 isolated blunt chest wall trauma patients presented to the ED in Morriston Hospital in 2012 and 2013 with complications recorded in 144 patients (11%). Data including demographics, independent and dependent variables were recorded for each of the patients. With the exception of recording of eleven patients\u2019 oxygen saturations, there were no missing variables in the dataset. Pre-injury anti-platelet therapy was recorded in 116 patients (9%) of the entire cohort. Aspirin was most commonly used antiplatelet medication , followed by NSAIDs , clopidogrel  and combined aspirin and clopidogrel . Warfarin was the most commonly used anti-coagulant  followed by Dabigatran . Haemorrhagic events (haemothorax) were recorded in 36 out of 144 (25%) patients who developed complications. No significant association was found between the variables pre-injury anti-coagulants and pre-injury anti-platelets. The only significant associations found were between anticoagulant use and chronic lung disease (p\u200a=\u200a0.001), and antiplatelet use and chronic lung disease (p<0.001). However this association led to no significant interactions in the model on multivariate analysis (p\u200a=\u200a0.77 and p\u200a=\u200a0.78 respectively). Results of the multivariable logistic regression analysis are outlined in As no current guidelines exist for the management of this patient group, recognition of the high risk patient in the ED is not always straightforward due to the nature of the injury and its recovery phase. The blunt chest wall trauma patient who walks into the ED with no immediate life-threatening injury will commonly develop complications up to 72 hours or more post injury, which may also prove life-threatening. 529. This results in an irreversible inhibition of platelet-dependent thromboxane formation. The antithrombotic action of aspirin  is due to inhibition of platelet function by acetylation of the platelet cyclooxygenase (COX) at the functionally important amino acid serineOver the last decade, the use of antiplatelet therapy has increased considerably, as a result of national and international guidelines promoting their widespread in high-risk populations and particularly in the elderly. Another difficulty facing emergency physicians in the management of trauma patients using pre-injury anti-platelets is the variation between patients in their response to the medication. Platelet function tests can be carried out on trauma patients in order to assess number and size of platelets and also platelet haemostatic function. The type of tests completed, specifically either global screening tests or specific assays will depend on the testing equipment available at that emergency department. The decision as to whether the blunt poly-trauma patient requires platelet transfusion therefore is dependent on a number of factors. In isolated blunt chest trauma however platelet function may not routinely be considered by the emergency physician even though delayed haemothorax is not an uncommon entity in this patient group. To date, no research exists investigating the effect of pre-injury anti-platelet use in blunt chest trauma. Pulmonary contusion occurs in 25\u201335% of all blunt chest traumas and is defined as an injury to the alveolar capillaries, in the absence of a lung laceration. In a recent study by Harr et al (2013), the use of pre-injury anti-platelet therapy was reported to be associated with a decreased risk of lung dysfunction in high risk blunt trauma patients who receive blood transfusions. One potential limitation of the study is that polytrauma patients were excluded so the results are only generalisable to isolated blunt chest wall trauma patients. The number of haemorrhagic complications was recorded on data collection however data were not collected regarding thromboembolic events in the study population and this information may have been beneficial to the clinician. Similarly the very small number of patients taking anti-platelet therapy other than aspirin precludes analysis into which therapy is most associated with specific complications. Lack of data regarding platelet function in individual patients and platelet transfusions may have influenced the study results.As a result of the study design and the inherent nature of patients, a number of the independent variables investigated were potentially interdependent and an increase in one variable inadvertently leads to an increase in another. Multivariable logistic regression with backward elimination techniques was used in an attempt to address this issue of collinearity. It is also possible that a confounding variable that influences the results was not considered in the data collection or analysis. It could therefore be suggested that the discovered association between anti-platelet therapy and chest wall complications is the result of both risk factor and outcome being related to common underlying unmeasured pathologies of some kind. In prognostic clinical research however this is difficult to overcome due to the nature of the study population and therefore the results of the study should be interpreted with this in mind.The use of the database to identify the patients for inclusion in this study may have resulted in a degree of selection bias. Errors may have occurred in the collation of the list of patients from the hospital database and similarly by the doctors completing the coding form in the ED. Similarly, as the data were being collected for each of the patients from their ED medical notes, reliance was placed on the information being both accurately and legibly documented. This may have led to some error in data collection and should be considered when interpreting the study results. The most appropriate method of overcoming a number of the study limitations is to complete a prospective study.This study has highlighted a number of well-recognised risk factors for the development of complications following blunt chest wall trauma. These included patient age, number of rib fractures, chronic lung disease and pre-injury anti-coagulant use. This is the first study in which pre-injury anti-platelet use has been reported as a risk factor for complications following isolated blunt chest wall trauma. Pathophysiological mechanisms differ substantially between blunt poly-trauma patients suffering trauma-induced coagulopathy and isolated blunt chest trauma patients and as a result, comparisons between such studies are not appropriate. The results of this study are therefore distinctive from any previous research and should be considered by emergency physicians managing isolated blunt chest trauma.Anti-platelet therapy is now a well-recognised risk factor for potential poor outcomes following severe traumatic head injuries and trauma clinicians are becoming increasingly aware of its negative impact in the elderly trauma patient. Despite the limitations associated with a single centre retrospective study, this results of this study have highlighted an important clinical finding that trauma clinicians should consider when managing the blunt chest wall trauma patient in the ED. A prospective multi-centre study is planned to further investigate the impact of pre-injury anti-platelet use on outcomes in blunt chest wall trauma patients."}
+{"text": "Modulating fire suppression efforts in mild weather conditions is an appealing but hotly-debated strategy to use unplanned fires and associated fuel reduction to create opportunities for suppression of large fires in future adverse weather conditions. Using a spatially-explicit fire\u2013succession model developed for Catalonia (Spain), we assessed this opportunistic policy by using two fire suppression strategies that reproduce how firefighters in extreme weather conditions exploit previous fire scars as firefighting opportunities. We designed scenarios by combining different levels of fire suppression efficiency and climatic severity for a 50-year period (2000\u20132050). An opportunistic fire suppression policy induced large-scale changes in fire regimes and decreased the area burnt under extreme climate conditions, but only accounted for up to 18\u201322% of the area to be burnt in reference scenarios. The area suppressed in adverse years tended to increase in scenarios with increasing amounts of area burnt during years dominated by mild weather. Climate change had counterintuitive effects on opportunistic fire suppression strategies. Climate warming increased the incidence of large fires under uncontrolled conditions but also indirectly increased opportunities for enhanced fire suppression. Therefore, to shift fire suppression opportunities from adverse to mild years, we would require a disproportionately large amount of area burnt in mild years. We conclude that the strategic planning of fire suppression resources has the potential to become an important cost-effective fuel-reduction strategy at large spatial scale. We do however suggest that this strategy should probably be accompanied by other fuel-reduction treatments applied at broad scales if large-scale changes in fire regimes are to be achieved, especially in the wider context of climate change.Despite the huge resources invested in fire suppression, the impact of wildfires has considerably increased across the Mediterranean region since the second half of the 20 Wildland fires are a major component of disturbance regimes in many regions th century across different Mediterranean regions Despite the huge amount of resources invested in fire prevention and suppression, the impact of wildfires has considerably increased since the second half of 20In mesic regions of the Mediterranean basin , fuel is now less limiting, and fire regimes appear to be mainly driven by the occurrence of climatically adverse conditions Given that wildfires are currently seen as one of the main drivers of forest landscape changes in many Mediterranean regions, wildfires occurring in mild weather conditions could become a tool to regulate the impact of undesired, destructive, large fires taking place in climatically adverse conditions 2 and an altitude that ranges from sea level to 3102 m. Catalonia has a typical Mediterranean climate with low winter precipitation and hot and dry summers. Moreover, its complex topography induces major variability in climatic and fire weather conditions across the territory. The vegetation is mostly comprised of forest and shrubland. Evergreen species occur in 60% of the total forest area, 73% of which is occupied by conifers , with sclerophyllous and deciduous species  covering the remaining 40% The study area was Catalonia, a region located in northeastern of Spain with a land area of 32,115 kmFocverd I fire suppression program) and 90s (Focverd II) st century, prescribed burning programs were also implemented among other efforts to reduce fire risk, but not at sufficiently broad scales to achieve effective reductions During the same period, wildfires burnt about 13% of the wildland area , and both the frequency of fire events and area burnt have increased since the pre-1970 period The MEDFIRE model short overview of the model. The complete description, calibration, and validation processes for the study area can be obtained from previous published work http://www.seles.info/). The current version of MEDFIRE (version 2) has two main sub-models https://sites.google.com/site/medfireproject/). The main purpose of the model is to examine the spatial interaction between wildfires, vegetation dynamics and fire suppression strategies. It was designed to assess how different drivers affect fire regime at short- and medium-term timescales through a quantitative evaluation of their effects on the distribution of the annual area burnt, fire size distribution, and landscape composition. Validation exercises carried out for different time windows with different climate and fire suppression data showed that the model was able to reproduce the basic descriptors of fire regime in our study area We present here a state variables that MEDFIRE uses to describe landscape context and conditions are spatially explicit variables in raster format at 100 m resolution. Land cover type (LCT) and time since last fire (TSF) are dynamic variables, while the static variables are: ignition probability, bioclimatic region, fire spread type (relief- or wind-driven), elevation, aspect and main wind direction.The fire sub-model uses a top-down approach: for each time-step (a year), fires are simulated until the potential annual area to be burnt is reached. Potential annual area refers to the area that is expected to burn according to the historical fire data (1975\u201399 period). According to previous research The vegetation dynamics sub-model assumes that forest cover types are relatively stable, so a type-conversion can only occur after burning. Succession without burning can occur only from shrubland to forest. This land cover change takes place depending on the availability of mature forest in neighbouring cells and the TSF of shrubland that will potentially change. Once a cell is burnt, this sub-model updates the land cover according to two post-fire regeneration approaches:The Applying non-spatial stochastic transitions, using a multinomial distribution with transition probabilities previously published by others By neighbourhood species contagion, considering the neighbours that were also burnt in the current year and shared the same pre-fire cover class. It is important to note that the model cannot handle the complexity derived from possible within-stand heterogeneity since each cell can only be described by a single dominant tree species.Two fire suppression strategies are implemented in the MEDFIRE model:The opportunistic strategy mimics firefighting actions based on the ability to take advantage of opportunities derived from old fire scars. These fires provide firefighting opportunities since they are easy to detect by fire brigades and they strongly decrease fuel load and therefore fire intensity. The implementation of the opportunistic strategy in MEDFIRE suppresses burning in a cell whenever its TSF is below a pre-specified threshold (expressed in years) (n years) .The active fire suppression strategy mimics the overall efficiency of firefighters to anticipate fire behaviour and reduce realized area burnt under determinate fire propagation conditions. This strategy was implemented through two different processes. First, we induced increases in the potential annual area to let burn so as to reproduce the effects of not suppressing small fires and therefore increase the total number of fires in a given scenario. By default, the MEDFIRE model simulates fires until the potential annual area to be burnt is reached, and so increases in potential area burnt result in a larger number of fires per year. Second, we introduced the concept of opportunities tied to fire-specific thresholds in spread rate. In areas in which spread rate is below a pre-specific threshold, firefighters are able to stop the fire spreading, which leads to decreases in the final area burnt nine different treatments of active fire suppression (acting only in years with mild climatic conditions) corresponding to situations of variability in general fire suppression efforts. The nine treatments were defined by combining three levels of potential area to be burnt with three levels of active suppression using spread rate thresholds: (a) the first three levels were simulated through variability in potential area to burn. Baseline annual distributions of area burnt were derived from 1975-99 wildfire statistics . To reproduce the effects of not suppressing small fires , we modified the mean of the lognormal distribution of area burnt in mild years according to the decreasing efforts of firefighters to suppress small fires: (1) High 7.74 ; (2) Average 9.14 ; and (3) Low 9.81   will remain stable in the future (35% is the percentage of adverse years in the period 1980\u20131999) or is set to increase (up to 70%), following recent research We assessed the effectiveness of an opportunistic fire suppression policy based on whether or not to allow unplanned fires to burn in mild weather conditions through scenarios characterized by a progressively decreasing active fire suppression policy . Specifiha/year)  and 2. (ha/year)  and 2. OTo evaluate the effect of opportunistic fire suppression strategies under the different scenarios, we calculated area suppressed as the difference between potential area to be burnt in a year and the final area burnt. We also tracked the area suppressed in adverse years according to the origin of the fire scar that created the firefighting opportunity: (1) scars of fires simulated in climatically adverse years, (2) scars of fires simulated in climatically mild years, and (3) scars of historical fires . The means and standard deviations of all these variables were used to describe the fire regime obtained under each simulated scenario. All statistical analyses were performed using R software, version 3.0.2 Scenarios with no and medium active fire suppression in mild years  allowed opportunistic suppression of 18\u201322% of the target annual area in adverse years (average from 7 to 9), the area suppressed in adverse years would increase to 26\u201337% (low from 13 to 15), the percentage of area suppressed in adverse years also increased to figures of up to 29\u201350% , the area suppressed was lower in scenarios with climate warming  has the potential to substantially reshape fire regimes and decrease the amount of area burnt under undesired, extreme climate conditions. However, the potential of this strategy is somewhat limited due to the complexity of the interactions between fuel availability, fire impact, and fire suppression strategies.Given the growing impact of wildfires, the effect of fire exclusion has been extensively studied and debated in many different Mediterranean ecosystems for decades now Fire management based on climate-adapted modulation of fire suppression shares some overlap with the management policy of prescribed burnings implemented in other Mediterranean ecosystems Moreover, in our study and in the current fire regime context, unplanned fires increase landscape heterogeneity but do not seem enough to offset the decade-long general trend towards homogenization due to land abandonment and the coalescence of natural vegetation patches The interaction between area burnt, fire suppression and climate warming had counterintuitive effects on the potential for opportunistic fire suppression strategies to reduce the amount of area burnt in climatically adverse years. The area burnt in adverse years in scenarios with climate warming is consistent with climate change bringing warmer and drier summers and increased fire weather risk i.e. prescribed burning or thinning followed by prescribed burning) is the likely key to effective implementation. In fact, recent research The effectiveness of this opportunistic fire suppression strategy is still relatively low compared to other fuel reduction strategies applied in different Mediterranean-type ecosystems From a purely economic standpoint, opportunistic \u2018let-burn\u2019 fire suppression strategies have a further benefit tied to the fact that they curb the economic losses caused by large fires while also saving on fire suppression resources. In fact, a recent study suggests that the potential savings associated to opportunistic strategies could be substantial To conclude, we suggest that to achieve the stand structure and fuel reduction goals required to minimize large fires in extreme fire weather, this strategy could be accompanied by other fuel-reduction treatments such as large-scale forest thinning or biomass extraction. Further studies are needed to assess the impact of novel fuel-reduction treatments on fire regime. Moreover, the possible impacts of these fire management options on biodiversity and a variety of ecosystem services should be carefully evaluated before cost\u2013benefit analyses can be developed. These potential fuel-reduction treatments should therefore also be evaluated in terms of social, economic and environmental cost\u2013benefit trade-offs."}
+{"text": "Transcriptomicanalyses have been conducted to study how mammalian early embryos cope with their immediate microenvironments especially when stressed from the application of assisted reproductive technologies, maternal nutrition or any other induced external factors. To study potential long term impacts from these stresses, description of early embryo epigenome is necessary. DNA methylation profiling of mammalian early embryo presents important challenges as they are rare biological material. Very recently, a genome-scale, base-resolution timeline of DNA methylation has been characterized for mouse embryo, howeverin vitro cultured embryos in presence of the methtyl donor S-adenosyl methionin showed that in addition to protein coding genes, IncRNAs were also impacted by the treatment. At the DNA methylation level, it showed global hypermethylation in treated embryos and parallel analysis revealed some similar function and network between early embryo transcriptome and methylome. Overall, BEGMP is the first developed and functional methylome platform for non-model spices which allows to survey the transcriptome and methylome from very restricted samples.Commercial platform specific to the study of the bovine methylome do not exist yet. We therefore set to develop one with the constraints of enabling to survey the general topology of the genomic methylome using the limited amount of starting material offered by early embryos and also to provide a cost effective platform with a complete data analysis pipeline. We report the development of the Bovine Embryonic Global Methylome platform (BEGMP) which allows global DNA methylation from as little as 7-8 ng of gDNA starting material (representing 10 expanded blastocysts). Samples are processed through a modified HpaII Tiny Fragments (HTFs) enrichment by ligation-mediated PCR (HELP) assay. Initial surveying of the methylome found in Day-7 and Day-12 bovine embryos suggests a transition during development of methylation marks in repeat containing elements in a class-specific manner showing the potential of the platform to describe the ontology of the establishment of methylation marks during early embryogenesis. The platform was also used to study the impact of embryonic culture conditions where both the transcriptome and the methylome were surveyed from the same samples. Treatment of"}
+{"text": "Clinical pharmacokinetic data on antiretroviral drugs are scarce in African HIV-1-positive patients. Most available pharmacokinetic data are derived from ethnically distinct Caucasian research volunteers. This presentation will focus on the clinical pharmacokinetics training and research outputs of an HIV Research Trust scholarship recipient in Uganda. The work highlights the need for post-marketing pharmacokinetic studies in the target populations in order to optimize therapy for patients in resource-limited settings."}
+{"text": "There exists a large body of evidence pointing to an essential role of sleep in memory consolidation -3. In paslow oscillations with gamma activity and clock-like delta oscillations. The model aims at reproducing evoked responses of auditory and visual stimuli at several frequencies. We extend previous results on the phase-dependent response of isolated cortex  to stimu"}
+{"text": "Two theoretical models dominate current understanding of actin-based propulsion: microscopic polymerization ratchet model predicts that growing and writhing actin filaments generate forces and movements, while macroscopic elastic propulsion model suggests that deformation and stress of growing actin gel are responsible for the propulsion. We examine both experimentally and computationally the 2D movement of ellipsoidal beads propelled by actin tails and show that neither of the two models can explain the observed bistability of the orientation of the beads. To explain the data, we develop a 2D hybrid mesoscopic model by reconciling these two models such that individual actin filaments undergoing nucleation, elongation, attachment, detachment and capping are embedded into the boundary of a node-spring viscoelastic network representing the macroscopic actin gel. Stochastic simulations of this \u2018in silico\u2019 actin network show that the combined effects of the macroscopic elastic deformation and microscopic ratchets can explain the observed bistable orientation of the actin-propelled ellipsoidal beads. To test the theory further, we analyze observed distribution of the curvatures of the trajectories and show that the hybrid model's predictions fit the data. Finally, we demonstrate that the model can explain both concave-up and concave-down force-velocity relations for growing actin networks depending on the characteristic time scale and network recoil. To summarize, we propose that both microscopic polymerization ratchets and macroscopic stresses of the deformable actin network are responsible for the force and movement generation. There are two major ideas about how actin networks generate force against an obstacle: one is that the force comes directly from the elongation and bending of individual actin filaments against the surface of the obstacle; the other is that a growing actin gel can build up stress around the obstacle to squeeze it forward. Neither of the two models can explain why actin-propelled ellipsoidal beads move with equal bias toward long- and short-axes. We propose a hybrid model by combining those two ideas so that individual actin filaments are embedded into the boundary of a deformable actin gel. Simulations of this model show that the combined effects of pushing from individual filaments and squeezing from the actin network explain the observed bi-orientation of ellipsoidal beads as well as the curvature of trajectories of spherical beads and the force-velocity relation of actin networks. Listeria monocytogenesin vivo systems are complemented by in vitro assays using plastic beads Listeria pathogen.Cell migration is a fundamental phenomenon underlying wound healing and morphogenesis Listeria pathogen Here we examine computationally the mechanics of growing actin networks. This problem has a long history starting from applying thermodynamics to understand the origin of a single filament's polymerization force In parallel to these microscopic theories, macroscopic elastic propulsion model Note that the widely used terminology could be confusing as the elastic propulsion theory is sometimes called mesoscopic rather than macroscopic. Both terms are justified: the macroscopic mechanics is described using continuum theory, but an actin layer of a few microns thin is certainly a mesoscopic system. The model we present is mesoscopic in the sense that it spans from the microscopic level of individual filaments to the macroscopic level of continuous description of an actin gel. The model is also hybrid because it takes into account both local discrete forces and global network stress. We will mostly use the term \u201chybrid\u201d throughout the paper.The first simple attempt to use hybrid modeling of the lamellipodial edge was recently made in Besides the force-velocity relation, the non-zero curvatures of the trajectories of motile objects in silico hybrid network showed that the combined effects of the macroscopic viscoelastic deformation and microscopic ratchets can explain both concave-up and concave-down force-velocity relations for growing actin networks, bistable orientation of the actin-propelled ellipsoidal beads, and peculiar curvature distributions for the actin-propelled trajectories of the beads.Below, we describe observations of ellipsoidal, rather than spherical, beads that cannot be explained by either microscopic or macroscopic model. This, as well as the complex force-velocity relation and curvature distribution described above, hints that perhaps a hybrid model with individual actin filaments pushing from the surface of a macroscopic deformable actin gel can explain the experiments better. Recent experiments and theory We developed a two-dimensional (2D) simplification of a 3D hybrid model , which iRecently, with our experimental collaborators, we reported observations of the ellipsoidal beads that were uniformly coated with an actin assembly-inducing protein (ActA) To see whether the two existing models of actin propulsion can explain this result, we simulated the motion of actin-propelled ellipsoidal beads as described in the Thus, the elastic propulsion model predicts that beads only move along their long axes, while microscopic ratchet model predicts that beads only move along their short axes, and neither model can explain the observation. In contrast, the full hybrid model predicts that the bead can move in both orientations due to the combination of the elastic squeezing and the geometric spreading of actin and switch infrequently between them  on its orientation are shown in We vary the Young's modulus of the actin network by varying the spring constant in our model as described in The effect of the ratio of the number of attached to the number of pushing filaments, role see , which iin silico\u2019 trajectories of the beads and compared them to the experimental observations . Effective viscoelastic behavior of the actin network emerges from the disassembly and breaking of the network. Further details about the model equations and parameters are described in Text S1Supplementary theoretical and computational methods.(PDF)Click here for additional data file.Video S1Simulation of an actin-propelled ellipsoidal bead with mesoscopic model, in which both the macroscopic elastic deformation of the tail and the microscopic branching of filaments are included.(MOV)Click here for additional data file.Video S2Simulation of an actin-propelled ellipsoidal bead with macroscopic elastic model alone, in which branching of individual filaments is not included.(MOV)Click here for additional data file.Video S3Simulation of an actin-propelled ellipsoidal bead with microscopic filament model alone, in which the elastic deformation of the tail is ignored.(MOV)Click here for additional data file.Video S4Simulation of an actin-propelled spherical bead with mesoscopic model, with all new filaments being created via autocatalytic branching.(MOV)Click here for additional data file.Video S5Similar to (MOV)Click here for additional data file.Video S6Similar to Video S4, except that half of the new filaments being created via autocatalytic branching and the other half via spontaneous nucleation.(MOV)Click here for additional data file.Video S7Simulation of an actin-propelled spherical bead with mesoscopic model.(MOV)Click here for additional data file.Video S8Similar to .(MOV)Click here for additional data file.Video S9Simulated force-velocity measurement for actin pedestal pushing elastic cantilever.(MOV)Click here for additional data file.Video S10Simulated force-velocity measurement for a force-clamped actin tail growing from spherical bead.(MOV)Click here for additional data file."}
+{"text": "Genetic variation in gene expression can be measured to estimate the extant of variation in gene expression within a population, and to determine to what degree expression alleles of different genes are connected within regulatory networks. Furthermore, determining whether variation in the expression of a gene is linked to local or distant effects allows us to make inferences about how heritable variation may change depending on gene function, the number of interacting partners, genetic architecture and evolutionary history [Genetic variation can cause changes in gene expression (mRNA abundance) among individuals. This so-called heritable variation in gene expression is affected by genetic variants that are co-segregating with the gene locus . We analyzed the transcriptomes of germinating sibling megagametophytes from two controlled-crossed families  with a custom microarray comprised of 32,000 spotted oligonucleotides, which represent over 25,000 unique white spruce genes. Each megagametophyte was split into two halves to provide technical replicates that were analyzed separately. A separate comparison of microarray results and RNA-Seq data has been carried out to validate the quality of the microarray.We set out to characterize segregating variation in gene expression in white spruce . The number of variable genes is comparable to that found between 50 nearly isogenic Drosophila lines [Analysis of two families of sibling megagametophytes (n=18) identified close to a thousand genes with segregating gene expression patterns in both of the two families. Approximately 10% of these genes were shared. Zero replicates are expected to have the same clustering pattern by chance alone . Preliminary comparative genomic hybridization data suggests a significant portion of genes which show segregating gene expression alleles also exhibit CNVs. In follow-up experiments, we will address the amount of dominance between the gene expression alleles by comparing gene expression in megagametophytes versus self-fertilized embryos."}
+{"text": "Triticum aestivum) is a main component of the daily diet but can cause three distinct forms of wheat allergy: Baker's asthma, wheat food allergy and wheat pollen allergy. The panel of wheat allergens is still incomplete. The aim of the study was to identify and characterize wheat allergens for the development of improved diagnostic tests and allergen-specific forms of treatment.Wheat  showed IgE reactivity with the complete recombinant glutenin whereas only 5% of Baker's Asthma patients (n=60) showed specific IgE reactivity.We isolated a cDNA coding for the C-terminal part of a low molecular weight glutenin which has not yet been described as an allergen. The C-terminal part as well as the full length protein were expressed as soluble proteins in We identified a low molecular weight as a novel major wheat food allergen which can be used for the development of component-resolved diagnostic tests for wheat food allergy and eventually for specific immunotherapy."}
+{"text": "End-expiratory breath-holds (BH) and Mueller manoeuvres (MM) elicit large increases in muscle sympathetic nerve activity (MSNA). In 16 healthy humans  we used functional magnetic resonance imaging with blood oxygen level-dependent (BOLD) contrast to determine the cortical network associated with such sympathoexcitation. We hypothesized that increases in MSNA evoked by these simulated apneas are accompanied by BOLD contrast changes in the insular cortex, thalamus and limbic cortex. A series of 150 whole-brain images were collected during 3 randomly performed 16-second end-expiratory BHs and MMs (-30 mmHg). The identical protocol was repeated separately with MSNA recorded from the fibular nerve. The time course of the sympathoexcitatory response to both breathing tasks were correlated with whole-brain BOLD signal changes. Brain sites demonstrating both positive (activation) and negative (deactivation) correlations with the MSNA time course were identified. Sympathetic burst incidence increased (p<0.001) from 29\u00b16 (rest) to 49\u00b16 (BH) and 47\u00b16 bursts/100 heartbeats (MM). Increased neural activity (Z-scores) was identified in the right posterior and anterior insular cortices , dorsal anterior cingulate (3.42), fastigial and dentate cerebellar nuclei . Signal intensity decreased in the left posterior insula (3.28) and ventral anterior cingulate (3.01). Apnea both activates and inhibits elements of a cortical network involved in the generation of sympathetic outflow. These findings identify a neuroanatomical substrate to guide future investigations into central mechanisms contributing to disorders characterized by elevated basal MSNA and exaggerated sympathetic responses to simulated apneas such as sleep apnea and heart failure. Obstructive and central apneas elicit entrained cyclical surges in efferent sympathetic vasoconstrictor discharge Although the key regulatory nuclei involved with the generation of sympathetic outflow are located within the brainstem, experimental evidence indicates that higher cortical regions also participate in its regulation per se at a time when any cortical neural patterns associated with the volitional motor effort, baroreceptor- and chemoreflex-mediated, emotional and sensory responses have dissipated To date, relatively few studies have integrated information obtained from fMRI-derived indices of brain neural activity with direct microneurographic recordings of muscle sympathetic nerve activity (MSNA) The purpose of the current investigation was to use fMRI in awake healthy humans to determine the brain regions associated with the reflex increases in MSNA evoked by end-expiratory breath holds and Mueller manoeuvres. Based on the results of prior human neuroimaging studies 2] provided written and verbal informed consent for the present investigation, which was approved by the Research Ethics Board of the University Health Network. All participants were unmedicated, normotensive non-smokers with no history of autonomic, sleep, cardiovascular or neurological disorders.Sixteen healthy volunteers [7\u2642 and 9\u2640, age 35\u00b114 years (range 20\u201365 years), body mass index 23\u00b14 kg/mTwo experimental sessions, the physiologic recording and the functional magnetic resonance imaging, were performed in a randomly assigned order on different days but at the same time of day. Participants were familiarized with the experimental procedures during a prior screening and orientation visit. Each individual completed a routine medical examination and MRI-readiness questionnaire to ensure safety within a high magnetic field environment. Participants arrived for each testing session approximately 3 hours after a light meal, which they were instructed to record in detail and replicate on the second study day, prior to the experimental test session. In addition, they were instructed to arrive well hydrated but to abstain from caffeinated, alcoholic and nicotine containing products for 24 hours before each test. Participants voided before instrumentation to minimize the effects of a distended bladder on sympathetic activity and arterial blood pressure 2O) of pressure for 16 seconds. A visual display of mouth pressure was provided continuously to help participants maintain the required level of negative pressure during the Mueller manoeuvres. All participants performed practice trials prior to data collection to familiarize themselves with these procedures and to ensure that the required level of negative pressure could be maintained for the entire 16 seconds. For the breath hold challenges, participants were instructed to hold their breath for 16 seconds following the end of a normal expiration.A minimum 10 minutes of quiet supine rest and spontaneous breathing preceded the performance of three 16 second end-expiratory breath holds  and Mueller manoeuvres . There were 30 seconds of rest that separated each apnea. The order of the 6 breathing tasks (3 BHs and 3 MMs) was randomly assigned between participants but kept consistent within each subject for the physiologic and fMRI test sessions. During the apnea protocol, participants wore a nose clip and breathed through a mouthpiece connected in series to a pressure transducer for the measurement of airway load pressure. After a stable baseline had been achieved, participants paused momentarily at end-expiration while a stopper with a small air leak was positioned into the end of the mouthpiece. Participants then generated and sustained -30 mmHg  was calculated from successive R-R intervals recorded from Lead II of an electrocardiogram (ECG), respiratory movements were determined by a pneumobelt connected to a pressure transducer and continuous estimates of arterial blood pressure (ABP) were collected non-invasively using automated photoelectric plethysmography  Analogue signals for blood pressure, respiratory movements, mouth pressure (200 Hz-sampling), the ECG (1000 Hz), and the raw neurogram (10 kHz) were collected with an on-line data acquisition and analysis system . Pre-breathing task baseline data were averaged over a minimum 60 second period before the first breath hold or Mueller manoeuvre. Peak MSNA and HR increases during each of the six breathing challenges were determined, and the mean of these responses was used for statistical analysis. Only pulse-synchronous bursts of MSNA activity with characteristic rising and falling slopes, and amplitudes that were at least thrice that of the between-burst baseline fluctuations , were included in the analysis. After an acceptable neural recording was obtained, the participant was instructed to maintain the leg in a relaxed position for the remainder of the study. Segments of the neural recording that showed evidence of mechanoreceptor activity caused by muscle tension were excluded from analysis. MSNA was analyzed for frequency (bursts per minute) and incidence (bursts per 100 heartbeats).2, see below) and MSNA data were performed using a computer-based software program (SAS). A critical significance level of p\u22640.05 was set for all physiologic comparisons.All physiologic data are expressed as means \u00b1 SD. Breath hold- and Mueller manoeuvre-mediated changes in all dependent variables were analyzed using a repeated-measures one-way ANOVA. Tukey's post hoc analysis was performed to estimate differences among means. Probability levels during multiple point-wise comparisons were corrected using Bonferonni's approach. Significant differences between breath hold and Mueller manoeuvre were analyzed using a paired t-test. Statistical analyses for HR, end-tidal carbon dioxide . Foam pads were positioned on either side of the head, under the elbows and knees to minimize head movement and participant discomfort during scanning. Gradient-echo echo-planar imaging-sensitive blood oxygen level-dependent (BOLD) contrast was used to identify cortical regions in which blood flow and/or metabolism changed (from baseline) during each of the apneas 2 measures were obtained during the neuroimaging sessions using an MRI-compatible vital signs monitor . Baseline ETCO2 data were averaged over all complete respiratory cycles collected during the 30 second period before the first breathing challenge. In addition, the ETCO2 during the first breath following each breathing challenge was compared to baseline.The methods and equipment described above for the apnea protocol were repeated during scanning. In addition, MRI-compatible goggles provided continuous visual feedback regarding the level of developed negative airway load pressure during the Mueller manoeuvres and headphones were used to provide instructions  and communicate with the participants during and between scanning periods. Continuous ECG and ETCO2 and/or perfusion variations) using the Linear Model of the Global Signal (LMGS) extension for SPM8 Whole cortical BOLD fMRI images were analyzed using statistical parametric mapping software  per se, while attempting to minimize cortical neural activity changes influenced by volitional, baroreceptor, chemical and/or sensory stimuli. For each participant, the average time course of the MSNA response elicited by the six breathing challenges was characterized and used to construct a model that was correlated with the BOLD fMRI time series data at each individual voxel in the brain. Specifically, the MSNA time course profile involved determination of the time delay  and the total duration of the MSNA response for each participant  or the MMs (41\u00b17 mmHg) were not different (p>0.18) from the baseline values obtained during the last minute prior to the start of the apnea protocol (40\u00b15 mmHg).The MNI coordinates and statistical scores of brain regions that demonstrated significant increases and decreases in BOLD signal intensity are shown in The aim of the current investigation in awake healthy humans was to identify, using BOLD fMRI time series images, the autonomic cortical network associated with apnea-induced muscle sympathetic nerve activity. Brain regions engaged by the MM and BH included the insular cortex, anterior cingulate cortex and cerebellum. In the present study there was concordance between the brain regions highlighted and those previously reported to be involved with the sympathetic response elicited by the non-volitional stresses of lower body negative pressure Although they do not replicate precisely the complex neural and chemical events triggered by obstructive and central apnea during sleep, the performance of such interventions, which are amenable to standardization, by awake volunteers has yielded novel insight into the magnitude and time courses of the hemodynamic and neural responses elicited by these stimuli in health and disease 2 values following the MM and BH (likely because both were performed at end-expiration and were of relatively short duration) argues against significant engagement of this population of receptors by the present protocol.With BH, this sympathoexcitation occurred sooner than with the MM. The increase in MSNA elicited by BH is mediated primarily by peripheral chemoreflex activation Because of the relatively large between-subject variations in the time delay  and duration  of the sympathoexcitatory responses, for each participant, the temporal BOLD regression model was based on their specific MSNA time delay and duration of sympathoexcitation elicited by the BHs and MMs, respectively. In comparison, the within-subject variations in the MSNA time delay  and duration  were relatively consistent. Therefore, we applied a statistical paradigm, which ensures that between-subject differences in the temporal MSNA response are accounted for  Two brain regions that demonstrated increased BOLD signal intensity matching the time course of the apneic MSNA responses were the right insular cortex and the dorsal portion of the anterior cingulate cortex (ACC). Both have been implicated as important cortical structures involved in the regulation of cardiovascular function. Direct electrical stimulation of the human right insula The role of other brain regions that displayed increased neural activation during the sympathoexcitatory response to the apneas, including the supramarginal gyrus, precentral gyrus, superior, middle and medial frontal gyri, are less well understood with respect to autonomic cardiovascular function. Activation of these regions has previously been observed during respiratory challenges including inspiratory loading It has long been recognized that the cerebellum plays a significant role in the regulation of autonomic cardiovascular function Several loci, including the ventral portion of the ACC and the left posterior insular cortex, exhibited decreased fMRI BOLD signal intensity during the periods of apnea-evoked elevated MSNA. These structures may have sympathoinhibitory functions during basal conditions. Their deactivation may be required for reflex-mediated sympathoexcitation to fully emerge. A similar pattern of decreased BOLD signal intensity within these two brain areas has been reported to accompany also the increased sympathetic vasoconstrictor response elicited by baroreceptor unloading Other cortical areas that demonstrated a similar pattern of fMRI signal change included discrete regions of the frontal cortex including the precentral gyrus, and middle/superior frontal gyrus, which encroaches upon parts of the premotor and supplementary motor areas. The main role attributed to the prefrontal cortex concerns executive function. The exact role of this brain area related to autonomic control is unclear but activation within a similar region has previously been linked with the processing of baroreceptor stimulation in humans Because high-frequency radio pulses emitted during the fMRI scanning sequences saturate the microneurographic recording, it is not possible to collect simultaneously both signals during the same session. We elected to acquire BOLD signal intensity images and MSNA recordings on two separate days but according to a stringent protocol designed to minimize day-to-day variability of our signals. Beforehand, each participant engaged in apnea training sessions and on both study days, participants followed a standardized protocol prior to each experimental session to ensure that diurnal variation, hydration status, daily physical activity, sleep duration, nutritional content and consumption time of the pre-test meal were all controlled for. A recent investigation, in which a protocol of 4 second quiescent periods between 4 second BOLD fMRI scanning periods was applied to capture intermittent recordings of a stable microneurographic signal, provides encouragement that this technical limitation might be overcome in the future Limitations to the current study include the need to record MSNA and BOLD fMRI data on separate experimental days. The corresponding assumption is that the magnitude and timing of the evoked MSNA response to the apneas are consistent over repeated sessions. Although the MSNA response to head-up tilt 2 observed post-BH and MM may have been caused by a relatively large inspiration at the end of the apnea due to a corresponding increase in respiratory drive, resulting in a larger tidal volume and a dilution of alveolar PCO2, and that without continuous recordings of arterial blood pressure and blood gases (O2 and CO2) we cannot precisely isolate the relative contributions of baroreceptor, peripheral and central chemoreceptor sensory input on the cortical BOLD responses.We acknowledge that the lack of increase in ETCOWe have attempted to minimize the confounding influence that apnea-induced changes in blood gases and intracranial pressure may have on the BOLD signal. However, although the LMGS method was used, it is still possible that some of the observed BOLD signal changes may originate from non-neuronal factors. Furthermore, we did not observe significant BOLD signal changes within key regulatory regions within the brainstem involved with the generation of sympathetic vasoconstrictor outflow . Factors that may have enhanced our ability to detect discrete brainstem autonomic nuclei include further minimization of participant head motion during the apneic challenges, and the inclusion of a second dedicated BOLD fMRI scanning session focused only on the brainstem. It is important to emphasize that the purpose of the present study was not to map cortical autonomic networks associated specifically with baroreceptor or chemoreceptor influences but to identify the brain regions involved with the generation or regulation of sympathetic vasoconstrictor outflow in response to these two apneic manoeuvres. Consequently, for each breathing challenge, fMRI image analysis focused on integrating data acquired over the time intervals when MSNA was highest and the potential influences of baroreflex and volitional stimuli were least. Identification of brain regions involved specifically with the detection and integration of these three afferent signals merits future investigation.This study establishes the functional organization of the cortical brain network associated in awake healthy individuals with the sympathoexcitatory responses elicited by Mueller manoeuvres (as simulated obstructive apnea) and breath holds . Importantly, a key strength of this investigation was its focus on healthy young individuals, in whom BOLD signal responses are unlikely to be affected unpredictably by age or the presence of co-morbidities. Specific brain regions that demonstrated increased BOLD signal that correlated with the time course profile of the MSNA signal included the right insular cortex, dorsal anterior cingulate cortex, cerebellum, and widespread areas of the fronto-parietal cortex. Conversely, brain areas that showed decreased fMRI signal during periods of augmented sympathetic vasoconstrictor outflow evoked by the apneas included the left insular cortex, ventral anterior cingulate cortex, precentral gyrus and hippocampus. It is plausible that these brain regions may be important for inhibiting sympathetic outflow in the rested state and that the removal of this sympathoinhibitory function during autonomic challenges is necessary to elicit the increases in MSNA observed during the apneas.The current findings provide a neuroanatomical substrate that may be utilized to help elucidate potential regions of central autonomic dysfunction in patient populations characterized by exaggerated basal and apnea-induced increases in MSNA such as heart failure and sleep apnea"}
+{"text": "Dear Editor,We read with great interest the article by Baris Afsar entitled \"The relationship between erythropoietin resistance and antibody response to hepatitis B vaccine in hemodialysis patients\" published in your valuable journal. He analyzed the relationship between anti-HBs response and erythropoietin (EPO) resistance among patients undergoing maintenance hemodialysis and demonstrated that EPO resistance is negatively associated with both anti-HBs levels and seroconversion status among these patients .Hyporesponsive to EPO therapy or EPO resistance and effectiveness of hepatitis B virus (HBV) vaccination in patients with end-stage renal disease (ESRD) are important issues among these patients. Unfortunately, EPO resistance is relatively common and it may be an important clinical observation since a hyporesponsive to EPO therapy and need to higher doses of EPO may be associated with increased mortality, an effect that persists after adjustment for the usually lower hematocrit in such patients -4.A variety of factors may cause patients to be relatively resistance to EPO including absolute iron deficiency which may be due to external blood losses, bone disease due to secondary hyperparathyroidism or the accumulation of aluminum in bone, chronic inflammation, the administration of angiotensin converting enzyme inhibitors and/or angiotensin II receptor antagonists, unsuspected hematologic disorders, development of pure red cell aplasia and etc. -9.Compared to the overall effectiveness of HBV vaccination in patients without renal failure (a response rate of over 90 percent), the effect of this vaccination is reduced among patients with ESRD because of the general suppression of the immune system associated with uremia. It appears that only 50 to 60 percent of these patients develop antibodies following HBV vaccination. The rate of response is higher among patients with chronic kidney disease not requiring dialysis, suggesting that the immune response is positively associated with the degree of renal function -12.Although it could be possible and the results of Afsar study suggested that EPO resistance was negatively associated with anti-HBs levels, however, the study has limitations including retrospective design, small number of patients, not available reliable information about the brand of vaccines and the results of the study cannot prove a cause and effect relationship between EPO resistance and anti-HBs levels. Therefore, further prospective researches with a larger number of patients are needed to highlight the underlying mechanisms of EPO resistance and relationship between it and anti-HBs levels and seroconversion status among HD patients."}
+{"text": "Urinary tract infection (UTI) is a well-recognized early complication in renal transplant recipients (RTR) and can have significant bearing on their outcome. The recent rise in incidence of extended spectrum beta lactamase (ESBL) producing bacteria causing UTI among RTR poses new and significant challenges in terms of management and outcome. Our aim is to analyze the effect of ESBL producing bacteria causing UTI in these patients and its impact on allograft function.We reviewed the medical records of 147 RTR who were followed at a tertiary care hospital affiliated transplant center between January 2007 and May 2013 and noted five RTR who developed episodes of ESBL producing bacteria related UTI during follow up. Multiple patient characteristics including demographics, immunosuppression, recurrences, allograft function and outcome were analyzed.Five patients (3.4%) out of 147 had ESBL producing bacteria related UTI. We found all patients to be above 60 years of age, with three out of five being females, and all five patients had diabetes mellitus. We identified a total of 37 episodes of UTI among these five patients during this period. Two of these patients had elevated creatinine values during the episodes of UTI and three of them developed bacteremia. Of the five patients, four of them had a favorable outcome except for one patient who developed persistent allograft dysfunction.RTR are at a higher risk for developing ESBL producing bacteria associated UTI. Early diagnosis along with appropriate and judicious use of antibiotics will ensure long term success in allograft and patient outcome. Renal transplants have become the standard of care for end stage renal transplant (ESRD), thereby increasing the number of patients on immunosuppressive regimen who are extremely susceptible to a host of infections in the post-transplant phase We would like to address the issue of extended-spectrum-beta-lactamase (ESBL) producing bacteria causing UTI among renal transplant recipients (RTR) We reviewed the medical records of 147 renal transplant recipients (RTR) who were followed at a tertiary care hospital affiliated transplant center between January 2007 and May 2013 and noted five RTR who developed episodes of extended-spectrum-beta-lactamase (ESBL) producing bacteria related urinary tract infection (UTI) during follow up. This study was approved by the Institutional review board at North Shore LIJ Hospital, NY. The patient records/information was anonymized and de-identified prior to analysis. The general policy for urinalysis for post-transplant visits at our center is as follows:First 2 weeks - twice a week2\u20134 weeks - once a week4\u201312 weeks - once in 2 weeks3 months-1 year - once a month1\u20132 year - once in 2 months2\u20135 years - once in 3 months>5 years - once in 6 monthsClean catch mid-stream urine sample is taken. If there is any evidence of UTI such as leukocytosis or positive nitrites/leukocyte esterase, then a reflex culture is sent. All these patients presented with fever and dysuria and were diagnosed with UTI based on urine microscopy and culture results. Antibiotic sensitivity testing of the cultures was used to confirm the presence of ESBL producing bacteria. All patients were on routine immunosuppression protocol consisting of tacrolimus or cyclosporine, mycophenolate mofetil, and prednisone and prophylactic regimen against bacterial infections consisting of cefazolin 1 gm preoperatively and Trimethoprim-Sulfamethoxazole (80/400) one tab daily life long post-transplant. After the treatment of an episode of UTI, urine cultures are done to confirm resolution of the infection. Subsequent episodes were identified when symptoms of UTI occurred with positive urine cultures for the bacteria. These patients are followed lifelong like other RTR, with concern for the recurrence of UTI. This study was approved by the Institutional review board at this health system.Five patients (3.4%) out of 147 had extended-spectrum-beta-lactamase (ESBL) producing bacteria related urinary tract infection (UTI). All patients were above 60 years of age and included 3 female and 2 male patients. Of the two male patients, one was diagnosed with benign prostatic hyperplasia (BPH). Four of them underwent live donor renal transplantation and one received kidney from a deceased donor. All the patients in our study were diabetic. None of them had a ureteral stent inserted in the immediate post-transplant phase. In our study 3 out of 5 patients had episodes of UTI due to non ESBL producing bacteria prior to contracting the ESBL producing one. We identified a total of 37 episodes of UTI among these five patients between January 2007 and May 2013. One of our patients required a ureteral stent later in the post-transplant phase during the course of treatment of urinary stone in the transplanted ureter. None of them were noted to have an episode of rejection. Interestingly two of these patients had elevated creatinine values during the episodes of UTI. One patient was noted to have progressively elevated creatinine during successive episodes of UTI resulting in persistent allograft dysfunction. Of the five patients described in this case study, three developed bacteremia and sepsis. One of them had acute pyelonephritis which progressed into full blown septicemia and shock requiring long term hospitalization and later on developed chronic allograft dysfunction. Carbapenems were the most commonly used treatment in our patients (1 gram ertapenem/meropenem intravenously once daily or 1 gram imipenem intravenously twice daily for 14 days). The potential risk factors we observed in patients other than the genitourinary surgery (kidney transplant) and bladder catheterization were diabetes, prior episodes of non ESBL UTI, ureteral obstruction and ureteral stent, of which all except the prior episodes of non ESBL UTI is applicable to UTI in general.Refer to Refer to Urinary tract infection (UTI) is the most common bacterial infection, representing 40 to 50% of all post-transplant infections As in general community acquired UTI, ESBL producing bacterial UTI is associated with numerous risk factors. In our case analysis we focused on age, gender, living or cadaveric donor kidneys, stent insertion during or post transplantation, antibiotic prophylaxis, immunosuppression, diabetes mellitus, rejection, recurrent episodes of UTI and urinary tract obstruction as possible risk factors in this patient population.There are contradicting data regarding the correlation of age and UTI. A study done in Spain found that age over 60 years is a significant risk factor for ESBL UTI It is a well-known fact that female patients have a higher risk of developing UTI, which is mostly due to difference in anatomy Studies which correlate the type of donor to the incidence of UTI are rare. A study in 2005 noted an increased incidence in UTI in patients who had cadaveric donors Ureteral stents are usually placed intraoperatively to reduce urologic complications post-transplant, the risk of infection being taken into consideration. Studies show that stenting predisposes to UTI and a high recurrence rate of UTI was seen even after stent removal Antibiotic therapy is a significant risk factor for development of ESBL producing bacteria Immunosuppression is an important risk factor for ESBL UTI. A study done by in 2010 showed a higher incidence of UTI in patients who had cyclosporine in their immunosuppression protocol Diabetes mellitus predisposes to UTI in general due to decreased local cytokine secretion in the urinary tract and this relationship has been proven by several studies Recurrent UTI can act as predisposing factor for development of ESBL UTI. A study done in 2011 showed over 75% of patients with ESBL had recurrent UTI in the past Functional or mechanical disorders of urinary tract are other risk factors associated with an increased risk of developing UTI UTI in RTR can have significant negative effects on the allograft kidney and can even lead to allograft failure ESBL producing bacteria related UTI is extremely difficult to treat given the very few drug options available to treat the condition Renal transplant recipients are at a higher risk of developing UTI due to ESBL producing bacteria. As many of the inherent risk factors are non-modifiable, this situation poses a special challenge. Potential adverse consequences of ESBL UTI may include sepsis as well as acute and chronic allograft dysfunction. Efficient management of these patients with a high index of suspicion, prompt diagnosis and use of appropriate antibiotics can result in successful allograft and patient outcome. Continued monitoring on a large scale with close attention to the treatment outcome will help understand and manage this evolving disease."}
+{"text": "Electrostatic forces play a large role in determining the strength of protein-ligand interactions, and the calculation of pKa value shifts upon ligand binding is therefore an important component of any accurate protein-ligand binding calculation. However, such pKa calculations are rarely performed in virtual screening experiments due to the unavailability of ligand solution pKa values and the difficulty in generating the required charge distributions for each ligand protonation state. We present a freely available web-based database of small-molecule pKa values that automates the task of retrieving protonation states and solution pKa values for small-molecule ligands so that these can be used with tools such as PRODRG and PDB2PQR for generating the necessary parameters for a structure-based pKa calculation of a protein-ligand complex. The database contains a total of 348 pKa values and represents a significant step towards performing accurate automated pKa value calculations in virtual screening experiments."}
+{"text": "Differences in mRNA expression levels have been observed in failing versus non-failing human hearts for several membrane channel proteins and accessory subunits. These differences may play a causal role in electrophysiological changes observed in human heart failure and atrial fibrillation, such as action potential (AP) prolongation, increased AP triangulation, decreased intracellular calcium transient (CaT) magnitude and decreased CaT triangulation. Our goal is to investigate whether the information contained in mRNA measurements can be used to predict cardiac electrophysiological remodeling in heart failure using computational modeling. Using mRNA data recently obtained from failing and non-failing human hearts, we construct failing and non-failing cell populations incorporating natural variability and up/down regulation of channel conductivities. Six biomarkers are calculated for each cell in each population, at cycle lengths between 1500 ms and 300 ms. Regression analysis is performed to determine which ion channels drive biomarker variability in failing versus non-failing cardiomyocytes. Our models suggest that reported mRNA expression changes are consistent with AP prolongation, increased AP triangulation, increased CaT duration, decreased CaT triangulation and amplitude, and increased delay between AP and CaT upstrokes in the failing population. Regression analysis reveals that changes in AP biomarkers are driven primarily by reduction in I A growing number of studies examine cardiac tissue mRNA expression levels in an attempt to characterize electrophysiological remodeling associated with disease conditions such as heart failure and atrial fibrillation et alLinking mRNA changes to AP and CaT alterations has several complications, as recently reviewed by Nattel et alDespite these challenges, mRNA expression data provides information on heterogeneity and variability in the heart, in both healthy and diseased states. In this study, we aim to show how computational modelling can be used to understand the electrophysiological consequences of differences in mRNA expression levels between failing and non-failing human hearts. The methodology proposed is flexible and can be applied to any set of mRNA measurements and models. We illustrate its potential by focussing on the ventricular component of the dataset recently obtained by Ambrosi AP and CaT properties are quantified across both populations and compared to experimental measurements obtained in failing and non-failing human ventricles. We then predict the electrophysiological response of human ventricular myocytes at different stimulation rates and quantify the relative importance of each ionic current in determining AP and CaT differences in the human non-failing and failing cell populations.et almRNA expression data The O\u2019Hara-Rudy (ORd) human ventricular endocardial model et alThe stimulation protocol mimics the one used by Lou As illustrated in To quantify the relative importance of ionic conductances in determining changes in the biomarkers, linear regression To determine the effectiveness of this fit, the correlation coefficient The closer https://computation.llnl.gov/casc/sundials/) called from Chaste. A backward differentiation formula method is used to integrate the differential equations with absolute and relative error tolerances 10http://www.cs.ox.ac.uk/chaste). Matlab data analysis scripts are also included. All simulations are performed on a 512 core cluster utilising 2.8GHz Intel processors at the Oxford Supercomputing Centre (OSC).All numerical simulations are performed using our open source cardiac simulation software Chaste et alAs shown in et alAs shown in Table S2 in As shown in CaTD80 is increased at all BCLs compared with the non-failing population  G\u2013I. At As shown in Our simulations show that CaTD3080 values display a complex behaviour that is dependent upon the BCL in both the non-failing and failing populations. At 1500 ms BCL, CaTD3080 values for the non-failing population display a bimodality in their distribution corresponding to two subpopulations of cells, the larger one close to the value shown by the original ORd model, and the other one with markedly reduced CaTD3080 values. The latter disappears with decreasing BCLs below 1000 ms in the non-failing population. In the failing population however, the bimodality appears for BCLs et alet alAs illustrated in At 1500 ms the median value for DAPCaT in the failing population is 17.4 ms, as opposed to 10.9 ms in the non-failing population. At a cycle length of 300 ms, the median value for the failing population is 13.1 ms and the median value for the non-failing population is 8.6 ms.In order to determine the potential correlation between the different biomarkers values shown above, We further exploit the potential of a population-based computational approach to investigate the relative importance of ionic properties in determining changes in each biomarker in failing versus non-failing human cardiomyoctes. The correlation found in the previous section with respect to AP and Ca biomarkers suggests that different ionic properties determine AP and Ca biomarkers values, respectively, within each population. We use regression analysis to establish which ionic currents determine biomarker values in the failing versus non-failing population. In both the failing and non-failing populations, long APD80 values are correlated with low Gund \u22120.9 . RegressAs expected from the strong correlation between APD80 and AP triangulation shown in As illustrated in Even when In the failing population alternans occur in 64 cells at 350 ms and in 2235 cells at a BCL of 300 ms, due to prolonged APD associated with low G  B,D, as In this study we have developed a population-based approach to investigate the potential of mRNA expression levels measured in failing human hearts to predict electrophysiological remodeling in AP and CaT, as measured experimentally. Our population-based approach takes into consideration natural variability that may arise from a variety of sources, as well as uncertainty associated with the extent to which mRNA expression affects functional channel conductance at the cell membrane, and uncertainty in electrophysiological measurements. This is in contrast to the traditional approach of considering unique values of ionic conductances in cardiac models of non-diseased and failing human cardiomyocytes mRNA data associated with GAP biomarkers (namely APD80 and APD3080) are correlated in both non-failing and failing cardiomyocytes, and are primarily determined by GCa biomarkers  are correlated (but only weakly correlated with AP biomarkers) and are primarily determined by Jionic mechanisms underlying the occurrence of alternans are different in the failing population versus the non-failing population: alternans are primarily favoured by low GThe non-failing and failing populations of human ventricular cell models are constructed based on the latest human ventricular AP model The failing cell model population is built by including 0\u201360% downregulation of GChanges in AP biomarkers are not strongly correlated with changes in CaT biomarkers, suggesting that different ionic mechanisms cause these biomarker changes. This is explicitly demonstrated through linear regression. In particular different causes determine the duration of AP and CaT in failing cardiac myocytes, namely GOur simulations also show significant rate-dependence in the ionic conductances underlying changes in AP triangulation, CaTD80, CaT triangulation and AP-CaT delay in failing and non-failing cardiomyocytes. In particular, the significance of IOur population based approach reveals conditions in which alternans may appear at longer BCLs than in the original ORd model. The form of alternans observed in the non-failing population cannot occur in the failing population, as the combination of parameters driving alternans in the non-failing population is outside the parameter range for the failing population. Similarly, the 2\u22361 block observed in the failing population does not occur in the non-failing population as Get alet alIn this study we have only examined one component of the mRNA expression dataset presented by Ambrosi et alThe non-failing human hearts studied are not necessarily healthy, and so care must be taken in extrapolation from these results to healthy humans et alWe do not include co-regulation of membrane ion channels in our study, as this information is not available from Ambrosi The presence of spatial heterogeneities in AP properties in the left ventricle is consistently reported in humans Our study inherits many of the difficulties in extrapolating from mRNA expression data to functional membrane ion channels as discussed in the introduction and reviewed in Supplement S1Supplementary figures and tables referred to in the text.(PDF)Click here for additional data file."}
+{"text": "Rapid changes in behavior require rapid changes in brain states, yet the brain must also remain stable in the face of noise and uncertainty. The problem is exemplified by motor readiness in which execution of a planned motor behavior is voluntarily delayed until the onset of a 'go' stimulus. Achieving such rapid changes between otherwise stable brain states remains a fundamental problem in computational neuroscience. Single-state attractor networks provide stability but require global changes to the attractor landscape to alter network state and such transitions are invariably slow. Multi-state attractor networks promise rapid transitions between co-existing stable states by direct perturbation of the state variables however the nature of the perturbation is critical. Here we explore the efficacy of a global perturbation for invoking state transitions in a bistable model of motor cortex based on phase-coupled neural oscillators .Motor cortex was modeled as a two-dimensional sheet 128x128) of phase-coupled neural oscillators that were locally coupled using a center-surround connection topology. This model exhibits bistability when the strength of the inhibitory surround is within a specific range. In such cases the oscillators spontaneously self-organize into either spatially synchronous patterns or spatiotemporal traveling wave patterns depending upon initial conditions. These patterns are reminiscent of those observed in primate motor cortex during voluntary 8x128 of  where thWe show that a global perturbation that is sinusoidally coupled to the phase of the mean-field can evoke a rapid transition from the synchronous state to the wave state. Our results demonstrate that an appropriately timed global perturbation can induce rapid transitions between distinct stable firing patterns and we posit that motor cortex may use a similar mechanism to transition rapidly from motor readiness to action."}
+{"text": "Integrin signaling regulates cell migration and plays a pivotal role in developmental processes and cancer metastasis. Integrin signaling has been studied extensively and much data is available on pathway components and interactions. Yet the data is fragmented and an integrated model is missing. We use a rule-based modeling approach to integrate available data and test biological hypotheses regarding the role of talin, Dok1 and PIPKI in integrin activation. The detailed biochemical characterization of integrin signaling provides us with measured values for most of the kinetics parameters. However, measurements are not fully accurate and the cellular concentrations of signaling proteins are largely unknown and expected to vary substantially across different cellular conditions. By sampling model behaviors over the physiologically realistic parameter range we find that the model exhibits only two different qualitative behaviors and these depend mainly on the relative protein concentrations, which offers a powerful point of control to the cell. Our study highlights the necessity to characterize model behavior not for a single parameter optimum, but to identify parameter sets that characterize different signaling modes. Cell migration is a carefully regulated process that is essential for embryonic development and life Talin binds to the integrin beta-tail and stabilizes the active, open integrin conformation Such questions are difficult to address by verbal reasoning alone. Mathematical modeling can help to integrate available isolated experimental information into a single model and permits the efficient analysis and comparison of model alternatives. Given the many states and complexes that need to be considered the dynamics of integrin activation can be best captured by a rule-based modeling approach Integrin activity is regulated by the interaction with the extra-cellular matrix  and intra-cellular cytoskeletal adaptors . We use a rule-based modeling approach, in order to capture the complexity of integrin signaling. This approach allows us to model integrin signaling compactly by a set of 30 biochemical reactions rules, which are summarized graphically in The basic dynamics of our model are as follows. Binding of ligand and/or talin stabilizes the open/active conformation of integrin . In case of outside-in signaling integrin signaling is initiated by binding of ligand  and internal signals . As discussed above both modes of signaling are observed only with group 1 parameters  and we wWe have developed a rule-based model to explore the roles of talin, PIPKI, and Dok1 in integrin activation and signaling. In spite of much detailed biochemical data a significant level of uncertainty remains because measurements are not fully accurate and the concentrations of signaling proteins are largely unknown and expected to vary substantially across different cellular conditions. It is generally infeasible to sample the entire physiological parameter space. We therefore addressed this challenge in modeling signaling pathways by restricting the sampled parameter space according to the quality of the available measurements. The width of the ranges was based on general rules as to the accuracy of different experimental methods as well as prior knowledge on physiologically reasonable ranges. This restriction enabled us to systematically analyze model dynamics with only Within the wide range of model dynamics, we observed two different qualitative behaviours: one group of parameter sets supported integrin activation both by outside-in or inside-out signaling, and was characterized by high levels of talin-integrin complex formation, a strong dependence of PIPKI recruitment on talin, low levels of integrin phosphorylation and high levels of PIPKI activation. The other group of parameter sets did not support inside-out signaling, and was characterized by high levels of Dok1-integrin complex formation, no dependency of PIPKI recruitment on the presence of talin and higher levels of integrin phosphorylation.Importantly, the most decisive parameters were the relative cellular protein concentrations. Accordingly, the total concentrations of network components can serve as powerful control points to achieve distinct network dynamics. Thus for low talin concentrations we predict impaired inside-out signaling, yet much Dok1-integrin complexes form in response to outside-in signaling which will direct downstream signaling via recruitment of a range of proteins, including Ras-GAP, the adaptor protein Nck, the non-receptor tyrosine kinase Csk, and the phosphatase SHP2 Previous experimental observations led to the suggestion of an integrin phosphorylation switch. Biochemical measurements revealed that phosphorylation of integrins and PIPKI would lower the talin-integrin affinity and enhance PIPKI-talin binding The simulation further revealed that the opening of the integrin conformation not necessarily leads to integrin phosphorylation. Because binding shields the integrin phosphorylation motif, strong recruitment of either Dok1 or talin to integrin tails will counteract integrin phosphorylation. Therefore integrin phosphorylation is indirectly regulated by recruitment of talin and Dok1. We observe that conditions which enable high levels of Dok1 signaling also allow for a sensitive, sustained phosphorylation response while talin-dependent signaling allows only for transient levels of high phosphorylation. Since talin is the more stable signaling platform, its stable interaction with integrin tails does not allow for high levels of integrin phosphorylation but a sustained level of open integrins. Our modeling therefore suggest, that integrin activation and integrin phosphorylation serve as independent nodes in integrin signal propagation. Finally our simulation suggests that outside-in and inside-out signaling differ in the kinetics of the activation process. Thus while outside-in signaling is biphasic with a rapid talin-independent and a slow talin-dependent activation phase, there is only the late talin-dependent activation phase in inside-out signaling.It has long been recognized that model behaviours should be analysed not for a single measured parameter set alone, but over a wider parameter range. Ensemble modeling strategies combined with various clustering algorithms have been used to reveal parameter sets that yield similar qualitative results Overall, our study illustrates how detailed biochemical measurements together with a thorough computational analysis can be used to reveal qualitative behaviors of biological signaling networks. Without biological data the space of possible parameter combinations is too large to be explored. Yet without the computational model it is impossible to integrate biological knowledge to grasp the dynamic range of biological networks and to estimate the possible impact of parameter variations under different cellular conditions.We use a rule-based approach to explore the roles of talin, Dok1, and PIPKI in integrin signaling dynamics We collected parameter values for all biochemical reactions from the literature and parameterized the model according to We use the following eight criteria to characterize model behavior.DOK\u2236INT formation in response to stimulus:TAL\u2236INT formation in response to stimulus:PIPKI-dependent TAL recruitment:TAL-dependent PIPKI recruitment:PIPKI phosphorylation in response to stimulus:INT phosphorylation in response to stimulus:Integrin activation by outside-in signaling:Integrin activation by inside-out signaling:Here, Based on the first two criteria, we selected the 2000 parameter sets (2%) which achieved the highest levels of TAL\u2236INT (group 1) and DOK\u2236INT (group 2). In order to identify the relevant parameters which characterize both groups, we further compared the distribution of group 1 and group 2 parameters set with their corresponding uniform sampling distributions and among each other. We computed the empirical cumulative distribution function Click here for additional data file.Text S1A computational analysis of the dynamic roles of talin, Dok1, and PIPKI for integrin activation - Supplementary Text.(PDF)Click here for additional data file."}
+{"text": "Population structure and kinship are widespread confounding factors in genome-wide association studies (GWAS). It has been standard practice to include principal components of the genotypes in a regression model in order to account for population structure. More recently, the linear mixed model (LMM) has emerged as a powerful method for simultaneously accounting for population structure and kinship. The statistical theory underlying the differences in empirical performance between modeling principal components as fixed versus random effects has not been thoroughly examined. We undertake an analysis to formalize the relationship between these widely used methods and elucidate the statistical properties of each. Moreover, we introduce a new statistic, effective degrees of freedom, that serves as a metric of model complexity and a novel low rank linear mixed model (LRLMM) to learn the dimensionality of the correction for population structure and kinship, and we assess its performance through simulations. A comparison of the results of LRLMM and a standard LMM analysis applied to GWAS data from the Multi-Ethnic Study of Atherosclerosis (MESA) illustrates how our theoretical results translate into empirical properties of the mixed model. Finally, the analysis demonstrates the ability of the LRLMM to substantially boost the strength of an association for HDL cholesterol in Europeans. Population structure and kinship represent genetic relatedness between samples at different scales, and are widespread confounding factors in genome-wide association studies (GWAS) that can decrease power and increase the false positive rate of tests of association While simple tests of association assume statistical independence between individuals, population structure and kinship indicate covariance between individuals based on the genetic similarity between individuals and the heritability of the phenotype Motivated by the empirical differences between the LMM and including principal components as fixed effects, we describe a unified framework that connects these models. This framework facilitates a statistical examination of the methods' differing frequentist vs. Bayesian interpretations, their differing approaches to inference and how these differences drive their empirical properties. We next introduce a summary statistic, the effective degrees of freedom, that measures overall model complexity and the influence of each principal component on the fit of the LMM. Leveraging the unified framework and the effective degrees of freedom, we propose a novel method, the low rank linear mixed model (LRLMM) using the algorithm of Lippert, et al. a posteriori (MAP) estimation of all parameters, the model does not have an explicit prior on regression coefficients, Considering the matrix of genotype data Now consider the linear mixed model (LMM)For simplicity, let the genetic similarity matrix We note that while It is well established that the eigen-value of each principal component serves as a metric of biological relevance in relation to any underlying population structure Since modeling principal components as fixed or random effects share the underlying regression model, the differences in their ability to account for population structure and kinship In both fixed and random effects models, the parameter of interest for the hypothesis test is the coefficient Alternatively, the LMM includes all principal components in the model and integrates over the random effect with respect to its prior distribution. The likelihood can be stated in terms of the genetic similarity matrix,Population structure and kinship are both confounding factors in GWAS since they produce covariance between individuals' phenotype values. Yet the dimensionality of these two processes are different. Population structure is a low dimensional process embedded in a high dimensional space so that a relatively small number of principal components represent the underlying population genetics A generalized metric of model complexity facilitates evaluation of the theoretical and empirical properties of competing regression models. In the simple case of comparing two fixed effects models, the most natural metric is the number of parameters. Thus compared to a model with The metric of model complexity introduced here can be generalized to arbitrary regression models with normally distributed errors. We consider the general theory first and then apply it to specific models. Letting Considering a fixed effects model with This generalized theory has been widely adopted as a metric of model complexity for penalized splines, nonparametric regression and generalized additive models where While the relationship between the LMM and including principal components as fixed effects has been previously discussed Alternatively, the LMM is able to model both population structure and kinship by considering the full eigen-spectrum. Yet assessing the model complexity is no longer trivial since all principal components are included while only 4 parameters are estimated. Therefore, we consider the effective degrees of freedom of the LMM in order to elucidate the statistical properties of the LMM as well as its biological interpretation.Ignoring fixed effects for simplicity, the estimated the fitted response values based on only the random effect areThis form of the effective degrees of freedom facilitates an interpretation of the influence of each principal component that is composed of a marker-based element, Returning to the biological interpretation of the effective degrees of freedom, we note that LMM relates the genetic similarity between individuals to the heritability of the trait To this point we have considered the standard LMM where the genetic similarity matrix is full rank and all principal components make a contribution to the phenotype Learning the partition of principal components using an LRLMM requires a metric of model complexity that facilitates the comparison of models with different number of principal components. The effective degrees of freedom is a natural metric of complexity that extends to low rank models and has the formIn order to identify relevant principal components, we fit a LRLMM where the rank varies from 0, where we fit the standard linear model, to the sample size, where the full rank LMM is used. Principal components are added to the model sequentially and the log-likelihood and effective degrees of freedom are evaluated for each rank. Since the order in which principal components are added to the model affects the optimal rank, we consider different orderings of the principal components based on 1) eigen-value, 2) squared correlation between principal component and phenotype (corSq), 3) eigen-value multiplied by squared correlation between principal component and phenotype  genard at http://mezeylab.cb.bscb.cornell.edu/Software.aspx.These methods are available in the software package We considered two distinct strategies for simulating genetic confounding and examined each separately. First, we simulated genetic confounding based directly on the principal components of a full rank genetic similarity matrix where we used 1000 European individuals from the Multi-Ethnic Study of Atherosclerosis (MESA) mal rank , S6, S7.We evaluated the statistical power of multiple methods under this model of genetic confounding for the same genetic data. We simulated genetic confounding by randomly selecting 10 principal components from the first 30 to affect the phenotype and drawing coefficients from We considered a second model of genetic confounding due to the effects of stratified markers. We evaluated the statistical power on the same genetic data where we simulated phenotypes by selecting the 5 markers most correlated with each of the first 10 principal components. Coefficients corresponding to these 50 stratified markers were drawn from In order to examine the type I error, we sampled phenotypes from 1000 individuals from Our analysis of GWAS data from four populations and two phenotypes from the Multi-Ethnic Study of Atherosclerosis (MESA) Applying the LRLMM sorting by degrees of freedom from fitting each principal component individually (LRLMM-DF) selects effective degrees of freedom that are substantially smaller than for the full rank model and the effective degrees of freedom is generally larger for height than for HDL cholesterol . MoreoveThe linear mixed model (LMM) has become a standard method to account for the confounding effects of population structure and kinship in GWAS datasets a priori, our novel LRLMM provides an alternative test of association that can boost the strength of an association or identify additional associations if it is a better fit to the data.The ability of our low rank linear mixed model (LRLMM) to boost the signal of a known association for HDL cholesterol in Europeans indicates that the LMM can overfit the data so that the random effect absorbs too much of the phenotype variance. If the true model is low rank, then the LRLMM will have greater power than the LMM. Alternatively, if the true model is high-dimensional then the full rank LMM is more appropriate. Since there is no way to know true dimensionality The LMM has been interpreted in the context of kinship With the growing interest in testing associations of rare variants, new problems of genetic confounding are arising due to the more recent origin and more localized distribution of rare compared to common variants Figure S1Simulated genetic similarity matrices and their eigen-spectra.a) The eigen-spectrum of 3 distinct populations is dominated by the the first 3 eigen-values. b) Kinship represented by 33 parent-offspring duos has a long tailed eigen-spectrum. c) The weighted sum of the genetic similarity matrices from (a) and (b) combine population structure and kinship so that the eigen-spectrum has a long tail, yet is dominated by the first 3 eigen-values. We note that the eigen-spectra are scaled by the largest eigen-value so that all spectra have the same scale. Moreover, we note that for simplicity the genetic similarity matrices were constructed directly and are not based on real or simulated genotype data.(TIFF)Click here for additional data file.Figure S2Estimated heritability based on 6 LMM methods for . Estimated heritability is shown for (TIFF)Click here for additional data file.Figure S3Estimated heritability based on 6 LMM methods for . Estimated heritability is shown for (TIFF)Click here for additional data file.Figure S4Estimated heritability based on 6 LMM methods for . Estimated heritability is shown for (TIFF)Click here for additional data file.Figure S5Estimated heritability based on 6 LMM methods for . Estimated heritability is shown for (TIFF)Click here for additional data file.Figure S6Mean squared error of estimated heritability across all simulation conditions for low rank linear mixed model (LRLMM). Plots shown here summarize the results of Figures S2, S3, S4, S5 in terms of mean squared error. Results are shown for the low rank linear mixed model (LRLMM) using only the relevant principal components (True) and the LRLMM using 4 orderings of the principal components: eigen-value, corSq, corSq*eigen-value and DF. Results are shown where the optimal rank for the LRLMM was determined by minimizing AIC, BIC, Generalized Cross Validation (GCV) or \u22122*log-likelihood (logLik). Results from the full rank LMM are shown in Figure S14 since the mean squared errors are much larger when the true model is low rank.(TIFF)Click here for additional data file.Figure S7Mean squared error of estimated heritability across all simulation conditions for full rank LMM. Results are shown for the same simulations as in (TIFF)Click here for additional data file.Figure S8Effective degrees of freedom for each principal component based on a linear mixed model (LMM) analysis of HDL cholesterol for four populations from the Multi-Ethnic Study of Atherosclerosis (MESA) dataset. Total effective degrees of freedom for each population are shown in the legend.(TIFF)Click here for additional data file.Figure S9Fraction of available degrees of freedom used by the linear mixed model (LMM) to account for population structure and kinship estimated using restricted maximum likelihood (REML). Effective degrees of freedom normalized by sample size are show for six phenotypes and four populations from the Multi-Ethnic Study of Atherosclerosis (MESA) plus the combined dataset. Error bars indicate 95% confidence intervals based on the log-likelihood surface.(TIFF)Click here for additional data file.Figure S10Manhattan plots for HDL cholesterol in Europeans from the Multi-Ethnic Study of Atherosclerosis (MESA). Results shown using Plink, EMMAX, GEMMA, FaST-LMM: full rank, FaST-LMM-SELECT and our low rank linear mixed model sorting by degrees of freedom from fitting each principal component individually (LRLMM-DF).(TIFF)Click here for additional data file.File S1Eective degrees of freedom.(PDF)Click here for additional data file."}
+{"text": "Listeria monocytogenes has the capacity to survive and grow in a diverse range of natural environments. The transition from a food environment to the gastrointestinal tract begins a process of adaptation that may culminate in invasive systemic disease. Here we describe recent advances in our understanding of how L. monocytogenes adapts to the gastrointestinal environment prior to initiating systemic infection. We will discuss mechanisms used by the pathogen to survive encounters with acidic environments (which include the glutamate decarboxylase and arginine deiminase systems), and those which enable the organism to cope with bile acids  and competition with the resident microbiota. An increased understanding of how the pathogen survives in this environment is likely to inform the future design of novel prophylactic approaches that exploit specific pharmabiotics; including probiotics, prebiotics, or phages.The foodborne pathogen  Listeria monocytogenes is a Gram positive foodborne pathogen capable of causing infection of the fetus in pregnant women and meningitis, meningoencephalitis or febrile gastroenteritis in non-pregnant individuals. The pathogen continues to cause large common-source outbreaks from ready-to-eat food sources and represents a significant cause of food-related mortality  tract and makes the transition from saprophyte to pathogen.L. monocytogenes faecal carriage in farm animals has been reported as 21.3% in cattle and 1.5% in sheep  over approximately 1 year  stool samples analyzed, which suggests between 5 and 9 annual exposures to L. monocytogenes per person. In the majority of cases L. monocytogenes carriage was transient, lasting between 1 and 4 days   during the passage from saprophytism to virulence   were mono-colonized with either Lb. paracasei CNCM I-3689 or Lb. casei BL23 prior to oral infection with L. monocytogenes. Passage from broth to the GI tract resulted in the upregulation of 520 protein coding genes and seven non-coding sRNAs, whereas 523 genes and three sRNAs were downregulated. The presence of Lactobacillus spp. resulted in enhanced effects upon numerous gene systems suggesting a major influence of the microbiota upon gene expression in L. monocytogenes. Many of the listerial genes that were positively influenced by the microbiota are potentially involved in adaptation to the gut environment and include genes encoding pathways involved in ethanolamine and propanediol metabolism that have been implicated in the gastrointestinal survival of Listeria   are at increased risk of infection  and three glutamate decarboxylase enzymes    system is particularly important for mediating pH homeostasis. The GAD system in ) Figure . Indeed L. monocytogenes as mutants in gadT2/D2  that operates separately from the canonical extracellular GAD (GADe) system  pathway and an agmantine (AgDI) deiminase system that contribute to pH homeostasis  which protect the cells from low pH . In L. monocytogenes LO28 the arginine catabolic genes of the ADI system (including arcA and arcC) and the arginine biosynthetic genes (including argG) are induced by low pH and anaerobicity and are under the influence of the transcriptional regulator ArgR  and enzymes of the biosynthetic pathway  are significantly induced in the GI tract of germ-free mice and are further induced by the presence of lactobacilli ] that senses bile (in particular the bile acid cholic acid) and regulates expression of two multidrug resistance (MDR) efflux pumps (MdrM and MdrT) that mediate bile tolerance and liver/gall bladder colonization  enzyme that has the potential to detoxify individual conjugated bile acids and contributes to listerial survival in the GI tract      is a potent inducer of the Sigma B regulon in L. monocytogenes is a non-fastidious and tractable target for demonstrating the barrier effect of probiotic commensals upon colonization or infection. In vitro cell culture studies indicate that cell invasion by L. monocytogenes can be inhibited by a variety of commensal bacteria   can inhibit Sigma B activity, thereby downregulating the expression of key virulence related loci  (Palmer et al., Listeria-specific bacteriophages or phage lysins can control bacterial growth in the GI tract (Coffey et al., L. monocytogenes in the GI tract should inform the future development of functional foods with the potential to reduce disease incidence.Increased understanding of the mechanisms by which The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "We next conducted a treatment study in the SCID-HuRAg mice, an RA animal model utilizing SCID mice implanted with synovium and cartilage from patients with RA and tofacitinib was administered via an osmotic mini-pump. Tofacitinib decreased serum levels of human IL-6 and IL-8 in the mice and reduced invasion of the synovial tissue into the implanted cartilage as well as accumulation of immune cells in the synovium.Taken together, orally available low molecular weight products such as tofacitinib targeting intracellular signaling molecules, would provide enormous power and flexibility in the treatment of RA.Rheumatoid arthritis (RA) is a representative autoimmune disease characterized by chronic and destructive inflammatory synovitis. The multiple cytokinesand cell surface molecules play a pivotal role in the pathogenesis of RA and binding of these molecules to their ligands on the cell surfaceinduce various signal intracellular transduction including phosphorylation of kinase proteins. The tyrosine kinase is the first intracellular signals to be phosphorylated and 14 tyrosine kinases are known to be involved in RA. Among them, members of Janus kinase (Jak) familyare essential for the signaling pathways of various cytokines and are implicated in the pathogenesis of RA. An orally available Jak3 inhibitor tofacitinib is currently in clinical trials for RA with satisfactory effects and acceptable safety . A phase"}
+{"text": "Dear Sir,A recent review article  was very2+ release channel is a key component of the excitation\u2013contraction coupling machinery in striated muscle. Nitric oxide produced by the cytokine- and endotoxin-induced inducible nitric oxide synthase during inflammatory processes influences the contractility of skeletal muscles (In vivo, the initial release of NO activates ryanodine receptors, but a higher concentration of NO inhibits ryanodine receptors. NO alters ryanodine receptor binding activity by S-nitrosylation or oxidation of several classes of cysteine residues associated with ryanodine receptor protein (The authors of the review  emphasiz muscles . In vivo protein . Influen protein .Future research needs to concentrate on case control studies, comparing the histology of diaphragms in infants dying from sudden infant death and death from other causes during the same season of the year to allow for the influence of seasonal viral infections. The degree of nitrosylation of cellular proteins should be compared between groups. Specific electrophysiological studies should be employed to assess the contribution of diaphragmatic flutter to apneas associated with viral respiratory tract infections in young infants."}
+{"text": "Most neurons in peripheral sensory pathways initially respond vigorously when a preferred stimulus is presented, but adapt as stimulation continues. It is unclear how this phenomenon affects stimulus coding in the later stages of sensory processing. Here, we show that a temporally sparse and reliable stimulus representation develops naturally in sequential stages of a sensory network with adapting neurons. As a modeling framework we employ a mean-field approach together with an adaptive population density treatment, accompanied by numerical simulations of spiking neural networks. We find that cellular adaptation plays a critical role in the dynamic reduction of the trial-by-trial variability of cortical spike responses by transiently suppressing self-generated fast fluctuations in the cortical balanced network. This provides an explanation for a widespread cortical phenomenon by a simple mechanism. We further show that in the insect olfactory system cellular adaptation is sufficient to explain the emergence of the temporally sparse and reliable stimulus representation in the mushroom body. Our results reveal a generic, biophysically plausible mechanism that can explain the emergence of a temporally sparse and reliable stimulus representation within a sequential processing architecture. Many lines of evidence suggest that few spikes carry the relevant stimulus information at later stages of sensory processing. Yet mechanisms for the emergence of a robust and temporally sparse sensory representation remain elusive. Here, we introduce an idea in which a temporal sparse and reliable stimulus representation develops naturally in spiking networks. It combines principles of signal propagation with the commonly observed mechanism of neuronal firing rate adaptation. Using a stringent numerical and mathematical approach, we show how a dense rate code at the periphery translates into a temporal sparse representation in the cortical network. At the same time, it dynamically suppresses trial-by-trial variability, matching experimental observations in sensory cortices. Computational modelling of the insects olfactory pathway suggests that the same principle underlies the prominent example of temporal sparse coding in the mushroom body. Our results reveal a computational principle that relates neuronal firing rate adaptation to temporal sparse coding and variability suppression in nervous systems. The phenomenon of spike-frequency adaptation (SFA) The widespread phenomenon of a dynamically suppressed trial-by-trial response variability in sensory and motor cortices In this study, we introduce an alternative and unified description in which a temporally sparse stimulus representation and the transient increase of response reliability emerge naturally. Our approach exploits the functional consequences of SFA in multi-stage network processing. Here, we show that the SFA mechanism introduces a dynamical non-linearity in the transfer function of neurons. Subsequently, the response onset becomes progressively sparser when transmitted across successive processing stages. We use a rigorous master equation description of neuronal ensembles To examine how successive adapting populations can achieve temporal sparseness, first we mathematically analyzed a sequence of neuronal ensembles , self-generating recurrent fluctuations strongly dominate the dynamics of interactions and produce highly irregular and variable activity To investigate the reliability of adaptive mapping from a dense stimulus to a sparse cortical spike response across successive processing stages we employed the adaptive population density formalisms s\u03c4\u200a=\u200a110 ms). This non-renewal statistics determines the shape of the transient component of the population response in The background input is modelled as a set of independent Poisson processes that drive both sub-networks .s\u03c4\u200a=\u200a110 ms) with the control network (s\u03c4\u200a=\u200a30 ms). Since the Fano factor is known to be strongly dependent on the firing rate, we adjusted the stimulus level to the latter such that the averaged steady state firing rates in both networks were mean-matched To reveal the effect of adaptation on the response variability, we employed the time-resolved Fano factor In the next stage of processing, the distribution of Material and Methods) to study the mean and variability of the cortical network responses to a wide range of signal strengths. We change the stimulation protocol to a brief signal with a duration of In the above comparison, we adjust the stimulus strength to achieve the same steady-state firing rate (tonic response) in the afferent and cortical ensemble. In a next step we studied the effect of adaptation on the detectability of a weak and transient peripheral signal, which might be impaired by the self-generated noise in the cortical network. To this end we employed the population density approach  for the cortical ensemble response in the above scenario. This calculation indicates that the response variability in the adaptive network is significantly lower than in the weakly adaptive network over a large range of the feed-forward coupling strength  did not change the time course of the Calcium response dynamics (B antagonist hydrochloride (CGP) using the same protocol and again found an increase in the response magnitude but no alteration of the response dynamics  produces correlated presynaptic input spike trains Our results here are of general importance for sensory coding theories. A mechanism of self-inhibition at the cellular level can facilitate a temporally sparse ensemble code but does not require well adjusted interplay between excitatory and inhibitory circuitry at the network level. This network effect is robust due to the distributed nature of the underlying mechanism, which acts independently in each single neuron. The regularizing effect of self-inhibition increases the signal-to-noise ratio not only of single neuron responses but also of the neuronal population activity focus attractor  were caught at the entrance of the hive, immobilized by chilling on ice, and fixed in a plexiglas chamber before the head capsule was opened for dye injection. We retrogradely stained clawed Kenyon cells (KC) of the median calyx, using the calcium sensor FURA-2 dextran  with a dye loaded glass electrode, which was pricked into KC axons projecting to the ventral median part of the Experiments were performed following the methods published in Szyszka et al The processing of imaging data was performed with custom written routines in IDL . In summary, changes in the calcium concentration were measured as absolute changes of fluorescence: a ratio was calculated from the light intensities measured at 340 nm and 380 nm illumination and the background fluorescence before odor onset was subtracted leading to \u22125M picrotoxin  or 5\u00d710\u22124M CGP54626 ) was bath applied to the brain after pre-treatment measurements. Measurements started 10 min after drug application. The calcium signals are analyzed in Matlab . The normalization of the responses are performed per animal and the plotted traces are the averaged values across subjects.For GABA blockage, a solution of 150 \u00b5l GABA receptor antagonist dissolved in ringer for final concentration (10"}
+{"text": "Ex vivo with BCG and IFN\u03b3 for intratumoral injection and attempts to circumvent this barrier thereby maximize the induction of anti-tumor responses. Autologous DC will be harvested from peripheral blood monocytes via leukapheresis. Following Ex vivo DC maturation, inoculation of the tumors will be performed 2 weeks later utilizing image guidance to ensure activated DC deposition at the peripheral aspect of the tumor thereby enhancing DC exposure to antigens from dead or dying tumor cells. Vaccination will be performed at least every week for 3 weeks, and subsequently at longer intervals dependent on harvested DC availability. Phase I/II study with DCVax\u00ae- Direct will enable evaluation of the safety, MTD, and responses in patients with solid tumors. The secondary objective addresses the feasibility, anti-tumor immune responses, PFS and OS. At the time of this poster submission, the 'First-in-man' patient has been consented for the study. We propose to present our initial findings at the SITC 2013 conference as more data will be available.Dendritic cells (DC) are acknowledged to be quintessential in the armamentarium to mount anti-tumor immune responses and have been utilized in varying capacities for cancer immunotherapy. Recent advancements & lessons leant from prior DC therapies have revealed that major barriers hinder the efficacy of cancer vaccination with DC, principal of which is the hostile environment of the local tumor milieu that inhibits activation and subsequent maturation of DC. This critical step is required to process and present antigens (tumor cell) to the downstream cascade of immune mediators. The therapeutic goals of cancer vaccination are the induction of tumor regression secondary to the production of tumor specific immune factors and local inflammatory cytokines with enhancement of long term anti-tumor surveillance to prevent recurrences. DCVax\u00ae- Direct  are autologous dendritic cells activated"}
+{"text": "In bulk heterojunction photovoltaic systems both the open-circuit voltage as well as the short-circuit current, and hence the power conversion efficiency, are dependent on the optical bandgap of the electron-donor material. While first-principles methods are computationally intensive, simpler model Hamiltonian approaches typically suffer from one or more flaws: inability to optimize the geometries for their own input; absence of general, transferable parameters; and poor performance for non-planar systems. We introduce a set of new and revised parameters for the adapted Su-Schrieffer-Heeger (aSSH) Hamiltonian, which is capable of optimizing geometries, along with rules for applying them to any  One principal goal of condensed matter theory is to understand the structure-property relationship of materials systems such that specific materials properties may be achieved via molecular design. The emergence of fascinating applications using The optical bandgap of organic molecules can be qualitatively derived from its dependence on the bond length alternation pattern, planarity, aromaticity, and/or electron-withdrawing/releasing substitutions. ab-initio calculations for the molecular geometries, Simpler quantum mechanical approaches that are computationally less expensive and can give good bandgap values for specific systems can be divided into two groups. The first group, including for example the H\u00fcckel, The second group of models includes electron-phonon interactions and can predict the fundamental excitations of conjugated systems, while simultaneously optimizing the molecular geometries. This group includes the Su-Schrieffer-Heeger model In our previous works Nevertheless, until now we had only demonstrated the transferability of the aSSH model for different chain lengths of the very polymers used to determine the parameters. For example, the parameters for sulfur were fit using the optical gap from p-n single junction solar cells. To exemplify our intended utility of the model as an in-silico design tool, we focus on the problem of finding an appropriate donor material for bulk heterojunction (BHJ) photovoltaic devices. In these BHJ devices, the electron donor absorbs photons to create electron-hole pairs while the acceptor material draws the electrons but not the holes from the donor. The number of photons absorbed that generate charge carriers directly contributes to the short circuit current (The aSSH Hamiltonian p-phenylene vinylene) (PPV), p-phenylene) (PPP), The fully transferable etc.; b) fused aromatic rings parallel to the conjugated path direction (red circles); c) fused aromatic rings perpendicular to the conjugated path direction (blue diamonds); d) copolymers from polymerization of any of the previous groups (yellow triangles pointing downwards); e) polycyclic aromatic hydrocarbons (PAHs) including polyacenes where the conjugated paths are greater than one dimension (violet triangles pointing upwards); and f) systems with explicit interchain Since all of the experimental data are taken from UV-vis absorption spectra reported in literatures, we will focus solely on the optical bandgaps as opposed to either the electronic or transport bandgaps. The agreement between the calculated and experimental gaps are shown in One straightforward way to modify the bandgap of PTh is to replace the Starting from PTh, one popular way in which researchers have been attempting to lower the bandgaps is to fuse adjacent rings by adding extra conjugated sulfur bridges. For a given  PTh of   can be sTh of  , the prototypical conducting polymer, is proportional to its bond-length dimerization amplitude. It is clear from Since PTh has a LUMO orbital , C band Opposite to the LUMO case, the HOMO wavefunction of PTh , V band e L band  also inc sharply .In summary, since the largest o PT32bT , the intThe predicted optical gaps for this group are shown in The important contribution of the perpendicular fused rings series to the aSSH model is in determining a new bridge bond In systems such as PITN with aromatic rings fused perpendicular to the conjugated pathway, the monomers themselves have lower bandgaps simply due to energy level splitting. In order to decrease the bandgaps for polymers consisting of perpendicular fused rings we must to enhance the electron hopping between the connected monomers. This enhancement can be achieved by introducing parallel fused ring monomers between each perpendicular fused ring monomer to form copolymers, examples of which are discussed in the copolymers section.Copolymers of donor-acceptor units have been leading the way in improving organic PV efficiency from 5% to 9%. stacking . [25] WiPAHs are essentially flakes of graphene, the Fermi energy of which varies linearly with wavevector through the Dirac point without undergoing the Peierls dimerization In order to reduce the optical gap of polyacenes, one can create nodes on the cene of  , the two in BBTD . This giThe accurate prediction of the optical bandgap of a generic materials system will remain as a grand challenge in condensed matter theory. Working towards that goal, we demonstrate a model Hamiltonian for virtually all the major types of From our calculations, the strategies of planarization or simple substitutions did not lead to the target optical gaps 1.2 eV. To reach the desired gaps, we suggest a copolymer of parallel and perpendicular monomers (both benzodithiophenes), which we find in general to be the best strategy by taking advantage of both the lower monomer gaps of perpendicular units and the enhanced electronic communication of the parallel ones. We also propose a small molecule oligomer (a thiophene capped anthracene) that arises from our analysis of PAHs, in particular of pentacene, with the aSSH model giving insights into the electronic structure of the molecules and how to modify them for lower gaps. With these examples, we put forth the aSSH model as an in-silico design tool to guide the search for optimized organic electronics.Figure S1Skeletal formulae of simple ring systems. Simple ring systems consist of monomers that are single aromatic rings that may contain single atoms or non-conjugated rings attached.(PDF)Click here for additional data file.Figure S2Skeletal formulae of parallel fused ring systems. Parallel fused ring systems consist of monomers wherein two or more aromatic rings are fused and all rings are part of the main conjugated pathway.(PDF)Click here for additional data file.Figure S3Skeletal formulae of perpendicular fused ring systems. Perpendicular fused ring systems consist of monomers wherein two or more aromatic rings are fused, but only one of the rings is connected to the main conjugated pathway.(PDF)Click here for additional data file.Figure S4Skeletal formulae of polycyclic aromatic hydrocarbons and derivatives. Polycyclic aromatic hydrocarbons are made entirely of fused aromatic carbon rings, while derivatives include simple heteroatom substitutions for hydrogen.(PDF)Click here for additional data file.Figure S5Skeletal formulae of copolymers. Copolymers refer to any system made of more than one type of monomer.(PDF)Click here for additional data file.Figure S6Skeletal formulae of - stacking systems. The (PDF)Click here for additional data file.Table S1Experimental and aSSH calculated optical gaps for simple ring polymers.(PDF)Click here for additional data file.Table S2Experimental and aSSH calculated optical gaps for parallel fused ring systems.(PDF)Click here for additional data file.Table S3Experimental and aSSH calculated optical gaps for perpendicular fused ring systems.(PDF)Click here for additional data file.Table S4Experimental and aSSH calculated optical gaps for polycyclic aromatic hydrocarbons and derivatives.(PDF)Click here for additional data file.Table S5Experimental and aSSH calculated optical gaps for copolymers.(PDF)Click here for additional data file.Table S6Experimental and aSSH calculated optical gaps for - stacking systems.(PDF)Click here for additional data file.References S1References for data contained in  Although some references for the Supporting Information may be the same as for the main article, their reference numbers may not be the same.(PDF)Click here for additional data file."}
+{"text": "Pitch constitutes a major dimension of auditory perception along which periodic (or near-periodic) sounds can be organized. Although the role of pitch is essential in the perception of music and important when dealing with source segregation in complex auditory scene, the neural mechanisms underlying pitch perception remain unclear . Many moWe propose here a model of pitch perception based on the synchrony produced within groups of peripheral neurons. We first describe how auditory stimuli can induce for peripheral neurons synchronous outputs. This stimulus-based synchrony is independent of the spiking neuron model and can thus be used to define two dual concepts : 1) the"}
+{"text": "The goal of this pilot study was to examine changes in self-reported levels of mindfulness in the context of an 8-week mindfulness telehealth intervention for military veterans with combat-related posttraumatic stress disorder (PTSD).Participants were 24 male combat veterans with PTSD aged 23 to 66 (M=55.2). Participants were randomized to either a mindfulness telehealth intervention or a PTSD psychoeducation telehealth condition. Both interventions consisted of two in-person and six telephone individual sessions. Measures were collected pre- and post-treatment and at 6-week follow-up and included the Mindful Attention Awareness Scale (MAAS), the White Bear Suppression Inventory (WBSI), and the Five Facets of Mindfulness Questionnaire (FFMQ).Significant condition by time interaction effects were found in the expected direction for the WBSI (p=.04) and FFMQ Describing facet (p=.02) and trends were detected for the MAAS (p = .07) and the FFMQ Observing facet (p = .07), indicating gains in skills for the mindfulness group over the course of the study. Results also suggest that a brief telehealth intervention introducing mindfulness skills may be effective in increasing levels of mindfulness as measured by these instruments.This study represents one of the few published studies to use multiple measures of mindfulness to examine changes in mindfulness skills and the first known published study to examine changes in mindfulness following a brief telehealth intervention. Limitations include a small sample size and lack of intent-to-treat analyses. A short treatment that does not require group participation and that can be easily accessed may be especially appealing to more reluctant participants, such as those with PTSD or other psychological disorders. Identifying the aspects of mindfulness that are sensitive to change represents a first step in determining whether adoption of mindfulness skills may be an important mechanism of action."}
+{"text": "General anesthetics are used during medical and surgical procedures to reversibly induce a state of total unconsciousness in patients. Here, we investigate, from a dynamic network perspective, how the cortical and cardiovascular systems behave during anesthesia by applying nonparametric spectral techniques to cortical electroencephalography, electrocardiogram and respiratory signals recorded from anesthetized rats under two drugs, ketamine-xylazine (KX) and pentobarbital (PB). We find that the patterns of low-frequency cortico-cardio-respiratory network interactions may undergo significant changes in network activity strengths and in number of network links at different depths of anesthesia dependent upon anesthetics used. Medical and surgical procedures most often involve the use of general anesthetics for reversibly producing total unconsciousness in patients. During such procedures, a multitude of physiological parameters including heart rate, respiration rate, movement and brain activity are observed to assess the level of anesthesia for the patient's safety. How anesthetics work and what quantitative measures are effective in assessing different levels of anesthesia have been the questions of intense research for years. The answers to these questions can potentially help design better depth-of-anesthesia monitoring systems and reduce the frequently-occurring intraoperative awareness Central modulation of the cardiovascular system via descending signals from the brain has been well recognized for a long time In this paper, using Granger causality measures Granger causality * denotes matrix adjoint, The nonparametric approach is based on widely used Fourier transform for both pairwise and conditional measures This study is a reanalysis of the data using the nonparametric spectral techniques. The details about the experiments that took place in the Institute of Pathophysiology in Ljubljana can be found in the article by Musizza and colleagues Simultaneous recordings of scalp EEG, ECG and respiration rate were performed on two groups of adult male Wistar rats weighing 250\u2013300 The original time series data sampled at 1000 Hz were lowpass filtered below 45 Hz and resampled at 200 Hz. The Fourier transforms and spectral quantities  were computed using moving time window of 1 minute with 0.5 minute overlap to look at the temporal variations. The time series within 1 min window were further broken into 4-sec segments with a 2-sec overlap. The 4-sec segments within 1 min window were used to compute the average spectral matrix. The spectral quantities such as power, coherence and Granger causality were thus derived from the average spectral matrices over time in intervals of 0.5 minute. We performed a permutation based statistical technique Here, we first evaluate the performance of the nonparametric Granger causality Stages of anesthetic awareness could be assessed more reliably by bi-or multi-variate measures such as coherence and Granger causality among cortico-, cardio- and respiratory activities than the univariate measure such as power of brain, cardiac or respiratory oscillations. Please see The respiratory modulation of cardiac activity rate variability is well known as respiratory sinus arrhythmia (RSA) Electronic Supplementary Material S1In this Electronic Supplementary Material S1, we include the power, coherence and Granger causality results for all rats in the KX group in Fig.  and for rats in the PB group in Fig. .(PDF)Click here for additional data file."}
+{"text": "This protein-protein interaction may represent a mechanism for facilitating the activation of PPAR transcriptional activity via the direct channeling of ligands between the binding pocket of L-FABP and the PPAR\u03b1LBD. The role of L-FABP in the delivery of ligands directly to PPAR\u03b1 via this channeling mechanism has important implications for regulatory pathways that mediate xenobiotic responses and host protection in tissues such as the small intestine and the liver where L-FABP is highly expressed.Fatty acid binding proteins (FABPs) act as intracellular shuttles for fatty acids as well as lipophilic xenobiotics to the nucleus, where these ligands are released to a group of nuclear receptors called the peroxisome proliferator activated receptors (PPARs). PPAR mediated gene activation is ultimately involved in maintenance of cellular homeostasis through the transcriptional regulation of metabolic enzymes and transporters that target the activating ligand. Here we show that liver- (L-) FABP displays a high binding affinity for PPAR subtype selective drugs. NMR chemical shift perturbation mapping and proteolytic protection experiments show that the binding of the PPAR subtype selective drugs produces conformational changes that stabilize the portal region of L-FABP. NMR chemical shift perturbation studies also revealed that L-FABP can form a complex with the PPAR ligand binding domain (LBD) of PPAR In vivo, due to their poor aqueous solubility, FAs are bound and transported by a class of intracellular lipid binding proteins (iLBPs) termed fatty acid binding proteins (FABPs) . Fo exposed . It is tt formed . The occ binding . InteresOur findings suggest that the overlapping binding specificity between L-FABP and PPAR LBDs represents an important component in a channeling mechanism that mediates cellular transport and selective accumulation of PPAR selective drugs in the intestine and liver where both proteins are highly expressed. L-FABP may act as a gate-keeper that is responsible for communicating the state of cellular metabolism and disposition of these ligands from the cytosol to the nucleus."}
+{"text": "Face-to-face meetings play a central role in the birth and maturation of communities. Intensive workshops filled with presentations, discussions and working group meetings have always been at the heart of the activities of the Genomic Standards Consortium (GSC). Such work-driven meetings are a key way in which the GSC fulfils its mission. Similarly, meeting reports provide a key mechanism for preserving and disseminating the consensus built at such meetings as they describe the range of speakers and participants present, topics covered and key outcomes and priorities agreed upon by the community.This issue contains a total of nine meeting reports, all from workshops held between April and December 2010. The first four describe GSC sponsored events. The first overviews the GSC 9 workshop at the J. Craig Venter Institute (JCVI) in April 2010  and the This issue also contains the first five meeting reports in SIGS contributed by external communities. The first describes a workshop held by the wider genomic annotation community as a step towards organizing a \u201cCritical Assessment of Functional Annotation Experiment\u201d (CAFAE) competition . The nexWe sincerely hope this special issue of meeting reports will pave the way for meeting report contributions from a wider range of related communities dedicated to creating and maintaining consensus-driven science."}
+{"text": "Cortical Up- and Down states are a salient feature of mammalian slow wave sleep and contribute predominantely to the low frequency (1Hz and below) delta power of the scalp electroencephalogram (EEG).The role of slow wave oscillations recently raised considerable attention from the observation that slow waves can be electrically stimulated , and thaA recent experimental demonstration of Up- and Down state switching under electrical stimulation was presented by Shu, Hasenstaub and McCormick . Their etime difference between the two impulses was studied quantitatively.In a previous study, we have proposed a minimal model mimicking the interplay between recurrent excitation and inhibition controlled by slow adaptive currents . By thisTo study stimulation at this level of description, we follow the established conductance-based cortex model by Compte et al.  which inWe observe self-generated Up-Down states in the absence of stimulation in accordance with the detailed study of . If we a"}
+{"text": "Obesity is one of the risk factors for non-communicable disease (NCD). The prevalence of overweight and obesity among the poor in Indonesia is increasing. Indonesia is also experiencing an epidemiological transition where the trend for causes of death is changing from infectious disease to NCD. Following previous studies on obesity among the poor, we study the risk factors for obesity in urban slum areas in order to seek for the appropriate health system solution to this matter.We used a case-control design with 70 cases of obese women and 70 controls of non-obese women (WHO-IASO-IOTF obesity criterion for Asian population was used to determine the obesity status). In-depth interviews were conducted to 18 women respondent from three different slum areas in Yogyakarta city. We performed data triangulation for qualitative data. This study was conducted in April - October 2011.The major risk factors for obesity among poor women living in urban slum areas were partly due to low level of physical activity (OR 8.0) and excessive carbohydrate intake (OR 1.5). The respondents stated that they couldn\u2019t buy the healthy food because its price is higher than carbohydrate-based food. This study documented the lack of information about affordable and healthy food being discussed by community health worker and health educator. From the study findings, the expected response from the health system was the government needs to improve awareness and promotion of healthy living especially within vulnerable population.Poor nutrition is not the only source of hunger among the poor, but also obesity. This finding highlights the importance of collaboration between public health centers and community groups in the slum area in order to create awareness of the obesity problem. Public policies that focus on urban poor population need to be improved."}
+{"text": "Alignment of sequence homologues corresponding to a structural domain is available, starting from a structure-based sequence alignment of the superfamily. Orientation of the length-variant (indel) regions in protein domains can be visualized by mapping them on the structure and on the alignment. Knowledge about location of length variations within protein domains and their visual representation will be useful in predicting changes within structurally or functionally relevant sites, which may ultimately regulate protein function. Non-technical summary: Evolutionary changes bring about natural changes to proteins that may be found in many organisms. Such changes could be reflected as amino acid substitutions or insertions\u2013deletions (indels) in protein sequences. LenVarDB is a database that provides an early overview of observed length variations that were set among 731 protein families and after examining >2 million sequences. Indels are followed up to observe if they are close to the active site such that they can affect the activity of proteins. Inclusion of such information can aid the design of bioengineering experiments.Protein domains are functionally and structurally independent modules, which add to the functional variety of proteins. This array of functional diversity has been enabled by evolutionary changes, such as amino acid substitutions or insertions or deletions, occurring in these protein domains. Length variations (indels) can introduce changes at structural, functional and interaction levels. LenVarDB (freely available at  Protein domains are functional and compact structural units of protein, which evolve with time by incorporating various changes in the form of amino acid substitutions and insertions. Insertion/deletion of contiguous stretch of amino acids (indels) can induce structural modifications, which can eventually impart functional diversity or affect stability or differences in quaternary arrangements of these protein domains. Analysis of indels among sequence homologues of domain superfamilies will provide an early understanding of the evolutionary changes of protein function from a handful of protein folds .Occurrence of indels is a continuous process and found frequently in loop regions, especially as \u2018nested forms\u2019 into previously inserted regions  or obserSupplementary Table S1). Unlike other indel databases   entry, c IndelFR , IndelPD IndelFR , IndelSc IndelFR , which dSupplementary Methods). Non-redundant homologues for each superfamily member were included in an alignment, which were importantly guided by structure-based sequence alignments obtained from PASS2, as it was more accurate than using any sequence-based alignment (Supplementary Methods). Statistical tests were carried out using R package  from PASS2 version 4  were uselignment  and to rlignment , were ma package .http://www.jmol.org/) and Jalview .The superfamily page summarizes the length variation features computed for each superfamily and its members at the time of database creation. Length variation is calculated at two levels, one with only the structural members of superfamily [average length variation (structure)] and the other with all the sequence homologues collected [average length variation (sequence)]. The length-variant group to which the particular superfamily belongs to  is noted, and information about any shuffling event (within length-variant groups) is mentioned. A separate panel enlists each member and its length, which is also hyperlinked to \u2018Member page\u2019. Dynamically created graphs are provided for easy visualization of the data provided. Length variation status of each homologue and its contribution in maintaining or changing the length variation status of the superfamily is featured in an interactive scatter plot. The relation between length variation and sequence identity (%) of every homologue collected for every superfamily member is represented by a heat map. Fluctuations in length, captured in the form of amplification/shrinkage from the domain length, are shown for all members in the form of a stacked bar graph. An estimate of hypothetical proteins and splice variants (found in the homologue sets) is also provided . To viewSupplementary Methods), are mapped on the multiple sequence alignment and 3D structure. SSBs  are also marked in a similar manner  and sequence identity (%) of every homologue with respect to the superfamily member can be accessed.Supplementary Movie S1 (http://caps.ncbs.res.in/download/lenvardb/)]. Frequently asked questions enlisted will enable users in analysing their query proteins from a length variation perspective.A user-friendly help page has been created to guide the access and features of the database. A video tour of the database has also been embedded in the home page for the same purpose [Supplementary Data) and integrated as \u2018Statistics\u2019 page in the database.Length variation parameter has been used for statistical analyses . The range of length variation [shown as box plots to represent the range of length variation (%)] in eukaryotic homologues is slightly higher than bacterial and archaeal homologues .Presence of insert domain has been analysed and found to occupy only 2% of the PASS2 starting dataset (8970 superfamily members), which gives the user an insight about one of the causes of length variations in LenVarDB  of Campylobacter jejuni dUTPase reveals the presence of a 20 residue-insert near the substrate binding domain and dimerization interface, which can regulate its functionality or oligomerization status (Supplementary Data). Further biochemical characterization can show if the presence of these indels (in the homologue) interferes with the pathogenic nature of this dUTPase in C. jejuni, which is known to be a gastric pathogen.Detection of multiple length variations (indels) in their spatial orientation within a protein domain structure can be useful in focusing on the deviations caused from its usual structure and function. Study of length variations in a homologue  is illustrated . LiteratLenVarDB is a comprehensive resource designed for researchers interested in protein domain biology. This database systematically and automatically gathers sequences, aligns them to pre-existing structure-guided PASS2 alignments and derives indel (length-variant)-prone regions of protein domain superfamilies. The web interface has been made interactive and readily available for the scientific community. The key advantage of LenVarDB over other indel databases is that it introduces evolutionary insights from all the closely and distantly related sequence homologues. LenVarDB allows users to identify the indel-prone regions, which can enable rational design of bioengineering experiments.Supplementary Data are available at NAR Online, including [27\u201332]."}
+{"text": "The GABAergic system is central to the development and functional maturation of the nervous system. Emerging evidence support the role of GABAergic dysfunction in neuro-developmental disorders. This review presents the molecules and mechanisms that underlie GABA system dysfunction in several neuro-developmental disorders presenting in childhood. The impact on synaptic plasticity, neuronal circuit function and behavior, followed by targeted treatment strategies are discussed. Neuronal circuits undergo structural refinement in response to changes in experience. Although this ability is present throughout life, there are sensitive periods of elevated plasticity when the brain is capable of intense restructuring of synaptic connections  positive basket cells which account for 50% of GABAergic interneurons in rodent cortex and are required for the generation of fast rhythmic, synchronous activity  of Ts65Dn brain at E14.5 . G-protein coupled inward-rectifying potassium (GIRK2) containing channels are over-expressed in Ts65Dn mice  is the most common non-inherited cause of intellectual disability and results from triplication of chromosome 21. The cognitive phenotypes of DS are reproduced in Ts65Dn mice, a model of Down syndrome and are posited to result from imbalance in excitation and inhibition. Several genes involved in the GABAergic systems are present on chromosome 21 and are triplicated in DS and the Ts65Dn mice. These include Olig1/2 and Grik2. Several groups show a decrease in the number of excitatory synapses and a relative increase in the inhibitory synaptic markers in the cortex and hippocampus of adult Ts65Dn mice  in the CA1 and DG. Several groups have rescued LTP upon acute or chronic treatment of Ts65Dn hippocampus with GABA antagonist  is the leading genetic cause of intellectual disability in girls. It is caused by mutations in the transcriptional repressor methyl-CpG-binding protein 2 (MeCP2). The MECP2 protein regulates gene expression by DNA methylation and MeCP2-mutant mice recapitulate many of the phenotypes RS. These mice, like girls with RS appear phenotypically normal early during development and then undergo severe regression with resulting impairment in respiratory function, loss of hand use, impairment in language, and motor function. Several studies suggest that an imbalance in excitatory and inhibitory neurotransmission contributes to the behavioral abnormalities in RS  mouse a model of FXS  is the most common single gene cause of intellectual disability and autism  interneurons and impairment in group 1 mGluR activation of low-threshold-spiking (LTS) interneurons have been reported in FX mice , a GABAA receptor agonist, that acts upon tonic GABA receptors significantly attenuated hyperactivity and prepulse inhibition in Autism Spectrum Disorder is postulated to result in part from deficient GABA neurotransmission. Reduced GABAA receptors and benzodiazapine binding sites are reported in the hippocampus and cingulate gyrus from neuropathological samples from individuals with autism , a structural barrier to plasticity thus enabling recovery from amblyopia (Pizzorusso et al., The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Considering cells as biofactories, we aimed to optimize its internal processes by using the same engineering principles that large industries are implementing nowadays: lean manufacturing. We have applied reverse engineering computational methods to transcriptomic, metabolomic and phenomic data obtained from a collection of tomato recombinant inbreed lines to formulate a kinetic and constraint-based model that efficiently describes the cellular metabolism from expression of a minimal core of genes. Based on predicted metabolic profiles, a close association with agronomic and organoleptic properties of the ripe fruit was revealed with high statistical confidence. Inspired in a synthetic biology approach, the model was used for exploring the landscape of all possible local transcriptional changes with the aim of engineering tomato fruits with fine-tuned biotechnological properties. The method was validated by the ability of the proposed genomes, engineered for modified desired agronomic traits, to recapitulate experimental correlations between associated metabolites. Considering cells as biofactories, we aimed to optimize their internal processes by using existing design principles acquired from engineering. Herein, we present a synthetic biology approach based on experimental and computational methodology that integrates genomic, transcriptomic, metabolomic and phenomic data to formulate a kinetic and constraint based model of tomato agronomic and fruit quality characteristics. The model has been used for exploring the landscape of all possible local transcriptional changes with the aim of engineering tomato fruits with improved biotechnological properties. The methodology was validated by the ability of the proposed engineered genomes with modified desired agronomic traits, to recapitulate correlations between associated metabolites that are found experimentally in a number of examples. Considering a cell as a DNA-based molecular factory http://solgenomics.net) and with extensive work on metadata analysis Solanum lycopersicum\u00d7S. pimpinellifolium. Following the LM approach, we have developed here a novel in silico optimization method that extensively explores single and multiple genetic perturbations to render a series of desired tomato phenotypes; i.e., show agronomical properties of biotechnological interest. Recently, large efforts in genome-scale modeling have been reported Previous works have considered modeling the global metabolism in silico modified fruit genomes to reproduce the correlations between metabolites empirically found in the fruit. We propose that the principles and practices learned from these engineering success cases can help to formulate a model to guide the design of new organisms with biotechnological applications.Finally, in order to close the design cycle imposed by LM, the genetic modifications suggested by our computational approach were experimentally verified. This was done by demonstrating the predicted ability of the InferGeneWe have extended our recently developed inference methodology, Transcriptomic and metabolomic data from these 50 RILs were normalized by the LOWESS method The next step was to construct an effective gene regulatory model able to predict autonomously the transcriptional processes that, by means of the model previously described, would generate a quantitative metabolic response. In this way changes at the transcriptional level resulting from the proposed genetic perturbations could be translated and predicted effectively into metabolic changes. For doing that, we used the microarray data obtained from fruits of 50 of the RILs to infer a network of gene-gene interactions. The CLR method provided the first sets  with single-gene alterations. LE24K20) or over-expression  in all lineages, respectively. By contrast, quality was highly increased achieving improvement ratios of 43.34% by gene knockout  and 227.31% by over-expression of LE15D07. Finally, taking into account not only the quality but also fruit production, ratios decreased to 15.32%  and 35.94%  using the two types of perturbations, respectively. Notice that all these rates of improvement were achieved in the lineages that provided maximum fitness in the wild-type TRN.After this, we ranked the list of knockout/over-expressed genes of the TRN according to two criteria directed to maximize: (i) the mean efficiency across all lineages in the case of goals such as acceptability and quality vs production; and (ii) the average of the maximum agronomic property reached by all possible TRN reconfigurations in the case of fruit quality . SpecifiLineages exhibited variability in their resistance to be optimized and this resistance changed with each target agronomic property. We computed the average number of single-gene perturbations to overcome an efficiency threshold given in the 169 RILs and the average probability of selecting the same gene-perturbation commonly for the whole set of RILs. The right panel in The next step in our study was to propose new genome re-designs including multiple perturbations. To do this, we sampled widely the landscape of the acceptability, quality and quality vs production of tomato fruits by introducing two-gene perturbations either by knockouts and over-expressions . Figure After generating our predictive model for the TRN and metabolism of tomato fruit, we use it to automatically design tomato genomes with extreme alterations for each of the 56 volatile compounds by introducing a set of genetic perturbations. We compared sets of genetic perturbations for all pairs of volatile compounds and then inferred their levels of correlations (see Methods). Hence, these predicted correlations were compared to the levels of correlations obtained from the experimental values for each volatile pair that often reflects their belonging or not to the same metabolic/regulatory pathway or to be or not structurally related. and 0.91  for geneand 0.91 . Notice ompounds  indicatiS. pennelli accession and therefore represent a completely different set of gene alleles from those in RILs used to construct the model. These ILs can be used as independent and useful test case to evaluate the validity of the model. We corroborated that a significant set of genetic perturbations suggested by computational design to optimize the phenotype observed were identified as genes differentially altered in the target phenotype  derived from another interspecific cross whose transcriptome and metabolome were also experimentally measured. Parents of these ILs are a different cultivar of tomato M82 and a henotype .LM is a methodology that is being implemented by large industries to optimize their production. In the process of decision making applied to the redesign of production systems, firstly, engineers evaluate systematically the addition or elimination of resources in each of the participating single processes; afterwards, multiple changes are considered trying to achieve maximum quality and production We have proposed several re-engineered genomes that improve desired agronomic properties of the fruit by targeting single or multiple genetic modifications. It has been previously reported that single under-/over-expressed of certain genes may affect fruit quality traits, being these key genes involved in the biosynthesis of a product of fruit metabolism or to a general ripening regulators  in controlling fruit size probably through the auxin pathway and the effect of auxin in altering fruit growth and ripening has been previously reported TILLINGTAL engineering Although it is not the objective of this paper, it does not escape our attention that some of the perturbations proposed are consistent with the biological processes associated to the trait and therefore the model could be used to reveal the molecular underpinnings of quality traits . Moreover, all 169 RILs (including the previous 50 ones) for which we had metabolite and phenotype data were used to train a linear model able to predict agronomic properties of the fruit from potentially predictor metabolites. In all cases transcriptomic and metabolomic data were first normalized using the LOWESS procedure For the construction of the effective TRN model and its later integration with the metabolism, we used steady-state mRNA expression profiles derived from RILs transcriptionally and metabolically characterized. The dataset contains pre-processed expression data from 50\u00d73\u200a=\u200a150 hybridization experiments using an array with 11876 probe sets spotted, and data for levels of 67 metabolites that were quantified over the same sample set. For this study, we only considered the 5592 genes whose expression values could be consistently found in more than 80% of the microarrays. We found 1057 TFs and 1962 genes with enzymatic activity after searching for the motifs transcription regulator and enzyme activity respectively in the functionally annotated tomato genome  with respect to the properties of interest obtained in a given RIL. Different properties of interest have been optimized, ranging from single metabolites defining the sweetness or sourness of the fruit, to linear combinations of a set of metabolites determining the quality in terms of flavor and taste and even further to include objective functions that try to integrate two of those goals with a trade-off and balanced weighting factors such as fruit quality and yield.We have addressed this optimization problem using two approaches. Firstly, we exhaustively enumerated all possible single gene knockouts and over-expression for each case to be optimized under a given selective pressure of interest. Second, we ranked all possible perturbations according to the new agronomic properties they would generate. The third step was to suggest genome reconfigurations that include multiple actions: gene knockouts, over-expressed genes, or both, in order to enlarge the combinatorial space of perturbed genomes. To do that, we have used an exhaustive method aimed at finding the global optimum in the space of all possible synthetic TRN. We started from the inferred model  and applied an optimization scheme. At each step of the optimization process, we selected each gene among the ones involved in the transcriptomic model to evaluate the effect of three possible approaches ; we updated the model with the genetic perturbation that provided the best score. Note that to simulate knockout or over-expression in the gene We computed the sets of single-gene perturbations, ?, by gene knockout or over-expression that alter significantly the levels of the 56 volatile metabolites representing the volatile compounds taking into account the global model. For the sake of the model we considered only those gene perturbations that would cause significant changes in the metabolite concentration higher than 1% Click here for additional data file.Dataset S2Single knockout and over-expressed genes to improve desired agronomic properties  and functional categorization of genes that induced high degree of improvement in those agronomic properties; notice that functional enrichment of all genes involved in the TRN was included. Gene ontology enrichment analyses were performed using the TFGD tool [TFGD]. It is also showed the functional categories significantly represented among those genes that were selected to describe the TRN of tomato fruit. A total of 19 cellular processes and 45 biological components were represented. Among these, genes related to cellular metabolic processes were the most abundant (p<0.0001), what makes sense since they were selected to predict cellular metabolism; whereas genes related to response to nutrient stimulus were present but the least common (p<0.1).(XLS)Click here for additional data file.Dataset S3Multiple combinations of knockout and over-expressed gene sets to improve desired agronomic properties .(XLS)Click here for additional data file.Dataset S4Experimental evidences of each gene perturbation proposed by the model to optimize the different scoring function used.(XLS)Click here for additional data file.Figure S1vs computer science.Synthetic biology of tomato fruit (PDF)Click here for additional data file.Figure S2From data to global models to redesign using an approach based on synthetic biology.(PDF)Click here for additional data file.Figure S3LASSO). Note that we used two different z-score levels ; and z\u200a=\u200a3 ) to included genes as possible predictors to be selected by LASSO. The dashed line plotted in  shows the parameter, tLASSO, and the level of z-score used to constructed the relationship between phenotype and metabolome.Phenotype prediction  by using the genotype described in the 50 RILs in which transcript levels were measured. Pearson coefficient correlation  between the predicted and measured phenotypic profile and number of genes  selected by LASSO method as predictors for different thresholds of the fitting parameter (t(PDF)Click here for additional data file.Figure S4Exhaustive exploration and statistical significance of the landscape of single desired agronomic properties of tomato fruit  perturbing its effective TRN locally. (A) Agronomic properties improved by perturbing a single gene as function of efficiency reached by that transcriptional perturbation with respect to the wild-type scenario; notice that only perturbations with positive mean efficiencies are plotted. Both agronomic properties and efficiencies of a single perturbation are average variables tested on the 169 RILs and error bars represent their minimum and maximum values in both axis. (B) Dependence between agronomic properties in the wild-type genome and the average of the agronomic properties resulting of all single perturbations in the wild-type TRN for each RIL; vertical error bars represent the best and worst optimized re-engineered TRN for a given RIL. (C\u2013D) Average number of single gene perturbations that overcome an efficiency threshold in the 169 RILS  and average probability of selecting the same gene-perturbation commonly in a set of RILs . Left and right columns represent perturbations in terms of single gene knockout or overexpression, respectively.(PDF)Click here for additional data file.Figure S5(A) Dendogram of the volatile compound correlations observed experimentally.  Dendograms inferred by the model defining the distance between volatile compound as the number of common genetic perturbations predicted to optimize the levels of each volatile compound.(PDF)Click here for additional data file.Figure S6U-test significance using random selection of gene perturbations (red bars) is shown . Error bars represent the standard deviations of scores obtained from three ILs. 16.7% of the over-expressed genes proposed by the model to minimize the level of linalool were significantly recovered in gene expression  proposed by the model to minimize the levels of volatile compounds  or, 1-nitro-2-phenylethane, 2-isobutylthiazole and benzylnitrile (B)) that were found significantly over-/under-expressed in the transcriptome of two ILs characterized experimentally with extremely low levels of those volatile compounds. The cut-off of the coefficient of variation between replicates was 75%. The Mann-Withney's pression . In addipression , respect(PDF)Click here for additional data file.Figure S7Correlations observed between agronomic variables and metabolites of different fruit genotypes generated by simulating all possible single gene knockout (A\u2013E) or over-expression (F\u2013J) in the wild-type genome model of the tomato fruit. Standard deviations of all metabolites or agronomic variables show the diversity generated by implementing each genetic perturbation in the 169 RILs. Note that we only plotted re-engineered genomes whose transcriptome predicted showed errors lower than 1% .(PDF)Click here for additional data file.Table S1The top 5 single-gene knockouts and over-expressions that maximize the agronomic properties of the tomato fruit based on improve only one objective.(PDF)Click here for additional data file.Table S2The top 5 single-gene knockouts and over-expressions that minimize the agronomic properties of the tomato fruit based on improve only one objective.(PDF)Click here for additional data file.Text S1Genome design based on single perturbations to fine-tuning phenotypes with biotechnological interests. Model validation: fine-tuning tomato phenotype of two experimental inbred lines by computational genome design. Prediction of phenotypic correlations in re-engineered tomato fruits.(PDF)Click here for additional data file."}
+{"text": "The Surviving Sepsis Campaign advocates giving early empirical antibiotics directed against all likely pathogens . The faiA prospective cohort study was performed in two UK teaching hospitals of patients presenting with sepsis to critical care between May 2010 and March 2011. Hospital computer systems and patient notes were used to extract the initial suspected source of sepsis, and later verified with true microbiology data. Overall mortality was measured and compared between correctly and incorrectly suspected source of sepsis patients.Of the 128 patients, the source of sepsis was wrongly identified in 30% (38/128)  (Figure Good antimicrobial governance requires early administration of narrow-spectrum antibiotics as best guess source-directed therapy from the outset, because de-escalation is often not practical. Our data reveal that in 30% of cases we incorrectly guess the source.We advise that in patients with severe sepsis or septic shock first-line antibiotics should remain broad spectrum with rigorous follow up to de-escalate as early as possible."}
+{"text": "Outcome measures were weekly alcohol consumption and frequency of binge drinking. Latent growth curve analyses to model individual change in alcohol use over time by condition revealed that participants in the experimental condition had significantly lower weekly alcohol consumption and frequency of binge drinking compared to participants in the control condition that sustained after three  and six  months follow-up, respectively. Additional linear regression analyses indicated that the intercept differences resulted from an increase in alcohol use for participants in the control condition compared to those in the experimental condition. The WDYD intervention was shown to be effective in preventing an increase in weekly alcohol consumption and frequency of binge drinking shortly after the intervention that sustained after three and six months post-intervention, respectively. Trial registration: Netherlands Trial Register NTR2665.The aim of the current study was to test whether the web-based brief alcohol intervention entitled \u201cWhat Do You Drink\u201d (WDYD) can sustain a reduction in alcohol use among heavy drinking students after one, three, and six months follow-up. A two-arm parallel group randomized controlled trial applying an ecological momentary assessment (EMA) approach with 30 data time-points was conducted in the Netherlands, 2010-2011. Students aged 18 to 24 years old who reported heavy drinking in the past six months and who were ready to change behaviour were included in the study. Participants were randomized into the experimental ("}
+{"text": "United Nations General Assembly Resolution 61/105 on sustainable fisheries (UNGA 2007) establishes three difficult questions for participants in high-seas bottom fisheries to answer: 1) Where are vulnerable marine systems (VMEs) likely to occur?; 2) What is the likelihood of fisheries interaction with these VMEs?; and 3) What might qualify as adequate conservation and management measures to prevent significant adverse impacts? This paper develops an approach to answering these questions for bottom trawling activities in the Convention Area of the South Pacific Regional Fisheries Management Organisation (SPRFMO) within a quantitative risk assessment and cost : benefit analysis framework. The predicted distribution of deep-sea corals from habitat suitability models is used to answer the first question. Distribution of historical bottom trawl effort is used to answer the second, with estimates of seabed areas swept by bottom trawlers being used to develop discounting factors for reduced biodiversity in previously fished areas. These are used in a quantitative ecological risk assessment approach to guide spatial protection planning to address the third question. The coral VME likelihood  of existing spatial closures implemented by New Zealand within the SPRFMO area is evaluated. Historical catch is used as a measure of cost to industry in a cost : benefit analysis of alternative spatial closure scenarios. Results indicate that current closures within the New Zealand SPRFMO area bottom trawl footprint are suboptimal for protection of VMEs. Examples of alternative trawl closure scenarios are provided to illustrate how the approach could be used to optimise protection of VMEs under chosen management objectives, balancing protection of VMEs against economic loss to commercial fishers from closure of historically fished areas. United Nations General Assembly Resolution 61/105 on sustainable fisheries The FAO International Guidelines for the Management of Deep Sea Fisheries in the High Seas What are vulnerable marine ecosystems and where are these likely to occur?What constitutes a significant adverse impact and how can the likelihood of interaction and risk of fisheries impact on VMEs be assessed?What might qualify as adequate conservation and management measures to prevent significant adverse impacts?This paper describes an approach for addressing these questions for bottom trawling activities in the SPRFMO Convention Area. The first two questions are addressed using a quantitative risk assessment framework An overview of the seabed topographic characteristics of the northern Tasman Sea study area west of New Zealand is shown in Catch and effort data for New Zealand high-seas bottom trawling in the SPRFMO Area were obtained from the New Zealand Ministry of Fisheries commercial catch and effort database. 1990 is the first full year represented in this database and 2006 is the end of the 2002\u20132006 reference period chosen by SPRFMO participants as the basis for mapping historically fished areas. 2002\u20132006 was also the time period covered by the data analyses used to develop the New Zealand management measures for their SPRFMO Area bottom fisheries This database includes data for foreign-flagged vessels that operated under charter to New Zealand companies. Whereas foreign flag charter vessel data were excluded from the SPRFMO Area impact assessment developed by New Zealand Hoplostethus atlanticus) targeted fishery and data were error-checked using standardised procedures routinely used for orange roughy-targeted trawl catch and effort analyses for this fishery Bottom trawl data for the period 1990\u20132006 were retrieved from the high seas versions of the Trawl Catch Effort and Landings Return (TCELR) forms, which provide tow-by-tow information with start and end date, time and location, fishing method, depth and estimated catch by species (kg) for each tow. This is primarily an orange-roughy  erroneous tows were excluded from analyses.All valid trawl tows for the period 1990\u20132006 were imported into ArcGIS\u00a9, incorporating a randomised jitter up to 0.5 minutes either side (latitude and longitude) of the reported positions to compensate for rounding to the nearest minute of reported start and end positions Tow lengths were determined in ArcGIS\u00a9 using an Albers equal area conic projection  and tow lines were then split by the boundaries of the 20-minute blocks constituting the New Zealand 2002\u20132006 SPRFMO Area bottom trawl footprint. Although the Albers projection does not conserve length, there is negligible distortion of length across the width of a 20-minute blocks (\u223c32 km), and these lengths were only used to determine proportional catches per segment within each block. The lengths of split tow segments within each block were determined and the proportional orange roughy and top ten species catches for each tow segment were calculated from the ratio of the tow segment length over the full tow length. The resulting tow segment data were summed by footprint block to determine the total number of tows (segments), the summed (cumulative) tow length and the total reported orange roughy and top ten species catches within each footprint block over the period 1990\u20132006.Two alternative measures of seabed swept are used in this paper, for two different purposes. Cumulative swept area is the simple sum of estimated areas swept over time, with individual areas of all tows simply being added together, without accounting for any overlap in tows. Cumulative swept area provides a measure of the repetitive impact in an area over time. This is essentially a measure of fishing intensity and is an appropriate measure of the increasing likelihood of interaction with vulnerable marine ecosystems in repetitively trawled areas. However, this measure ignores the fact than many tows may overlap and does not measure the area of the seabed that was actually swept. Actual swept area was therefore estimated by first merging overlapping trawls and then estimating the swept area of the resulting merged tows. This provides a measure of the seabed area that has actually been swept, correcting for any overlap in tows. This is an appropriate measure of the area of the seabed that has actually been impacted by fishing operations, for use in discounting the biodiversity or habitat suitability of an area.New Zealand vessels fishing in the SPRFMO Area average 48 m in length Even after jittering of tow start and end positions, many tow lines overlap, particularly in heavily fished areas. Actual swept area within each trawl footprint block was estimated using ArcGIS\u00a9 to generate polygon buffers 50 m either side of each of the tow lines (assuming 100 m door spread width). These buffered tow lines were dissolved into merged swept-area polygons which were then split by the boundaries of the trawl footprint blocks. Actual swept areas over the period 1990\u20132006 were calculated as the sum of the areas of the dissolved, split, buffered tow polygons within each block.2 in area, decreasing from 1,240 km2 in the Fiji Basin to 901 km2 at the southern end of the Louisville Ridge . Any particular trawl swept area will therefore impact a greater proportion of the area of a footprint block towards the south of the fished regions than towards the north. To enable comparison between blocks, cumulative and actual swept areas within each block were expressed as proportions of the total area of the blocks within which they occurred.The planar surface area of 20-minute bottom trawl footprint blocks decreases polewards as a result of convergence of longitudinal meridians. The New Zealand bottom trawl footprint blocks average 1,088 km2) bathymetric data set To enable comparison of seabed swept areas with areas of available fishable depth, the proportion of fishable depth within each footprint block was determined from the proportion of data points in the GEBCO 30 arc-second (\u223c1 km2) resolution maximum entropy (Maxent) model that predicts habitat suitability for six species of deep-sea, habitat-forming scleractinian corals , using global databases for 15 bathymetric, hydrographic, chemical and biological predictor variables. This global model incorporated all the available scleractinian reef-forming coral occurrence records for thespecies occurring in the New Zealand region from Tracey et al. G. dumosa\u200a=\u200a204; S. variabilis\u200a=\u200a191; M. oculata\u200a=\u200a118; E. rostrata\u200a=\u200a98; O. varicosa\u200a=\u200a20; L. pertusa does not occur in the New Zealand region). The predicted, combined habitat suitability for these species in the New Zealand region is shown in The global deep-sea scleractinian coral habitat suitability model developed by Davies & Guinotte 2) for each of the 20-minute blocks in the New Zealand SPRFMO Area bottom trawl footprint. Each data point included position (latitude/longitude), depth (from the underlying 30-arc-sec bathymetric data), and the overall predicted habitat suitability (0\u2013100%) for all scleractinian species combined. The scleractinian habitat suitability values for data points within each block were averaged over all depths to provide indices of overall coral habitat suitability per block, and over fishable depths (0\u20131600 m) to provide indices of fishable-depth coral habitat suitability per block.This scleractinian habitat model was used to generate 1600 data points  developed by Hobday The ERAEF productivity\u2013susceptibility analysis approach was further adapted in this study to directly address the two main questions arising out of y UNGA resolution 61/105: where are VMEs likely to occur? and what is the risk of fisheries interaction with these VMEs? These questions were expressed as the axes of a two-dimensional analysis, similar in concept to the PSA plots used in level-2 ERAEF assessments. Likelihood of VME Occurrence was plotted against Likelihood of Fishery Interaction to quantify the risk of significant impacts on VMEs in each footprint block. Risk indices for each of the 20-minute trawl footprint blocks along these two axes were quantified as described below.The ERAEF PSA approach uses quantified or ranked answers to a range of questions to provide integrated measures of productivity based on a number of measures or indicators The Scleractinia-combined habitat suitability values from Davies & Guinotte et al. et al. et al. Solenosmilia variabilis by Neil et al. Predicted fishable-depth VME likelihood values were then discounted for the effects of historical fishing in each block. The impacts of trawling, particularly the removal of fragile, habitat-forming species and resulting reduction in biodiversity, have been well documented et al. et al. Residual biodiversity discounting factors should ideally be determined from properly designed control-impact seabed biodiversity surveys in fished and unfished areas. However, no such surveys have been conducted for any of the SPRFMO bottom-trawled areas. Noting observations by Koslow The y-axis on ERAEF productivity-susceptibility plots measures the susceptibility of fisheries or areas to a particular impact. In the context of the questions posed by the UNGA requirements, the comparable y-axis in the risk assessments presented here measures the likelihood of fisheries interaction with VMEs in each of the footprint blocks. Of the two measures of seabed impact calculated, cumulative swept area (being a measure of fishing intensity) provides the most appropriate indicator of the likelihood of fishery interaction with VMEs. Areas that are repeatedly trawled each year are of more interest to the fishery and will have a higher likelihood of ongoing fisheries interaction with any residual VMEs. Cumulative swept area values for each footprint block were therefore used for the Fishery-Interaction axis in risk assessment plots.The predicted, discounted likelihood of occurrence of VMEs provides a measure of the potential benefit of closing each trawl footprint block, in terms of meeting UNGA requirements to protect areas likely to contain VMEs. Provided some meaningful measure of cost to industry of the closure of alternative footprint blocks can be calculated, the cost : benefit trade-off of alternative spatial closure scenarios can be evaluated and optimised against any specified cost and benefit objectives.For analysis of previously fished areas, quantitative measures of historical catch and effort can provide indices of fishing industry interest in an area. Strictly, these are retrospective measures of the cost that would have been incurred if those blocks had been closed historically. However, if the intention is to maintain stocks at sustainable levels in each area, rather than to pursue a policy of sequential depletion and movement to new fishing areas, then historical catch and effort provide appropriate measures of the ongoing suitability of the area for the fish species concerned, and of potential future value of the area to the fishing industry.New Zealand\u2019s high-seas spatial closures currently involve the closure of entire 20-minute footprint blocks, irrespective of depth Beryx splendens, B. decadactylus) and/or oreos  have contributed substantial catches in some areas or years. The top ten species catch was therefore considered to be a better measure of cost than orange roughy alone. While the relevance of historical catch as a measure of cost to industry may be questioned, it is worth noting that, during a marine protected area (MPA) planning process for the Antarctic Ross Sea region Either effort or catch could be used as measures of industry interest in particular areas, and therefore of the cost of closing those areas. However, loss of catch provides a more direct measure of cost of closures to industry than effort. The cost to industry of closing particular footprint blocks was therefore calculated as the total historical catch of the top ten species  within eet al. et al. et al. et al. Existing spatial closures in the New Zealand SPRFMO bottom trawl footprint close 40% of the blocks across the entire footprint Having determined the number of blocks (40%) to be closed in each fishing area, cost : benefit trade-off curves for alternative spatial closure scenarios were generated. The starting closure scenario for each fishing area was generated by sorting the footprint blocks in descending order of discounted, all-depths, average habitat suitability and closing the 40% of blocks with highest average habitat suitability. This starting scenario provides the highest overall, average, discounted habitat suitability that can be achieved by any 40% closure of blocks within each fishing area. Scenarios of decreasing overall average habitat suitability were then generated by opening the closed block with the highest historical catch (cost) and closing the block with the next highest average habitat suitability. This process was repeated, re-calculating the average habitat suitability and total cost of the revised closures at each step, until all blocks in each fishing area had been accounted for.This process generates cost : benefit trade-off curves starting from the closure scenario of highest average habitat suitability (benefit), and ending with the closure scenario of least historical catch lost (cost), with each sequential scenario along these curves having decreasing cost to industry, as well as decreasing average coral habitat suitability. To provide visually reciprocal declining conservation benefit and increasing retained catch curves, the cost to industry was plotted as percentage retained catch. The benefit and cost of the existing closures in each fishing area were calculated in the same way and plotted as points on these optimisation curves to provide a direct comparison of the value and cost of existing closures with the explored range of alternative scenarios.vs. cost to industry resulting from lost access to fishing areas. Such a process is described by Sharp and Watters Cost : benefit trade-off curves for each fishing area can be used to select an \u2018optimal\u2019 spatial closures at some point along the trade-off, given specified management objectives in terms of benefit and cost. Selection of a preferred position along the trade-off curves would usually be based on an iterative consultation between fisheries managers, industry representatives and other stakeholders, using pre-agreed objectives for each axis, comparing conservation benefit of spatial closures To achieve protection of at least 75% of the achievable range in average habitat suitability (maximum to minimum) across the alternative scenarios in each fishing area (75% of the benefit axis range).To retain at least 75% of the historical top ten species catch in each fishing area (75% of the retained catch axis).An optimisation approach such as this involves an explicit balancing of competing objectives related to maximising conservation and catch, using objective and quantitative measures for each axis. In generating examples of \u2018optimised\u2019 closure scenarios against these management objectives, the conservation objective was initially given precedence. If the fisheries cost reduction objective could not be achieved while retaining 75% of potential habitat suitability, then retained catch was allowed to decrease below 75% of historical catches to retain at least 75% of potential habitat suitability. However, if both objectives could be achieved across a range of alternative closure scenarios, then within this range of \u2018acceptable\u2019 alternatives, the objective of reducing cost to industry was given precedence, so that retained catch was maximised after ensuring protection of at least 75% of potential habitat suitability.Epigonus telescopus), oreos , spiky oreo , alfonsino, ribaldo (Mora moro), rattails (Macrouridae), seal shark  and boarfish , together contributed 12% of the total reported catch  in the western region is four times that on the Louisville Ridge and actual swept area in the western region is five times that on the Louisville Ridge . The ratAcross the entire western region, 7% of the all-depths footprint area, which amounts to 8% of the fishable depth footprint area, has actually been swept. Despite the fact that most of the trawl footprint on the Challenger Plateau lies within fishable depth and that this area has the longest fishing history, only 14% of the 20-minute block footprint in this area has actually been swept . In compThe minimum, maximum and average percentages of the fishable depth area swept per 20-minute block in the Lord Howe Rise (north and south combined), Challenger Plateau, West Norfolk Ridge and Three Kings Ridge (combined) and Louisville Ridge  fishing areas are summarised in The proportion of fishable depth area actually swept per block in the lightly fished Lord Howe Rise, West Norfolk Ridge and Three Kings Ridge areas averages 2% \u20133%, with less than 18% of the fishable area of the most heavily fished block having been swept . In the Goniocorella dumosa and Solenosmilia variabilis  is similar to that of the move-on areas (66.1%) and slightly higher than that in the closed areas (63.8%) . After dIndividual, discounted, VME-Likelihood/Fishery-Interaction risk assessment plots for the six main fishing areas are shown in Along the Louisville Ridge, as a result of the small areas of fishable depth on seamounts and the high proportions of these areas that have been swept, discounting has a substantial effect on residual VME likelihood. On the more lightly fished Northern Louisville Ridge, the effect of discounting is moderate and the discounted VME likelihood of closed blocks remains less than that of the open or move-on blocks. However, the effect of discounting is substantial on the heavily fished Central Louisville Ridge where the residual VME likelihood of open blocks is reduced to less than 40%, with closed blocks then having a higher VME likelihood than the open or move-on blocks .et al. Cost : benefit trade-off curves for six of the fishing areas are shown in Comparing the cost : benefit of existing closures , but this is achieved at the cost of reducing retained historical catch from 81% to 74%. The resulting proposed closures differ substantially from the current closures , with a et al. This approach does not address the question of implementation of a move-on rule. Reliance on move-on rules as a primary mitigation measure to avoid significant adverse impacts on VMEs has been increasingly criticised in recent years The optimisation approach taken in this paper is similar to that implemented in the conservation planning software package Marxan Lophelia pertusa whereas deep-sea coral reefs around New Zealand are dominated by Solenosmilia variabilis. Without true absence data these models tend to over-predict and are not prevented from predicting the occurrence of species that do not actually occur in a region. It should be noted, though, that in doing so these models are predicting a suitable environmental niche for the species included in the model, rather than the presence of the species itself. The niche may well be suited to an alternative species in other regions.In the absence of seabed survey data on benthic community composition and seabed geology, predictive habitat models provide the only source of information with which to objectively evaluate the likelihood of occurrence of VMEs in high-seas areas. However, there is scope for improving these models to reduce shortcomings they have in reliably predicting VME. For example, the global scleractinian habitat model of Davies &Guinotte Current global coral habitat suitability models predict high values for scleractinian habitat suitability across the entire depth range of the orange-roughy targeted bottom trawl fishery , providiThe most useful improvement that could be made to the reliability of predictive habitat models would be to conduct seabed biodiversity surveys to ground-truth the predictive models. Initial predictive habitat model results can be used to focus survey effort on selected areas where additional biodiversity and presence-absence data would have most power in improving model reliability. New Zealand is intending to conduct such survey work at selected sites in the SPRFMO Area in 2014. The results of ground-truthed, regionally tailored predictive VME habitat prediction models will provide an essential component for spatial planning and management initiatives in the South Pacific region."}
+{"text": "It could be hypothesized that when walking in a linear direction, the most efficient strategy would be to focus the force created by the push-off in the absolute opposite direction to the direction of propulsion. Forces in a medial or lateral direction could then be considered as loss of efficiency since these forces do not create movement in the intended direction. The aim of this study was to investigate if individual differences in push-off location of the forefoot resulted in difference in force direction. Three subjects with different push-off locations were identified through video gait analysis. The subjects were categorized as having either a lateral subject 1), central (subject 2) or medial (subject 3) push of location. The subjects walked over a force plate (Kistler) where medial and lateral forces were registered. The results showed distinct differences in force direction between the subjects during the propulsive period of gait (70%-100%) (see figure , centralDifference in force direction may lead to differences in propulsive efficiency. It could also be hypothesized that proximal segments need to compensate in order to keep a subject with medial or lateral force deviations walking in a linear direction of propulsion."}
+{"text": "The location specific motor pattern generation properties of the spinal cord along its rostro-caudal axis have been demonstrated. However, it is still unclear that these differences are due to the different spinal interneuronal networks underlying locomotions or there are also segmental differences in motoneurons innervating different limbs. Frogs use their fore- and hindlimbs differently during jumping and swimming. Therefore we hypothesized that limb innervating motoneurons, located in the cervical and lumbar spinal cord, are different in their morphology and dendritic signal transfer properties. The test of this hypothesis what we report here.Discriminant analysis classified segmental origin of the intracellularly labeled and three-dimensionally reconstructed motoneurons 100% correctly based on twelve morphological variables. Somata of lumbar motoneurons were rounder; the dendrites had bigger total length, more branches with higher branching orders and different spatial distributions of branch points. The ventro-medial extent of cervical dendrites was bigger than in lumbar motoneurons. Computational models of the motoneurons showed that dendritic signal transfer properties were also different in the two groups of motoneurons. Whether log attenuations were higher or lower in cervical than in lumbar motoneurons depended on the proximity of dendritic input to the soma. To investigate dendritic voltage and current transfer properties imposed by dendritic architecture rather than by neuronal size we used standardized distributions of transfer variables. We introduced a novel combination of cluster analysis and homogeneity indexes to quantify segmental segregation tendencies of motoneurons based on their dendritic transfer properties. A segregation tendency of cervical and lumbar motoneurons was detected by the rates of steady-state and transient voltage-amplitude transfers from dendrites to soma at all levels of synaptic background activities, modeled by varying the specific dendritic membrane resistance. On the other hand no segregation was observed by the steady-state current transfer except under high background activity.We found size-dependent and size-independent differences in morphology and electrical structure of the limb moving motoneurons based on their spinal segmental location in frogs. Location specificity of locomotor networks is therefore partly due to segmental differences in motoneurons driving fore-, and hindlimbs. Correlative analysis of the same type of neuron in different parts of the CNS has shown location specific morphological and electrotonic differences in pyramidal neurons of the hippocampus in the rat /16\u2009=\u20090.46 being the total number of neurons is 16. Another index used to measure last order cluster formations was the Peterson\u2019s index \u2009=\u20090.62. Both indexes may have values between 0 and 1. The indexes are closer to 1 if cervical and lumbar MNs are more similar and they are getting smaller with increasing differences between MNs of the two spinal segments. The significance of segmental cluster formation tendencies  was tested by comparing these homogeneity indexes with those of artificially generated cluster formations, where segmental origins of MNs were assigned randomly prior to the cluster analysis. For each actual dendrogram 100 other artificial dendrograms were generated reflecting grouping tendencies of the real set of MNs with their segmental origins artificially randomized. The mean value of indexes was calculated for the 100 artificial dendrograms and the mean was then compared with the actually found index by one sample t-test. If this test showed a significant difference between the real and artificial indexes, then we concluded that MNs tended to form homogeneous groups determined by their segmental location in the spinal cord.To check if MNs have a tendency to form last order clusters where cervical and lumbar MNs are segregated, homogeneity (or similarity) indexes were used to measure segmental homogeneity within clusters. Measuring segmental homogeneities is feasible since increasing segmental differences among MNs are reflected in their increasing segregation tendency to different clusters shown by the cluster analysis, and as a consequence of segregation, the clusters become more and more homogeneous in terms of segmental origins of MNs they contain. This way, increasing segmental segregation of MNs between clusters may be measured by segmental homogeneities (homogeneity indexes) within clusters. Two different homogeneity indexes were used. In addition to the Peterson\u2019s index  we defins index  and was The purpose of this study was to investigate differences between alpha motoneurons (MNs) located in the cervical and lumbar enlargements of the frog that innervate the muscles of forelimbs and hindlimbs. These MNs had ellipsoid or fusiform perikarya in the lateral area of the ventral horn. The dendritic arborization of these MNs could be divided into a dorsomedial, dorsal and lateral dendritic arrays with many dendrites extending to the lateral funiculus of the white matter. The lateral dendrites extended to the border of spinal cord where they formed a subpial meshwork Figure , charactThe mean surface area of somata for cervical MNs was about 35% bigger than that of the lumbar MNs but the difference did not reach the significant level because of the high variances in both spinal segments Table  was applThe total number of branch points was more numerous in lumbar MNs than in MNs of the cervical part of the spinal cord . The distributions of branch points over different path distance domains were also different . This indicates that difference in branch point frequencies was due to longer total length of dendrites with the same average tendency of branching in the lumbar MNs close to somata as also found by Dityatev et al. .Early analyses of dendritic orientation of limb moving MNs in frog spinal cord described three dendritic arrays that extended in the dorso-medial, dorsal and lateral directions ,43. BaseHere we compared orientation of MN dendrites in the lumbar and cervical levels of the cord. Polar histograms were created Figure  to show ms\u2009=\u2009Rmd) and inhomogeneous (Rms\u2009<\u2009Rmd) soma-dendritic membranes (see Methods) at different neuron resistances. Since it is difficult to infer how MNs\u2019 dendritic architecture affects electrical signal propagation, we used the graphical approach of the morphoelectrotonic transformation . By thimd) and the soma (Rms). Note that both Rmd and Rms are different in these two METs; Rmd is bigger, while Rms is smaller in Figure md makes the MET more compact, while the decreasing Rms has the opposite effect on compactness. When the geometry and the METs of dendritic arbors were compared, careful inspection found non-proportional changes in the MET size of dendritic branches relative to their morphological appearance  of the MET may be different Figure B\u2013C indicms\u2009<\u2009Rmd), cervical and lumbar MNs also differed in their mean MET distances measured to branch points.To compare different METs of dendrites (representing electrotonic architectures in different membrane models) of the same MN, a set of MET descriptors Table  was compDiscriminant analysis using MET descriptors classified cervical and lumbar MNs 100% and 95% correctly in all membrane models . Similar results were obtained when the number of descriptors was reduced. With just four descriptors  MNs were still classified 87% segmentally correctly. These results were cross validated by the 16-fold and the repeated random subsampling techniques  (in averms\u2009<\u2009Rmd) membrane. These values yield 84/533\u2009=\u20090.16 proximal to distal ratio for the geometrical size of branches, and 1.97/2.50\u2009=\u20090.79 and 1.94/1.68\u2009=\u20091.15 ratios in the METs with homogeneous and inhomogeneous membranes respectively. This observation suggests non-proportional changes in the size of dendrites during the MET, which depend on the distance of dendritic branch from the soma.In case of the two previously selected dendritic branches we calculated their geometrical and MET size ratios. The lengths of the proximal and distal branches were 84 and 533 \u03bcm respectively  membrane model with 1.4 M\u03a9 neuron input resistance was assumed.To investigate these changes further, log attenuations of PSPs to soma were determined from different regions of the dendrites located within 100 \u03bcm path distance domains from the perikaryon. Then, the computed attenuations were divided by the mean attenuation of PSPs measured from dendritic sites within 0\u2013100 \u03bcm from the perikaryon. These relative attenuations were not linearly related to the path distances of locations where PSPs were generated indicating again a non-proportional change in size of dendrites during the METs Figure . Relativ\u22126) from the same geometrical distance in lumbar and in cervical MNs both in the homogeneous (Rms\u2009=\u2009Rmd), Figure ms\u2009<\u2009Rmd, Figure The mean somatopetal log attenuations of PSPs were determined as a function of path distance from the soma in different membrane models of the cervical and lumbar MNs Figure . GeneralNerve cells with significantly different sizes are likely to be different electrotonically too. However, it remains an important question if neurons with different sizes keep their electrotonic difference if their comparison is based only on their topological structure and size-dependency is ignored. Here we studied this issue by using size-independent comparisons of dendritic signal transfer properties in cervical and lumbar MNs. This type of electrotonic comparison is feasible since electrotonic structure - in analogy to the geometrical structure - is not only defined by metric-related properties, but also by the branching structure (topology) of dendritic trees affecting the shape of distributions of voltage and current transfer properties over the length of dendrites.th, 25th, 50th, 75th and 90th percentiles .In this set of analysis a constant current was injected to generate steady depolarizations in the midpoints of all cylindrical compartments of the cable model and voltage and current transfers to soma were measured. These transfer values were then processed as summarized above.th percentiles of distributions for the lumbar MNs  and the generally shifted nature of percentiles relative to those of the cervical MN group  in their steady-state voltage transfer properties. These segmental differences between MNs were detected at all levels of background synaptic activities with some tendency of MNs to get more similar with the decrease of background activity.By using somatopetal voltage transfers, our first observation was the higher variabilities for all, except the 90t-test, p\u2009<\u20090.02). MNs were getting more and more similar with the decrease of overall synaptic activity  with a less obvious general shift in the standardized distributions Figure D. Cluste Figure A, B, as  Figure .While steady-state approach measures transfer properties when the generation of PSPs can be approximated by a constant current injection, many synaptic events are short in time and are better approximated by transient conductance changes. Propagation properties of these transient voltage signals are different than those under steady-state circumstances. Therefore, we extended our analysis and investigated transfers of voltage transients. In these simulations PSPs were generated by brief conductance changes in dendritic points. The changes in shape parameters  of transient PSPs were computed during their propagation to the soma and descriptors of these changes were created as described earlier. Box plots of these descriptors, once again, showed that lumbar MNs were more variable than the cervical ones in the way the amplitudes of voltage transients were reduced during their propagation to the soma Figure B\u2013C.t-test, p\u2009<\u20090.0005) than those calculated for clusters when segmental origin of MNs was artificially randomized  in these cases. Graphs of both homogeneity indexes tended to remain in the territory  where they represent no significant segregation of the two groups of MNs.  Cervical and lumbar limb-moving MNs of frogs have structurally different dendrites imposing different attenuations of voltage amplitudes during their propagation to the soma. 2) On the other hand, these structural differences in dendrites do not distinguish the two classes of MNs in the way how half-widths and rise times of transient potentials are changing during their dendritic propagation.We investigated morphological and electrical differences between cervical and lumbar spinal motoneurons (MNs) that innervate fore- and hindlimb muscles in adult frogs. We deliberately did not want to compare MNs according to the specific muscles they innervate ,45-48 raMNs undergo substantial developmental changes during embryological and postnatal life that affect the size of cell bodies, size and branching structure of dendrites and these changes are accompanied by physiological maturation of membrane properties like specific membrane resistance, neuron resistance, resting membrane potential, spike shapes and excitability . Some ofOverall, these findings suggest that MN maturation is highly dependent on rostro-caudal position of neurons and therefore intrinsic differences in morphology and electrical properties of MNs may be expected to occur along the rostro-caudal axis. These differences have been investigated in the present study.To investigate segmental differences between MNs, we used pair-wise comparisons of morophological and electrotonic properties, multivariate discriminant analysis and cluster analysis. These methods have been successfully applied in classifying spinal MNs in the turtle , tectal We used high-fidelity compartmental cable models with a set of different membrane properties to account for the variability in neuron resistances measured experimentally, to analyze the effects of the varying size of inhomogeneity in the soma-dendritic membrane and to mimic synaptic background activity. However, in our models we considered a passive membrane. This restriction is validated by a number of factors. Although there is an ever growing list of evidence that voltage-dependent ion channels are present in the dendritic membranes of different nerve cells  dendrites to total surface area and the low sensitivity of dendritic impulse propagation to the thickness of these dendrites we conclude, that the impact of 0.1\u20130.2 \u03bcm overestimation of diameters for the thinnest dendrites is unlikely to be significant in our study.We found segmental differences both in the numbers and distributions of branch points in dendrites of limb moving MNs of the cervical and lumbar segments. The bigger number of branch points in lumbar MNs does not merely mean more dendritic branches but also a topologically and electrotonically more complex dendritic architecture. Based on various morphological measures of dendritic complexity Dityatev et al.  found thLocations of branch points are related to signal propagation in the dendrites both in the presence and absence of voltage\u2013dependent ion channels. In dendrites with passive membrane, the current transfer effectiveness generally changes abruptly at branch points altering the \u2018cost\u2019 of moving a synapse to a geometrically different location in terms of the change in the soma potential during synaptic activity ,78. In dComparison of the orientation of dendritic arborization also demonstrated differences between cervical and lumbar MNs. We found that the ventromedial extension of dendritic trees is more powerful in the cervical MNs. Experiments using retrograde cell degeneration technique showed that the ventromedial area in the gray matter of the cervical segments corresponds to the terminal fields of contralateral tectospinal pathways that do not extend to lumbar segments in frogs . Axon teThe morphology of MNs located in cervical, lumbar and sacral spinal segments have been investigated in several studies -48,84-87Comparison of our data on the morphology of lumbar MNs of frogs with MNs of cats showed several differences between the two species. The MNs in the frog presented smaller, elongated cell bodies emitting fewer stem dendrites. The size of the dendritic trees was about the half of that found in hindlimb innervating MNs of mammals ,88. LumbThe organization of dendritic arbor seemed to be also different in lumbar MNs of frogs and cats. While the dendritic trees of cat MNs emerge in almost all directions without any obvious preference, the dendritic trees of frog MNs are organized into dorsal, lateral and dorsomedial groups. The lateral dendrites dendrites form a dense subpial meshwork running parallel with the border of the spinal cord. This subpial dendritic plexus is well developed in lower vertebrates including anurans but it is reduced in mammals.ms) and dedndrites (Rmd). However, the detailed membrane properties (Rms and Rmd) of these large neurons are still not well known. In addition, the effective membrane resistance may be dependent on the activation state of synapses received by MNs in the functioning spinal networks. Therefore we used two approaches. First, we compared the METs of MNs by assigning different physiologically realistic somatic input resistances (1.4 or 5 M\u03a9) [ms\u2009=\u2009Rmd) and inhomogeneous (Rms\u2009<\u2009Rmd) soma-dendritic membrane with a canonical Rmd\u2009=\u200920000 \u03a9cm2 value for the dendrites  of the same neuron  was investigated on the similarities/dissimilarities of voltage and current transfer properties of cervical and lumbar MNs by taking Rmd\u2009=\u200920000 \u03a9cm2 as a control value. Higher and lower levels of synaptic activities were modelled by decreasing the Rmd to 5000 \u03a9cm2 and increasing it to 50000 \u03a9cm2, while the Rms was kept constant at 500 \u03a9cm2[Our major aim was to test if limb moving MNs are different electrically in the cervical and lumbar segments of the spinal cord. Factors shaping the electrical properties of neurons include the specific membrane resistance of the soma (Rr 5 M\u03a9) ,18,19 wi 500 \u03a9cm2,33,34  on MNs Comparison of the METs with the original geometry of dendrites showed increasingly disproportionate changes in MET sizes in the more distant locations. This was observed independently of the size of soma-dendritic membrane inhomogeneity and the resistance of the neurons. According to the cable theory, in an infinite cylinder with passive membrane the voltage is decaying exponentially with distance if a steady current is injected  Which distance domains of the dendrites do differentiate between cervical and lumbar MNs and 2) How these distance domains do change when properties of the soma-dendrite membrane are altered?Two distance domains, whose separation was at ~1500 \u03bcm distance, could be identified from where voltage attenuations to soma were characteristically related to the segmental origin of MNs. In this context we found the followings: i) PSPs propagating along the passive dendrites of cervical MNs attenuated less to soma than PSPs in lumbar MNs if the synapses were closer than ~1500 \u03bcm. The relationship is the opposite if PSPs were generated farther than ~1500 \u03bcm from the soma. ii) These findings are independent of the size of neuron resistivity and the inhomogeneity of the soma-dendritic membrane surface.ms\u2009<\u2009Rmd) nature of the soma-dendritic membrane would be kept, while the neuron input resistance becomes lower with the overall increase in synaptic activity. However, the impact of background synaptic activity on membrane resistance is presumably bigger in dendrites than in the soma since ~95\u201398% of the membrane surface is given by the dendrites and the majority of synapses are received there in frog spinal MNs [The observation that these relationships are independent of the size of neuron resistance suggests implications for the control of PSP attenuations by the uniform decrease or increase of background synaptic activity that changes the effective membrane resistance over the soma-dendritic membrane -31. In tnal MNs . Consequnal MNs ,26,27 anGlobal comparison of log attenuations (MET) of cervical and lumbar MNs resulted in a nearly 100% segmentally correct classification by discriminant analysis. Electrical structures of MNs were further investigated by the voltage and current transfers in dendrites at different intensities of synaptic background activity. In these analyses we used standardized distributions of the transfer values to isolate structure-related electrical differences from those related purely to size. Such structural differences were suggested by the different numbers and distributions of branch points in MNs of the two spinal segments and by the different distance-dependence of log attenuations in the two groups of MNs.This way, it was relevant to ask directly whether the electrotonic differences between fore- and hindlimb moving MNs are entirely due to their different metric (size-related) morphological properties or they are  consequences of the different dendritic structures.Voltage transfer properties showed differences in the two groups of neurons both in steady-state and in case of transient signals. This suggests that identical inputs propagate differently in the dendrites of cervical and lumbar MNs and the level of depolarization reaching the soma or the nearby axon hillock may be different. Threshold potentials were investigated experimentally in putative MNs along the spinal cord in young frogs and no significant tendency of changes was detected according to the rostro-caudal positions of neurons  suggestiHowever, it is disputed if the major determinant of firing is to exceed a certain voltage threshold or to deliver enough current (charge) to the soma since experimental evidence exists to support each view depending on the conditions of action potential initiation  direction . Our resUnder steady-state conditions we detected a general tendency of increasing segregation (differences) between the limb moving MNs as the background synaptic activity was increased. This tendency was more pronounced if current rather than voltage transfers were considered. A similar tendency of increasing differences in electrotonic properties during higher synaptic activities was reported in a comparative study on different classes of spinal neurons, including MNs, in the cat .Our findings on segmental segregation tendencies of limb moving MNs based on their morphological and dendritic signal transfer properties are strengthened by the consistency of the results obtained with the many different and validated statistical approaches, independently of the type of homogeneity index used, the choice of hierarchical cluster analysis and the weighting factors of descriptors.structural differences in motoneurons along the rostro-caudal axis of the spinal cord. The location-dependent differences are likely to affect input\u2013output properties of these MNs.We showed location specificity of morphological and electrical transfer properties of the limb moving class of motoneurons in the frog spinal cord. Many of the location-specific differences were size-independent emphasizing the importance of The results present the first detailed systematic analysis of the location-dependent properties of spinal motoneurons and suggest that specificity of locomotor networks, which control fore- and hind limb movements, is partly due to differences in their motoneurons.These differences might reflect a basic initial segmental developmental pattern of MNs, which may then be refined according to the needs of specific muscles they innervate. This concept may obtain support from the experimental findings that the targets of these MNs are specified before the outgrowth of axon ,102. Furmax: Peak synaptic conductance; tmax: Time to peak of the synaptic conductance; Rmd: Specific dendritic membrane resistance; Rms: Specific somatic membrane resistance; RN: Neuron resistance.ANOVA: Analysis of variance; BRP: Branch point of a dendrite; CNS: Central nervous system; ENDP: End point of a dendrite; EPSP: Excitatory postsynaptic potential; Hox: Homeobox; MET: Morphoelectrotonic transformation; MN: Motoneuron; PAST: Palaeontological statistics; PSP: Postsynaptic potential; SEM: Standard error of means; SPSS: Statistical package for the social sciences; \u03bb: Space constant; gThe authors declare that they have no competing interests.AS wrote the program codes, run simulations, carried out statistical tests and contributed to drafting the paper. JS participated in running simulations and in data analysis. IW and AB reconstructed the neurons. AB also contributed to the body text. EW designed the study, participated in analysis and interpretation of data, and finalized the text. All authors read and approved the final manuscript."}
+{"text": "Methotrexate (MTX) is one of the most common disease modifying antirheumatic drugs used for the treatment of juvenile idiopathic arthritis (JIA). Reliable predictors for the efficacy of MTX therapy would be very helpful for the development of more personalized therapy in an early stage of the disease.We investigated whether Reduced Folate Carrier (RFC) (C347G), and Aminoimidazole Carboxamide Ribonucleotide Transformylase (ATIC) (G80A) gene polymorphisms were related to the efficacy of methotrexate in JIA patients with a polyarticular course.Ninety seven JIA patients with a polyarticular course were enrolled into the study. All patients received methotrexate treatment for at least for 6 months. The efficacy of treatment was judged by improvement in physician\u2019s global assesment, the number of affected joints, erythrocyte sedimentation rate and C-reactive protein. RFC and ATIC gene polymorphisms were determined by polymerase chain reaction- restriction fragment length polymorphism ( PCR-RFLP) analysis.The median age of the patients was 72 (12-92) months. The response rate to MTX was 45%. There was no significant association between RFC and ATIC polymorphisms and efficacy of MTX treatment .In this study the response to MTX was not associated with RFC and ATIC polymorphisms. The pharmacogenomics related to MTX is probably quite complex. One probably needs to study all polymorphisms in the related enzymes and associated pathways to predict response to MTX."}
+{"text": "Primary immune deficiencies (PID) are genetic disorders resulting in recurrent infections. Immunoglobulin replacement therapy in PID patients can be achieved intravenously (IVIG) or subcutaneously (SCIG) with similar efficacy and safety profiles but with different resource use and associated costs.SCIG and IVIG options for immunoglobulin replacement therapy in adult PID patients were compared in a cost-minimization model over three years of treatment. The model focused on direct medical costs for infusion supplies and personnel. A three-year budget impact model assessed the economic impact on the healthcare system of switching from IVIG to SCIG for PID patients of the BC Central Transfusion Registry. Sensitivity analyses were performed for both models to measure the effect of different modalities of IVIG treatment and of the proportion of patients switching from IVIG to SCIG.The cost-minimization model estimated SCIG treatment cost per patient over three years at $1978 compared to $7714 for IVIG, resulting in savings to the healthcare system of $5736, principally due to reduced hospital personnel costs. This figure varied from $5035 to $8739 for different modalities of IVIG therapy. Assuming that 50% of patients who received IVIG switched to SCIG, the budget impact model estimated cost savings for the first three years at $1,307,894 or 37% of the personnel and supply budget.This study demonstrated that rapid push home-based SCIG was less costly than hospital-based IVIG for immunoglobulin replacement therapy. This approach provides not only a beneficial option from the patient perspective but also results in significant savings to the healthcare system for immunoglobulin replacement therapy in adult PID patients in a Canadian context."}
+{"text": "Pteronotus parnellii is a widespread Neotropical bat and the only New World species to use high-duty cycle echolocation, a trait otherwise restricted to Old World taxa. Here we analyze morphological and acoustic variation and genetic divergence at the mitochondrial COI gene, the 7th intron region of the y-linked Dby gene and the nuclear recombination-activating gene 2, and provide extensive evidence that P. parnellii is actually a cryptic species complex.Molecular techniques are increasingly employed to recognize the presence of cryptic species, even among commonly observed taxa. Previous studies have demonstrated that bats using high-duty cycle echolocation may be more likely to speciate quickly. Central American populations form a single species while three additional species exist in northern South America: one in Venezuela, Trinidad and western Guyana and two occupying sympatric ranges in Guyana and Suriname. Reproductive isolation appears nearly complete . The complex likely arose within the last ~6 million years with all taxa diverging quickly within the last ~1-2 million years, following a pattern consistent with the geological history of Central and northern South America. Significant variation in cranial measures and forearm length exists between three of the four groups, although no individual morphological character can discriminate these in the field. Acoustic analysis reveals small differences (5\u201310 kHz) in echolocation calls between allopatric cryptic taxa that are unlikely to provide access to different prey resources but are consistent with divergence by drift in allopatric species or through selection for social recognition.This unique approach, considering morphological, acoustic and multi-locus genetic information inherited maternally, paternally and bi-parentally, provides strong support to conclusions about the cessation of gene flow and degree of reproductive isolation of these cryptic species. Central and northern South America are frequently cited as hotspots for speciation due to complex biological and geological processes in this area. The rise of the Central American land bridge some 3 million years ago caused a sudden mixing of previously isolated terrestrial species in the Great American Interchange while simultaneously isolating marine populations on the Atlantic and Pacific sides . The risPipistrellus].].Primer Click here for file"}
+{"text": "The proposal that dietary docosahexaenoic acid (DHA) enhances neurocognitive functioning in term infants is controversial. Theoretical evidence, laboratory research and human epidemiological studies have convincingly demonstrated that DHA deficiency can negatively impact neurocognitive development. However, the results from randomized controlled trials (RCTs) of DHA supplementation in human term-born infants have been inconsistent. This article will (i) discuss the role of DHA in the human diet, (ii) explore the physiological mechanisms by which DHA plausibly influences neurocognitive capacity, and (iii) seek to characterize the optimal intake of DHA during infancy for neurocognitive functioning, based on existing research that has been undertaken in developed countries . The major observational studies and RCTs that have examined dietary DHA in human infants and animals are presented, and we consider suggestions that DHA requirements vary across individuals according to genetic profile. It is important that the current evidence concerning DHA supplementation is carefully evaluated so that appropriate recommendations can be made and future directions of research can be strategically planned. It is argued that infants are capable of synthesizing n-3 and n-6 LC-PUFAs endogenously from their shorter chain precursors , while all n-6 PUFAs are derived from linoleic acid .  and arachidonic acid . These three fatty acids all carry out separate, complex functional roles in the body  than n-3 PUFA due to high intakes of beef, pork, poultry, wheat germ, and various cooking oils  to support optimum health across the lifespan, especially during pregnancy and lactation  are important for the function of the CNS at the cellular and neurobiological level. The concentration of DHA and other LC-PUFAs within the brain can alter the neuronal membrane fluidity and physical structure of neurons  in pregnancy found a significant association between low maternal seafood consumption (<340 g per week) and suboptimal neurocognitive outcomes in childhood  from Bangladesh found that maternal DHA supplementation from 25 weeks gestation until delivery had no effect on infant BSID-II mental and psychomotor performance outcomes at 10 months . However, this RCT revealed that children in the treatment group manifested significantly lower incidence of cognitive delay compared to their un-supplemented counterparts.A meta-analysis and systematic review of maternal d et al.  highlighd et al. . This RCIn summary, RCTs and epidemiological studies evaluating the potential neurocognitive impact of maternal DHA supplementation during pregnancy have revealed somewhat heterogeneous results in healthy term infants. Consequently, it may be premature to make unequivocal recommendations about any neurocognitive benefits of DHA supplementation in healthy term infants based on the currently available research findings.Over the years, many prospective observational studies have indicated that breastfed infants have a significant neurocognitive advantage over their formula fed counterparts  are positively correlated with infant neurocognitive outcomes  or placebo (un-supplemented formula). The majority of trials in healthy term infants have shown little or no consistent, beneficial effects on neurocognitive outcomes as a result of dietary LC-PUFA supplementation. However, infant LC-PUFA supplementation has resulted in no negative effects on growth, development or morbidity , Beyerlein et al.  were randomized to either very high dose fish oil (incorporating >250 mg DHA plus 60 mg EPA) or placebo (olive oil) per day from birth to 6 months. The study determined that while infants within the fish oil group had significantly higher DHA concentrations in erythrocyte and plasma phospholipids at 6 months of age relative to the placebo group, there was no significant difference between standard or composite scores of the BSID-III (third edition) at 18 months or on outcomes from the Child Behavior Checklist. In a subtest which explored the development of infant communication skills (n = 185), the study found that scores for later developing gestures and total number of gestures were significantly higher in the fish oil group compared to the placebo group at both 12 and 18 months. This finding is interesting since gestural skills in infancy are associated with visual recognition memory, deferred imitation and turn-taking skills  use infant formula and are constrained by the consideration that their study samples have chosen not to breastfeed, thereby reducing external validity of the findings  in order to increase breast milk DHA . Yet the number of children in the DHA group with low cognitive scores (indicative of mildly delayed development) was significantly smaller in the treated group compared with the control group. In pre-planned secondary analyses, the DINO study found DHA supplementation had a significantly positive effect on cognitive outcomes in girls compared to boys. The reason for differences in response to DHA as a function of gender remains unclear but may be related to the higher rate of LC-PUFA synthesis that has been identified in females  double-blind RCT provided supplementation to lactating mothers  and delta-6 desaturase (D6D) and influence the efficiency with which shorter chain n-6) and dihomogamma linolenic acid  to desaturation products, including the LC-PUFAs   has also found long term neurocognitive benefits from breastfeeding to be gender specific , many researchers suggest that further work should be undertaken in order to better define optimal DHA intakes before and during infancy.DHA is known to play a critical role in the developing human brain and there is evidence of its neurobiological importance during infancy  and thereby derive potentially more reliable conclusions , many manufacturers of infant formula include DHA and AA in certain formulations and market them as \u201csuperior products\u201d which provide a distinct neurocognitive advantage (Simmer et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Ultrasound-mediated drug delivery under the guidance of an imaging modality can improve drug disposition and achieve site-specific drug delivery. The term focal drug delivery has been introduced to describe the focal targeting of drugs in tissues with the help of imaging and focused ultrasound. Focal drug delivery aims to improve the therapeutic profile of drugs by improving their specificity and their permeation in defined areas. Focused-ultrasound- (FUS-) mediated drug delivery has been applied with various molecules to improve their local distribution in tissues. FUS is applied with the aid of microbubbles to enhance the permeability of bioactive molecules across BBB and improve drug distribution in the brain. Recently, FUS has been utilised in combination with MRI-labelled liposomes that respond to temperature increase. This strategy aims to \u201cactivate\u201d nanoparticles to release their cargo locally when triggered by hyperthermia induced by FUS. MRI-guided FUS drug delivery provides the opportunity to improve drug bioavailability locally and therefore improve the therapeutic profiles of drugs. This drug delivery strategy can be directly translated to clinic as MRg FUS is a promising clinically therapeutic approach. However, more basic research is required to understand the physiological mechanism of FUS-enhanced drug delivery. The LTSL system showed a higher leakage of doxorubicin at 37\u00b0C, but a faster release of doxorubicin at 42\u00b0C compared to the TTSL system indicating that lipid composition plays an important role on stability and release profile  chains  and polyamidoamine G3 dendron-based lipids having Gdstration .In our group we have investigated the potential of an MRI labelled phospholipid/lysolipid containing liposome to accumulate in tumours and release the drug under conditions of mild hyperthermia induced by FUS.We label the liposome nanoparticles with a lipid that consists of a DOTA  headgroup  44, 45], 4544, 4Although most research studies have focused mainly in thermoresponsive liposomes and FUS activation of drug release, there is limited work on the use of polymers (thermoresponsive or not) and their application in FUS triggered drug delivery. The effect of ultrasound on drug release from polymers was studied in 1989 by Kost et al. and indeed the authors found that ultrasound can increase the polymer degradation rate leading to 20 times higher release rate. Interestingly the authors observed that the release rate increased in proportion to the intensity of ultrasound proposing that cavitation appeared to play a significant role . Triggered drug delivery using an external physical force provides the required control of drug deposition in certain tissues avoiding exposure of healthy tissues to high (toxic) concentrations. The trigger induced delivery should be acute and the effect induced on nontargeted tissues nondamaging and reversible. Hyperthermia induced by a means like ultrasound can be exploited as an external trigger in drug delivery , 47.Mild hyperthermia can be induced by pulsed FUS that can reduce extreme tissue heating by allowing the tissue to cool down between US exposures . The incFUS can also induce nonthermal effects on tissues. Acoustic cavitation can be induced using microbubbles exposed to US . AcoustiAn important application of HIFU and microbubbles lies in the area of altering the permeability of the blood brain barrier (BBB). In a study in 2002, Mesiwala et al. observed that HIFU could alter BBB permeability. HIFU induced reversible, nondestructive, BBB disruption in a targeted area and this opening reversed after 72\u2009h. The authors showed with microscopy that HIFU either entirely preserved brain architecture while opening the BBB, or generated tissue damage in a small volume within the region of BBB opening. Further electron microscopy suggested that HIFU disrupted the BBB by opening capillary endothelial cell tight junctions, a mechanism that was not observed in other methods used to open BBB . The effect of FUS on tight junctions' integrity was later confirmed in a study investigating rat brain microvessels after this BBB disruption. The authors used immunoelectron microscopy to identify tight junctional proteins such as occludin, claudin-1, claudin-5, and submembranous ZO-1 after sonication. They found substantial redistribution and loss of occludin, claudin-5 and ZO-1. However, claudin-1 seemed less involved. Monitoring the leakage of horseradish peroxidase (MW 40\u2009KDa) the authors observed that the BBB disruption appears to last up to 4\u2009h after sonication . In a laHynynen and colleagues investigated the BBB FUS enhanced permeability in rabbits. Rabbit brains were exposed to pulsed focused ultrasound while microbubbles were intravenously administered. The BBB opening was measured by an MRI contrast agent evaluating the local enhancement in the brain. The authors found that low ultrasound powers and pressure amplitudes were found to cause focal enhancement of BBB permeability. Trypan blue injected before animals were sacrificed indicated blue spots in the areas of the sonicated locations . The autMcDannold et al. tested the safety of this method by searching for ischemia and apoptosis in areas with BBB disruption induced by pulsed ultrasound in the presence of gas bubbles and by looking for posttreatment effects up to one month after sonication. Pulsed ultrasound exposures (sonications) were performed in the brains of rabbits under monitoring by MRI. BBB disruption was confirmed with contrast-enhanced MR images. Whole brain histologic examination was performed using staining for ischemic neurons and TUNEL staining for apoptosis. Tiny regions of extravasated red blood cells scattered around the sonicated locations, indicated capillaries. Despite these vasculature effects, only a few cells in some of the sonicated areas showed evidence of apoptosis or ischemia. The authors found that ultrasound-induced BBB disruption is possible without inducing substantial vascular damage that would result in ischemic or apoptotic death to neurons . The method could find application in the delivery of large therapeutic molecules that do not normally permeate the BBB. Herceptin (trastuzumab), a humanized anti-human epidermal growth factor receptor 2 (HER2/c-erbB2) monoclonal antibody, was delivered locally and noninvasively into the mouse central nervous system through the blood-brain barrier under image guidance by using an MRI-guided focused ultrasound. The amount of herceptin delivered to the target tissue was correlated with the extent of the MRI-monitored barrier opening, making it possible to estimate indirectly the amount of Herceptin delivered. The method could be used to treat breast cancer metastases to the brain . It was Delivery of small molecules can also be enhanced with the use of HIFU cavitation disruption of the BBB. Treat et al. demonstrated relatively high concentrations of doxorubicin in the brain with minimal healthy tissue damage effects. The authors observed that doxorubicin accumulation in nontargeted contralateral brain tissue remained significantly lower. MRI signal enhancement in the sonicated region correlated strongly with tissue doxorubicin concentration, suggesting that contrast-enhanced MRI could perhaps indicate drug penetration during image-guided interventions .Ktrans\u2061 (the transfer rate constant from the intravascular system to the extracellular extravascular space) values were calculated for a predefined volume of interest in the sonicated and the control area for each mouse. The results demonstrated that Ktrans\u2061 in the BBB-opened region was at least two orders of magnitude higher when compared to the contralateral (control) side [Konofagou and coworkers assessed the spatial permeability of the BBB-opened region using dynamic contrast-enhanced MRI (DCE-MRI) in mice. The authors processed DCE-MR images using the general kinetic model and the reference region model. Permeability maps were generated and the ol) side .There are several parameters to affect the level of BBB enhanced permeability and the endothelial tight junctions disruption; the pulse sequence comprising short bursts, the spacing between bursts or the rate of infusion of the microbubbles, and the size of microbubbles were found to affect the effect on BBB disruption , 70.The method could be applied for a number of therapeutic applications. The brain-derived neurotrophic factor (BDNF) was delivered to the left hippocampus in mice through the noninvasively disrupted blood-brain barrier (BBB) using focused ultrasound. The BDNF bioactivity was found to be preserved following delivery as assessed quantitatively by immunohistochemical detection of the pTrkB receptor and activated pAkt, pMAPK, and pCREB in the hippocampal neurons. It was shown that BDNF delivered this way induced signalling effects in a highly localized region in the brain . However it is the area of targeting brain tumours that have attracted most interest in the FUS disrupted BBB . Mei andLiu et al. investigated the delivery of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) to glioblastomas in rats with induced tumours with the help of FUS. The authors found that FUS significantly enhanced the penetration of BCNU through the BBB in normal and tumour-implanted brains without causing bleeding. Surprisingly, treatment of tumour-implanted rats with focused ultrasound alone had no beneficial effect on tumour progression. However, treatment with focused ultrasound before BCNU administration controlled tumour progression and improved animal survival relative to untreated controls .Liu and colleagues recently assessed FUS-mediated delivery of an iron oxide magnetic nanoparticle (MNPs) conjugated to an antineoplastic agent, epirubicin. They used MNPs because of the favourable MR imaging characteristics, which could facilitate imaging. They demonstrated a substantial accumulation of MNPs, as well as epirubicin, up to 15 times the therapeutic range in the brain when delivered with FUS. They further showed decreased tumour progression in animals with brain tumours that received MNP with epirubicin via FUS .111I-labeled AP1-Lipo-dox using microSPECT. The authors confirmed that sonication increased liposomal doxorubicin concentrations in tumour areas (murine glioblastoma) and that molecular targeting acts synergistically with FUS [Receptors targeting liposomal nanocarriers have been combined with MRgFUS to treat brain tumours. In a recently presented study it was shown that pulsed HIFU and human atherosclerotic plaque-specific peptide-1- (AP-1-) conjugated liposomes containing doxorubicin (AP-1 Lipo-Dox) acted synergistically in an experimental brain tumour model. Prior to each sonication, AP-1 Lipo-Dox or unconjugated Lipo-Dox were administered intravenously, and the concentration in the brain was quantified. Drug injection with sonication increased the tumour-to-normal brain doxorubicin ratio of the target tumours by about twofold compared with the control tumours. Moreover, the tumour-to-normal brain ratio was the highest after the injection of AP-1 Lipo-Dox with sonication. The results of this study indicate that combining targeting strategies can substantially enhance delivery of chemotherapy in the brain . In a sewith FUS . Targeted gene transfer into central nervous system was investigated using MRI-guided focused ultrasound-induced blood-brain barrier disruption. The results of this study showed that MRI-guided FUS achieved plasmid DNA transfer across the opened BBB furthermore plasmid ware internalized into the neurons presenting heterogeneous distribution and numerous transparent vesicles were observed in the cytoplasm of the neurons in the sonicated region, suggesting vesicle-mediated endocytosis. BDNF (and BDNF-EGFP) expressions were markedly enhanced by the combination of ultrasound and pBDNF-EGFP-loaded microbubbles about 20-fold than that of the control group. The method by using MRI-guided FUS to induce the local BBB disruption could accomplish effective targeted exogenous gene transfer in the CNS. In this study the microbubbles were used as the plasmid carrier. The investigators conjugated plasmid onto the surface of microbubbles and they coated these carriers using polymers in a layer by layer technique .An exciting application is the delivery of therapeutic stem cells to the brain using FUS to potentially treat neurodegenerative diseases, traumatic brain injury, and stroke. MRI guidance was used to target the ultrasound beam thereby delivering iron-labeled, green fluorescent protein (GFP) expressing neural stem cells specifically to the striatum and the hippocampus of the rat brain. Immunohistochemical analysis confirmed the presence of GFP-positive cells in the targeted brain regions suggesting that MRIgFUS may be an effective alternative to invasive intracranial surgery for stem cell transplantation .Although a very efficient approach, the use of microbubbles to enhance drug permeation through tissues, it may require significant safety consideration. In a key study in 2005 Prentice et al. presented clearly in a well-designed experimental setup that there are important interactions between individual cells and violently cavitating microbubbles leading to large pores in the cell membrane (sonoporation) . These eDuring the last few years there has been an expansion in research in MRgFUS drug delivery. The main dosage forms tested in MRgFUS drug delivery strategy are the thermosensitive liposomes and the lipid based microbubbles that can be conjugated with drugs or other liposomes on their surface , 81.There is limited research in the area of using other responsive materials or nanocarriers. Rapoport discussed recently the potential of using micelles and FUS  for enhaIt is clear that already established delivery systems such as different structurally nanocarriers have not been investigated in combination with image guided FUS. It would be interesting to see the effect of FUS on the enhanced permeability of micelles, polymers (dendrimers cyclodextrins), or metal nanoparticles (gold-iron) to tissues. Thermosensitive materials have been hardly explored in this field. Polymers or proteins that respond to small change of temperature could form suitable image guided FUS triggered platforms. The effects of FUS in biological tissues with or without carriers will require a more thorough investigation to understand the short- and long-term effects of ultrasound in the body and the complex environments such as tumours, blood vessels, and bone. The mechanism of FUS induced hyperthermia and/or the FUS tissue permeability increase is not well understood at cellular and molecular levels. There is limited knowledge on the effects of FUS on genomic DNA and if certain proteins are overexpressed after FUS treatment. In addition to the above, the frequency of FUS drug delivery treatments (or dosing) and the long-term effects in the body will have to be investigated in preclinical studies in order to design a FUS drug treatment regime. An imaging modality will have to be used for accurate image guided FUS therapy. In the case of MRI clinically approved contrast enhancing agents will have to be added to the delivery system to monitor carriers' distribution in the treatment area as well as efficient and rapid release. Considering the approval in clinical applications, such treatments will require the control of several factors such as drug and drug carrier, MRI contrast enhancing agents, and MRgFUS parameters, and this could mean several regulatory hurdles. However, the fact that most of the components  have been tested in clinical trials is encouraging for such approach to move forward. Most of the current strategies to increase tumour specificity of nanocarriers include the use of tumour biomarkers for either targeting (receptors) or for triggered release  and/or the use of external stimuli such as light and ultrasound. Biomarkers and internal stimuli may vary in different tumours indicating that such nanocarriers for cancer treatments should be \u201cindividualised.\u201d External stimuli can be used independent the tumours characteristics and therefore guarantee a more uniform effect. FUS can be used as an external stimulus to activate drug delivery in tissues. It also shows the significant advantages of being noninvasive as well as controlled and focused. Overall MRgFUS drug delivery is a novel and valuable tool to increase drug targeting and tissue specific drug delivery. It is expected that future studies will prove the clinical efficacy of MRgFUS drug delivery applications."}
+{"text": "In this study we report on our recent technological and data analysis advancements to investigate the propagation and the interplay of spontaneous and electrically evoked activities in cultured networks. To do so, a novel high density MEA with on-chip stimulating electrodes was realized. It provides whole-array recordings from 4096 electrodes  and electrical stimulation from 16 electrodes located every 8 recording sites. Here, this device was used to interface hippocampal neuronal networks. From the second week in vitro [Principal Component Analysis (PCA) we can properly reconstruct the time course of spatiotemporal propagations with a minimal set of three components (i.e. explaining ~90% of the variance of the trajectories). The PCA classification based approach allowed us to characterize both intrinsic and electrically evoked network-wide propagations. Interestingly, our results show that electrical stimulation can evoke (i) distinctive propagations that depend on the specific spatial-temporal properties of the stimulus as well as (ii) propagations that are already expressed in the intrinsic 'repertoire' of network bursts. Here we will discuss these results and our observations on the interplay between intrinsic and electrically evoked network-wide propagations.High density microelectrode arrays (MEAs) provide extracellular recordings from thousand of electrodes ("}
+{"text": "This leads to both impaired migration to the locus of infection and increased infiltration into healthy tissues. In order to better understand the pathophysiologic mechanisms involved, we developed a coarse-grained phenomenological model of the acute inflammatory response in CLP -induced sepsis in rats. This model incorporates distinct neutrophil kinetic responses to the inflammatory stimulus and the dynamic interactions between components of a compartmentalized inflammatory response. Ensembles of model parameter sets consistent with experimental observations were statistically generated using a Markov-Chain Monte Carlo sampling. Prediction uncertainty in the model states was quantified over the resulting ensemble parameter sets. Forward simulation of the parameter ensembles successfully captured experimental features and predicted that systemically activated circulating neutrophils display impaired migration to the tissue and neutrophil sequestration in the lung, consequently contributing to tissue damage and mortality. Principal component and multiple regression analyses of the parameter ensembles estimated from survivor and non-survivor cohorts provide insight into pathologic mechanisms dictating outcome in sepsis. Furthermore, the model was extended to incorporate hypothetical mechanisms by which immune modulation using extracorporeal blood purification results in improved outcome in septic rats. Simulations identified a sub-population (about  The pathophysiology of sepsis is complex and our mechanistic understanding remains incomplete. Mathematical models of the inflammatory response have been providing intellectual frameworks to reason about the complexity of sepsis. Due to an incompletely understood system along with very limited data, our approach focuses on building simplified, falsifiable and predictive models, and offers a means to quantify parametric uncertainty. Based on the construct that deterministic ensemble models exhibit population-like behavior, we developed a population-based computational framework that incorporates dysregulated neutrophil hyperactivity as a cellular dysfunction in septic processes. We hypothesize that probability distributions of physiological parameters conditional on population observations can characterize the range of possible physiologic responses in a population. Comparing the parameter ensembles from different phenotypes reveals some factors that play an important role in the expression of such phenotypes, such as sepsis survival. This framework can serve as an effective tool to gain insight into the pathophysiology of severe sepsis and generate testable hypotheses that guide future experiments. Our approach holds promise as a tool for integrating domain knowledge and experimental data into a quantitative assessment of population dynamics. Sepsis is defined as infection accompanied by signs of systemic inflammation, such as fever, tachycardia, tachypnea, or an abnormal white blood cell count primed by interacting with inflammatory mediators that have entered the circulation as a consequence of a large local production by dedicated tissue macrophages at the site of infection and subsequent spill over of these mediators in tissue capillaries. Primed neutrophils express integrins, surface molecules that can interact with similarly activated capillary endothelial cells, resulting in rolling and activation. Activated neutrophils adhere to endothelial cells followed by transmigration into tissue Adequate recruitment of neutrophils to sites of infection is one of the early and important features of a successful immune response. Mounting evidence suggests that severe sepsis is characterized by impaired neutrophil migration to the primary infected site and deleterious accumulation of neutrophils in distant, yet uninfected organs, resulting in organ dysfunction and death To better understand the pathophysiologic mechanisms involved, we developed a population-based computational framework that incorporates distinct neutrophil kinetic responses in a compartmentalized model of CLP -induced sepsis in rats. Experimentally constrained model ensembles were generated to represent a heterogeneous population, data uncertainty and other unexplained sources of variability. We previously showed that uncertain deterministic ensembles collectively exhibited population-like behavior and suggested deterministic ensembles could be a coarse-grained strategy to model population heterogeneity in silico platform for generating and testing immunomodulatory interventions for sepsis. Presumably, insight as to dominant mechanisms at work would guide the rational engineering of improved HA devices resulting in an enhanced impact on outcome.The primary motivation of this work is the experimental observation that one form of extracorporeal blood purification, known as hemoadsorption (HA), was found to be beneficial in animal models of sepsis, including endotoxic shock survivor and non-survivor populations) which describe distinct distributions of parameter sets consistent with their experimental observations and heuristics. These ensembles were statistically generated using Markov-Chain Monte Carlo (MCMC) sampling of their posterior parameter distributions. Convergence diagnostics was applied to support that the sampling process had reached equilibrium. Prediction uncertainties in the model states were quantified over the resulting ensemble.We developed a compartmentalized, coarse-grained phenomenological model of the inflammatory response to an invading pathogen in the specific context of CLP-induced sepsis in rats. Model parameters sets were optimized to reproduce the time courses of mean plasma measurements from a cohort of septic rats, while insuring that some basic heuristic behaviors of the system in accord with published literature were maintained Simulation of the model ensembles successfully reproduced experimental observations and desired heuristic behaviors, and suggests that systemic activation of circulatory neutrophils impair their migration to primarily infected tissue, while promoting sequestration in lung tissue favoring local damage and presumably, mortality. Statistical analysis of the model ensembles obtained for separate populations provided useful insights as to key pathologic mechanisms associated with mortality in sepsis.We next simulated a hypothetical blood purification intervention on the calibrated model ensemble. Simulations suggest that this therapy might improve targeting of primed neutrophils to the primary site of infection while interfering with lung sequestration of activated neutrophils, but that there is also a potential for harm in animal with poorly responsive immune systems.We hypothesized that dysregulated neutrophil trafficking in severe sepsis may contribute to mortality survival for in silico septic rats: at the end of the simulation time (200 hours), both the following constraints should be satisfied: (1) the number of bacteria  for each parameter The proposed model reproduced quantitative dynamic features observed in CLP-induced septic rats, verifying the description of the model reflects the inflammatory responses in CLP-induced septic rats . InsteadImpaired neutrophil migration to infected tissue and deleterious neutrophil accumulation in lung were predicted in the simulation of the non-survivor population. It should be emphasized that the model prediction of dysregulated neutrophil trafficking is an emergent property of the model since no neutrophil data were used to constrain model behavior  on the Hessian of the cost function. Hessians were approximated by inverting the empirical covariance matrices of the survivor and non-survivor parameter ensembles The model parameters and their correlations reflect the influence of internal and external factors on the model. To explore potential factors that can differentiate the survivor population from the non-survivor population, we analyzed and compared the model parameter ensembles derived from the survivor and non-survivor cohorts. In the setting of parameter estimation of complex models, it has been well recognized that model behavior is very sensitive to a few directions called panels B, C, D). Large absolute magnitude of a coefficient  imply major contributions of that parameter to the principal component direction. Deviations from the diagonal line indicate the parameters that lead to different behaviors between the survivor and non-survivor models. These comparative plots between the survivor and non-survivor populations reveal parameter subsets that characterize mechanisms associated with mortality in the non-survivor population. This is especially applicable to the first principal components, but not exclusively given the non-negligible nature of other components to total variability in The coefficients of the linear combinations of the original variables contributing to the first three largest principal components, which represents the individual parameter's contributions to the corresponding principal components, are illustrated in While the correlation matrix provides merely bivariate information, the inverse correlation matrix reveals true multivariate interactions. The diagonal elements of the inverse of the correlation matrix are directly related to the multiple correlation of each parameter with the other parameters lose correlation, gain correlation, and flip correlation (5 C). The parameter pairs in the lose correlation group significantly lose their partial correlations in the non-survivor population. gain correlation implies the opposite. The parameter pairs in the flip correlation group change their direction of correlations (positive or negative) between two population. Sixty percent of the significant changes are found in the lose correlation group, which confirms the previous finding that a loss of regulation (correlation) in the non-survivor population is associated with mortality. We also identified some key parameters that are frequently involved in the significant changes of pair correlations. Among them are parameters 19 (time constant for neutrophil migration), and 13 (time constant for neutrophil priming), suggesting again that coordinated neutrophil functions are critical for survival. The most significant loss of correlation was observed in the pair of parameters 13 and 1 (PI activation threshold by bacteria), suggesting that a positive correlation between the PI activation threshold and the time constant for blood neutrophil priming is essential for survival , high mobility group box1 (HMGB1), creatinine (CRT) and alanine aminotransferase (ALT) were measured from The CLP-induced sepsis experimental protocol is a recommended proxy for human sepsis, where the infection spreads beyond a local focus, resulting in systemic symptoms, septic shock and a high mortality The network components and interactions of the model were compiled from available information in the literature and the general domain knowledge about the acute inflammatory response. Ordinary differential equations (ODEs) governing the phenomenological signaling interactions in the network were formulated based on the standardized steps presented in The following equation describes the population of bacteria -inflammatory blood cytokines  are also nonlinearly mapped from a higher-level state variable, which represents the systemic damage abstractly.The hypothetic mechanisms of action of the blood purification was implemented by assuming the HA device eliminates only three components in the circulation: activated neutrophils . All other algorithms used for this work were implemented in the MATLAB version 7.10.0.499 (The MathWorks). The source code used in generating results is available at http://code.google.com/p/source-code-sepsis-model/.The numerical integration of the systems of ODEs described above was implemented by using the SUNDIALS package (stiff directions in the parameter space can be identified by the principal component analysis of the Hessian matrix The The inverse of the correlation matrix can also be used to extract valuable information in multivariate data"}
+{"text": "Survival rates following traumatic cardiac arrest (TCA) are known to be poor but resuscitation is not universally futile . There aA suggested algorithm for TCA was developed based on the Greater Sydney Area Helicopter Emergency Medical Service's standard operating procedures and current available evidence.2 <1.3 kPa carries a grave prognosis in TCA. Given the high incidence of hypovolaemia, hypoxia and obstructive shock prior to TCA, the role of adrenaline and chest compressions are limited. Figure An algorithm for the general management of TCA can be seen in Figure The suggested algorithm is designed for a highly trained physician-led prehospital team and aims to maximise the number of neurologically intact survivors in out-of-hospital TCA."}
+{"text": "The chest X-ray lung cancer screening program of Mayo Lung Project (MLP) yielded mixed results of improved lung case survival but no improvement in lung cancer mortality. This paper analyzes the smoking patterns of study participants in order to examine possible behavioral ramifications of periodic lung cancer screening. Using a longitudinal difference-of-difference model, we compared the smoking behavior, in terms of current smoker status among all subjects and the intensity of smoking among those continuing smokers, between those who received periodic lung cancer screening and those who received usual-care. In both arms of this lung cancer screening trial, there was a sizable decline in cigarette smoking one year after participants received baseline prevalence screening. There was no significant difference in current smoker status between the intervention group receiving periodic X-ray screening and the control group receiving usual care. While we detect that the continuing smokers in the intervention group smoked more than their counterparts in the control group, the magnitude of the difference is not sufficient to explain a substantial difference in lung cancer incidence between the two groups. Our study shows that periodic lung screening in MLP did not decrease smoking behavior beyond the observed decline following the initial prevalence screening conducted at baseline for both the intervention and control groups. Our results also indicate, paradoxically, that participants assigned to the intervention group smoked more cigarettes per day on average than those in the control group. Lung cancer screening programs need additional cessation components to sustain the abstinence effect typically observed following initial lung screening. The Mayo Lung Project (MLP) was a clinical trial conducted between 1971 and 1983. It involved random assignment of male smokers to either a periodic (every 4-6 months) chest X-ray lung cancer screening program versus a usual care program that included the \"treatment as usual\" (TAU) recommendation to be screened yearly. The two trial arms then went through a prevalence screening, where 9,211 subjects were diagnosed as cancer-free and thus eligible for staying in the study. Those in the intervention arm then received periodic chest roentgenograms and three-day \"pooled\" sputum cytology studies thrice a year while lung-health questionnaires were delivered to both arms of the trial. The MLP results were mixed inasmuch as participants in the periodic screening program demonstrated longer case survival but worse lung cancer mortality as compared with those in the usual care program [Surprisingly, no attention has been paid to the smoking behavior of MLP participants, even though smoking status has been shown to be the most important predictor of lung cancer incidence and survival. This study examines the interaction between periodic lung cancer screening and smoking behavior reported in the MLP in order to better understand the behavioral contributors to observed outcomes.It is well established that smoking cessation could significantly reduce smokers' lung cancer mortality . FurtherThe MLP tracked smoking behavior at baseline and then annually for six years . We adopWe first compared smoking behavior at baseline and the first-year follow-up, and in both trial arms we found a dramatic increase in smoking abstinence and a large decrease in number of cigarettes smoked per day. Of the 9,211 smokers enrolled in MLP, 690 quit smoking in the screening intervention group and 692 quit in the control group. On average, participants in the screening intervention group cut down on their daily smoking by 5.69 cigarettes (p < 0.001) while the control group decreased by 5.71 cigarettes (p < .001). In all, approximately 42% of participants in both groups reported a decrease in the number of cigarettes consumed. In the sixth year since MLP's baseline screening, 53.6% of the participants in the intervention arm and 57.0% of participants in the control arm reported a reduction of the number of cigarettes smoked per day compared to their baseline smoking intensity.Results from the mixed model indicated that the screening intervention had no significant impact on current smoker status when compared to the control group, and that smoking intensity declined less in the intervention group than in the control group Table . OverallAmong the many studies that have analyzed the MLP data, this study is the first to look at the smoking behavior of the participants. The finding here that smokers in the intervention arm smoked more than those in the control group does not necessarily constitute an argument against lung cancer screening. First, it is not plausible that a difference of one or two cigarettes a day could lead to significantly different health conditions among continuing smokers, and in our study no between-group differences were noted in rates of abstinence. Secondly, we did observe a sizable decline in smoking among all participants after the prevalence lung cancer screening was administered to both groups at baseline. Since it was then that some prevention counseling was given to participants, given what we know about the strong proven effect of counseling on smoking cessation , this laFrom the viewpoint of \"risk compensation\" (whereby people adjust their risk behavior to adapt for the changed risk), it is not surprising to see that smokers in the intervention group smoked more cigarettes per day than those in the control group. The human phenomena of behaviorally offsetting exogenous risk modification has been noted and interpreted in different disciplines like economics, psychology and risk analysis -22, inclThe authors declare that they have no competing interests.LS conceived the topic, performed the analysis and drafted the manuscript. MI provided improvement suggestions. All authors read and approved the final manuscript."}
+{"text": "Efforts to develop genetic marker based approaches to breeding forest trees began in the late 1980s. Approaches based on first generation of markers, allozymes, were not feasible due to the very limited number of markers (<50). The first DNA-based markers, RFLPs, brought more hope as moderately dense genetic maps could be constructed to scan the genome and map quantitative trait loci (QTLs). This approach was quite effective toward mapping QTLs in many forest tree species but the approach could not be brought to application in tree breeding due to low levels of linkage disequilibrium (LD) in forest tree breeding populations and recombination between flanking markers and QTLs with each generation. The next generation of DNA markers based of the polymerase chain reaction (PCR), RAPD, AFLP and SSR, did not solve the LD and recombination problem, even though more markers were available and throughput increased.The situation began to change in the early 2000s with the availability of automated DNA sequencing technology and single nucleotide polymorphism (SNP) genetic markers. Now association studies could be performed where SNPs within candidate genes controlling complex traits could be identified and thus \u201csolving\u201d or minimizing the LD and recombination limitation. This approach to complex trait dissection has been widely applied in forest trees and the early approach of QTL mapping in segregating populations has been mostly abandoned. The association genetic approach has been used to find candidate gene SNPs associated to a broad array of quantitative traits of interest . However, like QTL mapping before, individual SNP x trait associations only account for a small proportion of the variation  and the total variation explained by all markers is generally less than 50%. In human genetics, this situation is called the \u201cmissing heritability\u201d and there has been great debate over whether this problem can ever be solved in complex trait dissection in humans. In a few agricultural systems however, notably dairy cattle, researchers are now accounting for nearly all the heritable variation.Efforts to realize genomics-based breeding in conifer tree improvement in the US have culminated under a collaborative research project funded by the USDA. The Conifer Translational Genomics Network Coordinated Agricultural Project (CTGN CAP) has successfully brought genomics-based breeding to application in the four major cooperative forest tree breeding programs in the US. The project has completed the basic research on allele discovery of economic traits in conifers, conducted the translational research, and provided education and training to tree breeders to realize this goal during the four-year project period (2007 to 2011). Genomics-based breeding can now be applied to the production of over 1.3 billion loblolly pine, slash pine and Douglas-fir seedlings planted annually in the US.The CTGN CAP obtained high-density single nucleotide polymorphic (SNP) genotypes (over 7000 SNPs) on nearly 10,000 loblolly pine, slash pine, and Douglas-fir trees from the breeding cooperatives. These data were used to estimate molecular breeding values that can now be used to make selections as an alternative to breeding values based on mature traits that can take many years to the time of evaluation and can be expensive to measure in field tests. The CTGN CAP was the first to apply the advanced Illumina Infininium SNP-genotyping technology that is now being used in the breeding of most major crops such as corn, wheat, tomato, potato, and many more.The CTGN CAP culminates a long-term investment by the USDA in this team of researchers and their work on the technological advancement of tree breeding in the US. USDA\u2019s efforts began more than 20 years ago with funding of a series of grants under the National Research Initiative Plant Genome Program and continued under the CSREES IFAFS and AFRI programs. Recently, NIFA has awarded a grant to members of this team to conduct full genome sequencing in loblolly pine, sugar pine, and Douglas-fir. The full genome sequence will soon allow tree breeders to practice genomics-based breeding using genetic variation from the entire genome (genomic selection), and thus minimizing or even eliminating the missing heritability problem in forest trees. The partnership between USDA research programs and this team of researchers has resulted in a modernization of tree breeding technology in the US that will secure US competitiveness in the production of forest products."}
+{"text": "Interaural level difference (ILD) is the difference in sound pressure level (SPL) between the two ears and is one of the key physical cues used by the auditory system in sound localization. Our current understanding of ILD encoding has come primarily from invasive studies of individual structures, which have implicated subcortical structures such as the cochlear nucleus (CN), superior olivary complex (SOC), lateral lemniscus (LL), and inferior colliculus (IC). Noninvasive brain imaging enables studying ILD processing in multiple structures simultaneously.In this study, blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) is used for the first time to measure changes in the hemodynamic responses in the adult Sprague-Dawley rat subcortex during binaural stimulation with different ILDs.Consistent responses are observed in the CN, SOC, LL, and IC in both hemispheres. Voxel-by-voxel analysis of the change of the response amplitude with ILD indicates statistically significant ILD dependence in dorsal LL, IC, and a region containing parts of the SOC and LL. For all three regions, the larger amplitude response is located in the hemisphere contralateral from the higher SPL stimulus. These findings are supported by region of interest analysis. fMRI shows that ILD dependence occurs in both hemispheres and multiple subcortical levels of the auditory system. This study is the first step towards future studies examining subcortical binaural processing and sound localization in animal models of hearing. The ability to accurately determine the location of an object, such as a predator or prey, is critical to the survival and prosperity of humans and animals. One of the most important contributors to our ability to localize objects is the sound localization capabilities of the auditory system. Sound localization is of primary importance in situations where visual information is limited or not available, such as when the object is outside of the field of view or during darkness. The mammalian auditory system relies on monaural and binaural cues to determine the location of a sound emitting object Much of our understanding of the neural mechanisms behind sound localization has come from psychophysical and lesioning studies. Studies on human subjects show that our ability to resolve the direction of high frequency sounds depends on ILD In contrast, functional magnetic resonance imaging (fMRI) is the leading noninvasive functional imaging technique fMRI studies of ILD processing have focused on the role of cortical structures although earlier studies suggest subcortical structures have an important role. Subcortical fMRI of humans In this study, we apply BOLD fMRI to study ILD processing in the rat, an animal with more sensitive hearing than humans at high frequencies This study was carried out in strict accordance with the recommendations in the Guidelines for the use of Experimental Animals of the University of Hong Kong. All animal experiments were approved by the Committee on the Use of Live Animals in Teaching and Research of the University of Hong Kong (protocol number 2041\u201309). All experiments were performed under isoflurane anesthesia and all efforts were made to minimize suffering.Normal male Sprague-Dawley rats  were prepared as in our earlier rat fMRI studies Broadband sound was produced using ultrasonic loudspeakers , driven by waveform generators , and delivered to both ears via custom sound tubes A standard block-design stimulation paradigm, similar to that used in our earlier studies 2, matrix \u200a=\u200a64\u00d764, and six 1 mm thick slices along the coronal view with 0.2 mm gaps. A spin-echo sequence was chosen instead of a gradient-echo sequence to reduce image distortion in the ventral brain where numerous subcortical auditory structures are located. The localization of the middle four slices is shown in All fMRI experiments were performed in a 7T small bore MRI scanner  with a receive-only quadrature surface coil  placed over the dorsal side of the head. Scout images were first acquired to determine the orientation of the brain relative to the scanner and to determine the coronal view. Spin-echo echo planar imaging images were acquired with TR \u200a=\u200a2000 ms, TE \u200a=\u200a43 ms, field of view \u200a=\u200a32\u00d732 mmThe 140 images from each experiment were first realigned to the mean image of the first experiment using SPM8 . Images were then smoothed in-plane with a low pass filter with full width at half maximum of one voxel. The first and last slices were subsequently discarded to avoid truncation artifacts caused by image registration and the remaining slices were numbered one to four. Brain regions activated by auditory stimulation were identified on a voxel-by-voxel basis using standard period cross correlation analysis, which had been applied in recent rat fMRI studies Voxel-by-voxel computation of the BOLD signal ratios was performed as follows. Each fMRI image was first flipped horizontally and registered to the original image. BOLD signal maps were then computed for the original and flipped images. Each original signal map was divided by its flipped counterpart to obtain the BOLD signal ratio map. There was one ratio map for each ILD. Linear regression was performed on each voxel of the seven ratio maps to obtain a map of the slope of signal ratio vs. ILD . Positive slope indicated the signal was greater at positive ILDs or when left ear SPL was greater than right ear SPL. Similarly, negative slope indicated the signal was greater at negative ILDs.Regions of interest (ROIs) were also drawn around the cochlear nucleus, superior olivary complex/lateral lemniscus (a group of voxels that borders the SOC and LL), dorsal lateral lemniscus, and inferior colliculus in each hemisphere using the rat brain atlas The broadband sound stimulus presented to both ears activates auditory structures in both hemispheres. The symmetry of the activation patterns changes with ILD. ILD dependence is quantified by the BOLD signal ratio slope map shown in To complement the above voxel-by-voxel analysis, Consistent activation is observed with BOLD fMRI in the cochlear nucleus (CN), superior olivary complex (SOC), lateral lemniscus, and inferior colliculus (IC) of both hemispheres during binaural stimulation. There are no statistically significant interhemispheric differences observed in the responses of the CN, SOC, dorsal lateral lemniscus (DLL), ventral and intermediate lateral lemnisci (VLL), and IC at ILD \u200a=\u200a0dB. Voxel-by-voxel and ROI analyses indicate statistically significant (p<0.05) interaural level difference dependence in the SOC/LL , DLL, and IC with the larger BOLD signals located in the hemisphere contralateral from the ear receiving higher sound pressure level (SPL) stimulus.Invasive electrical recordings have been used to examine ILD encoding at the neuronal level in various auditory structures. Starting in the brainstem, the SOC receives ascending inputs from both ears. The neurons of the medial nucleus of the trapezoid body (MNTB) in the SOC receive inputs from the contralateral CN and relay them to the lateral superior olive (LSO), another SOC nucleus Neurons in the lateral lemniscus, the next structure along the ascending auditory pathway, receive inputs from both hemispheres of the SOC and the contralateral CN. The majority of DLL neurons fire at a higher rate when the SPL in the contralateral ear is increased relative to that in the ipsilateral ear Auditory cortex neurons express a diversity of ILD dependences Noninvasive fMRI is well suited for system level studies of ILD processing while electrical recordings are well suited for neuronal level studies. fMRI has been used to study auditory motion processing and sound localization using ILD cues in human subjects Auditory fMRI studies have recently begun to use rats as subjects. Initial studies observed that the structures of the ascending auditory pathway with detectible BOLD responses included the CN, SOC, LL, IC, medial geniculate body, and auditory cortex Neurons in the auditory system can be divided into two main classes, monotonic or non-monotonic. Monotonic neurons have sigmoidal plots of firing rate with SPL and non-monotonic neurons have maximum firing rate at a SPL The BOLD signal ratio slope in the cochlear nerve (CoN) in The ROI analysis used in Animals were permitted to breath spontaneously in this study, as in our earlier rat fMRI studies The responses of auditory neurons to binaural stimulation may depend on the average binaural level, the average of the SPL in the two ears, in addition to the ILD This study used continuous imaging, which was successfully employed in our earlier rat auditory fMRI study In this study, we performed fMRI using binaural stimulation with broadband sound to measure changes in the BOLD signal in both hemispheres and multiple structures of the rat subcortex during different ILDs. Consistent hemodynamic responses are observed in the cochlear nucleus, superior olivary complex (SOC), dorsal lateral lemniscus (DLL), ventral and intermediate lateral lemnisci, and inferior colliculus (IC). Voxel-by-voxel and ROI analyses indicate statistically significant (p<0.05) ILD dependence in the SOC/LL , DLL, and IC with the larger signal located in the hemisphere contralateral from the higher SPL stimulus. These results are in close agreement with those of electrical recording studies and suggest that rat fMRI studies of the subcortical processing of other sound localization cues such as interaural time differences and spectral differences are also possible. This study has shown that ILD processing occurs in both hemispheres and multiple subcortical levels of the auditory system and lays the ground work for studying sound localization mechanisms in animal models of hearing.Figure S1fMRI slice localization. fMRI slice localization overlaid on a sagittal scout image acquired at the midline of the brain. The four 1.0 mm thick fMRI slices , indicated by parallel solid lines and labeled 1 to 4, are oriented orthogonal to the sagittal plane as shown. The interslice gap is 0.2 mm. The locations of the inferior colliculus (IC) and thalamus at midline are indicated. The anterior, posterior, dorsal, and ventral sides of the brain are also indicated.(TIF)Click here for additional data file.Figure S2fMRI time courses. fMRI time courses measured from the cochlear nucleus (CN), SOC/LL, dorsal lateral lemniscus (DLL), and IC. SOC/LL refers to a group of voxels that covers parts of the superior olivary complex and lateral lemniscus. Regions of interest were those defined in (TIF)Click here for additional data file."}
+{"text": "Ateles geoffroyi) across five long-term field sites in Central America using a well established ethnographic cross-site survey method. Spider monkeys possess a relatively rare social system with a high degree of fission-fusion dynamics, also typical of chimpanzees (Pan troglodytes) and humans (Homo sapiens). From the initial 62 behaviors surveyed 65% failed to meet the necessary criteria for traditions. The remaining 22 behaviors showed cross-site variation in occurrence ranging from absent through to customary, representing to our knowledge, the first documented cases of traditions in this taxon and only the second case of multiple traditions in a New World monkey species. Of the 22 behavioral variants recorded across all sites, on average 57% occurred in the social domain, 19% in food-related domains and 24% in other domains. This social bias contrasts with the food-related bias reported in great ape cross-site comparison studies and has implications for the evolution of human culture. No pattern of geographical radiation was found in relation to distance across sites. Our findings promote A. geoffroyi as a model species to investigate traditions with field and captive based experiments and emphasize the importance of the social domain for the study of animal traditions.Cross-site comparison studies of behavioral variation can provide evidence for traditions in wild species once ecological and genetic factors are excluded as causes for cross-site differences. These studies ensure behavior variants are considered within the context of a species' ecology and evolutionary adaptations. We examined wide-scale geographic variation in the behavior of spider monkeys ( Traditions in wild populations are defined as \u201cenduring behavior patterns shared among members of a group that depend to a measurable degree on social contributions to individual learning, resulting in shared practices among members of a group\u201d Ateles spp.) are well suited for a study of traditions because they possess several characteristics thought to promote social learning. Firstly, infants and juveniles are slow to develop compared to monkeys of a similar size and lifespan Pan troglodytes), bonobos (P. paniscus) and humans (Homo sapiens) A. geoffroyi comprises a number of gestures including embracing and pectoral sniffing, that likely function as greetings Spider monkeys (Cebus capucinus), documenting variation in behaviors involving extractive foraging and tool-use has been a main focus of previous cross-site primate studies With the exception of Perry et al. 's sensu McGrew Ateles with the skills needed for their highly arboreal lifestyle and specialized locomotion Of the three features that are fundamental for material culture (Scaptotrigona spp.) eating Ateles behavioral repertoire, but offer no indication that these behaviors are either learned socially or, in the case of tool-use, are being successfully transmitted between individuals. The aim of our study was to provide the first systematic evidence for traditions in spider monkeys, using a large sample of candidate behaviors across five distantly located populations of the same species with special emphasis on the domains in which the traditions occur. The similarity of their social system with that of humans To our knowledge, no systematic study of traditions across different populations of spider monkeys has been carried out, although several publications suggest potential behaviors that could show inter-community variation and patterns of transmission via social learning, including meliponid bee  study sites further highlights species differences in the distribution of traditions across domains. The mean percentage of traditions in the social domain across the nine chimpanzee study sites and across the six orangutan study sites was 42% and 34% respectively, which is lower than the mean value across the five spider monkey sites \u200a=\u200a0.04, p\u200a=\u200a0.914], or the number of absent behaviors shared between each pair of sites  , killer whales (Orcinus orca) and guppies (Poecilia reticulata)We documented behavioral variation across five populations of spider monkeys providing evidence for traditions, which is relevant for a better understanding of human cultural evolution A larger proportion of the 22 identified traditions belonged to the social domain. This may partially be a reflection of the species' behavioral repertoire, which includes a large number of social behaviors Watson and Caldwell Ficus root\u2019 performed by multiple individuals only in the Santa Rosa community, the selection for community identity through this marking variant may have led to a form of ritual, where most subgroup members are simultaneously involved. There was variation in the percentage of traditions in the social domain (43\u201367%) across the five study sites. Higher variation (0\u201364%) occurred across chimpanzee communities. It would be interesting to assess whether such variation is associated with variation in the degree of fission-fusion dynamics across populations. Additionally, a within-population examination of behavioral variation, where genetic and ecological differences between communities are likely to be negligible, would provide more detailed evidence for such social learning opportunities and potential traditions .Social behaviors have, by their very nature, a shared and often public quality, which is not necessarily the case for food-related or other subsistence-based behaviors as they are not reliant on the presence of at least one other individual to be performed The community identity hypothesis to partially explain the bias of traditions toward the social domain in spider monkeys does not however account for the large number of greeting behaviors that did not meet the criteria for traditions and were listed as \u2018universal\u2019. It is noteworthy that several of these greeting variants may involve high risk, such as embraces and pectoral sniffs, which involve close body-contact and leave the recipient vulnerable to bites Ateles species, A. geoffroyiGenetic variation across the site populations invariably exists. Whilst it is impossible to eliminate genetic variation in wild populations, it was minimized in this study by only examining individuals of one of the four Chlorocebus aethiops), individuals of the philopatric sex are preferred demonstrators of behavior than individuals of the migrating sex, and as a result of this selection highly localized traditions can emerge The geographic distribution of traditions may reflect patterns of innovation, diffusion and transmission, which can be affected by factors such as the dispersal of individuals between communities and restrictions imposed by geographical features Phoradendron leaf or rock feeding conveys a selective advantage for spider monkeys in communities where it is practiced over individuals in communities where it is not practiced. The consumption of the widely available Enterolobium cyclocarpum fruit by individuals only in Corcovado and Punta Laguna suggests another example of a feeding variant which conveys nutritional advantages for individuals that feed upon it over individuals that do not, although, it is always possible that other communities compensate by eating another food resource Whiten Enterolobium cyclocarpum can be unpredictable Site specific consumption of widely available food resources illustrates how ecological conditions may impact to promote or hinder innovation, or the subsequent maintenance of socially transmitted behaviors. Opportunities to innovate may be influenced by the accessibility of associated substrates or social resources which may be seasonal, rare or highly unpredictable in their availability In other species, captive and field based experiments have been instrumental in complementing findings from cross-site comparison studies and are invaluable for exploring social learning mechanisms and transmission processes The study was carried out in the field with free-ranging monkeys and was completely observational. Research was conducted at all times in accordance with the laws of participating countries. Approval and permission to conduct research was granted by the University of California IACUC committee, the Animal Studies Committee of Washington University # 20020071, the University of Chester Psychology Department Ethics Committee and approved by the University of Chester Animal Ethics Committee, the Animal Care Certification in compliance with the Canadian Council on Animal Care, the Costa Rica Ministry of Environment and Energy (MINAE) permit #s 418-2001-OFAU, 226-2002-OFAU and ACG-PL-030-2006, the Belize Forest Department permit # CD/60/3/09(05) and the Mexican government under the auspices of Pronatura, Peninsula de Yucatan, A.C. (PPY) # 1577105.A. geoffroyi was carried out were considered in our study, in order to minimize genetic influences on any behavioral variations observed. Five sites were selected for the study . Then, the list was reviewed by researchers at all participating field sites and care was taken to ensure researchers accurately identified behaviors across sites. This was achieved using detailed descriptions, photographs and video clips to clarify behaviors nuances. Based on the joint feedback, additions or consolidations of behaviors were made, leading to a final list of 62 behaviors ; and unknown - insufficient opportunity to observe a behavior to reliably know if it was present or absent. This last category was especially relevant for behaviors that require rare conditions or might be less likely to occur in the presence of observers, despite habituation.The survey consisted of two phases. Phase I required researchers to document the presence or absence of each of the 62 behaviors at their field site. Categories based on the following definitions were used: customary - behavior occurs in all or most able-bodied members of at least one age-sex class ; habitual - behavior is not customary but has occurred repeatedly in several individuals, consistent with some degree of social transmission; and present - behavior is neither customary nor habitual, but is performed multiple times by at least two individuals. Thus, in phase II performance of a behavior by only one individual at one site was classified as \u2018absent\u2019. A behavior variant was considered to be a tradition when it occurred at a habitual or customary level in at least one site while being absent in at least one other site without an ecological explanation Phase II required researchers to classify each observed behavior at their field site using one of the categories based on the following definitions derived from Whiten et al. Pearson correlations between the number of shared customary/habitual or absent behaviors and the distance between each pair of sites were run using SPSS v.15.0.Figure S1Ateles geoffroyi hand showing dramatic reduction in pollex  (Photograph by Claire J. Santorelli). Photograph illustrates area of reduced pollex on the left hand.(TIF)Click here for additional data file.Figure S2Map of Central America showing locations of the five field sites participating in the study. Arrows illustrate location of participating field sites within their host country.(TIF)Click here for additional data file.Table S1Definitions and domains of the 62 behaviors considered in the study.(DOC)Click here for additional data file.Table S2Prevalence of behavior variants across study sites.(DOC)Click here for additional data file.Table S3Distance (kilometers) between sites .(DOC)Click here for additional data file.Table S4Site information.(DOC)Click here for additional data file."}
+{"text": "In this study, we have used equilibium contrast CMR (EQ-CMR) to assess the interstium volume of patients after atrial redirection surgery, finding higher amounts than in healthy volunteers and correlations with known clinical markers of disease.After atrial redirection surgery (the Mustard and Senning operations) for transposition of the great arteries (TGA) the systemic right ventricle (RV) suffers from late systolic failure with resultant high morbidity and mortality. The mechanisms of late systemic RV failure are poorly characterised. We hypothesised that diffuse interstitial expansion representing diffuse fibrosis would be greater in the right ventricles of patients following Mustard or Senning surgery and that it would be associated with other markers of heart failure and disease severity in these patients.We used Equilibrium Contrast CMR to quantify interstitial expansion,Vd(m), in the septum and RV free wall of 14 consecutive adults presenting to a tertiary specialist clinic late after palliative surgery for TGA ). These were compared to an equal number of age and sex matched healthy volunteers from a denominator normal population of 86. Patients were also assessed with a standardised CMR protocol, NT-proBNP and cardiopulmonary exercise (CPEX) testing.Mean septal Vd(m) was significantly higher in the patients than in the control population . NT-proBNP was positively related to septal Vd(m)  was difficult to measure  with high and poor inter-observer reproducibility such that this analysis was abandoned.In this small preliminary study, septal interstitial expansion is seen in adults late after atrial redirection surgery for TGA. It correlates well with NT-proBNP and chronotropic incompetence and may have a role in the development of RV systolic impairment. Measuring interstitial expansion in the RV free wall is difficult using this methodology.British Heart Foundation."}
+{"text": "Differential expression analysis of digital gene expression data involves performing a large number of hypothesis tests that compare the expression count data of each gene or transcript across two or more biological conditions. The assumptions of any specific hypothesis-testing method will probably not be valid for each of a very large number of genes. Thus, computational evaluation of assumptions should be incorporated into the analysis to select an appropriate hypothesis-testing method for each gene.Here, we generalize earlier work to introduce two novel procedures that use estimates of the empirical Bayesian probability (EBP) of overdispersion to select or combine results of a standard Poisson likelihood ratio test and a quasi-likelihood test for each gene. These EBP-based procedures simultaneously evaluate the Poisson-distribution assumption and account for multiple testing. With adequate power to detect overdispersion, the new procedures select the standard likelihood test for each gene with Poisson-distributed counts and the quasi-likelihood test for each gene with overdispersed counts.The new procedures outperformed previously published methods in many simulation studies. We also present a real-data analysis example and discuss how the framework used to develop the new procedures may be generalized to further enhance performance."}
+{"text": "The title of the Symposium was \u201cEnvironmental Contaminants and Animal Health\u201d and the focus was on the insidious health risks posed to both humans and animals (wild & domestic) by the often ubiquitous synthetic and biological environmental chemicals. The scientific programme consisted of five overview-type keynote speeches along with a total of twelve invited talks on specific topics. The presentations addressed the \u201cclassical\u201d but still today highly pertinent environmental toxicants such as dioxins, PCBs and other persistent organic compounds; emerging contaminants such as diverse endocrine disruptors; biological toxins such as mycotoxins; and up-to-date biological assay methodologies available for detection and quantification of these environmental hazards. This special issue of Acta Veterinaria Scandinavica contains abstracts or full-length papers of the presentations given in the Symposium. The interested reader should notice that even for most of those presentations of which only the abstract is included here, the original slides (in pdf-format) can be found at the NKVet web site (http://www.nkvet.org/index.php?id=11).The 26"}
+{"text": "Dictyostelium, enables the rapid ablation or over-expression of genes, and the subsequent use of isogenic cell culture for the analysis of cell signalling pathways in pharmacological research. The model also supports an increasingly important ethical view of research, involving the reduction, replacement and refinement of animals in biomedical research. This review outlines the use of Dictyostelium in understanding the pharmacological action of two commonly used bipolar disorder treatments . Both of these compounds regulate mitogen activated protein (MAP) kinase and inositol phospholipid-based signalling by unknown means. Analysis of the molecular pathways targeted by these drugs in Dictyostelium and translation of discoveries to animal systems has helped to further understand the molecular mechanisms of these bipolar disorder treatments.Understanding the mechanisms of drug action has been the primary focus for pharmacological researchers, traditionally using rodent models. However, non-sentient model systems are now increasingly being used as an alternative approach to better understand drug action or targets. One of these model systems, the social amoeba  The following review will introduce bipolar disorder and Dictyostelium as a biomedical model. The review will then focus on two of the most widely used bipolar disorder treatments \u2013 valproic acid (VPA) and lithium \u2013 by firstly outlining current knowledge of cell signalling pathways regulated by each treatment, and then illustrating the use of Dictyostelium  to enhance our understanding of putative bipolar disorder-dependent cell signalling changes in both pathways.Bipolar disorder, a neurological condition that causes cyclic variation in mood, gives rise to a devastating effect on quality of life and significantly increases the chance of suicide 2Bipolar disorder  is a neurological condition giving rise to cyclic and extreme changes in mood. The two most widely occurring types of bipolar disorder are characterised by slightly different re-occurring states: type 1 describes recurrent mood swings from depression to mania, whilst type 2 describes recurrent mood swings from depression to euthymic (stabilised mood) behaviour or mild forms of mania Current treatments for bipolar disorder include lithium, anticonvulsant drugs , valproic acid (Depakote), gabapentin (Neurontin) and lamotrigine , antidepressants such as bupropion (Wellbutrin) or sertraline (Zoloft), neuroleptics  and benzodiazepines (e.g. lorazepam). These treatments require continuous long-term use and are thus non-curative. A decision on which treatment to use is normally based on individual symptoms. Poor response rates to drug treatment  occur in approximately 35\u201350% of patients, with significant side effects that often lead to non-adherence \u2022Genetics: Identifying the genetic basis of bipolar disorder is likely to provide the ultimate origin of the condition and is thus a fundamentally important approach. There is clear evidence that the occurrence of bipolar disorder has a strong genetic component \u2022Biochemistry: Understanding physical changes in individuals with bipolar disorder may provide an avenue to identify the molecular basis of the condition. For example, recent studies have shown bipolar disorder-dependent changes in brain volume \u2022Pharmacology: The identification and characterisation of changes in cell signalling caused by bipolar disorder treatments may both identify the molecular mechanism causing bipolar disorder, and enable the development of more efficacious treatments or treatments with reduced side effects. The vast array of genetic risk factors associated with bipolar disorder occurrence is expected to give rise to changes in only a limited number of signalling pathways that are then controlled by a small number of current bipolar disorder treatments. Thus understanding bipolar disorder-associated signalling pathways may help the treatment of patients with a wide array of causative factors. However, this approach is also complex since bipolar disorder treatments have numerous effects and/or targets, and the primary sites of action are often unknown. The majority of research into the molecular basis of bipolar disorder treatments has centred on valproic acid (VPA) and lithium.Research into bipolar disorder remains a hugely complex undertaking. This is primarily since there are no well accepted models for the condition 3Dictyostelium discoideum is one of these models listed as one of ten non-mammalian biomedical models recognised by the US National Institutes of Health (NIH). Dictyostelium is more complex than other models listed such as Sacchromycies cerevisiae (baker's yeast), Schizosaccharomyces pombe (fission yeast) or Neurospora crassa (filamentous fungus) since Dictyostelium cells undergo chemotactic and random movement. It also has rudimentary development mechanisms and related signalling pathways. On the other hand, Dictyostelium is simpler than other models listed such as Caenorhabditis elegans (round worm) and Drosophila melanogaster (fruit fly), Danio rerio (zebrafish), and Xenopus tropicalis (frog) since it lacks the much more complex developmental processes involved in the formation of these animals and lacks their basic neurological networks. Dictyostelium has evolved a strong niche for studies into cell movement and development The use of invertebrate, non-sentient model organisms can facilitate our understanding of the mechanism of drug action on cellular level whilst reducing the use of animals in research. Dictyostelium can be cultured by either growth in nutrient rich media (ingesting media via macropinocytosis) or in association with bacteria as a food source , and will continue to divide by binary fission until food or nutrients are depleted. Thus, in the presence of sufficient nutrients, large quantities of isogenic cells can be cultured and used for biochemical or cell signalling studies  and aggregation of \u223c100 000 cells to a single point, followed by a primitive developmental process leading to the formation of distinct cell types  in a mature fruiting body ( studies . Dictyosing body . This deDictyostelium has been fully sequenced Dictyostelium genome include a high AT/GC ratio (86:14) and an average open reading frame of 1756\u00a0bp with 1.9 introns per gene. Thus, Dictyostelium provides a simple model system that is well-characterised at a genetic level.The haploid genome of this Dictyostelium as a pharmacological and pharmacogenetic molecular model for VPA and lithium was initially based upon the observation that both drugs block development, thus enabling a range of studies to understand their mechanism(s) of action , that was accidently discovered to function in seizure control in the early 1960s de novo inositol synthesis 3) Not surprisingly, this gamut of therapeutic roles for VPA has been associated with a variety of cellular mechanisms. These range from increasing gamma aminobutaric (GABA) levels 5The mechanism of action for lithium has been of considerable interest since its re-discovery as a bipolar disorder treatment by Cade Despite the simple nature of this molecule (the third element on the periodic table), it still remains unclear how lithium functions in its therapeutic action. However, it has been widely shown to regulate four signalling pathways potentially associated with bipolar disorder: the inhibition of the enzyme glycogen synthase kinase (GSK3) A pharmacological approach to understand how VPA and lithium regulate cell signalling therefore requires the understanding of how these various pathways are modulated, and what genes and pathways are responsible for these drug effects. Here we will focus on the regulation of the MAP Kinase pathway and the inositol and phosphoinositol-dependent pathways.6Bipolar disorder has been associated with changes in neurotrophic signalling cascades, neuronal cellular atrophy and regional reductions in brain volume Lithium and VPA treatment have been shown to reverse or attenuate brain structural changes found in bipolar disorder Dictyostelium has shown that both VPA and lithium also up-regulate the activation of the MAPK pathway 3 production . However, a range of experiments suggested that VPA may function through blocking de-phosphorylation of pERK2  shows improved efficacy in seizure control Dictyostelium  induced a common change in mammalian neurons, and that this change could be reversed by the addition of exogenous inositol or by inhibition of PO activity , responsible for breakdown of InsP4\u20136, resulted in reduced InsP3 levels, whereas MIPP over-expressing cell extracts had an enhanced activity compared to wild type controls. MIPP activity was necessary for PO-inhibition dependent inositol phosphate regulation both in chemotaxis and in the production of InsP3. These data clearly establish PO as the regulator of MIPP activity. However, surprisingly, over-expression of MIPP gave a lithium hyper-sensitive phenotype.The mechanism of lithium-dependent inositol phosphate regulation has recently been further characterised in de novo synthesis of inositol. The increase in gene expression was also observed following both genetic and pharmacological inhibition of PO activity. However in all cases, this increased expression was dependent upon the presence of MIPP activity and was also induced by over-expression of the kinases responsible for the production of InsP4\u20136 from InsP3. Thus this work identified a gene regulatory mechanism where the activation or over-expression of MIPP leads to elevated expression of a range of inositol regulation genes in Dictyostelium. The results were then successfully translated to human cells (HEK293) to demonstrate that PO inhibition also up-regulates several IMPase genes and that this elevation is dependent on MIPP activity. It is of interest that IMPase polymorphisms have been associated with risk of bipolar disorder in family studies The origin of lithium hyper-sensitivity in cells over-expressing MIPP was found to be due to the elevated expression of a range of genes related to inositol signalling DictyosteliumDictyostelium cell movement, we investigated the role of phosphoinositide signalling as a target for VPA action Dictyostelium employed cells transformed with a PIP3 binding protein (PHcrac-GFP) enabling the time- and location-dependent monitoring of PIP3 production. VPA produced an acute (10\u00a0min) reduction in PIP3 production, also shown by reduced PIP2 and PIP levels using in vivo radio-labelling experiments P3). This data, for the first time, implicated phosphoinositide signalling as a potential target for bipolar disorder treatments. Considerable evidence suggests that elevated phosphoinositol signalling may be an underlying cause of bipolar disorder since a variety of studies have identified this effect in bipolar disorder drug-free patients A new mechanism of action for bipolar disorder drugs has been recently proposed based upon work in eriments , creatinDictyostelium has now extended the observation that bipolar disorder-treatment attenuates phosphoinositide-mediated signalling Dictyostelium cell line lacking all five PI3K genes 3, was also decreased following lithium treatment compared to untreated cells. Furthermore, these effects also occurred in conjunction with a decrease in the rate of PIP and PIP2 synthesis, although no changes in steady-state concentration of PIP2 levels were detected. This may be due to a small rapidly turned over pool of PIP2 that is quickly metabolised during chemostaxis providing a lithium sensitive target. Since the mechanism for inositol signalling attenuation by lithium is known to function through the uncompetitive inhibition of IMPase and IPPase 2 synthesis and PkbA phosphorylation. The results were then successfully reproduced in a human neutrophil cell line (HL60) where the translocation of a PIP3-binding GFP construct to cell membranes (as a readout for PIP3 production) was reduced following lithium treatment. Based on these studies in Dictyostelium investigating both VPA and lithium mechanisms of action, we can now propose a new extension of the current of inositol depletion hypothesis, whereby bipolar disorder treatments give rise to attenuated phosphoinositide signalling.Recent work on the effects of lithium on 8Dictyostelium provides distinct advantages.To help those diagnosed with bipolar disorder, ongoing research endeavours to identify the cell signalling changes that are targeted by the pharmacological agents, valproic acid and lithium. This approach overcomes the multitude of potential loci implicated in the aetiology of the disorder, but instead focuses on understanding the mechanism(s) leading to symptomatic control. It also enables the identification of new compounds that may be more efficacious or have reduced side effects in bipolar disorder treatment. Research in this area has traditionally used rodents as model organisms, however the increasing use of other simple model systems such as Dictyostelium and the animal brain respond by elevating pERK2 levels in the MAPK pathway. Analysis of this effect in Dictyostelium has proposed two mechanisms: VPA regulates increased pERK2 levels through inhibition of cAMP/PKA signalling, whereas lithium inhibits GSK3/A, with both effects leading to the reduced dephosphorylation of pERK2. The strong structural specificity of this effect in regards to VPA suggests novel compounds may be identified that show improved efficacy for MAPK regulation.Investigation of cell signalling regulated by VPA and lithium demonstrate that both Dictyostelium is the reduction of inositol-dependent signalling. Recently studies have suggested that cellular inositol phosphate levels are controlled by both inositol recycling and the MIPP-catalysed breakdown of higher-order inositol phosphate compounds (InsP4\u20136) regulated by prolyl oligopeptidase activity. This work has also discovered a transcriptional-based effect, whereby lithium treatment gives rise to altered transcriptional regulation of inositol-signalling related genes. In addition Dictyostelium-based research has discovered a potential key pharmacological target of VPA and lithium in attenuating phosphoinositol signalling, with both drugs causing an acute attenuation of phosphoinositol turnover. In the case of lithium, it is likely that this effect is through inositol signalling attenuation, whereas the mechanism controlled by VPA remains to be determined. These discoveries open up a exciting field of phosphoinositol research, with the promise of new therapies (based around the structure of VPA) showing increased efficacy in phosphoinositide regulation.Another cell signalling effect of VPA and lithium in Dictyostelium as a simple biomedical model for this research. A better understanding of these cell signalling changes may ultimately identify the underlying causes of bipolar disorder and will enable the development of better therapeutic treatments.This review has summarised current research aimed at unravelling the complex mechanisms of VPA and lithium in regulating cell signalling, and the important role of"}
+{"text": "The research on T cell immunosuppression therapies has attracted most of the attention in clinical transplantation. However, B cells and humoral immune responses are increasingly acknowledged as crucial mediators of chronic allograft rejection. Indeed, humoral immune responses can lead to renal allograft rejection even in patients whose cell-mediated immune responses are well controlled. On the other hand, newly studied B cell subsets with regulatory effects have been linked to tolerance achievement in transplantation. Better understanding of the regulatory and effector B cell responses may therefore lead to new therapeutic approaches. Mesenchymal stem cells (MSC) are arising as a potent therapeutic tool in transplantation due to their regenerative and immunomodulatory properties. The research on MSCs has mainly focused on their effects on T cells and although data regarding the modulatory effects of MSCs on alloantigen-specific humoral response in humans is scarce, it has been demonstrated that MSCs significantly affect B cell functioning. In the present review we will analyze and discuss the results in this field. B cells are a major cell type involved in adaptive immune responses, specialized in antigen presentation and antibody production. The balance between the different B cell subsets has been identified as an important factor for graft outcome. On one hand, effector B cells generate humoral rejection and pre-formed donor-specific antibodies (DSA) against human leukocyte antigen (HLA)-I or HLA-II that have been correlated to worst graft outcome. On the other hand, pro-tolerogenic B cell subsets have been identified. An increase in immature transitional and na\u00efve B cells has been related to tolerance  in recipients compromises long-term allograft survival  are expressed by transitional B cells, which are considered to be tolerogenic. Moreover, there is evidence of a subset of B cells with anti-inflammatory properties and the ability to secrete IL10, which down-regulation is known to be involved in the development of autoimmune diseases , antibody depleting strategies (plasmapheresis), plasma cell depleting agents , or complement-inhibitor agents (Eculizumab) have been reported to be efficient in promoting graft survival  induction therapy  and the stimuli used to trigger B cell differentiation and proliferation. MSC: B cell ratio is also an important point, as the most effective ratios used are very high and it is hardly observed a dose dilution effect, contrarily to what happens with the immunosuppressive effect of MSCs on T cells  the effect is diverse depending on the stimuli used to induce proliferation and/or differentiation.The activation of na\u00efve B cells requires three signals: B cell receptor (BCR) activation (via anti-Ig), T cell co-stimulatory help (via CD40/CD40L), and appropriate cytokines or toll-like receptor (TLR) activation , while memory B cells can be activated in the absence of BCR stimulation and triggered via stimulation of TLR or bystander T cell help only  models treated with MSCs.However, we also find some disparity in the results obtained in vitro effects of MSC on B cells, there are contradictory reports on the effects of MSC on B cells in animal models.Similar to the controversial + plasma cells in the bone marrow of MSC treated mice are also increased (Table Different groups have approached the treatment of a SLE model with MSCs. A single injection of human BM-MSCs combined with cyclophosphamide (CTX) increased survival, decreased proteinuria, and reduced the levels of circulating anti-dsDNA IgG in a MRL/Lpr mice model , there is evidence that MSC may be capable of inducing an adaptive immune response  induced substantial alloantibody production  in contrast to syngeneic cells injection in an immunocompetent host  developed alloantibodies  after hematopoietic stem cell (HSC) transplantation, none of them developed anti-MSC antibodies  in a rat kidney transplantation model is that the injected animals do not develop specific anti-MSCs antibodies while they do increase antibody levels against the third party when they are injected with the full fraction of bone marrow mononuclear cells , the number of injected cells, the number of injections, the route of administration or concurrent immunosuppression used. More The role of B cells in transplantation is multifaceted due to the opposed roles of different B cell subsets in tolerance and rejection. This enlightens the need for more refined immunosuppressive regimens to treat humoral rejection without compromising the effect of the pro-tolerogenic B cell subsets, namely transitional and regulatory B cells.Mesenchymal stem cells have proven immunomodulatory properties, suppressing inflammatory cell  functions, and differentiation and increasing or synergizing with regulatory cells such as Tregs.Their effect on B cells has been scarcely studied and although the results obtained are contradictory so far, it seems clear there is a close interaction between MSC and B cells. It appears that this interaction occurs partly through the modulation of T cell help by MSCs, but also in the absence of helper cells MSCs can inhibit activated B cells. The study of this threesome relation is of special interest in the transplantation setting. Another interesting point that remains to be studied is the potential of MSCs to induce pro-tolerogenic B cell subsets that have themselves proved immunomodulatory properties.The potential of MSCs in B cell immunomodulation appears to be promising and not fully understood. The advent of new and well designed studies can give important insights to fully picture the therapeutic role of MSCs in B cell mediated rejection.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Dental caries is one of the most prevalent chronic diseases affecting children in Sub-Saharan Africa. Previous studies show a higher prevalence of dental caries in children from low socio-economic status backgrounds. The purpose of this study was to determine the prevalence of dental caries among 12 year old children in urban and rural areas of Zimbabwe and establish preliminary baseline data.A descriptive cross-sectional study was conducted among 12 year old children at primary schools in Harare and Bikita district. A Pre-tested questionnaire was administered to elicit information from the participants on tooth cleaning, dietary habits and dental experience. Dental caries status was assessed using the DMFT index following World Health Organization (WHO) guidelines.Our results showed a high prevalence of dental caries in both urban (59.5%) and rural (40.8%) children. The mean DMFT in urban and rural areas was 1.29 and 0.66, respectively. Furthermore, our data showed a general lack of knowledge on oral health issues by the participants.There is high prevalence of dental caries among 12 years old school children in both urban and rural areas of Zimbabwe. This calls for early preventive strategies and treatment services. We recommend incorporation of oral health education in the elementary school curricula. Dental caries remains a major oral health disease affecting children world-wide . While tEstablishing baseline data on children dental caries and other oral health issues through regular national surveys is crucial for planning and development of intervention programs . UnfortuThe main focus of this study was to determine the prevalence of dental caries among twelve year old school children from low socio-economic status backgrounds in both urban and rural areas of Zimbabwe. Our results show a high prevalence of dental caries in both urban and rural children.Study design: This is a descriptive cross-sectional study designed to assess dental caries experience among 12 year old school children from low socio-economic status background attending public primary schools in Zimbabwe.Setting and study population: For convenience purposes, participants in this study were drawn from two primary schools in urban  and rural  areas respectively. The study population consisted of 12 year old children attending public primary schools. We particularly focused on this age group as it is the WHO recommended index age ,in this study; we observed a higher prevalence of dental caries among urban children who reported ever consulting a dentist . We did Despite limitations of this study which include use of a small convenient sample size drawn from only two schools coupled with our inability to verify the information reported on the questionnaire, our findings concur with previous studies done in Zimbabwe , 8 and sOur data shows a high prevalence of dental caries among 12 year old school children from low socio-economic status background in both urban and rural areas of Zimbabwe. This data may be of importance in the evaluation of the past and planning of future oral health prevention and treatment programs targeting young children in primary schools. A comprehensive community-focused oral health care intervention that includes oral health education in elementary schools and homes is recommended to increase general oral health awareness."}
+{"text": "To the Editor: Rabies was officially declared eliminated in nonflying mammals in metropolitan France during 2001\u20132008 by the World Organisation for Animal Health; the last case of rabies was believed to occur in a fox in 1998. However, rabies remained a public health concern because of the risk of translocation of infected dogs from enzootic areas and the natural circulation of bat rabies\u2013associated lyssaviruses (BRALVs). In 2008, France temporarily lost its rabies-free status following evidence of an indigenous case of rabies in a dog, linked to an index case in a dog infected in Morocco. In 2007, a domestic cat was found infected with a BRALV, an indication that, although bats are the primary hosts of this pathogen, other mammals may be infected (,,We compared the number of RPEP treatments in humans after bat-related exposures in the south of France with newspaper reports about rabies-related events over an 8-year period. In France, primary health care management of patients seeking RPEP is delivered through an official network of antirabies medical centers. All centers in the southern half of France were asked to provide the number of RPEP treatments that followed bat-related exposures in mainland France during 2002 through 2009. Of 22 centers, 18 participated in the study, reporting 326 RPEP treatments . Two mar\u2013The pattern of spikes in RPEP in the south of France seen after bat-rabies media reports supports the results of other studies that found effective newspaper reporting increases patient demand for RPEP (,Classical rabies virus has been transmitted to humans by bats in South America (Based on results of study we conducted in 2008 when RPEP increased 4.7 fold after 2 media releases within several weeks, it is possible that only 20% of persons with bat exposure typically seek RPEP in periods without media reports. Although the risk of human rabies acquired through exposure to European bats is rare, information should be provided to the French public to avoid direct contact with bats, including handling when found inside homes during the summertime. When available, bats should be submitted for rabies testing to determine whether RPEP is needed. Following these procedures should minimize both the potential risk for transmission and the number of expensive RPEP treatments."}
+{"text": "PREP (Prediction of risks in early onset pre-eclampsia) is a multicentre prospective cohort study aiming to develop and validate a prediction model in women admitted with early-onset pre-eclampsia for risk of adverse maternal outcome at 48 hours and until discharge. The primary outcome was a composite of adverse maternal outcomes and the secondary outcome a composite of adverse fetal outcomes.The planned model includes multiple predictor variables in combination to predict the risk of adverse outcomes in individual patients. We highlight the methodological challenges encountered in model development.The predictor variables were pre-selected based on symptoms, signs and results of investigations routinely taken during management of pre-eclampsia. Challenges included accounting for correlation between variables, choosing the most abnormal variable within a time period or from a pre-determined time point, inconsistency in ascertainment of the data points ie blood results available later than the signs and symptoms, modelling a combination of binary, ordinal and continuous variables and the approach in prioritisation of these variables.Clinician management such as anti-hypertensives and magnesium sulphate will affect the relationship between the predictor and outcome. We will include clinical management as a covariate and assess consistency in model performance across different treatment groups to account for this.Selecting the optimum type of prediction model posed a further challenge. Logistic regression focuses on the relationship between predictor variables and adverse outcomes whereas survival analysis takes into account the time to develop the outcome. The former may be statistically more suitable but the latter clinically more useful."}
+{"text": "Dye-assisted internal limiting membrane (ILM) peeling and gas tamponade is the surgery of choice for idiopathic macular holes. Indocyanine green and trypan blue have been extensively used to stain the ILM. However, the retinal toxicity of indocyanine green and non-uniform staining with trypan blue has necessitated development of newer vital dyes. Brilliant blue G has recently been introduced as one such dye with adequate ILM staining and no reported retinal toxicity. We performed a 23-gauge pars plana vitrectomy with brilliant blue G-assisted ILM peeling in six patients with idiopathic macular holes, to assess the staining characteristics and short-term adverse effects of this dye. Adequate staining assisted in the complete removal of ILM and closure of macular holes in all cases. There was no evidence of intraoperative or postoperative dye-related toxicity. Brilliant blue G appears to be safe dye for ILM staining in macular hole surgery. Internal limiting membrane (ILM) peeling, one of the most challenging procedures in vitreoretinal surgery, has been made easier with selective staining of this optically clear tissue with a number of vital dyes. Indocyan36) mixture and the patients were advised prone position for one week.After approval by the local institutional review board and ethics committee, six eyes of six patients  with idiP < 0.05.Statistical analysis of pre- and postoperative BCVA was performed using the two-tailed Wilcoxon signed ranks test. Differences were considered significant when P = 0.0325). Staining of the ILM was good in all cases and allowed for an easy and atraumatic removal of the ILM. The complete data on our patients is given in Four women and two men with a mean age of 64.6 years were included in the study. All patients were followed-up for 20 weeks postoperatively. All macular holes were completely closed in all patients in the first visit (one week) and remained closed at all subsequent four-weekly visits Fig.  and c. TWe did not observe any visual field defects in any of the patients that might have been caused by dye toxicity. There was no evidence of any retinal pigment epithelium abnormality or nerve fiber layer defect seen in the red-free photographs during any of the postoperative visits of all patients. No ocular or systemic side effects were noted.et al.[8et al,[Dye-related toxicity is a major concern in macular hole surgery as retinal damage caused by the dye may offset the visual gain facilitated by the successful closure of the macular hole. Reports of potential side effects of ICG point to either the dye\u2019s photosensitizing properties or to diet al. The dye et al.810 SchumAs the dye seeps under the detached retina surrounding the macular hole during surgery, it\u2019s toxicity to the retinal pigment epithelial cells may affect the final visual function adversely. ICG has been seen to cause damage to the retinal pigment epithelial and gangThere was absence of any visual field defect either within the area of the peeled ILM indicating trauma to the nerve fiber layer during ILM removal, or outside it indicating any dye-related toxicity in our study. None of the patients showed any retinal nerve fiber defects on red-free photographs as well. Although there were no studies documenting the postoperative duration for which BBG was retained in the eye, the absence of any visual field defects at the end of 20 weeks, pointed to the dye\u2019s lack of toxicity to retinal elements, as investigations on ICG-related field defects reported such events within the first few follow-up visits.All the patients in our series had macular holes measuring greater than 400 \u03bcm and we attributed the successful closure rate to BBG-assisted adequate removal of the ILM. Staining of the ILM was good in all cases, providing an excellent contrast and facilitating complete removal of the membrane atraumatically. The low potential toxicity and staining nature of BBG would make it safer than trypan blue or ICG. Studies with larger patient size would be possible when the dye becomes more easily available to vitreoretinal surgeons in India, in the future."}
+{"text": "Aggregation of tau is one of the main hallmarks of Alzheimer\u2019s disease and other tauopathies. Normally tau regulates microtubule (MT) dynamics and hence axonal function but in AD hyperphosphorylated, misfolded and aggregated tau has reduced interaction with microtubules. There is growing evidence that the proteolytic processing of tau may play a crucial role in the aberrant change of tau conformation and its aggregation. rTg4510 mice express the human four-repeat tau gene lacking the amino-terminal sequence (0N4R) and with a P301L mutation. Between four and ten months of age the mice develop progressive tau pathology and eventually neuronal loss. The aim of this work was to investigate the importance of tau cleavage at D421, the cleavage epitope for caspase-3 and caspase-6, and its role in tau aggregation. We ran a longitudinal study to measure the level and distribution of D421-caspase cleaved tau in rTg4510 between two and eight months of age to determine whether there is a correlation between the cleavage of tau and its conformational change.Total tau and D421-caspase cleaved tau levels in the cortex and hippocampus in each age group were quantified using a panel of proprietary AlphaScreen assays and by standard IHC methods. Tau aggregation was assessed using high-speed centrifugation of brain homogenates.The biochemical and immunohistochemical analyses of rTg4510 showed a time-dependent increase of caspase-cleaved tau at D421 in the cortex and hippocampus between four and eight months of age and importantly caspase-cleaved tau was shown to be associated with the insoluble fraction of tau. These changes are concomitant with progression of tau pathological changes previously observed in this model.Caspase-cleaved tau at D421 is associated with aggregated and insoluble tau. Our findings contribute to the discussion on whether therapeutics aimed at inhibiting caspase-mediated tau cleavage could be beneficial in slowing cleavage and aggregation, and hence potentially inhibit the pathological cascade in Alzheimer\u2019s disease."}
+{"text": "Bacillus cereus sensu lato group consists of six species . While classical microbial taxonomy proposed these organisms as distinct species, newer molecular phylogenies and comparative genome sequencing suggests that these organisms should be classified as a single species . How do we account for the underlying similarity of these phenotypically diverse microbes? It has been established for some time that the most rapidly evolving and evolutionarily flexible portions of the bacterial genome are regulatory sequences and transcriptional networks. Other studies have suggested that the sigma factor gene family of these organisms has diverged and expanded significantly relative to their ancestors; sigma factors are those portions of the bacterial transcriptional apparatus that control RNA polymerase recognition for promoter selection. Thus, examining sigma factor divergence in these organisms would concurrently examine both regulatory sequences and transcriptional networks important for divergence. We began this examination by comparison to the sigma factor gene set of B. subtilis.The Bc species-group utilizing 157 single-copy genes of the family Bacillaceae suggests that several taxonomic revisions of the genus Bacillus should be considered. Within the Bc species-group there is little indication that the currently recognized species form related sub-groupings, suggesting that they are members of the same species. The sigma factor gene family encoded by the Bc species-group appears to be the result of a dynamic gene-duplication and gene-loss process that in previous analyses underestimated the true heterogeneity of the sigma factor content in the Bc species-group.Phylogenetic analysis of the B. subtilis. Divergence of the sigma-controlled transcriptional regulons among various members of the Bc species-group likely has a major role in explaining the diversity of phenotypic characteristics seen in members of the Bc species-group.Expansion of the sigma factor gene family appears to have preferentially occurred within the extracytoplasmic function (ECF) sigma factor genes, while the primary alternative (PA) sigma factor genes are, in general, highly conserved with those found in  Bacillus consists of a heterogeneous group of Gram-positive heterotrophic aerobic or facultative anaerobic bacilli with the ability to form environmentally resistant, metabolically inert spores , based on classical microbial taxonomy  analysis (MEGA) . Other aThe authors declare that they have no competing interests.TS performed the data analyses included in the manuscript, except for Figures BacillaceaeSingle-copy genes used in the phylogenetic analysis of the . Annotations for each of the single-copy gene are from the Paenibacillus genome as submitted to Genbank, one of the outgroups included in the analysis.Click here for fileSigma factor genes identified in this study. Locus tags for genes found in each genome follow the locus tag identifier or sigma factor identifier for each ortholog.Click here for fileResults of MEME analysis of the sigma factor genes identified in iterative BLAST searches. MEME results for 10 motifs (nmotifs = 10) are shown, 7 of which follow phylogenetic patterns that differentiate PA from ECF sigma factors (Tables s Tables  and 3.Click here for fileResults of phylogenetic analysis of the sigma factors identified in Additional file Click here for file"}
+{"text": "Brain and Cognition describes a possible mechanism underlying the development and maintenance of attentional bias in depression and anxiety. Their findings regarding decoupling of prefrontal\u2013posterior brain regions adds to the existing evidence that fronto-limbic interactions facilitate the generation of task-relevant responses while inhibiting interference from emotionally distracting information. The authors employed electroencephalogram (EEG) and three mood induction methods  in healthy controls to explore state-dependent coherence between prefrontal and posterior cortical regions as a mechanism for modulating the impact that social-emotional information has on an individual. The findings suggest that prefrontal\u2013posterior decoupling is related to individual differences in the behavioral traits of absorption and in the propensity to ruminate. Higher scores in these traits were related to loosened coupling between prefrontal cortex (PFC) and posterior cortex. Conversely, healthy controls with lower scores on absorption and rumination showed stronger prefrontal\u2013posterior coupling. Results were interpreted as showing that less prefrontal\u2013posterior coupling may be related to loosening of control by the PFC over incoming social-emotional information, and consequently to deeper emotional involvement and absorption. Conversely, increased prefrontal\u2013posterior coupling may be related to strong control, with a consequent dampening of emotional experience and a lack of emotional engagement. When considering the neural substrates of emotional control, the limbic system has been suggested to play a key role. This set of brain regions includes frontal and medial temporal lobe structures. Although there is no universally accepted definition of what constitutes the limbic system, the anterior cingulate cortex (ACC) is thought to play an important role in emotional regulation. Numerous other functions have been ascribed to the ACC but here we focus on the specific role of the ACC on regulating emotion through attentional control.Despite the high prevalence of mood disorders, their underlying psychopathology remains poorly understood. A recent publication by Reiser et al.  in BrainThe ACC can be divided into dorsal (cognitive), and ventral  components. The dorsal ACC is thought to monitor for errors or processing conflicts that could disrupt performance and to recruit the dorsolateral PFC (DLPFC) to reallocate attentional resources as needed  but fail on tasks requiring conflict resolution that involve cognitive control (DLPFC-ACC). We suggest that closing the loop between the emotional and the cognitive brain is central to progress in the treatment of emotional disorders. These reciprocal regulatory mechanisms constitute a critical property of human adaption that facilitates the balance between processing task-relevant information and emotionally salient but task-irrelevant information. Successful goal directed behavior appears to be mediated by direct feedback connections between the DLPFC and the ACC especially when emotional distracters are present."}
+{"text": "Peptidoglycan (PG) is an essential net-like macromolecule that surrounds bacteria, gives them their shape, and protects them against their own high osmotic pressure. PG synthesis inhibition leads to bacterial cell lysis, making it an important target for many antibiotics. The final two reactions in PG synthesis are performed by penicillin-binding proteins (PBPs). Their glycosyltransferase (GT) activity uses the lipid II precursor to synthesize glycan chains and their transpeptidase (TP) activity catalyzes the cross-linking of two glycan chains via the peptide side chains. Inhibition of either of these two reactions leads to bacterial cell death. \u03b2-lactam antibiotics target the transpeptidation reaction while antibiotic therapy based on inhibition of the GTs remains to be developed. Ongoing research is trying to fill this gap by studying the interactions of GTs with inhibitors and substrate mimics and utilizing the latter as templates for the design of new antibiotics. In this review we present an updated overview on the GTs and describe the structure-activity relationship of recently developed synthetic ligands. The emergence of multidrug-resistant bacteria causes major public health problems, particularly in medical facilities where the lack of efficient antibiotics could jeopardize the advances made in the treatment of many diseases. New efficient antibiotics against multidrug-resistant strains are urgently needed to counter this worrying situation.N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc)-peptide attached to the membrane-bound undecaprenyl lipid carrier via a pyrophosphate group  is an essential net-like macromolecule that surrounds most bacteria, gives them their shape, and protects them against their own high osmotic pressure  structures  helix (66\u201396 in PBP1b)  end of the growing chain  against a variety of Gram-positive bacteria (10\u20131000 times better than vancomycin) and inhibits all the GTs tested at low concentration. Interestingly, no resistance has been observed, even after moenomycin was used extensively in animal feed  they provided a comprehensive structure-activity view shedding light on the entities required to design substrate-based inhibitors of the GTs. The disaccharide analogs were more active than their cognate monosaccharides. The best compound in the phosphate series was a disaccharide devoid of a peptide moiety  with a MIC value of 128\u2009\u03bcg/ml against S. aureus. The substitution of the C16 lipid chain by geranyl completely abolished the activity of the compounds. The specificity of these compounds for the donor and acceptor sites still needs to be determined. Except for compound 62, none of the compounds had antibacterial activity but the most active ones induced bacterial cell chaining similar to the phenotype observed with moenomycin , and a lipophilic moiety. As for moenomycin, the lipophilic part was essential for GT inhibition. A compound with a branched lipid was more potent than a compound with a linear one. An ether linkage between the pyrophosphate mimic and the lipophilic moieties was five times more efficient than an amide linkage. Compound 31 . The latter can serve as donor substrate and may not be efficient as an inhibitor.Shih et al.  have synl-Ala residue has an intermediate affinity. In the absence of peptide and upon substitution of the d-lactoyl of the MurNAc by a methyl group no binding was observed. The authors concluded that the d-lactoyl-l-Ala moiety is essential for substrate binding. We have shown that lipid II analogs with d-lactoyl have an inhibitory activity on GTs indicating that the l-Ala residue of these analogs is not required for binding and that a d-lactoyl group is sufficient (Dumbre et al., The same group has synthesized lipid II analogs with variable peptide moieties and evaluated their binding to the GTs (Shih et al., S. aureus. In analog 3 (Figure Huang et al.  reported3 Figure B. This i3 Figure . In the Glycosyltransferase is a validated antibacterial target that has not been fully explored in the past because of technical difficulties related to the intrinsic properties of the proteins and their substrates. Most of the studies on GT activity inhibition have focused on moenomycin and its derivatives. The adverse properties of moenomycin and the need for the lipid moiety to achieve full antibacterial activity have prevented its development as an antibacterial agent in humans. With the ongoing antibiotic resistance crisis, the GT step in PG synthesis has emerged as one of the major antibacterial targets for the development of new antibiotics. This interest has resulted in a major breakthrough in the last decade: crystal structures of GT and complexes with moenomycin have been elucidated, the preparation of substrates has been improved, new assays have been developed, and particularly extensive efforts in the synthesis of substrate and moenomycin analogs have been made. Attempts to screen small molecule libraries for GT inhibition have also been investigated. This dynamic will certainly contribute to our better understanding of the GT-substrate mimic interactions and the discovery of new small molecule lead compounds. The use of these ligands as templates for the design and synthesis of new molecules may deliver useful antibacterial drugs against resistant bacteria.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Onychoprion fuscatus), on Ascension Island to provide new insights about this classical example of a population of sub-annually breeding birds that was first documented in studies 60 years previously on the same island. We confirm that the breeding interval of this population has remained consistently sub-annual. By ringing >17000 birds and re-capturing a large sample of them at equivalent breeding stages in subsequent seasons, we reveal for the first time that many individual birds also consistently breed sub-annually . Ascension Island sooty terns appear to reduce their courtship phase markedly compared with conspecifics breeding elsewhere. Our results provide rare insights into the ecological and physiological drivers of breeding periodicity, indicating that reduction of the annual cycle to just two life-history stages, breeding and moult, is a viable life-history strategy and that moult may determine the minimum time between breeding attempts.Breeding periodicity allows organisms to synchronise breeding attempts with the most favourable ecological conditions under which to raise offspring. For most animal species, ecological conditions vary seasonally and usually impose an annual breeding schedule on their populations; sub-annual breeding schedules will be rare. We use a 16-year dataset of breeding attempts by a tropical seabird, the sooty tern ( The periodicity of animal breeding has long fascinated biologists who have often invoked ecological explanations of within and between-species variation in the timing of breeding and its evolution e.g. . Timing Diomedea spp.) and frigatebirds (Fregata spp.), there is annual breeding at colonies but it is well established that individuals within those populations breed only biennially Sterna bergii) on Aldabra Atoll Gygis alba) on Christmas Island (Pacific) Phaethon lepturus) on Ascension Island Sterna anaethetus) on Aldabra Atoll Puffinus nativitatis) on the Pitcairn Islands Puffinus lherminieri) and swallow-tailed gulls (Creagrus furcatus) on The Galapagos Islands Of all life-history stages, reproduction is probably most sensitive to an organism's ecology. This is true for almost all animal taxa that combat unpredictability of resources by interrupting breeding at different reproductive thresholds (e.g. some insects) and delaying implantation of embryos . However, such plasticity in the timing of breeding is not exhibited by birds Sula sula], white terns and red-billed tropicbirds [Phaethon aethereus] on Johnston Atoll in the central Pacific All birds undergo cycles involving both breeding and moult which together impose some temporal constraints on the timing of breeding The breeding interval of populations is not always the same as that of constituent individuals. For example, while individual white terns The classical example of sub-annual breeding at a population level is provided by the work of Chapin Some such as Newton 2 volcanic island and a constituent of the United Kingdom Overseas Territory (UKOT) of St Helena. It is isolated in the tropical South Atlantic midway between West Africa and South America. Although many scientific expeditions have visited the island, including The Beagle in 1838 2 of ocean. Sooty terns now constitute over 95% of avian biomass of the island with possibly as many as 750000 birds breeding in the 1950s The study was carried out on Ascension Island , a 97 kmWe monitored the interval between first hatching dates across 19 breeding cycles between 1996 and 2012 (inclusive) to establish the breeding interval of the populations at Mars Bay and Waterside colonies on the southern coast of the island see . Each coWe captured 17426 incubating adults between 1996 and 2012 (inclusive) using long-handled nets and ringed them (under a British Trust for Ornithology [BTO] ringing licence number A4318) with uniquely numbered BTO metal rings to study the breeding interval of individual birds. Birds were generally ringed in groups of 100 within a sub-colony before moving on to another sub-colony. This was done to minimise disruption to incubating birds. In a given season re-capture effort took place before ringing of birds to avoid re-capture of newly ringed birds. Pairs of fieldworkers walked through sub-colonies of incubating birds and ringed birds were targeted for re-capture. Most birds typically stand as they are approached and were caught by one person while the other noted their ring numbers. In this way the entire population of incubating birds at both colonies was surveyed. This was repeated a week later to maximise the probability of re-capturing both birds of incubating pairs \u2013 Ascension Island birds spend up to seven days away at sea before returning to relieve their partners of incubation duties d1 and d2 are the dates of hatching of first chick of the season, and of departure of the last tern the previous season, respectively, i is the mean incubation period (i.e. 29 days), c is the mean courtship period (i.e. 52 days), and s is the mean interval between the first egg date in the two colonies and the date of departure of the last bird from the two colonies.The breeding cycle of this pan-equatorially distributed species is composed of periods of courtship, incubation, chick-rearing and migration which we compared between birds on Ascension Island and conspecifics on other islands  to CPW and under which birds were ringed on this UKOT.The mean interval between first estimated hatching dates in successive breeding seasons was 289.4\u00b110.1 (\u00b195% confidence limits) days (N\u200a=\u200a17) at Mars Bay and 288.9\u00b18.7 days (N\u200a=\u200a19) at Waterside . The meaOut of a total of 17426 birds that were captured and ringed between 1996 and 2012 , and oveA comparison between sub-annually breeding sooty terns on Ascension Island and annually breeding conspecifics elsewhere revealed differences of a single day between incubation periods, six days between chick-rearing periods and 15 days between migration periods . HoweverWe provide strong evidence of consistent sub-annual breeding at both the individual and the population levels of sooty terns breeding on Ascension Island. Birds bred twice in the calendar years 2004, 2008 and 2012 and sub-annual breeding intervals translated into breeding peaks in different months of the year over the course of this 16-year study . RingingThe sub-annual breeding interval of the sooty tern population on Ascension Island appears to have remained constant for at least the last 140 years. From historical records Chapin . In the Ashmole Larus argentatus] Compared with the annually breeding populations of sooty terns, Ascension Island birds appear able to breed sub-annually by reducing the courtship period by 76 days. This matches the difference between annual and sub-annual breeding intervals. There appear to be some fundamental differences in the breeding biology of the population on Ascension Island compared with elsewhere. For example, laying peaks towards the end of the laying period 40\u201360 days after the first egg is laid on Ascension Island Breeding seasons evolve because most habitats are exposed to seasonality which results in organisms receiving maximum fitness benefits by restricting their breeding attempts to the most favourable times of the year Sturnus vulgaris]) are kept experimentally under constant equatorial photoperiods and temperature, and with access to ad libitum food , they show repeated circannual rhythms of gonadal maturation and moult which typically last less than 12 months and are often nearer to nine months Wingfield Bird species generally demonstrate a remarkable diversity in moult strategies between different locations, sexes and age classes Despite having studied the Ascension Island population of birds since 1990, we still know little about the physiological constraints on birds of this population in relation to the breeding cycle. Certainly, differences between moult strategies of birds breeding on Ascension Island and elsewhere warrant closer consideration but so too do other aspects of their comparative life history. As We provide strong empirical evidence for regular sub-annual breeding of a free-living avian species. For the first time we employ robust data to demonstrate that this occurs at the level of both the population (hypothesis 1) and the individual (hypothesis 2). We have also shown that the lengths of some constituent phases of the breeding cycle differ between Ascension Island birds and those elsewhere (hypothesis 3), identifying focal points for future research. Our findings increase understanding of the timing of breeding in relation to prevailing ecological conditions. It is clear that sooty terns breeding on Ascension Island may not experience an annual cycle in the availability of ecological resources but this may be overlain by ENSO and other generally unpredictable events. While this lack of an ecological signal translates into average breeding success per breeding attempt being lower for sub-annual breeders, this strategy potentially provides individual birds with more chances to breed during their lifetimes. Therefore, sub-annual breeding must be advantageous to Ascension Island birds despite their success per breeding attempt being lower. Further research is needed to identify other species with enduring and consistent sub-annual breeding cycles and, as result, to advance our understanding of breeding periodicity of vertebrates through the testing of proximate and ultimate causal explanations of the phenomenon."}
+{"text": "In highly seasonal tropical environments, temporal changes in habitat and resources are a significant determinant of the spatial distribution of species. This study disentangles the effects of spatial and mid to long-term temporal heterogeneity in habitat on the diversity and abundance of savanna birds by testing four competing conceptual models of varying complexity. Focussing on sites in northeast Australia over a 20 year time period, we used ground cover and foliage projected cover surfaces derived from a time series of Landsat Thematic Mapper imagery, rainfall data and site-level vegetation surveys to derive measures of habitat structure at local (1\u2013100 ha) and landscape (100\u20131000s ha) scales. We used generalised linear models and an information theoretic approach to test the independent effects of spatial and temporal influences on savanna bird diversity and the abundance of eight species with different life-history behaviours. Of four competing models defining influences on assemblages of savanna birds, the most parsimonious included temporal and spatial variability in vegetation cover and site-scale vegetation structure, suggesting savanna bird species respond to spatial and temporal habitat heterogeneity at both the broader landscape scale and at the fine-scale. The relative weight, strength and direction of the explanatory variables changed with each of the eight species, reflecting their different ecology and behavioural traits. This study demonstrates that variations in the spatial pattern of savanna vegetation over periods of 10 to 20 years at the local and landscape scale strongly affect bird diversity and abundance. Thus, it is essential to monitor and manage both spatial and temporal variability in avian habitat to achieve long-term biodiversity outcomes. Globally, savanna ecosystems are an important reservoir of biodiversity, but are undergoing rapid changes due to increased land use pressures including clearing, grazing and changes in fire regimes Seasonal and inter-annual variability in habitat attributes such as cover and resource availability are important components of species\u2019 habitat relationships, and can have an important influence on species\u2019 distribution patterns according to their mobility and ability to utilize changing habitat resources Wildlife respond to temporal variability in habitat attributes in a variety of ways including seasonal migration, nomadic dispersal movement, and shifting local patterns of habitat utilization and population dynamics In addition to climatic variability, land use disturbances  can alter vegetation structure and dynamics, particularly at local (1\u2013100ha) to landscape (100\u20131000s ha) scales and at 10\u201320 year time scales, with important consequences for the composition and abundance of woodland birds The capacity now exists to measure temporal and spatial heterogeneity in vegetation cover using historical archives of satellite imagery at moderately high spatial resolutions, i.e. freely available archival annual Landsat Thematic Mapper imagery with a 30 m resolution over a 18 year time span There is a relatively good understanding of local-scale (1\u201310 ha) relationships between savanna bird abundance and diversity, and habitat structure, composition and disturbance regimes Rapid global change is the most compelling issue for conservation sciences at present This study addresses the following questions for explaining spatial variation in bird diversity and abundance in tropical savanna landscapes: i) how important is temporal heterogeneity in vegetation cover relative to spatial heterogeneity? ii) how influential is local to landscape-scale heterogeneity in vegetation cover compared to regional-scale rainfall-driven variation in vegetation cover?We developed a conceptual model of how spatial and temporal factors may influence savanna bird assemblages at different scales, and from this identified four competing hypotheses to disentangle effects of spatial and long-term temporal heterogeneity in habitat, and rainfall-driven  and management-driven  heterogeneity . In thisWe postulate four competing models:Local habitat model: local-scale (1\u2013100ha) habitat structure explains diversity and abundance of savanna birds. Spatial and long term temporal heterogeneity at the landscape-scale is of less importance.Spatial heterogeneity model: the spatial landscape context is important for savanna birds. Consideration of variables describing heterogeneity across the landscape allows better prediction of savanna bird diversity and abundance.Temporal rainfall variability model: rainfall variability is the key driver of temporal variability in habitat attributes for savanna birds. Broad-scale temporal variability in rainfall in conjunction with local-scale vegetation structure are important predictors of savanna bird diversity and abundance.Temporal and spatial heterogeneity model: spatial and temporal heterogeneity in woody and herbaceous vegetation cover at local and landscape scales are important predictors of savanna bird diversity and abundance. Annual temporal heterogeneity in vegetation cover across the landscape reflects the impact of land management as well as broader scale climatic gradients.These four models were then used as a basis for constructing a set of alternative statistical models for testing the relative influence of spatial and temporal heterogeneity in habitat attributes at local and landscape scales on savanna bird species richness and abundance.The study focused on the Desert Uplands bioregion of Queensland, Australia , which hEucalyptus whitei), characteristic of low-fertility eucalypt savannas of northeast Australia. The location of the sites in a same ecosystem type ensured variation in the observed bird patterns was not influenced by spatial differences in vegetation communities. All surveys were conducted on leasehold land and permission to access and survey these properties were obtained by the landholders, namely the Bode Families  and Haydon Family (Penrice).Sites were located in a single regional ecosystem type, 10.3.9, , definedFifty 1-ha sites were surveyed in May-June 2004 and resurveyed in March-April 2005 and July-August 2006. Within each 1-ha site, eight five-ten minute diurnal bird counts were conducted over a four day period, and visual and aural observations were recorded. Each count represented the entire 1-ha area. At least two bird counts of each 1-ha plot were made per day at each site; one count in the morning between dawn and three hours after dawn, and the other a minimum of three hours after this period and before dusk. Studies of extensive bird survey data (over 500 sites sampled over 6 years) for these open, largely homogenous tropical savannas have demonstrated that repeated sampling of 1 ha areas, over multiple days and at different times of the day is the most appropriate method to count bird assemblages often dispersed across the landscape, and that distance sampling methods are not required Data used in the analyses were the total summed relative abundance of all the eight counts in each site for each year. All sites were located a minimum of 500 m from watering points to standardize the impact of grazing pressure across sites, and as far as practical from fence lines and roads. Sites were separated by a minimum of 1 km to avoid spatial dependence and all sites are located within a discrete unit of the mapped vegetation polygon (i.e. away from edges). Birds were recorded for all surveys at all sites, with each site having more than five species in total over the course of that season\u2019s survey.H) per seOreoica gutturalis, double-barred finch Taeniopygia bichenovii, grey-crowned babbler Pomatostomus temporalis, grey shrike thrush Colluricincla harmonica, singing honeyeater Lichenostomus virescens, weebill Smicrornis brevirostris, yellow-throated miner Manorina flavigula and zebra finch Taeniopygia guttata. These species represent the range of foraging and nesting guilds typical of woodland birds in the study area  Regulation 2006 and the  Commonwealth Scientific and Industrial Research Organisation Ecosystems Sciences Animal Ethic Committee Animal (Permit Number: 2AR 09\u201309). All surveys were by observation and no trapping or handling of birds was undertaken in this study.2 quadrats in a regular grid within each 50 m by 50 m plot. From this, we calculated the mean cover score for the full plot. Total tree and shrub frequency was calculated as the number of 0.5\u2013 m2 quadrats over which a tree or shrub was present.At the local-scale, habitat variables measuring vegetation structure and composition were recorded for each site. Basal area was measured from two diagonal corners of the 50 m by 50 m plot for live and dead trees. Mean basal area for each tree and size class and total live and dead basal area was calculated. Horizontal foliage projective cover was visually estimated for six height classes (0\u20130.5 m representing ground vegetation). Measures of percentage cover of bare earth, rock, litter, grass, sedges, herbs and forbs, and logs (>5 cm) were derived from 20 0.5\u2013 mSpatial and temporal variability in rainfall were derived from climatic data spatially interpolated from weather stations to 5-km grids on a daily time step and averaged to monthly surfaces for the period 1988 to 2006 An annual time-series of foliage projected cover and ground cover was derived from Landsat TM satellite imagery for the period 1988 to 2006. Foliage projected cover (FPC) was estimated by an empirical relationship between basal area, reflectance data and FPC, derived through regression analysis We calculated statistics for the ground cover and FPC surfaces using 5-km grids, which matched the resolution of the rainfall grid. Bird survey sites were overlaid on the grids with the number of bird survey sites located in each grid cell varying between four and eight. To measure landscape spatial heterogeneity for the dates for which we have bird survey data , we calculated a spatial mean and coefficient of variation of ground cover and FPC for each 5-km grid square.http://www.r-project.org) revealed significant positive temporal autocorrelation in FPC and ground cover at a 1 year lag for all sites as well as autocorrelation up to a 5 year lag, which was not always significant. Based on the autoregressive analysis, mean and variance time series statistics were calculated for ground cover and FPC over the short term (5 year autocorrelation lag) and long term (full time series). The autoregressive coefficients for 1 year and 5 year lags were also included in the explanatory variables as measures of temporal autocorrelation.Temporal variability in habitat for each site was measured from time series statistics for the mean value of FPC and ground cover in a 200 m circular buffer around each site (similar size to 1-ha field survey sites). Exploratory analysis of the FPC and ground cover time series data revealed approximately cyclical patterns of 8\u201310 years, particularly apparent in the ground cover data, suggesting significant temporal autocorrelation in vegetation cover. Autoregressive modelling using the \u201carima\u201d package in R , ranking according to Akaike\u2019s Information Criterion (AIC) values The time series statistics that measure similar characteristics, but at different temporal extents (e.g. mean FPC over the short term and long term), were generally found to be highly correlated. Univariate modelling and variable ranking showed that long-term statistics were always ranked higher than the short-term statistics, thus we excluded the short-term statistics from our models. The long-term mean and variance values for FPC were highly correlated with long-term mean and variance values for ground cover, respectively. Examination of the standard deviation in time series of FPC revealed relatively low temporal variability in FPC (5\u20138%) across all sites. Therefore temporal variance in FPC was not included in the models. The inclusion of either long term mean ground cover or long-term mean FPC in the final models varied among response variables depending on AIC ranking in the univariate generalized linear models. The final set of explanatory variables for each conceptual model is outlined in i being the best model compared to the alternative conceptual models To determine a final model for each conceptual model and each response variable, we modelled all combinations of the subset of parameters and selected the set of parameters with the best fit under that conceptual model . We rankiw) from all model combinations where the variable occurred We calculated the model averaged parameter estimate and associated unconditional standard error for each explanatory variable in the dominant model for each species. The model-averaged parameter estimate was calculated by summing the value of the parameter estimate multiplied by the Akaike weight  performed the strongest based on Akaike weights  and for We also found that model 4  was always ranked the highest and model 1  the lowest based on Akaike weight performance rankings . The ordHierarchical partitioning was performed on the full set of explanatory variables in the temporal and spatial variability model (model 4) since this model had the strongest support. The results revealed that temporal variables had particularly high independent effects for the yellow throated miner, grey crowned babbler, zebra finch and the singing honeyeater. Site-scale variables were particularly influential for the grey shrike thrush and the double barred finch. There was little differentiation between the site, landscape and temporal percentage independent effect for the weebill, crested bellbird and Shannon diversity for all birds .This study has made an important contribution to disentangling the effects of landscape spatial and temporal heterogeneity on the diversity and abundance of fauna populations in highly dynamic environments such as Australia\u2019s tropical savannas. We have taken advantage of multi-temporal archival Landsat Thematic Mapper imagery to quantify the influence of habitat variability on woodland birds at the appropriate spatial and temporal scales, thereby improving the predictive power of static species\u2019 distribution models. Our results highlight the importance of spatio-temporal habitat dynamics in savanna landscapes and the importance of defining habitat on a species-specific basis Species diversity showed a positive response to both temporal and spatial mean ground cover and negative response to spatial and temporal variability in vegetation cover, suggesting a link between overall woodland bird diversity and reduced spatial variability in vegetation cover and higher average ground cover at the landscape-scale. Overall, landscape-scale and site-scale spatial variables had higher independent effects on species diversity than temporal variables. This pattern supports the concept that while seasonal variation in vegetation cover can drive changes in composition of the bird community, there is still a core bird assemblage that is strongly linked to the amount of habitat resources present in a landscape over the long-term In savanna environments, regional heterogeneity in vegetation communities and cover is controlled largely by climate and soil characteristics, but at local to landscape scales, fire and grazing management practice  can play a significant role At a species level, there was a variety of responses, predicated on the differences in the life history and ecology of each species. For the weebill, a small, ubiquitous and sedentary canopy dwelling species, there was no significant difference in the performance of the four models and it is seemingly resilient to land use change  Globally, savanna landscapes are facing increasing and changing land use pressures, which will likely have serious implications for their fauna biodiversity This study advances our understanding of the relative importance of landscape spatial and temporal heterogeneity on fauna populations in highly dynamic environments such tropical savannas. It demonstrates that:Using remote sensing technology allows for combining spatial and temporal measures of habitat heterogeneity across several scales and significantly improves our ability to explain and understand savanna bird species dynamics and the complex relationship with landscape scale.While seasonal variation in vegetation cover can drive changes in composition of the bird community, core bird assemblages are strongly linked to the average amount of habitat resources present in the landscape and longer term (20 years) stability in vegetation cover.Species show individual responses to temporal and spatial changes in savanna landscapes, and as such habitat and landscape conservation goals must be both understood and defined on a species-specific basis.Temporal heterogeneity in vegetation cover at the local to landscape scale is shown to be of importance for explaining patterns of diversity and abundance in savanna birds and can have a greater influence than regional rainfall variability. This supports recent changes in thinking regarding rangeland ecology in that the management for landscape heterogeneity and mosaics of different disturbance regimes over longer time scales is more critical for conservation of native biota compared to more traditional utilitarian goals of short term sustainable, homogenous land management ideals."}
+{"text": "Converging evidence from over 40\u2009years of behavioral research indicates that higher testicular androgens in prenatal life and at puberty contribute to the masculinization of human behavior. However, the behavioral significance of the transient activation of the hypothalamic\u2013pituitary\u2013gonadal (HPG) axis in early postnatal life remains largely unknown. Although early research on non-human primates indicated that suppression of the postnatal surge in testicular androgens had no measurable effects on the later expression of the male behavioral phenotype, recent research from our laboratory suggests that postnatal testosterone concentrations influence male infant preferences for larger social groups and temperament characteristics associated with the later development of aggression. In later assessment of gender-linked behavior in the second year of life, concentrations of testosterone at 3\u20134\u2009months of age were unrelated to toy choices and activity levels during toy play. However, higher concentrations of testosterone predicted less vocalization in toddlers and higher parental ratings on an established screening measure for autism spectrum disorder. These findings suggest a role of the transient activation of the HPG axis in the development of typical and atypical male social relations and suggest that it may be useful in future research on the exaggerated rise in testosterone secretion in preterm infants or exposure to hormone disruptors in early postnatal life to include assessment of gender-relevant behavioral outcomes, including childhood disorders with sex-biased prevalence rates. Testicular androgens have a central role in human male development. In prenatal life, increased testicular androgens around 4\u20136\u2009weeks gestation masculinize the genitalia and initiate the sexual differentiation of the brain through hormonally dependent, sex-specific changes in the ultrastructure of the developing central nervous system  . After aIn infant boys, serum testosterone (T) concentrations that are gonadal in origin increase to pubertal concentrations between 1 and 3\u2009months of age and fall to prepubertal values around 6\u2009months of age \u20137. SalivIn view of evidence indicating the postnatal endocrine surge is necessary to establish normal adult male reproductive function, a reasonable question is whether it is also necessary to establish male behaviors that facilitate reproductive success. An early perceptive commentary  suggesteThe long delay in examining the postnatal developmental programing hypothesis in humans is understandable given the paucity of supporting evidence from studies in non-human primates. Investigations using a variety of mammalian species had established that higher androgen concentrations in prenatal life promoted a male behavioral phenotype in juveniles , includiAdditionally, pioneering researchers of human hormone\u2013behavior relations argued that the effects of androgens would be most apparent on behaviors showing large sex differences in expression, for example play preferences in childhood . ResearcThus, studies of hormone\u2013behavior relations in early postnatal life were likely further delayed because infants lack the physical and cognitive maturity to express known androgen-sensitive behaviors, such as aggression or toy play. In addition, few investigations specifically examined sex differences in infant behavior , 27. LimAlthough other research has shown that gender labels influence adult response to infants , 37, we Small sex differences in infant temperament may represent essential structures supporting the development of adult sex differences in socio-emotional behavior  and receAt the same time, studies on gender-linked toy preferences in infancy were ongoing in our lab using eye-tracking technology to measure infant interests , 46. AltIn a second eye-tracking study of 41 infants at 3\u20134\u2009months of age, we examined whether hormonal factors might contribute to early visual preferences by determining whether the ratio of the lengths of the second and fourth digits of the right hand   and saliInterpretation of the association between higher salivary T in male infants and visual attention to a group of figures representing male-typical social organization may be informed by our other finding that higher salivary T in male infants at 3\u20134\u2009months of age also predicted maternal ratings of greater negative affectivity on a well-established measure of infant temperament . FurtherIt is notable that although, we found associations between biological factors and gender-relevant behavior in our infant research, there were no sex differences in infant behavior at 3\u20134\u2009months of age. For that reason, we describe behavior measured at 3\u20134\u2009months of age as \u201cpre-emergent\u201d sex-linked behavior . We explEvidence of any organizational effects of postnatal T on behavior, however, requires establishing associations between postnatal concentrations of T and behavioral outcomes beyond the infantile period of transient HPG activation. For that reason, we tested whether postnatal T concentrations measured at 3\u20134\u2009months of age would predict gender-typical play behavior and activity levels in children in the second year of life . Play prSex differences in social relations include verbal ability and emotional processing. Therefore, it is noteworthy that in contrast to the absence of associations between postnatal T concentrations and toddler toy choices summarized above, higher T concentrations at 3\u20134\u2009months of age predicted higher scores on the autism spectrum disorder (ASD) scale of the Brief Infant-Toddler Social and Emotional Assessment  and loweOur findings in toddlers are consistent with those from our earlier research on infants. Associations between digit ratios and interest in gender-linked toys in the first and second year of life suggest prenatal androgens influence pre-emergent and emergent sex-linked object interests. Additionally, our findings of no association between T concentrations in the early postnatal period and toy interests suggest the postnatal developmental programing hypothesis may not extend to all aspects of gender-linked behavior. Findings from another lab  appear iOur research indicating androgen concentrations in early postnatal life may influence risk for ASD is interesting given a need to better understand the mechanisms that contribute to the sex-biased prevalence rate and the deficits in communication and social interactions that characterize ASD. Indeed, ASD, a neurodevelopmental disorder diagnosed more frequently in boys, is associated with impairments in social interactions, restricted and stereotypical behaviors, and communication delays . BecauseFinally, we have shown one measure of salivary T at 3\u20134\u2009months of age can predict aspects of infant and toddler behavior. In this relatively uncharted research area, these findings clearly require independent replication. Nonetheless, the general results of this growing body of research support the earlier speculation  that theThe author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Hepatocellular carcinoma (HCC) in a liver with advanced-stage chronic hepatitis C (CHC) is induced by hepatitis C virus, which chronically infects about 170 million people worldwide. To elucidate the associations between gene groups in hepatocellular carcinogenesis, we analyzed the profiles of the genes characteristically expressed in the CHC and HCC cell stages by a statistical method for inferring the network between gene systems based on the graphical Gaussian model. A systematic evaluation of the inferred network in terms of the biological knowledge revealed that the inferred network was strongly involved in the known gene-gene interactions with high significance"}
+{"text": "The purpose of this review is to characterize the type of patient who may benefit from alternate, nonsteroidal agents and to examine the current evidence behind their use.Evaluated the use of oral or IM low-dose methotrexate vs placebo in steroid-dependent asthma patients using either parallel or crossover design. 100 patients enrolled in study attending the ent and allergy centre (India)panchkula patients were on long term steroid therapy for more than 1 years. Age of patients between 30 to 50 years. Study comparing methotrexate, 10 mg weekly orally, or placebo.It was concluded that methotrexate allowed a good amount of reduction in oral corticosteroid compared to patients receiving placebo. The benefit of using methotrextate were very promising as compared to side effects of corticosteroids in steroid depoendent allergy diseases however, and should be balanced against the potential for side-effects associated with the use of methotrexate.With low dose weekly therapy of metotrextate we can reduce the side effects of prolonged steroids have suggested that methotrextate may have steroid-sparing benefits coupled to generally mild adverse events; although adverse effects were not of a serious nature they were observed in up to one-third of patients. Rare but potentially life-threatening adverse effects involving the pulmonary, hepatic and haematological systems remain of particular concern. methotrextate should therefore be considered as an adjunct to high dose inhaled STEROIDS in patients who require more than 10mg of predenisolone daily, and who experience severe and unacceptable steroid-related adverse effects. Treatment should only be initiated by physicians with experience in the use of the drug, and the relevant safety parameters should be closely monitored."}
+{"text": "Investigation of electrophysiologic radiation effects was performed on cells grown on a microelectrode array (MEA) allowing the monitoring of beat rate, spike shape, field action potential duration and signal conduction pathways across the electrode array. Data were analysed using the DrCell software [Since essentially no information is available on the effects of high linear energy transfer (LET) radiation on the heart, an assessment of possible late effects on the cardiovascular system is important with respect to the planning of manned long-term space missions , 2. In ooftware . In paraOur preliminary data indicate that primary cardiac cells possess a high robustness toward ionizing radiation as cultures receiving doses of up to 7 Gy still show unaltered electrophysiologic activity. This is exemplarily shown in Fig. Interestingly, in terms of the formation of double-strand breaks (DSBs) and cell cycle progression delay, the cultures showed a dose-dependent reduction in proliferation and DSB accumulation.Taken together, our electrophysiologic studies indicate that the large variations within the same treatment group of avian embryonic cardiomyocytes obscure the detection of radiation effects. To account for this problem, we will use in further studies human cardiomyocytes differentiated from iPS cells, as these cells resemble more closely the condition of an adult human heart and do not undergo developmental changes as embryonic cell cultures do."}
+{"text": "Spike-timing-dependent plasticity (STDP) is a learning rule that updates synaptic strengths based on the relative timing of pre- and post-synaptic spikes. Unlike rate-based Hebbian learning, STDP can potentially encode fast temporal correlations in neuronal activity, such as oscillations, in the functional structure of networks of neurons that have axonal and dendritic propagation delays. The motivation behind this study was to understand the different ways that spatiotemporal patterns can be learnt by the recurrent connections in a network of neurons with STDP present. This understanding is vital to uncovering the mechanisms by which basic learning and information processing tasks are performed throughout the brain. A specific example in which these mechanisms may contribute is in explaining how the brain can perceive the pitch of complex sounds up to 300Hz. This work employs and builds upon the analytical framework for learning with STDP used in a previous study .In this study, the changes made by additive STDP to synaptic strengths in recurrent networks with axonal delays receiving oscillatory inputs were investigated analytically with the Poisson neuron model and verified through simulations with leaky integrate-and-fire (LIF) neurons. Frequencies between 100-300Hz were considered, which correspond to the modulation frequencies found in the auditory brainstem representing the fundamental frequency of different natural sounds. The analysis and simulations found that connections were selectively potentiated and depressed based on their axonal delay in such a way that the delays of the strong connections in the network \u201cresonated\u201d with the input frequency Figure . The tra"}
+{"text": "We present the case report of a patient presenting with ST segment elevation myocardial infarction due to a subacute drug-eluting stent trombosis within the proximal segment of the left circumflex artery (LCX). Six days before a total chronic occlusion was treated at the mid segment of the LCX by overlapping two drug-eluting stents. Optical coherence tomography (OCT) was helpful to demonstrate stent underexpansion of the overlaping segment as the main mechanism of early stent thrombosis. This case is illustrative about the potential role of OCT to identify the mechanisms of ST and thus guiding the PCI procedure. Moreover, our case shows the capability of the Imagewire to cross a severe stenosis due to stent underexpansion that could not be crossed by the IVUS catheter. A 53-year-old male with a history of arterial hypertension and ex-smoker was admitted into our institution with unstable angina and preserved left ventricular ejection function. Coronary angiography showed multivessel calcified disease with a long calcified lesion in the proximal mid-left descending coronary artery (LAD), chronic total occlusion (CTO) of the mid circumflex artery (LCX) , and a s2) localized in the overlap segment with abundant remnant thrombus proximal and distal to the overlap segment. The proximal and distal segments of the stents presented good apposition and expansion. Progressive dilations of the overlapped segment with oversized noncompliant balloons were performed, but were ineffective to improve distal flow  is a life-threatening complication of PCI, with reported 6-month mortality rates of 29\u201345% . Drug-elOCT is a new imaging technique based on the analysis of backscattered near-infrared light that provides ultra-high image resolution 15\u2009microns) and has demonstrated its utility to identify coronary atherosclerotic plaque composition and guide during PCI procedures . This te\u2009microns Our patient presented an STEMI six days after PCI, and angiography revealed ST of LCX. OCT was helpful to demonstrate stent underexpansion of the overlapping segment as the main mechanism of early ST. This case is illustrative of the potential role of OCT to identify the mechanisms of ST and thus guiding the PCI procedure. Moreover, our case shows the capability of the ImageWire to cross a severe stenosis due to stent underexpansion that could not be crossed by the IVUS catheter."}
+{"text": "In 1911 and long before the availability of antiallergic drugs, Leonard Noon demonstrated that prophylactic subcutaneous inoculation with a grass pollen extract was effective in suppressing immediate conjunctival sensitivity to grass pollen . WilliamMajor advances in allergen immunotherapy have resulted from parallel studies performed in the United States. Lowell and Franklin in 1964 were the first to clearly demonstrate that a single allergen (ragweed) in a multiallergen mixture was effective in reducing seasonal allergic symptoms . JohnstoH2 responses in favor of TH1 responses in both the periphery and in target organs has developed in parallel [Our increasing knowledge of the mechanisms of immunotherapy has informed both novel approaches and the development of putative biomarkers that might predict the clinical response to immunotherapy. Prausnitz and Kustner publisheparallel -26.It is paradoxical that 100 years on we continue to use conventional high-dose subcutaneous injection immunotherapy with allergen extracts as gold standard therapy. A key question remains whether either B cell and/or T cell epitopes expressed by allergens are necessary singly or together for successful immunotherapy. Whether T-cell focused therapies alone are sufficient is currently being tested in the context of T-cell peptide immunotherapy ,28. OtheThese novel strategies will hopefully augment efficacy while improving the safety of immunotherapy, thereby making immunotherapy more broadly available to allergy sufferers, including patients with more severe allergic asthma. Further confirmation that immunotherapy has potential to induce remission and prevent progression of allergic disease should attract earlier interventions in children and young adults who are the group who may potentially benefit most from this disease-modifying treatment."}
+{"text": "The default response to protein antigens in the intestine is the induction of systemic and local hyporesponsiveness (OT). There is increasing interest in the role of dietary manipulation and probiotics in the development and prevention of allergic and other diseases. Little is known how the environment and nutritional factors modulate systemic and local immune responses. This presentation addresses immunological mechanisms at the interface of innate and adaptive immunity that determine how the body responds to orally administered proteins and how local microbiota may modify these.There is evidence that dendritic cells in the intestinal mucosa play a particular part in OT induction. They take up dietary proteins, which may be sampled in the lumen and migrate to the draining mesenteric lymph node, where they induce regulatory CD4+ T-cell differentiation. An important role of retinoic acid (Vitamin A) in this event has been identified. The regulatory properties of (tolerised) T cells are discussed and it is proposed that the gut microenvironment maintains homeostasis by conditioning dendritic cells to remain in a quiescent state. Inhibitory signalling via Toll-like-Receptors (TLRs) by commensal bacteria possibly contributes to this process.A regulatory innate and adaptive network controls how dietary antigens are taken up and presented to T lymphocytes by specialized antigen-presenting cells. Elucidating their nature and how they are influenced by external factors, including changes in the host\u2019s microbiota may help develop novel therapies for allergy and help understand diseases such as coeliac disease. Current immunotherapeutic approaches to specific oral tolerance induction (SOTI) will be discussed within the framework of oral tolerance induction in humans. Recent advances in our understanding of oral tolerance, the interactions between the innate and adaptive immune system, and the way in which intestinal microbiota may affect the outcome of intestinal antigen exposure will be addressed."}
+{"text": "The development of next-generation sequencing (NGS) technology opens new avenues for clinical researchers to make discoveries, especially in the area of clinical diagnostics. However, combining NGS and clinical data presents two challenges: first, the accessibility to clinicians of sufficient computing power needed for the analysis of high volume of NGS data; and second, the stringent requirements of accuracy and patient information data governance in a clinical setting.http://www.usegalaxy.org] environment at Amazon with specific versions of the tools used in the workflow. The VM launcher tool can reliably recreate the same virtual machine on several cloud environments. Once a baseline virtual machine is created, the tool can launch any number of clones to analyze samples in parallel. We describe herein a pilot project as an example of a working clinical analysis pipeline. In order to validate the clinical diagnosis of diseases with a genetic cause using NGS data, patient samples were collected by Dr Bharat Thyagarajan and staff at the Molecular Diagnostics Laboratory, University of Minnesota medical center-Fairview. The patient samples were analyzed using customized hybrid-capture bait libraries to boost read coverage in low-coverage regions, followed by targeted enrichment sequencing at the BioMedical Genomics Center. The NGS data is imported to a tested Galaxy single nucleotide polymorphism (SNP) detection workflow in a locked Galaxy virtual machine on Amazon's Elastic Compute Cloud (EC2). This project illustrates our ability to carry out CLIA-certified NGS analysis in the cloud, and will provide valuable guidance in any future implementation of NGS analysis involving clinical diagnosis.Cloud computing is a natural fit for addressing the computing power requirements, while Clinical Laboratory Improvement Amendments (CLIA) certification provides a baseline standard for meeting the demands on researchers in working with clinical data. Combining a cloud-computing environment with CLIA certification presents its own challenges due to the level of control users have over the cloud environment and CLIA's stability requirements. We have bridged this gap by creating a locked virtual machine with a pre-defined and validated set of workflows. This virtual machine is created using our Galaxy VM launcher tool to instantiate a Galaxy ["}
+{"text": "The information processing abilities of neural circuits arise from their synaptic connection patterns. Understanding the laws governing these connectivity patterns is essential for understanding brain function. The overall distribution of synaptic strengths of local excitatory connections in cortex and hippocampus is long-tailed, exhibiting a small number of synaptic connections of very large efficacy. At the same time, new synaptic connections are constantly being created and individual synaptic connection strengths show substantial fluctuations across time. It remains unclear through what mechanisms these properties of neural circuits arise and how they contribute to learning and memory. In this study we show that fundamental characteristics of excitatory synaptic connections in cortex and hippocampus can be explained as a consequence of self-organization in a recurrent network combining spike-timing-dependent plasticity (STDP), structural plasticity and different forms of homeostatic plasticity. In the network, associative synaptic plasticity in the form of STDP induces a rich-get-richer dynamics among synapses, while homeostatic mechanisms induce competition. Under distinctly different initial conditions, the ensuing self-organization produces long-tailed synaptic strength distributions matching experimental findings. We show that this self-organization can take place with a purely additive STDP mechanism and that multiplicative weight dynamics emerge as a consequence of network interactions. The observed patterns of fluctuation of synaptic strengths, including elimination and generation of synaptic connections and long-term persistence of strong connections, are consistent with the dynamics of dendritic spines found in rat hippocampus. Beyond this, the model predicts an approximately power-law scaling of the lifetimes of newly established synaptic connection strengths during development. Our results suggest that the combined action of multiple forms of neuronal plasticity plays an essential role in the formation and maintenance of cortical circuits. The computations that brain circuits can perform depend on their wiring. While a wiring diagram is still out of reach for major brain structures such as the neocortex and hippocampus, data on the overall distribution of synaptic connection strengths and the temporal fluctuations of individual synapses have recently become available. Specifically, there exists a small population of very strong and stable synaptic connections, which may form the physiological substrate of life-long memories. This population coexists with a big and ever changing population of much smaller and strongly fluctuating synaptic connections. So far it has remained unclear how these properties of networks in neocortex and hippocampus arise. Here we present a computational model that explains these fundamental properties of neural circuits as a consequence of network self-organization resulting from the combined action of different forms of neuronal plasticity. This self-organization is driven by a rich-get-richer effect induced by an associative synaptic learning mechanism which is kept in check by several homeostatic plasticity mechanisms stabilizing the network. The model highlights the role of self-organization in the formation of brain circuits and parsimoniously explains a range of recent findings about their fundamental properties. The computations performed by cortical circuits depend on their detailed patterns of synaptic connection strengths. While the gross patterning of connections across different cortical layers has been well described in some cases Self-organization typically relies on a combination of self-reinforcing (positive feedback) processes that are combined with a competition for limited resources. In the context of Neuroscience, an example of a self-reinforcing process may be that correlated firing of two groups of neurons may strengthen synaptic connections between them according to Hebb's postulate of synaptic plasticity, while the strengthened connections will in turn amplify the correlated firing of the neurons. An example for competition for a limited resource may be a synaptic scaling mechanism that limits the sum of a neuron's synaptic efficacies such that one synapse can only grow at the expense of others. The combination of self-reinforcing mechanisms with limited resources often gives rise to the formation of structural patterns, which may or may not have specific functional advantages. Here, we will offer an explanation for fundamental aspects of the fluctuations of synaptic strength and the distribution of synaptic efficacies based on self-organization.Specifically, recent evidence shows that the distribution of synaptic efficacies is highly skewed To investigate whether and how these properties can arise from self-organization induced by neuronal plasticity mechanisms, we have developed a self-organizing recurrent network (SORN) model. It extends a previous model We simulated networks of 200 excitatory and 40 inhibitory neurons for 10,000 time steps and observed the resulting activity patterns  and distTo estimate the probability distribution governing excitatory-to-excitatory synaptic strengths we bin connection strengths and divide the number of occurrences in each bin by the bin size. The bin sizes are uniform on the log scale. To mimic experimental procedures decay of connectivity, where a substantial fraction of the excitatory-to-excitatory synaptic weights get eliminated  model The network's activity state, at a discrete time The The time scale of a single iteration step in the model corresponds to typical membrane time constants and widths of spike-timing dependent plasticity (STDP) windows \u2014 lying roughly in the range of 10 to 20 ms. Note that in order to save computation time the homeostatic plasticity mechanisms described below are simulated to be much faster than in reality.The network relies on several forms of plasticity: STDP of EE and EI connections, synaptic scaling and structural plasticity of EE connections, and intrinsic plasticity regulating the thresholds of excitatory neurons.The set of Synaptic normalization proportionally adjusts the values of incoming connections to an excitatory neuron at each time step so that they sum up to one:intrinsic plasticity rule maintains a constant average firing rate in every neuron. To this end, a neuron that has just been active increases its threshold while an inactive neuron lowers its threshold by a small amount:An Note that the synaptic normalization and intrinsic plasticity mechanism operate faster in the model than they would in biological brains. This choice is warranted because of a separation of time scales and speeds up the simulations.Structural plasticity adds new synaptic connections between excitatory cells to the network at a small rate, which balances the synapse elimination induced by STDP. With probability Compared to the original SORN model, we introduce two additional forms of plasticity. Inhibitory spike-timing dependent plasticity (iSTDP) adjusts the weights from inhibitory to excitatory neurons to balance the amount of excitatory and inhibitory drive a neuron is receiving. If the inhibitory neuron spikes and the excitatory neuron remains silent in the subsequent time step (the inhibitory spike was \u201csuccessful\u201d in preventing the excitatory cell from spiking), the inhibitory weight is reduced by an amount Equivalently, we can write:Text S1Comparison of SORN weight distribution to experimental data.(PDF)Click here for additional data file.Text S2Parameter robustness analysis and long-term dynamics.(PDF)Click here for additional data file."}
+{"text": "CesA) genes have been shown to be involved in the deposition of primary and secondary walls. In Arabidopsis, three CesA  genes have consistently been associated with cells depositing secondary cell walls, while a different set of CesA genes have been shown to function during primary cell wall formation [Reviewed in 1]. These findings have been mirrored by studies of CesA gene orthologs in Populus and Eucalyptus[CesA genes and their functions, much less is known about the regulation of these genes. In a previous study, we investigated the promoters of CesA genes involved in primary and secondary cell wall formation by performing a phylogenetic footprinting analysis to identify cis-elements conserved in the promoters from orthologous Arabidopsis, Populus and Eucalyptus cellulose synthase genes [CesA gene promoters by investigating their conservation across different Eucalyptus species and to determine the regulatory function of these promoter regions and the proteins which bind to them.Cellulose is an important biopolymer produced by all plants and is used in a number of different industries, including for pulp and paper production. Cellulose is deposited into the plant cell wall by a large membrane-bound protein complex, which is composed of different cellulose synthase (CESA) proteins. The cellulose content and pattern of deposition in plant cell walls is highly variable depending on the function of the cell. All plant cells have a thin primary cell wall, but a number of plant cell types, including xylem cells, also deposit a secondary cell wall to give these tissues mechanical strength required to perform their function. Different cellulose synthase  promoter for involvement in spatio-temporal regulation by cloning the full-length (2 kb) promoter and a series of truncates thereof upstream of the \u03b2-glucuronidase (GUS) reporter gene. These constructs were used to transform Arabidopsis  and Eucalyptus . The GUCesA promoter sequences and cis-elements in 13 Eucalyptus species provided us with valuable insight into the relative conservation of specific promoters regions and the cis-elements within these regions. We found that the overall nucleotide diversity of the promoter sets varied greatly from promoter to promoter, but we could identify regions in the promoters that were as conserved as coding regions. We found that in many cases these localized decreases in nucleotide diversity corresponded to clusters of conserved cis-elements which were identified previously [EgCesA1 promoter. Using GUS expression analysis in Arabidopsis we identified a number of repression and activation sites within the promoter. We also observed a loss of leaf (vein) expression 800 bp upstream. One of the repeat elements fused to the 5\u2019UTR greatly enhanced overall GUS expression in a non-specific way. In a Eucalyptus background (ISSA), six of the seven truncates showed xylem-specific expression, but the 5\u2019UTR and repeat element fusion showed GUS expression in phloem and xylem. These regions have been used to construct bait vectors for Yeast-1-hybrid screening which is still ongoing.Studying the diversity of eviously . This waEucalyptusCesA promoters and cis-elements associated with primary and secondary cell wall formation, (2) investigate the expression patterns of truncated versions of the EgCesA1 promoter using the GUS reporter system and (3) test the EgCesA1 promoter regions affecting gene expression in a yeast-1-hybrid assay to identify possible regulators of this gene. We have identified regions in the promoter that were conserved and corresponded to previously identified cis-elements. Using this information we produced seven promoter truncates and discovered several regions and cis-elements in the EgCesA1 promoter which affect GUS expression patterns. These results will aid in understanding and elucidating transcriptional networks regulating xylogenesis in woody genera such as Eucalyptus.In this study we addressed three main objectives, (1) investigate the evolution of the"}
+{"text": "During speaking, auditory feedback is used to adjust vocalizations. The brain systems mediating this integrative ability have been investigated using a wide range of experimental strategies. In this report we examined how vocalization alters speech-sound processing within auditory cortex by directly recording evoked responses to vocalizations and playback stimuli using intracranial electrodes implanted in neurosurgery patients. Several new findings resulted from these high-resolution invasive recordings in human subjects. Suppressive effects of vocalization were found to occur only within circumscribed areas of auditory cortex. In addition, at a smaller number of sites, the opposite pattern was seen; cortical responses were enhanced during vocalization. This increase in activity was reflected in high gamma power changes, but was not evident in the averaged evoked potential waveforms. These new findings support forward models for vocal control in which efference copies of premotor cortex activity modulate sub-regions of auditory cortex. During normal human speech, speakers modulate their vocalizations to adjust to environmental conditions. For example, during phonation, altering the pitch of real-time auditory feedback a speaker receives results in alterations in the produced voice fundamental frequency To date, investigators have exclusively used non-invasive methods to measure brain activity in human subjects during vocalization-playback experiments using the subjects' own voice. Scalp electroencephalographic (EEG) and magnetoencephalographic (MEG) recordings have shown a reduction in the amplitude of auditory evoked responses when subjects vocalize compared to when they quietly listen to a recording of these same vocalizations The current experiments were carried out in order to directly measure the effects of vocalization on speech-sound processing by taking advantage of the high spatial resolution of implanted intracranial electrodes in neurosurgery patients undergoing epilepsy surgery. By recording evoked brain activity from electrode arrays placed on the lateral superior temporal gyrus (STG) it is feasible to study electrophysiological activity from auditory cortex with a combined spatial-temporal resolution that cannot be achieved using non-invasive methods. We used this recording approach during vocalization-playback experiments to test the hypothesis that vocalization-associated changes in speech sound processing occur mainly within localized areas of human auditory cortex and the overall nature of these changes would be attenuation. This hypothesis, which is an element of some forward models The subjects (N\u200a=\u200a10) in this report were patients  undergoing surgical treatment of medically intractable epilepsy who volunteered to participate in this research protocol. Their ages ranged from 20 to 62 years (mean 35.6 yrs). Written informed consent was obtained from each subject and all research protocols were approved by the University of Iowa Human Subjects Review Board. Subjects did not incur any additional medical risks by participating in these studies.Each subject completed an extensive pre-surgical assessment including detailed neurological examination, brain imaging , and neuropsychological evaluation. These tests confirmed normal speech and language functions in all subjects. No anatomic lesions were observed in the frontal lobe or temporal lobe auditory cortex in any subject. Standard audiometric testing was conducted and all patients were found to have normal hearing. All but one subject underwent preoperative sodium amobarbital (WADA) testing As part of a standard multi-disciplinary epilepsy surgery evaluation and treatment protocol, each subject was deemed to be an appropriate candidate for surgical placement of intracranial multi-contact recording arrays for the purpose of recording and anatomically localizing seizure events. During an implantation operation, custom manufactured high-density electrode arrays (see below) were placed on the pial surface of the exposed brain regions. The electrodes remained in place during a 14-day hospital stay during which time the patients underwent continuous video-EEG monitoring. This high-resolution EEG monitoring confirmed that the peri-Sylvian cortical areas pertinent to this study  did not show abnormal inter-ictal activity. At the completion of the monitoring period, the electrodes were removed and the seizure focus was resected. Resections in all 10 cases were restricted to the anterior temporal pole and mesial temporal lobe structures. The resections did not involve the STG. The surface recording arrays consisted of platinum-iridium disc electrodes embedded within a silicon sheet with 5 mm center-to-center spacing and 3 mm contact diameter . In eight subjects the high-density recording grid consisted of 96 contacts, while one had a 64-contact high-density grid. One subject received a 32-contact low-density grid (1 cm center-to-center contact spacing). Separate electrodes were implanted in the subgaleal space over the vertex to serve as reference contacts. The exact position of each recording electrode was localized using a combination of high-resolution digital photographs taken intra-operatively during electrode placement and removal, as well as thin-cut (1 mm) pre- and post-implantation MR and CT scans. Pre- and post- implantation MRIs were co-registered using a 3-D rigid-fusion algorithm implemented in Analyze software  Acoustic stimuli were presented during two separate sessions; a self-vocalization (SV) session and a passive listening  session. For both sessions, the subject was resting comfortably in their hospital bed or a recliner. During the SV session, each subject was instructed to speak the same utterance (e.g. \u201cbirthday\u201d) in a consistent manner using a normal, conversational speech intensity and rate, with an approximate two second interval between utterances. The entire vocalization session, consisting of approximately 50 utterances, was captured and recorded using a microphone  held by the subject approximately one inch from their mouth using the hand ipsilateral to the brain hemisphere from which recordings were obtained. In the PB condition, the recorded utterance was played back via a pair of headphones  placed in custom-fit, vented insert ear molds. The subjects heard their own vocal production that was amplified , passed unaltered through a harmonizer  and routed back to the headphones. The harmonizer was controlled with MIDI software  by a standard laboratory computer. The contribution of bone conduction during the SV block cannot be measured or manipulated; therefore we used a strategy employed by previous investigators to determine whether the sound intensity of stimuli could account for any observed differences in evoked responses Details of the electrode implantation method and data acquisition techniques used have been described previously Digitized voice signals were recorded simultaneously with the evoked brain responses using the TDT system to provide a common time scale for both the evoked cortical responses and voice signals. Stimulus-evoked potentials were created using a back-averaging method whereby the voice onset of each utterance was manually identified in the sound waveform using a thresholding technique. As the time intervals between the individual utterances were identical for both SV and PB conditions, the same voice onsets identified in the SV task were used for the PB task. From these onsets, individual trials of data blocks were created to evaluate brain activity before and after each voice onset. All individual voice and brain recording trials were manually inspected and discarded if artifacts were noted. The remaining trials were then averaged to create AEPs  for eachP-values to reflect these multiple comparisons. The MANOVA procedure was preceded by a principal component analysis (PCA) in order to reduce the dimensionality of the data vectors Statistically significant differences in evoked responses were determined using an analysis of variance method comparing responses recorded during the SV and PB conditions, for each electrode site, and for both AEP and HGB power responses. In the current experiments, the dependent AEP (or HGB power) measurement was treated as a multivariate response and assumed to be sampled from a multivariate distribution Two different analysis window durations were utilized when making statistical comparisons between brain responses during the SV and PB conditions. The AEPs observed on STG were found to have a polyphasic morphology with components extending to 500 ms beyond the onset of the utterances e.g.  and 4A, Analysis of the electrophysiological data using both AEPs and HGB ERBP has revealed consistent response patterns throughout our series of ten subjects. Findings from a representative subject with electrodes over the left, language-dominant hemisphere are presented in Examination of this subject's ERBP responses demonstrated a similar pattern of anatomic localization of sites showing significant changes across the two conditions . Again, All subjects with grids that covered adequate portions of the STG anterior and posterior to the lateral boundary of the TTS demonstrated a discrete area of activation where either the AEP or ERBP responses varied significantly between the SV and PB conditions. Findings from a subject with right hemisphere, non-language dominant electrode implants, and partial STG coverage, are shown in Variations across brain sites were also seen in the high gamma responses in this subject R149, . The samRegional STG response differences, with clear variation seen between sites located only millimeters away from each other, were observed in all subjects. Every subject in this series had at least one site on lateral STG that demonstrated either an increase in HGB power during SV compared to PB, or a categorical change in HGB response type with an \u201conset\u201d response during PB and a \u201csustained\u201d response during SV. Exemplars of such response-type changes are shown in Results evaluated across the entire subject series (N\u200a=\u200a10) demonstrate an overall similar pattern of responses along the lateral STG. In both left  and righThe response patterns seen across these 10 subjects show that there are a larger number of temporal lobe sites demonstrating significant vocalization-induced changes in the AEP responses than sites that show significant HGB power changes ,8A. The There is marked variability in the proportion of recording sites capturing responses that were significantly different for the SV and PB conditions. The degree to which specific recording results vary across experimental subjects likely results from small differences in electrode grid locations and the known inter-subject variability in the locations of specific auditory fields relative to gross anatomical landmarks. In some subjects, and during some experiments, the signal-to-noise ratio of auditory evoked responses to all classes of auditory stimuli was reduced as a result of increased electronic noise levels. In other instances, the number of effective stimulus presentations during an experimental session was reduced as a result of post-hoc rejection of artifact contaminated epochs. These factors contributed to a relative loss of statistical power in experiments performed in left hemisphere subjects 164, 173, and 178 and right hemisphere subject 175. In addition, subject 173 demonstrated overall diminished auditory cortical responses to other acoustic stimuli  during other experimental sessions.The results of the current experiments provide the first directly recorded electrophysiological evidence of vocalization-induced activity associated with speech-sound processing within human auditory cortex. The effects were predominantly suppressive in nature, consistent with reports from earlier experimental animal and non-invasive human studies. New findings include the observations that vocalization-associated effects occur within relatively-circumscribed regions of the lateral superior temporal gyrus, and activation at some STG sites is enhanced during vocalization. Changes were observed in both AEP and HGB power, but the results are not identical for these two different measures of brain activity.Normal hearing humans continuously make use of auditory information to adjust their vocalizations and optimize speech communication. A wide range of experimental approaches has been used to investigate the neural systems that subserve this sensory-motor integration in humans. One model postulates that when humans vocalize, the vocal motor system produces a motor speech template, or efference copy, that is utilized within auditory cortex to compare the auditory stimuli that is actually heard during vocalization, with the vocalization that the motor system intended to produce Our most detailed understanding of how auditory cortical neurons change their firing patterns during vocalization comes from experimental animal studies. In this setting, action potentials generated by individual auditory cortex neurons can be recorded using microelectrodes. This invasive method has been used extensively to study the basic functional properties of auditory cortical neurons in various species; however, it is very difficult to obtain these recordings in awake, vocalizing animals. The first reported microelectrode experiments of this type did not rely on spontaneous vocalizations, but relied instead on electrical stimulation of the brainstem central gray matter to evoke vocalizations in the squirrel monkey Auditory cortical microelectrode recordings in non-human primates obtained during spontaneous vocalizations have only recently been reported Investigators face unique challenges when seeking to pursue a similar experimental strategy in humans. Unlike monkeys, humans can be easily trained to perform vocalization tasks. However, safety considerations limit the types of human brain recording methods. Vocalization-induced changes in auditory processing have been characterized using non-invasive scalp EEG and MEG methods A number of lines of evidence suggest that the effects of vocalization will differ for different areas of human auditory cortex and that high-resolution recording methods are required to characterize this organizational pattern. Extrapolating from anatomical and physiological data derived from experimental animal studies, and more limited human studies, it is hypothesized that human auditory cortex is comprised of ten or more fields organized into core, belt and parabelt groups The current experiments were designed to examine this hypothesis directly using the opportunity to record from auditory cortex on the lateral STG of neurosurgical patients. By recording brain activity using electrode arrays positioned on the pial surface it is possible to examine responses with a high degree of spatial and temporal resolution. The results consistently demonstrated circumscribed areas of cortex along the lateral STG where responses differed during the self-vocalization and vocal playback conditions. The most consistently identified area was overlying the lateral terminus of the transverse temporal (Heschl's) sulcus (TTS). In this area, the amplitude of AEPs and HGB power were most often diminished during the SV condition. In some cases, there was intervening cortical tissue within this area of the STG that was acoustically responsive, but not significantly altered by vocalization.suppressive in nature, there were also clear examples of small areas of STG where HGB power was markedly increased during SV compared to PB. In those instances, the vocalization-induced increase in HGB power was not accompanied by amplitude increases of the average evoked potential and the effects of vocalization were only detected by analyzing bandpass power changes. This finding emphasizes the importance of analyzing both the phase-locked and non-phase locked activity recorded from intracranial electrodes, as previously reported by Crone and others Although the dominant vocalization-related effect was when vocalization-associated effects occur within auditory cortex. Single unit recordings obtained in marmoset auditory cortex clearly demonstrate that suppressive effects of vocalization begin more than one hundred milliseconds prior to onset of vocalization One of the questions that investigators seek to address with vocalization-feedback experiments is The recording montages used during MEG and EEG experiments are standardized across subjects and measure the summed activity of large populations of neurons. With these methods the waveform morphologies of auditory evoked potentials are well characterized with features that can be reliably identified and compared across subjects, and investigators have described vocalization-associated changes in amplitude and latency of the averaged auditory evoked potentials. This same approach is less well suited to the analysis of the current data set for a variety of reasons. The first is the large magnitude of the vocalization effect observed in the current study. In contrast to non-invasive studies where modest changes are observed in the averaged evoked waveforms, many of the responses recorded directly from STG are entirely absent during vocalization, or so severely attenuated that waveform components cannot be compared across the SV and PB conditions. The second factor that complicates this analysis is the high degree of variability observed in the AEP waveforms recorded from different sites along the STG. The AEP waveform recorded from the focus of maximum response within area PLST has been described previously and can be consistently identified across subjects, but this represents only a small portion of the STG from which auditory evoked responses are obtained in the current experiments on\u2019 response. A different, \u2018sustained\u2019 HGB response pattern was also observed whereby increases in power were maintained throughout the duration of the vocalization. At brain sites where vocalization was associated with diminished HGB power, this suppression was typically manifest as a decrease in the magnitude of the power throughout the response, without an obvious change in the overall temporal pattern of the response (Vocalization was also associated with alterations in the temporal patterns of HGB changes. These findings cannot be directly compared with previous studies because this is the first report where HGB power was directly measured in a vocalization-playback experiment using the subject's own voice. The temporal patterns of HGB power changes were complex and varied by vocalization condition, and location along the STG. The duration of the power changes also varied significantly for different brain sites and conditions. One commonly observed response type was characterized by a transient increase in HGB power soon after stimulus onset, consistent with an \u2018response . In contresponse . The strIn almost all cases, the onset of HGB power changes occurred after stimulus onset. In rare instances, power changes occurred prior to vocalization, but these sites did not conform to a consistent anatomical pattern across subjects and the significance of this finding is uncertain. This observation contrasts with the unambiguous findings in marmosets where suppression of neuronal firing was observed prior to vocalization onset A number of caveats must be considered when interpreting the results of the current experiments. Invasive recordings in humans allow investigators to record electrophysiological events with a degree of combined spatial-temporal resolution that cannot be achieved using non-invasive experimental approaches. However, the intracranial electrodes cover only a portion of auditory cortex. The effects of vocalization on auditory processing within presumed core and belt fields located in the supratemporal plane cannot be studied using electrodes positioned over the lateral STG. Also, direct recordings are only obtained from one hemisphere in each subject, precluding the ability to make within-subject comparisons of simultaneously recorded responses in right and left hemispheres.There are also limitations inherent to the SV versus PB experimental protocol irrespective of the brain recording method used. One is the assumption that the subject hears the same acoustic stimulus during both SV and PB conditions. In fact, the acoustic signals activating the cochlea are not identical in the two conditions. During vocalization, a portion of the total acoustic signal is conducted through bone and soft tissue and is attenuated and spectrally filtered before it reaches the cochlea. This bone-conducted signal cannot be precisely measured and therefore cannot be exactly replicated during playback Another limitation of the SV versus PB experimental design is that only certain aspects of the forward model are tested. The data in the current report, for example, provide no information concerning the stimulus specificity of the vocalization-associated alterations observed within auditory cortex. Other investigators, using non-invasive recording methods, have probed the specificity of response changes by altering the acoustic properties of the feedback stimulus and examining how brain responses are affected by induced mismatches between the intended vocalization and the speech signal heard by the subject"}
+{"text": "The results of these studies showed important differences in the serological findings of the two strains as reflected by the much higher numbers of MPs with bound IgG in the blood of MRL-lpr/lpr compared with NZB/W mice. These studies also showed that antibodies from MRL-lpr/lpr mice bound much better to MPs from apoptotic cells than those from NZB/W mice. Since particles in NZB/W blood bound to monoclonal anti-nuclear antibodies as well as MRL-lpr/lpr plasma, these findings indicate antigenic activity despite the lack of particle IgG complexes in NZB/W blood. Together, these studies indicate important differences in the serological features of the two strains as reflected by the capacity of antibodies to bind to MPs. These differences may impact on the process of immune complex formation and its consequences as well as the respective role of anti-DNA and other autoantibodies in nephritis in NZB/W mice.Systemic lupus erythematosus is a systemic inflammatory disease characterized by anti-DNA production in association with immune complex deposition. These complexes can deposit in the tissue to incite inflammation as well as stimulate cytokine production by plasmacytoid dendritic cells. While the properties of anti-DNA antibodies have been extensively characterized, little is known about the nature of the DNA in the immune complexes although its origin is generally considered to be cell death. Among sources of extracellular DNA, microparticles (MPs) are small membrane-bound vesicles released from activated and dying cells by a blebbing process. As shown by flow cytometry, these particles display DNA as well as other nuclear molecules in an antigenically accessible form as indicated by the binding of monoclonal anti-DNA antibodies as well as plasma from patients with lupus. Furthermore, plasma from patients with lupus contains increased number of particles with bound IgG, suggesting that MPs can form immune complexes found in lupus. To assess whether MPs play a similar role in murine lupus, we used flow cytometry to measure the presence of MPs with bound IgG in the blood of MRL-"}
+{"text": "Autonomous transcription of integrated retroviruses strongly depends on the genetic and epigenetic effects exerted by chromatin at the site of integration. These effects are mostly suppressive and proviral transcription can be ultimately silenced by mechanisms such as DNA methylation and histone modifications. Transcriptional silencing is a general feature of integrated retroviruses, however, the extent and frequency varies among the retroviral species. On that account, features determining the activity of individual integrated proviruses need to be identified.To address the role of the integration site at the whole-genome-scale, we performed clonal analysis of provirus silencing with an ASLV-derived and a HIV-derived reporter vectors and correlated the transcriptional silencing with the epigenomic landscape of the respective integrations. The analysis was performed in the human K562 cell line and particularly in HCT116-derived DNMT-deficient cell lines in order to analyse the role of DNA methyltransferases in the provirus silencing.de novo DNA methyltransferase activity [Dnmt3a-/- Dnmt3b-/- cells. The silencing of proviruses within the transcribed regions of genes is accompanied by DNA methylation of long terminal repeats and dependent on the presence of de novo DNA methyltransferases. Converse, silencing in intergenic regions is DNA methylation-independent.We demonstrate efficient provirus silencing in human K562 and HCT116 cell lines, which is strongly but not absolutely dependent on the Since CpG islands were reported as DNA methylation-resistant genomic regions, we designed an ASLV-derived reporter vector modified by insertion of the CpG island core element  into itsThese findings indicate that the epigenomic features of integration sites are crucial for their permissiveness to the proviral expression. Both ASLV and HIV proviruses require similar epigenomic environment for their stable expression and the increased frequency of stable HIV proviruses is probably the result of the integration preference, which favours permissive genomic regions."}
+{"text": "Discontinuation of drug intake in cocaine abusers commonly produces a variety of adverse withdrawal symptoms among which anxiety and depression-related behavior are prevailing during the initial period of abstinence. The aim of this study was to provide further insight into the neurobiological dysregulations that might contribute to these pathological states. Rats were treated with cocaine or saline for 14 days  and anxiety-related behavior was assessed in different paradigms (elevated plus-maze (EPM), confinement to an open arm of the EPM and shock-probe burying tests) for up to 4 weeks after withdrawal. Depression-like behavior was assessed by the forced swim test and sucrose preference test. Altogether our results demonstrated that cocaine withdrawal induced persistent heightened levels of anxiety that last for at least 28 days but did not affect depression-like behavior. We then used Fos immunohistochemistry to map neuronal activation patterns in withdrawn rats confined to one open arm of an EPM, and a double labeling procedure using Fos immunohistochemistry and in situ hybridization of glutamic acid decarboxylase or vesicular glutamate transporter mRNAs to identify the phenotype of the activated neurons. Our data showed that the exacerbated anxiety observed in cocaine withdrawn rats exposed to an elevated open arm was accompanied by an altered reactivity of the dorsal part of the medial prefrontal cortex , the paraventricular thalamic nucleus and the lateral and anterior areas of the hypothalamus. In the medial prefrontal cortex, we evidenced a negative correlation between Fos expression in its dorsal part and open arm-induced freezing in NaCl-treated rats but not in cocaine withdrawn rats. We also found that more than 65% of activated neurons were glutamatergic projection neurons. The present study provides new insights into the neuroanatomical regions and neuronal cell types that may underlie pathological anxiety during cocaine withdrawal. Cocaine addiction is a chronic brain disorder characterized by compulsive drug use and high risk of relapse. Like other drugs of abuse, cocaine induces both powerful positive reinforcing effects and negative affective states that emerge when access to the drug is prevented. Indeed, discontinuation of drug intake in cocaine abusers commonly produces a variety of adverse withdrawal symptoms, among which sleep disturbances, anxiety and depression-related behavior are prevailing during the initial period of abstinence The mechanisms and brain regions underlying dysfunctional aspects of anxiety processing in cocaine abstinent abusers are still poorly understood. Human and animal studies on the processing of negative emotions such as anxiety have implicated several medial prefrontal cortex (mPFC) regions and a set of limbic structures which includes the amygdala, insula as well as interconnected structures such as the hypothalamus In order to address this issue, we first assessed in rats anxiety-like behavior in different paradigms (elevated plus-maze (EPM), confinement to an open arm of the EPM and shock-probe burying tests) for up to 4 weeks after withdrawal from chronic cocaine treatment. In addition, we concomitantly assessed depression-like behavior by the forced swim test and sucrose preference test. Indeed, although the anxiogenic and depressive-like properties of cocaine withdrawal have been documented in numerous animal studies ad libitum. Once a day for 5\u20137 days before the treatment, rats were handled for few minutes to reduce the stressful effects of handling. All experiments were performed between 9:30 AM and 5:00 PM.Male Sprague-Dawley rats  weighing 200\u2013225 g upon arrival were housed in groups of four and maintained in a temperature-controlled environment on a 12-hour light/dark cycle (lights on at 7:00 AM) with access to food and water Every effort was made to minimize animal suffering and the number of animals used. All experimental procedures were performed in accordance with the European Community Council Directives (86/609/EEC) and the French guidelines (Act 87\u2013848 Minist\u00e8re de l\u2019Agriculture) on the care and use of laboratory animals. Authorization to conduct experiments on alive animals was obtained from the Direction d\u00e9partementale des services v\u00e9t\u00e9rinaires du Rh\u00f4ne (authorization number 69266242).Rats were administered cocaine hydrochloride   or saline (0.9%) in their home cage once a day for 14 days as previously described Independent groups of rats were used for each behavioral test and for each period of withdrawal.A Plexiglas EPM consisting of two open (50\u00d710 cm) and two enclosed (50\u00d710\u00d740 cm) arms with a black floor and arranged such as the open arms were opposite to each other was used. The maze was elevated 65 cm above the floor and located inside an isolated room with 10 lux of luminosity in the central zone.Rats were placed in the central zone facing an open arm and their behaviors videotaped during the 5-min test period. The behavioral parameters scored were the number of entries and the time spent in the open and closed arms . Exploratory movements of the head (head-scanning) and immobility times were also monitored.For this test, one open arm of the EPM was isolated from the central zone and the closed arms of the maze by a 40 cm high wall. The open arm was divided into two equal parts, one proximal and one distal in relation to the high wall. Rats were placed in the middle of the open arm facing the open space. The behavioral parameters scored during 5 min were the time spent in the distal zone of the open arm, the number of rearing, and the time spent head-scanning and freezing (defined as complete immobility with the exception of respiratory-related movements).The apparatus consisted of a Plexiglas cage  covered with 5-cm deep standard bedding material. A removable, electrified probe  was placed through a hole 2 cm above the bedding material and was connected to a Coulbourn precision shocker  calibrated to deliver a shock of 0.5 mA whenever the rat touched it with a forepaw or the snout.Rats were habituated (3\u20134 cage mates together) to the apparatus in the absence of the shock probe for 1 h each day for two consecutive days. On the third day, rats were tested individually with the electrified probe in place. Five min after the first shock, the current was turned off and the behaviors scored offline for 15 min following the first shock by an observer unaware of the treatment. Parameters measured were the duration of burying, the latency to return to the probe after the first shock and the total duration of immobility.Anhedonia was assessed daily during exposure to cocaine and withdrawal by way of the sucrose preference test. Briefly, rats were housed in a single cage and were presented with two pre-weighed bottles containing either a sucrose solution or tap water. Water and sucrose consumption were measured at 10:00 AM each testing day at which time the position of the sucrose bottle (left or right) was reversed to control for side preference. Sucrose preference was calculated as the ratio of sucrose intake to total fluid intake (weights per 24 h).The procedure was similar to that described previously Two hours after the onset of the open arm test, animals were deeply anesthetized with sodium pentobarbital  and transcardially perfused with saline followed by 4% paraformaldehyde. Free-floating coronal brain sections (30 \u00b5m thick) were processed using a standard immunohistochemical procedure as previously described Rats were assigned to four groups: cocaine-treated rats and saline-treated rats exposed to the open arm; cocaine-treated rats and saline-treated rats taken in their home cage to the experiment room but not exposed to the open arm. In each experiment, sections from rats of the four groups were immunolabeled at the same time.The antisense glutamic acid decarboxylase (GAD) probe Images were captured using a light microscope  equipped with a digital camera . All images were imported into Adobe Photoshop, adjusted for contrast and luminosity and assembled into plates.Bright field images of sectioned material were viewed with a Zeiss Axioskop 2 microscope equipped with an X/Y sensitive stage and a video camera (Lumenera Infinity 2) connected to a computerized image analysis system . The planes of the analyzed sections were standardized according to the atlas of Paxinos and Watson 2 was then determined and used to calculate the group means and for statistical analyses.The quantification was carried out by first delineating the brain sections and the regions of interest (ROI) at low magnification (\u00d7 4 objective). The ROI outlines were further refined under a \u00d7 10 objective and labeled cells then counted manually by an observer blind to the experimental groups. For each rat, at least two sections per structure were quantified bilaterally. The density of labeled cells per mmU test for pairwise comparisons. Correlations between Fos expression in each of the four sub-regions of the mPFC and the different behavioral scores were calculated according to the Spearman method. The sucrose consumption data were analyzed by a two-way ANOVA with one between-subject factor (treatment) and one within-subject factor (time). The level of significance was set at p<0.05. All values were expressed as mean \u00b1 SEM. Staview software was used for these statistical analyses.Since our data do not meet the assumptions of normality, they were analyzed by a non parametric Kruskal-Wallis test followed by a Mann-Whitney Our results showed that cocaine- and saline-treated rats display no major significant differences in anxiety-related parameters in the EPM after 2 days of withdrawal. No difference was observed in the total number of entries in the open arms , in the percentage of time spent in the open arms  or in thThe absence of differences in anxiety-related behavior between cocaine- and saline-treated rats in the EPM led us to postulate that a more anxiogenic environment, such as confinement to the open arm Finally, cocaine-treated rats were tested during withdrawal in another well-validated model of anxiety, the shock-probe burying test, allowing the investigation of different aspects of anxiety-induced behavioral reactivity. After receiving a shock from the electrified probe, rats may exhibit a passive or avoidance behavioral response (immobility) or an active defensive burying behavior directed at the probe. At 2 days of withdrawal, periods of time spent burying the probe were less and periods of immobility longer in cocaine-treated rats compared to saline-treated rats . This in1,10\u200a=\u200a0.89; ns) or throughout the following 28-day withdrawal period   for 2 days in order to define the concentration allowing an increase or a decrease in sucrose consumption to be measured Inset . The suc.10; ns) . In the .10; ns) .Possible alterations in brain reactivity of cocaine withdrawn rats were explored with the expression of the immediate early gene Fos as a marker of neuronal activation. Brain structures were selected on the basis of their relevance to anxiety-related behaviors 2), except in the piriform and primary visual cortices and the paraventricular thalamic nucleus where the densities of Fos-expressing cells were around 600 positive cells/mm2. There were no significant differences between saline- and cocaine-treated rats in these regions , ventral orbital and piriform cortices in both groups of rats whereas there was no change in the primary visual cortex . Two of In subcortical areas, open arm exposure enhanced the density of Fos-expressing cells in the paraventricular thalamic nucleus, hypothalamus , amygdala  and ventral subiculum in both groups of rats . It shouIn cocaine withdrawn rats, Fos response to open arm exposure was lower only in 3 of these quantitatively evaluated areas: the paraventricular thalamic nucleus (31% reduction), the anterior (29% reduction) and lateral (46% reduction) areas of the hypothalamus . In otheThe dorsal mPFC is one of the brain regions that exhibited the highest reactivity to open arm exposure and a region of high relevance in anxiety processing and anxiety disorders. We thus went further into the cellular analysis of cocaine-induced alterations in this cortical area.We first ensured that the decrease in Fos-expressing cell densities observed in cocaine withdrawn rats was not altered by cortical structural changes in terms of neuronal (NeuN-expressing cells) or astroglial cell (GFAP-expressing cells) packing densities . Our resWe then sought to determine the phenotype of the cortical Fos-activated neurons. Double labeling of Fos-labeled cells with vGlut1 mRNA or GAD mRNA  indicateFinally, we examined if there was a correlation between Fos expression in the different subdivisions of the mPFC and the behavioral data obtained in the open arm. Interestingly, we found a significant and selective negative correlation between Fos expression in the cingulate , dorsal prelimbic  cortices and the time spent freezing in NaCl-treated rats. This negative correlation was disrupted in cocaine withdrawn rats.Two major findings have emerged from the present study. First, we showed that cocaine withdrawal had a sustained effect on anxiety-related behavior, particularly that in response to highly challenging situations. In contrast, the same treatment did not affect depression-like behavior suggesting that in our experimental conditions, cocaine had a more profound effect on the mechanisms involved in anxiety regulation than those involved in mood regulation. Second, our anatomical data provide new insight into the neural substrates that may underlie pathological anxiety during cocaine withdrawal. Indeed, we showed that exacerbated anxiety observed in cocaine withdrawn rats placed in an anxiogenic environment was accompanied by dysfunctions within a restricted set of neuroanatomical regions including the dorsal mPFC and anatomically-related subcortical regions such as the paraventricular thalamic nucleus and specific regions of the hypothalamus.Our behavioral data increased our knowledge on the affective states induced by withdrawal from chronic cocaine exposure in rodents. While several studies have already reported a similar elevation of anxiety-related behavior in rodents exposed to the EPM These behavioral findings suggest that cocaine-induced neuroadaptations contribute to long-lasting impairment in the ability to cope with anxiogenic or stressful situations following drug exposure and withdrawal. They support previous observations indicating that persistent heightened levels of anxiety are expressed after protracted withdrawal periods when rats are placed in highly challenging situations such as that during the defensive burying test procedure In contrast, we found no alterations in behavior related to depression. We observed no evidence of helplessness or anhedonic states during withdrawal, two different aspects of depression that were respectively assessed by the forced swim test and the sucrose preference test. Previous data addressing this issue have yielded equivocal results, with some reporting no change To the best of our knowledge, no previous anatomical study has directly addressed the identification of the neural circuit dysfunctions underpinning the impaired expression or regulation of anxiety observed during cocaine withdrawal. Previous studies aiming at characterizing the neurobiological substrates of cocaine-induced anxiety have focused on the action of different receptors such as corticotropin-releasing factor This specific neuroanatomical effect in cocaine withdrawn rats is a novel finding of interest in many respects. Our results are in line with observations made in two other rodent models of pathological anxiety, high anxiety BALB/c mice The differential effect of cocaine withdrawal on the reactivity of the dorsal and ventral subdivisions of the mPFC is relevant in regard to the complex organization of this structure. Anatomical and functional studies have demonstrated a dorsoventral gradient along the mPFC, with the dorsal part  primarily interconnected to regions that reportedly affect cognition, and the ventral part  connected to autonomic/visceral related regions Our animal model also allowed us to go further into the cellular analysis of cocaine-induced alterations in the mPFC without the confounding obstacles commonly encountered in human studies such as polydrug abuse, premorbid psychiatric conditions and variable drug history. Since previous studies have reported the remodeling of cortical neuron dendrites Although Fos is considered as a generic marker of acute neuronal activation and/or changes in cellular signaling In conclusion, the present study provides new insights into the neuroanatomical regions and neuronal cell types that may underlie cocaine-induced disruption in ability to cope with highly anxiogenic situations. Our observations reinforcing the potential importance of the PFC in the negative sequelae of chronic cocaine exposure is in consonance with previous studies reporting neuroadaptations in cortico-striatal-limbic circuits that underlie behavioral and cognitive aspects of cocaine dependence"}
+{"text": "Acanthopagrus australis and Rhabdosargus sarba. The preference for a range of habitats by theses sparid species is evident by their detection on sand-flat, natural rocky reef and artificial reef habitats. The fish assemblage identified on the artificial reefs remained distinct from the adjacent rocky-reef, comprising a range of species drawn from naturally occurring rocky-reef and sand-flat. In addition, some mid-water schooling species including Trachurus novaezelandiae and Pseudocaranx georgianus were only identified on the artificial reef community; presumably as result of the reef's isolated location in open-water. We concluded that estuarine artificial reef assemblages are likely to differ significantly from adjacent rocky-reef, potentially as a result of physical factors such as reef isolation, coupled with species specific behavioural traits such as the ability of some species to traverse large sand flats in order to locate reef structure, and feeding preferences. Artificial reefs should not be viewed as direct surrogates for natural reef. The assemblages are likely to remain distinct from naturally occurring habitat comprised of species that reside on a range of adjacent natural habitats.If the primary goal of artificial reef construction is the creation of additional reef habitat that is comparable to adjacent natural rocky-reef, then performance should be evaluated using simultaneous comparisons with adjacent natural habitats. Using baited remote underwater video (BRUV) fish assemblages on purpose-built estuarine artificial reefs and adjacent natural rocky-reef and sand-flat were assessed 18 months post-deployment in three south-east Australian estuaries. Fish abundance, species richness and diversity were found to be greater on the artificial reefs than on either naturally occurring reef or sand-flat in all estuaries. Comparisons within each estuary identified significant differences in the species composition between the artificial and natural rocky-reefs. The artificial reef assemblage was dominated by sparid species including  Artificial reef development in south-east Australia has followed a similar pattern to the evolution of artificial reefs projects worldwide. During the 1960 s, artificial reefs were deployed within estuarine systems as they were cheaper to construct and typically provided proximate and economic access More stringent environmental regulations, combined with a growing body of research into how artificial reefs and fish assemblages interact Assessing the performance of an artificial reef is dependent on accurately monitoring the fish assemblages at both artificial and suitable naturally occurring habitats Most studies of estuarine artificial reefs have focussed on comparisons with non purpose built artificial reef structures such as revetment walls To provide a quantitative comparison of fish assemblages associated with artificial reefs  with adjacent natural habitats in three south-east Australian estuaries, baited remote underwater video (BRUV) data was selected from a summer to autumn period (Dec \u2013 May), 12\u201318 months post artificial reef construction. The predicted hypothesis based on previous studies that have investigated and compared artificial structure assemblages with those assemblages found on natural reef habitat is that after a minimum of 1 year post artificial reef deployment, the assemblage identified on the artificial reef would be comprised of a similar suite of species to those found on the natural rocky-reef. However the proportional distribution of assemblages associated with artificial reefs when compared to the rocky-reef would vary as an artefact of reef type, location and age. Hence, the aims of the study were to (i) identify dominant species and family groups, and; (ii) investigate the ability of the artificial reefs to support an assemblage comparable to those identified on the natural rocky-reef and to provide surrogate habitat to the broader estuarine fish community.All field studies outlined in this paper were authorised under a scientific research permit (permit No: P01/0059) issued by the NSW Department of Primary Industries under section 37 of the Fisheries Management Act 1994. This permit authorises the collection of fish in all waters of NSW. The estuarine sites sampled with baited remote under water video (BRUV) were not privately owned or protected and no endangered or protected species were involved in this study. All fish observations using BRUV was carried out in an ethical manner and no fish were euthanased as part of this study.The artificial reefs were constructed as part of a larger study to investigate the use of artificial reef in three coastal estuaries along Australia's south east coast in the State of New South Wales Reef location was determined through extensive constraints mapping of existing habitat, suitability of bottom type and depth for safe navigation and consultation with existing user groups. Final reef position within all three estuaries reflects these constraints and the experimental design was required to also accommodate these points.\u00ae)   were divThe Lake Macquarie artificial reefs were deployed approximately 180 m apart in depths ranging from 4.5 m to 6 m. The Botany Bay artificial reefs were deployed over a larger area with the distance between reefs ranging from 200\u2013500 m apart in depths ranging from 8 m to 14 m. The close proximity of BBAR1 and BBAR2 to an existing large port revetment wall led to the rapid accumulation of sediment and subsequent burial of these two reefs during the early stages of the project; thought to be a result of increased wave action and sand mobilisation, caused by wave refraction off the wall. As a result, only BBAR3 \u2013 BBAR6 have been included in this study. The six reefs deployed at the St Georges Basin site were deployed approximately 400 m apart in depths ranging from 4.5 m to 5.5 m. Three representative natural reef control sites and three sand-flat controls were additionally selected in each estuary.Samples were taken on randomly selected days six times per season . To enable a detailed examination of the assemblage structure between artificial reef and natural habitats, while also allowing comparisons between estuaries only a combined summer/autumn season spanning approximately 6 months was analysed in each estuary. . Reef age of the replicate artificial reefs constructed across the three estuaries was consistent in terms of the age and season of the data analysed. However due to variations of deployment times (T0) as a result of disparity in the individual consents for reef construction in each estuary and funding being allocated for reefs construction over a 3 year period, exact deployment and hence reef age could not be controlled.Replicate samples for each habitat type  were collected using three Mono BRUV units. The BRUVs were constructed based on the design of Cappo et al. (2004) and consisted of a stainless steel frame constructed as a mount for the camera and underwater housing. A bait arm (20 mm plastic conduit) extending 1 m from the face of the camera housing supported a plastic container, containing standardised bait , which was replenished prior to every deployment. Initial trials indicated that the standardised mixture provided a constant dispersal over the 30 minute deployment period under a variety of conditions. Cameras were set on \u2018short play\u2019 mode and the focus set to \u2018manual infinity\u2019. All sampling was done between 08:00 h and 16\u223600 h. Length estimates derived from Mono BRUV have been shown to be highly variable and potentially inaccurate. Studies have found that the measurements from Mono BRUV units could be out by as much as 30% and are only useful for looking at broader comparisons such as juvenile verses adult Video analysis was done by the same person A similarity matrix was constructed using fourth-root transformed data and the Bray-Curtis similarity measure for the three combined locations. Non-metric multidimensional scale (nMDS) ordination plot of relative abundance estimates (maxN) was constructed to visually explore patterns in fish assemblages among habitat types between within each estuary Overall patterns of variation in the assemblages identified for each estuary were analysed using metric multidimensional scaling (mMDS). To examine the nature of any significant effects between habitats, canonical analysis of principal coordinates (CAP) Differences between the dependent variables relative abundance 258 (max N); species richness (S) and diversity (Hs) associated with each of the habitat types in each of the estuaries were analysed using a one way analysis of variance. Where significant differences were found, a post-hoc test (Tukey) was performed to further investigate significant differences between categorical predictors.A total of 53 species  were identified across all three habitats in the three estuaries. The artificial reefs consistently exhibited the greatest number of species when compared to natural rocky reef and sand-flat. Botany Bay had the greatest number of species (43 spp.), regardless of habitat type, with Lake Macquarie and St Georges Basin recording similar species abundance (22 and 16 spp. respectively). Lake Macquarie was the only estuary where all species identified across the habitats were found to reside on the artificial reef. Botany Bay exhibited the greatest number of \u2018artificial reef only\u2019 residents, with 13 species identified as exclusively artificial reefs only. Lake Macquarie and St Georges Basin exhibited similar results with 7 and 6 species respectively identified exclusively on the artificial reefs  , signifiAcanthopagrus australis, Pagrus auratus, Microcanthus strigatus, Pelates sexlineatus and Trachurus novaezelandiae. A. australis was the only species observed as either a permanent or frequent artificial reef resident in all three estuaries. Other notable sparid species including P. auratus and Rhabdosargus sarba were also found to be permanent or frequent artificial reef residents in two of the three estuaries sampled  across all estuaries and habitats. More than 80% of species identified were found to be either scarce or rare. On the artificial reefs, the majority of species identified as permanent or frequent residents were found to be sparids or carangids including P. sexlineatus was identified with greater frequency on natural rocky-reef than on either artificial reefs or sand-flat habitats. No species were found to be permanent or frequent reef residents unique to one particular habitat type  between all combinations for habitat in all three estuaries. The graphical depiction of CAP correlates  illustra\u00ae) deployed on sand sites that were isolated from natural rocky-reef. This study exclusively used mono BRUV units for data collection. BRUVs as a stand alone method have been shown to be suitable for sampling mobile demersal and semi-pelagic fish associated with artificial reefs with the exception of heavily reef associated cryptic species When evaluating artificial reefs, locating comparable natural rocky-reef is practically very difficult Differences in fish communities among estuaries are not surprising. Abiotic factors including reef age, reef size, location (degree of isolation) T. novaezelandiae was found in higher abundance and frequency on the sand-flat than on the rocky-reef, but was found to be a key artificial reef associated species. Conversely, P. auratus was identified on rocky-reef but not on sand-flat, but was also found to be an important contributor to the artificial reef assemblage. These variations in species proportions between habitats may be in part attributed to the location or isolation of the artificial reefs or indeed the quality of the habitat itself. The patch design and relative isolation of the artificial reefs were vastly different to the fragmented rocky-reef controls; this is likely to have influenced the resultant artificial reef assemblage. Previous studies have found that differences in fish assemblages between artificial and natural reef habitats is in part explained by the movement of post settlement fish on and off an artificial reef A. australis that dominated the artificial reef community were identified regularly on sand-flat. A. australis are common in south-east Australian estuaries A. australis on the artificial reefs is a result of the species ability to travel between habitats, often over sand-flat, that may be perceived as a barrier for other less mobile or heavily reef associated species. However it should be noted that this species is also readily found on sand-flat demonstrating its ability to inhabit a range of habitats types. It is known that some reef associated species are capable of moving over bare sand Within all three estuaries, higher species richness, diversity and abundances were recorded on the artificial reefs when compared to the adjacent natural habitats, a result that is consistent with a number of related studies A. australis were prevalent on the artificial reefs in high numbers, classified as a permanent artificial reef resident (sighting frequency >75%) in Lake Macquarie and St Georges Basin. This is likely to be a combination of reef location combined with the feeding suitability of the artificial reef itself as the A. australis has a preference for feeding in habitats that have a large reef/sand interface A. australis was more abundant on artificial structures than on natural rocky reef P. auratus and R. sarba as additional key contributors to the artificial reef assemblage, whose highly mobile nature and feeding habits similar to that of A. australis may have also made the artificial reefs favourable habitat T. novaezelandiae  and Pseudocaranx georgianus  were correlated with the artificial reefs as a direct result of their transient nature. These species are capable of travelling large distances over reef devoid habitat While the location of the artificial reef relative to naturally occurring habitats is a major source of variation, it is unlikely that the location alone of the artificial reefs will dictate the resultant assemblage structure. Species specific behavioural traits such as feeding preferences are also likely to structure the assemblage. Hence, the system is not only being limited by its location, but also by the habitats favourability in terms of feeding preferences. The higher abundances and species numbers observed on the artificial reefs as part of this study may have also been as a result of reduced predation pressure related to the reef's location. Reef location has also been linked to top-down \u2018predator\u2019 control of community structure The relationship between the range of crevice sizes in a habitat and the sizes of organisms sheltering there has been extensively documented A. australis to be able to locate and reside on the artificial reefs in relatively high numbers, while feeding preferences such as increased edge to area ratios may have further attributed to the observed variation in assemblage composition. Our study demonstrated the value in incorporating sand-flat habitat in experimental designs as this helped establish species vagility. The use of stereo-video BRUV units to make accurate determination of fish length (and inferences of biomass) would be beneficial in future. Repeats of this study (or other similar studies using BRUV units) should aim to incorporate stereo-units as the inclusion of biomass estimates; particularly in light of density-dependent habitat selection effects of some species and the resultant effect upon individual fish size and condition Estuarine artificial reefs show the potential to play a beneficial role in the enhancement of habitats for a range of recreationally important sparid and carangid species. However, these reefs should not be viewed as direct surrogates for natural reef, rather as a hybrid assemblages made up of species that are found on a variety of adjacent natural habitats. Although the assemblage did share many species with adjacent natural habitats, some were identified on the artificial reef alone, resulting in an assemblage that remained distinct by its higher abundances, species richness and diversity. The positive correlation of sparids and carangids to the artificial reef appears to have been as a direct result of their mobility and feeding preferences. Mobility allowed species such as Table S1Elative abundance (mean maxN \u00b1 SEM), total count and frequency (%) for all species in A. Lake Macquarie (LM), B. Botany Bay (BB) and C. St Georges Basin (SGB) by habitat type identified by BRUV002E.(XLS)Click here for additional data file."}
+{"text": "Psoriasis is an immune-mediated disease characterised by chronically elevated pro-inflammatory cytokine levels, leading to aberrant keratinocyte proliferation and differentiation. Although certain clinical phenotypes, such as plaque psoriasis, are well defined, it is currently unclear whether there are molecular subtypes that might impact on prognosis or treatment outcomes.We present a pipeline for patient stratification through a comprehensive analysis of gene expression in paired lesional and non-lesional psoriatic tissue samples, compared with controls, to establish differences in RNA expression patterns across all tissue types. Ensembles of decision tree predictors were employed to cluster psoriatic samples on the basis of gene expression patterns and reveal gene expression signatures that best discriminate molecular disease subtypes. This multi-stage procedure was applied to several published psoriasis studies and a comparison of gene expression patterns across datasets was performed.Overall, classification of psoriasis gene expression patterns revealed distinct molecular sub-groups within the clinical phenotype of plaque psoriasis. Enrichment for TGFb and ErbB signaling pathways, noted in one of the two psoriasis subgroups, suggested that this group may be more amenable to therapies targeting these pathways. Our study highlights the potential biological relevance of using ensemble decision tree predictors to determine molecular disease subtypes, in what may initially appear to be a homogenous clinical group. The R code used in this paper is available upon request. Psoriasis is one of the most prevalent chronic inflammatory disorders caused by an interplay of genetic factors and the environment on the background of dysregulated immune system . The disAlthough the cause of psoriasis remains unknown, it is thought to be a complex and multifactorial disorder brought about by the combination of multiple susceptibility genes -6, a dysIn recent years, progress has been made in understanding the pathogenesis and treatment of psoriasis. Pathogenesis is mainly linked to activation of several types of leukocytes that control cellular immunity and to a T-cell-dependent inflammatory process in skin that accelerates the growth of epidermal and vascular cells in psoriasis lesions. Current therapeutic approaches against the disease take advantage of proteins or antibodies aiming either at specific inflammatory co-activators or more generally at immune cells . While tThe first large-scale and detailed gene expression studies of psoriasis identified various differentially expressed genes by comparing non-lesional and lesional skin against normal tissue -16. ReceIn this study, a computational methodology based on decision tree predictors is developed to discover molecular sub-groups from gene expression data and illustrate gene signatures associated with each group. The random forest (RF) algorithm  is used More specific to the current analysis, we first analysed gene expression profiles in normal and disease skin tissues, so as to define common differentially expressed genes. This core gene set was then used to group psoriatic tissue samples through RF clustering of real and synthetic data, as previously developed . This stMolecular profiling of psoriatic phenotypes followed by classification of tissue samples into appropriate disease classes has the potential to derive clusters of similar transcription responses from the entire repertoire of profiles generated. Especially in the case of a homogeneous clinical patient group, such as plaque-type psoriasis, the classification of transcriptional patterns into appropriate sub-groups may reveal distinct molecular mechanisms that may operate within this group and may explain variability in response and options of disease treatment. Overall, given the predictive nature of the decision model employed, such patient categorisations can lead to significant insights into disease mechanisms and novel, targeted therapeutic approaches.A pipeline Figure\u2009 for paticore set of genes expressed differentially across the three disease phenotypes and was used to derive disease-specific expression patterns in the RF-based procedure described in the following sections.Skin samples from psoriatic patients were either of inflamed, lesional type  or non-inflamed, non-lesional tissue . These were analysed together with skin samples from normal individuals (denoted as NN). Relevant gene expression measurements for the disease classes  were obtained through the Genetic Association Information Network . Differential expression analysis was performed and involved three pairwise comparisons between tissue datasets , resulting in three sets of differentially expressed probe sets per pair . A set of 228 probes was shared across all datasets Figures\u2009 and 2a aUnsupervised hierarchical clustering was carried out on the set of 206 core genes to explore and visualise the patterns of gene expression from normal (NN) to non-lesional (PN) and then to lesional (PP) skin samples. Figure\u2009Principal component analysis (PCA) was used to assess the clustering of samples when progressing from un-inflamed to inflamed skin. There was a clear distinction between lesional (PP) and non-lesional (NN and PN) phenotypes Figure\u2009c, manifeFN1, PDGFC, MYH10 are involved in the regulation of the actin cytoskeleton, which participates in fundamental processes such as the regulation of cell shape, motility and adhesion  (A) and Yao et al. 2008 [36] (B) to illustrate grouping of samples according to random forest clustering. Two distinct psoriatic groups are identified in involved tissue (PP01 green and PP02 purple), while NN and PN samples largely co-localise. Overall, clustering is comparable to GAIN data that is shown in figure 4.Click here for fileGraphical representation to illustrate the relationship between 19 highly discriminative genes and disease sub-groups according to Gini Index calculated from decision trees forest in the Gudjonnson dataset. The green band represents the first psoriatic group (PP01), light blue corresponds to the second psoriatic sub-group (PP02), yellow corresponds to healthy individuals (NN) and light green presents the non-lesional cases (PN) and are arranged clockwise followed by purple to orange rectangular bands that represent relevant genes. Genes and skin groups are ordered according to shared pairing links, as described previously.Click here for fileGraphical representation to illustrate the relationship between 27 highly discriminative genes and disease sub-groups according to Gini Index calculated from RF for the Yao dataset. Light blue to green rectangular bands represent the four skin-types  and are followed by purple to orange rectangular bands representing relevant genes (arranged clockwise). Genes and skin groups are ordered according shared pairing links. An overview of patterns of informative genes for prediction of each disease class can be visualised. Click here for filePathway enrichment in the Gudjonsson dataset.Click here for filePathway enrichment in the Yao dataset.Click here for fileExample of a decision tree for classification of tissue samples in appropriate disease classes. Heatmap illustrates expression values for 25 genes across 108 tissue samples and represents part of the heatmap shown in figure 2. A decision tree is a tree-like structure to relate gene expression measurements to sample phenotype class, with a view to deriving a predictive model. Nodes (rectangles) in the tree represent a test on gene expressions to derive a decision on a sample\u2019s class, edges (arrows) indicate the expression level of the variable that can best distinguish the samples and leaves  represent class predictions. The path from root to each terminal node equates to a list of conditions in the form of gene expression rules that can relate tissue samples to disease phenotype class.Click here for fileCorrelation between the two variable importance measures of gene selection, Gini Index and mean decrease in accuracy.Click here for file"}
+{"text": "Maternal diet during pregnancy and lactation, as well as early infant feeding, is suggested to play a role in the development of allergic diseases.A population-based birth cohort with a genetic susceptibility to type 1 diabetes was recruited in two study areas in Finland in 1997-2004 (n = 6753). Maternal diet during pregnancy and lactation was assessed by a validated, 181-item semi quantitative food frequency questionnaire. Age at introduction of foods in the infant diet and CMA were queried from parents up to the age of 3 yrs of the child, and register-based information on diagnosed CMA was obtained from the Social Insurance Institution. Sociodemographic and perinatal factors were derived from the Finnish Medical Birth Registry and inquired from parents. Parental asthma and allergic diseases were queried in a questionnaire. The associations between diet and CMA were analyzed by logistic regression comparing highest and lowest quarters to the middle half of consumption and adjusted for potential confounders.High consumption of cow's milk during pregnancy was more strongly associated with a decreased risk of CMA in the offspring  than maternal consumption during lactation, when considered simultaneously. Even taking into account the age of introduction of cow\u2019s milk in the infant diet, high maternal milk consumption during pregnancy remained inversely associated with CMA in the offspring . When stratified according to maternal allergic rhinitis and asthma, only children of non-allergic mothers seemed to benefit from high maternal cow's milk consumption during pregnancy . In children of allergic mothers, cow's milk consumption was neither risk nor a protective factor.in utero.High maternal consumption of cow\u2019s milk products during pregnancy may protect children from developing CMA, more so than maternal consumption during lactation. This association is evident only in children of non-allergic mothers. These results support data from animal studies on possible enhancement of tolerance already"}
+{"text": "These mutants carry a premature stop codon in the deltaD gene. Recently, our group showed that Notch signaling was directly involved in the control of cilia length in the KV cells given that the aei-/- mutant present shorter cilia in KV cells. The goal of this project is the characterization of the CBF and beat patterns of aei-/- KV cilia vs. wt cilia. We did spectral analysis of individual cilia associated with high-speed digital videomicroscopy. By decomposing and comparing the obtained frequencies with Fourier Transform we have identified significant differences in KV cilia motility pattern between the wt and the aei-/- mutants. So far, we show that not only are the cilia shorter in the KV of aei-/- mutants but also their motility pattern is different resulting in an overall destructive fluid flow.Motile cilia need to be coordinated and ciliary beat frequency (CBF) is characteristic of different types of cilia depending on their physiological function. In zebrafish, monociliated cells arise in the tailbud at the end of gastrulation in a transient spherical organ called Kupffer's vesicle (KV). Using zebrafish as a model, our group has been studying cilia length regulation and motility in wild-type (wt) and http://www.cedoc.org"}
+{"text": "The hole- and electron-doped compounds differ by their physical properties and their phase diagrams \u2009\u2212\u2009RON(V\u2009=\u20090))/RON(V\u2009=\u20090). Intensive fundamental and application studies of this phenomenon are underway since BRS-based devices are regarded as a new generation of alternative nonvolatile memory (Meijer The effect of bipolar resistive switching (BRS) observed in oxide-based heterostructures, including based on strongly correlated electron systems (SCES), such as HTSC  is directed to the surface in contrast to switching observed in hole-doped compounds.Recent studies of the BRS effect in various compounds revealed the essential role of the oxygen diffusion processes. Electric field of different polarity induces two resistive states of the degraded HTSC surface which is indicative of its separation into conducting and dielectric phases. The switching process gives rise to metastable states with different oxygen content in the interface area of the compound. It is this area that determines the resistive properties of the structure  and NCCO(001) grown by pulse laser deposition were used to produce HTSC-based heterostructures. Figure \u03b4\u2009= 1,0  phase. Both phases were epitaxial and (001)-oriented. The obtained results are consistent with other evidences of two phases coexistence after oxygen reducing even in perfect single crystals (Mang et al. Results of NCCO films structure study were reported elsewhere (Tulina et al. The value of the BRS effect was insignificant in the heterocontacts formed immediately after the ion milling of NCCO surface, the switching pattern corresponded to the electron-doped systems (see Figure The bipolar resistive switching has been experimentally observed in NCCO- and YBCO-based film heterojunctions.It has been shown that the surface layer of the studied HTSC films is oxygen degraded and can serve as an interface in HTSC perovskite-based heterostructures to create memory elements based on resistive switching.The switching polarity and the BRS effect value in the electron- and hole-doped compounds reflect the pattern of their oxygen doping."}
+{"text": "Effective delivery of aerosolized bronchodilators for patients with asthma is crucial for adequate therapy in critical care and emergent settings. Often administered with pressure-metered dose inhalers (pMDIs), bronchodilator delivery depends on the correct patient technique during administration  and the A point-of-care device for airflow measurement during bronchodilator delivery was designed and tested for use in resourcelimited settings. The handheld device was constructed from a clinical aerosol delivery tube with a bidirectional sensor for pressure differential detection about the aerosol element Figure . The cusCalibration of the assembled device over range of 0.5 to 3 l/ second enabled conversion of pressure difference to air flow with a mean measured tube resistance of 0.258 (kPa*second)/l. Robust signal responses to an adult subject's continuous respiratory maneuvers on the tube itself were demonstrated. Subject performance of the pMDI technique with subsequent tidal volume breathing was recorded and analyzed Figure .Design and calibration of a novel low-cost monitoring device for bronchodilator delivery monitoring enabled detection and recording of characteristic flow volume respiratory patterns for point-of-care diagnostics in resource-limited settings. Future work will require clinical testing and automated detection of the correct pMDI patient technique."}
+{"text": "We evaluate the Bayesian Network (BN) and Support Vector Machine (SVM) machine learning techniques on four distinct TFBS data sets and analyze their performance. We describe the features that are most useful for classification and contrast and compare these feature sets between the factors.Computational prediction of Transcription Factor Binding Sites (TFBS) from sequence data alone is difficult and error-prone. Machine learning techniques utilizing additional environmental information about a predicted binding site (such as distances from the site to particular chromatin features) to determine its occupancy/functionality class show promise as methods to achieve more accurate prediction of true TFBS Our results demonstrate good performance of classifiers both on TFBS for transcription factors used for initial training and for TFBS for other factors in cross-classification experiments. We find that distances to chromatin modifications  as well as distances between such modifications to be effective predictors of TFBS occupancy, though the impact of individual predictors is largely TF specific. In our experiments, Bayesian network classifiers outperform SVM classifiers.Our results demonstrate good performance of machine learning techniques on the problem of occupancy classification, and demonstrate that effective classification can be achieved using distances to chromatin features. We additionally demonstrate that cross-classification of TFBS is possible, suggesting the possibility of constructing a generalizable occupancy classifier capable of handling TFBS for many different transcription factors. Computational discovery of Transcription Factor Binding Sites (TFBS) is a difficult problem. Both methods utilizing Position-Weight Matrices PWMs,  and methWe identified regions of the human genome on chromosomes 1\u201322 found to bind a TF according to chromatin immunopreciptation for the factors c-Myc A BN using the K2 network-building algorithm A linear-kernel SVM using default parametersA linear-kernel SVM with attributes preprocessed into bins using the same MDL-based discretization technique as in the BN classifiers.We evaluated the classifiers' ability to discriminate high and low occupancy sites using 10-fold cross-validation of each sample and the area under the curve (AUC) metric; AUC is calculated as the area under a plot of true positive rates and false positive rates for the classifier, with an AUC of 1 indicating perfect classification performance and and area of .5 indicating equivalence to randomly assigning classes to test examples . We compared the algorithm and feature sets used for the best-performing classifier for each TF. For each TF, we also constructed classifiers on a per chromosome basis as described above, extracting training data from the other chromosomes. We also evaluated the performance of each best classifier on the other TFs in the study, using each sample as a training set and classifying each other sample from the other three TFs. Additionally, we evaluated the difference in performance between the classifiers when the feature-feature distances were excluded from the feature set, using cross-validation and the AUC as described previously. Finally, we performed an analysis of the agreement between TFs on relevant features based on number of times of a feature's inclusion in the cross-validation classifier using Cohen's kappa measure For the four TFs we analyzed  and features we utilized  we found that the Bayesian Network (BN)-based classifiers consistently outperformed Support Vector Machine (SVM)-based classifiers for all TFs, and achieved average AUC scores ranging from .71 (TCF4) to .94 (GABP). Area Under the Curve (AUC) scores achieved in per-chromosome classification were comparable to those achieved in cross-validation. The resultant classifiers have na\u00efve Bayesian network structures. Both TFBS-feature and feature-feature distances are predictive, but the feature-feature distances appeared to be the dominant predictors for all TFs. No features of either type appear to be universally predictive across all TFs. Classification of other TFs by a classifier trained on a different TF was universally inferior to performance of a classifier trained on the TF of interest, excepting the case of SRF. All TFs were capable of accurate cross-classification of the held-out SRF data set.In all cases, the BN classifier outperformed either of the SVM-based classifiers see . This reA surprising result of the classification experiments was the dominance of feature-feature distances over TFBS-feature distances in the best-performing classifiers. We therefore decided to rerun classification as above using TFBS-feature distances only. For this and all subsequent analyses, we chose to only construct BN classifiers as they had outperformed SVMs previously. In all cases, average AUC of classification improved with the inclusion of feature-feature distances relative to TFBS-feature distances only see . As withWe additionally constructed BN classifiers using feature-feature distances for each individual chromosome and TF, generating training data from the other chromosomes. Performance was quite comparable on average to the performance achieved in the randomly sampled data sets . HoweverTo identify whether or not common predictors were shared across the TFs, we performed a frequency count of all predictors which appeared in at least one classifier instance for all four TFs, over all cross-validations.; see We additionally explored the classification performance achieved using one TF's classifier on the data for the other three TFs. Cross-classification performance may both be an indicator of the suitability of one TF for predicting occupancy of another (perhaps for exploratory modelling purposes), as well as a general indicator of the commonality of features influencing occupancy of a TFBS. For this experiment, each sample from the previous experiments was used to train a BN classifier using the entire sample as training data. This classifier was then tested using each sample from each other TF, resulting in 100 AUC values for each TF-TF pair . Both TFSRF represents a unique data set relative to the other TFs in that its dataset appears to contain multiple strong motifs that differ from the \u201ccanonical\u201d SRF binding sequence; the TRANSFAC SRF PWM accounts for only about 33% of the sites reported by Valouev et al. While we were able to achieve good performance with occupancy classification overall, considerable variation in performance and in predictors was observed between the TFs. Biological differences are likely at play to some extent; for example, GABP is thought to bind at the majority of human bidirectional promoters In comparison with other work in the field, the analysis presented addresses several unanswered questions about occupancy classification, notably the question of whether or not accurate cross-classification of one TF by another is possible. The most directly comparable work is that of Chen et al. A more recent work is that of Won, Ren, and Wang We believe we have demonstrated the viability of occupancy classification as a method of accurately locating likely high-occupancy TFBS for multiple TFs, and these results suggest a multitude of future research directions for refining and expanding upon occupancy classification methods. An analysis of the impact of using occupancy classification as a supplement to or in lieu of biological data in a real-world analysis of a biological problem is still wanting, but we have begun to design such an analysis based on utilizing protein-protein interaction (PPI) network construction and the occupancy classification methodology that we have described here. Additionally, given the results of both the cross-validation and cross-classification experiments, it seems possible that a combination of occupancy classifiers trained on data from several TFs Click here for additional data file.Table S2A: Top 10 most frequently occurring predictors in the occupancy classifiers (per-TF and cumulative). B: Average class-conditional probability of high-occupancy status for smallest distance bin for top 10 most frequently occurring features in cross-classification (two-bin cases only). C: Average class-conditional probability of high-occupancy status for smallest distance bin for top 10 most frequently occurring features per-chromosome.(DOC)Click here for additional data file."}
+{"text": "Marsupials are born with immature lungs when compared to eutherian mammals and rely, to various extents, on cutaneous gas exchange in order to meet metabolic requirements. Indeed, the fat-tailed dunnart is born with lungs in the canalicular stage of development and relies almost entirely on the skin for gas exchange at birth; consequently undergoing the majority of lung development in air. Plane radiographs and computed tomography data sets were acquired using phase contrast imaging with a synchrotron radiation source for two marsupial species, the fat-tailed dunnart and the larger tammar wallaby, during the first weeks of postnatal life. Phase contrast imaging revealed that only two lung sacs contain air after the first hour of life in the fat-tailed dunnart. While the lung of the tammar wallaby was comparatively more developed, both species demonstrated massive increases in air sac number and architectural complexity during the postnatal period. In addition, both the tammar wallaby and fat-tailed dunnart had lower lung volumes and parenchymal surface areas than were expected from morphometrically determined allometric equations relating these variables to body mass during the neonatal period. However, lung volume is predicted to scale with mass as expected after the neonatal marsupial reaches a body mass of \u223c1 g and no longer relies on the skin for gas exchange. Decreased lung volume in the marsupial neonate further supports the maxim that cutaneous gas exchange occurs in the marsupial neonate because the respiratory apparatus is not yet capable of meeting the gas exchange requirements of the newborn. The fat-tailed dunnart The lung of the newborn tammar wallaby contains abundant surfactant Didelphis virginiana) have larger than predicted mass-specific lung volumes Traditional morphometric techniques have established that throughout development lung volume scales isometrically, and identically, in marsupials and eutherians Phase contrast imaging enhances edges of material boundaries, where differences in refractive index occur, for example the boundaries between different tissue types This study aimed to explore lung development in the tammar wallaby and fat-tailed dunnart during the first weeks of life using phase contrast imaging with a synchrotron radiation source. In addition, we aimed to calculate functional lung volumes and surface areas during development using three-dimensional (3-D) reconstructions of computed tomography (CT) data.Tammar wallabies and fat-tailed dunnarts from a laboratory colony were continuously monitored for signs of giving birth, and/or underwent regular pouch checks when approaching full-term , animals had their mouth and nares blocked with a quick setting polyether compound  to aid in prevention of air-loss and were immediately frozen on dry ice prior to being stored at \u221220\u00b0C in an evacuated zip lock bag with moist gauze to prevent desiccation. Specimens were maintained at \u221220\u00b0C until they were put on dry ice for air-transport to the Biomedical Imaging Centre, SPring-8 synchrotron, Hyogo, Japan. For imaging, pouch young were placed into a snug fitting plastic tube and held in place with a plastic pin that prevented movement during imaging. A cryostat was placed in the experimental hutch within the centre and a cold stream of air was directed over the specimen to ensure the sample was kept just above the freezing point, ensuring that ice crystals did not interfere with imaging.2. Since the beam size is limited  on the 20XU beamline, several images were taken in a raster scan and then tiled together to create the final image in animals that were larger than these dimensions. Images were conventionally corrected for dark current offset and full field non-uniformities before tiling (if required) Phase contrast enhanced single images and computed tomography data sets were acquired. To provide maximum edge enhancement to elucidate the lung structure, single images were acquired on the high coherence 20XU beamline, using a propagation distance of approximately 3.7 m and an X-ray energy of 17.7 keV. Images were recorded using a Hamamatsu phosphor charged-coupled device with pixel size of approximately 3\u00d73 \u00b5mLung surface areas and volumes were calculated using ImageJ . Firstly, each set of reconstructed images was thresholded  to create a binary image that could be easily segmented to highlight lung regions only. The images were then inverted so that the lungs appear white, and non-air filled structures are black, which is necessary for the morphological filters to run. These filters reduce any noise in the images. Volumes and surface areas were then calculated for each CT slice by using the \u201canalyse particle\u201d function which finds regions in the binary images between certain sizes (>30 and <3500 pixels) and counts their number, area and perimeter. Surface areas were calculated by summing the perimeter for each slice and the volume determined by summing the area and knowing the thickness of each slice was 1 pixel.Where appropriate, least-squares regression was fitted to log-log transformed data for allometric analysis. The equality of the slope of the regression lines for marsupials collected in this study was assessed using a parallel line analysis. All data analysis was performed in SigmaPlot 12 . Significance was considered at p<0.05.Thirty-six hours after birth, the lung of the tammar wallaby is a simple saccular structure , which iThe lungs of the newborn fat-tailed dunnart are more immature than those of the tammar wallaby. The plane radiographs of the developing fat-tailed dunnart  indicateOn the first day of postnatal life, the neonatal tammar wallaby and fat-tailed dunnart displayed lower lung volumes and parenchymal surface areas See  than werIt is generally accepted that viability of the newborn mammal depends on an adequately developed respiratory system. Indeed, the neonate must rapidly adapt to air breathing through clearance of fetal lung liquid, the onset of a rhythmic breathing pattern and establishment of a functional residual capacity In the 1 hour old dunnart, the two \u2018air bubbles\u2019 observed indicate that either the lung is grossly under-developed and is comprised of only two simple sacs or, alternatively, the architecture of the lung is more developed, but the airspace not completely cleared of fetal lung liquid, rendering the phase contrast non-existent in these fluid filled areas of the lung. In fact, the latter explanation is plausible given that light and electron microscopy demonstrated a thick septal wall within the primitive tubular structures and an over-abundance of surfactant in the airspaces The lung volumes determined in the present study represent the air-filled regions of the lungs (exclusive of the upper airways), not the morphological volumes determined in previous studies with traditional microscopic techniques. The calculation of air-filled volumes may over-estimate the functional or physiological lung volumes as they will undoubtedly include regions where gas exchange is limited; for example, larger airways and regions of the lung where thick interstitium and/or poor capillarisation prevent efficient gas exchange; see The low lung volume at birth in marsupials may relate to the stage of lung development; the earlier the stage the lower the volume and the greater the extent of cutaneous gas exchange. Microscopic morphology has determined that lung volume increases \u223c23 fold through development in humans and rats, There are numerous consequences to low lung volumes in newborns, including the greater tendency for alveoli (or air sacs) to collapse. Newborns often minimise this potential problem by maintaining a dynamic elevation of FRC above resting lung volume. In many newborns, this is achieved by a slowing of expiratory emptying (by braking action of the inspiratory muscles), coupled with narrowing of the glottis during expiration, to prolong the expiratory time constant 2O It is possible that the lung volumes reported in this study are lower than the functional lung volumes found in living neonates due to the lungs deflating below FRC at death. In addition, the possibility of diffusion of air from the lung into the vascular compartment and neighbouring tissues, and consequent underestimation of lung volume, during the preservation of animals must be considered as a potential limitation in this study. In contrast, morphometric estimates of lung volumes and surface areas are sometimes performed after fixation of the lungs to a given tracheal pressure; previous studies in the neonatal tammar wallaby have used 20 cm HThe surface area of the lung available for gas exchange in the wallaby and dunnart is also below values predicted from allometry , though The extensive lung development observed in the weeks after birth is not surprising given an increasing reliance on the lung for gas exchange. At the same time, there is a decrease in cutaneous surface area with respect to body size and an increase in the demand for oxygen, particularly as the capability for thermogenesis develops In summary, phase contrast imaging using a synchrotron radiation source confirmed that marsupials such as the fat-tailed dunnart and the tammar wallaby are born with structurally immature lungs when compared to eutherian mammals and underwent marked increases in architectural complexity during the postnatal period. In addition, these marsupials had lower lung volumes and parenchymal surface areas than were expected from morphometrically determined allometric equations relating these variables to body mass during the early neonatal period. These findings further support the maxim that cutaneous gas exchange occurs in the marsupial neonate because the respiratory apparatus is not yet capable of meeting the gas exchange requirements of the newborn."}
+{"text": "Human endogenous retroelements (which rely on an RNA intermediate before integration into the genome) can be classified into the non-long terminal repeat (LTR) class and the LTR class, represented by human endogenous retroviruses (HERV). Many HERV entered the primate germ line as infectious retroviruses at several time points during human evolution. Out of the six HERVsuperfamilies, HERV-K (HML-2) is considered to be the youngest and most transcriptionally active. Various studies have identified adaptive immune responses to HERV under certain disease conditions, but whether these represent beneficial or deleterious immune responses is unclear. We have focused on the study of adaptive immunity to HERV in the context of HIV infection, and will present data on the cell mediated and humoral responses to certain HERV families. We find that HERV specific T cell responses can be found at high frequency in certain HIV infected subjects, and specific antibody responses are also identified. The functional activities of these adaptive immune mechanisms may play a role in HIV pathogenesis."}
+{"text": "The human vasculature includes a vast network of microcapillaries networking the body and is a major target for non-carcinogenic effects of space radiation in the body. The brain microvascular system is crucial to healthy functioning of the brain and its pathology is not only a primary event in a range of neurodegenerative diseases but also an important influencing factor in many others. The vasculature is maintained by angiogenesis regenerating vessels as they are needed, this is particularly relevant if the blood\u2013brain barrier is damaged by agents such as space radiation, thereby creating the need for angiogenic regeneration. The resulting lack of vasculature due to the inhibition of re-growth of vessels can, in turn, lead to a negative feedback loop and further pathologies.Using three-dimensional human vessel cultures with human umbilical vein and brain microvascular endothelial cells, we have developed assays that determine at what stage angiogenesis is inhibited by ionizing radiation. The relative biological effect of high linear energy transfer (LET) 1 GeV Fe ions compared with low LET 1 GeV protons is only one for developing vessels but greater than four for mature vessels. This action of low LET protons on developing vessels was surprisingly effective (50% inhibition with 40 cGy exposure) and together with the effect of high LET ions may represent a significant hazard in the space environment.The morphology of developing vessels 5 days after exposure showed significant differences that suggest distinct mechanisms of inhibition. Cells exposed to protons failed to make connections with other cells. Conversely, cells exposed to Fe ions extended cellular processes and made connections to other cells but did not develop a central lumen. The microtubule and actin cytoskeletons showed differences indicating that motility at the extending tips of endothelial cells is inhibited by protons but not Fe ions. Actin-rich protrusive structures that contain bundled and dynamic microtubules showed a 65% decrease when exposed to high-energy protons but not with the same dose of high-energy Fe ions. Since protein kinase C (PKC) has long been known to stimulate angiogenesis, we hypothesized that rescue of the capillary phenotype after proton exposure would be possible by stimulating PKC before irradiation. One-day-old vessel cultures were treated with 30 and 60 nM phorbol ester (PMA) 15 min before irradiation. Stimulation of PKC restored capillary formation in proton-treated cultures but not in Fe ion-treated cultures. More specifically, stimulation of PKC by PMA was able to restore the tip motility that was inhibited by low LET ions [Further studies with various charged particles showed that low LET ion particles (Proton and He ions) with an LET lower or equal to 1 keV/\u03bcm inhibit vasculogenesis in the same way as protons. Higher LET charged particles  with an LET \u22658 keV/\u03bcm inhibit vasculogenesis in the same way as Fe ions.In conclusion, we have shown that low and high LET ions inhibit the formation of brain capillaries by different mechanisms. For low LET ions, inhibition involves regulation of PKC-dependent motile tips leading to a failure of cellular processes to migrate through the matrix and meet up with other processes. For high LET ions, the cells fail to complete angiogenesis by not migrating and forming tubular structures. This complexity of response opens up possibilities of greater control over angiogenesis and the resulting pathologies during coincident exposure or therapy. For exposure in space, knowledge of these mechanisms will enable more precise risk assessment and mitigation strategies. For radiotherapy, treatment could be manipulated to utilize the radiation effectively."}
+{"text": "Vesicle trafficking systems play essential roles in the communication between the organelles of eukaryotic cells and also between cells and their environment. Endocytosis and the late secretory route are mediated by clathrin-coated vesicles, while the COat Protein I and II (COPI and COPII) routes stand for the bidirectional traffic between the ER and the Golgi apparatus. Despite similar fundamental organizations, the molecular machinery, functions, and evolutionary characteristics of the three systems are very different. In this work, we compiled the basic functional protein groups of the three main routes for human and yeast and analyzed them from the structural disorder perspective. We found similar overall disorder content in yeast and human proteins, confirming the well-conserved nature of these systems. Most functional groups contain highly disordered proteins, supporting the general importance of structural disorder in these routes, although some of them seem to heavily rely on disorder, while others do not. Interestingly, the clathrin system is significantly more disordered (\u223c23%) than the other two, COPI (\u223c9%) and COPII (\u223c8%). We show that this structural phenomenon enhances the inherent plasticity and increased evolutionary adaptability of the clathrin system, which distinguishes it from the other two routes. Since multi-functionality (moonlighting) is indicative of both plasticity and adaptability, we studied its prevalence in vesicle trafficking proteins and correlated it with structural disorder. Clathrin adaptors have the highest capability for moonlighting while also comprising the most highly disordered members. The ability to acquire tissue specific functions was also used to approach adaptability: clathrin route genes have the most tissue specific exons encoding for protein segments enriched in structural disorder and interaction sites. Overall, our results confirm the general importance of structural disorder in vesicle trafficking and suggest major roles for this structural property in shaping the differences of evolutionary adaptability in the three routes. Vesicle trafficking systems are fundamental among cellular transport mechanisms; various cargo molecules are transported via different coated vesicles to their specific destinations in every eukaryotic cell. Clathrin-coated vesicles mediate endocytosis and the late secretory route, while the COat Protein I and II (COPI and COPII) vesicle trafficking routes are responsible for the bidirectional traffic between the ER and the Golgi apparatus. Despite similar basic principles, regulatory mechanisms and structural features of the three systems, their molecular machinery, functions, and evolutionary characteristics vastly differ. We investigated and compared these three routes and their basic functional protein groups from the structural disorder point of view, since disordered protein regions could provide a broad variety of functional and evolutionary advantages for them. We found that structurally disordered protein segments are most abundant in the clathrin system, which might explain the observed inherent plasticity, increased adaptability and exceptional robustness of this route. We support our hypothesis by two analyses on protein multi-functionality and tissue specificity, both being indicative of evolutionary adaptability. Clathrin pathway proteins stand out in both measures, with their disordered regions being largely responsible for their outstanding capabilities. The well-organized network of vesicle trafficking pathways is the basic communication mechanism between the different intracellular compartments and the environment, and as such it is crucial for the efficient transport of macromolecules within and between cells and their environment. Transport vesicles deliver various cargo molecules  to the plasma membrane and to specific membranous compartments, while being also responsible for maintaining the appropriate protein and lipid composition of various organelles. There are several specialized routes present in all eukaryotic cells playing distinct roles, being responsible for different directions of traffic between various source and target membranes of several organelles and for carrying various types of cargo. These systems have their own well-conserved macromolecular machinery with a specific coat protein complex on the surface of their vesicles, which usually lends the name to the whole system.While endocytosis and the late secretory route are mostly mediated by clathrin-coated vesicles, the early secretory pathway from the ER (endoplasmatic reticulum) to the Golgi apparatus and the retrograde transport backwards are mediated by the COPII (COat Protein II) and COPI (COat Protein I) routes, respectively In all three cases there is a specific multisubunit protein coat complex on the outer surface of the vesicles which can self-assemble as a lattice collecting and concentrating the appropriate adaptor-cargo complexes into membrane patches. This process is not only responsible for cargo selection, but through the generation of membrane curvature, it also enhances the budding and fission of vesicles In all three pathways vesicles are uncoated after formation, i.e. their cage-forming scaffold proteins and the adaptor proteins are stripped off either stepwise (COPII and clathrin) or at once (COPI). The precise timing of this procedure is still under debate Other similarities between these routes include the basic mechanisms of vesicle transport  and vesicle fusion with the target membrane. The key players of vesicle fusion are SNARE  proteins in all the three systems. SNAREs behave like molecular engines; they generate the pulling force required for placing the two membranes close enough for fusion. Instead of using ATP in force generation, a huge conformational change occurs when the SNARE protein in the vesicle membrane interacts with the appropriate SNARE proteins in the target membrane . The four SNARE coiled-coil homology domains assemble into a stable four-helix bundle, which is then disassembled in an ATP-dependent manner Despite this array of mechanistic, structural, and regulatory similarities, there are fundamental functional and evolutionary differences between the clathrin-mediated system and the other two. While COPI and COPII are essential for the viability of eukaryotic cells (without any of them the transport between the ER and the Golgi is completely abolished) and they only occur in the ER-Golgi-ER routes, the clathrin system seems to be less indispensable and more broadly relied on. Knock-outs of certain main clathrin components, such as AP-2 (Adapter-related protein complex 2) are unviable in case of multicellular organisms There are several differences in the complexity of the three pathways too. In the COPI and COPII systems, the adaptor subunits are part of the multisubunit coat complex and there is only one set of them for each pathway Although the functional and evolutionary differences between the systems have been previously studied, the inherent structural characteristics that could account for them have not been fully explored. Some previous works allude that long regions of certain clathrin-associated adaptor proteins are disordered, unstructured or unfolded Intrinsically disordered proteins and regions lack a well-defined structure; they function via an ensemble of possible conformations Given all the possible implications and advantages intrinsic disorder can have on the different vesicle trafficking mechanisms, studying its role in them is of indisputable importance. To our knowledge, the abundance of disordered regions was only improperly assessed for proteins in the clathrin pathway by secondary structure prediction methods Clathrin route proteins were collected from comprehensive reviews The protein sequences of the complete human (Homo sapiens) and yeast  proteomes were obtained from the UniProtKB release 2012_09) Whenever possible, the classification of proteins found in the literature was used. Seven large functional groups were defined: four of them were budding and fission-associated: i) coat proteins; ii) adaptors and sorting proteins; iii) enzymes and enzymatic activity related proteins; and iv) a general group for unclassified proteins. Only the proteins of these were classified according to the three main systems . The other three functional groups correspond to fusion-associated proteins: v) SNAREs; vi) multisubunit tethering complexes; and vii) other fusion regulators. In case of the human proteins, an extra functional group of fusion regulators playing a specific role in the regulation of neurotransmitter transport was added. The unclassified group includes all the proteins for a given system that could not be classified into the first three budding and fission-associated groups but still take part in these processes, many of them being transmembrane cargo-specific receptors. GEFs (Guanine nucleotide exchange factors) were not included in the analysis since they were only reported to act on their specific small GTPase. Although sometimes highly specific for the process, these proteins were not considered as part of the transport vesicles themselves.Prediction of intrinsic protein disorder was carried out using the IUPred method Prediction of disordered binding regions (DBRs) possibly involved in protein-protein interactions was carried out using the ANCHOR method k disordered residues; k\u200a=\u200a30, 50 and 100), and iii) ratio of residues in ANCHOR-predicted Disordered Binding Regions (DBRs). In case of the transmembrane proteins, residues belonging to the reported transmembrane segments were not taken into account for the calculation of any disorder metric.Standard measures generally used in the literature to describe the disorder content of proteins were calculated: i) relative disorder content or ratio of disordered residues , ii) ratio of residues in Long Disordered Regions (LDRs)  were performed using Wilcoxon Rank Sum Test. Comparisons of disorder measures in specific groups to the corresponding reference proteome values, were performed using Fisher's Exact Test.Transmembrane regions were assigned according to UniProtKB Orthology identification between human and yeast proteins was performed by the Inparanoid v7 program Interaction partners with the highest confidence (confidence level\u200a=\u200a0.9) were obtained from the STRING database 9.0 All tissue specific exons (TSEs) for the budding- and fission-associated human proteins of our dataset were collected from Wang et al. A comprehensive search in the Protein Data Bank (PDB) www.r-project.org). The Pymol molecular graphics tool [http://www.pymol.org/] and the DOG2 protein domain representation tool All data processing in this study was performed using scripts written in the Perl programming language. All analyses were implemented in the statistical analysis programming language R , and 3) the ratio of residues in predicted disordered binding regions (DBRs).Three different disorder metrics were used to explore the abundance of structural disorder and functionally important disordered sites in vesicle trafficking proteins: 1) the ratio of predicted disordered residues (hereafter referred to as disorder content), 2) the ratio of residues in predicted long consecutive disordered regions (LDRs) of different lengths . The mean number of DBR residues is also higher for human than for yeast proteins . The overall disorder content of vesicle trafficking proteins  is not statistically significantly different from that of the corresponding complete proteome  in either species.The disorder content of the equivalent functional categories in human and yeast shows no statistical differences for any of the pairs as assessed by the Wilcoxon Rank Sum Test. All disorder metrics showed similar tendencies  for the main functional groups of the two species , Table 1Fusion regulation proteins are among the least disordered ones  since thThe \u201cSNARE\u201d group is composed of proteins containing at least one v- or t-SNARE coiled coil homology domain and various types of family-specific domains. Even so, they show a surprisingly high deviation in disorder content with a few of them being mostly disordered and others being well structured. The members of the syntaxin family of SNAREs have disordered N-terminal regulatory regions that can be used by their direct regulatory partners (e.g. SM proteins) to modify their function. Several PDB complexes demonstrate how the disordered syntaxin N-tail folds up when bound to a globular SM partner . Our resAlthough its median disorder content is only the second largest (21.49%), the group of \u201cadaptor and sorting proteins\u201d (ASPs) has the most highly disordered (>50%) members. This group is very diverse, containing completely structured subunits of larger adaptor complexes  and also highly disordered adaptor proteins such as the epsins, DAB1 and DAB2 (Disabled homolog 1 and 2), HRS (Hepatocyte growth factor-regulated tyrosine kinase substrate) and NUMB (Protein numb homolog). The latter ones all have long LDRs enriched in binding motifs.Interestingly, the group of enzymatic activity related proteins (EARPs) is the most disordered (22.84%). This might be counterintuitive at the first glance, since enzymes are thought to be typically well-folded proteins. Indeed, this is the case for domains carrying enzymatic activity or for small single-domain enzymes, like the small GTPases. However, their direct regulators, the long GAPs (GTPase activating proteins), for instance, are considerably disordered. The increased structural disorder content of GAPs in general was already reported and accounted to their long flexible inter-domain linker regions Finally, the group of \u201cneurotransmitter transport specific regulators\u201d (NTSRs) contains distinct protein families: synaptotagmins, complexins, several neurotransmission-specific SM proteins, synaptophysin and tomosyn. Complexins are the most disordered family of our entire protein dataset (d.c. 76.25\u201398.51%), while the other members are highly ordered.The statistical comparison of human functional groups against their whole proteome reference value  showed tThe disorder content of all budding- and fusion-associated proteins involved in the three main vesicle trafficking systems regardless of their functional classification was also compared , Table 1The disorder content of the proteins in the COPI and COPII routes is not significantly different in either species. Similarly, the average disorder content of the proteins in each of the three main pathways does not significantly differ between human and yeast (as assessed by the Wilcoxon Rank Sum Test).The higher disorder content found in the clathrin-mediated route is partly due to the highly disordered clathrin light chains and mainly stemming from the several highly disordered proteins in the ASP and EARP groups. Overall, many of its proteins contribute to the observed effect. In case of the COPI and COPII pathways, most of the disorder contribution comes from a few outliers; namely, the huge, largely disordered Sec16 homologs for the COPII route, and a few highly disordered ArfGAPs (ADP-ribosylation factor GTPase-activating proteins) for the COPI route.Only the clathrin-mediated route showed significant enrichment in proteins with LDRs of all three lengths  when compared to the corresponding whole proteome reference values for both species .In order to show that structural disorder provides enhanced evolutionary adaptability and plasticity in the clathrin pathway, two appropriate measures were introduced. The first measure reflects the capability of proteins to participate in multiple pathways and to mediate interactions with diverse partners (moonlighting). Although the correlation between moonlighting ability and structural disorder of proteins has been previously described High confidence, non-vesicle trafficking related (off-pathway) interaction partners were collected for all budding- and fission-associated human proteins in the dataset . Out of For the most \u201cinteractive\u201d proteins these values were compared with different measures of predicted structural disorder and disordered binding sites . InteresAll these results suggest that apart from some subunits of large complexes of coats and adaptors, most of the proteins showing moonlighting capabilities are often highly disordered and have several LDRs and many predicted DBRs. Among the three main routes, the clathrin pathway is the only one rich in such proteins, thus the vast majority of non-vesicle trafficking related interactions are mediated by this pathway. Further attesting to the functional adaptability of the clathrin route is that we observed the partners of proteins in this route being the most diverse with respect to their main pathways/molecular functions. For example, for the COPII proteins the 50 off-pathway interactions involve only 40 unique non-vesicle trafficking interaction partners (more COPII proteins can interact with the same off-pathway partner) out of which 15 are subunits of the nuclear pore complex alone  and there are also several lysosome-associated proteins and secreted ones.All reported examples of TSEs for all budding- and fission-associated proteins in our data set were collected from Wang et al. Our results show that clathrin route associated proteins seem to be the ones which have most frequently acquired tissue-specific exons during their evolution: 33 of the 44 identified exons (75%) are located in 22 unique clathrin route associated proteins (\u223c31% of its proteins showing at least 1 TSE), while only 7 such exons were found for 5 COPII related proteins, 3 for 2 COPI associated proteins, and 1 in TMED2, a transmembrane cargo receptor shared between the COPI and COPII routes . TSEs showing the strongest tissue specificity , almost twice the value for the complete human proteome (22.81%). According to ANCHOR predictions, there are 39 DBRs that are either completely encoded or overlapping with the protein regions corresponding to the 44 exons, and 4 additional binding regions were found to overlap with the 5 residue neighborhood of TSE boundaries, which are most probably also affected by the presence or absence of the given TSE.The 33 TSEs present in the clathrin pathway proteins encode for a total of 970 residues. The disorder content of these TSE-encoded protein regions is higher in the clathrin route proteins (47%) than in the proteins associated with the other two routes (39.3%). 29 DBRs were found within the corresponding clathrin route related protein regions and the 4 binding regions that reside within 5 residues from the TSE boundaries are also found in association with these regions. The low number of TSEs in the proteins of the COPI and COPII routes do not allow statistical comparisons between the three pathways, but point to the fact that clathrin route proteins are far more prone to acquire such regions. We identified at least one Pfam \u2018entity\u2019  for 238 vesicle trafficking proteins in human. There were only 10 proteins for which no domain or family could be assigned. We further analyzed the Pfam patterns of highly disordered proteins, namely those with at least 70% disorder content or a high ratio of LDR residues (\u2265mean plus 2 times standard deviation or \u226550%). In some cases, such proteins are assigned to Pfam families based on evolutionary conservation, and yet they do not contain any folded domains. Such is the case of all the complexins (1\u20134), which belong to the synaphin family and are highly disordered (disorder content 76\u201398%) according to our predictions. Another example is the family of clathrin light chains, where both proteins show very high predicted disorder content (60% and 74%) and have no folded domains assigned.clearly show that there are several folded domains that are typically located in highly disordered proteins. These structured \u201cislands\u201d are usually surrounded by extended disordered regions on either or both of their sides, and tend to be the sole domain of the protein. Examples of such kind of domains include the ENTH  domain, the PID (phosphotyrosine interaction domain), the Sec16 domain, and the muHD , among others.Our data The highly disordered epsin type clathrin adaptors (1\u20133) have the unique ENTH domain at their N-terminus, which serves as a membrane interacting module, while the remaining part of the protein is completely disordered. Epsins 1 and 3 also contain UIM motifs (Ubiquitin Interaction Motifs) within their disordered regions along with the many identified adaptor protein- and clathrin-binding motifs Apart from the previously mentioned domains, we have found others, which are often surrounded by variable long disordered regions, but are also present in proteins that tend to have less disorder content. The BAR (Bin-Amphiphysin-Rvs) domain \u2013 involved in membrane curvature sensing \u2013 is present in the highly disordered amphiphysin (d.c. 60.58%), but also in endophilins , which have substantially variable disorder content (d.c. 7.12\u201335.60%). The protein kinase domain is present in AAK1 , but it is often part of other less disordered kinases as well.In summary, the vast majority of the domains that are always surrounded by highly disordered regions belong to clathrin pathway associated adaptor and sorting proteins . Their structural properties \u2013 having a single folded domain located at one of their termini, while the rest of their chain is highly disordered with embedded functional motifs \u2013 make them excellent candidates for the fly-casting mechanism. Additionally, previous studies have shown that these adaptors are able to form extended adaptor networks on the surface of the budding vesicle, some of them being responsible for recruiting clathrin as well To further investigate the role of disordered binding regions in building the adaptor network, we performed a systematic PDB search looking for clathrin coat specific protein complexes. We found several structures where the interaction of two clathrin adaptors is shown, and one of the partners uses its disordered binding regions to bind to the folded domain of the other one. In case of the multisubunit AP-2, one of the most studied key players of endocytosis, two long disordered regions connect the two \u03b1-adaptin ear domains to the major part of the huge complex. The recognition of cargo sorting signals is done by the major part, while the principal clathrin-binding region is located in the disordered \u03b22-adaptin hinge We also found structures where other non-adaptor clathrin pathway associated proteins interact with AP-2 or clathrin via their disordered segments. Amphihpysin, for instance, interacts with both (PDB IDs 2VJ0 and 1UTC) via two different disordered binding regions located in the long disordered segment following the BAR domain. Proteins from the EARP functional group also bind AP-2, in case of synaptojanin 1, two distinct constructs were shown to bind the \u03b1-adaptin domain (PDB ID: 1W80), while PIP5K1C (Phosphatidylinositol 4-phosphate 5-kinase type-1 gamma) interacts with the \u03b2 subunit (PDB ID: 3H1Z).We identified 56 human proteins that could be successfully matched to a yeast protein from our dataset using the Inparanoid 7.0 method. We focused on orthologous pairs involved in the budding and fission associated functional groups because they show higher abundance of disordered regions, they were the ones that could be reliably grouped according to the main routes and hence better distinguishing between those. We filtered these pairs for at least one of their members showing considerably high disorder content (>30%). From the resulting 8 protein pairs  one showed very similar disorder content (less than 5% difference); 5 pairs showed more disorder in the human ortholog than in the yeast ortholog; and in two cases the yeast protein showed higher disorder content.We analyzed two protein pairs in detail . The firIn the second pair, both proteins are highly disordered: human Sec16A (Protein transport protein Sec16A) and yeast Sec16 (COPII coat assembly protein SEC16), and according to their predicted disorder patterns , despiteVesicle trafficking routes have fundamental roles in the eukaryotic cell, providing the possibility of targeted macromolecule transport between the various intracellular compartments and also the cell and its environment. The COPI, COPII and clathrin-mediated vesicle trafficking routes comprise the major part of the transport network, being responsible for the different types, locations and directions of traffic involved in endocytosis, the early and late secretory pathways and the retrograde Golgi-ER transport. Despite their similarities, there are fundamental functional and evolutionary differences that strongly distinguish these routes, yet the structural characteristics that could account for these differences have not been previously described.In this work, we provided a systematic assessment of the potential functional involvement of structurally disordered protein regions in the main vesicle trafficking systems. Based on the functional requirements of their proteins and the inherent advantages that structural disorder could offer them, we expected such systems to heavily rely on disordered protein regions. Such regions have been widely recognized to be abundant in proteins related to signalling and regulatory roles The different measures of structural disorder that were used to describe the abundance and location of such protein regions in vesicle trafficking proteins allowed us to distinguish between major functional roles, in which disordered regions could be involved. While the overall disorder content of proteins provided a broad picture about the dependence of the given functional group or trafficking route on structural disorder, the ratio of residues located in predicted DBRs helped to estimate the involvement of these regions in protein-protein interactions. In those cases where the ratio of residues in LDRs is considerably more than those in DBRs, we could speculate that besides promoting protein-protein interactions, disordered regions might also serve as flexible linkers between structured domains, or as long spacers, assisting in fly-casting mechanism by providing the possibility for the motif-rich parts to reach farther.Despite the heterogeneity of proteins in the three major vesicle trafficking routes, we found that the proteins of these systems followed similar overall tendencies of structural disorder in the two species. The overall statistic comparison of human and yeast proteins showed that proteins involved in vesicle trafficking are only slightly more disordered in human. The equivalent functional groups in the two species showed very similar disorder contents, which reflect the well-conserved nature of vesicle trafficking proteins. These results are consistent with previous works showing that intrinsic disorder is not necessarily correlated with organism complexity The importance of disordered regions in vesicle trafficking is also well reflected by the fact that almost all the main functional groups have highly disordered (>50%) members in both species. The big differences observed between the disorder contents of different groups nonetheless imply that certain functions require the presence of disordered protein segments more than others.Not surprisingly, most coat proteins are mainly structured, since they tend to fold into rigid cage-like structures on the surface of all types of vesicles. Despite much different cage architectures, they all contain the same two types of folded building blocks: \u03b1-solenoids and \u03b2-propellers. Only the group of clathrin light chains (CLCs) was predicted to be largely disordered, while the different Sec31 COPII coat subunits possess a long disordered segment between their structured domains. The dynamic nature of the highly disordered CLC has an important role in the regulation of clathrin lattice assembly through allowing for large conformational switches, which also influence the conformation of the heavy chain knee regions Some of the proteins involved in fusion-related functions also showed a considerable amount of disorder, although most of the functional groups  here had rather low disorder content. The SNARE group was the most disordered among these in both species, since the different SNARE homology domains are unfolded in their monomeric form 2+-induced signal for this 2+ signal to complexins is not yet fully understood. According to our predictions, complexin regions forming the helixes in the complexes are unfolded in their monomeric state, just like the SNARE coiled coil homology domains that they are mimicking.The NTSR group, although showing relatively low overall disorder content, contains the most disordered protein family of our data set, that of complexins. These SNARE regulatory proteins are predicted to be almost completely unfolded. In their complexes the \u2018central helix\u2019 of complexins is interacting with one SNARE complex, while their \u2018accessory helix\u2019 forms a bridge to another SNARE complex, occupying the empty v-SNARE binding site to inhibit vesicle fusion. Their accessory helix was thought to compete with the v-SNARE homology domain for binding the prefusion t-SNARE complex, but recently it was shown rather to help organizing the t-SNAREs into a zigzag topology that is incompatible with fusion  The group of \u201cadaptor and sorting proteins\u201d showed the highest number of extremely disordered members, especially because of the non-complex-forming clathrin adaptors. Although it contains many fully structured complex subunits as well , it is quite evident that intrinsic disorder has a fundamental role in maintaining many of the functions carried out by this group, such as linking the coat scaffold to the cargo and to the membrane, helping vesicle coat assembly by binding the coat subunits, and communicating with other accessory proteins. The dependency on structurally disordered regions must be the largest in case of the clathrin system, since most of the individual clathrin adaptors, many of the accessory proteins and also some of its enzymes (like synaptojanins) have extremely long disordered tails with a large collection of several protein interaction motifs. Also, when searching for those solitary folded domains, which behave like structured \u201cislands\u201d, surrounded by extended disordered regions on either or both sides, most of the examples that we could identify belonged to the ASP group of the clathrin-mediated system. These proteins seemed to be the best candidates for the fly-casting mechanism, since they could behave as a fishing stick, their folded domain being fixed to the surface of the vesicle or to bigger protein complexes, while their disordered, flexible tail can freely reach for their various partner proteins over relatively long distances. This binding mode can be especially advantageous in the vesicle assembly process because it may enhance the speed of recognition and bring the coat components into close proximity to the surface of the budding vesicle. Unstructured proteins have larger capture radius that helps them efficiently utilize their many interaction motifs. Additionally, we collected several examples from the PDB that provide structural evidence for protein interactions mediated by the induced folding of disordered binding regions in clathrin system related proteins. Many of these structures showed the same domain, the AP-2 \u03b1-adaptin ear domain, facilitating specific interactions with disordered binding motifs of its partner proteins . The parThe functional importance of disordered regions was also well reflected by the conserved nature of their location, while the variability in their length and their low sequence similarity showed their increased adaptability and tolerance against mutations compared to folded domains. When investigating orthologous protein pairs from human and yeast, the location of disordered regions was found to be quite conserved, while their length appeared to be more subject to evolutionary change. In case of the Sec16 pair, the long disordered regions surrounding the structured domains were very well preserved, and even the lengths of the two proteins were highly similar. Since almost the entire length of the two long disordered \u201carms\u201d of the proteins is covered by predicted disordered binding sites in a well-conserved way, their essential role in the initiation of the COPII coat assembly is very likely. The level of conservation in these regions seems to heavily depend on the specific functional needs of the given protein. In case of the Sec24 orthologous pair, for instance, the human sequence has a considerably long N-terminal unstructured region, which is almost completely missing from the yeast counterpart. The presence of numerous predicted disordered binding regions implies that this region is the result of adaptive evolution. Since this protein is a key player in cargo recognition and binding, which obviously involves a larger repertoire of possible cargos in human, the emergence of such adaptive regions could provide indisputable benefits.Toxoplasma gondiiCaenorhabditis elegansOur results showing that the clathrin system is significantly more disordered than the COPI and COPII systems not only imply the larger dependence of this system on disordered protein segments and support the concept of highly dynamic networks formed by its proteins, but also explains much about the differences between the three routes from the evolutionary point of view Taken together, these observations on the many different adaptive changes manifest on clathrin-route related proteins strongly support the idea that it has been favoured by evolution over the two other main trafficking systems. Until now, the structural background of this phenomenon had not been established. In this study we show how structural disorder found in this system underscores its exceptional adaptability. We analyzed the moonlighting abilities and tissue specific functions of the proteins in the three main vesicle trafficking routes, as they are both strong indicative measures of adaptability. The clathrin route clearly stands out, having the highest number of non-vesicle trafficking interaction partners and the most verified tissue specific exons. The correlation between these abilities and the disordered nature of the corresponding proteins/protein regions in general had been previously suggested Clathrin-route associated proteins have significantly more off-pathway interactions than COPI- and COPII-route associated proteins. Out of the most \u201cinteractive\u201d 21 proteins, 19 are clathrin-route related, many of them having disorder regions . More than one third of all off-pathway interactions of the three routes are mediated by only 9 non-complex-forming clathrin adaptors, most of which have LDRs densely covered by predicted DBRs and/or are highly disordered, meaning that more than half of their residues reside in disordered regions. The clathrin-route proteins also show more ability to maintain tissue specific functions than the proteins in the other two routes. 75% of all TSEs were found in clathrin-route associated genes, together with approximately the same ratio of TSE encoded predicted DBRs residing in clathrin proteins. TSE-encoded protein regions are almost twice as disordered as the proteome average, and they have an increased capacity to host interaction sites (one in every 40 residues in our dataset). These findings are in good agreement with the general view that TSE-encoded protein regions are enriched in protein disorder In summary, we found many functional modalities enabled by disordered regions to be present in vesicle trafficking proteins. These include regulatory roles, the use of flexible linkers, mediating protein-protein interactions with proteins of the same route or others, or the quick assembly of large macromolecular complexes by fly-casting. Taken together, our results provide compelling evidence for the functional involvement of structural disorder in the main vesicle trafficking systems. The presence of highly disordered proteins in almost all the main functional groups of vesicle trafficking proteins emphasized the unquestionable importance of disorder for this cellular process in general. The remarkable differences in its abundance between the three main trafficking routes, however, provided structural background for long standing observations on the functional and evolutionary differences of these systems.Table S1Vescile trafficking-related human proteins. All human proteins related to vesicle trafficking, with various measures of predicted protein disorder.(XLS)Click here for additional data file.Table S2Vescile trafficking-related yeast proteins. All yeast proteins related to vesicle trafficking, with various measures of predicted protein disorder.(XLS)Click here for additional data file.Table S3Off-pathway interaction partners of vesicle trafficking proteins. The number of high confidence, non-vesicle trafficking related (off-pathway) interaction partners of proteins of the three vesicle-associated pathways in humans.(XLS)Click here for additional data file.Table S4Tissue-specific exons (TSEs) in budding- and fission-associated human proteins have been collected from Wang et al. . The resulting 44 coding exons are mapped onto Ensembl transcripts, and their various disorder parameters are given.(XLS)Click here for additional data file."}
+{"text": "Dear Editor,\u201cMineral and bone disease in black African hemodialysis patients: a report from senegal\u201d by Seck and all published in Nephro-Urology Monthly is an interesting paper .Disturbances in mineral and bone metabolism are common in patients with chronic kidney disease (CKD). Patients with CKD almost always develop secondary hyperplasia of the parathyroid glands, resulting in elevated blood levels of parathyroid hormone (PTH) . Normal Bone radiographs are not indicated for the assessment of bone disease of CKD. Seck and all used X-ray for detecting looser\u2019s zones and vascular calcifications. Bone radiographs are also useful in detecting calcification articular cartilages and periarticular tissues in renal osteodistrophy. On the other hand, osteosclerosis occurs in 9-34% of patients (CKD-MBD is a common worldwide problem in patients with CKD. Adequate dialysis and medical treatment are required for the limitation of the destruction of the disease. More effort is needed in this area."}
+{"text": "First we address some pathophysiologic factors contributing to metabolic dysfunction following TBI. We then examine how 13C NMR spectroscopy strategies have been used to investigate energy metabolism, neurotransmission, the intracellular redox state, and neuroglial compartmentation following injury. 13C NMR spectroscopy studies of brain extracts from animal models of TBI have revealed enhanced glycolytic production of lactate, evidence of pentose phosphate pathway (PPP) activation, and alterations in neuronal and astrocyte oxidative metabolism that are dependent on injury severity. Differential incorporation of label into glutamate and glutamine from 13C labeled glucose or acetate also suggest TBI-induced adaptations to the glutamate-glutamine cycle.The present review highlights critical issues related to cerebral metabolism following traumatic brain injury (TBI) and the use of  The primary advantage of this technique arises from its ability to distinguish 13C incorporation into multiple metabolites as well as into the specific carbon positions within the same metabolite, resulting in a detailed analysis of the metabolic \u201cfate\u201d of the 13C label , oxidative metabolism within, and interactions between, the neuron and astrocyte compartments (glutamate and glutamine labeling). By using  glucose as the substrate, injury-induced changes in the activity of the pentose phosphate pathway (PPP) can be assessed using the ratio between the lactate labeled in two carbon positions (doublet) via glycolysis (C2 and C3) and lactate labeled in the singlet C3 carbon position  to the labeling of glutamate labeled in the C4 position via the recycling of pyruvate from labeled oxaloacetate via malic enzyme using either  glucose or  acetate  or the unilateral controlled cortical impact (CCI) injury models of TBI. The FPI model can produce a diffuse pattern of neuronal and axonal injury, while CCI is often termed a more focal injury model due to the contusion induced  from microdialysis samples of CCI injured cerebral cortex in rats .As previously described, mitochondrial dysfunction is thought to play a key role in the pathophysiology of TBI. Studies using cytochrome C oxidase histochemistry as a measure of oxidative phosphorylation on the mitochondrial membrane, show a diffuse decrease in staining throughout the injured hemisphere of both FPI  studies using dynamic 13C NMR spectroscopy is a logical next step in advancing our understanding brain function after TBI.The studies reviewed above highlight alterations to a number of key metabolic processes during the period of metabolic depression following experimental TBI. Although these studies are valuable in their contributions linking the period of metabolic depression to qualitative changes in a number of metabolic processes, they are limited by their descriptive nature. 13C studies should be to understand the cellular basis of metabolic alterations following TBI. It is important to establish how individual cell types respond to TBI. For example, studies employing compartment specific labels (singly or in combination) could delineate a cell-type specific preference for a metabolic fuel that would preferentially enhance outcome. In addition, future studies of metabolic flux during the acute period of hyperglycolysis could provide direct evidence of the metabolic forces (increased neurotransmission and/or energetics) driving this need. Moreover, comparisons between findings from the acute period of hyperglycolysis and the period of metabolic depression could establish key time points and potential targets for metabolic intervention.One goal of future animal and clinical 13C NMR spectroscopy can be utilized to probe multiple aspects of the metabolic response to TBI, including changes in glycolysis, PPP activity, oxidative metabolism, and neuroglial metabolic compartmentation. As illustrated in the materials reviewed above, numerous experimental treatments that improve cerebral metabolism, reduce neuronal injury, and improve functional outcomes after TBI are currently being investigated, and future studies using 13C NMR spectroscopy to evaluate the metabolic responses to such treatments should provide valuable insights into the mechanisms of actions.TBI induces multiple primary and secondary injury mechanisms that can impact the supply of fuels and/or alter the functions of metabolic enzymes and proteins which can lead to deficits in energy availability. Dr's. Bartnik-Olson and Sutton prepared the initial draft of this manuscript, Dr's. Harris and Shijo contributed additions and edits to the final versions of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Emerging evidence suggests that endothelial diversity would be prominently driven by epigenetic mechanisms which also control the basal expression of endothelial-specific genes. This review outlines evidence for endothelial diversity since early stages of vascular development and how this heterogeneity is expressed in the umbilico-placental vasculature. Furthermore a brief picture of epigenetic mechanisms and their role on endothelial physiology emphasizing new data on umbilical and placental endothelial cells is presented. Unraveling the role of epigenetic mechanisms on long term endothelial physiology and its functional diversity would contribute to develop more accurate therapeutic interventions. Altogether these data show that micro- versus macro-vascular, or artery versus vein comparisons are an oversimplification of the complexity occurring in the endothelium at different levels, and the necessity for the future research to establish the precise source of cells which are under study.The endothelium is a multifunctional heterogeneous tissue playing a key role in the physiology of every organ. To accomplish this role the endothelium presents a phenotypic diversity that is early prompted during vascular development, allowing it to cope with specific requirements in a time- and site-specific manner. During the last decade several reports show that endothelial diversity is also present in the umbilico-placental vasculature, with differences between macro- and microvascular vessels as well as arterial and venous endothelium. This diversity is evidenced  From thchanisms .Ncx-1) knockout mice which fails to initiate cardiac contraction Vasculogenesis is the process by which vessels are formed from mesenchymal-derived hemangioblasts which differentiate into endothelial cells . CurrentGrowth and consolidation of the placental vascular tree occurs by angiogenesis. In this process single vessels are formed by endothelial precursor cells (EPCs) which differentiate into endothelial cells, and/or proliferate from endothelial cells. These vessels can spread in two ways, (1) non-branching angiogenesis, which implies an increase in the length of the villous vessels, and (2) branching angiogenesis, in which multiple short capillary loops are formed , increasDuring the last decade, the study of genome-environment interactions has revealed a plethora of mechanisms that modulate short and long term cellular physiology. These mechanisms involve mainly epigenetic processes which control chromatin accessibility in a gene- and cell-specific manner. Definition of epigenetics is still under debate mainly due to the several molecular mechanisms that it comprises and the heritability of these changes in an organism and its progeny; however, a simple and broad definition considers epigenetic mechanisms as \u201cchromosome-based mechanisms that change the phenotypic plasticity in a cell or organism\u201d .Figure 1). As an additional epigenetic mechanism, the presence of non-coding RNAs can post-transcriptionally repress gene expression. Detailed reviews of the diverse epigenetic mechanisms and their effects on gene expression are available  alter the structure of the chromatin, generating regions with a \u201cclosed chromatin\u201d conformation. Conversely, DNA demethylation . Initial steps of vascular development in the embryo seem to be influenced by both genetic and environmental stimuli which drive the emergence of two different populations of endothelial cells  activity has the opposite effect . Development of vascular dysfunction is accompanied by changes in SMC phenotype, which shift from a \u201ccontractile\u201d to a \u201csynthetic\u201d and \u201cpro-inflammatory\u201d phenotype with long term consequences in the contractile properties of vessels . IncreasPioneer studies by Notably, studies on endothelial cells from arteries and veins have revealed important differences between arterial and venous cells at the same vascular level. In fact the higher mitogenic response observed in PLEC  may reflin vitro need further examination. Two recent reports show that the differential gene expression between HUAEC and HUVEC is partially controlled by specific transcription factors. Overexpression of the venous-specific nuclear receptor COUP-TFII in HUAEC decreases the expression of arterial markers , and its down-regulation in HUVEC increases the expression of arterial markers such as VEGF-A, Dll and EphrinB2  and venous (HUVEC) endothelium support the concept that these cells are not a homogenous population, and the necessity of clarifying the precise source of cells when the term \u201cmacrovasculature\u201d is used. A general characterization shows that there is a different profile of phospholipids with higher levels of arachidonic acid-related species and heterogeneous expression pattern of selenoproteins  in HUAECEphrinB2 . Moreove pattern .Therefore, the phenotypic diversity in the umbilico-placental circulation is apparently commanded, at least in part, by an equivalent diversity in epigenetic mechanisms.In vivo VEGFR3, which is commonly expressed in lymphatic endothelium or during active angiogenesis  in HUAEC but decreases the expression of venous markers (COUP-TFII) in HUVEC . Laminarproteins  endothelproteins  in HUAEC2decreases placental venous microvascular endothelial cells viability with no effect on their arterial counterparts  increases the expression of the pro-angiogenic factor protease-activated receptor 2 in HUVEC and this effect is higher in HUAEC . Further studies should include control comparison between arterial and venous endothelial cells from the same branching level to rule out potential differences attributable to arteries and veins rather than micro- and macrovascular vessels. It is worth to note that most of the differences occurring among these cells types could be reverted by genetic manipulation. However, its persistence in vitro suggests that additional mechanisms controlling gene expression should be operating, arguing for a crucial role for epigenetics in this process.Altogether these data show that venous-arterial endothelial phenotypic diversity occurs among umbilical and placental vessels  and ARG2 (arginase-2) promoters by pyrosequencing in HUAEC, PLAEC and HUVEC, suggest the presence of site-specific differences between these cells. Methylation status at NOS3 promoter in umbilical and placental endothelial cells showed differences in three specific CpG between arterial and venous endothelial cells . Two of DNA methylation is one of the main epigenetic mechanisms that controls long term gene expression, showing a high reproducibility after every cellular replication and this characteristic is driven by the activity of DNA methyltransferase-1 (DNMT1). In IUGR HUAEC and HUVEC DNMT1 silencing shows a differential effect, reducing and increasing basal eNOS expression, respectively . SilenciAlthough the studies in PLAEC and PLVEC , and in Altogether these seminal data show that epigenetic mechanisms could be responsible for the phenotypic diversity of endothelial cells in the umbilico-placental unit, and these mechanisms would be operating in a cell- and gene-specific manner. The current research on the area is offering novel data about potential mechanisms but still further studies are required to have a comprehensive picture of the additional epigenetic mechanisms controlling the gene expression in physiological and pathophysiological conditions and its consequences in umbilico-placental functions.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The ranking of scores of individual chemicals within a large screening library is a crucial step in virtual screening (VS) for drug discovery. Previous studies showed that the quality of protein-ligand recognition can be improved using spectrum properties and the shape of the binding energy landscape. Here, we investigate whether the energy gap, defined as the difference between the lowest energy pose generated by a docking experiment and the average energy of all other generated poses and inferred to be a measure of the binding energy landscape sharpness, can improve the separation power between true binders and decoys with respect to the use of the best docking score. We performed retrospective single- and multiple-receptor conformation VS experiments in a diverse benchmark of 40 domains from 38 therapeutically relevant protein targets. Also, we tested the performance of the energy gap on 36 protein targets from the Directory of Useful Decoys (DUD). The results indicate that the energy gap outperforms the best docking score in its ability to discriminate between true binders and decoys, and true binders tend to have larger energy gaps than decoys. Furthermore, we used the energy gap as a descriptor to measure the height of the native binding phase and obtained a significant increase in the success rate of near native binding pose identification when the ligand binding conformations within the boundaries of the native binding phase were considered. The performance of the energy gap was also evaluated on an independent test case of VS-identified PKR-like ER-localized eIF2\u03b1 kinase (PERK) inhibitors. We found that the energy gap was superior to the best docking score in its ability to more highly rank active compounds from inactive ones. These results suggest that the energy gap of the protein-ligand binding energy landscape is a valuable descriptor for use in VS. Understanding the mechanism of ligand-receptor recognition plays an important role in the identification of novel compounds for pharmaceutical development http://pocketome.org/website for details). Henceforth, we will refer to this benchmark as the Pocketome benchmark. The second benchmark consists of 468 X-ray protein conformations of 36 pharmaceutically relevant protein targets from the Directory of Useful Decoys (DUD) The goal of this study is to investigate the contribution of intermolecular binding energy landscapes to the quantitative assessment of the quality of ligand recognition by protein receptors on a large and diverse benchmark of therapeutically relevant proteins. Based on studies performed in Two diverse benchmarks were used to investigate the ability of the energy gap to discriminate true binders from decoys. The Pocketome benchmark consists of 485 X-ray conformational ensembles (334 holo structures and 151 apo structures) of 40 domains from 38 therapeutically relevant protein targets  The receptors were set-up by deleting the chains, heteroatoms, and prosthetic groups not involved in the binding site definition. The protein atom types were assigned, and hydrogen atoms and missing heavy atoms were added. The added or zero occupancy side chains and polar hydrogen atoms were optimized and assigned the lowest energy. Tautomeric states of histidines and the rotations of asparagine and glutamine side chain amidic groups were optimized to improve the hydrogen-bonding patterns. The cognate ligands were deleted from the complexes only after hydrogen optimization.Coordinates of the ligands were extracted either from the crystallographic complexes or according to DUD. Bond orders, tautomeric forms, stereochemistry, hydrogen atoms, and protonation states were assigned automatically by the ICM chemical conversion procedure. Each ligand was assigned the MMFF in vacuo. Each conformer was locally minimized with relaxed bond lengths and bond angles using the MMFF-94 force field in order to remove any bias towards receptor-bound covalent geometry. The generated conformers were then placed into the binding pocket in four principal orientations and used as starting points for Monte Carlo (MC) optimization. The BPMC docking runs were performed using thoroughness setting of 2, which controls the basic number of BPMC steps to be carried out.The well-established ICM docking program was used for the docking calculations. ICM addresses the docking issue as a global optimization problem, implementing a biased probability Monte Carlo (BPMC) global stochastic optimization of the flexible full-atom models of the ligand in the set of grid potential maps representing the protein Evw, Eel, Ehb, Ehp, and Esf are van der Waals, electrostatic, hydrogen bonding, and nonpolar and polar atom solvation energy differences between bound and unbound states, respectively. Eint represents the ligand internal strain and \u0394STor is its conformational entropy loss upon binding. The \u03b1 coefficients are empirical weights that balance the different terms.For each docking simulation a stack of diverse binding poses was generated, and their respective scoring energies were evaluated using the ICM scoring function For each ligand-receptor pair, three docking runs were performed and 200 binding poses were obtained after each run. All binding poses accumulated after each run were merged in a single conformational stack, and only the geometrically unique solutions, with corresponding energies sorted from low to high, were retained. The energy gap between the lowest energy (best scored pose obtained from three docking runs) and the average energy of all other poses scored in the searched binding energy landscape was calculated and used as a score to discriminate true binders from decoys. If the lowest energy or the average energy of all other poses obtained from the docking runs were found to have a positive value, then those protein-ligand complexes were not included in the final dataset because of possible indication of protein-ligand clashes or other structural anomalies, such as high conformational strain. Performances of the energy gap and the best docking score were evaluated through retrospective SRC and MRC VS experiments aimed at separating known ligand binders from decoys. For the Pocketome benchmark, the evaluation of docking scores and energy gaps for true binders was performed by docking ligands co-crystallized within a given domain to the ligand binding pocket of all conformations of this domain. Henceforth, we will refer to those ligands as true binders. The cognate receptor structures were not included in ensemble docking calculations. The cross-docking effort was aimed at generating diverse decoy complex structures. For every domain, (i) the size range of all cognate  ligands was determined as the number of their heavy atoms and (ii) 20 ligands chosen randomly from a dataset of ligands of comparable size (\u00b120% of cognate ligand size) were docked into the ligand binding pocket of all conformations of this domain. For DUD benchmark, active ligands (we will refer to those ligands as true binders too) and decoys of a given protein target were docked to the ligand binding pocket of all conformations of this target. The performance of the energy gap was evaluated through MRC VS. For the PERK homology model we tested the performance of the energy gap on 32 compounds, including 20 active and 12 inactive, validated by in vitro kinase inhibition assay N top-ranked hits (both among true binders and decoys) predicted by VS, where N is the number of true binders for a given protein target. The discrimination abilities of the energy gap and the best docking score were systematically compared.Using the approaches proposed above, the binding energy landscapes of true binders and high-scoring decoys were obtained. We hypothesized that a significant difference between these two landscapes should be observed. The energy gap of the binding energy landscape was used as a score and was evaluated for its ability to distinguish true binders from decoys. The ROC (receiver operating characteristic) curve, or ROC AUC, was used to evaluate the performance of the energy gap. ROC curve analysis \u03c3 is calculated by performing 20 random statistical experiments in which the ranks are reshuffled, calculating individual ROC AUCs and calculating the root mean square deviation of those ROC AUCs. For each ROC AUC value obtained on a given subset of binders and decoys for a given structure, its P-value was calculated as the probability of obtaining the same AUC by random coincidence:erf is the error function \u03c3 is the standard deviation. P-values below 0.05 indicate that the ROC AUC values are statistically significance, while P-values greater than 0.05 indicate that the ROC AUC values are statistically less significant.To evaluate the statistical significance of the obtained ROC AUC values, we assumed that they are distributed according to Gaussian distribution with mean 0.5. The uncertainty The receptor and ligand preparations, the docking simulations, and the energy and gap evaluations were carried out with ICM 3.6-1e . The hardware facility employed in the present study was a 16 64-bit Intel XEON X5560 CPUs Linux-based cluster at New York University School of Medicine . It takes 20\u201340 seconds to dock one compound into one receptor and perform post docking conformational stack evaluation on a single CPU.In this study the data set was utilized to investigate the ability of the energy gap in the searched binding energy landscape to discriminate true binders from decoys. The evaluation of the best docking scores and the energy gaps for true binders and decoys was carried out as is described in the Materials and Methods section. As an example of a binding energy landscape and evaluation of the energy gap, the docking of Chk1 protein kinase inhibitor (PDB HET ID: 422) to Chk1protein kinase (PDB ID: 2br1) is presented in First, the energy gap was evaluated for its ability to distinguish true binders from decoys for each 485 single receptor conformation, included in the Pocketome benchmark, individually. The performances of the energy gap and the best docking score were measured as the area under the ROC curve, or ROC AUC . The resulting distributions of AUC values are presented in Previously, in Consideration of the receptor flexibility is crucial for structure-based drug design and VS methodologies In By using the energy gap, the binder/decoy discrimination ROC AUC value was improved for 77% protein domains when compared to the performance of the best docking score. The improvement was particularly high for the previously problematic cases (weak performance of the best docking score) with original AUC values below 0.9. For these cases we obtained improvement in 83% of protein domains .bona-fide\u201d \u22127.Furthermore, the performance of the energy gap in true binders/decoys discrimination was evaluated through MRC VS against 468 high resolution X-ray protein conformations of 36 pharmaceutically relevant protein targets from the Directory of Useful Decoys (DUD), which is one of the most challenging test sets for benchmarking VS. The biggest challenge comes from the fact that true binders included in DUD are selected based on experimental activity and independently from receptor X-ray structures. In addition to that, decoys included in DUD are \u201cN top-ranked hits sorted by the energy gap and the best docking score, where N is the number of true binders for a given protein target, are presented. Obtained results indicate that the energy gap rewards early recognition better compared to the best docking score in 50% of protein targets and in another 19% of protein targets the energy gap and the best docking score reward early recognition identically. These results certainly indicate that the energy gap outperforms the best docking score in its discrimination performance.Because successful VS ranks true binders early The folding landscape of proteins has two major phases, a) molten globule phase where the system has high entropy and energy, and b) native phase where the system has low entropy and energy We consider the case when half or more of the X-ray structures included in the dataset show AUC values greater than 0.9 as an indicator of a good performance. As it can be seen in The prediction of the ligand native binding pose is an essential problem in drug discovery. As we mentioned in the introduction, literature has already reported that the correct binding pose is often not the best scored solution, and consideration of a small set of representative docking solutions significantly increases the success rate of near native binding pose identification To further evaluate the discrimination ability of the energy gap, we tested its performance on a more sophisticated case: VS against a protein homology model. We applied the binding energy landscape analysis to PERK inhibitors that were recently discovered using homology models All of the docking experiments in this paper were performed with ICM, and logical questions could arise about the applicability of obtained results to other platforms. Consistency between our findings and results obtained in independent studies There is no doubt that it is difficult to avoid errors when evaluating the binding energy levels corresponding to different docking poses In this study we investigated the screening performance of the energy gap between the lowest energy (best scored pose) and the average energy of all other poses scored in the searched binding energy landscape to discriminate true binders from decoys. We performed the study based on the assumption that the energy gap calculated during docking is a measure of the binding energy landscape sharpness, an assumption which was previously proposed and supported in silico but may be biologically irrelevant due to its statistical mechanics profile: it may have a preference for many sites on the receptor and on other receptors at once. The presence of a funnel-shaped energy landscape, detectable by an energy gap as we have defined it here, may discriminate these artifactual ligands from physiologically relevant ligands exhibiting the same level of in silico complementarity in their final bound state. Based on obtained results, we can conclude that the energy gap reported by VS algorithms contains information distinguishing between these two scenarios. The successful integration of binding energy landscape scores (such as the energy gap investigated in this study) with the usual VS lowest energy score can improve the physiological relevance of well established approaches in VS for rational lead discovery, which are often adequate in discriminating binders from the background but generate many false positives. From this study, we suggest that in VS experiments the binding energy landscape analysis should be applied after all clearly structurally incompatible chemicals are filtered based on the lowest energy score. After this step all binding conformations within the boundaries of the native binding phase have to be investigated and analyzed in detail.VS is based on the assumption that the final state of the ligand-receptor complex contains all the necessary information for the discrimination of biologically relevant ligand-receptor complex conformations from biologically artifactual alternatives. Notably, a ligand may show excellent complementarity with a receptor target pocket Table S1PDB IDs, Swiss-Prot IDs and performance of 485 X-ray protein conformations included in the Pocketome benchmark.(XLS)Click here for additional data file.Table S2PDB IDs, Swiss-Prot IDs and performance of 334 holo X-ray protein conformations included in the Pocketome benchmark.(XLS)Click here for additional data file.Table S3PDB IDs, Swiss-Prot IDs and performance of 151 apo X-ray protein conformations included in the Pocketome benchmark.(XLS)Click here for additional data file.Table S4Swiss-Prot IDs and performance of 40 protein domains included in the Pocketome benchmark.(XLS)Click here for additional data file.Table S5Swiss-Prot IDs and performance of 40 protein domains when only holo structures included in the Pocketome benchmark were considered.(XLS)Click here for additional data file.Table S6Swiss-Prot IDs and performance of 36 protein domains when only apo structures included in the Pocketome benchmark were considered.(XLS)Click here for additional data file.Table S7The performance of the energy gap obtained from single-receptor conformation VS for 485 X-ray protein conformations included in the Pocketome benchmark when different energy cutoffs from the best docking score were applied to cluster binding conformations within the native binding phase.(XLS)Click here for additional data file.Table S8Complete MRC VS DUD benchmark.(XLS)Click here for additional data file."}
+{"text": "The glycosaminoglycan heparan sulphate (HS) has a heterogeneous structure; evidence shows that specific structures may be responsible for specific functions in biological processes such as blood coagulation and regulation of growth factor signalling. This review summarises the different experimental tools and methods developed to provide more rapid methods for studying the structure and functions of HS. Rapid and sensitive methods for the facile purification of HS, from tissue and cell sources are reviewed. Data sets for the structural analysis are often complex and include multiple sample sets, therefore different software and tools have been developed for the analysis of different HS data sets. These can be readily applied to chromatographic data sets for the simplification of data  have paved the way for bioassay technologies which utilize cell arrays to study the effects of multiple macromolecules on cells. Glycan bioassay technologies are described in which immobilisation techniques for saccharides are exploited to develop a platform to probe cell responses such as signalling pathway activation. This review aims at reviewing available techniques and tools for the purification, analysis and bioassay of HS saccharides in biological systems using \u201cglycomics\u201d approaches. Following the success of naming certain subdivisions of sciences with the suffix \u201comics\u201d, the term \u201cglycomics\u201d was coined to describe the comprehensive study of the glycome, with the glycome itself characterised as the complete set of glycan structures expressed at a particular time and spatial position in specific cells, tissues or organisms . This reO-glycosidic bond. In the case of keratan sulphate (KS) some forms are also linked via an N-asparaginyl bond. Proteoglycans are thus characterised by the vast diversity of GAG structures which decorate them. Members of the GAG family are long unbranched molecules which can be simplified into a repeating disaccharide structure, where one sugar is an uronic acid, either glucuronic acid (GlcA) or iduronic acid (IdoA) and the other is either an N-acetylated glucosamine acid (GlcNAc) residue or a N-acetylated galactosamine residue (GlcNAc). These sugar residues can be sulphated in different positions depending on the type of GAG. In the case of the simplest structural member of the family, hyaluronic acid, there is a repeat unit of GlcA and GlcNAc with no sulphate groups, which is in contrast to chondroitin sulphate , keratan sulphate  and dermatan sulphate (L-iduronate (which can be sulphated) and GalNAc-4- sulphate). Heparan sulphate (HS) is another type of GAG and is described in detail in the next paragraph. In general all GAGs are highly negatively charged which is essential for their functions which range from structural support in the matrix to lubricating joints, and regulating protein bioavailability and activity.Proteoglycans are widely distributed in animal tissues and are synthesised by nearly all types of cells . GlycosaHS is a ubiquitous linear polysaccharide molecule, belonging to the GAG family of macromolecules. HS chains are found covalently attached to core proteins to form HS proteoglycans (HSPG). Attachment of HS to different core proteins results in HS having the ability to alter its location and topography as core proteins such as syndecans and glypicans are targeted to the cell surface whereas perlecan, agrin and collagen XVIII are found in the extracellular matrix . In addiN-acetylglucosamine residue (GlcNAc). The glucosamine may remain acetylated (GlcNAc) or be sulphated (GlcNS) at the amino position, or may also be found in an unsubstituted form (GlcNH2)  thymidine. Cells numbers can be quantified using colorimetric products such as 3--2,5- diphenyltetrazolium bromide, a tetrazole (MTT) which is reduced by the mitochrondria of living cells [The ability of HSPGs to bind to different FGF growth factors and growth factor receptors to induce DNA synthesis or cell proliferation has been extensively studied ,123. Celng cells .Cell adhesion assays have been important in assessing the ability of cells to adhere to a surface. Cells can be suspended in a buffer and allowed to interact by gravity. The number of adhered cells can be ascertained with a haemocytometer or a Coulter counter to count the number of cells. Cell invasion assays have also been useful in assessing the ability of cells not only to adhere but also enter cells, such as myeloma cells. A hydrated type I collagen gel can be used to assess the distance and depth of cell invasion. Detection using phase microscopy has been useful in measuring the depth of cell invasion. Non-specific interactions can also be removed by protease digestion of non-invasive cells. These assays can provide information on a number of factors as they are easily manipulated using promoters or inhibitors .HSPGs are involved in the sprouting of new blood vessels from the existing microvascular system (angiogenesis) as they bind many inhibitors of this process . AngiogeA common method to study the downstream effects of different structures of HSPGs is by detection of different proteins and protein phosphorylation involved in different cellular signalling pathways . This isHigher throughput assays are now being favoured for the study of many molecules. The use of higher throughput (HTP) assays in the study of HS would improve the study of HS as difficulties in purifying HS mean that only small quantities of certain structures are available. Using a HTP assay means: reduced time for experiments; elimination of radioactive waste and reduction in chemical waste; reduction in quantities of HS saccharide and valuable consumables needed.Traditional cell based screening techniques using microtitre plates suffer from low numbers of samples which can be studied simultaneously. The sequencing of genomes has drastically changed the emphasis and direction of research. In this post-genome era emphasis has been put on validating specific gene targets with particular functions and disease states, and has led to biopharmaceutical companies increasing their cell based screening activities from 30% to 50% . The useDNA microarray platforms were first described and patented in 1998 for the analysis of the expression of different genes and quantitation of nucleic acid and protein interactions . Microarin situ hybridization (FISH), RNA using mRNA in situ hybridization and proteins using immunohistochemistry. Tissue arrays allow the simultaneous analysis of 1000 tissue biopsies [Many different types of cell array platforms have emerged to date. Tissue arrays contain arrays of cylindrical tissue biopsies from individual donor paraffin embedded tumour blocks which are placed in a certain position onto a \u2018recipient\u2019 paraffin block, using specialist equipment. Tissue arrays allow the parallel detection of DNA using fluorescence biopsies  and havebiopsies .glycoarrays or glycan arrays) has lagged behind other biological molecules, with scientific literature appearing only in 2003 [The use of microarrays for the study of carbohydrate interaction  and van de Waals hydrophobic interactions. Immobilization is strengthened by the removal of water between the immobilised carbohydrate and the hydrophobic surface .in vitro functional assays using cell biology approaches often require high cell numbers or larger amounts of reagents that are not always available, especially in the case of saccharides. Therefore, the development of slide-based functional screening assays may allow the screening and differentiation of different and larger populations of saccharide structures. Although array methods have been described employing living cells for RNAi transfection and small molecule responses [N-acetylgalactosamine (GlcNAc)residues, galactose  and N-acetylgalactosamine residues. Primary chicken hepatocytes express a well-defined C-type lectin that binds to non-reducing terminal N-acetylglucosamine residues, and was labelled with a fluorescent dye. A specific chamber was used to remove non-adherent cells (GlycoChip\u00ae Centrifugation Chamber) and adherent cells were measured using fluorescence detection. Chicken hepatocytes bound selectively to lectin derivatized with GlcNAc structures rather than spots of lectin with Gal or no modifications [Current esponses ,147,148,esponses ,152,153.However a more recent study shows that a slide-based technology utilizes the immobilization of saccharides onto aminosilane surfaces via a Schiff\u2019s base linkage with the reducing ends in order to assess cellular reponses to glycans . SignifiGlycomics techniques for the large scale structural and functional analysis of HS glycans now have real potential to be extended to study natural HS saccharide libraries, the production of which has recently been described , and als"}
+{"text": "Spike-wave discharges (SWD) are a striking phenomena detectable on the electroencephalogram (EEG) of all patients during absence seizures. There is experimental and clinical evidence to suggest that seizures can be terminated early through the use of short auditory stimulation , howeverIn this work we extend the model of  to accou"}
+{"text": "From September 14 to 16, 2011 the 12th symposium on Plant Protein Phosphorylation was held in T\u00fcbingen, Germany. The topic is as broad as the name suggests and covers all aspects of this important means of protein modification in plants. I have had the pleasure of attending the 2007 and the 2011 symposia. The interesting concept behind these meetings is to hear about the same biochemical mechanism operative in a multitude of experimental systems. The meetings are quite informal and present an excellent mix ranging from technology to biochemical experience and novel findings and tools.++ pathways and phosphoproteomics. It was hosted by the Zentrum f\u00fcr Molekularbiologie der Pflanzen (ZMBP) and the organizing committee chaired by Klaus Harter.The two-and-a-half-day program was divided into five double sessions: biotic interactions, hormone signaling, abiotic interactions, Mitogen Activated Protein Kinase (MAPK), and CaIn the biotic interactions session the role of phosphorylation in Pathogen-Triggered Immunity (PTI) was the central topic. Several speakers discussed differential phosphorylation events after turning on the PTI pathways. The first presentation was by Yuelin Zhang (Beijing) who discussed recent work on identifying targets of the MAPK pathway using a suppressor screen. To what extent cross talk between growth and PTI pathways exists at the level of the receptors was discussed by Cyril Zipfel (Norwich). Important points raised were whether the dynamics of receptor activation as observed in brassinosteroid receptors are directly applicable to the non-Arginine Aspartic Acid (RD) type of kinases that seem to feature in most PTI pathways. A very intriguing report was made by Iris Jarsch (Munich), suggesting a role for remorins to sequester receptors in small membrane micro domains. Looking in the very first events of membrane receptor activation, it appears that changes in heteromeric state of Flagellin Sensing 2 (FLS2) and BRI1 Associated Kinase (BAK1) can be seen a mere few seconds after ligand application . Speed was also the topic of a presentation from the host , showing evidence for direct activation of plasma membrane adenosine triphosphatases (PM ATPases) by the BRI1 receptor. Down-regulation by endocytosis of the FLS2 receptor, negative control elements such as phosphatases appear to play more and more important roles in controlling receptor activity and sensitivity  while genes have been identified that modulate the calcium signature of the PTI response .A much-explored theme in the signaling session was to isolate receptor-interacting proteins by direct pull downs or yeast interaction screens. This was used in approaches by Sorina Popescu (Ithaca) investigating reticulon-like proteins that regulate trafficking and activity of FLS2 and Sacco de Vries (Wageningen) looking at the interaction properties of members of the Somatic Embryogenesis Receptor-like Kinase (SERK) family of non-ligand binding coreceptors that includes BAK1(SERK3). Other work dealt with control of cellulose synthase by phosphorylation , subcellular relocalization of Pin-formed (PIN) proteins through phosphorylation by PINOID kinases  and several talks on the direct control of abscisic acid (ABA) signaling by Protein Phosphatase 2C (PP2C) enzymes  including interesting kinases that lack the conserved lysine in the catalytic domain called With No K (WNK)s; Esther G\u00f6rlich, Heidelberg). Using an alternative approach by comparing phosphorylation patterns in the presence or absence of a specific inhibitor of the salicylic acid (SA) response-mediating Casein Kinase 2 (CK2), an SA-induced phosphorylated p23 protein was identified that may act in a Heat Shock Protein (HSP) 90 complex . Clearly, molecular approaches using phospho-site mutants are generally applied to unravel functional relevance of the proteins under investigation.Arabidopsis S-phase Kinase Associated Protein 1 (SKP1)-like 5 (ASK5) kinase in linking adaptive regulation of the redox balance via control of the phosphorylation status of the pentose phosphate entry enzyme glucose 6-phosphate dehydrogenase (G6PD). To enlarge the scope of the downstream changes in phosphorylation patterns upon stress induction several talks  used ABA signaling as a starting point to describe genome-wide changes in the phosphoproteome. The challenges in these large-scale projects are obviously the reliability of the predicting software, the coverage obtained, and the required biological verification of the changes encountered. The last two talks in this session were given by Markus Teige (Vienna) and Thomas Gu\u00e9rinier (Orsay). Teige described an elegant approach to purify kinases that give specific changes to target transcription factors, in this case a member of the basic region Leucine Zipper (bZIP) family involved in metabolic reprogramming. This approach also highlighted the temporal and site specific dynamic changes in the phosphorylation pattern. A different set-up was used by Gu\u00e9rinier to identify peptide-based kinase assays to identify novel modulating kinase effectors such as nucleotides using Sucrose Non-fermenting 1 Related Protein Kinase 1 (SnRK1) as a model.The next session was devoted to abiotic signaling and started with Jay Thelen (Columbia) introducing a number of nice generally applicable tools to discover phosphorylation sites MUSite and Kinain vivo phosphoproteomics was used to identify direct targets of the CDPKs. How calcium is sensed intracellularly by Calcineurin B-like Proteins (CBLs) and associated CBL-Interacting Protein Kinases (CIPKs) was discussed by J\u00f6rg Kudla (M\u00fcnster) and showed a highly complex signaling network present at the PM and capable of decoding local changes in calcium and effecting directly sodium and potassium channels. From the same lab and in association with the group of Harter (T\u00fcbingen), Kenji Hashimoto presented results showing that the CBL1/CIPK1 pair acts as an important switch in translating light signaling into transcriptional changes. Then the MAPKs took center stage in talks by Souha Berriri (Evry) who used a gain-of-function screen for MAPKs first in yeast, as a tool to identify targets of the MAPK pathway. MAPK4 GOF mutants were then used to help delineate PTI and Effector-triggered Immunity (ETI) targets that run through the same MAPK cascade. The differences and similarities between human and plant innate immunity systems was discussed by Heribert Hirt (Evry) showing that Arabidopsis can be infected by Salmonella typhimurium, the major cause of food poisoning. Two kinases were identified that appear to act in a PTI pathway different from the MAPKs directly under control of PTI-related kinases. Genetic approaches were also employed by Roman Ulm (Geneva) having identified a phosphatase that mediates the UV-B stress response and by Marie Boudsocq (Harvard). In that work, CDPKs were identified that could mimick 22 amino acid flagellin fragment (FLG22) signaling and suggesting that alternative routes exist besides the classical MAPK pathway in PTI signaling. A constitutive CDPK under control of an inducible promoter was used to identify changes in the phosphoproteome .The following session dealt with a series of experimental systems used to gain more insight into the subcellular specificity in signaling systems. The calcium-dependent protein kinases (CDPKs) were presented by Tina Romeis (Berlin) as mediators and perhaps integrators of ABA and Pathogen Associated Molecular Pattern (PAMP) responses. Here The last sessions were devoted to technological advances in phosphoproteomics as being applied to a number of different systems. Themes that emerged were the necessity to use well-defined induction systems, the use of biological and technical replicates and the transient qualitative changes that could be captured.Arabidopsis that clearly showed the improvement of these methods coupled to improved search algorithms. In particular tyrosine phosphorylation appears to be as widespread in Arabidopsis as in our own cells! The effects on the phosphoproteome that can be distinguished after nutrient uptake can be separated into early and late events, involving both different proteins and different phospho-sites. The tools are available through improved web-based applications  were employed to provide reliable data. Further improvements in these procedures were presented by Wolfram Weckwerth (Vienna) using better software prediction coupled to metal oxide purifications and by Pururawa Mayank (Z\u00fcrich) using similar approaches but now to describe the pollen phosphoproteome. The last talk was given by Thomas Stratil (M\u00fcnich) returning to the exciting remorin proteins  of which one was also found to be important for Medicago root nodule development. It was directly associated with one of the symbiotic RLKs.Naoyuki Sugiyama (Tsuruoka) introduced Hydroxy Acid Modified Metal Oxide chromatography (HAMMOC) reported to increase the yield and specificity of phosphopeptides from complex digests. A number of examples were shown in both rice and Fifty-six posters of excellent quality were on display in front of the auditorium during the entire meeting and formed the central point of discussion during the coffee and tea breaks. In the short space allotted to this report it is unfortunately not possible to describe them all .in vivo determination of particular phospho-sites is feasible. An example of that can be found in a recent publication of the Jenny Russinova Lab  and better software have all resulted in a situation that Realization that most phosphorylation changes upon or during activation of a pathway are transient and also multiple will require time-lapse recording experiments at the second and minute time scale. So far this is only possible in single or few protein analyses; for an example of such an analysis using the Epidermal Growth Factor Receptor (EGFR; see Dengjel et al., Efforts to visualize first general and next specific phosphorylation events as is now relatively common in mammalian signaling systems (EGFR; Verveer et\u2009al.,"}
+{"text": "The development of novel methods to overcome the inevitable resistance that develops with common antibiotics is an important area of current research. Recent studies have shown that antimicrobial peptides (AMPs) have the potential to become excellent antibiotic compounds toward a broad-spectrum of Gram-positive and Gram-negative bacteria with less potential for bacterial resistance than conventional antibiotics Shai, . BecauseBacteria have difficulty in developing resistance to AMPs because the toxicity of AMP is mostly mediated by a non-specific process rather than by an interaction with a specific protein target. Most AMPs lyse bacteria by directly interacting with the lipid bilayer of the bacterial cell membrane and disrupting the lipid bilayer structure  liquid-disordered (ld) domain coexistences often referred to as \u201clipid rafts\u201d], two studies by the Almeida group demonstrated the permeabilizing activity of \u03b4-lysin in raft-like palmitoyl-2-oleoylphosphatidylcholine/cholesterol/sphingomyelin (POPC/Chol/SM) mixtures  encompassing several membrane disruptive mechanisms . These combined results indicate that the phase separation naturally occurring in eukaryotic membranes is likely to nullify the effect of cholesterol against membrane disruption by AMPs. This surprising result suggests either cholesterol is not as important in determining the selectivity of AMPs toward bacterial membranes as once supposed, or unknown additional factors mitigate this effect in eukaryotic cells.While biophysical studies have shown the ability of cholesterol to suppress the action of an AMP against a homogeneous lipid bilayer, recent studies have revealed that cholesterol does not have this same effect in heterogeneous lipid systems (Pokorny and Almeida, The mechanism of action of an AMP in a heterogeneous lipid system is depicted in Figure While the development of AMPs for antibiotic applications is highly important, it is essential to understand the origin of their bacterial selectivity. As mentioned above, recent studies have shown that AMPs easily disrupt the structure of heterogeneous lipid systems, and therefore cholesterol is unlikely to play a major role in reducing the toxicity or increasing the selectivity of AMPs. Since a natural eukaryotic cell membrane contains heterogeneous lipid systems and domains, cholesterol poor domains must be easily disruptable by an AMP. Further studies probing the role of cholesterol in different types of lipid bilayers with a variety of AMPs are essential to better understand the exact role of cholesterol on the toxicity and selectivity of AMPs. Such studies would aid in the design of more efficient AMPs."}
+{"text": "Large bowel seed bezoars are rare and are mostly due to seeds of sunflower, prickly pear cactus, sesame and cucumber. We present a rare case of sigmoid colon seed bezoar due to Box Myrtle seeds because of an underlying benign stricture. A bezoar is the result of the ingestion of indigestible or poorly digestible substances that accumulate in the gastrointestinal tract in the form of a mass. It can result from any substance that is capable of forming concretions within the gastrointestinal tract. The classification of a bezoar is according to the foreign material that constitutes its core and includes - trichobezoar (hair), phytobezoar (fruits or vegetable fibers), lactobezoar (milk curd), lithobezoar (rock-like substances) or combinations like trichophytobezoars.2 Cases o79A 35-year-old female patient presented in the surgery department with dull abdominal pain in the left paraumblical region. She gave a history of progressively worsening obstipation for the past 2 years for which she was using laxatives. No clinical features of obstruction were present. Her routine laboratory tests were normal, except for mild leukocytosis.\u201cKaiphal\u201d or Box Myrtle along with the seeds about 3 weeks ago. Based on the USG findings and history, a diagnosis of colonic seed bezoar was suggested. Contrast-enhanced CT scan of the abdomen revealed the presence of a mass-like lesion in the sigmoid colon involving an approximately 7-cm segment. It was composed of multiple tightly packed ovoid densities having a seed-like appearance, the size of individual seeds ranging from 4 to 8 mm. These showed a hyperdense periphery  with a relatively hypodense center  with air in the interstices, giving a mottled appearance. Mild associated inflammatory changes were present with circumferential mural thickening (3-4 mm) and stranding of the pericolonic fat [The abdominal radiograph showed localized mottled lucencies in the left lower abdomen. USG revealed mild wall thickening in the region of the sigmoid colon with the presence of an intraluminal, curvilinear, hyperechoic arc-like surface casting a prominent posterior acoustic shadow . Scanninonic fat . A tightThe patient was taken up for colonoscopy and the stricture was dilated. The seed bezoar was disimpacted and 300 g of largely undigested seeds were removed. Biopsy taken from the stricture revealed fibrosis, and no evidence of malignancy was detected.Seed bezoars occur after consuming large quantities of seeds either by eating the fruit together with the seeds or by eating the seeds themselves. In one retrospective study in Israel on fecal impaction by seed bezoars in the rectum in hospitalized patients, phytobezoars were found in 30 patients. The seed bezoars were composed of prickly pear seeds in 12 patients, watermelon seeds in 10 patients, sunflower seeds in 4 patients and popcorn kernel and pomegranate seeds in one patient each.[\u201cKaiphal,\u201d also known as Box Myrtle or Myrica esculenta, is a tree found abundantly in the Indian Himalayas. It bears small berry-like fruits that are usually consumed without seeds. Our patient had consumed large quantities of this fruit along with the seeds because of a lack of awareness. The seeds then became impacted in the sigmoid colon due to the presence of a benign short segment stricture. There is one case report of a patient who presented with large bowel obstruction, which was found to be due to a sesame seed bezoar in the sigmoid colon proximal to a benign postoperative anastomotic site stricture.[tricture.While plain radiographs of the abdomen may be useful in the evaluation of intestinal obstruction, bezoars themselves are only rarely identified. This is because the imaging feature of a bezoar is not characteristic, and can be mistaken for feces or abscess. USG may show the presence of an intraluminal mass with a hyperechoic arc-like surface showing marked acoustic shadowing and may CT scan is considered to be the imaging modality of choice for confirming gastrointestinal bezoars, and shows an intraluminal mass with air in the interstices or an inhomogeneous mass with a mottled gas appearance. CT scan also determines the point of obstruction; it can confirm that the bezoar is the underlying cause of obstruction and also helps detect the existence of additional bezoars. Our pati"}
+{"text": "M.avium and HIV drugs is unavoidable in HIV patients as for an improved life expectancy of HIV patients, additional medications have to be administered along with HIV drugs. The anti-M.avium drug rifabutin and protease inhibitor, ritonavir are associated with significant drug interactions involving the cytochrome P450 (CYP) enzyme system. Little information is available on the role of various drug delivery strategies in alleviations of interactions between anti-M.avium and anti-HIV drugs. The purpose of the present study was to evaluate effect of encapsulation of rifabutin and ritonavir in PLGA nanoparticles on the already known drug interaction exhibited by these drugs.Interaction between This study was designed including administration of rifabutin and ritonavir singly and in combination in free and nanoencapsulated form to swiss albino mice. Blood samples were taken following drug administration at various time intervals and pharmacokinetic parameters were assessed as: area under plasma drug concentration over time curve (AUC0-\u221e), mean residence time (MRT) and Cmax etc.Overall, nanoencapsulation was observed to avoid the known adverse drug interactions between RBT and RTV in the drug interaction study. .Our results clearly emphasize the potential of the PLGA nanoparticle formulation to minimize drug interactions as the encapsulated drugs did not result in any significant alteration in kinetic parameters upon co-administration. It can be reasonably stated that nano-encapsulation would not only permit intermittent dosing but also a more favorable pharmacokinetics which further can overcome the drug interactions."}
+{"text": "Subject blinding is critical to minimizing bias in randomized controlled trials (RCTs). Irritable Bowel Syndrome (IBS) is a complex and often chronic condition with physical and psychological components. For many patients, psychological issues such as anxiety and stress can exacerbate the existing condition. Given the mind-body relationship in this illness, we explored if an individual\u2019s belief in treatment and a belief in being randomized to an active treatment group could impact their self-reported health outcomes.In the parent study, data were gathered in a three-week randomized controlled trial (n=262) testing the therapeutic effect of an Augmented (supportive) patient-practitioner relationship versus a Limited patient-practitioner relationship versus wait list in reducing the symptoms of IBS. During the first three weeks of the trial, all treatments were given in the context of biweekly sham acupuncture treatments to allow the effects of patient-practitioner relationship to be isolated. The second three weeks of the trial began with a blind rerandomization of subjects in the two treatment arms to either continue sham acupuncture or begin real (insertive) acupuncture. Symptom data, expectations, and beliefs concerning blinding were collected at baseline, 3, and 6 weeks. Expectations of treatment group assignment (insertive or sham) and symptom improvement were collected after the first treatment and before weeks 3 and 6 data collection.For all six of our expectancy and belief variables, the Augmented and insertive treatment groups had more positive reports compared to the Limited and sham acupuncture group, respectively; this trend continued in reported symptom relief as well.The risk of subject unblinding may be related to qualities of the patient-practitioner relationship and treatment experience; a better understanding of blinding as a data safeguard is necessary."}
+{"text": "I read with great interest the recent manuscript by Siamak Rimaz on \u201c Effect of Gabapentin on Morphine Consumption and Pain after Surgical Debridement of Burn Wounds: A Double-Blind Randomized Clinical Trial Study\u201d published in Archives of Trauma Research . In thisThe family of opioid analgesics has been the backbone of analgesia in burn patients. However, it is well known that this group of drugs tend to have numerous side effects and recent data has implicated them as being capable of inducing pain N-methyl-D-aspartate (NMDA) receptor antagonists such as ketamine and gabapentin have recently became popular due to the marked opiate sparing effects. The effect of pain modulation on the descending pathways with the use of gabapentin has been shown in numerous studies , 3. Inde"}
+{"text": "To estimate the impact of the cold spell, excess mortality was calculated as the difference between observed and daily expected values. An overall 1578 (+25%) excess deaths among the 75+ age group was recorded in the 14 cities that registered a cold spell in February 2012. A statistically significant excess in mortality was observed in several cities ranging from +22% in Bologna to +58% in Torino. Cause-specific analysis conducted in Roma showed a statistically significant excess in mortality among the 75+ age group for respiratory disease (+64%), COPD (+57%), cardiovascular disease +20% ischemic heart disease (14%) and other heart disease (+33%). Similar results were observed for ER visits. Surveillance systems need to become are a key component of prevention plans as they can help improve public health response and are a valid data source to rapidly quantify the impact on health. Cold-related mortality is still an important issue and should not be underestimated by public health Authorities.In February 2012 Italy was hit by an exceptional cold spell with extremely low temperatures and heavy snowfall. The aim of this work is to estimate the impact of the cold spell on health in the Italian cities using data from the rapid surveillance systems. In Italy, a national mortality surveillance system has been operational since 2004 in 34 cities for the rapid monitoring of daily mortality. Data from this system were used to evaluate the impact of the February 2012 cold spell on mortality shortly after the occurrence of the event. Furthermore, a cause-specific analysis was conducted in Roma using the Regional Mortality Registry and the emergency visits (ER) surveillance system. Cold spell episodes were defined as days when mean temperatures were below the 10 Between January and February 2012 cold polar air from Siberia brought extremely low temperatures and heavy snowfall across most of Europe Near-real time surveillance systems are useful to monitor trends in health outcomes and detect anomalous peaks. Systems have been developed to monitor mortality Several studies have shown the effect of low temperatures and cold spells on health with peaks in both mortality, hospital admissions and ER visits The aim of this work was to provide a rapid estimate of the impact of the February 2012 cold spell on mortality in Italian cities using data from surveillance systems. For Rome only, mortality and ER visits by cause were analysed to better characterise the differential impact of cold on subjects with specific illnesses.th percentile of the February monthly distribution of a reference period (1995\u20132010).Meteorological data refer to the airport stations located closest to the city centre and were obtained from the Meteorological Service of the Italian Air Force. Mean temperature was considered as the exposure variable and cold spell episodes were defined as at least three consecutive days with mean temperatures below the 10The Italian mortality surveillance system was developed for the \u201cnear real-time\u201d monitoring of daily mortality in all cities with more than 200,000 inhabitants and to date includes 33 municipalities In order to investigate the potential biological mechanisms associated with the exposure to cold, cause-specific mortality data and ER visits, for Roma only were considered. Mortality data was retrieved from the Lazio Regional Mortality Registry, while ER visits were retrieved from the ER surveillance system. In 2012, a national ER surveillance system was set up to evaluate the potential impact of heat on non-fatal health outcomes during summer. ER visits by cause were examined for Roma only as this data was already available from the ER surveillance system during the February 2012 cold spell.Causes taken into account were: all natural causes (ICD-IX: 1-799), cardiovascular disease (ICD-IX: 390-459), ischemic heart disease (ICD-IX: 410-414), acute myocardial infarction (ICD-IX: 410-412), other heart disease (ICD-IX: 420-429), cardiac dysrhythmias (ICD-IX: 427), heart failure (ICD-IX: 428) respiratory disease (ICD-IX: 460-519), chronic obstructive pulmonary disease (ICD-IX: 490-496), acute respiratory infections (ICD-IX: 464-466 and 480-487) and injuries (ICD-IX: 800-959).As preliminary exploratory analysis, the mortality and ER visit trends were inspected to see whether the mortality during February 2012 was an exceptional event. A smoothing sine wave component was fitted to the dataset to account for seasonality trends in mortality, reducing noise associated with daily mortality variations in the data. For the identification of significant peaks in mortality, an upper limit was constructed using the Farrington method Secondly, to estimate the health impact of the cold spell on mortality, the excess was calculated as the difference between observed daily deaths and daily expected values from the beginning of the cold spell to the end of the month to account for a possible delay in the effect between exposure to cold and effect typically observed during winter. This approximates the lag period generally considered in time series studies of the effect of low temperatures on mortality For the cause-specific analysis conducted in Roma, excess mortality and excess ER visits were defined as the difference between observed and expected counts by cause for the month of February. As for mortality, the excess in ER visits was defined as difference between daily observed and expected values. The latter was constructed as mean value by calendar week and day of the week during the reference period of four previous winter seasons (2008\u20132011).When we consider mortality during the entire winter season (December\u2013March) an excess was observed in all cities that had an excess during the cold spell as well as several others . The excData from the Italian mortality surveillance system allowed us to rapidly evaluate the effect of the cold spell that occurred in February 2012 on mortality. A significant excess in mortality was observed in many Italian cities as a consequence of the cold spell and throughout the winter season of 2011\u20132012.Mortality trends typically show a peak during winter attributable to the seasonality of infectious disease, in particular influenza, as well as low temperatures and socio-economic factors A cause-specific analysis conducted only in Roma also suggests that most deaths were for respiratory and cardiovascular outcomes. Throughout the literature there are several explanations for this. In our study, respiratory deaths and ER visits registered the greatest proportion of the excess (+64% and +20% respectively) this could be partly due to the more rapid spreading of infections. Moreover, low temperatures may reduce natural response mechanisms of the upper respiratory tract and suppress immune responses to infections. Cold weather may also exacerbate chronic respiratory disease such as asthma and bronchitis Cold exposure may also trigger cardiac and cerebrovascular disease in susceptible individuals through inflammatory and coagulation responses th week of 2012 (30jan\u20135feb 2012) coinciding with the beginning of the cold spell episode A limit of the study is that the baseline was constructed only with 4 years of data, thus probably making it unstable, however we had no alternative as data availability was restricted to this period. On the other hand, total mortality excess estimates might be overestimated as we did not adjust for influenza epidemics. It has been suggested that seasonal trends and peaks in cardiac deaths are influenced by influenza epidemics Seasonal dynamics and patterns in mortality are to some extent dependent on previous season mortality trends The impact of the February 2012 cold spell on mortality in the Italian cities suggest that cold-related mortality is still a major problem and has several public health implications. In regions where extreme cold episodes are rare events and populations are unprepared to cope with these extreme conditions prevention plans should be implemented ensuring the collaboration and cohesive management between institutions and optimizing the often limited economic resources. Similarly to heat prevention programs, a cold prevention plan should comprise city-specific warning systems, near-real time surveillance systems and local prevention measures targeted to susceptible subgroups. It is clear that timeliness in terms of interventions and preparedness is crucial; especially for health services that have to be prepared to cope with an increase in the number of patients suffering from exposure to the cold, hypothermia and accidents, as well as respiratory infections and cardiovascular diseases. Information from surveillance systems, like those considered in our study for both mortality and ER visits, may be useful in public health decision-making, improving health service response and evaluating prevention measures. The identification of susceptible subgroups vulnerable to extreme cold is important in terms of public health planning and effective prevention Climate change scenarios predict a long-term trend of warming, as well as an increase in extreme events both in terms of temperatures and precipitation across Europe and in particular for the Mediterranean Basin"}
+{"text": "PIPA is designed to determine the feasibility of a prospective, multi-centre cohort study to assess the clinical and cost-effectiveness of cardiac magnetic resonance imaging (CMR) in patients who activate the primary percutaneous coronary intervention (PPCI) pathway. A key PIPA objective is to define a primary composite outcome that represents a clinically important change in management (proxy outcome for reduction in the future risk of a major adverse cardiovascular event (MACE)) as a result of an eligible patient having had CMR. A formal consensus method based on the modified nominal group technique is beingFormal consensus is being developed in three phases: (1) Systematic review to identify relevant literature; (2) Formulation of statements about how CMR changes patient management; (3) Consensus process, in which an interdisciplinary panel of stakeholders will complete an online survey , attend a face-to-face consensus meeting to discuss variation in anonymised survey responses, then re-rate the survey statements.Sixteen statements will be rated by twelve panellists . Final survey results will be presented as medians, interquartile ranges (IQR), counts and percentages. Statements with median scores of 7\u20139 and IQR of <3 will be considered to be in consensus and used to define the primary outcome.The primary composite outcome will be used to evaluate the effectiveness and cost-effectiveness of CMR to change clinical management in ways expected to prevent future MACE in this population."}
+{"text": "Biological systems fundamentally exist out of equilibrium in order to preserve organized structures and processes. Many changing cellular conditions can be represented as transitions between nonequilibrium steady states, and organisms have an interest in optimizing such transitions. Using the Hatano-Sasa Y-value, we extend a recently developed geometrical framework for determining optimal protocols so that it can be applied to systems driven from nonequilibrium steady states. We calculate and numerically verify optimal protocols for a colloidal particle dragged through solution by a translating optical trap with two controllable parameters. We offer experimental predictions, specifically that optimal protocols are significantly less costly than naive ones. Optimal protocols similar to these may ultimately point to design principles for biological energy transduction systems and guide the design of artificial molecular machines. Given the entropic driving force embodied in the second law of thermodynamics, creating and maintaining such organization requires staying far from equilibrium Much recent attention has focused on predicting optimal protocols to drive systems between equilibrium states with minimal expended work In this article, we take a first step towards this goal by optimizing the Hatano-Sasa Y-value, a quantity similar to dissipated work, for the paradigmatic model system tested in We consider a particle with spatial coordinate for Gaussian white noise As defined in arises in NESS transitions when the control parameters In some simple cases this corresponds to the system \u2018lagging\u2019 behind the changing control parameters. For transitions between equilibrium states this measure reduces to the standard dissipation governed by the Clausius inequality The ensemble average of the Y-value isDuring the driving process, the system's probability distribution over microstates fundamentally depends on the history of the control parameters Applying linear response theory in terms of the control parameter velocities The angle brackets In general, the detailed balance condition is violated in NESS and so the matrix The steady-state distribution is given by Though one can write down the geodesic equations for the metric [Eq. (6)] in the With the coordinate transformation In this coordinate system, geodesics are straight lines of constant speed. By the covariance of the geodesic equation, the optimal protocols are given byIn the absence of any particular information about the system's dynamical properties, a naive control strategy would change the control parameters at a constant rate, producing a straight line in control parameter space. The inverse diffusion tensor approximation [Eq. (4)] provides a recipe for choosing both a potentially nonlinear path through control parameter space, as well as a time-course along that path. The inverse diffusion tensor formalism can alternatively be used to optimize the time-course along a straight-line control parameter path. Such a protocol provides a benchmark against which an optimal protocol [Eq. (8)] can be compared. For the model considered here, we will find that an optimal straight-line protocol can be substantially better than the most naive (constant-speed) straight-line protocol. Furthermore, straight-line protocols are relatively straightforward to test experimentally.exactly optimal and agrees with the predictions of the linear response approximation [Eq. (4)]. In Ref. When As in the case of finding globally optimal protocols, the problem of finding optimal straight line protocols simplifies dramatically in forThe Euler-Lagrange equation implieswhich determines an implicit expression for The relation We validate the optimality of the geodesics [Eq. (8)] and compare with optimal straight-line protocols by calculating the average Y-value directly by integrating in time the Fokker-Planck equation describing the dynamical evolution of the particle probability distribution In full generality, the mean Y-value as a functional of the protocol Here angled brackets denote averages over the nonequilibrium probability density By integrating Eq. (13) against supplemented by initial conditionsNote that for a more complex system the first and second moments We solve these equations numerically and compare the performance of optimal straight lines against geodesics [Eq. (8)] and naive (constant-speed) straight-line protocols in If we neglect terms involving second- and higher-order temporal derivatives , we obtain an approximate solution to the Fokker-Planck system:Substituting this into the expression for the mean Y-value [Eq. (14)], we recover Eq. (28). The argument above suggests that the emergence of the inverse diffusion tensor from the Fokker-Planck equation may follow from a perturbation expansion in small parameters in vivo biological systems.We have taken the first step towards extending the geometric framework for calculating optimal protocols presented in Using a linear response approximation, we found the optimal mean Y-value for a model system of a colloidal particle  dragged through solution and subject to a time-dependent harmonic potential. We took as our control parameters the velocity and spring constant of the harmonic potential. As in Our predictions may be tested experimentally with existing hardware and methods. In Ref. Using the inverse diffusion tensor approximation in general allows us access to the full power of Riemannian geometry in calculating optimal protocols. However, such experimental tests can assess the range of validity of the approximation. Our alternate derivation of the inverse diffusion tensor via a \u201cderivative-truncation\u201d expansion et al. Moreover, we demonstrate that for simultaneous adjustment of In this paper we provide concrete theoretical predictions for experiments \u2013 specifically, we find that geodesics, optimal straight-lines, and naive straight-line protocols all are substantially more efficient than the protocols tested in Trepagnier, Given the greater generality embodied by the extension to NESS, and the accuracy of this approximation for a standard model system, optimal driving protocols derived in this framework promise greater applicability to models of biomolecular machines. Nevertheless, important hurdles remain: our model system experiences forces linear in position and has a steady-state distribution differing from the equilibrium one only in its average displacement. Molecular machines feature nonlinear force profiles, potentially nontrivial steady-state distributions, and often operate far from equilibrium. Thus our comparatively simple theoretical framework may need further elaboration to address the dynamics and efficiency of molecular machines with reasonable fidelity.Furthermore, the relatively simple model system we treat in this manuscript represents a new frontier for the analytical solution of optimal protocols under the inverse diffusion tensor approximation. For significantly more complicated models of greater biological interest, a simple general approach  would be a fully numerical method, involving the calculation of the inverse diffusion tensor at a grid of points in control parameter space, analogous to the approach in Finally, there remains the important open question of what quantity or quantities are to be optimized in faithful models of biological processes. In this paper, we made the choice of optimizing the Y-value which has been experimentally studied in this particular model system However, it is possible and perhaps likely that a properly defined average dissipated heat will be the biologically relevant quantity to optimize rather than the Y-value. We anticipate that a geometric approach to optimization will be applicable to these more general systems and notions of heat production in a relevant regime of parameter values and protocol durations. However, a more general construction will have to take into account the so-called housekeeping heat Our model consists of a particle with spatial coordinate for Gaussian white noise As defined in The ensemble average of the Y-value isApplying linear response theory in terms of the control parameter velocities The angle brackets The steady-state distribution is given by In order to calculate the time correlation functions in Eq. (23), we solve Eq. (18) for constant Recalling that Integrating over time yields the inverse diffusion tensor:The line element corresponding to the metric in Eq. (27) isTo find the explicit coordinate transformation making the Euclidean geometry manifest, we write the line element asThis suggests the coordinate transformation In this coordinate system, geodesics are straight lines of constant speed. To find optimal protocols in We validate the optimality of the geodesics [Eq. (31)] numerically via the Fokker-Planck equation In full generality, the mean Y-value as a functional of the protocol By integrating Eq. (32) against supplemented by initial conditions"}
+{"text": "Ion transport and epithelial barrier function were monitored by measuring short-circuit current (Isc) and trans-epithelial electrical resistance (TEER). Stimulation with linaclotide (1 \u00b5M) elicited a robust short-circuit current across mouse colonic epithelium. Isc reached a maximum within ten minutes following stimulation with linaclotide and remained steady during the duration of the study (60 min). Treatment of colonic mucosa with linaclotide induced release of cGMP from the apical, as well as, the basolateral side of the epithelium. The time course of cGMP accumulation in the basolateral bath of the Ussing chamber was linear with an estimated cGMP secretion rate equal to 23 fmol/min\u00d7cm2. The trans-epithelial electrical resistance of the colonic mucosa remained high over the course of the study indicating that the barrier to diffusion of cGMP between apical and basolateral sides remained intact throughout the study.. In summary, these data demonstrate that linaclotide-stimulated mouse colonic epithelium secretes cGMP from both the apical and basolateral sides and that cGMP is available in the submucosal interstitial space to inhibit colonic nociceptors.Linaclotide is a novel receptor guanylyl cyclase C (GC-C) agonist approved for treatment of abdominal pain and constipation in patients with irritable bowel syndrome with constipation (IBS-C). Linaclotide effects on bowel movements are mediated by the intracellular cGMP that is produced upon activation of GC-C. It is hypothesized that the effects of linaclotide on abdominal pain are mediated by extracellular cGMP, which was shown to decrease the activity of pain-sensing nerves . Here we"}
+{"text": "We also investigated the effects of various missense mutations in presenilin-1 associated with either FAD or frontotemporal dementia using both culture systems and knockin mice, and discovered their distinct molecular mechanisms. While FAD mutations cause partial to complete loss of \u03b3-secretase activity in cis, mutant proteins further interfere the function of wild-type proteins in trans. The implications of our in vivo studies to disease mechanisms will be discussed.Presenilins are the major genes responsible for familial Alzheimer\u2019s disease (FAD). To elucidate the pathogenic mechanisms underlying FAD mutations, we employ advanced genetic approaches to investigate the normal function of presenilin in the brain and the dysfunction caused by disease causing mutations. Through development and multidisciplinary analysis of a number of cell type specific conditional mutant mice, we defined essential roles of presenilins in processes that are highly relevant to AD pathogenesis, such as memory, synaptic function and age-related neuronal survival. Our detailed analysis further elucidated the mechanisms by which presenilins regulate these processes, and whether presenilins regulate these processes"}
+{"text": "One oFor neuraminidase and cyclin-dependent kinase II (CDK2), snapshots of MD simulation trajectories have been clustered based on different structural properties using a variety of clustering methods. To establish a possible correlation between docking performance and target conformational attributes the clustered snapshots have been subjected to extensive self- and cross-docking experiments as well as virtual screening using the GOLD docking programme. It is shown that conformationally similar snapshots do not necessarily result in a similar docking or virtual screening performance. The selection of the particular structural property on which to base the clustering appears to be the essential problem."}
+{"text": "Manihot esculenta) and neurolathyrism  are two distinct non-infectious upper motor neurone diseases with identical clinical symptoms of spastic paraparesis of the legs. They affect many thousands of people among the poor in the remote rural areas in the central and southern parts of Africa afflicting them with konzo in Ethiopia and in the Indian sub-continent with neurolathyrism. Both diseases are toxico-nutritional problems due to monotonous consumption of starchy cassava roots or protein-rich grass pea seeds as a staple, especially during drought and famine periods. Both foods contain toxic metabolites (cyanogenic glycosides in cassava and the neuro-excitatory amino acid \u03b2-ODAP in grass pea) that are blamed for theses diseases. The etiology is also linked to the deficiency in the essential sulfur amino acids that protect against oxidative stress. The two diseases are not considered reportable by the World Health Organization (WHO) and only estimated numbers can be found. This paper analyzes research performance and determines scientific interest in konzo and neurolathyrism. A literature search of over 21 years (from 1990 to 2010) shows that in terms of scientific publications there is little interest in these neglected motorneurone diseases konzo and neurolathyrism that paralyze the legs. Comparison is made with HTLV-1/TSP, an infectious disease occurring mainly in Latin America of which the clinical manifestation is similar to konzo and neurolathyrism and requires a differential diagnosis. Our findings emphasize the multidisciplinary nature of studies on these neglected diseases, which however have not really captured the attention of decision makers and project planners, especially when compared with the infectious HTLV-1/TSP. Konzo and neurolathyrism can be prevented by a balanced diet.Konzo  in the case of konzo, or the seeds of grass pea (Lathyrus sativus) in the case of neurolathyrism. These neurodegenerations are blamed on the presence of cyanogenic glycosides in cassava and a neuro-excitatory amino acid in grass pea. Both are linked to the deficiency of methionine and cysteine in the diet. These amino acids are needed for the protection of motor neurons against oxidative stress. Both cassava and grass pea are tolerant to adverse environments and become survival foods for the poor during drought-triggered famines and during wartime. The dependency on these crops may increase with global warming. The scientific interest in these neglected diseases is low and little change has been noted over the last two decades. This is especially obvious when compared with the scientific interest in HTLV-1/TSP, a viral disease with similar clinical symptoms which occurs mainly among poor people in Latin America in similar socio-economic settings.The irreversible crippling diseases konzo and neurolathyrism with identical clinical symptoms occur among poor subsistence farmers in Africa and Asia. The victims are mostly illiterate and among the poorest section of the population who can only afford the cheapest food in a monotonous diet: bitter cassava roots ( Manihot esculenta) and grass pea (Lathyrus sativus) are drought tolerant crops that can be survival food after a drought (the underground cassava-roots can even survive fire) Konzo and neurolathyrism are toxico-nutritional neurodegenerations that afflict many thousands of people among poor populations in low income countries, especially in Sub Saharan Africa and in the Indian Sub-continent, respectively. In both cases, the victims are mainly illiterate subsistence farmers living in remote rural areas. Those diseases are associated with high dietary exposure from improperly processed cassava roots in the case of konzo or grass pea seeds in the case of neurolathyrism. Both cassava  for all articles with the following key words: konzo, neurolathyrism, HTLV-1 associated myelopathy/Tropical spastic paraparesis in topic and in title with the current limits on timespan (from 1990 to 2010). The term \u2018lathyrism\u2019 covers both neurolathyrism and osteolathyrism. Osteolathyrism or experimental lathyrism is caused by the bone-deforming \u03b2-aminopropionitrile (BAPN) present in Lathyrus odoratushttp://www.ncbi.nlm.nih.gov/sites/entrez?otool=ibeuglib) but some overlap was noted on the categorization of the document types and the database has a medical orientation rather than multidisciplinary as in the Web of Science. The website http://Scholar.Google.com was not included because of a great number of subjects which comprise even unpublished or non-quoted publications. Articles listed in Web of Science are classified as A1 papers and used for evaluation purposes in many scientific institutes and universities.We searched the Web of Science database  and neurolathyrism  while publications on HTLV-1/TSP increased significantly . A significant increase (P<0.05) was observed in the citations of publications on the three diseases  were categorized as articles, about 6% for konzo and neurolathyrism and 8% for HTLV-1/TSP as reviews, 4.8% for konzo and HTLV-1/TSP and 9.1% for neurolathyrism as proceedings paper, 1.2% for konzo, 6.1% for neurolathyrism and 4.2% for HTLV-1/TSP as meeting abstract and 2% or less as letter or as note or as editorial material .Lathyrus sativus and \u03b2-ODAP for neurolathyrism publications. Motor neurone disease is the only term used for these two clinically similar diseases among the top ten keywords  often considered to be due to witchcraft. They are neglected and tend even to be ignored by the authorities in these countries, perhaps because they are somehow considered as damaging the reputation of the country in which they occur. HTLV-1/TSP is intrinsically more interesting to medical researchers because it is an infectious disease that has the risk of spreading, whereas neurolathyrism and konzo are non-infectious diseases that are confined to poor and mostly illiterate subsistence farmers and hence not appealing to work on. HTLV-1 TSP has a higher percentage of reviews and notes than konzo and neurolmathyrism as shown in This also reflects the low level of interest by political authorities as well as by institutes sponsoring research in these neglected diseases konzo and neurolathyrism which are known to be non-infectious diseases affecting only poor populations in remote rural areas. These diseases do not really capture the attention of decision makers and project planners to make efforts to control these diseases while there is a growing interest and concern in the infectious HTLV-1/TSP.During the same period there is an increase of the number of citations to published items on the three diseases, potentially indicating that those diseases are becoming important in terms of comparison with neurodegenerative diseases affecting more affluent populations. It may be interesting to note that, not unlike the popular media, the dramatic reports get more attention: the report on a new epidemic in Ethiopia, affecting 2000 patients There are fewer meetings at international level on those three diseases, which may explain why there is less than 10% of meeting abstracts or proceedings papers. Sponsors may not be well informed or do not see the opportunities to finance projects on konzo and neurolathyrism although our findings emphasize the multidisciplinary nature of studies on these diseases.Manihot esculenta during the same period (5035) is almost 6 times greater than those dealing with grass pea or Lathyrus sativus (859)  . This raThe root of bitter cassava is the staple food in konzo-affected areas and is one of the highest yielding starch crops in tropical regions and increasingly becoming an industrial product. For human consumption, a lengthy post harvest processing is necessary to remove the toxic cyanogenic metabolites. For this a stable peaceful environment is required. This processing however does not change the deficiency of the sulfur amino acids methionine and cysteine in the cassava roots. While one meal of unprocessed bitter cassava roots can be lethal and indeed sometimes suicidal, prolonged consumption of insufficiently processed roots as a staple food without variation can give rise to konzo. Konzo can be prevented by better processing of bitter cassava roots and by balancing the diet with cereals and other foodstuffs rich in sulfur amino acids such as fish that is out of reach of the very poor and during social instability. For poor subsistence farmers, cassava can be a survival food during drought and also during military conflicts. Banea et al Panax ginseng) Lathyrus sativus, that during the era of the Egyptian pharaoh's was a royal funeral offering. Konzo and neurolathyrism are neglected diseases that occur among poor, often illiterate subsistence farmers. Such socio-economic groups are often neglected by the authorities and these medical problems ignored. Konzo and neurolathyrism can be considered the emanation of an unjust and egoistic world.Grass pea is the most drought tolerant legume producing the cheapest protein, but containing a neuro-excitatory amino acid \u03b2-ODAP and can give rise to excito-toxicity under certain conditions of prolonged overconsumption, malnutrition and oxidative stress. This same neuro-excitatory amino acid \u03b2-ODAP is also identified in seeds and roots of Ginseng (One of the risk factors in the epidemiology of konzo and neurolathyrism is the availability of cassava roots or grass pea as the cheapest food and its use as staple in the diet with little or no additional nutrients. Both crops are tolerant to adverse environment and serve as survival foods during droughts and famine and this dependency may increase with further global warming"}
+{"text": "A 34-year-old healthy man presents requesting abdominal liposuction for excess abdominal fat. The patient had a strong preference for minimally invasive techniques. Therefore, High-intensity focused ultrasound (HIFU) therapy was performed.What is HIFU and how does it work?What is HIFU currently used for?What are some of the recognized shortcomings and complications of HIFU?What is the future of HIFU?High-intensity focused ultrasound is the result of the evolution of ultrasound from a simple diagnostic procedure to a therapeutic modality with broader potential. Ultrasound has long been an intriguing medical modality because of its noninvasive nature, low cost, and relatively low rate of complications.2 and have at least 1 cm of adipose tissue beyond the treatment area.7,8,11High-intensity focused ultrasound is most widely recognized in the treatment of benign and malignant solid tumors.,12Traditional shortcomings of HIFU include those of diagnostic ultrasound, most importantly that sound waves cannot pass through solid structures  and are impeded by air, limiting its use in hollow organs such as the lungs.6High-intensity focused ultrasound has only recently made its debut in the plastic surgery community, with preliminary studies being promising and exciting. It has been shown to be safe at much higher doses and duration than are typically necessary in the outpatient setting"}
+{"text": "Vascuologenesis is the de novo establishment of blood vessels and vascular networks from mesoderm-derived endothelial cell precursors (angioblasts). Recently a novel mechanism, by which some genetically deregulated and aggressive tumour cells generate \"micro-vascular\" channels without the participation of endothelial cells and independent of angiogenesis, has been proposed. This has been termed \"vasculogenic mimicry\" and has implications beyond angiogenesis and adds another layer of complexity to the current concept for the generation of tumour micro-circulation. We suggest this is common phenomenon in head and neck squamous cell carcinoma (HNSCC) cell lines and other aggressive tumour cell lines. We present experimental evidence of vasculogenic mimicry in HNSCC cell lines and compare them with other tumours and a positive control vascular cell line.The cell lines used were HUVEC, HN 2a, 2b (primary and metastatic tongue base squamous carcinoma cell line), HCT116 (colonic carcinoma cell line) and DU145 (prostate carcinoma cell line).Pilot experiments were undertaken to assess growth of a bank of tumour cell lines on (growth factor reduced) matrigel (Sigma) with standard media .A functional growth assay was performed by preparing the appropriate cell suspension in serum free medium plated onto either bare plastic or a well pre-coated with growth factor reduced type 4 collagen analogues.Phase contrast photomicrographs were taken at 4 hours and 24 hours. Image analysis was performed; particular features of interest were two dimensional area (surrogate of growth and migration), branch points and end point measurements (surrogate of intercellular complexity).There were observable differences in growth of the cells on laboratory plastic and collagen matrix. Tumour cells formed capillary like networks similar to HUVEC cells. Metastatic HNSCC cells lines were found to have vasculogenic properties similar to HUVEC cell lines when compared to cell lines from their corresponding primary tumour. The endothelial growth factor antibodies used did not inhibit or stimulate cell growth when compared to control but did discourage vascular mimicry. Other tumour cell lines also displayed this property.Tumour \"vasculogenic mimicry\" must still be regarded as a controversial issue whose existence is not proven. The clinical importance of this phenomenon however, is that it does explain the lack of complete efficacy of current anti-angiogenic treatments due to the added layer of complexity. It provides a feasible mechanism of early tumour vascular supply which can co-exist and incorporate with later angiogenic mechanisms. We suggest that \"vasculogenic mimicry\" maybe a common neoplastic phenomena which appears to also be dictated by the cells micro-environment. Its existence also suggests a further process that of the development of tumour mosaic vessels as the neo-vasculature integrates with the existing endothelial lined systems. Much attention has been focussed on the role of angiogenesis, i.e. the recruitment or co-option of new vessels into a tumour from pre-existing vessels such as capillaries and post-capillary venules. Currently, angiogensis is widely accepted as the mechanism by which tumours metastasize, however angiogenesis may not be the only mechanism by which tumours acquire a microcirculation. Maniotis et al. reported a novel mechanism by which some aggressive tumours acquire a blood supply and demonstrated the generation of micro-vascular channels by genetically deregulated and aggressive tumour cells without the participation of endothelial cells and independent of angiogenesis. This has been termed \"vasculogenic mimicry\" and has implications beyond angiogenesis and adds another layer of complexity to the current theoretical framework for the generation of tumour micro-circulation  at a seeding density of 2*10There were observable differences in growth of the cells on laboratory plastic and collagen matrix (P < 0.001), Figure . Tumour Metastatic cell lines (HN2B) were found to have vasculogenic properties similar to HUVEC cell lines when compared to cell lines from their corresponding primary tumour (HN2A). The clinical impact of this phenomenon will also be a function of tumour cell size enabling optimal stromal interaction as evinced by the growth of other tumour cell lines.The anti-endothelial antibody was not cytotoxic to any of the cell lines investigated. The antibody, however, did discourage vascular mimicry significantly P < 0.001). It may be hypothesized that the visible networks may not be tubes and not represent vascular channels but electron microscopy work suggests that they do [. It may Tumour \"vasculogenic mimicry\" Figure  must stiThe process of angiogenesis consists of multiple, sequential and independent steps with a vista of positive and negative regulators of angiogenesis being involved . HoweverThere is a consensus that the microcirculation of aggressive tumours is complex, and depending on the time of observation, could consist of mosaic vessels , co-opted vessels and/or angiogenic vessels. There is also strong evidence for the existence of an intratumoral, tumour-cell-lined, ECM-rich, patterned network that can provide an extravascular fluid pathway, now known as the fluid-conducting meshwork. The entire microcirculation in aggressive tumours is suggested to be made up of a combination of these elements, and it is the result of destructive tumour growth and remodelling. Alternatively, the PAS- and laminin-rich, fluid-conducting meshwork could be an early survival mechanism for nutrient exchange and the release of fluid pressure. This meshwork could eventually be replaced by endothelial cells from nearby angiogenic vessels or from the bone marrow. The fluid-conducting meshwork might provide a site for nutritional exchange for aggressive tumours, and might therefore prevent necrosis of the tumour. Alternatively, it might be analogous to an oedematous inflammatory response, in which increased blood pressure leads to the escape of fluid along connective tissue pathways in intra-tissue spaces. The complex geometry of the laminin-containing ECM covering that encases the spheroidal clusters of tumour cells could also form a suppressive shield against immune surveillance.Endothelial cells can generate tractional forces, appropriate matrices, cord-like tessellated structures because of a limited degree of cell-ECM attachment and a high degree of cell-cell attachment . The invEndothelial cell shape requirements in the context of growth and limited cell detachment typical of endothelial cell differentiation may be mediated by the mechanical properties of a continuous cytomatix, between the endothelial cell adhesion receptors and its nucleus and could determine the response of the cell to its changing architectural environment via a hard wired signalling mechanism. The extended ECM/cyto-matrix/nuclear matrix as a unit of structure/function is evidenced by comparable tubular structures formed in culture by highly invasive, interconnected primary and metastatic melanoma. These have similarities to cords or tessellations generated by a variety of other cell types including mammary epithelial cells on the appropriate substrate. It is assumed that more invasive cells generate cords similar to endothelium within the first few hours of culturing; patterned tubes completely acellular resemble the dimensions and patterning of networks in tumours ,8. HenceThe patterns of microcirculatory vessels have been shown to have a prognostic significance in melanomas with those with the presence of loops and networks doing worse ,9,10. HoIn criticism of our current study, the networks formed by the cultured cells do resemble microvascular channels but, fall short of being the compelling evidence of vascular mimicry published by Maniotis et al.  in theirclinical implications are, however, that there is still too little knowledge of how the many events are coordinated and integrated by the cancer cell, with conspiratorial help by the stromal component of the host. Before drug development can proceed with a legitimate chance of success, significant gaps in basic knowledge need to be filled. A tumour circulation not lined by endothelial cells would play an important physiological role in the maintenance and growth of aggressive tumours. This is observed in breast epithelial tumour cells which form disorganised masses which undergo phenotypic reversion to form acini resembling normal tissue. This reversion occurs simply by manipulating their surface receptors in a 3D assay. This continuous tumour extracellular matrix interaction and traction could contribute to tumour remodelling, its metastatic potential and vasculo-genetically patterned tumour derived abnormal vessels. The tubular structures formed in culture by highly invasive, interconnected primary and metastatic melanoma has similarities to cords or tessellation generated by a variety of other tumour cells on the appropriate substrate. Such vasculogenic triggers and their receptors could be the next target for refined pharmacological interventions in the treatment of metastasis, as important if not more than the recently trialled anti-angiogenic drugs. The important difference may be that they could be more specific and avoid the bystander cross receptor cardiac problems attendant with anti-angiogenic therapy.The The authors declare that they have no competing interests.All authors have contributed intellectually and to the writing of this manuscript. All authors read and approved the final manuscript."}
+{"text": "Lorenz von Seidlein discusses the study by Katherine Halliday and colleagues and explores the reasons why a school-based screening and treatment strategy for malaria might have failed.Please see later in the article for the Editors' Summary PLOS Medicine:This Perspective discusses the following new study published in doi:10.1371/journal.pmed.1001594Halliday KE, Okello G, Turner EL, Njagi K, Mcharo C, et al. (2014) Impact of Intermittent Screening and Treatment for Malaria among School Children in Kenya: A Cluster Randomised Trial. PLoS Med 11(1): e1001594. Katherine Halliday and colleagues conducted a cluster randomized controlled trial in Kenyan school children in an area of low to moderate malaria transmission to investigate the effect of intermittent screening and treatment of malaria on health and education.Falciparum malaria incidence is declining in many countries including in the formerly hyperendemic regions of sub-Saharan Africa PLOS Medicine, Halliday and colleagues describe a trial to evaluate intermittent screening and treatment in schools In this issue of The results cannot be attributed to methodological uncertainty, a frequent cause of negative study outcomes, since the trial was conducted in a large sample of schools according to the highest procedural standards. There was excellent follow-up of and adherence by study participants. Most likely, children found to be parasitaemic did benefit from early treatment but this outcome was not measured, as the investigators were interested in school-based rather than individual-based effects. Why did these individual effects not translate to school-wide outcomes? First investigators didn't treat all infections, rather only those of a sufficiently high density detectable by RDTs. Any child with a parasitaemia with a density below the RDT's detection threshold on that day remained untreated. The dimensions of this reservoir of infections with densities below the RDT's detection threshold are incompletely understood and are currently under investigation using new molecular tools. RDTs may require a parasite density of 100,000 parasites/ml Would the strategy have worked had the investigator screened and treated whole villages instead of school classes? Investigators in Burkina Faso have recently addressed precisely this question in a cluster randomised trial The evaluation of malaria elimination strategies requires considerable resources. Trials evaluating interventions to interrupt malaria transmission require populations living in a discrete geographic entity such as a village as unit of inference. To randomise villages in a statistically meaningful fashion involves tens of thousands of participants. Considering the time and resources required for such large undertakings, researchers use mathematical modelling to predict the outcome of interventions. Such models have been refined for more than a century and their popularity keeps growing despite the inherent complexity of vector borne diseases Plasmodium falciparum strains resistant to artemisinins are spreading through Southeast Asia It is easy to criticise retrospectively the failure of well-intended interventions and infinitely harder to predict success. But some of the more successful interventions could guide investigators and policymakers towards more promising strategies especially during an emergency. Increasing the coverage of populations at risk with effective interventions  should lead to the elimination and ultimately the eradication of falciparum malaria in the decades to come. That is if the pathogens and the vectors weren't constantly evolving. Mosquitoes resistant to the available insecticides are spreading through sub-Saharan Africa and Asia"}
+{"text": "The structural and functional integrity of the retinal pigment epithelium (RPE) is fundamental for maintaining the function of the neuroretina. These specialized cells form a polarized monolayer that acts as the retinal\u2013blood barrier, separating two distinct environments with highly specialized functions: photoreceptors of the neuroretina at the apical side and Bruch's membrane/highly vascularized choriocapillaris at the basal side. The polarized nature of the RPE is essential for the health of these two regions, not only in nutrient and waste transport but also in the synthesis and directional secretion of proteins required in maintaining retinal homoeostasis and function. Although multiple malfunctions within the RPE cells have been associated with development of age-related macular degeneration (AMD), the leading cause of legal blindness, clear causative processes have not yet been conclusively characterized at the molecular and cellular level. This article focuses on the involvement of directionally secreted RPE proteins in normal functioning of the retina and on the potential association of incorrect RPE protein secretion with development of AMD. Understanding the importance of RPE polarity and the correct secretion of essential structural and regulatory components emerge as critical factors for the development of novel therapeutic strategies targeting AMD. IntroductionRPE polarityApical secretion from the RPE\u2013 Matrix Metalloproteinase 2 (MMP-2) and Tissue Inhibitor of Matrix Metalloproteinase 1 (TIMP-1)\u2013 Hyaluronan\u2013 \u03b1B Crystallin\u2013 Pigment Epithelium-Derived Factor (PEDF)Basolateral secretion from the RPE\u2013 Fibroblast Growth Factor 5 (FGF-5)\u2013 Endothelin I\u2013 Vascular Endothelial Growth Factor (VEGF)\u2013 Cystatin CMechanisms of protein secretion/polarized secretion\u2013 Basolateral sorting signals\u2013 Apical sorting signals\u2013 Consequences of impaired RPE protein secretionConcluding remarksThe RPE consists of a monolayer of cells that form the retinal\u2013blood barrier (RBB). On either side of this cellular monolayer lie two contrasting environments that are critical for the correct functioning of the neuroretina. Immediately on the apical side of the RPE is a thin matrix known as the interphotoreceptor matrix (IPM) One of the main functions of the RPE is in the delivery of nutrients from the choroid to the photoreceptor cells, whilst transporting metabolic end products, ions and excess water in the opposite direction via protein secretion is the focus of this article, with specific emphasis on the importance of directional, targeted secretion of trophic/growth factors and structural/structure-related proteins.Maintenance of the structure and function of the microenvironments on either side of the RPE The RPE displays many similarities to other epithelial layers, including a hexagonal \u2018cobblestone\u2019 appearance, organization as a single monolayer, tight junctions between cells and a highly polarized nature. Morphologically, RPE cells display polarity with apical microvilli, pigment granules and well-developed tight junctions located on the apical side of the cell, as well as basally located nuclei and membrane infolding Proteins expressed by RPE cells can also be localized to either apical or basal plasma membrane (PM) , such asin vitro increases the overall levels of growth factor secretion The polarized organization of the RPE is crucial for its interaction with both its apical and basal side, as well as in the directionality of its protein secretion. It has been demonstrated that attainment of polarity Retinal pigment epithelium cells secrete a host of growth factors and structural/structure-related proteins Some examples of directional protein secretion from the RPE are discussed below. The function/dysfunction of the majority of proteins presented herein have direct links to AMD pathogenesis. For those that have not, to date, been directly linked with AMD, we hypothesize how their incorrect localization/function may lead to retinal degeneration based on their involvement in fundamental biological processes and on similarities of their mechanism of action with that of known molecular determinants of the disease.Matrix metalloproteinase and TIMPs are apically secreted by the RPE Matrix metalloproteinase and TIMPs (including MMP-2 and TIMP-1) are also present basally to the RPE, in the Bruch's membrane Hyaluronan is a widely distributed glycosaminoglycan, and is a major component of the ECM. It is secreted from the apical side of the RPE \u03b1B crystallin is a molecular chaperone induced by stress stimuli. By suppressing protein aggregation and inhibiting the proteolytic activity of caspase 3, it is able to play a role in cytoprotection The PEDF is highly expressed in the retina, where it serves as a neurotrophic factor Fibroblast growth factor 5 is known to play a role in a range of processes including angiogenesis via effects on proliferation and cell migration Endothelin I is a protein expressed in the retina and choroid Vascular endothelial growth factor is a pro-angiogenic growth factor that is secreted preferentially from the basal surface of the RPE Cystatin C is a reversible inhibitor of cysteine proteinases including papain and cathepsins B, H, L and S via the relatively well-characterized \u2018classical\u2019 secretion pathway. These proteins contain N-terminally located signal peptides, directing them co-translationally to the translocation apparatus of the ER via other, \u2018non-classical\u2019 mechanisms. These proteins typically lack a signal peptide, and are excluded from organelles that are essential during \u2018classical\u2019 secretion, such as the ER and Golgi. These mechanisms of secretion are reviewed in detail elsewhere via exosomes.A large number of soluble proteins are secreted from the PM via similar mechanisms. Thus, the basolateral versus apical sorting mechanisms in the secretory pathway is believed to rely on complex membrane trafficking pathways which also underpin the distinct specialization of the apical and basolateral PM domains. Targeting of proteins to a particular cell surface takes place at the level of the trans-Golgi network (TGN), following incorporation of apical and basolateral proteins into distinct vesicles In polarized cells, secretion requires an extra level of complexity and control to ensure certain proteins are targeted to, and released from the appropriate cell surface. Mechanisms required for such control have been studied extensively within the \u2018classical\u2019 secretion pathway, and have been reviewed in detail elsewhere via such endosomal pathways has been highlighted Basolateral sorting signals typically consist of tyrosine-based  or di-leucine-based peptide sequences, found in the disposed, cytoplasmic portion of transmembrane proteins Transforming growth factor-\u03b1 (TGF\u03b1) provides one of the relatively few examples of a typical basolateral signal in a secreted protein. Its precursor form (pro-TGF\u03b1) contains a dominant basolateral sorting signal within the cytoplasmic region that is subsequently cleaved to produce the soluble, mature form Apical sorting signals are much more diverse than basolateral signals and consist of post-translational modifications, rather than distinct peptide sequences. Perhaps the most extensively studied of these are N- and O-linked glycans, which are present on particular proteins. Two models have been proposed to explain how these glycans are involved in apical sorting via distinct subsets of endosomal compartments before reaching their final destination via transcytosis The route that apical proteins take to the PM seems as equally diverse as the signals that direct them. Many transmembrane proteins destined for the apical PM are transported from the TGN in different vesicles, and are then processed via a GPI anchor in its transmembrane domain. Subsequent cleavage then results in secretion of the soluble form Mechanisms for targeting secreted proteins for apical PM release are similar to those for transmembrane proteins. Glycans can promote such targeting, as is the case during apical sorting of rat growth hormone It is becoming increasingly apparent that directional protein secretion is a highly regulated and complex process, and that malfunctions occurring at any step in these pathways could lead either to increased/decreased levels of essential growth factors and structural proteins in the extracellular space or to their incorrect intracellular/extracellular localization. It is therefore possible that such malfunctions could serve as relatively overlooked mechanisms in the pathophysiology of the highly secretory RPE, with specific consequences for the development of retinal disorders such as AMD.Indeed, such alterations in protein secretion have been implicated in the development of other diseases. Such an example is the increase in growth factor secretion from cancer cells, leading to autocrine growth stimulation and metastasis Extracellular mislocalization of secreted proteins can occur as a result of changed cell polarity and alterations in directional secretion. Such alterations can also have implications in disease development. The presence of the Alzheimer's-linked, \u2018Swedish\u2019 double mutation in the amyloid precursor protein results in a proportion being mis-secreted from the apical, rather than basolateral PM via its proteolytic and ECM remodelling properties Some of the RPE-secreted proteins highlighted above have been shown to have altered secretion patterns during AMD development. MMP-2 is secreted at levels threefold higher in AMD RPE cells compared with healthy RPE One of the most abundantly expressed and secreted proteins of the RPE is the cysteine proteinase inhibitor cystatin C The tissues on either side of the RPE present two different microenvironments, each placing varying demands on the RPE in terms of protein requirements. High levels of particular growth factors and structural proteins that can be beneficial in one compartment can be detrimental in the other. Maintaining the correct concentrations of particular factors, in the correct location, at the correct time is therefore of critical importance for retinal health.This article highlights several examples of directional protein secretion by the RPE, all of which could play important roles in maintaining its surrounding extracellular environments. Malfunctions in trafficking/secretory pathways can lead to mis-localization of these proteins, which can ultimately manifest as a number of AMD symptoms.Therapies such as RPE transplants and gene therapy could offer improved treatments for AMD in the future. The importance of polarity and directional protein secretion in maintaining RPE/retinal functioning will be key considerations in the further development of such therapies."}
+{"text": "Cilia are small, hair-like structures occurring on the apical surface of most of vertebrate cells. Defects in cilia cause a range of developmental phenotypes grouped into conditions called ciliopathies. Our aim is to dissect the structure and function of cilia and signalling pathways mediated by this organelle. To evaluate this, we are performing a high-throughput siRNA screen using siRNA pools (from the Dharmacon mouse genome siRNA library) targeting over 19,000 separate transcripts and immunofluorescence staining of ciliated mIMCD3 (transformed mouse inner medullary collecting duct) cells to determine cilia number, length and morphology. Secondary datasets from the screen will include measurements of cell size and morphology, nuclear morphology and cell cycle profiles. We have successfully set up a facility for high-throughput high-content imaging, optimized a reverse transfection protocol and validated a series of positive and negative controls. We are currently completing the analysis of candidate hits and expect to obtain several hundred positive hits from the whole screen. We will present the first dataset from this screen with a discussion of prioritization strategies for the validation of the most relevant and interesting candidate hits."}
+{"text": "The characterization of miRNAs and their target mRNAs involved in regulation of the immune process is an area of intense research and relatively little is known governing these processes in allergic inflammation. Here we present novel findings defining the miRNA and mRNA transcriptome in eosinophilic esophagitis (EoE), an increasing recognized allergic disorder.Esophageal epithelial miRNA and mRNA from five paired biopsies pre- and post-treatment with glucocorticosteroids were profiled using Taqman and Affymetrix arrays. Validation was performed on additional paired biopsies, untreated EoE specimens and normal controls. Differentially regulated miRNAs and mRNAs were generated, within which miRNA-mRNA target pairs with high predicted confidence were identified.Compared to the post-glucocorticoid treated esophageal mucosa, of all the 377 miRNA sequences examined, 32 miRNAs were significantly upregulated and four downregulated in the pre-treated biopsies. MiR-214 was the most upregulated (150 fold) and miR-146b-5b, 146a, 145, 142-3p and 21 were upregulated by at least 10 fold. Out of 12 miRNAs chosen for validation by qRT-PCR, five  were confirmed and 11 shared the same trend. When the expression of the 12 miRNAs in the EoE mucosa was compared to unrelated normal mucosa, six  showed similar significant changes as in the paired samples and 10 of them shared the same trend. In the same five pairs of samples used to profile miRNA, 311 mRNAs were down-regulated and 35 were up-regulated in pre-treated EoE mucosa. Among them, 164 mRNAs were identified as potential targets of differentially regulated miRNAs. Further analysis revealed that immune-related genes, targeted and non-targeted by miRNAs, were among the most important genes involved in the pathogenesis of EoE.Our findings add to the accumulating body of data defining a regulatory role for miRNA in immune and allergic processes. Eosinophilic esophagitis (EoE) is an increasingly recognized antigen-driven disorder of the esophagus occurring in children and adults MicroRNAs (miRNAs) are small, non-coding 19\u201325 nucleotide long RNAs that constitute the most abundant class of regulators of gene expression The characterization of miRNAs and their target mRNAs involved in regulation of the immune process is an area of intense research This goal of this study was to characterize the miRNA profile of well documented EoE mucosal biopsies, before and after successful treatment with glucocorticosteroids, and to correlate this profile with dysregulated mRNA identified using the same cohort. These findings were further verified on an additional cohort of biopsies from patients with EoE as opposed to normal mucosa.Archival esophageal biopsies from seven pediatric patients before and after treatment for EoE were retrieved from the Department of Pathology at Rhode Island Hospital . The first five pairs were used for both miRNA and mRNA profiling and all seven were used for validation . Eight aPatient records were reviewed by a pediatric gastroenterologist (V.M.) to ensure that the clinical characteristics of the patients fit the diagnosis of EoE. The slides were reviewed by a pathologist (M.R.) to confirm the presence or absence of EoE. Classic features of EoE consist of numerous intraepithelial eosinophils greater than 15 per high powered field (HPF) (ranging from 35 to over 100 per HPF), superficial eosinophilic microabscesses, basal layer hyperplasia and subepithelial fibrosis. The posttreatment biopsy material consisted of normal appearing squamous mucosa with only rare intraepithelial eosinophils numbering less than 2 per HPF.A summary of the seven EoE patients\u2019 clinical information is presented in The study was performed according to a protocol approved by the institutional review board (IRB) of Lifespan/Rhode Island Hospital. The requirement of consent was specifically waived by the IRB committee.Eight 10 \u00b5m sections were cut from each block and mounted onto plain glass slides. If the biopsy section contained only epithelium, the sections were scraped from the slides and were ready for total RNA extraction. If biopsy sections contained sub-epithelium, the sections were deparaffinized, stained, dehydrated through graded alcohols using the Paradise FFPE reagent System  and subjected to LCM within 2 hours of deparaffinization. About 20,000 epithelial cells were captured on LCM Macro CapSure caps (Applied Biosystems) using the Arcturus XT LCM instrument (Applied Biosystems) and the captured cells in the caps were used to extract total RNA. In either case, only the RNA from the epithelial mucosa was extracted. RecoverAll Total Nucleic Acid Extraction Kits for FFPE tissues  were used for extraction. RNA was further purified and concentrated using the RNEasy Minelute Cleanup Kit , and then evaluated by the Agilent Bioanalyzer using an RNA 6000 Nano or Pico LabChip  as described previously Five nanograms of total RNA was reverse-transcribed using the Taqman MicroRNA Reverse Transcription Kit and the Megaplex RT primer Human Pool A (Applied Biosystems). The reverse-transcribed cDNA was then pre-amplified in 12 cycles of PCR using Taqman PreAmp Master Mix and the Megaplex PreAmp primers, Human Pool A (Applied Biosystems). The cDNAs were then diluted and loaded onto a Taqman Human miRNA Array card A (Applied Biosystems), which contains probes for 377 distinct miRNAs and a housekeeping gene (MammU6). The Array cards were run on an ABI HT7900 quantitative PCR (qPCR) instrument. Ct values were obtained for all miRNAs represented on the cards and fold changes in expression were calculated using the delta delta Ct (ddCt) method. Expression levels of MammU6 on the Array card were used as control for the purpose of ddCt calculation. The expression array data have been deposited in Gene Expression Omnibus (GEO) of National Center for Biotechnology Information (NCBI) and are accessible through GEO series accession number GSE36726.Expression of miRNAs that demonstrated high differential expression by array card in five matched EoE cases before and after treatment were confirmed again in those same matched cases as well as in two additional matched cases. In addition, the expression of these differentially expressed miRNAs was determined in eight new samples of EoE biopsy material and compared to ten biopsies from unrelated normal esophageal epithelium . Five naFifty nanograms of total RNA was amplified and reverse-transcribed into cDNA using Ovation FFPE WTA system . Five to ten micrograms of amplified cDNA from the amplification above was fragmented and labeled for Affymetrix array analysis using Encore Biotin Module (Nugen Technologies). Array hybridization and analysis were performed by Genomics Core Facility at the Center for Genomics and Proteomics  according to Affymetrix protocols .Affymetrix Gene 1.0 ST Array data was analyzed by Genomics Core Facility using Affymetrix Command Console and Expression Control. The expression array data have been deposited in GEO of NCBI and are accessible through GEO series accession number GSE36725.Functional annotation was performed using Partek Genomics Suite 6.0, Partek Inc, St. Louis, MI). Differentially regulated genes are selected based on the fold-change (FC), false discovery rate (FDR), and statistical significance . Target genes for miRNA were predicted using Ingenuity Pathway Analysis . The miRNA and mRNA in a pair have to be regulated in opposite directions and their interactions are either \u201cExperimentally observed\u201d or exhibit \u201cHigh (predicted) Confidence\u201d as defined by IPA. Functional pathway analysis and network analysis were performed using modules within IPA.Total RNA from five pairs of EoE biospies before and after treatment was extracted and miRNA expression levels were quantified by Taqman Low Density Array. Of all the miRNAs tested by the array, 36 of them were differentially regulated based on a paired t-test P-value of less than 0.05. Five transcripts were down-regulated after treatment and 33 were up-regulated. The absolute fold changes range from 1.6 to 151. Some miRNAs share the same target sites so that a total of 31 target sites were identified from all the miRNAs. MiR-373 and miR-520e share the same target sites while miR-373 is up-regulated and miR-520e is down-regulated post treatment and thus are excluded for further analysis. The differentially regulated miRNAs are listed in To validate the expression of the differentially regulated miRNAs discovered by Taqman Low Density Array in Paired biopsies from the same patient were used to profile the miRNA expression for the purpose of eliminating the inter-individual variation. However, as glucocorticosteroids were the major treatment component in our patient\u2019s cohort, miRNA expression following treatment may be related in part to the treatment effect. To test this hypothesis, we compared the miRNA expression of the mucosal biopsies from a new set of eight EoE patients with those from normal mucosa of ten additional pediatric esophageal biopsy samples from patients without any history of EoE. As shown in The major role of miRNA is to regulate mRNA expression at the transcriptional and translational level. We wished to determine how much of the mRNA expression in EoE is influenced by miRNAs. To profile the global mRNA changes in EoE, an Affymetrix GeneChip based mRNA gene profiling was conducted on five paired EoE biopsies before and after treatment. Total RNA was extracted from FFPE tissue sections and hybridized to Human Gene ST 1.0 Genechips. The Principle Component Analysis of data demonstrated that gene expression data from biopsies of the same status are highly correlated with each other . To screInformation regarding the miRNA-mRNA pairs is incorporated into a pathway network analysis on the 346 differentially regulated genes using IPA program. One of the top pathway networks IPA revealed is a gene regulatory network of more than 24 genes involving \u201cinflammatory response\u201d, \u201ccell-to-cell signalling and interaction\u201d, and \u201chematological system development and function\u201d . Within Given the finding that both targeted genes and non-targeted genes are equally represented in the network , we condLittle is known regarding miRNA regulatory pathways in allergic inflammation in general In our study 36 miRNAs were differentially expressed (32 upregulated and 4 downregulated) in EoE before and following treatment including 25 miRNAs at a level of 3 fold or more. Differential miRNA expression was correlated with differential mRNA expression in the same patients: 311 genes were found to be downregulated and 35 upregulated when comparing the pretreated to posttreated samples. Several of the mRNAs identified have been shown to play a role in EoE or in other allergic disorders. In general the results of this study are more heavily weighted towards miRNAs with increased expression levels and mRNAs with decreased expression levels in the inflammatory state as opposed to the treated samples. The opposing direction of the miRNA and mRNA expression is in line with miRNA\u2019s regulatory role on gene expression In an attempt to better define how much of the differential regulation of miRNAs in EoE was related to the effect of the glucocorticosteroid treatment on the allergic process as opposed to the allergic process alone we examined the expression levels of the miRNAs originally detected to those in additional material from EoE patients compared to control tissue from histologically normal appearing esophageal mucosa. The fold changes as detected by qPCR were significantly higher in the pre vs posttreatment tissue than in the EoE vs control tissue and not all of the qRT-PCR differential expression reached statistical significance. The differential expression of certain of these miRNAs such as miR-214, miR-142-3p and miR-29b appear to be influenced much more significantly by the treatment as opposed to the allergic process alone.Another important issue is to determine which cell types are responsible for the differential expression of miRNAs in this study. We purposely dissected areas of epithelium only and avoided submucosal stromal tissue in many cases employing LCM for this purpose. In addition to eosinophils the squamous epithelium in EoE also exhibits increased infiltration by T-cells and mast cells A number of miRNAs that were found to be differentially regulated in this study were implicated by others to play a role in allergic and inflammatory disorders Although miR-214 has been implicated in a number of neoplastic disorders, to date a role for miR-214 in inflammatory or allergic disorders has not been described. MiR-214 has been found to be elevated in models of renal injury and may play a role in epithelial mesenchymal transition Helicobacter pyloriBoth miR-146a and miR-146b were markedly increased in the epithelium of EoE patients. MiR-146a has been shown to regulate several physiological and pathophysiological pathways in hematopoietic cells as reviewed by Hua et al Increased expression of miR-21 was detected in both the pretreated EoE group as opposed to the post-treated group and in the EoE group as oppose to normal controls. MiR-21 is involved in the regulation of many different pathways and is considered an \u201concomir\u201d due to its widespread role in neoplasia. In allergic disorders miR-21 has been shown to be involved in the regulation of allergic lung inflammation by targeting IL12a (IL-12p35) a cytokine that contributes to polarization of Th cells toward Th2 cells MiR-203 down regulated three fold targets the ALOX15 gene (upregulated 10 fold) which encodes for arachidonate 15 lipoxygenase (15-LO). The 15-LO protein is upregulated in asthma As the human genome may encode over 1000 miRNAs, which may target about 60% of mammalian genes, several immune related genes which were dysregulated in our cohort had no complementary regulatory miRNA identified. Of these genes several have been shown to play a role in the pathophysiology of allergic disorders including EoE. TNFAIP6 the most significantly elevated mRNA in the pretreated biopsies as well as CPA a mast cell derived gene were both shown to be significantly upregulated in a previous study of EoE Our data implicate several miRNAs and miRNA-MRNA gene sets expressed in the epithelial layer in EoE. The identified gene expression changes provide additional diagnostic and therapeutic targets for EoE and other eosinophilic epithelial diseases.Table S1The full list of 346 differentially regulated mRNAs targeted by differentially regulated miRNAs.(XLS)Click here for additional data file."}
+{"text": "An extensive search through the Protein Databank (about 4500 nonredundant structures) was previously completed within our lab to analyze the energetic and geometric characteristics of an understudied molecular interaction known as an anion-quadrupole (AQ) interaction. Such an interaction occurs when the positively charged edge of an aromatic ring, resulting from a quadruple moment , renders the aromatic molecule noncovalently bound to a nearby anionic molecule. The study considered a very limited scenario of molecules that can participate in AQ interactions, consisting of the phenyl group of a phenylalanine (phe) amino acid as the aromatic participant and the carboxylate group of an aspartate (asp) or glutamate (glu) amino acid as the anionic participant. The results revealed anion-quadrupole pairs to be prevalent within most of the protein structures. It was also observed that the interaction energy for AQ pairs was heavily dependent on the angle between the anion and plane of the aromatic ring, favoring a more planar interaction.In light of these critical observations being made from such a limited scenario, only phe-glu and phe-asp pairs and in a reduced sample set of the PDB, we are now continuing this work of identifying AQ interactions using a greatly expanded strategy. We are following these four aims: 1. Optimizing the AQ-search program to run in a semi-parallel fashion and on a large cluster of processors in order to handle larger analyses, 2. Adding to our search additional anionic participants which will include non-protein structures such as DNA and small ligands, 3. Studying a subset of the AQ pairs with molecular dynamics simulations in buried and solvent exposed environments to observe non-static behavioral traits as well as the reproducibility of AQ interactions by force field parameters. 4. Building an online database for public access to our data and search program."}
+{"text": "Xenotropic murine leukemia virus-related virus (XMRV) was first identified in 2005 in a study of human prostate cancer patients with genetic variants of the antiviral enzyme, RNase L. Subsequent investigations in North America, Europe and Asia have either observed or failed to detect XMRV in patients  or normal, healthy control individuals. Among the confounding factors are the potential for lab contamination with similar or identical viruses or viral sequences originating in mice. In some studies, relatively contamination-resistant methods  suggest that either XMRV or a similar type of virus is present in some patients. Evidence for and against genuine infections of humans with this intriguing virus (and/or related viruses) will be discussed."}
+{"text": "Biologic therapies not only offer the prospect of improved patient outcomes in a variety of autoimmune diseases, but also the opportunity to explore the specific target's role in the underlying mechanisms of disease. Over recent years we have studied the role of regulatory T cells (Treg) in patients with rheumatoid arthritis before and after anti-TNF therapy. We have shown that Treg from patients with rheumatoid arthritis have defective suppressor function. This Treg defect is linked with abnormalities in the expression and function of CTLA-4. Anti-TNF antibody therapy did not reverse CTLA-4 dysfunction but instead induced the differentiation of a distinct and potent Treg population. These induced Treg were able to inhibit IL-17 production, in contrast to Treg from healthy individuals, patients with active RA or RA patients treated with etanercept, a modified TNF receptor. These results may provide mechanistic insight into the therapeutic benefit of switching between different anti-TNF agents and the differing incidence of tuberculosis between adalimumab and etanercept."}
+{"text": "Up to 70% of adolescents with moderate to severe unipolar major depression respond to psychological treatment plus Fluoxetine (20-50 mg) with symptom reduction and improved social function reported by 24 weeks after beginning treatment. Around 20% of non responders appear treatment resistant and 30% of responders relapse within 2 years. The specific efficacy of different psychological therapies and the moderators and mediators that influence risk for relapse are unclear. The cost-effectiveness and safety of psychological treatments remain poorly evaluated.Improving Mood with Psychoanalytic and Cognitive Therapies, the IMPACT Study, will determine whether Cognitive Behavioural Therapy or Short Term Psychoanalytic Therapy is superior in reducing relapse compared with Specialist Clinical Care. The study is a multicentre pragmatic effectiveness superiority randomised clinical trial: Cognitive Behavioural Therapy consists of 20 sessions over 30 weeks, Short Term Psychoanalytic Psychotherapy 30 sessions over 30 weeks and Specialist Clinical Care 12 sessions over 20 weeks. We will recruit 540 patients with 180 randomised to each arm. Patients will be reassessed at 6, 12, 36, 52 and 86 weeks. Methodological aspects of the study are systematic recruitment, explicit inclusion criteria, reliability checks of assessments with control for rater shift, research assessors independent of treatment team and blind to randomization, analysis by intention to treat, data management using remote data entry, measures of quality assurance, advanced statistical analysis, manualised treatment protocols, checks of adherence and competence of therapists and assessment of cost-effectiveness. We will also determine whether time to recovery and/or relapse are moderated by variations in brain structure and function and selected genetic and hormone biomarkers taken at entry.The objective of this clinical trial is to determine whether there are specific effects of specialist psychotherapy that reduce relapse in unipolar major depression in adolescents and thereby costs of treatment to society. We also anticipate being able to utilise psychotherapy experience, neuroimaging, genetic and hormone measures to reveal what techniques and their protocols may work best for which patients.ISRCTN83033550Current Controlled Trials  First depressive episodes tend to arise in vulnerable individuals exposed to current chronic psychosocial adversities and acute adverse life events -3. LaterOne randomised study in the UK showed that even in adolescent patients who were compliant with full active treatment for 6 months results were moderate; only 20% fully recovered, 30% achieved some level of remission, a further 30% had high number of residual symptoms and 20% did not respond to treatment at all . The posCognitive Behaviour Therapy (CBT) has been widely investigated and shown to be effective in the treatment of mild and moderate depressions in the short term ,14. ReceA small study of moderately to severely depressed young people attending clinical services has shown that patients may begin to relapse within 3 months of discharge, even in those fully recovered, and over the next 5-10 years some 50%-70% will relapse with a small group of patients never attaining remission over the third decade of life .There is now a growing evidence base for psychodynamic psychotherapy with adults ,21 incluSpecialist Clinical Care (SCC) refers to the active treatment process that is administered routinely in many but not all UK outpatient child and adolescent mental health services (CAMHS). Specialist Clinical Care is usually delivered through a multidisciplinary team and unlike CBT and STPP is available in the vast majority of all CAMHS across the UK. This treatment approach has recently been manualised and is now being taught to mental health practitioners working in mental health services . To dateFinally interpersonal psychotherapy (IPT), a conversational treatment with some principles derived from STPP  and SCC  has been shown to be efficacious and effective with children and adolescents with mild to moderate depression suggesting that relatively brief, active psychological treatments not focussed on distorted or abnormal cognitive processing treatments are indeed able to alleviate depressive symptoms and improve social functioning at least in the short term .In summary there is now substantial data that 3 active specialist psychological treatments  derived from different theoretical perspectives and requiring therapists to be trained in specific modalities of delivering treatment are efficacious and clinically effective in alleviating depressive symptoms and improving social function in the short term in at least 50% of depressed adolescents. It is likely, but yet to be demonstrated that SCC will have similar properties for the treatment of acute depressive episodes. In contrast there is no evidence that the successful management of acute depression in this age range has longer term benefits through reducing relapse and recurrence risk.The current randomised controlled trial was designed firstly to determine i) whether psychological treatment delivered to moderately to severe depressed adolescents would reduce risk of relapse and recurrence and if so ii) which was the most likely to reduce the risk of relapse 12 and 18 months after therapy began. This paper describes the design of this trial, how we will implement the protocols and analyse the results.The \"Improving Mood with Psychoanalytic and Cognitive Therapies\" (IMPACT) study is a pragmatic, relapse prevention superiority, randomised controlled trial. The study compares three interventions: Short Term Psychoanalytic Psychotherapy (STPP), Cognitive Behaviour Therapy (CBT) and Specialist Clinical Care (SCC) delivered for the treatment of moderate to severe depression in adolescents attending routine CAMHS clinics in the UK. Patients in any arm may receive Fluoxetine 20-50 mg as part of their treatment for reducing clinical symptoms and improving social function of the presenting episode. The use of an SSRI will adhere to UK NICE guidelines as demonstrated in the ADAPT study . The stuTo investigate the clinical effectiveness of psychological treatment in reducing the persistence and/or relapse of major depression in adolescents. In particular, to determine whether the specialist individual psychological treatments of CBT or STPP are more effective at reducing risk for relapse at 86 weeks after treatment had started compared to SCC. We will test a primary superiority hypothesis that STPP and CBT are both independently more effective at reducing relapse risk than SCC and a subsidiary hypothesis that STPP is more effective than CBT.To investigate the cost-effectiveness of psychological treatment and in particular to determine whether the additional costs of specialised treatment are justified by improvements in effectiveness and/or decreased use of health and social care services by 86 weeks follow up.Age 11 through 17 yearsCurrent DSM-IV unipolar MDD diagnoses with moderate to severe impairment.Generalised learning difficulties or a Pervasive Developmental DisorderCurrently taking another medication that may interact with an SSRI and unable to stop this medication.A primary diagnosis of Bipolar Type I, Schizophrenia and Eating DisordersNo other exclusions will be made in order to ensure that the sample is diverse and representative of the kind of cases that NHS CAMHS take on for treatment.The flow of participants from recruitment through to end of study is shown in figure The research team will approach local CAMHS within each of the trial sites and will introduce the study to staff allowing them to ask questions and become familiar with the objectives of the trial. Identification and initial screening of potential participants will then be done by clinical staff working within these clinics, following referral as per usual to specialist CAMHS. In many cases the clinicians involved in the initial assessments when the potential participants are referred to a service will be staff who are also delivering treatment as part of the group, based in clinics. At assessment clinicians will be asked to complete a depression screening tool (see appendix) specifically designed to assist referral to IMPACT. Once the potential participants are identified, clinicians will invite the young person and their carer(s) to take part in the trial. If they are interested their details will be passed to the research group.The participants will then be contacted by a researcher  who will then schedule an initial meeting during which the participants will be invited to sign a consent form. All research baseline assessments will be administered to the young person and their carer in parallel sessions by two research workers. After this, researchers will confirm whether the participants meet diagnostic and other entry criteria. If they do, participants will then be randomised into one of the treatment arms. Researchers will remain blind to treatment allocation.After consent has been obtained and the baseline assessment has been carried out, a trial ID will be assigned. Randomisation will be stratified by age, sex, region and scores on the Mood and Feelings Questionnaire (MFQ) . RandomiIMPACT is a pragmatic superiority trial that seeks to evaluate the treatments that could be used in standard NHS practice. Therefore, comprehensive treatment protocols will be used. These are based on usual clinical practice and have been developed for the trial. The rational for using treatment protocols is that: a) protocols aid dissemination of treatment methods into clinical practice; b) they help to standardize the intervention between therapists and across sites; and c) they form the bases for audiotape ratings of adherence to the intervention and thus ensure that the interventions have been given properly; and importantly d) that therapists in the SCC group do not give CBT or STPP interventions. The three treatments will be delivered at different levels of intensity, defined by the total number of sessions over the study period. The number of sessions for each treatment are as follows: SCC 12 individual sessions plus up to 4 family/marital sessions to be delivered over 20 weeks, STPP 30 sessions plus 6 parent sessions to be delivered over 30 weeks and CBT 20 individual sessions plus up to 4 family/marital sessions to be delivered over 30 weeks.SCC will consist of a psychosocial management programme with Fluoxetine in severe cases: The procedure will be a treatment course over 20 weeks maximum consisting first of 6 sessions over the first 8 weeks. If remission is not achieved psychosocial treatment will be extended for a further 6 sessions and Fluoxetine added. End of trial treatment will be denoted by week 20 from the first session. The content will involve a conversational approach with the patient and their parents and siblings if required. The treatment will emphasise the importance of action-oriented, goal-focused and interpersonal activities as therapeutic strategies. There will be no focus on changing cognitions and negative cognition-driven behaviours will not be deconstructed. Finally there will be no ongoing analysis with the patient about the putative unconscious origins of their symptoms. Advice will be given on personal activities, social behaviour, and school work and attention will be paid to immediate distressing events such as family difficulties. There will be a continuing focus on psycho-education, i.e. what depression is/co-morbid diagnoses/how common it is/its nature and the typical course of the disorder/how it affects the adolescent and those around them. More detailed attention will be paid to the consequences of any acute undesirable life events focused on the adolescents. Up to 4 family or marital therapy sessions for parents will be given where required within the 20 week period. Liaison with external agencies and personnel e.g. teachers, social care and peer group will be undertaken. Specific advice will be given on mental and physical hygiene. Helping oneself through engaging in pleasurable activities and diminishing solitariness will be strongly enforced.SCC will not use cognitive or reflective techniques related to analysis of unconscious motives and behaviours nor specific behavioural strategies. Very ill patients may require Fluoxetine before 6 sessions have been delivered. If Fluoxetine is added medical assessment sessions will occur and recorded. The standard protocol developed for the ADAPT study will be used whereby a test dose of 10 mg is given for 48 hours followed by 20 mg. If there is no improvement within 2-4 weeks dose can be adjusted upwards to 60 mg maximum (median dose in the ADAPT study was 30 mg with a range of 20 mg-50 mg). Both adverse events and side effects will be recorded for psychological as well as pharmacological treatments.The form of STPP to be used in the trial, which reflects the approach to psychodynamic work as it is practiced in child mental health services in the UK, has been manualised for the study. This manual draws on the work of other psychodynamic workers , includiCBT therapy in this trial is based on that developed for adults and has been adapted to include parental involvement and specific techniques for adolescents. CBT is an active, verbal therapy which is based on an individual formulation of the client's current problems and their associated antecedents, precipitating and maintaining factors. This formulation is shared with the client (and their parents).CBT is typified by an emphasis on 'collaborative empiricism', explicit, tangible and shared goals and clear structured sessions. Typically therapy has a number of phases which include assessment, psycho-education into the cognitive behavioural model of depression , the introduction of monitoring methods , behavioural activation and activity scheduling, linking thoughts, feelings and behaviours, identifying and challenging negative automatic thoughts, developing and reinforcing adaptive thoughts and relapse prevention strategies. Specific techniques have been developed to support therapy and to maintain engagement and optimism for change. Topics introduced within therapy session are extended and supported outside the session by tasks completed by the client between sessions and reviewed at each subsequent session. Delivery of the programme is flexible; typically it may include 12 sessions delivered weekly, followed by 8 biweekly sessions until the end of the treatment. CBT can be delivered to the adolescent alone or to parents and the young person together and this is determined by the formulation.To maximise the clinical validity of the outcome evaluations, these assessments will be made across multiple domains using multiple methods and sources.Major depression and co-morbidity - Schedule for Affective Disorders and Schizophrenia for School Aged Children (6-18 years) (k-SADS-PL) Monitoring suicidal adverse events across the treatment trial - Columbia Suicide Severity Rating Scale (C-SSRS)Outcomes of child and adolescent psychiatric disorders - The Health of the Nation Outcome Scale for Children and Adolescents (HoNOSCA)DSM-IV Borderline personality disorder - Zanarini Rating Scale for Borderline Personality Disorder (ZAN:BPD)Clinical Global Impressions Scale (CGI) Service use - Child and Adolescent Service Use Schedule (CA-SUS) ,43Self-report measure of depressive, anxiety, obsessive-compulsive and anti-social behaviour symptoms as well as global self-esteem - The Young Persons questionnaire (YPQ) containing the Mood and Feelings questionnaire (MFQ), revised manifest anxiety scale (RCMAS), short form of the Leyton Obsessional Inventory (LOI), the Rosenberg self esteem scale (RSES) and an antisocial behaviour checklist consisting of 11 items derived from DSM-IV clinical criteria for conduct disorder behaviour checklist questionnaire ,44-46Responses to low mood - Ruminative Response Scale Self--harming and risk-taking behaviour - The Risk Taking and Self-Harming Inventory for Adolescents (RTSHIA) Fundamental emotions - Differential Emotion Scale (DES-IV)Experiences associated with depression - Depressive Experiences Questionnaire (DEQ) Cognitive vulnerability to depression - Depressed States Checklist (DSC)Parenting - Alabama Parenting Questionnaire (APQ)Life events - Life Events Questionnaire (LEQ)Personality - NEO-Five Factor Inventory (NEO-FFI) Health-related quality of life - Euroquol (EQ-5D) Current friendship satisfaction - Friendships Questionnaire Symptom intensity - Symptom Checklist (SCL:90)Working Alliance - Working Alliance Inventory - Short form (WAI-S)Adolescent Integrative measure (AIM), adaptation of the HCAM - Hampstead Child and Adaptation Measure Family functioning (FAD)At baseline, all participants will be asked to collect saliva samples at waking, 30 minutes after waking and again at 22.00 hrs for two consecutive days, for cortisol assay. There is excellent correlation for cortisol levels between plasma and saliva and also between csf and plasma . Levels We will test whether the 5-HTTLPR s allele, the 5-HT2A G allele, and high cortisol predict i) time remission ii) time to relapse iii) differential response to a specific treatment modality. Naturalistic study has shown that higher morning cortisol in depressed adolescents is associated with longer duration of depressive episode regardless of severity and comorbidity at presentation . Since hThere is rapidly emerging evidence for distinctive neural structural abnormalities associated with affective disorders in young people compared to other psychopathologies . There iTo achieve these aims we will recruit 120 participants (40 from each treatment arm) in the East Anglia Region to a magnetic resonance imaging study. Of these 40 receiving CBT following randomization will have a second scan at 36 weeks. In addition 40 age and sex matched controls with no lifetime history of depression will be scanned once only.Structural MRI datasets  will be obtained for whole brain, multi-channel segmentation and voxel based morphometry and high resolution grey matter volume estimates in limbic and frontal cortical regions of interest defined a priori by a parcellated template image. Diffusion tensor imaging (DTI) data will be analyzed for whole brain analysis of fractional anisotropy measures of white matter integration and tractography of selected axonal tracts mediating connections between limbic and frontal regions of interest. Twelve diffusion-weighted directed volumes and 5 volumes without diffusion-weighting (b = 0) will be acquired. Acquisition time is ~10 minutes.52, the respiratory cycle and the inter-beat interval (RR) in electrocardiographic data will be simultaneously recorded in the scanner. Total acquisition time for all fMRI datasets is ~40 minutes.Functional MRI (fMRI) datasets will be acquired using Echo-planar images (EPI) depicting BOLD contrast at a sampling time (TR) of 2 seconds during performance of three tasks: a facial emotion processing task designed to activate amygdala and other limbic regions and two tasks involving executive and mnemonic processing of emotionally valent stimuli that will additionally activate prefrontal and medial temporal areas. We will also acquire fMRI data with participants in a no-task or resting state to investigate endogenous dynamics and functional connectivity in fronto-limbic circuits. For all fMRI data acquisitions, but especially for proper control of potential cardiorespiratory confounds in analysis of resting state dataFollow-up assessments will be conducted at 6, 12, 36, 52 and 86 weeks after the start of treatment. To monitor for any adverse events or side effects of therapy, the researchers will complete the Adverse events/Side effect questionnaire at each follow-up assessment throughout the treatment progress . Please IMPACT is a pragmatic superiority trial that compares SCC, CBT and STPP to reduce relapse in adolescents with DSM-IV defined moderate to severe depression. Cases with DSM-IV unipolar major depression will be randomly allocated to SCC, CBT or STPP and outcomes will be assessed at planned follow-up points by outcome assessors unaware of the treatment allocation.The proposed design of the trial will run in 6 CAMHS in each of the three centres, giving 18 clinics with a minimum of one therapist for each treatment modality in each clinic. Because IMPACT will involve more than two treatments, a number of comparisons can be made between treatment groups. We propose to make two: a) the two individual specialist treatments CBT and STPP will be compared; and b) the individual specialist treatments combined will be compared with SCC. A 2.5% two-tailed significance level has therefore been used in the power calculation. Additionally, power has been calculated according to each of the following hypothesis of comparisons: superiority, equivalence or non-inferiority. It has been assumed that 5 points on the self-report MFQ is the minimum clinically important difference. This is approximately 25% of the change in the MFQ scale from baseline to 28 weeks according to the results from the ADAPT trial  and is eAll analysis will be according to intention-to-treat principle. Characteristics of the treatment groups will be described at baseline. Preliminary analysis will investigate the pattern of missing follow-up data. The statistical analysis of the primary outcome measure (MFQ) and the secondary measures will estimate the treatment effect using a linear mixed effects models adjusting for pre-specified prognostic variables  and the time point of assessment. The model will include subject level random intercept and gradient effects and also random effect for therapist. Ordered categorical secondary outcome measures such as the CGI scales and suicidality rating scales will be analysed using the proportional odds model . A sub-gThe objective of the economic evaluation is to evaluate the relative costs and cost-effectiveness of the three treatments. Since STPP and CBT are more resource intensive than best practice SCC, their provision requires additional health service resources that could be used elsewhere. To ensure that such resource allocation is cost-effective, it is necessary to demonstrate that the additional resources spent can be justified, either in terms of saving as a result of reduced demand for other services or in terms of gains in effectiveness.The economic evaluation will take a societal perspective, including the use of all health, social care, education and criminal justice sector resources plus family costs in the form of travel to trial intervention sessions and productivity losses of the primary carer resulting from their child's illness. Economic information will be collected in interview at baseline and all follow-up points using the Child and Adolescent Service Use Schedule (CA-SUS), developed by the applicants in previous research in child and adolescent mental health populations and adapted for the purpose of the current study ,43. DataThe cost of the trial interventions will be calculated using a bottom-up costing approach  which wiCost-effectiveness will be assessed at the 86 week follow-up and will be measured in terms of quality adjusted life years using the EQ-5D measure of health related quality of life . Cost-efThe study protocol was approved Cambridgeshire 2 Research Ethics Committee, Addenbrookes Hosptial Cambridge, UK.The treatment efficacy and effectiveness for unipolar major depressions in post pubertal adolescents has established that combination psychological and SSRI treatment is the therapy of choice for establishing remission in the short term. Acute treatment appears highly satisfactory of around 70% of cases regardless of clinical characteristics. Currently there are very few clinical markers of poor treatment response to help guide clinicians. Severity and at presentation suggests a longer time to recovery but not treatment non response per se . In contThe current IMPACT study was designed not only to be informative in terms of effective and cost effective treatment in the short and extended medium term but uniquely in specifically focusing on reducing relapse risk in the longer term. A second and important addition is that one of the treatment arms will for the first time comprehensively test the effectiveness of a short tem psychoanalytically psychotherapy, STPP. Comparing the outcomes of those who received CBT, STPP and SCC will determine the relative clinical and economic benefits associated SCC and STPP. Furthermore, by collecting regular follow-up data throughout treatment and then at 52 and 86 weeks, we will be able to explore factors that might influence treatment response as well as the long term benefits associated with receiving CBT and STPP. Treatments will vary in length as stated within the respective clinical protocols therefore time to relapse will be calculated from the last treatment session given. Additionally, the IMPACT trial will give us the opportunity to examine the productivity losses and gains of each treatment. This will allow for a set of calculations regarding the treatment costs of each arm and therefore the overall economic effectiveness of providing one or more treatments' to prevent relapse.IMPACT is also the first study of depression in young people to include measurement of variables that can provide insights into the mechanisms that govern treatment response. Studies of depression in adults have attempted to establish genetic biomarkers of liability for treatment response to SSRIs. A recent metananlyses of the three published studies to date involving 2998 treated depressed adults in total found none of the studies reported results that achieved genome-wide significance, suggesting that larger samples and better outcome measures will be needed . Indeed thed); EQ-5D: Euroquol; FAD: The McMaster Family Assessment Device; HCAM: Hampstead Child and Adaptation Measure; HoNOSCA: The Health of the National Outcome Scale for Children and Adolescents; ICER: Incremental cost-effectiveness ratios; ID: Identification; IMPACT: Improving mood with Psychoanalytic and Cognitive Therapies; IPT: Interpersonal Psychotherapy; K-SADS-PL: Schedule for Affective Disorders and Schizophrenia for School Aged Children (6-18 years) present and lifetime; LEQ: Life Events Questionnaire; LOI: Leyton Obsessional Inventory; MD: Major Depression; MDD: Major Depressive Disorder; MFQ: Moods and Feelings Questionnaire; MRI: Magnetic Resonance Imaging; NEO-FFI: NEO-Five Factor Inventory; NHS: National Health Service; NICE: National Institute for Clinical excellence; OA: Outcome assessor; RCMAS: Revised Manifest Anxiety Scale; RCT: Randomised Controlled Trial; RSES: Rosenberg Self-esteem Scale; RTSHIA: The Risk Taking and Self-Harming Inventory for Adolescents; SCC: Specialist Clinical Care; SCL:90: Symptom Checklist; SD: Standard Deviation; SSRI: Selective Serotonin Reuptake Inhibitors; STPP: Short Term Psychoanalytic Psychotherapy; UK: The United Kingdom; WAI-S: Working Alliance Inventory - Short form; YPQ: Young Persons Questionnaire; ZAN:BPD: Zanerini Rating Scale for Borderline Personality DisorderADAPT: Adolescent Depression, Antidepressants and Psychotherapy Trial: The ADAPT Study; AIM: Adolescent Integrative Measure; APQ:Alabama Parenting Questionnaire; CAMHS: Child and Adolescent Mental Health Services; CA-SUS: Child and Adolescent Service Use Schedule; CBT: Cognitive Behavioural Therapy; CGS: Clinical Global Impressions Scale; C-SSRS: Columbia Suicide Severity Rating Scale; DEQ: Depressive Experiences Questionnaire; DES-IV: Differential Emotion Scale; DSC: Depressive States Checklist; DSM-IV: Diagnostic and statistical manual of mental health disorders (4The authors declare that they have no competing interests.IG and PF designed the trial and the multicenter implementation, SB completed the health economics design and contributed to calculating power for economic variables, JH RK MT BD and RS contributed to drafting the grant application with IG and PF. RK, PW and IG wrote the SCC manual, SR wrote the CBT manual, RS and MT facilitated writing of the STPP manual by a group of expert child psychotherapists, CR wrote the statistical and data analytic strategy and together with IG is responsible for the data collation, IG BD PW and ST devised the adverse events and side effects scale and collated measures with JH MT and PF, ST and IG drafted the paper, JS and IG wrote the neuroimaging design, JS designed the structural and functional neuroimaging protocol, and PW and IG designed and drafted the genetics and hormones strategy and protocol. All authors contributed to revisions of the manuscript prior to submission and approved the submitted draft."}
+{"text": "Childhood adversity can have life-long consequences for the response to stressful events later in life. Abuse or severe neglect are well-known risk factors for post-traumatic stress disorder (PTSD), at least in part via changes in neural systems mediating the endocrine response to stress. Determining the biological signatures of risk for stress-related mental disorders such as PTSD is important for identifying homogenous subgroups and improving treatment options. This review will focus on epigenetic regulation in early life by adversity and parental care \u2013 prime mediators of offspring neurodevelopment \u2013 in order to address several questions: (1) what have studies of humans and analogous animal models taught us about molecular mechanisms underlying changes in stress-sensitive physiological systems in response to early life trauma? (2) What are the considerations for studies relating early adversity and PTSD risk, going forward? I will summarize studies in animals and humans that address the epigenetic response to early adversity in the brain and in peripheral tissues. In so doing, I will describe work on the glucocorticoid receptor and other well-characterized genes within the stress response pathway and then turn to genomic studies to illustrate the use of increasingly powerful high-throughput approaches to the study of epigenomic mechanisms. Childhood adversity can have life-long consequences for the response to stressful events later in life . RepeateA first critical issue in understanding the relative risk conferred by early life adversity concerns the molecular mechanisms mediating altered HPA function as well as other pathways underlying vulnerability that respond in a manner that is both contingent upon the adversity and stable in the face of similar perturbations in later life. Epigenetic mechanisms include DNA methylation, histone modifications, and non-coding RNA. The methylation of cytosine in cytosine-guanine dinucleotides (CpGs) in the DNA itself  is the best understood epigenetic mark and the focus of the majority of current investigations. However other modifications to DNA, including hydroxymethylation (5-hmC) and other recently identified DNA modifications, are attracting increasing interest as potential gene regulatory mechanisms . It shouElucidating which regions of the genome are labile in response to early life adversity, how rapidly changes can occur, and the ontological time-course of epigenetic changes remains a matter of active investigation. As I discuss below, these epigenetic responses likely depend on the genomic loci under consideration. Humans are exposed to a variety of stressors throughout life, however early life stress appears to exert an profound effects on HPA function that is pervasive throughout life in part by altering epigenetic mechanisms in a stable manner. I will illustrate this point by discussing several studies in rodents that have provided foundational knowledge applicable to investigations in humans.7 splice variant of the GR promoter in the hippocampus and of the promoter of the GAD67 gene in the prefrontal cortex  to select nucleotides within the promoter. Another recent study has replicated the finding of enhanced DNA methylation at this splice variant and gone on to identify altered DNA methylation in additional splice variants of the GR promoter and show that this response to early adversity is brain region specific, not occurring in the anterior cingulate  and defined candidate genomic loci. A study using a microarray approach combined with methylated DNA immunoprecipitation to interrogate promoter regions in all known protein-coding genes found that evidence of hypo- and hypermethylation among hundreds of genes in hippocampi from suicide completers with a history of early life abuse compared to non-abused controls . This stWe documented changes in DNA methylation, H3K9 acteylation and gene expression across a 7\u2009Mb region flanking the GR gene hippocampus using a tiling microarray approach in rats . DiffereIn a follow-up to this study, we analyzed the GR locus in hippocampi of adult suicide victims who were abused early in life compared to non-abused controls . Abused + T-cells) can often be divided into functional classes that are dissociable by additional rounds of selection, making it difficult to know whether one has attained the necessary level of specificity. An additional method to address this problem is informatic. Data gathered by the Encyclopedia of DNA Elements (ENCODE) project and other large-scale genomics initiatives are providing multidimensional representations of epigenetic and functional genomic signatures from a large number of cell types  in rodents, and syntenic regions of the human genome that are epigenetically labile in conditions of early adversity . StudieMany animals, including rodents and humans, appear to have evolved to respond both to immediate threats to life and limb and to psychosocial stress associated with predation risk, including via the transfer of information about environmental conditions to the offspring via maternal factors. For example, a number of studies in wildlife ecology and comparative endocrinology over the past 20\u2009years have indicated that the influence of predators on stress in free-living animals is long-lasting, resembling stress effects in laboratory animal models of PTSD . Responsper se (Elucidating the biological mechanisms underlying effects of early social experiences on later mental health is challenging in humans for reasons that include technical/analytic complexity and limited access to relevant biological material. New methods that offer the ability to examine DNA methylation at single-nucleotide resolution genome-wide are advancing rapidly and, in tandem, a vast array of analytical tools and statistical methods are now available to normalize known technical biases, visualize epigenetic modifications, and identify differences among subjects . Genome-per se . Buccal The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Signals recorded from peripheral nerves may provide an effective and reliable means of controlling powered prosthetic limbs. Longitudinal intrafascicular electrodes (LIFEs) have been used to record extracellular motor activity from peripheral nerves in upper-limb amputees for periods up to several weeks and the ability to decode the activity and use it for single degree-of-freedom (DOF) control of a prosthetic arm has been demonstrated . However"}
+{"text": "Migraine attacks have been shown to interfere with normal function in the brain such as motor or sensory function. However, to date, there has been no clinical neurophysiology study focusing on the motor function in children with migraine during headache attacks. To investigate the motor function in children with migraine, twenty-six children with acute migraine, meeting International Classification of Headache Disorders criteria and age- and gender-matched healthy children were studied using a 275-channel magnetoencephalography system. A finger-tapping paradigm was designed to elicit neuromagnetic activation in the motor cortex. Children with migraine showed significantly prolonged latency of movement-evoked magnetic fields (MEF) during finger movement compared with the controls. The correlation coefficient of MEF latency and age in children with migraine was significantly different from that in healthy controls. The spectral power of high gamma (65\u2013150 Hz) oscillations during finger movement in the primary motor cortex is also significantly higher in children with migraine than in controls. The alteration of responding latency and aberrant high gamma oscillations suggest that the developmental trajectory of motor function in children with migraine is impaired during migraine attacks and/or developmentally delayed. This finding indicates that childhood migraine may affect the development of brain function and result in long-term problems. Headache is a common childhood complaint with up to 75% of children reporting a notable headache by the age of 15 years. Pediatric migraine is the most common cause of recurrent headache, occurring in up to 28% of teenagers Magnetoencephalography (MEG), as a relatively new technique, can noninvasively, directly, and quantitatively measure neuronal activity with excellent temporal resolution and good spatial resolution Based on literature: (1) white matter integrity is significantly damaged in migraine nd Edition Twenty-six children with a diagnosis of migraine who had acute migraine attack  were recruited from our Headache Clinic see . The parAll subjects performed a brisk left or right index finger tapping immediately after hearing a sound cue  square tone). Subjects were instructed to press a response button with the index finger that was ipsilateral to the tone see . The eyeThe neuromagnetic signals were recorded in a magnetically shielded room  using a whole head CTF 275-Channel MEG system  in Cincinnati Children\u2019s MEG Center prior to clinical treatment for the participants. This magnetic shielded room was designed to reduce environmental magnetic noise. Before data acquisition commenced, three electromagnetic coils were attached to the nasion, left and right pre-auricular points of each subject. These three coils were subsequently activated at different frequencies for measuring each subject\u2019s head position relative to the MEG sensors. Each subject was comfortably positioned in the supine position with arms resting on either side, during the entire procedure. The sampling rate of the MEG recording was 6000 Hz per channel. An acquisition window was set to 3000 ms per trial, with 2000 ms pre-trigger and 1000 ms post-trigger. The data were recorded with a noise cancellation of third order gradients and without on-line filtering. Subjects were asked to remain still. If head movement during a recording was beyond 5 mm, that dataset was indicated as \u201cbad\u201d and an additional trial was recorded.Three-dimensional Magnetization-Prepared Rapid Acquisition Gradient Echo sequences were obtained for all subjects with a 3T scanner . Three fiducial markers were placed in identical locations to the positions of the three coils used in the MEG recordings. With the aid of digital photographs, an accurate co-registration of the two data sets was obtained. All anatomical landmarks digitized in the MEG study were made identifiable in the (MRI). Pediatric brain templates developed by Imaging Research Center and MEG Center at CCHMC were used for group source comparison and visualization At the sensor level, MEG waveforms were manually averaged using DataEditor  and MEG Processor for identification of each temporal component after the removal of eye blinks and muscular activity. The averaged MEG data were preprocessed by removing the DC offset based on the pre-trigger baseline. An off-line high pass filter (1 Hz) and low pass filter (30 Hz) were applied for viewing. The latencies and amplitudes of each recognizable peak were measured for each subject.\u03b8 from the covariance C of the unaveraged MEG data and the lead field B\u03b8 using the equation: Synthetic aperture magnetometry (SAM) was used for localization of high-gamma oscillations of cortical source activity from the MEG data without averaging. SAM created a spatial filter for estimating source activity from the MEG data. SAM was an adaptive minimum-variance beamformer for which the output was a weighted linear sum of all the primary MEG sensors. At each coordinate voxel in source imaging, the SAM computed beamformer coefficients WThe effects of migraine on the latency and amplitude of neuromagnetic responses and SAM source power were analyzed with multiple analyses of variance (ANOVA). The fixed factors were the group  and age (categorized by quartiles). The dependent variables were latency, amplitude or SAM source power. Post-hoc comparison of two groups was performed with Student T-tests. The SAM values of voxels displaying the strongest signal power changes in the sensorimotor cortex were statistically compared with Student T-tests for migraine subjects and controls. The Pearson Correlation was used to identify the correlation in both groups between the corresponding latencies, amplitudes of neuromagnetic responses and the age. The differences of the correlation coefficients between the two groups  were determined by using the Fisher r-to-z transformation. The odd ratio of activity in brain areas other than the primary motor cortex among the migraine and control groups was analyzed with Fisher\u2019s exact tests. Significance was accepted at the level of 0.05 in all statistical analyses.As shown in As shown in The results of ANOVA analyses showed that the latency of MEFI following left finger movement was significantly affected by migraine (the group factor)  but not age. The latency of MEFII following left finger movement was not significantly affected by either migraine or age (p>0.05). The latency of MEF1 following right finger movement was significantly affected by both migraine  and age  while the latency of MEFII following left finger movement was significantly affected only by migraine  but not age. There was no significant interaction between group and age factors.In comparison to age-and-gender matched controls, the latencies of MEFI and MEFII responses (responding latency) elicited by left and right finger movements in children with migraine were significantly delayed (p<0.05). The quantitative measurements of the responding latency from finger movement in both children with migraine and controls are shown in The responding latencies in controls significantly correlated with age during the left finger movement , and the right finger movement . However, the responding latencies during left and right finger movement in the children with migraine did not significant correlation with age (p>0.05) . The difThere was no significant correlation between the responding latencies and the frequency of headache attack in the children with migraine (p>0.05).ANOVA analysis did not reveal significant effect of migraine and age factors on amplitude of MEFI and MEFII following right or left finger movement (p>0.05). There was no significant interaction between group and age factors in terms of the amplitude of MEFI and MEFII.In comparison to age-and-gender matched controls, there was no statistical difference in terms of the responding amplitudes from left finger movement or right finger movement. The quantitative measurements of the responding amplitude from both children with migraine and controls are shown in There was no significant correlation between responding amplitude from finger movement and age in both patients and controls (p>0.05). There was no significant correlation between responding amplitude and headache attack frequency in the patients (p>0.05).The MEG source imaging results were analyzed in an effort to determine the high gamma oscillations in the sensorimotor cortex . The higThe activation value elicited by right finger movement in the children with migraine was stronger than that in controls . The results of ANOVA analyses showed that the strength of activation value during left finger movement was significantly affected by migraine (the group factor) . The results of the present study have demonstrated that the abnormalities of motor function in children with migraine during headache attacks are noninvasively detectable using MEG and the abnormalities of motor cortical dysfunction can be characterized with the latency of MEFs evoked or elicited by finger movement One of the main findings in this study is that the positive correlation between responding latency and age in healthy children could not be found in children with migraine, showing the alteration of the developmental pattern in children with migraine compared with controls. The correlation efficient (or slope) differed between the two groups was also confirmed with the Fisher r-to-z transformation. Though aberrant brain activity in children with migraine during acute headache attacks has been found in the auditory, visual, and somatosensory systems It is unclear how migraine or headache attacks result in the delay of neuromagnetic response latency in the motor system in the developing brain. The aberrant latency observed in this study may be caused by the reductions in gray matter density in motor/premotor cortex Our results have demonstrated that neuromagnetic high gamma oscillation activation in children with migraine can be noninvasively measured with MEG. Our data have shown that high gamma (65\u2013150 Hz) oscillation activity is highly localized to the primary motor cortex in children with migraine and controls. The source locations indicated that these gamma oscillations were generated from the primary motor cortex that is consistent with previous reports Consistent with previous studies In conclusion, the abnormalities in the responding latency and source activation patterns suggest that there are neurophysiological changes in the motor cortices of children with migraine. The findings of this study may be helpful to further explore the underlying mechanisms of migraine and may facilitate the development of new therapeutic strategies in migraine treatment via alterations in cortical excitability. Recent reports have shown that normalization of cortical dysfunction may prevent and even cure migraine headache"}
+{"text": "Haemophilus influenzae (NTHi), a series of recent papers indicate that production and sensing of quorum signals are determinants of biofilm formation/maturation and persistence in vivo. In this mini-review I will summarize the current knowledge about quorum signaling/sensing by this organism, and identify specific topics for additional study.Quorum signals are diffusible factors produced by bacteria that coordinate communal responses. For nontypeable  Bacterial quorum sensing involves community-dependent regulation of bacterial gene expression by means of soluble signal molecules that are released in a density-dependent manner , and highlight potential areas for future study.Quorum sensing has been shown to coordinate group activities among bacterial populations, including formation and maturation of biofilm communities  in other strains  would be predicted to only have the Rbs system for uptake, orthologs of the Lsr system associated with quorum signal uptake and sensing in other bacterial species are found in 3/18 strains; in one of these the Rbs transporter is not found. Notably, in 3/18 strains there were no predicted sequences for either transporter. Thus, the potential exists for significant mechanistic diversity in quorum signal uptake  among different NTHi strains. We are currently addressing this important topic.More recently, the RbsB protein was shown to mediate uptake of DPD quorum signals for NTHi biofilms, recent work has demonstrated that NTHi quorum signals may impact Moraxella catarrhalis, an opportunistic pathogen that inhabits many of the same host environments within the airway. Growth of M. catarrhalis within a polymicrobial biofilm with nontypeable H. influenzae was shown to promote antibiotic resistance and persistence within the chinchilla infection model  is a subject for additional study. All sequenced NTHi strains have homologs to the QseB/C two-component signaling system that mediates sensing of AI-2/DPD signals for some other bacterial species; the role of these factors in sensing of quorum signal by NTHi is not presently clear. Finally, generation of NTHi mutant strains in which AI-2 quorum signal may be artificially induced would be of great help not only in clarifying the direct linkage of quorum signal to biofilm formation/maturation but also in defining the consequences of quorum sensing for the bacterial population.While present data clearly establish the importance of quorum signaling/sensing for some NTHi infection is not universally accepted  of biofilms in the persistence of NTHi bacteria in vivo. For example, prior to our demonstration of NTHi survival within neutrophil extracellular traps (NET; Hong et al., luxS mutants (Armbruster et al., Hi biofilms.It should also be pointed out that the relevance of biofilms for NTThe author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Despite the relevance of screening and brief intervention (SBI) to the prevention of dental pathology, particularly with tobacco and at-risk alcohol use, there has been little attention to the determination of its effectiveness in dental settings. Further, most SBI research efforts have focused on the treatment of single risk factors despite the fact that use of psychoactive substances tends to co-occur. There is also debate about the optimal timing of interventions for multiple risk behaviors, i.e., whether to intervene simultaneously or sequentially. This study was designed to test the efficacy of SBI practices aimed at dental patients who were both smokers and at-risk drinkers. Participants (N = 288) were randomized into four experimental conditions to test the efficacy of comparative interventions for tobacco and at-risk alcohol use when delivered separately and in combined forms, and to compare the effects of sequential versus simultaneous interventions. The results indicated that individuals in each of three active brief intervention (BI) groups  significantly reduced self-reported drinks per week and cigarettes per day compared with those in the wait-list control group. There was no advantage to the combined versus single-substance focused interventions as individuals changed both behaviors regardless of the treatment intervention received. No significant differences in self-reported drinks per week or cigarettes per day were found between those receiving simultaneous versus sequential interventions. These findings have implications for the design of BI aimed at multiple substance use and imply that no matter where a provider begins with respect to behavior-change focus, she or he may affect change in patients across multiple substance use behaviors."}
+{"text": "When we speak, we provide ourselves with auditory speech input. Efficient monitoring of speech is often hypothesized to depend on matching the predicted sensory consequences from internal motor commands (forward model) with actual sensory feedback. In this paper we tested the forward model hypothesis using functional Magnetic Resonance Imaging. We administered an overt picture naming task in which we parametrically reduced the quality of verbal feedback by noise masking. Presentation of the same auditory input in the absence of overt speech served as listening control condition. Our results suggest that a match between predicted and actual sensory feedback results in inhibition of cancellation of auditory activity because speaking with normal unmasked feedback reduced activity in the auditory cortex compared to listening control conditions. Moreover, during self-generated speech, activation in auditory cortex increased as the feedback quality of the self-generated speech decreased. We conclude that during speaking early auditory cortex is involved in matching external signals with an internally generated model or prediction of sensory consequences, the locus of which may reside in auditory or higher order brain areas. Matching at early auditory cortex may provide a very sensitive monitoring mechanism that highlights speech production errors at very early levels of processing and may efficiently determine the self-agency of speech input. Speaking includes the perception and monitoring of one's own speech for errors, which requires distinguishing self-generated acoustic signals from external signals The forward model framework applied to speech production suggests that a copy of speech motor commands (\u2018efference copy\u2019) allows for the prediction of sensory consequences of motor commands. This prediction is then compared to the actual sensory feedback, and mismatches between actual and predicted auditory signals are neurally encoded. Such a mismatch may occur in cases of speech production errors, but also when speech feedback quality is impaired. For example, this could be the case in a loud or noisy environment. For speech the comparison between predicted an actual verbal feedback makes it possible to distinguish our self-generated speech input from external speech, a function that is crucial for example in conversations.Brain imaging studies provide support for predictions of a forward model during speech production. Functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) studies in human participants presented modulated verbal feedback by manipulating the pitch of speech Findings from neurophysiological recordings in monkeys A confound in this In the current fMRI study, we investigate whether a match of predicted and actual feedback indeed results in net inhibition and as a consequence in reduced activity during speaking. Furthermore, we investigate the specificity of the predictions of the motor commands. We used a parametric design of feedback masking to address these two issues. During picture naming, participants either listened to their self-generated speech or they watched pictures and listened to their own pre-recorded speech on-line while a noise mask was superimposed at different intensity levels. Intensity levels ranged from zero to a maximum level at which participants could no longer hear their own speech. We predicted that unmasked verbal feedback resulted in decreased auditory cortex activity compared to listening to prerecorded speech. We further predicted that activity of auditory cortex increased parametrically with decreasing quality of verbal feedback during speaking. Finally, we predicted that the parametric noise mask did not alter auditory cortex activity during listening to pre-recorded speech.Eleven healthy volunteers  without any history of neurological or psychiatric disease participated in this study. They were right-handed according to the Edinburgh Handedness Inventory We used a 2 (task)\u00d74 (noise level) factorial blocked design see Figure 1The superimposed noise sound consisted of 1,500 ms of digital mono recording of pink noise . In the LIS conditions, the same pink noise recording was presented with the same timing as the PN conditions. Due to individual differences in voice and sensitivity to sound, the noise volume was determined separately for each participant before the actual scanning started. We adjusted the noise level in each individual subject based on an interactive procedure performed in the scanner before the actual experiment started. After being placed in the scanner, participants were asked to name pictures  while the noise was played. The volume of the noise was gradually increased until participants reported they could no longer hear themselves. Noise intensity was set at a level such that the subject consistently reported not to hear his/her own voice. The final noise volume was taken as maximum noise level intensity (level3). Intermediate intensity levels were obtained by decreasing the maximum level with 10 (level2) and 15 dB SPL (level1). This procedure resulted in an approximate level of noise intensity of 102 dB SPL on average (measured outside the scanner room). Given the subjects' own reports, the levels of noise employed, the approximate volume of subjects' voice (40\u201350 dB SPL), we may conclude that the subjects could not hear themselves in the loudest noise condition, irrespective of bone conduction. We next gave example trials of both speaking and listening conditions without added noise and asked the participants, again using an interactive procedure to subjectively equate levels of their own spoken input and the presented speech. Apart from the different noise levels used, the experimental protocol was similar to the one used in Christoffels et al. Each experimental block consisted of five trials of one of the eight conditions and lasted 15 s. Experimental blocks were interspersed with a fixation block that lasted 15 s, in which a symbolic instruction was visually presented for 1,500 ms to cue the task in the upcoming experimental block at 12 s after fixation block onset. Conditions were presented in four functional runs. Each run consisted of 24 experimental task blocks that alternated with fixation blocks. There were three repetitions of each condition per run, adding to a total of twelve repetitions of each condition for each participant. The block order varied pseudo-randomly between runs and run order was counterbalanced across participants. In all conditions, trials started with the presentation of a fixation cross for 1,550 ms, followed by the presentation of a picture for 1,000 ms. We chose stimulus presentation timing in such a way that the picture onset was 450 ms before the onset of the quiet interval between volume acquisitions (see Imaging Parameters) because participants needed at least this time to generate the response. In the PN conditions, participants responded in the next 1,000 ms of silence before the next functional volume was acquired. Presentation of the 1,500 ms noise was synchronized to picture presentation, which therefore covered the quiet interval between volume acquisitions. In the LIS conditions, presentation of the auditory picture word started 700 ms after picture presentation . See During each functional run, a digital audio recording was made of the participants' verbal responses. The audio-recordings indicated that the responses were of the same volume across the PN conditions.The pictures comprised twenty simple white-on-black line drawings, which were presented equally often in each condition across runs. Pictures from the Max Planck Institute for Psycholinguistics database were selected for high name agreement . Picture names corresponded to mono- and bisyllabic words of relatively high word frequency . For the LIS conditions, picture-naming responses were recorded for each participant in a separate session in a soundproof booth prior to the scanning session. This resulted in 20 unique auditory stimuli, which were presented in all listening conditions: i.e., one recording for each picture , for each participant.Prior to the fMRI experimental runs, a localizer run was administered with two PN conditions (PN0 and PN3), using ten novel pictures not used in the main experiment. In other respects the localizer run was identical to the experimental runs.3). We used a sparse sampling procedure for functional data 3) were acquired using a T1-weighted 3D \u201cmodified driven equilibrium Fourier transform\u201d (MDEFT) sequence .Imaging was performed on a 3 Tesla head scanner  located at the Maastricht Brain Imaging Center (M-BIC). Functional volumes were acquired using a T2*-weighted echoplanar sequence with blood oxygen level-dependent (BOLD) contrast  using a 2-way stereo headset. The headset served as ear defender but did not prevent participants from hearing their own voice in unmasked feedback conditions. Prior to scanning the volume of the noise was set individually via the audio system. An audio recording of the participant's responses was made for each run with a microphone attached to the headset. The presentation of each trial was synchronized with MR data acquisition by using an MR pulse to trigger each trial. Recordings of the participants' responses were checked for correctness in the speaking conditions and for lack of any responses in listening conditions, which revealed no naming errors and a very small number of missing responses (0.49%). During debriefing participants consistently reported that they did not hear their own voice during the loudest noise conditions, confirming that noise masking was successful.3. Pre-processed and Talairach-normalized functional volume time-series were used for the statistical analysis.Anatomical and functional images were analyzed using BrainVoyager QX . The first four functional volumes of each run were discarded to take the T1 saturation effect into account. The pre-processing steps of the functional images included slice scan time correction (using sinc interpolation), three-dimensional (3D) motion correction  to detect and correct for small head movements by spatially aligning the volumes of all functional  runs of each participant to the first volume of the first experimental run, linear trend removal and temporal high-pass filtering to remove drifts of three or fewer cycles per time course  For analysis of brain activity related to speech feedback we used a canonical hemodynamic response function  in a general linear model (GLM) Second, we analyzed the time series of the experimental runs of the localizer-tagged voxels using a 2 (PN and LIS)\u00d74  two-level RFX GLM. In the first level of the analysis, we calculated the beta coefficients for the eight conditions for each participant. In the second level, we tested the parametric contrast of  on the four levels of the PN condition across participants to specifically test for the predicted parametric pattern of decreasing BOLD signal amplitude with increasing quality of verbal feedback. Results were superimposed on the anatomical images and visualized using a Bonferroni-corrected threshold of p\u200a=\u200a0.05 to correct for multiple comparisons. We used a repeated measures analysis of variance (ANOVA) of the beta coefficients of the voxels that were significant for the contrast to test for the expected interaction between speaking and listening.3). Further, we found a second area in the right STG, located posterior to the first  and in left STG at or close to Heschl's sulcus . The average amplitudes of the maximum-statistic voxel time-locked to the PN and LIS blocks across the four noise levels revealed the predicted parametric pattern  (We also tested for the parametric effect in a whole-brain RFX analysis that was not restricted by the auditory cortex mask. We did not find any significant voxels for the parametric effect in this analysis.In the current study we parametrically manipulated feedback quality during self-generated and pre-recorded speech. We investigated the specificity of the predictions of the forward model of speech monitoring and assessed whether the consequences of a graded mismatch results in graded net inhibition or activation. We found that activity in early auditory cortical regions varied proportional to the parametric level of the noise mask during overt speech. The forward model prediction appears to be very specific. This suggests that modulation of cortical activity by the forward model may be a very sensitive mechanism, which may highlight even small speech production errors and may easily distinguish between self-generated speech and external speech.Modulation of activity in STG due to a feedback manipulation has been reported in previous studies We observed that only relatively small regions in the bilateral early auditory cortex responded to feedback parametrically. These regions are similar to the regions obtained by other studies using listening control conditions Our study revealed no parametric activity in brain areas outside of the auditory cortex. A number of previous monitoring studies did report activity in other brain areas when comparing normal versus altered feedback, such as the anterior cingulate cortex and supplementary motor area Our findings may have important implications for understanding speech-related deficits. For example, auditory activation by one's own voice in people who stutter has been found to be weaker compared to healthy control subjects An important implication of our study is that neurophysiological activity in auditory cortex is inhibited during unaltered speech feedback. Although we could not measure neurophysiological responses in our study, our results are consistent with electrophysiological recordings in humans and animals that showed inhibition of auditory neurons when listening to self-generated vocal sounds or speech In conclusion, using fMRI we were able to demonstrate a parametric attenuation of auditory cortex response in humans during overt speaking, visible as net reduction in BOLD response in auditory cortex. From our findings, it is clear that a forward model makes a very specific prediction of the expected self-generated auditory input resulting in neural cancellation in bilateral auditory cortex."}
+{"text": "Although domestic dogs play many important roles in rural households, they can also be an important threat to the conservation of wild vertebrates due to predation, competition and transmission of infectious diseases. An increasing number of studies have addressed the impact of dogs on wildlife but have tended to ignore the motivations and attitudes of the humans who keep these dogs and how the function of dogs might influence dog-wildlife interactions. To determine whether the function of domestic dogs in rural communities influences their interactions with wildlife, we conducted surveys in rural areas surrounding protected lands in the Valdivian Temperate Forests of Chile. Sixty percent of farm animal owners reported the use of dogs as one of the primary means of protecting livestock from predators. The probability of dog\u2013wild carnivore interactions was significantly associated with the raising of poultry. In contrast, dog\u2013wild prey interactions were not associated with livestock presence but had a significant association with poor quality diet as observed in previous studies. Dog owners reported that they actively encouraged the dogs to chase off predators, accounting for 25\u201375% of the dog\u2013wild carnivore interactions observed, depending on the predator species. Humans controlled the dog population by killing pups and unwanted individuals resulting in few additions to the dog population through breeding; the importation of predominantly male dogs from urban areas resulted in a sex ratios highly dominated by males. These results indicate that dog interactions with wildlife are related to the role of the dog in the household and are directly influenced by their owners. To avoid conflict with local communities in conservation areas, it is important to develop strategies for managing dogs that balance conservation needs with the roles that dogs play in these rural households. Dogs were domesticated over 14,000 years ago Our objective was to test whether the role and management of dogs influences the nature and frequency of dog-wildlife interactions. Using a survey of households in rural communities in Chile, we investigated the relationship between farm management practices and farmer-reported dog-wildlife interactions. In addition, the survey provided important information on dog management and demography, both relevant for improving dog population management in the future, particularly in wildlife conservation areas. By examining the role of dogs from a subsistence farming perspective, this study provides key insights into the role of the dog in farming and conservation. In so doing it elucidates the critical but socially sensitive tradeoff between dog as farm-protector and dog as wildlife threat.Oral informed consent was provided by an adult in each interviewed household in a standardized format. The general purpose of the survey was explained in Spanish to each research participant. Consent was obtained by having the interviewee state that they agreed to participate. The data was analyzed anonymously. The use of this survey and approach was approved by the Institutional Review Board at the University of Minnesota (1304E31141).The study area was located in the coastal range of the Chilean Temperate Forest between latitude 39\u00b041\u2032 S and 39\u00b058\u2032 S. Between 11 and 76 households were interviewed in 5 rural communities  adjacent to three different protected areas  see . The ecoPudu puda) and European hare (Lepus europaeus) and interference competition with the chilla fox  have been reported Leopardus guigna), puma (Puma concolor), Molina\u2019s hog-nosed skunk (Conepatus chinga), lesser grison , southern river otter (Lontra provocax), marine otter (Lontra felina), coypu (Myocastor coypus), invasive American mink (Neovison vison) Lycalopex fulvipes) Free-ranging dogs are common in the study area, and both predation on the Southern pudu  carnivores , referred to as dog-carnivore interaction, or b) herbivores or prey animals, particularly European hare and Southern pudus, referred to as dog-prey interaction. To assess the potential influence of the owner in the dog-carnivore interaction, we determined the percentage of dog owners who reported chasing off a particular predator species using dogs.We used generalized linear models with a logit link function to assess the probability of dog-carnivore and dog-prey interactions i.e. habitat composition around localities). Curi\u00f1anco (SITE) was used as the reference site because this locality was closest to the main city of Valdivia (We hypothesized that a higher number of dogs (DOGS) would increase the probability of dog-wildlife interactions at the household level. Site was used as a covariate because of differing proximity to urban areas at each locality  to determine the relative support for a model given the data for the set of candidate models. To account for model selection uncertainty we averaged the estimates of the coefficients of the main effect variables across all candidate models. To determine the relative importance of the predictor variables we calculated the sum of the Akaike weights over all of the candidate models in which the parameter of interest appeared To determine significant predictors for dog-carnivore and dog-prey interactions we used an information-theoretic approach. Models were created with all possible combinations of the predictor variables. For model selection purposes we utilized the Akaike information criterion corrected for small sample size (AICc). We calculated Akaike differences (\u0394AICc) and weights (We interviewed 146 households (approximately 59.6% of estimated households); only two people did not agree to participate. Of respondents, 123 had dogs and provided information about dog demography and management . We obsen\u200a=\u200a27) from nearby towns or localities was a more important input to the population than recruitment (12.4% versus 6.4%), and most of these imported dogs were males (P\u22640.005), and more female dogs were neutered than males . Exceptions include lesser grison and coypu that were observed by only two and nine respondents, respectively. Dog-wildlife interactions during the previous year were reported for all species  with theThe variables included in the best-ranked models (\u0394AICc <2) to explain the farmer-reported dog-carnivore interactions included POULTRY and DOGS. Averaged parameter estimate of presence of poultry in the household was positively associated with dog harassment and killing of carnivores see . AdequatAmong farm animal owners, the percentages of dog-carnivore interactions that were motivated by dog owners actively encouraging the dog to chase off a predator species were 75%, 62.5%, 38.9% and 25% for American mink, puma, fox and guigna, respectively. The only dog-prey interaction that was motivated by humans was the European hare, where 10% of the total interactions were encouraged by dog owners.This study investigated dog \u2013 wildlife interactions in the context of farm management and dog utility. In this study rural dogs were predominantly owned and free-roaming and their interactions with wildlife were significantly influenced by their role on the farm as well as by their management. Dogs appeared to interact with carnivores at the encouragement of their owners in the context of protecting livestock. In contrast, dog interactions with prey species were mostly undesirable from the farmer\u2019s perspective and seemed to be driven more by hunger and inadequate diet. The skewed dog sex ratio and high rate of externally-acquired dogs showed that the dog population was heavily managed by farmers, indicating a potential opportunity for informed interventions aimed at minimizing interactions with wildlife.Davlin and VonVille In our study we found that the farmer-reported interactions between dogs and wild animals were associated with their management and role on the farm. Interestingly, the models that best explained dog attacks on carnivores included poultry and the number of dogs, whereas the models that best explained interactions with prey included type of food provided and the number of dogs as the strongest predictors. Having a greater number of dogs seemed to be associated with a higher frequency of dog attacks on wild animals. This may be related to sampling effects  or to pack hunting behaviors. Silva-Rodriguez and Sieving The fact that dog-prey and dog-carnivore interactions were predicted by different variables has important implications for wildlife conservation. Minimizing impacts on prey will require different dog management strategies compared to impacts on carnivores in communities surrounding wildlife sanctuaries. In terms of dog-carnivore interactions, dogs that belonged to households with livestock had a higher likelihood of interacting with carnivores. In these circumstances, the use of dog breeds selected specifically for certain behavioral traits (i.e. shepherd or guardian breed dogs) could potentially minimize wildlife-human conflict and retaliatory killing of wildlife. Domestic dogs have been used to guard livestock against predator attacks throughout recorded human history Apteryx australis) out of a population of 900 within a six-week period The situation with dog-carnivore interactions is in contrast to the situation with dog-prey interactions as identified in this study. Here, dog-prey interactions are correlated with food quality and, for the most part, are perceived by the dog owner as negative and distracting the dog from the primary function of livestock and homestead protector. These behaviors are clearly detrimental to wildlife populations. For example, a study in New Zealand documented a single German shepherd that was estimated to have killed approximately 500 kiwis  in rural communities  [7], [43Table S1Summary of model selection to estimate the probability of owned dog interactions with carnivores and prey species. Models are ranked by AICc values. Columns include the number of variables (K), Akaike\u2019s Information Criterion (AICc), distance from the lowest AICc (\u0394 AICc), and Akaike\u2019s model weight (\u03c9i).(DOCX)Click here for additional data file.Questionnaire S1Dog\u2019s owner questionnaire.(DOCX)Click here for additional data file."}
+{"text": "The development of tissue-engineered vascular grafts for use in cardiovascular surgery holds great promise for improving outcomes in pediatric patients with complex congenital cardiac anomalies. Currently used synthetic grafts have a number of shortcomings in this setting but a tissue engineering approach has emerged in the past decade as a way to address these limitations. The first clinical trial of this technology showed that it is safe and effective but the primary mode of graft failure is stenosis. A variety of murine and large animal models have been developed to study and improve tissue engineering approaches with the hope of translating this technology into routine clinical use, but challenges remain. The purpose of this report is to address the clinical problem and review recent advances in vascular tissue engineering for pediatric applications. A deeper understanding of the mechanisms of neovessel formation and stenosis will enable rational design of improved tissue-engineered vascular grafts. Tissue engineering offers a strategy for constructing autologous grafts and thereby increasing the pool of potential autografts for use as vascular conduits . Using tResearch groups have used a variety of different approaches to develop tissue-engineered vascular grafts (TEVG). Several methods are now in use in the lab and at various stages of clinical development. These include in vivo engineering of blood vessels, using explanted native vessels as a living scaffold for tissue engineering, a variety of biodegradable polymeric scaffolds onto which cell types can be seeded, and scaffold-free approaches -9. The iScaffold materials must not only be biodegradable and non-immunogenic, but also must provide space for cell attachment while allowing for appropriate structural integrity until neotissue can form. Standard approaches involve the use of polymers of polyglycolic acid (PGA), polylactic acid (PLA), and poly e-caprolactone (PCL) in varying concentrations to meet the compliance specifications of the vascular system into which the graft is being introduced ,11. ElecMany cell types have been considered as possibilities for seeding vascular grafts ,15. SomeBone marrow mononuclear cells have been found to be a useful cell source as they are readily available from patients by means of bone marrow aspiration. There are several different approaches for purifying mononuclear cells from the bone marrow. The traditional approach has involved Ficoll centrifugal separation based on cell mass, but this takes several hours. A newer approach involves using a specially designed filter to separate out cells of a particular size . AlternaAlternative cell sources that might provide additional benefits include embryonic stem (ES) cells or induced pluripotent stem (iPS) cells, the latter offering a new autologous approach to developing pluripotent cells -19. All The traditional approach to placing cells on a scaffold for TEVG creation is static cell seeding, in which the patient's cells are pipetted directly onto a graft before being given several hours to attach. There are a number of recognized shortcomings of the static seeding method, including lower efficiency and inter-operator variability. A number of alternatives have been proposed, including dynamic, magnetic, vacuum, electrostatic, and centrifugal seeding . The leaIt will be important to have a deeper understanding of the mechanisms of neotissue formation and stenosis for an upcoming FDA approved clinical trial that is to be initiated at Yale School of Medicine to investigate the use of TEVGs in pediatric patients ,24. The Despite major advances in medical and surgical treatment, congenital heart disease (CHD) remains the leading cause of death due to congenital anomalies in the newborn period . Single An important cause of complications in EC TCPC is the conduit used to connect the inferior vena cava (IVC) to the pulmonary artery . Much ofBased on the success of animal studies, Shinoka performed a pilot clinical study in Japan in 2001 to evaluate the feasibility and safety of using TEVG as conduits for EC TCPC in patients with single ventricle cardiac anomalies -42. TwenComplications arising from the use of currently available synthetic vascular grafts are a leading cause of morbidity and mortality after congenital heart surgery . The lacIn order to better study the mechanisms of TEVG formation and stenosis in vivo, mouse models have been developed to recapitulate the results of the human trial. This approach includes a method for constructing sub-1 mm tubular scaffolds similar to the scaffold used in the clinical trial . These sA series of time course experiments using ovine and canine models demonstrated the stepwise morphologic changes and graft growth that occur when a seeded scaffold is implanted as a vascular interposition graft -6,49. ThExtensive histological and immunohistochemical (IHC) characterization has been performed to show the changes in TEVG over time in a murine model and these have documented the natural history of neovessel formation, the process of developing from a biodegradable tubular scaffold seeded with BM-MNC into a vascular conduit that resembles a native blood vessel. Six-months after implantation, the resulting neotissue possesses an internal monolayer of endothelial cells surrounded by inner smooth muscle layers, and an organized extracellular matrix. Some groups have hypothesized that stem cells within the bone marrow cell population differentiate into the cells of the neotissue . HoweverBased on these preliminary studies it has been hypothesized that seeded cells exert their effect via a paracrine mechanism by releasing chemokines that recruit host cells to the scaffold. These host cells are then critical for vascular neotissue formation and promote outward remodeling to maintain graft patency. IHC characterization demonstrated that the TEVG were initially infiltrated by host-derived monocytes and macrophages. Based on quantitative IHC data a correlation was noted between degree of early inflammatory response and graft patency. Specifically, the seeded grafts had significantly more macrophages in the early period compared to unseeded vascular grafts, suggesting that macrophage recruitment may be important in the process of promoting outward remodeling during neovessel formation. IL-1\u03b2 and MCP-1 were found to be produced in abundant quantity. Studies have been conducted on TEVG seeded with BM-MNC from either MCP-1 knockout mice or wild-type. These TEVG implanted into a SCID-beige vascular interposition graft model revealed that TEVG seeded with MCP-1 knockout BM-MNC developed significantly more wall thickening and luminal narrowing, suggesting that MCP-1 plays a critical role in inducing outward remodeling. Alginate microspheres were created and incorporated into the wall of the scaffold to provide controlled release of MCP-1. A study using this scaffold showed that an MCP-1 eluting scaffold can inhibit stenosis in the absence of BM-MNC seeding. These studies suggest that BM-MNC scaffolds transform into functional vessels by means of an inflammation-mediated process of vascular remodeling Figure  48]..48].According to this model, the seeded BM-MNC attach to the scaffold and begin to release MCP-1. Once implanted as an IVC interposition graft, MCP-1 recruits host monocytes, which infiltrate the scaffold and begin to direct or participate in vascular neotissue formation. This remodeling ultimately results in the formation of neovessels composed of a concentric layers of smooth muscle cells recruited from the neighboring native vessel wall embedded in an extracellular matrix with a monolayer of endothelial cells lining the luminal surface . Recent The findings of Shinoka's clinical trial in Japan are encouraging but also point to some of the possible issues with the use of vascular grafts in the pediatric population. Translational research groups can now return to animal models in the lab to improve TEVG outcomes . FurtherBM-MNC: Bone marrow mononuclear cells; CHD: Congenital Heart Disease; EC TCPC: Extra Cardiac Total Cavopulmonary Connection; IVC: Inferior vena cava; TEVG: Tissue-engineered vascular graft.CKB receives research funding from Gunze Ltd, the company that manufactured the scaffolds for the clinical trial. None of the funding for the work done in this manuscript was provided by Gunze Ltd.DRD and CKB both reviewed the literature and drafted the manuscript. Both authors read and approved the final manuscript.DRD is a Howard Hughes Medical Institute Medical Research Training Fellow and CKB is an Associate Professor of Surgery and Pediatrics and the Director of Tissue Engineering at Yale University School of Medicine."}
+{"text": "The male genital tract is suspected to constitute a viral sanctuary as persistent HIV shedding is found in the semen of a subset of HIV-infected men receiving effective antiretroviral therapy (HAART). The origin of this persistent shedding is currently unknown. Phylogenetic studies indicated that HIV in semen from untreated men arises from local sources and/or passive diffusion from the blood. We previously demonstrated in human and macaque low levels and localized infection of several semen-producing organs by HIV/SIV. Using a macaque model, this study investigates the impact of short term HAART (2\u20134 weeks) initiated either during the asymptomatic chronic stage or 4 h post-intravenous inoculation of SIVmac251 on the infection of male genital organs.in situ hybridization, SIV RNA+ cells were detected in all male genital tract organs from untreated and treated animals with undetectable blood viral load following HAART. Infected CD68+ myeloid cells and CD3+ T lymphocytes were detected pre- and post-HAART. In contrast, short term HAART initiated 4 h post-SIV exposure led to a drastic decrease of the male genital tissues infection, although it failed to prevent systemic infection. In both cases, HAART tended to decrease the number of CD3+ T cells in the male organs.Short term HAART during the chronic stage decreased blood viral load. No major impact of HAART was observed on SIV DNA levels in male genital organs using a sensitive nested PCR assay. Using Our results indicate that the established infection of male genital organs is not greatly impacted by short term HAART, whereas the same treatment during pre-acute phase of the infection efficiently impairs viral dissemination to the male genital tract. Further investigations are now needed to determine whether infection of male genital organs is responsible for long term persistent HIV shedding in semen despite HAART. Highly active antiretroviral therapy (HAART) significantly improved the clinical outcome among HIV-infected patients, leading in most patients to undetectable viremia (i.e. <50 copies/ml). Nonetheless, viral eradication is not achieved as HIV continues to replicate at low level in several tissues or remains under a latent form in several cellular and anatomical sites, called viral reservoirs. The male genital tract (MGT) is suspected to constitute such a pharmacological sanctuary or reservoir. Indeed persistent shedding of HIV RNA and infectious particles is detected in the semen of a subset of chronically-infected men under prolonged effective HAART in vivo due to the low level and localized nature of this infection Although the importance of tissue sanctuaries is being increasingly recognized Macaca fascicularis)  were imported from Mauritius Island and housed in the facilities of the Centre d'Energie Atomique (CEA) . Non-human primates (NHP) are used at the CEA in accordance with French national regulation and CEA facilities are fully authorized under the number B-92-032-02 for animal use and under the number 2005-69 for NHP breeding. These facilities are regularly inspected by national veterinary inspectors. The CEA is in compliance with ETS123 recommandations, Directive 86/609/CEE guidelines  for animal breeding and with Standards for Human Care and Use of Laboratory Animals . NHP are daily fed and inspected by animal caretakers who report directly to the veterinarians in charge of the animal facilities and animal welfare. The head of the veterinarian staff is empowered to interrupt the protocol in case of animal pathology or suffering. It should be stressed that none of the animal were specifically used for this work, since the male genital organs were collected at necropsy from animals that were euthanized in the course of other studies in vitro or in vivo) are suitable for the aims of the project (recommendation n\u00b01); the study is in the field of infectious diseases (recommendation n\u00b02); NHP are breed following the recommendation of the ETS123 and in accordance with the newly published European Directive (2010/63) (recommendation n\u00b09). The animals were used under the supervision of the veterinarians in charge of the animal facility and the protocols employed were reviewed by the Ethical Animal Committee of the CEA . The protocols and the use of male genital organs for the purpose of the work described herein were approved by the Ethical Animal Committee of the CEA under the number 11-005. The animals were sedated with ketamine chlorydrate , before virus injection, blood sample collection, and before receiving treatment, as previously described 20 adult male cynomolgus macaques  and PBMC-associated viral loads were assessed at several time points as previously described Total DNA and RNA were extracted from 2 distinct fragments of each tissue using RNeasy isolation kit or the QIAamp DNA Blood mini kit , respectively. RNA samples were depleted of contaminating DNA by DNase treatment  and submitted to reverse transcriptase reactions, using random hexamer primers  and M-MLV-Reverse Transcriptase  to generate cDNA. Total DNA from PBMCs was isolated using a commercial kit .et al5\u2032:CCTCCTCCAGGACTTGCATA and TatrevR1 5\u2032: CTGTTGATGACTGCCCGATA). A second nested PCR amplification (40 cycles) was performed with 3 \u00b5L amplimer and inner primers TatrevF2 5\u2032:GCAGCAATCCATATCCACAG and TatrevR25\u2032: GAGGGTCAGGCAGATGTTGT.A previously described sensitive nested PCR The following human mAbs and matching isotype controls were used at the indicated concentrations: anti-HLA-DR , anti-CD68 , anti-CD3  , anti-CD4 , anti-TIA-1 , with mouse IgG1 isotype control (Dako); anti-CD20 , with mouse IgG2a control (BD Biosciences). Immunohistochemistry was performed as previously described 35S-UTP-labeled riboprobe for the gag region of SIVmac251 Formalin-fixed, paraffin-embedded tissues were assayed for SIV RNA expression by radioactive and non radioactive ISH, using previously described The significance of the differences between values was evaluated using the appropriate non parametric test, as specified in the text or the figure legends. P<0.05 was considered statistically significant. Statistical analyses were performed using commercially available software .The pharmacokinetics of the three antiretroviral drugs used in the present study were previously assessed in blood plasma and PBMCs from cynomolgus macaques In situ hybridization for SIV gag RNA using either 35S or digoxygenin labeled riboprobes revealed positive cells in all the MGT tissues from both untreated and treated animals  had to be undertaken for all the male genital organs in order to measure the number of SIV+ cells. In accordance with the findings on viral DNA and with our previous findings on primary-infected macaques  animals . The senTo determine the nature of the infected cells, co-localization of SIV RNA+ cells with cell markers (CD3 for T lymphocytes and CD68 for myeloid cells) was performed. A mix of CD3+ and CD68+ infected cells was observed in MGT tissues from untreated animals, as we previously described In agreement with our published data We previously showed that AZT/3TC/IDV combination initiated 4 h post-intravenous inoculation of SIV and maintained for 4 weeks does not prevent systemic infection, although in all treated animals it prevents the peak blood viral load in vitro and in vivoThis study is the first to investigate the effect of HAART on the infection of semen-producing organs during chronic or acute stage. A number of observations in HIV+ men (reviewed in Persistent HIV shedding in semen has been shown to occur for a wide range of HAART regimens, including those based on the latest molecules, irrespective of the seminal concentrations achieved by the drugs Our results reveal that following 2 to 4 weeks administration of AZT/3TC/IDV during chronic stage, viral DNA and SIV RNA+ cells are still detected in the testis, epididymis, prostate and seminal vesicle of treated macaques with decreased systemic infection. Although precise quantification was hampered by the low level and focal nature of the infection, we did not observe any major impact of HAART on MGT organs infection. This contrast with our previous findings of a strong decrease of both viral DNA and RNA in the colon following the same HAART regimen and duration in situ hybridization for SIV and immunohistochemistry for cell markers, we confirmed the presence of infected macrophages and T lymphocytes in the MGT organs of untreated animals. In treated animals, both infected macrophages and lymphocytes were also detected. Despite our extensive screening of a large number of tissue sections, the relative proportion of infected macrophages and T lymphocytes could not be assessed, as accurate quantification was impaired by the low number of infected cells detected. However, the fact that productively infected CD3+ T cells were still detected at the end of the 4 week treatment period, and that the SIV DNA levels and SIV RNA+ cell number did not appear to be affected by the treatment, suggest that poor penetration of the antiretroviral drugs may also be a factor. Whether a longer and intensified treatment has more impact on male genital organs infection in our model will be tested in forthcoming experiments.The persistent detection of SIV nucleic acids in the genital organs of the treated macaques observed in our study could be due to either the existence of infected cells that would keep producing virus in the face of optimal drug concentrations during the 2\u20134 week period, or to low drug penetration in the organs. Unlike productively-infected CD4+T lymphocytes which are short-lived and usually rapidly eliminated following HAART In men receiving HAART, drastic decreases in both blood and seminal viral loads are usually observed within one month post treatment initiation versus untreated animals. This reduction did not appear to be linked to the organ infection levels, as the latter were not significantly different before/after treatment and between the organs. Therefore, we hypothesize that the reduced number of inflammatory infiltrates in MGT tissues may represent reduced systemic immune activation and T cell migration, in association with the lower blood viral loads in the treated animals Migration of T cells to non lymphoid tissues following virus-driven T lymphocytes expansion is a feature of chronic viral infection We previously reported that 2 weeks post intravenous inoculation, SIV infected all MGT organs of cynomolgus macaques and that the viral load in MGT organs during the acute stage was much higher than during the chronic stage In humans and macaques infected through sexual routes, productive systemic infection begins around 10 days following amplification at transmission site and in local lymphoid tissues In conclusion, we showed for the first time that short term HAART has no major effect on the infection of MGT organs when initiated during the chronic stage, whereas post-exposure treatment drastically decreases their infection. These results indicate that persistent HIV shedding in men receiving HAART with undetectable blood viral load may arise from viral production in several semen producing organs. Our work opens several perspectives. Studies on longer treatment duration, intensification and measurement of antiretroviral drugs in male genital organs are now needed to assess whether the MGT constitutes a long term reservoir. In addition the comparison of viral load and strains in semen with that in male genital organs during HAART will be crucial to decipher further the origin of HIV persistence in semen. These issues are currently under investigation in our laboratory."}
+{"text": "Threading of DNA through the central channel of a replicative ring helicase is known as helicase loading, and is a pivotal event during replication initiation at replication origins. Once loaded, the helicase recruits the primase through a direct protein\u2013protein interaction to complete the initial \u2018priming step\u2019 of DNA replication. Subsequent assembly of the polymerases and processivity factors completes the structure of the replisome. Two replisomes are assembled, one on each strand, and move in opposite directions to replicate the parental DNA during the \u2018elongation step\u2019 of DNA replication. Replicative helicases are the motor engines of replisomes powered by the conversion of chemical energy to mechanical energy through ATP binding and hydrolysis. Bidirectional loading of two ring helicases at a replication origin is achieved by strictly regulated and intricately choreographed mechanisms, often through the action of replication initiation and helicase-loader proteins. Current structural and biochemical data reveal a wide range of different helicase-loading mechanisms. Here we review advances in this area and discuss their implications. The ability to replicate is a universal characteristic of all living organisms. To produce descendants that are exact copies of the parental cell, the genetic information must be copied and transmitted from generation to generation. With the exception of a few viruses, the DNA double helix is the carrier of genetic information within the nucleotide sequences. Separation of the two strands by ubiquitous replicative DNA helicases reveals the parental nucleotide sequences for DNA polymerases to copy into new strands. Replicative helicases are closed ring structures with single DNA strands threaded through the ring during replication initiation via a process known as helicase loading. Although the problem of threading a very long linear DNA molecule through a circular helicase ring is fundamentally the same in all living organisms, a remarkable variety of loading mechanisms have evolved utilizing the basic principles of ring opening or ring assembly. Here we review recent advances in our understanding of helicase loading mechanisms in different organisms . We discoriC) where specialized replication initiator proteins bind to cause local melting of the DNA double helix and enable the loading of ring helicases. Replication initiators from all domains of life belong to a group of proteins known as AAA+ (ATPases Associated with various cellular Activities) proteins  prevents the formation of an active nucleoprotein complex, suggesting its importance in DnaA filament formation (E. coli) reduces the ATPase activity but does not prevent DnaA-ATP oligomerization , within the oriC. Recent structural data revealed that the DnaA filament can also wrap around single-stranded DNA using a continuous network of alternating \u03b13/\u03b14 and \u03b15/\u03b16 helices within the central cavity of the filament  to load the replicative helicase DnaC (not to be confused with the E. coli helicase-loader DnaC) in a two-protein strategy  domains  presenting an ATP-bound active site in the open state, defined as the ATP-end, and the opposite end of the filament terminates with a protein molecule presenting the arginine finger of Box VII, defined as the R-end  binding site in the E. coli oriC interrupts the series of DnaA binding boxes and likely disrupts the formation of a contiguous DnaA filament within the oriC extending through into the DUE, as suggested in the A. aeolicus helicase loading mechanism  or a spiral DnaC structure is not essential for DnaB ring opening.The A strand . This is hexamer  and therG. kaustophilus helicase-loader DnaI  SV40 (Simian Virus 40) DNA helicase has been suggested to function as a dodecamer (Origin-Binding Domain) domains, N-terminal relative to the helicase domain. OBDs bind to four pentanucleotide repeats within the SV40 core ori sequence  at its N-terminus  and the DNA-Binding Helix (DBH), that individually bind only one of the two strands. The DBL extensively interacts with the DNA while the DBH has more limited interactions with the DNA and dissociates during strand separation. The DBDs also combine with a DNA-binding activity residing on the helicase domains to melt the ori and load two head-to-head hexamers each encircling the opposite strand  and Cdc6 directed loading of archaeal and eukaryotic MCM double hexamers, the underlying loading mechanism of MCM is drastically different (reviewed in Xenopus egg extracts (Ring helicases often form head-to-head double hexamers (dodecamers) and some reports suggest that the dodecamer is the functional oligomer. One such helicase is the eukaryotic MCM replicative helicase. Although the formation of a dodecamer during SV40 LTag and E1 loading is reminiscent of the ORC  different architectures of replication origins requiring either specialized sets of different loading proteins or no loading proteins at all, (ii) subtle differences in helicase structures and mechanisms often associated with additional activities such as primer synthesis during replication, (iii) strict regulatory requirements to comply with complex life cycles, or (iv) genome economy when additional genes coding for accessory loading proteins need to be eliminated."}
+{"text": "Alternative splicing is a highly regulated process that greatly increases the proteome diversity and plays an important role in cellular differentiation and disease. Interactions between RNA-binding proteins (RBPs) and pre-mRNA are the principle regulator of splicing decisions. Findings from recent genome-wide studies of protein\u2013RNA interactions have been combined with assays of the global effects of RBPs on splicing to create RNA splicing maps. These maps integrate information from all pre-mRNAs regulated by single RBPs to identify the global positioning principles guiding splicing regulation. Recent studies using this approach have identified a set of positional principles that are shared between diverse RBPs. Here, we discuss how insights from RNA splicing maps of different RBPs inform the mechanistic models of splicing regulation. Technological advances in the past decade have created the unprecedented ability to explore alternative splicing in a genome-wide manner. As the depth of analysis has increased, the estimated proportion of human genes that produce alternative mRNA isoforms has increased, from 35% in 1999 Down syndrome adhesion molecule (Dscam) transcript in Drosophila melanogasterDscam transcript, which contains three clusters of 12, 48 and 33 mutually exclusive exons that can theoretically generate 38016 different alternative isoforms. A small molecule binding to an RNA riboswitch affects alternative splicing in the fungus Neurospora crassa by inducing changes in pre-mRNA structure There are many ways to regulate alternative splicing. RNA\u2013RNA interactions between distal sites are important for the regulation of mutually exclusive exons of the Genome-wide studies play a key role in understanding the regulation of alternative splicing in disease and normal physiology. Initial bioinformatic studies have identified putative regulatory RNA motifs by comparing exons with different splice site strengths in vivo splicing regulation have also been identified experimentally. Even though these elements most often map to intronic regions that are rapidly degraded upon splicing completion, they can be identified by the analysis of protein\u2013RNA interactions using UV crosslinking and immunoprecipitation  silence exon inclusion by antagonising the SR proteins To understand the general principles of splicing regulation, it is necessary to identify protein\u2013RNA interactions with high resolution in a genome-wide manner. However, a single genome-wide data set rarely provides significant insight into splicing regulation on its own. Partly, this is because protein-binding sites are most often located far from alternative exons, as shown by the first analyses of Nova\u2013RNA interactions using CLIP The success of genome-wide studies lies in the integration of multiple, independent data sets Studies of the polypyrimidine tract-binding protein (PTB) illustrate the need for independent protein\u2013RNA interaction and splicing data sets when building RNA splicing maps. Initially, CLIP data were used to identify interaction sites and select target exons to collect splicing data by RT-PCR analysis. This RNA splicing map indicated that PTB primarily silences exon inclusion when bound downstream of exons Drosophila orthologue of Nova, shows that position-dependent regulatory effects are highly conserved The similarity of the RNA splicing maps of the mouse Nova and of Pasilla, the The RNA splicing maps of hnRNP C and TIA proteins appear more restricted than other RBPs. hnRNP C exclusively silences exon inclusion when binding near the alternative exon a. By conTIA proteins enhance exon inclusion when binding downstream of alternative exons, with no evidence for silencing when binding to other sites near the alternative exons in vitro and in vivo analysis of introns that require hnRNP A1 or hnRNP H for efficient splicing showed that these proteins need to bind both ends of the intron to stimulate splicing The Heterotypic interactions between hnRNP A1 and hnRNP H could stimulate splicing by promoting RNA looping What do the common principles identified by RNA splicing maps tell us about the mechanisms of splicing regulation? The RBPs that share positional principles are not homologous to each other. Often they bind RNA with different domains such as KH in Nova, zinc finger in Mbnl and RRM in the other RBPs discussed above. The silencing effects, when binding near the branch point, splice sites or within the exon, could be explained by competition with core spliceosome components or SR proteins Further analyses of RNA splicing maps and other RBPs are likely to identify global, position-based splicing effects that differ from those determined so far. For example, SR proteins enhance exon inclusion by binding within the exon Above, we discussed the splicing effects of RBP binding sites proximal to alternative exons. The analysis of CLIP data and RNA splicing maps also suggests that RBPs can regulate splicing when binding only at positions distal to alternative exons Recently, TIA proteins, like Nova proteins, were found to silence exon inclusion when binding to the preceding exon Splicing decisions result from the integration of multiple variables, primarily changes in the expression of RBPs, changes in RBP activity because of signalling pathway-induced post-translational modifications The recruitment model proposes that certain splicing regulators, particularly those containing arginine-rich, positively charged regions (such as SR proteins), bind the hyperphosphorylated, negatively charged C-terminal domain of elongating RNA polymerase II (Pol II CTD) FOS gene Chromatin immunoprecipitation experiments have shown that the treatment of formaldehyde crosslinked cell lysate with RNase releases SR proteins from the E1a gene Finally, the splicing kinetics model proposes that the temporal window available for RBP assembly on nascent transcripts can affect splicing choice. This temporal window is determined by the kinetics of transition from the H to A splicing complexes. This model was first proposed to explain the effect of an elongation-defective mutant of RNA Pol II on the splicing of alternative 5\u2032 splice sites in the adenovirus Nova1\u2013/\u2013 Nova2\u2013/\u2013 brains have shown that the splicing effects of Nova proteins are restricted to the intron containing the Nova-binding sites To conceptualise how RBP binding at different positions affects splicing decisions, we can consider the splicing decision as a competition between commitment to three possible splicing pathways: exon skipping, upstream intron splicing and downstream intron splicing. The upstream and downstream intron splicing pathways both lead to exon inclusion. Splicing intermediates in Asymmetric splicing decision making could play a role in the previously described models. For instance, slow transcriptional elongation promotes the splicing of the downstream intron of fibronectin exon 33 We have discussed how understanding the global principles behind the regulation of alternative splicing can provide insights into the mechanisms of splicing regulation. To date, RNA splicing maps have only been determined for individual RBPs. It is clear, however, from individual alternative exons that their splicing is regulated by multiple RBPs acting either competitively or cooperatively The development of RNA splicing maps from the combination of genome-wide protein\u2013RNA interaction data with splicing profiles has allowed broad, position-based principles for splicing regulation to be inferred for a few RBPs. As the resolution and quantitative capacity of these methods improves with the development of iCLIP and RNA-seq, the ability to define these rules becomes more precise. At the same time, precise definition of these rules will help identify exons and RBPs that deviate from the basic splicing models. These deviations will help us better understand how multiple variables contribute to the regulation of splicing. To understand such integrated regulation, RNA splicing maps will need to be combined with analyses of other variables that contribute to alternative splicing decisions, such as splicing kinetics, transcriptional elongation speed, chromatin, the post-translational modifications of RBPs, RNA structure and the interactions of pre-mRNA with other noncoding RNAs. Finally, biochemical and kinetic studies of the insights gained from genome-wide analyses will be required to fully understand the mechanisms of splicing regulation."}
+{"text": "In clinical practice, out-toeing is often linked with an increased eversion and an increased medial pressure distribution. However, in the literature, there is little evidence for this relationship. On the other hand, as an increased eversion and an increased medial pressure distribution have been detected as risk factors for exercise-related lower leg pain (ERLLP) ,2, and i3D gait kinematics combined with plantar pressure profiles were collected from 400 healthy physical education students. After this evaluation, all sports injuries were registered by a sports physician during 3 years. Relationship between foot progression angle and the amount of eversion and the medio-lateral pressure distribution were tested with Pearson correlation. Cox regression analysis was used to investigate the effect of the foot progression angle on the development of ERLLP.R=.121) and the medio-lateral pressure distribution (R=.116). Cox regression analysis showed no significant differences for the foot progression angle between the injured and uninjured subjects.Forty-six subjects developed ERLLP and 29 of them developed bilateral symptoms thus giving 75 symptomatic lower legs. Bilateral lower legs of 167 subjects who developed no injuries in the lower extremities served as controls. Pearson correlation showed no significant correlation between the foot progression angle and the eversion excursion (The findings of this study suggest that the foot progression angle is not a risk factor for ERLLP as the foot progression angle is not related to the amount of eversion and the medio-lateral pressure distribution."}
+{"text": "Complex intervention guidance advocates pilot trials and feasibility studies as part of a phased approach to development, testing and evaluation of healthcare interventions. In this paper an example of a feasibility study and pilot trial for a randomised controlled trial (RCT) of pelvic floor muscle training for prolapse is used to explore challenges for progression to main trial.A four-centre feasibility study including pilot trial aiming to randomise 50 women with prolapse of any type or stage and who had had a pessary successfully fitted. We used published methodological categories to classify and analyse the problems that arose in our feasibility study. Subsequently we sought to locate potential solutions that might minimise the trade-off between an explanatory and pragmatic main trial.Algorithm for Decision-making after Pilot and feasibility Trials) which we subsequently used as a guide. The algorithm sought to: 1) encourage systematic identification and appraisal of problems and potential solutions; 2) improve transparency of decision-making processes; and 3) reveal tensions that exist between choices which lead to a pragmatic versus explanatory trial.The feasibility study pointed to significant potential problems in relation to participant recruitment, features of the intervention, acceptability of the intervention to participants and outcome measurement. Finding minimal evidence to support our decision-making regarding the transition from feasibility work to a trial, we developed an algorithm (ADePT; We have developed a decision-support tool that may aid future researchers to identify the most appropriate solutions to problems identified within pilot and feasibility studies."}
+{"text": "Recently introduced targeted drug delivery systems induce viral lytic gene expression and therefore require more sensitive method to quantify viral as well as cellular gene expression.Epstein Barr Virus (EBV) plays a significant role as a cofactor in the process of tumorigenesis and has consistently been associated with a variety of malignancies. EBV encoded RNAs (EBER1 and EBER2) are the most abundant viral transcripts in latently EBV-infected cells and their role in viral infection is still unclear. Formalin Fixed Paraffin Embedded (FFPE) tissues of surgically removed carcinoma biopsies are widely available form but have never been exploited for expressional studies previously in Pakistan. Immunohistochemistry (IHC) and Eight (8) lymphoma samples were screened to detect the EBV genome. Qualitative and quantitative expression of EBV Encoded RNAs  and anti-inflammatory cytokine (interleukin-10) in FFPE EBV positive lymphoma tissue samples were then analysed by using Reverse transcriptase Polymerase Chain Reaction (RT-PCR) and Real Time Polymerase Chain Reaction (qRT-PCR), respectively.In this study we have successfully quantified elevated expressional levels of both cellular and viral transcripts, namely EBER1, EBER2 and anti-inflammatory cytokine (IL-10) in the FFPE Burkitt's lymphoma (BL) specimens of Pakistani origin.These results indicate that FFPE samples may retain viral as well as cellular RNA expression information at detectable level. To our knowledge, this is first study which represents elevated expressional levels of EBER1, EBER2 and IL-10 in FFPE tissue samples of Burkitt's lymphoma in Pakistan. These observations will potentially improve current lacunas in clinical as well as diagnostic practices in Pakistan and can be further exploited to develop new strategies for studying cellular and/or viral gene expression. Epstein-Barr virus (EBV)  is a ubiBamHIA region of the viral genome namely BART transcripts .The amplified product was purified by using PureLink\u2122 Gel Extraction Kit  according to the manufacturer's instructions. The purified product was sequenced by using Genetic Analysis System Beckman Coulter (CEQ-8000 USA). These sequences were published in Genbank, EMBL and DDBJ  viral RNAs from the FFPE Burkit's lymphoma tissue samples. These results positively suggest the use of FFPE samples for research, more prominently in viral RNA profiling studies. In addition to that, we have also developed a real time PCR based assay in which a novel comparison of viral and cellular RNA is illustrated  lymphoma tissues. These results suggested that RNA isolated from FFPE samples preserve the majority of the characteristic expression. In addition to that elevated expression of anti-inflammatory cytokine (IL-10) was observed in the EBV+ (positive) samples in comparison with EBV- samples (undetectable or negligibly low levels of expression) which indicate its relevance with viral persistence in EBV transformed tumour cells. These studies will open novel avenues to study cellular and/or viral gene expression and will introduce new biomarkers and strategies to improve clinical as well as diagnostic practices in Pakistan.Expression of both viral RNA and cellular RNA are significantly high, in comparison with normal EBVThe authors declare that they have no competing interests.TIS have contributed to the conception, design, acquisition, analysis and interpretation of data and have been involved in drafting the manuscript as well as revising it critically for important intellectual content to be published and have given final approval of the version to be published.IQ has contributed to the critical revision of important intellectual content and has given final approval of the version to be published as well as provided supervision during this work."}
+{"text": "To make sense out of gene expression profiles, such analyses must be pushed beyond the mere listing of affected genes. For example, if a group of genes persistently display similar changes in expression levels under particular experimental conditions, and the proteins encoded by these genes interact and function in the same cellular compartments, this could be taken as very strong indicators for co-regulated protein complexes. One of the key requirements is having appropriate tools to detect such regulatory patterns.We have analyzed the global adaptations in gene expression patterns in the budding yeast when the Hsp90 molecular chaperone complex is perturbed either pharmacologically or genetically. We integrated these results with publicly accessible expression, protein-protein interaction and intracellular localization data. But most importantly, all experimental conditions were simultaneously and dynamically visualized with an animation. This critically facilitated the detection of patterns of gene expression changes that suggested underlying regulatory networks that a standard analysis by pairwise comparison and clustering could not have revealed.The results of the animation-assisted detection of changes in gene regulatory patterns make predictions about the potential roles of Hsp90 and its co-chaperone p23 in regulating whole sets of genes. The simultaneous dynamic visualization of microarray experiments, represented in networks built by integrating one's own experimental with publicly accessible data, represents a powerful discovery tool that allows the generation of new interpretations and hypotheses. In the current post-genomic era, an increasing amount of data is generated by the application of high-throughput technologies. Expression profiling analyses using DNA microarray approaches are extensively used to study global changes in gene expression patterns of multiple cell types and tissues under different conditions. Moreover, there are publicly accessible databases containing the experimentally established DNA binding sequences for transcription factors (TF). To identify interaction partners of a protein of interest, several large-scale methods such as yeast two-hybrid screens, tandem affinity purification followed by mass spectrometric analyses, and protein chips are commonly used. Proteome-wide studies to identify protein-protein interaction (PPI) partners for many proteins have resulted in several publicly available and well-curated databases, which can be used to elucidate and to explore PPI networks. The integration of this large amount of data from many sources in a comprehensive and insightful way requires the use of computational tools to combine, to manipulate and to visualize the information -3. VisuaSaccharomyces cerevisiae)  cellular component) in cellular compartment layers using the plugin Cerebral [PPI network generation and expression data integration using Cytoscape  in the presence and/or absence of p23 . Note that radicicol has been widely used in budding yeast as a specific pharmacological inhibitor of Hsp90. Hsp90 is the only known target of radicicol in vivo in this organism, although it should not be ignored that it has been shown to bind a few other proteins with a related ATP binding fold in vitro or in other organisms [i.e., proteins), and edges represent physical interactions of the proteins or correlations of expression levels of the respective genes across all given conditions. Furthermore, the intracellular localization for each node (protein) is obtained from the Gene Ontology (GO) database [Using a microarray experiment, we evaluated gene expression responses in yeast when the function of Hsp90 was disrupted by radicicol  or \"dynamically\"  Figure . PerformWhereas the more or less multidimensional dependency graphs generated by these binary comparisons are useful and yield interesting results, some patterns might only become apparent by investigating the data of all performed experiments simultaneously as highlighted in Figure Thus, it is the visual impression of animated color changes of clusters of nodes, which allows one to identify potential regulatory patterns. The order of the color changes for a given node is determined by the order of the graphs used to generate the animation. Whereas the order is irrelevant for our particular data set, we do not exclude that it may be important in others . Amongst all of the genes represented in the full data set, it is of course particularly those whose expression changes substantially (indicated by the red and green nodes) across all pairwise comparisons that define patterns  showed enrichment in functional terms associated with iron and ion homeostasis, whereas functions of those belonging to pattern B  fell into a mitochondrial function (respiration), kinase activity dependent on cyclins and progression through the cell cycle. Genes from pattern C  exhibit GO terms related with conjugation processes, catabolism of nitrogen sources and response to stress. The concomitant absence of Hsp90 and p23 induces the expression of stress-related proteins like Ssa4 (encoding one of the cytosolic Hsp70 isoforms), Hsp26, Hsp31, Ddr2. Interestingly, both chaperones might have a positive influence on the expression of genes (pattern D) related with mitochondrial protein import and carbon source metabolism , a phosphatase that positively regulates the Hsp90 chaperone machinery (Ppt1) [HSP82 encoding one of the two cytosolic isoforms) and for its co-chaperones Aha1, Cpr6 and Sti1 belong to this group of genes, thus implying that their regulation is not affected by the interplay between Hsp90 and p23.Following the identification of different patterns by this animation, we extracted the genes corresponding to each pattern  , or chroHere we have presented a novel approach to integrate experimental gene expression profiles with already available data. We were able to combine our own data from microarray experiments and data from public databases of PPIs, TF, and GO in a rational manner to address the global biological functions of Hsp90 and p23 both individually and, perhaps more interestingly, concomitantly.Several key features of our working pipeline Figure  allowed http://www.picard.ch/downloads/downloads.htm), we can speculate that Hsp90 and its co-chaperones maintain kinases responsible for Msn2/Msn4 repression in a functional state thereby regulating the stress-response  illustrate PPIs retrieved from public databases (with experimentally determined interactions; see Additional File Click here for file"}
+{"text": "Su Golder and colleagues carry out an overview of meta-analyses to assess whetherestimates of the risk of harm outcomes differ between randomized trials andobservational studies. They find that, on average, there is no difference in theestimates of risk between overviews of observational studies and overviews ofrandomized trials. There is considerable debate as to the relative merits of using randomisedcontrolled trial (RCT) data as opposed to observational data in systematicreviews of adverse effects. This meta-analysis of meta-analyses aimed toassess the level of agreement or disagreement in the estimates of harmderived from meta-analysis of RCTs as compared to meta-analysis ofobservational studies.Searches were carried out in ten databases in addition to reference checking,contacting experts, citation searches, and hand-searching key journals,conference proceedings, and Web sites. Studies were included where a pooledrelative measure of an adverse effect (odds ratio or risk ratio) from RCTscould be directly compared, using the ratio of odds ratios, with the pooledestimate for the same adverse effect arising from observational studies.Nineteen studies, yielding 58 meta-analyses, were identified for inclusion.The pooled ratio of odds ratios of RCTs compared to observational studieswas estimated to be 1.03 .There was less discrepancy with larger studies. The symmetric funnel plotsuggests that there is no consistent difference between risk estimates frommeta-analysis of RCT data and those from meta-analysis of observationalstudies. In almost all instances, the estimates of harm from meta-analysesof the different study designs had 95% confidence intervals thatoverlapped . In terms of statistical significance, innearly two-thirds , the results agreed (both studiesshowing a significant increase or significant decrease or both showing nosignificant difference). In only one meta-analysis about one adverse effectwas there opposing statistical significance.Empirical evidence from this overview indicates that there is no differenceon average in the risk estimate of adverse effects of an interventionderived from meta-analyses of RCTs and meta-analyses of observationalstudies. This suggests that systematic reviews of adverse effects should notbe restricted to specific study types.Please see later in the article for the Editors' Summary Whenever patients consult a doctor, they expect the treatments they receiveto be effective and to have minimal adverse effects (side effects). Toensure that this is the case, all treatments now undergo exhaustive clinicalresearch\u2014carefully designed investigations that test new treatmentsand therapies in people. Clinical investigations fall into two maingroups\u2014randomized controlled trials (RCTs) and observational, ornon-randomized, studies. In RCTs, groups of patients with a specific diseaseor condition are randomly assigned to receive the new treatment or a controltreatment, and the outcomes  of the two groups of patients arecompared. Because the patients are randomly chosen, differences in outcomesbetween the two groups are likely to be treatment-related. In observationalstudies, patients who are receiving a specific treatment are enrolled andoutcomes in this group are compared to those in a similar group of untreatedpatients. Because the patient groups are not randomly chosen, differences inoutcomes between cases and controls may be the result of a hidden sharedcharacteristic among the cases rather than treatment-related .Although data from individual trials and studies are valuable, much moreinformation about a potential new treatment can be obtained bysystematically reviewing all the evidence and then doing a meta-analysis. A systematic review uses predefinedcriteria to identify all the research on a treatment; meta-analysis is astatistical method for combining the results of several studies to yield\u201cpooled estimates\u201d of the treatment effect (the efficacy of atreatment) and the risk of harm. Treatment effect estimates can differbetween RCTs and observational studies, but what about adverse effectestimates? Can different study designs provide a consistent picture of therisk of harm, or are the results from different study designs so disparatethat it would be meaningless to combine them in a single review? In thismethodological overview, which comprises a systematic review andmeta-analyses, the researchers assess the level of agreement in theestimates of harm derived from meta-analysis of RCTs with estimates derivedfrom meta-analysis of observational studies.The researchers searched literature databases and reference lists, consultedexperts, and hand-searched various other sources for studies in which thepooled estimate of an adverse effect from RCTs could be directly compared tothe pooled estimate for the same adverse effect from observational studies.They identified 19 studies that together covered 58 separate adverseeffects. In almost all instances, the estimates of harm obtained frommeta-analyses of RCTs and observational studies had overlapping 95%confidence intervals. That is, in statistical terms, the estimates of harmwere similar. Moreover, in nearly two-thirds of cases, there was agreementbetween RCTs and observational studies about whether a treatment caused asignificant increase in adverse effects, a significant decrease, or nosignificant change (a significant change is one unlikely to have occurred bychance). Finally, the researchers used meta-analysis to calculate that thepooled ratio of the odds ratios  of RCTscompared to observational studies was 1.03. This figure suggests that therewas no consistent difference between risk estimates obtained frommeta-analysis of RCT data and those obtained from meta-analysis ofobservational study data.The findings of this methodological overview suggest that there is nodifference on average in the risk estimate of an intervention's adverseeffects obtained from meta-analyses of RCTs and from meta-analyses ofobservational studies. Although limited by some aspects of its design, thisoverview has several important implications for the conduct of systematicreviews of adverse effects. In particular, it suggests that, rather thanlimiting systematic reviews to certain study designs, it might be better toevaluate a broad range of studies. In this way, it might be possible tobuild a more complete, more generalizable picture of potential harmsassociated with an intervention, without any loss of validity, than byevaluating a single type of study. Such a picture, in combination withestimates of treatment effects also obtained from systematic reviews andmeta-analyses, would help clinicians decide the best treatment for theirpatients.http://dx.doi.org/10.1371/journal.pmed.1001026.Please access these Web sites via the online version of this summary atclinicalresearch; the UK National Health Service Choices Website also has a page on clinical trials and medical researchThe US National Institutes of Health provide information on CochraneCollaboration produces and disseminates systematicreviews of health-care interventionsThe clinical trials (in English and Spanish)Medline Plus provides links to further information about  There is considerable debate regarding the relative utility of different studydesigns in generating reliable quantitative estimates for the risk of adverseeffects. A diverse range of study designs encompassing randomised controlled trials(RCTs) and non-randomised studies (such as cohort or case-control studies) maypotentially record adverse effects of interventions and provide useful data forsystematic reviews and meta-analyses In theory, well-conducted RCTs yield unbiased estimates of treatment effect, butthere is often a distinct lack of RCT data on adverse effects In general RCTs are designed and powered to explore efficacy Given these limitations it may be important to evaluate the use of data fromnon-randomised studies in systematic reviews of adverse effects. Owing to the lackof randomisation, all types of observational studies are potentially afflicted by anincreased risk of bias (particularly from confounding) As both RCTs and observational studies are potentially valuable sources of adverseeffects data for meta-analysis, the extent of any discrepancy between the pooledrisk estimates from different study designs is a key concern for systematicreviewers. Previous research has tended to focus on differences in treatment effectbetween RCTs and observational studies Broad, non-specific searches were undertaken in ten electronic databases toretrieve methodology papers related to any aspect of the incorporation ofadverse effects into systematic reviews. A list of the databases and othersources searched is given in Because of the limitations of searching for methodological papers, it wasenvisaged that relevant papers may be missed by searching databases alone. Wetherefore undertook hand-searching of selected key journals, conferenceproceedings, and Web sources, and made contact with other researchers in thefield. In particular, one reviewer (S. G.) undertook a detailed hand searchfocusing on the Cochrane Database of Systematic Reviews and the Database ofAbstracts of Reviews of Effects (DARE) to identify systematic reviews that hadevaluated adverse effects as a primary outcome. A second reviewer (Y. K. L.)checked the included and excluded papers that arose from this hand search.A meta-analysis or evaluation study was considered eligible for inclusion in thisreview if it evaluated studies of more than one type of design  on the identification and/orquantification of adverse effects of health-care interventions. We wereprincipally interested in meta-analyses that reported pooled estimates of therisk of adverse effects according to study designs that the authors stated asRCTs, as opposed to analytic epidemiologic studies such as case-control andcontrolled cohort studies . Our review focuses on the meta-analyseswhere it was possible to compare the pooled risk ratios (RRs) or odds ratios(ORs) from RCTs against those from other study designs.Information was collected on the primary objective of the meta-analyses; theadverse effects, study designs, and interventions included; the number ofincluded studies and number of patients by study design; the number of adverseeffects in the treatment and control arm or comparator group; and the type ofoutcome statistic used in evaluating risk of harm.We relied on the categorisation of study design as specified by the authors ofthe meta-analysis. For example, if the author stated that they compared RCTswith cohort studies, we assumed that the studies were indeed RCTs and cohortstudies.Validity assessment and data extraction were carried out by one reviewer (S. G.),and checked by a second reviewer (Y. K. L.). All discrepancies were resolvedafter going back to the original source papers, with full consensus reachedafter discussion.2 orI2). We assessed the extent of heterogeneity ofeach meta-analysis using a cut-off point of p < 0.10 forChi2 test results, and we specifically looked for instances whereI2 was reported as above 50%. In the fewinstances where both statistics were presented, the results ofI2 were given precedence The following criteria were used to consider the validity of comparing riskestimates across different study designs. (1) Presence of confounding factors:Discrepancies between the results of RCTs and observational studies may arisebecause of factors  other than study design. We recordedwhether the authors of the meta-analysis checked if the RCTs and observationalstudies shared similar features in terms of population, interventions,comparators, and measurement of outcomes and whether they used methods such asrestriction or stratification by population, intervention, comparators, oroutcomes to improve the comparability of pooled risk estimates arising fromdifferent groups of studies. (2) Heterogeneity by study design: We recordedwhether the authors of the meta-analysis explored heterogeneity of the pooledstudies by study design  overlapbetween pooled sets of results by study design, and any differences in thedirection of effect between study designs, were presented. The results were saidto agree if both study designs identified a significant increase, a significantdecrease, or no significant difference in the adverse effects underinvestigation.Quantitative differences or discrepancies between the pooled estimates from therespective study designs for each adverse effect were illustrated by taking theratio of odds ratios (ROR) from meta-analysis of RCTs versus meta-analysis ofobservational studies. We calculated ROR by using the pooled OR for the adverseoutcome from RCTs divided by the pooled OR for the adverse outcome fromobservational studies. If the meta-analysis of RCTs for a particular adverseeffect yielded exactly the same OR as the meta-analysis of observational studies, then theROR would be 1.0 (and ln ROR\u200a=\u200a0). Because adverse eventsare rare, ORs and RRs were treated as equivalent The estimated ROR from each \u201cRCT versus observational study\u201dcomparison was then used in a meta-analysis  to summarize the overall ROR between RCTs andobservational studies across all the included reviews. The standard error (SE)of ROR can be estimated using the SEs for the RCT and observationalestimates:SEs pertaining to each pooled OR(RCT) and OR(Observ) were calculated from thepublished 95% CI.I2statistic, with I2 values of30%\u201360% representing a moderate level of heterogeneity Statistical heterogeneity was assessed using In total, 52 articles were identified as potentially eligible for this review. Onfurther detailed evaluation, 33 of these articles either compared differenttypes of observational studies to one another  or compared only the incidence of adverse effects(without reporting the RR/OR) in those receiving the intervention according totype of study We finally selected 19 eligible articles that compared the relative risk or ORsfrom RCTs and observational studies  [6],[114Two of the 19 articles were methodological evaluations with the main aim ofassessing the influence of study characteristics (including study design) on themeasurement of adverse effects The majority of the articles compared the results from RCTs and observationalstudies using only one adverse effect  Most  of the articles included only one type of intervention Although many of the meta-analyses acknowledged the potential for confoundingfactors that might yield discrepant findings between study designs, noadjustment for confounding factors was reported in most instances There were two instances where the authors of the meta-analysis performedsome adjustment for potential confounding factors: one carried outmeta-regression 2 or I2Thirteen meta-analyses measured the heterogeneity of at least one set of theincluded studies grouped by study design using statistical analysis such asChiI2\u200a=\u200a58.9%I2\u200a=\u200a58.8%The pooled sets of RCTs were least likely to exhibit any strong indication ofheterogeneity; only five (15%) Three of the four case-control studies, one of the four cohort studies, and14 of the 25 studies described as \u201cobservational studies\u201d alsoexhibited substantial heterogeneity.Authors of one meta-analysis explicitly tested for a difference between theresults of the different study designs In ten methodological evaluations the total number of participants wasreported in each set of pooled studies by study design In almost all instances the CIs for the pooled results from the differentstudy designs overlapped . HoweverIn most of the methodological evaluations the results of the treatment effectagreed between types of study design There were major discrepancies in one pooled set of results. Col et al. p-values from significance testing.There were other instances where although the direction of the effect was notin opposing directions, apparently different conclusions may have beenreached had a review been restricted to either RCTs or observationalstudies, and undue emphasis was placed on statistical significance tests.For instance, a significant increase in an adverse effect could beidentified in an analysis of RCT data, yet pooling the observational studiesmay have identified no significant difference in adverse effects between thetreatment and control group. RRs or ORs from the RCTs were compared to those from the observationalstudies by meta-analysis of the respective ROR for each adverse effect.I2\u200a=\u200a56%,95% CI 38%\u201367%)  with moderateheterogeneity(38%\u201367%) .x-axis show the magnitude of discrepancy, with thecentral ln ROR of zero indicating no discrepancy, or complete agreementbetween the pooled OR estimated from RCTs and observational studies. They-axis illustrates the precision of the estimates(1/SE), with the data points at the top end having greater precision. Thissymmetrical distribution of the RORs of the various meta-analyses around thecentral ln ROR value of zero illustrates that random variation may be animportant factor accounting for discrepant findings between meta-analyses ofRCTs versus observational studies. If there had been any systematic andconsistent bias that drove the results in a particular direction for certainstudy designs, the plot of RORs would likely be asymmetrical. The verticallytapering shape of the funnel also suggests that the discrepancies betweenRCTs and observational studies are less apparent when the estimates havegreater precision. This may support the need for larger studies to assessadverse effects, whether they are RCTs or observational studies.In Both figures can be interpreted as demonstrating that there are no consistentsystematic variations in pooled risk estimates of adverse effects from RCTsversus observational studies.There are no adverse effects for which two or more separate meta-analyseshave used exactly the same primary studies  to generate the pooled estimates. Thisreflects the different time periods, search strategies, and inclusion andexclusion criteria that have been used by authors of these meta-analysessuch that even though they were looking at the same adverse effect, theyused data from different studies in generating pooled overall estimates. Asit turns out, the only adverse effect that was evaluated in more than onereview was venous thromboembolism (VTE). There was some, but not complete,overlap of primary studies in three separate reviews of VTE with HRT and two separate reviews of VTE with oralcontraceptives .For the sensitivity analysis, we removed the three older meta-analysespertaining to VTE so that the modest overlap could be further reduced, withonly one review per specific adverse effect for the sensitivity analysis.The most recent meta-analyses for VTE , witha subgroup analysis based on different types of observational designs.Another important limitation to this review is the potentially unrepresentativesample used. Systematic reviews with embedded data comparing different studydesigns may have been missed. The search strategy used was limited to aliterature search to identify methodological papers whose primary aim was toassess the influence of study design on adverse effects and to a sift of thefull text of systematic reviews of adverse effects (as a primary outcome) fromthe Cochrane Database of Systematic Reviews and DARE. Nevertheless, it should benoted that the Cochrane Database of Systematic Reviews and DARE databases covera large proportion of all systematic reviews and that systematic reviews inwhich adverse effects are included as a secondary aim are unlikely to presentsubgroup analysis by study design for the adverse effects data.There was considerable heterogeneity between the comparisons of differentstudies, suggesting that any differences may be specific to particular types ofinterventions or adverse effects. It may be that particular types of adverseeffects can be identified more easily via particular types of study designsWhere no randomized data exist, observational studies may be the only recourseIn addition, it would be useful (based on a case-control type of design) to carryout an in-depth examination of the meta-analyses (and their included primarystudies) with substantial discrepancy amongst the RCTs and observationalstudies, as compared to other meta-analyses where RCTs and observational studieshad close agreement. Any future research in this area should look into the roleof confounding factors (such as different population selection and duration ofdrug exposure) between studies, and lack of precision in point estimates of riskfor rare events that could have accounted for discrepant findings amongst RCTsand observational studies.Our findings have important implications for the conduct of systematic reviews ofharm, particularly with regards to selection of a broad range of relevantstudies. Although there are strengths and weaknesses to each study design,empirical evidence from this overview indicates that there is no difference onaverage between estimates of the risk of adverse effects from meta-analyses ofRCTs and of observational studies. Instead of restricting the analysis tocertain study designs, it may be preferable for systematic reviewers of adverseeffects to evaluate a broad range of studies that can help build a completepicture of any potential harm and improve the generalisability of the reviewwithout loss of validity.Figure S1Meta-analysis of RORs from RCTs versus cohort studies, case-controlstudies and studies described as \u201cobservational.\u201d(DOC)Click here for additional data file.Table S1Characteristics of included studies.(DOC)Click here for additional data file.Text S1Sources searched for included studies.(PDF)Click here for additional data file.Text S2Example search strategy.(PDF)Click here for additional data file.Text S3Excluded studies.(PDF)Click here for additional data file.Text S4Duplicate data decisions.(PDF)Click here for additional data file."}
+{"text": "Aedes aegypti, via insecticides and breeding site removal. The sustained transmission of dengue in endemic settings together with its increasing global footprint indicates existing disease control strategies have been unsuccessful Dengue is the most important arboviral infection of humans. In endemic countries the scale of the dengue disease burden imparts an economic cost Ae. aegypti that carry transgenes that result in highly penetrant, dominant, late-acting, female-specific lethality Wolbachia, into strains of Ae. aegyptiWolbachia-infected Ae. aegypti are partially resistant to infection with DENV Wolbachia to invade insect populations Ae. aegypti populations. The life-shortening impact of some Wolbachia strains could also contribute to reductions in disease transmission Wolbachia (wMel and wMelPop strains) have now been successfully carried out in Cairns, Australia and have demonstrated that Wolbachia can establish itself at very high prevalence in field populations of Ae. aegyptiNovel vector control approaches to limit dengue virus (DENV) transmission include release of Wolbachia-infected Ae. aegypti have been released could take many years or decades to yield evidence that is suggestive of a benefit. Equally, the heterogeneity of dengue transmission poses challenges to traditional clinical trial approaches, as does the non-stationary nature of mosquito populations Wolbachia-infected Ae. aegypti, it is also relevant to other vector control interventions, such as genetically engineered male mosquitoes carrying a dominant lethal gene A critical challenge for all entomological approaches to control of vector-borne disease is how best to demonstrate efficacy in reducing disease transmission A. aegypti mosquitoes of nearly 100% in treatment clusters within 6 months after first release A. aegypti mosquitoes present in control clusters remain virtually free of Wolbachia for the entire study period.Cluster randomised trials (CRTs) are the gold standard design to provide evidence on the efficacy of an intervention that has community-wide impact We consider the incidence of DENV-seroconversions during a trial as a suitable primary endpoint and DENV-na\u00efve children aged 2\u20135 years living in each cluster as an optimal \u201csentinel\u201d cohort for serological surveillance. Young children are less likely to spend substantial periods of time outside of their residence and local community (and hence outside of the \u201ctreatment umbrella\u201d) than more mobile older children and adults. In addition, DENV-prevalence in older children is higher and those remaining na\u00efve and hence eligible for the study are potentially less representative of the full population .Two alternative designs are considered. The first is the classical parallel two-armed cluster randomised trial (PCRT) in which each recruited cluster is randomised to intervention or control, and the intervention is implemented simultaneously across the relevant clusters. Thus the control clusters provide contemporaneous controls for the intervention clusters. The other design considered is a stepped wedge cluster randomised trial (SWCRT) in which each cluster is assigned to the control treatment initially and clusters are subsequently crossed-over to the intervention in a random selection at fixed time points until eventually all clusters are under treatment SWCRTs have been most frequently used for evaluating interventions during routine implementation such as the evaluation of a vaccine on the community level following a successful individual randomised trial. From a logistic perspective, they are attractive, because the intervention can be rolled out in a step-wise fashion and evaluated. As clusters are their own controls, SWCRTs are less sensitive to between-cluster variation and thus might require a lower sample size compared to parallel designs Wolbachia-infected mosquitoes to ensure a persistent and homogenous effect in treatment clusters without undue contamination into untreated clusters that serve as controls. For dengue trials community considerations include the extent of daily movement within and between clusters that the surveillance cohorts are likely to undertake; if the clusters are too small this movement may be excessive, and cause further reduction in any treatment effect. Thus, data on movement patterns of children eligible to join the surveillance cohort together with more information on the limits of spatial dispersal of Wolbachia-infected mosquitoes are essential before the cluster formation stage of any trial. An approach that is widely adopted in CRTs is the so-called \u201cfried-egg\u201d design Cluster size and cluster separation are important considerations in the design of all CRTs, but they require particular attention in trials of vector control interventions, for which entomological and community considerations need be taken into account. Entomological considerations include the dispersal of Wolbachia intervention (or other community-based intervention) depend critically on the size of the intervention effect and on both the magnitude and the variability  of seroconversion rates between clusters. To assess this variability in an example, we used published data from 12 primary schools in Kamphaeng Phet, Thailand, followed over a 3-year period Sample size requirements for CRTs of a A mixed-effects Poisson-regression model fitted to these data gave coefficients of variation  for yearly DENV infection incidence of 0.27 for between-school variation, 0.57 for annual variation, and 0.85 for residual variation . A detailed description of the model used to derive these coefficients of variation can be found in We then used the incidence and variability data reported above to simulate hypothetical PCRT and SWCRT trials. Additional assumptions for the trial simulations were a study duration of 3 years and a surveillance cohort of 100 children in each cluster. We varied the intervention effect between a 40% and an 80% decrease of DENV seroconversion in intervention clusters compared to controls. Allowing for the fact that some children in intervention clusters will experience infections outside of the intervention area, we regard an effect of a 50%\u201360% reduction as realistic in our target population. Details regarding the set-up of the simulation study and the statistical analysis of simulated trials are provided in Sample size requirements for the two designs and for varying treatment effects are shown in A parallel cluster-randomised trial is the design of choice for testing novel entomological methods of dengue control. Under realistic assumptions we show it to require a substantially lower sample size than a stepped wedge design. Sample size requirements for a parallel design are relatively modest; our example gave a minimum sample size of 20 clusters (ten per study arm) with each cluster providing 100 person-years of follow-up per year and a follow-up duration of 3 years. Although careful planning and substantial funding are required to run such a trial, the benefits of having a robust evidence-base from which to promote programmatic roll-out and/or further optimisation of the strategy should prove invaluable.Text S1Statistical appendix containing: (1) a diagram of a parallel two-arm cluster randomised trial (PCRT) and a stepped wedge cluster randomised trial (SWCRT), (2) details regarding the determination of coefficients of variation for the Thailand data, and (3) details regarding the simulation study to compare PCRT versus SWCRT designs.(DOCX)Click here for additional data file."}
+{"text": "Available data show that future changes in global change drivers may lead to an increasing impact of fires on terrestrial ecosystems worldwide. Yet, fire regime changes in highly humanised fire-prone regions are difficult to predict because fire effects may be heavily mediated by human activities We investigated the role of fire suppression strategies in synergy with climate change on the resulting fire regimes in Catalonia (north-eastern Spain). We used a spatially-explicit fire-succession model at the landscape level to test whether the use of different firefighting opportunities related to observed reductions in fire spread rates and effective fire sizes, and hence changes in the fire regime. We calibrated this model with data from a period with weak firefighting and later assess the potential for suppression strategies to modify fire regimes expected under different levels of climate change. When comparing simulations with observed fire statistics from an eleven-year period with firefighting strategies in place, our results showed that, at least in two of the three sub-regions analysed, the observed fire regime could not be reproduced unless taking into account the effects of fire suppression. Fire regime descriptors were highly dependent on climate change scenarios, with a general trend, under baseline scenarios without fire suppression, to large-scale increases in area burnt. Fire suppression strategies had a strong capacity to compensate for climate change effects. However, strong active fire suppression was necessary to accomplish such compensation, while more opportunistic fire suppression strategies derived from recent fire history only had a variable, but generally weak, potential for compensation of enhanced fire impacts under climate change. The concept of fire regime in the Mediterranean is probably better interpreted as a highly dynamic process in which the main determinants of fire are rapidly modified by changes in landscape, climate and socioeconomic factors such as fire suppression strategies. Fire is a key disturbance in many terrestrial ecosystems Fire regimes are determined by complex interactions between climate, land use, vegetation attributes and the pattern of ignition As fire events do not only impact ecological communities but also have major negative effects on human activities, several agencies have devoted considerable efforts to suppress fires Very few studies have investigated the potential contrasting effects of climate change and fire suppression efforts on fire impact at the landscape scale Our premise is that improved fire-behaviour knowledge by fire brigades may currently constrain the occurrence of large fires and strongly influence the effective area burnt in the study area Pinus halepensis, 18.4% Pinus sylvestris, 11.7% Pinus nigra), while sclerophilous and deciduous species cover the remaining 39.7% .The study area was Catalonia a region located in the north-eastern corner of Spain). Catalonia is extensively covered with shrubland and forests (about 60%) but human presence since pre-historical times has led to large-scale changes in species composition and distribution of dominant species in historical and recent times. The majority of the study area has a Mediterranean climate, with winter precipitation and summer drought Fire is a major landscape driver in the region, with about 25% of the wild-land area  being burnt between 1975 and 2010 . Stand-rIn recent times, increased resource investment and efficiency in firefighting activity has lead to most of the fires being controlled at early stages in their development, especially near highly populated areas The MEDFIRE model is a novel spatially explicit stochastic model that simulates landscape composition changes derived from vegetation dynamics and wildfire disturbances in a Mediterranean context. The model simulates the primary processes of a landscape fire-succession model  [38]: veThe MEDFIRE model aims to examine the spatial interaction between wildfires and vegetation dynamics in heterogeneous landscapes. It has been designed to model different fire regime drivers to allow the investigation of their relative effects on the resulting annual area burnt distribution, fire size distribution and landscape composition at short- and medium-term time scales in a Mediterranean context. The model permits the characterization of the spatial variation in burning and land cover changes under different climatic scenarios and fire suppression strategies. The MEDFIRE model assumes that the main driver of the fire regime in the study area is climate State variables in the MEDFIRE model are spatial variables that describe the landscape context and conditions. They are represented in raster format and cover the full extent of the study area at 100 m resolution. The temporal scale is fixed and one time step represents one year; simulations are normally run for a few decades.land cover type (LCT) and time since last fire (TSF). LCT is a categorical variable whose states are divided into 13 land covers that can be affected by fire disturbance because of their burnable condition , and three land covers that cannot . Although several LCTs are burnable, and therefore contribute to fire spread, only shrublands and forests can undergo land cover changes. This approach may constrain the application of the MEDFIRE model in cases in which land abandonment or urbanization are widespread and rapid. Yet, we consider that the model is adequate in situations in which such land use changes are of minor importance compared to fire and forest maturation in determining landscape changes over the study time frame Pinus halepensis, Pinus nigra, Pinus pinea, Pinus sylvestris, Quercus ilex and Quercus suber) is representative of the Mediterranean landscapes dominant in Catalonia and other areas of the Western-Mediterranean Quercus species and other trees. TSF is an integer variable that is used as a surrogate of vegetation age and of timber volume, for cells belonging to shrubland and forest cover types only.The state variables whose values change as a result of spatial processes are Other spatial state variables describe additional landscape features but are static in the current version of the model: ignition probability, bioclimatic region, fire spread type, elevation, aspect and main wind direction . The ignFire disturbance and vegetation change processes are designed as two separate sub-models each of whose action needs to be completed before the next one starts. Each one-year time step, the fire disturbance sub-model is scheduled first, followed by the sub-module responsible for vegetation changes. The fire sub-model begins by setting the potential total area to be burnt. The sub-model simulates fires sequentially until the potential total area to be burnt is reached . For eacThe fire sub-model has been designed to allow the fire spread rate to partially depend on the main factors determining fire shapes in real landscapes active suppression) concerns opportunities generated in areas where spread rate (an indicator of fire intensity) is low enough to allow firefighting crews to stop a fire from spreading further. The second suppression strategy  is based on opportunities derived from recent burned areas (fire scars). Previous detailed knowledge of the location and low fuel loads in these areas is assumed to lead to a significant increase in firefighting capacity. The two suppression strategies differ in the mechanisms driving such reductions in effective area burnt: while the opportunistic suppression strategy takes advantage of opportunities derived from past fire history  and fire suppression strategies in determining the fire regime and its impacts.In MEDFIRE, forests are simply described using the dominant tree species for each grid cell . TherefoInitial LCT values were obtained using spatially explicit information on tree species distribution in Catalonia from the Spanish Forest Map and forest compositional data derived from forest inventories Available fire statistics for the 1975\u20131988 period were used to build input distributions for potential total area burnt and potential fire sizes. We differentiated between adverse and normal years of the 1975\u20131988 period using meteorological data. Spread type layers were based on We used available fire statistics for the period between 1989 and 1999 to validate fire regime descriptors generated by the MEDFIRE model. This period precedes the implementation in the year 2000 of key enhancements in Catalonia in fire fighting capacity involving the introduction of logical analyses of fire behaviour We ran 100 simulation replicates of the MEDFIRE model for this eleven-year period using meteorological records of summer weather conditions to determine adverse (4 years) and non-adverse years (7 years) in the model. To determine whether the modelled fire regime was compatible with observed data we compared the observed fire regime descriptor  with the corresponding interval containing 95% of simulated values. Given the spatial variation in fire regimes known to exist in Catalonia We then used available fire statistics for the period between 2000 and 2010 to examine the potential role of fire suppression processes in the study area. This period starts with the implementation in Catalonia of logical analyses of fire behaviour We defined nine fire suppression treatments : the firIf firefighting has impacted fire regime descriptors for the 2000\u20132010 period, we expect a lower overall burnt area and a smaller percentage of area burnt in large fires in the observed fire regime compared to the fire regime of simulations under the baseline scenario without firefighting. To test this hypothesis, we calculated, under the baseline scenario, the proportion of simulations replicates that produced fire descriptor values smaller than the observed values. These probabilities were calculated for the whole study area as well as for bioclimatic sub-regions. Because we controlled for climatic effects in our simulations, a low proportion of replicates meeting these conditions would indicate that fire suppression was indeed impacting the fire regime. In order to determine which firefighting strategies would be compatible with observed fire regime, we followed the same procedure as in the validation test. A given fire suppression treatment was deemed compatible with the observed fire regime if the observed values of both descriptors were within the 95% of simulated values. Given the spatial variation in fire regimes known to exist in Catalonia In a final simulation exercise, we used the MEDFIRE model to evaluate the potential role of firefighting practices in constraining the regional fire regime at a medium time horizon (20 years) under different assumptions of climate change. We defined fire regime scenarios by generating combinations of climatic and suppression treatments. Climatic treatments were defined by specifying whether the percentage of adverse years is equal to the percentage observed for the pre-2000 period (C0\u223635% adverse years); or it is 25% higher (C1\u223660% adverse years); or 50% higher (C2\u223685% adverse years), according to the trends described in Given the potential strong, but still uncertain effect of fire suppression strategies, we decided to use a relatively wide range of fire suppression treatments in conjunction with climate scenarios. However, and after preliminary results that showed similar outcomes compared to the baseline scenario, we discarded weak fire suppression treatments . We ran 100 twenty-year simulations under each fire regime scenario and used two-way ANOVA to analyze the main effects and interaction between climatic and fire suppression treatments on the two descriptors of fire regime.Observed total area burnt and percentage of area burnt by large fires in the period 1989\u20131999 were compatible with fire regime distributions modelled by the MEDFIRE model calibrated with data from an earlier period . When weWhen we inspected the outputs of the MEDFIRE model for the 2000\u20132010 period, we found considerable variation across fire suppression treatments in the total amount of area burnt; with average reductions over the no-suppression scenario of up to 84%  were compatible with observed fire statistics for the study period in Catalonia  A. The oThe total amount of area burnt was highly dependent on climatic treatments as tested using ANOVAs . ScenariLarge-scale changes in fire regimes are expected in a world in which climate change and human activities are on the rise. Recent reviews We also identified some potential avenues to implement this integration and address this question, albeit further examination of this complex issue is obviously needed. Assessments of fire suppression impacts on fire regimes are often performed using a long time perspective and do not include short-term changes in vegetation derived from the fire itself per se recent, short term, fire size distribution patterns in our study region. This suggests that the current high fire suppression efficiency may be leading to changes in the relative weight of factors in the future fire regime by decreasing the opportunities that arise from past fires.Impacts of fire suppression on fire regimes are difficult to identify Adverse climatic conditions are a key element in determining current fire regimes in Mediterranean areas Further investigation of interacting mechanisms and feedbacks between factors potentially affecting fire impact is merited. Our results suggest that fire regimes in areas under strong human and climate change influence are not likely to be under stable fire regimes but rather show short term impacts of the idiosyncratic contributions of the different factors in the system. In the case of Mediterranean landscapes, one could predict a strong increase of fire impacts in the near future. However, it is not clear whether this will be the case under current levels of fire suppression and landscape changes leading to shifts in dominant vegetation and the expected feedbacks between these factors The concept of fire suppression opportunity associated with known and predictable factors affecting fire spread opens the way to landscape management approaches aiming at effectively changing fire regimes. In general, as the global emphasis on fire suppression policies increases, there will be a need to evaluate the effects of direct fire suppression and indirect fire management, through fuel modifications, on fire size distributions. There will also be a need to understand how fire regimes will be naturally affected by climatic changes operating through changes in fire weather conditions or changes in dominant forest cover types. Finally, the potential to alter fire regimes will involve the creation of new landscape configurations that may have critical impacts on biodiversity patterns. In the case of opportunistic fire suppression, interactions between past fire history and fire impact may increase the degree of autocorrelation in the spatial pattern of fire patches, potentially affecting ecological processes such as regeneration or colonisation of early successional species associated with fire Figure S1Statistical distributions for the total area burnt (A) and the percentage of area burnt by large fires (B) obtained after 100 simulations of the MEDFIRE model for the 1989\u20131999 period. Results are presented for the whole study area (ALL) and for the three bioclimatic sub-regions: North-East (NE), North-West (NW:) and South-Central (SC). Black squared dots indicate the statistics of total area burnt (A) and the percentage of area burnt by large fires (B) omitting from the observed data the single largest fire occurred in 1994. Boxplot description is as in the manuscript.(TIF)Click here for additional data file.Table S1Three-way ANOVA tables summarizing the results of twenty-year simulated fire regimes scenarios in terms of the total area burnt (A) and percentage of area burnt by large fires.(DOC)Click here for additional data file.Appendix S1Sub-model Description. This appendix describes details of the two sub-models of the MEDFIRE model, the fire sub-model Forest growth and the vegetation dynamics sub-model.(DOC)Click here for additional data file.Appendix S2Initialization of model variables. This appendix describes the main data sources employed to initialize spatial state variables and parameters used in the MEDFIRE model and described in (DOC)Click here for additional data file."}
+{"text": "Recent efforts to improve survival in patients with locally advanced esophageal carcinoma have combined both systemic and local therapy. However, the role of neoadjuvant chemoradiotherapy in technically operable IIa-III esophageal carcinoma is still unresolved. We have read with interest the report from Hurmuzlu and coll  on the oThe report is of great speculative interest given the consistently poor prognosis of OC whatever the therapeutic strategy adopted: so far, in fact, there is no general consensus on the appropriate treatment for such a dreadful condition. Specifically, the role of chemo-radiotherapy administered pre-operatively in resectable cstage IIa-III OC is still discussed.Scarce data are available from the literature and these are not consistent. In fact some experiences ,3 concluIn this scenario of substantial absence of a large base of methodologically correct evidence and agreed guidelines we consider the results from  of signiThe authors declare no conflicts of interestAll authors read and approved the final manuscript."}
+{"text": "The mucosa of the intestinal tract represents a finely tuned system where tissue structure strongly influences, and is turn influenced by, its function as both an absorptive surface and a defensive barrier. Mucosal architecture and histology plays a key role in the diagnosis, characterization and pathophysiology of a host of gastrointestinal diseases. Inflammation is a significant factor in the pathogenesis in many gastrointestinal diseases, and is perhaps the most clinically significant control factor governing the maintenance of the mucosal architecture by morphogenic pathways. We propose that appropriate characterization of the role of inflammation as a controller of enteric mucosal tissue patterning requires understanding the underlying cellular and molecular dynamics that determine the epithelial crypt-villus architecture across a range of conditions from health to disease. Towards this end we have developed the Spatially Explicit General-purpose Model of Enteric Tissue (SEGMEnT) to dynamically represent existing knowledge of the behavior of enteric epithelial tissue as influenced by inflammation with the ability to generate a variety of pathophysiological processes within a common platform and from a common knowledge base. In addition to reproducing healthy ileal mucosal dynamics as well as a series of morphogen knock-out/inhibition experiments, SEGMEnT provides insight into a range of clinically relevant cellular-molecular mechanisms, such as a putative role for Phosphotase and tensin homolog/phosphoinositide 3-kinase (PTEN/PI3K) as a key point of crosstalk between inflammation and morphogenesis, the protective role of enterocyte sloughing in enteric ischemia-reperfusion and chronic low level inflammation as a driver for colonic metaplasia. These results suggest that SEGMEnT can serve as an integrating platform for the study of inflammation in gastrointestinal disease. Mucosal histology plays a key role in the diagnosis, characterization and propagation of a host of gastrointestinal diseases, and the development of computational models capable of producing spatial architecture comparable to histology will enhance the evaluation of hypotheses for those diseases. Inflammation is a significant factor in the pathogenesis of a series of gastrointestinal diseases, and affects the maintenance of the mucosal architecture by morphogenic pathways. We have developed the Spatially Explicit General-purpose Model of Enteric Tissue (SEGMEnT) to investigate the behavior of enteric epithelial tissue as influenced by inflammation. SEGMEnT integrates cellular and molecular pathways governing morphogenesis and inflammation to generate a variety of pathophysiological processes from a common platform and knowledge base. Beyond reproducing healthy and disease ileal mucosal dynamics, SEGMEnT provides insight into a range of clinically relevant cellular-molecular mechanisms, including a novel putative role for Phosphotase and tensin homolog/phosphoinositide 3-kinase (PTEN/PI3K) as a key point of crosstalk between enteric inflammation and morphogenesis, the protective role of enterocyte sloughing in enteric ischemia-reperfusion and the mechanism of chronic low level inflammation as a driver for colonic metaplasia. These results suggest that SEGMEnT can serve as an integrating platform for the study of inflammation in gastrointestinal disease. The gut epithelium faces unique challenges in striking a balance between its receptive role in the absorption of nutrients and fostering synergistic interactions with commensal microbes versus retaining sufficient defensive barrier function to prevent microbial invasion and heal tissue injury effectively within this complex environment. The clinical relevance of the structure-function relationship of the gut mucosa is readily evident in the fact that histological characterization of intestinal mucosal architecture is a mainstay in the diagnosis of intestinal disease SEGMEnT provides a platform for instantiating conceptual models (hypotheses) representing baseline, healthy systems, which can then be used to explore, through differential perturbations, different disease trajectories SEGMEnT is a cell-level ABM: an object-oriented, discrete event, rule-based computational modeling method consisting of populations of computational entities (agents) that follow programmed rules governing their behavior with respect to the environment and interactions with other agents SEGMEnT aims to replicate the dynamically stable morphology and cellular populations of the healthy ileum, while matching the spatial distribution of molecular signaling gradients reported in the literature. SEGMEnT also reproduces the effects of inhibition of various signaling pathways by matching resultant phenotypic alterations of the crypt-villus architecture as reported in the literature. SEGMEnT is used to investigate two general types of potentially pathogenic conditions: 1) those resulting from acute insults/perturbations, namely local tissue injury resulting in a wound and the response to enteric ischemia-reperfusion, and 2) chronic conditions that result in a persistent alteration of the homeostatic set-point of the crypt-villus architecture. For this latter case we use the example of colonic metaplasia of the ileal pouch following restorative surgery for ulcerative colitis, thought to be induced by chronic, low-level inflammation due to fecal stasis Simulations with SEGMEnT fall into three categories: 1) those representing the baseline healthy state of the gut mucosa, 2) those reproducing previously published single-molecule/gene knockout/inhibition experiments, and 3) those reproducing published experiments investigating specific pathophysiological conditions. For details of the underlying biology in SEGMEnT and the development process see the Materials and Methods and the Supplementary Materials Integral to the use of computational models as a means of integrating mechanistic knowledge is the ability of those models to replicate baseline, healthy behavior Selective pathway component knockout and/or inhibition studies are a mainstay of molecular biologyThe Wnt pathway is a fundamental pathway to gut morphology, and the consequences of its inhibition are well documented Computational models provide detail into the progression of events; here, one can observe that gut epithelial cells quickly differentiate as the \u03b2-catenin destruction complex is activated. The increased Hh signal from the newly differentiated cells leads to the production of the Wnt inhibitor, secreted frizzled-related protein 1 (SFRP1), which quickly eliminates all Wnt activity. At this point, the crypt no longer exists, there are few proliferating cells, and the villi have lost significant cellularity; within two days, the last of the differentiated villus cells will have undergone apoptosis and the tissue is dead. Unfortunately, at this time, quantitative experimental data characterizing the dynamic properties of the respective cell populations and their respective molecular signatures is not available, but qualitatively, the output from SEGMEnT matches that seen in experiment in terms of crypt-villus atrophy and subsequent death Hh inhibition, while less studied, represents the diametrically opposed case to the Wnt pathway While experimental inhibition of PTEN does not change epithelial architecture (in the long term) from the normal state in the absence of inflammation Simulation of PTEN inhibition demonstrates a \u201cnull\u201d consequence of SEGMEnT's PTEN representation on baseline morphogenesis; we hypothesize that its role would only become significant in the perturbation case involving inflammation. All organisms have evolved in a heterogeneous and potentially dangerous environment and thus have to be able to deal with injury in order to maintain their bodily integrity. The inflammatory response is a highly conserved system that represents an organism's initial active response to these threats, providing initial containment and control and prompting the subsequent healing process SEGMEnT simulations of localized epithelial injury demonstrate the ability of the simulated tissue to heal itself after the infliction of a localized wound to the mucosa. A tissue wound/injury is represented by activating sufficient toll-like receptor (TLR4) signaling to cause all cells on the villi to die simultaneously by necrosis  Arrow 1.Intestinal ischemia/reperfusion (I/R) is a significant clinical pathophysiological entity. When an individual is under extreme stress, e.g. severe injury, blood loss or shock, the body's response is to divert blood flow away from the enteric circulation towards the more immediately critical organs such as the heart and brain, sacrificing intestinal ischemia for immediate survival. Additionally, certain types of major thoracic or abdominal surgery require a temporary occlusion of intestinal blood flow, leading to a period of enteric ischemia. The reperfusion phase involves a rapid influx of blood and circulating immune/inflammatory cells into an endothelial surface that has been primed by the ischemic period, which results in an acute activation of the inflammatory response We test the hypothesis that GEC sloughing is protective to I/R injury by performing simulations where FABP-mediated sloughing is deactivated . The laccolonic metaplasia of the pouch epithelial tissue Metaplasia is the reversible transformation of one type of tissue architecture into one resembling another type of tissue. It is distinct from neoplasia or dysplasia insomuch that the cells themselves do not exhibit dysfunctional growth but rather alter their differentiation path towards a different terminal cellular phenotype. Metaplasia is reflective of an alteration of the tissue environment that subsequently favors the new cellular phenotype, and is therefore often seen in chronic disease states. One example of this is seen in the small intestine following definitive surgery for ulcerative colitis resulting in the creation of an \u201cileal pouch:\u201d after removal of the colon and rectum, the rectal vault is reconstructed by creating a looped pouch of the terminal ileum. This ileal pouch then serves as a neo-reservoir for the stool in an attempt to more closely approximate normal bowel habits for these patients. However, this process now changes the tissue environment for the ileal mucosa in the pouch. Even though the composition of the intestinal contents entering the pouch may not be considerably different than before, now the previously transitive luminal contents are subject to stasis, which results in an alteration of the environment for the ileal mucosa and can result in Chronic, low-level inflammation has been associated with colonic metaplasia, and has been implicated as a mechanism driving the alterations seen in the mucosal architecture Simulations were performed with SEGMEnT to demonstrate the plausibility of a hypothesis previously published in the literature that prolonged low-level inflammation, acting as a persistent perturbation to the signaling network, would lead to a change in the morphology of the epithelial layer SEGMEnT dynamically represents and integrates existing knowledge concerning homeostasis and inflammation in the ileum and provides a computational platform to augment the exploration of the cellular/molecular processes involved in intestinal wound repair, ischemia/reperfusion injury, and colonic metaplasia/pouchitis. SEGMEnT successfully replicates the dynamically stable morphology and cellular populations of the healthy ileum, while qualitatively matching the spatial distribution of molecular signaling gradients consisting with the existing qualitative histological criteria utilized and reported in the literature SEGMEnT follows in a line of prior spatially explicit computational models investigating the dynamics of cell populations and signaling within the intestinal crypts SEGMEnT incorporates and integrates the features seen in the spatial gut models concerning the Wnt/Notch pathways with the inflammatory components and processes seen in the gut inflammation models. As such, it is able to extend the scope of its representation to investigate how inter-pathway specific interactions can affect other pathways in the overall signaling network. This capability allowed the instantiation of a novel hypothesis concerning a link between inflammation and morphogenesis through the PTEN/PI3K pathway. Additionally, prior spatial gut models all utilized a fixed crypt topology (i.e. height/depth) upon which their cellular components moved, and therefore are not able to examine metaplasia, ischemia/reperfusion or injury and repair, all conditions that result in some distortion of the baseline crypt-villus architecture. SEGMEnT expands on these prior approaches by allowing for dynamic alteration of these critical histological dimensions; in this fashion it crosses over into some of the capabilities represented in the other arm of spatial crypt-villus modeling that is more focused on looking at factors that actually generate the tissue topology 2 area of tissue on a single processor with 2 GB of memory. Capturing the healing of surgical anastomosis or the \u201cpatchiness\u201d of inflammatory bowel exacerbations or environmental enteropathy will require the representation of substantially larger surface area of the gut; as such, current work is being done to implement SEGMEnT HPC to investigate the scaling issues associated with simulating physiologically/anatomically relevant areas and volumes of enteric tissue. SEGMEnT HPC is designed to represent arbitrarily large and customizable epithelial surfaces.SEGMEnT also allows the representation of multiple crypt-villus complexes and their associated external tissue structures, simulating significantly larger sections of intestinal tissue. The benefits of this have already been demonstrated in the simulations of healing local tissue injury, where a damaged villus is represented as being adjacent to the uninjured tissue involved in affecting it repair. The current version of SEGMEnT can represent up to 1.4 mmSEGMEnT is a work in progress, representing an instantiation of a minimally sufficient set of components and interactions to achieve a face valid representation of the mechanisms involved in maintaining the enteric mucosal architecture (morphogenesis) and its response to an initial set of perturbations (inflammation). The modular control organization of SEGMEnT  has beenSEGMEnT is implemented using the agent-based modeling software, Repast Simphony 2.0 developed at Argonne National Laboratory \u22128 m) are aggregated by cells (spanning 10\u22126 m), which interact to form tissue (10\u22123 m2). This is also true with respect to temporal scales, where the time scales on which SEGMEnT operates span several orders of magnitude. Signaling events  occur on a time scale from approximately 10\u22123 s to 1 s, while it can take \u223c103 s for the consequences of that event (the secretion of a protein) to manifest. An individual cell performs physical actions  approximately every 103 s, and ultimately survives for \u223c104 s. SEGMEnT then makes the implicit assumption in the time it takes for a cell to perform a physical action, any signaling events that would occur in the region of space which the cell occupies will have already occurred; thus, simple time-delayed rules give similar results to a differential equation based model, but at a fraction of the computational cost. Explicit details regarding the underlying biology and modeling methodology can be found in the Supplementary Materials SEGMEnT is a knowledge-based model incorporating the inter-relationships between the various cellular and molecular entities present in the enteric tissue. Parameters for these relationships were extracted from the literature, when possible; fitting emphasized the relational qualities between processes. The multi-scale nature of the SEGMENT is apparent in the hierarchical ordering of events and components. Molecular events , Bone Morphogenetic Protein (BMP), Phosphotase and tensin homolog/phosphoinositide 3-kinase (PTEN/PI3K), Sonic Hedgehog Homolog (Hh), Tumor Necrosis Factor (TNF)-\u03b1, Interferon (IFN)-\u03b3, RIP Kinase, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-\u03baB), Janus Kinase (JAK), Signal transducer and activator of transcription 3 (Stat3), and reactive oxygen species (ROSs), and Interleukin (IL) 6,10,13, and 15 signaling pathways. Full details of the implementation of these signaling relationships are presented in the Materials and Methods.(TIF)Click here for additional data file.Figure S2Simulation distributions of free Bone Morphogenetic Protein (BMP) and BMP binding to epithelial cells. Panel A shows the distribution of free molecular Bone Morphogenetic Protein (BMP) concentrations in SEGMEnT: free BMP is shown as blue, and having a uniform density throughout the tissue. This corresponds to histological data showing a uniform density of free BMP from the bottom of the crypt to the top of the villus (see llus see  with sim(TIF)Click here for additional data file.Table S1Primary molecular components included in SEGMEnT.(PDF)Click here for additional data file.Table S2Rules for molecular interactions in SEGMEnT.(PDF)Click here for additional data file.Table S3Physical characteristics, published and derived time delays, and model-implemented time delays for signaling events involving molecular components included in SEGMEnT.(PDF)Click here for additional data file.Table S4Additional features and capabilities to be added to SEGMEnT.(PDF)Click here for additional data file.Text S1Detailed description of underlying biology and its implementation in SEGMEnT. These materials provide a detailed description of the biological processes, modeling assumptions and implementation of the biological knowledge into SEGMEnT. These materials also provide descriptions of how the simulation experiments were performed.(PDF)Click here for additional data file."}
+{"text": "Whether this translates into a clinical benefit in HIV-infected patients residing in malaria-endemic regions is unknown. We studied the incidence of malaria, as defined by blood smear positivity or a positive Plasmodium falciparum histidine-rich protein 2 antigen test, among 444 HIV-infected women initiating antiretroviral treatment (ART) in the OCTANE trial . Participants were randomized to treatment with PI-containing vs. PI-sparing ART, and were followed prospectively for \u226548 weeks; 73% also received cotrimoxazole prophylaxis. PI-containing treatment was not associated with protection against malaria in this study population.HIV protease inhibitors (PIs) show antimalarial activity  The majority of HIV-infected individuals live in malaria-endemic regions, and available evidence suggests that the interaction between HIV and malaria infection is complex, synergistic and bidirectional. Reported effects include increased HIV replication resulting from immune activation in vitro activity against the two most important malaria parasites, Plasmodium falciparumP. vivaxin vivo activity against rodent malaria parasites Plasmodium falciparum-infected erythrocytes HIV protease inhibitors (PIs) have moderate To explore the effect of PI-based ART on HIV-infected people residing in malaria-endemic regions of sub-Saharan Africa we undertook a retrospective study examining the incidence of malaria in a group of women enrolled in AACTG 5208 P. falciparum histidine-rich protein two (HRP2) by antigen-capture immunoassay forms the basis of most rapid diagnostic tests for falciparum malaria. This water-soluble protein is released into the circulation of individuals infected with P. falciparum, and has been shown to persist in the circulation after clinical symptoms of malaria have resolved and parasites have been cleared from the circulation. It has been reported to remain in the blood for 7 days following treatment in 62\u201399% of patients, for 14 days in 35\u201398% of patients, and for 28 days in 27\u201392% Detection of The OCTANE study (AACTG 5208) consisted of two concurrent randomized trials; detailed methods and primary results have been published P. falciparum Histidine-rich protein 2 [HRP2]) was detected in the plasma samples that were collected at study visits. All available samples from each participant at the relevant sites were tested for HRP2 antigenemia using a commercially available ELISA kit . Each plasma sample was tested in duplicate as stated in the manufacturer's instructions with positive and negative controls on every plate. Evaluation of this kit before the study indicated that it was more sensitive than other commercially available plate-based HRP2 ELISA kits and was between 30 and 120 fold more sensitive than malaria rapid diagnostic kits (data not shown).The current study includes data obtained from participants enrolled at the six OCTANE study sites where malaria transmission has been reported to occur . Study subjects were considered to have malaria if they had a positive blood smear, a positive malaria rapid diagnostic test (RDT), or if malaria antigen (http://www.openepi.com). Multivariate analyses were not performed given the small numbers of samples with a confirmed diagnosis of malaria.As malaria was not detected in two of the study sites and some participants changed ART regimen and/or received cotrimoxazole, a drug with known prophylactic activity against malaria in HIV-infected populations HRP2 antigenemia was assessed by examining available plasma samples totaling 3,516 from 444 women. All available samples where a diagnosis of malaria had been made by blood smear, on-site rapid diagnostic test or HRP2 ELISA where also tested for malaria in our laboratory using immunochromatographic rapid diagnostic tests . An additional 113 samples from these 444 women were tested for malaria during the original study (on site blood smear or RDT). As blood smear slides were not retained these diagnoses could not be revalidated. Therefore, laboratory data for malaria were available from a total of 3629 samples from 444 subjects  of the 3629 samples tested  of study subjects were taking daily cotrimoxazole prophylaxis at the time of blood sampling . While tIn this study, we observed a low incidence of malaria as defined by positive malaria smears, RDTs, and antigenemia, and did not find that PI-based ART was associated with a lower incidence of malaria. Fifty three (20%) of the women in the study had at least one episode of laboratory-confirmed malaria over the study interval, 34 (64%) of these women were receiving PI-based ART at the time of malaria diagnosis .Although the results indicate that PI therapy did not exert a protective effect against malaria in this population, a number of circumstances that may have masked a protective effect should be considered. In the first instance, it is possible that the low numbers of malaria diagnosis made in our cohort underpowered the study and prevented the identification of a protective effect. While this study was predicted to have sufficient power to answer our question when it was first designed, there was a significant reduction in the prevalence of malaria in many parts of Africa in the interval between design and study execution The high rate of cotrimoxazole prophylaxis (80%) observed in our study population, an intervention with a protective effect against malaria in HIV-infected populations, may have also impacted our results by reducing the episodes of malaria. While pharmacokinetic interactions are also possible when drugs are co-administered, and are a particular concern with ritonavir, a drug well known to affect the pharmacokinetics of many drugs including antimalarials, an interaction of this drug with cotrimoxazole seems unlikely to be an explanation for any lack or antimalarial effect observed among subjects in the current study. Both groups receiving cotrimoxazole, regardless of their ART treatment regimen had reduced episodes of malaria .A pharmacodynamic interaction may be associated with the inability of PI-based ART to protect the current cohort of women from malaria infection. While the primary mode of action of cotrimoxazole is understood, the antimalarial mode of action of the PIs is still not known. A better understanding of the basis of the antimalarial effect of PIs may enable prediction of clinically significant pharmacodynamic interactions. Both cotrimoxazole and individual PIs may also have off-target effects that alter the activity of the other drug or additional drugs that may be used to treat HIV-infected patients with opportunistic pathogens. These interactions must be understood to ensure the use of the most effective drug treatment regimens. The ability of the PIs to modulate aspects of the immune system, decrease the expression of CD36 and interfere with the phagocytosis of parasitized erythrocytes Indirect antimalarial benefits, that were not examined in this study, including reduced cytoadherence"}
+{"text": "Circadian rhythms of behavior and physiology are generated by central and peripheral circadian oscillators entrained by periodic environmental or physiological stimuli. A master circadian pacemaker in the hypothalamic suprachiasmatic nucleus (SCN) is directly entrained by daily light-dark (LD) cycles, and coordinates the timing of other oscillators by direct and indirect neural, hormonal and behavioral outputs. The daily rhythm of food intake provides stimuli that entrain most peripheral and central oscillators, some of which can drive a daily rhythm of food anticipatory activity if food is restricted to one daily mealtime. The location of food-entrainable oscillators (FEOs) that drive food anticipatory rhythms, and the food-related stimuli that entrain these oscillators, remain to be clarified. Here, we critically examine the role of peripheral metabolic hormones as potential internal entrainment stimuli or outputs for FEOs controlling food anticipatory rhythms in rats and mice. Hormones for which data are available include corticosterone, ghrelin, leptin, insulin, glucagon, and glucagon-like peptide 1. All of these hormones exhibit daily rhythms of synthesis and secretion that are synchronized by meal timing. There is some evidence that ghrelin and leptin modulate the expression of food anticipatory rhythms, but none of the hormones examined so far are necessary for entrainment. Ghrelin and leptin likely modulate food-entrained rhythms by actions in hypothalamic circuits utilizing melanocortin and orexin signaling, although again food-entrained behavioral rhythms can persist in lesion and gene knockout models in which these systems are disabled. Actions of these hormones on circadian oscillators in central reward circuits remain to be evaluated. Food-entrained activity rhythms are likely mediated by a distributed system of circadian oscillators sensitive to multiple feeding related inputs. Metabolic hormones appear to play a modulatory role within this system. Behavior and physiology are regulated by a hierarchically organized system of circadian oscillators located in the brain and in most peripheral tissues and organs Figure . CircadiThe role of food intake in the regulation of circadian clocks was first revealed by studies of circadian activity rhythms in food-restricted rodents. Acute and chronic food restriction elicit well-known behavioral and physiological responses to maintain metabolic homeostasis. Acute deprivation recruits neural circuits that promote arousal and food seeking behavior. Chronic caloric restriction induces physiological adaptations to facilitate the extraction and storage of energy from ingested nutrients and to reduce energy expenditure. If caloric restriction is chronic and food availability is limited to a particular time of day, further adaptations can occur in the temporal regulation of metabolism and food seeking behavior. These adaptations involve entrainment of circadian clocks in the brain and in peripheral organs and tissues by stimuli associated with food intake.Physiology and behavior are regulated by circadian clocks that induce daily rhythms in synchrony with environmental cycles. In mammals, a master circadian clock is located in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus Weaver, . The SCNad-libitum, behavior and physiology lose circadian organization. However, if food is provided once every 24 h in a reduced amount, food anticipatory activity rhythms emerge and circadian rhythms of physiology are restored  for circadian regulation of food-anticipatory behavior, the neural and molecular mechanisms of this SCN-independent circadian function are not yet well-understood. The daily rhythm of food anticipatory activity exhibits canonical properties of circadian clock control  should exhibit a daily rhythm that is induced by or is synchronous with scheduled feeding. The factor should be capable of shifting the phase of one or more food-entrained rhythms (a requirement for co-activation by 2 or more factors is possible). Blocking the factor may prevent shifting of one or more food entrained rhythms . To be considered a candidate as an output of FEOs responsible for driving food anticipatory activity (or other food entrained rhythms) the factor should exhibit a daily rhythm that correlates strongly with locomotor activity (or other rhythms), under a variety of conditions . Enhanced expression of the factor may increase the amplitude of food anticipatory activity (or other rhythms), while blocking the factor should attenuate or prevent expression of food anticipatory activity (or other rhythms). Attenuation could be modest or negligible if there are multiple redundant output signals. Food anticipation could also be enhanced or attenuated by factors that are downstream from FEOs, or that converge downstream via other pathways. Therefore, the observation that manipulation of a factor alters the amount of food anticipatory activity does not alone permit a strong conclusion that the factor is either an input or output of FEOs.The synthesis and secretion of corticosterone (CORT) from the adrenal gland is under control of descending neural (autonomic) and hormonal (adrenocorticotropin) signals, interacting with circadian oscillators intrinsic to cells of the adrenal gland  in lateral hypothalamic orexin neurons, the VTA and the nucleus accumbens shell . All of these areas express circadian rhythms of clock gene expression, and are innervated by dopaminergic projections from the VTA  at a fixed time of day, with regular chow available ad-libitum , correlated positively with locomotor activity counts during the preceding 3 h  is synthesized in the periphery and in the brain. In the periphery GLP-1 is derived from preproglucagon synthesized in L cells of the intestine and alpha cells of the pancreas  and melanocortin-4 (McR4) receptors. One population of arcuate neurons synthesizes POMC, a precursor for \u03b1, \u03b2, and \u03b3-melanocortin-stimulating hormones (MSH) which function as agonists at Mc3R and Mc4R receptors  and enhanced levels have been reported in mice lacking both Mc3 receptors and leptin assessed  or to the use of knockout mice obtained from different sources remains to be evaluated.The melanocortin system plays a critical role in the regulation of metabolism and feeding. \u03b1-MSH potently inhibits feeding  are derived from prepro-orexin synthesized exclusively in a population of neurons distributed within the dorsomedial, perifornical and lateral hypothalamic areas  could induce daily temporal windows of vulnerability to excessive reward seeking behavior. Second, feeding stimulated at irregular mealtimes could result in disrupted timing of metabolic processes, with negative consequences for metabolic functioning and health (Arble et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Epilepsy surgery is highly effective in treating refractory epilepsy, but requires accurate presurgical localization of the epileptogenic focus. Briefly, localization of the region of seizure onset traditionally dependents on seizure semiology, scalp EEG recordings and correlation with anatomical imaging modalities such as MRI. The introduction of noninvasive functional neuroimaging methods, including single-photon emission computed tomography (SPECT) and positron emission tomography (PET) has dramatically changed the method for presurgical epilepsy evaluation. These imaging modalities have become powerful tools for the investigation of brain function and are an essential part of the evaluation of epileptic patients. Of these methods, SPECT has the practical capacity to image blood flow functional changes that occur during seizures in the routine clinical setting. In this review we present the basic principles of epilepsy SPECT and PET imaging. We discuss the properties of the SPECT tracers to be used for this purpose and imaging acquisition protocols as well as the diagnostic performance of SPECT in addition to SPECT image analysis methods. This is followed by a discussion and comparison to F-18 FDG PET acquisition and imaging analysis methods. Epilepsy surgery can be highly effective in treating refractory epilepsy if performed in properly selected patients with well-delineated ictal foci . The greThe introduction of noninvasive neuroimaging methods, such as single-photon emission computed tomography (SPECT), positron emission tomography (PET), and magnetic resonance imaging (MRI), has dramatically changed presurgical epilepsy evaluation. These imaging methods have become powerful tools for the investigation of brain function and an essential part of the evaluation of epileptic patients. Of these methods, only SPECT has the practical capacity to image blood flow functional changes that occur during seizures in the routine clinical setting. Although functional MRI (fMRI) could, in theory, be used for this purpose, it is impractical due to patient movement during most types of seizures, a problem that is overcome by the timing and technique of SPECT imaging. In this paper, we review basic principles of epilepsy SPECT, SPECT tracers, imaging acquisition, the diagnostic performance of SPECT, and imaging analysis methods. This is followed by a discussion and comparison to PET tracer acquisition methods and imaging analysis methods.SPECT radiopharmaceuticals used for measuring regional cerebral blood flow (rCBF) are lipophilic agents which are transported from the vascular compartment to the normal brain tissue compartment by diffusion and are distributed proportionally to regional tissue blood flow. After this first phase of transport (during the first pass through the brain), the tracer is essentially irreversibly trapped in the tissue compartment and does not change its relative distribution over time. These properties are essential in ictal SPECT, since the tracer is essentially trapped during the first few seconds after injection and maintains that distribution for hours, allowing the patient to be stabilized and imaged at rest, but the emission of photons still reflects the tracer distribution pattern seconds after injection. The two major blood flow agents used in brain SPECT imaging are technetium-99m hexamethyl-propylene amine oxime (Tc-99m HMPAO) and Tc-99m ethyl cysteinate dimer (Tc-99m ECD) , 4.To understand the uptake mechanism of Tc-99m hexamethyl-propylene amine oxime (Tc-99m HMPAO), a three-compartment analysis model can be used for analysis . In thisThe second tracer commonly used in brain SPECT to measure regional cerebral perfusion is Tc-99m ECD . This raSeveral studies reported higher extracerebral background activity with Tc-99m HMPAO than with Tc-99m ECD due to the slower clearance rate of Tc-99m HMPAO from the blood \u201310. ThisLee et al. demonstrated that Tc-99m HMPAO has a similar localization rate (82%) to that of Tc-99m ECD (71%) in patients with TLE , with a higher degree of hyperperfusion in the Tc-99m HMPAO group . For patIn-single photon emission computed tomography (SPECT) of the brain, dual and triple-head Anger gamma cameras are now in common use and can provide very high resolution images  extrinsic resolution) . The resIn order to perform these studies, Tc-99m HMPAO must be readily available at the patient's bedside allowing for rapid injection by a trained technologist or other personnel immediately available at the time of seizure onset. The ictal injection should be performed in a rapid bolus fashion such that the entire tracer is injected during the first onset of seizure (ictus). The patient is then sedated and transferred to the SPECT scanner within several hours to acquire the brain SPECT scan which will indicate the regional cerebral perfusion at the time of ictus. This method is feasible since Tc-99m HMPAO is irreversibly trapped in the epileptogenic hyperemic region at the time of seizure, and during the period between injection and scan, there is essentially no redistribution. The subsequent scan  will still show hyperemia (increased tracer counts) in the region of the epileptogenic focus.The sensitivity of ictal SPECT is theoretically higher than that of interictal SPECT because of the large CBF increase from the baseline that occurs during the ictal phase . This isThe traditional qualitative visual analysis of a SPECT perfusion study involves comparison of each cerebral region with the contralateral side. Limitations of interpretation of SPECT by conventional visual assessment include difficulty in the detection of subtle changes that can be associated with inhomogeneous baseline perfusion patterns, variation in the amount of injected radioisotope, time of injection, and patient positioning . Also, tz score >+3).For a more objective and quantitative analysis, Zubal et al. proposed a subtraction method in which coregistered ictal and interictal images were normalized based on total pixel counts in the brain and then subtracted from each other . Therefot or F statistic). Criteria for accepting voxels  can be set for voxel height (p) and extent of contiguous cluster of voxels (k). For visualization of the results, a pseudocolor scale can be applied to accepted significant voxels, which are then overlaied in a semitransparent fashion onto the MRI of either the normative atlas or the patient's own MRI anatomy. The most recent version of SPM (SPM2) combines the general linear model to create the statistical map and the random field theory to make statistical inference about regional effects. Software for SPM analysis is available as Freeware from the Welcome Department of Imaging Neuroscience . Although the SPM package includes most of the programs required for image processing and analysis, visualization of images and some processing or image editing and reformatting may require more dedicated biomedical image processing software. Statistical parametric mapping refers to the construction and assessment of spatially extended statistical processes used to test hypotheses about functional imaging data. In rCBF SPECT or F-18 FDG PET image data analysis, this translates to methods to test hypotheses about regionally specific effects . When two image data sets are evaluated by SPM, all voxels contained within the scans are compared in the same space on a voxel-by-voxel basis using linear constraints to test hypotheses for specific focal effects using a univariate statistical test. The resulting statistical parameters are then assembled onto an image . Differences of one map compared with the map derived from the other scans are interpreted as regionally specific effects, attributable to some alteration in brain function from one scan to the other. The significance of these differences is assessed using statistical tests  .  FigureApproximately 10\u2009mCi F-18 FDG I.V is injected. The tomograph should be of the latest generation, multislice to cover the entire brain. The 3D acquisition mode should be used to accommodate lower dosimetry and to improve the count statistics of the data. Measured attenuation correction should be employed. The image should be reconstructed with the standard clinical reconstruction including all necessary corrections . A set of calibration phantoms including at the minimum the Hoffman brain phantom and the uniform cylinder should be run periodically to assess scanner stability . Subject conditions during the performance of PET scans should be fully characterized and standardized whenever possible. PET studies should be performed during \u201ca resting state\u201d . Procedures to minimize head movement during scans should be implemented using well-tolerated head immobilization procedures. The use of medications and the behavioral state of patients at the time of the scan also should be carefully considered.F-18 FDG PET is typically seen in patients with hippocampal sclerosis on MRI. This is illustrated in Presurgical evaluation and the surgical treatment of nonlesional neocortical epilepsy is one of the most challenging areas in epilepsy surgery. Fluorodeoxyglucose (FDG) PET shows hypometabolism in a majority of patients with nonlesional temporal lobe epilepsy (TLE), even in the absence of hippocampal atrophy. In extratemporal epilepsy where the MRI scan is normal, there is a less likely chance to find the epileptogenic focus by F-18 FDG PET hypometabolism alone. Interictal FDG PET studies will have limited usefulness in the presence of multiple hypometabolic regions in patients with multifocal brain syndromes, such as in children with tuberous sclerosis. Such children with multifocal lesions represent a special challenge during presurgical evaluation. The goal of functional imaging in these cases is to identify the epileptogenic lesions and differentiate them from nonepileptogenic ones. In this context, ictal rCBF SPECT may have useful clinical applications but may be technically challenging when seizures are short, as is particularly common in frontal lobe epilepsy and in children who have infantile spasms that are associated with multifocal cortical dysplasia .  FigureAlthough FDG PET images can be analyzed visually, additional information can be obtained by semiquantitative analysis, such as left-to-right asymmetry indices. Semiquantitative analysis using the asymmetry index is generally considered significant when a difference of 15% or greater exists between the affected and contralateral sides . QuantitAlthough regional hypometabolism is typically present in the temporal lobe ipsilateral to EEG seizure onset, other brain regions may also show patterns of glucose hypometabolism . For exaFDG PET reflects glucose metabolism of the brain as an indirect measure of neuronal function while SPECT represents cerebral blood flow changes. Although PET has higher spatial resolution and lower background activity, one of the limitations of FDG-PET for the evaluation of epilepsy during the ictal phase is its low temporal resolution. This is due to a tracer uptake period (30\u201345 minutes) that is significantly longer than the average seizure duration (1-2 minutes), which leads to a mixture of interictal-, ictal-, and postictal-phase images, and this makes only interictal PET feasible. FDG is glucose analogue which is actively transported into metabolically active cells and then temporarily held in the intracellular space due to phosphorylation by hexokinase. However, this is a reversible event, and FDG uptake is both slower and shorter lasting than incorporation of SPECT tracers. Therefore, PET is used to obtain clinical information during the interictal phase. The sensitivity of interictal PET is higher than that of interictal SPECT, as described in a previous meta-analysis by Spencer . One potIctal SPECT and interictal FDG-PET were found to have similar sensitivity , 37\u201339. The importance of precise localization using a statistical analysis method (such as SPM) and an automated registration mapping method (such as AIR) is illustrated in The introduction of noninvasive neuroimaging methods, such as single-photon emission computed tomography (SPECT), positron emission tomography (PET), and magnetic resonance imaging (MRI), has dramatically changed presurgical epilepsy evaluation. Previous studies have demonstrated the diagnostic performance of each imaging modality and the value of quantitative analysis of ictal and interictal regional cerebral blood flow SPECT and F-18 FDG PET images. Overall, ictal SPECT has the highest diagnostic sensitivity for both temporal and extratemporal lobe epilepsy, and PET is known to have high sensitivity for the evaluation of extratemporal lobe epilepsy. PET can be employed as a complimentary imaging modality to SPECT in neocortical epilepsy. Quantitative image analysis can further improve diagnostic accuracy of ictal and interictal SPECT and F-18 FDG PET."}
+{"text": "The cerebellum input stage has been known to perform combinatorial operations on input signals. In this paper, two types of mathematical models were used to reproduce the role of feed-forward inhibition and computation in the granular layer microcircuitry to investigate spike train processing. A simple spiking model and a biophysically-detailed model of the network were used to study signal recoding in the granular layer and to test observations like center-surround organization and time-window hypothesis in addition to effects of induced plasticity. Simulations suggest that simple neuron models may be used to abstract timing phenomenon in large networks, however detailed models were needed to reconstruct population coding via evoked local field potentials (LFP) and for simulating changes in synaptic plasticity. Our results also indicated that spatio-temporal code of the granular network is mainly controlled by the feed-forward inhibition from the Golgi cell synapses. Spike amplitude and total number of spikes were modulated by LTP and LTD. Reconstructing granular layer evoked-LFP suggests that granular layer propagates the nonlinearities of individual neurons. Simulations indicate that granular layer network operates a robust population code for a wide range of intervals, controlled by the Golgi cell inhibition and is regulated by the post-synaptic excitability. Understanding how the granular layer process information appears critical to understand the cerebellar function, since signals coming into upper cortical layers are provided by the granular layer. The granule cells form the largest neuronal population in the mammalian brain and regulate information transfer along the major afferent systems to the cerebellum. The granule layer receives excitatory input primarily from mossy fibers and inhibition via synapses from interneurons like Golgi cell. Mossy fiber input excites both the granule cell and inhibitory interneurons like the Golgi cell. The granule cell is a small neuron with 3\u20135 dendrites. Timing in the cerebellar granular layer plays a key role via passage-of-time representation (POT), learning or adaptation to movements O is resting [Ca], and F is the Faraday's constant. [Ca] is the calcium channel dynamics as reported in . We also simulated the \u201cspot\u201d on the AdEx spiking neuron based network model. The speed in Adex model (data not shown) and detailed biophysical model are different. However, AdEx network model could reproduce the spiking patterns whereas the detailed model could reproduce both firing and ionic channel properties such as extracellular evoked potentials .Click here for additional data file."}
+{"text": "Utilizing tumors as a source of vaccination antigens in immunotherapy has demonstrated promising results with minimal toxicity. Unfortunately, researchers have failed to overcome the overpowering suppressive effects of the tumor microenvironment. Recently we demonstrated that the proximity of the vaccination injection site to the primary tumor site dictates CD8 T-cell priming within the draining lymph node. Glioma-bearing mice vaccinated in tumor-distal sites had increased functional responses and survived significantly longer than glioma-bearing mice vaccinated in tumor-proximal sites due to immunosuppressive properties of the tumor inhibiting the priming of a tumoricidal response in the draining lymph nodes. Tumor induced immunosuppression is a complex interplay between the tumor and its surrounding microenvironment. We discovered an excess of soluble CD200 protein in the cerebral spinal fluid and cervical lymph nodes in tumor bearing mice. CD200 has been well characterized to be immunosuppressive in multiple graft rejection models, but has not been clearly defined as a factor in tumor-induced suppression. CD200 is highly expressed on a variety of human tumors including melanoma and glioblastoma and is co-expressed on tumor stem cells. CD200 is thought to be a mechanism by which these cells escape immune surveillance. Researchers have shown that specific peptide domains within the CD200 protein have antagonist activity (act as competitive inhibitors for CD200) for the CD200R. Together these data lead us to the development of our central hypothesis that tumor-induced immunosuppression is reversible using select competitive inhibitors of CD200. We have synthesized several competitive inhibitors by inoculating mice with tumor lysate vaccines. Preliminary data show that these inhibitor peptides derived from CD200 reverse immune suppression within lymph nodes, significantly extending survival of vaccinated glioma GL261-bearing and breast carcinoma EMT6-bearing mice. Due to the homology between human and mouse CD200, we further hypothesize that the use of CD200 inhibitors will be translatable to human cancers. IMPACT: This study is designed to elucidate and overcome the mechanism of tumor-induced immunosuppression and has major implications for the design of translational research approaches and future clinical trials. If our hypothesis is correct, the use of a competitive inhibitor may overcome the suppressive properties of the tumor in both the sentinel lymph nodes as well within the tumor microenvironment, ultimately leading to the development of novel therapeutics that increase the efficacy of cancer immunotherapy."}
+{"text": "Cross-sectional and longitudinal sequence analysis at both the population and individual level have facilitated tracking of the HCV epidemic across the world and enabled the development of tests of viral diversity in individual patients in order to predict spontaneous clearance of HCV and response to treatment. Immunological studies in HIV-positive cohorts have highlighted the role of the CD4 Studies of the natural history of acute hepatitis C virus (HCV) infection have been restricted in number due to the silent nature of early infection. Insights have been gained from studies in humans and the chimpanzee model, but these have been limited in size due to the lack of availability of subjects and restrictions on the use of primates in laboratory experiments. The global rapid rise of acute HCV in human immunodeficiency virus-1 (HIV-1)-infected men who have sex with men (MSM) is providing the opportunity to study the natural history of acute HCV infection in greater detail and on a larger scale than has been possible previously. Understanding the determinants of spontaneous clearance and response to treatment is important and may provide opportunities for vaccine development as well as new treatment strategies. While the impact of HIV on the evolution of HCV should not be underestimated, new insights from studies in the HIV-positive population are likely to apply also to HIV-negative patients with HCV. We review advances in the understanding of the evolution of HCV in HIV-infected patients at a population and individual level and discuss how further knowledge may be gained from the ongoing study of such patient cohorts.Reports of sexually transmitted acute HCV infection occurring in HIV-positive MSM in The Netherlands, France, Germany, Switzerland and the UK first appeared in the scientific literature between 2004 and 2005 .This remarkable rise in the incidence of acute HCV in HIV-positive MSM is continuing and is likely to herald a serious health burden over the coming years. Already, infection with HCV is emerging as a major cause of morbidity and mortality in individuals infected with HIV and is set to surpass AIDS-defining illnesses as a cause of death in patient populations who have access to highly active antiretroviral therapy . Surprisingly, while intravenous drug use is a risk factor in a minority of cases within each cohort, statistically, the strongest risk factors for transmission of HCV are unprotected anal sex and the use of permucosal (but not intravenous) recreational drugs  had a lower peak VL and a shorter time to peak viraemia in evolving spontaneous clearance than progressing infection. In humans, viral clearance usually occurs within 3 months of diagnosis in both HIV-infected and uninfected cohorts  and the viral RNA polymerase does not have proof-reading capacity so the possibility of variation within the HCV genome is extremely high (HCV replicates rapidly (the estimated daily production of virus is 10dN) to synonymous substitutions per synonymous site (dS); the dN/dS ratio. HCV may be subject to positive (dN/dS >1), purifying (dN/dS <1) or neutral (dN/dS\u200a=\u200a1) selection pressures and these may change at different times during infection. The dN/dS ratio model relies on the assumption that silent synonymous mutations are not subject to selection pressure. While these do not result in amino acid changes, regions of the genome that display synonymous variation may have secondary non-coding functions. HCV core and NS5B RNA, for example, contain multiple stem\u2013loops that are found in all HCV genotypes throughout both regions, as well as several strikingly conserved unpaired regions, one of which coincides with a region of the genome to which ribosomal access is required for translation initiation  and measures of diversity such as the Hamming distance (the mean number of amino acid differences between strains) may be used to quantify the composition of the quasispecies population. Selection pressure can be quantified by examining the ratio of non-synonymous substitutions per non-synonymous site , a 28 aa structure within the HCV E2 envelope protein (dN/dS <1) is the major force moulding viral population structure at this time in HIV-negative  or agammaglobulinaemia exhibit lower genetic diversity, however, due to a lack of positive immune selection pressure . This supports the hypothesis that individuals who acquire HCV sexually are subject to a smaller, less diverse inoculum, possibly due to local effects at the mucosal level, although the effect of recreational drugs on the immune system could also partly explain this difference.HIV-infected patients with sexually acquired HCV are more likely to spontaneously clear infection than those infected via intravenous drug use  and the central nervous system ; the E2 HVR-1 and the IFN sensitivity determining region (ISDR) within NS5A . The rol+ and CD8+ acquired immune response.The key role of both innate and acquired immune responses in the control of early HCV infection is supported by a large body of evidence  are associated with spontaneous clearance and response to treatment in HIV-positive and -negative individuals  cell responses are also strongly associated with outcome during acute HCV  and DQB1*0301 (OR\u200a=\u200a2.22) are associated with spontaneous resolution of acute HCV  may be found within the viral quasispecies in the HCV structural and NS proteins (+ selection pressure is as much as 32\u200a%; this is significant, but lower than that observed in early HIV infection (30\u201360\u200a%; + responses are weaker (This is important, as CD8de novo escape variants and compartmentalization of the virus. The key role of the CD4+ response in controlling infection is highlighted in HIV-positive cohorts. Many questions remain unanswered however. Firstly, the predictive role of baseline viral diversity in defining spontaneous clearance may be increased using techniques in which viral genetic diversity may be assessed in greater depth. Such analyses may also assist in predicting the response to treatment. The time at which the quasispecies diversity reaches a threshold level may define the suitability and timing of treatment and with the advent of newer treatments for HCV such as the protease inhibitors bocepravir and telapravir could potentially be used to target treatment for appropriate individual patients. Finally, the availability of larger cohorts of patients may facilitate the definition of particular protective epitopes which may be used in future vaccine development.The emerging epidemic of acute HCV in HIV-positive MSM has allowed the study of acute HCV infection on a large scale. Studies of viral evolution have shown that immune control of infection is hampered by rapid diversification due to switching dominance of viral quasispecies, superinfection, generation of"}
+{"text": "Recent literature reports an increased incidence of venous thrombosis following thalidomide use in the treatment of diseases with disease-related thrombotic risks such as malignancy, as well as concomitant use with chemotherapy and/or systemic corticosteroids. We report a case of deep vein thrombosis (DVT) and pulmonary embolism (PE) following thalidomide use in a patient with erythema nodosum leprosum (ENL) reaction who was concurrently treated with prednisolone, as well as a review of relevant literature. The benefit of the immunomodulatory effects of thalidomide was discovered accidentally in 1965 when it was given to patients with leprosy as a sedative to relieve their suffering. Subsequently, researchers noticed an unexpected clinical improvement in the signs and symptoms of ENL. Since then, the off-label use of thalidomide has become increasingly popular due to its effectiveness in the treatment of a variety of malignant and non-malignant conditions refractory to other treatments. Although common adverse effects of thalidomide therapy are well-documented in literature since its introduction, some of the uncommon risks associated with its use are still being discovered. In the recent past, there has been an increased incidence of adverse events being reported in patients treated with thalidomide including thromboembolic complications such as deep vein thrombosis (DVT) and pulmonary embolism (PE). Many studies have reported thomboembolic events with thalidomide when used in combination with multi-drug chemotherapy regimens for the treatment of multiple myeloma ,3A 60-year old man from Sri Lanka presented with a history of sudden onset breathlessness and right sided pleuritic chest pain. 5 days before he had developed a painful swelling of his right leg while he was being treated in the hospital for recurrent episodes of ENL. 3 years ago he was diagnosed to have lepromatous leprosy following a positive slit skin smear for mycobacterium leprae. He was commenced on World Health Organization (WHO) multi-drug therapy (MDT) regimen for multi-bacilary (MB) leprosy, which was complicated by type II lepra reaction (ENL) with right sided panuveitis and treated with oral prednisolone 30 mg/day with gradual tapering to 10 mg/day. He continued to develop recurrent episodes of ENL reactions since the completion of MDT-MB which was managed only with prednisolone. 3 months before the current admission he was started on a second course of MDT-MB treatment for new skin nodules with a positive slit skin smear for mycobacterium leprae. 3 weeks before he was commenced on thalidomide 100 mg twice daily in addition to oral prednisolone of 15mg per day for refractory ENL. He did not have recent major surgery, prolonged immobilization or recent diagnosis of any malignancy. There was no history suggestive of past venous or arterial thrombosis and tendency to develop thrombosis in his family.On examination he was dyspnoeic at rest without central cyanosis. He had leonine facies and generalized erythematous skin with multiple nodules. His right leg was swollen with pitting ankle oedema figure  while ha3 which normalized following withdrawal of thalidomide. His liver and renal function tests were within normal limits.During initial evaluation a venous doppler ultrasound of the lower limb confirmed a deep vein thrombosis in the right femoral vein. Subsequently a computed tomography pulmonary angiography (CTPA) confirmed pulmonary emboli in the right and left main pulmonary arteries with right lower lobe lung collapse and a mild pleural effusion figure . His iniHe was started on enoxaparin and warfarin concomitantly and the target INR of 2.5 was achieved on day 7. Thalidomide and anti leprosy therapy were stopped temporarily while low dose corticosteroid being continued. After one week his dyspnoea and general condition improved.Thalidomide was first approved in 1992 for treatment of ENL by the Federal Drug Authority and its availability has led to its therapeutic use and approval for multiple myeloma, as well as its off-label use in several other diseases such as crohn's disease, lupus erythematosus, and solid organ malignancies of kidney, brain and breast. The exact mechanism of action of thalidomide remains incompletely defined and likely differs depending on the clinical entity treated. It appears to have several immunomodulatory properties, including suppression of TNF-[alpha] production, down-regulation of cell-surface adhesion molecules involved in leukocyte migration, decreasing circulating helper T cell to suppressor T-cell ratio, and inhibition of IFN-[alpha], all of which may play a role in the treatment of ENL.  While teMajority of data on thalidomide and thromboembolism currently comes in the cancer setting, particularly in multiple myeloma, and particularly in combination with chemotherapeutic agents.  The poteThe Research on Adverse Drug events And Reports (RADAR) project identified 695 reported cases of venous thromboembolism (VTE) between 1998 and 2006 among cancer patients on treatment that include chemotherapy and/or dexamethasone with thalidomide. [Presently, there are no guidelines on the optimal antithrombotic prophylaxis in the non-cancer clinical setting for the use of thalidomide. Although the pro-thrombotic action of thalidomide in the cancer setting has been accepted, there seems to be a similar and well documented risk in the non-cancer setting as well, which could lead to life-threatening complications such as in our patient. The potential thrombotic risk in the non-cancer setting of thalidomide should be emphasized due to following reasons; oral corticosteroids being commonly used in dermatological and various non-cancer conditions; reports of thromboembolic events appear to be spontaneous and symptomatic; and the majority of thromboembolic events develop shortly after initiation of therapy, most within the first eight weeks as in our patient. The potential risks in the off-label use of thalidomide in the non-cancer setting should be emphasized and extrapolating from studies done in multiple myeloma, the use of antithrombotic prophylaxis may be effective when thalidomide is used in settings such as ENL.Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of thrombosis journal.The authors declare that they have no competing interests.RA carried out the literature search and drafted the manuscript; WB did the critical revision for important intellectual content in the manuscript and given the final approval of the version to be published; RC helped substantially in literature search and drafting the manuscript. All authors read and approved the final manuscript."}
+{"text": "An understanding of short-term memory requires models of neural networks which are able to sustain activity in the absence of external input for several seconds. About half a century ago,  predicte"}
+{"text": "Many current DNA microarray and other high-throughput data meta-analysis studies concentrate on deriving a concordant list of genes across many experiments to discover the \"true\" genes responsible for a particular disease process or biological pathway or cellular response Figure . HoweverWe describe a meta-analysis approach that allows comparison and contrast of gene lists at the level of categorical annotation (pathway or Gene Ontology annotations). This categorical evaluation compares enriched annotations between gene lists Figure , and disThe approach was tested using two gene lists, genes involved in the response to denervation in muscle (a literature compendium), and in skin . Using the categorical comparison highlights known biological processes that are common in the two cases, while also allowing one to easily see areas of difference that are not apparent from examining the gene lists alone.categoryCompare is available as a Bioconductor package, and a web interface (using RApache) has also been developed to facilitate use in the wider research community."}
+{"text": "Understanding the ecological consequences of roads and developing ways to mitigate their negative effects has become an important goal for many conservation biologists. Most mitigation measures are based on road mortality and barrier effects data. However, studying fine-scale individual spatial responses in roaded landscapes may help develop more cohesive road planning strategies for wildlife conservation.Tyto alba and stone marten Martes foina). We addressed the following questions: 1) how highways affected home-range location and size in the immediate vicinity of these structures, 2) which road-related features influenced habitat selection, 3) what was the role of different road-related features on movement properties, and 4) which characteristics were associated with crossing events and road-kills. The main findings were: 1) if there was available habitat, barn owls and stone martens may not avoid highways and may even include highways within their home-ranges; 2) both species avoided using areas near the highway when traffic was high, but tended to move toward the highway when streams were in close proximity and where verges offered suitable habitat; and 3) barn owls tended to cross above-grade highway sections while stone martens tended to avoid crossing at leveled highway sections.We investigated how individuals respond in their spatial behavior toward a highway and its traffic intensity by radio-tracking two common species particularly vulnerable to road mortality (barn owl Mortality may be the main road-mediated mechanism that affects barn owl and stone marten populations. Fine-scale movements strongly indicated that a decrease in road mortality risk can be realized by reducing sources of attraction, and by increasing road permeability through measures that promote safe crossings. For many species, roads represent particularly strong barriers to migration, dispersal, and genetic exchange as a result of changes in habitat quality, mortality and avoidance behavior due to traffic intensity, noise, and road surface characteristics To date, there has been a considerable number of studies for a wide range of species that describe patterns of road mortality and barrier effects and the environmental variables that are associated with them, thus yielding substantial insights into how some road and landscape features promote those effects One way to improve our ability to estimate both road-kill and barrier effects and to optimize mitigation measures is to move from the description of their patterns and covariates toward the study of individual behavioral responses to roads and the environmental variables that influence them Tyto alba) and stone martens (Martes foina) are good examples of such species with distinct behavior and ecological requirements. The barn owl is the most widely distributed owl species and is usually found in open habitats such as farmlands and grasslands associated to humanized areas Some species are particularly sensitive to road-related features resulting in an almost absolute avoidance of roads  versus olfactory). Barn owls may tend to avoid noisy highways whereas stone marten may ignore them. We expected habitat selection and movement properties in the vicinity of the highway to be strongly affected by traffic intensity followed by habitat suitability. Finally, suitable and continuous habitat close to the highway may explain preferences in the location of crossing events for both species. Additionally, our a priori expectation was that road features at crossing and road-kill sites should be similar if the probability of being killed was only affected by the individual crossing decisions. All in all, this information should allow for the identification of more efficient measures to minimize both barrier effects and the risk of mortality.In this paper we investigate how individuals responded in their spatial behavior towards a highway and its traffic at different spatial resolutions . We used the barn owl and the stone marten to help identify the sources of disturbance and attraction that may not be directly evident from the patterns of road-mortality. Specifically, we assessed 1) how highways affected the species home-range location and size in the immediate vicinity of these structures, 2) which road-related features influenced their habitat selection, 3) the role of different road-related features on movement properties, and finally, 4) the characteristics associated with crossing events and road-kills. Although both species have high road mortality rates, different responses to highways may arise from their distinct use of sensory systems , the remaining individuals were two years or older . All stoD_highway\u00d7Traffic is included in the most supported model for both species; indicating that individuals tended to avoid the highway when the traffic intensity increased  and 736 and 416 movements away from the highway (AWA) for barn owls and stone martens, respectively. As expected, the distance from the starting point of the segment to the highway was the most relevant factor for both species . Both spWhen considering only those movements in the vicinity of the highway we found that landscape variables describing habitat quality were related to movement directionality. The most supported model for both species demonstrated that movements toward the highway were explained primarily by a high percentage of suitable vegetation in the road verges . Stone martens were less vulnerable than barn owls, with r values of 0.002 and 0.007, for the same respective groups.Six of the marked barn owls and five of the marked stone martens crossed the highway during our monitoring. Barn owls crossed the highway 29 times during 1175 hours of radio-tracking, while stone martens did so on 70 occasions during 866 hours of monitoring. Therefore, barn owls and stone martens living next to the highway crossed it approximately 0.30 and 0.97 times per day (assuming 12 hour activity period), respectively. Using data from all marked barn owls we calculated a risk of being road-killed per crossing event Barn owl highway crossings were best explained by models containing verge features . The likelihood of a barn owl crossing a highway was higher at sections that were above-grade, with wide road verges and a higher proportion of herbaceous cover in the verge . Stone mBetween January 2003 and December 2009, BRISA recorded 11 barn owls and 13 stone martens killed within the section of highways covered by the home ranges of the individuals tracked. The comparison between the sites used for crossing and the sites where road-kills were found demonstrated that owls tended to be killed on highway sections where they preferred to cross but when traffic was high  and 3. SA more integrated understanding of the relationship between road-kills and barrier effects can help provide for the more efficient management of roads and their environmental impacts. We explored this integration by investigating the individual behavioral responses towards roads at different spatial resolutions in two species commonly found as road casualties, providing valuable information on the factors associated with the risk of mortality The first response of individuals towards highways occurs when establishing their home ranges. Our study shows that if there is available habitat, barn owls and stone martens may not avoid locating their home ranges in the vicinity of the highways, at least at the traffic volumes we observed. However, given the location of territories, highways are not barriers to movement but may be acting as an artificial home range boundary for barn owls. In fact, there are many examples of species using linear structures to define boundaries As expected, barn owls and stone martens used those areas with a higher habitat quality, including those in the vicinity of the highways. Interestingly, traffic intensity affected the habitat use of both species, but seems to have no influence on the decision to cross or move next to the highway. Stone martens and barn owls in particular relied greatly on their auditory system to locate prey - a critical factor in hunting Both species avoided using the vicinity of the highway when traffic intensity was high. Nevertheless, individuals moved towards the highway when in close proximity to streams and in places where verges offered suitable habitat, i.e., locations at which they may encounter a high abundance of small mammals Barn owls, on the other hand, seem particularly vulnerable to be killed when crossing highways, even though they crossed less often than martens. Some highway sections may be functioning as attractive sinks, especially those with suitable verges (wide with herbaceous cover) and the ones at which barn owls tend to cross (above-grade sections). Barn owls frequently locate their prey by flying only 1\u20133 meters above the ground 2 for barn owls 2 for stone martens The crossing and mortality rates of the individuals monitored during our study allowed us to estimate the risk of being killed at each crossing event, which in turn can be translated into a potential mortality rate of 48\u201396 barn owls and 70\u2013245 stone martens per 100 km of highway each year , representing suitable habitat for the stone marten in Mediterranean regions of the Iberian peninsula This study was conducted along two highway sections under private concession by BRISA Auto- Estradas de Portugal, S.A. in Alentejo province, Southern Portugal: 69.5 km on the A2 for barn owls and 18.7 km on the A6 for stone martens . Both hiBetween April 2008 and September 2009 we marked and radio-tracked 11 barn owls and 11 stone martens. All individuals were captured at locations less than 1.5 km from the highways  method to estimate the location and size of home-ranges using the LoCoH Home-range Generator for ArcGis 9.1 . The NNCH is an extension of the Minimum Convex Polygon (MCP) that identifies areas of high and low use density by taking the union of the MCP associated with k-1 nearest neighbors We evaluated the effect of road- and landscape-related features on the individual's locations by comparing the properties at the actual radio locations with the data obtained from a set of random points obtained within each home-range. We used the Schoener's Index (>1.6 and <2.4) to select independent locations D_highway\u00d7Traffic; Road-related features included average distance to the highway as well as to paved and unpaved roads. Traffic intensity was estimated as the number of vehicles that used the highway during the hour of the location. Because the influence of traffic is expected to decline as the distance to the road increases, we included an interaction term between highway traffic intensity and the distance to the highway, both obtained within the same hour  with a binomial distribution and a logit link using independent locations/random points as the response variable We monitored movements to assess whether, and if so how, these animals responded to the highway and its traffic. With these analyses we attempted to: 1) identify at which distance from the highway and at which traffic volume individuals were more likely to move toward the highway within their home-ranges, and 2) evaluate which road- and landscape-related features influenced movement directionality next to the highway. Thus, for the first objective we defined movements as sections joining two successive locations  and then classified sections in two types: move towards the highway (TOW) and move away from the highway (AWA). We extracted the following variables: 1) distance from starting point of the segment to the highway, 2) light-vehicles intensity and 3) truck traffic intensity. We designed five candidate models using all combinations of non-correlated variables. We ran binomial GLMM models with a logit link using the type of movement as the response variable  and individuals as a random effect, as described in the habitat selection analysis.lS) and final location (lF) of the segment. We used the distance to the highway at the starting point (lD_highwayS) and the difference of each variable by subtracting the value of the variable at lS from lF for the following road variables: light-vehicles and truck traffic, and the percentage of suitable road verges (trees and shrubs for stone martens and herbaceous cover for barn owls). A similar procedure was performed for forest/cropland area and distance to streams (landscape variables).To examine which road- and landscape-related features influenced the directionality of the movements next to the highway, we selected all movement sections within twice the mean location error distance to the highway for each species. Then, we extracted information on the road- and landscape-related features within a buffer with a radius equal to the mean location error of the starting location  road-related features fully explain their movements, 2) movements are affected only by landscape-related features, and 3) both types of variables explain their movements. We ran binomial GLMM models with a logit link using the type of movement  as the response variable and individuals as a random effect, following the same procedures as described above.We used GLMM to describe highway crossings by comparing the crossing sites with random sites on the highway. Crossing sites were defined as the point where the line delineated by two consecutive locations (less than one hour apart) crossed the highway. We then described three groups of road-related variables within a buffer defined by the telemetry error . CandidaRoad-related variables were provided by BRISA  and IgeoE (two-lane paved roads). Fieldwork was performed to describe road verges every 100 m . A land use map was prepared using Google Earth  to identify forest, main streams, buildings, urban areas and unpaved roads. We calculated home-ranges using Arcview 3.2 and ArcGis 9.3 and the Animal Movement extension program Table S1i -minAIC), Wi (Akaike weight).Summary of the candidate habitat selection models for barn owl and stone marten: AIC (Akaike Information Criterion), \u0394AIC (AIC(DOCX)Click here for additional data file.Table S2i -minAIC), Wi (Akaike weight).Summary of the candidate models on barn owl and stone marten movements directionality within home-range: AIC (Akaike Information Criterion), \u0394AIC (AIC(DOCX)Click here for additional data file.Table S3i -minAIC), Wi (Akaike weight).Summary of the candidate movements directionality next to the highway models for barn owl and stone marten: AIC (Akaike Information Criterion), \u0394AIC (AIC(DOCX)Click here for additional data file.Table S4i -minAIC), Wi (Akaike weight).Summary of the candidate highway crossing models for barn owl and stone marten: AIC (Akaike Information Criterion), \u0394AIC (AIC(DOCX)Click here for additional data file.Table S5Summary of the candidate crossing vsi -minAIC), Wi (Akaike weight).. road-kill sites models for barn owl and stone marten: AIC (Akaike Information Criterion), \u0394AIC (AIC(DOCX)Click here for additional data file."}
+{"text": "HIV-1 is capable of evading CTL immune response through mutations in residues both within the epitopes and in sequences flanking the epitopes leading to viral diversity - a major obstacle for vaccine design. The present study aims at identifying the HLA-restricted CTL escape mutations primarily in the asymptomatic phase, and examining a correlation between such mutations and disease progression.gag sequences was inferred using the Neighbour-Joining method in MEGA 5 to monitor viral evolution and to study CTL escape. ELISPOT will be used for mapping of the immunodominant CTL epitopes in gag with an emphasis on identifying a possible correlation between such immune responses and disease progression.In a prospective study, a cohort of select seropositive drug-naive subjects categorized into one of three clinical groups , based on the archived clinical records at YRG CARE, are being monitored for two years with repeated sampling at 6-month intervals. The phylogenetic analysis of the gag have been sequenced from ten patients each at the base level. Escape mutants in several known immunodominant CTL epitopes have been identified in many of the subjects. The viral isolates phylogenetically clustered with the reference subtype C sequences. Additionally, multiple sequences from individual viral isolates clustered together indicating genetic-relatedness. Sequence analysis with REGA HIV-1 Subtyping Tool further confirmed the subtype C identity of all the viral isolates.Twenty plasmid clones of The preliminary data are suggestive of viral escape in the chronic phase of the viral infection."}
+{"text": "Intraosseous ganglia can affect the carpal bones of the hand and must be considered in the differential diagnosis of wrist pain. A 38-year-old female presented with a 14-month history of left wrist pain and a radiolucent cystic lesion was seen computed tomography (CT) scanning. Characteristic radiographic findings of a cyst in association with a fine sclerotic rim was apparent. We report an unusual presentation of a ganglion cyst in the lunate bone with excellent treatment outcome. Intraosseous ganglion cysts (IGC) of the carpal bones located in the lunate are among the rarely seen pathologic conditions. Carpal bA 38-year-old female presented with a 14-month history of left wrist pain and a radiolucent cystic lesion found on conventional radiographs and computed tomography (CT) scanning . The patThe intraosseous ganglion was described by Fisk in 1949 Intraosseous ganglion cysts of the carpal bones located in the lunate are one of the rarely seen pathologic conditions. This case had an unusual presentation in the lunate bone with excellent treatment outcome."}
+{"text": "Studies in both human patients and retinal degeneration mouse models have suggested that microglial cells play a role in pathogenesis; however, the underlying mechanism is unknown. In this study, Stephen Tsang and colleagues describe a novel mouse model in which the expression of circulating bone-marrow-derived microglial cells can be temporally and specifically controlled using the Mafia transgene. They report that ablation of the microglial cell population accelerates retinal degeneration, concomitant with an increase in the expression of certain inflammatory cytokines. These findings implicate inflammation as a key contributory factor in Goldmann-Favre syndrome and suggest potential targets for the development of therapies relevant to this and related neurodegenerative disorders."}
+{"text": "While neural synchronization is widely observed in neuroscience, neural oscillations are rarely in perfect synchrony and go in and out of phase in time. Since this synchrony is not perfect, the same synchrony strength may be achieved with markedly different temporal patterns of activity (roughly speaking oscillations may go out of the phase-locked state for many short episodes or few long episodes). Recent developments in the time-series analysis allowed for the investigation of the temporal variations of phase-locking with a high temporal resolution . ProvideRecent study  of neuraHere we study neural oscillations recorded by EEG in alpha and beta frequency bands in a large sample of healthy human subjects at rest and during the execution of a simple motor task. While the phase-locking strength depends on many factors, dynamics of synchrony has a very specific temporal pattern: synchronous states are interrupted by frequent, but short desynchronization episodes. The probability for a desynchronization episode to occur decreased with its duration  this type of patterning is a generic phenomenon in the brain, ii) it may have some functional advantages for oscillating neural networks receiving, processing, and transmitting information, iii) it may be grounded in some general properties of neuronal networks calling for the development of appropriate nonlinear dynamical theory.To further investigate these conjectures we numerically studied a system of two and three coupled simple neuronal models (of Morris-Lecar type) and showed that fast kinetic of ionic conductances leads to the emergence of short desynchronized events when the coupling strength is below the full synchronization threshold. We further show that coupled neural oscillators exhibiting short desynchronizations require smaller values of synaptic connections between them of weaker common synaptic input to induce specified levels of synchrony strength than oscillators of the same frequency exhibiting more prolong desynchronizations.The results may suggests that whenever a  synchronous cell assembly must be formed to facilitate some function, short desynchronization dynamics may allow for efficient formation and break-up of such an assembly."}
+{"text": "Natural Killer (NK) cell responses are shaped by the integration of signals transduced from multiple activating and inhibitory receptors at their surface. Biochemical and genetic approaches have identified most of the key proteins involved in signal integration but a major challenge remains in understanding how the spatial and temporal dynamics of their interactions lead to NK cells responding appropriately when encountering ligands on target cells. Well over a decade of research using fluorescence microscopy has revealed much about the architecture of the NK cell immune synapse \u2013 the structured interface between NK cells and target cells \u2013 and how it varies when inhibition or activation is the outcome of signal integration. However, key questions \u2013 such as the proximity of individual activating and inhibitory receptors \u2013 have remained unanswered because the resolution of optical microscopy has been insufficient, being limited by diffraction. Recent developments in fluorescence microscopy have broken this limit, seeding new opportunities for studying the nanometer-scale organization of the NK cell immune synapse. Here, we discuss how these new technologies, super-resolution imaging and other novel light-based methods, can illuminate our understanding of NK cell biology. Natural Killer (NK) cells are classified as lymphocytes of the innate immune system because they are capable of directly killing virus-infected or transformed cells without prior priming. Therefore their responses need to be tightly regulated to allow proper distinction between diseased cells and neighboring healthy tissues. To ensure this, NK cell activation is shaped by the balance of signals induced from inhibitory and activating germline-encoded receptors expressed on their surface. Integration of signals from cell surface receptors takes place across a dynamic structured interface formed at the contact between NK cells and target cells \u2013 the immune synapse . AssemblNK cells are activated through surface receptors that can recognize signs of disease on other cells using different strategies. Receptors such as natural-killer group 2 member D (NKG2D) recognize ligands that are encoded in our genome and can be expressed or up-regulated on diseased or infected cells \u2013 a strategy sometimes called recognition of induced self. Alternatively, Fc receptor CD16 interacts with the Fc portion of antibodies to trigger an attack on opsonized target cells in the process of antibody-dependent cellular cytotoxicity (ADCC). Some other NK cell receptors, including natural cytotoxicity receptors NKp44 and NKp46, are less well understood. Engagement of activating receptors initiates downstream signaling cascades . Cells could be imaged when plated on activating surfaces, such as slides coated with antibodies or protein ligands, or protein-rich planar lipid bilayers. Particularly useful is that the protein composition of bilayers and coated slides can be precisely controlled \u2013 allowing quantitative studies regarding numbers of ligands used to stimulate immune cells. The application of TIRF microscopy to studies of immune synapses made it possible to observe proteins organize into discrete assemblies on a micrometer to sub-micrometer-scale, named microclusters, where (at least some) signaling takes place. Microclusters of TCR were detected and shown to be involved in signaling while migrating from the periphery of the synapse toward the center  microscopy. This allows imaging of processes happening at the interface between a cell and a coverslip with strongly decreased background fluorescence . This study established that microclusters of KIR2DL1 within the inhibitory NK cell synapse moved from the synapse periphery to the center  revealed how the cortical actin mesh \u2013 which underlies all cell surface membranes \u2013 is remodeled upon NK cell activation  has been applied by several groups , focusedUsing TIRF microscopy as well as optical tweezers coupled with confocal microscopy, motile sub-synaptic vesicles containing LAT were seen to repeatedly move between clusters of SLP-76, where they decreased motility, highlighting that both vesicular LAT and surface clusters of LAT can play a role in TCR signaling . A subseClearly, much can be gained by the application of super-resolution imaging to the study of NK cell signaling \u2013 to detect small changes in protein localization, nanocluster size distribution and molecular density within clusters during the process of target cell recognition. Indeed, the importance of the nanoscale organization of receptors was highlighted in a recent study using fluorescence correlation spectroscopy (FCS) using murine NK cell models . By recoBy applying techniques drawn from chemistry and physics, it becomes possible to interrogate important problems in biology \u2013 such as deciphering spatial and temporal details of signal integration in NK cells. High and super-resolution imaging has already established the importance of the nanometer-scale organization of proteins in T and NK cell membranes for appropriate signaling outcomes. An important paradigm emerging from the studies described here is that interactions between receptors and signaling proteins are controlled in part by the dynamics of supramolecular clusters rather than by isolated protein\u2013protein interactions as once imagined. In the near future, super-resolution imaging techniques will reveal much about the spatial and temporal dynamics that underlie NK cells making appropriate decisions during immune surveillance of target cells.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Dynamin is a super-family of large GTPase proteins that polymerise during their biological activity. Dynamin polymers form around lipid tubes and contribute to the membrane fission and scission of nascent vesicles from parent membranes. Here we used the NCBI Gene Expression Omnibus (GEO) database and the BioGPS gene expression portal to study differential dynamin gene expression in normal human organs or tissues. From the GDS1096 and GDS596 dataset, we downloaded the relative expression levels of dynamin-related genes (presented as percentages), with respect to all of the other genes on the array (platform Affymetrix GPL96), which includes the best characterised human genes. The expression profiles of dynamin in the central nervous system (CNS) are clearly distinct from the expression profiles in the other organs or tissues studied. We found that the classical dynamin DNM1 and DNM3 genes reach their maximum expression levels  in all normal human CNS tissues studied. This is in contrast to the expression profile in the other normal human organs or tissues studied, in which both dynamin DNM1 and DNM3 genes showed approximately 50% maximal expression. This data mining analysis supports the concept that there is a relationship between the synapse and the molecular function of dynamin, suggesting a new field of work in the study of neurodegenerative diseases. We have focused our attention on the expression profiling of dynamin genes in several normal human organs or tissues, using the NCBI Gene Expression Omnibus (GEO) database. We have chosen to study dynamin genes because dynamin is a super-family of GTP-binding mechanochemical proteins that are involved in fundamental processes, such as the scission of nascent vesicles from parent membranes and mitochondrial fusion and/or fission. In addii) the classical dynamins and dynamin-like proteins that tubulate and sever membranes and are involved in clathrin-mediated endocytosis and other vesicular trafficking processes ; (ii) the guanylate-binding proteins, which are induced by type II interferons and anti-inflammatory cytokines (GBP1 and GBP2); (iii) the proteins on the outside of the outer mitochondrial membrane that participate in mitochondrial fusion and contribute to the maintenance and function of the mitochondrial network (MFN1 and MFN2); (iv) proteins in the mitochondrial inter membrane space that are involved in mitochondrial fusion, and in which mutations in the gene are associated with optic atrophy type 1 (OPA1); and (v) Mx proteins, which are involved in resistance against viral infections (MX1 and MX2). Taken together, these proteins constitute a large set of GTPase proteins that polymerise within each group or family according to the dynamin molecular function GDS10. This daThe CNS consists of the brain and spinal cord, where synapses are the dynamic structures through which all nervous system signals traverse. Dynamin polymerisation in membrane fission is thought to play a significant role in the synapse (Gene Ontology GO:0003373) which is suggestive of the concept of a relationship between synapses and dynamins. SeveralThe authors declare that they have no competing interests.AR carried out the downloading of gene expression data from the NCBI-GEO database, helped design the study, and contributed to writing the manuscript. LA wrote the manuscript and helped design the study. Both authors read and approved the final manuscript."}
+{"text": "Neurons in sensory pathways exhibit a vast multitude of adaptation behaviors, which are assumed to aid the encoding of temporal stimulus features and provide the basis for a population code in higher brain areas. Here we study the transition to a population code for auditory gap stimuli both in neurophysiological recordings and in a computational network model. Independent component analysis (ICA) of experimental data from the inferior colliculus of Mongolian gerbils reveals that the network encodes different gap sizes primarily with its population firing rate within 30 ms after the presentation of the gap, where longer gap size evokes higher network activity. We then developed a computational model to investigate possible mechanisms of how to generate the population code for gaps. Phenomenological (ICA) and functional (discrimination performance) analyses of our simulated networks show that the experimentally observed patterns may result from heterogeneous adaptation, where adaptation provides gap detection at the single neuron level and neuronal heterogeneity ensures discriminable population codes for the whole range of gap sizes in the input. Furthermore, our work suggests that network recurrence additionally enhances the network's ability to provide discriminable population patterns. Behaviorally relevant auditory signals such as speech, or the reverberations that convey information about the spatial environment, are characterized by temporal features in the lower millisecond range. The intrinsic time scales of neurons that represent the auditory information in the downstream cortical processing centers are, however, much slower A central stage in the ascending auditory pathway is taken by the inferior colliculus (the auditory midbrain), which collects most afferent projections and transfers them to the thalamo-cortical system In this paper, we investigate the transformation from a temporal to a population representation using the simple paradigm of gap stimuli. We re-analyzed in-vivo recordings from anesthetized gerbils to show that such transformation indeed takes place at the level of the inferior colliculus. We then construct a computational model suggesting that the heterogeneity of biophysical properties of the neurons, particularly of their adaptation time constants, can explain the in-vivo phenomenology.All experiments were approved according to the German Tierschutzgesetz (AZ 55.2-1-54-2531-57-05 Regierung von Oberbayern). For more details see original data publication We re-analyzed previously published single unit recordings from 91 inferior colliculus neurons of young adult Mongolian gerbils with best frequencies from 2 to 12 kHz Due to the limit on the total length of the stimulus, the number of times the sound pulses are repeated per pulse train varies, as illustrated in The mean population rate response to each stimulus is shown in The spike times were translated into post-stimulus time histograms For our independent component analysis (ICA), we employ the FastICA algorithm The ICs are normalized, An important step is to find the minimum value of As a neuronal model, we use the integrate-and-fire neuron, where the membrane voltage The membrane time constant  is used as a criterion for discriminability. As a linear classifier we use the LIBSVM support vector machine implementation provided by the SHOGUN machine learning toolbox We began by constructing Temporal features of auditory stimuli on the millisecond scale are preserved in the time course of the firing rates of inferior colliculus neurons For each gap size in ICA found 3 population patterns  In order to encode arbitrary gap lengths, we require several neurons with different adaptation time constants, whose islands of high discrimination accuracy cover the whole range of possible gaps lengths. (2) If gap lengths are to be encoded by spike count, the number and size of parameter islands in which spike counts of a single neuron differ for different gap sizes generally improves with an increased number of output spikes. This spike rate may be increased by multiple factors, such as input rate, input connectivity, and recurrent connectivity.As a next step we studied a network of adapting neurons see  and inveWe first compared heterogeneity to homogeneity in classifying gap pairs of 4\u20138 ms, 6\u201312 ms and 8\u201316 ms with non-connected networks. We constructed the heterogeneous network by randomly choosing each neuron's We next looked into the advantage of network recurrence by conducting the same experiment, this time with excitatory network recurrence  gap encoding in the gerbil inferior colliculus is consistent with heterogeneity in adaptation, and that (2) this encoding is best achieved at moderate recurrent drive from the network.We finally asked, whether the observed population activity patterns not only encode gaps within the tight constraints of our paradigm, but also show some degree of invariance against changes of the parameter regime. First, we analyzed the gerbil data obtained for the same gap sizes but with varying durations of the preceding noise pulses and compared their projections onto the onset and delayed onset ICs (from 128 ms pulses) to projections of the original 128 ms pulses. For short gap sizes (dark dots), the independent components capturing onset and delayed onset responses were relatively invariant with respect to pulse length . DeviatiNext, we did the same analysis for our simulated network with heterogeneous adaptation and excitatory and inhibitory recurrent couplings. Also there, onset and delayed onset components showed gradual and systematic deviations . ParticuFrom these tests, we conclude that heterogeneous adaptation allows a linear classifier to extract gap durations with some degree of invariance to pulse lengths and background rate and thus likely provides a robust code for gap size that only changes gradually with variations of the stimulus paradigm.We investigated gap encoding in the inferior colliculus, through both analysis of experimental data from gerbils and simulation of neural networks. Our independent component analysis revealed that, when presented with stimuli containing multiple gap sizes, neurons responded with three prominent population patterns: onset, delayed onset, and sustained. Only the onset and delayed onset components showed gap-encoding capacity. In our computational effort to understand gap processing in inferior colliculus, we employed a simple input/network/read-out paradigm that emulated some of the basic features of the auditory midbrain. Then, starting from a single adapting neuron, we showed that experimentally-observed population patterns could arise from heterogeneous adaptation in a network. Moreover, network recurrence could serve to further enhance the network's ability to provide discriminable population patterns.discrimination tasks in rodents are rather rare. In Psychophysical experiments in gerbils nd 64 ms .The inferior colliculus is a very heterogeneous brain structure, morphologically and physiologically In light of this variety of receptive fields, it may not come as a surprise that there are only few general theories on inferior colliculus function. One of these theories The translation from time to rate can occur by means of adaptation (as in our model) but can also result from intricate combinations of inhibition and excitation via delay lines otential  linearlyOur model can be generalized to also describe population coding of amplitude-modulated (AM) signals. Neurons in the inferior colliculus discharge phase-locked to AM stimuli Adaptation is ubiquitous along sensory pathways"}
+{"text": "Ankle joint sprain and the subsequent development of chronic ankle instability (CAI) are commonly encountered by clinicians involved in the treatment and rehabilitation of musculoskeletal injuries. It has recently been advocated that ankle joint post-sprain rehabilitation protocols should incorporate dynamic neuromuscular training to enhance ankle joint sensorimotor capabilities. To date no studies have reported on the effects of dynamic neuromuscular training on ankle joint positioning during landing from a jump, which has been reported as one of the primary injury mechanisms for ankle joint sprain. This case report details the effects of a 6-week dynamic neuromuscular training programme on ankle joint function in an athlete with CAI.The athlete took part in a progressive 6-week dynamic neuromuscular training programme which incorporated postural stability, strengthening, plyometric, and speed/agility drills. The outcome measures chosen to assess for interventional efficacy were:  CumberlaCAIT and SEBT scores improved following participation in the programme. The angle of ankle joint plantar flexion decreased at the point of initial contact during the drop landing and drop vertical jumping tasks, indicating that the ankle joint was in a less vulnerable position upon landing following participation in the programme. Furthermore, GRFs were reduced whilst walking post-intervention.The 6-week dynamic neuromuscular training programme improved parameters of ankle joint sensorimotor control in an athlete with CAI. Further research is now required in a larger cohort of subjects to determine the effects of neuromuscular training on ankle joint injury risk factors. The human ankle joint is one of the most frequently injured joints in the human body, with lateral ligament sprains being the most common type of ankle injury . FollowiThe treatment and rehabilitation of individuals with CAI poses a significant challenge for clinicians, and has enormous healthcare and economic costs . A numbeOne of the primary mechanisms of ankle joint sprain involves aberrant ankle joint positioning upon initial contact with the ground during the transition from an unloaded to a loaded state  . HoweverThus the objective of the present study was to examine the effect of a 6-week dynamic neuromuscular training programme on parameters of sensorimotor function in an athlete with chronic ankle instability (CAI).The 19-year-old athlete  was injured whilst competing in a line-out during an amateur rugby union game, in January 2008. The mechanism of injury involved a \"forced inversion\" of the left ankle joint as a result of landing awkwardly from the line-out jump. The athlete was unable to continue participation in the game and that evening attended the Accident and Emergency Department of a nearby hospital. X-ray imaging failed to reveal any bony abnormality. The ankle joint was markedly ecchymotic and edematous and the athlete was prescribed simple analgesics and given crutches to use for mobilization. He was advised to progress from non-weight bearing (NWB) to full-weight bearing (FWB) and normal function as pain permitted.Following the initial injury the athlete who himself was an under-graduate physiotherapy student consulted one of the authors (ED). On examination mechanical instability was evident upon anterior drawer testing. Initially it was decided to institute a course of manual therapy. Anterior-posterior (AP) mobilisations of the inferior tibiofibular and talocrural joints were performed once a week for a period of six weeks in keeping with positional faults noted on assessment (i.e. restriction in weight-bearing dorsiflexion and reduced posterior glide of the fibula at the inferior tibiofibular joint). In conjunction with this manual therapy the athlete was prescribed some simple static postural stability exercises. These included single leg stance exercises with eyes open and eyes closed. Following this course of treatment the athlete was fully weight-bearing and the swelling had largely resolved.Despite these measures, six months following the initial injury the athlete continued to complain of limitations during functional activities which were adversely affecting his level of sports participation. He described how he felt that he was \"struggling\" to reach the same level of sporting performance compared to his pre-injury status. Furthermore the athlete complained of recurrent episodes of his ankle joint \"giving way\" with increasingly innocuous activities, and a generalized feeling of ankle joint \"weakness\". During this six month period the athlete also reported one other significant inversion injury which required a short period of NWB.At this time it was decided to undertake further radiological investigation. Magnetic resonance imaging (MRI) revealed fluid in the peroneal sheath suggestive of tenosynovitis, as well as thickening of the ATFL with some discontinuity of fibres at the fibular attachment in keeping with a grade 2 tear. At this stage the athlete decided to withdraw from formal sports participation primarily due to academic commitments.The athlete did however occasionally participate in recreational sporting activities but again was limited due to regular episodes of ankle joint \"rolling\". In October 2009 the opportunity arose to enroll the athlete who was now in his final year as an under-graduate physiotherapy student in a dynamic neuromuscular training programme. This opportunity arose as the primary author (JOD) was due to undertake a research project for the part fulfillment of his M.Sc. degree, and subsequently chose to design a case study to investigate the effect of a dynamic neuromuscular training programme on ankle joint function in a subject with CAI. Full approval for the study was received by the University Human Research Ethics Committee and informed subject consent was acquired. The subject had no previous history of lower limb injury nor did he suffer with diabetes, peripheral neuropathy or any other condition known to effect postural stability or proprioception.The novelty of this case is that it is the first to report on the effects of a dynamic neuromuscular training programme on ankle joint positioning during jump landing in a subject with CAI. In addition to measures of ankle joint kinematics during jump landing we also investigated the effects of the intervention on other important aspects of ankle joint function, such as walking kinetics, postural stability as well as self-reported ankle joint function as measured by the CAIT.The severity of ankle joint instability was initially assessed using the CAIT . Prior tDeficiencies in postural stability have been shown through prospective research to be a predictor of ankle joint injury development ,14. FurtOne measure of dynamic postural stability commonly employed by clinicians and researchers alike is the SEBT. Previous research has shown that subjects with CAI have decreased performance on the SEBT as measured by reach distance, compared to non-injured controls ,17. DuriPrevious research has suggested that an increased plantar flexion touch-down angle upon landing from a jump could precipitate the onset of an ankle joint sprain . Thus, aDuring performance of the drop landing the participant initially stood on the non-injured leg and was required to \"step\" off the 35 cm high platform and land on the centre of the force-plate on the injured leg. This methodology has previously been described by Delahunt et al . For thePrevious research has suggested that the gait profile of subjects with CAI differs from non-injured control subjects ,24-26. SEqually, subjects with CAI have also been shown to have a dorsiflexion deficit and altered shank-rearfoot coupling ,25. ReceWe chose to investigate the rearfoot angular displacement at the point of IC with the force-plate during walking as well as the peak ground reaction force components during the stance phase. IC was defined as the point when the vertical component of ground reaction force exceeded 10 N. Lower limb joint angular displacements were captured at 200 Hz by 3 CODA mpx1 motion analysis units, while ground reaction forces were captured at 1000 Hz with a walkway embedded force-plate . The athlete performed 10 gait trials at self-selected walking pace with the average value of the ten trials being utilized for the analysis of differences between the pre- and post-intervention conditions.SMD = difference in mean outcome between groups/mean of the SD of the pre- and post-intervention outcomesA modified standardized mean difference (SMD) was calculated for the outcome measures as follows: The athlete took part in a progressive 6-week dynamic neuromuscular training programme incorporating postural stability, strength, plyometric, and speed/agility drills Table .To date little or no research has been done to develop a treatment or impairment based classification system that addresses the multi-factorial nature of CAI, hence a comprehensive multi-component programme was implemented. Exercises were to be progressed from simplistic to increasingly complex, and were based on a compilation of previously published rehabilitation protocols to reflect current practices coupled with elements that addressed the functional demands of this particular individual -9. GivenFollowing the intervention the athlete again completed the CAIT questionnaire. His post-intervention CAIT score was 27, differing from the pre-intervention score by 23 points . There was however a reduction in the peak vertical, lateral and braking components of ground reaction force (Table Following the six week training programme there was no change in rear-foot frontal plane angular displacement (2.16 The primary outcome from this study was that a dynamic six-week neuromuscular training programme resulted in improvements in a number of sensorimotor insufficiencies that have been associated with CAI.The results of the present study concur with those of McKeon et al  and HaleDecreased postural stability has been identified as a risk factor for ankle joint sprain ,14. It hAberrant ankle joint positioning during the transition from an unloaded to a loaded posture has been identified as a risk factor for ankle joint injury . SpecifiDuring walking no change was noted in the position of rear-foot inversion which further corroborates the findings of McKeon et al . HoweverThe present study does have a number of limitations. Firstly it is a case report and thus extrapolation to all subjects with CAI requires careful consideration. Therefore, further studies with a randomized controlled design are required to fully determine the effects of dynamic neuromuscular training programmes on ankle joint sensorimotor control. Furthermore, during the pre- and post-intervention test session we did not record any lower limb electromyographic activity. This would have afforded us a greater understanding of ankle joint sensorimotor control, and in particular the initiation and magnitude of muscle activity . This maThe 6-week dynamic neuromuscular training programme improved parameters of ankle joint sensorimotor control and subjective function in an athlete with CAI. Further research is now required in a larger cohort of subjects with CAI to determine the effects of neuromuscular training programmes on ankle joint injury risk factors.The authors declare that they have no competing interests.JOD and ED conceived and performed the study and drafted the manuscript. FK participated in the design of the study, evaluation of the data and writing the manuscript."}
+{"text": "These mTOR inhibitors impart a pronounced inhibitory effect on inflammation, an early component with diverse ramifications influencing the progression of DR. These inhibitors suppress IKK and NF-\u03baB along with downstream inflammatory cytokines, chemokines, and adhesion molecules. In proliferative DR, mTOR inhibitors suppress several growth factors that play pivotal roles in the induction of pathological angiogenesis. Lead mTOR inhibitors in clinical trials for ocular indications present an attractive treatment option for chronic use in DR with favorable safety profile and sustained ocular pharmacokinetics following single dose. Thereby, reducing dosing frequency and risk associated with chronic drug administration.Novel therapeutics such as inhibitors of PI3K/Akt/mTOR pathway presents a unique opportunity for the management of diabetic retinopathy (DR). Second generation mTOR inhibitors have the prospect to be efficacious in managing various stages of disease progression in DR. During early stages, the mTOR inhibitors suppress HIF-1 Blindness as a consequence of diabetic retinopathy from long-standing or poorly controlled diabetes causes profound adverse psychological effects to the diabetic patient. Diabetic retinopathy has a significant economic impact on society in terms of healthcare resources that are required and the potential of loss in the workforce. The number of people at risk of blindness from diabetic retinopathy in the United States alone continues to rise, and diabetic retinopathy is the leading cause of blindness in the industrialized world covering a wide age range in adults . DiabetiAnti-VEGF-A therapeutics has become a dominant approach for the management of ocular neovascular diseases , 7. OngoWithin the past seven years, two drugs targeting VEGF were approved for combating ocular neovascularization. Both these drugs, Macugen (pegaptanib) and Lucentis (ranibizumab) were approved for exudative age-related macular degeneration. More recently, Lucentis has received approval for use in patients suffering visual impairment due to macular edema secondary to central and branch retinal vein occlusion , 9. The The success of anti-VEGF treatments has produced an unprecedented understanding of the factors and pathogenic mechanisms operant in several retinal neovascular diseases and has demonstrated that therapeutic agents considered initially only in the realm of anticancer agents have demonstrated efficacy in combating ocular neovascularization. Could a similar story be on the horizon for mTOR inhibitors for which the principal indication has also been in the treatment of cancers?Other antiangiogenic approaches for ocular angiogenic diseases involve growth factors , steroid compounds, or kinase inhibitors . No mTOR inhibitors which target the mammalian target of rapamycin are currently being clinically evaluated for their efficacy in nonproliferative or proliferative stages of diabetic retinopathy. Only two mTOR compounds, Sirolimus  and Palomid 529  are currently being evaluated in NIH-sponsored trials for ocular indications. Sirolimus is being evaluated to treat diabetic macular edema which is a frequent manifestation of diabetic retinopathy, for ARMD, and for uveitis. Palomid 529 is being evaluated for ARMD , 10. TheAn active PI3K/Akt pathway has been linked to glucose dysmetabolism in retinal tissue. The direct effect of high glucose on retinal endothelial cells imparts a promigratory phenotype with increased fibronectin and alpha (v) beta-(3) integrin expressions which appears to be concomitant with the activation of PI3K/Akt pathway . ElevateExperimental findings  suggest in vitro finding that the mRNA and protein expression of the anti-angiogenic factor PEDF is reduced by glucose as well as insulin raises interesting implications for the diabetic retina. These common physiological metabolites are elevated in type 2 diabetics, and it has been shown that these metabolites are dependent on the mTOR pathway for their destabilizing effect on PEDF -chromen-6-one, is a first-in-class allosteric dual mTORC1 and mTORC2-omid 529 . The safClinically relevant adverse events have been experienced with the use of TORC1 inhibitors, Sirolimus, and its analogs, when administered via systemic administration as described in In this model, when Palomid 529 is compared head to head with a murine anti-VEGF antibody, the anti-VEGF antibody treatment appears to inhibit both pathological and normal angiogenesis while Palomid 529 inhibits predominantly pathological angiogenesis. This is shown by presence of avascular space around optic nerve in control, increased with anti-VEGF treatment but essentially lacking with Palomid 529 treatment. This observation suggests that the inhibitory actions of Palomid 529 influencing the PI3K/Akt/mTOR pathway is mediated by normalizing the signaling activity level of this pathway rather than promoting a suppressive blockage leading to subnormal function. In support of this viewpoint is the observation that neonatal vascularization in the oxygen-induced retinopathy mouse pups was not adversely affected and perhaps eases concerns regarding the induction of adverse events in young patients when using Palomid 529.In addition, upon closer inspection at higher magnification, anti-VEGF antibody did not appreciably inhibit glomeruloid formation (\u201cmicroaneurysms\u201d), while Palomid 529 showed significant inhibition of this vascular malformation, see Palomid 529 has completed 4 of 6 cohorts of the company's ongoing intravitreal Phase 1 human age-related macular degeneration trial. The NEI is also conducting its own Phase I trial in age-related macular degeneration with subconjunctival administration. Preliminary results in the intravitreal study have shown significant reduction of retinal thickness as evidenced by OCT in two of the three patients at the 4th cohort (0.5 micrograms). Positive data has also been observed with the NEI trial. The outcome of these trials will be very instructive with regards to future application of this drug, other drugs of its class, and to other angiogenic ocular diseases. Clinical trial data on safety and efficacy of dual mTOR inhibitors is emerging, particularly for the treatment of a variety of cancers. There have been widespread concerns that the novel dual mTOR inhibitors with their potent capacity to cause extensive and diffuse blockade of downstream signaling will exhibit additional and perhaps unpredictable side effects beyond what has already become apparent from the side effect profile of the early generation mTOR inhibitors. However, from the limited clinical data that has emerged using dual mTOR inhibitors, the prognostic outlook for the utility of these agents in providing improved therapeutic outcomes with reduced tachyphylaxis appears encouraging . For theIt has been suggested that mTOR inhibition in the setting of hyperinsulinemia and type 2 diabetes would be a particularly attractive therapeutic modality . The useFrom a drug development standpoint, the PI3K/Akt/mTOR pathway has presented some unique challenges . The higIn order to prevent or delay drug resistance and minimize ancillary side effects of mTOR inhibition, selective dual inhibitors of mTOR complexes as well as combination therapy with other agents such as VEGF antagonists will be crucial for the development of new therapeutic options to manage the complex vasculopathy of diabetic retinopathy. A significant therapeutic opportunity exists in that mTOR inhibitors reduce VEGF mRNA stability , thereby\u03b1, it may be possible to approach anti-angiogenic therapy from a dual approach in combination with anti-VEGF monoclonal antibodies  or VEGF-trap while minimizing the potential for overlapping toxicities and at the same time selectively targeting the operant mechanism(s) in the pathobiology of diabetic retinopathy. Dual mTOR inhibitors capable of synergizing with anti-VEGF therapeutics that either inhibit a distinct regulatory site on the same pathway or inhibit a parallel prosurvival pathway would provide a broader mechanistic intervention of the angiogenic process. Because mTOR inhibitors have a direct anti-angiogenic effect, mediated via modulation of HIF-1Several Phase I studies have investigated the safety profile of combination therapy using bevacizumab and mTOR inhibitors sirolimus, everolimus, or the dual mTOR inhibitor WYE-125132 in cancer patients \u2013117. PreAn analogous approach can be taken by linking mTOR inhibitors with other antagonists or agents where the mechanism of action targets an alternate pathway, thereby augmenting the potential for additive or synergistic outcomes on efficacy measures. The combinatorial drug approach with mTOR inhibitors can be extended to be coadministered with an entire class of anti-inflammatory agents as combination therapy. The mTOR inhibitors in combination with Nepafenac, currently in clinical trials for non-proliferative diabetic retinopathy and macular edema, would appear to be a feasible combinatorial-drug approach to combat diabetic retinopathy. Experimental findings using topical 0.3% Nepafenac 4x/day in diabetic rats for up to 9 months has demonstrated reductions in superoxide, cyclooxygenase-2, PGE-2, and leukostasis and prevention of functional changes in oscillatory potential as well as vasculopathy including apoptosis, regions of acellularity, and degeneration of pericytes .The multi-drug approach might provide the therapeutic advantage that lower doses of each of the combined agents would be required for efficacy with the benefit of minimizing potential toxicities. This strategy can be justified on the evidence that extensive cross-talk of pathways underlie the angiogenic signaling cascade and that the vasculopathy innate to diabetic retinopathy involves a myriad of initiators. Particularly, attractive would be the combinations of mTOR inhibitors with triamcinalone (Kenacort) or dexamethasone (Ozurdex) both of which have developed either scleral or intravitreal sustained drug delivery formulation and first-in class biodegradable device technologies for drug delivery to the retina. Several studies have investigated the benefit of combining mTOR inhibitors with established glucocorticoid anti-inflammatory agents in cancer patients. The mTOR inhibitors not only potentiate the apoptotic effect of steroids, but confer enhanced sensitivity to glucocorticoids, thereby, potentially allowing sustained efficacious and chronic use of these drugs in ophthalmology to treat ocular angiogenic and inflammatory diseases without having to increase dosage over time. The clinical utility of glucocorticoids in ophthalmology is extensive but is hampered by side effects as well as the development of glucocorticoid resistance imposing a limit on the duration of use and clinical utility. The combined use of rapamycin with dexamethasone appears to impart the benefit of not developing resistance to the biological effects of dexamethasone as well as enhancing the proapoptotic caspase-3 signaling . The molTransscleral delivery of triamcinalone and Lucentis has been successfully applied in animal models using electrically facilitated macroesis methodology . DexametDue to anatomical and physiological barriers, the eye presents a myriad of challenges as a target organ for drug delivery. Recent advances in drug delivery technology including formulation, polymer chemistry, nanotechnology , microdrThe optimal drug delivery approach depends, to a substantial extent, on the physiochemical and pharmacokinetic properties of the pharmacological agent to be administered. Some of the highlighted techniques, although optimized for ocular surface or anterior pole diseases, have resulted in sufficient enhancement of drug penetration that they also have utility for pharmacological treatment of ocular diseases of the posterior segment. Several of the anti-inflammatory and anti-VEGF pharmacological agents that are proposed in this review to be used in combination with mTOR inhibitors have been administered to the ocular surface using one of the described drug delivery or formulation technologies to treat retinal diseases. For instance, nanocomposites have been used to deliver Diclofenac , and topA microparticle formulation containing an antagonist to a leukocyte antigen applied topically to the ocular surface has demonstrated sufficient ocular penetration to influence leukocyte dynamics and vascular leakage in the retina, both manifestations of diabetic retinopathy . Use of Additional techniques and methods have been optimized with the specific aim of treating diseases of the posterior pole \u2013145. TheThese biodegradable or nonbiodegradable intraocular implants can be placed in the vitreous or via cannulation in the suprachoroidal space  to lowerOf particular interest, in light of the theme of this review, is the use of microemulsion to enhance the corneal permeation of the mTOR inhibitor everolimus with sustained stability of the drug  and the While it is unlikely that a single drug will be efficacious for managing all the various stages of diabetic retinopathy, combination or sequential therapeutic agents are more apt to yield beneficial results. Combinatorial use of a dual mTOR inhibitor with anti-VEGF antibodies or VEGF-trap could neutralize cross-talk inducers of VEGF expression and be a powerful combination approach to ocular anti-angiogenic therapy. Compelling evidence for enhanced efficacy of combined drug therapy to combat ocular angiogenesis has been previously presented, and the evidence underscores the extensive overlap of regulatory signaling involved in the angiogenic cascade . Potent \u03b1-mediated downstream activation of growth factors. As the disease progresses and the characteristic lesions are proliferative in nature, the inhibition of PI3K/Akt/mTOR pathway would provide an effective means to abrogate neovascularization by shutting down prosurvival growth factors, modulating the inflammatory cascade, preventing angiogenesis, and promoting apoptosis of nascent vessels. The combination of mTOR inhibitors with anti-inflammatory agents also provides a rational-based approach to combat ocular angiogenesis and early hemodynamic changes in the retina. The mTOR inhibitors are uniquely suited to address both early and advanced manifestations of diabetic retinopathy. The mTOR inhibitors have the potential to delay or prevent the progression of retinal microangiopathies by helping to avert breakdown of blood-retinal barrier by modulating HIF-As we continue to unravel the complexity of the initiating factors that contribute to the microangiopathy observed in progressive diabetic retinopathy and gain further understanding of the natural progression of the disease it is imperative that emerging therapeutics like mTOR inhibitors be well contemplated in the context of their mechanism of action, stage progression of the retinopathy, and the critical timing of pharmacological intervention. A drug can be ineffective or even result in adverse effects if implemented during an inappropriate stage of disease progression. Therefore, managing of the complex vasculopathy in diabetic retinopathy will require elucidating the proper timing of when to administer the therapeutic agent for optimal efficacy. Regardless of the enigmatic components that remain with regards to the elucidation of the molecular pathways operant in diabetic retinopathy, these novel classes of therapeutics are likely to produce better patient outcome for managing the widespread and devastating disease of diabetic retinopathy. The mTOR inhibitors, particularly when combined with other pharmacological agents would appear to be a promising therapeutic modality.The second-generation mTOR inhibitors discussed in this review are well positioned to fulfill several key criteria for being an optimal therapeutic for treatment of ocular angiogenesis: (1) targets neovascularization by specific mechanism, (2) delays or prevents the angiogenic phase of the disease, (3) demonstrate specificity and selectivity for aberrant vessels, (4) has a formulation for long-term delivery with no apparent toxicity associated with chronic administration, (5) stabilize, or prevent further deterioration of vision, (6) prevent or delaying late-stage complications of the disease such as detachment and scarring.Dr. Jacot has no proprietary or commercial interest in any materials presented in this review. Dr. Sherris is President and Chief Executive Officer of Paloma Pharmaceuticals, Inc. and has proprietary and commercial interests in Palomid 529 mentioned in this review."}
+{"text": "Infections with Hepatitis viruses B and C pose major problems both short and long term respectively after HSCT. The key to prevention for Hepatitis B disease remains vaccination for HBV-na\u00efve patients and judicial use of anti-viral therapy in both pre- and post-transplant settings for HBV-infected patients. HBsAg positive grafts to HBV-na\u00efve recipients result in transmission of the virus in about 50%. The newer anti-viral agents have enabled effective treatment of post-transplant patients who might be lamivudine-resistant or might develop so. Selecting a previously infected donor who has high titres of surface antibody for HBsAg positive patients gives the best chance for immunological clearance. The most challenging aspect of preventing HBV reactivation remains the duration of anti-viral therapy and timing of its withdrawal as most reactivations and often fatal ones occur after this period. Hepatitis C, on the other hand affects long-term survival with early onset of fibrosis and cirrhosis. Early effect of Hepatitis C virus on the immune system remains conjectural. The standard combination therapy seems to be effective, but data on this front remains sparse, as in the case of the use of newer antiviral agents. HSCT from HCV infected grafts result in more consistent transmission of the virus and pre-donation treatment of donors should be undertaken to render them non-viremic, if possible. The current understanding and recommendations regarding prevention and management of these infections in HSCT recipients are discussed. Haematopoietic Stem Cell Transplantation (HSCT) has evolved over the last three decades from a procedure limited to high-risk haematological malignancies with high risk of morbidity and mortality to a much more widely applicable one across age and donor barriers. Given the explosive expansion of indications for HSCT and the new and novel techniques of transplantation, the nature of complications, particularly the opportunistic infections have evolved as well. Hepatitis B and C virus infections are widely prevalent amongst the general population, though differentially across the various continents. The impact of these infections on transplant outcome is getting better recognised. A recent guideline published jointly by the CIBMTR, CDSC and other organisations have tried to address these issues from a global perspectiveOver 350 million people are HBV carriers worldwide, with the infection being endemic in several countries. The prevalence of chronic hepatitis B infection in endemic areas range from 5\u201325%, whereas, that in non-endemic regions are less than 0.5%The course and outcome of HBV infection depends on two factors: age at infection and the host-virus interaction. Neonatal infection usually results in persistent infection, but acquisition of the virus later in life most commonly result in acute hepatitis. Whilst acute viral hepatitis is self-limiting, a small minority <5%) can progress to fulminant hepatic failure. About 10% of those infected after the first two years of life would be a chronic carrier, with 20% of those developing cirrhosis. Again, 25% of those with hepatitis B associated cirrhosis could develop hepatocellular carcinoma% can proreverse seroconversion. In the context of autologous transplants, this risk was deemed to be greatest in patients transplanted for myelomaHBV reactivation post-transplant is characterised by rising levels of HBV DNA in blood during the period of severe immunosuppression preceeding the rise in liver enzymes (ALT and AST) at the onset of immune recovery. Unless serially monitored, this sequence of events might be missed, as the HBV load might not be as high at the onset of clinical hepatitis which marks the recovery of cellular immunity. Although any chemotherapeutic or immunosuppressive agent used during conditioning increases the risk of HBV reactivation, steroids pose the greatest risk. Steroids facilitate replication of HBV through a glucocortcoid responsive element in the viral DNAEvery HSCT recipient should be screened for evidence of past or current HBV infection. The screening should comprise of anti-HBc, HBsAg and anti-HBs (AII). This should be carried out in every patient much before HSCT, ie before initiation of chemotherapy for malignancy or transfusion for non-malignant disorders or at the earliest stages of consideration for HSCT.If the above parameters are negative, the patient should be immunised with two doses of hepatitis B vaccine at 3\u20134 weeks interval before initiating chemotherapy or transfusion and preferably the third dose at 6 months (AII). This is often not possible in patients undergoing chemotherapy for newly diagnosed cancers. The third dose in these patients should be administered a few months after completion of chemotherapy. The chances of response to immunisation are over 90% in normal individuals, but this is much lower in patients undergoing chemotherapy (less than 60%).Past exposure to HBV in a HSCT recipient increases the risk of HBV reactivation post-transplant depending on the sero-status. The possible scenarios are described in Donors should be routinely screened using same parameters as the recipient. The possible scenarios with donor-recipient sero-status are detailed in All patients who are positive for either HBsAg or HBV-DNA and those who receive grafts from similar donors are at the highest risk of HBV reactivation (defined as \u2018High Risk\u2019). Those who are negative for HBsAg or HBV-DNA pre-transplant but have low anti-HBs titres or those receiving grafts from HBsAg positive donors who are rendered non-viremic following antiviral therapy are deemed to be at risk of HBV-reactivation albeit lower (defined as \u2018Low Risk\u2019). Such patients should be closely monitored for viral load and liver function .There are two approaches to address this.Intervening on diagnosis of hepatitis B reactivationPre-emptive intervention pre-transplant.5 copies/ml) are at the greatest risk of HBV reactivationThe current evidence weighs heavily in favour of preemptive intervention (AI). In patients who go to autologous HSCT with high viral load . Extended use of lamivudine, not only results in reduction of HBV reactivation and the resultant complications, but also impacts HBV-associated mortalityImmunity to HBV can be adoptively transferred from the donor to the recipient. Anti-HBs positive marrow donation has resulted in durable anti-HBs expression in the recipientPatients who are anti-HBs and anti-HBc positive pre-transplant are considered to be at negligible risk of HBV reactivation. However, over 50 cases of reverse seroconversion have been reported in the literature, following both autologous and allogeneic transplantation, with an approximate overall risk of 1%In UK for example, the risk of acquiring hepatitis B through transfusion is I in 150,000. The same is not true for many Asian or Latin American countries, where the disease is endemic and prevalent in upto 25% of the population in certain areas. The importance of active immunisation in unexposed patients before administration of blood products cannot be overemphasised (AII). However, this is not always practicable and a proportion of patients would be poor-responders. All patients should have the serological profile repeated prior to HSCT, even if they were HBV-na\u00efve and immunised prior to chemotherapy. This is because of the possibility of reverse seroconversion through the period of cytotoxic and immunosuppressive therapy which most would be exposed to prior to transplantation (AIII).Anti-HBs negative HSCT recipients who have recived a graft from HBV-na\u00efve donor and have not been immunised or have failed to mount a response to vaccination are at increased risk of acquiring HBV from an infected partner. Those who experience loss of anti-HBs post-transplant are also at similar risk. Late hepatitis from sexual transmission has been reportedGlobally, about 170 million people are chronically infected with Hepatitis C virus (HCV) and about 3\u20134 million more are infected each year. The major mode of transmission is via infected blood products and infected needles shared by drug-users or percutaneous procedures. The prevalence of chronic HCV infection is higher in Africa and South East Asia than in Western Europe and North America. However, the disparity is not as pronounced as in HBV, largely because of the millions infected in these places through blood transfusion before 1992, when second generation anti-HCV testing came into being (WHO factsheet). Unsafe blood products still contribute to majority on newly acquired HCV in countries with high prevalence of the infection.Majority of patients infected with hepatitis C do not have acute clinical manifestations, unlike HBV. However, 80% of those infected develop chronic infection and 20% of chronic HCV infected cohort develop cirrhosis of the liver after 20\u201330 years with 1\u20135% developing HCC. Prior to the identification of hepatitis C in 1989 and effective screening in 1992 onwards, several million people were infected globally through blood transfusion. In a look-back study, Seattle identified that 32% of 355 patients who received a transplant in 1987\u201388 were infected with HCVAssociated iron overload.History of excessive alcohol intake.H/O hepatitis C for over 10\u201315 years.Clinical evidence of chronic liver disease.HCV infection in the recipient without any evidence of liver damage is not a contraindication for HSCT. The only short term risk is probably associated with VOD. However, all HSCT recipients should be assessed with careful history, examination and liver function test for the risk of HCV infection (BIII). Anti-HCV antibodies must be tested in all HSCT recipients (AII). Those with history of transfusion before 1992 (this may vary according to the country of origin), IV or inhaled drug abuse, tattoos and unexplained rise in liver enzymes, should undergo nucleic acid testing for HCV despite a negative anti-HCV (AII). Anti-HCV response takes 6 months to be detected or may never be detectable in a small proportion of individuals or during or immediately after prolonged and heavy chemotherapy or immunosuppressionPatients with evidence of cirrhosis or hepatic fibrosis should not be considered for conventional conditioning (DIII).Two studies have suggested that the risk of VOD is increased in patients with HCV infection and raised ALT pre-transplant, whilst others have suggested to the contrary. However, in patients with iron overload with HCV infection with raised ALT, VOD prophylaxis could be recommended routinely, in the absence of any conclusive evidence to the contrary (BIII).Donors who are HCV-RNA positive invariably transmit HCV to uninfected recipient. Recipients show evidence of viremia in the immediate post-transplant periodThe standard treatment for chronic hepatitis C infection is a combination of interferon and ribavirin, which produces 80% sustained virological response in genotypes 2 and 3 and 40\u201350% in genotype 1Treatment for chronic HCV should be considered in all HSCT recipients in collaboration with a hepatologist. The indications are listed in Treatment should be initiated with full-dose peginterferon and ribavirin.Dose modifications should be made based on tolerance and cytopeniasThe treatment should be continued for 24\u201348 weeks depending on response.Sustained Virological Response (SVR) is defined as negative HCV-RNA 24 weeks from completion of treatmentBased on the current evidences, the following can be recommended (BIII):Limited data suggests improved outcome in HSCT recipients infected with HCV who respond to combination therapy.As mentioned above, HCV-RNA positive donors universally transmit virus to the recipient immediately following stem cell infusion. Donors who are anti-HCV positive but HCV-RNA negative are unlikely to infect the recipient. Based on these premises, it might be logical to attempt viral clearance in the donor prior to stem cell harvest, if feasible. There are few reports on success of this methodHepatitis viruses B and C are widely prevalent in the general population and affect the outcome of HSCT. Prevention is the key to overcoming problems related to these viruses. However, proper strategies adopted in transplanting infected patients or grafts from infected donors can minimise both short- and long-term complications and fatal outcomes."}
+{"text": "Three dimensional pharmacophore models can be considered as an ensemble of steric and electronic features in space, which are necessary to ensure intermolecular interaction with a specific target in order to trigger or to block biological activity . By idenCavKA (Cavity Knowledge Acceleration), our own in-house strategy employs the information of Co-crystallised ligand-receptor complexes for an automatic pharmacophore creation. Ligand features interacting with the binding site are detected and Grid  force fiOur method is compared to LigandScout  and a cu"}
+{"text": "There is general agreement that mitochondria play an important role in the aging process, but the role of mitochondrial oxidative stress remains controversial. Most previous work looking at mitochondrial oxidative stress has focused on damage to DNA, proteins, and lipids with age or in response to manipulation of cellular antioxidants. The interaction between oxidative damage and aging has been called into question in recent years by studies demonstrating little effect on aging and lifespan in mice with genetically modified antioxidant systems . A notabThere is growing appreciation for a more subtle role for oxidative stress in aging. This perspective recognizes the important role of reactive oxygen and nitrogen species in regulating adaptive responses to physiological stress  . One cha2O2 production from aged mitochondria. Therefore, the results from the paraquat experiments suggest that reversible redox inhibition of in vivo mitochondrial energetics may contribute to the mitochondrial aging phenotype.Our laboratory is interested in whether redox inhibition of mitochondrial function contributes to age-related energy deficits in vivo in mouse and human skeletal muscle , 5. Sieg2O2 production. SS-31 reduced the high mitochondrial H2O2 production from aged permeabilized muscle fibers from the extensor digitorum longus, but had no effect on young fibers. In the aged mice, one hour after in vivo treatment with SS-31 the cellular redox status measured by GSH:GSSG was more reduced. This was accompanied by improved mitochondrial coupling (P/O) and maximum ATP production in vivo in the skeletal muscle, while there was no effect on the mitochondrial energetics in young skeletal muscle. In addition to the improvements in muscle energetics, one hour and one week of SS-31 treatment resulted in improved muscle performance and increased exercise tolerance, respectively, in the old mice. This rapid reversal of in vivo energy deficits supports the hypothesis that mitochondrial deficits in aged skeletal muscle are, at least in part, due to reversible redox sensitive inhibition. Thus assessing the role of mitochondrial oxidative stress in aging and disease will require careful attention to changes to the in vivo redox environment and the mechanisms by which these changes can affect cell function.Our recent article in Aging Cell  further The mechanisms linking mitochondrial redox changes, regulation of metabolic fluxes, and reversal of dysfunction by SS-31 remain unclear. One potential mechanism is the post-translation modification of mitochondrial protein thiols with age. There are several rapidly reversible redox sensitive modifications of protein thiol groups that have been shown to affect the activity of mitochondrial proteins. This has been a relatively understudied area in the context of aging. However, in light of our results with SS-31 this warrants further attention. SS-31 has also been shown to interact directly with cardiolipin and preserve mitochondrial morphology . Given tExpanding the mitochondrial oxidative stress theory of aging to include reversible redox signaling opens new avenues for the development of potential therapeutics. This shift identifies the mitochondrial and cellular redox environment as potential targets for therapeutic intervention to reverse tissue dysfunction in age. Perhaps even more clinically relevant is the potential to focus on short-term treatment to reverse dysfunction. Translation of this strategy to humans would allow clinicians to treat elderly patients after mitochondrial or significant muscle dysfunction is identified, thus bypassing the need for costly long-term preventative treatments."}
+{"text": "Planarians are members of the Platyhelminthes (flatworms). These animals have evolved a remarkable stem cell system. A single pluripotent adult stem cell type (\u201cneoblast\u201d) gives rise to the entire range of cell types and organs in the planarian body plan, including a brain, digestive-, excretory-, sensory- and reproductive systems. Neoblasts are abundantly present throughout the mesenchyme and divide continuously. The resulting stream of progenitors and turnover of differentiated cells drive the rapid self-renewal of the entire animal within a matter of weeks. Planarians grow and literally de-grow (\u201cshrink\u201d) by the food supply-dependent adjustment of organismal turnover rates, scaling body plan proportions over as much as a 50-fold size range. Their dynamic body architecture further allows astonishing regenerative abilities, including the regeneration of complete and perfectly proportioned animals even from tiny tissue remnants. Planarians as an experimental system, therefore, provide unique opportunities for addressing a spectrum of current problems in stem cell research, including the evolutionary conservation of pluripotency, the dynamic organization of differentiation lineages and the mechanisms underlying organismal stem cell homeostasis. The first part of this review focuses on the molecular biology of neoblasts as pluripotent stem cells. The second part examines the fascinating mechanistic and conceptual challenges posed by a stem cell system that epitomizes a universal design principle of biological systems: the dynamic steady state. Schmidtea mediterranea (Smed) and Dugesia japonica (Dj). Both have excellent regenerative abilities and clonal strains originating from single animals are used. Whether a particular research group works on S. mediterranea or D. japonica is mainly a question of habit and results are so far assumed to be comparable. Other planarian model species include Schmidtea polychroa  and Dugesia ryukyuensis  . The genome of S. mediterranea has been sequenced , which additionally includes the parasitic clades Cestoda (tapeworms), Trematoda (flukes) and Monogenea (fish gill parasites). \u201cPlanaria\u201d is a colloquial term that generally refers to free-living members of the order Tricladida. Planarians have long since attracted the attention of biologists due to their astonishing regenerative abilities, food supply dependent scaling of body size and their great abundance of adult stem cells. The fresh water species are easy and cheap to maintain in the laboratory and several species are studied. The two \u201cworkhorses\u201d are Superficially, fresh water planarians may seem rather boring \u2014 flattened, mostly drab-colored worms without visible appendages Fig.\u00a0. A closepluripotency of Neoblasts . Neoblasts are likely even totipotent , but the use of donor Neoblasts from asexual animals in the above experiments precluded the reconstitution of sexual reproduction and thus the formal demonstration of totipotency. Neoblasts as naturally occurring pluripotent adult stem cells are remarkable, because adult stem cells in other model systems are lineage-restricted and somatic pluripotency exists only transiently during early embryonic development. A further unusual feature of planarian Neoblasts is their high basal mitotic activity. The resulting stream of progenitors drives the continuous turnover of all planarian tissues, which are likely devoid of any long-lived cell types. Dynamic turnover characterizes also the vertebrate intestine, for example . It is therefore important to stress that the term \u201cNeoblasts\u201d in the planarian literature and explicitly also in this text needs to be understood as a general reference to the planarian stem cell system, inclusive of pluripotent stem cells, earliest postmitotic progeny and any possible intermediate stages. The source of such ambiguity is not the use of a historical term, but the current lack of knowledge regarding the planarian stem cell system. Instead of introducing new terminology, I will therefore adapt the term \u201ccNeoblasts\u201d (\u201cclonogenic Neoblasts\u201d) from Wagner et al. for explicit references to pluripotent stem cells  is highly expressed in an abundant cell population between the gut branches  resulted in gradual Neoblast depletion and eventual death of the animals. The concomitant and massive upregulation of transposon transcription and the enrichment of piRNA-like RNA in CBs demonstrated a function of CBs and smedwi-3 in transposon silencing  and especially smedwi-2(RNAi) in comparison to the gradual decline after PRMT-5(RNAi) strongly suggests that the planarian PIWI proteins are required for more than transposon silencing, as are their germ line counterparts in other organisms  phenotypes suggest a role in Neoblast differentiation as well as self-renewal  depletes Neoblasts with very similar kinetics to Smed-PRMT-5(RNAi), consistent with a scaffold function of methyl-RG/TUDOR interactions in CBs  causes rapid chromatoid body disassembly and Neoblast loss within a matter of days   does not affect Neoblast maintenance, but prevents gonad regeneration  dramatically emphasizes the cryptic pluripotency of germ line cells  are landmark achievements also because they introduce this dimension to Neoblast research. Starting from a cell population sorted according to size and complexity ((X1)FS), the authors report seven whole-animal reconstitutions out of 130 single cell transplant attempts  causes the accumulation of mitotic Neoblasts at the expense of progenitors  leads to eye defects in regenerating, but not in uninjured animals , that orchestrate embryonic axis establishment   in non-regenerating animals causes the conversion of the tail into a head and the emergence of ectopic heads all along the body edge (Gurley et al. Smed-prep in non-regenerating animals indicates the participation of similar factors. The challenge over the coming years will be the cell biological dissection of the signaling cascades and their influence on gene regulatory networks.An influence of patterning signals over lineage choices necessitates region-specific cell fate determinants or factors mediating regional differentiation competence. An example for the former could be the LIM-homeodomain transcription factor Both the regionalization of the planarian body plan and its astonishing regenerative abilities are therefore likely two different sides of the same coin: a pluripotent differentiation hierarchy under the influence of a regulative patterning system. The uniquely dynamic body architecture of planarians arises from the intimate entwinement between the stem cell lineage and the patterning systems. Progenitors differentiate according to patterning signals into cells that produce patterning signals. The end of cell fate choices therefore once again becomes a beginning and the pattern continuously replaces itself. How such pattern of signals manifests itself in the physical shape and proportions of the planarian body plan is possibly the most fascinating challenge posed by the model system. Meeting it will require a multidisciplinary systems biology approach, combining cell biology, biophysics and mathematical modeling. The prize are fundamental insights into a universal design principle of biological systems, the dynamic steady state.piwi+, bruno+ and PDX10+ positive stem cells occur within the posterior growth zone of several annelid species, which adds new segments during growth (Giani et al. piwi, vasa and nanos and, at least in the case of the cnidarians, are able to regenerate the germ cells as well (Mochizuki et al. piwi+ stem cells that also give rise to the germ line (Funayama et al. piwi+ stem cells (reviewed by K\u00fcrn et al. Finally, how unusual are planarians and their pluripotent adult stem cell system in the context of evolution? Interestingly, Neoblast-like somatic stem cells are being discovered in a growing list of animals. C. elegans completely lacking adult somatic stem cells and somatic cell turnover occupies the \u201cstatic\u201d extreme of the spectrum. Similarly, the mechanisms segregating the pluripotent germ line from somatic lineages range from differentiation from pluripotent somatic stem cells in hydra, planarians or sponges via embryonic epigenesis in mouse to the segregation of maternally inherited \u201cimmortal\u201d germ plasm in fly and C. elegans (Extavour piwi and other germ line genes in the pluri- and multipotent stem cell systems of invertebrates, but generally not in the lineage restricted vertebrate stem cells, would indeed fit this picture. Or are cNeoblasts and other pluripotent invertebrate stem cells pre-meiotic germ cells instead that have maintained the ability to contribute to the somatic lineages? Clearly, studying the embryonic origins of Neoblasts and similar cells in other emerging invertebrate model systems now provide experimental opportunities to approach the evolution of pluripotency and animal stem cell systems in general.Flatworms are therefore neither unique in possessing pluripotent somatic stem cells, nor are they the only animals that undergo continuous turnover. Rather, stem cell systems across the animal kingdom come as a continuum of potencies and activities, in which Planarians mark a dynamic extreme. Hydra is situated nearby, displaying continuous body turnover, yet driven by independent multi- and unipotent cell lineages. Vertebrates with extremely tissue-specific turnover rates and tissue-specific stem cells reside somewhere in the middle, while Extavour . Based oExtavour . Tissue Planarians as model system contribute unique perspectives to current problems in stem cell research.smedwi-1 expressing cells, the isolation of pure cNeoblast preparations, the establishment of in vitro culture conditions and the localization of cNeoblasts within their tissue microenvironment represent important future milestones.Their first asset is an abundance of adult stem cells, so called cNeoblasts. The recent demonstration of cNeoblast pluripotency in single cell transplants has been an important achievement (Wagner et al. Second, Neoblasts are the sole source of new cells in planarians and they divide continuously to replace all differentiated cell types. Planarians therefore exist in a dynamic steady state between a single proliferating stem cell type and multiple short-lived differentiated cells. Maintenance of the steady state constitutes a universal problem in any stem cell containing tissue, yet the phenomenon remains poorly understood. Their complete turnover within a matter of weeks makes planarians uniquely suitable for studying the underlying mechanisms and conceptual principles. Key challenges include the identification of signaling systems controlling Neoblast proliferation and differentiated cell turnover, the orchestration of progenitor differentiation downstream of the pluripotent cNeoblasts and a systematic analysis of cell movements at steady state and during regeneration. The development of planarian transgenesis tools are especially important in addressing these questions.S. mediterranea. Moreover, even random injury remnants can restore the body plan by regeneration. Understanding the mechanisms that maintain and re-establish the dynamic steady state between Neoblasts and differentiated cells within the exact shape, size and proportions of the planarian body plan constitutes possibly the greatest frontier in planarian stem cell research. A crucial missing link between morphogenesis and the stem cell system is the currently unknown intersection point of patterning signals with progenitor fate choices. The origin and mechanisms of the mechanical forces required to convert signaling patterns into physical shape represents a further frontier. As for any steady state, understanding the planarian body plan in mechanistic detail will ultimately require mathematical modeling. Quantitative measurements are a crucial prerequisite to move into this direction and data relating to such parameters as progenitor production rates, cell flows and cell turnover rates will represent important contributions.Third, the ability of planarians to maintain their body plan in face of constant turnover is simply fascinating. Planarians grow and de-grow by changing overall cell numbers depending on food availability, leading to a 40-fold variation in body size between 0.5 mm and 20 mm in the case of What planarians can uniquely contribute to our understanding of stem cells is the systems perspective: an integrated view of the stem cell and its descendants as a dynamic steady state."}
+{"text": "Since the first report of the efficacy of thalidomide in refractory multiple myeloma  (MM), thSo what does this all mean in the grand scheme of MM therapy in 2012? Although the data identify a small subset of MM patients will likely be affected, SPMs remains a serious issue especially with regard to the myeloid malignancies . We haveThe Arkansas group is presently studying the baseline whole bone marrow gene-expression profiling, proteomic analyses and single-nucleotide polymorphisms (SNPs) to identify patients who may have the propensity to develop SPMs. This will be most important in the context of low risk (or standard risk) patients who have a longer life expectancy than the high-risk patients . The ris"}
+{"text": "Striatal dopamine (DA) is thought to code for learned associations between cues and reinforcers and to mediate approach behavior toward a reward. Less is known about the contribution of DA to cognitive flexibility\u2014the ability to adapt behavior in response to changes in the environment. Altered reward processing and impairments in cognitive flexibility are observed in psychiatric disorders such as obsessive compulsive disorder (OCD). Patients with this disorder show a disruption of functioning in the frontostriatal circuit and alterations in DA signaling. In this review we summarize findings from animal and human studies that have investigated the involvement of striatal DA in cognitive flexibility. These findings may provide a better understanding of the role of dopaminergic dysfunction in cognitive inflexibility in psychiatric disorders, such as OCD. In a constantly changing environment behavior has to be adaptive and flexible. Cognitive flexibility is the ability to adapt goal-directed behavior in response to changing situational demands. Cognitive flexibility is one of the cognitive domains that are grouped together as executive functions or executive control  previously. Depending on the operationalization of the reversal task used, this can be a reversal of all sorts of cues, but the choice options remain the same.intradimensional set-shift, new stimulus exemplars  are presented but the relevant stimulus dimension does not change between trials. Successful shifting requires maintenance of the current rule  and adapting behavior accordingly. In an extradimensional set-shift, not only are the stimulus exemplars novel, but the reinforced dimension has also changed. This requires a response shift to a dimension that has previously been irrelevant and bypassing of an acquired attentional bias . The WCST requires matching of a multi-dimensional cue card to one of four reference cards according to a specific stimulus aspect. The attentional set-shifting task has been developed as a non-human primate version of the WCST  or stimulus sets consisting of multiple sensory dimensions ; rodent bowl digging procedure , damage to different prefrontal areas results in dissociable deficits in separate forms of cognitive flexibility. Damage to the orbitofrontal cortex (OFC) is thought to specifically impair reversal learning, but not attentional set-shifting  may code a quantitative prediction error that serves as a teaching signal to guide behavior and is essential for a range of learning situations  impaired performance during probabilistic reversal learning  binding [, whereas in prefrontal regions, increased activation was observed following correct responses  manipulations and measurements and can extend and specify findings obtained in human subjects. Here, we will discuss animal studies that have used pharmacological manipulations of the DA system or DA depletion to investigate in what way DA in prefrontal and striatal regions contributes to cognitive flexibility.In rodents, lesioning DAergic projections in the nucleus accumbens core  impairs both spatial discrimination and reversal learning on a T-maze amphetamine and cocaine increase release of DA and other monoamines by blocking catecholamine re-uptake or promoting DA release  impaired spatial reversal learning in an operant chamber by increasing the number of perseverative errors. Administration of a D2/D3 antagonist (raclopride) or selective D3 antagonist (nafadotride) had no effect  increased both the number of discrimination errors and of perseverative and learning errors in the reversal phase  impairs early, but not late stages of reversal learning /substantia nigra pars reticulata (SNr) and thalamus. Output neurons in the indirect pathway project via globus pallidus pars externa, subthalamic nucleus to GPi/SNr, thalamus and cortex. Activity in these pathways can be differentially modulated by activation of D1 or D2 receptors in the striatum  aids the acquisition and relearning of behavioral responses to a particular stimulus, whereas suppression  of D2-mediated transmission (indirect pathway) may be required to allow reorganization of ongoing behavioral patterns. These results are in line with previous findings reporting impaired reversal learning after local stimulation of D2 receptors, while during set-shifting blocking D1 receptors impaired maintenance of the new strategy and stimulation of D2 receptors induced perseverative responding  are available. In the nucleus accumbens, these levels are higher during acquisition of a rule shift compared to simple rule acquisition in a T-maze set-shift paradigm  release in the MPFC is elevated and prolonged during performance of a spatial reversal session in a skinnerbox, compared to release in a discrimination session preceding reversal , whereas suppression of D2-mediated transmission in the accumbens and the indirect pathway is required for the reorganization of behavioral patterns. A transient elevation in DA potentiates connections in the direct pathway to initiate movement toward reward, whereas a transient dip in DA potentiates connections in the indirect pathway to suppress movements that are no longer rewarded , availability of D2-receptors can be related to performance during reversal but not discrimination learning  and higher order (rule or task switch) processes in a similar way. It is unclear if D2-mediated effects in animals depend on DA synthesis capacity.In general, these conclusions are similar to those based on human data, as discussed in the previous section. However, unlike what was reported in humans, DIndividual variability in executive functioning may be subserved by a strong genetic component  is strongly expressed in medial spiny neurons in the striatum, where it is stimulated by D2 receptor. A1-allele carriers show a reduced number of available D2 receptors [ regulates re-uptake of DA from the synaptic cleft in striatal regions, whereas its influence in the PFC is less pronounced  gene /Methione (Met) polymorphism at codon 158 of the Catechol-Despite the inconsistent effects of COMT genotype on perseverative errors in the WCST, the COMT Val/Met genotype is associated with differential activation patterns in the PFC during other cognitive paradigms , whereas increased availability of D2 receptors impairs task switching, suggesting different involvement of D2 receptors in these tasks. Striatal D1 signaling, mediated by DARPP-32 function, also contributes to cognitive functioning, although this has not yet been verified using specific measures of cognitive flexibility. Presumed lower levels of prefrontal DA, mediated by COMT-genotype appear to facilitate behavioral adaptation in both reversal learning and task-switching paradigms  and induces specific deficits in cognitive flexibility. Although discrimination and reversal learning are not affected, these mice make more errors and need more time to complete an extra-dimensional set-shift  is associated with cognitive performance in both humans and animals.The D2 receptor levels in the ventral midbrain  in mice impairs extra dimensional set-shift. This concurs with the improved set-shifting performance after COMT-inhibition in rats. However, presence of the Val-polymorphism in humans has been associated with a behavioral advantage during reversal learning and task-switching suggesting that confirmation of these studies is needed before we can draw conclusions.Caution should be exerted when interpreting results from animals in which a receptor is completely knocked out as compensatory mechanisms (such as increased neurotransmitter levels) during development may contribute to the observed deficits. Also, in the case of complete knock-outs it is not possible to locate the neurobiological substrate of the impairment as the knock-out is present throughout the brain. Finally, mice with intermediate expression of specific receptors (heterozygotes) are useful for studying gene-dosage effects on behavior, which could be particularly relevant when compared to differences in receptor expression levels observed in humans.OCD is a psychiatric disorder that is characterized by recurrent intrusive, unwanted thoughts (obsessions) that are often accompanied by repetitive ritualistic behaviors (compulsions). Although the precise neurobiological substrates underlying OCD symptoms are not known, structural and functional imaging studies show alterations in frontal and orbitofrontal cortices and basal ganglia in OCD patients  have been observed in OCD patients during performance of task switching paradigms  is not altered, whilst OCD patients may be impaired on higher order flexibility tasks . Irrespective of the presence of behavioral impairments, activity and connectivity in neural circuits regulating flexible behavior  are altered in OCD patients during task execution. Considering the modulatory effect of DA in these neural circuits, it is possible that altered striatal DA contributes to different activity in these circuits during task performance.As far as we know, studies directly linking measurements of cognitive flexibility to alterations in DA signaling have not been performed in OCD patients. The most consistent alteration in the DA system is changed DA receptor binding, mostly in striatal regions. Replication of these findings, especially of both DAnimal models of psychiatric disorders cannot reflect all aspects of the disease , the DAT-knockdown mouse that shows stronger and more rigid grooming behavior, has been proposed as an OCD-model based on DA hyperactivation . How does the supportive role of DA in cognitive flexibility  compare to its role in initial learning about rewards? The question whether DA is necessary for learning has been addressed by studying acquisition of learning in DA deficient mice\u2014the conclusion was that loss of DA may impair, but does not inhibit reward learning  to the substantia nigra) and expression of D2 receptors on MSN's of the indirect pathway   or D2 (indirect pathway) expressing neurons. When a reward is presented unexpectedly, or when a stimulus that predicts reward is presented, a transient increase in DA release occupies low affinity D1 receptors and activates the direct pathway, allowing facilitation of response execution and prompting reward-related learning. Switching of behavioral patterns on the other hand might require reduced occupancy of high affinity D2 receptors. Omission of an expected reward following altered reinforcer contingencies results in transient reductions in striatal DA levels and diminished inhibition of the indirect pathway by D2 receptors, resulting in inhibition of the previously successful response. Both facilitation of behavioral adaptation by deactivation of striatal D2 receptors and facilitation of the acquisition of the \u201cnew\u201d behavioral response by striatal D1 activation suggests the importance of phasic fluctuations in striatal DA levels during execution of cognitive flexibility. This may be illustrated for the D2-mediated response: both continuously higher and lower tonic D2 activation could impair detection of the transient reduction of DA. As tonic DA may be related to general synaptic factors such as synthesis capacity, uptake activity and metabolic efficiency, all these factors may influence flexible responding through D2 receptor dependent transmission. However, it is difficult to separate tonic from phasic DA signaling with most manipulations used. Tonic prefrontal DA  determines the control of cognitive flexibility. Considering the complexity of DA modulation in frontostriatal circuitry  on reversal learning tasks is not impaired in OCD patients. On reversal learning tasks, if any behavioral effect is found, it is a slowing of response times rather than an effect on the amount of errors that are made. Differences in accuracy have been observed in attentional set-shifting and task switching paradigms. It is possible that reversal learning may be a paradigm that is too simple for gross behavioral abnormalities to be observed in OCD patients. Increased reactions times on flexibility tasks, however, do suggest altered cognitive processing in OCD patients during cognitive flexibility and the measurement of reaction times should therefore be included in studies investigating differences in cognitive flexibility between healthy controls and OCD patients. The altered recruitment of frontostriatal circuitry during the execution of reversal learning as well as task switching is another indication for altered cognitive processing in OCD patients. Altered DA signaling is a potential contributor to changes in frontostriatal activity when performing cognitive tasks. Altered activity in the frontostriatal circuit  during reversal learning, as observed in OCD patients is also found in subjects with polymorphisms in the D2 gene that result in reduced binding to D2 receptors. Most likely, however, abnormalities in prefrontal regions and 5-HT modulation in OCD patients also contribute.So how do these findings relate to altered cognitive flexibility in OCD patients? If cognitive flexibility can indeed be used as an endophenotype for OCD, do the alterations in DA signaling that have been observed in OCD patients comply with the proposed role for DA in cognitive flexibility? The most replicated alteration in the DA system of OCD patients is reduced binding to DAn important step in investigating the possibility of altered cognitive processing in cognitive flexibility tasks as an endophenotype for OCD would be the replication of studies using cognitive flexibility tasks in OCD patients with the use of strictly defined patient and control groups. Considering that altered neural correlates of OCD could be symptom dimension-specific (van den Heuvel et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The Pharmacophore Alignment Search Tool (PhAST) is a string-based approach to virtual screening. Molecules are represented by linear sequences which describe their respective pattern of interaction possibilities. The problem of molecule linearization is tackled by applying Minimum Volume Embedding in combination with a Diffusion Kernel to the molecular graph ,2. LineaSignificance of chemical similarity was determined in form of p-values of global alignment scores, calculated in an approach that was adapted from its original application to local sequence alignments of protein sequences utilizing Marcov chain Monte Carlo simulation . BonferrPhAST was employed in two prospective applications: A screening for non-nucleoside analogue inhibitors of bacterial thymidine kinase yielded a hit with a distinct structural framework but only weak activity. Screenings for drugs that are not members of the NSAID  class as modulators of gamma secretase resulted in a potent modulator with clear structural distinction from the reference compound."}
+{"text": "Most species and the PFTs they represent were ubiquitously distributed along the topoedaphic gradient, but with varying abundances. Overstory-understory comparisons suggest that while future species composition of these woody communities is likely to change, PFT composition is not. Canonical correspondence analysis (CCA) ordination and variance partitioning  indicated that woody species and PFT composition in developing woody communities was primarily influenced by intrinsic landscape location variables  and secondarily by plant-induced changes in soil organic carbon and total nitrogen content. The ubiquitous distribution of species and PFTs suggests that woody plants are generally well-suited to a broad range of grassland topoedaphic settings. However, here we only examined categorical and non-quantitative functional traits. Although intrinsic soil properties exerted more control over the floristics of grassland-to-woodland succession did plant modifications of soil carbon and nitrogen concentrations, the latter are likely to influence productivity and nutrient cycling and may, over longer time-frames, feed back to influence PFT distributions. Woody plant encroachment into grasslands has been globally widespread. The woody species invading grasslands represent a variety of contrasting plant functional groups and growth forms. Are some woody plant functional types (PFTs) better suited to invade grasslands than others? To what extent do local patterns of distribution and abundance of woody PFTs invading grasslands reflect intrinsic topoedaphic properties versus plant-induced changes in soil properties? We addressed these questions in the Southern Great Plains, United States at a subtropical grassland known to have been encroached upon by woody species over the past 50-100 years. A total of 20 woody species  were encountered along a transect extending from an upland into a playa basin. About half of the encroaching woody plants were potential N Increases in the abundance of trees and shrubs have been reported in ecosystems world-wide -3. The r2-fixing to non-fixing; from deep rooted to shallow rooted; and from mesophytic to xerophytic in water relations . Thus, the discrete upland cluster, grove and drainage woodland communities represent examples of topoedaphic mediation of woody plant encroachment and community development. In this study we sought to determine if there were fundamental differences in the species and PFT composition of these communities that might shed light on how the shrub encroachment process plays out on upland and lowland portions of grassland landscapes. Our assessments of species and PFT composition and abundance were conducted across a local landscape-scale gradient. As such, they are not confounded by differences in climate, weather or land use history that can occur when comparing species abundance and community structure at multiple sites within a region or across bioclimatic zones. Here we only selected several categorical functional traits to define different PFTs, which we believe represent a wide range of functional traits that are important. However, including more detailed quantitative traits such as seed size or leaf traits may make our case stronger by providing other important aspects of the community assemblage.P. aculeata, the woody species and PFTs in playa communities were also present and typically common in cluster, grove, and woodland communities  have been dying in cluster communities [1] as was evidenced by its absence in our sampling (Table 2). A. farnesiana, representing the same PFT as P. glandulosa, also occurred in clusters, but was not represented in the shrub layer (Table 3) and hence may not persist in the community. However other N2-fixing woody species occur in the shrub layer, so this PFT could still be represented in future vegetation states even with the demise of the current N-fixing PFTs in the tree layer. Prosopis overstory plants were doing well in the other communities (Table 2); and, with the exception of playa communities, was well-represented in the shrub class (Table 3). This suggests that overstory trees of this PFT will be replaced when they die. These observations centered around N2-fixing, deciduous PFTs are consistent with ordination results  and suggest two things: (i) significant changes in the species composition of each of these woody plant communities may be forthcoming; and (ii) species-specific rather than PFT-specific differences are driving the compositional dynamics of the woody communities developing on grassland. In other words, while some species may eventually be lost, the PFTs they represent will not be.The woody communities on this former grassland site are relatively young (< 60-100 y of age) and may still be developing. Their species and PFT composition in the future may, to a large extent, depend upon the extent to which the present-day dominants are represented in the understory shrub layer. Overstory Prosopis plants  perspective  on this former grassland, P. glandulosa can quickly grow roots deeper than the zone utilized by grasses, which enhanced their survival during the earlier stage of their life history [P. glandulosa is an important mechanism of vertical water redistribution. However, the hydraulic lift is temporal dynamic and its effect on understory shrubs varies [P. glandulosa trees [Rooting depth is an important functional trait in savanna ecosystems because niche separation of soil water use at different depth was believed to be an importance mechanism to tree-grass coexistence ,50. In o history . Later is varies . Overallsa trees ,52. Our Relative basal area of evergreen and deciduous woody species are relatively stable along the topoedphic gradient . Faculta2-fixation potential are not necessarily reliable indicators of ecosystem processes related to resource use [The number of woody species in shrub cluster communities and their patterns of occurrence at this site are strongly related to the size/age of the overstory trees . Soils aurce use  or decomurce use . 2-fixing PFTs at our site, P. glandulosa was clearly the most aggressive initial invader of the historical grasslands [2-fixation. In addition, most of the other non N2-fixing woody PFTs at this site are bird-dispersed; and the establishment of livestock-dispersed P. glandulosa provides a perching structure attracting birds disseminating seeds of other woody PFTs [P. glandulosa plants colonizing grasslands may therefore be a secondary or coincidental factor influencing the encroachment of other woody PFTs \u2013 a conjecture consistent with our finding that patterns of species and PFT presence/absence and abundance were primarily a function of differences in intrinsic soil physical properties and secondarily related to modifications of SOC and TN by early-establishing shrubs  appears to be important in initiating the transition from grassland to shrubland across the catena gradient at this site, our survey gives little reason to expect that the shrubland communities that subsequently develop are following any particular or predictable assembly rules that might consistently reflect PFT responses to changes in microclimate and soils occurring in the transition from grassland to shrubland or woodland. The lack of strong patterns in woody species or PFT occurrence within the four woody plant communities developing on contrasting topoedaphic settings may reflect the fact that PFTs can exhibit considerable convergence in resource use [The results from our study are consistent with assertions of random community assembly  in that urce use  and that"}
+{"text": "The analysis of structure-activity relationships (SAR) is a central task in medicinal chemistry. The association between chemical structures of biologically active molecules and multiple property and assay data provides the basis for selection, optimization, and evaluation of potential drug candidate molecules.In an endeavour to facilitate the navigation of complex data landscapes and enable intuitive access to SAR information, an interactive SAR analysis platform is being developed at Roche. Focusing on information-rich data visualizations, we aim at supporting the medicinal chemists in their decision-making process, rather than making quantitative or qualitative predictions. The \u201cSAR Analyzer\u201d integrates cutting-edge visualization techniques and enhances them with key capabilities such as real-time interaction with the data, an intuitive user interface, and functionality to easily extract and navigate multi-property data.Here we show how two complementary approaches are integrated in the SAR Analyzer. The \u201cSAR Map\u201d visualization provides a holistic view of the distribution of molecular structures and properties in a data set . MoleculBoth concepts depart from classical SAR data analysis and support scientific reasoning by making SAR information accessible in an intuitive visual way. Linking both approaches allows the analysis of SAR data on different levels of detail and helps to address questions that are relevant in different stages of a medicinal chemistry research project."}
+{"text": "Substantial progress has been made in the treatment of leukemia in childhood. Despite this, leukemia remains a leading cause of pediatric cancer-related mortality and the prognosis is guarded for individuals with relapsed or refractory disease. Standard therapies are associated with a wide array of acute and long-term toxicities and further treatment intensification may not be tolerable or beneficial. The curative potential of allogeneic stem cell transplantation is due in part to the graft-versus-leukemia effect, which provides evidence for the therapeutic capacity of immune-based therapies. In recent years there have been significant advances in the development and application of immunotherapy in the treatment of leukemias, including the demonstration of activity in chemotherapy-resistant cases. This review summarizes immunotherapeutic approaches in the treatment of pediatric leukemia including current results and future directions. Leukemia is the most common form of cancer in childhood. Acute lymphoblastic leukemia (ALL) accounts for approximately 75% and acute myelogenous leukemia (AML) about 20% of pediatric leukemia. Juvenile myelomonocytic leukemia (JMML) and Philadelphia chromosome positive chronic myelogenous leukemia (CML) are rare  effect associated with allogeneic SCT is an immunologic reaction mediated by donor lymphocytes against foreign antigens expressed on leukemia cells. This GVL effect plays an important role in leukemia-free survival after transplantation  represents the most commonly employed and effective form of immunotherapy for childhood leukemia. SCT can be curative for all subtypes of pediatric leukemia and consensus guidelines for transplantation of acute leukemias have been published  can be curative for the treatment of post-transplant relapse, which provides further evidence of the potential of immunotherapy to cure leukemia. Complete remission (CR) rates of 70% or higher are observed in the setting of chronic phase CML, with lower rates (0\u201330%) in accelerated and blastic phase CML, ALL, AML, and JMML  gene product  have the ability to recognize target antigens on malignant cells. Notably, healthy stem cell donors may have pre-existing leukemia-associated antigen-specific CTLs that can expand in transplant recipients, which may contribute to the eradication of leukemia after allogeneic transplantation  (NCT01287104).Natural killer (NK) cells are lymphocytes of the innate immune system that can mediate a potent GVL effect early after SCT  through gene therapy techniques. In general, the external domain of CAR constructs consists of a monoclonal antibody variable fragment (Fv), while the internal domains include components of the T cell receptor signaling and often a co-stimulatory signaling domain. CAR transduced cells are designed to enable immune effectors to bind to and induce cellular cytotoxicity against malignant cells that express target differentiation antigens  were first generated against human differentiation antigens there has been the expectation that they would be used to treat hematologic malignancies  and antibody-dependent cellular cytotoxicity (ADCC). In CDC, the Fc receptor of the MoAb fixes the complement protein C1q and triggers cell death by the activation of the complement cascade. ADCC is mediated by Fc interaction with and activation of effector cells such as NK cells and macrophages. Importantly, ADCC requires functional immune effector mechanisms, which may be deficient in the setting of childhood leukemia  in combination with chemotherapy for adults with NHL .A study of the anti-CD22 MoAb epratuzumab in combination with standard chemotherapy was recently completed through the COG (NCT00098839). This trial included an initial cohort with an upfront epratuzumab monotherapy phase  demonstrated improved event-free, relapse-free, and overall survival rates without an increase in fatal toxicity, suggesting that perhaps lower and fractionated dosing of this novel agent may be effective and more tolerable than previously tested regimens , which is an anti-CD33 MoAb linked to calicheamicin, a potent antitumor antibiotic. Clinical trials of gemtuzumab ozogamicin as a single agent and in combination with chemotherapy have been conducted in the setting of pediatric AML  has been used in the development of recombinant immunotoxins that target human differentiation antigens  and less frequently \u03b1-emitters   fusion protein, which has potential utility in T-ALL  is undergoing clinical development for the treatment of B-lineage hematologic malignancies in children and adults. In a Phase II trial for adults with ALL in MRD+ CR, this agent induced clearance of MRD and a high relapse-free survival rate in most patients  in the context of HLA. The generation of a successful T cell response requires the interaction of an appropriate T cell receptor with its cognate antigen/HLA complex as well as co-stimulation or a \u201csecond signal.\u201d This second signal can be supplied in the form of an appropriate cytokine or by direct cell-to-cell interaction through accessory molecules.Numerous leukemia-associated antigens capable of inducing a T cell mediated immune response have been targeted with cancer vaccines. Examples include translocation fusion products, lineage-specific antigens, genes that are expressed aberrantly or in higher than normal levels, histocompatibility antigens and viral-associated antigens expressed by malignant cells. Various antigen sources have been used in vaccine trials. Peptides with defined sequences can be readily synthesized for clinical use and these have been employed most commonly.bcr/abl breakpoint peptide  and to avoid specific HLA allele restriction. The ready access to peripheral blood or bone marrow blasts makes this particularly applicable for leukemia vaccine trials. Blasts from children with B-precursor ALL can be rendered capable of presenting antigens by incubation with CD40 ligand and interleukin-4, thus, overcoming their ability to induce T cell anergy (Cardoso et al., The optimal immunotherapy reagents and regimens are expected to vary between diseases and individual cases. Critically important is the need to overcome the immune deficits associated with childhood leukemia and its treatment (Haining et al., Although great strides have been made in the curative treatment of childhood leukemias, further progress will require novel therapeutic approaches (Wayne et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Effective management of peripheral viral loads with anti-retroviral drugs can delay or halt CD4 cell loss for decades. However, patients still face the potential of developing significant HIV-1 associated neurocognitive disorders (HAND). Challenges obtaining relevant clinical samples limit the detailed investigation of the aetiology and neuropathology of HAND and therefore we do not understand the impact of vaccines that confer partial protection on long term neuropathology.We are using immunohistochemical analysis of brain sections from the experimental infection of macaques with SIV to model neuropathology in situations where peripheral viral loads are under effective control.We have established that chronic infection with attenuated SIV, where peripheral viral loads are below detection, still results in pathological changes . We have now extended these studies using a unique conditional live attenuated, doxycycline dependent virus, SIVrtTA. Removal of doxycycline 3 weeks after infection, at the end of the primary viremia results in detectable neuropathological changes in astrocytes, oligodendrocytes, microglia and perivascular macrophage 40 weeks later.We are also investigating the effects of vaccines that confer partial protection on the neuropathology of wild-type SIV infection. A vaccine study using SIV Gag based vaccines comprising three primes with rDNAgag followed by a rAdgag boost resulted in significant delay in acquisition of SIVmac251 administered by low-dose intra-rectal challenge. Furthermore, there was a significant blunting of the primary viremia, but no significant suppression of set-point viral loads compared with naive challenge controls. We are determining the impact of vaccination on the frequency of virus infected cells in the brain collected 20-30 weeks after infection and also comparing the frequency and intensity of neuropathological changes in infected vaccinated and control macaques.These data will enable us to establish the likely neurological benefit of vaccines that do not provide protection against detectable infection."}
+{"text": "Most neurons in the nervous system communicate by sending and receiving stereotyped electrical pulses called action potentials or spikes. The computational capabilities of neural circuits centrally rely on the input-output relations of single neurons. This relation is commonly characterized by its output spike rate in response to a temporally continuous constant input current, sometimes in the presence of additional current fluctuations . If the"}
+{"text": "Traumatic brain injury (TBI) is a contributing factor to approximately one-third of all injury-related deaths in the USA annually. Updated statistical records for TBI in Egypt are lacking. The current research is aiming to estimate the prevalence of TBI in Egypt in order to develop a comprehensive TBI prevention program.A 1-year period  descriptive epidemiological study of moderate and severe TBI cases admitted to the emergency department, Cairo main university hospital. The data collection sheet included personal data , incident-related data  and both clinical and radiological findings.Table TBI is a serious public health problem in Egypt. Further data interpretation over wider periods of time should be conducted for better understanding of TBI prevalence is highly recommended to develop effective injury prevention programs."}
+{"text": "Epstein-Barr virus (EBV) is associated with AIDS-related lymphomas and other malignancies. We have previously shown that the proteasome inhibitor bortezomib is an activator of EBV lytic gene expression and that these effects are mediated by ER stress and the unfolded protein response (UPR) . We inve"}
+{"text": "The current paradigm for studying hepatitis C virus (HCV) dynamics in patients utilizes a standard viral dynamic model that keeps track of uninfected (target) cells, infected cells, and virus. The model does not account for the dynamics of intracellular viral replication, which is the major target of direct-acting antiviral agents (DAAs). Here we describe and study a recently developed multiscale age-structured model that explicitly considers the potential effects of DAAs on intracellular viral RNA production, degradation, and secretion as virus into the circulation. We show that when therapy significantly blocks both intracellular viral RNA production and virus secretion, the serum viral load decline has three phases, with slopes reflecting the rate of serum viral clearance, the rate of loss of intracellular viral RNA, and the rate of loss of intracellular replication templates and infected cells, respectively. We also derive analytical approximations of the multiscale model and use one of them to analyze data from patients treated for 14 days with the HCV protease inhibitor danoprevir. Analysis suggests that danoprevir significantly blocks intracellular viral production (with mean effectiveness 99.2%), enhances intracellular viral RNA degradation about 5-fold, and moderately inhibits viral secretion (with mean effectiveness 56%). The multiscale model can be used to study viral dynamics in patients treated with other DAAs and explore their mechanisms of action in treatment of hepatitis C. Chronic infection with hepatitis C virus (HCV) remains an important health-care problem worldwide despite significant progress in the development of HCV therapy since the discovery of the virus in 1989. Current treatment options are focused on direct-acting antiviral agents (DAAs) that target specific steps of the HCV life cycle. Danoprevir, one of the DAAs that inhibit the HCV NS3-4A protease, has induced substantial viral load reductions in patients receiving therapy. We study the viral decline during therapy using a multiscale age-structured model that accounts for the dynamics of intracellular viral replication, and which includes the major steps in the HCV life cycle that are targeted by DAAs. We examine the biological parameters contributing to different phases of the viral decline after treatment initiation. We also explore the mechanisms of action of danoprevir and estimate its treatment effectiveness. The multiscale model provides a theoretical framework for studying virus dynamics in hepatitis C patients treated with other DAAs currently in clinical development, and may help one to optimally combine drugs with complementary modes of action to maximize the HCV cure rate. Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and a leading reason of liver transplant in the world. About 130\u2013170 million people are chronically infected with HCV in vivo antiviral effectiveness remain unclear. Yet such information is critical for combining PIs with other direct-acting antiviral agents (DAAs) that have independent mechanisms of action to yield highly potent drug cocktails.The approval in 2011 of two HCV protease inhibitors (PIs), telaprevir and boceprevir, to be used in combination with PEG-IFN/RBV, marked an undisputable milestone for HCV therapy, with the SVR rate in phase 3 clinical trials higher than 70% in HCV genotype 1 treatment-naive patients Mathematical modeling of HCV kinetics has provided valuable insights into the modes of action of PEG-IFN/RBV in vivo antiviral potency of danoprevir in blocking different stages of viral replication, e.g., reducing intracellular viral RNA production, enhancing its degradation, and inhibiting viral assembly or secretion.In this paper, we use a multiscale model of HCV infection and treatment that includes the age structure of infected cells, as well as the dynamics of intracellular viral replication, in order to understand the effects of PI therapy. An approximation of this model was applied to understanding the kinetics of viral decline observed during the first two days following one dose of daclatasvir, a DAA that inhibits the HCV NS5A protein The viral kinetic data we analyzed are from eight treatment naive patients who were infected with HCV genotype 1 and treated with danoprevir monotherapy (200 mg tablets three times a day) for 14 days in vivo antiviral effectiveness of therapy . Let Combining the equations governing the vRNA kinetics and the cell infection dynamics given by e an ODE  if  wereUnlike the standard biphasic model, three different antiviral effects of therapy with DAAs can be distinguished in the multiscale model, namely blocking vRNA production . For the pre-therapy model, we note that LetWe assume that that see  after inWe first approximate the viral load decline by assuming that after therapy is initiated infected cells remain at their steady-state distribution, i.e., Using tain see (15)wherein vitro cell culture systems have shown that under potent therapy vRNA declines continuously and that a complete eradication of vRNA can be obtained after weeks of treatment Alternatively, we can approximate the viral load decline by neglecting all new infections after the onset of therapy, i.e. assuming With an exponential decay in vRNA production during treatment, the Using this new equation for tain see (17)In thUnder effective drug therapy, the viral load decreases and the rate of new infections, The presence of three exponential terms in the long-term approximation Three exponential terms do not mean that a triphasic viral decline will always be observed during therapy. In fact, we show in dictions . In Textin vitroWe analyzed patient data using the long-term approximation of the multiscale model under therapy. The long-term approximation  has 11 pic model . Because),  and  , which a decline .The long-term approximation of the multiscale model provides good fits to the viral load data. The best fits are shown in ents see . Becauseth mean  .The viral load decline after day 2 is due to a combined effect of the loss of infected cells, with rate vir was  , i.e., 3The estimate of ound see , which istimate  .We also tested the sensitivity of our estimates to changes in the values of ifferent . Specifiin vitro, in the HCV replicon model, as well as in treatment-naive and treatment-experienced patients in combination with PEG-IFN/RBV in vivo antiviral efficacy remain unclear.Direct-acting antiviral agents that interfere with various intracellular molecular processes in the HCV life cycle are revolutionizing therapy for patients chronically infected with HCV The standard biphasic viral dynamic model is commonly used to study HCV dynamics in patients on therapy and to estimate the values of parameters such as the virion half-life, the productively infected cell loss rate, and the effectiveness of therapy in blocking viral production. By fitting this model to the viral load decline in HCV patients receiving high daily doses of IFN, Neumann et al. In this paper, we introduced a more sophisticated multiscale model including intracellular viral replication that can be used to study the viral kinetic changes in patients treated with DAAs. Unlike the standard biphasic model that only considers the effect of treatment in reducing the average viral production/release per infected cell Analysis of the multiscale model  shows thWhen therapy only moderately blocks viral assembly/secretion, as shown with danoprevir  or IFN [Why danoprevir and telaprevir enhance the intracellular viral RNA degradation rate remains unclear. It might result from the restoration of cellular antiviral capabilities Approximately two days after the start of danoprevir therapy, a subsequent and persistent phase of viral decline was observed that was about three times faster than typically found during IFN-based therapy in vivo fitness of drug-resistant HCV variants, and quantify the effects of resistant variants on the kinetics of HCV RNA decline. In addition, the current model assumes constant drug efficacy. Pharmacokinetic/pharmacodynamic models could be included to describe the time-varying treatment effectiveness The long-term approximation in which all new infections are neglected agrees well with the prediction of the full model in the context of an effective therapy. However, the approximation cannot be applied to the full data set from three patients  in which viral rebound was observed during the 2-week monotherapy. Virologic escape during danoprevir monotherapy was reported to be HCV subtype dependent and mainly due to the emergence of drug resistance associated with the substitution R155K In the context of potent therapy leading to a continuous viral decline, mathematical analysis of the standard biphasic model has shown that an additional effect of drug in blocking infection and/or viral entry has no or very limited effect on the kinetics of viral decline Another limitation of our model is that we have assumed that In summary, we employed a multiscale model that includes both intracellular RNA replication and extracellular infection dynamics to study the viral load change in HCV patients treated with DAAs. We determined the biological parameters that contribute to different phases of viral decline after initiation of therapy. Applying the model to viral load data from patients treated with a new HCV protease inhibitor, danoprevir, suggests that danoprevir significantly blocks intracellular viral production and enhances viral degradation, while it moderately inhibits viral assembly/secretion. The multiscale model provides a theoretical framework that can be used to explore the mechanisms of action of other DAAs and thus should be useful in furthering drug development for HCV and for optimizing antiviral therapy.Text S1Model analysis and approximation.(PDF)Click here for additional data file."}
+{"text": "The cell division cycle comprises a sequence of phenomena controlled by a stable and robust genetic network. We applied a probabilistic genetic network (PGN) to construct a hypothetical model with a dynamical behavior displaying the degree of robustness typical of the biological cell cycle. The structure of our PGN model was inspired in well-established biological facts such as the existence of integrator subsystems, negative and positive feedback loops, and redundant signaling pathways. Our model represents genes interactions as stochastic processes and presents strong robustness in the presence of moderate noise and parameters fluctuations. A recently published deterministic yeast cell-cycle model does not perform as well as our PGN model, even upon moderate noise conditions. In addition, self stimulatory mechanisms can give our PGN model the possibility of having a pacemaker activity similar to the observed in the oscillatory embryonic cell cycle."}
+{"text": "The classical form of diagnostic imaging includes X-ray-based imaging systems, magnetic resonance imaging (MRI), and sonographic imaging. Such imaging systems in a given clinical situation document the findings which reflect the end effect of molecular/biochemical changes associated with a particular disease condition. The lack of information at molecular or cellular level as a precursor to a disease condition resulted into emergence of \u201cMolecular Imaging.\u201d This approach is expected to provide an imaging tool that enables visualization, characterization, and measurement of biological events at molecular and cellular level both in human being and other living species. Broadly speaking, molecular imaging investigates molecular signature of the disease through measurement and characterization of biological processes in a molecular or cellular compartment and thus enables opportunities to replace population-based treatment methods by personalized genotype/phenotype-adapted concepts. If this In other words, cell growth or destruction responsible for biochemical changes can be visualized and quantified by using molecular imaging techniques so as to delineate disease pattern specific to an individual(s) in its early stages. Such findings would score in terms of personalized medicine based on physiological and/or biochemical changes particularly when it is well known that anatomical/structural changes in a given disease condition appear much later than the biochemical changes.A wide range of fast emerging techniques rely on visualization of biological events or biochemical changes in a biological system. These include molecular nuclear medicine, magnetic resonance spectroscopy (to identify proteins produced during the progression of the disease), and bioluminescence imaging. These techniques can also be successfully deployed to differentiate between rapidly proliferating tumor cells and normal cells. In addition, these techniques can be used to depict angiogenesis of formation of new blood vessels. Thus the quantification of cellular changes with time enables characterization of disease process.Nuclear medicine with latest developments in terms of positron emission tomography (PET) radiopharmaceuticals and fusiThus, the hybrid imaging owing to its capability to provide physiostructural information shall continue to be the cornerstone in molecular imaging. It wouldIn the era of personalized medicine molecular imaging with appropriate biomarkers/probe would initiate a concept of individualized imaging and hence individualized diagnosis as well as treatment. Such tre"}
+{"text": "The membrane proximal external region (MPER) of the HIV surface glycoprotein gp41 is the binding site for several potent broadly neutralizing antibodies. These antibodies recognize highly conserved linear peptide epitopes and antigens derived from this region have the potential to be important components of a vaccine directed against HIV-1. Highly conserved peptide epitopes for these antibodies are sterically obscured from the immune system by an intimate association with the viral membrane and by the presence of a large trimeric glycoprotein spike. As a result, previous attempts to immunize with linear peptides have failed to elicit broadly neutralizing antibodies.In order to better mimic the structural features of the MPER domain with an eye towards better understanding of epitope-antibody interactions near membranes, peptide mimics derived from HIV gp41 have been synthesized with a variety of structural changes including positioning of the epitope with respect to the membrane as well as the presence and nature of an anchoring transmembrane domain. These peptide mimics have been incorporated into membrane bilayer mimics called \u201cNanodiscs,\u201d which are ~10 nm-diameter structures composed of a phospholipid bilayer ringed by an apolipoprotein-derived scaffold protein.We have examined the affinity of HIV-1 neutralizing antibodies to these membrane-bound peptides to better understand the binding of these neutralizing antibodies to epitopes on or near a membrane. Significant differences in binding have been observed between peptides with different transmembrane domains.We have chemically synthesized peptide mimics of gp41 and incorporated them into artificial membrane bilayers. The peptides are anchored with both native and artificial transmembrane domains, and both the presence and nature of the transmembrane domain modulates antibody binding. Membrane presentation of peptide antigens with an appropriate transmembrane domain may be an important feature of vaccine design."}
+{"text": "Following the discovery of the vasorelaxant properties of nitric oxide (NO) by Furchgott and Ignarro, the finding by Bredt and coll. of a constitutively expressed NO synthase in neurons (nNOS) led to the presumption that neuronal NO may control cerebrovascular functions. Consequently, numerous studies have sought to determine whether neuraly-derived NO is involved in the regulation of cerebral blood flow (CBF). Anatomically, axons, dendrites, or somata of NO neurons have been found to contact the basement membrane of blood vessels or perivascular astrocytes in all segments of the cortical microcirculation. Functionally, various experimental approaches support a role of neuronal NO in the maintenance of resting CBF as well as in the vascular response to neuronal activity. Since decades, it has been assumed that neuronal NO simply diffuses to the local blood vessels and produce vasodilation through a cGMP-PKG dependent mechanism. However, NO is not the sole mediator of vasodilation in the cerebral microcirculation and is known to interact with a myriad of signaling pathways also involved in vascular control. In addition, cerebrovascular regulation is the result of a complex orchestration between all components of the neurovascular unit  also known to produce NO. In this review article, the role of NO interneuron in the regulation of cortical microcirculation will be discussed in the context of the neurovascular unit. Nitric oxide (NO) is a small inorganic, labile gaseous molecule originally identified as endothelium-derived relaxing factor (EDRF) mediating relaxation of blood vessels . CBF autoregulation is the primary mechanism ensuring that the flow and supply of oxygen, glucose, and nutrients through the vascular beds remain within the upper and lower limits of the autoregulatory range (50\u2013160 mm Hg) during fluctuations in systemic arterial pressure. NVC is the dynamic link between neuronal energy needs and hemodynamic changes. In the cortex, NVC depends on the complex interplay between neurons, astrocytes, and microvessels  that form the \u201cneurovascular unit\u201d , hydrogen ions, and adenosine produced by ATP catabolism in response to neuronal activity  attenuate the CBF increase induced by stimulation of the basal forebrain  and NO-synthesizing fibers as well as from the brainstem 5-hydrotryptamine (5-HT) afferents in both rat and human   and O2 (PaO2) provoke dilation and constriction, respectively. In several mammalian species including humans, it has been reported that blockade of NO synthesis with NOS inhibitors attenuates CBF responses to hypercapnia   channels to induce dilation of cerebral parenchymal arteries  channels. This is consistant with the presence of hypercapnic vasodilation in isolated arteries in concert with NOS participation in the acidosis-induced vasodilation  or thalamocortical \u2014results in increased cortical CBF associated with the recruitment of distinct populations of interneurons and cyclo-oxygenase (COX)2 pyramidal cells neurons is stimulated by glutamatergic neurotransmission  NMDA increases NO production around arteries as demonstrated by the accumulation of NO degradation products in the cerebrospinal fluid surrounding the arteries -2-amino-3-(3-hydroxy-5-t-butylisoxazol-4-yl) propionic acid (ATPA)  seems to result from different stimulation frequencies. Indeed, ionotropic nNOS inhibition reduces CBF responses to all stimulation frequencies by 50%  , is capable of increasing NOS activity in vivo through an IP3-dependent mechanism  dependent mobilizing agent cyclic ADP-ribose   gene, and accessory \u00df subunits that modulate channel gating  Ca2+ in astrocytic endfeet determines the nature of the vascular response with moderate elevations causing dilation and larger elevations causing constriction. The constrictive responses in preconstricted arteries in brain slices incubated in artificial cerebrospinal fluid with stable levels of oxygen seem to be entirely dependent on BK channels   is often used as a marker of changes in neuronal spiking activity. In reality, fMRI detects CBF through the arterial spin label method or blood oxygenation levels (BOLD) which reflects the shift of the ratio between the local concentration of oxygenated and deoxygenated hemoglobin due to increased oxygen extraction and increased oxygen supply. Unfortunately, the relationship between hemodynamic changes and the actual underlying response is still poorly understood. Anatomical and physiological data about NOS interneurons strongly suggest a non-linear relationship between neuronal activity and fMRI signals. In fact, NOS interneurons account for 0.3% of all cortical neurons but for about 50% of the vascular response to neuronal stimulation. In addition, the inhibition of nNOS with 7-NI clearly reduces the BOLD response upon electrical forepaw stimulation while the somatosensory-evoked potentials are still clearly detectable and only slightly reduced in amplitude (Burke and Buhrle, However, interneurons may act as \u201clocal integrators\u201d of cortical activity and therefore have important implications for the resulting neuronal activity and functional brain imaging (Buzsaki et al., NOS interneurons are strategically positioned close to blood vessels and seem to be involved in the control of CBF. In NVC, the mechanisms by which NO intervenes are particularly complex. Actual data suggest that NO from interneurons play a cGMP-dependent mediator role in the initiation of the vascular response to neuronal activation followed by a cGMP-independent modulatory role of astrocytic signals, which could lead to a vasodilation at moderate concentrations or a vasoconstriction at higher concentrations. NO from different sources also seems to coordinate the signal propagation of vasodilation upstream as well as the length of the response. The involvement of inhibitory NOS interneurons in NVC implies that the relationship between neuronal activity and CBF is non-linear. Therefore, a better understanding of the role of NOS interneurons in the control of CBF will allow a better modelization and interpretation of BOLD signal used in fMRI studies.Since the discovery that NO is a powerful vasodilator, we have made many observations to support its pivotal role in the cerebrovascular regulation. However, a complete understanding of the origin of NO and the pathways by which it controls the vascular tone is still missing. Additional studies will have to be conducted to further determine how NO intervene in NVC, how it is released upon activation and how it interact with astrocytes. As pharmacological blockers show evident limitations when it comes to cell-type specificity, new techniques to unveil the direct involvement of NOS expressing interneurons in NVC have yet to be developed. A few transgenic mice models like the Arx (Colombo et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Introduction. As minimally invasive surgery becomes the standard of care in neurosurgery, it is imperative that surgeons become skilled in the use of image-guided techniques. The development of image-guided neurosurgery represents a substantial improvement in the microsurgical treatment of tumors, vascular malformations, and other intracranial lesions. Objective. There have been numerous advances in neurosurgery which have aided the neurosurgeon to achieve accurate removal of pathological tissue with minimal disruption of surrounding healthy neuronal matter including the development of microsurgical, endoscopic, and endovascular techniques. Neuronavigation systems and intraoperative imaging should improve success in cranial neurosurgery. Additional functional imaging modalities such as PET, SPECT, DTI (for fiber tracking), and fMRI can now be used in order to reduce neurological deficits resulting from surgery; however the positive long-term effect remains questionable for many indications. Method. PubMed database search using the search term \u201cimage guided neurosurgery.\u201d More than 1400 articles were published during the last 25 years. The abstracts were scanned for prospective comparative trials. Results and Conclusion. 14 comparative trials are published. To date significant data amount show advantages in intraoperative accuracy influencing the perioperative morbidity and long-term outcome only for cerebral glioma surgery. Frame-based navigational systems are the most traditional guidance option  and have the advantage of being extremely accurate because a rigid head frame is fixed to the skull. Disadvantages include patient discomfort during frame placement, time taken to calculate the trajectory, and inability to project or image where the biopsy probe is. In fact it is a\u201cblind\u201d procedure via a small burr hole without having control over the stereotactic pathway and any complications (bleeding or missing the preplanned aim) during the surgery  may be inaccurate mostly because of scalp movement, geometrical distortion in the images, and movement of the patient with respect to the system during surgery. Another relevant source of inaccuracy is the so-called brain shift (movement of the brain relative to the cranium between the time of scanning and the time of surgery). Due to these sources of error, the usefulness of surgical navigation may diminish during the surgical procedure. As dynamic changes of the surgical field regularly occur during the surgical procedure, the surgeon is faced with a continuously changing intraoperative field for which the preoperative data does not provide any information. It is clear that only intraoperatively acquired images will provide the neurosurgeon with the online information he needs to perform real intraoperative image-guided surgery. A number of high-tech tools for use during neurosurgical procedures have been developed in recent years, like intraoperative navigated ultrasound and dedicated moveable intraoperative CT units. However, MRI currently is and definitely will be in the future the superior imaging method for intraoperative image guidance.After the era of X-ray view boxes, technological evolution permitted the use of real-time imaging such as fluoroscopy and intraoperative ultrasound. The introduction of computed tomography (CT) in the 1970s and magnetic resonance imaging (MRI) in the 1990s led to neuronavigation systems for surgical planning and working. Whether image guidance techniques are advantageous remains questionable for the last decades. Valuable information from numerous large prospective randomized trials are not available to date and a definite effect on long-term outcome needs yet to be proven. Therefore, the surgeon is left to decide on a case-by-case basis whether to perform surgery with or without neuronavigation. Beside this there will be an increasing pressure on neurosurgeons to justify the costs involved by showing that patients will actually benefit from complex image-guided treatments.A PubMed literature search using the terms\u201cimage guided neurosurgery\u201d was performed. More than 1400 articles were published during the last 25 years. All the abstracts were scanned for interesting historical and technical notes but especially for comparative clinical trials (either retro- or prospective), which is the focus of this overview.Image guidance in neurosurgery is today a frequently used tool for operations of many brain lesions, mostly for small and deeply subcortical located brain tumors or cavernomas . The incdetailed preoperative planning ;integration/fusion of MRI/CT images and functional data ;limited surgical exposure;more precision in approach;more precision in biopsy;more precision in catheter/electrode placement;guidance and control of tumor resection/foreign body removal;optimizing the size of intraoperatively buildt cranial reconstruction devices;monitoring complications (using intraoperative MRI or ultrasound).The most important step in the development of cranial neuronavigation was the availability of intraoperative MRI (ioMRI) which has led to a variety of differently designed systems and concepts . NowadayThough neuronavigation has become a routinely used addition to the neurosurgical armamentarium, its impact on surgical results has not yet been examined sufficiently for all indications. The most important and best examined use of neuronavigation and ioMRI is for cerebral glioma surgery. To achieve total tumor resection is the primary goal of these operations, but its positive effect on survival of the patients was controversially discussed for several decades , 10. HowP = 0.023). Postoperative rates of new neurological deficits did not differ between patients in the intraoperative MRI group (three [13%] of 24) and controls . No patient for whom use of intraoperative MRI led to continued resection of residual tumour had neurological deterioration [P < 0.01) reduced mean percentage of tumor volume following additional further resection after iMRI and they concluded that MRI in conjunction with multimodal navigation and an intraoperative updating procedure enlarges tumor-volume reduction in glioma surgery significantly without higher postoperative morbidity [In a retrospective single center analysis the median survival periods of patients receiving gross total resection for malignant astrocytoma  and neuronavigation (versus no neuronavigation) were 16 (versus 9) months and 16 (versus 10) months, respectively. The percentage of a gross total resection was significantly higher in the neuronavigation group compared to that in the no-navigation group (64.3% versus 38.2%). Neurological deterioration occurred in 4 of 42 (9.5%) and in 6 of 34 (17.6%) patients after surgery with neuronavigation and surgery without neuronavigation . In anotioration , 28. In orbidity .Although the number of prospective randomized studies is low at the moment, the controversies to use image-guided neurosurgery for the resection of cerebral glioma (either low or high graded) increasingly are unjustified. That is what Kubben et al. concluded in their review, too . The sufFrameless stereotactic neurosurgery is increasingly being used for the biopsy of intracranial tumors and the resection of deep-seated lesions where reliance on surface anatomic landmarks can be misleading, as well as in movement disorders, psychiatric disorders, seizure disorders, and chronic refractory pain \u201345. NascOne of the goals of brain surgery is to avoid damage to eloquent cortex and subcortical white matter. Diffusion tractography remains the only noninvasive method capable of segmenting the subcortical course of a white matter tract and has rapidly become an important clinical tool that can delineate functionally important white matter tracts for surgical planning \u201318, 46, The intraoperative use of MR imaging in neurosurgery has just started and future developments in this technology will surely add to the rapidly evolving field of MRI-guided neurosurgery . PreoperRobots are used more routinely nonremotely, for precision in carrying out certain procedures, such as skull base approaching craniotomies . The typImage-guided surgery is technically demanding and a learning curve has to be completed. Minor inaccuracies in the handling of the technical equipment might translate into major surgical errors. These errors, once implemented are systemic errors that propagate through the whole procedure. Navigation systems might become an important cornerstone in neurosurgery education. While today neurosurgery education takes place in the OR and to a lesser degree in cadaver and hands-on workshops the systematic development of education and training modules using navigation technology might offer a new way to develop and improve the perceptive and locomotive capabilities necessary to perform surgery on an organ that has a complex three-dimensional anatomy which is to a large extent hidden from direct visual perception . HoweverSince the integration of 3D image processing and real-time tracking of smart tools, the feasibility of image-guided approaches of many application in cranial surgery has been proven. Currently, the question whether the implementation of an extremely costly high-tech tool like the MRI in the neurosurgical operating room represents a technical overkill restricted to only a very small number of high-class neurosurgical centers, or whether it is and will be a major breakthrough in modern neurosurgery cannot be clearly answered, possibly except for the surgery on cerebral glioma. As an increasing number of ioMRI units will be installed in neurosurgical operating theatres worldwide, one have to await the increasing scientific evaluation of this technology, which will help to define the future role of neuronavigation and its integrated functional imaging and physiological data."}
+{"text": "Patients with non-Hodgkin's lymphoma (NHL) are in need of better predictive and prognostic markers; this to be able to more accurately inform them in the clinical setting about their likely future and to better inform clinicians and clinician-researchers about treatment decisions. One of the major impediments to the development of such markers in NHL has been the relative lack of access to well-preserved tumor tissue as the bulk of these cancers reside in secondary lymphoid organs. Procurement of tissue from affected lymph nodes for molecular risk stratification only has not yet been adopted as standard clinical practice.One of the ways a biomarker with clinical value in NHL could be developed is through analysis of shed tumor products in plasma or serum from patients carrying NHLs. This is the approach taken by He et al., 2011 in work reported in this issue of Oncotarget [The authors demonstrate that they could identify the rearranged Ig genes in primary human NHL-derived DNA and also in paired DNA derived from patient's plasma. They went on to show that they could amplify rearranged Ig fragments from an additional set of NHL patients using just plasma as a source of DNA. To support the analysis of the large collection of DNA sequence tags generated from each sample they developed a set of novel software algorithms for Ig gene identification. In summary, in the majority of patients analyzed the authors were able to identify the tumor-derived Ig sequences and also to enumerate the frequency of these in the input DNA.One of the most important questions related to this innovative work is whether the approach chosen has identified a tumor mass marker in patients with NHL and whether such a features can be clinically exploited. To answer this question, the further development of this potential new biomarker will need to proceed in an organized and logical manner to fully explore its ultimate potential. First, it will be necessary to conduct a new study using a larger collection of paired patient samples (primary tumor and paired plasma) to generate data on the sensitivity and specificity for plasma-derived DNA testing referenced against tumor DNA as the gold standard. Tests in large cohorts of individuals without known NHL may also be needed to obtain estimates on false positive calls.Next, and possibly within the same trial, initial estimates for this marker as a tumor mass marker should be obtained. Here, development will be complicated by the absence of validated test that accurately measure total body tumor burden in NHL. Nonetheless, a study correlating results from serial cross-sectional imaging with normalized numbers of tumor specific Ig-tags could be designed. For such a study it would be important to also perform the DNA test serially past completion of the induction chemotherapy program to obtain estimates on the temporal relation of CT findings and Ig-DNA levels. Somewhat complicating such an analysis is the current uncertainty as to what lymphoma cells (live cells or dead cells) actually contribute to and in what proportion to the plasma-detectable DNA.Future detailed clinical development of this marker would probably best be done within specific NHL subtypes and targeted to clinical situations in which current tumor mass assessments are semi quantitative at best. Within the setting of B-cell-derived NHLs, a number of clinical applications could be envisioned:Diffuse large B-cell lymphoma (DLBCL), the most common NHL subtypes is treated relatively uniformly using the R-CHOP regimen as front-line therapy. Currently, only approximately 45-50% of patients are cured. While further risk stratification using either clinical tools  or imaging tools (like PET-CTs performed during or after completion of planned therapy) can be accomplished, one wonders whether serial quantitative IgH DNA analysis as described here could be used to predict which patients are cured and which subset will relapse.A similar scenario can be identified in mantle cell lymphoma (MCL) for which intensified regimens like the NORDIC regimen can achieve remission-free states and possible cures in a substantial subset of cases. Could plasma-based IgH DNA analysis performed after the completion of the chemo-auto-Tx protocol be used to identify long term survivors?Finally, with the recent resurgence of maintenance therapy approaches in follicular lymphoma (FL), could IgH DNA analysis be used to identify patients that may most benefit from such an intervention?In summary, the elegant pilot study by He et al , has ope"}
+{"text": "Non-coding RNAs are key players in many cellular processes within organisms from all three domains of life. The range and diversity of small RNA functions beyond their involvement in translation and RNA processing was first recognized for eukaryotes and bacteria. Since then, small RNAs were also found to be abundant in archaea. Their functions include the regulation of gene expression and the establishment of immunity against invading mobile genetic elements. This review summarizes our current knowledge about small RNAs used for regulation and defence in archaea. In the last years more and more bacterial RNA populations have been analyzed with deep-sequencing methodologies revealing also a high amount of cis-encoded antisense RNAs  were found.The first experimental identification of an archaeal sRNA population was performed with the euryarchaeon Sulfolobus solfataricus. Here, two different approaches were used: experimental RNomics  than trans-encoded sRNA (125) were detected. Although an increasing number of cis-antisense sRNAs are being identified, the number of trans-encoded sRNAs has so far been higher than the number of cis-antisense sRNAs found. This is the first case, where cis-antisense RNAs outnumber the trans-encoded sRNAs  and the trans-encoded sRNAs (21\u00a0%) were conserved in M. mazei and Methanosarcinabakeri and M.acetivorans. Several of the cis-antisense sRNA candidates are encoded on the opposite strand to transposase genes indicating a post-transcriptional regulation of transposon mobility by antisense RNAs, a mechanism previously observed for insertion elements in S. solfataricus . Up to now the expression of 88 out of 130 randomly selected sRNA candidates was confirmed using northern blot analyses. Differential expression in response to the nitrogen source was confirmed for 18 small RNAs, representing the first prokaryotic regulatory RNAs potentially involved in nitrogen stress response. Based on these findings and the strong conservation a crucial role of sRNAs in the nitrogen or general stress response has been proposed for M. mazei  were sequenced using HTS. Six different cDNA libraries were constructed from RNA isolated from cultures grown at standard growth conditions, low salt conditions and high temperature, each at exponential and stationary phase. Altogether 145 H. volcanii revealed the presence of 11 tRFs, suggesting that these types of small RNAs are also active in archaea. Northern blot analyses showed the stable presence of these fragments in the cell . Demonstration of sRNA sequestering the predicted ribosome binding site as well as the translation start codon of its target mRNA in vitro strongly argues that the interaction is likely to inhibit translation initiation, a mechanisms up to now exclusively described for bacterial sRNAs. Additional evidence was obtained by a genetic approach that this sRNA is involved in regulating the metabolic switch from methanol to methylamines fueled methanogenesis, most likely by the above-mentioned post-transcriptional regulation .Very recently, target analysis based on whole transcriptome changes in mutant strains combined with genome-wide in silico target predictions using the tool IntaRNA  which is subsequently processed by Cas6 or related enzymes into short, regulatory crRNAs   recognize a stable hairpin the lies immediately upstream of their cleavage sites  within these proteins coined the classification as Cmr (Cas module RAMP) proteins. Isolated P. furiosus Cmr module complexes contained six to seven Cas proteins  and mature crRNAs  complex targets and cleaves RNA instead of DNA  and a crRNA . Here, a spacer from one of the genomic CRISPR loci was cloned into a Haloferax plasmid and potential PAM motifs were added adjacent to this spacer sequence. Using this method, six different PAM sequences were identified which are required for target recognition during the defence reaction in H. volcanii. This is the first CRISPR group for which more than two PAM sequences have been identified. Using the plasmid-based invader set-up it was shown that the CRISPR/Cas system of H. volcanii is targeting DNA. Cells which could escape the defence reaction did so by deleting the complete cas gene cassette or the protospacer on the plasmid or the corresponding spacer in the chromosomal CRISPR locus .Since there is only limited sequence information available concerning archaeal viruses it is often not possible to identify PAM sequences for archaeal CRISPR/Cas systems by matching spacer sequences to viral sequences. Therefore, plasmid-based invader sequences have been established and successfully been used  the genes for the aCascade unit  and (b) a proposed Cascis unit (CRISPR-associated complex for the integration of spacers) . The transcription of the cascade genes is modulated by changes of environmental parameters, like UV-light exposure or high ionic strength, indicating a tight regulation of cas genes in vivo. The two multi-subunit complexes aCascade and Cascis could be generated by the reconstitution of all individually insoluble recombinant proteins encoded within the operons, which suggests interaction and coordination of these Cas proteins  or RNA (e.g. CMR complex)? The targeting of DNA allows for the usage of spacers that derive from either the sense or the antisense strand of a viral genome. Targeting RNA of mobile genetic elements would limit the choice of protospacers to sequences that are complementary to the given mRNA. On the other hand, DNA targeting poses the problem of discriminating viral DNA from host DNA as any genomic CRISPR sequence would provide a crRNA target. This discrimination is achieved by the use of PAM sequences as described above. PAM sequences were not observed to be required in the targeting of the CMR complex. Therefore, this mechanism might have evolved to free the CRISPR/Cas system from the requirement of certain protospacer flanking sequences and would provide an antiviral defense system that can complement DNA-targeting CRISPR/Cas subtypes.The described identification of diverse small non-coding RNA families in archaea showcases the growing realization of the importance of these RNA species in this third domain of life. Modern high-throughput sequencing methods will reveal the RNome composition of further archaeal species. This information can then be combined with necessary functional studies on individual sRNA and crRNA molecules together with the identification of their target sites and should help us to validate the full scope of their influence on cellular processes."}
+{"text": "This review describes the development towards actomyosin based nanodevices taking a starting point in pioneering studies in the 1990s based on conventional in vitro motility assays. References are given to parallel developments using the kinesin\u2013microtubule motor system. The early developments focused on achieving cargo-transportation using actin filaments as cargo-loaded shuttles propelled by surface-adsorbed heavy meromyosin along micro- and nanofabricated channels. These efforts prompted extensive studies of surface\u2013motor interactions contributing with new insights of general relevance in surface and colloid chemistry. As a result of these early efforts, a range of complex devices have now emerged, spanning applications in medical diagnostics, biocomputation and formation of complex nanostructures by self-organization. In addition to giving a comprehensive account of the developments towards real-world applications an important goal of the present review is to demonstrate important connections between the applied studies and fundamental biophysical studies of actomyosin and muscle function. Thus the manipulation of the motor proteins towards applications has resulted in new insights into methodological aspects of the in vitro motiliy assay. Other developments have advanced the understanding of the dynamic materials properties of actin filaments. Molecular motors transport and sort cargoes in cells and underlie both cell-, and organism-motility. As such they are key effectors in the running of cellular fabrication and analysis systems, e.g., those requiring transportation of building blocks and signalling molecules between the nucleus and the cell periphery  is more limited unless the results are essential for full understanding of the developments of actomyosin based devices. For further details on the microtubule\u2013kinesin system, the interested reader is referred to some quite comprehensive review articles  the resulting contact angle has been in the range 70\u201380\u00b0 and with good actomyosin motility. When using vapour phase silanization of thermally grown SiO2 in a fume hood . In an independent study of motility on various polyelectrolyte substrates at about the same time  of HMM propelled actin filament sliding is correlated with the surface charge   for which U-turns are at all possible is given by the following expression:kT is the Boltzmann factor, LP is the actin filament persistence length, d is the width of a band along the filament (centred on the filament) where myosin heads are available for attachment, f is the duty ratio and Gbind is the average binding energy of the attached myosin heads. This expression suggests  that channel widths <300\u00a0nm would not allow U-turns of HMM propelled actin filaments. The product nheads is known, then Gbind can be determined on basis of measurements of wu because LP (\u03bcm) has been determined for sliding actin filaments  , the mean value is within the previously determined range of 10\u201320\u00a0kT  were attached to surface immobilized microtubules on a circular (800\u00a0\u03bcm wide) pick-up zone using biotin\u2013streptavidin links. This assembly of the final device was followed by addition of analyte (GST). Following binding of GST to the microtubule-bound antibodies it was concentrated at the device edges during a period of hours by means of kinesin driven transport.Proof-of-principle concentration/separation and detection schemes have been described recently using the microtubule\u2013kinesin motor system. In one case Fig.\u00a0 Lin et  biotinylNotable for the mentioned proof-of-principle devices is that concentration of the analyte for detection was rather slow compared to existing high-sensitivity methods  useful device is to extend the shelf-life to months or, preferably years. An important finding in this connection is that we recently  to societal levels  and molecular motor driven motion and force-generation play key roles in these contexts. Not unexpectedly, there have been efforts to exploit self-organization phenomena in nanotechnology for the formation of more or less complex nano-, micro- or even macroscale structures. However, unlike in the biological systems the building-blocks in artificial systems often suffer from heterogeneity with respect to size, shape and intermolecular interaction sites. Therefore, it is of interest to produce hybrid systems were the perfection of biological building blocks  are used to guide self-organization of non-biological molecules or particles. This may be useful for creating structures on different levels of hierarchial organization. Also motor driven transport of cytoskeletal filaments has been exploited in such applications. For instance, stable or meta-stable filament bundles of different shapes and length scales may form  in angular sliding direction is drawn from a Gaussian distribution with mean value 0 and standard deviation given by:In addition to the above applications in biosensing and self-organization it is also of interest to consider biocomputation based on molecular motor driven filaments and other motile objects. [for further applications, see reviews (Agarwal and Hess Moreover, a computational process utilizing HMM propelled actin filaments, requires a certain degree of control of transport direction at network nodes and the agents should only be allowed to move forward through the network (Nicolau et al. Of great interest would be the quite realistic development in the near future of practically useful and commercially viable motor driven lab-on-a-chip systems for biosensing in medical diagnostics, environmental and bioterrorism monitoring etc. Moreover, the developments of self-organized systems deserve further exploration. In these studies it would be of interest not only to exploit wild-type but also engineered biological motors (e.g., Tsiavaliaris et al."}
+{"text": "DNA amplification is a powerful technique that has had an immense impact on scientific research in the past 2 decades. While polymerase chain reaction (PCR) is still the most popular method, alternative methods of DNA amplification are constantly being developed. In addition, the extraordinary versatility of PCR has led to its use in novel ways that have opened new avenues of research. These novel methods for DNA amplification and the versatility of PCR are highlighted in DNA Amplification: Current Technologies and Applications.The 17 chapters in this book are divided into 4 sections that focus on enzymes (3 chapters), thermal cycling methods (6 chapters), isothermal methods (6 chapters), and the detection of non-DNA analytes by DNA amplification (2 chapters). Each chapter has a thorough description of methods and highly detailed protocols for applying the technique to at least 1 specific application. Several excellent chapters describe the uses of Phi29 DNA polymerase and of applications using isothermal rolling circle amplification. A chapter on multiple-displacement amplification details the isothermal amplification of total genomic DNA and should prove extremely useful for amplifying DNA in limited amounts, such as DNA from clinical samples. The final 2 chapters describe use of either real-time PCR or rolling circle amplification to detect and quantify non-DNA analytes, such as serum cytokines, with much greater sensitivity than conventional enzyme-linked immunosorbent assay methods.This book is not for the novice scientist, as it does not describe basic DNA amplification fundamentals; rather, it is directed at those with a solid background in molecular biology who desire knowledge of cutting-edge applications. Although many of the detailed protocols will not be applicable to certain laboratory situations, the versatility of most of the methods described will allow them to be easily adapted to other studies. Therefore, this book will be a good addition to the library of researchers in molecular biology or to molecular diagnostics laboratories planning to expand their horizon beyond standard PCR amplification techniques."}
+{"text": "Sickle cell disease is one of the most prevalent genetic diseases worldwide; affecting 1/400 individuals of African descent as well as people of Arab, Indian and Hispanic descents.10The emergence of cardiac complications in sickle cell disease patients could be attributed to the increasing life expectancy observed in these patients. Recent data indicates that 86 to 90% of patients survive to beyond 20 years of age.The mechanism underlying cardiac dysfunction in sickle cell anaemia has been extensively studied and multiple mechanisms have been proposed. In addition to the impaired microvascular circulation from intravascular plugs of sickled erythrocytes, other contributory factors include: extensive fibromuscular dysplastic narrowing of small cardiac arteries, non-inflammatory focal degeneration and apoptosis, platelet abnormalities or similar stimuli for endothelial and smooth muscle proliferation.16Data from clinical studies evaluating left ventricular systolic function using load-independent measures of myocardial contractility have revealed significant systolic dysfunction in sickle cell anaemia patients.19It has been recognised that ischaemic phenomena associated with sickle cell anaemia could elicit morphological and functional abnormalities in the cardiac conducting system, resulting in paroxysmal arrhythmia and could further worsen the ventricular dysfunction.10In the presence of left ventricular diastolic dysfunction, atrial fibrillation and indeed any form of arrhythmia causes significant cardiac decompensation. Atrial fibrillation in sickle cell disease is believed to be due to increase in atrial size with accompanying advanced atrial remodelling and profound global electrophysiological changes in refractoriness. Additional factors affecting atrial refractoriness include autonomic impairment, scars, and changes in the cellular membrane function.21In the light of this, one pertinent question needs to be addressed: what is the clinical utility of P-wave dispersion in sickle cell anaemia? A step towards unravelling this puzzle would involve the examination of the relationship between P-wave dispersion and measures of left ventricular function in sickle cell anaemia patients, and the comparison of the indices with those of appropriately matched controls. In this connection, the article in this issue, \u2018P-wave dispersion: relationship to left ventricular function in sickle cell anaemia\u2019 is of relevance. The authors showed that P-wave duration and P-wave dispersion were significantly increased in sickle cell anaemia and that P-wave dispersion had a negative correlation with indices of left ventricular diastolic function. This novel study provides an interesting insight into the potential value of this simple electrocardiographic tool in the evaluation of ventricular function in sickle cell anaemia. This is especially useful in resource-limited areas of developing countries where access to modern investigative modalities is lacking. Major challenges in the use of this tool are the difficulty in standardisation of methods and the lack of acceptable normal limits of P-wave dispersion in the general population.It is expected that this pilot study will stimulate further research efforts to determine the diagnostic/normal cut-off values, and specificity and sensitivity, as well as the long-term prognostic significance of increased P-wave dispersion in sickle cell disease."}
+{"text": "Here, ccorps is applied to the problem of identifying structural features of the kinase atp binding site that are informative of inhibitor binding. ccorps is demonstrated to make perfect or near-perfect predictions for the binding affinity profile of 8 of the 38 kinase inhibitors studied, while only having overall poor predictive ability for 1 of the 38 compounds. Additionally, ccorps is shown to identify shared structural features across phylogenetically diverse groups of kinases that are correlated with binding affinity for particular inhibitors; such instances of structural similarity among phylogenetically diverse kinases are also shown to not be rare among kinases. Finally, these function-specific structural features may serve as potential starting points for the development of highly specific kinase inhibitors.The protein kinases are a large family of enzymes that play fundamental roles in propagating signals within the cell. Because of the high degree of binding site similarity shared among protein kinases, designing drug compounds with high specificity among the kinases has proven difficult. However, computational approaches to comparing the 3-dimensional geometry and physicochemical properties of key binding site residue positions have been shown to be informative of inhibitor selectivity. The Combinatorial Clustering Of Residue Position Subsets ( ccorps) method is introduced and used to synthesize kinome-wide structure datasets with a kinome-wide inhibitor affinity screening dataset consisting of 38 kinase inhibitors. ccorps identifies structural features of the kinase binding site that are correlated with an inhibitor binding and uses these features to predict if this inhibitor will be capable of binding to uncharacterized kinases. This paper demonstrates the ability of ccorps to accurately predict inhibitor binding and identify features of the kinase binding site that are unique to kinases capable of binding a given inhibitor.The kinases are a group of essential signaling proteins within the cell and are the largest family of enzymes encoded by the human genome. The high degree of binding site similarity shared across the protein kinases has made them difficult targets for which to design highly selective inhibitors, but kinome-wide binding site analysis can help predict unintended off-target inhibitions. Given the increasingly large number of available kinase structures, kinome-wide comparative analysis of binding sites is now possible. In this paper, the Combinatorial Clustering Of Residue Position Subsets ( The protein kinases constitute the largest enzyme family encoded by the human genome, with currently 518 known sequences, making up 1.7% of all human genes atp binding site. However, due to the large number of existing protein kinase domains and the high degree of (atp) binding site similarity among them, designing highly selective inhibitors has proven difficult. For example, type I kinase inhibitors that only target the atp site have typically been found to have low selectivity across the kinome atp site and the immediately adjacent allosteric site. By also binding to the allosteric site, type II inhibitors are able to make additional highly specific interactions, thereby allowing them to be more selective The bulk of this effort has been directed at identifying inhibitors that bind at the Identifying highly specific structural features that can be uniquely targeted by inhibitors can be facilitated by comparative analysis of multiple kinase structures atp binding site and targeting residue variability at a few key positions atp and allosteric sites) simultaneously Many of the effective inhibitor selectivity strategies involve exploiting the differences in the size of the A review of related work is given below. Recent work has illustrated that local structural similarity exists among phylogenetically diverse groups of kinases The PharmMap method Huang et al. have utilized a knowledge-based approach to constructing a minimal binding site \u201cfingerprint\u201d that captures only a pre-specified set of well-studied, structurally selective features, such as the size and hydrogen-bonding ability of the gatekeeper residue feature) kinase binding site pairs. The CavBase atp binding cavities from multiple families across the kinome Rather than relying upon pre-specified structural features, the recently developed Pocketfeature method decomposes a binding site into all possible \u201cmicro-environments\u201d atp binding pocket was demonstrated to be effective at identifying possible instances of inhibitor cross-reactivity and further emphasized the importance of taking into account subtle conformational changes in the binding site.Recent work by Jackson et al. demonstrated a related structural clustering approach to predicting kinase inhibitor binding affinities individual kinases, exhibiting a variety of binding site conformations and bound ligands, provides a vast quantity of structure data that remains unexploited by existing approaches. Much of the difficulty in incorporating multiple conformations per individual kinase sequence into existing analyses stems from the non-uniform distribution of available kinase structures, with kinases such as CDK2 having more than a hundred available crystallographic structures while other kinases have only a single (or no) available structure. Finally, the availability of multiple kinase structures known to bind a given inhibitor and other kinase binding sites known not to bind that same inhibitor provides a rich set of structural examples and counter-examples beyond a single instance of pairwise similarity. Existing receptor-based methods focus on identifying meaningful pairwise similarity to a characterized kinase known to bind a given inhibitor. These methods currently do not account for the similarity of a given kinase binding site to other kinase sites that have been characterized to not bind the inhibitor in question.However, despite the successes of existing approaches, several outstanding problems to identifying structural features of the kinase binding site that are predictive of inhibitor selectivity remain. The reliance upon a single, representative structure precludes the ability of existing methods to identify features common only to active conformations if an inactive structure is chosen as representative (and vice versa). Additionally, choosing one representative structure disregards the role that binding site flexibility and plasticity may play in inhibitor interactions. Furthermore, the availability of multiple structures for ccorps) method. ccorps solves the following problem: given a set of sequence-aligned kinase domains , predict whether a given kinase domain binds the given inhibitor. Taking a set of kinase binding site residue positions as input, ccorps identifies clusters of kinases that share structurally and chemically similar subsets of residue positions. Given a particular kinase with unknown ability to bind a particular inhibitor, ccorps identifies kinase binding sites that share similar residue positions that are both known to bind and not to bind the inhibitor . Finally, ccorps aggregates the residue position subset similarities for all possible To this end we have developed the Combinatorial Clustering Of Residue Position Subsets  method is designed to solve a very general semi-supervised learning problem:The Combinatorial Clustering Of Residue Position Subsets . 3-position subsets are used in this work because they allow for a unique 3-dimensional lrmsd superposition and are more computationally tractable than subsets of size In order to identify locally similar features among substructures, all The dissimilarity between a pair of substructures is quantified by a combination of structural distance and chemical feature dissimilarity introduced in pca) to obtain a low-dimensional embedding. Our previous work Text S3. The dimensionality-reduced feature vectors are then clustered to identify sub-groups that share strong structural similarity. The number of clusters is not known beforehand and the number of clusters will vary depending on the set of positions being compared. The Gaussian Mixture Model (gmm) clustering method implemented in the mclust package For a given set of residue positions, we can calculate a matrix of pairwise distances between substructures using the distance measure defined above. Each row can be thought of as a feature vector that represents how different a protein is with respect to all other proteins in terms of the selected residues. The distance matrix is highly redundant. We use Principal Component Analysis . Identification of HPCs is performed by selecting a minimum threshold for the label purity of clusters, and then selecting all clusters with equal or greater label purity than this minimum as HPCs; we used the strictest purity threshold possible (1.0 or 100% purity) in this work .A cluster that is dominated by one annotation label can be used to predict the label for other structures in that cluster whose annotation is unknown. We therefore call such clusters \u201chighly predictive\u201d  used to decide which of the two or more label classes to assign to the structure requires the definition of a decision boundary procedure. For example, given a set of annotation labels containing the label classes ccorps is a semi-supervised approach, the labels for the training structures are known and can be used to empirically estimate a vote count decision boundary. For example, given structure falsehpc or a truehpc, across all true and false labels, respectively.Because svms were selected in this paper. First, an svm (linear kernel) is trained using the vote vectors of labeled training set substructures. For example, the decision boundary determined by training an svm on vote vectors is shown in svm decision hyperplane the unlabeled structure falls within. As illustrated in false label. For training svms and calculating the svms, libSVM Given the vote vectors calculated for all labeled training set substructures in the dataset, it is then possible to train any number of classifiers in order to determine a decision boundary. To compute a decision boundary in the vote space for classifying unlabeled proteins, ccorps an extensive dataset of 48 families was automatically constructed using the Pfam database ccorps and the utility of the distinguishing structural features identified. The overall classification accuracy of ccorps (Text S2) when applied to the validation dataset demonstrates the ability of ccorps to identify structural features that distinguish functionally different protein homologs and the ability of ccorps to generalize to non-kinase protein families.To validate the predictive ability of the structural features identified by ccorps to be predictive of inhibitor binding ability are presented. Then, cases of these predictive structural features that are common to phylogenetically diverse sets of kinases are highlighted. Finally, the performance of ccorps for predicting the binding ability of inhibitors across the kinome is quantified and compared to the related approach of Jackson et al. First, we will introduce the components of the kinome structure and affinity datasets used in this work. Next, structural features of the kinase binding site that are identified by atp binding site presented here, a dataset of protein kinase binding site structures was assembled and then mapped to the affinity dataset of Karaman et al. atp binding site and the analysis of shared structural features between major kinase families that is presented later in this paper.In order to enable the kinome-scale analysis of the protein kinase pfam:Pkinase and pfam:Pkinase_Tyr  in release 25 of pfam . After the binding site residue positions to analyze were selected, as detailed in the following section, and proteins having one or more gaps at those positions were excluded, a total of 1958 structures remained. These 1958 structures correspond to 208 unique kinase proteins. The distribution of sequences and structures across the seven major kinome families is shown in The kinome structural dataset was constructed from all structures (domains) annotated as belonging to pdb:2pl0 or pdb:3hec were selected as candidate binding site positions. Candidate positions were eliminated if they corresponded to highly gapped columns in either the pfam:Pkinase or pfam:Pkinase_Tyr Multiple Sequence Alignments (msas). After filtering, 27 binding site residue positions remain (shown in pdb:3hec). Imatinib was chosen as a reference inhibitor for selecting the binding site positions to include in the analysis because it is of the large type II kinase inhibitor variety and extends both into the atp binding pocket as well as the neighboring allosteric pocket. The cutoff distance of 5 \u00c5 was selected in order to be consistent with the binding site selection cutoff chosen by Jackson et al. Text S1.All residues having one or more atoms within 5 \u00c5 of one or more imatinib atoms from the imatinib-bound structures shown in : 30, 38,in vitro competition binding assay by Karaman et al. ncbi RefSeq IDs provided by Karaman et al. The affinity  by thresholding the affinity values at 10 true; false). This 10 In order to simplify the problem of correlating structural features with binding affinities, the binding affinity . Given the 27-position binding site , kinases incapable of binding flavopiridol are colored black  and kinases lacking affinity annotation are colored white (undefined label). As shown in true labels exist and are considered to be HPCs by ccorps.By incorporating the affinity annotation labels for a particular inhibitor, further observations can be made about the association between the 3-position substructure shown in ccorps.The existence of true-only clusters indicates that the 3-positions shown in incapable of binding flavopiridol can also be observed in s are also informative because they identify particular structural versions of the 3-position substructure in Furthermore, the existence of clusters containing only kinases ccorps for each of the 38 different inhibitors within the affinity dataset. For each of the inhibitors, the affinity labels can be mapped separately onto the same substructure clustering as shown in ccorps computation .Finally, while flavopiridol is discussed in detail here for illustration, the same analysis was computed by s varies greatly depending on the inhibitor considered. While the flavopiridol-annotated substructure clustering contains multiple HPCs for both true and false labels, the correspondingly annotated clustering for other inhibitors, such as VX-745, PI-103 and imatinib, contain only false HPCs. This result demonstrates that the substructures that are informative of inhibitor binding are inherently inhibitor-specific. That is, a subset of binding site positions that are predictive for one inhibitor are not necessarily predictive for another inhibitor.Examination of the affinity-annotated substructure clusterings shown in one 3-residue substructure. However, all 2925 clusterings are computed and all HPCs detected in these clusterings are used to predict binding affinity. The particular three-residue subset shown in s in all clusterings are used to predict affinity, each casting one \u201cvote.\u201dIt is important to note that Numerous instances of cross-family affinity for both type I and II kinase inhibitors have been identified, as was clearly illustrated by the kinome affinity maps created by Karaman et al. agc, camk, tk} would have an affinity purity of Each individual cluster, across all 2925 clusterings and all 38 inhibitors, was evaluated to calculate the purity of both affinity labels and family-level phylogenetic labels. For example, a cluster containing 3 distinct kinase sequences with affinity labels ccorps that have true-majority clusters). Only these true-majority clusters are plotted in the cluster distribution shown in true and false).In order to build intuition for interpreting the cluster distributions, the cluster distribution for VX-680  is examiccorps have low affinity purity as well as low phylogenetic purity. This is to be expected because highly conserved portions of the kinase atp binding site are known to exist. Structural features that consist of conserved residue positions will be common to many kinases from different families due to the fact that these positions are so heavily conserved, which explains the low phylogenetic purity of these clusters. Furthermore, these conserved features are unlikely to be correlated with the affinity for a particular inhibitor because most inhibitors have been engineered to not have broad cross-reactivity across the kinome. Staurosporine is an exception as it is a very non-selective inhibitor due to its interaction with highly conserved binding site features; the cluster distribution corresponding to staurosporine (As can be seen in osporine  is markeccorps. This observation is interesting because it illustrates that kinases sharing sequence similarity (relative to kinases outside the family) have multiple common structural features that are not informative of the ability of these kinases to bind VX-680 and are therefore unlikely to be good features to target in design studies. Because ccorps only incorporates clusters with high affinity purity , these conserved structural features that are not indicative of VX-680 binding are ignored by ccorps when predicting affinity for unannotated kinases. This observation can also be made for each of the other inhibitors as shown in Examination of the extremes of the VX-680 cluster distribution reveals further insights into the frequency of structural similar features among kinases with different degrees of sequence similarity. Clusters having a phylogenetic purity of 1.0  but having low affinity purity exist, and for VX-680 276 such clusters were identified by s that are phylogenetically diverse. The HPCs selected by ccorps correspond to the right-most column of points in only structures with known VX-680 affinity. As can be noted in s exist at a range of phylogenetic purity values. ccorps identified a total of 2707 HPCs for VX-680, and 1786 (66%) of these HPCs contain proteins belonging to two or more distinct kinase families. This result demonstrates that ccorps is capable of identifying cross-family structural features that are associated with VX-680 binding. Furthermore, this result is not unique to VX-680. As shown in Another interesting extreme of the VX-680 cluster distribution to examine is the existence of HPCccorps identified relatively fewer true-majority clusters. For example, only 133 clusters with affinity purity ccorps for SB-431542 and all of these happen to be HPCs. However, even among this relatively low number of HPCs, 69 (52%) of the clusters contain kinases from two or more families. As demonstrated by the corresponding distributions for all 38 inhibitors in Examination of the cluster distributions across each of the inhibitors reveals a wide range of observations. While many inhibitors have a cluster distribution similar to that of VX-680, for some inhibitors ccorps to classify an unlabeled kinase is to identify the cluster to which the unlabeled kinase belongs. If the associated cluster is an hpc, the label for the hpc is transferred to the unlabeled kinase. Non-informative clusters containing a mix of labels (non-HPCs) do not contribute to the label prediction process. This \u201cco-clustering\u201d analysis approach is repeated for all of the 2925 substructure clusterings and the final label prediction for an unlabeled kinase is then selected as detailed in The approach used by ccorps to predict the binding of each inhibitor for proteins within the annotated structural dataset was assessed using the cross-fold validation approach described in the following section. For each of the 38 inhibitor annotation label sets, an independent evaluation of ccorps was performed. No information was shared among the evaluations in order to validate the predictive ability of ccorps to identify structural features predictive of the binding ability of each inhibitor independently.The ability of s for identifying substructure positions indicative of functional specialization, cross-fold validation was performed for each family within our dataset. The structures within a protein family were first divided into 70% sequence identity groups (nr-clusters) so that no protein in a test set shares nr-clusters, the number of structures in the test set varies with each fold. In each fold, structures that were part of the test set are marked with label unknown, and are disregarded when calculating the purity of clusters  curve for the set of predictions, which evaluates the sensitivity ) at each specificity ) value. The roc curves for the predictor constructed by ccorps are shown in auc) for each roc curve is listed in pr) curve for each inhibitor can be found in pr curve plots the precision ) versus the recall .For each of the 38 inhibitors included in the affinity dataset, ccorps to the work of Jackson et al. actives) in the top 5% of most confident predictions ranked by ccorps, not directly comparable between ccorps and Jackson et al. In order to make a direct comparison of the performance of ccorps achieves high predictive performance across the 38 inhibitors tested. As quantified by rocaucccorps achieved perfect or near-perfect predictive ability for 8 of the 38 inhibitors: AMG-706, CHIR-265, CP-690550, CP-724714, Lapatinib, PTK-787, Roscovitine and SB-431542. Furthermore, ccorps is demonstrated to be very competitive with the method by Jackson et al. ccorps significantly improved on Jackson et al. As shown in Text S3) and used to predict inhibitor binding for the full 38 inhibitor dataset presented here. The prediction performance for the binding site sequence-based approach is shown in ccorps by a significant margin for several inhibitors: Staurosporine, Sunitinib, SU-14813, PKC-412, JNJ-7706621, VX-680. These 6 inhibitors on which ccorps significantly underperforms are 6 of the top 7 inhibitors in terms of number of kinases inhibited. That is, the aforementioned 6 inhibitors are relatively promiscuous and tend to interact with a large number of kinases across several kinase families. Furthermore these same 6 inhibitors also have the 6 highest hpc counts across the entire dataset. This result indicates that ccorps has difficulty predicting inhibitor binding for broad spectrum inhibitors and is discussed further in the following section. In the cases of JNJ-7706621 and VX-680, the performance difference is only significant in terms of the enrichment score. ccorps significantly outperforms the binding site sequence-based approach for several narrow spectrum inhibitors including, but not limited to: Lapatinib, CP-724714, CP-690550, SB-431542, VX-745. Overall, when ccorps performed better than the sequence-based approach the magnitude of the performance difference tended to be larger than when it performed worse. It should also be noted that the standard deviations of the differences between in ccorps and the sequence-based approach  and lck structure pdb:2pl0 (black), both with bound imatinib inhibitor (red). The (TIF)Click here for additional data file.Figure S2Substructure clustering for one 3-position subset of the -amylase binding site alignment. In each scatter plot above, the dimensionality-reduced feature vectors computed by ccorps are shown. Each point shown is one feature vector and each feature vector represents one protein substructure. Tightly grouped points correspond to binding site substructures with high structural and chemical similarity. Plots A, B and C above all show the same clustering with different sets of annotation labels applied (labels are denoted by color): (A) cluster ID labeling; (B) 3-tier EC labeling; (C) 4-tier EC labeling. Solid ellipses indicated clusters identified automatically as HPCs. Dashed ellipses indicate subsets of non-hpc clusters that would have been considered HPCs if the clustering step had distinguished each as a separate cluster.(TIF)Click here for additional data file.Dataset S1s that contain kinases from two or more of the kinome families.The complete set of 41,964 true-majority HPC(CSV)Click here for additional data file.Text S1Details on the mapping and alignment of positions among structures within the kinase dataset.(PDF)Click here for additional data file.Text S2ccorps to predict the EC classification for an extensive dataset of 48 families constructed using the Pfam database: a large-scale validation experiment.Using (PDF)Click here for additional data file.Text S3ccorps method.Details of the (PDF)Click here for additional data file.Table S1Accuracy of predicted EC classifications for Pfam protein families in cross-fold validation. Predictions are made at all 4 tiers of the EC hierarchy.(PDF)Click here for additional data file.Table S2ccorps for the kinase inhibitors using a 50% sequence identity clusters for cross validation.Affinity prediction performance of  For each of the 38 inhibitors in the affinity dataset of Karaman et al., the prediction performance of ccorps and the sequence-based method is shown below. While the mean auc values and enrichment scores are close, the standard deviations of the differences between the corresponding columns  highlight that the two methods have complementary strengths.(PDF)Click here for additional data file."}
+{"text": "The development of pancreatic necrosis is a significant complication of acute pancreatitis and can result in progressive multiple organ failure and death. Recently, in an attempt to reduce the high morbidity and mortality from open necrosectomy, minimal access techniques have been developed.2 pressure (8mmHg) permits visualisation of the retroperito- neum, and standard laparoscopic graspers and a suction device can be placed through additional port sites in the unit to allow removal of necrotic tissue  can be used to gain retroperitoneal access  and alloc tissue . Post-opThe technique of minimally invasive necrosectomy has been well described previously"}
+{"text": "Sticht et al. [Here, we present results of detailed thermodynamic analysis of the CAI inhibitor binding to HIV-1 capsid protein and mutants thereof carrying mutations in the inhibitor binding pocket. The effect of the peptide on protein dimerization is determined and the minimal peptide sequence responsible for efficient inhibition is identified using microcalorimetry technique.-1) and unfavorable entropic contribution , and no protonation was observed during binding. The effect of several mutations inside the CAI binding pocket on dissociation constants determined by VP-ITC was similar as characterized by fluorescence polarization with fluorescently labeled CAI [The isothermal titration calorimetry was used to examine the binding of CAI inhibitor to the wild-type capsid protein as well as the mutant variants. CAI binds to the capsid protein with favorable enthalpic contribution (-12.5 kcal.molThe CAI binding site is very promising target for new antiretrovirotics. The detailed thermodynamic characterization of CAI binding to HIV-1 capsid protein performed within this study describes the complex formation and can help in further development of new HIV-1 assembly inhibitors."}
+{"text": "Potential photoactivation of certain pharmaceuticals, cosmetic ingredients and natural products by sunlight  has to be considered early on in development in order to avoid serious adverse effects . Current clinical trial registration guidelines  structure-property relationships ((Q)SPR) offers a valuable strategy to reduce experimental testing if an appropriate precision level of the underlying model is guaranteed.insilico analysis  of quantum chemical as well as classical molecular descriptors  has led to predictive photosafety classifiers. Model validation was performed with a proprietary external test set of an in vitro photosafety assay .A diverse data set of known phototoxicants and non-phototoxicants including various molecular chemotypes  was compiled. After geometry optimization the maximum absorption wavelength of each compound was calculated by semi-empirical methods followed by subsequent computation of molecular descriptors. Our Our photosafety models are currently applied in a prospective manner in the prioritization, classification and labeling of newly designed molecules."}
+{"text": "The neural mechanisms underlying processing of auditory feedback during self-vocalization are poorly understood. One technique used to study the role of auditory feedback involves shifting the pitch of the feedback that a speaker receives, known as pitch-shifted feedback. We utilized a pitch shift self-vocalization and playback paradigm to investigate the underlying neural mechanisms of audio-vocal interaction. High-resolution electrocorticography (ECoG) signals were recorded directly from auditory cortex of 10 human subjects while they vocalized and received brief downward (\u2212100 cents) pitch perturbations in their voice auditory feedback (speaking task). ECoG was also recorded when subjects passively listened to playback of their own pitch-shifted vocalizations. Feedback pitch perturbations elicited average evoked potential (AEP) and event-related band power (ERBP) responses, primarily in the high gamma (70\u2013150 Hz) range, in focal areas of non-primary auditory cortex on superior temporal gyrus (STG). The AEPs and high gamma responses were both modulated by speaking compared with playback in a subset of STG contacts. From these contacts, a majority showed significant enhancement of high gamma power and AEP responses during speaking while the remaining contacts showed attenuated response amplitudes. The speaking-induced enhancement effect suggests that engaging the vocal motor system can modulate auditory cortical processing of self-produced sounds in such a way as to increase neural sensitivity for feedback pitch error detection. It is likely that mechanisms such as efference copies may be involved in this process, and modulation of AEP and high gamma responses imply that such modulatory effects may affect different cortical generators within distinctive functional networks that drive voice production and control. In order to maintain effective vocal communication, the brain needs to finely control the acoustical parameters of self-generated vocal sounds. This important function requires online monitoring and control of the vocal motor commands that drive voice production via sensory feedback mechanisms. A well-accepted theory Electrophysiological recordings in animals In the present study, we investigated the neural mechanisms of audio-vocal integration for voice pitch monitoring by recording directly from auditory cortex of human subjects using high-resolution electrocorticography (ECoG) signals in an auditory feedback pitch perturbation paradigm. We hypothesized that active vocal production (speaking) would lead to the enhancement of the evoked potentials in response to pitch perturbation in cortical auditory areas. In addition, due to previously reported correlation between high gamma oscillations (70\u2013150 Hz) and single-unit and BOLD activity Ten subjects ; all right-handed except for 1 female (R180)) undergoing surgical treatment of medically intractable epilepsy volunteered to participate in this research protocol. Written informed consent was obtained from every subject and all research protocols were approved by the University of Iowa Human Subjects Review Board. Subjects did not incur any additional medical risks by participating in these studies.All subjects completed an extensive pre-surgical assessment including detailed neurological examination, brain imaging , and neuropsychological evaluation that confirmed normal speech and language functions . No anatomic lesions were observed in the cortical regions of interest to this study  in any subject. Audiometric testing was conducted and all patients were found to have normal hearing. All subjects underwent preoperative sodium amobarbital (Wada) testing to determine hemispheric language dominance. The left hemisphere was dominant for language in nine subjects and bilateral language representation was noted in one subject (L162). Experiments were conducted in a specially designed and electromagnetically-shielded private patient suite in the University of Iowa General Clinical Research Unit. All subjects participated in a multi-disciplinary epilepsy surgery evaluation and treatment protocol. Each subject was deemed an appropriate candidate for surgical placement of intracranial recording arrays for the purpose of recording and anatomically localizing seizure events in order to then excise the seizure focus.Custom manufactured high-density electrode arrays (see below) were implanted on the pial surface of the exposed brain regions. The surface recording arrays consisted of 96 platinum-iridium disc electrodes embedded within a silicon sheet with 5 mm center-to-center spacing and 3 mm contact diameter . The exact position of the recording grid differed somewhat between subjects as grid placement was based on patient-specific clinical considerations for each subject. In all subjects the coverage provided by the array included significant portions of the STG, including a previously described posterior lateral superior temporal auditory area  and CT (0.45\u00d70.45\u00d71.0 mm voxel size) scans. Pre- and post- implantation CT and MRIs were co-registered using a 3-D rigid-fusion algorithm implemented in FMRIB\u2019s Linear Image Registration Tool The experiment consisted of two blocks of speaking and two blocks of listening to playback. During the speaking blocks, subjects were asked to actively produce and sustain a steady vocalization of the vowel sound/a/for approximately 2 seconds at their conversational pitch and loudness. This vocal task was repeated 40 times during each block with subjects taking short breaks (1\u20132 seconds) between successive utterances, and vocalizing at their own pace. During each vocalization trial, subjects were presented with a downward (\u2212100 cents) pitch shift stimulus in their voice auditory feedback. The onset of pitch shift stimuli in each vocalization trial was randomized between 500\u20131000 ms after the vocalization onset and the total duration of stimuli was 200 ms. These parameters have been well-studied in normal subjects using non-invasive techniques Each subjects\u2019 voice was recorded using a condenser microphone , amplified  and pitch-shifted through a harmonizer . All parameters of the pitch-shift stimuli  were controlled by MIDI software  running on a standard laboratory computer. The Max/Msp software generated a TTL pulse to mark the onset of pitch-shift stimuli for time-locked averaging of the recorded brain potentials. The voice, feedback and TTL signals were recorded on a TDT data acquisition system  with sampling frequency of 12 kHz. Subjects received their voice auditory feedback through a pair of earphones  placed in custom-fit, vented insert ear molds. A 10 dB gain was adjusted between the voice and its auditory feedback to partially mask the effect of air-borne and bone-conducted feedback. At conversational levels, subjects maintained their voice loudness at about 70\u201375 dB and received their feedback (through earphones) at 80\u201385 dB during speaking blocks. The feedback loudness during speaking was measured using a sound level meter implemented in the Max/Msp program and the feedback gain was adjusted to ensure that the feedback loudness during playback was the same as that during speaking blocks. We acknowledge that it is not possible to fully equalize the total sound energy delivered to the ear between speaking and playback blocks as bone conduction cannot be eliminated during speaking.Research recordings were initiated several days post-implantation after subjects had fully recovered from implantation surgery. The electrocorticogram (ECoG) signals were recorded directly from the cortical surface of awake patients during the presentation of pitch-shifts in their voice auditory feedback. ECoG recordings were simultaneously acquired with voice, feedback and TTL signals using the TDT system under both speaking and playback blocks. The ECoG signals were first filtered  and then digitized with a sampling frequency of 2034.5 Hz. Digitized data were then resampled offline at 2000 Hz in MATLAB software  for further processing.Recordings from all 96 ECoG channels were manually inspected to ensure that they were not contaminated by epileptiform activity or artifact and electrical line noise was removed using a notch filter at 60 Hz. Average evoked-potentials (AEPs) were calculated by first band-pass filtering  the ECoG signals and then segmenting them into epochs encompassing \u2212300 ms before to 1000 ms after the onset of each pitch-shift stimulus, as marked by the TTL pulses. The time stamps of stimuli were further verified by extracting the pitch contour of the voice feedback channel and confirming that the pitch-shift onset lined up with the onset of the TTLs. Following segmentation, artifact rejection was carried out by excluding ECoG epochs with amplitudes exceeding +/\u2212500 \u00b5V. Individual epochs were then subjected to baseline correction by removing the mean amplitude of the baseline from \u2212300 to \u2212100 ms prior to the onset of the stimulus from each trial. The choice of this baseline time window allowed us to capture pre-stimulus changes in the AEPs up to 100 ms prior to the onset of pitch shifts. The individual trials were then averaged to calculate the AEP for each recording contact. As seen in the example AEP waveform , responsThe spectral power of the recorded brain activity was similarly calculated on an individual trial basis using the \u201cspectrogram\u201d function in MATLAB with a 256 ms Hamming window and 1 ms time steps for frequencies from 0 to 300 Hz. Event-related band power (ERBP) was extracted separately for each frequency band by calculating the log transform of normalized power (relative to baseline from \u2212300 to \u2212100 ms) across the time-series within event-related epochs ranging from \u2212300 to 1000 ms from stimulus onset. The log transformation function was used to ensure that the data are normally distributed for statistical analysis. The single-trial spectral power time series were then averaged over the total number of trials for speaking and playback conditions separately and results were represented as a time-frequency plot of power for each individual contact. The difference between power responses to pitch-shift stimuli during speaking vs. playback was analyzed for each of these seven frequency bands separately by first dividing the post-stimulus averaged power traces into 5 ms time bins and then statistically comparing the mean of each bin with the mean of baseline (\u2212300 to \u2212100 ms) for the same frequency band using a paired t-test. T-tests were FDR-corrected (q\u200a=\u200a0.01) accounting for the total number of time bins and electrode contacts. For each frequency band, significant power changes (relative to baseline) for speaking and playback were determined if the mean power was significantly different from that of the baseline for at least 6 consecutive time bins (30 ms) within the post-stimulus time window. In those contacts where such significant changes in power were identified in one of the speaking or playback (or both) conditions, a second FDR-corrected paired t-test  was performed to assess differences between power responses to speaking vs. playback. Contacts meeting these criteria were considered to be modulated by condition in response to pitch shifts for a specific power band if the difference between the mean of power during speaking and playback was at least significant for six consecutive time bins (30 ms). Such modulation could be seen to be either an increase or a decrease in power as a result of speaking compared with playback condition.Speaking\u2212AEPPlayback)/(|AEPSpeaking|+|AEPPlayback|) in which AEPSpeaking and AEPPlayback were the peak amplitude of the AEP responses during speaking and playback conditions respectively. Similarly, the MI for the high gamma responses was defined as (HGSpeaking\u2212HGPlayback)/(|HGSpeaking|+|HGPlayback|) in which HGSpeaking and HGPlayback were the peak magnitude of the high gamma power responses during speaking and playback. Results of this analysis are separately shown for the AEP and high gamma responses by plotting color-coded circles over the contacts that showed significant AEP or high gamma modulation. In the figures, a positive MI (graded red circles) indicates a significant enhancement of responses during speaking compared with playback and graded colors show the degree of speaking-induced enhancement with MI\u200a=\u200a+1 for maximum enhancement. Accordingly, a negative MI (graded blue circles) indicates a significant speaking-induced attenuation of responses and value \u22121 implies maximum attenuation.The relative amount of change in the AEP and high gamma power responses during speaking compared with playback was quantitatively measured by calculating the modulation index (MI) in all contacts for which the AEP and high gamma responses were significantly different during speaking compared with playback. For the AEPs, the MI was defined as  pitch-shift stimuli were calculated by extracting the pitch frequency of the recorded voice signals in Praat We observed a consistent response pattern on STG auditory cortex in response to PSS in our 10 subjects. Like this exemplar subject (R186), the other 9 subjects also demonstrated this response pattern of a focal subregion of posterior STG showing AEP and high gamma responses to PSS. In all 10 cases the responses clustered immediately adjacent to the TTS in recordings from both left and right hemisphere subjects. This anatomic consistency is illustrated by plotting the topographical distribution of the normalized mean of the high gamma power within a 0\u2013500 ms post-stimulus time window in The focal nature of the high gamma responses observed on STG is reflected in the fact that of the total number of 960 recording contacts (96 contacts in 10 subjects), significant high gamma responses (relative to baseline) were elicited in only 180 (19%) and 112 (12%) individual contacts during speaking and playback conditions respectively. A total number of 86 (9%) contacts had significant high gamma responses during both speaking and playback conditions. A FDR-corrected (q\u200a=\u200a0.01) paired t-test showed that the onset latencies of high gamma responses were significantly shorter during speaking  compared with playback  condition (p<0.001). For the majority of these contacts, the high gamma responses remained significantly above baseline for about 200\u2013300 ms and returned to their baseline level in about 500 ms after the onset of the stimulus.enhancement of high gamma power during speaking compared to playback. Conversely, there were some sites on STG that showed attenuation of high gamma power during speaking compared to playback. A total number of 74 contacts exhibited speaking-induced modulation and the vast majority  showed enhancement in high gamma responses as opposed to attenuation . Sites demonstrating these different response types were in close (<15 mm) anatomic proximity. The calculation of the MI showed variable degrees of speaking-induced modulation of high gamma responses to pitch-shifted voice feedback  during speaking compared with playback and only 2 (5%) contacts showed AEP attenuation during speaking. The mean value of the MI for contacts showing AEP enhancement and attenuation during speaking was 0.36 (std: 0.09) and \u22120.27 (std: 0.08), respectively.Examination of the AEP responses to PSS revealed similar response patterns as that of the high gamma responses. The overall extent of activation as indicated by statistically significant differences of AEP amplitude compared to baseline was similar to high gamma responses. Namely, across all subjects, 220 (23%) and 114 (12%) contacts significantly responded to pitch-shift stimuli during speaking and playback respectively. Within these contacts, 95 (10%) contacts had significant AEP responses during both speaking and playback conditions. A FDR-corrected (q\u200a=\u200a0.01) paired t-test did not show a significant difference between AEP latencies during speaking  compared with playback  condition. Statistical comparison between AEP amplitudes during speaking and playback revealed significant differences in 41 (4%) contacts, representing response modulation during speaking  and 4. OFor the contacts that showed a significant modulation of both the AEP and high gamma responses , results of the analysis showed the AEP and high gamma MIs were not correlated . This indicates that the degree of speaking-induced enhancement or attenuation in the high gamma power responses was not correlated with the degree of AEP modulation during speaking.Even though AEPs were elicited in response to PSS in all ten subjects, significant differences across conditions were identified in 5 of 6 subjects with right hemisphere  and 2 ofIn the total number of 10 subjects, vocal responses could not be measured in one subject (L162) due to the fact that during the recording session, the voice and feedback signals were mixed and recorded together on one channel and therefore voice F0 contour could not be separately extracted for this subject. For subject R210, none of the post-stimulus time bins were significantly different from the mean of the pre-stimulus F0 (baseline). For the 8 remaining subjects, analysis of the vocal responses showed that each of these 8 subjects significantly compensated (q<.05) in response to downward (\u2212100 cents) feedback pitch perturbation by raising their vocal pitch output in the upward direction. All subjects except for R175 returned their voice F0 to the baseline after compensating for downward pitch perturbation in their voice auditory feedback. The measures of the vocal response onset, offset and peak latencies along with the peak magnitude for all subjects are summarized in enhanced during speaking compared with playback condition. In addition, a number of contacts were identified within the STG that although they were clearly responsive to the acoustic tasks, they showed no evidence of speaking-induced modulation of AEP or high gamma responses. Moreover, our data show that even though the AEP and high gamma responses were similarly localized within circumscribed regions of the STG near the TTS, the anatomical pattern of speaking-induced modulation did not fully overlap for the AEP and high gamma responses. Calculation of the modulation index (MI) measure indicated variable degrees of speaking-induced AEP and high gamma modulation within the STG for each individual subject and we did not observe a consistent pattern of spatial distribution for the extent of modulation across a group of 10 subjects. As can be seen in The present study provides evidence for speaking-induced modulation of auditory cortical responses to unexpected perturbations in voice pitch feedback. We found that the pitch-shift stimuli elicit AEP responses within non-primary areas of human auditory cortex  that are enhanced during active vocal production of a vowel sound as compared to passive listening to playback of the same self-produced vocalizations. ERBP responses were found to be most prominently elicited within high gamma frequency range (70\u2013150 Hz) and similar to the AEPs, these responses were predominantly These findings suggest that encoding pitch error in voice auditory feedback for vocal motor control is mediated by complex neural processes in distinct cortical networks within the non-primary human auditory cortex. These neural processes are reflected through the activity of neural systems that generate both low and high-frequency oscillations. The low-frequency components of these oscillations emerge as neural activities that are evoked by pitch perturbations and contribute to generation of high-amplitude phase-locked AEP responses as well as increased induced ERBPs at frequencies below 20 Hz. The low frequency AEP components are thought to be generated by more global neural circuits that orchestrate synchronized activity between different regions for performing specific functions In this context, one possible interpretation of the AEP and high gamma responses to pitch-shifted feedback in the present study is that they may reflect mechanisms of stimulus feature representation as well as sensory-motor interactions that facilitate feedback-based monitoring of voice for vocal pitch control. It is possible that the evoked AEPs in the present study may arise from changes in post-synaptic membrane potentials of neuronal assemblies in a focal subregion of the STG that receive synaptic input from lower-order subcortical and cortical auditory pathways as well as other non-auditory cortical areas . Based upon our data, it can be suggested that the cortical networks within those areas that show a significant AEP response without speaking-induced modulation of AEP activity may only involve neural processes that encode the features of the pitch-shift stimulus in the auditory feedback. However, those regions that exhibit a significant modulation of AEP responses during speaking may include neural circuits that receive synaptic input from cortical vocal motor areas and may serve as a neural substrate for comparison between sensory (i.e. auditory) and internally-predicted feedback (e.g. efference copies) for detecting pitch perturbations. Therefore, it can be suggested that access to internal predictions can selectively enhance neural sensitivity to feedback perturbations and consequently lead to the elevation of post-synaptic membrane potentials within specific cortical auditory networks.With relevance to this discussion, the high gamma responses to feedback pitch perturbations can be interpreted as an indication of increased spiking activities as a result of auditory representation and perception of pitch shifts in voice feedback as well as the output of pitch error detection mechanisms that drive the compensatory vocal responses through long-range synaptic projections from the auditory to vocal motor cortex. Our data suggest that different cortical auditory networks subserve these two distinct functional mechanisms as it is shown that the high gamma responses are modulated during speaking compared with playback only in a focal sub-region of the STG in the vicinity of the transverse temporal sulcus. Speaking-induced modulation of high-gamma activity has also been reported in a recent study showing that the enhanced responses are mainly distributed in the posterior portion of the STG along with ventral pre-motor areas and high-gamma enhancement in these areas is correlated with the peak of vocal compensation magnitude during speaking Early evidence for motor-induced modulation of auditory cortical processing is provided by studies showing that induced vocalizations via electrical stimulation of the central gray caused reductions of spontaneous firing rates of neurons within auditory cortex of squirrel monkeys Despite the generally suppressive nature of motor-driven modulation of auditory cortical activity, studies have suggested that efference projections play a key role in increasing neural sensitivity for detecting unexpected perturbations in voice auditory feedback. Single unit recordings in marmosets\u2019 auditory cortex show that the majority of suppressed neurons during vocalization increased their firing rates in response to pitch-shifted feedback The patterns of STG activation observed in the present study are consistent with data from functional imaging. For example, bilateral STG activation was demonstrated in response to normal and pitch-shifted voice auditory feedback during vowel phonations The present findings can be discussed in the context of proposed audio-vocal integration models of speech production and control Even though direct evidence for the presence of a motor-related activity in the sensory (e.g. auditory) system has not previously been established, a large number of studies have provided supporting evidence for the existence of an efference copy mechanisms that can modulate neural processing of sensory feedback in different sensory  modalities Lastly, the analysis of the behavioral data showed consistent results in terms of the nature of vocal responses to pitch-shifts in the auditory feedback. A large sub-group of the tested subjects (8 out of 10) exhibited an upward (compensatory) change in their voice pitch in response to downward stimuli. However, we observed a large amount of variability in response properties of the vocal behavior see  and it w"}
+{"text": "The pharmaceutical industry is approaching unsustainable research costs to develop new drug therapies for mental disease because of the high failure rate in clinical trials. These failures are due to limitations of pre-clinical studies in animal models that fail to predict the efficacy of new drugs in human subjects. The gap between pre-clinical trials and clinical trials is particularly difficult in complex mental diseases such as Alzheimer\u2019s disease because of the complex dynamics of the brain and the multiple chemical pathways that drugs can affect.However, many biological mechanisms associated with Alzheimer\u2019s disease are now understood, and computational power and methods have reached the point for practical modeling of pathologies of Alzheimer\u2019s disease. Numerical models can combine the information from animal studies of brain circuitry with data from human clinical trials of drug actions. Furthermore, complex interactions of multiple receptor targets can be predicted by a biophysical model of brain function.We introduce numerical models of neuronal microcircuitry that are associated with symptoms of Alzheimer\u2019s disease. The emphasis is on the dynamics of these neural systems and how their dynamics are modified by therapeutic drugs. Unlike the current state-of-the-art methods of estimating therapeutic efficacy, the computational platform yields a significant increase in the predictive correlation with data from clinical trials.To develop a biophysical model for functional cognitive performance, we implemented a conductance-based computer model of multicompartment neuronal cell types in a cortical brain circuit for working memory using preclinical data on receptor pharmacology of catecholamine and cholinergic neurotransmitters. The pathology of Alzheimer\u2019s disease was subsequently implemented as a loss of synapses and neurons and decreased cholinergic tone and the model as further calibrated the model with clinical ADAS-Cog results on acetylcholinesterase inhibitors and 5-HT6 antagonists. As an independent validation, we reproduce clinical data showing that ApoE genotype, implemented as a specific synapse loss and a decline in cholinergic tone, reduces the network performance much more in mild cognitive impairment conditions than at later stages of Alzheimer\u2019s disease pathology.As a further example, we explore the reason for the differential effect of memantine, an NMDA subunit selective weak inhibitor in early and late Alzheimer\u2019s disease pathology. The preferential inhibition of the NMDA-NR2C/NR2D subunits that are located on inhibitory interneurons compensates for the greater excitatory decline observed with stronger pathology.This quantitative systems pharmacology mechanistic disease model uses the full human pharmacology for clinical candidates in a humanized calibrated model of Alzheimer\u2019s disease. Complementary to traditional animal models, the model has potential to assess the potential off-target effects of disease-modifying drugs, the consequences of pharmacologically active unique human metabolites, the effect of comedications and the impact of a small number of well-described genotypes."}
+{"text": "When pain is assessed in research, it is most commonly assessed using patient-reported outcome measures (PROMS). These measures can provide information about pain severity, distress and qualities, but they are unable to provide information about the underlying mechanisms contributing to pain perception. Quantitative Sensory Testing (QST) comprises non-invasive tests which can identify abnormalities in pain processing on a localised and widespread level. The aim of this study was to explore the relationship between the measurement of pain thresholds by two different QST methods and the measurement of pain severity by a validated PROM.. A digital algometer (Somedic) with a 1cm probe was used to assess pressure pain thresholds (in kPa) three times at each site. A MSA Thermotest (Somedic) was used to measure hot pain thresholds (in Celsius) four times at each site. Pain thresholds were tested at the painful knee and the pain-free forearm. Self-reported pain severity was assessed using the WOMAC questionnaire. Spearman-Rank Correlation Coefficients (CC) were calculated to determine the strength of correlation between pain thresholds and pain severity.Patients on the waiting list for a total knee replacement because of osteoarthritis were approached about this study, and 107 patients attended a QST sessionPain severity in the knee significantly correlated with pressure pain thresholds at the knee  and the forearm . No significant correlation was found between pain severity in the knee and heat pain thresholds at the knee  or the forearm .This study found a small but significant positive correlation between self-reported knee pain severity and pressure pain thresholds, but not heat pain thresholds. This suggests that as pain worsens, patients become more sensitive to pressure pain at the osteoarthritic knee and the pain-free forearm. Increased pain sensitivity at a pain-free distant body site, such as the forearm, suggests involvement of the central nervous system and widespread pain sensitisation. The addition of Algometry as an outcome measure in clinical trials and pain studies could improve understanding of the mechanisms contributing to self-reported pain severity, by identifying the presence and extent of pain sensitisation. We are currently using QST in a large randomised controlled trial of pain control in arthroplasty (the APEX study), to explore the relationship between pain sensitisation and pain severity in osteoarthritis patients, and the influence of pain sensitisation on outcomes after joint replacement."}
+{"text": "We have read with great interest the case presentation entitled 'Successful Right Ventricular Tachycardia Ablation in a Patient with Left Ventricular Non-compaction Cardiomyopathy' by Honarbakhsh et al. in the recent issue of the journal . They suIn conclusion, differential diagnosis of ARVD/C should be kept in mind in patients with multiple arrhythmia foci from different parts of the right ventricular myocardium."}
+{"text": "The interface includes energy gradients and is parallelized. For large molecules such as ubiquitin a reasonable speedup (up to a factor of six) is observed for up to 16 cores. The SCF convergence is greatly improved by PCM for proteins compared to the gas phase.An interface between semi-empirical methods and the polarized continuum model (PCM) of solvation successfully implemented into GAMESS following the approach by Chudinov  Continuum solvation models such as the polarized continuum model (PCM) This paper is organized as follows. 1) We review the relevant expressions for the semi-empirical/PCM interface. 2) We present results of solvation free energies and compare them to previous results. 3) We test the numerical stability for geometry optimizations and vibrational analyses. 4) We present timings and parallelization speed-ups for protein-sized systems. 5) We summarize our findings and provide possible ideas for future improvements.In PCM, a molecule (the solute) is placed inside a solvent-cavity usually described by introducing interlocked spheres placed on the atoms of the molecule. The solvent is described as a polarizable continuum with dielectric constant For C-PCM the ASCs et al.Here, The electrostatic interaction of the ASCs Optimization of the molecular geometry in the PCM field requires the derivative of The semi-empirical/PCM interface was implemented in a locally modified version of GAMESS et al. for twenty smaller ammonium and oxonium type molecules used in that study. The structures were generated from their SMILES string (see We compared our implementation to that of Chudinov ring see  using OpGeometry optimizations used a convergence threshold of The Mean Absolute Deviations (MADs) of vibrational frequencies between solvated (s) and gas-phase (g) calculations were calculated byWe also carried out single point energies and gradients calculations for Chignolin (PDB: 1UAO), Trypthophan-cage (PDB: 1L2Y), Crambine (PDB: 1CRN), Trypsin Inhibitor (PDB: 5PTI) and Ubiquitin (PDB: 1UBI). The proteins were all protonated with PDB2PQR et al. et al. uses the original PCM implementation of Miertus, Scrocco and Tomasi et al. uses a more elaborate scheme to reach convergence of the solvation free energies by subdividing the surfaces incrementally.The electrostatic solvation free energies are presented in To test the numerical accuracy of the PCM gradients we optimized the molecules listed in In four cases  the vibrational analyses yields imaginary frequencies between 26 and 200 cmIn The cost of optimizing the wavefunction in PCM is between two (Crambine) and three (Chignolin and Tryptophan-cage) times more expensive than without. For Chignolin, which is the smallest protein in our test set, it took 21 SCF iterations to converge in PCM while only 13 for PCM/DIIS and 14 for PCM/SOSCF. The other proteins converged within 17 iterations without convergence acceleration and within 14 iterations with. For absolute timings regarding larger proteins, Crambine, Trypsin Inhibitor and Ubiquitin finished in 1293, 3455 and 6732 seconds with PCM without convergence accelleration, but are slower  with PCM and DIIS enabled. Using SOSCF did not result in an appreciable decrease in CPU time. The increase in CPU time when using DIIS is due to the extra matrix operations associated with this method, which represent the computational bottleneck for sem-empirical methods.Evaluating the ASC potential derivative  analyticThe relative speedup from running in parallel in the gas phase is shown on et al. An interface between semi-empirical methods and the polarized continuum model (PCM) of solvation successfully implemented into GAMESS following the approach by Chudinov For very small systems we found some numerical instability problems in the gradient which caused geometry convergence failure, but geometry optimization appears robust for larger molecules. The use of PCM occasionally introduces imaginary frequencies in the Hessian analysis, but this was also found for RHF/STO-3G PCM calculations and even in a few semi-empirical gas phase calculations so these problems do not appear to be specific to the to the current implementation. We therefore consider the current implementation a working code for all practical purposes, but welcome feedback from readers who encounter numerical stability problems for large molecules.For semiemprical methods the most time CPU-intensive part of the calculation remains the solution of the SCF equations. This part of the code was already parallelized in GAMESS and we show, for the first time, that this implementation applies to semi-empirical methods and the new PCM interface. For large molecules such as Ubiquitin a reasonable speedup (up to a factor of six) is observed for up to 16 cores.It will be interesting to see how much the numerical stability and computational efficiency will improve once the interface is combined with the recently developed FIXSOL/FIXPVA2 method developed by Li and coworkers Text S1Analytical derivative of the interaction potential.(PDF)Click here for additional data file.Figure S1Speedup by using multiple cores single gas phase gradient evaluation.(TIFF)Click here for additional data file."}
+{"text": "It will outline results obtained from mouse and rat models for various Nrg1 isoforms/isoform types , which have been exposed to different forms of stress  and housing conditions . These studies suggest Nrg1 as a prime candidate for GxE interactions in schizophrenia rodent models and that the use of rodent models will enable a better understanding of GxE interactions and the underlying mechanisms.Schizophrenia is a multi-factorial disease characterized by a high heritability and environmental risk factors. In recent years, an increasing number of researchers worldwide have started investigating the \u201ctwo-hit hypothesis\u201d of schizophrenia predicting that genetic and environmental risk factors (GxE) interactively cause the development of the disorder. This work is starting to produce valuable new animal models and reveal novel insights into the pathophysiology of schizophrenia. This mini review will focus on recent advancements in the field made by challenging mutant and transgenic rodent models for the schizophrenia candidate gene  The two-hit hypothesis of schizophrenia states that a combination of genetic and environmental risk factors causes the development of schizophrenia  is a genetic target for schizophrenia research   and experimental animal research .Animal models can incorporate genetic and environmental risk factors at different stages of development, thereby more accurately mimicking the aetiology of schizophrenia, and help elucidate interactions between those factors and underlying mechanism  has a significant impact on animal models of neurodegenerative diseases  might be responsible for the earlier onset of hyperactivity.Nrg1 mutant mice might also support the activation of dopaminergic pathways .Other genetic mouse models of schizophrenia have been reported to benefit from more complex enriched housing environments . All mice displayed robust stress-induced increases in serum corticosterone, although the response was more pronounced in young Nrg1 mutants compared to WT mice. The study suggested that there is no pronounced effect of mutant transmembrane domain Nrg1 on the endocrine and behavioral effects of acute restraint stress. Nevertheless, Nrg1 modified corticosterone release in young Nrg1 mutants and the anxiety-like response of hyper-locomotive older Nrg1 mice, confirming that the gene plays a role in how an organism responds to environmental manipulations. The phenomenon of a disconnected behavioral and endocrine stress response of older Nrg1 mice  is consistent with other mouse models  receptors in the hippocampus and pituitary glands of Nrg1 mutant rats under baseline conditions could then result in a more pronounced negative feedback loop thereby increasing the inhibition of HPA axis activity following acute restraint stress. Interestingly, shifts in the balance of glucocorticoid and mineralocorticoid receptor levels in humans can create a vulnerability to psychiatric disease, especially among genetically predisposed individuals  species differences  in control but not mutant mice. Social defeat also altered the lipopolysaccharide and concanavalin A-stimulated cytokine response of the spleen in a genotype-specific manner (see study for details). In the brain, stress decreased interleukin-beta mRNA levels in the prefrontal cortex of mutant mice only, whereas striatal interleukin-beta was down-regulated in controls and up-regulated in Nrg1 mice. Finally, hippocampal BDNF mRNA levels were elevated in control mice and reduced in mutant mice whereas tumor necrosis factor-alpha was up-regulated in Nrg1 mice only. Reduced striatal BDNF levels might have been involved in the disrupting effects of social defeat stress on the spatial memory of Nrg1 mutant mice  was the only candidate for a possible interaction between a genetic predisposition for schizophrenia and heavy cannabis abuse [ so that a high level of transparency and standardization of test conditions across research sites will be crucial.Recent research utilizing genetic rodent models has revealed an interactive relationship between Nrg1xE and their consequences for schizophrenia have to be evaluated further, an involvement of the GABAergic, glutamatergic and BDNF systems seems likely. Importantly, environmental (risk) factors not always induced adverse  effects in Nrg1 mutants, which should be taken into account when looking into GxE interactions [for genotype-specific effects of environmental factors see also (Tucci et al., Nrg1xE summarized in Table Although the exact nature of The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Cellular metabolism continuously processes an enormous range of external compounds into endogenous metabolites and is as such a key element in human physiology. The multifaceted physiological role of the metabolic network fulfilling the catalytic conversions can only be fully understood from a whole-body perspective where the causal interplay of the metabolic states of individual cells, the surrounding tissue and the whole organism are simultaneously considered. We here present an approach relying on dynamic flux balance analysis that allows the integration of metabolic networks at the cellular scale into standardized physiologically-based pharmacokinetic models at the whole-body level. To evaluate our approach we integrated a genome-scale network reconstruction of a human hepatocyte into the liver tissue of a physiologically-based pharmacokinetic model of a human adult. The resulting multiscale model was used to investigate hyperuricemia therapy, ammonia detoxification and paracetamol-induced toxication at a systems level. The specific models simultaneously integrate multiple layers of biological organization and offer mechanistic insights into pathology and medication. The approach presented may in future support a mechanistic understanding in diagnostics and drug development. Cellular metabolism is a key element in human physiology. Ideally the metabolic network needs to be considered within the context of the surrounding tissue and organism since the various levels of biological organization are mutually influencing each other. To mechanistically describe the interplay between intracellular space and extracellular environment, we here integrate the genome-scale metabolic network model HepatoNet1 at the cellular scale into physiologically-based pharmacokinetic models at the whole-body level. The resulting multiscale model allows the quantitative description of metabolic behavior in the context of time-resolved metabolite concentration profiles in the body and the surrounding liver tissue. The model has been applied to three case studies covering fundamental aspects of medicine and pharmacology: drug administration, biomarker identification and drug-induced toxication. Most notably, our multiscale approach fosters an improved quantitative understanding of drug action and the impact of metabolic disorders at an organism level, based on a genome-scale representation of cellular metabolism. Computational models such as the one presented include various aspects of human physiology and may therefore significantly support rational approaches in medical diagnostics and pharmaceutical drug development in the future. Human metabolism is an integral component of whole-body physiology and its dysfunction plays a key role in many systemic diseases. Frequent symptoms of metabolic diseases are changes in exometabolism In recent years, modeling approaches have been developed describing biological processes at different levels of physiological organization based on multiple, divergent mathematical formalisms For analyses at the cellular level, metabolic network reconstructions are an important tool of bottom-up systems biology. Cellular metabolism gathers a multitude of upstream regulatory events onto the various layers of cellular organization such as the transcriptome and metabolome representing an important angle point in the physiology of an organism. Metabolic networks are typically described by stoichiometric matrices and intracellular flux distributions are inherent variables in such models. First stoichiometric models on human metabolism at genome-scale encompassed generic collections of metabolic biochemistry in human cells in vitro experiments with more or less well-defined media conditions, they do not suffice for considerations of in vivo metabolism, where the cell is embedded in the ever-changing environment of the surrounding tissue and organism. Therefore, human metabolism can only be fully understood by an integrative analysis which simultaneously considers the whole-body context. This allows in particular the quantification of cellular boundary conditions and the interference with intracellular states and processes. Several approaches for combining models covering different levels of biological organization have been described before While metabolic network models are applicable to the investigation of We here apply dFBA to describe human metabolic networks within the context of whole-body PBPK models . The relative enzyme activity (relE(t)) is the time-resolved ratio of the inhibited reaction rate v(t) and the uninfluenced reaction rate 0v (I\u200a=\u200a0 \u00b5M). Next, relE(t) is used to quantify the effect of enzyme inhibition in the metabolic network. The additional constraint for the FBA step imposed on the specific flux in the metabolic network is defined as:E(t)v corresponds to the flux through the affected enzyme at each time step which is defined as the product of the unperturbed flux E(0)v which is calculated by FBA and the relative enzyme activity relE(t). Therefore, the set of constraints changes over time such that the extracellular exchange rates identified with FBA also evolve dynamically. This allows on the one hand quantifying the effect of compound-induced extracellular perturbations on metabolic states. On the other hand, time-resolved exchange fluxes determined with FBA may interfere with the mass balance of the PBPK model such that direct coupling needs to be considered (see section below).Indirect coupling is used for the simulation of regulatory modifications such as drug-induced inhibition of metabolic enzymes , 2. In tMetabolic clearance and formation processes are simulated by direct coupling since they directly interfere with the mass balance of the PBPK model. Direct coupling therefore describes the influence of active processes at the cellular level on the distribution of compounds at the whole-body scale. To this end, a feedback update loop is considered which consists of the following steps : (1) TheWhile the exchange rates in the PBPK model and metabolic network are identical for the metabolic reference state, these rates will differ if internal and external network perturbations are imposed. Without any impairment of enzyme reactions in the metabolic network, the clearance or production rates calculated by FBA will reach the upper bound (step 2). In this case, the rates of the coupled model are identical to those of the PBPK model alone. In contrast, the rates calculated by FBA will decrease if for instance enzyme activities are impaired due to restricted functionality or structural network errors . ConsequAs a first example we analyzed drug action of allopurinol in the treatment of hyperuricemia with a multiscale PK/PD model. Purine metabolism provides a large number of drug targets In clinical practice, high plasma levels of uric acid (above 470 \u00b5M) are referred to as hyperuricemia which may result from inborn errors of purine metabolism and even more often from impaired renal excretion of uric acid, which is considered in the following. Hyperuricemia can lead to diseases like gout where uric acid is deposited into tissues, especially in the joints To estimate the inhibitory concentration of allopurinol and its active metabolite oxypurinol, a coupled PBPK model was developed see . ExperimIn the next step, a PBPK model for uric acid was created, which allowed describing changes in uric acid concentration as a mechanistic consequence of allopurinol inhibition in hepatic purine metabolism  resulting in a reduced ammonia detoxification capacity. Pathogenesis of UCD was exemplarily assumed as a linear decrease of the enzyme activity of ornithine transcarbamylase (OTC), leading to complete impairment of the enzyme  [56]. SiWith the coupled model and the above described constraints, simulation was performed within a time range of 21 days. After 24 h, UCD starts developing which led to a decreasing urea production rate after 30 h. At the same time, the glutamine and alanine fluxes began to rise and the rate of ammonia uptake began to decrease. In the new steady state (after 6.5 days), ammonia uptake rate was 0.072 \u00b5mol/L/min  and glutAbove model is a representation for an average patient. Since the model, however, structurally includes many potential causes for inter-individual variability at a large level of mechanistic detail, it may be used to analyze pathogenesis on a populations scale as well. Such individual differences may include physiology Our final example deals with drug-induced toxication by addressing downstream effects of drug dosing on metabolic functionality at the cellular level. We here chose overdosing of paracetamol, one of the most common reasons for liver failure To quantify the metabolic impact of perturbations in the enzyme activities on whole liver functionality, indirect coupling of a paracetamol PBPK model and HepatoNet1 was used to determine the effect of a paracetamol overdose on a large amount of functional liver objectives. HepatoNet1 was previously validated with 123 physiological functions which represent essential tasks for liver metabolism We started our analyses with the development of PBPK models of the parent drug paracetamol the three metabolites  and NAPQI , respectively as well as time of trough concentrations at 24 h after drug administration (t24h)  . Out of We next analyzed, whether the flux underlying the different optimal values changed during the application of different doses of paracetamol. This could explain why more objective functions are affected after the toxic dose of paracetamol, which is to be expected by network robustness We here integrate genome-scale metabolic networks, comprising thousands of biochemical reactions, into PBPK models to analyze metabolism at the level of the human organism. The approach is based on dFBA Our approach combines well-established computational modeling approaches from different biological scales. At the organism scale, standardized PBPK models which are routinely used in pharmaceutical drug development provide a generalized description of the distribution of substances within the human body. At the cellular scale, metabolic network reconstructions represent core building blocks of bottom-up systems biology which describe fundamental cellular biochemistry. Our coupling approach therefore provides a generic framework for a wide range of possible applications. Notably, all these applications can be addressed without the need for further model curation or modification.To illustrate our approach, we exemplarily integrate HepatoNet1 In a first application example we investigate a multiscale PK/PD approach, where indirect coupling is used to mechanistically describe the pharmacological effect of the purine analogue allopurinol on the biosynthesis of uric acid. The PK of the exogenous drug as well as its resulting downstream PD effect on the formation of endogenous metabolites are quantified allowing a comprehensive evaluation of drug safety and drug efficiency. For multiple oral administrations of 200 mg allopurinol we predict a 69.3% decrease of uric acid concentration in the venous plasma which is in quantitative agreement with clinical data The identification of quantitative biomarkers for metabolic disorders is the second application example. As a complement to classical qualitative biomarker identification Drug-induced toxication following paracetamol overdose is the third application example. We demonstrate how paracetamol impairs metabolic capacity by affecting a broad range of different metabolic functions. The specific metabolic impact is illustrated for a therapeutic (1 g) and a toxic (15 g) dose of paracetamol. The results show a larger metabolic impact on single hepatic functions following the toxic dose of paracetamol. Also, more metabolic functions are affected after the higher dose (24 vs. 20 functions). Since a considerable number of fluxes is affected, we conclude that paracetamol toxication induces flux rerouting which is used by the hepatocyte to compensate for network perturbations thereby conferring cellular robustness. Notably, this effect which has been shown before for microorganisms Describing the impact of a compound on the body and the cell is the fundamental question in pharmacodynamics. Classical approaches describe this interference with rather phenomenological models Taken together, the presented approach integrating organ-specific metabolic networks into PBPK models provides many opportunities for scientific research, clinical applications and drug development as outlined by the prototypical examples discussed above. It is only by such multiscale models that a mechanistic understanding of organ dysfunction and disease etiology at a system level will be achieved. This will be greatly supported by the reconstruction of further genome-scale metabolic networks which will become available in the future At the whole-body level, PBPK modeling quantitatively describes all ADME-related processes of endogenous and exogenous compounds within mammalian organisms The PBPK models considered in this study were all built with the software tools PK-Sim and MoBi for which academic licenses are available free of charge  usually less literature data is available and (2) these parameters often have significant sensitivity although the overall dynamic behavior of the PBPK models is robust  and v represents the intracellular flux distribution. The overall solution space is confined by a set of additional constraints (A\u00b7v\u2264b) which represent for example substrate availability.Stoichiometric models provide a mathematically formal way to capture the basic biochemistry of cellular metabolism into an analytical framework. Assuming steady state of the system, all intracellular metabolites can be balanced in linear systems of equations, which are usually underdetermined since they encompass much more unknown reaction rates than linear independent mass balance equations. Flux distributions can be identified with stoichiometric models by using FBA To illustrate our approach, we here exemplarily use HepatoNet1, a tissue-specific network reconstruction of hepatic metabolism Text S1Important additional texts, tables, equations and figures.(PDF)Click here for additional data file."}
+{"text": "Our proposal to investigate the whole phase relation dynamics is motivated by the phenomenon of relative coordination observed in the movements of fish fins described by von Holst [Both oscillatory phenomena and the dynamics of integration and segregation in the brain are fields of intense study in current computational neuroscience. It is often suggested that moments of phase-locking (as moments of integration) between functionally distinct neuronal groups represent meaningful functional brain states; and moments of phase-scattering (as moments of segregation) represent transitions between such states. The main evidences for such claim come from investigations on the well-known visual binding problem . Despiteon Holst  and latton Holst . In dynaon Holst   and their behavioral correlates. Despite the strong simplifying assumptions involved, the theoretical results shown here suggest a \u201cdifferent/new\u201d approach to analyze empirical data in neuroscience where regimes of phase relation might be as relevant as phase locking events for how brain-environment dynamics give rise to behaviour. We conclude with some expansions of phase density and phase coherence measurements for bigger oscillatory networks in sensorimotor systems."}
+{"text": "Graves-Basedow disease (GBd) since late fifties has been considered to be autoimmune thyroid disorder where the presence of thyroid stimulating antibodies (TSAb) may lead to hyperthyroidism, thyroid orbitopathy and thyroid dermopathy. During last years it was generally accepted that development of Graves-Basedow disease is dependent on the presence of two or three groups of factors - genetic and environmental or genetic, environmental and endogenous. Familial clustering of GBd, familial presence of thyroid autoantibodies and high concordance in the incidence and clinical course of the disease in monozygotic siblings all suggested that several genes decide about susceptibility to this disorder and likely its phenotypes. On the other hand environmental agents and endogenous factors served as triggers important to the development of the disease, its clinical course and response to given therapy. It was believed that finally, development of GBd (and other autoimmune disorders) is a consequence of lack of balance between the formation of self reactive T cells and central and peripheral tolerance. As a result thyroid was infiltrated by self reactive T cells that in turn affected B cells and led to the production of thyroid stimulating antibodies.vice versa. Some findings suggest that in prone classically hyperthyroid patient the administration of methimazole can provoke switch off of TSAb generation and start of TBAb followed by block of thyroid hormones biosynthesis and quite rapid morphological damage of thyroid cells. It is a pity that in other hypothyroid patient administration of thyroxine can switch on the generation of TSAb and switch off the production of TBAb. Second, it is more and more obvious that autoimmune thyroid disorders and differentiated thyroid cancer (DTC) especially of papillary type (PTC) share some genetic factors (RET/PTC1) and environmental and epidemiological features. In addition presence of GBd disease in patients with DTC leads to increased mortality of cancer patients. Third, microarray DNA analysis of thyroids from GBd patients with severe course of the disease led to the identification of seven additional genes either overexpressed or underexpressed that may be responsible for high level of TSH-R Abs, large goiter size and high free T3/free T4 ratio, features characteristic for patients that poorly respond to anti-thyroid drug therapy. In addition to these clinical observations, the pathogenesis of GBd during the last two-three years was strongly affected by studies suggesting that non sufficient peripheral tolerance was a key to autoimmunity in general, including mechanisms leading to development of Graves-Basedow disease. In a way we returned to Volpe hypothesis developed in the 70-ies of the previous century that pointed out the role of T-suppressor cells. At present the name suppressor cells was postponed and we know that control of self reactive T cells is a function of T regulatory cells (Tregs). It has been proven that block of activation of Tregs both in experimental animals and humans led to the development of generalized fatal autoimmunity. The mechanism of appropriate Tregs activation concerning first signal (MHC-TCR) and especially second costimulatory signals (CD28-B7-1(CD80) or CD28-B7-2 (CD86)) will be presented and their role for the thyroid autoimmunity discussed. The progress in our knowledge concerning autoimmunity as a whole and GBd as a thyroid autoimmune disorder clearly shows that pathogenesis of this disorder is more complex than previously expected and that personalized approach to given patient based on clinical and molecular findings is more important than the hope that single finding (light in corridor) brings a positive solution for all patients with Graves-Basedow disease.Most recently etiopathogenesis of GBd became further complicated by both clinical and molecular findings. First, GBd can be clinically presented as a hypothyroidism depending on the switch of TSAb production to thyroid blocking antibody (TBAb) production as well as"}
+{"text": "Systemic treatment of patients with early-stage cancers attempts to eradicate occult metastatic disease to prevent recurrence and increased morbidity. However, prediction of recurrence from an analysis of the primary tumor is limited because disseminated cancer cells only represent a small subset of the primary lesion. Here we analyze the expression of circulating microRNAs (miRs) in serum obtained pre-surgically from patients with early stage colorectal cancers. Groups of five patients with and without disease recurrence were used to identify an informative panel of circulating miRs using quantitative PCR of genome-wide miR expression as well as a set of published candidate miRs. A panel of six informative miRs  was derived from this analysis and evaluated in a separate validation set of thirty patients. Hierarchical clustering of the expression levels of these six circulating miRs and Kaplan-Meier analysis showed that the risk of disease recurrence of early stage colon cancer can be predicted by this panel of miRs that are measurable in the circulation at the time of diagnosis . Colorectal cancer (CRC) is the third leading cause of cancer mortality that affects men and women equally. Worldwide it accounts for approximately one million new cancers and one-half million deaths representing 10 percent of cancer deaths microRNAs (miRNAs or miRs) are small, non-coding RNAs that play a significant role in controlling the activities of cellular pathways both in physiology and pathology see e.g. . The disBeyond these analyses of normal and diseased tissues, more recent reports have shown that miR species can be detected in the circulation 6-fold for miRs in serum samples To measure miRs in the circulation, we established quantitative RT-PCR From the above pilot study we selected two patient samples from the recurrence-free (NRec) and recurrence (Rec) group for an unbiased genome-wide miR analysis. We picked patients from the above pilot study that had shown the most differential expression of candidate miRs. We reasoned that a comparison within such a sample pair might offer a greater chance of picking up recurrence-specific miRs. We analyzed this pair of patient samples using SYBR Green qPCR based genome-wide miR expression arrays for 760 miRs set up in our laboratory, using commercially available reagents . The respective result for the top 70 miRs is shown in To evaluate whether the circulating miRs identified in the above pilot study can predict disease recurrence in low-risk patients, we used a separate, independent group of thirty patients with early stage colon cancer with known outcomes. Fifteen of these patients had disease recurrence within an average of 25 months whereas the other fifteen remained recurrence-free. The clinical characteristics of patients in this validation set at the time of their initial diagnosis is provided in Expression of the six miRs derived identified in the pilot study was measured by qRT-PCR and the resulting data are shown as raw Ct values as well as a concentration range in A blinded hierarchical clustering analysis The current study evaluates the possible use of circulating microRNAs (miRs) to identify colon cancer patients with a high risk of disease recurrence inspite of a diagnosis of early stage, low-risk disease indicated by established tumor staging. This could help identify those individuals that would benefit from closer surveillance and/or additional systemic therapy and would avoid over treatment of patients that will not benefit due to their low risk  and miR-596 (upregulated). miR-103 was significantly down-regulated (p\u200a=\u200a0.038) in blood samples from patients with disease recurrence compared to recurrence-free patients . In inteThe risk of recurrence of early stage colon cancer may be predicted by monitoring miRs in patient blood samples collected at the time of the initial diagnosis.The collection and use of biospecimen was approved by the Institutional Review Board (IRB) of Georgetown University under Protocol #2007-345 most recently on 10/24/2012. All patients sign a consent form permitting the use of donated tissue and body fluid samples. The consent forms and their content was reviewed and approved by the IRB. Serum samples (<1 ml) were processed after removal of personal identifiers. miR isolation was described previously PCA and hierarchical clustering were performed based on the mean centered and scaled miR expression levels. The clustering methods used XLSTAT (Addinsoft Inc.) within Excel (Microsoft Inc.) on OSX 10.7.5. These methods allow for the calculation of significance between the hierarchical clusters and derive p-values using Fisher's exact test. Prism 5.0 (Graphpad) software was used for other tests and display of the data."}
+{"text": "The hippocampus is a brain structure that is involved in the formation and recall of episodic memories, including space-related behavior. Place-specific hippocampal activity patterns change dramatically if the animal is exposed to the same maze in different lab environments  . Global During hippocampal remapping the spatial activity pattern of grid cells undergoes locally coherent rotations and translations , but it We employed a model in which a superposition of grid cell outputs give rise to place cells for a single environment . We inveThe grid layer thus provides a low dimensional parameterization of the different place maps without any synaptic plasticity in the projections, thereby indexing spatial memories. This result suggests that different independent modules are present in the entorhinal cortex and that their grid fields co-realign during global remapping."}
+{"text": "This paper examines the effects of parallelizing an unsupervised feature acquisition algorithm using General-Purpose computing on Graphics Processing Units (GPGPU). Previous work in feature learning has established the effectiveness of hierarchical learning methods that refine large quantities of elementary features into small numbers of intermediate-level features. Some of the most effective of these methods alternate between template matching layers that combine features and sub-sampling layers that perform feature scale and/or position invariance. This approach is inspired by the mammalian ventral visual pathway. One such approach that produces highly informative features is a spiking convolutional network trained with STDP-based learning . When us"}
+{"text": "Thyroid gland, previously supposed not to have any impact on spermatogenesis and male fertility, are now being recognized as having important role in male reproductive functions. Most of the studies on the effect of thyroid hormones on male fertility were conducted between the years 1970 and 2000 . The undIn rats rendered thyrotoxic by T4 resulted in decreased serum gonadotropin levels , decreasThe two most common types of thyroid diseases are hypothyroidism and hyperthyroidism. Studies assessing the role of hypo- and hyperthyroidism in male infertility have also been conducted in human subjects. Hypothyroidism may result in a decrease in the sex hormone binding globulin (SHBG) levels and a decrease in total serum testosterone levels, as well as a decrease in the LH and the follicle stimulating hormone (FSH) levels . In case"}
+{"text": "Vaccination is one of the most valuable weapons against infectious diseases and has led to a significant reduction in mortality and morbidity. However, for most viral hemorrhagic fevers caused by arenaviruses, no prophylactic vaccine is available. This is particularly problematic as these diseases are notoriously difficult to diagnose and treat. Lassa fever is globally the most important of the fevers caused by arenaviruses, potentially affecting millions of people living in endemic areas, particularly in Nigeria. Annually, an estimated 300,000 humans are infected and several thousands succumb to the disease. The successful development of the vaccine \u201cCandid#1\u201d against Junin virus, the causative agent of Argentine hemorrhagic fever, proved that an effective arenavirus vaccine can be developed. Although several promising studies toward the development of a Lassa fever vaccine have been published, no vaccine candidate has been tested in human volunteers or patients. This review summarizes the immunology and other aspects of existing experimental arenavirus vaccine studies, discusses the reasons for the lack of a vaccine, and proposes a plan for overcoming the final hurdles toward clinical trials. The literature search was based on PubMed, Embase, and Web of Science. The initial search term used was \u201cLassa OR Junin OR Machupo OR Guanarito OR Sabia AND (vaccine OR vaccination).\u201dTitles and abstracts were screened to exclude irrelevant publications.Arenaviridae contains four important species that cause severe hemorrhagic zoonoses in humans. Together, they have an important impact on public health in endemic regions , which encode two genes each Natural reservoirs include different species of rodents, depending on the arenavirus Little is known about the pathogenesis of the diseases caused by arenaviruses. A putative explanation for the severe symptoms is an immunopathology caused by an imbalanced host\u2013pathogen interaction with a perpetuated excessive reaction of host immune cells combined with delayed viral clearance Treatment options for the patients are limited. In addition to intensive care, the broad-band antiviral drug ribavirin has proven to be effective if administered early in the course of the disease (before day 6) The only currently available vaccine is Candid #1. This attenuated JUNV strain was generated through multiple passaging and provided good protection in clinical trials against argentine hemorrhagic fever (AHF) with an excellent safety profile Although there has been much effort to develop vaccines against LASV, none have been effective enough to warrant clinical trials. In this review, we summarize the work that has been done toward the development of vaccines against hemorrhagic fever caused by arenaviruses and discuss the current obstacles toward a licensed vaccine.The role of neutralizing antibodies (nAbs) in the control of arenavirus infections is controversial, but has been studied for LASV and JUNV in both human patients and animal models. The use of convalescent plasma has also been studied. Monkeys and guinea pigs are protected against Lassa fever by treatment with plasma from convalescent animals containing high titers of nAb In a placebo-controlled treatment study of JUNV, however, convalescent plasma of human AHF survivors benefited AHF patients with acute disease The role of nAbs during vaccination and natural infection has also been investigated.Heterologous vaccination with an apathogenic, related virus has been tested for two pairs: LASV/Mopeia virus (MOPV) and JUNV/Tacaribe virus (TACV). Cross-protection was demonstrated for LASV/MOPV without the appearance of nAbs In the case of JUNV/TACV, two groups Experiments in marmosets confirmed cross-protection between TACV and JUNV Knowledge of protective T-cell epitopes is essential for the development of vaccines based on cellular immunity.k) mice d restricted epitope NP 118\u2013126 of LCMV induces cross-protection to other Old World arenavirus homologues but not to the New World homologue Ter Meulen and colleagues screened for T-cell clones in Lassa fever survivors using recombinant antigen A human T-cell epitope identified at position 289\u2013301 in LASV GPC is highly conserved within Old and New World arenaviruses. CD4+ T-cells from a Lassa fever reconvalescent donor reacted to this epitope when the sequences were changed to the homologue sequences of other arenaviruses In another study, HLA-A02 and HLA-A03 restricted, protective epitopes were identified for different arenaviral pathogens In The most relevant vaccine trials are summarized in A successful example of a live vaccine for an arenavirus is JUNV Candid#1 (C#1), which confers reliable and safe protection against severe AHF. It is licensed in Argentina for the vaccination of people living in high-risk areas. A recent review summarizes the historical development and biological properties of the vaccine The use of live-attenuated strains or related apathogenic viruses for vaccination has a long history, starting with vaccinia virus for the prevention of smallpox or the yellow fever virus 17D strain An interesting live-attenuated vaccine candidate is the chimeric virus ML-29. Lukashevich generated a recombinant virus carrying the LASV S-segment and the MOPV L-segment by co-infection of Vero cells with both virus species Virus-like particles containing GP1, GP2, NP, and Z Gamma-irradiated LASV did not protect rhesus macaques against challenge, despite an increase in anti-LASV antibodies. This was attributed to the lack of adequate cellular immunity 2O2. The vaccine induced T-cell responses when high concentrations (50 \u00b5g) of inactivated virus were used in mice In contrast to these findings, Amanna et al. recently reported a LCMV vaccine based on purified LCMV particles inactivated by 3% HS. typhimurium and vaccinia virus were genetically modified to express LASV NP and LCMV NP. Mice inoculated with a recombinant vector showed LASV NP\u2013specific IgA and specifically reactive splenocytes Mastomys natalensis); vaccination could be accomplished in a manner similar to that of rabies vaccination in foxes An attractive way to deliver antigen for vaccination is oral uptake. In many instances, the mucosa is the first part of the host to come into contact with a pathogen. Oral application is furthermore minimally invasive and vaccination campaigns can be performed with less effort. Recombinant virus vectors have been in use since the early 1980s The biggest advantage is the use of genetically defined material. The antigen can be optimized to elicit the desired immune response. Safety aspects, such as the production of replication-incompetent viruses, are more easily addressed The different virus platforms allow the selection of a vector that has a similar tropism to that of the target virus  vectors have been modified to express LASV NP In 2004, the construction of a recombinant vesicular stomatitis virus (rVSV) carrying LASV glycoprotein was described The attenuated yellow fever strain 17D (YFV 17D) is one of the oldest and most successful virus vaccines ever used. Use of recombinant YFV 17D is therefore promising because its safety and potential to elicit immunity are known. The addition of foreign genes to the YFV genome further attenuates the replication capacity of the virus. Some recombinant YFV 17D-based vaccines are already in clinical trials. A general review of YFV 17D vectors has been published recently Another vaccine vector that proved effective in guinea pigs against LASV challenge is a Venezuelan equine encephalitis virus (rVEE) replicon particle expressing GP or NP Plasmid DNA can be used to express and deliver target genes into the host to induce immunity. Antigen-presenting cells and other body cells take up plasmid DNA and the ensuing protein synthesis from the plasmid DNA leads to MHC I and II presentation of peptides encoded by the plasmid DNA Although DNA vaccines have an excellent safety profile in humans, their rather weak immunogenicity may require prime-boost vaccination with other vectors.The development of vaccines against arenaviruses started shortly after the identification of JUNV as the causative agent of AHF in the 1950s. These efforts culminated in the introduction of the licensed Candid#1 vaccine in the 1990s, which led to a significant decrease in mortality and morbidity to AHF We will focus on LASV in the Discussion because it is by far the most important pathogenic arenavirus clinically and has an important impact on public health. Approximately 100,000 to 300,000 cases including several thousand fatal outcomes are estimated to occur annually in West Africa Firstly, LASV is a neglected tropical disease. Affected countries are Nigeria, Ivory Coast, Mali, Guinea, Sierra Leone, and Liberia. The specific socioeconomic problems related to LASV vaccination are probably the biggest hurdles to be crossed. People who are at the highest risk of infection are also the poorest in the above-mentioned endemic countries. Poor hygiene and sanitation in these countries increases the probability of LASV exposure. Furthermore, many people living in these countries are unable to pay for vaccination. Prime-boost vaccination campaigns are difficult to organize due to the poor infrastructure. The low commercial value of a LASV vaccine makes the development of such vaccines an unattractive prospect for pharmaceutical companies. Instead, international nongovernmental organizations  and foundations must provide the necessary financial support. Governments of the endemic countries should also contribute by logistically supporting clinical investigations in LASV patients and helping to organize phase II clinical trials for vaccine studies after phase I safety trials have been conducted in Western countries. As Nigeria is the biggest local economic power and among the top 10 oil-producing countries worldwide, it could take a substantial lead in these actions  Studies of the role of T-cells during pathogenesis ; (ii) identification of the correlate of protection in survivors; and (iii) identification of the most promising vaccine concept . The scientific community should meet in an international conference on LASV vaccines and discuss the different approaches.In our opinion, the experimental basis is at a sufficient stage of advancement for clinical trials to proceed. Much work done in different animal species (including nonhuman primates) has demonstrated the safety and efficacy of several vector systems for vaccination against LASV infection.What will be the most promising vector system for clinical trials? MOPV in humans will probably offer the most effective protection against subsequent LASV infection, but the risks involved in using a nonattenuated BSL-3 agent (BSL-2 in Europe) in clinical trials are currently too high. The same is true for the recombinant MOPV-LASV assortant ML-29. DNA vaccination would be cheap and safe, but it is highly questionable whether a single application would be sufficient for protection. As inactivated virus particles seem to be ineffective, we think that the most promising vaccine will probably be a system based on recombinant virus vectors  for which safety data  are available. Safety aspects can first be assessed in clinical trials outside of West Africa to circumvent political and logistical problems in the endemic countries. We hope to see LASV vaccine candidates moving into clinical trials within the next few years. Clinical approval of a LASV vaccine would not only bring decades of hard work to a successful end but would also justify the resources  that have been used."}
+{"text": "A central aim of the Whole System Demonstrator (WSD) programme is to find out how telehealth can help people manage their own long-term health conditions and to evaluate the potential benefits of this technological intervention within a randomised control trial. However, the adoption of this intervention at local level will entail significant changes in practice of care, in the division of health care work and in traditional professional-patient relationships and so will be contingent on the support of frontline health professionals directly responsible for its delivery. This was the rationale behind this theme 4 sub study within the Whole System Demonstrator evaluation study.To examine health professionals\u2019 views and experiences of implementing telehealth and their retrospective judgements of barriers and facilitators to its success.We undertook a 2-year qualitative longitudinal study. The method of data collection was semi-structured in-depth interviews with a purposive sample of frontline health professionals. The first year comprised baseline qualitative interviews with key health professionals directly involved in the delivery of telehealth in three Whole System Demonstrator sites: the London Borough of Newham, Cornwall and Kent. Interview participants included community matrons, teleheath monitoring nurses and general practitioners who deliver care to patients with long-term conditions. Follow-up interviews were conducted around one year later, prior to the end of the study and all interview data were thematically analysed and managed by NVivo.Currently under embargo by DH.Currently under embargo by DH."}
+{"text": "To the Editor: More than three quarters of critically endangered species of amphibians are threatened by infectious disease; several are already extinct (Litoria castanea), which was presumed to be extinct, was rediscovered in the Southern Tablelands of New South Wales, Australia. This species of frog had not been seen for 30 years, and a chytrid fungus, Batrachochytrium dendrobatidis, was thought to be the reason  parasites forming plasmodia-like structures 10\u201320 \u03bcm in diameter . PlasmodLitoria booroolongensis) that had similar brain lesions and intralesional myxozoan parasites  or an infectious process might be possible causes. Staff in the zoo\u2019s breeding program were questioned and indicated that the opportunity for introduction of a toxin was low. In addition, results for virus isolation and fungal and bacterial cultures were negative. We retrospectively reexamined histologic sections of an endangered booroolong frog (DNA was extracted from brain tissues (20 mg) by using the PureLink DNA Kit . To test for myxozoans, we used a highly Myxozoa-specific PCR to amplify the complete internal transcribed spacer of the ribosomal DNA (Cystodiscus axonis (syn. Myxidium sp. \u2018brain\u2019), as the most closely related sequence  and 1 of 5 eastern banjo frogs (Limnodynastes dumerilii).PCR produced a 973-bp amplicon with DNA from brain and liver of the yellow-spotted bell frogs and the booroolong frog. DNA from the frogs showed 100% identity with each other, as did sequences from brain and liver. A BLASTN (Cystodiscus spp. parasites of frogs are emerging and have spread widely along the eastern coast in the past 40 years; they were first detected in a frog collected in 1966 (Cystodiscus parasites in frogs endemic to Australia and in the invasive cane toad (Little information exists about the pathologic significance of myxozoan parasite in frogs and tadpoles (Frog myxozoan parasites are yet to be documented as a cause of population decline; yet, the frequent presence of these parasites in moribund animals in captivity, including the yellow-spotted bell frog, demonstrates the need to monitor parasites in endangered frog populations worldwide. On the basis of our necropsy findings in the central nervous system of 2 yellow-spotted bell frogs, we encourage other investigators to consider the potential role that myxozoan parasites may play in wild and captive populations of declining frogs worldwide."}
+{"text": "Theory posits that community dynamics organize at distinct hierarchical scales of space and time, and that the spatial and temporal patterns at each scale are commensurate. Here we use time series modeling to investigate fluctuation frequencies of species groups within invertebrate metacommunities in 26 boreal lakes over a 20-year period, and variance partitioning analysis to study whether species groups with different fluctuation patterns show spatial signals that are commensurate with the scale-specific fluctuation patterns identified. We identified two groups of invertebrates representing hierarchically organized temporal dynamics: one species group showed temporal variability at decadal scales (slow patterns of change), whilst another group showed fluctuations at 3 to 5-year intervals (faster change). This pattern was consistently found across all lakes studied. A spatial signal was evident in the slow but not faster-changing species groups. As expected, the spatial signal for the slow-changing group coincided with broad-scale spatial patterns that could be explained with historical biogeography . In addition to spatial factors, the slow-changing groups correlated with environmental variables, supporting the conjecture that boreal lakes are undergoing environmental change. Taken together our results suggest that regionally distinct sets of taxa, separated by biogeographical boundaries, responded similarly to broad-scale environmental change. Not only does our approach allow testing theory about hierarchically structured space-time patterns; more generally, it allows assessing the relative role of the ability of communities to track environmental change and dispersal constraints limiting community structure and biodiversity at macroecological scales. Theory posits that ecological communities consist of species groups that operate in different scaling regimes, wherein the sets of abiotic and biotic organizing variables differ across hierarchical scales Ecologist have developed tools that allow for an assessment of the hierarchical, multiscale structure of ecological systems from either a spatial The aim of this paper is to study the space-time duality in the hierarchical organization of communities by assessing spatial signals in the cross-scale structure of time series. More specifically, we test the hypothesis that spatial scales of observations are commensurate with the temporal scales of community dynamics at different hierarchies of ecological organization. That is, broad-scale spatial patterns should match temporal patterns that unfold on broader  time scales, and finer-scale spatial patterns should be associated with temporal processes on shorter (e.g. yearly) time scales. We test these conjectures using macroinvertebrate communities in lakes that serve as excellent model systems. First, previous research has shown that community dynamics follow partly theoretical predictions; that is, the temporal dynamics are hierarchically organized with faster and slower dynamics clearly operating in different temporal scaling regimes Spatial processes on community structure can take a variety of forms, including dispersal limitation and source-sink dynamics or mass effects, species extinctions and evolutionary processes We expect that if historical biogeography in the form of ecoregion delineations is the spatial analogue to temporal community change at decadal scales All field sampling and laboratory analyses reported in this study are part of the Swedish National Lake Monitoring Program, and are therefore regulated by the Swedish Agency for Marine and Water Management (HaV). All data are made freely available to the public and no permission for use of the data is therefore required. It is also confirmed that the field studies did not involve endangered or protected species.\u22121), acidity status  and lake size (0.11 to 5.43 km2) Twenty-six lakes from the Swedish National Lake Monitoring Program were selected for this study based on longest available time series. These lakes were environmentally heterogeneous, spanning gradients in water clarity . For this study we used water quality data that were obtained from surface water samples (taken at 0.5 m depth), which were collected once in summer  and autumn (October) at a mid-lake station in each lake. Previous research has shown that the mid-lake samples are representative for other lake areas 42\u2212 concentration), nutrients , and water clarity . All physicochemical analyses were done at the Department of Aquatic Sciences and Assessment following international (ISO) or European (EN) standards when available Water was collected with a Plexiglas\u00ae sampler and kept cool during transport to the laboratory. Samples were analyzed for electrical conductivity, water temperature, and variables including those indicative of acidity . Benthic invertebrates were collected from wind-exposed, vegetation-free littoral habitats in late autumn (October\u2013November) each year. Five samples were taken using standardized kick sampling with a hand net (0.5 mm mesh size). Each sample was taken by disturbing the bottom substratum for 20 seconds along a 1 m long stretch of the littoral region at a depth of c. 0.5 m; thus a total area of 1.25 mBecause no unified statistical procedure exists that allows testing the space-time duality of hierarchically organized systems, we used an approach that involves a sequence of independent statistical tests. The steps of this approach are summarized in We used a multivariate time series modeling approach, which breaks down the overall temporal structure of communities into independent temporal patterns shown by different groups of species within an assemblage Through a forward selection procedure, these PCNMs are related to the community data sets by means of RDA. The RDA retains significant PCNM variables and these are linearly combined in ways to extract temporal patterns from the species matrices; that is, the RDA identifies species with similar temporal patterns in the species \u00d7 time matrix and uses their temporal pattern to calculate a modeled species group trend for these species based on linearly combined PCNMs. The significance of the temporal patterns of all modeled species groups revealed by the RDA are tested by means of permutation tests.2 values of the canonical axes. The overall temporal structure of the whole community can then be deduced from the number of significant canonical axes in the RDA models.The RDA relates each modeled species group trend with a significant canonical axis. The R software generates linear combination (lc) score plots, which visually present the modeled temporal patterns of species groups that are associated with each canonical axis. Based on the number of significant canonical axes, the number of modeled species groups with different temporal patterns can be deduced. The ecological relevance of these temporal patterns can be quantified, using adjusted RBecause the canonical axes are orthogonal, the PCNM-RDA approach reveals temporal patterns of species groups that are independent from each other. Because temporal trends can be assessed at different scales, this method is useful for more accurately assessing the organization of ecological communities from a complex adaptive systems perspective All relevant steps in the analysis, from conversion of the linear time vector to PCNM variables, to calculation of modeled species group trends to visual presentation of the results in form of lc score plots were carried out with the \u201cquickPCNM\u201d function implemented in R 2.6.0 statistical software package Variance decomposition was used to assess the relative importance of environmental and spatial factors shaping the long-term assembly of species groups. Separate analyses were carried out for each modeled species groups identified across lakes. To account for the temporal structure of each species group explicitly in the analysis, species, environmental and spatial matrices were prepared in the following ways  as rows. The values comprised the correlation coefficients resulting from the correlation between species raw abundances and the modeled temporal scores (linear combination scores) of canonical axis one from the time series models of each lake. The second species matrix was constructed in a similar way but using correlation coefficients derived from the correlations with the second canonical axis. Using the correlation scores associated with significant temporal patterns revealed through time series modeling, rather than time-averaged abundance data of each taxon, better accounts for the explicit temporal structure of species-group change over time in the metacommunity analyses. That is, the correlation scores, but not the time-averaged species abundance, capture the taxa contributions to the modeled temporal changes of species group; because the correlation scores reflect the relative strength of individual taxa contributing to species-group change, structural changes in abundance as a function of modeled group change is accounted for in the analyses.Regarding the environmental matrix, we followed a similar approach as with the construction of the species matrices. Spearman rank correlations between environmental variables and the modeled species group trends were carried out to identify the set of abiotic variables contributing to species group change through time. Those variables with significant correlations were retained and the absolute values of their Spearman rank correlation coefficients were used as predictor variables in the environmental matrix. To avoid overfitting in posterior variance partitioning analyses, significantly correlated environmental variables were excluded from the matrix. Also here, the correlation coefficients, rather than the time-averaged values of environmental variables, account explicitly for the relative strength of abiotic variables and their relative contribution to species-group change over time, and should therefore better reflect the temporal structure of species-environment associations compared to time-averaged units of environmental variables.Regarding the spatial matrix, we carried out spatial analyses using the RDA-PCNM procedure outlined above. For these analyses the geographical X (north-south) and Y (east-west) coordinates of each lake composed the explanatory variable matrix, which was then converted into spatial PCNMs using the quickPCNM function. These spatial PCNMs were then related to the matrices of species groups by means of a forward selection in RDA. The spatial PCNMs that were retained in the model, and which therefore explained significant spatial structure in the data sets, were extracted and compiled in a spatial predictor matrix for the variance partitioning analyses.To determine the relative importance of local environmental variables and spatial  processes on the temporal dynamics of species groups, we conducted variation partitioning according to Peres-Neto et al. We classified species according to traits related to flying strength following The time series analyses using the RDA-PCNM approach detected significant temporal structure associated with different species groups of invertebrates in all of the twenty-six lakes between 1988 and 2007. Significant temporal structure was associated with canonical axes 1 and 2 in the RDA models, indicating the presence of two species groups with independent temporal fluctuation frequencies in the invertebrate communities across all lakes studied. The patterns associated with the first group of species explained on average >50% and the second species group on average <30% of the adjusted variance across all lakes in the models. The temporal structure of the first species group comprised change at broad temporal  scales . These p4-N were found for only selected lakes. Water temperature was generally a weak correlate of the temporal patterns of the slow group, perhaps because the temporal sampling resolution did not allow us to capture its full variability.The importance and strength of environmental correlates of temporal patterns varied with species groups and were evident in the slow rather than the faster species groups across lakes . TemporaCaenis luctuosa, Caenis spp., Cloeon dipterum, Cloeon spp. (Ephemeroptera), Athripsodes bilineatus, Oecetis sp. (Trichoptera), Capnia artra (Plecoptera), Cladotanytarsus sp., Psectrocladius sp., Conchapelopia sp., Tanytarsus sp. (Diptera), Oulimnius sp. (Coleoptera), Helobdella stagnalis (Annelida), Hydracarina, Ceratopogonidae) were found in the slow and faster species groups, but their strength and the significance of their contribution to species group patterns varied among lakes.Spearman rank correlation analyses revealed that the number of taxa explaining the modeled temporal frequency patterns ranged 3\u201340 (slow groups) and 2\u201317 (faster groups). Many invertebrate taxa  and spatial factors  were significant in the variance partitioning; however, the variance explained by these fractions was generally low. The spatial fraction captured the importance of broad-scale spatial processes, whereby the sets of species contributing to species group change differed along an east-west geographical gradient (Tanypodinae (correlation score with RDA axis 1: \u22120.94), the stonefly Capnia atra (\u22120.52) and the mayfly Metretopus borealis (\u22120.45) correlated with the temporal change of the slow groups in lakes towards the west (lakes with white squares in Asellus aquaticus (0.54), the mayfly Leptophlebia vespertina (0.52), and the mollusc Pisidium sp. (0.52)  . ApproxiDespite theory predicting that community dynamics are commensurate in space and time depending on the scales of ecological hierarchies at which these dynamics are explored Capnia atra in the arctic-alpine ecoregion and Asellus aquaticus in the boreal ecoregion; Researchers have often invoked historically contingent effects to describe species diversity in plant and animal communities at broad spatial scales While the relatively good correspondence of the spatial signal with ecoregion patterns in this study supports the interpretation of historical biogeography influencing community dynamics, we acknowledge that the determination of underlying causes is difficult Capnia artra, Leptophlebia vespertina, Metretopus borealis) are either weak flyers Asellus aquatics, Pisidium sp.). Taken together, these results suggest that dispersal between lakes across the observed west-east gradient is limited and that the spatial signal resulting from the spatial patterns of our study is most likely due to dispersal limitation. This interpretation is in agreement with an increasing body of evidence that dispersal limitation due to biogeographically defined boundaries rather than mass effects (source-sink dynamics) between macroecological spatial units describes historical community assembly of metazoans The dispersal traits analysis of the taxa that explained the slow species groups of invertebrates revealed that, despite the species groups being dominated by females that can fly>than 1 km before laying eggs, >80% of the taxa were weak flyers at the adult stage 2-values by the number of explanatory variables 2-values across species groups rather than on the actual values of these estimates.We expected to observe a spatial signal in the form of a finer-scale spatial pattern also in the faster species groups but the variance partitioning analysis failed to detect such an effect. Our hypothesis and underlying theory are therefore only partly supported. However, we acknowledge that this may be due to limitations with our approach. The temporal patterns of the faster species group showed fluctuation cycles on much shorter (roughly 5 years) time spans that explained less variance in the time series models compared to the slower species groups. We assume that while time series modeling was sensitive enough to identify distinct temporal patterns in the invertebrates, the sampling resolution for the faster species groups might have been either too coarse or the identified patterns too weak for detecting a significant spatial signal for these species groups. Also, the temporal patterns of the faster species groups were more variable across the lakes compared to the slower groups, suggesting that the faster group may be driven more by system intrinsic factors relative to an extrinsic control of the slower species group We conclude by highlighting two aspects of our study related to methodology and inference. Regarding the former, our approach was based on the PCNM methodology, which has identified patterns of hierarchically structured community dynamics. Although, refinements of the original PCNM procedure in spatial or time series modeling using canonical ordination have been suggested Regarding inference, our primary interest was to test the space-time duality of ecological patterns across hierarchical scales. However, our results allowed for inferences beyond this goal. Having included both spatial and environmental factors in the analysis provided opportunities to assess the relative importance of both factors in long-term community change. We found that not only space but also environmental variables were associated with the temporal dynamics of the slow group of invertebrates. This scale-specific imprint of environmental variables has also been found in previous studies and was due to broad-scale processes related to reduced acid deposition and climatic variability"}
+{"text": "The discovery of microRNAs (miRNAs) has led to a paradigm shift in our basic understanding of gene regulation. Competing endogenous RNAs (ceRNAs) are the recent entrants adding to the complexities of miRNA mediated gene regulation. ceRNAs are RNAs that share miRNA recognition elements (MREs) thereby regulating each other. It is apparent that miRNAs act as rheostats that fine-tune gene expression and maintain the functional balance of various gene networks. Thus MREs in coding and non-coding transcripts have evolved to become the crosstalk hubs of gene interactions, affecting the expression levels and activities of different ceRNAs. Decoding the crosstalk between MREs mediated by ceRNAs is critical to delineate the intricacies in gene regulation, and we have just begun to unravel this complexity. CEBPA, inhibiting its translation. miR-328 functions as a decoy by competing with CEBPA mRNA for the hnRNP E2 binding site, thereby preventing the translational inhibition of CEBPA mRNA. This function is in addition to its canonical function of suppressing PIM1 protein kinase translation, but nonetheless is critical to the regulatory control of the blast cell oncogenesis.In recent years, advances in genomic sequencing have led to several discoveries that can be considered exceptions to the central dogma of molecular biology. Much of the DNA that does not encode proteins has been shown to code for various types of functional RNAs that have important regulatory roles. The complexities in gene regulation increased logarithmically following the identification of microRNAs (miRNAs). miRNAs are 18\u201322 nucleotide long, evolutionarily conserved single-stranded RNA molecules that play a significant role in maintaining cellular identity and homeostasis Bartel, . miRNA mcis by enhancer sequences or in trans by genes that encode transcription factors (that act as activators or repressors) or RNA binding proteins. Recently, several studies have demonstrated that both coding and non-coding RNA molecules can regulate gene expression in trans by acting as sponges of miRNAs  with a binding site for miR-399, a phosphate starvation-induced miRNA. However, miR-399 binding does not induce degradation of the IPS1 transcript due to mismatched nucleotides in the binding site, but rather results in sequestration of miR-399 from other target transcripts. Thus, IPS1 can effectively function as a sponge inhibiting the number of miR-399 molecules available for regulating its target PHO2 mRNA. The Arabidopsis thaliana pho2 mutant is a phosphate over-accumulator. This mutant carries a mutation in the PHO2 gene, encoding a ubiquitin-conjugating enzyme (UBC24), that leads to a reduction in full-length transcripts. , using a combined computational and experimental approach. PTEN is a tumor suppressor gene, mutations in which have been implicated in several cancers. Further subtle changes in PTEN dose can dictate critical outcomes with respect to tumor initiation and progression   and thus it is oncogenic and involved in the progression of epithelial cancers  it can be noted that these MREs can also influence the levels and activity of other mRNAs (trans regulation) by competing for the miRNAs. mRNA mediated cis and trans regulation is schematically represented in Figure In a third study, large scale analysis of gene expression data with matched miRNA expression profiles in human glioblastomas identified ~7000 genes that can act as miRNA sponges or target decoys . They showed that MREs are conserved between PTEN and PTENP1 and, as a consequence, overexpression of PTENP1 3\u2032UTR correspondingly increased cellular levels of PTEN by sequestering all miRNAs that inhibit PTEN. This in turn led to growth inhibition. The authors also observed a direct correlation between the expression of PTEN and PTENP1 in normal human tissues and prostate tumor samples suggesting these to be co-regulated. Further there was a direct relationship between PTENP1 copy number and PTEN expression in colon cancer tissues, indicating that PTENP1 transcript levels can regulate PTEN expression and thus act as a tumor suppressor  and Enhancer of Zeste (EZH2) to PTEN promoter region and catalyzes the formation of H3K27me3 chromatin mark  and large intergenic noncoding RNAs (lincRNAs). Notably, recent global analysis of Argonaute (Ago) bound transcripts through high-throughput sequencing of RNAs isolated by crosslinking immunoprecipitation (HITS-CLIP) technique suggests miRNA mediated regulation of lncRNAs  in self-renewing embryonic stem cells compared to differentiating embryonic stem cells (20 vs. >500 copies/cell). Thus the sponge effect of linc-RoR can disappear once the embryonic stem cells start to differentiate.The ability of lncRNAs to function as ceRNA was first demonstrated in muscle differentiation  locus and considered circular testis-determining RNA  that can help identify ceRNAs for a given mRNA. The program examines the co-occurrence of MREs in the mRNAs (3\u2032 UTRs) on a genome-wide basis to predict ceRNAs for a specific mRNA targeted by miRNAs  of miRNAs with the ceRNAs. Although various miRNA target prediction programs use algorithms to include seed sequence matches, evolutionary conservation of binding sites, and flanking secondary structures Bartel, , they prSeveral biochemical techniques have also enabled the experimental identification and functional validation of ceRNAs. For instance, Argonaute high-throughput sequencing of RNAs isolated by crosslinking immunoprecipitation (Ago HITS-CLIP), photoactivatable-ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) and RNA immunoprecipitation are some platforms that, by providing a footprint of all the miRNAs physically bound to a given RNA, can enable identification of MREs and will provide insights on ceRNA regulatory networks  and proteins of a gene further challenge the identification of relevant target genes. The unknown unknowns.\u201dOverall, the normal functioning of cells depends on the maintenance of balance between complex regulatory systems. This is achieved by dynamic and fine adjustments and through the ability to rapidly return to normal threshold levels when imbalances are detected. If the system fails to balance beyond threshold levels, the cells manifest a disease condition. The challenges we face is in understanding how this balance is maintained in physiological conditions and conversely, how it is altered in disease. The recent ENCODE project results suggest that about 85% of the human genome is transcribed, the majority of which are lncRNAs (Djebali et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Recent attempts of disentangling direct from indirect dependences of amino acid types between residue positions in multiple sequence alignments have revealed that inferred residue-residue proximities can be sufficient information to predict a protein fold without the use of known three-dimensional structures. Here, we propose an alternative method of inferring coevolving site pairs from concurrent and compensatory substitutions between sites in each branch of a phylogenetic tree. Substitution probability and physico-chemical changes  accompanied by substitutions at each site in each branch of a phylogenetic tree are estimated with the likelihood of each substitution, and their direct correlations between sites are used to detect concurrent and compensatory substitutions. In order to extract direct dependences between sites, partial correlation coefficients of the characteristic changes along branches between sites, in which linear multiple dependences on feature vectors at other sites are removed, are calculated and used to rank coevolving site pairs. Accuracy of contact prediction based on the present coevolution score is comparable to that achieved by a maximum entropy model of protein sequences for 15 protein families taken from the Pfam release 26.0. Besides, this excellent accuracy indicates that compensatory substitutions are significant in protein evolution.Residue-residue interactions that fold a protein into a unique three-dimensional structure and make it play a specific function impose structural and functional constraints in varying degrees on each residue site. Selective constraints on residue sites are recorded in amino acid orders in homologous sequences and also in the evolutionary trace of amino acid substitutions. A challenge is to extract direct dependences between residue sites by removing phylogenetic correlations and indirect dependences through other residues within a protein or even through other molecules. Rapid growth of protein families with unknown folds requires an accurate  The evolutionary history of protein sequences is a valuable source of information in many fields of science not only in evolutionary biology but even to understand protein structures. Residue-residue interactions that fold a protein into a unique three-dimensional (3D) structure and make it play a specific function impose structural and functional constraints in varying degrees on each amino acid. Selective constraints on amino acids are recorded in amino acid orders in homologous protein sequences and also in the evolutionary trace of amino acid substitutions. Negative effects caused by mutations at one site must be compensated by successive mutations at other sites Extracting essential information from the evolutionary sequence record have been attempted using global statistical models. A Bayesian graphical model was applied to disentangling direct from indirect dependencies between residue positions in multiple sequence alignments of proteins Here, we report an alternative approach of inferring coevolving site pairs from concurrent and compensatory substitutions between sites in each branch of a phylogenetic tree. First, for each protein family, its phylogenetic tree a priori probability distribution of a parameter Assuming that substitutions occur independently at each site, a likelihood If The correlation between sites The following characteristic changes accompanied by substitutions whose correlations indicate coevolution between sites have been used as 1. Occurrence of amino acid substitution.The most primary quantity is one  in the 2-dimensional sequence-position space, and the mean Euclidean distance from every true contact to the nearest predicted site pair (MDTNP). The MDPNT and MDTNP, which were defined and used in Accuracies of predictions based on the overall coevolution score and on the direct information (DI) score The filter The accuracy of three-dimensional structure prediction based on inferred distance constraints will depend on false positive rate and also fold type. The reliability of predicted coevolving site pairs decreases with decreasing value of coevolution score, and coevolving site pairs are selected in the decreasing order of coevolution score. Therefore, prediction accuracy tends to decrease as the total number of predicted sites pairs increases; see In In In The dependences of the accuracy of predicted contacts on their number are shown in It is shown in As expected, prediction accuracy is different between proteins. However, it is unexpected that prediction accuracy may be slightly lower for Multiple subsets of a full alignment are generated by using different values of threshold Some data points in The present method is based on co-substitutions between sites. As shown in Here, with respect to the prediction accuracy of contact residue pairs the present method has been shown to be comparable to the DI method Prediction accuracy of contact residue pairs is different between the protein families. Possible reasons for false positives include (1) statistical noise due to an insufficient number of sequences, insufficient diversity of sequences, and incorrect matches in a multiple sequence alignment and an incorrect phylogenetic tree, (2) structural and functional constraints from other residues, which are not taken into account in the calculation of partial correlation coefficients from a correlation matrix, within a protein or even through other molecules involved in a molecular complex such as oligomerization, protein-substrate, and protein-DNA, (3) structural variance in homologous proteins, although each Pfam family is assumed to be iso-structural. Especially, for proteins whose functional states are homomeric, inter-residue and intra-residue contacts must be discriminated.Of course prediction accuracy depends on the size of sequences used and their diversity. A general trend is that prediction accuracy becomes better as increasing number of sequences used, although the diversity of sequences in protein families is more effective than the number of sequences itself. Also, the presence of many deletions in sequences reduces the value of including those sequences. The present subset  from their parent nodes in a phylogenetic tree are used to get less sequences but as diverse sequences as possible. The maximum number of sequences to be tried for the present method will correspond to a dataset generated by In order to get useful numbers  An accurate multiple sequence alignment will be critical to increase prediction accuracy, because phylogenetic inference for co-substitutions as well as tree topology is based on alignments. In the present calculations, sites that correspond to deletions in a target protein structure are excluded in the optimization of tree branches and in the calculation of partial correlation coefficients. The calculation of partial correlation coefficients by including those sites has been attempted for the Kunitz_BPTI and RNase_H domain families. No improvement was obtained at least for these protein families.It has been shown that site pairs giving the significant values of partial correlation coefficients for substitutions, which concurrently occurred in branches of a phylogenetic tree and would be mostly compensatory substitutions, well correspond to contact site pairs in protein 3D structures. In compensatory substitutions, the fitness of first mutations must be negative, and successive mutations must occur to compensate the negative effect of the first mutation. A time scale in which compensatory mutations successively occur is much shorter than the time scale of protein evolution that is the order of fixation time for neutral mutations, otherwise negative mutants will be eliminated from a gene pool by selection. Thus, negative substitutions and their compensatory substitutions are expected to be observed as concurrent substitutions in the same branch of a tree. If substitutions are completely neutral, there will be no correlation in time when substitutions occur. Thus, a fact that contact site pairs can be well predicted by the present method indicates that compensatory substitutions are significant in protein evolution. Significance of compensatory substitutions was also indicated by a fact that likelihoods of phylogenetic trees can be significantly improved by taking account of codon substitutions with multiple nucleotide changes So far remarkable improvements in the accuracy of contact prediction were all achieved by extracting essential correlations of amino acid types between residue positions from multiple sequence alignments Residue-residue interactions maintaining secondary structures appear to be more easily detected by the joint distribution of amino acid types between the sites than concurrent substitutions. In general, the present method less detects secondary structure interactions between neighboring sites along a sequence than the other. Marks et al. From a such viewpoint, methods of extracting direct correlations of amino acid types between sites may be better for extracting direct dependences between sites than those of detecting compensatory substitutions in a tree. However, interactions between closely-located sites do not necessarily result in distinct correlations of amino acid types between the sites. Residue-residue interactions that are less specific to amino acid type are such interactions. For example, hydrophobic interactions are relatively non-specific, but significantly contribute to residue-residue interactions inside protein structures. In the case of membrane proteins, most of amino acids embedded in membrane are hydrophobic. Even in the case that residue-residue interactions are too non-specific to result in distinct correlations of amino acid types between sites, physico-chemical changes due to substitutions may require compensatory substitutions, and therefore the interactions may be identified by detecting compensatory substitutions. Membrane proteins may be this case; see 7tm_1 in The DI method based on the joint distributions of amino acid types may be simpler and faster than the present method based on co-substitutions in a phylogenetic tree. However, the joint distributions of amino acid types calculated from a multiple sequence alignment include more or less phylogenetic bias, but there is no such a bias in the present method. Thus, the both types of methods are complementary to each other.A Bayesian graphical model was applied to disentangling direct from indirect dependencies between residue positions in multiple sequence alignments of proteins de novo prediction of three-dimensional structure is desirable to catch up with the high growing speed of protein families with unknown folds.Determination of protein structure is essential to understand protein function. However, despite significant effort to explore unknown folds in the protein structural space, protein structures determined by experiment are far less than known protein families. Only about 36% of the Pfam manually curated families  include at least one member whose structure is known. In the case of domains of unknown function (DUFs), which are rapidly growing in the Pfam-A, some 26% of DUFs have at least one structurally determined protein within a family or within a clan ab initio folding of protein. de novo prediction of protein structure, but their conformational samplings are not efficient enough to fold longer proteins than at most 100 residues.The vast conformational space of protein makes it difficult to determine protein structure by On the other hand, the accuracy of the present contact prediction is insensitive to sequence length; see The present contact prediction based on coevolving site pairs is comparable to the method Figure S1Dependence of PPV on the number of characteristic variables used. For each protein in (PDF)Click here for additional data file.Figure S2Coevolving site pairs versus DI residue pairs. Residue pairs whose minimum atomic distances are shorter than 5 \u00c5 in a protein structure and coevolving site pairs predicted are shown by gray filled-squares and by red or indigo filled-circles in the lower-left half of each figure, respectively. For comparison, such residue-residue proximities and predicted contact residue pairs with high DI scores in (PDF)Click here for additional data file.Figure S3Dependence of MDPNT on the number of predicted contacts. The dependences of the mean Euclidean distance from predicted site pairs to the nearest true contact in the 2-dimensional sequence-position space on the total number of predicted contacts are shown for each protein fold of (PDF)Click here for additional data file.Figure S4Dependence of MDTNP on the number of predicted contacts. The dependences of the mean Euclidean distance from every true contact to the nearest predicted site pair in the 2-dimensional sequence-position space on the total number of predicted contacts are shown for each protein fold of (PDF)Click here for additional data file.Figure S5Dependence of MDPNT on the number of sequences used. The mean Euclidean distance from every predicted site pair to the nearest true contact in the 2-dimensional sequence-position space is plotted against the total number of homologous sequences used for each prediction. The total numbers of coevolving site pairs predicted for each protein are equal to one third of true contacts. The filled marks indicate the points corresponding to the number of used sequences listed for each protein family in (PDF)Click here for additional data file.Figure S6Dependence of MDTNP on the number of sequences used. The mean Euclidean distance from every true contact to the nearest predicted site pair in the 2-dimensional sequence-position space is plotted against the total number of homologous sequences used for each prediction. The total numbers of coevolving site pairs predicted for each protein are equal to one third of true contacts. The filled marks indicate the points corresponding to the number of used sequences listed for each protein family in (PDF)Click here for additional data file.Table S1Dependence of contact prediction accuracies on phylogenetic trees.(PDF)Click here for additional data file.Data S1Coevolution scores, overall coevolution score and rank of each site pair in each protein.(BZ2)Click here for additional data file."}
+{"text": "Image contrast between normal tissue and brain tumours may sometimes appear to be low in intraoperative ultrasound. Ultrasound imaging of strain is an image modality that has been recently explored for intraoperative imaging of the brain. This study aims to investigate differences in image contrast between ultrasound brightness mode (B-mode) images and ultrasound strain magnitude images of brain tumours.Ultrasound radiofrequency (RF) data was acquired during surgery in 15 patients with glial tumours. The data were subsequently processed to provide strain magnitude images. The contrast in the B-mode images and the strain images was determined in assumed normal brain tissue and tumour tissue at selected regions of interest (ROI). Three measurements of contrast were done in the ultrasound data for each patient. The B-mode and strain contrasts measurements were compared using the paired samples t- test.The statistical analysis of a total of 45 measurements shows that the contrasts in the strain magnitude images are significantly higher than in the conventional ultrasound B-mode images (P\u2009<\u20090.0001).The results indicate that ultrasound strain imaging provides better discrimination between normal brain tissue and glial tumour tissue than conventional ultrasound B-mode imaging. Ultrasound imaging of tissue strain therefore holds the potential of becoming a valuable adjunct to conventional intraoperative ultrasound imaging in brain tumour surgery. Assuming that the stress applied to the tissue is uniform, the calculated and displayed strain values should in ideal circumstances be proportional to the modulus of elasticity (Young's modulus) of the tissues. The imaging technique is therefore often also referred to as ultrasound elastography and the corresponding images are often called elastograms.Prior to modern neuroimaging, the neurosurgeon could detect pathological tissue by palpating the suspected areas of the brain during surgery. The tumour would be felt as a region with different elasticity compared to the surrounding normal brain, as such tumours most often have a firmer consistency than normal tissue. Even today when an operating microscope is used, the surgeon may palpate the tissue using the surgical instruments in order to find areas of the brain with differences in tissue hardness. This manual inspection of tissue hardness may aid to identify remaining tumour tissue that may be difficult to detect with direct visualisation using the operating microscope. Ultrasound imaging can also be used for the assessment of tissue hardness through imaging of strain images and conventional brightness mode images have not been published so far.Several research groups have investigated the use of ultrasound elastography in imaging brain tumours -3. Howevet al., the use of ultrasound strain imaging in combination with ultrasound B-mode imaging led to a higher area under the receiver operating characteristics (ROC) curve then by using ultrasound B- mode images alone [The clinical performance of ultrasound strain imaging has been evaluated more thoroughly in breast tumours. In a study by Burnside es alone .strain ratio between strain levels in assumed tumour and in assumed normal tissue. This has resulted in several recent papers on the use of strain ratio  for diagnostic purposes. One study compared the performance of B-mode images, strain images and strain ratio in differentiating benign and malignant tumours in a group of 227 women with focal breast lesions [et al. compared the diagnostic performance of ultrasound B-mode sonography and strain rate in differentiation of malignant and benign breast masses and found no significant difference in the area under the ROC curve [A few ultrasound machines have implemented the option of calculating the  lesions . The autThese and other studies indicate that ultrasound strain imaging may to some extent provide an improvement in diagnostics of some tumours compared to using conventional ultrasound alone. It might be asked what features of strain imaging do account for an increase in diagnostic performance compared to conventional B-mode imaging. Ultrasound is able to produce B-mode images with high spatial and temporal resolution, but the contrast resolution may be limited compared to other imaging techniques like Magnetic Resonance Imaging (MRI) or Computed Tomography (CT). The difference in brightness intensity between the lesion to diagnose and the normal tissue may in some cases appear to be low, thus having a poor contrast resolution. An improved image contrast would probably lead to improved diagnostics of these low-contrast lesions. It could be speculated that the ultrasound strain images might possess a higher image contrast than conventional ultrasound. The imaging of strain is related to other properties of tissue than the generation of ultrasound B-mode images, and therefore holds the potential to provide unique information about tissue pathology .It is therefore of clinical interest to make comparisons of attributes like image contrast between the two modalities, to assess potential differences in imaging of lesions.In this study we have processed and analysed ultrasound data acquired during surgery of glial tumours in order to compare the image contrast in conventional ultrasound images (B-mode) versus the image contrast in ultrasound strain images. We have performed a quantitative comparison of image contrast between ultrasound strain images generated by the natural pulsation of the brain parenchyma and the corresponding B-mode images. The measurements of image contrast have been performed in the peripheral parts of the tumour, covering the transition from cancerous tissue towards more normal brain tissue. The hypothesis of the study was that the contrast between tumour and normal tissue is higher in the ultrasound strain images than in the ultrasound B-mode images.Regional Research Ethics Committee of Central Norway approved the study protocol and the use of previously acquired ultrasound data in this retrospective study. The anonymous ultrasound data used in this study has been acquired with the patient's informed consent as a part of a prior study.Ultrasound radiofrequency (RF) data was acquired during surgery of 15 glial tumours. The patients were diagnosed by histopathology. Eight patients had low-grade glioma (WHO-grade I and II) and 7 patients had high-grade astrocytoma (WHO grade III & IV). The data were acquired after craniotomy with the 10\u2009MHz flat linear probe  kept motionless on intact dura. An engineer (TS) adjusted the settings of the ultrasound scanner  prior to acquisition, aiming to provide ultrasound B-mode images with a homogenous appearance but avoiding brightness saturation. The acquired data covered at least one cardiac cycle in time.The axial strain was calculated by differentiation of time delays that were estimated by processing of the ultrasound RF-data. The time delays were calculated by implementing in Matlab  a method initially suggested by Cabot , which hThe B-mode and strain magnitude images were analysed with measuring methods implemented in Matlab. For each dataset a total of three measurements of contrast for both strain and B-mode were done at three different locations in the images. That is, a different location in the image was selected for each measurement. All three measurements for a given tumour were done at the same image frame, i.e. at the same point in time. With reference to the B-mode images, the measurements were performed in the hyperechoic tumour and the surrounding isoechoic regions presumably representing normal brain tissue.2 in the images.The procedure for obtaining the contrast measurements is illustrated in Figure The second step of the measurements was to calculate the contrast between expected cancerous tissue and normal tissue for both image modalities. The calculation was based on the local minimum and maximum values found closest to the cross mark (X) in the respective plotted curves, i.e. the local extrema close to the tumour border as identified by the operator.The maximum allowable lateral range for the amplitude picking was defined with the aid of a low-pass (LP) filtered version of the curves , using a significance level \u03b1\u2009=\u20090.05. Normal quantile plots (Q-Q plots) were used for assessment of the sample populations' probability distribution. The independent samples t-test was used to investigate differences in contrast between the subgroups of low-grade and high-grade gliomas for a given image modality.For each glial tumour 15 cases) three analyses of contrast were done on ultrasound strain magnitude and B-mode images, giving a total of 45 measurements for each modality. The measurements were performed at depths between 0.7 and 3.0\u2009cm, with the average measurement depth being 1.9\u2009cm for the 45 samples. Table 5 cases tl\u2009=\u200924) and high-grade gliomas (Nh\u2009=\u200921). The normal probability distributions of the sample populations were confirmed by inspection of Q-Q-plots. For the glial tumours as a whole the contrasts between tumour and presumably normal tissue in the strain images were significantly higher than the corresponding contrast in the B-mode images (P\u2009<\u20090.0001). For the subgroup of patients with high-grade gliomas the contrast in the strain images were significantly higher than the contrast in the B-mode images (P\u2009<\u20090.0001), and the same was observed for the subgroup with low-grade gliomas (P\u2009<\u20090.0001).The difference in contrast between the two image modalities was statistically investigated for all contrast measurements of the tumours (N\u2009=\u200945), and for the measurements in the subgroups low-grade gliomas  nor the B-mode images (P\u2009=\u20090.25).In this study we have performed measurements of strain magnitude and brightness intensity across the ultrasound depicted border of glial tumours, with subsequent analysis of differences in contrast between the image modalities. The results of the analyses show a significantly higher contrast between tumour tissue and presumed normal tissue in the strain images, as compared to the B-mode images. From Table In our processed strain images we have indeed seen that noise can be present in parts of the image. This is typically seen in regions with low intensity in the B- mode image, for example when imaging homogenous tissue like the brain stem and deeper white brain matter that appear hypoechoic compared to other brain tissue. However, our measurements are intentionally performed in the transition zone from tumour to presumed normal brain tissue. In this short distal range we expect the data to be least influenced by noise, with the B-mode intensity ranging from the hyperechoic tumour to the isoechoic areas with presumed normal tissue. The inspection of the strain magnitude curves did not indicate any abrupt change of signal level within the spatial distance analysed, as could be expected if the strain processing produced invalid results.It can be argued that the measurements performed in the transition zone from tumour to normal tissue impose a selection bias for the contrast analysis. This is the region that is of interest to the surgeon, but it is also the region where we should expect the strain images to be least affected by noise. The contrast measurements are only valid for analysis of image contrast between glial tumour tissue and adjacent normal tissue. It should not be interpreted to represent differences in contrast resolution between the image modalities in general.The methodology for the analysis of image contrast in the peripheral parts of tumour involves a subjective assessment of the approximate position of the depicted tumour border and manual reading of the displayed strain magnitude and brightness curves. Even if the implemented method of analysis is not fully automatic, the measurements were obtained by following a standardized procedure, as outlined in the Methods section. Quantitative image quality measures will usually imply some subjective decisions about where to perform the analysis in the image. It is therefore difficult to establish a method without some kind of manual intervention. However, the calculation of additional measures like e.g. the contrast-to-noise ratio (CNR), or signal-to-noise ratio (SNR) would increase the robustness of the image assessment and should be considered in future studies . It woulAs discussed above there are different factors that may have affected the measurements. However, we have found the obtained measurements to be quite robust and we believe that the differences in contrast found between ultrasound strain magnitude and B-mode intensity should represent actual differences between the image modalities.diagnostic parameter as its value may be heavily dependent on which regions are selected for comparison and is therefore prone to variations between observers and within the patient population, which has also been pointed out by others [Ultrasound strain imaging in brain surgery is a quite novel approach and we have not found other studies performing a similar comparison between strain images and conventional B-mode images. It is therefore difficult to compare our results with previous findings. Some studies have however explored the use of strain ratio for diagnostic purposes, but the similar ratio for B-mode intensity has not been reported. The strain ratio is a quantitative index but should not be considered as an objective y others . It shoudiagnostic value of ultrasound strain imaging of brain tumours has not been assessed in this study. This would require a comparison between image findings and histology, which was not available for the current study. Glial tumours are diffuse infiltrating and tumour cells are likely to be present also beyond the border zone seen in the ultrasound B-mode image [The de image . ScatterThe results obtained should provide a rationale for further technical developments and investigations of methods for real-time intraoperative ultrasound strain imaging of brain tumours. The ultrasound strain magnitude images possess a higher contrast between tumour and normal brain tissue in the peripheral parts of the tumour than the conventional B-mode images. This suggest that the surgeon may use imaging of strain to improve detection of remaining tumour towards the end of surgery, compared to using conventional ultrasound imaging alone.in vivo data acquired during brain tumour surgery. The strain magnitude images have a significantly higher contrast between normal tissue and tumour tissue than conventional B-mode images. We conclude that for glial brain tumours, ultrasound imaging of strain holds the potential to become a valuable adjunct to conventional brightness mode imaging. However, the practical aspects of acquisition and display of strain images in real time as well as evaluation of diagnostic value must be addressed in future studies.Off-line processing of ultrasound RF-data to yield strain magnitude images has been performed on The authors declare that they have no competing interests.TS contributed to the study design, acquisition of data, data analyses and drafting of manuscript, RB contributed to the study design and implementation of the strain processing methods and measurements method in Matlab, MI performed the measurements and contributed to the statistical analyses and drafting of manuscript, OS contributed to data acquisition and drafting of manuscript and GU contributed to the study design, acquisition of data and drafting of manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2342/12/11/prepub"}
+{"text": "There is clinical evidence to recommend the use of partially hydrolyzed infant formulas (HA-IF) for at risk children as an option for prevention of allergic diseases, particularly atopic dermatitis/eczema . As cow's milk allergic infants are at risk of developing allergy to newly introduced foods at weaning, we aimed to extend the concept of HA-IF to egg, another potentially allergenic food.Hydrolyzed egg (HA egg) was produced using a specific combination of heat and enzymatic treatments of whole egg. Characterization and reproducibility of the product was assessed using Size Exclusion Chromatography. Residual antigenic proteins  were quantified using ELISA. Allergenicity of the HA egg was tested both in vitro (serotonin release assay) and in vivo . The capability of HA egg to induce oral tolerance to ovalbumin was assessed in both rat and mouse models.HA egg production was shown to be highly reproducible in terms of peptide profiling, residual allergenic proteins and in vivo benefits. Composition of HA egg, as compared to whole egg showed a clear shift towards peptides <1000 Da. The content of major allergenic proteins was reduced by at least 1000 fold in comparison to whole egg. The allergenicity of HA egg was also highly reduced in vitro and almost no allergic response (assessed by RMCPII quantification in sera) was observed in rats preliminary sensitized to ovalbumin and orally challenged with HA egg. Moreover, we showed that HA egg is able to induce oral tolerance to ovalbumin when used in similar quantity as whole egg.In conclusion, we have shown that the concept of \"low allergenicity linked to induction of oral tolerance\" can be applied to other food allergens than cow's milk. A small human SOTI trial with HA eggs is being launched."}
+{"text": "To the Editor: Several New World hantaviruses cause hantavirus pulmonary syndrome (HPS) in the Americas. All hantaviruses that cause HPS are hosted by the rodent family Muridae, subfamily Sigmodontinae (New World rats and mice). Since the Sin Nombre virus (SNV) was documented in 1993  G antibody reactive with SNV antigen by using enzyme immunoassay  ranged f,Zygodontomys brevicauda  and Oligoryzomys fulvescens (reservoir of Choclo virus, a known agent of HPS in Panama [The prevalence of SNV-reactive antibody in rural workers indicates that at least one hantavirus is endemic in rodents in northern Colombia and is frequently transmitted to rural residents. This finding further supports mounting evidence that hantaviruses and HPS are a Pan-American problem (Despite the prevalence of antibodies to a hantavirus in humans in northern Colombia, we did not find any human illnesses. None of the SNV antibody\u2013positive volunteers reported illness compatible with HPS; however, some hantaviruses may cause mild or no illness. Surveys have shown hantavirus antibodies (13%\u201340% prevalence in Paraguay and northern Argentina [O. fulvescens in northern Colombia underscore the importance of physician awareness and surveillance for HPS. A systematic survey of sigmodontine rodent populations that will identify the hantaviruses and their hosts is imperative.Infection in rural workers and the likely presence of"}
+{"text": "There is a pressing need for modeling of the symbiotic and at times dysbiotic relationship established between bacterial microbiomes and human mucosal surfaces. In particular clinical studies have indicated that the complex vaginal microbiome (VMB) contributes to the protection against sexually-transmitted pathogens including the life-threatening human immunodeficiency virus (HIV-1). The human microbiome project has substantially increased our understanding of the complex bacterial communities in the vagina however, as is the case for most microbiomes, very few of the community member species have been successfully cultivated in the laboratory limiting the types of studies that can be completed. A genetically controlled ex vivo model system is critically needed to study the complex interactions and associated molecular dialog. We present the first vaginal mucosal culture model that supports colonization by both healthy and dysbiotic VMB from vaginal swabs collected from routine gynecological patients. The immortalized vaginal epithelial cells used in the model and VMB cryopreservation methods provide the opportunity to reproducibly create replicates for lab-based evaluations of this important mucosal/bacterial community interface. The culture system also contains HIV-1 susceptible cells allowing us to study the impact of representative microbiomes on replication. Our results show that our culture system supports stable and reproducible colonization by VMB representing distinct community state types and that the selected representatives have significantly different effects on the replication of HIV-1. Further, we show the utility of the system to predict unwanted alterations in efficacy or bacterial community profiles following topical application of a front line antiretroviral. The vaginal mucosa is composed of a stratified squamous epithelium covered by a mucous and glycogen rich layer that supports colonization by highly complex and remarkably diverse bacterial communities. The symbiotic relationship between the bacterial community fed by the carbon sources provided by the vaginal epithelial cells (VEC) creates both physical and chemical barriers that serve as part of the front line defenses against infection. Doederlein and colleagues are credited with the first report of cultivation of vaginal bacteria in 1892 exclusively isolating Lactobacilli concluding that they were important contributors to vaginal health In addition to impacting antimicrobial therapy, clinical associations have established that BV VMBs increase susceptibility to infection by HIV-1 and other STI Recent clinical reports have established that vaginal applicants can alter VMB composition L. crispatus (CST I), L. gasseri (CST II), L. iners (CST III) and L. jensenii (CST V). VMB with multiple Lactobacillus species rather than a single predominant organism are categorized as CST IVA. VMB that lack Lactobacilli and are commonly designated as BV are categorized as CST IVB.Cultivation-independent clinical sampling approaches including vaginal swabs, tissue biopsies and IVR evaluations have provided insights into VMB composition. These approaches have highlighted the dynamic and kinetically fluid interactions among VMB community members and with the VEC but are complicated by the genetic and environmental diversity influences that confound interpretation of these massive data sets. Specifically, next generation sequencing studies completed by several groups have solidly established the complexity and dynamic nature of VMB communities as well as the impact of race, menstruation, sampling method, etc. Using this categorization system and a PCR-based approach to characterize cryopreserved VMB collected from women undergoing routine gynecological exams, we have extended our recently reported VEC stratified multilayer culture system We previously reported the establishment of a stratified squamous VEC multilayer culture system with an apical air-interface that produces the necessary carbon sources for colonization by several single species commensal bacteria common to the vagina SX-1 (an R5 strain that infects through CD4 and the CCR5 coreceptor expressed on both TZM-bl and MDM) were stained with X-gal (48 h pi) to localize b-gal+ cells. In situ X-gal staining of infected cultures provided the opportunity to identify the number and size of HIV-1 replication foci  staining  in the Vion foci . UninfecMDM offered many advantages for study of natural HIV-1 infection including important signaling pathways active in these professional immune cells that are inactive in TZM-bl cells. For this reason, VEC-MDM co-cultures were also optimized and evaluated as shown for VEC TZM-bl . For botSX-1 (MOI of 1) led to increased genomic titers with lower amounts of virus produced in both apical and cellular fractions from VEC-TZM-bl co-cultures than was detected in VEC-MDM transwells infected in parallel  simulating vaginal exposure to HIV-1. The transwell system also provided for the opportunity to model three compartments associated with HIV-1 infection. Specifically, the co-culture apical surface was subjected to gentle lavage to collect virus associated with female to male transmission, the cell fraction was harvested to quantify active viral replication and integration and, finally, the basal compartment was sampled to measure virus that transcytosed the multilayer modeling potential spread to systemic sites. Samples were analyzed by HIV-specific quantitative RT-PCR from each compartment harvested at 24, 48, or 72 h pi. The initial inoculum of 1,000 TCID50 of HIV-1Chlamydia trachomatis, cytomegalovirus, herpes simplex virus, human papilloma virus, Mycoplasma genitalium, Neisseria gonorrhea, Trichomonas vaginalis, Ureaplasma spp or detectable yeast (Candida spp) were excluded from additional study. Finally, as indicated by PCR detection of the presence of Y chromosome sequences, samples from women who had recent sexual intercourse also were excluded. Using these criteria, seven VMB representing 5 of the 6 CST and a range of NSs were selected for testing  in contrast to our previous inability to viably colonize multilayers with this single species 2 supplemented normal air environment consistent with the natural environment created in the human vagina.Aliquots of the selected samples were thawed and tested for general bacterial viability by creating a 10-fold dilution series in Mann-Ragosa Sharpe (MRS) broth to quantify bacterial titer iversity . The tariversity . UncolonTwo VMB communities of intermediate  and extreme population diversity  were selected to illustrate the quantitative increase in multiple species as shown Peptinophilus spp, group B streptococcus, Aerococcus spp, Dialister spp, and A. vaginae) suggesting that for such bacteria, the VEC multilayer provided a potentially enhanced environment relative to the vaginal mucosa. Similarly, a few bacteria maintained or had slightly lower titers or were lost from the population at 48 h in a community dependent fashion . Unexpectedly, in the tested CST III VMB, L. crispatus failed to thrive in contrast to our data from single species colonization To identify limitations of the VEC culture system, we evaluated colonization by multiple VMB looking for specific genus or species-level community members that consistently failed to increase in titer. The vast majority of identified community members increased or maintained genomic titers relative to the levels predicted by the original inoculum . In factLactobacillus spp colonization We also assessed the inflammatory state established by each of the CST representatives and as previously observed with commensal single species L. iners and group B streptococcus; Based on the successful colonization of VEC co-cultures and successful HIV-1 infections of the co-cultures, we tested the hypothesis that colonization by the VMB CST representatives would alter HIV-1 infection/replication as indicated by genomic titers in the cellular fractions. Three replicate studies were completed and the outcomes are presented as average HIV-1 genomic burden in the context of uncolonized or specifically colonized VEC co-cultures established with either TZM-bl or MDM , genomicL. iners and group B streptococcus but included at least 4 additional bacterial species that contributed to enhanced HIV-1 replication , collected \u223c60 d earlier from the same woman as the most suppressive VMB, showed a distinct community profile that was dominated again by  p<0.05, . These b vaginae . These o vaginae . AerococMB types . Study oClinically, VMB appear to alter the efficacy of vaginally-applied antiretroviral compounds through unknown mechanisms. Conversely, molecular evaluations have indicated that selected vaginal applicants alter the composition of VMB Prevotella spp, total Streptococcus and total Enterococcus. A complete loss of Corynebacterium was observed in the TFV-treated CST IVB cultures. Reductions in total Enterococcus also were observed as were a number of additional bacteria common to the CST IVB community including Dialister, S. sanguinegens, Peptostreptococcus spp, total Staphylococcus, Eggerthella spp and Veillonella spp. TFV treatment increased a few bacteria types within each community but generally to a lesser degree than seen with the reductions. In the CST IVB community, a single application of TFV treatment was associated with increased levels of Aerococcus spp, A. vaginae, the BVABs, and G. vaginalis. Paradoxically, the amount of G. vaginalis sialidase DNA was reduced. Collectively, these preliminary studies suggest the VMB colonized multilayer co-culture model will be of substantial use for prediction of vaginal applicant impact upon the VMB but additional association with clinical data will be required.A limited preliminary study of the impact of TFV upon VMB composition was completed to determine if the colonized co-culture system could be used to complete in vitro assessments of potential VMB toxicity. For this evaluation the profiles of the suppressing CST III VMB from a pool of three cultures treated with TFV or three parallel cultures that were treated with vehicle alone were compared . SimilarThere has been a pressing need to develop a model system to study the intact VMB in the context of VEC and professional immune cells. Since the earliest descriptions of the bacteria that colonized the human vagina there have been many efforts to cultivate the complex communities in the laboratory. Recent success with cultivation-independent approaches has established an accurate picture of the community members and the impact of external influences upon the VMB L. iners) could be seen consistently in the established VMB. Further studies will be required to evaluate the impact of such differences that have been widely reported in clinical studies of the same woman over time . The reproducibility of the established VMB indicates the utility of the culture system but may reveal a limitation of the cultures with regard to certain community profiles. Further CST representatives will need to be tested to more fully validate the VEC multilayer system.Our VEC multilayer culture system provides the necessary environment to support colonization by intact, transplanted VMB representing 5 of the 6 established CST . The curCryopreservation of the VMB sample allowed for repeated analyses and development of mechanistic studies to understand the relationships formed between bacterial community members and between the VMB and the underlying host cells. This was completed in a defined genetic background provided by the immortalized VEC and controlled culture conditions. Further, the model provides opportunity for controlled introduction of influences that would not be possible in clinical research settings. The refinement provided by the established co-cultures also enables the opportunity to begin to study the molecular dialogs between professional immune cells common to the vaginal mucosa and the surrounding VEC in the context of controlled colonization by selected VMB. Such studies will include evaluation of the metabolome and signaling molecules common to each VMB. Two elegant clinical evaluations were recently reported showing the metabolome and proteome of vaginal fluids collected from women before and after treatment for BV that identified a number of metabolic markers and signaling molecules associated with BV The established co-cultures also allow for study of STI outcomes in the context of the VMB including life-threatening HIV-1 transmission and infection as described in this report. It has been estimated that HIV-1 infection requires 200\u20132,000 exposures to virus during vaginal intercourse but during BV episodes and coincident inflammation in the vaginal mucosa the risk of HIV-1 transmission is significantly increased The application of next generation sequencing has also recently shown that the vaginal application of candidate microbicides and other products altered the composition of the VMB of treated women. These studies mark the beginning of improved toxicity screening of candidate compounds but are expensive, labor-intensive and rely upon clinical materials emphasizing the need for a model system capable of screening vaginally-applied compounds for impact on the VMB prior to clinical evaluation. As proof of concept, we tested the impact of a single application of TFV upon HIV-1 in the context of colonized cultures and also assessed the community changes . AlthougRecent clinical trials of topical vaginal microbicides designed to reduce HIV-1 transmission including CAPRISA 004 have shown the potential of a TFV gel formulation. The impact of vaginally-applied 1% TFV gel on VMB community composition has not been reported but in clinical trials that included assessment of the microflora there were indications of altered community profiles based on Nugent scoring G. vaginalis is an initial colonizer setting up for more damaging VMB and biofilm formation The culture system also provides the first opportunity to study bacterial interactions, products and signaling during the formation of the pathogenic biofilms associated with BV. Other cell culture models have been used to evaluate the initial adhesion and potential order of introduction of bacterial species that overwhelm otherwise healthy VMBs The VEC multilayer model also provided three compartments that each represent specific aspects of vaginal tissue as well as support of study of the HIV-1 infection cycle. Using HPV E6/E7 oncoprotein immortalized rather than cancerous cells has provided the opportunity for expanded numbers of available cells of the same genetic background without the issues associated with oncogenic transformation. The immortalization process does alter the cell's physiology but the expansion limitations and difficulties associated with tissue procurement to create primary cells require the use of such cell cultures for initial screens. Subsequent confirmation studies with cryopreserved primary progenitors are warranted for some candidate evaluations.During our foundational evaluations of the culture system we intentionally avoided the addition of exogenous hormones essentially modeling the transition between the luteal and follicular phase with the VEC co-cultures. Future work will include the addition of progesterone and/or estrogen to reflect levels associated with specific stages of the menstrual cycle. Subsequent studies will allow for the evaluation of components of seminal fluid, over the counter vaginal applicants and ultimately provide a system to evaluate the potential toxicity of candidate compounds and probiotics.The goal of the designed studies was two-fold. The first experiments were completed to establish the potential of the VEC culture system and to create data sets that showed the reproducibility and consistency of VMB colonization from cryopreserved clinical material. The second phase of the study design was undertaken to establish the impact of selected CST representative VMBs upon HIV-1 replication in the refined VEC co-culture models. The resulting culture system also provided preliminary data for the impact of a single dose of TFV on HIV-1 replication and on the representative VMB community composition. Collectively, the data show that the culture system provided an effective environment to support colonization by the diverse and highly complex bacterial communities associated with both health and dysbiotic BV states. Controlled replicate cultures were established to study the VMB effect upon HIV-1 infection independent of host genetics, hormonal or environmental factors, yeast, the presence of other STI or genital pathogen or by the natural fluctuations of the VMB observed in recent cultivation-independent evaluations. The presented data represent results from studies in VEC from a single genetic background under highly controlled conditions but have been completed in limited fashion in two additional cultures with similar outcomes.5 cells were plated while 106 cells were plated in 24 well format transwells . Each culture was allowed to stabilize at 37\u00b0C, 5% CO2 for 16 h before the apical medium was removed to create the air-interface. Basal chambers were refed with antibiotic-free medium every other day as described Immortalized V19I VEC were cultured as described previously 3 in phosphate-buffered saline (PBS) after extensive washing to remove the bacterial medium. Inocula were either 50 \u00b5l for a 24 transwell or 10 \u00b5l for a 96 well transwell. Clinical samples were diluted in sterile PBS based on the total bacterial genomic titer in the clinical sample as determined by 16S rDNA PCR.Indicated bacterial strains were cultured as described To collect VMB, healthy women undergoing routine gynecological examinations were informed of the scope of the study and with their consent were sampled by gentle rubbing of a sterile calcium alginate swab on a mid vaginal wall location. Vaginal swabs were immediately placed into sterile PBS and transported to the processing lab on ice. All work was completed with care to protect the identity of the patient with full approval of the UTMB IRB. Vaginal samples were aliquoted for standard DNA extraction and cryopreservation in a sterile glycerol solution before storage at \u221280C. Molecular evaluations of the VMB composition were completed by PCR  targetinBacterial viability was quantified by addition of 10 ul of the inoculum to 90 ul Mann-Ragosa Sharpe (MRS) broth  followed by serial 10-fold dilution and culture at 37\u00b0C for 48 h. Bacterial growth in each dilution was assessed and allowed for estimation of the viable titers of bacteria that were supported by this broth culture.Collection of VMB samples and creation of MDM populations from venous blood collected from health volunteers was complete with the full approval of the University of Texas Medical Branch's institutional review board. Only adult subjects were enrolled in the study and provided written informed consent prior to collection of materials.SX-1 a chimeric M-tropic virus (R5) encoding the majority of the HIV-1JRFL envelope protein in an HIV-1NL4-3 backbone  was diluted to create an MOI of 1 relative to the susceptible cells in the co-culture HIV-1  was added to multilayer cultures 16 h after colonization by the indicated bacterial strains or VMB communities. A titered stock of HIV-1For histology and immunolabeling studies, multilayers were fixed in 2% formaldehyde for 10 minutes at 4\u00b0C, then washed with PBS. Wells were then incubated with X-Gal buffer L. crispatus or the indicated VMBs Click here for additional data file."}
+{"text": "Basal ganglia circuits in Parkinson\u2019s disease constitute a prominent example of neural system of coupled inhibitory and excitatory neurons, which exhibit synchronous activity . The phaThe conductance-based network models of subthalamo-pallidal circuitry of basal ganglia have being shown to reproduce the intermittent temporal patterns of phase-locking observed in experiments with high fidelity . We starWe used geometric dynamical systems and singular perturbation methods to reduce the full model to a simpler set of equations. Mathematical analysis was completed using three slow variables with two different time scales. Intermittently synchronous oscillations are generated by overlapped spiking which crucially depend on the geometry of slow phase plane and the interplay between slow variables as well as the strength of synapses. Two slow variables are responsible for the generation of out-of-phase stable solution and the other slower variable for irregular and intermittent activity pattern. The results of analysis can be traced to particular values of biophysical parameters , which are known to be impacted in Parkinson\u2019s disease."}
+{"text": "Allergen Specific Immunotherapy (SIT) for respiratory allergic diseases is able to significantly improve symptoms as well as reduce the need for symptomatic medication, but SIT also has the capacity for long-term clinical effects and plays a protective role against the development of further allergies and symptoms. The treatment acts on basic immunological mechanisms, and has the potential to change the pathological allergic immune response. In this paper we discuss some of the most important achievements in the documentation of the benefits of immunotherapy, over the last 2 decades, which have marked a period of extensive research on the clinical effects and immunological background of the mechanisms involved. The outcome of immunotherapy is described as different levels of benefit from early reduction in symptoms over progressive clinical effects during treatment to long-term effects after discontinuation of the treatment and prevention of asthma. The efficacy of SIT increases the longer it is continued and immunological changes lead to potential long-term benefits. SIT alone and not the symptomatic treatment nor other avoidance measures has so far been documented as the therapy with long-term or preventive potential. The allergic condition is driven by a subset of T-helper lymphocytes (Th2), which are characterised by the production of cytokines like IL-4, and IL-5. Immunological changes following SIT lead to potential curative effects. One mechanism whereby immunotherapy suppresses the allergic response is through increased production of IgG4 antibodies. Induction of specific IgG4 is able to influence the allergic response in different ways and is related to immunological effector mechanisms, also responsible for the reduced late phase hyperreactivity and ongoing allergic inflammation. SIT is the only treatment which interferes with the basic pathophysiological mechanisms of the allergic disease, thereby creating the potential for changes in the long-term prognosis of respiratory allergy. SIT should not only be recognised as first-line therapeutic treatment for allergic rhinoconjunctivitis but also as secondary preventive treatment for respiratory allergic diseases. Allergy is a systemic disease with a local response following allergen exposure. Rhinitis, asthma and Bronchial Hyperresponsiveness (BHR) are closely related and a systemic pathway, involving the bloodstream and bone marrow, contributing to the cross-talk between the upper and lower airways .The close relationship between allergic rhinitis and allergic asthma and the co-morbidity of upper and lower airway diseases has been carefully described elsewhere -4. In asAllergen specific immunotherapy (SIT) produces a decrease in symptoms and in the need for medication, but SIT also has the capacity for long-term clinical effects and for the prevention of the development of further allergies and symptoms. The treatment acts on the basic immunological mechanisms responsible for causing symptoms and has the potential to change the immune response and the pathological pathways responsible for the allergic symptoms . SIT is The year 2011 marked the 100th anniversary of the first publication on SIT by Leonard Noon . Since tThis paper highlights and examines some of the most important developments and information regarding the potential benefits of SIT achieved over the last 10-20 years - a period marked by much clinical activity, explorative as well as confirmative studies on SIT and the publication of international guidelines to support clinical practice ,20-22. ADifferent immunological effector cells are responsible for allergic inflammation -25. The The benefits and the clinical effects of SIT should be evaluated and analysed in terms of the immunological changes that follow the treatment. SIT acts by influencing basic immunological mechanisms  resultinStudies have shown that symptomatic improvement correlates with reductions in eosinophils and IL-5 expression in the nasal mucosa  during tDifferent IgG4 related immunological effects acting as a competitive response to that of specific IgE, result in clinical effects as reduction in symptoms and the need for medication, and a reduced inflammatory response to allergen presentation Figure .\u2022 Inhibition of mediator release could be caused by direct inhibition of the allergen-IgE interaction or through co-aggregation of the inhibitory Fc\u03b3RIIB and Fc\u03b3RI \u2022 SIT-induced IgG inhibited histamine release from basophils \u2022 Specific IgG antibodies acts by a \"dilution\" of the antigen exposure to specific IgE antibodies by binding to epitopes on the surface of the allergen, and thereby directly reducing the antigen presenting capacity by the relevant cell types \u2022 IgE-facilitated antigen presentation results in the activation and subsequent proliferation of allergen-specific T-cells at extremely low concentrations of allergen and activates Th2 cells which then produce important cytokines  inducing further IgE synthesis \u2022 Immunotherapy-induced specific IgG antibodies can also affect and inhibit IgE- facilitated antigen presentation (FAP) and activation of Th2-cells, and thereby significantly reduce the allergic response ,45,48There is a time dependence in serum inhibitory activity of Facilitated Antigen Binding which seem to be consistent with the continued increase in clinical benefits following prolonged treatment with immunotherapy The first priority for respiratory allergic patients is usually the treatment of allergic symptoms as these appear as a consequence of allergen exposure. Different symptomatic drugs have the capacity to reduce the symptoms either on a rescue basis or when taken daily ,22. FromTogether with the significant reduction in allergic symptoms, several studies on SIT have documented a significant reduction in the need for symptomatic drugs on short term as well as during long-term treatment -54 even The World Allergy Organization has proposed a model for the standardisation of clinical trials of allergen specific immunotherapy for respiratory allergic symptoms . They suDifferent methods for combining symptom score and intake of rescue medication have been described ,67 but tIn this paper the effects of immunotherapy are categorised into the following levels of benefit whose immunological characteristics are explained above.\u2022 Early effect - reduction in symptoms/need for medication\u2022 Progressive effect - further reduction in symptoms/need for medication and reduction in hyperresponsiveness/late-phase response\u2022 Persistent effect - long-term reduced symptoms/need for medication long-term reduced hyperresponsiveness/late phase response after end of treatment period\u2022 Preventive effect - prevention of new sensitivities and progression of disease (rhinitis into asthma)\u2022 Immunological effect - immune modulation and tolerance - immunological changes that lead to a potentially curative effectThese correspond to the different levels of clinical effects which can be claimed for the registration of products for SIT as defined by the EMA   children treated for 3 years with pollen immunotherapy (grass and/or birch) showed a consistent reduction in their symptom score rated by Visual Analogue Score (VAS) and by objective measures of conjunctival sensitivity (CPT). The children were tested respectively two and seven years after discontinuation of treatment ,90. The th birthday. Only 22% of the placebo treated children were free of asthma compared to 72% of the SIT treated children. The children were initially treated for four years with individual mixtures of allergens and the clinical effect as well as the potential prevention of asthmatic symptoms was dose related - the strongest being in children who received the highest doses of allergen [The Preventive Allergy Treatment study (PAT)  was the allergen . In a twallergen .An early study by Johnstone showed that SCIT could reduce the risk of development of new allergic sensitisations as they found that no children during a 4 year course of high dose immunotherapy developed new IgE sensitisations compared to 25% of those in the control group . In the In one study, monosensitised children treated for three years with SIT compared to non-treated controls, showed a significant reduction in the development of new allergic sensitivities  although none of the control patients remained free of the development of one or more new sensitisations . In the A very large follow-up study including more than 7182 monosensitised patients with different allergies and with allergic rhinitis and/or asthma were treated with SCIT for four years and compared to 1214 open controls treated only with symptomatic drugs. Sixty-eight percent of controls had developed one or more new sensitisations compared to 27% in immunotherapy treated patients and at a follow-up visit three years after termination of the treatment period, 75% of controls had developed new sensitizations compared to 25% in the active group . In a grp < 0.01). The significant improvements in allergic rhinoconjunctivitis symptom and medications scores as well as in the conjunctival sensitivity to birch and grass observed to persist at five-year follow-up, also persisted at the ten-year follow-up. As at the five-year follow-up, fewer actively treated subjects had developed asthma at the ten-year follow-up (odds ratio 2.5 (1.1-5.9) [p = 0.0075) and the odds ratio for not developing asthma was 4.6 ) in favour of SIT over the ten-year period. The study also showed that bronchial hyperresponsiveness at baseline was associated with an increased risk of later development of asthma (p = 0.002) and in children with seasonal allergic rhinitis evaluation of BHR should be recommended in the indication for immunotherapy.The long term asthma preventive potential of SIT was first described in a tree pollen immunotherapy study in which 36 adult patients received immunotherapy. During the long-term six year follow-up period after the termination of treatment with standardised tree pollen allergen extracts for two years, none of the patients initially suffering from rhinitis alone had developed asthma during the eight-year study period . The fiv1.1-5.9) . After tNeither symptomatic treatment nor different avoidance measures for allergy have so far documented the long-term or preventive benefits. Various strategies for the prevention of the development of allergic rhinoconjunctivitis and asthma have been proposed including allergen avoidance, pharmacological treatment (antihistamines and steroids) and SIT. Allergen avoidance is hardly applicable for many allergen sources and only a limited reduction in exposure can be achieved by modification of life habits  . SecondaA potential tertiary preventive measure for worsening of asthma through early treatment with inhaled steroids in children with episodic wheezing has been suggested, but recent studies on the capacity of inhaled steroid therapy during early symptomatic episodes of wheezing to delay progression to persistent disease have failed to show any preventive potential ,110.Allergen specific immunotherapy is the only treatment that interferes with the basic pathophysiological mechanisms of the allergic disease and thereby carries the potential for changes in the long-term prognosis of respiratory allergy. SIT should be recognised not only as first-line therapeutic treatment for allergic rhinoconjunctivitis but also as secondary preventive treatment for respiratory allergic diseases. Together with the long term clinical experience available, SIT is an important treatment for prevention of asthma in patients with allergic rhinitis and it makes asthma control easier to accomplish. Immunotherapy seems to reduce the development of new allergic sensitivities as measured by skin prick test as well as specific IgE measurements, and long term follow-up on immunotherapy studies demonstrate that specific immunotherapy with modern pharmaceutically standardised allergen extracts shows persistent long term effect on clinical symptoms after termination of treatment and long-term, preventive effect on later development of asthma in children with seasonal rhinoconjunctivitis. These are important added benefits to the immediate clinical effect which is comparable to other treatment options and has shown to progressively improve during treatment periods. It is so far the only treatment for allergic diseases which has shown to be able to prevent worsening of disease and development of asthma. In these years, a number of large ongoing clinical studies with the primary purpose of establishing the EMA guideline documentation needed for registration of pharmaceutical products will certainly add further to our basic knowledge about the potential immunological modifications and long-term options. This is of great importance for the optimization of the future treatment of the increasing number of patients suffering from respiratory allergic diseases.SIT: Allergen Specific Immunotherapy; SCIT: Subcutaneous Immunotherapy; SLIT: Sublingual Immunotherapy; BHR: Bronchial Hyperresponsiveness; CPT: Conjunctival Provocation Test; VAS: Visual Analogue Scale.The authors declare that they have no competing interests.LJ wrote the manuscript. MB revised and added to the manuscript. UW revised the manuscript. All authors read and approved the final manuscript."}
+{"text": "The eye is a unique and necessary organ that is constantly exposed to the environment. In an immune-privileged environment such as the eye, a delicate balance exists between immune responses that limit damage and those responses that can result in irreversible damage. Ocular inflammation and infection are therefore potentially blinding events. Efforts to analyze the delicate balance between helpful and harmful immune responses in the eye have involved a variety of animal studies and models which analyze not only the specific etiologic agents of infection and the contributions of their products in inflammation and vision loss but also the underlying host factors responsible for those responses. Other studies have probed the development of novel therapeutics based on endogenous host factors as well as pathogen-specific targets and have tested these with routinely used therapeutics in improved regimens in an effort to improve visual outcome. The ultimate goal is to provide patients with the appropriate treatment that rescues vision regardless of disease.ex vivo model of herpes simplex virus 1 (HSV1) corneal infection to demonstrate that neutrophils are important in T-cell recruitment and control of HSV1 replication via synthesis of IP-10. The following three papers address epidemiological issues with studies on microbiological profiles and treatment outcomes of scleritis, chronic postoperative endophthalmitis, and fungal ocular infections. The key message of these studies is the importance of early identification and determination of drug susceptibility and proper therapeutic and/or surgical intervention in saving useful vision. The seventh and eight papers discuss the use of corticosteroid therapy in endophthalmitis and other types of ocular inflammation. The seventh paper reviews the visual outcome of cases of filtering bleb-associated endophthalmitis treated with or without intravitreal dexamethasone, while the eighth paper reviews the clinical use of loteprednol etabonate in a variety of ocular inflammatory conditions. The final paper of the special issue discusses hyperactivation of the renin-angiotensin system in inflammation and retinal neural dysfunction. The authors suggest that inhibition of this system may be a novel therapeutic approach to preventing or treating inflammation-based ocular diseases.The scope of this special issue involves a wide variety of areas in ocular infection and inflammation highlighting recent developments in the epidemiology, pathogenesis, and treatment of various types of ocular infections and inflammation. The first paper of this special issue reviews the challenges of cataract surgery and visual rehabilitation in patients with uveitis. This discussion also includes management pearls in combating complications that arise in this particular group of patients. The second and third papers continue the theme of inflammation, analyzing chemotactic cytokine production in the cornea. The second paper reports a time course effect in the synthesis of IL-8 and MCP by stromal cells stimulated with LPS. The third paper uses an This special issue includes the following papers: \u201cCataract surgery in uveitis,\u201d \u201cIL-8 and MCP gene expression and production by LPS-stimulated human corneal stromal cells,\u201d \u201cResident corneal cells communicate with neutrophils leading to the production of IP-10 during the primary inflammatory response to HSV-1 infection,\u201d \u201cClinico-microbiological profile and treatment outcome of infectious scleritis: experience from a tertiary eye care center of India,\u201d \u201cChronic postoperative endophthalmitis: a review of clinical characteristics, microbiology, treatment strategies, and outcomes,\u201d \u201cSupport of the laboratory in the diagnosis of fungal ocular infections,\u201d \u201cIntravitreal dexamethasone in the management of delayed-onset bleb-associated endophthalmitis,\u201d \u201cAdvances in corticosteroid therapy for ocular inflammation: loteprednol etabonate,\u201d and \u201cRenin-angiotensin system hyperactivation can induce inflammation and retinal neural dysfunction.\u201dMichelle CalleganMichelle CalleganMeredith Gregory-KsanderMeredith Gregory-KsanderMark WillcoxMark WillcoxSusan LightmanSusan Lightman"}
+{"text": "Hepatitis D virus (HDV) infections remain a worldwide health problem. However, the clinical impact of these infections is often underestimated, and therapeutic options for the infections are often unexploited. Gulsun et al. have addressed both these issues in the paper \"Treatment of chronic hepatitis D; a 9 years retrospective analysis\" published in this issue of Hepatitis Monthly.The present study was conducted in Diyarbakir, Eastern Turkey, where chronic hepatitis D is one of the most prevalent liver diseases. HDV causes liver failure due to cirrhosis and hepatocellular carcinoma in a significant proportion of hepatitis B surface antigen (HBsAg) carriers. Over 8 years, The authors enrolled 46 patients with florid hepatitis D. These patients showed the typical features of HDV infections; most of them were young adult men with concomitant hepatitis B virus (HBV) infections that were positive for the antibody to hepatitis B antigen and not for the HBe antigen.Treatment of hepatitis D is a formidable problem because HDV totally depends on the replication machinery of the hepatocytes for its replication and has no specific transcriptases that can be targeted by antivirals. Efforts to target the concomitant HBV infection were in vain, and neither lamivudine nor adefovir could ameliorate hepatitis D or abrogate the underlying HBV infection. The authors used the only currently available therapeutic agent, pegylated interferon-alpha (PEG-IFN-\u03b1), for treating patients. The use of INFs for treating hepatitis D was introduced long back in 1980 after considering the efficacy of cytokines in treating hepatitis B. INF use is still based on the experiences from common practice rather than conclusive evidence from clinical trials, and many questions regarding the use of INFs in the management of HDV patients remain unanswered; some of these were answered in the study by Gulsun.These authors determined whether long-term therapy is more efficacious than 1-year therapy. Their results showed that both long-term and 1-year therapy had the same outcomes; this finding is similar to that of another Turkish study [Importantly, in this study, PEG-INF-\u03b1 treatment was more successful than in most previous studies; it achieved a sustained virologic response (SVR) rate of 41%. The good therapeutic outcome obtained with PEG-IFN-\u03b1-2a in this study may be attributable to the relatively young age of the patients  because young age is correlated with less fibrosis, and in previous studies, fibrosis has been shown to reduce the efficacy of IFN-\u03b1 treatment. The age-specific analysis has indeed shown that the decline of viremia under therapy was more significant and the decrease of the Knodell score was higher in patients younger than 35 than in those older than 35, and in keeping with a better liver function in less advanced disease, side effects were minor, and only 5 patients required episodic reductions of therapy. Among the other studies that reported outcomes of PEGIFN treatment, a French study [Though the data obtained by Gulsun et al. are encouraging, the clinical significance of the SVR rates after IFN treatment achieved in this and other studies is unclear. Hepatitis D is sustained by a double viral infection, which makes the evaluation of therapeutic endpoints more complex. The long-term significance of achieving virologic and clinical therapeutic targets other than absence of HBsAg has not been assessed so far. The viral titers during infections caused by HDV are much lower than those during infections caused by HBV and hepatitis C virus. The infectivity of HDV is very high and titers of the virus well below the detectability threshold of current assays might recapitulate cell to cell transmission of HDV within the liver and reactivate infection if the HBsAg is around. Thus, a long-term follow-up study of our patients is needed to clearly establish the therapeutic role of PEG-IFN in treating chronic hepatitis D."}
+{"text": "Proper indications for second-look surgery in patients with colorectal cancer have always been a controversial subject. The surgical literature suggests benefit in a reoperation, where a limited extent of cancer is discovered and then resected with negative margins. However, patients are often subjected to a negative exploratory laparotomy or an intervention that is unable to achieve an R-0 resection; in these circumstances, little or no benefit occurs. Unfortunately, an unsuccessful repeat intervention may place the patient in a worse condition, especially if morbidity occurs. This paper seeks to identify the clinical parameters of a primary colorectal cancer and a followup plan that are associated with cancer recurrence that can be definitively addressed by the second look surgery. New surgical technologies, including cytoreductive surgery with peritonectomy and perioperative intraperitoneal chemotherapy with hyperthermia, are suggested for use in this group of patients. This new management strategy used in patients with local-regional recurrence may result in a high proportion of patients converted from a second-look positive patient to a long-term survivor. Second-look surgery in colorectal cancer patients who develop progression after the surgical removal of the primary malignancy has been extensively explored in the surgical literature \u20135. IndicThese paper constitute an important part of the evolution of colorectal cancer surgery. Griffin and colleagues (reviewing the Wangensteen effort) and Minton and colleagues insist, in their summary statements, that symptomatic and asymptomatic second-look surgery in patients with colorectal cancer must be considered as an important option in patient management and constitutes the major rationale for meticulous follow-up management strategies \u20138. UnforDespite much discussion and multiple publications, the modern revisions of the indications for second-look surgery have never been forthcoming. Wangensteen and colleagues suggested reoperation based on lymph node positivity at the time of primary colon or rectal resection. Minton sought to more effectively select his patients for second look by using a progressively rising CEA blood test. However, patients operated on for symptoms (rather than progressively rising CEA blood tests) had the same benefits at second-look surgery. In both of these clinical experiments, some patients were found to be disease-free (negative second look) and suffered from the morbidity and even an occasional mortality associated with repeat laparotomy. Also, in too many patients, the disease had progressed to an unresectable state. The indications for second look did not select out those patients most likely to benefit from reoperative surgery. This paper seeks to identify the clinical parameters and follow-up strategies of a primary colorectal cancer that are associated with a pattern of treatment failure that can be definitively addressed with a second-look surgery. We identify the clinical features of the primary disease process that will allow the cancer surgeon to most knowledgeably select patients for a successful second-look surgery. Also, the use of tumor markers and CT in follow-up are integrated into follow-up regimens. In addition, we identify more effective treatment options for colorectal rectal cancer eradication in the operating room at the time of reoperation. The use of cytoreductive surgery with peritonectomy combined with perioperative hyperthermic chemotherapy are presented as a new and more effective combined management plan to be added to the reoperative surgery. Documentation of improved survival of a subset of patients is the goal of this revised approach for the surgical evolution of second-look surgery in colon and rectal cancer patients.In 1948, Wangensteen at the University of Minnesota initiated a new plan for improved management of intra-abdominal cancer [These favorable data regarding patients \u201cconverted\u201d from a positive second look to long-term survival were offset, at least in part, by the impact this management plan had on the entire group of patients. Extensive surgical procedures to remove recurrent disease led to an operative mortality of 17% in the patients who had a positive second look. Also, in the patients with the symptomatic second look, there was a 15% operative mortality. In interpreting these formidable mortality statistics, it must be pointed out that this high operative mortality occurred in patients identified as having progressive disease. These patients would presumably have gone on to die of this disease in the near future. However, their lives were cut short as a result of the operative mortality. Perhaps most damaging to the concept of a planned second look were the two patients (3.2%) who died postoperatively after a negative exploration. These patients dying with a negative second look may have been long-term survivors in the absence of this aggressive surgical treatment strategy. There have been efforts to refine the indications for second-look surgery. In the mid-1970s, a collaborative effort of the Peter Bent Brigham Hospital and the Mallory Gastrointestinal Laboratory searched for clinical relationships between the carcinoembryonic antigen (CEA) and the natural history of surgically treated colorectal cancer. Sugarbaker and colleagues determined that serial carcinoembryonic antigen assays determined at 3 monthly intervals after a colon or rectal cancer resection would detect occult recurrent disease approximately 6 months prior to clinical signs and symptoms . These rAttiyeh and Sterns collected data on 32 patients who underwent second-look surgery for \u201ca significant CEA elevation\u201d following a curative resection for adenocarcinoma of the large bowel . Not surPerhaps the most reliable data regarding the possible benefits of second-look surgery in colorectal cancer patients comes from the prospective evaluation of this strategy reported in 1985 . Minton As a result of this and other efforts to use postoperative monitoring of CEA in patients at high risk for recurrence of colon and rectal cancer, a standard of practice has evolved in patients surgically treated for colorectal cancer. If a progressive rise in the CEA blood test occurs, patients should be considered for reoperation. Radiologic tests should be performed to show that the elevated CEA determination occurs in the absence of systemic disease or unresectable disease in the abdomen or pelvis. Minton and colleagues should be credited with establishing a strong rationale for meticulous follow-up of colorectal cancer patients and a reasonable likelihood of benefit from second-look surgery.Goldberg and coworkers pooled data in a prospective follow-up of 1247 patients with resected stage 2 or stage 3 colon cancer . 548 patThere can be no doubt that the second-look approach initiated by Wangensteen established a new paradigm for a reoperative approach to patients with colorectal cancer. Also, the data on sites of recurrence carefully collected by this group has had a profound effect upon the surgical technology used for primary colorectal cancer resection. Gunderson and Sosin reported the anatomic sites of surgical treatment failure that were identified at the time of reoperation in 74 patients . They reIn a historically important paper that had an influence on surgical technology for colorectal cancer resection, Lofgren et al. examined the pattern of surgical treatment failure in a special group of 47 patients. These patients had a local-regional recurrent disease but were lymph node negative within the primary cancer specimen . From thAs shown in Sugarbaker and coworkers suggested that peritoneal carcinomatosis and local failure are caused by the same mechanism . SurgicaHowever, not all the cancer cells disseminated from the primary malignancy must implant locally. Some may gain access to the free peritoneal cavity. Cancer cells within intraperitoneal blood clot will later be organized as recurrences within abdominal adhesions. Free cancer cells will move along with peritoneal fluid to distant sites such as the pelvis, beneath the right hemidiaphragm, or in the right and left paracolic sulcus. With small amounts of intraperitoneal fluid, peritoneal seeding proximal to the resection site is expected. With larger amounts of ascites fluid or with mucinous cancer cells, distant spread of carcinomatosis will occur. Cancer cells may enter the portal venous system and cause liver metastases. However, cancer cells present within venous blood spilled at the time of primary cancer resection may find their way into the free peritoneal cavity. These free cancer cells may cause resection site recurrence or carcinomatosis.Second-look surgery has a much greater likelihood of success now than in the past. The knowledgeable use of systemic chemotherapy has reduced the proportion of patients who succumb to progression of systemic micrometastatic disease. The surgical technology for liver resection of colorectal metastases has evolved over the last two decades; liver secondaries are resected if the patient can be made clinically disease-free by liver surgery with minimal morbidity and almost no mortality . Also, sExtended lymph node dissections so that all possible sites for lymphatic dissemination from colon or rectal cancer are now advocated . AlthougThe new concept in colorectal cancer resection demands complete clearance of the primary malignancy and total containment of the malignant process during the colon or rectal cancer resection . UnfortuOne requirement of colorectal cancer surgery currently not standard of practice should be added to primary cancer resection in order to thoroughly evaluate patients for this revised second-look approach. A cytology of the peritoneal surface of the primary tumor  should occur prior to a colorectal cancer resection. Also, aspiration of fluid for a cytological study of the space beneath the right lobe of the liver and of the pelvis should occur. Finally, a cytological study of the whole abdomen following the completion of the colorectal cancer resection is important. Patients with cytologically positive colon or rectal cancer are at high risk for death from progressive disease . These pWith a group of colorectal cancer patients identified who are at high risk for local-regional recurrence and with a new and more effective liver resection and peritoneal surface treatment strategies available, a consistent application of second-look surgery should be clinically tested. This comprehensive treatment plan would include three groups of patients: (1) patients at high risk for recurrence by surgical and pathologic findings, (2) patients in the follow-up with symptoms or signs that suggest disease progression, and (3) patients that show a progressive rise in CEA. However, in order to keep the morbidity and mortality with this reoperative surgery at a minimum, ineligibility requirements for this group of patients should be enumerated. The final ineligibility requirement listed in There is some data regarding a timely second-look surgery in colorectal cancer patients at high risk for local-regional recurrence . Elias aPrior to the second-look surgery, the patients would have radiologic tests to rule out systemic disease. CT scan of chest, abdomen, and pelvis is suggested. Also, a PET scan is necessary. A colonoscopy to examine the entire colon looking for second primary tumors and suture line recurrence is a requirement. In patients who have a positive second look, there will be cytoreductive surgery which would involve the necessary peritonectomy procedures and visceral resections . FollowiThe evaluation of this clinical project must be prospective and thorough. The primary endpoint for the study, which will require approximately a 10-year follow-up, is the percent of patients converted from a positive second look to long-term survival. A secondary endpoint would be the percentage of patients who have a positive second look as compared to those who have a negative second look. A third endpoint is a comprehensive morbidity and mortality assessment of both positive and negative second-look procedures. At the end of data accumulation, a summary of the credits and debits of this approach using the revised second-look surgery will become available .A large proportion of health care costs occur within the last 6 months of life. For gastrointestinal cancer, recurrence within the abdomen and pelvis allowed to progress to intestinal obstruction, fistula, or abscess brings about a clinical situation which requires extensive and expensive healthcare. Clear guidelines for reoperative colorectal cancer surgery to prevent this devastating clinical situation are not available. Can a reoperative surgical procedure add a reasonable length of good-quality life? Which patients will profit from a surgical intervention and which patients should be told that further surgery is not an option? If a second-or third-look surgical intervention is beneficial when should it be performed? Early, before symptoms occur, or later after patients have lost gastrointestinal function? If the revised guidelines suggested in this paper for second-look surgery are placed into practice, can we prevent local-regional failure in a significant proportion of patients and thereby significantly reduce health care costs? This group of patients at high risk for loss of local control may benefit in terms of quality of life and improved survival by proactive early intervention rather than palliative surgery after symptoms of local-regional disease has occurred.A new management plan for patients at high risk for intraabdominal colorectal cancer recurrence is suggested. There are three criteria by which to select patients for a second look: (1) a high risk of local-regional recurrence of cancer, (2) a rising CEA blood test, or (3) symptoms and signs of disease recurrence. Accumulated data shows that early intervention results in a high likelihood of being converted from a second-look positive group to a long-term survivor. New cytoreductive surgical techniques including peritonectomy and HIPEC will be used eradicate abdominal and pelvic recurrence. Also, improved techniques for management of limited liver metastases in combination with peritoneal carcinomatosis are appropriate. From this literature review, the credits and debits for a revised second-look approach to colorectal cancer were formulated. The major credit will be the proportion of patients converted from a positive second look to a long-term survivor. The debits will be morbidity and mortality of the second look for all patients and the cost of the interventions. Important will be morbidity and mortality of those patients who have a negative second look. A projected incidence of positive versus negative second look is 50%. A projected survival of patients with a positive second look converted to a disease-free status is 50% at five years."}
+{"text": "Graves\u2019 disease (GD) is the paradigm of an anti-receptor autoimmune disease with agonistic auto-antibodies against the thyrotropin receptor (TSHR) being the underlying pathogenic mechanism. TSHR belongs to the category of tissue-restricted antigens (TRAs), which are expressed by medullary thymic epithelial cells (mTECs) and thereby induce central T cell tolerance. In order to understand the association between TSHR gene polymorphisms and GD we tested the hypothesis that TSHR gene variants affect susceptibility to GD by influencing levels of TSHR transcription in the thymus. The results indicate that thymic glands from normal children homozygous for the rs179247 predisposing allele of TSHR had significantly fewer TSHR mRNA transcripts than carriers of the protective allele. In addition, in heterozygous, the TSHR predisposing allele was expressed at a lower level than the protective one as demonstrated by Allele Specific Transcript Quantification. The effect of TSHR SNP rs179247 was thymus-specific and not observed in thyroid glands. These results constitute first evidence for the involvement of central tolerance in the loss of tolerance to TSHR in GD and underscore the concept that variable expression levels of major target autoantigens in the thymus influence the predisposition to autoimmunity presumably by changing the threshold of tolerance."}
+{"text": "Anolis sagrei), Asian glass lizards (Dopasia gracilis), green anoles (Anolis carolinensis), green iguanas (Iguana iguana), and a central bearded dragon (Pogona vitticeps). Purulent to ulcerative-necrotizing dermatitis and hyperkeratosis were diagnosed in pathological examinations. All animals tested positive for the presence of ranavirus by PCR and a part of the major capsid protein (MCP) gene of each virus was sequenced. Three different ranaviruses were isolated in cell culture. The analyzed portions of the MCP gene from each of the five different viruses detected were distinct from one another and were 98.4-100% identical to the corresponding portion of the frog virus 3 (FV3) genome. This is the first description of ranavirus infections in these five lizard species. The similarity in the pathological lesions observed in these different cases indicates that ranaviral infection may be an important differential diagnosis for skin lesions in lizards.Ranaviral disease in amphibians has been studied intensely during the last decade, as associated mass-mortality events are considered to be a global threat to wild animal populations. Several studies have also included other susceptible ectothermic vertebrates (fish and reptiles), but only very few cases of ranavirus infections in lizards have been previously detected. In this study, we focused on clinically suspicious lizards and tested these animals for the presence of ranaviruses. Virological screening of samples from lizards with increased mortality and skin lesions over a course of four years led to the detection of ranaviral infections in seven different groups. Affected species were: brown anoles ( Iridoviridae) are increasingly important pathogens in conservation and medicine of ectothermic vertebrates . It has been demonstrated that these viruses have caused numerous mass mortality events in various wild and captive amphibian species around the world, reviewed in , the type species of the genus ranavirus. The sequence from the isolates from the brown anoles  also showed the highest identity values (99.6%) to the corresponding nucleotides of FV3. Comparing amino acid (aa) sequences, both anole ranaviruses were 100% identical to FV3. The ranavirus detected in the green iguana  showed 100% identity to corresponding nucleotide sequences from fish ranaviruses (European sheatfish virus (ESV) [GenBank:JQ724856] and European catfish virus (ECV) [GenBank:FJ358608]). Obtained nucleotide sequences from the central bearded dragon  were 100% identical to sequences from ranaviruses detected in different tortoises from Germany (= isolate from Testudo marginata (CU60/09), Testudo hermanni (5187/07) and Testudo kleinmanni (882/96) .Sequencing of the obtained 500\u00a0bp portion of the MCP gene demonstrated that the three isolates from the brown anoles (both from 2008 and the isolate from 2011) were identical to one another, but that each of the ranaviruses detected in the five different lizard species were distinct from one another . Skin lesions such as purulent to ulcerative-necrotizing dermatitis and hyperkeratosis were found in association with ranaviral infection in all cases.Five different ranaviruses were detected in five different lizard species  or dermatomycosis are common findings in microbiological examinations. Some primary pathogens have also been described: Chrysosporium anamorph of Nannizziopsis vriesii (CANV) is the etiologic agent of an emerging deep fungal dermatitis (\u201cyellow fungus disease\u201d) in bearded dragons [Devrisea agamarum is frequently isolated from spiny tailed lizards (Uromastyx spp.) with dermatitis and cheylitis [Various infectious and non-infectious agents can cause skin lesions in lizards. In captive reptiles, deficiencies in husbandry  can provoke skin diseases or are often a predisposing factor. Different parasites  or neoplasms  can also affect the skin. Secondary infections with bacteria  seem to be caused by herpesviruses; a distinct herpesvirus has also been detected in papillomas of green lizards (Lacerta viridis). Poxviruses have been found repeatedly in association with skin lesion in crocodilians and pox-like viruses have also been detected sporadically in other reptiles, reviewed in [Lacerta viridis) with wart-like skin lesions: herpes-like, reo-like and a papilloma-like virus [Chlamydosaurus kingii) with pox-like skin lesions, as well as a green iguana (Iguana iguana) and a spiny tailed lizard (Uromastyx spp.) with hyperkeratosis) [Iridoviridae).A number of viruses have been detected in connection with skin alterations in reptiles: fibropapillomatosis in sea turtles and grey patch disease in green turtle hatchlings  ,37 have In European amphibians, acute ranavirus infection has been described in association with systemic haemorrhages, whereas chronic ranaviral disease has been characterized by skin ulcerations without gross internal lesions, reviewed in . Skin ulIt has been demonstrated previously that some ranaviruses are able to switch hosts between different chelonian families ,15 and tRana temporia) in the UK infected by a ranavirus, it has been hypothesized that the animals are adapting to the presence of ranavirus [Since all three identical ranaviruses from brown anoles (ASRV) detected in the years 2008 and 2011, as well as the slightly different ranavirus from a green anole (ACRV) clustered most closely to another American ranavirus (FV3), we speculate that these anoles brought the virus with them into Germany from the United States. A weakened immune system due to the stress of transport, dehydration and coinfections with endoparasites - as well as with additional viruses in some animals  - may have favoured the clinical development of disease. By characterizing an MHC class I locus in different populations of common frogs (anavirus . It woulAt least one lizard species (Asian glass lizard) had been in contact with other reptilian and amphibian species prior to testing. Since ranaviruses are able to switch between hosts, it is possible that other confiscated species from this case were also infected. Unfortunately, no data about these animals is available.During the last decade, the reports of ranavirus infections in reptiles have markedly accelerated. The rising awareness of these viruses in chelonians as important infectious agents causing ulcerative-necrotizing stomatitis may have contributed to the high number of case reports in these species. The frequent detection of ranaviruses in lizards during this study could be related to the use of more sensitive diagnostic methods (PCR). In addition it may be surmised that the global trade of reptiles and amphibians in combination with the wide host range of ranaviruses has strengthened the emergence of the infection. This is of significant importance for wild and captive animals. Ranaviral disease should therefore be considered as a possible differential diagnosis for dermatitis in different species of lizards and newly imported animals should be quarantined.The authors declare that they have no competing interests.Anolis sagrei and isolated the viruses from the Anolis sagrei. She also wrote the corresponding parts of the paper. KOH carried out the pathological examination of the Dopasia gracilis and provided pictures. JW treated the Dopasia gracilis and the Iguana iguana and provided clinical data and pictures. HB treated the Anolis sagrei and the Anolis carolinensis, performed coprological examination, short pathological examination and provided clinical data and pictures. KM and PG treated the Pogona vitticeps and provided clinical data and pictures of the diseased animal. PZ carried out the pathological examination of the Pogona vitticeps and provided the histology picture. IB carried out the virological testing for the presence of AdV. BR treated the Anolis sagrei in northern Germany and provided clinical data. REM conceived of the study, participated in its design and coordination, advised ACS during her practical work and helped to draft the manuscript. All authors read and approved the final manuscript.ACS carried out the virological testing for the presence of ranaviruses (including sequencing) and drafted the manuscript. SB carried out the pathological examination of the"}
+{"text": "Neuroscientists are becoming increasingly interested in modeling brain functions however, capturing underlying biophysical mechanisms requires plausible, biologically realistic models at the cellular level. Moreover, the (often conflicting) demands of biological realism and computational tractability have to be accommodated. Recent publications highlight the interaction of astrocytes with multiple synapses: if we are to fully appreciate this dynamic and coordinated interplay between cells, then more research on bidirectional communication between astrocytes and neurons is required. For example, a better understanding of astrocyte-neuron coupling may lead to providing building blocks for studying the regulatory capability of astrocytic networks on a larger scale. This special topic presents nine papers which cover a range of issues from computational models of astrocyte-neuron interactions to the role of astrocytes in neurological disorders.In the paper by Gordleeva et al.  the basi2+ change in astrocytes in response to neuronal activity is modeled using linear equations. Their paper suggests that glutamate release from astrocytes above certain intracellular Ca2+ concentrations provides a non-linear positive feedback signal to neurons. The threshold of focal ictal discharge (ID) generation is lowered when an excitatory feedback-loop between astrocytes and neurons is included. Simulations show that astrocytes can contribute to ID generation by directly affecting the excitatory/inhibitory balance of the neuronal network. Witcher and Ellis (In the paper by Wade et al.  it is shnd Ellis  highlighnd Ellis  concludeIn short, while the papers in this special topic are representative of current thinking in the field, they also draw attention to the fact that research into astrocytes and their interaction with neurons is still very much in the embryo stage."}
+{"text": "The genesis of both theory of neural field modeling and forward solutions for neuroimaging modalities and empirical methods to obtain connectivity datasets necessary to simulate the human brain dynamics has lead to the development of a whole-brain simulator, built within a freely available neuroinformatics platform called the Virtual Brain (TVB) -3. TVB a"}
+{"text": "An accurate segmental myocardial blood flow (MBF) quantification can be performed by means of signal deconvolution techniques. The accuracy of MBF estimates relies on the precise identification of the tracer arrival time in the myocardium (tOnset). Voxelwise MBF quantification is likely to be more subject to such error than segmental MBF analysis due to the lower signal-to-noise ratio of myocardial signal intensity curves. Automated tOnset detection methods would be therefore warranted. The aim of this study was to assess the importance to of tOnset identification on voxelwise MBF quantification and to describe an automated algorithm to detect the optimal tOnset which minimizes the error in MBF estimates.Perfusion data were obtained from an hardware perfusion phantom  and from patients during adenosine-induced hyperaemia (140\u00b5g/kg/min) using 0.075mmol/kg Gadobutrol  injected at 4ml/minute followed by a 20 ml saline flush. A pre-bolus technique was used for quantification.Images were acquired on a Philips Achieva 3T (TX) system, equipped with a 32-channel cardiac phased array receiver coil  with a saturation recovery gradient echo method .Data were analysed using a made-in-house software, which uses second derivative test followed by an iterative Fermi deconvolution which repeats the deconvolution for values of tOnset\u00b14 heart beats from the tOnset value obtained from derivative test to identify the optimal tOnset that minimize the error between the actual myocardial curve and the fitted curve obtained after deconvolution. The results of perfusion estimation with a visually selected tOnset and with an optimized tOnset were compared.Figure Figure Perfusion estimates based on DCE-CMR have many desirable characteristics including high sensitivity in identifying the tissue at risk, however MBF estimates are biased by many factors including the tracer arrival time into myocardium tissue, and therefore attempts to quantify MBF without using the tOnset may be premature.The authors acknowledge financial support from the Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London."}
+{"text": "Coronary angiography and the extent of coronary luminal stenosis has historically been the main factor used in guiding decisions regarding revascularisation in patients with stable coronary artery disease. More recently, revascularisation based on invasive fractional flow reserve (FFR) measurements has been shown to result in a significant benefit for event free survival. Cardiac magnetic resonance (CMR) perfusion imaging has been shown to be superior to nuclear perfusion imaging and has the potential to become the non-invasive test of choice.The MR-INFORM study is a prospective, multi-centre, randomized controlled, non-inferiority, outcome trial. It will compare the efficacy of the two investigative strategies for the management of patients with suspected coronary artery disease. Patients presenting with stable angina are randomized into two groups: The FFR-INFORMED and the MR-INFORMED group Figure .All patients undergo CMR perfusion scanning at 1.5T (various vendors) at baseline. The patients in the MR-INFORMED arm of the trial will have their subsequent management based on the results of the CMR scan. Those patients with significant ischaemia will have coronary angiography and revascularisation guided by the results of the MR scan i.e stenting in arteries that demonstrate ischaemia . All patients with non-significant ischaemia will have medical therapy optimized. The baseline scan in the FFR-INFORMED arm will remain blinded and the patient will go on to have coronary angiography with FFR measurement in those arteries with a stenosis of 40 - 99%. The revascularisation decision in this group will be based on an FFR<0.8 below which a stenosis is physiologically significant. All patients will have a cardiovascular risk assessment at baseline, 6 months and 12 months and their medical therapy is optimized.The principal hypothesis is that selecting patients with stable angina for revascularisation and optimal medical therapy (OMT) or OMT alone based on CMR myocardial perfusion is non-inferior to selecting patients based on routine coronary angiography and fractional flow reserve (FFR) in terms of subsequent major adverse cardiac events.The primary end-point will be the composite of major adverse cardiac events at one year, defined as death, myocardial infarction and repeat revascularisation table .In recruitment phase.The MR-INFORM trial will compare the role of MR perfusion with routine coronary angiography and fractional flow measurements for guiding the management of patients with stable angina and an intermediate to high likelihood of coronary artery disease. Noninferiority of MR perfusion imaging to the current invasive reference standard (FFR) would establish MR perfusion imaging as an attractive non-invasive alternative to current diagnostic pathways. The results will help to inform national and international guidelines on the investigation and management of coronary artery disease, and ultimately lead to improved patient care.Biomedical Research Centre (BRC), Bayer Schering Pharma."}
+{"text": "In computational molecular biology, the conformational analysis of a molecule refers to the identification of conformations - the clusters of molecular configurations sharing a large-scale geometric structure - and the description of conformation dynamics. These data help to describe the structures and functions of molecules which are relevant in biology. In applications such as computational drug design, they help to identify suitable compounds for disrupting processes involved in disease mechanisms. Today, many computational methods for conformational analysis are mesh-based: they involve discretizing configuration space using regular lattices, and simulating trajectories on energy landscapes. These methods suffer from the \u2018curse of dimensionality\u2019 in that the cost increases exponentially with the number of atoms in the molecule. Given that many important molecules in biology - such as proteins - have thousands of atoms, the curse of dimensionality severely limits the applicability of these methods. Finding an alternative approach to conformational analysis that does not suffer from the curse of dimensionality would enlarge the set of molecules and biological processes which may be studied using computational methods.We construct a mesh-free method  using raOur findings demonstrate that one does not need meshes for conformational analysis. For the specific problem we study in our paper \u2013 that of finding conformations and computing conformation transition rates \u2013 our findings suggest that mesh-free methods may be just as accurate as mesh-based methods, while costing less computationally. Our findings emphasize the utility of using ideas from different mathematical fields when devising new methods to tackle computational challenges."}
+{"text": "Cardiovascular disease (CVD) is a major contributor to the burden of disease and the number one cause of death worldwide. From 1990 until today, more people have died from coronary heart disease than from any other cause. CVD is regularly treated with minimal or non-minimal-invasive off- or on-pump cardiothoracic surgery and interventions related to the outcome of the surgical procedures are regularly evaluated in clinical trials, but heterogeneity in outcome reporting hinders comparison of interventions and limits the ability of research synthesis. This problem is encountered by core outcome sets (COS) that should be measured and reported \u2013 as a minimum \u2013 in all clinical trials for a specific clinical field.We are developing a COS for clinical trials measuring the efficacy and effectiveness of pre-, intra- or postsurgical interventions in non-minimal-invasive off- or on-pump cardiothoracic surgery . Recommendations on COS development given by the Core Outcome Measures in Effectiveness Trials (COMET) Initiative and the Outcome Measures in Rheumatology (OMERACT) Initiative were followed. We will reach consensus on core domains in a 3-round eDelphi exercise involving adult patients in need or after cardiothoracic surgery, cardio-thoracic surgeons, anaesthesiologists, nursing staff and researchers with expertise in this field of research. We aim to agree on measurement instruments for each of the identified core domains subsequently.The eDelphi is currently being carried out. We will present identified core outcome domains at the COMET V Meeting.The proposed COS aims to provide methodological guidance in future cardiothoracic surgical clinical trials. This does not imply that primary outcomes should always and exclusively be those of the COS. However, to assure the comparability of results across trials the outcomes included in this COS should be considered for inclusion besides measuring trial-specific clinical endpoints."}
+{"text": "Injecting white noise currents has been shown to increase mean firing rate in several types of neuron. This speed up is generally attributed to the fact that depolarizing currents on the tails of the noise distribution push cells past spike threshold sooner than they would have otherwise. As part of a larger effort to understand the dynamic properties of rat subthalamic (STN) neurons, we have performed perforated patch recordings of these tonically active neurons in brain slices, exposing them to contiguous sequences of brief current pulses drawn from a Gaussian distribution. Pulsed noise disrupted firing pattern with no significant change in rate over a wide range of noise amplitudes, so long as the pulse durations were brief (<2 ms). With longer pulse durations, neurons increased their firing rate with noise, with greater increases for pulses of larger magnitude and longer duration. However, individual neurons displayed varying degrees of noise-induced speed up.We used phase resetting methods to understand the noise-induced changes in the mean and variance of the recorded interspike interval distributions. For each cell, a phase response curves (PRC) was derived by using linear interpolation to estimate the phase of the neuron between spikes, followed by a linear regression to estimate the sensitivity of the cell to input perturbations at each phase. We then compared Monte Carlo simulations of a one-dimensional phase model to predict the response patterns of individual neurons. Surprisingly, simulation results produced a good match to experimental mean and variances even at noise levels leading to autocorrelation histograms with no visible periodicity (CVs ~ 0.4).We then investigated simulations results in detail to understand the dynamic mechanism that underlies the noise-induced speed up in these neurons. Plots of the mean phase as a function of time revealed that the noise-induced phase advance occurred early in an interspike interval, well before trajectories approach the time of the next spike. This phase advance can be understood as \u2018noise-induced drift\u2019 in the Stratanovich interpretation of stochastic differential equations, with possible supralinear contributions for pulses of finite duration. Current research uses artificially constructed PRCs to examine how the increasing spread of the phase distribution during each intervals leads to an asymmetric sampling of the noise-induced drift, preventing the early noise-induced speed up from being canceled by an expected noise-induced slowing as the PRC approaches zero near the time of the next spike."}
+{"text": "Subthreshold oscillations are observed in a wide variety of neurons in the nervous system . TheyNeuronal intrinsic subthreshold oscillations and dynamic synapses underlie several computational properties both at the single neuron and the network levels. Traditionally, intrinsic oscillations and dynamic synapses have been studied separately and their interaction has attracted almost no attention. In this work, we use a conductance-based neuron model and a dynamic synapse to investigate how intrinsic subthreshold oscillations and the short-term plasticity of a depressing synapse act together to shape its resonant properties and the corresponding input/output transformation. Our results suggest that factors such as the maximum hyperpolarization level, the oscillation amplitude and frequency or the resulting firing threshold can be modulated by synaptic depression. This shapes the postsynaptic neuron's resonant properties arising from the subthreshold oscillation and leads to complex channel-specific input/output relations. Thus, a low-cost modification in synaptic parameters can produce a significant different response. This complex synaptic-dependent input/output transformation allows the implementation of cost-effective information discrimination mechanisms in single neurons by just tuning the depression level of the synaptic channel without modifying the intrinsic neural dynamics."}
+{"text": "Primary gastrointestinal lymphoma is a rare entity, commonly involving stomach, small bowel, and colorectum. The usual location for small bowel B cell lymphoma is distal ileum due to abundant lymphoid tissue. We are reporting the case of a 53-year-old lady presumptively diagnosed as Crohn's disease on clinical and radiological grounds but histopathologically proven to be an unusual variant of isolated primary non-Hodgkin's lymphoma. Gastrointestinal (GI) lymphomas may clinically be confused with other GI tumours as well as with inflammatory bowel disease. About 5% of all lymphomas primarily involve the GI tract. The small intestine is the site of origin of about 15\u201325% of primary GI lymphomas, with stomach being the most common site affected. GI lymphomas arise from the lymphoid tissue within the wall of small intestine which is abundant in the ileum. Primary GI lymphoma is usually localized to a single segment of the intestine, with multicentricity seen in 15\u201320% of cases [We report the rare case of a 53-year-old lady presenting with features, which was clinic-radiologically diagnosed to be jejunal stricture secondary to Crohn's disease (CD) on the basis of clinical and radiological features and was reported to be a case of non-Hodgkin's lymphoma (NHL) of B cell type (uncommon in jejunum) on histological evaluation. Our report emphasizes the importance of considering lymphoma in the differential diagnosis of jejunal stricture presenting with small bowel obstruction.A 53-year-old lady presented to us with chief complaint of left-sided abdominal pain associated with multiple episodes of bilious vomiting over duration of 3 months. She had episodes of diarrhoea for the initial week of onset of symptoms which had improved with oral antibiotics. There was no history indicative of immunosuppression. The general physical and abdominal examinations of the patient were within normal limits. Her blood parameters were within normal limits. Ultrasonography of abdomen revealed evidence of concentric wall thickening of small bowel loops in the left lumbar and paraumbilical region measuring approximately 9\u2009mm with loss of wall stratification. Contrast Enhanced Computed Tomography (CECT) abdomen showed stricture with thick enhancing walls in proximal jejunum measuring 4\u2009cm in length with surrounding fat stranding and dilated proximal and collapsed distal bowel loops. A focal area of proximal jejunum was also thickened. It also showed evidence of hyperemia with dilated mesenteric vessels. These features were suggestive of inflammatory pathology, with a differential diagnosis of Crohn's disease or chronic infectious process such as tuberculosis. Colonoscopy was unremarkable.She was thereafter planned for surgery. Intraoperatively there was a jejunal stricture present at approximately 1.5 feet distal to duodenojejunal flexure with surrounding fibrosis and mesentery and transverse colon adhered to the segment with associated mesenteric lymphadenopathy Figures .The histopathology report showed diagnosis of non-Hodgkin's lymphoma of B cell type. Immunohistochemistry was positive for CD20, CD3, and LCA and was negative for CD117 and Pan CK. The postoperative period of the patient was uneventful and the patient was given the chemotherapy based on R-CHOP regimen .Primary gastrointestinal non-Hodgkin's lymphomas (PGINHL) are one of the rare lymphoproliferative neoplasms arising from lymphatic tissue below the mucosal membrane of the gastrointestinal tract (GIT), accounting for less than 5% of GIT lymphomas . The criPGINHL is usually associated with haemorrhage and perforation and rarely with stricture formation. Although stricture formation might be one of the predictable complications of PGINHL, it has not been reported in previous studies; in a prospective trial of 56 patients with intestinal lymphoma, there were no reported cases of bowel stricture [The main modality of treatment for intestinal lymphoma is chemotherapy. Surgical intervention is usually reserved for complicated lymphomas like in obstruction or perforation. The most common chemotherapeutic regimen includes R-CHOP for B cell lymphoma.Intestinal lymphomas may masquerade as Crohn's disease or chronic infectious disorders. On the other hand, there may be some causal association between the two pathologies, although so far it is unclear. Hence a differential diagnosis of lymphoma should always be considered while dealing with such patients. Endoscopy with deep biopsies followed by immunophenotypic studies should be considered as a part of evaluation so as to reach to a definite diagnosis and timely intervention."}
+{"text": "Increasing numbers of paediatric patients with congenital heart defects are surviving to adulthood, albeit with continuing clinical needs. Hence, there is still scope for revolutionary new strategies to correct vascular anatomical defects. Adult patients are also surviving longer with the adverse consequences of ischemic vascular disease, especially after acute coronary syndromes brought on by plaque erosion and rupture. Vascular tissue engineering and therapeutic angiogenesis provide new hope for these patients. Both approaches have shown promise in laboratory studies, but have not yet been able to deliver clear evidence of clinical success. More research into biomaterials, molecular medicine and cell and molecular therapies is necessary. This review article focuses on the new opportunities offered by targeting microRNAs for the improved production and greater empowerment of vascular cells for use in vascular tissue engineering or for increasing blood perfusion of ischemic tissues by amplifying the resident microvascular network. in vitro before implantation in the patient. MiR modification strategies can also be used directly in ischemic tissues to regulate angiogenesis. Extracellular vesicles (EVs) carrying the \u2018desired\u2019 cargo of miR can be isolated from stem or progenitor cells for direct injection into ischemic tissue.Schematic of application of miRs in vascular tissue engineering. Cells from patient could be collected, expanded and be subjected to miR modulation strategies to generate cells of desired specification. Pluripotent stem cells can be modulated to inhibit self-renewal and promote differentiation toward a desired progenitor cell. Also miR modulation of the progenitor cells may permit maintenance of the cells in a progenitor state or differentiation toward specific progeny thereby facilitating a modular cell therapy strategy. The modified cells can be loaded onto scaffolds for implantation or can be used to generate intact tissues and organs  Moreover, bone marrow-derived circulating cells can adhere to and/or infiltrate into the different layers of blood vessels i.e., formation of small vessels from a pre-existing vascular structure) or vasculogenesis (defined as the de novo formation of blood vessels starting from stem cells). However, stem and progenitor cells are now known to contribute to both vasculogenesis and angiogenesis. For the former, they can differentiate into vascular cells which represent the building blocks of new vessels. For the latter, they can act in a paracrine manner  to promote angiogenesis. The vascular biology community started to use the term \u201cpost-natal vasculogenesis\u201d when evidence of the existence of \u201cendothelial progenitor cells\u201d able to integrate in blood vessel structure were proposed by Asahara and others The vasculature is one of the first organ systems to develop and it forms an extensive network throughout the body mediating gas exchange, transport of nutrients and waste products, as well as delivering cells and mediators involved in immunity. Blood vessels mainly consist of endothelial cells (ECs) that line the internal surface of the entire vascular system and mural cells, A healthy and functional vasculature is essential to ensure tissue perfusion. Congenital and acquired vascular diseases create the need for surgical anatomical repair, endarterectomy and by-pass or replacement of (portions of) large vessels. The possibility to use portions of autologous vessels is limited in some patients, due to extensive atherosclerosis disease, previous harvest or insufficient time to proceed with harvest (such after aneurysm rupture). Biological homografts, xenografts and prosthetic grafts are currently used in the operating theatre, but they present some limitations, especially as substitute for smaller vessels such as coronary arteries and the lower leg and foot arteries where limited run-off  is a significant determinant of flow rate and long-term patency. Moreover, in the context of paediatric surgery, they have the major limitation of not being able to remodel and grow in synchrony with postnatal cardiothoracic development. Hence, VTE, based on the use of (bio) materials that can be combined with stem cells and other cellular and molecular products, is currently being investigated as a revolutionary option that would meet these clinical needs. Vascular pathology does not only relate to macrovascular disease. It also affects the microcirculation, which can worsen tissue ischemia induced by obstruction of large arteries. Moreover, there are clinical situations where microangiopathy can cause tissue ischemia independently of arterial occlusion. Diabetes mellitus is one of the main causes of microangiopathy. New therapeutic solutions that would enable improved blood perfusion by enhancing the microcirculation in ischemic tissues are the object of intense basic and clinical research. Gene- and cell-based therapeutic neovascularization has been developed for more than 20\u00a0years and is now ready to deliver clinical success. The field has been reviewed in many articles For both VTE and therapeutic angiogenesis, optimally functional vascular cells are required and researchers are working to develop protocols that enable improved performance of fully differentiated cells and increase the production and quality of vascular cells from stem and progenitor cells. An obvious approach to improve cell quantity and quality is to manipulate the molecular pathways controlling the regulatory processes contributing to cell survival, growth and cell phenotype. MiRs have the capacity to modulate relevant molecular signalling through post-transcriptional inhibition of multiple target genes. Importantly, the expressional manipulation of relevant miRs has been shown to induce stem cell differentiation into vascular cell lineages In this article, we discuss the clinical needs and state-of-the-art approaches for VTE and therapeutic angiogenesis; we summarize the most relevant information on miRs involved in vascular biology and stem cell differentiation to vascular lineages and we propose how miR targeting could be used to improve VTE and to promote therapeutic angiogenesis. We also discuss the remaining obstacles toward clinical translation.22.1Congenital heart disease (CHD) includes different anatomical defects in the thoracic vessels and/or in heart vessels and chambers. Overall, it affects approximately 1% of all live births, making it the most common birth defect worldwide. The most complicated CHD cases require surgical correction using prosthetic replacement grafts in the form of conduits and patches. However, these prosthetic materials lack growth potential. Consequently, as the infant grows over time, multiple operations are needed to remove the previous graft and implant a new one to fit the larger cardiovascular system. Improvements in cardiac surgery techniques and use of better prosthetic materials have led to a remarkable improvement in early survival rate with a parallel increase in the number of patients with adult CHD 2.2http://aaa.screening.nhs.uk/statistics)Abdominal and thoracic artery aneurysms develop from the combined effect of luminal pressure and weakening of the arterial wall. The most common site for aneurysm formation is in the infra-renal abdominal aorta. In the United Kingdom, the prevalence of abdominal aortic aneurysm is as high as 1.5% in men aged over 65-years  and stimulation of angiogenesis in the ischemic area could be synergic to improve clinical outcomes. MiRNA targeting could come in focus for improving both approaches.i.e. atherosclerosis in the coronary arteries. Diabetes mellitus (DM) heavily contributes to the prevalence and severity of IHD through aggravation of atherosclerosis and induction of microvascular disease Ischemic heart disease (IHD) is characterized by reduced blood supply to the heart caused by coronary artery disease (CAD), VTE could be also a potential option in patients with end-stage peripheral arterial disease (PAD). PAD affects 1 in 5 of the population over 60\u00a0years of age . Rest pain, ulceration or tissue necrosis define a situation when PAD has progressed to critical limb ischemia (CLI), which puts the patients at risk of losing their leg. Surgical bypass of the affected iliac or femoral artery are possible therapeutic options for these patients. Autologous veins that are more durable are preferred to prosthetic conduits in cases where bypass is performed below the knee level. Current state-of-the-art in peripheral vascular surgery is (when possible) the use of autologous veins taken from a leg (saphenous vein) or arm . When autologous conduits are not available, synthetic grafts made or either gelatin coated Dacron or expanded PTFE can be used. However, the patency rates of synthetic grafts are inferior to autologous conduits While revascularization  focuses on restoring arterial blood flow, therapeutic angiogenesis seeks to improve the microcirculation by stimulating new blood vessel formation. Increasing numbers of \u201cproof-of-concept\u201d studies in small animal models of ischemia point to therapeutic angiogenesis as a way to improve myocardial and limb perfusion. Evidence from these studies fuelled the concept that molecular and cellular therapies able to stimulate angiogenesis could aid therapy optimization and even represent an alternative option for those ischemic patients who are not eligible for revascularization. Nevertheless, further work is needed to achieve the clinical success of therapeutic angiogenesis. In view of recent literature from our groups and others , expanded polytetrafluoroethylene (such as Gore-Tex\u00ae), and several types of xenografts and homografts. The use of these vascular conduits is quite satisfactory in large diameter applications. However, they perform poorly in smaller vessel replacement. The blood-contacting surface and the biomechanical properties of the graft are believed to be important variables in causing patency in small vessels. Acellular or decellularised scaffolds have proved useful, as they provide the natural cues needed for recipient's cells to grow on the scaffold in terms of mechanics and composition 4Tissue engineering (TE) involves seeding cells in three-dimensional matrices to form living tissue products having structural and functional properties that can be used to restore, maintain or improve tissue function. Success depends on the right combination of cells, a scaffold , and the necessary signals. TE approaches directed to building vascular conduits promise to overcome the limitations of the vascular grafts currently used in clinical applications. Moreover, the utilization of matrices already approved for clinical application could help to fast-track the translation of the tissue engineered product to patient's bedside.Vascular ECs and mural cells (VSMCs and pericytes) are the essential components in vascular architecture and hence essential building blocks for vascular tissue engineering (VTE) For any TE approach, ideally cells should be autologous or non-immunogenic and easy to acquire and culture in a clinical-grade manner. 55.1MiRs are endogenous small non-coding (nc) RNAs. MiRs are encoded by autonomous miR genes or intronic sequences embedded in protein coding genes. A large proportion of miRs are clustered in polycistronic units. The canonical miR biogenesis for autonomous miR genes starts with RNA polymerase II-mediated transcription, producing a primary miR (pri-miR) of variable length. This is followed by pri-miR cleavage by a nuclear RNase complex, Drosha/DGCR8, generating a precursor miR (pre-miR) that has a hairpin-like secondary structure\u00a0In the aforementioned described clinical settings, therapeutic miR targeting could help to: 1) enhance the quantity and/or quality of cells available for cell-based therapeutic angiogenesis and/or for VTE; 2) promote stem cell differentiation to vascular cells to be seeded in the scaffolds see ; 3) impr5.2in vitro and in vivo regulators of vascular EC function, proliferation and growth, it is sensible to suggest that ad hoc miR targeting could be applied alone or in combination with GFs to improve endothelial coverage and endothelial function in VTE. Initial evidence for a functional role of miRs in vascular ECs was provided by the observation that mice carrying a Dicer hypomorphic allele die prenatally with severely disrupted blood vessel formation accompanied with retarded expression of early endothelial markers ECs form the inner layer of any blood vessel ensuring vascular homeostasis; and have an essential role during developmental and post-natal angiogenesis. Pre- or post-implant vascularization of TE structures is essential for their engraftment. Moreover pre- or post-implant endothelization of the VTE lumen is mandatory to enable the grafted vascular conduit to mimic healthy blood vessels, where the endothelium contributes to regulation of vascular dilatation with no intimal hyperplasia, calcification, atherosclerosis and thrombosis. In VTE, EC growth and maintenance have been traditionally promoted using GFs such as VEGF and TGF\u03b2 One of the major hurdles in using fully differentiated ECs in VTE is that after about 70 cell cycles, ECs can no longer divide thereby potentially affecting the functionality of the construct in situ VTE approach takes advantage of the regeneration potential of the host cells to regenerate a blood vessel in situ following vessel implantation. The advantage of this approach (which is treated in more details in the 5.4 section) would be that the graft preparation would need less extensive in vitro culture and manipulation).An alternative approach to seeding ECs directly onto scaffold would be to recruit progenitor cells from the circulation. The immature cells would eventually differentiate into ECs on the lumen of the scaffold. This in vitro and were later found to play a critical role in endothelial (dys)function, inflammation and atherosclerosis in vivo  to support its perfusion. Currently, the vascular architecture has not been engineered so precisely. However, the feasibility of using pericytes in VTE was shown in a recent study which used bi-layered elastomeric poly (ester-urethane) urea scaffolds 6 cells) were derived from human skeletal muscles and bulk seeded onto the scaffolds using a rotational vacuum seeding device in less than 2\u00a0min At a more advanced stage of VTE optimisation, the engineered vessel should contain in vitro using a co-culture system with ECs. Pericytes induced a paracrine activation of angiogenesis response by ECs through the release of miR-132 ex-vivo inhibition of miR-132 expression with an antagomir in the pericytes before their transplantation in mice with IHD compromised the regenerative properties of these cells in vitroRecently, our group have succeeded in isolating and expanding a clonogenic population of pericyte progenitors (the \u201cBristol pericytes\u201d) from saphenous vein left overs of patients undergoing coronary artery bypass graft surgery From the above, overexpressing miR-132 levels in pericytes would improve their ability for reparative vascularisation. However, few miR overexpression strategies have been developed due to the caveat that miR mimic oligos are unstable, have transient effects and would require multiple administrations Ischemic diseases are shown to impair the pericyte recruitment to capillaries Collectively, these studies suggest the promises of human pericyte populations in VTE and therapeutic angiogenesis and stimulate more research on these cells and their therapeutic use. Finally, the possibility to empower pericytes through miR targeting is emerging.5.4It is now well established that the smooth muscle layer of the blood vessel contributes an important role in ensuring vessel homeostasis and functions. In addition to their vascular physiological roles, VSMCs are also important players in the vascular remodelling processes observed under pathological conditions\u00a0VSMC function was recently found to be heavily influenced by miRs in vivo significantly reduced neointimal formation, demonstrating for the first time the potential of VSMC miRs as therapeutic targets for treatment of vascular disease via 2\u2032O-Methyl-modified antagomirs Another important candidate would be the miR-221/-222 cluster. These miRs were found to be expressed in normal arteries and significantly up-regulated after balloon angioplasty via induction of miR-24 Collectively these studies highlight the important role played by miRs in maintaining the phenotype of VSMC. Direct and/or indirect modulation of these miRs would be beneficial in maintaining the \u201coptimal\u201d phenotype of VSMC for VTE. Along with miRs, GFs and environmental cues also play important roles in VSMC phenotype modulation. For example, studies conducted in human primary pulmonary VSMCs showed that PDGF signalling is a potent inducer of the synthetic phenotype and propose that it acts Similar to ECs, VSMCs can become senescent, which is detrimental for the VTE process. The limited replicative capacity of adult vascular cells is due in part to the progressive shortening of the telomeres with donor age 5.5in vitro that were later decellularised and stored till the time of patient need in vitro remains a major challenge. VSMCs are the major producers of ECM. The successful generation of tissue engineered blood vessels in vitro has been estimated to require almost 8\u201324\u00a0weeks of cell culture time to generate adequate ECM necessary for arterial grafts In an effort to produce \u2018off-the-shelf\u2019 vascular grafts with an adequate ECM, Dahl et al. seeded human VSMC onto PGA scaffolds 5.6in vitro protocols for human embryonic stem cells (ESCs) differentiation to endothelial progenitor cells and ECs in vivo inhibition of the mentioned miRs (using antagomirs), also showed that miR-200c and -150 played an important role in chick embryonic blood vessel formation The re-population of a decellularised matrix with a patient's own stem cells can potentially create a living structure with subsequent long-term preservation of mechanical and biological properties. A number of studies have focused on techniques to promote vascular differentiation from stem cells. With the discovery of miRs, a new route to enhance stem cell differentiation to vascular lineages has presented itself. The possibility to achieve efficient generation of unlimited supplies of vascular cells and vascular progenitor cells from stem cells would be highly beneficial for VTE and therapeutic angiogenesis. Our group and others have established Another study showed miR-126 to be abundantly expressed in mesodermal progenitor cells derived from stem cells and to regulate mature EC function. However, lack of an embryonic lethal phenotype with genetic miR-126 deletion suggests that miR-126 does not command early endothelial lineage commitment and it becomes relevant later during vascular differentiation Dar et al. recently showed successful generation of pericytes from human ESCs and induced puripotent stem cells (iPSCs) MiR-143 and -145 are very well characterized in the vasculature and are positioned as a central target of multiple growth factor signalling pathways influencing VSMC differentiation and maintenance. A recent report has shown that overexpression of miR-145 can regulate the fate and phenotype of human ESC-derived pre-VSMCs as they fully differentiated to VSMCs MiR-1 expression is reported to be increased during differentiation of mouse ESCs to VSMCs Ex vivo manipulation of PACs with anti-miR-15a/16 improved survival and migratory capacity of these cells and increased post-ischemic recovery of mice with limb ischemia in vitroMiR targeting could be additionally used to empower patient-derived autologous progenitor cells and circulating proangiogenic cells to be employed both in VTE and for direct transplantation into ischemic tissue. Moreover, we suggest that miR targeting approaches might improve the release of endothelial chemoattractant messengers from VSMCs seeded in scaffolds, which should facilitate the endothelization of the graft after its implantation by promoting EC migration from the bordering native vasculature as well as by recruiting blood circulating endothelial progenitor cells. Bone marrow (BM)-derived proangiogenic cells (PACs), which were previously known as early endothelial progenitor cells (EPCs), have been implicated in both native and therapeutically guided angiogenesis 6As discussed earlier in this review, miRs have an essential role in vascular biology and pathology as well as in stem cells differentiation into vascular cells. To fully utilise the power of these master regulators in VTE, there are several aspects that needs to be answered effectively. Firstly, the choice of miR modulation strategies needed to give the desired effect in VTE should be carefully considered. Secondly, how these strategies would be delivered/used in a VTE perspective. We will look into the approaches for therapeutic miR delivery strategies in the following section.Studies conducted over the last decade clearly show that miRs are involved in almost all types of cellular processes, making them an attractive therapeutic target that could be used in VTE. The clinical studies conducted so far using GFs to enhance or modulate the cell source in VTE has met with limited success. The limitations of current techniques could be effectively overcome by the adequate use of \u201cmiR drugs\u201d. Strategies for miR-based therapies are based on either the restoration of suppressed genes by inhibiting the specific miR and or the delivery/overexpression of the miRs that suppress those target genes that have a desired effect on the cell source or signal used in VTE. However, care must be taken when targeting miRs that have multiple targets to avoid unexpected side effects. MiRs are differently involved in the maintenance of a variety of cell types. Therefore it cannot be excluded that the same miR can be advantageous to the cell population we want to target, but have negative side effects on other cells or tissues. Hence, it becomes evident that a finely tuned \u201cmiR drug\u201d delivery is needed to avoid potential harmful side effects. For example, the aforementioned miR-34a involved in vascular cell senescence 6.1Selecting the right miR drug delivery strategy for VTE is crucial in determining the success of the construct. The major challenges in delivering plasmid and oligonucleotide-based miR therapies are nuclease degradation, limited cell membrane permeability, and generally transient activity. Delivery strategies must be selected based on the class of miR therapy chosen and also on the target tissue. For instance, for localized applications, such as vascularising a tissue engineered construct that can be easily accessed, a direct tissue injection can be optimal. Controlled release of miRs could be achieved by using biodegradable scaffolds that can simultaneously act as a tissue template and as a source of sustained miR release ex-vivo deliver miR therapy to cells to modulate cell differentiation or survival as required for the VTE construct. In a recent report Devalliere et al. report on a new approach for enhanced EC transplantation using targeted NPs transfection to deliver proangiogenic miR-132 to cultured ECs before their transplantation, thereby sensitizing cells to the effects of endogenous GFs Another approach would be to 6.2via exosomes has been shown to modulate cross-talk between ECs and VSMCs via chemical linkers, antibodies or by specific tags. Use of EVs with biodegradable scaffolds with desired release profiles would allow constant and gradual release of EVs for the desired effect. A major advantage is that EVs would allow harnessing the paracrine effects of stem and progenitor cells without having to administer live  stem cell populations. This would help in easier clinical translation with regard to safety, regulation and complexity. However a major challenge that needs to be addressed is how to isolate the required quantity of EV for VTE. The current gold standard in isolation relies on ultracentrifugation etc. Moreover, the EV membrane could be engineered to contain epitopes guiding targeting and delivery into specific cell types. From the above, it is apparent that more studies are required to optimize the angiogenic potential of EVs for their effective use in VTE and therapeutic angiogenesis.Functionally competent mature miRs are released by cells as conjugates with (lipo)proteins 6.3The studies discussed here indicate that miR therapeutics can have wide applications for VTE supporting the enthusiasm for further exploration of miRs as novel therapeutic candidates. However numerous challenges remain in the path toward clinical translation of miR therapeutics for VTE. miRs are master regulators targeting several regulatory networks at the same time. Though this can be highly advantageous in certain scenarios, the promiscuity of miRs also makes the process of selecting the right therapeutic miR candidates very challenging. There is inevitable overlap between key genes controlling pluripotency and differentiation on the one hand cancer initiation and development on the other Another important factor that needs to be considered is that tissue repair by VTE is a multi-step process that requires variable levels of miR modulation depending on the stage of the TE process. Identifying the miRs that are modulated during biological vascular repair in the body would be very important for VTE. The best outcomes in miR therapy for VTE might occur when the temporal provision of miR modulators are matched to these biological repair processes. MiR modulation strategies are based on the presumption that relatively modest changes in the expression of target mRNAs are sufficient to evoke therapeutic benefits. An interesting study by Mukherji et al. showed that mRNA targets by miRs display threshold effects such that the mRNA can be efficiently modulated when it is present at relatively low levels compared to miR 7in vitro using either an inducible or suicide cassette. This would allow constitutive expression of miRs and stringent governance of temporal expression to target dysfunctional gene expression. This may also open up new alternatives for obtaining autologous cells in a more time efficient manner for VTE. However, it is important to be careful with implementing the exciting miR targeting technologies because a complete understanding of all the processes is still lacking. As a consequence, miRs have not yet reached clinical application. From a translational point of view, ex-vivo use of miR targeting for improving the production and functional properties of cells to be either used for therapeutic angiogenesis approaches via direct transplantation into ischemic tissue or as building blocks for bioengineered scaffolds would improve the risk profile of any \u201cmiR drug\u201d. This would also facilitate the entrance into the clinical arena via a first-in-man clinical trial, which is now enthusiastically anticipated by the whole community of basic and clinical scientists whose attention has been captured by miRs.Development of a tissue engineered vessel that is mechanically robust, biologically functional and clinically compatible is extremely challenging. From a clinical perspective, time and cost are important factors that need to be considered for VTE. The most successful approaches so far have utilised vascular cells and the process still require long times for vessel generation. MiR modulation of cells for use in VTE is an exciting, underexplored avenue. As discussed in this review, a number of miRs have been reported to control vascular cell and stem cell properties that determine vital therapeutic outcomes in VTE. It may be possible to combine several modulatory strategies to harness the \u2018right\u2019 miR expression signature for a desired clinical benefit. miR expression levels in vascular cells or progenitor cells could be manipulated BHF Centres of Regenerative Medicine (CE); Leducq Transatlantic Network in Vascular microRNA (MIRVAD) (CE); Sir Jules Thorn award 2014 (MC); the National Institute for Health Research (NIHR) through the Bristol Biomedical Research Unit (BRU) in Cardiovascular Medicine (GDA). The views expressed are those of the author(s) and not necessarily those of the National Health System, the NIHR or the Department of Health."}
+{"text": "This study sought evidence for a specific cerebellar contribution to cognition by characterising the cognitive phenotype of Spinocerebellar Ataxia Type 6 (SCA-6); an autosomal dominant genetic disease which causes a highly specific late-onset cerebellar degeneration. A comprehensive neuropsychological assessment was administered to 27 patients with genetically confirmed SCA-6. General intellectual ability, memory and executive function were examined using internationally standardised tests . The patient group showed no evidence of intellectual or memory decline. However, tests of executive function involving skills of cognitive flexibility, inhibition of response and verbal reasoning and abstraction demonstrated significant impairment at the group level with large effect sizes. The results demonstrate an executive deficit due to SCA-6 that can be conceptualised as parallel to the motor difficulties suffered by these patients: the data support a role for the cerebellum in the regulation and coordination of cognitive, as well as motor processes that is relevant to individual performance."}
+{"text": "Rosai-Dorfman disease (RDD) is a rare entity that usually involves the lymph nodes but extranodal involvements have been seen in numerous cases, although RDD with cardiovascular involvement is extremely rare. We describe a case of a young male who presented with intermittent palpitations and was found to have a left atrium mass. Our case not only emphasizes the rarity of the above lesion but also highlights the importance of modern-day imaging like computed tomography, Cardiac Magnetic Resonance Imaging (CMRI), and PET scan in characterizing such nonspecific lesions and directing appropriate line of treatment. RDD should be considered as one of the differentials even for isolated cardiac lesions. Rosai-Dorfman disease (RDD) is a rare, benign histiocytic proliferative disorder with massive cervical lymphadenopathy as the most common clinical presentation. Various extranodal lesions of RDD have been reported in the literature but involvement of the cardiac system is rare. The etiology of RDD is unknown and confirmation of the diagnosis still relies on immunohistochemistry analysis. We report a case of a young male presenting with intermittent palpitations and demonstrating a mass in the left atrium on imaging. Imaging like cardiac MRI, CT, and PET scan has proven to be immensely valuable in outlining such nonspecific lesions.A 27-year-old African American male without any significant past medical history presented with intermittent palpitations and left ventricular hypertrophy on electrocardiogram (ECG). Two-dimensional (2D) transthoracic echocardiography showed an echodense mass in the left atrium. Further evaluation with Cardiac Magnetic Resonance Imaging (CMRI) demonstrated a heterogeneous broad base mass arising from the posterior superior wall and roof of the left atrium. The mass was located approximately at the expected location of coumadin ridge and measured 1.9 \u00d7 1.5\u2009cm and demonstrated mild postcontrast enhancement . It arisPatient was further evaluated with Computed Tomography Angiography (CTA) of chest for better anatomical evaluation of the mass, which confirmed a cardiac region mass which is difficult to distinguish from the mediastinum and is located at the roof and posterior superior wall of the left atrium similar to the description on the CMRI . The mas18F-fluorodeoxyglucose positron emission tomography has proven to be a valuable imaging technique for distinguishing neoplastic lesions from benign lesions and evaluating the extent and processes of the disease. It not only demonstrates the complete staging of the disease but also can provide functional information about the disease activity to guide biopsy. FDG PET imaging in our patient demonstrates foci of increased uptake in the mediastinum and right perihilar region, corresponding to soft tissue findings on the previous CT study , an inflammatory myofibroblastic tumor (which has a background proliferation of spindle cells associated with an infiltrate of mononuclear inflammatory cells and ALK-1 positivity), metastatic malignant melanoma (in which cells are positive for Melan-A), Hodgkin's disease (which shows characteristic Reed-Sternberg cells and positivity for CD15 and CD30), and fungal or mycobacterial infections  . LiteratCardiac involvement in RDD is a rare occurrence and can mimic sarcoma, granulomatous disease, lymphoma, or benign atrial myxoma. Difficulty in evaluation of a cardiac mass by imaging is a frequently encountered scenario. Computed tomography (CT) helps us understand anatomical extent while magnetic resonance (MR) imaging and positron emission tomography (PET) scan can analyze morphology and metabolic features of a mass. Imaging helps in better characterization of a cardiac mass and also plays a pivotal role in assessment of its complications by demonstrating involvement of adjacent structures and mass effect or looking for a potential source of thrombus. Many pertinent clinical questions determining further management can be very well answered by appropriate imaging. Hence we illustrate the CT, MR, and PET findings of RDD presenting as a left atrial mass.Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy) is a rare entity with extremely uncommon involvement of the heart as an extranodal lesion. Imaging plays an important role in the diagnosis and management of lymphoproliferative disorders like Rosai-Dorfman disease which commonly present as nonspecific lesions. Although immunohistopathology remains as the main stay for confirmation of the disease, CT, MRI, and PET scan imaging are extremely useful in early detection and localization of the mass. PET scan is also a sensitive indicator for early prediction of treatment response in RDD. Through this case, we not only stress the importance of maintaining a high index of imaging suspicion for RDD but also delineate the significance of imaging in management and follow-up of such cases."}
+{"text": "We present a case report of food protein-induced enterocolitis (FPIES) to mushrooms and highlight the caveats of diagnosing acute FPIES in clinical practice, particularly in older children and when solid foods are involved. The current clinical diagnostic criteria need to be revised based on the recent evidence to avoid under-diagnosis of FPIES."}
+{"text": "Aspergillus niger (AnPEP) has been identified as being able to accelerate breakdown of gluten in food using an in vitro digestion system. Such digests have been analysed in terms of coeliac disease t-cell epitope levels[Coeliac disease and IgE-mediated allergy to wheat are immune-mediated conditions which are thought to be triggered by digestion-resistant wheat proteins. Recently, a prolyl endopeptidase from pe levels but havein vitro batch gastric digestion model to break down a bread matrix with different amounts of AnPEP. SDS PAGE and immunoblots have been used to monitor protein digestion, and mass spectrometry has allowed for epitopes important to IgE-mediated wheat allergy and coeliac disease to be tracked. Sera were obtained from a Spanish patient panel with allergy to wheat induced by exercise and/or NSAIDs and used for additional immunoblots.We have used an SDS PAGE and immunoblotting with anti-gluten antibodies show more effective breakdown of gliadins and LMW glutenins in the presence of AnPEP. The impact of digestion on the IgE-reactivity of gluten by immunoblotting has been correlated with resistant proteins and peptides mapped by mass spectrometry. Use of 200 mg AnPEP/ g substrate showed the largest difference in digestion kinetics of gluten proteins however increased breakdown was still visible using 20 mg AnPEP/ g substrate.AnPEP alters the patterns and pathways of gluten in a simulated gastroduodenal digestion system. The potential application of such enzymes to modify the allergenic potential of cereals is discussed."}
+{"text": "Working memory (WM) is the ability to transiently hold and manipulate goal-related information to forthcoming actions. In primates performing delayed-response tasks, the neural correlate of WM is the emergence of selective persistent activity in the prefrontal cortex (PFC), during the delay period \u2013 i.e., the increase of neuronal firing rates compared to baseline in response of specific stimulatory cues. Neuronal firing during such persistent activity can be highly irregular, with a coefficient of variation (CV) of the interspike interval distribution larger than one. The origin of this increased irregularity is a matter of debate, as it is not known whether it stems from inherent properties of neurons or the plasticity of their synaptic connections or both. Astrocytes, the main type of glial cells in the cortex, have recently emerged as potential active players in synaptic plasticity due to their proposed ability to regulate synaptic neurotransmitter release in response to neuronal activity. Because available WM models do not take into account astrocytes, we investigated the possible role of astrocyte regulation of synaptic plasticity in the emergence of persistent neuronal firing in WM and its statistics. Our modeling study suggests that selective persistent activity could indeed emerge from astrocyte-mediated short-term synaptic facilitation triggered by the brief presentation of a stimulatory cue Figures . Bifurca"}
+{"text": "Rapid development of high-throughput -omics  and genetic engineering technologies together with an array of new metabolic modeling tools during this century has led to the emergence of new fields of biological research termed systems biology and synthetic biology. The successful exploitation of these developments is evidenced by the creation of increasing number of genetically engineered recombinant cells with superior characteristics  for growth under well-controlled optimal conditions, typically realized in biotechnological processes. This leads to non-efficient use of protein synthesis capacity (translation machinery) and energy for bioprocesses. As translation capacity is believed to be one of the growth-limiting factors, at least in the bacterium max) of cells comes from two studies of E. coli investigating the effects of heterologous protein expression on \u03bc  of target molecule production-related proteins. On the other hand, recombinant protein titers could be significantly elevated by allocating more proteome resources for target protein expression at the expense of lower synthesis of non-essential proteins even at the same \u03bc and/or protein synthesis rate.A conceptually similar approach of creating reduced-genome strains for industrial purposes has been applied in few cases before . It is important to point out that knowing functions/essentiality for more proteins is not the objective per se \u2013 it is actually more important to know the functions/essentiality of the proteins with the biggest translational burden (abundance\u2009\u00d7\u2009length), as their deletion presumably leads to stronger effects. The good news here is that for many organisms, the proteome mass (a good proxy for length) distribution follows the Pareto principle \u2013 ~20% of proteins make up ~80% of the proteome mass , alternative substrate transport and catabolism and cellular movement (flagellar).The second strategy targets proteins with unknown functions with the biggest translational burden. Beneficial for both approaches is the growth screen of all the Keio collection single -type models for in silico analysis and design of lean-proteome strains. Recently, we have seen serious progress into this direction by the development of a novel single-cell model (Abner et al., Lastly, one would greatly benefit from an Based on the recent rapid advances in high-throughput mutant generation and proteomics technologies together with the emerging novel whole-cell modeling approaches, we conclude that the time is ripe for the metabolic engineering community to directly focus on proteome optimization leading to the creation of lean-proteome strains with superior target molecule production characteristics.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Agrobacterium research story started from the search for the causative agent of crown gall disease more than 100 years ago. Agrobacterium tumefaciens was first isolated from grapevine galls in 1897 and later isolated from Paris daisy in 1907  from a bacterial tumor-inducing (Ti) plasmid. Transfer to the plant occurs via a type IV secretion system (T4SS), after which T-DNA is integrated into the plant host genome  was completed in 2001  system and conjugal opines. Lang and Faure  and chromosomal virulence gene (chv gene) products. The current knowledge of how A. tumefaciens senses and reacts to different plant-derived signals are summarized in the review article by Subramoni et al.  phosphorylation and translocation into the plant nucleus to induce defense gene expression. On the other hand, Agrobacterium may hijack VIP1 to help T-DNA enter the plant nucleus. Based on the current knowledge of plant defense responses against Agrobacterium infection, Pitzschke , and subsequently activate plant defense responses, a process known as Pattern-recognition receptor-Triggered Immunity (PTI)  from Agrobacterium biology and how Agrobacterium transforms plants. These contributions demonstrate how a highly active research community in plant and microbial sciences can elucidate important pathogenesis questions. Future research on Agrobacteium will continue to advance our understanding of plant-pathogen interactions, and provide new insights useful for plant genetic engineering.With this Research Topic we provide a platform for scientists to share their understanding of The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "It has become the reference sequence for understanding the diversity among thousands of rice cultivars and its wild relatives as well as the major cereal crops that comprised the food source for the entire human race. This review focuses on the accomplishments in rice genomics in Japan encompassing the last 10\u00a0years which have led into deeper understanding of the genome, characterization of many agronomic traits, comprehensive analysis of the transcriptome, and the map-based cloning of many genes associated with agronomic traits.The map-based genome sequence of the The online version of this article (doi:10.1186/s12284-016-0107-4) contains supplementary material, which is available to authorized users. Oryza sativa ssp. japonica cv. Nipponbare remains as the only monocot genome that has been sequenced to a high-quality level. It has therefore become a reference for sequencing of other cereal crops with much larger genome sizes such as maize .The latest genome assembly was constructed as a joint effort of the Rice Annotation Project Database (RAP-DB) of the National Institute of Agrobiological Sciences (NIAS) and the Michigan State University (MSU) Rice Genome Annotation Project to update and validate the reference IRGSP Nipponbare genome sequence and provide a unified set of pseudomolecules to the rice research community  that provides a viewer for Illumina reads of the japonica cultivar Koshihikari and indica cultivar Guangluai-4 mapped to the Nipponbare genome, showing the alignments, single nucleotide polymorphisms (SNPs), and gene functional annotations. The RAP-DB is updated on a regular basis so that it can provide researchers with the latest information on characterization of rice genome structure and function. Recent advances in DNA sequencing technologies resulted in generation of massive genome sequencing data in a considerable number of rice cultivars and species. To facilitate efficient visualization of rapidly emerging large-scale sequencing data, a novel web-based browser, Tasuke (http://tasuke.dna.affrc.go.jp/), with various functions to show the variation and read depth of multiple genomes, as well as annotations and SNP data of hundreds of cultivars aligned to a reference genome at various scales, has been developed for efficient utilization of emerging NGS data of rice cultivars  to clarify the diversity in the twelve wild rice genomes  rice accessions with 179 RFLP markers led to development of a rice diversity research set of germplasms (RDRS) in indica, aus and japonica accessions available for the detailed genetic studies and rice improvement  gene  or BB genomes (O. punctata). These genomes diverged from a common ancestor only ~2 Mya. This result suggests that the RFT1 gene may have originated from Hd3a by a recent duplication although a possible deletion of RFT1 within the other species could not be ruled out. The Nipponbare reference sequence could contribute insights into the molecular mechanisms underlying genomic evolution and selection in rice which would benefit breeding programs to modify and control flowering time through efficient utilization of different genes or gene alleles.A series of comparative genomic studies among various species in the genus gon Fig.\u00a0a, b. Simons Fig.\u00a0d. UnlikeTos17 insertion mutant panel (Hirochika Tos17 mutant lines have been successfully used in tagging specific genes (See reference list at https://tos.nias.affrc.go.jp/doc/references.html).The rice genome sequence of Nipponbare has been pivotal in the development of a system for discovering the biological functions of approximately 32,000 genes identified in rice. This has been addressed early on with the development of resources for functional genomics such as the hhttps://dbarchive.biosciencedbc.jp/en/kome/desc.html) have been very useful for functional characterization of many genes. Both these resources are still widely used up to the present by researchers around the world particularly in systematically assigning functions to many predicted genes in the genome, in addition to other resources such as T-DNA insertion lines  providing an overview of the transcriptional changes throughout the growth of the rice plant in the field, and RiceFREND (http://ricefrend.dna.affrc.go.jp/) for co-expression analysis of these genes. These resources are now widely used for deciphering gene functions and analysis of rice gene networks. Combining the massive field transcriptomic data and meteorological information with statistical model construction, we have also succeeded, to some extent, in predicting fluctuation of gene expression, or transcriptome dynamics , encodes a B-type response regulator that is suppressed under long-day conditions for which Ghd7 is responsible , is involved in the photoperiodic flowering pathway by regulating the transcription level of a flowering repressor, Grain number, plant height and heading date 7 (Ghd7) gene , a so-called plant activator that protects plants from diseases by activating plant innate immune system  has been identified based on an extensive analysis of the genes associated with grain color in about 50 rice cultivars, tracing the origin to tropical japonica  has been recently discovered through screening and genetic analysis of the NIAS rice collection which have a great potential for improvement of rice yield under drought conditions by controlling the root system architecture in rice  gene selected in high-yield rice breeding programs increased the photosynthesis rate  gene limits endosperm cell number and grain length. Defective alleles lead to increase in grain size and yield . Rice being an integral part of Japanese agriculture is very much a part of these programs. Several ongoing MAFF-funded research projects focus on using the genome information of various crops for the development of various technologies to boost next-generation agriculture. As a part of that major project, the development of rice genomics resources and informatics tools are expected to contribute in such areas through attempts of various sectors to develop rice cultivars that address the specific needs of various rice producing regions in Japan considering the environmental changes in rice cultivation due to climate change.In Japan, rice genomics has been a part of major research programs of the Ministry of Agriculture, Forestry and Fisheries (MAFF) that address various issues in sustainable food production and agriculture. Foremost among these issues are the rapid aging of farm workers and depopulation of farming communities which would eventually affect agricultural production in the not so distant future. In breeding programs, various efforts are being initiated to integrate rice genomics technology to the development of novel varieties to reinvigorate Japanese agriculture. The new basic plan for food, agriculture and the rural areas which serve as the guideline for advancing the reform of measures and efforts by the entire nation so as to enable Japan\u2019s agriculture and rural areas to accurately respond to structural and other changes in the economy and society (As the rice research community embarks on various efforts in rice genomics, more rice genome sequence and transcriptome profiles will be generated in the very near future. Elucidating the molecular mechanisms controlling many biological processes will be supplemented by information to be obtained from other technologies such as proteomics, metabolomics (Okazaki and Saito IRGSP, International Rice Genome Sequencing Project; NGS, next-generation sequencing technology; RAP-DB, Rice Genome Annotation Project Database"}
+{"text": "Vertebrate vision is based on light-mediated alterations of the cyclic GMP concentration in outer segments of retinal photoreceptors. These chemical signals are converted by cyclic nucleotide-gated (CNG) channels into electrical signals that are further processed within the retina and, finally, the visual cortex of the brain. Dysfunctional cGMP signaling is associated with visual impairment and has been identified in several types of inherited blinding diseases. In particular, loss-of-function mutations in CNG channel subunits expressed in cone and rod photoreceptors were identified to cause achromatopsia  and retinitis pigmentosa, respectively. Besides displaying functional defects, the pathologies of both diseases are characterized by retinal degeneration that may be triggered by profound alterations in the cGMP and Ca2+ homeostasis. Our laboratory has generated genetic mouse models to dissect the molecular pathways underlying the multifaceted pathomechanisms of achromatopsia and retinitis pigmentosa. Complementary to these studies viral expression vectors based on AAVs (adeno associated virus) have been developed to rescue vision in genetic mouse models. These gene therapy approaches have now evolved to a point that allows clinical application in human patients in the near future. Our current approaches in this exciting new field will be discussed."}
+{"text": "Variability is an inherent and important feature of human movement. This variability has form exhibiting a chaotic structure. Visual feedback training using regular predictive visual target motions does not take into account this essential characteristic of the human movement, and may result in task specific learning and loss of visuo-motor adaptability. In this study, we asked how well healthy young adults can track visual target cues of varying degree of complexity during whole-body swaying in the Anterior-Posterior (AP) and Medio-Lateral (ML) direction. Participants were asked to track three visual target motions: a complex (Lorenz attractor), a noise (brown) and a periodic (sine) moving target while receiving online visual feedback about their performance. Postural sway, gaze and target motion were synchronously recorded and the degree of force-target and gaze-target coupling was quantified using spectral coherence and Cross-Approximate entropy. Analysis revealed that both force-target and gaze-target coupling was sensitive to the complexity of the visual stimuli motions. Postural sway showed a higher degree of coherence with the Lorenz attractor than the brown noise or sinusoidal stimulus motion. Similarly, gaze was more synchronous with the Lorenz attractor than the brown noise and sinusoidal stimulus motion. These results were similar regardless of whether tracking was performed in the AP or ML direction. Based on the theoretical model of optimal movement variability tracking of a complex signal may provide a better stimulus to improve visuo-motor adaptation and learning in postural control. Intentional postural tracking of visual cues is used in balance assessment  and rehaHealthy movement behavior on the other hand assumes the maintenance of some degree of intrinsic variability and flexibility in the motor output. Optimal movement variability is associated with complex interactions across multiple control systems, feedback loops and regulatory processes that enable an organism to function and adapt to the demands of everyday life ,8. It haBased on this theoretical paradigm, visuo-motor learning should allow the system\u2019s intrinsic variability to be maintained or even exploited. One way to attain this goal in postural tracking practice is to introduce visual cues of varying degree of organized complexity. However, one question that needs to be addressed first is how well humans can track with their gaze and posture a visual target that moves in an unpredictable, chaotic pattern. Evidence from auditory synchronization research introduced the notion of strong anticipation as a new framework for explaining the coordination of tapping behavior with chaotic signals . In thisIn a recent study examining the dynamic response of posture and gaze to visual target motions of varying complexity , gaze waThe aim of the present study was to examine how well healthy adults can track (with their whole body) visual target cues that differ in the degree of complexity  during voluntary visually guided sway in the Anterior-Posterior (A/P) and Medio-Lateral (M/L) direction. This was reflected in the degree of target-performance (posture and gaze) coupling assessed using both linear (coherence) and non-linear metrics (Cross-Approximate entropy). We hypothesized that participants would entrain their posture and gaze better to the chaotic rather than the noise or periodic visual target motion because chaos is an inherent feature of biological motion.Ten (10) healthy young male adults , recruited from the university students, volunteered to participate in this study. All participants were free from any neurological or musculoskeletal impairment and had normal or corrected to normal vision. Participants gave their informed consent prior to their inclusion in the study. The experiment was performed with the approval of Aristotle University\u2019s ethics committee on human research in accordance with the Declaration of Helsinki. Participants gave their written informed consent prior to their inclusion in the study.Two adjacent force plates  recorded the ground reaction forces at 100 Hz during experimental task performance. The resultant vertical ground reaction force normalized to the participant\u2019s Body Weight (BW) was displayed as a yellow dot in real-time via an overhead projector  on a large projection screen  located in front of the standing participant at a distance of 1.5 m, at eyelevel . The forPosture and gaze data were collected in a single experimental session at the Motor Control and Learning laboratory of Aristotle University of Thessaloniki, Greece. At the starting position , the parTarget signals were constructed using custom Matlab  algorithms while the data series were accessed and displayed through the main Labview  application onto the monitor. The maximum peak-to-peak amplitude of the target signals was scaled to 90% of BW in both directions. Each signal comprised 6000 data points. The position of the stimulus on the monitor was updated at a rate of 50 Hz providing 120 seconds of continuous target stimulus motion. All target signals had the same median frequency (0.25 Hz) that corresponds to the dominant frequency of self paced sway as this was estimated by pilot tests and prior experiments . This rehttp://people.sc.fsu.edu/~jburkardt/m_src/brownian_motion_simulation/brownian_motion_simulation.m) with input, integers M  = 2, N (the number of time steps) = 10000 [we choose 6000 data points (4000:10000)], the d (diffusion coefficient) = 10.0 and the real T  = 1.0.This signal was selected as it provides an non-periodic motion structure, but also affords continuous smooth pursuit eye movement responses. Furthermore, work by Collins and Deluca [Three signals of different degree of complexity  were used Deluca , have suIn order to compare how well one\u2019s postural sway and gaze was coupled to the visual target motions two different metrics of coupling were calculated in Matlab : the spectral coherence (Coh) and Cross Approximate Entropy (CrossApEn). These two measures estimate the magnitude and the temporal structure of the association respectively between a) the resultant force vector and the target stimulus motion b) the gaze (eye coordinate in the respective target\u2019s direction) and the target stimulus motion in the AP and ML directions.Spectral coherence measures the degree of correlation between two signals in the frequency domain. The magnitude-squared coherence is estimated as a function of sway frequency with values between 0 and 1 that indicate how well force and gaze couple to the target stimulus motion at the dominant sway frequency of 0.25 Hz . Cross-AThe effect of direction and target stimulus motion on the performance-target coupling was evaluated employing a 2 (direction) x 3 (stimulus complexity) repeated measures ANOVA. Significant interactions between factor levels were further analyzed by performing pairwise (t-tests) comparisons between the respective factor levels after adjusting p values for multiple comparisons.Group results for the force-target coherence are plotted in Group results for the gaze-target coherence are plotted in Group results on the Cross ApEn metric are shown in A significant main effect of visual motion complexity on the gaze-target Cross ApEn  = 95.031, p = .001)suggests that gaze was also sensitive to the visual stimuli motion complexity . SimilarThe novel finding of this study is that humans can track, with their gaze and posture, the complex motion of a visual target equally well or even better than the motion of a target moving periodically, regardless of whether tracking is performed in the AP or ML direction. This finding was confirmed by both metrics of performance-target coupling used in this study.As expected, gaze showed a higher degree of coherence and lower Cross ApEn with the sinusoidal than the brown noise motion suggesting tighter coupling to the predictable target motion. Moreover, gaze synchronized better to the complex target motion as revealed by the lower Cross ApEn between gaze and the Lorenz attractor than the sinusoidal signal. Gaze in our task was defined by the direction of the visual axis (the line connecting the centre of the fovea and the point of fixation) in the two-dimensional coordinates of the projection screen. This reflected the eye and head movement in smoothly pursuing the target since the stimulus motion was sufficiently slow to eliminate the recruitment of eye saccades. The more synchronous gaze-target coupling when tracking the Lorenz attractor signal suggests that the complex target motion imposes a higher demand on attending to the visual target as opposed to the sinusoidal stimulus motion which is more predictable. Our findings complement previous evidence showing that the complexity of the visual stimulus elicits reciprocal complexity in the response of the smooth pursuit gaze behavior . Eye-traGaze-target coherence was still higher for the sinusoidal than the Lorenz attractor signal when the target was moving in the AP direction, whereas in the ML direction there was no difference between the two target motions. This difference in the AP direction could be due to the additional visuo-motor transformation required for tracking the vertically moving target and converting this information into forward-backward sway. The fact that gaze demonstrated a greater coupling to the sinusoidal than the Lorenz stimulus motion in the frequency domain may be attributed to the smaller amplitude of the gaze signal. As it is evident from Force-target coupling was greater when the target was moving periodically than randomly . This finding complements previous evidence showing that a predictable target moving in the ML direction is tracked with a shorter time delay and higher accuracy than an unpredictable one . MoreovePostural sway synchronized better with the periodic than the more complex target motion as indicated by the lower force-target Cross ApEn for the sinusoidal than the Lorenz attractor visual motion. The fact that posture showed a more synchronous coupling with the sinusoidal stimulus motion suggests that participants were able to predict the target motion and adjust their posture employing an open loop type of control without necessarily attending to the stimulus when tracking the sine wave. Our results are in agreement with experimental evidence from the tapping literature suggesting that synchronizing with biologically variable auditory rhythms involves similar internal processes as with other variable rhythms , but different from those involved with a regular metronome ,29. SpecEntrainment of posture and gaze to the target motions of varying complexity was similar regardless of whether tracking was performed in the AP or ML direction. Of note here is the fact that during the experiment, special attention was given to maintain a consistent stance width across all trials performed in both directions. AP tracking was expected to result in greater entrainment than tracking in the ML direction because visual information about self-motion and orientation is available predominantly in the AP ,34and toThe results of the present study revealed that humans can track, with their gaze and posture, the complex motion of the visual stimulus equally well or even better than the motion of a target moving predictably. This novel finding complements recent multidisciplinary research proposing that information exchange is improved between complex long-range correlated systems . HealthyIn sum, based on our findings we propose that tracking of visual cues of a higher degree of complexity could be ecologically more sound and a better type of stimulus for optimizing visuo-motor learning while maintaining functional variability in the motor output. This type of practice may enable the human system maintain and use its functional degrees of freedom and adaptability. In this context, further studies should be designed to assess the sensitivity of the human perceptual-motor systems to the (long-range correlated) structure of fluctuations in environmental stimuli. This investigation may contribute to optimize human/environment interactions in several contexts, as the use of rhythmic auditory stimulation for gait rehabilitation in Parkinson\u2019s patients . DespiteS1 DatasetCoherence and Cross Approximate Entropy data for all subjects.(XLSX)Click here for additional data file."}
+{"text": "Introduction. Cadaveric dissections and prosections have traditionally been part of undergraduate medical teaching. Materials and Methods. Hundred and fifty-nine first-year students in the Faculty of Medicine, University of Colombo, were invited to participate in the above study. Students were randomly allocated to two age and gender matched groups. Both groups were exposed to identical series of lectures regarding anatomy of the abdomen and conventional cadaveric prosections of the abdomen. The test group  was also exposed to cadaveric cross-sectional slices of the abdomen to which the control group  was blinded. At the end of the teaching session both groups were assessed by using their performance in a timed multiple choice question paper as well as ability to identify structures in abdominal CT films. Results. Scores for spatial and radiological anatomy were significantly higher among the test group when compared with the control group . Majority of the students in both control and test groups agreed that cadaveric cross section may be useful for them to understand spatial and radiological anatomy. Conclusion. Introduction of cadaveric cross-sectional prosections may help students to understand spatial and radiological anatomy better. Cadaveric prosections have been fundamental to understanding the complexities of the human body structure and have played a pivotal role in gross anatomy teaching in medical education . DissectTraditionally anatomy has been taught on a regional basis. However cross-sectional anatomy is routinely encountered by clinicians. With the advent of modern medical imaging, more and more cross-sectional images of human anatomy are available as teaching material for modern day students. Can we improve spatial understanding of anatomy and imaging by exposing students to cadaveric cross-sectional specimens? We attempted to answer this question in a carefully designed case control study.n = 84, 52.8% female n = 75, 47.2%) first-year students in the Faculty of Medicine, University of Colombo, were invited to participate in the above study. Written informed consent was obtained and the consenting students were randomly allocated to two age and gender matched groups. Both groups were exposed to identical series of lectures regarding anatomy of the abdominal cavity. Control group was exposed to conventional cadaveric prosections of the abdomen. The test group  was exposed to a session containing prosected cadaveric cross-sectional slices of the abdomen to which the control group  was blinded. At the end of the teaching session understanding of the spatial anatomy of the abdomen among both groups was assessed by using their performance in a timed pretested and validated multiple choice question paper (SA). In addition ability to identify structures in abdominal CT films was also tested in a structured examination using abdominal CT scan films (RA). Individual marks of each component were added to arrive at the final cumulative scores (CS).Hundred and fifty-nine  first-year medical students participated in the study. Male female distribution and mean age were nearly equal in both groups.159 .Scores for spatial anatomy (SA) and radiological anatomy (RA) as well as the cumulative scores (CS) were higher among the test group when compared with the control group. Differences observed among the scores were statistically significant . Similarly vast majority in both groups (control 97.6% test 97.4%) also thought that radiological imaging may be used more often as adjunct to teaching anatomy.Sound knowledge of anatomy has been considered cornerstone of medical education . This isCertainly the concept of using cross-sectional imaging as an adjunct for teaching anatomy is not new. As early as 1985, 68% of medical schools in the United States were using some form of radiological imaging in undergraduate teaching . Over tiEarly ingenious attempts have been made to incorporate cross-sectional anatomy into medical curricula. Oh and colleagues used clay models of internal organs and used cut surfaces of the models to teach students how to interpret cross-sectional diagnostic imaging . PlasticIn our study we noted statistically significant improvement in spatial anatomical scores as well as radiological anatomy interpretation scores when students were exposed to cadaveric cross sections. Although there are multiple reviews on use of cross-sectional radiological imaging material as teaching aids for students \u201314, hardOur study also explored the perceptions of the students regarding use of cadaveric cross-sectional imaging in anatomy teaching. Interestingly enough, significant proportion of both test and control groups thought that cross-sectional prosections may be extremely helpful in understanding anatomical concepts. Even though we did not use imaging as a teaching tool in our study, majority of both test and control groups felt that radiological imaging would be a useful adjunct to learning anatomy. This is in keeping with many other studies where integration of radiological anatomy to traditional anatomy courses was received with welcome arms by both students and instructors .Although we propose to use cadaveric prosections and radiological imaging as an adjunct to conventional anatomy teaching we still do not advocate sole reliance of cross-sectional imaging for purposes of teaching anatomy. Indeed there have been rising concerns regarding falling quality of anatomical education with ever decreasing course times and limited availability of cadavers for dissection . AlthougOur study illustrates that cadaveric cross-sectional prosections can be used as an adjunct to improve spatial anatomical knowledge among students and to improve the ability to accurately interpret the radiological imaging. We recommend incorporation of prosected cadaveric cross sections as well as radiological imaging material as adjuncts to conventional anatomical curricula."}
+{"text": "The cost of next-generation sequencing is now approaching that of the first generation of genome-wide single-nucleotide genotyping panels, but this is still out of reach for large-scale epidemiologic studies with tens of thousands of subjects. Furthermore, the anticipated yield of millions of rare variants poses serious challenges for distinguishing causal from noncausal variants for disease. We explore the merits of using family-based designs for sequencing substudies to identify novel variants and prioritize them for their likelihood of causality. While the sharing of variants within families means that family-based designs may be less efficient for discovery than sequencing of a comparable number of unrelated individuals, the ability to exploit cosegregation of variants with disease within families helps distinguish causal from noncausal ones. We introduce a score test criterion for prioritizing discovered variants in terms of their likelihood of being functional. We compare the relative statistical efficiency of 2-stage versus1-stage family-based designs by application to the Genetic Analysis Workshop 18 simulated sequence data. Most genome-wide association studies for discovering common variants associated with disease traits have been conducted using a case-control design with unrelated controls. Not only are unrelated individuals easier to identify and enroll than are entire families (particularly multiple-case families), but the statistical efficiency per subject genotyped is typically higher using unrelated controls than using unaffected siblings or other relatives . HoweverWe consider a 2-stage design using individuals from a family study for discovery of novel variants and screening, followed by association testing in an independent data set using the linear regression of the phenotype on the genotype. A subset of members is selected for sequencing, preferentially sampling those with the most extreme phenotypes. We rank all the variants identified in these individuals using a novel score test and select those most likely to be causal for genotyping and association testing in the replication data set. These designs are compared with a single-stage family-based design in which all available members are sequenced .Bayes factor criterion. Following the principles described in Petersen et al N = 157).We arbitrarily fixed the total number of variants to be prioritized at 100, but the general principles for design of 2-stage designs -24 couldrelative performance of the 1-stage and 2-stage designs). Because treatment is itself related to blood pressure, it is both a confounder and an intermediate variable on a causal pathway, so neither ignoring it nor covariate adjustment is appropriate. This problem was extensively discussed at Genetic Analysis Workshop 13 [It is also possible that more appropriate adjustment for time-dependent treatment data would improve power for all these analyses (although it's unlikely to affect the kshop 13 ; see refkshop 13 -29 for dThe authors declare that they have no competing interests.ZY participated in statistical analysis. DCT developed the statistical method. Both authors participated in drafting and revising the manuscript. Both authors read and approved the final manuscript."}
+{"text": "The transgenerational inheritance of stress-induced epigenetic modifications is still controversial. Despite several examples of defense \u201cpriming\u201d and induced genetic rearrangements, the involvement and persistence of transgenerational epigenetic modifications is not known to be general. Here I argue that non-transmission of epigenetic marks through meiosis may be regarded as an epigenetic modification in itself, and that we should understand the implications for plant evolution in the context of both selection for and selection against transgenerational epigenetic memory. Recent data suggest that both epigenetic inheritance and resetting are mechanistically directed and targeted. Stress-induced epigenetic modifications may buffer against DNA sequence-based evolution to maintain plasticity, or may form part of plasticity\u2019s adaptive potential. To date we have tended to concentrate on the question of whether and for how long epigenetic memory persists. I argue that we should now re-direct our question to investigate the differences between where it persists and where it does not, to understand the higher order evolutionary methods in play and their contribution. Arabidopsis epigenetic recombinant inbred line (epiRIL) populations that have no DNA sequence variation but epigenetic variation in DNA methylation were created by crossing wild-type \u201cColumbia\u201d with mutants deficient in DNA methylation. The patterns created by recombination in these Arabidopsis epiRILs led to a range of stress-tolerance and phenotypes similar to the natural range in accessions within six to nine generations , nucleosome occupancy and recombination. The effect is an altered epigenome that regulates stress response. In some cases the signature of the stress experience remains in the epigenome after relief from the stress, providing a \u201cmemory.\u201d If this memory conditions the response to stress during subsequent development, the organism is said to be epigenetically primed. If the memory of the stress experienced by a parent conditions the response of its progeny, this epigenetic priming may be transgenerational. Following Arabidopsis, priming for antibacterial defense involves active demethylation of TEs that leads to transcriptional activation of defense regulators via hormonal signals , its silencing and the epigenetic maintenance of silencing during warmer temperatures  was sequential so that initial, incomplete post-transcriptional silencing shifted to transcriptional silencing over generations once a copy number of 40 was reached. EVD bore the seeds of its own destruction; its molecular suppression of post-transcriptional silencing generated RdDM that led to its transcriptional silencing. These findings (and others reviewed in A number of stresses can mobilize TEs  and supp pathway . Transpo pathway . Variati pathway  or even  pathway . FederofAlthough the majority of stress-induced chromatin modifications do not persist past gametogenesis (reviewed in UBP1b gene in Arabidopsis, the AltSB aluminum tolerance locus of sorghum, and the regulation of desiccation tolerance via inducible siRNAs at the CDT-1 element of Craterostigma plantagineum (Mu killer locus in maize may be highly prevalent. Via siRNAs, Mu killer heritably silences the MuDR transposon (Mu killer derives from an inverted duplication of a partially deleted MuDR element (If the re-setting of stress-induced epigenetic modification at gametogenesis exists to allow encoding of transgenerational memory at new, responsive elements how might we see its signature in the genome? In some known cases, the epigenetic regulation of stress response is fixed in the genome at TE-derived sequences and heritable: Examples include the siRNA-based silencing of the tagineum . In addiansposon . Mu kill element  and this element  and is s element . Coupled element  these re element .Reversible epigenetic regulation may have advantages in fluctuating environments. Epigenetic and genetic variation co-evolve . This neThese models might account for the seeming variability in observations of epigenetic phenotypic plasticity and transgenerational epigenetic responses to stress. A rapid accumulation of epigenetic variation in response to stress would be visible in the phenotype of the first one or several generations if washed-out or rapidly sunset. Alternatively, a stress-induced burst of epigenetic modification might be visible in the first generation but largely disappear after re-setting with only a proportion fixed following the re-set generation. A rapid re-setting of stress-induced epigenetic variation followed by neutral accumulation to a new fitness maximum would only become visible once epigenetic variation exceeded genetic variation, or following another stress-induced burst. This model is illustrated in Figure Theoretically a brief, transgenerational epigenetic memory ensures plasticity, but the dual inheritance of genetic and epigenetic variation ensures adaptation . If re-sWhen we consider the evidence for epigenetic transgenerational inheritance in response to stress we should consider whether it will be visible in an individual epigenome and whether the ebb and flow of visible epigenetic modifications limits or contributes to plasticity. The framework for population and species-level studies of genetics can now be applied in epigenetics to inform our understanding . It is tThe author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Activation of dopamine receptor type-5 (DR5) has been known to reduce systemic blood pressure, most likely by increasing renal vasodilation and enhancing natriuresis in the kidney. However, the mechanism of DR5 in natriuresis and vasodilation was not clearly known. We have previously shown that DR5 is localized to primary cilia of proximal renal epithelial and vascular endothelial cells. We here show that selective activation of DR5 specifically induces calcium influx only in the primary cilia, whereas non-selective activation of dopamine receptor induces calcium fluxes in both cilioplasm and cytoplasm. Cilia-independent signaling induced by thrombin only shows calcium signaling within cytoplasm. Furthermore, calcium activation in the cilioplasm by DR5 increases length and mechanosensory function of primary cilia, leading to a greater response to fluid-shear stress. We therefore propose a new mechanism by which DR5 induces vasodilation via chemical and mechanical properties that are specific to primary cilia. Thus, understanding cilia-specific proteins and signaling pathways is crucial to pharmacologically intervene in the pathogenesis of ciliary diseases. The localization of various proteins within the bulb of a cilium has just been recently understood (Mohieldin et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The inhalation of combustion-derived nanoparticles leads to adverse health effects in the airways. In this context the induction of membrane-coupled signalling is considered as causative for changes in tissue homeostasis and pro-inflammatory reactions. The identification of these molecular cell reactions allowed to seek for strategies which interfere with these adverse effects. In the current study, we investigated the structurally different compatible solutes mannosylglycerate (firoin) from thermophilic bacteria and ectoine from halophilic bacteria for their capability to reduce signalling pathways triggered by carbon nanoparticles in target cells in the lung. The pre-treatment of lung epithelial cells with both substances decreased the particle-specific activation of mitogen-activated protein kinases and also the endpoints proliferation and apoptosis. Firoin applied into the lungs of animals, like ectoine, led to a significant reduction of the neutrophilic lung inflammation induced by particle exposure. The pro-inflammatory effect of carbon nanoparticles on human neutrophil granulocytes ex vivo was significantly reduced by both substances via the reduction of the anti-apoptotic membrane-dependent signalling. The data of this study together with earlier studies demonstrate that two structurally non-related compatible solutes are able to prevent pathogenic reactions of the airways to carbon nanoparticles by interfering with signalling events. The findings highlight the preventive or therapeutic potential of compatible solutes for adverse health effects caused by particle exposure of the airways. The inhalation of combustion-derived carbonaceous nanoparticles leads to adverse health effects in the airways including lung cancer, chronic obstructive pulmonary disease, and fibrosis During the last years, we aimed to develop preventive strategies based on the knowledge of these molecular events which occur during the interaction of environmentally relevant combustion-derived nanoparticles and lung epithelial cells. For that purpose, we screened substances which are well tolerated by epithelial cells for their ability to prevent membrane-coupled cell stress events triggered by carbon nanoparticles. We identified the \u2018compatible solute\u2019 ectoine as effective in preventing cell stress reactions triggered by carbon nanoparticles. Ectoine prevented the downstream consequences of the specific changes in the lipid raft induced by nanoparticles Pyrococcus furiosus and has been described to be an effective stabilizer of proteins under temperature stress Compatible solutes are defined as small, organic, mostly neutral or zwitter-ionic compounds, which are able to stabilize cell functions In the present study we tested the preventive effects of the compatible solutes ectoine and firoin on particle-exposed lung epithelial cells. The investigations of ectoine and firoin as examples of compatible solutes coming from halophilic and thermophilic bacteria were performed as a proof of concept for the strategy to use different kinds of compatible solutes as preventive substances in the airways. Comparing two chemically independent substances with respect to their efficacy might provide valuable information for further efforts to find substances for molecular prevention. Both substances were tested for their capacity to prevent CNP-induced apoptosis and proliferation and the respective signalling events specifically triggered by environmental model particles in lung epithelial cells. Furthermore, the effects of firoin on lung inflammation in the in vivo system was studied. The possible value of firoin on the prevention of anti-apoptotic effects was investigated in human peripheral blood neutrophils. The efficacy of firoin in the in vivo and the ex vivo systems was compared with the previously published preventive effects of ectoine.The human study was approved by the local ethics committee on human research of the Heinrich-Heine University D\u00fcsseldorf and written informed consent was obtained from all study subjects before enrolment. Animal studies according to German animal welfare legislation were approved by the responsible authority (LANUV NRW).CNP, 14 nm diameter  were characterized and prepared as described earlier RLE-6TN cells Protein isolation and Western blotting were performed as described earlier Female Fisher 344 rats  were instilled intratracheally with 2.5 mg/kg CNP suspended in 0.4 ml PBS as described earlier 2O2. After block with goat serum, sections were stained over night with phospho-Erk1/2 or phospho-JNK1/2 using the corresponding Western blot antibodies and detected with HRP-coupled secondary antibody and AEC substrate and counterstained with hematoxylin. Neutrophil elastase was stained accordingly with the rat specific antibody . The specific staining was performed using diaminobenzidine. The specificity of the staining was controlled by parallel approaches without primary antibody and with isotype controls.Tissue preparation, sections, and immunohistochemical staining were performed as described 4 events per sample and positive cells were considered as apoptotic. Different treatment groups were normalized to spontaneous apoptosis of untreated cells.Peripheral blood was collected from young, healthy, male volunteers (age 31.2\u00b17.3 yrs). Volunteers with ongoing medication were not included in the study. Neutrophil isolation was performed as described Statistical analyses were performed using IBM SPSS statistics 22. Figures display mean values and standard errors. As indicated in the figure legends, different kinds of analyses were performed. Normally distributed samples were analysed by one-way ANOVA with the indicated post hoc significance testing. Small sample size groups were compared employing the non-parametric Mann-Whitney-U test. Corrections for multiple testing were performed when applicable.2], the phosphorylation of the MAPK was determined at the time point of maximal activation . This particle exposure conditions were chosen from earlier dose response experiments on MAPK activation in which no cytotoxic side effects were observed In a first approach to investigate the beneficial effects of the compatible solutes ectoine and firoin, the phosphorylating activation of the MAPK Erk1/2 and JNK1/2 was investigated in the cell culture system with rat lung epithelial cells (RLE-6TN). Both markers in earlier studies proved to be specific for CNP, as bigger non-nanoparticles did not trigger these cell reactions The functional relevance of the prevention of cell stress signalling was also tested by measuring the respective endpoints specifically mediated in lung epithelial cells by these MAPK. For this purpose, the most efficient compatible solute concentrations which inhibited phosphorylation of Erk1/2 and JNK1/2 were used to interfere with the cascade leading to proliferation and apoptosis induced by CNP treatment. BrdU incorporation and activation of caspase-3 were measured in RLE cells, respectively. In accordance with the MAPK findings, the incorporation of BrdU as well as the activation of caspase-3 triggered by carbon nanoparticle stress was significantly reduced when the cells were pre-exposed to the compatible solutes . The in As a major outcome of CNP exposure, lung inflammation was investigated for its sensitivity to firoin treatment. In a first approach, increasing doses of the substance were applied together with the particles in rats . The memAlthough compatible solutes, as hydrophilic substances, are not considered to interact with the hydrophobic carbon particles, they might influence particle characteristics in a way that less pro-inflammatory events are triggered after particle-cell interaction. Therefore, as a proof of principle, the application of firoin was separated from the application of CNP. Animals were treated twice with firoin prior to the exposure to CNP . Again, Previous studies identified the role of ectoine not only in reducing the pro-inflammatory response of epithelial cells to CNP, but also to restore normal levels of apoptosis in CNP-treated neutrophils. To evaluate whether firoin also has a beneficial effect on this pro-inflammatory event, human peripheral blood granulocytes from healthy volunteers (n\u200a=\u200a7) were pre-treated ex vivo with increasing doses of firoin 2 h prior to CNP exposure [33 \u00b5g/ml]. Cells were analysed after 6 h of particle exposure for the expression of anti-apoptotic Mcl-1 protein and apoptosis rates were determined flow cytometrically after 16 h using the early apoptotic marker Annexin V. As an internal control, the experiment was also performed in the presence of 1 mM ectoine. Pre-treatment of 1 mM firoin significantly restored natural apoptosis rates which were reduced by the exposure of the neutrophils to CNP . The samWith the current findings we describe preventive effects of two structurally unrelated compatible solutes on membrane dependent signalling pathways induced by carbon nanoparticles. The major results are: (i) the pre-treatment of lung epithelial cells with firoin and ectoine leads to reduced CNP-specific MAPK activation responsible for aberrant proliferation or apoptosis (ii) the application of firoin as earlier demonstrated for ectoine, has preventive effects on neutrophilic lung inflammation (iii) in the presence of firoin and ectoine, the anti-apoptotic effects of CNP on peripheral human neutrophils are prevented and natural apoptosis rates are restored.MAPK activation by CNP as model particles for ultrafine ambient air particles can be specifically and dose dependently reduced by the application of both compatible solutes. Accordingly, proliferation and apoptosis which both occur in cultured lung epithelial cells after CNP exposure depending on the pre-disposition of the individual cell were significantly reduced in these experiments. The reduction of proliferation and apoptosis demonstrate the physiological relevance of the signalling pathways via Erk1/2 and JNK1/2 for these in vitro endpoints. The findings corroborate the causal link between the signalling pathways activated by CNP and the specific outcomes.Besides possible effects on tissue homeostasis and remodelling, the most prominent effect of inhaled ambient particles is the induction of inflammatory responses. The recent data show that both markers of membrane-dependent signalling are induced in the lung epithelium also in vivo by CNP and that the prevention of this cellular reaction by an intervention strategy can be correlated to a reduction of neutrophilic inflammation in rat lung. The link between MAPK activation and the expression of neutrophil-attracting chemokines has earlier been demonstrated in a study in which human bronchial epithelial cells have been exposed to CNP Applying firoin either together with or prior to the particles into the lungs of animals resulted in a mild (20% to 30%) but significant reduction of neutrophilic lung inflammation 48 h after particle exposure. This effect, however, is stronger in other experimental systems. We recently demonstrated an ectoine-caused reduction of the inflammatory response by 50% in CNP-treated C57/Bl6 mice 12 h after particle exposure The success of the strategy to apply the compatible solute prior to the particle exposure underlines the preventive way of action of compatible solutes, mediated by the stabilization of the membrane-coupled signalling complexes. However, from the animal experiments it cannot be concluded that the preventive effect of firoin on the lung inflammation is exclusively mediated by the reduction of pro-inflammatory reactions of the epithelium. Although not studied at a functional level it is evident, that in both animal experiments firoin treatment has no effect on the number of macrophages in the lung at the time point of analysis. This can partially be explained by the observed predominant effect of compatible solutes on the expression of the neutrophil recruiting chemokine cinc-1 in epithelial cells. On the other hand, a direct effect of firoin on neutrophils cannot be excluded.We earlier described that during an ongoing inflammation, CNP in neutrophils counteract the natural apoptosis. Apoptosis of neutrophils is an important regulatory mechanism of an acute inflammation Studies comparing chemically different compatible solutes revealed different specific effectivity with respect to their stabilizing capacity on proteins in vitro We are aware that the main strategy to prevent adverse effects of air pollution has to be the improvement of air quality. However, modern life style as well as non-anthropogenic sources of air pollution often set limits to measures of air hygiene In conclusion, the data of the current study show that firoin, like ectoine, is a compatible solute which has beneficial effects on adverse effects in the airways after exposure to combustion-derived nanoparticles. Both substances which are chemically and structurally not related have very similar efficacy in the prevention of pathogenic endpoints induced by carbon nanoparticles in vitro and in vivo."}
+{"text": "The blood\u2013cerebrospinal fluid barrier (BCSFB) established by the choroid plexus (CP) epithelium has been recognized as a potential entry site of immune cells into the central nervous system during immunosurveillance and neuroinflammation. The location of the choroid plexus impedes in vivo analysis of immune cell trafficking across the BCSFB. Thus, research on cellular and molecular mechanisms of immune cell migration across the BCSFB is largely limited to in vitro models. In addition to forming contact-inhibited epithelial monolayers that express adhesion molecules, the optimal in vitro model must establish a tight permeability barrier as this influences immune cell diapedesis.\u00ae and the ECPC4 line to primary mouse choroid plexus epithelial cell (pmCPEC) cultures for their ability to establish differentiated and tight in vitro models of the BCSFB.We compared cell line models of the mouse BCSFB derived from the Immortomouse\u00ae or the ECPC4 tumor cell line did not express characteristic epithelial proteins such as cytokeratin and E-cadherin and failed to reproducibly establish contact-inhibited epithelial monolayers that formed a tight permeability barrier. In contrast, cultures of highly-purified pmCPECs expressed cytokeratin and displayed mature BCSFB characteristic junctional complexes as visualized by the junctional localization of E-cadherin, \u03b2-catenin and claudins-1, -2, -3 and -11. pmCPECs formed a tight barrier with low permeability and high electrical resistance. When grown in inverted filter cultures, pmCPECs were suitable to study T cell migration from the basolateral to the apical side of the BCSFB, thus correctly modelling in vivo migration of immune cells from the blood to the CSF.We found that inducible cell line models established from the ImmortomouseOur study excludes inducible and tumor cell line mouse models as suitable to study immune functions of the BCSFB in vitro. Rather, we introduce here an in vitro inverted filter model of the primary mouse BCSFB suited to study the cellular and molecular mechanisms mediating immune cell migration across the BCSFB during immunosurveillance and neuroinflammation. The choroid plexus (CP) is a highly-vascularized structure that folds from the ependymal lining of the lateral, third and fourth ventricles in a convoluted fashion into cerebrospinal fluid (CSF)-filled ventricular spaces. In contrast to brain microvessels at the blood\u2013brain barrier (BBB), CP microvessels are fenestrated and allow for free diffusion of molecules from the blood into the CP stroma. Highly-polarized epithelial cells, which cover the entire surface of the CP, establish a barrier between the blood and the CSF, the blood\u2013cerebrospinal fluid barrier (BCSFB). While preventing the free diffusion of blood components into CSF, the BCSFB regulates the transport of metabolites and is considered the major source of the CSF . Par+ Th17 cells into the CNS. Last but not least, the CP mediates neutrophil invasion into the CNS after traumatic brain injury Sucrose across the BCSFB rat in vitro model [In depth characterization of the primary mouse CPEC cultures in the present study demonstrated this approach to be a valid in vitro model to study immune functions of the mouse BCSFB. Primary mouse CPECs were isolated and grown at high purity and formed contact-inhibited monolayers. CPECs maintained expression of CPEC specific molecules and developed mature junctional complexes. Primary mouse CPEC established a tight barrier with high trans-epithelial electrical resistance (TEER) values comparable to the TEER measured across primary CPEC cultures from different species , 55, 56 ro model . Furtherro model  and the ro model  and threro model .Taken together cultured pmCPEC maintain important barrier characteristics of CPECs in vivo and are thus a suitable model for the mouse BCSFB in vitro.To study T cell migration across the BCSFB in vitro, the pmCPEC cultures were adapted to grow on an inverted porous filter membranes as previously described in . InteresTaken together in the present study, we have successfully established an inverted in vitro filter model of the mouse BCSFB with barrier characteristics resembling that of the BCSFB in vivo. We provide proof of principle that this model is suited to study T cell migration from the blood to the CSF side across the BCSFB. This model of the mouse BCSFB can be used to investigate whether different immune cell subsets can cross the BCSFB and enable the cellular and molecular mechanism involved to be defined.\u00ae and from the commercially available ECPC4 are not suited for this purpose. Rather pmCPECs growing on inverted Transwell filters were defined as a reliable in vitro model for experiments mimicking the T cell migration from the blood vessel side to the apical side facing the CSF. Moreover, our adapted \u2018inverted\u2019 BCSFB model is suitable for addressing not only the immune cell subset extravasation but also the passing of substances and pathogens, taking into account the correct orientation of the polarized cells as it occurs under physiological conditions within the brain.A suitable tool for reproducible high throughput investigations of the molecular and cellular mechanisms that mediate the migration of specific immune cells into the CNS via the mouse BCSFB is missing to date. Here we show that cell line models derived from the Immortomouse"}
+{"text": "Information concerning the roles of different brain regions in recognition memory processes is reviewed. The review concentrates on findings from spontaneous recognition memory tasks performed by rats, including memory for single objects, locations, object\u2013location associations and temporal order. Particular emphasis is given to the potential roles of different regions in the circuit of interacting structures involving the perirhinal cortex, hippocampus, medial prefrontal cortex and medial dorsal thalamus in recognition memory for the association of objects and places. It is concluded that while all structures in this circuit play roles critical to such memory, these roles can potentially be differentiated and differences in the underlying synaptic and biochemical processes involved in each region are beginning to be uncovered. Different types of information can be used to establish whether a stimulus or set of stimuli have been encountered before and thus it may be argued that recognition memory has multiple component aspects. For example, judgments can be made on whether an individual item is novel or familiar and/or whether an item has been previously associated with another item, a particular location or context. In addition judgments can be made using an item's relative familiarity or the recency of the last encounter with that item 1.1novel object preference (OR), in which the rats\u2019 exploration of a novel object is compared with that of a familiar object; (b) object location (OL), which tests the animals\u2019 ability to detect the movement of a familiar object to a novel location; (c) object-in-place (OiP) in which animals\u2019 discriminate between familiar objects that have been previously associated and those that are newly associated with particular places; (d) temporal order (TO) which examines the animals\u2019 ability to differentiate between familiar objects presented at different times previously.As this review will focus on experimental evidence from rodent studies, we will briefly outline object recognition paradigms in the rat. Object recognition memory tasks depend on the use of this species\u2019 instinctive tendency to explore novel items or a novel location. These tasks thus avoid lengthy training regimes or reinforcement schedules 2There is now overwhelming evidence demonstrating that the perirhinal cortex plays a critical role in judging the prior occurrence of individual items; relevant work from both behavioural and electrophysiological studies has been reviewed extensively elsewhere 2.1A number of studies have revealed the essential role of the perirhinal cortex in novel object recognition. Thus tasks in which the subject must discriminate between novel and the prior occurrence of infrequently repeated individual items, as for example, visual delayed matching or non-matching to sample tasks with \u2018trial unique\u2019 stimuli, in monkeys 2.2In 2000 Bussey et al., demonstrated that a combined lesion in the perirhinal and postrhinal cortex significantly impaired object-in-place associative recognition memory. This study was followed by others showing that selective ablation of the perirhinal cortex produced the same impairment While the precise contribution of the perirhinal cortex in object-in-place memory clearly requires systematic investigation, its importance in object identity and in detecting stimulus familiarity is generally agreed and these processes are likely to be critical for successful object-in-place performance. As will be discussed later in this review a number of studies indicate a role for the hippocampus and also the medial prefrontal cortex in processing the spatial location of the objects, and the formation of object\u2013location associations.2.3Recognition memory judgements concerning objects may also encompass how recently objects were encountered or the order in which they were encountered. Excitotoxic lesions of the perirhinal cortex produce significant deficits in temporal order memory for a sequence of two objects 3The role of the hippocampus in single item object recognition memory has prompted much debate. Some studies have reported that lesions in the hippocampus produce significant impairments 3.1The hippocampus has a clearly demonstrable role in object recognition memory tasks which have a spatial component, such as the object-in-place task. Thus lesions in the hippocampus or fornix impair object-in-place and also object location tasks Electrophysiological evidence thus suggests that the CA1 hippocampal subfield is critically involved in processing object-in-place memory 3.2There is accumulating evidence supporting a role for the hippocampus in memory for sequences of stimuli and for recognition memory involving recency judgements Studies have shown that hippocampal subfields make differential contribution to temporal order memory. For example, Hoge and Kesner 4Functional imaging in human subjects has implicated the prefrontal cortex in recognition memory processes 4.1In contrast to the difficulty in establishing a direct role for the medial prefrontal cortex in single item recognition memory, lesions in the medial prefrontal cortex significantly impair object-in-place associative recognition memory 4.2The medial prefrontal cortex has been shown to play an important role in temporal order and recency memory 5In humans and non-human primates damage to the medial dorsal thalamus (MD nucleus) produces recognition memory deficits 6The evidence reviewed above establishes that the perirhinal cortex, medial prefrontal cortex, hippocampus and MD thalamus all contribute to aspects of recognition memory. In particular, selective bilateral ablation of these regions has demonstrated that each is necessary for both object-in-place and temporal order memory. Further, investigations have been made to assess the extent to which object-in-place and temporal order memories depend on functional interactions between these brain regions. A disconnection analysis has been used to address this issue: a unilateral lesion is placed in each of two different regions of interest  in either the same or opposite hemispheres. If the two brain regions are required to cooperate during a task, then this will not be possible when the two lesions are in opposite hemispheres (crossed lesions) as neither hemisphere has an intact circuit. However, when both lesions are in the same hemisphere , the circuit remains intact in the contralateral hemisphere. While it is possible that interhemispheric  connections might allow circuits to be completed in the crossed lesion case, the findings reported below demonstrate that such commissural communication is insufficient to restore performance in the case of object-in-place and temporal order memory as investigated.Using this experimental strategy it was found that disconnection of the medial prefrontal cortex from the perirhinal cortex disrupted both object-in-place and temporal order memory, while having no effect on single item recognition or object location memory: crossed lesions resulted in major deficits in both object-in-place and temporal order memory while unilateral lesions were without effect There is anatomical evidence that would support these interactions, as the medial prefrontal cortex receives a direct projection from the hippocampus and MD, and is reciprocally connected with the perirhinal cortex 6.1Our disconnection studies reveal that object-in-place memory is mediated by a cortico-thalamic-hippocampal network, but what might be the functional contributions of each region within the circuit? Bilateral lesion studies have revealed dissociations in the contributions of the perirhinal cortex, medial prefrontal cortex, and hippocampus in single-item recognition and object location memory There is also evidence that object-place information may be integrated within the hippocampus. Thus hippocampal and medial prefrontal firing patterns have been shown to be strongly correlated during object-in-place performance Further disconnection studies have shown that MD thalamus provides an additional component to these associative recognition and temporal order memory circuits. Disconnection of MD from the medial prefrontal cortex impaired object-in-place and temporal order performance: the interaction between MD and medial prefrontal cortex is equally as necessary as the structures themselves The MD thalamus provides a significant input into the medial prefrontal cortex Further information can be obtained concerning the putative role of a specific brain region by seeking effects upon memory acquisition and retrieval by temporarily inactivating the region during one or other of these processes. Local infusion of the AMPA receptor antagonist NBQX through an implanted cannula temporarily blocks excitatory neurotransmission, so inactivating a specific region for a restricted time . Reversibly inactivating MD bilaterally in this way produces a greater impairment when MD is inactivated during retrieval than during acquisition of object-in-place memory These results imply that the engram for object-in-place memory is unlikely to be stored in MD thalamus . Moreover, inactivation of MD during acquisition does not so impair the functioning of medial prefrontal cortex that acquisition is totally prevented. Thus MD cannot be the only route by which information is transferred from perirhinal cortex to medial prefrontal cortex during acquisition. It is possible that the impairment produced during retrieval is because of consequent disruption of medial prefrontal cortex through a general loss of incoming MD activity rather than a loss of specific information transfer from MD.In contrast, similar reversible inactivation experiments using infusions into perirhinal cortex, hippocampus and medial prefrontal cortex establish that each of these structures is necessary during both acquisition and retrieval of object-in-place memory The above data indicate the importance of the functional integrity of circuits involving the perirhinal cortex, hippocampus, medial prefrontal cortex and MD thalamus for associative recognition memory processes. However, recent findings emphasise that the particular neural processes necessary for such memory differ for the different areas. MD is more important for retrieval than acquisition of object-in-place memory 6.2The perirhinal cortex, medial prefrontal cortex, hippocampus and MD thalamus also cooperate during temporal order memory. While lesion studies do not enable us to define the cognitive contribution to temporal order memory made by each region, there is evidence that the perirhinal cortex and medial prefrontal cortex contain neurons which code for the recency of stimulus presentation and evidence that the hippocampus contains \u2018time cells\u2019 which provide a representation of time duration between stimuli 7This review has outlined evidence that demonstrates that object recognition memory is not a unitary process, as the ability to judge the prior occurrence of a stimulus or stimuli can be achieved using different forms of information, dependent on different brain regions. Recognition memory that involves multiple items and their contextual associations or the temporal order in which items are encountered depends on interactions within a circuit involving the perirhinal cortex, hippocampus and medial prefrontal cortex. Further, these forms of recognition memory also involve interactions between the medial prefrontal cortex and MD thalamus. However, evidence is accumulating that the component parts of this circuit make different contributions to the memory and display differences in the underlying synaptic and biochemical processes involved."}
+{"text": "Progress in headache research suggests that migraine pathophysiology involves inherited abnormal brain functions and that the initiation of headache depends on flow of nociceptive signals that originate in pain-sensitive intra- and extra-cranial organs conveyed through peripheral nociceptors to central trigeminovascular neurons. Despite this progress, little is known about the identity of the pain fibers that mediate the initiation phase, or what activates them.To assess the extent of presence of inflammatory molecules in periosteum tissues that were taken from calvarial areas where the head hurts.We compared number of copies of gene transcripts (mRNA) that encode proteins that play known roles in inflammatory and immune responses and number of copies of molecules that regulate the expression of those genes (miRNA) in periosteum tissues of 27 chronic migraine (CM) patients and 17 control subjects.36/524 mRNAs and 27/726 miRNAs were differentially expressed in the periosteum of CM patients compared to control subjects. Of these, 25 genes were up-regulated  whereas 11 were down-regulated . Of the 27 post-transcripts, expression was low for 11  and high for 16  miRNA sequences.The findings suggest that the molecular environment in which periosteal pain fibers exist contain abnormal expression of genes that promote inflammation; a condition that is likely to lower their activation threshold, when symptoms appear at the onset of an attack, or activate them chronically."}
+{"text": "Furthermore, single-cell studies indicate that DNA damage responses generate substantial variation in repair activities across cells. This review focuses on fluorescence imaging methods that offer a quantitative description of DNA repair in single cells by measuring protein concentrations, diffusion characteristics, localizations, interactions, and enzymatic rates. Emerging single-molecule and super-resolution microscopy methods now permit direct visualization of individual proteins and DNA repair events in vivo. We expect much can be learned about the organization of DNA repair by linking cell heterogeneity to mechanistic observations at the molecular level.DNA repair safeguards the genome against a diversity of DNA damaging agents. Although the mechanisms of many repair proteins have been examined separately  The DNA repair machinery also controls mutation rates that generate genetic variation in response to environmental changes. These conflicting tasks are finely tuned to achieve sufficient plasticity without compromising evolutionary stability. Mechanisms that create and control variation in DNA repair are therefore central to the survival of species. At the molecular level, heterogeneity is introduced by the stochastic occurrence of individual chemical reactions and molecule encounters. As a result, even seemingly homogeneous biological populations show differences between their individual components, such as variability in protein expression levels of clonal cells A central source of heterogeneity specific to DNA repair lies in the variety of exogenous and endogenous DNA damaging agents, ranging from UV light and radiation to alkylating chemicals and reactive oxygen species. The resulting diversity of toxic and mutagenic lesions favors a modular organization of repair in conserved pathways each involving a series of enzymes. Environmental changes cause further variation in the DNA repair system by triggering DNA damage and stress responses that induce specific repair proteins or activate large sets of genes through global regulatory networks. Cells thus face the difficult task of maintaining the proper balance of the entire repair system over a wide range of conditions to ensure that lesions are removed fast and accurately without accumulation of toxic intermediates Although the main repair pathways have been identified and characterized using genetic, biochemical, biophysical, and cell biological approaches, we are still far from understanding the overall organization of DNA repair in cells. For instance, it is unclear how the different repair components cooperate to create functioning pathways, how the pathways coordinate and integrate with other cellular processes, and how environmental changes modulate the organization of the repair system. In short, a full systems-level description of DNA repair is needed, ideally based on the mechanisms of the individual enzymes. Many mysteries about DNA repair would be solved if the proteins could be directly observed in action inside single living cells, thus overcoming limitations inherent to measuring averages over large populations of molecules and cells. Building on single-cell microscopy, which has been performed for several hundred years, recent advances in instrumentation, biological labels and image analysis methods have orchestrated a shift in the way the data are analyzed with attention to quantitative evaluation of cell phenotypes and identifying the sources of their variation in vitro . These approaches resolve molecular heterogeneity that cannot be separated biochemically, including repair complexes of different composition and stoichiometry as well as molecular subpopulations with different chemical modifications. Time-trajectories of individual molecules reveal dynamic heterogeneity, such as transient DNA-binding events, weak protein interactions, unsynchronized or stochastic enzymatic activities, and protein conformational dynamics in vivo observations is challenging due to the lack of control over intracellular conditions and difficulty of delivering probes in a non-invasive manner. Most progress on this front has been made using fluorescence microscopy in bacterial model systems. Hereafter, we discuss several example studies and hint at the challenges that need to be addressed in order to apply these techniques to study the organization of DNA repair in vivo.On the molecular scale, single-molecule methods have been very successful in unraveling many mechanisms of reconstituted DNA repair machinery 2We first consider the molecular origins of cell heterogeneity. Single-cell experiments uncovered variation in protein expression levels across cells and over time using genetically encoded fluorescent proteins. These studies showed that gene expression is a stochastic process and a fundamental source of cell individuality at the molecular level e.g. the type and dose of damage, state in the cell cycle, nutrient availability) and translating them into appropriate outputs  Bacillus subtilis energy stress response involving the alternative sigma factor \u03c3B is temporally modulated by stochastic pulses of gene activation with the strength of the response controlled by the frequency, not the magnitude of the pulses DNA damage responses belong to a class of cellular decision-making processes sulA gene expression Another example of controlling noise is the bacterial SOS response that counteracts double-strand breaks and replication-blocking lesions by inducing or repressing a large number of genes including those responsible for nucleotide excision repair, homologous recombination repair, mutagenesis, and inhibition of cell division. After cell variation in the SOS response was originally investigated using snapshots of Beyond heterogeneity introduced by stochastic molecular events, DNA damage can have different effects on cells at different stages in the cell cycle or during cell aging. For example, certain types of alkylation lesions block transcription and progression of replication forks, and therefore are less detrimental to cells in a stationary phase. Finally, DNA damage and repair cause mutations and genome rearrangements which irreversibly diversify cells in a clonal population. Taken together, single-cell experiments and theoretical studies suggest that stochastic events and cell variation play an important role in the organization and activity of the repair machinery.3in vitro measurements due to their dependence on many other varying parameters: In the simplest view, the reaction kinetics are dictated by the enzymatic rates and the fluctuating concentrations of substrates and proteins in the cell. Importantly, the overall repair rate also includes the search time to locate a repair site, which itself depends on the protein mobility as well as the concentration, spatial distribution, and accessibility of the sites in the cell. These factors are further influenced by the local structure and global packaging of chromosomes. Substrate affinities and enzymatic rates may be enhanced by chemical modifications and cooperation with other repair factors that signal damage sites, or alternatively be repressed by competing enzymes in the case of overlapping, branching or conflicting repair pathways. We summarize quantitative fluorescence microscopy approaches that address these aspects, in particular the spatial distribution and movement of proteins in cells.Building quantitative models of DNA repair is a difficult task because the determining factors, namely the reaction kinetics of the repair proteins, cannot be directly predicted from Assembly of repair proteins into complexes provides a mechanism to increase their local concentration at damage sites and orchestrate a series of reactions, as for replication forks Transient repair activities in the absence of distinct foci can be probed by measuring protein mobility using Fluorescence Recovery After Photobleaching (FRAP); a method that monitors the replenishment of fluorescent proteins into a previously photobleached area inside single cells A. Rapid in vivo fluorescence correlation spectroscopy Alternatively, changes in protein mobilities can be measured on a confocal microscope using However, extracting quantitative information from FRAP and FCS curves requires precise knowledge of the laser focus size and geometry and works most reliably if the focus is placed inside a spatially homogenous sample, which limits the applicability to small bacteria whose dimensions are similar to the size of a diffraction-limited focus. Particular care has to be taken when analyzing heterogeneous populations of proteins due to ensemble averaging. The data fitting procedures with multiple free parameters and correction terms generally do not allow assigning a unique result for a mixture of diffusing populations or anomalous diffusion modes without making significant model assumptions 4Escherichia coli replication in minimal growth medium involves just two forks per cell, with only few or single copies of a protein type per fork The action of individual molecules is crucial for the function of the whole cell Fluorescence microscopy reaches single-molecule sensitivity by maximizing photon collection using high numerical aperture objectives, minimizing loss of signal with high-quality optical components, and reducing background noise through laser excitation tailored to the fluorophore spectrum and a small detection or excitation volume The advent of super-resolution fluorescence microscopy ex vivo, fixed cells, or slow processes in live cells due to the requirement to record several thousand frames of blinking molecules to reconstruct a single image. Advanced localization analysis algorithms detect higher densities of molecules per frame Resolution down to a few tens of nanometers is achieved by Stochastic Optical Reconstruction Microscopy (STORM) Beyond super-resolution microscopy of cellular structures, PALM can be extended to follow the movement of individual molecules in live cells Furthermore, PALM provides a direct way of counting molecules in cells 5E. coli cells using photoactivated single-molecule tracking In vitro single-molecule studies elucidated how Pol1 binds DNA primers in vivo reaction kinetics, calling for live-cell measurements to investigate the spatial organization and coordination of Pol1 and Ligase in reaction pathways.We recently reported imaging individual base-excision repair events in live Fusions of Pol1 and Ligase with photoactivatable fluorescent protein PAmCherry In vitro studies showed sliding on stretched DNA for a range of DNA-binding and repair proteins including p53 E. coli RNA polymerase appeared to encounter promoters by direct collision without significant sliding in vivo. For lac repressor tetramers, present at about five copies per cell, facilitated diffusion does occur in E. coli, confirmed by measuring single-molecule association rates on pairs of operator sites in close proximity Pol1 and Ligase tracks recapitulated the organization of the chromosome into ellipsoidal lobes Pol1 and Ligase tracks showed several examples of entire repair cycles including the diffusion trajectory to locate a lesion, transient binding for DNA repair, and continued diffusion 6in vivo photophysics. Promising strategies are under development for labeling intracellular proteins with bright synthetic photoswitchable fluorophores in vivo. Single-molecule F\u00f6rster Resonance Energy Transfer (FRET) provides information on intra- and intermolecular distances with millisecond temporal resolution in vivo, purified and labeled proteins were inserted into the cell membrane or internalized by microinjection Key advances to aid live-cell single-molecule imaging, localization microscopy, and molecule counting include the creation of more photostable and brighter fluorescent proteins as well as understanding and controlling their The methods and pioneering studies discussed here show that a molecular description of DNA repair as it occurs in single cells is within reach. The next challenge will be the integration of these observations to uncover the fundamental organization principles of DNA repair.The authors declare there are no conflicts of interest."}
+{"text": "Drosophila larval brain stem cells (neuroblasts) have emerged as an important model for the study of stem cell asymmetric division and the mechanisms underlying the transformation of neural stem cells into tumour-forming cancer stem cells. Each Drosophila neuroblast divides asymmetrically to produce a larger daughter cell that retains neuroblast identity, and a smaller daughter cell that is committed to undergo differentiation. Neuroblast self-renewal and differentiation are tightly controlled by a set of intrinsic factors that regulate ACD (asymmetric cell division). Any disruption of these two processes may deleteriously affect the delicate balance between neuroblast self-renewal and progenitor cell fate specification and differentiation, causing neuroblast overgrowth and ultimately lead to tumour formation in the fly. In this review, we discuss the mechanisms underlying Drosophila neural stem cell self-renewal and differentiation. Furthermore, we highlight emerging evidence in support of the notion that defects in ACD in mammalian systems, which may play significant roles in the series of pathogenic events leading to the development of brain cancers. In the presence of NICD, the corepressors associated with Su(H) binding are displaced with Mastermind and other gene coactivators, leading to activation and transcription of Notch target genes (reviewed in ). Given , E(spl) ,103.dpn activity does not recapitulate the neuronal hypoplasia seen in Notch pathway mutants  mutant neuroepithelial cells promotes brain tumour formation [lola mutants, newly born post-mitotic neurons can dedifferentiate and assume neural stem cell-like properties, leading to tumour formation in the optic lobe of the adult brain [Tumours can arise in optic lobes due to dysregulated signalling in neuroepithelial cells or dedifferentiation of neurons. Derepression of the Hippo pathway in ormation . After normation . In lolalt brain .Drosophila neuroblasts. With the identification of the type\u00a0II neuroblast lineages in Drosophila that are analogous to mammalian neural stem cell lineages, we anticipate that unravelling the molecular machinery controlling the self-renewal and differentiation of type\u00a0II neuroblasts and INPs will provide valuable insights relevant to our understanding of mammalian neural stem cell biology and the pathological processes involved in neural stem cell-dependent brain tumour formation and disease progression.Much of our basic knowledge about the molecular machinery controlling neural stem cell homoeostasis and ACD has been gained from Although the core components and the regulatory machinery needed for the segregation of asymmetric cell fate determinants in the neuroblast have been determined, it remains largely unresolved how their asymmetry translates into different cell fate acquisitions by their progeny. In type\u00a0II neuroblast lineages, the INPs are subject to progressive restrictions in their developmental potential, thus allowing them to undergo a limited number of cell division cycles to generate GMCs that give rise to post-mitotic neurons without disrupting the homeostasis of the neuroblast pool. The molecular gatekeepers and mechanisms upholding the developmental barrier, which under normal conditions prevent immature INPs from dedifferentiating and assuming neural stem cell-like properties, are only now slowly beginning to be identified. This area of research deserves special focus, as the developmental switch from neural stem cell to precursor cell identity is a likely key event in the pathogenic cascade responsible for the transformation of neural stem cells to tumourigenic cancer stem cells.Drosophila research in the coming years. Advances in lineage tracing and single-cell transcriptome analysis technologies can be readily adopted for use in this model organism, which will allow us to dissect the molecular identity of individual cells in the fly brain, as well as identify new Notch target genes involved in the complex interplay of genetic networks generating the cell type\u00a0diversity of the brain.The brain consists of a vast variety of neuronal cell types. How this cellular diversity is generated is one of the greatest unsolved mysteries found in the intersection between stem cell and developmental biology. It is clear that the Notch signalling pathway plays a pivotal role in this process. How Notch signalling asymmetries integrate into the spatiotemporal molecular code underlying neuronal cell diversity promise to be a fruitful avenue of Drosophila neuroblasts. The type\u00a0II neuroblast lineages are an excellent comparative model for the study of mammalian neural stem cell lineages due to the presence of analogous transit-amplifying cell populations, which may be regulated by evolutionarily highly conserved mechanisms. In the future, it is critical to further understand how INPs undergo maturation and how they are prevented from dedifferentiation. The neuroepithelial stem cells in the larval optic lobe will continue to serve as an alternative good model to study the transition from SCD to ACD as well as tumourigenesis. Besides, a recent Drosophila study revealed that mutations in l(3)mbt cause brain tumour induction due to soma-to-germline transformation of the l(3)mbt-deficient cells [Drosophila are likely to provide important insight into the pathological mechanisms underlying the generation of soma-to-germline transformation-induced tumours.A number of promising research directions are emerging in the study of nt cells . In humant cells ). StudyiDrosophila neuroblast self-renewal, cell fate specification and ACD regulation may be readily applicable and transferable for the unravelling of the mechanisms governing human neural stem cell biology and the pathological lesions underlying tumour formation derived from cancer stem cell populations. In this review, we present results from recent studies, which shows that the ACD apparatus and regulatory machinery required for polarity axis formation and control of ACD are operational in a number of neuroblastoma cell lines, and in human and rodent brain tumour specimens. Importantly, ACD seems to be compromised in brain tumours with a preponderance of SCD over ACD compared with wild-type tissue. This change in mode of cell division in cancer stem cells is accompanied with cell fate specification defects promoting a tumourigenic phenotype in the resulting progeny. Thus, these results encouragingly suggest that many of the molecular players and cellular processes identified in Drosophila neuroblasts are also actively involved in regulating human neural stem cell lineages.The genes encoding the core proteins of the ACD apparatus and the asymmetrically localized polarity proteins and cell fate specification determinants are highly conserved in evolution. Therefore the findings obtained from studying Drosophila neuroblast model, the genetic amenability of the fly and the availability of large RNAi stock collections targeting most genes in the fly genome are going to help advance and accelerate the discovery of genes regulating ACD. This will further our understanding of the regulatory networks controlling neural stem cell homoeostasis and help elucidate the pathological series of changes underlying the transformation of neural stem cells to tumour-forming neural cancer stem cells.From the perspective of mitigating hyper-proliferation in brain tumours it is quite an interesting and surprising observation that the treatment of neuroblastoma cells with a MYC inhibitor was shown to change the balance between ACD and SCD in favour of cells undergoing ACD . This ra"}
+{"text": "This paper presents a dark region detection and enhancement method with low computational complexity for low-cost imaging devices. Conventional contrast enhancement methods generally have an oversaturation problem while brightness of the dark region increases. To solve this problem, the proposed method first divides an input image into dark object and bright background regions using adaptively partitioned blocks. Next, the contrast stretching is performed only in the dark region. The major advantage of the proposed method is the minimized block artifacts using optimally partitioned blocks using fuzzy logic and a refining step to accurately detect boundaries between two regions. Experimental results show that the proposed method can efficiently enhance the contrast of backlit images without the oversaturation problem. Because of low computational complexity, the proposed method can be applied to enhance very low light-level video sequences for video surveillance systems. Recent advances in digital image processing systems enable users to easily acquire high quality images using compact, inexpensive digital cameras. However, a limited dynamic range is still a bottleneck of the camera technology  is a global contrast enhancement method for solving the unbalanced illumination problem in the image  clustering method that estimates the distribution of the brightness in the image to adaptively select the optimal threshold value  color space, and performs contrast enhancement for only V channel, which contains brightness information. To evaluate the effectiveness of the proposed method, this paper compared the proposed method with gain-controllable clipped histogram equalization (GC-CHE)  is computed asTable The gain-controlled clipped histogram equalization (GC-CHE) method (Kim and Paik In order to demonstrate the performance of the proposed method, we first used subjective comparison as shown in Fig. This paper has presented a method to enhance the contrast of two-mode brightness image. Conventional contrast enhancement methods have over-saturation and color distortion problems. To solve these problems, the proposed method divides the image into dark and background regions using adaptively partitioned blocks by two optimal threshold values computed by fuzzy C-means clustering in the V channel of the HSV color space. The proposed contrast stretching process is performed only in the detected dark region. The major advantage of the proposed method is the minimized block artifacts due to adaptively partitioning the image according to the optimal threshold and the refining step to detect the dark regions. The proposed method automatically segments backlit region and the background region. It does not need manual seed region selection for segmentation and has low segmentation complexity than heavy segmentation methods such as graph cut-based method. Experimental results showed that the proposed method can better enhance the contrast than existing methods in the sense of both minimizing over-saturation in the bright background region and preserving details in the dark region."}
+{"text": "A 7-lb, 39-week-old newborn was born to a 45-year-old G14P8238 woman by cesarean delivery for prolonged rupture of membranes. The patient presented with desquamation of the palm and a leathery appearance of the skin to the right dorsal hand and circumferential forearm with frank ischemia to the thumb.What are the causes of neonatal compartment syndrome?What factors  correlate with neonatal compartment syndrome?What are the signs and symptoms of neonatal compartment syndrome?What options are available for the treatment of neonatal compartment syndrome?,The cause of neonatal compartment syndrome is often unclear. The literature differentiates the causes for compartment syndrome as either extrinsic or intrinsic. Extrinsic causes include oligohydramnios, umbilical loops, or amniotic bands. Intrinsic causes include arterial embolus and neonatal hypercoagulability.1In a case series of 24 patients published by Ragland et al,,In a majority of reported cases of neonatal compartment syndrome, some degree of skin desquamation was noted on the arm as a heralding sign.1,6Treatment options for these patients are often limited and are dependent on the degree of ischemia. A decision to emergently go to the operating room is often clouded by the unclear clinical picture. The risk of anesthesia in newborns is significant, with neonates less than 30 days old having a significantly higher mortality rate than older children.4Amputation in the neonate should be carefully planned. Important goals when considering amputation include preservation of limb length and maintaining good soft-tissue coverage over the bony portions of the extremity. Adequate length and soft-tissue durability are necessary for potential future prosthesis fitting and use. If the neonate undergoes amputation too early, he or she may not have sufficient soft-tissue coverage, which can limit the ability to preserve adequate length. This was an important consideration in our patient who will likely undergo delayed amputation in hopes of preserving soft-tissue coverage and limb length.To some extent, neonatal compartment syndrome continues to remain an enigma. Because of the low incidence and limited discussion in the literature, there is not a clear understanding of causation for the event or correlating factors. This syndrome displays a varied clinical presentation and therefore treatment plans for each neonate should be individualized."}
+{"text": "To provide an educational update on structural imaging appearances of neuroendocrine tumours (NET), in the age of molecular imaging.PET/CT with Ga-68 DOTA-TATE and F-18 fluorodeoxyglucose (FDG) is providing new understanding of neuroendocrine tumours including patterns and heterogeneity of disease. This is also providing new insights of structural imaging findings including CT and MRI. It is also important to be aware of the limitations of PET/CT imaging, and we outline indications where structural imaging has a high impact for patient management. These changing paradigms are translating to revised imaging protocols in our institution that are enabling personalised medicine with appropriate selection of management for an individual patient. It is also allowing us to understand the structural imaging appearances of heterogeneity within the same tumour type. A range of new targeted therapies including peptide receptor radionuclide therapy (PRRT) are now available to treat patients with non-resectable metastatic NET. New patterns of response are emerging which are important to recognise, including cystic necrosis which may initially masquerade as progressive disease due to enlargement.We have a large population of patients with neuroendocrine tumours at Peter MacCallum Cancer Institute, providing wide experience of this spectrum of imaging findings across various subtypes of NET. We present a pictorial review of our experience."}
+{"text": "Iron is required in a variety of essential processes in the body. In this review, we focus on iron transport in the brain and the role of the divalent metal transporter 1 (DMT1) vital for iron uptake in most cells. DMT1 locates to cellular membranes and endosomal membranes, where it is a key player in non-transferrin bound iron uptake and transferrin-bound iron uptake, respectively. Four isoforms of DMT1 exist, and their respective characteristics involve a complex cell-specific regulatory machinery all controlling iron transport across these membranes. This complexity reflects the fine balance required in iron homeostasis, as this metal is indispensable in many cell functions but highly toxic when appearing in excess. DMT1 expression in the brain is prominent in neurons. Of serious dispute is the expression of DMT1 in non-neuronal cells. Recent studies imply that DMT1 does exist in endosomes of brain capillary endothelial cells denoting the blood-brain barrier. This supports existing evidence that iron uptake at the BBB occurs by means of transferrin-receptor mediated endocytosis followed by detachment of iron from transferrin inside the acidic compartment of the endosome and DMT1-mediated pumping iron into the cytosol. The subsequent iron transport across the abluminal membrane into the brain likely occurs by ferroportin. The virtual absent expression of transferrin receptors and DMT1 in glial cells, i.e., astrocytes, microglia and oligodendrocytes, suggest that the steady state uptake of iron in glia is much lower than in neurons and/or other mechanisms for iron uptake in these cell types prevail. However, in conditions with excess iron uptake from the gut or parenteral iron infusion, the iron-binding capacity of transferrin can be exceeded leaving to pathological deposition of iron widely in the body, a clinical condition called hemochromatosis  It facilitates iron uptake at the apical cell membrane in for instance duodenal enterocytes , and Ni2+, VO2+, Pb2+ (group 2), but with decreasing efficiency, and group 1 being markedly more effectively transported than group 2. Zn2+ is not transported by DMT1  family. This highly conserved protein family consists of a varied group of membrane-bound divalent cation transporters  and TMD6 are crucial for Nramp symport of metal ions and H+ ions  mouse and in the Belgrade rat. Both of these rodents have a spontaneous G185R missense mutation in DMT1 located in the conserved TMD4 region , Belgrade rats absorb some intestinal iron despite defects in DMT1 function. A murine DMT1 knockout model shows a more severe phenotype than seen in the animals with the G185R missense mutation .The gene expression of the DMT1 in the brain presumably solely relies on the 1B isoform of the N-terminal that is expressed together with both IRE isoforms (+/\u2212 IRE) in the mouse brain  Receptor-mediated transcytosis leading to release of holo-transferrin inside the brain interstitium; and (2) Receptor-mediated endocytosis of transferrin followed by reduction of iron inside endosomes and retro-endocytosis of apo-transferrin to the luminal surface. Fe59Fe-125I] transferrin leads to formation of non-transferrin-bound 59Fe in the brain, which also favors hypothesis I on iron being detached from transferrin within the brain endothelial cells , there is no evident quantitative transport of transferrin through the BBB  in an effort to explain the apparent absences of DMT1 and ferroportin, it was hypothesized that iron would be transported through the brain endothelial cells without the involvement of an endosomal escape mediated by DMT1 with little or no iron being pumped out of the trafficking vesicles into the cytosol (Moos et al., s Figure  targetins Figure . Gene exs Figure , which cs Figure . On the s Figure . Therefos Figure . Furthers Figure . We belis Figure . In supps Figure . ProbablA recent study suggests that brain endothelial cells should be regarded as more than a simple conduit where iron is merely transported through, but as a reservoir of great importance in the regulation of brain iron homeostasis via signaling from the brain interior to regulate the trafficking of the transferrin receptors cycling (Simpson et al., Whether circulatory iron excess leads to iron deposition in the brain in hemochromatosis is site of dispute. Recent studies imply that hereditary hemochromatosis can affect the handling and acquisition of iron with neurons and glia (Bartzokis et al., In contrast to brain capillaries, neurons upregulate their expression of the transferrin receptor and transferrin binding in iron deficiency (Moos et al., in vitro (Pelizzoni et al., in vivo. Concerning a role for DMT1 for non-transferrin bound uptake in vivo the evidence is unclear. Probably, such uptake would require the expression of the 1A isoform in the cellular membrane of neurons but this is not the case (Pelizzoni et al., Neurons take up non-transferrin bound iron The role of DMT1 for neuronal iron handling in pathological studies is vaguely studied, but some interesting data have occurred. Mice mutated in DMT1 better overcome the toxic insult than control littermates in an experimental model for Parkinson\u2019s disease, probably because the tendency towards iron accumulation is reduced (Salazar et al., in vitro but the in vivo evidence is more scarce (Burdo et al., in vivo but clearly in vitro and in primary rat astrocytes (Qian et al., in vivo and in vitro conditions could possibly be attributed to the much higher proliferating state of cultured cells in vitro.There is solid evidence for DMT1 expression in astrocytes Western blot analyses of DMT1 purified from neurons and astrocytes show that the molecular mass of DMT1 in the two cell types differs (Pelizzoni et al., Cultured astrocytes seem to harbor distinct routes through which NTBI enters the cells. One route mediates the uptake of ferrous iron and depends on DMT1 and ascorbate (Lane et al., The importance of DMT1 for cellular iron uptake is evident, but many questions regarding its regulation remain. Insight into this highly complex regulation will increase the understanding of cellular iron uptake among neurons and glia and shed light on the treatment of diseases with altered iron metabolism. Vital questions on the understanding of iron transport at the BBB not only includes the role of DMT1, but also the roles of proteins like Steap and ferroportin for iron transport. Future studies should address these proteins and their roles for iron transport in experimental models of the BBB.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Genes work in concert as a system, not as independent entities, to mediate disease states. There has been considerable interest in understanding variations in molecular signatures between normal and disease states. The selective-voting convex-hull ensemble procedure accommodates molecular heterogeneity within and between groups and allows retrieval of sample-specific sets and investigation of variations in individual networks relevant to personalized medicine. The wor1 was applied to data from the differentially expressed genes. A general idea of the algorithm including levels of parallelism is given in Figure Normalized RNA-seq data for 208 samples  from TCGA breast carcinoma data set were downloaded and analyzed by the edgeR package, which identified 2,882 differentially expressed genes with at least a 2-fold difference between tumor and normal samples and at 1% false discovery rate. The convex-hull voting methodA parallel-for loop is used within the R code allowing multiple processors within a node to concurrently perform the voting calculations of different sample pairs within one iteration. Then multiple jobs are submitted to perform the randomized iterations. This turns a computationally intensive problem into a data intensive problem since each iteration produces just over 6 GBs of data.The final runtime of one iteration of the large dataset was just under 34 hours and up to 32 iterations can run concurrently. The entire run of 100 iterations using this large data set took less than a week time.Future work will involve the parallelization of the entire computationally and data intensive steps in a way that reduces the complexity of job submission and scalability of the entire job. Computing paradigms such as Hadoop are being explored for this task."}
+{"text": "Spontaneous activity patterns propagate through many parts of the developing nervous system and shape the wiring of emerging circuits. Prior to vision, waves of activity originating in the retina propagate through the lateral geniculate nucleus (LGN) of the thalamus to primary visual cortex (V1). Retinal waves have been shown to instruct the wiring of ganglion cell axons in LGN and of thalamocortical axons in V1 via correlation-based plasticity rules. Across species, retinal waves mature in three stereotypic stages (I\u2013III), in which distinct circuit mechanisms give rise to unique activity patterns that serve specific functions in visual system refinement. Here, I review insights into the patterns, mechanisms, and functions of stage III retinal waves, which rely on glutamatergic signaling. As glutamatergic waves spread across the retina, neighboring ganglion cells with opposite light responses (ON vs. OFF) are activated sequentially. Recent studies identified lateral excitatory networks in the inner retina that generate and propagate glutamatergic waves, and vertical inhibitory networks that desynchronize the activity of ON and OFF cells in the wavefront. Stage III wave activity patterns may help segregate axons of ON and OFF ganglion cells in the LGN, and could contribute to the emergence of orientation selectivity in V1. Retinal waves have been observed in many species including primates . They are preceded by cholinergic waves  and localized bursts of activity mediated by gap-junctional coupling among nearby ganglion cells , individual stage III waves encompass smaller areas of the retina  and lateral geniculate nucleus (LGN), two major targets of ganglion cell axons  mice  or cones (12 types). Cone bipolar cells can further be divided into those that respond to light increments  and those that respond to light decrements . Pharmacological blockade of either iGluRs or gap junctions is sufficient to block stage III activity in ganglion cells and bipolar cells . Simultaneous recordings of bipolar cell voltage and excitatory input to ganglion cells, indicate that OFF cone bipolar cells release glutamate as their voltage returns to baseline from the wave-associated hyperpolarization . DL-threo-beta-benzyloxyaspartate (TBOA), an antagonist of EAATs, synchronizes excitatory input to ON and OFF ganglion cells, indicating that EAAT-mediated uptake limits the spread of glutamate and is critical for patterning stage III waves  and in V1.TeNT mice). In TeNT mice, ON cone bipolar and ON ganglion cells are connected by fewer synapses at maturity  and by a Career Development Award from the Research to Prevent Blindness Foundation.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "An emerging issue in neuroimaging is to assess the diagnostic reliability of PET and its application in clinical practice. We aimed at assessing the accuracy of brain FDG-PET in discriminating patients with MCI due to Alzheimer's disease and healthy controls. Sixty-two patients with amnestic MCI and 109 healthy subjects recruited in five centers of the European AD Consortium were enrolled. Group analysis was performed by SPM8 to confirm metabolic differences. Discriminant analyses were then carried out using the mean FDG uptake values normalized to the cerebellum computed in 45 anatomical volumes of interest (VOIs) in each hemisphere (90 VOIs) as defined in the Automated Anatomical Labeling (AAL) Atlas and on 12 meta-VOIs, bilaterally, obtained merging VOIs with similar anatomo-functional characteristics. Further, asymmetry indexes were calculated for both datasets. Accuracy of discrimination by a Support Vector Machine (SVM) and the AAL VOIs was tested against a validated method (PALZ). At the voxel level SMP8 showed a relative hypometabolism in the bilateral precuneus, and posterior cingulate, temporo-parietal and frontal cortices. Discriminant analysis classified subjects with an accuracy ranging between .91 and .83 as a function of data organization. The best values were obtained from a subset of 6 meta-VOIs plus 6 asymmetry values reaching an area under the ROC curve of .947, significantly larger than the one obtained by the PALZ score. High accuracy in discriminating MCI converters from healthy controls was reached by a non-linear classifier based on SVM applied on predefined anatomo-functional regions and inter-hemispheric asymmetries. Data pre-processing was automated and simplified by an in-house created Matlab-based script encouraging its routine clinical use. Further validation toward nonconverter MCI patients with adequately long follow-up is needed. \u202218F-FDG-PET/CT analysis of metabolic differences between MCI converting to AD and HC\u2022Large and very well controlled cohorts from EADC-Consortium were investigated.\u2022Data were analyzed by a friendly-to-use Matlab-based script and Support Vector Machine.\u2022Excellent discrimination between MCI and HC \u2022Highest accuracy reported so far in MCI and promising implementation in clinical routine The metrics chosen to evaluate hypometabolism may carry variability in accuracy as high as the difference in accuracy between different biomarkers . The comRecently, using various automated image-based classification methods, efforts have been made to discriminate AD and MCI patients from healthy controls by MRI , FDG-PETMost of these studies were conducted in large cohorts of patients from the Alzheimer's Disease Neuromaging Initiative (ADNI) database and reached a statistical accuracy in discriminating AD patients from controls of 93% when using three biomarkers   and highIn fact, although effective disease-modifying drugs are still in the pipeline, there is no doubt that these should be used as earlier as possible in the natural history of the disease since a critical issue in MCI is the possible conversion to AD and biomarkers able to predict this event with high accuracy would allow for all possible therapeutic intervention to be immediately implemented. As a consequence, the need of an early diagnosis in faint symptomatic patients is mandatory and even in the era of amyloid-PET, the demonstration of synaptic dysfunction at specific brain sites maintains a high positive predictive value . In the In the present study we aimed at evaluating the accuracy of a method implementing automated Volume of interest (VOI)-based segmentation and Support Vector Machine in discriminating a large sample of patients with MCI who later converted to AD from healthy controls. All clinical-neuropsychological diagnosis and FDG-PET have been collected in five centers of the European Alzheimer's Disease Consortium (EADC). The accuracy of the present method was evaluated by comparison with an already validated discriminating technique  by the a22.1Patient and control selection and definition as well as PET technical details in the five EADC centers have been reported in previous papers . Local e2.22O template  in each hemisphere (90 VOIs) as defined by the AAL Atlas .The dataset to be analyzed was obtained by an in-house created Matlab-based script that automatically processed mean FDG uptake signal intensity from each of the 90 AAL VOIs. The mean signal intensities computed for each VOI were normalized within each subject to the average intensity of the cerebellar VOIs included in AAL as defined by nvvoi,x is the normalized FDG value relevant to the right (r) or left (l) hemisphere and abs stands for the absolute value.Data from control subjects were first analyzed by applying a General Linear Model (GLM) to evaluate the effect of age and gender and consequently correct FDG-PET analyses accordingly. This analysis was restricted to controls in order to separate possible physiological weakening of metabolic activity with age (and gender differences) from the effect of pathological conditions whose probability increases with age. Discriminant analysis was performed by a non-linear classifier based on the Support Vector Machine (SVM) method with Radial Basis Functions . The proThe two basic datasets were made up by the normalized values relevant to the 90  AAL regions and by the normalized values relevant to the 24  anatomo-functional homogeneous meta-VOIs. Two other datasets were obtained by adding hemispheric values to each of the previous ones: 90 VOIs plus 45 asymmetry values for the AAL regions  and 24 VOIs plus 12 asymmetry values for the meta-VOIs. This last dataset  was then the starting point to explore the accuracy of a smaller set of variables by the application of a step-wise backward selection procedure .http://www.pmod.com) was used for automatic, voxel-based evaluation of scans with the \u2018Alzheimer\u2019 option computing the \u2018Probability of ALZheimer\u2019 or PALZ score. The PALZ score  we evaluated accuracy, sensitivity, specificity, positive and negative likelihood ratios, odds ratio and the area under the Receiver Operating Characteristic (ROC) curve (AUC). All these parameters were evaluated by a cross-validation procedure which entails the separation between the model fitting and testing to enable generalization of results and to prevent overfitting (the adaptation to features peculiar only to the study sample). Cross-validation was implemented by the \u2018leave-one-out\u2019 technique in which each subject was classified by a model fitted to all remaining ones, so creating a virtually-independent testing set with the same size of the original sample. As a by-product of the SVM training we could calculate the ranking for each region, that is a rough measure of how relevant is a particular feature to the outcome of the classifier.All parameters measuring discrimination capability were estimated with their 95% confidence intervals (CIs) which were computed according to the characteristics of each parameter. The Wald interval with exact binomial probabilities was applied to sensitivity, specificity and accuracy ; CIs forDiscriminant analysis by SVM and following ROC curve analysis and accuracy measurements were performed by using the Statistics Toolbox of Matlab R2014a .3In the preliminary comparison of whole brain FDG values at the group level using SPM8, relative hypometabolism was found in the bilateral precuneus, and posterior cingulate, temporo-parietal and frontal cortices, as expected  and for the partition into 24 meta-VOIs . No significant effect was found for age or for the age\u00a0\u00d7\u00a0region interaction. Normalized regional values were accordingly corrected for the effect of gender.GLM analysis of normalized regional FDG values in the control subjects as a function of age and gender showed a significant effect of region, and region\u00a0\u00d7\u00a0gender interaction for both the partition into 90 AAL regions  and low negative likelihood ratios (the ratio between the probabilities of negative test in patients with respect to controls) and by the high diagnostic odds ratios (the ratio between the odds of positivity in patients with respect to controls). The values of these parameters are reported in The same measures  are reported for the classification based on the PALZ-score. We first considered the classification based on the standard fixed threshold  which yielded a high specificity (.92) but a relatively low sensitivity for MCI-converter patients. A different threshold (8116) drawn from the point on the ROC curve closer to the optimal one (sensitivity\u00a0=\u00a0specificity\u00a0=\u00a01) yielded a higher sensitivity (.77) but lower specificity  are showed in 4Our data confirm and strengthen not only the value of FDG PET analysis as a valuable tool in the diagnostic process for AD but also the capability of automated classifiers to accurately identify the disease at the stage of MCI, in our sample on average 2\u00a0years before conversion.In a clinical setting in which neuroimaging is considered to be a supportive feature, effective tools for automatic identification of AD-related hypometabolic patterns at the individual level are needed. In this respect, the relevance of automated image-based classifications in clinical routine increases if the implemented method will overcome the accuracy of 90%, reached by the consensus diagnostic criteria for AD as validated against neuropathology , which iThe proposed method shows an accuracy of 91% in discriminating MCI-converters from healthy controls with an area under the ROC curve of almost 95% being superior to previous investigations in MCI patients applying similar techniques based on unimodal biomarkers and reporting sensitivity and specificity slightly higher than 80% .In this respect the accuracy of our analyses is comparable to those of investigations seeking to classify AD-dementia and healthy controls , even whWe compared our results with the ones obtained by the PALZ-score, a procedure which was applied to discriminate AD patients from healthy elders with high sensitivity and specificity, both around 93% according to Besides the high accuracy achieved by our classification method, its potential interest in everyday clinical routine lies in the implementation of a readily available anatomical atlas and in the use of an in-house Matlab-based script able to assess and sort fully automatically in a few minutes the uptake values in more than hundred segmented VOIs and meta-VOIs making them available for further statistical analyses. The processing time and the use of the script are easier than similar VOI and meta-VOI analyses in which computation time is longer and automation procedures are more complex .The Parahippocampus Gyrus/Amygdala/Hippocampus/Insula complex was found to be among the most valuable 6 meta-VOIs in discriminating MCI-converters from controls both for its uptake values and for asymmetry index. This replicates the findings of Gray et al. who found by SVM, in AD and healthy control cohorts, the right hippocampus and amygdala to be among the few regions showing changes in cross-sectional and longitudinal data, the amygdala being the only region accounting for the difference between stable and converting MCI . The impOn the other hand, although MCI/AD diagnostic criteria usually point to temporo-parietal and posterior cingulate cortex hypometabolisms we also found the frontal and orbitofrontal cortices among the predictors accounting for the highest accuracy both for uptake and asymmetry values. These regions involved in episodic memory encoding and retrieval have been previously described to be hypometabolic in MCI converters in several studies  and corrThe presence of the Postcentral Gyrus/Precentral Gyrus/Supplementary Motor Area complex among the most discriminating meta-VOIs underscores an interesting methodological issue. These regions showed relatively increased uptake at the group level as compared to controls (results not shown), likely due to the semi-quantitative nature of the analyses, that is, in a context in which large portions of the brain have a relatively decreased uptake, preserved regions show a proportionally higher uptake. The higher the difference between affected and spared regions, the higher the probability of neurodegeneration. This is consistent with the study by Chen and coworkers analyzing changes in FDG uptake in MCI and AD patients . LookingThe evaluation of asymmetries added value to the analyses and fits with the clinical experience in image reading that often highlights differential hemispheric uptake at the very early stages of the disease while bilateral and more symmetric involvement is rather a feature of overt stages . On the A rather unexpected result of this study is the lack of a statistically significant effect of age on brain metabolism. The effect of aging on brain blood flow and metabolism is indeed a well known phenomenon, especially in the frontal regions . HoweverA limitation of the study is that MCI-converters were discriminated only with respect to healthy controls. Further studies are needed to test if the capability of the used automatic classifier to identify MCI patients about 2\u00a0years before conversion will also apply to cohorts of MCI-non-converting to AD or to patients bearer of other confounding pathological conditions. In this respect to properly select the latter groups for statistical analyses a follow-up time as long as 7\u00a0years is required  and thesIn conclusion, in this study we reached a particularly high accuracy in discriminating MCI-converters from healthy controls thanks to the application of a non-linear classifier based on SVM preceded by individuation of anatomo-functional meta-VOIs, normalization to cerebellum and evaluation of inter-hemispheric asymmetries. It has to be underscored that this quite complex and time-consuming data pre-processing was automated and simplified by the in-house created Matlab-based script encouraging its implementation in clinical routine to assist in the diagnosis of AD in aMCI possibly along with MRI and CSF biomarkers.Even in the era of amyloid PET imaging that has been licensed by regulatory Agencies to exclude rather than to confirm AD, FDG-PET maintains a role not only as a marker of disease evolution but also as an important diagnostic biomarker in the early stages of the disease.None of the authors declares any conflict of interest."}
+{"text": "The inferior fronto-occipital fasciculus (IFOF) is historically described as the longest associative bundle in the human brain and it connects various parts of the occipital cortex, temporo-basal area and the superior parietal lobule to the frontal lobe through the external/extreme capsule complex. The exact functional role and the detailed anatomical definition of the IFOF are still under debate within the scientific community. In this study we present a fiber tracking dissection of the right and left IFOF by using a q-ball residual-bootstrap reconstruction of High-Angular Resolution Diffusion Imaging (HARDI) data sets in 20 healthy subjects. By defining a single seed region of interest on the coronal fractional anisotropy (FA) color map of each subject, we investigated all the pathways connecting the parietal, occipital and posterior temporal cortices to the frontal lobe through the external/extreme capsule. In line with recent post-mortem dissection studies we found more extended anterior-posterior association connections than the \u201cclassical\u201d fronto-occipital representation of the IFOF. In particular the pathways we evidenced showed: a) diffuse projections in the frontal lobe, b) fronto-parietal lobes connections trough the external capsule in almost all the subjects and c) widespread connections in the posterior regions. Our study represents the first consistent in vivo demonstration across a large group of individuals of these novel anterior and posterior terminations of the IFOF detailed described only by post-mortem anatomical dissection. Furthermore our work establishes the feasibility of consistent in vivo mapping of this architecture with independent in vivo methodologies. In conclusion q-ball tractography dissection supports a more complex definition of IFOF, which includes several subcomponents likely underlying specific function. Human cognition is supported by large-scale cortical and subcortical networks subserved by bundles of axons, connecting cortical and subcortical neurons. In the literature, white matter fibers are usually classified as commissural (between hemispheres), projection  or association fibers . Particularly the latter are subdivided into short and long association fibers.The inferior fronto-occipital fasciculus (IFOF) is the longest associative bundle and it connects various parts of the occipital cortex, temporo-basal area and the superior parietal lobule to the frontal lobe Post mortem anatomical dissection and in vivo diffusion MRI fiber tractography are current techniques that have enabled the segmentation of specific white matter fiber bundles and have been used to study the main course of the IFOF at the level of the insula and the temporal lobe Even though fiber tractography with the Diffusion Tensor Imaging (DTI) model has strongly contributed to our knowledge about fiber pathways, it suffers from several serious shortcomings in resolving extent, origin and cortical termination The main goal of the present work was the fiber tracking dissection of the anatomy of the IFOF by using a q-ball residual-bootstrap reconstruction of a HARDI data-set in 20 healthy subjects, in order to 1) extend the in vivo diffusion MRI studies with a model suitable of overcoming the well-known DTI limitations, 2) evaluate a new tractography approach for the definition of the IFOF based on a simple single-subject region of interest (ROI) drawing.Research was performed in compliance to the Code of Ethics of the World Medical Association (Declaration of Helsinki) and the standards established by our Institution. The Committee on Human Research at the University of California, San Francisco (UCSF) approved the study protocol. Written informed consent was obtained from all participants.The study cohort consisted of twenty subjects . Handedness was confirmed by the Edinburgh Handedness Inventory scale. Fifteen patients out of twenty resulted right-handed, two left-handed and three with no dominance. All subjects had no history of psychiatric, neurological or cognitive impairment and provided written informed consent to participate in this study.2 in plane resolution) and HARDI  datasets were acquired.Subjects were scanned with a Signa 3T General Electric Medical Systems scanner. 3D high-resolution T1-weighted IRSPGR  atlas using FSL linear and non-linear transformations (FMRIB\u2019s FLIRT and FNIRT registration tools).HARDI datasets were corrected for movement and eddy-current distortions using FMRIB Software Library (FSL). The original gradient table was consequently rotated 2. The signal was fit to spherical harmonics of even orders up to 4 and orientation distribution functions (ODFs) with constant solid angle factor were estimated from the data using the methods of Tristan-Vega et al. 3 seed points per voxel uniformly distributed across the three dimensions.A single plane ROI was defined on the coronal FA color map of each subject. The selected coronal plane was the one passing through the anterior commissure, on which it is easy to select the anterior-posterior (green coded) tracks of the left external/extreme capsule. At this level the coherence and anisotropy of the expected bundles is very high and easily identified. In each subject the seed ROI was defined in order to fully cover this region and a couple of voxels at the margin. The average dimension of the seed ROIs was around 15\u00d715 mmhttp://trackvis.org). In order to select the posterior termination of the IFOF, a coronal plane perpendicular to the ac-pc line was applied at the level where the parieto-occipital and calcarine sulci meet. A careful inspection of results was performed by a neuroradiologist with 8 years experience (EC): firstly we excluded the presence of tracking artifact such as streamlines creating loops or passing through several GM regions; secondly we excluded that susceptibility distortions may have affected the outcome of the tracking Tracking was regulated using an FA threshold\u200a=\u200a0.15 and max angle\u200a=\u200a60\u00b0 as stopping parameters in the algorithm Cortical gray matter segmentation and parcellation was performed with Freesurfer (Desikan-Kyliany Atlas) in order to obtain volumes of interest (VOIs) in the T1-weighted anatomical scans native-space 3 resolution MNI atlas was segmented and parcellated analogously to what was done for the T1-weighted images and used to classify the different subcomponents of the IFOF on a group basis.Streamline density maps were computed in the subjects\u2019 native space and thresholded to obtain binary masks containing all voxels that were visited by at least one streamline in the residual bootstrap tractography. These masks were spatially normalized to the MNI space using the linear and non-linear transformations computed for the co-registration of the FA maps to the FSL MNI atlas. The masks of the different subjects in the MNI space corresponding to the various tracks or sub-components were summed and normalized to obtain percentage probabilistic maps. A 3D rendering of the different tracks was obtained selecting an inferior threshold of 20% on the probabilistic maps using the FSL viewer. The 2\u00d72\u00d72 mmThe IFOF was successfully identified using q-ball in all the subjects. The resulted tracks were more extended than the \u201cclassical\u201d fronto-occipital representation of the IFOF . For claFibers we identified spread towards different portion of the frontal region when entering the frontal lobe \u20135. BasedAt the level of the external/extreme capsule IFOFq fibers were gathered together. As they entered the temporal stem they spread and project to lingual, pericalcarine and lateral occipital cortices , cuneus . IFOF function and anatomy are still matter of debate. Recent findings have raised questions about the detailed cortical connectivity of the IFOF. Direct cortical stimulation results in brain tumor patients suggested IFOF might contribute to language functions and might represent a crucial pathway of the ventral semantic stream Since last century (Dejerine 1895) anatomists have formulated a classical definition for the IFOF as an association pathway between ventro-occipital and orbitofrontal regions. In vivo tractography (DTI) results reported in DTI atlases of human brain white matter pathways, have corroborated this interpretation For the first time we confirmed in vivo all the previously mentioned novel post-mortem results in a group of 20 healthy subjects with an up to date tractography algoritm such as q-ball. The anatomical dissection approach described by Martino et al. in 14 subjects was able to identify IFOF terminations both within and outside the occipital lobes. Our results are consistent with their anatomical description. In all our subjects there were occipital terminations in both the hemispheres especially towards pericalcarine and lateral occipital cortex. In contrast with Martino\u2019s et al. manuscript there were also terminations towards the lingual gyrus, which they reported being reached by only optic radiation terminations. Due to their proximity and parallel course IFOF and optic radiation In line with Martino et al. findings there were posteriorly extra occipital terminations towards temporal and parietal lobes The second parietal area found to be highly connected (100%) to frontal cortex through the IFOFq was the superior parietal lobe. In their paper Martino et al. refer to this connection as \u201cthe dorsal fibers of the IFOF that course in the superior portion of the sagittal stratum, along the superior portion of the lateral surface of the atrium, terminate into the convexity surface of the superior parietal lobe\u201d. We delineated this portion of the IFOFq in all the subjects. This connection has an inferior to superior path and departs from the rest of the IFOFq, which instead runs caudally around the atrium of the lateral ventricle. Interestingly the superior parietal gyrus through the IFOFq appears to be highly connected with the premotor and prefrontal areas implicated in movement planning -B. Our fOur results provided also new insights into the frontal lobe areas reached by IFOFq termination. The anterior organization of the IFOFq appears to be far more complex than connections that reach just the inferior frontal gyrus and the orbitofrontal cortex. In most of the subjects (19 out of 20) a wide bilateral \u201cfan shape\u201d organization of the IFOFq was found to be directed towards premotor and prefrontal area of the superior frontal and middle frontal gyri . The latter terminations showed larger inter-subjects variability. Therefore, by averaging and applying a threshold to the results on the MNI space, these terminations were not particularly evident on the 3D rendering  and 2.By combining q-ball tractography and Freesurfer parcellation we provided on a large group of individuals a consistent demonstration of Sarubbo et al. post mortem findings The previously mentioned paper on spherical deconvolution dissection of fronto-occipital connections External/extreme capsule ROI based dissection approach provided a delineation of the inferior fronto-occipital fasciculus very consistent across subjects. This methodology is efficient and easily applied. This could be really important for example in brain tumor application, where the brain anatomy distortions complicate the fiber tracking results. The anterior commissure is clearly identifiable on the sagittal color map. The coronal plane passing through it, contain the external/extreme portion of the IFOFq. At this level all the IFOFq pathways gather together and pass necessary to this \u201cgate\u201d.th order spherical harmonic in fitting data because the residual bootstrap methodology is more accurate with more degrees of freedom th order harmonics strike a good balance between fitting the data well and preserving degrees of freedom. Although very appealing, we did not use CSD to find tracking directions because the computational times required make the combination of CSD with residual bootstrap tracking impractical.We are aware that diffusion modeling and fiber tracking methodology are techniques quickly developing. Therefore we believe that as novel methods become available an in-vivo delineation of the IFOF more precise and accurate will likely be possible, especially in single subjects. Within tracking methods available nowadays, we chose q-ball residual-bootstrap fiber tracking, mainly because it has been shown to perform better than either deterministic or probabilistic tracking The choice of stopping parameters (FA threshold of. 15 and a 60\u00b0 angle) was based on our experience with our tracking methodology in pre-surgical planning in brain tumors on routinely acquired HARDI protocol There is no convincing in vivo data published to date demonstrating both frontal and posterior termination of the IFOF. We have described an anatomy of the IFOF based on in vivo dissection by q-ball that presents a more complex structure compared to previous results with other diffusion tractography algorithms and ROI definitions. Our results suggest that the IFOF is an associative pathway that does not exclusively connect the inferior ventral portion of the inferior frontal and orbitofrontal region with the occipital lobe. In the frontal lobes our results show a wider spread of projections over the prefrontal cortex, both in the middle and in the superior frontal gyrus. Posteriorly the IFOF appears to be connected not only to occipital and occipital/temporal regions but connections toward the inferior parietal  were consistently found in all subjects. This complex anatomy of the IFOF revealed by post mortem and confirmed by q-ball tractography is compatible with a complex multifunctional role of this pathway. Other techniques such as functional imaging, magnetoencephalography or subcortical direct stimulation during awake surgery are possible candidates to further validate the existence of a more complex anatomy and functionality of the IFOF."}
+{"text": "The ability to inhibit the activity of the MAPK pathway in BRAF-mutant melanoma has led to profound improvements in clinical outcomes for patients with advanced BRAFV600-mutant melanoma. Notably the additional of a MEK-inhibitor to a type-I BRAF inhibitor results in greater inhibition of MAPK-signaling resulting in improved partial and complete response rates, and prolongation of progression free and overall survival without increasing toxicity in normal cells. Three phase 3 clinical trials have shown highly consistent clinical outcomes defining the combination of a BRAF and MEK-inhibitor as a new standard of care for advanced BRAFV600-mutant melanoma. However resistance to the combination therapy occurs in the vast majority of patients necessitating the development of further novel strategies to overcome resistance. Intriguingly early genomic analyses of tumor tissue from patients progressing on combined BRAF and MEK-inhibition suggest reactivation of the MAPK-signaling as one mechanism of resistance. One strategy to overcome this is to inhibit MAPK-signaling downstream at key signaling nodes such as the cell cycle regulator CDK4. Our preclinical studies show that adding the CDK4-inhibitor palbociclib to a BRAF inhibitor will prevent the emergence of resistance. An alternative strategy is to combine BRAF-inhibitors with therapies that target other mechanisms of disease control such as the host response or tumor metabolism. It is clear that therapeutic combinations either sequentially or concurrently, will continue to define new standards of care for patients with advanced BRAF-mutant melanoma."}
+{"text": "The heart is the principal site of involvement in non-hereditary ATTR amyloidosis and a major driver of treatment options and prognosis in hereditary forms of the disease. The goals of cardiac imaging in amyloidosis are to aid diagnosis, provide prognostic information, track disease progression and evaluate response to therapy.Echocardiography has long been the mainstay of cardiac evaluation in amyloidosis, particularly that of diastolic dysfunction, but its precision is limited and both inter and intra-observer variability constrain its capacity to detect changes. The recent refinement of myocardial strain imaging provides more reproducible and more sensitive evaluation of systolic impairment, which may be overlooked in amyloidosis, and the longitudinal strain pattern of relative apical sparing strongly supports diagnosis of amyloidosis.Two investigations that are transforming our understanding of cardiac amyloidosis are bone scintigraphy and cardiovascular magnetic resonance (CMR).CMR with gadolinium contrast has proved to be invaluable for identification of cardiac amyloid, showing characteristic patterns of global subendocardial and transmural late gadolinium enhancement associated with abnormal myocardial and blood pool kinetics. The recent refinement of phase-sensitive inversion recovery sequence is highly sensitive and specific, producing findings that are virtually pathognomonic for amyloid. CMR is inferior to echocardiography for evaluating diastolic function but can assess the heart's structure and systolic function with greater accuracy and precision. A key advantage of CMR is its unique ability to give insight about tissue composition through myocardial tissue characterization. T1 mapping studies can quantify the massive expansion of the extracellular space caused by amyloid deposition as well as evaluating the myocyte response to it, i.e. associated hypertrophy or cell loss. The ability to independently track changes in amyloid load and myocardial cell mass will be invaluable in assessing new therapies. One significant limitation of CMR is its incompatibility with most implanted pacemakers and ICDs, an issue that may be addressed by the development of dynamic equilibrium CT, in which gated five minute contrast-enhanced scans have shown excellent potential for diagnosis and quantification of cardiac amyloid.99mTc-3, 3-diphosphono-1, 2-propanodicarboxylic acid (DPD) localizes to the heart in patients with cardiac ATTR amyloidosis with incredible sensitivity and high specificity. The mechanism remains unknown, but virtually all patients with clinically significant cardiac ATTR amyloidosis show Grade 2 or greater localization to the heart using the simple Perugini Grade 1-3 scoring system. Indeed, scans in apparently healthy individuals who have undergone predictive genetic testing for hereditary ATTR amyloidosis have shown that Grade 1 DPD uptake occurs before symptoms or abnormalities on echo or CMR have developed, reflecting the earliest evidence of cardiac ATTR amyloid. DPD scintigraphy is not completely specific for ATTR amyloid in that positive scans occur in a small proportion of patients with  cardiac AL amyloidosis and some other very rare types, but Grade 2 or 3 cardiac uptake in the presence of a consistent echo and/or CMR and in the absence of a monoclonal gammopathy is in practice sufficient to make a non-invasive diagnosis of cardiac ATTR amyloidosis.It has been known for decades that bone scintigraphy tracers can localize to cardiac amyloid deposits, but the enormous potential of this tool has only been fully realized in recent years. Studies have confirmed that"}
+{"text": "A-rho and GABAA receptors, has a dichotomic action on radially migrating neurons by acting as a GO signal in lower layers and as a STOP signal in upper cortical plate (CP), respectively. Metabotropic GABAB receptors promote radial migration into the CP and tangential migration of interneurons. Besides GABA, the endogenous GABAergic agonist taurine is a relevant agonist controlling radial migration. To a smaller extent glycine receptor activation can also influence radial and tangential migration. Activation of glutamate and GABA receptors causes increases in intracellular Ca2+ transients, which promote neuronal migration by acting on the cytoskeleton. Pharmacological or genetic manipulation of glutamate or GABA receptors during early corticogenesis induce heterotopic cell clusters in upper layers and loss of cortical lamination, i.e., neuronal migration disorders which can be associated with neurological or neuropsychiatric diseases. The pivotal role of NMDA and ionotropic GABA receptors in cortical neuronal migration is of major clinical relevance, since a number of drugs acting on these receptors  may disturb the normal migration pattern when present during early corticogenesis.Neuronal migration in the cortex is controlled by the paracrine action of the classical neurotransmitters glutamate and GABA. Glutamate controls radial migration of pyramidal neurons by acting primarily on NMDA receptors and regulates tangential migration of inhibitory interneurons by activating non-NMDA and NMDA receptors. GABA, acting on ionotropic GABA During early brain development, mostly during embryonic phases and in some species also during early postnatal periods, newly generated neurons must migrate from their site of origin to their final target in a distinct brain area and a certain subregion, e.g., a specific layer at a certain site of the cerebral cortex. The distances that neurons must travel depend on the cell type and on the species and range from a few hundred micrometers to many millimeters. One exciting question in neuroscience is how newly generated neurons find their correct way to their final position. Over the last two decades we learned that the neuronal migration process is controlled by a number of different mechanisms. Transcription factors control the identity and the laminar position of developing neurons -derived cortical interneurons in the MZ of flat-mount cortices  fulfill two important and different functions in the embryonic cortex Figure . On the reelin, which is secreted from early born Cajal-Retzius neurons located in the MZ  12.5) and migrates tangentially over long distances from their generation site at the pallial-subpallial boundary to the CP  to the developing cerebral cortex  the AMPA/kainate receptor, a usually Ca2+-impermeable glutamate receptor. Three (GluR1-3) of the four known subunits for AMPA receptors are expressed at prenatal stages in the developing cortex, while the GluR4 subunit appears only postnatally  the NMDA receptor, a Cain vitro studies using different models of cortical neuronal migration indicate that NMDA receptors also control radial neuronal migration in the cerebral cortex. In cell dissociates of murine embryonic cortical cells and cortical slice cultures, Behar et al. -like kinases . In addition, a Ca2+ increase also activates Lis1-dependet rho-kinases, which are involved in connecting the microtubules in a Clip170 dependent manner to the actin cytoskeleton and dynein motor complexes . Interestingly, mutations in Lis1 and DCX have been directly linked to human neocortical migration disorders  and micromolar GABA initiated chemokinesis (increased random movement). In a subsequent study Behar et al.  GABAB receptor controlled the migration from the IZ into the CP; and finally (iii) GABAA receptor activation provided the stop signal to terminate migration in the upper CP  during late embryonic stages accelerated radial migration in the murine neocortex  reducing presynaptic glutamate release; (iv) inhibiting glutamate receptor function; and (v) modulating neuronal activity by inhibiting voltage-gated sodium and Ca2+ channels. The most potent anti-epileptic drugs are often unspecific and act via several of these mechanisms. In experimental studies, anti-epileptic drugs were administered in clinically relevant doses to pregnant rats during the last week of gestation , anesthetics required for surgical operation of pregnant women, or drug abuse  may have profound effects on neuronal migration patterns in the cortex of the unborn child. These drugs often act on glutamate and/or GABA receptors and, when reaching the immature brain, may change the migration pattern of cortical pyramidal cells and GABA interneurons. Anti-epileptic drugs have a wide range of actions  and at different developmental periods? The answer to this question will provide important information to understand tangential and radial migration patterns.What are the roles of other transmitter system beside glutamate and GABA? There are a few reports that other classical neurotransmitters like dopamine or serotonin are also implicated in the control of neuronal migration genetic causes of neuronal migration disorders? Although this field strongly developed over the last decade (for review, LoTurco and Bai, What are the migratory pathways and mechanisms in primates? The vast majority of information on neuronal migration comes from experimental studies on rodents. However, some early events in neocortical development are different between rodents and primates (for review Rakic, Although the last two decades provided a large amount of experimental data on the role of glutamate and GABA on neuronal migration in the cerebral cortex, a number of questions need to be addressed in order to understand the function of these two classical neurotransmitters and other transmitters in more detail.In summary, a variety of studies provide substantial evidence that the classical neurotransmitters GABA and glutamate influence neuronal migration and may thus directly contribute to the pathogenesis of neuronal migration disorders. However, the effects of these neurotransmitters are not uniform, but depend on the brain region, identity and maturational state of the migrating neuron and the neurotransmitter receptor subtypes involved. Awareness of the complex interplay between neurotransmitter action and cellular migration processes may help to prevent migration disorders during fetal development.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase TrkB support neuronal survival during development and promote connectivity and plasticity in the adult brain. Decreased BDNF signaling is associated with the pathophysiology of depression and the mechanisms underlying the actions of antidepressant drugs (AD). Several transgenic mouse models with decreases or increases in the amount of BDNF or the activity of TrkB signaling have been created. This review summarizes the studies where various mouse models with increased or decreased BDNF levels or TrkB signaling were used to evaluate the role of BDNF signaling in depression-like behavior. Although a large number of models have been employed and several studies have been published, no clear-cut connections between BDNF levels or signaling and depression-like behavior in mice have emerged. However, it is clear that BDNF plays a critical role in the mechanisms underlying the actions of AD. The neurotrophin brain-derived neurotrophic factor (BDNF) supports neuronal survival during development and promotes connectivity and plasticity in the adult brain by activating its tyrosine kinase receptor TrkB  or CA3 regions of the HC, which are brain regions implicated in spatial memory and in the regulation of emotionality and mood, leads to antidepressant-like effects and to enhancement of the antidepressant-like activity of paroxetine in rodent behavioral despair models  in the human BDNF gene in which valine  is substituted with methionine (Met) in codon 66  reduces activity-dependent BDNF release and impairs hippocampal function  or other strategies that decrease TrkB activity. Third, there are gain-of-function models that enhance either BDNF expression or TrkB activity. This review will summarize the results from these BDNF and TrkB genetic models that are related to mood disorders.(\u00b1)] mice are vital and fertile. Their BDNF mRNA and protein levels in brain are approximately 50% of their wildtype littermates  mice have increased appetite and are usually obese  mice also show mild impairments in learning and memory. They display impaired contextual memory but have normal cued memory  mice also display impaired fear extinction behavior in a fear conditioning paradigm (\u00b1) mice is indistinguishable from littermate controls  mice demonstrate an anxiety- and depression-like behavioral phenotype  mice are resistant to classical ADs in models of behavioral despair  mice do not show any clear baseline anxiety- or depression-like behaviors, but they are more vulnerable to stress and the effects of ADs are blocked in these mice.The anxiety- and depression-like behavioral phenotypes of these mice are even more complex. Some of the studies found that anxiety-like behaviors of BDNFSpatially restricted BDNF KO mouse lines have been produced by crossing mice carrying floxed BDNF (flBDNF) alleles with lines expressing Cre recombinase under a tissue-specific promoter Table . Mood-reInducible mice with temporally restricted manipulations of BDNF have also been made. In these mice, a pharmacological compound, such as tamoxifen or doxycycline, is used to either activate or inactivate gene expression. Monteggia et al.  used thiTo study more localized effects of BDNF deletion, Adachi et al.  injectedChen et al.  producedThe Met-mice mice have also been tested in several other studies. Both Val/Met and Met/Met knock-in mice show impairments in a spontaneous olfactory discrimination test  mice display a 50% reduction in BDNF levels throughout their entire lifespan, their behavioral phenotype is mild and varies from laboratory to laboratory. These discrepancies might be due to developmental compensatory mechanisms, variations in genetic backgrounds  mice. The behavioral results vary widely depending on the laboratory and the spatial location and temporal timing of the transgenes.Taken together, the large number of studies using mice with decreased BDNF expression has not yielded any clear connections between depression and BDNF. Several of the studies found opposing behavioral effects or no effects at all. Even though BDNF(\u00b1) mice and other approaches to decrease BDNF signaling have not provided any conclusive evidence regarding the connection between BDNF and depression-like behavior. Therefore, there is growing interest in genetic models of TrkB signaling . This mutation does not influence the activity of the receptor, but if the pharmacologically inert kinase inhibitor 1NMPP1 is given  under the Thy1 promoter have enhanced TrkB signaling (Koponen et al., The roles of neurotrophins in depression and in the mechanisms underlying antidepressant effects have been widely studied. BDNF deficient mice are the most used model for these studies. These models have demonstrated a key role for BDNF-TrkB signaling in the mechanisms underlying the actions of ADs (MacQueen et al., By contrast, there is no consensus as to whether decreases in BDNF activity cause depression-like behavior in mice since the results vary between different studies. The main difference between these studies is likely the temporal and spatial resolution of BDNF deficiency. However, other factors, such as developmental compensatory mechanisms, genetic backgrounds (Jacobson and Cryan, Another possible reason for the failure to demonstrate an association between BDNF and mood disorders is that in most mouse models BDNF or TrkB are manipulated in most or all brain areas. However, there is evidence that manipulations of BDNF or TrkB signaling in different brain areas result in differential effects (Eisch et al., In summary, while the importance of BDNF and TrkB in the antidepressant response is clear, further experiments in more refined mouse and rat models and in humans are necessary to clarify the role of BDNF signaling in depression and anxiety disorders.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Familial amyloid polyneuropathy (FAP) is a severe hereditary disease, due to production by the liver of a genetic variant transthyretin (TTR) resulting in tissue amyloid deposits. Cardiac involvement is of major prognostic value. Diphosphonate scintigraphy has been proposed as a diagnostic tool for TTR-related cardiac amyloidosis, but there is no consensus on the optimal radiopharmaceutical. Consequently, we compared the cardiac uptake of two 99mTc-labelled tracers: diphosphono-propanedicarboxylic acid (DPD) and hydroxymethylene diphosphonate (HMDP) in patients with TTR-FAP.122 consecutive patients with TTR-FAP were prospectively included and received randomly DPD or HMDP. Acquisitions (whole-body (WB) and chest SPECT) were performed 3 hours after intravenous injection of the tracer. Quantification of myocardial uptake on WB acquisitions was performed by use of the ratio between the geometric mean of either total or average counts of a region of interest (ROI) drawn over the heart area and the WB total or average counts . Quantification on SPECT acquisitions was performed by the ratio between 3D isocount volume of interest generated over the myocardium and a standard volume in the right lung (H/L). Quantification of soft tissues uptake was performed by use of ratio between average counts of a ROI drawn over the lumbar spine and a ROI drawn over soft tissues of the lower limb (B/ST) on the WB acquisition.The DPD and HMDP groups of patients had similar age , sex , TTR mutation  and activity of the tracer . Quantitative parameters derived from whole body acquisition were significantly greater with DPD compared to HMDP  as well as H/L derived from SPECT acquisition . The uptake by soft tissues was also greater in the DPD compared to HMDP group .The present study shows that in patients with TTR FAP, the uptake of DPD in heart and other soft tissues is superior to that of HMDP. This suggests that DPD should be prioritized for initial assessment of patients suspected of cardiac involvement of TTR-related amyloidosis. Further study is required to assess whether this difference impacts the diagnostic performance and whether DPD is more accurate for the assessment of therapy response."}
+{"text": "The integration of Human T-lymphotropic virus type I (HTLV-1) is known to be diverse but biased towards genomically active regions. Each infected clone is identified by a unique integration site position. The integration site position is known to be associated with the expression pattern of the provirus and its propensity to expand in vivo but it is not known how it would impact the gene expression of the host genes. The viral transactivator Tax has been shown (mostly in vitro) to be capable of altering the expression of many host genes however it is not known what role the genomic integration site may have in determining the alteration of host gene expression or how the gene expression pattern would vary from one infected T-cell clone to another. We have developed a panel of HTLV-1 infected T-cell clones. CD4+ T-cells were isolated from HTLV-1 infected individuals and cloned by limiting dilution. Each clone was cultured in the presence of integration inhibitor to prevent super infection and defined by a single unique integration site. Uninfected T cell clones were also established in the same way. In order to address this question and to analyze gene expression pattern, total RNAs were isolated from each clone for RNA sequencing (RNA-seq). We will present the results of high-throughput sequencing of the human and viral mRNA, highlighting the similar and variable between the different clones.# Poster award winnder - 2nd place"}
+{"text": "The burgeoning field of epigenetics is beginning to make a significant impact on our understanding of tissue development, maintenance, and function. Epigenetic mechanisms regulate the structure and activity of the genome in response to intracellular and environmental cues that direct cell-type specific gene networks. The inner ear is comprised of highly specialized cell types with identical genomes that originate from a single totipotent zygote. During inner ear development specific combinations of transcription factors and epigenetic modifiers must function in a coordinated manner to establish and maintain cellular identity. These epigenetic regulatory mechanisms contribute to the maintenance of distinct chromatin states and cell-type specific gene expression patterns. In this review, we highlight emerging paradigms for epigenetic modifications related to inner ear development, and how epigenetics may have a significant role in hearing loss, protection, and regeneration. In 1942, C. H. Waddington coined the term epigenetics by combining the words epigenesis and genetics  can convert neonatal non-sensory epithelial cells into hair cell-like cells, loss of cellular plasticity at later postnatal ages could largely impact clinical application of this method  and histone deacetylases (HDACs). Histones undergo acetylation to yield a more relaxed chromatin conformation resulting from a net change in the overall charge and reduced electrostatic interactions. HATs transfer the acetyl moiety from acetyl coenzyme A to specific lysine residues on the histone tail. Acetylated histones also act as a signal that recruits bromodomain-containing proteins, which are primarily transcription factors and cofactors to target genes activating their transcription  have defined a class of developmentally regulated genes as \u201cbivalent\u201d since these genes are marked with both active H3K4me3) and repressive (H3K27me3) histone modifications 3\u20139, Enhancer of Zeste, Trithorax) domain-containing and non-SET domain-containing proteins. The argine-specific protein arginine methyltransferases (PRMTs) are responsible for methylating arginine residues on the histones. HMTs and PRMTs together have over 60 different family members all of which use S-Adenosyl methionine (SAM) as a cofactor and methyl donor group  are subdivided into SET  is one of the best studied and most mechanistically understood epigenetic modifications that is well conserved among most plant, animal and fungal models  was discovered as another relatively abundant cytosine modification in mouse Purkinje neurons and ESCs  causes CHARGE syndrome, a multiple anomaly disorder that is a common cause of deaf-blindness in humans  and EZH2 (Weaver syndrome) -specific methyltransferase 2D  is associated with Kabuki syndrome  are associated with both genitopatellar syndrome (GPS) and Say-Barber-Biesecker variant of Ohdo syndrome . Additionally, noise is one of the most common causes of hearing loss, and one of the most common occupational illnesses in the United States. The formation of reactive oxygen species (ROS) is the major cause that underlies the molecular pathology of hair cell death related to noise induced trauma as well as aminoglycoside antibiotic and cisplatin treatment  over-expression is a general and powerful approach for regenerative medicine (Cohen and Melton, The epigenetic modifications made during inner ear development remain mostly unknown at this time. However, cofactors of repressive complexes such as NuRD and PRC2 have been reported to be present in the neonatal mouse organ of Corti. The NuRD cofactors including LSD1 are present throughout most of the organ of Corti from E18.5 until P4, then completely absent by P7, and are detectable again from P8 through P21 (Layman et al., Unlike mammalian hair cells, hair cells in the avian basilar papilla and utricle are rapidly regenerated after ototoxic injury (Corwin and Oberholtzer, The cell type specific distribution of histone modifications, DNA methylation, and chromatin remodeling events needs to be characterized during inner ear development from a multipotent progenitor cell to a terminally differentiated cell. The mammalian inner ear offers unique challenges for evaluating the epigenome given the limited number of cells across a diversity of cell types. Transcriptomic analysis of the mammalian inner ear during development by microarray or RNA-seq may provide a starting point for analyzing epigenetic modifications that may regulate the expression of specific target genes and microRNAs (Elkan-Miller et al., Given that epigenetics is a cornerstone of development and cellular reprogramming, it seems likely that understanding and manipulating the epigenome holds enormous promise for preventing and treating hearing loss in humans. Epigenetics also offers an important window to understanding how ototoxic compounds and noise affect gene regulatory networks and how these epigenetic modifications may be manipulated and overcome utilizing epigenetic therapeutics. Understanding epigenetic mechanisms has become a major focus for research in most biological systems. The field of hearing research could greatly benefit from the vast amounts of information that can be garnered from epigenetic work in other biological systems to gain a better understanding of the complex gene regulatory networks being regulated in the inner ear.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Activity of sensory areas continuously varies reflecting both changes in external sensory stimuli and in internal states of the organism that do not necessarily always have a precise relationship to sensory inputs. An important aim in systems neuroscience is to develop quantitative models that may explain how state-dependent representations are generated and how they can be best interpreted. State-dependent modulations of cortical activity are in part mediated by changes in activity of various subcortical neuromodulatory nuclei. A prominent example is the Locus Coeruleus (LC), which can modulate both ongoing changes of cortical states and their responses to sensory inputs. However, a quantitative model of how the temporal fluctuations of LC firing affect ongoing and stimulus-driven primary cortical dynamics is currently missing.Here we investigated how LC modulates the ongoing cortical states and the sensory information carried by cortical firing using a combination of neurophysiological experiments and data-driven dynamic-system models of cortical state changes. We performed simultaneous recordings of neural activity in primary somatosensory cortex and both ipsilateral and contralateral LC in urethane anaesthetized rats during spontaneous activity and during electrical stimulation of the contralateral hind paw. On the basis of this data, we have constructed a novel data-driven dynamical system model of cortical states dynamics. This model extends and generalizes recent simple effective models  by incluWe first fitted dynamic systems models of cortical states that either did or did not contain LC-cortical interactions. We found that models omitting the LC noradrenergic input to cortex tend to describe the dynamics of spontaneous activity of S1 cortex reasonably well. However, including ipsilateral  LC activity as input to the models make the prediction of cortical states and of single trials responses much better. We then investigated which aspects of the LC dynamics help the model to increase cortical state predictability. We found that ipsilateral LC firing activity at low frequencies (< 10 Hz) correlated positively with slow (1-6 Hz) fluctuations of cortical power. The insertion of ipsilateral LC input to the model captured this dynamics by creating additional low frequency (1-6 Hz) state variation of model activity that correlated, both in power and phase, to those observed in real cortical activity. We finally investigated how these dynamical systems models can be used to predict single trial sensory evoked responses and to understand how this dynamics shapes the information representation of sensory stimuli. We derived an explicit mathematical rule predicting the trial-by-trial variability of cortical responses to stimuli arising from LC-modulated cortical state dynamics, and found that subtracting this variability from single trial cortical responses approximately doubles the amount of mutual information about the somatosensory stimuli that could be extracted from cortical responses."}
+{"text": "Plasmodium falciparum malaria remains one of the most serious health problems globally. Immunization with attenuated parasites elicits multiple cellular effector mechanisms capable of eliminating Plasmodium from the liver. However, malaria liver stage immunity is complex. The anatomic site of priming of naive Plasmodium-specific CD8 T cells, be it in the lymph nodes draining the site of Plasmodium antigen deposition by the mosquito or in the liver, may in fact determine the specificity of the effector CD8 T cells. The participation of particular antigen-presenting cells , acute phase proteins, phagocytic activity, and cytokine-mediated pro- and anti-inflammatory responses are all part of the liver-inherent immune system (Wunderlich et al., The liver is also a central player in the defense against Plasmodium liver stages nor delays parasite development (Sahu et al., Efforts to develop a successful malaria vaccine have been the focus of substantial research activities for decades. Immunization with live-attenuated sporozoites can elicit sterile immunity. Whether attenuation is achieved by irradiation or genetic modification, CD8 T cells play an essential role in the resulting sterilizing protection in several experimental models. Inoculation of infectious sporozoites under chemoprophylaxis also confers long-lasting sterile protection against homologous parasite strains in humans, although the exact mechanism is unclear. Chloroquine, the first drug used for chemoprophylaxis, neither eliminates Unlike whole organism vaccines, most subunit vaccine candidates fail to induce substantial and lasting protection. Novel approaches are therefore under investigation to identify antigens responsible for protection against the different parasite stages (Chia et al., Plasmodium in the liver. A more thorough understanding of the mechanisms leading to sterile protection is a prerequisite for developing a malaria vaccine that protects the 40% of the world's population at risk of infection. We thank all contributing authors for bringing a broad range of expertise to this Frontiers Topic.We hope that this Frontiers eBook offers insight into the many efforts aiming at breaking the life cycle of The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The activity of the brain exhibits stereotypical patterns at various temporal and spatial scales. Novel techniques such as functional magnetic resonance imaging (fMRI) allow the simultaneous recording of the macroscopic activity from all brain regions while subjects perform various tasks, such as passive hearing and active visual recognition. How neural activity is related to cognitive tasks is a long-standing question for the neuroscience community. This study examines an interesting aspect of this broad question, namely the comparison between the resting state (when the subjects is idle) and evoked activity during a task. Neural activity patterns consist of the correlations of firing activity between cortical regions - or functional connectivity - at a slow time scale (hundreds of ms), which can be related to data obtained from fMRI.The cortex has an intricate architecture of connections, both local and long-range. The latter have been mapped for the whole human cortex using diffusion techniques . A recen"}
+{"text": "Transcranial direct current stimulation (tDCS) modulates cortical neural activity and hemodynamics. Electrophysiological methods  measure neural activity while optical methods (near-infrared spectroscopy-NIRS) measure hemodynamics coupled through neurovascular coupling (NVC). Assessment of NVC requires development of NIRS-EEG joint-imaging sensor montages that are sensitive to the tDCS affected brain areas. In this methods paper, we present a software pipeline incorporating freely available software tools that can be used to target vascular territories with tDCS and develop a NIRS-EEG probe for joint imaging of tDCS-evoked responses. We apply this software pipeline to target primarily the outer convexity of the brain territory  of the middle cerebral artery (MCA). We then present a computational method based on Empirical Mode Decomposition of NIRS and EEG time series into a set of intrinsic mode functions (IMFs), and then perform a cross-correlation analysis on those IMFs from NIRS and EEG signals to model NVC at the lesional and contralesional hemispheres of an ischemic stroke patient. For the contralesional hemisphere, a strong positive correlation between IMFs of regional cerebral hemoglobin oxygen saturation and the log-transformed mean-power time-series of IMFs for EEG with a lag of about \u221215 s was found after a cumulative 550 s stimulation of anodal tDCS. It is postulated that system identification, for example using a continuous-time autoregressive model, of this coupling relation under tDCS perturbation may provide spatiotemporal discriminatory features for the identification of ischemia. Furthermore, portable NIRS-EEG joint imaging can be incorporated into brain computer interfaces to monitor tDCS-facilitated neurointervention as well as cortical reorganization. Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that involves application of low intensity direct currents at the scalp for the modulation of central nervous system excitability in humans  is defined by neural activity closely related, spatially and temporally, to rCBF. The neurovascular unit (NVU) consists of the endothelium, glia, neurons, pericytes, and the basal lamina Dutta, . NVC dysThe constant supply of ATP using oxygen and glucose is mediated by the regulation of large cerebral arteries and cerebral microvascular pressure  contact surface was used for anodal stimulation and a SPONSTIM-25  electrode with 25 cm2 contact surface was used as the return electrode (cathode) for bipolar tDCS  surface. If the electrode montages for tDCS and EEG are identical, e.g., when being reciprocally energized, then the tDCS current flow field can serve as the EEG lead vector field assuming the conductivity tensor as a constant scaling factor  has already been shown in a stroke patient  and detectors based on our prior work  and EEG  time-series for each hemisphere. Generally, the first IMF contains the highest frequency components and the oscillatory frequencies decrease with increasing IMF index. IMFs containing peak power >50 Hz were discarded and then the log (base-10) transformed mean power of IMFEEG data was computed  was selected based on prior work  into a set of intrinsic mode functions (IMFs) was performed using the Hilbert-Huang Transform (HHT) for rSO2  starting at the 11th trial, i.e., after cumulative 550 s of anodal tDCS.The cross correlation function with lead/lag < 20 s for the 3rd IMF\u2014the most common across significant positive and negative cross-correlations\u2014is shown in Figure In this methods paper, we investigated the bipolar tDCS montage from our prior works with a software pipeline incorporating freely available software packages to design a NIRS-EEG probe for joint imaging of tDCS-evoked response. The software pipeline was applied in a ischemic MCA stroke case based on our prior works  approach to adjust for short separation SD measurement in order to improve the probe sensitivity to brain tissue , France. The publication of this article was funded by the open access fund of the Leibniz Association.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The cuticle provides a physical barrier against water loss and protects against irradiation, xenobiotics, and pathogens. Components of the cuticle are perceived by invading fungi and activate developmental processes during pathogenesis. In addition, cuticle alterations of various types induce a syndrome of reactions that often results in resistance to necrotrophs. This article reviews the current knowledge on the role of the cuticle in relation to the perception of pathogens and activation of defenses. Arabidopsis thaliana and help to understand its biosynthesis  can stimulate the migration of the nucleus inside the conidia toward the site of primary germ tube emergence  and accumulation of defense-related genes , a predominant component of the potato cuticle. When etiolated cucumber hypocotyls are gently abraded, cutin monomers from hydrolysates of cucumber, apple, and tomato cutin induce the production of H2O2  protein genes were not associated with cutinase-induced resistance responses of bean leaves in response to cutinase action , ET, or jasmonic acid (JA) pathways and expression of the cutinase gene of F. solani in Arabidopsis thaliana mutants of the SA , ET  and of the JA (jar1) pathways clearly show fully independence of cutinase-induced protection on SA, ET, and JA. A number of genes identified from microarray experiments showed an earlier and stronger expression after inoculation with Botrytis cinerea of CUTE plants compared to wild types. Fifteen genes were selected and overexpressed in Arabidopsis thaliana and eight of these provided increased tolerance to Botrytis cinerea. These genes included members of the lipid transfer protein (LTP), the peroxidase (PO), and the protein inhibitor (PI) gene families. Members of the LTPs, PER, and PIs could each contribute in part to the observed resistance induced by Botrytis cinerea in CUTE plants .A number of studies have reported on lcr (lacerata) mutant is impaired in a gene coding for a cytochrome P450 monooxygenase involved in the formation of \u03c9-hydroxy fatty acids in yeast and could be involved in cutin biosynthesis  mutant that is characterized by a deficient fatty acid \u03c9-alcohol dehydrogenase activity (bdg (bodyguard) mutants compared to WT plants  is allelic to lacs2 (fdh (fiddlehead) is mutated in a gene encoding a protein involved in the synthesis of long-chain lipids (pec1 (permeable cuticle 1) is characterized by a knockout of ATP BINDING CASSETTEG32 (ABCG32), an ABC transporter localized at the plasma membrane of epidermal cells; available evidence suggests that ABCG32 exports cutin precursors for the synthesis of the cuticular layer in the epidermal cell  mutant characterized by downregulated ABA-dependent wax biosynthetic genes  that could explain this result are not known. In the same article, the authors show that only cutin monomers of SlSHINE3-overexpressing leaves induced the expression of defense genes in tomato  mutant exhibits enhanced susceptibility to the biotrophic fungal pathogen E. cichoracearum but enhanced resistance to the necrotrophic fungal pathogens Botrytis cinerea and Alternaria brassicicola. RST1 is plasma membrane protein and is possibly involved in suppressing the biosynthesis of cuticle lipids; the increased levels of cutin monomers and cuticular waxes in rst1 suggest this. Despite this, rst1shows a clear departure from the behavior of other mutants since the permeability of the cuticle is normal . The acp4 mutants were tested in the context of systemic acquired resistance (SAR); they are able to generate a mobile SAR signal from lower leaves inoculated with bacteria but unable to perceive it in the upper leaf. The acp4 also display cuticular defects with reduced levels of fatty acids, alkanes and primary alcohols compared to WT plants associated with ultrastructural changes and an increased cuticular permeability  applied to leaves was shown to increase resistance to Botrytis cinerea and lead to the production of reactive oxygen species -carboxy-29,79-dichloro dihydrofluorescein diacetate (DCF-DA) a fluorescent probe for ROS  compared to the corresponding wild type ecotype Ler  gene, which encodes a nuclear protein of RNA-processing multi-protein complexes, making it likely that small-RNA signaling is involved in the cuticular defect syndrome. The importance of the SE gene was confirmed with double mutants such as lcr-se and bdg-se that suppress the abnormal cuticle syndrome and resistance to Botrytis cinerea. These results support the hypothesis that various cuticular defects might induce a common signaling pathway that depends on the SE gene  was developed and used for an datasets . This le SE gene . It willBotrytis cinerea or its inoculation medium through the epidermis wall into the cells where they might trigger a faster and more intensive defense reaction. The surprising potential for defense against Botrytis cinerea unveiled in CUTE plants and in the various cuticle mutants warrants further research to understand the molecular basis of this phenomenon .The evidence provided by the effect of ectopic treatments with cutin monomers, overexpression of cutinase, ectopic treatments with cutinase and various cuticular mutants with increased permeability lead several scenarios that might explain the resistance of plants in relation to defective cuticles . A permeArabidopsis thaliana to Botrytis cinerea. This is intriguing, since Botrytis cinerea releases cutinase and lipase during the penetration of leaves (Arabidopsis thaliana leaves resistance and ROS are induced (in planta is sufficient for penetration but not for inducing resistance. Alternatively, Botrytis cinerea, like other pathogens, might suppress induced defense responses in the plant. One possible suppressor could be oxalic acid, a know pathogenicity factor of Botrytis cinerea (Arabidopsis thaliana against Botrytis cinerea (Botrytis cinerea (Sclerotinia sclerotiorum (Arabidopsis thaliana is susceptible to Botrytis cinerea, despite the release of cutinase and lipase.A puzzling question concerns the full susceptibility of f leaves  yet no r induced . Possibl cinerea  and supp cinerea . Several cinerea . Also, t cinerea  or Sclerrotiorum . This miArabidopsis thaliana mutants or ecotypes that lack an increase in resistance to Botrytis cinerea after treatment with fungal cutinase. A series of mutants and ecotypes could be identified, all displaying an increased in susceptibility to Botrytis cinerea. These results are now being followed up; one predicts that such mutants could be blocked in either a putative receptor for cutinase-generated monomers or alternatively in any step downstream of it.How plants perceive changes in the level of cutin monomers is still not known and is a question that needs to be addressed. The experimental evidence accumulated so far makes it reasonable to assume that plants are equipped to perceive cutin monomers or other related products possibly by receptors. A genetic screening would be an approach of choice to identify such receptors. In fact, we are currently screening Using the available genome-wide gene expression microarray data, one can identify common genetic elements during the resistance syndrome in cuticle deficient mutants. Using the MASTA , differeAnother intriguing question is the chemical nature of the fungitoxicity in the diffusates of cuticular mutants. It is not clear whether the same chemical causes the observed activity for each mutant; a bioassay-assisted chemical identification is under way to clarify this point.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Patients with classic Hodgkin lymphoma (cHL) that has relapsed after autologous or allogeneic transplant have limited treatment options and a poor prognosis. Immunotherapy with agents that target the PROGRAMMED DEATH 1 (PD-1) receptor have demonstrated clinical activity with durable responses in early-phase clinical trials in this patient population; however, patients with a history of allogeneic stem cell transplantation (SCT) were intentionally excluded from participation in those studies due to concerns for reactivation of graft-versus-host disease (GVHD). We describe the clinical course of two patients with advanced cHL and prior treatment with allogeneic stem cell transplantation (SCT) that were treated with the PD-1 inhibitor pembrolizumab. Both patients had no active graft-versus-host disease (GVHD) at the time initiation of therapy and were maintained on low-dose prednisone. Treatment with pembrolizumab was well tolerated and not associated with reactivation of GVHD. Both patients responded  and remain on therapy as of November 30, 2015. This report indicates that immunotherapy targeting the PD-1 pathway can be safely administered to patients with cHL and a history of allogeneic SCT and produce tumor responses. Further studies in this patient population are needed. The safety and therapeutic activity of monoclonal antibodies targeting the PROGRAMMED DEATH 1 (PD-1) receptor in advanced classic Hodgkin lymphoma (cHL) has been demonstrated in two recent publications . Both stA 30-year-old man was diagnosed with stage IIA cHL in 2007 and treated with standard ABVD  for 6 cycles. No evidence of FDG-avid malignancy was identifiable on PET-CT obtained after 2 cycles. He proceeded to receive adjuvant radiotherapy to the right neck and chest area. His disease relapsed 6 months later and he was treated with salvage ICE  followed by autologous SCT in March of 2008. Less than six months after autologous SCT the patient was found to have biopsy-proven relapsed disease in the lungs. He was treated with GVD  and underwent nonmyeloablative allogeneic SCT from a matched related donor in January of 2009. His post-transplant course was complicated by acute GVHD involving the skin and gut treated with corticosteroids. He underwent a mediastinoscopy in August 2009 to investigate mediastinal lymphadenopathy and was found to have relapsed disease. Withdrawal of immunosuppression was attempted; however, follow-up imaging demonstrated progressive disease in the fall of 2009. At that time, grade 1 GVHD of the liver was found on biopsy done to investigate elevated transaminases. He arrived at our institution in November of 2009 for a second opinion and was treated with single-agent everolimus as part of a clinical trial (NCT01022996) . After 1The second patient is a 30-year-old man who was diagnosed with stage IIIS cHL in 2008. His disease was initially treated with first-line ABVD followed by adjuvant radiotherapy. He relapsed less than a month after the end of radiotherapy. He was subsequently treated with salvage ICE and progressed after 2 cycles. Therapy with GVD followed and he later underwent autologous SCT in April 2009 with adjuvant radiotherapy. In April 2013 the patient developed biopsy-proven recurrent disease that was treated with brentuximab vedotin followed by GVD with good response. The patient underwent nonmyeloablative allogeneic SCT from a matched related donor in January 2014 without complications or evidence of GVHD. In July 2014 the patient developed biopsy-proven relapsed disease in the axial skeleton with significant pain. Subsequent treatment regimens were ineffective and included single-agent brentuximab vedotin and on-study with panobinostat and everolimus. Similar to patient 1, by July 7, 2015 the patient had exhausted all reasonable therapies and consented to off-study pembrolizumab (2 mg/kg/dose repeated every 3 weeks). At the time of initiation of therapy he had no evidence of active GVHD and was maintained at the dose of 2.5 mg of prednisone daily  and remain on treatment without evidence of disease progression. Treatment with pembrolizumab in these two patients was not associated with reactivation of GVHD.The current report is the first to describe the safe and successful use of pembrolizumab in patients with cHL who had previously been treated with allogeneic SCT. Although the PD-1 pathway has been implicated as an escape mechanism for malignant stem cells following allogeneic transplant , data onOur limited experience cannot necessarily be extrapolated to all patients who present with relapsed cHL after having failed previous treatment with allogeneic SCT. It is important to note that both of our patients had no evidence of active GVHD at the time of therapy with pembrolizumab and were maintained a low-dose prednisone regimen. This may have contributed to safe administration of this agent. These encouraging results with respect to safety and efficacy in this important group of patients should spur additional testing of PD-1 inhibitors in this patient population."}
+{"text": "Loligo duvauceli.Recent advances in the insilico virtual screening paves way towards efficient discovery of new drugs on the basis of drug target evaluation and analysis. The present study is thus an attempt to assess the anti-HBV like activity of Bis 2-(ethyl hexyl) phthalate [BEHP] from the black pigmented ink of South Indian squid, Loligo duvauceli were dissected and the ink was subjected to crude solvent extraction. Chromatographic profiles were assessed by TLC and HPTLC. Fractionation of the bio active compounds was done by Silica gel column chromatography and the active fraction was subjected to GC-MS analysis. In vitro analysis of the anti-HBV like activity was assessed by pre incubating the HBV positive serum samples with the active fraction by performing ELISA. In silico virtual screening was analyzed with the latest bio informatics tools and databases.Fresh ink glands from in silico analysis supported the preliminary screening results of ELISA and indicated the anti-HBV like activity of BEHP.TLC and HPTLC profiles yielded a compound with the Rf value of 0.76. The antimicrobial fraction upon GC-MS analysis revealed a chromatogram with nine peaks with BEHP possessing a highest percentage of area normalization (91%) with other few minor constituents. The ELISA results were negative for all the pre incubated HBV positive serum samples. Docking scores and the This present study suggests that BEHP could be a novel anti-HBV agent and a promising candidate to combat viral hepatitis in near future with further clinical and toxicity evaluation."}
+{"text": "Spontaneous and sensory evoked spindle bursts represent a functional hallmark of the developing cerebral cortex in vitro and in vivo. They have been observed in various neocortical areas of numerous species, including newborn rodents and preterm human infants. Spindle bursts are generated in complex neocortical-subcortical circuits involving in many cases the participation of motor brain regions. Together with early gamma oscillations, spindle bursts synchronize the activity of a local neuronal network organized in a cortical column. Disturbances in spindle burst activity during corticogenesis may contribute to disorders in cortical architecture and in the activity-dependent control of programmed cell death. In this review we discuss (i) the functional properties of spindle bursts, (ii) the mechanisms underlying their generation, (iii) the synchronous patterns and cortical networks associated with spindle bursts, and (iv) the physiological and pathophysiological role of spindle bursts during early cortical development. It has been suggested that delta brushes in human preterm infants correlate with so-called spindle bursts recorded in rodents during the early postnatal period . At. At18]. Simultaneous multielectrode recordings in the barrel cortex and in the ventral posteromedial nucleus (VPM) of the somatosensory thalamus of P0-P1 rats in vivo have demonstrated that the majority of spontaneous cortical spindle bursts and also gamma oscillations are not generated within S1, but rather in subcortical structures or outside of S1 Figures  18]. At. At18]. Similar to the spindle bursts in S1, spontaneous spindle bursts in V1 are also largely generated in the sensory periphery. Spontaneous retinal activity, so-called \u201cretinal waves\u201d (for review ), providWhereas a large amount of experimental data has shown that retinal waves provide the main trigger for the cortical V1 spindles bursts, it is not completely understood which pacemaker drives the spontaneous activity in S1 and how spontaneous activity is generated in the somatosensory periphery. In P3\u2013P6 rats spontaneous whisker movements occur during active sleep and are correlated with activation of whisker-related cortical columns in the barrel cortex . In newbIn summary, these data indicate that neocortical spindle bursts in newborn rodents (and delta brushes in human fetus during the third trimester or in preterms) are generated by central pattern generator (CPG) circuits in spinal cord, brainstem, and motor cortex (for CPG circuits in mature brain see \u201344).Neuropharmacological studies provided insights into the molecular mechanisms underlying the generation and modulation of neocortical spindle bursts. In vivo  and in vSingle-cell recordings revealed additional insights into the mechanisms underlying the generation of spindle bursts. Spindle bursts in V1  and S1  are accoSpindle bursts in the cerebral cortex of newborn rats can be elicited , 35 and As discussed above, spatially confined spindle bursts in newborn rat cortex synchronize a local neuronal network resembling a neocortical (pre-) column . Beside Beside this intrahemispheric synchronization between different cortical regions, spindle bursts also interact between both hemispheres (interhemispheric). In vivo simultaneous recordings of spontaneous activity in homotopic cortical areas in both hemispheres at the same stereotaxic coordinates and depth have demonstrated that the amount of interhemispheric synchronization in newborn rats is initially rather low and increases during the first postnatal week . This inIt is not surprising that intra- and interhemispheric interactions of spontaneous activity in the spindle burst frequency range can be also observed in developing human cerebral cortex at early stages. Using EEG and functional magnetic resonance imaging (fMRI) Omidvarnia et al. could demonstrate in premature and full term human babies the existence of an \u201celectric resting-state network\u201d that shows functional intra- and interhemispheric interactions in the 8\u201315\u2009Hz frequency range .In summary, several in vitro and in vivo studies have demonstrated that spindle bursts represent elementary states of intra- and interhemispheric synchronization in the very immature cerebral cortex.An increasing amount of experimental and clinical data strongly indicate that spindle bursts play an important role in the physiological development of the cerebral cortex. Experimental evidence indicates that spindle bursts may be particularly suited to interfere with early neurodevelopmental processes, and thus disturbances in spindle burst activity may cause long-term structural and functional disorders.At early stages of development spontaneous and sensory-evoked activity patterns influence a variety of developmental processes, such as neurogenesis , apoptosFor this activity-dependent control of neuronal survival the phosphatidylinositol 3-kinase pathway plays an important role, while the MAPK/extracellular signal-regulated kinase or the calcium/calmodulin-dependent protein kinase pathway is not directly involved . Since oUsing in vitro and in vivo models it has been recently shown that an experimentally induced inflammation by application of the endotoxin lipopolysaccharide induces rapid (<2\u2009h) alterations in the pattern of spontaneous spindle bursts and gamma oscillations in neonatal rodent cerebral cortex, which subsequently leads to increased apoptotic cell death . These iIn summary, these experimental data suggest that any disturbances in the spontaneous activity of the developing cerebral cortex (including spontaneous spindle bursts) induce acute dysfunctions, which may cause long-term disorders. However, it remains to be elucidated whether spindle burst in particular can be causally related to neurodevelopmental disturbances. It has been recently shown in extremely preterm infants that the properties of neocortical bursts recorded with EEG and their scaling relationships correlate significantly with later cognitive development . These cWhile it is generally accepted that early electrical activity shapes the maturation of neocortical circuits , it remaAnother unresolved issue is that both spindle bursts and gamma oscillations can be observed during the same period of early development. Intriguingly, both activity patterns share many features. They can be observed in early postnatal rodent brain from the day of birth . FuFinally, it would be most interesting and important to correlate specific patterns of spontaneous activity  recorded by means of full-band direct-current EEG in preterm und full-term human neonates with the acute functional state and with the further development of the child, as impressively done by Vanhatalo and colleagues , 67.Spatially confined spindle bursts and delta brushes represent the most prominent physiological activity patterns in the developing cerebral cortex of newborn rodents and preterm human infants, respectively. Spontaneous and stimulus-evoked spindle bursts can be observed in various neocortical areas of different mammalian species and play important roles in the early development of cortical networks. However, it remains to be studied in more detail how exactly spindle bursts influence the maturation of the cortex and how a potential long-term dysfunction due to disturbances in spindle burst activity can be prevented by early intervention. Since this important type of brain activity is already present in the human fetus in utero (either spontaneously occurring or related to sensory inputs from the uterine environment), a better understanding of the physiological relevance of spindle burst oscillations is of major clinical relevance."}
+{"text": "Non-viral gene delivery vectors are widely used for the delivery of genetic materials into mammalian cells. Currently, there is a need to develop cheap and efficient transfection agents for use in production of recombinant proteins via transient gene expression. There are several barriers that non-viral vectors must overcome for successful transfection, these include cellular internalisation, endosome escape, protection of DNA and delivery of DNA into the nucleus. The ability to escape the endosome and gain entry to the nucleus are of the two primary barriers to successful transfection. The processes involved in the pathways for cellular uptake, intracellular trafficking, and nuclear entry are still not fully understood. More detailed understanding of the pathways involved in transfection is needed in order to develop highly efficient transfection agents.This work investigates the use of three series of cationic diblock copolymers as transfection agents for the production of recombinant proteins, as well as examining the pathways the polymers used for delivery of DNA into the nucleus. The diblock copolymers were synthesised using 'living' radical polymerization techniques, with each series using the same first block poly(2-dimethylaminoethyl acrylate) (PDMAEA). This polymer can self-degrade through a self-catalysed hydrolysis mechanism to a negatively charge and nontoxic poly(acrylic acid) in a time-dependent manner. The second block consists of N-(3-(1H-imidazol-1-yl)propyl) acrylamide (ImPAA) or butylacrylate (BA) or a combination of both. The three series of polymers were first tested for their ability to bind/release and protect pDNA before transfection studies occurred. Transfection studies were performed in Human Embryonic Kidney (HEK293) cells where internalisation pathways into the cell, endosomal escape and nuclear entry were investigated before recombinant protein yields determined. Several chemicals were used to investigate the internalisation pathways and endosomal escape , which is known to block the nuclear pores, was added before transfection. Our results show that 48 h post-transfection, transfection efficiency is significantly reduced to less than 5%. We confirmed that reduced transfection efficiency is not due to any toxic effects caused by the WGA. Our results demonstrate that entry occurs primarily though the nuclear pores, and not during mitosis when the nuclear membrane is temporarily disintegrated as the cells would have undergone at least one cell division during the 48 h period.The results presented here attempts to improve our understanding of the pathways involved in the successful delivery of pDNA. The three series of cationic diblock copolymers investigated are highly effective at escaping the endosome with polymer A-C3 achieving the highest level of transfection efficiency. The A-C3 polymer/pDNA complexes showed a preference to the clathrin-mediated endocytosis (CME) cellular entry pathway. Through the addition of WGA it can be suggested that pDNA either complexed with the A-C3 polymer or alone, enters the nucleus via the nuclear pores and not during mitosis. The ability to rationally design cationic polymers to overcome the barriers to successful transfection could result in the next generation of highly efficient transfection agents used in transient gene expression systems."}
+{"text": "Anaplastic transformation of well-differentiated papillary thyroid carcinoma at distant metastasis sites is rare. To the best of our knowledge, this is the first report of an autopsy case of anaplastic transformation of papillary thyroid carcinoma in multiple lung metastases presenting with a malignant pleural effusion.We report an autopsy case of a 61-year-old Japanese man with anaplastic transformation of papillary thyroid carcinoma with multiple lung metastases presenting with a malignant pleural effusion, which was difficult to diagnose by cytological examination before the autopsy. He presented with a 1-month history of progressive dyspnea, and examination of the left pleural effusion revealed a bloody exudate with an increase in thyroglobulin; however, malignant cells in the pleural fluid were negative for thyroglobulin.It is important to be aware that anaplastic transformation of differentiated thyroid carcinoma could develop in lung metastases and could be a cause of a malignant pleural effusion. Papillary thyroid carcinoma is the most common malignant tumor of the thyroid and has a relatively favorable prognosis. However, anaplastic transformation of well-differentiated papillary thyroid carcinoma is considered rare and is associated with a very poor prognosis . Anaplas131I) until 2003 for multiple lung nodules that were diagnosed as metastases of thyroid carcinoma. A chest X-ray obtained upon his admission to our hospital revealed a massive left-sided pleural effusion , TP53 and PIK3CA, has reportedly been associated with anaplastic carcinoma, and chromosomal abnormalities are also common [131I therapy has been considered to be associated with an increase in the probability of anaplastic transformation [131I in the metastatic sites was associated with development of anaplastic changes [131I therapy was performed in five of seven cases of anaplastic transformation of papillary thyroid carcinoma in distant metastatic sites, including our patient [131I therapy is definitely associated with the pathogenesis of anaplastic transformation, so further clinical cases need to be examined.The presence of transitional zones between the differentiated and undifferentiated components suggests the anaplastic transformation of pre-existing papillary thyroid carcinoma. Although the molecular pathogenesis of anaplastic transformation is not completely understood, some gene mutations, including the o common . In addiormation , 12, 13. changes . Post-op patient , 8. HoweTo the best of our knowledge, we report the first case of anaplastic transformation of papillary thyroid carcinoma in multiple lung metastases presenting with a malignant pleural effusion. It should be kept in mind that anaplastic transformation of differentiated thyroid carcinoma could develop in lung metastases and could also be a cause of malignant pleural effusion.Written informed consent was obtained from the patient\u2019s next of kin for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal."}
+{"text": "Fundus albipunctatus is a recessive auto somal disease. It is a rare form of apparently stationary night blindness characterized by the presence of myriad symmetrical round white dots in the fundus with a greater concentration in the midperiphery. The fundus shows a multitude of subtle, tiny yellow-white spots at the posterior pole, sparing the fovea and extending to the periphery (A et B). The retinal blood vessels, optic disc, peripheral fields and visuel acuity remain normal. Fluoresce in angiography shows mottled hyperfluorescence exceptat the fovea (C et D). Differential diagnosis are the retinitis punctat a albescens and the Oguchi disease. No effective treatment is available to restore full receptor cell function however, high oral doses of beta-carotenemay lead to an improvement in night blindness."}
+{"text": "Chromosomal aberrations such as deletions, duplications and translocations of DNA segments can lead to highly significant positive correlations of gene expression levels of neighboring genes. This should be utilized to improve the analysis of tumor expression profiles. Here, we develop a novel model class of autoregressive higher-order Hidden Markov Models (HMMs) that carefully exploit local data-dependent chromosomal dependencies to improve the identification of differentially expressed genes in tumor. Autoregressive higher-order HMMs overcome generally existing limitations of standard first-order HMMs in the modeling of dependencies between genes in close chromosomal proximity by the simultaneous usage of higher-order state-transitions and autoregressive emissions as novel model features. We apply autoregressive higher-order HMMs to the analysis of breast cancer and glioma gene expression data and perform in-depth model evaluation studies. We find that autoregressive higher-order HMMs clearly improve the identification of overexpressed genes with underlying gene copy number duplications in breast cancer in comparison to mixture models, standard first- and higher-order HMMs, and other related methods. The performance benefit is attributed to the simultaneous usage of higher-order state-transitions in combination with autoregressive emissions. This benefit could not be reached by using each of these two features independently. We also find that autoregressive higher-order HMMs are better able to identify differentially expressed genes in tumors independent of the underlying gene copy number status in comparison to the majority of related methods. This is further supported by the identification of well-known and of previously unreported hotspots of differential expression in glioblastomas demonstrating the efficacy of autoregressive higher-order HMMs for the analysis of individual tumor expression profiles. Moreover, we reveal interesting novel details of systematic alterations of gene expression levels in known cancer signaling pathways distinguishing oligodendrogliomas, astrocytomas and glioblastomas. An implementation is available under  Copy number changes of genes are frequently found in different types of cancer Over the last years, several approaches have been developed for the analysis of tumor expression profiles in the context of chromosomal locations of genes. Methods like CGMA  Generally, HMMs provide a sound mathematical grounding for the analysis of biological sequences However, this only addresses the first limitation by overcoming the restrictive first-order state-transition process. Independent from that, extensions of the standard emission process have been initially realized in speech recognition by the integration of autoregressive emission distributions enabling the modeling of state-specific direct local dependencies within a range of successive measurements To overcome this, we develop a novel model class of autoregressive higher-order HMMs enabling an improved modeling of local dependencies between successive measurements. Autoregressive higher-order HMMs simultaneously utilize higher-order state-transitions in combination with autoregressive emissions as novel model features. Globally, this model class has very general modeling capabilities including mixture models, standard first-order HMMs and higher-order HMMs as special cases. We motivate the development of autoregressive higher-order HMMs by considering the analysis of individual tumor expression profiles in which local dependencies of gene expression levels are frequently caused by deletions and duplications of underlying chromosomal regions. The existence of such local chromosomal dependencies between expression levels of genes in close chromosomal proximity is clearly shown for three different types of cancer in We apply our autoregressive higher-order HMMs to the analysis of publicly available breast cancer and glioma gene expression data. We first systematically evaluate the performance of autoregressive HMMs to predict overexpressed genes in breast cancer with known underlying increased gene copy numbers. Then, we analyze to which extent these results are transferable to other similar breast cancer expression profiles. We further complement this by a sensitivity analysis evaluating the robustness of autoregressive HMM predictions. Next, we perform an in-depth comparison study to related existing methods on breast cancer gene expression profiles, where we first investigate general characteristics of predicted differentially expressed genes followed by the identification of overexpressed genes with known increased copy numbers. Finally, we consider different types of gliomas and demonstrate that autoregressive HMMs are useful tools to reveal systematic differences in expression levels of genes in known cancer signaling pathways.The materials part provides a brief overview of the considered data sets. The methods part gives a detailed description of the model class of autoregressive higher-order HMMs.This section shortly introduces the considered breast cancer and glioma data sets.Pollack et al. A breast cancer data set by We created a glioma gene expression data set based on data from the Repository for Molecular Brain Neoplasia Data  This section develops the basics of the model class of autoregressive higher-order HMMs in the context of the analysis of tumor expression profiles. This includes a detailed model description, a general characterization of the model class, the integration of prior knowledge into the training of the model, basics of the model training and the model initialization.S : \u200a=\u200a{\u2018\u200a=\u200a\u2019,\u2018\u2212\u2019,\u2018+\u2019}. Considering the usually observed distribution of log-ratios  algorithms Since we propose autoregressive Gaussian emissions as a novel model feature, we briefly summarize important steps of the estimation of the corresponding autoregressive means. The maximization step of the emission parameter estimation part of the log-posterior leads to a state-specific system of linear equations that enables to update the basic mean and the corresponding coefficients for each autoregressive mean. Standard solvers for systems of linear equations can be used to compute the solution of the given system. We utilize the publicly available Jama package Specific details of the estimation of initial state, transition and emission parameters of the autoregressive higher-order HMM and a computational scheme of the training algorithm are given in Appendix B in For the identification of differentially expressed genes in tumors, an initial autoregressive HMM must be specified to enable a good adaptation of the model to the data during the training. We transfer initial model and prior settings described in This basic initialization strategy has led to robust results in With the goal of performing exhaustive comparisons of different autoregressive HMMs, we trained each HMM with an autoregressive emission process of order In this section, we first systematically compare different autoregressive HMMs for their performance to identify overexpressed genes with underlying increased copy numbers in breast cancer. Next, we analyze to which extent the obtained results can be transferred to other similar breast cancer gene expression profiles. This is complemented by performing a sensitivity analysis to study the robustness of predictions obtained by autoregressive HMMs. After that, we compare the performance of autoregressive HMMs to related existing methods. Here, we first investigate the different methods for general characteristics of their predictions of differentially expressed genes. We further compare the different methods based on their identification of overexpressed genes with underlying increased copy numbers in breast cancer. Finally, we transfer autoregressive higher-order HMMs to different types of gliomas and perform an in-depth systematic analysis of differentially expressed genes with respect to known cancer signaling pathways.Pollack et al. We utilize breast cancer gene expression and corresponding gene copy number data by Seifert et al. Here, we do this in analogy to To analyze the performance of the identification of overexpressed genes with underlying increased copy numbers by different autoregressive HMMs, we used fifty percent of the breast cancer gene expression data set. We trained each initial AR. This is also reflected in closely related array comparative genomic hybridization (aCGH) data analysis pipelines, where models are initially adapted and later used for the analysis of a single individual data set, but where transfers of trained models to other data sets are typically not done. However, a successful transfer of trained HMMs from one data set to a new data set can especially save time for the analysis of large data sets by avoiding time-consuming training steps. Thus, we transferred all previously trained autoregressive HMMs to other similar breast cancer gene expression profiles to evaluate the reached model performances after this transfer in analogy to our previous study.The results are summarized in Thus, this study indicates that a careful transfer of previously trained autoregressive HMMs to other similar tumor expression profiles can be realized, but one should keep in mind that a faster analysis of large data sets may result in reduced accuracy of predictions.We additionally performed a sensitivity analysis by systematically varying initial model parameters and prior parameter settings to analyze the robustness of the predictions made by autoregressive HMMs. Since this is generally very time-consuming, we focused on those parameters that are expected to have the greatest influence on the prediction of differentially expressed genes. We first tested twelve different model initializations and trained corresponding autoregressive HMMs on fifty percent of the breast cancer gene expression data set using identical prior hyperparameter settings. Specific details are given in Table S1 in y stable  and widey stable . Similary stable .We next tested twelve different prior parameter settings and trained the corresponding autoregressive HMMs utilizing our generally considered fixed initial model parameterization described in the methods section. Details of the tested prior parameter settings are provided in Table S1 in In summary, this study indicates that changes of the initial model parameter settings and of the prior parameter settings do not substantially affect the predictions of autoregressive HMMs. Thus, the predictions of autoregressive HMMs are robust with respect to reasonable changes of initial parameter settings.To compare the identification of differentially expressed genes by autoregressive HMMs to related methods, we analyzed the breast cancer gene expression data set We applied all methods with their proposed initial standard settings to all breast cancer gene expression profiles. We note that experts of specific methods might be able to further improve the predictions by fine-tuning of specific model parameters. The different methods implement specific algorithms to adapt their initial parameters or test statistics to the data followed by the prediction step. All methods except ChARM, DSHMM, AR. The classification of gliomas according to these subtypes has important implications for the prognosis and the treatment of glioma patients A representative global overview of how strongly oligodendrogliomas, astrocytomas and glioblastomas are affected by under- and overexpression in specific cancer signaling pathways with respect to random expectations is shown for the top 300 genes in Figure S8 in In more detail, considering underexpressed genes, we observe that the same cancer signaling pathways are always affected by nearly the same number of genes independent of the type of glioma  only higher-order state-transitions or (ii) only autoregressive emissions did not lead to performances reached by the best-performing autoregressive HMMs that combine these two features simultaneously. The best-performing models had state-transitions of order two to three in combination with autoregressive emissions of order two to four. For the analysis of other data sets, we suggest to consider the most parsimonious model of the best-performing models. That is, one may use the HMM with second-order state-transitions and second-order autoregressive emissions. Since this only involves second-order state-transitions, such a model can also be trained within reasonable time on large data sets. Altogether, our results clearly indicate that autoregressive higher-order HMMs are valuable tools for the analysis of individual tumor expression profiles.Currently, autoregressive higher-order HMMs enable to analyze expression levels of genes in tumor with respect to their linear chromosomal order. This linear processing of gene expression levels allows to improve the predictions via the modeling of existing local chromosomal dependencies. This provides a solid basis that could be further extended by taking prior knowledge about underlying transcriptional networks e.g.  or spatiText S1Mathematical basics of the prior distributions for initial state, state-transition and emission parameters and details of the chosen prior hyperparameters are given in the section 'Appendix A: Prior distributions\u2019. A detailed derivation of the Bayesian Baum-Welch algorithm for autoregressive higher-order HMMs is given in the section \u2018Appendix B: Bayesian Baum-Welch algorithm\u2019. An in-depth analysis of identified hotspots of differential expression in gliomas is given in the section \u2018Appendix C: Application of Autoregressive Higher-Order Hidden Markov Models to glioma data\u2019. The supporting Figures S1\u2013S8 are provided in the section \u2018Supporting Figures\u2019. The supporting Tables S1\u2013S4 are given in the section \u2018Supporting Tables\u2019.(PDF)Click here for additional data file."}
+{"text": "The visual pigment in rod photoreceptors, the G protein-coupled receptor rhodopsin is organized in tracks of dimers thereby providing a signaling platform for the dynamic scaffolding of the G protein transducin. Illuminated rhodopsin is turned off by phosphorylation catalyzed by rhodopsin kinase (GRK1) under control of Ca2+-recoverin. The GRK1 protein complex partly assembles in lipid raft structures, where shutting off rhodopsin seems to be more effective. Re-synthesis of cGMP is another crucial step in the recovery of the photoresponse after illumination. It is catalyzed by membrane bound sensory guanylate cyclases (GCs) and is regulated by specific neuronal Ca2+-sensor proteins called guanylate cyclase-activating proteins (GCAPs). At least one GC (ROS-GC1) was shown to be part of a multiprotein complex having strong interactions with the cytoskeleton and being controlled in a multimodal Ca2+-dependent fashion. The final target of the cGMP signaling cascade is a cyclic nucleotide-gated (CNG) channel that is a hetero-oligomeric protein located in the plasma membrane and interacting with accessory proteins in highly organized microdomains. We summarize results and interpretations of findings related to the inhomogeneous organization of signaling units in photoreceptor outer segments.Vertebrate photoreceptor cells are exquisite light detectors operating under very dim and bright illumination. The photoexcitation and adaptation machinery in photoreceptor cells consists of protein complexes that can form highly ordered supramolecular structures and control the homeostasis and mutual dependence of the secondary messengers cyclic guanosine monophosphate (cGMP) and Ca The present article, however will address issues, which had been investigated in more recent years showing that the photoreceptor outer segment is not a well-stirred compartment, but appears rather inhomogeneous. Publications indicating different aspects of heterogeneity date back several decades, but have been mainly interpreted as signs of the natural ageing and renewal process in outer segments. For example, gradients along the longitudinal axis of outer segments have been described for second messenger molecules  of rhodopsin block its dimerization both The supramolecular organization of nearly immobile rhodopsin imposes a conceptual problem on the mechanistic understanding of the phototransduction cascade, which operates on a millisecond time base with high sensitivity. Intuitively one might predict that arrays of paracrystalline rhodopsin would slow down the activation kinetics. The investigation of how the diffusion properties of rhodopsin and transducin are affected by specific supramolecular assemblies is not trivial, and has so far been investigated only by computational analyses that incorporate available experimental data. Results were not always intuitive, because rhodopsin supramolecular assemblies and molecular crowding in discs imply anomalous and anisotropic diffusion paths for peripheral membrane proteins such as transducin, which significantly differ from the classical free diffusion case. In a first approach to the problem, Monte Carlo simulations of rhodopsin-transducin encounters in both the classical free diffusion and emerging paracrystalline rafts scenarios suggested that an unexpected favorable effect on the temporal response of early phototransduction reactions may occur, if rhodopsin molecules were packed in highly ordered assemblies  would not allow a significant competition with the binding of transducin  form of the receptor and does not act upon the unbleached receptor  showed shortened light responses indicating a reduced lifetime of light-activated rhodopsin  were interpreted as lipid raft structures and biochemical fractionation studies pointed to the existence of lipid rafts in rod outer segments. Detergent resistant membranes or lipid rafts can be isolated from sucrose step gradients of cell suspensions that are solubilized with a low concentration of the nonionic detergent Triton X-100. Main features of lipid rafts are high cholesterol content, saturated fatty acids, glycolipids and the marker protein caveolin  it was suggested that ROS-GC1 is crucial for the intracellular trafficking of peripheral membrane proteins  correlate with type 12 of Leber congenital amaurosis causing a severe form of blindness at early age  part (Sugimoto et al., +/Ca2+, K+-exchanger (Schwarzer et al., CNG channels are heterotetrameric proteins consisting, in rod and cone cells, of three \u03b1\u2013subunits and one \u03b2\u2013subunit (Weitz et al., Signaling proteins in photoreceptor cells form building blocks and signaling modules involving the disc membranes as platforms. These units might preferably exist of transitory protein complexes that are determined by the affinities of their binding partners and their lateral and longitudinal diffusion. This flexible regulatory network of proteins therefore creates the heterogeneous distribution of signaling units in the outer segment under conditions of a crowded intracellular environment. It will be a future challenge to investigate how the exchange, flow and mutual interaction of key factors in signaling units determines the preciseness of visual phototransduction and adaptation.KWK developed the concept of the manuscript, wrote the first draft and approved the final version. DDO added to all parts of the manuscript and approved the final version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "We describe a case of pneumococcal round pneumonia in an elderly smoker and it demonstrates the role of inflammatory biomarkers and follow-up imaging in ruling out more ominous diagnoses. Plain chest radiograph revealed right base infiltrate. A computed tomography (CT) scan of the chest is shown  by the age of eight . It is an adults . Differen adults ."}
+{"text": "The main objective of this paper is to investigate how archaeological fish remains and written historical records can contribute to the reconstruction of long-term developments of fish communities along the Austrian and Hungarian Danube. Although such approaches are sensitive to various factors, the chronological subdivision and relative quantification of proxy data demonstrate environmental and faunal changes from Prehistory onwards. Intensification of fisheries, decline of large specimens and massive exploitation of small and young fish point to increasing pressure along the chronological sequence towards Early Modern times. One result of this impact was the establishment of regulations and laws to protect such fish. At the same time, the rise of aquaculture and common carp cultivation can be viewed as another upshot of human impact on the Danube\u2019s environment. Finally, the massive import of salted marine fish reflects a compensation for the undersupply caused by overexploitation of the Danube fish fauna and points to the growing demand for fish as food in late medieval and Early Modern times. The Danube comprises a multitude of aquatic environments along its course from the German Schwarzwald to Austria, Hungary and further south into the Carpathian Basin. Although the river endangered riparian communities by recurring flooding, humans also exploited the natural habitats along the Danube as documented by numerous archaeological sites along the Austrian and the Hungarian part (river km 2135\u20131886 and 1796\u20131581). Excavations here uncovered refuse deposits containing fish remains and prove that fishing has substantially contributed to human nutrition since the Neolithic B\u00f6k\u00f6nyi .The successful identification of many fish bones to species level is certainly based on the availability of reference collections. The investigations of such archaeological remains as proxy data address many societal and ecological questions. Cultural preferences influence various social levels as comparing monastic and aristocratic households or civil sites including latrines and waste disposal places Galik . Many faEcological approaches usually relate to manmade faunal changes or impacts on ecosystems  analysing the influence of recovery methods on the resulting species list, (2) investigating whether the relative abundance of fish species differs on large spatial and temporal scales, (3) identifying size distributions and (4) comparing the fish remains from the early modern period with written documents to reveal differences between two distinct types of proxy information.The archaeoichthyological material comes from sites along the Danube in Austria and Hungary. The Austrian river section is characterized by alpine influences in terms of velocity and temperature. Downstream of Bratislava and Gy\u00f6r the character shifts towards a lowland river, also reflected by a change from a dominance of rheophilic and eurytopic to more limnophilic cyprinids  was overwhelmingly represented in the prehistoric contexts at both sections of the Hungarian Danube but it remained absent in Austria\u2019s prehistoric site at the Danube tributaries. The Roman-, medieval- and late/post-medieval contexts revealed similar patterns at least for the Vienna Basin and the upstream section of the Hungarian Danube. Although common carp appears quite opposite in the Roman contexts, the decline in abundance from medieval- to late/post-medieval contexts reveal similar pattern at the Hungarian and Austrian sites. The frequencies of pike are similar in Roman contexts as well as the decrease in abundance towards late/post-medieval sites in the Austrian sites and sites at the upstream section of the Hungarian Danube . The late medieval latrine in the Vienna Basin contained schraetzer  and ruffe . Pikeperch (Sander lucioperca) was particularly well represented in the Roman contexts at the Austrian and Hungarian Danube but appeared in smaller proportions in later periods and at the Austrian tributaries  was clearly a regular catch around the Danube, but it remains rare at the Austrian tributaries. Its highest frequency in Austria occurred in the Roman period  occurred in high proportions in all chronological periods at the Danube tributaries in Austria, along with rare evidence of Danube salmon (Hucho hucho) and grayling  imply occasional catches at Austrian sites. Salmonids as well as burbot did not occur in any Hungarian site.Brown trout  were present in the Austrian late medieval- as well as in the Roman latrine. Bullhead (Cottus gobio) was documented in the sites related to the Danube and along the tributaries, for example at the medieval castle. Although small fish were present in Roman and medieval times, masses accumulated in the late medieval context only.Loaches (Anguilla anguilla) occurred in the late medieval latrines in the Vienna Basin and in St. P\u00f6lten. Other remains demonstrated the import of marine fish back as far as the reign of the Imperium Romanum. The most abundant species was Atlantic chubb mackerel (Scomber scolias). While the medieval castle yielded only a single specimen, the latrines produced large numbers of herring vertebrae. Other imported species included cod as stock fish (Gadus morhua) and flatfish, mainly plaice (Pleuronectes platessa) but also sole (Solea solea) and turbot  in monastic contexts and in the cesspit filling of the tavern in Salzburg (Fig.\u00a0Besides above-described species native in the Danube, catadromous eel (urg Fig.\u00a0; Table\u00a01Most of the material indicated cyprinids in the size range of 30\u201340\u00a0cm and sometimes even larger Fig.\u00a0. The RomThe written sources confirm the fish species detected in the archaeological records but also complement and complete the ichthyo-faunal evidence. Besides sterlet and beluga sturgeon, Schmelzl  additionArchaeological fish remains produce distorted pictures that are biased by taphonomic history, beginning with fishing, trade and consumption and ending with preservation. Beyond methodological factors such as the expertise or the method of recovery, which massively influence the richness of species by \u201csampling\u201d efforts, the state of preservation and inconsistent quantities of identifiable bones impedes chronological and contextual comparisons. The proxies provide a reliable signal at least for the regularly hand-collected large fish species, bearing in mind that limited material may reflect regional\u2014rather than diachronic variations.However, as a recurring nutritive resource, large migratory sturgeons were targeted from prehistoric times on at the Hungarian part of the Danube. The first Austrian sturgeon remains date to the Roman period, while the prehistoric site Ansfelden is located outside their natural migration routes and no evidence of prehistoric sturgeon exploitation has been proven to date along Austria\u2019s Danube. Besides the archaeologically evidenced sterlet and beluga sturgeon, a higher variety of sturgeon species is expectable Schmelzl . The AusThe remains from the Roman latrine in the Vienna Basin indicate another pattern as the late/post-medieval latrine fillings. The Roman site reveals the use of only a few small sized fishes although the sediment was carefully sieved. Even smaller sizes and intensified exploitation of juvenile cyprinids and other small species indicate changes in fisheries in the late/post-medieval times in Austria. Historical records refer to these environmental impacts, in particular fishing laws such as introduced by Albrecht V in 1412 for the Austrian part of the Danube Uhlirz . They prKarpfen, Seekarpfen\u201d and \u201cThei\u00dfkarpfen\u201d most probably from the Tisza River. Besides these forms, Bohemian reared common carp was transported to the Viennese fish market as well (Wacha Common carp and other cyprinids and pike are abundant and important fish in Austria and Hungary and probably mirror an increase of fishing intensity towards the medieval- but a decrease of specimens towards the late/post-medieval periods. The Austrian common carp remains reflect human impact at the ecosystem, too. Comparable to Hungarian Neolithic exploitation (Bartosiewicz ll Wacha .The documentation of assumed ecological differences and changing fish communities between the Austrian and the Hungarian part of the Danube is hampered by the aforementioned methodological insufficiencies and is restricted to mainly larger eurytopic species. Even such hand-collected and large fish remains indicate that species such as sturgeon, common carp or pike had been transported to remote sites at Austria\u2019s Danube tributaries, outside their natural habitat. At a finer level, the sieved samples reveal a correspondence of species composition and Danube habitats in the Vienna Basin and the tributary sites. The conspicuous absence of trout in early medieval Ansfelden might be explained as a pattern of Slavic people\u2019s preference for cyprinids, whereby potential taphonomic conditions or environmental changes may also have played a role. Typical species in the samples such as schraetzer and ruffe indicate exploitation of local Danube fish in the Vienna Basin Zauner . A good Freyung\u201d yielded, beyond few Atlantic chub mackerel remains, vertebrae resembling small-sized herring and strongly indicating the import of Atlantic fishes. The late medieval eel remains may represent preserved and transported fish as well, but historical records show that eel migrated towards two Austrian regions. The first was the Lainsitz in Lower Austria, where eel entered from the Elbe-system. The second was Lake Constance via the Rhine River (Spindler Imported and preserved marine fish certainly reflect a demand for Mediterranean cuisine and life style in land-locked Central Europe in Roman times (H\u00fcster-Plogmann Spindler . NonetheSpindler \u2014even to Spindler  associatSpindler . AlthougSpindler .Concluding, our investigations demonstrated the potential of using fish remains and written historical records for reconstructing long-term changes of the Danube\u00b4s fish communities but also certain limitations as well as the dependence from the methodological approaches e.g. of sampling. Although only proxy data are involved, the species found and the frequency of bones clearly indicate the relation between the fish community and human interaction and impact on the Danube\u2019s environment. Our results strongly encourage improvement and standardization of archaeological recovery methods and routine screening for fish remains. Such data can provide historical investigations at finer chronological and geographical resolutions along the various riverine habitats of the Danube. They have the potential to enlighten even local changes in ecology and fish population. The incorporation of new and well established bio-molecular methods with still rising potential and reliability such as analyses of stable isotopes (Barrett et al."}
+{"text": "HTLV-1 gene expression is controlled by the key regulatory proteins Tax and Rex. The concerted action of these proteins results in a two-phase kinetics of viral expression that depends on a time delay between their action. However, it is difficult to explain this delay, as Tax and Rex are produced from the same mRNA. In the present study we investigated whether HTLV-1 may produce novel mRNA species capable of expressing Rex and Tax independently.Results revealed the expression of 3 alternatively spliced transcripts coding for novel Rex isoforms in infected cell lines and in primary samples from infected patients. One mRNA coded for a Tax isoform and a Rex isoform, and 2 mRNAs coded for Rex isoforms but not Tax. Functional assays showed that these Rex isoforms exhibit activity comparable to canonic Rex. An analysis of the temporal expression of these transcripts upon ex vivo culture of cells from infected patients and cell lines transfected with a molecular clone of HTLV-1 revealed early expression of the dicistronic Tax/Rex mRNAs followed by the monocistronic mRNAs coding for Rex isoforms.The production of monocistronic HTLV-1 mRNAs encoding Rex isoforms with comparable activity to canonical Rex, but with distinct timing, would support a prolonged duration of Rex function with gradual loss of Tax, and would be consistent with the two-phase expression kinetics. A thorough understanding of these regulatory circuits will shed light on the basis of viral latency and provide groundwork to develop strategies for eradicating persistent infections."}
+{"text": "The launch of seed development in flowering plants (angiosperms) is initiated by the process of double fertilization: two male gametes (sperm cells) fuse with two female gametes  to form the precursor cells of the two major seed components, the embryo and endosperm, respectively. The immobile sperm cells are delivered by the pollen tube toward the ovule harboring the female gametophyte by species-specific pollen tube guidance and attraction mechanisms. After pollen tube burst inside the female gametophyte, the two sperm cells fuse with the egg and central cell initiating seed development. The fertilized central cell forms the endosperm while the fertilized egg cell, the zygote, will form the actual embryo and suspensor. The latter structure connects the embryo with the sporophytic maternal tissues of the developing seed. The underlying mechanisms of double fertilization are tightly regulated to ensure delivery of functional sperm cells and the formation of both, a functional zygote and endosperm. In this review we will discuss the current state of knowledge about the processes of directed pollen tube growth and its communication with the synergid cells resulting in pollen tube burst, the interaction of the four gametes leading to cell fusion and finally discuss mechanisms how flowering plants prevent multiple sperm cell entry (polyspermy) to maximize their reproductive success. Arabidopsis and maize the embryo sac develops according to the Polygonum type  is formed during the processes of microsporogenesis and microgametogenesis from the microspore mother cell by meiosis and two successive mitotic divisions resulting in the formation of a tricellulate pollen grain. The vegetative cell encases the two sperm cells, which are connected with the vegetative cell nucleus by the generative cell plasma membrane, forming the male germ unit (MGU). MGU formation ensures the simultaneous delivery of both gametes to the ovule , which binds to the S-locus pollen tube membrane protein P. r. pollen S (PrpS) and activates a Ca2+-dependent signaling cascade resulting in pollen inhibition and programmed cell death  in papilla cells  gradient  at the pollen grain adhesion site , which can be stimulated by D-serine , calmodulin-like proteins (CMLs), calcium-dependent protein kinases (CDPKs), and calcineurin B-like proteins (CBLs) are expressed in the pollen tube and are thought to control different cell-cell communication events indicated by their localization and overexpression phenotypes. The presence of these different Ca2+cyto receptors around the sperm cells and at the pollen tube tip indicate an essential role of Ca2+ signals both during pollen tube growth and double fertilization  mutant or its target HALF FILLED (HAF), pollen tube growth is severely affected and either slowed down or prematurely terminated. NTT encodes a C2H2/C2HC zinc finger transcription factor involved in ECM production and is essential for programmed cell death in the transmitting tract upon pollination  forms this gradient through GABA degradation. At moderate concentrations GABA stimulates pollen tube growth and thus likely supports growth toward the ovule  was not effected in the double mutants , MPK3 and MPK6, were identified in In summary, our current understanding of ovular pollen tube guidance is very limited, but a whole orchestra of small molecules derived from the ovule seem to be involved in pollen tube growth support and attraction, and multiple signaling networks are required in pollen tubes to respond to the diverse set of signals and to direct their growth behavior.Arabidopsis , including those representing a subgroup of defensin-like (DEFL) polypeptides , a small hydrophobic precursor protein of 94 aa was reported as an egg apparatus-specific protein required for micropylar pollen tube guidance  mutants show defects in central cell maturation; both haploid nuclei are smaller and often fail to fuse. Pollen tubes grow in the direction of an unfertilized maa ovule but loose their way just before entering the micropyle. Moreover, mutant female gametophytes attracted two pollen tubes at a high frequency  LOST IN POLLEN TUBE GUIDANCE1 (LIP1) and 2 (LIP2) have been identified, which are preferentially expressed in the pollen tube. Both proteins show membrane localization due to a palmitoylation site and are involved in the AtLURE1-dependent guidance mechanism. fer ovules , which leads to the inhibition of a plasma membrane H+-ATPase resulting in the suppression of cell elongation in the primary root -anchored protein LORELEI (LRE) and the Mildew Resistance Locus O (MLO) family protein NORTIA (NTA). Both genes are expressed in synergid cells and show a similar pollen tube overgrowth phenotype  in the pollen tube membrane , which generate only one sperm-like germ cell  and GENERATIVE CELL SPECIFIC 1 (GCS1), also known as HAPLESS 2 (HAP2) . It was further shown that in the absence of the potential fusogen GCS1/HAP2, attachment of male to the female gamete occurs but no membrane fusion is visible, implying that the protein mediates membrane fusion as a component of signaling events, or more likely that it is directly involved in the fusion event  mutant. This mutant produces more than one sperm pair, which is released simultaneously at the gamete fusion site. After fertilization, polyploidy resulting from multiple fertilization events was observed in the developing endosperm, but not in the embryo  or a number of highly specialized cell types , both female gametes appear in an arrested state until activated through fertilization. In contrast, parthenogenetic egg cells do not arrest and initiate cell division without fertilization. The central cell, however, requires fertilization in most plant species, even in those containing parthenogenetic egg cells. Its activation is closely related to seed development as both parthenogenetic embryogenesis and seed development arrest at an early stage without central cell fertilization , which was shown to be delivered by sperm cells, becomes translated in the zygote and acts in the YODA (YDA) MAPK pathway during zygote elongation /Pelle-like kinase gene Arabidopsis tremendous progress has been made in the past couple of years to understand the underlying cellular and molecular mechanisms that regulate pollen tube growth and guidance, sperm delivery and gamete interaction resulting in blocks to polytubey and polyspermy. Little is known about the activation of gametes and thus seed development immediately after fertilization. Many of the processes described above involve conserved mechanisms and proteins. Some of these proteins are highly polymorphic and species-specific, allowing female flower organs to discriminate self from alien pollen grains/pollen tubes to avoid reproductive failure after pollination and fertilization with incompatible gametophytes and gametes, respectively. In summary, we have learned that species-specific or even ecotype-specific molecules and plant family-specific mechanisms are required during compatible interactions. These are used by papilla cells to control pollen germination, by transmitting tract cells during pollen tube growth and by the ovule and female gametophyte cells during the last steps of pollen tube journey. Moreover, even sperm cell discharge is regulated in a species-preferential manner. Whether gamete interactions depend on species-specific molecules remains to be shown. Up to now the final processes of fertilization seem to involve partly conserved proteins even from lower to higher eukaryotes. The knowledge generated can now be used to investigate, for example, speciation mechanisms or can be applied to overcome hybridization barriers between species. Initial attempts enabling ovules to attract pollen tubes from unrelated plant families have been successful (M\u00e1rton et al., in vivo still limit its utilization for reproduction biologists. Concerted efforts are now required to understand the molecular mechanisms of double fertilization in crop plants, which significantly differ from Arabidopsis in both reproductive structures and genetic repertoire.Efficient and successful fertilization of all developed ovules is a key to reproductive success and essential for high crop yield. Using the model plant The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Accurate quantification of insulin resistance is important for diagnosing and determining the efficacy of treatment in patients with equine metabolic syndrome (EMS). The euglycemic-hyperinsulinemic clamp (EHC) is a gold-standard method for measuring insulin sensitivity (IS) but the complexity of the technique limits its use in research. The use of proxies based on fasting values offers an attractive alternative.To evaluate the validity of proxies calculated from basal plasma glucose and insulin concentrations that predict insulin sensitivity measured with the EHC in the horse.The EHC was conducted in 29 horses of different breeds with a wide range of IS including 12 patients diagnosed with EMS. Basal plasma and insulin concentrations were determined from blood samples collected prior to the EHC. In addition, the ability of proxies to detect changes in IS during a weight gain study in nine Standardbred horses was also included.Insulin sensitivity indexes calculated from the EHC  were correlated (r2 = 0.47 \u2013 0.71) to quantitative insulin sensitivity check index (QUICKI) and to the reciprocal of the square root of insulin (RISQI) as well as to the homeostatic model assessment of insulin resistance (HOMA-IR). The proxies were unable to accurately predict changes in IS during the weight gain study.Proxies for screening of IS in the horse may be useful but their ability to detect diet-induced variations in IS appears to be limited."}
+{"text": "We recovered 35 mutations that form abnormally enlarged cells with multiple, often polyploid nuclei and incomplete cell walls. These mutants represent seven genes, four of which have previously been implicated in phragmoplast or cell plate function. Mutations in two loci show strongly reduced transmission through the haploid gametophytic generation. Molecular cloning of both corresponding genes reveals that one is represented by hypomorphic alleles of the kinesin-5 gene RADIALLY SWOLLEN 7 (homologous to tobacco kinesin-related protein TKRP125), and that the other gene corresponds to the Arabidopsis FUSED ortholog TWO-IN-ONE . No mutations that completely abolish the formation of cross walls in diploid cells were found. Our results support the idea that cytokinesis in the diploid and haploid generations involve similar mechanisms.Cytokinesis in plants involves the formation of unique cellular structures such as the phragmoplast and the cell plate, both of which are required to divide the cell after nuclear division. In order to isolate genes that are involved in  Plants have adopted a unique mechanism of separating daughter cells in mitosis. This mode of cytokinesis involves two specialized organelles, the phragmoplast and the cell plate \u20133. The pin vitro ; the relative abundance of individual neutral sugars was measured with respect to all six sugars analyzed [weight%]; all values represent the average of three measurements, with the standard deviation listed in brackets . \u2020: .(PDF)Click here for additional data file."}
+{"text": "Post-mortem computed tomography (PMCT) has been proven for its appropriateness to become an integral part of routine pre-autoptic forensic investigations either in the field of forensic investigation of fatal medical error or in hospital quality management. The autoptic investigation of unexpected and peri-interventional deaths can be usefully guided by post-mortem imaging which offers significant added value in the documentation of misplacement of medical devices before dissection with the risk of artificial relocation and the detection of iatrogenic air embolism. Post-mortem CT angiography (PMCTA) augments PMCT in the search for sources of hemorrhages and for the documentation of vascular patency and unimpaired perfusion after general and cardiovascular surgery or transvascular catheter-assisted interventions. Limitations of PMCT and PMCTA in medical error cases are method-related or time-dependent including artifacts by early post-mortem tissue change. Thromboembolic complications including pulmonary embolism, the differentiation of ante- and post-mortem coagulation and the detection of myocardial infarction remain areas with compromised diagnostic efficiency as compared to autopsy. Furthermore, extended survival periods after a complication in question impedes visualization of contrast agent extravasation at vascular leakage sites. PMCT and PMCTA contribute substantially for proving a correct interventional approach and guide forensic or clinical autopsy in the reconstruction of adverse medical events with fatal outcome. Post-mortem imaging could also assume a new role as an alternative in a clinicopathological setting if autopsy is not achievable when the probability in the individual case is acceptable to answer specific questions. During the last 10\u00a0years, post-mortem computed tomography (PMCT) has developed to become a tool for routine work in more and more institutes of forensic medicine across Europe and worldwide . PMCT coThere is a rising number of reports about the advantages of post-mortem imaging in cases with fatal outcome after medical intervention \u201318. AutoHence, PMCT shows the potential to become a valuable tool that adds further information after unsuspected in-hospital deaths even if an autopsy diagnosis is not achievable due to patient/family consent , 19, inoTaking into account the experiences of forensic radiologists and forensic pathologists with the application of post-mortem imaging in the assessment of suspected medical malpractice, PMCT has established its role for radiologically accessible morphological findings which are indicative for or against an iatrogenic injury caused . The limSince some years, post-mortem CT angiography has expanded the range of options in the reconstruction of potential medical error since it facilitated the search for hemorrhage sources  as well In the Hamburg Institute of Legal medicine, over a period of 6\u00a0years about 2000 PMCT investigations have been performed after in-hospital deaths. The responsibility of the Institute of Legal Medicine for the morgue includes fatalities with unknown manner of death from the city of Hamburg but also all in-hospital deaths from the university medical center Hamburg-Eppendorf. This enables the post-mortem CT examination on request by clinical colleagues in cases of naturally certified deaths as well as in cases in which public prosecution decides to stop further investigations in primarily certified unclear manner of death. Until 2012, a 4-slice MDCT (MX 8000) have been used, thereafter a 16-slice MDCT . A whole-body CT from top to thigh  is the standard; additionally, dedicated scans of the cranium, the brain and the thorax with higher resolution  may complement the exam.200 hospital fatalities have been examined with multiphase post-mortem CT angiography (MPMCTA) after performance of PMCT according to reported standard methods . The intPost-mortem computed tomography contributes greatly to perpetuate evidence of the position of foreign bodies at time of death and before any autopsy procedure could artificially displace it. The unrecognized misplaced intubation includes esophageal positioning, bronchial intubation, esophageal or tracheal perforation but also disconnection or dislodgement of the tracheal tube. Extra-anatomical gas detection such as gas accumulation in the deep cervical and mediastinal tissues points to a complication, occasionally seen after misplaced tracheotomy or coniotomy. It remains challenging in PMCT to detect a source of gas/air escapes, especially in the thoracic and abdominal cavity but following their 3D-path in soft tissues has advantages over the autopsy. PMCT gives evidence of pneumothorax after jugular and subclavicular medical puncture; the mediastinal shift due to tension pneumothorax cannot be depicted at autopsy in a comparable quality. The transvenous placement of central venous lines, gastric tubes and electrodes from cardiac pacemakers or defibrillators with irregular loops and bending or misplaced pleural drainages are quite illustrative on 3D reconstructions. Figure\u00a0In intensive care units, ventricular assist devices, aortic balloon pumps and extracorporal membrane oxygenation (ECMO) systems have become increasingly in use in patients with cardiac and respiratory failure as a bridge for recovery, transplantation or ultima ratio. PMCT easily identifies the position of the incoming and outgoing components as well as the location of pump systems. Depending on the type of system used, conclusions can be drawn on the underlying organ dysfunction in the terminal phase of life of the patient .After percutaneous coronary intervention (PCI), the myocard sometimes shows an enhancement which seems to be due to contrast medium deposits that still have not been washed out completely. If these areas correspond to the drainage of a coronary artery, this may be taken as an indication for sudden interruption of coronary perfusion before death or immediate cardiac arrest after contrast medium application.If a series of gas bubbles is observed in a coronary artery after fatal outcome during a PCI procedure, it should be clarified if a gas embolism could have happened even though safety devices should prevent unobserved gas bubble transport through the angiography catheter. Post-mortem gas formation is a very unlikely explanation when gas detection is restricted to the coronary arteries. Another differential diagnosis is the replacement of blood by gas via unlocked catheters which had not been removed from the body immediately after the procedure.Coronary perforations with cardiac tamponade and dissections are typical fatal complications after transvascular cardiac interventions, sometimes resulting in aortic dissections Fig.\u00a0. PerforaPMCTA may rarely fail to demonstrate the exact source of a bleeding which resulted in a cardiac tamponade. The tamponade is usually firmly clotted in these cases and prevents contrast medium from leaking out of a rupture due to the massive pressure in the pericardial sac and adherence of blood clots to the surface of the traumatized tissue.Transvascular valve placement refers predominantly to the transcatheter aortic valve implantation (TAVI) which utilizes bioprostheses made of bovine pericardium mounted on a balloon-expandable stainless-steel or cobalt-chromium stent. The positioning of the valve, its relation to the coronary ostia with potential constriction effects and the unimpeded perfusion of the aortic outlet as well as signs of incompatibility of the aortic diameter and the expanded frame with the risk of valve insufficiency can be visualized by PMCTA. The expanded wires of the frame may complicate a subsequent coronary stenting procedure. The lower border of the valve graft is at risk to interfere with the anterior sail of the mitral valve and its papillary suspension which is observable via 3D reconstruction and virtual endoscopy .The valve may be implanted via a transfemoral or transapical approach which could result into additional suturing problems at the points of sheath/catheter entry after termination of the intervention. PMCT/PMCTA demonstrates resulting hemorrhages into the soft tissues of thigh and retroperitoneum  or into the pleural space and into the mediastinum .\u00ae or to catheter radiofrequency or cryoablations, mostly at the level of the openings of the pulmonary veins into the left atrium for the treatment of cardiac arrhythmias.A catheter-induced trauma may also refer to balloon dilatations of the aortic valve, to transcatheter approaches of the mitral valve such as annuloplasty and mitraclipPerforations from one into another cardiac chamber.Myocardial contrast medium deposits in case of incomplete disruptions.Perforation into the pericardial sac with resulting tamponade.Perforation into the mediastinum and/or the pleural space if the rupture continues above the level of the pericardial reflection lines on the great vessels.These procedures may result intoPMCTA facilitates the diagnosis by following the path of extravasated contrast agent.Endovascular aneurysm repair (EVAR) has been widely adopted for abdominal aneurysms\u2014extendable into the iliac arteries\u2014and thoracic (TEVAR: thoracic EVAR) aortic aneurysms. The blood flows through the endograft which represents an artificial lumen reducing the pressure in the aneurysm. There is a growing application of endovascular graft stenting even in emergencies with ongoing aneurysm ruptures or aortic dissections.A major cause of complications in abdominal EVAR is the failure of the seal between the proximal, infra-renal aneurysm neck and the endovascular graft; unsuitable fit between the aortic wall and the graft with compromised seal and an instable anatomy may elevate the risk , 27. RecThe diagnostic value of PMCT(A) after fatal outcome of open surgical interventions is generally much higher with the detailed knowledge of the preexisting morbidity, the sequence of ante-mortem interventions and preceding complications to the last operation. Full access to the patient history at the time of radiology report would be a given in clinical pathology, but it is not self-evident in the forensic area for the time of post-mortem reporting.A typical scenario of suspected medical error is a challenged decision to wait and see instead of starting surgical exploration in case of abdominal pain. Figure\u00a0The majority of patients following thoracotomy or laparotomy-based adverse events die of protracted multi-organ failure with circulatory shock. PMCT shows laparotomy-related complications of abdominal surgery such as postoperative ischemia of the bowel with indirect radiological signs as in the living, a paralytic ileus with bowel distension and the presence of multiple gas\u2013fluid levels. Peritonitis from suture insufficiency after bowel resection, postoperative respiratory failure with pneumonia, wound infections with abscess formation or pyelonephritis are suspected reasons for a septic multi-organ dysfunction syndrome but mostly PMCT offers indirect signs of these conditions only.General soft tissue edema as well as fluid in the peritoneal and pleural cavities is indicative of failure of kidneys, heart and liver. Maximum pulmonary edema without major post-mortem change and pleural effusions demonstrate respiratory failure and sometimes overhydration. The extracardial distribution of contrast medium deposits in the kidneys or in extra-renal organs indicate ante-mortem contrast enhanced imaging in excretion mode-dependent short-term intervals before death and creates an impression of the extent of renal failure.Hemorrhages from dehiscent vessel anastomoses or ligatures after resections of abdominal organs are visualized; however, a collapse of major vessels as a sign of hemorrhagic shock is usually missing because of massive transfusion or hyperhydration.Liver failure is associated in PMCTA with a general elevated tissue enhancement and simultaneous enhancement of arterial and portal structures on the arterial phase images indicating the presence of open arterioportal venous shunts.Fatal outcome after preceding liver transplantation could be due to hepatic artery/portal vein stenosis or thrombosis which are caused by rejection, clamp injury, intimal injury by perfusion catheters or anastomotic ischemia due to a disrupted vasa vasorum.\u00a0Figure\u00a0Coronary bypass surgery includes aortocoronary venous bypasses, left internal mammary artery (LIMA) and right internal mammary artery (RIMA) bypasses which are identified in PMCT by clips in characteristic formation . PMCTA iThe diagnosis of gastric or duodenal ulcers could involve the forensic question how successful a laceration of a bleeding artery at the ulcer bed has been terminated by gastroduodenoscopy. Even at autopsy given the sutured ulcer bed this question may be difficult to assess if gastric and bowel contents do not allow to differentiate within a short time interval. PMCTA helps to identify the sufficiency of vessel closure if not hindered by unspecific contrast extravasation due to post-mortem gastric mucosal destruction.Endoscopic retrograde cholangiopancreatography (ERCP) may be complicated by a rupture of bile duct or pancreatic duct which causes post-ERCP pancreatitis, often promoted by papillotomy or by sampling of suspicious adjacent tissues by endosonographically guided fine-needle aspiration. The post-mortem PMCT diagnostic criteria are direct and indirect signs of bleeding, edema of pancreas and surrounding tissues and accentuation of the renal fascia; in exceptional cases this is combined with the risk of air embolism if gas insufflation into the duct system has not been stopped in time.Specific complications such as a compromised organ perfusion by relocation of vessel disposals should be proved by means of MPMCTA. This is also true for hemodynamically significant dissection or leakage.PMCT after neurosurgical interventions refers to hemorrhage, stroke and traumatic brain injury, the latter indicated by fracture lines, coup and contrecoup lesions. The early post-mortem change with dedifferentiaton of gray and white matter of the brain in PMCT as well as an impaired rendering in the posterior cranial fossa limits sometimes the diagnostic validity and post-mortem MRI could sometimes be the better option for guidance of neuropathological examinations. The enhancement of the intracranial vessels with the MPMCTA transfemoral approach can be blocked by an increased brain pressure. A pronounced block may serve as an indication for intravital brain death. It is possible in some cases to overcome this effect by direct cannulation of the great cervical vessels for contrast agent application Fig.\u00a0a, b.Fig.Medical malpractice allegations after deaths were between 1990 and 2000 in Germany occasion for approximately 4.4\u00a0% of the judicial autopsies; the trend is likely to be increasing since then . The usuIf the patient dies from the effects of treatment failure, negligent homicide, grievous bodily harm with lethal consequences or even manslaughter come into consideration. Among the typical error categories are found primarily the omission of necessary diagnostic or therapeutic procedures and perioperative complications . The forFrequent underlying causes of medical errors are lack of \u201cerror culture\u201d, possibilities for confusion , communication errors among those administering treatment, workload, lack of clarity about the responsibilities and inadequate patient monitoring. Typical case scenarios of unexpected death in hospital, sometimes in the context of medical malpractice allegations, are sudden and fatal deteriorations after surgical and minimally invasive intervention, delayed or fault diagnosis and treatment, death after failed resuscitation , and generally a mismatch between low estimated and risk fatal outcome. All of these are typical scenarios for a potential added value of a multimodal post-mortem analysis including imaging methods. However, under-/overdosage of medical drugs necessitate toxicological investigations and allergic reactions to medical drugs and contrast agents will be evaluated mainly by medical history and laboratory markers.A decline of clinical autopsies results in an overestimation of the sensitivity of clinical ante-mortem diagnosis . ClinicoMPMCTA turns out to be a new method with a highly standardized and evaluated methodology , 25, 33 discrete bleeding sources in small arterial branchesvenous leakages without recognizable lacerations of small venes/venoles, which is typical for the renal bed, mesenterial veins and venous plexus in the pelvic regionbleedings through miniscule defects caused by perforations with tiny instruments such as catheter tipsmultiple bleeding sources which succeed each other at various time pointsMultiphase post-mortem CT angiography contributes to the detection of hemorrhage sources even in cases in which autopsy fails , 14. BloThe concept of MPMCTA distinguishes arterial and venous sources nevertheless early venous enhancement does occur in the arterial phase, particularly in the portal vein . The intDue to the reluctance of medical doctors concerning informed autopsy consent and inadequate prioritization by the legislature  post-morThe evidence for an isolated use of the results of post-mortem imaging in forensic cases is still limited: autopsy remains the gold standard for the morphological diagnosis of thromboembolic complications as post-mortem imaging is restricted to probabilistic approaches concerning the quality of obliterating material in a vessel. Myocardial infarction remains an autopsy- and histology-based diagnosis  even if Another obstacle is the early post-mortem change  with hypArrhythmogenic cardiac deaths due to coronary heart disease are a further example of the limits of current post-mortem imaging . AutopsyPost-mortem cross-sectional imaging has demonstrated essential benefits as an adjunct to forensic autopsy. Enhanced by angiography methods, it facilitates the reconstruction of anatomical conditions in the region of an adverse event during operation. This refers to the anatomical proximity of unintentionally injured structures, the search for sources of bleeding as well as the question of perfusion delivery after vascular procedures. The availability of these techniques should be considered in appropriate cases.Post-mortem imaging allows comparisons with ante-mortem imaging in individual cases and could help in the expert\u2019s delimitation of ex ante and ex-post judgements by clarification of situational conditions in the very moment of a challenged medical action or decision.Taking into account the still limited availability of expertise in post-mortem radiology, a cooperative assessment via teleradiology expert networks could be a preferable option .The combination of imaging and autopsy, histology and toxicology could enhance the cost efficiency of criminal proceedings by accelerated setting the course and avoidance of costly follow-up assessments . Further"}
+{"text": "We report a case of 64-year-old male with prostate cancer and coagulation disorder presented with abdominal distension. He underwent abdomen and pelvis ultrasound for assessment of ascites, which showed localized fluid collections identified at the left and right iliac fossa. After that, non enhanced abdomen and pelvis CT scan was performed and showed heterogeneous organized collections identified along the psoas muscles bilaterally, causing focal contour bulge representing haematoma. Prostate cancer is the second most common urological malignancy to be associated with paraneoplastic syndromes after renal cell carcinoma and one of these syndromes is a hemorrhagic disorder. We report a case of 64-year-old male with prostate cancer and coagulation disorder in form of bilateral psoas muscles hematoma.A 64-year-old man with prostate cancer, bone metastasis and coagulation disorder presented with abdominal distension. He underwent abdomen and pelvis ultrasound for assessment of ascitis, which showed localized fluid collections identified at the left iliac fossa with volume approximately 74 ml and right iliac fossa with volume approximately 48 ml ,Figure 2Prostate cancer is the second most common urological malignancy to be associated with paraneoplastic syndromes after renal cell carcinoma and one of these syndromes is a hemorrhagic disorder. These syndromes tend to occur in the setting of late stage and aggressive tumors with poor overall outcomes. Paraneoplastic syndromes represent a constellation of conditions that are caused by the presence of malignancy, but not attributable to direct tumor invasion or compression. Up to 8% of patients with cancer are estimated to be affected by paraneoplastic syndromes . RecogniHematoma of the psoas muscle in prostate cancer patient is generally secondary to a coagulation disorder. Treatment is two-fold: management of the underlying prostate cancer and supportive therapy for the coagulation disorder."}
+{"text": "Micrasterias denticulata is an exceptional organism due to its complex star-shaped, highly symmetric morphology and has thus attracted the interest of researchers for many decades. As a member of the Streptophyta, Micrasterias is not only genetically closely related to higher land plants but shares common features with them in many physiological and cell biological aspects. These facts, together with its considerable cell size of about 200 \u03bcm, its modest cultivation conditions and the uncomplicated accessibility particularly to any microscopic techniques, make Micrasterias a very well suited cell biological plant model system. The review focuses particularly on cell wall formation and composition, dictyosomal structure and function, cytoskeleton control of growth and morphogenesis as well as on ionic regulation and signal transduction. It has been also shown in the recent years that Micrasterias is a highly sensitive indicator for environmental stress impact such as heavy metals, high salinity, oxidative stress or starvation. Stress induced organelle degradation, autophagy, adaption and detoxification mechanisms have moved in the center of interest and have been investigated with modern microscopic techniques such as 3-D- and analytical electron microscopy as well as with biochemical, physiological and molecular approaches. This review is intended to summarize and discuss the most important results obtained in Micrasterias in the last 20 years and to compare the results to similar processes in higher plant cells.The unicellular freshwater alga  Micrasterias has an exceptional position due to its highly ornamented, star-shaped morphology with deep indentations and furcated lobe tips . By their beauty, their high symmetry and their flat, disk-shaped cell architecture facilitating any microscopic analysis as well as their close relationship to higher plants .ogenesis , 1970a aMicrasterias cell consist of a constant number of 11 cisternae throughout the cell cycle and that they switch a several times during morphogenesis to form the different vesicle populations that contain cell wall precursors for septum-, primary- and secondary wall formation. These results obtained by standard chemical fixation were confirmed in a later study on high pressure frozen Micrasterias cells  syndrome , into the expanding semicell and returns to the cell center at the end of morphogenesis. Coincidently the chloroplast which has duplicated before mitosis, expands itself into the growing semicell. Its shape copies the outer cell shape at the end of development. Both organelle movements are cytoskeleton dependent  clearly show that the cellulose content of the primary wall of the outgrowing lobes is much lower than that of the indentations in which the cell wall is thicker and less extensible. This technique also demonstrates unambiguously the considerable difference in thickness and cellulose content between the growing primary and the non-growing secondary cell wall. The degree of pectin esterification which determines the calcium-binding capacity accounts for the flexibility of the cell wall during primary wall growth. A combination of immuno TEM, immuno fluorescence, de-esterification studies and calcium measurements by TEM-coupled electron energy loss spectroscopy (EELS) has shown  which leads to wall stiffening and growth cessation. Enzyme activity assays provided evidence for the existence of a pectin-desterifying enzyme in M. denticulata. Moreover, enhanced desterification by experimental addition of a pectin methylesterase that de-esterifies pectins in higher plants, resulted in growth inhibition and shape malformation of Micrasterias  in the primary cell wall suggests an involvement of the recognized AGP type 2 proteoglucans  by an antibody directed against higher plant epitopes  suggests that these xyloglucans are secreted in Micrasterias similar to higher plant cells. Interestingly the secondary wall of Micrasterias  but not the primary wall also contains mixed-linked glucans [-\u00df-D-glucans; Ulva lactuca and in the liverwort Lophocolea bidentata by -\u00df-D-glucanase digestion . Thus precise definition of a developmental stage of Micrasterias is easily possible by a TEM image of just a few Golgi bodies and their associated vesicles. As mucilage vesicles are delivered from the dictyosomes consistently, also in non-growing cells  or sodium nitroprusside (SNP) selectively suppressed secondary wall formation in Micrasterias  has yielded first information on the 3-D architecture of Golgi stacks in M. denticulata .Dictyosomes of see also . In growsee also  they havticulata . This metrans-Golgi cisternae were found to be in contact with these trans-ER cisternae. This finding is particularly interesting as \u201ctrans-ER\u201d systems are well known from mammalian cells  in which the cell pattern is only expressed at one half of the cell. Only at the patterned side of the cell calcium influxes were measured or visualized by fluorescent markers, whereas at the non-patterned side no fluorescent signals were visible and outward directed currents were measured  which is regarded as key molecule for intracellular signaling and is involved in developmental and growth processes of higher plants but also in programmed cell death and defense mechanisms  and antagonists  inhibited cell growth and evoked substantial cell shape aberrations when applied to early developmental stages . Particularly the classic acetylcholine-receptor agonist nicotine additionally suppressed formation of the secondary cell wall. The presence of cholinergic receptors in Micrasterias was concluded from these results. They are obviously involved in growth of this alga and thus, like in higher plant cells, represent a basis for light induced differentiation  the dictyosomes become involute, the number of their cisternae decreases and vesicle production is either reduced or completely inhibited . AbnormaMicrasterias is highly adapted to UV-B irradiation, which may explain the worldwide distribution and the presence of this group of algae even in high mountain areas or Polar Regions. It remains to be investigated how the considerable UV-B resistance of Micrasterias is achieved. As in other algae, a protecting function of the surrounding mucilage envelope or of the thick secondary cell wall, absorbance by particular metabolites and/or a very well developed physiological repair system may account for it  represents a key molecule in biotic und abiotic stress and induces programmed cell death (PCD) in plant and animal cells.Unfavorable environmental conditions such as UV irradiation, high light intensities, drought, salinity or man-made entry of heavy metals by traffic or agricultural practices, as well as compounds like herbicides may cause oxidative stress in higher plants but also in aquatic photosynthetic organisms. Among the different reactive oxygen species (ROS) hydrogen peroxide . As the activity of caspase-like proteins known to be involved in PCD of plant cells .Oxidative stress following different kinetics of increased ROS production is also evoked in Micrasterias inhabit, the algae may face rapidly changing osmolarities of their surroundings water by evaporation during high temperature periods as well as by dilution during rain. Additionally the cells are endangered by increase in salinity which may occur due to agricultural practices such as fertilization or to road salt. In contrast to salt tolerant green algae such as Dunaliella, Chlamydomonas or Chlorella that have developed metabolic strategies to cope with elevated salinity  up to 26 mosm/kg results in a steady decrease of the cell number as indicated by a particular cell division assay . Similar structural alterations of mitochondria are known from higher plant cells under anoxic conditions . They increase in size by fusion with ER compartments and are finally absorbed by huge ER cisternae that pervade the cytoplasm. In contrast to our earlier assumptions  it becomes evident that one and the same organism is capable of performing different PCD pathways. This suggests that different stress inductors may activate different cellular reactions. An increase in caspase-3-like activity as found after oxidative stress in Micrasterias  and is also well known from stress response in higher plant cells . Additionally and more specifically, electron dense precipitations in bag-like structures were found in random distribution along the inner side of the cell wall under CrVI impact. The latter structures contained Cr as measured by EELS along with elevated levels of iron and oxygen. As these Cr containing bags were located outside of the plasma membrane these results indicate that Cr is extruded from the Micrasterias cell in form of an iron-oxygen compound  were found in Cd exposed cells. Vesicles were no longer found at the cisternal rims or in surrounding of the dictyosomes indicating a loss in secretion activity. The remaining inoperable dictyosomes consisted of only a few ring-shaped cisternae that were frequently surrounded by dilated ER cisternae . Also the kinetics of ROS production during Cd exposure of Micrasterias corresponds to that during salt stress , excretion by mucilage vesicles and intracellular compartmentalization seem to be the most important detoxification strategies of Micrasterias that allow survival of the cells at least within certain concentration and duration limits.In summary these results show that physiological reactions of Micrasterias is well suited as model system in plant cell biology for multiple reasons. The alga reveals an exceptional multipolar tip growth with several lobes developing simultaneously at the same plane. The continuously changing growing and non-growing zones of the primary cell wall allow for studying growth regulation in directly adjacent areas within one and the same cell and has high potential for providing insight into involvement of the cytoskeleton or ionic components in growth and cell shape formation. The alga develops two distinctly distinguishable cell walls that in their composition both resemble that of higher plant cells. The flexible highly pectic primary wall of Micrasterias is similar to cell walls in tip growing plant cells such as pollen tubes or root hairs and the protective thick cellulose-rich secondary wall corresponds to walls of non-growing higher plant parenchymatic cells. The extremely large dictyosomes that correspond to the large cell size provide excellent possibilities for investigating their function. They are enveloped by a huge ER sheath, consist of a constant number of 11 cisternae during the entire cell cycle and produce vesicle continuously even in non-growing periods. As most of their products are already well defined they lend themselves not only for basic cell biological studies on the function of the secretory machinery but represent also highly sensitive indicators for any kind of stress. Experimental or environmental impact on Micrasterias is easily recognizable not only by cell shape malformations but also by characteristic structural and functional reactions of the dictyosomes. They occur during high salinity or oxidative stress in the same way as during impact by different metal or herbicide pollutants indicating that dictyosomes in Micrasterias are highly sensitive stress sensors. Also degradation of dictyosomes under severe stress, achieved by detachment of single cisternae at both side of a Golgi stack occurs similarly during different stress scenarios. Degraded dictyosomes are absorbed by ER cisternae reflecting the high similarity between Golgi and ER membranes as also known from higher plant cells.This review shows that the alga Micrasterias cells are capable of coping with environmental pollution to a considerable degree. This is accomplished by an obvious physiological flexibility as well as by the capability of the Micrasterias cell of performing autophagy, and of compartmentalizing pollutants in cell walls and vacuoles, respectively, by excreting them via constant mucilage production. The molecular players that are involved in these processes as well as a possible regulation by signal molecules such as phytohomones remains to be investigated. Further establishment of molecular tools and sequencing of essential regulators combined with employment of high resolution 3-D microscopic techniques will enable the next steps for elucidating cell shape formation and for understanding intracellular stress response regulation. By its exceptional features and its close relation to higher land plants Micrasterias may help in detecting plant specific cellular processes and pathways that would remain undiscovered when only using \u201cclassical\u201d model system such as Arabidopsis.Despite their natural adaptation to oligotrophic, low salt-concentrated waters, The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "SHANK3, a gene that has been strongly linked to autism spectrum disorders, is known to be a major cause of the neurobehavioural manifestations of PMS. Buxbaum and co-authors assessed the effects of Shank3 deficiency in three different strains of laboratory mice. Their extensive behavioural tests demonstrate that phenotypes observed in Shank3-deficient mice are largely similar regardless of strain. This indicates that differences in genetic background are unlikely to account for the high variability in disease phenotypes observed in individuals with PMS. This unexpected finding suggests that modifier loci do not play a role in PMS pathogenesis, and other potential contributory factors should be explored to gain a deeper understanding of the underlying disease mechanisms. 667Page The genetic background in which a disease-associated mutation is expressed can have a profound impact on the resulting disease phenotype. The identification of so-called \u2018modifier genes\u2019 can therefore provide insights into disease pathophysiology and could also reveal novel targets for therapeutic intervention. In this study, Joseph Buxbaum and colleagues sought to determine whether modifier loci affect the severity and range of autistic behaviours and developmental deficits associated with the genetic disorder Phelan-McDermid syndrome (PMS). Deletion of"}
+{"text": "Invasive Group-B streptococcal (GBS) disease is a leading cause of infant mortality and morbidity worldwide. GBS colonises the maternal rectum and vagina and transmission of bacteria from a colonized mother to her infant at birth is an important risk factor for GBS disease. GBS disease has also been associated with case reports of transmission via infected breast milk raising questions about mode of acquisition and transmission of this enteric pathogen and the development of neonatal disease. However, most breastfed infants remain unaffected by GBS in breast milk. Mechanisms associated with transmission of GBS in breast milk and potential factors that may protect the infant from transmission remain poorly understood. Understanding factors involved in protection or transmission of GBS infection via breast milk is important both for premature infants who are a high-risk group and for infants in the developing world where breastfeeding is the only sustainable infant feeding option. In this review we discuss the proposed mechanisms for GBS colonization in breast milk on one hand and its immune factors that may protect from transmission of GBS from mother to infant on the other. Innate and adaptive immune factors, including serotype-specific antibody and their significance in the prevention of infant disease are presented. We further report on the role of human oligosaccharides in protection from invasive GBS disease. Advances in our knowledge about breast milk and immunity in GBS disease are needed to fully appreciate what might mitigate transmission from mother to infant and protect neonates from this devastating disease and to contribute to the development of novel prevention strategies, including maternal immunization to prevent infant disease. Early onset (EO) GBS disease (disease presenting in the first six days of life) accounts for approximately 60\u201370% of all GBS disease. GBS serotypes Ia, Ib, II, III and V are responsible for most EO disease [12]In the USA EO disease rates have declined from 1.4 per 1000 live births in 1990 GBS colonizes the rectum and vagina, and maternal colonization is a pre-requisite for EO disease and a risk factor for LO It has been suggested that GBS initially colonizes the infant's oropharyngeal mucosa when contact with maternal vaginal secretions occur at the time of birth Therefore, there appears to be a dichotomy between cases of LO disease through infected breast milk and the potential benefits of the components of breast milk which protect the majority of infants from invasive disease. The underlying mechanisms of GBS transmission or protection through breast milk, are not fully understood, but are important to elucidate, particularly in the context of premature infants who are a high risk group and for infants in the developing world where breastfeeding is the only sustainable infant feeding option. In this review we focus on the peculiarities of GBS that may aid transmission in breast milk and the role of immune parameters such as antibody in breast milk on the other hand that may help protect the breastfed infant from GBS disease.22.1Few studies have identified presence of GBS in breast milk, and methodological differences make comparisons difficult 3 to 109\u00a0cfu/mL of GBS at any point, representing a reservoir of potential infection for the neonatal gut The variety of delivery, treatment and storage methods of breast milk offers potential for GBS contamination. Human breast milk may contain 10Very recently, best practices on the use of breast milk in the context of prevention of GBS neonatal disease have been proposed, including the search for GBS in milk at the time of recurrent GBS neonatal disease and in cases of mastitis in mothers of high-risk preterm neonates admitted to neonatal intensive care units 2.2Two main mechanisms of acquisition have been proposed: following colonization of the neonatal oropharynx at the time of birth, mothers may develop colonization of the milk ducts through ascending infection from the neonate, due to the retrograde flow of milk associated with suckling. The infant is then reinfected as the concentration of bacteria increases in the breast milk GBS may infect the submucosa of the gastrointestinal tract either through a defect in the epithelial cell layer, or by concomitant infectious agents 33.1l-selectin and CD14, which may mediate differentiation and growth of B cells Breast milk is the main source of non-pathogenic bacteria to the infant gastrointestinal tract. Intestinal bacteria are one of the most important stimuli for the development of mucosa-associated lymphoid tissue (MALT) in the neonatal small intestine Human breast milk is known to contain factors that can modulate toll-like receptor (TLR) signaling, including soluble TLR2, which can competitively inhibit signaling through membrane TLR2 4Neonates have low levels of SIgA and SIgM It is currently hypothesized that SIgA represents the crucial primary protective component of breast milk 5SIgA production is enhanced by Interleukin-6 (IL-6) whilst the production of secretory components is enhanced by TNF-\u03b1 and TGF-\u03b2 causes class switching towards B cells producing IgA Vibrio cholerae, Campylobacter, Shigella, Giardia lamblia and respiratory tract infections was significantly related to the content of SIgA antibody in breast milk against these pathogens SIgA antibodies present in breast milk are specific for numerous enteric and respiratory pathogens. In studies from resource-poor countries, breast milk-mediated protection against infections with SIgA is more resistant to proteolysis than other immunoglobulins and is therefore able to function in the gastrointestinal tract S. pneumoniae and Haemophilus influenza to human retropharyngeal cells Breast milk contains SIgA antibodies against bacterial-adhesion-site-like pili N. meningitidis-specific IgA antibodies in breast milk up to six months post partum in vaccinated infants H. influenzae vaccine in the third trimester and remained higher at seven months post partum. [69]The effect of third trimester maternal immunization with a single dose of licensed quadrivalent meningococcal vaccine on the potential protection of infants, including by breast milk demonstrated elevated 6As described above, high levels of breast milk SIgA could offer protection to neonates via interference of antibody with the carbohydrate-mediated attachment of GBS to nasopharyngeal epithelial cells. Through this mechanism, colonizing organism load may be reduced with a consequent reduction in morbidity and mortality caused by GBS in the neonatal period In transition milk, low or moderate IgA antibodies to CPS type III GBS, were detected in approximately 63% of a cohort of 70 Swedish women To determine the effect of maternal immunization with GBS CPS-II and CPS-III antibody on postnatal protection from disease a rodent model has been used, where increased survival in pups exposed postnatally to breast milk with high titers of antibody compared to low titers was shown, supporting the beneficial added effect of breast milk antibody following vaccination 7S. pneumoniaeEscherichia coli (E. coli) E. coli and Campylobacter jejuni toxin can be neutralized by oligosaccharides Vibrio cholera and E. coliOligosaccharides prevent cell adherence for GBS type Ib and II polysaccharides are of interest as they are virtually identical to certain oligosaccharides present in human milk 8Most neonatal infections occur via mucosal membranes in the respiratory, gastrointestinal, and urinary tracts, yet there is only limited protection at these vast mucosal surfaces during the neonatal period. Breast milk provides considerable amounts of specific SIgA antibodies that are produced as a result of microbial and food antigens the mother has previously encountered. Such SIgA antibodies from breast milk provide protection to the neonate at the mucosal surface. Breast milk additionally contains high concentrations of non-specific protective molecules, such as lactoferrin that has bactericidal, viricidal, and fungicidal properties. Milk oligosaccharides might block adherence of microorganism at the mucosal surface by functioning as receptor analogues.H. influenzae infections, as well as wheezing illness may persist for years after breastfeeding. However, the role of breast milk antibody in protection from neonatal GBS disease remains poorly understood. Current research is evaluating transport, persistence and function of GBS antibodies and other immune-constituents in breast milk. These studies aim to identify protective factors involved in the passive transfer of immune components in breast milk and associated protection from colonization and infant disease. Additionally, research correlating neonatal colonization with antibody levels in breast milk would provide insight into possibly protective factors from disease.There is increasing data from recent publications that enhanced protection against diarrhea, respiratory tract infections, otitis media and None declared.KLD developed the research idea, undertook the literature review and prepared the first draft of the manuscript. BK developed the research idea and substantially contributed to the drafting and revision of the manuscript.Wellcome Trust/Imperial Global Health Fellowship and the Royal College of Physicians Thomas Watt Eden Fellowship. BK is funded by the MRC and the NIHR.KLD is funded by a"}
+{"text": "Missing data represent a potential source of bias in randomized clinical trials (RCTs). A simple approach that makes use of the responses subsequently obtained via reminder is proposed to assess the validity of the inferences from a missing at random (MAR)-based primary analysis of incomplete RCTs.We explored mechanism behind the reminder responses in two pragmatic RCTs - the TATE and STarT Back trials - by utilizing the fact that data that are recovered through reminders would otherwise have been missing. The present approach considered two data scenarios: (i) with the actual dataset and (ii) with a modified dataset, where outcome responses obtained after a certain number of reminders were treated as missing. The impact of the reminder responses was assessed by comparing the estimates from MAR-based analyses between the two data scenarios.In the TATE trial, the reminder approach showed that an MAR-based analysis was likely to yield biased estimates of treatment effect. Therefore, further sensitivity analyses were required under a range of plausible missing not at random (MNAR) assumptions. However, in the STarT Back trial, this approach showed that an MAR-based analysis was likely to yield an unbiased estimate of treatment effect.The proposed reminder approach can be used to assess the robustness of the MAR assumption by checking expected consistency in MAR-based estimates. If the results deviate, then MAR-based estimates are likely to be biased, and analyses incorporating a range of plausible MNAR assumptions are advisable at least as sensitivity tests for the evaluation of treatment effect."}
+{"text": "Head and neck cancers (HNCs) are aggressive tumors that typically demonstrate a high glycolytic rate, which results in resistance to cytotoxic therapy and poor prognosis. Due to their location these tumors specifically impair food intake and quality of life, so that prevention of weight loss through nutrition support becomes an important treatment goal. Dietary restriction of carbohydrates (CHOs) and their replacement with fat, mostly in form of a ketogenic diet (KD), have been suggested to accommodate for both the altered tumor cell metabolism and cancer-associated weight loss. In this review, I present three specific rationales for CHO restriction and nutritional ketosis as supportive treatment options for the HNC patient. These are (1) targeting the origin and specific aspects of tumor glycolysis; (2) protecting normal tissue from but sensitizing tumor tissue to radiation- and chemotherapy induced cell kill; (3) supporting body and muscle mass maintenance. While most of these benefits of CHO restriction apply to cancer in general, specific aspects of implementation are discussed in relation to HNC patients. While CHO restriction seems feasible in HNC patients the available evidence indicates that its role may extend beyond fighting malnutrition to fighting HNC itself. Head and neck cancer (HNC) is a collective term for cancers originating from the lip, oral and nasal cavity, paranasal sinuses, pharynx, larynx and trachea. Approximately 90% of HNCs are head and neck squamous cell carcinoma (HNSCC) originating from the mucosal lining (epithelium) of these regions.,Frequent comorbidities of HNCs include various feeding difficulties and malnutrition that are often aggravated by tobacco and alcohol abuse and a general unhealthy lifestyle,,-Like most aggressive tumors, HNCs exhibit a high rate of and dependence on glycolysis to meet their metabolic demandsIn this review I am going to present three main rationales for the implementation of CHO restricted and KDs in HNC patients. Briefly, these are (1) targeting the altered tumor cell metabolism; (2) increasing the radio- and chemosensitivity of malignant cells while protecting normal cells; (3) accounting for the altered metabolism of the tumor-bearing host. Due to the various problems regarding food intake, the question remains whether CHO restriction is feasible in HNC patients. In the final part of this paper, I therefore address specific aspects and practical issues of such a dietary intervention.-in vivo and in vitro measurements, Warburg showed that compared to normal tissues, tumors would take up several times more glucose from the surroundings and ferment the majority of it to lactate even in the presence of sufficient oxygen that would normally suppress lactate production. This metabolic phenotype of increased glucose uptake and lactate production is therefore known as the Warburg effect or aerobic glycolysis since it also happens in normoxic conditions.A hallmark of HNC, like most cancers in general, is their high avidity for glucose uptake. Otto Warburg and his co-workers at the former Kaiser Wilhelm-Institute for Biology in Berlin were the first to quantify glucose uptake and energy generation in a large variety of animal and human tumors18F)fluoro-2-deoxy-D-glucose (FDG). FDG is structurally similar to glucose except for the substitution of an OH group by the positron emitter 18F. Similar to glucose it therefore enters the cells through glucose transporters and gets phosphorylated by the enzyme hexokinase. Unlike glucose, however, FDG cannot be further metabolized after phosphorylation to FDG-6-phosphate and stays trapped inside the cell until it decays. The amount of assimilated FDG is quantified by the standardized uptake value (SUV) which expresses the ratio between the measured tissue activity and the injected activity standardized to body weight. In HNC FDG-PET in combination with computer tomography (PET/CT) has shown great benefit for tumor and lymph node staging, detection of an unknown primary tumor, radiation treatment planning, evaluation of therapy response and long-term surveillance,-The Warburg effect is the basic principle behind molecular imaging using positron emission tomography (PET) with the glucose analog 2--acetate PET measurements of tumor perfusion and oxidative metabolism in a small cohort of HNSCC patients that indicated that tumors utilizing predominantly glycolysis are more resistant to ionizing radiation than those with high cellular respiration,,et al.The correlation between glycolytic rate and tumor aggressiveness is not only reflected on the side of glucose influx and hexokinase activity, but also at the final step of glucose fermentation in which pyruvate gets reduced to lactate. A large proportion of HNSCC overexpress lactate dehydrogenase 5, the enzyme that catalyzes this conversion, and this was correlated with poor prognosis,,,,-On a molecular level HNC is a heterogeneous disease, complicating prognostication and the search for causative factorsTP53 gene is found to be mutated in approximately 60% of all HNSCC, and its protein product p53 inactive in another 20% due to degradation by the human papilloma virus oncoprotein E6,,,-TP53-induced glycolysis and apoptosis regulator (TIGAR) is often observed in tumor cells, causing an up-regulation of the oxidative and non-oxidative PPP which are important for the production of NADPH and ribose-5-phosphate (an anabolic intermediate needed for nucleotide production), respectivelyThe tumor suppressor p53 is one example since its activity and stability can be regulated through lysine methylation and acetylation by various histone-modifying proteins. Although epigenetic silencing of p53 seems rare in HNSCC,,-,,et al.,SDHC gene encoding the C subunit of the TCA cycle enzyme succinate dehydrogenase. As a consequence succinate accumulates in the mitochondria and leaks out into the cytosol where it inhibits certain prolyl hydroxylase enzymes leading to stabilization of HIF-1\u03b1 and aerobic glycolysisHRAS transformation impairs mitochondrial respiration which subsequently increases glycolysis without compromising mitochondrial mass or contentFinally, p53 plays an important role in mitochondrial DNA (mtDNA) repair and stability, and some studies have shown associations between mutant p53 and mtDNA mutationsin vitro experiments have shown that cancer cells are particularly vulnerable to glucose (and glutamine) restriction,,-,,,,,The shift in HNC metabolism towards aerobic glycolysis concurrently provides high energy production, cytotoxic stress resistance, building blocks for rapid proliferation and the ability to migrate out of the cell compartment. However, this comes at the expense of metabolic flexibility. The genetic and epigenetic alterations found in HNC cells in conjunction with mitochondrial defects and hypoxia leave these cells extremely dependent on a steady supply of nutrients, especially glucose. Numerous -,et al.CHO restriction and its replacement with fat elevate free fatty acids and decreases glucose concentrations in serum. Fatty acids\u2014in particular the saturated ones\u2014have been shown to inhibit the key glycolytic enzymes hexokinase, phosphofructokinase, pyruvate kinase and lactate dehydrogenase-The role of hypoxia in up-regulating glycolytic enzymes and glucose entry into the cells is well established. Already Warburg was aware of the poor capillary network of tumor tissue and hypothesized that tumors are more vulnerable to simultaneous glucose and oxygen deprivation due their worse \u201cchannels of supply\u201d,,CHO restriction has the ability to counteract signaling through the phosphatidylinositol-3 kinase\u2212Akt\u2212mammalian target of rapamycin (PI3K\u2212Akt\u2212mTOR) pathway. This pathway is activated by insulin and growth factors such as insulin-like growth factor-1 (IGF-1) and its effect is, among others, an up-regulation of glycolysis,Conflicting and often negative results concerning an association between IGF-1 and cancer have been reported for a variety of cancers including HNC,,Insulin inhibition may be less effective in later stages of tumor progression as genetic and epigenetic alterations accumulate and chronically activate the PI3K\u2212Akt\u2212mTOR pathwayIn summary CHO restriction and KDs in particular exert systemic effects on oncogenic signaling pathways that counteract tumor glycolysis but\u2014owing to the complexity of the signaling networks involved and the large genetic heterogeneity of HNC tumors\u2014need to be further investigated.,-The relationship between inflammation and HNSCC becomes apparent from a Hungarian study showing an increased prevalence of oral inflammatory, premalignant and cancerous lesions among diabetics compared to healthy controlset al.P<0.0001) risk factor for locoregional failure and death. Although detailed information on the composition of the nutritional support was lacking, it is clear that the standard nutrition support formulas used at that time contained a high percentage of high glycemic CHOs which would lead to blood sugar and insulin spikes and fuel inflammation. It is also clear from these results that the treating physician should not only focus on the quantity of calories, but that their quality might be more important for patient survival.It therefore seems prudent to limit high blood glucose spikes that may particularly occur with nutritional support containing simple sugars. In a retrospective analysis of data from the RTOG 90-03 trial involving 1,073 HNSCC patients, Rabinovitch ,,-,The optimal treatment of HNC requires a multidisciplinary approach in which radiation therapy constitutes the major modality besides surgery-With few exceptions, normal tissues readily oxidize ketone bodies thereby decreasing the mitochondrial NADP+/NADPH ratio. This in turn increases the amount of reduced GSH available for scavenging ROSCHO restriction also up-regulates lipid oxidation which increases the intracellular NAD+/NADH ratio and thus amplifies the NAD+-dependent activity of SIRT1in vitro data indicate that ketone bodies themselves can have anti-proliferative effects on some tumor cells,,,,CHO restriction may also impair tumor re-growth during radiotherapy fractions and delay the accelerated proliferation that is known to start in HNSCC at some point during radiation treatment. We have previously reviewed the wealth of preclinical data showing that CHO restriction alone delays tumor growth in a variety of tumor models-Some preclinical studies have further shown that CHO restriction either in the form of overall calorie restrictionIn summary, there is evidence that CHO restriction acts as a cytotoxic sensitizer in tumor tissue while simultaneously protecting normal tissue which supports its implementation during standard treatment for HNC. The main effects are summarized in ---,,Unintentional weight loss is a common problem in HNC patients. It is often present already at the time of diagnosis and indicates malnutrition or an early cachectic state. Weight loss is usually influenced by disease- and treatment-associated problems with food intake such as dysphagia, xerostomia, mucositis and anorexia. Cachexia differs from malnutrition or physiological states of low calorie intake in that it is characterized by a progressively increasing change in whole-body metabolism that induces a continuous loss of skeletal, but not visceral, tissue. It is driven by a complex interaction between the tumor and its host involving a multitude of heterogeneous factors that are, however, mostly connected to chronic systemic inflammation,et al.et al.,These metabolic alterations indicate a general dysfunction in the utilization of glucose and an increased demand on fat as an energy source. This is quite contrary to the metabolism of tumor tissue that mainly utilizes glucose. It has therefore been recommended to account for these metabolic differences between the tumor and its host through either a high-fat low-CHO diet or a KDIn HNC patients, even \u201csufficient\u201d energy and protein intakes have been shown to be insufficient for preventing significant weight and lean tissue loss during treatment,-,,,Despite the evidence outlined above showing how CHO restriction counteracts tumor glycolysis, accounts for the altered metabolism of the tumor-bearing patient and may even improve the tolerability of radiation treatment, some authors still question the scientific rationale for the KD and deny any possible benefitsStudies so far have shown that individual dietary counselling during radiotherapy of HNC is more effective than standard or no dietary advice for preventing long-term weight loss and improving quality of life, although the effects of these interventions on mortality have not been assessedIn conclusion, CHO restriction in the HNC patient seems feasible and therefore realistic, but requires additional time and effort as it has to be tailored towards the individual patient. This, however, is a general problem in HNC patients, and efforts on nutritional counselling generally seem to pay off. Clearly, the tolerability of and response to CHO restricted diets is also individual and some patients reach ketosis more easily than others. Hopefully future studies will show which patients benefit most from CHO restriction. Currently a phase I clinical trial (NCT01975766) at the university of Iowa recruits HNSCC patients to investigate the safety of a KD plus concurrent chemoradiation with a secondary outcome being progression-free survival. Until the results are published, this paper hopefully encourages physicians to make their own experience with offering CHO restriction to their patients as a non-toxic approach to fight HNC."}
+{"text": "Here, we present a new computational modelling approach for estimating viral fitness that relies on common sparse cross-sectional clinical data by combining statistical approaches to learn drug-specific mutational pathways and resistance factors with viral dynamics models to represent the host-virus interaction and actions of drug mechanistically. We estimate in vivo fitness characteristics of mutant genotypes for two antiretroviral drugs, the reverse transcriptase inhibitor zidovudine (ZDV) and the protease inhibitor indinavir (IDV). Well-known features of HIV-1 fitness landscapes are recovered, both in the absence and presence of drugs. We quantify the complex interplay between fitness costs and resistance by computing selective advantages for different mutants. Our approach extends naturally to multiple drugs and we illustrate this by simulating a dual therapy with ZDV and IDV to assess therapy failure. The combined statistical and dynamical modelling approach may help in dissecting the effects of fitness costs and resistance with the ultimate aim of assisting the choice of salvage therapies after treatment failure.Despite the success of highly active antiretroviral therapy (HAART) in the management of human immunodeficiency virus (HIV)-1 infection, virological failure due to drug resistance development remains a major challenge. Resistant mutants display reduced drug susceptibilities, but in the absence of drug, they generally have a lower fitness than the wild type, owing to a mutation-incurred cost. The interaction between these fitness costs and drug resistance dictates the appearance of mutants and influences viral suppression and therapeutic success. Assessing  in vivo viral infection dynamics. This approach enables us to estimate mutant fitness characteristics. We illustrate our method by predicting fitness characteristics of mutant genotypes for two different antiretroviral therapies with the drugs zidovudine and indinavir. We recover several established features of mutant fitnesses and quantify fitness characteristics both in the absence and presence of drugs. Our model extends naturally to multiple drugs and we illustrate this by simulating a dual therapy with ZDV and IDV to assess therapy failure. Additionally, our modelling approach relies only on cross-sectional clinical data. We believe that such an approach is a highly valuable tool in assisting the choice of salvage therapies after treatment failure.Mutations conferring drug resistance represent major threats to the therapeutic success of highly active antiretroviral therapy (HAART) against human immunodeficiency virus (HIV)-1 infection. Viral mutants differ in their fitness and assessing viral fitness is a challenging task. In this article, we estimate drug-specific mutational pathways by learning from clinical data using statistical techniques and incorporate these into mathematical models of  Understanding the accumulation of mutations and associated genotypic and phenotypic changes is critical for prediction of treatment failure and selection of optimal patient-specific treatments in vitro settings in vitro fitness measures  learning drug-specific mutational pathways from cross-sectional in vivo data and modelling viral infection dynamics on these genotype lattices, and (ii) by coupling the resistance factor, an abundant and accessible in vitro measure of drug resistance, to drug efficacy and rate constants of the virus-host dynamics in vivo. This approach allows to leverage sparse clinical data for the estimation of in vivo fitness characteristics, which is a first step towards analyzing and ultimately predicting clinical outcomes of drug combinations and assessing causes of therapy failure.The objective of this article is to enable estimation of in vivo data is based on continuous-time conjunctive Bayesian networks in vitro data by isotonic regression models. The integration is finally achieved by a quantity common to both approaches, the estimated/predicted waiting time for different mutations.Specifically, our statistical approach to estimate mutational pathways from There has been great interest in performing simulations of antiretroviral therapy to assess treatment outcome. Recent studies We estimate fitness characteristics of mutants for two antiretroviral drugs from two different major drug classes: zidovudine (ZDV), a nucleoside reverse transcriptase inhibitor, and indinavir (IDV), a protease inhibitor. Then, we characterize the interplay between fitness costs and resistances in mutant selection during therapy by computing selective advantages of different mutant genotypes. Finally, we illustrate how our model extends to multiple drug therapy by simulating a dual therapy with ZDV and IDV and examine reasons for virological failure in such a setting.We used a dataset obtained from the Stanford HIV Drug Resistance Database described in Using this dataset, the resistance factors of the genotypes and the partially ordered set (poset) of resistance mutations were estimated using isotonic conjunctive Bayesian network (I-CBN) models. In conjunctive Bayesian networks, a partial order is used to encode dependencies among mutations. A genotype is formally defined as a subset of mutations. The set of genotypes compatible with the order constraints of the poset is called the genotype lattice . In the We used a drug efficacy of in vitro assays and some in vivo observations. The agreement holds true for general reported ranges of fitness costs  of alid see . Across In addition to estimated fitness characteristics, the viral load time courses predicted by our model gave insights into the dynamics of different mutations. In the TAM-2 pathway, we observed a transient disappearance of mutation 70R before its eventual fixation, as was reported earlier We again used the Stanford HIV Drug Resistance Database The estimated fitness costs, resistance factors and selective advantages  agreed wIn addition to these general fitness trends, specific characteristics of particular mutations were also in line with prior findings. The minor mutation 71V is known to play a compensatory role Nijhuis et al. As with ZDV, we studied parameter identifiability by considering an ensemble of fits with an RMSD stimates  to be veThere is great interest in using viral dynamics models to study antiretroviral treatment to assess therapy outcomes and simulate clinical trials We observed that there are different regimes of the individual drug efficacies . Subsequent to this, we were able to simulate the dual therapy and assess genotypic reasons of therapy failure.in vivo mutational landscapes. Our approach relies on typical and frequently available clinical data, which consists of left-censored observations, as opposed to extensive time course measurements of different mutant genotypes, that are generally scarce. Mutations are detected through their appearance in specific mutant genotypes and our model describes how their dynamics is coupled. Although there is considerable debate on appropriate measures of fitness and clinically relevant quantifiers in vivo clinical relevance as correlations between fitness measures and standard treatment outcome markers, such as viral load, We have presented an HIV-1 infection dynamics model with statistically learned drug-specific in vivo fitness characteristics has relied on detailed viral load measurements of different mutant strains, which is rarely possible in realistic clinical situations. Our approach utilized statistical learning methods to estimate mutational landscapes from clinical data that were then incorporated into a mechanistic viral dynamics model. Our results are also in agreement with an earlier study So far, mechanistic modelling of HIV infection has mainly used fixed fitness costs with the infection dynamics being examined for different values of these fitness costs The simulation of antiretroviral treatments has generated interest, particularly in the context of assessing therapy failure and in explaining puzzling clinical observations. For example, clinical trials have shown in vivo mutation landscapes aimed at capturing the complex competition dynamics between the different mutant strains. It was based on a simplified representation of drug pharmacokinetics (PK) and effect. If detailed data on drug PK and patient-specific viral load dynamics and baseline characteristics are available, a population-pharmacokinetic/pharmacodynamic analysis would be the appropriate approach to account for inter-individual variations The presented viral infection dynamics model incorporating drug-specific There are several mechanisms of resistance in HIV-1 infection. In addition to the mechanisms included in the two-stage virus dynamics model, features such as the compensatory Gag mutations in vivo mutational landscapes and allows for the estimation of mutant fitness characteristics. Importantly, it relies only on cross-sectional clinical data and, as demonstrated, extends naturally to combination therapies. We believe that it is a promising approach to analyze treatment outcomes with drug combinations or to study optimal switching strategies.In summary, we have presented a new approach to model HIV-1 infection dynamics that incorporates drug-specific The viral infection cycle was described by the two-stage model presented in vice-versa), we set Mutations in the viral genome occur during the process of reverse transcription, but manifest themselves only after the viral DNA has been integrated into the host genome. Hence, mutations were modelled to occur between early infected cells . However, as in In detailed mechanistic models with nonlinearities, parameter identifiability and sloppiness in estimation is a common concern More details on the RMSD threshold and the number of fits considered are provided in the Supplementary For dual therapy with ZDV and IDV, the poset was constructed by combining the posets of the individual drugs. If If ode15s in MATLAB R2010b with relative and absolute tolerances of For simulations of the dual therapy with ZDV and IDV, we used the variable order ODE-solver Figure S1Cumulative histograms of correlations of fitnesses between valid fits and best fit.(PDF)Click here for additional data file.Figure S2Distribution of mechanistic waiting times from 1000 simulations of the virus dynamics model.(PDF)Click here for additional data file.Figure S3Two compartment pharmacokinetic model for ZDV and fluctuating drug-effect.(PDF)Click here for additional data file.Figure S4Variability of resistance factors under ZDV and IDV therapy.(PDF)Click here for additional data file.Figure S5Predicted mutational abundance from 500 hybrid deterministic-stochastic simulations of IDV monotherapy.(PDF)Click here for additional data file.Figure S6Cumulative histograms of correlations of fitness costs between fits with varying RFs and the best fit.(PDF)Click here for additional data file.Table S1Parameters of viral dynamics model used in the simulations.(PDF)Click here for additional data file.Table S2Statistical and mechanistic waiting times to observe mutations under ZDV and IDV monotherapy.(PDF)Click here for additional data file.Table S3Conservation of estimated fitness characteristics of ZDV and IDV mutants amongst valid fits.(PDF)Click here for additional data file.Table S4Statistical and mechanistic waiting times to observe mutations under ZDV monotherapy with ZDV concentration described by a two-compartment pharmacokinetic model.(PDF)Click here for additional data file.Table S5Mean and variance of observed resistance factors for ZDV and IDV mutants.(PDF)Click here for additional data file.Table S6Median of mechanistic waiting times predicted from 500 hybrid deterministic-stochastic simulations of the model for IDV monotherapy.(PDF)Click here for additional data file.Text S1Model descriptions, parameter sensitivity, pharmacokinetics and hybrid deterministic-stochastic simulations.(PDF)Click here for additional data file."}
+{"text": "Cardiac remodeling describes the heart's multimodal response to a myriad of external or intrinsic stimuli and stressors most of which are probably only incompletely elucidated to date. Over many years the signaling molecules involved in these remodeling processes have been dichotomized according to a classic antagonistic view of black and white, i.e., attributed either a solely maladaptive or entirely beneficial character. By dissecting controversies, recent developments and shifts in perspective surrounding the three major cardiac signaling molecules calcineurin (Cn), protein kinase A (PKA) and calcium/calmodulin-dependent kinase II (CaMKII), this review challenges this dualistic view and advocates the nature and dignity of each of these key mediators of cardiac remodeling as a multilayered, highly context-sensitive and sophisticated continuum that can be markedly swayed and influenced by a multitude of environmental factors and crosstalk mechanisms. Furthermore this review delineates the importance and essential contributions of degradation and proteolysis to cardiac plasticity and homeostasis and finally aims to integrate the various aspects of protein synthesis and turnover into a comprehensive picture. Heart failure is the leading cause of death in industrialized countries , maternal cardiac growth during pregnancy and exercise-induced cardiac hypertrophy are all considered physiological entities of hypertrophy, pathological hypertrophic responses are observed upon sustained neurohumoral activation and abnormal mechanical stretch of the myocardium as common findings of various cardiac disease entities. These include but are not limited to ischemic events , pressure overload conditions such as arterial hypertension and aortic valve stenosis, genetic disorders due to alterations in key sarcomeric or metabolic proteins as well as infectious and toxic triggers  can be optimized (remodeled) by technicians (key mediators) to perform according to the present demand by employing different fuel (metabolic), spare parts and logistics . These remodeling efforts can either be construed as long-lasting, sustainable and deliberate optimizations , or endeavors can be targeted at drastic, short-term improvements which will not be sustainable for a longer period of time but provide immediate and powerful responses to increased demands . Furthermore, it appears crucial whether the demand will have to be fulfilled infinitely  or whether periods exist when the machine can (temporarily) cool down and reduce its output (as in exercise-related hypertrophy).Allegorically, cardiac plasticity could be referred to as the maintenance and adjustment of a machine subjected to heavy and undulating workload. The machine  driving these changes of the machine may be similar or even the same in various aspects of remodeling. However, their intentions, perspectives and approaches may be different depending on a vast number of environmental, extrinsic and intrinsic factors.Finalizing this allegorical approach, the technicians  as well as shifts in perspective in terms of relative importance of select mechanisms in cardiac remodeling .Calcineurin (Cn), one of the heart's most intensively studied enzymes, is a calcium-dependent serine/threonine phosphatase controlling key functions and processes in response to a wide range of stress stimuli. Calcineurin is composed as a heterodimer of catalytic (CnA) and smaller regulatory subunits (CnB) with CnA-alpha and CnA-beta as well as CnB1 constituting the relevant myocardial isoforms  dichotomy has evolved into a more sophisticated view of calcineurin in particular and cardiac remodeling in general  to be protective after myocardial infarction  as effectors of multiple upstream cascades modify NFAT-dependent DNA-interaction and integrate various pathways into meticulously tuned stress responses  shades of gray in cardiac remodeling rather than confined to the black-and-white dualism that dominated the last decades of research in the field of cardiac remodeling.Protein kinase A or cyclic AMP-dependent Kinase (PKA) constitutes the canonical downstream effector of the \u03b2-adrenergic cascade in myocardial signaling. Activation of the beta-adrenergic receptor (\u03b2AR), perhaps the heart's most crucial subclass of G-protein coupled receptor (GPCR), by catecholamines primarily elicits an increase in cellular cAMP via induction of cytosolic adenylyl cyclase  crosstalk of PKA with CaMKII, perhaps the most intricately intertwined protagonists and pathways of myocyte remodeling.The (erratic) viewpoint of PKA as a detrimental player in cardiac remodeling and heart failure was significantly stimulated by the adverse cardiac phenotype observed in a transgenic mouse model overexpressing constitutively active PKA  as the most intriguing elicitor  and respective sensors and counterparts are integral parts of (sub)cellular signaling in many compartments of each cell. They contribute greatly to the myocyte's stress response and remodeling efforts  may serve as another illustration of the complexity of cardiomyocyte signaling and remodeling mechanisms.Calcium-Calmodulin-dependent Kinase II (CaMKII) is at the center of multiple cardiac signaling cascades and modulates the heart's response to various extrinsic and intrinsic stimuli , calcium handling proteins  as well as various calcium and sodium channels , but sometimes even phosphorylate a protein at the exact same amino acid position  by inducing proteolysis, thereby selectively repressing myocyte enhancer factor-2 (MEF2) activity and shutting out CaMKII signaling tracks  cardiac remodeling. As previously delineated both signaling pathways  critically contribute to the pressure overload-induced phenotype of adverse remodeling, but knockout of both cardiac CaMKII genes demonstrates the supremacy of CaMKII for the maladaptive nature of remodeling in this setting, while calcineurin\u2014when isolated from CaMKII crosstalk and interdependency\u2014also seems to trigger beneficial processes in terms of a more physiological remodeling phenotype , but has been shown to be dephosphorylated by calcineurin, the third pivotal mediator of cardiac remodeling covered in this review  remodeling accelerates and cardiac function declines  coupling as well as multiple other cellular pathways which modulate the heart's quintessential function: force-generation for contraction of blood to supply the body with oxygen  target parts of the contractile apparatus such as troponin I (MuRF-1) and myosin heavy chain (MuRF-1 and \u22123). In congruence, MuRFs  have been shown as essential modulators of the hypertrophic remodeling process /desmin-related myopathies (DRM), generally clustered as a subgroup of the heterogeneous group of dilated cardiomyopathies (DCM), also highlight the critical implications of the UPS for remodeling research. They prove beyond doubt that loss of degradation capacities\u2014which is generally due to mutations in sarcomeric proteins, that render these mutated proteins less stable in the constant wear and tear, or even cause them to be misfolded from the beginning\u2014is indeed causative and crucial for the development of hypertrophic remodeling and deterioration of cardiac function in its wake  lead to hypertrophic cardiomyopathy (HCM) associated with impairment of the UPS, establishing cMyBPC as the paradigm of HCM-studies , it appears very likely that a number of ubiquitin ligases targeting PKA, CaMKII and CnA are still unidentified and may be very important for a comprehensive picture of the mechanisms that control cardiac remodeling  or lead to improvement of UPS function itself  intricately affect each other and prove the cardiac remodeling processes to be comprehensive and minutely tuned programs that integrate all cellular pathways into a highly plastic and flexible machinery Figure .In summary, this review provides some thought-provoking impulses on emerging or ongoing controversies and shifts in perspective surrounding myocardial remodeling rather than trying to comprehensively cover the myriad of elaborate mechanisms of cardiac signaling.Therefore the two key messages are:Protagonists of cardiac remodeling demonstrate multifaceted crosstalk and significant interdependency in a highly context-sensitive nature. Therefore it is our opinion that they cannot be easily classified in terms of a black and white dualism but appear to roam a gradual continuum of \u201cfifty (or more) shades of gray.\u201dWhile protein synthesis and its regulation remain paramount for our understanding of cardiac adaptations, a shift in perspective has occurred in recent years as the mechanisms of maintenance and turnover of proteins have increasingly been recognized as essential aspects of sustained homeostasis\u2014or to put it in other words: \u201cGrowing tired (?)\u2014get a shrink before burn-out!\u201dThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Staphylococcus spp. are the most important Gram-positive causative agents of sepsis and are responsible for ~ 50% of sepsis and pyoinflammatory diseases in Ukraine. Up to 70% of Ukrainian staphylococci are also methicillin resistant which is determined by the genetic cassette SCCmec encoding the mecA \u03b2-lactam resistance gene. Besides mecA, some types of SCCmecs can also carry different genes of resistances to antibiotics like vancomycin etc. Until now nine types of SCCmec have been discovered based on the genetic construction, described and epidemiologically traced worldwide. It is now clear that new SCCmecs with enhanced antibiotic resistance characteristics are naturally appearing due to anthropogenic activities. Ukraine being geographically on a crossroads between Asia and Europe, having a big borderline with four countries-member of the EU and three non-EU European countries and exploiting a medical system where any antibiotic is easy to get without a doctor prescription can have a really dramatic impact on the SCCmec evolution in Europe. For this reason, a rapid screening assay with the following analysis of the SCCmecs is very much needed for the early identification of new SCCmecs in Ukraine and prediction of new epidemiological waves in Europe.Sepsis and its after-effects are currently significant problems in hospital medicine. Successful treatment depends on the early detection of the etiological agent of the sepsis and of any antibiotic resistances. Bacteria that belong to mec in Ukrainian staphylococci.was to elaborate a PCR rapid diagnostic test to reveal SCCStaphylococcus spp. isolates obtained from patients of the Institute of Traumatology and Orthopaedics of the NAMS of Ukraine.Four PCR-based assays -4 for memec was developed and implemented.A new \u201cin house\u201d multiplex PCR test based on  for the mec has been now created and constantly supplemented.A rapid PCR-based test for \u03b2-lactam resistance identification is now available in Ukraine. A collection of Ukrainian MRSA from different regions with PCR-determined presence of SCCmecs with the detailed analysis of new SCCmec variants may impact prediction of new epidemiological waves in Europe.We recommend to organize project based on direct bacteria identification using SCCmec for implementation rapid screening in Ukraine. The epidemiological monitoring of Ukrainian SCC"}
+{"text": "How a living cell responds to exogenous materials is one of the fundamental questions in the life sciences. In particular, understanding the mechanisms by which a cell recognizes exogenous double-stranded DNA (dsDNA) is important for immunology research because it will facilitate the control of pathogen infections that entail the presence of exogenous dsDNA in the cytoplasm of host cells. Several cytosolic dsDNA sensor proteins that trigger innate immune responses have been identified and the downstream signaling pathways have been investigated. However, the events that occur at the site of exogenous dsDNA when it is exposed to the cytosol of the host cell remain unknown. Using dsDNA-coated polystyrene beads incorporated into living cells, we recently found that barrier-to-autointegration factor (BAF) binds to the exogenous dsDNA immediately after its appearance in the cytosol and plays a role in DNA avoidance of autophagy. Our findings reveal a novel pathway in which BAF plays a key role in the detection of and response to exogenous dsDNA. The rapid detection of exogenous materials and subsequent responses are important for the survival of living cells in variable environments.Understanding intracellular fates of exogenous dsDNA after endosome breakdown is also important for the development of appropriate dsDNA carriers that ensure an efficient and yet safe nucleic acid delivery system. Many non-viral dsDNA carriers, including lipid-based and polymer-based DNA carriers, have been developed and are widely used for transgene expression.in vitro.We recently reported the use of DNA-coated beads in which barrier-to-autointegration factor (BAF) acts as a cytosolic dsDNA sensor in mammalian cells.in vitro,The physiological significance of this BAF-mediated sequestration of exogenous dsDNA from autophagy remains unknown. Because autophagy is believed to act as an intracellular defense system that leads the targets to degradation, BAF acts in a somewhat opposite manner from its defense function. We speculate that BAF-mediated NE-like membrane assembly may function as a stronger defense system against exogenous dsDNAs than autophagy by rapidly compacting and isolating the DNA to prevent gene expression and replication. In fact, it is known that BAF can compact viral DNAs by bridging them In conclusion, direct visualization of BAF-mediated detection of exogenous dsDNA exposed to the cytosol of host cells shows an intimate link between the detection of exogenous dsDNA and subsequent intracellular responses. Our bead-mediated method will provide new insight into such responses to the entry of exogenous materials into a cell."}
+{"text": "Economic evaluation alongside trials is often based on data collected through self-reported questionnaires. Consequently, there are consistent problems with incomplete (missing) data irrespective of how well data collection methods are designed. Missing data poses a significant problem when conducting economic analyses of clinical trials, potentially leading to incorrect conclusions being drawn concerning an interventions\u2019 cost-effectiveness.Trials which collect economic data through multiple sources, such as hospital records in addition to patient self-reports, present an efficient and relatively simple means of investigating the impact different sources of data may have on the outcome of the economic evaluation of a trial. The present study uses data from a large randomised controlled trial of a family based intervention which collected health care resource use via both self-report, as well as through Hospital Episode Statistics (HES) data, sourced from the Health and Social Care Information Centre (HSCIC), to explore one method of dealing with missing data.Multiple Imputation (MI) is the recommended statistical approach for evaluating the impact of missing data. Using data from the randomised controlled trial, we are able to compare two datasets; one derived via multiple imputation of self-reported data which contained missing values, and the other being HES data, which is assumed to be an accurate and objective representation of actual health care resource use.These data sets allow us to assess the effectiveness of multiple imputation at estimating the \u2018truth\u2019 and explore how the different methods of data collection can impact on final cost-effectiveness results."}
+{"text": "The ability to form associations between aversive threats and their predictors is fundamental to survival. However, fear and anxiety in excess are detrimental and are a hallmark of psychiatric diseases such as post-traumatic stress disorder (PTSD). PTSD symptomatology includes persistent and intrusive thoughts of an experienced trauma, suggesting an inability to downregulate fear when a corresponding threat has subsided. Convergent evidence from human and rodent studies supports a role for the medial prefrontal cortex (mPFC)-amygdala network in both PTSD and the regulation of fear memory expression. In particular, current models stipulate that the prelimbic (PL) and infralimbic (IL) subdivisions of the rodent mPFC bidirectionally regulate fear expression via differential recruitment of amygdala neuronal subpopulations. However, an array of recent studies that employ new technical approaches has fundamentally challenged this interpretation. Here we explore how a new emphasis on the contribution of inhibitory neuronal populations, subcortical structures and the passage of time is reshaping our understanding of mPFC-amygdala circuits and their control over fear. Exposure to threats triggers a powerful form of learning that mediates the expression of survival-promoting behavior. The neural circuitry underlying this learning has been dissected largely through the use of Pavlovian fear conditioning, in which animals develop an association between a neutral conditioned stimulus (CS) and an aversive unconditioned stimulus , which plays a central role in fear responding to discrete cues as well as contexts. BLA cell types include principal excitatory neurons and a sparse, heterogeneous population of GABAergic interneurons  has emerged as a potential key player in long-term memory expression with reciprocal connectivity to the CeA  that ultimately gives rise to long-term fear and extinction memory. This will in turn help pinpoint with better clarity the dysfunctional mechanisms of fear processing that underlie conditions like PTSD. The new insights described here suggest that while these disorders may involve some degree of mPFC and BLA dysfunction, they might ultimately be more effectively addressed by treatments directed at extended fear regulatory circuits that are nevertheless heavily influenced by mPFC-BLA networks.This work was supported by NIH grant MH105414 (RLC), a Young Investigator Award from the Brain and Behavior Research Foundation (RLC), and a Human Frontiers Science Program Long-Term Fellowship (LT000191/2014-L) (MAC).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Cystic Fibrosis (CF) lung disease is characterized by liquid hyperabsorption, airway surface dehydration, and impaired mucociliary clearance (MCC). Herein, we present a compartment-based mathematical model of the airway that extends the resolution of functional imaging data.in vitro to gauge the fraction of airway epithelial cells that have functional ciliary activity.Using functional imaging data to inform our model, we developed a system of mechanism-motivated ordinary differential equations to describe the mucociliary clearance and absorption of aerosolized radiolabeled particle and small molecules probes from human subjects with and without CF. We also utilized a novel imaging metric This model, and its incorporated kinetic rate parameters, captures the MCC and liquid dynamics of the hyperabsorptive state in CF airways and the mitigation of that state by hypertonic saline treatment.We postulate, based on the model structure and its ability to capture clinical patient data, that patients with CF have regions of airway with diminished MCC function that can be recruited with hypertonic saline treatment. In so doing, this model structure not only makes a case for durable osmotic agents used in lung-region specific treatments, but also may provide a possible clinical endpoint, the fraction of functional ciliated airway. Cystic Fibrosis (CF) is an autosomal recessive disease that arises from a defect in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. CF affects multiple organ systems, with the most detrimental effects occurring in the lungs Inhaled agents that reverse osmotic gradients in the airways are used to treat the ASL dehydration defect associated with CF. Hypertonic saline (HS) is one such osmotic agent that has been shown to increase both MCC and lung function in patients with CF in vivo method utilizes Technetium 99m sulfur colloid (Tc-SC) as the non-absorbable particle probe and Indium 111-DTPA (DTPA) as the small molecule probe. The probes are delivered together in a liquid aerosol. in vitro studies have demonstrated a relationship between DTPA and airway surface liquid absorption rates in vivo in CF airways and in vitro in CF airway cell cultures in vitro and in vivoOutcome measures and biomarkers that quantify the basic pathophysiology of CF lung disease are needed to allow for the rapid screening of new therapeutics for CF. Ideally, these screening methods seek to quantify the basic pathophysiology of CF lung disease. Mucociliary clearance scans, which quantify the clearance of a radiolabeled particulate from the lungs, are one such functional imaging method for studying outcomes in CF. We have expanded this method to include measuring the clearance of a radiolabeled small-molecule that can be absorbed as well as cleared via MCC. Similar techniques have been used in the past to resolve the individual components of lung clearance Herein we present a compartment-based model of particle and small molecule clearance from the human respiratory tract that uses functional imaging data to inform model structure and quantitate parameter values. Our goal in developing this model is to better resolve the specific physiological mechanisms that contribute to the composite functional imaging result. We believe that these mechanism-specific measurements may provide more sensitive and specific evaluations of therapeutic efficacy than the currently used image-derived metrics. The challenge is to construct a mathematical representation of the physiology that can resolve the underlying mechanisms and their interactions.There have been a number of compartment-based pharmacokinetic (PK) models for inhaled pharmaceuticals Starting from the original model of Sakagami A fraction of the large airways  and hypertonic saline on alternating study days DTPA is assumed to deposit in the same regions and clear by MCC at the same rate as Tc-SC; DTPA absorption is then captured by regressing the parameters Our model predicts that both Tc-SC retention and liquid absorption will follow trajectories within narrow envelopes based on the predicted upper and lower 95% confidence intervals (CIs) of the model parameters. These CI envelopes are derived using all possible combinations of the upper and lower 95% CIs and nominal values of the model parameters to generate the extreme values of model predictions. It has been proposed that the apparent increase of MCC following HS treatment occurs by increasing the rate at which MCC occurs ter FFCA , which dOur model also agrees with the previous reports that absorption, represented by In order to verify that hydration increases the fraction of functional ciliated area, we imaged CF HBE cultures  before and after addition of 10 in vivo and in vitroThe failure of the CF airway epithelium to secrete We have developed a model that considers the basic mechanisms governing small molecule and particle probe clearance from physiologically distinct compartments of the lung. The combination of these mechanisms is reflected in the imaging result. Compartment or mechanism specific results provide additional insight into CF lung pathophysiology and therapeutic mechanisms of action. They may also provide more sensitive and accurate predictions of therapeutic efficacy than analyses of the composite imaging data as the compartmental description incorporates the inherent time-correlation of mass transport within the model structure.Our physically descriptive model includes central and peripheral lung compartments. The central zone includes large airways, intermediate and small airways, and alveoli while the peripheral zone includes only intermediate and small airways and alveoli lsqnonlin  and nlparci  yielded wide parameter confidence intervals, approximately An alternative, and more highly parameterized, model than that shown in While a two-compartment model, like that proposed by Sakagami in Results section may fail to include mechanisms that could manifest on timescales longer than the 80 minute imaging period. To address the question of model appropriateness on the timescales of our data, we compared our model to the following alternative model structures with AIC as the basis for quantitative comparison:The model structure presented in Case 1. Exclude Case 2. Include The AIC values of each case above, in comparison to the model in et al.in vitro findings presented here, that our estimation of FFCA as a model parameter is grounded in realistic physiology.In non-CF subjects, FFCA is found to be in vitro studies have related DTPA hyperabsorption to liquid hyperabsorption Our model asserts that the rate of DTPA absorption  may help to differentiate their functional effects. The limited time scale of imaging (80 minutes) in the current study may have also limited assessment of small airway mucociliary clearance. Extended-duration imaging studies may yield additional data that can inform processes with slower rates and model parameters such as Our original study see  describein vivo imaging data is ongoing. The model also predicts that FFCA is reduced in patients with CF as compared to the healthy population. We used this prediction as a hypothesis about inducing a functional change in vivo that can be tested in vitro. To further elucidate this phenomenon, and validate that such behavior is possible, we performed in vitro studies with HBE cell cultures. A quantitative visual assay of ciliary movement demonstrated that a larger fraction of the cell culture surface was activated after the addition of hypertonic saline vs. isotonic saline.Response to HS inhalation was apparent in terms of both decreased absorption and increased MCC as compared to IS inhalation. These trends are reflected in our modeled result. Our model suggests that the observed increase in MCC following HS inhalation is due to an increase in FFCA rather than an increase in MCC rate, and a detailed analysis of this hypothesis using the Some previous imaging studies have shown significant differences in whole lung MCC between CF and non-CF subjects Applications of this model may include the design of dosing regimens for agents targeting changes in MCC and/or absorption. For example, the timeline of the effects associated with an osmotic therapy (correction of liquid absorption defects) could be assessed independently of the resulting secondary effects . Dosing timed in accordance with the duration of the counter-absorptive effect may provide more continuous clearance from the lungs and patient benefit, though outcome assessment is beyond the scope of the model at present. The model could also be used to resolve the pharmacodynamics of medications with subtle, complex, or multiple therapeutic effects, to the degree that these agents impact MCC and absorption.in vivo in a real-time manner. This model should, therefore, be extendable to other treatments, both present and future, that target the liquid hyperabsorption and MCC deficiency present in cystic fibrosis.Our physiologically motivated compartmental model is able to reproduce the clearance behavior of both large particle (Tc-SC) and small molecule (DTPA) radiolabeled probes as informed by functional imaging data. The model asserts that liquid absorption rate is increased in the peripheral lung of patients with CF as compared to non-CF subjects, and that hypertonic saline will decrease the rate of absorption in patients with CF to near non-CF levels. Our model also attributes increased MCC induced by hypertonic saline treatment to an increase in airway surface area with functional ciliary clearance, as opposed to an increased rate of clearance. The physiology inherent to the model structure and parameterization allow for increased sensitivity in gauging the effects of hypertonic saline Data from previously reported clinical imaging studies were utilized in vitro studies have demonstrated a relationship between DTPA and ASL absorption. Since DTPA has no known route for intracellular transport this relationship is presumably due to the contribution of paracellular liquid flows. Changes in DTPA absorption in response to osmotic therapies have previously been demonstrated both in vitroin vivoThe aerosolized probes were delivered simultaneously by nebulizer using a technique that deposited aerosol primarily in the airways Discussion).Sakagami Regression of model parameters, regardless of model structure, was performed sequentially as follows. Model parameters were estimated using nonlinear least-squares regression . Akaike Where a Gaussian distribution represents the maximum likelihood of the data and k is the number of free parameters in the model. Thus, the model with the least value of AIC is deemed most appropriate in terms of model fit and parsimony. Yamaoka and colleagues Where in vitro imaging assay to measure the fraction of the epithelium that has functional MCC in order to test our hypotheses that FFCA is decreased in CF and that hydration can recruit areas of otherwise non-functional cilia. Fully differentiated human bronchial epithelial (HBE) cell cultures were viewed using a phase-contrast objective (Nikon Eclipse TI). These cultures were derived from lungs removed at the time of lung transplantation and prepared using previously described methods approved by the University of Pittsburgh IRB We developed an ging see  for datatine see  for dataFigure S1Shown is the initial posterior frame of a Tc-SC imaging series. The dotted outline of the right lung is a tracing of the outline of the lung as it appears in a transmission scan. The filled in blue rectangle is the (TIF)Click here for additional data file.Figure S2A pseudo-color image of non-CF HBE cells under 10\u00d7 enhancement is shown. The viewing frame is identical to that in (TIF)Click here for additional data file.Table S1Raw Tc-SC and In-DTPA counts in whole lung ROI and central lung ROI over the length of imaging.(PDF)Click here for additional data file.Table S2FFCA in CF HBE cells is shown at baseline compared to a 5 ul addition of either isotonic or hypotonic saline.(PDF)Click here for additional data file.Table S3FFCA in CF HBE cells is shown at baseline, after one 10 ul addition of basolateral DMEM, and after a second, sequential addition of basolateral DMEM.(PDF)Click here for additional data file.Video S1A video of ciliary motion in non-CF HBE cells under 10\u00d7 phase-contrast enhancement is shown. The viewing frame is identical to that in (AVI)Click here for additional data file."}
+{"text": "Recent advances such as the generation of mouse models expressing fluorescently labeled receptors, of TAT based peptides that can disrupt a given heteromer pair, or of heteromer-selective antibodies that recognize the heteromer in endogenous tissue have begun to elucidate the physiological and pathological roles of receptor heteromers. In this review we have focused on heteromer-selective antibodies and describe how a subtractive immunization strategy can be successfully used to generate antibodies that selectively recognize a desired heteromer pair. We also describe the uses of these antibodies to detect the presence of heteromers, to study their properties in endogenous tissues, and to monitor changes in heteromer levels under pathological conditions. Together, these findings suggest that G protein-coupled receptor heteromers represent unique targets for the development of drugs with reduced side-effects.Over the last decade an increasing number of studies have focused on the ability of G protein-coupled receptors to form heteromers and explored how receptor heteromerization modulates the binding, signaling and trafficking properties of individual receptors. Most of these studies were carried out in heterologous cells expressing epitope tagged receptors. Very little information is available about the  B receptors, members of the family C of G protein-coupled receptors (GPCRs), form constitutive heteromers  shifted competitive radiolabeled leucine-enkephalin displacement curves by unlabeled leucine-enkephalin (a \u03b4 OR agonist) into non-competitive curves  as well as in cells co-expressing both receptors  the binding affinity of selective synthetic agonists is decreased while that of endogenous peptidic agonists is increased  TAT fused peptides that disrupt \u03bc OR-\u03b4 OR heteromerization in vitro compared to cells expressing individual receptors  found them to be expressed in the same neuroblastoma cell line . These included (i) additive effects on signaling in N18TG neuroblastoma cells by a combination of opioid and cannabinoid ligands  suggested possible interactions between these receptors (Teixeira-Clerc et al., Although reagents that selectively disrupt CB1R-AT1R heteromers and ligands that selectively target this heteromer pair have not as yet been generated, antibodies that selectively recognize this heteromer have Table . In addiIn this review we describe how a subtractive immunization strategy can be successfully used to generate monoclonal antibodies that are selective for a given heteromer pair and that can be useful for examination of endogenous heteromers. Even though the procedure is time consuming, and requires a number of controls during screening procedures for determining the heteromer-selectivity of the antibodies, there are many advantages to developing the heteromer selective antibodies. These include the fact that they recognize a unique epitope that is present only in cells/tissues expressing the heteromer of interest, and thus they could be used to map the targeted heteromer in endogenous tissue and to monitor changes in heteromer levels during pathological conditions. In addition, heteromer-selective antibodies are also useful to discriminate the contribution of the heteromer from individual receptor homomers for a given signaling response. Finally, in select cases heteromer-selective antibodies have been useful to block a biological response. In this case the antibodies could be used as therapeutic targets in pathological conditions where heteromer levels are upregulated in addition to being useful in the identification of heteromer-selective/biased ligands. Thus, heteromer-selective antibodies represent unique and invaluable tools that would help in our understanding of the physiological roles of GPCR heteromers in endogenous tissues.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Sclerolinum contortum symbiosis inhabits sulfidic sediments at deep-sea hydrocarbon seeps in the Gulf of Mexico. A single symbiont phylotype in the symbiont-housing organ is inferred from phylogenetic analyses of the 16S ribosomal ribonucleic acid (16S rRNA) gene and fluorescent in situ hybridization. The phylotype we studied here, and a previous study from an arctic hydrocarbon seep population, reveal identical 16S rRNA symbiont gene sequences. While sulfide is apparently the energy source for the symbionts (and ultimately the gutless host), both partners also have to cope with its toxicity. This study demonstrates abundant large sulfur crystals restricted to the trophosome area. Based on Raman microspectroscopy and energy dispersive X-ray analysis, these crystals have the same S8 sulfur configuration as the recently described small sulfur vesicles formed in the symbionts. The crystals reside adjacent to the symbionts in the trophosome. This suggests that their formation is either extra- or intracellular in symbionts. We propose that formation of these crystals provides both energy-storage compounds for the symbionts and serves the symbiosis by removing excess toxic sulfide from host tissues. This symbiont-mediated sulfide detoxification may have been crucial for the establishment of thiotrophic symbiosis and continues to remain an important function of the symbionts.The siboglinid tubeworm  Hydrogen sulfide is an energy-rich source for chemolithoautotrophic, sulfur-oxidizing bacteria, but it is also highly toxic to aerobic organisms because of its inhibition of the respiratory enzyme cytochrome c oxidase at even nanomolecular concentrations , has been reported from hydrocarbon seeps in the Arctic Sea . We demonstrate the presence of large sulfur crystals within the trophosome, restricted to posterior areas of the animals that are exposed to sulfide in the sediments, using high-pressure freezing and freeze substitution for light microscopy (LM), scanning electron microscopy, Raman microspectroscopy and energy dispersive X-ray analysis (EDX). We further provide evidence from electron micrographs that symbiotic bacteria produce extracellular sulfur deposits resulting in gigantic crystals. We propose that the endosymbionts play a major role in sulfide detoxification by producing non-toxic sulfur crystals from excess hydrogen sulfide that enters the worm, thus enabling the host to reside in an environment with an abundant energy source for its symbionts and reduced competition and predation because of its toxicity to most other fauna.Since the discovery of the symbiotic lifestyle of Siboglinidae much emphasis was put on the nutritional relationship et\u2009al., ; 1991a,.Sclerolinum contortum tubeworms . Most of the tube was straight and buried in mud, but the anterior end was curled and extended above the seafloor (We discovered three hydrocarbon seep sites at depths between 2000 and 2700\u2009m in the Gulf of Mexico with dense populations of S.\u2009contortum specimen from WR 269 based on 16S rRNA gene sequence (Supporting information). The software pintail  from a Guaymas Basin vent and an uncultured bacterium (98% similarity) associated with tubes of the vestimentiferan Lamellibrachia sp. from cold seeps of the Mediterranean Sea  (Supporting information) , 5.4 to 8.6\u2009cm in length, revealed abundant, giant crystals that were even visible through the worm's tube under the dissecting microscope Fig.\u2009A. Two ki\u22121 ] fixative and buffer  the same distribution patterns of crystals in the trophosome are present in ffer see  never deSeveral facts point to a symbiont origin of the sulfur crystals. Their occurrence is limited to the symbiont-housing organ and adjacent to symbionts, rather than distributed among symbiont-containing and symbiont-free host tissue. Furthermore, both bacterial sulfur vesicles and sulfur crystals have the same sulfur S8 configuration.Thiorhodospira sibirica and other members of Ectothiorhodospiraceae  are known from many free-living bacteria of the families obacilli . For somS.\u2009contortum may serve not only as energy generation and storage for the bacteria themselves, but also provide another benefit for the host in this mutualistic association. Sulfide oxidation to elemental sulfur will reduce the amount of toxic sulfide in the host and thus help the host to deal with exposure to the sulfide that the symbionts require. Such behaviour in which the partner provides goods to the other at no costs, but as an automatic, coincident consequence of a selfish trait is termed by-product benefit and is considered one of the driving forces in the evolution and maintenance of mutualism (West We suggest that the oxidation of sulfide to elemental sulfur performed by the symbionts of S.\u2009contortum. Sulfide conversion into different non-toxic sulfur compounds, mostly sulfite, sulfate, or thiosulfate, is a widespread phenomenon of free-living animals and of animals associated with thiotrophic bacteria in sulfidic environments. Sulfide oxidation activity has been demonstrated in Nereis polychaete worms (Solemya reidi (Saduria entomon detoxifies sulfide to thiosulfate and sulfite (Bythograea thermydron to thiosulfate and sulfate (Many animals are capable of detoxifying sulfide without the aid of symbionts. However, none of these animals produce large sulfur crystals such as we detected in te worms  and the ya reidi . The iso sulfite , the venS.\u2009contortum exploit the energy contained in sulfide and provide nutrition to the gutless host (S.\u2009contortum to inhabit environments with higher sulfide levels than would otherwise be possible. We suggest that the sulfide-oxidizing and -detoxifying function of the symbiont was potentially as important in the evolution of the symbiosis as the more obvious nutritional benefits to the host.The sulfur-oxidizing endosymbionts of"}
+{"text": "We describe a case with three focal atrial tachycardias (ATs) and focal atrial fibrillation (AF) originating from the interatrial septum (IAS) near the atrioventricular node (AVN). Contrast-enhanced computed tomography demonstrated the association of fat deposition within the anterior IAS near the AVN with successful ablation sites of these ATs and AF. This is the first report that the intramural fat deposition in the IAS could be associated with the formation of AT and AF re-entry circuits originating near the AVN. Atrial tachycardia (AT) originating near the atrioventricular node (AVN) has been shown to originate from calcium channel-dependent tissue located close to the AVN . HoweverA 69-year-old man was referred to our hospital with palpitations. His electrocardiogram showed a regular AT with narrow QRS AT-1, Fig. , Fig. 1aThis case presented both focal ATs and focal AF originating from the IAS near the AVN. Contrast-enhanced CT demonstrated a heterogeneous fat pad in the interatrial septum surrounded by focal triggers for these atrial arrhythmias. The induction of these ATs with programmed stimulation and behavior during entrainment mapping was consistent with micro re-entry as the tachycardia mechanism. These ATs may have shared a central common pathway, as suggested by the proximity of their successful ablation sites across the IAS near the AVN Fig. . In addiThis is the first study to report that the intramural fat deposition in the IAS could be associated with the formation of AT and AF re-entry circuits originating near the AVN. Further study will be required to investigate the association of fat depositions in the IAS with atrial tachyarrhythmias originating near the AVN."}
+{"text": "The emerging links between our gut microbiome and the central nervous system (CNS) are regarded as a paradigm shift in neuroscience with possible implications for not only understanding the pathophysiology of stress-related psychiatric disorders, but also their treatment. Thus the gut microbiome and its influence on host barrier function is positioned to be a critical node within the brain-gut axis. Mounting preclinical evidence broadly suggests that the gut microbiota can modulate brain development, function and behavior by immune, endocrine and neural pathways of the brain-gut-microbiota axis. Detailed mechanistic insights explaining these specific interactions are currently underdeveloped. However, the concept that a \u201cleaky gut\u201d may facilitate communication between the microbiota and these key signaling pathways has gained traction. Deficits in intestinal permeability may underpin the chronic low-grade inflammation observed in disorders such as depression and the gut microbiome plays a critical role in regulating intestinal permeability. In this review we will discuss the possible role played by the gut microbiota in maintaining intestinal barrier function and the CNS consequences when it becomes disrupted. We will draw on both clinical and preclinical evidence to support this concept as well as the key features of the gut microbiota which are necessary for normal intestinal barrier function. However, it is currently unclear whether this effect was mediated via maternal microbial transmission or through microbiota-independent events. Nonetheless, those infants with altered microbiota composition exhibited a higher level of infant GI symptoms and allergic reactions, highlighting the functional consequences of aberrant colonization patterns in early life  is a stress-related functional brain-gut-microbiota axis disorder associated with an altered gut microbiota profile  water supply identified an increased rate of IBS two years after the outbreak  are evolutionarily conserved type I transmembrane proteins that function as pattern recognition receptors (PRRs) and recognize microbial components  of one or a limited number of microbial genus(era)/species in the gut microbiota that confer(s) health benefits to the host Gibson, . PreclinThe area of microbiome research needs to move beyond purely compositional assessments to understanding the potential mechanisms by which dysbiosis contributes to the pathophysiology of disease. Preclinical research points to a role of the gut microbiome in brain function and behavior with a number of potential pathways being investigated. The possibility that these effects might be mediated by alterations in intestinal permeability is supported by converging lines of evidence. This includes evidence linking stress to both compromised barrier function and microbiota disruption with the ensuing systemic inflammation mediating the impact on the expression of neuropsychiatric symptoms (see Figure The Microbiome Institute has conducted studies in collaboration with several companies including GSK, Pfizer, Wyeth and Mead Johnson. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The host interferon (IFN) response represents one of the first barriers that influenza viruses must surmount in order to establish an infection. Many advances have been made in recent years in understanding the interactions between influenza viruses and the interferon system. In this review, we summarise recent work regarding activation of the type I IFN response by influenza viruses, including attempts to identify the viral RNA responsible for IFN induction, the stage of the virus life cycle at which it is generated and the role of defective viruses in this process. In addition, the wide host range of the virus and the potential for genome reassortment between human influenza viruses and those of other species mean these viruses present a pandemic threat. To establish a productive infection and thus cause disease, influenza viruses must overcome host innate immune responses that are very rapidly activated during infections. The interferon (IFN) family of antiviral cytokines play a major role in these responses and are critical in restricting the early stages of virus infections prior to the activation of the adaptive immune system. The IFNs and other innate immune mediators have serious implications for the outcome of influenza virus infections in terms of disease severity, since highly pathogenic viruses are often associated with excessive cytokine responses . In this2The IFNs are expressed and secreted following the detection of viral components within infected cells; subsequent binding of IFN to its cognate receptor at cell surfaces leads to the upregulation of hundreds of different interferon-stimulated genes (ISGs) that establish an \u2018antiviral state\u2019 to efficiently limit further replication and spread of the virus  and the type III IFNs (IFN-\u03bb) are directly upregulated following virus infection; these are the major IFNs secreted following influenza virus infections in vitro and in vivo . In contThe IFN induction cascade becomes stimulated following the recognition of certain molecular structures that are absent in uninfected cells, termed pathogen-associated molecular patterns (PAMPs). For RNA virus infections, these PAMPs are predominantly certain features of viral RNA that are not usually present in cellular RNAs, such as regions of double-stranded RNA (dsRNA) or the presence of a 5\u2032-triphosphate (5\u2032ppp) or a 5\u2032-diphosphate (5\u2032pp) group. The pathogen-recognition receptors (PRRs) play a critical role in the distinction of self from non-self molecules by binding to PAMPs within infected cells. Two types of PRRs have been implicated in the induction of IFNs by influenza viruses, with the role of a particular PRR depending on the cell type and nature of the viral stimuli. The Toll-like receptor (TLR) family of transmembrane proteins are able to recognise a wide range of microbial ligands, and signal downstream through either MyD88 (myeloid differentiation primary response 88) or TRIF (Toll-interleukin-1 receptor (TIR)-domain-containing adaptor inducing interferon (IFN)-\u03b2) adaptor proteins to stimulate IFN expression, depending on the particular TLR , consisting of RIG-I, MDA-5 and LGP2. These receptors are essential for IFN induction during RNA virus infections of non-pDC cell-types, and mice that are deficient in RLR signalling pathways are extremely susceptible to RNA viruses despite possessing intact TLR systems . Both RIRIG-I and MDA-5 each recognise different types of viral RNA, with RIG-I most efficiently activated by short stretches of 5\u2032ppp or 5\u2032pp dsRNA while MDA-5 is activated by longer stretches of dsRNA in a 5\u2032 phosphate-independent manner; these PRRs have therefore been shown to recognise different families of RNA viruses . Knockdo3The influenza virus genome is composed of eight different segments of single-stranded negative-sense viral RNA (vRNA) that exists in virions in the form of viral ribonucleoproteins (vRNPs) which are the minimum units required for viral transcription and replication . vRNPs a4If naked cRNAs and vRNAs were generated during the replication of the influenza virus genome, cRNA:vRNA hybridisation would lead to the formation of RIG-I and MDA-5 ligands, activation of the IFN response and restriction of virus replication. To avoid this, influenza virus employs strategies to evade detection by RLRs, thus allowing the virus to replicate efficiently without inducing IFN. Firstly, unlike other RNA viruses that replicate exclusively in the cytoplasm, influenza virus transcription and replication is nuclear. Since RIG-I and MDA-5 are confined to the cytoplasm, nuclear genome replication means that cRNA and progeny vRNAs are generated at a site that is inaccessible to these PRRs. Secondly, the synthesis of full-length cRNA from vRNA and vice versa is very closely coupled to encapsidation; the interaction between the first nucleoprotein monomer and polymerase at 5\u2032 end of the RNA is thought to nucleate the sequence-independent encapsidation of the nascent RNA . Consequ5in vitro transcription reactions, in addition to the expected ssRNA transcript  respectively that are highly conserved across segments and virus subtypes (with the exception of a U4C variation in the 3\u2032 terminus of some genome segments) . These sto cells  suggestito cells  have alsto cells . This maWhile short free RNAs with the conserved 3\u2032 and 5\u2032 terminal sequences of vRNA forms a panhandle structure , evidencThe number of vRNA molecules within an infected cell vastly outnumbers cRNA, with the proportion of vRNAs to cRNAs estimated at between 10:1 and 40:1, depending on the segment . For thi77.1in vitro transcription reactions or by RNA extractions from infected cells have been shown to induce IFN, yet such free RNAs would not be expected to be generated during virus infections due to vRNA and cRNA encapsidation. Two studies therefore addressed the nature of the \u2018genuine\u2019 viral PAMPs responsible for activating RIG-I during influenza virus infections. Naked viral RNAs generated by The identification of influenza virus RNA, and in particular vRNA, as ligands of RIG-I in these studies is not surprising, given that the vRNA panhandle possesses the characteristics required for RIG-I activation. What remains to be determined however is how the vRNA panhandle structure is able to form in infected cells, since replication of the virus genome is so closely coupled to encapsidation of the nascent RNA. Two scenarios can be envisaged regarding RIG-I activation during influenza virus infections. The first is that free vRNA, forming a panhandle, is generated erroneously at some point in a virus infection; if this is the case, when and how is this free RNA species generated? The second is that RIG-I can somehow recognise vRNA within the context of a vRNP. Since the polymerase obscures the genome termini, the latter of these scenarios would presumably require displacement of the polymerase from the vRNA promoter for RIG-I recognition. Interestingly, the individual polymerase subunits have been found to associate with RIG-I in an RNA-independent manner ; althoug7.2Since influenza viruses replicate in the nucleus and RIG-I resides in the cytoplasm, incoming and progeny genomes traversing the cytoplasm are the most obvious candidates for triggering IFN induction, and there is some debate about the contribution of each of these to RIG-I activation by influenza viruses. Full-length genome replication requires ongoing viral protein synthesis due to the requirement for concurrent encapsidation by NP and newly synthesised polymerase ; the traIncoming viral nucleocapsids have been implicated in RIG-I activation by members of the Bunyaviridae, which also possess segmented negative-sense RNA genomes with a 5\u2032ppp panhandle structure ; activatde novo synthesised polymerase and NP are required to stabilise the cRNA and prevent its degradation by host nucleases  functioning as a more significant PAMP population later in infection. The nature of the PAMPs that are generated in the presence of cycloheximide but not in the presence of cellular transcription inhibitors has not yet been elucidated, and although the sensitivity of IRF3 activation to viral transcription inhibitors may superficially suggest that viral mRNAs can function as IFN inducers, the fact that influenza virus mRNAs are 5\u2032 capped and polyadenylated like host mRNAs makes this unlikely. Moreover, viral mRNAs cannot be detected in RIG-I immunoprecipitations from infected cells, the immunostimulatory activity of RIG-I associated RNA is sensitive to calf intestinal phosphatase treatment (which removes 5\u2032 phosphates), and RNA capable of inducing IFN is still generated in RNP reconstitutions containing a transcription-defective viral polymerase . It is oucleases . Unencap7.3The observations that influenza viruses only activate the IFN response in a fraction of infected cells with both wild-type and NS1-defective viruses  Chen et stronglyin vivo has been questioned. However, several recent studies have suggested an important role for DIs in natural influenza virus infections and in disease outcome. Internal deletion DI viruses similar to those identified in vitro have been detected in samples from infected mice (de novo during in vivo infections (in vivo comparisons of the effects of DI-poor or DI-rich influenza virus preparations have shown that the presence of high numbers of DIs is associated with enhanced IFN-\u03b2 expression in the lungs of infected mice and a reduction in animal morbidity (Influenza virus readily generates DI genomes; DI influenza viruses were first identified in the 1950s as \u2018incomplete\u2019 non-infectious viruses that were selected for upon serial passage of the virus in embryonated chicken eggs at high multiplicity  and theyted mice , poultryted mice  and humated mice . Furtherfections  and the fections . Evidencfections . Subsequfections . Perez-Cfections . We havefections . Recent orbidity . Moreoveorbidity  protectsorbidity . This prorbidity . What reorbidity , internaorbidity  or affecorbidity . Perhapsorbidity , form a orbidity ; thus, i8in vitro and in vivo? Lastly, why are influenza DIs better able to induce IFN than non-defective virus? Multiple factors are likely to influence IFN induction by influenza virus during an infection, including the rate of virus replication, its ability to actively antagonise IFN induction, the rate of DI generation by the viral polymerase and also factors conferred by the host; by gaining a broader comprehension of all of these contributing elements, we can more fully understand the interactions between influenza virus and the IFN system and apply this understanding to the development of novel anti-influenza therapies.Innate immune responses, including the IFNs, play a critical role in determining the pathogenicity and outcome of an influenza virus infection: efficient activation of the IFN system early in infection effectively restricts viral replication and eliminates the virus, while excessive activation of innate immune responses actually increases tissue damage in the host. Here, we have outlined recent advances in the study of the IFN induction by influenza viruses and the identity of the PAMPs produced during influenza virus infection; however, several unanswered questions remain. Assuming the influenza virus panhandle is recognised by RIG-I during infection, it is unclear how this RNA structure is able to form in infected cells: if the panhandle is formed by free unencapsidated RNA, how and when in the virus life cycle is this RNA generated? Conversely, if the panhandle structure can be formed by RNA encapsidated into RNPs, how are the polymerase and/or NP displaced in order to expose the genome termini? What are the viral PAMPs that are generated in conditions when progeny genome synthesis has been blocked? What are the reasons for the cell-to-cell differences in activation of the IFN promoter during influenza virus infections"}
+{"text": "Muscle regeneration in the adult occurs in response to damage at expenses of a population of adult stem cells, the satellite cells. Upon injury, either physical or genetic, signals released within the satellite cell niche lead to the commitment, expansion and differentiation of the pool of muscle progenitors to repair damaged muscle. To achieve this goal satellite cells undergo a dramatic transcriptional reprogramming to coordinately activate and repress specific subset of genes. Although the epigenetics of muscle regeneration has been extensively discussed, less emphasis has been put on how extra-cellular cues are translated into the specific chromatin reorganization necessary for progression through the myogenic program. In this review we will focus on how satellite cells sense the regenerative microenvironment in physiological and pathological circumstances, paying particular attention to the mechanism through which the external stimuli are transduced to the nucleus to modulate chromatin structure and gene expression. We will discuss the pathways involved and how alterations in this chromatin signaling may contribute to satellite cells dysfunction during aging and disease. Adult muscle is a very stable tissue, with very few fibers being replaced during the normal life of the organism. However, it has a remarkable capacity to regenerate in response to tissue damage. Upon injury, either physical or genetic, changes in the injured microenvironment  lead to the activation, expansion and differentiation of a population of muscle-resident stem cells called satellite cells  and early and late MRFs, that act together with Mef2 and Six proteins to recruit chromatin modifying complexes and regulate muscle gene expression. Reprogramming of satellite cells nucleus entails the coordinated activation and repression of discrete subset of genes to progress through the myogenic program. For instance, committed myoblats keep myogenic identity but repress late muscle genes while continuing to proliferate. Finally, cells switch-off lineage-determination genes and genes necessary for cell cycle progression and activate late muscle-differentiation markers . Of them, Dnmt1 is responsible for maintaining methylation after DNA replication whereas Dnmt3a and Dnmt3b catalyze The DNA methylation pattern influences and is also influenced by histone modifications, the second layer of epigenetic modifications. In eukaryotic cells the DNA is packed together with histones and other proteins to fit into the limited space of the nucleus, in a structure called chromatin. The basic unit of the chromatin is the nucleosome that is made up of 147 base pairs of DNA wrapped around an octamer of histone proteins called \u201ccore\u201d, which contains two copies of each histone,   or repress  gene expression. Further, in some cases it can prime associated genes for future regulation  and cell-autonomous modifications . Understanding how this chromatin signaling modulates cell fate will assist us in the rational design of pharmacological therapies to improve satellite cell function in physiological  or pathological  conditions.2+ -sensitive HDAC4, which, in spite of its name lacks of known endogenous deacetylase activity, has been shown to regulate satellite cell function through promoting activation of Pax7-positive cells, although the leading mechanism remains largely unknown  activity is necessary to release class II HDACs from Mef2 transcription factors at the onset of muscle differentiation  transcription factors  and members of the Transforming Growth Factor \u03b2 (TGF\u03b2) superfamily are fundamental in the regulation of satellite cells function.in vitro and contributes to the beneficial effect of HDACi treatment in vivo in a mouse model of muscle regeneration  that activate muscle resident cells /STAT pathway responds to cytokines such as IL-6 or leukemia initiating factor (LIF). The pathway is activated upon binding of IL-6 to the IL-6R-gp130 receptor which leads to JAK activation and phosphorylation of Stat proteins on tyrosines residues. Phosphorylated Stats are able to heterodimerize and translocate into the nucleus  and Bone Morphogenetic Proteins (BMPs) pathways to adult muscle regeneration.The Notch signaling pathway plays a fundamental role in the establishment of cell fate decisions in several tissues. In muscle it has been shown to be essential both during embryogenesis and in the adult. Activation of the Notch signaling starts with the expression of Notch ligand delta-like (Dll) in differentiating cells. Dll binds and activates the membrane receptor Notch in satellite cells, leading to the cleavage of the cytoplamic portion of the protein and nuclear translocation of the intracellular domain  the phosphatidil-inositol 3 kinase (PI3K)/Akt/mTOR axis, the Protein Kinase A (PKA)/CREB pathway  is an evolutionary conserved pathway essential for tissue morphogenesis during development. The pathway is activated upon interaction of the extra-cellular ligands Shh, Ihh and Dhh with the transmembrane receptor Patched1 (Ptch1), which leads to the activation of smoothened (Smo) and translocation to the nucleus of Gli transcription factors , Reactive Oxygen Species (ROS) and the NADNO is a free radical synthesized from the amino acid L-arginine by three different isoforms of NO synthase )\u2014mediates MyoD deacetylation and inhibition of transcription , proliferation (Cyclin D1) and differentiation (Myogenin) of satellite cells. Both Yap and Taz are expressed in skeletal muscle , which bind to MCAT elements  located in the promoter or enhancer regions of key genes that regulate commitment  and to an impaired regeneration potential associated to a dysfunction of the satellite cell compartment  and changes in the epigenome and the proteome have been shown to affect stem cell function in old tissues  converge to modulate the function of aged satellite cells. The relative contribution of aberrant environmental cues and cell-intrinsic changes to aged satellite cells function can now be partially explained by work in Mu\u00f1oz-C\u00e1noves lab. By distinguishing old (20\u201324 months) from geriatric (over 28 months) mice, Sousa-Victor et al. have dissected the transcriptional changes associated to the aging process, that ultimately depends on Polycomb-mediated silencing of the p16/INK4 locus  stem cell niche is resistant to age and disease (Formicola et al., Muscle regeneration is a multi-step process that entails the coordinated activation and repression of discrete transcriptional programs. In this review we aimed to highlight the key role of signaling pathways in transmitting the extra-cellular information to the chromatin of satellite cells to regulate gene expression. The temporal pattern of activation in response to extra-cellular cues, the interplay amongst the pathways and the activation and/or repression of downstream effectors are fundamental for the fine-tuned control of muscle regeneration. Deciphering the muscle-specific chromatin signaling is particularly important for the rational design of novel pharmacological approaches aimed to improve satellite cells function in old and diseased muscles. Being pharmacologically manipulable and potentially reversible, both signaling cascades and the epigenome are attractive targets for the design of novel therapeutic interventions.Finally, numerous studies have revealed a striking similarity between adult and embryonic myogenesis, regarding the pathways and the mechanisms affecting muscle stem cell function (see Buckingham and Rigby, The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Interventions aiming to improve health systems should engage people on the front lines of health care delivery. Evaluations of these interventions should focus on the multiple change processes and outcomes resulting from their implementation into dynamic social systems. The PRIME intervention was designed to build health workers\u2019 (HWs) skills by supporting and motivating them emotionally in their challenging work environments with the goal of improving treatment and attracting patients to health centres (HC) in Eastern Uganda. We conducted a cluster-randomised trial (CRT) to evaluate the impact of PRIME on health outcomes in the community and a parallel mixed-methods study to examine the effect of PRIME from the perspective of HWs and patients enrolled in the trial.Twenty HCs were enrolled in the CRT; 10 were randomized to the intervention with the primary endpoint of health outcomes measured in community-level clusters over two years. Mixed-methods included 306 HW communication assessments investigating the change in HW interpersonal skills with patients, 10 in-depth interviews exploring HWs interpretations and enactment of the intervention, 13 focus group discussions with community members discussing perceptions of change relating to PRIME, and 1200 patient exit interviews at HCs over three time points assessing patients\u2019 satisfaction with their treatment seeking experience.Post PRIME implementation, mixed-methods evaluations revealed that interpersonal communication was rated 10% higher (p<0.008) by patients consulting with HWs in intervention HCs. HWs revealed that improvement of technical skills and use of new technologies had a positive effect by increasing feelings of professionalism coupled with patients\u2019 positive feedback; however, HWs also felt unsupported in other aspects including increased workload, and lack of recognition, payment and supervision leading to demotivation. Patients reported increased satisfaction with certain aspects of the treatment seeking experience, but also highlighted other areas of HCs needing improvement.CRTs of health system interventions focus on assessing the intended impact the intervention using a singular primary endpoint evaluation. Our results reveal that despite a lack of significant effect in the CRT primary health outcomes, the mixed-methods study demonstrated impacts including benefits, consequences, motivations, and interpretations from the perspective of the people who are central to the health system dynamic PRIME was intending to change. We will discuss what can and cannot be achieved and brought to light through a CRT model of evaluation of people-centred health system interventions and what this means for informing the design and implementation of future health system interventions."}
+{"text": "Despite the combined antiretroviral therapy has improved the length and quality of life of HIV infected patients, the survival of these patients is always decreased compared with the general population. This is the consequence of non-infectious illnesses including cardio vascular diseases. In fact large studies have indicated an increased risk of coronary atherosclerotic disease, myocardial infarction even in HIV patients on cART. In HIV infected patients several factors may contribute to the pathogenesis of cardiovascular problems: life-style, metabolic parameters, genetic predisposition, viral factors, immune activation, chronic inflammation and side effects of antiretroviral therapy. The same factors may also contribute to complicate the clinical management of these patients. Therefore, treatment of these non-infectious illnesses in HIV infected population is an emerging challenge for physicians. The purpose of this review is to focus on the new insights in non AIDS-related cardiovascular diseases in patients with suppressed HIV viremia. The introduction of potent combined antiretroviral therapy (cART) has dramatically increased the survival of HIV infected patients and has changed their causes of morbidity and mortality from AIDS-related opportunistic infections to serious non AIDS events (SNAEs) .Currently achieving undetectable viral load has become the minimum objective achievable with antiretroviral therapy; otherwise the safety of the therapy, the reduction of residual viremia, the eradication of the virus from the reservoirs and the reduction of the process of immune activation and chronic inflammation are still challenges for scientific research.In particular to date is not well cleared the mechanisms for the establishment and maintenance of chronic immune activation. All available data suppose the presence of multiple and complex mechanisms acting synergistically and may contribute to the pathogenesis of SNAEs: viral factors, microbial translocation (MT), immune activation, systemic inflammation and side effects of therapy. Residual viremia, defined as the continuous persistence of the virus also at low levels despite effective cART, could be responsible of the chronic generalized inflammation and of the activation of the coagulation system. In addition the damage of mucosal barrier in the gastrointestinal tract (GI) increases MT into the circulating blood and increase the risk of systemic complication such as immune activation.The deleterious effect of the status of immune activation on the host immune system is still unclear. Undoubtedly an important consequence of the general status of inflammation is the ability of HIV to infect and kill activated CD4 T-helper cells with the impaired homeostasis of CD4 T cells and memory B cells by the fibrosis of lymphoid tissue; all that may contribute to the consequent inability of the host to control a wide range of potential pathogens. In fact the persistent immune activation makes CD4 T cells more susceptible to infection and causes a vicious cycle increasing the production of soluble inflammatory markers such as IFN-\u03b3, inflammatory cytokines (i.e. IL-6) and indoleamine 2,3-dioxygenase (IDO) .The excellent results now routinely achieved by cART have made the occurrence of opportunistic infections increasingly less frequent; at this time however it is common to observe cases of patients with undetectable blood levels of HIV-RNA, significant recovery of immunological status and SNAEs including cardiovascular diseases Fig.\u00a0. For thiA large body of evidences in scientific literature supports the epidemiological observation of an increase of morbidity and mortality related to clinical and sub-clinical cardiovascular diseases (CVD) in HIV patients in the era of cART. A significantly higher risk of acute myocardial infarction (AMI) was observed in HIV infected patients compared with uninfected in veterans aging cohort study virtual cohort (VACS-VC) that analyzed data collected in 82,459 veterans followed for an average of 5.9\u00a0years; unexpectedly the highest risk was found in patients in cART and with HIV-RNA less than 500\u00a0copies/ml  .The possibility that residual immune activation (and the consequent inflammation) is related to persistent virus replication has suggested that more potent anti-retroviral regimen  may be more effective in reducing the HIV-associated immune activation. In one study intensification was carried out for 10\u00a0weeks with cART regimens  consisting of drugs that were not used previously in the enrolled patients. Since the median levels of viremia were not significantly different between pre-intensification and post-intensification period, the authors concluded that the levels of residual virus replication, and thus immune activation, may depend on the size of stable reservoir compartments that are established prior to the initiation of cART . AnotherAnother potentially interesting therapeutic concept for the reduction of high levels of inflammation and to control CVD is to use non pharmacological tools of intervention such as physical activity. Several published studies indicate that physical activity could represent a beneficial non-pharmacological intervention to reduce chronic inflammation. Currently available data are limited, nonetheless increasing evidence suggests that the introduction of regular physical exercise in the clinical management of HIV-infected individuals may have a significant therapeutic impact in reducing inflammation and CVD. For example Longo et al.  conducteOn the basis of these evidences, several authors proposed that regular physical exercise should be further studied as a potential anti-inflammatory, non-pharmacological approach to be used to treat HIV residual disease and non-AIDS-defining illnesses in cART-treated HIV-infected individuals \u201394.Likewise, lifestyle interventions are another non pharmacological tool reputed able to reduce cardiovascular risk in general population: nevertheless a recent randomized pilot study with a follow-up 36\u00a0months evidenced that a multidisciplinary lifestyle intervention resulted in a slight improvement in some cardiovascular risk factors and did not prevent cIMT progression in HIV-infected patients with Framingham scores\u00a0>10\u00a0% . FurtherIn cART treated HIV-infected individuals with undetectable viremia the level of immune activation is dramatically reduced compared to baseline  but rarely goes back to normal levels. This immune activation is associated with long-term sequelae of HIV infection such as accelerated atherosclerosis, neurological disease, and several other conditions that may modify the quality of life of HIV-infected subjects. In addition, the residual viral replication appears to be a uncontrolled determinant of the levels of immune activation in HIV patients treated with cART.The goal of practitioners is changed in the last years: in fact if initially it was to reach undetectable plasma levels of HIV viremia, now it is to prevent the premature aging and improve the quality of life of all patients. For this reason it becomes necessary to control the hidden effects of HIV, to develop safe antiretroviral regimen and discover new scores to predict the non AIDS related manifestations."}
+{"text": "Results from two randomised global trials (SOFT & TEXT) designed to newly define the most effective components of adjuvant endocrine therapy for premenopausal women with endocrine responsive disease, showed that for some, those with high risk of relapse, the use of the aromatase inhibitor exemestane together with ovarian function suppression with GnRH analogue (triptorelin) yielded the most favourable treatment outcome compared with tamoxifen. For women with low risk of relapse, treatment with tamoxifen was similar to ovarian function suppression together with either exemestane or tamoxifen. For women with intermediate risk of relapse, ovarian function suppression added to tamoxifen was not inferior to exemestane, while it resulted in superior outcomes compared to tamoxifen alone. Now, these trials provide critical information for the adjuvant treatment of premenopausal women with endocrine responsive breast cancer and are important for the development of future trials for further improvement of adjuvant endocrine therapies for the younger population. Adjuvant endocrine therapy for premenopausal patients with endocrine responsive breast cancer includes tamoxifen given either after (neo) adjuvant chemotherapy or immediately after surgery, without previous chemotherapy, either alone  or with ovarian function suppression for 2\u20135 years using GnRH analogue (mostly European standard). Trials in advanced disease indicated that the combination of GnRH analogue and tamoxifen is superior in terms of clinical efficacy compared with each of the two treatments alone , 2. SOFTP < 0.001).The results of the trials are extensively described in two recent papers published in the New England Journal of Medicine , 4. The Results from SOFT for patients who remained premenopausal after completing chemotherapy indicated substantial improvements in 5-year disease-free survival for women assigned to exemestane-ovarian function suppression (83.8%) or to tamoxifen-ovarian function suppression (80.7%) compared with tamoxifen alone (77.1%) .Adding ovarian suppression to tamoxifen increased the adverse events that patients experienced, most notably menopausal symptoms, but the adverse event profiles of exemestane-ovarian function suppression versus tamoxifen ovarian function suppression were similar to those observed for aromatase inhibitors (AI) versus tamoxifen in postmenopausal women. Patients self-reported differences with respect to specific symptoms from the three treatments, but the overall quality-of-life assessment did not favour any of the three treatments. The most interesting development after the publication of the two trials was related to the St. Gallen consensus panel deliberations . The panThe panel considered that factors arguing for the inclusion of ovarian function suppression are, in case of young age (35 or less), persisting premenopausal oestrogen level after adjuvant chemotherapy, or involvement of four or more axillary nodes. Fewer panel members considered grade-3 disease or an adverse result from a multiparameter molecular marker test as indications for ovarian function suppression (with either tamoxifen or exemestane).Future developments in the field will include the following:The definition of a risk scale to help in the choice of proper endocrine therapy components.Treatment efficacy of the various endocrine therapy components during a longer follow\u2013up.Attempt to improve the yield of ovarian function suppression by the use of GnRH antagonists and the addition of drugs which enhance the efficacy of endocrine agents such as those recently described in advanced disease for postmenopausal women ."}
+{"text": "Developmental gene regulatory networks robustly control the timely activation of regulatory and differentiation genes. The structure of these networks underlies their capacity to buffer intrinsic and extrinsic noise and maintain embryonic morphology. Here I illustrate how the use of specific architectures by the sea urchin developmental regulatory networks enables the robust control of cell fate decisions. The Wnt-\u03b2catenin signaling pathway patterns the primary embryonic axis while the BMP signaling pathway patterns the secondary embryonic axis in the sea urchin embryo and across bilateria. Interestingly, in the sea urchin in both cases, the signaling pathway that defines the axis controls directly the expression of a set of downstream regulatory genes. I propose that this direct activation of a set of regulatory genes enables a uniform regulatory response and a clear cut cell fate decision in the endoderm and in the dorsal ectoderm. The specification of the mesodermal pigment cell lineage is activated by Delta signaling that initiates a triple positive feedback loop that locks down the pigment specification state. I propose that the use of compound positive feedback circuitry provides the endodermal cells enough time to turn off mesodermal genes and ensures correct mesoderm vs. endoderm fate decision. Thus, I argue that understanding the control properties of repeatedly used regulatory architectures illuminates their role in embryogenesis and provides possible explanations to their resistance to evolutionary change. Robustness, the perseverance of phenotype through genetic and environmental changes (de Visser et al., cis-regulatory analyses conducted for many nodes (e.g., Nam et al., The current model of the sea urchin developmental regulatory networks encompasses all the embryonic territories up to gastrulation and is one of the most elaborate of its kind (Saudemont et al., Within the sea urchin regulatory network, specific network architectures are repeatedly used to control various patterning events at different embryonic territories (Ben-Tabou de-Leon and Davidson, Extensive research had shown the extreme conservation of the role of the Wnt-\u03b2catenin signaling pathway in primary axis formation and endoderm specification across metazoan (Petersen and Reddien, hox11/13, blimp1, foxa, and bra, in a staggered manner [Figure \u03b2catenin-Tcf switch directly activates the expression of a set of endodermal regulatory genes, At Mesenchyme blastula stage, \u03b2catenin clears from the mesodermal nuclei, first from the skeletogenic lineage and then from the non-skeletogenic mesoderm [Figure glial cells missing [GCM, Figures S. purpuratus, Figures The Delta-Notch signaling pathway is highly conserved in metazoan and controls glial vs. neural differentiation (Gaiano and Fishell, The tier of cells where GCM is first activated, Veg2, give rise to both endoderm and non-skeletogenic mesoderm lineages Figure , 12 hpf.Previous theoretical studies of three component circuits show that feedback circuitry is more efficient than other architectures in buffering noise in the inducing signal while keeping high responsivity to the level of the signal (Hornung and Barkai, The gene regulatory networks that pattern the secondary embryonic axis, the dorsal-ventral axis of the sea urchin embryo, use similar circuit architectures to those discussed above. Nodal signaling directly activates the ventral ectoderm regulatory genes that then interact with each other to form subdomains within the ventral ectoderm [Figure As we gain more information on the structure and function of gene regulatory networks we can start asking why are specific architectures used more than others and why are they so deeply conserved? A recent paper revealed remarkable conservation of regulatory gene expression dynamics between two sea urchin species after 40 million years of independent evolution (Gildor and Ben-Tabou de-Leon, Direct activation by a signaling pathway might be a general strategy used by developmental gene regulatory networks to guarantees a uniform timely response of a set of key regulatory genes. This strategy could also explain the deep conservation of the role of Wnt and BMP pathways in primary embryonic axes specification. If the activation of the downstream gene regulatory network was in a cascade of regulatory interactions, there were only a few regulatory changes required to replace Wnt or BMP with alternative signaling input. It is much less likely to replace Wnt or BMP signaling when they activate the entire set of genes that define the endoderm or dorsal ectoderm specification, respectively. Thus, the direct activation of large sets of regulatory genes by signaling pathways might be important for clear cut cell fate decision on one hand, and on the other hand imposes a strong constraint on the use of these signaling pathways in developing embryos.Similar argument could explain the extreme conservation of well-studied compound positive feedback circuits. Specifically, the compound positive feedback circuit that controls the lock down of endoderm cell fate specification was conserved across 500 years of echinoderm evolution (Hinman et al., The author confirms being the sole contributor of this work and approved it for publication.This work was supported by the Marie Curie Carrier Integration Grant FP7-PEOPLE-2012-CIG, grant number 321758.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The utility of blood-based omic profiles for linking environmental exposures to their potential health effects was evaluated in 649 individuals, drawn from the general population, in relation to tobacco smoking, an exposure with well-characterised health effects. Using disease connectivity analysis, we found that the combination of smoking-modified, genome-wide gene (including miRNA) expression and DNA methylation profiles predicts with remarkable reliability most diseases and conditions independently known to be causally associated with smoking . Bioinformatics analysis reveals the importance of a small number of smoking-modified, master-regulatory genes and suggest a central role for altered ubiquitination. The smoking-induced gene expression profiles overlap significantly with profiles present in blood cells of patients with lung cancer or coronary heart disease, diseases strongly associated with tobacco smoking. These results provide proof-of-principle support to the suggestion that omic profiling in peripheral blood has the potential of identifying early, disease-related perturbations caused by toxic exposures and may be a useful tool in hazard and risk assessment. Ongoing efforts in this direction focus on the characterization through in vitro testing, including toxicogenomic profiling, of biological pathways whose perturbation by chemicals leads to the manifestation of toxicityThe relative insensitivity of epidemiological investigations for the detection of environmental and other health hazards and the quantification of associated risks underlines the need for novel Exposure to tobacco smoke is one of the best studied examples of a common exposure with proven causal association with a variety of human diseases51We examined the impact of smoking on genome-wide gene expression and CpG methylation profiles in blood leukocytes of a total of 649 current, former and never smokers within two general population-based prospective cohorts, the Northern Sweden Health and Disease Study and EPIC Italy . Our anaExpression differed between current and never smokers for a total of 350 transcripts  corresponding to 271 differentially expressed genes (DEGs) , the majority showing loss of methylation in current smokers . In agre10Comparison of the miRNA profiles (only measured in 226 subjects from the Swedish cohort) showed 26\u2009miRNAs to be overexpressed and 8 underexpressed in current smokers  . No signThe Comparative Toxicogenomics DatabaseThe mechanistic basis of the ability of DEGs and DMGs to predict smoking-related diseases was explored by conducting pathway analysis (ConsensusPathDB)To reduce the complexity of the list of DEGs and DMGs, we searched for genes with potential master-regulatory roles using GORevengeTo obtain a more global view of the organization of the smoking-related hub genes, we looked for networks of interactions between them using the online resource Search Tool for the Retrieval of Interacting Genes (STRING)We examined further the role of the hub genes in smoking-related diseases by first selecting those DEGs/DMGs identified by the Comparative Toxicogenomics Database as being associated with a specific disease (lung cancer) or with two disease categories (cancer and cardiovascular disease), all well known to be strongly linked to smoking . Subsequent use of ConsensusPathDB and Cytoscape to identify and visualize the interactions between these genes showed  that hub\u22123), including hub gene TGFBR3, and 5\u2009DMGs (p\u2009=\u20090.028).The ability of the DEGs and DMGs to predict smoking-related diseases results from the fact that these gene sets overlap significantly with lists of genes known independently to be linked with these diseases. Because our disease-predictive profiles reflect perturbations caused by tobacco smoke in apparently healthy smokers, the presence in them of genes also differentially altered in patients with smoking-related disease would provide a possible basis for linking exposure with early steps of disease pathogenesis. To explore this possibility, we went on to compare our smoking-related profiles with profiles reported to be differentially modified in blood cells of patients with two diseases strongly associated with smoking, namely lung cancer and coronary heart disease. In relation to lung cancer we used two published gene expression signatures observed in patients with non\u2212small cell lung cancer\u22125), including hub genes NEDD4L and TGFBR3, and 27\u2009DMGs (p\u2009=\u20090.10), including hub genes BCL2L1 and CDKN1A. Furthermore, comparison with a list of 59 genes highlighted in the same report as having been found significantly associated with the coronary heart disease case/control status in this and 4 other comparable studies (\u22123) including hub gene NEDD4L and 3\u2009DMGs (p\u2009=\u20090.34).For the corresponding analysis of coronary heart disease we used the data from the most recent and largest published study studies , showed The above observations demonstrate that genes (including genes with major regulatory roles) differentially expressed in blood leukocytes of subjects with diseases causally associated with tobacco smoke exposure are found with high statistical significance to be also differentially expressed in smokers without these diseases. Analogous overlaps were also found, albeit at lower statistical significance, for genes with smoking-induced CpG methylation changes.We agnostically examined in blood leukocytes of apparently healthy subjects the effects of tobacco smoke exposure on multiple types of genome-wide (omic) profiles and their association with disease. Given the extensive amount of independent epidemiologic knowledge available regarding the health effects of tobacco, our analysis serves as a proof-of-principle evaluation of the utility of blood-based omic profiles in relation to the identification of health hazards potentially associated with exposure to environmental and other toxic agents. In addition, as regards the health effects of smoking per se, the use of omic profiling as in the present study may provide new evidence for diseases not previously linked with smoking, as well as support for the identification of individuals with high susceptibility to tobacco-associated diseases.\u22125). Furthermore, the methylation changes at the 49\u2009CpG sites modified by smoking in either tissue are highly correlated . While these observations relate to just one gene, they imply that DNA methylation changes under the influence of an external exposure may be qualitatively similar across tissues regardless of the tissue-specific basal expression levels, thus providing a biological justification for the use of blood-based CpG methylation data in the prediction of effects in other tissues.In agreement with many previous studies we identified LRRN3 and AHRR as the top expression and methylation gene targets, respectively  and S2. 10We conducted disease connectivity mapping using as input the DEG/DMG lists obtained with the pooled cohort dataset, rather than the smaller lists of genes replicating between the two cohorts, having in mind the significant overlap of the former with previous reports8910The combination of DEGs and DMGs shows a remarkable ability to predict almost all diseases or conditions for which there is sufficient or suggestive epidemiological evidence of a causal link with smoking, as well as diseases or conditions known to be closely associated, as precursors or late-stage complications, with such diseases . The setFor a number of omics-based disease predictions, the epidemiological evidence is negative or too limited to support a causal link with tobacco smoking521The identification of schizophrenia and disorders with psychotic features as a disease category potentially associated with tobacco smoking is of particular interest. This could possibly reflect an inverse causation effect, i.e. subjects with undiagnosed disease tending to smoke more as a result of nicotine-induced release of dopamine leading to relief of symptoms2324Finally, a small number of specific diseases for which the evidence of a causal association with smoking has been characterized as sufficient was not predicted by omic profiling and therefore they may be considered as false negatives. These diseases include erectile dysfunction, reduced female fertility as well as a number of conditions related to pulmonary infection . For the first of these diseases the most common cause is arteriosclerosis, which is correctly predicted to be associated with smoking, and a likely explanation for the failure to predict it may be related to the fact that only 9 genes are currently linked by the Comparative Toxicogenomics Database to this disease. As regards reduced female fertility, it is possible that this condition may result from the known ability of cigarette smoke to cause increased follicle death and altered hormone outputThe partly overlapping nature of many of the health conditions involved precludes a proper quantitation of the predictive ability of omics profiling. However an indicative estimate can be obtained by taking as the total number of predictions the conditions represented by the number of rows of 5Pathway analysis  using thAmong the genes significantly modified in smokers we identified 40\u2009hub genes  which pl272830313233in vitro with cigarette smoke extractThe smoking-modified hub genes appear to be organized primarily around two sub-networks of major importance in multiple cellular functions, namely TGF-\u03b2 (centred on SMAD2) and EGFR/ERBB2 (centred on the EGFR-SRC axis) signaling, which are in turn highly linked to a UBC node . The UBCThe above discussion indicates that hub genes altered in blood cells of apparently healthy smokers play important roles during the pathogenesis of smoking-related diseases in target tissues other than blood. This in turn suggests that such hub genes form part of adverse outcome pathwaysOur study demonstrates that the combination of changes in gene expression (including miRNA) and CpG methylation in blood leukocytes of smokers is able to predict with high sensitivity and specificity diseases which occur in tissues other than blood or hematopoietic tissues and whose incidence is affected by tobacco smoking. We have also shown that there is a close similarity in the effects of cigarette smoke on the expression and CpG methylation of the AHRR gene in blood leukocytes and the lung of smokers. Taken together, these observations are compatible with the reported operation of common gene regulation networks across different tissues which are more highly connected than within-tissue networks41www.envirogenomarkers.net) and involved subjects from the European Prospective Investigation into Cancer and Nutrition study (EPIC-ITALY) and the Northern Sweden Health and Disease Study (NSHDS) (44The study was conducted in the context of the European EnviroGenomarkers project ( (NSHDS) 4445. BotThe EnviroGenomarkers project was originally designed as two nested case-control studies, one for B-cell lymphoma and one for breast cancer. The participants included 93 incident cases with breast cancer, 229 incident cases of B-cell lymphoma and 327 controls. No participant was diagnosed with disease within less than 2 years of blood sample collection and for this reason all participants were treated as apparently healthy at recruitment. In order to minimize effects on the omic profiles, subjects were included in the current study only if the processing of their blood samples had been completed within 2\u2009hours of collectionRNA and DNA extraction from buffy coats, genome-wide analysis of gene expression (Agilent 4\u2009\u00d7\u200944K human whole genome microarray platform) and CpG methylation (Illumina Infinium HumanMethylation450 platform), miRNA expression profiling , and the corresponding data quality assessment and preprocessing, were conducted as described previously462intensities of mRNA or miRNA expression as dependent variables, with the Array Studio software package  and R software (version 3.0.2). Date of isolation, labeling, and hybridization for RNA expression, date of analysis for methylation and batch number for miRNA expression were also included in the models as random variables to account for technical variation. All analyses additionally adjusted for sex, age, BMI and cohort . Owing to the design of the EnviroGenomarkers project, described above, future disease  and case-control status were also included as fixed variables. Inclusion of these incident cases did not appear to bias the resulting lists of smoking-related signals  which provides manually curated information about chemical-gene/protein interactions, chemical-disease and gene-disease relationships. The lists of genes  were introduced into tool (gene names not recognized were replaced by synonyms selected from GeneCards) and the returned list of enriched diseases with Bonferoni-corrected p\u2009<\u20090.05 collected.Diseases or conditions enriched with smoking-modified genes were identified using the \u201cset analyzer\u201d tool of the Comparative Toxicogenomic Database ."}
+{"text": "Every year 150 persons are killed by avalanches in North America and Europe. Search for victims is resource-intensive and time consuming to do if the avalanche spans a large geographical area in rough terrain. Survival decreases rapidly with time to extrication. More than half of avalanche victims are partial buried and visible on the surface.The objective was to evaluate feasibility of using a rotor-wing unmanned aerial vehicle to support situation assessment in search and rescue operations in the mountains.The study took place in the mountains of Setesdalen (Hovden) in Norway. Two simulated scenarios were set up: a) An avalanche  and b) an injured skier trapped in a narrow canyon with unstable snow overhead. We used a radio controlled multirotor UAV equipped with a three-antenna digital avalanche transceiver (Mammut Pulse Barryvox) for beacon search and a HD video camera (GoPro HD Hero 3) for visual air search. Live video, turn directions and digital signals from the avalanche beacon were wirelessly transmitted to a ground station. Beacon search in the avalanche was blinded to the pilot.Remote aerial visual searches at different altitudes identified ski tracks into the canyon, objects in the snow and outer boundaries of the avalanche. Fine search from fixed altitude with an avalanche transceiver localized two avalanche beacons buried in the snow repeatedly.An UAV is an effective tool carrier and save time in rough terrain which spans a large geographical area. It is a safe supplement to human resources in high-risk work environments like an avalanche. An UAV equipped with an avalanche transceiver and a HD camera can enhance situation assessment and provide useful decision-making support for pre-hospital services and ski patrols in the mountains."}
+{"text": "In utero hematopoietic cell transplantation (IUHCT) is a non-myeloablative non-immunosuppressive transplant approach that allows for donor cell engraftment across immunologic barriers. Successful engraftment is associated with donor-specific tolerance. IUHCT has the potential to treat a large number of congenital hematologic, immunologic, and genetic diseases either by achieving high enough engraftment levels following a single IUHCT or by inducing donor specific tolerance to allow for non-toxic same-donor postnatal transplants. This review evaluates donor specific tolerance induction achieved by IUHCT. Specifically it addresses the need to achieve threshold levels of donor cell engraftment following IUHCT to consistently obtain immunologic tolerance. The mechanisms of tolerance induction including partial deletion of donor reactive host T cells by direct and indirect antigen presentation and the role of regulatory T cells in maintaining tolerance are reviewed. Finally, this review highlights the promising clinical potential of in utero tolerance induction to provide a platform on which postnatal cellular and organ transplants can be performed without myeloablative or immunosuppressive conditioning. In utero hematopoietic cell transplantation (IUHCT) seeks to take advantage of this developmental phenomenon. In multiple animal models, IUHCT has been shown to be a non-myeloablative non-immunosuppressive transplant approach that allows for engraftment across immunologic barriers and is associated with the induction of donor specific tolerance . A single in utero transplant may result in high enough levels of donor cell engraftment to treat the target disease. Alternatively, IUHCT may be used to induce donor specific tolerance which would allow for postnatal same-donor transplants with non-toxic conditioning regimens to increase donor cell engraft to clinically relevant levels. Tolerance achieved by IUHCT may also be used to permit postnatal same-donor organ transplants without immunosuppressive conditioning. To date, IUHCT has only been clinically successful in the treatment of severe combined immunodeficiency disorder  superantigen system demonstrated that partial deletion of donor reactive host lymphocytes occurs via both the indirect and direct route of antigen presentation following IUHCT (+CD25+Foxp3+ T regulatory cells to this process remains unclear. Studies have shown an increase in the percentage of Treg cells (as well as the Treg/Teff ratio) in the thymus and spleen of chimeric mice following IUHCT related to deletion of the Teff population but not an increase in the absolute number of Treg cells . In the murine model, allogeneic donor cell engraftment was minimally increased when postnatal same-donor transplants were performed in the absence of any conditioning regimen . Acceptance of donor skin grafts, a classic method of assessing donor specific tolerance, has been repeatedly demonstrated in the murine model of IUHCT with success dependent on the levels of donor cell chimerism (himerism . A renalhimerism . Donor chimerism .In utero hematopoietic cell transplantation is a non-myeloablative non-immunosuppressive transplant approach that allows for donor cell engraftment and donor specific tolerance across immunologic barriers. It has the potential to treat a large number of congenital hematologic, genetic, and immunologic disorders which, because of advances in prenatal care, can be diagnosed before birth and before the maturation of the fetal immune system. Studies in murine and preclinical large animal models suggest that, in limited circumstances, a single IUHCT may result in high enough levels of donor cell engraftment to ameliorate the target disease. However, even in the absence of obtaining therapeutic levels of engraftment, the major benefit of IUHCT may be in the reliable induction of donor specific tolerance to allow for postnatal non-myeloablative same-donor cellular transplants to enhance engraftment to target levels with minimal treatment related toxicity. Although less clinically relevant at the current time, a similar approach of tolerance induction by IUHCT to allow for postnatal organ transplants without immunosuppression may hold promise in the future. In order to embrace the full potential of in utero tolerance induction for postnatal cellular and organ transplants, additional insights into the mechanisms involved in the induction and maintenance of tolerance including the role of peripheral regulatory cells as well as the barriers to engraftment that prevent the acquisition of donor specific tolerance in all recipients of IUHCT must be investigated.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Plant cell-to-cell communication is mediated by nanopores called plasmodesmata (PDs) which are complex structures comprising plasma membrane (PM), highly packed endoplasmic reticulum and numerous membrane proteins. Although recent advances on proteomics have led to insights into mechanisms of transport, there is still an inadequate characterization of the lipidic composition of the PM where membrane proteins are inserted. It has been postulated that PDs could be formed by lipid rafts, however no structural evidence has shown to visualize and analyse their lipid components. In this perspective article, we discuss proposed experiments to characterize lipid rafts and proteins in the PDs. By using atomic force microscopy (AFM) and mass spectrometry (MS) of purified PD vesicles it is possible to determine the presence of lipid rafts, specific bound proteins and the lipidomic profile of the PD under physiological conditions and after changing transport permeability. In addition, MS can determine the stoichiometry of intact membrane proteins inserted in lipid rafts. This will give novel insights into the role of membrane proteins and lipid rafts on the PD structure. Plamodesmata (PDs) are nanopores connecting the cytoplasm of adjacent cells to facilitate intercellular communication. PDs generate symplastic communication pathways to transport small molecules below the size exclusion limit and selected bigger molecules. This in turn plays important roles for the cell fate and development, viral movement and transport of metabolites and miRNA  between two adjacent cells with an axial highly packed central element of endoplasmic reticulum named desmotubule Hepler, . The celAFM was invented  Hemler, . TetraspMongrand et al.  analyzedin vitro purified PD vesicles under different physiological conditions. As stated in Figure It has been widely accepted that complementary structural techniques including AFM and MS are needed to understand and predict the behavior of intact membrane proteins  and/or a decrease in the abundance of plasmodesmal callose binding protein (PDCB1). It has been shown that PDCB1 overexpression augmented callose accumulation resulting in a reduction of green fluorescent protein (GFP) diffusion. Therefore, there is an association between PDCB-mediated callose deposition and plant cell-to-cell communication (Simpson et al., 2O2 concentrations. Interestingly, protein clustering in lipid rafts depends on cholesterol presence (Simons and Toomre, In our experimental design we have proposed to work under different physiological conditions to analyse variations on PD constitution and conformation in response to environmental stimuli. It is reported that changes on PD permeability by pathogen infection have been observed after increasing callose deposition on the cell wall near to the PD neck, which reduces channel diameter (Zavaliev et al., These proposed experiments would allow us to postulate a structural PD membrane model Figure  where spIn this perspective article, we have discussed the potential use of complementary state-of-the-art AFM and MS to characterize the PD lipid and protein structure from native conditions. We envisage that novel studies in the near future combining this with plant genomics could lead to an integrative view on the PD role for cell-to-cell communication throughout plant development.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Deciphering these interaction patterns is crucial for understanding the mode/mechanism(s) through which an individual microbial community transitions from one state to another . Statistical correlation techniques have been traditionally employed for mining microbial interaction patterns from taxonomic abundance data corresponding to a given microbial community. In spite of their efficiency, these correlation techniques can capture only 'pair-wise interactions'. Moreover, their emphasis on statistical significance can potentially result in missing out on several interactions that are relevant from a biological standpoint. This study explores the applicability of one of the earliest association rule mining algorithm i.e. the 'Apriori algorithm' for deriving 'microbial association rules' from the taxonomic profile of given microbial community. The classical Apriori approach derives association rules by analysing patterns of co-occurrence/co-exclusion between various '(subsets of) features/items' across various samples. Using real-world microbiome data, the efficiency/utility of this rule mining approach in deciphering multiple  association patterns between 'subsets/subgroups' of microbes (constituting microbiome samples) is demonstrated. As an example, association rules derived from publicly available gut microbiome datasets indicate an association between a group of microbes  that are known to have mutualistic metabolic associations among themselves. Application of the rule mining approach on gut microbiomes (sourced from the Human Microbiome Project) further indicated similar microbial association patterns in gut microbiomes irrespective of the gender of the subjects. A Linux implementation of the Association Rule Mining (ARM) software  is freely available for download from the following link:  Recent advances in high-throughput sequencing technologies have enabled life sciences researchers to investigate structure and functional relationships between various organisms constituting a microbial ecosystem (referred to as microbiome). Deciphering such relationships and interpreting them in the context of the studied environment is a prime objective of contemporary microbiome research initiatives. Inferences drawn by analysing (and comparing) patterns of co-occurrence of various microbes (taxa) constituting microbial communities (sampled across space and/or time) are expected to aid in (1) obtaining better understanding of inter-microbial interactions in various environmental niches (2) identifying specific microbial interaction patterns that directly or indirectly determine the stability of a given microbial community, and (3) studying and understanding the mode/mechanism(s) by which a microbial community transitions from one state to another .Typically, identification of microbial interactions (i.e. their co-occurrence patterns) is done by employing correlation coefficient measures such as Pearson, Kendall, Spearman, Kullback-Leibler Distance, or a dissimilarity measure like Bray Curtis. To eliminate spurious correlation artefacts that may result due to differences in sequencing and/or sampling depth, the input (taxa) abundance matrix is usually subjected to various normalization techniques prior to computing correlation coefficients. Rows (in the abundance matrix) corresponding to organisms having (a) null observations in a majority of samples, or (b) low abundance values (below a specified threshold), are usually purged from the abundance matrix prior to analysis.A wide variety of algorithms and statistical tools are currently available for visualizing and analysing networks that are generated using results obtained in such correlation analyses. These tools help in identifying pairs of microbes having positive/negative correlations in their abundance patterns and visualize the identified pairs in form of interaction networks. Nodes and edges in such networks correspond to pairs of microbes having a positive/negative correlation. Recent methods like CoNet  improve The overall topology and patterns of inter-connectivity observed in the generated network(s) provide valuable biological insights with respect to 'pair-wise' microbial interactions. Although, such insights help in predicting/understanding the functional/metabolic exchanges that potentially occur between the identified member pairs, in a real-world scenario, the nature/complexity of inter-microbial interactions is significantly beyond simple 'pair-wise' interactions. It is well known that the metabolic potential of any naturally occurring microbial community is defined by the combined action of several 'groups/subsets' of resident microbes that interact due to mutual dependencies in terms of shared reactant/intermediate metabolites and other essential enzymes. This scenario calls for exploration, development and application of novel algorithms, tools, and suitable data-mining techniques that can go beyond prediction and analysis of simple 'pair-wise' interactions.Given the complexity of interactions within microbial communities, the aim of the present study is to explore the applicability of one of the earliest association rule mining algorithm, the 'Apriori algorithm' , for deriving 'association rules' from microbial abundance data. The derived rules are expected to indicate biologically meaningful co-occurrence/co-exclusion patterns between 'subsets/subgroups' of microbes/ taxa constituting these microbiome samples. Various customisations performed for adapting the Apriori approach for microbiome data are appropriately described. Validation experiments that highlight the efficiency of this 'customised' Apriori approach in deciphering association rules between various microbial groups in real-world microbiome datasets are also detailed.The principle and methodology of the classical Apriori approach is first summarised using the classical 'market-basket' analysis problem as a representative example. An introduction to various parameters/thresholds (employed in the Apriori approach) that determine the overall confidence of the derived/mined association rules is also included in this summary. Subsequently, an explanation of various customisations that were done for making the Apriori rule mining approach efficient and amenable for analysing microbial abundance data is provided.The classical Apriori algorithm is based on the principle of frequent pattern mining. It is primarily a deductive approach that derives/extracts conclusions (or 'rules') by identifying the presence of correlations, frequent patterns, and/or associations between various (subsets of) features/items in existing information. Performing Apriori analysis on given information/data involves the following two steps -Candidate-set generation. This step involves finding those features/items that occur (in the given information/data) with a frequency that exceeds a specified threshold (referred to by the term 'support-count'). Occurrence of a feature is defined in terms of its presence/absence in the given data. Such a group of frequently occurring feature/items constitute the 'candidate-set'. In the classical 'market basket' example, the Apriori property is employed with the objective of analysing the purchasing behaviour of customers by observing their individual co-purchasing patterns with respect to certain items (or) groups of items. For this purpose, data pertaining to purchase history (of various customers) is first analysed for generating a candidate-set that contains items that are 'frequently' purchased by customers (the frequency being defined by the 'support-count' parameter)Associative Rule mining. This steps analyses items in the candidate set for identifying/mining 'association' rules which essentially indicate the presence of a group given the presence of the other. This mining process involves the following steps. Initially, all possible groups/subsets that can potentially be formed using items in the candidate-set are first generated. Conditional probabilities between each pair of 'groups' are subsequently computed. Rules are generated based on pairs whose conditional probability value exceeds a user-defined threshold . In the context of the market-basket example, co-purchasing patterns between various items in the candidate item set are identified/ mined. The association rules mined in this example indicate the likely-hood of a customer purchasing a group of items given that he/she has purchased another item or group of items.The classical 'association rule mining' process was customised for identifying analogous associations between microbial groups (in microbiome samples) in the following manner.Microbial abundance data does not capture the abundances of various microbes/taxa  in terms of 'mere' presence/absence. Appropriate methods are therefore required to decide a suitable (minimum) abundance threshold for reporting a taxon to be 'present' in the sample being analysed. For individual taxa, the (minimum) abundance threshold was computed/ defined using one of the following parameters/strategies. These strategies are illustrated in Strategy I: A taxon whose  abundance proportion (in a sample) exceeds 0.1% is considered as 'present' (in that sample).nd and 3rd quartile range of the computed mean/median value.Strategy II: For a taxon, compute its mean/median abundance value across various samples. A taxon is reported as 'present' (in a sample) only if its abundance value (in that sample) lies between the 2Strategy III: A distance matrix is created based on Manhattan distances computed between individual abundance values of a taxon (in each of the samples). The distance values are then hierarchically clustered (and progressively merged) until 2 clusters remain. The taxon is reported as 'present' only for those samples whose abundance values constituted the biggest cluster. In case of a tie, the hierarchical clustering (and progressive merger) process is continued until a stage wherein the final resulting clusters differ in size.The support-count parameter , is subsequently employed to retain only those taxa that are reported as 'present' in at least 65% (i.e. close to two-thirds) of the samples constituting a given microbiome dataset. Taxa retained in this manner constitute the final 'candidate (taxa) set'.In spite of retaining the classical rule mining procedure using a confidence value of 0.65, an additional \u2018scoring process\u2019 was adopted for filtering out spuriously predicted rules. This scoring process involved the following steps. A predetermined proportion of reads (e.g. 75%) were drawn from each individual sample (from amongst multiple samples constituting a microbiome dataset) and a normalized taxonomic abundance table was generated based on the classification of various drawn reads. Rules were generated from this abundance table. This process of rule generation was repeated several times (the number of repetitions defined by the end-user). Rules that appeared consistently in at least two-thirds of the iterations are retained. The Apriori algorithm, customised for deciphering association rules from microbiome abundance data, was evaluated using the following datasets -445 samples from publicly available microbiome datasets from two previous studies , 3 whichGut Microbiome datasets from the HMP i.e. the Human Microbiome Project . AvailabThe rationale behind choosing the above mentioned datasets for evaluating the customised Apriori algorithm is the following -All evaluation datasets correspond to microbiome samples taken from the human gut. At the current juncture, there is availability of several research papers and reviews that provide information with respect to the physiological interdependence of various bacterial genera residing in the human gut. Such information would primarily help in validating whether the association rules generated contain the expected set of interacting genera.In prebiotic datasets, comparison of the association rules generated at various phases  would help in identifying a core set of genera that are always seen to be associated irrespective of the transition state. Moreover, the generated association rules would help in understanding microbial interaction dynamics associated with this transition.HMP datasets were obtained from subjects belonging to the same geography. A comparison of association rules generated using datasets from male and female subjects would help in observing patterns of similarities/differences between human gut microbial interactions in male and female subjects.Taxonomic assignments for individual reads  were obtained using RDP classifier . Abundance tables were generated based on the number of reads assigned to individual genera in each of the samples. For each of the validation datasets, With respect to the number of rules having three or more genera, graphs generated from both studies .As seen in the results obtained in the prebiotic datasets, graphs generated from HMP studies  also indIn order to evaluate if the same set and similar number of rules are generated at higher threshold values, the above experiments (on prebiotic as well as HMP datasets) were also performed with higher \u2018confidence value\u2019 and \u2018support count\u2019 thresholds. Tables On a similar note, the process of candidate taxa generation in the above experiments utilized strategy I  for defiAll three strategies require almost similar amounts of time for process execution and the time is observed to scale as per the number of iterations. In all three strategies, the number of rules appears to reach a plateau after approximately 200\u2013500 iterations depending on the number of samples in the dataset. Overall, results seem to follow a logical pattern and clearly suggest that smaller datasets require higher number of iterations to arrive at a robust set of predictions and vice versa.Strategy III is observed to results in fewer numbers of rules as compared to the other two strategies. Being relatively more stringent in its approach, it is reasonable to adopt strategy III for datasets with higher number of samples. In datasets with very few samples, it is reasonable to expect that this strategy may not generate any association rules. For example, in the prebiotics dataset, the number of rules generated was null .The last decade has witnessed the development of several specialised tools/algorithms catering to various stages of microbiome data analysis viz. host-sequence decontamination \u201313, contIn silico identification/characterization of association patterns typically involves finding 'statistically significant' co-occurrence/ co-exclusion patterns from a given dataset \u201336. FromDespite its utility in facilitating life sciences researchers to obtain a systems-level understanding of the structure, function and dynamics of microbial communities, employing the Apriori approach for mining association rules from microbiome data has a few limitations. The process of populating/building a 'candidate item set' (with frequent item sets) involves iterative inclusion/extension of one additional item to a frequent subset followed by 'support-count' validation. The iteration continues until no further successful extensions to the frequent subset are found valid from a support count perspective. This procedure necessitates scanning through the same data multiple times, thereby rendering the process computationally inefficient. However, it is important to note that the time taken for generating the candidate item set is not a direct function of data size. The actual number of associations present in the data determines the execution time of the program. Values summarized in As described above, identifying groups of frequently co-occurring features (i.e. frequent item set) constituting the candidate item set is challenging from an implementation perspective. In order to address the challenge associated with this computationally expensive step, an alternative strategy  from such a network of significantly correlating feature pairsStep 3: Reporting a clique as an 'association rule' if all possible combinations of features in that clique satisfy the 'confidence value' threshold The above strategy was based on the assumption that an ideal candidate set should contain 'only' those features that have a statistically significant correlation (Pearson or Spearman) between their abundance profiles. From a computational perspective, steps 1 and 2 (indicated above) are relatively inexpensive as compared to the process of generating a candidate item set. Step 3 is common to both processes.Although the alternative strategy showed improved performance in terms of computational efficiency, results summarized in This study explores and demonstrates the applicability of the 'Apriori algorithm' for deriving 'association rules' from the taxonomic abundance profiles of various samples constituting a given microbiome dataset. The derived rules indicate the pattern of interactions between 'subsets/subgroups' of microbes/taxa constituting these samples. Various customisations performed for adapting the Apriori approach for microbiome data have been described. Results of the validation experiments highlight the efficiency of this 'customised' Apriori approach in deciphering biologically relevant association rules.S1 FileA zip archive containing microbial abundance tables which were employed for deciphering association rules using the customised version of the Apriori algorithm.(ZIP)Click here for additional data file."}
+{"text": "However, this approach has been routinely successful only in the treatment of congenital immunodeficiency diseases that include an inherent NK cell deficiency despite the existence of normal maternal immunity in either setting. These observations raise the possibility that fetal NK cells function as an early barrier to allogeneic IUHCT. Herein, we summarize the findings of previous studies of prenatal NK cell allospecific tolerance in mice and in humans. Cumulatively, this new information reveals the complexity of the fetal immune response in the setting of rejection or tolerance and illustrates the role for fetal NK cells in the final endorsement of allospecific prenatal tolerance.The primary benefits of  In utero hematopoietic cellular transplantation (IUHCT) remains a promising intervention for treatment of a wide variety of congenital disease . Indeed, the greatest clinical success has been realized in the treatment of NK cell deficient SCID (xSCID or ADA-SCID) whereas the use of IUHCT for the treatment of congenital diseases in which the fetal immune system is not defective has been uniformly unsuccessful  This incIt has been postulated that competition between the donor and recipient cells for a limited number of available host hematopoietic stem cell (HSC) niches is responsible for the clinical failure of IUHCT in the treatment of hemoglobinopathy , 2006. FStudies in murine and primate models of IUHCT support the presence of an early gestation immune barrier to allotransplantation ,b. In a In the complexity of the developing fetus, successful prenatal engraftment likely requires that all components of the immune system develop tolerance. Similarly, failed engraftment in clinical cases that do not involve immunodeficiency likely results from a lack of tolerance in one or more components of the fetal immune response. In either case, an intrinsic immune barrier to prenatal allotransplantation exists within the fetal host and awaits further delineation. In the greater context, a better understanding of the critical parameters regulating the emergence of self-tolerance may explain the pattern of success and failure of IUHCT.Previous studies reveal that T cell self-recognition is established before birth in most strains of mice including the C57BL6/J and Balb/c inbred strains. The first measurable indicator of self-recognition is the emergence of phenotypically mature T cells as early as E17 . Phenotymicrochimerism (<0.1%) following IUHCT between MHC class I-matched or mismatched strain combinations. These findings seem to conflict with subsequent studies (macrochimerism (1\u20132%) but may be reconciled through an understanding of the different measures of tolerance. Skin-graft acceptance has been shown to reflect T cell rather than NK cell tolerance whereas tolerance to a hematopoietic graft reflects both. NK cells fail to reject allogeneic skin grafts in the absence of IL-15 activation . Importantly, this barrier was found to be critically dependent on the level of circulating chimerism . Remarkably, we found that the chimerism threshold reliably predicts the binary outcome of either engraftment or rejection which is the arguably most meaningful measure of prenatal tolerance induction. Furthermore, the chimerism threshold proved to be irrelevant in IUHCT between congenic strains of mice which are immunologically matched reducing the likelihood that limiting-dilution kinetics were the cause of failed engraftment below the chimerism threshold . During the period of NK cell depletion, chimerism levels remained stable or increased slightly. When the host NK cells were allowed to return following withdrawal of the depleting antibody, abrupt rejection was observed in all of the animals. These findings defined a critical relationship between a threshold level of donor chimerism and the development of donor-specific NK cell tolerance. In a larger context, the significance of this threshold lies in the identification of the minimum level of antigen exposure during the T and NK cell education that is necessary for durable recognition as self.The essence of this hreshold . Lastly,cis-recognition of the donor ligands during development in the absence of trans-interaction directly with the donor cells or with host APC\u2019s. The cis-recognition of donor antigens by tolerant host NK cells may selectively prevent the apoptosis of \u201cfriendly\u201d phenotypes during the selection of the mature NK cell repertoire. Support for this mechanism comes from the recent report by d transgenic B6 mice and found that the co-expression of Ly49A conferred a resistance to apoptosis. Consistent with this postulate, high levels of trogocytosis were found on the surface of phenotypically friendly NK cells that express donor-specific inhibitory receptors when compared to the phenotypically hostile NK cells that do not express these inhibitory receptors. Subsequent to their developmental selection, the cis-recognition of transferred donor-MHC by phenotypically friendly NK cells might provide a continuous exposure to the donor ligands affecting their maturation, survival and function , the process of self-education should include a mechanism to compensate for the low probability of effector cells to encounter appreciable levels of donor ligand. We have recently reported that donor-to-host MHC transfer (trogocytosis) might function in this role . Trogocyfunction . In thisin vivo elimination of host NK cells prevents the chronic rejection seen in sub-threshold chimeras and establishes that the effectors of this response reside within the fetal recipient. Collectively, these findings argue against the existence of a clinically relevant maternal immune barrier to IUHCT and should be reconciled with those of previous reports concluding that a maternal immune response toward the transplanted cells leads to engraftment loss in allogeneic IUHCT.A maternal immune response toward the donor cells has been proposed as a barrier to prenatal allo-transplantation resulting in the delayed chronic rejection of the donor graft . As discIn the study by 6cells/fetus) which provided a large number of mature T cells to the fetus (approximately 109 mature T cells/kg). These large T cell doses may have resulted in a significant graft-vs-host reaction that may have diminished the maternal\u2013fetal immune barrier leading to a greater exposure of the fetal cells to the maternal immune system. The high chimerism levels seen in this model likely compounded the exposure to the donor alloantigens leading to a functionally significant maternal immune response and precipitous fetal loss. Conversely, mature T cells are absent from the fetal liver donor cell populations used in other studies and chimerism levels are much more modest at the lower doses that were used  in this strain combination, we have reliably detected engraftment in 100% of the offspring despite the use of immunologically normal wild-type dams (However, the reported early engraftment rate in this study is unusually low given the relatively large number of transplanted fetal liver cells. Using the same methodology to prepare and prenatally transplant a similar dose of MHC mismatched fetal liver donor cells (2 \u00d7 10ype dams . The reain vitro study of differentiating CD34+ hematopoietic progenitors indicates that CD94/NKG2A expression precedes the expression of HLA-specific KIR receptors by human NK cells (The gestational time frame in which human fetal NK cells develop the capacity for allorecognition has not been directly elucidated. The finding of mature cytotoxic NK cells in human cord blood provides clear evidence that this occurs prior to birth . It is cNK cells . For thiNK cells . A subseSuccessful engraftment in IUHCT likely requires tolerance in all components of the host immune system. Our studies in the murine model have indicated that a minimum level of circulating ligand is necessary to induce and maintain tolerance. This level seems to be higher for NK cells than the level required for other components of the immune system. Thus, the chimerism threshold might represent the minimum qualification in the education of the developing NK cells and NK cell tolerance as the final endorsement of donor recognition. The study of NK cell repertoire formation, maturity, and trogocytosis in prenatal transplantation will not only facilitate understanding of the NK cell barrier, but will also contribute to the overall understanding of NK cell biology.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The objectives of this survey were to establish the prevalence of symptoms of post-traumatic stress in mixed staff groups working in adult and paediatric intensive care settings and to examine the main themes in staff descriptions of the most traumatic event they had experienced at work.A total of 355 health professionals working on three adult and four paediatric units at two centres were asked to rate their current level of post-traumatic stress symptoms on the Trauma Screening Questionnaire (TSQ).n = 33/193 (17%) vs. AICU n = 13/162 (8%), P < 0.001). For the 172 staff who provided a description of the most traumatic event they had experienced, the following themes were most commonly endorsed: patient death (and particularly untimely deaths on adult units); handling distressed families; and concerns about the quality of care and dealing with staff conflict (see Figure Paediatric/neonatal intensive care staff were more likely to score above the clinical cutoff point for post-traumatic stress symptoms on the TSQ in relation to an incident at work than adult intensive care staff in this sample (PICU A significant minority of staff reported clinically significant levels of post-traumatic stress related to their work. The facts that post-traumatic stress levels were higher on paediatric units despite their lower rates of mortality and that untimely deaths were frequently mentioned by adult unit staff suggest it may be that untimely deaths are particularly hard to deal with. More research is needed on the prevalence of distress in staff working in these settings."}
+{"text": "The auditory efferent system originates in the auditory cortex and projects to the medial geniculate body (MGB), inferior colliculus (IC), cochlear nucleus (CN) and superior olivary complex (SOC) reaching the cochlea through olivocochlear (OC) fibers. This unique neuronal network is organized in several afferent-efferent feedback loops including: the (i) colliculo-thalamic-cortico-collicular; (ii) cortico-(collicular)-OC; and (iii) cortico-(collicular)-CN pathways. Recent experiments demonstrate that blocking ongoing auditory-cortex activity with pharmacological and physical methods modulates the amplitude of cochlear potentials. In addition, auditory-cortex microstimulation independently modulates cochlear sensitivity and the strength of the OC reflex. In this mini-review, anatomical and physiological evidence supporting the presence of a functional efferent network from the auditory cortex to the cochlear receptor is presented. Special emphasis is given to the corticofugal effects on initial auditory processing, that is, on CN, auditory nerve and cochlear responses. A working model of three parallel pathways from the auditory cortex to the cochlea and auditory nerve is proposed. However, several lines of neuroanatomical evidence demonstrate the presence of an efferent network originated in the auditory cortex that reaches the cochlear receptor through OC neurons  bundles by Rasmussen , 1960, tThe functionality of the corticofugal pathways to OC neurons has been proven by recent evidence demonstrating that auditory cortex activity can modulate afferent responses even at the level of sensory transduction  and lateral (LOC) olivocochlear neurons located in the SOC . These opposite results could be explained by the differential generating mechanisms of click-evoked OAE with that of DPOAEs  that generate the DPOAEs, but measurements were obtained from a distant location in the cochlear partition at the 2f1\u2013f2 frequency. Future experiments should clarify whether the corticofugal effects are different if the subject attention is directed to the primary tones (f1 and f2) or to the DPOAE frequency (2f1\u2013f2).Contradictory results have been obtained in visual attention tasks with auditory distractors in humans. For instance, Puel et al.  showed tBoth ears are connected through the uncrossed MOC pathway that is activated by contralateral sounds (de Venecia et al., In summary, here we reviewed the growing anatomical and physiological evidence supporting the presence of an efferent network from auditory cortex to OC neurons. Cortical descending effects on CN, auditory nerve and cochlear responses are proposed to be produced by three parallel pathways from auditory cortex to the crossed and uncrossed MOC neurons and to LOC neurons. These connections are probably activated during selective attention, learning induced plasticity and other cognitive functions.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Perceptual phenomena such as spatio-temporal illusions and masking are typically explained by psychological (cognitive) processing theories or large-scale neural theories involving inter-areal connectivity and neural circuits comprising of hundreds or more interconnected single cells. Subcellular mechanisms are hardly used for such purpose. Here, a mechanistic theoretical view is presented on how a subcellular brain mechanism of integration of presynaptic signals that arrive at different compartments of layer-5 pyramidal neurons could explain a couple of spatiotemporal visual-phenomenal effects unfolding along very brief time intervals within the range of the sub-second temporal scale. Zeitgeist of nanophysiology which is set to deal with processes taking place between different compartments of single cells perceptual contents are encoded by the neocortical pyramidal neurons (PN);(ii)afferent presynaptic input from stimulation becomes explicitly perceived when the activity of thalamo-cortical microcircuits that represents specific sensory contents is synchronized with the activity of thalamo-cortical non-specific modulatory microcircuits; this system involves layer-4 PN that are activated mostly by first-order and higher-order feedforward connections from thalamus and layer-5 PN as an essential link in integrating the cascaded thalamo-cortico-thalamic processes by sending cortico-thalamic efferents to higher-order thalamic relays such as pulvinar;(iii)modulatory presynaptic input essential for long-range integration (top\u2013down connectivity) and contextual effects from higher level cortex and/or from non-specific reticulo-thalamic alerting system arrives at the apical dendrite compartment of PN;(iv)for perceptual integration to be available for conscious experience (representing objects and scenes), temporal coincidence of the somatic presynaptic input and apical-dendritic presynaptic input is necessary;(v)the varying contents of explicit perception are extracted and selected from the active type-PN neurons by the coincidence detection mechanism; this mechanism makes part of the available information accessible for consciousness;(vi)this cellular/subcellular mechanism is subject to neuronal plasticity effects in learning and constitutes a device where actual sensory input and contextual information from long- and short-term memory interact;(vii)the temporal dynamics of activity of the PN units is explicated in excitatory post-synaptic potentials (EPSPs) and spiking as dependent on the level of EPSP depolarization; it is subject to varied inhibitory effects by GABA-ergic interneurons;(viii)feed-forward sensory effects are somatic-compartment driven whereas top\u2013down and collateral modulation effects are apical dendrite (including tuft) compartment driven.Information contents of objects and scenes are encoded in the multiple modules of cortex, ordered along the afferent processing stages retina-LGN-V1-V2-V4-IT. However, most of information reaching these cortical areas benefits from the cascaded system of thalamic relays . It is wdirect part in the feed-forward retina-LGN-V1 object representation and perception stream, the activity of layer-5 cells can be considered as a \u201clitmus test\u201d of whether certain contents carried by PN of other layers have been integrated to a conscious percept.Although layer-5 PN do not take any 2+ spikes does. This substantiates the importance of modulatory brain processes in addition to the straightforward sensory afference and provides a convincing argument for the common effects of biased perception being under the contextual and arousal systems control.  target stimuli are presented together with contextual stimuli, (b) temporal parameters of the duration and succession of the stimuli are compatible with the time constants of activity of the timing of presynaptic inputs and plateau waves of EPSPs of the coincidence detection mechanism, (c) the somatic presynaptic input of the layer-5 PN cells signaling about certain perceptual content and the dendritic apical compartment input of the same layer-5 cells can originate from different stimuli inputs, (d) the temporal delay to conscious access of the perceptual contents is determined by the slowest link in the hierarchical modules which represent the object and scene contents. This set of premises makes it possible that target stimulus\u2019 contents-signaling activity of the PN is modulated by the contextual stimulation so that illusory shifts of perceptual delays of different content in real time may occur. Moreover, in some stimulation conditions these premises allow a stimulus that follows to substitute a preceding stimulus in conscious experience.I posit that non-specific mechanism which brings the non-conscious specific representation to consciousness because any explanation requires a process that is activated by the flash but acts on the representation of the target . In the coincidence detection based binding mechanism apical-dendrite presynaptic input implements the non-specific counterpart and somatic presynaptic input implements the specific target-content counterpart. As the target stimulus is physically present also when subjectively suppressed during MIB, by definition the apical presynaptic input to the PNt neuron representing the target should be insufficient during MIB although the somatic input for PNt must be sustained . When a flash is presented, its transient response evokes non-specific presynaptic input to apical dendrites of the PNt neuron and as the PNt related EPSP was already at the near threshold level, plateau-wave spiking of the PNt is ignited at once . This leads to the conscious perception of the target. The sustained part of PNf signaling necessary for the flash-stimulus perceptual content representation takes time and only after a delay of about 100 ms specific somatic and contextual dendritic pre-synaptic inputs coincidence is processed, resulting in the delayed awareness of the flash. When the flashed object is presented, two processes are triggered \u2013 the process for representation of the contents of the flashed stimulus and the boost of or perturbation in the contextual process presynaptically alerting the PN neurons at their apical-dendrite compartment. This facilitated (or reset) contextual activity leads to binding of the already present pre-conscious PNt-activity with global consciousness-level representation. This binding process takes little time because there is no need for build-up of the content-specific neural representation for the target as it is pre-consciously already present. Recently, a novel temporal illusion was presented by Figure 1) represents an earlier external time moment than the internal state iii  for the PNbg representing diffuse background color. This explanation either suggests that sensory consciousness emerges right there where the corresponding perceptual contents coding PN are located  or assumes a higher level integrative locus where \u201call comes together\u201d with a temporal delay.Another intriguing temporal illusion was presented by + spikes. However, because this delay is too short for any associative input to arrive to the tuft region of the dendrite in response to the target-evoked perturbation, initially there is no target experience. Processing is pre-conscious. After some more time has lapsed, this associative, tuft-area directed presynaptic input arrives , but it coincides with the mask-stimulus evoked Na+ spikes produced by the neurons that encode mask features. Because certain features of target and mask are shared by the target-responsive and mask-responsive cells , mask-responsive cells receive also the associative presynaptic Ca2+activity initiating input to the dendrite\u2019s upper compartment (this was evoked by the preceding target). Because this input is coincident with Na+ spikes, a plateau wave is produced primarily for the neurons representing the mask features instead of the neurons representing exclusively the target features . We must remember here that the associative input in response to a perturbation by a stimulus has a longer delay to reach the apical compartments of the dendrites of the neurons compared to the delay it takes for the initial basal input to arrive to the cell. This basic fact is the crucial precondition for BAC firing based binding of the later presented stimulus with conscious representation instead of the first presented, briefly offset stimulus. Thus, the target-evoked dendritic Ca2+ mediated EPSP appears after a delay, is spread also to dendrites of other cells , and coincides with the fast Na + based somatic EPSP/spiking process of the mask-related cells. It is exactly then and there when and where the coincidence detection device sets in, but as a result, the masking stimulus is emphasized for awareness. An open question here is this: what are the relative roles of the (i) specific top\u2013down associative backpropagation from the higher nodes of representations of specific input and (ii) non-specific (\u201cdiffuse\u201d) thalamocortical modulation mediated by the directed arousal system? In backward masking, if a brief target stimulus  is rapidly followed by a masking stimulus, target may not be consciously perceived and the masking stimulus is explicitly experienced instead . Majorit2+ membrane activity exactly at the time when the feedforward somatic input to the lower level PN neurons encoding S2 surface orientation arrives there. This temporal coincidence allows to produce a plateau-wave in the neurons that carry information about S2 surface orientation, which leads to perceptual integration of this feature with the higher level neural activity representing S1 shape. The result is illusory binding of S1 shape and S2 surface orientation in the perceived object. The temporal asymmetry of misbinding between the two attributes separated in time speaks against the response bias explanation of the illusion.In certain specific mutual masking experimental protocols, illusory misbinding of features of the two successive, spatially overlapping targets occurs when intermediate stimulus onset asycnhronies (SOAs) separate targets in time. For example, this happens when S1 and S2 are stimulus-objects with two integrated within-object, task-relevant features in each . When ceFigure 1, i changes very fast to a state as in Figure 1, iii). The changing object\u2019s perceptual values are fast to conscious perception. With the flashing object there is a temporal handicap: because the flashed object is a newly appearing one, it takes time to prepare the bottom\u2013up plus top\u2013down contextual reentrance for apical presynaptic input. This means that the somatic plus apical input coincidence detection for the PN of the flashed object has a longer delay. The same subjective moment in time presents the observer with different perceptual values of the changing and invariant objects: for the flashed feature this value comes from a bit more distant past while for the changing object it is more contemporary.I will end the examples of illusions with the much celebrated flash-lag effect FLE; . When anThe present theoretical account capitalizing on the contextual modulation by the BAC firing mechanism has an advantage over the above mentioned alternative theories put forward for explaining the listed phenomena. Each of these theories is narrowly bound to certain one specific phenomenon while the present theoretical approach can explain a multitude of phenomena in a single theoretical framework. Sure enough, although the temporal parameters of the listed phenomena have a largely coinciding order of magnitude of the temporal scale , the precise timing values may differ. Therefore, in future research it is important to find the ways to test specific predictions related to precise timing of the phenomena vis-\u00e0-vis the timing of the subprocesses of the BAC firing, contextual modulation, mechanism. Although this is technically complicated with human subjects, one way would be to measure directly the BAC firing processes in the conditions across different experimental settings that produce these different phenomena.  is also implicated in the slow 5-HT induced glutamatergic response  associated with serotonergic, dopaminergic and BDNF related endophenotypes , 2015a,bresponse . So the response , which aVisual phenomenology as related to GABA and glutamate levels in visual cortex was investigated by Of course, another direction of development for the present approach could be computational modeling e.g., , 2015. Win vitro methods. Understandably enough, this type of research can not provide data directly relevant for consciousness phenomena. Nevertheless, among the scarce research linking top\u2013down contextually modulated perceptual behavior in vivo and cellular events there are studies with results consistent with the present hypothesis. Using the method of cortical cooling of V3 and V2, An obvious limitation of this paper concerns the mutual isolation of the perceptual level phenomena I explained and the mechanistic level of explanation at the (sub-)cellular level. Because of the space constraints I can not present an in-depth treatment of this issue. For a more detailed discussion of the neuronal level mechanistic description of the foundations of the present theory of the illusory phenomena different publications can be recommended see . On the Another limitation of the present article is its \u201cfixation\u201d at the layer 5/6 units without explicating whether other layers of neurons may be necessary or even whether other kinds of local circuits capitalizing on the effects of neurons situated in other layers (except layer 5) could produce similar results. For example, layer 2/3 and layer 6-to-4 neurons can be assembled together so as to model a rich repertoire of the perceptual phenomena . Future There are two big groups of neurobiological theories of the mechanisms of explicit conscious perception possibly to be used for explaining why our subjective experience of the real world is not always veridical and sometimes even deprives us from seeing distinct reality: (i) distributed global processing theories, stressing the importance of the large network and computations performed by that network ; (ii) local integrative modules based theories stressing the significance of the cellular and sub-cellular mechanisms for the whole global network functioning and particularly for upgrading the preconscious information processing activities in order to acquire the status of phenomenal experience of the processed contents . The group (i) does not provide specific hypotheses for the fine time scale psychophysical phenomena. Group (ii) theories are specific enough to provide experimentally testable predictions for certain psychophysical phenomena unfolding over a fine time scale. The key principle according to which the testable predictions can be formulated concerns the temporal coincidence of presynaptic inputs arriving from different cerebral regions within a critical time-window such that this satisfies the working-parameters of the BAC firing mechanism. According to this theory, the sources of presynaptic inputs to distal and basal compartments of the layer-5 neuron\u2019s membrane that are capable of producing coincidence of these inputs are to be integrated (bound) for subjective experience. Now, the task is to see under what experimental stimulation conditions this coincidence occurs and ascertain whether the corresponding psychophysical illusory phenomenon can be thus mechanistically explained. We saw that there are indeed a couple of such phenomena. This makes the BAC firing based theory of visual phenomenology a falsifiable theory. Last but not least, expression of the subcellular and synaptic mechanisms of the brain is strongly influenced by the endophenotypes which are regulated by common genetic variability. Because this variability is associated with personality traits predictive of adaptive resilience and vulnerability, individual differences in perceptual phenomenology as based on the effects of this hypothetical mechanism might be explored with a purpose. It is \u2013 bearing in mind the possibility to develop perceptual express tests of vulnerability.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Cardiac troponin I (cTnI) is well known as a biomarker for the diagnosis of myocardial damage. However, because of its central role in the regulation of contraction and relaxation in heart muscle, cTnI may also be a potential target for the treatment of heart failure. Studies in rodent models of cardiac disease and human heart samples showed altered phosphorylation at various sites on cTnI (i.e. site-specific phosphorylation). This is caused by altered expression and/or activity of kinases and phosphatases during heart failure development. It is not known whether these (transient) alterations in cTnI phosphorylation are beneficial or detrimental. Knowledge of the effects of site-specific cTnI phosphorylation on cardiomyocyte contractility is therefore of utmost importance for the development of new therapeutic strategies in patients with heart failure. In this review we focus on the role of cTnI phosphorylation in the healthy heart upon activation of the beta-adrenergic receptor pathway (as occurs during increased stress and exercise) and as a modulator of the Frank-Starling mechanism. Moreover, we provide an overview of recent studies which aimed to reveal the functional consequences of changes in cTnI phosphorylation in cardiac disease. Cardiac troponin I (cTnI) and its binding partner cardiac troponin T (cTnT) are the biomarkers of choice for the diagnosis of myocardial damage , 2. Upon2+ [2+]), cTnI binds actin at multiple sites maintaining tropomyosin at the outer domain of actin, and thereby blocks myosin-binding sites on the thin filament and prevents force development. In systole (high intracellular [Ca2+]), Ca2+ binds to cTnC and induces a conformational change in the troponin complex. This results in the release of cTnI from actin and a shift of tropomyosin closer into the grove of the actin filament, thereby enabling actin-myosin interactions and cardiomyocyte force development ..2+ sensiStudying cTnI phosphorylation in different disease phenotypes and at different disease stages will help us to gain a better understanding of the role of PKC-mediated cTnI phosphorylation in cardiac disease. Additionally, with this increasing knowledge about cTnI phosphorylation in cardiac disease, cTnI phosphorylation patterns at the different PKA- and PKC-phosphorylation sites may become promising biomarkers since cTnI phosphorylation status can be determined from blood samples after acute cardiac insult."}
+{"text": "This article addresses the steady three-dimensional flow of an Oldroyd-B nanofluid over a bidirectional stretching surface with heat generation/absorption effects. Suitable similarity transformations are employed to reduce the governing partial differential equations into coupled nonlinear ordinary differential equations. These nonlinear ordinary differential equations are then solved analytically by using the homotpy analysis method (HAM). Graphically results are presented and discussed for various parameters, namely, Deborah numbers  During the past few years, study of the boundary layer flow of nanofluids over a linear stretching surface has become more and more attractive because of its numerous applications in industrial manufacturing. With regard to the sundry application of nanofluids, the researchers have been given considerable attention to improve heat transfer using nanofluids. Regular fluids, such as ethylene, water, glycol mixture and some types of oil have low heat transfer rates. Therefore it is necessary to improve some physical properties such as thermal conductivity and heat transfer rate of conventional fluids by the utilization of nanoparticles in base fluid. The term nanofluid was first time introduced by Choi Sakiadis However, to the best of author's knowledge, no attempts have thus far been communicated with regards to free convective boundary layer flow of three-dimensional Oldroyd-B nanofluid over a stretching surface. The aim of the present article is to study the free convective boundary-layer flow of three-dimensional Oldroyd-B nanofluid fluid flow over a stretching sheet. The Oldroyd-B fluid model was employed to describe rheological behavior of viscoelastic nanofluid. The Oldroyd-B fluid model is important because of its applications in the production of plastic sheet and extrusion of polymers through through a slit die in polymer industry. The considered stretched flow problem involves problem involves the significant heat transfer between the sheet and the surrounding fluid. The extrudate in this mechanism starts to solidify as soon as it exits from the die and then sheet is collected by a wind-up roll upon solidification. Physical properties of the cooling medium, e.g., its thermal conductivity has pivotal role in such process. The success of whole operation closely depends upon the viscoelastic character of fluid above the sheet. By applying boundary layer approximations a system of nonlinear partial differential equations is obtained. Then, invoking suitable similarity transformations, we reduced the system into nonlinear ordinary differential equations. This system of coupled nonlinear ordinary differential equations is then solved analytically by using the homotpoy analysis method (HAM). The variations of different flow controlling parameters on the velocity, temperature and concentration profiles are addressed.Consider a steady three-dimensional Here The similarity variables are introduced asThe physical quantities of interest are the local Nusselt number In terms of dimensionless form one hasf\u0127, g\u0127, \u03b8\u0127, and \u03c6\u0127 is of key importance because they control the convergence of the series solution. The most suitable value of these auxiliary parameters is calculated by considering minimum square error which is given byThe problems containing non-linear coupled ordinary differential The aim of this section is to analyze the influence of the various physical parameters on the velocity, temperature and nanoparticle fields respectively. rameter  . In factIn Numerical values for the velocity gradients This study has analyzed the effects of the heat generation/absorption on three-dimensional flow of an Oldroyed-B nanofluid over a bidirectional stretching sheet. From the present investigation, the main observations were as follows:Qualitatively, effects of the Deborah numbers The temperature profile as well as thermal boundary layer thickness were increased by increasing both the Brownian motion parameter The temperature of the fluid and thermal boundary layer thickness is enhanced when there is a increase in the heat generation parameter The concentration profile was decreased with the increase of the Brownian motion parameter It was noted that the thermophoresis parameter An increase in the heat generation parameter The magnitude of the local the local Nusselt number \u2212The magnitude of the local the local Sherwood number \u2212"}
+{"text": "In thoracic electrical impedance tomography (EIT) electrodes are placed around the human thorax. Weak alternating currents are applied via two electrodes and the resulting potentials are sensed by the remaining electrodes. The measured voltages are then converted into moving real-time images showing heart and lung functions rather than its structures. EIT is non-invasive and can thus be employed over several hours right at the bedside. However, for mid and long term measurements stable electrical electrode skin contact and a skin friendly patient interface are required.2 and the skin contact impedance was measured once with dry and once with wetted electrodes in the 10 healthy volunteers. An electrically non-conductive oil-in-water liquid emulsion, called ContactAgent (CA), was used to wet out the textile electrodes. Mid-term stability was then measured over a period of 4 hours in the 40 patients. To avoid any undue burden measurements with dry electrodes were not repeated in patients.In this study the electrical skin contact of a novel textile-based electrode assembly comprising 32 active electrodes integrated in a vest-like structure was assessed in 10 healthy volunteers and in 40 patients undergoing robot-assisted radical prostatectomy. The study protocol was approved by the ethics committee of the medical board Hamburg (PV374) and written consent was obtained from all patients. The electrode assembly was connected to the Swisstom BBSkin contact impedance of the dry electrodes was higher than 2'000 Ohm. After applying the contact agent, skin contact impedance dropped below 500 Ohm and remained there for the next 4 hours.In spite of being non-conductive, the CA markedly decreased skin contact impedance. Possible explanation are that the CA increases the adherence of the textile electrode to the skin, increases the effective electrode contact area while displacing the air pockets both, within the yarns of the textile layer and between the electrode and the skin thereby improving the dielectric properties of the skin-electrode system. We conclude that the new patient interface in combination with the special CA provides a stable electrical contact between electrodes and the skin for at least 4 hours."}
+{"text": "We present a 31-year-old female with repaired tetralogy of Fallot (TOF) and right-sided aortic arch (RAA) with left-sided patent ductus arteriosus (PDA) originating from the left brachiocephalic artery. This is a rare finding but most common site for a PDA in TOF and a RAA. To the best of our knowledge, this is the first demonstration of this rare finding on MRI in the literature. We present a 31-year-old female with repaired tetralogy of Fallot (TOF) (transannular patch repair of the right ventricular outflow tract) and right-sided aortic arch with left-sided patent ductus arteriosus (PDA) originating from the left brachiocephalic artery, which is a rare finding, but most common site for a PDA in individuals with TOF and a right-sided aortic arch. To the best of our knowledge there are no other cases in the literature demonstrated on MRI.The patient underwent cardiac magnetic resonance imaging (MRI) as part of investigations prior to pregnancy but was otherwise asymptomatic. MRI demonstrated a right-sided aortic arch with mirror image branching and a tubular structure connecting the left brachiocephalic artery to the distal pulmonary trunk see . The magIn Edward's developmental model of the aortic arch the development of the right-sided aortic arch with mirror image branching occurs due to involution of the dorsal segment of the left arch between the left subclavian artery and descending aorta \u20133. The rOther documented positions of the PDA in patients with tetralogy of Fallot include origins from an aberrant left subclavian artery in a right aortic arch, from a diverticulum which also gives off the aberrant left subclavian artery, and from the left common carotid artery in the context of aberrant left subclavian artery, and, rarely, there can be a right PDA connected to the right pulmonary artery. The PDA can arise from the right subclavian artery in a left aortic arch or from a diverticulum when in conjunction with an aberrant right subclavian .Supplementary Video 1: 3D volume-rendered cine of the whole heart showing the PDA connecting the left brachiocephalic artery to the distal pulmonary trunk.Supplementary Video 2: Maximum intensity projection time resolved MRA showing the PDA enhancing with contrast during the arterial phase. The PDA originates from the left brachiocephalic artery and drains into the distal pulmonary trunk."}
+{"text": "In vivo experimental models showed that Beta2GPI cannot be detected in vascularized organs in resting conditions, while it can be over-expressed after pro-inflammatory stimulus. In this condition autoantibodies recognize the molecule, fix complement (C') and eventually induce clotting. This finding is in line with the observation that although the presence of aPL is a necessary pre-condition, APS-associated clotting is triggered by an additional 'second hit', frequently related to innate inflammatory immune responses.Antiphospholipid antibodies (aPL) are both diagnostic markers for, and pathogenic drivers of, antiphospholipid syndrome (APS). Beta 2 glycoprotein I (Beta2GPI)-dependent aPL, the most important subset, mediate different--and not necessarily alternative--thrombogenic mechanisms, mainly on the basis of their reactivity with Beta2GPI expressed on cells that participate in the coagulation cascade. in vivo model of fetal loss supports a mechanism of aPL-mediated acute placental inflammation, other models and the histopathological examination of APS placentae do not support an inflammatory signature. Beta2GPI can be detected on endothelial cells of uterine vessels in resting conditions and its presence is increased during pregnancy in uterine endothelium and trophoblast. This finding does support the hypothesis that Beta2GPI -dependent aPL recognize their antigen on placental tissues. There is evidence that the antibodies may inhibit the growth and differentiation of trophoblasts, and eventually cause defective placentation so explaining the APS obstetric manifestations.Recurrent pregnancy complications associated with aPL cannot be explained solely by thrombosis, and alternative pathogenic mechanisms have been reported. Although one th domain of the Beta2GPI was shown to compete with the molecule binding to the membrane of cells involved in the pathogenesis of the syndrome . The passive infusion of the peptide was protective against the effect of polyclonal human APS IgG fractions on experimental thrombus formation and fetal loss induction. Moreover, a human monoclonal antibody against the immunodominant epitope of the Beta2GPI (Domain I) was shown to induce fetal loss and to trigger clotting by fixing C' in na\u00efve mice. A similar monoclonal antibody lacking the CH2 fragment in the Fc gamma portion was still reacting with the Beta2GPI but no more able to activate C'. The C' non-fixing monoclonal antibody was protective by competing with the pathogenic one when passively infused in na\u00efve mice and evaluated for both the induction of thrombus formation and the induction of fetal loss.Why antibodies with similar antigen specificity produce different clinical manifestations is not clear. The formation of immune complexes on the membrane of cells with different biological functions may at least in part explain the diverse effects mediated by the autoantibodies (i.e. clotting versus defective placentation). Altogether this finding strongly supports the pivotal role of Beta2GPI as the main tissue target for aPL. Accordingly, new approaches have been tried in order to interfere with the antibody binding and its consequences. A synthetic peptide displaying a similarity in the PL-binding region of the VNone declared."}
+{"text": "Transmission of extracellular signals into the cell often relies on the binding of extracellular signaling molecules to membrane receptors. How membrane receptors transmit these signals into the cell and activate intracellular signaling cascades has been an intense field of research over the last 20\u2009years. Basically, two competing models have been proposed. In the first model, binding of signaling molecules promotes ligand-induced dimerization/oligomerization of receptors. According to the second model, binding of signaling molecules triggers ligand-induced conformational changes within preformed dimeric/oligomeric receptors.For many years, the model of ligand-induced dimerization was the preferred model to explain the activation of many single transmembrane-spanning receptors that rely on the (trans)phosphorylation of their intracellular domains. One of these receptors is the prolactin receptor (PRLR), which belongs to the cytokine receptor family that is devoid of intrinsic kinase activity but constitutively interacts with the JAK2 tyrosine kinase. PRLR activation triggers first trans-phosphorylation of two JAK2 molecules (each bound to one PRLR molecule), followed by receptor phosphorylation by JAK2 and recruitment of STAT5 molecules promoting further downstream signaling events.Frontiers in Endocrinology  in a single study and went beyond the current status by exploiting further techniques such as blue native gel electrophoreses and time-resolved fluorescence resonance energy transfer (TR-FRET). This presents the first application of the TR-FRET technology to cytokine receptors. TR-FRET is based on the energy transfer between the energy donor terbium cryptate (Tb) and an energy acceptor. Due to the long-lived fluorescence properties of Tb, measurement can be performed after a time delay of 50\u2013150\u2009\u03bcs to avoid interference with cellular autofluorescence, thereby considerably improving the signal-to-noise ratio of the assay  appear to consolidate the proposed PRLR activation model and is likely to provide additional insights . AccordiThe author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Cross-frequency coupling (CFC) between neural oscillations has received increased attention over the last decade, as it is believed to underlie a number of cognitive operations in different brain systems. Coupling can take different forms as it associates the phase, frequency, and/or amplitude of coupled oscillations. These specific forms of coupling are a signature for the underlying network physiology and probably relate to distinct cognitive functions. Here I discuss three caveats in data analysis that can lead to mistake one specific form of CFC for another: (1) bicoherence assesses the level of phase-amplitude and not of phase-phase coupling (PPC) as commonly accepted; (2) a test for phase-amplitude coupling (PAC) can indeed signal phase-frequency coupling (PFC) when the higher frequency signal is extracted using a too narrow band; (3) an oscillation whose frequency fluctuates may induce spurious amplitude anticorrelations between neighboring frequency bands. I indicate practical rules to avoid such misidentifications and correctly identify the specific nature of cross-frequency coupled signals. SO the slow oscillation and FO the fast oscillation in this paper. Notably, the pitfalls presented here are by no means linked to the specific nature of neural signals and are equally applicable to the cross-frequency analysis of any dynamical signal.Cross-frequency coupling (CFC) refers to the coupling between oscillations of distinct frequencies. In neuroscience, CFC has been observed with neural oscillations in a wide range of frequencies, across numerous brain systems, animals, and recording techniques , fFO frequency (frequency of FO), and fSO + fFO frequency (sum of frequencies). As a measure based on phase that is loosely related to the coherence measure assessing 1:1 phase-locking  if the modulation is locked to the signal component at frequency fSO, i.e., if there is PAC  In general, any modulation of amplitude of FO oscillation by a slower SO oscillation yields a spectral signature at frequency O Figure , and itsO Figure . The levC Figure . Strong C Figure . In otheC Figure ,b.fSO and fFO will yield two peaks in the bicoherence map: one expected at the  pair but also another at the  pair. More generally, Jirsa and M\u00fcller showed through simulations that significant bicoherence measures are also found for models of phase-frequency or amplitude-frequency coupling (Jirsa and M\u00fcller, What is the practical value of the bicoherence measure for unveiling specific forms of CFC? It is clear that bicoherence should not be used to study cross-frequency PPC. Instead PPC should be investigated using either the method developed by Sauseng et al.  or the mWhile numerous methods exist for the identification of PAC in neural recordings (Canolty et al., It is thus likely that a significant portion of the numerous cases of PAC reported in the literature (Jirsa and M\u00fcller, The exposed confusion between PFC and PAC measures also makes evident the unrighteous imbalance in the attention that these two types of CFC have received. Indeed PAC has been much more investigated experimentally than PFC (Jirsa and M\u00fcller, The third pitfall is closely related to the second pitfall, because it also stems from the consequence of inappropriate bandwidth for FO extraction when FO frequency evolves. Different for the second pitfall, frequency fluctuations need not be tied to any specific slower oscillation. When components from non-overlapping sub-bands within the modulated frequency range are extracted, there will be a consistent dependence between the amplitude of such components (illustrated Figure I reported three possible pitfalls in neural data analysis that can lead to the misidentification of different forms of CFC between neural oscillations. In particular I describe how measures tailored to detect PAC or AAC may in certain circumstances also signal other dynamical features of the neural signal associated with frequency modulation. Of course this does mean that one should a priori favor these alternative interpretations over PAC/AAC, but that extra caution must be taken to nail down the specific form of coupling. Acknowledging these pitfalls is indeed important since specific CFC signatures can be related differently to neural mechanisms for CFC generation and to cognitive operations mediated by CFC. Other warnings have previously been issued about the statistical validity of some CFC tests: for example PAC measures may indeed simply reflect non-stationarity of the neural signal (Aru et al., The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In time-of-flight positron emission tomography (TOF PET) one of the main factors limiting the time resolution is the time evolution of the scintillation process. This can be avoided by using exclusively the Cherenkov light produced in a suitable material. Sub 100 ps FWHM timing has already been experimentally demonstrated but with a drawback of relatively low detection efficiency due to the photodetectors used. In this work silicon photomultipliers (SiPMs) are considered as a photodetector in Cherenkov TOF PET. The detection efficiency can be significantly improved by using SiPMs, however, at room temperature the SiPM dark counts introduce a significant source of fake coincidences. SiPM samples from different producers were tested in a simple back-to-back setup in combination with lead fluoride Cherenkov radiators. Results for coincidence timing, detection efficiency and effects of dark counts at different temperatures and SiPM overvoltages are presented."}
+{"text": "Listening to speech is often demanding because of signal degradations and the presence of distracting sounds . The question how the brain achieves the task of extracting only relevant information from the mixture of sounds reaching the ear  is still open. In analogy to recent findings in vision, we propose cortical alpha (~10 Hz) oscillations measurable using M/EEG as a pivotal mechanism to selectively inhibit the processing of noise to improve auditory selective attention to task-relevant signals. We review initial evidence of enhanced alpha activity in selective listening tasks, suggesting a significant role of alpha-modulated noise suppression in speech. We discuss the importance of dissociating between noise interference in the auditory periphery  and noise interference with more central cognitive aspects of speech processing . Finally, we point out the adverse effects of age-related hearing loss and/or cognitive decline on auditory selective inhibition. With this perspective article, we set the stage for future studies on the inhibitory role of alpha oscillations for speech processing in challenging listening situations. In ecological listening situations, auditory signals are rarely perceived in quiet due to the presence of different auditory maskers such as distracting background speech or environmental noise. Thus, sounds from different sources greatly overlap spectro-temporally at the level of the listener's ear. What are the neural correlates that facilitate selective listening to relevant target signals despite irrelevant auditory input  oscillations are an important tool for top\u2013down control as they regulate the inhibition of masker information during speech processing in challenging listening situations.Neural oscillations in the alpha frequency range (~10 Hz) are the most dominant signal measurable in the human magneto- and electroencephalogram (M/EEG), going back to their first description by Berger . The earOnly within the last two decades, the functional significance of alpha oscillations has been recognized and furthermore its ubiquitous role across sensory modalities  process but critically depends on \u201ctop\u2013down\u201d attentional control. For instance, in a multi-talker situation, target and distracting talker switch roles permanently, as the listener decides to change the conversational partner. In such a situation, M/EEG alpha power would be constantly at a high level; however, the deployment of alpha power onto the different processing channels would be changing continuously.What is the functional role of high alpha activity for word processing in noise? To answer this question, it is essential to distinguish between interpretations in which alpha activity is related to target processing from these related to noise processing. It is possible that the reduced intelligibility of words in noise leads to sub-optimal word processing and thus to less alpha suppression in brain areas relevant for speech processing  to assess the influence of alpha modulations on listening success under adverse acoustic conditions. Moreover, future studies could record the electrocorticogram (ECoG) directly from the cortical surface to track alpha sources and reveal the interplay between frequency bands. Such higher spatial resolution would allow to differentiate between alpha activity in brain regions associated with processing the masker or the signal. As of now, we are left to speculate how spatially specific alpha oscillations might operate, for example along a cochleotopic gradient in primary auditory cortex. The best data to infer from stems from visual cortex, where for example Buffalo and colleagues recorded with two electrode tips in attended vs. non-attended receptive fields less than a millimeter apart and report attention-dependent opposing, and deep-layer-specific alpha changes  during speech perception in ecologically valid listening situations, (2) in the presence of energetic and informational maskers, and (3) for aging and hearing-impaired listeners.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Concern that European forest biodiversity is depleted and declining has provoked widespread efforts to improve management practices. To gauge the success of these actions, appropriate monitoring of forest ecosystems is paramount. Multi-species indicators are frequently used to assess the state of biodiversity and its response to implemented management, but generally applicable and objective methodologies for species' selection are lacking. Here we use a niche-based approach, underpinned by coarse quantification of species' resource use, to objectively select species for inclusion in a pan-European forest bird indicator. We identify both the minimum number of species required to deliver full resource coverage and the most sensitive species' combination, and explore the trade-off between two key characteristics, sensitivity and redundancy, associated with indicators comprising different numbers of species. We compare our indicator to an existing forest bird indicator selected on the basis of expert opinion and show it is more representative of the wider community. We also present alternative indicators for regional and forest type specific monitoring and show that species' choice can have a significant impact on the indicator and consequent projections about the state of the biodiversity it represents. Furthermore, by comparing indicator sets drawn from currently monitored species and the full forest bird community, we identify gaps in the coverage of the current monitoring scheme. We believe that adopting this niche-based framework for species' selection supports the objective development of multi-species indicators and that it has good potential to be extended to a range of habitats and taxa. The majority of European forests are semi-natural ecosystems, heavily influenced by anthropogenic management and exploitation Ecological indicators are a useful and widely adopted tool for assessing biodiversity health and ecological change et al. http://www.ebcc.info/index.php?ID=459) which comprises 33 species selected on the basis of being abundant, widespread and characteristic of forests according to expert opinion Butler et al. Butler A pool of 80 candidate forest indicator species was identified, including all species categorised as having >10% of their breeding population using European forest habitat The new species' selection algorithm (SpecSel) is based on the concept of minimal dominating sets i, SpecSel compares the average sensitivity score of all minimal dominating sets containing i species with that of the minimal dominating set(s) containing i-1 species plus the single most sensitive species not included in that set, the minimal dominating set(s) containing i-2 species plus the two most sensitive species not included etc , ii) the set with the lowest average sensitivity score (hereafter SENSITIVE) and iii) the set identified by piecewise regression as the optimal breakpoint when relating indicator set size to average sensitivity (hereafter BREAKPOINT) \u2013 and discuss the relative merits of each.For each indicator set size, the algorithm described above identified the species' combination(s) that best met the two selection rules; for some set size categories, more than one combination had the lowest average sensitivity score because some species had the same sensitivity scores and were interchangeable. A previous application of this approach to UK farmland birds We also identified indicator combinations for several alternative contexts, applying the same procedure described above to each but excluding species and/or resources not relevant to the specific habitat type or community from the initial requirements matrix and species' pool. Firstly, we derived regional indicator sets for four regions of Europe ). The PECBMS is an association of experts and national organizations cooperating through the European Bird Census Council (EBCC) and BirdLife International, with technical assistance from Statistics Netherlands. This scheme collates population trend data from annually operated national breeding bird surveys from across Europe to generate supra-national trends; indices based on these data have been taken up as official statistics of biodiversity health and sustainable development by the European Union MINIMAL, BREAKPOINT, SENSITIVE and, for the pan-European and regional indicators, existing multi-species indicators) to that of an index based on the population trends of all species in the candidate pool from which the sets had been drawn (hereafter COMMUNITY). We expected a significant positive relationship between the inter-annual changes of each indicator and COMMUNITY and that the scale of change would be greater for our indicator sets than for the COMMUNITY i.e. the slope of any regression with inter-annual change in COMMUNITY as the dependent variable and the inter-annual change of one of our indicators as the predictor variable would be less than one. To test these, Type II major axis regression, implemented in the \u2018lmodel2\u2019 package in R x and y variables Using equivalent methods to these used to calculate existing pan-European and regional indices Bombycilla garrulus, Cyanopica cyanus and Tringa ochropus did not meet our inclusion criteria. Between them, these 30 species covered 164 of the 191 resource types used by the full community.Between them, the 80 species that met our criteria for inclusion in the candidate species' pool covered 191 resource types , S2, S3.MINIMAL contained eight species, with an average sensitivity score across constituent species of 48.5  and nine (North region indicator). There was some overlap in the species' composition of these sets, and they were identical for South, West and East indicators, but no species was present in all (SENSITIVE set varied between 26 (conifer-dominated forest indicator) and 39 (South region indicator)  . Piecewi species . Breaks MINIMAL set of the pan-European indicator are currently covered by PECBMS. When the candidate species' pool was restricted only to those currently covered by PECBMS, a minimum of nine species were required to provide full resource coverage, with Accipiter gentilis and Tetrao urogallus, the two species from the original indicator not currently covered by PECBMS, replaced by Accipiter nisus, Buteo buteo and Parus cristatus  and SENSITIVE (which was lower) sets; for the South indicator, the COMMUNITY index was very similar to that of the MINIMAL index.The temporal trends between 1980 and 2011 of each alternative Pan-European indicator set are shown in The smallest indicator set providing full coverage of the resources exploited by the wider community of 80 European forest bird species contained eight species. The average sensitivity across constituent species increased (sensitivity score decreased) with the addition of each extra species to the indicator set, up to a set of 40 species, but piecewise regression identified a breakpoint set at 15 species, beyond which the rate at which sensitivity increased with increasing set size slowed. Exploration of additional indicator sets, designed to represent particular regions and forest types or restricted to species currently covered by PECBMS, revealed a degree of overlap with this main pan-European indicator set, but the differences identified emphasised the need to consider indicator objectives when selecting constituent species.The indicator sets identified in this study correspond well with the key indicator attributes: that an indicator should be representative, reactive, respond predictably and be straightforward to measure, analyse and interpret MINIMAL set introduces increasing redundancy into the indicator. This trade-off between redundancy and sensitivity is explored in more detail below.A reactive indicator is comprised of the most sensitive species possible because they are more likely to respond to ecological change et al. Our species' selection protocol uses an equivalent resource requirements matrix to that used by Wade MINIMAL set for the pan-European indicator are currently covered by PECBMS, with pan-European population data for these species readily available. However, the selection of two species not currently covered by PECBMS identifies a possible gap in this monitoring scheme in terms of forest bird species. Our results suggest that including the \u2018missing\u2019 species, Accipiter gentilis and Tetrao urogallus, in future PECBMS indicators should be seriously considered. These species are monitored by other methods in a number of countries so it might be possible to incorporate these data for analysis and interpretation of the minimal dominating set as a forest bird indicator. The derivation of PECBMS-only indicator sets further supports the suggestion that current coverage does not embrace a fully representative suite of species. Only 58 of the 80 species in the initial candidate species' pool are currently covered and the total niche space occupied by these species is approximately 10% smaller than that of the full community. Restricting the initial species' pool to those currently covered by PECBMS reduced the total niche space occupied by candidate species for all indicator types explored, suggesting that any indicator based on currently covered species would not be fully representative of the wider target community and could be unresponsive to certain changes to forest habitats. In all cases, the \u201cmissing\u201d resources (i.e. those used by the wider community but not by PECBMS species) were related to diet rather than nest site and were almost exclusively associated with ground-dwelling vertebrate prey in different habitat types, suggesting that improved monitoring coverage of raptors and owl populations would be beneficial The final attribute of a good indicator is that it should be easy to measure, analyse and interpret. Six of the eight species in the Columba palumbus (sensitivity score of 78) replaced by Pyrrhula pyrrhula and Columba oenas (sensitivity scores of 15 and 30 respectively), with Columba oenas then replaced by Tetrao tetrix and Emberiza rustica (sensitivity scores of 24 and 9 respectively) in the optimal combination of ten species. Inclusion of generalist species in the indicator may be a concern because it reduces the probability of the indicator acting as an early warning system At small indicator set sizes, average sensitivity scores fell sharply with increasing indicator set size as the generalist species (included to ensure full resource coverage in sets with fewer species) were replaced by combinations of more specialised species that, between them, offered the same coverage. For example, the increase from the optimal set of eight species to the optimal set of nine species for the pan-European indicator saw SENSITIVE set, i.e. that with the lowest average sensitivity score, was at least three times larger than the MINIMAL set and, in the case of the broadleaf-dominated forest indicator, was 5.5 times the size. However, the rate of increase in sensitivity with increasing number of species declined once the particularly generalist species had been replaced. With the addition of each species to the smallest set, redundancy within the indicator is likely to increase, with a greater number of species exploiting each resource type. Redundancy in an indicator increases the sampling effort required to gather data beyond the minimum required MINIMAL sets compared to that of the other alternative species' sets for each indicator type . We would also expect the objectively selected species' sets to be more \u2018future-proof\u2019 than the current sets. Our results show that, on average, European woodland bird populations have remained relatively stable over the past three decades, although individual species have shown marked increases and declines in population (www.ebcc.info/). However, the regional indicators suggest that this overall stability masks population declines in the North, which are offset by increases in other regions. No pan-European forest-type specific indicators currently exist but our BREAKPOINT and SENSITIVE sets for both broadleaf- and conifer-dominated forest closely align to their respective COMMUNITY indicators and we would recommend adopting them more formally. These indicators suggest that, whilst populations of species associated with broadleaf-dominated forests have remained broadly stable, those of species related to conifer-dominated forests have declined by around 10%.Varying the species selected for a particular indicator had a significant impact on index value and the subsequent inference drawn about wider community it reflected. Whilst the pattern of temporal dynamics was broadly similar across alternative species' sets for the same indicator type, the extent of inter-annual change varied meaning that absolute index values were markedly different. Thus, for example, an index based on the The majority of ecological indicators developed to date are not selected using objective criteria and may therefore not be truly representative; there is a risk they will not reflect environmental changes affecting resources used by the wider community but not by the indicator species. Our analyses suggest this is true of the current pan-European forest bird indicator, with constituent species not covering the full range of resource types used by the European forest bird community it is intended to represent. We have applied an objective, niche-based framework to species' selection to identify a pan-European forest bird indicator that ensures representativeness and other key indicator attributes are met. By comparing indicator sets drawn from species currently covered by PECBMS and the full forest bird community using this framework, we have identified potential important gaps in coverage and recommend that greater inclusion of raptor and owl species would be particularly beneficial. More generally, we show that optimal species' composition and indicator size will be driven by specific indicator objectives and policy needs, both in terms of the initial pool of candidate species and how key characteristics such as sensitivity and redundancy are traded-off. We believe that adopting this niche-based framework for species' selection supports the objective development of multi-species indicators and, in light of previous applications to link land-use change and population trends Figure S1Relationship between the number of species in the indicator and the average sensitivity score of constituent species in the most sensitive combination for that set size for the pan-European and alternative indicators drawn solely from species currently covered by PECBMS.(TIFF)Click here for additional data file.Figure S2Temporal dynamics of the East region woodland bird indicator, drawn from species currently covered by PECBMS, between 1982 and 2011.(TIFF)Click here for additional data file.Figure S3Temporal dynamics of the West region woodland bird indicator, drawn from species currently covered by PECBMS, between 1980 and 2011.(TIFF)Click here for additional data file.Figure S4Temporal dynamics of the North region woodland bird indicator, drawn from species currently covered by PECBMS, between 1980 and 2011.(TIFF)Click here for additional data file.Figure S5Temporal dynamics of the South region woodland bird indicator, drawn from species currently covered by PECBMS, between 1989 and 2011.(TIFF)Click here for additional data file.Figure S6Temporal dynamics of the broadleaf-dominated woodland bird indicator, drawn from species currently covered by PECBMS, between 1980 and 2011.(TIFF)Click here for additional data file.Figure S7Temporal dynamics of the conifer-dominated woodland bird indicator, drawn from species currently covered by PECBMS, between 1980 and 2011.(TIFF)Click here for additional data file.Table S1Matrix of summer foraging resource requirements.(DOCX)Click here for additional data file.Table S2Matrix of winter foraging resource requirements.(DOCX)Click here for additional data file.Table S3Matrix of nesting resource requirements.(DOCX)Click here for additional data file.Table S4Reliance scores used in the calculation of species' sensitivity scores.(DOCX)Click here for additional data file.Table S5SENSITIVE sets for the pan-European, forest-type and regional indicators.(DOCX)Click here for additional data file.Table S6MINIMAL sets for the forest-type and regional indicators drawn solely from species currently covered by PECBMS.(DOCX)Click here for additional data file.Table S7BREAKPOINT sets for the forest-type and regional indicators drawn solely from species currently covered by PECBMS.(DOCX)Click here for additional data file.Table S8SENSITIVE sets for the pan-European, forest-type and regional indicators drawn solely from species currently covered by PECBMS.(DOCX)Click here for additional data file."}
+{"text": "The reported electrophysiological properties revealed by electrical imaging using high-density microelectrode arrays can be subdivided between spiking activity originating from retinal ganglion cells (RGCs) and local field potentials (LFPs) reflecting strong trans-membrane currents within the GCL. RGCs in rd retinas show increased and rhythmic spiking compared to age-matched wild-type retinas. Fundamental spiking frequencies range from 5 to 15 Hz in various mouse models. The rhythmic RGC spiking is driven by a presynaptic network comprising AII amacrine and bipolar cells. In the healthy retina this rhythm-generating circuit is inhibited by photoreceptor input. A unique physiological feature of rd retinas is rhythmic LFP manifested as spatially-restricted low-frequency (5\u201315 Hz) voltage changes. Their spatiotemporal characterization revealed propagation and correlation with RGC spiking. LFPs rely on gap-junctional coupling and are shaped by glycinergic and by GABAergic transmission. The aberrant RGC spiking and LFPs provide a simple readout of the functionality of the remaining retinal circuitry which can be used in the development of improved vision restoration strategies.In this review, I present and discuss the current understanding of aberrant electrical activity found in the ganglion cell layer (GCL) of rod-degenerated ( Imaging the electrical activity in three-dimensional neuronal tissue such as the retina relies on sensors which monitor changes of the transmembrane potential or of intracellular ion concentrations. The generation of action potentials leads to changes of intracellular calcium, which are revealed by fluorescence imaging of calcium indicators. For an introduction to calcium imaging in the retina and a comparison with electrical recording see the literature  and temporal resolution (~20 \u03bcs) as electrical imaging, in accordance with previous studies  mouse retinas.In retina research, the most studied retinal layer from a physiological perspective is the ganglion cell layer (GCL), due to its easy accessibility in Among the first results revealed by electrical imaging of the GCL was the wave-like spiking activity  in the developing retina  Analysis of pair-wise RGC activity demonstrated functional coupling driven by either reciprocal/gap-junctional coupling between RGCs, by common input from one presynaptic bipolar cell, or by a combination of both modalities , while this value declines for rd10 (5\u20137 Hz) or nob mice (4 Hz). However, the reported rhythmicity is not seen in all RGCs and appears to vary over time  low-frequency extracellular voltage changes have been reported by different labs (Ye and Goo, In rod-photoreceptor degenerated mouse retinas (A quantitative analysis of the detected LFP size is inherently difficult, as they develop over time in size and amplitude. However, two qualitative LFP features are worth noting. Their size at maximal amplitude extends over an area of ~200 \u03bcm (see Figure rd1 and rd10 retinas. In rd1 retinas the \u201cpulsatile\u201d LFPs propagate at a median speed of 8 mm/sec (Menzler and Zeck, rd10 GCL it is unclear if LFP propagation occurs (Menzler et al., As for the spiking properties, spatial electrical imaging the LFPs reveals qualitative differences between The current knowledge about the retinal neurons involved in the generation of rhythmic activity and the corresponding functional readout using electrical imaging is summarized in Figure rd retinas.In the following last section, I discuss how aberrant ganglion cell activity and the spatio-temporal LFP dynamics affect strategies for visual restoration in rd mouse models previous work has revealed changes of bipolar cell morphology (Strettoi et al., rd1 and in rd10 retina retain their synaptic connections with higher visual centers (Bi et al., A prerequisite for visual restoration in patients who are blind due to loss of photoreceptors is the survival of inner retinal neurons and their synaptic connections to higher visual areas. In Strategies for restoration of vision may therefore address the following questions, assuming that the lessons learned in blind mice translate to the human case. How can the aberrant ganglion cell activity be overcome by external stimuli and to what degree do external stimuli evoke near-physiological RGC response patterns?The first question has been tackled by employing pharmacological intervention (Toychiev et al., rd1 RGCs. Common to the electrical stimulation approaches in blind retinas is the very small percentage of activated OFF RGC responses (Goetz et al., The second question of how close the artificially-evoked responses in blind retinas resemble light-activated activity in healthy retinas has been addressed for electrical (O\u2019Hearn et al., In future, electrical imaging of the retinal GCL may improve future vision strategies in two ways. First, it can indicate if vision restoration is successful by comparing the artificially induced RGC patterns to physiological patterns. Several of the above cited studies performed a basic characterization of the induced activity, which can easily be extended to a comprehensive electrophysiological picture. Second, electrical imaging and analysis of the RGC population activity in blind retinas may reveal to what degree the aberrant rhythmicity impairs the coding of artificially evoked responses. Studies in frog and in cat retinas indicate a beneficial effect of oscillatory retinal activity for visual coding (Ishikane et al., GZ wrote the manuscript.Funding of this work was in part obtained from the German Federal Ministry of Education and Research through grant no. 1312038.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Bovine leukemia virus (BLV), a B-lymphotropic oncogenic retrovirus sharing common biological and structural features with the human T-cell leukemia virus I and II (HTLV-I and II), is the etiologic agent of enzootic bovine leucosis. One major feature of the BLV infection is the absence of viremia. It is widely accepted that BLV latency, due to the RN! polymerase II 5\u2019-LTR-driven transcriptional and epigenetic repression is a viral strategy to escape from the host immune system and allow tumor development. Recently, it has been demonstrated by deep sequencing and bioinformatics analysis that the BLV genome encodes a cluster of micro-RNAs which is predicted to be transcribed by RNA polymerase III suggesting that the silencing dogma in BLV transcriptional regulation is only partially correct. Here, we demonstrated by chromatin immunoprecipitation assays that BLV miRNAs were indeed transcribed in vivo by RNA polymerase III through a type II RNAPIII promoter similar to the one directing tRNAs transcription. We also showed that an activating epigenetic environment surrounds the miRNAs cluster. Overall, our results provide new insights into a better understanding of the molecular mechanisms regulating gene expression of oncogenic retroviruses."}
+{"text": "Improve the ability to infer sex behaviors more accurately using network data.A hybrid network analytic approach was utilized to integrate: (1) the plurality of reports from others tied to individual(s) of interest; and (2) structural features of the network generated from those ties. Network data was generated from digitally extracted cell-phone contact lists of a purposeful sample of 241 high-risk men in India. These data were integrated with interview responses to describe the corresponding individuals in the contact lists and the ties between them. HIV serostatus was collected for each respondent and served as an internal validation of the model\u2019s predictions of sex behavior.We found that network-based model predictions of sex behavior and self-reported sex behavior had limited correlation (54% agreement). Additionally, when respondent sex behaviors were re-classified to network model predictions from self-reported data, there was a 30.7% decrease in HIV seroprevalence among groups of men with lower risk behavior, which is consistent with HIV transmission biology.Combining the relative completeness and objectivity of digital network data with the substantive details of classical interview and HIV biomarker data permitted new analyses and insights into the accuracy of self-reported sex behavior. Since the first cases of HIV were reported among high risk men in 1981, global HIV prevention research has been dominated by individual-level assessments that utilize self-reported behavior to determine risk of HIV acquisition. Methodologies used in collecting self-reported risk behavior such as computer assisted surveys or online health diaries have contributed to improving the accuracy of sensitive sex behavior data To date, researchers have mostly utilized the reports of one network member on a second and suggested that such dyadic reports reflect more upon the rater\u2019s behavior than the network member of interest Newer social network research that leverages existing digital communication networks such as emails Accurate inference of sex behavior can be further strengthened by linking distinct HIV transmission risks to specific behaviors. In terms of both HIV transmission and acquisition, for example, vaginal sex presents a much lower risk compared to anal sex This study compares network-generated sex behavior to self-reported data by combining linked cell phone contact list data with respondent interviews. Interviews of respondents included self-reported behavior and the reported behavior of others in contact lists, many who were themselves respondents. The study then compares both sets of data to HIV serostatus to determine the approach that most accurately reflects sex behavior using a mixed-effects model The setting for this study was in a large city in Southern India. The study took place at a constellation of 20 well characterized social venues- \u201ccruising areas\u201d -where MSM congregate to socialize and where paid and unpaid sex is common. The study population included the following: individuals identifying as male between 18\u201339 years of age who visit one of the 20 venues, report anal/oral intercourse with another man within the previous 12 months, own and are in possession of at least one cell-phone at the time of recruitment, speak English or one of two local languages, and were able and willing to provide written informed consent for study participation. Protocols were approved by institutional review boards at the University of Chicago and SHARE-India.Time Location Cluster Sampling (TLCS) was conducted In order to determine when network saturation was achieved, we followed recruitment through a redundancy curve Figure 2To overcome interviewer and respondent burden from classic name generators that require recall and cataloguing names in a roster, the use of a SIM card reader was adopted Figure 3The following individual and relational characteristics were collected from respondents about themselves and about each MSM network member in their cell phone contact list. Variables were based upon those in previous work with this population All study respondents provided dry blood spots for HIV testing and three sequential antibody tests  were conducted using methods described previously th attribute of alter i as reported by ego j, ij(\u2013k)X are the set of all attributes of alter i except the kth attribute as reported by ego j, j\u03b3 represents the random effect specific to respondent j, and g represents a link function. For binary attributes we used a logit link. Sex behavior had multiple categories corresponding to a multinomial link. We used leave-one-out procedures to test model fits and the basic assumptions of the mixed effects model. We also applied a block model The network-based mixed effect model predictions of MSM sex position incorporate the reports of other network members on the individual of interest and structural network features such centrality and bridging Comparing self-reported attributes of 241 respondents to the model predictions was of central importance in the analysis. This provided a comparison of one\u2019s self-reported identification (i.e. sex position) versus the perception of this identification by others and a quantitative prediction of this perception given the network data. For sex position, we used a logistic mixed effects model, where individuals were classified as either being insertive or receptive. Because MSM in this context can also be versatile, engaging in both insertive and receptive sex, we used a thresholding approach. The threshold approach is. is an extension of Krackhardt\u2019s work on Consensus Structures All procedures were approved by Institutional Ethics Committees in the United States and India. As is typical of social network analysis, we collected limited information on third parties that are provided by consented study respondents social and sex sub-networks of the cell-phone network were also analyzed separately. The network-based model predictions of sex behavior incorporate the reports of other network members on the individual of interest as well as structural features of network members such as centrality and bridging MSM study respondents were recruited until the chance of a new respondent already being part of the network was >95%. All respondents were in the contact list of at least one other respondent. This process resulted in a network of MSM  and an augmented MSM network including those who were not interviewed directly  Figure 4Our primary results indicate that network-based model predictions of sex position and self-reported sex position had limited correlation (54% agreement). Further, there was variability in this agreement based upon network type: the agreement between self-report and model predictions within the sex network was 36% and agreement in the social network was 61% See Figure 5type of network, but how it was classified differed depending on the type of behavior reported: versatile behavior (both insertive and receptive) in the sex network was misclassified by self-report as insertive . Attributes such as religious affiliation are more likely to be comparable between self-report data and network predictions because they tend to be explicit in this context and less dynamic than sex behavior.Not only did self-report behavior differ from model predictions by tive See Figure 6The overall HIV seroprevalence rate in this population was high at 23.4%. Seroprevalence rates have been shown to vary by self-reported risk behavior with receptive MSM in this setting having the highest rates of infection followed by versatile (both insertive and receptive) and then insertive Our network model represents a shift in how sexual behavior can be inferred. Significantly, it shifts the current reliance on self-reported data by incorporating sex behavior reports from a plurality of network members and using structural features of networks to predict sex behaviors.Validating whether the network model predictions improve upon self-report is difficult due to the challenge in measuring sex behavior objectively. Self-reported behavior is often not highly associated with HIV infection, an observation that may be due to social desirability bias, measurement error, sexual network characteristics  The reason for modest congruence between the network model and self-reported sex behavior is likely driven by the potential response bias secondary to social desirability of self-reported behaviors. However, it may also be driven by dissonance between a sexual identity typical in the Indian context The approach discussed in this paper offers an important step in moving beyond the monolith of self-report data which form the current foundation of most HIV prevention research. This conventional approach can lead to potential systematic underestimation of sex behavior in cases of heterogeneous risk potential (such as the MSM case), which in turn can limit the interpretation and implementation of HIV research results. By removing these limitations, the new approach might, for example, allow for emerging biomedical interventions to be distributed more efficaciously to individuals more at risk, such as self-described \u201cinsertive\u201d MSM who also assume receptive sex positions. A digitally-derived network model that leverages hybrid network analytic approaches improves inference of sex behavior in emerging global HIV epidemics. The increasing availability of digital communication technology among international populations could allow for greater inference capacity as well as dissemination of future HIV interventions."}
+{"text": "Altitude-related cough is a troublesome condition of uncertain aetiology that affects many visitors to high altitude. The traditionally held belief that it was due solely to the inspiration of cold, dry air was refuted by observations and experiments in long duration hypobaric chamber studies. It is likely that altitude-related cough is a symptom of a number of possible perturbations in the cough reflex arc that may exist independently or together. These include loss of water from the respiratory tract; respiratory tract infections and sub-clinical high altitude pulmonary oedema. The published work on altitude-related cough is reviewed and possible aetiologies for the condition are discussed. Once started, there was no escape. The cold dry air compounded the irritation in the throat and the victim\u2019s body would be shaken by the hacking cough until randomly flung free of its spell. The nights at base camp as well as on the mountain were often punctuated by staccato bursts of noise disturbing the sleep of the sufferer and all those around\u2019.This description by the late Joe Tasker is typical of the debilitating, paroxysmal cough that is well known within the mountaineering community to effect visitors to high altitude-3. Four The first formal study of cough at high altitude took place during the 1994 British Mount Everest Expedition when 10 subjects trekking from 2800 m to Everest Base Camp at 5300 m underwent nocturnal cough frequency monitoring. NocturnAltitude-related cough has traditionally been attributed to the inspiration of the cold, dry air which characterises the high altitude mountain environment. InteresIn the next major hypobaric chamber study, Operation Everest III, during which 8 subjects again underwent a simulated ascent of Mount Everest, Mason et al.[Citric acid cough threshold was measured at sea level, 5000 m, the return to 5000 m and at 8000m. There was no difference between either 5000 m or the return to 5000 m and the sea level control, which may have been due to inadequate study power. A maximum of 8 people could be accommodated in the hypobaric chamber, whereas power calculations based on previous work suggesteIf altitude-related cough is not simply due to the inspiration of dry, cold air, what might its aetiology be? There are a number of potential mechanisms. Each will be considered in turn:\u2013 Acute mountain sickness (AMS).\u2013 Sub-clinical high altitude pulmonary oedema.\u2013 Changes in the central and peripheral control of cough.\u2013 Loss of water from the respiratory tract.\u2013 Respiratory tract infections.\u2013 Bronchoconstriction and asthma.\u2013 Vasomotor-rhinitis and post-nasal drip.\u2013 Gastro-oesophageal reflux.Acute mountain sickness (AMS) is a common condition that effects healthy individuals on ascent to altitude. The incidence of AMS is dependent upon both the altitude and speed of ascent. Rarely Despite both AMS and cough occurring commonly at high altitude, there was no demonstrable relationship between AMS and cough in any of the published papers,8,12,13.High-altitude pulmonary oedema (HAPE) is a non-cardiogenic, hydrostatic pulmonary oedema which occurs predominantly in unacclimatised individuals up to 72 hours after ascent to a new altitude. The prevalence depends upon the altitude, the rate of ascent and individual susceptibility. Some individuals are susceptible to developing the condition repeatedly on ascent to altitude. While tAlthough only a minority who go to high altitude develop HAPE, some workers hypothesise that the majority of people ascending to altitude may develop sub-clinical pulmonary oedema. Evidence cited in favour of this argument includes the fall in forced vital capacity (FVC) on ascent to altitude; changesThe apparently simple question question as to whether altitude-related cough could be a manifestation of sub-clinical pulmonary oedema reveals the ongoing uncertainty that exists regarding the identity of the afferent pathways responsible for cough. It is still unclear as to whether pulmonary oedema can cause cough in humans. If it can, is there a sufficient stimulus in asymptomatic subjects with subclinical pulmonary oedema at altitude to activate such a pathway? Cough is not a common clinical feature in cardiogenic pulmonary oedema. The main anatomical sites that are responsible for cough are located above the segmental airways (division 4),26. ThisThe natural history of HAPE, which is associated with a recent gain in altitude and improves dramatically with descent, is similar to the cough seen in Operation Everest III. HoweverPost-hoc analysis of data from the 1994 British Mount Everest Medical Expedition demonstrated a relationship between the citric acid cough threshold and the dynamic ventilatory response to CO2[Respiratory control undergoes profound changes with acclimatisation to high altitude. The cense to CO2.As a result of these findings Thompson et al. studied While the neuronal pathways that mediate the citric acid cough threshold remain debated they include stimulation of airway sensory nerves including the rapidly adapting receptor (RAR). Cough iMason et al. measured2 agonists and there was no evidence of bronchial hyper-reactivity to a methacholine challenge. In a follow up study, subjects susceptible to exercise-induced cough underwent voluntary isocapnic hyperpnoea to over 90 litres/minute with a variety of inspired air conditions[It is still possible, despite the increase in nocturnal cough frequency and decrease in citric acid cough threshold observed under the controlled environmental conditions of Operation Everest III that watnditions. Cough fThese findings raise the possibility that, at least in a subgroup of sufferers, altitude-related cough may be caused by water loss from the respiratory tract. How this water loss might stimulate afferent cough pathways is not known but possible mechanisms include physical distortion of afferent nerve endings and chanOther factors may also increase respiratory water loss. There is evidence of subjective nasal blockage and an increase in nasal resistance at altitude which will likely result in increased mouth breathing,57. WateRespiratory tract infections are the commonest cause of acute cough at sea level,60. Sign1 or PEF associated with the fall in citric acid cough threshold at either Everest Base Camp[Cough may be the only presenting symptom of asthma,67. Bronase Camp. Althougase Camp-71, Pollase Camp could dease Camp demonstrUpper airway cough syndrome  is one of the most common causes of chronic cough. Nasal bGastro-oesophageal reflux has been reported in up to 40% of patients with chronic cough at sea level-76 but nA potential cause for the change in citric acid cough threshold seen on exposure to hypobaric hypoxia would be an alteration in nebuliser output consequent upon the reduced barometric pressure. Barry studied the output of 3 types of nebulisers in a hypobaric chamber up to an altitude equivalent of 5300 m. The outOur current understanding of the epidemiology and aetiology of altitude-related cough remains limited. From the published work, to date, the only conclusions that can be drawn are that altitude-related cough exists and its prevalence increases with increasing altitude; it is associated with a decrease in the citric acid cough threshold; is not solely due to the inspiration of dry, cold air, as has traditionally been thought, and the increased sensitivity to inhaled citric acid does not appear to be related to the changes in the central control of ventilation that occur with acclimatisation.Exploration of the aetiology of altitude-related cough has been limited by the logistical difficulty of carrying out robust research in the high altitude environment or in hyIt seems most likely that, as at sea level, altitude-related cough is a symptom of a number of possible perturbations in the cough reflex arc that may exist independently or together. The most likely aetiological factors are infection or water loss from the respiratory tract leading to trauma of the respiratory mucosa and tracheo-bronchitis, and sub-clinical pulmonary oedema. Respiratory water loss and sub-clinical pulmonary oedema could both be precipitated or worsened by exercise. Future work should investigate the role of these aetiologies as well as quantifying the prevalence of altitude-related cough in larger populations at altitude and to correlate better the relationship between clinical cough and inspired tussive challenges.The author declares that he has no competing interests."}
+{"text": "Relevant miRNAs involved in oxidative stress can prevent ROS-mediated damage to DA neurons, suggesting that specific miRNAs may be putative targets for novel therapeutic targets in PD.Parkinson's disease (PD) is the second most common neurodegenerative disorder. This chronic, progressive disease is characterized by loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and the presence of cytoplasmic inclusions called Lewy bodies (LBs) in surviving neurons. PD is attributed to a combination of environment and genetic factors, but the precise underlying molecular mechanisms remain elusive. Oxidative stress is generally recognized as one of the main causes of PD, and excessive reactive oxygen species (ROS) can lead to DA neuron vulnerability and eventual death. Several studies have demonstrated that small non-coding RNAs termed microRNAs (miRNAs) can regulate oxidative stress  Point mutations and multiplications in the SNCA gene locus in familial PD, are directly associated with high levels of \u03b1-Syn mRNA and proteins in the frontal cortex  pathway is deregulated as PD progresses (Ramsey et al., Although numerous studies have provided evidence that miRNAs play a role in PD pathogenesis by regulating oxidative stress, the field is still in its infancy. Actually, the causal factors inducing oxidative stress in PD connect and interact with each other rather than function independently, which make it difficult to elucidate the function of related miRNAs totally. In addition, accumulating evidences mainly confirmed from animal and cell models, and related miRNA studies in PD patients are limited to the difference expression in the brain Table . To dateYX and YC conceived the article and wrote the manuscript. YC reviewed and edited the manuscript. All authors read and approved the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Primary motor symptoms of Parkinson\u2019s disease such as bradykinesia and rigidity are associated with increased oscillatory and synchronized activity in the beta frequency band 10-30Hz) throughout the cortical-basal ganglia-thalamic circuitry  as wellTwo types of data from were recorded from subjects with Parkinson\u2019s disease during the implantation of deep brain stimulation electrodes. We performed microelectrode recordings of neuronal units and local field potentials from the subthalamic nucleus. We also recorded surface EEG from prefrontal and motor areas recorded simultaneously with the recordings in the subthalamic nucleus. The analysis of these data reveals complex patters of correlations between synchrony in cortical circuits (which can be studied noninvasively) and synchrony in the basal ganglia circuits (which requires invasive procedures for investigation).These results are used to guide the development of computational models to study how activity in the subthalamo-pallidal circuits can be entrained by the oscillatory cortical input. We used conductance-based models for the excitatory-inhibitory networks of neurons from the subthalamic nucleus and the external segment of Globus Pallidus ,5 and suThe biologically-realistic temporal patterns of synchrony, which are generated by the subthalamo-pallidal model network  are obse"}
+{"text": "Measurements of cardiac conduction velocity provide valuable functional and structural insight into the initiation and perpetuation of cardiac arrhythmias, in both a clinical and laboratory context. The interpretation of activation wavefronts and their propagation can identify mechanistic properties of a broad range of electrophysiological pathologies. However, the sparsity, distribution and uncertainty of recorded data make accurate conduction velocity calculation difficult. A wide range of mathematical approaches have been proposed for addressing this challenge, often targeted towards specific data modalities, species or recording environments. Many of these algorithms require identification of activation times from electrogram recordings which themselves may have complex morphology or low signal-to-noise ratio. This paper surveys algorithms designed for identifying local activation times and computing conduction direction and speed. Their suitability for use in different recording contexts and applications is assessed. It can provide important quantitative electrophysiological information about the underlying tissue microarchitecture and is widely used in both laboratory Besides the characteristics of the underlying tissue microarchitecture, other factors affecting propagation speeds include curvature of the wavefront The data modalities most frequently encountered in the context of conduction velocity estimation are the extracellular electrogram Distances between measurement sites are usually known, within a reasonable tolerance. For example, laboratory electrode arrays have a predefined precision arrangement, optical mapping has a calculable pixel diameter and the spacings between electrodes on a non-deformed multi-pole catheter are also known. In contrast, the annotation of local activation times (LATs), on often complex and noisy fractionated electrogram signals or optical mapping recordings, can sometimes be difficult to define. This has led to the use of other approaches to analyse these signals In the laboratory environment, data are frequently collected using regularly spaced micro-electrode arrays Activation maps may be constructed using concurrent recordings  is a measure of the energy of a signal and is proportional to the square of the product of signal amplitude and frequency The NLEO can be used to identify active and inactive regions of the signal and subsequently calculate the proportions of each for use as a measure of electrogram fractionation 2.4The traditional maximum gradient and signal peak markers for activation in electrogram signals may be difficult to identify or be unreliable if the sample rate of the data is too low or the morphology of the deflection is fractionated, such as for electrograms obtained from diseased tissue. For spatially local electrodes, activation time-delays between nearby recordings may be reliably measured, instead of through differences between absolute timings, by using a cross-correlation of the filtered signal global activation maps by measuring the activation delays between neighbouring electrodes and then choosing absolute times for all electrodes which best fit the delays N electrodes, a matrix problem is solved in the least-squares sense, \u03c4ij, and TN is set to directional activation maps, see Time delays have also been used for constructing 2.5maximum modulus lines, defined as maxima and minima across the different scales of the transform, and through the relationship between the wavelet transform and the derivative of the signal, enables identification of the onset of activation.Wavelet decomposition approaches to identifying electrogram activation times have been explored for ventricular electrograms The wavelet transform has also been used with optical mapping data 2.6Convolution is a process frequently used to filter signals. The generation of an electrogram recording itself can be framed as a convolution of transmembrane potentials. The process of deconvolution can therefore be used to extract localised tissue activation 2.7Template matching is an automated process of comparing segments of an electrogram signal, or specific electrogram complexes, to a library of deflection morphologies. The library of reference complexes may be generated mathematically 2.8The use of spatial voltage gradients and the surface Laplacian between multiple electrodes have both been shown to produce an improved measure of activation time than standard time-derivative approaches, particularly for fractionated electrograms 2.9active when the first derivative in time  and therefore can be modelled as a time shift of this signal, based on the row r and column c of the electrode, \u03c32 and n is the index of the sample. This is illustrated in \u03c4r and \u03c4c describe the time delay between the rows and columns respectively and these are estimated by maximising the probability fs is the sample rate and d the inter-electrode distance.Statistical approaches to measuring conduction velocity across high-density grids of electrodes have been considered for measuring fetal cardiac activity 44.1We list in Both finite difference and polynomial surface fitting techniques are widely used in the literature with optical mapping recordings and micro-electrode array data. Although finite difference approaches are straightforward to implement, they are not as effective at handling missing data as polynomial surface-fitting techniques 4.2Propagation wavefronts are three-dimensional in intact myocardium. Many of the techniques outlined in this review operate on two-dimensional data collected from either the epicardial or endocardial surface and are therefore inherently limited in their ability to determine true wavefront speed. The conduction velocity of wavefronts that are not travelling exactly tangential to the recording surface will be over-estimated. This is especially true in thicker structures, such as the ventricular walls, where transmural propagation is common. However, it should be noted that this is a limitation of the recording technology and many methods could work with volumetric data equally well. One example is the polynomial surface fitting technique which has been extended to compute three-dimensional wavefronts using data recorded using plunge electrodes in a volume of tissue 4.3The relationship between CV and other functional and structural factors has been investigated in many clinical studies, with the motivation of understanding the electroanatomic substrate underlying cardiac arrhythmias in order to guide ablation therapy. CV has been found to correlate with bipolar electrogram amplitude in atrial flutter reentry circuits The rate dependence of CV has been shown to be a more important indicator of AF initiation than electrogram fractionation, where conduction was seen to slow immediately prior to AF Late-gadolinium enhanced magnetic resonance imaging (LGE-MRI) has been used to identify areas of fibrosis and delineate scar tissue in patients with AF 4.4Local normalised CV vector fields can be further analysed by applying vector calculus operations to elicit a more qualitative interpretation of the data. The divergence of the two-dimensional CV vector field, The divergence and curl operators have been applied to CV vector fields from simulated Ectopic foci have been successfully identified using divergence maxima, providing the CV vectors surround the foci 4.5\u2022Identifying local activations in complex fractionated signals consisting of many low-amplitude deflections. A greater understanding of the electrogram and its decomposition in terms of local cellular activity is needed.\u2022Conduction velocity mapping during atrial fibrillation would improve the identification of focal sources and those regions of the chamber perpetuating arrhythmogenic activity.\u2022Real-time generation of complete-chamber conduction velocity mapping during simple rhythms is needed to augment existing clinical diagnosis of arrhythmias.\u2022Estimating the level of uncertainty in computing the conduction velocity of propagating wavefronts in three-dimensional tissue using two-dimensional surface measurements and algorithms.Activation time mapping and conduction velocity mapping are important metrics for understanding the structural and functional electrophysiology in both the laboratory and clinical environment. However, challenges still remain:None declared."}
+{"text": "Input data files for inferring the relationship among the family Kyphosidae, as presented in   Specifications TableValue of the data\u2022The provided nexus-files holds sequence data and alignments and can be directly utilised in future studies in the evolution of perciform fishes.\u2022Kyphosus and Neoscorpis collected worldwide groups in clades reflecting the presence of 12 species of Kyphosidae in total. This will facilitate species identification by matching mitochondrial nucleotide sequences of future kyphosid catches by allowing for comparison with sequences obtained in this study.The phylogenetic trees supplied in newick-file format together with tables presented by \u2022Supplied tree-files in newick format, and the evolutionary relationship inferred by 1Alignments of nucleotide nuclear and mitochondrial data are provided as \u2018.nex\u2019-files and \u2018.xml\u2019-files for analysis in MrBayes 2sensuDetailed descriptions of how DNA sequences were obtained and analysed can be found in the material and methods section in A nexus-input file [morph_pars_matrix.nex] with morphological character states inferred for 43 species, representing 584 museum specimens listed by"}
+{"text": "Disease-specific autoantibodies directed against post-translation citrullinated proteins/peptides (ACPAs) are specific serological markers for rheumatoid arthritis (RA) and have been accepted as one of the classification criteria for the disease. Beyond diagnosis these autoantibodies have also been shown also to predict disease severity. These autoantibodies can be detected several years prior to the clinical onset of RA, with increasing titers overtime, as disease onset is established.Citrullination is a post-translational modification of proteins in which arginine is converted into citrulline, an unnatural amino acid which is not encoded by DNA. The reaction is catalyzed by calcium-dependent peptidyl arginine deiminase (PAD). Citrullinated proteins have been detected in the synovial membranes and synovial fluid of patients with various forms of arthritis. Protein citrullination has been shown to be involved in immune tolerance breakdown in experimental autoimmune arthritis. Only small amounts of citrullinated proteins is found in the normal synovial tissue, whereas active citrullination has been clearly associated with RA. In addition, ACPAs are strongly associated with increased risk of developing RA in healthy individuals. Their presence in RA patients is associated with a more erosive arthritis and poorer response to therapy .It is reasonable to assume that citrullinated peptides are among the earliest arthritic autoantigens that may be suitable as potential candidates for specific immune tolerance induction. The finding of an immunodominant citrullinated peptide as antigen-specific immunomodulatory agents capable for restoration of the altered autoimmune response in RA seems to be an interesting target for intercepting the disease.The possible mechanisms by which autoantigens or their derivatives induce specific tolerance are based on frequent administrations of low dose soluble antigens. By these means administration of a synthetic peptide could manipulate the interaction of antigen presenting cells (APCs) with lymphocytes. This tolerogenic presentation displayed on MHC class II-expressing T cells (T-APC) induces partial signals in Ag-specific T cell clones including deletion, anergy and suppression of the autoreactive cells.Administration of a citrullinated filaggrin peptide as a prophylactic measure to prevent collagen induced arthritis prior to induction in DBA mice has been shown to be successful and to protect mice from developing arthritis . This stHowever, one of the difficulties in developing effective tolerogenic peptides for immune tolerance strategies in RA is the selection of a specific antigen since the autoimmune response is against multiple targets; diverse citrullinated proteins in different synovial structures. The question is, therefore, which specific citrullinated autoantigens drives the immune response in RA and whether those antigens are the best to be employed for immune tolerance restoration. It was shown that the most prevalent citrullinated autoantigens, in arthritic joints are: citrullinated fibrinogen, vimentin, collagen type II and \u03b1-enolase .Therefore we constructed a multi-antigenic peptide for immune tolerance specific for RA. The peptide is composed of sequence of known citrullinated autoantigens  in analogy to the mix of citrullinated peptides that are used currently in diagnostic sera tests. One of our peptide comparator was a short filaggrin peptide composed of five amino acid . This miThe multi epitope citrullinated peptide we tailored termed Cit-ME was injected to adjuvant induced arthritis rats and was shown to attenuate arthritis manifestations . The ameThe putative mechanisms of the Cit-ME peptide are demonstrated in Figure Another option that remains to be explored is the possibility to employ tolerance induction by oral administration of the peptide. It was shown that oral administration of peptide derived from collagen type II 250-270) was able to suppress the cellular and humoral immune response in collagen-induced arthritis . Chicken0 was ablAnother important issue refers to the relevance of administration of tolerogenic citrullinated peptide at initial stages of ACPA detection prior to the clinical symptoms of arthritis for prevention of the arthritis or even to reduce disease severity.We believe that specific peptide therapy may provide an opportunity to divert patients with an incoming inflammatory condition from developing diseases such as RA, furthermore such an approach seems to be specific avoiding unnecessary exposure to nonspecific immunomodulatory agents."}
+{"text": "In this data article we provide topologies and force field parameters files for molecular dynamics simulations of lipids in the OPLS-aa force field using the GROMACS package. This is the first systematic parameterization of lipid molecules in this force field. Topologies are provided for four phosphatidylcholines: saturated DPPC, mono-cis unsaturated POPC and DOPC, and mono-trans unsaturated PEPC. Parameterization of the phosphatidylcholines was achieved in two steps: first, we supplemented the OPLS force field parameters for DPPC with new parameters for torsion angles and van der Waals parameters for the carbon and hydrogen atoms in the acyl chains, as well as new partial atomic charges and parameters for torsion angles in the phosphatidylcholine and glycerol moieties  Specifications table\u2022New parameterization for lipids compatible with the OPLS-aa force field was derived.\u2022Provided files allow one to perform simulations of lipid bilayers with high accuracy.\u2022New lipids models are suitable for use with proteins parameterized in the OPLS-aa force field.1Quality of molecular dynamics simulations ultimately depends on the accuracy of the force field parameters. Unfortunately derivation and validation of the force field for given classes of molecules is a tedious and lengthy process. Particularly time consuming is the derivation of torsional potential which is also a key factor for quality of molecular structure in classical simulation. Lipid bilayers are essential macromolecules and component of all living cells thus of high scientific interest also in modeling studies. High quality force fields for lipids started to be intensively developed during the last few years  dihedral potential. The RB coefficients were found by minimizing the least-square function of the differences between the QM and MM total potential energies and the corresponding Ryckaert\u2013Bellemans potential values.2.3The Hybrid Methods for Interaction Energies (HM-IE) method was used for accurate but efficient energy evaluation 2.4sn-glycero-3-phosphocholine), POPC , DOPC , PEPC  and cholesterol. The order of atoms in all molecules matches CHARMM-GUI membrane builder Provided data include topology files of four lipid species: DPPC (1,2-dipalmitoyl-The authors declare that there is no conflict of interest on any work published in this paper."}
+{"text": "Automated mage registration in cardiac myocardial perfusion is a necessity before quantitative perfusion can be widely accepted in clinical practice. Increasingly complex motion correction algorithms are being developed to deal with cardiac motion. However, the impact of these improvements has not been evaluated in terms of the final clinical diagnosis. Advanced motion correction methods are associated with increased computational overhead and the potential of introducing subtle registration errors, which can be hard to detect and quantify. The aim of this study was to compare the performance of the various automated correction methods in terms of their impact on diagnostic accuracy.This was a retrospective sub-study using data from the CE-MARC trial . A 50-patient sample was selected such that the distribution of risk factors and disease status within the sample was representative of the full CE-MARC cohort. Three strategies for motion correction with the mutual information image similarity metric were used: 1) independent translation correction for all slices, 2) translation correction for the basal slice with transform propagation to the remaining two slices, assuming identical motion for these slices, 3) rigid correction (translation and rotation) for the basal slice with transform propagation as in (2) and 4) deformable correction in all slices. Contours depicting the myocardium and a region within the left blood pool were drawn on the dynamic frame exhibiting the best visual contrast on the three slices. These contours were propagated to the remaining frames (and slices) of the dataset using each motion correction strategy. Quantitative myocardial blood flow (MBF) estimates were obtained using Fermi-constrained deconvolution and myocardial perfusion reserve (MPR) indices were calculated from the ratio of stress to rest MBF estimates. The presence of myocardial ischaemia was assessed using the consensus diagnosis of invasive, quantitative X-ray angiography and myocardial Single Photon Computed Tomography (SPECT) imaging. Receiver Operator Characteristic (ROC) curves were generated for each motion correction strategy  provides a diagnostic accuracy equivalent to the progressively more complex methods of motion correction.This work was funded by the Top Achiever Doctoral scholarship awarded by the Tertiary Education Commission of New Zealand."}
+{"text": "Acute coronary syndrome (ACS) represents the most common cause of death worldwide. Percutaneous coronary intervention (PCI) is the management of choice in patients with ACS and occurrence of intra-procedural thrombotic complications are an independent predictor of mortality and other major adverse cardiovascular events in patients undergoing PCI. According to current guideline, anticoagulation therapy is indicated during PCI in order to reduce the risk of thrombotic complications such as stent thrombosis. Among currently available anticoagulant drugs, bivalirudin demonstrates a lower incidence of bleeding risk, despite it is associated with an increased risk of stent thrombosis. The aim of this paper is to discuss the pharmacology of bivalirudin and the clinical evidences of its use in patients undergoing PCI for ACS. I.Coronary artery disease (CAD) represents the most common cause of death worldwide. According to characteristic electrocardiographic modifications, ACS are classified in: ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI) and unstable angina (UA) if cardiac biomarkers are negativePCI is the management of choice in patients with ACSII.Bivalirudin is a transient and reversible thrombin inhibitor, preventing initiation and continuation of clot formation . It is aCurrently, the recommended dose for patients undergoing PCI is a bolus of 0.75 mg/kg followed by an infusion of 1.75mg/kg/h for the duration of the procedureIII.Randomized trials testing the use of bivalirudin in STEMI setting are listed in The first study assessing bivalirudin safety and efficacy in STEMI setting was the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI), performed in a large population of 3602 STEMI patient undergoing primary PCITaken together these data demonstrated a lower incidence of bleeding with bivalirudin without any reduction on mortality. The Minimizing Adverse Haemorrhagic Events by TRansradial Access Site and Systemic Implementation of angioX (MATRIX) was a randomised, multicentre trial comparing transradial against transfemoral access in patients with ACS undergoing PCI. Patients were randomized (1:1) to radial or femoral access and to receive bivalirudin, stopped at the end of PCI or prolonged infusion for at least 4\u20136 hours, or UFH with provisional GPIIV.Randomized trials testing the use of bivalirudin in NSTEMI setting are listed in The Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) was a prospective, open-label trial, enrolling patients with moderate- or high-risk NSTE-ACS, with a prevalence of NSTEMI patients (59%)V.Randomized trials testing the use of bivalirudin in the management of stable or unstable angina are listed in The HIRULOG was a double blind trial enrolling patients with unstable angina or post-infarction angina undergoing urgent PCIAs suggested by latest ESC guideline on myocardial revascularization among PCI patients with negative biomarkers, bivalirudin reduced bleeding without affecting mortality and might therefore be considered for use in patients at high risk for bleedingVI.Several meta-analyses have been recently published in order to clarify the role of bivalirudin for patients undergoing PCI in different setting of patients. Cavender and Sabatine performed a meta-analysis of 16 studies enrolling patients for planned PCI and randomly assigned to bivalirudin or heparin (UFH or low-molecular weight heparin) with or without a GPIWhether bivalirudin is also superior to UFH alone is still not well established. A meta-analysis of Cassese et al. investigates the efficacy and safety of bivalirudin versus UFH in patients treated with PCI without planned use of GPIVII.It is widely demonstrated that the use of bivalirudin in patients undergoing PCI due to acute coronary syndrome or stable angina significantly reduces incidence of major bleeding; however it is associated with a higher risk of early stent thrombosis, which is mainly related to more frequent acute events. MATRIX results, for the first time, demonstrated that death for all causes was reduced in patients treated with bivalirudin after a radial access. BRIGHT trial demonstrated that a prolonged bivalirudin administration significantly reduced the incidence of the early stent thrombosis. Further randomized clinical trials are needed to evaluate the safety and efficacy of bivalirudin in the era of PCI through radial artery with the use of new P2Y12 inhibitors and bioadsorbable scaffold even in high bleeding risk patients in which bivalirudin seems to be safe as reported in some case report"}
+{"text": "Integration of novel image reconstruction and processing methods into clinical workflow has been hampered by difficulties in implementing these techniques into the vendors' softwares. While all vendors allow modification of imaging sequences, implementation of novel reconstruction techniques is not available in any of them. Currently, the workflow includes manually exporting the data, performing the custom reconstruction using stand-alone Matlab or C++ implementation, and then visualizing the results on a different workstation. This process usually requires an expert user and is not feasible in common clinical workflow. In this work, we developed a simple software tool that enables researchers to rapidly integrate post-processing and reconstruction methods developed in any programming language on any type of workstation via internet connection and directly visualize the data on the scanner console and store the data via clinical PACS system.Figure Figure We proposed and developed a software tool that allows researchers to test and validate different reconstruction/processing techniques in a smooth workflow combined with the MR machine.NIH: R01EB008743-01A2."}
+{"text": "It is known that mRNA folding can affect and regulate various gene expression steps both in living organisms and in viruses. Previous studies have recognized functional RNA structures in the genome of the Dengue virus. However, these studies usually focused either on the viral untranslated regions or on very specific and limited regions at the beginning of the coding sequences, in a limited number of strains, and without considering evolutionary selection.Here we performed the first large scale comprehensive genomics analysis of selection for local mRNA folding strength in the Dengue virus coding sequences, based on a total of 1,670 genomes and 4 serotypes. Our analysis identified clusters of positions along the coding regions that may undergo a conserved evolutionary selection for strong or weak local folding maintained across different viral variants. Specifically, 53-66 clusters for strong folding and 49-73 clusters for weak folding (depending on serotype) aggregated of positions with a significant conservation of folding energy signals  were recognized. In addition, up to 7% of these positions were found to be conserved in more than 90% of the viral genomes. Although some of the identified positions undergo frequent synonymous / non-synonymous substitutions, the selection for folding strength therein is preserved, and thus cannot be trivially explained based on sequence conservation alone.The fact that many of the positions with significant folding related signals are conserved among different Dengue variants suggests that a better understanding of the mRNA structures in the corresponding regions may promote the development of prospective anti- Dengue vaccination strategies. The comparative genomics approach described here can be employed in the future for detecting functional regions in other pathogens with very high mutations rates. Flavivirus genus of the Flaviviridae family, which also consists of additional human pathogenic viruses such as Yellow Fever (YFV), West Nile (WNV), Japanese Encephalitis (JEV) and Tick Borne Encephalitis (TBEV), which cause potentially lethal diseases )As we have already noticed before, previous studies have discovered several structural elements at the 5' end of the capsid gene (at the beginning of the coding region) and proposed that they take part in replication and translation regulation -24. It iIn this work, we presented a large scale comparative genomic analysis based on hundreds of viral variants in each one four different DENV serotypes. We suggested that positions along the coding region with a significant conservation of folding associated signals are grouped in 49 - 73 clusters related to partially overlapping local genomic regions that may tend to undergo an evolutionary selection for a strong or weak folding. We showed that the reported signals of conserved MFE selection cannot be explained basing on amino-acid, dinucleotide, or mutational bias only and are not necessarily a consequence of other (non-direct) constraints imposed on specific sequence patterns, and/or formation of particular secondary structures. We believe that further molecular biology studies guided by the computationally predicted positions may promote discoveries of novel regulatory mechanisms of the DENV and other viruses; some of them may help developing new vaccination strategies.Data preparation. 1,670 complete coding sequences of 4 DENVserotypes  were downloaded.We first translated the nucleotide coding regions and then aligned the resulting amino acid sequences by Clustal Omega package  with defA list of accession numbers corresponding to the analyzed genomes can be found in Additional file Genome randomization models. To investigate selection for folding strength, wild-type minimum free folding energy (MFE) values were compared with corresponding sequence-randomized controls which preserve certain nonrandom features of the naturally occurring sequences. To exclude the possibility that the obtained signals were simply due to amino acid selection pressure , as opposed to selection for the folding strength, we restricted our randomized variants to maintain the amino acids order and content (and thus the encoded protein), by sampling from the set of synonymous codons for each amino acid position. To model evolutionary constraints (not necessary related to folding) imposed on synonymous variability in different genomic positions  we maintained the distribution of synonymous codons (and thus nucleotides) for each column in the interserotype multiple alignment matrix . This was achieved by random permutations of synonymous codons for each column in the alignment matrix; in the case of multiple amino acids in a column, each amino acid was permuted separately  for each sequence separately was used. Although efficient methods exist for preserving the amino acids (e.g. permutation of synonymous codons) or the dinucleotides content  separatleotides  which isFor each one of 1,670 wild-type sequences, we computed 1,000 randomizations basing on each one of the randomization models, resulting in more than 3 million variants.Local minimum free folding energy profiles. Minimum free folding energy (MFE) is a thermodynamic energy involved in maintaining a secondary structure available to perform physical work while being released, and thus is characterized by non-positive values. mRNA secondary structure is believed to be in the most stable conformation when minimum amount of free energy is exerted .The local minimum free folding energy profiles (MFE-profiles) were constructed by applying a 39 nt length sliding window to a genomic sequence Figure : in eachMinimum free folding energy significance test. In order to assess the statistical significance of the folding strength in a particular position in a sequence, we compared the MFE values in this position with the MFE values in the corresponding position in each one of the randomized variants by calculating an empiric p-value - a proportion of the randomized values as extreme as in the wild type. Positions with MFE related p-value < 0.05 were defined as having a \"suspected\" MFE related signal; due to a high false discovery rate (Benjamini - Hochberg approach) of MFE signals in individual sequences we went further and compared the positions of suspected signals across different genomesConservation of local folding signals. Due to genetic variability on the one hand, and possible inaccuracies in sequencing and multiple alignment on the other, positions selected for a significant strong (weak) folding in different genomes may be shifted one with respect to the other. To account for these possible displacements when quantifying the conservation of MFE related signals across different sequences, we defined a Folding Signal Conservation Index (FSCI) at a particular position as a percentage of different aligned sequences which have at least one signal inside a 5 nt length genomic neighborhood of this position . Those positions with significantly conserved folding signals  which had conservation levels higher than achieved in all corresponding randomized variants were defined as positions that undergo a conserved evolutionary selection for strong/weak folding (MFE-selected positions).The resulting positions are not independent: parts of them belong to intersecting genomic regions and could be possibly attributed to the same or partially-overlapping folding elements. Therefore we defined clusters of MFE-selected positions; each cluster consists of all positions with significant signal conservation such that the distance between two consecutive positions in a cluster is no more than 44 nt . According to this definition positions within a particular cluster correspond to partially - overlapping genomic windows ; in contrast positions belonging to different clusters are thought as independent with respect to the performed local MFE analysis.We emphasize that conservation of MFE related signals was analyzed for each serotype, and folding signal direction separately; specifically, in each case we accounted for positions selected for only one folding direction, either strong or weak. Moreover, the analysis of signal conservation was performed with respect to the evolutionary-constrained model only, since (in contrast to the dinucleotide-preservation or any other model based on a single sequence) it takes into consideration the co-evolution of viral variants and their phylogenetic dependencies.Robustness of folding signal conservation to folding window size. To estimate the robustness of the MFE-selected positions with respect to the folding window size we repeated the analysis described above with folding windows twice as large as initially (78 nt instead of 39 nt). We then defined a robustness measure as the percentage of the 44 nt genomic regions corresponding to MFE-selected positions  which have more than 50% overlap with at least one 83 nt genomic region corresponding to an MFE-selected position .One-versus-rest (OVR) model. In order to estimate the expected number of suspected MFE related signals  in random and in order to generate a null model for estimating the statistical significance of MFE signal conservation in different positions, we simulated MFE suspected signals in randomized variants according to the following procedure named One-Versus-Rest (OVR) model: for each one of the N randomized variants corresponding to a specific wild-type sequence, we identified iteratively its MFE-related suspected signals with respect to the rest of the N-1 random variants :j are their relative frequencies .here n is the number of distinct elements in the corresponding alphabet,; and pThis variability measure takes values between 0 and 1, and describes how dispersed the distribution of the alphabet elements is: higher values correspond to more uniform nucleotide / codon usage; lower values correspond to more biased nucleotide / codon usage, indicating that some nucleotides / synonymous codons are preferred.The variability measure was computed for each serotype separately. The synonymous variability index was computed based on the consensus amino acid (the most frequent amino acid) in each position in the multiple alignment. In order to neutralize biases due to poor high number of indels and low consensus values( high amino acid variability), we filtered out positions with consensus levels of less than 90%, and number of gaps of more than 10% . In addition, positions corresponding to singleton amino acids Methionine and Tryptophan  were excluded.The variability profiles were constructed by applying a 44 nt sliding window along the alignment and averaging at each step the nucleotide / synonymous variability values at positions within the corresponding window. The window size was defined in a way that each such window matches the 39 nt genomic region in which the folding for the corresponding positions was predicted + a 5nt allowed shift used in MFE signals conservation analysis Figure .The z-score normalized synonymous variability was constructed by computing in each position a z-score with respect to 1000 variants based on randomized multiple alignments :.Software. Multiple alignments were performed with Clustal Omega package (v.1.2.0). Folding energies were predicted with RNAfold function from Vienna package (v.2.1.9) adapted by us to work with sliding windows. Other computations were performed using Matlab\u00ae software (MathWorks Inc.). For high performance computing, a Linux based cluster system was employed.DENV - Dengue Virus; MFE - Minimum Free Folding Energy; FSCI - Folding Signal Conservation Index; OVR - One versus Rest; FDR - False Discovery Rate.A patent application describing this work was submitted. The authors declare that they have no other competing interests.EG and TT analyzed the data and wrote the papersupplementary_analysis.docx. This file includes the following additional analyses: Multiple alignment conservation scores; Enrichment of DENV genes with clusters of positions with a significant conservation of folding energy signals and distribution of these clusters over different genes.Click here for filedenv_accession_numbers.csv. This file includes GenBank accession numbers for sequences analyzed in this studyClick here for file"}
+{"text": "Prominent spikelet activity was demonstrated in hippocampal CA1 pyramidal neurons in awake behaving 0 mV that. HoweverHere we investigate the emergence of spikelets using mathematical analysis and numerical simulations of compartmental single-neuron models. Somatic spikelets are produced in the models upon orthodromic (somatic) stimulation. We find that spikelet occurrence depends on three main factors: A) Activation voltages of somatic channels need to be larger by several millivolts (~10 mV) than activation voltages of axonal sodium channels. B) The spike initiation zone  has to be electrically segregated from the soma. C) The impedance mismatch between soma and AIS needs to be sufficiently large. In this way, weak orthodromic stimuli can trigger APs at the AIS that fail to activate somatic sodium channels and manifest as somatic spikelets. Stronger stimuli lead to full-size APs at the soma, either through axonal APs that backpropagate to the soma ('shouldered APs') or direct somatic AP generation ('full-blown APs').in vitro preparations: First, the dendritic current sink in vitro is diminished due to \"dendritic pruning\" in slices. Next, the fraction of sodium channels usually available for (somatic) spiking is larger in vitro due to the overall lower spiking activity and lower resting membrane potential. Finally, the difference in activation voltages between somatic and axonal sodium channels under in vitro conditions might be smaller than under in vivo conditions as the activation voltage of sodium channels might be controlled by neuronal activity, which is typically much higher in vivo than in vitro.Through analysis and simulations we isolated the cell parameters that allow for spikelet generation and identified possible causes of spikelet absence in In our models, somatic spikelets represent APs that are only propagated down the axon, but are not backpropagated to the soma and the dendrites. Consequently, such a mechanism might be involved in the control of dendritic plasticity and/or in the homeostatic regulation of somato-dendritic firing rates without affecting the axonal output of a neuron."}
+{"text": "A variety of environmental toxicants have been shown to induce the epigenetic transgenerational inheritance of disease and phenotypic variation. The process involves exposure of a gestating female and the developing fetus to environmental factors that promote permanent alterations in the epigenetic programming of the germline. The molecular aspects of the phenomenon involve epigenetic modifications (epimutations) in the germline (e.g. sperm) that are transmitted to subsequent generations. The current study integrates previously described experimental epigenomic transgenerational data and web-based bioinformatic analyses to identify genomic features associated with these transgenerationally transmitted epimutations. A previously identified genomic feature associated with these epimutations is a low CpG density (<12/100bp). The current observations suggest the transgenerational differential DNA methylation regions (DMR) in sperm contain unique consensus DNA sequence motifs, zinc finger motifs and G-quadruplex sequences. Interaction of molecular factors with these sequences could alter chromatin structure and accessibility of proteins with DNA methyltransferases to alter de novo DNA methylation patterns. G-quadruplex regions can promote the opening of the chromatin that may influence the action of DNA methyltransferases, or factors interacting with them, for the establishment of epigenetic marks. Zinc finger binding factors can also promote this chromatin remodeling and influence the expression of non-coding RNA. The current study identified genomic features associated with sperm epimutations that may explain in part how these sites become susceptible for transgenerational programming. A number of environmental factors have been shown to induce the epigenetic transgenerational inheritance of disease and phenotypic variation Germline epigenetic transgenerational inheritance has been described in several different organisms including plants, flies, worms, rodents, and humans Previous studies have shown that different exposures produce distinct sets of transgenerationally altered differential DNA methylation regions (DMR) in male germ cells, termed epimutations de novo methyltransferases in the genome Recent studies have investigated a variety of DNA-protein interactions that are involved in the establishment of DNA methylation. For example, the presence of protein binding factors in CpG-poor regulatory regions is one feature that would influence DNA methylation A variety of approaches have been used to identify DNA sequence patterns (motifs) that could be functionally relevant from the perspective of gene expression regulation The main goal of the current study was to identify genomic features associated with the environmentally induced epigenetic transgenerational inherited sperm epimutations. Previously described transgenerational differential DNA methylation regions (DMR) in the rat sperm were investigated The presence of EDM1 was tested in a variety of transgenerationally altered DMR from sperm and from somatic Sertoli and granulosa cells The two DNA motifs identified from the analysis of the DMR groups were then compared to a database of eukaryotic transcription factor binding sites. The top five similarities of known transcription factors binding sites for each motif are shown in The possibility that an altered density of EDM1 or EDM2 motifs could be observed in DMR sets versus the random set was examined. No significant changes were observed for the density of EDM1 or EDM2 in DMR from the exposure groups in reference to the random set . Given tEDM2 was observed to be a G/C rich sequence. Interestingly, previous reports show that G quadruplexes associate with zinc finger binding sites Schematic visualization of the features analyzed in selected sets of transgenerational DMRs previously confirmed for the vinclozolin and other exposure DMR groups are shown in A follow up experiment was done to help confirm the observations regarding the genomic features associated with the transgenerational DMR (i.e. epimutations). A more recently developed dichlorodiphenyltrichloroethane (DDT) induced transgenerational set of DMR in F3 generation sperm was investigated The phenomenon of environmentally induced epigenetic transgenerational inheritance is a germline mediated process Identification of DNA sequence motif incidences was performed in different sets of previously identified sperm and somatic cell DMR sequences. Two motifs were identified that are associated with the DMR sets from different environmental exposures. Two different motifs were identified, EDM1, which is an A/T rich motif that is present in the transgenerational vinclozolin DMR set, and EDM2 that is a G/C rich motif present in the other germline transgenerational DMR sets investigated . The incidence of EDM1 is over-represented only in the vinclozolin lineage sperm DMRs, but is not over-represented in the somatic cell vinclozolin lineage DMR sets tested. These observations suggest the somatic cell epigenetic modifications are secondary to the germline epigenetic modifications and probably occur through alternate developmental mechanisms. EDM2 shows the opposite pattern of EDM1, being over-represented in the DMRs of all the exposure lineages, except for vinclozolin.An analysis of known motifs with a database of transcription factor motifs shows that zinc finger motifs are associated with the sperm epimutations. Further analysis of the presence of these transcription factor binding sites in promoter DMR regions of the exposure sets shows that zinc finger transcriptome factor consensus DNA binding motifs for Krox, Sp1, Znf219 and Rreb1 are over-represented in the majority of the transgenerational sperm DMR sets investigated. These observations suggest that zinc finger containing DNA binding factors may have a role in the molecular mechanism of epigenetic transgenerational inheritance of sperm epimutations. UFH3Beta might also be relevant, since it follows the same patterns as these zinc finger binding factors. Interestingly, previous studies have highlighted the role of zinc fingers in epigenetic reprogramming. For example, the zinc-finger protein UHRF1 has recently been shown to have a role in maintaining DNA methylation in specific genomic regions in mammals Neurospora crassa A/T-rich sequences are shown to be a fundamental recognition site for de novo DNA methylation Another genomic feature analyzed was the density of the incidence of EDM1 or EDM2 within the DMR. Because of the possibility that even if over-representation of individual matches does not occur, a cluster incidence of these motifs might occur. The density of EDM1 or EDM2 in the DMR was determined and no difference was found between any of the exposure DMR groups and the random sequence set . Since EThe other DNA motif obtained was called EDM2 and it was found to have guanine rich regions. Previous studies have shown that CpGs with high methylation are generally not present in G-quadruplexes (GGGG), which suggests that DNA methylation is restricted when G-quadruplex features exist The motif associated with the vinclozolin DMR (EDM1) was found to be distinct from the motif associated to the other exposure DMR (EDM2). One speculative mechanism to explain the difference is the variable signaling mechanisms of the compounds generating the transgenerational germline epimutations. While vinclozolin is a known anti-androgenic compound An initial experiment to help validate the presence of these genomic features in the transgenerational sperm epimutations used a recent DDT sperm DMR set for analysis Observations lead to the speculation that the mechanism of the transgenerational epigenetic programming of germline epimutations may be in part based on the action of zinc finger motifs and G-quadruplex sequences that can alter chromatin structure and accessibility to proteins. This alteration may allow an opening of DNA that alters the action of DNA methyltransferases or interacting factors. G-quadruplex regions would be more prone for this opening to epigenetic marks to occur. The zinc finger factors may interact with other proteins to promote this chromatin remodeling and/or altered expression of non-coding RNA. The current study identified a number of motifs and genomic features potentially associated with the DMR involved in the environmentally induced epigenetic transgenerational inheritance of sperm epimutations. Future studies are now needed to further investigate the specific proteins involved and developmental aspects of these epimutations.\u22127 instead of the p-value cut-off of 10\u22125 used in these publications. The DMR data sets were reduced in size, based on the above statistics, to allow for creation of the DNA motifs by the web-based tools used, which have size limitations. The GEO accession number (GSE57693) for these previous publications and additional information on the data access and bioinformatics can be found at www.skinner.wsu.edu/arrays.Exposure sets of DMR sequences used to perform the bioinformatic analyses were obtained from previous studies from our group showing transgenerational epigenetic changes in the F3 generation sperm and somatic cells ab initio motif discovery algorithms, which search for recurring patterns in a set of DNA sequences and (ii) assessment of statistical over-representation of previously characterized motifs (from transcription factor binding site databases) in sequences ab initio motif discovery. GLAM2 considers insertions or deletions that are a variable and not incorporated by other algorithms Find Individual Motif Occurrences, available online on MEME suite) is a general-purpose web-based tool for identifying candidate binding sites \u22126 and the scan was on both strands. The sequences with matches of motifs were counted and the percentage of the sequences with matches was calculated in for each DMR dataset. The number of motif matches per sequence was also counted to determine the density of motif matches per DMR dataset. In addition to these analyses, comparison of created motifs with known motifs of transcription factors was performed with STAMP. STAMP is a web-based bioinformatic toolbox used to detect similarities of input motifs to motifs representing transcription factor binding sites, which are present in a database that include binding sites information from several organisms http://www.R-project.org). For this, matches for GGGG and WWWW motifs were interrogated, respectively. The number of matches per sequences was then obtained and the density of matches per sequence sets was calculated. Figures showing visualization of all motif incidences  were created using CLC Workbench .Two main computational methods exist to identify shared motifs in sets of sequences: (i) application of Incidences of motifs between the DMR from different treatments and random sets were tested with Fisher\u2019s test. Comparison of density of motif incidences between treatment sets of DMR and random sets were performed with Student\u2019s t-test. The average of the distributions of G quadruplexes and A/T strings was also compared with Student\u2019s t-test between the treatment DMRs and random sets.Figure S1Validation with DDT DMR data set. (A) Distribution of A/T string (WWWW) incidence in the DDT DMR data set. The percent of DMR with A/T string sequences are presented compared to the random sequence data set. (B) Distribution of G quadruplexes (GGGG) incidence in the DDT DMR data set. The percent of DMR with G-quadruplexes are presented compared to a random sequence data set.(PDF)Click here for additional data file."}
+{"text": "Mycobacterium tuberculosis (MTB) is the causal agent of the disease tuberculosis (TB). Metabolic adaptations are thought to be critical to the survival of MTB during pathogenesis. Computational tools that can be used to study MTB metabolism in silico and prioritize resource-intensive experimental work could significantly accelerate research.Mycobacterium tuberculosis (MTB). We have validated the accuracy of E-Flux-MFC for predicting changes in lipids and metabolites during a hypoxia time course using previously published metabolomics and transcriptomics data. We have further validated the accuracy of the method for predicting changes in MTB lipids following the deletion and induction of two well-studied transcription factors (TFs). We have applied the method to predict the metabolic impact of the induction of each of the approximately 180 MTB TFs using a previously generated and publically available expression data set.We have developed E-Flux-MFC, an enhancement of our original E-Flux method that enables the prediction of changes in the production of external and internal metabolites corresponding to gene expression measurements. We have used this method to simulate the changes in the metabolic state of E-flux-MFC can be used to study global changes in MTB metabolites from gene expression data associated with environmental and genetic perturbations. The application of this method to a data set of MTB TF perturbations provides a resource for studying the large number of TFs whose functions remain unknown. Most TFs impact metabolites indirectly through the propagation of gene expression changes through the regulatory network rather than through their direct regulons. E-Flux-MFC is also applicable to any organism for which accurate metabolic models are available.The online version of this article (doi:10.1186/s12918-015-0206-7) contains supplementary material, which is available to authorized users. Mycobacterium tuberculosis (MTB) is the causal agent of the disease tuberculosis (TB). With more than 9 million new cases of active disease and nearly 1.5 million deaths in 2013, TB is a global health emergency of substantial proportions 68]. In ophoP knockout data are available in NCBI\u2019s Gene Expression Omnibus (GEO) at accession number GSE22854. The dosR knockout and wild type hypoxic transition data are available at GEO accession GSE8829. The hypoxic time course and transcription factor overexpression data are available at GEO accession GSE43466 and on tbdb.org. We provide our complete model as an SBML file in Additional file The"}
+{"text": "One of the biggest mysteries in cancer research remains why mutations in certain genes cause cancer only at specific sites in the human body. The poor correlation between the expression level of a cancer gene and the tissues in which it causes malignant transformations raises the question of which factors determine the tissue-specific effects of a mutation. Here, we explore why some cancer genes are associated only with few different cancer types , while others are found mutated in a large number of different types of cancer . We do so by contrasting cellular functions of specific-cancer genes with those of general ones to identify properties that determine where in the body a gene mutation is causing malignant transformations. We identified different groups of cancer genes that did not behave as expected . Analysis of these three groups demonstrates the importance of environmental impact for understanding why certain cancer genes are only involved in the development of some cancer types but are rarely found mutated in other types of cancer. Cancer cells accumulate genomic mutations, which give a growth advantage to these cells. To unravel the molecular mechanisms underlying cancer growth, many cancer genomes of different cancer types have been sequenced. Thereby, a large amount of frequently mutated genes has been discovered. Strikingly, the pool of mutated genes found in cancer patients differs a lot from cancer type to cancer type. This suggests that the growth advantage, which a mutation confers to the cancer cell, varies with the cell type and therefore different sets of mutations are selected in different tissues.Some genes are associated to tumorigenesis in a broad variety of tissues  while others are mutated only in very few cancer types (specific-cancer genes) . An examSurprisingly, cancer genes are not overexpressed in the tissues from which the tumor originate4The purpose of this study is to determine possible mechanisms by which the cellular environment affects the tissue specificity of cancer genes. We do so by first systematically identifying factors that determine if a gene is associated with only a few or many cancer types. Therefore, we computed a cancer gene specificity score from mutation data of 21 different cancer types . We usedet al. studyA recent studyFollowing the intuition that a high significance in a single tumor type and a low significance in the pan-cancer set are indicative of a specific-cancer gene, and vice versa, that a high pan-cancer significance paired with lower significance in single tumor types is characteristic for general-cancer genes , we defiAs it has been previously described that cancer genes do not tend to be overexpressed in the tissues from which the cancer developsTo begin with, we investigated the relation between the cancer gene specificity score and the number of tissues in which the respective protein has been detected . The corNext, we restricted ourselves to highly specific-cancer genes, i.e. those only involved in one type of cancer. We asked if the tissue where the respective protein is most abundant tends to be the one from which cancers originate that carry mutations in this protein. We only considered solid tumors for the analysis of cancer gene expression to facilitate the association between cancer types and tissue origins and retrieved protein abundance measurements from more than 60 healthy tissuesTo further investigate cellular functions overrepresented among specific- or general-cancer genes, we implemented a variant of the gene set enrichment analysis (GSEA), a computational method capable of detecting overrepresentation of functional classes on one end of an ordered list of genes with respect to the other end of the list (see Methods). We applied the method to the coreCancer set ordered with respect to the specificity score to detect Gene Ontology (GO) functions associated with cancer-specific and cancer-general genes. The cancer genes considered here might have been studied to an uneven amount of times. As a result the observed difference in number and type of functional annotation of the top and bottom of the specificity ordered cancer gene list, could be an artifact of an elevated research attention towards cancer-general genes. To exclude this possibility, we investigated how often cancer-general genes are studied as compared to cancer-specific genes . We obseWe further investigated if our initial hypothesis that the higher number of functional annotations associated with cancer-specific genes is (a) caused by a higher level of functional diversity and (b) is not due to any study bias. Therefore, we compared the pairwise GO semantic similarity of all pairs of genes within the 30 most specific and within the 30 most general cancer genes (again excluding genes studied more than 500 times from the coreCancer set). We found that, indeed, general cancer genes tend to show a higher pairwise similarity as compared to specific-cancer genes . This suInterestingly, functional categories related to DNA repair, whose suppression is a hallmark of most cancer types, are missing from the list of terms enriched among the general-cancer genes. Another intriguing observation is that genes involved in immune response are enriched at the top and the bottom of the specificity ordered cancer gene list . Closer As both DNA repair and cellular immune response are processes that cells perform in response to damage caused by mutagens or infection by pathogens, we investigated if external context effects might explain the different functional associations of specific- and general-cancer genes. Therefore, we considered cellular exposure to different mutagens, viruses and chemicals as sources of specificity in the following analyses.Cancer genes can be grouped into three classes: oncogenes, tumor suppressors, and DNA repair (or stability) genesTo investigate why DNA repair proteins are associated on average with fewer cancer types than oncogenes or tumor suppressors, we extended the coreCancer gene set (which contained only 8 DNA repair genes from the set of 270 DNA repair genes annotated in GO) by adding known (somatic and germline) cancer genes from the literature (see Methods). This increased the total number of cancer genes from 224 to 670 (with 38 DNA repair genes). However, this was done at the price of the specificity ranking, as we did not have information about the strength of the association between a cancer type and a gene for most of the genes. Within this list, we associated each cancer gene with the tissues and cell types in which it had been reported to drive cancer development. We refer to this list as the extCancer (extended cancer) gene set.Skin cancer was significantly associated with the highest number of NER genes . The high number of NER pathway genes in skin cancer makes sense, as UV light causes covalent links between adjacent pyrimidines. These dipyrimidines can be repaired by NER. However, pyrimidine transitions are frequent at unrepaired sites. Accordingly, C to T mutations are the most frequent mutation in skin cancersColon has the highest number of MM genes; again, this association is significant . Base substitution mismatches happen during DNA replication, and intestinal cells are the most rapidly dividing cells typesBreast, leukemia, lung, and lymphoma have the highest proportion of DSBR genes with respect to the other DNA repair pathways. Double-strand breaks (DSBs) can occur under physiological and pathological conditions192021Brain, kidney, ovary, and uterus show less pronounced differences in the DNA repair pathways associations.We categorized DNA repair genes in the extCancer set into different DNA repair pathway classes. We considered the pathway classes nucleotide excision repair (NER), mismatch repair (MM), and double-strand break repair (DSBR), as these have a low gene overlap . This reThe associations are even stronger when only specific-cancer genes are considered: all specific-cancer genes in the DSBR class are associated with estrogen-related tissues . All specific-cancer genes in the MM class are associated with rapidly dividing tissue  implying a 6.5-fold enrichment of genes in the NER, MM or DSBR pathway among germline mutated cancer genes. We wondered if this is caused by a general tendency of germline mutated cancer risk genes to encode DNA repair genes. Indeed, we observed a strong enrichment of DNA repair genes among germline mutated cancer genes as compared to somatically mutated , while in external factors like distinct environmental mutagens, such as UV-, hormones or tobacco exposure explain their specificity.As demonstrated in a previous section, genes involved in the immune system show a bimodal distribution of cancer gene specificity scores in the coreCancer set : we founTo understand what causes the differential specificity of innate and non-innate immune response genes , we applied GSEA analysis to the subset of the 47 cancer genes with a function in the immune response. The strongest functional category enriched among specific-cancer genes involved in the immune response was \u2018integral component of plasma membrane\u2019 . Inspection of the analyzed gene set revealed that, among the ten most specific immune response cancer genes, five were bound to or an integral part of the plasma membrane . Four of these five proteins  have described roles in antiviral adaptive response, inflammatory response to viral infection, or viral host cell entry252627As viruses recognize their target cells by their membrane protein composition, we investigated if viral host cell tropism (the specificity with which viruses infect host cells) might relate to cancer gene specificity. For this, we retrieved host-virus protein-protein interaction information from VirusMenthaEBV, in the herpes family, infects B cells and epithelial cells and causes several types of lymphomas and nasopharyngeal cancerHPV infection is associated with cervix cancerHIV infects immune system cells  and increases cancer risk indirectly through immune suppressionFor each tumor type we counted the number of proteins in the extCancer set interacting with proteins from different viruses. We considered viruses that have been implicated in carcinogenesis and for which we had sufficient PPI data: namely, Epstein-Barr virus (EBV), human papillomavirus (HPV) type 16, and human immunodeficiency virus (HIV) type 1. The infection cycle and involvement in cancer of the three investigated types of viruses is very different:We wondered if we would see a difference in the number of proteins with germline versus somatic mutations among the EBV, HPV and HIV viral protein interaction partners. However, we did not detect any significant differences between their numbers.As many of the PPIs listed in VirusMentha are from small scale experiments, we aimed to confirm that the observed effect is not due to a study bias towards cancer-related proteins. Therefore, we retrieved those PPIs from an independent resource In three of the seven investigated cancer types, we observed a clear association between tissues and chemicals specifically absorbed by or targeting the respective tissue origin of the cancer see : specifiThis approach reproduced known associations between carcinogens and cancer types . From the 18 significant associations between chemicals and cancer types , 15 remaThe strong association between genes involved in one type of cancer and chemicals specific to the environment of the tissue from which the cancer originates confirmed again the impact of environmental factors on the specificity of cancer genes.It is an open question why some genes cause specifically one type of cancer but do not seem to be involved in other types. A general lack of agreement between expression location of cancer genes and location of pathology was noted a few years ago45With the advent of large scale sequencing studies of cancer genomes from different cancer types, it has become evident that many genes are only found mutated in a small number of cancer types1On an anecdotal level, there is evidence that cell type-specific differences in signaling cause cell type-specific differences in disease manifestation. An example is APC, which shows a strong association with colon cancer, which can be explained by its fine tuning of Wnt-dependent proliferation in rapidly dividing colon crypt cellsHere, we systematically quantify functional differences between cancer genes associated with few different cancer types versus cancer genes involved in many different types of cancer. In contrast to the aforementioned cell type-specific functional differences as a contributor to cell type-specific pathology, we identify the environment of the cell as an important factor that determines the effect of a mutation on cancer development. Conversely, we find signaling related functions strongly enriched among general-cancer genes.Most importantly, we identified DNA repair in response to cell type- and environment-specific factors as an important contributor to cancer gene specificity. This might explain why cancer genes are often expressed at low to average levels in the tissues in which they drive cancer development: DNA repair genes usually have a low basal expression level, and their expression only increases after DNA damage occursThe relation between DNA repair and tissue-specific diseases has been noted before. For example, it has been shown that genetic defects in the NER pathway lead to Xeroderma pigmentosum, a hereditary skin malignancy often accompanied by skin cancer, due to accumulation of UV-induced mutationsInterestingly, most of the DNA repair genes with relevance in cancer are germline mutated. The high number of DNA repair genes among cancer risk genes has been noted previously24Another source of specificity that we identified are host-virus protein-protein interactions. Viral tropism depends mostly on the host factor\u2019s membrane receptor composition, as they are hijacked by the virus to function as entry gates into the cell for the virus . This can lead to erroneous conclusions when not taken into accountIn our analyses, we demonstrate the importance of environmental impact for understanding why certain cancer genes are only involved in the development of some cancer types but are rarely found mutated in other types of cancer. The lack of success to explain cancer gene specificity from cell endogenous properties alone (such as relating expression levels to location of pathology) has been puzzling researchers for decadesWe restricted the analyses described here to drivers of cancer undergoing non-silent mutations as the large number of sequenced exomes used in this study provided us with the means to define a high confidence set of cancer drivers. However, the extent to which other alteration types play a role in cancer progression becomes increasingly clear: differential expression of numerous genes in cancer cells have been observed for decades, copy number alterations and epigenetic changes have been systematically cataloged in recent yearsRecent researchThe ongoing cancer genomes sequencing projects will allow to apply the here described method to define cancer-specific genes on an increasing scale. At the same time, efforts to map gene-chemical and host-virus interaction networks for a multitude of environmental pathogens will expand our knowledge on interactions between environmental factors and human genes. A future challenge will be to use network approaches to take the step from identifying general mechanisms that govern cancer gene specificity to predicting causal relations between specific pathogens or chemicals and carcinogenesis. This might reveal the involvement of previously considered harmless factors in disease even without the consultation of epidemiological data.The here described contributors to cancer gene specificity illustrate how important it is to incorporate both cell endogenous and exogenous information to understand why a single mutation could have different effects on different cell types. It remains to be tested how much the cellular environment also contributes to the intra-cancer type mutational heterogeneity and to which degree differential exposure to pathogens explain why two patients with the same cancer type can differ so substantially in the mutated gene set.The analyses in this manuscript were done on two cancer gene sets: the specificity-scored coreCancer set and the larger extCancer set. To construct the coreCancer, we retrievedThe extCancer gene set was compiled by merging coreCancer with all cancer genes from the cancer gene census (downloaded 08/27/2014)A variant of the GSEA algorithmGenes were functionally classified based on uniprot keywords (downloaded 09/08/14)Semantic similarity of gene pairs was computed as the mean of the similarity of all GO terms All interactions between chemicals and genes were retrieved from CTDHow to cite this article: Schaefer, M. H. and Serrano, L. Cell type-specific properties and environment shape tissue specificity of cancer genes. Sci. Rep.6, 20707; doi: 10.1038/srep20707 (2016)."}
+{"text": "From a clinical perspective, impaired tissue O2 transport is a key pathophysiological mechanism shared by cardiopulmonary diseases, such as chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF). In addition to arterial hypoxemic conditions in COPD, there is growing evidence that cerebral and muscle blood flow and oxygenation can be reduced during exercise in both isolated COPD and CHF. Compromised cardiac output due to impaired cardiopulmonary function/interactions and blood flow redistribution to the overloaded respiratory muscles  may underpin these abnormalities. Unfortunately, COPD and CHF coexist in almost a third of elderly patients making these mechanisms potentially more relevant to exercise intolerance. In this context, it remains unknown whether decreased O2 delivery accentuates neuromuscular manifestations of central and peripheral fatigue in coexistent COPD-CHF. If this holds true, it is conceivable that delivering a low-density gas mixture (heliox) through non-invasive positive pressure ventilation could ameliorate cardiopulmonary function/interactions and reduce the work of breathing during exercise in these patients. The major consequence would be increased O2 delivery to the brain and active muscles with potential benefits to exercise capacity . We therefore hypothesize that patients with coexistent COPD-CHF stop exercising prematurely due to impaired central motor drive and muscle contractility as the cardiorespiratory system fails to deliver sufficient O2 to simultaneously attend the metabolic demands of the brain and the active limb muscles.Impairment in oxygen (O Impaired tissue O2 transport due to altered perfusive and/or diffusive mechanisms are key pathophysiological abnormalities shared by two common cardiopulmonary diseases: chronic obstructive pulmonary disease (COPD) and chronic heart failure with reduced left ventricular ejection fraction (CHF). Unfortunately, COPD and CHF coexist in approximately 1 out of 3 elderly patients with a primary diagnosis of either disease  under the stress of physical activities. The consequences of derangements in O2 delivery are particularly relevant to tissues requiring a fine-tune balance between O2 delivery and utilization during exercise, such as the central nervous system (CNS) and the active skeletal muscles. Despite these previous considerations, however, it remains unknown whether in patients with COPD-CHF overlap (1) decreased O2 delivery leads to deficits in cerebral and active limb muscle oxygenation and, if this shows to be the case, (2) whether those deficits accentuate neuromuscular manifestations of central and peripheral fatigue, respectively.Respiratory-mechanical  and gas-exchange (hypoxemia) abnormalities are known to impair the cardiac output  and electromyographic (M-wave) responses. In order to fully activate the muscles under scrutiny, it is crucial to use a stimulation  of supramaximal intensity. Of note, forceful voluntary contractions before stimulation are required to avoid the potential bias of exercise-induced potentiation when assessing fatigue , as estimated by twitch interpolation Merton, , is the 2 delivery may affect muscular performance and the rate of development of both central and peripheral fatigue  are thought to underlie the rapid development of peripheral muscle fatigue with reduced O2 delivery  and central  fatigue  causes substantial increases in respiratory muscle work, possibly leading to diaphragm and expiratory muscle fatigue  might independently contribute to the development of fatigue during exercise.The competition for blood flow between respiratory and active lower limb muscles and the development of peripheral locomotor muscle fatigue independent of changes in CaOExpiratory flow limitation and lung hyperinflation that are only partially reversible to bronchodilator therapy are pathophysiological hallmarks of COPD . Utilization of this intervention in combined COPD-CHF patients is expected to slow the rate of central and peripheral fatigue development and enhance physical capacity. We envisage that further improvements in cardiopulmonary function/interactions and exercise tolerance of COPD-CHF patients would be reached by adding a low-density gas mixture  to NIPPV. We also reason that further increases in cerebral and skeletal muscle O2 delivery would be induced by progressively increasing inspired O2 fraction in different hyperoxic heliox gas mixtures. This would allow us to interrogate individual contributions of each of these interventions on systemic O2 delivery.We propose to test our hypothesis by investigating the neuromuscular consequences  of improved cerebral and active limb skeletal muscle O2 delivery-to-utilization (mismatching). Arterial blood gases will be assessed at rest and during exercise. Neuromuscular function via femoral and phrenic nerve magnetic stimulation will be evaluated before and immediately after exercise to investigate changes in evoked electromyographic and mechanical responses of the quadriceps and respiratory muscles.Standard cardiopulmonary responses, 2 delivery and/or decreasing O2 requirements within the brain and active limb skeletal muscle positively impact upon tolerance to exertion in patients with combined COPD-CHF. This might set the scene for randomized controlled trials with pharmacological , non-pharmacological  and dietary  interventions that might delay central and peripheral neuromuscular fatigue development in this patient population.Despite mounting evidence that COPD-CHF overlap represents a growing cause of physical incapacity in the western world (Rutten et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Surveillance programs were grouped by whether they systematically conducted prenatal ascertainment to capture diagnosed cases  or did not . Programs with prenatal ascertainment monitored birth defects among live births, stillbirths, and elective terminations, and included collection of information from prenatal sources, such as prenatal diagnostic facilities.In August 2014, a total of 19 population-based birth defects surveillance programs in the United States reported to CDC the number of cases of spina bifida  and post-fortification periods (1999\u20132011). These prevalence estimates were multiplied by the average number of live births in the United States for the selected periods to estimate the annual number of NTD cases nationwide. Prevalence estimates were also calculated by type of surveillance program  and maternal race/ethnicity . The estimated annual number of NTDs prevented was calculated as the difference between the estimated annual number during the pre-fortification period and the estimated annual number during the post-fortification period using prevalence estimates from programs with prenatal ascertainment.A decline in NTDs was observed for all three of the racial/ethnic groups examined between the pre-fortification and post-fortification periods . The posThe birth prevalences of anencephaly and spina bifida during the pre-fortification (1995\u20131996) and post-fortification periods  for programs with and without prenatal ascertainment were estimated. Overall, a 28% reduction in prevalence was observed for anencephaly and spina bifida using data from all participating programs; a greater reduction (35%) was observed among programs with prenatal ascertainment than for programs without prenatal ascertainment (21%) . The preThe birth prevalence of NTDs during the post-fortification period has remained relatively stable since the initial reductions observed during 1999\u20132000, immediately after mandatory folic acid fortification in the United States. The updated estimate of approximately 1,300 NTD-affected births averted annually during the post-fortification period is slightly higher than the previously published estimate ; multiplThe reduction in NTD cases during the post-fortification period inversely mirrors the increase in serum and red blood cell (RBC) folate concentrations among women of childbearing age in the general population. Fortification led to a decrease in the prevalence of serum folate deficiency from 30% to <1%, and a decrease in the prevalence of RBC folate deficiency from 6% to no measureable deficiency . A recen\u03bcg of folic acid per day through fortified food or supplements  than non-Hispanic white women (30%) report consuming \u2265400 plements . A commoplements . Personsplements .What is already known on this topic?A decline in the prevalence of neural tube defects (NTDs) was reported during the period immediately after mandatory folic acid fortification in the United States, which translated to approximately 1,000 births occurring annually without anencephaly or spina bifida that would otherwise have been affected.What is added by this report?The prevalence of NTDs during the post-fortification period has remained relatively stable since the initial reduction observed immediately after mandatory folic acid fortification in the United States. Using the observed prevalence estimates of NTDs during 1999\u20132011, an updated estimate of the number of births occurring annually without NTDs that would otherwise have been affected is 1,300.What are the implications for public health practice?Current fortification efforts should be maintained to prevent folic acid\u2013sensitive NTDs from occurring. There are still opportunities for prevention among women with lower folic acid intakes, especially among Hispanic women, to further reduce the prevalence of NTDs in the United States.The findings in this report are subject to at least one limitation. The prevalence data used in this study might not be generalizable to the entire United States, but only to the extent that NTD prevalence in other states/territories not examined could differ from NTD prevalence in the states/territories represented in this analysis.The initial decline in NTD prevalence reported immediately after mandatory folic acid fortification has been maintained after more than a decade since implementation. Mandatory folic acid fortification remains an effective public health policy intervention."}
+{"text": "We report the presence of an anomalous papillary muscle inserting into the basal antero-septum in patients with hypertrophic obstructive cardiomyopathy (HOCM) investigated by means of cardiac MRI.9 consecutive patients with HOCM and 13 age- and gender-matched controls without this condition were interrogated using a Siemens Espree MRI machine. A diagnosis of HOCM was established on the basis of asymmetric antero-septal left ventricle hypertrophy and systolic anterior motion of the mitral apparatus.100% of HOCM patients and 62%  of controls demonstrated an anomalous papillary muscle connecting the left ventricle basal antero-septum with the apex, noticeable on a long axis view acquired on an SSFP sequence. This particular structure contracts during during systole as seen in Figure An anomalous papillary muscle connecting the basal antero-septum with the left ventricular apex and contracting during systole is more commonly seen in HOCM patients than in controls. Further larger studies are needed to elucidate the importance of this anatomical finding in the physiology of left ventricle outflow tract obstruction."}
+{"text": "Understanding the consequences of fragmentation of coastal habitats is an important topic of discussion in marine ecology. Research on the effects of fragmentation has revealed complex and context-dependent biotic responses, which prevent generalizations across different habitats or study organisms. The effects of fragmentation in marine environments have been rarely investigated across heterogeneous habitats, since most studies have focused on a single type of habitat or patch. In this study, we assessed the effects of different levels of fragmentation . We measured these effects using assemblages of macro-invertebrates colonizing representative morphological groups of intertidal macroalgae . For this purpose, we constructed artificial assemblages with different combinations of morphological groups and increasing levels of fragmentation by manipulating the amount of bare rock or the spatial arrangement of different species in mixed assemblages. In general, our results showed that 1) fragmentation did not significantly affect the assemblages of macroinvertebrates; 2) at greater levels of fragmentation, there were greater numbers of species in mixed algal assemblages, suggesting that higher habitat complexity promotes species colonization. Our results suggest that predicting the consequences of fragmentation in heterogeneous habitats is dependent on the type and diversity of morphological groups making up those habitats. The continuous destruction and degradation of natural habitats is occurring at an alarming rate throughout the world; impacts are widespread and pervasive across a range of habitats, with large, consistently negative effects on associated assemblages . CoaThe concept of \u201chabitat fragmentation\u201d is very broad and includes a variety of processes and alterations resulting from changes of natural landscapes, like loss, degradation, subdivision or isolation of habitat patches . DespiteHere, we present a study on the effects of macroalgal composition on the colonization of fragmented habitats. For this purpose, we constructed artificial habitats by combining patches of the three main morphological groups of intertidal macroalgae in rockpools in the North of Portugal  and manipulated the number and sub-division of patches of habitat whilst maintaining the overall habitat area constant. In doing so, we focused on the habitat subdivision effect , rather First, we tested whether (1) colonization of increasingly fragmented habitats  depends on the type of the habitats being fragmented (i.e. morphotypes that make up the habitat). We tested this hypothesis by comparing the diversity and structure of assemblages of benthic macro-invertebrates colonizing artificially fragmented in two types of configuration: monotypic or mixed algal assemblages. Monotypic algal assemblages were fragmented by patches of bare rock; in mixed algal assemblages we modified the spatial configuration of different algal morphotypes. Second, we tested whether (2) animal species richness and the influence of fragmentation are affected by habitat diversity (i.e. 1-morphotype vs 2-morphotype assemblages). To examine this hypothesis we contrasted monotypic vs mixed-assemblages to establish whether there were indeed greater numbers of species in mixed algal assemblages and used a log response analysis to assess whether observed animal species richness was different from what would be expected based on numbers of species fund in monotypic algal assemblages.Lithophyllum incrustans Philippi and including, among the others Phymatolithon lenormandii (J.E. Areschoug) W.H. Adey. (b) Turf-forming species grouped primary space-holders with limited vertical height (~5 cm length), including the articulated calcareous Corallina elongata J. Ellis & Solander and Jania rubens (Linnaeus) J.V. Lamouroux spp. (c) Canopy space-holder species included Mastocarpus stellatus (Stackhouse) Guiry and Chondrus crispus Stackhouse, that reach a maximum frond-length of ~20 cm and form a secondary cover in many rock-pools [Mastocarpus stellatus and Chondrus crispus have very similar architecture and it has been shown that there are no major differences in assemblages of macroinvertebrates colonizing these two species in natural patches [Our study included the main macroalgal morphological groups  in thesck-pools ; these sck-pools . These t patches , we deciMacroalgae were collected in spring- early summer 2006 from intertidal platforms in Carre\u00e7o and Viana do Castelo . No specific collection permits were required to perform this research since no endangered or protected species where involved in this research project. At the start of the experiment and whenever fieldwork was carried out, we reported our sampling locations and procedures to the relevant maritime authorities, namely the Port Authority of Caminha and the Port Authority of Viana do Castelo. Sampling sites are granitic rocky shores, exposed to northwest oceanic swells and characterized by large rock-pools often dominated by macroalgal assemblages (see detailed description in ). Boulde2 (low fragmentation) to 9 cm2 (high fragmentation). The scale of this manipulation was constrained by the maximum size that the experimental habitats could be constructed , turf (T) and canopy (C) . In eachs et al. ), withous et al.  and thers et al.  but suchs et al. . Matias s et al.  showed ts et al. . Based on = 4) and immediately attached to rock-pools in order to maximize recovery from the stress associated with the construction procedures. Patches were left in rock-pools for approximately 30\u201360 days (i.e. every patch was deployed for at least 30 days). After this accommodation/recovering period all patches were removed from the rock-pools and transported back to the laboratory to verify that all planned treatments  did not change during this accommodation period. Finally, all patches were defaunated using freshwater baths [A total of 72 patches were sequentially constructed  from boulders from the same shore and weighted as before [Previous studies have shown that assemblages of macroinvertebrates associated to macrophytes (e.g. seagrasses) are not always shaped by the structural complexity of the plant only, but also by the amount of biomass or surface area . We ests before . These bFirst, hypotheses about colonization of increasingly fragmented habitats were tested using a two-way ANOVA. Assemblage is the fixed comparison with three levels: a) monotypic  or b) mixed  assemblages. Fragmentation is a fixed factor with three levels . These analyses were done using the following response variables: species richness (i.e. number of species), animal species richness/biomass ratio and abundance of two major taxonomical groups were tested. Univariate data transformation was decided following the Cochran\u2019s Test of homogeneity of variances; means of levels from significant factors were compared using Student-Newman-Keuls (SNK) tests . Entire Second, we examined the numbers of colonizing species in algal assemblages with different levels of habitat diversity  to establish whether there were on average greater numbers of species in mixed-algal assemblages. Note that we did not conduct formal statistical analysis of this contrast due to potential confounding effects associated with differences in total availability of habitat  and/or differences in habitat configuration (e.g. the presence of edges with bare rock patches) between 1-morphotype vs 2-morphotype assemblages. We then proceeded to test whether observed animal species richness in mixed assemblages was different from what would be expected from expectations based on numbers of species in monotypic algal assembles. We used a net diversity index that consists of calculating a log response ratio that represents the proportional response to mixed assemblages as a function of the response to monotypic assemblages. This procedure is analogous to that used to investigate the complementarity effects on biodiversity-ecosystem functioning research  or classDM are obtained where the number of species in mixed patches is greater than the value expected by adding up the numbers of species calculated from monotypic patches. Negative values of DM indicate smaller numbers of species in mixed patches than expected from the numbers of species calculated from monotypic patches. The expected number of species in each mixed patch was calculated as:EAB is the expected number of species in a mixed patch with groups A and B; p is the relative proportion of each group in relation to total biomass of the mixed patch; S is the average number of species per gram of biomass of each morphological group found in monotypic patches. Differences in the expected number of species in each mixed assemblages were assessed using a two-way ANOVA with Assemblage as a fixed comparison with three levels  and Fragmentation as a fixed comparisons with three levels .Positive values of In total, 13046 individuals from 108 morpho-species (hereafter species) of macroinvertebrates were sampled. On average, mixed macroalgal assemblages were colonized by up to 30% more species  than monotypic assemblages . The most abundant groups were gastropods and amphipods , contribMacroalgal identity had a significant effect on number of species of macroinvertebrates . In asseAnalysis of the relative abundances of species of colonizing algal assemblages revealed significant differences between all three morphological groups  in all three types of mixed assemblages , althougOur study showed that 1) macroalgal identity had a significant effect on number of species of macroinvertebrates in monotypic patches ; 2) the Corallina elongata from those colonizing of canopy species (Mastocarpus stellatus and Condrus crispus). Interestingly, we found that there were more species in patches of M. stellatus and C. crispus than in patches of C. elongata, which is contrary to previous observational studies . A potential explanation for this disparity might be that the deposition of sediment in synthetic assemblages may be different from natural assemblages. Turf-forming species entrap large amounts of sediment that are incorporated as a structural component of the turfs [When analysed in separation, each morphological group was colonized by different assemblages, mainly driven by major differences in assemblages colonizing patches of he turfs , which ihe turfs , 54. We he turfs , 55. Finhe turfs ).When algal assemblages were composed of different morphotypes, we found that mixed macroalgal assemblages were colonized by up to 30% more species than monotypic assemblages. This increase in numbers of species could be attributed to greater diversity of habitats in mixed-algal assemblages. Alternatively, greater numbers of species in mixed algal assemblages could be attributed to greater total cover of algae than monotypic assemblages (but see ). Our anOur results showed very little effects of fragmentation on the diversity of benthic assemblages colonizing monotypic patches. This overall lack of a clear effect of fragmentation suggests three possible explanations: (1) there was indeed an effect of fragmentation but by sampling the experimental patch as a whole (as opposed to sampling each sub-unit separately) we failed to detect effects occurring at smaller scales; (2) there were no major effects of fragmentation in our experimental patches and the results can be discussed in light of evidence showing the great complexity in fragmentation effects; (3) there were no major effects of fragmentation due to our choice of scale of manipulation of patch-size leading to a mismatch between the scale at which animal assemblages respond to changes in habitat structure and the scale at which we manipulated fragmentation. Here, we discuss these three possibilities and highlight potential limitations in our experimental approach. The first explanation is that there were indeed fragmentation effects but we were not able to detect them at patch-scale. Our results showed that numbers of species of benthic invertebrates colonizing mixed algal assemblages were greater than expected when these assemblages were fragmented, which suggests that increased habitat complexity created in highly fragmented patches with two morphological groups may have promoted species colonization. These results were subtle and responses may be the result of modified interactions between the different types of patches , which greatly affects the variability and diversity of assemblages of benthic organisms within heterogeneous habitats . SimilarAlternatively, our manipulation of fragmentation as habitat subdivision did not have any major effects on benthic assemblages. While there is widespread evidence for effects of habitat fragmentation , it is n2) is comparable with previous studies investigating the colonization of benthic habitat patches. In our study we simulated an 87.5% reduction in patch-size as result of sub-division of continuous habitat patches.Finally, as mentioned above, we must acknowledge the possibility that our experimental manipulation was not able to capture the effects of fragmentation in these experimental patches. One of the key aspects of detecting effects of changes in habitats is to ensure that the scale at which animal assemblages respond to changes in habitat structure  correspOur study, by testing the effects of fragmentation in patches with different algal identities while controlling for overall habitat size, is important for expanding the current understanding of the role of structure of patches in explaining variability in patterns of diversity and abundances of benthic assemblages. Our evidences suggest that fragmentation effects maybe limited when it is not associated to habitat reduction and in fact fragmentation effects may well be positive through habitat complexity enhancement. Generally, marine systems have a greater degree of connectivity than terrestrial systems because of the fluid medium . The extS1 Fig(DOCX)Click here for additional data file.S2 Fig(DOCX)Click here for additional data file."}
+{"text": "MicroRNA arrays possess a number of unique data features that challenge the assumption key to many normalization methods. We assessed the performance of existing normalization methods using two microRNA array datasets derived from the same set of tumor samples: one dataset was generated using a blocked randomization design when assigning arrays to samples and hence was free of confounding array effects; the second dataset was generated without blocking or randomization and exhibited array effects. The randomized dataset was assessed for differential expression between two tumor groups and treated as the benchmark. The non-randomized dataset was assessed for differential expression after normalization and compared against the benchmark. Normalization improved the true positive rate significantly in the non-randomized data but still possessed a false discovery rate as high as 50%. Adding a batch adjustment step before normalization further reduced the number of false positive markers while maintaining a similar number of true positive markers, which resulted in a false discovery rate of 32% to 48%, depending on the specific normalization method. We concluded the paper with some insights on possible causes of false discoveries to shed light on how to improve normalization for microRNA arrays. Normalization is an essential step of microarray data preprocessing MicroRNAs (miRNAs) are a prevalent class of small single-stranded non-coding RNAs that negatively regulate gene expression by inducing mRNA degradation and translational repression, and are involved in a wide variety of cellular functions such as proliferation, differentiation, and apoptosis In this paper, we report the results from an empirical evaluation of normalization methods using a pair of miRNA array datasets generated at Memorial Sloan Kettering Cancer Center The use of human tumor tissues in our study was approved by the Memorial Sloan Kettering Cancer Center Institutional Review Board.Analysis of variance (ANOVA) has been successfully used to model the relation between mRNA gene expression and sample group, which attributes gene expression variation to factors such as marker effect, sample effect, and stochastic noise Let Let In the setting of marker-specific comparisons , we assume that (1) Different from normalization, randomization requires no modeling of array effects and it removes their confounding effect by balancing them between two sample groups. The mean of the observed expression Hence the difference in the observed average expression between cases and controls isThat is, the difference in observed means is biased by The variance of the observed expression Thus the presence of array effects influences both the accuracy and precision of the estimate of The randomized dataset in our study included 192 arrays. Agilent miRNA arrays have an 8-plex block design, with eight arrays on each slide arranged as two rows and four columns. When assigning arrays to sample groups we used the blocked randomization design with row and column balance in order to ensure the best balance. There are six possible configurations where the numbers of cases and controls are equal on any row and any column of a slide We carefully planned our study for generating the randomized dataset. All 192 arrays were ordered from the same manufacture batch. Their hybridization and production were processed in one run by a single experienced technician at the Memorial Sloan Kettering Cancer Center Genomics Core Lab. As a result of the uniform array handling, We analyzed the data both with and without background subtraction, and found similar results in terms of the relative performance of normalization methods. We report the results for the analyses without background subtraction here. There was minimum variation among replicates for the same probe We assessed evidence against the null hypothesis of equivalent expression, using the t statistic comparing two sample groups in the randomized data We preprocessed the non-randomized data with array normalization followed by probe summarization on the log2 scale. We applied commonly-used methods for normalization and used the same approach to probe summarization as for the randomized dataset. The normalization methods we used were median normalization, quantile normalization, cyclic loess normalization, and variance stabilizing normalization . BrieflyThe preprocessed data were analyzed for differential expression using the same approach as that for the randomized dataset. The resulting p-values and the differential expression status based on the non-randomized data were compared with the differential expression status derived from the randomized data using ROC curves and cross tabulation, respectively For the purpose of evaluating the effect of normalization on the accuracy of biomarker discovery, we called the randomized data as the benchmark data and the non-randomized data as the test data. Among the 3,523 markers on the Agilent array, 351 markers (10%) were identified to be differentially expressed in the benchmark data, indicating a moderately abundant level of asymmetric differential expression. Without normalization, 1934 markers (55%) were identified to be differentially expressed at a p-value cutoff of 0.01 in the test data, which was associated with a true positive rate (TPR) of 185/351 (53%), a false positive rate (FPR) of 1749/3172 (55%), and a false discovery rate (FDR) of 90%. Almost all of the false positive markers had very low expression levels and some of the false negative markers had medium to high expression levels in the benchmark data .With normalization, the number of differentially expressed markers was reduced to 639  for median normalization, 708  for quantile normalization, 732  for cyclic loess normalization, and 723  for variance stabilizing normalization. We also evaluated how accurately the test-data p-values ranked the markers using the ROC curve and observed similar results . NormaliWe next examined whether an addition of a batch adjustment step before array normalization can further improve the accuracy of differential expression detection. We compared the accuracy of calling differentially expressed markers with versus without batch adjustment, in combination with each normalization method tested in our study. It showed that normalization alone called highly similar markers positive to normalization combined with standardization, and moderately similar to normalization combined with ComBat .When comThere are two possible mechanisms through which false negative  markers can occur as a result of array effects and attempted removal of array effects by normalization: one is by introducing bias to the data, and another is by increasing (or decreasing) the variability of the data. In order to examine these two possibilities we looked at scatter plots of the following summary statistics: (1) mean expression differences between two tumor groups for the benchmark data versus that for the test data, in order to look at the level of biases in the test data; and (2) marker-specific standard deviations for the benchmark data versus that for the test data, in order to look at the change of data variability.We generated similar scatter plots for the test data after median normalization . Median Similar plots showed that quantile normalization effectively corrected the bias caused by array effects; however, it overly compressed the variability of the data . The falWe utilized a pair of miRNA array datasets on the same set of tumor samples to perform an objective and absolute assessment of normalization performance under genuine data characteristics. Comparing with previous reports on the assessment of normalization methods for miRNA arrays, our approach provides an important alternative evaluation that challenges the critical assumption of the all-gene methods and offers insights on their performance when the assumptions are violated In the presence of array effects, normalization and batch adjustment can improve the accuracy of detecting differentially expressed markers. However, the number of false positive markers can still be close to the number of true positive markers as demonstrated in our study.There is a critical need to develop efficient methods to normalize miRNA array data with both effective bias correction and proper variability reduction so that miRNAs having disease relevance can be identified in an accurate manner.Figure S1Scatter plot comparing group means in the randomized dataset. True positive markers, false negative markers, and false positive markers, as determined in the non-randomized data  in comparison with the randomized dataset as the benchmark, are indicated as \u201cx\u201d in black, blue, and red, respectively. True negative markers are indicated as black dots.(DOCX)Click here for additional data file.Figure S2ROC curves comparing the two-sample t-statistic p-values for the test dataset with (A) no normalization, (B) median normalization, (C) quantile normalization, (D) cyclic loess normalization, and (E) variance stabilizing normalization, with the gold standard .(DOCX)Click here for additional data file.Figure S3Comparison of differential expression analysis of the test data before versus after batch adjustment. Each Venn diagram compares differentially expressed markers identified in the test data after normalization following no BEC (yellow circle) versus those with BEC (using either standardization (green circle) or ComBat (blue circle)).(DOCX)Click here for additional data file.Figure S4Results of differential expression analysis of the test data before and after batch adjustment, in comparison with the gold standard derived from the benchmark data. Each Venn diagram compares differentially expressed markers identified in the test data after normalization following no BEC (yellow circle) or BEC (using standardization (green circle) or ComBat (blue circle)) versus those identified in the benchmark data (red circle).(DOCX)Click here for additional data file.Table S1List of normalization methods examined in our study.(DOCX)Click here for additional data file."}
+{"text": "The allergen-induced IgE-mediated effector cell activation is the key mechanism in acute allergic inflammation. The aim of this study was to produce human monoclonal IgE antibodies specific for major allergens and the corresponding allergens to study basophil activation.Monoclonal human IgE antibodies specific for the major birch pollen allergen Bet v 1 and for the major grass pollen allergen Phl p 5 and the corresponding allergens as well as a hybrid protein consisting of the Bet v 1 and Phl p 5 allergens were expressed. Using circular dichroism spectroscopy we compared the fold of the hybrid protein with that of the mixture of the two allergens. Rat basophil leukemia cells transfected with the human Fc\u03b5RI receptor were then loaded with the monoclonal IgE antibodies or patients serum containing polyclonal allergen-specific IgE and then exposed to the allergens and the hybrid protein to study basophil activation.We found that basophil activation was obtained with a mixture of two monoclonal IgE antibodies and the hybrid protein which increased in magnitude with rising concentrations of allergen-specific IgE antibodies. Thus increases in allergen-specific IgE lead to the release of larger amounts of mediators. When polyclonal IgE from allergic patients was used, basophil activation was obtained already with lower concentrations of the hybrid protein. An augmentation of the number of IgE epitopes thus increased the allergenic activity and thus the \"potency\" of the allergen. Preliminary titration experiments of the two monoclonal IgE antibodies also suggested that equimolar concentrations of the IgE antibodies with different specificity were most efficient in causing basophil activation, most likely due to the formation of large immune complexes.Results obtained in our molecular model for human basophil activation show that the levels of allergen-specific IgE dictate the extent of basophil degranulation and that the number of IgE epitopes determines the potency of an allergen to induce degranulation. The model should be useful to explore the factors determining allergen-induced basophil activation and to study therapeutic strategies controlling this event. This study was supported by grant P23318-B11 and in part by grants P23350-B11 and F4605 of the Austrian Science Fund (FWF)."}
+{"text": "Accurately describing synaptic interactions between neurons and how interactions change over time are key challenges for systems neuroscience. Although intracellular electrophysiology is a powerful tool for studying synaptic integration and plasticity, it is limited by the small number of neurons that can be recorded simultaneously in vitro and by the technical difficulty of intracellular recording in vivo. One way around these difficulties may be to use large-scale extracellular recording of spike trains and apply statistical methods to model and infer functional connections between neurons. These techniques have the potential to reveal large-scale connectivity structure based on the spike timing alone. However, the interpretation of functional connectivity is often approximate, since only a small fraction of presynaptic inputs are typically observed.Here we use in vitro current injection in layer 2/3 pyramidal neurons to validate methods for inferring functional connectivity in a setting where input to the neuron is controlled. In experiments with partially-defined input we inject a single simulated input with known amplitude on a background of fluctuating noise. In a fully-defined input paradigm we then control the synaptic weights and timing of many (1024) simulated presynaptic neurons. By analyzing the firing of neurons in response to these artificial inputs, we ask 1) How does functional connectivity inferred from spikes relate to simulated synaptic input? and 2) What are the limitations of connectivity inference?Using likelihood-based models of functional connectivity, we find that individual current-based synaptic inputs are detectable over a broad range of amplitudes and conditions. Detectability depends on input amplitude and output firing rate, and excitatory inputs are detected more readily than inhibitory Figure . Moreove"}
+{"text": "Electron microscopy has revealed an abundance of material in the clefts of synapses in the mammalian brain, and the biochemical and functional characteristics of proteins occupying synaptic clefts are well documented. However, the detailed spatial organization of the proteins in the synaptic clefts remains unclear. Electron microscope tomography provides a way to delineate and map the proteins spanning the synaptic cleft because freeze substitution preserves molecular details with sufficient contrast to visualize individual cleft proteins. Segmentation and rendering of electron dense material connected across the cleft reveals discrete structural elements that are readily classified into five types at excitatory synapses and four types at inhibitory synapses. Some transcleft elements resemble shapes and sizes of known proteins and could represent single dimers traversing the cleft. Some of the types of cleft elements at inhibitory synapses roughly matched the structure and proportional frequency of cleft elements at excitatory synapses, but the patterns of deployments in the cleft are quite different. Transcleft elements at excitatory synapses were often evenly dispersed in clefts of uniform (18 nm) width but some types show preference for the center or edges of the cleft. Transcleft elements at inhibitory synapses typically were confined to a peripheral region of the cleft where it narrowed to only 6 nm wide. Transcleft elements in both excitatory and inhibitory synapses typically avoid places where synaptic vesicles attach to the presynaptic membrane. These results illustrate that elements spanning synaptic clefts at excitatory and inhibitory synapses consist of distinct structures arranged by type in a specific but different manner at excitatory and inhibitory synapses. Synaptic formation, maintenance, and plasticity rely on coordination between multiple types of structural proteins spanning the synaptic cleft, the gap separating the pre- and postsynaptic membranes  tomography, we delineate the structure and distribution of elements bridging the synaptic cleft at excitatory and inhibitory synapses in disassociated hippocampal cultures. High-pressure freezing and freeze substitution combined with EM tomography enables resolution of individual molecules in the synaptic cleft  in serial virtual sections ~1.4 nm thick calculated from tomograms. Two clefts each from excitatory and inhibitory synapses from two experiments were segmented and rendered, selecting only elements connected across the entire cleft in the sampled areas. Ten examples of each type of transcleft element, five from each of two experiments, were selected for measurements to determine the average dimensions of their filamentous elements using the 3D measurement function in Amira. The middle, upper, and lower diameters as well as the cleft angle of the transcleft elements were measured to find their mean thickness throughout their length and their degree of incline toward the postsynaptic membrane. Each type of element was also counted to sample its abundance within the cleft. For purposes of measurement, the length of the cleft was divided into equal sized peripheral and central zones, defining the peripheral zone as the two outermost quartiles of the cleft area in the tomogram and the center as the two innermost quartiles. The abundance of each type of transcleft element in each zone was calculated to determine which cleft element types were concentrated in the central or periphery of the cleft. Type-specific measurements included the ratio of the heights of type A cleft elements\u2019 central bulges from the presynaptic membrane and from the postsynaptic membrane to determine bias in the central bulge\u2019s position as well as the extent of presynaptic attachment in type D cleft elements.The mean cleft width was measured with the 3D measurement function in Amira\u2014five measurements from the central region and five from both peripheral regions in experiments 1 and 2. Cleft width was determined as the separation between the outer limit of the presynaptic membrane and the outer portion of the postsynaptic membrane. The area of cleft occupied by cleft elements was also calculated, with each type of cleft element extrapolated as a cylindrical object. These measurements are expressed with one standard deviation from the mean of the data.Tomograms were made from four freeze-substituted synapses, two excitatory and two inhibitory. These were identified in 100\u2013120 nm thick sections based on criteria previously established for freeze-substituted hippocampal cultures  was the largest among the cleft elements at inhibitory synapses (Table  nm was tIn order to investigate relationships between transcleft elements and synaptic vesicle docking sites, maps of the distributions of transcleft elements in excitatory and inhibitory synapses were overlaid with renderings of synaptic vesicles attached to the presynaptic membrane. In the clefts of both excitatory and inhibitory synapses, transcleft elements were absent under attached synaptic vesicles Figure , includiElectron microscope tomography of intact hippocampal culture synapses reveals five types of discrete elements crossing the synaptic cleft at excitatory synapses. This picture differs from images derived from cryoelectron microscopy of synaptic clefts in organotypic hippocampal slices where some cleft elements appear regularly spaced 8.2 nm apart when analyzed at resolution of 5\u201310 nm (Zuber et al., Transcleft elements in the present study are analyzed in virtual sections from tomograms derived from freeze-substituted cultures, resolving individual elements as small as 2\u20135 nm. Preparing synapses for EM tomography by freeze-substitution has the advantage over cryoelectron microscopy that the heavy metal stain introduced during freeze-substitution provides images with a high signal-to-noise ratio, resulting in clear definition of individual protein segments in virtual sections of tomograms (Chen et al., At least a dozen species of molecules extend across the synaptic cleft (Missler et al., The neurexin/neuroligin complex is an example of a possible candidate for a match with one of the types of transcleft element. The ectodomains of neurexin1\u03b2 and neuroligin1 form heterotetramers that crystallize into a lateral, sheet-like structure under physiological conditions (Tanaka et al., cis and trans interactions ~26 nm high by 7 nm wide. The crystal structure of the cis N-cadherin dimer exhibits the straight shape and a shaft 4 nm in diameter typical of filamentous type B cleft elements. The ectodomains of complexes of NetrinG2 and NetrinG2 ligand are ~16 nm in height by ~8 nm wide at a resolution of ~2\u00c5\u2008 (Seiradake et al., The cadherins, netrins, and ephrins might also be represented among the types of transcleft elements. The ectodomains of N-cadherin (Harrison et al., Identifications of transcleft element types can be inferred by comparing known distributions of transcleft molecules with the distributions of the five cleft element types. For example, immunogold labeling has shown that N-cadherin and protocadherin adhesion systems are located at the periphery of the cleft (Uchida et al., No transcleft elements lie under docked vesicles suggesting a strategic role for the organization of transcleft elements in synaptic vesicle release and recycling. Involvement of several transcleft molecules in modulation of the synaptic vesicle cycle during long-term potentiation has been posited (Gottmann, The transcleft elements at inhibitory synapses, like those at excitatory synapses, appear as discrete structures in tomograms prepared by freeze-substitution. These transcleft elements are readily classified into four types roughly corresponding to four of the types at excitatory synapses despite the narrower synaptic clefts. Some of these shorter transcleft elements might represent truncated versions of the corresponding elements in excitatory synapses, because many classes of transcleft molecules engage in alternative splicing and express multiple isoforms (Missler et al., The transcleft elements at inhibitory synapses exhibit structural and organizational features distinct from those at excitatory synapses. The width of the cleft at inhibitory synapses is 10 nm as compared to 16 nm at excitatory synapses. Indeed, clefts of inhibitory synapse typically exhibit elongated, discontinuous postsynaptic specializations and thinner cleft widths (Linsalata et al., Final molecular identification of the elements in the synaptic cleft will require additional approaches. It may be useful to examine the transcleft elements after acute knockdown of different species of transcleft molecules, as any deletions of entire types of transcleft elements could reveal an obvious pattern. Immunolabeling could also be used to verify the location of different types of transcleft molecules, while mass spectrometry analysis could determine copy numbers of each type of transcleft molecule. Through the combination of these techniques, it should be possible to identify each of the types of structures present in the clefts of excitatory and inhibitory synapses and provide definitive information about their numbers and distributions. These data will help clarify how the different proteins bridging the synaptic clefts at excitatory and inhibitory synapses maintain their multiple functions (Missler et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Human African Trypanosomiasis (HAT) is a Neglected Tropical Disease (NTD) targeted for elimination. The declining prevalence of infection will change the demands on health systems to effectively detect cases. Detection of HAT currently relies on vertical surveillance programs where patients are identified in their villages and then required to travel long distances to HAT treatment centres (HTC). New diagnostics and interventions could change the future of service delivery of case detection and treatment; as local services would reduce out-of-pocket (OOP) expenditures and the inconvenience of travelling long distances. It is proposed that the integration of programs into the local health centres (LHC) could be modelled to forecast outcomes related to service delivery, patient accessibility, time spent in the system and resources used with current and new interventions.\u00ae. The model simulates patients\u2019 movement through the health system within a specified area. Different health system structures of both integrated  and non-integrated  approaches were constructed in the model. Data from current and new diagnostic and treatments have been simulated through the model in order to measure the impact of switching from a non-integrated to integrated health system.A discrete-event simulation (DES) health systems model has been developed using SIMUL8Preliminary results suggest that integrated systems with new technologies will increase accessibility, decrease patient wait times but also require additional costs for training and for improving health infrastructures at the local level.An integrated health system could lead to improvements in coverage of treatment and reducing inequity in access to HAT treatment. While the initial additional costs of these interventions could be offset by savings in OOP payments, affordability to health systems should be carefully assessed. The analysis shows that health systems\u2019 modelling is an informative tool for investment decisions regarding an integrated approach."}
+{"text": "The use of unmanned aerial vehicles (UAVs) for ecological research has grown rapidly in recent years, but few studies have assessed the disturbance impacts of these tools on focal subjects, particularly when observing easily disturbed species such as waterfowl. In this study we assessed the level of disturbance that a range of UAV shapes and sizes had on free-living, non-breeding waterfowl surveyed in two sites in eastern Australia between March and May 2015, as well as the capability of airborne digital imaging systems to provide adequate resolution for unambiguous species identification of these taxa. We found little or no obvious disturbance effects on wild, mixed-species flocks of waterfowl when UAVs were flown at least 60m above the water level (fixed wing models) or 40m above individuals (multirotor models). Disturbance in the form of swimming away from the UAV through to leaving the water surface and flying away from the UAV was visible at lower altitudes and when fixed-wing UAVs either approached subjects directly or rapidly changed altitude and/or direction near animals. Using tangential approach flight paths that did not cause disturbance, commercially available onboard optical equipment was able to capture images of sufficient quality to identify waterfowl and even much smaller taxa such as swallows. Our results show that with proper planning of take-off and landing sites, flight paths and careful UAV model selection, UAVs can provide an excellent tool for accurately surveying wild waterfowl populations and provide archival data with fewer logistical issues than traditional methods such as manned aerial surveys. Aerially sourced data is critical to the understanding and census of many ecological systems, such as the use of remotely sensed satellite imagery to investigate the impacts of climate change or the movement ecology of nomadic species  or estimIn recent years rapid advances in the quality, availability and range of sensors in commercial unmanned aerial vehicles (UAVs) have lead to their widespread use in the fields of ecology and conservation . UAVs caA further advantage of UAVs that is seldom raised is that the aerial photography based approach provides a bank of images from which individual species can be independently counted, verified and archived for future analysis or audit. This creates a transparent census technique that increases the usability and cost effectiveness of information gathered if images are made available to other researchers. While aerial photography taken from both manned aircraft and UAVs has proven effective for monitoring large terrestrial mammals , identifRecent technological advances appear to have overcome these issues, so the present study had two central aims: (1) To assess disturbance effects on waterfowl from various UAV models that may render a survey invalid, and (2) to assess whether an airborne digital imaging system could provide adequate resolution for unambiguous identification of small bodied waterfowl.This work was carried out under scientific permits from the New South Wales Office of Environment and Heritage (licence no.: SL101457) and was approved by the University of New England Animal Ethics Committee (authority no.: AEC14-104).2 in area with approximately half of the water surface covered with vegetation. The surrounds are characterised by a narrow band of eucalypt dominated open woodland and agricultural pasture (Fulica atra), Pacific black duck (Anas superciliosa), grey teal (Anas gracilis), hardhead , Australasian shoveler (Anas rhynchotis), pink-eared duck , musk duck (Biziura lobata), blue billed duck , and black swan (Cygnus atratus). For a complete species list for each site see supplementary material. While birds were present in every area of the lake, distribution of taxa was not uniform; for example dabbling duck species (Anas sp.) were more common near the shore whilst diving birds and swans preferred open water.Field tests of disturbance from UAVs were undertaken at two locations in New South Wales, Australia between March and May 2015 with both sites visited on a total of 6 separate occasions. Little Llangothlin Lagoon  is a per pasture . Whilst 2 lake that is managed by local authorities to maintain consistent water levels year round. The main lake supports populations of Australian pelican (Pelecanus conspicillatus) and Australian darter (Anhinga novaehollandiae) but the majority of waterfowl in the region congregate at the adjacent sewage works (2) consists of constructed ponds of varying turbidity separated by gravel embankments that provided areas for roosting of waterfowl, surrounded by a dense border of Typha spp. rushes. Bird numbers at the sewage works remained stable at approximately 40 individuals at each visit with species including grey teal, pink-eared duck, Pacific black duck, hardhead, and black swan. During the day the majority of waterfowl were found basking on embankments between ponds rather than on the water surface, providing a contrast to the Little Llangothlin Lagoon site. Both study sites were regularly visited by a range of avian predators including white-bellied sea-eagle , marsh harrier (Circus approximans), and whistling kite , all of which prey on small bodied waterfowl  caused the greatest level of disturbance and flee behaviour  and 4, pDisturbance from multi-rotor UAVs was more subtle; the DJI Phantom multirotor when flown at 15 m altitude, resulted in birds swimming away from the UAV when approached. Birds remained vigilant and continuously swam ahead of the field of view of the on-board video camera without taking flight. The larger 8-rotor system (Kraken-130) caused little disturbance at any altitude. The only recorded response occurred at 40 m altitude where roosting birds could be seen to tilt their heads to look up at the UAV, but no further response was noted and birds continued roosting or preening activities  and Snow Geese (Chen caerulescens) (Anas platyrhynchos) (Many studies have quantified anthropogenic disturbance to wild birds from stimuli such as pedestrians and vehicles . With thlescens) , and semhynchos)  with minOn repeated flights at varying altitude with different UAV models our results show that if flown with care and attention to potential sources of disturbance, UAVs can prove an effective solution for aerial surveys of waterfowl populations . Our finIt has long been thought that birds, and waterfowl in particular, react differently to silhouettes of predators  and non-predators  flying above them. Early studies  found thLegislation governing the use of UAVs in public areas has lagged behind their increasing popularity although some positive changes in regulations have taken place recently . While sHigh resolution digital images allowing the easy identification of waterfowl species were produced by both the Phase-1 camera  and the One of the biggest advantages of using UAVs to collect high-quality digital images is that it allows researchers to archive the results of each survey for future reference, re-assessment, validation, or meta-analysis. While automated systems for counting birds from aerial photographs have been in use for some time , they arWhen attempting to accurately identify waterfowl to species level using UAV photography there are many trade-offs that must be considered. Ideally, using a very high resolution camera such as the Phase 1 medium format camera (50 megapixels) allows the UAV to fly at higher altitudes covering a large area footprint  with a medium focal length lens (80 mm) and still gather images of suitable quality . Due to 2) wetland and easily identifying waterfowl would come from a combination of a digital camera with a minimum 36 megapixel full-frame sensor combined with a fixed wing UAV with long straight wings to cover large wetlands in a single survey. That is not to say that other combinations of UAVs and cameras are unsuitable, but that this combination appears to offer the longest flying time combined with high-quality imagery suitable for species identification at an approximate resolution of 7.2 mm per pixel that was required to achieve our desired accuracy in identification. Prior to deployment, careful consideration should be given to all of the trade-offs mentioned above before embarking on a waterfowl survey using UAVs as different conditions or availability of hardware may necessitate a slightly different approach. Where possible, the take-off and landing sites should be carefully selected to remain out of sight of the target birds and flight paths should be programmed to approach tangentially to the main flock of birds. Where possible, any turning manoeuvres or sharp drops in altitude should be performed away from the shore with the UAV flying at a fixed altitude across the study area to minimise any potential for disturbance.Based on our findings, the best results for successfully surveying a medium sized (>1 km10.7717/peerj.1831/supp-1Supplemental Information 1List of bird species observed at two study sites, Little Llangothlin Lagoon and Lake Cargelligo sewage works, NSW between March and May 2015.Click here for additional data file."}
+{"text": "Cymbopogon citratus using hydrodistillation and solvent-free microwave extraction methods. Furthermore, extractions of the oils were also carried out with a slight in pH variation and compared, \u201cGC\u2013MS evaluation of C. citratus (DC) Stapf oil obtained using modified hydrodistillation and microwave extraction methods\u201d . The current article contains one table exhibiting a list of compounds in the four different methods of extraction. Comparative studies amongst the various methods of extraction are highlighted in the table.This article describes the various chemical components as obtained from the oils in the leaves of  Specifications TableValue of the data\u2022The data highlight and point out various chemical compounds obtained in acid and base media, which are absent in water-distilled medium. The data are remarkable, indicating that pH variation brings about the extraction of important compounds which are absent in both water-distilled and microwave extraction.\u2022pH variations in essential oil extraction is certain to influence the various chemical components when compared with the conventional method of hydrodistillation.\u2022The data present more components in the pH media than water distilled and microwave extraction.1The data presented here is a Table showing the various chemical compounds obtained from different media of extraction.2The data were obtained by carefully distilling the plant materials using different extraction media which are water-distilled, microwave extraction, acid-distilled and alkaline-distilled. Slight variation of acid and base (5% each of citric acid and sodium bicarbonate). Most of the compounds exist in trace amount with exception of the high molecular alkanes, obtained from the microwave extraction method.The various chemical components were analyzed and identified by GC\u2013MS analysis as previously described"}
+{"text": "Adaptive technology holds great promise for sensorimotor rehabilitation in people suffering from spinal cord injury, neuromuscular disease and stroke. With a long-term goal of developing adaptive technology for diagnosis and rehabilitation of neuromuscular dysfunction, we begin the development of a self-organizing neural network (SNN) that compensates for reduced neural drive. We suggest that the self-organizing architecture that adds or deletes nodes online to generate suitable compensatory muscle excitation Figure  is an ap"}
+{"text": "During embryogenesis, cortical interneurons are generated by ventral progenitors located in the ganglionic eminences of the telencephalon. They travel along multiple tangential paths to populate the cortical wall. As they reach this structure they undergo intracortical dispersion to settle in their final destination. At the cellular level, migrating interneurons are highly polarized cells that extend and retract processes using dynamic remodeling of microtubule and actin cytoskeleton. Different levels of molecular regulation contribute to interneuron migration. These include: (1) Extrinsic guidance cues distributed along migratory streams that are sensed and integrated by migrating interneurons; (2) Intrinsic genetic programs driven by specific transcription factors that grant specification and set the timing of migration for different subtypes of interneurons; (3) Adhesion molecules and cytoskeletal elements/regulators that transduce molecular signalings into coherent movement. These levels of molecular regulation must be properly integrated by interneurons to allow their migration in the cortex. The aim of this review is to summarize our current knowledge of the interplay between microenvironmental signals and cell autonomous programs that drive cortical interneuron porduction, tangential migration, and intergration in the developing cerebral cortex. During mouse embryogenesis, cortical interneurons (cINs) are generated in the ventral subpallium. Distinct proliferative regions can be identified in this area, including the lateral ganglionic eminence (LGE), the medial ganglionic eminence (MGE), the caudal ganglionic eminence (CGE) and the preoptic area (POA). While the MGE, CGE and POA contribute to the generation of cortical interneurons (cINs)  9, followed by the generation of LGE at E10 and CGE at E11 Smart, . GEs hisNkx2-1 transcription factor  lead to a loss of Lhx6 and Lhx8(7) expression, both necessary for the formation of MGE-derived INs  expression shifts the fate of cINs toward globus pallidus GABAergic neurons and into cholinergic INs from the striatum , NPY and reelin fates  of multipolar GABAergic cells  phosphorylation is detected. Cortical interneuron progenitors are thus blocked from completing cell cycle  and accumulate in the GEs. Interestingly, the lack of cyclin D2 in SVZ progenitors lead to the production of lower number of PV but not SST cIN subtypes   \u201ccage\u201d surrounds the nucleus and a large array of MTs connects this structure to the centrosome , frequent on stable and long-lived MTs. The phenotype was partially rescued by treating the cells with taxol, a MT stabilizing agent, indicating that establishment of a correct migration needs a minimal amount of stable MTs  , binding and activating GDNF Family Receptor \u03b11 (GFR\u03b11). GDNF-mediated effects did not result from expression of Rearranged During Transfection (RET) or Neural Cell Adhesion Molecule (NCAM), two classical co-receptor signaling molecules  that cleaves and releases the active form of HGF/SF , were found to increase cINs motility In vivo, the loss of either Nrg-1 or ErbB4 causes migration defects and reduces the number of INs in the cortex  is a strong attractant for cINs and can have both short and long-range effects depending on the isoform recruited. CRD-Nrg1, is membrane bound and acts on neighboring cells. It is mainly expressed by LGE cells and contributes to the formation of a permissive migration corridor for cINs. It is sensed by cINs as they probe their environment and inhibition of their branching behavior leads to a decreased ability to follow Nrg-1 gradient  stream and located above the VZ/SVZ surface  and this process is coordinated with projection neurons migrating radially to form the cortical layers. Avoidance of the CP do not require repulsive cues coming from the projection neurons but rather the formation of a permissive corridor in the MZ and IZ thanks to chemokine signaling. CXCL12 is secreted by proliferating cortical cells from SVZ and IZ and it is a strong attractant molecule for migrating cINs  7 and P11. When transplanted in older cortices, younger cINs die by apoptosis later than resident cINs -mediated in miR-200a regulation necessary for the maintenance of CXCR4 levels. PTMs occur in most proteins and often contribute to their functions and subcellular behaviors. Not many studies were developed to investigate the contribution of PTMs on brain development but there is evidence that they can regulate different aspects of cIN development. For example, it was demonstrated that acylation of SHH N-terminus changes its efficacy as a signaling molecule and greatly enhances its ability to ventralize early LGE progenitors  might be at play during corticogenesis. Post-transcriptional and PTMs can oppose or reinforce genetically-encoded and/or extrinsically-mediated signaling. A recent study explored the role of miRNA in distinct aspects of cINs development (Tuncdemir et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "This review focused on airway dysfunctions and orthodontic treatment modalities. A systematic search of the dental literature was performed using PubMed and Web of Science library database. Different combinations of search terms related to airway and orthodontic treatment were used. Any Non-English articles were excluded. Among titles found, abstract and full articles were reviewed. References from all the relevant articles were hand-searched to include more articles. Forty articles which were found relevant were included in the review. Surgical, orthopedic and fixed appliance therapy has been advocated by clinicians to treat patients with airway dysfunctions. These treatment modalities differ from patient to patient and have to be considered based on lot of criterion.The reviewed studies were not convincing in providing information about the orthodontic treatment modalities; further research regarding the same could be encouraging. The mutual interaction between the pharyngeal structures and the skeletal relationship is a subject of interest for the orthodontists and maxillofacial surgeon. Orthodontists believe that evaluation of soft tissues including facial contours, neuromuscular function, tongue, tonsil, adenoids and nasal polyps should be an integral part of orthodontic diagnosis and treatment planning.2There was no final conclusion attained in the attempt to establish cause - and - effect relationship between nasal obstruction, craniofacial morphology and occlusal features. Mouth breathing influence the facial form, and is considered a predisposing factor to the development of the \u201clong face syndrome\u201d or \u201cadenoid facies\u201d.6Obstructive sleep apnea (OSA) syndrome is characterized by temporary occlusion of the upper airway several times during the night which may result in hypoxia and sleep fragmentation and that the main symptoms were chronic tiredness, day-time somnolence associated with snoring and intellectual deterioration.Studies on the changes of upper airway dimensions have consisted of analyzing the post-treatment effects of RME with dental casts, human skull models, 2-dimensional cephalometricradiographs, 3-dimensional imaging techniques including magnetic resonance images, Computed Tomography(CT), Cone-beam computed tomography (CBCT) systems, acoustic rhinometry and computed rhinomanometry.13Among all the existing 3D imaging techniques, CBCT has become an alternative technique to CT scanning for a comprehensive head and neck evaluation due to its significantly lower overall effective radiation dose and greater spatial resolution than medical CT, high contrast between the hard and soft tissues, lower cost and easier access and availability to dentists.16a) Surgical Treatment: Several studies have reported that there was relative narrowing of the airway space after mandibular surgical set-back.24It was found that maxillomandibular advancement increased airway dimensions by increasing the distance from the occipital base to the pogonion. An increase of this distance showed a significant correlation with an improvement in the apnea-hypopnea index and a decreased pressure effort of the upper airway.26b) Orthopedic Treatment: The sagittal dimension of the upper airway was significantly increased following functional appliance therapy in growing Class II patients.RME/FM) therapy did not affect at all the volume of maxillary sinuses and actually inhibited the normal expected increase of the volume of the pharynx when compared with a control group comprising normal individuals.The RME therapy improved the nasal airway ventilation and was detected by computational fluid dynamics.c) Fixed Appliance Therapy: There was no study reported in the literature regarding the effect of fixed orthodontic treatment on the airway dimensions. The effect of extraction versus non-extraction treatment on oropharyngeal airway volume with the aid of CBCT showed no significant differences in the oropharyngeal airway volume.40The reviewed studies were not convincing in providing information about the impact of different orthodontic treatment modalities on airway; further studies are mandatory regarding the same."}
+{"text": "Tumor infiltrating lymphocytes are studied for their potential as new clinically useful prognostic and predictive biomarkers in patients with triple negative and HER-2/neu amplified breast cancer. This area of research could also help guide the development of novel therapeutic approaches for these diseases. Over the recent years, new results from multiple groups have pointed towards Tumor Infiltrating Lymphocytes (TILs) as prognostic and predictive biomarkers in breast cancer. This is not a new concept. For instance, it has been known since 1940s that a subtype of breast cancer that characteristically exhibits a very large proportion of stromal lymphocytic infiltrate, called medullary carcinoma, has been associated with excellent prognosis after aggressive local therapy in spite of high histologic grade and axillary lymph node metastases . HoweverTo study the association between TILs (detected on H&E stain) and survival, investigators utilized tumors collected from breast cancer patients who participated in randomized clinical trials of adjuvant chemotherapy. The advantage of this approach is the availability of samples from large cohorts of patients with abundance of data on clinical characteristics of their disease and their outcomes. By using such an approach, Loi and colleagues have demonstrated that a high proportion of TILs (>50%) in tumors of women with operable, triple negative breast cancer enrolled in a large adjuvant chemotherapy trial called BIG 2-98, was strongly associated with favorable disease free (p=0.014) and overall (p=0.029) survival . In theiOther studies looked at association between levels of TILs and the likelihood of achieving a complete pathologic response (pCR) following neo-adjuvant chemotherapy for breast cancer. Complete pathologic response is a surrogate biomarker that is generally considered to indicate a lower likelihood of recurrence and a higher chance of survival . Loi andWhat are the implications of these findings to current clinical practice? Perhaps, the results of the above studies could lead to the routine practice of reporting the levels of lymphocytic infiltrates in the pathology reports of patients diagnosed with breast carcinoma ? Before that occurs, the methodology of interpreting TILs and the cut off values for lymphocyte predominant breast cancer will need to be standardized. This data will also require future validation by other groups in prospectively designed clinical trials with pre-specified immune correlative endpoints. Regardless, the findings from the above analysis are already providing crucial clues for future clinical research. As an example, these studies corroborate pre-clinical work by others suggesting that perhaps some conventional anti-neoplastic drugs such as platinum agents or trastuzumab could induce anti-tumor responses at least in part by modulating the host immune system ,17,20\u201323"}
+{"text": "Previous in vitro and in vivo studies demonstrated that HIV protein nef plays a key role in impairing cellular and systemic cholesterol metabolism in HIV disease, but clinical support for these findings is lacking. Here we present the data of comparative lipidomic analysis (330 lipid species) of plasma samples from HIV-negative subjects, patients infected with WT HIV-1 strain and patients infected with nef-deficient strain of HIV-1. We determine which effects of HIV on plasma lipidome are explained by the presence of nef. The data can be used to evaluate cardiovascular risk in HIV disease and to assess the role of nef in HIV-induced disturbances in systemic lipid metabolism. The full impact of nef deficiency on lipid and lipoprotein metabolism in HIV-infected patients is presented in the accompanying study \u201cLipid Metabolism in Patients Infected with Nef-deficient HIV-1 Strain\u201d  Specifications Table\u2022The data can be used to assess the effect of HIV disease on lipid metabolism.\u2022The data can be used to assess the role of HIV nef in modifications of lipid metabolism in patients with HIV disease.\u2022The data can be used to evaluate cardiovascular risk in HIV disease.Value of the data12n=6) were all members of the SBBC cohort. They were compared with patients infected with Nef-positive (WT) HIV-1 strain (n=6) and six HIV negative subjects selected from a group of healthy volunteers. Description of the patients is presented in the main paper Patients infected with nef-deficient strain of HIV-1 . Lipid concentrations were calculated by relating the peak area of each species to the peak area of the corresponding internal standard.Lipidomic analysis was performed as described previously"}
+{"text": "REELIN (RELN) is a large (420 kDa) glycoprotein that in adulthood is mostly synthesized in GABAergic neurons of corticolimbic structures. Upon secretion in the extracellular matrix (ECM), RELN binds to VLDL, APOE2, and \u03b13\u03b22 Integrin receptors located on dendritic shafts and spines of postsynaptic pyramidal neurons. Reduced levels of RELN expression in the adult brain induce cognitive impairment and dendritic spine density deficits. RELN supplementation recovers these deficits suggesting a trophic action for RELN in synaptic plasticity. We and others have shown that altered RELN expression in schizophrenia (SZ) and bipolar (BP) disorder patients is difficult to reconcile with classical Mendelian genetic disorders and it is instead plausible to associate these disorders with altered epigenetic homeostasis. Support for the contribution of altered epigenetic mechanisms in the down-regulation of RELN expression in corticolimbic structures of psychotic patients includes the concomitant increase of DNA-methyltransferases and the increased levels of the methyl donor S-adenosylmethionine (SAM). It is hypothesized that these conditions lead to RELN promoter hypermethylation and a reduction in RELN protein amounts in psychotic patients. The decreased synthesis and release of RELN from GABAergic corticolimbic neurons could serve as a model to elucidate the epigenetic pathophysiological mechanisms acting at pyramidal neuron dendrites that regulate synaptic plasticity and cognition in psychotic and non-psychotic subjects. REELIN (RELN) is an extracellular matrix (ECM) glycoprotein that controls neuronal cell migration and the lamination of the corticolimbic structures during embryonic development  which exhibit a 50% reduction in RELN content have significantly reduced dendritic spine densities and also show a deficit in LTP , behavioral, and cognitive deficits associated with reduced RELN expression (mRNA and protein) are observed in subjects with SZ and BP disorder. In different post-mortem brain cohorts, we and others have demonstrated that RELN expression is reduced by approximately 50% in the prefrontal cortex (PFC), temporal cortex, hippocampus, and caudate nucleus of patients with SZ and BP disorder  has been identified in the vicinity of the regulatory region of the RELN gene  and DNA methyltransferase 3a (DNMT3a) in neocortical and striatal GABAergic neurons , enhance spine density, and relieve SZ-like epigenetic behaviors (Tremolizzo et al., All authors contributed equally to the ideas and editing of the manuscript.AG is supported by the following NIH grants AA022538, R01 MH093348, R01 MH101043, DRG is supported by AA022538. HJC is supported by a SHRF Establishment Grant, and a NSERC Discovery grant.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The firing rate of a neuron is largely determined by correlations in synaptic drive. Correlations in neurotransmitter release between different active sites arise from both synchronous activity in the presynaptic population and the number of independent release sites per neuron. Recent work has shown that the number of release sites on each neuron is modified during long-term plasticity . Such chTo understand how correlations from synaptic dynamics and from presynaptic synchrony shape the postsynaptic response, we studied a model of multiple release site short-term plasticity and derived exact results for the crosscorrelation function of vesicle occupancy and neurotransmitter release, as well as the postsynaptic voltage variance . Using aThese effects arise because, above a certain level of correlation, activity in the presynaptic population is overly strong resulting in wastage of the pool of releasable neurotransmitter. As the nervous system operates under metabolic constraints it is likely that this phenomenon provides an activity-dependent constraint on network architecture."}
+{"text": "Although the general public perceives cannabis as one of the less harmful illicit drugs, the past decades saw a surge in treatment demands for CUDs UNODC, . CannabiEven though a substantial part of regular cannabis users will not experience any clear negative social and health consequences of cannabis, this does not imply that CUDs are less severe than other Substance Use Disorders (SUDs). The mental health issues associated with CUDs are substantial and often include comorbid psychiatric disorders including depression and anxiety , paired with an insufficient capacity to keep these under control are thought to play a prominent role in SUDs . The fronto-limbic network is primarily involved in emotion regulation, salience attribution and the integration of motivational information  into decision processes.While the comorbidity between CUDs and other psychiatric disorders is widely accepted, neurocognitive studies mostly study disorders in isolation. Comorbid symptoms are often even controlled for by excluding such participants. A 3-year longitudinal epidemiological study specifically investigated the role of mental health factors in non-dependent versus dependent heavy cannabis use  methods.The worldwide high treatment demands for CUDs, but the significant lack of studies investigating it warrant new studies that investigate neurocognitive functions in cannabis users with a clinically diagnosed CUDs. Uncovering the common and unique neurocognitive mechanisms and associated (epi)genetics underlying CUDs and highly comorbid disorders like depression and anxiety can provide valuable knowledge for improving current state-of-the-art treatments and for developing new neuroscience based interventions, such as neurocognitive training (e.g., approach-action retraining; Wiers et al., The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Recent Genome-Wide Association Studies (GWAS) have revealed numerous Crohn's disease susceptibility genes and a key challenge now is in understanding how risk polymorphisms in associated genes might contribute to development of this disease. For a gene to contribute to disease phenotype, its risk variant will likely adversely communicate with a variety of other gene products to result in dysregulation of common signaling pathways. A vital challenge is to elucidate pathways of potentially greatest influence on pathological behaviour, in a manner recognizing how multiple relevant genes may yield integrative effect. In this work we apply mathematical analysis of networks involving the list of recently described Crohn's susceptibility genes, to prioritise pathways in relation to their potential development of this disease. Prioritisation was performed by applying a text mining and a diffusion based method . Prospective biological significance of the resulting prioritised list of proteins is highlighted by changes in their gene expression levels in Crohn's patients intestinal tissue in comparison with healthy donors. Biological functions are rarely a consequence of the activity of a single molecule and arise from the interactions between multiple components of biological systems. Since the completion of the human genome project in 2003, high-throughput techniques have generated a large amount of molecular-interaction data in the human cells. The need to analyse the role of associated interaction networks at a system-wide level, rather than focusing on single interactions, led to a change in perspective in the investigation of biological systems and to the development of Systems Biology approaches When a network-based viewpoint is applied to disease, the disease phenotype is associated with global perturbed networks instead of single failing components Genetic studies have revealed numerous susceptibility gene variants in common diseases such as Crohn's, but the function of individual gene variants in disease induction remains unclear. Here we use a list of Crohn's susceptibility genes to prioritise genes to serve as a seed to define a putative Crohn's disease network. We then use graph theory to probe hypotheses about its topological structure and to analyse how proteins implicated as being linked to Crohn's disease by this network may relate with their neighbours in the rest of the proteome. Biological relevance of the prioritised list and of its associated interactions is supported by microarray and functional classification data.This article is organised as follows. First, we prioritise a list of candidate disease genes obtained from literature GWAS reports by applying both a diffusion-based and a text-mining approach. The relevance of our prioritised list is next examined by comparison with differentially expressed genes in biopsies from patients with Crohn's disease. We then build a proteome interaction network of the associated prioritised proteins and we investigate its topological, functional features and relationships with other proteins in the proteome. Correlation between topological localisation and functional role supports the biological relevance of the datasets interactions. The network associated with disease shows enrichment in hubs nearest neighbours and topological segregation of the prioritised list. In the light of our observations, we conclude by highlighting proteins in the network associated with disease with noteworthy topological and functional properties that may warrant further experimental investigation.In what follows we prioritise a list of candidate genes associated with Crohn's disease and test its enrichment among the set of differentially expressed genes in patients affected by Crohn's disease. We then build a molecular interaction network from this list and test correlations between the network topology and its functional organisation. In each section we first provide a brief review of the relevant methods, we then describe in more detail our particular application. The technical details of the methods applied are described either in the section Genome-Wide Association Studies have identified a large number of candidate disease genes for Crohn's but the role of each in disease pathogenesis is unclear In diffusion based methods, random walkers are released from a set of known disease genes and diffuse along the links of the proteome; in such a way, nodes that are more connected to disease proteins are more frequently visited and prioritised Accounting for the results of this comparative analysis, we selected 171 SNPs and 354 genes associated with Crohn's disease from the Catalog of Published Genome-Wide Association Studies We analysed the global and local topological organisation of the sub-network that we have built in the previous section. Characteristic graph-theoretical distributions and metrics show signatures of hierarchical modularity and preferential attachment; these properties resemble the ones of other biological networks, this supporting the biological viability of the network that we associated with Crohn's disease see . The denSince disease is often caused by perturbation in the communication between bio-molecules We then investigated if proteome hubs are over-represented in the network associated with Crohn's and we analysed if the number of hubs in the list of prioritised proteins is over-represented when compared to the total number of hubs in the NCBI proteome. The p-value obtained by a hypergeometric distribution does not show a significant over-representation see . We thenThe global features of preferential attachment and hierarchical modularity suggest the presence of sub-graphs characterising the network at a local level. We now address the problem of identifying such topological modules and analysing their potential correlation with proteins associated with disease. More specifically, we searched for over-represented subgraphs (motifs) when compared to randomised versions of the same network. Algorithms for the search of network motifs explore the full combinatorial set of graphs of a given dimension. Since the computational time grows exponentially with graph dimension, small motifs comprising three or four nodes are usually analysed d31710), . InteresSaccharomyces cerevisiae. In order to determine how well such datasets characterise the protein interaction network of Saccharomyces cerevisiae, the authors investigated the relationship between the topology of the protein interaction maps and the known functional properties of the protein. In all four datasets strong correlations were found between the network's structure and the functional role and sub-cellular localisation of its protein constituents. By measuring the tendency of proteins to interact with other proteins of the same functional or localisation class they concluded that most functional classes appear as relatively segregated sub-networks of the full protein interaction network.Based on the assumption that proteins with similar functional properties interact with one another, protein interaction maps have been frequently used to generate hypotheses on the functional role of proteins of unknown functional classification In the spirit of this analysis, we examined whether the protein network that we associated with Crohn's disease leads to a similar correlation with the functional properties of the prioritised proteins. We performed a functional classification by applying the PANTHER  Classification System ries see  section.In this work we have prioritised a list of genes associated with Crohn's disease and developed a graph-theoretical analysis of the molecular interaction network resulting from this list. Prioritisation was performed by applying both a diffusion based method (GPEC) bour see . FASLG ibour see . ATF4 isbour see . A tableftp://ftp.ncbi.nlm.nih.gov/gene/GeneRIF/interactions.gz) which integrates three databases: Biomolecular Interaction Network Database i-th element represents the probability of the walker being at node 171 SNPs and 354 genes associated with Crohn's disease were downloaded from the Catalog of Published Genome-Wide Association Studies http://www.ncbi.nlm.nih.gov/geo/ accession number GSE20881). http://www.ncbi.nlm.nih.gov/geo/geo2r). GEO2R performs comparisons on original submitter-supplied processed data tables using the GEOquery and limma R packages from the Bioconductor project (http://www.bioconductor.org). The Benjamini and Hochberg false discovery rate method was selected by default to adjust p-values for multiple testing. We used these values as the primary statistics by which to interpret results, selecting as differentially expressed genes those whose p-value was less than The microarray dataset analysed is available at Gene Expression Omnibus , (b) average clustering coefficient distributions; (c), (d) topological coefficient distributions. A formal definition of these distributions is reported in the Appendix.(TIFF)Click here for additional data file.Figure S2Failure-attack tolerance to node removal. Series of plots representing how the number of interactions and the number of secondary extinctions vary when removing nodes randomly (black circles), from the highest to the lowest degree (red circles) and from the lowest to the highest degree (green circles). (a) Number of interactions in the network associated with Crohn's against percentage of removed nodes; (b) Number of secondary extinctions in the network associated with Crohn's against percentage of removed nodes; (c) Number of interactions in a random network against percentage of removed nodes; (d) Number of secondary extinctions in a random network against percentage of removed nodes.(TIFF)Click here for additional data file.Figure S3Failure-attack tolerance to SNP removal. Plots representing how the number of interactions varies when removing nodes associated with the SNPs locus windows (blue) and when removing the same number of nodes from the highest to the lowest degree (red circles) and from the lowest to the highest degree (green circles).(TIFF)Click here for additional data file.Figure S4Enriched biological processes. Chart summarising the biological precesses that are enriched in the prioritised list of proteins. P-value threshold was set to (TIFF)Click here for additional data file.Figure S5Enriched protein classes. Chart summarising the protein classes that are enriched in the prioritised list of proteins. P-value threshold was set to (TIFF)Click here for additional data file.Figure S6Enriched molecular functions. Chart summarising the molecular functions that are enriched in the prioritised list of proteins. P-value threshold was set to (TIFF)Click here for additional data file.Figure S7Enriched pathways. Chart summarising the pathways that are enriched in the prioritised list of proteins. P-value threshold was set to (TIFF)Click here for additional data file.Table S1Topological metrics. Table summarising the topological properties of the disease network and of (PDF)Click here for additional data file.Table S2Training set. Table listing the Entrez IDs included in the training set with their literature references.(PDF)Click here for additional data file.Table S3Segregated enriched categories. Table summarising the segregated enriched categories containing STAT3, JAK2, VDR, FASLG (see section '(PDF)Click here for additional data file.Workbook S1Network associated with Crohn's disease and enrichment tables. Workbook containing the candidate SNPs and Entrez IDs (Sheet 1), the prioritised Entrez IDs (Sheet 2), the network associated with Crohn's disease (Sheet 3), the NCBI proteome network (Sheet 4), the interactions among the proteins associated with the (XLS)Click here for additional data file.Information S1Supplementary Text and Supplementary Tables.(PDF)Click here for additional data file."}
+{"text": "Insulin has frequently been used as a stimulatory factor in routine in vitro embryo production (IVP) and is added in supra-physiological concentrations to different media. Meanwhile, insulin as a key metabolic hormone is elevated in patients with metabolic syndrome or diabetes, syndromes known to impair fertility.This study compared in vitro-used and in vivo-measured insulin concentrations and elucidates explanations and risks for this difference.Eleven in vivo-studies measuring insulin in serum or follicular fluid have been compared to nine IVP-protocols using insulin. In vitro concentrations were much higher than in vivo while not much is known about the different activity and stability of insulin in vitro versus in vivo. We measured insulin concentrations before and after maturation in an experimental trial using a quantitative ELISA (Mercodia bovine insulin ELISA Immunoassay) and can report stable quantities after 22 hours of incubation.The uncritical use of supra-physiological insulin levels in vitro might have negative consequences for the developing embryo as insulin has direct effects on metabolism and could even influence the epigenetic programming of the metabolism with unknown consequences for the offspring later in life. Still, insulin may react differently in in vitro models where one explanation is different stability or activity of insulin. More precise dose effect studies have to be done to draw conclusions about consequences of the use of as high doses."}
+{"text": "Although the existence of a central pattern generator system modulated by sensory information has become broadly accepted in the control of gait, many findings indicate that the cortex also plays a role of primary importance in human walking  and deoxygenated (HHb) form. Although some pitfalls are to consider using fNIRS during gait , the advantages of fNIRS, such as non-invasiveness, highly portable make it a promising method for studying the cortical activation patterns associated with whole-body tasks by wearable multichannel fNIRS system , little is known about brain activity during everyday motor tasks and when a patient undergoes gait training. Like fMRI, fNIRS is a non-invasive imaging technique for measuring local variations of hemoglobin concentration changes related to neuronal activity by the phenomenon of neurovascular coupling. By measuring absorption properties of hemoglobin at two or more wavelengths, fNIRS exploits the changes of the wavelength-dependent extinction spectra of the oxygenated  and primary motor (M1) and somatosensory (S1) cortical regions during treadmill walking (with arm swing) at 1 km/h  following functional activation  might be relevant (Mandrick et al., No standardized methods for fNIRS data analysis have been established yet. Up to date, the only invariant is that different experimental designs require different analysis techniques driven by the underlying neurophysiological mechanism and with a good comprehension of neurovascular coupling. For gait, increased cortical processing is related to large gait parameter changes (Gwin et al., The potential of fNIRS application in the study of human brain activation during gait is promising, motivating further application-specific development toward neuroscience and clinical questions. The investigation of cortical activity by fNIRS presents real advantages especially when measurement in ecologically valid conditions is required. However, neuroimaging of gait is not straightforward and remains difficult. A signal-processing method to extract walking-related components has still to be proposed for fNIRS signals during gait. Also while fNIRS use during gait training in clinical settings might be viewed as an interesting diagnostic tool, many potential confounding variables resulting from disease itself and from extracortical changes need to be carefully controlled.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Current research in gastroenterology and hepatology  made great and rapid progress in new methods, in biomedical technology, and last but not least in practical application of basic scientific achievements during the last decade.Original research articles focusing on new, advanced studies in clinical and experimental research in gastroenterology and hepatology that have a potential to influence our daily practice and further clinical and experimental research were sent to this journal to be published by many leading gastroenterology specialists. Helicobacter pylori Infection, Atrophy, Dysplasia, and Cancer in Its Subtypes,\u201d the prevalence of the precancerous gastric lesions  in a large cohort of patients within the region with a high risk of gastric cancer was described. The metastatic involvement of the posterior lymph nodes along the common hepatic artery  was identified as a prognostic factor in the retrospective study: \u201cPrognostic Value of Metastatic No.8p LNs in Patients with Gastric Cancer.\u201dWe bring ten articles in this special issue focused on the most interesting topics in gastroenterology and hepatology research. One of the leading areas of advanced studies in gastroenterology is cancer research. Colorectal cancer is one of the most common malignancies worldwide in terms of incidence and mortality. Although clear progress in both diagnosis and treatment has been achieved, efficacy of surgery and chemotherapy remains unsatisfactory due to late diagnosis. A possible new prognostic marker and therapeutic target in this disease is discussed in the article \u201cATAD2 Overexpression Identifies Colorectal Cancer Patients with Poor Prognosis and Drives Proliferation of Cancer Cells.\u201d The aim of another article dealing with the colorectal cancer \u201cMolecular Features and Methylation Status in Early Onset (\u226440 Years) Colorectal Cancer: A Population Based, Case-Control Study\u201d was to define the frequency of known hereditary colorectal syndromes and to characterise genetic and epigenetic features of early nonhereditary tumours in order to elucidate possible pathogenetic mechanisms. Colonoscopy plays an important role in colorectal cancer screening in many countries worldwide. Quality of colonic cleansing achieved is crucial for good quality of colonoscopy screening. Possible improvements in the field of low volume colonoscopy cleansing were described in the article \u201cA Randomized Controlled Trial Evaluating a Low-Volume PEG Solution Plus Ascorbic Acid versus Standard PEG Solution in Bowel Preparation for Colonoscopy.\u201d Second malignancy, which is discussed in a special issue in more detail, is the third most common cause of cancer-related death in the world: the gastric cancer. In the article \u201cThe Prevalence of Gastric Intestinal Metaplasia and Distribution ofThe research based on the use of experimental animals still plays an important role in gastroenterology and the rat is one of the most extensively used experimental animal models.The study \u201cSurgical Anatomy of the Gastrointestinal Tract and Its Vasculature in the Laboratory Rat\u201d investigated the functional anatomy and vasculature of the stomach, liver, and intestine in the laboratory rat and compared it with human morphology. Syzygium cumini (L.) Skeels aqueous extract in experimental mice model of indomethacin-induced gastric damage was proven in article \u201cAnti-Inflammation Property of Syzygium cumini (L.) Skeels on Indomethacin-Induced Acute Gastric Ulceration.\u201dNonsteroidal anti-inflammatory drug-induced gastropathy and ulcers represent an important complication related to one of the most commonly used drugs worldwide. Possible mucosal protective effect ofResearch in hepatology is represented in three articles: \u201cAssessing the Effect of Leptin on Liver Damage in Case of Hepatic Injury Associated with Paracetamol Poisoning,\u201d \u201cLower Viral Response to Pegylated Interferon Alpha 2a Treatment of Chronic Hepatitis B in Roma People in Eastern Slovakia,\u201d and \u201cSerum Liver Fibrosis Markers for Predicting the Presence of Gastroesophageal Varices in Liver Cirrhosis: A Retrospective Cross-Sectional Study.\u201dThe special issue cannot be a complete overview of research in the field of gastroenterology and hepatology. However, we believe that it is an interesting look at this area and provides a preview with an important impact on clinical medicine.Ilja Tacheci Ilja Tacheci Jithinraj Edakkanambeth Varayil Jithinraj Edakkanambeth Varayil Zuzana ZelinkovaZuzana ZelinkovaMarcela KopacovaMarcela KopacovaMiroslav ZavoralMiroslav Zavoral"}
+{"text": "For the nervous system it has been recently demonstrated that the CNP/GC-B/cGMP/cGMP-dependent protein kinase type I (cGKI) signaling pathway is essential for sensory axon branching at the dorsal root entry zone of the spinal cord and at the rhombomeres of the hindbrain during embryonic development . Also in; NPRB haHere, we describe that the lack of GC-B in addition leads to a peripheral phenotype which is manifested in auditory threshold loss and altered wave amplitudes and latencies of stimulus-evoked auditory brainstem responses (ABR). Our preliminary results indicate that this deficit is related to a combined afferent and efferent fiber phenotype.We will further investigate the functional consequences of bifurcation loss of ANF on central hearing function and central plasticity. This may lead to sound localization problems, a progressive aging phenotype  and an i"}
+{"text": "Eschericia coli\u201d In this data article we report on the purity and post translation modification of bacterially expressed and purified recombinant hippocalcin (HPCA): a member of the neuronal calcium sensor protein family, whose functions are regulated by calcium. MALDI-TOF in source decay (ISD) analysis was used to identify both the myristoylated or non-myristoylated forms of the protein. MALDI-TOF ISD data on the identity of the protein, amino acid sequence and myristoylation efficiency are provided. This data relates to the article \u201cSingle-Column Purification of the Tag-free, Recombinant Form of the Neuronal Calcium Sensor Protein, Hippocalcin Expressed in  Specifications Table\u2022Confirms the identity of the bacterially expressed HPCA purified in a single step.\u2022Demonstrates the ability to properly myristoylate the bacterially expressed HPCA with high efficiency\u2022Identifies the first amino acid residue of expressed HPCA\u2022Provides a benchmark approach to characterizing critical aspects such as myristoylation in bacterially expressed neuronal calcium sensor proteins in particular and modified proteins in general.Value of the data1Purified HPCA was analyzed through mass spectrometry. MALDI-TOF ISD analyses were independently carried out with the myristoylated and non-myristoylated forms of HPCA. 2HPCA was purified as previously described Rat HPCA coding region was amplified by PCR and inserted into the bacterial expression vector pET 21d between NcoI and HindIII sites. Sequencing of the construct was performed in both directions (GeneWiz Inc.)."}
+{"text": "The therapeutic approach to the management of pulmonary hypertension (PH) is based on strategies to decrease pulmonary vascular resistance (PVR) whilst ensuring optimal cardiorespiratory support to improve oxygenation. The goal is to maintain appropriate systemic blood pressure, ensure oxygen release to tissues and minimize lesions induced by oxygen and ventilation.Inhaled nitric oxide (iNO) remains the mainstay of treatment for this condition. As an inhaled agent it reaches the alveolar space and diffuses into the vascular smooth muscle of the adjacent pulmonary arteries where it causes vasodilation by increasing guanosine monophosphate (cGMP) levels without affecting systemic vascular tone. Although iNO significantly reduces the need for extracorporeal membrane oxygenation, almost 25-40% of iNO-treated infants are considered iNO non\u2013responders.A complementary vasodilatory pathway in the lung is mediated by cyclic adenosine monophosphate (cAMP); prostacyclin stimulates adenylyl cyclase in vascular smooth muscle cells and causes an increase in intracellular cAMP and vasodilation of the systemic and pulmonary circulatory systems. If given as an inhaled drug the vasodilatory effects of prostacyclin tend to be limited to the pulmonary circulation, making this strategy appealing when acute pulmonary vasodilation is needed. Inhibition of the cGMP-degrading phosphodiesterase (PDE5) and inhibition of the cAMP-degrading phosphodiesterase PDE3) are two other promising therapies. Sildenafil is a PDE5 inhibitor, the predominant PDE isoform in the lung responsible for the breakdown of cGMP. It acts by enhancing NO-mediated vasodilation and may facilitate iNO discontinuation in infants with critical illness. Milrinon are two One of the most potent vasoconstrictors described in the pulmonary vasculature is Endothelin-1 (ET-1). Inhibition of ET-1 mediated vasoconstriction could be achieved by administration of an endothelin receptor antagonist (Bosentan). Bosentan lowers pulmonary artery pressure and PVR in children with diverse causes of PH and may improve oxygenation in neonates with persistent pulmonary hypertension; it has also been successfully used as an adjunctive treatment for children receiving long-term prostacyclin therapy.Although a great deal of progress has been made in recent decades in PH treatment, it remains a devastating illness that requires further studies to adapt the therapy to pediatric lung and its peculiar vasculature."}
+{"text": "The Aberdeen Varicose Vein Questionnaire (AVVQ) is validated and frequently used as a patient-reported disease-specific quality of life (QoL) outcome in trials of varicose veins. The AVVQ comprises a manikin diagram where patients draw their varicose veins and 12 questions including pain, skin changes, use of support stockings, appearance and impact. AVVQ scores range from 0 to 100 (worst possible QoL), with the manikin diagram contributing up to 22 points, depending on the extent of the varicose veins.Our experience of using the AVVQ in the NIHR HTA funded CLASS trial comparing varicose vein treatments suggested that (i) a proportion of patients fail to complete the manikin diagram; (ii) scoring the manikin diagram was time-consuming and (iii) it was not possible to directly capture AVVQ responses from participants electronically (there was a need for a paper questionnaire). We therefore investigated the potential to use the AVVQ without the manikin diagram.Using retrospective data from CLASS, we correlated the AVVQ (scored with and without the manikin diagram) against two clinical measures of disease severity. Individuals with more severe disease had higher AVVQ scores (regardless of whether the manikin diagram component was included or not).In a prospective study of test-retest reliability involving 32 patients with varicose veins, we demonstrated good level of agreement between paired diagrams. In the same study, there was high level of agreement between two independent scorers.Our results suggest that the AVVQ could be used without the manikin diagram, which could result in cost/time savings for trials."}
+{"text": "Myocardial hemorrhage, in association with microvascular obstruction (MVO), has recently been speculated to be a new independent predictor of adverse outcomes following acute myocardial infarction (AMI) ,2. HowevMyocardial hemorrhage was artificially induced in a porcine model via intracoronary injection of collagenase as previously described . The stuGroup 1 demonstrated minimal infarction  with significant hemorrhage as indicated by T2* (Figure Our novel findings demonstrate that hemorrhage is an important component of ischemia-reperfusion injury and may not simply be a bystander but an active contributor to cell damage and inflammation beyond the initial ischemic insult. A mechanistic understanding of the pathophysiology of reperfusion hemorrhage in vivo in the setting of AMI by CMR will potentially aid better management of the high-risk patients who are prone to adverse long-term outcomes.The studies were funded by the Heart and Stroke Foundation of Canada, Grant# 000334."}
+{"text": "Little is known about how best to implement SBIRT services in pediatric health care settings or who, optimally, should provide brief interventions when on-site behavioral health is available. The objective of this presentation is to present results from a cluster randomized trial examining implementation of adolescent SBIRT services for substance use within a US federally qualified healthcare system. Two different implementation models for conducting brief interventions (BIs) were compared using randomization at the clinic level to either: the Generalist Model (BI provided by primary care provider) or the Specialist Model .Multilevel logistic regression modeling was used to examine differences by Condition in rates of successful delivery and documentation of the following services: (a) screening , (b) brief advice , and (c) brief intervention . Due to the organization transitioning to a new electronic medical record (EMR) in month 6 of the study, data on BA and BI are currently limited to extractions from the new EMR.Multilevel logistic regression analyses taking into account the cluster-randomized design showed no significant differences between Generalist and Specialist conditions in rates of screening , with significant volatility over time (<.001) and variation by sites. In the post-EMR transition, Generalist sites were not significantly more likely to deliver appropriate BA  or BI  than Specialist sites. Site-level intraclass correlations were higher than anticipated. Future analyses will examine practices for the full implementation period and subsequent to the removal of implementation support resources.Both service delivery models showed promise for delivering BIs but the high rates of variability within sites demonstrate a need for further examination."}
+{"text": "The present work aims to reproduce certain changes observed experimentally in the EEG power spectrum over the frontal head region during general anesthesia induced by propofol. These observations include increased delta (0-4 Hz) and alpha 8-12 Hz) activities [2 Hz actiThis shows that neglecting inhibitory action in the cortex but considering thalamic GABAergic action suffices to reproduce the data. From a modeling point of view, our reduced mathematical model is low dimensional and remains analytically treatable while still being adequate to reproduce observed changes in EEG rhythms. Moreover, it is shown that the propofol concentration acts as a control parameter of the system and that propofol-induced changes in the stationary states of the model system lead to changes in the corresponding nonlinear gain function that result in EEG power modulation: increases of power over the frontal region can be caused by an increase in the gain function of thalamocortical network. The results suggest that intra-thalamic inhibition from reticular neurons to relay cells plays an important role in the generation of the characteristic EEG patterns seen during general anesthesia."}
+{"text": "Recent genetic and functional studies have revealed striking similarities in the protein networks and molecular mechanisms altered in cancer and Parkinson's disease, as illustrated here for the converging signaling pathways of parkin and Ret . These sin vitro during transfection of human T-cell lymphoma DNA in 3T3 fibroblasts [The proto-oncogene RET encodes a receptor tyrosine kinase that is the canonical glial cell line-derived neurotrophic factor (GDNF) family receptor. The name stands for \u201crearranged during transfection\u201d since Ret was found to be fused to a putative zinc finger protein rfp roblasts . In the roblasts . Thus faroblasts , 5. To droblasts .Parkin is encoded by the PARK2 gene and was originally identified as a gene mutated in some familial forms of PD. In the meantime, PARK2 mutations have also been found in sporadic forms of PD and account for most autosomal-recessive PD cases . Parkin To investigate a potential crosstalk of parkin and Ret we generate two mouse models and analyzed their phenotype. The first mouse model was parkin and Ret double-deficient mice which showed an accelerated dopaminergic cell loss specifically in the substantia nigra and dopaminergic fiber loss in the striatum compared to no alterations in parkin- and a moderate degeneration in Ret-deficient mice . The douin vivo survival function of parkin in close crosstalk with the Ret signaling cascade, converging on mitochondrial integrity control to properly maintain substantia nigra dopaminergic neurons and their innervation in the striatum. This also puts the Ret receptor in an important position in the protein network altered in PD patients.To address the molecular mechanisms of this genetic crosstalk between parkin and Ret, we went ahead and focused on analyzing the effect on mitochondria in more detail . We founincreasing parkin and Ret downstream signaling might be beneficial for PD and Hirschsprung disease patients and cancer patients with a parkin loss of function mutation, decreasing Ret signaling should be the strategy for cancer patients with enhanced Ret signaling. Perhaps parkin loss prevents the Ret MEN2 phenotype in mice and man. Further experiments are needed to shed more light on the molecular mechanism of parkin and Ret crosstalk also in the context of cancer.The identification of mitochondria, the power plants for energy production in all cells including cancer cells, as a common target of parkin and Ret signaling suggests that this crosstalk might not only be important in dopaminergic neurons, but perhaps also in cancer cells. While"}
+{"text": "A majority of patients who undergo hip replacement surgery report good clinical outcomes at 1\u00a0year followup. This is reflected in high-mean utility scores (EQ-5D index), high-mean VAS scores of self-reported health state (EQ-VAS), patient satisfaction scores with the outcomes of surgery (VAS Satisfaction), and low-mean VAS scores of pain (VAS Pain) . HoweverThe current study by Greene and colleagues combines the detail of a multicenter cohort study nested within the solid framework provided by a national joint registry and serves as an example for future PROM studies . Greene Because therapeutic options for patients with poor outcomes after total hip replacement are limited, it is important to try to identify those patients at highest risk for complications or dissatisfaction before they undergo the procedure. Low-risk patients could undergo hip replacement immediately and, ideally, high-risk patients would undergo perioperative optimization in order to lower the risk of a poor outcome. The perfect prediction model would allow for an accurate prediction of the risk of a poor outcome, based on a number of readily available predictors, and it would explain close to 100% of the variance of the PROM score. Unfortunately, no such model exists now.2-values probably underestimate the true explained PROM score variance because the PROM scores are not normally distributed but left-skewed. However, it is clear that there is much room for improvement in all four studied PROMs, and in the predictive models that we can derive from them.Greene and colleagues have shown that roughly 10% of the variance in the EQ-5D index and EQ-VAS scores can be explained by the Charnley classification and the preoperative PROM score . Three pMuch of the PROM score variance described in the study by Greene and colleagues is currently unexplained. The added value of new predictors should be studied in conjunction with all currently known predictors. Candidate predictors include the preoperative radiographic severity of osteoarthritis, which appears relevant in some PROM dimensions . The rolFuture studies should not only focus on discovering unknown predictors, but should also try to replicate findings of previous studies, thereby minimizing the risk of publication bias. Both discovery and replication studies need consecutive cohorts of hip replacement patients. Future studies should also use the probability of a clinically important difference or patient acceptable symptom state as a primary outcome measure, as these probabilities are more relevant for individual patients we encounter in clinical practice who either do or do not achieve an acceptable state or relevant improvement . Recentl"}
+{"text": "Streptococcus pneumoniae (the pneumococcus) is a common colonizer of the human nasopharynx. Despite a low rate of invasive disease, the high prevalence of colonization results in millions of infections and over one million deaths per year, mostly in individuals under the age of 5 and the elderly. Colonizing pneumococci form well-organized biofilm communities in the nasopharyngeal environment, but the specific role of biofilms and their interaction with the host during colonization and disease is not yet clear. Pneumococci in biofilms are highly resistant to antimicrobial agents and this phenotype can be recapitulated when pneumococci are grown on respiratory epithelial cells under conditions found in the nasopharyngeal environment. Pneumococcal biofilms display lower levels of virulence in vivo and provide an optimal environment for increased genetic exchange both in vitro and in vivo, with increased natural transformation seen during co-colonization with multiple strains. Biofilms have also been detected on mucosal surfaces during pneumonia and middle ear infection, although the role of these biofilms in the disease process is debated. Recent studies have shown that changes in the nasopharyngeal environment caused by concomitant virus infection, changes in the microflora, inflammation, or other host assaults trigger active release of pneumococci from biofilms. These dispersed bacteria have distinct phenotypic properties and transcriptional profiles different from both biofilm and broth-grown, planktonic bacteria, resulting in a significantly increased virulence in vivo. In this review we discuss the properties of pneumococcal biofilms, the role of biofilm formation during pneumococcal colonization, including their propensity for increased ability to exchange genetic material, as well as mechanisms involved in transition from asymptomatic biofilm colonization to dissemination and disease of otherwise sterile sites. Greater understanding of pneumococcal biofilm formation and dispersion will elucidate novel avenues to interfere with the spread of antibiotic resistance and vaccine escape, as well as novel strategies to target the mechanisms involved in induction of pneumococcal disease. Streptococcus pneumoniae colonizes the upper respiratory tract in humans. Colonization occurs on the mucosal surface of the nasopharynx during childhood and persists asymptomatically in healthy individuals into adulthood , the majority of work with pneumococcal biofilms has relied on in vitro model systems in which host-specific factors have not been included or examined. The nasopharyngeal environment contains a mucosal surface of respiratory epithelium and their secretions. This environment provides challenges to the bacterial organisms with low nutrient availability and also a lower temperature than the remaining body (approximately 32\u201334\u00b0C rather than 37\u00b0C)  and D39-C08P2 (a laboratory strain with an erythromycin cassette inserted downstream of the dihydrolipoamide dehydrogenase gene), natural transformation only occurred in bacteria colonizing the nasopharynx  whereas the natural transformation efficiency during sepsis was very low and similar to what has been presented in the literature (efficiency of 3 \u00d7 10\u22129)  without exogenous addition of CSP or antibiotic pressure  repaired genetically and functionally. These studies supported that natural transformation during co-colonization can improve fitness by expanding the gene pool available for adaptation to the host environment  to investigate whether the in vitro revealed that poor biofilm formers showed an increased biomass in the presence of good biofilm-forming strains. This increased fitness was not directly associated with acquisition of genetic factors as strains had the same colonization efficiency before and after co-colonization experiments. This fitness increase was also observed in co-colonization experiments with unencapsulated and encapsulated strains. In addition to providing an optimal environment for genetic exchange, co-colonization may also provide a haven for poorly colonizing strains when an effectively colonizing strain is also present. These data are supported by epidemiological studies showing the detection of rare serotypes or non-typeable pneumococci significantly more often in individuals colonized with multiple strains than with single strains  have been limited by short coexistence times between the bacteria and epithelial cells  in the nasopharyngeal secretions constitutes well described \u201cdanger signals\u201d potentially recognized by bacterial cells  resulted in dispersion of EF3030 and D39 from the nasopharynx and caused dissemination of pneumococci into the lungs or middle ear. These data show that host-derived inter-kingdom signals alone or in conjunction with IAV infection cause active dispersal of bacteria from the biofilm, which can subsequently disseminate to normally sterile sites and cause symptomatic infection , ply (pneumolysin), pavA (adhesin), and licD2 (opaque phenotype), were down-regulated during biofilm growth, consistent with previous reports  in dispersed populations compared to biofilm-grown bacteria. In addition, biofilm bacteria had a lower baseline ATP level, suggesting low metabolic activity. Genes regulating carbohydrate metabolism have been associated with tissue-specific disease . In addition, our model could also be used to study a wider range of pneumococcal strains, such as clinical isolates that are not currently virulent in mouse models.IAV-induced responses triggered the dispersion of a distinct population of pneumococci, suggesting that pneumococci recognize inter-kingdom signals. This model of pathogenesis with co-infection of IAV and pneumococci may be adapted to model co-infection and the transition to disease for other upper respiratory tract commensals that also experience increased virulence after IAV infection (e.g., Future studies capitalizing on the RNA-seq data should focus on the role of carbohydrate metabolism, bacteriocin receptors, and other genes encoding surface proteins upregulated during invasive disease as these may represent novel targets for developing therapeutics. The transcriptional differences found between the pneumococcal populations explain the differences in virulence, however, future goals will involve understanding the mechanism involved in the induction of disease.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Our results provide experimentally testable hypotheses to explain several experimental observations and theoretical support to the hypothesis of a functional role for the gap junction couplings in astrocyte networks. In particular, dynamic control of the topology of gap-junction couplings by neuronal activity suggests a novel type of neuron-glia communication.In recent years, astrocytes, one of the main types of glial cells, have been suggested to be active players in neuronal communication. While previously considered to form syncytia with little or no spatial organization, emerging experimental evidence suggests that astrocytes could actually organize into real networks coupled by gap junction channels, with complex topologies that may depend on the brain region. Intercellular calcium waves (ICW) are considered the main pathway for cell-to-cell signaling in these networks. However, it is still not understood why the extent of these ICW depends on the brain region or the experimental protocol considered. To investigate the hypothesis that this variability could actually be linked to the heterogeneous properties of astrocyte networks we studied ICW propagation in biophysically realistic models of three-dimensional astrocyte networks Figure  keeping"}
+{"text": "Corneal blindness caused by limbal stem cell deficiency (LSCD) is a prevailing disorder worldwide. Clinical outcomes for LSCD therapy using amniotic membrane (AM) are unpredictable. Hydrogels can eliminate limitations of standard therapy for LSCD, because they present all the advantages of AM  but unlike AM, they are structurally uniform and can be easily manipulated to alter mechanical and physical properties. Hydrogels can be delivered with minimum trauma to the ocular surface and do not require extensive serological screening before clinical application. The hydrogel structure is also amenable to modifications which direct stem cell fate. In this focussed review we highlight hydrogels as biomaterial substrates which may replace and/or complement AM in the treatment of LSCD. Damage to the outer limbal region of the cornea due to chemical  and mechanical (e.g. extended contact lens wear) injuries, congenital disorders (e.g. Stevens Johnson syndrome) or bacterial and viral infections, causes destruction and depletion of resident adult stem cells et al. A diverse range of clinical methodologies, presenting inherent benefits and limitations, are currently available for treating LSCD The basis for LSCD therapy is the transplantation of progenitor limbal epithelial cells (LEC) into the damaged cornea. The foundations of modern treatment approaches for LSCD were laid when a surgical procedure using autologous conjunctival limbal autografts for contralateral cases of this condition was described Therapy for LSCD progressed with the use of amniotic membrane (AM). AM alone was demonstrated as sufficient to treat partial  LSCD ex vivo expansion of LEC, a technique that eliminates the need for removing the limbus from a healthy eye The main clinical benefits of AM include the ability to promote epithelialisation Key problems encountered with LSCD therapy that limit therapeutic outcomes include: (i) variations in treatment outcomes due to structural heterogeneity of AM scaffolds and differences in the severity of LSCD, (ii) a poor understanding of mechanisms underlying corneal repair mediated during LSCD therapy, (iii) limited supplies of donor tissue which is essential in cases of bilateral total LSCD and (iv) inadequate means for eliminating long-term immunosuppression that is necessary following transplantation of allogeneic sources of LEC.Solutions proposed for these challenges include: (i) the use of alternative cell types, corneal prostheses and cell storage strategies to alleviate problems with limbal tissue availability, (ii) the use of structurally uniform biomaterials for the delivery of LEC to the damaged ocular surface to eliminate variations in LSCD treatment and (iii) the use of biomaterials with well-characterised and easily modified structures to understand mechanisms by which LEC reverse the symptoms of LSCD.The main uses for biomaterials applied to reconstruction of damaged corneal epithelium include hydrogels for LEC delivery Structural modification of biomaterials to enhance LEC adhesion The integration of a range of compatible biomaterials with complementary functions for the construction of artificial systems may lead to the development of sophisticated medical devices with the potential to considerably enhance the efficacy and predictability of LSCD therapy. Those systems may be designed specifically to treat the differing extents of LSCD, with combined delivery of drug and cell therapies. Hydrogels, in particular, present key properties which indicate their suitability for the culture and/or delivery of LEC .Hydrogels for the design of corneal prosthetics are also becoming increasingly popular. Collagen In this article we highlight several well-established and emerging hydrogel systems and discuss their suitability for treating LSCD.Hydrogels are multi-component systems consisting of a 3D network of polymer chains and water Fibrin gels are prepared by the combination of fibrinogen and thrombin, or from autologous serum et al. Previous reports demonstrated that the majority of individuals within a group presenting LSCD regained their vision following treatment with fibrin-cultured LEC, and this outcome was sustained over long-term periods ex vivo) of LEC; subcultivation of limbal holoclones preserved stem and progenitor cells in the basal layer of fibrin-based epithelial sheets Subsequent studies demonstrated that fibrin gels were capable of supporting the stem and/or progenitor phenotype of LEC in vitro conditions demonstrated that MSCs co-cultured with LEC or LEC conditioned medium, rapidly differentiated into cells that were phenotypically and morphologically similar to corneal epithelial cells Interestingly, another progenitor cell type, mesenchymal stem cells (MSCs), encapsulated in fibrin gels induced reconstruction of the damaged corneal surface, and these cells expressed the corneal epithelial cell specific marker, cytokeratin 3 (CK3) when they were transplanted in vitro systems. The requirement for effective logistics to deliver LSCD therapy together with the practicality of fibrin-cultured LEC, suggest that this hydrogel can form part of cell preservation and transportation technologies for wide ranging applications in corneal reconstruction therapies.Therefore, fibrin hydrogels are clearly capable of maintaining the phenotype and directing the fate of stem cells, indicating that they may be exploited to understand the fundamental biology of LSC differentiation and self-renewal. The positioning of limbal holoclones on fibrin-cultured epithelial cells Collagen is the most abundant structural protein in the cornea, and is biocompatible, biodegradable, possesses low immunogenicity and can maintain LEC adhesion, proliferation and differentiation in vitroin vivo in a rabbit corneal injury model Magnetically oriented collagen fibre scaffolds were recently applied to the regeneration of human hemi corneas By contrast, conventional collagen hydrogels are plastically compressed or chemically cross-linked to enhance mechanical strength before their use in the formation of stratified LEC 1-Ethyl-3-(3-dimethyl aminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS) cross-linked recombinant human collagen-based artificial corneas are one of the first examples of these constructs tested on humans. In a Phase I clinical trial, this biosynthetic scaffold was transplanted to the damaged cornea of ten patients with vision loss Simultaneous use of collagen hydrogels as corneal tissue replacements and as delivery systems for LEC may lead to the development of KPro capable of treating LSCD.Silicone hydrogels comprise lotrafilcon A, balafilcon A, senofilcon A and comfilcon A, and are mainly used to produce second generation, soft contact lenses for the correction of refractive errors and as ocular bandages which aid re-epithelialisation of the cornea +/CK12+/CK19+) and expressed p63 Recent reports suggest that in addition to application as a visual aid and an ocular bandage, silicone hydrogels may be applied to LSCD therapy Despite the therapeutic benefits of silicone lenses for PED and LSCD, further research is needed to improve the biocompatibility of this biomaterial. The high modulus  of these lenses causes mechanical interaction with ocular tissue which lead to papillary conjunctivitis and disruption of the tear film structure d-mannuronic acid and \u03b1-l-guluronic acid, which when cross-linked by multi-valent cations  form into gels Alginates are polysaccharides found in brown algae and bacteria, consisting of unbranched binary co-polymers of 1\u20134 linked \u03b2-The use of alginate hydrogels for ocular therapy is relatively novel. Only a small number of studies have been performed to examine the manner that alginate may be applied for ocular reconstruction. Alginate microspheres incorporated into collagen hydrogels were previously demonstrated as a viable composite construct for controlled drug delivery as well as human corneal epithelial cell growth These preliminary studies have highlighted the potential of alginate gels as culture systems for LEC. Because the structure of alginate gels can be modified to direct cell phenotype, particularly stem cell differentiation The mucoadhesive polysaccharide, chitosan is biocompatible, biodegradable and displays unique haemostatic activity and wound-healing properties that makes it attractive for use in biomedical applications d,l-lactic acid promoted wound healing of alkali-burned corneas in vivo and decreased scar tissue formation Synthetic chitosan membranes supported the viability and growth of corneal epithelial cells in a manner comparable to AM in situ gel-forming material for ocular drug delivery The well-characterised abilities of chitosan for ophthalmic drug delivery may be exploited together with the capacity of this polymer for cultivation of corneal epithelial cells. Chitosan polymers can increase precorneal drug residence times to slow down drug elimination by the lacrymal flow, by increasing solution viscosity and by interacting with the negative charges of the mucus Chitosan hydrogels may therefore be used to create a device which delivers both LEC and ocular drugs that enhance the effects of these cells, thus constituting a novel strategy to treat LSCD.Gelatin is a mixture of peptides and proteins produced by acid and alkaline processing  of collagen extracted from skin, bone and connective tissue +/K+-ATPase, and N-cadherin] The success of gelatin gels for the culture of CEC and stromal cells indicate that LEC may be well-supported by these scaffolds. Gelatin gels were previously shown to provide stable mechanical support for CEC sheets Soluble ocular drug insert matrices comprised of raw gelatin \u00ae, is a manufactured drug carrier for either local or systemic drug delivery through the ophthalmic route. This eye medical device was reported to prolong the activity of the insulin through gradual release aided by the slow and constant tear production from the lachrymal system \u00ae was greater and longer lasting than that produced by eyedrops with an equivalent amount of these drugs \u00ae can be worn with contact lenses, in a hydrated form; this hydrogel as well as other gelatin hydrogels may serve as a growth factor and/or drug-release feeder device to maintain LEC delivered to the ocular surface using silicone lenses.The absorbable gelatin sponge, Gelfoam\u00ae) Hydrogels at the early experimental stage before application as substitutes for AM include hyaluronic acid (HA) d,l-aspartamide (PHEA-EDA) were previously suggested as a suitable material for the release of limbal cells for corneal regeneration HA gels chemically cross-linked with poly(N-2-hydroxyethyl) (2-aminoethylcarbamate)-\u00ae was previously reported as capable of supporting LEC and maintaining the stem phenotype of these cells. Mebiol\u00ae supported limbal explant proliferation and LEC cultured on this gel expressed LSC markers (ATP-binding cassette sub-family G member 2 and p63), transient amplifying cell markers  and cornea differentiation marker (CK3) \u00ae was shown to restore a nearly normal ocular epithelial surface in eyes with unilateral LSCD in rabbit models The thermosensitive, synthetic polymer gel, Mebiolin vitroBy contrast, PHEMA sponges used to construct the porous skirt material in the Chirila KPro require improvements in biocompatibility ex vivo expanded cells) carrier for LSCD with a further reduction in risk, as it is derived from an autologous muscle biopsy.The novel muscle-derived hydrogel, myogel We have already crossed the threshold for major change in LSCD therapy from conventional AM-based methodologies to more versatile and practical methods involving natural and synthetic biomaterial systems.Fibrin and collagen hydrogels have developed beyond the pre-clinical stage, and they are currently proven as viable for the treatment of LSCD and as corneal prosthetics, respectively. Other hydrogels present unique properties including intrinsic anti-scarring capabilities (chitosan), efficient mass transfer abilities  and properties appropriate for tissue engineering , which indicate them as excellent candidates for the treatment of LSCD.The structures of \u2018clean\u2019 hydrogel systems may be manipulated to alter their physical and chemical properties, internal porosity, and surface topography to induce predictable changes in cell behaviour. Therefore, these biomaterials applied to the treatment of LSCD may potentially enable a more in-depth understanding of the mechanisms underlying the reversal of pathological symptoms of this disorder, which may introduce a novel field of ophthalmic medicine.We conclude that given the considerable body of evidence demonstrating the efficacy of hydrogels in reconstruction of the damaged cornea, AM can certainly be replaced or complemented with these biomaterials for the treatment of LSCD.None."}
+{"text": "While treating potentially violent patients in the emergency department (ED), both patients and staff may be subject to unintentional injury. Emergency healthcare providers are at the greatest risk of experiencing physical and verbal assault from patients. Preliminary studies have shown that a team-based approach with targeted staff training has significant positive outcomes in mitigating violence in healthcare settings. Staff attitudes toward patient aggression have also been linked to workplace safety, but current literature suggests that providers experience fear and anxiety while caring for potentially violent patients. The objectives of the study were (1) to develop an interprofessional curriculum focusing on improving teamwork and staff attitudes toward patient violence using simulation-enhanced education for ED staff, and (2) to assess attitudes towards patient aggression both at pre- and post-curriculum implementation stages using a survey-based study design.t-test to assess changes in staff attitudes. We used the validated Management of Aggression and Violence Attitude Scale (MAVAS) consisting of 30 Likert-scale questions grouped into four themed constructs.Formal roles and responsibilities for each member of the care team, including positioning during restraint placement, were predefined in conjunction with ED leadership. Emergency medicine residents, nurses and hospital police officers were assigned to interprofessional teams. The curriculum started with an introductory lecture discussing de-escalation techniques and restraint placement as well as core tenets of interprofessional collaboration. Next, we conducted two simulation scenarios using standardized participants (SPs) and structured debriefing. The study consisted of a survey-based design comparing pre- and post-intervention responses via a paired Student One hundred sixty-two ED staff members completed the course with >95% staff participation, generating a total of 106 paired surveys. Constructs for internal/biomedical factors, external/staff factors and situational/interactional perspectives on patient aggression significantly improved . Staff attitudes toward management of patient aggression did not significantly change (p=0.542). Multiple quality improvement initiatives were successfully implemented, including the creation of an interprofessional crisis management alert and response protocol. Staff members described appreciation for our simulation-based curriculum and welcomed the interaction with SPs during their training.A structured simulation-enhanced interprofessional intervention was successful in improving multiple facets of ED staff attitudes toward behavioral emergency care. Patients with behavioral emergencies often present to the emergency department (ED) in acute agitation.9Recent surveys of healthcare workers have identified a need for early communication of clear roles and responsibilities of hospital security and ED staff to improve safety during WPV events.20Our study used a multi-modality, team-based approach to create a novel simulation-enhanced patient safety curriculum targeting staff attitudes toward patient aggression and interprofessional collaboration during the management of patients with behavioral emergencies in the ED. We assessed the potential success of the program through direct analysis of staff attitudes towards management of aggression with a validated survey instrument. Our hope was that this intervention would allow for a coordinated team approach that would improve safety for both patients and staff members.t-test for our survey data analysis using IBM SPSS 21.0 software, and our study was approved by NYU School of Medicine\u2019s Institutional Review Board as expedited review under the title, \u201cSimulation-based Team Training for Care of Acutely Agitated Patients in the Emergency Department (i14-00846)\u201d in May 2014.We examined changes to staff attitudes as a result of this intervention via the Management of Aggression and Violence Attitude Scale (MAVAS), a published survey from a British nursing education group that has shown reliability and internal validity for assessment of staff attitudes toward patient aggression.Describe and demonstrate effective interprofessional teamwork and communication skills to treat the patient with a behavioral emergency in the ED.Identify roles and responsibilities of members of an interprofessional team that care for acutely agitated patients.Display effective violence mitigation and de-escalation techniques.Appropriately apply physical restraints and medical interventions during treatment of the agitated patient in the ED.Demonstrate improvement in attitudes toward patients with behavioral emergencies through a better understanding of factors contributing to patient aggression.As the care of the agitated patient requires balancing a complex range of clinical, communication and teamwork skills, we felt that applying David Kolb\u2019s experiential learning theory as our educational framework would best suit our needs.Our educational team derived a 30-minute introductory interactive lecture from core elements of validated aggression management courses. Key components of the didactics including crisis management principles, de-escalation techniques, and proper application of restraints were summarized in a pre-session handout that was distributed to our learners prior to beginning of the session. Moreover, ED leadership constructed formal roles and responsibilities prior to the didactic session. These roles were described in detail in the pre-session handout and re-enforced with staff during the didactic session (see We recruited healthcare professionals to act as SPs and trained them in conjunction with our content experts to simulate two agitated patient scenarios typically encountered by ED staff members. The course participants were expected to use the de-escalation techniques in an interprofessional manner discussed during the didactic session to calm the simulated agitated patients. The simulations were designed so that de-escalation techniques would only be partially successful, and the team would then need to apply physical restraints and medical therapy to complete the scenarios. A code phrase, \u201cmickey mouse,\u201d was designated as a \u201ctime out\u201d should participants or SPs feel that they were in physical danger or out of their comfort zone during the scenarios, while the educator team closely monitored each simulation encounter from the control room. At the completion of each immersive simulation, the interprofessional group of participants immediately proceeded to a structured debriefing session led by health professions educators specifically trained in educational theory and debriefing concepts. We ensured that the main discussion points focused on participant attitudes towards factors contributing to patient aggression as well as interprofessional collaboration and communication skills demonstrated during the encounters.The first scenario involved a patient who was brought to the ED by paramedics for evaluation of altered mental status and minor head trauma. The patient appeared to be intoxicated with alcohol and became angry and threatening during the triage process. The participants were required to use the de-escalation techniques demonstrated during the didactic session, recognize that the patient had head trauma as evidenced by a scalp laceration, order a head computed tomography and diagnose a subdural hematoma that was due to an acute fall from a standing position. Discussions focused on workflow and restraint placement as a large consumption of manpower and resources, especially on weekend overnight shifts when many intoxicated patients presented simultaneously in the ED.The second scenario featured a physically and verbally aggressive patient with underlying psychiatric illness who initially responded to de-escalation by staff. However, he quickly became more aggressive and dangerous despite participants\u2019 attempts. He was later found to have ingested phencyclidine, requiring medical therapy and safe restraint placement. Facilitators often needed to intervene during this second simulation to halt the scenario and correct participant errors, using a strategy similar to \u201crapid cycle deliberate practice\u201d training.Engaging and securing administrative support was key to the successful implementation of our intervention. To minimize disruption of clinical care, sessions were incorporated within already established training time periods for nurses and resident physicians. For nursing, we incorporated this course into their annual competency training. Simulation didactics for the residents were scheduled on a weekly basis in the simulation center and 10 of those sessions were used for this course.In total, we conducted 10 three-hour sessions from July to September 2014. One hundred sixty-two ED staff members completed the course with >95% staff participation, generating a total of 106 paired pre-post surveys. See the The results of the MAVAS survey reflected our staff participants\u2019 immediate changes in attitudes toward patient aggression factors as a result of our course except in the construct of clinical management of aggression. As our curriculum objectives focused heavily on prevention and recognizing factors contributing to aggression rather than the specific medical management of aggression, the survey accurately reflected our intended interventions. In fact, we wished to deliberately not discuss details of clinical decision-making while caring for our targeted population for the purposes of this course. Our agitated ED patients present with a breadth of medical and psychiatric etiologies, and management depends heavily upon the unique circumstances and ultimate diagnoses of a particular patient encounter.Staff participants overwhelmingly endorsed and welcomed the SPs in the hands-on components of the course and frequently commented on how having SPs in the simulations significantly increased fidelity and helped recreate a realistic scenario for them. Many in fact forgot that they were participating in a simulation altogether and experienced the same fear, anxiety and frustrations that they felt while caring for an agitated patient in a prior clinical shift. Although none of the SPs or learners used the \u201ctime out\u201d even once or suffered any injuries during the course, we paid close attention to the play of the scenarios in the control room to observe for latent safety lapses. As mentioned above, educators entered the simulation room on multiple occasions to pause the scenario and intervene in the second case with the acutely aggressive patient.This course was time and resource intensive for the instructors. Even with an average of 15\u201320 learners per session, we required 10 sessions to completely train our department. Each session required at least nine to ten instructors and assistants to run the simulations and lead the interprofessional debriefing sessions. We found that having a core team of nursing, physician and police educators, at least one of whom was trained in immersive simulation and debriefing structure and techniques, was critical to ensuring continuity and consistency between sessions. Our program benefited from the availability of a robust simulation center at our institution. We believe that other educators and administrators interested in implementing this curriculum can still successfully conduct the simulations and debriefing sessions in small meeting rooms or other office spaces within a hospital or learning environment. With regards to program evaluation, the cohort of educators and researchers for our pilot study were also in leadership positions within the department, which may have confounded our participants\u2019 responses to the MAVAS survey.Additional work includes longitudinal data collection of staff attitudes over longer time periods, comparison of different methods of training and curriculum design, as well as a higher level of evaluation in the definitions of translational educational research to include patient outcomes or direct indices of care safety and quality.In order to promote sustainability, stricter implementation of the defined roles and quality improvement initiatives need to occur on a consistent basis with buy-in from administration and staff members across all professions. A qualitative analysis of ongoing barriers and staff concerns to sustaining these efforts and caring for our agitated patient population may bring more key issues to light. Finally, the curriculum can be re-enforced with repeat sessions at scheduled intervals with shorter didactics or targeted to new staff hires and incoming physician trainees.An interprofessional simulation-based team-training curriculum successfully improved staff attitudes toward the factors impacting the care of patients with behavioral emergencies in the ED. We hope the next steps in interprofessional education research will lead us toward sustainable and outcomes-based measures to improve patient and staff safety utilizing team effectiveness in caring for the potentially aggressive patient."}
+{"text": "The inputs from the two eyes interact in a nonlinear fashion. This interaction can be either excitatory or inhibitory: Excitatory interaction (combination) occurs first in the primary visual cortex but little is known about the site of the inhibitory interaction (suppression). To investigate the latter, experimental paradigms typically present distinct inputs to the eyes . Here we used magnetoencephalography (MEG) source imaging to establish the site of the cortical neural signature of interocular suppression in visual cortex.We presented different noise stimuli to each eye: The target-noise was presented for contrasts ranging between 0 and 32 %. The mask-contrast was presented to the other eye at fixed contrast (32%). We flickered the two noise stimuli (4 and 6 Hz) to elicit a frequency-tagged steady-state visual evoked response (SSVER) that was readily detectable in MEG traces . Four paUsing the power of the cortical responses to the frequency-tagged stimuli, we constructed contrast response functions for all the ROIs Figure . To inveWe characterized dichoptic suppression in the visual cortex with MEG. This suppression occurs as early as the primary visual cortex. The suppression between the inputs of varying contrast was also well defined in the MEG power signal. The temporal resolution of MEG cortical imaging enables the analysis of the phase shifts and delay of the steady-state visual-evoked response between cortical regions. When combined with individual visual cortical mapping, our method provides a temporally and spatially precise tool for the detailed elucidation of suppression in the visual processing induced by dichoptic masking."}
+{"text": "Cerebral microhemorrhages (MH) are diminutive focal bleedings which can be detected best by MRI using susceptibility-weighted imaging sequences (SWI). They can be found in a variety of neurologic diseases. The pattern of distribution can lead to the underlying pathomechanism . SurvivoRetrospectively, we examined 20 patients with cerebral MRI (including SWI) who had suffered from severe ARDS and received ECMO therapy. The MRI slides were anonymized and analyzed by two experienced neuroradiologists. Based on the distribution pattern and characteristic, a modified HACE score (mHCS) was surveyed [Six of 20 patients (30%) showed multiple MH with emphasis in the splenium of the corpus callosum. Eight patients had sporadic MH in the parenchyma of the brain but not in the corpus callosum. The remaining six patients had no intracerebral alterations. The distribution of MH with involvement of the splenium resembled that seen in HACE survivors.Based on these results, we postulate that hypoxemia is one of the main players in the development of splenium-associated MH, not only in HACE but also in severe ARDS and other diseases accompanied with severe hypoxemia. Further investigations have to examine potential triggers and special circumstances concerning ARDS treatment which lead to MH in this distinctive pattern."}
+{"text": "Seabirds and other land-breeding marine predators are considered to be useful and practical indicators of the state of marine ecosystems because of their dependence on marine prey and the accessibility of their populations at breeding colonies. Historical counts of breeding populations of these higher-order marine predators are one of few data sources available for inferring past change in marine ecosystems. However, historical abundance estimates derived from these population counts may be subject to unrecognised bias and uncertainty because of variable attendance of birds at breeding colonies and variable timing of past population surveys. We retrospectively accounted for detection bias in historical abundance estimates of the colonial, land-breeding Ad\u00e9lie penguin through an analysis of 222 historical abundance estimates from 81 breeding sites in east Antarctica. The published abundance estimates were de-constructed to retrieve the raw count data and then re-constructed by applying contemporary adjustment factors obtained from remotely operating time-lapse cameras. The re-construction process incorporated spatial and temporal variation in phenology and attendance by using data from cameras deployed at multiple sites over multiple years and propagating this uncertainty through to the final revised abundance estimates. Our re-constructed abundance estimates were consistently higher and more uncertain than published estimates. The re-constructed estimates alter the conclusions reached for some sites in east Antarctica in recent assessments of long-term Ad\u00e9lie penguin population change. Our approach is applicable to abundance data for a wide range of colonial, land-breeding marine species including other penguin species, flying seabirds and marine mammals. Ecologists are increasingly turning to historical abundance data to understand past changes in animal abundance and more broadly the ecosystems in which animals occur. If assessed correctly, historical abundance data can provide insights into the rates and causes of past population change and make important contributions to ecological and management studies . In pracThere is now widespread recognition that counts of animal populations are often subject to detection bias, and that the extent of bias may vary over time and space due to aspects of a species\u2019 biology, the type of counting methods used, and the environmental conditions under which a population survey is undertaken ,4. This There are two forms of detection bias associated with animal abundance counts: (1) perception bias, where animals are missed even though they are within an observers\u2019 view, and (2) availability bias, where animals are missed because they are outside the observers\u2019 view and hence not available for detection . AvailabIn the Southern Ocean, penguins have been subject to the most temporally and spatially intense population survey effort  and havePygoscelis adeliae) count data from east Antarctica where (1) few data on phenology or attendance were available prior to our study, (2) many population counts are of adults as well as nests and chicks, and (3) there has been no re-assessment of historical population data. Our re-constructed abundance estimates, which take account of biases and uncertainties, alter the some of the conclusions about long term population change in a recent global assessment of this species that compared historical published estimates with recent satellite-derived estimates )In addition to providing a large body of new data on daily changes in colony attendance, the time-lapse cameras also have the potential to provide data on diel changes in attendance. This can be done by re-programming the cameras to take multiple photographs each day. Any consistent and significant within-day variation in colony attendance could affect abundance estimation. While it would not be possible to adjust historical counts for time of day effects because no time data were collected in the past, the uncertainty could be accounted for by incorporating this variation into the adjustment curves.-1 respectively over the past 50 years [In colonial-breeding species, availability bias is time-dependent and strongly related to breeding phenology. In this situation, using contemporary availability data to adjust counts obtained decades ago could result in biased abundance estimates if phenology has changed substantially over the intervening period. In the northern hemisphere, analyses of long-term phenology data have revealed significant advances in the timing of spring breeding events such as arrival of many migrant bird species . In east50 years , and the50 years . NeverthThe approach taken in this study for Ad\u00e9lie penguins could be applied more broadly to a wide range of colonial, land-breeding marine species including other penguins, flying seabirds and marine mammals. The common life history characteristics of these species\u2019 groups that makes these methods appropriate and amenable are (1) their tendency to form large, dense breeding aggregations, making large numbers of animals visible to observations from a fixed point, (2) their variable attendance at colonies within the breeding season, leading to the potential for population counts to be biased because of varying availability of animals to detection in population surveys at colonies, and (3) the remoteness of many breeding colonies and the difficulty that researchers may have in accessing the colonies for population counts at an optimal time. Re-assessing historical data for these species\u2019 groups using the methods described here would help to ensure that reliable inferences are made about the nature, form and cause of past changes in marine populations and ecosystems.S1 File(DOC)Click here for additional data file.S2 File(DOC)Click here for additional data file."}
+{"text": "Reason for Erratum:Aba Elements were reported incorrectly as \u201cis Aba.\u201d The correct title is: Genotypic and Antimicrobial Susceptibility of Carbapenem-Resistant Acinetobacter baumannii: Analysis of ISAba Elements and blaOXA-23-like Genes Including a New Variant.Due to a typesetting error in the title, the ISThe publisher apologizes for this error and the original article has been updated. This error does not change the scientific conclusions of the article in any way."}
+{"text": "To the Editor+ T cells tumor infiltration boosted by the anti-angiogenic drug [Zaniboni and Formica recently published a review article considering preclinical and clinical data in the current context of optimal therapeutic sequences in metastatic colorectal cancer . Their cnic drug .Taken all together, these different features must lead us to reconsider anti-VEGF and anti-EGFR combinations, focusing not only on the association but also on the prospect of perspective for combinations with immunomodulatory agents like checkpoint inhibitors."}
+{"text": "Previous studies on telemedicine have either focused on its role in the management of chronic diseases in general or examined its effectiveness in comparison to standard post-discharge care. Little has been done to determine the comparative impact of different telemedicine options for a specific population such as individuals with heart failure (HF).Systematic reviews (SR) of randomized controlled trials (RCTs) that examined telephone support, telemonitoring, video monitoring or electrocardiographic monitoring for HF patients were identified using a comprehensive search of the following databases: MEDLINE, EMBASE, CINAHL and The Cochrane Library. Studies were included if they reported the primary outcome of mortality or any of the following secondary outcomes: all-cause hospitalization and heart failure hospitalization. Thirty RCTs  were included. Compared to usual care, structured telephone support was found to reduce the odds of mortality and hospitalizations due to heart failure . Telemonitoring was also found to reduce the odds of mortality and reduce hospitalizations related to heart failure  compared to usual post-discharge care. Interventions that involved ECG monitoring also reduced the odds of hospitalization due to heart failure .Much of the evidence currently available has focused on the comparing either telephone support or telemonitoring with usual care. This has therefore limited our current understanding of how some of the less common forms of telemedicine compare to one another.Compared to usual care, structured telephone support and telemonitoring significantly reduced the odds of deaths and hospitalization due to heart failure. Despite being the most widely studied forms of telemedicine, little has been done to directly compare these two interventions against one another. Further research into their comparative cost-effectiveness is also warranted. Heart Failure (HF) is a complex debilitating syndrome that results from a cardiac dysfunction that impairs the ability of the ventricle to fill with or eject blood. Living with this disease, individuals with HF experience a substantially high rate of deaths and further cardiac illness. This has led many of those who care for HF patients to believe that they may benefit from more frequent monitoring and follow-up than would otherwise be possible under the current standard of care. This has, in turn, led to the introduction of telemedicine as a potential means for reducing the likelihood of worsening cardiac illness or the prospect of repeated and lengthy hospital readmissions.Earlier research comparing usual care to a variety of telemedicine interventions demonstrated that the use of telemedicine significantly reduced all-cause mortality and hospital admissions related to heart failure\u20134. It waDespite these potential benefits, the evidence has been somewhat limited in that studies generally focused on the impact of very broadly defined multifaceted telemedicine interventions as they compared to usual care only rather than on how these inherently different technologies compared to one another. This inconsistency may in part be due to the fact that the definition of telemedicine has varied substantially in their intensity, invasiveness and complexity across studies. Earlier findings regarding the impact of telemedicine for the management of HF have also been relatively inconsistent with more recent ones.In 2013, a systematic review and network meta-analysis found no significant reductions in all-cause mortality or all-cause hospital readmissions associated with interventions of remote monitoring when compared to usual care for recently discharged patients with heart failure. This reAn overview of reviews and network meta-analysis of the literature were conducted to quantify, summarize and compare the rates of death, hospitalization and hospitalization due to heart failure for individuals with chronic heart failure who received standard care after discharge or other forms of telemedicine. Network meta-analysis, also known as mixed-treatment comparisons meta-analysis or multiple-treatments meta-analysis would allow the integration of data from direct  and indirect comparisons  \u20139. SimulUnlike previous reviews, this analysis will not only examine the potential impact of telemedicine against usual care, it will also examine the comparative effectiveness of these different interventions against one another. Interventions compared included usual care and the following five forms of telemedicine: Structured telephone support (STS) which involves regular follow-up calls between the health professional and the patient; Telemonitoring systems which involve the transmission of information on symptoms and signs (TM); Telemonitoring systems and regular telephone follow-up combined; Telemedicine systems involving video monitoring (VIDEO); and Telemedicine systems involving electrocardiographic transmissions (ECG).Relevant systematic reviews of randomized controlled trials were identified by searching the following databases until December 2012: The Cochrane Library, Medline, Embase and CINAHL. The search strategies are described in Prospective enrolment of consecutive patients with objectively confirmed coronary artery disease with symptomatic heart failure (New York Heart Association [NYHA] Class I-IV) characterized by impaired left ventricular function (Left Ventricular Ejection Fraction \u2264 45%).Patients randomized to receive telemedicine  or usual care. The aforementioned telemedicine strategies are briefly described in Table A in One or more of the primary outcome or secondary outcomes were reported. The primary outcome measure was all-cause mortality. Secondary outcome measures included all-cause hospitalization  or hospitalization due to heart failure .Study selection was conducted by two independent reviewers. All abstracts were examined and reviews were included if they considered the impact of telemedicine interventions in adult heart failure patients. Randomized controlled trials from identified reviews were reviewed in full length and included in the network meta-analysis if they satisfied all of the following criteria:Coronary artery disease patients with preserved left ventricular function (left ventricular ejection fraction >45%)Had an acute coronary syndrome or coronary artery bypass surgery within 12 weeksHave rheumatic heart disease, severe aortic or mitral valvular heart diseaseHave a medical condition likely to limit survival to < 1 yearReside in a nursing facility or receive home visitsAre unable or unwilling to provide informed consentStudies were excluded if patients met any of the following exclusion criteria:Two reviewers (AK and SH) independently assessed the eligibility of the studies identified in the initial search for inclusion in the review and independently extracted the data from papers considered potentially eligible using a standardized data abstraction form. Both reviewers independently assessed the methodological quality of included reviews using the AMSTAR tool  and the Bayesian network meta-analyses and direct frequentist pairwise meta-analyses were conducted for all outcomes. For the primary analysis, the frequency data from each trial were used in the network meta-analysis using WinBUGS ,13. BayeAssessment of model fit for NMA comprised of assessment of the deviance information criterion (DIC) and the residual deviance in comparison with the number of unconstrained datapoints . Models A network meta-analysis also requires that studies are sufficiently similar in order to pool their results. We assessed available study and patient characteristics to ensure similarity and to investigate the potential effect of heterogeneity on effect estimates. Inconsistency was assessed by comparing statistics for the deviance and deviance information criterion in fitted consistency and inconsistency models. Additionally, fixed effects models with vague priors were conducted.2).  and telemonitoring [0.53 ]. No other significant differences were observed across treatment comparisons ], telemonitoring interventions [0.64 ] and telemedicine that included the transmission of electrocardiographic data [0.71 ] all significantly reduced hospitalizations due to heart failure compared to usual care. The remaining comparisons did not show favor for one intervention over the other  data transmission were also significantly more effective in reducing hospitalizations due to heart failure when compared with usual care. There were no other significant differences found across the interventions compared. This review and network meta-analysis adheres to PRISMA reporting standards Click here for additional data file.S1 FigEffect estimates from the network meta-analysis occupy the bottom left part of the diagram, the estimates from the pairwise meta-analyes occupy the top right part of the diagram and the diagonal corresponds to the comparison. The odds ratios and 95% Credible Intervals for the comparisons in this diagram should be read from left to right . Significant results are underlined and in bold.(TIF)Click here for additional data file.S2 FigEffect estimates from the network meta-analysis occupy the bottom left part of the diagram, the estimates from the pairwise meta-analyes occupy the top right part of the diagram and the diagonal corresponds to the comparison. The odds ratios and 95% Credible Intervals for the comparisons in this diagram should be read from left to right . Significant results are underlined and in bold.(TIF)Click here for additional data file.S1 File(DOCX)Click here for additional data file."}
+{"text": "To evaluate effects of Cajal-like cells on human renal pelvis and proximal ureter on peristalsis.63 patients submitted to nephrectomy due to atrophic non-functional kidney associated with hydroureteronephrosis were included as study group and 30 cases with nephrectomy due to other reasons were included as control group. Samples from renal pelvis and proximal ureters were obtained and sections of 5\u03bc form paraffin blocks of these samples were prepared; layers of lamina propria and muscularis mucosa were examined by immune-histochemistry using CD117 in order to determine count and distribution of Cajal-like cells.During immune-histochemical examinations of sections, obtained from renal pelvis and proximal ureter of hydronephrotic kidneys by CD117, Cajal-like cells number determined in lamina propria and muscularis propria was statistically significantly lower compared to control group (p<0.001). Distribution of Cajal-like cells in renal pelvis and proximal tubulus was similar under examination by light microscope, and also both groups were not different from each other regarding staining intensity of Cajal-like cells by c-kit.Significantly reduced number of Cajal-like cells in study group compared to control group, shows that these cells may have a key role in regulation of peristalsis at level of renal pelvis and proximal ureter in urinary system. Cajal's interstitial cells have been identified by Ramon Cajal about 120 years ago as primitive intestinal neurons .Cajal-like cells (CLC) were demonstrated in urinary system firstly in 1999 . During In this study, count and distribution of CLC in renal pelvis and proximal ureter of patients who had undergone nephrectomy due to non-functional kidney associated with hydroureteronephrosis were compared to that of patients submitted to nephrectomy due to some other reasons and without hydroureteronephrosis. Our aim was to show whether CLC are reduced or not in renal pelvis and ureter of completely non-functional kidneys compared to control group. If CLC are significantly reduced in non-functional hydronephrotic kidneys, this would show that CLC are potentially among cells controlling peristalsis in pelvis and ureter.Between January 2000 to February 2010, 63 patients with nephrectomy due to non-functional kidney associated with hydroureteronephrosis were included as study group and 30 patients with nephrectomy due to other reasons were included as control group at Ba\u015fkent University Ankara central and Adana Teaching and Research Hospital. The patients without hydronephrosis whose collecting tubules system were intact with renal function and without systemic metastasis of renal tumors were chosen for control group. The study group was entirely composed of patients who developed hydroureteronephrosis due to ureteral obstruction and stone resulting in atrophic non-functional kidney. Out of the paraffin blocks of the samples obtained from kidney pelvis and proximal ureters, 5\u03bc sections were prepared and the sections were put on slides with polylysine, and in order to determine count and distribution of CLC, their lamina propria and muscularis mucosa layers were examined immune-histochemically using CD117.As mast cells are also positively stained by CD 117, these cells were discriminated from CLC by using toluidine blue before histopathological examination of CLC. Sections of 5\u03bc were transferred on slides and they were kept within solution of toluidine blue  for an incubation period of 15 minutes following de-paraffinisation process, then they were rinsed by tap water, dried and kept within xylene for 5 minutes. Samples on slides were covered by lamella and examined under light microscope. Mast cells showed granular meta-chromatic staining.Orange-brown staining was accepted as positive due to chromogen used in microscopic valuation of samples. Five serial sections were examined for each patient. Number of Cajal cells with CD117 positive was counted on lamina propria and muscularis propria of samples of renal pelvis and ureter at 10 HPF (x400) area and the mean was determined. Cells with round nucleus and cytoplasm with intensely granular staining were considered to be mast cells and cells with fusiform cytoplasm and nucleus were considered as CLC.Data analysis was done by SPSS for Windows 11.5. Shapiro Wilk test was used to determine whether distribution of continuous variables was close to normal or not. Descriptive analysis included: mean\u00b1standard deviation for age (minimum-maximum); median for cells count (minimum-maximum); and subject number and (%) for nominal variables. Student t test was used to investigate the significance between groups for mean age; and Mann Whitney test was used to investigate the significance of median cell count. Similarity of gender distribution was analyzed by Pearson \u03c7-square test. Results were accepted statistically significant for p<0.05.The mean age was 43.5 (2\u201372 years) for 63 patients  with nephrectomy due to atrophic hydronephrotic kidney. The mean age was 58.6 (38\u201382 years) for 30 patients  with nephrectomy due to renal tumor and without hydronephrosis. At microscopic examination, CLC were brown due to chromogen used for immunohistochemical staining. These cells stained by anti c-kit showed radial branched extensions. The distribution of CLC number according to groups is shown on Cajal-like cells count determined on lamina propria and muscularis propria obtained from sections of hydronephrotic renal pelvis by immunohistochemical CD117 examination was statistically significantly reduced compared to control group A. DistriCajal-like cells determined on renal pelvis lamina propria and muscularis propria in study group and control group are shown in Cajal-like cells count determined on both lamina propria and muscularis propria of sections obtained from proximal ureter was statistically significantly reduced compared to control group B. Cajal-In this study based on results showing that CLC play a role in regulation of urinary system motility as in gastrointestinal system, significant reduction in number of Cajal cells with CD117 positive staining was shown in layers of lamina propria and muscularis propria of renal pelvis and proximal ureter of patients submitted to nephrectomy due to hydroureteronephrosis. This result indicates that interstitial CLC are also closely associated with peristalsis in urinary system.Cajal-like cells have been firstly identified as primitive intestinal neurons in 1893, and then they have been associated with neurons and intestinal smooth muscle cells . AdditioIn the studies carried out during following years, interstitial CLC were detected in all organs of the urinary system and connection between them and urinary system disorders were tried to be revealed \u201310. StudIn a study carried out in recent years in order to understand vesicoureteral reflux mechanisms and structural changes they induce in the urinary system, 32 patients with vesicoureteral reflux at varying degrees were compared with 8 control cases regarding presence of intramural c-kit positivity cell and it was determined that collagen stroma replaced smooth muscle bundles and these was remarkable reduced in interstitial cells. It was accepted that interstitial CLC provided automatic rhythm and ureteral peristaltism coordination in ureters and a relation was thought to exist between the loss of interstitial CLC and vesicoureteral reflux and impaired active ureteral valve mechanisms . AnotherSolari and colleagues determined that human UPJ contained many c-kit positive Cajal cells and their number was very low in obstruction of ureteropelvic junction compared to control group or they were completely absent in UPJ obstruction. In that study, it was claimed that CLC were responsible of ureter peristalsis . KuzgunbKuvel and colleagues conducted a study to investigate underlying basic histopathology at intrinsic UPJ obstruction and to associate this with surgical treatment results, and they examined the obstructed segment of 32 cases with intrinsic UPJ obstruction; the segment of UPJ with chronic obstruction in 15 cases with nephrectomy due to chronic obstruction associated with lithiasis, tumor and reflux; and lastly they examined also normal ureteropelvic junction segment of 30 patients submitted to nephrectomy due to renal tumor or trauma; then they evaluated CLC in these segments. Cells positive with c-kit for immunohistochemical staining of CD117 monoclonal antibody were generally spread and in rare lining and they were not in regular interaction. These cells were observed to have morphological aspects of CLC cited in literature and were readily discriminated from mast cells showing positive staining. When distribution and density of C-kit positive Cajal cells alterations at intrinsic UPJ obstruction segments were compared to normal ureter segments and chronically obstructed ureter segments, intrinsic UPJ obstruction segments were similar except proximally to surgical area limit and no statistically significant difference was present. However, c-kit positive cells were higher at proximal and distal edge margins of intrinsic UPJ segments compared to obstruction area. According to these results, authors suggested that CLC are responsible of intermediate mechanisms having a role between pacemaker cells and innervations in state of a direct role in pathogenesis of intrinsic UPJ obstructions .When we go over the studies that Solari and Kuvel related to CLC in UPJ junction obstruction, the fact that these cells decrease in cases with UPJ obstruction compared to control group stands out. This result may be interpreted as these cells don't function in functionally or anatomically obstructed UPJ. In our study, proximal ureter and renal pelvic segments without any peristaltic function were evaluated and our findings and results of studies conducted in patients with UPJ obstruction are similar, since in our study number of CLC in muscularis propria and lamina propria of non-functional pelvis and proximal ureter are significantly lower. Therefore according to these results, CLC could be reduced in ureter with loss of motility and their function could also be diminished.In recent years, studies about localization, number, function of CLC in urinary system and their role in pathophysiology of urinary system disorders are increasing in parallel to advances in pathological and immunohistochemical diagnostic tools. In electron microscopy trials, morphological alterations of CLC in obstructed urinary system may be revealed and if necessary, in association with electrophysiological trials, most of unknown ultrastructural changes of these cells may be demonstrated.Neurophysiological trials in association with better understanding of association of structural aspects and peristalsis of CLC in urinary system, will lead to better understanding of function of these cells in urinary system and the development of new treatment modalities for urinary system pathologies related with peristalsis."}
+{"text": "Iron is the fourth most abundant mineral in the Earth's lithosphere   and ability to form large microbial mats, they have proven elusive to cultivation under laboratory conditions. This elusiveness has caused confusion in the past, where taxonomy was inferred exclusively by morphological and ecological characteristics .One of the problems aerobic Fe(II) oxidizing microbes must overcome is the presence of highly reactive oxygen species (ROS) that are produced via Fenton chemistry in the presence of oxygen and iron. Catalase and superoxide dismutase are the most common defense mechanisms against ROS and surprisingly both strains feature only a minimal set of catalase and peroxidase genes. This may be compensated by a number of truncated hemoglobins that are highly conserved and found in other FeOB such as Interestingly, strains ES-1 and ES-2 differ in their strategies to generate ATP. While ES-2 relies on the alternative complex III and a bacterial ATPase, ES-1 employs Cytochrome bc1, and a bacterial/archaeal-type ATPase in addition to the bacterial ATPase. The advantages of a second ATPase are presently unknown and the distribution of such redundant systems throughout the genomes of iron oxidizing microbes may provide clues to their respective niche adaptation in the future.Mariprofundus ferrooxydans PV-1  to a prophage gene cluster identified in in vitro research is required to unravel these survival strategies.Neither of the two strains features any of the unique extracellular structures such as sheaths or stalks often associated with FeOB. Genome analysis revealed that strain ES-1 feature a single large gene cluster dedicated to exopolymer synthesis, while ES-2 harbors two separate large EPS clusters in addition to two gene clusters possibly involved in cellulose synthesis. The presence of exopolysaccharide (EPS) gene clusters may provide clues how those strains prevent self-encrustation by iron-oxyhydroxides but further Gallionella sp. SCGC AAA018-N21 have been released (BioSample: SAMN02256456) and a future comparative genomics analyses will undoubtedly reveal further insights in lifestyle adaptation and contribute to a more robust taxonomic framework.Recently, the draft genome sequences of The research presented by Emerson et al. contributes significantly to our understanding of neutrophilic freshwater iron-oxidizing bacteria and their taxonomic relations to each other. However, the intriguing features found in both genomes\u2014either commonly shared or specific to the individual strains\u2014have created a large, new research space waiting to be investigated.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Comparison of polymorphism at synonymous and non-synonymous sites in protein-coding DNA can provide evidence for selective constraint. Non-coding DNA that forms part of the regulatory landscape presents more of a challenge since there is not such a clear-cut distinction between sites under stronger and weaker selective constraint. Here, we consider putative regulatory elements termed Conserved Non-coding Elements (CNEs) defined by their high level of sequence identity across all vertebrates. Some mutations in these regions have been implicated in developmental disorders; we analyse CNE polymorphism data to investigate whether such deleterious effects are widespread in humans. Single nucleotide variants from the HapMap and 1000 Genomes Projects were mapped across nearly 2000 CNEs. In the 1000 Genomes data we find a significant excess of rare derived alleles in CNEs relative to coding sequences; this pattern is absent in HapMap data, apparently obscured by ascertainment bias. The distribution of polymorphism within CNEs is not uniform; we could identify two categories of sites by exploiting deep vertebrate alignments: stretches that are non-variant, and those that have at least one substitution. The conserved category has fewer polymorphic sites and a greater excess of rare derived alleles, which can be explained by a large proportion of sites under strong purifying selection within humans \u2013 higher than that for non-synonymous sites in most protein coding regions, and comparable to that at the strongly conserved trans-dev genes. Conversely, the more evolutionarily labile CNE sites have an allele frequency distribution not significantly different from non-synonymous sites. Future studies should exploit genome-wide re-sequencing to obtain better coverage in selected non-coding regions, given the likelihood that mutations in evolutionarily conserved enhancer sequences are deleterious. Discovery pipelines should validate non-coding variants to aid in identifying causal and risk-enhancing variants in complex disorders, in contrast to the current focus on exome sequencing. For example, beta thalassemia and haemophilia B are both instances of human diseases caused by mutations affecting transcription-factor binding sites in regulatory sequences  with Absent Radii (TAR) syndrome when no exonic mutations were found in affected individuals at that locus The effect of mutations in coding sequence is a well-characterised phenomenon whereby non-synonymous changes alter the resulting protein product. Therefore, these non-synonymous changes tend to be under stronger purifying selection than synonymous mutations. There are only rare instances where synonymous changes have been demonstrated to have phenotypic effects cis-regulatory modules often depend on a signal of evolutionary conservation Generally it has only been when exome sequencing fails to identify any causative mutations that non-coding DNA is surveyed. Now that whole genomes are being sequenced in greater numbers, such as in the 1000 Genomes Project Here, we focus our efforts on sequences that are conserved across all jawed vertebrates and that likely define a set of developmental regulatory elements , yet their conservation cannot be explained by our current knowledge of transcription-factor binding sites, since most known binding targets are only 4-10 bp long. In fact the rate of evolution of known binding sites is faster than that of CNEs. One possibility would be if the binding sites overlap each other and the order of overlap is necessary to retain the proper function of the cis-regulatory module , synonymous sites from coding regions, and non-exonic sequences that do not overlap any CNEs or other annotated regulatory features. The non-synonymous sites act as a positive control, since it is known that a subset of non-synonymous changes is counteracted by relatively strong purifying selection We compared the proportion of polymorphic sites and the derived allele-frequency spectra of single nucleotide polymorphisms (SNPs) in CNEs with other regions of the human genome, for the purpose of exploring selective constraint in CNEs, and in a wider context understanding the evolutionary forces that define large From There are two broad explanations for the excess of substitutions that have occurred in Restricted Variable Regions of CNEs (compared with neighbouring NVRs): they could be neutral  changes persisting through genetic drift, or they could be adaptive changes fixed by selection. The first possibility would imply relaxed purifying selection acting on these sites, which should be apparent in greater within-species polymorphism. On the other hand, in the second case, purifying selection could be of comparable strength in the NVRs and RVRs. In order to investigate whether selective constraint in both classes of CNE sites is comparable, we therefore looked at both the proportion of polymorphic sites and spectra of derived allele frequencies. The imputation accuracy for low coverage imputed SNPs in the 1000 Genomes Project was highest for SNPs with an allele count of at least six We note that the G+C content varies considerably in the different classes of constrained sites , and that an increase in G+C content is associated with an increase in heterozygosity in the human genome Previous studies have shown that UltraConserved Elements (UCEs) defined by human-mouse-rat comparisons experience stronger purifying selection than coding regions NVRs within CNEs exhibit a similar proportion of sites that are polymorphic relative to non-synonymous sites . The lowp-value \u200a=\u200a0.9045) and the non-synonymous spectrum of derived alleles at the transcriptional and developmental genes (trans-dev genes) the CNEs are associated with. Strong purifying selection is expected at these trans-dev genes, since they are fundamentally important to vertebrate development and amongst the most highly conserved of all vertebrate genes  and contained approximately 5% UTR sequences. Nevertheless we found evidence for strong purifying selection: there was no significant difference between the observed derived allele frequency spectra in CNE-NVRs  relative to instances of the same motif outside of the bound region that are not deemed functional The different patterns of polymorphism observed at CNEs and protein coding loci can be interpreted in terms of their consequences for the molecular biology of the organism carrying the mutations. Non-synonymous changes can have major effects on protein structure and function, particularly through truncation. One might expect that there will be a specific number of non-synonymous changes in any coding sequence that might render the resultant protein completely non-functional, whereas other more conservative changes might have little or no effect on protein function. This would be reflected in a wide spectrum of selective pressures at a limited number of non-synonymous sites, with some being essentially immutable  and others having relatively high derived-allele frequencies. CNEs represent an entirely different form of functional unit, possibly mediating their action through the binding of large numbers of transcription factors. In general, transcription factor binding sites are highly redundant with a rapid turnover rate  is biased downward relative to the spectra at both types of coding sequence. The results are clearer with the 1000 Genomes dataset because, albeit at low coverage, the whole genome sequencing approach captures a greater number of rare variants outside of the exome.Unlike earlier studies, we have focused specifically on deeply conserved, pan-vertebrate, non-coding elements that have high regulatory potential during early development. Given their likely functional roles, we wanted to examine the strength of selective constraint at base pair resolution within these elements. We find different levels of purifying selection, as measured by both evolutionary conservation and human variation, across these large elements and show that some NVR sites are under consistently stronger purifying selection than non-synonymous sites in coding sequences, critically suggesting that mutations in NVRs within CNEs are likely to be deleterious.The focus on exome-wide sequencing may benefit identifying causal variants in diseases/disorders that follow Mendelian patterns of inheritance We have combined deep, historical phylogenetic footprinting with the occurrence of SNPs and their derived allele frequencies in human populations to identify two classes of sites (Non Variable Regions and Restricted Variable Regions) in CNEs that experience different effects of selective pressure. Increasingly, approaches are combining phylogenetic footprinting with population genomics to effectively identify evolutionarily conserved non-coding sites that are likely to be functional and thus contribute to phenotypic variability and genetic disease Homo sapiens, Macaca mulatta, Mus musculus, Gallus gallus, Xenopus tropicalis, Danio rerio and Takifugu rubripes. Out of \u223c7000 human-fugu CNEs spanning a combined length of \u223c 800,000 bp, we identified a subset of 1809 CNEs spanning 318286 bp that could be aligned across all seven species. Clustalw with default parameters was used to align the fasta sequences. Fasta sequences for the seven vertebrate species can be downloaded from the CONDOR website using the list of CNE IDs provided in Text S1.CNE sequences in fasta format were downloaded from the CONDOR database We defined two classes of sites within CNEs based on their conservation across the six vertebrate species by masking the human sequence. Custom Perl scripts were used to distinguish between sites that are identical in all six species (NVRs) and those that vary in at least one species (RVRs). In instances where the presence of the alternate allele in the human reference sequence made a non-variable region a variable region, the site was reclassified as a Non-Variable Region that is polymorphic. There were 27 polymorphic sites reclassified in this way. 161361 bp across 1809 CNEs were non-variable in all seven species while 156925 bp were variable in at least one species.The Biomart The non-coding regions for the HapMap analysis only were randomly chosen from five different chromosomes. In the analysis of the 1000 Genomes Project data, the main dataset in this study, genomic regions within 5\u20136 kb away from the CNEs in the analysis that do not overlap known exons and CNEs constitute the non-coding control. The distance of 5\u20136 kb was small (corresponding to 0.006 cM in the human genome), so the sites would be exposed to the local reduction in effective population size due to any background selection. Previous analyses . An excess of rare derived alleles is observed in CNE-NVRs, CNE-RVRs and Non-synonymous sites relative to Synonymous and Non-coding controls when the full spectrum (Derived Allele Count (DAC) >\u200a=\u200a1) of variants is used.(TIFF)Click here for additional data file.File S1List of CNE accession numbers from the CONDOR database (DOC)Click here for additional data file."}
+{"text": "The Patient Reporting and Action for a Safe Environment (PRASE) study, evaluated a ward-level intervention using ward-specific patient feedback to improve patient safety. We discuss choice of outcomes for patient safety trials.A multi-centre, cluster randomised control trial was conducted over 12 months in 33 wards. Joint primary outcomes were a new routinely collected monthly ward-level measure, the patient safety thermometer (PST), and the patient measure of safety (PMOS) completed by around 25 study participants per ward at baseline, six and 12 months.The PMOS had the advantage of providing a patient view on 44 safety related items; however researchers spent an average of 25 minutes with each patient collecting data and the measure was confounded as it also formed part of the intervention. Advantages of using routinely collected PST data included the objective nature of the data and low costs, however a ceiling effect was observed and spurious data could not be verified. The overall PST percentage of harm free care included previous harms and therefore could not be solely contributed to the trial intervention. We conducted a post-hoc analysis on the percentage of care free from new (ward-specific) harm.Given the use of ward-specific patient feedback, different areas were targeted for improvement on different wards meaning choice of outcome measure was difficult to identify. The PST allowed routinely collected data to be used as an outcome but lack of experience with the measure made it difficult to define a priori."}
+{"text": "Merops apiaster has only rarely \u2013 and if so mostly anecdotically \u2013 been documented in the literature record, although such behavior would substantially save time and energy. In this study, we quantify burrow re-occupation in a German colony over a period of eleven years and identify ecological variables determining reuse probability. Of 179 recorded broods, 54% took place in a reused burrow and the overall probability that one of 75 individually recognized burrows would be reused in a given subsequent year was estimated as 26.4%. This indicates that between-year burrow reuse is a common behavior in the study colony which contrasts with findings from studies in other colonies. Furthermore, burrow re-occupation probability declined highly significantly with increasing age of the breeding wall. Statistical separation of within- and between-burrow effects of the age of the breeding wall revealed that a decline in re-occupation probability with individual burrow age was responsible for this and not a selective disappearance of burrows with high re-occupation probability over time. Limited duty cycles of individual burrows may be caused by accumulating detritus or decreasing stability with increasing burrow age. Alternatively, burrow fidelity may presuppose pair fidelity which may also explain the observed restricted burrow reuse duty cycles. A consequent next step would be to extend our within-colony approach to other colonies and compare the ecological circumstances under which bee-eaters reuse breeding burrows.Re-occupation of existing nesting burrows in the European bee-eater  Merops apiaster)  Fig. is a widter) Fig.. Bee-eatter) Fig.. Eggs arter) Fig. composedBee-eaters regularly use the same breeding walls over several years  indeed found no evidence for any burrow reuse ; or alternatively (2) a decline in re-occupation probability is due to the fact that during colony establishment, unconstrained construction of high-quality burrows is possible, while in later years, burrows are built increasingly in suboptimal parts of the breeding wall with regard to, for example, soil properties or predation risk .In this study, we investigate between-year burrow reuse and its dynamics in a European bee-eater colony in southern Germany across a period of eleven years. We document that, in contrast to what is reported in the literature, between-year burrow reuse is common in this study colony. Furthermore, we test competing hypotheses that could explain mechanistically an observed general decline in re-occupation probability with increasing age of the breeding wall by statistically separating within- from between-burrow effects. More precisely, we test the hypothesis that (1) a decline in re-occupation probability is due to a limited duty cycle of individual burrows, for example caused by increasing contamination with detritus or parasites or a decrease in burrow stability over time  with binomial error structure and logit link function. We transformed the original covariate age of the breeding wall (ranging from 1 to 10) by subtracting 5.5 such that  estimates for the intercepts in our models are given for the median age of the breeding wall . We included study year and breeding burrow identity as random intercept effects as well as random slope effects for age of the breeding wall on breeding burrow identity in our models to control for pseudoreplication due to the lack of independence resulting from multiple observations of the same burrow or from the same year. We refrained from including in addition a random slope effect for age of the breeding wall on study year due to the observed lack of convergence when fitting such models. We estimated the overall re-occupation probability using a binomial GLMM with the intercept as only fixed effect and burrow identity and study year as random intercept effects to obtain an unbiased estimate for overall mean re-occupation probability (including appropriate standard errors) which is controlled for pseudoreplication.We tested for the fixed effect of the within-burrow age of the breeding wall effect precisely models the age of individual burrows and thus tests our burrow age hypothesis, while the between-burrow age of the breeding wall effect tests our burrow quality hypothesis.Not all the burrows could be monitored across the entire study period due to first appearance of burrows after establishment of the breeding wall in 2003) and/or disappearance before the end of the observation period  took place in a nesting burrow which had already been used in a previous year, indicating that reusing burrows is a common breeding site selection strategy in the bee-eater breeding wall under study. Altogether, 424 burrow-year observations have been recorded for 82 different, individually recognized burrows over the whole observation period  or due to a selective disappearance of burrows with relatively high re-occupation probabilities with increasing age of the breeding wall . Using within-burrow centering of the covariate age of the breeding wall to disentangle within- from between-burrow effects, we found that a decline in re-occupation probability of individual burrows with age , but not selective (dis-)appearance  was responsible for the observed pattern across time  indicated that individual burrows differed in their re-occupation trajectories with increasing age. To control for the fact that the data are right-hand censored, that is, more data points are available for older than for younger burrows, we restricted the analysis to 316  observations of 59  burrows which were first occupied between 2003 and 2010. By excluding those burrows that could be monitored for only 2 or 3\u00a0years, we test for the robustness of our analysis. The analyses of the restricted data set yielded very similar results .Re-occupation probability showed a highly significant decline with increasing age of the breeding wall  (Heneberg Merops philippinus) . This might simply be due to an elevated risk of collapsing for older burrows which might not always be observable from outside. Additionally, bee-eaters do not normally remove indigestible regurgitates of their offspring or other detritus from their burrows . Thus, it seems not to be the case that high-quality burrows with an associated higher reuse probability were built early during colony establishment. Still, the first burrows in newly established breeding walls of burrowing birds are usually built along the upper margin, whereas lower burrows follow only later (Ursprung Martes foina) and European badgers (Meles meles) is indeed higher when burrows are located in closer proximity to the ground (Sieber Vulpes vulpes) excavate burrows from the top (Heneberg Declining burrow reuse probability over time was not attributable to the selective disappearance of high-quality burrows (Ursprung . While td Sieber , red foxHeneberg . BesidesHeneberg  or rainwHeneberg  should pNaturally, the present study is limited to a within-colony approach when trying to understand the ecological conditions that promote or hinder nesting burrow reuse in European bee-eaters. It would therefore be worthwhile to extend the approach taken here over the breeding range of the species as, for example, the availability and quality of breeding walls and the demographic and genetic composition of populations may well differ, especially in the margin regions of the distribution. Based on quantitative data from many different populations, such an extension will promote a better understanding of the ecology and ultimately conservation of a European flagship species for conservation and for studying population responses to environmental change."}
+{"text": "HLA-B and MAPK10) that are involved in defense against endemic pathogens such as malaria. Genes that encode functions related to skin pigmentation (SCL4A5) and cutaneous glands (EDAR) are also found in regions with anomalous ancestry patterns. These results suggest the possibility that ancestry-specific loci were differentially retained in the modern admixed Colombian population based on their utility in the New World environment.The human dimension of the Columbian Exchange entailed substantial genetic admixture between ancestral source populations from Africa, the Americas and Europe, which had evolved separately for many thousands of years. We sought to address the implications of the creation of admixed American genomes, containing novel allelic combinations, for human health and fitness via analysis of an admixed Colombian population from Medellin. Colombian genomes from Medellin show a wide range of three-way admixture contributions from ancestral source populations. The primary ancestry component for the population is European , followed by Native American  and African . Locus-specific patterns of ancestry were evaluated to search for genomic regions that are enriched across the population for particular ancestry contributions. Adaptive and innate immune system related genes and pathways are particularly over-represented among ancestry-enriched segments, including genes ( The arrival of Columbus in the New World precipitated a massive and sudden exchange of life forms between the American and Afro-Eurasian hemispheres. European colonization and trade in the Americas entailed a bidirectional exchange of numerous species of plants, animals and microbes, many of which until that time had been evolving separately for millions of years. The conquest and settlement of the Americas, along with the African slave trade, also included exchanges among a variety of human populations. These biological and cultural exchanges, which were often intentional although sometimes not so, had a tremendous impact on the trajectory of human history in the centuries that followed. Among other effects, the exchange of crops and livestock allowed for a major increase in the global population, whereas the introduction of microbes that cause infectious disease had devastating effects on the na\u00efve populations to which they were introduced.Columbian Exchange in his seminal book of the same name1493: Uncovering the New World Columbus Created by Charles MannThe historian Alfred Crosby referred to this massive transfer of life as the The modern human species emerged out of Africa and spread throughout the world starting between 60\u2013100,000 years ago4in situ within ancestral populations\u2019 endemic geographic regions. Some of these alleles may have drifted to high frequency within the ancestral populations by chance, whereas others are likely to have been swept to fixation based on selection pressures that were distinct to the ancestral populations\u2019 environments678678101112131415678978Admixture rapidly brings together population-specific (or enriched) alleles that have not previously co-existed in the same genetic background, and thereby can be considered to result in the creation of completely novel human genomes. Population-specific (enriched) alleles are sequence variants that evolved to population-characteristic frequencies i.e. their relationship to health and fitness in a particular environment. We posit that these pre-evolved ancestral population-specific alleles may have been selected in the modern admixed population based on their utility in the new environment. The new environment could be a new physical environment, for populations that were transported to new regions, and/or a new ecological environment based on the mixing of previously isolated human populations and their associated microbial fauna.In this study, we sought to address what it means when genomic variants that have been separated for tens-of-thousands of years are suddenly brought back together over the course of a few hundred years. In other words, is the process of modern admixture somehow related to human health and fitness? Our working hypothesis is based on the well-supported axiom that specific allelic variants (SNPs) have evolved separately in ancestral human populations based on their regional-specific utility, We evaluate these ideas here via a study of the relationship between ancestry, admixture and fitness in Colombian genomes. The Colombian population is a particularly interesting subject for study in this regard owing to its high levels of ethnic admixture192021222426Admixed Colombian genome sequences from Medellin were compared with a number of world-wide populations that are likely to be closely related to Colombian ancestral source populations . To do tThe close clustering of the East Asian with the Bolivian Native American populations  is consiP\u2009=\u20091.8\u2009\u00d7\u200910\u22127). Similarly, the relative level of Native American female ancestry was significantly higher for the Colombian population compared with the country with the next highest level . The Colombian population also shows a smaller, but not insubstantial, excess of African ancestry along the male lineage .A number of previous studies have uncovered sexual asymmetry in the contributions of different ancestral populations to admixed Latino genomes20212223The three-way continental ancestry origins of individual chromosomal segments across the entire genome were determined for all 60 individuals in the Colombian population as described in the Materials and Methods. Chromosome paintings that show the locations of ancestry-specific segments across the chromosomes of two Colombian individuals are shown in i.e. anomalous) ancestry proportion combination values. Chromosomal segments that bear such anomalous ancestry proportion combinations are the ones that are identified by the ancestry-enrichment statistical test applied here . When the ancestry-enrichment analysis technique is applied to population-wide ancestry proportion combination data, numerous statistically significant ancestry-enriched chromosomal segments are revealed across the entire genome  were used for these analyses. There are numerous genes in these regions that were previously identified to show evidence of positive selection in populations from one of the three ancestral regions that contributed to the modern admixed Colombian population; there are also a number of genes in ancestry-enriched regions that show evidence for a role in various health-related phenotypes based on previous selection and association studies .Having identified genomic loci with anomalous ancestry contribution levels, we then interrogated the genes located in these regions for previously identified signatures of natural selection and for associations with health-related traits. Only ancestry-enriched chromosomal segments that were highly statistically significant ( studies . In partHLA-B gene located in the major histocompatibility complex (MHC) on chromosome 6 is found in an African ancestry-enriched chromosomal segment  to immune system cells. HLA-B is a highly diverse gene with numerous allelic variants; high sequence diversity of HLA genes is thought to facilitate the ability to counter a diverse repertoire of foreign antigens. Indeed, HLA gene diversity levels among global populations are positively correlated with regional-specific levels of pathogen richness, with African populations having the most diverse repertoire of HLA allelesHLA-B allelic diversity levels world-wide show a strong positive correlation with malaria selective pressureHLA-B locus may have helped the Colombian population to more effectively counter malaria and/or other pathogenic agents. The MAPK10 gene is another immune-related gene that is located in an Asian-enriched ancestry segment in the Colombian population, and alleles of this gene were recently shown to be selected for malaria resistance in MalaysiaThe  segment . HLA-B iSCL4A5 and EDAR. The SCL4A5 gene is located in a genomic region enriched for European ancestry in the Colombian population. Positive selection at this locus has previously been associated with the evolution of decreased melanin skin pigmentation as European and Asian populations radiated out of AfricaSome other interesting genes from ancestry-enriched regions include EDAR gene has received considerable attention recently owing to an interesting connection between the phenotype it encodes and evidence of population-specific positive selection9EDAR encodes a cell surface receptor that is involved in the development of hair follicles and cutaneous glands, and there is evidence for positive selection of EDAR alleles in Asian and Native American populations. The selected allele reduces evaporation from exposed facial structures and upper airways, which is thought to represent an adaptation to cold and dry environments in East Asia. In the admixed Colombian population, EDAR is found in a chromosomal segment that is depleted for Asian (Native American) ancestry P-values reported here should be taken with some caution.The significant over-representation of ancestry-enriched genes among components of the immune system includes genes that map to pathways involved in both the innate and adaptive immune response . The relResults from our analysis of 60 Colombian genome sequences from Medellin point to high levels of three-way continental admixture, with contributions from African, Native American and European ancestral source populations, consistent with previous genetic studies1920212223It should be noted that different regions of Colombia show very distinct demographic patterns. For example, whereas people from Medellin have primarily European ancestry, the Atlantic and Pacific coastal regions are home to much larger populations of Afro-Colombians. Thus, the admixture patterns reported here for Medellin can not be taken to represent country-wide patterns of Colombian genetic ancestry. Indeed, studies on the genetic ancestry of Colombians sampled from different regions of the country often yield very different results1920212223Interestingly, the genetic ancestry and admixture results obtained here for the population of Medellin can be considered to be at odds with the demographic data for the city. Medellin is considered to have a population that is almost entirely descended from Europeans. In the 2005 census, 93.4% of the population of Medellin was classified as Euro-descendent, whereas 6.5% of individuals identified as Afro-Colombian and only 0.1% identified as Native AmericanThe distinction between genetic ancestry and ethnic self-identification in Medellin may be related to two important cultural concepts rooted in many Latin American societies: Mestizaje and Blanqueamiento39The relationship between genetic ancestry and ethnic self-identification has recently been studied in depth for five Latin American countriesColombian genome sequences also show strikingly asymmetrical patterns of sex-specific admixture with the male lineages dominated by European ancestry and female lineages comprised of more Native American ancestry . These r20212223When regional-specific ancestry contribution patterns are compared across the entire population of Colombian genomes studied here, it becomes very clear that the patterns of admixture are non-random . There ain situ in their ancestral regions, based on local selective pressures, over many thousands of years. When the populations that bore these alleles arrived in the New World, the pre-existing adapted alleles were ready to be rapidly re-assorted into novel admixed genomes. In other words, the long, slow process of natural selection had already occurred in the ancestral source populations to generate a standing pool of genetic variation with a wide variety of adaptive utility. From this existing pool of genetic variation, numerous ancestry-specific segments containing adaptive alleles were readily accessible for re-assortment. In this way, the enrichment of ancestry-specific segments in the Colombian population, based on their utility in the New World environment, could have occurred much more rapidly, i.e. within the relatively short time span following Columbus\u2019 arrival in the Americas. The ability to rapidly shape admixed genomes over such a time span, with anomalous combinations of ancestry-specific alleles, is supported by the highly asymmetrical patterns of sex-specific admixture observed for Latino populations.We envision that the particular \u2018selection\u2019 process that occurred for the admixed Colombian population, based on assortment among pre-existing ancestry-specific alleles, was somewhat distinct from the concept of natural selection as typically formulated. Adaptive, also referred to as positive or directional, natural selection is most often considered to occur via the fixation of novel mutations based on differential reproductive success. This process starts with the introduction of new alleles by mutation at very low population frequencies and thus is relatively slow; it typically takes place on the order of tens- or hundreds-of-thousands of yearsA similar approach to search for evidence of selection based on ancestry-enrichment has been conducted in two recent studies of admixed African American populations43Interrogation of the functional roles of genes located in the anomalously admixed genomic regions detected here suggests that the retention of ancestry-specific alleles in the Colombian population is most closely tied to immune system function . This prColombia is located in the tropics, traversed by the equator, and has a high burden of infectious disease caused by a variety of pathogenic agents. Compared with other countries in the region and around the world, Colombia has a very high level of pathogen richness as measured by the number of known pathogens in the country (n\u2009=\u2009244)17Susceptibility to cholera, which is endemic to South East Asia, is known to be strongly influenced by host genetic factors4749MICB locus along with additional significant SNPs at the adjacent HLA-B and HLA-C lociHLA gene alleles and susceptibility to dengue in Asian populations5556There have also been numerous studies that have identified host genetic factors that appear to mitigate susceptibility to dengue fever52535556th century United States provides compelling statistical evidence for an association between genetic ancestry and susceptibility to yellow fevere.g. social and/or economic) factors that could explain this difference and concluded that their findings support the existence of host genetic factors that mitigate the severity of yellow fever infections among individuals with African ancestry.As of this time, there are no known host resistance alleles associated with susceptibility to yellow fever. However, it has long been thought that populations with different genetic ancestries had differing degrees of susceptibility to yellow fever, suggesting a genetic component to susceptibility to this pathogen. In particular, populations with African ancestry were thought to have reduced susceptibility to yellow fever5859HBB) that evolved independently and provide increased resistance to malaria6667Malaria poses a particularly grave and consistent threat to public health in Colombia with both endemic and epidemic transmission regimesThere is a clear connection between the infectious disease burden in Colombia, for a number of the most common pathogen agents found in the country as described above, and host genetic factors that mediate susceptibility and resistance. Many of these host genetic factors are likely to be population-specific (or enriched) alleles that initially evolved within ancestral source populations. The results obtained from our ancestry-enrichment analysis indicate that the modern admixed Colombian population may have had the opportunity to draw from a variety of these ancestry-specific resistance alleles to assemble a diverse repertoire of immune system related genes capable of countering threats from the wide variety of pathogens found in the New World environment. In addition to being of interest from an evolutionary perspective, these results may have implications for better understanding the genetic determinants of health in highly admixed Latin American populations.n\u2009=\u2009264) and genotypes characterized using SNP microarrays (n\u2009=\u2009257) from a number of sources2627i.e. SNP calls) characterized using complete genome sequences and microarrays from these different studies (and formats) were merged using the program PLINK v1.90A total of 581 whole genome sequences or genotypes, taken from a variety of sources, were analyzed here see . Whole g26rays n\u2009=\u20097 from a Allele sharing distances between pairs of genomes were computed as the fraction of differences between SNP calls. Principal components analysis of the resulting pairwise allele sharing distance matrix was performed using the prcomp program from the R package v3.1.2Normalized ratios of the difference between admixture fractions for the X chromosome versus the autosomes were used to infer sex-specific admixture contributions for each of the three ancestral source populations. The admixture difference ratio , Asian (CHB) and European (CEU) chromosomal segments, for the entire population at a specific genomic locus, given the population-average levels of African, Asian and European ancestry. This probability is expressed as:Chromosomal regions with anomalous patterns of ancestry, when considered as an ensemble across the entire population of 60 Colombian genomes (120 chromosomes), were identified via ancestry-enrichment probability values. These values were computed as the trinomial probability of observing a particular numerical combination of African  anomalous patterns of ancestry identified in this way were interrogated for their potential functional significance using several sources of information. Genes that lie within these regions were compared to sets of genes previously identified as being subject to positive (adaptive) selection in a number of studies678910Genomic regions with highly statistically significant ."}
+{"text": "This report is the first characterization of the histology and ultrastructure of the barred owl conjunctiva. The inferior eyelid was dominated by a large disk-shaped plate covered by a non-keratinized stratified squamous or cuboidal epithelium of variable thickness. The apical surface of the plate epithelium varied from flat to long microvilli or even short cytoplasmic extensions similar to those seen in the third eyelid. All specimens had a few goblet cells filled with mucous secretory granules in the plate region. The underlying connective tissue was a dense fibroelastic stroma. Eosinophils were surprisingly common in the epithelial layer and underlying connective tissue in the plate and more distal orbital mucosal region. The orbital mucosa contained goblet cells with heterogeneous glycosylation patterns. The leading edge and marginal plait of the third eyelid are designed to collect fluid and particulate matter as they sweep across the surface of the eye. The palpebral conjunctival surface of the third eyelid was covered by an approximately five-cell-deep stratified squamous epithelium without goblet cells. The bulbar surface of the third eyelid was a bilayer of epithelial cells whose superficial cells have elaborate cytoplasmic tapering extensions reaching out 25 \u03bcm. Narrow cytofilia radiated outwards up to an additional 15\u201320 \u03bcm from the cytoplasmic extensions. Lectin labeling demonstrated heterogeneous glycosylation of the apical membrane specializations but only small amounts of glycoprotein-filled secretory granules in the third eyelid. Strix varia) was made possible when we were given access to birds which had been recently euthanized due to unrecoverable injuriesBirds, especially owls, have eyes that are large compared to their body mass to allow them to meet the demands of rapid flight, prey detection, and night vision. The eyelids, including the third eyelid (membrana nictitans), contribute to the formation and spreading of the precorneal tear film and play an essential protective role in clearing debris from the surface and preventing desiccation of the tear film during flight . AlthougThe gross and microscopic anatomy of eyelids in raptor species such as owls and hawks has been well-described . The infThe third eyelid moves across the cornea in a dorsonasal to ventrotemporal direction in owls , 2. In sThe elaborate epithelium of the third eyelid and unusual inferior plate are two of the most distinctive features of the barred owl eyelids and are the special focus of this paper.Ocular tissues were collected from one juvenile and five mature barred owls immediately after euthanasia was performed on birds with terminal injuries . The bir2, pH 7.4) within 30 min of euthanasia. After a minimum of 24 hrs, the tissues were rinsed and further dissected. For routine histology, tissues were embedded in paraffin, sectioned and stained using hematoxylin and eosin. For lectin labeling studies, tissues were rinsed in 50 mM glycine in HWB to block free aldehyde groups, dehydrated with a series of increasing concentrations of ethanol, infiltrated by butyl-methylmethacrylate (BMMA) and then the resin was polymerized at 4\u02daC using ultraviolet light [The entire eye and surrounding tissues were dissected bluntly and immersed in 2% paraformaldehyde in HEPES Wash Buffer  software multifocus software option on a Leica M205FA stereoscope to acquire an image with an extended depth of focus. To improve the contrast in the melanocyte-rich region, images were collected using the high dynamic range option of the LAS software.For the panoramic views of the conjunctiva, a series of overlapping brightfield images of paraffin sections was acquired using a 10x objective on a Leica DM5500B microscope equipped with a Leica DFC290 camera. The LAS software was used to create the composite image and the software\u2019s shading correction option ensured a uniform background illumination during collection of the brightfield images. The resulting composites were pasted onto a uniform background and linear adjustments of the contrast level of the entire image were made using Photoshop . The higher magnification, single field of view images of paraffin sections were taken using the LAS multifocus software feature to combine 3\u20135 optical planes in a single extended depth of focus image and then an identical linear adjustment to the contrast level of the entire image was made to each of the images.Wide-field fluorescence microscopy was performed on 0.5 \u03bcm acrylic resin cross-sections. No image processing steps were performed on fluorescent images other than cropping or re-sizing images to fit the journal requirements and to add text.2O), incubated in freshly prepared 0.4% thiocarbohydrazide for 30 min, rinsed in dH2O, and re-incubated in 1% osmium tetroxide for 1 hr. The second exposure to osmium caused a significant blackening of the tissue and resulted in superior contrast in the electron microscope. After further dH2O rinses and dehydration with an ethanol series, tissues were embedded in an epoxy resin . Thin sections were counterstained with uranyl acetate and Reynold\u2019s lead citrate solution prior to viewing using a JEOL 1400 transmission electron microscope. The Photoshop Unsharp Mask Filter  was applied to all digital electron micrographs.Specimens were fixed for greater than 24 hrs in 2% paraformaldehyde in HWB, rinsed with HWB, and further fixed using the osmium-thiocarbohydrazide-osmium technique . BrieflyAs is typical in birds, the lower eyelid was larger and more mobile than the superior eyelid. The outer marginal edge of each eyelid was deeply pigmented and puckered into \u201csausage-like segments\u201d  similar The keratinized epidermis adjacent to the eyelid margin was relatively thin with typically 2\u20133 layers of nucleated cells. The epidermis in this region contains sparse numbers of melanocytes and is lightly pigmented. As the epithelium turns inward to form the palpebral conjunctival surface, it became much thicker with up to 10 layers of nucleated cells; the number of melanocytes and level of pigmentation increased dramatically Figs . A largeThe eyelid\u2019s marginal zone remained keratinized for the approximately half the distance to the plate region and then tapers down to 5\u20136 non-keratinized layers before blending into the plate epithelium . There wThe endothelial cells lining conjunctival blood vessels were readily labeled by a variety of lectins including those with specificity against N-acetylgalactosamine 4 isolectThe palpebral surface of the orbital zone in both the superior and inferior eyelids had an irregular surface with mucosal pleats that presumably flatten out as the eyelid extends across the globe . Well-diOrganized conjunctiva-associated lymphoid tissue (o-CALT) was observed in three of the six birds (not shown). Single lymphoid follicles were found pressed up against the orbital epithelium but not in more proximal regions of the palpebral conjunctiva nor in the third eyelid. Lymphoid cells from the follicle penetrated into the overlying follicle-associated epithelium (FAE) and filled basolateral pockets between epithelial cells. Goblet cells were excluded from the FAE.The tapered leading edge of the third eyelid was covered by a pigmented, non-keratinized stratified squamous epithelium. The palpebral surface of the third eyelid was covered by an approximately five-cell-deep stratified squamous epithelium. Lectin staining did not reveal any glycoprotein-filled vesicles in these cells except for an occasional mucous cell near the junction with the superior or inferior eyelids. On the bulbar surface of the third eyelid, the pigmented, stratified squamous epithelium soon turned into an unpigmented, bilayer of epithelial cells. It was the apical membrane of the superficial cells in this bilayer that gives rise to the distinctive \u201cfeather duster\u201d architecture of the third eyelid. The structure of the apical membrane of these cells was so unique that it is difficult to describe it in terms normally used to characterize other epithelia. The apical surface of the cells was occasionally flat but more commonly formed domes or had elaborate protrusions . The domThe normal anatomy of the owl (Strigiformes) eye has been well-described . The hisAs previously described in other birds, no sebaceous glands were observed in either eyelid. This is consistent with avian skin in general not having sebaceous glands but rather the epidermal epithelium as a whole producing the phospholipids and neutral fats usually produced by those glands . WhetherButeo buteo) described the dense meshwork of collagenous fibers in this region but did not discuss the superficial epithelial layer [The palpebral conjunctiva in mammals is generally described as having marginal, tarsal and orbital zones but more appropriate terminology in raptors would be marginal, plate and orbital zones. The marginal zones of both eyelids were highly vascularized which is consistent with an earlier report that small-caliber palpebral arteries are particularly prone to injuries resulting from lacerations . There ial layer . In the The anatomy of the third eyelid is well-suited for its proposed role in cleansing the eye\u2019s surface of debris. As it passes over the eye, fluid and particulate matter presumably flows across the superficial surface of the leading edge until it passes over the marginal plait, which is a fold or pleat of tissue that runs along the length of the free margin. Fluid and debris in the sulcus formed by the junction of the marginal plait with the third eyelid\u2019s superficial surface would be then carried to the medial canthus and lacrimal ducts during retraction of third eyelid , 26. TheThe apical membrane specialization of the third eyelid\u2019s bulbar epithelium has an interesting phylogenic distribution. At the base of the avian tree of life, the Paleognathae (raites and tinamous) are a distinct radiation from the Neoganathae , 8. The Organized conjunctiva-associated lymphoid tissue (o-CALT), consisting of a well-developed lymphoid follicle in intimate contact with palpebral epithelium, has previously been described in chickens, turkeys, and mammals such as humans, rabbits, and Guinea pigs \u201332. The The consistent presence of granulocytes in the conjunctiva was an unexpected finding. Differentiating eosinophils from heterophils in routinely stained sections can be difficult in birds but the histochemical demonstration that the granules in these cells were peroxidase-positive established them as eosinophilssince avian heterophils lack peroxidases . The rolTwo of the six birds used in this study had ocular lesions noted in their initial clinical examinations . The preThe barred owl results in the present study form a foundation for future comparative studies with a phylogenic background that may give insight into the adaptive significance and evolutionary history of the morphological traits of the third eyelid and inferior fibrous plate in other raptors and more distant radiations."}
+{"text": "The Blood Brain Barrier (BBB) in Non-Human Primates (NHP) can be non-invasively opened through the use of Focused Ultrasound (FUS) in conjunction with microbubbles. This procedure allows for a targeted, transient opening in the BBB of the NHP which can be utilized to facilitate drug delivery. While FUS has been used to deliver various pharmacological compounds to promote neurogenesis or treat cancer, no group has investigated if drug delivery can affect behavioral responses. In this study, we show the effects of targeted ME-FUS drug delivery on the responses of NHP to a decision making task.The ME-FUS procedure was conducted on three (n = 3) NHP under general anesthesia (isoflurane) and in stereotactical positioning to ensure accurate targeting.Microbubbles  were administered IV at the onset of applying the FUS . The putamen region of the basal ganglia was targeted for all behavioral experiments. After the ME-FUS procedure there was a three hour recovery period allowing the NHP to fully recover normal motor functions impaired from the general anesthesia.IM injections of haloperidol  in the awake monkey were administered five minutes prior to the start of behavioral testing. The NHPs were trained to complete a reward magnitude bias and dot direction coherence task for water reward. One day after the ME-FUS procedure BBB opening and safety of the procedure was verified with contrast enhanced T1-weighted and T2-weighted MRI scans respectively.The BBB was successfully opened in the putamen region of each NHP for all ME-FUS procedures. No damage from the ME-FUS procedure was detected with the T2-weighted MRI scans. Delivery of haloperidol after BBB opening was shown to nullify a significant difference of reaction time between the contralateral and ipsilateral hands to the ME-FUS procedure observed with the saline controls. This significant difference in reaction time between hands was observed when haloperidol was administered without BBB opening. Delivery of haloperidol after BBB opening also negated a significant difference in reaction time between the high and low reward cues observed with the saline controls. Overall preliminary results show that FUS-induced BBB opening in NHP can be used to facilitate delivery of D2 antagonists to the putamen region causing significant effects on motivation and reaction time."}
+{"text": "Providers of bariatric surgery within the National Health Service (NHS) are required to provide psychological assessment and intervention, yet operational definitions regarding the purpose and scope of this input are lacking. This has led to significant variation in the provision of psychology, with some providing an assessment-only service and others providing a more comprehensive package of intervention throughout the patient pathway. The aims of this paper are to document the current psychology provision and service models of National Health Service (NHS) bariatric surgery services in the UK.Psychologists belonging to a bariatric psychology forum completed a survey. This focused on provision of psychological assessment and intervention throughout the bariatric pathway as well as the ratio between psychology resources and number of bariatric procedures per year. We obtained information from 22 NHS services which provide 3691 procedures per year.There is significant variation in the ratio between psychology resources and number of bariatric procedures undertaken per service. Whilst all services offer pre-surgery psychology assessments, less than one-third routinely assess all potential bariatric surgery candidates. Over 90% of services offer pre-surgery individual interventions and 41% offer pre-surgery groups. None of the services routinely offer post-surgery assessments but 68% offer post-surgery assessment and intervention following referral. None offered post-operative structured psychological group interventions.There are significant disparities and inconsistencies in the provision of psychology resources in relation to surgery volume in the NHS. Most of these resources are directed at pre-surgery assessment and this raises issues regarding the function of these assessments. Rather than focusing on assessing psychological (un)suitability for surgery, an evidence-based approach involves psychologists offering pre-operative interventions to improve readiness for surgery and post-operative interventions to address recurring or emerging difficulties which impact on outcomes. The rates of bariatric surgery have increased exponentially in the UK in the last decade . IndividThese can be roughly categorised as a) pre-existing psychological difficulties, b) psychological difficulties specifically related to the behaviour changes involved in bariatric surgery and c) post-operative development of new difficulties or reactivation of pre-existing difficulties.Rates of anxiety, depression , personaIn terms of post-operative psychological difficulties, these divide into those which are rare but potentially catastrophic, and subclinical difficulties associated with adjustment to major changes in the individual\u2019s weight, shape and identity. BED (or loss of control eating) is the most common eating disorder to re-emerge following bariatric surgery and is predictive of poorer weight loss at 12\u00a0months and 24\u00a0months . ConversMost of the literature on bariatric psychology practice has historically focused on pre-surgery psychological assessments and a number of studies have highlighted the lack of standardisation and wide variation in assessment methods, outcome decisions and recommendations ,15. PrevMost of the literature documenting bariatric psychology practice focuses on the methods, outcomes and frequency of psychological assessments and there is limited information regarding service provision beyond this. However, in the U.S., there are guidelines  which ma57 psychologists belonging to a UK obesity/bariatric psychology online forum hosted by the British Psychological Society (BPS) were asked to complete a survey which was emailed back to the authors (DR). Membership of this forum consists of psychologists who work in bariatric surgery and/or weight management services. It is not possible to ascertain how many of the 57 psychologists who were sent the survey work in bariatric surgery compared to non-surgical weight management services. Respondents were asked to a) provide information on the ratio of psychology input to number of patients and the type of team that the psychologist worked in b) the scope of the psychology service throughout the bariatric pathway. We intentionally restricted our sample to NHS providers of bariatric surgery as opposed to private healthcare providers in order to keep the organisational and financial framework standardised. The NHS Research Ethics Authority guidelines and online review tool indicated that this survey of psychologists does not fulfil criteria for formal research and therefore ethical review by an NHS Ethics Committee was not required.We obtained data from psychologists working in 22 NHS bariatric surgery services and this represents 39% of the psychologists belonging to the BPS online forum. We used data from the National Bariatric Surgery Register (NBSR)  to identTable\u00a0The total number of procedures across 21 (data not provided by one site) services is 3691. The NHS data available from 2012\u20132013 (which corresponds to when this survey was conducted) indicates that 8024 NHS bariatric procedures were undertaken in this year  and therThe variation in the amount of available psychology time and number of procedures is striking. For example, service R which performs 250 procedures has the same amount of psychology input (.2 WTE) as service C which performs 45 procedures. Additionally, service S has more than twice as much psychology provision as similar high volume services U and V.Of the 22 services that provided data, 13(59%) psychologists worked within the bariatric team, 5(23%) were part of a specialist weight management service, 3(14%) worked in a clinical health psychology department and 1(4%) worked in an eating disorder service. The majority of respondents (91%) attended the bariatric multidisciplinary team meeting.Respondents provided data on the amount of psychology assessment and intervention they provided throughout the bariatric surgery pathway.Participants were asked if their service offered pre-surgery psychology assessments and if so, whether this was routine for all patients. All 22 services indicated that they provide pre-surgery psychological assessments, however the majority of these services only assessed selected patients. Only seven services (32%) actually assessed all new patients , with the rest relying on triage by another member of the multidisciplinary team.Respondents were asked whether they provided individual or group psychological interventions prior to surgery. Twenty (91%) services reported that they provided individual interventions for pre-operative patients. These primarily focused on providing interventions for eating difficulties  in order to facilitate preparation for surgery. Nine (41%) services indicated that they provide pre-surgery groups for patients and these varied widely from solo seminar sessions to 12 session programs.Fifteen (68%) services indicated that they have the capacity to offer post-surgery psychological assessment and intervention but this was not routinely provided. Individuals were referred by other members of the multidisciplinary team. Fifteen (68%) services offered post-surgery individual psychological interventions. Support groups were provided by some services but none reported that they were currently providing structured, focused therapy groups to address post-operative difficulties or adjustment.Respondents were asked to indicate how frequently they thought that other members of the multidisciplinary team perceived the function of the pre-surgery psychological assessment as being to control access to bariatric surgery through \u201cgatekeeping\u201d. The gatekeeping role refers to whether others (team/patients) view the purpose of the psychological assessment as being the determination of suitability for surgery. Table\u00a0Respondents were asked for their view of where psychological input was most needed across the bariatric pathway and the responses are shown in Table\u00a0This survey data reveals stark differences in the level of psychology provision across NHS bariatric services in the UK reflecting adhoc arrangements rather than systematic planning based on volume of patients and psychological need. Similarly to other surveys of service provision ,22, mostThe data indicates that whilst most services offer pre-surgery assessments, only one-third assess all bariatric surgery candidates. This is significantly different from the practice reported in other surveys ,19,20 whThe results from this survey indicated that a surprisingly low number of services (41%) provide pre-operative groups for bariatric candidates and this reflects a divergence from the evidence base. Pre-surgery groups increase patient\u2019s preparedness and readiness for bariatric surgery and are associated with increased ability to implement and adhere to post-operative changes . PatientTwo-thirds of services offer post-operative assessments and follow up appointments but these are not routine for all patients. Therefore, the onus is on other members of the multidisciplinary team to detect and highlight psychological difficulties as they continue to see patients post-operatively and there is a lack of post-operative psychological follow up appointments. This approach is vulnerable to individual differences in level of skill, confidence and sensitivity and research demonstrates that health professionals are generally poor at detecting distress . Whilst Whilst some of the services offered support groups, none provided structured post-operative intervention groups. A meta-analysis of post-operative groups and weight lossconcluded that psychological interventions alongside surgery are associated with better outcomes in terms of weight loss than bariatric surgery alone .Whilst aThe aim of this survey was to document the range of psychological input across a bariatric surgery pathway rather than focusing on the technical aspects of this input . However, in order to make the most meaningful interpretations it would be helpful to gather detailed data about the amounts of psychological input provided before and after surgery in order to optimise comparison and make meaningful conclusions about the likely impact on patient care. Whilst this survey provides data on how many of the psychologists offer input at various junctures in the pathway, we do not know how many patients actually receive this input. A further limitation of this study is that it is not possible to calculate a precise response rate. The survey was distributed via an online forum and the members consist of a mix of psychologists working in bariatric surgery or weight management services and the precise membership numbers of each group is unknown. It is equally difficult to obtain accurate information about the number of NHS bariatric units in the UK as submission to the National Bariatric Surgery Register is voluntary. In order to address these shortcomings, we used data on the total number of bariatric procedures carried out by the NHS in the same year that this survey was undertaken and calculated that the total number of procedures performed by the services included in this sample accounted for a significant proportion of these.Bariatric surgery involves a psychologically vulnerable client group undergoing a psychologically challenging and demanding procedure that is dependent on significant behaviour change and the development of new coping skills. This survey indicates that there is significant variation in the provision and scope of NHS bariatric psychology services in the UK. There is a need for a clear and consistent relationship between the amount of psychology resources and surgery volume. In addition, guidelines are needed regarding the minimum  level of psychological input throughout a bariatric surgery pathway. It is striking that most of the psychological input seems to be directed at pre-operative assessment yet delivering pre and post-operative interventions is likely to have more impact on outcomes. Given the prevalence of mental health problems amongst this population, psychological complications should be expected and having the capacity, resources and skills to respond to these is critical. In order to make optimum use of psychologist\u2019s skills, we need to configure bariatric psychology services to provide pre-surgery interventions focused on improving readiness and preparation for surgery, and post-surgery interventions which counteract emerging difficulties which could jeopardise weight loss and psychosocial outcomes."}
+{"text": "Sound-shape associations involving consistent matching of nonsense words such as \u2018bouba\u2019 and \u2018kiki\u2019 with curved and angular shapes, respectively, have been replicated in several studies. The purpose of the current study was to examine the robustness of previously noted sound-shape associations when shape variations (angular and curvy) are embedded in schematic expressions of emotions (sad and happy). Results revealed consistent matching tendencies based on sound-emotion expression mapping irrespective of the particular shape of the expressions. We suggest that internally simulating the facial expressions/oral gestures may have played a significant role in driving the matching preferences. Recent studies that reveal consistency in different kinds of sound-meaning associations, and the increasing scope of multimodal activations in the brain raise questions about the extent of arbitrariness in language  leading to comparable acoustic characteristics\u2014raising and lowering of filtered frequency components referred to as formants e.g., . ListeneEach of the four computerized schematic drawings of faces was presented individually three or four times with randomly chosen word pairs see . The aurt test, t(49)\u2009=\u20091.59, p\u2009>\u2009.05). The sad curve face and the sad angular face was each matched more frequently with words containing the /o/ vowel sound. The preference for the /o/ vowel sound did not differ between these two faces \u2009=\u20090.35, p\u2009>\u2009.05).As If the acoustic characteristics associated with the exact shape of the facial expressions were being mapped onto the acoustic characteristics of the words presented aurally, the shape differences within each emotional category (curved vs. angular versions of happy and sad faces) would have resulted in a notable difference in the choices of vowel sounds; however, a difference did not emerge. We cannot rule out the potential influence of emotional contagion e.g., , in thatIn sum, the current study in conjunction with the previous ones on sound-symbolism demonstrate that cross-modal matching may allow for non-arbitrary associations of the vocal\u2013verbal signal with aspects of inanimate and animate entities (including the self and others). When two or more aspects co-occur, these may compete with one another or one may supersede the others in guiding the associations; in the current study, the facial expressions took precedence over the angularity or curviness of the expressions. Also, there exists the possibility of covert imitation of the oral gestures alone (retraction of lips and rounding or protrusion of lips), devoid of any emotional meaning, to aid this kind of auditory visual matching task (see"}
+{"text": "Our laboratory has characterized and cloned a human betaretrovirus resembling the mouse mammary tumor virus (MMTV) from biliary epithelium and lymph nodes of patients with the autoimmune biliary disease, primary biliary cirrhosis (PBC). Evidence for betaretrovirus infection has been detected mainly in patients\u2019 lymphoid tissue by RT-PCR and immunohistochemistry in approximately 75% of PBC patients. However, the viral burden was observed to be far less in the liver and we could only identify viral sequence in a third of patients using RT-PCR. Other labs have been unable to confirm our data using PCR of hepatic DNA. Not surprisingly, the betaretroviral association with PBC has become a controversial issue. In order to provide more robust evidence of infection in patients with liver disease, we have isolated an infectious betaretrovirus from lymph nodes. We cloned and sequenced the proviral isolates and confirmed viral particles by electron microscopy. We have also conducted ligation-mediated PCR studies with next generation sequencing and found proviral integration sites both in vivo and in vitro. To date, we have identified more than 3,000 integration sites in perihepatic lymph nodes, liver and isolated biliary epithelium in the majority of patients with PBC and seldom in patients with other liver diseases. These data confirm the presence of an MMTV-like virus in patients with autoimmune liver disease. Ongoing studies using biliary disease mouse models with MMTV infection and randomized controlled anti-retroviral trials for patients with PBC will be required to further characterize the association of human betaretrovirus infection with PBC."}
+{"text": "Epigenetic modifications have the ability to change the susceptibility to metabolic diseases like obesity. DNA methylation can change during a life course due to environmental exposures like diet.To determine the effects of dietary methyl-group intake during pregnancy on the DNA methylation pattern of mother and child. In addition, the association between the DNA methylation pattern of the mother and child on body composition/weight gain of the infant during the first year will be studied.Validated questionnaires are used to obtain information about lifestyle and environmental factors that can influence DNA methylation. A food-frequency questionnaire was developed and validated to categorize women in groups according to their methyl-group intake. Women fill out a 7-day dietary record to have information about macro- and micronutrient intake. Body composition is followed up by means of the bio-electrical impedance method. Blood samples are collected during pregnancy and until 1 year postpartum. Cord blood is taken and mouth epithelial cells are obtained from the infants at 6 and 12 months. Samples will be analyzed for global DNA (de)methylation by liquid chromatography-mass spectrometry and specific target genes involved in DNA (de)methylation and genes linked with obesity/adiposity by pyrosequencing.We have recruited 166 and 95 expectant mothers and fathers respectively, who are followed up in UZ Leuven. Our first results give an indication that the intake of methyl-groups during pregnancy is stable, except for a decrease in total folate intake in the second and third trimester. Also, global DNA methylation analysis shows that maternal methylation is rather stable over pregnancy, with a small decrease  in methylation by the end of pregnancy.With this study we will gain insight on the effect of maternal nutrition on offspring DNA methylation and potentially identify DNA methylation biomarkers at birth that can mediate problems with metabolism/obesity."}
+{"text": "Synaptic plasticity alters the strength of information flow between presynaptic and postsynaptic neurons and thus modifies the likelihood that action potentials in a presynaptic neuron will lead to an action potential in a postsynaptic neuron. As such, synaptic plasticity and pathological changes in synaptic plasticity impact the synaptic computation which controls the information flow through the neural microcircuits responsible for the complex information processing necessary to drive adaptive behaviors. As current theories of neuropsychiatric disease suggest that distinct dysfunctions in neural circuit performance may critically underlie the unique symptoms of these diseases, pathological alterations in synaptic plasticity mechanisms may be fundamental to the disease process. Here we consider mechanisms of both short-term and long-term plasticity of synaptic transmission and their possible roles in information processing by neural microcircuits in both health and disease. As paradigms of neuropsychiatric diseases with strongly implicated risk genes, we discuss the findings in schizophrenia and autism and consider the alterations in synaptic plasticity and network function observed in both human studies and genetic mouse models of these diseases. Together these studies have begun to point toward a likely dominant role of short-term synaptic plasticity alterations in schizophrenia while dysfunction in autism spectrum disorders (ASDs) may be due to a combination of both short-term and long-term synaptic plasticity alterations. The recent advances over the past several decades in molecular biology, human genomics, and bioinformatics has helped to enable the identification of numerous candidate genes and distinct genetic mutations in a variety of human neuropsychiatric illnesses that may be the responsible agents for causing their symptomology. Based on the genetic mutations identified by human genomic analyses, many of these mutations have been introduced into the mouse genome to create genetic mouse models of these human diseases in the hope that the invasive and precisely refined experimentation permitted in mice will help to reveal the details of the molecular and neuronal dysfunction underlying these diseases. Despite the availability of these powerful experimental tools, the daunting molecular, anatomic, and functional complexity of the central nervous system demands that targeted and well-considered hypotheses be generated within this overwhelming complex system in order to direct experimental investigations to the systems and processes where dysfunction is most likely to be found in each unique disease.When considering the underlying mechanistic causes of the dysfunction and symptomology of neuropsychiatric diseases, a thoughtful consideration of the most prominent features and most characteristic symptoms of each disease is a useful starting point for hypothesis generation. It has been proposed that the core commonality of dysfunction amongst neuropsychiatric diseases is a deficit in the information processing performed both by and between the various neural microcircuits located throughout the brain , the disease is also characterized by both \u201cnegative\u201d symptoms  as well as severe cognitive deficits that may in fact contribute more substantially to functional disability and quality of life than the more prominent positive symptoms  have been proposed as candidates underlying altered synaptic plasticity . The plausibility of this interpretation is supported by the broadly reported findings indicating that neuronal degeneration and death, pervasive alterations in neuronal and synaptic morphology, and deficits in synaptic maintenance are fundamental characteristics of AD pathology. Thus, while the memory deficits of AD do indeed imply neuronal and neural circuit dysfunction, these dysfunctions are likely a consequence of significant alterations in functional connectivity between neurons that affect neural circuit architecture rather than modulatory changes in neuronal function that serve to sculpt information processing in a largely intact and functional neural circuit. Taken together, both the symptomology and the profound degeneration and neuronal derangements present in AD dementia suggest that the underlying disease dysfunction in most cases is not likely primarily due to subtle changes in neuronal function such as alterations in synaptic plasticity mechanisms.In considering the cognitive deficits present in Alzheimer's disease (AD), for example, while there is some waxing and waning of symptomology, the memory deficits characteristic of AD dementia are largely persistent, pervasive, and progressive. While these memory deficits are possibly due in part to deficits of long-term plasticity, the major pathology underlying the dementia is likely to be predominantly the consequence of the neuronal death and degeneration that would fundamentally alter the connectivity of neural circuits involved in memory formation and storage  caused by the genetic mutations that is required to create an accurate functional representation of human disease in mouse models is known for only a very small subset of these implicated genes. Here we discuss the findings in genetic mouse models of schizophrenia that meet these criteria. Intriguingly, studies among these mouse models have revealed that, while long-term synaptic plasticity is relatively intact, a striking preponderance of short-term plasticity alterations suggesting that the neural circuit dysfunction caused by these genetic risk variants may likely be due in large part to alterations in presynaptic function that fundamentally impact synaptic computation Table .de novo, and account for 1\u20132% of sporadic schizophrenia cases , synapses onto layer V neurons in the mPFC\u2014although showing normal basic synaptic transmission and paired-pulse ratios\u2014demonstrated enhanced synaptic depression during high-frequency stimulus trains and reductions in the initial phase of the synaptic potentiation (short-term potentiation) induced by the high frequency stimulus train for LTP induction  within the nucleus which are involved with repressing translation of their target mRNAs  is a gene that was implicated in schizophrenia through its discovery as the gene disrupted by a chromosomal translocation that cosegregated with mental illness in a family pedigree prominently affected by schizophrenia, bipolar disorder, and major depression \u2014CA1 hippocampal synapses . The authors suggest that, as SWRs during rest are believed to orchestrate sequential \u201creplay\u201d of place cell activity in order to maintain spatial information, the absence of sequential replay of place cells during SWRs observed in calcineurin-deficient mice may underlie the severe spatial WM deficit previously described , their findings consistently point toward network-dysfunction in the context of alterations in synaptic plasticity. Although none of these studies provides an unequivocal causal link between synaptic plasticity deficits and the observed network dysfunction, these results nonetheless compellingly suggest that calcineurin deficiency or hypofunction in schizophrenia may lead to similar synaptic plasticity alterations that would lead to significant changes in the information processing performed by neural circuits.Dysfunction in NRG1 signaling pathways has been implicated in the pathophysiology of a variety of neuropsychiatric diseases including schizophrenia  interneurons known to be fundamental to regulating synchronized network activity  that serves to terminate cycles a G-protein signaling by converting active G\u03b1 subunits to their inactive state . The reduced activity of these presynaptic Ca2+ channels in RGS2-deficient synapses results in reduced neurotransmitter release in response to APs. When RGS2 is present in presynaptic terminals these hippocampal synapses are either depressing or non-facilitating by paired-pulse paradigms, indicative of a high presynaptic Pr. RGS2-deficient synapses, however, show paired-pulse facilitation suggesting that in the absence of RGS2 the presynaptic Pr is decreased. In additional support of this action at voltage-gated Ca2+ channels, RGS2-deficient synapses required more extracellular Ca2+ for the same degree of NT release as WT synapses yet both synapses showed indistinguishable NT release in response to hypertonic sucrose challenges. The results of this study indicate that RGS2 deficiency leads to changes in presynaptic function that result in changes in short-term synaptic plasticity and further suggests that a similar scenario may likely result in cases of RGS4 deficiency.The paper that best describes the possible synaptic mechanism and impact of RGS4 deficiency upon presynaptic function, however, is a report that examines the effects of RGS2 deficiency\u2014rather than RGS4 deficiency\u2014upon synaptic function in cultured hippocampal neurons  upon postsynaptic receptor blockade. Each of these results is consistent with a role of dysbindin in enhancing the Pr of presynaptic NT release (and dysbindin deficiency leading to reduced NT release), most likely through an action of dysbindin that enhances the Ca2+ sensitivity of the NT release machinery. This study convincingly illustrated that dysbindin deficiency altered ST plasticity by transforming a modestly facilitating synapse into a strongly facilitating synapse. This finding supports the possibility that dysbindin-deficient synapses in the mammalian CNS would have similar alterations in ST plasticity that would be expected to significantly alter synaptic and neural circuit computation.Perhaps the most informative study of dysbindin function was performed at the glutamatergic neuromuscular junction (NMJ) in 2+ flux into synaptosomes upon depolarization all consistently point toward a decrease in the presynaptic Pr of NT release in dysbindin-deficient synapses mice. Furthermore, although not reaching statistical significance, this study performed assays to determine Pr more directly and showed a ~35% reduction in presynaptic Pr in dysbindin-deficient mice. Thus, although this study did not directly examine either short-term or long-term plasticity by traditional electrophysiological assays, taken together these findings strongly support a reduced presynaptic Pr due to dysbindin deficiency that would be expected to lead to alterations in short-term plasticity in neural circuits in the mammalian mPFC.A recent study of synaptic transmission onto layer V pyramidal neurons in the mPFC in dysbindin-null mice reported a number of findings consistent with the altered presynaptic function described at the Drosophila NMJ  is a heterogeneous neurodevelopmental with an approximate 1% prevalence in the population that has a heritability supporting a strong genetic component  show reduced functional connectivity while local microcircuitry and short-range connections show evidence of enhanced connectivity Mundy, . AssessmAlthough a number of mouse models of autism based on human genetic findings have been made, neuronal and synaptic function have been most thoroughly explored in mice modeled upon Rett syndrome (MECP2 gene deletion) and fragile X syndrome (FMR1 gene deletion). While both of these human disorders are syndromic in nature and manifest a variety of clinical features in addition to ASD symptomology, important insights about synaptic plasticity alterations underlying autism symptomology can still be gleaned from these mouse models despite these potentially complicating factors. Both Fmr1 and Mecp2 null mice demonstrate deficits in long-term memory and learning that are consistent with the possibility of an underlying deficit in long-term synaptic plasticity , and acoustic mismatch negativity (MMN) appear to reflect information processing abnormalities within relatively simple and isolated neural circuits (Clements et al., The progress in unraveling the mechanisms underlying neural circuit dysfunction in human neuropsychiatric diseases has been enormously accelerated by the recent advances in human genomics that have enabled the identification of an abundance of candidate genetic risk variants that may be the responsible agents for causing disease symptomology. Specifically, the identification of highly penetrant risk genes for schizophrenia and autism has led the creation of etiologically valid mouse models for these diseases that have enabled detailed investigations directed at identifying synaptic, neuronal, and neural circuit dysfunction. Studies in these mouse models have revealed both neural circuit dysfunction as well as a variety of synaptic plasticity alterations that may be responsible for this dysfunction given the critical role of synaptic plasticity in sculpting information flow within neural circuits. Overall, while mouse models of schizophrenia have shown a preponderance of short-term plasticity alterations consistent with disease symptomology, mouse models of autism appear to present a more balanced combination of both short-term and long-term plasticity alterations that may be consistent with the more profound dysfunction present in the clinical picture of this spectrum of disorders.in vivo imaging, electrophysiology, and optogenetics are beginning to help reveal new levels of details of normal neural circuit that will enable more sophisticated assessment of neural circuit function in disease. Taking these considerations together, the strategic approach to understanding neural circuit dysfunction in neuropsychiatric disease is rapidly evolving on multiple technical fronts and now seems poised to shortly make major revelations regarding the mechanisms of neural circuit dysfunction in these diseases.These initial successes with schizophrenia and autism strongly suggests that, despite the failure to date to identify highly penetrant genetic risk variants for many of the more common neuropsychiatric diseases such as anxiety disorders and major depression, this strategic approach may represent the necessary pathway forward for these diseases as well. Yet, beyond negotiating the complexities of the genetic architecture of neuropsychiatric diseases, in order to effectively identify neural circuit dysfunction and resolve the underlying neuronal and synaptic mechanisms that lead to it, additional considerations need to be thoughtfully addressed. As a symptomology-based approach to neuropsychiatric disease has revealed significant overlapping disease phenomenology, dissecting the causes of unique forms of neural circuit dysfunction underlying disease will likely require further identification and utilization of more simplified, quantifiable endophenotypes that examine precisely defined parameters more directly and more closely related to alterations in specific brain regions and functions. In addition to the advantage that assays of such endophenotypes are readily translatable to assess neural circuit dysfunction in mouse models of disease, assessing the genetic risk variants contributing to individual endophenotypes\u2014compared to the global risk for disease based upon symptomology\u2014should facilitate dissecting disease mechanisms due to the likely identification of a much smaller and more manageable number of genes responsible for dysfunction. Finally, although our current understanding of even the most fundamental aspects of normal neural circuit function remain rudimentary, the continuing technical advances in The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Nonetheless, the evaluation of LEP-related GBO might contribute to uncover residual pain perception even in those totally non-communicative patients, even though it is still debated whether or not GBO can be reliably assessed at single-subject level.Future studies should be fostered in an attempt to shed some light on the role of combined LEP-GBO analysis in pain perception assessment in DOC patients.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "What are the effects of chess training\u2014especially on scholastic achievement among school-aged students? Can chess instruction facilitate the acquisition of scholastic competency? The current state of the research literature is that chess training tends not to provide educational benefits. This article provides a critical review of research on the effects of chess training on the scholastic achievement levels of school-aged students.Various studies and conference presentations .In another recent study Kazemi et al.  examinedThe chess group participants registered significantly higher posttest metacognitive ability scores and higher posttest mathematics test scores than the non-chess group participants. A major conclusion of the study is that chess instruction improves significantly the mathematical abilities and the metacognitive capacities of school-aged students.In a third study, Trinchero  examinedThese last four studies lend support to the view that chess training has positive cognitive effects on regular school-aged students. In addition, there are some studies that address the issue of cognitive effects of chess training on school-aged students with disabilities.Scholz et al.  investigIn a second study Barrett and Fish  investigThis study had some interesting results. First, there was a significant relationship between chess instruction and end-of-year grades. Second, there was a statistically significant relationship between chess instruction and mathematics TAKS test scores.This study provided support that chess instruction facilitates transfer of cognitive skills from chess to mathematics for students in special education.These latter two studies using special education students indicate that chess instruction has the potential to promote mathematics achievement among students in special education.In a third study Hong and Bart  examinedAll participants were tested prior to and after the intervention with the following several instruments: (a) the Test of Nonverbal Intelligence\u2014Third Edition (TONI-3) to measure cognitive ability in a language-free manner; and (b) a Chess Skill Rating method using chess software to assess level of chess competency.TONI-3 posttest scores and chess skill ratings were significantly correlated after controlling for TONI-3 pretest scores. This statistical finding suggests that chess instruction that produces higher chess skill ratings may lead to gains in levels of non-verbal intelligence among students at risk for academic failure.These studies indicating positive effects of chess training among students with disabilities support the view of Storey  who extoBut why would chess training lead to improvements in scholastic achievement? To play chess well, one must attend to and comprehend chess positions and induce patterns among the pieces, an indication of fluid intelligence and concentration capacity. The chess positions can be very complex with up to 32 pieces from six piece types arrayed on a 64 square board.One must then formulate and evaluate possible moves, an indication of executive functioning and critical thinking. For example, middle game positions often permit 30 different legal moves at every turn. The chess player must ideally evaluate positions resulting from such moves selecting the move that produces the position most advantageous to the player. The chess player must evaluate chess moves and their resulting positions without actually moving any pieces. There are thus substantial demands on visual working memory.In chess, one must engage in this sequence of (1) position comprehension, (2) pattern induction, and (3) move formulation and evaluation relatively quickly. This coordinated set of cognitive skills required in competent chess play likely transfers to the learning of mathematics and related fields that also often require comprehension, induction, analysis, and evaluation of complex phenomena. This constitutes a theoretical framework why chess training likely has cognitive benefits. This cognitive explanation for the benefits of chess training is compatible with comparable explanations provided by Storey  and TrinThe research reported thus far provides evidence that chess training has salutary cognitive and educational effects among school-aged students. However, the argument of Gobet and Campitelli  needs toHowever, such rigorous experimental inquiry involving, for example, random placement of participants into experimental and control groups is costly and difficult to implement in a school setting. What is needed is an increase in the quality and quantity of empirical studies to determine the extent to which the acquisition of chess expertise facilitates the acquisition of scholastic expertise among students.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Demyelinating plaques may induce headache through disruption of the pathways, which are implicated in the pathogeneses of migraine. We report a case of 25-year-old female patient, who presented with status migrainosus fulfilling the criteria of international classification of headache disorder. She was eventually diagnosed with multiple sclerosis (MS) after an extensive work-up and long-term clinical and radiological follow-up.At the onset of status migrainosus, magnetic resonance imaging (MRI) revealed the presence of several demyelinating lesions fulfilling Swanton criteria. She was started on migraine prophylactic treatment but there was no subsequent response. One year later, she presented with recurrent status migrainosus and a follow-up MRI revealed multiple gadolinium-enhancing lesions in the brain. She was treated with abortive migraine medications. Within the following 2 year, she developed ascending parasthesia and weakness of both lower limbs indicative of incomplete transverse myelitis in association with recurrent status migrainosus. A diagnosis of MS was established based on a follow-up MRI that satisfied the revised 2010 McDonald criteria. Both the headache and neurological signs improved with IV methylprednisolone therapy. Her headache entered remission after initiation of a disease modifying therapy.Status migrainosus can be the initial presentation of MS. Unresponsiveness to migraine prophylactic therapy in the presence of active demyelinating plaque in MRI brain may pose a diagnostic challenge and a diagnosis of MS might be considered. Multiple sclerosis (MS) can cause various neurological symptoms depending on the location of demyelinating plaques   level. A follow-up MRI brain with gadolinium revealed multiple new enhancing lesions with an open-ring pattern Figure\u00a0. A lumbaThe patient was diagnosed with MS according to the revised 2010, McDonald criteria since she presented with incomplete transverse myelitis and after MRI showed dissemination in time and space . The presence of demyelinating lesions at brainstem may explain the presentation of MS onset with migraine headache (Gee et al. The causal relationship between migraine and MS, in our case, was suggested by the subsequent improvement of headache with a DMT. On the other hand, a response to corticosteroids such as methylprednisolone does not necessarily this causal relationship as both conditions may show improvement with the use of corticosteroids. Both migraine and MS are relatively common in young females and both may accidentally co-exist. The prevalence of migraine in patients with MS is between 20% to 45% (Kister et al. Migraine and MS share several features. Both have a relapsing-remitting course affecting the central nervous system with occasional chronic evolution, more prevalent in women of childbearing age, and both appear to be influenced by hormonal changes; i.e., less exacerbations throughout the first two trimesters of pregnancy (Kister et al. The mechanism behind the association of MS and migraine is debatable and several hypotheses were introduced. First, headache may be induced by the inflammatory demyelinating MS lesions by disrupting the pathways implicated in the pathogenesis of migraine (Kister et al. Status migrainosus in the presence of demyelinating MRI features at the initial presentation may pose diagnostic dilemma. Failure to respond to prophylactic migraine therapy in view of progressive demyelinating features on follow-up MRIs may point to another relatively common neurological disorder such as MS among young women.Written informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal."}
+{"text": "A 51-year-old woman presented to the emergency department after sustaining a transverse volar laceration over the middle phalanx of her right small finger. On physical examination, the patient was unable to flex her finger at the proximal or distal interphalangeal joint.How would you classify the aforementioned injury?What are the challenges involved in treating this acute injury?What is the importance of hand therapy and follow-up after tendon repairs?What are options for reconstruction after a failed primary tendon repair?Flexor tendon injuries are categorized into 5 zones defined by anatomical landmarks. Zone 1 consists of injuries in the space distal to the flexor digitorum superficialis insertion. Subsequent zones are demarcated at their proximal margins by the A1 pulley (zone II) as seen in the aforementioned injury, the distal edge of the carpal tunnel (zone III), proximal edge of the carpal tunnel (zone IV), and proximal to the carpal tunnel (zone V). This classification helps guide prognosis and management of flexor tendon injuries, as the anatomical characteristics of each dictate the ease of repair and the required stringency of postoperative follow-up.1Zone II tendon injuries are difficult to treat as the flexor digitorum superficialis and flexor digitorum profundus tendons are vulnerable to adhesion formation or rupture after primary repair.3Appropriate postoperative hand therapy is crucial in regaining flexor function. Stressed tendons heal faster and are stronger, develop fewer adhesions, and have better function than tendons that remain immobilized.3When tendon repairs rupture within 3 weeks of the initial tendonorraphy, the tendon can be readvanced and repaired primarily.6Our patient successfully underwent delayed secondary repair of the flexor digitorum profundus tendon and the flexor digitorum superficialis tendons 18 days after initial presentation. However, she failed to return for follow-up on the first postoperative day or participate in hand therapy. She presented 10 days later and was found to have suffered a rupture of her primary repair due to premature removal of the dorsal blocking splint. The patient was subsequently lost to follow-up. This unfortunate case underscores the importance of meticulous surgical technique and patient compliance in postoperative follow-up to obtain optimal results."}
+{"text": "Persons who died of Ebola virus disease at home in rural communities in Liberia and Guinea resulted in more secondary infections than persons admitted to Ebola treatment units. Intensified monitoring of contacts of persons who died of this disease in the community is an evidence-based approach to reduce virus transmission in rural communities. Transmission of Ebola virus occurs through direct contact with blood or other body fluids of an infected person after symptoms have developed. During an outbreak of Ebola virus disease (EVD), monitoring persons (termed contacts) who have exposure to persons with EVD is the most effective way to identify and isolate new cases rapidly before transmission can occur  guidelines for monitoring contacts of -persons with EVD treat all contacts equally  of Liberia (July\u2013December 2014) (>3 days of admission or recovery) at the time of admission to an ETU, and between persons who were buried safely by trained burial teams and those buried by untrained persons (in Guinea only). Additional details on statistical analyses are included in the Data for Liberia and Guinea were combined. We used generalized estimating equations with a negative binomial distribution to compare the number of secondary infections between groups, including between persons with EVD who died at home in the community and those admitted to an ETU, between persons who were severely ill (death <3 days after admission) and those less ill  persons were confirmed by using laboratory analysis  as having EVD . Most  persons with EVD who had outcome data; 99 (31%) resulted in e status . When wee status , panel AWe found no significant difference in the mean number of secondary infections between those who died <3 days after admission to the ETU  and those who died later in their hospitalization or recovered  , panel BIn rural outbreaks in Liberia and Guinea, Ebola virus transmission was driven by contact with persons who died of EVD at home, and isolation before death was associated with 88% fewer secondary infections. Possible reasons for a larger number of secondary cases associated with deaths at home in the community include 1) a higher per-contact probability of transmission caused by higher levels of viremia or more exposure to body fluids during terminal illness and death (Because we did not find an increase in secondary infections according to severity of illness at the time of ETU admission (a proxy for level of viremia), we believe that factors associated with the death are critical in transmission. Traditional burial practices in West Africa include touching and washing the body after death (Yamin et al. used a stochastic modeling approach to integrate epidemiologic data on Ebola from Liberia to identify potential intervention targets (In Guinea, we did not find burials reported as safe to have had an effect on reducing the number of secondary infections. Although some of the safe burials might have been misclassified, it is more likely that traditional mourning practices occurred before safe burial teams arrived (Classifying contacts of persons who died of EVD at home in the community as high-risk, regardless of whether they were reported to have received a safe burial, is an evidence-based approach to prioritizing those persons who should receive more rigorous monitoring. Intensive follow-up could include assignment of highly trained staff to evaluate high-risk contacts more frequently, provision of incentives to complete the 21-day monitoring period, and housing high-risk persons in managed voluntary quarantine facilities.Additional information on statistical analysis for secondary infections with Ebola virus in rural communities, Liberia and Guinea, 2014\u20132015."}
+{"text": "The small GTPase Ran regulates the interaction of transport receptors with a number of cellular cargo proteins. The high affinity binding of the GTP-bound form of Ran to import receptors promotes cargo release, whereas its binding to export receptors stabilizes their interaction with the cargo. This basic mechanism linked to the asymmetric distribution of the two nucleotide-bound forms of Ran between the nucleus and the cytoplasm generates a switch like mechanism controlling nucleo-cytoplasmic transport. Since 1999, we have known that after nuclear envelope breakdown (NEBD) Ran and the above transport receptors also provide a local control over the activity of factors driving spindle assembly and regulating other aspects of cell division. The identification and functional characterization of RanGTP mitotic targets is providing novel insights into mechanisms essential for cell division. Here we review our current knowledge on the RanGTP system and its regulation and we focus on the recent advances made through the characterization of its mitotic targets. We then briefly review the novel functions of the pathway that were recently described. Altogether, the RanGTP system has moonlighting functions exerting a spatial control over protein interactions that drive specific functions depending on the cellular context. Xenopus eggs  interacts with karyopherin-\u03b2 proteins with high affinity, while it dissociates in its GDP bound form (RanGDP). RanGTP binding to importins and exportins have very different consequences: it stabilizes the exportin-cargo interaction whereas it destabilizes the importin-cargo interaction Figure .The RanGEF (guanine nucleotide exchange factor) RCC1 associates with the chromatin inside the nucleus, whereas RanGAP (GTPase activating protein) is cytoplasmic. As a consequence the predominant form of Ran in the nucleus is bound to GTP, while in the cytoplasm it is bound to GDP. Thereby NLS proteins transported to the nucleus by importins are released and accumulate in the nucleoplasm, whereas NES proteins in complex with exportin-RanGTP are transported out of the nucleus Figures .Although the nucleo-cytoplasmic transport is no longer needed when a cell enters into mitosis, its complex molecular machinery is recycled to promote MT assembly around the chromatin and to direct the organization of the bipolar spindle  through the FPI fellowship BES-2010-031355. Work in the Vernos lab was supported by the Spanish ministry grants BFU2009-10202 and BFU2012-37163, co-financed by the European Regional Development Fund (ERDF/FEDER). We also acknowledge support of the Spanish Ministry of Economy and Competitiveness, \u201cCentro de Excelencia Severo Ochoa 2013-2017,\u201d SEV-2012-0208.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "A receptors, scaffold proteins and structural molecules. This implies a dynamic modulation of receptor intracellular trafficking and receptor surface lateral diffusion, along with regulation of the availability and distribution of scaffold proteins. This Review will focus on the mechanisms of the multifaceted molecular reorganization of the inhibitory synapse during postsynaptic plasticity, with special emphasis on the key role of protein dynamics to ensure prompt and reliable activity-dependent adjustments of synaptic strength.The plasticity of inhibitory transmission is expected to play a key role in the modulation of neuronal excitability and network function. Over the last two decades, the investigation of the determinants of inhibitory synaptic plasticity has allowed distinguishing presynaptic and postsynaptic mechanisms. While there has been a remarkable progress in the characterization of presynaptically-expressed plasticity of inhibition, the postsynaptic mechanisms of inhibitory long-term synaptic plasticity only begin to be unraveled. At postsynaptic level, the expression of inhibitory synaptic plasticity involves the rearrangement of the postsynaptic molecular components of the GABAergic synapse, including GABA A receptors (GABAARs) clustered at synapses, tonic conductance arises from extrasynaptic GABAARs typically composed of \u03b11/4/6\u03b2\u03b4 and \u03b15\u03b2\u03b3. It is well known that inhibitory transmission is crucial to tune neuronal excitability and to regulate network integration. In particular, at network level, inhibitory synaptic signals are fundamental for generating coherent oscillations and selection of cell assemblies  receptors mediate the majority of inhibitory signals in the brain. GABAergic inhibition consists of a fast and precisely timed component generated by the vesicular release of GABA in the synaptic cleft (phasic inhibition), and of a persistent tonic conductance due to receptor activation by ambient GABA (tonic inhibition)  will not be addressed here, since they have been extensively discussed in excellent reviews , as observed in cultured neurons, in slices and in vivo  that tightly modulate receptor intracellular trafficking by acting on specific sites of receptor intracellular domains. It has been initially demonstrated that the intracellular application of preactivated CaMKII potentiates GABAergic currents evoked with exogenous GABA pulses by increasing the phosphorylation of Ser 383 of GABAA receptor \u03b23 subunit , PP2A and calcineurin  administration  have been mutated to phenylalanine have been probed for some cognitive aspects. The Y365/7F mice exhibit aberrant endocytic pathway due to the compromised GABAAR-AP2 interaction, leading to increased accumulation of synaptic GABAAR on pyramidal neurons of the CA3 region of the hippocampus. The resulting potentiated inhibitory transmission in these Y365/7F mice correlates with specific CA3 hippocampal-dependent deficits in spatial object recognition, such as the inability to discriminate between displaced and non-displaced objects, despite intact object recognition memory   at synapses by the interaction of the receptor \u03b2 subunit with gephyrin  as specialized compartments where receptors mobility can be transiently reduced and confined, similarly to synapses. It has been demonstrated that GABAARs in hippocampal cells  or by dampening inhibition with GlyR and GABAAR antagonists  trains of depolarizing stimuli; (ii) pharmacologically-induced increased excitatory neuronal activity (4AP); or (ii) strong NMDA receptor activation  correlates with reduced GABAAR synaptic dwell time and increased confinement area through the calcineurin-mediated dephosphorylation of Ser 327 of the \u03b32 subunit .An opposite regulation of GABAAR dynamics on short-term synaptic plasticity has not been addressed yet. Nevertheless, the fact that GABAARs desensitized state(s) can live for milliseconds-to-seconds periods , which controls surface receptor content to finally tune inhibitory synaptic efficacy. Remarkable technical and conceptual progresses achieved during the last decade have revealed that surface receptor lateral mobility is crucial to allow fast and persistent adjustments of ready-to-be-activated receptors at the synapse. Indeed, receptor lateral diffusion sustains (i) the constant renewal of synaptic receptors; and (ii) the activity-regulated dynamic redistribution of surface receptors to, within and from the synapse. The importance of postsynaptic protein dynamics in synaptic plasticity has been further reinforced when the notion of the postsynaptic scaffold has evolved from a \u201cpassive tether for synaptic receptors\u201d towards a dynamic scenario in which receptor-scaffold interactions could be modulated over a wide range of time and intensities to ultimately regulate receptor diffusion trapping.The correct functioning of the synapse relies on the balance between the stability of synaptic structures and the dynamics of its molecular components, a concept that is fundamental for basal synaptic transmission and for the activity-dependent tuning of synaptic strength. This Review highlights the importance of postsynaptic protein dynamics for the expression of plasticity at inhibitory synapses. A large body of evidence collected over the last 20 years has documented the highly coordinated, yet not fully elucidated, regulation of GABAAR subtypes to selected anchoring proteins would provide an additional level of complexity in the study of the modulation of receptor-scaffold interactions in basal conditions and during synaptic plasticity. For instance, in perisomatic synapses of CA1 pyramidal cells, in a subset of inhibitory synapses in cortical neurons, in cerebellar Purkinje neurons, the GABAAR \u03b11 subunit is preferentially associated with the dystrophin-glycoprotein complex, whereas the \u03b12 subunit better interacts with gephyrin , should be analyzed during activity dependent synaptic reorganization. In this regard, the preferential binding of GABAThe deeper investigation of the intracellular biochemical pathways activated during the plasticity of inhibitory synapses will also be fundamental to elucidate which mechanisms are shared with the plasticity of excitatory synapses for the future understanding of the coordination of activity-dependent adjustments of excitatory and inhibitory synaptic strength. The relevance of this issue lies in the functional crosstalk between excitatory and inhibitory synapses. That is, activity-dependent changes at excitatory and inhibitory synapses will not only result in altered E/I balance but also, at network level, they can be differently integrated to ultimately promote Hebbian plasticity or homeostatic stabilization of neuronal network activity  and to exposure to drugs  (Maffei et al., in vivo start to be unveiled, as in the case of dynamic regulation of surface GABAAR and gephyrin levels during fear memory consolidation and after monocular deprivation (Chhatwal et al., in vivo for a more realistic description of the postsynaptic determinants underlying activity-dependent changes of inhibitory synaptic strength and their coordination. With the growing technological progress in neurophotonics, it is desirable to achieve in vivo the accuracy already obtained in vitro about the precise involvement of receptor and scaffold dynamics in the expression of inhibitory synaptic plasticity.Several lines of research have recently attempted to characterize The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Stem Cell Research & Therapy, Lamirault and colleagues described a strong analysis of progenitors in blood and bone marrow of patients collected after AMI, and correlated these levels to bone marrow mononuclear cell (BM-MNC) therapy efficacy and smoking status. The main results are that BM-MNCs can override smoking alteration in endothelial lineage and confirm that endothelial progenitor cells are probably not by themselves the active component of BM-MNC in AMI. This paper allows one to better appreciate the cellular complexity of cell therapy approach in AMI.Endothelial progenitor cell therapy and stem cell therapy have been proposed in regeneration of acute myocardial infarction (AMI). In the previous issue of  Stem Cell Research & Therapy, Lamirault and colleagues described a strong analysis of hematopoietic progenitors and EPC in blood and bone marrow (BM) of patients collected after acute myocardial infarction (AMI), and correlated these levels with bone marrow mononuclear cell (BM-MNC) therapy efficacy and smoking status [Endothelial progenitor cell (EPC) therapy and stem cell therapy have been proposed in regeneration of myocardial infarction and peripheral arterial disease. However, there remains an ongoing need to understand what could be the cellular active component appropriate for each clinical situation to make this cell therapy approach impossible to circumvent. In the previous issue of g status .The first insight from this study is the specific impairment of the endothelial lineage in active smokers. Indeed, the authors described BM activation during the days following AMI whereas EPC numbers were found lower in active smokers, suggesting a specific lack of activation of the endothelial lineage . This isThese results are not in favor of a mixed lineage between hematopoietic and endothelial lineages and the hemangioblast existence in adults. Indeed, EPCs have been described as clonally different from hematopoietic progenitors in patients with myeloproliferative disorders . This diThe second highlight of this study is that cardiac BM cell therapy overrides EPC impairment observed in AMI patients. The cell subset responsible for the beneficial effects of BM cell therapy are not yet identified, but a multitude of studies have been published and have demonstrated that intracoronary BM\u2012MNC delivery led to a left ventricular ejection fraction (LVEF) improvement. However, most of these trials did not have real biological exploration in parallel to BM\u2012MNC therapy and several remaining questions exist about the active component and patient\u2019s eligible for BM cell therapy.Although Lamirault and colleagues\u2019 results shows an absence of correlation between the EPC level and improvement after BM-MNC injection that is descriptive, the findings from this study provide strong evidence that, despite EPC involvement in physiological regeneration due to correlation with the LVEF in placebo group patients, EPCs are probably not the cell type responsible for clinical improvement in the BM-MNC therapy approach. This result is in accordance with several previous hypotheses. First, strong data from preclinical models suggest that BM-MNCs do not differentiate into endothelial cells, and that their paracrine effect is most probably responsible for the angiogenic process . Second,in vitro as mesenchymal stem cells or EPCs. Mesenchymal stem cells induce blood flow recovery in vivo to the same degree as in healthy controls, in contrast to the reduced ability that has been described for BM-MNCs and EPCs from patients with cardiovascular disorders [A recent meta-analysis found that younger patients and patients with a more severely depressed LVEF at baseline benefit from this adjunctive therapy and also 5 to 7 days after AMI produced a superior improvement in global cardiac function (LVEF) when compared with an earlier or delayed delivery time . Howeverisorders  \u2013 thus misorders , BM-MNCsIn conclusion, Lamirault and colleagues fill a gap in our knowledge by identifying in a large biological study associated with a cell therapy trial that BM-MNCs can override smoking alteration in endothelial lineage. This result allows us to confirm that EPCs are probably not by themselves the active component of BM-MNCs in AMI, and contributes to better appreciation of the cellular complexity of the cell therapy approach in AMI.AMI: Acute myocardial infarction; BM: Bone marrow; BM-MNC: Bone marrow mononuclear cell; EPC: Endothelial progenitor cell; LVEF: Left ventricular ejection fraction.The author declares that he has no competing interests."}
+{"text": "The central, lateral and basolateral amygdala (BLA) nuclei are essential for the formation of long-term memories including emotional and drug-related memories. Studying cellular and molecular mechanisms of memory in amygdala may lead to better understanding of how memory is formed and of fear and addiction-related disorders. A challenge is to identify molecules activated by learning that subserve cellular changes needed for memory formation and maintenance in amygdala. Recent studies show that activation of synaptic receptors during fear and drug-related learning leads to alteration in actin cytoskeleton dynamics and structure in amygdala. Such changes in actin cytoskeleton in amygdala are essential for fear and drug-related memories formation. Moreover, the actin cytoskeleton subserves, after learning, changes in neuronal morphogenesis and glutamate receptors trafficking in amygdala. These cellular events are involved in fear and drug-related memories formation. Actin polymerization is also needed for the maintenance of drug-associated memories in amygdala. Thus, the actin cytoskeleton is a key mediator between receptor activation during learning and cellular changes subserving long-term memory (LTM) in amygdala. The actin cytoskeleton may serve as a target for pharmacological treatment of fear memory associated with fear and anxiety disorders and drug addiction to prevent the debilitating consequences of these diseases. This review describes and discusses the mechanisms whereby actin cytoskeleton in amygdala mediates fear and drug-associated memory formation. In fear conditioning (FC) a conditioned stimulus  is associatively paired with an aversive unconditioned stimulus  and conditioned place aversion (CPA). In CPP an associative memory is formed between environmental cues and the rewarding affective state produced by the drug treatment leading to the preference of this environment. CPP is mediated by a circuit that includes the BLA  or after G-actin interactions as a polymer (F-actin). Actin cytoskeleton polymerization in amygdala during and shortly after FC and CPA learning is needed for memory formation as inhibition of actin polymerization at these time points impairs LTM. Microinfusion of cytochalasin D, an actin polymerization inhibitor, into rat LA immediately before or after FC training impaired fear LTM but not short-term fear memory  memory a CPA paradigm. CMW learning induced rearrangements in actin cytoskeleton (increase in the ratio of F-actin to G-actin) in the amygdala  are essential for FC memory acquisition  insertion into LA synapses an event needed for FC memory formation  comprising of a GluA1 MPR site with phospho-mimicking aspartates instead of serines  was used  Although actin is needed for basic neuronal functions including synaptic transmission and morphogenesis interfering with functions of actin cytoskeleton in amygdala has no effect on fear memory acquisition but specifically on its consolidation. A tenable hypothesis is that actin cytoskeleton affects neuronal functions in amygdala needed specifically for fear memory consolidation; (2) The actin cytoskeleton in amygdala is involved in maintenance of certain memories. Moreover, the results indicate that perpetually proper actin cytoskeleton dynamic is part of a mechanism required for maintaining memory long after it has been consolidated; and (3) Interruption with actin cytoskeleton mediated functions in amygdala is sufficient for impairing memory formation. Other neuronal molecular events shown to be needed for the formation of memory such as protein synthesis could be mediated by actin cytoskeleton or are required for memory formation in addition to actin cytoskeleton at same or different time points.The observations above indicate that actin cytoskeleton mediates between learning and memory formation in amygdala. A sequence of events involving the actin cytoskeleton in amygdala leading to memory formation and maintenance is suggested. Learning leads to the activation of receptors and channels in the synapse above a certain level (for FC, see Blair et al., Much evidence indicates that the actin cytoskeleton is needed for the formation of memory in amygdala. However, central questions remain to be answered. For instance, are the alterations in cellular morphology such as changes in spine number and structure known to be subserved by actin cytoskeleton required for memory formation in amygdala? Do changes in synaptic transmission regulated by actin cytoskeleton required for memory formation? Studies aimed to answer such questions will provide vital insights into the roles of actin cytoskeleton in formation of memory and its maintenance in amygdala. Furthermore, future studies are needed to evaluate whether the actin cytoskeleton may serve as a target for pharmacological treatment of fear memory associated with fear and anxiety disorders and of drug addiction to prevent the debilitating consequences of these diseases.RL wrote the manuscript. The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Small non-coding RNAs are known as a clinically relevant category of non-coding RNAs (ncRNAs) that have gained growing attention for their therapeutic values. miRNA and siRNA are of the most important and well-documented types of small ncRNAs. These regulatory RNA molecules are short\u2013approximately 22 nucleotides long\u2013with a similar mechanism of generation in which they are excised from longer double-stranded RNA precursor molecules. Both miRNA and siRNA target protein-coding genes via an antisense-based strategy and follow the same processing manner to reach gene-silencing effect  have been indicated to deliver the tumor suppressor miR-145 to metastatic breast cancer cells, thereby inhibiting tumor cell growth and suppressing cell invasion  specific peptide selected by phage display to a polymer-based nanocarrier was used for the delivery of siRNA specific to Fas (an apoptosis inducer) to cardiomyocytes under hypoxic conditions (Nam et al., The capacity of small ncRNAs in specifically silencing the expression of disease-associated genes underlines their importance as novel forms of therapeutic intervention in numerous human disorders. Nanocarriers, due to some tunable features, represent huge potential to overcome delivery issues concerned with miRNA/siRNA-based pharmaceutical platforms. Recent findings highlight the significance of phage display methodology in providing a wide variety of peptides to be used for targeting of nanocarriers to desired cells. Although still in its infancy, phage peptide libraries are receiving growing attention for targeted cellular delivery of miRNA/siRNA therapeutic cargoes. Active targeting of nanocarriers through surface modification with phage selected peptides will provide new opportunities for taking advantage of the tremendous potential of small ncRNAs in the clinical setting. The quickly advancing role played by phage peptide libraries in the territory of targeted delivery of RNA therapeutics has roots in the surprising diversity of these libraries and the convenience of their screening over a wide variety of cellular targets that cover numerous human diseases. Cell-targeting peptides derived from phage display libraries have raised hopes for researchers to take great strides toward the cherished goal of targeted delivery of miRNAs and siRNAs into the same cells that should take these therapeutic agents.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Viscum album) preparations not only are among the most common types of treatments used in integrative medicine but also have been among of the most commonly prescribed cancer treatments in Germany per se in 2010 [ Viscum album via selective inhibition of COX-2 protein expression provide a further rationale for an antitumor role of mistletoe in view of the close relationship between cancer and inflammation [The importance of integrative medicine in oncological care is increasing in accordance with growth of its evidence base. In central Europe, white-berried mistletoe  pharmaceutical process involving high-speed mixing of mistletoe extracts; they used an in vitro model to discern tumoricidal from host resistance mechanisms of action.Shifting upstream to laboratory research, R. Kuonen and colleagues present newWe hope this special issue contributes to the evidence base of mistletoe therapy and stimulates further robust research to establish its place in oncological treatment."}
+{"text": "Low and Middle Income Countries (LMIC) are facing an epidemiological transition from communicable to non-communicable diseases challenging public health agencies which traditionally have concentrated on maternal or infectious  diseases ,2. At thThe traditional view that emergency care is peripheral and costly is contestable since empirical data demonstrates that simple, effective strategies can be utilized . Myths tEmergency departments (ED) encounter a wide array of diseases from communicable infections to mass-scale trauma; with such a large spectrum of disease, it is immensely challenging to accurately define the burden posed on an emergency department. There is a dearth of such information, particularly in LMIC, surrounding the epidemiology of emergency conditions which in turn limits the degree to which appropriate policy and health system development can be informed. This is particularly true in LMIC like Pakistan where basic disease burden information within EDs is not available. Given that EDs are such a critical component of any healthcare system, it is imperative to ensure that this evolution, particularly within LMIC is based on a sound understanding of the epidemiology of conditions being addressed by such systems.This special issue of this journal focuses on the development and pilot testing of the Pakistan National Emergency Department Surveillance System (Pak-NEDS) within seven major tertiary healthcare centers across Pakistan. A full description of how this surveillance system was piloted is presented in \"The Pakistan National Emergency Department Surveillance Study (Pak-NEDS): Introducing a pilot surveillance\". The remaining papers present key findings from the first round of data collection. The feasibility and benefits of piloting such a surveillance system to accurately quantify the burden of diseases requiring emergency care and to guide prevention efforts is demonstrated throughout these papers.Data presented in the poisoning study revealed that over half of all poisoning cases presenting to the ED were intentional and 44% were due to ingestions or inhalation of poisonous chemicals. These findings clearly indicate the necessity for the provision of improved mental health services and regulatory control over hazardous chemicals in Pakistan.Five percent of all injury patients  registered through Pak-NEDS incurred a fall-related injury with 70% of patients being within the productive age-group of 15-44 years. Studies such as \"Pattern of fall injuries in Pakistan: The Pakistan National Emergency Department Surveillance (Pak-NEDS) study\" help address the paucity of information surrounding fall-related injuries and demonstrate the need for future research to be focused on safety measures both at home and within the workplace.Whilst drowning remains a heavy burden on health systems in LMIC, limited data very often leads to ineffective prevention strategies. The study entitled \"Pattern of Presenting Complaints Recorded as Near-Drowning Events in Emergency Departments: A National Surveillance Study from Pakistan\" presented in this special issue reveals that even with the existence of surveillance systems such as Pak-NEDS there is still a major underreporting of drowning and near-drowning events. Greater emphasis needs to be placed on data source selection, site locations, ED care standards and multisector collaboration in Pakistan.Estimating the true burden of burn injuries, particularly with limited or no specialized tertiary burn centers is extremely difficult without adequate surveillance. Scalds and flame burns were the commonest cause of burn injury (70% and 18% respectively) of those discharged from the ED as highlighted in \"Burn injury characteristics: Findings from Pakistan National Emergency Department Surveillance Study\". Such data further serves to reinforce knowledge on prevention strategies surrounding the use of kerosene stoves and wood-based cooking fuel.EDs offer an excellent opportunity to collect epidemiological data on intentional injuries among children . The papThe burden on Pakistan's healthcare systems due to bomb blast injuries is explored in \"Bomb blast injuries: an exploration of patient characteristics and outcome using Pakistan National Emergency Departments Surveillance (Pak-NEDS) data\". The majority of the patients were young males predominantly in Peshawar and Karachi. Utilization of ambulance services was low. Such findings highlight the need for strengthened pre-hospital services and challenges faced by EDs in responding to such events.The use of Pak-NEDS data to describe the extent and characteristics of patients who are dead on arrival (DOA) from the perspective of pre-hospital and ED care is presented in this special issue. Such data is instrumental in promoting simple, cost-effective pre-hospital care systems. A second paper on pre-hospital care entitled \"Ambulance use in Pakistan: An analysis of surveillance data from emergency departments in Pakistan\" focuses on examining the use of ambulance services in Pakistan. Of the patients where mode of transport information was available, only four percent were brought to the ED by ambulance highlighting the underutilization of such services.One of the core requirements of any emergency system is to be able to provide effective triage of patients as they enter the ED. Only one of the seven hospitals involved with the Pak-NEDS study had a formal triage system in place, with the others relying on a first-come first-serve basis. In \"How vital are the vital signs?\" the use of vital signs to help guide triage decisions, resource allocations and ultimately improve patient mortality is explored.The potential development of specific pediatric emergency care departments and guidelines for the commonest causes of pediatric illness presenting to EDs is discussed in \"The Pediatric Disease Spectrum in Emergency Departments across Pakistan: Data from a Pilot Surveillance System\". This paper reports that pediatric cases represented a tenth of all general ED patients registered through Pak-NEDS with injury-related visits accounting for over half of this group highlighting the need for reinforcement of pediatric trauma services and standardized protocols for violence against children.The paper focusing on traumatic brain injuries (TBI) assesses emergency care access and out-of-pocket treatment costs associated with TBI in Pakistan. Findings showed that 49% of victims were as a result of road traffic injuries, followed by falls (22%). The overwhelming majority presented to the public hospitals (98%) however access to attending level physicians within the ED was as low as 1% which falls outside international guidelines for care of severe TBI patients. The high costs of TBI imaging and its subsequent clinical implications in LMIC settings is also discussed.With chest pain being the second most common cause of ED visits, the ability to accurately interpret clinical signs and diagnose underlying conditions is crucial in preventing adverse outcomes. \"Burden of chest pain in a low-and middle-income country: analysis of emergency department surveillance data\" provides a much needed analysis of the burden of chest pain in a LMIC setting. The limited available data highlights the need for the gap between international guidelines and current practice in Pakistan to be closed.As healthcare and technology continue to advance, the spectrum of disease being treated within EDs continues to widen. It is therefore imperative that in this context of increasing demand on emergency services, the true burden of disease being treated within EDs needs to be accurately defined. An ED-based surveillance system in a low-income context like Pakistan, allows the generation of such data. The papers in this special issue clearly demonstrate the feasibility of capturing the burden of disease within EDs within limited resource settings. A surveillance system can be set up and implemented in multiple EDs with a central data and reporting center. The challenges can be confronted and this special issue should provide ample lessons for future endeavors.The authors declare that they have no competing interests."}
+{"text": "An important counterpart of clinical Positron Emission Tomography (PET) for early diagnosis of neurological diseases is its low resolution. This is particularly important when evaluating diseases related to small hypometabolisms such as epilepsy. The last years, new hybrid systems combining PET with Magnetic Resonance (MR) has been increasingly used for several different clinical applications. One of the advantages of MR is the production of high spatial resolution images and a potential application of PET-MR imaging is the improvement of PET resolution using MR information. A potential advantage of resolution recovery of PET images is the enhancement of contrast delivering at the same time better detectability of small lesions or hypometabolic areas and more accurate quantification over these areas. Recently, Shidahara et al (2009) proposed a new method using wavelet transforms in order to produce PET images with higher resolution. We optimised Shidahara\u2019s method (SFS-RR) to take into account possible shortcomings on the particular clinical datasets, and applied it to a group of patients diagnosed with refractory epilepsy. FDG-PET and MRI images were acquired sequentially and then co-registered using software tools. A complete evaluation of the PET/MR images was performed before and after the correction, including different parameters related with PET quantification, such as atlas-based metabolism asymmetry coefficients and Statistical Parametric Mapping results comparing to a database of 87 healthy subjects. Furthermore, an experienced physician analyzed the results of non-corrected and corrected images in order to evaluate improvements of detectability on a visual inspection. Clinical outcome was used as a gold standard. SFS-RR demonstrated to have a positive impact on clinical diagnosis of small hypometabolisms. New lesions were detected providing additional clinically relevant information on the visual inspection. SPM sensitivity for the detection of small lesions was increased from 70% to 90%."}
+{"text": "Bovine leukemia virus (BLV), a B-lymphotropic oncogenic retrovirus sharing common biological and structural features with the human T-cell leukemia virus I and II (HTLV-I and II), is the etiologic agent of enzootic bovine leucosis. One major feature of the BLV infection is the absence of viremia. It is widely accepted that BLV latency, due to the RNA polymerase II 5\u2019-LTR-driven transcriptional and epigenetic repression is a viral strategy to escape from the host immune system and allow tumor development. Recently, it has been demonstrated by deep sequencing and bioinformatics analysis that the BLV genome encodes a cluster of micro-RNAs which is predicted to be transcribed by RNA polymerase III suggesting that the silencing dogma in BLV transcriptional regulation is only partially correct. Here, we demonstrated by chromatin immunoprecipitation assays that BLV miRNAs were indeed transcribed in vivo by RNA polymerase III through a type II RNAPIII promoter similar to the one directing tRNAs transcription. We also showed that an activating epigenetic environment surrounds the miRNAs cluster. Overall, our results provide new insights into a better understanding of the molecular mechanisms regulating gene expression of oncogenic retroviruses."}
+{"text": "Confirming the position of Nasogastric tubes (NGT) in critical care is a controversial area. The National Patient Safety Agency (NPSA) guidance  advocateTo determine if new guidance for NGT confirmation would influence time off EN and calories delivered.Quality improvement project over two different 4 week time frames, before and after the change in NGT confirmation policy in a general/trauma ICUData was collected on 32 patients, 16 at each data point. See table All patients acquired a cumulative calorie deficit over the time they were studied (average of 11 days). The change in NGT confirmation practice had a detrimental effect on time off EN and amount of EN provided. The size of increase in calorie deficit between the two time periods is only partly attributable to the change in NGT confirmation. Other factors influenced EN delivery in our patients, between the two data points such as non-compliance with our fasting guidelines for surgery and airway procedures. We speculate that the change in NGT confirmation may have led to an excessively risk-averse approach in which the problems of cumulative calorie deficit were under-appreciated. The current NGT confirmation practice for ICUs in our organisation is being reviewed. It is proposed once again to permit ICU trainees who have successfully completed relevant competency training to confirm position of NGT on x-ray. We intend to repeat data collection once this change has been implemented.No external funding was sought for this project."}
+{"text": "A prototype was fabricated and tested showing good agreement between numerical simulations and experimental results. Through numerical simulation, we show that the metasurface antenna has the ability to provide beam steering by phasing all the resonators appropriately.We present a true metasurface antenna based on electrically-small resonators. The resonators are placed on a flat surface and connected to one feed point using corporate feed. Unlike conventional array antennas where the distance between adjacent antennas is half wavelength to reduce mutual coupling between adjacent antennas, here the distance between the radiating elements is electrically very small to affect good impedance matching of each resonator to its feed. A metasurface antenna measuring 1.2 The hypothesis of a medium that simultaneously have negative permittivity and permeability in a given frequency and the experimental realization of this hypothesis brought great interest to the scientific and engineering communities1367212Antennas with dimensions smaller than the wavelength of free space are typically referred to as electrically-small antennas. This type of antennas has much interest especially in wireless communication systems requiring small form factor where it can be applicable in personal communication systems , military applications, unmanned aerial vehicles, and more99161820Over the past few years, metamaterials have been used in many different ways to miniaturize antennas, such as complementary split-ring resonator (CSRR) loaded antenna22917In this work, we present first generation of metasurface antennas operating in the microwave regime. Unlike classical and traditional antennas where radiation is initiated by enhanced concentration of current density by exploiting wavelength-based resonance, the metasurface antenna concept presented in this work is based on an ensemble of electrically-small resonators whose resonance strongly resembles classical circuit resonance, however with the difference that the impedance elements have spacial dimension thus allowing coupling to external fields. The ensemble of the electrically-small resonators gives high degree of freedom for controlling the magnitude and phase of the current over a large portion of the metasurface. While each of the resonators does not constitute a good radiator if it were considered individually, the ensemble of elements acting together provide excellent radiation characteristics facilitated by good impedance matching due to tailored inter-element couplingThe particular electrically-small resonators chosen for demonstrating the metasurface antenna concept are the electrical ring resonator (ERR) reported earlier in the literature\u03bcm.The unit cell considered in this work is the cross resonator element reported earlier to develop high absorbing surface is shown in Fig. 1The Commercial program CST Microwave Studio was used to model the proposed antennaA via with diameter of The metasurface antenna presented here is an array of An Measurements of gain were performed in an anechoic chamber, see Several factors contributed to the slight variation between the experimental and simulation results. The second layer of the structure was chosen to have very low dielectric constant (RT5880LZ) because the transmission line width needed to achieve specific impedance is highly sensitive to the dielectric constant of the material. The transmission line widths were calculated using standard microstip transmission line equations which were based on approximations. Furthermore, the RT5880LZ substrate was difficult to etch resulting in small miss-alignments and line-width discrepancies in the final design. Finally, we note that the positioning of the antennas was done manually, hence, misalignment between the transmitting and receiving antenna could have affected the accuracy of the antenna gain measurements.\u03b8  facilitates its use on variety of platforms.How to cite this article: Badawe, M. E. et al. A True Metasurface Antenna. Sci. Rep.6, 19268; doi: 10.1038/srep19268 (2016)."}
+{"text": "Multi-assay algorithms (MAAs) can be used to estimate HIV incidence in cross-sectional surveys. We compared the performance of two MAAs that use HIV diversity as one of four biomarkers for analysis of HIV incidence.Both MAAs included two serologic assays (LAg-Avidity assay and BioRad-Avidity assay), HIV viral load, and an HIV diversity assay. HIV diversity was quantified using either a high resolution melting (HRM) diversity assay that does not require HIV sequencing (HRM score for a 239 base pair env region) or sequence ambiguity . Samples were classified as MAA positive  if they met the criteria for all of the assays in the MAA. The following performance characteristics were assessed: (1) the proportion of samples classified as MAA positive as a function of duration of infection, (2) the mean window period, (3) the shadow (the time period before sample collection that is being assessed by the MAA), and (4) the accuracy of cross-sectional incidence estimates for three cohort studies.The proportion of samples classified as MAA positive as a function of duration of infection was nearly identical for the two MAAs. The mean window period was 141 days for the HRM-based MAA and 131 days for the sequence ambiguity-based MAA. The shadows for both MAAs were <1 year. Both MAAs provided cross-sectional HIV incidence estimates that were very similar to longitudinal incidence estimates based on HIV seroconversion.MAAs that include the LAg-Avidity assay, the BioRad-Avidity assay, HIV viral load, and HIV diversity can provide accurate HIV incidence estimates. Sequence ambiguity measures obtained using a commercially-available HIV genotyping system can be used as an alternative to HRM scores in MAAs for cross-sectional HIV incidence estimation. HIV incidence is the rate of new HIV infections in a population. Reliable incidence estimates are needed to monitor and respond to the HIV/AIDS epidemic. Longitudinal cohort studies and cross-sectional surveys have been used to estimate HIV incidence. Cross-sectional incidence estimation may be preferred in some settings Serologic assays have been developed for cross-sectional HIV incidence estimation. However, these assays can overestimate incidence because some individuals with long-term HIV infection are misclassified as assay positive env region is quantified using a high resolution melting (HRM) diversity assay that does not require sequencing Multi-assay algorithms (MAAs) have recently been developed that provide accurate cross-sectional HIV incidence estimates for populations in the United States (US), where most HIV infections are subtype B pol region as a measure of HIV diversity. Previous studies have used pol region sequence ambiguity to measure HIV diversity for HIV incidence analysis pol region consensus sequences generated using an HIV genotyping system developed for HIV drug resistance testing . While this approach is more labor-intensive and costly than measuring HIV diversity using the HRM diversity assay, the ViroSeq system is commercially available and is used in a large number of laboratories in the US and elsewhere.While the HRM diversity assay offers many advantages for measuring HIV diversity, it is not widely available. For this reason, we also evaluated the performance of a MAA that includes sequence ambiguity in the env or the level of sequence ambiguity in pol region data from population sequencing). Samples were considered to be MAA positive  if they met the criteria for all of the assays in the MAA.The two MAAs evaluated in this report include a limiting antigen avidity assay recently developed by the US Centers for Disease Control for HIV incidence estimation  the proportion of samples classified as MAA positive as a function of duration of infection, (2) the mean window period , (3) the shadow (the time period prior to sample collection that is being assessed by the MAA The Multicenter AIDS Cohort Study (MACS), AIDS Linked to the IntraVenous Experience (ALIVE), HIV Network for Prevention Trials (HIVNET) 001/001.1, Johns Hopkins Hospital Clinical Cohort (JHHCC), HIV Prevention Trials Network (HPTN) 061, and HPTN 064 studies were conducted according to the ethical standards set forth by the institutional review boards of the participating institutions and the Helsinki Declaration of the World Medical Association; participants provided written informed consent. The work reported here included analysis of stored samples and data from those studies; this work was approved by Institutional Review Boards at the participating institutions. No participants were recruited or followed during the course of this work.Stored plasma and serum samples collected 1 month to >8 years after seroconversion were acquired from cohort studies in the US  the HPTN 064 cohort (low incidence) Testing with the LAg-Avidity and BioRad-Avidity assays was performed previously env was amplified. A smaller env region  was then amplified in a nested polymerase chain reaction (PCR) that included a fluorescent, duplex-dependent DNA dye . After the nested PCR step, the samples were analyzed using a LightScanner instrument ; in this step, samples were warmed, and the fluorescent dye was released as the DNA duplexes melted. The negative derivative of fluorescence vs. temperature (\u2013dF/dT) was plotted against temperature to yield the melting peak for each sample. The width of the melting peak (which corresponds to the level of genetic diversity in the amplicon) was reported as the ENV1 HRM score. HRM scores were determined using the DivMelt software package  The HRM diversity assay was performed as previously described pol sequence data using 6\u20137 primers and to manually edit assembled sequences to yield a single consensus sequence . Mixed base positions were identified according to the manufacturer\u2019s instructions. The final consensus sequence was exported in FASTA format. A Perl script was used to calculate the number of mixed base positions in each sequence and to determine the percentage of bases in each sequence that were ambiguous: sequence ambiguity (%)\u200a=\u200a[(number of mixed base positions)\u00d7(100)]/. FASTA sequence data were submitted to GenBank  and were assigned accession numbers KF729799-KF729936.The ViroSeq HIV-1 Genotyping System was used to generate HIV Samples were classified as MAA positive if they met the criteria for all component assays. Samples were classified as MAA negative if they failed to meet the criteria for one or more of the component assays. MAAs were evaluated using statistical methods described previously Samples that were missing HRM diversity assay or sequence ambiguity results (sample not available or assay failure) were excluded from the analysis. The potential impact of these missing values was assessed using a secondary analysis that incorporated the partial information available for these samples ; this analysis assumed that samples missing diversity data and samples with diversity data were not systematically different with regard to the relationship between being MAA positive and the duration of infection.Incidence estimates for the HPTN 064, HIVNET 001/001.1, and HPTN 061 cohorts were calculated using the following formula: Incidence\u200a=\u200a[(# MAA positive samples)\u00d7(100)]/[\u00d7(mean window period)] We evaluated two new 4-assay MAAs that include the BioRad-Avidity assay, the LAg-Avidity assay, HIV viral load, and HIV diversity . The mean window period and shadow obtained for each MAA are shown in Models for the probability of MAA positive classification as a function of duration of infection were generated for each of the two MAAs . For comThe two MAAs were also used to estimate HIV incidence in three clinical cohorts  impacted the performance of the MAAs. If the diversity measure was simply removed from the MAA (leaving a non-optimized 3-assay MAA with the same cutoffs for the other three assays), the proportion of samples classified as MAA positive still approached zero . However, some samples from individuals with long-term infection (4\u20138 years) were classified as MAA positive (data not shown). This is reflected in the longer mean window period (175 days) and longer shadow (411 days) of the non-optimized 3-assay MAA compared to the two MAAs that include a diversity measure. The shadow for this MAA means that incidence is being assessed more than a year before sample collection, which does not meet our pre-specified requirements for MAA performance. We also compared the two new MAAs to an optimized 2-assay MAA includes the BioRad-Avidity assay (cutoff<40%) and the LAg-Avidity assay (cutoff<2.5 OD-n) This report demonstrates that HIV diversity is a useful biomarker for cross-sectional HIV incidence estimation when combined with other assays in a MAA. The HIV incidence estimates generated for three clinical cohorts using the two MAAs described in this report were nearly identical to point estimates of HIV incidence based on longitudinal follow-up. An advantage of these MAAs is that they do not include CD4 cell count data, which may be difficult to obtain in cross-sectional surveys. Therefore, these MAAs allow the entire incidence assessment to be conducted using stored plasma or serum samples.In these MAAs, a hierarchical approach is used for testing. Serologic assays, which are less costly and easier to perform, are performed first, followed by HIV viral load. HIV diversity assessments are required only for the small subset of samples with results that fall below the assay cutoffs for the two serologic assays and above the cutoff for HIV viral load. The cutoffs used for the serologic assays  was selected in a previous study that compared the performance of eight different regions for inclusion in MAAs for HIV incidence estimation pol gene or another gene).Regardless of the method use to quantify viral diversity for HIV incidence estimation, it is important to note that the level of genetic diversity varies considerably in different regions of the HIV genome The sequence ambiguity measure used in the MAA in this report is based on the percentage of mixed base positions detected in a consensus sequence derived from population sequencing. Detection of mixed base positions is impacted by numerous factors, including the methods and platform used for sequence analysis Both the HRM diversity assay and the sequence ambiguity assay use DNA primers for reverse transcription and PCR. The ViroSeq system also uses DNA primers for HIV sequencing. The HRM diversity assay has been used successfully for analysis of subtype A, B, C, and D HIV with relatively few assay failures This study only included samples from the US, which are likely to be from individuals with subtype B infection. Further studies are needed to evaluate the performance of HIV diversity-based MAAs in populations infected with other HIV subtypes since serologic assays may perform differently in some subtypes In summary, this report describes novel MAAs for cross-sectional HIV incidence estimation in US populations. Future studies will explore the use of HIV diversity-based MAAs for analysis of HIV incidence in populations with other HIV subtypes.Table S1Source of samples used for analysis.(PDF)Click here for additional data file.Table S2Testing considerations for the HRM diversity assay and sequence ambiguity analysis.(PDF)Click here for additional data file."}
+{"text": "Egg belongs to the list of ingredients that must be labeled because of its frequent involvement in food allergies especially in childhood. Several thermal processes are commonly applied to egg and it is known that some egg-allergic people can tolerate well-cooked egg. Food allergens are characterized by their ability to elicit IgE antibodies (sensitization) in susceptible individuals and to display several IgE-binding epitopes. Allergenic potential influenced by different structural levels  can be greatly impacted by all modifications of these structures due to processing. Our work aimed to analyze the impact of pasteurization and boiling of egg and its fractions on in vivo reactivity and its relation to IgE-binding profiles to egg allergens/fractions in a cohort of children allergic to egg.Allergic children  were recruited, all had positive skin prick-tests (SPT) to raw whole egg and egg white and 80% to raw egg yolk. Reactivity to pasteurized and boiled fractions was evaluated by SPT. Sera samples taken at inclusion were used to draw profiles of IgE-reactivity against known allergens and proteins of egg white and against fractions of egg yolk by ELISA. Relative STP data and IgE-binding profiles were analyzed by hierarchical classification to evidence typical profiles of reactivity in this cohort.Pasteurization had very limited impact on structure of egg and only 10% and 5% of children STP became negative with pasteurized  whole egg or egg white. Boiling  greatly changed structure of egg products and had a higher effect than pasteurization since 55%, 27% and 67% of children SPT remained positive to boiled egg and yolk and white fractions. Two typical STP behaviors were evidenced by classification in this cohort. IgE-binding profiles largely differed among children but three typical profiles where extracted from data. Contingency analysis revealed links between typical STP and IgE-binding profiles with possible explanation of tolerance to cooked egg."}
+{"text": "Therapeutic developments across a range of primary tumours have resulted in more cancer patients with cerebral metastatic disease undergoing active management and imaging surveillance. There has been an increase in the caseload and range of disease presenting to oncology and neuro-oncology MDTs. In this lecture I will present examples of intracranial metastases, discuss differences in appearance according to primary site and tips for differentiating from primary intracranial tumours and non-neoplastic mimics."}
+{"text": "The borderline personality disorder is a common mental disorder. It is frequently associated with various mental co-morbidities and a fundamental loss of functioning. The borderline personality disorder causes high costs to society. The aim of this study was to perform a systematic literature review of existing economic evaluations of treatments for borderline personality disorder.We performed a systematic literature search in MEDLINE, EMBASE, PsycINFO and NHSEED for partial and full economic evaluations regarding borderline personality disorder. Reported cost data were inflated to the year 2012 and converted into US-$ using purchasing power parities to allow for comparability. Quality assessment of the studies was performed by means of the Consensus on Health Economic Criteria checklist, a checklist developed by a Delphi method in cooperation with 23 international experts.We identified 6 partial and 9 full economic evaluations. The methodical quality was moderate . Most evaluations analysed psychotherapeutic interventions. Although ambiguous, most evidence exists on dialectical-behavioural therapy. Cognitive behavioural therapy and schema-focused therapy are cost-saving. Evidence on other interventions is scarce.The economic evidence is not sufficient to draw robust conclusions for all treatments. It is possible that some treatments are cost-effective. Most evidence exists on dialectical-behavioural therapy. Yet, it is ambiguous. Further research concerning the cost-effectiveness of treatments is necessary as well as the identification of relevant cost categories and the validation of effect measures. The ICD-10 defines BPD by the following characteristics: emotional instability, lack of impulse control, disturbances in self-image, aims and internal preferences, chronic feelings of emptiness, intense and unstable interpersonal relationships, self-destructive behaviour, including suicide gestures and attempts According to the International Classification of Diseases 10BPD is a common disorder. In two epidemiological studies based on US-American samples the point-prevalence and lifetime prevalence of BPD was 1.6% and 5.9% respectively BPD is strongly associated with Axis-I disorders. 84.5% of BPD patients are suffering from a 12-month co-morbid Axis-I disorder Related to the effectiveness of psychological treatments for BPD a recent review of the Cochrane Collaboration concluded that psychotherapy , mentalization-based treatment in a partial hospitalisation (MBT), transference-focused therapy (TFP), cognitive behavioural therapy (CBT), dynamic deconstructive psychotherapy (DDP), interpersonal psychotherapy (IPT)) plays an important role in the therapy of BPD. However, the evidence base is not very robust There are only few studies on the economic burden of BPD. Jerschcke et al In light of this medical and economic burden the necessity to identify effective and efficient treatments is evident.To analyze the costs and the efficiency of treatments partial and full economic evaluations are the methods of choice. In partial economic evaluations only the costs of at least two alternatives are compared. This kind of evaluation is also called cost analysis A full economic evaluation does not only compare costs of at least two alternatives but also their effects There are different approaches to perform a partial or a full economic evaluation. The first approach uses primary data collected along a clinical trial evaluating the clinical effectiveness of the specific treatment. Other approaches are based on secondary data and/or decision analytic modelling, e.g. decision trees or Markov models.The aim of this study was to perform a systematic literature review of economic evaluations of treatments for BPD.We conducted a systematic literature search in MEDLINE, EMBASE, PsycINFO and NHSEED in August 2013 based on the following strategy: (cost OR economic) AND . The literature search was not restricted by publication year.The eligibility of the studies was assessed in two steps. First titles and abstracts were screened. Articles considered as relevant were obtained and the full text was screened. All original studies reporting cost or cost-effectiveness data of BPD were included. Articles were excluded if theywere conference abstracts, editorials, letters or reviewswere no economic evaluationreported no data from a control grouppresented no data for BPDdid not document the method of cost assessmentwere not written in English or German.The extraction process consisted of three steps. First study characteristics were identified. Afterwards the different cost categories considered in the studies were documented. Finally the costs were extracted. Two transformations of the cost data were performed. First, costs per patient were calculated if cost data related to groups or populations. Subsequently all costs were inflated to the year 2012 and converted into US-$ using purchasing power parities (US-$ PPP) to ensure comparability of the data We used the quality checklist developed by the Consensus on Health Economic Criteria (CHEC) project The results of the systematic literature search are presented in The results of the assessment of methodological quality are presented in There are criteria which were not fulfilled by some evaluations and could have an influence on the validity of the findings of this review. Firstly, ten analyses did not identify all important and relevant costs Indirect costs were only measured by three evaluations. Indirect costs caused by sickness absence, early retirement and mortality were assessed by van Asselt et al Nine full economic evaluations investigated psychotherapeutic interventions . Five evMentalization based partial hospitalization (MBT) MBT is based on the assumption that BPD results from a failure in mentalization which is the ability to reflect about oneself in relation to others and understand their state of mind Finally one evaluation compared schema focused therapy (SFT) with transference focused psychotherapy (TFP) Four partial economic evaluations investigated psychotherapeutic interventions . One evaThe results of the partial economic evaluations are presented in DBT was cost saving compared to TAU MBT was cost-saving compared to TAU in one partial economic evaluation CBT was cost saving in comparison to TAU in one partial economic evaluation In one partial economic evaluation measuring only indirect costs of SFT and TFP the results were ambiguous Crisis intervention after emergency room care was cost saving in comparison to TAU in one economic evaluation A combination of a joint crisis plan and TAU was cost saving in comparison to TAU in one economic evaluation The ICER are presented in ICER based on cost per avoided parasuicide event ranged from a dominance (cost savings and better effects) of DBT to 76,000 US-$ PPP per event avoided by DBT DBT dominated CCT in terms of costs per avoided parasuicide event and cost per gained QALY The comparison of MBT and TAU TAU dominated MACT CBT was cost saving and less effective in comparison to TAU SFT dominated TFP The aim of this paper was to review the existing economic evaluations of treatments for BPD. DBT is the best evaluated treatment for BPD . However, the evidence is ambiguous. Based on a RCT by Turner et al MACT was dominated by TAU in terms of avoided parasuicide events and showed an unfavourable ICER in terms of QALY. As the cost estimation of MACT was solely based on Brazier's regression model it is possible that the ICER of MACT was overvalued MBT was more effective and more costly than TAU We used a threshold of 50,000 US-$ PPP per QALY. This threshold was based on the cost-effectiveness of dialysis in end-stage renal disease As evidence for the cost-effectiveness of psychotherapy of BPD is scarce we want to present a further publication which did not meet the inclusion criteria of this review but provides valuable information to complement our findings and to support future research. The study by Soeteman et al evaluated the cost-effectiveness of psychotherapy for cluster B personality disorders Although we identified 15 partial or full economic evaluations in total, it is difficult to draw general conclusions from the existing economic evidence. The results of this review must be viewed with caution and should be regarded as preliminary. There are various reasons for this. Firstly, there are several different treatment options for BPD, and we identified - at best - only one full economic evaluation and one partial economic evaluation for most of these treatments. This means that the amount of evidence per treatment option is very limited. Secondly, the reviewed economic evaluations used different comparators which make comparisons between treatments options difficult. Thirdly, effect measures employed in the economic evaluations varied and were sometimes difficult to interpret. While there are different rules of thumb to interpret or classify incremental cost per QALY ratios, there are no useful threshold values for incremental costs per unit of other effect measures such as avoided parasuicide events or recovered patients. Fourthly, even if studies apparently employed identical effect measures they turned out to differ substantially when regarded more carefully: The six studies that employed avoided parasuicide events for measuring effects used three different definitions for this effect measure. Moreover, of the six studies that employed QALY based on the EQ-5D, three studies did not apply the EQ-5D in a direct patient interview but used a mapping algorithm to transform scores from other instruments into EQ-5D values. Yet, the validity of mapping algorithms is inferior compared to the direct application of the EQ-5D The economic evidence is not sufficient to draw robust conclusions. It is possible that some treatments are cost-effective. The evidence on DBT is the most extensive but ambiguous. Further research is needed which avoids the methodological shortcomings of existing studies. The assessment of costs was heterogeneous and partly even biased. Future research should identify relevant cost categories in cost-of-illness studies. These findings should be incorporated in economic evaluations. Moreover, different and partly even inappropriate approaches to effect measurement were employed and unvalidated instruments were used. Validation studies should be performed and instruments should be chosen whose results can be interpreted in an economic context. A consensus on cost and effect measurement is highly needed.Checklist S1PRISMA 2009 Checklist.(DOC)Click here for additional data file."}
+{"text": "Meles meles), that (i) males show higher body mass senescence rates than females and (ii) this sex difference is largely attributable to sex-specific downstream effects of the intensity of intra-sexual competition experienced during early adulthood. Our findings provide rare support for the view that somatic maintenance costs arising from intra-sexual competition can cause both individual variation and sex differences in senescence.Males and females frequently differ in their rates of ageing, but the origins of these differences are poorly understood. Sex differences in senescence have been hypothesized to arise, because investment in intra-sexual reproductive competition entails costs to somatic maintenance, leaving the sex that experiences stronger reproductive competition showing higher rates of senescence. However, evidence that sex differences in senescence are attributable to downstream effects of the intensity of intra-sexual reproductive competition experienced during the lifetime remains elusive. Here, we show using a 35 year study of wild European badgers ( A majorIt has been hypothesized that sex differences in senescence rates arise from the differing strength of intra-sexual reproductive competition experienced by males and females ,11. EvolFrom a mechanistic perspective, it has also been hypothesized that individuals may suffer resource allocation trade-offs between the expression of competitive morphologies and behaviour and their simultaneous allocation to somatic maintenance, which might thereby lead to steeper senescent declines later in life in the sex that experiences stronger intra-sexual competition ,14. ThisMeles meles). We use 11 782 captures of 2074 known-age individuals to directly compare the age-related body mass trajectories of males and females, and then investigate whether the observed sex difference in body mass senescence rates is attributable in part to downstream effects of intra-sexual competition experienced during early adulthood. Variation in body mass explains considerable variation in both survival and reproductive success in mammals [Here, we test both predictions using 35 years of longitudinal data from a long-term field study of the European badger  and  mammals ,26,28. I mammals ,28. Whil mammals ,30.per se; following [Specifically, we test two key predictions: if somatic maintenance costs arising from intra-sexual reproductive competition play a key role in generating sex differences in senescence rates: (i) male European badgers should show a faster rate of late-life decline in body mass than females and (ii) this sex difference in senescence rate should be attributable in part to downstream effects of the intensity of intra-sexual reproductive competition experienced in early adulthood. To address the second prediction, we test for sex-specific downstream effects of three proxies for the strength of reproductive competition experienced during an individual's early adulthood  on their rate of body mass senescence later in life, while controlling for any effect of \u2018current\u2019 badger density on their body mass during the senescent period. We also address the possibility of downstream effects on senescence rates of generalized foraging competition in early adulthood , by exaollowing .2.2 site were approximated by bait marking in spring [We use data from the long-term Woodchester Park field study , where the resident high-density European badger population has been continuously monitored since the 1970s . Each yen spring , and badn spring . In a den spring , the autn spring .(a)All statistical analyses employed linear mixed-effects models using the \u2018lmer\u2019 function of lme4  in R v. a priori list of candidate models was defined (see below) and then ranked based on AICc. In the interests of parsimony, more complex models were removed from the analysis if a simpler nested version of that model attracted greater support (a lower AICc) [R2 formulations, respectively [As the analyses used an observational dataset with a large number of candidate explanatory variables and demanded comparisons of nested and non-nested models, we implemented the information theoretic (IT) model selection approach using Akaike's information criterion correcting for small sample size (AICc) . For eacer AICc) . Followier AICc) . Akaike er AICc) . To calcectively . Model f(b)(i)To determine whether the sexes differ in their age-dependent body mass trajectories in late life, a set of 21 candidate models  was defined with body mass (kg) as the response term. We used a quadratic age term to capture the curvilinear relationship between chronological age and body mass. Models that included age (in years) as a categorical fixed factor had no support in comparison to quadratic age models and are therefore not discussed further . In order to preclude the detection of a quadratic age term due to increases in body mass in early life (rather than an accelerating late-life decline), our senescence models only included individuals aged 5 years and over . This dataset comprises 1241 measures from 297 individuals . We also compared the explanatory power of threshold models and quadratic models to capture age-related changes in body mass (as in  have rep(ii)downstream effects of reproductive competition on body mass senescence trajectories, while also controlling statistically for effects of current competition on body mass during the senescent period and (ii) reduce the colinearity between the density metrics used to describe the competitive environment in early adulthood and the equivalent \u2018current\u2019 density metrics calculated during the senescent period.In order to determine whether the strength of intra-sexual competition in early adulthood influences the rate of body mass decline in late life, we defined early adulthood as the first 2 years after sexual maturation . The fiduring the senescence period, by contrasting the explanatory power of the early adulthood and \u2018current\u2019 life versions of the relevant intra-sexual competition metric.The modelling process used the best-supported model from \u00a72b(i)  and investigated the effects of three additional predictors that provide proxies for the strength of local intra-sexual reproductive competition in early adulthood: adult male density, adult female density and adult sex ratio . Juveniles (less than 1 year old) were excluded from each as they are unlikely to compete for reproductive opportunities . If allo(c)Local density metrics were estimated by first calculating an annual value for the local density of each class of individuals  around each badger sett, defined as the total number of unique badgers of each class caught within a 280 m radius of each sett in each year. This search radius provides coverage equal to the mean territory size of a social group across the study period (24.5 ha), constitutes a probable spatial scale for local competition and avoids making assumptions about the relative contributions to local competition of within- or extra-group individuals . Annual The annual value for local sex ratio (LSR) for each sett was defined as the ratio of local adult male density to total local adult density . The proxies for the strength of intra-sexual competition in \u2018early adulthood\u2019  for each individual badger were determined by identifying all of the setts at which it was caught during its second and third years of life, and then averaging the relevant annual values of the focal metric for those setts . Likewise, the local population density during the \u2018juvenile period\u2019 for each badger was calculated as a weighted average, over all of the setts at which the badger was caught in its first year of life, of the sum of the annual values for local juvenile density and local total adult density. Finally, the \u2018current\u2019 life values for each of the proxies for the strength of intra-sexual competition were considered to be the annual value of that metric calculated for the sett at which the badger was caught when the focal body mass measure was taken.3.(a)a). The best-supported linear mixed-model confirms that this decrease in body mass in late life remains after controlling for the effects of social group, year, month of capture, current social group size and both selective disappearance and terminal effects , suggests that both sexes show late-life declines in body mass, and that males show steeper late-life declines than females a. The beheavier individuals from the dataset within increasing age . There was no support for a sex difference in the terminal effect . There l effect . Failure(b)a), whereas female body mass senescence rates were unaffected by early adulthood local male density (figure 2b). The magnitude of the sex difference in body mass senescence rate is therefore predicted by the intensity of intra-sexual competition experienced by males during early adulthood, with individuals that experienced low adult male densities in early adulthood showing a negligible sex difference in senescence rate (figure 2c), while those that experienced high adult male densities in early adulthood showed a marked sex difference in senescence rate (figure 2d). Weaker support was also found for a general (i.e. not sex-specific) downstream effect of the total adult density experienced in early adulthood, whereby both males and females that experienced higher total adult densities in early adulthood showed slightly faster rates of body mass decline in late life .Direct comparison of the explanatory power of the three proxies for the strength of intra-sexual reproductive competition in early adulthood indicated that early adulthood male density had the strongest support as a predictor, while early adulthood female density and local sex ratio had none . The wei4.Our longitudinal analyses reveal a clear sex difference in the rate of late-life decline in body mass in European badgers; males show faster rates of decline than females. As body mass is positively associated with reproductive success ,22 and sMultiple lines of evidence suggest that intra-sexual reproductive competition is more intense among male European badgers than females; males contest matings within and between groups, show higher rates of bite-wounding and mortality than females, and the species shows male-biased sexual size dimorphism ,30. As swithin a male's lifetime is important, as it is not predicted by classical evolutionary approaches that consider sex differences in senescence solely a product of sex differences in mean mortality schedules [c,d). As such, our findings provide support for the hypothesis that sex differences in senescence rate arise in part from somatic maintenance costs entailed in intra-sexual competition.However, our results also suggest that both the individual variation and sex difference in late-life body mass dynamics in this population arise in part from downstream effects of the intensity of intra-sexual competition experienced in early adulthood. A direct comparison of the sexes revealed support for a positive effect of early adulthood local male density on the rate of body mass senescence in males but not females. This apparent downstream effect of the intensity of intra-sexual competition experienced chedules . Such dochedules ,14. Indetotal adult density experienced in early adulthood, as our analysis revealed no support for such a model. Our analysis did reveal weak support for a general (not sex-specific) downstream effect of the total adult density experienced in early adulthood on the senescence rates of all individuals , as competing these models revealed stronger support for an effect of early adulthood male density . Likewise, all of our models control for the previously documented effects of social group size on a badger's current body mass [We were able to evaluate several potential alternative explanations for the statistical evidence that male density in early adulthood predicts the rate of late-life decline in body mass among males. First, this finding cannot be readily attributed instead to a sex-specific downstream effect of the ce costs ), but itody mass ,47. As oThat the local adult sex ratio experienced in early adulthood had no detectable effect on late-life body mass declines in either sex is not unexpected, as the strength of male\u2013male competition for matings at any one time may be largely unrelated to the local density of females for two reasons. First, as females can exhibit asynchronous oestrus over a long reproductive season  and second, as only a subset of adult females within a group successfully breed ,28.Given recent interest in the evolutionary consequences of female\u2013female competition , it is nTogether, our findings provide rare support for the view that sex differences in senescence rates arise in part from downstream effects of trade-offs between allocation to intra-sexual reproductive competition and somatic maintenance ,14, and"}
+{"text": "Acinetobacter baumannii is an opportunistic pathogen causing pneumonia, respiratory infections and urinary tract infections. The prevalence of this lethal pathogen increases gradually in the clinical setup where it can grow on artificial surfaces, utilize ethanol as a carbon source. Moreover it resists desiccation. Carbapenems, a \u03b2-lactam, are the most commonly prescribed drugs against A. baumannii. Resistance against carbapenem has emerged in Acinetobacter baumannii which can create significant health problems and is responsible for high morbidity and mortality. With the development of quantitative proteomics, a considerable progress has been made in the study of carbapenem resistance of Acinetobacter baumannii. Recent updates showed that quantitative proteomics has now emerged as an important tool to understand the carbapenem resistance mechanism in Acinetobacter baumannii. Present review also highlights the complementary nature of different quantitative proteomic methods used to study carbapenem resistance and suggests to combine multiple proteomic methods for understanding the response to antibiotics by Acinetobacter baumannii. Acinetobacter baumannii is one of the six opportunistic pathogens grouped into ESKAPE pathogens that are linked to the highest degree of mortality as described by Infectious Disease Society of America  and increased expression of biofilm forming protein  and nutrient transporters . Vashist et al., identified more proteins with significant role in the carbapenem resistance of Acinetobacter as compare to Siroy et al.  and metabolic enzymes as well as downregulation of surface antigen and OmpW. They also showed that overproduction of these proteins/enzymes have been achieved by enhanced transcription, translation  and folding  pattern for label-free (LC-MS/MS) and labeled (iTRAQ) methods  differential proteome analysis of Acinetobacter baumannii on the surface of host epithelial cells and other surfaces  using 2D-DIGE and MALDI-TOF/TOF as well as iTRAQ/SCX-LC-MS/MS. They also checked the effects of biofilm inhibitory compound  on the biofilm formation. This multiple-approach strategy showed a unique lifestyle of A. baumannii involved in biofilm formation  of Acinetobacter  and secretion systems for delivery of virulence factors while FSEP fraction have extracellular enzymes with degradative activity and role in oxidative stress response (Mendez et al., Induction of proteins associated with signaling, putative virulence factors and various stress responses at different stages of Acinetobacter which will improve future developments in the pathogenesis of the Acinetobacter and its therapy (Soares et al., A. baumannii have been identified using 2DE and MALDI-TOF/TOF mass spectrometric analysis. Immunogenic proteins could serve as antigen for the development of vaccines and passive immunotherapies against A. baumannii infections (Bonin et al., Proteomic experiments also identified differentially expressed lipoproteins as well as proteins responsible for inflammatory/coagulation pathways and kallikrein-kinin system of Acinetobacter baumannii. Merits and demerit of different methods used in the quantitative proteomics have been listed in the Table There are number of limitations of quantitative proteomic methods that hamper the study of the carbapenem resistance mechanism of Acinetobacter baumannii which helps in the subsequent studies. Quantitative proteomic methods are also unable to give direct confirmation of the role of protein in the carbapenem resistance. Similarly the result of quantitative proteomics is also influenced by protein extraction procedure. These limitations conclude that quantitative proteomics help to a large extent in the study of carbapenem resistance but it requires help of other methods for confirmation. Therefore, we can say that emergence of quantitative proteomics is really an added advantage in the study of carbapenem resistance.Table A. baumannii. Phosphoproteomics and immunoproteomics have also emerged to understand virulence and pathogenesis of carbapenem resistant strain of A. baumannii. Every proteomic method has its own merits and demerits (Table Fluorescence based DIGE methods and isobaric based iTRAQ methods in combination with LC-MS/MS are more popular approach used to study carbapenem resistance mechanism of ts Table  but theyts Table . LiteratAcinetobacter baumannii.The quantitative proteomics has overcome some of the limitations of other approaches for investigating carbapenem resistance. With the development in the quantitative proteomics, new opportunities are now open to study difficult and challenging tasks. Because of complementary nature of different quantitative proteomic methods, it has been suggested to combine multiple quantitative proteomic methods for the better understanding of carbapenem resistance in The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Metabotropic glutamate receptor 5 has been suggested by many rodent studies to be a promising target for the development of novel analgesic drugs. The lack of approved compounds has prevented proof-of-concept studies in human subjects. Here we describe preclinical and translational studies of the mGlu5 negative allosteric modulator (NAM), fenobam.Fenobam was tested for analgesic efficacy and toxicity in mouse models. We also tested the plasma levels after oral dosing of fenobam in healthy volunteers, and collected any adverse events following oral dosing compared to placebo.The mGlu5 NAM Fenobam is effective in a wide variety of preclinical pain models in mice with no evidence of the development of analgesic tolerance on daily dosing. No obvious toxicities were observed in mice, or in several studies in healthy human volunteers.Fenobam has robust analgesic activity and shows a good safety profile. Fenobam therefore represents a useful tool for proof-of-concept studies in human subjects."}
+{"text": "Dear Editor,In the article entitled \"Laboratory profiles of treatment-seeking subjects with concurrent dependence on cannabis and other substances: A comparative study\", authors have focused on the systemic adverse effects of cannabis consumption through the evaluation of routine hematological parameters. Cannabis is extensively studied for its effects on the central nervous system, while its long term effects on other organs and systems are not much considered. Endocannabinoid system plays a key role in the modulation of hypothalamic-pituitary-adrenal axis and sympathetic nervous system. It is involved in regulating various cardiovascular activities such as heart rate, blood pressure and the baroreflex. Data emerged from studies performed on patients affected by myocardial infarction have shown that cannabis consumption increases the risk of myocardial infarction in the hour after use, as well as the mortality in a dose-dependent manner . Moreove"}
+{"text": "Humans have the remarkable ability to tune into a particular voice even in loud noisy environments. The neural underpinnings of this amazing perceptual phenomenon are not yet fully understood. Recent EcoG  and MEG Our model does not require training on the background noise or prior exposure to the target speech. Along with using bottom-up spectro-temporal features and pitch features, the model can also accommodate top-down attentional mechanisms to generate segregated phase locked neural representations to target speaker\u2019s speech envelope. The model comprises of a feature extraction stage followed by clustering stage. The feature extraction stage mimics the auditory pathway starting from a cochlear representation followed by a multi-resolution analysis of the cochlear output using a bank of band-pass filters , to provide a rich timbre representation. Dominant pitch tracks are extracted from the sound mixture and processed through the same set of band-pass filters as the timbre channels. The output of the feature extraction stage comprising of the pitch and timbre channels are transduced into a spike-based representation using leaky integrate and fire neurons with time constants tuned to the bandwidth of the multi-resolution band-pass filters. The clustering stage comprises of a bank of coincidence detector neurons. Using the pitch signals as anchors the coincidence detector neurons can segregate the two sources from the mixture timbre representation. Thus, the output of the coincidence detector neurons comprises only of responses phase locked to the envelope of a single source.This model does not require any weight learning, is unsupervised and can segregate sources online. Previous studies on correlation based sound segregation employed network of neurons with intrinsic oscillator dynamics . In this"}
+{"text": "The structure of food webs is frequently described using phenomenological stochastic models. A prominent example, the niche model, was found to produce artificial food webs resembling real food webs according to a range of summary statistics. However, the size structure of food webs generated by the niche model and real food webs has not yet been rigorously compared. To fill this void, I use a body mass based version of the niche model and compare prey-predator body mass allometry and predator-prey body mass ratios predicted by the model to empirical data. The results show that the model predicts weaker size structure than observed in many real food webs. I introduce a modified version of the niche model which allows to control the strength of size-dependence of predator-prey links. In this model, optimal prey body mass depends allometrically on predator body mass and on a second trait, such as foraging mode. These empirically motivated extensions of the model allow to represent size structure of real food webs realistically and can be used to generate artificial food webs varying in several aspects of size structure in a controlled way. Hence, by explicitly including the role of species traits, this model provides new opportunities for simulating the consequences of size structure for food web dynamics and stability. Animal communities form complex networks of interspecific interactions; the most traditionally studied type of such networks is the food web The lack of mechanistic models using body mass to explain or predict food web structure There is also mounting evidence that other traits than body mass can modify the probability or strength of predator-prey links Here I test whether a body mass based modification of the niche model represents size structure of feeding interactions in food webs realistically. Moreover, I introduce a novel extension of the niche model which directly includes empirically observed prey-predator body mass allometry S) and connectance (C), the original niche model generates a food web matrix using a simple set of instructions. Each species is assigned a position on a one-dimensional niche axis by drawing a random number The niche model ks sensu . A predaAlthough it has been shown that body mass can be used as a basis for sorting species in food webs A body mass based modification of the niche model uses body mass to calculate species niche values Here I propose further extensions of the body mass based niche model to incorporate predator-prey body mass allometry well known from empirical data and include a second predator trait to move from a simple body mass dependence of predator-prey interactions to multiple-trait based approach I carried out extensive simulations in R 2.15.1 ure e.g. . In the In the case of the original niche model, a different approach had to be used. I set the number of species and connectance as above and generated food web structure. Then, I calculated body masses form the niche values  using a method proposed by Heckmann et al. Food webs generated by the models were compared using several measures of network structure. I analysed the prey-predator body mass allometry using standardized major axis regression (SMA regression), which is frequently used to estimate allometries because it treats errors in both the explanatory and response variable equally Species richness and connectance were kept constant, although these parameters are important for addressing other questions, such as stability and robustness of food webs Both the original niche model and the two traits model produce food webs with the distribution of predator-prey body mass ratios (PPMR) comparable to empirical data from different habitats . Food weIndividual models differ in the strength of the effects of predator and prey mass on the probability of occurrence of individual feeding links; also the set of \u201cforbidden\u201d links (i.e. links that never occur) varies . In the )  D, as in)  C. The dThe prey-predator body mass allometry in model food webs with total body mass range of 10 orders of magnitude  was simiTotal body mass range of the food webs  in model generated food webs is that real food webs seem to contain a large proportion of predators feeding on prey larger than themselves . This coThe original niche model does not capture the relationship between predator and prey masses faithfully compared to empirical data. When the total mass range is set to 10 orders of magnitude, mean PPMR and the slope of the prey-predator mass allometry estimated by SMA regression correspond well to real data , althougThe two traits allometric model generates food webs that capture predator-prey body mass relationships in real food webs well. When the effect of predator foraging trait is absent and predation is governed exclusively by prey-predator body mass allometry, predator mass explains on average 82% of prey mass variance, which corresponds to empirical data analyses by Brose et al. ncreases  as a natncreases . This efThe comparison of twelve standard descriptors of food web structure  shows thThe original niche model The two traits allometric model could be used to fit empirical data by specifying masses of individual species based on measurements and by choosing the parameters of the allometry of optimal prey mass and predator mass corresponding to a real food web in question or by optimizing parameter values to obtain the best possible fit. Stochastic food web models have been fitted to empirical data in this fashion The explicit inclusion of species body mass to the niche model I did not include prey traits other than body mass in the modifications of the niche model discussed in this paper for the sake of simplicity. However, recent results suggest that closely related prey are consumed by similar sets of predators but closely related predators have less similar diets; this asymmetry of the role of species similarity may be a consequence of differences in the roles of predator and prey traits Script S1R script containing the code for the models used in the paper. The script contains a function niche.model which generates a food web using the original niche model and calculates species body masses from the niche values, a function niche.replicated which produces a list of n webs based on the original niche model, a function two.traits.model which generates a food web using the two traits allometric model and a function two.traits.replicated which produces a list of n webs based on the two traits allometric model.(R)Click here for additional data file."}
+{"text": "The purpose of this study is to identify obstacles and incentives associated with implementation of Information and Communication Technologies (ICTs) in elderly home-based care services, from a healthcare professional perspective. The use of ICTs in elderly homecare is heralded as part of the solution to many of the imperatives currently challenging healthcare systems, but deploying new technology and practice innovations in this complex system can be a challenge. There is poor understanding of what healthcare professionals regard as vital when implementing ICTs in elderly homecare, thus the likelihood of successful implementation is threatened.The following research question guided our study: How do healthcare professionals describe incentives and obstacles related to implementation of ICTs in home-based care for the elderly?Two focus group interviews with 6 participants in each group were conducted. The informants represented home-based care in a Norwegian municipality and were healthcare professionals in direct patient care or nurse managers administrating care services for the elderly. Through content analysis of the transcribed interviews, incentives and obstacles regarding implementation were identified.From a healthcare professional perspective the main incentive to implement ICTs was the practical use in daily care; different patient groups were identified where the use of ICTs potentially could increase the elderly persons\u2019 ability to live more independently in their own home for a longer period of time. The potential for a more precise clinical assessment of home-dwelling elderly receiving care services as well as more rational time use for staff were also described as incentives. Obstacles related to implementation where uncertainty about legislation regulating the use of ICTs, concerns about which impact ICTs may have on relationships with patients, and ethical issues related to the use of ICTs in home-based care, such as surveillance and tracking of persons unable to give informed consent.This study identified three incentives related to implementation: 1) positive impact on patients\u2019 degree of autonomy and independency; 2) increased efficiency in day-to-day practice and 3) increased effectiveness in clinical assessments. The main obstacles identified were: 1) uncertainty concerning legislation regulating the use of ICTs, 2) ambiguity towards which role ICTs will play in the day-to-day contact with patients and 3) ethical issues related to the use of ICTs in home-based care."}
+{"text": "A variety of research questions can be addressed using expert panels to synthesize existing knowledge and issue recommendations. This panel's presentations describe the use of innovative methods for engaging expert panels comprised of implementation scientists and clinical managers in complex recommendation processes to match implementation strategies with evidence based practices in real world service settings as part of the Veterans Health Administration (VA) funded 'Expert Recommendations for Implementing Change' (ERIC) project (QLP 55-025).Powell describes the use of a web-based modified-Delphi processes to obtain expert consensus on a compilation of discrete implementation strategies. Waltz describes the use of a concept mapping method to characterize the interrelationships among the strategies in the compilation. Finally, Matthieu describes the methods used to engage multiple stakeholders to develop a structured recommendation process that applies the implementation strategies to specific practice changes in the VA.The innovative sequence of methods used highlights the value of structured tasks that support transparent, quantitative characterizations of expert panel recommendations. The majority of this expert panel's activities involved asynchronous use of a variety of software platforms, reducing logistical barriers often involved in engaging a large panel of experts. Activities that required synchronous consensus meetings also utilized technology to host structured discussions and post-discussion voting that provided participants with real time feedback on the recommendation outcomes.The sequence of methods employed in the ERIC project can serve as a model for developing context-sensitive expert recommendations for other dissemination and implementation initiatives.Building expert consensus for characterizing discrete implementation strategiesImplementation Science, Implementation Research Coordinators from the VA QUERI program, and faculty from the NIH-funded Implementation Research Institute. The Expert Panel was engaged in a three-round modified Delphi process to generate consensus on strategies and definitions. The first and second rounds involved web-based surveys that prompted comments on implementation strategy terms and definitions. The initial survey was seeded with strategy terms and definitions from the Powell et al. (2012) compilation. After each round, iterative refinements were made to the compilation based upon participants' feedback. The third round involved a live, web-based polling process and consensus process that yielded a final compilation of 73 strategies and definitions. This presentation highlights the advantages and challenges associated with using asynchronous and live web-based methods for obtaining wide participation of experts.Efforts to identify, develop, and test implementation strategies have been complicated by the use of inconsistent language and inadequate descriptions of strategies in the scholarly literature. A literature-based compilation of strategies was developed to address this problem ; however, its development was not informed by the participation of a wide-range of implementation and clinical experts. This presentation describes our effort to further refine that compilation for use in the VA by establishing expert consensus on strategy terms, definitions, and categories that can be used to guide implementation research. Purposive sampling was used to recruit an expert panel comprised of implementation science experts and VA clinical managers. Specifically, a reputation-based snowball sampling approach was used in which an initial list of experts was developed by members of the study team. This list included the editorial board of the journal Concept mapping: harnessing the power of an expert panel to conceptualize relationships among 73 implementation strategiesAfter obtaining the compilation of discrete implementation strategies in the earlier phase of the Expert Recommendations for Implementing Change (ERIC) project, we were faced with a practical challenge of how to realistically ask experts to consider 73 different implementation strategies when making recommendations. One strategy to reduce the cognitive burden of a complex multicomponent recommendation development process is to organize strategies by similarity. Concept mapping is a method that allows you to engage an expert panel in a structured task that can be completed asynchronously and online. For this study, expert panel members were given a deck of virtual \"cards\", each with one of ERIC's 73 implementation strategies. Participants then sorted these cards into piles on the basis of similarity and then rated each strategy in terms of its relative importance and relative feasibility considering all 73 implementation strategies. The benefit of concept mapping is the ability to quantitatively characterize how your target audience conceptualizes a wide range of topics. For the ERIC project, concept mapping provided us with a structured, participant driven approach to organizing our data into 9 expert-derived categories. This organization scheme was then used to structure additional expert panel tasks. This presentation will focus on concept mapping as a tool for characterizing an expert panel's shared understanding of key concepts to be used in a subsequent recommendation process. While data from the ERIC project will be used to illustrate this method, discussion will include how this method can be used to support active and structured stakeholder engagement in a variety of dissemination and implementation activities.Development and application of a menu-based choice framework to structure expert recommendations for implementing complex practice changes in the VAThe Expert Recommendations for Implementing Change (ERIC) project sought to utilize methods to support a highly structured and transparent recommendation process that actively engaged key stakeholders throughout the project's execution. The ERIC project's penultimate activity involves a menu based choice (MBC) task. MBC methods are used in consumer marketing research for product development and these tasks are useful for providing a context rich structure for making decisions that involve multiple elements. In ERIC's MBC tasks, panelists were presented with 73 implementation strategies structured into nine categories. They were tasked with building multi-strategy implementation approaches for particular clinical practice changes being implemented across three settings, each with specific relative strengths and weaknesses .The clinical practice changes were identified by national VA leadership as high priority areas for clinical quality improvement efforts . Scenarios describing these practice changes were developed using key informant interviews with front line providers, clinical managers, health service researchers, and implementation scientists. These experts all practice in the respective area and were able to provide common and realistic challenges they face in routine service delivery in VA settings. ERIC project staff then expanded the scenarios to address varying organizational contexts  and across levels of evidence . Stakeholders were repeatedly engaged in an iterative process of evaluating the scenarios for reliability, credibility, and transferability. This presentation will highlight the critical role partnering with key stakeholders plays in executing this structured recommendation method.Primary funding for this research was provided by the U.S. Department of Veterans Affairs Veterans Health Administration's Mental Health Quality Enhancement Research Initiative (QLP 55-025)."}
+{"text": "Cardiotoxicity is a dose-limiting side-effect of cancer chemotherapeutics such as anthracyclines. The drug-induced cardiac toxicity is currently monitored with repeated assessments of the left ventricular ejection fraction (LVEF) using multigated equilibrium radionuclide ventriculography (MUGA) or echocardiography. However, the plasma cardiac biomarker B-type natriuretic peptide (BNP) has been suggested for early identification of cardiac dysfunction. The aim of the study was to compare LVEF obtained by MUGA and plasma BNP as predictors of developing congestive heart failure (CHF) or death in a population of anthracycline-treated cancer patients.We prospectively followed 333 cancer patients referred to our department for routine monitoring of LVEF with MUGA and measurement of BNP, January-December 2004. Study end points were hospitalization for CHF and death during follow-up 2004-2010. Data were obtained from the Danish National Patient Registry.During follow-up , 21 of the patients were admitted to hospital with a diagnosis of CHF and 194 of the patients died. BNP levels were significantly higher and LVEF lower in the group of patients that developed CHF. Using cut-off points of BNP>100 pg/ml  and LVEF <50%  both significantly predicted CHF. Using the same cut-off points only BNP  and not LVEF  was predictive of overall death. In multivariate Cox analysis both BNP and LVEF were independent predictors of CHF while age remained the only independent predictor of overall death.In cancer patients treated with cardiotoxic chemotherapy both BNP and LVEF can significantly predict subsequent hospitalization with CHF. In addition, BNP and not LVEF has a prognostic value in detecting overall death. This prospective study based on the hitherto largest study population supports BNP as a clinical relevant method for monitoring chemotherapy-related cardiac failure and death. Cardiotoxicity associated with intensive chemotherapy affects life quality and overall survival of cancer patients. According to estimates cancer survivors in the US and Europe have a higher risk of cardiovascular death than the actual risk of tumor recurrence B-type natriuretic peptide (BNP) is one of the suggested biomarkers with well-recognized diagnostic and independent prognostic implications in heart failure patients. BNP is secreted by the ventricles in response to end-diastolic pressure and volume So far, only a few studies have investigated the value of BNP in prediction of clinically endpoints such as manifest cardiac dysfunction following cardiotoxic chemotherapy Therefore, the aim of the study was to evaluate BNP concentration and LVEF obtained by multigated acquisition equilibrium radionuclide ventriculography (MUGA) as predictors of hospital admission for congestive heart failure (CHF) and mortality (death of any cause) in a population of anthracycline-treated cancer patients.The study was designed as a prospective study of 333 cancer patients treated with cardiotoxic chemotherapy with the aim of comparing the predictive value of plasma BNP concentration and LVEF assessed by MUGA for detection of cardiotoxicity and death following cancer treatment. We have previously published data from the same cohort comparing baseline BNP and LVEF as determined by MUGA obtained during chemotherapeutic treatment Data concerning hospital admissions of the patients were obtained from the Danish National Patient Register . The Danish National Patient Register (DNPR) is a nationwide register covering all hospital admissions in Denmark. Every Danish citizen has a personal identification number assigned at birth or immigration which is used by public authorities including DNPR. Each hospital admission is routinely reported to DNPR using the international classification of diseases codes for diagnoses and surgical procedure (ICD-10) 99mTc-labelled human serum albumin was injected. LVEF were calculated with GE software programs . A subgroup of 73 patients had more than one examination (MUGA and BNP).LVEF was obtained by multigated acquisition radionuclide ventriculography according to the routine procedure of the department as described in details previously Blood was drawn following 20 minutes of rest on the scanner bed prior to the administration of tracer and the BNP concentration was measured in plasma using an ADVIA Centaur two-side sandwich immunoassay technique based on chemiluminescence  first hospitalization for CHF were included in analyzes. Univariate and multivariate analyses were carried out using Cox proportional hazards regression with age, BNP and LVEF included as covariates. BNP and LVEF were analyzed both as continuous and dichotomized values. Statistical analyses were performed with the use of IBM SPSS (version 20.0).Differences in age, LVEF and BNP according to development of cardiac failure and all-cause mortality were analyzed using unpaired-sample t test. The plasma concentration of BNP were log-transformed before analyzes to ensure normal distribution. The chi-squared test was used for categorical data with dichotomized values for BNP and LVEF. Receiver operating characteristic (ROC) curves were drawn for plasma BNP concentration and LVEF to predict an adverse outcome  and area under the curves (AUC) were calculated. The prognostic value of BNP and LVEF for predicting either CHF or mortality was studied using Kaplan Meier method and significance was tested using the log rank test. Only (time to) the In total 333 patients  were included in the study. The mean follow up was 1,360 days . Tumor types were breast cancer (24%), various hematological malignancies (35%), uterine/ovarian cancer (10%). The remaining had a wide variety of miscellaneous types of tumors (30%).During the follow up period 21 patients were admitted to hospital due to a diagnosis of congestive heart failure (CHF) and 239 patients died. Values of age, BNP and LVEF are listed for patients divided in groups according to CHF and all-cause mortality in first hospitalization for CHF and time to death) stratified by the selected cut-off values as described above. The Kaplan-Meier curves for cut-off values of BNP>100 pg/ml and LVEF<50% are shown in Kaplan-Meier analyses were carried out for the major end points . When only dichotomized values of BNP and LVEF were entered in the model BNP>30 pg/ml and LVEF<50% remained statistically significant for detection of CHF . In a multivariate analysis of BNP and LVEF as dichotomized values according to overall death, age was the only significant independent predictor of overall death . In addition BNP>100 pg/ml showed a borderline significant value of 0.077 as an independent predictor of overall death .n\u200a=\u200a10), predicted CHF .Of the 73 patients with more than one examination no changes in BNP concentration  and no changes in LVEF  were found from the first to the last examination. In this subgroup, 5 patients were subsequently hospitalized with CHF. Only one of these 5 patients had a significant increase in BNP from below to above the cut-off of 100 pg/ml and in none of the patients, LVEF fell >10% point from the first to the last examination. For the whole group of multi-examined 73 patients, neither an increase in BNP (n\u200a=\u200a36) nor a decrease in LVEF of more than 0.10%-point from the first to the last examination or a final LVEF determination of less than 0.50  in 333 anthracycline-treated cancer patients. The most important finding was that both BNP and LVEF independently predicted congestive heart failure. However, only BNP and not LVEF was associated with overall mortality. Although the level of BNP can be influenced by e.g. adipositas, pulmonary and renal disease and drugs such as angiontensin converting enzyme inhibitors, BNP can predict over-all mortality in a wide range of other patient categories such as hypertension, stroke and diabetes In the literature the reported incidence of cardiovascular toxicity from anticancer treatment is highly variable and depends on the type of drug being used. The patients in the study cohort were treated with anthracycline-containing chemotherapy regimens. Anthracyclines are widely used and have well-known cardiotoxic effects with a reported incidence of 0.9\u201326% or BNP>30 pg/ml) were combined 18 of the 21 patients with CHF were identified suggesting that BNP possess meaningful and additive information to the current surveillance based on MUGA. However, by combining BNP and MUGA only 1 more patient was identified compared to BNP>30 pg/ml alone and 150 patients had either BNP>30 pg/ml or EF<50, increasing the number of \u201cfalse positives\u201d compared to BNP>30 pg/ml as the only measure.In this cohort of cancer patients, 21 of the 333 patients were admitted to hospital for congestive heart failure during the follow-up period. If the current recommendations for surveillance of cardiotoxicity in relation to chemotherapy are followed where cardiotoxicity is defined by LVEF<50% (determined by a single examination), only 48% (10 patients) were correctly identified of developing CHF and accordingly 52% of the patients (11 patients) with subsequent cardiac failure were overlooked. Increasing the threshold of LVEF to <55% did not change the number of heart failure patients that would have been identified (10 patients with cardiac failure had LVEF<55%). In comparison a BNP>30 pg/ml could identify 79% (17 patients) of these patients overlooking 21% (4 patients). This emphasizes that the current method based on LVEF is suboptimal in detection of subtle alterations in left ventricular function and that even small increases in BNP  might be applicable in identifying patients at risk of developing cardiac dysfunction. At the routinely used cut-off value of BNP (>100 pg/ml) a substantial part of the patients with subsequent heart failure were not identified (13 patients corresponding to 62%) suggesting that the cut-off value should be decreased if measurements of BNP is applied in the monitoring of cardiotoxicity. However, a major challenge is that 135 patients had BNP levels above 30 pg/ml, resulting in a substantial number of \u201cfalse positives\u201d. This probably reflects a moderate transient increase in BNP during treatment due to acute/subacute cardiotoxicity that only in some patients are irreversible It was also speculated if serial measurements of BNP could have improved the diagnostic performance of chemotherapy-induced CHF, since it is well known that repeated measurements in patients with chronic heart failure provide incrementally unique information Several published studies have investigated the role of BNP in diagnosing and risk stratification of chemotherapy-associated cardiotoxicity, however most studies have simply compared BNP levels with LVEF measured by MUGA or echocardiography at baseline or during/after treatment with antracyclines as we did also in our previous publication There are multiple reasons for these conflicting results including inadequate sample size (most studies include <100 patients), heterogeneity of the studied population with regards to cancer diagnosis, age (adults vs. children), chemotherapeutic agent and treatment regime/cumulative dose. Furthermore, the timing of blood samples drawn for BNP measurements, the laboratory methods and cut off values contributes to the inconsistency of the results. In this study BNP was measured at same the session where MUGA was performed which typically is when half of the cumulative dose of anthracyclines has been given.Only a few published studies have investigating the use of BNP as predictor of a true clinical end-point such as manifest congestive heart failure. In a study by Pichon et al Several studies have used NT-ProBNP which despite a longer half-life are considered comparable to BNP In addition, a limited number of studies have investigated the possibility of using BNP and other biomarkers in the early detection of anthracycline-induced cardiotoxicity in children/long-term survivors of childhood cancer with the majority of studies supporting BNP as a useful biomarker of myocardial dysfunction Importantly, the current results presented here, based on the hitherto largest cohorts of patients (333 patients) investigating BNP as a predictor of clinical manifest congestive heart failure, clearly show that BNP has an important predictive value comparable or even superior to the currently recommended more time-consuming, radiation exposure involving and expensive MUGA.There are some important limitations to the study; the incidence of congestive heart failure in the present study might be a conservative estimate since only clinical manifest congestive heart failure treated in hospital and outpatient clinics are recorded. It is possible that we have overlooked patients with subclinical cardiac impairment or patients with only vague clinical symptoms, which would not be categorized as CHF (DI1427 or DI50-509) in the Danish national patient registry.Furthermore, we have no detailed information on the chemotherapeutic regime, including the cumulative dose of anthracyclines and/or addition of thoracic radiotherapy. This is notable since the cumulative dose of anthracyclines and the addition of other cardiotoxic chemotherapeutics including trastuzumab and also thoracic radiotherapy are established risc factors for developing chemotherapy-related CHF In conclusion, this is the largest patient data set (333 patients) reported till date investigating both plasma BNP concentration and LVEF as predictors of chemotherapy-related cardiotoxicity using distinct clinical end points: hospitalization with a diagnosis of congestive heart failure and overall death. This prospective study shows that for cancer patients treated with cardiotoxic chemotherapy both BNP and LVEF significantly predicted congestive heart failure. Only BNP and not LVEF had diagnostic implications in predicting overall mortality supporting BNP as a clinical relevant factor for monitoring chemotherapy-related cardiac toxicity and death.A future prospective clinical trial should focus on standardization of the use of BNP concentration for diagnosing patients with irreversible cardiac damage, including determining optimal cut-off level and timing of BNP requiring several samples. In addition, a future focus should be on therapeutic-decision making  based on BNP concentration compared to the current approach with assessment of LVEF ideally in a randomized study."}
+{"text": "Post-occlusive reactive hyperaemia (PORH) is a measurement of the vasodilatory capacity of the microvasculature that is associated with cardiovascular disease, peripheral arterial disease and foot ulceration. Reliability of its measurement in the toe for clinical and research purposes has not been adequately assessed. This study assesses both the intra and inter-tester reliability of four methods of assessing PORH in the toe.A within-subject repeated measures design was used. Forty-two participants underwent PORH testing using four methods: pressure measurement with photoplethysmography; an automated laser Doppler technique with local heating; an automated laser Doppler technique without local heating; and a manual laser Doppler technique. Participants underwent testing on two occasions with a three to 14 day interval. Intra-class correlation coeficients and limits of agreement were used to assess reliability.Laser Doppler measurement with a heating probe was found to be the most reliable method of PORH measurement. Index of the area under the curve of pre- and post-occlusion and peak perfusion as a percentage of baseline were the most reliable variables.PORH can be reliably measured using laser Doppler when combined with a heating probe. Further research is required to determine clinical utility of photoplethysmography in the measurement of PORH as a measure of microvascular dysfunction in the periphery."}
+{"text": "Flow cytometric analysis and flow cytometric cell sorting (FACS) have revolutionized the understanding of immune cell biology and proved an indispensible tool not just for immunologists but for those interested in inflammatory processes. Right through from the early days of impedance-based flow cytometry counter devices to the first fluorescence-based flow cytometry instruments where side and forward scatter parameters with one or two florescent color instruments to state-of-the-art multicolour flow cytometric and mass cytometry with over 38-antibody panels, we are discovering new cell types and multiple immune cell phenotypes that exhibit a diverse array of functions. Today most laboratories use flow cytometry as a powerful technique to support their fundamental biological and medical research. Our own work has used flow cytometry to successfully measure mammalian  leucocyte function  and apoptosis (shedding of CD16 from neutrophils and fluorescently labeled annexin V binding to apoptotic cell surfaces, DNA hyplodiploid peak assessment of permeabilised cells, macrophage efferocytosis (phagocytosis of apoptotic cells and to sort highly pure non-perturbed neutrophils from autofluorescent eosinophils  and from"}
+{"text": "Immune based therapies for cancer are emerging as promising strategies to treat a number of malignancies. A more thorough biomarker assessment of the patients may provide insights into the variability in response to such immune therapies. In a Phase I/Ib clinical trial with the survivin-targeting vaccine DPX-Survivac, we showed the induction of robust immune responses in ovarian cancer patients. In this study, we investigated the potential of proteomic and metabolomic analysis of plasma to identify surrogate biomarkers for efficacy, recurrence and adverse events (AE) in vaccine recipients.Plasma from patients enrolled in a Phase I (n=18) or Phase Ib (n= 22) trial was collected at baseline and post-treatment time points. Metabolomic analysis was conducted using a targeted assay for 58 metabolites by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Proteomic analysis was performed by depletion of albumin and IgG, protein digestion with trypsin, labeling with stable isotopes (TMT reagents) followed by quantitative proteomic analysis by LC-MS/MS. Data analysis was conducted using Skyline, Bioconductor suite and in-house R algorithms in order to correlate profiles with treatment outcomes.Plasma metabolomic profiles correlated with the vaccine dosing and the treatment schedule. Of the 58 metabolites that passed the quality control threshold, a panel of four metabolites was found to correlate with recurrence whereas a panel of five metabolites correlated with Grade 3 injection site reaction (ISR). The proteomic analysis resulted in the identification and quantification of 158 plasma proteins. Four proteins correlated with recurrence while another four proteins correlated with ISR. Notably, the levels of proteins and metabolites at the study baseline samples were most indicative of recurrence and ISR.The use of metabolomic and proteomic techniques can complement traditional methods for immune monitoring in clinical trials for cancer vaccines and other immune therapies. We demonstrate that a panel of metabolites and proteins in plasma measured at the study baseline correlate with the potential for recurrence and AE. Potential association of novel biomarkers with the strength of immune response could be used for developing an informed approach in patient selection and to personalize treatment options. Due to relatively smaller samples size in this study, these findings require validation in a larger patient cohort."}
+{"text": "PET/MR imaging offers the possibility to achieve in one-shot both functional information provided by PET imaging and morpho-functional information with excellent soft tissue contrast provided by MRI. As a result of a typical PET/MR acquisition, each voxel carries a large amount of multivariate information that can be combined into a single image for a synthetic multi-parametric viewing (image fusion). This work is aimed to explore and introduce a reliable fusion scheme able to blend the useful information carried out from each modality into a single meaningful image. The proposed approach consists of a transformation of the source images followed by a blending and a consecutive reconstruction of fused image into the original domain. Following this scheme, three different transformations of source images  and two blending procedures  were considered. For a comprehensive assessment of the fusion schemes under investigation, the results were evaluated both qualitatively and quantitatively on a dataset of 60 naturally coregistered. FDG-PET/MR studies of different anatomical districts in presence of neurological as well as oncological findings. The quality of fused images was assessed by experts who visually evaluated the loss of useful information with respect to the original modalities. Quantitatively, the information loss was estimated by means of a boundaries-preservation based metric as well as a metric based on mutual information. Preliminary results show that the fusion scheme composed by a wavelet-domain transform and a gamma-blending better depicts useful information of the original modalities. In particular, the proposed approach allows to better unveil the MR signal underlying PET signal in fused images in oncological as well as neurological studies. Furthermore, the use of a gamma-blending procedure ensures the best performances in a fully automated manner."}
+{"text": "A growing literature in human social genomics has begun to analyze how everyday life circumstances influence human gene expression. Social-environmental conditions such as urbanity, low socioeconomic status, social isolation, social threat, and low or unstable social status have been found to associate with differential expression of hundreds of gene transcripts in leukocytes and diseased tissues such as metastatic cancers. In leukocytes, diverse types of social adversity evoke a common conserved transcriptional response to adversity (CTRA) characterized by increased expression of proinflammatory genes and decreased expression of genes involved in innate antiviral responses and antibody synthesis. Mechanistic analyses have mapped the neural \u201csocial signal transduction\u201d pathways that stimulate CTRA gene expression in response to social threat and may contribute to social gradients in health. Research has also begun to analyze the functional genomics of optimal health and thriving. Two emerging opportunities now stand to revolutionize our understanding of the everyday life of the human genome: network genomics analyses examining how systems-level capabilities emerge from groups of individual socially sensitive genomes and near-real-time transcriptional biofeedback to empirically optimize individual well-being in the context of the unique genetic, geographic, historical, developmental, and social contexts that jointly shape the transcriptional realization of our innate human genomic potential for thriving. Homo sapiens is attributable in large part to our capacity to self-organize into complex social systems or \u201cmetaorganisms\u201d The spectacular adaptive success of Initial indications that social environments might significantly affect the functional activity of the human genome came from studies dissecting leukocyte gene expression profiles into genetic and environmental components IL1B, IL8, PTGS2), whereas down-regulated transcripts were involved in Type I interferon innate antiviral responses  and in antibody production  1 (IgG1) antibodies (a pattern subsequently linked to fight-or-flight threat responses from the sympathetic nervous system) A prototypic example comes from studies of social isolation, which is one of the most robust epidemiologic risk factors for chronic illness and mortality Following the initial analyses of social isolation, a diverse array of studies has begun to document similar leukocyte transcriptome shifts in other adverse social conditions, including low socioeconomic status (SES) Subsequent studies using experimental animal models has shown that CTRA gene expression profiles can be induced in leukocytes by repeated social threat IL6IFNBMechanistic studies in animal and cell culture systems have also shown that activation of fight-or-flight signaling pathways in the sympathetic nervous system (SNS) plays a major role in evoking CTRA gene expression profiles . SNS actCsf3) and thereby enhances monocyte differentiation and development A second pathway inducing the CTRA involves broader and more durable changes in the transcriptional underpinnings of immune cell growth and development. Bioinformatic decomposition of transcriptome shifts in the heterogenous leukocyte population initially identified the primary cellular mediators of CTRA transcriptome shifts as myeloid lineage immune cells such as monocytes and dendritic cells NGF gene that supports the growth and differentiation of the SNS nerve fibers innervating lymph nodes A third pathway by which adverse social conditions can induce persistent transcriptional alterations in immune cells involves up-regulation of the There has been great interest in the possibility that epigenetic marks such as histone acetylation or DNA methylation might mediate social influences on human gene expression. Environmental conditions clearly influence epigenetic profiles in human immune cells TP53Beyond the immune system, studies have recently begun to map relationships between social conditions and gene expression in diseased tissues such as breast, ovarian, and prostate cancers Transcriptional defense programs such as the CTRA presumably evolved to help adapt molecular physiology to the types of sporadic and transient threats that generally characterized our ancestral environments. In the contemporary human social ecology, however, chronic activation of these transcriptional defense programs by purely symbolic or anticipated threats likely acts to undermine health by promoting inflammation-related chronic diseases such as Type II diabetes, atherosclerosis, neurodegeneration, and metastatic cancer while simultaneously undermining host resistance to viral infections One recent study by Fredrickson and colleagues took this approach to ask which kind of \u201chappiness\u201d might best oppose the CTRA What else might molecular indicators of well-being tell us about the best way for humans to live? Several randomized controlled experimental studies have shown that contemplative practices such as mindfulness meditation, physical practices such as yoga and Tai Chi, and cognitive-behavioral stress management programs can all reduce proinflammatory gene expression in people confronting significant life adversity Although studies have begun to examine both the positive and negative impacts of broad social climates such as SES and social stability, little is presently known about how these influences are transmitted via concrete social networks. It should be possible to map the flow of social genomic influences through networks of individuals and observe the contagious development of coordinated \u201ccultures\u201d of gene expression. Network genomics analyses could clarify a wide range of issues ranging from the distributed nature of individual resilience to basic questions regarding human evolution and gene-culture interaction. Emergent systems-level capacities lie at the heart of individual well-being, group selection, and our hypersocial life history strategy Network genomics analyses are complicated by the fact that people actively shape and select their social environments. These active network dynamics are mediated by brains and nervous systems that are themselves transcriptionally plastic and thus sensitive to both biological and social influences Functional genomics occupies a unique nexus between basic human nature, as reflected in the evolved regulatory programming of our genome to generate successful human life, and the environmentally contingent realization of that innate potential for thriving Perhaps the most transformative implication of prescriptive social genomics lies in the new opportunities it provides to us as individuals as we seek to optimize our own personal well-being. Given the diverse array of genetic, developmental, historical, and socioenvironmental factors that shape our realized transcriptomes, there may not exist any single intervention that enhances biological well-being for everyone. However, we should still be able to empirically optimize our personal well-being by selecting the lifestyle components that best work for us in the context of our own particular life circumstances. Determining what works at the individual level has historically been complicated by the fact that the primary objective indicators of well-being involve disease and mortality events that generally occur decades after their environmental precipitants and leave little room for a do-over. Our emerging ability to monitor the molecular underpinnings of human well-being in everyday life using portable real-time RNA sequencing interpreted through evaluated molecular biomarkers such as the CTRA and BIT gene sets provides a wholly new opportunity to discover what works for us personally, long before those molecular dynamics coalesce into overt disease. Continuous real-time molecular biofeedback opens up a new era of human molecular self-awareness and biological self-determination. If we judge societies at least in part by the extent to which they help each of us realize our genomically endowed potential for well-being, then the molecularly quantified self could represent one of our own society's most significant achievements. After all, each of our human genomes is fundamentally a system for converting environmental information into molecular resources according to the accumulated wisdom of 4 million years of hominid evolution, and those who stand to gain most from the insights they afford are we whose lives they create."}
+{"text": "We scored the EEG for activity states and spectral analysis was performed to evaluate correlations to the synchronous extracellular glutamate fluctuations underlying Mecp2 inactivation as compared to WT. Significant alterations in sleep structure due to dark cycle-specific long wake states and poor quality of slow-wave sleep were associated with a significant increase in glutamate loads per activity cycle. The dynamics of the activity-state-dependent physiological rise and fall of glutamate indicative of glutamate homeostasis were significantly altered in the KO mice. Colorimetric quantitation of absolute glutamate levels in frontal cortex also indicated the presence of significantly higher levels in KO. This study for the first time found evidence of uncompensated sleep deprivation-like EEG biomarkers that were associated with glutamate homeostatic dysfunction in the Mecp2 KO mice.Mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (Mecp2) cause most cases of Rett syndrome (RTT). Currently there is no cure for RTT. Abnormal EEGs are found in 100% of RTT cases and are associated with severe sleep dysfunction, the cause of which is not well understood. Mice deficient in MeCP2 protein have been studied and characterized for their neuropathological and behavioral deficits to better understand RTT. With the goal to study the non-ictal EEG correlates in symptomatic Mecp2 KO mice (Mecp2 Rett syndrome (RTT) is an X-linked, neurodevelopmental disorder which is a common cause for genetic mental retardation in girls, one in every 8500 live births. The gene defect in males usually results in severe clinical manifestations and fatality. Infants with Rett syndrome seem to grow and develop normally for 6\u201318 months, but then regress developing and lose skills and abilities. Autistic-like behaviors also commonly appear at this stage. Mutations in the gene encoding Mecp2 (methyl-CpG-binding protein 2) are known to cause the majority of cases  on a C57BL/6 background . The Bird Mecp2-deficient mice were bred and housed behind a barrier in the animal facilities at Johns Hopkins Medical Institutions with a standard 12-h light on/off cycle with food and water available ad-libitum. These facilities meet Federal and NIH regulations for animal care and are accredited by the American Association for Accreditation of Laboratory Animal Care. All animal experimentation was conducted in accordance with protocols approved by the guidelines of the Johns Hopkins of Animal Care.The present study utilized a mouse model of Mecp2 deficiency developed by Jacky Guy and Adrian Bird  and wild-type mice  used in this study were all aged between 6\u20137 weeks. Under general anesthesia, mice were surgically implanted with electroencephalograph . Incomplete wake cycles at the beginning and end of the recording session were not included in this analysis.To calculate glutamate loads associated with each wake cycle , every p < 0.0001). Similarly, mean percent rate of fall of glutamate with sleep onset was \u22123.26 \u00b1 1.24%/5 min and also significantly slower than WT (p = 0.02). Comparing glutamate homeostasis within WT mice for transition to wake vs. sleep states showed the dynamics were significantly different .Brain glutamate levels measured in frontal cortex of WT and KO mice at 7 weeks of age (both from recorded and na\u00efve mice) were significantly higher in KO mice than in WT controls , matching previously reported studies in this mouse model.Weights of the WT , KO males and HET females in the breeding colony was recorded over 7 weeks, demonstrated that HET mice showed no weight lag compared to age-matched WT females in the period when they are not symptomatic. However, KO males start to show a weight lag at 3 weeks of age when compared to WT males that was initially not significant but became significant at 7 weeks of age. Twenty-four hour videos associated with the EEG recording also revealed the same poor nesting behaviors in symptomatic KO mice compared to the WT Figure  that havin-vivo glutamate homeostasis biomarkers that clearly differentiated a symptomatically progressive KO mouse from its age-matched WT littermate. Firstly, we found that symptomatic KO mice had severe sleep dysfunction that was circadian- and activity cycle-dependent, and could be reliably quantitated by the activity state scoring of 24 h continuous EEGs. The resultant hypnograms represented a chronic sleep deprivation-like profile that was not followed by compensation. Secondly, the sleep microstructure and quality of SWA during NREM was also consistently and significantly altered in the symptomatic KO mice. Impaired NREM and REM dynamics and poor SWA were biomarkers in the symptomatic KO mice during the progressive deterioration phase that ends in early mortality in this model. Thirdly, activity-dependent glutamate homeostasis was observed in both WT and KO, but KO mice showed a significant increase in activity cycle-associated glutamate loads associated with the long wake cycles. Since these abnormal activity-dependent glutamate changes were relative to wake/sleep state and did not represent the actual base load, we ascertained absolute glutamate concentrations in the frontal cortices. Glutamate levels measured from fresh frozen brain tissue of recorded and na\u00efve KO mice at 7 weeks of age were significantly higher than age-matched WT littermates. Together these findings suggest that chronically elevated glutamate levels may underlie the disease progression in this mouse model of Rett syndrome. Finally, glutamate homeostatic mechanisms associated with transitions to and from wake and sleep states, were severely disrupted in the symptomatic KO mice. The percent rate of rise and fall of glutamate was tightly tied to activity states as determined by EEG. The dynamics of this change of glutamate concentrations associated with transitions between waking and sleep states were severely and significantly altered in the KO brains in-vivo. Specifically, the distinct and significant differences between the dynamics of the rates of rise of glutamate associated with wake and rates of fall associated with sleep onset detected in WT were obliterated in KO mice, which suggested severe homeostatic dysfunction. In summary, we found a triad of sleep disorder biomarkers in KO mice that represented both a disintegrated ultradian rhythm and a dark cycle aggravation that could underlie the higher absolute glutamate concentrations detected in the KO forebrains. Chronic sleep architecture dysfunction and poor sleep quality in KO mice could be one of the mechanisms underlying regression in weight gain, poor nesting and poor learning memory in these mice  examined in this study, the MeCP2 is missing from the entire brain cell population, there is evidence that it still results in location- and temporal-specific alterations in synaptic physiology (Kang et al., Very few studies have investigated how or whether extracellular glutamate is regulated across sleep-waking states (Dash et al., The EEG pattern of NREM sleep is dominated by SWA. SWA is defined as the EEG power in the 0.5\u20134 Hz band during NREM sleep, and is a reliable measure of the amplitude and number of slow waves during this phase of sleep. SWA is an established marker of sleep pressure, increasing with the duration of waking and dissipating throughout sleep. Sleep deprivation studies in WT rodents and humans have shown a tendency toward NREM compensation by increase in SWA during sleep cycles following sleep periods of sleep deprivation. With the inherent sleep-deprivation-like profile detected in all KO hypnograms, not only did the NREMs following the long wake cycles fail to show any compensatory increase in SWA, in contrast, the poor SWA NREMs typical to the KO mice persisted following the long wake cycles. These impairments were statistically significant. Mecp2 KO mice showed a severe impairment in glutamate homeostasis associated with SWA during NREM. Glutamate levels decreased at a faster rate during NREM sleep periods with high SWA than during those with low SWA. In rats the rate of decrease in glutamate during sleep after sleep deprivation was twice as fast as the average decrease during spontaneous NREM sleep (Dash et al., in-vivo biomarkers to ascertain effect on modulating regression and preventing fatality.Chronic impairment of sleep and glutamate homeostasis underlies the regression in symptomatic Mecp2 KO mice. Continuous 24 h EEG and glutamate recordings allow quantification of the impairment, which can be used as biomarkers of regression. Recent work using viral delivery of Mecp2 cDNA has shown promise by significantly ameliorating the disease in female mutant mice (Garg et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The problem of natural convective boundary layer flow of nanofluid past a vertical plate is discussed in the presence of nonlinear radiative heat flux. The effects of magnetic field, Joule heating and viscous dissipation are also taken into consideration. The governing partial differential equations are transformed into a system of coupled nonlinear ordinary differential equations via similarity transformations and then solved numerically using the Runge\u2013Kutta fourth-fifth order method with shooting technique. The results reveal an existence of point of inflection for the temperature distribution for sufficiently large wall to ambient temperature ratio. Temperature and thermal boundary layer thickness increase as Brownian motion and thermophoretic effects intensify. Moreover temperature increases and heat transfer from the plate decreases with an increase in the radiation parameter. Solar energy is probably the most suitable source of renewable energy that can meet the current energy requirements. The energy obtained from nature in the form of solar radiations can be directly transformed into heat and electricity. The idea of using small particles to collect solar energy was first investigated by Hunt Nield and Kuznetsov It has been seen that the buoyancy forces stemming from the heating or cooling of the continuously moving surface alter the flow and thermal fields and thereby the heat transfer characteristics of the manufacturing process Raptis and Perdikis The present work deals with the natural convection flow of an electrically conducting nanofluid past a vertical plate in the presence of nonlinear thermal radiation. Effects of Joule heating and viscous dissipation are also taken into account. Mathematical model proposed by Buongiorno We consider laminar two-dimensional boundary layer flow of nanofluid past a vertical plate located at ture see . Using tture see .g is acceleration due to gravity, The radiative heat flux expression in Eq. (3) is given by the Rosseland approximation flow see . In thisHowever if we avoid above mentioned assumption the radiative heat flux in Eq. (3) results in a highly nonlinear radiation expression which is the subject of current study. Hence the energy equation for nonlinear thermal radiation will be:Using the dimensionless variables The quantities of practical interest in this study are the local skin friction coefficient The dimensionless mathematical problems given in Eqs. (10)\u2013(13) with the boundary conditions (15) have been solved for the numerical solutions via shooting method. The code for shooting method with fourth-fifth-order Runge-Kutta integration using adaptive step size has been developed in MATLAB. The computations have been performed on 64 bit Core i-7 machine with 8GB RAM. To assess the accuracy of code, the results are compared with Kuznetsov and Nield The present work investigates the influence of nonlinear thermal radiation on the natural convective boundary layer flow of an electrically conducting nanofluid past a vertical plate. Different from the linear radiation problem, the present problem is governed by an additional temperature ratio parameter. Mathematical model incorporates the effects of Joule heating and viscous dissipation in the energy equation. The solutions are computed numerically by shooting method with fourth-fifth-order Runge-Kutta integration technique. The major conclusions are listed below:Temperature increases and profiles become S-shaped with an increase in temperature ratio parameter and decrease in thermal radiation parameter revealing the existence of the point of inflection for temperature distribution.Unlike previously reported results on thermal radiation effect, current results are valid for both small Temperature Increase in the strengths of Brownian motion and thermophoresis effects results in the decrease of heat transfer from the plate.Temperature The points c, d and e still hold in case of linear radiation and differences in the behaviors of parameters (except the radiation parameter) are only quantitative.With the inclusion of non-linear radiation term, which allows both small and large temperature differences in the flow, the current work may lead to better understanding of the absorption of incident solar radiation and its transition into the nanoparticle working fluid. Further natural convection in nanofluids has vital importance in next generation solar film collectors, nuclear reactor application, heat exchangers etc."}
+{"text": "The orchestration of gene-expression programs is essential for cellular homeostasis. Epigenetic processes provide to the cell a key mechanism that allows the regulation of gene-expression networks in response to environmental stimuli. Recently epigenetic mechanisms such as histone-modifications have been implicated with cognitive function and altered epigenome plasticity has been linked to the pathogenesis of neurodegenerative and neuropsychiatric diseases. Thus, key regulators of epigenetic gene-expression have emerged as novel drug targets for brain diseases. Numerous recent review articles discuss in detail the current findings of epigenetic processes in brain diseases. The aim of this article is not to give yet another comprehensive overview of the field but to specifically address the question why the same epigenetic therapies that target histone-acetylation may be suitable to treat seemingly different diseases such as Alzheimer's disease and post-traumatic stress disorder. The term epigenetics has been introduced by Conrad Waddington to describe heritable changes of a phenotype that does not depend on altered DNA-sequence  build the nucleosome around with 147 bp of DNA is wrapped. The histone tails are subjected to post-translational modification including acetylation, methylation, phosphorylated, ubiquitination, sumoylation, or ADP-ribosylation  family, the MYST  family, the p300/CBP family and several other HATs do not belong to any of these families . The mechanistic insight from such data is limited. More recently, researchers have started to study histone-acetylation during memory formation via ChIP-sequencing which allows for a genome-wide analysis. For example, the levels of H4K12 acetylation in the coding region of learning-induced hippocampal genes were linked to better memory performance in young when compared to old mice  and neuronal cell death patients develop memory disturbances and eventually lose the ability of managing the daily life. A small number of AD cases (ca. 5%) is caused by mutations in amyloid precursor protein (APP) gene or the genes that mediate its processing . As a consequence the brain produces more of the AD-associated amyloid-beta 42 (A\u00df42) peptide  administration of the HDAC inhibitor sodium butyrate reinstates cognitive function and synaptic plasticity in a mouse model that allowed forebrain-specific and inducible overexpression of the p25 protein (CK-p25 mice) . PTSD can develop as a result of a terrifying and traumatic event, which could involve physical harm or was experienced as extremely threatening  acetylation, a marker for transcriptional activation (Kouzarides, c-fos and egr-2 resulting in impaired fear extinction. This data suggests that histone-acetylation is a critical regulatory process of fear extinction. However it will be critical to elucidate the role of the relevant enzymes and define the histone-acetylation patters for the relevant genes. Especially since HDAC1 and HDAC2 appear to have opposing roles in fear extinction. This is however also true for AD, where HDAC2 but not HDAC1 inhibition is able to reinstate memory function (Guan et al., Successful extinction of fear memories required HDAC1 mediated repression of immediate early gene such as In conclusion there is substantial evidence that the mechanisms that orchestrate histone-acetylation are involved in fear extinction and there is indeed further data suggesting a role of epigenetic mechanisms in the pathogenesis of PTSD (Zovkic et al., The epigenome transfers environmental stimuli into long term adaptive changes and thus provides to neurons a mechanisms that allows for the compromise between stability and flexibility. Epigenetic changes have been observed in various brain diseases and epigenetic drugs such as HDAC inhibitors show beneficial effects in animal models for apparently different brain diseases such as AD or PTSD. Interestingly, epidemiological data links early life psychiatric diseases such as PTSD to late onset AD. One common feature amongst such diseases is that they are associated with epigenetic alterations and it can be speculated that disease associated epigenetic changes\u2014if not treated\u2014predispose the system for further de-regulation in response to additional environmental risk factors. Thus, the various brain diseases may be viewed as different places in the epigenetic landscape that are off the main path but still interlinked. Epigenetic changes can be transient, long-lasting or even transmitted across generations but they are always reversible and thus hold great potential for future therapeutic approaches that aim to treat the correct patient population for a given disease.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Harvesting wild animals may exert size-independent selection pressures on a range of morphological, life history, and behavioral traits. Most work so far has focused on selection pressures on life history traits and body size as morphological trait. We studied here how recreational fishing selects for morphological traits related to body shape, which may correlate with underlying swimming behavior. Using landmark-based geometric morphometrics, we found consistent recreational fishing-induced selection pressures on body shape in two recreationally exploited marine fish species. We show that individuals with larger-sized mouths and more streamlined and elongated bodies were more vulnerable to passively operated hook-and-line fishing independent of the individual's body size or condition. While the greater vulnerability of individuals with larger mouth gapes can be explained by the direct physical interaction with hooks, selection against streamlined and elongated individuals could either involve a specific foraging mode or relate to underlying elevated swimming behavior. Harvesting using passive gear is common around the globe, and thus, size-independent selection on body shape is expected to be widespread potentially leaving behind individuals with smaller oral gapes and more compact bodies. This might have repercussions for food webs by altering foraging and predation. Hunters and fishers nonrandomly harvest animals based on the traits they carry, which results in phenotypic and potentially genetic changes  and relatively low fishing and anthropogenic pressure so as to sample a rather natural assemblage.The basis of our approach was to compare the geometric body shape of individuals captured by hook-and-line recreational fishing (fished sample) and a random sample (population sample) of individuals from the population jointly sampled at the same locality and time. We focused on two commonly targeted coastal fish species, Penaeus vannamei, of similar size and shape) was used, and sessions were performed from an anchored recreational boat in random places within the study area. To obtain the random sample of the population, we used an experimental active net designed for scientific assessment of fish assemblages inhabiting P. oceanica seagrass  following Al\u00f3s et al. . NaturalD. annularis and 302 individuals of S. scriba were sampled with both gears. Fish were measured  and weighted , and a digital image of the left lateral size of each individual was taken using a digital camera (Olympus E300)  to confine the analysis to a narrow size range, that matched in both fishing gears. Although the mean size did not differ between the origin of the sample (see the electronic supporting information S2), limiting the body shape analysis to fish within the same narrow size interval controlled for possible allometric effects of size on body shape and ensured that our morphological results were size independent.A total of 473 individuals of 00) Fig. . We procFish with different condition due to variation in food resource intake are likely to have different body proportions influencing their body shape and hence our analysis  insertion of the pelvic fin, (x) posterior corner of the upper jaw, (xi) corner of the pre-operculum, (xii) corner of the insertion of the pectoral fin, and (xiii) upper corner of the operculum. The raw coordinates were superimposed using general Procrustes superimposition (GPA) as implemented in the function procGPA from the shapes library  nonsignificant variables or interactions, the partial effects of the variables of interest were tested using a permutation approach. In addition, a linear discriminant analysis (LDA) was completed with the multivariate residuals after removing the effects of size, condition, and study site. The reliability of the differences between sampling methods inferred from LDA was checked via leave-one-out cross-validation. Finally, the shape corresponding to the averaged LDA scores for each one of the sampling methods was regressed on the arching-free shape descriptors for allowing an intuitive visualization and interpretation of the differences in body shape attributable to each of the gear samples  was constructed by the shape descriptors (columns) of each fish (rows). The explanatory variables were fish size and fish relative condition (continuous variables), study site  analysis was performed to explore whether different regions of the fish body varied independently  on body shape revealed that all of these explanatory variables had statistically significant effects in the case of is Table . The preba Table . The prex) (which was related with the mouth gape) was found to be larger for vulnerable individuals compared to the random population sampled by trawling . The first PLS axis (variance explained 61.6%) depicted a pattern of covariation that involved the streamliness of the trunk and the position of the mouth: Deeper fishes also had a mouth in a more ventral position than shallower fishes . While the first PLS axis (68.0%) showed the same pattern of D. annularis, the second PLS (14.6%) axis showed that deeper and shorter individuals had larger mouths than shallower and elongated fishes . For mere physical reasons, individuals with larger mouth areas will be more prone to ingest hooks or lures than individuals with small mouths (Lewin et al. We also found that a shallower and more elongated body had a higher vulnerability to be harvested by recreationally fished hooks. The physiological literature on fish swimming kinematics strongly supports the hypothesis that shallower and more elongated fish encompass more actively swimming individuals within a population (Br\u00f6nmark and Miner Although there is large plasticity inherent on body shape (Langerhans and DeWitt Three key messages can be derived from our work. First, fishing can select for a certain combination of morphological traits independent of body size. This selection process is likely due to two processes: direct selection caused by the physical features of the hooks relative to the size of the mouth and possibly as a by-product of direct selection on behavioral traits. The latter awaits further empirical analysis by studying behavior in the wild and linking behavior and morphology to vulnerability to fishing. However, collecting detailed spatial data by tracking wild animals in their free environment is technologically challenging (Krause et al."}
+{"text": "The visual perception of body movements shows interesting dynamical properties. Biological motion perception can show perceptual multi-stability with respect to the perceived walking direction . In addiThe core of the model is a two-dimensional neural field , whose fA version of the model for the representation of static stimuli reproduces quantitatively electrophysiological results on neural adaptation in area IT . The mod"}
+{"text": "Results pointed to robust resting baseline differences between groups. Aggressive individuals had lower relative glucose metabolism in the medial orbitofrontal cortex correlating with poor self-control and greater glucose metabolism in other regions of the default-mode network (DMN) where precuneus correlated with negative emotionality. These brain results were similar while watching the violent media, during which aggressive viewers reported being more Inspired and Determined and less Upset and Nervous, and also showed a progressive decline in systolic blood-pressure compared to controls. Furthermore, the blood-pressure and brain activation in orbitofrontal cortex and precuneus were differentially coupled between the groups. These results demonstrate that individual differences in trait aggression strongly couple with brain, behavioral, and autonomic reactivity to media violence which should factor into debates about the impact of media violence on the public.Media portraying violence is part of daily exposures. The extent to which violent media exposure impacts brain and behavior has been debated. Yet there is not enough experimental data to inform this debate. We hypothesize that reaction to violent media is critically dependent on personality/trait differences between viewers, where those with the propensity for physical assault will respond to the media differently than controls. The source of the variability, we further hypothesize, is reflected in autonomic response and brain functioning that differentiate those with aggression tendencies from others. To test this hypothesis we pre-selected a group of aggressive individuals and non-aggressive controls from the normal healthy population; we documented brain, blood-pressure, and behavioral responses during resting baseline and while the groups were watching media violence and emotional media that did not portray violence. Positron Emission Tomography was used with [ While visual media is replete with images of violence, only a small minority in the population engages in real-life violent behavior. Critically, whether a person will act violently depends on individual trait variations which play a prominent role in how visual media is experienced and processed Stimuli with violent themes can prime, or perhaps facilitate existing trait tendencies 18F]fluoro-deoxyglucose using positron emission tomography (PET) were obtained at three conditions: at resting baseline, during exposure to violent media, and during exposure to emotional, non-violent media. Blood pressure (BP) and behavioral ratings of state affect were collected intermittently during the movie presentations. We expected that aggressive individuals would have a distinct intrinsic brain activity pattern at resting baseline and during passive viewing of the violent media compared to emotional media.To test our hypotheses regarding baseline and media viewing differences as a function of trait aggression, we recruited a group of healthy aggressive individuals with a history of assault behavior and a group of non-aggressive healthy controls. Measurements of glucose metabolism with [This research protocol was approved by the ethical review board of Stony Brook University and conducted accordingly. All participants provided written informed consent prior to participation. Approval number BNL-381.th percentile on the Physical Aggression scale  or those who reported they did not engage in physical fights and scored at 50th percentile or below on the Physical Aggression scale  were chosen for the study (mean age 25.15) A total of 54 males who responded to advertisement for healthy controls and healthy individuals with history of physical fights, were evaluated for their physical assault tendencies and other inclusion/exclusion criteria. Individuals were initially screened by phone and then seen at Brookhaven National Laboratory by a physician for general exclusion criteria which included current or past psychiatric disorders , neurological disease, significant medical illness, current treatment with medication (including over the counter drugs) and head trauma with loss of consciousness >30 minutes. Normal physical examination and laboratory tests were required for entry and pre-scan urine tests ensured the absence of any psychoactive drugs. Individuals were classified as aggressive (Ag) or non-aggressive (Na) depending on their responses on the Physical Aggression subscale of the Buss-Perry Aggression Questionnaire  Negative Emotionality  reflecting tendency toward emotional distress, alienation from others and aggressive behavior; Positive Emotionality  reflecting enduring positive affect through interpersonal engagement, and Constraint measuring tendencies toward self-control. Several lines of evidence have shown that high levels of NEM as Neuroticism are robustly associated with violence and aggression Stress Reaction which is linked to low frustration tolerance; Aggression which reflects the tendency to respond with retaliatory response style; and Alienation which is the most predictive primary scale of aggressive behavior. We also assessed attention and inhibitory control using a performance based measure, the Attention Network Task (ANT), that captures reaction-time performance on Alerting (response readiness), Orienting (scanning and selection), and Conflict (inhibitory control) in attention In addition to the Buss-Perry Aggression Questionnaire, the Multidimensional Personality Questionnaire (MPQ) There were three 40-minute imaging conditions: resting baseline, where participants were instructed to rest with eyes open, a video presentation of violent scenes, and a video presentation of emotional scenes not portraying violence. The two videos  were edited from R-rated movies and documentary films. The violent media presentation contained 20 scenes of violent acts encompassing the depiction of intentional acts of violence from one individual to another . The emotional media presentation contained 19 emotionally intense and action filled but non-violent scenes . The length of each of the violent or emotional scenes was between 1\u20134 minutes; these scenes were separated by a black screen that appeared for 30 seconds which signaled the next scene. The level of valence and intensity of each of the violent and emotional scenes was evaluated internally in the laboratory (data not shown) for valence and intensity and sequenced to optimize with the dynamics of FDG uptake (most intense scenes during the first 10 minutes of FDG uptake period). During the movie presentations, state levels of emotional reactivity were assessed using the Positive and Negative Affective Schedule (PANAS) with adjectives of mood states  3 full-width half-maximum, 63 slices) in 3D dynamic acquisition mode. Static emission scan started 35 min after FDG injection and continued for the next 20 min. Arterialized blood was used to measure FDG in plasma. During the uptake period of FDG, subjects were resting with eyes open (no stimulation) or watching a movie  in a quiet dimly lit room with a nurse by their side to ensure that they did not fall asleep. Metabolic rates were computed using an extension of Sokoloff\u2019s model The 25 subjects were scanned 3 times with PET-FDG in counterbalanced order on separate days and under 3 conditions: resting baseline, violent scenes, non-violent emotional scenes. The scanning procedure is standardized and was described before Prior to the analysis, each participant\u2019s PET image was mapped onto the Montreal Neurological Institute (MNI) template and smoothed via a Gaussian kernel with full width half maximum at 16 mm. Normalized metabolic images were analyzed using Statistical Parametric Mapping (SPM) The behavior and personality indices  were anaWell Being, Social Potency, Social Closeness and Achievement. Not surprisingly, the groups were substantially different on Negative Emotionality and inhibitory control. Individuals from the Ag group, reported more NEM, with high scores on the NEM subscales, Alienation, Aggression and Stress Reaction. The Ag group also demonstrated poor inhibitory control, reporting less self-Control on the MPQ and also showed increased latency to respond specifically in the Conflict condition of the ANT. This performance measure of inhibitory control correlated with self-reported aggression such that more latency as a result of conflict in attention was seen in those with more trait aggression as measured by two different self-report scales .As documented in Control  whereas those in OFC showed the opposite pattern revealing a negative correlation with NEM  and positive correlation with Control .The normalized brain metabolic measures were characterized by robust group effects at resting baseline, involving hyperactivity in the DMN and caudate, and dampened OFC metabolism in Ag as compared to Na . These rListed in Upset  while in the Ag group, systolic BP progressively decreased  in response to the violent media as compared to emotional media . Systolic and diastolic BP did not differ between the groups at resting baseline (p>0.05). Diastolic BP was not different between the groups in any of the conditions.As documented in Upset  and Nervtermined . In-lineal media . A compaTo examine the coupling of BP with glucose metabolism between the groups, we conducted ROI analyses to assess the correlation between regional metabolism during the violent media exposure and changes in systolic BP at time 37 , was associated with lower volumetric measures and lower metabolism of the OFC Control, we found that the lower resting metabolism in the OFC the higher were NEM and lower Control scores. In contrast the higher resting metabolism in precuneus the higher was NEM and lower Control trait scores. Supporting this finding are recent findings of higher precuneus with reduced conscientiousness and openness The most robust finding in this study is relative hyperactivity of the DMN during resting baseline with relative hypoactivity of the OFC and cerebellum in Ag compared to Na. The documented over-activity in components of the DMN may reflect a neural marker of enduring traits fostering inwardly directed attention to self-referential information stemming from years of social and cognitive learning Other over activated regions at baseline among Ag participants included the sensory motor area and caudate. One could speculate that this increased activity during rest would have a role in compromised responses during a cognitive task. A recent study proposed that striatal dopamine circuits, particularly the caudate, may provide a mechanism for the active suppression of the DMN under conditions that require increased processing of external stimuli  relative to internal, self-directed processing The fusiform gyrus was uniquely activated during violent media viewing in Ag, perhaps suggesting increased attention to facial representation of socially relevant cues Control scores further support the reliable implication of OFC in the externalizing continuum.In our study, the Ag participants showed a pattern of reduced OFC activity relative to the Na in the both resting baseline and violent media conditions. The OFC plays a role in externalizing/impulsive behavior, and regulating emotional and social behavior This OFC hypoactivity is consistent with other studies where exposure to violent media is associated with decreased OFC activation. In a study that examined components of the fronto-parietal network in response to aggressive video cues, reduced levels of OFC activation were found Familiarity with violent material could breed desensitization Nervous and Upset and more Inspired and Determined during the media violence  while their systolic BP progressively decreased. In stark contrast, The Na mood and BP responses to the violent media may be associated with a threat evaluation producing sympathetic activation, resulting in BP increase in the Na group. In a study with healthy adolescents, participants viewing violent movie clips experienced increased BP compared to baseline; however, prior exposure to violence was associated with lowered BP There is further evidence in this study supporting the desensitization hypothesis. The Ag group reported being less Indeed, the documented pattern of BP under-reactivity in Ag was associated with hypoactivations in the OFC  and hypeThere are several limitations in this study that constrain our interpretation power and generalizability. First, there may have been too few participants in the study to ascertain group by condition interactions and to conduct correlations between trait and brain measures. Second, the inclusion of males only in this study was done to control for potentially differential emotional reaction patterns of activation as a function of sex. However, this approach prevents us from making any claims about female response to violent media. Future studies must include females. Third, the experimental design did not include an acute test of aggression following the media condition. Future studies could include such a test to document aggressive responses following violent media as a function of brain response during the violent media. Fourth, there are brain activity results during violent video games finding anterior cingulate involvement"}
+{"text": "Prostate cancer treatment has evolved through the varying eras of therapy from one of predominantly hormonal agents without much effective cytotoxic therapy until the use of docetaxel was found to improve overall survival in the pivotal TAX-327  and SWOGProstate cancer remains the second leading cause of death in the United States. While treatment for early-stage low-risk prostate cancer has been largely controversial with the advent of the prostate specific antigen (PSA) screening controversy, treatment for metastatic castration-resistant prostate cancer (mCRPC) has evolved with great strides in the past decade, though remains incurable to this day. Docetaxel as a treatment for mCRPC brought about improvement in overall survival . To dateThe AR is a 110-kDa steroid receptor encoded by the gene located in Xq11-12 in the same family of nuclear hormone receptors as the estrogen, progesterone, and glucocorticoid receptors . The AR Addressing the issue of resistance is of relevant importance given the notion that all CRPC tumors will fail treatment eventually. Provocative findings show gain-of-function mutation in 3\u03b2-hydroxysteroid dehydrogenase type 1 (3\u03b2HSD1) enzyme that renders an alternative pathway to resistance by inhibition of degradation and therefore provides a rapid route of conversion of an adrenal-derived dehydroepiandrosterone (DHEA) to the more potent androgen dihydrotestosterone (DHT), which can activate the AR . IncreasIn summary, much progress has been made in the past decade alone in mCRPC therapy, but a lot remains to be done to further elucidate mechanisms of resistance and to circumvent these resistance mechanisms. The AR remains to be a versatile foe from progression of localized prostate cancer to advanced and metastatic prostate cancer and beyond castration-resistance. Provocative findings of transcriptional regulatory pathways and methods of inhibiting them will usher in an exciting era of targeting the AR in CRPC.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "A new methodology termed Single Amino Acid Mutation based change in Binding free Energy (SAAMBE) was developed to predict the changes of the binding free energy caused by mutations. The method utilizes 3D structures of the corresponding protein-protein complexes and takes advantage of both approaches: sequence- and structure-based methods. The method has two components: a MM/PBSA-based component, and an additional set of statistical terms delivered from statistical investigation of physico-chemical properties of protein complexes. While the approach is rigid body approach and does not explicitly consider plausible conformational changes caused by the binding, the effect of conformational changes, including changes away from binding interface, on electrostatics are mimicked with amino acid specific dielectric constants. This provides significant improvement of SAAMBE predictions as indicated by better match against experimentally determined binding free energy changes over 1300 mutations in 43 proteins. The final benchmarking resulted in a very good agreement with experimental data (correlation coefficient 0.624) while the algorithm being fast enough to allow for large-scale calculations (the average time is less than a minute per mutation). Developing methods for accurate prediction of effects of amino acid substitutions on protein-protein affinity is important for both understanding disease-causing mechanism of missense mutations and guiding protein engineering. For both purposes, there is a need for accurate methods primarily based on first principle calculations, while being fast enough to handle large number of cases. Here we report a new method, the Single Amino Acid Mutation based change in Binding free Energy (SAAMBE) method. The core of the SAAMBE method is a modified molecular mechanics Poisson-Boltzmann Surface Area (MM/PBSA) method with residue specific dielectric constant. Adopting residue specific dielectric constant allows for mimicking the effects of plausible conformational changes induced by the binding on the solvation energy without performing computationally expensive explicit modeling. This makes the SAAMBE algorithm fast, while still capable of capturing many of the explicit effects associated with the binding. The performance of the SAAMBE protocol was tested against experimentally determined binding free energy changes over 1300 mutations in 43 proteins and very good correlation coefficient was obtained. Due to its computational efficiency, the SAAMBE method will be soon implemented into webserver and made available to the computational community. PLOS Computational Biology Methods paper.This is a in vivo interactions occur in the crowded cellular environment, mutations may not only impact binding affinity but also could perturb protein interaction networks resulting in a loss or gain of interactions. Such changes in binding and interactions are frequently implicated in diseases and understanding of their molecular mechanisms is crucial for deciphering the origin of diseases. In particular, the effect of mutations on binding free energy (binding affinity) is considered to be an important component of the overall disease effect  . The motivation was that while some compounds listed in the heteroatoms section of PDB file may be biologically important, the vast majority of them are crystallographic artifacts (as ions for example). Thus, the resulting pruned database (tDB) consists of 1326 single point mutations from 43 proteins. Both datasets are available for download from .rSASA); rSASA = 1 corresponding to totally exposed residue in the protein) of the residue in the monomeric (rSASAm) and complex (rSASAc) states, as well as their mutual difference (\u0394rSASA = rSASAm \u2212 rSASAc). Thus residues are considered to be at the interface if they are in COR, SUP and RIM regions; and are away from the interface if they are in SUR and INT regions. RIM and SUR locations indicate that the residue is exposed to the water solvent when the complex is formed. The parameters of each location types are provided in We assigned the location of mutated residues in the protein-protein complex based on five categories  as previously described  by compuprofix module from Jackal package to rebuild these regions Eq (9) iH) hydrophobicity scale [rSASA. For example, a residue being exposed to the water phase will have large contribution to HYRD while practically zero if buried inside the protein. Having in mind that Hj indexes have opposite signs for hydrophobic and hydrophilic amino acids, such a formulation qualitatively describes the physical basis of the hydrophobic effect. The corresponding formula is:\u0394\u0394HYDR.The term accounting for the hydrophobicity was modeled using Wimley-White  was taken into account as well. We computed the number of HB for WT  atoms located at distance shorter than 2.4 \u00c5. Since the nitrogen acceptor is much weaker than oxygen, for simplicity it was not considered. Similarly the geometry of the hydrogen bond was not taken into consideration. Only polar  and charge  amino acids were taken into account.The impact of the mutations on the formation of hydrogen bonds , true negative (tn), false positive (fp), or false negative (fn). The explanation of the assignment procedure is provided in the The quality of the predictions was described by six parameters: accuracy, precision, sensitivity, specificity, negative predictive value (NPV) and Matthews correlation coefficient (MCC) ,53:accuOne of the goals of SAAMBE development is to develop fast algorithm capable of large-scale calculations. Thus, the execution time is an important component of the investigation. The execution time was monitored as a function of the number of amino acids in the corresponding complex (sequence length) and as a function of the geometrical shape of the complex (monitored via the largest dimension of WT complex).To verify the agreement between experimental and predicted values of the change of binding free energy due to single point mutation we calculated the Pearson correlation coefficient. In the paper all reported correlation coefficients were significantly different from zero with p-value smaller than 0.01.We also performed five-fold cross validation test for the tDB. It was done by randomly partitioning the tDB into five subgroups of approximately equal size. Each combination of four subgroups was used for training, while the fifth\u2014for testing the model. Then correlation coefficients were averaged over different cross-validated sets.S1 TextA\u2014Distribution of the RMSD within charged ; polar  and other  groups of residues. RMSD was estimated based on the deviation of the last heavy atom in a side chain of the residue in the protein-protein complex and in unbound part. Both protein-protein complex and its each partner were minimized for 5000 steps in NAMD. The inserted graph illustrates the average RMSD of the residues within CRG, PLR and OTR groups for WT (dark grey) and MT (light grey) structures. The analysis was performed for all entries in tDB (see manuscript for details); B\u2013The distribution of the change in RMSD of 1) CRG and PLR residues (orange) and 2) CRG and OTR residues (green) for WT  and MT (dash-dot line and solid circles) structures calculated for each case in tDB; Table A\u2014The standardized weights of significant energy terms in predicting the change in binding free energy due to single amino acid substitution; Table B\u2014Variance Inflation Factor calculated based on the Pearson\u2019s correlation coefficient; Table C\u2014Variance Inflation Factor calculated based on the Spearman\u2019s correlation coefficient; Table D\u2014Variance Inflation Factor calculated based on the Kendall\u2019s correlation coefficient.(DOCX)Click here for additional data file."}
+{"text": "We also observed that the allelic methylation patterns for the vast majority of the cis-regulated loci were shared between the somatic and germ cells from the same individual. These results demonstrated the interaction between genetic and epigenetic variations and suggested the possibility of widespread sequence-dependent transmission of DNA methylation during spermatogenesis.Differential methylation of the homologous chromosomes, a well-known mechanism leading to genomic imprinting and X-chromosome inactivation, is widely reported at the non-imprinted regions on autosomes. To evaluate the transgenerational DNA methylation patterns in human, we analyzed the DNA methylomes of somatic and germ cells in a four-generation family. We found that allelic asymmetry of DNA methylation was pervasive at the non-imprinted loci and was likely regulated by  To identify the genomic loci whose methylation statuses were likely to be sequence dependent, we performed a genome-wide survey of the degree of ASM by combining the data generated by the methylated DNA immunoprecipitation sequencing (MeDIP-seq) technology and the Illumina SNP genotyping platform. The methylation patterns of the SNP tagged ASM loci were compared between the somatic and germ cells. Sanger sequencing of the cloned bisulfite PCR products was also performed on a number of genomic regions to validate the candidate ASM events.To understand the possible roles of Seven PBSs and two sperm samples were collected from the family members  and genoP\u2009<\u20090.05; Promoter DNA methylation has a well-established role in the inactivation of genes on the X-chromosomes in females. We divided the promoters of X-chromosomal genes into two subtypes according to whether they were associated with adjacent CpG islands (CGIs) and observed that the normalized methylation signals for the CGI-associated promoters were significantly higher on the X-chromosomes than on the autosomes in PBSs from the females  for each heterozygous SNP that was covered by 10\u00d7 or greater in the PBSs. Generally, our MeDIP-seq approach did not show obvious strand bias of sequencing reads for the majority of heterozygous SNPs. The mean values of the percentages of reference allele supporting reads for the heterozygous SNPs were only slightly deviated from 0.5 . Furthercis-acting regulatory variants1011cis-acting genetic factors.Various studies had shown that most of ASM events at the non-imprinted loci could be defined as methylation quantitative trait loci (mQTL) and were most likely to be linked to Nearly all the published studies that documented ASM events in human were based on targeted methods that can only analyze the methylation patterns of predefined genomic regions or loci45We applied the same analysis strategy described above and identified ~ 4, 000 ASM events across the human genome. These ASM events showed significantly allelic asymmetry of DNA methylation and also showed a strong genotype-dependent effect on their methylation levels . Previou13t-test. All the potential ASM regions detected by our MeDIP-seq approach were confirmed by the results of cloned bisulfite PCR sequencing  even when we further corrected the potential effects of read depths by regression analyses.Only a small percentage of the ASM associated tag SNPs was located in genomic regions with well-studied regulatory roles, including promoters, CGIs and CGI shores, while the majority of them were located in other genomic regions without well-defined functional roles . Howevercis-regulated ASM events identified in one type of somatic tissue could be detected in other tissue types from the same individual, raising the possibility that the allelic methylation pattern might be present at quite early stages during embryonic developmentRecent studies had proved that the cis-acting genetic variants456It has becoming increasingly clear that asymmetry of DNA methylation between the two homologous chromosomes in human is pervasive at non-imprinted loci and is usually regulated by cis-acting variants as opposed to parental originThe ASM events identified in our study were different from genomic imprinting. The methylation levels of the ASM events at non-imprinted loci were dependent on the genotypes of cis-regulated ASM events were almost absolutely dependent on the genotypes of adjacent genetic variants. For a given sequence-dependent ASM event, the allelic asymmetry of DNA methylation could be observed in both unrelated individuals with distinct genetic background and in different tissues from the same individualHRAS, TP53 and TGFB1 and the expression of miR-663 itself was likely regulated by DNA methylation in multiple cell lines1718It remains controversial on whether the DNA methylation polymorphisms can be stably maintained between generations in human. In mammals, the two rounds of extensive epigenetic reprogramming during early embryogenesis and germ cell development appear to be effective in preventing the perpetuation of epigenetic variation between generationscis-regulatory genetic variants around the most significant association signals. Since the cis-effects of genotypes on DNA methylation are likely to be local and discrete, the ASM tag SNPs may also serve as an effective surrogate for refining the nearby regulatory variants.The identification of ASM tag SNPs may also have important implications for the interpretation of association signals from genome wide association studies. It is usually difficult to pinpoint the location of the true This study was approved by the ethical committees of Shenzhen Second People\u2019s Hospital and Peking University Shenzhen Hospital, and the experiments were carried out in accordance with the principles set out in the WMA Declaration of Helsinki and the NIH Belmont report. All individuals of this four-generation Chinese Han family with no history of genetic disorders signed an informed consent form permitting the collection and use of their blood samples in the study. Semen samples were obtained from G2M and G3M by masturbation into sterile containers after 3\u20135 days of sexual abstinence and left to liquefy at 37\u2009\u00b0C. Genomic DNA was extracted for the PBCs from all the seven family members and for the sperm samples from two male members using the Qiagen DNA Genomic-tip kit according the manufacturer\u2019s instruction .DNA was fragmented as described in the DNA bisulfite protocolMAQ was used to align the sequencing reads to the UCSC reference human genome (hg18) with the default parametersP\u2009<\u20090.05). ASM events fulfilling the following criteria were removed from further analysis to reduce the false positives: (i) the ASM tag SNPs supported by only one PBS and (ii) the tag SNPs showing inconsistent allelic preference across different individuals. False discovery rates (FDRs) were calculated by combining the binominal P values of all SNPs from all individuals to address the problem of multiple testing corrections.The software package SAM tools was used to generate the pileup file for each sampleAfter quantification, DNA was bisulfite converted using the EpiTect Bisulfite Kit . Bisulfite-specific primers with a minimum length of 18\u2009bp were designed using the online program MethPrimerHow to cite this article: Tang, A. et al. Analysis of a four generation family reveals the widespread sequence-dependent maintenance of allelic DNA methylation in somatic and germ cells. Sci. Rep.6, 19260; doi: 10.1038/srep19260 (2016)."}
+{"text": "This review is intended to evaluate the research findings and potential clinical applications of drug transport systems, developed based on the concepts of the structure/function and physiological role(s) of high density lipoprotein type nanoparticles. These macromolecules provide targeted transport of cholesteryl esters (a highly lipophilic payload) in their natural/physiological environment. The ability to accommodate highly water insoluble constituents in their core regions enables High density lipoproteins (HDL) type nanoparticles to effectively transport hydrophobic drugs subsequent to systemic administration. Even though the application of reconstituted HDL in the treatment of a number of diseases is reviewed, the primary focus is on the application of HDL type drug delivery agents in cancer chemotherapy. The use of both native and synthetic HDL as drug delivery agents is compared to evaluate their respective potentials for commercial and clinical development. The current status and future perspectives for HDL type nanoparticles are discussed, including current obstacles and future applications in therapeutics. High density lipoproteins (HDL) participate in reverse cholesterol transport in mammals to deliver the peripherally accumulated excess cholesterol to the liver . The strThe use of lipoproteins and particularly HDL  as drug (1)Enhanced safety and efficacy yielding a sturdy, non-leaking preparation due to a structure stabilized by apolipoproteins, particularly apolipoprotein A-I (apo A-I).(2)Biocompatibility and safety, shown by several pharmaceutical formulations, made up of essentially the same ingredients as rHDL .(3)The receptor-mediated uptake of the payload, carried in the core of the HDL particle Figure  makes thBecause of the concerns about infectious agents and the reproducibility of samples of human plasma HDL, its use for drug delivery in a clinical setting seems impractical. Consequently, most of the research activity in the last 20 years has focused on the development and evaluation of rHDL drug delivery vehicles Table . In a prCommercial development of HDL drug delivery vehicles has been hampered, at least to a degree, by the availability of the protein component apo A-I . SufficiAlternatives to apo A-I or other full length apolipoproteins may be appropriately found via the application of mimetic peptides  in the aBecause liposomes are the most widely used drug delivery vehicles, especially for cancer chemotherapy, it is worthwhile to compare their performance with lipoprotein based drug delivery vehicles in general and with rHDL in particular. Liposomes are spherical lipid based bilayers, generally with a diameter in the 100\u2013200 nm range, with the capacity to improve the delivery and therapeutic efficacy of intravenous drug formulations . LipoproThe natural payload of circulating HDL particles, cholesteryl esters, are known to be primarily delivered via a specific mechanism (selective delivery) using the scavenger receptor type B1 (SR-B1) receptor . This meReconstituted HDL type nanoparticles have been extensively studied as drug delivery agents for the purpose of developing enhanced chemotherapy strategies . CombineThe overexpression of the SR-B1 receptor by most cancer cells and tumors  appears 1.As mentioned above, tumor specific delivery of anti-cancer agents may be possible while protecting normal tissues and thus avoiding side effects.2.This approach may also be applicable to personalized (or precision) therapy where tumor biopsy samples may be assessed for their SR-B1 expression to select those patients that are most likely to be responsive to therapy.3.The tumor selective drug delivery concept may have particular relevance to pediatric cancer therapy  where thThere have been only a handful of reports describing the potential use of rHDL nanoparticles for the treatment of cardiovascular disease. These include Tanshinone IIA loaded reconstituted high density lipoproteins (TA-rHDL) for atherosclerotic plaque targeting mechanism in a foam cell model . The phaNucleic acids, including anti-sense nucleotides, siRNA and non-coding RNAs have been used extensively to modulate gene expression and more recently have been considered for therapeutic applications . AlthougSubsequently, extensive research on several delivery strategies has led to the design of novel transport systems that are likely to overcome most, if not all, of these barriers to effective nucleic acid therapeutics . EarlierAccordingly, the delivery of siRNA via lipoprotein carriers has been studied extensively  while coAn HDL-mimicking peptide-phospholipid nanoscaffold (HPPS) for siRNA delivery has been developed by The concept of delivering therapeutic agents via HDL type transport vehicles has come a long way since the original postulates of The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "We offer some perspectives and commentary on the sedation of obese patients in the intensive care unit (ICU).Sedation in morbidly obese patients should conform to the same broad principles now current in ICU practice. These include a general presumption against benzodiazepines as first-line agents. Opioids should be avoided in any situation where spontaneous breathing is required. Remifentanil is the preferred agent where continuous stable opioid levels using an infusion are required, because of its lack of context-sensitive accumulation. Volatile anaesthetics may be an option for the same reason but there are no substantial, controlled demonstrations of effectiveness/safety in short-term use in the ICU setting. Propofol is a valuable resource in the morbidly obese patients but the duration of continuous sedation should not exceed 6\u00a0days, in order to avoid propofol infusion syndrome. Alpha-2 agonists offer a range of theoretically positive features for the sedation of morbidly obese patients, but at present there is a lack of pharmacokinetic data and a critical mass of high-grade clinical data. Dexmedetomidine has the attraction of not causing respiratory depression or obstructive breathing during sedation and its sympatholytic effects should help deliver stable blood pressure and heart rate. Ketamine has a poor tolerability profile in adults so its use in the ICU context is largely confined to paediatrics.None of the agents currently available is ideal for every situation encountered in the management of morbidly obese patients. This article identifies additional research needed to place sedation practice of obese patients on a more systematic footing. Nowadays obesity is undoubtedly more prevalent than in earlier times ,2. This 2. The proportion of critically ill patients meeting that condition is still relatively small (\u224810%) . In. In16]. Concerns over possible nephrotoxicity with sevoflurane ,27 and mSurveys of sedation practice on several continents indicate a general tendency against very long-term use of propofol -30. ThisNevertheless, propofol is a well-defined and widely relied upon sedative for short- and medium-term use ,33. It hAlpha-2 agonists offer a range of theoretically positive features in the sedation of morbidly obese patients Table\u00a0 but suffUse of ketamine is substantially confined to paediatrics, in part because of concerns about its tolerability profile in adults . SystemaThe risk of serious respiratory adverse events with intravenous ketamine is low . In the In general, the newer S-ketamine form has a better tolerability profile than the previously available racemate.Combinations such as ketofol (ketamine plus propofol) and ketodex (ketamine plus dexmedetomidine) have been reported to offer attractive features for procedural sedation but much of that experience has been accrued in paediatrics . The fewPerhaps the most striking aspect of Table\u00a0acquiring robust pharmacokinetic data for the alpha-2 agonists and for S-ketamine in obese patientscontrolled comparisons of clonidine and dexmedetomidinefull characterization of the effects of benzodiazepines on the upper airways and on respiratory drive/muscle function in obese patientsevaluation of multimodal sedative regimens.The to-do list for the immediate future to rectify that situation includes:investigation of the short-term  and longer-term (\u22653\u00a0months) impact of sedation choices on cognitive dysfunction -54the interplay between sedation delivery and the day\u2013night cycle and sleep quality as it relates to OSAS in non-intubated patients.Other themes we should like to see investigated in morbidly obese ICU patients include:Avoid supine positioning: respiratory mechanics is improved in the sitting (or \u2018beach-chair\u2019) position.Endotracheal tubes should be the default airway choice for morbidly obese patients in most sedation cases.Avoid long-acting sedatives-there should be an intention towards rapid emergence of the patient from sedation after any procedure.Avoid drugs with respiratory depressant effects that reduce the breathing frequency and depth.Avoid drugs that cause or exacerbate obstructive breathing in non-intubated patients.Monitor breathing and depth of sedation.We support the view  that theWe offer the following practical advice on the sedation of morbidly obese patients vulnerable to OSAS and obesity\u2013hypoventilation syndrome."}
+{"text": "The model exhibits stable global dynamics in the asynchronous irregular regime and stable propagation of multiple synfire waves. Background noise generated by waves destabilizes wave propagation, providing a negative feedback signal limiting their number.In models of the cortex, synaptic connectivity is often assumed to be random within broad constraints such as interlayer connection densities. Alternatively, the connectivity could include richly structured circuitry. A recent study  demonstreffective connectivity: strength-dependent chain traversal probabilities averaged over noise fluctuations. By excluding chains with sub-threshold traversal probability we derive a family of effective coupling graphs (ECGs) parameterized by the global activity level. The distribution of wave activity in steady states is largely confined to the islands of circulation: strongly connected components (SCCs) and their associated out-components (OCs) in optimally chosen ECGs. A condensed ECG (cECG) allows the relationship between activity and effective connectivity to be visualized  and variability in chain strengths to obtain a recurrent system with a topography. We study emergent patterns of activity propagation in such a system. Ongoing endogenous activity due to branching of waves and regulation of wave activity by noise feedback is typically found. Across model realizations and runs, ongoing activity manifests diverse steady-state patterns and transitions. We argue that steady states arise jointly and consistently with an d Figure .The system is implemented both as a large-scale network of integrate-and-fire neurons and as a reduced model with binary-state pools as basic units. The reduced model exhibits activity patterns very similar to those of the full model and provides a valuable tool for studying the latter. We propose that the principle whereby activity patterns arise in concert with dynamically tuned effective connectivity applies to a broad class of networks with complex topologies."}
+{"text": "The formation of SCFA is the result of a complex interplay between diet and the gut microbiota within the gut lumen environment. The discovery of receptors, across a range of cell and tissue types for which short chain fatty acids SCFA appear to be the natural ligands, has led to increased interest in SCFA as signaling molecules between the gut microbiota and the host. SCFA represent the major carbon flux from the diet through the gut microbiota to the host and evidence is emerging for a regulatory role of SCFA in local, intermediary and peripheral metabolism. However, a lack of well-designed and controlled human studies has hampered our understanding of the significance of SCFA in human metabolic health. This review aims to pull together recent findings on the role of SCFA in human metabolism to highlight the multi-faceted role of SCFA on different metabolic systems. Short chain fatty acids (SCFA) are the primary end-products of fermentation of non-digestible carbohydrates (NDC) that become available to the gut microbiota. They represent the major flow of carbon from the diet, through the microbiome to the host. The discovery that SCFA appear to be the natural ligands for free fatty acid receptor 2 and 3 (FFAR 2/3), found on a wide range of cell types, including enteroendocrine and immune cells, has led to renewed interest in the role of SCFA in human health.SCFA are produced mainly through saccharolytic fermentation of carbohydrates that escape digestion and absorption in the small intestine and the pathways of SCFA production are relatively well understoodAkkermansia municiphilla have been identified as key propionate producing mucin degrading organisms.Ruminococcus bromii, such that absence of the organism significantly reduces resistant starch fermentation.Faecalibacterium prausnitzii, Eubacterium rectale, Eubacterium hallii and R. bromii, appear to be responsible for the major fraction of butyrate production.in vitro fermentation data and animal models. In silico modeling of the complex dynamic relationships between dietary substrate, microbiota composition and substrate production holds promise enabling predictions of SCFA production from diet-gut microbiome interactions.Metagenomic approaches have facilitated characterization of bacteria responsible for SCFA production. Acetate production pathways are widely distributed among bacterial groups whereas pathways for propionate, butyrate and lactate production appear more highly conserved and substrate specific. For example, propionate production although distributed across a number of phyla is dominated by relatively few bacterial genera.Roseburia intestinalis, Eubacterium rectale and Clostridium symbiosum along with increased butyrogenesis was observed on low-fat, high fiber feeding. Increases in CD3+ intra-epithelial lymphocytes and CD68+ lamina propria macrophages were also observed on high fat, low fiber diets suggesting increased inflammation in the absence of saccharolytic breakdown of fiber. Whether these changes translate into long-term impacts on host metabolism require intervention studies of longer duration. Changes in the microbiota of patients with inflammatory bowel disease (IBD) have been linked with decreased bacterial diversity and a loss of butyrate producing organisms such as F. prausnitzii.The field has been hampered by a lack of methodology to measure SCFA production directly in human studies, although recent work suggests that stable isotope techniques may hold promise.13C-acetate as a tracer for liquid phase of gastric emptying.It is important to consider the site of SCFA production and the biological gradient across the various down-stream tissues to fully understand the biological effects of SCFA in humans. This is particularly pertinent for the translation of findings from animal studies which often utilize oral SCFA supplementation or high dietary fiber supplementation to induce changes in SCFA production. Oral SCFA are rapidly absorbed and oxidised, best exemplified by the use of sodium There is a strong biological gradient for each SCFA from the gut lumen to the periphery which leads to differing cell and tissue SCFA exposure . The semIt is well established that SCFA, and butyrate in particular, are important substrates for maintaining the colonic epithelium. Butyrate is the preferred fuel utilised by coloncytes and the primary site of butyrate sequestration in the body is the gut epithelium.A potential regulatory role for SCFA in glucose homeostasis, mediated through FFAR 2/3, has led to significant interest in pharmacological interventions targeting this receptor mediated pathway in metabolic disease.In addition to the direct SCFA derived signal from the gut there are concomitant signals, generated by primary SCFA production in the gut lumen. Gut hormones produced by the enteroendocrine cells in the colonic epithelium also exert beneficial effects on glucose homeostasis. The mechanisms of gut hormone driven effects on glucose homeostasis have been comprehensively reviewed elsewherede novo lipogenesis (DNL) and cholesterogenesis, both of which appear to be inhibited by propionate.SCFA elicit effects on lipid metabolism and adipose tissue at several levels. In the liver, the fate of acetate is in vivo. Tantalising evidence of the role of SCFA in appetite regulation has recently appeared in a study using selective modulation of colonic propionate in humans which demonstrated that propionate appears to induce short-term appetite regulation though PYY and GLP-1 mediated mechanisms.The role of SCFA in appetite regulation and energy intake has recently been reviewed in detail elsewhere.An exciting area of recent investigation has arisen from the discovery that SCFA play a role in regulating the immune system and inflammatory response. Early work at the turn of this century had demonstrated the potential role of butyrate in immune regulation when it was shown that butyrate inhibits nuclear factor kappa \u03b2 (NF-\u03ba\u0392) activation in macrophages and also inhibits histone deacetylation (HDAc) in acute myeloid leukemia.The liver hosts a range of cell types that interact via small molecules and secondary immune cytokine signaling. Gut barrier permeability is thought to be a key factor in determining the pro-inflammatory load reaching the liver.The role of SCFA also extends to peripheral immune function. A recent study has demonstrated that acetate mediates joint inflammation in a murine gout model through inflammasome assembly and IL-1\u03b2 production that is partially FFAR2 dependent.the key molecular link between diet, the microbiome and health? The renewed interest in SCFA, coupled with the revolution in the tools available to dissect the complex molecular biology associated with cell signaling and metabolism, is beginning to provide evidence of the central role of SCFA in the diet-gut microbiome-host metabolism axis. There are however some key questions remaining that require further investigation. 1) Is the microbiome a passive substrate-degrading system or are signaling molecules actively involved in microbiome-host \u201ccrosstalk\u201d? Undoubtedly the answer to this quandary is yes, the molecules produced through microbiota activity provide important regulatory signals to the host and in the \u201c-omics\u201d revolution, metabolomics is a key enabling technology which will enable the identification of the repertoire of signals between microbiome and host. 2) Can the microbiota and its function be manipulated in a predictable way to have a clinically relevant impact on disease risk? The answer to this is highly likely to be yes, but probiotic studies designed to change microbiota diversity have been far from convincing in terms of outcome measures in metabolic healthIn Western societies and developing countries, what role do changes in diet and microbiome function play in future risk of disease? There is an increasing focus on the prevention of diseases that cluster around obesity, inactivity and a Western-type diet because of the present and predicted future economic health burden. The multifaceted roles of SCFA suggest that they may play an important role over the life-course in protecting the body against deteriorating metabolic control and inflammatory status associated with Western lifestyles. Whether manipulating the diet-gut microbiome-host metabolism axis represents a panacea for prevention of these leading causes of morbidity and mortality remains to be seen but it is a tantalising prospect because of the wide ranging benefits that could be brought about through relatively simple and cost-effective interventions if they could be targeted appropriately.It is tempting to overlook the potential for small ubiquitous microbiota derived molecules like SCFA to act as important molecular signals between the microbiota and host or as metabolic substrates regulating host cellular metabolism. A continually emerging body of evidence supports the role of SCFA as key mediators of cell function in a range of local, intermediary and peripheral tissues (summarised in"}
+{"text": "RNA interference is a cellular mechanism by which small molecules of double stranded RNA modulate gene expression acting on the concentration and/or availability of a given messenger RNA. Almost 10 years after Fire and Mello received the Nobel Prize for the discovery of this mechanism in flat worms, RNA interference is on the edge of becoming a new class of therapeutics. With various phase III studies underway, the following years will determine whether RNAi-therapeutics can rise up to the challenge and become mainstream medicines. The present review gives a thorough overview of the current status of this technology focusing on the path to the clinic of this new class of compounds.  C. elegans the mechanistic details of the RNAi pathway have been largely characterized. The discovery of RNAi fueled an extensive research aimed towards the application of this novel tool for therapeutic purposes as well as for further understanding of the mechanisms of gene regulation. These investigations led to the identification of short sequences of double-stranded RNAs (dsRNAs) as molecular mediators of RNAi  or short interfering-RNAs (siRNAs). siRNAs are transcribed as long dsRNAs that are transported into the cytoplasm and cleaved by DICER to yield siRNAs of 19 to 24 nucleotides with phosphorylated 5'-ends and hydroxylated 3'-ends. The cleaved RNAs are subsequently incorporated into a multiprotein complex named RNA-induced silencing complex (RISC). Using the thermodynamic stability of the ends as the main criteria, the RISC incorporates one of the strands known as the guide or antisense strand (AS) into the complex; while the other strand, known as the passenger or sense strand (SS), is discarded and degraded  is an evolutionary conserved, endogenous process for post-transcriptional regulation of gene expression. Since the discovery of RNAi in al., 1998). With tal., 1998, showingal., 2003). The pral., 2003). siRNAsal., 2003; Martineal., 2003). By faral., 200341]). Th). ThC. eal., 2003), blunt al., 2003), asymmeal., 2003) and asyal., 2003).., 2002[shRNAs are expressed in cells by delivery of plasmids or through viral or bacterial vectors, .The present review focuses on recent advances relevant to the use of siRNAs as therapeutic tools. In the following sections we will first address general challenges associated with the use of siRNAs as drugs. We will also discuss in detail different strategies used to improve the pharmaceutical properties of therapeutic siRNAs; such as chemical modifications, delivery strategies as well as the key elements that should be taken into account when designing siRNA-based compounds. Finally we will give a brief update on preclinical and clinical developmental programs highlighting the specific contributions of each of these programs to the field of RNAi therapeutics. Traditional pharmaceuticals or \u201csmall molecules\u201d typically tackle diseases by targeting proteins. Most small molecules target membrane proteins and/or receptors that are readily available to bind to these agents. This means that a whole range of targets, mostly present in the cytoplasm or nucleus of cells, are not available for traditional targeting. In contrast to small molecules, siRNAs can be designed to target virtually any gene; including the traditionally \u201cundruggable\u201d targets. On the other side, the avenue primed by discoveries in the genetics field in the last decade has significantly boosted the identification of new drug targets for diseases with previously unknown subjacent mechanisms. Observational human genetic studies have significantly contributed to the validation of targets for a given condition  facilit., 2013[., 2002[RNAi based compounds are chemically synthetized and therefore considered New Chemical Entities (NCEs) from a regulatory standpoint; however some of the characteristic features of these compounds are closer to those of New Biological Entities (NBE). One of these characteristics is an enormous specificity for the target against which they are designed. The specificity displayed by siRNAs to recognize their target enables the design of compounds to target dysfunctional proteins encoded by genes with single point mutations in one allele, hence opening a new path for the treatment of genetic disorders . In add3[., 2002). This hin vivo efficacy of siRNA based agents is dependent on intact siRNAs to reach the cytoplasm of their target cell, given the size and charge of naked siRNAs this task has stemmed more complicated than anticipated . The foUnmodified oligonucleotides are extremely sensible to degradation by nucleases. Nucleases cleave the phosphodiester bonds of nucleic acids and play essential roles in diverse cellular processes such as DNA repair, DNA replication and RNA splicing. Nucleases are also a fundamental part of the defense system of biological organisms . Nuclea., 2001[As mentioned above, modifications of the siRNA molecule must be compatible with the endogenous RNAi pathways. As a general rule, the SS and the 3'-proximal part and 3'-overhang of the AS are more amenable to chemical modification; on the contrary the 5' phosphate, the 5' proximal part and central positions of the AS are more sensitive, especially to multiple or bulky modifications . The 5'., 2001; Wang et., 2001), in add., 2001). Oligonucleotides are synthetized using solid phase phosphoroamidite chemistry. As such, amidites are incorporated into a growing chain as building blocks to obtain a full length single strand with the adequate length and sequence. Two complementary strands are thereafter hybridized to yield a siRNA. The availability of modified phosphoroamidites significantly simplifies chemical modification of siRNAs, thus most modifications can be incorporated without significantly altering the synthesis process. There are three groups of modification used to improve stability of siRNAs: (1) modification of the phosphodiester backbone, (2) sugar modifications and (3) modification of the ribose ring and nucleoside bases. This review will focus on the modification used in compounds in clinical development or in compounds that are close to reach this goal.., 2009[., 2004[., 1995[., 2003[., 1994[Nucleotides composing RNA and DNA are linked to each other by phosphodiester linkages. These bonds are negatively charged at physiological pH and are easily cleaved by endo- and exonucleases. Modification of this negatively charged backbone is typically used to enhance oligonucleotide resistance against nuclease degradation. The most widely used phosphate backbone alteration is the phosphorothioate (PS) modification in which the non-bridging oxygen atom in the phosphate backbone is replaced by a sulfur atom. The PS modification introduces chirality to inter-nucleotide linkages, one of the stereochemistries provides resistance to nuclease-mediated cleavage . Althou., 2009). An alt9[., 2004). On the4[., 1995). Phosph5[., 2003). Morpho3[., 1994); thus t., 2003[., 2013[Modification of the sugar moiety of nucleotides is widely used with the main purpose of enhancing siRNA nuclease resistance and hybridization properties. Free residues of the sugar ring can be modified at different positions or even the whole ribose ring can be substituted for a different sugar. The most frequently modified positions of the ribose are the 2' and 4'. Structural analyses of the silencing complex have revealed specific requirements of siRNAs to be able to induce gene silencing. These studies indicated that the 2'-OH group of the ribose ring is not specifically required for the silencing activity. On the other hand, the formation of an A-helix between the mRNA and the AS strand is strictly required for activity because the RISC complex uses the major groove to recognize the mRNA-AS-strand duplex. Modifications to the 2'-OH of the sugar ring do not fall within this category but are on the other hand required for the nuclease mediated breakdown of the oligonucleotide backbone . Accord., 2003; Chiu an., 2003; Prakash., 2003). Both t., 2003). 2'-O-M., 2003). The 2'., 2003). The mo3[., 2013). In add3[., 2013). Other 3[., 2013). The complete 5-carbon ribose sugar can be substituted for another sugar. This is the case of 2'-deoxy-2'-fluoro-beta-D-arabinonucleic acid (FANA) modified nucleotides which are based on arabinose rather than on ribose . This mThe goal pursued when modifying nucleoside bases is to increase duplex stability while maintaining and improving native base pairing recognition and hydrogen bonding. These modifications are significantly less used than sugar and backbone modifications. Examples of nucleobase modifications include 5-bromo, 5-iodo- substitutions of uracile, 2-thio, 4-thio, dyhydro and pseudouracil. A thorough review of nucleobase modifications is out of the scope of this review and can be found in the works of Peacock and coworkers (2011) or Bram., 2014[Delivery of siRNA into their target tissue and cellular internalization are still major challenges that limit full exploitation of RNAi therapeutics . siRNAs., 2004[Pharmaceuticals administered systemically need to reach and exit the circulatory system to reach their target organ. Systemic administration of compounds is performed by means of the enteral or the parenteral route. Molecules entering the body through the enteral route need to remain stable in the adverse conditions of the gastrointestinal (GI) tract until absorption takes place. This entails resistance to an acidic environment and to enzymes present in the GI tract. Molecules absorbed by the GI lining are thereafter required to reach the circulatory system after crossing the GI epithelium. Entrance through the parenteral routes is certainly less aggressive than the enteral route but requires the compound to be stable in the extracellular space and in circulation. In addition, molecules below 60 kDa are rapidly cleared by the kidneys; in accordance to this the elimination half-life of an intravenously (IV) injected unmodified siRNA has been shown to be of approximately 6 min , indica., 2004). These Once a given RNAi therapeutic has reached its target cell it needs to reach the cytoplasm where it can exert its action. The main entrance route of oligonucleotides to reach the cytoplasm is the use of one of several endocytotic pathways. Thereafter, the molecule is required to escape from the endosome before the action of enzymes and the acidification that takes place during endosome maturation degrades the compound . ., 2007[The major route of excretion of naked oligonucleotides is the kidney and to some extent the liver. As mentioned above siRNAs fall below the size threshold for renal filtration, accordingly, 70 % of an IV injected dose of a siRNA is found in the bladder 60 minutes after administration; most of the remaining amount of compound is cleared from circulation by the liver .Biodistribution patterns observed following systemic administration of RNAi mediators indicate that their pharmaceutical properties need to be improved in order to be of value as therapeutic agents. Stability against nucleases can somewhat be overcome by chemically modifying the molecule. Other issues such as reduction of kidney clearance; increased uptake by target organs, optimization of cellular uptake and endosomal escape need however to be addressed by formulation. ., 2012[Rozema and coworkers  elegant., 2012). -/- mice significantly reduced the silencing efficacy of otherwise active siRNA loaded LNPs. These researchers also showed that the requirement of an endogenous delivery system such as the ApoE mediated hepatocyte uptake can be substituted by an exogenous targeting system. To demonstrate this phenomenon trivalent NAG residues were linked to the PEG moieties that shield the LNP. Administration of these exogenously targeted LNPs to apoE-/- showed a NAG dose-dependent improvement in activity  to solvExcretion of siRNAs takes place at the level of the kidney; IV administered siRNAs without a carrier fall below the filtration threshold of the kidney and are therefore rapidly taken up by the kidney and excreted in urine . As menSolid tumors develop their own vasculature in order to cover their need in nutrients and oxygen supply. These newly formed vessels are product of aberrant angiogenesis signals that result in the formation of fenestrated and leaky blood vessels . In add., 2009[., 2010[One of the first approaches designed to deliver siRNAs to tumors was by means of liposomes and LNPs . Using 9[., 2010) showed 9[., 2010). Clinic9[., 2010). Formulations composed of a highly charged cationic lipid (AtuFECT01), neutral helper lipids, 1% PEG and a 2'-O-methyl stabilized siRNA, named lipoplexes, were found to differentially deliver their siRNA cargo into the endothelial vasculature of several organs following IV administration in animal models . The goThe pharmaceutical properties of siRNA based therapeutics designed to have local action are different from those required by molecules designed for systemic administration. The stability of locally applied molecules needs to withstand the particular characteristics of its site of action rather than those of serum. Furthermore, reduced stability in serum can be considered an advantage for local indications in order to reduce unintended systemic side effects that may arise due to presence of the compound in systemic circulation. Size and other physical properties of the molecule/carrier system condition the entrance and clearance from the local site. Because systemic effects are unwanted for locally administered products increasing the size of the compound with a carrier is not usually required for these particular indications because avoidance of kidney clearance is not specifically needed. Size does also condition the ability of a given compound to enter the target organ. Most locally accessible tissues such as the skin or the eye are extremely well protected from external aggressions; this protection usually entails a thick physical barrier and different kinds of chemical barriers. Different strategies can be used to overcome the above mentioned barriers and deliver compounds locally. Physical approaches to deliver siRNAs across the stratum corneum barrier include microneedles , intradA combination of dissolvable microneedles and a modified siRNA has been used to overcome the stratum corneum of the skin in order to improve cellular uptake. This approach has been used to obtain a proof-of-concept study on the possibility of silencing a gene in the epidermis . CD44 iMost programs developing siRNAs for eye conditions seek modifying gene expression in the retina. For this purpose siRNAs are intravitreally injected, thus administered very close to their site of action. In this scenario strategies to improve siRNA design have been focused on increasing cellular uptake and half-life in vitreous humor. ., 2013[in vitro. In vivo analysis of their activity indicated that the structure and pattern of modification of these compounds enables uptake by retinal cells and ensures even distribution throughout the mouse retina. According to these in vivo analyses the diffusion of the compound throughout the vitreous humor and uptake by the retina is a relatively slow process. Analysis of the biodistribution of the compound 2-3 h after injection showed that the compound was only present in the ganglion cell layer at that time-point and uniform staining of the retina was not observed until 24h after injection  incorporate modifications to the molecule precisely to achieve the above mentioned goals. The specific design of these compounds consist of a 19 nt antisense strand and a shorter sense strand (<15 nt); this results in an asymmetric duplex that includes a single strand tail that is usually phosphorothioated. In addition, the strands include stabilizing 2'-F and 2-'O-Me modifications and a sterol conjugate on the SS to improve cellular uptake . Followal., 2013). The pr., 2011[A different approach was pursued by Ahmed and coworkers 2011), chemic1, chemicThe apparent contradiction of the results of Byrne et al. 2013) and Ahm3 and Ahm., 2010[Gene-silencing efficacy varies significantly depending on the target gene and specific sequence chosen . Factor., 2010). Method., 2010; Patel e., 2010; Pei and., 2010). The re., 2010). Recent., 2010). Inclus., 2010). On the., 2010). Other ., 2010). Finall., 2010; Liu et ., 2010) siRNAs are chemically synthetized molecules that frequently contain chemical modifications that do not necessarily occur naturally in biological organisms. As mentioned previously, siRNAs are regulated as NCEs. However, the mechanism of action these molecules entails using a biological path to exert their action; hence siRNAs have some attributes in common with NBEs. The toxicities observed in response to siRNAs can thus arise as a consequence of their particular chemistry and/or the chemistry of their delivery vehicle but can also be due to activation of intended or unintended biological pathways  hybridization dependent toxicities and b) hybridization independent toxicities. Hybridization dependent toxicities arise from the interaction of siRNAs with other oligonucleotides through Watson and Crick base-pairing. Hybridization independent toxicities of siRNAs are not related to base-pairing  and areToxicities due to base-pairing can be due to exaggerated pharmacology (EP) or off-target effects (OTEs). The former is caused by inhibition of the targeted gene to an extent that causes deleterious effects; the latter are caused by direct or indirect modulation of genes that are not intentionally targeted. ., 2011[in silico data with relevant biological data such as effect of genetic deletions, pharmacological modulation or pattern of expression in relevant tissues. Thereafter in vitro and in vivo experiments can be set up in order to evaluate the relevance of the potential off-target for the specific therapeutic purpose of the molecule. siRNAs can modulate unintended genes by an RNAi mechanism, induced by the SS or the AS, or by miRNA-like effects . Predic., 2014[Modulation of gene expression by siRNAs can very efficiently change the disease state but if the pharmacological effect is greater than desired the very advantages of this drug class can be responsible for causing deleterious effects. In the RNAi field the extent and relevance of exaggerated pharmacology is dependent on the selected target gene. As such, exaggerated pharmacology is completely irrelevant for compounds targeting exogenous sequences such as viral genes; but can be relevant when targeting host genes. Relevance of EP should be addressed taking into account available data for the target gene: pattern of expression, biological consequences of deletion and/or modulation using genetic or pharmacologic tools and specific elements of the developmental program and selected candidate such as potency, administration route, dosing frequency and acceptable levels of toxicity . In add., 2014). Other Most of the toxicities related to siRNAs are linked to either its chemistry or to the characteristics of the delivery vehicle . Modifi., 1994[., 2002[., 1997[., 2014[As seen in previous section \u201cModification of the phosphodiester backbone\u201d, backbone modifications are widely used to reduce nuclease activity; the most commonly used of these modifications is the replacement of a non-bridging oxygen on the backbone between two ribonucleotides with a sulphur to create a PS linkage. This modification not only enhances stability but also increases cellular uptake . Phosph., 1994). Activa4[., 2002). These 2[., 1997). Phosph7[., 2014). ., 2010[LNAs are formed by linking 2' and 4' carbons of the ribose ring by a methylene bridge . The br., 2010). In add., 2010) and may., 2010). Howeve., 2001[Chemical substitution at the 2'-hydroxyl group of the sugar moiety 2'-O-Me, 2'-F or 2'-MOE are extensively used to improve stability and reduce immunogenicity. These modifications increase the melting temperature of the oligonucleotide carrying them rendering more stable molecules and reduce immunostimulatory effects . The br., 2001). These ., 2001). In the., 2001). Finally, compounds using lipid based vehicles such as LNPs can cause infusion-related reactions, elevation of cytokines and activation of the complement cascade . Studie., 1990[., 2006[Cells have the ability to defend themselves against the entrance of exogenous genetic material. This essential function in defense against infection becomes a hurdle trying to artificially introduce an oligonucleotide for therapeutic purposes. The recognition of foreign DNA or RNA by the innate immune system induces the production of type I interferon and pro-inflammatory cytokines. The innate immune has the ability of recognizing pathogen associated material by means of germ-line pattern recognitions receptors (PPR) that promote rapid responses to microbial pathogens during the invading phase. These receptors recognize conserved pathogen-associated molecular patterns (PAMPs) which are not present in the host and are usually important for pathogenicity and/or survival of the pathogens . PAMPs ., 1990). 2-5-ol., 1990). RIG-1 ., 1990; Marques0[., 2006). MDA-5 0[., 2006; Zheng e0[., 2006). ., 2008[., 2005[., 2006[., 2008[Toll Like Receptors (TLRs) are mainly expressed in immune cells and are crucial for detection of pathogen-derived products and activation of immunity . Activa8[., 2005; Diebold5[., 2006). It sho6[., 2008). in vitro studies should be performed using a mixed population of primary immune cells such as fresh peripheral blood mononuclear cells to test immunogenicity in vitro, but most importantly, signs of immune activation should be monitored in vivo by examining cytokine levels and activation of inflammatory pathway genes at a short time-point and 24 hours after administration . As menal., 2013).With two compounds in phase III and several compounds in advanced phase II the RNAi filed is certainly getting closer to the market. Table 2., 2013[., 2007[Patisiran (ALN-TTR02) targets transthyretin (TTR) and is the most advanced candidate in the RNAi pipeline (phase III) . This c3[., 2007). Most i3[., 2007). Six-mo., 1995[Revusiran (ALN-TTRsc) is an adaptation of patisiran into the new NAC-based delivery platform. This compound is currently in phase II for another type of TTR-amyloidosis: familial amyloidotic cardiopathy (FAC). In this type of amyloidosis cardiac amyloid deposition leads to cardiac wall thickening and heart failure . The ch., 2006[ALN-PCS02 is a LNP formulated siRNA targeting proprotein convertase subtilisin/kexin type 9 (PCSK9), a key protein in the regulation of cholesterol homeostasis. PCSK9 enhances degradation of hepatic LDLR, thus resulting reduced hepatic LDL-cholesterol clearance. Loss of function mutations in PCSK9 have been described in humans and are associated with reduced LDL cholesterol and coronary heart disease . A phas., 2006). Furthe., 2006).TMK-ApoB was one of the first compounds based on RNAi to reach clinical trials. The program, terminated in 2010, used a siRNA targeting Apoliprotein B (ApoB) encapsulated in first generation LNPs. The phase I clinical trial was halted due to unexpected immune stimulation. The preclinical evaluation of this product had not anticipated the subsequent events observed in the phase I trial thus raising the question whether preclinical models were good predictors of the immune response. Much has been learnt since the mentioned trial and new formulations have been designed in order to reduce the immunostimulatory properties of LNPs; this has been partially achieved by modifying the composition of LNP as well by reducing the infusion rates while administering the compound . In add., 2008[ND L02-s0201 is a siRNA targeting Heat Shock Protein 47 (HSP47) formulated in vitamin A-conjugated LNPs under development by Nitto Denko for the treatment of fibrotic diseases of the liver . HSP47 ., 2008). Inhibi., 2008). The viTKM-PKL1 is a LNP formulated RNAi trigger that targets polo kinase 1 (PLK1). PLKs are a family of proteins with important roles in cell cycle regulation. PLK1 can override certain regulation points in the cell cycle causing genetic instability and promoting tumor development . One phAtu027 is Silence Therapeutic's clinical candidate for cancer. The product is a modified siRNA targeting Protein Kinase N3 (PKN3) formulated in lipoplex nanoparticles. The particular lipid composition of the formulation facilitates delivery to the vascular endothelium. PKN3 is a downstream effector of phosphatidylinositol 3-kinase (PI3K), a kinase that controls a transduction pathway commonly dysregulated in several forms of cancer. Silencing PKN3 stabilizes the vasculature and attenuates inflammatory responses in tumors reducing vasculature leakage and permeability; as a consequence there is a reduction in extravasation of metastatic cells and a reduction in the number of metastases in animal models . A phasInitial biodistribution studies showed that systemically administered siRNAs are excreted through the kidney, thus it seemed logical to develop compounds to treat conditions related to a tissue that is seemingly exposed to these compounds following IV administration. QPI-1002 is a naked siRNA modified with alternate 2'-O-Me on both stands targeting p53 under development by Quark Pharmaceuticals. This compound has completed a phase I clinical study for kidney injury in acute renal failure and a phase II for the prophylaxis of delayed graft function in deceased donor kidney transplant patients. This phase II trial finished in 2014 and failed to meet its primary endpoint which aimed a 30 % relative risk reduction compared to placebo. The sponsor, however highlighted, that this endpoint was indeed met in a certain set of the population. The company is planning a phase III trial to start in 2015. In terms of safety, targeting an exogenous genome, completely different from that of the host organism seems an ideal situation. Off-target effects are theoretically greatly reduced and issues with exaggerated pharmacology are not relevant.With this in mind several companies are developing compounds that target viral genomes. The most advanced of these compounds is Arrowhead Corporation's ARC520 . This c., 2010[., 1993[TKM-Ebola is a combination of three siRNAs that target three genes of the Zaire strain of the Ebola virus: the polymerase L, VP24 and VP35 . The po0[., 1993). The coRXI-109, a self-delivery siRNA, targets Connective Tissue Growth Factor (CTGF) and is being developed for the treatment of hypertrophic scaring and keloids. Self-delivery siRNAs (sd-siRNA) are asymmetrical double stranded RNAs are thought to combine the potency of siRNA with the improved biodistribution of antisense oligonucleotides. RXI-109 is a chemically stabilized sd-siRNA that incorporates hydrophobic moieties for improved cellular uptake . The coThe eye offers several advantages as a target organ for RNAi therapeutics. It has a relatively low content in RNases, and it is quite isolated from the rest of the body, limiting the access of the compound administered into this organ to systemic circulation . These The most advanced programs for ocular indications are Quark's QPI-007 designed to silence Caspase 2, currently in Phase II/III for the treatment of Non-arteritic Anterior Ischemic Optic Neuropathy (NAION) and Sylentis' bamosiran SYL040012), targeting \u03b22-Adrenergic Receptor (ADRB2) for the treatment of glaucoma, in phase IIb. QPI-1007 is a 19-nt modified siRNA that has shown to be safe when injected intravitreally (IVT) to animal models and humans . The coSYL1001 is a naked 19-nt siRNA targeting transient receptor potential vanilloid-1 (TRPV1) for the treatment of ocular pain. TRPV1 is a cation channel permeable to calcium activated by stimuli such as heat, low pH and capsaicine; this receptor is present in several structures of the eye where it has been related, among other roles, to nociception . This compound has shown to be safe when administered in eye drops to animals models and humans and is undergoing a phase I/II for the treatment of ocular pain associated to dry eye disease, a condition for which no specific treatment currently exists .The encouraging advances observed in the clinical setting have enabled further research in the field of RNAi therapeutics. Most preclinical pipelines are taking advantage of the discoveries and lessons learned from the compounds that are currently advancing though clinical trials. Problems identified in developmental programs of both siRNAs and ASOs have been taken back to the lab in order to find innovative ways of solving them. As such, a great deal of programs in preclinical research are taking advantage of the innovations made to facilitate delivery of siRNA based compounds to the liver; but we are also starting to see new approaches to deliver siRNAs to organs outside the liver, incorporation of algorithms to reduce toxicity, instability etc. Table 3th OTS meeting). The biodistribution of the siRNAs and the knock-down of the target gene, monitored by measuring the serum levels of the encoded protein, appear to be equivalent to those observed in response to SQ-administration. These results open up a new avenue for needle free administration for liver targeting Alnylam has, in the last few years, been very active in incorporating new candidates to its preclinical pipeline; particularly candidates that target genes that require down-regulation in the liver. In the last months they have implemented their newly presented delivery platform into most of their preclinical candidates, hence shifting the delivery strategy from one based on LNPs to a NAC based delivery. Reasons for this shift include a better efficacy/toxicity ratio and a patient-friendlier administration route: subcutaneous instead in intravenous. In addition, the NAC delivery platform is fully own by Alnylam, excluding the requirement of licensing external intellectual property. Among the preclinical candidates only one, ALN-PCSsc, uses the first generation standard chemistry (STC) NAcs; whereas the newer candidates use the improved version of this technology: enhanced stabilization chemistry (ESC). Recent data have also shown that NAC conjugated siRNAs can also be administered to mice via inhalation using high pressure microsprays  that most likely require reduction of gene expression in the liver. According to recent press releases these new programs might pursue a multi-target approach. Multi-targeting is an obvious direction for the field, as silencing multiple targets in a given disease would most likely increase potency. As of today, multi-targeting has only been approached to tackle viral infections   and can., 2011[Delivery of compounds outside the liver is another of the challenges that the RNAi field will face in the upcoming years. A few steps towards this direction have already been taken and hopefully the fruit of this labor will start to generate strategies that can be taken into clinical trials in the next few years. Examples of this include Silence Therapeutics' Atu111, a compound that targets Angiopoietin-2. This compound uses a delivery platform of poly-lipoplexes developed by the company that has been shown to deliver RNAi triggers into the lung endothelial cells. Another of the most likely goals for this technology is achieving delivery to the central nervous system. The long-lasting effects of RNAi make this difficult-to-reach organ an ideal target for RNAi based approaches. Several receptors present in the blood-brain barrier, such as the transferrin receptor, have been used in order to develop delivery strategies for RNAi triggers into the central nervous system. These techniques need however to be refined in order to be fully exploited for therapeutic use . The last decade has witnessed the remarkable evolution of the use and exploitation of RNA interference with the aim of developing therapeutics. It has been a rough path characterized by volatility in support and funding. The introduction of chemical modifications as well as the development of innovative carriers with the ability of delivering RNAi triggers closer to their site of action, have significantly improved the pharmaceutical properties of these compounds. In addition, the robust of long lasting gene knock down seen in several human trials has shown that RNA interference is in fact a very promising tool in the therapeutic landscape. The following years will be crucial to see if this technology is able to give hold up to the expectations and whether RNA interference indeed becomes a new class of medicines. The authors apologize to colleagues whose relevant primary publications and ongoing research have not been cited because of space constraints but whose work has helped move the field forward. The authors would like to thank B. Vargas and L. Company for useful discussions and suggestions and for reading the review. The authors are all employees and stockholders of Sylentis S.A.U., a Spanish biotechnology company focused on developing gene silencing technology based therapies."}
+{"text": "However in-vitro evidence, seems to underline a possible negative effect of HPV in increasing blastocyst apoptosis and in reducing the endometrial implantation of trophoblastic cells. On these bases we believe that a new scientific approach is necessary to better understand the real role of male and female HPV infection in infertility and early pregnancy development.Current evidence about in-vivo and in-vitro studies regarding this topic.English literature review of manuscripts focused on HPV infection and human reproduction was conducted. We performed a critical analysis of evidence and possible bias affecting both in-vivo studies is due to the inappropriate timing of HPV effects evaluation since evidence about in-vitro studies strongly suggests that a large part of HPV negative effects occurs during a very early stage of embryo development. All the efforts of the scientific community to investigate the real role of HPV in human reproduction disorders cannot underestimate the severe BIAS of actual evidence in postulating new hypothesis and research projects which are fundamental to clarify if HPV may be associated with unexplained couples infertility and early miscarriages.The biggest limitation of the If the relationship between HPV gametes infection and early human reproduction step impairment will be confirmed, the HPV male and couple vaccination may represent a reliable option to improve fertility in some couples affected by infertility actually classified as \u201cidiopathic\u201d but maybe linked to HPV infection. Currentelopment -6. Howevic cells -15. Despic cells , in our ic cells . The higAnyway the interesting results of Perino et al. should be interpreted with caution since several Authors reported approximately 24% of cervical HPV-DNA detection in women with ongoing pregnancy ,18.Other 3 available studies  failed in-vivo studies conducted till now  are affected by different BIAS which probably led to confusion in considering the final results. The first possible BIAS is related to the HPV types detected: all the cited studies focused in particular on high-risk (Hr) genotype 16 and 18 extending the search only to few other Hr-genotypes or low risk HPV 6/11. The second BIAS is related to the sample detection methods of HPV presence which did not permit to rule out the possible contaminations derived by the passage through the genital tract. Adjunctively the study by Conde-Ferraez et al. and Ticconi et al., focusing only on cervical HPV detection, did not consider the possible BIAS related to the viral clearance  which can lead to an underestimation of the problem [in-vitro evidence which demonstrated that HPV sperm infection seems to have a possible role in adverse blastocyst development [We believe that all the  problem . The thielopment ,14. In pelopment ,13,20.in-vitro evidence on this field represents a good starting point to plan new perspective studies and to avoid the above mentioned BIAS.On these bases we believe that a new scientific approach is necessary to better understand the real role of male and female HPV infection in early pregnancy development and infertility. We think that the recent in-vitro studies, that HPV-31 infection and HPV-16 E6 and E7 oncogenes caused both a decrease in 3A trophoblastic cells number and a low trophoblast-endometrial cells adhesion in the first week after the exposure [Yet in 1996 Cabrera et al. in a murine experimental study demonstrated that spermatozoa carrying HPV-16 and \u221218 viral genome can be transfected into a mouse blastocyst with viral DNA localization both in the inner cells mass and trophoblastic cells . The conexposure ,13. The exposure . These fThese effects were also confirmed by Gomez et al. who found a 3- to 6- fold greater rate of apoptosis in trophoblastic cells transfected with a plasmid containing the entire HPV-16 genome and a progressive decrease of trophoblast invasion ability 25.2-57.6%) from day 3 until day 15 after transfection compared to negative controls . Also Ho.6% from The reasons which could explain the reduction of invasiveness of trophoblastic cells were suggested by Boulenouar et al. who found a down-regulation of E-cadherin  in trophoblastic cells expressing HPV-16 viral genome .Although all the considered studies have important limitations (which should not be underestimated) linked to the in-vitro artificial and experimental conditions, most of the analyzed data suggested a possible adverse effect of HPV infection in early pregnancy development and maybe in idiopathic couple infertility. The demonstration that also the spermatozoa can act as a vector of HPV viral genome into oocyte  force thThis fact acquires an even greater importance since the recent estimated prevalence of HPV sperm infection is about 10% (95% CI:7\u201314%) in general male population and 16% (95% CI:10\u201323%) in men affected by unexplained infertility [So, focusing the investigations on HPV implications in human reproduction, it is mandatory to shift the older concept of infection with female gender target (i.e. oncologic risk in infected women respect to men) and to start in considering the HPV infection as a couple or, even better, a men problem.in-vivo studies are not useful to completely understand the HPV exact role in human infertility because study methods, patients selection and idea conception seem to be inadequate.In agreement with this new conception, it is intuitive that all the available in-vivo studies is due to the inappropriate timing of HPV effects evaluation since evidence about in-vitro studies strongly suggests that a large part of HPV negative effects are carried out during a very early stage of embryo development (within the first two weeks after conception). These effects are very difficult to be demonstrated by clinical studies since it is possible to detect a causal-effects ratio on human reproduction only starting from the third week after conception (five week of amenorrhea). In this way all clinical studies lose a large part of negative effects demonstrated by in-vitro experimental studies.The biggest limitation of the Anyway clinical evidence can elucidate the consequences of HPV in late embryos development and pregnancy evolution. The detection of HPV in the placental tissue  lead to in-vitro and in-vivo further studies.In conclusion all the efforts of the scientific community to investigate the real role of HPV in human reproduction disorders cannot underestimate the severe BIAS of previous evidence in postulating new hypothesis and research projects. Even if the choice of more appropriate laboratory techniques (ISH rather than PCR) could partially solve the BIAS linked to potential contamination of specimen, shifting the attention on men and couples rather than only on women represent a first step to solve the dilemma. As suggestion to Clinicians interested in the topic we invite to focus the attention on idiopathic infertile couples undergoing ART cycles, theoretically the most appropriate cohort to plan both We must definitively understand if the hypothesized adverse effects of HPV in human reproduction is only a supposition derived from a \u201cinconclusive\u201d scientific speculation or if we are faced to a new important discovery which can potentially clarify the exact mechanism of some cases of unexplained couples infertility and of early miscarriages linked to HPV infection.So If the suspected HPV role in early human reproduction impairment will be confirmed by well conducted further studies, the couple vaccination before attempting both spontaneous and assisted pregnancy could be a reliable and effective tool .The rationale for proposing the use of HPV vaccination (Gardasil\u00ae or Cervarix\u00ae) in couple attempting ART cycle is based on the evidence that in man the HPV sperm infection seems associated with some spermatic parameters impairment  and in win-vitro and epidemiological studies on this field.If in infertile couple the fertility rate will result increased after vaccination, this can be considered an indirect confirmation of our hypothesis and a suggestion to start more appropriate Improvement in the knowledge of HPV-DNA sperm infection mechanisms, timing, and link to fertility impairment may explain some of the actual \u201cidiopathic\u201d male and couple infertility.The authors declare that they have no competing interests.MN & SG carried out literature search, critical analysis of data and written the manuscript. AA carried out language revision and critical comment. GBN and GA participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript."}
+{"text": "Different studies in the literature examined the fate of the ascending aorta and aortic root after valve replacement and various factors such as bicuspid aortic valve and aortic valve pathology were studied. The effect of the left ventricular end diastolic diameter (LVDD) has not been yet examined.In this retrospective study we analyze for the first time the effect of the left ventricular end-diastolic diameter and its role on the aortic expansion after aortic valve replacement one year after the procedure.Forty three consecutive patients took part in this study. All of them underwent aortic valve replacement (AVR) in our Institution between the years 2012-2013 with either mechanical or biological prosthetic aortic valve.After aortic valve replacement there was a decrease in the ascending aorta and aortic root dimensions . Left ventricular end-diastolic diameter and ejection fraction did not changed significantly after AVR. There were the correlations between the preoperative ascending aortic size and the preoperative and after the first year left ventricular end-diastolic diameter . Postoperatively there was also a correlation between the ascending aortic size and the preoperative and after the first year left ventricular end-diastolic diameter .In conclusion, in this retrospective study we showed that there was a correlation between the preoperative and postoperative aortic size (ascending aorta and aortic root) and the postoperative left ventricular end-diastolic diameter. Although it is early for definite clinical conclusions, however it is the first study which tried to analyze this relationship."}
+{"text": "Severe forms of alpha and beta thalassaemia have been estimated to affect approximately 68000 births annually. Individuals who carry thalassaemic genes are protected against death from malaria infection; the global distribution of thalassaemic genes thus matches the historical distribution of malaria.Screening programmes are a vital tool to counter the thalassaemias by:(i) identifying individual carriers and allowing them to make informed reproductive choices, and (ii) generating population level gene-frequency estimates, to help ensure the optimal allocation of public health resources. For both of these functions it is vital that the screen performed is suitably sensitive.One popular first-stage screening option for beta thalassaemia in low-income countries is the One Tube Osmotic Fragility Test (OTOFT). Here we introduce a population genetic framework within which to quantify the likely sensitivity and specificity of the OTOFT in different epidemiological contexts. We demonstrate that the co-occurrence of alpha thalassaemia, and other malaria related erythrocyte poly-morphisms such as Southeast Asian Ovalocytosis and glucose-6-phosphate dehydrogenase deficiency, could reduce the sensitivity of OTOFTs for beta thalassaemia to below 70%. Our results highlight a potential hazard of the widespread application of OTOFTs and emphasize the fact that the public health impact of any single genetic adaptation to malaria cannot be considered in isolation."}
+{"text": "The calcium-sensing receptor (CaSR) is a widely expressed homodimeric G-protein coupled receptor structurally related to the metabotropic glutamate receptors and GPRC6A. In addition to its well characterized role in maintaining calcium homeostasis and regulating parathyroid hormone release, evidence has accumulated linking the CaSR with cellular differentiation and migration, brain development, stem cell engraftment, wound healing, and tumor growth and metastasis. Elevated expression of the CaSR in aggressive metastatic tumors has been suggested as a potential novel prognostic marker for predicting metastasis, especially to bone tissue where extracellular calcium concentrations may be sufficiently high to activate the receptor. Recent evidence supports a model whereby CaSR-mediated activation of integrins promotes cellular migration. Integrins are single transmembrane spanning heterodimeric adhesion receptors that mediate cell migration by binding to extracellular matrix proteins. The CaSR has been shown to form signaling complexes with the integrins to facilitate both the movement and differentiation of cells, such as neurons during normal brain development and tumor cells under pathological circumstances. Thus, CaSR/integrin complexes may function as a universal cell migration or homing complex. Manipulation of this complex may be of potential interest for treating metastatic cancers, and for developmental disorders pertaining to aberrant neuronal migration. B receptor, several taste receptors, and GPRC6A . In addition to the eight metabotropic glutamate receptor subtypes, other members of this relatively small GPCR subfamily include the GABA2+. However, in addition to Ca2+ ions the receptor can also be activated by a several other di- and trivalent cations and organic molecules such as the polyamines  fully and rapidly activates the receptor.The CaSR is a large heptahelical transmembrane glycoprotein consisting of 1078 amino acids with a molecular weight of approximately 120 kilodaltons. Like other members of the metabotropic glutamate receptor family, it likely exists in the plasma membrane in a dimeric configuration  present in the endosteal surface  translocate from the fetal liver to the bone marrow where hematopoiesis occurs throughout adulthood. A characteristic of bone that likely contributes to an attractive microenvironment for stem cells is the high concentration of calcium ions at the HSC-enriched surface of the endosteum (the endosteum is the thin vascular membrane of connective tissue that lines the surface of the bony tissue that forms the medullary cavity of long bones). In fact, the bone endosteal surface has been shown to act as a niche for circulating CaSR-expressing HSCs to preferentially localize to the bone  by promoting HSC adhesion to ECM proteins such as collagen I and fibronectin /Akt and PLC\u03b2 signaling pathways were identified as mediators in the migratory effect. These results suggest that the presumed extracellular Ca2+ gradient present in bone is an initiating factor for the homing of osteoclast precursors, and may play a role in the initiation of bone remodeling . The CaSR is expressed in both normal breast ductal epithelial cells and in primary breast cancer cells. Stimulation of the CaSR has been shown to promote the migration of several metastatic bone-preferring breast cancer cell lines. Highly bone metastatic MDA-MB-231 breast cancer cells display more robust migration compared to the MCF7 and T47D breast cancer cells, which have a much lower metastatic potential in vitro angiogenesis . During lactation, activation of the CaSR in normal mammary epithelial cells down-regulates PTHrP in milk and in the circulation, and increases CaIn contradiction to the studies described above demonstrating CaSR expression up-regulation in breast cancer progression, another study of CaSR protein expression in 148 cases of breast cancer using tissue microarray by immunohistochemistry reported lower CaSR expression in breast cancer lesions compared with paired non-tumor tissues , elevated CaSR expression and increased proliferation was demonstrated compared to a non-skeletal metastatic, epithelial-derived prostate cell line .Intriguingly, and also similar to the CaSR, the integrins contain multiple divalent cation binding sites in the extracellular domain  is high and bone has a high concentration of these two ECM proteins  the findings outlined above and others indicating a role for \u03b21-containing integrins in cancer metastasis to bone, 2) the considerable body of evidence demonstrating elevated CaSR expression in prostate, breast, and kidney cancers that metastasize to bone, and (3) the presence of CaSR-\u03b21 integrin macromolecular complexes in thyroid carcinoma cells  was first demonstrated using a rat striatal cDNA library where it was determined that the receptor is expressed in both neurons and glia , glial fibrillary acidic protein , and myelin basic protein (oligodendrocyte differentiation marker) when compared to age-matched wild-type littermates  in the early postnatal cerebellum provides an excellent model system to delineate the molecular properties of neuronal migration. GCPs originate in the rhombic lip during late embryonic stages and then migrate rostrally to a secondary germinal layer, known as the external granule-cell layer of the cerebellum, where they continue to proliferate after birth. In rodents GCPs proliferate in the periphery of the external granule layer-cerebellar basement membrane interface over postnatal days 5\u201320 Figure . VariousThe role of \u03b21 integrins in cerebellar GCP proliferation and migration has been well documented. Potent stimulants of GCP proliferation such as sonic hedgehog and SDF-1 have been shown to induce GCP proliferation only in the presence of \u03b21 integrin mediated adhesion to laminin .We have recently demonstrated that the CaSR, together with integrins, functions as a cell-surface chemoattractant receptor expressed on the surface of cerebellar GCPs to facilitate GCP differentiation into mature granule cells, and to simultaneously guide their movement during cerebellar maturation (Tharmalingam et al., 2+ released by the Bergmann glia. Tangentially migrating unipolar GCPs in the external granule layer sprout a third axon that allows the GCPs to attach to Bergmann glial fiber tracts to undergo radial migration into the internal granule layer. Bergmann glial fibers have been shown to generate radially expanding transglial Ca2+ waves that initiate at a central point and expand radially to encompass multiple Bergmann glial processes (Hoogland et al., 2+ waves generated by Bergmann glia could locally activate the CaSR expressed on GCPs to promote radial migration. Another potential source of CaSR activation may be from polyamines. Polyamines such as spermine and spermidine are potent agonists of the CaSR and polyamine concentrations are elevated during postnatal cerebellar development and then subsequently decline to adult levels (Jasper et al., 2+ ions, to stimulate the CaSR and guide GCP migration in the developing brain.A key question to be addressed is, what is the source of the CaSR stimulus in the immature cerebellum? One possibility is that activation of the CaSR may be mediated by local extracellular CaDefects in GCP migration result in medulloblastoma, the most common cause of malignant brain tumors in children under four (Hatten and Roussel, in vitro using DAOY cells which are transformed human cerebellar granule cells. Wei et al. (2+. In addition to protons, this receptor is also activated by the benzodiazepine anxiolytic drug lorazepam (Huang et al., 2+ signals and activation of the ERK signaling pathway, thereby providing a mechanistic explanation of how the acidic environment may influence transformed cell function and/or survival. This action is lost on differentiation, suggesting a link between OGR1 activity and proliferative behavior of the transformed neurons (Huang et al., 2+ signaling through OGR1 and CaSR appears to be opposite in the two cell types. In normal granule cells, OGR1-dependent Ca2+ signaling is slow and small while CaSR-dependent intracellular Ca2+ signaling is fast and large, whereas the opposite occurs in DAOY cells (Wei et al., Medulloblastoma has been modeled i et al.  studied i et al. . They ex+ and Ca2+ (Kingsley et al., OGR1 is functionally expressed in brain tumor cells and changes in its activity may be relevant to acidosis in tumors. Both OGR1 and CaSR have been implicated in several brain disorders that are exacerbated by changes in the concentrations of extracellular HCell migration is a multistep process that requires continuous coordinated formation and disassembly of cytoskeletal proteins (Webb et al., activation of the CaSR resulted in increased cell migration by promoting cell surface expression of \u03b21 integrins, but surprisingly, stimulation of the CaSR did not increase the cell surface expression of the CaSR itself (Tharmalingam et al., The CaSR and integrins are both abundantly localized in caveolae-rich microdomains (Breitwieser, B receptor and the metabotropic glutamate receptors, are known to undergo closure of their large extracellular Venus flytrap domains upon agonist binding (Tsuchiya et al., At the molecular level, one potential mechanism for functional cooperation between the CaSR and integrins is via a protein-protein interaction between the CaSR homodimer and the integrin heterodimers within a tetrameric complex, or as part of a larger complex containing additional proteins. A direct protein-protein interaction would require that the CaSR homodimer and integrin heterodimers are either physically in contact with each other, which has not yet been directly demonstrated, or present with additional proteins that influence each other by conformational changes within a macromolecular complex. In this scenario, we propose a working model whereby an agonist-induced conformational change in the CaSR induces flipping of the associated integrin heterodimers into an active conformation. Both the integrins and the CaSR possess large extracellular domains. Although no studies directly examining conformational changes in the CaSR have been reported, other members of this GPCR subfamily such as the GABA2+, which in turn promotes cell adhesion and migration (Tharmalingam et al., 2+ have been shown to be important for integrin inside-out activation (Rowin et al., 2+ increases cell adhesion and migration by specifying the location and timing of cell process retraction (Sjaastad et al., 2+ gradients which increase toward the rear of cells (Brundage et al., 2+ has also been linked to increased contractility and adhesion disassembly mediated by calpain, a Ca2+ dependent protease (Doyle and Lee, 2+ may promote integrin inside-out activation at the migrating front while simultaneously inducing adhesion disassembly at the rear of the cell, which then translates into cellular migration.An alternative mechanism to consider is a series of biochemical events that entail stimulation of CaSR/integrin complexes followed by the activation of intracellular signaling cascades. Activation of the CaSR is linked to several intracellular signaling pathways which could modify integrin conformation from within the cell. Our previous work in thyroid carcinoma cells provided evidence for an indirect mechanism in which stimulation of the CaSR induces activation of PLC and release of intracellular CaIn contrast to thyroid carcinoma cells, CaSR-integrin actions mediating migration of GCPs during cerebellar development appears to be mediated not by phospholipase C, but rather by the ERK and Akt signaling (Tharmalingam et al., We propose that stimulation of the CaSR activates phosphorylation of ERK2 and Akt which then signals the insertion of microdomains containing co-localized CaSR-integrin complexes Figure . Upon enThe CaSR and GPRC6A are close structural paralogs that are widely expressed in many organs. Both receptors are activated and/or modulated by cations and amino acids.The CaSR and integrins share no sequence homology but both are membrane proteins that function as dimers and possess multiple cation binding sites. Both proteins also undergo large conformational movements into an activated state after agonist stimulation. CaSR/integrin protein complexes have been identified in thyroid carcinoma cells and in cerebellar granule cells, and may exist in other tissues and cells.The CaSR has been shown to play an essential role in cellular differentiation and migration in several cells and tissues, and CaSR-mediated cellular migration likely occurs, at least in some cells, via the activation of CaSR/integrin protein complexes. In thyroid carcinoma cells, the CaSR together with integrins facilitate cellular migration. In the developing cerebellum, activation of the CaSR induces neuronal differentiation and migration. Notably, stimulation of the CaSR in cerebellar neurons did not change the level of plasma membrane expression of the CaSR itself, but instead promoted the trafficking of integrins to the cell surface. Thus, it appears that cerebellar granule cell migration is mediated by a CaSR-induced increase of integrins to the neuronal plasma membrane.In addition to thyroid carcinoma cells and cerebellar granule neurons, the question arises as to what other cells and tissues might utilize the CaSR/integrin system? In light of the widely distributed expression of the CaSR in many organs and cell types, together with the ubiquitous expression of the integrins, could CaSR/integrin protein complexes function as a universal cell migration/homing complex?In a given tissue or cell type the physiological role of the CaSR may change under pathological conditions. For example, upon transformation from normal to cancerous cells, some evidence suggests that the CaSR is associated with different or opposite effects on cell proliferation vs. metastasis. This phenomenon might be compatible with, or linked to, the evolving concept that rapid cell division and proliferation must be arrested prior to metastasis and tumor cell tissue invasion, and that factors operating to promote either cell division or metastatic tissue invasion might be mutually exclusive (e.g., see Matus et al., Both authors contributed equally to the text; ST created and prepared the figures.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "To evaluate the feasibility of MRgFUS ablation in selected pancreatic and hepatic primary tumors.After giving their informed consent 5 patients with histologically proven unresectable pancreatic adenocarcinoma and 1 patient with unresectable right lobe HCC  underwent MRgFUS treatment on a dedicated 3T unit featuring the ExAblate 2100 system (InSightec). The system is composed by a 200-element transducer located within the MR table. The MR guidance allows a detailed depiction and visualization of the lesion; moreover, the use of the proton resonance frequency (PRF) shift method allows a real time monitoring of the temperature inside the target lesion and the adjacent anatomical structures, in order to ensure adequate tissue ablation and safe ablation margins. The treatment was performed in general anesthesia with breath control. After the procedure, gadolinium-enhanced gradient echo T1-weighted sequences were performed in order to evaluate the ablated area and the absence of possible local complications. Clinical and imaging follow-up was performed with both MR and CT at 3 and 6 months after treatment respectively for the patient with HCC and those with pancreatic cancer.Treatment was successfully performed in all patients without any adverse events during or after the procedure. MR images acquired immediately after treatment demonstrated necrosis of ablated area within the lesion in all cases; in particular the HCC was completely non-enhancing. At short term clinical follow-up, all the patients with pancreatic cancer referred reduction of pain symptoms due to infiltration of the celiac plexus. However follow-up imaging demonstrated recurrence of pathologic tissue within the ablated area, even if there was no local progression of the disease. Two patients with pancreatic cancer underwent radiotherapy after treatment, while the remaining one underwent another MRgFUS ablation.Our preliminary clinical experience suggests that MRgFUS is a feasible and repeatable ablative technique in patients with unresectable and device-accessible hepatic and pancreatic lesions."}
+{"text": "Cattle risk factors  were more strongly associated with herd risk than area-level measures of badger social group density, habitat suitability or persecution (sett disturbance). Highest risks were in areas of high badger social group density and high rates of persecution, potentially representing both responsive persecution of badgers in high cattle risk areas and effects of persecution on cattle bTB risk through badger social group disruption. Average badger persecution was associated with reduced cattle bTB risk (compared with high persecution areas), so persecution may contribute towards sustaining bTB hotspots; findings with important implications for existing and planned disease control programmes.Bovine TB (bTB) is endemic in Irish cattle and has eluded eradication despite considerable expenditure, amid debate over the relative roles of badgers and cattle in disease transmission. Using a comprehensive dataset from Northern Ireland (>10,000\u2009km Mycobacterium bovis, has proven difficult to control and eradicate in Irish cattle, despite most EU countries being officially disease free. Intensive ongoing efforts to control the disease are based on a Government sponsored regime of tuberculin testing and slaughter of infected cattle, an expensive programme for both farmers and the government234Bovine tuberculosis (bTB), caused by the bacterium Meles meles) has been identified as a major factor contributing towards the difficulty of bTB eradication in Ireland781012The presence of a wildlife reservoir of infection . The perturbation hypothesis states that when a badger sett is disturbed or some resident badgers killed, surviving social group members are more likely to disperse, increasing contact rates with badgers in neighbouring social groups and potentially spreading bTBWe combined data on the cattle and badger populations in Northern Ireland to produce a comprehensive list of risk factors concentrating on aspects of bTB risk potentially influenced by interactions between the two host populations. We also addressed several other important issues including the impact of international, cross-border cattle imports. By identifying herd-level risk factors of bTB infection, we aim to aid the eradication programme by informing farmers, veterinarians and policy-makers on the strategies most likely to reduce disease incidence. We specifically address the following questions: i) What are the cattle-related risk factors for herd-level bTB detection (herd breakdowns)? ii) Is cattle bTB risk associated with badger social group density and/or habitat suitability? iii) Is badger persecution  associated with increased bTB risk?Anonymised tuberculosis test results (tuberculin skin test) and animal movement data for all active cattle herds  in Northern Ireland during the period 2004 to 2011 were made available from the Animal and Public Health Information System APHIS curated n\u2009=\u2009212, 2  and an index of habitat suitability derived from a spatially explicit Species Distribution Model (SDM) associating badger main sett presence with landscape features (for full methodology of sett classification seeData describing the badger population were provided courtesy of DARD from the \u2018Badger Survey of Northern Ireland 2007/08\u201922M. bovis) within a given year and 0 otherwise . Herds with unconfirmed or inconclusive skin test results scored 0. The aim was to identify potential risk factors associated with new herd breakdowns so herds undergoing a continuing breakdown were excluded from the risk-set  until the calendar year following that in which the breakdown had been declared over, which occurs after two subsequent negative follow-up tests occurring at least 60 days apart (i.e. a breakdown extending over two years would only be counted in the first year). A summary of the number of herds in each category is given in P\u2009<\u20090.1 in univariable models were retained , so changes in incidence cannot be unambiguously associated with persecution at a particular time point. The study period was split into two year intervals  and the selected cattle-badger model was fitted to data from each interval separately. Herd-level predictions of bTB risk were extracted and used to calculate expected bTB incidence by badger main sett density. Preliminary analysis showed persecution risk was low but had a strongly right-skewed distribution. Herds in areas with persecution indices in the upper quartile of the distribution (probability of sett disturbance >0.35) were perceived as high persecution areas representing 29%  of the land area with active cattle herds compared with herds in other areas .To further investigate relationships among cattle and badger variables, we conducted a descriptive analysis comparing temporal trends in bTB incidence in cattle in areas with high and low badger persecution, both before and after the badger population data were collected (autumn-winter 2007/08) in order to infer the directionality of any identified relationships between persecution and bTB incidence. High incidence in areas subsequently found to have relatively high persecution would be consistent with persecution being largely a response to high local bTB risk. We also reasoned that if persecution reduced risk we might expect a disproportionately large decrease in incidence immediately after the badger survey in areas with high persecution compared with low persecution areas, over and above any longer term incidence trends. However, such an effect might be obscured if patterns of persecution changed dramatically in the period immediately after the badger survey . Areas with the highest social group density and highest rates of persecution were in the south-east of the region i.e. Co. Down  and high rates of persecution remained at elevated risk of breakdown (bTB hotspots) regardless of temporal trends in bTB incidence in the rest of the country. In low persecution areas the weak positive association between social group density and incidence was similar before (2004\u20132007) and after (2008\u20132011) collection of badger population data. Breakdown risks before the badger survey were greater in high compared with low persecution areas, especially at higher badger social group densities  and a low rate of persecution and so the predicted bTB incidence in areas of low persecution tracked the overall decreasing trend in cattle bTB incidence better than the high persecution profile . Areas wensities . High peIn our population scale comparison of bTB risk factors for new herd breakdowns, cattle-related factors were a far better predictor of bTB risk than badger-related factors in terms of model fit. Herd size was a key predictor and high bTB risks have been previously associated with large herds in the UK and Ireland1011293031323436373538394042Variation in incidence of bTB in cattle associated with the badger population was small in comparison with cattle variables but high badger social group density, habitat suitability and badger persecution were associated with elevated cattle bTB risk. The highest risks were found in areas of high badger social group density coupled with high rates of persecution through sett interference, with two potentially non-exclusive explanations for such an association. Firstly, badger persecution may be initiated in response to high local cattle bTB prevalence in an effort to protect herds from (re)infection, especially where badgers are common and, hence, a more visible perceived threat and accessible target47An important consideration is whether these findings, based on data from Northern Ireland can be extrapolated to other parts of the British Isles. The relative influence of badgers on bTB dynamics in Great Britain and the Republic of Ireland has been widely debated, with large scale badger culling trials in each country yielding dramatically different results and policy recommendationsBadger population density in Ireland (in both Northern Ireland and the Republic of Ireland) is thought to be low, having remained relatively stable whilst the population in Great Britain has increased122212M. bovis between the two host populations occurs relatively frequentlyDespite the population-scale dataset used, our models had relatively modest predictive power and considerable unexplained variation, indicating that the selected variables did not capture all of the dynamics of the system and that, in common with many observational studies, unquantified covariates were likely to have had an influence on outcomes. Most of the herd-level predictors identified in a global review of bTB risk factors2505110How to cite this article: Wright, D. M. et al. Herd-level bovine tuberculosis risk factors: assessing the role of low-level badger population disturbance. Sci. Rep.5, 13062; doi: 10.1038/srep13062 (2015)."}
+{"text": "The outbreak of Ebola virus disease (EVD) in West Africa has outstripped available resources. Novel strategies are desperately needed to streamline operations. The present norm of requiring negative results on polymerase chain reaction for EVD convalescent patients to be discharged is not evidence-based and often results in asymptomatic patients competing for beds in dangerously crowded Ebola Treatment Units, posing risks to ward staff and patients and the community if infected persons are turned away. We summarize the relevant data and call for a change in discharge criteria for convalescent patients that can safely help reduce the strain on resources and direct energies where they are most needed. In the longer term, research is needed to assess the true infectivity of EVD convalescent patients to establish evidence-based criteria and guidelines for discharge. The outbreak of Ebola virus disease (EVD) in West Africa has been declared a public health emergency of international concern by the World Health Organization (WHO),and testing PCR negative has become the norm.In the last 15 years mobile laboratories have been routinely installed in epidemic areas to perform diagnostic testing for EVD by testing of blood by real-time polymerase chain reaction (PCR). With the assay at hand, patient discharge criteria of being asymptomatic for 3 days In addition to the operational challenges caused, there is little justification of the PCR-negative requirement on scientific grounds. The viral load in EVD closely parallels the clinical status9The epidemic has continued to accelerate dramatically in West Africa. Many areas of Liberia and Sierra Leone have passed tipping points in which ETUs can no longer accommodate the case load and measures are being implemented for community-based management. Bed capacity has reached a critical level in some areas. Novel but evidence-based strategies are desperately needed to streamline operations to meet this challenge. To reduce the community \u201cviral load\u201d and optimize use of limited bed and laboratory capacity, we recommend that convalescent patients should be discharged if asymptomatic for 48 hours and independently mobile, with appropriate counseling regarding possible infection risk and a basic discharge kit for infection control. This approach will have the additional benefit of enabling already constrained EVD testing laboratories to focus primarily on testing of new cases, thereby increasing the rate at which EVD PCR-negative suspect cases are identified and discharged, reducing the risk of ward-based EVD transmission to these individuals and freeing up additional beds. More conservative policies requiring blood or even urine to be reverse transcription-PCR (RT-PCR) negative before discharge may be maintained in centers and laboratories where capacity remains sufficient to perform such testing without unduly impacting the flow of patients. In the longer term, research is needed to establish evidence-based criteria and guidelines for safe discharge. This research must include collection of a wide range of bodily fluids from convalescent EVD patients and the testing of samples by both RT-PCR and, importantly, cell culture to detect infectious virus."}
+{"text": "Introduction: Prostheses for upper-limb amputees are currently controlled by either myoelectric or peripheral neural signals. Performance and dexterity of these devices is still limited, particularly when it comes to controlling hand function. Movement-related brain activity might serve as a complementary bio-signal for motor control of hand prosthesis.Methods: We introduced a methodology to implant a cortical interface without direct exposure of the brain surface in an upper-limb amputee. This bi-directional interface enabled us to explore the cortical physiology following long-term transhumeral amputation. In addition, we investigated neurofeedback of electrocorticographic brain activity related to the patient\u2019s motor imagery to open his missing hand, i.e., phantom hand movement, for real-time control of a virtual hand prosthesis.Results: Both event-related brain activity and cortical stimulation revealed mutually overlapping cortical representations of the phantom hand. Phantom hand movements could be robustly classified and the patient required only three training sessions to gain reliable control of the virtual hand prosthesis in an online closed-loop paradigm that discriminated between hand opening and rest.Conclusion: Epidural implants may constitute a powerful and safe alternative communication pathway between the brain and external devices for upper-limb amputees, thereby facilitating the integrated use of different signal sources for more intuitive and specific control of multi-functional devices in clinical use. Multi-functional prostheses for upper-limb amputees are usually controlled by electromyogram (EMG) signals of the remaining muscles. However, since present approaches afford the user only limited dexterity and intuitive control of these devices, particularly when patients are affected by higher levels of limb amputation , they often meet with rather low acceptance in clinical practice . In reseThe common denominator between these different approaches is that they all acquired control signals from the peripheral neural system close to the amputation site, thereby being potentially affected by the act of wearing the prosthesis and by possible variability with regard to electrode position, force, limb position, and transient EMG changes .Control signals from the central neural system recorded directly from the brain may overcome some of the present limitations of peripheral control sites. Movement-related brain activity might serve as a complementary bio-signal for intuitive motor control of hand prosthesis. Such brain\u2013computer or brain\u2013machine interfaces (BCI/BMI) for prosthetic control have been investigated in able-bodied individuals using both non-invasive approaches with surface electroencephalography (EEG) recordings  and invaExperience with brain interfaces and prosthetic control in patients with severe motor deficits such as tetraplegia, stroke or amputation is, on the other hand, fairly limited .subdural grids  procedure to treat the pain.As a candidate for long-term cortical stimulation to reduce his chronic pain, the patient underwent implantation of an electrode array covering the left sensorimotor cortex to determine treatment response and optimal stimulation sites for maximum pain reduction. Indication for implantation, array location and duration of implantation were determined solely by clinical criteria. The patient also gave informed consent to a study (including publication of data and photographs) investigating a BCI approach for virtual hand prosthesis control during this time, which was conducted in accordance with the declaration of Helsinki and the guidelines of the local ethics committee. The results of the pain evaluation study do not constitute part of the present report.Figure 1).The electrode grid was implanted during awake surgery without direct exposure of the brain surface. Craniotomy and initial epidural grid placement were performed with an image-guidance approach described earlier . For refFigure 2). This procedure was repeated several times to obtain an optimal orientation of the implant in the epidural space. It is worth mentioning that the whole mapping procedure took less than 15 min. Once implantation had been completed, the electrode grid was secured on the dura and externalized with percutaneous extensions connecting to the external component of the BCI set-up.We applied a procedure known as signal modeling for real-time identification and event detection (SIGFRIED) within the BCI2000 framework  which haFigure 4B). This interface allowed for bi-directional exploration of cortical physiology in this patient by virtue of its ability to record brain activity related to phantom hand movements and to map cortical stimulation-induced sensations in the phantom hand. These physiological measures were then related to the patient\u2019s cortical anatomy after co-registration of the electrode contacts to the three-dimensional reconstruction of the patient\u2019s brain magnetic resonance image.The epidurally implanted 8 \u00d7 8 electrode array consisted of platinum contacts with 4 mm contact diameter (2.3 mm exposed), and 5 mm center-to-center distance , covering parts of the left somatosensory, primary motor, and premotor cortex  at the sites where stimulation provided optimal pain control. As the described study was finished after the evaluation period, the pain treatment is not part of the present report.Figure 3) from the patient\u2019s perspective .The integrated system consisted of an internal component, the implanted epidural neural interface for ECoG recordings, externalized with percutaneous extensions connecting to the external components. These external components consisted of a recording and processing unit and a feedback unit. Recording of ECoG signals was performed with a monopolar amplifier  with a high-pass filter at 0.15 Hz and a sampling rate of 1000 Hz. Online processing of brain signals was performed with a BCI2000 framework  equippedThe patient performed seven sessions, each of them on a separate day, with a total of more than 700 trials. In each session, classification of phantom hand movement versus rest was explored offline. From the third session onward, brain signals were also classified online and feedback of electrocorticographic activity was provided for real-time control of the virtual hand prosthesis. In each trial, the patient received a visual and an auditory cue to extend his phantom hand for 4 s  followed by a 4-s relaxation period. The patient was instructed to parallel this cycle with his phantom hand. During the online sessions, feedback was provided in accordance with phantom movement-related brain activity by the virtual hand prosthesis which performed a hand opening motion according to the given instructions from the patient\u2019s perspective while he was observing his hand. During the relaxation period the virtual hand was closing again. A short break was taken after every run .r2 scores for the discrimination between phantom hand movements and rest for each frequency bin and each channel. The three channels with the highest r2 values for the frequency band of 130\u2013145 Hz were chosen for feedback, because this was the topographically most circumscribed band for discrimination between phantom movement and rest. We considered the decoding of phantom hand movement from a small cortical area beneficial, as we intended to provide feedback of very specific cortical activations. Permutation tests with 105repetitions confirmed that the r2 values were significantly greater than 0. The selected channels and frequency band were kept constant throughout the training period.Prior to the five feedback sessions, two screening sessions were performed to select channels and features for online control, estimating the spectral power of all electrode channels up to 200 Hz and computing During the feedback sessions, the spectral power of these three channels in the frequency band of 130\u2013145 Hz was computed every 40 ms from a data buffer of length 500 ms. This was performed using an autoregressive model  with a model of the order of 16 . These pTo assess the patient\u2019s ability to modulate his brain activity in accordance with the feedback task, i.e., his performance in gaining control of the virtual hand prosthesis, we calculated the average prosthesis movement time divided by the total feedback duration phase. We also measured a baseline condition to monitor natural perturbations of brain activity, which, while not related to the task, could have distorted the online control performance during the feedback task. This baseline condition consisted of several ECoG recordings throughout the 2-week study period; during recording the patient was at rest with his eyes open. All in all, about 30 min of this spontaneous baseline ECoG activity were recorded for offline analysis, segmented into trials of the same structure and processed in the same manner as the feedback sessions. For statistical analysis, the distribution of performance values per run in each feedback session was compared with the distribution of performance values for the baseline data (Wilcoxon rank-sum test).Figure 4B).The approach implemented here allowed for sufficient positioning of the epidural implant on the area of the sensorimotor cortex related to phantom hand movements and proved feasible and safe for recording ECoG signals without direct contact to brain tissue in an upper-limb amputee  and the cortical stimulation  both revealed mutually overlapping representations and indicated preserved somatotopic organization of the sensorimotor cortex despite long-term amputation without prosthesis use and despite accompanying intractable phantom limb pain. Sensations of the phantom hand could be elicited with high spatial resolution by epidural stimulation, revealing preserved sensory connectivity to the somatosensory hand knob area . Interestingly enough, electrodes showing the highest r2 values in the high gamma band for phantom hand movement projected to the very same area, indicating preserved but posteriorly shifted cortical hand representation for motor control .The high-gamma frequency power . His performance in closed-loop control of the virtual prosthesis, i.e., online movement control during the feedback task, was significantly higher than in the baseline condition (49.1 \u00b1 10.6%) from the third feedback session on .From the third feedback session onward, the patient was able to initiate prosthesis movement in more than 95% of the trials, indicating preserved task-contingent brain activity during phantom movement  of eight upper-limb amputees during real finger movement of the intact side and during phantom finger movements . They obThe Osaka ECoG group were the first to apply an implantable BCI approach to an amputee . Within However, some essential questions concerning the clinical viability of implantable BCI approaches for amputees remained unanswered. For instance, is a high-level upper-limb amputee capable of generating contingent cortical activity with intuitive motor commands for gaining online-control of a hand prosthesis? Are these signals robustly detectable over several days without the necessity of re-calibration or periodical updating of the neural decoding? Are less invasive approaches for BCI control, such as epidural implants and a few decoding channels, feasible in this group of patients? Does cortical reorganization following long-term amputation compromise the detection of natural movement-related brain signals?epidural implant that provided real-time feedback of motor-related electrocorticographic brain activity to operate a virtual hand prosthesis following long-term high-level limb deficiency.We therefore introduced a methodology to implant a cortical interface without direct exposure of the brain surface in an upper-limb amputee, and implemented a closed-loop set-up based on an In accordance with earlier reports on able-bodied individuals , we coulIn addition, throughout the feedback sessions, no adjustments of the parameterization between the recorded brain signals and the BCI control algorithms were necessary. These findings are in accordance with a report of multiple-day ECoG BCI control with fixed parameters in an able-bodied patient for seizure localization . SimilarDespite long-term amputation (26 years ago) and despite intractable phantom limb pain throughout this period, channels projecting onto the somatosensory hand knob of the affected hemisphere provided sufficient information about the phantom hand movement to allow robust and stable prosthesis control, indicating that the somatotopic organization of the corresponding brain has been at least partially preserved. This demonstrated that even patients with long-term deficiencies may be suitable recipients of implantable BCI devices that address prosthetic control.Electrocorticography studies in patients without motor deficits have shown specific movement-related spectral changes, i.e., decreases in the low-frequency band (8\u201332 Hz) with a larger cortical distribution and increases in the high-frequency band (76\u2013100 Hz) with a more focused projection onto the sensorimotor cortex . In addiWe consequently detected a circumscribed increase of cortical activity in the high gamma band during phantom hand movement. Interestingly enough, these electrodes projected to the somatosensory hand knob area, the very same area in which cortical stimulation elicited sensations of the phantom hand. This observation indicated that the same cortical area with sensory connectivity to the missing hand presented the posteriorly shifted cortical hand representation for motor control. These findings are in accordance with previous observations in epileptic patients who underwent implantation of subdural electrode grids in the sensorimotor region . These sThe BCI set-up enabled us to make an update of the control signal as often as every 40 ms. However, our algorithm did not provide visual feedback until five consecutive 40 ms epochs had been classified consistently, thus avoiding a noisy control signal or false positive feedback. This trade-off between immediacy and contingency was sufficient both for robust BCI control and for the patient to comprehend that there is a direct link between his phantom movement and the virtual prosthesis movement. This is in agreement with earlier psychophysical studies in which participants who were repeatedly exposed to an artificially introduced 250 ms delay between voluntary actions and sensory consequences perceptually combined their voluntary actions with the sensory consequences and perceived that the delay was shortened by approximately 100 ms .Due to the lack of cortical implants allowing for wireless BCI control, we designed an interface by connecting the intracranial implant to an external online processing framework for recording and BCI control. To this end, extension leads were externalized through the skin and thus limited the possible duration of this set-up. Wireless devices capable of fast and reliable information transfer will be required for future clinical applications of this novel approach . This woThe present findings indicate that cortical neural prosthesis might serve as a natural source of information to facilitate new control strategies by combining brain and peripheral nerve signals  and to sIn conclusion, epidural implants may constitute a powerful and safe alternative communication pathway between the brain and external devices for upper-limb amputees. Such implanted brain interfaces can support decoding movement intention of the missing hand in an intuitive way. This might provide additional information on the standard myoelectric and neural biosignals applied in upper-limb prosthesis, thereby facilitating the integrated use of different signal sources for more specific control of multi-functional devices in clinical use.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Moderate skeletal muscle dysfunction is a relevant feature in patients with mild COPD and preserved body composition. Several epigenetic events are differentially expressed in the limb muscles of these patients, probably as an attempt to counterbalance the underlying mechanisms that alter muscle function and mass. The study of patients at early stages of their disease is of interest as they are a target for timely therapeutic interventions that may slow down the course of the disease and prevent the deleterious effects of major comorbidities.Muscle dysfunction is a major comorbidity in Chronic Obstructive Pulmonary Disease (COPD). Several biological mechanisms including epigenetic events regulate muscle mass and function in models of muscle atrophy. Investigations conducted so far have focused on the elucidation of biological mechanisms involved in muscle dysfunction in advanced COPD. We assessed whether the epigenetic profile may be altered in the vastus lateralis of patients with mild COPD, normal body composition, and mildly impaired muscle function and exercise capacity. In vastus lateralis (VL) of mild COPD patients with well-preserved body composition and in healthy age-matched controls, expression of DNA methylation, muscle-enriched microRNAs, histone acetyltransferases (HTAs) and deacetylases (HDACs), protein acetylation, small ubiquitin-related modifier (SUMO) ligases, and muscle structure were explored. All subjects were clinically evaluated. Compared to healthy controls, in the VL of mild COPD patients, muscle function and exercise capacity were moderately reduced, DNA methylation levels did not differ, miR-1 expression levels were increased and positively correlated with both forced expiratory volume in one second (FEV Chronic Obstructive Pulmonary Disease (COPD) is a highly prevalent condition that represents a major cause of death in developed countries. COPD also imposes a substantial economic burden in the health care systems as patients may require long hospital stays or costly therapeutic interventions for acute exacerbations. Comorbidities such as skeletal muscle dysfunction with and without muscle loss are characteristic features of patients with COPD even at early stages of their disease Several factors and mechanisms have been shown to participate in the etiology of COPD muscle dysfunction Moreover, histone acetylation, defined as the balance between histone acetyltransferases (HTAs) and histone deacetylases (HDACs) also seemed to regulate muscle plasticity in response to environmental factors including muscle mass maintenance in a variety of models In muscular dystrophies and sarcopenia, increased levels of small ubiquitin-related modifier (SUMO) ligases were shown to underlie muscle wasting through premature senescence of satellite cells in experimental models On these grounds, we hypothesized that the epigenetic profile may be altered in the vastus lateralis of patients with mild COPD and normal body composition who already exhibited impaired muscle function and exercise capacity. Accordingly, the study objectives were as follows: 1) to assess DNA methylation and miRNA expression levels of muscle-specific and non-muscle specific but abundantly expressed in muscles, protein acetylation events, myogenic transcription factors, and SUMO-2/3 in the vastus lateralis of patients with mild COPD and preserved body composition, 2) to identify muscle fiber type composition and sizes, and 3) to analyze potential correlations between the different study variables among the patients. Specimens from the vastus lateralis were also obtained in sedentary controls for the purpose of the investigation, and both patients and control subjects were clinically and functionally evaluated. or cardiovascular disorders, acute exacerbations in the last 3 months, limiting osteoarticular condition, chronic metabolic diseases including diabetes, suspected para-neoplastic or myopathic syndromes, and/or treatment with drugs known to alter muscle structure and/or function including systemic corticosteroids. COPD patients and healthy controls were qualified as sedentary after being specifically inquired about whether they were conducting any regular outdoor physical activity, going regularly to the gymnasium, or participating in any specific training program.Hospital del Mar, Barcelona). Informed written consent was obtained from all individuals.The current investigation was designed in accordance with both the ethical standards on human experimentation in our institutions and the World Medical Association guidelines (Helsinki Declaration of 2008) for research on human beings. Approval was obtained from the institutional Ethics Committees on Human Investigation  of both groups of patients and control subjects using the open muscle biopsy technique, as described previously Muscle sample specimens were always cleaned out of any blood contamination with saline. They were immediately frozen in liquid nitrogen and stored in the \u221280\u00b0C freezer  for further analysis or immersed in an alcohol-formol bath for 2 h to be thereafter embedded in paraffin. Frozen tissues were used for immunoblotting techniques, while paraffin-embedded tissues were used for the assessment of myosin heavy chain isoforms . All subjects were prevented from doing any potentially exhausting physical exercise 10 to 14 days before coming to the hospital to undergo the surgical procedures.Blood samples were drawn at 8:00 am after an overnight fasting period in both patients and healthy controls.Total DNA was isolated from vastus lateralis muscle of all study subjects using QIAmp DNA Mini Kit  Global 5-methylcytosine (5-mC) in DNA was quantified in the vastus lateralis of both patients and healthy controls using MethylFlash Methylated DNA Quantification Colorimetric Kit  following the precise manufacturer's instructions and previous studies Total RNA was first isolated from snap-frozen skeletal muscles using Trizol reagent following the manufacturer's protocol . Total RNA concentrations were determined photometrically using the NanoDrop 1000 .12\u201318 primers and the Super-Script III reverse transcriptase following the manufacturer's instructions (Life technologies).MicroRNA RT was performed using TaqMan microRNA assays (Life Technologies) following the manufacturer's instructions. First-strand cDNA was generated from mRNA using oligo(dT)T method (2\u2212\u0394\u0394CT) for relative quantification was employed TaqMan based qPCR reactions were performed using the ABI PRISM 7900HT Sequence Detector System  together with a commercially available predesigned microRNA assay, primers, and probes as shown in Protein levels of the different molecular markers analyzed in the study were explored by means of immunoblotting procedures as previously described PVDF membranes were scanned with the Molecular Imager Chemidoc XRS System  using the software Quantity One version 4.6.5 (Bio\u2013Rad Laboratories). Optical densities of specific proteins were quantified using the software Image Lab version 2.0.1 (Bio-Rad Laboratories). In order to validate equal protein loading among various lanes, SDS-PAGE gels were stained with Coomassie Blue, and the cytoskeletal protein vinculin  and anti-MyHC-II antibodies , respectively, as published elsewhere T- test. Correlations between clinical, physiological and biological variables were explored using the Pearson's correlation coefficient among both groups of patients. A level of significance of P\u22640.05 was established.Data are expressed as mean (standard deviation). Comparisons of physiological, clinical, molecular and structural variables between the two study groups were analyzed using the Student's P\u22640.05.The sample size chosen was based on previous studies The percentage of muscle methylated DNA to total DNA did not differ between patients and control subjects .1) and quadriceps muscle force . Moreover, the patients also exhibited a moderately reduced exercise capacity as measured by maximal exercise test on a cycloergometer and six-minute walking test together with a mild reduction in quadriceps muscle force as determined by voluntary maneuvers. Additionally, signs of chronic illness were also detected in the blood of the patients as shown by increased levels of fibrinogen and globular sedimentation velocity parameters compared to levels in the healthy controls. Importantly, in the vastus lateralis, a significant rise in the expression levels of miR-1 was observed in the patients compared to those in the healthy controls. Furthermore, significant positive correlations were found between FEVInterestingly, the mild COPD patients already exhibited a significant reduction in their exercise capacity as well as in muscle force generation of the quadriceps. These findings are in line with previous reports in which moderate muscle weakness was also shown to occur in COPD patients at early stages of their disease Despite the relevance of DNA methylation in cell fate and development, no significant differences were observed in this epigenetic parameter between patients and healthy controls. It is likely that the balance between DNA methylation and demethylation plays a relevant role in muscle development during myogenesis but not in differentiated skeletal muscle cells. In view of these findings it would be possible to conclude that DNA methylation does not seem to contribute to muscle dysfunction in COPD patients, at least in mild COPD.In the current investigation, a significant rise in the expression levels of miR-1 was observed in the vastus lateralis of the patients compared to control subjects. In keeping with, a recent study conducted by our group (unpublished observations) showed that miR-1 expression was also upregulated in the lower limb muscles of patients with moderate and severe COPD and preserved body composition. Nevertheless, miR-1 expression together with other muscle-specific microRNAs was downregulated in the vastus lateralis of patients with severe COPD and pronounced muscle wasting as well as in the diaphragm muscle of patients with moderate-to-severe COPD (unpublished observations). Independently of the classic transcription factors, muscle development and repair after injury are also regulated by muscle-specific microRNAs that target different signaling pathways 1 and the force generated by the quadriceps muscle. Again these findings reinforce the concept that miR-1 is likely to be involved in the maintenance of muscle mass and function in COPD at early stages of the disease. In addition, in the muscles of the patients, significant correlations were also found between miR-1 levels and the expression of miR-486 and miR-133, which are highly involved in muscle proliferation and differentiation. These observations may also indicate that in skeletal muscles, microRNAs possibly operate in a network fashion in order to ensure a continuous muscle repair process after injury, at least in patients with well-preserved body composition.Importantly, significant positive correlations were found between miR-1 expression levels in the lower limb muscle of the patients and the degree of the airway obstruction as measured by FEVMuscle mass loss may be the result of hyperacetylation of proteins through several mechanisms that render proteins more prone to catabolism by ubiquitin-ligase activity of several HTAs, and by dissociation of proteins from cellular chaperones Premature senescence of primary myogenic cells and other cell models A first limitation in the current investigation has to do with the fairly small number of subjects studied. However, on the basis of the relatively \u201cinvasive\u201d nature of this investigation, with patients with very mild or mild COPD patients and healthy controls undergoing a muscle biopsy from the vastus lateralis, we felt discouraged to recruit more patients and controls for the purpose of this investigation. Moreover, as abovementioned in the corresponding A second limitation in the study is related to its relatively descriptive nature. However, on the basis of currently available literature, it is not possible to answer the questions that the study addresses. Therefore, the present investigation represents a first attempt to assess the pattern of epigenetic events that take place in the lower limb muscles of patients with mild COPD. Most of the investigations conducted so far have focused on the study of patients with advanced COPD, in whom most of the molecular events underlying COPD muscle dysfunction have been identified. Nonetheless, elucidation of the events that may take place in muscles of patients with very mild COPD is of relevance as therapeutic measures could be applied at earlier stages of the disease.Moderate skeletal muscle dysfunction is a relevant feature in patients with mild COPD and preserved body composition. Several epigenetic events are differentially expressed in the limb muscles of these patients, probably as an attempt to counterbalance the underlying mechanisms that alter muscle function and mass. The study of patients at early stages of their disease is of interest as they are a target for timely therapeutic interventions that may slow down the course of the disease and prevent the deleterious effects of major comorbidities.File S1Detailed methodologies.Figure S1 in File S1. Representative immunoblot of vinculin protein content as the loading control in the vastus lateralis of both patients and healthy controls. Figure S2 in File S1. Representative immunohistochemical preparations corresponding to the staining of type II fibers in the vastus lateralis of a healthy control subject and a patient with mild COPD.(DOCX)Click here for additional data file."}
+{"text": "Increasing evidence has suggested that well-resourced programs are more likely than low-resourced programs to deliver comprehensive care to individuals with co-occurring conditions and achieve greater client access and retention. But there is limited understanding of the service delivery process that allows high-capacity programs to reduce their wait times for treatment entry and their rates of dropout.To examine the indirect association of program capacity factors with wait time and retention via mental health and HIV prevention services in publicly funded addiction health services (AHS).We conducted multilevel cross-sectional analysis of 108 publicly funded program data merged with Los Angeles County Participant Reporting System data from 2010 to 2011 for 13,478 adults entering AHS. Multilevel negative binomial regression models were used to test direct and indirect relationships between program capacity and days to enter treatment (wait time) and days in treatment (retention).Findings show that compared to Whites, Latinos and African Americans served in high-capacity programs reported shorter wait times and higher retention rates. As hypothesized, the role of HIV testing and mental health service coordination played an indirect role in the relationship between program capacity and shorter wait times.Findings suggest that coordinated comprehensive services in AHS may contribute to reduction of outcome disparities in access to care. Delivery of comprehensive care may allow programs to develop effective networks to reduce wait time. Implications for health-care reform implementation and program planning are discussed."}
+{"text": "In particular, they identify how the high-conductance state caused by Poissonian background bombardment can provide the fast membrane reaction time required for precise sampling. They provide analytical derivations of the activation function at the single-cell level as well as for the synaptic interaction and investigate the convergence behavior of the sampled distribution at the network level.An open question was whether neuron models that describe the biological processes of nerve cells endowed with deterministic action potential generation mechanisms can support stochastic sampling as described with the more abstract spiking forms in Buesing et al. . An answO'Connor et al.  employ tOur work implements a biologically-inspired algorithm for the purposes of training Boltzmann machines (Neftci et al., The performance of event-driven CD on the MNIST hand-written digit recognition task was robust to spike probabilities that deviate slightly from the Boltzmann distribution, even though such distributions violate the assumptions of CD formulated for training RBMs. This suggests that event-driven CD provides a general learning framework for biologically-inspired spiking RBMs and is consistent with wide range of neural samplers.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Induced Resistance for Plant Defense focuses on the understanding the mechanisms underlying plant resistance or tolerance since these will help us to develop fruitful new agricultural strategies for a sustainable crop protection. This Topic and their potential applications provide a new sustainable approach to crop protection. This technology currently can offer promising molecules capable to provide new long lasting treatments for crop protection against biotic or abiotic stresses.In this century the human being must face the challenges of producing enough to feed a growing population in a sustainable and environmentally friendly way. The yields are with increasing frequency affected by abiotic stresses such as salinity, drought, and high temperature or by new diseases and plagues. The Research Topic on Hyaloperonospora arabidopsidis, authors identify an impaired in BABA-induced Immunity 1 (IBI1) gene, encoding an aspartyl-tRNA synthetase (AspRS). This mutation seems to block both priming SA-dependent or SA-independent responses to BABA, indicating unilateral control of BABA-induced resistance by IBI1 , \u03b2-aminobutyricacid (BABA), cis-jasmone (CJ), and a combination of the three compounds, which involve SA and/or JA-dependent signaling pathways, Walters et al.  study ifHeavy metals like cadmium are an important source of contamination and a serious problem in the modern agriculture. We need further research on this abiotic stress. Some important novel insights into cadmium sensing have been studied and it seems to induce a rapid mobilization of defense mechanisms through the activation of specific signaling transduction pathways  response , as a novel priming agent and as a tool for studying priming mechanisms. The work review the priming phenomenon and the importance of reactive oxygen species (ROS) as key signaling molecules that contribute to control of plant development as well as to the sensing of the external environment and priming induction (Borges et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Today sensitivity of the MRI is not enough compared to the nuclear methods, such as positron emission tomography and single photon emission computed tomography. Challenging its extension to the nanometre scale could provide a powerful new tool for the nanosciences and nanomedicine. To achieve this potential, innovative new detection strategies are required to overcome the severe sensitivity limitations of conventional inductive detection techniques. In this regard, we perform embodiment of nanodiamonds in dendrimer matrix as additional fluorescent optical and magnetic (together with Gd (III)) imaging modalities of the MRI. New hybrid system composed of dendrimer-gadolinium Gd (III) - nanodiamond as a new contrast agent for MRI was studied. Poly(propilene-imine) PPI and poly(amidoamine) PAMAM dendrimers with fixed size of nanocavities will be used as host material to protect organism against the toxicity and also to increase relaxivity of contrast agent (resulting in the increases MRI resolution). Nanodiamond as biocompatible platform to functionalize the contrast agent will be used. This bimodal hybrid system enables to use smaller amount of the contrast agent and could permit the decrease of the lateral toxicity. This bimodal hybrid system as MRI agent is providing double information (magnetic and fluorescent) about the damaged cell.investigation of new hybrid system composed of dendrimer-gadolinium Gd(III)-nanodiamond as a new contrast agent to improve the MRI resolution and to reduce lateral toxicity in comparison with today used. The main idea is to use this bimodal contrast agent allowing more efficient performance of the MRI with attractive biological applications in diagnosis and therapy. In this report structural investigations by SEM and TEM, spectroscopic studies by Raman scattering, absorption, fluorescence and magnetic features by EPR measurements are discussed. Obtained results are demonstrating great potential of this bimodal imaging agent with unique magnetic and optical imaging capabilities."}
+{"text": "Clockwise or counterclockwise, rotational, upbeating nystagmus is seen in patients with posterior canal benign paroxysmal positional vertigo during left or right head-hanging test, respectively. Rotating of nystagmus in opposite direction to the ear tested or even reversal of initial positioning rotational nystagmus is not usual and has never been reported before. We propose a new variant of posterior canal benign paroxysmal positional vertigo due to unusual behavior and location of the otoliths inside the membranous labyrinth. Unexpected rotational direction may lead to confusion about the site. The examiner should be aware of this abnormal or atypical variant of posterior canal benign paroxysmal positional vertigo. Freely floating otoliths inside the canal or those adhering to the cupula can provoke nystagmus and vestibular disturbance during sudden head motion in patients with benign paroxysmal positional vertigo (BPPV). Diagnosis of posterior canal benign paroxysmal positional vertigo (PC-BPPV) is based on a transient upbeating clockwise or counterclockwise rotational nystagmus in the presence of latency, adaptation, and habilitation associated with a brief and intense sense of vertigo during head-hanging maneuver. Very few studies have been published about simultaneous and spontaneous reversal of peripheral positioning nystagmus during provocative head movements in patients with BPPV. Those are related to canalolithiasis of the lateral canal and posterior canal occurrence has never been reported before \u20133.Rotating of nystagmus in opposite direction to the ear tested or even spontaneous reversal of initial positioning rotational nystagmus is not usual. We propose a new variant of posterior canal benign paroxysmal positional vertigo due to unusual behavior and location of the otoliths inside the membranous labyrinth. Possible underlying mechanisms have been discussed.video-link) . Latency was very brief (5 seconds). First phase of nystagmus appeared immediately after bringing the patient's head to head-hanging position and lasted 15 seconds followed by a \u201csilent phase\u201d for another 10 seconds as seen on video. Then, a second phase of nystagmus appeared lasting for 40 seconds. Whole event happened in 80 seconds. The intensity of the first-phase nystagmus was stronger than that of second phase. Maximal slow phase velocity was calculated as 6 and 3 degrees/sec for the first phase and second phase of nystagmus, respectively. However, the second-phase nystagmus lasted longer. The patient was completely cured after one single Epley maneuver for the left side. Schematic view of rotatory, torsional, and upbeating nystagmus (clockwise) during head-hanging position in patients with a common left-sided PC-BPPV is seen in A 38-year-old woman with a medical story of head induced vertigo for less than two weeks was admitted to the outpatient clinic. She had no evident associated problem and could be defined as an \u201cidiopathic\u201d case. A verbal consent and a signed informed consent were obtained from the patient. The procedures were in accordance with the ethical standards of the Declaration of Helsinki and of the institutional review board. Diagnosis of PC-BPPV was based on medical history and the presence of upbeating rotational nystagmus during head-hanging maneuver when the affected ear is down. However, there was no nystagmus on the right side. But, on the left side, counterclockwise, rotational, torsional, and upbeating nystagmus was seen initially which was later followed by clockwise rotational nystagmus while keeping the head at the hanging position which confirmed a left-sided PC-BPPV. The patient was also subjected to head-roll and straight head-hanging maneuvers which were not remarkable. Inversion of the nystagmus was documented when the patient got back to sitting position. Videonystagmography  recording confirmed a new variant of PC-BPPV  and an excitatory clockwise upbeating rotational nystagmus . It is aHowever, if the otoliths are located in the long arm of the posterior canal close to the common crus it may result in ampullopetal flow initially. When the head is brought to left hanging position, debris will fall under the influence of gravity creating an endolymphatic flow toward the ampulla which will cause inhibition of the ipsilateral side and stimulation of the contralateral side which also leads to activation of contralateral superior oblique and ipsilateral inferior rectus muscles. Their contraction will result in torsional counterclockwise upbeating nystagmus as seen in this case. Eventually, the cupula deflection will end when the particles reach their lowest position as the head is kept at hanging position. Then, a burst of endolymphatic reflux in the opposite direction dragging the clot away from the cupula will result in clockwise upbeating nystagmus when maintaining the head rotation to the pathological left side.Spontaneous reversal of nystagmus in this case indicates that at least ampullopetal as well as ampullofugal flows can occur during single head movement. Reversal of initial positioning nystagmus in benign paroxysmal positional vertigo during maintaining the head position is quite unusual and an interesting finding. This phenomenon is defined as the appearance of a reverse nystagmus in the opposite direction after cessation of the original provoked positional nystagmus during head movement. Translation of torsional counterclockwise nystagmus on the left ear's head-hanging position to the true clockwise nystagmus is quite interesting. Reversal of positioning geotropic nystagmus to apogeotropic nystagmus in cases with lateral canal BPPV has been attributed to short-term adaptation of the vestibule-ocular reflex \u20134. HowevSuperior canal benign paroxysmal positional vertigo (SC-BPPV) and nonampullary PC-BPPV are quite rare due to basically anatomic considerations since the superior canal is higher than both posterior and lateral canals and posterior arm of superior canal descends directly into the common crus which explains continuous self-clearing of the otoliths from the canal. Otoliths found at the superior canal can stimulate posterior canal or SC-BPPV can somehow turn into PC-BPPV. In 1995, Agus described a \u201creversed\u201d PC-BPPV with a downbeating positional nystagmus characterized by torsional components clockwise for the right and counterclockwise for the left head-hanging positioning . VannuccThe presented geotropic form of PC-BPPV is different from all previously reported cases due to its unique and evidence-based characteristics. Typical nystagmus due to posterior canal excitation should be expected in a vertical-torsional pattern having the linear component of its fast phase directed upward. Reversal of rotational axis in this case could be explained by the presence of first ampullopetal and then ampullofugal flow of the endolymph during single head movement. Otoliths located at the nonampullary side of the posterior canal that could lead to a downbeating nystagmus need more clarification since there is always a component of previous superior canal involvement in the reported cases. Besides, we do not prefer to use the term \u201capogeotropic\u201d for patients with downbeating nystagmus which may lead to confusion in the nomenclature since apogeotropic nystagmus of the lateral canal describes the otoliths located close to the cupula and apogeotropic nystagmus of the posterior canal describes the otoliths located away from the cupula. However, otoliths located away from the cupula in the posterior canal may cause geotropic nystagmus as seen in this case. The term of nonampullary PC-BPPV or common crus PC-BPPV is more suitable to describe this atypical geotropic posterior canal canalolithiasis with reversal of rotational axis. However, this is an evolving subject. The location, type of dispersion, or the nature of debris could be different as well. As new interesting cases detected this issue will be clearer and a more appropriate classification of PC-BPPV is going to appear.Reversal of spontaneous nystagmus is a rare condition and is basically due to endolymphatic flow and clot movement in the opposite direction away from the cupula which is characteristic feature of canalolithiasis. Our data indicate that the reversal of positioning of the nystagmus in this patient with PC-BPPV is related to unusual location of the otoliths in the long arm or the nonampullary end of the posterior canal. Atypical counterclockwise torsional upbeating nystagmus on the left head-hanging position is followed by true clockwise nystagmus by inversion of the direction of clot movement due to spontaneous reflux of the endolymph. Unexpected rotational direction may lead to confusion about the site. The examiner should be aware of this abnormal or atypical variant of PC-BPPV.Spontaneous reversal of axis of the up-beating nystagmus from counter clockwise to clockwise rotation at left head-hanging position."}
+{"text": "Describe the use of current imaging techniques to reach a correct diagnosis of hepatocellular carcinoma.Emphasise the knowledge of complementary tools for the evaluation of early response to treatment tumour.Our cases will be presented in a pictorial essay mode.It is important to consider:The radiologic diagnosis of HCC can be made by either CT or MRI methods.Typically, HCC enhances during the arterial phase due to the presence of an intense arterial blood supply of the hepatic arteries.TC dual Energy: Dual-energy CT (DECT) is an innovative imaging technique that operates on the basic principle of application of two distinct energy settings that make the transition from CT attenuation\u2013based imaging to material-specific or spectral imaging. DECT can also aid in evaluation of response to therapy and detection of oncology-related disorders.MDCT perfusion: non-invasive method of quantification of tumour blood supply, related to the formation of new arterial structures (neoangiogenesis), which are essential for tumour growth.Dual energy and perfusion CT are innovative techniques to detect suspicious lesions of hepatocarcinoma.Dual Energy CT also helps to reduce radiation exposure by using low dose imaging protocols without affecting diagnostic purpose.The Perfusion provides information on the neovascularization of an injury  and assesses early therapeutic response ."}
+{"text": "Delay in diagnosis and initiation of antibiotic treatment has been shown to increase mortality. Biomarkers can play an important role in diagnosis and prognosis of sepsis. We aimed to evaluate the correlation between septicemia and high-density lipoprotein (HDL) level in burned patients.A prospective study conducted at Al-Sadr teaching hospital, Maysan, Iraq, during the period from April to September 2013. Blood samples were collected from patients every other day to measure the level of HDL and triglycerides. Other blood samples were collected in blood culture tubes for culturing to verify septicemia depending on the clinical evidence.Seventy-five patients Table  were admThere was a strong correlation between HDL level and septicemia in burn patients. The HDL value is a good biomarker for sepsis; it decreases below normal level and continues to diminish and reach an immeasurable level at the advanced stage of septicemia."}
+{"text": "The recent decade has witnessed the great improvement of contrast-enhanced ultrasound (CEUS) and its extensive use in clinical practice, which is undoubtedly the major breakthrough in the field of diagnostic ultrasound in recent years. The concept of CEUS can be looked back to 60s in the last century, whereas only in 2000s CEUS regained increasing attention in both clinical practice and basic research. The current popularization of CEUS is largely due to the emergence of low acoustic power contrast-specific imaging mode and microbubble-based contrast agent filled with inert gas. After administration of ultrasound contrast agent intravenously, the low acoustic power contrast-specific imaging mode facilitates visualization of the nonlinear signals from the microbubbles in the circulation and suppresses the linear signals from the surrounding tissues, which leads to an improved signal-to-noise ratio and facilitates depiction of macro- and microcirculation of the region of interest (ROI) noninvasively. The low acoustic power also limits the damage to the microbubbles under acoustic push; thus, more microbubbles will remain in the circulation and a long time CEUS depiction is available .CEUS has greatly reshaped the role of ultrasound in clinic practice. It has been demonstrated that CEUS is helpful in characterization and detection of focal lesions in various organs such as liver, gallbladder, pancreas, and kidney. In the commentary titled \u201cContrast-Enhanced Ultrasound (CEUS) in the Diagnosis of Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma: Controversy over the ASSLD Guideline,\u201d the authors proposed an interesting issue in the area of CEUS for liver lesion diagnosis that CEUS has been dropped out from the ASSLD guideline as an imaging modality for clinical diagnosis of HCC, which is one of the hot spots and arouses a lot of different opinions from scholars worldwide. One of the reasons for the drop-out is that some authors believe that CEUS is not able to make differentiation between hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) , 3. The Pancreas is another organ of interest for nonhepatic CEUS that three related articles were presented in this special issue. In the article \u201cUtility of Contrast-Enhanced Transabdominal Ultrasonography to Diagnose Early Chronic Pancreatitis,\u201d using the quantitative CEUS, the authors found that the ratio of blood flow in the superior mesenteric artery and pancreatic parenchyma increased with the grade of chronic pancreatitis and was significantly higher in patients with chronic pancreatitis than in patients with early chronic pancreatitis and control participants, which indicated that CEUS may be a safe and convenient method for diagnosis of early chronic pancreatitis. This attempt is interesting; however, more evidence is needed to testify the conclusion. In the article titled \u201cApplication of Contrast-Enhanced Ultrasound in Cystic Pancreatic Lesions Using a Simplified Classification Diagnostic Criterion,\u201d the cystic lesions of the pancreas were classified into four simplified types: type I unilocular cysts; type II microcystic lesions; type III macrocystic lesions; and type IV cystic lesions with solid components or irregular thickening of the cystic wall or septa. The results of enhanced CT were considered the gold standard. Finally, CEUS has obvious superiority over US in the classification in cystic pancreatic lesions and CEUS results showed substantial agreement with CT. The results indicated that CEUS might be more accurate in the diagnosis of cystic pancreatic lesions. This study is clinically relevant since more and more cystic pancreatic lesions have been detected in clinical practice due to the wide-spread application of modern imaging techniques and its management is sometimes a dilemma. In the article of \u201cContrast-Enhanced Endoscopic Ultrasonography for Pancreatic Tumors,\u201d the authors found that contrast-enhanced endoscopic ultrasonography could be useful for distinguishing pancreatic cancer from other solid pancreatic lesions and for histological differentiation of pancreatic cancer. The information provided in this article is also meaningful in clinical practice .In the article of \u201cUse of Contrast-Enhanced Ultrasound (CEUS) to Study Relationship between Serum Uric Acid and Renal Microvascular Perfusion in Diabetic Kidney Disease,\u201d the authors found that hyperuricemia in diabetic kidney disease patients was associated with a renal ultrasound image suggestive of microvascular hyperperfusion. The CEUS parameter AUC1 holds promise as an indicator for renal microvascular hyperperfusion, while AUC2 might be a useful indicator of declining glomerular filtration rate in DKD patients with decreased excretion of uric acid. Thus, CEUS might be an imaging marker for early diagnosis of diabetic kidney disease. This result is meaningful since till now there is no imaging method that can be used to depict the hyperperfusion in early diabetic kidney diseases.CEUS is also extensively involved in ultrasound-guided intervention procedures in that CEUS is useful to guide puncture and evaluate the treatment response. In the article titled \u201cThe Role of Contrast-Enhanced Ultrasound in Selection Indication and Improve Diagnosis for Transthoracic Biopsy in Peripheral Pulmonary Lesions,\u201d the authors used CEUS to guide transthoracic biopsy for peripheral pulmonary lesions, which yielded a high diagnostic success rate of 96.3% versus 80% for conventional US guidance. Therefore, CEUS is useful to guide biopsy since it can avoid the areas of necrosis in the lesions and more satisfactory specimens can be expected.Some new techniques are also tentatively used together with CEUS. In the article \u201cApplication of Combined Two-Dimensional and Three-Dimensional Transvaginal Contrast Enhanced Ultrasound in the Diagnosis of Endometrial Carcinoma,\u201d the authors concluded that 3D-CEUS  is a useful supplement to 2D-CEUS, which may offer direct, accurate, and comprehensive diagnosis of early endometrial carcinoma. However, the real impact of this new technique on clinical practice needs more confirmation in future studies. The inter- and intraobserver variability should also be evaluated.Despite of the above-mentioned advances, in the level of physics, the present CEUS technology is hard to suppress all the tissue signals since the tissue can also generate nonlinear signals. On the other hand, it is found that the tissue does not generate a subharmonic response ; thus, subharmonic imaging has been proposed as a novel method for isolating ultrasound microbubble signals while suppressing the surrounding tissue signals. In the review article titled \u201cRecent Experiences and Advances in Contrast-Enhanced Subharmonic Ultrasound,\u201d the authors summarized recent advances in the use of subharmonic imaging in vivo. It is anticipated that this new technique may improve the signal-to-noise ratio compared with the current CEUS technique, which will finally provide more detailed information about the microcirculation in the ROI and it has more potential in the future.The contributions in this special issue illustrate the recent advances in the area of CEUS. The results and the opinions have enriched the understanding of CEUS, which is helpful for clinical practice. It can be expected that CEUS may have a more extended application in the future.Hui-Xiong XuHans Peter WeskottJi-Bin LiuRong-Qin Zheng"}
+{"text": "Visual evoked potentials is an important visual electrophysiological tool which has been used for the evaluation of visual field defects in primary open-angle glaucoma and is an appropriate objective measure of optic nerve function. Significant correlations between the magnitude of the VEP parameters and MD of Humphrey static perimetry suggest that the impaired visual cortical responses observed in glaucoma patients can be revealed by both electrophysiological and psychophysical methods. In addition, the severity of global glaucomatous damage evidenced by reduction in MD could depend on the delay in neural conduction from retina to the visual cortex as revealed by the significant correlation between VEP latencies and MD which also supports the validity of the VEP testing in progression of glaucoma. Primary open-angle glaucoma is described distinctly as a multifactorial optic neuropathy that is chronic and progressive with a characteristic acquired loss of optic nerve fibers. Such loss develops in the presence of open anterior chamber angles, characteristic visual field abnormalities, and intraocular tension that is too high for the continued health of the eye. It manifests by cupping and atrophy of the optic disc, in the absence of other known causes of glaucomatous disease. Thus the clinical diagnosis of POAG is commonly based on increase in intraocular pressure, characteristic optic nerve head cupping, and typical visual field defects which are assessed by standard static threshold perimetry, using an automated system such as Humphrey field analyzer (HFA). HFA however does not selectively reveal which structures contribute to the impairment of the visual system observed in glaucoma. It has been suggested that damage to the ganglion cells and/or their axons produce glaucomatous visual field defects. In this context, electrophysiological testing provides specific and unique information. Electrophysiological tests like visual evoked potentials can contribute to detection of glaucomatous optic neuropathy since they are compatible with the functions of retinal ganglion cells, and they make it possible to study different aspects of visual functions. The visual evoked potential is the objective measurement of visual function monitored at the level of the occipital cortex with scalp electrodes. It is recorded with a uniform stimulus check size and a slow reversal rate throughout the field. This paper summarizes many of the studies pertaining to the significance of visual evoked potentials in the assessment of visual field defects in primary open-angle glaucoma. Included are the previous works related to the clinical utilization of VEPs for the objective assessment of typical visual field defects of POAG.The assessment of visual field defects with visual evoked potential has been a hard task. Ever since visually evoked cortical potentials were first used as a diagnostic aid the important question has been whether they could detect visual field defects. In earlier investigations , light-fLater, methods of stimulating the temporal and nasal parts of the retina separately with flash and checkerboard stimulation were introduced. Finally, a sophisticated method of separating the signals from retinal areas stimulated simultaneously was devised. However, there are few reports of the clinical application of these techniques. Since it is believed that elevation of intraocular tension causes pressure on the retinal nerve fibers bundles as they course into the optic nerve and results in the loss of visual function which is known to produce an alteration of the VEP waveforms; many earlier studies were interested in correlating VEP findings with perimetric defects. However, because the VEP is dominated by the central macular responses and reflects mainly macular function, it was altered only when the central visual field was disturbed .Field defects with VEP have also been demonstrated using localized retinal stimulation \u20135. The lModerate defects (occupying third to three quarters of affected quadrant)\u2014either no VER was obtained on stimulation of retina corresponding to defective field quadrant or a phase delay was observed. Severe defects (three quarters to the whole quadrant tested)\u2014In most cases, no VER was obtained from quadrants tested but in three cases small responses showing a phase shift were observed. They also conducted VER recordings with patient fixating centre of the 22\u00b0 screen (full-field), the central 8\u00b0 only and also the centre of the screen when the central 8\u00b0 was occluded . These tests did not show significant phase changes except in four cases with large field defects. The amplitude of the response from the eyes with moderate and severe defects was markedly reduced by comparison with that of the normal eye. Using this technique, an objective assessment of localized visual field defects was attempted, although it was based mainly on unilateral field defects.Visually evoked cortical potentials were studied in six patients with a homonymous and six patients with a bitemporal hemianopia by presenting a pattern reversal stimulus separately to a temporal or nasal retinal area and by recording the responses from leads over the hemispheres . HomonymBoth the topographical position and the dimension and degree of the diminished sensitivity of the visual field are important for changes in the evoked potentials, the nearer to the centre the visual field defect is localized, the larger the changes of the VEPs are expected to be. Thus a small relative scotoma located near the centre may affect significant changes on the VEP while a large absolute scotoma in the periphery may cause only minor changes in VEP .The larger latency increments have been reported when measured in eyes with large field defects  but therIncreased pattern VEP latency was significantly correlated with both the severity and location of visual field defects and the degree of cupping and pallor of the optic disc in another study .However, some of the earlier works have demonstrated a poor sensitivity of the VEP to detection of CSG in patients with superior visual field defects due to the dominance of the inferior hemifield signal to the full-field VEP response .P < 0.05) in eyes with OAG in a previous study [Mean defect (MD) indicative of diffuse nonspecific nerve fibre loss correlated significantly . When the two tests were compared, absolute latency and field loss were poorly correlated but interocular differences showed much stronger correlation with the sum of field losses determined with static perimetry. This was true for both upper and lower hemifield testing. Thus once interindividual variability was eliminated; severity of field loss was mirrored by prolongation of VEP latency. The pattern VEP was compared to the Octopus 2000R automated perimeter in the assessment of central visual function in chronic simple glaucoma (CSG) in 90 patients  in two age bands 40\u201360 years and 61\u201380 years  VEP demoIn recent years, multichannel pattern visual evoked potentials have begun to be compared to Humphrey perimetry in the assessment of central visual function in primary open-angle glaucoma. The multi-channel checkerboard reversal PVEPs waves to full-field and half-field stimulus of 25 normal persons and 74 patients with primary open-angle glaucoma were recorded and analyzed in a study . All patP < 0.05) results were obtained with the perimetric MD value for all stimulations and with the neuroretinal rim area of the optic disc which again supports the validity of the VEP technique in glaucoma. Correlation coefficients were highest  for the peak time of the blue-yellow VEP. VEP measurements with presumable stimulation of single neuronal pathways can detect glaucomatous optic nerve damage in a considerable fraction of patients with visual field loss as glaucoma is associated with blue color vision disturbances . They stIn spite of these results and the fact that there were no other confirmative reports about the usefulness of BY-VEP, there remains still uncertainty whether the Blue Yellow-VEP becomes pathologic before visual field or optic disc damages appear and whether it is able to predict these defects. P < 0.01) delayed P100 latency when compared with controls and correlated with mean deviation  (P < 0.001) and the P100 amplitudes were also significantly (P < 0.01) lower in POAG eyes than in control eyes and correlated with MD (P < 0.001). No significant correlations (P > 0.05) were found between electrophysiological parameters and corrected pattern standard deviation (CPSD), index of localized visual field damage, of 24-2 Humphrey Perimetry. Retinocortical time (RCT: difference between VEP P100 and PERG P50 latencies) and latency window (LW: difference between VEP N75 and PERG P50 latencies) were significantly (P < 0.01) longer in POAG eyes than in control eyes and correlated with MD . He concluded that in patients with open-angle glaucoma the reduction of the index of global visual field damage (MD) could be ascribed to two sources of functional impairment: one retinal (impaired PERG) and one postretinal (delayed RCT and LW). In the postretinal impairment, a postsynaptic degeneration at the level of the lateral geniculate nucleus could be suggested.To evaluate whether glaucomatous visual field defects could be related to an impaired retinal function, to a delayed neural conduction in postretinal visual pathways, or both; visual field by Humphrey perimeter  and simultaneous recordings of visual evoked potential (VEP) and pattern electroretinogram (PERG) were assessed in 21 subjects with open-angle glaucoma (POAG) and in 15 age-matched controls . VEP in P < 0.001) between P100 amplitude and HFA24/2 MD and MD values in their POAG patients were negatively correlated with the latency time of P100.To assess the presence of normal or abnormal pattern visual evoked potential (VEP) responses in patients with ocular hypertension and open-angle glaucoma (OAG), a study was performed on 80 normal control subjects, 68 ocular hypertension patients with intraocular pressure (IOP) < 18\u2009mmHg under pharmacological treatment and 84 OAG patients with intraocular pressure (IOP) < 18\u2009mmHg under pharmacological treatment  VEPs usiWith the multifocal technique, visual evoked potentials (VEPs) can be recorded simultaneously from many regions of the visual field in a matter of minutes. Recently, the multifocal visual evoked potential technique (mfVEP) has generated considerable interest, especially among those seeking objective measures of glaucomatous damage. If both eyes of an individual are normal, then mfVEPs recorded for monocular stimulation of each eye are essentially identical. However, the amplitude and waveform of the mfVEP responses vary across individuals, as well as across the visual field within an individual. These variations are related to cortical anatomy and to the cortical sources contributing to the mfVEP. The mfVEP is predominantly generated in V1. Although there are undoubtedly extrastriate contributions, these contributions are probably smaller for the mfVEP than for the conventional VEP. The mfVEP is not a small version of the conventional VEP. To determine the relationship between spatially localized multifocal visual evoked potentials (mfVEPs) and Humphrey visual fields (HVFs) in patients with unilateral field defects, Humphrey visual fields and mfVEPs were obtained from 20 patients with unilateral field losses due to either ischemic optic neuropathy or glaucoma . MonoculThe monocular and interocular results were consistent with a linear relationship between the amplitude of the signal portion of the mfVEP response and linear HVF loss. One way to produce this relationship would be if both the signal in the mfVEP and linear HVF loss were linearly related to the percentage of local ganglion cells lost.To detect ganglion cell damage with the mfVEP requires methods for analyzing the responses and for displaying the results. A method for detecting ganglion cell damage has been described . This meUsing the techniques described therein, the relationship between the amplitude of the mfVEP and the sensitivity loss of the HVF was discussed. The evidence supports a simple model in which the amplitude of the signal portion, but not the noise portion, of the mfVEP response is proportional to HVF loss where HVF loss is expressed in linear, not dB, units. It was hypothesized that both the signal in the mfVEP, and the sensitivity of the HVF, are linearly related to ganglion cell loss. A theoretical approach was developed which allowed a direct comparison of the efficacy of the mfVEP and HVF in detecting glaucomatous damage. In short, when the mfVEP has a large SNR it will often be superior to the HVF in detecting damage. On the other hand, when the mfVEP has a small SNR, the HVF will probably be superior. In summary, the authors concluded that the mfVEP has a place in the clinical management of glaucoma, although it is not likely to replace static automated achromatic perimetry in the near future. However, this is an evolving technology and the future will undoubtedly see major improvements in the mfVEP technique. The multifocal VEP (mfVEP) technique is still in infancy and there are as yet no studies to determine its reliability compared with other methods of investigation. Another study was conducted to compare latencies of conventional visual evoked potentials (cVEPs) and multifocal VEPs (mfVEPs) in the same patients  75 eyes To investigate the changes of color pattern reversal visual evoked potential (CPR-VEP) of primary glaucoma using different temporal frequencies CPR-VEP was recorded using Vision Monitor visual electrophysiograph at different temporal frequencies  and different color stimulations  in 41 cases (70 eyes) with primary glaucoma (glaucoma group) and 13 normal subjects (26 eyes)   P100 wavTo investigate the difference in color pattern reversal visual evoked potential (CPR VEP) between primary open-angle glaucoma (POAG) and primary angle closure glaucoma (PACG) patients CPR-VEP were obtained in 17 eyes of 12 POAG patients, 56 eyes of 41 PACG patients, and 26 eyes of 13 age-equivalent normal persons at an ascending series of temporal frequency , and color stimulation   P100 wavA very recent study was undertaken to evaluate the color Doppler imaging (CDI) and pattern visual evoked potential (P-VEP) examinations in primary open-angle glaucoma (POAG) patients and investigate the relation between flow velocities measured by CDI and P-VEP examination in POAG patients , 65 POAGP < 0.001) correlated with value of mean defect (MD) in dB. Our results correspond with recent study [With an attempt to assess the correlation of visual field indices with VEP parameters in primary open-angle glaucoma, we conducted a study on a larger cohort of 100 POAG patients and 200 control subjects of central Indian population ; we obsent study  which rent study  who haveFrom this paper, it can be concluded that VEP is an important visual electrophysiological tool which has been used for the evaluation of visual field defects in primary open-angle glaucoma. It is endowed with an added advantage of objectivity. The electrophysiological test like VEP is a more objective measure of optic nerve function because it is not influenced by cognitive factors or the motor skills of the subject as compared with the psychophysical tests. Further significant correlations between the magnitude of the VEP latencies and the size of visual field defect and optic disc cupping or pallor over the years confirm the validity of VEP method in primary open-angle glaucoma. Further, the correlation obtained by us between all the electrophysiological VEP parameters and MD of Humphrey static perimetry suggests that the impaired visual cortical responses observed in glaucoma patients can be revealed by both electrophysiological and psychophysical methods. In addition, the severity of global glaucomatous damage evidenced by reduction in MD could depend on the delay in neural conduction from retina to the visual cortex as revealed by the significant correlation between VEP latencies and MD."}
+{"text": "In pediatric and adult patients after stem cell transplantation (SCT) disseminated infections caused by human cytomegalovirus (HCMV) can cause life threatening diseases. For treatment, the three antivirals ganciclovir (GCV), foscarnet (PFA) and cidofovir (CDV) are approved and most frequently used. Resistance to all of these antiviral drugs may induce a severe problem in this patient cohort. Responsible for resistance phenomena are mutations in the HCMV phosphotransferase-gene (UL97) and the polymerase-gene (UL54). Most frequently mutations in the UL97-gene are associated with resistance to GCV. Resistance against all three drugs is associated to mutations in the UL54-gene. Monitoring of drug resistance by genotyping is mostly done by PCR-based Sanger sequencing. For phenotyping with cell culture the isolation of HCMV is a prerequisite. The development of multidrug resistance with mutation in both genes is rare, but it is often associated with a fatal outcome. The manifestation of multidrug resistance is mostly associated with combined UL97/UL54-mutations. Normally, mutations in the UL97 gene occur initially followed by UL54 mutation after therapy switch. The appearance of UL54-mutation alone without any detection of UL97-mutation is rare. Interestingly, in a number of patients the UL97 mutation could be detected in specific compartments exclusively and not in blood. Under special condition such as immunosuppression, the virus can be reactivated and may lead to severe diseases. The HCMV genome comprised about 230\u00a0kb with more than 250 open reading frames. Transplant recipients have a high risk to develop a primary infection or recurrent infection with human cytomegalovirus (HCMV) The development of multidrug resistant HCMV infection and disease with mutations in the UL97- and the UL54-gene after allogeneic hematopoietic cell transplantation (HCT) can be life-threatening. Therefore a rapid and close meshed monitoring of HCMV infection and viral load under therapy after HCT is mandatory Diagnosis of resistant HCMV infection is mostly performed by genotypic assays of UL97 and UL54 genes. A basic problem is the interpretation of unknown or rarely reported point mutations. To concern this, Marker Transfer Analysis is needed and a web-based data base for HCMV drug resistance mutations was established New compounds with different mechanism of action are under investigation 2The UL97 gene encodes for the viral phosphotransferase. Beside many other targets like for example pUL44, pUL69 3The UL54 gene of HCMV encodes for the viral DNA polymerase. Like a wide range of DNA polymerases, the UL54 protein has conserved functional regions . Mutatio4Risk groups for the development of disseminated HCMV diseases are patients with impaired immune system including patients with AIDS, transplant recipients, congenitally HCMV-infected premature infants and patients with immune deficiency, but prevalence data are limited. The risk to develop a resistant HCMV infection in transplant patients depends on different factors such as serostatus, type of transplant and the level of immunosuppression 5Therapy against HCMV diseases is due to three antiviral drugs. The nucleoside analogue ganciclovir (GCV) is used as gold-standard. The L-valyl ester of ganciclovir valganciclovir  can be administrated orally and is rapidly absorbed and hydrolyzed to ganciclovir 66.1The gold standard and mostly used genotypic method for the detection of resistant HCMV strains is Sanger sequencing of PCR products from the UL97 and the UL54 genes Other methods for the detection of drug resistance associated mutations are restriction fragment length polymorphism (RFLP) and real time PCR assays. Both methods allow a detection of resistant mutations in the UL97 gene. The RFLP is based on restriction endonuclease recognition sites in PCR products of the UL97 gene. Mutations result in gain or loss of these restriction sites and in comparison to a wildtype control, detection of mutations can be performed by digest of the PCR product followed by agarose gel electrophoresis. With different enzymes a pattern of fragments could be compared. Other advantages are that amplification can be made directly from material of the patient; it is fast, cost saving, easy to perform and mixtures of wildtype and mutant strains can be detected. Nevertheless, the RFLP analysis is restricted to known mutations that lead to a gain or loss of restriction sites. New mutations cannot be detected using this method Real-time PCR using melting curve analysis for the detection of specific UL97-mutation is a very fast and sensitive method. It also allows a semiquantitative detection of wildtype and mutant mixtures out of patient material and a simultaneously detection of different mutations in the same approach. Equally to RFLP analysis, the real time PCR approaches can only detect known mutations. The assays cannot distinguish between different mutations and polymorphisms near known mutations can influence the melting curve 6.2The phenotypic characterization of isolates extracted from patient materials is very time consuming for HCMV and has only restricted use in routine diagnostics, since it is prerequisite to get a viral isolate. Nevertheless if a viral isolate is available, it is possible to check beside GCV the susceptibility also to PFA and cidofovir. However it remains important in cases with unclear genotypic results or detecting of new mutations.50 (inhibitory dose 50%) values which define the halfmaximal reduction of the number of HCMV plaques resulting from in vitro culture without anitiviral compound. Standardization of these PRAs is still a problem, especially in context of definitions of cut-off levels for resistance, which also depends on the availability of suitable therapy-na\u00efve wild-type virus strains. Nevertheless, these assays are necessary to confirm new mutations and to clarify unclear genotypic results Different types of Plaque reduction assays (PRAs) were described which are based on the determination of a required drug concentration necessary to reduce viral growth in cell culture, the IDAn interesting tool for the correlation of genotypic results to a specific potentially resistant phenotype was published by Chevillotte et al. 7Marker Transfer Analysis comprised the incorporation of a not described UL97- or UL54- mutation in the wildtype background of HCMV followed by o phenotypic characterization of the resulting recombinant HCMV strain in comparison to the wildtype. The large and complex genome of HCMV was a huge problem in early time period of antiviral testing. Using homologous recombination by cotransfection, multiple segments of HCMV-DNA was cotransfected into HFF Escherichia coli strains where the recombination of HCMV BAC with a PCR product containing the unknown mutation, can be controlled. The most effective one was published by Tischer et al. E.coli without any foreign sequences. The resulting BAC mutant DNA is then transfected into HFF and after propagation, phenotypic characterization can be performed. The characterization of the recombinant HCMV-BACs is normally done using PRA.A milestone for the generation of recombinant HCMV mutants was the development of HCMV as bacterial artificial chromosome (BAC). Different methods for the reconstitution of HCMV-BAC mutants were described 8Multidrug resistance in patients under antiviral treatment of HCMV diseases is described by different groups Typically, multidrug resistance phenotypes appear after long term treatment span weeks or months. Normally therapy of a HCMV disease with a positive DNAemia in whole blood or plasma starts with the donation of GCV as drug of choice. In most cases the viral load decreases. Mutations in the UL97 gene can be observed shortly before a first viral peak value. After a therapy switch to either PFA or CDV the viral load decreases again. After weeks of treatment, additional UL54 mutations can be observed before the viral load increases again 9The development of drug- or multidrug resistant HCMV infection in patients after SCT might cause severe clinical problems. Mutations in the UL97 can lead to resistance to GCV while mutations in the UL54 gene region can cause resistance to all three antiviral drugs GCV, CDV and PFA. Since GCV is the first choice for treatment, mutations in the UL97 gene appear first followed by UL54 mutations after therapy switch resulting in a multidrug resistant phenotype.There are limited reports about the development of multidrug resistance in transplant recipients"}
+{"text": "Many proteins and signaling pathways are present in most cell types and tissues and yet perform specialized functions. To elucidate mechanisms by which these ubiquitous pathways are modulated, we overlaid information about cross-cell line protein abundance and variability, and evolutionary conservation onto functional pathway components and topological layers in the pathway hierarchy. We found that the input (receptors) and the output (transcription factors) layers evolve more rapidly than proteins in the intermediary transmission layer. In contrast, protein expression variability decreases from the input to the output layer. We observed that the differences in protein variability between the input and transmission layer can be attributed to both the network position and the tendency of variable proteins to physically interact with constitutively expressed proteins. Differences in protein expression variability and conservation are also accompanied by the tendency of conserved and constitutively expressed proteins to acquire somatic mutations, while germline mutations tend to occur in cell type-specific proteins. Thus, conserved core proteins in the transmission layer could perform a fundamental role in most cell types and are therefore less tolerant to germline mutations. In summary, we propose that the core signal transmission machinery is largely modulated by a variable input layer through physical protein interactions. We hypothesize that the bow-tie organization of cellular signaling on the level of protein abundance variability contributes to the specificity of the signal response in different cell types. Cell function is determined by highly organized networks of biological molecules. An important class of protein pathways maintains the transmission of signals from the cell membrane to the nucleus. These signaling pathways are reused for different purposes at an evolutionary scale and in different cell types of the same organism. However, it is largely unknown how this flexibility is achieved and how this flexibility is balanced with the high degree of evolutionary conservation of some signaling proteins and the need for robustness against intra- and extra-cellular perturbations.We show how functional roles of signaling proteins determine patterns of evolutionary conservation, protein abundance (the average over different human cell lines and its variability) and disease mutations. Projecting pathway annotations on protein-protein interaction (PPI) networks, a picture emerges in which PPIs between variable and less conserved receptors and stable and conserved proteins of the core signal transmission machinery largely modulate signaling activity in a tissue-specific manner. This has important implications for the distribution of disease mutations in signaling pathways, which need to be considered for the understanding of their effect. Proteins do not act in isolation but interact with other proteins to fulfill important cellular functions. Often proteins are organized into pathways, which are tightly controlled cascades of protein binding events (and those of other biomolecules). One important cellular function controlled by pathways is the transmission of extra-cellular signals from the cell membrane to the nucleus to provoke a response to changes in the environment of the cell. Signaling pathways are often active in many different cell types and are conserved at a large evolutionary scale One characteristic of signaling pathways is the bow-tie (or hourglass) architecture in which signals sensed by receptors converge onto a core consisting of a smaller number of proteins followed by a diverse response of transcription factors. The bow-tie property has been observed in different human signaling pathways such as those downstream of epidermal growth factor receptor The robustness of pathways needs to be in balance with flexibility allowing pathways to vary their response to similar stimuli at different time points or in different cell types of the same organism. One intuitive though largely unexplored link to the bow tie model comes from investigations of protein-protein interaction (PPI) networks associated with gene expression information: it was observed that tissue-specific proteins tend to bind to core cellular proteins, possibly to modulate housekeeping cellular processes in a cell type-specific manner The mechanistic understanding about how activation of the same signaling pathways can lead to cell type-specific responses is rather anecdotal and involves diverse mechanisms such as cell type-specific feedback loops Recently a mass spectroscopy analysis accomplished by Mann and co-workers F values to estimate the biological variability among cell lines. F values were computed by dividing the between-cell variation by the within-cell variation. Thereby we successfully eliminated any dependencies between the protein abundance and variability caused by technical biases  In this study, we used the To analyze how protein conservation relates to protein expression abundance and diversity of proteins involved in human pathways, we analyzed the conservation of all proteins in the expert-curated Reactome database To identify cellular processes that differ in their phylogentic conservation and cross-cell variability, we selected all Reactome pathways that are expected to be general and not restricted to only some cell types (ten pathways): Cell cycle, DNA replication, and chromosome maintenance [DR], Extracellular matrix organization [MO], Gene expression and RNA processing [GE], Membrane trafficking [MT], Metabolism [MB], Signal transduction [ST], Apoptosis [AP], Developmental Biology [DB], Transmembrane transport of small molecules [TM], and Cell-Cell communication [CO]. Several other Reactome pathways are restricted to very specific body cell types , or are of low coverage , and were neglected for further analysis , more variable  and less abundant  (see A fraction of the proteins (18.7% from the 4069 Reactome proteins that we could associate with at least one of the investigated features) participates in more than one pathway. We compared the distributions of mean abundance, abundance variability and phylogenetic conservation among exclusive proteins associated only with one pathway to the distributions associated with proteins involved in several pathways. We observed that exclusive proteins are significantly less conserved (ney) see .Next, to elucidate the common and variable elements in 11 cell types with respect to the ten Reactome pathways, we considered only proteins found exclusively in one pathway. We observed large differences with respect to the three investigated features among human functional pathway classes . In geneTo elucidate in more depth the protein abundance variability in signal transduction pathways, we investigated whether we can relate the molecular function of proteins in signaling pathways to their abundance, variability and conservation. For this purpose, we chose two complementary protein classification strategies and signaling resources. (a) We assigned, where non-ambiguously possible, signaling proteins in Reactome to one of the following Gene Ontology and UniprotKB categories: membrane-bound receptor, phosphatase, kinase, transcription factor, adaptors, and GTPase binding (see Methods for details). (b) We retrieved the full set of proteins and their classification into signaling-related sections  from the signaling pathway database SignaLink P<0.01, Wilcoxon-Mann-Whitney). The difference between the transmission and the output layer was for both data sources not (Reactome) or only marginally  significant. The conservation of proteins of the transmission layer was significantly larger than of proteins of both the input and the output layer . In summary, taking a mechanistic view on signaling pathways where an input layer receives signals from the environment, a transmission layer integrates and proceeds the signal and an output layer orchestrates the transcriptional response, two patterns emerge: (i) In terms of conservation, we see a bell shaped curve with a high conservation of the transmission layer and lower conservation of the input and output layer (P<0.05). This suggests that modulators in the transmission layer contribute less to cell type specific differences.We observed large differences in conservation, mean abundance and abundance variation for different classes within both sets of annotated signaling proteins see . Next, wut layer  and S5. ut layer . There iut layer . These rP<e\u221216; Wilcoxon-Mann-Whitney), while mean abundance and abundance variability did not show significant differences between the protein sets. This is in agreement with the higher number of proteins of the transmission layer among the proteins associated with multiple pathways .We also compared the investigated features associated with proteins exclusively members of one signaling pathway (1253 proteins) to those associated with proteins re-used in several signaling pathways (235 proteins) see . We obseTo investigate how our observation of a lowly variable and strongly conserved transmission layer might help to understand general principles by which signaling pathways are modulated in a tissue-specific manner, we overlaid our sets of signaling proteins (merged from Reactome and SignaLink) with PPI network data from the database HIPPIE P<10\u221216; Wilcoxon-Mann-Whitney). As the difference in variability is highest between the input and the transmission layer, the results met our expectation.We tested the hypothesis that PPIs between input and transmission layer tend to happen between proteins with a larger difference in variability than for PPIs between the transmission and the output layer, within one layer, or randomly chosen PPIs . To testP<10\u221216; Wilcoxon-Mann-Whitney). We can reproduce the same results when permuting the links between randomly sampled interacting protein pairs between the input and the transmission layer. This demonstrates that the observed differences can be attributed to both the different network positions of proteins in signaling pathways and a tendency of variable input layer proteins to physically interact with stably expressed transmission layer proteins.To test if the observed difference in variability between interacting proteins between the input and the transmission layer can be solely attributed to the membership of the participating proteins in different layers, we compared the distribution of variability differences for interacting proteins to those of randomly sampled, non-interacting protein pairs where one protein is from the input and one is from the transmission layer . StrikinThese observations suggest that PPIs between the input and the transmission layer might have an impact on the tissue-specificity of signaling.The higher conservation of the signal transmission layer is in agreement with the bow-tie (or hourglass) model proposing the presence of a conserved core with variable input and output layers modulating the signal response . The low occurrence rates for all mutation categories  indicate that no mutations are tolerated in these proteins to maintain cellular integrity. Among the lowly conserved proteins the most strongly enriched functions were all related to sensory and olfactory perception (P\u200a=\u200ae\u2212195). The lower rate of disease mutations as compared to all SNPs within this group likely reflects the tolerable effect of mutations within the sensory system on cell viability.Both germline and somatic mutations can lead to disease by perturbation of signaling pathways, e.g. in cancer P\u200a=\u200a0.0005; Wilcoxon-Mann-Whitney; see With respect to protein expression, we found that signaling-related proteins with somatic cancer mutations have a significantly lower protein abundance variability .We also found a weak though significant tendency for disease proteins with somatic mutations to be more highly expressed than proteins with germline mutations in signaling pathways  but also provide novel hypotheses on the organization of human signaling pathways (as discussed in the following). Some of our central findings are drawn from the analysis of protein abundance variability across cancer cell lines. As we are here interested in studying normal cellular properties, we demonstrate that there is a good agreement between protein variability across cancer cell lines and across normal cells.We report significant correlations between phylogenetic conservation and both protein abundance (positive correlation) and abundance variability (negative correlation). These observations suggest on one hand that evolutionary conserved proteins could have an essential general function for every cell type see . This isIt has been observed before The decreasing protein abundance variability from the input to the output layer might be surprising  show contrary patterns and are associated to a higher degree with central and housekeeping genes We show how this general pathway organization principle shapes the distribution of disease mutations. As it has been discussed before In summary, to understand cell type-specific signaling mechanisms and, more general, to understand \u201cwhat makes a cell type\u201d, we need to distinguish between core proteins conserved through evolution, and those recently acquired and incorporate information on protein concentration to interaction networks. Ideally this should be complemented by structural information to distinguish between competing and compatible interactions F values dividing the between-cell variability by the within-cell variability on the standardized label-free quantification intensities, thereby eliminating the dependence between variation and abundance  using the HomoloGene search tool. We considered conservation in Pan troglodytes, Mus musculus, Rattus norvegicus, Gallus gallus, Danio rerio, Drosophila melanogaster, Anopheles gambiae, Caenorhabditis elegans, Schizosaccharomyces pombe, Saccharomyces cerevisiae, Eremothecium gossypii, Arabidopsis thaliana, and Oryza sativa.Homology information for proteins was extracted from the NCBI database (i is constructed as a subtree of the full phylogenetic tree T. Branch lengths are mapped as weights to the set of edges E. The conservation score is then computed as:i is the set of edges associated with subtree Ti and w(e) the weight corresponding to edge e. For an example of the conservation score computation see A phylogenetic tree was constructed using inferred phylogenetic relationships between these species Proteins involved in the 22 top-level pathway classes in the Reactome pathways database To construct the set of germline mutations, we retrieved all disease mutations from OMIM We computed enrichment of functional categories among the proteins falling into the first and the last quantile of the conservation distribution. We used the web tool DAVID Figure S1Correction for relation between protein abundance and variability. (A) Highly abundant proteins are associated with a lower variability . (B) Correcting with intra-cell variance eliminates this dependence .(TIF)Click here for additional data file.Figure S2F values associated with human housekeeping genes and mouse lowly and highly variable proteins. (A) We compared the distribution of F values associated with housekeeping genes  versus all other human genes. The protein products of the housekeeping genes were associated with a significantly lower F values than other proteins . (B) We compared the distribution of F values associated with the least variable quarter and the highest variable quarter of mouse proteins. Protein abundances were measured in 28 healthy mouse tissues and proteins were mapped to human. The lowly variable mouse proteins are associated with lower variability across human cell lines .(TIF)Click here for additional data file.Figure S3Computation of a phylogenetic tree-based conservation score. For each human protein we created a phylogenetic tree of species in which the protein is conserved. The conservation score is then computed as the sum of all branch lengths present in the pruned subtree divided by the sum all all branch lengths present in the full phylogenetic tree. As an example the score computation is illustrated for a protein only conserved in mammals. Blue edges constitute the phylogenetic subtree connecting mammalia (in which the protein is conserved). Branches leading to taxa in which the protein is not conserved are shown in gray. The score is computed as the sum of branch lengths associated with edges in the subtree (0.11527) divided by the sum of branch lengths in the full phylogenetic tree (2.33187). Hence, in the shown example the conservation score would be (TIF)Click here for additional data file.Figure S4Features of exclusive and re-used pathway proteins. The boxplots show distributions of conservation, abundance variability, and mean abundance of proteins being part of one (Exclusive) or several (Multiple) general cellular pathways (A\u2013C) or signaling pathways (D\u2013F).(TIF)Click here for additional data file.Figure S5Conservation, mean abundance and variability associated with different pathway classes. The plots on the left are generated from SignaLink proteins and their annotations . On the right, the respective distributions for Reactome signaling proteins and their functional annotations based on UniProt and GO are shown .(TIF)Click here for additional data file.Figure S6Protein conservation and abundance variability associated with different pathway layers of Reactome signaling proteins. Protein conservation (A) and abundance variability (B) are shown. The input layer consists of receptors, the transmission layer of adaptors, kinases, phosphatases and GTPases and the output layer of transcription factors.(TIF)Click here for additional data file.Table S1Reactome pathways. The table lists Reactome pathways and associated protein counts . The last column indicates reasons for merging pathways or excluding them from the analyses.(XLS)Click here for additional data file."}
+{"text": "WNT signaling in microglia and the glioma microenvironment Gunnar Schulte WNT signaling is important during embryonic development and organogenesis having specific roles in the development of the CNS such as regulation of neural tube formation, axon guidance and CNS stem cell regulation. Our work has recently established a role of WNT signaling in the regulation of the brain\u2019s macrophages, the microglia and thus WNTs emerge as novel regulators of CNS inflammatory responses. First of all, it appeared that b-catenin levels are elevated in microglia in Alzheimer disease (AD) brains as well as microglia cells in AD mouse models. Employing in vitro studies of primary mouse microglia isolated from newborn mouse pups indicated that both WNT-3A and WNT-5A induce diverse signaling routes in microglia leading to differential proinflammatory modulation of the cells. Interestingly, the net effect of WNT stimulation on the inflammatory potential of mouse microglia is context dependent. While WNTs increase inflammatory markers when giving to microglia alone, they are able to act in an anti-inflammatory manner when microglia are activated by prestimulation with lipopolysaccharides. Our findings thereby indicate that WNTs act on microglia as a homeostatic regulator, further underlined by yet unpublished data that suggest that WNT-5A is elevated in human glioma associated with a distinct inflammatory signature of the tumor as well as a substantial invasion of microglia."}
+{"text": "Botulinum neurotoxin A (BoNT A) is the first-line treatment for cervical dystonia. However, although BoNT A has a favorable safety profile and is effective in the majority of patients, in some cases the treatment outcome is disappointing or side effects occur when higher doses are used. It is likely that in such cases either the target muscles were not injected accurately or unintended weakness of non-target muscles occurred. It has been demonstrated in clinical trials for spastic movement disorders that sonography-guided BoNT A injections could improve treatment outcome. As the published evidence for a benefit of sonography-guided BoNT injection in patients with cervical dystonia is scarce, it is the aim of this review to discuss the relevance of sonography in this indication and provide a statement from clinical experts for its use. The clear advantage of sonography-guided injections is non-invasive, real-time visualization of the targeted muscle, thus improving the precision of injections and potentially the treatment outcomes as well as avoiding adverse effects. Other imaging techniques are of limited value due to high costs, radiation exposure or non-availability in clinical routine. In the hands of a trained injector, sonography is a quick and non-invasive imaging technique. Novel treatment concepts of cervical dystonia considering the differential contributions of distinct cranial and cervical muscles can reliably be implemented only by use of imaging-guided injection protocols. Botulinum neurotoxin A (BoNT A) is the first-line treatment for cervical dystonia (CD) and focal spasticity  showed a low accuracy of muscle localization when using anatomical landmarks only . In these studies, EMG was used not only for injection guidance but as well for muscle selection. Nevertheless, a recent review did not show an overall better outcome compared to clinical muscle selection and anatomical needle placement   has been published in a small number of patients (Bhidayasiri Positron emission tomography (PET) has been used in two studies to identify hypermetabolic and presumably dystonic muscles, whereas injection was performed under CT or ultrasound guidance  shows comparable anatomic precision as US, the latter is a non-invasive technique causing no additional discomfort for the patient nor exposing the patient to radiation or any further risks. US allows real-time visualization of muscles and the adjacent anatomical structures so that the entire injection procedure of BoNT A can be followed.Availability of US in central Europe neurological clinics is high as neurovascular ultrasound is part of clinical routine diagnostics and almost all clinicians are familiar with the US machine on-site. Detailed recommendations on the technical requirements, procedure, and documentation of US-guided BoNT injection have been recently published Occurrence of adverse events after BoNT A injections Presence of complex dystonic patterns with a high probability of involvement of deeper located muscles which are more difficult to access .Secondary non-responders without neutralizing antibodies against BoNT APreferably, US guidance should be applied in the following cases:US guidance should be included in future clinical studies.In conclusion, due to the advantages of US-guided BoNT A injections and the experience of the authors in clinical practice, the authors summarize their opinion as follows:"}
+{"text": "Patients with hereditary breast cancer constitute a considerable fraction of overall breast cancer sufferers. The contribution of genetic factors to the development of breast cancer in the admixed and highly consanguineous population of the western region of Saudi Arabia is thought to be significant as the disease is early onset . The curWe have performed whole-exome sequencing of seven cases of breast cancer patients with positive family history of the disease using the Agilent SureSelect\u2122 Whole-Exome Enrichment kit and sequencing on the SOLiD\u2122 platform.In addition to identifying two rare or novel mutations in BRCA2, we have identified several coding single nucleotide variations that affect genes controlling DNA repair in the BRCA1/2 pathway. The disruption of these pathways is very likely to contribute to breast cancer susceptibility.Our findings suggest that whole exome sequencing is a powerful tool for identifying mutations associated with hereditary breast cancer that might be missed by using other classical genetic testing strategies. Moreover, this will guide the treatment of breast cancer patients who have failed to respond to first-line therapies, thus, it is a great leap towards applying personalized medicine in Saudi Arabia.This project is partly funded by NSTIP grant 09-BIO-818-03."}
+{"text": "Peritoneal dialysis is troubled with declining utilisation as a form of renal replacement therapy in developed countries. We review key aspects of therapy evidenced to have a potential to increase its utilisation. The best evidence to repopulate PD programmes is provided for the positive impact of timely referral and systematic and motivational predialysis education: average odds ratio for instituting peritoneal dialysis versus haemodialysis was 2.6 across several retrospective studies on the impact of predialysis education. Utilisation of PD for unplanned acute dialysis starts facilitated by implantation of peritoneal catheters by interventional nephrologists may diminish the vast predominance of haemodialysis done by central venous catheters for unplanned dialysis start. Assisted peritoneal dialysis can improve accessibility of home based dialysis to elderly, frail, and dependant patients, whose quality of life on replacement therapy may benefit most from dialysis performed at home. Peritoneal dialysis providers should perform close monitoring, preventing measures, and timely prophylactic therapy in patients judged to be prone to EPS development. Each peritoneal dialysis programme should regularly monitor, report, and act on key quality indicators to manifest its ability of constant quality improvement and elevate the confidence of interested patients and financing bodies in the programme. Over the last 15 years the proportion of all dialysis patients treated with peritoneal dialysis (PD) declined significantly in developed countries [A general shift towards a higher age at start of dialysis treatment and increasing comorbidity cannot in whole explain the causality of this problem . Other pThe fall in PD utilisation is a concern since PD is a precious renal replacement modality that offers patients the convenience of home treatment, flexible schedule and increased freedom perception, less haemodynamic instability issues, and higher quality of life . PD abolIn Europe there is a domination of haemodialysis (HD) as a starting modality in late-referred chronic kidney disease (CKD) patients . Late reA significant impact of predialysis education or timely referral on the choice of peritoneal dialysis is shown in the summary in Unplanned and suboptimal initiation is the term proposed to include dialysis initiation in hospital and/or with a central venous catheter (CVC) and/or with a patient not starting on their chronic modality of choice . Rates oAcute unplanned start of peritoneal dialysis is generally offered to patients in two clinical scenarios: the patient had previously been given some information on dialysis modality and he opted for PD before the unexpected fast deterioration in kidney function happened or after a brief discussion in the hospital about the renal replacement modalities the patient finds peritoneal dialysis acceptable. Provided there is no uremic encephalopathy, pericarditis or colitis, severe hyperkalemia or pulmonary congestion, or another factor demanding dialysis sooner than within 48 hours, acute unplanned start of peritoneal dialysis is a feasible, effective, and safe option.The PD catheter should be placed as soon as possible and an early start of PD with low fill volumes (750\u20131000\u2009mL), automated PD tidal regime with a cycler in supine position can be started. The treatment time is variable, from 6 to 12 hours . With suDedicated catheter insertion team available 24/7 is the necessary condition for acute unplanned start of peritoneal dialysis. If there is an experienced and dedicated nephrologist performing catheter insertions available at the dialysis unit many logistic and operative schedule barriers for PD catheter insertion  may be more easily tackled. The set-up of interventional nephrology catheter insertion service was reported to enable growth of PD programmes . The incAt some dialysis centres (including the author's) there are a long-term experience and positive results with divided care for establishment of vascular access for HD between interventional nephrologists and vascular surgeons . It mayThe patient population reaching end-stage CKD is growing in age, frailty, comorbidity, and dependance. This is one of the major obstacles for institution of PD as it is a form of self-delivered home based therapy. The overwhelming association of having a strong social support network and being functionally able with choosing PD emphasizes the need for assisted PD . The Fre\u201cThere is no evidence to withhold PD as a treatment option because of fear of development of EPS\u201d was the final conclusion of an ISPD statement on length of time on PD and encapsulating peritoneal sclerosis (EPS) . AlthougThe usage of new biocompatible solutions is associated with stabilisation of peritoneal transport rate , lower pAfter 4-5 years of treatment, the patients who are identified as EPS prone  may be treated with prophylactic tamoxifen , 58 and To properly monitor the patients on PD regular measurement of peritoneal membrane transport status is recommended. In patients with consistent rise in the speed of small solute transport, effluent carcinomic antigen-125 (CA-125) and interleukin-6 (IL-6) can be monitored as well . The com Staphylococcus aureus catheter infection rates below 1 in 240 patient-months [There are several key parameters which are universally accepted as quality of service indicators in the field of peritoneal dialysis. Peritonitis rates below 1 episode in 18 patient-months  and Stapt-months  are wellPD should be regarded as a safe and efficient form of renal replacement modality; however the declining numbers of patients in PD programmes in developed countries are a cause for concern. Several strategies summarized in"}
+{"text": "Pollination is a critical ecosystem service affected by various drivers of land-use change, such as policies and programs aimed at land resources, market values for crop commodities, local land-management decisions, and shifts in climate. The United States is the world's most active market for pollination services by honey bees, and the Northern Great Plains provide the majority of bee colonies used to meet the Nation's annual pollination needs. Legislation requiring increased production of biofuel crops, increasing commodity prices for crops of little nutritional value for bees in the Northern Great Plains, and reductions in government programs aimed at promoting land conservation are converging to alter the regional landscape in ways that challenge beekeepers to provide adequate numbers of hives for national pollination services. We developed a spatially explicit model that identifies sites with the potential to support large apiaries based on local-scale land-cover requirements for honey bees. We produced maps of potential apiary locations for North Dakota, a leading producer of honey, based on land-cover maps representing (1) an annual time series compiled from existing operational products and (2) a realistic scenario of land change. We found that existing land-cover products lack sufficient local accuracy to monitor actual changes in landscape suitability for honey bees, but our model proved informative for evaluating effects on suitability under scenarios of land change. The scenario we implemented was aligned with current drivers of land-use change in the Northern Great Plains and highlighted the importance of conservation lands in landscapes intensively and extensively managed for crops. Maintaining human prosperity and quality-of-life standards requires landscapes that sustainably deliver ecosystem services valued by society. Decisions that improve the sustainability of landscapes call for information on the simultaneous responses of multiple ecosystem services to changes in land use and climate as a more comprehensive approach to safeguard against unintended, and potentially negative, outcomes of land management or policy actions Socioeconomic factors are exerting considerable influence on decisions affecting land use in the Northern Great Plains of North America, a region of major agricultural production Euro-American settlement of the Northern Great Plains brought conversion of vast tracts of grassland to cropland, and while grasslands continue to be converted to cropland, periods in recent decades have seen some reversal of that land-change dynamic As incentives have risen for landowners to maximize crop acreages, Congress has reduced total allowable acreage enrollments for the CRP. The highest cap allocated for the program was 39.2 M acres  during 2002\u20132007 Concurrent interests in achieving national energy independence There have been increasing concerns about declines in pollinators over past decades A principal contributor to declines in honey bees (as well as native bees) is the loss of floral sources of pollen and nectar in the landscape The Northern Great Plains carries great importance for U.S. honey production and pollination services. Commercial beekeepers from states as far away as coastal areas transport honey bees to the prairies each summer to produce honey, a crop valued at more than $256.5M nationally in 2011, with about 50% of the contribution coming from the Northern Great Plains Although CRP lands in the Northern Great Plains have abundant polyfloral sources of pollen for pollinators, there is little information available to quantify the magnitude of that ecosystem service across large geographic extents or its contribution to national pollination services. Government policies and programs that target land resources exert influence on land-management decisions at the local level. Decisions are made parcel by parcel, but tend to accumulate to regional patterns of change We describe here a prototype model we developed to quantify the influence of land use on honey bees in the Northern Great Plains to inform decisions affecting conservation programs that target delivery of national pollination services. Our objectives were to (1) develop an approach to map regional-scale habitat suitability for honey bees based on their nutritional needs from the local landscape, (2) evaluate the efficacy of available land-cover data for monitoring effects of interannual land-cover change on landscape suitability for honey bees, and (3) demonstrate how our approach can be used to assess outcomes for honey bees from drivers of land-cover and land-use change. These objectives are the foundation for a module on honey bees in a larger, integrated assessment tool developed to evaluate effects of policies, programs, climate, and other drivers of land change simultaneously across multiple ecosystem services We prototyped our approach for North Dakota, the Northern Great Plains state with the highest production of honey among all 50 states in most years We specified landscape criteria based on industry standards professional beekeepers use to place hives in the Northern Great Plains. These criteria consider the potential of sites to produce honey crops and to provide the nutrition needed to ensure the health of honey bees. We developed landscape criteria to support apiaries of 100 hives , canola (a group of cultivars developed from Brassica napus and B. campestris), and sunflowers (Helianthus annuus), the three crop types needed for our analysis. All three types have been distinguished annually in map products in North Dakota since 2002, prior to which alfalfa was aggregated with grassland hay crops not nutritious for bees. We used information on woody cover types from the same two sources we used for grassland cover, the CRP and NDGAP products. The dataset for CRP-enrolled lands contained information on the years for which the conservation treatments were under contract, which enabled us to update our land-cover maps annually for both woody and grassland parcels. The NDGAP data we used for the remainder of the landscape was a single, static map derived from a collection of Landsat imagery spanning 1992\u20131998. We amended the NDGAP information with the relatively high-resolution wetland cover delineated by the National Wetlands Inventory (NWI) We compiled annual land-cover maps from multiple sources, as no single source provided all information needed to assess landscape suitability for bees. We encountered expected differences in data vintages, resolutions, and origins . We filled the remainder of the landscape each year with data from the static NDGAP and NWI product sources. We processed all geospatial data in an equal-area map projection  under CRP contract were set to expire between 2007 and 2010 Initial results from the analysis of landscape suitability  online distribution site A relatively sparse number of locations met our initial land-cover criteria. We found the requirements likely were challenged by limitations in the source information we used for the annual land-cover maps. Less than half the woodlands in the landscape actually had been mapped correctly as woodlands in the NDGAP product North Dakota requires that all apiaries be registered with the state by quarter-section legal units, so we obtained  and mapped annual registered locations of apiaries for visual comparison with potential apiary locations produced by our model . We did Our annual series predicting potential apiary locations revealed a legacy of patterns from the mosaic of Landsat imagery used by NASS to develop the crop-type maps, particularly for years 2002\u20132004 . DespiteAn important motivation to evaluate effects of land change on honey bees is to provide information on how resource managements programs and policies can influence pollination services. We highlighted predicted locations that depended on CRP-enrolled lands to meet criteria for siting apiaries . LandownOur results for the scenario application representing pre- and post-incentive years to expand production of biofuel crops revealed a reduction in landscape suitability for large apiaries between 2002 and 2010 . The modOur approach to assess landscape suitability for honey bees provides the foundation for a module in a larger, integrated framework to assess multiple ecosystem services simultaneously to inform decisions on land management and policy, as well as evaluate outcomes from government conservation investments Informal visual comparison of the distribution of locations predicted by our model for 2002 with registered locations of apiaries for that year exhibited some general similarities . Both main situ with commercial apiaries.Results from our analyses helped us identify several ways to refine our model. First, the approach we developed to identify potential apiary locations was successful in implementing local landscape requirements across a statewide extent, but the all-or-nothing recipe for 100 hives is limiting. A shift from a model based completely on expert opinion to one developed statistically from data on number of hives and honey production relative to landscape setting would enable predicting suitability across a range of apiary sizes, as well as contribute information towards understanding how land-cover changes in the Northern Great Plains could affect the supply of honey bee colonies for national pollination needs. Second, we also should incorporate seasonal influences from weather into our model because of effects on plant flowering and nectar flow. Even if land-cover types were held constant across years, different weather conditions would provide substantially more or substantially less pollen and nectar because of variations in moisture and growing degree days. Third, we used centroid locations within grassland patches that met criteria for areal extent and proximity to roads to identify potential apiary sites. For future model refinement we could retain the areal and proximity requirements for grasslands, but instead use centroids from the legal mapping units (quarter sections) that beekeepers register. This would densify the number of point locations around which we could analyze land-cover components  and woulThe data we assembled to compile a land cover time series for North Dakota were a mix of annual and static information, and the vintages of the static sources were not always well matched to the annual sources. The Northern Great Plains have had low rates of annual land-cover conversion  For initial trials of our model we used the NDGAP land-cover product because it offered an array of grassland and woodland subclasses that allowed us to discard those we expected to be poor for bees. The downside to using this product was relatively low rates of mapping accuracy for grassland and woodland classes. For that reason we used non-cropland land-cover information from the NLCD for our subsequent example application because NLCD had a better rate of accuracy for mapping woodland and grassland cover  [75], [9Until recently, annual mapping of land cover for the United States has been untenable at mid-resolution spatial scales. Improvements in technology and free access to Landsat data There are legitimate reasons for the errors in operational-scale land-cover products. Spatiotemporal ambiguities in the spectral characteristics of land cover make it difficult to optimize a classification system for all cover types at once for all places in the landscape Although we found that the land-cover products currently available lack sufficient local accuracy to enable monitoring of actual landscape suitability for honey bees, our model does achieve the goal to provide a way to evaluate how different policies, programs, and market incentives could influence land cover and alter landscape suitability for honey bee colonies. Land-cover maps can be developed to meet various scenario criteria e.g., , and ourThe scenario we employed showed marked differences in landscape suitability prior and subsequent to agricultural and energy drivers currently influencing change in the Northern Great Plains . The lanWe developed a modified moving-window approach to tally land-cover components within local-scale proximity to potential apiaries for statewide or larger regional assessments of landscape suitability for honey bees. Our work responds to a need to estimate effects from various scenarios of land change that can result from major drivers such as market values, shifts in climate, or how national programs and policies for land resources are implemented. Because the approach is sensitive to local-scale information, results based on existing land cover time series generated from remotely sensed data may reveal more about limitations in land-cover products than about actual land-cover change. Our model therefore currently is more valuable for assessing outcomes from different scenarios of land-use change than for monitoring actual changes in landscape suitability. New approaches for monitoring land-cover change with remotely sensed data are emerging e.g.,  that eveOur model was parameterized based on expert opinion for a set of land-cover criteria sufficient in floral sources to support apiaries of approximately 100 hives. These criteria highlighted the best landscapes for bees in North Dakota, but is not very representative of the range of numbers of hives commercial beekeepers typically place in apiaries. Having demonstrated a method that successfully implements local-scale criteria across a large geographic extent, our future efforts will focus on developing a more sophisticated model to provide predictions covering a more realistic spectrum of apiary sizes and environmental conditions. This would be a move towards estimating the number of colonies that could be contributed from the Northern Great Plains to meet national pollination demands under different land-change scenarios.Our motivation to develop an approach to assess landscape suitability for honey bees is to support a larger, integrated effort to evaluate multiple ecosystem services in concert. This capability is needed to provide information for land resource agencies and policy makers on potential outcomes for ecosystem services from drivers of change. Our initial efforts already have highlighted the importance of conservation lands for honey bees in landscapes extensively cropped in cover types having little pollen or nectar value for bees. Incorporating our model into the larger, integrated framework of ecosystem service models Table S1Information on source data.(DOCX)Click here for additional data file.Table S2Accuracy of grassland and woody land cover in maps from the National Land Cover Database and the North Dakota GAP Analysis Program.(DOCX)Click here for additional data file."}
+{"text": "The relationship of cholesterol with stroke is much less clear than its relationship with myocardial infarction, thus confounding the interpretation of results with cholesterol-lowering trials  These data are important to predict stroke outcomes in currently ongoing trials now testing PCSK9 or cholesterol ester transfer protein inhibitors. Specifications TableValue of the data\u2022These data, as obtained through already published literature reinforce the idea that also reduction of stroke, contrary to what previously believed, can be explained by reduction in cholesterol , both in statin and non-statin trials.\u2022Recently published data from IMPROVE-IT perfectly fit the regression line from other source data on such relationship.\u2022These results now allow a prediction of the reduction in stroke in trials now testing the PCSK9 inhibitors and the cholesterol ester transfer protein (CETP) inhibitor anacetrapib.1Data provided here are the characteristics of source trials used for the construction of the meta-regression of reduction in stroke as a function of reduction in total cholesterol.2We had previously carried out a meta-regression by using inverse variance weighted linear regression of the log RR for total stroke against the percent of TC reduction as the explanatory variable. Weights in each study were the reciprocals of the variances for the logarithm RR for stroke. The meta-regression had yielded the following equation:p=0.0017). This equation indicates that some benefit from cholesterol-lowering intervention on the risk of stroke can be expected when the percent reduction of serum cholesterol is >2\u20133%, the clinical benefit becoming statically significant when TC is reduced by ~8%.The regression coefficient for percent TC reduction was significantly different from zero (We have now compared the reduction in stroke observed in IMPROVE-IT 3."}
+{"text": "The emulsifying ability of OSA-modified and native starch in the granular form, in the dissolved state and a combination of both was compared. This study aims to understand mixed systems of particles and dissolved starch with respect to what species dominates at droplet interfaces and how stability is affected by addition of one of the species to already formed emulsions. It was possible to create emulsions with OSA-modified starch isolated from Quinoa as sole emulsifier. Similar droplet sizes were obtained with emulsions prepared at 7% (w/w) oil content using OSA-modified starch in the granular form or molecularly dissolved but large differences were observed regarding stability. Pickering emulsions kept their droplet size constant after one month while emulsions formulated with OSA-modified starch dissolved exhibited coalescence. All emulsions stabilized combining OSA-modified starch in granular form and in solution showed larger mean droplet sizes with no significant differences with respect to the order of addition. These emulsions were unstable due to coalescence regarding presence of free oil. Similar results were obtained when emulsions were prepared by combining OSA-modified granules with native starch in solution. The degree of surface coverage of starch granules was much lower in presence of starch in solution which indicates that OSA-starch is more surface active in the dissolved state than in granular form, although it led to unstable systems compared to starch granule stabilized Pickering emulsions, which demonstrated to be extremely stable. Formulations based on emulsions are present in many fields, such as processed foods, paints and coatings, personal care products, agro-chemicals and pharmaceuticals, among others. Emulsions are defined as a two-phase system consisting of two immiscible liquids of different composition, one of which is in the shape of droplets, dispersed in the other one. Emulsion droplet stabilization is often achieved through the addition of amphiphilic molecules such as emulsifiers, which decrease the interfacial tension between the phases and increase the steric hindrances and/or the electrostatic repulsion between the droplets ,2.The use of particles to stabilize emulsions, instead of surfactants, has received substantial and increased research interest because of their distinctive characteristics and promising technological applications in a range of fields \u201312. A PiThis special type of emulsion was originally observed independently by Ramsden  and PickProperties such as shape, size and hydrophobicity of the particles may affect the stability of the emulsion. Particles should also have partial dual wettability for both phases. The contact angle of the particles to the surface of the droplet is a characteristic of the hydrophobicity. Therefore, particles that are partially hydrophobic (i.e. contact angle of approximately 90\u00b0) are better stabilizers because they bind better to the surface of the droplets. This leads to the spontaneous accumulation of particles at the oil-water interface with subsequent stabilization against coalescence by volume exclusion and steric hindrances , i.e. thin situ since the surface coverage starch granules can be partially gelatinized creating a more impermeable layer at the droplet surface , of approximately 2 \u03bcm. The particles were also observed under SEM and it was observed that they were uni-modal but with some aggregates of granules generating the peak at 10 \u03bcm  at 50 mg starch/ml oil (For emulsions prepared with OSA-modified starch in the granular form or in solution at 7% (w/w) oil, similar droplets sizes were obtained, which decreased as the amount of starch was increased , as expeh/ml oil  but highh/ml oil . The stah/ml oil .Previously, chemically modified (OSA) potato and barely starches in solution have been used to stabilize emulsions and results showed that it was possible to generate an emulsion with OSA-starch as the sole emulsifier since as its high molar mass and branched polymer structure allowed it to be adsorbed at the interface, leading to steric stabilization of emulsions ,21. The However, huge discrepancies were observed in the stability of emulsions prepared with OSA-modified starch in the two different forms. While emulsions prepared with starch granules maintained a constant droplet size after one month, indicating high stability, emulsions formulated with dissolved starch were very unstable showing variations up to 113% in particles size between fresh and stored emulsions . BackscaAll Pickering emulsions were stable for several weeks at room temperature and neither coalescence nor Ostwald ripening was observed showing little change in appearance and emulsions layer height, according to previous results where no variations were observed even after several months ,9. An exThe highest BS values were observed in all cases at the top of the cell (from 8 to 12 mm) indicating the presence of emulsion droplets in this region. A BS decrease was observed with time at the top accompanied with a simultaneous increase at the bottom, promoted by the sedimentation of the unadsorbed granules in the continuous phase or small starch granule stabilized emulsion droplets dense enough to sink due to a large enough starch to oil ratio . This prNo transmitted light was observed along the cell at the beginning of the monitoring time. However, a TS increase was noticed in the middle of the cell (from 2 to 8 mm) while sedimentation was taking place. The thickness of this front changes being smaller for higher starch concentrations since a higher emulsion index was obtained. The % of transmitted light is inversely proportional to the amount of starch added according to the corresponding BS profiles. Larger variations in clarification fronts heights were observed at lower starch concentrations.For emulsions formulated with higher starch concentrations (200 and 400 mg starch per ml of oil) oil droplets settled at the bottom of the cells . These dLarger BS variations along the height of the cell were observed in emulsions prepared with dissolved starch. An example of the BS profiles of emulsions prepared with OSA-modified starch in the dissolved state is shown in Larger variations in the BS profiles were observed  for emulAdsorbed macromolecules which are soluble in the continuous phase give rise to steric stabilization mainly with entropic contributions but destabilization may occur if the surface coverage is insufficient. It could allow the macromolecules to form bridges between particles and the non-adsorbed macromolecules may be depleted from the vicinity of the surface and can give rise to depletion flocculation ,33,34.The BS front velocities of emulsions droplets were obtained from the slope of the phase thickness (delta H) of the clear phases, from BS profiles versus time. They were much higher for emulsions prepared with lower starch concentration, exhibiting values in the range 13 or 17\u03bcm/s for 50 or 100 mg/ml oil confirming that destabilization phenomena occurred faster. Emulsions prepared with 400 mg starch per ml oil showed the lowest migration velocity value and the smallest BS variations (16%). This was in good agreement with microscope observations. Larger droplets coalesced fast even forming a continuous thin oily film. This explains the red color observed at the top of the cells after the addition of oil soluble dye .Turbiscan stability index (TSI) was also calculated. In order to compute it, the intensity of light toward the complete cell height was compared mathematically, based on a scan-to-scan difference. It sums all the variations detected in the samples in terms of size and/or concentration and is defined by the following equation:Variations in the range 6\u201315% were observed with the lowest variations at the highest starch concentration.), and droplet size distributions, did not change after one month of storage at room temperature  oil content showed extreme stability. Mean volume diameters  small sediment appeared at the bottom caused by the unadsorbed starch granules. Similar behavior was previously reported when Pickering emulsions were prepared with several starch types at the same oil content .As it was aforementioned, from PSD results, emulsions stabilized with OSA-modified starch in the dissolved state showed high instability as observed in A slight creaming was noticed at the top of the cell, Emulsions with 7% (w/w) oil content  were preEmulsions formulated using a combination of OSA-modified starch granules and OSA starch dissolved (mixtures) were unstable and coalescence was clearly observed under the microscope  and oil Microscope images shown in. Sedimentation of unadsorbed granules was observed at the bottom of BS profiles, while a clarification process was observed in the middle of the cell of the TS profiles (results not shown).Finally, a set of experiments was performed to prepare emulsions stabilized by native starch, both in the granular form and in solution, and also by combining OSA-modified starch granules with native starch dissolved simultaneously.Emulsions stabilized by native starch granules lead to larger sizes compared to emulsions stabilized by the OSA-modified starch granules, being in the range 30\u201382 \u03bcm  accordinThe opposite effect was obtained with the native starch dissolved leading to lower mean droplet sizes in the range 14\u201378 \u03bcm. Similar sizes were obtained when emulsions were stabilized by mixtures of OSA-modified starch granules and native starch dissolved. Micrographs also revealed the presence of granules in the continuous phase which means that the native starch in the dissolved state was surprisingly more surface active than the OSA-modified granules. However, the stability of these of emulsions was rather poor, coalescence took place quickly and presence of free oil at the top of the samples was readily observed . values after one month storage. These differences between the two types of starches were also reflected in emulsions stabilized by granules, according to previous results  values after one month under storage, up to 26%.Moreover, emulsions stabilized by native starch in solution showed larger variations in stability  and size (\u0394d) were obtained with Turbiscan Lab , compare results . Emulsio20. Results indicated that there was an influence of both of kinetic factors during emulsion formation and the physical-chemical properties of the hydrophobically modified starch, such as the degree of substitution, the molar mass, and radius. It was reported that adsorption of larger molecules was favored by mass transport to the interface in turbulent flow fields and also that these larger molecules will have higher substituent density and adsorption energy than smaller ones [The adsorption at emulsions droplets of OSA-modified potato and barely starches was studied by other authorsler ones . Taking Results revealed that it is possible to create an emulsion with OSA-modified starch isolated from Quinoa as the sole emulsifier.Similar droplet sizes were obtained when emulsions were prepared at 7% (w/w) oil content and stabilized using OSA-modified starch in the granular form or on the dissolved state but large differences were observed regarding their stability. Pickering emulsions kept their droplet size constant and were stable against coalescence and other destabilization processes, while emulsions formulated with OSA-modified starch in solution exhibited high instability shown as a clear coalescence process in Turbiscan Lab. Higher emulsions index were obtained at higher oil content for both types of emulsions.Emulsions stabilized by a combination of OSA-modified starch in granular form and in solution with a 7% (w/w) oil content had larger mean droplet sizes and no significant differences were obtained with respect to the order of addition. All emulsions containing mixtures of granules and dissolved starch were unstable due to coalescence and the presence of free oil was clearly observed in all cases. The same trend was also observed when emulsions were prepared by combining OSA-modified granules with native starch in solution.The degree of surface coverage of starch granules was much lower in presence of starch in solution. This is an indication that OSA-starch is more surface active in the dissolved state than in granular form, although it led to unstable systems compared to starch granule stabilized Pickering emulsions, which were found to be extremely stable.S1 FigA) Mixtures of OSA-modified starch in the form of granules and on the dissolved state added at the same time. B) Added first in the form of granules. C) Added first on the dissolved state. D) Mixtures of OSA-modified granules and native starch on the dissolved state added at the same time. Note: Oil red EGN was added to visualize the eventual presence of free oil.(TIF)Click here for additional data file."}
+{"text": "Chronic recurrent multifocal osteomyelitis (CRMO) is a non \u2013 infectious inflammatory bone disorder of yet to be determined etiopatology. However, it is considered that the imbalance between pro- and anti- inflammatory cytokines plays the main role in the disease expression. CRMO represents the most severe form of chronic nonbacterial osteomyelitis and predominantly affects children and adolescents, primary girls. The clinical presentation is variable onset of bone pain with or without fever, local soft tissue swelling or warmth with an unpredictable clinical course and spontaneous remissions. Methaphyses of long bones are the most specific affected sites. CRMO is a diagnosis of exclusion because of its clinical presentation and laboratory findings that are not disease-specific and vary between patients.Here we present two cases of CRMO, first in 9-year-old girl localized in left clavicle and the second one in a 5-year-old girl with oligo-focal form. In both cases onset of the disease was characterized with bone pain and local soft tissue swelling without fever. Laboratory findings included elevated inflammatory markers (C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), leucocytes count). Radiographs, bone scan and MRI in both girls showed specific signs indicating osteomyelitis . A needle biopsy was performed and the pathohistological findings indicated osteomyelitis. Microbiological findings were negative. Both patients were initially treated by antibiotic. During the first week of antibiotic therapy older girl was developed DRESS \u2013 drug rash with eosinophilia and systemic symptoms. The recurrence of the symptoms, multifocality, lack of evidence of causative factor and imaging characteristics of the bone lesions led us to CRMO diagnosis. In both girls we applied treatment with NSAID and corticosteroids (prednisone 1 mg/kg for two weeks with subsequent reducing of dosage for four weeks). In the same time both patients were subjected to hyperbaric oxygen therapy.In the same time both patients were subjected to hyperbaric oxygen therapy. After six months clinical remission was achieved in the both children but with residual bone impairments on MRI scans.After six months clinical remission was achieved in the both children but with residual bone impairments on MRI scans.Since CRMO is self limited and benign disease the question is whether oxygen barotherapy truly helps or is it natural course of the disease. According to the literature data residual bone impairments are expected, which suggest an up to 50% rate of residual impairments.Thus, the development of effective treatment algorithm and enlightened of pathofisiology of CRMO will be essential in the future.None declared."}
+{"text": "Screening asymptomatic individuals remains the subject of intense debate in medicine. In the beginning of 2014 the use of screening for breast cancer in women was seriously questioned based on studies from Canada (Toronto) and the Netherlands (Leiden). It was shown that, particularly in women over 70\u00a0years, screening for breast cancer might even bring more harm than benefit in terms of over diagnosis and thus overtreatment. With respect to carotid artery disease, in September of this year the United States Preventive Services Task Force (USPSTF) published a recommendation to oppose the screening of the general adult population to detect asymptomatic carotid artery stenosis [How about screening individuals with asymptomatic coronary artery disease? In a review article from the Netherlands (Rotterdam) a systematic review of guidelines on imaging of asymptomatic coronary artery disease showed the light in 2011 [evidence and/or general agreement that the procedure is not useful/effective and in some cases may be harmful\u2019. The inherent guideline recommendations were twofold: 1) coronary calcium detection by CT is not recommended to identify individuals with coronary artery disease, and 2) coronary CT angiography is not recommended as a screening test in asymptomatic individuals without clinical suspicion of coronary artery disease.Over the past years cardiac computed tomography (CT) has emerged as a screening tool - in addition to the proven use of major risk factors - to detect coronary artery disease in an early stage of its process \u20137. Both Apart from the lack of usefulness of applying CT in asymptomatic individuals one should always be aware of the risk of radiation exposure using ionising imaging modalities to detect patients with coronary artery disease. To that purpose, the American Heart Association (AHA) very recently issued a scientific statement on cardiac imaging, published online on 29 September 2014 in the journal Circulation [To conclude, although screening for coronary artery disease -especially using advanced ionising cardiac imaging techniques  - may be"}
+{"text": "A 52 year old female presented for two weeks of acute onset dyspnea onexertion. She was found to be hypoxic with a room air saturation of88%. Baseline echocardiogram was normal with the exception ofaortic root dilation. Right and left heart catheterizations wereperformed. The coronary arteries were normal in original and withoutdisease. The right heart catheterization demonstrated normal pulmonarypressures and \u201cno evidence of intra-cardiac shunt\u201d. Repeatechocardiogram was performed with agitated saline contrast andrevealed a small amount of right to left shunting across theintra-atrial septum with cough while supine and significant right toleft shunting while upright; these findings were consistent with thepresence of a patent foramen ovale (PFO) and platypnea-orthodeoxiasyndrome. The patient underwent percutaneous closure of her PFO withan Amplatzer device, and exhibited rapid resolution of her symptomsand hypoxia. She is off oxygen and has returned to work as a nursepractitioner. The case highlights the importance of clinical vigilanceand consideration of this syndrome in the differential diagnosis ofunexplained hypoxia. Our patient had a dramatic and positive outcome:complete alleviation of dyspnea and oxygen dependence after PFOclosure. A 52-year-old female presented for two weeks of acute onset dyspnea on exertion. She was found to be hypoxic with a supine room air saturation of 88%. She underwent extensive evaluation by numerous specialists throughout Texas without a diagnosis. Routine chemistry, coagulation panel, and CBC were unremarkable. A D-dimer was negative and BNP was 20. Chest X-ray was unremarkable aside from hiatal hernia. ECG was sinus rhythm with nonspecific ST changes. Patient underwent CT of the chest which was negative for pulmonary embolism but showed dilation of the ascending aorta to 4.6\u2009cm. Baseline echocardiogram was normal with the exception of aortic root dilation. Right and left heart catheterizations were performed. The coronary arteries were normal in original and without disease. The right heart catheterization demonstrated normal pulmonary pressures without step up in oxygen saturation suggestive of intracardiac shunt. Given persistence of symptoms, limited exercise tolerance, and need for supplemental oxygen, the patient was referred for a second opinion. Repeat echocardiogram was performed with agitated saline contrast and revealed a small amount of right to left shunting across the intra-atrial septum with cough while supine and significant right to left shunting while upright; these findings were consistent with the presence of a patent foramen ovale (PFO) and platypnea-orthodeoxia syndrome. The patient underwent percutaneous closure of her patent foramen ovale with an Amplatzer device and exhibited rapid resolution of her symptoms and hypoxia. She is off oxygen and has returned to work as a nurse practitioner.Platypnea-orthodeoxia syndrome is an uncommon disorder characterized by dyspnea and arterial desaturation in the upright position with improvement in the supine position. The development of this syndrome requires two components: a shunt  and a functional component that promotes abnormal shunting when the patient moves from a supine to an upright position.Platypnea-orthodeoxia syndrome is likely an under-recognized cause for dyspnea and positional hypoxia. Our patient had both required features for the syndrome, intra-atrial shunt and a functional component that promotes shunting. She had a patent foramen ovale as well as aortic root dilation. Dilation of the aortic root typically causes the intra-atrial septum to become more horizontal. This horizontal intra-atrial septum aligned the patent foramen ovale with inferior vena caval inflow, the \u201cperfect storm\u201d to provoke shunting while upright. In an autopsy study of 965 subjects, probe-patent PFO was present in 27 percent of subjects with equal distribution among gender. The size of the PFO was 1 to 10\u2009mm in diameter in 98% of the autopsied hearts . HoweverThe platypnea-orthodeoxia syndrome is a rare condition with paradoxical dyspnea (platypnea) and arterial desaturation when patient is upright and resolution of symptoms with improvement in saturation when patient is supine (orthodeoxia) . The mecThere are several case reports in the literature of platypnea-orthodeoxia syndrome in the setting of patent foramen ovale and aortic root dilation. The case highlights the importance of clinical vigilance and consideration of this syndrome in the differential diagnosis of unexplained hypoxia. Our patient had a dramatic and positive outcome: complete alleviation of dyspnea and oxygen dependence after PFO closure.The opinions or assertions contained herein are the private views of the authors and are not to be construed as reflecting the views of the Department of the Army or the Department of Defense."}
+{"text": "Experiments have demonstrated that cortical and sensory neurons prefer to response to signals with characteristics of long-term correlation or 1/f noise feature better than signals with no correlation like white-noise-type  based onTo further reveal the key factors dominating the preference of neuronal dynamics to colored and white noise, we systematically varied the values of Na+ and K+ channel time constants and channel rate constants. Figure In sum, this study demonstrated that ionic channel time constant of sodium inactivation and potassium activation may be the dominating factors accounting for the neuronal spiking sensitivity favorable to signals with temporal correlations."}
+{"text": "Ubiquitin and the ubiquitin-like modifier SUMO are intimately connected with the cellular response to various types of DNA damage. A striking feature is the local accumulation of these proteinaceous post-translational modifications in the direct vicinity to DNA double-strand breaks, which plays a critical role in the formation of ionizing radiation-induced foci. The functional significance of these modifications is the coordinated recruitment and removal of proteins involved in DNA damage signaling and repair in a timely manner. The central orchestrators of these processes are the ubiquitin and SUMO ligases that are responsible for accurately tagging a broad array of chromatin and chromatin-associated proteins thereby changing their behavior or destination. Despite many differences in the mode of action of these enzymes, they share some striking features that are of direct relevance for their function in the DNA damage response. In this review, we outline the molecular mechanisms that are responsible for the recruitment of ubiquitin and SUMO ligases and discuss the importance of chromatin proximity in this process. The cellular response to compromised genome integrity is a vital process that is tightly regulated by a number of post-translational modifications (PTMs) that dictate the course of action at the sites of DNA damage. While ensuring that proper action will be taken to eliminate the threat, these regulatory circuits at the same time avoid unnecessary and potentially hazardous activation of DNA repair pathways. In this review, we will focus on ubiquitin and the small ubiquitin-like modifiers (SUMO)-1, -2, and -3, which are central players in this process, where they in tight conjunction with other PTMs \u2013 most notably phosphor-modifications but also another ubiquitin-like protein modifier Nedd8 \u2013 activate signaling cascades and coordinate mobilization of the proper DNA repair machinery . Rather Modification of chromatin and chromatin-associated proteins by these PTMs in response to DNA double-strand breaks (DSBs) results in the formation of the characteristic ionizing radiation-induced foci (IRIF) that mark the sites of DNA damage . In contFigure 1).An important mechanistic difference between the DSB-induced phosphorylation and ubiquitin/SUMO response at IRIF lies in the way their activity is regulated. While the activity of ATM is kept dormant in undamaged cells only to be unleashed upon the detection of DSBs , most ofFigure 2). RNF8 and RNF168 are two RING ubiquitin ligases that play an important role in the DSB-induced ubiquitylation response and act downstream of the ATM-dependent phosphorylation triggered by DNA damage  triggers the accrual of ubiquitin and SUMO ligases . Two ubiquitin ligases, UBR5 and TRIP12, target RNF168 for proteasomal degradation and depletion of these ligases results in supraphysiological steady-state levels of RNF168 giving rise to superfluous activation of the ubiquitylation response at DSBs . Also activation of the DNA damage response by herpes simplex virus type 1 is prevented by the viral ubiquitin ligase ICP0 targeting RNF8 and RNF168 . RNF146 selectively interacts with PARylated proteins at DSBs resulting in their ubiquitylation. Although its activity is not confined to PARylated proteins at DSBs  (PAR)-dependent ubiquitin ligase RNF146, also known as Iduna, since DNA damage-induced PARylation not only induces its translocation but also releases its ubiquitin ligase activity . For yeast Siz2 it has been shown that once recruited it SUMOylates chromatin-associated proteins at DNA damage in a rather promiscuous fashion, a process that has been referred to as group modification  that facilitates the canonical ubiquitylation of histone H2A at residue K119 , employscription .RNF4 is a SUMO-targeted ubiquitin ligase (STUbL) that selectively ubiquitylates proteins that have been modified by chains consisting of the highly related SUMO2 and SUMO3 modifiers, in particular under conditions of proteotoxic or genotoxic stress . In respAnother recruitment mechanism is employed by the ubiquitin ligase RNF138, which stimulates repair of DSBs by homologous recombination. This ubiquitin ligase contains three zinc finger (ZnF) motifs that specifically interact with ssDNA overhangs at lesions . AccordiThe generation of ssDNA is also important for the recruitment of the budding yeast SUMO ligase Siz2 to DSBs. Siz2 belongs to the family of PIAS ligases which have been found to be involved in the DNA damage response not only in yeast but also in human cells, in particular PIAS1 and PIAS4. Originally it was proposed that the conserved SAP domain in these SUMO ligases facilitates recruitment by binding to ssDNA which triggers a wave of early SUMOylation at DSBs . HoweverThe detailed insights in the recruitment mechanisms that regulate chromatin association of DNA damage ubiquitin and SUMO ligases and the important role of proximity in DNA damage-induced protein modifications stands in sharp contrast to our modest understanding of how these PTMs regulate the fate of the modified proteins. Importantly, ubiquitylation and SUMOylation have been shown to be stimulators of protein recruitment, retention and extraction, supposing opposite actions that are hard to reconcile in one mechanistic paradigm, raising questions of what determines the final biological outcome of these modifications. For example, RNF8-mediated ubiquitylation forms the docking platform for critical DNA repair proteins , while aAll authors listed, have made substantial, direct and intellectual contributions to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Pathophysiology of cluster headache (CH) is not well-known. Although posterior hypothalamus has been suggested to play a pivotal role, evidence exists of a more diffuse involvement of the central nervous system including brainstem and cerebral cortex. In this regard, we recently observed increased motor cortical excitability in episodic CH patients both outside and inside bout.The sound-induced flash illusions (SIFI) represent an example of multisensory integration, and provide a tool to indirectly explore the excitability state of the visual cortex. SIFI arSIFI were examined in ten untreated patients with episodic CH and in twelve age- and sex-matched healthy volunteers. Five out of the ten patients were evaluated both inside  and outside bout. Visual stimuli were accompanied by beeps in different combinations to evaluate both fission illusion (one flash presented with a number of beeps varying between 0 and 4) and fusion illusion (2-4 flashes accompanied by only one beep).The fission but not the fusion illusion was significantly reduced in CH patients with respect to healthy controls. No significant differences were observed between bout and outside bout phases in patients evaluated both in the ictal and interictal state.The present results provide evidence of increased visual cortical excitability in CH that is detectable not only during the bout, but also in the pain-free period. This is in agreement with previous findings by our group of increased motor cortex excitability in CH inside and outside bout.These results strengthen the notion that an abnormal cortical excitability state exists in CH. Moreover, findings in CH patients are very similar to those observed in migraine with aura patients, thus suOn such bases, we suppose that visual cortex hyperexcitability could play a pathogenic role in CH as well as in migraine with aura. This suggestion may also be supported by the rather frequent occurrence of aura symptoms in CH sufferers.Written informed consent to publication was obtained from the patient(s)."}
+{"text": "CaT) and P type calcium channels (ICaP) can cause local regenerative spikes to occur in the dendrite after receiving a parallel fiber (PF) stimulus [Due to the lack of sodium channel expression in the Purkinje cell (PC) dendrite, the passively propagated sodium spikes can hardly be detected in the dendrite. However, the substantial expression of T type calcium channels (Istimulus .+ current (IKA) [+ current (IKV3) and hyperpolarization-activated cation current (Ih). In our model, in agreement with experimental observations [CaT amplifies the EPSP caused by PF synaptic input to boost the EPSP close to the spike threshold. Around the spike threshold there is an obvious spike delay due to the interactive role of IKA and ICaT. Above the spike threshold, high threshold activated ICaP takes over and depolarizes the dendrite rapidly, finally leading to the generation of dendritic spikes. The amplitude of dendritic spikes doesn't increase further with the stimulation intensity and is mainly determined by the struggle among ICaP, IKV3 and high conductance calcium activated K+ currents (IBK). Injecting a negative current can eliminate the PF input evoked dendritic spikes by lowering the membrane potential which implies less activation of the ICaT and subsequent less amplification of the EPSP. We also find that the simulated dendritic spikes can't propagate to the whole dendrite due to the regulating role of mainly IBK and IKV3. Surprisingly by partially blocking IKV3 and IBK parallel fiber evoked dendritic spikes can propagate to the whole dendrite because of the broadening of its width.In this study, with the previously published PC dendrite model  from ournt (IKA) , high thrvations , the EPSThe calcium influx by dendritic spikes is vital to a lot of calcium dependent processes like synaptic plasticity. Understanding the mechanism of generation of the local dendritic spikes evoked by PF stimulus and how their localized nature works will help us better explore how information is processed in the PC dendrite."}
+{"text": "The dramatic increasing prevalence of autism spectrum disorders (ASDs) , togetheTaken together, these autism-associated neuroimmune changes could help in identifying novel therapeutic target for a better future management of ASDs.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Primary treatment strategies for SMA aim at boosting SMN protein levels, which are insufficient in patients. SMN is known to partner with a set of diverse proteins collectively known as GEMINs to form a macromolecular complex. The SMN-GEMINs complex is indispensible for chaperoning the assembly of small nuclear ribonucleoproteins (snRNPs), which are key for pre-mRNA splicing. Pharmaceutics that alleviate the neuromuscular phenotype by restoring the fundamental function of SMN without augmenting its levels are also crucial in the development of an effective treatment. Their use as an adjunct therapy is predicted to enhance benefit to patients. Inspired by the surprising discovery revealing a premier role for GEMINs in snRNP biogenesis together with in vivo studies documenting their requirement for the correct function of the motor system, this review speculates on whether GEMINs constitute valid targets for SMA therapeutic development.The motor neuron degenerative disease spinal muscular atrophy (SMA) remains one of the most frequently inherited causes of infant mortality. Afflicted patients loose the  Owing to a key nucleotide substitution between the two genes, exon 7 of SMN2 is often skipped, generating a truncated protein (SMN\u03947) that is unstable and rapidly degraded. SMA is thus the result of insufficient amounts of SMN protein and its levels are generally inversely correlated with the severity of the disease, hence making SMN2 copy number the predominant modifier of the neuromuscular phenotype  is a primarily early-onset disorder characterized by spinal motor neuron loss and atrophy of the proximal limb and intercostal muscles. Considering that available therapies are, at best, palliative, SMA remains one of the most frequently (~1:6000 newborns) inherited causes of infant mortality. Afflicted patients have a homozygous loss of the SMN2 gene, enhancement of SMN2 exon 7 inclusion via antisense oligonucleotides (ASOs) or replacement of mutant SMN genes with functional copies by means of gene therapy vectors. Their effectiveness is highly dependent on targeting the relevant tissues at the appropriate time during disease progression, with recent studies indicating a high requirement in the motor system early during the course of the disease , which are crucial for pre-mRNA splicing  in the 5\u2032 end of intron 7, thereby displacing factors that normally repress exon 7 inclusion  modification developed in collaboration with academia by ISIS pharmaceuticals  vectors to replace SMN and, thereby, rescue severe SMA mice has been a remarkable success story. This is in part due to the choice of scAAV-9 as a vector, considering its ability to both penetrate the brain and infect motor neurons in addition to other cell types. Furthermore, rapid transgene expression by virtue of its dimeric inverted-repeat genomic structure is a pivotal aspect of its potency. Independent groups reported that lifespan and motor ability were essentially rescued in severe SMA mice treated with scAAV9-SMN  inhibitor that has been reported to promote a dramatic phenotypic improvement in an intermediate SMA mouse model . Primarily, levels of SMN strongly dictate the capacity of cell extracts to produce snRNPs , are still unclear including the involvement in precise detail of other key members of the SMN-GEMINs complex. The withdrawal of SMN's participation as the primary architect of snRNP assembly raises questions about its exact role in this remarkable engineering feat. Considering that some have snRNP-independent functions Cauchi, , does SMBox 1\u25a0 How is the SMN-GEMINs complex assembled and what are the principal chaperones involved in this process? Although great strides were made in understanding the involvement of the SMN-GEMINs complex in snRNP assembly, little is known about how this large macromolecular machine is itself assembled. Molecular and real-time cell imaging studies will be crucial in delineating this process and identifying novel factors that provide chaperoning activities.\u25a0 Does up-regulation of Gemins confer a convincing strong suppression of the SMA phenotype in animal models? Evidence favoring modulation of the disease-associated pathways through supplementation of Gemin protein levels has been sparse, and in vivo genetic studies are essential to address this issue conclusively.\u25a0 Can genetic and small-molecule therapeutic candidates that improve snRNP assembly independent of increasing SMN levels be identified? High throughput screens are not new in the SMA field, hence technology and knowhow is already existent. The application of an SMA-associated phenotype that is directly linked to perturbation in snRNP assembly will be a fundamental issue in the design of such screens, which hold the promise of uncovering novel SMA therapeutic targets and candidates.in vivo studies (Table Drosophila as that observed for SMN (Chang et al., Gemin2 in an +/\u2212Smn background induce an enhanced motor neurodegenerative phenotype that correlates with disturbed snRNP assembly (Jablonka et al., Drosophila motor ability, hence resulting in phenotypes that mimic those uncovered on SMN deficiency (Chan et al., The highlighted molecular and structural studies provide a compelling case for the candidature of GEMINs as modifiers of SMA, presumably through suppression of defective snRNP synthesis, which is the hallmark consequence of SMN paucity. Strong support is provided by es Table . To thisRecent studies highlighting the prominent role of GEMINs in snRNP assembly, and the indispensability of this activity for the correct functioning of the motor system give a strong impetus for investigations that attempt at answering key open questions Box . ConclusThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "PLOS ONE editors that there is substantial overlap in content between this article and another article published in PLOS ONE by different authors: \"MicroRNA-302a Suppresses Tumor Cell Proliferation by Inhibiting AKT in Prostate Cancer\"  [It has been brought to the attention of the There is a substantial overlap in the text, and multiple figures appear similar or identical despite labels and legends indicating that the data were obtained from different cell and tissue types (prostate cancer cell lines and tissues in the above-mentioned article versus colon cancer cell lines and tissues in the retracted article).10.1371/journal.pone.0124410) [PLOS ONE editors have been unable to verify the integrity of the work. In light of these concerns, the PLOS ONE editors retract this article.Our follow-up in relation to how the overlap with the article by Zhang et al. (DOI:"}
+{"text": "Healthcare professionals often label patients as \u2018non-compliant\u2019 when prescribed therapies seem to fail to be effective. This is often used as a derogatory term of criticism of patient behaviour, as though patients are personally liable for their lack of response and continued ill health. Those of us who have experienced having been prescribed long-term medication, requiring multiple daily doses, will readily admit to the difficulty of complying fully with complex regimens despite the best will in the world. The article by Osamor in this issue (page 29) explores the importance of social support in the management of a chronic disease in Africa and confirms the importance of such support in ensuring compliance with prescribed medication. Given the evidence from elsewhere that familial and social support is of importance in lessening the likelihood of developing cardiovascular disease and increasing the likelihood of compliance with treatment, the results are not surprising, and are important for those teaching medicine and planning treatment programmes in Africa. Hopefully the results will stimulate further African research in this important area.Coronary artery bypass grafting (CABG) has produced excellent symptomatic relief from angina for many patients and enhanced survival in selected sub-groups. Symptomatic relief is inevitably time-limited by durability of the venous conduits. When symptoms recur due to vein graft failure and a percutaneous intervention is not feasible, patients and clinicians face a difficult dilemma, particularly if there is a patent left internal thoracic artery anastomosis to the left anterior descending coronary artery that may be jeopardised at the time of repeat median sternotomy. Such patients are inevitably older with multiple co-morbidities. Duvan and colleagues (page 25) report their experience with redo off-pump CABG via a posterolateral thoracotomy to access branches of the circumflex coronary artery. This report serves as a timely reminder of an alternative revascularisation strategy that may well be acceptable to both patients and referring cardiologists when severe symptoms persist despite optimal medical therapy.The precise relationship between obesity and coronary disease remains unclear. Zand-Parsa and colleagues (page 13) add a new level of complexity by demonstrating that obesity, as determined by waist-to-hip ratio (WHR), was correlated with severity of coronary artery disease by two independent scoring systems, whereas body mass index (BMI) was not. Clinicians will be aware of considerable ethnic variation in patterns of distribution of adipose tissue and this is not always considered in comparisons of BMI and WHR. It may, in part, account for some discrepancies, and the establishment of regional norms may be necessary.Laboratory experimental work by Burma (page 4), using pre-constricted internal mammary artery (IMA) rings in a tissue bath, showed that leptin caused relaxation of these arterial segments. These findings led the authors to raise the intriguing hypothesis that obese subjects who had a left IMA bypass graft would actually have better  myocardial perfusion compared to non-obese subjects. The risks and benefits of obesity in patients with coronary disease are far from settled!"}
+{"text": "Humans are unique both in their cognitive abilities and in the extent of cooperation in large groups of unrelated individuals. How our species evolved high intelligence in spite of various costs of having a large brain is perplexing. Equally puzzling is how our ancestors managed to overcome the collective action problem and evolve strong innate preferences for cooperative behaviour. Here, I theoretically study the evolution of social-cognitive competencies as driven by selection emerging from the need to produce public goods in games against nature or in direct competition with other groups. I use collaborative ability in collective actions as a proxy for social-cognitive competencies. My results suggest that collaborative ability is more likely to evolve first by between-group conflicts and then later be utilized and improved in games against nature. If collaborative abilities remain low, the species is predicted to become genetically dimorphic with a small proportion of individuals contributing to public goods and the rest free-riding. Evolution of collaborative ability creates conditions for the subsequent evolution of collaborative communication and cultural learning. The initial value of collaborative ability were chosen randomly and independently from a uniform distribution on . To avoid the appearance of negative fitness values in numerical simulations, I introduced upper boundary on individual efforts xmax = (1 + b)/c. I used zero lower boundary on x. Electronic supplementary material, figures S1\u2013S5 summarize the results.In numerical studies of the basic model, I used all possible combinations of the following parameter values: expected benefit per individual"}
+{"text": "Mutations in hemojuvelin (HJV) are the most common cause of the juvenile-onset form of the iron overload disorder hereditary hemochromatosis. The discovery that HJV functions as a co-receptor for the bone morphogenetic protein (BMP) family of signaling molecules helped to identify this signaling pathway as a central regulator of the key iron hormone hepcidin in the control of systemic iron homeostasis. This review highlights recent work uncovering the mechanism of action of HJV and the BMP-SMAD signaling pathway in regulating hepcidin expression in the liver, as well as additional studies investigating possible extra-hepatic functions of HJV. This review also explores the interaction between HJV, the BMP-SMAD signaling pathway and other regulators of hepcidin expression in systemic iron balance. Juvenile Hemochromatosis (JH) is an autosomal recessive disorder caused by a failure to prevent excess iron entry into the bloodstream, and characterized by progressive tissue iron overload  or, more commonly, hemojuvelin  -linked membrane protein that is a member of the repulsive guidance molecule (RGM) family  signaling pathway  superfamily of ligands  on the hepcidin promoter  protein is detectable in human and rodent serum.  of endogenously produced sHJV HJV mRNA is also highly expressed in skeletal muscle and heart , that can act as feedback inhibitors of BMP-SMAD signaling and hepcidin expression   family member neogenin is also proposed to function as an HJV interacting protein that modifies BMP-SMAD signaling and iron homeostasis Figure . In partHepcidin suppression by erythropoietic drive appears to be mediated by secreted factor(s) released by proliferating red blood cell precursors in the bone marrow , epidermal growth factor (EGF), endoplasmic reticulum stress, gluconeogenic signals and the Ras/RAF and mTOR signaling pathways (Oliveira et al., Understanding the genetic basis for JH has yielded important insights into the molecular mechanisms of systemic iron homeostasis. Hepcidin and its receptor ferroportin are key regulators of body iron balance, and the BMP-SMAD pathway via the co-receptor HJV is a central regulator of hepcidin production Figure . KnowledJodie L. Babitt has ownership interest in a start-up company FerruMax Pharmaceuticals, which has licensed technology from the Massachusetts General Hospital based on the work cited here and in prior publications. All other authors declare the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "We report the performance assessment results of the proposed algorithm on real ABP signals from spontaneously breathing subjects.We describe the first automatic algorithm designed to estimate the pulse pressure variation (Our assessment results indicate good agreement between the automatically estimated The proposed automatic algorithm is able to give reliable estimations of  Excessive blood loss due to severe medical conditions can result in insufficient tissue perfusion, which can lead to organ failure. Clinicians need to plan the course of fluid therapy carefully in order to maintain tissue perfusion \u20133. HowevDynamic variables such as stroke volume variation   availabl (MGHDB) . It shou (MGHDB)  introducThe subsequent sections explain a novel statistical signal model for ABP signals recorded from spontaneously breathing subjects and the n represents the discrete time index and (i) denotes the We have adopted the notation used in  with minprocess model, . The MAM-PF is a hybrid version of the marginalized particle filter (MPF) and maximum a-posteriori particle filter (MAP-PF), which leverages the advantages of the MPF and MAP-PF. In  in  could beshown in , which fThe proposed algorithm is the first automatic method described in the literature especially designed to estimate and track the lgorithm  which onlgorithm . PreviouA limitation of our previously described algorithm adopted by Philips in their Intelliveu MP70 monitors is that it may not work adequately in regions of abrupt hemodynamic changes  and it iThe major algorithm design difference of the proposed algorithm with respect to previously published algorithms , 22 is tFigures The algorithm\u2019s assessment was based on only 11 subjects with pre-recorded ABP data. Additionally, for each subject five lgorithm .We have described the first automatic"}
+{"text": "Advances in plant science research will lie at the center of efforts to address global food security as demand for agricultural production is predicted to more than double by 2050. A key determinant of plant productivity and thus crop yield is efficient nutrient transport between sites of net nutrient synthesis and acquisition to sites of net utilization. Transfer cells (TCs) play key roles in optimizing such nutrient transport processes in plants, and thus research on these anatomically specialized cell types has the potential to contribute new approaches for improving plant performance. The collection of reviews and research articles in this Research Topic on Transfer Cells provides a valuable contribution to advancing our understanding of these important cell types in plant biology.trans-differentiate from existing cell types by developing extensive wall ingrowths. The resulting increase in plasma membrane surface area enables increased densities of membrane transporters to optimize nutrient transport across apoplasmic/symplasmic boundaries at sites where TCs form. Key challenges in TC biology include understanding the signals and genetic pathways required for initiating and building the unique wall ingrowths that define TC identity. This knowledge in turn will provide a basis to investigate physiological and genetic factors explaining the variability observed in TC differentiation, even among equivalent anatomical situations in highly related species.TCs BETL9 and BETL9like, two lipid transfer genes similar to END-1 expressed specifically in barley endosperm TCs. While the functions of these genes remain unknown, BETL9 is expressed exclusively in the basal endosperm transfer layer (BETL), but protein product accumulates in maternal tissue adjacent to this layer. In contrast, BETL9like is expressed specifically in the endosperm aleurone layer. The expression domains of these genes completely surround the filial tissues, suggesting a protective role at the maternal-filial interface. The miniature1 (mn1) mutant in maize is defective in a BETL-specific cell wall invertase (INCW2), resulting in reduced hexose levels and wall ingrowth development in this tissue. Silva-Sanchez et al.  and GSL11 were induced specifically at low temperature in vte2, only disruption of GSL5 substantially reduced this phloem parenchyma TC-specific production of callose, but had no effect on the low temperature photoassimilate export phenotype of vte2. Adams et al. (Senecio) and companion TCs (pea and Senecio), consistent with the role of these TCs in supporting photoassimilate export from leaves. In contrast, responses to stress such as application of methyl jasmonate caused increased wall ingrowth deposition in phloem parenchyma TCs alone, indicating cell specific responses of TCs to different signals and possibly different roles for these TCs .Arabidopsis provides a powerful genetic system to study TC biology (Arun Chinnappa et al., s et al.  report aCollectively, the insights into TCs provided in the reviews and research articles assembled for this Research Topic establish a valuable platform for continued investigation of these fascinating cell types in plants. Further research on TCs may unlock key possibilities for improving crop yield and thus contribute to the rapidly approaching challenge of addressing global food security.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "This report describes a patient presenting with a narrow complex tachycardia in the context of prior myocardial infarction and impaired ventricular function. Electrophysiological studies confirmed ventricular tachycardia and activation and entrainment mapping demonstrated a critical isthmus within an area of scar involving the His-Purkinje system accounting for the narrow QRS morphology. This very rare case shares some similarities with upper septal ventricular tachycardia seen in patients with structurally normal hearts, but to our knowledge has not been seen previously in patients with ischemic heart disease. Introduction Monomorphic ventricular tachycardia (VT) is commonly seen in patients with prior myocardial infarction and impaired left ventricular systolic function. In most cases of ischemic VT the QRS morphology during tachycardia is broad, as ventricular activation emerges from a critical isthmus of slow conduction and spreads away from the exit site passively without involvement of the specialized conduction tissue of the His-Purkinje system (HPS) . In a miA 62 year old man, with a history of remote inferior wall myocardial infarction, coronary artery bypass surgery and a dual chamber implantable cardioverter defibrillator (ICD) presented with multiple shocks related to recurrent ventricular tachycardia with a cycle length (CL) of 340 ms despite anti-arrhythmic drug therapy with sotalol. Coronary angiography revealed a chronic total occlusion of the right coronary artery, with moderate atheroma in the left coronary artery. An electrophysiology study was performed using the VelocityTM 3D mapping system , a hexapolar catheter at the bundle of His, a decapolar catheter at the right ventricular apex and a roving irrigated-tip mapping catheter . A 12-lead electrocardiogram (ECG) in sinus rhythm showed Q waves in V1-3, a QRS duration of 102ms and T wave inversion in the inferolateral leads .Baseline sinus intervals revealed an atrio-His (AH) and His-ventricular (HV) intervals of 132 and 45ms respectively . Anterograde testing demonstrated smooth, decremental atrioventricular nodal conduction with no jump in the AH interval. Retrograde testing demonstrated decremental midline VA conduction. A narrow complex tachycardia (CL 340ms) was induced easily (and reproducibly) with programmed stimulation with a single extrastimulus from the right ventricle, with a QRS morphology which was very similar, but not identical, to the QRS morphology during sinus rhythm and a normal axis . During His-synchronous ventricular premature beats did not advance the subsequent His signal, it was not possible to entrain the tachycardia from the atria, and the tachycardia cycle length did not increase with the development of catheter induced right bundle branch block. Activation mapping localized the earliest ventricular signal to the base of the left ventricle approximately 2 cm below the His catheter within the border zone of a large area of scar on the inferior left ventricular wall . A mid-dRadiofrequency energy was delivered at this site with termination of the tachycardia after 16 seconds. No Purkinje potential was recorded at this site either during tachycardia or during sinus rhythm. The tachycardia was non-inducible with programmed stimulation subsequently. The patient made an uneventful recovery and remains well 6 months later with no recurrence of ventricular tachycardia.We have described a patient with ischemic heart disease presenting with VT with a narrow QRS morphology in whom the successful ablation target at the posterior basal septum revealed a low amplitude, mid-diastolic signal and no Purkinje potential. The QRS morphology during tachycardia was almost identical to that seen during sinus rhythm except for a subtle change in the polarity of limb lead I and V4. This suggests that the majority of ventricular activation occurred via the His-Purkinje system with a small degree of fusion accounting for the subtle differences between tachycardia and sinus rhythm. In fact subtle alternans in the cycle length was noted occasionally during tachycardia and was associated with beat to beat variation in the presence of the small S wave in limb lead I .Ventricular tachycardia with a relatively narrow QRS morphology is well recognized in patients with idiopathic fascicular VT of which there are three main types: (1) left posterior fascicular VT with RBBB and superior axis, (2) left anterior fascicular VT with RBBB and inferior axis and 3) the very rare upper septal VT with a normal QRS morphology and normal axis  the very. FirstlyIn patients with structural heart disease involvement of the His-Purkinje system during ventricular tachycardia is uncommon, but well recognized . Lopera Hayashi et al. described 4 patients with prior myocardial infarction in whom VT involving the His-Purkinje system was observed . In all Sakamoto et al. described a patient with previous inferior myocardial infarction in whom a relatively narrow complex tachycardia (QRSd 120ms) was induced which was similar but not identical to the QRS morphology in sinus rhythm . In thisThe clinical significance of this case is that VT with HPS involvement  should occasionally be considered in the differential diagnosis of a narrow complex tachycardia. In our patient VA dissociation was observed facilitating the recognition of VT, although 1:1 VA association would certainly be possible if retrograde VA conduction were sufficiently rapid. The differential diagnosis of a narrow complex tachycardia with VA dissociation includes junctional tachycardia with retrograde block, AV nodal reentry tachycardia (AVNRT) with upper common pathway block, orthodromic AV reentry tachycardia (AVRT) associated with a nodofascicular accessory pathway as the retrograde limb of the circuit and upper septal fascicular VT. Differential pacing during tachycardia and the location of the successful ablation site excluded all of the above possibilities however, leaving VT with HPS involvement as the best explanation for our findings.We cannot be certain of the precise mechanism of this tachycardia, however reentry is likely given that the tachycardia was easily and reproducibly initiated with programmed stimulation from the ventricle, the tachycardia could be reproducibly entrained, and there was a mid-diastolic signal at the successful ablation site suggesting a critical isthmus involving, or close to, the HPS in the region of the posterior basal LV septum. Activation mapping identified a localized focal area of earliest activation suggesting that micro-reentry was the likely mechanism. We assume that the narrow QRS morphology and nearly identical morphology to sinus rhythm is due to the involvement of the proximal HPS with balanced anterograde activation of all the main branches of the HPS. The proposed mechanism of this tachycardia is shown in In summary we have described a patient with scar-related ischemic VT with a narrow QRS morphology with a mechanism different to that normally seen in this context. The presence of a mid-diastolic potential and the absence of a pre-systolic Purkinje potential is unusual and the nearly identical QRS morphology to sinus rhythm is very unusual for VT and might lead to an erroneous diagnosis of supraventricular tachycardia unless alert to the possibility of this rare form of scar-related VT."}
+{"text": "Two invasive tests are mainly used to select patients affected by NPH for surgery: measuring resistance to CSF outflow and Tap Test. Cerebral blood flow (CBF) have been demonstrated to be reduced in iNPH patients, mainly in basal ganglia (BG) and periventricular white matter (PVWM) regions. Perfusion MRI might be of value as a diagnostic and predictive tool. The rule of diffusion MRI in determining brain damage in PVWM and BG areas have been investigated. The aim of this study is to identify relationship between cerebral perfusion and microstructural damage of brain tissue measured by perfusion and diffusion MRI in PVWM and BG areas before and after tap-test and after sugery in patients who underwent VP shunt.23 patients were included in this study. MRI related rCBF and apparent diffusion coefficient (ADC) were calculated in all the cases. Regions of interest were located in PVWM and BG areas. Each patient underwent lumbar infusion test and tap test. After these tests were performed, patients have been clinically evaluated and another MRI was performed with the same protocol. Patients have been then divided into two groups: the first cohort that improved after Tap test, and the second one that did not. Only the first group underwent surgery and were clinically and radiological assessed again a month after VP shunt implantation. A descriptive statistical study was performed using non parametrical tests.All the 13 patients surgically treated presented a clinical improvement after surgery; an significative increase in rCBF in both periventricular and basal ganglia regions after tap-test and surgery; a decrease in ADC values in periventricular region and an increase in ADC values in basal ganglia regions. The 10 negative patients shown a reduction in rCBF in both PVWM and BG after tap-test; a decrease in ADC values in PVWM and an increasing in ADC values in BG region.Since trend of rCBF acquired by perfusion MRI agreed with invasive tests results it could be considered a predictive and effective method in the management of patients with probable iNPH. Authors hypothesized decrease in ADC value in PVWM region as a reduction of transependimal edema; and increase in ADC value in basal ganglia area as a reduction in chronic cytotoxic edema due to chronic blood flow impairment."}
+{"text": "It is al., 2015). Computal., 2015). P-glycoprotein (Pgp) is a good example of clinical relevant drug transporter  cancer . The liAntimicrobial resistance is another global issue with prime concern. Efflux pump is noted to be one of the factors contributing to drug resistance of microorganisms . SimilaIt should not be overlooked that Pgp plays important roles in ADMET profiles of the administered drugs. Thus, drug-drug interaction, adverse effects and toxicities are the issues that should be concerned when many drugs are co-administered  is found in non-responsive refractory epilepsy patients and is noted to be a contributing factor of resistance against anti-epileptic drugs  and placenta protective mechanism. Amyloid-\u03b2 is a pathologic protein of AD and its accumulation leads to neuronal damages . Pgp efIn summary, Pgp is a drug transporter of clinical importance in which many aspects of this transporter and its interacting ligands are need to be fully elucidated. Clinical relevance of Pgp and therapeutic applications of its interacting ligands render the study regarding this transporter an active research area with continual interest. The study relating to Pgp expression also could be of great benefit for understanding the unsolved problems. In clinical aspect, adjustment of dosing regimen and careful drug monitoring also take part in an effective treatment along with a maximum safety.This project is supported by the Office of the Higher Education Commission, Mahidol University under the National Research Universities Initiative and Annual Government Grant under Mahidol University (2556-2558 B.E.).The authors declare they have no conflict of interest."}
+{"text": "Erratum:The original version of this article unfortunately contained a mistake in the section entitled \u201cRevision surgery\u201d. The corrected text is given below:Corrected text:(Page 5: Results - Revision surgery)Revision surgery of either hip after the second THA surgery was slightly more common in simultaneously operated patients compared to the patients operated with a staged procedure .The unadjusted risk of revision for the simultaneously operated patients compared to the patients operated with staged procedure was  . When adjusting for sex, age, diagnosis and type of prosthesis fixation this difference in the risk estimates disappeared ."}
+{"text": "The mammalian genome encodes three Aurora kinase protein family members: A, B, and C. While Aurora kinase A (AURKA) and B (AURKB) are found in cells throughout the body, significant protein levels of Aurora kinase C (AURKC) are limited to cells that undergo meiosis (sperm and oocyte). Despite its discovery nearly 20 years ago, we know little about the function of AURKC compared to that of the other 2 Aurora kinases. This lack of understanding can be attributed to the high sequence homology between AURKB and AURKC preventing the use of standard approaches to understand non-overlapping and meiosis I (MI)-specific functions of the two kinases. Recent evidence has revealed distinct functions of AURKC in meiosis and may aid in our understanding of why chromosome segregation during MI often goes awry in oocytes. Many cancers aberrantly express AURKC, but because we do not fully understand AURKC function in its normal cellular context, it is difficult to predict the biological significance of this expression on the disease. Here, we consolidate and update what is known about AURKC signaling in meiotic cells to better understand why it has oncogenic potential. AURKC and reported high transcript levels in testes and oocytes  and AURKB  in the kinase domain  having the highest levels   Figure . The mut) Figure . A subse) Figure , occurs ) Figure  suggesti) Figure  or c.436) Figure  producedn = 2) of the study limits the impact of this finding  , which disrupts the function of both AURKs, is BUB1 localization altered and SAC non-functional , cytokinesis and correction of K-MT attachments. AURKC specific inhibition (AURKC-LA) does not alter the localization of SAC component BUB1 in oocytes suggesting that both AURKB and AURKC regulate SAC activation in meiosis  (Gabillard et al., in vitro (Baldini et al., in vitro and inhibits tumor growth in vivo (Payton et al., More than 70 clinical trials have been conducted on Aurora kinase inhibitors. First generation inhibitors failed due to low efficacy and high toxicity (Goldenson and Crispino, Many advances have been made regarding our knowledge of AURKC as a regulator of chromosome segregation, but many questions remain. Does AURKC have unique, MI-specific substrates and do they differ between sperm and oocyte? What cofactors are needed for full AURKC activation? Does AURKC function outside of the CPC? Does AURKC drive meiotic events when expressed in mitotic cells giving rise to tumors? Not until we have a complete understanding of the function and substrates of AURKC in meiotic cells can we begin to understand the significance of its expression in cancer cells. However, once these and other meiomitotic protein studies are complete, this class of proteins represent a promising diagnostic and therapeutic cancer target.SQ was supported by an NIH grant K12-GM093854. This work is supported by a NIH grants R01-GM112801 and P30 CA072720 to KS.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Diagnostic studies using dynamic contrast enhanced (DCE) MRI perfusion imaging typically evaluate perfusion in terms of the myocardial perfusion reserve (MPR), which is the ratio of stress to rest myocardial blood flow (MBF) measurements. The aim of this study was to establish whether or not, in the case of absolute MBF quantitation, the MPR exhibits a diagnostic advantage over the stress MBF measurements alone.This was a retrospective sub-study using data from the CE-MARC trial . The CE-MARC trial collected quantitative X-ray angiography data and Single Photon Computed Tomography (SPECT) imaging data as well as DCE-MRI cardiac perfusion data from 752 randomised patients. This allowed a unique gold-standard assessment for the diagnosis of myocardial ischaemia to be generated for this study; being the consensus diagnosis of anatomical (X-ray angiography) and functional (SPECT) imaging. Fifty patients were selected such that the distribution of risk factors and disease status within the sample was representative of the full CE-MARC cohort. Quantitative myocardial blood flow estimates were obtained using four commonly used perfusion models in order to ascertain whether the results were consistent across analysis methodologies. These models were: Fermi-constrained deconvolution, model independent deconvolution, the uptake model and the one compartment model. The three cardiac slices from the MRI data sets were subdivided into 16 segments according to the American Heart Association (AHA) recommendations for perfusion imaging. Rest and stress MBF estimates were established for each of these segments and the MPR was calculated. Using the minimum perfusion score Receiver Operator Characteristic (ROC) curves were then generated using MPR and stress MBF as the diagnostic measure. A DeLong, DeLong, Clarke-Pearson comparison was used to test for statistically significant differences in the Area Under the Curve (AUC) values between the MPR and stress MBF ROC curves.There was no significant difference in diagnostic performance between stress MBF and MPR with any of the four models Figure . The areOur results demonstrate that stress MBF measurements perform as well as MPR in diagnosing myocardial ischaemia. This implies that the rest MBF measurement does not add any significant information to the diagnosis and could potentially be removed from the investigation protocol without any reduction in diagnostic performance.This work was funded by an NIHR doctoral training fellowship."}
+{"text": "Management in patients with coexisting coronary artery disease and lung carcinoma is usually a two-stage operation, with the cardiac surgery procedure followed by pulmonary resection at a later time. Delayed tumor resection on the other hand may be detrimental. Off-pump coronary artery bypass grafting could facilitate concomitant lung resection at one stage via median sternotomy. T-bar retractor may be a useful tool in the surgical approach of this combined operation. Traditionally, management in patients with coexisting coronary artery disease (CAD) and lung carcinoma is a two-stage operation, with the cardiac surgery procedure followed by pulmonary resection at a later time. This is because the systemic heparinization and coagulation disorders make the lung resection operation more difficult.Delayed tumor resection on the other hand may increase the possibility of metastasis; the immunosuppressive effects of CBP may increase the tumor growth and dissemination. With the development of coronary artery surgery, especially off-pump coronary artery bypass grafting (OPCABG), many surgeons prefer to perform cardiac surgery and pulmonary resection simultaneously. Avoidance of extracorporeal circulation may decrease the incidence of postoperative complications and saves the patient from a second procedure, which includes another general anesthetic and incision , 2.\u03b2 blockade, LAD was opened and LIMA was anastomosed to it. At this point we used again the \u03a4-bar for retracting the left hemithorax which gave us very good exposure and access to left upper lobe  and lung resection were decided. Following general anesthesia, single lumen endotracheal intubation was used. After median sternotomy the left internal thoracic artery was harvested by using the T-bar retractor. Using heart stabilizer and per lobe . LIMA waThere are two strategies for patients with coexisting coronary artery disease and lung cancer: a staged approach with revascularisation preceded by 2-3 weeks of lung resection or a single combined procedure of coronary artery bypass surgery and lung resection.The advantages of staged procedure are stable revascularised myocardium at the time of lung resection; there is no issue of bleeding, lateral thoracotomy with full node access. Disadvantages are delay of compelling lung surgery, two thoracotomies in quick succession, and the use of anticoagulants after CABG. Also, there is evidence that the revascularisation procedure compromises the immune system and therefore the risk of tumor spread is not negligible. The advantages of synchronous treatment are that the patient undergoes one operation and there is no delay between the CABG and resection for lung carcinoma. Disadvantages are the chance of unstable myocardium during lung resection and potential bleeding related to heparinization especially with CBP; left lower lobectomy is difficult with median sternotomy.Some surgeons suggest that only stage I, and maybe limited stage II disease, which does not show other features of aggressive disease  should be considered for a combined approach . Left poUsing the T-bar for concomitant off-pump CABG and left upper lobectomy via median sternotomy proved valuable in treating our patient. The instrument offered satisfactory access to left lung allowing safe dissection of the pulmonary artery and vein branches and provided adequate exposure for lymph node dissection. Even the area of the pulmonary ligament as also the left lower lobe could be safely approached with appropriate adjustments of the T-bar.In this case report, the utility of T-bar rises to prominence as a valuable tool for easier approach of the left lung via median sternotomy."}
+{"text": "Behavior relies on the distributed and coordinated activity of neural populations. Population activity can be measured using multi-neuron recordings and neuroimaging. Neural recordings reveal how the heterogeneity, sparseness, timing, and correlation of population activity shape information processing in local networks, whereas neuroimaging shows how long-range coupling and brain states impact on local activity and perception. To obtain an integrated perspective on neural information processing we need to combine knowledge from both levels of investigation. We review recent progress of how neural recordings, neuroimaging, and computational approaches begin to elucidate how interactions between local neural population activity and large-scale dynamics shape the structure and coding capacity of local information representations, make them state-dependent, and control distributed populations that collectively shape behavior. In complex animals, information about behaviorally important variables such as sensory signals or motor actions is carried by the activity of populations of neurons Recent progress in understanding the contribution and the interplay of each of these key ingredients arises from both technical and conceptual developments. Experimental methods now allow measuring and manipulating up to hundreds of neurons simultaneously in behaving animals and permit a direct link between population codes and behavior We review here how these developments facilitate the convergence of knowledge gained from invasive multi-neuron recordings, neuroimaging data, and mathematical modeling, and begin to reveal the organization and computations of neural population codes at multiple scales of organization. For simplicity, we mostly focus on the encoding of sensory variables, but the concepts are relevant for the generic encoding of any variable .The computational properties of population codes are usually quantified using measures of the information they carry about sensory stimuli How a neural population represents information is partly determined by the diverse selectivity of individual neurons The scaling of information with population size depends on the structure of tuning preferences and of trial-to-trial response correlations, and its investigation can provide important insights. It can indicate how many neurons would be sufficient to achieve a desired level of sensory accuracy (assuming that the decoding mechanisms or later processing stages do not discard any of this information). Its extrapolation to infinite population size sets an upper bound on the information that can be achieved by a population with the considered response properties.The scaling of information with population size is often studied by averaging information over subpopulations that are randomly sampled from the recorded neurons. This approach typically reveals a steady increase of information with population size A, and leThe above results are part of an emerging picture that a small-dimensional subspace of the experimentally measured activity suffices to explain the population dynamics underling sensory processing Studies on the auditory system suggest that those neurons contributing the most to a population code are those that respond sparsely over time, and do so with precisely timed temporal spike patterns In higher association regions the heterogeneity of cortical neurons expresses itself as patterns of selectivity to multiple sensory and task-related variables, which can be mixed in complex, sometimes nonlinear ways This high-dimensional population representation by mixed selectivity may seem at odds with reports of small subpopulations effectively encoding primary sensory information. However, sparseness and high dimensionality of mixed nonlinear selectivity can coexist and may even combine optimally under appropriate conditions The computational properties of a population code depend also on the pattern of response correlations between neurons When tools for simultaneous multi-neuron recordings became widely available in the 1990s, two divergent views were proposed about the impact of noise correlations between firing rates. The first holds that noise correlations of firing rates \u2013 if modulated by the stimulus \u2013 may act as a separate coding mechanism complementary to firing rates The potential impact of correlations on population coding has been studied extensively using model-based approaches that quantify stimulus information under various assumptions about correlation structures or readout mechanisms Besides determining the amount of information carried by neural populations, noise correlations in firing rates may also be indicative of important computational functions Correlations between spike times can also contribute to population codes, for example by facilitating the readout of temporal response patterns in a relative latency code. Individual neurons can encode stimuli by their response latency  Finally, correlations between spike times may also ensure the transmission of information across areas, for example by facilitating the impact on post-synaptic targets Local neural activity not only depends on the current sensory input but also on the current brain state This state-dependence must have profound \u2013 but largely unexplored \u2013 implications for how population codes operate. State-dependence may imply that populations transmit information only using codes that are robust to state fluctuations . Alternatively, downstream areas may extract variables indicating the current state from network activity . These measurements lack cellular-level resolution but can be easily applied to multiple brain areas and complex tasks, and are sensitive to both supra- and sub-threshold activity. Importantly, they have the potential to capture indicators of cortical state that cannot be easily extracted from the spiking activity of a few neurons alone Advances in single-trial data analysis have expanded the use of mass signals to study sensory transformations, permitting researchers to study the same questions using neuroimaging, multi-neuron recordings, and computational models. For example, recent neuroimaging studies extracted features of population activity influencing the variability of single-trial percepts Additional insights can be gained from mass signals by decomposing them into specific frequency bands and separating the sensory information carried by power and phase of individual bands. Recent work, based on both invasive (LFP) and non-invasive (EEG and MEG) recordings, has individuated the phase of low-frequency activity as a particularly informative feature of mass activity An important population coding principle emerging from the analysis of mass signals  between the phases of neural oscillations measured by LFP at multiple distant sites Another approach to clarify the neural basis of the sensory information carried by different components of MEG/EEG signals is based on the use of information theoretic or stimulus-decoding methods Understanding the properties and principles of cortical population codes requires identifying the most informative patterns within the spatio-temporal complexity of multi-neuron activity and understanding how coding properties are affected by large-scale state changes. Invasive recordings provide detailed access to the heterogeneity, temporal precision, and correlation structure of multi-neuron activity, properties which recent computational studies highlight as being crucial for shaping the information-coding properties of a population. Mass signals, on the other hand, provide more direct access to large-scale changes in network state and connectivity, other crucial properties that shape information coding and which can account for trial-by-trial variations in cognitive tasks. Combining insights from both mass signals and multi-neuron recordings is a key challenge for the future.In light of the reviewed properties of population codes several questions emerge about the integration of microscopic and macroscopic structure of population codes . For exaTo enhance our understanding of population coding, future developments of methods for high-dimensional data analysis and neural modeling will be necessary as well. Recent work has provided improvements in analytical techniques for reducing high-dimensional datasets and extracting the relevant sensory representations"}
+{"text": "The putative mRNA targets of human miRNAs and the targets mapped to AGO clipped regions are collected from TargetScan and StarBase respectively. The lncRNA targets of human miRNAs (up to GENCODE 11) are downloaded from miRCode database. miRNA targets on the rest of the GENCODE 19 lncRNAs are predicted by our algorithm for finding seed-matched target sites. These putative miRNA-lncRNA interactions are mapped to the Ago interacting regions within lncRNAs. To find out the likelihood of an lncRNA-mRNA pair for actually being ceRNA we take recourse to two methods. First, a ceRNA score is calculated from the ratio of the number of shared MREs between the pair with the total number of MREs of the individual candidate gene. Second, the P-value for each ceRNA pair is determined by hypergeometric test using the number of shared miRNAs between the ceRNA pair against the number of miRNAs interacting with the individual RNAs. Typically, in a pair of RNAs being targeted by common miRNA(s), there should be a correlation of expression so that the increase in level of one ceRNA results in the increased level of the other ceRNA. Near-equimolar concentration of the competing RNAs is associated with more profound ceRNA effect. In lnCeDB one can not only browse for lncRNA-mRNA pairs having common targeting miRNAs, but also compare the expression of the pair in 22 human tissues to estimate the chances of the pair for actually being ceRNAs. Availability: Downloadable freely from http://gyanxet-beta.com/lncedb/.Long noncoding RNA (lncRNA) influences post-transcriptional regulation by interfering with the microRNA (miRNA) pathways, acting as competing endogenous RNA (ceRNA). These lncRNAs have miRNA responsive elements (MRE) in them, and control endogenous miRNAs available for binding with their target mRNAs, thus reducing the repression of these mRNAs.  A major part of the transcriptome of higher eukaryote does not code for any protein, but functions as regulatory RNAs. Long noncoding RNAs (lncRNAs) are long transcripts  that in many ways are similar to protein coding transcripts, except for the lack of a meaningful coding sequence (CDS) or open reading frame (ORF) CeDB, of human lncRNAs that can potentially act as ceRNAs (based on the newly available GENCODE 19 annotated lncRNAs). Recently, databases describing lncRNA-miRNA interactions, like miRCode CeDB, the users can also browse for miRNA targets on recently available GENCODE 19 lncRNAs not available from other databases. Moreover, the objective of lnCeDB is not just describing lncRNA-miRNA interactions, but providing researchers with a database of human lncRNAs that can potentially act as ceRNAs to protein coding genes. The chances of an lncRNA-mRNA pair for actually being ceRNA depend not only on the fact that they are targeted by common miRNA(s), but also other factors like relative concentrations of individual component ceRNAs and the number of shared MREs. lnCeDB is built by taking into consideration these varied and complex features.Due to the availability of huge lncRNA datasets from recent GENCODE versions A previously published database of ceRNAs, ceRDB, provides data of mRNAs that can putatively act as ceRNAs, but it does not have information about lncRNAs CeDB, is that they do not offer the option to the users to check the co-expression of the ceRNA pair and the shared miRNAs. Following from the observation by Ala et al, to estimate the chances of an lncRNA-mRNA pair for actually being ceRNAs in particular tissues, lnCeDB offers users the possibility to browse for lncRNA-mRNA pairs targeted by common miRNAs (sorted by the number of shared miRNAs of the pair) and compare the expression of the pair in 22 human tissues , but also on the number of miRNA responsive elements (MRE), number of distinct miRNAs targeting both transcripts and the concentration and cellular levels of the competing RNAs. A study by Ala et al provides a comprehensive view on the ceRNA network and the possible outcome of perturbation in the components (miRNA and competing RNA levels) of the network CeDB different from the existing databases on ceRNA. In lnCeDB, the ceRNA score, along with the provision for checking relative expressions of the ceRNA pair over different tissues, offer users a better assessment of the potential ceRNAs. We believe, therefore, that lnCeDB addresses the finer aspects of post transcriptional gene expression regulation in human.To assess the likelihood of an lncRNA-mRNA pair to act as ceRNAs, we provide two different methods. In the first approach, we calculate the P-value for each ceRNA pair by hypergeometric test, similar to the study by Sumazin et al CeDB contains dataset for human genome wide lncRNAs that potentially can act as ceRNAs. Presently we have miRNA targets on 22286 lncRNAs out of 25978 lncRNA transcripts in GENCODE 19. miRNA targets for lncRNAs in GENCODE 11 were collected from miRCode database and targets for newly enlisted lncRNAs in GENCODE 19 were predicted by our algorithm (see section 2). Among the 22286 lncRNAs with putative miRNA target sites, 15842 lncRNAs were predicted to be working as potential ceRNAs. lnCeDB.Among the putative lncRNA-miRNA interactions, 72 interaction pairs were mapped to the Ago-interaction sites within lncRNA transcript loci which contained 41 miRNAs targeting 27 lncRNA transcripts. ceRNAs specifically corresponding to these PAR-CLIP supported miRNA target interactions are browsable in lnConserved human miRNA targets on mRNAs were collected from TargetScan miRNA targets on 6090 mRNAs were collected from StarBase; these targets were predicted from CLIP-Seq data by five most widely used miRNA target prediction tools (see section 2).Users can compare the cellular levels of the competing RNAs to estimate the chances of the pair for actually being ceRNAs by viewing the tissue specific expression of a ceRNA pair over 22 human tissues. Presently we have tissue specific expressions for 7017 lncRNA genes and 17701 protein coding genes.CeDB. The reported lncRNA-ceRNAs include lncRNA HULC acting as ceRNA of the gene PRKACB CeDB.A small number of lncRNAs are reported and experimentally verified as ceRNAs. Experimentally validated lncRNA ceRNAs are identified in lnUsers can browse for ceRNA candidates for a protein coding gene  and/or lncRNA gene  and/or miRNA name. lncRNA-mRNA pairs targeted by common miRNAs are displayed as potential ceRNAs. The list of ceRNAs is sorted by the number of shared miRNAs. The miRNA targets for a particular lncRNA or mRNA can also be browsed in our database by choosing a particular lncRNA/mRNA from the ceRNA list. By choosing a particular record for a ceRNA pair, users can view the RNA-Seq expressions of the lncRNA-mRNA pair over 22 human tissues in form of a heat map (if the expression data for the corresponding lncRNA and mRNA is available) and a bar chart with actual FPKM values appearing in tool tip text. The users can also view the co-expressed miRNAs shared between the ceRNA pair in each of the 22 tissues. CeDB, we have tried to explore the potential sponge activity of recently annotated lncRNAs in the miRNA mediated gene regulation networks at human genome wide scale. Unlike other ceRNA databases, lnCeDB includes but is not limited to miRNA targets on protein coding and lncRNA transcripts predicted from Ago interaction sites within them. The advantage is that it reduces the false positive target detection in our miRNA-target interaction dataset and enhances the reliability of the prediction. At the same time, the dataset is not limited to predictions from only a few cell lines where AGO PAR-CLIP were performed. Also, in lnCeDB we considered, for the first time, that ceRNA activity largely depends on the relative concentration of the components of a ceRNA network, i.e. the pair of competing RNAs and also the miRNAs they compete for. The provision for checking the tissue specific expression for a potential ceRNA pair (whenever available) along with the co-expression of shared miRNAs, gives the user a higher chance of identifying the most likely ceRNA candidates in a tissue of interest.As competing endogenous RNAs are crucial new determinants of gene expression regulation CeDB is the lncRNA maternally expressed 3 (MEG3) and a transcript (the longer isoform) of the protein coding gene Myeloid Cell Leukemia Sequence 1 (MCL1). MEG3 is a maternally expressed imprinted gene encoding a number of alternatively spliced lncRNA transcripts. It interacts with the tumour suppressor P53, and is supposedly a tumour suppressor itself. MEG3 is expressed in many normal tissues including breast, colon, liver, ovary but its expression is lost in many tumour cells. Interestingly, it has been reported that MEG3 is targeted by miRNAs CeDB over other ceRNA databases as no other ceRNA database allows the users to check the co-expression patterns of the competing RNAs and the shared miRNAs in different tissue types. Some other interesting observations from lnCeDB are MEG3 and CMPK1 as potential ceRNA pair with near-equal expression signature in colon and ovary and MALAT1-PRKACB potential ceRNA pair in liver.One interesting example of a putative ceRNA pair identified by lnWe believe this database will help researchers in deciphering the larger and more complex scenario of miRNA mediated gene regulatory networks in human in the real world of ceRNAs.We collected predicted miRNA target sites on human mRNA transcripts from TargetScan. The miRNA-mRNA interactions mapped to the AGO interacting regions were collected from StarBase database We used a 25 base window on the target to run a modified version of the Smith-Waterman alignment  was downloaded from UCSC genome browser We generated the ceRNA score of an lncRNA-mRNA pair targeted by common miRNAs to measure the likelihood of a lncRNA to act as ceRNA to a protein coding gene. The ceRNA score was calculated keeping in mind the observation by Ala et al We implemented another measure to assess the likelihood of a ceRNA pair to regulate each other via shared miRNAs. This approach was similar to what has been used in the study of Sumazin et al TM\u200a=\u200aTotal number of miRNAs in the human genomepm\u200a=\u200aNumber of miRNAs interacting with the mRNA (protein-coding)nm\u200a=\u200aTotal number of miRNAs interacting with the lncRNA (non protein-coding)cm\u200a=\u200aNumber of miRNAs shared between the ceRNA pairCeDB was developed using PHP-mySql.The miRNA target finding algorithm was implemented in JAVA and the web interface of the database ln"}
+{"text": "In recent years it has become apparent that aminoacyl-tRNAs are not only crucial components involved in protein biosynthesis, but are also used as substrates and amino acid donors in a variety of other important cellular processes, ranging from bacterial cell wall biosynthesis and lipid modification to protein turnover and secondary metabolite assembly. In this review, we focus on tRNA-dependent biosynthetic pathways that generate modified cyclic dipeptides (CDPs). The essential peptide bond-forming catalysts responsible for the initial generation of a CDP-scaffold are referred to as cyclodipeptide synthases (CDPSs) and use loaded tRNAs as their substrates. After initially discussing the phylogenetic distribution and organization of CDPS gene clusters, we will focus on structural and catalytic properties of CDPSs before turning to two recently characterized CDPS-dependent pathways that assemble modified CDPs. Finally, possible applications of CDPSs in the rational design of structural diversity using combinatorial biosynthesis will be discussed before concluding with a short outlook. Aminoacyl-tRNA synthetases (aaRSs) represent an ancient and ubiquitous tRNA-utilizing enzyme family that possesses the unique catalytic capability of specifically attaching amino acids to the correct tRNA-adaptors needed during the translational process . Thus, tin vivo functions of modified CDPs. It has been suggested that they might be involved in different biochemical communication phenomena . T. T1-N73 W. viridescens) [The catalytic mechanism of CDPSs can be described by a sequential ping-pong model . After sdescens) ,55. The In addition to the actual active site nucleophile, a second highly conserved residue inside the surface accessible pocket  exists that seems to be important for the coordination of the \u03b1-amino group of the substrate aminoacyl moiety. Together with another conserved residue (Y178) this glutamate plays a critical role in the correct positioning of the aminoacyl group for subsequent nucleophilic attack by the catalytic serine residue . After iRecently, two formerly unknown biosynthetic systems have been identified and characterized that are able to produce modified CDP natural products in a tRNA-dependent fashion . In the Nocardiopsis dassonvillei and Nocardiopsis alba [N. dassonvillei genome was conducted resulting in the identification of the first putative nocazine gene cluster  can have a marked influence on the recognition of the second aminoacyl-tRNA substrate, as well as product formation and thus CDPS specificity [ in vitro transcription can be employed to introduce small specific sequence changes into tRNAs  which generally do not influence the overall structure of the tRNA and do not hinder aminoacylation [CDPs are naturally quite limited regarding the modulation of their peptide backbone as they consist of only two building blocks arranged with a predefined connectivity. It follows that besides the ligation of additional peptidic building blocks to side chain functional groups present in the CDP, only the alteration of monomer identity does represent a feasible diversification approach. CDPS-derived CDPs possess an additional limitation regarding their structure, imposed by the intrinsic catalytic properties of the CDPS family, since the use of aminoacyl-tRNAs as substrates dictates that only the 20\u201322 proteinogenic amino acids do represent valid building blocks for the assembly of CDPs. As discussed above, CDPS-specificity mainly depends on the identity of the aminoacyl moiety bound to the tRNA, although recent results indicate that the first base pair in the acceptor stem (Ncificity . This imcylation . On the The first strategy is referred to as residue-specific incorporation and yields a globally modified proteome containing a desired non-canonical building block at all positions normally occupied by a certain proteinogenic amino acid . This is in vivo fermentation approaches aimed at the production of new modified cyclic dipeptides. Up until now, only five of the putative tailoring enzymes identified in CDPS-gene clusters have been studied, with most of them displaying a relatively broad substrate specificity which would make them useful for CDP diversification approaches. The various kinds of putative CDPS tailoring enzymes have already been discussed in The second general strategy to alter the structure of peptide natural products is the tailoring of an already assembled peptide scaffold by specific modification enzymes . For theIn conclusion, the biosynthesis of modified cyclic dipeptides by CDPSs represents the so far most complex and widely distributed tRNA-dependent process reliant upon aaRS homologs found in secondary metabolism. Although much has been learned about CDPSs over the past ten years, many open questions still remain, including: what are the exact specificity determinants that determine if a given CDPS produces a whole set of CDPs or only a single compound? What new kinds of modifications can be introduced into CDPs by various tailoring enzymes? For what purpose and under which conditions are modified CDPs produced in nature? These are only some of the broader still inadequately answered questions regarding CDPSs. Finally, it will be interesting to see in which way CDPSs and their associated modification enzymes will be employed in synthetic biology approaches aimed at the production of valuable small molecules. In the end, as is often the case, possible applications will strongly depend on the vision and creativity of researchers and their ability to apply the fundamental insights gained in interesting and meaningful ways."}
+{"text": "To determine the diagnostic performance of DWI volumetry for the assessment of complete response after CRT in patients with locally advanced rectal cancer and to compare with volumetry on standard T2- weight MRI, by means of volumetric signal intensity measurements.We retrospectively analyzed 25 patients with locally advanced rectal cancer. Patients underwent pre and post-CRT standard T2 weight MRI and DWI MRI. We placed free-hand regions of interest and each tumour-containing section to determine pre and post-CRT tumour volumes.Histologic findings were the standard of reference.Volumetry of the viable tumour remmants based on signal intensity characteristic on DW images after CRT was shown to be more valuable than volumetry of the tumour based on morphologic T2w images for the differentiation between a pCR and residual tumour in locally advanced rectal cancer."}
+{"text": "Missing cost and outcomes data is a common problem for health economists analysing RCTs. Systematic reviews of the economic evaluation literature suggest that many analysts use crude methods  which are vulnerable to bias and may underestimate uncertainty. Multiple imputation (MI) is more appropriate if data are missing at random, but raises a number of methodological and practical challenges. Two case study RCTs assessing the cost-effectiveness of new interventions are used to explore these challenges.The first RCT is a small trial (n=100) of an intervention which aims to improve physical function in patients with a chronic condition. The second is a cluster RCT  of an intervention which aims to instil healthy practices related to nutrition and exercise in primary school children. We describe challenges at each stage of analysis.The challenges discussed will include: understanding the prevalence and pattern of missing data; selecting appropriate imputation methods; identifying variables to include in the model and stratifying by random allocation; imputing non-normally distributed costs and bounded EQ-5D values; achieving convergence; accounting for clustering (i.e. multilevel MI); bootstrapping to obtain accelerated bias-corrected confidence intervals; and conducting sensitivity analyses.We use these case studies to address the challenges of implementing current guidelines for handling missing data in cost-effectiveness analysis as well as to identify gaps in current knowledge and priorities for future research."}
+{"text": "This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. In the absence of high-level evidence base for follow-up practices, the duration and frequency are often at the discretion of local centres. By reviewing the existing literature and collating experience from varying practices across the UK, this paper provides recommendations on the work up and management of lateral skull base cancer based on the existing evidence base for this rare condition.\u2022 Patients should be followed up to a minimum of five years with a prolonged follow-up for selected patients. (G)\u2022 Patients should be followed up at least two monthly in the first two years and three to six monthly in the subsequent years. (G)\u2022 Patients should be seen in dedicated multidisciplinary head and neck oncology clinics. (G)\u2022 Patients should be followed up by dedicated multidisciplinary clinical teams. (G)\u2022 The multidisciplinary follow-up team should include clinical nurse specialists, speech and language therapists, dietitians and other allied health professionals in the role of key workers. (G)\u2022 Clinical assessment should include adequate clinical examination including fibre-optic rigid or flexible nasopharyngolaryngoscopy. (R)\u2022 Magnetic resonance imaging and positron emission tomography combined with computed tomography imaging should be used when recurrence is suspected. (R)\u2022 Narrow band imaging can be used in the follow-up in selected sites. (R)\u2022 Second primary tumours should be part of rationale of follow-up and therefore adequate screening strategies should be used to detect them. (G)\u2022 Patients should be educated with regard to the appearance and detection of recurrences. (G)\u2022 Patients with persistent pain should be investigated to exclude recurrent disease. (R)\u2022 Patients should be offered support with tobacco and alcohol cessation services. (R) In the UK, the structure of these clinics is often arbitrary and reflects institutional and clinician-led practices with very little evidence to support any one system.Evidence to support follow-up for early detection of tumour recurrence is lacking. However, there is a belief that follow-up clinics have inherent value and to date all published studies recognise this fact.In order to rationalise follow-up, patients could be divided into low and high risk. This is well recognised in thyroid cancer, but it is not the case in all other types of head and neck cancer especially squamous cell carcinoma (SCC). It is a belief that, this categorisation could help to determine which patients should be followed for more than five years. It would also help to establish which screening test may be needed in order to detect recurrence or second primaries.The length of follow-up is generally five years although there are many clinicians who follow-up patients for longer periods or even for life.\u2022Patients should be followed up to a minimum of five years with a prolonged follow-up for selected patients (G)At present, there is no evidence that high frequency of follow-up visits confers any benefit in terms of morbidity and mortality. However, there is evidence that the majority of clinicians in the UK support the follow-up of patients, in regular high-frequency intervals in the first two years when the risk of locoregional recurrence is high followed by a decrease in frequency after the second year. The follow-up in the first two years should be between four to eight weeks and from three to six months thereafter.\u2022Patients should be followed up at least two monthly in the first two years and three to six monthly in the subsequent years (G)At present, 90 per cent of the clinicians treating head and neck cancer in the UK see the patients in dedicated head and neck clinics for the duration of the follow-up.\u2022Patients should be seen in dedicated multidisciplinary head and neck oncology clinics (G)At present patients are followed up by their treating clinicians and their teams. Allied health professionals including speech and language therapists, dieticians and clinical nurse specialists may offer specific follow-up in their areas of expertise, but this is usually in addition to the medical follow-up. The introduction of the clinical nurse specialist and the key worker role in the management of patients with head and neck cancer has opened lines of communication between the patient and family and the clinical team\u2022Patients should be followed up by the dedicated multidisciplinary clinical teams (G)\u2022The multidisciplinary follow-up team should include clinical nurse specialists, speech and language therapists, dietitians and other allied health professionals in the role of key workers (G)Traditionally, clinical assessment has been the most important aspect of the follow-up in patients treated for head and neck cancer. The clinical evaluation is done by inspection, palpation and at present with fibre-optic rigid or flexible nasopharyngolaryngoscopy. Rigid stroboscopy can also be used in patients who have been treated for laryngeal cancer.\u2022Clinical assessment should include adequate clinical examination, including fibre-optic rigid or flexible nasopharyngolaryngoscopy (R),Currently there is evidence that magnetic resonance imaging (MRI) and positron emission tomography combined with computed tomography (PET\u2013CT) scanning are superior at detecting recurrence and second primaries.\u2022Magnetic resonance imaging and PET\u2013CT imaging should be used when recurrence is suspected (R)\u2022Narrow band imaging can be used in the follow-up in selected sites (R),The incidence of second primary tumours varies between 5 and 12 per cent at five years. There is good evidence to indicate that patients with head and neck SCC have an increased risk of developing second primary malignant tumours.\u2022Second primary tumours should be part of rationale of follow-up and therefore adequate screening strategies should be used to detect them (G)In laryngeal cancer, especially in those patients treated with transoral laser microsurgical excision, it is advisable to perform second-look microlaryngoscopy,,Pain complaints must be regarded as a serious warning sign of recurrent disease during follow-up of HNC patients,There is no evidence that the use of tumour markers is any value in the follow-up of patients with head and neck SCCs. The use of tumour markers in the follow-up of patients with thyroid cancer is addressed elsewhere in these guidelines.It has been recognised that the education of patients plays an essential role in the detection of recurrences. The vast majority of recurrences are diagnosed following the occurrence of new symptoms and thus patients should be educated about the need to seek help when appropriate. It has also been recognised that continuing smoking and alcohol drinking increases the risk of recurrence and second primary tumours. It is therefore imperative that patients are advised and offered support with regards to the detrimental effects of tobacco smoking and alcohol addiction.\u2022Patients should be educated with regards to the appearance and detection of recurrences (G)\u2022Patients with persistent pain should investigate to exclude recurrent disease (R)\u2022Patients should be offered support with tobacco and alcohol cessation services (R)\u2022The aims of follow up of patients after treatment for head and neck cancers are manifold\u2022The frequency of follow-up is higher in the first two years, with reduced frequency subsequently, finishing at five years\u2022Medical, nursing and allied health professionals all play important roles in providing follow up care\u2022Change in patient symptoms during follow up is the most frequent indication of recurrent disease and must be regarded seriously, even if clinical examination reveals no abnormalities."}
+{"text": "Protein structural biology aims to link snapshots of three-dimensional macromolecular structures to their biological function. The high-resolution information that is obtained traditionally by x-ray crystallography or nuclear magnetic resonance (NMR) experiments is instrumental for understanding their functional properties, their biological roles, and their potential roles in diseases (\u201cfunction follows form\u201d). Yet, proteins are not rigid and/or static entities: their dynamics and flexibility are essential for proper functioning and molecular movement, which is an important aspect of living matter. Many proteins even completely lack a well-defined 3D-structure under physiological conditions, the so-called intrinsically disordered proteins (IDPs). Up to 35% of human proteins are predicted to possess intrinsically disordered regions (IDRs) of at least 30 consecutive disordered residues, that play important roles in cell signaling and regulation . Their work showcases how rigorous kinetic and structural analysis yields definitive conclusions that selectivity is a function of a conformational change after binding (induced-fit) and the resulting slow dissociation rate of Gleevec from the Abl kinase, whereby the flexibility in the famous and highly conserved DFG-loop plays an important role . They exemplify that protein flexibility at the N- and C-terminal extremities accounts for an increased number of binding partners and how new roles may emerge by the evolutionary addition of an intrinsically disordered extension. Indeed, often IDRs play a role in molecular recognition and binding events, whereby they can undergo a folding transition induced by the partner protein (\u201cform follows function\u201d). By a large scale thermodynamic assessment of mostly binary protein-protein interactions of ordered-ordered and ordered-disordered protein complexes, Kragelund and colleagues help shedding light on the debated role of kinetics and thermodynamics in the binding properties of IDPs . Through this capacity for interaction with other molecules, protein flexibility can also be linked to disease . They highlight that intra-domain ordered and intra-domain disordered regions show high propensity for disease-related mutations, while inter-domain disordered regions are enriched in common variants. Their analysis offers interesting perspectives for the further development of the field of protein flexibility and disorder. It also supports the fact that, in the field of IDPs, computational approaches play a major role. As such, Craveur et al. show that the concept of structural alphabets is suitable to analyze the dynamics and flexibility of proteins. In their comprehensive review they advocate that structural alphabets are required to begin to understand the complexity of protein flexibility by discriminating flexibility from mobility and deformability.The benign role of protein flexibility is also nicely illustrated in the Varadi et al. review the current characterizations of IDPs by combining computations and experiments. The mini-review identifies key developments in the field, including the employment of experimental data into structural refinement in search of the functional repertoire of IDPs. With regard to wet-lab experimental approaches, several emerging techniques allow to overcome some of the technical problems of studying IDPs and to obtain essential information on protein dynamics. In their original research paper, Barran and collaborators exemplify the potential of ion-mobility mass spectrometry to track conformational changes in unstructured proteins on a millisecond timescale . They characterize the effect of two small molecule compounds RITA and nutlin-3 on their IDP targets with a multi-technique approach. The minireview by Belle and coworkers showcases the power of site-directed spin labeling with electron paramagnetic resonance to investigate flexible regions and fuzziness in proteins . The information obtained by NMR can generate conformational ensembles that visualize the conformations that IDPs sample under functional conditions. Because protein disorder can be evaluated at the residue level with NMR, Nielsen and Mulder compiled a small database of disorder-containing proteins using experimental NMR chemical shift data in their original research paper that is felicitously entitled \u201cThere is Diversity in Disorder \u2013 \u2018In all Chaos there is a Cosmos, in all Disorder a Secret Order\u201d\u2019. They demonstrate that those proteins span the full spectrum of disorder, yet segregate into two classes: proteins mostly disordered but with small segments of order scattered along the sequence, or structured proteins with small segments of disorder inserted between the different structured regions. This study is also illustrative for the concept of \u201cform and function follow (NMR) frequency.\u201dThe IDP field is also one of the few areas in structural and molecular biology where the experiments provide support to computations to achieve an accurate understanding of the conformational properties of these complex proteins. D3-concept was introduced for IDPs by revealing the interconnections between protein intrinsic Disorder and Degenerative Diseases (Uversky, F3-concept for flexible proteins, since \u201cFunction Follows Flexibility.\u201d Whereas in the past intrinsic disorder could cause frustration because IDRs were considered frivolous and flamboyant, their flirtatious behavior flaunted formidable features. We hope this e-book can stimulate the research community to finally stop fumbling for the fugacious forms of flexible proteins and bring their functional framing to fruition.Recently the Uversky, . In analBoth authors made substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The heart's regular electrical activity is initiated by specialized cardiac pacemaker cells residing in the sinoatrial node. The rate and rhythm of spontaneous action potential firing of sinoatrial node cells are regulated by stochastic mechanisms that determine the level of coupling of chemical to electrical clocks within cardiac pacemaker cells. This coupled-clock system is modulated by autonomic signaling from the brain via neurotransmitter release from the vagus and sympathetic nerves. Abnormalities in brain-heart clock connections or in any molecular clock activity within pacemaker cells lead to abnormalities in the beating rate and rhythm of the pacemaker tissue that initiates the cardiac impulse. Dysfunction of pacemaker tissue can lead to tachy-brady heart rate alternation or exit block that leads to long atrial pauses and increases susceptibility to other cardiac arrhythmia. Here we review evidence for the idea that disturbances in the intrinsic components of pacemaker cells may be implemented in arrhythmia induction in the heart. Defects in these cell-intrinsic capacities to elicit spontaneous action potentials (APs) can lead to disturbances of the rate and rhythm of heart beats, and can induce numerous clinical arrhythmia syndromes: (i) SAN dysfunction has been postulated to be a source of sinus nodal re-entry  tachyarrhythmia  components of pacemaker cells may be implicated in arrhythmia induction in the heart.To understand abnormal SAN function it is essential to first understand the normal function of intrinsic properties of pacemaker cells and their modulation by brain-heart signaling. Experimental and theoretical data over the past two decades indicate that pacemaker cells residing in the SAN entrain their AP BI variability (BIV) by regulation of intracellular electric and mechanical coupling  close to the cell surface membrane; LCRs activate membrane electrogenic clock molecules (\u201cM clock\u201d), mainly the Na+/Ca2+ exchanger. Na+-Ca2+ exchange current, the f-channel current, and K+ channel current, other components of the M clock, concurrently drive the diastolic membrane depolarization to ignite the next AP. The Ca2+ and M clocks entrain each other through electrical and chemical signaling: Ca2+ activation of calmodulin -adenylyl cyclase (AC)-dependent protein kinase A (PKA) and Ca2+/calmodulin-dependent protein kinase II (CaMKII). Both of these signaling pathways affect phosphorylation of proteins of both clocks . Additionally, cAMP positively shifts the f-channel activation curve. Based on the coupled-clock theory, a change in the activity or in the quantity of every molecule within the M or the Ca2+ clock or a change in the chemical coupling signaling of both clocks will perturb the function of the other clock, and thus alter the degree of entrainment between them. For example, in rabbit pacemaker cells, reduction in Ifactivity or in Ca2+ clock proteins leads to reduction in the coupled-clock phosphorylation activity and LCR signal . Based on the coupled-clock theory, the stochasticity of LCR periods  not only depends upon stochasticity of spontaneous RyR activation, but also upon stochastic sarcolemmal ion channel openings and closings that regulate the cell Ca2+ balance. The amplitude and timing of LCR Ca2+ signals to M clock proteins report the efficiency of clock coupling, i.e., a weaker LCR signal to M clock proteins that occurs later in time reports less-efficient clock coupling. Consequently, changes in the steady-state AP BI and the BIV embody contributions of both clocks. Reduction in the degree of synchronization between the clocks disturbs the ability to maintain the basal average AP BI, leading not only to a reduction in the average AP BI, but also to an increase in variability around the prolonged average AP BI.Even under normal conditions, spontaneous AP BIs of mammals including human pacemaker cells are not constant, but vary around the average AP BI, due to stochastic properties of intrinsic mechanisms of the coupled-clock system  of pacemaker cells residing in SAN tissue also entrain the rate and rhythm of electrical impulses that emanate from the SAN Jalife, . These iin vivo. Although mechanisms of HRV may vary from one patient to another, documentation of the relationship between HRV and different arrhythmias in human patients  are analyzed in patients with arrhythmogenic events: during the events when the entropy of the system increases  or Ca2+ clock  produces increases in AP BI and AP BIV that are related to increases in LCR period and LCR period variability  caging of intracellular Cain vivo.Similar to direct pharmacological inhibitors of coupled-clock proteins, mutation and genetically induced gene deletion of different components of the coupled-clock system are associated with arrhythmias fI) consists of three HCN members   mediate L-type Ca2+ channels that play distinct roles in mediating Ca2+ balance in the pacemaker cell. Both Cav1.2 and Cav1.3 channels are expressed in SAN, and Cav1.3 expression in the atria and SAN cells is higher than in ventricular myocytes  and is characterized by severe bradycardia  an increase in adenosine level in human SAN tissue, an endogenous metabolite of the heart, through adenosine A1 receptor upregulating, can lead to SAN dysfunction (Lou et al., Changes in heart rate and rhythm are harbingers of the appearance of arrhythmogenic events. Reduction in the degree of synchronization of any intrinsic clock functions of pacemaker cells or in the synchronization among pacemaker cells residing in the SAN can be associated with arrhythmia occurrence. The extent to which restoring normal synchronization of intrinsic clock periods within pacemaker cells and among pacemaker cells can prevent arrhythmogenic events awaits further elucidation. In our opinion, future work requires a focus on the connection between dysfunction of inherent intrinsic mechanisms associated with different cardiac diseases and cardiac arrhythmias. This connection can be explored in genetically manipulated mouse models, in animals like rabbit, dog and sheep with heart failure or atrial fibrillation, and in human-derived cardiomyocytes or human SAN. This knowledge will contribute greatly to our understanding of cardiac impulse initiation in health and in cardiac disease.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Fungal secondary metabolism is often considered apart from the essential housekeeping functions of the cell. However, there are clear links between fundamental cellular metabolism and the biochemical pathways leading to secondary metabolite synthesis. Besides utilizing key biochemical precursors shared with the most essential processes of the cell , enzymes for secondary metabolite synthesis are compartmentalized at conserved subcellular sites that position pathway enzymes to use these common biochemical precursors. Co-compartmentalization of secondary metabolism pathway enzymes also may function to channel precursors, promote pathway efficiency and sequester pathway intermediates and products from the rest of the cell. In this review we discuss the compartmentalization of three well-studied fungal secondary metabolite biosynthetic pathways for penicillin G, aflatoxin and deoxynivalenol, and summarize evidence used to infer subcellular localization. We also discuss how these metabolites potentially are trafficked within the cell and may be exported. Filamentous fungi produce a diverse range of low molecular mass natural products (NPs) often associated with unique bioactive properties. Prominent among these fungal secondary metabolites (SMs) are compounds beneficial to human society such as antibiotics, pigments, fragrances or pharmaceuticals Demain, . ConversWhile knowledge of the enzymology and genetics of fungal SM production has advanced greatly in recent years, scant information is available on the cell biology of their biosynthesis. Where are SM compounds assembled within the cell? Since pathways for fungal primary and secondary metabolism often draw upon the same chemical starting materials, how do cells channel and apportion the supply of shared molecular precursors to primary and secondary metabolic pathways? The answer to these questions will require greater understanding of the cellular and developmental processes that define the fungal metabolome.Penicillium chrysogenum, aflatoxin produced by Aspergillus parasiticus and deoxynivalenol (DON) produced by Fusarium graminearum. Each compound represents a separate class of fungal NPs: peptide (penicillin), polyketide (aflatoxin) or terpene (DON). Each pathway for biosynthesis of these SMs involves enzymes targeted to multiple subcellular locations. Genetically engineering fungi so that enzymes for SMs may be physically co-localized or localized to particular organelles can have significant impact on flux through pathways and ultimate biosynthetic yield of NPs  where they are synthesized and modified whereas, with time, defective or aged proteins ultimately may be targeted to the vacuole or proteasome for proteolysis. Deciding on the subcellular location of a catalytically active protein therefore requires judgment and may be inferred based on the timing of peak enzyme activity or NP accumulation or by co-purification of organelles with active enzymes.Determining whether an enzyme is located in the fungal cytosol often has been a process of elimination. For example, if no discernible localization pattern within the cell is detected using electron microscopic immunolocalization -L-cysteinyl-D-valine synthetase (ACVS) and isopenicillin N synthase (IPNS). Transmission electron microscopy coupled with immunogold labeling of either ACVS or IPNS under penicillin producing conditions seems to show non-specific dispersal of electron dense gold particles throughout hyphal cross sections although largely excluded from vacuoles  that catalyzes the penultimate step in penicillin biosynthesis; this enzyme also may be localized to peroxisomes. PCL labeled at the N-terminus with cyan fluorescent protein co-localized with yellow fluorescent protein labeled IAT in dual tagged strains of P. chrysogenum  synthesis. Indeed, Maggio-Hall et al.  demonstrF. graminearum and have been shown to be distinct from the \u201ctoxisome\u201d itself . Nevertheless, peroxisomes are a potential source of acetyl CoA which is the precursor of both the mevalonate and trichothecene pathways. In F. graminearum peroxisomes are highly motile in cells during the process of toxisome formation. But in cells with fully formed toxisomes, peroxisomes may establish close stationary contact with the toxisomes (Video Peroxisomes are not known to be important for trichothecene biosynthesis in es Video .The endoplasmic reticulum (ER) is a conserved organelle of eukaryotic cells consisting of a double membrane structure. Its membranous network may be found throughout the cell but is most closely associated with nuclei since it adjoins the nuclear membrane (perinuclear ER). The ER is highly dynamic and also may form tubular or reticulate structures within the cell often more highly concentrated toward the hyphal tip and septa  is present in the plasma membrane and in small motile vesicles  of cell lysates derived from protoplasts resulting from cultures induced to synthesize aflatoxin , the ER , and mitochondria (F1 ATPase). Biochemical assays of the V fraction for the presence of mitochondrial and cytoplasmic enzymes were negative  to vacuoles (\u22652.5 \u03bcm) compared to non-induced cultures as determined using light microscopy  transporters  encoding a predicted 14-membrane spanning domain MFS transporter associated with trichothecene synthesis and resistance  trichothecene biosynthesis and (2) trichothecene traffic and export thus may involve different cellular compartments. We have proposed a model Figure  whereby Based on the three examples of cellular compartmentalization examined in this review, each has a separate developmental pattern associated with localization of their unique SM pathways. The enzymatic components of the penicillin, aflatoxin and trichothecene pathways are variously localized to peroxisomes, endosomes, the cytosol, the ER or perhaps more specialized vesicular structures.P. chrysogenum and conditions that induce penicillin synthesis increase the number of peroxisomes per cell  relative to vacuoles (>2.5 \u03bcm) in toxigenic cells (Chanda et al., F. graminearum under conditions conducive to trichothecene biosynthesis (Menke et al., In each case, induction results in clear cytological repatterning reflective of their subcellular specialization for SM biosynthesis. Intact peroxisomes are important for synthesis of penicillin G in Fusarium toxisomes? Each exemplifies an adaptation of the preexisting machinery of primary metabolism for the more specialized task of synthesis, traffic and export of secondary metabolites. Additionally, are terpene SMs like trichothecenes produced within the same structures as terpene primary metabolites such as sterols? Both the fungal sterol and trichothecene biosynthetic pathways carry out oxygenation reactions catalyzed by cytochrome P-450 oxygenases. Is there a common site within the ER for all cytochrome P-450s? Each might be expected to share a common NADPH:cytochrome P-450 reductase and rely upon the electrochemical gradient across the ER membrane.In the future, studies should concentrate on whether the compartmentalization of biosynthetic pathways, represented in this review by examples of peptide, polyketide and terpene compounds, are part of conserved evolutionary adaptations for synthesis of these compound classes Figure . For exaCo-compartmentalization of SM biosynthetic enzymes might be expected to allow certain types of selective advantage. Co-localization of consecutive enzymes in a SM biosynthetic pathway may promote pathway efficiency through proximity. Localization to the site where pathway precursor metabolites also occur may serve to channel metabolites toward SM synthesis. For example, both polyketides and terpenes ultimately are derived from acetyl CoA, but acetyl CoA may be synthesized in several locations within the cell, for example, as a result of \u03b2-oxidation of fatty acids in mitochondria or in peroxisomes or by pyruvate decarboxylation in the cytosol. Do the terpene and polyketide pathways utilize the same or different subcellular sources of acetyl CoA?Compartmentalization of SM biosynthetic pathways not only brings together enzymes as a functional unit but also sets the pathway apart from the rest of the cell. This is especially important if products and intermediates may be toxic to the producing cell. Compartmentalization also may facilitate export of products by exocytosis although the exact mechanisms of SM export have yet to be determined for any filamentous fungus.Certainly it is clear that relatively little is known about the cellular compartmentalization of secondary metabolic pathways in filamentous fungi. Given the importance of these compounds to industry, food safety and public health, and the importance of understanding the regulation and expression of the fungal secondary metabolome, this research doubtlessly will be a fertile area of exploration for years to come.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Our results suggest that 38 miRNAs were differentially expressed in the skin of patients compared to controls. We identified 13 miRNAs which were significantly differentially expressed in lesional skin of patients compared to healthy control skin. Further, 29 miRNAs were found to be significantly differentially expressed between non-lesional skin of patients and healthy control skin. Interestingly, three miRNAs were specifically down-regulated in the lesional skin compared to non-lesional skin from patients with NSV. In conclusion, for the first time the present study suggests the crucial role of differentially expressed miRNAs in NSV patients from Gujarat.miRNAs are small conserved non-coding RNA molecules that post-transcriptionally regulate gene expression by targeting the 3\u2019 UTR of specific mRNA for degradation or translational repression. miRNAs have been shown to be promising biomarkers for different diseases. At present, the expression and function of miRNAs in human skin is largely unknown. The aim of the present study was to detect the differentially expressed miRNAs in non-segmental vitiligo (NSV) patients and to explore the potential role of these miRNAs in vitiligo pathogenesis. We performed the whole miRNA profiling of lesional as well as non-lesional skin from four NSV patients and four healthy skin samples from controls using TaqMan"}
+{"text": "Microarray gene expression datasets has concerned great awareness among molecular biologist, statisticians, and computer scientists. Data mining that extracts the hidden and usual information from datasets fails to identify the most significant biological associations between genes. A search made with heuristic for standard biological process measures only the gene expression level, threshold, and response time. Heuristic search identifies and mines the best biological solution, but the association process was not efficiently addressed. To monitor higher rate of expression levels between genes, a hierarchical clustering model was proposed, where the biological association between genes is measured simultaneously using proximity measure of improved Pearson's correlation (PCPHC). Additionally, the Seed Augment algorithm adopts average linkage methods on rows and columns in order to expand a seed PCPHC model into a maximal global PCPHC (GL-PCPHC) model and to identify association between the clusters. Moreover, a GL-PCPHC applies pattern growing method to mine the PCPHC patterns. Compared to existing gene expression analysis, the PCPHC model achieves better performance. Experimental evaluations are conducted for GL-PCPHC model with standard benchmark gene expression datasets extracted from UCI repository and GenBank database in terms of execution time, size of pattern, significance level, biological association efficiency, and pattern quality. The adoption of microarray technology provides the biologists to be competent at monitoring thousands of genes expression in a solitary experiment on a small chip with the existence of several microarray gene expression datasets that openly exist on the Internet. The dataset in it comprises huge count of gene expression values and emphasizes a precise method to differentiate between the knowledge and useful information from these microarray gene expression datasets. The application of support vector machines (SVM) has been shown to be of superior performance during the analysis of microarray gene expression data when compared to the other classification algorithms such as decision trees and linear discrimination. The top ranked informative genes using a filtering algorithm in  with resOn the other hand, the DNA microarray technology evaluates the expression level of thousands of genes at the same time. With this evaluation, certain genes could be related to an exact type of cancer, whereas many of them consist of irrelevant or redundant features that result in a high influential factor on the speed and accuracy of classification. Developing predictive and prognostic classifiers to recognize the patient highly requires action and forms as the most excellent candidate form for specific treatments. As microarrays construct as much of data from every specimen,  the methMoreover, the connections between morphometry and molecular characterization in the TCGA and REM BRANDT datasets as shown in  failed iBased on the gene expression profiles, the selection of gene with the recognition of the optimal subset of relevant genes is one of the foremost challenges in cancer classification. Genomic regulation forecast single-peaked distributions method of expression value decays according to power laws in  with theKidney paired donation (KPD) programs as presented in  provide 3 in [2. O3 induced new type of reaction that oxidative pressure and previous leaf senescence, seen as decrease appearance of photosynthesis and carbon fixation-related genes, increases expression of senescence-associated genes. Biclustering technique is capable of detecting positively and unenthusiastically coregulated genes in [Gene expression was caused by O3 in , with thgenes in . These bThe methods involved in gene selection are classified into filter and wrapper approaches. The filter approach of gene selection selects the top ranked genes on the basis of their individual discriminative power without concentrating on and including any induction algorithm. Also, genes are evaluated using different types of common individuality measures in data, and the performance of filter-based gene selection is measured efficiently. It is highly advantageous for high-dimensional data outstanding to its linear time complexity, but it cannot find out the synergy result or suppressible in the middle of genes. The wrapper method, in contrast, assesses applicant gene subsets using an induction algorithm. Since the predictive accuracy of the induction algorithm determines the integrity of the selected subsets, it is competent to allow correlations among genes but is often computationally expensive.The temporal and spatial correlations and the reliability in the trajectory of datasets of moving objects as shown in  are repeMethod for trajectory segmentation and sampling based on the representativeness of the (sub)trajectories in the MOD as shown in  failed tThe problem of mining based on heuristic search viewed as a biclustering problem has been lengthily studied in the area of gene expression analysis. The concept of gene expression analysis follows dissimilar formulations of biclustering problems in the circumstance in order to detain various biological associations in the middle of correlated genes and experiment conditions. Classifying trajectories on road networks was not efficient and effective methods for pattern-based classification were discussed in .On the basis of the aforementioned techniques and methods applied, the proposed work uses improved Pearson's correlation proximity-based hierarchical clustering (PCPHC) model to develop biological associations between genes. PCPHC model captures the biological fact that follows a hierarchical clustering model for identifying the biological analysis between genes. To identify the biological association of genes, genes comprising of similar expression patterns are organized using the improved Pearson's correlation proximity model. An efficient pattern growing method GL-PCPHC adopts Seed Augment algorithm which uses average linkage method on rows and columns in order to mine sufficient patterns by growing seed into maximal level.to discover the significant biological association between the genes using improved Pearson's correlation proximity-based hierarchical clustering,to exhaustively mine the gene data analysis using similarity diversion analysis,to adopt global PCPHC model to mine GL-PCPHC patterns,to expand maximal GL-PCPHC pattern that adapts average linkage methods on rows and columns using Seed Augment algorithm.The PCPHC model makes use of a Seed Augment framework and adopts an average linkage method to mine patterns. Experiments using both synthetic and genuine datasets confirm that the PCPHC model facilitates higher level of quality and also the mining method is considerably efficient. Empirical studies show that the adoption of the PCPHC model improves the quality of the mined patterns compared to the significantly more efficient state-of-the-art heuristic search when it is used to mine strict patterns. The contribution of mining biological association between genes using improved Pearson's correlation proximity-based hierarchical clustering (PCPHC) for gene expression data analysis includes the following:The rest of the paper is structured as follows. Mining biological association between genes using improved Pearson's correlation proximity-based hierarchical clustering (PCPHC) for gene expression data analysis is divided into two parts with the illustrative framework of PCPHC as shown in The first part involved in PCPHC is to apply the hierarchical clustering model to the input gene dataset with the similarity between two genes expression pattern being measured using the improved Pearson's correlation proximity. The second part in PCPHC is to address the pattern growing method by applying Seed Augment algorithm which uses average linkage method on rows and columns to obtain maximal GL-PCPHC model with genes consisting of similar expression patterns being constructed and the biological association between genes being measured.R\u201d and columns \u201cC\u201d with the intersection of rows and columns being a log ratio factor. Each row denotes the expression of a gene across all experiments whereas each column representing the gene expression levels from a single experiment with the intersection is denoted by a log ratio factor. The log ratio factor for gene expression data is defined as log2 (C/R), where C is the gene expression level observed for the testing sample of gene dataset and R is the gene expression level observed for the training sample. A gene expression dataset from a microarray experiment is symbolized by a real-valued expression matrix:R = {r1,\u2026, rn} form the expression patterns of genes and the columns C = {c1,\u2026, cn} represent the expression profiles of samples with log ratio factor denoted by wij being the measured expression level of gene i in sample j. The similarity diversion analysis is present with a novel GL-PCPHC model. The PCPHC model requires that all the genes in a PCPHC model should support the pattern growing method, in the sense that the condition values of a gene in different genes should maintain the ordering relationship between the genes with the conditional values in the similar gene being similar enough. Seed Augment algorithm performs the biological association between the genes.The representation of gene expression data is in the form of an expression matrix. The expression matrix consists of rows \u201cAn efficient and improved Pearson's correlation proximity mines the PCPHC patterns and adopts the average linkage method on rows and columns to mine PCPHC patterns. Then, a new GL-PCPHC mining method using Seed Augment algorithm extracts the PCPHC patterns as seeds and expands them into maximal GL-PCPHC.Due to the significant characteristics of gene expression data, gene-based clustering presents several new challenges. With the application of improved Pearson's correlation proximity-based heuristic clustering, the challenges are addressed using twofold.First, with the introduction of gene-based hierarchical clustering algorithm, minimum dependence on prior knowledge is required, which usually is not available before the cluster analysis using gene expression data. Second, due to the experimental complexity involved in the expression matrix, gene expression data comprises a huge amount of noise. Therefore, with the application of improved Pearson's correlation proximity-based heuristic clustering for gene expression data, it significantly extracts relevant information by removing certain level of noise.Gene-based hierarchical clustering for gene expression dataset produces a hierarchical series of clusters which is illustrated by a tree, called dendrogram. The leaves of dendrogram for gene-based hierarchical clustering not only generate the format ion of the clusters but also record the similarity between the clusters. By removing the dendrogram at certain level, a specific number of clusters for gene dataset are obtained. In improved Pearson's correlation proximity-based hierarchical clustering, each log ratio factor of the gene expression matrix is colored on the basis of the ratio of fluorescence measure whereas the rows of the gene expression matrix are reordered on the basis of the hierarchical dendrogram structure with the help of a constant node-ordering. Once the cluster is being formed, the original gene expression matrix is transformed into a colored table, where higher patches of color denote the genes sharing similar expression patterns.R, C) with R representing rows and C denoting the columns, the methodology followed to mine PCPHC patterns is carried out as follows. The gene expression datasets are represented as vectors as given below:vi,j represents the value of jth feature f for the ith gene value and f denotes the features. The proximity level between the two gene values vi and vj is obtained with the corresponding vectors vi\u2032 and vj\u2032 using the improved Pearson's coefficient for a measurable dimension dim, where dim\u2009i = 1,2,\u2026, n is given below:\u03bcvi and \u03bcvj are the average values of two vectors vi\u2032 and vj\u2032, respectively.Given an expression matrix EM =  obtained from the URL The yeast gene expression datasets consist of 8 attributes and 1484 instances with classification associated tasks. The attributes used here for the evaluation of gene expression datasets are Sequence Name (accession number for the SWISS-PROT database), mcg , gvh , alm (score of the ALOM membrane spanning region prediction program), mit  of mitochondrial and nonmitochondrial proteins), erl ), binary attribute, pox , vac , and nuc .The GenBank database is comprised of data from large-scale projects  quality score information and consists of integers ranging from 0 to 100; individual files (daily-nc) for new or updated sequence entries, where \u201cMM\u201d represents month and \u201cDD\u201d represents year; data files (wgs) for the sequence-overlap contigs of all whole genome shotgun (livelists), which contains lists, generated weekly on Sunday evening at approximately 6:00\u2009pm EST/EDT, of all nucleotide and protein accession numbers for the sequences in GenBank; and so on.At first, the biological processes are observed and analyzed for processing. The improved Pearson's correlation proximity-based hierarchical clustering (PCPHC) model is used with the analysis of biological process association and the performance of the PCPHC is measured in terms of execution time, biological association efficiency, pattern quality level, and accuracy rate and gene expression level. Execution time is the average amount of time consumed to perform the whole process in PCPHC model and mechanism with the existing mining discriminative patterns for classifying trajectories (MDP) and triple spectral clustering-based consensus clustering (SC3), measured in terms of milliseconds (ms).Biological association efficiency is an effective way of biological features associated together in PCPHC and MDP, SC3 measured in terms of percentage (%). Pattern quality level is defined as the amount of accuracy in pattern mining based on the gene expressions and is measured in terms of score points. Accuracy rate is judged by comparing numerous capacities from the same or different sources in gene expression data to attain improved percentage:Gene expression data at each data point designed a DNA microarray that represents the ratio of expression levels of an exacting gene under different experimental conditions. Gene expression level is measured based on the gene count taken for experimental purpose.The improved Pearson's correlation proximity-based hierarchical clustering (PCPHC) model is compared with the mining discriminative patterns for classifying trajectories (MDP) method and triple spectral clustering-based consensus clustering (SC3). Procedures in different orders lead to different pattern association strategies in PCPHC model when compared with the MDP method and SC3 model.Finally, it is being observed that the improved Pearson's correlation proximity-based hierarchical clustering (PCPHC) model develops biological associations between genes and correlated genes identified as a linear order. The PCPH model requires that the rows in a PCPHC support Seed Augment framework and adopts an improved Pearson's correlation proximity-based model to mine patterns. Empirical studies show that the adoption of the PCPHC model improves the quality of the mined patterns.The improved Pearson's correlation proximity-based hierarchical clustering (PCPHC) model is an efficient model which exhaustively mine the similarity diversion strategy interpretively. A global PCPHC (GL-PCPHC) model adopts pattern growing method to mine GL-PCPHC patterns and discover significant biological associations between genes. PCPHC model allows linear orders and Seed Augment algorithm adopts two different growing strategies on rows and columns in order to expand a seed PCPHC model into a maximal GL-PCPHC pattern. The high rate of expression levels between gene datasets is also simultaneously measured using the improved Pearson's correlation. Experimental studies show that the PCPHC model outperforms all the current models, and, importantly, it leads to the discovery of more quality patterns. The experimental result of PCPHC model attains the improved gene expressional data, minimal execution time, 10. 085% effective biological association based on feature set, 4.5% maximal accuracy rate, and better pattern quality level based on the significance level."}
+{"text": "Phylogenetic diversity (PD) has been successfully used as a complement to classical measures of biological diversity such as species richness or functional diversity. By considering the phylogenetic history of species, PD broadly summarizes the trait space within a community. This covers amongst others complex physiological or biochemical traits that are often not considered in estimates of functional diversity, but may be important for the understanding of community assembly and the relationship between diversity and ecosystem functions. In this study we analyzed the relationship between PD of plant communities and land-use intensification in 150 local grassland plots in three regions in Germany. Specifically we asked whether PD decreases with land-use intensification and if so, whether the relationship is robust across different regions. Overall, we found that species richness decreased along land-use gradients the results however differed for common and rare species assemblages. PD only weakly decreased with increasing land-use intensity. The strength of the relationship thereby varied among regions and PD metrics used. From our results we suggest that there is no general relationship between PD and land-use intensification probably due to lack of phylogenetic conservatism in land-use sensitive traits. Nevertheless, we suggest that depending on specific regional idiosyncrasies the consideration of PD as a complement to other measures of diversity can be useful. Land-use change is one of the primary drivers of biodiversity loss th century posed considerable threats to biodiversity in grasslands, e.g. due to dramatic habitat loss and extinction of less competitive species In Central Europe managed grasslands are one of the most abundant and species-rich ecosystems a priori choice of specific traits is not always straightforward In general previous studies of plant biodiversity-ecosystem functioning relationships have shown that species richness enhances ecosystem functions For conservational purposes the response of rare species to land-use intensification is of great interest. Rare species are in general more vulnerable to land-use intensification than common species Socher et al. In this study we use species abundance data to analyze the PD of plant communities in local grasslands (150 sites) across land-use intensification gradients in three regions in Germany. In particular we aimed to answer the following questions:Are there regional differences in the response of phylogenetic diversity to land use?Does land-use intensification decrease phylogenetic diversity of plant communities in grasslands?Does phylogenetic diversity of common and rare species assemblages show different relationships with respect to land-use intensification?For a better understanding and interpretation of the relationship between PD and land-use intensification, information on the phylogenetic signals in traits relevant for landuse are of interest . Thus, we used a set of traits that are likely to be sensitive toland use and tested for phylogenetic signal in those traits.www.biodiversity-exploratories.de). The Biodiversity Exploratories represent three typical regions in Germany covering a south-west \u2013 north-east gradient and each region comprises grasslands and forests under a range of land-use types and intensities Our study is part of the Biodiversity Exploratories project, a large German research project to investigate the relationships between land-use, biodiversity and ecosystem functioning . The study did not involve protected or endangered species.\u22121 year\u22121), mowing frequency (number of cuts year\u22121) and grazing intensity (livestock units\u00d7days of grazing ha\u22121 year\u22121) Land-use information for each of the 150 grassland plots was obtained by yearly interviews with farmers and land-owners between 2006 and 2010. The acquired information included fertilization level . For each plot, vascular species richness and their relative abundance in percent cover was estimated. The species were further grouped into common and rare species based on their abundance for each year and region separately, taking into account local (plot) abundance and distribution (number of plots occupied) of each species. Common species were defined as the top 10% in terms of total abundance across plots occupied by a species, while the bottom 90% of the species were defined as rare. Based on these data we calculated the species richness of all, common and rare species as the average richness per plot across the three years. Note that the analyses of plant species richness from our study sites have been already published elsewhere Phylogenetic relatedness of species was obtained from a well resolved and dated phylogeny of the Central European flora According to the data sharing regulations of the Biodiversity Exploratory Project and in accordance with the rules of the German Science Foundation DFG, the data will be made publicly available no later than five years after collection.2/g). As traits related to reproduction we used data start of flowering (month of the year). Data on the SLA were taken from the LEDA trait data base We compiled functional trait data from different data bases. As traits related to productivity we included the maximal plant height (cm) and specific leaf area  as a factor to analyze whether PD differs among regions and whether the relationships between PD and LUI differ among regions (region\u00d7LUI interaction). To assess whether rare species assemblages respond more strongly to increasing land use than common species, we compared the slope of the regression lines with an ANCOVA by testing the significance of the LUI\u00d7\u201crarity\u201d interaction. All statistical analyses were conducted in R A total of 282 vascular plant species were recorded in the three regions from 2009 to 2010 . We founAverage total, rare and common species richness differed among regions . Total aOverall, average PD strongly varied among regions. But note that the differences depended on the PD-metric used and whether rare/common species were considered . When alIn general we found that for both common and rare species PD was not or only weakly affected by increasing land-use intensity. The relationships did not vary among regions except for rare species MPD , Fig. 2.Land-use intensification is one of the major threats to global biodiversity in grasslands Dinnage Many studies dealing with phylogenetic community structure use only one phylogenetic diversity index like NRI or NTI  and (\u22121 * effect size MNTD), respectively) Although common and rare species might differ in several traits It is well known that regional peculiarities and species pools influence regional phylogenetic diversity Differences in PD among regions may, to some extent, be also due historical land use rather than current The theory behind phylogenetic patterns along disturbance gradients relies on several hypotheses about distribution of ecological traits across phylogenetic trees Appendix S1Phylogenetic tree of plants in three regions in Germany used in this study.(TIFF)Click here for additional data file.Appendix S2Phylogenetic signal in 7 traits considered as sensitive to land use for all, common and rare species in the three regions  and in all regions combined. Significant values are in bold.(DOCX)Click here for additional data file.Appendix S3Mean (\u00b1SE) values and regression slopes of species richness for total, common and rare species assemblages in three regions in Germany.(TIF)Click here for additional data file.Appendix S4Correlation coefficients and significance of the respective regression slopes from (DOCX)Click here for additional data file.Appendix S5Relationships between presence/absence based mean pairwise distance (effect size MPD), mean nearest taxon distance (effect size MNTD) and land-use intensity (LUI) in three regions in Germany.(TIF)Click here for additional data file.Appendix S6Mean (\u00b1SE) values of presence/absence based MPD and MNTD effect sizes for total, common and rare species assemblages in three regions in Germany.(TIF)Click here for additional data file."}
+{"text": "Intensive care units are high-risk areas for infections caused by antibiotic-resistant bacteria. Care of ICUs patients involve close contact with hospital staff and provide opportunities for cross-contamination from the environment and from other patients. The resulting colonization of patients is generally accepted as a prerequisite for causing most of nosocomial infections including hospital - aquired pneumonia and VAP. Information about microorganism which cause particular infections and colonization in ICU is essential to prepare local antibiotic guidelines and should be taken into account in implementing empirical treatment.The aim of the study was to create ICU's microbiological map of pneumonia based on specimens received from non-directed bronchoalveolar lavage.2 units/mL), pneumonia (colony forming \u2265103 units/mL). We analyzed the types of bacteria which caused colonization or pneumonia and their antibiotic-sensitivity.We analyzed the results of the non-directed bronchoalveolar lavage (NBL) collected from patients hospitalized in the ICU during last 5 years. Every patient admitted to the ICU had NBL taken and was categorized to one of three groups: no infection, colonization (colony forming< 10See tables 3The NBL is a useful method to identify infection and colonization of lower airways. It allows to create microbiological map of ICU's residual pathogens and their drug sensitivity, and as a consequents gives intensivist opportunity to implement suitable antibiotic treatment."}
+{"text": "Plasmodium sp.). Recent surveillance discovered two invasive and two thermophilic mosquito species that were new for the Austrian fauna . These species increase the possible spectrum of vector-borne communicable diseases in Austria. But until today Flaviviridae and Bunyaviridae have only been detected in context with the endemic mosquito species. Little attention was given to control pests and to develop sustainable, useful and affordable projects for controlling the dynamic of these indigenous mosquito populations. We emphasize the need for integration of mosquito control aspects, which up to now were ignored within contemporary Austrian river construction projects and we ask for a Europe wide consideration of mosquito control within the EU-Waterframework Directive (WFD); in particular we recommend mosquito control elements within fish ladders which are prescribed for water storage structures all over Europe. We also report on a material which allows the pulling of mosquitoes in the dimension of landscape management. We present our experience and emphasize the great advantage of actions working in connection with constructive river engineering.Since 2001, we have repeatedly detected pathogens during mosquito field studies in Austria (e. g. West-Nile-, Tahyna-, Usutu-virus and"}
+{"text": "The pathogenesis of macular hole formation is widely accepted as a tractional force at the vitreo-retinal interface in fovea. We report a case of macular hole after intravitreous aflibercept injection for age-related macular degeneration (AMD) associated with contraction of the retinal pigment epithelium (RPE) at the edge of a fibrovascular pigment epithelial detachment (PED).A 94-year old man with neovascular AMD affecting his left eye accompanied by a fibrovascular PED was examined for severe vision loss. Although RPE tear in his left eye was identified before the first aflibercept intravitreous injection performed in order to treat neovascular AMD, he received three aflibercept injections as induction treatment. After induction treatment, a full thickness macular hole was identified associated with the contracted rolled RPE edge beneath the retina.Macular hole is commonly formed associated with tangential vitreous traction. Current report suggests that rapid contraction of the RPE underneath the retina can be one of the causes of a macular hole, and one of the side effects of anti-VEGF therapy for neovascular AMD. Neovascular Age-Related Macular Degeneration (wet AMD) is the major cause of legal blindness among the elderly people in many countries. Anti-vascular endothelial growth factor (VEGF) therapy is now the major treatment in order to prevent severe vision loss and possibly improve vision. Tears of the retinal pigment epithelium (RPE) are recognized as complication of wet AMD in patients with pigment epithelial detachments (PED) . AlthougA 94-year-old man presented with sudden visual disturbance of his left eye. At the first visit, the best corrected visual acuity (BCVA) in the right eye was 0.046 log MAR and in the left eye was 1.7 log MAR. The axial length of the right eye was 23.46\u00a0mm, and that of left eye was 23.47\u00a0mm. Fundus examination showed multiple drusen in the right eye, and subretinal bleeding and vascularized PED associated with wet AMD in the left eye. Fluorescein (FA) and Indocyanine (IA) angiography showed occult with no classic choroidal neovascularization (CNV) in the fovea and an RPE tear at the edge of PED. OCT showed a large PED and serous neurosensory retinal detachment. (Figure\u00a0RPE tear is well known as the complication of wet AMD, especially common in the patients with PED . AlthougIn this case, the patient received aflibercept injections for his wet AMD with vascularized PED. Tear of RPE at the edge of the PED occurred before the first injection and the rolled RPE flap involuted underneath the retina. Rolled RPE flap associated with subretinal fibrosis resulted in traction on the fovea from underneath the retina during aflibercept treatment. The contracted fovea above and beneath retina was split and there was progression to a full thickness macular hole. He didn\u2019t receive surgical procedure for closing macular hole, because the macular hole was over an area devoid of RPE due to the RPE tear and that surgical closure of the hole would not likely lead to improvement in vision. His BCVA remained stable during further observation.To our knowledge, this is the first case report of macular hole formation secondary to an RPE tear and contraction of the RPE edge and subretinal fibrosis following multiple intravitreal aflibercept injections. Although the incidence of full thickness macular hole formation, as a complication after anti-VEGF therapy is low, one should be mindful of such complications associated with anti-VEGF injections.Macular hole is commonly formed associated with tangential vitreous traction in the fovea. Current report suggests that rapid contraction of the RPE underneath the retina can be one of the causes of a macular hole, and one of the side effects of anti-VEGF therapy for neovascular AMD.Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the editor of this journal."}
+{"text": "This article reports a cDNA collection representing more than 2000 new, full-length transcripts from a high-quality cDNA library. A large number of cDNA inserts were sequenced from a high-quality library of chicken bursal lymphocyte cDNAs. Comparisons to public gene databases indicate that the cDNA collection represents more than 2,000 new, full-length transcripts. This resource defines the structure and the coding potential of a large fraction of B-cell specific and housekeeping genes whose function can be analyzed by disruption in the chicken DT40 B-cell line. Large-scale genomic and cDNA sequencing projects have revealed thousands of new genes whose open reading frames (ORFs) are highly conserved during vertebrate evolution, but whose precise cellular functions remain unclear. Although functional analysis by gene disruption is possible after transfection of murine embryonic stem cells and the breeding of knockout mice , these win silico gene structure prediction methods have a high error rate and often do not correctly annotate the intron-exon structure of genes. Only full-length cDNAs unambiguously define the boundaries of the transcription units within whole-genome assemblies and cloned full-length cDNAs are also of immense practical value to complement mutant phenotypes and artificially express the encoded protein [The recent release of the chicken genome sequence  greatly  protein . For the protein ,12. Alth protein  and othe protein , relativHere we describe a project to sequence and characterize a large number of full-length cDNAs from bursal lymphocytes. The corresponding genes are likely to be expressed in DT40 and this should facilitate their analysis by targeted gene modifications. In combination with the recently released cDNAs from other tissues , the burThe overall strategy for producing the greatest possible number of new full-length cDNAs expressed in bursal lymphocytes is outlined in Figure The plasmids corresponding to the remaining 2,796 ESTs were chosen for full insert sequencing by bidirectional primer walks. Once the end of the walks had been reached, the sequences of the full-length cDNA inserts were assembled. From the BLAST search results the most likely methionine start codon was assigned to each sequence. About 15% of the cDNA sequences showed evidence for premature frameshifts in the form of short ORFs and stretches of conserved sequence in a different frame further 3'. If overlapping ESTs were found in the public databases, the cDNA sequences were edited to correct the likely reverse transcription error, otherwise these sequences were discarded.A total of 2,272 high-quality chicken full-length cDNA clones were sequenced and assembled, manually annotated with respect to their likely translation start codon and deposited both at The Bursal Transcript Database website  and in tThe most remarkable feature noted in the analysis of 5' UTRs of the bursal cDNAs is a very high GC content (67%). This supports the observation that the GC content of 5' UTRs is particularly high in warm-blooded species . On the The accurate prediction of the translation start codon remains difficult and in some cases our annotations remain tentative. Sequences surrounding the translation start codons are not random and in mammals match the consensus GCCRCCaugG (where aug is the start codon and R is either A or G) . The mosA detailed analysis shows that the riken1 collection of cDNA sequences contains 4,406 AUG codons upstream of the annotated translation start codons in 2,218 of the bursal cDNAs. Nine hundred one of these alternative start codons were in the same reading frame as the annotated ORF. An in-frame stop codon within the 5' UTR region was present downstream of 501 of these 901 alternative start codons. The total number of ORFs present in 5' UTR regions of riken1 cDNAs was 1,289.We have checked whether the context of the annotated AUG start codons differs from the context of the alternative upstream AUG sequences of the bursal cDNAs. We therefore extracted 10-bp long sequences surrounding the annotated start codons and the alternative upstream AUGs and visualized sequence variability using the sequence logo software  Figure . The annAll full-length cDNAs were compared to the collection of transcripts predicted from the chicken genome sequence by the Ensembl system . The traFigure When compared to available chicken ESTs or cDNAs in the public databases, some of the bursal cDNAs showed significant structural differences most likely due to differential transcript processing. In addition, the bursal cDNA collection has been used to define a large number of intragenic single-nucleotide polymorphisms (SNPs) .All full-length cDNAs were compared to the Pfam database , which sTables There are 22 full-length cDNAs in our collection containing Pfam domains annotated by the GO term 'molecular function unknown'. Experimental information concerning the molecular mechanisms of action is very sparse or nonexistent for proteins sharing these evolutionarily conserved domains. Highly similar human proteins exist for the chicken proteins, an example being the human protein BM02. Taking into account the ease of targeted genome modification and availability of numerous functional assays, the DT40 cell line is an attractive model system to provide first insights into the functions of the evolutionarily conserved domains described above.All the full-length cDNA sequences are stored within the Bursal Transcript database . This dain vitro or for complementation of mutant DT40 phenotypes with the added convenience that the cDNA sequences are not only known, but also available as cloned pieces of fully sequenced DNA.The cDNAs from bursal lymphocytes represent one of the largest full-length cDNA collections in the chicken, comprising about one third of all currently available, experimentally verified transcripts and will be of general interest to researchers using the chicken as an experimental model as well as to the poultry industry. The resource has already been integrated with the chicken genome sequences to build a unigene catalog , to defiLMO1 locus. This sequence was present as a stuffer of the lambda vector used for the library construction and the clones containing it were removed from further analysis. In total, the 5' single-pass sequencing of 14,976 clones yielded 11,116 high-quality ESTs of the riken1 library.The riken1 library was synthesized from mRNA of 2-week-old CB strain bursal lymphocytes using the biotinylated cap trapper method ,31. The BLAST searches against the 'All non-redundant GenBank CDS' database showed that approximately 80% of the 5' EST sequences matched GenBank entries with a score of at least 50. This score threshold was chosen because it allowed us in most cases to align the putative start codon of the query sequence to the EST. These sequences were chosen and clustered  to removSufficient plasmid template for numerous sequencing reactions was prepared from the clones corresponding to the selected ESTs. All plasmids were then sequenced with a primer complementary to a plasmid sequence 3' of the cDNA insertion site. Subsequently, custom-made 20-mer primers based on available sequences were used for sequencing until the 3' and 5' ends of the cDNA inserts were reached. All sequences were processed as described previously , except Gallus gallus ESTs from the public databases. If the short ORF could be corrected by adopting the sequence of an overlapping EST, the cDNA sequence was edited. The type of editing was recorded and the corresponding riken1 clone was annotated as likely to be defective. In total, 293 cDNAs were removed because either a likely artificial frameshift could not be corrected by using sequences of overlapping ESTs or they contained multiple stop codons in all three reading frames or they showed evidence for unspliced introns. All cDNA clones are freely available upon request to the corresponding author and their sequences have been submitted to the EMBL public database (accession numbers AJ719267-AJ721138 and AJ851370-AJ851825).The integrity of the conserved ORF within each assembled cDNA sequence was manually examined by inspecting BLAST search results against the public protein and EST databases. To facilitate this task, a new EstSet module was added to FOUNTAIN . The useThe sequences surrounding the annotated start codons (10 bp upstream and downstream) were exported and submitted for information content visualization by the WebLogo software . Subsequ-6) run on the binary database files downloaded from the National Center for Biotechnology Information (NCBI). Functional classes were assigned according to Pfam to GO mapping provided by the InterPro database. The XML information exchange standard was used to interface the BLAST program outputs with the FOUNTAIN package.The riken1 cDNAs were compared with the collection of predicted chicken transcripts downloaded from the Ensembl ftp site  using th"}
+{"text": "Multiple sequence alignment algorithms are very important tools in molecular biology today. Accurate alignment of proteins is central to several areas such as homology modelling, docking studies, understanding evolutionary trends and study of structure-function relationships. In recent times, improvement of existing progressing programs and implementation of new iterative algorithms have made a significant change in this field.We report an alignment algorithm that combines progressive dynamic algorithm, local substructure alignment and iterative refinement to achieve an improved, user-interactive tool. Large-scale benchmarking studies show that this FMALIGN server produces alignments that, aside from preservation of functional and structural conservation, have accuracy comparable to other popular multiple alignment programs.The FMALIGN server allows the user to fix conserved regions in equivalent position in the alignment thereby reducing the chance of global misalignment to a great extent. FMALIGN is available at  The advent of large genome projects has led to an explosion of sequence data in public databases. Analysis of protein families, understanding their evolutionary trends and detection of remote homologues are now the primary objectives. Genome annotation and analysis tools like fold prediction, homology modelling, protein-ligand docking and clustering algorithms rely heavily on accurate multiple alignments to provide a genome-wide perspective.The most popular approach for multiple sequence alignment has been the progressive alignment method . A multiIn this paper, we present an alignment algorithm that combines the properties of both progressive alignment methods and iterative refinement algorithms. This algorithm offers the user the selective advantage of guiding the course of alignment by simultaneous inputs of multiple conserved motif regions that in turn guarantees retention of structure/function in the final alignment. FMALIGN is an alignment server that provides the user to obtain a control over the alignment by providing important conserved regions as input to the alignment program to achieve a more structurally relevant and functionally useful alignment of protein sequences. It employs the sequential branching method to identify the closest pair of sequences and subsequently includes the next closest sequences to generate a guided tree using UPGMA , which iThe algorithm of FMALIGN (Fixed Motif ALIGNment) program combines three main criteria: (a) Progressive global alignment method, (b) substructure  conserved region fixation and (c) iterative refinement of alignment with identification of more conserved regions. The procedure involves three steps: (i) identification and fixing of the specified sequential conserved regions. This alignment method requires specific regions of the sequences to be aligned as anchor and these anchors are generally meant for sequentially conserved parts which do not undergo many changes. (ii) derivation of the progressive multiple sequence alignment guided by the tree. During this step, excluding the fixed anchored regions, the rest of the sequences are divided into several sub-segments that are aligned employing a dynamic alignment algorithm in a sequential order from N to C-terminus. The phylogenetic guide tree has been derived using Unweighted Pair Group Method with Arithmetic Mean (UPGMA)  which isFMALIGN server can accept amino acid patterns for multiple motifs provided by the user. It also provides option to the user to search motifs within their sequences using FINDMOTIF routine or to obtain them for the alignment by providing a link to SMoS , a strucTo assess the performance of FMALIGN in comparison to other programs, Sum-of-Pair-score (SPS) and Column-Score (CS) alignment scoring scheme  are applFMALIGN derived alignments retain high degree of conservation in secondary structures. Six members from the globin family were selected comprising a wide range of sequence identity between them (7% to 61%). Conserved regions for six aligned globin sequences were identified by the FINDMOTIF routine starting from CLUSTALX  alignmenIn order to evaluate the FMALIGN server, the results have been compared with 10 other alignment programs and objective criteria were employed to assess the quality of an alignment. We selected the BAliBASE benchmark alignment database  to compaReference 1 alignments consist of a small number of equidistant sequences of similar length, i.e. the percent residue identity (% ID) between any two sequences is within a specified range and no large extensions or insertions have been introduced.Reference 2 contains alignments of a family of closely related sequences with >25% ID, plus up to three 'orphan' sequences . It is designed to evaluate program accuracy according to two criteria: (i) the stability of the family alignment when orphans are introduced into the sequence set and (ii)the quality of the alignment of the orphan sequences.Reference 3 checks the ability of the programs to correctly align equidistant divergent families into a single alignment. The reference alignments consist of up to four families, with <25% ID between any two sequences from different families.Reference 4 and 5 contain alignments of upto 20 sequences including N/C-terminal extensions (upto 400 residues) and insertions (upto 100 residues), respectively.This dataset is designed to study the effect of sequence length and percentage identity on the performance of the alignment program and provides a basis for the remaining tests. The overall performance of FMALIGN server for this dataset is comparable to the two best performing alignment programs, like PRRP  and CLUSIt is possible to assess the performance of the methods to align divergent 'orphan' sequences (10\u201320% ID with the family and between orphans) with a family of highly related (>25% ID) sequences using this data set. It is also interesting to observe the disruption of the family alignment due to the introduction of orphans. Figure This allows the assessment of the programs to correctly align approximately equidistant divergent families (<20% ID) composed of highly related sequences (>25% ID) into a single multiple alignment. Figure This dataset includes large N/C-terminal extensions to investigate whether the programs are capable of aligning the core blocks flanking the extensions. No large internal insertions are introduced at this stage. Mostly local alignment strategies out-perform the global methods. PILEUP  is the only program based on a global alignment method which does reasonably well compared to other global methods. Performance of FMALIGN is comparable to the best three methods  are calculated using a standard program kindly provided by the authors of BAliBASE. The inter-motif regions are aligned in FMALIGN by normal progressive alignment using standard substitution matrices like BLOSUM62. The gap penalties used in this version of FMALIGN are all maintained according to standard multiple alignment parameters. Benchmarking at the superfamily level has also been done utilizing both structural and sequential conserved regions. The dataset is wide enough to include proteins from different structural classes and of different length. The average sequence identity for this dataset was less than 30% since the proteins are related at the superfamily level. The performance of FMALIGN has been tested against one of the best performing multiple sequence alignment (T-Coffee) as well as structure based alignment tool (COMPARER). Studies on large and different datasets revealed an overall better performance of FMALIGN server for all categories in BAliBASE benchmarking database. It works especially well at lower sequence identity range, such as superfamily level, where no two proteins are more than 25% identical to each other in comparison to other popular methods like CLUSTALX and T-Coffee. It is well-known that automatic multiple sequence alignments at poor sequence identity are often subject to careful manual validations and improvements to avoid offsets of critical functionally important residues. FMALIGN can sensitively address this issue to avoid manual intervention subsequent to final alignment. FMALIGN-derived alignments also show a high conservation of secondary structural elements and provide better alignments for comparative modelling. The implementation of this alignment algorithm can be used to include new members into an existing protein superfamily with the help of motif regions that provide a reliable approach to connect protein sequences with their structural homologues within a particular superfamily. FMALIGN is available via the following URL S.C. had carried out the benchmarking, was involved in the development of the server and has written the first draft of the manuscript. N.B. had written the initial part of the code and P.A. has written the latter part of the code and developed a web server. R.S. had initiated the idea, was involved in discussions and in the critical reading of the manuscript.Fixed Motif ALIGNmentFMALIGN SPS Sum-of-Pairs Score"}
+{"text": "The authors showed that the number of first-author publications was associated with matching into residency programs that were ranked higher in Doximity's reputation and research output rankings. Additionally, the h-index of these applicants was associated with matching into higher ranked residency programs by research output.Doximity's reputation rankings are widely used by residency applicants in the United States. However, questions have emerged regarding their accuracy and transparency.,Scopus and grouped the publications to develop a first-author h-index for each residency program.We utilized the PubMed database to identify the first-author publications of RO residents who graduated between 2015 and 2019 that were published from the start of RO residency until three months after the completion of residency as previously described.Our results are shown in Doximity's residency reputation ranking is calculated by asking board-certified physicians to nominate up to five programs that provide the best clinical training."}
+{"text": "Brain cancer is the most aggressive one among various cancers. It has a drastic impact on people's lives because of the failure in treatment efficacy of the currently employed strategies. Various strategies used to relieve pain in brain cancer patients and to prolong survival time include radiotherapy, chemotherapy, and surgery. Nevertheless, several inevitable limitations are accompanied by such treatments due to unsatisfactory curative effects. Generally, the treatment of cancers is very challenging due to many reasons including drugs\u2019 intrinsic factors and physiological barriers. Blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) are the two additional hurdles in the way of therapeutic agents to brain tumors delivery. Combinatorial and targeted therapies specifically in cancer show a very promising role where nanocarriers\u2019 based formulations are designed primarily to achieve tumor-specific drug release. A dual-targeting strategy is a versatile way of chemotherapeutics delivery to brain tumors that gets the aid of combined ligands and mediators that cross the BBB and reaches the target site efficiently. In contrast to single targeting where one receptor or mediator is targeted, the dual-targeting strategy is expected to produce a multiple-fold increase in therapeutic efficacy for cancer therapy, especially in brain tumors. In a nutshell, a dual-targeting strategy for brain tumors enhances the delivery efficiency of chemotherapeutic agents via penetration across the blood-brain barrier and enhances the targeting of tumor cells. This review article highlights the ongoing status of the brain tumor therapy enhanced by nanoparticle based delivery with the aid of dual-targeting strategies. The future perspectives in this regard have also been highlighted. It has a severe impact on people's lives due to failure in treatment efficacy of this cancer  is a complex, compact, and specific dynamic interface that exists between the central nervous system  and blood capillaries  which restricts the transport and diffusion of therapeutic drugs to the brain from the blood  is a compact and complex structure due to endothelial cell tight junctions  diffusion, diffusion through aqueous channels, paracellular transport, and active transport Warren, . Physico3.Generally, the treatment of cancer is very challenging due to many reasons. The microenvironment of tumors owe several special characteristics including low extracellular pH, higher interstitial fluid pressure, and irregular vasculature which combined with other cellular events  pose multidrug resistance (MDR) toward anticancer drugs  that work directly on target structures i.e., soluble factors or cell surface receptors and (ii) that use dual-targeting for delivery of a therapeutically active drug, e.g., effector cells and effector molecules  transient opening of BBB caused by \u201cnano-toxicity\u201d or \u201cnano-effects\u201d of the nanocarriers, or stimulus from surface coated surfactants on nanocarriers, leading to diffusion of drugs or drug-loaded carriers into brain parenchyma; (ii) adsorption of drug-loaded carriers on the surface of brain capillary endothelial cells (CECs), with subsequent release of the drug from the vehicle leading to increased drug concentration facilitating gradient and ultimately diffusion of the drugs into the brain; (iii) carrier-mediated transport of the drugs and drug-loaded nanocarriers through endocytosis, trans-cytosis, and/or exocytosis by brain capillaries, resulting in direct penetration to brain cells or parenchyma  clearance and increasing their circulation times. Endocytosis by cells is another fate of the adsorbed drug-loaded nanocarriers, often followed by exocytosis which leads to penetration of the drug-loaded carriers to brain cells or parenchyma. Endocytosis could occur by virtue of random uptake by caveolaes on the cells of plasma soluble molecules along with plasma  nanoparticles (PLGA NP) were fabricated to circumvent the BBB and off-target side effects at the organ level. The prepared polymeric nanoparticles were evaluated for their pharmacodynamic and pharmacokinetic profiles in CD \u2212 1 mice. Nanoparticles loaded with bevacizumab showed a boosted bioavailability as compared to free drug on one hand and an increased bevacizumab resident time in the brain along with mimicked penetration was observed on another hand -poly (lactic acid) nanoparticles with a cyclic peptide targeting platelet-derived growth factor receptor that is over expressed on the surface of both myeloma cells and cancer fibroblast cells. The 7.p\u2009<\u2009.001)  is a pressing obstacle in the way of therapeutics targeting brain cancers and tumors. The available treatment drugs suitable to target brain cancers are thus rendered from their therapeutic potential  and was conjugated to doxorubicin-loaded PLA nanoparticles. The findings of the study indicated that peptide decorated nanoparticles showed an affinity for both endothelial cells and the tumor environment. The fabricated peptide-functionalized nano particles also showed more accumulation at the tumor site as compared to nanoparticles complex without peptide conjugation  is another hurdle that is a prominent obstacle in the delivery of chemotherapeutics to brain tumor cells -based NPs are advised (Weissig et\u00a0al.,"}
+{"text": "To the editor,I thank the authors of \u201cPercutaneous tibial nerve stimulation versus electrical stimulation with pelvic floor muscle training for overactive bladder syndrome in women: results of a randomized controlled study   .\u201d I supWhat is the ranking of IVES and PTNS among the treatment options in patients with idiopathic OAB? Some authors listed the treatment options in idiopathic OAB as follows; first-line - behavioral therapy , second-line - pharmacologic , and third-line - neuromodulation/chemodenervation . IVES is involved in pelvic floor muscle training as a first-line treatment option   . On theAs a result, IVES and PTNS appear to be effective therapies used both as first-line treatment, as well as in managing refractory patients with idiopathic OAB. This needs to be expressed more clearly. Would it be more effective on the first line or the third line? or in other words; is there a difference in response to IVES and PTNS in antimuscarinic naive and refractory patients with OAB? Clarification of the ranking of both PTNS and IVES among treatment options in patients with OAB will be possible with the increase of qualified studies addressing this issue. This would make it easier to understand the rankings of IVES and PTNS among treatment options in patients with idiopathic OAB.The Author"}
+{"text": "Mental disorders are a major cause of work disability among working age population. Psychotherapy has been shown to be an effective treatment for mental disorders, but the evidence mainly comes from small scale randomised trials with a relatively short follow-up.We used population-based register data to examine the association between statutory rehabilitative psychotherapy and change in depression or anxiety related work disability using a quasi-experimental interrupted time series analysis.All those who started rehabilitative psychotherapy in 2011-2014 comprised the study group. The study group included 10436 participants who were followed from three years prior to four years after the onset of rehabilitative psychotherapy, resulting in 83488 observations. Annual total number of mental health related work disability months was calculated based on total number of annual compensated sickness absence and disability pension days.The onset of rehabilitative psychotherapy marked a decline in depression or anxiety related work disability as compared to the counterfactual trend. Specifically, a 20% decrease in the level  as well as a 48% decrease in the slope  of work disability was detected. The decline was steepest in the oldest age-groupProviding statutory psychotherapy may decrease work disability at the population level. Further evidence for causal inference and the potential heterogeneity of the association is required."}
+{"text": "This article investigates the unexplored potentials of vortices or orbital angular momentum (OAM) beams using the low-cost and high-gain dielectric reflectarray antennas (RAs) at the terahertz (THz) band. It proposes a paradigm to enable 3D beam-steering or OAM multiplexing by a single structure via tilted OAM beams. That, in turn, requires reaching the maximal attainable angles either to send multiple beams to different receivers or to focus the OAM beams of different modes in a desired direction. For this reason, two concepts are addressed in this work: (i). generating a single 3D steered OAM beam and (ii) producing multiple off-centered OAM beams with different modes. A volumetric unit cell is adopted to be accurately tuned through the aperture to steer the generated beams towards the desired direction(s). The proposed paradigm can be utilized to produce RAs with beam-steering or OAM multiplexing capabilities as candidates for THz indoor communications.  \u2022Employing tilted OAM beams at the terahertz band for wireless communications\u2022Applying OAM multiplexing using a passive reflectarray antenna\u2022Producing multiple off-centered OAM beams with different modes Optical materials; Antennas; Metamaterials The dramatic increase in the usage of online services during the Covid-19 pandemic, the ever-growing internet demand, and the ultra-high requirements of the fifth generation (5G) networks form a critical necessity to accelerate the development of wireless communication systems. To bear the burden of the multiple gigabits per second (Gbps) data rates expected within the next few years, expanding the application, transport, and network layers' capacities of communication systems would be inevitable D. .One of the solutions nominated for the physical layer is employing the spatial distribution of the electromagnetic (EM) wave during its propagation, which can be acquired by designing angular momentum (AM)-based structures. Given that AM has two components, the spin angular momentum (SAM) and orbital angular momentum (OAM). OAM-based structures can allow the simultaneous data exchange of several OAM modes through the same frequency D.  without The OAM multiplexing is usually achieved by generating different concentric modes that are stemmed from the same point . In that\u2022A single tilted OAM beam with  flexible control on the direction of the beam and a new method to produce multiple off-centered OAM beams of different modes using a single feeder. To the best of the authors' knowledge, this is the first work suggesting OAM multiplexing using a passive structure. Here, different scenarios of OAM beams are addressed in terms of the azimuth angle The prior scenarios will be validated by virtue of simulations as the fabrication at 330 GHz was not possible at this juncture.However, the excellent ability to control the phase-magnitude characteristics and the high gain has made metasurfaces a tailored fit candidate to shape OAM beams Z. Y. . That haThis contribution solves for the first time two critical challenges related to OAM beams. Firstly, it highlights the capability of controlling the direction of OAM beams at the THz band to achieve the required line-of-sight (LoS) for multiple beams of different modes. Furthermore, it proposes a novel design with OAM multiplexing without PIN diodes and varactors, which would be very expensive and complex to be built at 330 GHz. Both designs can play considerable roles in the development of the physical layer of the current wireless networks.Three single-layer RAs of 82 red beam . As showred beam A, a reflAs it is known, the phase distribution of the elements over the RAs' aperture should follow the shape of the desired beam. To generate a pencil beam, a specific phase distribution would be required that mimics several concentric circles to produce a spherical wavefront. The phase variation over an aperture of equation : by controlling the values of 2  upon reasonable request.Further information and resources related to this study will be fulfilled by the lead contact Ali Ali (This paper did not generate new unique reagents.The geometry of the unit cell is selected and simulated to achieve a reflection phase range of 300\u00b0 or above. Then the phase distribution of OAM was obtained by adding the component to change the spherical wavefront generated by Metrics are given and this could be verified in the responses of the proposed structures."}
+{"text": "This Research Topic gathers different contributions  describing immune related adverse events in cancer patients with preexisting autoimmune diseases or exposed to immunotherapy. Furthermore, the topic discusses new approaches to discover new biomarkers that predict the development of adverse events post immunotherapy.Zhou et\u00a0al.), introduces a case report describing autoimmune encephalitis (AIE), for the first time, as a neurological immune-related adverse event (n-irAE) of toripalimab (a new immune checkpoint inhibitor targeting PD-1) in metastatic melanoma patient. This has revealed the safety profile of this new immune checkpoint inhibitor and further studies are required to validate this finding in other cancer types.The first article of this Topic  which occurred four years after nivolumab introduction and lasted despite nivolumab discontinuation in a patient whose metastatic renal carcinoma is still controlled after more than two years without any anticancer treatment. This may highlight the potential association between irAE and response to immune checkpoint inhibitors. This underlines the existence of late-onset and long-lasting irAEs even after discontinuation of treatment, which should encourage clinicians to remain vigilant over the long term.The connection between the development of autoimmune reactions and immune checkpoint inhibitors has been investigated in Haas et\u00a0al. proposed a new immune checkpoint receptor, Siglec-7, which its expression could improve CD8+ T cell anti-tumour immune response and potentially improve approaches for personalized medicine and for T cell-driven autoimmune diseases and cancer.Dey et\u00a0al.. Authors found that the efficacy of immunotherapy was improved in patients who developed on-treatment irAEs. This was independent of severity of iAEs or the need for steroid treatment, which is important in allowing patients to remain on treatment and derive optimal clinical benefit. Further research is warranted to establish the correlation between incidence of irAEs and efficacy in this patient population.The efficacy of anti-PD-L/anti-CTLA-4 immunotherapy in lung cancer patients and the potential of developing irAEs were assessed in Glehr et\u00a0al. concluded that finding predictive biomarkers for irAEs in cancer patients treated with immunotherapy is challenging and requires further studies.Alternatively, a computational approach by We hope that the reader will find in this Research Topic a useful reference for the connection between autoimmune diseases and the application of immunotherapy in cancer patients, and recent approaches to find new predictive biomarkers to reduce the risk of irAE development and help in optimization therapy selection for patients.The author confirms being the sole contributor of this work and has approved it for publication."}
+{"text": "Brain stimulation therapies as biologically-oriented treatment methods can play an important role in treating certain psychological disturbances and psychiatric diseases. Step by step they successfully have been implemented in the field of mental health together with the different psychotherapy methods. While these types of therapies are less frequently used than medication and psychotherapies, they hold promise for treating certain mental disorders that do not respond to other treatments. These have included depression, posttraumatic stress disorder, anxiety disorder, Alzheimer's disease, and dementia. Non-invasive brain stimulation (NIBS) has been proposed as an intervention strategy for mental disorders. NIBS has immediate effects on neural excitability but also after effects  oriented modalities is a psychologically-oriented treatment method which can lead to behavior change, changes in cognition, emotions and significant improvements in psychological symptoms and mental health. Contemporary Psychotherapy modalities include Cognitive Behavioral Therapy (CBT), Rational Emotional Behavioral Therapy (REBT), Acceptance Commitment Therapy (ACT), Mindfulness and Schema therapy, among others. While neurostimulation and psychotherapy use different mechanisms, both can influence and change human psychological states and mental health. That is the main reason why this Research Topic attracts scientific attention for future discussion.This Research Topic offers several investigations into the empirical data and related papers comparing the effectivity of new biologically-driven treatment methods based on neurostimulation and the psychologically-driven treatment methods based on psychotherapy. is a systematic review and meta-analysis aimed to critically evaluate and determine the effectiveness and safety of Mindfulness-based Interventions in alleviating the feeling of loneliness. Despite several methodological limitations, the review found significant improvement in loneliness when mindfulness intervention with an average length of 8-week duration was introduced to the population with generally no mental health issues. Given the current rise in loneliness levels, clinicians and the public can consider applying mindfulness intervention to alleviate loneliness when there is no existing mental health condition.The first article of this Research Topic  is a pilot study that underscored feasibility issues surrounding concurrent TMS administration and mindfulness-based practice in the form of listening to audio-guided meditation exercises. They concluded that It is possible that learning and practicing Mindfulness Cognitive Behavioral Therapy (MCBT) immediately before or immediately after TMS treatment sessions would have worked better for achieving the goals they identified. The results of their study highlight numerous feasibility issues with MBCT via guided audiotapes during TMS treatment. Future work should draw on these shortcomings to evaluate the appropriateness of MBCT for depressed patients undergoing neuromodulation.There is a growing interest in combining TMS with other concurrent psychotherapeutic interventions to optimize treatment outcomes. A very interesting article on this Research Topic  aimed to investigate the effects of a half-open continuous group cognitive behavioral therapy (CBT) with a cognitive behavioral analysis system of psychotherapy elements as a follow-up treatment for all ECT patients, regardless of response status after ECT, on reducing depressive symptoms and promoting psychosocial functioning. During group CBT, Post-ECT symptom reduction was not only maintained but there was a tendency toward a further decrease in depression severity. This reduction could be sustained 6 months after the end of the group, regardless of response status after ECT treatment. Aspects of quality of life and emotion regulation strategies improved during group CBT, and these improvements were maintained 6 months after the end of the group. Their approach might not only help to further reduce depressive symptoms and prevent relapse but also promote long-term psychosocial functioning by improving emotion regulation strategies and psychological quality of life. A study conducted by Lyby et al. aimed to compare two multidisciplinary occupational rehabilitation programs based on multimodal cognitive behavioral therapy on self-rated health and work ability. The results revealed that both groups improved on the selected outcomes. Within-group contrasts and effect sizes showed that the inpatient group showed larger effect sizes at the end of rehabilitation and 12 months post-intervention for work-related outcomes than the outpatient group.The part of this Research Topic is also a pilot study Grycuk et al. aimed to explore experiences and perceptions of transcranial direct current stimulation (tDCS) among participants diagnosed with schizophrenia. Five themes were identified: (a) motivation for study enrolment; (b) concerns about tDCS; (c) factors reducing the fear of tDCS; (d) experience of tDCS; (c) perceived effects of tDCS. After the first session, participants no longer felt anxious about the remaining ones. Strategies to improve treatment experience and study recruitment have been identified. Future perspectives from a case report on Transcranial Magnetic Stimulation Cognitive Behavioral Therapy, and Psychopharmacological Treatment for Post-traumatic Stress Disorder were presented in the article of Seybert et al. The last article on this Research Topic is focused on Risk assessment of electroconvulsive therapy in clinical routine: A 3-year analysis of life-threatening events in more than 3,000 treatment sessions. The beneficial risk profile of ECT performed in the standard care of psychiatric hospitals suggests a more generous indication of this treatment method. They recommend that ECT facilities collect their own safety data to allow a reliable judgment of their institutional ECT risk profile.The next two articles are focused mostly on the impact of rTMS on mental health. The article of This Research Topic gathers different contributions highlighting novel impacts of Neurostimulation and Psychotherapy on Mental Health (Richter et al., LM wrote the first draft. KR provided critical comments and Editorial suggestions for revisions. All authors agreed on the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Women with a diagnosis of non-affective psychosis have a lower fertility rate than the general population. However, perinatal outcomes in mothers with non-affective psychosis are under-researched. What is the general fertility rate (GFR) of women with a lifetime diagnosis of non-affective psychosis in Scotland? Does such a diagnosis affect the outcome of pregnancy? An \u2018exposed\u2019 cohort with non-affective psychosis and at least one pregnancy was established using a combined dataset derived via data linkage in local safe havens of routine psychiatric and maternity data from two Scottish regions:Grampian (NHSGr): Aberdeen Maternity and Neonatal Databank (AMND); psychiatric casenotesGreater Glasgow and Clyde (NHSGG&C): SMR02; PsyCIS bespoke psychiatric databaseExposed women were matched to women without a diagnosis of non-affective psychosis, by maternal age (NHSGG&C only), year of first birth, parity and deprivation, sourced from AMND/SMR02 in a 3:1 unexposed:exposed ratio.Demographics and pregnancy outcomes of exposed versus unexposed women were analysed to describe effect of psychosis on pregnancy. Many challenges were encountered in terms of having legal agreements in place between institutions and safe havens, constructing cohorts and datasets within each study site and joining the data to analyse the overall cohort. Challenges with the data itself included discrepancies between the variables measured in datasets in different sites and missing information within patient records, particularly in earlier years.Preliminary results for the NHSGG&C region show that the average GFR for exposed women aged 15-44 from 2005 to 2014 was 14.38 compared to the general population rate of 55.26. The number of women ever having a miscarriage was significantly higher in the exposed group . However during the study period (1996 to 2014), more unexposed women had miscarriages . There were no significant differences in pregnancy complications for the study period. The mean birthweight of babies was lower  and more babies were admitted to neonatal units  in the exposed group.Results for the NHSGr region and the combined dataset will also be reported.This work highlights that there remain hurdles to linking data across sites, despite availability of rich datasets within Scotland. Women with non-affective psychosis within NHSGG&C region had a lower fertility rate on average than the general population and some poorer outcomes, such as birthweight and rate of admission to neonatal units."}
+{"text": "Recent years have seen a great advancement in the emerging field of Neural Computation, a study of the brain using neuronal network models. As a consequence, another field of science is being developed titled \u2018Computational Psychiatry\u2019 where neuronal network models of psychopathology help understand the possible etiology for mental disorders. With Computational Psychiatry we can begin and reformulate mental disorders as brain disorders. Etiological diagnosis in psychiatry will be the next breakthrough which will allow to effectively treat mental disorders and will bring psychiatry back to the realm of medicine Computational Psychiatry together with advances in technology, will transform psychiatry beyond recognition: With the development of the connecting internet and sensor technology  mental status examination can be easily extracted and delivered over distance (tele-psychiatry). With the help of AI the extracted psychiatric phenomenology can be interpreted to match most of the diagnostic process of a skilled psychiatrist. Once achieved a continual psychiatric monitoring coupled with new technology of wireless dry-electrode electrophysiological brain imaging can begin and collect big-data. Big-data analysis stand a good chance to reveal the etiological correlations between mental disorders and their brain-related origins. Thus, etiology for mental disorders can begin to unravel. Neural modulation technology will be the answer for effective therapeutic interventions .I am in a preliminary effort to develop a Digital application in the field of Psychiatry"}
+{"text": "Illicit drug toxicity poisoning (overdose) continues to be a public health emergency in British Columbia (BC) with record high rates of illicit drug toxicity during the COVID-19 pandemic. In 2021, 2224 people died of overdose in BC with some of the highest rates recorded in rural and remote regions. Understanding the geographic variations in overdose mortality risk is necessary to avoid disproportionate risk resulting from service access inequity. Using novel linked administrative health data from the BC Provincial Overdose Cohort we estimated the odds of fatal overdose per event (2015 - 2018) using both conventional logistic regression and Generalized Additive Models (GAM). The results of GAM were mapped to identify spatial-temporal trends in the risk of fatal overdose. We found that the likelihood of fatal overdose was about 20% higher in rural areas than in large urban centers, with some regions reporting odds 50% higher than others. Temporal variations in fatal risk exhibit an increasing trend over the entire province. However, risks in the Interior and Northern BC increased earlier and faster. The results of this study demonstrate the importance of geography to health outcomes and suggest that rural and remote regions may lack harm reduction services to counteract the province-wide increase in illicit drug toxicity death."}
+{"text": "ECT is a potentially life-saving treatment for patients with severe or treatment resistant depression. Cognitive function disturbances following ECT are generally transient, but could be of longer duration in some casesTo assess the cognitive side effects in patients with affective disorders treated with a course of electroconvulsive therapy (ECT).Cognitive functions of patients who undergo ECT was assessed prior to start of treatment, midway of the course of treatment and after end of the course of treatment using Montreal Cognitive Assessment (MoCA). We did a retrospective analysis of MoCA scores of 15 patients who received bilateral ECT in 2017-2018. In order to assess the efficacy of ECT in the treatment of their illness, we did a retrospective analysis of Montgomery Asberg Depression Rating Scale (MADRS) scores of 18 patients who received bilateral ECT in 2017-2018Only 7% of the patients who underwent ECT in our sample did have significant cognitive decline as per their MoCA scores. 28% of patients achieved complete remission in their depressive symptomes. 22% of patients continued on maintenance treatment. 95% of patients showed significant improvement in their symptoms following treatment with ECT where there symptoms reduced to either mild or minimal depressive symptoms.Cognitive side effect was not a significant side effect in our sample of patients. We did see an improvement in cognitive function in a significant number of the sample of patients as they progressed with treatment, which coincided with improvement in their affective symptoms."}
+{"text": "Introduction The COVID-19 pandemic impacted significantly on dental service delivery across England.Objective To explore how and why the pandemic affected antibiotic prescribing by primary care dentists.Methods Mixed-methods study: secondary analysis of routinely collected NHS dental antibiotic prescribing data from before and during the pandemic; and an online survey of dentists (NHS and private) across England's regions.Results  Dental antibiotic prescribing increased 22% in the pandemic's first year, with regional variation from a 12.1% increase in London to 29.1% in East of England. Of 159 dentists surveyed, 60% had prescribed 'many more' antibiotics. Some urgent dental centres required antibiotics before accepting referrals, irrespective of clinical appropriateness. Diagnosing remotely was hard. Antibiotics were used to delay aerosol generating procedures and fill gaps in services. Widespread frustration existed.Discussion Maintaining access to urgent dental care during a future pandemic would include availability of high-grade personal protective equipment for dental teams. Everyone must understand the impact of restricted dental access on antibiotic overprescribing and hence antibiotic resistance.Conclusion Reduced dental access and changes in dental service delivery because of the pandemic increased antibiotic prescribing. Ensuring uninterrupted access for all to effective urgent dental care is an important element of global efforts to tackle antibiotic resistance.Zusatzmaterial online: Zu diesem Beitrag sind unter 10.1038/s41415-022-5104-y f\u00fcr autorisierte Leser zus\u00e4tzliche Dateien abrufbar. Remote management of patients during the COVID-19 pandemic resulted in increased antibiotic prescribing in each of England's regions. Most dentists were not confident managing patients with acute dental conditions remotely. Ensuring access to face-to-face dentistry is an important part of efforts to tackle antibiotic resistance.Dentists felt frustrated about being prevented from providing the dental procedures needed to provide safe and effective care to people in pain. Many also expressed concern about the impact of increased antibiotic prescribing on antibiotic resistance and their experience of increased patient expectation that antibiotics are appropriate for toothache.Preparedness plans for future pandemics should recognise that antibiotics are not a substitute for dental procedures and dentistry was the only part of the NHS to experience an increase in antibiotic prescribing during the COVID-19 pandemic. Planners should aim to ensure sufficient face-to-face urgent dental care provision immediately upon implementation of pandemic restrictions.Zusatzmaterial online: Zu diesem Beitrag sind unter 10.1038/s41415-022-5104-y f\u00fcr autorisierte Leser zus\u00e4tzliche Dateien abrufbar. Antibiotics are not routinely recommended to prevent local or distant site infections (such as infective endocarditis).7 from a complete closure of all NHS and private dental practices (23 March to 7 June 2020)8 followed by a staged restoration of dental services in line with the easing of COVID-related safety measures , where appropriate. Only designated NHS urgent dental centres (UDCs) could provide dental procedures on referral from other services.8The COVID-19 pandemic has had a significant impact on dentistry in England,ures see .9 During10 This study aimed to describe that increase and to explore dentists' perspectives about why it occurred.Dentistry was the only part of the NHS in England which experienced an increase in antibiotic prescribing during the first year of the COVID-19 pandemic.A mixed-methods study consisting of two parts: i) secondary analysis of routinely collected NHS prescribing data; and ii) a survey of dentists (NHS and private) working across England since at least April 2019 (before COVID-19).11 Monthly totals for each of NHS England's seven regions were provided for the period January 2019 to September 2021. Prescriptions dispensed from prisons, hospitals and private prescriptions were not included.The total number of antibiotic items  dispensed by community pharmacists in England relating to NHS dental prescription forms (FP10D) were sourced from the NHS Business Services Authority.12 In the absence of more up-to-date figures, population estimates for 2020 were used to calculate the 2021 rates.To enable comparisons between regions, the rate of prescriptions dispensed per 1,000 of the population were calculated. Mid-year population estimates for 2019 and 2020 were obtained from the Office for National Statistics.11As these datasets were publicly available and completely anonymised, ethical approval was not required .An online survey of dentists working in primary dental care settings in England since March 2019 was undertaken using the Qualtrics XM tool. Participants were recruited via the online Facebook group 'For dentists by dentists' during the three-month period July to September 2021. The sample size of 136 responses was calculated by assuming that at least 90% of dentists would have increased their antibiotic prescribing since the start of the COVID-19 pandemic compared to the previous 12 months (the primary research question). Dentists who had not practised clinical dentistry in primary dental care in England since March 2019 were excluded.The survey consisted of 20 questions (see online Supplementary Information), with a mixture of multi-choice and free-text answers and was piloted with ten dentists from across NHS England's regions. Data were analysed using descriptive and inferential statistics to explore factors which may have affected dental antibiotic prescribing during the pandemic.Ethical approvalfor the survey was gained from University of Manchester UREC Ref. 2021-12282-19832 dated 29/06/2021. All participants consented to participate in the study and to have their data used as part of the research.A 22% increase in the number of NHS dental antibiotic prescriptions occurred in the first year of COVID-19 restrictions  compared to the previous year . The greatest increase occurred in the first phase when dental practices were closed (March to June 2020) . Since tIn the year before COVID-19 pandemic restrictions, all regions experienced reducing rates of dental antibiotic prescribing see . After tIn total, 159 dentists responded to the survey from across all seven NHS regions. Most were UK dental school graduates (84%) and 58% identified as women see .Table 1 Forcing dental practices to not see patients face to face during the early stages of the pandemic led to a reduction in the level of patient care and an unnecessary increase in the prescribing of antibiotics'.'Overall, 89% (141/159) of dentists reported that their dental antibiotic prescribing had increased in the first year of the pandemic (April 2020 to March 2021) compared to the previous year. Just three dentists reported prescribing antibiotics less often. Most had prescribed antibiotics remotely (n = 128) at least once during the initial two months when practices were closed:Most respondents felt that they understood the national guidelines for remote management issued on 25 March 2020, although nearly three-quarters  reported that local guidelines did not align well with national guidelines. As shown in online Supplementary Table 2, most dentists from each of the regions (except the South West) reported this poor alignment and there was no significant difference between the regions (p = 0.587). The South West was the only region where most  felt the local and national guidelines aligned well and generally had the lowest overall rate of dental antibiotic prescribing see .[Antibiotics] were almost a prerequisite for getting an appointment, even though it doesn't work for pulpitis'.'Common issues reported about this misalignment between local and national guidelines and protocols related to local mandating of antimicrobial prescribing  before acceptance of a referral by a UDC for treatment, irrespective of the referring dentists' assessment about whether antimicrobials were appropriate:Patients were refused to be seen at an urgent dental centre for treatment until they'd had antibiotics''I had to prescribe for a loose tooth as [the UDC] wouldn't see the patient otherwise'.'Half of the dentists  reported that, during the first phase of COVID-19 restrictions (23 March to 7 June 2020), their referrals to a UDC had been rejected because the patient had not first taken antibiotics:We were told we had to follow the [local] protocols for prescribing two antibiotics at the same time'.'In more than one of the regions, dentists reported that dual prescribing of antibiotics had been required:We had such limited capacity in our UDC''Some areas still do remote prescribing in a UDC. The service is commissioned to do this'.'Various reasons were proposed for this misalignment between effective care for people with acute dental problems and the practices operated by some UDCs, including insufficient availability of face-to-face urgent dental appointments and mainstreaming of remote prescribing.Fewer than half  of respondents were confident remotely diagnosing and just one-quarter  were confident remotely treating patients with acute dental pain or infection. Dentists who had worked in UDCs during the first year of COVID-19 were significantly more confident (p = 0.001) remotely diagnosing patients with acute dental conditions  than the other dentists  (see online Supplementary Table 2).I can no longer [provide] a quick extirpation at an urgent appointment like I would have done and therefore I am prescribing a lot more antibiotics''Massive increase in patients being referred in [to the endodontic referral practice] who have had irreversible pulpitis managed with multiple courses of antibiotics (obviously) without success'.'Some dentists were concerned that they were unable to provide the dental procedures which are normally indicated for the treatment of toothache. Removal of an inflamed dental pulp (extirpation) was classified in NHS standard operating procedures as an aerosol generating procedure (AGP) and hence was subject to additional infection prevention and control measures in dental practices. Even though antibiotics do not cure this type of toothache, some dentists were nevertheless prescribing antibiotics until a dental procedure could be provided for the patient.Delaying AGPs was an enduring problem for some, with 23 respondents reporting it as still being an issue after April 2021.Yes more [antibiotics] as patients demanded them'.'Over three-quarters  reported patients requesting antibiotics more often during the first year of the COVID-19 pandemic than the previous year:The difficulty I came across was the inaccurate description of the acute dental pain of the patients in order to get the antibiotics or painkiller'.'Other dentists felt that patients would report their symptoms in such a way as to negotiate for their preferred treatment outcome:Patients now think they can call for antibiotics when they wouldn't before and they use the fact they have COVID as an excuse as to why they can't come in. (Maybe scepticism but patients who have been told extraction is needed etc)'.'Dentists suggested that remote management of patients (with AAA) during the pandemic had had a lasting effect on patient expectations about the ability to use antibiotics to avoid a dental procedure:There are still not enough urgent dental slots within our service and we are still offering antibiotics as the first line treatment'.'Several dentists (from more than one NHS region) raised the continued use of remote antibiotic prescribing to fill gaps in NHS dental service provision as an issue not covered by the quantitative questions within the survey:I feel horribly compromised as I feel this is far from ideal and I worry about antibiotics''I felt that the AAA guidelines were totally against all I had been taught about treating dental pain, but I felt that I had no choice but to prescribe antibiotics on many occasions as we were not allowed to treat patients face to face''We were forced to prescribe antibiotics remotely''I lied a lot. When patients had pulpitis, I told them to say that I'd prescribed antibiotic as a means of being seen at the Hub. Antibiotic would not have been appropriate''It was a minefield!'.'Running throughout the 'free-text' comments was a sense of frustration. Many dentists felt their autonomy in clinical decision-making was being 'compromised', that they had 'no choice' in clinical decision-making and that were being 'forced' to provide care in a way which they felt was inappropriate:Remote management of patients during the COVID-19 pandemic resulted in dramatic increases in antibiotic prescribing in each of England's regions, with an overall increase of 22% in the first year of the pandemic compared to the year before it. A variety of factors have been identified which may have impacted on dental antibiotic prescribing as a result of the COVID-19 pandemic, including dentists finding it hard to diagnose patients remotely, UDCs requiring antibiotics to have been prescribed irrespective of their clinical appropriateness, the use of antibiotics to delay AGPs, and to fill gaps in NHS dental service provision. Many expressed concerns about the enduring impact of increased antibiotic prescribing during the pandemic on antibiotic resistance and on increased patient expectations about antibiotics being appropriate for toothache and for avoiding dental procedures.7 Even larger increases have been reported in primary dental care in Scotland (49%)13 and in the public health dental clinics of Alberta, Canada (76%).14 By contrast, reductions in dental antibiotic prescribing at the start of pandemic restrictions were reported in primary dental care in Australia (20%)15 and in Qatar, only 7% of patients managed remotely with teledentistry were prescribed antibiotics.16 In France, a similar increase (17%) was experienced in 2020 compared to 2019.17 Further research is indicated to understand the reasons for these differences between countries.England is not the only country to experience increased dental antibiotic prescribing related to remote management of patients during the pandemic.11 A House of Commons (HoC) Health Select Committee (HSC) review on the impact of COVID-19 on the NHS18 noted that people were returning in pain as they were being given antibiotics instead of procedures to treat the cause of the problem. The HSC also noted that staff in dental practices need access to 'particular types' of personal protective equipment (PPE), such as filtering facepiece respirators, to maintain the safety of staff and patients. A joint 'lessons learned' report from the HSC and HoC Science and Technology committees about the COVID-19 pandemic recognised that dentistry had been particularly badly affected because of the prevalence of AGPs during routine care.19 Ensuring access to face-to-face dentistry for people with toothache is an important part of efforts to deliver the government's vision to keep antibiotics working as effectively as possible for as long as possible and involves seemingly unrelated issues, such as the availability of appropriate PPE for dental teams during a pandemic.The widespread sense of frustration expressed by dentists about their inability to provide effective care for patients with severe toothache reflects issues identified in a survey of Scottish dentists.Confusion about the way some local guidelines and protocols did not reflect national guidelines on the management of dental patients with acute dental conditions was a significant concern. Further research is indicated to understand this issue from the perspective of UDCs and other organisations involved with the delivery of dental care during the COVID-19 pandemic. Preparedness plans for national emergencies should ensure clarity about the 'where appropriate' element of any future AAA approach. Training for implementation of emergency plans should also ensure that those responsible for commissioning and managing the delivery of NHS dental services understand the essential role of effective antibiotics for treating life-threatening infection and the futility of antibiotics for toothache such as pulpitis.20 An ethnographic study undertaken shortly before COVID-19 in out-of-hours (OOH) dental clinics and general dental practice found that dentists working OOH tend to be more confident at providing urgent dental care, especially numbing difficult teeth and for anxious patients.21 To ensure that the dental workforce is prepared to deal with a future pandemic and to improve access to urgent dental care for the whole population, it is suggested that the future NHS general dental services contract should include a requirement to provide urgent dental care to patients who are not regular attenders at that practice.Those with experience of working in the UDCs were more confident diagnosing and treating patients with acute dental conditions remotely than others in primary dental care. A systematic review of factors influencing dental antibiotic prescribing found an issue around the level of skill and self-belief of some dentists about providing dental procedures during urgent appointments.22 This pattern of dental hospitals rapidly transitioning to UDCs was reflected elsewhere in the country,21, although most other regions had fewer dental hospitals to serve their populace.23,24 Analysis of care provided for patients before referral into UDC hubs found that half of their patients had received a course of antibiotics before their onward referral into a UDC for treatment, with many appearing to be an inappropriate use of antibiotics.25,26 No differences were apparent in the survey results between the NHS regions, although the relatively low number of participants per region made statistical comparison inappropriate. Future preparedness planners should include evidence from around the UK about the best way to deliver UCDs quickly during a pandemic in areas with and without dental hospitals.Interestingly, in the first month of the pandemic restrictions, the London region experienced a markedly different pattern in the rate of dental antibiotic prescribing compared to the other six regions. This drop in dental antibiotic prescribing by primary care dentists may reflect the existence of multiple dental hospitals in the capital which rapidly became UDC hubs.It is important to highlight that this study's quantitative analysis was limited to antibiotic prescribing by NHS dentists and includes neither dental antibiotic prescribing in dental hospitals nor private dental practices, which account for around 25% of primary care dental provision in England. No source of routinely collected data exist for these settings. Given the restricted access to healthcare services experienced during the pandemic, it is also likely that many antibiotics were issued to people with acute dental conditions outside of NHS primary dental care . Further research is indicated to understand the magnitude of antibiotic prescribing for acute dental problems in other healthcare settings, to understand reasons for dental attendance in these settings and to identify care pathways so that safe and effective care can be provided for those patients through dental procedures, rather than antibiotic prescriptions.Reduced dental access and changes in dental service delivery because of the pandemic increased antibiotic prescribing. Ensuring uninterrupted access for all to high-quality urgent dental care is an important element of global efforts to tackle antibiotic resistance. This includes availability of appropriate PPE for dental teams during a pandemic and training of the wider team about appropriate treatment for acute dental conditions. Understanding the essential role of effective antibiotics for treating life-threatening infections and their futility for many acute dental conditions should be fundamental knowledge for everyone involved with planning, managing and delivering dental services.Supplementary Information (PDF 165KB)"}
+{"text": "This cohort study examines the association of the use of leukotriene-receptor antagonists during pregnancy with the risk of neuropsychiatric events in offspring. The present cohort study aimed to address this research question.Leukotriene-receptor antagonists (LTRAs) are a class of medications used for treating allergic airway diseases, including asthma and allergic rhinitis.STROBE) reporting guideline for cohort studies.We used data from the entire National Health Insurance Research Database to identify pregnant women and their offspring from 2009 to 2019 in Taiwan. The details of study cohort identification are provided in the eAppendix in International Classification of Diseases, Ninth Revision, Clinical Modification codes for 2009 to 2015 and International Statistical Classification of Diseases, Tenth Revision, Clinical Modification codes for 2016 to 2019 .Cox proportional hazards models were constructed to estimate the associations between prenatal LTRA exposure and NEs among offspring with covariate adjustment. A robust sandwich estimator was used to account for the dependences between siblings. We also performed Cox proportional hazards models to investigate the association between the duration of LTRA use (1-4 weeks vs >4 weeks) and cumulative LTRA dose (1-170 mg vs >170 mg) and NEs among offspring. The adjusted covariates are described in the eAppendix in A total of 576\u2009157 mother-offspring pairs (1995 LTRA-exposed children and 574\u2009162 nonexposed children) were identified in the original study population. After propensity score matching, 1988 LTRA-exposed children and 19\u2009863 nonexposed children were included in the subsequent analyses . Among tThis first nationwide cohort study extended previous studies by examining the association between LTRA use during pregnancy and risk of NEs in offspring and found that prenatal LTRA exposure was not associated with increased risk of ADHD, ASD, and Tourette syndrome in offspring. The main strength of this study is the inclusion of the whole Taiwan population data. Study limitations include the nonrandomized design, inability to detect risk beyond the first several years of life, and uncertain generalizability to non-Asian populations.In conclusion, this study found that LTRA use during pregnancy was not associated with significant risk of NEs in offspring. Clinicians prescribing LTRAs to pregnant women with asthma or allergic rhinitis may be reassured by our findings of no increased risk of NEs in offspring. Our findings should be confirmed by further replication studies."}
+{"text": "Alison Crawshaw will talk about her participatory research that uses design thinking to develop community-based strategies to improve health outcomes in migrant populations. She will summarise the benefits of using community-based approaches and co-designing public health initiatives with affected migrant communities, bringing in lessons learned from a recent project with the Congolese community in London."}
+{"text": "The median is a robust summary commonly used for comparison between populations. The existing literature falls short in testing for equality of survival medians when the collected data do not form representative samples from their respective target populations and are subject to right censoring. Such data commonly occur in prevalent cohort studies with follow-up. We consider a particular case where the disease under study is stable, that is, the incidence rate of the disease is stable. It is known that survival data collected on diseased cases, when the disease under study is stable, form a length-biased sample from the target population. We fill the gap for the particular case of length-biased right-censored survival data by proposing a large-sample test using the nonparametric maximum likelihood estimator of the survivor function in the target population. The small sample performance of the proposed test statistic is studied via simulation. We apply the proposed method to test for differences in survival medians of Alzheimer\u2019s disease and dementia groups using the survival data collected as part of the Canadian Study of Health and Aging. For right-censored failure time data, Brookmeyer and Crowley proposed a testing procedure for comparing 3 Although their procedure was based on comparing median point estimates, they implicitly assumed that the failure time distributions are members of the same location family. Brookmeyer and Crowley defined a weighted Kaplan\u2013Meier estimate to determine the sample median, however, the non-parametric estimate assumes the group survival distributions are equivalent. Given that members of a location family can be identified by their medians, these authors essentially test the equality of the underlying survival distributions. Rahbar et al. highlight this testing dichotomy by explaining that equality of distributions implies equality of medians whereas the converse statement is not necessarily true.4 Reid validated the bootstrapping procedure of Efron applied to the sample median for right-censored data and discussed the associated confidence interval properties.6In studies examining a survival time outcome for multiple groups/strata, it is typically of interest to the researcher to compare quantities related to the survival distribution such as the median. For example, Rahbar et al. compared the median waiting times for trauma patients to receive red blood cells using data from the Prospective Observational Multi-Center Major Trauma Transfusion study and, Brookmeyer and Crowley compared the median survival times for subjects receiving four types of cancer treatment using data from a Phase III colorectal cancer clinical trial.4 Using the asymptotic distribution of the Kaplan\u2013Meier estimator and an application of the functional delta method, Rahbar et al. derived a quadratic test statistic with an asymptotically chi-squared distribution.7 In this article, we propose an extension to the method of Rahbar et al. for the case in which the failure time data are both length-biased and right-censored using the nonparametric maximum likelihood estimator (NPMLE) of the unbiased survival function.8 We note that when the observed failure times are length-biased, the censoring mechanism is informative yielding an NPMLE which places mass on both the observed failure/censoring times of the prevalent cohort study.811 Thus, the unbiased survival function estimator is fully defined over the entire real line establishing the existence of the median point estimate. While other product-limit estimators for left-truncated right-censored failure time data may be applied , the survival function estimates may not yield a median point estimate when censoring is high. Although there may be instances in which the median point estimate exists when utilizing the bootstrapping procedure of Efron, some bootstrap samples may not yield median estimates requiring them to be discarded.5 In addition to ensuring the existence of the median point estimate, our use of the NPMLE of the unbiased survival function is motivated by its efficiency compared to all other nonparametric estimators.9Recently, Rahbar et al. proposed a hypothesis testing procedure for comparing population medians using right-censored failure time data which does not require the location family assumption.In Section 2., we define the notation for prevalent cohort studies with follow-up resulting in length-biased right-censored failure time data and describe how the asymptotic representation of the NPMLE of the unbiased survival function may be utilized to define a statistic for testing differences between multiple population medians. In Section 3., we generate simulated failure time data from prevalent cohort studies with follow-up to assess the performance of the proposed testing procedure and in Section 4., we apply our testing methodology to the Canadian Study of Health and Aging (CSHA) dataset to compare median survival between various dementia/Alzheimer\u2019s disease groups. We provide some extensions and future research directions in Section 5.215 Let the fixed constant 1619 Let 8:9 Using the relationship between the unbiased and length-biased survival functions given in equation . The percentiles of the central Let 2.122 In 10 and Huiart and Sylvestre.23Although the proposed testing procedure is based on determining differences between the unbiased survival function medians, a question that may be posed is whether the correct conclusion will be reached when testing for equality of the length-biased population medians instead. Using the weak convergence of the length-biased survival function NPMLE equation  may be f3To assess the performance of the proposed hypothesis test, we generated samples of length-biased right-censored failure time data from various distributions to control for the values of the unbiased population medians. Specifically, we considered three failure time distributions: uniform distribution with support We generated multiple length-biased right-censored failure time data sets and computed the empirical test sizes and empirical powers when the medians of the distributions were equal and different, respectively. We considered the case in which To assess how the power of the hypothesis test varied depending on the group sample sizes, we simulated length-biased right-censored failure time data from three groups with different medians . The qrlt function"}
+{"text": "As significance of medically unexplained symptoms increases in general practice it is important to discuss psychopathological comorbidity regarding the impact of health anxiety indicating sufferers excessive care use.To study the impact of health anxiety in depression with somatic symptoms.50 patients with depression with somatic symptoms compared to 79 patients with psychodermatological disorders with complaints of pathological skin sensations completed the Hospital Anxiety and Depression Scale (HADS) and the Short Health Anxiety Inventory (SHAI). The Mann-Whitney U-Test was applied. The psychosemantic method \u201cClassification of sensations\u201d was used to differentiate patients\u2019 bodily experience. Factor analysis was performed.Scores on HADS-anxiety and SHAI were significantly higher in depression , although there were no significant differences on HADS-depression. Factor analysis showed a polarization of bodily experience categories in depression as the first factor  included negative emotions with somatic sensations of exhaustion and the second factor  included pleasant sensations and positive emotions with the negative sign of factor loadings. In psychodermatological disorders the first factor  was quite similar, however the second factor  included skin and general somatic sensations illustrating the higher concern with somatic symptoms.Higher health anxiety in depression with somatic symptoms compared to psychodermatological disorders (more concerned with bodily experience) could be associated with patients\u2019 complaints of emotional state indicating differences in psychological mechanisms. The research was supported by Russian Foundation for Basic Research with the Grant 20-013-00799."}
+{"text": "Medical trainees rely on supportive personal relationships when navigating the challenges encountered during residency training.A qualitative study conducted at our institution suggested that an additional barrier to effective communication between residents and their support persons (SP) is dissonance between residents\u2019 personal and professional identities.7We developed a virtual open house (VOH) to invite residents\u2019 self-selected SPs into the residency community and provide them with greater insight into the clinical and non-clinical training environment.All 72 postgraduate year PGY1-4 residents in our emergency medicine (EM) residency training program and their self-selected SPs received an electronic invitation to attend a two-hour VOH in April 2021. The VOH was scheduled during protected educational conference time due to prior studies suggesting that wellness interventions are perceived as a time burden and are limited by a lack of available time. As the aim of the VOH was to create an opportunity for residents to share details of their training environment, content selection was shaped largely by resident input. A VOH Task Force, created and led by HV, consisted of a select group of residents representing each postgraduate training year as well as individual resident leads of extracurricular committees. Session content, structure, and format were informed by Kern\u2019s six-step approach to curriculum developmentDuring the VOH, the residency program director first provided an overview of the impact of COVID-19 on the resident training experience and oriented guests to the broader hospital system. After this introduction, resident representatives summarized the day-to-day clinical responsibilities and non-clinical opportunities that characterize each residency training year. Additional residents then provided updates on the current projects and activities of various resident-led special interest committees . During each of these segments, speakers included photos and videos to better familiarize attendees with the physical work environment and the specific members of the residency community. The program then concluded with an opportunity for large-group discussion and reflection among all attendees. While the virtual modality limited the use of interactive educational strategies, we incorporated a combination of formal presentation, large-group debriefing, and reflection to deliver session content.This study received institutional review board exemption from the University of Southern California. We conducted a mixed-method analysis of participants\u2019 experiences attending the VOH. Immediately after the conclusion of the VOH, all residents and guest attendees received an electronic invitation to complete an anonymous survey regarding their experiences attending the VOH . This su12Additionally, six months after the conclusion of the VOH, we conducted two virtual focus groups with a convenience sample of SPs who had attended the VOH. Focus groups were scheduled at a delayed time point to explore any sustained perceptions or impacts of the VOH experience. Five SPs participated in each of the two focus groups, both of which were led by AJ given her experience in focus group facilitation. A semi-structured interview guide was developed by AJ and HV and aimed to explore a deeper understanding of the VOH experience as well as probe for any change in the conversational dynamic between SPs and residents following the VOH . InterviWe used an inductive thematic analysis approach.Of the 155 individuals who attended the VOH 60 (38.7%) were residents, 86 (55.5%) guests, and 11 (7.1%) faculty members. Forty residents (66%) and 47 guests (54.7%) responded to the post-VOH survey. Of the SPs who responded to the post-session survey, 89% were parents or other relatives. Additional demographic information for SPs is found in The SPs reported that participation in the VOH facilitated subsequent dialogue with their residents and provided them with an increased sense of comfort and familiarity with the residency training environment. Representative quotations are included in the Participants also appreciated the opportunity to virtually \u201cmeet\u201d their residents\u2019 colleagues and supervisors, finally \u201cput[ing] faces to names.\u201d They were comforted by gaining an increased understanding of the emotional and structural support provided by the residency program and by directly witnessing the collegiality among trainees and faculty members. Several participants referenced the physical and emotional separation caused by the COVID-19 pandemic and reported that their concerns about their residents were alleviated by receiving greater insight into, and familiarity with, the residency community.The focus groups also provided insights into areas for improvement during future iterations of the VOH. Participants requested the addition of virtual breakout rooms to provide them with opportunities for more intimate, small-group conversations. They also voiced enthusiasm for more longitudinal forms of connection to the residency community . Future iterations of this innovation can modify the frequency of VOH events and add in-person or hybrid activities when social distancing restrictions are lifted. Additionally, educators can consider including explicit instruction to SPs on effective support and communication techniques and incorporating didactic components on well-being and burnout. To enhance our understanding of the impact of a VOH, future studies should explore resident perceptions of changes to their perceived social support networks and the quality and quantity of dialogue with SPs after participation in a VOH.Our innovation involved a single institution and medical specialty, which may limit its generalizability. The SPs were self-selected by residents; individuals who attended and completed the post-session surveys may have been susceptible to varying levels of response bias. Additionally, as we did not establish levels of pre-existing medical knowledge among SPs, the perceived utility of the VOH in offering topics for future conversation may not be broadly applicable. Our qualitative findings are limited by the small sizes of our focus groups and the social desirability bias inherent to many focus group discussions. In addition, frank discussion from SPs regarding their VOH experience may have been inhibited by use of a member of program leadership (AJ) as the focus group facilitator.Despite these limitations, the use of a VOH may help encourage future dialogue between residents and their SPs about the residency training experience. Residency program leaders should consider adopting interventions aimed at reducing identity dissonance by incorporating residents\u2019 support persons into the residency community."}
+{"text": "Most studies examine the consequences of self-perceptions of aging (SPA). Little is known about the antecedents. The possible selves framework suggests that earlier life experiences can shape people\u2019s scenarios about their own aging. We examine the association between early-life informal caregiving experiences and SPA later in life using data from the HRS Retrospective Life History Mail Survey and the Psychosocial and Lifestyle Questionnaire . Participants reported up to five periods of unpaid caregiving (\u2265 6 months) with family members. SPA was measured by the HRS 8-item scale. Step-wise linear regression revealed that compared with people who had not been caregivers, early-life caregivers reported more negative SPA later in life . The association holds after controlling for health-related and demographic covariates. Future research and interventions should focus on the consequences of early-life caregiving on the caregiver\u2019s scenarios about their own aging."}
+{"text": "A cochlear implant (CI) is a prosthetic device used to treat severe to profound hearing loss. A CI bypasses the damaged inner ear and directly stimulates the auditory nerve with an array of electrodes, providing sound information. To achieve ideal speech perception outcomes, it is important to minimize the mismatch between the assigned frequency range to each electrode on the array and the frequency range naturally represented by the neural element stimulated by the electrode  to understand the cortical processing of frequency changes in CI users and its contribution to variability of CI outcomes measured behaviorally. The authors examined the scalp-recorded cortical acoustic change complex (ACC) evoked by the frequency change contained in a pure tone in adult CI users. Results showed that the latency values of ACC peak components were negatively correlated with behavioral performance on speech perception and frequency change detection. The variation in CI speech outcomes can be partially explained (about 16\u201320%) by the variability of cortical encoding of frequency changes reflected by the ACC.Neurologically, CI users' auditory system may display great variation in central auditory processing of sound features, which has been considered an important contributor to variability in CI outcomes , a neural representation of the pitch of complex sounds in the upper auditory brainstem, to a Mandarin lexical tone in 43 monolingual English-learning infants at 7 and 11 months of age. Infants were semi-randomly assigned to receive either no intervention or a 4-week music intervention involving active music listening and synchronizing body movements to the musical beats at 9 months of age between the two sessions of FFR testing. Results showed that the FFR pitch-tracking accuracy was resistant to decline that was seen in the group receiving no intervention, suggesting that music intervention during critical period can maintain the auditory systems' ability to track acoustic properties of non-native speech.While CI users' brain can learn new modality of hearing after implantation Kim et al. used a neurofeedback training paradigm to enhance the attentional modulation of cortical auditory evoked responses in NH listeners. This study provided a novel direction of possibly using the neurofeedback training approach in CI users. The authors randomly assigned young NH adults to either the Experimental or the Placebo Group to listen attentively to repeated trials of target words in a distractor noise. While the Placebo Group received a feedback based on participants' performance accuracy (\u201ccorrect\u201d and \u201cincorrect\u201d) in the behavioral task of selecting an utterance with a higher pitch, the Experimental Group received a visual feedback based on EEG responses (neurofeedback) that reflected the strength of attentional modulation on cortical auditory evoked responses during the training. After four sessions of training, the Experimental Group exhibited consistent improvement in the attentional modulation of the evoked responses to the training stimuli and a better performance in the SiN task, whereas the Placebo Group did not show such an effect.Effects of active training may be enhanced if selective attention, which is critical for speech understanding in noise (Lawrence et al., In summary, the current collection of recently published papers discussed cortical encoding of frequency changes and if the pitch percept changes over time in CI users using a short electrode array. It also collected papers examining the effects of music training and neurofeedback-based selective attention training in NH listeners, which provide novel training approaches for CI users. We look forward to future editorial work that promotes the understanding of neurological changes in auditory system following deafness, cochlear implantation, auditory training, and neurofeedback training.FZ drafted this editorial and other authors provided feedback. All authors contributed to the article and approved the submitted version."}
+{"text": "Declining physical function significantly worsens quality of life in dementia care dyads. Caring for people living with dementia (PLWD) at home is both physically demanding and emotionally stressful. Physical exercise is strongly recommended as a way of sustaining or improving overall function in dementia care dyads. However, little is known regarding the impact of home-based dyadic exercise interventions. We present results from a secondary analysis of data from a multicomponent translational study, Reducing Disability in Alzheimer's Disease \u2013 North West (RDAD-NW). We report results from an examination of the mediating role of exercise on the trajectory of change in physical function over time for both PLWD and their care partners."}
+{"text": "In this multimedia article, we demonstrate an extreme in situ liver surgery under total vascular exclusion with right hepatic vein and inferior vena cava grafts for an intrahepatic cholangiocarcinoma in a centre with experience in highly complex hepatobiliary surgery and liver transplantation. This surgical approach after neoadjuvant chemotherapy provides an opportunity for surgical salvage in patients with large tumors invading the hepatocaval confluence. This patient was considered unresectable at another hospital and referred to our unit. We performed an accurate preoperative assessment with new generation 3D modelling to plan the type of vascular reconstruction that would allow adequate hepatic venous outflow and the volume of the future liver remnant sufficient to avoid postoperative liver failure. For hemodynamic management of the patient, we performed a total hepatic vascular exclusion with veno-venous bypass without intraoperative adverse events. We used a cryopreserved carotid artery graft after previously planning the most appropriate diameter and length for right hepatic vein reconstruction. The inferior vena cava was reconstructed with gore-tex graft. During the hospital stay there were no postoperative complications. The patient is free of disease. We conclude that patients with advanced malignant liver disease should always be referred to highly specialized liver surgery centers to assess the most appropriate oncological management and the possibility of surgical resectability.The online version contains supplementary material available at 10.1245/s10434-022-12787-4. There are different scenarios in liver surgery in which the location of the tumor makes it difficult to achieve a tumor-free resection. One of these surgical and hemodynamic challenges is the invasion of the three hepatic veins and inferior vena cava by a malignant primary tumor. Experience in liver transplantation and complex hepatobiliary surgery together with advances in anesthetic management and preoperative planning have allowed initially unresectable tumors to be safely removed.We present the case of a 52-year-old man who was diagnosed with intrahepatic cholangiocarcinoma with vascular invasion. The patient was referred from another hospital. The computed tomography (CT) and magnetic resonance imaging (MRI) reported a mass of approximately 7.89 cm in the left hepatic lobe with peripheral expansion toward segments 5-8. The tumor had the following relationships with venous structures: (1) invasion of the left and middle hepatic vein (at its confluence with the cava); (2) contact with the confluence of the anterior branch of the right hepatic vein; (3) intrahepatic vena cava infiltration over a length of approximately 7.64 cm; (4) a free inferior hepatic vein; and (5) portal vein with minimal contact at the level of the extrahepatic portal vein. The\u00a0CT and an 18-FDG PET-CT ruled out the presence of distant disease and lymph node metastases. A next-generation three-dimensional modelling software was used for surgical planning, volumetry, and venous drainage calculations.The technique planned was an extended left hepatectomy with reconstruction of the vena cava with a Gore-Tex prosthesis above the inferior hepatic vein that was not infiltrated and a repair of the right hepatic vein with a carotid graft obtained previously from a tissue bank. Surgery was planned under total vascular exclusion with a veno-venous bypass. During occlusion, in situ hypothermic perfusion was performed through the left portal vein. Operative time was 420 minutes with blood loss of 400 ml and without transfusions. The patient was discharged on the tenth postoperative day without complications, and he is 1-year disease-free.2 Our group decided to perform it in vivo to avoid the additional risk of warm ischemia and possible complications associated with portal, arterial, and biliary anastomoses. Second, although our group has experience in liver resections within situ hepatic vein reconstruction with partial vascular occlusion, in this case we decided to opt for total vascular occlusion with placement of a veno-venous bypass because the patient needed both right hepatic vein and vena cava reconstruction.4 For the right hepatic vein graft, a graft from the tissue bank was chosen to avoid the complications that can occur with an autologous graft.5The first decision to be made in these cases is whether to perform the liver resection ex vivo or in vivo.Highly specialized units in hepatobiliary surgery and transplantation with experience in extreme liver surgery are crucial to be able to operate on patients who are considered unresectable in other centers. Today, these patients must be evaluated by expert committees in complex cases to offer the possibility of a safe surgery with good oncologic outcomes.Supplementary file1 (MP4 194250 kb)Below is the link to the electronic supplementary material."}
+{"text": "Daniel Diethei is an expert in computer science, human-computer interaction and mobile health. He will support the workshop participants during the world coffee at the discussion table for computer science."}
+{"text": "Individuals with severe mental illnesses (SMI) often present the knowledge about a task but in real-time do not perform it fully, or not as efficient as planned. This performance gap may be explained by difficulties with Executive Functions (EF).The aim of the presentation is to describe how people with and without SMI experience and perform grocery task. This, with considering this path from several directions including the subjects\u2019 point of view using eye-tracking device during task performance.Forty-three individuals had answered questions in regards to their shopping habits and performed the Test of Grocery Shopping Skills (TOGSS). The actual performance was accompanied by wearing an eye-tracking device which recorded the behavior and eye movement. We hypothesized that significant differences will be found between people with SMI and controls both in the routine grocery habits and in observed performance.No significant differences in age or gender. The groups differed significantly only in education, with the SMI group having fewer years of education. As a weekly routine, SMI subjects perform less frequent shopping (40%) than control group subjects (67%). TOGSS sub-outcomes indicated performance efficiency (time and redundancy) were significantly higher in the research group than in the matched control group (p <.01), with the SMI group spending a longer time performing the task and entering more aisles than required \u2013 redundancy.These preliminary findings indicate that individuals with SMI spend more time dwelling while selecting ingredients. Besides the path in the supermarket, it might explain their performance in other everyday activities.No significant relationships."}
+{"text": "In the global vaccination efforts against COVID-19, there is a general concern of refugees being left behind.The WHO played a major role in the campaign by citing the importance of refugee populations in receiving vaccinations and lobbied the Bangladeshi government to revise the vaccination plan to include the FDMN as an objective group.,Over 150 states have adopted COVID-19 vaccine strategies to include refugees\u2014but inclusion in policy does not always translate into equitable access.Marginalised groups remain vulnerable to the threat of COVID-19 and the world-wide community must ensure displaced populations will not be left behind in the global vaccination drive. The vaccine programme for the FDMN in Cox's Bazaar illustrates how equitable vaccine access and culturally sensitive vaccine outreach programmes contributes to overall success of global vaccination efforts.AMA conceptualised and wrote the paper.None."}
+{"text": "Genetic testing is well established in many areas of clinical medicine, is increasingly used in clinical psychiatry and it becomes increasingly important to understand the scope and limitations of the different genetic tests applied. The recommended genetic work-up of patients with neurodevelopmental disorders  includes conventional karyotyping (low resolution) able to detect chromosomal rearrangement and structural variants , testing for fragile X-Syndrome, screening for deletions and duplications down to 20 Kb by Comparative Genomic Hybridisation (CGH), able to detect Copy Number Variation . Sanger sequencing is used for mapping of single base pair genetic variants in single genes but unable to identify deletions or duplications. The more advanced Next Generation Sequencing (NGS) have enabled to detect variants in panels of 10-100 (or more) genes, or in all coding regions using Whole Exome Sequencing . Whole Genome Sequencing (WGS) analysis enables also the detection of all size range and types of genetic variation including CNVs, trinucleotide repeats and translocations. All this led to an impressive change in interpreting genomic variants that need to be strictly linked to clinical information before it can be used by clinicians to improve diagnosis or care. Bioinformatic tools to annotate variants, predict their effects and select the genes and genomic regions of interest are needed to guide the clinical work followed with careful evaluation of the prioritized variants based on the clinical knowledge (https://www.cost.eu/actions/CA17130/#tabs|Name:overview).No significant relationships."}
+{"text": "The origin of the heartbeat and the intricacies of cardiac pacemaker automaticity have captivated the interest of physiologists for over 70\u00a0years. This continues to be a vibrant and innovative area of research, where state-of-the-art imaging, genomic, transgenic and bioengineering modalities, coupled with classical electrophysiological and computational techniques have enabled unprecedented insight into the fundamentals of automaticity. This Research Topic is intended to hold up a mirror to the current activities in the field; we invited commentaries and original contributions from leading experts on themes relating to the functional or developmental aspects of pacemaker activity and its dysregulation in the context of conduction system disease.DiFrancesco evocatively considers landmark discoveries that underscored the concept of \u201cfunny\u201d (f-) current (If)-based pacemaking and summarises the current and future clinical applications of these findings. These include the development of Ivabradine (Procolaran\u00a9), an If blocker widely prescribed as a heart rate lowering therapy for stable angina and heart failure, and the potential for biological pacemaking based on transfer of HCN channels (the molecular basis of the If current) in the diseased conduction system. An important characteristic of If is its direct regulation by cyclic adenosine monophosphate (cAMP), and in the second article, Porro et al. review our current understanding of the structure-function relationships that underlie cAMP-mediated changes in HCN conformation and gating. The authors contextualise their exciting recent advances in deciphering how binding of cAMP to the Cyclic Nucleotide-Binding Domain changes HCN-channel conformation via interaction with cytoplasmic C-terminal C-linker. Moreover they highlight how detailed insight into channel structure has led to the development of novel peptide tools such as TRIP8bnano . Building upon their previous work determining a role for phosphatidylinositol-3-phosphate kinase (PI3K) in sinus node rate by modulation of basal If half-activation  channels that show significant expression in the sinus node in comparison to its molecular marker Hcn4. In addition, the article suggests new potential candidates for stretch-dependent regulation of pacemaker activity and discusses the possible mechanisms of interplay between mechanosensitive channels and the current model of sinoatrial automaticity in relation to the proposal of the \u201cmechanical clock\u201d by Another important factor potentially regulating pacemaker activity on a beat-to-beat basis\u2013independently of autonomic input\u2013is mechanical force. Cyclical stretching of atrial tissue during the cardiac cycle is predicted to regulate stretch-activated channels in several cell types in the sinus node, including pacemaker cells, fibroblasts and endothelium , 2021. T+ channels in pacemaker activity has been hotly debated. Indeed, K+ channels critically contribute to the balance between inward and outward currents during the automatic action potential cycle. Small-conductance calcium activated K+ (SK1-3) channels play an important role in automaticity by matching necessary outward current with intracellular calcium dynamics. However, excessive calcium release can induce inhibition of pacemaking by over-activation of SK channels. Next, a review article by Weisbrod discusses expression and pathophysiological roles of SK channes in the heart - an important summary of the known functional properties of these channels, also highlighting their therapeutic potential in cardiac arrhythmias and in heart failure.The functional role of Kin silico manipulation of ion channels and proteins controlling intracellular calcium dynamics. Five computational articles in this Research Topic provide new insights into pacemaker activity. First, the study by Yang et al. addresses an important question arising from the existence of electrical and calcium dependent oscillators in pacemaker cells. This manuscript suggests that the degree of self-organisation of RyR-dependent calcium release sites underlies variability in the pacemaker interbeat, by generating oscillations of the Na+/Ca2+ exchanger current (INCX). The activity of NCX thus reflects the degree of organisation of the calcium oscillator. Since NCX also couples to membrane voltage, this phenomenon explains the intrinsic variability of sinus node cell firing under both basal conditions and autonomic activation.Numerical modelling of pacemaker activity has proved to be an important tool to widen mechanistic understanding of automaticity by Alghamdi et al. investigate how ion channel remodelling may explain differences in pacemaking between neonatal and adult sinus node myocytes and their response to acetylcholine. In follow on studies the authors utilize a mathematical model of the rat sinus node action potential to interrogate the mechanisms by which sinus node function slows in advanced age, arriving at a predominant role for ICa,L, remodelling in age-related sinus bradycardia . Zhang and colleagues also demonstrate the utility of multiscale modelling in improving understanding of atrial fibrillation susceptibility following a gain-of-function mutation in the transcription factor Pitx2c  and in an additional article  the authors apply numerical simulations and theoretical analysis to provide new insight into the mode of action of If block with clinical concentrations of ivabradine.Next, two articles by the Zhang group combine mathematical models with previously reported experimental data to provide mechanistic insight into the physiological modulation of sinus node function across the lifespan. Presenting an updated computational model for neonatal rabbit sinus node myocytes, Mandla et al. explore how recent progress in chromatin biology, bioinformatics, and human genetics has enabled unique insight into transcriptional regulators and genomic loci critical for pacemaker cell development. The authors discuss recent exceptional work defining the sinus node cis-regulatory landscape  model of SND. Radiofrequency ablation of the sinus node resulted in pacemaking from subsidiary sites in a proportion of animals, leading the authors to speculate upon its role as a dominant pacemaker in SND. Finally, Bidaud et al. demonstrate that genetic ablation of G-protein-gated inwardly rectifying potassium channels (responsible for IKAch current) counteracts slowed pacemaking induced by exercise training in mice by preventing transcriptional and electrical remodelling of pacemaking ion channels. This work builds on findings by D\u2019Souza and Boyett demonstrating that a microRNA network orchestrates reduced sinus node ion channel expression in a range of situations where dysfunctional pacemaking is observed, including exercise training  and genetic/epigenetic influences. Further adding to the complexity are interactions between dormant and firing myocytes and increasingly well-recognized myocyte-nonmyocyte  crosstalk. In the era of precision medicine, our ability to integrate and follow these networks in vivo in refined SND models with multiomics technologies and multiscale computer modelling will become as important as our capacity to dissect the role of each component. In the meantime, gene therapy (with HCN2/SkM1 or microRNAs) and pharmacological IKAch inhibition show particular promise as emergent therapies for SND management.In sum, the articles in this Research Topic offer a wealth of insight into basic sinus node automaticity while highlighting new themes in its development, physiology and adaptation to disease. The challenge for the field (as for writing concluding remarks!), is how to distil diverging and ever-evolving appreciation of fundamental sinus node biology into the major outstanding questions that preclude identification of new therapeutic targets for SND\u2013a disease that will become increasingly more common as the population ages, and for which palliation by pacemaker implant is the only available therapeutic option. The articles in this Research Topic reiterate that normal pacemaking arises from interactions between the ion channel/Ca"}
+{"text": "Gerofit is a clinical exercise program for Veterans ages 65 years and older with multi-morbidities and functional limitations that place them at elevated risk for institutionalization. It was declared a VHA \u201cBest Practice\u201d in 2017 and was selected for widespread dissemination and implementation, with over 30 Gerofit programs spanning the country. The original Gerofit program consists of supervised, facility-based exercise, offered 3 days per week in a group setting. Each exercise prescription incorporates aerobic training, progressive resistance training, and specialized exercises for balance and physical function. Everything changed in March 2020 when facilities began receiving orders to shut down face to face encounters and social distancing measures were put in place. Within six weeks, all of our sites had transitioned to group-based virtual classes, aptly called Gerofit to Home (GTH). This symposium includes 2 presentations that explore the effect of GTH on physical functioning and health-related quality of life outcomes in veteran participants during the pandemic: one focusing on resilience among GTH adopters vs. non-adopters in patients formerly participating in facility-based Gerofit; and the second focusing on patients enrolled directly in to GTH (no facility-based experience). The third presentation describes differences in physical function and health gains among Gerofit participants with and without peripheral artery disease (PAD). The fourth and fifth presentations describe augmented models of care to enrich the Gerofit experience for a) participants with supplemental nutrition programming and b) advanced physical therapy trainees through a Gerofit resident training model."}
+{"text": "The companion dog is an emerging model in translational geroscience and offers novel opportunities to investigate aging biology and potential gerotherapeutics. However, there is a scarcity of validated tools and clinical outcome measures to characterize and understand the impact of aging in this translational species. Here we report on a multi-center, cross sectional veterinary clinical study, where we evaluated a clinical questionnaire  to assess frailty and an owner assessment tool (VetMetrica HRQL) to evaluate HRQL in 451 adult companion dogs. Results support evidence of validity for the tools by confirming expectations that frailty and HRQL deteriorate with age. CFI scores were significantly higher (higher frailty) and HRQL scores significantly lower (worse HRQL) in old dogs (\u2265 7 years of age) compared to young dogs (\u2265 2 and < 6 years of age). Body size  was not associated with CFI or total HRQL score. However, older, larger dogs showed faster age-related decline in HRQL scores specific to owner-reported activity and comfort. Findings suggest that the clinician-assessed CFI and owner-reported VetMetrica HRQL may be useful tools to evaluate two determinants of healthspan in dogs: the accumulation of frailty and the progressive decline in quality of life. Establishing validated tools that operationalize the assessment of canine healthspan is critical for the linking pathophysiological mechanisms to aging phenotypes in the companion dog and for accelerating the development of gerotherapeutics that benefit both human and veterinary medicine."}
+{"text": "In insurance-based healthcare systems, healthcare insurers are interested in engaging citizens in care procurement to contract healthcare services that matter to people. In the Netherlands, an amendment to the Health Insurance Act was set forth in 2021 to formalize and strengthen the engagement of the insured population with healthcare insurers\u2019 procurement cycles. This study explores the role of Dutch healthcare insurers in operationalizing citizen engagement in procurement cycles before changes occur linked to the amendment to the Health Insurance Act.A phenomenological qualitative design was employed in two phases: (1) we consulted academics and policy experts on the role of healthcare insurers regarding citizen engagement; (2) we conducted focus groups with representatives of healthcare insurers to understand how citizens\u2019 engagement is being operationalized. Transcripts of the interviews with experts and detailed notes of focus group meetings were analysed using a qualitative inductive approach. Selected excerpts were analysed on discourse and content and organized by a coding scheme following a rigorous and accelerated data reduction technique.We identified four strategies used by healthcare insurers to operationalize citizen engagement: (1) broadening their population health orientation; (2) developing and improving mechanisms for engaging citizens; (3) strengthening features of data governance for effective use of value-driven data; (4) implementing financial and incentive mechanisms among healthcare providers in support of value-based healthcare. However, regulated market mechanisms and low institutional trust in healthcare insurers undermine their transition from merely funding healthcare towards becoming people-centred value-based healthcare purchasers.Dutch healthcare insurers seem to be strengthening the community orientation of their functioning while enhancing the end-to-end experience of the insured. The expected practical effects of the amendment to the Health Insurance Act include broadening the role of the council of insurees in decision-making processes and systematically documenting the efforts set forth by healthcare insurers in engaging citizens. Further research is needed to better understand how the regulated competitive market could be hampering the engagement of citizens in healthcare procurement decision-making and value creation from the citizens\u2019 perspective.The online version contains supplementary material available at 10.1186/s12961-022-00939-7. To achieve the goals of providing care and resources to foster good health among populations, healthcare systems are increasingly engaging citizens in co-designing the system \u20133. The iTerms such as citizen, patient, customer/client and insured encompass different roles; these roles shape both relationships and behaviours . In theiIn insurance-based healthcare systems, procurement is a core function of healthcare insurers\u2019 business models. Procurement practices have evolved in tandem with healthcare systems becoming responsive to citizens\u2019 needs, expectations and preferences . Hence, Healthcare insurers have a unique position to serve patients in their healthcare needs and support the broader population in accessing people-centred value-based healthcare services. In fulfilling their function of procuring people-centred value-based healthcare services, healthcare insurers are developing their data strategies to gain insights into value creation from the citizens\u2019 perspective, notably by collecting people-reported data . Yet, thHealthcare insurance in the Netherlands has its roots in solidarity values. It developed from the financial assistance from guild \u201ccollecting-boxes\u201d for specific groups in the seventeenth century to a social insurance model with Sick Funds (adopted in 1941) for part of the population under a certain income level; and, more recently, towards a population-wide social health insurance model since the introduction of the Health Insurance Act in 2006 \u201315. The wet verzekerdeninvloed)  not working good enough and fast enough. (\u2026) we try with the law to push that mechanism a little forward or to push it to accelerate. And the law isn't very important in the sense that it's introducing all kinds of new things. It's more sort of getting into law a lot of things which are already there and working\u201d (Expert_7.110). The second aspect is addressing the low institutional trust of the public in the role of\u00a0healthcare insurers in the Dutch healthcare system . However, preparing for this evolution is not yet fully embedded in the corporate culture and strategy of some of the participating healthcare insurers. Nevertheless, all representatives of participating healthcare insurers agreed on the central role of citizen engagement for the evolution from healthcare insurer to health insurer to occur in Dutch society.population health orientation of the healthcare insurer; (2) empowering the insured people by developing and improving mechanisms whereby citizens can be engaged; (3) strengthening features of data governance at all levels for effective use of value-driven data; (4) implementing financial and incentive mechanisms among healthcare providers in support of value-based healthcare by offering and testing new approaches to healthcare procurement  broadening the engaged;  strengthHealthcare insurers are broadening their population health orientation by partnering with other actors towards improving the health status and outcomes of communities. This broadening is facilitated by regional partnerships and coalitions of healthcare insurers, such as those with municipalities and citizen-led movements  and experience (PREMs) measures are still very limited. The low availability of patient-reported data is linked to the trust levels of care providers and citizens in healthcare insurers\u2019 uses of these data. For example, care providers are reluctant about the potential benefits of sharing these data in the context of the data protection legislation , facilitating opportunities for shared learning. Conversely, a limited market share in a region could have implications for a healthcare insurer\u2019s willingness to invest in that region  broadening their population health orientation; (2) developing and improving mechanisms for engaging citizens, notably insured people; (3) strengthening features of data governance at all levels for effective use of value-driven data; (4) implementing financial and incentive mechanisms among healthcare providers in support of value-based healthcare by offering and testing new approaches to healthcare procurement. However, citizens\u2019 low institutional trust in the role of healthcare insurers in the healthcare system undermines progress.Successful implementation of value-based care across the health system requires citizens (including insured people and patients) to be engaged in health policy decision-making processes , 5, 18. Healthcare insurers have been strengthening their regional orientation, with varying degrees of maturity and cooperation with other actors in the health system, such as competing healthcare insurers, municipalities, care providers and communities. This regional orientation is partially influenced by the historical background of healthcare insurers. It is also a means of operationalizing people-centred value-based care by better addressing communities\u2019 care needs and expectations and enhancing end-to-end citizens\u2019 experiences. Additionally, healthcare insurers could be better positioned for strengthening a trust-based relationship with citizens by being closer to communities. Yet, the lack of clarity about the role of health system actors in citizen engagement serves to perpetuate power imbalances in the system . If healThe current health information landscape is not sufficiently robust to support healthcare insurers in operationalizing care procurement policies anchored in people-centred value-based principles. Aside from the healthcare insurers\u2019 poor availability of care quality and outcome data  , unclearwet verzekerdeninvloed). Also, this study helps in understanding tensions between the healthcare insurers\u2019 historical background and their positioning and functioning in a regulated competitive market. The entire research team was involved in data collection to strengthen the study\u2019s validity, and two researchers (\u00d3BF and VB) led the data analysis. Reliability was strengthened with cascading rounds of data collection, comprehensive data use and continuous data analysis. Generalizing the findings to other countries with insurance-based healthcare systems, including those in low- and middle-income countries according to the World Bank\u2019s classification, should be done with caution. For example, contextual factors, such as the organization and digitalization of the healthcare system, the broader policy environment and power distribution among actors in the system, and the extent to which these affect applications of citizen engagement by healthcare insurers, are heterogeneous. Yet, this study can help inform other countries with insurance-based healthcare systems in steering their healthcare insurers towards inclusive governance approaches by strengthening citizens\u2019 engagement in health policy decision-making. This is particularly relevant in contexts of limited resources and increasing health expenditure, where the citizens\u2019 voice can play an active role in defining priorities and steering healthcare insurers\u2019 healthcare procurement policies towards people-centred value-based values. A limitation of the study relates to having selected only the four largest health insurance companies (with 81% of the market share); we acknowledge that healthcare insurers with lower market share could have generated different narratives and contributed to maximal theoretical representation. Finally, another limitation is the limited opportunity for citizens to exercise their voice and be involved in this research. Although all study participants are themselves citizens, and we ensured the participation of representatives of the council of insurees of the participating healthcare insurers, pursuing other meaningful forms of involving the broader public offers an opportunity to better understand how citizens perceive being engaged by healthcare insurers in healthcare procurement decision-making processes.This study was enriched by engaging representatives of the four largest healthcare insurer groups in the Netherlands, including varying views of experts and engaging representatives of the council of insurees of each participating healthcare insurer. Our findings are relevant to understanding how healthcare insurers are operationalizing citizen engagement before changes are introduced to their business model because of the amendment to the Health Insurance Act  and patients\u2019 representatives. In general, healthcare insurers already had in place many initiatives supporting citizen engagement. The immediate practical effect of the amendment to the Health Insurance Act will likely be twofold: broadening the role of the council of insurees in decision-making processes, and systematically documenting the efforts set forth by healthcare insurers in engaging citizens. Also, other financial mechanisms are deemed necessary to streamline value creation across actors, such as a pooled budget. Further research is needed to better understand how the regulated competitive market could be hampering the engagement of citizens in healthcare procurement decision-making and value creation from the citizens\u2019 perspective.Additional file 1. Template for semi-structured interviews with academics and policy experts.Additional file 2. Invitation letter.Additional file 3. Discussion statements to be debated with healthcare insurers\u2019 representatives.Additional file 4. Supporting quotes from experts and healthcare insurers\u2019 representatives."}
+{"text": "Physical abuse of children in schools is common in Nigeria, but its prevalence and forms are yet to be clearly studied.To determine the prevalence and pattern of physical abuse of children in Secondary Schools in Ilorin NigeriaCross sectional survey of secondary school students aged 11-18 years in Ilorin Nigeria using multistage random sampling technique with proportional allocation was done. Respondents completed the ICAST-CI questionnaire which covers child abuse in educational institutions. Prevalence and pattern of child abuse was computed.Table 1: Pattern of physical abuse in School in the last 12 monthsPhysical abuse of children is extremly commonplace in public secondary schools in Nigeria. it is neccessary to explore other ways of dealing with children in educational institutions.No significant relationships."}
+{"text": "The COVID-19 pandemic has harmed many people's mental health globally. Whilst the evidence generated thus far from high-income countries regarding the pandemic's impact on suicide rates is generally reassuring, we know little about its influence on this outcome in lower- and middle-income countries or among marginalised and disadvantaged people. There are some signals for concern regarding the pandemic's potentially unequal impact on suicide rates, with some of the affected demographic subgroups and regions being at elevated risk before the pandemic began. However, the evidence-base for this topic is currently sparse, and studies conducted to date have generally not taken account of pre-pandemic temporal trends. The collection of accurate, complete and comparable data on suicide rate trends in ethnic minority and low-income groups should be prioritised. The vulnerability of low-income groups will likely be exacerbated further by the current energy supply and cost-of-living crises in many countries. It is therefore crucial that reassuring messaging highlighting the stability of suicide rates during the pandemic does not lead to complacency among policymakers. Excess et al., et al., et al., Despite the pandemic's evident harmful mental health impact, a recent analysis of suicide rates in 33 nations (and regions of countries) over the first 9\u201315 months of the pandemic revealed little evidence of heightened suicide risk  was greater compared to preceding rate rises. This increase was particularly evident among males in low sociodemographic index (SDI) states and among males and females in the high SDI states  of suicide rates is also urgently needed in all countries (Baran"}
+{"text": "Kassem et al., examines the critical fixation points and durations associated with superior decision-making within an elite group of Australian Rules football players. Whilst watching game-based video clips players were asked to identify \u201cthe best option\u201d in the developing play. Findings support previous conclusions . Understanding an individual's visual search behavior has provided important information regarding the link between oculomotor control, visual perception and attention allocation in task execution. The development of this understanding can originate from examining the inter-individual differences in visual search behavior as a function of expertise, or exploring intra-individual differences between successful and unsuccessful mastery attempts  goalkeepers during a 1 vs. 1  scenario. Quiet Eye of professional football goalkeepers was analyzed as a shooter (opponent) dribbled with the ball 20 m from the goal line and shot the ball when reaching a pre-defined line at 11 m. Results highlight that the typical use of mean values to describe the Quiet Eye was not necessarily a prominent characteristic of successful performance. This is partly explained through interactions between the goalkeeper, their opponent and the environment, changing trial-to-trial, which may mean an information source in one trial may not emerge or may not be a successful determinant in the next trial with Quiet Eye patterning emerging through the performer-environment relationship  assumed the vantage point of a central defender on a soccer field and visualized situations with 10 virtual moving teammates and 11 opponents, where they were required to track 4 \u201ctarget players.\u201d Visual tracking performance was higher in soccer players than in non-soccer players regardless of whether tracking players moving in soccer-specific trajectories or pseudo-random trajectories. Differences in gaze activity between groups of participants varied according to the spatial distribution of the virtual players, which also affected visual tracking performance. There was some indication that using soccer-specific trajectories might not be sufficient to replicate the representativeness of the \u201cfield\u201d conditions with future work to consider increasing saliency of player's discernible features such as postural cues.Virtual reality (VR) technology provides an alternative method of understanding perception-action coupling  an opponent's incoming punch. Similar to previous research (e.g., Mann et al., Limballe et al. demonstrate that expert combat athletes did not deteriorate significantly following a gaze-contingent blur manipulation. The only significant difference was between the central blur and peripheral blur conditions. Gaze data was predominantly located on the head, trunk and distal ends of the opponents two arms, similarly found in previous martial arts studies (e.g., Ripoll et al., With previous research demonstrating the limited impact blur has in various sporting tasks The goal of this Research Topic was to examine the emerging approaches to understanding the role of visual search in human movement. The varying aspects covered in this Research Topic highlights the continued growing interest in understanding visual search behavior in human movement and the articles within the topic provide insightful ideas for continuing to develop future research.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
+{"text": "Bladder cancer assessment with non-invasive gene expression signatures facilitates the detection of patients at risk and surveillance of their status, bypassing the discomforts given by cystoscopy. To achieve accurate cancer estimation, analysis pipelines for gene expression data (GED) may integrate a sequence of several machine learning and bio-statistical techniques to model complex characteristics of pathological patterns.Numerical experiments tested the combination of GED preprocessing by discretization with tree ensemble embeddings and nonlinear dimensionality reductions to categorize oncological patients comprehensively. Modeling aimed to identify tumor stage and distinguish survival outcomes in two situations: complete and partial data embedding. This latter experimental condition simulates the addition of new patients to an existing model for rapid monitoring of disease progression. Machine learning procedures were employed to identify the most relevant genes involved in patient prognosis and test the performance of preprocessed GED compared to untransformed data in predicting patient conditions.Data embedding paired with dimensionality reduction produced prognostic maps with well-defined clusters of patients, suitable for medical decision support. A second experiment simulated the addition of new patients to an existing model : Uniform Manifold Approximation and Projection (UMAP) methodology with uniform data discretization led to better outcomes than other analyzed pipelines. Further exploration of parameter space for UMAP and t-distributed stochastic neighbor embedding (t-SNE) underlined the importance of tuning a higher number of parameters for UMAP rather than t-SNE. Moreover, two different machine learning experiments identified a group of genes valuable for partitioning patients  and showed the higher precision obtained by preprocessed data in predicting tumor outcomes for cancer stage and survival rate (six classes prediction).The present investigation proposed new analysis pipelines for disease outcome modeling from bladder cancer-related biomarkers. Complete and partial data embedding experiments suggested that pipelines employing UMAP had a more accurate predictive ability, supporting the recent literature trends on this methodology. However, it was also found that several UMAP parameters influence experimental results, therefore deriving a recommendation for researchers to pay attention to this aspect of the UMAP technique. Machine learning procedures further demonstrated the effectiveness of the proposed preprocessing in predicting patients\u2019 conditions and determined a sub-group of biomarkers significant for forecasting bladder cancer prognosis. Machine learning  and bio-statistics offer a wide range of methodologies to build models able to estimate several aspects of cancer from gene expression data . A distinguishing feature of machine learning models is that they afford to predict from data rather than infer, a typical paradigm of statistics . PredictPrevious work introduced double discretization procedures to characterize GED applicable when modeling bladder cancer survival rate (supervised binary classification) . The preGene expression data were collected by  and releentclass1pt{minimamentclasspt{minima\u201cLog-z\u201dEach GED was log-transformed and values standardized. Continuous values were discretized by Classification and Regression Trees .\u201cUniform\u201dCumulative distribution function of each GED was estimated and, through a quantile function, mapped to a uniform distribution with data normalization in the interval . The number of quantiles (51) introduced a pre-binning of the data followed by CART discretization after uniform mapping.\u201cNormal\u201dCumulative distribution function of each GED was estimated through a quantile function mapped to a normal distribution with data standardization. The number of quantiles (51) introduced a pre-binning of the data followed by CART discretization after normal mapping. It should be noted that Uniform and Normal data mapping produced a \u201cdouble discretization\u201d on data as demonstrated in the previous exploration: operational sequences are synthesized in Fig. Three alternative discretization approaches derived from the procedure previously investigated in  constituuantiles 1 introduTrees are hierarchical structures, starting with a root value (a feature or GED) and descendant sub-trees generated from parent nodes: each split into branches is called edge. The end of a branch is called a leaf. The characteristics of trees are the existence of exactly one path (connected sequence of edges) between any pair of nodes and their acyclicity because there is no loop in their topology. Large numbers of trees operating as an ensemble are called forests. Feature spaces could be represented by forest embedding, collecting leaf value sequence for each observation to obtain a similarity matrix resembling the procedure applied by  on prostDimensionality reduction produces a representation that helps identify relevant data patterns. For example, in , the autinternal cluster validation indexes like Davies-Bouldin index  [External cluster validation methods have been estimated for the final comparison between pipelines. Validation indicators included Fowlkes-Mallows index [Several clustering techniques were implemented to sub-divide the dimensionally reduced forest embedding matrix and assess the goodness of the resulting bi-dimensional maps: hierarchical density-based spatial clustering of applications with noise , mini-be., DBI) , silhouee., DBI) , and Cale., DBI) . Internaws index , Rand inws index , adjustews index , normaliws index , homogenws index . ExternaThe investigation was subdivided into two experimental conditions, each with a different tree ensemble embedding. The first condition was a complete embedding of the GED by the tree ensemble from which t-SNE and UMAP generated a bi-dimensional prognostic map, revealing cancer patients\u2019 population patterns. The second condition was a partial embedding obtained by training the tree ensemble on 75% of the data. This situation simulates the addition of 25% unseen patients to an existing model to verify the behavior of each analysis pipeline under extreme circumstances. Indeed, it is unlikely that the model will categorize a large cohort of patients all at once; consequently, the second experimental condition could be interpreted as a \u201cstress test\u201d to check model reliability compared to the baseline condition of fully embedded data.Demonstration of how the proposed analysis sequence leads to the creation of bi-dimensional prognostic maps to support medical decision-making Evaluation of a partial GED embedding to simulate the addition of new patients to an existing forest embedding Investigation of the parameter space for t-SNE and UMAP to highlight those that impact the low dimensional embedding and should be tuned when employing these techniquesTest the performance of a classification model on six classes of tumor outcomes using the original GED set  while scanning the configuration of parameters that optimizes data fitting. Traditionally parameter evaluation could be examined through linear regression to find non-deterministic linear relationships between parameter values . In the analysis . RegardiPrognosis prediction is still considered a challenge in bladder cancer . In thisTwo methodologies were employed to score the genes\u2019 influence in predicting tumor stage and survival. It could be possible that genes of the set pre-selected by the database authors might have different involvement in the pathological status of the patients; thus, they could be evaluated concerning their importance in determining the disease outcome. Using the labels obtained during the complete embedding by the single and double discretization pipelines with t-SNE or UMAP and a forest of trees classifier, the genes after preprocessing Fig.  were ranGenerally, discretization transforms features closer to a knowledge-level representation than continuous data . In the ractions , and genMedical doctors may not be acquainted with machine learning techniques; consequently, an effective tool for GED interpretation might enhance the visual understanding of multi-dimensional GED datasets . Research presented by this study focuses on 2D t-SNE and UMAP reduction because we explored the possibility of producing discernible patterns in the data that summarize the disease progression in patients. Similar to other works in the literature, this investigation adopts an intermediate step to transform GED data distributions by decision tree embedding. This phase should pull out interesting characteristics in the input samples that are otherwise not directly observable. For example, pathways of associated genes or gene pairs with combined effects may be reflected by high correlations or network attributes . A diffeThe benefit of discretization was demonstrated by a supervised machine learning experiment that tried to classify the six classes of outcomes from the raw or preprocessed GED. While the original dataset resulted in a balanced accuracy slightly above the chance level (The relevance characterization using relative gene importance identified a subset of genes by their prominence in defining tumor stage and patient survival. Results of this machine learning experiment are included in Table Table This study evaluated if GED discretization approaches could be integrated into a new analysis pipeline extending patient identification by tumor stage and survival. Complete data embedding created precise prognostic maps suitable for data-driven medical decision-making. In a second numerical experiment using partially embedded data to simulate new patients\u2019 inclusion in the model, performance seems stable only applying the Uniform double stage discretization sequence and UMAP non-linear reduction. Findings on both experimental conditions support using the UMAP technique in omics data analysis as emerging in recent literature on the same topic. However, a further investigation of UMAP parameter space did not identify a significant subset of relevant parameters to consider for speeding up algorithm tuning. This situation underlines the importance of adjusting multiple UMAP parameters for precision medicine studies. A machine learning procedure to establish gene importance in determining six classes of outcomes has been demonstrated through feature permutation or recursive feature elimination. Through this methodologies, a subset of relevant genes for bladder cancer prognosis has been identified. Another machine learning experiment showed how the classification of patients using the preprocessed data with single or double discretization pipelines achieved higher accuracy than unprocessed data. The numerical experiments in the current investigation testing three distinct preprocessing sequences based on single or double discretizations helped to discriminate more effectively six possible patients\u2019 outcomes given a bladder cancer GED dataset from a cross-sectional study."}
+{"text": "Sirolimus-coated balloons (SCB) have demonstrated much promise as an alternative drug eluting device to the existing paclitaxel coated balloon platforms for the treatment of peripheral arterial disease (PAD). They have been well tested pre-clinically and have demonstrated anti-restenotic effects as well as clinical safety in its use for treatment of coronary artery disease. The existing approved SCBs have thus far demonstrated good short-term patency (12-months) and did not exhibit any major adverse events or device related shortcomings in its use for treatment of PAD. There are several studies ongoing which aim to further investigate the efficacy of existing SCBs and establish a direct comparison of its outcomes compared with plain balloon angioplasty. Also, SCB utility to salvage failing arteriovenous fistulas for haemodialysis patients has also been explored. We review the current progress made in the establishment of SCB in the treatment of PAD as well as highlight ongoing studies investigating the role of SCB in various settings. Peripheral arterial disease (PAD) is a chronic atherosclerotic disease affecting the arterial vasculature of the lower limbs, resulting in progressive narrowing  was introduced to mitigate the effects of NIH, with a typical onset of 1\u2009month after PTA , with demonstrable lower restenosis rates compared to paclitaxel devices Abizaid . The useSelution SLR\u2122  and MagicTouch\u2122    rate of 2.3%, no major LEA or death and improvement in 1 or more categories on the Rutherford Classification in 73% of patients. Primary patency rate as assessed by Duplex ultrasound was 88.4% and freedom from restenosis was 91.2%. 12- and 24- month data , a pilot prospective, non randomised, single-arm, multi\u2014investigator single-center study was carried out  and grafts (AVG). A pilot prospective single center clinical study on the use of The interest in the use of sirolimus products in the treatment of PAD has led to several studies being conducted to investigate its efficacy and safety. The LIFE-BTK trial LIFE-BTK  NCT0422  for femoropopliteal lesions, released preliminary data of six patients (three treated with PCB and three with SCB) demonstrated safety and efficacy of both PCB and SCB. This is at present the first-in-literature data and its eventual findings would be helpful in shaping the role of sirolimus DCB in the peripheral vasculature. Another study, the SIRONA trial  in treatment of the femoropopliteal artery, is also presently in recruitment phase. These studies would be a first step in determining the place of sirolimus DCB among its contemporaries. An IDE BTK RCT comparing Selution\u2122 and POBA is about to start with lead centres in the US, Europe and Asia. All these studies will need to take note the lessons of the paclitaxel-based studies in PAD where follow-up was at best variable and patient level follow-up data missing. More pre-clinical testing of the SCBs in different animal models are also required especially for the AVF and PAD settings to look at pharmarcokinetics of the balloon. More data looking at the use of SCBs in different parts of the AVF circuit are warranted especially as we are beginning to realise that drug may have differential effects on different types of stenotic lesions , atherectomy to address the calcium issue and DCB to minimize NIH will be required.We conclude that sirolimus DCBs represent a promising alternative in treatment of disease of the peripheral vasculature, although further studies are required to establish its clinical efficacy and safety as well as cost effectiveness in terms of mortality benefits and reduced time to reintervention compared to PCB and plain POBA."}
+{"text": "Pediatric surgical oncology (PSO) represents one of the most challenging sub-specialties in the field of pediatric surgery, due to potentially life-threating procedures and the wide field of presentation and location of children's solid tumors.In this Research Topic of Frontiers in Pediatrics we selected different studies covering both technical and strategical innovations which are necessary for a modern surgical management of pediatric solid tumors.Losty in \u201cTraining in Pediatric Surgical Oncology\u201d highlights the current required skills and related challenges in a worldwide setting of centers with a relative low case-load due to the rarity of pediatric malignancy.The first requirement for the optimal treatment of pediatric cancer is a well-trained surgeon in pediatric oncology; To provide a structured surgical training according to the different tumors' location, vascular, thoracic and urology rotations are encouraged in the 1st years of residency, followed by a specific training in high volume centers with established international fellowship program in PSO  are promoting international fellowship programs and the current trend of improved centralization will help young surgeons to be trained in high-volume centers .Persano et al. in \u201cBurned-Out Testicular Tumors in Adolescents: Clinical Aspects and Outcome\u201d describe one of these challenging situations. The authors define the clinical presentation of the burned-out testicular tumors as a well-distinct entity, with histology peculiarities in absence of local testicular symptoms, underlying their poor prognosis.Pediatric tumors Show a heterogeneity in their clinical presentation, Carvalho et al. in \u201cDiagnostic Errors in Wilms' Tumors: Learning From Our Mistakes\u201d shares the experience and diagnosis complications in one of the largest Pediatric Oncology Institution of America Latina.Other than clinical heterogeneity, surgeons should know the potential pitfalls of radiology presentation pf pediatric tumors at diagnosis. Authors emphasize the importance of a multidisciplinary team and the integration of biology in addition with radiologic findings to reach a high diagnostic accuracy for Wilms tumors.Theilen et al. in \u201cMultidisciplinary Treatment Strategies for Wilms Tumor: Recent Advances, Technical Innovations and Future Directions,\u201d reviewing the role of imaging technology and genetics in clinical practice.Multidisciplinary strategy has a fundamental role in PSO as described by Hemorrhage During Induction Chemotherapy in Neuroblastoma: Additional Risk Factors in High-Risk Patients\u201d by Voglino et al., reporting the effectiveness of conservative treatment for localized hemoperitoneum and thoracic drain placement for hemothorax.Once the diagnosis is confirmed and neo-adjuvant chemotherapy is initiated, several complications can be observed, some of them requiring surgical evaluation as described in \u201cMachavoine et al. in \u201cLocoregional Control and Survival in Children, Adolescents, and Young Adults With Localized Head and Neck Alveolar Rhabdomyosarcoma\u2014The French Experience,\u201d enhancing the role of lymph node surgery and secondary resection of the primary tumor and their positive influence on event-free survival (EFS) for alveolar rhabdomyosarcoma.Studies of large cohort of children with specific tumors included in national or international protocols can modify the surgical strategy as described by Qi and Zhan in \u201cRoles of Surgery in the Treatment of Patients With High-Risk Neuroblastoma in the Children Oncology Group Study: A Systematic Review and Meta-Analysis\u201d discuss another important Research Topic about the intraoperative surgical strategy such as resection's completeness. The meta-analysis they provided confirms the recent studies regarding the positive influence of the extent of resection on EFS in High Risk Neuroblastoma  to a myofibroblastic tumor with a peritoneal carcinomatosis, with excellent oncology outcome at low term follow up after 12 months. A modified hyperthermic intraoperative cytoreductive surgery is reported, with a reduced intraperitoneal normothermic infusion(30 min) and a modified dosage of doxorubicin.Ngo et al. in \u201cCase Report: Transoral Endoscopic Thyroidectomy via Vestibular Approach in Pediatric Thyroid Cancer\u201d provide an example of the increasing tendency to extend the application of MIS to several types of tumors locations, reporting for the first time an innovative approach in pediatric population providing didactic intraoperative views and trocar positioning description. Authors discuss their novel approach providing a comprehensive technical description and their surgical results.Over the years, minimally invasive surgery (MIS) gained popularity in PSO ; Ngo et Vatta et al. in \u201cRobotics-Assisted Pediatric Oncology Surgery\u2014A Preliminary Single-Center Report and a Systematic Review of Published Studies\u201d shows the state of the art of a recent evolution of MIS by describing the application of robotics in PSO, with promising results in recently published cohorts of pediatric patients treated for different solid tumors .Abdelhafeez et al. with their original article \u201cIndocyanine Green\u2013Guided Pediatric Tumor Resection: Approach, Utility, and Challenges\u201d describe the currently largest cohort of pediatric patients in literature who benefit from FGS. Authors describe the feasibility of FGS and the current limitations of this technique represented by tissue-penetration and background noise of adjacent organs with current fluorophore probes.FGS is one of the most promising technology advances in PSO and Pelizzo et al. in \u201cProliferation Pattern of Pediatric Tumor-Derived Mesenchymal Stromal Cells and Role in Cancer Dormancy: A Perspective of Study for Surgical Strategy\u201d study investigate the role of mesenchymal stromal cells as a potential risk factor for local relapse, defining their role in cancer cells dormancy, in addition to their well-known role on drug sensitivity and the subsequent tumor progression and metastasis.Surgeons must be aware of tumor's risk of local relapse after surgery, Sundquist et al. provide an example of multidisciplinary scientific collaboration in PSO with the study protocol presentation \u201cA Phase II Trial of a Personalized, Dose-Intense Administration Schedule of 177Lutetium-DOTATATE in Children With Primary Refractory or Relapsed High-Risk Neuroblastoma\u2013LuDO-N.\u201d This study protocol involves different subspecialities  in a common project with the aim of studying an alternative molecular radiotherapy for the most challenging Neuroblastoma presentations (refractory and relapsed high-risk neuroblastoma), in order to improve event free and overall survival rate in high-risk patient population (Survivorship improvement of childhood cancers highlights the functional sequelae impact of chemotherapy and surgery .Special Considerations for Tympanoplasty Type I in the Oncological Pediatric Population: A Case-Control Study\u201d by Richard et al. raise the problem of chronic tympanic membrane perforation in children who survive after cancer treatment, providing surgical optimized strategies in terms of timing and technique.The results of \u201cYoung You et al. in \u201cConsiderations for Balance Between Fundamental Treatment and Improvement of Quality of Life of Pediatric Thyroid Cancer Patient: Comparative Analysis With Adult Using Propensity Score Matching\u201d further study the postoperative quality of life in children with thyroid malignancy, reporting promising outcomes and suggesting to limit total thyroidectomy when is safe and feasible for children, allowing a best functional outcomes.This Research Topic and all these manuscripts illustrate the current advances on surgical management of pediatric malignancies, highlighting the role of a multidisciplinary approach and the emerging impact and effectiveness of translational surgery, a surgical discipline that serves as bridge across basic science, technology innovations, different medical specialty, and surgery.Both authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "This editorial features the selection of highlights articles published in Frontiers in Cardiovascular Medicine  in 2021. Our criteria for selection include: whether the topic addressed in the study is highly relevant and timely importance in cardiovascular medicine, show the quality and breadth of the papers published in this section, as well as geographical variety; whether the article is often viewed, downloaded, and cited; and whether the article is well-written and has good readability. Following are the highlight papers in the General Cardiovascular Medicine Section of the year 2021 .Empagliflozin in Patients With Heart Failure: A Systematic Review and Meta-Analysis of Randomized Controlled Trials .\u2013 The prevalence of heart failure (HF) is increasing and leads to high mortality . This syDoes Prenatal Exposure to CNS Stimulants Increase the Risk of Cardiovascular Disease in Adult Offspring? (Rorabaugh).\u2013 The long-term negative effects of prenatal exposure to central nervous system (CNS) stimulants on adult offspring's cardiovascular system have received much attention recently. This review summarized the current knowledge of the impact of prenatal exposure to cocaine, methamphetamine, nicotine, and caffeine on adult cardiovascular function. This study suggested that exposure to CNS stimulants during the gestational period can negatively impact the adult heart later in life. The observations in this paper provided important implications for clinicians and researchers that pregnant women should be more strictly recommended to avoid CNS stimulant exposure.The Long-Term Impact of Bariatric Surgery on Development of Atrial Fibrillation and Cardiovascular Events in Obese Patients: An Historical Cohort Study .\u2013 The prevalence of obesity is increasing worldwide and is highly associated with an increased incidence of metabolic diseases. This study demonstrated that Roux-en-Y gastric bypass (RYGB) surgery in patients with obesity improves the metabolic profile and was associated with lower cardiovascular events, while did not demonstrate a benefit for atrial fibrillation prevention in the young population. This paper provided recommendations for clinical researchers that longer time follow-up is needed to evaluate the benefit of bariatric surgery on AF.Quality Assessment of Published Systematic Reviews in High Impact Cardiology Journals: Revisiting the Evidence Pyramid .\u2013 A growing number of systematic reviews and meta-analyses are published in recent years and used as sources of evidence in clinical and animal cardiology guidelines \u20134. HowevRoutine Oxygen Therapy Does Not Improve Health-Related Quality of Life in Patients With Acute Myocardial Infarction-Insights From the Randomized DETO2X-AMI Trial .\u2013 Oxygen therapy has been used in patients with acute myocardial infarction (MI) worldwide. Limited studies have been focusing on oxygen therapy's effects on health-related quality of life (HRQoL). This study investigated the impact of routine oxygen supplementation on HRQoL 6\u201310 weeks after hospitalization with acute MI and suggested that routine oxygen therapy provided to acute MI patients did not improve HRQoL up to 1 year after MI occurrence, regardless of MI subtype. This study also provided important evidence that oxygen therapy should be used more carefully in patients with hypoxemia.Impact of the 2019 Novel Coronavirus Disease Pandemic on the Performance of a Cardiovascular Department in a Non-epidemic Center in Beijing .\u2013 The 2019 novel coronavirus disease (COVID-19) has become a global pandemic since 2020. This research paper investigated the impact of the COVID-19 pandemic on the normal performance of a cardiovascular department in a large non-epidemic hub center in Beijing, China. This study indicated that the hub-and-spoke model could be effective in limiting the collateral damage for patients affected by cardiovascular diseases when the medical system was stressed by disasters, such as the COVID-19 pandemic.High-Normal Serum Magnesium and Hypermagnesemia Are Associated With Increased 30-Day In-Hospital Mortality: A Retrospective Cohort Study .\u2013 Serum magnesium level homeostasis is important for cardio-physiological regulation. The association between serum magnesium levels and acute cardiovascular events remains to be studied. This study investigated the association of admission serum magnesium level with all-cause in-hospital mortality in critically ill patients with acute myocardial infarction (AMI). High-normal serum magnesium and hypermagnesemia are both independent predictors of 30-day in-hospital mortality in ICU patients with AMI. Serum magnesium detection in the patient is simple and low cost. This study indicated that routinely monitoring serum magnesium levels might be acted as a potential predictor for AMI.From Clinical Clues to Final Diagnosis: The Return of Detective Work to Clinical Medicine in Cardiac Amyloidosis .\u2013 Cardiac amyloidosis is characterized by extracellular protein fibril deposition in the myocardium. Limited evidence and guideline recommendations are provided for the diagnosis and management of cardiac amyloidosis . In thisAssociation of N-Terminal Pro-brain Natriuretic Peptide With Volume Status and Cardiac Function in Hemodialysis Patients .\u2013 This study enrolled patients who had been receiving hemodialysis for >3 months and analyzed the relationship between N-terminal-pro-brain natriuretic peptide (NT-pro BNP) level and body fluid status in dialysis patients with reduced cardiac ejection function (EF). This paper suggested that NT-pro BNP could be a predictive factor for volume overload in hemodialysis patients with or without EF declines.Energy Drink-Associated Electrophysiological and Ischemic Abnormalities: A Narrative Review .\u2013 An increasing number of cardiovascular adverse effects, emergency room visits, and deaths have been linked to the consumption of energy drinks , 9. ThisJX and PL had the idea for the article and revised the article. LW and LP drafted the article. All authors contributed to the article and approved the submitted version.This work was supported by the grants from National Key Research and Development Project (2018YFE0113500 to JX), National Natural Science Foundation of China (82020108002 to JX), Innovation Program of Shanghai Municipal Education Commission (2017-01-07-00-09-E00042 to JX), the grant from Science and Technology Commission of Shanghai Municipality (21XD1421300 and 20DZ2255400 to JX), Natural Science Foundation of Shanghai (19ZR1474100 to LW), and the \u201cDawn\u201d Program of Shanghai Education Commission (19SG34 to JX).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "School climate is recognized as important for adolescent mental wellbeing. However, there is a lack of longitudinal studies, and most research focus on school climate as an antecedent of mental wellbeing while the relation could be in the opposite direction or bidirectional. Further, no study has examined this relation with analyses that separate between- from within-person variability to properly assess intraindividual developmental processes.Using a random-intercept cross-lagged panel model we investigated the longitudinal reciprocal relations of perceptions of a caring school climate and mental wellbeing across three time points  in adolescence, and if socioeconomic position (SEP) predicted perceptions of a caring school climate and mental wellbeing at each time point. The sample consisted of 1508 Norwegian adolescents .Results showed positive cross-lagged effects at the within-person level from mental wellbeing to later perceptions of a caring school climate across all time points , but no similar effects in the opposite direction. Positive concurrent effects from SEP were observed at one time point for mental wellbeing , and all time points for perceptions of a caring school climate , indicating SEP to be related to intraindividual fluctuations mainly in perceptions of a caring school climate.The findings support a unidirectional temporal relationship from mental wellbeing to perceptions of a caring school climate and underscore the importance of investigating the subject longitudinally and as a function of within-person fluctuations. From a public health view, the findings support the importance of systematic efforts to promote mental wellbeing to facilitate positive school experiences of adolescents of all social classes.\u2022\u2002The study found a unidirectional temporal relation at the within-person level in adolescents where mental wellbeing predicted perceptions of a caring school climate, but not the other way around.\u2022\u2002The findings underline the importance of systematic public health efforts to promote mental wellbeing as one avenue to facilitate positive school experiences of adolescents of all social."}
+{"text": "A 10-year-old male child reported to our department with a chief complaint of a nonerupted tooth in the upper front region of jaw. The patient's mother gave a history of trauma to anterior teeth in upper jaw 6 years back due to a road traffic accident, resulting in the intrusion of the left primary central maxillary incisor. The intruded tooth reappeared spontaneously and exfoliated normally. In the present scenario, clinical examinations showed impacted permanent maxillary left central incisor and the presence of a small hard nodule in the palatal aspect and in the labial vestibule of the same tooth. A Cone-Beam Computed Tomography (CBCT) radiographic examination was carried out in order to diagnose the cause of an impacted tooth and revealed dilaceration of permanent left central incisor along the length of a tooth. Hence, the final diagnosis was made as impacted dilacerated permanent left central incisor (due to trauma). Management of impacted dilacerated permanent teeth was done by surgical exposure with orthodontic traction."}
+{"text": "The Ohio Department of Medicaid added the PELI as one of five quality incentive points used to determine Medicaid per diem reimbursement rates with the goal of improving person-centered care among Ohio\u2019s nursing homes (NHs). The purpose of this study was to explore if the degree of PELI implementation had an impact on quality as defined by deficiencies and star rating. Multinomial logistic regression of 1,300 NH-year observations was used to understand the relationships between survey star ratings/deficiency scores on PELI implementation controlling for organizational characteristics of the NH. We find complete PELI implementation statistically significantly increased the probability of being a 4- or 5-star survey-rated facility. Complete PELI implementation is associated with small improvements each year that add up. Organizational change takes commitment and persistent effort over time to see changes in quality as reflected by star ratings and deficiencies. Recommendations for practice and policy will be discussed."}
+{"text": "Germany is increasingly recruiting foreign healthcare staff due to the shortage of skilled workers. This diversity of professional and cultural backgrounds poses a challenge to everyday life in inpatient care. Previous studies have focused on the renegotiation of professional identities and competencies in nursing or medicine. In contrast, this study sheds light on group-specific mechanisms through a comparative analysis: How do doctors and nurses deal with diversity in the workplace? Where do profession-specific differences emerge and what does this mean for future interventions?Eight group discussions (June 2019 to October 2020) were conducted with groups of doctors and nurses with and without a migration background in four hospitals in two federal states in Germany; including 22 nurses and 10 doctors (n = 32). The data were analysed using the documentary method to examine professional meaning-making processes. The results were validated intersubjectively.The respective handling of diversity in the workplace is influenced by different professional group identities. The situation is precarious for nurses with a migration background - especially for those with an academic degree, as nursing is still an apprenticeship profession in Germany. In the medical profession, on the other hand, diversity does not lead to significant controversies, even if cultural differences are discussed.Dealing with diversity is negotiated within professional groups. As nursing or medical \u2018communities of practice\u2019 (E. Wenger), these have a mediating role through which they can mitigate institutional and individual barriers to the integration of migrants in the workplace.Physicians and nurses need more specific, iterative cross-occupational and cross-cultural education.Management should support in accommodating different expectations and abilities."}
+{"text": "Since 2017, the National Poll on Healthy Aging (NPHA) has surveyed older adults on a vast array of topics related to health, health care and health policy. With robust nationally representative samples of 2,000 adults age 50-80, the poll\u2019s format allows for the fielding of timely questions with important public health and policy implications. For example, polls examining delayed care during the COVID-19 pandemic and experiences of physical deconditioning and falls helped to demonstrate the ways in which the pandemic may have long-lasting effects if strategies are not implemented to address them. In this presentation we will discuss how the NPHA has increased awareness of the facilitators and barriers to healthy aging and where gaps exist in supporting older adults to live with optimal health and well-being. This presentation will also describe how researchers can access publicly available NPHA data to inspire their own future research."}
+{"text": "Humans\u2014both children and adults\u2014crave to make meaning of reality Tronick, . DevelopThe socio-emotional skills provide the developing child with the ability to maintain an optimal regulation of inner states and to adjust them to fit with the ongoing changes occurring in the surrounding environment. Emotion regulation . They reported reduced microstructural integrity in the cerebellum of individuals with SPD, especially in the superior and middle cerebellar peduncles. They also reported on minor microstructural integrity of cerebral peduncles in the same subjects compared to typically developing controls, which might link to abnormal tactile and auditory behaviors. These findings are critical to inform early diagnostic approaches and treatments for children with SPD.Valori et al.) has targeted the sensorimotor processing alterations that characterize many individuals with autism spectrum disorders (ASD). The authors have highlighted how innovative technologies\u2014such as head-mounted displays in the context of immersive virtual reality\u2014might be used to create explorative environments to improve the perceptual and motor experience of the world in children with ASD. By highlighting the challenges and the benefits of virtual vs. natural environments for the sensorimotor profile of children with ASD, Valori et al. provide valuable insights for clinicians and researchers to further integrate technologies into beneficial tools for more innovative functional diagnosis and treatment.The group of Teresa Farroni . Their findings suggest that an early alteration in the electrophysiological processing of prosodic stimuli\u2014especially a lower mismatch response in the frontal lobe during fearful prosodies\u2014was significantly associated with higher scores at the M-CHAT.Using event-related potentials (ERPs), Chen et al. contributed to the field by publishing a simplified model of learning accomplishment profiling (C-LAP), demonstrating appropriate sensitivity in training and validation in a community of Chinese toddlers between 24 and 36 months.As applying research findings and data-driven models to specific therapeutic and rehabilitation settings is never an immediate process, disposing of flexible and straightforward evidence-based tools for behavioral and sensory profile evaluation is a crucial resource for clinicians. Zheng et al. test the efficacy of an early sensory stimulation program (5-ISS) to improve preterm infants' socio-emotional development. In this randomized controlled trial, they successfully documented that providing sensory neuroprotection to preterm infants during the intensive care unit stay can improve socio-emotional and stress regulation outcomes.Preterm infants are exposed to a sensory environment they are unprepared to cope with. Intense lights and sounds and invasive and painful procedures constitute\u2014in the partial absence of caregivers' neuroprotection and closeness\u2014a well-known source of developmental risk that might alter the neurobiological pathways of preterm infants' sensory processing. Ludwig and Welch contribute wisely to the article collection by providing a theoretical discussion of the socio-emotional and socio-cognitive implications of the polyvagal regulation of the parasympathetic system in mammals and humans, especially\u2014in both the evolutionary and ontogenetic frameworks. By updating previous theoretical propositions and confronting them with the most recent data from scientific investigations, they build the rationale by which early parent-infant socio-emotional exchange would be craven my mutual autonomic state plasticity. According to this model, the authors also provide insights for enhancing our approaches to treating mother-infant dyads in atypical and risky conditions.Gori et al. explored how blind individuals subjectively experience the restrictions and isolation that came together with the mitigation strategies adopted to cope with this unprecedented healthcare emergency. In their study, blind individuals had similar challenges to sighted controls in adapting to the modified life conditions; nonetheless, the source of more incredible frustration and stress for blind subjects were practical and logistical issues . These findings highlight the need to develop tailored responses to the condition of the most fragile individuals when adopting country-level responses to large-scale emergencies.Finally, focusing on the contingent condition of the COVID-19 pandemic, The picture we obtained from this Research Topic needs to be more conclusive. Yet, this article collection might illuminate specific open questions and directions of future investigations that will contribute to our understanding of the mechanisms by which\u2014in typical and atypical developing conditions\u2014we make sense of reality by relying on our senses.LP drafted the initial version of the manuscript. All authors contributed critically and agreed upon final submission."}
+{"text": "Cognitive Adaptation Training (CAT) is a psychosocial intervention focusing on reducing the impact of cognitive disorders on daily functioning in people with severe mental illness (SMI). Similar to many evidence based practices (EBP), implementation of CAT in routine care lags behind, despite the established effectiveness of the intervention. This so called \u2018science-to-service gap\u2019 is a widespread problem in mental health care. We developed an innovative implementation program to facilitate implementation of CAT and similar interventions in routine care.The aim of this study is to evaluate the effectiveness of the implementation program and to determine factors that impede or facilitate the implementation process.We conducted a multicenter cluster randomized controlled trial comparing the implementation program to a single training program in four mental health institutions  in The Netherlands. Focus groups, semistructured interviews and questionnaires were used at multiple levels of service delivery . Assessments took place before, during and after implementation and at follow-up, adding up to a total duration of 14 months. Data were analyzed using multilevel modeling.Data collection is complete and analyses on the effectiveness of the implementation program are ongoing. Preliminary analyses show that team climate (p<.008) and organizational climate (p<.043) significantly predict the attitudes of mental health providers toward EBP.This implementation research may provide important information about the implementation of psychosocial interventions in practice and may result in a program that is useful for Cognitive Adaptation Training, and possibly for psychosocial interventions in general.No significant relationships."}
+{"text": "Poor indexing and inconsistent use of terms and keywords may prevent efficient retrieval of studies on the patient-based benefit-risk assessment (BRA) of medicines. We aimed to develop and validate an objectively derived content search strategy containing generic search terms that can be adapted for any search for evidence on patient-based BRA of medicines for any therapeutic area.We used a robust multistep process to develop and validate the content search strategy: (1) we developed a bank of search terms derived from screening studies on patient-based BRA of medicines in various therapeutic areas, (2) we refined the proposed content search strategy through an iterative process of testing sensitivity and precision of search terms, and (3) we validated the final search strategy in PubMed by firstly using multiple sclerosis as a case condition and secondly computing its relative performance versus a published systematic review on patient-based BRA of medicines in rheumatoid arthritis.We conceptualized a final search strategy to retrieve studies on patient-based BRA containing generic search terms grouped into two domains, namely the patient and the BRA of medicines . The relative performance of the content search strategy was 85.7% compared with a search from a published systematic review of patient preferences in the treatment of rheumatoid arthritis. We also developed a more extended filter, with a relative performance of 93.3% when compared with a search from a published systematic review of patient preferences in lung cancer. Medicines are used for a known therapeutic benefit including cure, delaying disease progression, relieving symptoms, or preventing comorbidities. Every medicine also carries a risk of side effects, from minor to severe. A thorough understanding of both benefits and risks of every pharmacotherapeutic intervention should underpin the effective medicine management cycle of prescribing, dispensing, administering, and monitoring of effect . BalanciThe methodical and regular review of the efficacy and safety parameters of a medicine is called a benefit-risk assessment or analysis (BRA) or benefit-risk ratio evaluation. BRA is primarily an exercise that balances two dimensions: the dimension of benefit that includes not only therapeutic efficacy but also improvement of quality of life, and the dimension of risks that consists of the safety profile of the given medicine and the potential risk of unintended adverse events anticipated on the basis of the mechanism of action . The dimDespite the use of quantitative and structured approaches to evaluate the benefits and risks of medicines, the BRA remains heavily influenced by the value judgments of clinical experts . This prThere has been a steady increase in studies eliciting patients' preferences and perspectives on their medicines , 10. TheWhile some search strategies have been proposed to identify the literature on patients' knowledge, views, and preferences about their health and health care \u201316, we cWe developed a content search strategy to retrieve studies on patient-based BRA of medicines using an iterative process: (1) developing a search term bank, (2) refining the search strategy, and (3) validating the final strategy . This coWe compiled a list of search terms  from two sources: (1) existing search strategies used to retrieve studies on patients' knowledge and information needs, experiences, views, and preferences \u201316 and  as a set of relevant records against which the search strategy is tested and validated to determine its performance parameters . ThroughWe performed our term frequency analysis in two rounds: in the first round we retained the terms with sensitivity higher than 1%, and in the second round we retained the terms with precision greater than 2%. We set the minimum thresholds of frequency of occurrence by multiple testing of various combinations to obtain optimal performance. We aimed for a minimum of 80% for sensitivity and 20% for precision. The balance between sensitivity and precision was determined with the thresholds 1% and 2%, with consensus among all authors. For an extended search strategy, we aimed for a minimum of 90% for sensitivity at the cost of any precision. In the extended search strategy, we included all the terms that surpassed the 1% sensitivity threshold .In this refining exercise, we chose type 2 diabetes mellitus (T2DM) as a case condition to test the performance of each search term. We chose T2DM for four reasons: (1) T2DM is highly prevalent and associated with significant excess risk in cardiovascular morbidity and mortality , (2) treFor terms relevant to T2DM and its management, we used this search string:Diabetes Mellitus / therapy[MeSH] OR Diabetes Mellitus, Type 2 / drug therapy[MeSH] OR Diabetes Mellitus, Type 2 / therapy[MeSH] OR Hypoglycemic Agents / administration & dosage[MeSH] OR Hypoglycemic Agents / therapeutic use[MeSH] OR Hypoglycemic Agents / adverse effects[MeSH] OR Hypoglycemia / prevention & control[MeSH] OR Blood Glucose / drug effects[MeSH] OR Glucagon-Like Peptides / therapeutic use[MeSH] OR Insulin / therapeutic use[MeSH] OR Insulin / administration & dosage[MeSH].To determine a gold standard reference set for performance measurements in this refining exercise, we combined\u2014in PubMed\u2014all candidate search terms (using OR) with the T2DM search string (given above) using AND. We screened on title and abstract level all retrieved records for relevant studies on patient-based BRA of medicines in T2DM; this constituted our gold standard reference set. We then tested in PubMed, one by one, each of the terms in our bank by combining them (using AND) with the T2DM search string.We removed redundant terms that retrieved irrelevant studies. We added synonyms and alternative terms to the search terms. We applied truncation techniques to selected search terms\u2014in other words, a deliberate shortening of a search term by adding a wildcard character  to retrieve other variants of the word due to differences in descriptions, language, or spelling , 29. TerWe validated the approach at two levels. First, we validated the search strategy in a case condition and computed its performance parameters. Second, we tested its relative performance by comparing it to the search approach in a published systematic review.We validated the proposed final search strategy in PubMed by conducting a search of existing literature on patient-based BRA of disease-modifying drugs used to treat multiple sclerosis (MS) as a case condition. The choice of MS was based on (1) factors related to the disease, where patients experience significant pain and disability during their disease journey and may face multiple relapses and remissions, and (2) factors related to the newer, more-effective treatment options, which are also associated with increased risks of severe adverse events . These tWe used this search string:Multiple sclerosis OR Multiple Sclerosis [MeSH Terms] OR Multiple Sclerosis / therapy [MeSH Terms] OR Multiple Sclerosis, Relapsing-Remitting / drug therapy [MeSH Terms].We ran the search in PubMed in August 2020, with (using AND) and without the proposed search strategy and applied a ten-year filter for the publication date (from August 2010 to August 2020). Search A was based on the search string of MS combined with the developed search strategy (using AND) and search B was based on the search string of MS alone. We screened all records in search A on title and abstract level. We considered a study as relevant if the outcomes of interest included the preferences of MS (any subtype) patients toward their medicines, ideally specified according to clinical or convenience attributes describing various treatment scenarios. We did not exclude any study based on the methodology . We categorized articles as either relevant (true positives) or not relevant .We then ran the search for articles on MS and its treatment, using the above search string alone, with the same ten-year filter for the publication dates (search B). We screened all records in search B on title and abstract level. The false negatives were considered the relevant articles that were only detected without adding the search strategy (detected only by applying the string to retrieve articles on MS and its treatment\u2014search B). These were the relevant articles that the search strategy failed to detect. The remaining articles retrieved without the use of the search strategy were the true negatives. Because there is no established standard to ensure identifying all relevant articles on MS and its treatment \u2014thus ideSystematic reviews aim to comprehensively locate and appraise research on a particular question, using structured and replicable procedures at each step of the process . The appWe compared the performance of our developed content search strategies to the results of a published systematic review on patient preferences for disease-modifying antirheumatic drug (DMARD) treatment in rheumatoid arthritis (RA) . In thisWe combined the developed strategy (using AND) with the following search terms:Rheumatoid arthritis OR RA OR rheumatic diseases OR disease-modifying antirheumatic drugs OR DMARDs OR antirheumatic agents OR Arthritis, Rheumatoid / drug therapy [MeSH] OR Arthritis, Rheumatoid / therapy [MeSH] OR Antirheumatic Agents / therapeutic use [MeSH] OR Biological Products / therapeutic use [MeSH].We ran the search in PubMed in December 2020. We calculated the relative performance of the content search strategy in PubMed by dividing the number of articles included in the systematic review and detected by the search strategy by the total number of articles included in the systematic review and cited in PubMed .We compared the performance of the extended content search strategy to the results of a published systematic review on patient preferences for lung cancer treatment . In thisWe combined the extended content search strategy (using AND) with the following search terms:Lung Neoplasm [MeSH] OR Antineoplastic Agents [MeSH] OR lung cancer [tiab]We ran the search in PubMed in July 2021. We calculated the relative performance of the content search strategy in PubMed by dividing the number of articles included in the systematic review and detected by the extended search strategy by the total number of articles included in the systematic review.We conceptualized a final search strategy to retrieve studies on patient-based BRA after a series of refining rounds. The search terms are grouped into two domains: (1) domain of the patient and (2) domain of the BRA of medicines . The repWe further refined the search strategy when we added the concept of medicine or treatment to the approach. Many retrieved studies discussed patients' participation in physical activity and screening activities rather than eliciting patients' preferences about their medicines. Most studies were retrieved using the term \u201cparticipation,\u201d so we deemed terms related to participation  as redundant (sensitivity of each term below 1%). Similarly, most of the studies retrieved using the term \u201cpatient satisfaction\u201d (not treatment satisfaction) focused on patients' assessment of health services, programs, and use of devices (sensitivity below 1%), so we removed this search term.We included in our initial bank of search terms as many entries that identified articles relevant to patients' preferences and choice behavior as possible , given the inconsistencies in the nomenclature and indexing about patients' preferences and perspectives on medicines. We noticed during the refinement stage that the term \u201cpatient\u201d was more often used in studies examining the BRA of medicines, but the terms \u201cuser\u201d and \u201cconsumer\u201d were more often used in studies about devices and services. We excluded the latter terms in the final search strategy (sensitivity of each term below 1%). We used truncation on selected free-text entries to reduce the number of terms . The simultaneous use of both the MeSH term and the corresponding free text yielded more results than either alone. This was the rationale for the final strategy containing double entries to be searched in \u201cAll fields OR in MeSH.\u201dThe refining component was based on the search terms identified in the screening of seventy studies focused on patient-based BRA of medicines  from varWhile refining the compiled search terms, we found selected entries (free text and controlled vocabulary) with passable sensitivity (more than 1%) but very low precision (less than 2%). These entries, if used together, increased the sensitivity of the search strategy but decreased the precision. These search terms were in both domains: (a) the patient , and (b) the BRA of medicines . We built an extended search strategy containing the final refined strategy combined with all these additional terms .We validated the final search strategy by combining it  with the relevant search terms for MS in PubMed. Search A returned 304 results: 63 relevant (true positives) and 241 not relevant to patient-based BRA of DMARDs . A search using only the relevant search terms for MS (Filter applied: in the last 10 years\u2014search B) returned 43,901 hits including 75 relevant  and 43,825 true negatives. False negatives are the relevant articles that the search strategy failed to detect. All relevant articles  are listed with their corresponding keywords and MeSH terms in The systematic review on patient preferences for DMARD treatment in RA included 36 unique studies . We usedThe systematic review on patient preferences for lung cancer treatment included fifteen unique studies . We usedWe developed a high-performance, objectively derived search strategy for patient-focused BRA of medicines. This search filter had high sensitivity for studies about patients' preferences and perspectives on the benefits and risks of their medicines, with excellent specificity and accuracy, and acceptable precision. Our proposed content search strategy was more targeted to retrieve studies on how patients perceive the effectiveness of their medicines and whether the potential benefits outweigh the harms when compared with another search filter designed to identify existing literature on patients' knowledge, views, and values . The maiPatient-centered care encompasses shared decision-making, support for self-management, patient information, patient empowerment, care planning, the integration of medical and nonmedical care, and good communication between clinicians and patients . It is aWe detected the search terms mostly used in studies relevant to patient-focused BRA of medicines by developing a bank of search terms and iteratively refining these terms. Although the terms for the domain of the patient are relatively consistent, those terms relevant to the domain of benefits and risks of medicines are variable. Most search terms in the domain were extracted as free text from the screened articles. The MeSH terms of Benefit Risk Assessment and Risk Assessment were neither precise nor sensitive in retrieving articles pertinent to patient-based BRA of medicines. Specific entries corresponding to patient-based risk assessment or patient-based benefit-risk assessment were not found below these terms in the MeSH hierarchy. It seems that the concept of patient-based BRA has not yet been identified under the larger concept of risk assessment or BRA in general.Despite the relative consistency in the use of keywords and MeSH terms in the domain of patients and their preferences, we did not incorporate any of these terms in the search syntax of our validation case of MS\u2014with and without the proposed content search strategy. The main reason was to detect the largest possible number of publications that address patient-based BRA of drug therapy in MS. For example, the use of certain terms  in the syntax for MS would have precluded retrieving articles where the keywords used to describe patient preference were respondents' attitude, patient engagement, or opinion of individuals. Screening of the many publications related to MS and its treatment in the last ten years allowed us to detect more precisely the true and\u2014more importantly\u2014the false negatives of the proposed content search strategy. The benchmarking of the pool of articles included in our validation versus those included in two published systematic reviews on patient-based BRA of medicines in MS permitted an optimal calculation of the performance parameters. Testing our content search strategy against a completed systematic review permitted us to calculate the relative performance of our generic search strategy versus the sophisticated and thorough research approach adopted in systematic reviews. It also allowed us to test it in a different case condition.The success of an empirically derived content search strategy is estimated by the generalizability of the gold standard adopted in its validation. Despite being costly and time-consuming, hand-searching is still viewed as the method of choice . The manA key point in developing search strategies is striking a balance between the sensitivity and specificity for the intended end users. It is hard to determine when a search strategy is completed, as there are no fixed measures or criteria for performance parameters for this purpose . MoreoveThis is the first study, to our knowledge, to develop a content search strategy that contains generic keywords and MeSH terms and subheadings that retrieve published data on patient-based BRA of medicines with high sensitivity, specificity, and accuracy. It can be used to identify the evidence on patient preferences and perspectives on their medicines in any therapeutic area when combined (using the Boolean operator AND) with search entries pertinent to a given disease or condition. This research-based search strategy can replace subjectively derived and unvalidated strategies currently used in the field of patient-based BRA, which rely more on expert opinions and are regarded as methodologically weak in standard biomedical evidence hierarchies , 49.The main study limitation is that the search strategy was designed and validated using only one database, PubMed. All search strategies must be developed for a specific database , due to This search strategy for identifying patient-based BRA of medicines can be used with confidence by not only information specialists but also clinicians or regulators with limited bibliographic search skills in a wide range of clinical areas where there is a need or wish to integrate patients' perspectives in the assessment of medicines. Its metric-based performance can inform prospective users of the retrieval rate they can expect in their search. An extended search strategy is also proposed to be used for a more exhaustive search. The methods used to develop and validate the search filter can also be replicated in other complex search domains."}
+{"text": "Nearly 70 years ago, in 1954 a follow-up study of 577 San Mateo County residents over 50 years of age was carried out. Correlations between factors studied and morbidity were not conclusive, but suggested relationships between low economic status, low hemoglobin high caloric intake, low thiamine intake and low ascorbic acid intake and nervous system disease . The Perspective on chronic long-lasting anorexia nervosa attempts to integrate the insufficient knowledge in this area and the impact of severe eating disorders on life course and brain health . A novel approach to the Differential effects of sleep disturbance and malnutrition on late-life depression among community dwelling adults demonstrates that while both sleep disturbance and malnutrition are significantly associated with late-life depression malnutrition may be more critically associated with depression in community-dwelling older adults . This may offer an insight into the mechanism through which late-life depression is a risk factor for dementia.These articles demonstrate the complexity of interactions between nutrition and mental health. They will hopefully facilitate further research and clinical implications.The author confirms being the sole contributor of this work and has approved it for publication."}
+{"text": "First Person is a series of interviews with the first authors of a selection of papers published in Biology Open, helping researchers promote themselves alongside their papers. Yuta Koui is first author on \u2018 Yuta KouiDescribe your scientific journey and your current research focusMy research interest is studying how various types of cells communicate with each other to develop organ-specific functional properties. My PhD work focused on the crosstalk between hepatocytes and non-parenchymal cells such as liver sinusoidal endothelial cells and hepatic stellate cells in liver development and liver diseases. As a postdoctoral fellow, I am studying functional interactions between nervous and vascular systems: my interdisciplinary research program focuses on two major neuro-vascular interfaces. The first neuro-vascular interface is the coordination and integration of functional branching patterns of sensory nerves and blood vessels in the skin. The second neuro-vascular interface is a brain-specific unique vascular structure that establishes blood brain barrier (BBB) formation. As a first step towards characterizing brain vascular cells in the latter project, I decided to characterize the cellular origin of brain endothelial cells and accessory pericytes. Our lineage tracing studies clearly demonstrate that hepatic leukemia factor (Hlf)-expressing cephalic paraxial mesodermal cells contribute to endothelial cells and pericytes in the developing brain vasculature.How would you explain the main finding of your paper?Hlf) in the head mesenchyme of mouse embryos and discovered that Hlf marks head mesenchymal cells, which mainly contribute to endothelial cells and pericytes of blood vessels in the brain. Taken together, our findings suggest that Hlf-expressing head mesenchymal cells generate brain endothelial cells and pericytes.Blood vessels compose the indispensable circulatory network for every tissue to transport oxygenated or deoxygenated blood and maintain organ-specific function by interacting with tissue parenchymal cells. Blood vessels in the brain are highly specialized because they develop the BBB, which limits transportation of substances between the bloodstream and the brain parenchyma. These unique properties raise a question of how endothelial cells and accessory pericytes of blood vessels emerge during brain development. We identified a unique expression of hepatic leukemia factor  helped to establish high resolution whole-mount RNA What do you enjoy most about being an early-career researcher?Working as an early-career researcher gives me a great opportunity to develop my scientific career. In my current laboratory at the National Heart, Lung, and Blood Institute, I enjoy interdisciplinary collaborations that allow me to view my current projects and experimental approaches from a new perspective.What's next for you?Given that our lineage tracing studies indicate the contribution of Hlf-expressing cephalic mesenchymal cells in the vasculature of hindbrain, midbrain, and diencephalon but rarely in the cerebral cortex, it is interesting to examine what controls such differences in the contributions of Hlf-expressing cells. From the aspect of my research career, my broad goal is to make a lasting contribution to the scientific community, not only with primary research findings, but also by providing mentorship to the next generation of junior scientists."}
+{"text": "Religious and cultural beliefs strongly influence people's attitudes and behaviors that, in turn, may positively or negatively affect both individual and public health. In this regard, we aimed to collect and analyze evidence on the impact of religion in the current COVID-19 pandemic.We performed a scoping review investigating both scientific and grey literature available on the topic from the onset of the pandemic to September 2021. Pubmed, Web of Science and Google Scholar were investigated and a hand-search on Google was also performed. Studies dealing with religion and COVID-19 were included and narratively summarized according to topics.46 articles were included in the review. Predominant topics emerged were 1) religious pilgrimages and rituals worldwide being relevant to COVID-19 outbreaks, especially in the first pandemic wave 2) difficulties to engage the Closed Religious Communities  in which community way of life, restrictions in using media and resistance to comply to preventive measures were identified as significant COVID-19 risk 3) COVID-19 unofficial treatments and vaccine hesitancy also supported by concerns on the religious acceptability of vaccine composition or firm interpretation of the Ramadan fasting 4) a fuel of religious discrimination 5) religious communities and leaders strongly trusted in conveying COVID-19 information.Our findings highlighted how religion has represented both a risk for the spreading of the virus and a precious opportunity to convey evidence-based and culturally-sensitive COVID-19 information engaging people in fighting the pandemic. To be prepared for similar future challenges, scientists, politicians and health professionals need to acknowledge the role that culture and religion have in influencing people's lives to design specific health policies and strategies to ensure that all people are effectively engaged in health production and protection.Religion has represented both a risk factor for COVID-19 outbreaks and a resource to convey evidence-based information and overcome resistance to implementing COVID-19 preventive measures.Health policy should become more sensitive to religious and cultural issues acknowledging the role played by religion in facing complex global health challenges."}
+{"text": "Correction: BMC Public Health 21, 2038 (2021).https://doi.org/10.1186/s12889-021-12103-xThe corrected Abstract of this article  should rThis corrected Abstract replaces the previous one. The original work attempted to quantify the relative harm to health from electronic nicotine delivery systems (ENDS) compared to smoked tobacco. As such it used various biomarker studies and previously modelled estimates of smoking-related health loss. However, we now consider that the data limitations with the selected studies and the assumptions involved in our method, are too problematic to allow for a valid quantitative assessment. The original manuscript text remains below to show the approach taken, but interested readers are directed to the correction file that explains the specific limitations with the studies and limitations with the analysis. This correction file also details some potential ways in which future studies can help advance knowledge of this topic. Our revised conclusion is therefore that despite our previous analysis, given the data and methods limitations in the biomarker studies we identified, it seems premature to develop quantitative estimates of the relative harm to health from using modern ENDS (vaping) compared to tobacco smoking.At the request of the Editor, we now outline our reasoning for this more cautious conclusion below.1) The identified studies did not address potentially major toxicants involved in vaping  and only included biomarker measurements for a small proportion of the likely total number of toxicants.As an example, neither of two key toxicants  were coThe biomarkers we used from the five selected studies only included a total of seven biomarkers . Yet, tobacco smoke contains over 7000 chemicals, hundreds of which are toxic and around 70 of which are known to cause cancer . AlthougThe limited selection of biomarkers available for our analysis, therefore, warrants more caution than we initially expressed in the estimated potential relative health impact of vaping vs smoking.2) Incomplete compliance with being an \u201cexclusive vaper\u201d  creating the risk that estimates of toxicant levels and risks of relative harm were too high for this group.This was a likely problem with all of the five studies except the confinement study , and eve3) Selected studies were likely to be confounded by extraneous sources of toxicants .endogenous production of COHb in the body [Only one of the five selected studies was a confinement study , that inthe body .4) Only two of the five identified studies were randomised controlled trials .n\u2009=\u200910 subjects  from the non-industry funded trial [Our study included only two randomised controlled trials (RCTs) , 8; the ed trial  noted soThe study by Boykan et al.  involvedNga et al.  drew on Oliveri et al.  used a mThe three observational studies all have the potential problem of confounding from unmeasured and unknown confounders, and the problems of potential non-exclusive vaping (as detailed above). But below we detail some of the more specific potential problems with these studies:5) Some included studies were very short-term.Usage patterns among short-term users of ENDS may have differed from those exhibited by more experienced ENDS users, which may have affected their biomarker measurements. This was potentially relevant to the RCT involving only five days of ENDS use , or the 6) Two of the five studies were industry-funded.Two of the five selected studies , 13 were7) Vaping device heterogeneity and modernity \u2013 impacting external validity.Only two of the included studies exclusively involved the more modern cartridge-based ENDS devices , 8. With8) Potentially different trajectories between smoking and vaping \u2013 impacting external validity .The five selected studies all represented points in time in the long-term trajectory of ENDS use by individuals and within populations, and include diverse brands and product types (of both ENDS products and comparative tobacco brands). Trajectories of ENDS use and smoking may diverge further in the future. For example, smoked tobacco products have changed little over many decades and it seems likely that many people who smoke will continue smoking long-term at approximately the same intensity and exhibit similar levels of biomarkers, and experience similar levels of harm. However, this outcome seems less certain for ENDS use. ENDS users/vapers may be more or less likely to continue ENDS use long-term compared to people who smoke. There may also be future changes to ENDS technology and usage patterns that affect exposure levels among ENDS users . This may mean that the biomarker levels observed in ENDS users in the five studies may not represent longer term biomarker levels with continued ENDS use and hence the approach we used to estimating relative harm may be inaccurate.9) Various other study limitations.Discussion Section of the published article, we considered additional limitations. These include the limited number of disease categories selected (only four main groupings), the lack of weighting of the different biomarkers within the linked disease categories (due to lack of adequate data), and the likelihood that toxicant exposure and subsequent risk of cardiovascular disease is non-linear. We considered using data on the latter relationship [In the tionship , but givPotential next steps for progressing the science on estimating the relative harm of vaping vs smoking.High quality long-term cohort studies with health outcome measurements should ultimately provide important information on the relative harm of vaping vs smoking. Such studies may also provide earlier provisional information by using biomarkers and physiological measures.(i)a greater number of biomarkers and physiological measures that cover a wider range of toxicant types (as discussed above);(ii)three randomised study arms ;(iii)adequate time periods to allow for stability in ENDS use behaviours and for adequate wash-out periods for all the key toxicants so that stable levels are achieved;(iv)verification methods to ensure no dual use (ENDS and smoking) and assessment of other toxicant exposures . Although the latter can be largely addressed with the randomisation process, such data may inform interpretation and generalisability ;(v)funding that is fully independent from industry.But perhaps the best short-term way to explore this topic is to conduct additional and larger confinement studies where these involve:Additional information can also come from theoretical studies  or \u201cin All such information is urgently required as policy-makers around the world are having to make decisions on vaping and smoking regulation to get the optimal balance between: (i) facilitating access to vaping to assist smokers to quit or reduce harm from ongoing nicotine dependence; and (ii) minimising youth uptake of both vaping and smoking."}
+{"text": "Neuroinflammation is a hallmark of many neurological diseases, including traumatic brain injury (TBI), which is usually characterized by two pathological hallmarks: activation of microglia and infiltration of blood-borne macrophages . Until rTmem119 gene expression in frozen brain sections of TBI (Day 7) by RT-PCR and using in situ hybridization experiments; they further confirmed its upregulation, specifically in the contused area and surrounding regions, along with increased microglial activation. These findings are consistent with a study showing the increased Tmem119 mRNA level in frozen tissue of the frontal cortex from patients with Alzheimer\u2019s , Li and colleagues found a reduced Tmem119 mRNA level in CD11b+CD45Int microglia (bulk population) on Day 1 post-intracerebral hemorrhage  is most likely a compensatory pathway. On the contrary, if reactive microglia, indeed, show downregulation of Tmem119 gene expression, then this downregulation is likely a negative regulation leading to less TMEM119 expression on the plasma membrane. Given that two studies mentioned earlier have shown an overall upregulation of Tmem119 gene expression in microglia (in both homeostatic and active forms) in the injured tissues  and Notch proteins, it is very likely that a full length (FL) of TMEM119 can also be cleaved into an extracellular domain (ECD) and intracellular domain (ICD) fragments. This hypothesis can be confirmed using the anti-TMEM119 (extracellular) antibody (#ANR-175) by Western blot. This antibody hypothetically should label both the full-length protein and the ECD fragment  and blood-infiltrating macrophages. Western blot analysis targeting the extracellular or intracellular domain of TMEM119 could also be informatic for the activation of microglia. In addition, our Tmem119-tdTomato reporter mice could be another useful tool to track all microglia phenotypes (both homeostatic and reactive microglia) CR and WE contributed ideas and wrote the final manuscript. Both authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "A history of traumatic brain injury (TBI) is often associated with acquired epilepsy, which is associated with psychiatric co-morbidity, that when undetected might lead to misdiagnosis and mistreatment.The objective is to present the case of a 47-years-old male with a history of TBI and undetected acquired epilepsy, with a subsequent treatment resident mood disorder that was lead to a full clinical remission once epileptic activity was controlled using anti-seizure monotherapy.After compulsory admittion to our inpatient psychiatric unit because of suicidal ideation and persistent aggressive behavior with volatile mood swings, the patient was fully evaluated and his psychiatric and medical histories were recorded. A brain CT scan and EEG were performed. Laboratory tests excluded other medical co-morbidity.The patient had a previous history of TBI and subsequent multiple episodes of mood disorders that failed to reach full remission even if treated with antidepressives and antipsychotics for adequate time and dosage according to current quidelines. EEG was positive for epileptiform activity with sporadic slow theta waves and right frontotemporal epileptic-like features while the patient was free of clinical seizures. Carbamazepine was initiated and titrated up to 1200mg daily leading to the full remission of the initial clinical symptoms along with the EEG findings\u2019 improvement. The patient remained stable with his functionality at its utmost recovery during the two-years follow-up evaluations.TBI induced epilepsy might be under-diagnosed in the absence of clinical seizures leading to the mistreatment of the associated psychiatric disorders that could be the only clinical presentation of the underlying pathology.No significant relationships."}
+{"text": "Radical resection for cancer of the splenic flexure requires careful consideration of the dissection line so that blood flow in the remnant bowel is maintained, particularly when the root of the inferior mesenteric artery (IMA) is already occluded. Intraoperative indocyanine green (ICG) imaging is a promising method for evaluating blood perfusion of organs and vessels. However, there are few reports on the use of ICG to determine the dissection line in patients with altered blood flow. In this article, we describe two cases of successful resection of splenic flexure cancer (SFC) in patients with an occluded IMA under ICG guidance.en bloc. Case two was a 77-year-old man with a diagnosis of stage II SFC in whom the root of the IMA appeared to be occluded by arteriosclerosis. Computed tomography showed that the LCA was anastomosed to the accessory middle colic artery (AMCA)\u00a0while the left branch of the MCA was joined to the marginal artery. Intraoperative ICG imaging revealed that the left side of the colon was perfused by the AMCA and not the MCA. By preserving the AMCA-LCA arcade, we were able to safely divide the left branch of the MCA. Both patients were discharged with no symptoms of bowel ischemia or recurrence of cancer during follow-up.Case one was a 76-year-old man with a diagnosis of stage III SFC who had previously undergone endovascular aortic repair without reimplantation of the IMA. Intraoperative ICG imaging revealed that the left side of the colon was perfused mainly by the left branch of the middle colic artery (MCA). We performed a hemicolectomy with preservation of the MCA-left colic artery (LCA) arcade and resected an enlarged lymph node Interindividual variation in vessel branching patterns and dominant vessels in the descending and distal transverse colon may result from congenital factors or acquired disease. Detailed information on blood perfusion is required to avoid postoperative bowel ischemia. This report is the first to focus on patients with SFC and altered blood flow. We show that ICG imaging might be a reasonable option for determining an adequate surgical dissection area. In radical surgery for colorectal cancer (CRC), the feeder vessels are commonly divided at the root, and perfusion of the remnant bowel is preserved by other vessels. However, some patients have an altered blood flow pattern and perfusion area because of cardiovascular disease or previous resection of CRC. Moreover, the typical division of vessels may cause postoperative bowel ischemia (BI), particularly in patients with splenic flexure cancer (SFC) and an occluded inferior mesenteric artery (IMA). Therefore, surgeons need to consider whether or where they should divide vessels.Intraoperative indocyanine green (ICG) fluorescence imaging is emerging as an alternative to computed tomography (CT) angiography for the assessment of blood flow and branching patterns in arteries -3. ICG iCase oneThe patient was a 76-year-old man who visited our institution with a complaint of bloody stool. The patient was receiving clopidogrel as anti-platelet therapy for the previous lacunar infarction, and he had stage G3b chronic renal failure. Detailed examination revealed a neoplastic lesion involving almost the entire circumference of the splenic flexure Figure , and sweDuring the surgery, the left branch of the MCA was clamped using a laparoscopic approach Figures , 2b. On The postoperative course was uneventful. Pathological examination of 15 harvested LNs revealed that one was metastatic; this LN corresponded to the enlarged LN seen on preoperative CT. The patient did not receive any adjuvant chemotherapy because of chronic renal dysfunction but has shown no signs of recurrence during 15 months of follow-up.Case twoThe case was a 77-year-old man who was admitted to our institution for investigation of symptoms of angina and found to have anemia during his hospital stay. The patient was previously diagnosed with moderate aortic regurgitation and received clopidogrel. Detailed examination revealed advanced colon cancer on the splenic flexure Figure . CT did Surgery was performed using a laparoscopic approach. The AMCA and the left branch of the MCA were identified Figures , 4b. WheParalytic ileus (Clavien-Dindo grade 2) occurred on postoperative day three but improved rapidly. The patient was discharged on postoperative day 10. Pathological examination of 16 harvested LNs revealed no metastasis. There have been no signs of recurrence during six months of follow-up.Blood flow in the descending colon and distal transverse colon is supplied mainly by arterial branches from both the superior mesenteric artery (SMA) and IMA and partially by the internal iliac artery (IIA). However, arterial communications, including the collateral arteries  and marginal vessels  and their branching patterns or dominant vessels in each area, vary among individuals . In addiThe AMCA is typically identified as the artery that arises separately from the SMA near the first jejunal artery proximal to the MCA and runs along the inferior border of the pancreas toward\u00a0the splenic flexure ,13. A syAltered blood perfusion must also be considered in patients undergoing vascular surgery for AAA after a prior left-sided colectomy. The absence of flow in the SMA is a well-recognized contraindication of EVAR. Brewster et al. warned in the early 1990s that prior colon resection could impair collateral circulation . Since tThis study has several limitations. First, this report presents a small number of cases based on the clinical experience at a single institution, and there was no control group. Second, the intensity of ICG fluorescence was not quantitatively evaluated. Nevertheless, this ICG fluorescence imaging could be a simple and reliable option when performing SFC resection in patients with an occluded IMA.We performed SFC resection in two patients with an occluded IMA under ICG guidance. To our knowledge, this is the first report on the value of ICG imaging in patients with an occluded IMA who require CRC surgery. We discussed in this report that we should not underestimate the impact of prior colectomy on the risk of BI after AAA repair. In conclusion, we propose that ICG imaging can be used in cancer surgery with altered blood flow to ensure safety, particularly when the patients are vulnerable to extended surgical resection."}
+{"text": "We thank Shen and colleagues for their interest in our paper on the use of noninvasive ventilation in older adults with COVID-19 [We believe that the relatively high NIV failure rate in our study is multifactorial. First, participants in our study were significantly older than the sample enrolled by Arabi and colleagues (76 vs 58\u00a0years) in a study cited by the authors . DespiteWe remain cautious about judging the appropriateness of NIV administration in the setting of an extraordinary disruption of standard treatment pathways during the studied period. Due to a shortage of ICU beds, the propensity to limit life-sustaining (LST) treatment was likely higher than before the pandemic , 4. NeveComparison between the primary NIV and primary IMV group suggested a higher 30-day mortality rate in the former group. This observation was confirmed in a sensitivity analysis excluding patients in whom LST was limited when primary respiratory support modality was used. Conversely, another sensitivity analysis excluding all patients with LST limitation showed no difference between the groups. It might suggest that this difference is driven by high mortality in patients primarily treated with NIV who were subsequently intubated. This is in-line with our analysis showing an association between pre-intubation NIV duration and 30-day mortality. Nevertheless, we agree that further studies are needed to establish optimal respiratory support modes in different patient populations of critically ill patients."}
+{"text": "These platforms must ensure that the tissue complexity is recapitulated and maintained to provide reliable novel scientific outcomes. The Research Topic covers various strategies for creating permissive environments, where cells can organize according to a proper architecture . The microfluidic platform was validated as a suitable model for intestinal drug transport studies by correlating the transport of small molecule drugs to the corresponding human absorption data.Microfluidic devices are suitable to investigate complex constructs with accurate and controllable environment by high resolution spectroscopies and real-time imaging. A microfluidic platform compatible with advanced widefield- and confocal microscopy was developed to recapitulate an in vitro models, a bioengineered 3D platform based on human intrahepatic cholangiocyte organoids cultured onto polyethersulfone hollow fiber membrane replicated the biological structure and function of native bile ducts . This platform may be suitable for studying cholangiopathies and therapeutic strategies.In the context of Marzagalli et al. presented an organ-on-chip (OOC)-based approach for recapitulating the immune cell migration under physiological fluid flow. This model was used to study the infiltration within a 3D tumour matrix, and activation against neuroblastoma cancer cells in a fully-humanized, fluid-dynamic, and clinically relevant-sized environment.Kakni et al., developed organoids consisting of a simple columnar epithelium patterned into crypt-like and villus-like structures. These organoids reflecting the structural and functional characteristics of the in vivo counterparts, could represent a powerful new tool for studies related to diseases, microbiota nutrient absorption and drugs.In the last years, organoid models using pluripotent stem cells have been implemented for diagnostic and therapeutic utilities. Boucard et al. They investigated the capacity of primary and immortalized fibroblasts of distinct origins to degrade a fibrin-based biomaterial establishing that fibrin degradation through the secretion of serine protease.In tissue engineering, the impact of the cell type on the degradation of biomaterials has been studied by Sivasubramanian et al., developed a hybrid nanoplatform that harnesses the tumour microenvironment factors for dual targeted magnetic resonance imaging and assessment of tumour oxygen status by photoacoustic imaging. They reported the fabrication of a novel enzyme responsive T1 magnetic resonance imaging contrast agent that can modulate oxygen in the tumour microenvironment via the catalytic conversion of H2O2 to O2.Multifunctional platforms that perform diagnostic functions and serve as responsive biomaterials to tumour microenvironment are encouraging. Lin et al., explored the protective effect of GDF11 on neurons in vitro, and a lentiviral vector to induce GDF11 overexpression with the aim to create and maintain a local microenvironment conducive to nerve regeneration.Peripheral nerve transection is one of the most common peripheral nerve injuries. Although neurons have a limited ability to regenerate, axons have a great potential for regeneration. To find an effective treatment strategy for sciatic nerve injury, Tang et al., investigated the effects of tissue origins on the adipogenic capacity of the decellularized matrix exploring the mechanisms that decellularized adipose-derived matrix promotes adipose tissue formation and provides further insight into tissue specificity, which could be applied in different tissue repair and regeneration.In the tissue engineering scenario decellularized matrices are used as natural scaffolds to promote the differentiation of implant cells and tissue remodelling. Owing to the removal of immunogenic components, the decellularized matrix has good biocompatibility and safety, which can be used in autologous, allogeneic, and xenogeneic tissue engineering. Kuan et al., synthesized a sonosensitizer of Eu-doped CaCO3 to combine with low-intensity ultrasound as a non-invasive treatment for the body sculpture for body sculpture. The CaCO3: Eu had good biocompatibility and could produce ROS in adipocytes for lipolysis. The results showed that developed sonosensitizer could effectively inhibit the adipogenesis, after treated with low-intensity ultrasound, without skin burning and charred sounding tissue.Finally,"}
+{"text": "Providing care support to rural Alzheimer\u2019s disease and related dementia (ADRD) caregivers has always been challenging, but particularly with the COVID-19 pandemic, new barriers have emerged for families in accessing care support. Delivered via telehealth, Harmony at HOME (H@H) provides dementia care mastery for caregivers of persons with ADRD in the skills of assessing and modifying the home environment to promote \"person-environment fit,\" whereby increasing functional activity engagement and minimizing maladaptive behaviors. To enhance care supports specific to the needs of rural communities, this study reports the findings of two focus groups with rural caregivers who participated in the H@H intervention. Focus groups were aimed to identify the needs of caregivers in rural communities to guide adaptation approaches for future implementation of the H@H intervention in these underserved areas. Additional studies to assess real-world efficacy of the adaptations to H@H are needed as a next step toward implementing this intervention in clinical, home care settings."}
+{"text": "Extant literature suggests that adults with higher education are more likely to avoid poor health outcomes and to rate their health as better than individuals with less education. The current study builds on prior research by analyzing the association between educational attainment and the perceived need for future help with activities of daily living (ADLs), often measuring disability in the literature. 2011-2014 National Health Interview Survey (NHIS) data for adults in the United States age 40 to 65  were analyzed using multivariate regression analysis. Among non-Hispanic Whites, increased years of education predicted stronger anticipation of the need for future ADL assistance. For non-Hispanic Blacks, this relationship was reversed at the some-college level. Education was not predictive of perceived future ADL assistance need for all other racial-ethnic groups. Results of this study suggest education has a unique impact on anticipation of future need for ADL assistance among non-Hispanic Whites."}
+{"text": "Climate change seriously threatens health and wellbeing with projected health burdens estimated to cost USD 2-4 billion a year by 2030. Adaptation in the health sector is critical to keep pace with the ongoing consequences of the climate crisis and the impacts projected to occur in the next decade and beyond. Yet estimates by the WHO indicate that climate finance targeting the health sector to date is extremely low: less than 0.5% of multilateral climate adaptation funding has targeted the health sector. In this study, we trace and quantify the amount of adaptation financing targeting the health sector from both multilateral and bilateral sources using publicly available information on the OECD-DAC database and Climate Funds Update. We find that between 2009-2019 only 0.39% of multilateral and bilateral climate adaptation funding targeted health-related efforts specifically. Despite the relatively higher number of health-related projects in Sub-Saharan Africa compared to other regions, a smaller amount of funding is allocated per project compared to other regions. Regional variations in funding are concerning as the countries with the most vulnerability to the climate crisis coincide with regions getting the least amount of funding per project. There is a significant gap in globally financed adaptation efforts in the health sector. Swift and committed remediation is needed to minimise the spiralling risk of high negative health outcomes.\u2022\u2002Between 2009-2019 only 0.39% of multilateral and bilateral climate adaptation funding targeted health-related efforts specifically.\u2022\u2002The countries with the most vulnerability to the climate crisis coincide with regions getting the least amount of funding per health project."}
+{"text": "Stress is a term that was firstly coined by Hans Hugo Bruno Selye, aimed at referring to environmental aspects challenging the balance of physiological functions . The noxGlobal epidemiological data show that the current knowledge on the mechanisms involved in the stress-related diseases and the therapeutic arsenal against these diseases need to be broadened, in order to pave ways for novel and efficient therapeutic approaches interfering directly with the morbidity and mortality. The understanding that environmental situations are able to impair mental health resulting in associated diseases was recently strengthened during the COVID-19 pandemic, in which neuropsychiatric manifestations remarkably coincided with increases in morbi-mortality related to non-infectious diseases . Since tSarlon et al. provided evidence-based on the complexity of the autonomic changes in humans with major depressive disorders (MDD). These authors reported that humans with MDD display alterations in the autonomic reactivity to acute stress exposure, as revealed by the association of symptom severity with higher sympathetic arousal in an emotion-driven imaginative and retrieval-generated stressor condition and a higher respiratory rate in the relaxed condition. Such correlation with symptoms was not detected for arterial pressure, thus supporting respiratory reactivity as a useful and easy-to-obtain index for autonomic function in patients diagnosed with MDD.The first article entitled \u201cHeart Rate Variability Changes in Patients With Major Depressive Disorder: Related to Confounding Factors, Not to Symptom Severity?\u201d from Oliveira et al. reported on the role of adrenoreceptors expressed in the medial prefrontal cortex (mPFC) in the amplitude of the cardiovascular responses to an acute session of stress. Prelimbic (PL) and infralimbic (IL) are subregions of this cortical area implicated in physiological and behavioral responses to aversive threats. Although slightly different, the noradrenergic neurotransmission mediated by \u03b1-1 and \u03b1-2 adrenoreceptors in both PL and IL mPFC subregions plays a facilitatory role in cardiovascular and autonomic responses to restraint stress.The second article \u201cBoth Prelimbic and Infralimbic Neurotransmissions Modulate Cardiovascular Responses to Restraint Stress in Rats\u201d from Gecaite-Stoncience et al. studied the fatigue and psychophysiological reactions in patients under high risk of heart attack. They investigated the links between cardiovascular responses to mental stress and fatigue in coronary arterial disease (CAD) patients after acute coronary syndrome (ACS). Findings showed that anticipatory cardiovascular reactivity to mental stress challenge was diminished in CAD just after ACS.The third article authored by Bertagna et al. followed the hypothesis that maternal separation stress may increase ethanol consumption in adulthood in a sex-dependent manner, by provoking neuroadaptations in some encephalic areas. This study reported that neuronal activation patterns in basolateral and central amygdala subregions were modified and this was related to sex differences in rodents undergoing maternal separation stress.The manuscript \u201cMaternal Separation Stress Affects Voluntary Ethanol Intake in a Sex Dependent Manner\u201d by Morais-Silva et al. in the article \u201cCardiovascular Reactivity to a Novel Stressor: Differences on Susceptible and Resilient Rats to Social Defeat Stress\u201d used social interaction test (SIT) to identify a degree of susceptibility to produce exacerbated cardiovascular responses to social defeat stress (SDS) in rodents. By using the SDS exposure followed by the SIT, this study reported resting tachycardia and greater pressor responses to an acute session of restraint stress, a novel stress paradigm that evoked responses that contrasted to resilient\u2013not susceptible\u2013animals. They proposed that the increases in the magnitude of the cardiovascular reactivity to a novel stressful stimulus may be related to an augmented risk of developing cardiovascular diseases.Enfu Tao et al. tested a novel and small size distention balloon methodology to assess irritable bowel syndrome in mice. These authors validated their small size distention balloon for evaluation of post-weaning visceral hypersensitivity induced by maternal separation stress.Stressful events in early life are known to produce several alterations in adulthood. Early maternal separation is a model of choice to evaluate the implication of stress in the pathophysiology of gastrointestinal diseases later in life. The report \u201cMaternal separation induced visceral hypersensitivity evaluated via novel and small size distention balloon in post-weaning mice\u201d by We are grateful to the Frontiers in Neuroscience, Frontiers in Physiology and Frontiers in Neurology for supporting this Research Topic. The articles collected for the topic will extend the knowledge in the Autonomic Neuroscience and Integrative Physiology fields. This Research Topic adds novel information on the mechanisms potentially involved in the organization of responses to stress and on the pathophysiological processes, thus supporting therapeutic advances aimed at reducing stress-related morbidity and mortality."}
+{"text": "In 2020, about one in four women in Burkina Faso faced an unmet need for family planning (FP). Between 2013 and 2017, Burkina Faso implemented a performance-based financing (PBF) program to improve primary health care service provision (including FP) at rural health centers. Our prior work revealed that PBF did not lead to a reduction in unmet need for FP, in spite of FP being an explicitly targeted service. Our current study assesses supply-side factors that have likely contributed towards this lack of effect at population level, by examining changes in facility-based indicators relevant to the provision of FP induced by PBF.We used facility-based survey data from 406 PBF and 117 control facilities collected before and after the PBF implementation. To compare changes in FP service provision, we examined changes in a number of relevant indicators including: a. the types of FP methods offered by facilities; b. trainings received by different FP providers; and c. available stocks of modern contraceptives. We relied on a difference-in-differences (DID) regression model to estimate the impact of PBF on these indicators.We observed a significant positive impact on the number of staff qualified to provide injectables, implants and IUDs  as well as the number of facilities offering IUDs  and a significant reduction in the number of facilities experiencing stock-outs of female condoms  and implants .Given the significant positive impacts on the number of qualified staff, facilities providing IUDs and a reduction in stock-outs of female condoms and implants attributable to the PBF intervention without showing signs of negative effects on the indicators measured supply-side factors might not have been the main reason for the lack of effect of the PBF program on unmet need for FP.\u2022\u2002Supply-side factors might not have been the main reason for the lack of effect of the PBF program on unmet need for FP.\u2022\u2002Further research is needed to explore other potential underlying reasons."}
+{"text": "To understand the pathway and diverse levels of functional impairment for people with traumatic brain injury (TBI) and spinal cord injury (SCI) as they transition from inpatient rehabilitation (IR) hospital setting to ongoing care and support under the National Disability Insurance Scheme (NDIS) in Australia.The Australasian Rehabilitation Outcomes Centre (AROC) has data on almost every inpatient rehabilitation episode of care since 2002, including TBI and SCI. AROC data is de-identified with a statistical linkage key (SLK-581). The NDIS dataset contains identified administrative data on participants of the scheme from which the SLK-581 was derived. Datasets were restricted to TBI and SCI records and the SLK with key dates used to link records together. The linkage was done in multiple passes with different levels of information with each link being validated using secondary information relating to date of injury, date of admission and geographical location.Over the period 2012-2019, approximately 2,000 records from AROC episodes were linked to an NDIS participant following data validation and individual review of borderline matches We will compare the functional independence of the individual upon leaving rehabilitation with their need for support under the NDIS. Functional independence in rehabilitation is measured by clinicians using the Functional Independence Measure (FIM), a tool that requires clinicians to be trained and credentialed in its use as it is part of the funding model for IR in Australia. Need for support under the NDIS is measured by the funded supports available to a participant under the plan. We expect to demonstrate a correlation between FIM scores and funded supports and identify and analyse any unexpected results.These results will inform resource allocation within the NDIS. This project demonstrates how de-identified research datasets can be linked with administrative datasets to draw new and powerful insights into government service delivery and population health while maintaining privacy. Challenges to accurate linkage can be overcome through iterative and non-deterministic approaches."}
+{"text": "The RAPID-2 intervention has been developed to support women with symptoms of mild-to-moderate anxiety in pregnancy. The intervention consists of supportive discussions with midwives, facilitated discussion groups and access to self-management materials. This paper reports the development of a training programme to prepare midwives and maternity support workers to facilitate the intervention.Kern\u2019s six-step approach for curriculum development was used to identify midwives and maternity support workers training needs to help support pregnant women with anxiety and facilitate a supportive intervention. The stages of development included feedback from a preliminary study, stakeholder engagement, a review of the literature surrounding midwives\u2019 learning and support needs and identifying and supporting the essential process and functions of the RAPID intervention.Midwives\u2019 reported training needs were mapped against perinatal mental health competency frameworks to identify areas of skills and training needed to facilitate specific intervention mechanisms and components. A training plan was developed which considered the need to provide training with minimal additional resources and within midwives\u2019 scope of practice. The training plan consists of two workshop teaching sessions and a training manual.Future implementation is planned to include a post-training evaluation of the skills and competencies required to fully evaluate the comprehensive programme and deliver the RAPID-2 intervention as planned. In addition, the RAPID-2 study protocol includes a qualitative evaluation of facilitators\u2019 views of the usefulness of the training programme. Each year in the UK approximately 750,000 women use midwifery services, and 14% will experience symptoms of anxiety \u20136. For wThe RAPID intervention is the first midwife-led intervention to be evaluated for pregnant women with symptoms of mild to moderate anxiety and the first to include midwifery support workers (MSWs) as co-facilitators. Preliminary work was conducted to design and develop the intervention and a small scale study was completed 2016 in an NHS Trust in England (RAPID-1). The design and development work, including stakeholder and service user engagement, conceptual and theoretical frameworks and outcome measures has been reported in a previous paper .The RAPID intervention comprises three components: 1) One-to-one pre-group introductory meeting with the midwife facilitator; 2) Facilitated group discussion sessions. Midwife and maternity support workers (MSWs) help to initiate discussions by asking women about their feelings and wellbeing during the week. The role of facilitator is to cultivate and model the opportunities for peer support through shared learning and experiences rather than leading discussions. Facilitators also help women introduce discussion topics they may find difficult to introduce themselves. Facilitators will also support women\u2019s wellbeing and signpost and support women to access specialist or supportive services where appropriate; 3) A choice of self-help materials for women to access between groups. The choice of materials is based on service user preferences and relevance in a UK healthcare context . To enhance the fidelity of an intervention, it is essential facilitators receive appropriate training to prepare them to deliver the intervention as planned [The RAPID-2 study is planned to be conducted in 2022 and aims to test the feasibility of a midwife facilitated intervention for pregnant women with symptoms of mild to moderate anxiety  was reported to increase midwives\u2019 comfort and competence to identify and care for women with psychosocial issues during the postnatal period . A very A literature review was conducted to identify midwives training and support needs to support women\u2019s mental health and wellbeing.Midwives can feel uncomfortable as they feel they lack expertise to respond appropriately to women\u2019s perinatal mental health (PMH) concerns and can be unsure of the actions they should take . AlthougThere is little published literature on the role of the MSW in supporting women\u2019s mental and emotional health. The Maternity Support Worker Competency, Education and Career Development Framework  propose The targeted training needs assessment focused on midwives\u2019 reported needs to support women\u2019s wellbeing (as reported in stage 1) and facilitators\u2019 training needs to support the mechanisms of change underpinning the RAPID intervention.The theory underpinning RAPID includes: 1) Social support theory; 2) Therapeutic relation theory; 3) Mind-body approaches; 4) Cognitive-behavioural mechanisms . It is cThe RAPID intervention will require midwives and MSWs to provide care, support and guidance within their current scope of practice. Midwives and MSW facilitators will not be expected to deliver therapeutic content, but to provide care to support women\u2019s wellbeing and signpost and support women accessing specialist services where appropriate.Midwives require additional training and support as they transition to group facilitators , 29. In The Perinatal Mental Health Curricular Framework The Competency Framework for Professionals Working with Women who have Mental Health Problems in the Perinatal Period Caring for Women with Mental Health Problems: Standards and Competency Framework for Specialist Maternal Mental Health Midwives The following established competency frameworks were accessed to: 1) consider the scope of midwifery practice , and; 2)Individual competencies within these frameworks, which were considered useful and relevant for facilitating the intervention were mapped into domains, considering the methods of training and highlighting potential useful resources Table\u00a0.Table 1TSpecific objectives for the training were developed by identifying the essential process and functions of components of RAPID to maintain the overall study objectives while enabling facilitator flexibility within different contexts. The RAPID-2 study is considered a complex intervention as it: 1) includes several interacting components; 2) is sensitive to the context in which it is delivered; 3) has a causal chain linking the intervention to outcomes; 4) has a range of possible outcomes . Due to An integrative review by Brunero et al.  reportedWhile most training programmes are delivered face-to face there is a growing need to deliver far reaching resources using on-line technology, particularity in the current COVID-19 pandemic. Midwives have reported to prefer attending study days to receive PMH education as opposed to online delivery which may be reflective of interactive approaches to skills development . Other sBefore training, midwife and MSW facilitators initially felt uncomfortable when women disclose mental health concerns. Their concerns were addressed through practical skills and guided role-play activities, learning techniques to manage potentially challenging situations and signposting women to further supporting services. All facilitators felt they had developed an understanding that they were not required to provide all of the answers to address women\u2019s concerns . The traFollowing the evaluation of the current literature, educational approaches and feedback from stakeholder group, the facilitator training plan was designed and approved by the mental health professional trainers, midwifery professionals and researchers. The training plan consists of workshop teaching, discussion and exercises and a training manual with information and self-complete exercises table\u00a0. Two traThe effectiveness of mental health training programmes for healthcare professionals has been evaluated through pre-post training knowledge tests, attitudinal scales, clinical audit an self-report measures  .Reaction (post-training questionnaire): the quality of the manual and workshops; participants\u2019 overall satisfaction with the training.Learning (post-training questionnaire): awareness of the symptoms of anxiety in pregnancy; awareness of coping strategies for women with mild to moderate anxiety in pregnancy; awareness of other supportive services for women with anxiety in the local area; feeling prepared to deliver the intervention; feeling confident to talk to women about anxiety / support women with anxiety within current scope of practice / provide women with evidence-based information to support their wellbeing / recognise emergency situations and take appropriate actionsBehaviour : ability to respond appropriately to women\u2019s situations and concerns about anxiety; ability to support and guide the use of self-help resources; ability to facilitate and manage group discussionsResults : Women\u2019s views on participating in the intervention; facilitators views on the wider benefits of the training on their practiceEvaluation of the training programme plays an integral role in the RAPID-2 feasibility study, to assess the usefulness of the programme and preparing facilitators to deliver the intervention and identifying the optimal programme content and timing. Evaluation and analysis will be completed by the lead researcher (KE) and discussed with the study advisory group and engagement with service users. The plan is to evaluate the training at two time points: 1. A training evaluation questionnaire (delivered post-training); and 2: a qualitative evaluation of facilitators views of the usefulness of RAPID-2 training (delivered post-intervention). The Kirkpatrick model  of evaluA process evaluation is planned which will follow the framework developed by Grant, et al.  to exploThe RAPID programme of research has developed an intervention manual, training materials, and workshops ready for testing in the RAPID-2 study. The RAPID-2 training intervention was developed through an iterative process, reflecting on facilitators\u2019 feedback from the preliminary RAPID study. The use of the Kern\u2019s six-step approach for curriculum development assisted the training programme development. The framework enabled established perinatal mental health competencies, evidence-based and theoretical approaches, educational strategies and midwives reported training needs to be synthesised to produce a comprehensive overarching training framework. The ultimate aim is to demonstrate the benefit of a midwife facilitated intervention which can be implemented with minimal resources into current models of maternity care and provide, timely support for women with mild to moderate anxiety symptoms, to prevent an escalation of symptoms and improve women\u2019s ability to cope."}
+{"text": "Research has documented the increased risk of cognitive impairment among older adults living in socioeconomically disadvantaged neighborhoods. Much less is known about the factors that moderate this risk. We conceptualized self-perception of aging (SPA) as a potential moderator because it reflects core beliefs about the self at older ages but is also closely linked to late-life health. Guided by the diathesis-stress model that postulates the interactive roles of cognitive styles and stressors in shaping health outcomes, we hypothesized that more positive SPA would buffer the effects of neighborhood adversity on cognitive function. Using data from the Health and Retirement Study (2008\u20132016), the analytic sample consisted of adults aged 54 and older . Cognitive function was assessed by the Telephone Interview for Cognitive Status. The neighborhood indicators included 1) poverty rates at the census tract level, 2) perceived neighborhood social cohesion, and 3) perceived neighborhood disorder. Three-level growth curve models were separately estimated for each neighborhood indicator\u2019s effect as well as its interaction with SPA on the 8-year cognitive function trajectories. Findings showed that higher poverty rates, more disorder, and less cohesion were associated with lower initial levels of cognitive function but slower rates of cognitive decline. SPA partially moderated the linkage between neighborhood adversity and the level of cognitive function. More positive SPA was associated with reduced negative effects of living in neighborhoods with higher poverty rates and more physical disorder. These findings highlight the intersection of an individual-level psychological factor and a contextual-level factor in shaping late-life cognition."}
+{"text": "Major Depressive Disorder (MDD) is a widespread debilitating neuropsychiatric disorder. While a broad range of drugs to treat MDD are available, a large portion of the patients fail to achieve a complete and sustained remission. It is estimated that only about half of the patients will be responsive to currently available antidepressant treatment  promoter was found in the hippocampus of rat pups with poor maternal care  and NR3C1 (encoding the glucocorticoid-receptor) in individuals with MDD and childhood adversities  specifically in the nucleus accumbens increased depressive-like behaviors, while DNMT inhibition with RG-108 decreased depressive-like behaviors in mice , a methyl donor that is used by DNA methyltransferases (DNMTs) to catalyze DNA methylation, can increase global DNA methylation. Therefore, many studies examined the effect of SAM administration as a monotherapy or an add-on to antidepressant treatment. The overall effects of SAM administration in MDD were analyzed in several thorough systemic reviews, which concluded that SAM shows promising results although additional larger randomized double-blind studies with long-term follow-up are required (Galizia et al., Bdnf gene promoter leading to increased brain Bdnf mRNA and protein levels (Sales et al., In na\u00efve newborn and adult rodents, systematic administration of the DNMT inhibitors 5-aza-2-deoxycytidine or 5-azacytidine reduced depressive-like behaviors through demethylation of the Disentangling whether changes in DNA methylation are the cause or result of MMD is very difficult in human studies which can measure mostly associations. However, several studies found that DNA methylation can predict behavioral outcomes, including major depression, in humans (Ursini et al., BDNF and SLC6A4 genes (Booij et al., The notion that manipulating DNA methylation has an impact on MDD encouraged studies measuring DNA methylation levels as potential biomarkers to predict MDD and its severity in vulnerable populations as well as treatment outcomes. For example, blood methylation levels were measured in several cohorts to successfully predict antenatal and postpartum depression (Guintivano et al., BDNF and SLC6A4 genes in MDD patients (Li et al., A recent systematic review on DNA methylation in depression and the effects of MDD treatment on DNA methylation concluded that findings from studies that aimed to search for biomarkers for MDD treatment outcome are inconsistent; with some studies showing significant results while others had mixed findings. This is most likely due to larger heterogeneity compared to other studies, types and stages of treatment and small sample sizes in some of the studies. Overall, the most consistent effects were increased methylation of the Taken as a whole, a growing body of evidence support a role for DNA methylation in MDD (see summary in The author confirms being the sole contributor of this work and has approved it for publication.This research in EL lab is supported by the Estates Committee of the Israeli Ministry of Justice.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "The COVID-19 pandemic has clearly demonstrated the urgent need for a cross-border and structured European mechanism to exchange, organise and access reliable health information between countries, especially in the area of population health. Population health information, defined by data on health status, health determinants and healthcare systems performance, allows for oriented research to increase the knowledge base in Europe and underpin political decision-making. Its exchange requires timely and topical provision of high-quality health information. There are many indirect effects of the COVID-19 pandemic that affect health through various pathways including secondary consequences on health and wellbeing due to delayed prevention, diagnosis and medical treatment. Within the Population Health Information Research Infrastructure (PHIRI) we look at four use cases measuring the impact of COVID-19 on population health and demonstrating how a broad variety of routine data can be pooled and/or used for secondary analysis in a distributed way across Europe aiming to facilitate research by making scalable, reproducible methods available. These use cases represent pilot activities for the benefits and added value of an infrastructure supporting federated analysis by bringing together data from different European countries and feeding the results into the federated research infrastructure. In over 20 data hubs, data is mobilised and ready to be analysed in a distributed manner. The use case outputs will be processed in an interoperable way by formalising data models, data management processes and analytical pipelines, all of which are part of the client-server PHIRI federated infrastructure implemented as here 10.5281/zenodo.6483177. The workshop aims to ensure a better understanding of COVID-19 impacts in specific subgroups and risk settings by conducting research through real-life use cases of immediate relevance. The FAIRified use cases analysis results focusing on comparisons between countries are presented and provide actionable outcomes to guide policy makers in preparedness and response scenarios. Knowledge and expertise developed across Europe is shared in this workshop. The four presentations will focus on selected aspects of COVID-19 impacts on population health. The first presentation will be on direct and indirect determinants of COVID-19 infection and outcomes in vulnerable population groups with reference to inequalities. This will be followed by a contribution of COVID-19 related delayed care in breast cancer patients. The third presentation looks at the impacts of COVID-19 on perinatal health inequalities followed by the fourth on insights in COVID-19 related changes in population mental health. Exchange with the audience will facilitate knowledge and opinion exchange through an interactive Mentimeter poll during the session.\u2022\u2002The results will support the exchange of knowledge and expertise by facilitating insights in the impacts of COVID-19 in specific subgroups and risk settings compared across European countries.\u2022\u2002Actionable outcomes to guide political decision-making in preparedness and response scenarios will be provided."}
+{"text": "Acute myeloid leukemia (AML) is a molecularly and cytogenetically complex disease that has proven difficult to treat with a plateau in long-term disease-free survival over the last several decades of less than 30% at 5 years. In the past five years, a number of novel agents and combinations have been FDA approved for the treatment of AML. The understanding of novel mechanisms which can be therapeutically targeted for the treatment of AML continues to expand rapidly. In addition attempts to exploit the immune system as a mechanism treat leukemia is expanding beyond allogeneic hematopoietic stem cell transplantation (HSCT) to check point inhibition and T-cell therapies such as BiTE and CAR-T technology. This has led to an increasing number of clinical trials in the treatment of AML as well as in the area of maintenance therapy after intensive induction or consolidative transplantation.The goal of this Research Topic was to explore novel pathways in AML which could be exploited for therapy of either upfront or relapse/refractory AML as well as in the maintenance setting including maintenance therapy post allogeneic transplantation.Alotaibi et al. describe a series of cases of AML treated with FLT3 inhibitors which developed BCR-ABL1 mutations. This mutation provides an alternative therapeutic target and identifying this mutation at relapse after FLT3 inhibitor failure should be a priority. In the second paper focusing on relapsed AML therapy, Watts et al. introduce a CD3xCD123 bispecific antibody (APVO436). This paper explored the therapeutic and pharmacodynamic effects of APVO436 in 14 relapsed/refractory AML/MDS patients who failed treatement with hypomehylating agents +/- venetoclax. With single agent use at a range of dose levels, in vivo immunomodulatory and anti-leukemic activity was demonstrated via T-cell activation as well as a median overall survival of 282 days. This paper supports further investigation of the potential benefits of APVO436.Seven manuscripts in this topic explore a variety of aspects AML therapy, five of which focus on allogeneic transplantation including maintenance. In the first of the papers that focus on non-transplant therapy, Wang et al. presented a case study of stem cell transplantation using a decitabine-containing preconditioning regimen in TP53 mutated myelodysplastic syndrome. Nine TP53 mutated patients received decitabine preconditioning followed by myeloablative allogeneic HSCT. 89% of patients were alive and progression free at a median follow up of 42 months. Given the extremely poor prognosis of TP53 mutated myeloid malignancy patients, this preliminary evidence of efficacy by decitabine containing conditioning regimens should be explored in larger populations.Five manuscripts focus on allogeneic stem cell transplantation ranging from conditioning regimens through DLI to reviews of maintenance options post-transplant. Salhotra and Stein. presented a review article that discussed the role of newer radiation based conditioning regimens such as total marrow irradiation (TMI) in patient with high-risk AML undergoing allogenic HSCT in remission or with active disease. They also discuss mechanisms associated with leukemia relapse and treatment options available after relapse following allo-HSCT using intensified conditioning regimens. This comprehensive review provides background on currently used radiation and chemotherapy preparative regiments as well as describing new techniques to deliver radiation using total marrow and lymphoid irradiation which allow for better disease control and improved clinical outcomes. However, relapse remains the primary cause of transplant failure so they further discuss adoptive immunotherapy and maintenance therapies to improve relapse-free outcomes.Stadler et al., the use of preemptive and therapeutic donor lymphocyte infusion (preDLI and tDLI) in relapsed myeloid malignancies is explored when using a novel, quantitative PCR-based high-sensitivity chimerism (hs-chimerism). This technique allows for redicition of relapse more than a month before clinical diagnosis. They compared a historic cohort of patients who received preDLI or tDLI prior to hs-chimerism to 32 patients who received these therapies after. At 2 years from first DLI the hs-chimerism group had a very impressive overall and disease-free survival, early 3 times that of controls. This was a result of both reduced relapse incidence with a larger proportion of patients receiving preemptive DLI as well as decreased non-relapsed mortality. This paper supports the value of hs-chimerism for directing DLI after alloSCT and warrants exploration in larger populations across multiple centers.In a brief research report by Manobianco et\u00a0al. discuss the mechanisms of treatment being targeted for post-transplant maintenance therapy for AML. This includes a discussion of FLT3 inhibitors, histone deacetylase inhibitors, IDH1 & 2 inhibitors, hypomethylating agents, bcl2 inhibitors, and checkpoint inhibitors. The review includes data for their use as well as a discussion of recruiting clinical trials. Nayak and Chen review these agents as well as hedgehog inhibitors and other immunomodulatory agents such as lenalidomide.The final two manuscripts in the Research topic provide comprehensive reviews of post-transplant maintenance therapy for AML after allogeneic HSCT. The manuscripts presented in this Research Topic provide hope for novel treatments for acute myeloid leukemia before and after transplant, but also highlight the desperate need for expanding our repertoire to treat this complicated disease with a mortality rate of nearly 70% which has not improved over the last decades despite an array of novel therapies.The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "The European Academy of Paediatric Dentistry (EAPD) has developed this best clinical practice guidance to help clinicians manage deep carious lesions in primary teeth.Three expert groups conducted systematic reviews of the relevant literature. The topics were: (1) conventional techniques (2) Minimal Intervention Dentistry (MID) and (3) materials. Workshops were held during the corresponding EAPD interim seminar in Oslo in April 2021. Several clinical based recommendations and statements were agreed upon, and gaps in our knowledge were identified.There is strong evidence that indirect pulp capping and pulpotomy techniques, and 38% Silver Diamine Fluoride are shown to be effective for the management of caries in the primary dentition. Due to the strict criteria, it is not possible to give clear recommendations on which materials are most appropriate for restoring primary teeth with deep carious lesions. Atraumatic Restorative Technique (ART) is not suitable for multi-surface caries, and Pre-formed Metal Crowns (PMCs) using the Hall technique reduce patient discomfort. GIC and RMGIC seem to be more favourable given the lower annual failure rate compared to HVGIC and MRGIC. Glass carbomer cannot be recommended due to inferior marginal adaptation and fractures. Compomers, hybrid composite resins and bulk-fill composite resins demonstrated similar values for annual failure rates.The management of deep carious lesions in primary teeth can be challenging and must consider the patient\u2019s compliance, operator skills, materials and costs. There is a clear need to increase the use of MID techniques in managing carious primary teeth as a mainstream rather than a compromise option. The European Academy of Paediatric Dentistry (EAPD) proposes this best-practice guidance to help practitioners manage deep caries in children during the delivery of oral health care. A similar statement has been published by a Joint ORCA and EFCD Expert Delphi Consensus Statement . The management of dental caries in children has shifted towards controlling caries according to an individual treatment plan including risk estimation, early diagnosis and prevention plan to keep dentition healthy and arrest initial lesions if needed Parent expectations (motivation and compliance)CostClinician competenceMaterials availableWith a move towards MID vs. conventional restorative methods, it can be confusing to know which technique to use. This guidance aims to provide clinicians with the best evidence-based recommendations for treating deep carious lesions in primary teeth where available or to recommend good clinical practice where evidence is weak.Conventional management MID Materials Three expert groups were invited by EAPD to undertake systematic reviews of the available literature for the management of deep carious lesions in primary teeth, in particular focussed on:Conventional management: M Duggal, S Gizani, E Stratigaki, HJ Tong, K Seremidi, D Kloukos, MID: S Albadri, R Santamaria, A BaniHani, S Hu, M Maden Materials: N Kr\u00e4mer, K Bekes, S Amend, C Boutsiouki, D Kloukos, N Lygidakis, R Frankenberger This new guideline is based on the reviews presented by the invited experts in the 12th EAPD virtual interim meeting in Oslo in April 2021. The discussions were carried out by those attending the three working groups consisting of invited speakers and nominated delegates from the EAPD member countries. Each working group was moderated by two members of the EAPD Clinical Affairs Committee (CAC).Discussions were carried out and conclusions were reached by agreement and consensus, and the recommendations from the workshops were presented on the final day of the interim meeting by the CAC moderators. This was used as a basis by the CAC members to develop the guidance.The selection criteria for the three groups is summarised in Table . Due to Direct Pulp CappingIndirect Pulp CappingPulpotomyPulpectomyThe systematic review and meta-analysis by Stratigaki et al. 2022, concentrated on the following techniques:The evidence demonstrated that pulp reaction to the treatment and applied medicament rely on the status of the pulp before the intervention, and the conditions under which the pulp is being treated , and Rubber Dam Isolation).Use the least invasive technique for the best predictable clinical outcome.There was a unanimous agreement that a restoration providing a good coronal seal is essential for the management of vital pulp in primary teeth.Indirect Pulp Capping (IPC) and Pulpotomy (PP) have high success rates and can be recommended as effective treatment modalities for the management of deep caries in primary teeth.Direct pulp capping has limited use in daily clinical practice in the event of pulp exposure, except in very restricted non-infectious conditions and on asymptomatic teeth.Calcium hydroxide has the poorest success rate of all commonly used pulpotomy medicaments, and therefore it is recommended that calcium hydroxide should not be considered as a material suitable to be used as a pulpotomy medicament.Formocresol (FC), Ferric Sulphate (FS) and Mineral Trioxide Aggregate (MTA) all demonstrate similar success rates when used as pulpotomy medicaments. Given that concerns have been expressed regarding the potential toxic effects of certain medicaments, such as formocresol, it is recommended that clinicians should use alternatives, such as FS or MTA that have similar reported outcomes.Pulpectomy is not recommended as a first line of treatment for deep caries management of vital primary molars, due to the existence of more conservative successful alternatives. Nevertheless, pulpectomy may be considered over extraction in certain situations where tooth loss would compromise the child\u2019s dental health and long-term occlusion  or such as in the absence of a permanent successor.Clinicians should consider clinical success as a primary indicator of a successful outcome, rather than considering further interventions based on radiographic failure alone.More studies are needed to compare medicaments within the same techniqueFurther comparison studies are needed between techniques with longer follow-up ratesMore studies are needed to compare irrigation disinfectant medicaments for pulp and surrounding tissuesThe use of 38% Silver Diamine Fluoride (SDF)The use of pre-formed metal crowns (PMCs) using the Hall TechniqueSelective (one step) and step-wise caries removalThe use of Atraumatic Restorative Technique (ART)Evidence provided by the umbrella review by BaniHani et al., 2021 was used to consider the usability of the following MID techniques for managing deep carious lesions in primary teeth:The use of 38% SDF once or twice per year can be advantageous for caries arrest, with better outcomes for two applications per year. It is recommended that clinicians should consider the use of 38% SDF in children with a high caries risk, to avoid/delay the need for more invasive treatments in very young children.The use of pre-formed metal crowns (PMC) using the Hall technique (HT) for the management of dentinal caries in primary teeth can reduce the risk of pain and restoration failure for caries in the primary teeth. The Hall technique (HT) reduced discomfort and was preferred by patients and parents.Selective (one-step) or step-wise caries removal offer some advantage over complete caries removal for the avoidance of pulp exposure for lesions extending to inner third or quarter of dentine. In the absence of other signs and symptoms indicating irreversible pulpitis, these techniques should be considered to avoid pulp exposure and the need for pulp therapy.The failure rates for ART when used to restore multi-surface caries is unacceptably high. Therefore, this technique is not recommended for the restoration of multi-surface carious lesions. ART could be considered as an adequate management option for single surface  in certain instances for primary teeth.Further investigation is needed into the effectiveness and safety of the HT, as there has only been one systematic review to date.Comparison studies are needed into the cost effectiveness of different MID treatments modalitiesAmalgamGlass Ionomer cements (GIC)Glass carbomersCompomersCompositesFull coverage crownsThe systematic reviews by Amend et al. Within the parameters chosen for the review, it was determined there was no evidence from well-designed, randomised clinical studies in children available to determine which materials are most effective for deep caries in primary teeth. This implies that most of the recommendations are based on low-grade evidence and expert opinion.The European Academy of Paediatric Dentistry based on Minamata Convention do not recommend the further use of Amalgam in the restoration of primary teeth\u00a0Minamata .Due to the low evidence studies (high or unclear risk of bias), additional considerations regarding application technique  could not be considered.Glass Ionomer Cements (GIC), High Viscosity GIC (HVGIC) and Resin Modified Glass Ionomer Cements (RMGIC) are recommended for occlusal (class I) restorations in primary teeth.High Viscosity GIC (HVGIC) and Resin Modified Glass Ionomer Cements (RMGIC) are recommended with caution for occluso-proximal (class II) restorations of primary dentition. These materials are not recommended in multi-surface reconstructions.Metal Reinforced GIC (MRGIC) are not recommended in the restoration of primary molars.Glass Carbomer is not recommended for both occlusal (class I) and occluso-proximal (class II) restorations of primary carious molars due to the high failure rate.Compomers are recommended for both occlusal (class I) and occluso-proximal (class II) restorations of primary carious molars.Hybrid and bulk-fill composite resins are recommended for both occlusal (class I) and occluso-proximal (class II) restorations of primary carious molars.It is recommended to use a calibrated polymerization lamp and ensure adequate polymerization, omitting the monomers at the surface.Due to lack of evidence, it was not possible to consider dentine etching times and margin cavity preparation.Due to the selection criteria, only one RCT with Preformed Metal Crowns (PMC) was included in the review, using the Hall Technique (HT) in vital primary molars . The study was found to have a low annual failure rate, but a high risk of bias, therefore clear recommendations could not be given due to lack of evidence.There is a lack of RCTs evaluating restoration techniques in primary anterior teeth. In the one included trial with high risk of bias Operator experience should be clearly statedA precise report of the numbers of patients lost to follow-up is essentialRecommendations for management of deep carious lesions in primary teeth were developed in line with the strength of the evidence Fig.\u00a0.Fig. 1FlIt is recommended that application of 38% SDF can be advantageous for caries arrest, with better outcomes for biannual application.Indirect Pulp Capping (IPC) or selective and step-wise caries removal, and Pulpotomy (PP) have high success rates and can be recommended as effective treatment modalities for the management of deep caries in primary teeth.The use of formocresol for pulpotomy is no longer recommended, due to the availability of more biocompatible medicaments.ART technique is not recommended for the restoration of multi-surface carious lesions.Glass carbomer cannot be recommended due to inferior marginal adaptation and fractures.MRGIC cannot be recommended due to loss of anatomical form and marginal intergrity.Pre-formed metal crowns (PMCs) using the Hall technique are recommended as a treatment option for the management of dentinal caries.The use of PMCs for endodontically treated primary molar teeth is recommended.Compomers are recommended for both occlusal (class I) and occluso-proximal (class II) restorations of carious primary molars.Hybrid and bulk-fill composite resins are recommended for both occlusal (class I) and occluso-proximal (class II) restorations of carious primary molars.GIC, RMGIC and HVGIC are more favourable given the lower annual failure rate compared to MRGIC.oStudies should record the use of radiographic assessmentpThe depth of caries should be specified using an objective classification such as that proposed by the ICDASFocus conducting trials with more appropriate study designs and standardised methodology, particularly in relation to use of randomisation and allocation sequence concealment diagnostic and outcome measuresQuality of life, patient preference, cost effectiveness and burden of care and impact of different treatments modalities on future complianceThe EAPD interim seminar identified further research needs, to improve comparability of studies to include:The management of deep carious lesions in primary teeth can be challenging and must consider the patient\u2019s compliance, operator skills, materials and costs. The lack of high quality RCTs meant that for some consensus statements only a low level of evidence was available.One of the important outcomes of this review was that Minimal Intervention Dentistry (MID) techniques appear to be effective in arresting the progression of dentinal caries in primary teeth when compared to no treatment and conventional restorations. There is some evidence of improved patients reported outcomes with such techniques, however further research is required. A major advantage of MID for the management of dentine carious lesions is that many of these techniques can be carried out without aerosol generation. There is a clear need to increase the emphasis on utilising MID techniques in managing carious primary teeth as a mainstream rather than compromise option in circumstances where the conventional approach is prohibited due to cost or co-operation (Splieth et al, Due to the heterogenicity of the studies and the reviews, it was not possible to develop guidance using best-practice methods, such as GRADE. Detailed and explicit criteria for ratings of quality and grading of strength, as well as consensus protocols, and input from patients and parents will make judgments more transparent for future guideline development and recommendations."}
+{"text": "A large body of literature suggests that childhood trauma exposure is a non-specific risk factor for development of eating disorders (EDs) later in life. One potential mechanism through which early traumatic experiences may increase the risk for EDs is represented by long-lasting changes in the body stress response system.We investigated the activity of the hypothalamus-pituitary-adrenal axis and of the sympathetic nervous system in adult ED patients with or without a history of childhood trauma exposure.We recruited 35 women with EDs, admitted to the Eating Disorders Center of the Department of Psychiatry of the University of Naples \u201cLuigi Vanvitelli\u201d. Participants filled in the Childhood Trauma Questionnaire (CTQ), to assess exposure to childhood trauma. They were instructed to collect saliva samples at awakening and after 15, 30 and 60 minutes, in order to measure cortisol levels and salivary alpha-amylase (sAA), a marker of the sympathetic nervous system activity.According to the CTQ cut-off scores, 21 ED women were classified as maltreated  participants and 14 women as no-maltreated  ED participants. Compared to noMal ED women, Mal ED participants showed significantly decreased cortisol awakening response (CAR) and sAA morning secretion.Present findings confirm that childhood trauma exposure impairs the CAR of adult patients with EDs and show that also the morning secretion of sAA is decreased in childhood maltreated adult ED patients. Therefore, our study shows for the first time a dampening in the basal activity of both components of the endogenous stress response system in childhood maltreated adult ED women."}
+{"text": "School leaders are credited with an important role when it comes to school health promotion. During the COVID-19 pandemic, much health-related information was available and had to be interpreted and acted upon by school leaders. Therefore, it is crucial that they have sufficient health literacy as the ability to gain access to, understand and use health-related information. A study in Germany showed that limited health literacy among school principals was associated with low levels of health promotion activities. This paper explores the association between school leaders\u2019 health literacy and school health promotion in Switzerland, addressing the following questions: 1. What is the relationship between health literacy of school leaders and the implementation of school health promotion? 2. Does health literacy explain variance above and beyond other antecedents, such as principals individual mental health and attitudes?The quantitative analysis is based on an online survey conducted among school leaders in the German- and French speaking parts of Switzerland in June 2021 as part of the project \u201cCOVID-19 health literacy school principals survey\u201d. The final sample comprised N = 339 school leaders. The data were analyzed using stepwise regression with health literacy, stress, wellbeing and attitudes toward school health promotion as antecedents and COVID-19 related school health promotion as the outcome.The results show that health literacy of school principals has played an important role in the implementation of school health promotion during the COVID-19 pandemic. It explains additional variance beyond other antecedents.One way to promote implementation of school health promotion is to strengthen the health literacy of school leaders."}
+{"text": "Cryopreservation of embryos has become an efficient method in Assisted Reproductive Technologies (ART) and these methods are currently performed at nearly all fertility centers around the globe. Cryopreservation of supernumerary embryos has contributed to an increase in cumulative pregnancy rates and as a consequence, an increasing number of children are being born through these techniques worldwide. However, long-term follow-up studies of children born through ART are scarce, and concerns about the long-term health effects on individuals conceived through ART have been raised. The relevant genomic transformations that occur at the time cryopreservation is usually applied to embryos may have potential epigenetic risks. With advances in multi-omic single cell technologies, new ways to assess the (epi)genomic status during early embryo development have now become feasible. These novel strategies could provide a revolutionary opportunity to understand the actual impact of ART, but also may help future developments aiming at increase both their efficiency and safety. Here we outline insights in current knowledge and research on the impact of cryopreservation on embryos, the possible consequences at epigenetic level and how emerging new high-throughput technologies can be used for their assessment. In Vitro Fertilization (IVF) in 1978, success of Assisted Reproduction Technologies (ART) has greatly increased. This has been achieved through continuous improvements in culture methods, sperm preparation, fertilization techniques and ovarian stimulation protocols that gradually yielded improved outcomes in terms of pregnancy and live birth rates. More than 3.3\u00a0million treatments are performed every year and to date it has been estimated that 10\u00a0million children have been born through ART worldwide  for reducing ice formation, maintain osmolarity and subsequently preserve structure and viability of cells . CryopreCurrent vitrification combines CPAs such as dimethyl sulfoxide (DMSO), Ethylene glycol (EG) and sucrose or trehalose, during a timely controlled exposure and the cooling and warming rates are controlled through the sample volume . The dirde novo deposition after fertilization  and subsequently zygote genome activation (ZGA). The reprogramming is characterized by a robust initial erasure of epigenomic marks, lasting until totipotency acquisition, which then enables a free way towards self-differentiation. Along further development, the new epigenome is gradually established along the cell lineage establishment creating a new embryonic self-identity . This shlization . H3K27melization . The emelization .The application of IVF techniques and cryopreservation methods overlap in the time with this wide remodeling of the nascent genome . ExposurStill there is a lack of knowledge about how methylation is reloaded after thawing, how chromatin structure is restored after drastic changes in the cell structure and how fidelity of transcriptional activity is maintained after interchanges of cytoplasmic components as consequence of water influxes caused by changes in osmotic states. However, the new insights about epigenome regulation and cell fate determination in the early embryo invite to hypothesize that a sudden forced arrest, such as that induced by cryopreservation, could have consequences over these highly dynamic and fine-regulated processes.The success of cryopreservation lies in the avoidance of damage caused by ice crystal formation, which is controlled through both an equilibrated concentration of cryoprotectants and adapted cooling rates to effectively interchange cytoplasmic and extracellular water. The variability attained through described changes in osmotic and oxidative stress, the potential toxic effects of CPAs, the changes in size and morphology of embryonic cells and on global embryo polarity, can all potentially interfere with genome integrity and functionality and transmit epigenetically inherited marks. During embryo culture the increase of ROS could also have a harmful effect over the embryo culture . With thAfter widespread demethylation metastable epialleles are established along developmental progression and their variability depend on stochastic factors, periconceptional environment exposures and genomic conditions . A recenImpact of ART over histone modification has been currently analysed to a lesser extent due to their technical limitations. Recent studies using high-throughput technologies have reported variations in the methylation degree and the histone modification patterns (H3K4me3) in cord blood cells of new-borns and foetuses originated through IVF . Very inA multi-omic analysis based on cord blood of different IVF techniques, revealed a higher number of differentially expressed genes in children born after FET . A studySubstantial research has been performed in animal models with wide demonstration of epigenetic long-term consequences of reproductive and embryo technology . The funUp to date the epigenetic impact of ART has been mostly analysed by focusing on one specific genomic epigenetic layer. In another situations, many studies focused in specific candidate gene regions on array-based or PCR technologies, that could underestimate the impact over the whole genome. New approaches based on integrative methodologies at single-cell level become a more adapted strategy to provide a wide landscape . The devRecently single-cell multi-omic technologies have improved efficiency with a very low input of cells, as the case of single-cell nucleosome, methylation and transcription sequencing (scNMT-seq) and single-cell nucleosome occupancy, methylation and RNA expression sequencing (scNOMeREseq) . One advThe integration of spatial and single-cell transcriptomics data has been used to profile genomic expression of organs during early development ; a high-Cryopreservation has become essential in clinical reproductive medicine and it is widely applied at IVF units worldwide. The continuous increase in the number of children born after cryopreservation and the lack of knowledge regarding their long-term consequences is a growing concern in the field. The recently developed high-throughput technologies at single-cell level are providing meaningful insights about early embryo biology. As discussed in this review, these cutting-edge technologies have shown the possibility to simultaneously analyse different epigenetic layers at one single cell level what can be applied to widely assess the impact of current methods applied in ART. In addition, these multi-omic approaches can unveil unknown details about epigenetic alterations in the preimplantation embryo, bringing a new tool for validating of the current IVF methods and could also potentially contribute to their further development. Some limitations arise in the application of these techniques, especially those concerning the capture of appropriate signals that truly represent the intended resolution, but fortunately their application is continuously being developed and improved. The design of studies based on supernumerary embryos of IVF cycles can contribute to gain an essential knowledge to increase surveillance of children born after ART. Under a more comprehensive assessment, in animal models, these technologies applied in the early embryo combined with new emerging high-resolution spatial omics, could provide mechanistic insights as well as a wide and measurable landscape about the impact of ART with downstream consequences. Nowadays there exists a higher tendency towards cryopreserving embryos at blastocyst stage, but still there is a lack of knowledge about which is the more convenient timepoint for embryo cryopreservation considering health consequences. The morphological embryo assessment is the most common criteria up to date; however, it should not be disregarded that an epigenetic criterion could potentially complement future decisions concerning a safer prognosis in terms of impact. ART are highly demanded and very often the unique path to accomplish reproductive parental projects in our modern societies. The application of these novel technologies in research arises as a good opportunity to reduce uncertainties concerning the health of children conceived through ART."}
+{"text": "Reducing racial/ethnic disparities in health and functioning among older adults are salient key goals in the U.S. health policy. This study examined whether and how the functioning have progressed between White and minority populations in late midlife in recent years. We analyzed the Health and Retirement Study (HRS) among adults ages 45-64 years across two time periods (2004-2010 and 2010-2016). Using generalized linear regression, we modeled changes in activities of daily living (ADL) and changes in instrumental activities of daily living (IADL) as a function of race/ethnicity and sequentially adjusted for period specific risk factors including sociodemographic factors, health insurance, health behaviors and social networks. Oaxaca-Blinder Regression Decomposition (OBRD) techniques are used to assess the contributions of these factors to the observed trends in ADL/IADL. We find changes in ADL is significantly higher for Blacks  and US-born Hispanics  after adjusting for all the risk factors in the second period. About two-thirds of the disparity in functional status of adults is explained in our OBRD model and more than 70% of these explained differences among minorities is related to socio-demographic factors. This probably occurred due to the differences in income and net wealth which began to widen during the time of 2008 financial crisis. Although recently there is a decline in disability trends for older adults in U.S., our findings point to an increase in racial/ethnic disparities in functional status for adults in late midlife."}
+{"text": "The recent COVID-19 pandemic confronted many societies with profound public health challenges. Although primarily a \u2018somatic\u2019 health concern, it becomes clear that Covid-19 and its aftermath also proved to have a substantial impact on mental health and wellbeing of the population in general and on vulnerable subgroups, such as young people and the elderly, in particular. An important public mental health concern in this context is the possible adverse influence of this pandemic on suicidality. Recent studies show that during the outbreak of the coronavirus disease the suicide mortality did not rise, rather on the contrary. However, the impact of the increased number of people with mental distress related to Covid-19 on suicidal ideation as well as the long-term impact on suicide rates is unclear. Also the long-term impact of the Covid-19 restriction measures greatly hindering adequate mental healthcare services and suicide prevention initiatives is uncertain. This workshop will focus on suicidality trends since the pandemic onset in different countries, suicide figures, experiences in the field of suicide prevention and on attitudes towards seeking help. Ann John from UK will talk about suicide trends during Covid-19 pandemic and will present suicide data of 35 countries collected by the international Covid-19 Suicide Prevention Research Collaboration. Fabrice Jollant will present data about the impact of Covid-19 pandemic on suicide attempts in France, and will discuss in this context the new national suicide prevention strategy. John Cachia will show the importance of a broad mental public health approach to suicide prevention in Malta. And finally, Saska Roskar from Slovenia will show how prevention of suicidality in individuals working themselves in the field of mental health can be hindered by self-stigma.\u2022\u2002We must remain vigilant about the possible long-term mental health impact  of the Covid-19 pandemic.\u2022\u2002Pandemics like Covid-19 highlight certain weaknesses in suicide prevention strategies."}
+{"text": "The need to improve essential medicine supply in the public sector is of paramount importance to ensure that the drugs used in treatment regimens are accessible, acceptable, safe, cost effective and affordable to the population.To assess the role of post-basic pharmacist assistants at primary healthcare clinics in order to make recommendations aimed at improving essential medicine supply management.The study covered five provinces namely: Eastern Cape, Free State, Gauteng, KwaZulu-Natal and Mpumalanga.A qualitative, exploratory, descriptive research design was followed, using a semi-structured interview guide to collect data from 11 District Pharmaceutical Service Managers together with medicine availability reports review. Data analysis was performed using Colaizzi\u2019s seven steps.The study found that there is a shortage of post-basic pharmacist assistants in primary healthcare clinics, which affects the management and availability of medicine supplies. Placement of the post-basic pharmacist assistants would improve medicine supply management in the primary healthcare clinics.At least one post-basic pharmacist assistant should be appointed at each primary healthcare clinic in order to ensure efficient medicine supply management and consistent medicine availability.The study provides evidence that primary healthcare clinics without post-basic pharmacist assistants are more likely to have erratic medicine supply management practices and confirms that post-basic pharmacist assistants play a positive role in the medicine supply management processes in primary healthcare clinics. Essential medicine stockout is experienced in primary healthcare clinics, sometimes resulting in patients being turned away from facilities without receiving their prescribed medicines. At times, patients are advised by nurses or community healthcare workers to travel to other facilities presumed to have more stock  spend half of their total health expenditure on medical products. Improving access to essential medicine is a prerequisite for establishing universal health coverage and achieving the international goals relating to maternal and child health, as well as communicable diseases, specified in the Sustainable Development Goals (SDGs) adopted by the United Nations WHO . The neeAccording to the South African Pharmacy Council (SAPC) , there iIn South Africa, out of the 3074 clinics surveyed in the Health Systems Trust National Healthcare Facilities Baseline Audit, 84% had no input from a pharmacist or post-basic pharmacist assistant  the difference that pharmacist assistants are making in medicine supply management within the primary healthcare clinics.The study\u2019s aim was to assess the role of pharmacist assistants at primary healthcare clinics in order to make recommendations for improving essential medicine supply management.Zuma and Modiba  recommenThe medicine supply management framework is focused on the selection, procurement, distribution and use of essential medicines, with related management support systems including planning and organisation of health services, financial management, information management and human resource management being central in the management of essential medicines  appointed post-basic pharmacist assistants and the availability of essential medicines over a period of 12 months.Semi-structured interviews were conducted with the district pharmaceutical services managers in their offices, with regard to the medicine supply management practices at the primary healthcare clinics. The interviews aimed to obtain participants\u2019 recommendations on how to promote good medicine supply management practices at primary healthcare clinics in the 11 districts. Interviews were audio recorded with the permission of the interviewees.Data analysis is the systematic organisation and synthesis of research data. Qualitative data collected from the document review and the semi-structured interviews can be analysed using Colaizzi\u2019s  seven stThe seven steps were applied for this study in the following manner: Collected data were read for understanding and to familiarise the researcher with the content. The data files were reviewed to identify and extract significant statements in relation to the study objectives. Meanings were extracted from the experiences of the participants. Data were organised by formulating meanings into clusters of themes and discrepancies between various clusters of data were observed. A detailed description was presented by integrating the results into a detailed description of the participants\u2019 experiences. A fundamental description of the meaning of the experience was produced through identification of essential themes. The results were then shared with the participants for their comments and inputs as a final validating step. The themes and sub-themes are presented under the results section of the article.Ethical clearance for this study was obtained from UNISA College of Human Sciences Ethics Committee, approval number: 90195108CREC. Gatekeepers\u2019 permission was obtained from the provincial research committee and identified District Managers. Potential participants were provided with an information sheet detailing purpose, process, potential benefits and risks associated with participation in the study. In all, 11 district pharmaceutical services managers provided informed consent for participation in the study. Anonymity was promoted by using pseudonyms to label reported information. Permission to record the interview proceedings was obtained in writing from the participants.Gray, Grove and Sutherland  proposedCredibility was ensured through purposive selection and engagement, over time, of information-rich participants who were qualified pharmacists. Data collected were referred back to the participants for confirmation. Dependability was promoted through the use of standard data collection tools for the two districts. Confirmability was achieved through an audit trail of audiotaped records of the interviews, as well as analysed documents reviewed by independent co-coders. Participants\u2019 quotes were reported as stated during the interviews. Authenticity was ensured by referring back to the participants for their confirmation of the data collected. Transferability was ensured by describing the context in which the study was conducted. The research design, data collection as well as analysis procedures are presented in detail for anyone interested in conducting a similar study \u2013 to understand how the study was executed.Eleven district pharmaceutical services managers participated in the study: four of them were male and seven were female. The average experience in the medicine supply management was at least 5 years for each of the participants.The following three themes emerged from the study:There is a shortage of post-basic pharmacist assistants in primary healthcare clinics.Post-basic pharmacist assistants\u2019 placement in primary healthcare clinics improves medicine availability.There is a defined role for post-basic pharmacist assistants in the primary healthcare clinics.The study found that 10 of the 11 districts had at least one post-basic pharmacist assistant placed in the quarter of the primary healthcare clinics under their jurisdiction whereas in one remaining district, there were no post-basic pharmacist assistants placed to manage medicine supply in the primary healthcare clinics.The participants explained the shortage as follows:\u2018Not all our clinics have the pharmacist assistants, most of the time medicine supply is carried out by nurses.\u2019 \u2018Pharmacist assistants are very scarce in our district, we are dependent on nurses to manage medicines.\u2019 The findings are in line with those of Ogbodu, Maputle and Mabunda , who repIn 10 districts where at least a quarter of their primary healthcare clinics had post-basic pharmacist assistants, the average medicine availability was at an average of 95% \u2013 the figure was in line with an acceptable norm of 95%. In one district without post-basic pharmacist assistants, the average medicine availability was an average of 88%.The district pharmaceutical service managers explained as follows:\u2018We are doing well on medicine availability thanks to the availability of (Pharmacist) assistants in our clinics.\u2019 \u2018My district is forever below 95% availability as I don\u2019t have dedicated pharmacist assistants to manage stock and place orders.\u2019 Bateman  indicateThe findings of the document analysis were discussed with the pharmaceutical services managers at district level to understand the role of the post-basic pharmacist assistants in the medicine supply chain, with due consideration of the medicine supply chain framework, which focuses on selection, procurement, distribution and rational medicine use. The study found that post-basic pharmacist assistants play a major role in procurement (ordering) and distribution of essential medicines. However, the pharmacist assistants have a minor role in selection and rational medicine use.Sub-theme 3.1. Post-basic pharmacist assistants have a limited role to play in the selection of essential medicines: The pharmaceutical services managers within the districts indicated that selection of essential medicines is a highly technical process that is reserved for the pharmacists in the established structures such as pharmaceutical therapeutic committees; thus, the pharmacist assistant has a limited impact on the selection of essential medicines.The participants stated:\u2018The pharmacist assistants (post basic) are mid-level workers therefore, they have no role in selection of essential medicine.\u2019 \u2018Selection of medicines is beyond the scope of the pharmacist assistants (post basic).\u2019 Ziba et al.  agreed tSub-theme 3.2. The post-basic pharmacist assistants play a major role in the procurement of essential medicines: The district pharmaceutical services managers unanimously agreed that post-basic pharmacist assistants have a major impact on the procurement (ordering) of essential medicines because they are specifically prepared to manage medicine supply at primary healthcare clinics.The participants reported as follows:\u2018The availability and provisioning of essential medicines is [sic] positively improved when there is a post-basic pharmacist assistant, because nurses have little interest in medicine stock management as a result oflong patient queues in the clinics.\u2019 \u2018The post-basic pharmacist assistants understand the ordering process for essential medicines, making the medicine ordering process smooth in the clinics.\u2019 Sub-theme 3.3. Post-basic pharmacist assistants play a major role in the distribution of essential medicines: The National Stop Stock-Out Audit indicated that the causes of stockouts were related to logistical challenges between the depots and primary healthcare clinics, at both provincial and district levels  in our district have improved distribution of essential medicines by ensuring proper placement and follow of orders.\u2019 \u2018There is a network created by the pharmacist assistants (post basic) to move medicines between the facilities, which is very helpful in improving availability of medicines in the clinics.\u2019 This study confirmed that at primary healthcare clinics where there are post-basic pharmacist assistants, medicine availability was above 90%, which the district pharmaceutical services managers attributed to the placement of the post-basic pharmacist assistants, as the workforce is dedicated to ensure that medicines are distributed, as scheduled, from the depots to the facilities. Furthermore, post-basic pharmacist assistants champion the movement of excess stock between facilities.Sub-theme 3.4. Post-basic pharmacist assistants play a limited role in the rational use of essential medicines: The district pharmaceutical services managers did not consider rational medicine use as an area of independent practice for the post-basic pharmacist assistants. As such, their impact was found to be limited.The district pharmaceutical services managers expressed their views as follows:\u2018Post-basic pharmacist assistants are not independent practitioners, as such may not contribute much to rational medicine use.\u2019 sic] a meaningful role in rational medicines as professional nurses do not view them as peers.\u2019 \u2018It is difficult for post-basic pharmacist assistant to make [South African Pharmacy Council  supportsThe study found that primary healthcare clinics without post-basic pharmacist assistants were more likely to have erratic medicine supply management practices. In addition, the study results confirmed that post-basic pharmacist assistants play a positive role in the medicine supply management processes in primary healthcare clinics.The findings are supported by various authors including Stop Stockout  who repoMokgathla and Kadama  reportedSouth Africa can learn from other African countries. Malawi, for example, has identified the medicine supply chain as a priority to overcome key barriers to consistent medicine supply in nurse-driven settings. A new approach was implemented through training and deployment of an enhanced pharmacy assistant cadre. The programme demonstrated that pharmacy certified or qualified candidates improve performance in the medicines supply chain and increase access to medicines at public healthcare facilities (Ziba et al. This study was based on the data collected over a 12-month period with regard to medicine availability and the placement of the pharmacist assistants at primary healthcare clinics, which enabled assessment of trends over a longer period across 685 primary healthcare clinics. Of these clinics, 256 were found to be without a pharmacist assistant employed to manage medicine supply.The study was conducted based on the data and experiences of district pharmaceutical services managers in 11 out of 52 health districts in South Africa. As such, the findings are not generalisable.The study has demonstrated that post-basic pharmacist assistants are essential in medicine supply management in primary healthcare clinics. South African National Department of Health should allocate funds and strive to appoint at least one post-basic pharmacist assistant at each primary healthcare clinic to improve medicine supply management and medicine availability.Further studies should be conducted to explore whether the post-basic pharmacist assistants should be capacitated to play an advisory role in rational medicine use \u2013 as they are, in most cases, the only pharmacy personnel available at a primary healthcare clinic.The data collected through the study revealed that post-basic pharmacist assistants play a positive role in the medicine supply management in primary healthcare clinics. Post-basic pharmacist assistants\u2019 placement at each primary healthcare clinic will contribute towards improving medicine stock management and promoting consistent medicine availability in the primary healthcare clinics."}
+{"text": "Whilst there have been some significant improvements in treatments and patient outcomes for some cancers, for other cancers there has been little change in survival rates for many years. Side effects resulting from the toxicity of agents towards normal cells and tissues and the development of drug resistance continue to limit the effectiveness of traditional and molecular-targeted anti-cancer agents. Other challenges include pharmacokinetics (PK) and delivering sufficient amounts of the active drug to tumour cells in vivo. There is an ongoing need for new anti-cancer agents with novel mechanism(s) of action and the identification of new putative cellular targets and therapeutic strategies that are both potent and selective towards cancer cells.Biomedicines Special Issue \u2018Novel Anti-Cancer Agents and Cellular Targets and Their Mechanism(s) of Action\u2019.Addressing some of these therapeutic challenges, this book presents a collection of eight research articles and two reviews reproduced from the themed Traditional cytotoxic chemotherapeutic agents remain a vital part of treatments for many cancers, but their efficacy is severely restricted by their lack of selectivity and dose-limiting toxicity towards healthy cells and tissue. Affibody or antibody drug conjugates provide an opportunity to target or deliver cytotoxic agents specifically to cancer cells, exploiting a tumour-specific antigen specifically recognised by the conjugate for targeted delivery. Rinne et al. report on a human epidermal growth factor receptor 3 (HER3) affibody drug conjugate with a tubulin polymerisation inhibitor as its cytotoxic \u2018payload\u2019 for targeted delivery to HER3-overexpressing cancer cells . The autA different approach to using affibody drug conjugates to selectively target cancer cell microtubules is presented by Kwon and colleagues . In tripOne cancer type with particularly poor outcome is glioblastoma (GBM), which has a five-year median patient survival rate of less than 5%. The invasion of cancer cells into healthy brain tissue makes tumour resection particularly challenging, resulting in high rates of tumour recurrence. This has stimulated interest in pharmacological inhibition of cell migration as part of the regime for treating glioblastomas. Ketchen et al. report on the migratory plasticity of GBM cells and how the pharmacological inhibition of mesenchymal migration, via the inhibition of cellular communication network factor 1 (CCN1), promotes cells to \u2018switch\u2019 to an alternative means of migration known as ameboid migration . This woWith our increased understanding of cancer biology and of oncogene-driven molecular addictions, this has resulted in considerable research effort to exploit and target these addictions within specific cancers via molecular targeted anti-cancer drugs and through rational drug design approaches. However, it is also clear that whilst such agents can present important advantages over traditional agents such as their increased cancer selectivity, other challenges remain such as the ability of cancer cells to adapt and develop resistance. This concept of some targeted agents being perhaps \u2018too targeted\u2019 has led to a resurgence of interest in the discovery of novel chemical entities with polypharmacological anti-cancer properties and in phenotypic drug discovery. The natural world continues to be a valuable source of novel chemicals with anti-cancer activity. Eldeeb et al. report on their testing of ten novel isatin sulfonamide derivatives for anti-cancer activity against hepatic cancer cell lines and associated in vitro mode of action and molecular docking studies .A major challenge in phenotypic drug discovery and development is that of target deconvolution. Wu et al. report on an isoflavone derivative from fermented soybean, 8-hydroxydaidzein, which shows promising activity against chronic myeloid leukemia (CML) cells, with the authors reporting effects via multiple mechanisms of action . NikoleoA major cause of treatment failure in vivo is the metabolic detoxification or inactivation of anti-cancer drugs by isoforms of the cytochrome P450 (CYP) family of enzymes. In other cases, the activity of specific CYP isoforms can result in the generation of more active, or cytotoxic, metabolites. Pors and colleagues review the role of CYP isoforms in breast cancers and how they influence different standard-of-care (SoC) treatments . Importac-myc oncogene [For molecular targets in oncology that are considered \u2018undruggable\u2019, or perhaps more accurately \u2018difficult to drug\u2019, a potential solution to this druggability problem is RNA interference (RNAi)-based therapeutics. A key barrier to this latter approach, however, is the susceptibility of short interfering RNA (siRNA) to degradation in vivo by nucleases in serum. Approaches to counteract this and improve siRNA stability include chemical RNA modifications or siRNA extension with a \u2018protective\u2019 short DNA hairpin loop sequence. Another approach attracting considerable research interest is siRNA delivery within biodegradable nanoparticles which is discussed by Habib, Ariatti and Singh in their review article focused on RNAi-based nanotherapeutics in the context of the \u2018undruggable\u2019 oncogene .A challenge with any anti-cancer agent is ensuring its sufficient delivery to the tumour in vivo. Poor in vivo biodistribution/PK often contributes to the in vivo failure of otherwise promising drugs. The ability to \u2018visualise\u2019 drug delivery in vivo provides the opportunity to assess whether this is an issue and for developing more effective drug delivery systems. Vepris et al. report on their development of novel poly(lactic-co-glycolic acid) (PGLA) fluorescent nanoparticles as delivery agents that enable in vivo molecular imaging through the phenomenon of photon triplet-triplet annihilation (TTA) upconversion .The final article in this Special Issue book focuses on 5-fluorouracil (5-FU) drug resistance in colorectal cancers (CRC), where 5-FU is part of the standard-of-care, and pharmacogenomic analyses using publicly available resources to predict agents that can overcome 5-FU resistance depending on the particular CRC mutational signature .In summary, this Special Issue collection of articles provides some examples of the many different approaches being used to tackle the multiple challenges that remain in the global battle against cancers. These range from the evaluation of novel compounds for anti-cancer activity and elucidation of their mechanism(s) of action to overcoming drug resistance and advances in targeted drug delivery and molecular imaging for the validation of effective delivery."}
+{"text": "Gliomas make up nearly 40% of all central nervous system tumors, with over 50% of those being high-grade gliomas. Emerging data suggests that electrophysiologic events in the peri-tumoral region may play a role in the behavior and progression of high-grade gliomas. While seizures in the peri-tumoral zone are well described, much larger and slowly propagating waves of spreading depolarization (SD) may potentially have roles in both non-epileptic transient neurologic deficits and tumor progression. SD has only recently been observed in pre-clinical glioma models and it is not known whether these events occur clinically. We present a case of SD occurring in a human high-grade glioma using gold-standard subdural DC ECoG recordings. This finding could have meaningful implications for both clinical symptomatology and potentially for disease progression in these patients. Our observations and hypotheses are based on analogy with a large body of evidence in stroke and acute neurological injury that have recently established SD as cause of transient neurological deficits as well as a fundamental mechanism of ischemic expansion. Whether SD could represent a mechanistic target in this process to limit such progression is a high priority for further clinical investigations. Mechanisms of infiltration of high-grade glioma are topics of high interest given that their behavior is atypical for most neoplasms . Glioma Recent work has focused increasingly on the role that physiological phenomena may play at the infiltrative border of high-grade glioma. Huberfeld and Vecht have described a relationship between seizures and glioma that may be beyond simple association . They noIn addition to the role of seizures, a recent preclinical study has implicated massive slow-moving waves of spreading depolarization (SD) in the early stages of glioma development in an immunocompetent murine model . These SSince the occurrence of SD has implications for both clinical symptomatology and potentially for disease progression, we sought to explicitly evaluate whether SD could occur in human glioma patients similar to the recent observations in the murine model. We enrolled three human subjects undergoing resection of high-grade glioma in an observational IRB approved study (UNM HRPO# 19-392). Under this IRB approved protocol, we prospectively consented patients to have a subdural electrode strip placed during their clinically indicated surgical resection. Electrode strips were all placed adjacent to the tumor resection bed and removed at bedside, similar to the removal of a surgical drain. We performed intra-operative and post- operative subdural DC ECoG monitoring for up to 3 days post operatively in these subjects and recorded instances of neurological deficits, seizures, and SD.All three patients presented with episodes of seizures or transient deficits such as extremity weakness and aphasia see . All subIn one subject, we were able to clearly detect four definite SD with characteristic DC shift and transient suppression of high frequency activity see . These eWhile these findings are preliminary, this is an important initial observation to confirm the occurrence of SD in a human subject with high grade glioma as hypothesized by animal data. Although the number of participants is limited, these preliminary observations and the current literature suggests SD could be considered in the progression of high-grade glioma. Further monitoring of patients with longer monitoring periods is of great importance to determine the exact role of SD in high-grade gliomas. If SD occurs outside of the acute perioperative period, it would have additional implications for these patients. First, SD has been shown to be related to transient neurological deficits, most notably demonstrated in a recent series of patients we studied with chronic subdural hematoma, where in one subject aphasia was time-locked to a cluster of recurrent left temporal SD . We alsoEven more intriguing is the possibility that SD could potentially be involved in excitotoxicity and edema progression. Glutamate appears to play a central role in the process of both epileptogenesis and tumor infiltration through multiple mechanisms ,19. WhilThe second parallel between acute neurological injuries and high-grade glioma centers around vasogenic edema formation. When SD occurs on a background of metabolic compromise (such as ischemic penumbra), it is accompanied by a wave of spreading ischemia . In an eThe parallels of glutamate excitotoxicity and extensive vasogenic edema formation between acute stroke and glioma expansion are therefore worth further investigation. There is evidence that glioma cells may be relatively resistant to these excitotoxic effects  and thatIn summary, we present the first human case of SD occurring in a patient with high-grade glioma. One potential implication of this finding is as a potential cause of non-seizure transient neurological deficits in such patients. Even more intriguing is the plausible hypothesis, building on recent paradigm shifting findings in ischemic stroke, that SD could play a role in the pathogenesis of tumor progression. Early ischemic expansion after stroke (over days) and malignant tumor expansion of high-grade glioma (over months) may share some pathological processes characterized by glutamate excitotoxicity and vasogenic edema formation. While the initiating factors may differ, it is plausible that SD could represent a common physiologic mechanism of progression. The role and involvement of SD should therefore be studied further in patients with high-grade glioma as this could represent a novel therapeutic target."}
+{"text": "The organized sports sector has received increased interest as a setting to stimulate physical activity among inactive target groups. To include many inactive people and to obtain population health benefits, it is important that effective sporting programs are sustained (i.e. continuation of program activities) over a long period of time. This study identified the factors influencing the long-term sustainability of these kind of sporting programs located within local sports clubs in the Netherlands.Fourteen Dutch sporting programs aimed at increasing physical activity levels of inactive population groups and funded within the National Action Plan for Sport and Exercise (NAPSE) were the focus of this study. The programs were developed by ten Dutch National Sports Federations (NSFs) and implemented by different sports clubs in the Netherlands within a three-year funded implementation period (2008-2011). This research consisted of semi-structured face-to-face interviews with the program coordinators of the NSFs (n = 14) and semi-structured telephone interviews with representatives of sports clubs that provided the programs  six and a half years after the funding period ended (November 2017-March 2018). A sustainability framework with five pre-specified main themes  guided data collection and (deductive) thematic analysis.Ten of the fourteen NAPSE funded sporting programs were sustained at the level of the NSFs. Most factors facilitating (+) and impeding (-) the long-term sustainability of the programs were common to both NSFs and sports clubs, like program adaptation (+) and a lack of program financing (-). Program evaluation (+) and high program costs (-) were specific factors mentioned by NSFs, while factors related to human resources (e.g. lack of volunteers (-)) or the sports club nature ) applied to sports clubs. The factors were summarized in the form of a checklist.Key factors influencing the long-term sustainability of the sporting programs were identified. The results can be used to develop strategies to promote long-term sustainability of these kind of programs and inform funding guidelines in countries with a similar organized sports infrastructure."}
+{"text": "The intestinal microbiota has been indicated to have a role in the pathophysiology of AN.Aim of this study was to analyze fecal microbiome profiles of AN women before and after weight restoration and to combine them with fecal metabolomic profiles according to a multi-omics approach.The gut microbiome and fecal metabolites were characterized in 21 underweight AN women and after weight restoration and compared with those of 20 healthy women. Microbiome data were correlated with the relevant fecal metabolites.AN subjects showed a decreased intra-individual bacterial richness, an increased Bacteroidetes-to-Firmicutes abundance ratio and significant changes in the relative abundances of several bacteria at different order levels in both the underweight and weight-restored condition compared to healthy women. The untargeted metabolomic procedure allowed the characterization of 224 metabolites involved in energy, lipid and amino acid metabolism. A genetic algorithm identified 49 relevant metabolites. The relationships among these fecal metabolites and bacteria genera showed structures of different complexity in the 3 groups. In particular, a quarter of those relationships showed a divergent direction in the acute phase of AN than in the weight-restored phase or normal controls. Finally, in acute AN 70% of those correlations showed a negative sign suggesting a prevalent metabolites consummation by gut microbiome.Our results provide a picture of the connections between gut bacteria and fecal metabolites in both the acute phase of AN and after short-term weight restoration. Further studies should aim to investigate the significance of gut microbiome perturbations in development and treatment of AN."}
+{"text": "Mucormycosis is an opportunistic mycosis common in poorly-controlled insulin dependent diabetic patients particularly with ketoacidosis. Fungal osteomyelitis is a life-threatening condition affectation of the nose and paranasal sinuses within the orofacial region.We present a 63-year-old diabetic male patient with maxillary mucormycotic osteomyelitis threatening his better seeing eye and review the clinical symptoms, relevant imaging, and management.We highlight a rare pattern of craniofacial fungal bone infection with maxillary and orbital involvement that ultimately spared the optic nerve. This case report offers the clinician a review of important clinical and diagnostic findings that can help direct the need for orbital exenteration.Maxillary mucormycotic osteomyelitis is an aggressive infection that needs to be addressed promptly to prevent fatal consequences. \u2022Fungal maxillary osteomyelitis must be addressed immediately to avoid compromise of cranial nerves and loss of vision.\u2022An understanding of MRI findings suggesting Mucor orbital involvement is essential to monitoring osteomyelitis progression.\u2022Sparing the orbit near the better-seeing eye is critical to post-recovery quality of life. Family and psychosocial history is noncontributory.After soft tissue and bone biopsy confirmed mucormycosis, the patient underwent a left infrastructure maxillectomy with orbital sparing and two subsequent debridements. Extensive resection of the left zygomatic arch, left hard and soft palate and the surrounding soft tissues was performed . During Surgical resection resulted in a large hard palate defect with an oral-nasal-maxillary continuity. Surgery was performed by the Head and Neck surgeon on call. Post-operative magnetic resonance imaging (MRI) revealed residual enhancement of the inferior rectus muscle as well as subtle asymmetric enhancement along the optic nerve sheath on the left compared to the right. as increased caliber with signal intensity changes within the nerve.Pathological exam of intraoperative specimens identified the presence of broad nonseptate hyphae under special stains such as hematoxylin and eosin (H and E), Periodic acid\u2013Schiff (PAS). These features were consistent with deep fungal invasion of bone. In the inpatient setting, the patient was given an infusion of isotonic saline with dextrose to stabilize cardiovascular status and 20\u00a0milliequivalents/\u00a0h of IV potassium chloride with IV regular insulin for management of the ketoacidosis. The patient had a gastrostomy tube placed and was discharged with subsequent outpatient treatment including three months of Amphotericin B and improved diabetic management. Post-surgically he was fitted with a palate obturator which was well tolerated and allowed normal speech and nutrition by mouth.3The most common clinical presentation of mucormycosis is nasal and paranasal sinus infection which begins with inhalation of spores into the paranasal sinuses of a susceptible host Recent COVID-related manifestations of maxillary mucormycosis osteomyelitis have a distinct pattern of facial bone involvement similar to that of our case. One case series reported 14 patients with comorbid COVID and diabetes presented with various mucor involvement of the maxilla, zygoma, and orbital rim Radiography may be useful as a supportive diagnostic aid rather than being a definitive diagnostic modality. The anatomical extent of  ROCM has been classified into stage I , stage II , stage III , and stage IV  This patient in the case was originally thought to have compromise of the optic nerve based on imaging findings and presentation. There was indication of increased caliber with signal intensity changes within the nerve suggesting direct invasion of the optic nerve on MR imaging, which supported the indication for total exenteration. Optic nerve involvement can be due to arterial or venous occlusion, nerve infarction, or direct infiltration of the optic nerve. Infarction is seen as high-signal intensity of the nerve on diffusion-weighted imaging Even if the orbit can be spared, patients with advanced disease are often still left with a major mid-face deformity following maxillectomy which impairs normal speech and swallow. Reconstructive options include prosthetic obturators and bone transfer. A prosthetic palatal obturator is a simple and inexpensive post-surgical restorative option 4Immunocompromised patients are vulnerable to fatal fungal infections involving the bones and soft tissues of the oral cavity. Treatment should be undertaken as soon as the diagnosis of rhino-orbital mucormycosis is suspected to limit progression of disease and resulting facial disfiguration as well as possible death. Sparing the orbit particularly in the case of disease near the better or only-seeing eye is critical to post recovery quality of life. In this case report we have highlighted these important MRI findings in the case of patient a with facial osteomyelitis that had mild to moderate orbital findings but ultimately was successfully treated without compromise to his vision.N/A.Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.Not commissioned, externally peer-reviewed.N/A.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.Adam Bender-Heine M.D.N/A.JA was involved in the writing of the manuscript. ABH was involved in the editing/supervision of the manuscript.None."}
+{"text": "Increasing evidence suggests the important role of social connections and family support in maintaining optimal cognitive status among older adults. This symposium includes four studies from China and the U.S with a focus on generating actionable evidence to inform the development of strategies that target psychosocial resilience and family support to promote cognitive health. Using data from the 2006, 2010, and 2014 waves of the Health and Retirement Study, the first study assessed the impact of social isolation on cognitive function, and how sleep disturbance mediated the association on cognitive decline. The study findings suggest addressing sleep disturbance might be a viable way to mitigate the negative effect of social isolation on cognitive function. Companion piece includes another HRS-based study that assessed the impact of loneliness on psychological resilience and cognitive health in later life. Findings from this study show loneliness is indirectly associated with baseline cognitive status and accelerated cognitive decline through deteriorating phycological resources. The third study used a prospective longitudinal design and applied group-based trajectory modeling to identify distinct family functions among 170 Chinese stroke survivors. Four family function trajectories were identified; healthy and stable family function was associated with better cognition and quality of life. Lastly, the fourth study aimed to use an experienced-based co-design approach to develop a cognitive training intervention to promote cognitive health in older Chinese immigrants in the U.S. This approach allows researchers to engage end-users early and to optimize the development of a culturally and linguistically relevant cognitive training intervention."}
+{"text": "The brain is the only known example of truly general intelligence, which is of great enlightening significance to the study of artificial intelligence (AI)  that represent the collaboration between AI and neuroscience.Zhao and Zeng proposed a brain-inspired synaptic pruning (BSP) algorithm, which can effectively modulate neural network architecture by pruning redundant synapses while retaining valid synapses during the learning process (Zhao and Zeng). Experimental results demonstrated that the BSP algorithm can significantly compress the network, showing its strengths and effectiveness in different sizes and the number of training samples on the network. Similarly, Liang and Zeng constructed a brain-inspired impulse neural network with the mechanism of human creativity, which can compose melodies with different styles of composers or genres (Liang and Zeng). It has been the first attempt to create musical melodies using biologically plausible ANN with the spike-timing-dependent plasticity learning rule. These two studies show that AI inspired by brain structures and functions is promising and moving toward human-like intelligence.There are 2 papers hitting on the topic of AI inspired by neuroscience. Zhang et al.). The computational modeling suggests that the unique membrane properties in human neocortical neurons might improved the signal transmission accuracy. (2) Using electroencephalography (EEG) as input data, a machine learning method called random forest was used to detect schizophrenia . The computational algorithm not only produces a diagnostic recommendation, but also helps the clinicians to locate key areas and/or connections in the brain associated with schizophrenia. (3) An ANN was pre-trained and exploited as a classifier achieving 74% accuracy on the EEG data of newly recruited subjects . This may greatly facilitate the development of brain-computer interfaces (BCI) by reducing the reliance of complex decoding algorithms. (4) The last review article comprehensively summarized the applications of reinforcement learning in BCI . Various reinforcement learning-based neural decoders have demonstrated impressive results and can be seamlessly integrated into more versatile and realistic BCIs. The aforementioned papers emphasize that the AI approaches are key techniques to make more discoveries and understand brain, even profit neural diseases and robotics.There are 4 papers focusing on the application of AI in neuroscience. (1) A detailed neocortical network model  was presented to compare the capacities for signal processing between the human and rodent (Although there is no article presenting a complete closed-loop iteration in current Research Topic, this will potentially be a great work in the future. More recently, a single cortical neuron has been well approximated as a 5\u20138 layer deep ANN (Beniaguev et al., All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
+{"text": "Previous studies applying the Lausanne Trilogue Play (LTPc), a semi-structured method for observing family dynamics, highlighted dysfunctional interaction patterns in the families of individuals affected by restrictive eating disorders (REDs). Family-centered approaches are considered the first-line treatment for severe cases of REDs in adolescence.To investigate family functioning in the families of adolescents with severe REDs assessed before and 6 months after a multidisciplinary family treatment program that combined psychodynamic psychotherapy, parental role intervention and triadic or family-centered intervention.Sixty-seven families of adolescent patients diagnosed with REDs were assessed for eligibility between July 2017 and October 2020. Family functioning was assessed using the clinical version of LTPc. Nutritional counseling and neuropsychiatric monitoring were also provided.We observed a significant change in the family functioning score for the LTPc phase 2, in which the father interacts with his daughter while the mother acts as a silent observer. This suggests that the fathers, when playing an active role, could improve dyadic family functioning. The treatment was not found to change triadic functioning: a 6-month treatment may not be long enough to modify interactions at the triadic level.A brief multidisciplinary treatment program may significantly improve family functioning in the families of patients diagnosed with severe REDs. Although appropriate clinical trials are needed to further test the efficacy of this treatment, our study reinforce the concept that treatment programs targeting the individual patient and both the parents should be a first-line approach in adolescents with severe REDs.The authors declare that they do not have a significant financial interest, consultancy or other relationship with products, manufacturer(s) of products or providers of services related to this abstrac."}
+{"text": "Plant genetic engineering is one of the most popular advances in plant science and has in recent years become part of mainstream discussion in society . This ise.g., K-Domain technology)  and innovative applications as well as updates on well-established genetic engineering technologies    will be lencing) , solve pBacillus thuringiensis (Bt) and other bacteria has been successfully used for insect pest control. In a paper by Ravanfar et\u00a0al., transgenic curry tree (Bergera koenigii) was produced by expressing the pesticidal protein Cry1Ba1 derived from Bacillus thuringiensis. Interestingly, this transgenic can be produced for potential use as trap plants for the suppression of Asian citrus psyllid (Diaphorina citri) populations toward the protection of citrus groves from citrus greening.Transgenic plant expression of pesticidal proteins derived from Song and Han. Keratin-like (K) domain is a conserved protein domain of tens of MIKC-type MADS-box genes in plants. K-domain technology utilizes the expression of the K-domain of a blueberry SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 to regulate plant growth and resulted in grain yield increase by 13 to 100% under different experimental conditions. This K-domain technology opens a new approach to increasing crop yield through its potential to mimic the K-domains of multiple MADS-box genes.Another application of using transgenic plants utilizing the K-domain technology to increase maize yield was presented by Shi et\u00a0al., summarizes the recent applications in diverse plant species, thus providing a better understanding and advice for functional gene analysis related to crop improvements. As the viral vector construction of tobacco rattle virus (TRV) is an important factor of an efficient VIGS system, many modifications have been undertaken based on the original TRV vector to obtain better silencing efficiency in different species. The development of the VIGS system is strongly affected by the selection of Agrobacterium strain, inoculum concentration, environmental factors, and proper positive controls. All improvements to VIGS technology speed up the application of this tool for identifying the candidate genes involved in various aspects of plant biology), including plant-environment interactions, plant growth and development, metabolic processes, and other cellular processes in plants.In plants, non-transgenic crop breeding with high production in diverse plants is presented by virus-induced gene silencing (VIGS) genetic tools. VIGS exploits an RNA-mediated antiviral defense mechanism [post-transcriptional gene silencing (PTGS)] for functional gene analysis to fulfill some of this promise in diverse aspects. The plant\u2019s natural defense mechanism is induced by a virus infection, and some endogenous genes that are homologous to viral genomes could also be silenced at the same time. Modification of the viral genome into a recombinant viral vector containing sequence homologous to host genes causes homologous silencing of endogenous genes in plants. The review by Wang et\u00a0al., in bread wheat genes using PHYTOENE DESATURASE (TaPDS) and PHOSPHATE2 (TaPHO2) as targets. Smaller inserts (~100 nucleotides) were more stable and conferred higher silencing efficiency and longer silencing duration, compared with larger inserts. This VIGS genetic technology has a high potential for a rapid and effective functional genomics tool for high-throughput gene function studies in aerial and root tissues and many plant species.The Brome mosaic virus (BMV)-based VIGS vector involved the establishment of a simple and effective VIGS procedure by Picea glauca) by Cui et\u00a0al., for target traits modification needed to speed up breeding. This CRISPR/Cas9 system based on somatic embryogenesis was proven for conifers and was optimized based on codon bias in white spruce and a spruce U6 promoter. This conifer-specific CRISPR/Cas9 system was used for multi-site genome editing to target the gene encodes 1-deoxyxylulose 5-phosphate synthase of white spruce by Agrobacterium-mediated transformation and is valuable in gene function research and trait improvement.The application of CRISPR/Cas9 was used for efficient multi-site genome editing in coniferous species  was applied to create two predictor models in Agrobacterium-mediated gene transformation of tobacco by Niedba\u0142a. Through precise and efficient data interpretation, ANN could help optimize the gene transformation conditions in Agrobacterium-mediated gene transformation studies. A study by Nguyen and. Searle developed a simple, efficient and rapid hairy root transformation system for common vetch to facilitate functional gene analysis. The authors show that the infection of the hypocotyls on 5-day-old in vitro or in vivo, soil-grown seedlings with Rhizobium rhizogenes using a stabbing method on vetch explants was effective at producing transgenics in shoot and hypocotyl-epicotyl explants. This simple method also produces contaminant-free transgenic hairy roots for downstream study and shoots could be helpful in plant propagation.The optimization of plant Brassica napus by Yin et\u00a0al.. This research primarily focused on the development of stably inherited minichromosomes and their precise characterization and tracking over different generations. A 0.35-kb direct repeat of the Arabidopsis telomeric sequence was transformed into Brassica napus to produce artificial minichromosomes, which were analyzed by multifluorescence in situ hybridization (multi-FISH), genome resequencing, and insertion of site-specific PCR, primer extension telomere rapid amplification (PETRA).Artificial minichromosomes are the next-generation technology for plant genetic engineering and represent an independent platform for expressing foreign genes and tools for studying the structure and function of chromosomes. This technology for telomere-associated chromosome truncation has been applied successfully in mammals and plants and used as an independent platform for stacking multiple foreign genes without gene segregation. The truncated minichromosome was employed as a platform to receive foreign genes in In summary, the studies collected on this Research Topic reveal advances in next generation sequencing and gene editing technologies that have revolutionized plant science research and empowers plant biotechnologists to manipulate target gene(s) more precisely and effectively in genetic engineering. We believe that a breakthrough in plant genetic engineering is being made and is going to drive a second Green Revolution that is the key to feeding our future.RK prepared the draft. All authors listed have made a substantial, direct, and intellectual contribution to the work and have approved it for publication.This work was supported by the Science Committee of the Ministry of Education and Science of the Republic of Kazakhstan (AP14869076) to RK.We thank all authors and reviewers for their contributions to this Research Topic and the support of the editorial office.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Current guidelines do not recommend subsequent mRNA COVID-19 vaccination in patients who experience immediate allergic reactions to the first dose. Our findings indicate that graded dosing of this vaccine is safe, efficacious, and useful for treating these individuals with allergy. Emerging data on the recently approved Moderna and Pfizer severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA coronavirus disease 2019 (COVID-19) vaccines have demonstrated that they are a critical tool in combating the spread of and mortality and morbidity due to COVID-19 infection.A US Centers for Disease Control and Prevention working group has speculated that patients with an adverse allergic reaction to the first dose of mRNA COVID-19 vaccines could consider a subsequent dose of the Janssen adenovirus-based vaccine, but the safety and efficacy of a mixed series have not been adequately studied,We report our experience with graded dosing to a second dose of Pfizer vaccine in patients who experienced an immediate hypersensitivity reaction (within 4 hours) to a first dose of any mRNA COVID-19 vaccine. This was a retrospective observational study approved by the Institutional Review Board at Montefiore Medical Center/Albert Einstein College of Medicine (IRB #: 2021-12803). Ten patients seen at our allergy clinic who met these criteria were identified by retrospective chart review. We compared COVID-19 spike antibody levels before and after administration of the vaccine using graded vaccine dosing. Details of the characteristics of all the patients are described in Only 1 patient (10%) developed mild symptoms during graded dosing , whereasIn our case series, only 2 patients had excipient skin testing with medications containing PEG; the rest underwent graded dosing without excipient testing. All of the patients in our series tolerated the procedure regardless of testing, suggesting that graded vaccine administration without excipient testing is safe.Because 2 (or more) doses of these mRNA vaccines are crucial for protection against the SARS-CoV-2 virus, graded dosing is imperative for those experiencing immediate hypersensitivity reactions. Customizing the graded dose protocol on the basis of severity of the prior reaction did not change the outcome. The same protocol can be also used for administrating booster doses to these patients. This graded vaccine dosing regimen should be an effective tool for promoting complete vaccination and booster doses and for mitigation of vaccine hesitancy in patients who had developed an immediate allergic reaction to the first dose.To our knowledge, this is the first case series to report the safety of graded dosing of COVID-19 mRNA vaccine by using a customized protocol for each patient and also for demonstrating the efficacy of graded dosing by comparing pre-graded and post-graded dose administration antibody levels in patients who had an immediate reaction to the first dose. Our findings confirm and complement the findings of Toung et\u00a0al."}
+{"text": "The latter \u201cfilters and amplifies\u201d incoming signals to generate a multifaceted yet unambiguous instruction for residing stem cells. As a theoretical basis, the concept of the stem cell niche is a robust model describing the general principle of stem cell fate control. However, modeling the stem cell fate and its time-course apart from native tissue is complicated. In some cases  even the entity itself is described as a dynamic focus of stimuli and can hardly be localized for investigation.The stem cells of an adult organism possess an amazing ability to support tissue renewal throughout life and take part in a complex framework of events after damage, where they present a valuable source of tissue \u201cspare\u201d elements. Their shift from quiescence towards differentiation or self-renewal is controlled by a In this Research Topic, the majority of researchers focus on chosen objects to hypothesize their role in stem cell control and put them to experimental tests to conclude on their importance in cell fate definition. Studied objects in this field range from matrix proteins and cytokines to transcription factors or synthetic biomaterials that mimic the tissue conditions or at least some of them.After a seminal work by Pagliarosi et al. from the R. Gaetani group. They present a very original view of ECM as a complex bioactive network that facilitates, regulates, and may control cell fate is presented and supported by strong data including findings by the authors. Stromal/supporting cells, mechanical stimuli, presence of soluble factors, and cellular cross-talk are covered with an accent made to each component\u2019s role in the generation of the microenvironment of the cardiac tissue matrix. Based on these, the authors proposed the application of recent knowledge on the 3D culture and artificial tissues that may reproduce native control of differentiation. A similar level of rigor is found in a review by Ma et al. covering the concept and role of ECM in musculoskeletal plasticity. ECM is pointed to as a critical component of musculoskeletal niches, allowing stem cell entry and exit, transitional niche formation, or modulation of niche composition/environment. This overview of the role of ECM stresses that besides progenitor cell fate, the ECM takes plays an active role in reprogramming mature cells, especially in changing conditions .Summary of recent data on ECM in control of cardiac renewal and regeneration has been presented by Jiang et al. found that dECM facilitated mesenchymal-to-endothelial phenotype switch in seeded adipose-derived mesenchymal stromal/stem cells (MSC), which correlated with an influx of pro-regenerative M2-macrophages. In contrast, dECM alone was widely invaded by M1-macrophages associated with damage and inflammation. Respectively, MSC-seeded dECM has shown active adipogenesis outcomes in nude mice while dECM alone has failed to provide mature fat at the site of implantation. This is one of few reports on dECM inducing active reprogramming of stromal cells to endothelial ones.Yang et al. supports the role of ECM in stem cell differentiation control, demonstrating that testis-derived decellularized ECM (dECM) alone was a sufficient platform for mouse spermatogonial stem cell long-term culture and differentiation to spermatids once being induced properly. Besides providing a feasible culture model using dECM hydrogel authors highlight the importance of SSC contact with tissue-specific ECM to function properly. Similar findings using the dECM approach were reported by Novoseletskaya et al., who found that human MSC enhances differentiation potency to 3 lineages  once cultured on dECM obtained from long-term cultured MSC to obtain cell sheets. These findings suggest the importance of ECM-controlled stiffness and integrin signaling support in the function of stromal-type niches.The work of in situ. Moisenovich et al. used recombinant spidroin 1 (rS 1/9)\u2014an insoluble insect scleroprotein  to successfully activate nestin-positive NPCs at the site of brain damage in mice. The putative mechanism included activating the influence of rS 1/9 degradation products on resident NPCs. Thus, a xenogeneic protein was successfully used to invoke pro-regenerative and survival effects in mammalian resident NPC.Finally, recombinant proteins from non-mammalian species may provide an interesting biomimetic approach to induce and support neural progenitor cells (NPC) in vitro making them autonomous properties of these cell cultures. This becomes especially important when we isolate primary MSC or stem cells for the needs of regenerative medicine (cell therapy or tissue engineering). In that case, both efficacy and safety may be impacted by tissue and site of origin.A cell\u2019s origin provides a significant bias even when it is isolated and cultured for a significant period of time. Epigenetic and transcriptomic fingerprints defined by tissue and developmental environment still influence how the cell acts and functions Kulebyakina and Makarevich, who suggests that resident MSC retaining high expression of Hox genes after birth might be the \u201cpro-regenerative\u201d subpopulation responding to damage differently from Hox-negative MSC. Furthermore, they draw attention to the regenerative capacities of human endometrium and speculate on the role of HOXA10 and HOXA11 in the mediation of numerous healings without scarring that occurs in every menstrual cycle. Thus, a novel role of Hox genes  has been proposed in tissue renewal which involves cyclic damage of endometrium.The autonomous properties of cells driving their regenerative potency and cell fate are the focus of a hypothesis paper by Groeneveldt et al. Comparative analysis of skeletal stem and progenitor cells (SSPC) from the periosteum of maxilla, mandible, or tibia demonstrated that despite the large extent of similarity, anatomic origin has a great impact on osteogenic properties of periosteal SSPC. For example, in ectopic bone formation animal test maxilla-derived periosteal SSPC failed to generate bone while cells from the mandible were as effective as tibial ones. This highlighted that even cells of similar tissue origin possess site-dependent features which should be evaluated and taken into account for regenerative medicine and tissue engineering implication of those.A good example of site-specificity influence on stem cell fate is provided by Wang et al. focused on the site-dependent profile of adipose-derived MSC isolated from subcutaneous fat or infrapatellar fat pads trying to imply a concept of tissue-specific lineage preference during differentiation. Using transcriptomic and proteomic analyses they successfully identified a significant discrepancy between these cell types depending on their source. They demonstrated that cells from the subcutaneous compartment showed higher proliferation and an incline towards adipogenic differentiation compared to their infrapatellar fat counterparts that were pro-chondorgenic. One of the putative reasons for autonomous properties might be a significant difference in local ECM environments highlighted in other papers in this Research Topic.Cell fate shifts during the development of an organism are a well-studied field in embryology and is a fruit field for investigation of adult stem cells\u2019 properties and modes of operation under different settings.Zhang et al. provide a cutting-edge development-driven study, shedding light on the asymmetrical pattern of growth in cartilage formation that eventually allows the formation of sophisticated shapes in these elements of the human skeleton. Lineage tracing experiments of Col2+, Prrx1+, and Gli1+ cells provided an important point that a switch between cell division and cell influx exists immediately after joint cavitation to form epiphyseal cartilage. These findings contribute to understanding of factors that control the shape of organs and tissues and make way to further targeted investigation of mechanisms that govern these cells\u2019 subpopulations and their cross-talk.Kurenkova et al. from the A Chagin Group focuses on the above-mentioned SSPC, with a focus on their niches in different compartments. A thorough summary of current literature proposes that all described niches have a site-specific repertoire of signals that can be divided into primary or modulating depending on their role: maintaining basic SSPC functions  or adaptation to a change of conditions respectively. Eventually, among a myriad of signaling molecules Wnt, hedgehog, and inflammatory cytokines were highlighted as indispensable regulators in all described niches of SSPC of mesenchymal origin.A review by Milichko and Dyachuk provides insights into the function of glial cells, focusing on the recently discovered heterogeneity of Schwann cells, stemness of certain sub/populations of the human nervous system, and their origin in development. Extensive comparative and descriptive analysis of both embryonic and adult Schwann cells and their potency draws attention to their future use to stimulate nerve system renewal or regeneration.A review by in vitro.Yang et al. developed an original model implying a magnetically-driven dynamic system to culture alveolar cells in circulating flow, providing mechanical stimuli for adequate long-term culture and distribution of cells. Furthermore, the authors have demonstrated that silica particles uptake to validate functional properties and obtained a controllable and highly reproducible model that allows investigation of lung physiology and disease in a tissue-like environment.Significant attention has also been paid to techniques and models that can be implied for stem cell research, disease modeling, or used to support stem cells\u2019 properties Cho et al. using a sophisticated model of this classic approach involving a pressure-assisted network for droplet accumulation (PANDA). The tunable and robust generation of artificial niches was demonstrated and 3D microtissues from MSC and podocytes were obtained to eventually suggest their use in tissue-mimicking with the expansion of PANDA application to other niches and cell types. An approach for cell sheet generation has been proposed by Cheng et al., who used human platelet lysate (HPL) to obtain thicker cell sheets enriched with connective tissue and demonstrated the anti-fibrotic and pro-angiogenic properties of their secretome. The soluble factors of HPL might find use in the generation of tissue-engineered constructs for tissue repair and replacement.The \u201cHanging drop\u201d model was developed by Domnina et al. in their study, which used endometrial MSC in spheroids and found that compaction resulted in cell protection from oxidative stress. Interestingly, compaction decreased anti-apoptotic and anti-autophagy genes suggesting a pathway to programmed elimination of damaged cells in 3D culture. The authors demonstrated a HIF-1\u03b1-dependent increase in the therapeutic efficacy of secretome samples obtained from spheroids compared to routine culture. Thus, a switch to a 3D environment altered the MSC viability control program and regenerative capacity. A paper by Hu et al. also focused on cell viability control and showed that apo- and necroptosis in nucleus pulposus-derived stem cells due to compression may be activated via heat shock protein 90 (HSP90). Beyond a basic understanding of a widely spread degenerative disease, this study provided an interesting therapeutic target for future drug development.The spatial status of cells and compaction are highlighted by in vitro. For many researchers and translational scientists working in regenerative medicine controlled reprogramming of adult cells it remains a goal to be reached and the current Research Topic covers certain endeavors in the field.Cell fate and control are associated with many amazing phenomena including rapid change of cellular identity from one type to another or induction of pluripotency Wang et al. involved a wide array of stem cells from mouse embryo adult testis, brain, and bone marrow using a MEF cell line as control. Their transcriptomic analysis provided an array of genes  that might overlap and bridge between cell type-specific regions and thus in the future may provide targets for reprogramming control or stimulation of SC renewal. Seeking molecular pathways and targets that may induce cell transdifferentiation has led Dai et al. to a study where canine adipose MSC and insulin-producing cells (IPC) were screened, and eventually Foxa1, Pbx1 and Rfx3 were validated to provide prospective targets for induction of MSC-to-IPC reprogramming in future experimental protocols and cell-replacement therapy.A bioinformatic study by Lopatina et al. who convincingly demonstrated that EVs released from tumor endothelial cells are mediators of non-metastatic carcinogenesis. A potent ability of tumor-derived EVs to \u201ccorrupt\u201d local immunity via reprogramming of stromal and immune cells by factors carried in tumor-generated EVs have been shown.Among soluble factors that regulate cell fate extracellular vesicles (EVs) were in the spotlight and our Research Topic included a work by The articles collected in this Research Topic indicate that contemporary understating of how a cell \u201ccommits and performs\u201d implies the existence of a complicated network of signals, stimuli, and interactions that guide towards maturation, putting it to a halt or even reverse. Researchers investigating how stem cell fate is defined will endeavor to evaluate each known element\u2019s role and impact. Futures challenges will soon need to be addressed, such as when we try to understand how the integral complex system of cell fate definition works.Despite these challenges, we believe that a precise description of the crucial factors that control and comprise the niche and provide tissue-specific features accompanied by the development of new techniques to investigate cell fate will eventually build a new understanding of how stem cells are controlled in different settings."}
+{"text": "Informal caregivers are the backbone of the long-term healthcare system in the United States and crucial in supporting the rapidly increasing aging population. Previous studies have illustrated the negative effects that the caregiving role can have on caregiver mental health, but few studies have examined the singular role of experiencing financial difficulty on caregiver mental health. The aim of this study was twofold: to measure how financial difficulty in 2015 correlates with caregiver depression in 2015, and to examine whether financial difficulty in 2015 can predict caregiver depression in 2017. We used two-wave panel data from the National Study on Caregiving  to conduct both regression and lagged dependent variable (LDV) regression analyses to investigate the cross-sectional and longitudinal effect of financial difficulty on caregiver depression, respectively. Caregiver depression was measured using the 2-item version of the Patient Health Questionnaire-9 (PHQ-2), and financial difficulty was self-reported. Results show that caregivers who did not experience financial difficulty in 2015 had 0.46 times the odds of not being depressed  in 2015, compared to those who noted that they did experience financial difficulty. In performing a LDV analysis, outcomes showed that financial difficulty in 2015 was significantly associated with caregiver depression in 2017 , implying that current reported financial difficulty may influence caregiver depression two years later. Conclusions from this work provide support for the development of financial interventions for caregivers experiencing financial difficulty that could play a role in alleviating their depressive symptoms."}
+{"text": "Enzyme design and engineering strategies are typically constrained by the limited size of nature\u2019s genetic alphabet, comprised of only 20 canonical amino acids. In recent years, site-selective incorporation of non-canonical amino acids (ncAAs) via an expanded genetic code has emerged as a powerful means of inserting new functional components into proteins, with hundreds of structurally diverse ncAAs now available. Here, we highlight how the emergence of an expanded repertoire of amino acids has opened new avenues in enzyme design and engineering. ncAAs have been used to probe complex biological mechanisms, augment enzyme function and, most ambitiously, embed new catalytic mechanisms into protein active sites that would be challenging to access within the constraints of nature\u2019s genetic code. We predict that the studies reviewed in this article, along with further advances in genetic code expansion technology, will establish ncAA incorporation as an increasingly important tool for biocatalysis in the coming years. The availability of an expanded genetic code provides a more precise means of probing biological mechanisms by allowing more subtle substitutions of individual atoms or functional groups within the active sites of proteins of interest. Early successful examples of this approach include the use of fluorinated tyrosines to probe proton-coupled electron transfer processes in ribonucleotide reductases . This apc peroxidase (CcP) by N\u03b4-methylhistidine (Me-His)  creating an electron-deficient ferryl oxygen with reduced proton affinity (\u2018the pull\u2019)  (Further evidence of the link between ferryl pkcat for guaiacol oxidation (*) gave modest improvements in conversions in cyclopropanation reactions of styrene with ethyl diazoacetate in the presence of reductant under established anaerobic conditions  centre when coordinated by the Me-His ligand  with a less electron-donating Me-His led to a five-fold increase in igand  as a non-canonical catalytic nucleophile to promote a range of transformations in designer enzymes (Lactococcus lactis (LmrR), a small homodimeric protein with a large hydrophobic pore, was selected as a protein scaffold phosphine to unmask the reactive aniline side chain. X-ray crystallography confirmed that the pAF side chain was positioned close to Trp96, which contributes to the recognition of aromatic substrates in the LmrR binding pocket (kcat and a 26,000-fold increased efficiency over aniline in solution (The Roelfes lab have employed g pocket . Althougsolution . Introdusolution . In the Integrating ncAAs into enzyme engineering and design methodologies unlocks a wealth of new opportunities in biocatalysis research. The studies outlined in this review highlight how the availability of an expanded alphabet of amino acids can provide new avenues to explore enzyme mechanisms, enhance biocatalyst properties and design enzymes with new catalytic functions which would be challenging to access using the standard set of canonical amino acids. Importantly, the properties of enzymes made using an expanded genetic code can be tuned and optimised through directed evolution to deliver proficient and selective biocatalysts. Moving forward, continued expansion of the genetic code will allow the installation of a greater diversity of ncAAs with interesting functional side chains. Access to these new functional elements will enable the development of enzymes with entirely new modes of catalysis. For example, recent studies have shown how the introduction of photosensitizers can open up new photochemical processes mediated by proteins ("}
+{"text": "Advancements in mental health research depend upon continuing development of the data landscape, including the creation of population cohorts that combine different types of data from a variety of sources. The present project aimed to produce a new, multi-faceted mental health e-cohort to benefit further research.Taking advantage of a standing research resource \u2013 the SHARE Scotland research register  \u2013 we administered an online survey of mental health, treatment use and wellbeing. Over 10,000 individuals  took part in the survey; all participants consented to secure linkage of their routinely-collected health records with questionnaire data and over 90% also consented to the research use of genetic data gained from diverted blood samples. We linked questionnaire responses with routinely-collected health data and genetic data within a Trusted Research Environment to create a large cohort enhanced for mental health research.In this presentation we describe the cohort, summarise responses to the mental health questionnaire and give some example research uses of the linked data. Focussing on depression, we contrast the prevalence of self-reported diagnoses of depression (27% of the sample) with diagnostic codes from routinely-collected hospital admission and national prescribing data and examine predictors of each.Estimates of multimorbidity prevalence vary markedly depending on how many LTCs are counted, with absolute differences in estimated prevalence largest for people in middle-age and with lowest SES. Further research is needed to support implementation of a uniform approach to defining how many conditions to include in multimorbidity measures."}
+{"text": "The precise location and role of all types of hydroxyls in zeolites are still enigmatic, and their control permits tailoring of novel properties increasing the efficiency of catalysts and adsorbents in industrial processes for cleaner energy. Often referred to as bridged hydroxyls [Si\u2013O(H)\u2013Al], they are formed when a proton is bound to one of the oxygens adjacent to an aluminum. This hydroxyl group is at the heart of the remarkable properties of zeolites in acid-catalyzed reactions, as these sites and the reactants are confined in a well-defined molecule-sized environment. Other hydroxyl groups called silanols [Si\u2013O(H)] are also present in the zeolite structure and their role is still not fully understood. Both the BAS and silanols are considered as defects of zeolite framework structures yet they hold the key to transforming inert perfect pure-silica frameworks such as quartz into chemically active materials.The ideal crystalline framework of zeolites is perturbed by hydroxyl groups. In pure silica zeolites the framework is neutral, however, the introduction of AlBAS and silanols have been investigated for decades, during which time different characterization methods were employed in order to optimize the properties of zeolite-based catalysts, and will continue to intrigue researchers for years .Various direct and post-synthesis approaches have been developed either to create or heal BAS or silanol groups in zeolites. Synthetic control of the distribution of Al in high-silica zeolites is critical due to the enormous number of Al arrangements and their effect on the catalytic performance of zeolites . The disThe main techniques used to characterize hydroxyls in zeolites are X-ray diffraction and infrared (IR) and nuclear magnetic resonance (NMR) spectroscopy . TheoretSilanols present a different but equally important type of hydroxyl group because they can act as sites for further functionalization, i.e. introducing metals into the zeolite framework . Post-syThe properties of BAS are one of the major concerns when it comes to designing zeolitic catalysts . Regardi\u00a0transitional states of reactive intermediates in the confined void; this is described as the solvation effect . At relaBesides acidic activity, hydroxyl groups play a key role in bifunctional catalysts by providing anchor points to disperse metals .The understanding of hydroxyls in acidic catalysts is continuously progressing; the constant evolution of synthesis and characterization methods will undoubtedly reveal more about the role of silanols in catalysis and allow tuning of new active sites. For example, Lewis Acidic sites possessing hydroxyl groups may arise from the formation of extra-framework Al species that canin situ and operando techniques. Considering the above statements, several additional questions need to be answered: how do silanols impact the local and extended environments of BAS? Is there a synergetic effect between silanols and neighboring BAS upon activity or hydrogen mobility?exist in different oxide and hydroxide forms . Still, 2 emissions.From this, we can clearly see that hydroxyls in zeolites demand further understanding. They belong to the \u2018Zeolite Crystal Engineering\u2019 toolbox for designing new materials for catalysis and adsorbents. Advances in the understanding of hydroxyls in zeolites will provide endless opportunities for discovering zeolites with original properties not previously known Fig. . In the"}
+{"text": "Task-sharing treatment approaches offer a pragmatic approach to treating common mental disorders in low-income and middle-income countries (LMICs). The Friendship Bench (FB), developed in Zimbabwe with increasing adoption in other LMICs, is one example of this type of treatment model using lay health workers (LHWs) to deliver treatment.To consider the level of treatment coverage required for a recent scale-up of the FB in Zimbabwe to be considered cost-effective.A modelling-based deterministic threshold analysis conducted within a \u2018cost-utility\u2019 framework using a recommended cost-effectiveness threshold.The FB would need to treat an additional 3413 service users (10 per active LHW per year) for its scale-up to be considered cost-effective. This assumes a level of treatment effect observed under clinical trial conditions. The associated incremental cost-effectiveness ratio was $191 per year lived with disability avoided, assuming treatment coverage levels reported during 2020. The required treatment coverage for a cost-effective outcome is within the level of treatment coverage observed during 2020 and remained so even when assuming significantly compromised levels of treatment effect.The economic case for a scaled-up delivery of the FB appears convincing in principle and its adoption at scale in LMIC settings should be given serious consideration.Further evidence on the types of scale-up strategies that are likely to offer an effective and cost-effective means of sustaining required levels of treatment coverage will help focus efforts on approaches to scale-up that optimise resources invested in task-sharing programmes. Task-sharing approaches offer an evidence-based and pragmatic approach to treating common mental disorders (CMD) in low-income and middle-income countries (LMICs).Few studies have evaluated the implementation of treatments for CMD at scale,We undertook a threshold analysis to assess the level of treatment coverage needed for a scale-up of the FB recently implemented in Zimbabwe to be considered cost-effective investment.The threshold analysis was undertaken within a \u2018cost-utility\u2019 framework with treatment benefit quantified as the avoidance of years lost due to disability (YLD)Modelling was undertaken to estimate the YLD avoided through treating CMD using the FB rather than a usual care comparator. This used evidence and data on treatment effect and treatment contacts from the FB clinical trial described elsewhere.We identify the level of treatment coverage  required for the investment in the scale-up of the FB to be considered cost-effective based on a prespecified cost-effectiveness threshold (CET). We refer to the cost-effective treatment coverage as the \u2018number needed to treat\u2019 (NNT). To evaluate the NNT, the annual fixed costs of delivering the FB programme in Zimbabwe were estimated inclusive of resource inputs invested in the initial implementation of the scale-up and programme infrastructure required to sustain the programme year-on-year . We then convert these fixed costs into their \u2018opportunity cost\u2019 equivalent (C)\u2014the quantity of YLD that could have been averted had the resources subsumed within the programme\u2019s fixed costs been invested in alternative health promotional activity. This is calculated as:where \u2018where \u2018INB\u2019 is the incremental net benefit per service user of FB treatment, equal to the YLD avoided through replacement of usual care with the FB less the opportunity cost of additional LHW time inputted to FB treatment-related activity: clinical assessments, PST sessions, indirect costs (defined below), case assessment work and peer group attendance. The opportunity cost of treatment activity is again expressed as the YLD that would otherwise be averted (if LHW time was used elsewhere) and is estimated using the same method applied to fixed costs.In addition to the NNT we also report the incremental cost-effectiveness ratio (ICER) for the FB programme :The base case ICER is calculated assuming an annual level of treatment coverage equivalent to the recorded number of patients seen by the FB during 2020 (obtained from programme management information).A Markov model was used to estimate the YLD that could be avoided if a cohort presenting with CMD received FB treatment in place of usual care. A Markov approach was selected because it is amenable to projecting service user outcomes over extended time horizons.A visual description of the model is provided in the 10.1136/ebmental-2021-300317.supp1Supplementary dataThe per cent of service users entering remission during each monthly cycle  was infeThe monthly per cent of remitters who relapse  was estiOver each modelling cycle a percentage of the cohort are also assumed to die , building space used to house central programme activities and associated running costs. The annual cost of used building space was estimated using the purchase value of the property converted to an annualised cost, applying a discount rate of 3% and an asset lifetime of 80 years. As central overhead costs are shared across other non-FB activities, the central programme team estimated that 40% of overheads would be attributable directly to the FB.The number of clinical assessments undertaken to determine treatment eligibility for every service user treated was inferred based on fieldwork data received from all clinics, collected as part of wider ongoing research on programme implementation, identifying the mean percentage of patients clinically assessed who had at least one FB session (36%); and an assumed 39% case detection rate through clinical screening as observed within the FB clinical trial.et al,The duration of LHW time allocated to PST sessions was estimated using the mean frequency of sessions reported in the FB trial data, assuming 45 min per session. For every minute of LHW direct treatment time, we assumed an additional minute would be required for preparatory and other clinical and administrative tasks (we refer to these as \u2018indirect costs\u2019). Time spent by LHW and supervisors reviewing patients was assumed to take an average of 13.5 min per patient. These assumptions were informed by treatment resource requirements reported by Araya LHWs are expected to engage in patient \u2018mobilisation\u2019. This typically consists of a talk given in a clinic waiting area promoting mental health awareness and the FB. Time allocated to mobilisation was estimated based on the mean number of mobilisation sessions over 1 month reported by a sample of LHWs interviewed during fieldwork for wider ongoing research. A group mobilisation talk was assumed to last 15 min. City health department district health promotion officers provide supervisory input to the FB programme. In consultation with programme leads, this was assumed to consist of a weekly 30 min visit to each clinic providing the FB.The cost of usual care was estimated using health professional contact data self-reported over follow-up by participants in the control group of the FB clinical trial ). Assumptions regarding the quantity of time allocated to each contact are found in the footnote to All costs are reported in US dollars at 2019 price levels. We have followed published guidanceDeterministic sensitivity analyses were undertaken to examine the effect of compromised levels of treatment effect assumed for treatment in routine settings  on the NNT. We also report the NNT using alternative CETs: $300 per YLD averted  and $1200 per YLD averted\u2014equating to GNI per capita, the level currently recommended by the WHO for identifying \u2018very cost-effective\u2019 health programmes.All analyses were conducted using Microsoft Excel and Stata V.15. We follow published guidance on the reporting of economic evaluations.Estimates of fixed programme costs, costs of treatment, costs of usual care and the incremental benefit of treatment per service user are presented in The NNT required for programme cost-effectiveness was 3413 service users per year. The ICER for the FB at 2020 treatment coverage levels (12 364 service users seen by the FB over 12 months) was $191 per additional YLD averted. At this level of treatment coverage, the ICER is below the base case CET of $600 per YLD averted.In one-way sensitivity analysis the NNT was relatively insensitive to an increasing prevalence ratio for CMD between FB and usual care treatment: at a ratio above 0.88, the NNT begins to increase substantially . RegardiA threshold analysis was used to evaluate whether scale-up of the FB, a task-sharing model for treating CMD in Zimbabwe, was cost-effective. We identified incremental fixed and variable programme costs and the YLD avoided through replacement of usual care with the FB. \u2018Usual care\u2019 amounted to very little in terms of active treatment input: only 10% of the participants attending health clinics randomised to usual care in a clinical trial of the FB had any contact with counselling for CMD,We estimated that 3413 service users would need to have been treated annually for the scale-up to be cost-effective, equivalent to only 10 per year across 340 trained LHWs known to have been active in delivering the FB. Treatment effectiveness in routine practice may not match that observed within a clinical trial: practitioners may deviate from the intended treatment model and patients may be less engaged. However, even with a significant reduction in effect , the required NNT remained modest in magnitude: equivalent to 31 service users treated per active LHW per year (or just under 3 per month). When judged against recorded levels of treatment coverage during 2020 , this seems a plausible goal, although most treatment contacts during this period took place on an outreach basis outside of health clinics due to the COVID-19 pandemic.A two-way sensitivity analysis of the ICER estimated at the 2020 treatment coverage level highlights the importance of achieving adequate levels of coverage to mitigate the risk of compromised treatment effect. There has been little research conducted into which types of strategy for implementing scale-up offer the most effective and cost-effective methods of sustaining higher coverage levels in CMD populations.Our study has limitations. Scale-up costs were estimated using anticipated rather than actual expenditures incurred; actual costs were not available from the relevant funding organisation. While actual costs could have deviated from our assumptions, we note that our core findings around the NNT value are relatively insensitive to a substantial increase in assumed costs of scale-up . The anaOur modelling did not allow for recurrent treatment episodes or variability in treatment response according to service user characteristics . The uncertainty this introduces to our main conclusions is difficult to assess. Our sensitivity analysis was \u2018deterministic\u2019 rather than \u2018probabilistic\u2019, and as such we did not account for all aspects of uncertainty simultaneously, including sampling uncertainty relating to the key parameters of relevance. Finally, we did not evaluate wider health system resource impacts arising from the scale-up of the FB. Additional (unreported) analysis of data from the FB clinical trial showed that wider health professional contacts were infrequent, with only small differences in mean costs of service contacts between the trial arms and between participants who either scored \u22659 or <9 on the SSQ at 6 months. The main trial analysis also reports that fewer patients receiving FB treatment were referred for antidepressant medication. Taken to together, these findings suggest that modelling of wider service use effects would have been unlikely to change our main conclusions.Our study also has strengths. This is the first attempt at assessing the cost-effectiveness of investing in the scale-up of a task-sharing model for treating CMD within routine practice in an LMIC. We anchored our modelling to evidence on treatment effectiveness derived from the same geographical and service context within which scale-up of the FB took place and our assessment of costs used data directly relating to a major programme scale-up initiative. Our analysis has also been pragmatic in considering the uncertainties and risks to achieving a cost-effective scale-up and linking cost-effectiveness to treatment coverage levels, a key implementation outcome relevant to the cost-effectiveness of scale-up and a measurable outcome for services.The economic case for the scale-up of the FB appears convincing in principle based on evidence from Zimbabwe and its adoption at scale in similar LMIC settings should be given serious consideration. Investing in evidence on the types of scale-up strategies likely to offer a cost-effective means of sustaining required levels of treatment coverage will help focus efforts on approaches to scale-up that optimise resources invested in programmes."}
+{"text": "The Covid-19 pandemic has transformed the world since the beginning of 2020 and many aspects of health care provision has changed dramatically. Despite not being regarded as a frontline field at first look, Child and Adolescent Psychiatry (CAP) has been highly impacted by the pandemic as a fundamentally biopsychosocial branch. CAP specialty training has also become a different experience due to the reprioritization of health care services along with the restricting rules of the \u2018new normal\u2019. In this symposium presentation, we will discuss the effects of the Covid-19 pandemic on the training and practice of CAP specialty trainees and early career specialists through the results of the \u2018Early Career Psychiatrists in Europe during COVID-19 outbreak\u2019 survey study, organized by the EPA and EFPT. The survey covers different areas including reorganization of training/practice during the pandemic, personal experiences with Covid-19 and adoption of Telepsychiatry practices. This pan-European study is expected to shed a light on the emerging issues for young doctors in CAP to plan necessary improvements on a European scale.No significant relationships."}
+{"text": "Major Depressive (MDD) and Bipolar Disorder (BD) are chronic relapsing condition in which mood episodes are interspersed with periods of euthymia. Impairments in Executive Attention (EA) are a trait characteristic of mood disorder that persists also during remission. Similarly prefrontal dysfunctions are crucial in the genesis and maintenance of Obsessive-Compulsive Symptoms (OCS), which are highly comorbid in both MDD and BD.The aim of this study is to test a model in which deficits in EA mediate the relationship between the OCS and the relapse in a cohort of patients with MDD and BD.Sixty-four euthymic subjects with BD and MDD performed the Attentional Network Task Revised (ANT-R), that gauges EA in a standard conflict task. Here we adopted a drift diffusion model to measure the task efficiency as the drift rate in incongruent trials. Patients also completed at baseline the YBOCS, a questionnaire that evaluate the severity of OCS. All the participants have been followed-up for up to 5 years and relapses have been recorded.The association between OCS and time in euthymia was fully mediated by the EA so that greater OCS were associated with poorer executive functions  that in turn predicted a sooner relapse . This held true even when controlling for classic predictors of recurrence such as previous episode distance, the duration of illness and medications.Treatment targeting executive functions could hence be crucial in preventing relapses in subjects with mood disorders experiencing obsessive compulsive-symptoms.No significant relationships."}
+{"text": "Theoretical consideration and experimental demonstration reveal that the contrast variation in a birefringence image of an off-axis SiC wafer corresponds to the in-plane shear stress field. For the nondestructive characterization of SiC wafers for power device application, birefringence imaging is one of the promising methods. In the present study, it is demonstrated that birefringence image contrast variation in off-axis SiC wafers corresponds to the in-plane shear stress under conditions slightly deviating from crossed Nicols according to both theoretical consideration and experimental observation. The current results indicate that the characterization of defects in SiC wafers is possible to achieve by birefringence imaging. Here we consider that the Z axis is tilted at \u03b8 from [0001] toward  for simplicity. In this case, the in-plane shear stress field around the TED is expressed as follows ], small contrasts of TEDs were observed, and one can identify their Burgers vectors as 1/3. The birefringence contrast of TED-I with the Burgers vector of 1/3[Fig. 3et al., 2017et al., 2018et al., 2021Previously, some researchers have reported that birefringence image contrasts in off-axis SiC wafers correspond to defects such as micropipes and dislocations (Ma & Sudarshan, 20045.We have theoretically and experimentally demonstrated that the birefringence image contrast variation with the incident direction slightly inclined from the principal axis under conditions slightly deviating from crossed Nicols corresponds to the in-plane shear stress. The current results indicate that the characterization of dislocations in an off-angle wafer such as 4H-SiC for power devices is possible by birefringence imaging."}
+{"text": "Clozapine, the antipsychotic of choice for treatment-resistant schizophrenia, has a narrow therapeutic range and high interpatient variability in the dose-response relationship. Serum clozapine levels are essential both for therapeutic dosing and to monitor adherence. Use of venepuncture and prolonged result turnaround times with standard laboratory based methods for drug monitoring together contribute to the suboptimal use of clozapine.A novel portable point-of-care (POC) device has been developed to measure whole blood clozapine concentrations using an automated homogenous immunoassay. It is as accurate and reliable as standard laboratory methods but only requires a drop of blood obtained by finger prick and can produce a result in minutes. We pioneered clozapine POC testing in the acute inpatient setting during the outbreak of the COVID-19 pandemic.We report on the use of POC clozapine testing in the management of 4 acutely psychotic patients with treatment resistant schizophrenia.POC testing offered a more practical, less invasive and quicker alternative to conventional methods for monitoring of clozapine levels. Near immediate availability of clozapine levels expedited clinical decisions and helped ensure safe clozapine prescribing to severely unwell patients in a time of crisis. By facilitating patients\u2019 early safe discharge from hospital, clozapine point of care testing also reduced length of hospitalisation.Point of care monitoring of other psychotropic medications in addition to clozapine brings about the prospect of personalised precision medicine for patients with severe mental illness, both in the acute setting and in the community."}
+{"text": "The editors of the Journal of Mother and Child/Medycyna Wieku Rozwojowego invite you to read our latest quarterly issue, the last in 2021. The topics discussed herein encompass antenatal treatment of respiratory distress syndrome and breastfeeding\u2014also in premature infants\u2014as well as maternal ultraprocessed food intake and child labour manipulation.We start reading with a secondary observational analysis of the Lifestyle Intervention for Two (LIFT) randomized controlled trial data. Since there is a paucity of data related to mechanisms of health effects and dietary intake of ultraprocessed foods (UPF), the authors of this article aim to determine an association between maternal UPF intake and gestational weight gain (GWG) and neonatal body composition.We continue with pregnancy-related studies, referring specifically to prematurity. We can read the results and authors\u2019 conclusions based on a bidirectional (226 prospective and 42 retrospectives) cohort study performed to compare the respiratory distress syndrome and neonatal death among preterm twins from 28 to 34 weeks born < 14 days  and after 14 days  of completion of a single course of antenatal steroids.Then we present two interesting articles concentrating on breastfeeding. Raczy\u0144ska and colleagues have analyzed the advantages of side-lying position (SLP) and semielevated position (SEP) during bottle-feeding in premature infants. They provide evidence that SLP reduces the number of choking episodes during feeding and improves the proportion of milk consumed. Another group, Grzyb et al., present Polish women\u2019s opinions and experiences regarding breastfeeding in public. Based on a one-time 11-question survey that depicts women facing criticism while breastfeeding in public, the authors find it necessary to create dedicated places for breastfeeding in public places.The issue closes with an interesting study aimed at looking into the existing trends of child labour abuse in Addis Ababa and analysing the sociocultural barriers that impede nongovernmental organizations. The key message from the findings of this study is that the Winrock International (2008) approach of CIRCLE experience with an awareness-raising plan is recommended.We hope that the presented papers meet your expectations and encourage you to read other issues of our journal."}
+{"text": "Studies on fear conditioning have made important contributions to the understanding of affective learning mechanisms as well as its applications . However, central mechanisms of sleep related consolidation of fear memory in humans have been almost neglected by previous studies.In the current study we aimed to test effects of sleep and a period wakefulness on fear conditioned responses.In our experiment in a group 18 healthy volunteers event-related brain potentials (ERP), heart rate variability (HRV) and behavioral responses were recorded during a fear conditioning procedure presented twice, before daytime sleep (2h) or control intervention (a period of wakefulness) and after. The conditioning procedure involved pairing of a neutral tone (CS+) with a highly unpleasant sound (UCS+).Differential conditioning manifested itself in the contingent negative variance (CNV)-like slow ERP component. Both period of sleep and wakefulness resulted in an increased amplitude of the CNV to CS+. But we did not find an interaction effect of Time (Pre-Post) by Intervention (Sleep-Wake), suggesting that sleep did not affect the conditioned response differently as compared to a period of wakefulness. An apparent increase in HRV after a period of wakefulness did not affect fear conditioned responses .To summarize, the data indicate that fear memories are consolidated with the course of time with no beneficial effect of sleep; relearning of fear causes stronger differential responses as measured by slow wave amplitude but not behavior; increase of HRV does not affect fear learning."}
+{"text": "Cell technologies actively used in the treatment of many diseases. These technologies are based on manipulating the patient\u2019s cells outside the body, as a result of which cells acquire a higher therapeutic potential.No doubt the essential role of immune cells and their biologically active products in the pathogenesis of depression, which allows to view the modulated immune cells as model objects for developing new approaches to immunotherapy for depression.(CBAxC57Bl/6) F1 depressive-like male mice, developed under the long-term social stress, were undergoing the transplantation of syngeneic immune cells with in vitro caffeine-modulated functional activity. Recipient\u2019s behavior, immune and nervous systems functional activity were studied.It was found that immune cells isolated from depressive-like mice and treated in vitro with caffeine change their properties and after intravenous administration to syngeneic depressive-like recipients have a significant positive psycho- and neuroimmunomodulatory effects, affecting the main depression pathogenetic mechanisms: behavioral editing ; hippocampal neurogenesis stimulation against the background of increased BDNF; modulation of cytokine production by brain cells, indicating a decrease in neuroinflammation; modulation of the immune system functional activity .The results serve as an experimental substantiation of a fundamentally new approach to immunotherapy of depression based on the introduction of immune cells with functional activity modulated outside the body and open up the possibility of developing new methods of immunotherapy of depressive states in humans.No significant relationships."}
+{"text": "E. coli include integral membrane translocon SecYEG, peripheral ATPase SecA, and SecDF, an ancillary complex that enhances polypeptide secretion by coupling translocation to proton motive force. Atomic force microscopy (AFM), a single-molecule imaging technique, is well suited to unmask complex, asynchronous molecular activities of membrane-associated proteins including those comprising the Sec apparatus. Using AFM, the dynamic structure of membrane-external protein topography of Sec system components can be directly visualized with high spatial-temporal precision. This mini-review is focused on AFM imaging of the Sec system in near-native fluid conditions where activity can be maintained and biochemically verified. Angstrom-scale conformational changes of SecYEG are reported on 100 ms timescales in fluid lipid bilayers. The association of SecA with SecYEG, forming membrane-bound SecYEG/SecA translocases, is directly visualized. Recent work showing topographical aspects of the translocation process that vary with precursor species is also discussed. The data suggests that the Sec system does not employ a single translocation mechanism. We posit that differences in the spatial frequency distribution of hydrophobic content within precursor sequences may be a determining factor in mechanism selection. Precise AFM investigations of active translocases are poised to advance our currently vague understanding of the complicated macromolecular movements underlying protein export across membranes.The translocation of specific polypeptide chains across membranes is an essential activity for all life forms. The main components of the general secretory (Sec) system of  Escherichia coli . We. We40]. The broad nature of the SecYEG\u2219DF histogram is suggestive of conformational dynamics as transiently occupied conformational states cause broad shoulders in height distributions. Kymograph analysis of SecYEG\u2219DF protrusions confirmed this assertion b,d. The While this data supports the previous results indicating an interaction between SecYEG and SecDF, defining exactly how this interaction affects the mechanism of SecDF remains unclear. Modifications to the experiment, including introducing more members of the holotranslocon, are being considered as future directions for studying how SecDF fits into the current models for protein translocation, and the limitations of such studies are described below see .With a knowledge base in place regarding the topographic signatures of individual and co-assembled Sec system components, we extended AFM studies to Sec system machinery undergoing active translocation. Two precursor species with different final destinations were employed. One is destined for the outer membrane: outer membrane protein A ; and the other is destined for the periplasm, galactose-binding protein (pGBP).Recent biochemical work has shown that aspects of translocation, including the apparent rate constant of the translocation reaction, depend on precursor species . We postDefining two stages of the translocation reaction: initial and plateauThe starting material for all assays consisted of co-assembled SecYEG\u00b7SecA. To probe the translocase in the process of translocation, we used precursors containing disulfide-stabilized loops of either 44 or 59 aminoacyl residues near the C termini of pGBP and pOmpA, respectively. Translocation of oxidized precursors is initiated, but stalls at the loop, which is too large to pass through the channel in the translocon a. A timeTo define the initial state of the system, translocation of either pOmpA or pGBP was allowed to proceed in saturating ATP for only 30 s, at which point ADP-AlF3 (ADPAlF) was added to halt further hydrolysis  and resting state (ADP), independent of the two precursor species tested. We also quantified the quaternary structure of SecA in the active translocases at the plateau stage of activity . We analVolume analysis applied to translocases exposed to ATP followed by ADPAlF, which stabilizes the transition state, shows notably different results SecA readily dissociates from the translocase when engaged with pOmpA, but the majority of SecA remains associated with the translocase when engaged with pGBP. It has been previously reported that SecA binds tightly to the SecYEG/pOmpA complex but is readily released upon ATP hydrolysis . The res(ii)2 in the translocase dissociates to monomer in the presence of the transition state analog ADPAlF, but remains dimeric (or higher order) in ATP or ADP. These results did not change substantially between the two precursor species that were studied. This is in agreement with previous work showing that precursor-stimulated ATP hydrolysis leads to SecA monomerization [The quaternary structure of SecA in the active translocase is dimeric (or higher order) in the hydrolysis (ATP) and resting (ADP) state and becomes monomeric in the transition state (ADPAlF). These changes in SecA quaternary structure were essentially independent of the two precursor species. Previous research has shown that dimeric SecA is prevalent ,49, at lrization . We note(iii)Active translocases exhibit topographically distinct conformations that vary with precursor species on the time scale of AFM imaging. We attribute the conformational differences to SecA-driven structural rearrangements within the translocase. 2 has been reported in at least three different orientations, and SecA protomers are thought to act with little cooperativity and slide or rotate about the interface [AFM measurements provide structural corroboration for the significant precursor-dependent differences recently observed in the translocation reaction, including in the apparent rate constant and in the extent of precursor translocation . Yet sevnterface ,50. HencWhat physical property of the precursor triggers the observed differences in translocase topography? The overall length and hydrophobicity of pOmpA and pGBP are similar a. One faa) Traditional hydrophobicity plots for pGBP (red) and pOmpA (black). (b) Fourier transform of hydrophobicity shows overall agreement between the two precursor species except around a spatial frequency of 0.017 1/aa (arrow).A distinction between pOmpA and pGBP in the periodicity of hydrophobicity.  the interaction force between the tip and the macromolecular sample and (ii) the interaction between the sample and the underlying supporting surface. The first concern can be alleviated via quantitative agreement analysis between AFM images and simulated images based on crystal structures . FurtherThe topographic data of active Sec translocases presented here indicates that pGBP and pOmpA are transported across the cytoplasmic membrane by mechanisms that are distinct. However, there remains the formal possibility that all the mechanical steps required for translocation are the same for both precursors, but differing kinetics gives rise to our observations. During hydrolysis, the system could spend substantially more time in one conformation when engaging pGBP compared to pOmpA. Further work with higher time resolution will be required to distinguish between these possibilities. We also point out that our AFM experiments on stalled complexes at coarsely separated translocation stages were not designed to discriminate between translocation step models such as the power stroke mechanism and the Brownian ratchet. Future studies using continuous monitoring of individual translocases over time could provide insight into this fundamental question. AFM has been used to shed light on the interactions between translocon SecYEG and SecDF in supported lipid bilayers. A next step in this line of inquiry would be to image the full bacterial holotranslocon, incorporating SecYEG and SecDF along with SecA and insertase YidC. Yet the holotranslocon exhibits large membrane-external components on both sides of the bilayer: SecA on the cytoplasmic side and the P1 domain of SecD on the periplasmic side. Experience suggests that maintaining the full activity of the holotranslocon during AFM imaging will likely require a polymer cushion ,54. The Research carried out over the past decade has demonstrated that AFM imaging can uniquely characterize the activity of the general secretory system in near-native conditions. AFM provides access to conformational dynamics data in real time; this information complements traditional methods which are often limited to static snapshots. The comprehensive view of membrane activities that AFM makes available is well suited to unraveling complex pathways, such as the Sec system, which involves multiple proteins with time-varying stoichiometries undergoing difficult-to-synchronize dynamics. With recent advances in both AFM hardware and software, the method is poised to play an increasingly important role in unraveling fundamental Sec system mechanisms."}
+{"text": "Biosignals as measurement of the human body's functions provide useful information regarding human condition. Thus, the analysis of biomedical signals has become one of the most important methods for both interpretations and visualization in numerous research areas such as inter alia biology or medicine. They also play a very important role in health monitoring, diagnosis, but also as a source of data for the control purposes (in Human-Machine Interfaces). It has also led to development of numerous modern instruments designed for their detection, storage, transmission, and analysis. As the biological signals appear to be random (stochastic), it is impossible to predict their value in any time instant and therefore only statistical measures may be used in order to determine their features.Recent advances in signal computational methods have enabled the biomedical signals in an efficient way in order to extract appropriate features and has been an interesting subject for numerous research groups for over 40 years. More and more sophisticated methods are being developed and applied including various classifiers and filters. This Research Topic should focus on the most current trends in analysis of the most popular biosignals such as EEG, ECG, EMG, which would be processed for various applications such as inter alia clinical  or control (human-machine interaction).In this Research Topic titled \u201cCurrents in Biomedical Signals Processing\u2014Methods and Applications\u201d a collection of contributions showing new advancements and applications of advanced processing of biosignals for various applications was presented.Binkowska et al. was focused on association between long-term cannabis use and memory impairments. Based on authors' thorough literature review\u2014very few studies have examined this relationship, in particular in a poly-drug context, when cannabis was combined with other addictive substances. For this purpose the authors used event-related potentials for the examination of the recognition process in a visual episodic memory task in both cannabis users (CU) and cannabis poly-drug users (PU). The hypothesis stated that both groups (CU and PU) will have their behavioral and phychophysiological-indicators of memory processes affected with the use of cannabis alone or with other substances, with the PU patients expressing stronger changes. The obtained results proved alterations in recognition memory processing in both groups compared to the healthy participants from the control group (CG), and these were at most visible in cannabis poly-drug users (PU), while there was no significant effect for patients using cannabis alone. The paper proves that the use of cannabis with other substances results with the biggest disturbance in the brain function. The authors applied analysis of electroencephalography (EEG) signals for this study, which is non-invasive.The paper Kwasniewicz et al., where the authors used brain signals for the purpose of message credibility evaluation. No similar studies could be found in the literature and the efficiency of the obtained results was over 0.7. The authors found out appropriate brain areas active depending on positive or negative message reliability.Another study involving analysis of EEG signals was presented in Jakubowska et al., the authors used EEG signals, where they assessed visual working memory (VWM) capacity. The authors tired to assess the efficiency of training conducted on a Real-Time Strategy (RTS) video game (StarCraft II) for the purpose of VWM capacity improvement. The study involved 62 participants, who took part in two EEG sessions (before and after the StarCraft II-based training).Also in Xu et al.; where the authors applied topological data analysis (TDA) in order to analyse and understand the brain signals. This paper is a short review and shows the opportunities in analysis of EEG signals brought by the TDA, which differs from traditional signal processing methods and has a very wise potential usage in among the others Brain-Computer Interfaces (BCIs).Analysis of the EEG signals, which is a very challenging task mostly due to the nature of these signals, was also presented in paper Jurczak et al., the authors compared the most popular methods applied for the electrooculography (EOG) artifacts removal\u2014independent component analysis (ICA) and regression with the convolutional neural network (CNN) in order to eliminate the eye blinking artifacts. The obtained results showed much higher performance of the CNN method than the one given by regression or ICA.As mentioned above\u2014analysis of the EEG signals is difficult among the others due to these signals' non-stationarity. Also the electroencephalography signals are prone to various external and internal artifacts occurrence, where the internal artifacts are frequently related with physiological activity, such as the one related with eye movement and blinking. The eye blinking (EB) artifacts strongly affect the signals' quality. In Barry et al. the authors focused on using more invasive brain signals\u2014electrocorticography (ECoG). The main aim of this work was to examine ECoG spectrogram images for training proper and reliable cross-patient seizure classifiers. In this paper, the data collected from 113 patients was converted into RGB spectrogram images. For classification purposes five different convolutional neural networks (CNN) were applied, which gave the cross-patient classification (seizure/non-seizure) accuracy of 87.9%, while the appropriate trained ResnEt50-based models provided efficiency of 95.7%, which is very high.In Lan et al., where the authors decided to use them for the rat bone marrow mesenchymal stem cells (rBMSCs) osteogenic differentiation quantitative measurement. The study showed that the OCNN enabled successful distinguishing of differentiated cells at a very early stage and gave better prediction performance compared with the single morphological parameters. Based on the conducted experiments it is possible apply the OCNN-based online learning models for further rBMSCs osteogenic differentiation recognition.Another study using deep learning algorithms such as convolutional neural networks, in this case the osteogenic convolutional neural network (OCNN), was presented in Haraguchi et al. described the use of less common signals, namely magnetoencephalography (MEG), where the effect of menstrual cycle on brain activity has been analyzed. In this work, the authors focused on objective quantitative MEG parameters in order to investigate the effects of the menstrual cycle on spontaneous neural oscillations. The study involved 25 healthy female participant, with normal, regular menstrual cycle. The testing was conducted twice: during menstrual period (MP) and outside period (OP). The authors of this paper showed that it is possible to use the menstrual cycle as an accurate interpretation of functional neuroimaging in clinical practice.The authors of Bartosik et al. statistical analysis was applied for the purpose of selecting the most important personality features based on attractiveness assessment. Based on authors thorough literature study and on their research experience they claimed that trust is based on facial appearance appraisal, which is made based on facial morphological characteristics, such as among the others color, complexion, shape, etc. In order to select appropriate features the authors modeled a backward step-wise logistic regression; they also analyzed the results of the psychological tests together with the attractiveness and trust survey.In Boschen et al., the authors presented Fast Scan Cyclic Voltammetry (FSCV), which has been used for many years in animal models, but has not been applied on humans. The main aim of this work was to bring interest into using the FSCV in human clinical studies. This article showed also some technical challenges, which may limit its clinical implementation, but these can be overcome while properly addressed.In paper As mentioned above\u2014analysis of biomedical data is a very challenging task, but this makes is very interesting. We hope that our Research Topic will be found interesting to readers and researchers in fields of medicine, biomedical engineering or neuroscience.All authors reviewed and accepted the manuscript for submission.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Venkadesh and Van Horn in \u201cIntegrative Models of Brain Structure and Dynamics: Concepts, Challenges and Methods\u201d. This paper introduces theoretical frameworks to interpret empirically measured brain connectivity including the graph data structure that can be used to indicate connections between regions as well as analyze local and global properties, as well as modularity to characterize independent and dependent communities of neural networks. Next, they dwell on mechanisms acting on multiple timescales that govern the reciprocal relationship between neural network structure and its intrinsic dynamics with special focus on the macroscopic scale. It was concluded that multimodal imaging provided a more accurate depiction of structure-function relationships in the brain.This special issue highlights state-of-the-art quantitative techniques to translate the relation between structural and functional brain connectivity, or jointly analyze brain structure and function to understand the aberrations in neurological diseases and neuropsychiatric disorders. The technical advancements in multimodal imaging technology for investigating brain structure and function are succinctly summarized by Safai et al. in \u201cMultimodal Brain Connectomics-Based Prediction of Parkinson's Disease Using Graph Attention Networks\u201d with translation to Parkinson's disease (PD). The paper illustrates why multimodal features are beneficial in analyzing structure-function connections and predicting PD. The authors use a graph attention network based deep learning classification framework with feature sets derived from fMRI-based functional connectivity, diffusion MRI based structural connectivity as well as a combination of both. They show that the multimodal feature set outperforms models based on unimodal features for predicting PD. The GAT architecture also allowed them to outperform previous classification models of PD based on brain imaging data, highlighting the utility of deep learning.Structure-function relationships were further analyzed by Wang et al. bring in an interesting perspective about the utility of functional connectivity derived from white matter, which is traditionally used to investigate structural connectivity, in their paper titled \u201cAltered Homotopic Functional Connectivity Within White Matter in the Early Stages of Alzheimer's Disease\u201d. The authors combined resting state fMRI with diffusion tensor imaging (DTI) so that they could point to an anatomic basis for altered white matter homotopic functional connectivity that they observed in early stages of Alzheimer's disease. The study demonstrates that it is possible to imagine other uses for a given modality than is traditionally used for. Further, investigation of structure-function relationships in the brain may not be boxed into data fusion of fMRI and DTI modalities, but rather also be investigated by using the functional signal available in diffusion MRI. This provides a new perspective for multimodal data fusion.Chen et al. provide an illustration of how structural connectivity investigations have translational potential in the clinical. They investigated structural alterations in depressed individuals with and without suicidal ideation as well as healthy controls. It was observed that the generalized fractional anisotropy value showed differences in particular regions of the brain such as the corpus callosum and anterior cingulate. Changes in the corpus callosum is known to affect emotional processing, working memory and cognitive control. Similarly, the cingulate gyrus regulates emotions. Network-based statistics analysis indicated that interconnections between these subnetworks were significantly weaker in depressed individuals with suicidal ideation as opposed to both the control groups. This enriches our understanding of suicidal ideation in terms of concomitant structural connectivity alterations in the brain and provides therapeutic targets that can be pursued in future studies.In their paper titled \u201cAssessment of Disrupted Brain Structural Connectome in Depressive Patients with Suicidal Ideation Using Generalized Q-Sampling MRI,\u201d Fu et al. in their paper titled \u201cWhole-Brain Functional Network Connectivity Abnormalities in Affective and Non-Affective Early Phase Psychosis.\u201d They investigate both static and dynamic functional connectivity abnormalities in early phase of psychosis, a time period when intervention may be most effective. They also use these tools to identify commonalities and differences between affective and non-affective psychosis. These findings have a significant bearing on future studies which may devise therapies targeting early psychosis.Likewise, the translational potential of functional connectivity is demonstrated by Lei et al. integrate known findings of alterations in neuroplasticity and energy metabolism in Type-2 Diabetes with those reflected in structural and functional brain connectivity derived from MRI. The paper proposes brain connectivity to be the link between neural plasticity and energy metabolism. Specifically, they hypothesize that diabetes may lead to abnormalities in neuroplasticity and energy metabolism in the brain through multiple pathological pathways, ultimately leading to cognitive impairment that may reflect to MRI structural connectivity and functional connectivity, respectively. They also integrate our knowledge of pathological processes underlying Alzheimer's disease (such as A\u03b2) with those underlying diabetes. Their review illustrates how functional and structural brain connectivity may provide pathways to understand existing mechanistic models of altered brain function in disorders.In their review titled \u201cAltered Structural and Functional MRI Connectivity in Type 2 Diabetes Mellitus Related Cognitive Impairment: A Review,\u201d Robinson et al. investigate structure-function correspondence in the hippocampus  in their paper titled \u201cNeurofunctional Segmentation Shifts in the Hippocampus\u201d. The study addresses how to reconcile disparate findings of structural and functional organization within the hippocampus, with cytoarchitecture favoring dorsal-ventral layering while neurofunctional topography supporting anterior-posterior and medial-lateral functional differentiation. The uniqueness of the study lies in the fact that it uses high resolution MRI data acquired at 7T and uses metanalytic connectivity modeling in addition to traditional measures of connectivity. The study suggests that cognitive processing and stimulus features may influence how the hippocampus activates, and reflects a further need to study the functional properties of the hippocampus using a wide variety of stimuli in order to infer structure-function correspondence in the hippocampus. This may be critical for understanding the basis of hippocampal involvement in disorders such as post-traumatic stress disorder and schizophrenia.In a basic science application with potential translation to the clinic, Shi et al. provide an illustration of the use of a non-MRI modality such as functional near infrared spectroscopy (fNIRS) to understand bran function. The authors evaluate the response of the cerebral cortex to different upper limb movement patterns. Such processes are difficult to study using MRI given its restrictive environment. The study highlights the role of non-MRI modalities in investigating brain structure and function.Finally, In conclusion, the special issue highlights many methodological advances in investigating brain structure, function and their inter-relationships using brain connectivity, reviews prior literature on these topics and illustrates the utility of such methods in understanding brain function in both health and disease.GD, VA, and MI edited this special issue. AS and GD contributed to writing the first draft of the editorial. VA and MI made edits to the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Although effective vaccines against COVID-19 have been developed with the unprecedented speed, insufficient vaccine uptake suggests that many people are unwilling to get vaccinated worldwide. The aim of this study was to assess factors influencing intention to get vaccinated against COVID-19 in five Western Balkans countries.Total of 700 unvaccinated respondents aged 18-75 participated in the study. Intention was assessed by a single item gauging the likelihood of getting vaccinated on a 5-points Likert scale. Multiple linear regression was used to determine whether socio-demographics  and attitudes towards vaccination predict intention to get vaccinated.Proportion of respondents willing to get vaccinated against COVID-19 ranged from 22.6% in Serbia to 40.4% in Montenegro. In Bosnia and Herzegovina and Albania stronger intention to get vaccinated in the future was associated with confidence in vaccine safety  and efficacy , higher feeling of danger of the disease  and higher social responsibility . Confidence in vaccine efficacy  and social responsibility , accompanied with higher sense of susceptibility to the disease , were significant predictors of intention in Serbia. In North Macedonia willingness to get the vaccine was significantly associated only with social responsibility , while in Montenegro age was the single predictor ;Results of this study suggest that vaccination campaigns should focus on specific set of socio-psychological factors in each country, enhancing confidence in vaccine efficacy and appealing to collective responsibility as most prevalent determinants of vaccination intention in Western Balkans.\u2022\u2002Specific set of socio-psychological factors influenced vaccination intention in each country.\u2022\u2002Most prevalent factors influencing intention to get vaccinated against COVID-19 were confidence in vaccine efficacy and social responsibility."}
+{"text": "Through this study, we aimed to test the association between the exposure to metals measured in indoor dust and metabolic outcomes among children living in areas with environmental exposure to metals.The project \u201cHealth impacts of environmental exposure to airborne pollutants in the sites of Brescia and Taranto, Italy: increase knowledge to address preventive intervention of local and global relevance\u201d (ISEIA) enrolled 130 children aged 6 to 13 years  resident from pregnancy in highly industrialized areas of the Brescia province, Northern Italy. Metabolic outcomes including BMI, fasting blood glucose and blood creatinine were measured. The concentration of a mixture of 10 metals in indoor dust was determined through an X-ray fluorescence portable analyzer (p-XRF). Linear regressions and Weighted Quantile Sum (WQS) regression were applied to test for the association between metal exposure and metabolic outcomes. All models were adjusted for age, gender, socio-economic status and area of residence.A significant association was observed between Cd and blood creatinine  when considering each individual metal separately in the model. WQS regression showed a positive significant association between the mixture of metals and fasting glucose  identifying Mn, Cr and Cu as the elements with the higher weights, while a marginally significant association was found between the metal mixture and blood creatinine  where Cd and Ti showed the highest weight.We assessed the potential association between exposure to metals in indoor household dust and blood glucose and creatinine. Our results contribute to clarifying the role of metal exposure in the burden of non-communicable diseases although further studies are needed to better understand the relationship between metal exposure and metabolism.\u2022\u2002The metal mixture in indoor household dust is associated with an increase in fasting glucose.\u2022\u2002Cd concentration in indoor household dust is associated with an increase in blood creatinine."}
+{"text": "Blunt abdominal injury can be a cause of significant morbidity and mortality in patients who have sustained trauma even at low velocity. We report on an unusual case of a 50-year-old male who developed a traumatic spigelian hernia and caecal perforation after falling off a pushbike and impacting on the handlebar. We have also discussed some of the considerations taken in the assessment and surgical management of this case. Blunt abdominal injury and the concurrent increase in intra-abdominal pressure can result in bowel or abdominal organs to herniate through a disruption of abdominal musculature or fascia , 2. KnowA 50-year-old male presented as a trauma to the Emergency Department (ED) after falling off a pushbike at low speed and forcefully landing on the end of the handlebar resulting in a painful lump to the right lower quadrant. The lump was initially small at the time of injury; however it had expanded in size on examination in ED. It was soft, but tender and irreducible with overlying abrasions. On arrival he was mildly tachycardic with a borderline blood pressure  that resA computed tomography (CT) trauma series scan of his abdomen  revealedIn the emergency laparotomy, the findings were caecal perforation with faecal contamination extending into the right retroperitoneum and the associated haematoma. A limited right hemicolectomy from terminal ileum to hepatic flexure was performed with a side-to-side functional end-to-end stapled anastomosis. The abdomen was copiously irrigated, and a drain was inserted into the retroperitoneal defect. The spigelian hernia was closed primarily in two layers with 1.0 nylon suture. Post-operative recovery was complicated by pain and ileus but the patient made an eventual recovery with supportive, non-operative management and was discharged home on Day 10.First described by Selby in 1906, a traumatic spigelian hernia occurs as a result of a defect at the semilunar line, lateral to the rectus abdominis muscle , 4. GiveIn our case presentation, there was a high index of suspicion for a TAWH based upon clinical history and examination findings despite the low velocity of injury. An unusual finding was the depth of injury extending to the retroperitoneum and towards the right adrenal, suggesting that focal blunt trauma can manifest similar to a penetrating injury. This case highlights the advantage of CT in examining for additional traumatic intra-abdominal or retroperitoneal injuries, thus reinforcing CT as the modality of choice for investigating TAWH and their immediate complications , 6. AlthHowever in an emergency setting, laparotomy is the recommended approach for complicated TAWH as up to 50% of TAWH cases are likely to have other intra-abdominal injuries such as mesenteric or bowel injury requiring surgery . Closure(i)Blunt abdominal injury can cause disruption of the abdominal wall resulting in traumatic hernias.(ii)Focal blunt abdominal trauma can potentially have a deep zone of injury and manifest similar to a penetrating injury.(iii)An expanding mass in the context of abdominal trauma is concerning for vascular or intra-abdominal injury. Further imaging is useful in determining appropriate surgical intervention.(iv)CT is the imaging modality of choice to investigate for traumatic abdominal wall hernias and identifying potentially complicating factors.(v)Mesh reinforcement can be considered in the repair of traumatic abdominal wall hernias that are not contaminated."}
+{"text": "The literature highlights low vaccination coverage among most minority or ethnic pediatric communities in EU, including migrants. In addition to being less likely to get a vaccine, such communities may be vulnerable to developing certain infectious diseases. It is particularly important in the context of the current humanitarian crisis connected with Russia's aggression towards Ukraine. Identification of potential barriers to vaccination and system gaps is crucial to further ensure that underserved pediatric communities benefit from the same level of protection as the general population in terms of disease prevention and control, including those diseases which can be prevented by routine vaccinations. The proposed workshop moderated by well-known experts of the subject (Bernardette Kumar and Maria Ganczak) will be based on the results from qualitative data collected as a part of the 5-year RIVER-EU  project which tackles health system barriers among selected underserved communities living in four countries: Ukrainian migrants in Poland, females with a Turkish and Moroccan migration background in the Netherlands, marginalized Roma communities in Slovakia and migrants/refugees in Greece. This interactive workshop will provide short (5 minutes per country) comparisons of the health system barriers to vaccination against MMR  and Human Papillomavirus (HPV) in children living in different underserved communities, and contrast barriers to vaccination experienced by the community members with barriers perceived by the health care professionals. International comparisons of in-depth information collected during qualitative studies (interviews and focus groups) will help to provide an increased understanding of the health system determinants of low vaccine uptake in their specific multi-factorial contexts that will vary in terms of geography, size, wealth, health sector structures, culture and vaccination law. Such qualitative research is particularly valuable regarding its potential for producing comprehensive and refinement analyses adjusted for understanding the voices of underserved communities. The session will go beyond describing those. Based on the presentations the participants will be divided into 4 groups to discuss (15 minutes) the Key Barriers; Key Facilitators to vaccination; Main lessons Learnt; Ways forward for the future to increase vaccine uptake among underserved pediatric communities to reduce the burden of vaccine preventable diseases. These 4 groups of workshop participants will be led by experts from the MEMH and IDC sections. Then, concluding remarks will be presented by each group (5 minutes per group). The final resume delivered by session chairs will end the workshop.\u2022\u2002The health system barriers to child vaccination among underserved communities vary among European countries, and the optimal way to adequately address them is likely to be context specific.\u2022\u2002The RIVER-EU project gives an opportunity to discuss lessons already learnt around the different components of the vaccination process and to pinpoint ways forward for the future to reduce the VPD."}
+{"text": "Preference-based person-centered care (PCC) is the gold standard for delivering high quality care in nursing homes (NH). A public health crisis makes it difficult for NH leaders to make decisions that honor residents\u2019 preferences for care and activities while balancing the safety of others in the NH community. Based on the Operational Framework to Guide Decision-making During the COVID-19 Pandemic, the purpose of this symposium is to discuss several projects that are growing the evidence-base for person-centered risk management during a public health crisis. Data presented can guide NHs in balancing safety and risk during a public health crisis. Our first presentation speaks to the adoption of preferences as an important measure of care quality prior to a crisis, the next two presentations speak to how risk perceptions of NH staff and residents can support PCC delivery during a crisis, and the final presentation provides a potential evidence-based quality improvement strategy for integrating PCC in the pandemic recovery phases. First Dr. Abbott will present on the impact of using the preferences for everyday living inventory as a quality and safety indicator in NHs, then Dr. Carpenter will present on direct-care staff members risk perceptions while during the COVID crisis, followed by Dr. Behrens who will discuss residents\u2019 risk perceptions around having their preferences honored during the COVID crisis, and finally Ms. Heilbrunn will discuss an ongoing clinical trial evaluating the impact of using the ECHO platform to improve infection control and care quality during the COVID crisis."}
+{"text": "Neighborhood infrastructure challenges and changes are possibly understood and experienced in unique ways across the lifespan. This study presents findings on neighborhood conditions and underexplored solutions from the perspective of older adults in Detroit, Michigan. This project obtained multiple perspectives on these issues from older Detroiters through interviews (n-19) and professionals working on climate concerns in the region (n=5). The research was designed using community-based research approaches including having older adults as members of the research team from instrument design to dissemination. One emergent theme, the importance of legacy as motivation in addressing environmental concerns, will be highlighted. This presentation will conclude with a discussion of next steps for this work."}
+{"text": "Frontiers in Human Neuroscience, we collected a series of articles that highlight the emerging use of thalamic neuromodulation for difficult-to-treat neurological disorders. First, a perspective article by Mendon\u00e7a et al. argues for the use of neuromodulation targeting the thalamus for uncommon movement disorders. Two review articles then showcase the expanding use of deep brain stimulation (DBS) and Responsive Neurostimulation (RNS) to target discrete nuclei of the thalamus for treating intractable epilepsies . Finally, three original research reports complement these reviews by using both DBS and RNS to control seizures in adult and pediatric patients via thalamic stimulation .The thalamus is considered the \u201ccentral forum\u201d of the brain where most principal connections converge and diverge, principally creating the temporal scaffold in which disparate anatomical brain regions are organized into a coherent module subserving behavior. Harnessing this extensive network through neuromodulation has traditionally addressed numerous difficult-to-treat movement disorders such as essential tremor and Parkinson's disease. The therapeutic potential of stimulating this phylogenetically ancient brain structure for other neurological disorders has gained considerable attention since the turn of the 21st century. Even if not stimulated directly, biomarkers, or neural signatures from the thalamus are increasingly being used to assess the therapeutic success of disparate types of neuromodulation technologies. This increased clinical utilization raises the question: Do \u201call roads\u201d eventually lead to the thalamus for neuromodulation? In this Research Topic of Mendon\u00e7a et al. argues for the consideration of DBS for medically refractory, post-lesional movement disorders. But how can the effectiveness and risk of DBS be assessed for such rare disorders in the absence of randomized controlled trials? The authors eloquently use Holmes tremor (HT), a post-lesional movement disorder, to illustrate the ethical imperative to consider DBS among heterogeneous patient populations based on an \u201cN-of-1\u201d trial design approach.Deep brain stimulation is an established therapy for the management of motor symptoms in patients with medically refractory Parkinson's disease and essential tremor. The current challenge is implementing DBS for movement disorders that may not develop in the context of a degenerative disease, but rather from a static brain lesion. A perspective article by Mendon\u00e7a et al. found that ventral thalamic VTAs have significantly higher connectivity with a previously described HT lesion network map than non-thalamic VTAs. In other words, even with dissimilar lesion locations, the ventral thalamus is a candidate neuromodulation network node for HT. The authors conclude that generation of a database through a paired and iterative N-of-1 trial approach for uncommon movement disorders will ensure both DBS electrode placement and parameter optimization when combined with patient-specific connectivity mapping of responses.Because the ventral thalamus is targeted in more than half of reported DBS cases for HT, the authors use previously reported electrode coordinate information to create a network connectivity map based on simulated volumes of tissue activated (VTA). Using this individualized approach, Feigen and Eskandar). Now, with the emergence of a closed-loop system, clinicians are evaluating the ability to use thalamic recordings to deliver tailored stimulation. Beaudreault et al. and Roa et al. showcase the utility of the RNS System to reliably detect and treat seizures at several thalamic targets, including the ANT and central median (CM) nuclei. These studies are exciting from a methodological perspective and add to the scant literature on thalamic closed-loop neuromodulation for pediatric epilepsies .The treatment of drug-resistant, intractable epilepsies has entered a new frontier with the use of thalamic neuromodulation . Agashe et al. substantiates this interest by providing a case report and survey of the literature on CM-DBS for a genetic epilepsy characterized by thalamocortical dysfunction. The authors show that CM-DBS produced a significant reduction in generalized tonic-clonic seizures in a cognitively normal patient. Zillgitt et al. further supports the targeting of CM for idiopathic generalized epilepsy (IGE) by providing an illustrative case using the RNS System. In fact, CM-RNS for the treatment of IGE has led to the initiation of a prospective single blind, multi-center, randomized study (NAUTILUS). The field waits in anticipation for the trial's results as surgical options for genetic generalized epilepsies have historically been limited.Of note is the off-label use of these stimulation technologies to control seizures by targeting CM: An intralaminar thalamic nucleus that has garnered considerable interest from epileptologists and neurosurgeons alike (Miliarium Aureum, a point where all roads were said to eventually converge. The studies herein support this metonymy of a centrally located brain structure with the power to influence far-reaching neural networks. Though a question remains: Is the thalamus a promising stimulation target merely because of its anatomical location, or are off-target effects of its \u201croads\u201d responsible for observed success? Several recent articles hint at the latter, whether it is stimulation of the mammillothalamic tract for intractable epilepsy (Freund et al., The thalamus is emblematic of the Roman Empire's Mendon\u00e7a et al.; Watson et al., What can we expect in years to come? The use of thalamic biomarkers to guide therapy decisions, further individualization of thalamic electrode placement through network-based approaches and exploring the therapeutic potential of stimulating other thalamic nuclei, such as the central lateral nucleus for restoring conscious arousal (Kundishora et al., All authors drafted, revised, and approved final version of the editorial."}
+{"text": "Artificial Intelligence (AI) holds tremendous potential for aiding in the customization and tailoring of interventions. This talk will focus on the initial development of an adherence support system to maintain older adults' engagement with at-home cognitive training and assessment delivered via mobile devices. As part of the NIA funded Adherence Promotion with Person-centered Technology (APPT) project, a reminder and adherence support system is being developed to automatically detect adherence lapses and provide just-in-time reminders with tailored messaging to facilitate reengagement. The results of an initial study (N=40) will be presented in which participants were delivered reminders via SMS text messaging that were either tailored or not tailored to their self-reported motivation to engage with the intervention. Tailored messages were perceived as more motivating, and qualitative data informed additional ways in which messages might further be tailored based on individual preferences to support adherence."}
+{"text": "The effective reproduction number (Rt) represents the average number of secondary cases generated by an infected person. During an outbreak, near-real-time monitoring of Rt constitutes a key indicator for detecting changes in disease transmission and assessing the effectiveness of interventions. The estimation of Rt usually requires identifying infected cases in the population which is in practice challenging from available data. The purpose of this study was to compare Rt estimates for COVID-19 surveillance in France based on three data sources of different sensitivity and specificity for identifying infected cases.By applying a statistical method developed by Cori et al., we estimated Rt using (1) confirmed cases identified from positive virological tests among the tested population (2) suspected cases recorded by a national network of emergency departments (3) hospital admissions for COVID-19 recorded by a national administrative system to manage hospital's organization.From June 2020 to March 2022, the estimates of Rt in France showed similar temporal trends regardless of the dataset. Estimates based on the daily number of confirmed cases provided an earlier signal that the two other sources, with a lag of 3 and 6 days compared to estimates based on emergency department visits and hospital admissions, respectively.The COVID-19 experience has proven that monitoring temporal changes in Rt was a key indicator to help public health authorities controlling the outbreak in real time. Having data on infected people in the population to estimate the Rt is not straightforward in practice. As this study has shown, the opportunity of using more readily available data, provided that it is highly correlated with the spread of infection, gives a practical solution for monitoring the COVID-19 epidemic and any epidemic in general.\u2022\u2002The effective reproduction number (Rt) is a key parameter to monitor transmission during epidemics but its estimation from available data is often a critical issue.\u2022\u2002Based on COVID-19 experience, data sufficiently correlated with the spread of infection may be appropriate to estimate Rt and monitor its temporal trend."}
+{"text": "Room-temperature phosphorescence (RTP) from metal-free materials has recently attracted the interest of the scientific community in a variety of imaging fields owing to the fact that it provides high-resolution information independent of the autofluorescence and dual-colored emitting characteristics, which are advantages that fluorescent materials and phosphorescent heavy-metal complexes do not possess. State-of-the-art advances in security, sensors, and bioimaging have been proposed using the aforementioned advantages. This Research Topic includes ten articles on the latest advances in this research area.Yang et al.) reports oxygen sensing using thianthrene derivatives doped into amorphous polymer matrices. The thianthrene chromophores show dual emission of fluorescence and RTP in the polymers because folding-induced spin\u2013orbit coupling of the chromophores greatly enhances the RTP characteristics. Ratiometric imaging owing to the dual fluorescence and the enhanced RTP allows easy quantitative detection of oxygen under a variety of conditions. Furthermore, the relationship between the RTP intensity and oxygen concentration provides quantitative information about the oxygen permeability in solid materials.Suppression of triplet deactivation, including oxygen quenching, is an important factor to enhance the RTP properties. An article by  investigates the change of the triplet nonradiative processes of RTP chromophores doped in a polymer host under inert conditions depending on different preparation techniques of the films. Residual solvents and the role of guest chromophores in enhancing the intermolecular interactions of the polymer matrices are proposed as reasons for the different nonradiative deactivation from the triplet state. For the interaction between the guest chromophore and polymer host, the tendency of smaller triplet deactivation using polymers with lower molecular weights is also introduced.As different triplet-quenching characteristics independent of oxygen, a study by (Kusama and Hirata) investigates the nonradiative process from the triplet state of guest chromophores under the oxygen-free condition from the viewpoint of the intramolecular nonradiative transition of the guest and the endothermic intermolecular triplet quenching between the guest and molecular host. Experiments using large different persistent RTP yield depending on thermo-reversible amorphous/crystal changes of the host\u2013guest solid reveal that the different diffusion constants of the molecular host are largely related to the magnitude of the endothermic intermolecular triplet quenching.A study by  in air. The authors explain that the C\u2013Cl or C\u2013NH2 groups on the surface of the CNDs provide rigidity via hydrogen bonding, reducing the nonradiative transition from the triplet state. This allows persistent RTP even when the CNDs are not surrounded by a solid matrix.The topic of triplet deactivation is also related to RTP from carbon nanodots. Vasilev et al. explains efficient triplet generation by photoexcitation of synthesized porphyrin derivatives using the photon up-conversion properties. Although the triplet-generation capability is often small for heavy-atom-free chromophores with a small energy gap, an adequate triplet generation yield is obtained for the synthesized heavy-atom-free porphyrins.Research regarding the triplet generation yield is also crucial for enhancing the RTP characteristics. Cao et al. introduces benzophenone (BPO) doped with thianthrene (TTR). Analysis using different concentrations of TTR indicates that the triplet\u2013triplet energy transfer from the BPO host to the TTR guest after excitation of BPO contributes to enhance the RTP yield. A TTR/BPO material with an optimized TTR concentration shows RTP with 46% quantum efficiency and a lifetime of 9.17\u00a0ms from isolated TTR under ambient conditions.As other report focusing on the contribution of triplet generation to the RTP characteristics, Takewaki et al. reports mechano/thermoresponsive RTP chromism from solids of thienyl diketone derivatives. Although thienyl diketone derivatives form the skew conformer generate green RTP in the crystalline state of the solid, an amorphous state containing some of the thienyl diketone derivatives shows yellow RTP characteristics after grinding. After heating of the amorphous state, the crystalline state with green RTP characteristics is recovered.Research regarding the relationship between the RTP characteristics and the conjugated backbone may be crucial for providing additional insight into enhancing the RTP characteristics, Zhang et al.). The derivatives show different delayed emission spectra in the crystalline state, doped state in the amorphous polymer, and dissolving state in degassed organic solvents. The delayed emission has multi-exponential decay characteristics, and the magnitude of the average time of decay is from 1\u00a0\u00b5s to 100\u00a0ms.9,10-Diphenylfluorescence derivatives substituted with bromine as guest chromophores showing delayed emission characteristics are reported by anthracene (DCPA) and acridine (AD) [(DCPA) (AD)2]. [(DCPA) (AD)2] shows long-lived triplet excitons as the RTP characteristics with a lifetime of 325\u00a0\u03bcs. The authors propose that the long-lived triplet state, as well as separation of the molecule orbitals, between DCPA and AD of the crystals contributes to a greater change of the long-distance exciton transfer and good electron\u2013hole separation ability, resulting in excellent photoelectric response performance.In addition to the RTP characteristics, utilization of stabilized triplet excitons is also crucial for expanding applications. Although metal-free RTP materials and their applications have been reported recently, the articles in this themed issue provide proposals and novel insight for previously unclear points regarding the photophysical processes related to the triplet state from the viewpoint of RTP. The editors believe that this Research Topic of articles will inspire readers to consider the idea of improvement of a variety of opto-electronics and photonics applications, as well as enhancement of the RTP characteristics."}
+{"text": "To support reduction of Clostridium difficile infection (CDI), in 2008 the Scottish Antimicrobial Prescribing Group recommended that all NHS boards in Scotland restrict the use of antibiotics associated with a high risk of CDI. In NHS Grampian the policy for antibiotic prophylaxis in orthopaedic surgery was changed in June 2010. Trauma patients undergoing internal fixation or arthroplasty received flucloxacillin or co-amoxiclav before the policy change and flucloxacillin and gentamicin after the policy change. Previous studies have found similar policy changes resulted in an increase in post-operative acute kidney injury (AKI) and this study examined rates of post-operative AKI before and after this policy change in the NHS Grampian region of Scotland. Patients undergoing elective arthroplasty received either flucloxacillin or co-amoxiclav or cefuroxime before the policy change and cefuroxime afterwards.All NHS Grampian patients who underwent an orthopaedic surgical procedure with prophylaxis during the period 01 June 2008 to 31 May 2012 were selected. Cases were linked to local creatinine data to detect post-operative AKI. Cases were further linked to national coverage data: (i) hospital discharge data to create the Charlson score for comorbidity, (ii) patient-level community prescribing data to identify previous exposure to any medicines which predispose to renal impairment, (iii) patient-level infection data to identify any post-operative CDI and (iv) Scottish Renal Registry data for case exclusion purposes. Segmented regression analyses of interrupted time series were used to evaluate changes in level and trend associated with the intervention and estimate effect sizes. 3,870 trauma cases and 5,475 elective cases were examined. There was a significant increase in AKI rate following the policy change (We found that a change in orthopaedic antibiotic prophylaxis policy in NHS Grampian to flucloxacillin plus gentamcin was associated with an increase in post-operative AKI. This is consistent with observations in other boards and supports the new recommendation away from this policy made by SAPG in 2012. In cohort of trauma patients we found the change in policy was associated with an increase in post-operative AKI rate."}
+{"text": "Normal tissue toxicities in head and neck cancer persist as a cause of decreased quality of life and are associated with poorer treatment outcomes. The aim of this article is to review organ at risk (OAR) sparing approaches available in MR-guided adaptive radiotherapy and present future developments which hope to improve treatment outcomes. Increasing the spatial conformity of dose distributions in radiotherapy is an important first step in reducing normal tissue toxicities, and MR-guided treatment devices presents a new opportunity to use biological information to drive treatment decisions on a personalized basis.MR-linac devices offer the potential for advancements in radiotherapy (RT) treatment of head and neck cancer (HNC) by using daily MR imaging performed at the time and setup of treatment delivery. This article aims to present a review of current adaptive RT (ART) methods on MR-Linac devices directed towards the sparing of organs at risk (OAR) and a view of future adaptive techniques seeking to improve the therapeutic ratio. This ratio expresses the relationship between the probability of tumor control and the probability of normal tissue damage and is thus an important conceptual metric of success in the sparing of OARs. Increasing spatial conformity of dose distributions to target volume and OARs is an initial step in achieving therapeutic improvements, followed by the use of imaging and clinical biomarkers to inform the clinical decision-making process in an ART paradigm. Pre-clinical and clinical findings support the incorporation of biomarkers into ART protocols and investment into further research to explore imaging biomarkers by taking advantage of the daily MR imaging workflow. A coherent understanding of this road map for RT in HNC is critical for directing future research efforts related to sparing OARs using image-guided radiotherapy (IGRT). Radiotherapy (RT) treatment of head and neck cancer (HNC) has inspired the development of advanced methods for increased conformity of dose distributions to tumors and organs at risk (OARs) because of the anatomical complexity of the region and its propensity for changes throughout the course of treatment . As the IMRT was a substantial improvement normal tissue sparing compared to standard 3D conformal therapy, yet further improvement can be achieved as the field aims toward personalized care. The traditional workflow includes a planning computed tomography (CT) that is used for dose optimization. OAR sparing methodologies used in the treatment planning stage depend on the planning strategy used, such as 3D conformal planning, IMRT, and volumetric modulated arc therapy (VMAT) which differ in complexity and time requirements. 3D conformal planning initializes with setting up beam orientations followed by iterative changes to meet required dose constraints. IMRT begins with target and OAR delineations, followed by defining dose constraints and objectives, in order to calculate the dose with a dose optimization algorithm to create the best treatment plan. VMAT adds new degrees of freedom to the IMRT planning approach and allows for beams to be on while the gantry rotates around the patient, creating an \u2018arc\u2019 that is highly conformal to the target. IMRT is established to have an increasing conformal dose distribution  and aid Traditionally, the exact thresholds and constraints used in this inverse planning process are empirically driven values drawing on both the experience of the dosimetrist/oncology team and published reports  for geneFollowing treatment planning, IMRT utilizes a quality assurance protocol (IMRT QA) to verify the complex dose distributions by directly measuring doses with a radiation detector prior to treatment . This stWhile IGRT using X-ray and CT-based imaging has become routine for clinical use over the last decade, the use of high-field MR-guided adaptive RT (MRgART) has remained unutilized in the US until the FDA approval of the Elekta  Unity MR-Linac for treatment in 2018 . Since tOne way the clinical workflow for an MR-linac can differ from conventional therapy is by its use of a combined CT/MR simulation (MR-sim) protocol for delineation of tumors and OARs for treatment planning. Future advances in the generation of Synthetic CTs (sCT) from an anatomical MR image can enable clinics to adopt an MR-only, reducing clinical workflow constraints by eliminating the need to acquire a CT thus simplifying the MR-guided workflow ,26. In tConsidering the therapeutic ratio as a primary metric of success in ART, it is crucial to understand NTCP models and how they are used in treatment optimization in ART. NTCP models are mathematical functions that relate the probability of developing a particular side effect to the radiation dose delivered to an OAR. Historically, the Lyman-Kutcher-Burman (LKB) was a common modeling method in NTCP modelling . NowadayNTCP models could directly be used for dose optimization in adaptive workflows to minimize normal tissue toxicity and improve treatment outcomes. Specifically, NTCP models may be used to determine whether a patient would benefit from mid-treatment adaptive replanning. In a clinical context, this may be done by superimposing the original treatment plan onto a mid-treatment simulation image and calculating dose volume histogram parameters and corresponding NTCP values . If the Dosimetric Impact of Anatomical ChangesOne problem with the conventional process for RT is the issue of inter-fractional deformation of the patient\u2019s anatomy , which iART was originally described by Yan et al. in 1997  as a re-ex_aequo, ARTOAR, ARTreduco, and ARTtotale. ARTex_aequo describes the strategy to maintain planned dose to the target volume and OAR through serial plan verification. ARTOAR describes the strategy of reducing the dose to the OARs while maintaining target dose. ARTreduco describes the approach of maintaining the planned dose to the target but updating the CTV contour according to the changes in patient anatomy to reduce OAR dose. Finally, ARTtotale includes an updated CTV shape to conform to the deformed anatomy in addition to an amplified dose to the target volume and reduced OAR dose. All of these methods include an intentional reduction in dose to the OARs and therefore a reduction in NTCP. Theoretically, ART using MRI could be employed to spare OARs based on functional imaging following one of these strategies, but this approach is relatively still unexplored and thus not clinically applicable yet. Possible future applications for these strategies will be discussed in the \u2018direction of the technology: quantitative biomarker\u2019 section to follow.The adaptive strategies aimed at reducing OAR dose include ARTEven within these varying ART intentions, the adaptation interval may still vary depending on the clinical constraints and devices available, as demonstrated by Heukelom and Fuller in There are several ongoing phase II clinical trials ongoing to explore OAR sparing using MRgART. These include MR-Adaptor, Martha trial and Insight 2.reduco framework for sparing OARs and reducing the probability of locoregional failure. Symptom questionnaires and video-strobe for vocal cord function are completed each week to monitor radiation-induced toxicities.The Bayesian Phase II Trial of Magnetic Resonance Imaging Guided Radiotherapy Dose Adaptation in Human Papilloma Virus Positive Oropharyngeal Cancer is currently recruiting patients and was initially registered 21 July 2017 ,44. The ex_aequo depicted in The \u201cMRI-Guided Adaptive RadioTHerapy for Reducing XerostomiA\u201d in Head and Neck Cancer (MARTHA)  trial istotale strategy will be utilized to include a new re-plan at weeks two and four of treatment to account for anatomical changes in patients. The HPV negative oropharyngeal cancer patients who are non-responders will be evaluated for increasing prescribed RT dose which will split from responding patients after ten fractions based on apparent diffusion coefficient (ADC) measurements of the tumor. Part one will produce preliminary feasibility outcomes for the overall study, and part two outcomes include a comparison of overall dose and parotid gland dose between adaptive arms and assesses safety of the dose escalation protocols used.The study entitled, \u201cOptimising Radiation Therapy in Head and Neck Cancers Using Functional Image-Guided Radiotherapy and Novel Biomarkers\u201d is currently recruiting patients and was first posted to clincialtrails.gov on 27 January 2020 . The stuAs more clinical trials for ART in HNC advance and adaptive strategies becomes more common-place with technological advances to ease the clinical burden, further optimization schemes will become necessary given the array of options clinicians will have in adapting treatment plans. Decision-making processes to incorporate new information gathered with on-line adaptive workflows will be more complex and require investigation. Regarding the initial treatment plan, decisions are made about the segmentation of the OAR and the dose constraints added to the IMRT plan optimization algorithms. Both processes are common areas for implementation of improved decision-making processes, especially with the advent of artificial intelligence in RT ,47,48 AnMost of the methods for increasing the therapeutic ratio that have been discussed are directed towards improving spatial conformality of the dose distribution around the tumor and minimizing the dose to nearby OARs. Evidence shows that further improvements in outcomes can be achieved using biomarkers to inform on the treatment strategy for both target and OAR dose adaptations . On MR-lDiffusion weighted imaging is a MRI method to measure Brownian motion of water molecules within tissue and characterize the diffusion as a singular apparent diffusion coefficient (ADC). The ADC biomarker was shown to be useful for prediction of salivary function in response to radiation and could serve as a decision-making tool within an adaptive framework . \u2206ADC reDCE MRI provides quantitative information on the kinetic parameters, such as perfusion and permeability, associated with the transient injection of contrast agent (CA) into the imaging volume . By direMR Relaxometry refers to mapping techniques used to acquire quantitative measurements of tissue parameters such as T1 & T2 relaxation coefficients to characterize tissue volumes. MR Relaxometry measurements of radiation-induced injury have been demonstrated in brain ,62 and lreatment ,67. Consreatment , findingeference ,70. Thiseference ,72.The general study of high-dimensional quantitative values from varying imaging modalities is commonly referred to as radiomics. Pre-defined features are extracted from the image intensity of a segmented region of interest (ROI) to generate many candidate biomarkers applicable across a broad range of applications. These features include basic descriptions of intensity within the ROI, geometric features related to the shape of the ROI, and texture features composed of higher-order metrics for intensity heterogeneity . FeatureHNC present unique challenges for the effective delivery of RT due to the anatomical complexity and propensity for inter-fractional changes in anatomy . The las"}
+{"text": "Introduction: We previously reported on the United States' regulatory environment evolving to accommodate an emerging boom in gene therapy research. Several important developments have transpired in the 2 years since that article was published, including the coronavirus disease 2019 (COVID-19) pandemic and the drive for large-scale testing of vaccines containing recombinant or synthetic nucleic acid molecules. This report highlights key developments in the field with a focus on biosafety and issues of note to biosafety professionals with responsibilities over clinical research.Discussion: We provide guidance for performing risk assessments on the currently approved gene therapy products as well as the most utilized types of investigational products in clinical trials. Areas of focus include the prominent approaches utilized in the three major areas of research: oncology, infectious diseases, and rare diseases.Conclusion: The COVID-19 pandemic has created several opportunities for continued growth in gene therapy. National vaccination campaigns will result in greater public acceptance of gene therapy research. Technological advancements that made the vaccine race possible will spur the next generation of research. Advancements born in the developed world set the stage for the creation of therapeutics to treat greater numbers in the developing world and have the potential for massive benefits to global public health. Biosafety professionals and Institutional Biosafety Committees play key roles in contributing to the safe evidence-based advancement of gene therapy research. Biosafety professionals responsible for clinical research oversight must be aware of emerging technologies and their associated risks to support the safe and ethical conduct of research. Researchers focused on improving the wealth of knowledge on gene transfer technology and redesigning vectors for increased safety along with incorporating additional safeguards as recommended by Food and Drug Administration (FDA) guidance. The National Institutes of Health (NIH) Office of Science Policy (OSP) sequentially loosened the regulatory requirements for gene therapy research over subsequent versions of NIH guidelines as the regulatory oversight focus shifted to the FDA.3We previously reported on the United States' regulatory environment evolving to accommodate an emerging boom in gene therapy research.4As the FDA is tasked with assessing the safety and efficacy of therapeutic products and regulating their approval, it is a logical progression for that agency to have an increased role in overseeing clinical trials involving recombinant or synthetic nucleic acid molecules as the field matures and the technology becomes mainstream. The FDA took several steps to aid this transition, including the creation of various guidance documents regarding the manufacture of gene therapy products as well as the design of clinical trials for such products. Although several tracks already exist for prioritized review of investigational new drugs (INDs), the FDA created the Regenerative Medicine and Advanced Therapies designation to allow for expedited review of biologics, such as \u201cgene therapies, including genetically modified cells, which lead to a durable modification of cells or tissues,\u201d specifically used to treat serious or life-threatening diseases where preliminary clinical evidence indicates that the drug has the potential to address unmet medical needs.5 COVID-19 vaccine are currently administered at community vaccination sites, chain pharmacies, and even athletic stadiums.6\u20138Within the past decade, use of recombinant or synthetic nucleic acid molecules in clinical trials has gone from limited to early phase trials utilizing small numbers of major academic medical centers to large late phase trials with each utilizing tens or hundreds of sites across the United States and globally. As of this writing, all coronavirus disease 2019 (COVID-19) vaccines with FDA emergency use authorization were produced with recombinant DNA technology containing either messenger RNA (mRNA) derived from recombinant plasmids or a recombinant adenovirus as the active ingredient. To date, >300 million doses have been administered in the United States as the population strives toward herd immunity.Since our earlier report, several major developments have transpired within the field of gene therapy research with significance to biosafety and biosafety professionals with responsibilities over clinical trials. The highlights are outlined here with a focus on the changing regulatory environment, emerging science, and the biosafety challenges they represent.9 The data plateaued in 2020 as the COVID-19 pandemic caused unprecedented widescale disruptions in the clinical research sector.10\u201312 The disruption was most severe in April 2020 when the number of non-COVID-19-related new trials was 50% of the number reported in January 2020 (pre-COVID-19). April 2020 also set the high-water mark for reported trial suspensions on clinicaltrials.gov with >1000 clinical trial suspensions citing COVID-19 as the principle cause.3 When discussing the state of gene therapy research during COVID-19, Peter Marks, Director of the FDA Center for Biologics Evaluation and Research (CBER) stated, \u201cAlthough the 2020 [gene therapy IND] number is essentially flat, that flatness needs to be interpreted in the setting of COVID-19. I actually take the number of submissions during this COVID-19 time to be somewhat remarkable.\u201d13The number of IND applications submitted to the FDA for gene therapy products set records each year from 2017 to 2019 .9 The da14 As gene therapy studies progress to later phase trials, the studies require larger numbers of research subjects meeting the inclusion and exclusion criteria of the various trials, which inevitably requires larger numbers of research sites.The inflection point in IND submissions to the FDA took place in 2016 , arrow, 15As later phase studies searched beyond major academic medical centers for sites with pools of research subjects with the diseases being studied, smaller research sites without existing IBCs were inevitably required. This phenomenon drove a surge of IBC registrations for clinical research sites utilizing commercial services to externally administer IBC reviews . BetweenIndependently administered IBCs are following in the footsteps of the rapid growth of independent central Institutional Review Boards (IRBs) in the 1980s and 1990s. As more clinical research moved from the halls of academia into small private research sites without their own research oversight structures there was a growing need for an independent option that sites could use. Various independent IRBs grew rapidly in the 1980s and 1990s during a time where late phase clinical trials were moving into privately owned small research sites. Independently administered IRBs, where a commercial entity administers the board reviewing research, demonstrated several benefits in the form of faster study initiation, greater consistency, and more effective review of multisite research.16\u201318 The central IRB review concept was considered so beneficial that the NIH instituted a single IRB policy for NIH funded studies . The Federal government followed suit with revisions to the Common Rule (45 CFR 46), the rule of ethics in the United States regarding biomedical and behavioral research involving human subjects, to require a single IRB of record for all federally funded research .By 2006 the transition to commercially administered IRBs was proving so successful that the FDA issued specific guidance to industry on how to work with central IRBs and academic centers who used to be the nucleus for IRB review determined use of an independent commercially administered IRB improved study start-up time even within the academic setting.19The NIH allows institutions to utilize multiple IBCs, creating a situation where an institution can rely on an externally administered IBC with reviewer expertise in the clinical environment and human gene transfer research, whereas retaining their locally administered IBC for basic science research involving laboratories and animal models.If we want a glimpse at the future of IBC review for multisite clinical trials we only need to look at the transition from local to independent IRB administration for the past 20+ years. Having a single entity perform the reviews poses several potential benefits in the form of faster study initiation, greater consistency in reviews across research sites, and easier management and regulatory oversight of multisite research. Likely as more gene therapy trials enter later phase, the need for and utilization of independent commercially administered IBCs will increase in kind.20\u201333The FDA approved the first product containing recombinant DNA in 2015, an oncolytic herpesvirus approved for use in melanoma. Since then the FDA has issued 15 approvals for therapeutics containing recombinant or synthetic nucleic acid molecules. When the products are categorized by disease indication, we can gauge the level of progress gene therapy has made in each type of disease. Seven of the eight approved oncology products are chimeric antigen receptor (CAR) T cells against B cell malignancies. Six FDA approvals have been issued for infectious disease vaccines, although four of them are emergency use authorizations for vaccines against SARS-CoV-2 intended to quell the COVID-19 pandemic. Two adeno-associated virus (AAV)-based gene transfer vectors have been approved for use in diseases caused by rare inherited mutations. Luxturna was approved for subretinal injection to treat retinitis pigmentosa, a disease caused by mutations to the RPE65 gene that causes night blindness in children and progress to complete blindness in adolescence. Zolgensma was approved to treat spinal muscular atrophy, a neuromuscular disease caused by mutations to the SMN1 gene that typically results in children being unable to control the muscles required for breathing and dying by 2 years of age.Six FDA-approved products comprise viral vectors. AAV-based vectors are currently the only FDA-approved gene transfer vectors intended to treat diseases caused by rare inherited mutations. Viral vectors based on replication-deficient human adenovirus 26 as well as replication competent yellow fever strain 17D204 and the Indiana strain of vesicular stomatitis virus have been approved for use as infectious diseases vaccines.34\u201336FDA-approved drugs contain a package insert describing the drug, associated risks, and handling instructions. Requirements for the format and content of this document are outlined in 21 CFR 201. Unprecedented levels of success are simultaneously taking place in different disease indications. The major developments are summarized as follows.37\u201345 Whereas research and development of a vaccine can last years or decades, Moderna and the National Institutes of Allergy and Infectious Diseases collaboratively developed a vaccine in 2 days once the SARS-CoV-2 sequence was posted online. Within 6 weeks Moderna was able to produce and ship the first batch of vaccine for testing at the NIH.mRNA-based technology came to the forefront in the Spring of 2020 as the Pfizer/BioNtech and Moderna COVID-19 vaccines were among the first to enter clinical trials. Moderna Therapeutics was the first to publicize the speed by which these vaccines could be produced. 46 The first vaccines to receive FDA emergency use authorization were both mRNA based. As of this writing , 67.1% of adults in the United States have received at least one dose of a COVID-19 vaccine, 96% of which were mRNA-based vaccines.5Whereas the speed with which mRNA vaccines can be developed and produced was remarkable, the efficacy was equally impressive as both Moderna and Pfizer's clinical trial data both showed efficacy at \u223c95%.47When interviewed on COVID-19 vaccines, Dr. Peter Marks said, \u201cI think anyone involved in vaccinology, when we saw how effective these mRNA vaccines were against COVID-19, it was a surprise. We were expecting them to be \u2018okay effective,\u2019 but to see them so effective across the entire age spectrum, the different ethnic and racial backgrounds, was one of the most pleasant surprises in an otherwise bleak year.\u201d48\u201350 Rather than depending on traditional and time-consuming culture-based methods for developing and manufacturing vaccines, this new era utilizes recombinant DNA technology to create designer vaccines intended to utilize the bodies' cells to make the targeted antigen rather than manufacturing it in a factory. The speed with which vaccines have been developed, tested, mass produced, and distributed during the COVID-19 pandemic is unprecedented and bodes well for a new era on the war against infectious diseases.The success of mRNA-based vaccines as well as the previously mentioned recombinant virus-based vaccines create hope for a new era of vaccinology.51 Newly developed vaccines against major causes of death in the developing world  are also approaching clinical trials.52\u201356Already as the COVID-19 pandemic begins to quell pharmaceutical companies are taking aim at their next ambitious targets. A recombinant vesicular stomatitis virus (VSV) - based vaccine against Ebola has already obtained FDA approval. Highly virulent agents such as Nipah virus are in the cross hairs for future vaccines. Vaccines against more common agents associated with high morbidity, including fetal pathogens such as Zika virus, herpes simplex viruses, and cytomegalovirus, have been developed and are approaching clinical trials.57\u201361 Oncology research in particular is shifting away from conventional treatment strategies that employ chemotherapy, radiation, or surgery and focusing on targeted immunotherapies.62 mRNA-based cancer vaccines are a promising alternative for a personalized treatment strategy designed to target tumor-associated antigens that are preferentially expressed in cancerous cells, such as growth factors or antigens that are unique to malignant cells arising from somatic mutation.58\u201366 The availability of high-throughput sequencing of tumor biopsies allows for the identification of neoantigens specific to the patient's tumor and the development of mRNA-based vaccines targeting them.68With the success of mRNA-based vaccines, a number of large pharmaceutical companies are redirecting resources to focus on developing mRNA-based drugs for applications beyond infectious diseases.69\u201371CAR T cells have been successfully applied to treat resistant or refractory B cell leukemias and lymphomas. To date, the FDA has issued seven approvals for CAR T cell therapies and the number is likely to grow as hundreds of CAR T cell trials are currently taking place around the globe.Gene transfer technology allows the modification of T cells to express alternatives to their endogenous T cell receptors. First-generation CARs comprised an extracellular antigen-binding moiety, a transmembrane domain and the intracellular CD3 zeta chain responsible for signal transduction from a T cell receptor . The mosAutologous CAR T cells, where the donor and recipient are the same patient, typically require 2\u20134 weeks to progress from the initial leukaphereses product, through manufacturing and quality control testing before release for clinical use. As replication-deficient retroviral or lentiviral vectors are commonly used to transduce the T cells with the construct encoding the CAR, the final product must be tested for replication competent virus before release. Given the risk of insertional mutagenesis leading to oncogenic transformation, the FDA recommends a long-term follow-up period of up to 15 years for recipients of the cellular product.Toxicities from CAR T cell therapies range from mild to severe and life-threatening, of note being cytokine release syndrome (CRS) and neurotoxicity. The severity of the CRS correlates with tumor burden. It is currently unknown if cerebral edema resulting from CAR T cell therapy is triggered by severe CRS or if a separate mechanism is at play. Study of the mechanisms involved is hampered by the lack of adequate animal models. However, both CRS and neurotoxicity are largely reversible with well-established treatment regimens. A description of the CAR T cell utilized as well as the associated risks and long-term follow-up period must be present in the IRB-approved informed consents utilized in clinical trials. CAR T cells have also been engineered with safety mechanisms to eliminate them in cases of severe toxicity such as drug-inducible apoptosis and constitutive expression of surface epitopes that can be targeted with FDA-approved monoclonal antibodies.72\u201375 As the starting material does not originate from cancer patients prior conditioning from tumor-derived suppressor cells and T cell exhaustion are no longer a concern as well as insults from prior chemotherapy regimens. Off-the-shelf T cells are manufactured in advance and are intended to be readily available in a frozen state. Rather than requiring a patient to undergo leukapheresis and wait weeks for the manufactured product to be delivered for infusion, off-the-shelf CAR T cells only require thawing and transport to the infusion suite. Furthermore, the cells are manufactured from pools of healthy donors that allow for mass production and economies of scale to reduce costs rather than creating a single product for each patient with an autologous approach.\u201cOff-the-shelf\u201d CAR T cell products derived from healthy donor T cells may mitigate several long-standing issues with autologous CAR T cell therapies.Gene editing technology makes off-the-shelf CAR T cell products possible , 2C. Sur77 The T cells can be engineered to utilize Boolean logic for greater precision and avoid on target, off tumor effects such as attacking nonmalignant bystander cells expressing one of the antigens targeted by the CAR T cells. This approach would require multiple different targeted antigens to be present on a cell before CAR T cell-mediated killing. Dominant negative or suppressive receptors can also be utilized to avoid attacking nonmalignant bystander cells.CAR T cells can be engineered to express multiple receptors that allow for combinatorial antigen-sensing circuits.78 Other approaches include employing other cell types such as CAR natural killer cells and CAR macrophages.Although CAR T cells have been greatly successful in treating B cell leukemias and lymphomas, they have had limited success in treating solid tumors. A likely cause for this phenomenon is the immune-suppressive tumor microenvironment. Designing CAR T cells for this purpose is an area of active study focusing T cell trafficking to the tumor, and abrogating the T cell's ability to accept suppressive signals whether they be contact dependent  or independent .79 Over 7000 rare diseases affect >30 million people in the United States. Many rare conditions are life-threatening and most do not have treatments. The Orphan Drug Act creates incentives for development of orphan drugs to treat such diseases.80 Given the small number of individuals affected by any one rare disease or condition, a pharmaceutical company that develops an orphan drug may reasonably expect the drug to generate relatively small sales in comparison with the cost of developing the drug and consequently to incur a financial loss. Recent advancements in clinical use of recombinant DNA technology create opportunities for addressing great unmet medical need in the realm of rare diseases. \u201cI am very excited for the field because I feel like we're beginning to get to a critical mass,\u201d where a single method or product can be deemed safe and then adapted for many uses, said Dr. Peter Marks, head of the FDA CBER that regulates gene therapies.81The 1983 Orphan Drug Act defines a rare disease as a disease or condition that affects <200,000 people in the United States.83 The basic biology of AAV vectors is summarized elsewhere.84 AAV is a small virus with a 4.7\u2009kb single-stranded DNA genome giving it a limited payload capacity. Wild-type (WT) AAV is a Risk Group 1 organism that typically infects humans between 1 and 3 years of age. The resulting asymptomatic infection frequently results in both cellular and humeral immunity directed against capsid proteins.86 AAV vectors can infect both dividing and nondividing cells.Two drugs based on AAV-based vectors have already received FDA approval for treatment of rare diseases, the aforementioned Luxturna and Zolgensma. AAV-based vectors are a popular tool for gene transfer to address single gene mutations.87\u201389 To date, 12 different AAV serotypes have been identified with capsids binding to different cellular receptors granting each serotype enhanced tropism for different cells and tissues.90 Whereas WT AAV is dependent on a helper virus for replication, commercially available packaging systems provide the necessary genetic material for viral replication in trans through multiple plasmids and enable creation of AAV vectors without utilizing a contaminating helper virus.91Whereas WT AAV may integrate into host genomes at specific AAV integration sites, AAV vectors devoid of the Rep gene tend to form episomes in the nucleus of transduced cells. Genomic integration is observed at 0.1\u20131% of transduction events, which has caused some concern about cancer risks. Whereas tumorigenesis was observed in a neonatal mouse model, it has not been observed in large animal studies or human trials.92 Multiyear transgene expression after gene transfer to the liver has been observed in humans and large animals.94 Transgene expression in hepatocytes leads to antigen specific tolerance, which may be beneficial for diseases where intravenous infusion of therapeutic proteins leads to production of neutralizing antibodies that decrease efficacy.95Intravenous infusion of AAV results in trafficking to the liver, making AAV an attractive vector for hepatic gene therapy trials.93 Transgene expression takes place in a dose-dependent manner.93 Unfortunately, vector doses also correlate with anti-AAV capsid immune responses that can lead to elimination of transgene expressing cells. As AAV vectors are unable to replicate in host cells, transgene expression is diluted as transduced cells divide. Although AAV has traditionally exhibited an excellent safety profile, clinical trials utilizing high doses , especially in subjects with pre-existing conditions, have caused some to express concern.96\u201398Although AAV is a popular gene transfer vector it has some drawbacks. Pre-existing neutralizing antibodies can interfere with the efficacy of the gene transfer vector when administered intravenously and may require administration of higher doses.99 The transient nature of mRNA and high-safety profile allows for it to be utilized to restore or replace therapeutic proteins without relying on viral vectors. Delivery through lipid nanoparticle grants the mRNA access to the cellular cytosol leading to translation of the encoded protein without risks for insertional mutagenesis into the host cell genome. Reliance on cellular biosynthetic machinery allows the protein product to receive requisite post-translational modification and be trafficked to the appropriate subcellular compartment or be excreted based on the encoded leader sequence.Whereas AAV vectors provide long-term gene expression, mRNA-based technology is an attractive approach for developing therapies for rare monogenic diseases due to its transient expression profile.The mRNAs are not immunogenic eliminating concerns of neutralizing antibodies from repeated exposure to the gene transfer vehicle, which is a common concern with viral vectors. Unlike the permanent nature of viral vector-based gene transfer, mRNA is present transiently in cells limiting toxicity concerns. Owing to the nonpermanent nature of mRNA therapy, one has the ability to titrate the dose within an individual to identify an efficacious dose level and the ability to stop dosing in the event of an unexpected safety concern.Packaging mRNA in lipid nanoparticles confers upon it sufficient environmental stability to be administered by injection into target tissues or nebulized for use in the respiratory tract for diseases such as cystic fibrosis. Nebulization creates the potential for droplets, aerosols, and contamination of the treatment area. A risk assessment should be performed to ensure adequate containment and decontamination strategies are in place.1 Gene therapy trials no longer require registration with the NIH OSP or consideration for review by the former NIH Recombinant DNA Advisory Committee. Appendix M of NIH Guidelines, which provided the bulk of guidance regarding IBC review of human gene transfer research, was removed from the 2019 version of NIH Guidelines. From that point forward, IBC review would be comparable with other types of nonexempt recombinant DNA and was covered under NIH Guidelines Section III-C-1. The documents previously required to register clinical trials with the NIH are now recommended for IBC review under the FAQ page titled Points to Consider for IBCs Reviewing Human Gene Transfer Protocols.3The landscape for performing IBC review of clinical trials has changed considerably for the past few years.100 This document is required to obtain an IND from the FDA. The CMC document is routinely considered confidential and sponsors or CROs may be hesitant to divulge it without justification.IBCs sometimes face difficulties in obtaining the necessary information to perform a risk assessment and should take pre-emptive action to facilitate IBC review of clinical trials before their submission. IBCs overseeing research at academic medical centers should have the requisite expertise as well as codified policies and procedures for review of clinical trials. Guidance should be posted online detailing the documents required for IBC review. Clinical research personnel may have different backgrounds than laboratory research personnel and may be unfamiliar with the nature of IBC review. Unlike investigators in biomedical laboratories, clinical investigators typically do not create the investigational product containing the recombinant or synthetic nucleic acid molecules. As such, they are dependent on the study documentation sent to them from the pharmaceutical company serving as the research sponsor or the contract research organization (CRO) running the clinical trial. A detailed description of the design of the investigational product is typically found in the Investigator's Brochure (IB) in a section titled, Physical, Chemical, and Pharmaceutical Properties and Formulations. If the IB does not provide sufficiently detailed information for the IBC to perform a risk assessment, study personnel can request additional information from the sponsor or CRO. If study contacts are unable to answer the IBC's questions about the design of the investigational product, it may be beneficial to request the portion of the Chemistry Manufacturing and Controls (CMC) document detailing the design and manufacture of the investigational product.Biosafety in Microbiological and Biomedical Laboratories are written for research in the laboratory setting and more comprehensively address facilities for plant and animal research than the clinical setting. Once investigational products receive FDA approval confusion can arise regarding whether research oversight is required. On label use of approved drugs is not considered research and can be conducted without research oversight as standard of care. However, off label use of drugs containing recombinant or synthetic nucleic acid molecules brings those materials back under the IBC's purview for research purposes.Clinical use of recombinant or synthetic nucleic acid molecules pose added challenges for IBCs and biosafety professionals. NIH Guidelines and the 101\u2013103 Yet, this important benefit of single IRB review can be lost because a similar mandate does not currently exist for biosafety reviews. Whereas approval from a central IRB may be issued in days, patient access can be delayed if IBC reviews are not completed just as quickly. This delay can be several weeks, when awaiting approval from an IBC that meets only once per month, or longer if the IBC requires multiple review cycles to issue approval.As the field of gene therapy matures and hundreds of studies progress toward late stage multisite trials, sponsors and CROs experience great efficiencies when utilizing independent, externally administered IBCs that are centrally administered. Centrally administered IBCs provide sponsors and CROs a single point of contact for submission, tracking and managing large multisite studies. Study-level documents are only submitted once and site-level personnel utilize the same forms, policies, and procedures across all sites to submit site-specific information . The efficiencies of centrally administered IBC review are comparable with those that drove the requirement for single IRB review of federally funded multisite clinical trials. A key benefit of single IRB review is the opportunity for faster testing of investigational products as well as increasing patient access to clinical trials that may result in life-altering or life-saving outcomes to individuals suffering from conditions with no approved treatment alternatives. Major academic medical centers are beginning to see centralized IBC review as necessary infrastructure for large-scale clinical trials.In this report, we highlight recent advancements in the field of gene therapy as well as some of the associated challenges that may be faced by biosafety professionals and IBCs with responsibilities over clinical research. We provide guidance in performing risk assessments for the currently approved gene therapy products as well as the most utilized types of investigational products in clinical trials. We also provide guidance for obtaining the necessary information to perform IBC reviews for these investigational products.The COVID-19 pandemic has created several opportunities for continued growth of the gene therapy field. Efforts to vaccinate >70% of adults in the United States with vaccines containing recombinant or synthetic nucleic acid molecules will result in greater public acceptance of gene therapy research. Technological advancements that made the vaccine race possible will spur the next generation of gene therapy research. Advancements born in the developed world set the stage for the creation of therapeutics to treat greater numbers in the developing world and have the potential for massive benefits to global public health.Biosafety professionals and IBCs have always played key roles in contributing to the safe evidence-based advancement of gene therapy research. Biosafety professionals responsible for clinical research oversight must be aware of the changing regulatory landscape as well as emerging technologies and their associated risks to support the safe and ethical conduct of research."}
+{"text": "Resource intensive and costly End-of-Life (EOL) care is a significant healthcare policy concern in the U.S. In addition to the high Medicare spending, out of pocket (OOP) expenses are also high during EOL adding considerable stress during terminal days. The Medical Marijuana Laws (MMLs) is a significant policy in this context. Previous studies have shown increased use of MM among older adults, better pain management, influence on site of death as well as evidence of reduction in Medicare expenditure on drugs in states with MMLs. In this study, we explore the association between MML and OOP expenses during EOL using data from the Health and Retirement Study exit and core interviews from 1995 to 2018. We use a difference in differences (DD) and event study models to examine this question. We find evidence of increased OOP expenses on drugs and doctor visits with the effects concentrated among the early implementing states, among decedents who are White and among cancer patients. Despite its growing acceptance in palliative medicine, affordability of MM could pose a significant hurdle to terminally ill patients especially since MM and related costs are not covered by insurance."}
+{"text": "Introduction: Public Mental Health Services in Lombardy  has 27 Departments for Mental Health and Addiction Services and a number of private residential facilities. With the reorganization of the entire Healthcare system to deal with COVID-19, Regional Health Authorities recognized mental health as a priority and authorized the continuation of mental health services for the general population. Objectives: To review the initiatives and procedures implemented in Lombardy during the Covid-19 pandemic in relation to the organization of Psychiatric Services and continuity of psychopharmacological treatment. Results: Hospital admissions for acute psychiatric disorders in patients positive for COVID-19 required a dedicated area in the psychiatric ward or alternatively, a medical ward supported by psychiatric staff. Psychiatric hospital activity for patients negative for Covid-19 has been maintained as usual. The activity in the Mental Health Centers has been maintained in patients suffering from severe mental disorders as well as in those with serious social problems or judicial sentences. Particular attention was paid to patients\u2019 clinical monitoring and drug administration. Long-acting Injection antipsychotics were often preferred to oral treatment to ensure adherence and continuity of care. Appropriate e-health technologies were used to reach patients and their families, for monitoring patients and avoiding drop-outs of patients with serious diseases. Conclusions: Maintaining continuous monitoring of patients in contact with mental health services is essential for a careful assessment of their condition from both a psychopathological and medical point of view during pandemic.No significant relationships."}
+{"text": "Covid-19 databases have detailed information about each affected person in Brazil, but it has flaws in counting the number of cases, which are underreported. We aimed to construct and correct the cases dataset by linking different sources of data observations to study the pandemic evolution in Brazilian municipalities.Using the electronic Unified Health System (e-SUS), a public and governmental database, we calculated the pandemic curves of COVID-19 cases. We applied the following approaches to investigate data anomalies a) to perform a descriptive analysis and compare these results with a non-governmental database using Dynamic Time Warping distance; b) to verify and correct municipalities data anomalies linking to other public governmental database namely National Council of Health Secretaries (CONASS) with e-SUS. c) To apply a K-means DTW Barycenter Averaging in clustering analysis to describe the general behaviors of pandemic in Brazilian Municipalities.Around 10% records of cases in the e-SUS public governmental database were underreported. After the linkage and the data updating procedure, the time-dependent clustering analysis presents no anomalies and more interpretable results. The clustering analysis provided eight different behaviors of COVID-19 curves of cases. The degree of intensity for prevalence and incidence rates were identified according to eight clusters from the lowest to highest.Using the matching procedure based on Dynamic Time Warping distance to correct the municipalities unreported cases, we provided a richer dataset to support a clustering time dependent analysis to characterize the Pandemic evolution in Brazil. These results may be explored in future deprivation social studies."}
+{"text": "Identity and integrity  are important elements for psychosocial development in later stages of life as described in Erikson\u2019s life-span developmental theory. This study aimed to develop an intervention program to increase the sense of identity and integrity among older adults. The program included two types of workshops to examine the combined impact of searching for one\u2019s post-retirement identity and clarifying personal goals and purpose for later life. The first workshop, Introductory of Active Aging, focused on providing the knowledge and skills necessary to prepare for life after retirement. The second workshop, Creating Your Life History, focused on a life review and composing one\u2019s life history using the guided autobiography method developed by Birren. The study used a crossover design with a one-week break interval between the two workshops. Each workshop was conducted weekly with a two-hour session over four weeks. Thirty-eight participants aged 60 to 80 attended both workshops between October and December 2021 at a community center in Tokyo, Japan. The sense of identity and integrity were assessed using the Japanese version of the Erikson Psychosocial Inventory Scale (EPSI) at baseline and after completing both workshops (9th week). The scores of both identity and integrity increased significantly among participants who completed two workshops in sequence. This crossover study showed no statistical difference in the effects of each workshop. Further work is needed to monitor the long-term impact of these workshops in clarifying one\u2019s identity and achieving satisfaction with self in later life."}
+{"text": "Recently video gaming, have attracted considerable attention for its possible beneficial therapeutic effects, the possibility for testing behavior in safe artificial environments and as a tool for professionals and patients to build specific competencies for the everyday life. Also, a substantial amount of research suggests that videogaming might improve the participants social and cognitive skills and emotional regulation. There is little or no evidence that videogaming increases long term aggression or leads to physical aggression. At a medium secure forensic psychiatric in-patient ward, the patients and staff engage in weekly E \u2013 Sport sessions (primarily counterstrike) to further the recovery process.To provide a standardized description of how E-sport is organized and used in the recovery process among forensic psychiatric patients.The Template for Intervention Description and Replication (TIDieR) checklist and guide is widely used to in health research to describe interventions in clinical trials and other health research contexts. By use of TIDieR we describe a newly developed E-sport intervention, in which staff members and patients in a medium secure forensic psychiatric ward engage in weekly E-Sport sessions (primarily counterstrike) to improve patient\u2013staff relationship.The E-sport intervention is detailed by use of the 12 TIDieR items and practical experiences and insights will be described.This standardized and detailed description of how is used in a recovery-oriented process in forensic psychiatry can be used for future studies that wishes to implement the intervention or for research studies replicating the treatment.No significant relationships."}
+{"text": "Psychological responses to an impending or recent death have received minimal attention in the research literature. I will present data to demonstrate the high levels of psychological distress  reported by caregivers of a loved one with a life-threatening illness. I will report on studies that have examined how grief symptoms change over time, or not, as in the case of symptoms of Prolonged Grief Disorder (PGD) \u2013 a new addition to the Diagnostic and Statistical Manual of Mental Disorders -5-Text Revision (DSM-5-TR). A case will then be made for addressing psychological struggles of caregivers of patients who are dying in the intensive care unit (ICU). I will then present a conceptual model and manual of our psychosocial intervention (EMPOWER), which we designed to reduce symptoms of PGD and posttraumatic stress disorder (PTSD) by targeting symptoms of experiential avoidance and promoting adaptive coping."}
+{"text": "Limited research explores the contextual and cultural nuances within African American dementia dyads within the United States and how these factors influence decision-making processes. Through a secondary data analysis of semi-structured interviews, we examined decision-making processes in five African American dementia dyads related to how they navigated decisions for the person living with Alzheimer\u2019s disease and related dementias (ADRD) across five unique contexts . Analysis revealed that within dyads, persons living with ADRD were involved in the decision-making processes, but the level of the involvement in decision making by the caregiving networks varied across dyads. Understanding the context in which decisions are made  has important implications in clinical practice and research. Interventions should be tailored to reflect these contextual and cultural nuances."}
+{"text": "Trait-like anomalies of subjective experience have been empirically identified as schizophrenia-specific markers of vulnerability in several clinical and genetic high-risk populations. Recently, Parnas and colleagues have identified and preliminarily explored a composite score  within the Minnesota Multiphasic Personality Inventory (MMPI) that approximates such construct). SDO differs from the MMPI psychoticism scale, and includes presents items very similar to Self Disorder investigated by EASE .This study is a confirmatory analysis of the correspondence of Self-Disorder Scale (SDO) of the MMPI with some items of EASE, in a population of adolescents. These items are present in psychotic and in at risk mental state subjects.We administered MMPI and EASE to 34 help seeker adolescent patients and correlate all dimensions of MMPI with EASE total score and its domains.MMPI SDO scores significantly correlated with schizophrenia-spectrum diagnosis and high-risk mental states.SDO is an MMPI analogous of Self Disorders and can be used as a useful screener to detect patients at potential risk for schizophrenia spectrum disorders, that could be further explored with the EASE.No significant relationships."}
+{"text": "Important conceptual and methodological advances have been achieved in the last decades with a significantly better understanding of the anatomic and functional connectivity of the brain , or the so-called \u201cminimal common brain\u201d  Radiological advances in neuroimaging of white matter; (2) Effect of radiotherapy on patients performance in a high eloquent area; (3) Clinical/surgical implication of diffuse gliomas in eloquent areas; (4) White matter plasticity.Brabec et al. in an original study investigated tumor-related hyperintensities and white matter signals with both linear and spherical tensor encoding (LTE and STE). Their goal was to investigate whether STE could be used to suppress white matter signals and enhance the conspicuity of glioma hyperintensities unrelated to white matter. The results of this study suggest that STE-DWI may be relevant in clinical settings for diagnosis or radiotherapy planning, where the presence of a pathology-related hyperintensity may improve detection or delineation. STE-DWI could also be useful to visualize tumor-related hyperintensities within white matter tracts which may be not visible with LET-DWI, contributing to the differential diagnosis between shifted/dislocated and infiltrated white matter fibers. The authors found that the highest signal differences between LTE-DWI and STE-DWI were observed predominately in major white matter tracts suggesting that the inclusion of STE-DWI in as a complementary diffusion sequence would be able to better show lesions \u201chidden\u201d under white matter in these tracts.Two articles in this issue focused on neuroimaging of white matter in patients with gliomas. Friedrich et al., who investigated the impact of different types of damage on the fiber architecture of the affected white matter in patients treated for gliomas. The authors analyzed patients during the post-treatment follow-up with morphological MR, O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET images, and Constrained spherical deconvolution (CSD) algorithm to detect fiber density. They also compared the results with the patients' global performance status. They found that the structural and metabolic imaging changes after multimodal therapy in glioma patients were associated with a significant reduction in local white matter fiber density. The total fiber loss in contrast-enhancing lesions and T2/FLAIR hyperintense regions was associated with a significant risk of lowered performance status, while the total fiber loss caused by resection and regions with increased FET uptake did not impact general performance. This study suggests that apart from resection cavities, reduction in local fiber density is greatest in contrast-enhancing recurrent tumors, but total fiber loss induced by edema or gliosis or damage related to radiotherapy has an equally detrimental effect on the patients' performance status due to the large-scale white matter networks affected.Advances in neuroimaging of white matter in gliomas were also described by Chavaz et al., which investigated the spectrum of neurological triad improvement  in patients with DIPG treated by re-irradiation (re-RT). Patients at first progression were assessed by clinical benefits on neurological triad and were categorized as \u201cresponding\u201d or \u201cnon-responding\u201d to re-RT. The authors conclude that a median re-irradiation dose of 20 Gy may provide a neurological benefit in two-thirds of patients with an improvement of at least one symptom of the triad, but the survival from the start of re-RT to death was not different between responding and non-responding DIPG patients.The impact of oncological treatment in gliomas on performance status is even more important in cases where the surgery is not possible for instance in diffuse intrinsic pontine glioma (DIPG). This aspect was considered by Aabedi et al., summarized in a review paper the actual knowledge regarding the clinical implications of gliomas involving white matter language tracts. In this article, the authors discussed the advantages and limitations of methods commonly used to identify white matter tracts during surgery proposing a multimodal mapping paradigm to optimize postoperative language outcomes. This review also provided a discussion on local and long-range adaptations that take place as the language network undergoes remodeling after tumor growth and surgical resection. Some of the probable cellular mechanisms underlying this plasticity were also discussed in this article. Their contribution gives an overview of emerging developments in targeting the glioma-neuronal network interface to achieve better disease control and promote recovery after injury.On the other hand, for supratentorial gliomas, the possibility to achieve a complete surgical resection remains one of the most important prognostic factors. A total or supra-total resection in tumors harboring language areas/networks still represents one of the major challenges in neurosurgical practice. Duffau, provides details regarding the role of myelin plasticity in gliomas. The goal of this review article was to describe the implications of constant interactions between WM tracts and gliomas. The author discusses literature results on the interaction between white matter and gliomas through the myelin status, also concerning the origins of this tumor, the patterns of dissemination of glioma cells, and the functional consequences of glioma infiltration on personalized management. In addition, this article suggests new directions for a more individualized treatment plan and new research targets in patients with gliomas.One of the most intriguing theories to promote recovery after injury is linked to the possibility to increase white matter plasticity, which has been considered impossible or very low in the past times. In his review article This Research Topic provides new insights into neuroimaging techniques, available treatment options, and future directions for individualized treatment in patients with gliomas. The necessity to tailor both surgical resection and irradiation planning based on the patient-specific anatomical/functional organization but also to the infiltration pattern along white matter fibers seems already necessary to improve the onco-functional balance at the individual level Duffau, . New neuFurther studies are needed in all the fields of neuro-oncology to achieve better results for these patients. Only a multimodal, multidisciplinary and open-minded approach to this disease would be able to decode and change the interplay between brain white matter and gliomas.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
+{"text": "The difficulties in social interaction present in individuals with autism spectrum conditions may are related with the abnormal attentional processing of emotional information. Specifically, it has been hypothesized that the hypersensibility to threat shown by individuals with autism may explain an avoidance behaviour. However, this hypothesis is not supported by research and the underlying psychological mechanisms of social interaction in autism still unclear.The aim of the present study was to examine attentional processing biases by administering a computer-based attentional task in a sample of 27 children with autism spectrum conditions and 25 typically developed participants (age 11-15 years).The initial orienting of attention, the attention al engagement, and the attentional maintenance to different emotional scenes in competition  were measured by recording the eye movements during a 20 seconds free-viewingtask.The main findings were: i) children with autism spectrum conditions showed an initial orientating bias towards threatening stimuli; and ii) while typically developed children revealed an attentional engagement and attentional maintenance bias towards threatening stimuli, children with autism spectrum conditions did not.The findings of the present study are consistent with the affective information processing theories and shed light on the underlying mechanisms of social disturbances in autism spectrum conditions."}
+{"text": "Two pairs of biological systems acting over long distances have recently been defined as major participants in the regulation of physiological and pathological tissue reactions: i) the nervous and vascular systems form various blood-brain barriers and control axon growth and angiogenesis; and ii) the nervous and immune systems emerge as key players to direct immune responses and maintain blood vessel integrity. The two pairs have been explored by investigators in relatively independent research areas giving rise to the concepts of the rapidly expanding topics of the neurovascular link and neuroimmunology, respectively. Our recent studies on atherosclerosis led us to consider a more inclusive approach by conceptualizing and combining principles of the neurovascular link and neuroimmunology: we propose that the nervous system, the immune system and the cardiovascular system undergo complex crosstalks in tripartite rather than bipartite interactions to form neuroimmune cardiovascular interfaces (NICIs). Caenorhabditis elegans) to fruit flies (Drosophila melanogaster) to zebra fish (Danio rerio) have expanded current notions regarding the functionality of the relationships of three systemically acting tissues: the nervous system, the immune system and the cardiovascular system. Whereas C. elegans have developed a well-organized nervous system consisting of 302 stereotyped neurons , they lack a cardiovascular system. However, they have acquired an emerging primitive innate immune system consisting of sessile muscle cells that are capable of phagocytosis of danger-signaling macromolecules including infectious organisms. Of note, this nematode innate immune system is regulated by neuronal inputs   . We phen (ATLOs) . Subseqund CCL19 . These igression . Meanwhigression .In parallel studies, we searched for molecular cues of a poorly understood form of dementia, i.e., vascular dementia, that had previously be linked to Alzheimer\u2032s disease: Distinct brain areas including the choroid plexus and areas heavily burdened by Alzheimer plaques in mouse and human brains were examined in parallel with murine and human atherosclerotic plaques. Interestingly, the classical complement component C1q was found to form high-affinity complexes with Apolipoprotein E and inhibition of the C1q-mediated inflammatory pathway using siRNA treatment in mice reduced both atherosclerosis and Alzheimer plaque (intermediate) burdens . Using lAll these studies raised the possibility that ATLOs may be a model to study how the atherosclerotic arterial wall may directly crosstalk with the peripheral nervous system. Using a multitude of imaging methods including tissue clearing, we recently observed that the components of the peripheral nervous system in the artery adventitia adjacent to atherosclerotic plaques underwent marked restructuring . AtherosFuture work should be directed towards a more detailed understanding of the morphology and function of the adventitia and other peripheral nervous system NICIs. These studies would characterize the axon tips in the adventitia of diseased artery segments using quantitative electron microscopy and morphologically delineate the neuroimmune junctions. Moreover, a more complete functional characterization of the sensory nervous system including the pain receptors/nociceptors on atherosclerosis progression may yield new information on the adventitia NICI when scRNA-seq approaches are employed . We also"}
+{"text": "Evidence from clinical trials has traditionally been used to support regulatory drug approval, whereas real-world evidence (RWE) has been used for post-marketing surveillance studies. With the enaction of the 21st Century Cures Act, the Food and Drug Administration (FDA) is evaluating the potential use of RWE to support new indications for an approved product or to satisfy post-approval study requirements. Yet the substantial evidence standard remains unchanged for FDA approval. To date, the FDA has issued guidelines or frameworks for using RWE for regulatory decisions. However, many methodological challenges remain unanswered when using RWE in gerontology research. This Pharmaceutical Care and Outcomes Research Interest Group-sponsored symposium consists of leading experts in the country to address these problems. The four papers in this symposium will address methodological challenges that are unique in gerontology research. Specifically, The first paper will introduce the FDA drug evaluation process, focusing on the key considerations for evaluating RWE in regulatory decision making; the second paper will discuss possible challenges related to data sources from which RWE are generated in aging research; the third paper will provide a case example of some of the challenges in using RWD sources to generate RWE in the Alzheimer\u2019s Disease setting; and the fourth paper will provide recommendations for improving gerontology research based on RWE going forward."}
+{"text": "Physical activity participation is a preventive factor in improving physical and cognitive functions. Both physical and social environments are essential in evaluating older adults\u2019 opportunities to participate in physical activities. This study aims at assessing the multidimensional environment in physical activity participation and examining how the change in the multidimensional environments could affect their participation in physical activities.This paper combined the nationally representative data, the China Longitudinal Aging Social Survey data 2014\u20132018, and the county-level administrative data extracted from various statistical yearbooks. It used the latent variable cross-lagged panel model to capture the dynamic relationship between environment and physical activities. Additionally, the dynamic analytical model considers a multidimensional environment, including indoor-, outdoor-, human-, social-environment, etc., by adding the latent variables.The descriptive statistics show that older adults who are in a better environment  are more likely to frequently participate in physical activities (three times or more per week). The results of the latent cross-lagged panel models indicate that every one percent increase in the multidimensional environmental index is expected to cause a 4.1% increase in the likelihood of participating in physical activities among Chinese older adults. Discussion: In addition to the continuous efforts to improve the physical environment, policymakers and researchers should pay more attention to the social environment to encourage more older adults to participate in physical activities."}
+{"text": "Idiopathic rapid eye movement sleep behavior disorder (iRBD) is an important non-motor complication of Parkinson's disease. At the same time, iRBD is considered to be the prodromal stage of \u03b1-synucleinopathy. This high risk of conversion suggests that iRBD becomes a nerve It is a window for early research on degenerative diseases and is the best candidate for neuroprotection trials. A wide range of neuroimaging techniques has improved our understanding of iRBD as a prodromal stage of the disease. In addition, neuroimaging of abnormal iRBD is expected to be a potential biomarker for predicting clinical phenotypic transformation. This article reviews the research progress of neuromolecular imaging in patients with iRBD from the perspective of iRBD transforming synucleinopathies. Idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) is a parasomnia mainly characterized by the loss of muscular atonia and dream enacting behaviors during REM sleep , 2. The 123Iodine-metaiodobenzylguanidine (123I-MIBG) cardiac imaging.Currently, more and more studies are looking for early neuroimaging evidence of iRBD transformation in order to detect structural and functional abnormalities in the iRBD brain earlier . Among nConsidering all these factors, we review the latest research on molecular imaging between iRBD and \u03b1-synucleinopathies. The molecular neuroimaging markers that predict the early transformation of iRBD were the place we pay the closest attention to in this article. A comprehensive understanding and review of neuroimaging techniques to explore phenotypic conversion in iRBD will be able to guide future research in this field and further facilitate the clinical management of this disease.via a direct pathway. Intermediate neurons in turn inhibit glycinergic and gamma-aminobutyric acidergic neurons via spinal anterior horn motor neurons, resulting in skeletal during REM sleep skeletal muscle movements being inhibited during REM sleep  showed behavioral abnormalities during REM sleep similar to those of human RBD . PreviouEM sleep . In addiEM sleep . Under nEM sleep .18F] fluorodeoxyglucose (FDG) positron emission tomography (PET) is an assay targeting glucose metabolism visualization in the brain, with higher metabolic rates presenting high signal changes , which is the priority area for patients with MSA. In contrast, the other five patients showed hypermetabolic changes in the left cingulate gyrus, right frontal lobe and right temporal lobe, which are the preferentially affected regions of PD patients  was determined using ty of PD . Expressty of PD . TherefoSingle photon emission computed tomography is a neuroimaging tool to measure regional cerebral blood flow (rCBF) . Using SThe main pathological alteration in PD is degeneration of the substantial nigra-striatal dopaminergic pathway . StriataIn vivo study of noradrenergic changes in 17 patients with iRBD using 11C-MeNER as a tracer revealed that tracer uptake levels were decreased in the locus coeruleus to the thalamus and red nucleus regions in patients with iRBD compared to normal controls  cardiac imaging is a commonly used imaging technique to diagnose cardiac sympathetic function , and Henan Province Medical Science and Technology Tackling Provincial Ministry Key Projects (SBGJ202102033).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "A Primary Care Model Programme had been implemented in Hungary between 2013-2017 in which group practices were established that employed - among others - nonprofessional health workers  to facilitate access for the most disadvantaged population groups. The health of mediators, themselves mostly disadvantaged ethnic Roma, was monitored every odd year of the Programme.A repeated cross-sectional health interview survey had been implemented inviting all health mediators who were employed at the time of the survey. The same questionnaire was used in all 3 surveys with items from the European Health Interview Survey 2009 and validated versions of other scales.Positive changes occurred in the health status of mediators during 5 years of follow-up. Significant improvement in mental health occurred among those who completed on-the-job vocational training. By 2017, significant increase in sense of coherence was observed among those who obtained vocational qualification as opposed to those who did not. The proportion of highly stressed mediators showed a significant increase among those with no vocational training. Improvement was detected in all mediators in health awareness, dysfunctional attitudes, psychological stress and smoking prevalence.Significant improvement in mental status among those who obtained on-the-job vocational qualification were observed during follow-up of ethnic Roma health mediators in the programme in which they were equal members of the primary health care team. Employment of health mediators in primary care teams not only contributed to improving access to care for disadvantaged groups but also improved the mental health of mediators themselves.\u2022\u2002Nonprofessional health mediators are important members of primary care teams servicing disadvantaged populations.\u2022\u2002Significant improvement in mental status during 5 years of follow-up occurred among Roma health mediators who received vocational training and were equal members of primary health care teams."}
+{"text": "This mini-review focuses on current knowledge regarding maternal regulation of the paternal genome in early embryos of mammalian livestock species. Emphasis has been placed on regulatory events described for maternally imprinted genes and further highlights transcriptional regulation of the post-fertilization paternal genome by maternal factors. Specifically, the included content aims to summarize genomic and epigenomic contributions of paternally expressed genes, their regulation by the maternal embryo environment, and chromatin structure that are indispensable for early embryo development. The accumulation of current knowledge will summarize conserved allelic function among species to include molecular and genomic studies across large domestic animals and humans with reference to founding experimental animal models. Mammalian spermatozoa contain highly compacted chromatin, thus providing stability and protection from environmental influence during sperm transport within the female reproductive tract. The completion of spermatogenesis results in protamination of sperm chromatin to replace histones, resulting in tightly compacted and condensed chromatin within the nucleus of the mature spermatozoa . GenomicUnique genomic and epigenomic phenotypes of mature spermatozoa can include transgenerational inheritance stemming from environmentally induced modifications of the epigenome . Followide novo methylation established in the germline at ICRs that remain stable in somatic cells post-fertilization, thus maintaining parent-of-origin expression . Imprinting is an essential epigenetic mechanism that regulates monoallelic expression with the addition of a methyl group to the cytosine of genomic DNA, thereby preventing transcription stemming from the inability of transcription factors to access DNA and bind promoters . The inhpression . The secpression . Active pression . Such reDecades of research using mouse models have demonstrated that the paternal genome has a major influence on placental development . More reOCT4, which is restricted to inner-cell mass (ICM) lineages in mice but ubiquitous throughout trophectoderm and the ICM of cattle and human embryos (IGF2) is among the most well-described paternally expressed/maternally imprinted genes. Early developmental roles of IGF2 as a growth hormone appear regulated by the expression of the maternal growth suppressor PHLDA2, demonstrating the complex yet crucial role of maternal interaction with a paternally expressed growth factor , where transgenic loss-of-function in mice demonstrates a reduction and increase in birth weight, respectively (IGF2 include Beckwith\u2013Wiedemann (overgrowth) and Silver\u2013Russel (growth restricting) syndromes (www.geneimprint.com). Bovine MKRN3, MAGEL2, and NDN are three protein-coding maternally imprinted genes that are regulated by DNA methylation in placental tissues controlled by the PWS-DMR  located on chromosome 21 (human chromosome 15) in the promoter of the SNRPN gene  during spermatogenesis results in a densely methylated sperm genome except for CpG islands (CGIs) that are predominately hypomethylated in mature sperm  is an additional example of a maternal factor that asymmetrically remodels paternal and maternal bovine pronuclei and also drives ICM cell numbers in preimplantation embryos , which typically encode RNAs that are required for early embryonic development. Thus, the expression of MEGs is often more abundant in oocytes and then decreases until EGA. Knockdown of DPPA3 in bovine oocytes suggests a protective mechanism for the maternal pronucleus from 5mC oxidation to 5hmC as demonstrated by increased levels of 5hmC in DPPA3 knockdown embryos. In effect, DPPA3 may be described as a maternal transcript that regulates paternal zygotic gene expression by modulation of the epigenome in a parent-specific pattern. In humans, DPPA3 can inhibit TET2 and TET3 activities by directly binding to the catalytic domain of these enzymes. Like DPPA3, GSE (gonad-specific expression gene) preferentially binds to the paternal chromatin at the pronuclear stage and plays a role in the maintenance of 5mC as demonstrated by 5hmC accumulation in GSE knockdown mouse embryos (The precedence for epigenetic pathways of maternal origin that control the regulation of paternal contributions to early embryo development has been exemplified in plants, insects, and lower mammalian model species as evolutionary divergent . DPPA3 ( embryos . The pat embryos . Combinein vitro embryo production.The growth of -omics technologies in the 21st century, coupled with gene editing strategies, increased awareness of male fertility, and environmental factors that contribute to reproductive deficiencies has maneuvered most livestock industries toward genomics-driven approaches to reproduction that require a unique marriage to research in basic sciences. Advances to describe the regulation of gene expression and unique epigenetic modifications to the genome include key differences in parent-of-origin expression that appear species specific in many cases. Modulation of the paternal genome is partially regulated by the maternal environment and dependent upon protein, methyltransferases, and non-coding RNAs of maternal origin. The complexity of maternal regulation of the paternal genome requires further understanding of epigenetic mechanisms that may be inherent to the embryo or modulated by a dynamic and plastic environment stemming from oocyte development through the preimplantation embryo. Clear emphasis on research that addresses trophectoderm function to mitigate pregnancy loss has further illustrated the role of maternally imprinted genes in livestock embryos. The maternal regulation of paternally expressed monoallelic genes will ultimately influence reproductive efficiencies in livestock and other large animals where concern for gene\u2013environment interactions continues to develop as an emergent field required for global sustainability in food production with high relevance to"}
+{"text": "Frostbite is a localized cold thermal injury, as a result of tissue exposure to temperatures below freezing point for a prolonged period of time. The spectrum of injury is broad; thus, frostbite injuries may have deleterious effects with the possibility of losing part or whole extremities. We aim to present the case of a 38-year-old male patient evaluated with multiphase technetium-99m-methylene diphosphonate bone scintigraphy. This methodology may accelerate clinical management of frostbite injuries because it provides precise clinical-imaging correlation by determining the extent of injury and can accurately predict the level of amputation if required. Frostbite is a localized cold thermal injury, caused by tissue exposure to temperatures below freezing point for a prolonged period of time  for a prolonged period of time  bone scintigraphy may hasten clinical management of frostbite injuries as it furnish high and precise clinical-imaging correlation by determining the extent of injury and can accurately predict the level of amputation if required Fig.\u00a0 Mangana.The spectrum of injury is wide, and thus, frostbite injuries may have devastating effects with the possibility of losing part or whole extremities. Therefore, it is paramount for medical staff to have the proper knowledge of the benefits of imaging techniques to provide a certain diagnostic approach. Magnetic resonance and bone scintigraphy are superior to X-rays and allow early intervention in cases of severe frostbite, thus preventing secondary infection  bone scintigraphy assesses tissue viability in an effort to allow early debridement of soft tissue and early coverage of ischemic bony structures with an almost unerring accuracy: specificity 99% and sensitivity 96% .Bone scans can be used not only to predict tissue activity, but also to assess the response of the lesion to treatment. Reduced perfusion (not absent) indicates the possibility that viable tissue exists and needs specific therapy such as thrombolytic treatment (Gao et al. Imaging protocol includes a three-phase scan. Firstly, an early tissue phase or planar blood flow phase immediately after intravenous administration of 20\u201330\u00a0mCi 99mTc-MDP is useful to identify the vasculature and to delimit the level of vascularization (Fig.\u00a0Frostbite injuries may be varied and its clinical spectrum. However, it is complex to precisely identify viable tissue with only clinical examination. Hence, a variety of imaging diagnostic techniques have intended to address this rising issue with limited results. Bone scintigraphy provides a strong clinical-imaging correlation that identifies the depth and extent of tissue injury and can reliably predict the level of amputation if necessary."}
+{"text": "Clozapine is an atypical antipsychotic used in the management of Treatment-Resistant Schizophrenia (TRS). Despite its efficacy, Clozapine is associated with rare but clinically important haematological side effects of neutropenia and agranulocytosis, thus warranting regular monitoring of full blood count (FBC) white blood count (WBC) and neutrophil count (NC).Clozaril Patient Monitoring service (CPMS) supervises the prescribing of Clozapine and haematological testing for patients. Amber and Red alerts are issued by the CPMS when WBC and NC values fall below specified levels, Clozapine treatment is either suspended or discontinued completely.We present a case of 35-year-old Caucasian lady with a history of schizophrenia who was maintained on Clozapine treatment for 10 years and whose Clozapine was necessarily stopped because of red alerts. This lead to a significant deterioration in her mental state and level of functioning necessitating a prolonged hospital admission.Detailed retrospective review of this patient's CPMS results over a 2-year period identified consistently higher levels of WBC and NC, when the blood tests were conducted in the afternoon compared to mornings.Literature review supported the phenomenon of a diurnal variation of WBC and NC levels in a proportion of patients prescribed Clozapine.With clear knowledge of this patient's diurnal trends in WBC and NC count, it was possible to liaise with CPMS and restart her Clozapine treatment, leading to a significant improvement in her mental state and level of functioning.We recommend that clinicians consider this phenomenon of diurnal variation in blood parameters in patients with frequent amber and red alert results who are at risk of having their Clozapine medication discontinued.Close collaboration with CPMS and haematological advice may lead to a more nuanced approach to blood sampling, whereby afternoon samples are used in certain at-risk patients."}
+{"text": "ADHD is associated with impairments in different inhibitory functions, including suppression of an already initiated response and inhibition of distracting information. This work used a protocol that combines the Stroop-matched and stop-signal tasks to examine the association between the frequency of ADHD symptoms and different inhibitory abilities in a young adult.To investigate how the symptoms of inattention and hyperactivity / impulsivity are associated with three forms of inhibition evaluated by the Stroop-matched / stop-signal task: inhibiting an automatic response, controlling interference and canceling a response.38 participants  completed Adult ADHD Self-Report Scale (ASRS) assessing ADHD symptoms before performing the task. Reaction times, accuracy and stop-signal reaction time  were calculated for each task condition.There was a significant correlation of ADHD symptoms and SSRT in the condition with the higher perceptual load . This correlation was negative , which indicates that participants with higher ADHD symptoms frequency had more efficient inhibitory processes in this condition.(1) the perceptual load of the task influences the cancellation of responses; (2) individuals with higher frequency of ADHD symptoms may have a better inhibitory capacity when the perceptual load is high, possibly reflecting a lower availability of attentional resources to process distracting information.No significant relationships."}
+{"text": "Prenatal maternal stress is an important phenomenon. Evidence on this topic suggests that women who experience high stress during pregnancy are more likely to deliver preterm infants.The goal of this study was to evaluate the influence of Yoga exercises training on stress reduction during pregnancy.In the current study we included 20 women who participated in the Yoga exercises training during pregnancy. The control group included 20 women who were in the reading control condition during pregnancy. Women were eligible to participate if they were experiencing elevated levels of perceived stress or pregnancy-specific anxiety (PSA), as indicated by responses to the Perceived Stress Scale and the PSA scale on a screening questionnaire. Women enrolled between 12 and 26 weeks gestation were randomly assigned to either the Yoga exercises training or to the reading control condition. Effects of training were analyzed by means of an ANOVA with repeated measurements.ANOVA has revealed (p<.05) that women in the Yoga exercises training experienced larger decreases from pre- to postintervention in pregnancy-specific anxiety and pregnancy-related anxiety than participants in the reading control condition.This pilot study suggests that Yoga exercises training during pregnancy can effectively reduce pregnancy-related anxiety. However, it is necessary to do further research on the impact of Yoga exercises on stress reduction during pregnancy."}
+{"text": "The COVID-19 pandemic has led to physical distancing measures across a range of countries to control the spread of the virus. Evidence referring to contact dynamics in different socioeconomic populations is still sparse and may contribute to the explaining of socioeconomic inequality of infections.Data came from two early COVID-19 hotspots in Germany using the CORONA-MONITORING-lokal study (CoMoLo). The sample  was restricted to working age (18-67 years). We calculated the association of individual education and occupation status  and self-reported private and professional contact reductions. Using weighting factors , we performed multivariate Poisson regressions  with different sets of covariates: hotspot, age, sex, country of birth, household size, contact level before physical distancing measures and home office.The descriptive analyses show a clear socioeconomic gradient in private  and professional contact reductions . The multivariate analyses confirm these associations, with a stronger gradient for professional contacts  as well as for professional contact reduction when occupational status is considered instead of education.Our results show disadvantages in groups with lower educational or occupational status in private and professional contact reductions in the first pandemic wave. This might result in a higher risk of infection. Preventive measures that a) adequately explain the importance of contact restrictions and b) facilitate the implementation of these reductions seem necessary to better protect structurally disadvantaged people during epidemics.\u2022\u2002Groups with lower educational or occupational status were less likely of being able to reduce their private and professional contacts in the first wave of the pandemic.\u2022\u2002Socioeconomic differences were more pronounced in professional contact reduction compared to private contact reduction."}
+{"text": "Bioengineering and Biotechnology. Ten papers were accepted for publication from 18 open submissions. A summary of these accepted papers is outlined below.Biomedical intelligence, especially precision medicine, is considered as one of the most promising directions in healthcare development. However, these technologies have also brought new challenges and issues. In 2021, this research topic was supported by Frontiers again and included three collaborating journals, namely, Frontiers in Genetics, Frontiers in Public Health, and Frontiers in Cancer B Hepatocellular Carcinoma Achieving Complete Response: An Individualized Risk-Based Machine Learning Study\u201d by Qi-Feng Chen et al., the authors proposed a retrospective, real-world study on surveillance strategies for Barcelona Clinical Liver Cancer stage B hepatocellular carcinoma (BBHCC) patients with complete response (CR) after curative treatment to support clinical decision making. The data in this paper were collected from the Cancer Center of Sun Yat-sen University, part of which were used as training dataset and the rest as validation dataset. The random survival forest method was applied to calculate the disease progression hazard per month, and follow-up schedules were arranged to maximize the capability of progression detection at each visit. The primary endpoint of the study was the delayed-detection months for disease progression. The proposed new surveillance schedule may provide a new perspective concerning follow-up for BBHCC patients with CR.In the paper entitled \u201cSurveillance Strategy for Barcelona Clinic Liver In the paper entitled \u201cDeep Learning Assisted Neonatal Cry Classification via Support Vector Machine Models\u201d by Ashwini K et al., the authors presented a short-time Fourier transform (STFT) technique to transform the neonatal cry auditory signals into a spectrogram image. The deep convolutional neural network (DCNN) was used to extract features for neonatal cry classification with spectrogram images as input. Support vector machine (SVM) was used as the classifier based on the features automatically extracted. The study showed that the combination of using DCNN-based feature extraction and using the SVM classifier provided promising results. Specifically, the RBF kernel provided the highest classification accuracy of infant cry.Cancer Based on LASSO\u201d by Ke Xue et al., the authors proposed a risk-scoring model to identify potentially robust predictors of metastasis through a minimal number of genes. Enrichment analysis of differential gene expression from multiple datasets was used to gain insight into the mechanism of pancreatic cancer metastasis. The study showed that six Epithelial-Mesenchymal Transition related genes can be used to reliably predict pancreatic cancer metastasis, assess clinical outcomes, and facilitate future personalized treatment for patients with ductal adenocarcinoma of the pancreas.In the paper entitled \u201cIdentification of Key mRNAs as Prediction Models for Early Metastasis of Pancreatic In the paper entitled \u201cAn Intelligent Control Model of Credit Line Computing in Intelligence Health-Care Systems\u201d by Rong Jiang et al., the authors introduced a dynamic permission intelligent access control model that incorporated a credit line calculation to reduce the risk of patient privacy leakage when medical data are accessed. More specifically, the credit limit and credit interval according to the authorization rules were matched to control the access intelligently. The proposed method was validated using real patient data provided by a Grade-III Level-A hospital in Kunming, China.Cancer Post-hepatectomy Using Machine Learning and Study of Correlation With Immune Infiltration\u201d by Xiaowen Qian et al., the authors introduced an mRNA-based model to predict the risk of recurrence after hepatectomy for liver cancer and explore the relationship between immune infiltration and the risk of recurrence after hepatectomy. This paper investigated gene expression profiles of liver cancer patients, and selected 18 mRNAs as biomarkers for predicting the risk of recurrence of liver cancer using a machine learning method. The authors evaluated the immune infiltration of the samples and conducted a joint analysis of the recurrence risk of liver cancer. These findings are helpful for early detection, intervention, and the individualized treatment of patients with liver cancer after surgical resection. The scientific novelty in this paper is that it uses Machine Learning to forecast the recurrence risk of liver cancer post-hepatectomy.In the paper entitled \u201cRecurrence Risk of Liver In the paper entitled \u201cTwo-stage Deep Neural Network via Ensemble Learning for Melanoma Classification\u201d by Jiaqi Ding et al., the authors presented an ensemble method that can integrate different types of classification networks for melanoma classification. U-net was used to segment the lesion area of images to generate a lesion mask, thus resizing images to focus on the lesion. In addition, a squeeze-excitation block was added to models to emphasize the informative features. Then, five classifiers were used to classify dermoscopy images. Finally, the proposed ensemble network was used to integrate the classification results from the five classifiers. The proposed classification framework was validated using the ISCI 2017 challenge dataset with good result. The scientific novelty in this paper is that it uses Deep Neural Network to make full use of the rich and deep feature information of images for melanoma classification.Cancer Gene Panel Discovery\u201d by Hui-O Chen et al., the authors introduced a pipeline that can contextualize genes by using text-mined co-occurrence features. Biomedical Natural Language Processing (BioNLP) techniques were used for literature mining in the cancer gene panel. The produced cancer gene panel was validated with the mutational landscape of different cancer types. The receiver operating characteristic (ROC) curve analysis confirmed that the neural net model has a better prediction performance. The key insight is that the use of text-mined co-occurrence features can contextualize each gene. This study examined several existing gene panels and demonstrated that part of the gene panel set can be used to predict the remaining genes for cancer discovery.In the paper entitled \u201cCombining Polygenic Risk Score and Voice Features to Detect Major Depressive Disorders\u201d by Yazheng Di et al., the authors proposed a biomarker of major depressive disorders (MDD) by combining the polygenic risk scores (PRSs) and voice features. Data in this study were collected from 3,580 women with recurrent MDD and 4,016 healthy people. PRS was constructed as a gene biomarker by p value-based clumping and thresholding. Voice features were extracted using the i-vector method. n the paper entitled \u201cContextualizing Genes by Using Text-Mined Co-Occurrence Features for In the paper entitled \u201cClassification of Diabetic Foot Ulcers Using Class Knowledge Banks\u201d by Yi Xu et al., the authors presented a method that used class knowledge banks (CKBs) consisting of trainable units to effectively extract and represent class knowledge, and to better utilize the knowledge in the training data. Each unit in a CKB is used to compute similarity with a representation extracted from an input image. The averaged similarity between units in the CKB and the representation can be regarded as the logit of the considered input. In this way, the prediction depended not only on input images and trained parameters in networks, but also on the class knowledge extracted from the training data and stored in the CKBs. The experimental results showed that the proposed method effectively improved the performance of diabetic foot ulcers infection and ischemia classifications.\\In the paper entitled \u201cChronological Age Prediction: Developmental Evaluation of DNA Methylation-Based Machine Learning Models\u201d by Haoliang Fan et al., the authors proposed a blood epigenetic clock in Southern Han Chinese (CHS) for chronological age prediction with machine learning algorithms. The correlation coefficient was analyzed for the experimental individuals to select five genes from a candidate set of nine age-associated DNA methylation (DNAm) biomarkers. The DNAm-based profiles of the CHS cohort were generated by the bisulfite targeted amplicon pyrosequencing (BTA-pseq) from 34 cytosine-phosphate-guanine sites of five selected genes. These four chronological age prediction models were evaluated using several machine learning algorithms, including stepwise regression, support vector regression, and random forest regression. The random forest regression appeared to achieve the best performence with a median absolute deviation of 1.15 years for the targeted cohort.In conclusion, we would like to thank all the authors who submitted their original articles to our Research Topic. We highly appreciate the contributions of the reviewers for their suggestive comments. We would also like to acknowledge the guidance from the Editor-in-Chief and staff members of Frontiers."}
+{"text": "The activity of the hypothalamic-pituitary-adrenal (HPA) axis is characterised by complex dynamics spanning several timescales. This ranges from slow circadian rhythms in blood hormone concentration to faster ultradian pulses of hormone secretion and even more rapid oscillations in electrical and calcium activity in neuroendocrine cells of the hypothalamus and pituitary gland. Here, we focus on the system's oscillations on the short timescale. We highlight some of the mathematical modelling and experimental work that has been carried out to characterise the mechanisms regulating this highly dynamic mode of neuroendocrine signalling and discuss some future directions that may be explored to enhance understanding of HPA function. \u2022Fast dynamics in HPA axis activity is important for physiological function.\u2022Coupling mathematical modelling and experimental approaches can shed light on the mechanisms underlying these dynamics.\u2022Recent computational and experimental advances are enabling a deeper understanding of the system at multiple scales. Oscillatory dynamics underlies neuroendocrine signalling and control. The stress-responsive hypothalamic-pituitary-adrenal (HPA) axis is a good example of this, where the pulsatile release of vital glucocorticoid hormones  from the adrenal glands results in an ultradian oscillation in blood glucocorticoid concentration. The mean period of these oscillations varies between species, and is typically approximately hourly in rodents , and 1\u20133Central control of glucocorticoid secretion is mediated by neurons in the hypothalamic paraventricular nucleus (PVN) expressing corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP). These neuropeptides are released into the hypophyseal portal vessels at the median eminence, thus stimulating adrenocorticotrophic hormone (ACTH) secretion from anterior pituitary corticotroph cells. In turn, ACTH stimulates the synthesis and secretion of glucocorticoids from the adrenal cortex. Glucocorticoids exert their influence over a wide range of timescales, and these effects are mediated by both the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) . GlucocoMicrodialysis studies have shown that the ultradian glucocorticoid oscillation in the blood is paralleled within brain tissue ,7. SeverThe amplitude of the ultradian glucocorticoid rhythm is modulated in a circadian manner by the hypothalamic suprachiasmatic nucleus (SCN) through direct and indirect connections to the PVN, which regulate CRH gene expression and CRH secretion. The sensitivity of the adrenal cortex to ACTH is also under circadian control with sensitivity peaking during the active phase; an effect that appears to be dependent on a direct SCN polysynaptic neuronal connection to the adrenal via the autonomic nervous system  as well The question of how the HPA axis generates ultradian pulsatile dynamics in hormone secretion has remained a puzzle ever since episodic cortisol secretion was observed in man over half a century ago . UltradiNeural signalling to the anterior pituitary is encoded in the dynamic patterns of hypothalamic peptides released into the hypophyseal portal vessels. This has led to the basic hypothesis that there exists a neural oscillator generating pulsatile bursts of CRH/AVP secretion, in turn driving pulsatile secretion of ACTH and glucocorticoids; a concept that bears strong similarity to the tightly correlated pulsatile secretion of gonadotrophin-releasing hormone and luteinizing hormone . Indeed,To date, there has been relatively little biological description of the neural oscillator mechanism(s) involved in controlling PVN activity and the pulsatile secretion of CRH and AVP, and this is perhaps the main reason for the lack of modelling impetus in this area. Ex\u00a0vivo studies demonstrating episodic CRH release from cultured hypothalamic explants from the macaque suggest that an oscillator mechanism resides within the hypothalamus . UltradiAnother hypothesis, which has been proposed and explored primarily through mathematical modelling, has been that the negative feedback action of glucocorticoids on the system can cause it to become dynamically unstable, giving rise to ultradian oscillations in secretory activity. In this scenario, the system as a whole would function as a pulse generator. Ultradian oscillations have been explored through systems of differential equations in which variables describe the overall secretory activity of an entire cell population; mathematical analysis of these \u201cblack box\u201d models of the HPA axis has shown that an ultradian oscillation can indeed arise from negative glucocorticoid feedback in the system. Most models have considered negative glucocorticoid feedback at the level of both the hypothalamus and the anterior pituitary, and it is this dual-feedback mechanism that generates the system-level ultradian oscillation .A key feature of dual-feedback models is that the CRH, ACTH and glucocorticoid oscillations are generated at the same frequency. However, some experimental studies have found a lack of tight concordance between basal CRH/AVP secretion and ACTH and glucocorticoid pulsatility , as wellWork suggesting that feedforward and feedback interactions between the pituitary and adrenal can give rise to ultradian oscillations in the system implies that the corticotroph cells of the pituitary play a central role in controlling the dynamics of the system: these cells must integrate the dynamic output from the hypothalamus and the oscillatory activity generated within the pituitary-adrenal system. Mathematical models of corticotroph activity have focused on describing the mechanisms of action potential firing, primarily through the Hodgkin-Huxley formalism. In particular, systems of ordinary differential equations describing several ionic currents present in these cells have been used to describe their spontaneous and secretagogue-induced electrical activity.Ca-L) and to a lesser extent for T-type, in the generation of action potentials. While these models mainly focus on the central role of calcium currents, they also account for potassium currents. These include the delayed-rectifier potassium channels (IK-dr) and the voltage and calcium-activated (IK\u2013Ca) large conductance potassium (BK) and small conductance potassium (SK) channels.Action potentials in corticotrophs are calcium-dependent and associated with rises in intracellular calcium concentration . Early mThe role of potassium channels has been explored in detail in later models, specifically for analysing secretagogue-induced firing ,37. Thesnear and BKfar) distinguished by their spatial association with L-type calcium channels [near channels represent stress-regulated exon (STREX)-type channels, while BK-far channels represent ZERO-type BK channels lacking the STREX exon. There is currently no experimental proof of the physical association of these variants with calcium channels in corticotrophs; however, recent modelling and experimental results indicate that an increase in the association between BK and calcium channels and a change in their activation constant could underlie the changes in firing activity recorded in chronic stress [BK channels play a central role in mediating the spiking-to-bursting switch. CRH reduces BK currents in a PKA-dependent manner ,40; pretchannels . It has c stress .Contrary to CRH, stimulation with AVP only increases firing frequency without changing the firing pattern , althougWe have highlighted some of the modelling and experimental approaches that have been used to investigate the fast and complex dynamics of the HPA axis. These models have helped to deepen our understanding of the system's behaviour, yet many questions remain. Here, we identify some of the challenges that we believe can be addressed through a combination of experimental and modelling approaches informing each other.It is the case for most models that complexity comes at the cost of scale; system-wide models consider each of the compartments of the axis as \u201cblack boxes\u201d, while models exploring the role of molecular components are generally limited to single cells. Recent improvements in computing power should allow linking these spatial scales and defining system-wide models consisting of individually modelled cells. Such multiscale models may allow exploration of the impact of changes of single cell function on system-level dynamics. In addition, they may enable understanding of the role of cellular heterogeneity in the HPA system, which has been experimentally described at the level of electrical activity , calciumThe generation of multiscale models will require a deeper biological understanding of the molecular processes at the level of single corticotrophs, such as the intracellular pathways and cellular dynamics controlling the secretion of ACTH from vesicles. Understanding how corticotrophs communicate with each other and with other pituitary cell types will enable linking single-cell function to tissue-level population activity. Functional cellular networks have been described for other cell types in the pituitary , but it Beyond understanding the \u201cbasal\u201d dynamic function of the HPA axis, mathematical models of this system can be adapted to explain how its dynamic activity changes depending on the physiological or environmental context. This has been explored for conditions such as acute psychological stress  and infl10.13039/501100000265Medical Research Council (MR/N008936/1). NR acknowledges financial support from the\u00a0Medical Research Council (MR/V012290/1).JJW acknowledges financial support from the Nothing declared."}
+{"text": "A large body of research has confirmed that from childhood to old age most individuals feel significantly younger or older than their chronological age. Up to now, however, there is no clear theoretical understanding as to why younger adults tend to feel on average older and older adults tend to feel on average younger. We adopt a motivated social-cognition perspective on subjective age and examine age-differential antecedents and correlates of subjective age across the adult life span. Results from a cross-sectional study  and a 9-month longitudinal study  highlight the dynamic link between subjective age bias and individual (motivation and emotion) as well as social factors . We discuss the role of reciprocal dynamics between individuals and social contexts in explaining why individuals adopt a younger or older subjective age."}
+{"text": "Electronic healthcare records (EHR) are the main data sources that facilitate epidemiology research. Routinely collected data such as primary and secondary care are now easily linked to produce novel and high impact research. There are, however, rich data locked in the free text of clinical letters that are not otherwise translated into EHRs. It is highly desirable to be able to extract this information to strengthen the body of information in existing EHRs.The Swansea Collaborative in Analysis of NLP Research (SCANR) group at Swansea University has been established to evaluate the usage of Natural Language Processing platforms for obtaining new clinical data.To use Clix Enrich to extract SNOMED concepts from a variety of clinical free texts and produce EHRs from the extraction process. SNOMED concepts contain common items of interest such as diagnosis, medication and symptoms, as well as contextual concepts such as historical reference and negation. Clix Enrich uses the SNOMED dictionary to encode clinical free text (pre-co-ordinated) and find contextually correct SNOMED concepts (post co-ordinated). We used Clix Enrich to extract meaningful clinical terms from MS and Epilepsy consultant letters, as well as presenting complaint fields from a Welsh Emergency Department (ED). We tailored Clix Enrich to extract a wide variety of clinical terms from each source (fourty texts per source) and validated the extraction accuracy with clinical experts in each domain. Clix Enrich was able to accurately extract the correct diagnosis for MS, Epilepsy and ED attendance , dosage and frequency of anti-epileptic medication and MS modifying therapy  and EDDS score (94%). We note a probable source of discrepancy in extraction accuracy between letter sources in the frequency of abbreviated terms, particularly within the presenting complaint field of the ED sample. Clix Enrich can be used to accurately extract SNOMED concepts from clinical letters. The resulting datasets are readily available to link to existing EHRs, and can be linked to EHRs that adopt the SNOMED coding structure, or backward compatible hierarchies. Clix Enrich comes with out-of-the-box extraction methods but the optimum way to extract the correct information would be to build in custom queries, thus requiring clinical expertise to validate extraction."}
+{"text": "The multifaceted roles of Innate Lymphoid Cells (ILC) have been widely interrogated in tumor immunity. Whereas Natural Killer (NK) cells possess tumor-suppressive properties across multiple types of cancer, the other ILC family members can either promote or inhibit tumor growth depending on the environmental conditions. The differential effects of ILCs on tumor outcome have been attributed to the high degree of heterogeneity and plasticity within the ILC family members. However, it is now becoming clear that ILC responses are shaped by their dynamic crosstalk with the different components of the tumor microenvironment (TME) . Recent This Research Topic features several review and original research articles on the different facets of innate lymphocytes in the context of cancer. This includes basic underlying mechanisms of anti-tumor action as well as translational and clinical advances in this area of research. The topic spans different areas of NK cell as well as ILC research with emphasis on their role during tumor development and progression.NK cells are the prototype innate lymphoid cells exhibiting potent cytolytic function that provide host defense against infection and tumors. They are able to kill tumor cells if these show surface markers associated with oncogenic transformation. Due to this property NK cells control tumor growth at least in the early phase of tumor development and thus they are essential in tumor surveillance. Once target cells are recognized the balance of activating and inhibitory receptor signaling regulates their effector function against tumor targets . These pLi and O\u00b4Sullivan review the spatiotemporal dynamics of host factors (tissue-specific and systemic) that lead to progressive dysfunction of NK cells while a tumor progresses. These include heterogeneous tumor architecture, temporal disease states, diverse cellular subsets in the microenvironment and the complex changes in NK cell states in response to all these factors. Understanding of these different signals that NK cells are confronted with may help identify new therapeutic targets to increase effectiveness of NK cell therapy for cancer.NK cells are of utmost importance in host protection during tumor development. Seliger and Koehl. This review highlights different factors contributing to immune escape or immunosurveillance by NK cells as well as benefits and limitations in clinical NK cell-based immunotherapies such as adoptive cell transfer-based approaches and engineered NK cell-based immunotherapies. Supported by preclinical and clinical studies additional possibilities for NK cells in cancer patient treatment are suggested via combination therapies, potentially leading to further clinical advances.Based on the underlying mechanisms of tumor cell evasion from NK cells a rationale for improvement of NK cell-based cancer immunotherapies is presented by Tumino et\u00a0al. focus on polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and report on their strong suppressive effect on NK cell numbers and anti-tumor activity in patients with primary or metastatic lung tumors. By complementing in vitro cell culture experiments the authors revealed that exosomes derived from PMN-MDSCs are responsible for a reduced NK cell-mediated anti-tumor activity and suggest potential for PMN-MDSCs as prognostic marker for clinical outcome.Witalisz-Siepracka et\u00a0al. review the different roles of JAK/STAT3 signaling in the dynamic interplay between NK and tumor cells. The authors include literature on how tumor cell-intrinsic STAT3 drives evasion from NK cells but also how STAT3 may regulate NK cell cytotoxicity, cytokine production and anti-tumor responses in vivo.Concentrating on the underlying signaling pathways of tumor-NK cell interactions del Rio et\u00a0al. aimed to address this topic and present data from a mouse xenograft model suggesting that NK cell anti-tumor function is independent of PD-L1 expression on A20 tumor cells.As mentioned above multiple approaches are being investigated to relieve NK cell immunosuppression in the tumor microenvironment. Immune checkpoint blockade inhibiting the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis seems not only acting on T cells but also on NK cells. However, the role of NK cells in PD-1/PD-L1 context is still a matter of debate . del RioWarner et\u00a0al. discusses emerging evidence that shows that ILCs can impact early tumor development by regulating immune responses against transformed cells, as well as the environmental cues that influence ILC activation in premalignant lesions.ILCs regulate immune responses by responding and integrating diverse signals within local microenvironments and as such are ideally suited to sense malignant transformation and regulate tumor immunity. However, as ILCs have been associated with anti-tumor and pro-tumor activities, they have been suggested to exert dual functions during carcinogenesis by promoting or suppressing the malignant outgrowth of premalignant lesions. Bouyarou and Golub provide an overview of the known roles and actions of ILCs in HCC with an emphasis on the importance of diverse signaling pathways in the tuning of their responses.Hepatocellular carcinoma (HCC) is one of the deadliest cancers worldwide. However, the role of the ILCs in HCC is still not well defined. Wagner and Koyasu review the current understanding of ILCs role as the first line of defence against melanoma development and progression and discuss the possibility to harness their therapeutic potential.ILCs are preferentially enriched in barrier tissues such as the skin, with emerging evidence indicating their role in the control of melanoma. Wu et\u00a0al. review the roles of ILC2s in solid tumors and propose that ILC2s could serve as a predictor for tumor prognosis and a new therapeutic target after immunotherapy resistance.ILC2s are important mediators of type 2 immunity and play important roles in allergic diseases, helminth infections, and tissue fibrosis . StudiesDespite the growing body of research on ILCs, there are still plenty of knowledge gaps of how these cells are shaped by disease- and tissue-specific cues. This Research Topic features several articles that highlight our current knowledge about ILCs in tumor surveillance, pinpoint gaps in our understanding and discuss the possibilities to harness their therapeutic potential.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Supporting this notion, Inagaki et al. showed that phasic activation of PPN/MRN neurons using optogenetics mimics the effect of the Go cue and triggers directional licking, while optogenetic inhibition of PPN/MRN neurons blocks Go cue-triggered licking. These findings of Inagaki et al. are consistent with previous studies in rats, cats and monkeys showing that lesions or silencing of the PPN/MRN prevents the initiation of cue-triggered motor responses.4 More importantly, state space analysis of neural activity can help us go beyond the notion of activation, which also provides a functional interpretation of population activity present in a specific brain region in a task.1This research subtly combines computational neuroscience with the dissection of \u201csensory-motor\u201d neural circuits. Decoding neural circuits can guide us to explore how the nervous system calculates optimal behavioral strategies from variable and complex external stimuli.1 Notably, a classification framework was used to describe the neuronal activity mode. \u201cGo cue direction\u201d (Dgo) represents the cue response, \u201cdelay coding direction\u201d (CDdelay) is a neuronal correlate of motor planning, and \u201cresponse coding direction\u201d (CDresponse) is a neuronal correlate of motor command. The power of the classification framework of these modes is in the ability to precisely analyse the population activity pattern during the transformation from planning to execution in response to Go cue signals and decode the process. During the delay period, the authors showed that motor-selective preparatory activities were mainly contained in CDdelay patterns in the activity space. The selective preparatory activities were rapidly reorganized into nonselective Dgo patterns and direction-selective CDresponse patterns after the onset of the Go cue. The causal relationships between different activity patterns were also confirmed by optogenetic manipulation.In this issue, Inagaki et al. demonstrated three different neuronal activity modes for motor planning and movement initiation by using neural electrophysiology recording in vivo combined with dimensionality reduction methods.5 The severity of FOG can be alleviated by external cues that initiate movement. Inagaki et al. suggested that the information from an external cue may bypass the dysfunctional basal ganglia in PD and reach the ALM through the midbrain-thalamus-cortical circuit to initiate movements, which may explain why cue-triggered movement disturbances rarely occur in PD patients.1 Deep brain stimulation (DBS) targeting specific neuronal populations of the PPN has become a common treatment for FOG in PD.5 Taking into account the \u201cswitch\u201d role of the PPN in the execution of movement, further elucidation of the working mechanism of DBS will help to develop more effective therapeutic regimens for FOG in PD.These are longstanding but important questions about differences between animal manipulation and human therapeutic strategies. Indeed, freezing of gait (FOG), characterized by self-initiated motor deficits, is one of the main motor symptoms in patients with Parkinson\u2019s disease (PD).4 The approaches used in the decoding model in this study might help us to assemble the pieces of the puzzle of brain computation and to better integrate these separate disciplines for neuronal population activity dynamics analysis in various contexts.1 Thus, the decoding method developed by Inagaki et al. may help us not only understand the causal relations between neural activity and motor control but also improve the brain-computer interface.Motor control based on motion intention decoding has been a very important direction in the field of brain-computer interfaces and is of great significance in both theoretical research and practical applications."}
+{"text": "Mental ill health is the leading cause of sickness absence with high economic burden. Workplace interventions aimed at supporting employers with prevention of mental ill-health in the workforce are urgently required. Managing Minds at Work (MMW) is a digital intervention targeting support for line managers in any work setting to promote better mental health at work through a preventative approach.To describe the design and development of the MMW digital training programme, prior to feasibility testing. We adopted a collaborative participatory design involving co-design (users as partners) and principles of user-centred design (pilot and usability testing). Agile methodology was used to co-create intervention content with a stakeholder community of practice. Development processes were mapped to core elements of the Medical Research Council (MRC) framework for developing and evaluating complex interventions.The program covers five broad areas: (i) promoting self-care techniques among line managers; (ii) designing work to prevent work-related stress; (iii) management competencies to prevent and reduce stress; (iv) having conversations with employees about mental health; (v) building a psychologically safe work environment. Pilot and usability testing (n = 37 surveys) aligned with the Technology Acceptance Model (TAM) demonstrated that MMW was perceived to be useful, relevant, and easy to use by managers across sectors, organization types and sizes. We identified positive impacts on manager attitudes and behavioural intentions related to preventing mental ill-health and promoting good mental well-being at work.MMW is a digital training programme for line managers that has been co-created using rigorous development processes and aims to support employers with primary prevention in mental health. The next step is to explore the feasibility and acceptability of this intervention with line managers in diverse employment settings.We used co-creation and participatory design to create Managing Minds at Work - a new digital intervention to support line managers in preventing mental ill-health at work.The next step is to explore the feasibility and acceptability of this intervention with line managers in diverse employment settings."}
+{"text": "Given the need to ensure equity of timely access to post-acute care among minority groups in rural areas, there is a pressing need to understand disparities in the start of home healthcare among minorities with Alzheimer's disease and Related Dementia (ADRD). This study investigates differences in the timing of initiation of home healthcare services following acute hospitalization for ADRD patients by race/ethnicity and rural and urban locations. A secondary analysis was conducted among older adults with ADRD using Medicare data, discharged to home following an episode of acute hospitalization in 2016-2017. The study outcome was a delay in the start of home healthcare after two days of hospital discharge, defined as a home health latency. Compared to non-Hispanic Whites residing in urban areas, Blacks living in urban areas and Hispanics living in rural areas have a significantly higher odd of home health latency 1.15  and 1.06 , respectively."}
+{"text": "Frontiers in Cardiovascular Medicine: Insights in General Cardiovascular Medicine: 2021, is to bring together excellent manuscripts of high-quality and high-citation potential, all of which gave been contributed by our editorial board members. Our criteria for selection include whether the topic addressed is focused on new discoveries and developments, current advances and challenges, as well as future prospects in the field of cardiovascular medicine research. This collection represents the quality and breadth of the papers published in this section, as well as the geographical variety of our scientific community. The rest of this editorial provides an overview of the articles included in the Insights in General Cardiovascular Medicine: 2021 collection .The Post-thrombotic Syndrome-Prevention and Treatment: VAS-European Independent Foundation in Angiology/Vascular Medicine Position Paper .\u2013 Post-thrombotic syndrome is a common and potentially risky complication of deep vein thrombosis that significantly affects patients' life quality. However, there are still great uncertainties in diagnosis, prevention, and treatment due to limited evidence-based approaches to clinical management. This position paper provided a practical framework and guidance for clinicians in PTS management.Diabetes and Its Cardiovascular Complications: Comprehensive Network and Systematic Analyses .\u2013 There is currently no cure for diabetes. This review highlights current advances in the study of diabetes mechanisms using multi-omics analytical approaches and recent findings on the relationship between diabetes and other biological processes. This review provides important information for the prediction, diagnosis, and treatment of diabetes that could be useful for both clinicians and researchers.EMbedding and Backscattered Scanning Electron Microscopy: A Detailed Protocol for the Whole-Specimen, High-Resolution Analysis of Cardiovascular Tissues .\u2013 Analysis of cardiovascular tissue ultrastructure is complex. The current commonly used study methods have limitations such as low resolution and low signal-to-noise ratio. This protocol developed a new experimental method and provided a novel approach for imaging cardiovascular pathophysiological processes.Identification of Novel Single-Nucleotide Variants With Potential of Mediating Malfunction of MicroRNA in Congenital Heart Disease .\u2013 Genetic mutation is the major cause of congenital heart defects (CHDs). This study identified miRNAs-mediated regulating on single-nucleotide variants from 3'-UTR of CHD-associated genes. This study suggests that miRNA-related gene regulation may be important but overlooked in the etiology of human congenital heart disease, suggesting that miRNA-related gene regulation should receive more attention in future CHD studies. The observations in this paper have important implications for clinicians.Screening for Asymptomatic Coronary Artery Disease via Exercise Stress Testing in Patients With Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis .\u2013 This systematic meta-analysis studied the exercise stress testing (ETS) screen program for asymptomatic cardiovascular diseases in type 2 diabetes mellitus, demonstrating its moderate sensitivity and specificity in the initial screening. ETS is a very promising tool due to the advantages of being non-invasive, relatively inexpensive, easily available in most centers, and the fact that it involves no radiation. Further additional studies are warranted to address the detailed flow and timing of ETS.Relevance of Cor Pulmonale in COPD With and Without Pulmonary Hypertension: A Retrospective Cohort Study .\u2013 Pulmonary hypertension (PH), a complication of chronic obstructive pulmonary disease, is usually mild to moderate but can be severe in some patients. This paper suggests that cor pulmonale is associated with disease severity, providing recommendations for clinical researchers that cor pulmonale might be used to predict PH-COPD prognosis.Cognitive Impairment in Heart Failure: Landscape, Challenges, and Future Directions .\u2013 This review summarizes research advances in the screening, diagnosis, and management of cognitive impairment (CI) in patients with heart failure, as well as the latest preventive therapies. The prevalence of CI in heart failure patients adds a greater burden on the patients' poor prognosis and worsening life quality. This paper provides important directions for clinicians and researchers that future research addresses the knowledge gaps in the field forward CI in heart failure.Diagnostic and Therapeutic Management of the Thoracic Outlet Syndrome. Review of the Literature and Report of an Italian Experience .\u2013 This paper reviews the diagnostic, therapy, and management of Thoracic Outlet Syndrome (TOS). A report in Italy was also analyzed. It provides recommendations for clinical researchers in the treatment of TOS.Cardiorespiratory Responses During High-Intensity Interval Training Prescribed by Rating of Perceived Exertion in Patients After Myocardial Infarction Enrolled in Early Outpatient Cardiac Rehabilitation .\u2013 Exercise training is an effective strategy to improve cardiorespiratory and benefits the cardiovascular system , 2. ThisDetermination of Agrin and Related Proteins Levels as a Function of Age in Human Hearts .\u2013 A variety of strategies have been studied to promote endogenous proliferation of cardiomyocytes and promote cardiac injury repair , 4. ThisVascular Stem/Progenitor Cells in Vessel Injury and Repair .\u2013 This review summarizes the latest research progress on Vascular Stem/Progenitor Cells in vessel injury and repair. Stem/progenitor cells play an important role in the regeneration and recruitment of damaged vascular cells during vascular repair. This paper discusses potential future research directions for stem cell therapy and provides important ideas for researchers in this field.Rutaecarpine Inhibits Doxorubicin-Induced Oxidative Stress and Apoptosis by Activating AKT Signaling Pathway .\u2013 Rutaecarpine in doxorubicin-induced cardiotoxicity. This finding provides a new potential therapeutic option for the treatment of doxorubicin-induced cardiotoxicity.Cardiotoxicity is one of the main adverse reactions of doxorubicin in clinical cancer therapy applications , 6. ThisValosin Containing Protein as a Specific Biomarker for Predicting the Development of Acute Coronary Syndrome and Its Complication .\u2013 This paper analyzes human serum samples and found that serum valosin containing protein (VCP) levels could act as a biomarker to predict the development of acute coronary syndrome (ACS) and its complication, ventricular dysfunction. Biomarker identification is important for disease diagnosis and treatment. This study could provide important information for clinicians and researchers that VCP should be involved with the diagnosis and treatment of ACS.NAP1L5 Promotes Nucleolar Hypertrophy and Is Required for Translation Activation During Cardiomyocyte Hypertrophy .\u2013 Cardiac hypertrophy is a compensatory response of the heart to increased hemodynamic stress under various pressures, and if not relieved, it gradually develops into heart failure. This study showed the new role of Nap1l5 in translation control during the progression of cardiac hypertrophy. This paper provides a new potential therapeutic target for the treatment of cardiac hypertrophy and heart failure.Computed-Tomography as First-line Diagnostic Procedure in Patients With Out-of-Hospital Cardiac Arrest .\u2013 Coronary angiography is critical in patients with suspected causes of coronary arrest. This study reported that computed tomography scans can improve outcomes after out-of-hospital cardiac arrest (OHCA). This observation provides information for clinicians and investigators that CT should be routinely included in the diagnostic workup of OHCA regardless of the presence or absence of an ischemic ECG patterns.Association of Body Weight Variability With Progression of Coronary Artery Calcification in Patients With Predialysis Chronic Kidney Disease .\u2013 This paper explores the clinical significance of bodyweight variability (BWV) in patients with predialysis chronic kidney disease. It found that high BWV is independently associated with the progression of coronary artery calcification. This study provides important evidence of a high association between BWV and coronary artery calcification, and should be of concern to clinicians.Clinical Characteristics for the Improvement of Cushing's Syndrome Complicated With Cardiomyopathy After Treatment With a Literature Review .\u2013 Cushing's syndrome (CS) complicated with cardiomyopathy is a rare clinical type with high mortality. This study retrospectively reviewed case reports from literature and demonstrated that cortisol played an important role, and hypercortisolemia can improve significantly after remission. This is an interesting finding, but the detailed mechanism needs further study.Comparability of Heart Rate Turbulence Methodology: 15 Intervals Suffice to Calculate Turbulence Slope \u2013 A Methodological Analysis Using PhysioNet Data of 1074 Patients .\u2013 This study focused on common variations in the number of intervals after ventricular premature contraction (VPC) that are used to calculate turbulence slope (TS). Heart rate turbulence (HRT) is a characteristic heart rate pattern triggered by a VPC. This paper provides important information for clinicians that HRT occurred at early intervals after the VPC, whereas TS calculated from a later time interval reflected overall heart rate variability rather than differential responses to VPC.Left Ventricular Strains and Myocardial Work in Adolescents With Anorexia Nervosa .\u2013 Cardiovascular disease is a common complication of anorexia nervosa (AN). This study suggests that the cardiac function in AN patients was preserved. The paper outlines that global longitudinal strain was higher in AN patients, while the clinical significance required further investigation.A Novel Risk Score to Predict In-Hospital Mortality in Patients With Acute Myocardial Infarction: Results From a Prospective Observational Cohort .\u2013 This study developed a novel HAMIOT  risk score to predict in-hospital mortality of MI patients using 10 highly predictive variables. Using this tool, the risk score is easily calculated and the variables are easily obtained during hospitalization, offering a useful method for clinicians to predict the risk of mortality.Renal Denervation Attenuates Adverse Remodeling and Intramyocardial Inflammation in Acute Myocardial Infarction With Ischemia\u2013Reperfusion Injury .\u2013 Acute myocardial infarction (AMI) is the most severe symptom of coronary artery disease and the leading cause of morbidity and mortality worldwide. This paper studied the protective effects on renal denervation (RDN) in myocardial ischemia/reperfusion (I/R) pigs. This data provides compelling evidence for the applicability and efficacy of RDN and suggests that this treatment strategy needs further development.JX, PL, PC, and MA are topic editors of this special issue and contributed to writing and revising of this editorial. LW, JL, and YL drafted the editorial. All authors contributed to the article and approved the submitted version.This work was supported by the grants from National Key Research and Development Project (2018YFE0113500 to JX), National Natural Science Foundation of China (82020108002 to JX), Innovation Program of Shanghai Municipal Education Commission (2017-01-07-00-09-E00042 to JX), the grant from Science and Technology Commission of Shanghai Municipality (21XD1421300 and 20DZ2255400 to JX), Natural Science Foundation of Shanghai (19ZR1474100 to LW), and the \u201cDawn\u201d Program of Shanghai Education Commission (19SG34 to JX).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "In the first part of the talk I will show that using a computational approach, namely the Drift Diffusion Model, the efficiency of executive attention (EA) is associated with effortful control, the self-regulatory aspect of temperament in a sample of n=427 healthy subjects. Then I will demonstrate how, applying the same model, EA measured through the same conflict resolution task predicts longitudinally a sooner relapse in a sample of n=64 subjects with bipolar and depressive disorders. Lastly I will discuss how EA is associated with obsessive compulsive symptoms in the same clinical population and how they interact in predicting the course of illness. Altogether these results suggest that there is an association between self-reported effortful control and EA and that treatments targeting executive functions could be crucial in preventing relapses in subjects with mood disorders experiencing obsessive compulsive-symptoms.No significant relationships."}
+{"text": "Timely knowledge mobilization has become increasingly critical during the COVID-19 pandemic and complicated by the need to establish or maintain lines of communication between researchers and decision-makers virtually. Our recent pan-Canadian research study on the mental health and substance use health (MHSUH) workforce during the pandemic identified key policy barriers impacting this essential workforce. To bridge the evidence\u2013policy gap in addressing these barriers, we held a facilitated virtual policy dialogue. This paper discusses the insights generated at this virtual policy dialogue and highlights how this integrated knowledge mobilization strategy can help drive evidence-based policy in an increasingly digital world.We held a 3-hour virtual policy dialogue with 46 stakeholders and policy decision-makers as the final phase in our year-long mixed-methods research study. The event was part of our integrated knowledge mobilization strategy and was designed to generate stakeholder-driven policy implications and priority actions based on our research findings. The data collected from the virtual policy dialogue included transcripts from the small-group breakout rooms and main sessions, reflective field notes and the final report from the external facilitator. Coded data were thematically analysed to inform our understanding of the prioritization of the policy implications and action items.Facilitated virtual policy dialogues generate rich qualitative insights that guide community-informed knowledge mobilization strategies and promote evidence-informed policy. Our policy dialogue identified actionable policy recommendations with equity as a cross-cutting theme. Adapting policy dialogues to virtual formats and including technology-assisted facilitation can offer advantages for equitable stakeholder participation, allow for deeper analysis and help build consensus regarding evidence-based policy priorities.Our facilitated virtual policy dialogue was a key knowledge mobilization strategy for our research on the capacity of the Canadian MHSUH workforce to respond to the COVID-19 pandemic. Our policy dialogue allowed us to engage a diverse group of MHSUH workforce stakeholders in a meaningful action-oriented way, provided an avenue to get feedback on our research findings, and generated prioritized action items that incorporated the knowledge and experience of these MHSUH workforce stakeholders.The online version contains supplementary material available at 10.1186/s12961-022-00857-8. Timely knowledge mobilization is a growing concern in social science and health research. This has become increasingly critical during the pandemic and complicated by the need to establish or maintain lines of communication between researchers and decision-makers virtually. Our study on the mental health and substance use health (MHSUH) workforce was funded by a Canadian Institutes of Health Research COVID-19 grant and illustrates promising practices in timely knowledge mobilization using rich qualitative data from a facilitated virtual policy dialogue.The MHSUH workforce is in critical demand. MHSUH needs and concerns have become even more widespread across Canada during the COVID-19 pandemic and may continue to increase through the anticipated echo pandemic, as the lingering impacts of financial stress, social isolation and bereavement take their toll . While 6Exacerbating rising population health needs, health system disruptions during the pandemic have impacted MHSUH service provision , 9\u201311. OThere is a dearth of data on the MHSUH workforce in Canada relative to comparable countries such as the United States . We secupolicy dialogues throughout this paper; however, these processes are also described as deliberative dialogues or stakeholder dialogues. Policy dialogues are versatile strategies to elicit broad input from diverse stakeholders on policy-relevant research evidence and generate targeted policy directions [Policy dialogues constitute an \u201cinteractive knowledge-sharing mechanism\u201d and allow research evidence to be brought together with the knowledge and experience of those who will be involved in, or affected by, policy-making on specific high-priority issues ( p. 2). Grections . As a knrections , 22. As We held a 3-hour virtual policy dialogue via Zoom in June 2021 as the final phase in our mixed-methods study on the capacity of the MHSUH workforce in Canada. The event was part of our integrated knowledge mobilization strategy and was designed to generate stakeholder-driven policy implications and priority actions based on our research findings. The objectives of the policy dialogue were to share the key findings of our research, assess and foster consensus regarding the policy implications of these findings, and identify priority action items to move towards evidence-informed policy-making. The format and plan for the policy dialogue were designed by the research team, the study\u2019s pan-Canadian expert advisory committee, and an expert facilitator external to the research team, who was hired for the event (see Table Focus 1). Ideas were brainstormed using the online tool and participants were able to see the ideas generated on the screen. Each small group was then asked to collate their ideas as best as possible and identify their top three policy implications.Two weeks before our virtual policy dialogue, in preparation for the event, all participants received an evidence brief of our preliminary study findings on the impact of the pandemic on the capacity of the MHSUH workforce in Canada. Following a research presentation, participants were divided into virtual breakout rooms with six or seven participants in each room. Breakout rooms were preassigned to ensure a mix of stakeholder sectors in each group and to allow participants to speak in their preferred language (French or English). In each breakout room, discussion was facilitated by a team member who was familiar with the research study and trained in the use of the GDSS software. The small groups were asked to reflect on and discuss the possible policy implications of our research findings (Focus 2).Following the small-group discussion, the external facilitator engaged the whole group in a discussion of the top three policy implications of each group, highlighting the key points, clarifying the possible policy directions and creating a synthesized list of the ideas generated. These ideas were then individually ranked by participants using the GDSS software to determine which policy directions were considered the highest priority. The same process was followed to identify and prioritize key action items and next steps based on the identified policy implications  coding framework based on the preliminary results of our main research study  codes for categorizing emerging data from the policy dialogue . Through discussion led by the external facilitator, this list was condensed by collating similar items together and offering participants a chance to respond and discuss individual items. Participants then voted on their top five choices individually and anonymously. The ten top-ranked policy implications are presented in Table The ranking exercises resulted in 38 potential policy implications of the research findings  and Focus 2 (action items and next steps), as well as the themes identified in the transcripts, we created a synthesized set of actionable policy recommendations that arise from our research findings  than an in-person event. This allowed for a variety of voices to be more readily mobilized since stakeholders across Canada could attend more easily, overcoming a criticism of in-person events that can be resource intensive and exclusionary . By makiOther technological advantages of the virtual format included using the web-based GDSS software for brainstorming and ranking ideas and recording the group discussions. Using the GDSS technology allowed for more structured discussion and made it easy to bring ideas together from the various breakout rooms for plenary discussion and prioritization in a virtual environment. Researchers planning virtual policy dialogues should consider factoring in the costs associated with this or similar technology, as well as the costs of engaging an expert external facilitator. The Zoom video platform also allowed for recording and full transcription of each small-group discussion session. We were then able to analyse the rich qualitative data from these transcripts, making for a deeper analysis than would be possible if we only had access to written notes from these groups.understanding policy implications from the research and developing a consensus-driven list of actionable solutions to address this variation from conventional policy dialogue guidance. Priority-setting approaches may be particularly valuable in a virtual setting, where time and the power of in-person connection are constrained. At the same time, participants may feel that priority-setting is rushed or forced in a virtual dialogue.We included as an objective for our policy dialogue to assess and foster consensus regarding the key policy implications and priority action items arising from our research study. We did this through our facilitated prioritization (ranking and voting) exercises, incorporating an adapted nominal group technique as a consensus identification strategy. Each small group\u2019s top three ideas (based on the breakout room discussions) for both focus questions were collated into a long list by the expert facilitator, then ranked in order by priority individually. Generally, research on policy dialogues suggests that participants value not emphasizing the need for consensus since it is unlikely policy-makers or stakeholders would commit themselves to a particular solution without further input and processes . HoweverFollowing the policy dialogue, we held a meeting to develop a call-to-action paper and infographic, building on the priorities and themes identified. We also incorporated these into a webinar conducted as part of the Canadian Health Workforce Network\u2019s annual webinar series. Along with more traditional research deliverables of peer-reviewed journal articles and conference presentations, these created a diverse and integrated knowledge translation strategy for our study. Working with stakeholders in this way also allowed us to grow our network for individuals and organizations from across Canada who have knowledge, experience and interest in the MHSUH workforce and who continue to work with us on our research in this area.Our virtual policy dialogue had some limitations. Despite the advantages of the virtual format, some participants may have been less comfortable with the Zoom video conferencing technology or may have had challenges with access due to Internet connectivity issues. Given the capacity issues that we identified in our study, we also knew that many stakeholders would have pandemic-induced fatigue or burnout, including around attending virtual events. We kept the dialogue to 3 hours with this in mind and offered ways for stakeholders to stay engaged with the research following the policy dialogue. Nevertheless, a full-day event may have generated further discussion and ideas.We obtained feedback from participants at the end of the virtual policy dialogue via a quick online survey. However, only 11 participants completed this, making the data of limited value. It may have been helpful to send a follow-up survey to assess how participants viewed the virtual policy dialogue process.Finally, although we made a serious effort to invite a diverse range of stakeholders, we were not able to engage with all potentially impacted MHSUH groups. The resulting interpretations of our research in terms of policy implications and actionable solutions only reflect the views of those who were in the virtual room and are thus constrained by a potential lack of diversity in providers, perspectives and lived experiences.Adapting conventional in-person policy dialogues to virtual formats may offer researchers a way to engage a greater diversity of voices with study findings and more routinely use evidence to inform policy decision-making. Future studies using facilitated virtual policy dialogues as a knowledge mobilization strategy could incorporate ways to evaluate the process  and outcomes (focusing on subsequent engagement by stakeholders with the generated policy recommendations). Our inclusion of an adapted nominal group technique and interactive GDSS technology should be evaluated as an evolution of policy dialogues that potentially allows for more equitable participation by stakeholders and may help foster consensus on next steps.Facilitated virtual policy dialogues provide rich qualitative insights that can guide a community-informed knowledge mobilization strategy and promote evidence-informed policy. Our facilitated virtual policy dialogue was a key knowledge mobilization strategy in our mixed-methods study on the capacity of the Canadian MHSUH workforce to respond to the COVID-19 pandemic. As the final phase of our research, this facilitated virtual policy dialogue allowed us to engage a diverse group of MHSUH workforce stakeholders in a meaningful action-oriented way, provided an avenue to get feedback on our research findings, and generated prioritized action items that incorporated the knowledge and experience of these MHSUH workforce stakeholders.Additional file 1: Initial (deductive) coding scheme for the policy dialogue based on main research study.Additional file 2: Adapted (inductive) coding scheme for the policy dialogue."}
+{"text": "In most mammals, retinal ganglion cell axons from each retina project to both sides of the brain. The segregation of ipsi and contralateral projections into eye-specific territories in their main brain targets\u2014the dorsolateral geniculate nucleus and the superior colliculus\u2014is critical for the processing of visual information. The investigation of the developmental mechanisms contributing to the wiring of this binocular map in mammals identified competitive mechanisms between axons from each retina while interactions between axons from the same eye were challenging to explore. Studies in vertebrates lacking ipsilateral retinal projections demonstrated that competitive mechanisms also exist between axons from the same eye. The development of a genetic approach enabling the differential manipulation and labeling of neighboring retinal ganglion cells in a single mouse retina revealed that binocular map development does not only rely on axon competition but also involves a cooperative interplay between axons to stabilize their terminal branches. These recent insights into the developmental mechanisms shaping retinal axon connectivity in the brain will be discussed here. The accurate processing of visual information relies on the precise tuning of visual system connectivity. In most mammals, including rodents and humans, each hemisphere of the brain receives afferences from retinal ganglion cells (RGCs) of the same  and opposite  side of the body . However, in vivo dynamic analyses at the cellular scale are essential to provide mechanistic clues regarding the influence of patterned neuronal activity on retinal axon branch dynamics . Tackling this issue is challenging in mice but accessible in other optically transparent vertebrates such as albino Xenopus tadpoles. While retinotectal projections are entirely crossed in Xenopus, unilateral ablation of the tectum  drives the axonal rewiring of RGCs contralateral to the ablation site. These axons thus innervate the remaining ipsilateral tectum, which they would not normally target. This surgical approach generates an artificial binocular system compatible with the in vivo monitoring of branch dynamics underlying inter-eye axonal competition. Using this experimental system, Rhuthazer et al. demonstrated that RGC axons from both eyes have the same probability to form new branches in all tectal territories. However, retinal axons preferentially drive branch elimination in territories dominated by the opposite eye, while stabilizing new branches in appropriate territories, two NMDA receptor-dependent processes , revealing a contribution of intra-eye axonal competitive interplay in binocular mapping , reduces calcium wave frequency. This impact on retinal spontaneous activity is absent when a PKA-phosphodeficient mutant of SNAP25 is overexpressed. Their results suggest that PKA is required in SACs to decrease retinal spontaneous activity . AC1 is the only adenylyl cyclase identified to influence the development of binocular maps (Ravary et al., \u2212/\u2212 mice (Dunn et al., \u2212/\u2212 mice differs from the one associated with the overall elevation or reduction of cAMP concentration in the retina. Whereas AC1\u2212/\u2212 mice exhibit overlapping ipsi and contralateral territories in both the dLGN and SC, modulating cAMP concentration in both retinas does not impact binocular mapping. Further investigations of the AC1-dependent regulation of visual maps\u2014using retina-specific conditional mutants or retinocollicular coculture systems mixing retinal and collicular explants from different AC1 genotypes\u2014identified RGCs as the cell type involved, ruling out a contribution of AC1 in their postsynaptic targets (Nicol et al., To identify the source of the cAMP signals that modulate the patterns of retinal waves, spontaneous activity and calcium concentrations have been recorded in the developing retina of AC1 knockout mice (AC1While the molecular mechanisms involving AC1 and shaping eye-specific territories have not been explored, molecular clues have emerged from studies investigating the role of AC1 in the refinement of somatosensory thalamocortical projections. Thalamic- or cortex-specific AC1 conditional knockout mice revealed that this cAMP-synthetizing enzyme is required in presynaptic neurons to control axonal branch remodeling in the somatosensory system like in retinal projections (Suzuki et al., \u2212/\u2212 mice phenotype that associates alterations in binocular mapping to unaffected retinal waves (Dhande et al., The cAMP-dependent pathways mentioned above have been identified in studies focusing on inter-eye competition. However, intra-eye cooperative interactions, which contribute to the costabilization of terminal arbors of neighboring RGCs, also rely on a cAMP-dependent mechanism. The latter has been identified by preventing cAMP signaling in a subset of RGCs within a single retina using a genetically-encoded cAMP scavenger while labeling these RGCs differentially from their neighbors with intact cAMP signaling (Louail et al., The development of binocular maps is governed by balanced competitive and cooperative mechanisms that refine initially exuberant ipsi and contralateral territories. These mechanisms are dependent on spontaneous activity in the retina and a complex interplay between axonal branches from the same and opposite retina. cAMP signaling is involved in many steps of these cellular processes. While the overall mechanisms influencing both the generation of waves of activity in the developing retina and the interplay between axonal branches of RGCs from both eyes are mostly understood, the description of the competitive and cooperative intra-eye interactions and the molecular mechanisms governing all steps of binocular mapping will benefit from further investigations.CF and XN wrote the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In this manuscript, a method for maneuvering a spacecraft using electrically charged tethers is explored. The spacecraft\u2019s velocity vector can be modified by interacting with Earth\u2019s magnetic field. Through this method, a spacecraft can maintain an orbit indefinitely by reboosting without the constraint of limited propellant. The spacecraft-tether system dynamics in low Earth orbit are simulated to evaluate the effects of Lorentz force and torques on translational motion. With 500-meter tethers charged with a 1-amp current, a 100-kg spacecraft can gain 250 m of altitude in one orbit. By evaluating the combined effects of Lorenz force and the coupled effects of Lorentz torque propagation through Euler\u2019s moment equation and Newton\u2019s translational motion equations, the simulated spacecraft-tether system can orbit indefinitely at altitudes as low as 275 km. Through a rare evaluation of the nonlinear coupling of the six differential equations of motion, the one finding is that an electrodynamic tether can be used to maintain a spacecraft\u2019s orbit height indefinitely for very low Earth orbits. However, the reboost maneuver is inefficient for high inclination orbits and has high electrical power requirement. To overcome greater aerodynamic drag at lower altitudes, longer tethers with higher power draw are required. Space, particularly in low-earth orbits, is littered with dangerous debris monitored by the National Aeronautics and Space Administration (NASA) who together with the United States Space Force issues warnings of impending space collisions . EcuadorSpacecraft in low Earth orbit have a limited lifetime due to deceleration from aerodynamic drag that eventually cause low-earth orbiting satellites to re-enter (but on on-command). Reboost maneuvers can be conducted to keep them on station, however once the propellant is expended the spacecraft loses its maneuvering capability.Spacecraft equipped with electrodynamic tethers are able to take advantage of Earth\u2019s magnetic field and maneuver to avoid collision by generating miss-distance, or alternatively, reboost using electrical power, which can be generated from solar arrays. Such propellant-less maneuvers could extend spacecraft lifetime significantly; however, the effectiveness of maneuvering using electrodynamic tethers depends on several variables, including orbit eccentricity, inclination, altitude, and the charge and length of the tether. Various trajectories and tether configurations are illustrated via computer simulation investigating the functional limits of electrodynamic maneuvers in low Earth orbits. The proposed developments should prove especially useful for CubeSat whose extensive use of commercial off-the shelf components for their subsystems makes their cost a small fraction of the cost of traditional satellites, and thus likely ubiquitously lack propulsion systems to maintain low cost.Aerospace. This manuscript will study utilization of electric tethers to generate angular momentum, which propagates through the six coupled nonlinear equations of motion forming the basis for modern spacecraft attitude control and guidance proposed in 2007 [Propellant-free space maneuvers  are curr in 2007 , formula in 2007 . The met in 2007 , and man in 2007 , which w in 2007 . This maDevelopments presented in this manuscript follow the nature of the 1998 NASA study , which fThis manuscript will add to the current state of the art by evaluation of the effects of Lorentz torque alone propagated through the full 66-term Euler\u2019s moment equation and resultant coupled translational motion through the modification of angular velocity vector components appearing in Newton\u2019s translational motion equations leading to translational motion.While the coupling effects are nominally small (hundreds of meters), the evaluation illustrates useful propellant-free maneuvering capability not previously articulated by evaluation of the capability in five disparate sample low-earth orbits using simulations. The effect is also illustrated to be capable of changing orbital inclination tens of millidegrees . A rare illustration of computation accuracy is offered foremost to illustrate the numerical precision of the simulation, which is included in According to Chasle , mechaniEquation (1) reparametrizes the better-known formulation on the left of the equation into the lesser-known regression form on the right of the equation by defining a matrix of presumed \u201cknowns\u201d and a vector of parameters potentially to be estimated. The regression matrix is defined in Equation (2), while the regression vector is defined in Equation (3) with the variables\u2019 definitions in Meanwhile Equation (5), whose components are defined in tions in ). ModifiFour of the main disturbance forces acting on Earth orbiting spacecraft . This torque depends on the magnetic moment MM and magnetic field B. Variables for Equations (6)\u2013(8) are defined in Environmental forces and torques are included in the validating simulation, while magnetic forces and torques are the focus of the investigation of useful production of translation. Aerodynamic drag force is calculated using Equation (6), where re model ,32 undermodel [\u03bc ,34, as rmodel [\u03bc , orbit aA) and current (I) passing through n coils will generate a torque that can rotate a spacecraft. Similarly, an electrically charged tether can produce translational motion using the Lorentz force in Equation (9). Based on the orientation of the tether . A magnetorquer with vector area  can be reduced by proportionately increasing tether length (L) to produce an equivalent Lorentz force. Tethers of varying lengths and charge are simulated to determine the limits of electrodynamic maneuvering efficiency.Not all orbits are ideal for electrodynamic maneuvering. The strength of the magnetic field will vary depending on the spacecraft\u2019s eccentricity, inclination, and altitude. Circular equatorial orbits at various altitudes are simulated first to understand the best-case scenario performance of an electrodynamic tether reboost. Orbit inclination and tether deflection angle are additional independent variables that will be investigated to test the effectiveness of the maneuver. Tether deflection can be caused by aerodynamic drag. When deployed at low altitudes, the tether will deflect behind the spacecraft if there is insufficient end mass to keep the tether taut. This deflection can reduce reboost efficiency. To increase energy efficiency, current  and (5), simulation models were created and run in MATLAB/SIMULINK R2021a. Depictions of the simulations are included in To verify that the simulation is producing accurate results, the numerical solver and step size was chosen to limit the numerical error. The maximum precision obtainable is called machine precision for floating point arithmetic. As the quaternion normalization necessitates unity normalization, the difference between the calculated normalized quaternion and unity is utilized to represent the numerical accuracy of the simulation with various simulation step sizes and solver properties. Several solver and step size combinations are investigated to determine an option that produces accurate results, where After presenting simulations performed to validate accuracy in This section illustrated a well-known adage: computer simulations can seemingly be made to indicate very different things. Visual inspection of Utilizing the most accurate integration solver and step-size iterated in 3 size was simulated deploying 500-m tether system charged to 1 amp. The total mass of the spacecraft is 100 kg. All data presented in this manuscript use the same spacecraft model. The simulations are used to iterate initial orbit parameters and tether deflection angle.A microsatellite of 1 mWith these results (tabularized and depicted for ease of reading), the next section describes the results in a narrative including how they can be interpreted from the perspective of previous studies and of the working hypotheses. The findings and their implications are discussed in the broadest context possible, and future research directions are also be highlighted.In this manuscript, the dynamics of orbital boost maneuvers for microsatellites using electrodynamic tethers is investigated. This manuscript offers a novel contribution by evaluating the effects of both Lorentz force and Lorentz torque propagation through the full sixty-six term Euler\u2019s moment equation and resultant coupled translational motion through the modification of angular velocity vector components appearing in Newton\u2019s translational motion equations. Computational accuracy is also provided to demonstrate the numerical precision of the simulation.Electrodynamic tethers are a viable instrument for reboosting satellites in low Earth orbit, provided that sufficient power generation is available. Mass and budget savings from eliminating the need for expendable propellant can save billions of dollars over a 10-year period . SmallerFurther investigation of the effectiveness of the propellant-free reboost using electrodynamic tethers will require a study of the power requirements of the tether system and detailed design of the system. Limitations introduced by the power generation capabilities of microsatellites will reduce the effectiveness of the reboost maneuver. Mechanical properties of the tether must also be modelled in greater detail to understand deployment, lifetime analysis, and libration modes.Following these results illustrating the ability to generate propellant-free translational maneuvers by modifying the angular velocity with rotational maneuvers utilizing energy from the Earth\u2019s magnetic field, future research will focus on methods to generate predicted maneuvers to command generating specified translational maneuvers. The previously cited  elaborat"}
+{"text": "Prevention of early recurrent ischaemic stroke remains a priority in people with TIA or ischaemic stroke. A number of trials have recently been completed assessing the efficacy of short-term dual antiplatelet therapy (DAPT) versus single antiplatelet therapy early after minor or moderate stroke or high-risk TIA. We present an Expedited Recommendation for use of dual antiplatelet therapy early after ischaemic stroke and TIA on behalf of the ESO Guideline Board. We make a strong recommendation based on high quality of evidence for use of 21-days of dual antiplatelet therapy with aspirin and clopidogrel in people with a non-cardioembolic minor ischaemic stroke or high-risk TIA in the past 24\u2009hours. We make a weak recommendation based on moderate quality evidence for 30-days of dual antiplatelet therapy with aspirin and ticagrelor in people with non-cardioembolic mild to moderate ischaemic stroke or high-risk TIA in the past 24\u2009hours."}
+{"text": "Ventriculus terminalis (VT) is a cystic embryological remnant within the conus medullaris that normally regresses after birth. In rare cases, it may persist into adulthood and give rise to neurologic symptoms. The pathogenesis remains unclear but is thought to be related to failed embryonic regression with other proposed possible etiologies including vascular disturbances. We present an intriguing case of a slow-growing VT in a woman with progressive neurologic symptoms who experiences symptomatic relief following thoracic laminectomy and fenestration. Our case is the first to present a unique association with polyarteritis nodosa and only the third to report a case of documented enlargement of the VT over time successfully treated with surgical fenestration. The ventriculus terminalis (VT) or \u201cfifth ventricle\u201d is a small ependymal-lined residual lumen in continuity with the central canal of the conus medullaris. VT is normally present in all humans during fetal development and typically regresses completely after birth -3. Its pA 57-year-old female with a past medical history significant for polyarteritis nodosa on immunosuppression with Azathioprine presented to the neurosurgery clinic with progressive right lower extremity shooting pain, numbness and tingling over the past six months. On physical examination, she had trace weakness in right lower extremity dorsiflexion as well as right foot eversion with diminished vibratory and pin-prick sensation in her bilateral lower extremities. Magnetic resonance imaging (MRI) of the thoracic and lumbar spine with and without contrast was obtained which demonstrated a cystic lesion in the conus medullaris spanning the thoracic 11 to thoracic 12 levels  . This clWe present an intriguing case of a slow-growing VT in a woman with progressive neurological symptoms. Despite its progressive growth, pathology was negative for neoplasm and she experienced symptomatic relief following thoracic laminectomy and fenestration. To the best of our knowledge, we are the first to report a possible association with polyarteritis nodosa and only the third to report a case of enlarging VT successfully treated with surgical fenestration."}
+{"text": "Primary: To improve the quality of medical handover by increasing trust-wide completion rate for agreed quality standards from baseline to 80% by July 2019To standardise the medical handover across all 5 boroughs within the trust by July 2019Secondary: To separately assess the completion rate for new patient checks in relation to baselineNot only is there a recognised variation in the medical handover across Pennine care foundation trust's (PCFT) 5 boroughs , but there also appears to be diminished adherence to quality standards to a varying extent. This was shown to result from a combination of human factors and process errors consequently leading to near-miss clinical incidents. This project was therefore designed to highlight and address these issues in order to promote patient safety.Having identified the problems and agreed on quality standards, baseline data were gathered through May 2019 with the primary outcome measure being the percentage completion rate for quality standards across all handovers. Changes were made to the handover document in June 2019 followed by introduction of a new handover document and post-intervention data collection through July 2019. Doctors\u2019 satisfaction with the new handover document using a typical 5-level Likert scale was measured using a trust-wide online survey.Our results showed a considerable Trust-wide improvement in the completion rate for agreed quality standards from 54% at pre-intervention to 77% at post-intervention with all 5 boroughs demonstrating improvement to varying extents. This is noted to be reasonably close to the project aim of improving the completion rate from baseline to 80%. With regards to new patient checks, there was a marginal Trust-wide increase in completion rate from 53% at pre-intervention to 56% at post-intervention. Additionally, the trust-wide online survey measuring doctors\u2019 satisfaction with the new handover revealed a majority (82%), either strongly agreed (27.3%), or agreed (54.6%), that the new handover document has improved the overall quality of handovers.Trust-wide standardisation of the handover has now presented the opportunity to benchmark boroughs within PCFT against one another in terms of adherence to quality standards and alignment with best practice relating to patient safety. While substantial improvement may have been made in the overall quality of handovers across the trust, the inter-borough disparity in the extent of improvement identified gaps for future follow-up or related projects."}
+{"text": "Effective health information systems (HIS) are critical towards achieving timely response to preventive chemotherapy neglected tropical diseases (PC-NTDs) and their eventual elimination. Strengthened HIS enable prompt case detection and effective response to halt disease transmission and prevent probable outbreaks. This study aimed to assess the importance and feasibility of implementing recommendations for improving surveillance core functions, support functions and surveillance attributes concerning PC-NTDs in Kenya.A descriptive web-based Delphi process comprising of two survey rounds was used to achieve group consensus on the importance of recommended actions and feasibility of their implementation. In the first round, participants were enrolled to complete a five-point likert-type self-administered electronic questionnaire comprising of 60 statements across 12 sub-domains on the importance of recommendations. In the second round, participants reappraised their responses following completion of a questionnaire with 56 rephrased statements on feasibility of implementing the recommendations to improve PC-NTDs surveillance and response. Data from both rounds were analysed using descriptive statistics and thematic analysis performed for the open-ended responses.Sixty-two key stakeholders actively involved in surveillance and response activities in seven PC-NTDs endemic counties in Kenya were invited to participate. Of these, 50/62 completed the first round (81\u2009% response rate) and 45/50 completed the second round (90\u2009% response rate). Consensus was achieved (defined as >\u200970\u2009% agreement) on the importance (93\u2009%) of recommendation statements and feasibility (82\u2009%) of implementing the important recommendations. Stakeholders agreed on the importance and feasibility of specific recommendations across the 12 sub-domains: case detection and registration, reporting, data analysis, feedback, epidemic preparedness and response, supervision, training, resources, simplicity, acceptability, stability and flexibility. However, there was lack of consensus on the feasibility of conducting routine data analysis, increasing supervision of surveillance activities at lower levels and retaining trained surveillance staff across all levels.Consensus among health stakeholders on implementation of the important and feasible recommendations will inform relevant strategies for strengthening specific surveillance system functions in view of PC-NTDs in Kenya.The online version contains supplementary material available at 10.1186/s12913-021-07075-y. Public health surveillance systems are a critical component of health information systems (HIS) and involve systematic collection, analysis and interpretation of health data resulting in timely information dissemination to prompt appropriate response action . In 1998Strengthened surveillance systems will facilitate disease elimination programmes by improving existing HIS with regard to case detection and public health response activities targeting disease transmission foci and outbreaks prevention . TherefoIn the Kenyan context, majority of the NTDs are amenable to PC and other basic sanitary interventions . EssentiA shift in focus of NTD programmes from donor-funded agencies to local stakeholders to motivate country\u2019s self-reliance to curb NTDs, underpins the importance of in-country perspectives and decision-making to achieve sustainable impact . SustainThe Delphi technique is a scientific approach involving sequential surveys where a series of rounds are used to obtain individual expert opinions to establish consensus among participants , 24. TheA two-round descriptive web-based Delphi survey was utilised in the current study. The factors assessed in the survey were retrieved from key findings of three previous studies \u201328. The Initially, three main domains  were identified. The three main domains were pre-defined from information retrieved from the Centres for Disease Control and Prevention (CDC) updated guidelines for evaluating public health surveillance systems . Core fuThe survey involved stakeholders selected from NTDs endemic regions in Kenya. Kenya comprises of 47 counties that are endemic of at least one or more NTDs. However, stakeholders were enrolled from seven specific regions including Baringo, West Pokot, Narok, Kilifi, Kwale, Embu and Kitui counties that are co-endemic of at least three or more PC-NTDs. Selection of regions co-endemic of three or more PC-NTDs was aimed at obtaining stakeholders\u2019 perspectives considering the integrated disease surveillance and response approach . The PC-The survey involved 50 health personnel responsible for overseeing surveillance and response activities at the sub-national level. The sub-national health system constitutes the county and sub-county levels with peripheral levels comprising of lower level facilities (dispensaries) and community health units . Study pstrongly agree, agree, neither agree nor disagree, disagree and strongly disagree with provision of a do not know option. Consensus was defined as >\u200970\u2009% of participants either \u201cagreeing\u201d or \u201cstrongly agreeing\u201d with the recommendation statements in each of the two rounds. The questionnaires had an additional comment section to elicit open responses from participants having further information not captured in the likert-scale statements. Questionnaire used in the first round consisted of 12 sub-categories with 60 statements. In the second round, statements considered important by participants were retained from the first round and rephrased. The questionnaire used in the first round comprised of statements phrased in a manner to prompt responses from participants regarding importance of the recommendation statements. In the second round, the statements were rephrased to elicit participants\u2019 opinions on the feasibility for implementing important recommendations at the sub-national level.Due to the Coronavirus disease (COVID-19) pandemic situation and considering precautionary measures recommended by the Ministry of Health (MOH) in Kenya, an electronic web-based self-administered questionnaires was designed using Google forms and data was securely transferred from the forms to Google spreadsheets. The five-point likert scale online questionnaires were used to obtain data from the participants provided as supplementary files  & 2. ResAn initial first round involved administering the online survey tool to selected stakeholders responsible for overseeing and making decisions on surveillance and response activities in NTD endemic regions in Kenya. Their responses on importance of recommendation statements were obtained, analysed and the statements rephrased to assess feasibility for implementing important recommendations. The final second round involved administering the revised web-based tool and providing participants with the outcome report of the previous first round. Priority was accorded to county health stakeholders\u2019 perspectives since they are the key decision makers on health system functioning at the sub-national level, which is a devolved function overseen by county governments in Kenya . The iniExported data from the Google spreadsheets were analysed using Stata Version 14.0 . Descriptive statistics were used to summarise categorical variables and frequency distributions were described for participant responses measured on the five-point likert scale. Reliability and coherence between items in questionnaires used in both rounds were independently tested using Cronbach\u2019s Alpha coefficient. The calculated coefficients ranged from 0.81 to 0.95 indicating sufficient reliability and inter-item correlation. The final questionnaires used in the first and second round comprised of recommendation statements with an average of five questions in each sub-category. All questionnaire items were retained and none was excluded following factor analysis, based on the principal component analysis, to ascertain the statements relevance as constructs in each of the sub-domains. A level of consensus of above 70\u2009% is considered appropriate for Delphi studies , 32. TwoApproval for the study was obtained from the Faculty of Health Sciences Research Ethics Committee of the University of Pretoria in South Africa (Ethics Reference No: 27/2018) and the Institutional Research and Ethics Committee of Moi University/Moi Teaching and Referral Hospital in Kenya . Additionally, the National Commission for Science, Technology and Innovation (NACOSTI) provided research authorisation to undertake the study in accordance with relevant guidelines and regulations . Permission was granted by the MOH, county health authorities and written informed consent was obtained from all study participants.Sixty-two participants were recruited in the first round of the survey and a response rate of 81\u2009% was obtained. The final sample size was 50 participants following exclusion of those who did not consent (n\u2009=\u20095) and those who were unavailable (n\u2009=\u20097) to participate in the study. The median number of years of work experience for participants in their current designation was 10 years IQR: 8\u201312 years). Majority (64\u2009%) of participants were members of the County Health Management Committee (CHMC) with 36\u2009% being part of the Sub-County Health Management Committee (SCHMC). The second round of the Delphi survey involved 45 participants translating to a response rate of 90\u2009% since five out of the 50 participants in the previous round were unavailable to participate in the second round. The stakeholders were grouped into various areas of work including health management ; disease surveillance (county and sub-county disease surveillance and response coordinators and NTDs coordinators); public health  and health information  (Table\u00a0 years. MStakeholders agreed on the importance (98\u2009%) and feasibility (100\u2009%) of updating surveillance guidelines currently in use at the sub-national levels and were further in consensus (82\u2009%) on the need to update the available standard case definitions for PC-NTDs. Further, participants agreed on the importance of training health workers on practical use of the standard case definitions. However, there was non-consensus (69\u2009%) on the feasibility of training all health workers on use of PC-NTDs standard case definitions. There was further non-consensus on the importance (70\u2009%) of providing case registers specific for registration of PC-NTDs cases.\u201cHaving in place case registers for registering PC-NTDs only may not be practical and cost effective since we have many other conditions to be registered and it would be easier to do this using one common register\u201d (Participant 5).\u201cIt is only feasible to issue facilities designated as treatment sites with the registers since they receive NTD patients more often compared to the other facilities\u201d (Participant 16).\u201cProviding registers specific for NTDs to all levels might require additional resources which are currently unavailable\u201d (Participant 32).Furthermore, participants disagreed (66\u2009%) on the need to confirm all PC-NTDs cases at the lower surveillance levels. Nonetheless, participants reached consensus (90\u2009%) on the importance of increasing the number laboratory facilities at the peripheral levels to confirm PC-NTDs, although there was non-consensus (35\u2009%) on the feasibility of having additional laboratories at lower surveillance levels.\u201cIt will not be quite possible to always confirm all the NTDs due to low capacity of the lower levels to undertake case confirmation due to unavailability of laboratory facilities\u201d (Participant 4).\u201cConfirmation of all PC-NTDs at the lower levels would require increased provision of laboratory facilities and equipment in the region to achieve this target\u201d (Participant 8).\u201cConfirming all cases requires adequate supply of laboratory reagents and supplies that may not be the case for most of the lower levels\u201d (Participant 29). There was agreement among stakeholders on the importance (98\u2009%) and feasibility (71\u2009%) of adequately equipping existing laboratories at the facility level and providing sufficient number of skilled laboratory personnel to enhance PC-NTDs case confirmation. Further findings showed agreement on the importance and feasibility of ensuring reporting forms are always readily available and on providing updated reporting guidelines across all surveillance levels. Stakeholders were also in consensus on the importance (90\u2009%) of listing all the PC-NTDs in the reporting forms but there was non-consensus (55\u2009%) on the feasibility of including all the diseases in the existing report forms. Further, participants agreed (88\u2009%) on the need to ensure immediate reporting of PC-NTD cases to improve planned response actions. However, there was non-consensus on the achievability (66\u2009%) of immediate case reporting on first detection. There was unanimity among stakeholders on the importance and feasibility of adopting electronic reporting tools to improve transmission of PC-NTDs surveillance data. Participants further reached consensus on the importance and feasibility of providing regular training on PC-NTDs reporting and allocating ample time for preparation and submission of surveillance reports.Stakeholders had a converging opinion on the importance (98\u2009%) and feasibility (93\u2009%) of enhancing analysis of PC-NTD surveillance data. Participants also agreed on the need to conduct routine data analysis (84\u2009%) and undertake periodic trend analysis (90\u2009%) for PC-NTDs. However, there was lack of consensus on the feasibility of conducting regular data analysis (31\u2009%) and periodic assessment of PC-NTDs trends (60\u2009%).\u201cWe first need to improve the quality and quantity of data collected on PC-NTDs to be able to undertake routine analysis of these data\u201d (Participant 9).Moreover, participants were in consensus on the importance and feasibility of enhancing training on data analysis, formulation of coherent action thresholds and provision of sufficient data analysis tools and equipment considering PC-NTDs.There was consensus among stakeholders on the importance and feasibility of improving feedback specific to PC-NTDs and providing timely and regular feedback across all surveillance levels. In addition, participants agreed on the need and feasibility of adopting electronic feedback mechanisms and enhancing feedback on PC-NTDs to lower surveillance levels. Agreement was also reached on the importance and feasibility of updating outbreak preparedness and response protocols for all PC-NTDs and having well-constituted outbreak response teams at the sub-national level to adequately respond to PC-NTDs outbreaks. Participants further reached consensus on the need and feasibility of provision of sufficient emergency supplies in anticipation of probable outbreaks and providing frequent training on PC-NTDs epidemic preparedness and response.Stakeholders reached consensus on the importance (100\u2009%) and feasibility (91\u2009%) of enhancing supervision of PC-NTDs surveillance activities at the sub-national levels. There was further agreement on the need to undertake regular supervision (92\u2009%) of surveillance activities concerning PC-NTDs and heightening the frequency of supervisory visits (84\u2009%) at the peripheral levels. However, participants disagreed (51\u2009%) on the feasibility of consistently conducting supervision of surveillance activities and there was lack of consensus (22\u2009%) on the possibility of increasing the frequency of supervisory visits at the lower levels.\u201cConducting regular supervision of surveillance activities requires resources for transportation and purchase of other materials which may not be feasible at this time due to other priority activities\u201d (Participant 12).\u201cDue to the nature of the region which has very poor terrain, this pose a challenge to accessing some of the remote regions and conducting frequent supervision at the peripheral levels may not be practical\u201d (Participant 16).Participants were in consensus on the necessity and feasibility to formulate supervisory schedules, train all health personnel on supervisory activities and establish supervisory teams capable of providing support supervision for PC-NTDs surveillance activities. Moreover, stakeholders agreed on the importance and feasibility of resource provision to support supervisory activities and involvement of the community levels to support supervision of PC-NTDs surveillance activities.\u201cSupport supervision should be strengthened especially at the peripheral levels with the involvement of the community units throughout the process\u201d (Participant 13).\u201cSupervision of surveillance activities at the peripheral level requires the involvement of community health workers working within a functional community health unit\u201d (Participant 21).Stakeholders had converging points of view on the importance and feasibility of enhanced and regular training on PC-NTDs surveillance activities. Participants further agreed on the need and feasibility of availing sufficient training materials and tools across all surveillance levels. However, participants ruled out consensus on the importance (70\u2009%) of involving all health workers in training concerning surveillance activities for PC-NTDs.\u201cInvolving all the health workers in the region in surveillance training might not be cost effective and practical given the scarcity of resources set aside for conducting training\u201d (Participant 2).\u201cThis may not be feasible but we only need to ensure that an adequate number of staff are trained on surveillance of NTDs that are common in the region then they can pass on the knowledge gained to other health workers in their area of work\u201d (Participant 39).There was unanimity on the importance (100\u2009%) of limiting high turnover of trained surveillance staff. However, stakeholders lacked consensus (27\u2009%) on the feasibility of retaining trained surveillance personnel across all surveillance levels.\u201cRetention of health workers across surveillance levels may not be feasible since health workers are frequently transferred whenever there is need to adjust to given work circumstances\u201d (Participant 3).\u201cThis might not be feasible since staff progression and transfers normally happen regularly so it is better to train other staff to replace the ones transferred\u201d (Participant 37).The stakeholders concurred on the need and feasibility of increased funding provision and logistical support for PC-NTDs surveillance activities and provision of electronic communication equipment for transmission of surveillance data. There was also consensus (82\u2009%) on the importance of involving more health personnel in PC-NTDs surveillance activities but from a practical perspective, there was lack of consensus (40\u2009%) among stakeholders on providing additional staff to be engaged in the surveillance activities. There was further lack of consensus on the importance (66\u2009%) of increasing the number of designated surveillance focal persons.\u201cThis might lead to duplication of roles of the surveillance staff already in post, so the available staff should be able to handle all surveillance issues efficiently\u201d (Participant 38).Additionally, stakeholders concurred on the need and feasibility of improving the surveillance data transmission and communication channels and providing reliable means of transport to facilitate surveillance activities.Recommendation statements on improving simplicity, acceptability, stability and flexibility of the surveillance system concerning PC-NTDs were assessed in the two rounds. Findings showed that participants reached consensus regarding the importance and feasibility of simplifying existing reporting guidelines and forms, simplifying PC-NTDs case definitions for ease of application by health workers and simplifying methods of data collection and analysis of surveillance data. Further, there was unanimity among stakeholders on the need and feasibility for health managers across all levels to support PC-NTDs surveillance activities and for all health workers to consider PC-NTDs of public health importance in the endemic regions. In addition, participants agreed on the need and feasibility of promptly addressing challenges facing PC-NTDs surveillance activities and provision of adequate resources to support surveillance of the neglected tropical conditions. Stakeholders also reached consensus on the importance and feasibility of the existing surveillance system to adapt to reporting all PC-NTDs  and for the system to adapt to changes in information needs regarding the diseases .Sensitivity analysis was undertaken with the assumption that participants with neutral responses were in agreement with the recommendation statements on both perspectives of importance and feasibility Tables\u00a0 and 5. CSurveillance and response system improvement can only be guided by what is important, feasible, acceptable and tailored to the needs of system users. This Delphi survey identified critical and feasible recommendations for consideration and implementation by decision makers. The back and forth process of providing feedback based on an analysis of opinions from a group of participants enabled reaching consensus on the pertinent recommendations and the feasibility of their implementation . The surThe study revealed that despite abundant evidence on the endemicity of NTDs amenable to chemoprophylaxis interventions in Kenya, there is limited data generated through the HIS to adequately guide evidence-based approaches for informed planning and implementation of sustainable interventions . FindingEffective reporting systems limit the burden on public HIS in regions endemic of tropical diseases by informing the establishment of sentinel sites for assessing disease control interventions for targeted conditions . This isRecommendations on enhanced data analysis for PC-NTDs are in line with efforts to ensuring public health surveillance and response systems institute rigorous data analysis and management tools that are vital in assessing attainment of elimination goals , 42, 43.Having non-functional community health units that lack the capacity to coordinate supervisory activities in PC-NTDs endemic regions, may explain participants\u2019 lack of agreement on the feasibility of undertaking regular supervision at peripheral levels. Essentially, engagement of community health personnel is critical to achieving effective implementation of NTD interventions . The neeThe study approach enabled an extensive assessment on the cardinal and feasible recommendations based on consensus among concerned stakeholders, which are pertinent to improving disease surveillance and response to PC-NTDs in Kenya. First, the survey focused on assessing stakeholders\u2019 perceptions at the sub-national level, because this level provides first contact to healthcare services for communities living in NTD endemic regions. However, subsequent surveys could further assess stakeholders\u2019 perspectives at the national surveillance level, since decisions made at the national level may influence implementation of feasible recommendations sub-nationally. Secondly, important recommendations that lacked consensus on feasibility for implementation in the second round were not subjected to further inquiry. However, further subsequent investigations considering these recommendations will aid in ensuring optimal performance of the overall surveillance system. Thirdly, due to the existing COVID-19 pandemic while conducting the study, it required strict adherence to physical distancing measures between the interviewer and study participants. Therefore, the Delphi consensus survey that can be conducted electronically was an appropriate methodological approach for collating stakeholders\u2019 views and assessing consensus among the participants. However, criticisms regarding the validity of the Delphi technique relate to a form of bias in its conduct, in that the consensus reached can be influenced by the way the researcher administers the data collection tool to the group of experts . AdditioSustained efforts to control and eliminate PC-NTDs are hinged on optimal functioning of HIS. Essentially, surveillance and response activities form part of the definitive phase to achieving NTDs elimination through halted disease transmission . AchieviNo funding received.Additional file 1Additional file 2"}
+{"text": "Calcitonin gene-related peptide (CGRP) has long been in the focus of migraine research as an indicator but also as a key mediator involved in the generation and aggravation of migraine attacks  but its 10In the present longitudinal pioneering study, the group of Patricia Pozo-Rosich used saliva to measure CGRP levels in 22 females suffering from episodic migraine of different frequency compared to 22 healthy controls . They apIn comparison to CGRP measurements in other compartments like plasma or tear fluid, sampling and assessment of the peptide in salivary appears elegant and easy to repeat, however, the method requires high compliance of participants, since it can be confounded by several factors and depends on careful handling and extraction protocols. The observation that the CGRP concentration in saliva is higher compared to circulating plasma CGRP may indicate a concentrated release from trigeminal afferents which sparsely innervate the salivary glands ,20 and aIn conclusion, the present study is relevant by mainly reviving some decisive questions about the effects of CGRP in the trigeminovascular system and in migraine: What comes first: trigeminal afferent activation or CGRP release? Is CGRP released from trigeminal afferents and drives the pain phase of migraine attacks, or is it just a bioindicator for vigorous activation of trigeminal afferents? Can migraine attacks occur without head pain though with increased CGRP release? Is the CGRP release from peripheral or central trigeminal structures also responsible for neurological symptoms like photo- and phonophobia and how does this occur? Are there indeed different types of migraine, dependent on CGRP levels and possibly other peptides of the calcitonin family or non-peptide mediators like nitric oxide? And finally, can salivary CGRP levels be used to stratify patients and their anti-migraine treatment targeting the CGRP signalling system?"}
+{"text": "Combining the stress process model of caregiving and life course perspective, this study examined the long-term influences of childhood abuse on perpetrating parent-adult child relationships and adult child well-being in the context of caregiving. Using a sample of family caregivers from the Wisconsin Longitudinal Study , we investigated whether contact frequency and emotional closeness with an abusive parent mediate the longitudinal effects of parental childhood abuse on adult child caregivers\u2019 depressive symptoms and the moderating effects of self-acceptance and mastery on this mediational association. Key findings indicate that maternal childhood abuse may negatively affect emotional closeness between an adult child caregiver and perpetrating mother . This could lead the adult child caregiver to experience increased depressive symptoms . Although the mediation paths for the effect of maternal childhood abuse on depressive symptoms via emotional closeness with mothers did not differ by caregivers\u2019 level of psychological resources, we found that psychological resources significantly moderated the association between maternal childhood abuse and depressive symptoms . Further research may explore this phenomenon in light of the heterogeneity of contemporary families. Practitioners working with adults with a history of parental childhood abuse who are caregiving for their perpetrator are encouraged to employ a trauma-informed approach to maximize the caregivers\u2019 health and well-being."}
+{"text": "Public misconceptions about antibiotic use persist despite the efforts of antibiotic awareness campaigns. These campaigns have often followed a top-down approach and have not sought input from the public. Communities need to see antibiotic campaign messages as relevant, accessible and important in order to have an influence on health-seeking behaviour and antibiotic use.To develop a series of evidenced-based infographics (EBIs) on antibiotic use for common infections in children and to evaluate their effectiveness at increasing parents' understanding of antibiotic use and antibiotic resistance.There were three phases to this research. In Phase 1 we set out to identify and summarize scientific evidence for the use of antibiotics for three common infections in children . Phase 2 focused on co-design of a series of prototype EBIs for each infection in focus groups with parents of young children and graphic designers, to test the face and content validity. Phase 3 tested the feasibility of EBIs in increasing parents' understanding about antibiotic use and the perceived relevance of antibiotic resistance in an online survey.n\u2009=\u2009998). EBIs improved knowledge by more than a third across the board . Respondents confirmed that EBIs were novel and potentially useful, corroborating our focus group findings.We iteratively co-produced 10 prototype EBIs. Parents found the evidence displayed in the EBIs novel and relevant to their families. Parents did not favour EBIs that were too medically focused. The way the information was displayed influenced their understanding. Parents preferred one health message per EBI. We included eight EBIs in a national survey of parents (Co-designed EBIs have the potential to succinctly change parents' perceptions about antibiotics for acute respiratory tract infections in children. Further research should test EBIs in real-world settings to assess their reach as a potential public-facing intervention."}
+{"text": "Patients with substance use disorders (SUD), specifically opioid use disorder (OUD) and injection drug use (IDU) utilize healthcare resources for prolonged inpatient treatment of serious infections stemming from their addictions. For a variety of reasons, physicians treating these patients refuse to send these patients home to receive outpatient parenteral antimicrobial therapy (OPAT), and instead keep the patient in the hospital for several weeks or longer to complete treatment for the injection-related infections. Patients who do not have history of IDU are sent home with a PICC line to receive OPAT once they are no longer acutely ill and therefore no longer meet criteria to remain inpatient, which is the established standard of care. Patients with OUD and IDU are not allowed the same standard of care, and furthermore do not receive adequate, if any, therapy for their primary problem and reason for their serious infection \u2013 the addiction.Flow chart of the MAT-OPAT processMedication-assisted treatment (MAT) with buprenorphine-naloxone has been approved for treating adults with opioid use disorder as part of a comprehensive treatment program that also includes counseling and behavioral therapy. Until now in our healthcare system there has been no comprehensive and integrated program to safely discharge patients with OUD and IDU to receive OPAT via a PICC line, while simultaneously treating their addiction. We describe the implementation of a MAT-OPAT program. Please refer to the chart included.We present a successful case of a 36-year-old male with a history of endocarditis associated with IV drug use and the intervention of the Healthcare System to link the patient to appropriate Infectious disease, behavioral health and medication adherence treatment for opioid abuse. The patient completed the IV antibiotic therapy and remained enrolled in the behavioral health program with a successful outcome.MAT-OPAT implementation in large healthcare system with continuous outpatient support that includes Infectious Disease services, behavioral health and drug abuse rehabilitation therapy can be a successful strategy to minimize readmisi\u00f3n, cost and complications in patients with history of IV drug use and infections that require prolonged intravenous antibiotic therapy.All Authors: No reported disclosures"}
+{"text": "Syphilitic myelitis, also known as tabes dorsalis, is a disease affecting the posterior columns of the spinal cord and dorsal roots and presents as sensory ataxia and neuropathic pain and less commonly as paresthesia and gastrointestinal disturbance. Tabes dorsalis is the clinical manifestation of a previous infection with syphilis, and the average latency period from initial infection to presentation of symptoms is approximately 25 years. This is a rarely encountered manifestation of syphilis since the widespread usage of antibiotics. Penicillin G is the mainstay therapy of neurosyphilis and has been shown to improve and resolve spinal cord lesions associated with tertiary syphilis. We present a case of tabes dorsalis in a 56-year-old female with a history of extensive autoimmune disease who initially presented with neck pain and numbness of the right lower extremity. The unique nature of this case lies in the patient\u2019s clinical course, as her symptoms were initially attributed to her history of autoimmune disease. A reactive CSF-VDRL  test and MRI findings led clinicians to suspect neurosyphilis and begin penicillin G. The patient began to show significant clinical improvement after penicillin G therapy was begun and was discharged to a rehabilitation facility to continue antibiotics and begin aggressive physical therapy. Treponema pallidum, a gram-negative spirochete, is the causative organism of the sexually transmitted infection known as syphilis  every four hours) therapy for a total of 14 days. After receiving IV penicillin G, she reported significant clinical improvement. Our patient was stabilized and transferred to acute rehab to continue IV antibiotics and begin aggressive physical therapy.Tabes dorsalis is a rarely encountered neurological manifestation of syphilis in the antibiotic era. Norwegian physicians in the late 19th century began to further understand syphilis by describing the unique evolution of this infection in 1400 patients with primary and secondary syphilis . This leTabes dorsalis is the neurological manifestation of a previous infection with syphilis after an average latency period of 25 years. Affecting the posterior columns of the spinal cord and dorsal roots, this disease commonly presents as ataxia and neuropathic pain and less commonly as paresthesia. Although physical examination findings can vary, the presence of characteristic findings such as the \u201cflip-flop\u201d sign or \u201ccandle-guttering\u201d appearance on enhanced T1-weighted MRI images, hyperintense lesions on T2-weighted MRI images, and a positive CSF-VDRL test can establish the diagnosis of neurosyphilis. Upon diagnosis, penicillin G therapy is the mainstay therapy, and lesions have been shown to improve and resolve with adequate antibiotic coverage. Although the occurrence of tabes dorsalis is rarely seen today since the widespread usage of antibiotics, this case reminds of the importance of a wide differential and thorough social history in patients immigrating from other countries and complaining of vague neurological symptoms."}
+{"text": "Image segmentation is a branch of digital image processing which has numerous applications in the field of analysis of images, augmented reality, machine vision, and many more. The field of medical image analysis is growing and the segmentation of the organs, diseases, or abnormalities in medical images has become demanding. The segmentation of medical images helps in checking the growth of disease like tumour, controlling the dosage of medicine, and dosage of exposure to radiations. Medical image segmentation is really a challenging task due to the various artefacts present in the images. Recently, deep neural models have shown application in various image segmentation tasks. This significant growth is due to the achievements and high performance of the deep learning strategies. This work presents a review of the literature in the field of medical image segmentation employing deep convolutional neural networks. The paper examines the various widely used medical image datasets, the different metrics used for evaluating the segmentation tasks, and performances of different CNN based networks. In comparison to the existing review and survey papers, the present work also discusses the various challenges in the field of segmentation of medical images and different state-of-the-art solutions available in the literature. Image segmentation involves partitioning an input image into different segments with strong correlation with the region of interest (RoI) in the given image , 2. The The earlier image segmentation models were based on traditional image processing approaches , 5 whichMedical image segmentation is difficult task due to various restrictions inflict by the medical image procurement procedure, the type of pathology, and different biological variations . The anaThe present work covers the recent literature in medical image segmentation. The work provides a review on different deep learning-based image segmentation models and explains their architecture. Many authors have worked on the review of medical image segmentation task. \u2009 Firstly, the present study provides an overview of the current state of the deep neural network structures utilized for medical image segmentation with their strengths and weaknesses\u2009 Secondly, the paper describes the publicly available medical image segmentation datasets\u2009 Thirdly, it presents the various performance metrics employed for evaluating the deep learning segmentation models\u2009 Finally, the paper also gives an insight into the major challenges faced in the field of image segmentation and their state-of-the-art solutionsAll the aforementioned survey literatures discuss the various deep neural networks. This survey paper does not only focus on summarizing the different deep learning approaches but also provides an insight into the different medical image datasets used for training deep neural networks and also explains the metrics used for evaluating the performance of a model. The present work also discusses the various challenges faced by DL based image segmentation models and their state-of-the-art solutions. The paper has several contributions which are as follows:The organization of the rest of the paper is given in Deep learning is the most essential approach to artificial intelligence. Deep learning algorithm uses various layers to construct an artificial neural network. An artificial neural network (ANN) consists of  input laThis section provides a review of different deep learning neural networks employed for image segmentation task. The different deep neural network structures generally employed for image segmentation can be grouped as shown in A convolutional neural network or CNN see  consists\u2009 The fully connected layers in CNN cannot manage different input sizes\u2009 A convolutional neural network with a fully connected layer cannot be employed for object segmentation task, as the presence of number of objects of interest in the image segmentation task is not fixed, so the length of the output layer cannot be constantDifferent CNN models have been reported in the literature, including AlexNet , GoogleN\u2009 It is not fast for real time inference and it does not consider the global context information efficiently.\u2009 In FCN, the resolution of the feature maps generated at the output is downsampled due to propagation through alternate convolution and pooling layers. This results in low resolution predictions in FCN with fuzziness in object boundaries.In fully convolutional network (FCN), only convolutional layers exist. The different existing in CNN architectures can be modified into FCN by converting the last fully connected layer of CNN into a fully convolutional layer. The model designed by  can outpAn advanced FCN called ParseNet  has beenx to latent space representation, while the decoder predicts the output from this representation. The different types of encoder-decoders based models generally employed for medical image segmentation are discussed as follows:Encoder-decoder based models employ two-stage model to map data points from the input domain to the output domain. The encoder stage compresses the given input, U-Net model  has a do\u2009 U-Net model can perform efficient segmentation of images using limited number of labelled training images\u2009 U-Net architecture combines the location information obtained from the downsampling path and the contextual information obtained from upsampling path to predict a fair segmentation mapThe U-Net model offers the following advantages:\u2009 Input image size is limited to 572\u2009\u00d7\u2009572\u2009 In the middle layers of deeper UNET models, the learning generally slows down which causes the network to ignore the layers with abstract features\u2009 The skip connections of the model impose a restrictive fusion scheme which causes accumulation of the same scale feature maps of the encoder and decoder networksU-Net models also have few limitations, stated as follows:To overcome these limitations, the different variants of U-Net architecture have been proposed in the literature: U-Net++ , AttentiIt is also an FCN-based model employed for medical image segmentation . VNet ar\u2009 It cannot be implemented in real time as it takes around 47\u2009seconds to train the network for classification task of 2000 region proposals in a test image.\u2009 The selective search algorithm is a predetermined algorithm. Therefore, learning does not take place at that stage. This could lead to the generation of unfavourable candidate region proposals.Regional convolutional network has been utilized for object detection and segmentation task. The R-CNN architecture presented in  generateTo overcome these drawbacks, different variants of R-CNN, fast R-CNN, faster R-CNN, and mask R-CNN have been proposed in the literature.In R-CNN, the proposed regions of image overlap and same CNN computations are carried again and again. The fast R-CNN reported by  is fed wK different potential boundary boxes with their respective scores representing position of object. These bounding boxes fed to fast R-CNN generate the precise classification boxes.In R-CNN and fast R-CNN, the proposed regions were created using a process of selective search and were a slow process. So, in faster R-CNN architecture given by , a singlHe et al. in  extended\u2009 It controls the resolution of feature responses in CNNs\u2009 It converts image classification network into a dense feature extractor without the requirement of learning of any more parameters\u2009 employs conditional random field (CRF) to produce fine segmented outputDeepLab model employs pretrained CNN model ResNet-101/VGG-16 with atrous convolution to extract the features from an image . The useThe various variants of DeepLab have been proposed in the literature including DeepLabv1, DeepLabv2, DeepLabv3, and DeepLabv3+.In DeepLabv1 , the inpIn DeepLabv2 model, multiple atrous convolutions are applied to input feature map at different dilation rates. The outputs are fused together. Atrous spatial pyramid pooling (ASPP) segments the objects at different scales. The ResNet model used the atrous convolution with different rates of dilation. By using atrous convolution, information from large effective field can be captured with reduced number of parameters and computational complexity.DeepLabv3  is an exDeepLabv3+  consistsThe different deep neural networks discussed in the above sections are employed for different applications. Each model has its own advantages and limitations. Deep learning networks had contributed to various applications like image recognition and classification, object detection, image segmentation, and computer vision. A block diagram representing deep learning-based system is given in This basic layout of deep learning models shown in  is emploA 2D and 3D CNN based fully automated framework have been presented by  to segmeChrist et al. in  presenteGordienko et al.  reportedPoudel et al. in  developeIn , authorsData is important in deep learning models. Deep learning models require large amount of data. The data plays an important role. It is difficult to collect the medical image data as there are data privacy rules governing collection and labelling of data and also it requires time-consuming explanation to be performed by experts . The medThe medical imaging is performed in different types of modalities , such as\u2009 True positive (TP) represents that both the actual data class and the class of predicted data are true.\u2009 True negative (TN) represents that both the actual data class and the class of predicted data are false.\u2009 False positive (FP) represents that the actual data class is false while the class of predicted data is true.\u2009 False negative (FN) represents that the actual data class is true while the class of predicted data is false.A metric helps in evaluating the performance of any designed model. The metrics provide the accuracy of the designed model. The popular metrics employed for assessing effectiveness of any designed segmentation algorithm are represented in terms of the following :\u2009 True pPrecision is an evaluation metric that tells us about the proportion of input data cases that are reported to be true and represented in .(1)PreciRecall represented in  gives thF1 score tells about models accuracy as represented in the following equation. It is defined as the harmonic average of the precision and recall values :(3)F1\u2009scIt gives the percentage of pixels in a given input image which are correctly classified by the model :(4)PixelIntersection over union (IoU) or Jaccard index  is a metIt is defined in the following equation and termed as twice the amount of intersection area between the segment predicted and the ground truth divided by the total number of pixels in both the predicted segment and ground truth image :(6)dice=The medical image segmentation field has gained advantage from deep learning, but still it is a challenging task to employ deep neural networks due to the following.The different challenges related to the dataset include the following:Limited Annotated Dataset. Deep learning network models require large amount of data. The data required for training is well annotated. The dataset plays an important role in various DL based medical procedures [ocedures . In mediocedures . Also, pocedures  are not The size of the existing medical image datasets can be increased by (a) application of image augmentation transformations like rotating image by different angles, flipping image vertically or horizontally, cropping, and shearing image. These augmentation techniques can boost the system performance. (b) The application of transfer learning from efficient models can provide solution to the problem of limited data . (c) FinClass Imbalance in Datasets. Class imbalance is intrinsic in various publicly available medical image datasets. A highly imbalanced data poses great difficulty in training DL model and makes model accuracy misleading, for example, in a patient data, where the disease is relatively rare and occurs only in 10% of patients screened. The overall designed model accuracy would be high as most of the patients do not have the disease and will reach local minima [l minima , 89.The problem of class imbalance can be solved by (a) oversampling the data; the amount of oversampling depends on the extent of imbalance in the dataset. (b) Second, by changing the evaluation or performance metric, the problem of dataset imbalance can be handled. (c) Data augmentation techniques can be applied to create new data samples. (d) By combining minority classes, dataset class imbalance problem can also be handled.Sparse Annotations. Providing full annotation for 3D images is a time-consuming task and is not always possible. So, partial labelling of information slices in 3D images is done. It is really challenging to train DL model based on these sparsely annotated 3D images [D images . In caseIntensity Inhomogeneities. In pathology images, colour and intensity inhomogeneities [eneities  are commFor correcting intensity inhomogeneities , differeComplexities in Image Texture. In medical images, there may be different artifacts present during manipulation of images. The different sensors and electronic components used for capturing images create noise in the image [he image , 91. In To remove different artefacts and noises from the image, different image enhancement techniques are used before segmentation. The image enhancement technique suppresses the noise in the image and preserves the integrity of the edges of the image.The important challenging issues related to the training of DNN for robust segmentation of the medical images are as follows:Overfitting the Model. Overfitting of the model refers to the instance when the model learn the details and regularities in training dataset with high accuracy compared with the unprocessed data instance. It mainly occurs while training the model with a small size training data [ing data .Overfitting can be handled  by (a) iMemory Efficient Models. Medical image segmentation models require large amount of memory [f memory . In ordeSimpler models and model compression techniques can reduce memory requirements for a DL model.Training Time. The training of deep neural network architecture needs time. In image segmentation, fast convergence of training time for deep NN is required.The solution to this problem is (a) application of batch normalization . It refeVanishing Gradient. Deep neural network faces the problem of vanishing gradient [gradient . It occuThere are several solutions to the problem of gradient vanishing. (a) By upscaling the intermediate hidden layer output using deconvolution and softmax , the auxComputational Complexity. Deep learning algorithm performing feature analysis needs to operate at a high level of computational efficiency. These algorithms need high performance computing devices and GPU [ and GPU . Some ofThe image segmentation techniques have come far away from manual image segmentation to automated segmentation using machine learning and deep learning approaches. The ML/DL based approaches can generate segmentation on large set of images. It helps in identification of meaningful objects and diagnosis of diseases in the images. The image segmentation techniques discussed in the paper can be explored by future researchers for application to various datasets.The future work may include a comparative study of the different existing deep learning models discussed in the paper on the publicly available datasets. Also, different combination of layers and classifiers can be explored to improve the accuracy of image segmentation model. There is still a requirement of an efficient solution to improve performance of image segmentation model. So, the various new deep learning model designs can be explored by future researchers.Deep learning-based automated diagnosis of diseases from medical images had become the latest area of research. In the present work, we had summarized the most popular DL based models employed for segmentation of medical images with their underlined advantages and disadvantages. An overview of the different medical image dataset employed for segmentation of diseases and the various performance metrics utilized for evaluating the performance of image segmentation algorithm is also provided. The paper also investigates the different challenges faced in segmentation of medical images using the deep networks and discusses the different state-of-the-art solutions to overcome these challenges.With advances in technology, deep learning plays a very important role in segmentation of images. The different studies reviewed in"}
+{"text": "From the very beginning of the COVID-19 pandemic older adults have been at the heart of public debate. Early articles argued that public representation of older persons displayed a a resurgence of ageist stereotypes and beliefs in (inter)national media . Yet studies confirming this are absent up to now. In this paper, we present findings on the representation of Dutch older adults during the first six months of the COVID-19 crisis in The Netherlands. We analysed 1141 articles about older adults of the five largest newspapers using quantitative content analyses and discourse analysis to systematically explore patterns, sentiments and meaning in the articles. We show that the majority of these articles were published in general news and that older adults were rarely (2%) cited in these articles. Most prominent adjectives were vulnerable and weak. Most prominent substantives were attention, long-term care facility and loneliness. The sentiment was largely negative. Additionally, we find three discursive frames predominate: \u2018an older people\u2019s disease\u2019, \u2018vulnerability\u2019 and \u2018solidarity\u2019. This evidences that the Dutch reporting on older adults during COVID-19 reproduced a discourse of dependency highlighting and further emphasizing the sociopolitical context before COVID-19 while drawing out earlier ageist tendencies. On the basis of our findings and drawing on advisory experiences, we discuss implications for policy, education and practice and how we can reframe and differently address older adults specifically in terms of language and their more (un)conscious positioning in (public) debate."}
+{"text": "Following the publication of the original article , errors The sentence currently reads:These findings indicate that chicory increases uric acid excretion by intestines, which may be related to the stimulation of intestinal uric acid excretion via down-regulating the mRNA and protein expressions of ABCG2.The sentence should read:These findings indicate that chicory increases uric acid excretion by intestines, which may be related to the stimulation of intestinal uric acid excretion via up-regulating the mRNA and protein expressions of ABCG2.The original article  has been"}
+{"text": "During the last year, primary prevention programs for childhood obesity have not obtained the goal in decreasing the prevalence of obesity in pediatric population. This phenomenon remains a crucial issue for the future translating itself in major health problems for the next young-adult generation. However ectopic adipose tissue distribution shows the same obesogenic effect also in slim people. Therefore, the use of adequate language is essential to develop consciousness of overall healthy lifestyle throughout the population. We therefore propone to replace \u201cobesogenic effect\u201d with adipose tissue related alterations also in childhood population. The cornerstone of each single primary prevention program is education especially in pediatrics. A pivotal role for the success of education is played undoubtedly by an appropriated use of language which needs to be simple, self-explicative and identificatory . AlthougA substantial obstacle for obtaining good results for primary prevention programs are current environmental influences on lifestyle promoting excessive intake of pro-atherosclerotic foods combined with substantial lack of physical activity mainly due to technology over use. This leads consequently to a continuous increase of body weight through society. The recent COVID-19 restriction abolishing movement of the population almost completely together with promotion of over-the-counter food also at home through delivery systems might explicate a clear atherosclerotic and pro-diabetogenic effect . These m"}
+{"text": "The life course perspective concept of \u201clinked lives\u201d suggests that the lives of adult children and older parents are interconnected and consequential for the well-being of members of both generations. In this work, we consider the association between tension among adult siblings and older mothers\u2019 psychological well-being. We focus specifically on tension in the adult sibling relationship because research has shown that negative relationship quality is especially consequential for well-being. We consider this association in the context of caregiving because this is a time when offspring are often required to coordinate with each other to provide assistance. We utilized data from 304 older mothers (average age = 78) and 736 of their adult children (average age = 49) from the Within-Family Difference Study (WFDS) II. First, we examined the direct association between adult sibling tension and mothers\u2019 reports of depressive symptoms. Second, we examined whether the association between sibling tension and mothers\u2019 depressive symptoms was moderated by mothers\u2019 need for care. Preliminary results indicated no direct effect of sibling tension on mothers\u2019 depressive symptoms. However, moderation analysis revealed that sibling tension was associated with an increase in mothers\u2019 depressive symptoms among mothers who reported needing assistance. These findings highlight the importance of understanding the interconnected nature of adult family relationships especially in the context of later-life family caregiving. In particular, the findings reveal that older mothers in need of care are especially vulnerable to tension in the relationships among their adult children."}
+{"text": "Throughout the Covid-19 pandemic, testing for SARS-CoV-2 to allow early identification and isolation of those likely to be infectious has been a cornerstone of public health strategies to interrupt transmission of infection. An early reliance on reverse transcription polymerase chain reaction (RT-PCR) to confirm infection in those showing \u2018typical\u2019 signs and symptoms associated with Covid-19 was quickly supplemented with the use of rapid antigen detection tests (RDTs), particularly as the use case scenarios for testing changed from a focus on containment to a situation where testing has a much wider role as part of efforts to ease societal restrictions The advantages of RDTs come at a cost of lower and more variable sensitivity. Rt-PCR  is highly sensitive for detection of SARS-CoV-2, but has been criticised for its continued detection of the virus long after an individual is likely to remain infectious EBioMedicineIn this article of Wagenh\u00e4user and colleaguesThe ability of RDTs to quickly pick up the majority of individuals with high levels of virus is undeniable but these tests do still miss people who are likely to be infectious and also risk falsely classifying uninfected individuals as positive. RDTs alone cannot be relied on to prevent outbreaks but, used in combination with Covid-19 symptom profiles and as triage to RT-PCR, can be a useful component of strategies to allow routine hospital procedures to continue. This study clearly emphasises the need for careful evaluation of RDT testing strategies for any given use case scenario prior to widespread roll-out.JD was solely responsible for the writing of the commentary.The author declares no conflict of interest."}
+{"text": "Shortage of physicians in rural areas can lead to lower diagnosis and underestimation of dementia prevalence in these communities. We used data from the nationally representative Health and Retirement Study and a 20-percent sample of Medicare claims to study rural-urban differences in dementia prevalence. The survey dementia diagnosis is free from medical assessment while the claims diagnosis needs a physician diagnosis. We estimated the trends in dementia prevalence from (2002-2016) based on cognitive tests (using survey data) and diagnosis codes (using claims data) utilizing ordinary least squares regression. Dementia prevalence based on diagnosis codes declined in both urban and rural areas over the course of the study, with a sharper decline in urban areas. Dementia prevalence using diagnosis codes showed significantly higher rates in urban areas during all years . Dementia in the cognitive test sample was higher in rural areas , a difference that was significant only in 2004. Our results indicate lower dementia prevalence rates in rural areas in claims based sample compared to survey sample which its dementia prevalence is free medical assessment. Claims data are valuable sources for tracking dementia in the US population, however they are based on medical diagnosis.In rural areas, where there is shortage of physicians and a lack of access to health care services, claims based studies may underestimate dementia rates."}
+{"text": "Solid organ transplant recipients are reliant upon a combination of lifelong immunosuppressant medicines to maintain functioning of their grafts. Therapeutic drug monitoring (TDM) is a well-established approach for guiding therapy, which involves individualization of drug dosage by maintaining drug concentrations within a pre-defined target range. TDM is routinely performed during treatment with calcineurin- and mTOR inhibitors and is sometimes undertaken during mycophenolate usage. Consensus reports have established optimal TDM practices for these agents . While fFontova et al. reported lower whole blood and intracellular tacrolimus concentrations after the night dose compared to the same morning dose. These results suggest 24-h variations in both the extent and rate of absorption of tacrolimus due to circadian fluctuations in drug metabolising enzymes and efflux transporter proteins. Some transplant centres may estimate the area-under-the-concentration-time curve (AUC) of some immunosuppressant agents, which is likely a more robust overall measure of drug exposure. AUC can be determined through inclusion of a limited number of concentration-time points in a multiple linear regression equation or use of a population pharmacokinetic model applied in a Maximum a posteriori Bayesian estimator  in kidney and heart transplant recipients, documenting large between-subject pharmacokinetic variability and the influence of frequently used concomitant medication on MPA exposure. Wang et al. confirmed a negative effect of concomitant proton pump inhibitor treatment on the bioavailability of mycophenolate mofetil dispersible tablets. These data support previous recommendations for more personalized treatment with MPA3. However, the optimal frequency of MPA TDM or which clinical events should prompt determination of MPA AUC need to be further established.While there is consensus around the need for monitoring of the calcineurin- and mTOR inhibitors, assessment of plasma levels of antimetabolites is often not performed. Sallustio has written an excellent review on the topic. The conclusion is that the verdict is still out. Available studies of tacrolimus largely describe a poor correlation between concentrations in the blood and in PBMCs but so far only identified the haematocrit value as a consistent determinant of distribution. Future studies should employ methods, which allow for elucidation of a more complex relationship including temporal delays in achieving equilibrium, and the role of specific drug transporters and drug metabolizing enzymes in addition to haematocrit.Another area of interest is measurement of intracellular concentrations of immunosuppressants in immune cells circulating in the blood ). It is conceivable that intracellular concentrations hold actionable information, which might ultimately lead to further improvements in TDM. Shi et al. identified patient adherence to immunosuppressant therapy as one of the most crucial factors for long-term allograft survival in a systematic review and meta-analysis. They suggested that clinicians should ideally establish a long-term intervention protocol to foster immunosuppressant adherence. To realize this goal, a multidisciplinary team-led, intervention approach combined with smartphone monitoring was recommended.TDM can also assist with checking patient compliance with therapy. In summary, while TDM is routinely used for several immunosuppressant agents there are still much to learn in this field. Further research is required into optimal references ranges to target in different patient cohorts and under varying immunosuppressant combinations; how to best perform dosage adjustments based on exposure measurements and patient response; sources of pharmacokinetic variability associated with these agents; whether other novel mediums and methods could be used to better access drug exposure or immune response; and how to influence patient behaviour to ensure adherence with immunosuppressant treatments. With few new immunosuppressive medicines under development in the transplant field the continued pursuit of novel methods to better personalize the medicines we currently have is warranted."}
+{"text": "Scientific Reports 10.1038/s41598-019-54542-y, published online 19 December 2019Correction to: The original version of this Article contained an error in the Data Availability section, which did not contain the accession codes for the data. This information is now included and in Data Availability,\"The datasets analyzed during the current study are available from the corresponding author on reasonable request.\"now reads\"The datasets analyzed during the current study are available from NCBI GEO database with the accession number GSE178500.\"The original Article has been corrected."}
+{"text": "New technologies with the potential to improve population health are being continually introduced through research and innovation. To improve care with available resources, it is necessary to promote the most cost-effective technologies, respecting organizational, social and ethical issues. This can be a concern in recent years with the growth in pharmaceutical expenditure being driven by new medicines for complex diseases, including cancer and orphan diseases, often though with limited health gain . This caHealth Technology Assessment (HTA) has become an indispensable tool to inform health decisions and contribute to best practices, whether in the clinical or management scope. Furthermore, it has been widely used to improve health policies. This Research Topic seeks to debate in way the current challenges for the application of health technology innovation - specifically the use of rational and evidence-based approaches.Publications contained in this Research Topic (n = 23 studies) summarized information regarding to health technologies  focusing on reporting of therapeutic risk management ; available evidence of effectiveness and/or safety of medicines (n = 5); drug utilization research (n = 1); effectiveness of other interventions  (n = 2); methodological studies (n = 2); health litigation (n = 3); implementation science (n = 4); cost-effectiveness analysis (n = 1); and digital technologies (n = 1).Calderon-Ospina et al.; Lima et al.) alongside the adults/elderly . Another study analyzed adverse neonatal outcomes in adolescent pregnancy .ADRs are a predominant public health problem especially among the elderly, hospitalized and those patients on multiple medicines. Aspects related to safety regarding the use of medications among children were also studied . Another study collected data from pediatric intensive care units (PICU) in a teaching hospital. The authors observed that most of children were exposed to at least one potential DDI during PICU stay and there was increased of length of stay in children with major or contraindicated DDIs .One study collected information from the database of the Brazilian Surveillance Agency, known as Notivisa, where reports of suspected serious adverse drug reactions (SADR) mainly with IV dosage forms and off label drugs, were observed demonstrating the need for further drug research in this area including the use of better dosage forms among children .Another study analyzed the prevalence of ADRs in a population with Alzheimer\u2019s disease. Data were collected through interviews with patients and caregivers who obtained their medication for Alzheimer\u2019s at a public pharmacy in Brazil, complemented by the prescribing data system. Most patients had at least one ADR, mainly due to psychiatric disorders . We believe this provides guidance to others experiencing such concerns.The risks of adverse neonatal outcomes in younger pregnant adolescents properly followed through group prenatal care, delivered by specialized public services, were also analyzed. Data were obtained from medical records and interviews with a multidisciplinary team that treated these patients. The lower incidence of adverse outcomes was observed in younger pregnancy adolescents that followed the prenatal care model . Risperidone was the antipsychotic associated with the highest risk of switching. Previous research conducted in Brazil has also shown greater effectiveness of olanzapine versus risperidone in routine clinical care (Switching between second-generation antipsychotics (SGA) is a common clinical practice in the treatment of schizophrenia and schizoaffective disorders due to differences in the tolerability and safety profiles of the different anti-psychotics , as wellcal care .Pedroso et al.). Appropriate empiric use of antibiotics is important to reduce morbidity, mortality and costs associated with antimicrobial resistance . Overall, the hospital mortality was lower in the group who received empirical broad-spectrum antibiotic therapy (EAT), although the antibiotic therapy guided by blood cultures (ATGBC) also reduced the mortality in these patients . This is important to help guide future treatment approaches.Almost 30% of new antiepileptic drugs have drug-resistant forms of the disease. A cohort study assessed the impact of a number of genetic factors and their possible association with treatment response to phenytoin. Little more than half of the evaluated subjects were non-responding to phenytoin and the decreased function alleles of CYP2C9 were predictive of vestibular-cerebellar ADR to phenytoin .A 16-years cohort constructed by deterministic and probabilistic matching, through three databases of the Brazilian public health system, assessed the impact on liver graft survival with two different calcineurin inhibitors (tacrolimus or cyclosporine). Younger patients had a longer graft survival time than older ones. The use of tacrolimus was also more prevalent and had a better survival rate. Older age and the greater time ratio without using an immunosuppressant were identified risk factors for liver graft loss. White-skinned patients and tacrolimus-based regimens are factors for improved graft survival .The use of proton pump inhibitors (PPI) in ambulatory care was analyzed based on aggregated utilization data from the National Health Insurance database. Despite the tolerability and clinical benefits, potential long-term side effects have been observed with PPIs. There is a concern that patients receive PPIs in high doses and for a long period of time resulting in health authorities seeking to encourage rapid transfer from a healing to a maintenance dose. Overall, pantoprazole was the PPI most frequently used by hospitalized patients . This is important with the envisaged greater role of pharmacists to help with healthcare  evaluated the impact of medication reviews from community pharmacies in elderly patients with type 2 diabetes under real-life conditions. The study shows that medication reviews performed by community pharmacists reduced the frequency and number of drug-related problems even though the pharmacies had to face obstacles such as lack of cooperation by the prescriber or lack of reimbursement . This is important for the future especially if community pharmacists are the principal healthcare provider, and often the first point of contact for patients across countries . This is important given rising prevalence rates for diabetes across countries with an appreciable impact on morbidity, mortality and costs if not properly managed . The findings can be used to improve the care of these patients in the future. Others initiatives can be used to increase knowledge translation and strengthening capacity core teams of health professionals  to evaluate patients\u2019 health-related quality of life (HRQoL) with hematological malignancies and their symptom experience in daily clinical practice as well as in research . These papers are important to give guidance to the authorities in Brazil as they seek to tackle the increasing costs of litigation . Such approaches are essential to improve the health of patients.Three qualitative studies emphasized the importance of considering patient preference for the development of guidelines and to develop strategies for behavioral change communication. Vasconcelos et al.. The authors concluded that even among high-quality CPGs, the implementation strategies report can be improved, especially concerning monitoring of implementation outcomes and selection of strategies based on relevant implementation barriers . Studies have shown that multiple activities involved in the implementation and monitoring of adherence to guidelines helps enhance their use and impact  was also studied by d impact . In addid impact .Bulaj et al.). This will be an increasing area of research as the use of technologies grows to monitor medicine use and outcomes across sectors.Digital health encompasses several technologies, which have the ability to monitor the human body continuously and uninterruptedly, collecting physiological data, and enabling the improvement of clinical practices. These technologies enable the integration of pharmacotherapies with self-care, lifestyle interventions and patient empowerment, while concurrently advancing patient-centered care, integrative medicine and digital health ecosystems (In this Research Topic, a particular emphasis, was given to the technological development of new health care/services approaches describing processes regarding the introduction and implementation of technologies into health systems; the knowledge translation; evidence-based policy and its utility as a guide for implementation of health-promoting technologies; big data analytics for health policy in decisions making; and real-world cases. We will continue to monitor the situation to provide future guidance."}
+{"text": "In the original article, there was a mistake in Additionally, in the original article, there was an error in the identification of type II IS cells  of VIP+ interneurons projecting to the stratum radiatum).VIP in the Hippocampus, Second Paragraph.A correction has been made to section The corrected paragraph is shown below.VIP+INs dendritic trees and axon projections  include two subtypes: (a) interneurons with cell bodies located at the stratum pyramidale (SP) or near and projecting to the stratum Oriens/Alveus border  oriens lacunosum-moleculare (OLM) interneurons innervating the distal dendrites of pyramidal cells at the stratum lacunosum-moleculare (SLM) and (b) VIP+INs that project their axons to the stratum radiatum  or at SR/SP and targeting interneurons controlling synaptic transmission to proximal dendrites of pyramidal cells in the SR  was described targeting INs within the O/A in CA1 but also both INs and pyramidal cells within the subiculum (Francavilla et al., Detailed immunohistochemistry studies fully characterized hippocampal The authors apologize for these errors and state that they do not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "MLL-rearranged infant acute lymphoblastic leukemia (MLL-r iALL) undergo intense therapy to counter a highly aggressive malignancy with survival rates of only 30\u201340%. The majority of patients initially show therapy response, but in two-thirds of cases the leukemia returns, typically during treatment. The glucocorticoid drug prednisone is established as a major player in the treatment of leukemia and the in vivo response to prednisone monotreatment is currently the best indicator of risk for MLL-r iALL. We used two different single-cell RNA sequencing technologies to analyze the expression of a prednisone-dependent signature, derived from an independent study, in diagnostic bone marrow and peripheral blood biopsies. This allowed us to classify individual leukemic cells as either resistant or sensitive to treatment and show that quantification of these two groups can be used to better predict the occurrence of future relapse in individual patients. This work also sheds light on the nature of the therapy-resistant subpopulation of relapse-initiating cells. Leukemic cells associated with high relapse risk are characterized by basal activation of glucocorticoid response, smaller size, and a quiescent gene expression program with cell stemness properties. These results improve current risk stratification and elucidate leukemic therapy-resistant subpopulations at diagnosis.Infants with  Translocations of the MLL gene on chromosome 11q23 lead to fusions of the N-terminus of MLL to the C-terminus of one of many known translocation partner genes. The majority of infant ALL patients carry one of three recurrent types of MLL translocations in which the MLL gene becomes fused to either AF4 , ENL , or AF9  , , 3, MLL-In our analyses, we found that an activity-quiescence continuum is the most prominent feature separating resistant cells from sensitive cells. Although unlikely to be directly associated with prednisone, it reflects the well-documented resilience of quiescent cells to chemotherapy and suggests that the resistance signature might represent not only prednisone resistance but also multiple therapy-escape mechanisms. This view is further supported by several classes of genes we found enriched in resistant cells. Detection of general mediators of drug resistance and efflux transporters argues for broad therapy resistance, while stemness markers typical of leukemic stem cells might help escape drug-induced cell death and maintain replicative potential. Taken together, these results argue for a model where prednisone monotreatment selects for cells that are small, quiescent, and generally resistant to chemotherapy, setting the stage for future research to characterize them more in depth and decode their therapy-resistance mechanisms.There are several aspects and limitations of this study that will need to be addressed in order to help translate this knowledge to the clinic. scRNA-seq is not yet a routine lab technique and application of bulk RNA-seq to detect the gene signature suffers from quantification problems owing to the smaller RNA content of resistant cells. Identification of an easily detectable hallmark could help offset this problem and simplify the quantification of resistant cells. However, investigation of clonality and mutation analysis might be required to identify DNA-based hallmarks that are not affected by the smaller size of resistant cells. Despite considerable success, two patients in the cohort were misclassified by our method. At this stage we cannot exclude that specific mutations might act as epistatic factors, bypassing the drug escape mechanisms and resulting in relapse development. Finally, validation of this signature on vast numbers of patients\u2014while essential for inclusion in upcoming trials\u2014is problematic both due to the technique and to the rarity of the disease.Taken together, these results demonstrate how single-cell sequencing can be used to further our understanding of cancer cell population dynamics and use them for accurate risk assessment. Eventually, elimination of these therapy-resistant cells during early phases of the treatment may well prevent relapse occurrence in a substantial number of cases, leading to increased survival.Supplementary methodsSupplementary Table 1Supplementary Table 2Supplementary Table 3Supplementary Table 4Supplementary Figure 1Supplementary Figure 2Supplementary Figure 3Supplementary Figure 4Supplementary Figure 5Supplementary Figure 6Supplementary Figure 7Supplementary figure legends"}
+{"text": "Memory imprecision is a hallmark of age-related cognitive decline and mild-cognitive impairment (MCI) and is characterized by increased memory interference and decreased stability of memory representations. Evidence from humans, non-human primates and rodents demonstrate reduced hippocampal neurogenesis, excitation-inhibition imbalance and inflexible hippocampal remapping during age-related cognitive decline and MCI. Developing strategies to reverse cognitive decline during aging and Mild Cognitive Impairment necessitates an understanding of molecular, cellular, circuit and network mechanisms that support memory functions of the hippocampus. Over the last decade we have built a multifaceted program grounded in basic neuroscience that is aimed at improving memory in aging and MCI. We have demonstrated how we can Rejuvenate the aged hippocampus by selectively increasing neurogenesis and how we can Re-engineer connectivity of aged inhibitory microcircuits to improve memory precision in aging. Ongoing efforts include strategies to Repairing neurogenic niche fitness by targeting intercellular communication in the aging hippocampus. In today\u2019s talk I will present a fourth approach catalyzed by our discovery of the first transcriptional regulator of neural stem cell expansion in the adult hippocampus. We will present data in support of this claim and convey how this discovery may guide strategies to maintain cognitive reserve embodied in the pool of neural stem cells in the adult hippocampus."}
+{"text": "OBJECTIVES/GOALS: Development of interventions that improve social functioning (SF) in first episode psychosis (FEP) is hindered by a poor understanding of the neural mechanisms underlying SF deficits. This research aims to identify neural correlates of social functioning in FEP, and to evaluate whether this substrate is malleable in response to cognitive training. METHODS/STUDY POPULATION: This is a secondary data-analysis of participants in an ongoing randomized clinical trial investigating whether 12 weeks of targeted cognitive training is neuroprotective in FEP, versus treatment as usual. Baseline and post-training assessments include a brain MRI, three measures of SF, and a neurocognitive battery. Healthy controls complete MRI only. Differences in cortical thickness (CTh) and gray matter volume (GMV) in regions of interest between FEP and controls will be determined with ANCOVA. Multiple linear regression will be used to determine the relationship between neural substrate and SF in FEP. Linear mixed models will be used to examine the relationship between change in CTh and GMV and change in SF. Data collection is ongoing for this study. RESULTS/ANTICIPATED RESULTS: In preliminary data including 12 FEP and 9 healthy controls, FEP demonstrated cortical loss in the right superior frontal cortex and the right isthmus-posterior cingulate. Greater cortical thickness in the posterior cingulate cortex was associated with better social functioning across multiple measures when controlling for global cognition. Gray matter volume in the parahippocampal gyrus was also associated with better social functioning. Preliminary results evaluating whether targeted cognitive training is neuroprotective in these regions of interest in a manner that is associated with improved social functioning will also be presented. DISCUSSION/SIGNIFICANCE OF IMPACT: Preliminary results link the posterior cingulate and parahippocampal gyrus to SF in FEP. Further research will investigate the contribution of changes in these brain regions to improved SF. The identification of biological treatment targets for SF may lead to development and optimization of novel interventions to alleviate SF deficits in FEP."}
+{"text": "In the appropriate clinical context, ST-segment elevation on electrocardiogram (ECG) necessitates prompt evaluation for coronary artery occlusion requiring reperfusion with percutaneous coronary intervention. Conversely, the etiology of ST-segment elevation may be representative of an alternative diagnosis other than myocardial infarction. We report the case of a patient with a history of primary bone sarcoma who presented for further evaluation of a large pericardial effusion identified on an outpatient echocardiogram and was found to have ST-segment elevation on ECG in the absence of any cardiopulmonary symptoms. The ECG abnormalities were attributed to a likely persistent current of injury resulting from a mass in the interventricular septum, likely representative of a metastatic lesion of his known malignancy. This case highlights the importance of maintaining a broad differential for ST-segment elevation, particularly in patients without symptoms of angina and those with a history of aggressive or relapsing cancer to minimize\u00a0the morbidity and mortality of invasive procedures. Elevation of the ST-segment on electrocardiogram (ECG) typically generates a list of potential diagnoses comprising common etiologies , as well as less common etiologies  . CardiacA 28-year-old, active-duty military male with relapsed, refractory, metastatic, malignant, giant-cell-rich, primary bone sarcoma presented to the Emergency Department (ED) by cardiology instruction for evaluation of a large pericardial effusion with possible early tamponade physiology that was identified on an outpatient transthoracic echocardiogram (TTE). The echocardiogram was performed to further evaluate findings from a positron emission tomography (PET) scan completed three days prior\u00a0that demonstrated findings concerning for cardiac metastasis to the interventricular septum with extension into the right ventricular outflow tract, along with an interval increase in the size of a pericardial effusion when compared to a PET scan from five months prior Figure . At the In the setting of ST-segment elevation, additional concern was raised by the discovery of hypokinesis of the septal myocardium on bedside echocardiogram, though it should be noted that this area of myocardium was being impinged upon by a 47 mm \u00d7 23 mm mass in the interventricular septum  with stable values on repeat assays performed at six-hour intervals.\u00a0The patient was then admitted to the Coronary Care Unit and monitored closely for signs of cardiac tamponade . He subsequently required pericardiocentesis for a large pericardial effusion concerning for tamponade physiology based on mitral inflow velocities. Based on cytology with negative infectious labs, the effusion was deemed secondary to his malignancy. Following a seven-day hospitalization and extensive multidisciplinary discussions with the patient and his family regarding the prognosis, the patient elected to forgo any further cardiac imaging and was discharged home with hospice, where he died shortly after discharge.We present a case of characteristic ST-segment elevation suggestive of anteroseptal STEMI in a patient with no risk factors for coronary artery disease, a recently identified cardiac mass, and without any correlating symptoms. Our patient\u2019s troponin T assay was found to be elevated above the 99th percentile of the upper reference limit on initial assessment without a subsequent rise and/or fall, and thus did not meet the criteria for myocardial infarction according to the Fourth Universal Definition of Myocardial Infarction . Given tVarious cases of patients with cardiac tumors presenting with ECG changes have been reported dating back to as early as 1934 . We consA review of ECG characteristics of metastatic cardiac tumors presenting with ST-segment elevation published by Akgun et al. in March 2020 described particular ECG features that could potentially assist in identifying the etiology and prevent inappropriate and unnecessary interventions . The autThis case report describes a young, active-duty military patient with classic findings of an anteroseptal ST-segment elevation myocardial infarction on ECG with elevated troponin level that ultimately appeared to be attributable to a current of injury from an interventricular septal mass. We consider this an important case to report as it reinforces the importance of maintaining a wide differential diagnosis for ST-segment elevation, particularly in the context of a patient with known metastatic malignancy and absence of typical anginal symptoms, risk factors, or signs of developing heart failure to help prevent unnecessary morbidity and mortality."}
+{"text": "Many vaccine candidates with promising results in preclinical testing fail in human trials. New complex human tissue models have the potential to improve the predictability of vaccine safety and efficacy in human clinical trials. There is a need for better models to improve preclinical testing of vaccines. This Perspective article argues that advanced mucosal human tissue models could present a solution to this pressing problem in the future. Vaccine development involves highly complex and expensive processes that have been classified by regulatory bodies into 2 stages: preclinical  and clinical (human). Potential vaccine candidates can fail at either stage. Before being introduced into the market, potential vaccines must be assessed for toxicity, immunogenic response stimulated, efficacy, and public health impact. This phase of the vaccine development process is usually done with 2D in vitro cultures of human cell lines as well as animal models such as mice and small primates. Proper formulation of vaccine candidates further requires a better understanding of host\u2013pathogen interactions. Although useful, data generated using animal models do not directly translate to the human system. Considerable physiological and immunological disparities exist between humans and animals while 2D human cell cultures lack the complexity of the in vivo tissue. For example, Toll-like receptor expression on innate immune cells such as the dendritic cells critically dictate the type of immune response . Toll-liCurrent advances in tissue engineering and cell biology have provided many tools for the development of complex in vitro 3D test systems relevant for studying human diseases and vaccine development. These 3D models have high in vitro\u2013in vivo correlation with the native tissues from which they are derived. They therefore have the advantage of assisting in better characterization and elucidation of the mechanism of host\u2013pathogen interactions compared to 2D cultures of the same cells. Presently available 3D models include self-organizing and cell-supporting matrix models such as organoids and spheroids as well as scaffold based in vitro complex models . FurtherNeisseria gonorrhoeae, and Streptococcus pneumoniae and other pathogens can be assessed using these in vitro 3D human mucosal models. Potential applications of these 3D in vitro models during the vaccine development include assessment of toxicity testing and the type, quality, and quantity of the immune response elicited. These models can also be applied to study the cell-mediated immune response as well as immune interference and/or cross-reactions between coadministered or other vaccines. The data generated may directly correlate with the human response, thus speeding up the vaccine development process. There is, therefore, an increasing interest in the potential impact of these models in the vaccine development process. This interest is reflected in the addition of the advanced human tissue models work package to the recently installed Inno4Vac consortium under the EU-funded Innovative Medicine Initiative (IMI), which is aimed at accelerating vaccine development and manufacture [Infections usually start at exposed mucosal surfaces of the respiratory tract, gut, and reproductive tracts. Currently, in vitro 3D mucosal models have successfully been implemented to elucidate the subtle differences in the interaction of various pathogens and their virulence factors with their human host. The role of the mucosa in the establishment of immunity against infections such as SARS-CoV-2, influenza, or even strictly human-specific pathogens like measles virus, ufacture .Although these proposed ideas are provocative, we are still decades away from a fully integrated system similar to the human body due to currently existing challenges related to integration and long-term culture of the models with immune cells. Furthermore, a connected multi-organ system consisting of the plethora of human organs/tissues is currently not possible due especially to differences in cell culture media formulations for the different tissues. The development of a universal cell culture media formulation like the human blood capable of sustaining long-term culture, proliferation, and differentiation of all the different cell types will be critical to attain this goal. However, the currently available models can be used to assess sera from vaccinated individuals as well as convalescent patients for their protective effect against reinfections. They can also be utilized for toxicity tests, assess viral vector infectivity, and lipid nanoparticle transfection efficiency. Coupled with in silico predictive systems, in vitro 3D human tissue models can provide a platform for high-throughput screening of potential therapeutics and vaccine candidates. There is, therefore, optimism that complex immunocompetent 3D in vitro models will provide better models for early identification of toxicity and complications in the vaccine and drug development process, thus saving cost and time.Finally, for these in vitro 3D models to be fully integrated into the vaccine development process, advancement of the models by incorporating multiple cellular components, improving microfluidic systems alongside other state-of-the-art technologies to overcome the current shortcomings are needed to improve their predictability and reliability."}
+{"text": "Planar fractal microstructure is observed on the silver film treated by positive corona discharge for the first time. Due to the abundant positive ions driven by the electrical field of positive polarity, surface modification is mainly induced by the plasma oxidation effect, resulting in a large scale of dendritic pattern with self-similarity and hierarchy. In contrast, negative ions dominate the plasma-film interaction under negative corona discharge condition, leading to a different surface morphology without fractal characteristics. A growth model based on the modified diffusion-limited aggregation (DLA) theory is proposed to describe the formation of the dendritic fractal structure, whilst the physics behind is attributed to the electric field directed diffusion of the positive ions around the surface roughness. Numerical simulation verifies the high density of the hot spot in the dendritic pattern, which may enable potential applications in fractal photonic metamaterials. Micro/nano-structures are of great importance for the ability to promote light\u2013matter interaction, facilitating the rapid development of optoelectronic devices and bringing broad application prospects . ConcurrAt present, there exists a wide variety of way to produce fractal structures. For example, Raveendran et al. report that the noble metal nanodendritic substrates are formed by electrodeposition method  and demoIn this work, we report the formation of planar dendritic fractal microstructure on a silver surface treated by positive corona discharge at atmospheric pressure. Recently, much effort has been paid to atmospheric plasma for its application in surface treatment and nanocomposite synthesis . Especia2 by magnetron sputtering  and the deposition thickness of the film can be precisely controlled. The setup of the microplasma system used for surface modification is illustrated in 3) (2O2 (x) are generated via the excitation and ionization of water and nitrogen in air  . Both ox 3)  substrate with low-cost. Using crystal violet as detection molecule, experiments demonstrate an enhancement factor as high as 10In conclusion, we report the spontaneous formation of fractal microstructure on a silver surface subject to the microplasma. At atmospheric pressure, surface modification via positive corona discharge produces a large-scale dendritic pattern with self-similarity. In contrast, the negative corona discharge generates the completely different morphology of randomly distributed dots. We also propose a growth mechanism to explain how the microstructure morphology can be turned from random scattered dots to fractal dendrites by altering the discharge polarity. Simulation via a modified DLA model reveals the growth process of fractal pattern, and the physics behind is attributed to the electric field directed diffusion of the positive ions with high oxidation activity in the plasma area. This work provides a simple and fast way to produce cost-efficient metallic fractal structure with a high surface area, which may facilitate the on-chip light matter interaction due to its high hot spot density. The fractal nanostructures with unequalled optical performance provide potential applications in low-cost SERS detection and fractal photonic metamaterials."}
+{"text": "The high prevalence of atrial fibrillation (AF) in the overall population and its association with substantial morbidity, increased mortality and health care cost has instigated significant basic and clinical research efforts over recent years. The publication of multiple new high-quality randomized multi-center trials in the area of AF management and the rapidly evolving technological progress in terms of diagnostic possibilities and catheter ablation in recent years demanded a revision of the previous ESC AF Guidelines from 2016. The 2020 guidelines provide up-to-date, evidence-based guidance for the management of AF. One of the most important innovations is the presentation of a new concept for structural characterization of AF (the \u201c4S AF scheme\u201d) replacing the traditional classification based on its temporal pattern alone . The 4S-AF-scheme highlights the importance of systematic assessment of stroke risk, severity of symptoms, total AF burden and underlying substrate as the foundation for effective and individualized AF treatment for each and every patient. Further novelties relate to the presentation of an easy and intuitive management pathway (\u201cABC pathway\u201d) and strengthening the recommendations for early rhythm control, in particular the role of first line catheter ablation in heart failure. Another core component of the guidelines is the focus on patient involvement to achieve optimal outcomes. Patient education, shared decision making and incorporation of patient values and patient reported outcome of treatment interventions as well as integrated care by a multidisciplinary team all have a central role in the proposed management pathway for AF. Globally atrial fibrillation (AF) is the most common cardiac arrhythmia in adults and the number of patients affected continues to rise with a currently estimated life time risk of 1 in 3 [The last decade has seen significant advances in the understanding of the mechanism of AF and its treatment. The ESC Guidelines 2020 [Early identification and commencement of appropriate treatment for AF may prevent potentially deleterious consequences such as stroke and heart failure as well as progression of the underlying substrate. Despite the intuitive usefulness of AF screening hard evidence from randomized studies supporting a prognostic benefit and cost-effectiveness of AF screening has long been lacking. The 2020 guidelines recommend systematic screening for patients aged >75 years or those at high risk of stroke (IIaB)  and oppoMobile health technologies have revolutionized AF screening with a multitude of commercially and medically available wearable monitors  in additA future development in AF screening to look out for will be the application of machine learning and artificial intelligence to sinus rhythm ECGs to identify patients with paroxysmal AF . For patients with cardiac devices with automated continued monitoring and tracing storage, regular device interrogation to screen for atrial arrhythmias is recommended. Atrial high-rate episodes (AHRE) are most commonly defined as paroxysmal episodes of atrial rates >175\u2013180 bpm lasting >5\u20136 min detected by CIEDs. If visual inspection of the intracardiac electrogram confirms the presence of AF, it may be referred to as \u201csubclinical atrial fibrillation\u201d. It is recommended that these patients undergo screening for risk factors and co-morbidities associated with AF, but it remains controversial which exact burden of AHRE and subclinical AF mandates medical treatment. It is unknown whether any rate or rhythm control intervention at this stage may prevent progression to clinical AF and no recommendation in regards to their initiation are given. 2DS2-VASc \u2265 2 in men and \u22653 in women) and AHRE durations >24 h. The cut off of >24 h is supported by large-scale trials, such as the ASSERT trial [The need and benefit of anticoagulation in AHRE is currently investigated by two ongoing large scale randomized trials  is now included as well. The temporal pattern and total burden of AF are not part of the stroke risk assessment in the current guidelines.Stroke Risk: As in previous guidelines, the recommended assessment tool for stroke risk estimation remains the well-known CHASymptom Severity: The severity of symptoms should be evaluated in a standardized manner with the EHRA symptom score ranging from 1 to 4 or via quality-of-life questionnaires. Importantly, a symptom-rhythm correlation should be established to differentiate from symptoms due to underlying co-morbidities.Severity of AF burden: Assessing the AF burden includes not only the traditionally used classification of the temporal pattern into paroxysmal, persistent and permanent AF but also the total AF burden defined as the percentage of time in AF for a defined time frame. Higher AF burden have been associated with higher stroke risk  and mortSubstrate Severity: A growing body of evidence showed that the severity and extent of left atrial structural and electrical remodeling has prognostic value for patients with AF. Technological improvements in non-invasive imaging modalities , cardiac CT) as well as invasive high density electro-anatomical contact mapping has allowed for more detailed assessment of the underlying substrate of AF. Nowadays, it is commonly acknowledged that left atrial size alone is not able to accurately define the disease state. Atrial wall fibrosis  and wallThe 4S AF scheme includes a comprehensive cardiovascular assessment including the following domains: To counterbalance the growing complexity of AF management due to a multiplicity of available treatment options, the 2020 guidelines have introduced an easy intuitive treatment algorithm to ensure effective and appropriate AF management for all patients: the ABC pathway (summarized in 2DS2-VASc score of 1 in men or 2 in women should be considered for anticoagulation (IIa B) and men with a score of \u22652 or women \u22653 have a clear I A recommendation. The guidelines emphasis the dynamic nature of many risk factors, and hence, all patients, particularly those with initially low scores, should be periodically re-evaluated. Despite the development of a new risk score, including several other clinical risk factors, imaging and biomarkers not included in the CHA2DS2-VASc score, the latter continues to have the best evidence for predicting thromboembolic risk [Optimal stroke protection remains at the heart of AF management. Oral anticoagulation can reduce risk of ischemic stroke by 65% at the cost of an increase of hemorrhagic stroke of 0.3%/year . Consistlic risk . InitiatA clear preference is given to new oral anticoagulants  over Vitamin K antagonists given the compelling evidence for better safety and efficacy with overall statistically significant mortality reduction compared to Warfarin . Exempt In case of absolute contraindications to anticoagulation, a left atrial appendage occlusion may be considered, but the class of recommendation remains IIbB as in 2016. The concept of LAA occlusion is limited by acknowledging that AF acts also as a risk marker of stroke risk and mechanical LAA occlusion may, therefore, only be a partial substitute for anticoagulation. Incomplete occlusion may even increase the risk for thrombus formation. Additionally, current commercially available percutaneous devices (WATCHMAN and AMULET) require a period of dual antiplatelet therapy with Aspirin and Clopidogrel for 1\u20136 months to avoid device related thrombus during re-endothelialization followed by long-term aspirin monotherapy. At the time of the guideline publication, available randomized outcome data for percutaneous LAA occlusion were limited to the Watchman device, but further studies are currently in progress. The randomized multi-center open-label COMPARE LAAO trial comparing the Watchman and other LAA occlusion devices to usual care of antiplatelet therapy or nothing started recruiting in January 2021 . In 2021A special challenge represents anticoagulation in the context of acute (ACS) or chronic coronary syndrome (CCS) requiring percutaneous coronary intervention. In general, the recommendations for duration of triple therapy have been shortened compared to previous guidelines. For uncomplicated PCIs, early cessation (\u22641 week) of aspirin and continuation of dual therapy with oral anticoagulation and a P2Y12 inhibitor (preferably Clopidogrel) for 6 to 12 months (ACS) ,34,35,36The second pillar of the ABC pathway refers to symptom control by means of rate or rhythm management with medication, cardioversion or invasive therapies. Elimination or amelioration of symptoms has always been one of the major driving forces for therapy. However, the positive effect of restoring and maintaining sinus rhythm goes beyond symptom control and has been shown to also increase exercise capacity  and qualIn terms of rate control, no significant changes have been implemented compared to the 2016 Guidelines. It remains part of the general background therapy for all AF patients, particularly for those with failed or contraindicated rhythm control attempts. The optimal target heart rate remains unclear, but generally, an initial lenient heart rate control of <110 bpm is accepted, with a more stringent control recommended in case of persistent symptoms or interference with cardiac resynchronization therapy.Rate control can be achieved by means of a mono- or combination therapy of betablocker and/or non-dihydropyridine calcium channel blocker and/or digoxin. Previous findings from observational studies of excess mortality of digoxin use in atrial fibrillation patients ,47 were It should be noted that drugs traditionally used for rate control did not show prognostic benefit for heart failure patients with reduced ejection fraction. A meta-analysis in 2014 found that betablocker did not provide prognostic benefit in the presence of AF  and no nDespite optimal management for AF, including anticoagulation and optimal rate control, patients still suffer from stroke, coronary syndromes, heart failure and cardiovascular death at a rate of approximately 5% per year ,52. DataThe 2020 Guidelines were published prior to the seminal EAST AFNET 4 study  and baseThe assumption that rate and rhythm control were equal in terms of prognosis was based on multiple large randomized studies from the early 2000s comparing medical rhythm vs rate control in non-heart failure patients  and hearTwo large prospective multi-center randomized trials have dominated the debate of rhythm control in AF in the last years: the CABANA trial ,60 from The importance of timing of rhythm control initiation in reference to the time of diagnosis is still under debate, and it should likely not be the only decisive factor. Complete characterization of the AF disease state of the individual patient is the cornerstone for decision making regarding rhythm control. However, evidence is building up to support early rhythm control approaches. The findings of EAST AFNET4 and other recently published randomized trials with good results obtained for catheter ablation as first line treatment in paroxysmal AF ,61,62 asVarious options to achieve rhythm control are available and can be used complementarily. The pros and cons of the modalities need to be discussed with the patient to allow for an informed decision based on their preference as well as on the clinical profile. Cardioversion by means of synchronized electrical shocks remains the first-line treatment for hemodynamically unstable patients, whereas hemodynamically stable patients may be treated with electrical or pharmacological  cardioversion. A new recommendation in the 2020 guidelines involves a \u201cwait-and-watch\u201d delayed-cardioversion strategy for recent onset symptomatic atrial fibrillation. This strategy has been shown to be non-inferior to early cardioversion in achieving a return to sinus rhythm, with a spontaneous conversion rate of 69% within 48 h . For long-term pharmacological rhythm control, no new antiarrhythmic drugs have been introduced and the options in 2020 remain limited to class I  or III  drugs. Yet, better understanding of their proarrhythmogenic potential in certain patient groups , avoidance of combination of antiarrhythmic drugs and implementation of appropriate monitoring of proarrhythmic factors has improved the safety profile of AADs in daily practice, as demonstrated in large scale trials ,72. The Catheter ablation has become a well-established, safe and superior alternative to antiarrhythmic drugs for restoration and maintenance of sinus rhythm and symptom control with multiple randomized trials in paroxysmal AF ,68,69,70In drug-refractory AF and failed percutaneous ablation, hybrid approaches combining endo- and minimal invasive epicardial ablation have become an increasingly employed option and should be considered (IIaB). In 2020, the CONVERGE trial demonstrated successful rhythm control of longstanding persistent AF with maintenance of sinus rhythm in 67% at 1 year by means of combined epi- and endocardial ablation .Catheter ablation was demonstrated not only to be feasible and safe in heart failure ,74 but hRhythm control benefit in the population of HFpEF patients is less well investigated. The above-mentioned subgroup analysis of the CABANA Study included 79% of HFpEF patients and, together with observational data ,78, suggBased on the above-mentioned trials, the 2020 ESC Guidelines recommend to consider AF catheter ablation for heart failure with a reduced ejection fraction, independent of symptom status, to improve prognosis (IIa B). If atrial fibrillation with rapid conduction is the suspected cause of heart failure (\u201ctachy-cardiomyopathy\u201d), the class of recommendation for catheter ablation has been upgraded to I B. The CAMERA-MRI study  was evenTraditionally rhythm control trials use a cut-off of >30 s of atrial arrhythmia recurrence as the definition of treatment failure. However, it has been argued that a single self-limited short-lived recurrence of atrial arrhythmia following therapy may be an overly stringent criterion for failure . AssessmMultiple scores have been developed for pre-procedure prediction of AF recurrence after ablation with the aim to improve patient selection and individualize treatment to reduce recurrence rate. A recent metanalysis  found 13The third pillar of the ABC pathway relates to systematic assessment, identification and aggressive treatment of all cardiovascular risk factors and comorbidities associated with AF. Isolated management of specific conditions alone is often insufficient, as commonly, they are not the sole contribute to AF. In addition to encouraging intense lifestyle modifications to achieve normal body weight, reduce alcohol intake and increase physical activity, a particular focus is on optimal control of hypertension, sleep apnea treatment as well as addressing other well-known cardiovascular risk factors, including diabetes mellitus, hyperlipidemia and smoking. All of these have been identified to have a negative impact on the clinical course of AF and contribute to negative atrial remodeling. The guidelines reinforce the importance of patient education and involvement in order to achieve optimal outcomes.The 2020 Guidelines provide a comprehensive, extensively referenced overview and guidance for the increasingly complex management of atrial fibrillation. Importantly, they emphasize the need for integrated care of AF patients and the essential role of assessment and treatment of comorbidities to achieve optimal outcome. However, the intense research in the field of AF as well as the rapid technological progress in the area of mobile health technologies and catheter ablation underline the dynamic nature of evidence-base care exemplified by the multitude of new evidence published only within the last year since the publication of the 2020 Guidelines. In our opinion, most importantly, the role of early rhythm control initiation in general and the superiority of catheter ablation to achieve it in particular should be highlighted to a greater extent and a more differentiated approach beyond symptom status alone should be adopted. Despite the substantial evidence in favor of catheter ablation to restore and maintain sinus rhythm as well as decreased procedural complication rates and procedure times with contemporary technologies and workflows, many referrers still reserve this valuable option as escalation treatment for patients with failed drug therapy only. Based on the available data, we emphasize the importance of early referrals to centers offering catheter ablation to evaluate patients for this still-underutilized treatment option. Numerous open questions in regards to AF management remain, including the optimal management of AHRE and subclinical AF as well as of very late presenting patients with significantly advanced AF. Additionally, better characterization of drivers of AF related complications  to stratify and individualize treatment strategies  will take a central role in further research efforts."}
+{"text": "Informal caregivers provide a substantial amount of social support to older adults which can be stressful and lead to poor self-care. When stressed, caregivers of persons living with chronic illness are less vigilant and less motivated to engage in self-care behaviors that are important for maintaining their own physical and emotional health. Support interventions can encourage self-care by helping caregivers to focus on values, solve problems, and transform their goals into action. In this symposium, we will discuss the iCareMe study, a randomized controlled trial (RCT) (NCT03988621) that tests a virtual support intervention which utilizes health coaching to increase self-care behaviors in caregivers of older adults living with chronic illnesses, such as heart failure and dementia. The first session will discuss the translation of self-care theory to the basis for the \u201cVirtual Caregiver Coach for You\u201d (ViCCY) intervention and will provide an overview of the iCare4Me randomized control trial designed for caregivers of persons living with advanced heart failure. The second session will describe the adaptation of the iCare4Me RCT to caregivers of persons living with dementia. The third session will highlight findings from a qualitative descriptive study examining the characteristics of effective health coaching used in these two RCTs. Finally, the last session will share findings from a cross-sectional analysis examining moderators of self-care in heart failure caregivers. Together, these presentations will illustrate the unique and innovative approach that iCare4Me has taken to improve self-care in caregivers of older adults living with chronic illness."}
+{"text": "Early life adversity (ELA) is a broad term used to describe environmental conditions that negatively impact normal development  Novel Mechanisms and Potential Therapies, (2) Insights Regarding Prenatal Stress, (3) Cumulative vs. Dimensional Models, (4) The Moderating Effects of Sex, and (5) Gene by Environment Interaction.Islam and Kaffman point out that ELA perturbs myelin development in humans, non-human primates and rodents. The authors review novel mechanistic insights from recent studies in rodents and discuss specific examples of how insights from animal studies coupled with the development of novel myelinating agents provide a promising new pharmacological frontier to treat cognitive and behavioral consequences of ELA in humans. Guadagno et al. review recent findings showing that some forms of adversities disrupt the development of perineural nets surrounding GABAergic neurons in rodents and humans. They propose that disruption of these structures located around neurons alters inhibitory/excitatory outputs in fronto-limbic circuits that are responsible for threat detection and anxiety. This is a novel and intriguing mechanistic animal model nicely complements Hanson and Nacewicz proposal that disruption of inhibitory/excitatory balance drives ELA mediated changes in amygdala volume .Several papers provided novel mechanistic insights that may lead to the development of new screening tools and interventions. Coplan et al. report that the kynurenine pathway is dysregulated in the brain of adult macaque females exposed to variable foraging demand -a form of ELA- as infants, with concentrations of kynurenine metabolites in cerebrospinal fluid (CSF) serving as good markers of the different routes of the pathway. This is the first study to describe changes in kynurenine metabolites in an animal model of ELA, providing a novel mechanism and a potential therapeutic target to address neuroimmune modulation seen in some early adversities. Duffy and Roth provide a thoughtful discussion about the challenges of using peripheral epigenetic markers of DNA methylation to predict changes in the prefrontal cortex using a maternal-maltreatment rat model.Duffy et al. reviewed elegant mechanistic studies in rodents indicating that prolonged parental stress alters non-coding small RNA content in the sperm that in turn guides differences in neurodevelopment, physiology, and behavior in the offspring. These preclinical findings provide a novel conceptual framework for evaluating similar changes in non-coding small RNAs sperm content seen in stressed men. Fitzgerald et al. highlights the chronicity of prenatal stress in clinical settings as opposed to the more acute stress used in rodent models of prenatal stress. The authors explore differences in outcomes between chronic and acute prenatal stress and advocate for the inclusion of more chronic prenatal stress paradigms in rodents.Several authors focused on prenatal stress as an important area of productive translational work. Vlasova et al. found structural MRI changes in both gray and white matter of 1 year old infants diagnosed with iron deficiency during the perinatal period . Interestingly, repleting iron stores during the perinatal period did not reverse the MRI changes suggesting that earlier preemptive supplementation of iron, especially during the prenatal period, might be necessary.Perinatal iron deficiency is associated with abnormal neurodevelopment and is commonly seen in early adversities associated with severe poverty and famine. Using a naturalistic non-human primate model of prenatal iron deficiency, Ceniceros et al. present surprising and thought-provoking results in macaques suggesting that maternal relocation during pregnancy reduced measures of anxiety in 3\u20134 month old offspring. These findings were also seen in infants that were cross-fostered postnatally and are consistent with the notion that mild-stressors during the prenatal period might have an inoculative/protective effect on neophobia in the offspring. Finally, Georg et al. used machine learning to identify variables that increase parental stress in response to infants with early regulatory disorder . The authors suggest that interventions that reduce parental stress will likely improve long-term outcomes in infants with regulatory disorder.Hanson and Nacewicz propose an inverted-U-allostatic load model as a conceptual framework to explain inconsistent findings on the effects of ELA on amygdala size. Simply put, low-moderate levels of adversity lead to relative amygdala expansion whereas sustained and severe activation of the amygdala during childhood and adolescence leads to excitatory neurotoxic-mediated dendritic atrophy, possibly cell death, and a reduction in amygdala volume. The authors propose that physical or mental perception of \u201centrapment/inescapability\u201d is a critical dimension driving changes in excitatory/inhibitory balance and ultimately amygdala volume.Several articles provided interesting insights into a central debate between the \u201ccumulative risk model\u201d in which multiple stressors are simply added to predict health outcomes . These findings underscore the need for additional preclinical work studying the effects of \u201csimple,\u201d \u201cmultiple,\u201d and \u201cco-occuring\u201d stressors on neurodevelopment. Such work will better mimic clinical settings and help address the different predictions made by the cumulative and the dimensional models  impacted USVs mainly in females indicating that males and females are affected differently by different forms of adversities. An interesting follow up question is whether exposing pups to both stressors simultaneously, as was done by Orso et al. would impact both sexes and whether the magnitude of the changes would be enhanced in the presence of this complex stress.Ultrasonic vocalizations (USVs) in rodent pups is the equivalent of an infant cry and an effective mechanism to solicit maternal care. Kwon et al. extended these earlier findings to show that susceptible alleles of the FKBP gene interact with ELA to modulate volumetric changes in the left orbitofrontal cortex and the left middle temporal gyrus in non-symptomatic individuals. Wood et al. examined the effects of peer-rearing and the serotonin transporter alleles on baseline and stress-induced monoamine levels in a large cohort of infant macaques. Infants that were raised with peers in the absence of a mother had different baseline and stress-induced monoamine levels compared to infants raised by their mother in a more complex and naturalistic social context. This work also provides new insights into earlier findings in humans showing that individuals the \u201cshort\u201d allele are more sensitive to ELA compared to individuals with the \u201clong\u201d allele , NIMH R01MH119164 (AK), NIMH R01MH117141 (RH), R01MH115910 (RH), NIDA DA038588 (MS), NIDA R01 DA052909, NICHD HD077623 (MS), and NIH's Office of the Director, Office of Research Infrastructure Programs, P51OD011132 .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "In this Special Issue of Biomedicines, we have many insightful reviews and research papers on the subject \u201cMacrophages in Health and Non-infectious Disease\u201d, but first; we should discuss briefly the current situation in the field.Macrophages are a highly heterogeneous group of cells with highly variable receptor profile and functional activities responsible for regulation and maintenance of multiple processes, including inflammation and innate immune response.The chronic inflammation is a pathogenic mechanism of many diseases and the leading cause of morbidity and mortality in the world, especially in developed countries. The exact causes of uncontrolled inflammation are still to be discovered despite many recent advances in the field of innate immunity .Innate immunity is a conserved mechanism of host defense against different types of pathogens and aggressive factors. Pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) serve as main inflammatory initiators. However, it should also be mentioned that, important for the initiation of atherosclerosis-related sterile inflammation, modified low-density lipoproteins (LDL), while belonging neither to PAMPs nor to DAMPs, are able to induce non-infectious inflammation. Every cell has organelles called mitochondria which can be the source of DAMPs (and thus stimulate innate immunity). When cells are damaged, mitochondrial DAMPs get released. Mitochondria are eukaryotic organelles having their origin from bacteria and carrying their own genome and some features of bacteria such as phospholipid cardiolipin in the mitochondrial inner membrane. The ability of defective mitochondria to induce immune response was shown due to similarity between bacteria and mitochondria on molecular level.Inflammasomes are involved in a response to PAMPs and DAMPs stimuli, which results in the production of pro-inflammatory cytokines, IL-18 and interleukin-1\u03b2 and cellular death. Mitochondria plays an important role in the initiation and regulation of NLRP3 inflammasome . NLRP3 aOur views on the mechanisms of chronification of inflammation are shown in This Special Issue has many interesting discoveries and reviews which will be mentioned briefly below.Kauerova with coauthors  investigVishnyakova with coauthors  comparedFiorelli with coauthors  evaluatePireaux with coauthors  found thElchaninov with coauthors  studied Martin-Cordero with coauthors  found thMelnikov with coauthors  studied Kochumon with coauthors  summed tAkata with coauthors  discoverLee with coauthors  found thKovaleva with coauthors  showed t+ macrophages. The authors also discovered that the content of anti-inflammatory CD163+ macrophages in adipose tissue was higher in post-obese men than obese men and non-obese men.Ara with coauthors  found thRossi with coauthors  reviewedMesaros with coauthors  reviewedOsman with coauthors  wrote a Skuratovskaia with coauthors  reviewedSukhorukov with coauthors  discusseYegorov with coauthors  describeK\u00fcbler with coauthors  studied In conclusion, we would like to express our hope that the high-quality standard of publications established in this Special Issue (SI) will be continued in the next version of SI."}
+{"text": "Neurons and glia are highly polarized cells with extensive subcellular structures extending over large distances from their cell bodies. Previous research has revealed elaborate protein signaling complexes localized within intracellular compartments. Thus, exploring the function and the localization of endogenous proteins is vital to understanding the precise molecular mechanisms underlying the synapse, cellular, and circuit function. Recent advances in CRISPR/Cas9-based genome editing techniques have allowed researchers to rapidly develop transgenic animal models and perform single-cell level genome editing in the mammalian brain. Here, we introduce and comprehensively review the latest techniques for genome-editing in whole animals using fertilized eggs and methods for gene editing in specific neuronal populations in the adult or developing mammalian brain. Finally, we describe the advantages and disadvantages of each technique, as well as the challenges that lie ahead to advance the generation of methodologies for genome editing in the brain using the current CRISPR/Cas9 system. The development of the Cre/Lox technology and its utilization for gene targeting in embryonic stem (ES) cells in mice in the 1990's has allowed researchers to develop genetically modified mice. This technology has provided the means to address the link between genes, neuronal function, and behavior  technology have led to various applications to rapidly generate transgenic mice models as well as to perform Genetically engineered animal models are an invaluable tool for understanding gene function and disease mechanisms in the brain. When combined with the Cre-LoxP system and viral vectors, they allow spatial and temporal regulation of specific gene function for further investigation. There are two types of genetically-modified animal models: transgenic models, in which a foreign gene together with a promoter is introduced into a safe harbor region such as Rosa26  does not reach the nucleus and thus is not integrated into the genome  have been developed to introduce a long DNA donor up to 4.9 kb into mouse fertilized eggs for HDR  abolishes the protein from targeted cells , which lacks nuclease activity and thus simply binds to specific genomic sites, was developed to modulate gene function via transcriptional control  system utilizes a VP64-p65-Rta (VPR) based transcriptional enhancer fused to dCas9 and was recently established for enhancing specific neuronal gene expression , which enable researchers to correct or alter single base pairs at desired genomic locations , indel formation probably occurs in the majority of transduced cells without GFP integration. Therefore, fusing a tag to the N terminal of an endogenous target using this approach could potentially lead to knockout of the gene of interest.As NHEJ is an error-prone process, the integration of the insert can be associated with indel formation at both junctions of insertions. In the study reporting HITI  was developed based on the original HITI method  . These methods have the advantage of significantly reducing the time by short-cutting the cross-breeding process. Future applications of these methodologies could expand genome editing technology to non-model animals such as monkeys , and this poses specific challenges to neuroscience applications. AAVs can achieve widespread neuronal transduction but can only carry a load of 4.7 kb, complicating the AAV-based delivery of Cas9. Possible solutions include the use of short promoters in AAVs (Swiech et al., In conclusion, rapid advancements in methodologies for gene manipulation and protein tagging in the brain have been advancing our understanding of protein signaling in the brain. Future implementation of these techniques in combination with optogenetic control of protein localization and signaling using photo-sensing domains such as light-oxygen-voltage LOV2 (Yazawa et al., All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "To investigate in how the current COVID-19 pandemic affects patient\u2019s perceptions of emergency physician empathy and communication. Patients cared for by Emergency Department physicians with the lowest satisfaction scores were surveyed within one week of discharge via phone. Using questions from the Consultation and Relational Empathy (CARE) survey, patients rated their satisfaction with their Emergency provider\u2019s empathy and communication on a scale of 1 to 5 and provided feedback on how the patient-provider interaction could be improved. Demographic data and patient responses to CARE survey questions were compared between pre-COVID-19 and during COVID-19 time. Patient\u2019s open-ended responses were analyzed for themes related to the impact of COVID-19 on the patient-provider relationship.Patient median quantitative scores were 5 (4-5) across all five questions of pre-COVID-19 and 5 (4-5) during COVID-19 for all questions except two (showing care and compassion), median 5(5-5). Female patients rated provider empathy and communication lower than mens. There was no differences across age strata. A shift in provider focuses to COVID-19 only care (N=3), and an understanding of the stress on healthcare processes (N=13) from open-ended responses themes emerged of patients who want to minimize interactions within the emergency department (N=3). The external factor of the current pandemic did not negatively impact patient\u2019s satisfaction scores. Many patients express leniency and gratitude for emergency providers during this challenging time. Their responses seem to mirror current societal views of frontline healthcare workers. A greater emphasis has been placed on patient satisfaction in healthcare with the implementation of the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey, which measures patient satisfaction in hospitals nationwide. Patient satisfaction has been associated with improved patient adherence to treatment and better clinical outcomes . In the While this prior work has placed the emphasis on improving provider interpersonal skills to improve patient satisfaction, it is well-understood that the doctor-patient relationship is multifactorial with many external factors contributing to how both the provider and patient view a given medical encounter . PhysiciIn recent months, medicine has experienced an unprecedented external factor with the outbreak of the coronavirus pandemic. In the early stages of the COVID-19 pandemic, the healthcare community and general public anxiously awaited the development of a vaccine as well as evidence-based interventions that improve outcomes in patients with COVID-19. However, at present as vaccine rollout remains in progress, the emphasis still remains on containing outbreaks via social distancing, mask use, symptom detection, isolation, and contact tracing, and clinically supportive treatment for patients infected with the novel coronavirus . Given pGiven that the patient-provider relationship is impacted by external factors and the landscape of our local healthcare system is rapidly evolving in response to COVID-19, our study aims to investigate what impact this pandemic has on patient satisfaction. We compare perceptions of emergency medicine physicians\u2019 empathy and communication before COVID-19 and during COVID-19. In addition, it aims to examine how patients\u2019 perceptions of physician empathy and communication potentially are impacted by multiple contextual factors, such as baseline patient demographic data versus healthcare system changes implemented in response to the pandemic. et al.,  fault. It\u2019s a little different with the virus now,\u201d and \u201c[the provider] was going through a lot.\u201d This understanding and leniency extended beyond care or compassion for the provider to diagnostic expectations with a perception that knowledge of and treatment for this virus is evolving and everyone is \u201clearning on the fly\u201d as \u201cwe don\u2019t know much about this [the virus] right now.\u201d The patient-provider relationship is influenced by external context, as much as it is influenced by the patient and physician themselves. Within the context of the COVID-19 pandemic, societal perceptions of emergency medicine providers and patients\u2019 interaction with the healthcare system have changed. This cross-sectional survey study of patients recently discharged from the emergency department, both before and during the pandemic, shows that patients\u2019 perceptions of provider empathy and communication are positive during both time periods. Furthermore, and of equal importance, we did not see a decline in patients\u2019 perceptions of provider empathy and communication after the onset of the COVID-19 pandemic and despite the stresses and challenges that naturally have resulted from this. Overall, quantitative scores for emergency provider empathy and communication averaged greater than four on a five-point scale, with median scores of five across all five questions before and during the pandemic. For this reason, the study was underpowered to detect a statistically significant difference if one existed. Patients\u2019 qualitative responses expose themes consistent within the broader societal framework during the pandemic such as social distancing (minimizing interactions in the emergency department), increased awareness of the virus\u2019s impact (a focus on COVID-19), and patient understanding of changes to healthcare delivery brought about by the COVID-19 pandemic (under the circumstances). Overall patients gave high ratings on perceived provider empathy and communication both before and during the pandemic despite sampling patients cared for by providers with the lowest patient satisfaction scores. These high ratings could have been biased by participant selection, as of the 708 patients identified, only 221 gave responses. To decrease likelihood of patients reporting skewed positive feedback, members of the research team explained to each patient at the beginning of the call that their answers were anonymous, members of the research team were not involved in their care, and participation would not impact their ability to receive future care within our institution. Given small effect size and positively skewed survey results, a focus on how pandemic factors affect the patient-provider relationship was more apparent in the qualitative analysis. Thematic analysis of the open-ended responses showed that the majority of patients who referenced COVID-19 in regards to impact on satisfaction with their provider did so in a way that showed leniency towards the provider amidst the current pandemic. Patient comments centered around an understanding that providers are dealing with challenging times and even if the provider did do something that would otherwise give the patient a poor perception of the physician, the patient placed blame on the current circumstances instead of the provider. Patients at our institution seemed to mirror current societal views of health care workers as heroes in light of the current pandemic , 17. WitBeyond the pandemic, patient perceptions of emergency physician empathy and communication varied based on patient-related factors. Similar to prior work on the patient-provider relationship, our patient population\u2019s ratings of provider satisfaction were also impacted by patient sex , 10. OveTo the best of our understanding, no prior study examines how the external stress of the COVID-19 pandemic affects patient satisfaction with their emergency department care. During these unprecedented times for the medical community, patients recognize the unique stressors forced upon healthcare workers and seem to be both supportive of providers and understanding of the demands placed on them. This global external factor has not been a detriment to the patient-doctor relationship or provider satisfaction, but rather was the underlying foundation impacting patient praise for and support of emergency medicine providers. Patient satisfaction scores of perceived emergency provider empathy and communication remained positive despite the onset of the COVID-19 pandemic. Qualitative analysis also showed mostly positive feelings towards providers and an understanding of the evolving landscape of healthcare. Patients at our institution seem to mirror societies\u2019 positive feelings towards frontline healthcare workers during the pandemic as well as recognition of emergency physician\u2019s increased and evolving focus on COVID-19 and the challenges that come with this. Our study provides insight on how COVID-19 impacted patient satisfaction. Future work could include exploring patient satisfaction in the emergency department post COVID-19 to see how pandemic media attention has impacted patients\u2019 view of frontline workers long term as well as investigating patient satisfaction surrounding other external healthcare stressors such as natural disasters to see if the same leniency applies. This study is limited in scope as we sampled patients only evaluated in and discharged from a single-institution tertiary-care emergency department. We also chose to sample patients only seen by providers with the lowest patient satisfaction scores in order to target potential quality improvement interventions prior to the arrival of COVID-19. This may have resulted in biased results that would not be generalizable for providers with higher satisfaction scores. With the arrival of the pandemic, the scope of the research question evolved to a more general focus on how external contextual factors influence the patient-provider relationship, particularly unprecedented events such as the COVID-19 pandemic. With this purposeful sampling, we may have missed out on feedback from patients evaluated by providers with overall higher satisfaction ratings. Additionally, utilization of the CARE survey has never been validated in the Emergency Department setting. Another limitation was our study was underpowered to detect a statistically significant difference between pre COVID-19 and during COVID-19 scores as we did not predict the positively skewed ratings, even amongst the poorer performing providers, across all five CARE survey questions. Given the unexpected arrival of the pandemic, our statistical analyses were also subject to unequal numbers of patients in our pre-COVID19 and during COVID-19 groups. However, with the shift in the local context, the research question also shifted in hopes of providing emergency medicine and all healthcare providers with data on how the pandemic is impacting their patients\u2019 perceptions of their care. Lastly, because the pre-COVID-19 CARE survey scores were already so high, it is difficult to quantify the impact of the pandemic on post-COVID19 CARE survey scores.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.None declared."}
+{"text": "Burn wound infections are a serious complication of thermal injury. Among the many factors that may limit effective wound healing in patients with burn, bacterial infection and poor cell recruitment appear as the leading causes for prolonged healing. Thus, a novel strategy that aims to prevent bacterial infection within the wound, while at the same time providing structural scaffolding that promotes endogenous tissue repair, would be of great interest. As a nutritional protective barrier for the wound, we developed a thermosensitive collagen-based matrix called MeshFill (MF) that contains all nutrition required for cell growth with the ability to fill up all the cavities and void areas in wounds regardless of their geometry. In a previous study, MF was successfully combined with partial-thickness mesh grafted skin in a porcine model and improved healing and aesthetic outcomes. In the present work, we report on the development, and in vitro and in vivo testing of a new formulation of MF containing silver nanoparticles (AgNPs), which simultaneously prevent bacterial infection and promote skin regeneration.Methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (PA) was examined in vitro. The wound healing efficacy of the formulation was evaluated in a silicon ring splinted delayed wound healing model in rats. The splinted full-thickness wounds were generated on the back of rats and treated with either MF or MF/Ag with different concentrations of AgNPs or were bandaged with no treatment (NT) as a control. The healing process was monitored for 18 days. Clinical wound measurements and histological assessments were performed to compare different treatment regimensWe fabricated MF/Ag formulation by loading different concentrations of AgNPs in MF hydrogel. The antibacterial activity of MF/Ag formulation against The results of in vitro antibacterial study showed MF/Ag released a sufficient concentration of silver which caused a marked reduction in colony forming units (CFU) of MRSA and PA as compared to MF alone. MF/Ag did not show any cytotoxicity to human fibroblast. Moreover, the result of the animal study confirmed the safety and efficacy of applying different concentrations of AgNPs loaded in MF without compromising the healing outcome in our rat model.These findings suggest that AgNPs loaded MF would be a safe, nutritional, flowable hydrogel that provides an ideal moisture environment for healing while protecting the wound from bacteria and can potentially be used as a functional scaffold in partial-thickness mesh grafted skin in burn patients."}
+{"text": "This study examined the association between neighbourhood physical environment and cognition among community-dwelling older people and identifies whether this association varies among different older age groups. Data came from a cross-sectional survey data with 2,081 older people living in 12 public housing estates in Hong Kong. We merged individual data with neighbourhood physical environment data from community audit and GIS. Multivariable linear regression model was used. Young-old who resided in neighbourhoods with a higher land use mix and more public transport terminals, were associated with better cognition. Only the number of community centres was positively associated with the cognition for old-old. A curvilinear association was found between cognition and the number of active leisure facilities in the overall sample and young-old. Our findings could inform urban planners and policymakers on planning community facilities and physical environments based on the needs of older people in different age groups."}
+{"text": "Myelination is essential for signal processing within neural networks. Emerging data suggest that neuronal activity positively instructs myelin development and myelin adaptation during adulthood. However, the underlying mechanisms controlling activity-dependent myelination have not been fully elucidated. Myelination is a multi-step process that involves the proliferation and differentiation of oligodendrocyte precursor cells followed by the initial contact and ensheathment of axons by mature oligodendrocytes. Conventional end-point studies rarely capture the dynamic interaction between neurons and oligodendrocyte lineage cells spanning such a long temporal window. Given that such interactions and downstream signaling cascades are likely to occur within fine cellular processes of oligodendrocytes and their precursor cells, overcoming spatial resolution limitations represents another technical hurdle in the field. In this mini-review, we discuss how advanced genetic, cutting-edge imaging, and electrophysiological approaches enable us to investigate neuron-oligodendrocyte lineage cell interaction and myelination with both temporal and spatial precision. Myelination refers to the process of wrapping axons with compact layers of the plasma membrane, and it occurs primarily postnatally  serotypes exhibit dominance in neuronal tropism with constitutive promoters driving the gene expression -mediated Ca2+ entry induced by current injection  in OPCs from the murine hippocampus. Thus far, it is unclear whether such plasticity and potentially other types of synaptic plasticity exist at an individual synapse level and whether those types of synaptic plasticity are required for local translation of myelin proteins. Additionally, it is known that OPCs are motile and have filopodia-like protrusions constantly extending and retracting  microscopy utilizes the intrinsic CH2 symmetric stretching vibration of the enriched lipid structure to image myelin sheaths (Wang et al., in vivo fluorescence microscopy (Schain et al., in vivo imaging of myelin. The long-term stability and phototoxicity of these label-free imaging techniques still need to be characterized for time-lapse in vivo imaging studies spanning multiple days.Besides imaging oligodendroglial cells and myelin sheaths with genetically labeled fluorescence proteins, a couple of label-free in vivo in various behavioral paradigms will offer further insights into the mechanisms that control activity-dependent myelination.We have now reached a widely accepted notion that neuronal activity positively regulates myelin development and adaptation during adulthood. It is clear that activity-dependent myelination is a fairly dynamic process, and future studies will require the design of specific experimental paradigms to capture the dynamics with great temporal and spatial precision. Future studies using a multidisciplinary approach addressing whether inputs from just a few synapses are sufficient to initialize the expression and translation of myelin-specific mRNAs within OPC processes and whether there is any preferred neuronal firing pattern for initiating downstream cellular events will enhance our understanding of the functional role of neuron-OPC synapses. Additionally, monitoring oligodendroglial cellular behavior and tracing key intracellular signaling molecule\u2019s activity JH and WS wrote the manuscript. WS conceived the project and supervised the overall progress. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "The University of North Georgia\u2019s Personal Enrichment, Action, Knowledge Series (PEAKS) was developed as a monthly series of engaging and seasonally appropriate presentations and activities designed to expressly meet the needs of the region\u2019s large and quickly growing older adult population during the Covid-19 pandemic and resultant isolation. The PEAKS programs are available virtually to allow for broad participation throughout the 30 county UNG service region. While we developed PEAKS to specifically reach-out to older adults in our region, we have found that our audience is actually multi-generational, actively engaging with our speakers and one another. AFU underpinnings for PEAKS include Principle #8 - To enhance access for older adults to the university's range of health and wellness programs and its arts and cultural activities; and #9 - To engage actively with the university's own retired community."}
+{"text": "While boundary-driven acoustic streaming resulting from the interaction of sound, fluids and walls in symmetric acoustic resonances have been intensively studied in the literature, the acoustic streaming fields driven by asymmetric acoustic resonances remain largely unexplored. Here, we present a theoretical and numerical analysis of outer acoustic streaming flows generated over a fluid\u2013solid interface above which a symmetric or asymmetric acoustic standing wave is established. The asymmetric standing wave is defined by a shift of acoustic pressure in its magnitude, i.e.,  Acoustic streaming is the steady flow driven by acoustic energy dissipation in a viscous fluid. The acoustic energy dissipation in a fluid could occur from two different mechanisms, dissipation in the boundary layers and attenuation in the bulk of the fluid . The resIn most micro-acoustofluidic systems of interest where standing waves are typically generated, the acoustic streaming fields are generally dominated by boundary-driven acoustic streaming. As early as 1787, the German physicist Chladni  observedIn this work, we investigate the outer acoustic streaming fields near a fluid\u2013solid interface (FSI) by combining the basic theory of acoustofluidics and the limiting velocity method. A generalized standing wave field either symmetric or asymmetric to the acoustic pressure node is considered. We verify numerically the outer acoustic streaming in the symmetric case with the classical theory of Rayleigh streaming, and discuss the outer acoustic streaming patterns in various asymmetric acoustic resonances. Our analysis of outer acoustic streaming in asymmetric acoustic resonances elucidates fundamental physical aspects and further has potential applications in micro- and nanoparticle manipulation.In micro-acoustofluidics systems of particular interest where standing waves are typically excited, the acoustic streaming field that has received more attention than any other is that which arises from acoustic dissipation near FSIs, which, in most cases, could disturb the movements of particles  induced by the acoustic radiation force. Here, we aim to analyze and compare this type of acoustic streaming driven by symmetric and asymmetric acoustic resonances. The basic acoustic streaming equations have been presented in the We assume that the time variation of each of the first-order acoustic quantities is sinusoidal with Here, outside the boundary layer, the first-order acoustic velocity is irrotational and has only an Here, for a 1D standing wave in the Hence, by substituting Equation (2) into (3), the limiting velocity that drives the outer acoustic streaming field for the generalized 1D standing wave case presented in Equation (1) is obtained, which followsIt is interesting to notice that the limiting velocity that drives the outer acoustic streaming field is independent of the pressure shift We now take up the outer acoustic streaming flows associated with a 1D standing wave over a FSI, assuming a slip-velocity condition at the boundary. As shown in The special case However, for the asymmetric cases, i.e., For the acoustic pressure and velocity distributions presented in We have demonstrated here that outer acoustic streaming flows driven by 1D symmetric and asymmetric standing wave fields near a FSI could behave very differently. The results for symmetric acoustic resonances replicate the characteristics of Rayleigh streaming: Nodes of acoustic pressure and limiting velocity (or outer acoustic streaming) share same locations; that is, on a slip-velocity boundary which drives circulations of outer acoustic streaming the direction of limiting velocity always goes from acoustic pressure nodes to adjacent antinodes. For asymmetric acoustic resonances, it is interesting to notice that acoustic streaming nodes on a slip-velocity boundary always locate at the channel center wherever the acoustic pressure nodes are, enabling spatial separation of acoustic pressure nodes and acoustic streaming flows. Asymmetric acoustic resonances could potentially be generated in fluid channels where neighbor FSIs are not orthogonal . In a fluid channel of irregular cross-section, the acoustic pressure field may slightly vary in other directions  of the channel, which, however, will not greatly affect the resulting acoustic streaming field. This is based on the fact that it is the gradient of the acoustic velocity in the main standing wave direction that determines the distribution of limiting velocities (and thus the location of acoustic streaming vortices and the streaming velocity magnitudes), as described in Equations (A12) and (A13). Therefore, although it is assumed here a 1D standing wave in the"}
+{"text": "We define a string theory analogue of the Hartle-Hawking state and give a canonical calculation of its entanglement entropy from the reduced density matrix. Our result matches with the geometrical replica trick calculation on the resolved conifold, as well as a dual Chern-Simons theory calculation which will appear in our next paper [Progress in identifying the bulk microstate interpretation of the Ryu-Takayanagi formula requires understanding how to define entanglement entropy in the bulk closed string theory. Unfortunately, entanglement and Hilbert space factorization remains poorly understood in string theory. As a toy model for AdS/CFT, we study the entanglement entropy of closed strings in the topological A-model in the context of Gopakumar-Vafa duality. We will present our results in two separate papers. In this work, we consider the bulk closed string theory on the resolved conifold and give a self-consistent factorization of the closed string Hilbert space using extended TQFT methods. We incorporate our factorization map into a Frobenius algebra describing the fusion and splitting of Calabi-Yau manifolds, and find string edge modes transforming under a xt paper . We find"}
+{"text": "Chronic lymphocytic leukemia (CLL) is characterized by having one of the strongest familial risks of any cancer.Genome-wide association studies have identified common variants mapping to over 40 regions of genome that influence the risk of developing sporadic CLL. Sequencing of familial CLL has implicated rare loss-of-function mutations in shelterin complex genes in CLL predisposition.As well as providing new insights in the developmental basis of CLL, the cancer gene discovery initiatives have potential to inform the development of new therapeutic agents.,,,Chronic lymphocytic leukemia (CLL) is an indolent B-cell malignancy that has a strong inherited component, as evidenced by the 8-fold increased risk seen in relatives of CLL patients.,,,GWAS have so far identified single nucleotide polymorphisms (SNPs) at 43 independent genetic regions that influence the risk of developing sporadic CLL.To the extent that they have been deciphered, most cancer GWAS risk regions map to noncoding regions of the genome and influence disease risk by altering gene regulation.,Families segregating CLL have provided evidence for Mendelian susceptibility; however, until recently, the identification of rare alleles with large effects has been elusive. The identification of this class of susceptibility is especially important because mutations are causal and provide direct insight to cancer biology, in contrast to GWAS associations. By performing whole-exome sequencing of CLL families, loss-of-function mutations in Protection of Telomeres 1 (POT1) and other components of the shelterin complex have been demonstrated.Recent studies have provided the first direct evidence for inherited predisposition to CLL. As well as providing new insights in the developmental basis of CLL, these gene discovery initiatives have the potential to impact on risk prediction and on the successful development of new therapeutic agents. Since much of the inherited risk of CLL still remains unexplained additional studies based on larger datasets offer an opportunity to identify new risk regions and susceptibility genes. Deciphering the function of GWAS risk loci is an important step toward testable hypotheses regarding the biological processes involved in pathogenesis. Elucidating the mechanisms through which noncoding variants exert their effect is, however, challenging as the genotyped SNP is not generally a strong candidate for causality. While studies to fully elucidate the regulatory mechanisms underpinning risk regions are in their relative infancy, such endeavors are likely to involve high-throughput systems such as massive parallel reporter assays and exploration of tissue-specific effects in appropriate model systems and CRISPR-Cas9-mediated disruption of candidate regulatory elements."}
+{"text": "Dear Editor,Neoadjuvant chemotherapy (NACT) in breast cancer reduces the size of breast carcinomas to improve operability . The reRecently, Edlund and colleagues have established an expression-based classifier for prediction of neoadjuvant chemotherapy response that offers some important advantages . InitiaThe present study of Edlund and colleagues represents an important progress in research on NACT with the limitation that a reliable recommendation of not to treat can only be made for a subgroup of the patients. The novel 20-gene classifier will become clinically relevant as soon as alternative treatments to taxane/anthracycline-based NACT such as inhibitors of PARP, cyclin-dependent kinases 4/6 or immune checkpoints will be introduced into clinical routine. In this case, patients that will not respond to the conventional taxane/anthracycline-based therapy will be reliably identified by the present classifier and hence can be treated with a more efficient alternative. The author declares no conflict of interest."}
+{"text": "To encourage an active learning environment during the observation stage of high-fidelity simulation, an observation tool was created to help students recognise and record the technical and non-technical skills identified whilst watching their peers. Future work will involve quantifying any educational benefits of the tool across the medical student cohort. Simulation-based education has become an established means of enabling medical students to both learn and practise technical and non-technical skills in a safe environment. As a result of large student numbers, the use of simulation in an undergraduate setting typically entails students alternating between participating and observing roles.High-fidelity simulation (Hi-Fi SIM) has been incorporated throughout the undergraduate medical curriculum at King\u2019s College London (KCL). The aims of these sessions are two-fold: to enhance student knowledge and appreciation of the use of technical and non-technical (human factors) skills in clinical situations and to provide students the opportunity to develop and practise these skills in a low-risk environment. Evaluation of this programme has resulted in positive feedback regarding the learning opportunities provided through active participation in the simulation. In contrast, mixed responses have been attained in relation to the observation component with the majority of students requesting a more active observer role. In addition, many students report uncertainty as to the technical and non-technical skills they are expected to look for whilst watching their peers.Previous research on simulation based education has advocated the use of observation tools in order to encourage directed as opposed to passive observation, a situation which has been reported to result in enhanced learner outcomes for the observer , 2. In lThe observation tool was subsequently trialled with year two KCL undergraduate medical students undergoing Hi-Fi SIM. During each half day simulation session, two medical students participated in one of four 10-min clinical scenarios involving the management of an acute clinical case focused at the level of skill expected from a year two KCL medical student. The remaining members of the group observed the scenario via a live video link. At the start of the simulation session, students were introduced to the observation tool which provided an explanation of its purpose and intended use. During each 10-min simulation, half of the observers were asked to complete an \u2018A\u2013E technical skills\u2019 sheet and the other half an \u2018A\u2013E non-technical skills\u2019 sheet. Students alternated between the two sheets throughout the half-day session to ensure everyone had the opportunity to complete each of the sheets at least once. Every scenario was followed by a 20-min debrief with two clinically qualified tutors during which time students were encouraged to discuss and reflect on any of the skills they identified from using the A\u2013E sheets.The observation tool was positively received by both the students and faculty involved in the simulation sessions. In particular, students commented that completing the sheets encouraged them to observe each simulation and enabled a more diverse debriefing which included both technical and non-technical factors. Tutors also identified a more in-depth analysis of the observed simulation during the debrief when compared with previous experiences without an observation tool. Following these encouraging reports, the intention is to use the observation tool as a teaching aid in all years of the KCL simulation-based undergraduate programme and to formally research whether their use translates into quantifiable differences in the acquisition of knowledge on technical and non-technical skills."}
+{"text": "This cohort study investigates whether serious hypoglycemia is reduced in a Medicaid population receiving calcium-channel blockers with insulin secretagogues. Because insulin secretion by the pancreas is mediated by calcium influx in beta cells through calcium channels,4 we conducted a population-based observational study on the hypothesis that concomitant use of CCBs may be associated with reduced rates of serious hypoglycemia in insulin secretagogue users.Serious hypoglycemia is a major, potentially fatal adverse event caused by insulin secretagogues.STROBE) reporting guideline. We used claims data from the Medicaid programs of 5 US states , supplemented with Medicare claims for dual enrollees, from January 1, 1999, to December 31, 2011, and used the self-controlled case series design. Our methods were described in detail in a previous study.5 Users (aged \u226518 years) of insulin secretagogues  or metformin (negative-control object drug) who were enrolled in Medicaid for at least 180 days immediately before the first object drug\u2013specific observation time .5 The self-controlled case series design inherently controls for all time-invariant confounders, and we further controlled for time-varying potential confounders (eTables 1 and 2 in the This self-controlled case series study was approved by the institutional review board of the University of Pennsylvania, which waived the requirement for informed consent because the use or disclosure of the protected health information involved no more than minimal risk to the privacy of individuals, and the research could not practicably be conducted without the waiver or alteration and without access to and use of the protected health information. We followed the Strengthening the Reporting of Observational Studies in Epidemiology (The number of individuals who met inclusion criteria and the patient characteristics for each object drug\u2013specific sample are presented in Calcium-channel blockers used concomitantly with insulin secretagogues were associated with reduced rates of serious hypoglycemia compared with the use of insulin secretagogues without CCBs. Although the reduced RRs for metformin suggest an inherent effect of CCBs rather than a drug interaction, further studies are needed to elucidate the mechanism. Limitations of this study include lack of data on actual intake of drugs, lifestyle, and health behaviors; however, such factors would have introduced bias only if they were varying within persons across the CCB-exposed and -unexposed time and associated with both CCB use and serious hypoglycemia. Generalizability beyond the Medicaid population needs further investigation. Our findings may help clinicians with cardiovascular drug choice for patients treated with insulin secretagogues. Our findings also suggest that it may be important to monitor whether glycemic control is sufficient without dose adjustments when patients receiving glucose-lowering agents are coadministered a CCB."}
+{"text": "Mitochondria produce energy as ATP that essential for muscle contraction and movement. We hypothesize that age-related decreases in the capacity to generate ATP in muscle plays a major role in loss of mobility with aging. In SOMMA, we use high-resolution respirometry to measure the activity of electron transport system (ETS) in permeabilized muscle fibers from muscle biopsies. This allows us to assay ETS function in a highly controlled ex vivo experiment at the myocellular level, removed from other potentially limiting physiological factors including supplies of substrates and oxygen. We are also measuring the maximal capacity to generate ATP (ATPmax) in vivo by 31PMRS. ATPmax reflects the rate of phosphocreatine replenishment via oxidative phosphorylation. Analysis from the first 113 participants indicates that ATPmax correlates with Maximal OXPHOS , and Maximal ETS capacity . This suggests that these approaches provide complementary information on skeletal muscle energetics."}
+{"text": "New discoveries are a critical priority for the pharmaceutical industry. However, the use of fixed incremental cost-effectiveness (ICER) thresholds for health technology assessment (HTA) may compromise incentives to innovate and affect future treatment options. This paper highlights the impact of generic drug price policies on pharmaceutical innovation in the context of fixed ICER thresholds and proposes a new consideration for the cost-effectiveness analysis (CEA).There is a direct causal relationship between HTA and the market price of a drug; in jurisdictions where HTA agencies apply fixed ICER thresholds as an important reimbursement listing criterion, the incremental cost of a new drug is expected to be proportional to its incremental benefit over the comparator. However, the comparator price is subject to market forces or sudden policies and may change markedly affecting the cost-effectiveness assessment (e.g.\u00a0where the comparator patent has expired). Since recent generic price regulations increased the price gap between drugs\u2019 generic and patented versions, it is harder to achieve a sufficient level of incremental benefits in order to offset incremental prices of new treatments. Consequently, even promising drugs may have challenges to show attractive ICERs and research and development (R&D) investments may become unattractive in certain disease area.In order to promote innovation in therapeutic fields with unmet medical needs, a compromise would be to include the comparator\u2019s patented price in the CEA instead of the generic drug. By identifying the relevant disease areas, decision makers and HTA authorities could therefore convey the importance of investing in these therapeutic areas to manufacturers."}
+{"text": "Current evidence on the effects of Care Coordination (CC) on older adults\u2019 well-being and health service utilization is inconsistent. Previous studies are mostly limited to regional data and focus mostly on nurse-led CC instead of layperson Care Coordinators like family caregivers. This study explores the effects of having CC in a national sample of U.S. older adults and whether the coordinators\u2019 professionalism impacts the effect of having CC on multidimensional health outcomes .Data were from the 2016 and 2018 waves of the Health and Retirement Study (HRS) . Multivariate regression models were used to examine the effects of CC on multidimensional health outcomes in 2016 and the longitudinal effects of having CC. We also tested the effect of Care Coordinators\u2019 professionalism on the multidimensional health outcomes. All models controlled for sociodemographic characteristics and health status.Findings suggest that having CC doesn\u2019t have a positive effect on older adults\u2019 health outcomes. Having CC was associated with an increased number of acute diseases  and nonacute diseases  in longterm. The results regarding cross-sectional effects show that receiving care from a Coordinator was related to increased health service utilization. Participants with professional Care Coordinators were more likely to report receiving person-centered care .This study demonstrates the limited effects of CCs on older adults\u2019 physical health outcomes, and emphasized the importance of care coordinators\u2019 qualifications."}
+{"text": "The coronavirus disease 2019 (COVID-19) pandemic is placing enormous strain on the global health care systems. The pandemic has led to a global decline in the number of stroke hospitalizations and interventions  -6.The first COVID-19 infection was recorded in Vietnam on January 23, 2020. The country has entered the fourth wave of the COVID-19 pandemic from late-April 2021 with an exponential increase in the number of cases, mostly due to the rapid spread of new coronavirus variants. At the time of writing this paper , there had been 6595 cases confirmed in the last 45 days (n\u2009=\u20094888 in two provinces to the east of Hanoi: Bac Ninh and Bac Giang) out of a total of 8165 registered cases across the country since inception .st wave of the pandemic [Bach Mai Hospital (BMH) is a major hospital in Hanoi, Vietnam. The stroke center at BMH has the largest catchment of patients across Northern Vietnam  with\u2009~\u20098In this article, we share our experiences of the Stroke Center of BMH in the treatment of stroke patients in the context of the COVID-19 pandemic in Vietnam that could be useful for similar settings in other countries. Two main strategies have been employed to retain our stroke care services: 1) strengthening telemedicine to provide support for other hospitals that treat stroke; and 2) using a shipping-container Isolation Unit to maintain the treatment for stroke.th wave, only those in need of urgent medical interventions should be admitted to the stroke center. This includes patients with 1) subarachnoid hemorrhages requiring coiling/clipping, 2) intracerebral or intraventricular hemorrhage for which an intervention is indicated. For ischemic stroke (IS), only those with large artery occlusion occurring within the 0-6 hours window and potentially eligible for mechanical thrombectomy are prioritized for admission to a stroke center. The patients must be tested for COVID-19 prior to transfer with results being reported to the telemedicine team during the transfer. Patients with an IS other than large artery occlusion are to be treated with intravenous thrombolysis, if eligible, under the guidance of virtual consultations with the telemedicine team at local hospitals.Our first approach is to strengthen telemedicine by using virtual consultations that connect\u2009~\u2009700 stroke doctors from all hospitals across Northern Vietnam to pre-hospital triage patients with suspected stroke. During the 4We have developed a local protocol for triaging stroke patients during the pandemic  patient fear of contracting COVID-19 [Our local statistics show that the proportions of patients receiving reperfusion (IS) and clipping or coiling (hemorrhage stroke) were higher in May 2021 compared to the figures of earlier months (Our shipping-container SIU at BMH is the first purpose-built unit for isolation of stroke patients with suspected COVID-19 to be used in a hospital setting in Vietnam. The findings provide evidence that our strategies, including the use of telemedicine, triage protocols, and the shipping-container SIU have brought benefits in maintain best practice care for patients with acute stroke at our center during the era of COVID pandemic. Our experiences could be useful for similar settings in other countries around the world."}
+{"text": "To develop a responsive and sustainable template for long-term course evaluation for PsychED UpTo obtain rich, meaningful and specific feedback across multiple domains which can be translated into course improvementsTo work collaboratively with students interested in medical education having previously participated in the courseTo empower current students with the knowledge that their input is valuablePsychED Up is an innovative extra-curricular course for 3rd year medical students at King's College London delivered by psychiatry trainees, senior students and actors. It is in its second year of running and focuses on the hidden curriculum in medicine, exploration of holistic care and communication skills at the mind-body interface. Input from people with lived experience is used to shape teaching.Decided evaluation focusFace-to-face discussionsSurvey for faculty to determine what specific feedback content would be most usefulFinalised the questionnaireCollaborative design and refinement of questions, confirmed sub-sections and scope of questionnaireEmbedded evaluation in course development sessions thus engaging the entire faculty in evaluation processes at the start of the new termIncluded rationale at the startTailored questions so faculty have more useful responsesGreater quantity of prompted questionsSpecific questions for large group presentation, small group teaching, actors\u2019 performances and students\u2019 reflectionsThoughtful combination of quantitative ratings and open-space questionsReduced time between course sessions and obtainment of feedbackQuality and quantity of feedbackHigh response rates: 32/30 (2 duplicates) mid-term, 29/30 end-of-termHigh-quality filling of open-space feedback allowed consolidation of themes to improve the courseRevised questionnaire:Co-designing the feedback form with previous students from the course and faculty brought focus to the questions. They were more specific and were organised into sub-sections for different domains. This led to responses that were relevant, enriched with depth and breadth and provided faculty with richer, more personalised responses. More detailed reflections in feedback were thought to be due to better student understanding of the rationale for questions, and knowledge that their input would help improve the course. We have set up a robust system for collecting long-term feedback for PsychED Up. We will continue to make iterative amendments, and supplement questionnaire feedback with focus groups."}
+{"text": "OBJECTIVES/GOALS: Young women (18 \u2013 45 years of age) with breast cancer have complex medical and psychosocial needs. Educational materials are often used as tools in patient-centered communication. However, these materials disseminate complex health information in print-heavy formats and can be difficult to understand for women with varying health literacy levels. METHODS/STUDY POPULATION: In the first phase of this study, the principal investigator (PI) will recruit 40 diverse women to participate in four focus groups (FG) to explore the perceived usefulness of the most frequently used cancer educational materials. The PI will also obtain demographics and heath literacy levels of the FG participants using the Newest Vital Sign. In the second phase, the PI will assess the literacy demands of the ten most frequently used cancer educational print materials and five most frequently used websites described by the FG participants. The perceptions of the usefulness of materials and the literacy demands will then be used to appraise the effectiveness of materials within patient-centered cancer communication. RESULTS/ANTICIPATED RESULTS: Results from this study will provide a patient-centered blueprint that will be used to design more effective educational materials that treatment centers can incorporate into their patient-centered cancer communication process. The next step of this research will be to determine providers\u2019 perceptions of cancer education materials used to exchange information within the patient-centered communication process. This will complement the patient findings and inform the development of the provider aspect of a communication intervention centered on designing educational materials for women with various health literacy levels within the patient-centered cancer communication process. DISCUSSION/SIGNIFICANCE OF IMPACT: Detecting the usefulness of cancer educational materials, as perceived by young women with breast cancer, is foundational to developing communication interventions that improve cancer outcomes. This study will identify how materials can be improved in the critical informational-exchange component of the patient-communication process."}
+{"text": "Wlds mutation, which arose spontaneously in C57Bl/6 mice, remarkably delays the onset of Wallerian degeneration of axons. This remarkable phenotype has transformed our understanding of mechanisms contributing to survival vs. degeneration of mammalian axons after separation from their cell bodies. Although there are numerous studies of how the Wlds mutation affects axon degeneration, especially in the peripheral nervous system, less is known about how the mutation affects degeneration of CNS synapses. Here, using electron microscopy, we explore how the Wlds mutation affects synaptic terminal degeneration and withering and re-growth of dendritic spines on dentate granule cells following lesions of perforant path inputs from the entorhinal cortex. Our results reveal that substantial delays in the timing of synapse degeneration in Wlds mice are accompanied by paradoxical hypertrophy of spine heads with enlargement of post-synaptic membrane specializations (PSDs) and development of spinules. These increases in the complexity of spine morphology are similar to what is seen following induction of long-term potentiation (LTP). Robust and paradoxical spine growth suggests yet to be characterized signaling processes between amputated but non-degenerating axons and their postsynaptic targets.The  Wlds mutation has dramatically revised our understanding of mechanisms contributing to survival vs. degeneration of mammalian axons after separation from their cell bodies. The Wlds mutation occurred spontaneously in a colony of C57Bl/6J mice at the Olac breeding colony in Bicester England, and was discovered because of its signature effect\u2014axons that are separated from their cell bodies appear intact at the light and electron microscopic level for many days, and are able to conduct action potentials for up to 2 weeks  What changes occur in spines contacted by orphaned synapses, but are not exhibiting signs of degeneration?Our quantitative electron microscopic analysis addresses two questions: (1) What is the timing of degeneration of orphaned synaptic terminals in Wlds mice and identify previously uncharacterized early ultrastructural changes prior to the time that orphaned synapses begin to exhibit typical signs of Wallerian degeneration. In addition, we document striking alterations in the structure of dendritic spines contacted by synapses of orphaned axons including dramatic hypertrophy of spine heads, enlargement and segmentation post-synaptic membrane specializations (PSDs), and development of spinules. These increases in the complexity of spine morphology are very similar to what is seen following intense synaptic activity and induction of LTP , and significant differences over days post-lesion .We carried out additional analyses to quantify changes in synapse parameters . First, neuropil . In C57BWlds mice, the percent of presynaptic terminals that were MSTs increased to approximately threefold higher than control by 16 days. Statistical analysis by 2-way ANOVA revealed significant differences between genotypes , whereas differences over days post-lesion were not significant .We also calculated the percent of presynaptic terminals that were MSTs . In uninWlds mutation. Although the mutation was discovered over 3 decades ago and the mutant protein has been identified as a fusion protein made up of the amino terminal 70 amino acids (N70) fragment of ubiquitination factor U4B, the complete coding region of NAD+ synthesizing enzyme nicotinamide adenyltransferase 1 (NMNAT1), and an 18 amino acid linking region, the cell biology that underlies the signature phenotype remains mysterious. Most previous studies have focused on Wallerian degeneration of axons, particularly in the peripheral nervous system, but to our knowledge, there have been only two previous studies focusing on consequences of the mutation on degeneration of CNS synapses  changes in spines contacted by orphaned synapses, and especially whether in this model of lesion-induced synapse plasticity, spines in Wlds mice exhibited the remarkable changes in ultrastructure previously reported in the striatum following cortical lesion  The timing of degeneration of orphaned synaptic terminals in l lesion ; (3) ultA previous study of consequences of the mutation on degeneration of CNS synapses  documentWlds mice. There are minimal signs of degenerative changes in presynaptic terminals at 4 days post-injury at a time when amputated axons in WT rats and mice exhibit full-blown degeneration. Even at 8 days post-lesion, most presynaptic terminals of orphaned axons in Wlds mice still appear relatively normal, although some exhibit ultrastructural abnormalities that might represent previously uncharacterized early degenerative changes including large, elongated membrane bound areas with empty lumens and atypical membrane structures. Typical presynaptic degeneration does eventually occur, however. At 12 days, some terminals exhibit dark-dense degeneration, although many terminals still appear relatively normal but at 16 days post-injury, synaptic terminals of orphaned axons exhibit the full extent of degeneration seen in WT C57Bl/6 mice.Our results demonstrate that onset of degeneration of presynaptic terminals of the perforant path is similarly delayed by many days in Wlds mice suggests that the mutation does not alter the actual mechanisms of synapse degeneration, and instead maintains the synapse in a viable state. It is unknown how such synaptic terminals of orphaned axons operate physiologically. The presence of large numbers of synaptic vesicles suggests that orphaned terminals may remain capable of packaging neurotransmitter, but it is unknown whether the terminals actually release neurotransmitter onto the postsynaptic neuron when there is no cell body to generate action potentials. Indeed, the physiology of orphaned axons and their terminals is essentially un-explored, except that peripheral nerve axons do remain capable of propagating action potentials when stimulated electrically  from the orphaned axons during the time that they are protected from degeneration. Our results do not provide a definitive answer but do provide a basis for formulation of questions.The postsynaptic mechanisms underlying the dramatic hypertrophy of spines are unknown. Spine hypertrophy could be a manifestation of the One question is whether hypertrophy is limited to spines contacted by preserved orphaned axons or whether it is a general postsynaptic response involving all spines including those contacted by un-injured axons. A previous study that assessed synaptic degeneration in the striatum up to 10 days after cortical lesions reported that very complex spines on striatal neurons contacted by both degenerating and non-degenerating synapses . A caveaWlds mice supporting the conclusion that there is hypertrophy of non-denervated spines.Definitive identification of spines contacted by synaptic terminals of orphaned axons is less of a complication in the present study because about 95% of the synapses in the outer molecular layer of the dentate gyrus derive from the ipsilateral entorhinal cortex, and thus will eventually degenerate following complete entorhinal cortex lesions. The inner molecular layer of the dentate gyrus contains synapses of the dentate commissural/associational system, which do not degenerate, and there is essentially no overlap in the terminal fields of these two afferent systems. Nevertheless, spines with complex morphology were evident in the non-denervated inner molecular layer of trans-synaptic signaling that could be related to neurotransmitter release by orphaned axons or release of some other signaling molecule. It would be informative to create chimeras where presynaptic neurons were from one strain and postsynaptic neurons were from another. The question would be whether postsynaptic neurons from Wlds mice exhibited spine hypertrophy when there was degeneration of synaptic contacts from WT mice. If future studies indicate that hypertrophy is not an intrinsic effect of the mutation on the postsynaptic neuron, then identification the trans-synaptic signal is of great interest and could suggest new ways to protect postsynaptic neurons from denervation-induced atrophy. It would also be of great interest to assess whether other unique ultrastructural features, especially spine hypertrophy, were seen in other strains of mice with delayed Wallerian degeneration (SARM1 knockout mice for example).Although a limitation of the present study is the use of a single technical approach (electron microscopy), our findings do point to questions for future studies. For example, the dramatic hypertrophy of spines suggests some sort of Wlds mice is not straightforward because synapse loss is delayed, extending into the early phase of new synapse formation in WT C57Bl/6 mice between 4 and 8 days post-lesion. At 8 days post-lesion in Wlds mice, most synapses that will eventually degenerate have not yet begun to exhibit degenerative changes. This mix of orphaned synapses that will eventually degenerate and new synapses compromises EM quantification of the time course of new synapse formation. By 12 days, the numbers of intact synapses and degenerating synapses in Wlds mice are equivalent to what is seen in C57Bl/6 mice, and then numbers of intact synapses increase between 12 and 16 days. These data are consistent with previous studies of sprouting of different inputs to dentate granule cells after entorhinal cortex lesions. Sprouting of septal cholinergic axons is delayed and less extensive in Wlds mice (In the model system of reinnervation of dentate granule cells following entorhinal cortex lesions, synapse replacement is reflected by loss and then replacement of non-degenerating synapses over time. There is no categorical marker or definitive morphology to identify new synapses, although tracing studies have demonstrated that some are multi-synapse terminals . Defininlds mice . Sproutilds mice .Wlds mutation was discovered during studies of axonal pathophysiology, specifically Wallerian degeneration of peripheral nerve axons. It is highly unlikely that this spontaneous mutation would have been noticed otherwise because there are to our knowledge no reports of any phenotype in un-injured mice with the Wlds mutation. Discovery of the Wlds mutation happened in much the same way as our discovery of other murine genetic backgrounds that confer protection against excitotoxic neurodegeneration (The neration . The inineration . One wonThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation, to any qualified researcher.The animal study was reviewed and approved by Institutional Animal Care and Use Committee at the University of Virginia.OS planned the study, analyzed the data, and wrote the manuscript. PF and JY prepared EM samples and contributed to writing the manuscript. All authors contributed to the article and approved the submitted version.OS is a co-founder and has economic interests in the company \u201cAxonis Inc.\u201d, which holds a license on patents relating to axon regeneration. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Melioidosis is an infectious disease most commonly found in places with tropical climates. Definitive diagnosis can be confirmed by culture or pathological results of blood or infected organ. However, imaging study is helpful in providing early provisional diagnosis and guiding therapy. Point-of-care ultrasound can be currently performed bedside by non-radiological staff such as emergency physicians or intensivists. We present the case of a pediatric patient who got diagnosed with melioidosis after detection of multiple splenic and hepatic abscesses by point-of-care ultrasound, leading to early diagnosis and appropriate empirical antibiotic selection, resulting in good treatment outcome. Burkholderia pseudomallei, which is a bipolar-staining Gram-negative aerobic bacillus most commonly found in the soil and water of places with tropical climates, especially South East Asia and Northern Australia  titer 1:1280) confirming the diagnosis of melioidosis. IV meropenem was continued for 10 days and then switched to ceftazidime following the antibiotic sensitivity result. The child recovered after four months of hospitalization and was finally discharged home with normal cognitive and mental function.His blood culture result showed This case report highlights the use of POCUS examination in making early diagnosis in patients with a suspicion of melioidosis. Making a diagnosis of melioidosis in children is challenging as the initial presentation may be non-specific. Melioidosis is less common in children compared with adults and has been reported to constitute 5 to 15% of all cases . MoreoveThe intra-abdominal organ most commonly affected by melioidosis is the spleen followed by liver and kidneys. A recent study including 27 Thai children who had confirmed diagnosis by either serology and/or culture reported that children with confirmed melioidosis had a higher proportion of liver and splenic abscess when compared with non-confirmed cases  . One or Abscesses appear on ultrasound as hypoechoic lesions, target lesions, and multiloculated lesions . SplenicCases of melioidosis with liver and/or splenic abscess may not have abdominal signs or symptoms . AbdominThese results lead to a suggestion that patients with a suspicion of melioidosis such as those who live or come from the endemic area should undergo imaging for early detection of the intra-abdominal abscess even if the patient is asymptomatic or has normal abdominal examination. If the imaging shows splenic abscess with or without liver involvement, it is highly suggestive of melioidosis.With the advance of POCUS examination in recent years, pediatric emergency physicians and intensivists are now able to perform POCUS in the emergency department (ED) or ICU . Due to For pediatric patients, POCUS has been used previously to detect various non-traumatic intra-abdominal pathologies with high diagnostic accuracy, such as appendicitis (sensitivity of 86% and specificity of 91%)  and intuPOCUS performed by a trained physician team can be helpful in early provisional diagnosis of melioidosis, which is a less common disease in the pediatric population, by detecting cases of splenic and/or hepatic abscesses in endemic areas. This results in promptly appropriate treatment while waiting for the definitive pathological diagnosis and therefore decreases morbidity and mortality of the patients."}
+{"text": "Hg concentrations in lichens ranged from 142 ng g\u22121 at sampling sites located north of the chlor-alkali plant to 624 ng g\u22121 in lichens collected south of the chlor-alkali plant. A north-south gradient of Hg accumulation in lichens along the Ossola Valley channel was observed, highlighting that the area located south of the chlor-alkali plant is more exposed to the dispersion of Hg emitted into the atmosphere from the industrial site. Long-term studies on Hg emission and dispersion in the Ossola Valley are needed to better assess potential impact on ecosystems and human health.We present the first assessment of atmospheric pollution by mercury (Hg) in an industrialized area located in the Ossola Valley , in close proximity to the Toce River. The study area suffers from a level of Hg contamination due to a Hg cell chlor-alkali plant operating from 1915 to the end of 2017. We measured gaseous elemental Hg (GEM) levels by means of a portable Hg analyzer during car surveys between autumn 2018 and summer 2020. Moreover, we assessed the long-term dispersion pattern of atmospheric Hg by analyzing the total Hg concentration in samples of lichens collected in the Ossola Valley. High values of GEM concentrations (1112 ng m As was recognized in 2013 by 127 world countries with the signing of the UNEP Minamata Convention, further scientific efforts are needed to improve atmospheric Hg monitoring and characterization of Hg sources in order to reduce risks associated with Hg contamination 38].With the aim of assessing the impact of Hg pollution on air quality in the contaminated area around the chemical plant located along the Toce River, in the present study we investigated spatial and temporal changes in Hg distribution coupling short-term measurements of GEM concentrations in air to the measurement of Hg concentration in epiphytic lichens collected in the Ossola Valley at selected sampling points around the chemical plant.Results were related to wind pattern along the Ossola Valley channel.This research was carried out in the Ossola Valley  . The Osshttps://prtr.eea.europa.eu/#/facilitydetails?FacilityID=162&ReportingYear=2017; accessed on 26 September 2020).The valley hosts about 66,500 inhabitants and the main town is Domodossola, with about 18,000 inhabitants. Most industrial activities are localized close to this area. However, the biggest industrial plant is located close to Pieve Vergonte town (about 2493 inhabitants), and was used in the last century mainly for Dichlorodiphenyltrichloroethane (DDT), sulfuric acid and cloro-soda production. This latter product was obtained using a Hg-cell chlor-alkali plant, which was discontinued at the end of 2017 for conversion to non-Hg technology. The chlor-alkali facility reported total annual releases of Hg to air and water in the European Pollutant Release and Transfer Register (E-PRTR) managed by the European Environment Agency .The climate of the Ossola Valley was defined through long-term (2002\u20132020) data collected at the Fomarco (hamlet of Pieve Vergonte) and Domodossola meteorological stations operated by Agenzia Regionale per la Protezione Ambientale del Piemonte  and DL = 0.3 ng m\u22123 (average time being 30 s) for Hg determination in air. The dynamic range covers four orders of magnitude  \u22121 at incerved by , who fou\u22121) but at the Bosco Tenso site . The spatial gradient of Hg contamination can be explained considering the topography of the Ossola Valley. In fact, our finding is in agreement with literature data showing that in industrial areas where metallic Hg is handled, prevailing wind direction and topography are accountable for the dispersion pattern in the surrounding areas [In our study we observed a specific spatial gradient of Hg in lichens along the valley channel, and the highest concentration of total Hg was not observed near the industrial area , is wider with respect to the lower valley at the southern lichen sampling site (Bosco Tenso) surrounded by 1000\u20131500 m high mountains. The peculiar morphology of the Ossola Valley plays a fundamental role in modifying the atmospheric boundary-layer flow that undergoes a channeling along the valley, determining the observed spatial pattern of lichen contamination. In addition, it is necessary to take into account that another factor may have influenced the higher concentrations of total Hg measured in lichens collected at the Bosco Tenso site. In fact, in wooded areas the uptake capacity of lichen is higher than in open areas . MoreoveData presented in this paper provide the first evidence of atmospheric GEM concentration and its deposition in areas surrounding a chlor-alkali plant located near the Toce River in the Ossola Valley .Determining or predicting Hg concentration in the atmosphere is of crucial importance in identifying sensitive areas requiring ecosystem and health protection. We showed how an integrated investigation of airborne Hg analytical measurements and biomonitoring can be employed to locate Hg emission sources and to identify areas where Hg inhalation exposure may be of concern.Our study highlights that the wind pattern in the Ossola Valley and its morphology imply that the area located south of the chlor-alkali plant is more affected by dispersion of Hg emitted into the atmosphere from the industrial site. The ongoing reclamation at Pieve Vergonte industrial site will likely decrease the mercury emissions, but contaminated soils around the facility will remain a long-term potential source. Therefore, further studies are necessary to avoid or minimize risks for ecosystems and human health deriving from the dispersion of this airborne Hg. In this sense, greater effort should be directed towards continuous GEM measurements, together with an in-depth study of how meteorological factors  could help understand Hg emission/deposition cycles, Hg dispersion and potential future contamination trends. Moreover, a better characterization of soil chemico-physical properties should be planned, together with measurements of Hg emission from soil, to improve our knowledge on Hg cycling and soil potential for Hg volatilization."}
+{"text": "The aim of the research was to create a model of steel fibre distribution in a Steel Fibre Reinforced Concrete space using statistical probability means. The model was created in order to better understand the behaviour of the composite under operating conditions. Four statistical distributions  were examined to find the distribution that best described fibre settling phenomenon caused by manufacturing process conditions. In the next stage the chosen statistical distribution was adapted to create the model of steel fibre distribution in a Steel Fibre Reinforced Concrete space. The model took into account technological conditions such as vibrating time and properties such as consistency of the tested concrete. The model showed a good agreement with the real fibre distribution. Steel Fibre Reinforced Concrete (SFRC) is a widely described composite construction material of constantly growing popularity due to some improved properties in comparison to ordinary concrete. The addition of steel fibres influences for instance the flexural strength of a concrete transforming it from brittle to quasi-plastic material . It alsoSteel fibres are generally assumed to be randomly distributed in concrete and SFRC is treated as an isotropic material ,21,22,23Description of the fibre distribution in the composite space is not a new issue. Various methods were used to describe this phenomenon such as geometric method ,29 or prThere are some probability functions which could describe fibre distribution. In previous study the author described fibre distribution using Kumaraswamy distribution . In thisThe Beta probability distribution originates from 1676 when Isaac Newton wrote a letter to Henry Oldenbeg where he evaluated s series . Since ts series . ProbabiKumaraswamy distribution was proposed in 1980 by Poondi Kumaraswamy in order to describe hydrological random variables such as daily rainfall and daily stream flow ,34. The Three Parameter Beta (TPB) distribution derived in 1984 by James B McDonald  is a genGeneralised Transmuted Kumaraswamy (GT-Kw) distribution was proposed in 2019 by Aliyu Ishaq at al.  in orderThe experiment design assumed conducting the research on specimens that during casting were characterised by different consistency (according to Vebe method) and vibration time see . The desThe choice of hooked type of fibre was due to its popularity in the global civil and structural engineering market ,42. TwenIn order to simulate fibre distribution in a given space of dimensions the same as the tested cubic specimens, a computer self-authored program named CHI-Curvefit 2.0 was applied. The program was created in 2021 and based on Visual Basic for Applications. The four statistical distributions described by the Equations (1)\u2013(8) were used to find the best fit with tested distributions of fibres along the vertical axis The search for the best fit was based on chi-square test measuring goodness of fit. The purpose of the program was to check out what values of distribution parameters provide the best fit. The program also compared the calculation results with the critical chi-square value calculated for the given number of degrees of freedom and the significance level equal to 5%.Another self-authored program Fiberdist 2.0  written After 28 days of curing, specimens were cut in half along the vertical axis see . Varied Each specimen\u2019s cross-section was divided into 10 sectors. Overall number of fibres and numbers of fibres in each sector was counted see . Mean vaZ axis. The parameters were calculated separately for different vibrating time and consistency of concrete  testing it can be stated that the GT-Kw probability distribution is characterised by the best fitting of the curve and is more suitable for describing fibre distribution of steel fibres in the composite space than other discussed distributions. The model based on GT-Kw distribution can precisely describe fibre distribution.On the basis of chi-square (\u03c7Multi-parameter distributions (such as for example the GT-Kw distribution) are more complex in calculations and require more time to calculate than two parameters distributions (such as Beta and Kumaraswamy distributions), yet bearing in mind using modern computer technology enabling quick calculations and optimised programs the advantage of GT-Kw distribution is essential.To achieve fast results properly describing fibre distribution without complicated calculations the two parameters Beta or Kumaraswamy distributions may be applied. Yet the results will not be as precise as for the GT-Kw statistical distribution."}
+{"text": "Developing this studyrequired a balance between ideal study-design principles and feasibility.SIMPLIFY will be the largest multicenter, randomized, controlledmedication-withdrawal study in CF. This study is uniquely positioned to providetimely evidence on whether the daily treatment burden can be reduced amongindividuals on CFTR-modulator therapy.The care for individuals with cystic fibrosis (CF) with at least one F508delmutation will greatly change as a result of the unparalleled clinical benefitsobserved with the new triple-combination CFTR (CF transmembraneregulator)\u2013modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI).Incorporating ETI into the standard of care creates new motivation andopportunity to consider reductions in overall treatment burden and evaluatewhether other chronic medications can now be safely discontinued without loss ofclinical benefit. SIMPLIFY is a master protocol poised to test the impact ofdiscontinuing versus continuing two commonly used chronic therapies in peoplewith CF who are at least 12 years of age or older and stable on ETI therapy. Theprotocol is composed of two concurrent randomized controlled trials designed toevaluate the independent short-term effects of discontinuing hypertonic salineor dornase alfa, enabling individuals on both therapies to participate in one orboth trials. The primary objective for each trial is to determine whetherdiscontinuing treatment is www.clinicaltrials.gov(NCT 04378153).Clinical trial registered with  The landscape of clinical care and treatment for individualswith cystic fibrosis (CF) is poised for remarkable change after the discovery of a noveldisease-modifying therapy that restores protein function to the CFTR (CF transmembraneregulator) . ElexacaA high treatment burden and complexity have led people with CF and their providers tocall for research identifying ways to reduce the overall treatment burden withoutsacrificing the incremental health gains achieved through the addition of therapies overtime \u20139. The iA rigorous evaluation of the impact of treatment withdrawal through a randomizedcontrolled trial is an ideal approach to assess both safety and efficacy outcomes from aframework of clinical equipoise and mitigates the risks of confounding throughindication bias inherent in observational study designs. There are limited examples oftreatment-withdrawal trials for chronic therapies in either CF or other diseases. Todate, the most notable example in CF was a multicenter, randomized withdrawal trial ofinhaled corticosteroids . AlthougTo address the need for timely and rigorous evaluation of chronic medication withdrawalin CF in the context of ETI use and fewer daily symptoms of disease, the SIMPLIFYprotocol was developed: it is a master protocol including two randomized controlledtrials to test the impact of discontinuing versus continuing chronic therapies in peoplewith CF on highly effective CFTR-modulator therapy. SIMPLIFY investigates the withdrawalof two relatively burdensome and commonly used inhaled medications , hypertoSIMPLIFY was designed to independently test the effect of discontinuing hypertonic salineor dornase alfa as compared with continuing each therapy, hypothesizing no clinicallymeaningful short-term impact on lung function or safety outcomes would occur betweenthose discontinuing therapy and those continuing therapy. The design of the SIMPLIFYtrial required complex consideration to balance ideal design principles withfeasibility. Here we report the SIMPLIFY design and the key considerations informing thelargest medication-withdrawal study in CF. Further study details, including the StandardProtocol Items: Recommendations for Interventional Trials checklist and a schedule ofassessments, are provided in the online supplement .The SIMPLIFY study is sponsored by the CFF and is currentlyenrolling across 80 participating adult and pediatric centers in the CF TherapeuticsDevelopment Network (TDN). The TDN consists of 91 research centers across the UnitedStates and a coordinating center in Seattle, Washington, dedicated to conductingstudies to cure and control CF . Adata-1)\u2009\u2a7e\u200970 and those 18 years and older with appFEV1\u2009\u2a7e\u200960 may enroll if they have been on ETIand either or both mucolytic therapies  for at least 90 days before screening. Study A will enroll approximately 400subjects . Study B will enroll approximately 400subjects . Subjects on both hypertonic saline and dornasealfa may participate sequentially in both studies. Additional eligibility criteriafor the study population are listed in SIMPLIFY is a master protocol with two concurrent, 6-week,randomized controlled trials , eachde1,antibiotic use, pulmonary exacerbations, adverse events, and patient-reportedoutcomes, will be evaluated at all sites at each study visit and/or over theduration of the study for event-based outcomes. Additional measurements will beconducted at selected sites with the capabilities to conduct these procedures:multiple-breath washout at Weeks \u22122, 0, and 6 among approximately 400subjects across both studies to evaluate changes in the lung-clearance index (LCI)and mucociliary-clearance (MCC) scans among approximately 60 subjects across bothstudies using inhaled radiolabeled particles and imaging techniques at Weeks 0 and 6to evaluate changes in MCC. All subjects will in addition be asked to completeelectronic participation questionnaires at the completion of each study regardingthe use of ETI, hypertonic saline, dornase alfa, mechanical airway-clearancetherapy, and antibiotics approximately every 28 days for up to 24 weeks after theirfinal study visit at Week 6. For subjects who participate in a second subsequenttrial within SIMPLIFY within 24 weeks of completing the first, the post-studyquestionnaires from the first study will be stopped early.For each study (A and B), clinical and safety outcomes, including ppFEV1 of 40\u201359) may be enrolledinto study A  upon interim review of safety data by thedata-monitoring committee after at least 25% enrollment is complete  were notincorporated. Rather, with input from the CFF\u2019s Success with TherapiesResearch Consortium, SIMPLIFY was designed to use time-triggered ecologicalmomentary assessment through the deployment of standardized daily electronicquestionnaires to all participants, regardless of treatment assignment \u201322. Thesnoninferiorto continuing treatment after establishment of chronic ETI, as measured by the6-week mean absolute change in ppFEV1. The choice of primary endpoint wasinformed by clinicians who ranked decreases in lung function as the most importantindicator of health deterioration in people with CF  demonstrates the ability of the sites to overcome COVID-19restrictions and the enthusiasm of the CF community to address the researchquestions posed in SIMPLIFY.The trial protocol was approved by the institutional reviewboard in March of 2020, and the first site was activated for enrollment in August of2020. The TDN extensively tracked the status of clinical research across the networkand initiated the start of the trial when over 90% of sites reported reopening fornew interventional studies. No adaptations were made to the trial protocol forcoronavirus disease (COVID-19), and enrollment was thus limited to sites able tocollect the key study endpoints via in-person clinic visits, with particularattention paid to abiding by institutional guidelines for aerosol-generatingprocedures. Although clinical research has shifted toward telemedicine during thepandemic and adoption of remote data collection for endpoints such as pulmonaryfunction, prior data from CF trials indicate that there may be significantlyincreased variability in the measurement of the average change in lung functionusing handheld spirometers at home as compared with using clinic spirometry. Thisincreased variability alone, independent of any potential systemic bias induced byusing remote versus clinic-based spirometry, would have a significant impact on theplanned sample size for the trial .Initial1 within this timeframe.Although the ppFEV1 has been the most frequently used efficacy outcomemeasure of lung function in CF clinical trials  should be attributed, particularly if they are delayed.SIMPLIFY represents a major shift in CF clinical research from focusing on theadditive effects of new therapies to improve clinical outcomes to now determiningwhether no meaningful changes will occur in these outcomes with the discontinuationof such therapies. Despite this distinction, trials testing new drugs and withdrawalstudies like ours are both focused on trying to improve the lives of those with CF,and assuredly new and effective drugs will be needed going forward. Communityengagement remains a necessity for determining the future of withdrawal trials inCF, including providing input on the therapies studied and key study-designattributes that promote ethical and feasible trial designs. This engagement mustinclude people with CF (and their families) and medical teams who help to direct andmonitor clinical care decisions, as so greatly benefited the development of thisstudy. As a collaborative study linked to SIMPLIFY, the QUEST  study launched by the CFFSuccess with Therapies Research Consortium is enrolling subjects completing SIMPLIFYto characterize the perspectives of research participants about treatment withdrawaland treatment burden in the context of triple-combination CFTR-modulator therapy(NCT 04320381). The QUEST study is critical for providing patient-centered data tobetter understand the experience of those participating in withdrawal trials andfactors that determine both participation and medication choices after the study.These data will also inform future medication- or therapy-withdrawal trials in CF.As is apparent in the design of SIMPLIFY, striking a balance between feasibility andideal study-design principles is challenging yet can be achieved throughprioritization of study aims and acknowledgment of limitations that will benecessary to account for in the interpretation of study results. With the broadinput of the CF community, SIMPLIFY represents the largest multicenter, randomized,controlled medication-withdrawal study in the modulator era of CF. Carefulinterpretation of results from SIMPLIFY will provide timely evidence to informimportant care decisions as to whether or not the daily treatment burden among thoseon CFTR-modulator therapy can now be considered."}
+{"text": "Mycobacterium tuberculosis infection and is at risk of developing active tuberculosis.The World Health Organization (WHO) estimates that one fourth of the world\u2019s population has End TB strategy global control targets, novel regimens that can overcome deficiencies of existing treatments are needed to accelerate the decline in global tuberculosis incidence.\u2013To meet the tuberculosis-related sustainable development goals and the With these innovative clinical trials to evaluate potential tuberculosis regimens, patient adherence and retention in trials is critical to establish robust efficacy and safety profiles for investigational regimens. In the phase 2 trial that supported initial registration of bedaquiline with the United States of America Food and Drug Administration in 2012, patient adherence and retention were problematic. The drug was approved but received a black box warning \u2013 that is, the highest warning for drugs and medical devices \u2013 due to a death imbalance between the bedaquiline-containing experimental arm (10 deaths) versus the control arm (2 deaths).WHO\u2019s recommendation to intensify the use of digital health technologies to contain the coronavirus disease 2019 (COVID-19) pandemic, has potential as a strategy to promote adherence and retention to tuberculosis treatment during clinical trials and in routine care.,Directly observed therapy by video recording serves as another viable clinical monitoring tool in the context of COVID-19. This protocol was developed as a flexible, low-burden method of providing remote directly observed therapy via smartphones, and involves patients video-recording themselves taking their medications or conducting a live-video call with an assigned health-care worker, and transferring the videos using a secure interface to workers for review. Studies have demonstrated the feasibility of this approach for monitoring medication ingestion among tuberculosis patients with a high fraction of expected doses observed, all while minimizing staff time and travel, an important feature to mitigate risk of contracting COVID-19.With robust evidence from their effective use in the context of tuberculosis control programmes, these tools can be used in tuberculosis clinical trials to support and monitor patients throughout the course of trial participation and achieve high levels of retention. Ensuring the successful execution of innovative trials designed to identify potentially transformative new tuberculosis regimens will contribute to the global effort to accelerate the decline and eventual elimination of this disease."}
+{"text": "A cornerstone of the global initiative to eradicate polio is the widespread use of live and inactivated poliovirus vaccines in extensive public health campaigns designed to prevent the development of paralytic disease and interrupt transmission of the virus. Central to these efforts is the goal of inducing mucosal immunity able to limit virus replication in the intestine. Recent clinical trials have evaluated new combined regimens of poliovirus vaccines, and demonstrated clear differences in their ability to restrict virus shedding in stool after oral challenge with live virus. Analyses of mucosal immunity accompanying these trials support a critical role for enteric neutralizing IgA in limiting the magnitude and duration of virus shedding. This review summarizes key findings in vaccine-induced intestinal immunity to poliovirus in infants, older children, and adults. The impact of immunization on development and maintenance of protective immunity to poliovirus and the implications for global eradication are discussed. Vaccines containing live attenuated poliovirus have been the mainstay of immunization campaigns for decades, and remain a critical component of efforts to eradicate wild-type virus5. Oral polio vaccine (OPV) replicates extensively in the gastrointestinal tract and is distinguished by its ability to induce intestinal immunity, and decrease virus shedding upon subsequent exposure of individuals to live virus6. In contrast, inactivated polio vaccine (IPV), while inducing strong systemic immunity and protection from paralytic disease, has little effect on virus replication in the intestine following an OPV challenge in subjects previously not exposed to live virus7.Successful implementation of the polio endgame will depend on immunization strategies that not only prevent paralytic disease, but also limit enteric replication of the virus and minimize the risk of transmission of potentially neurovirulent strains8. Coupled with this change was the recommendation to include at least one dose of IPV in immunization strategies to prime individuals against potential exposure to type 2 poliovirus, and to boost population immunity against all three serotypes3.Concerns over the safety of OPV due to rare cases of vaccine-associated paralytic polio (VAPP) caused primarily by the type 2 component of the vaccine, and the introduction of vaccine-derived polioviruses (VDPV) into areas of low population immunity, led to the removal of the type 2 component from trivalent OPV (tOPV) and a globally synchronized switch from tOPV to bOPV (types 1 and 3) in 201615. These trials revealed a marked difference in the degree of protection induced by tOPV versus bOPV and IPV against strain-specific enteric poliovirus replication as measured by recovery of type 2 virus in stool. To gain insight into the ability of combined bOPV and IPV regimens to induce intestinal immunity, mucosal antibody responses have been studied within the context of these trials18. Consistent with early observations, these studies demonstrate an important role for neutralizing antibody responses mediated by IgA in limiting replication of poliovirus in the intestine 23.Vaccination regimens consisting of IPV, bOPV, and combinations thereof have since been evaluated in clinical trials to assess rates of seroconversion and virus shedding in response to a monovalent OPV (mOPV) challengeThis review summarizes current findings in mucosal immunity to poliovirus and provides a theoretical framework for interpreting observed differences in vaccine-induced intestinal immunity to bOPV and IPV regimens across age groups. The broader implications for the prevention of poliovirus infection and transmission within global eradication efforts are discussed.24. An overarching goal for combined vaccine use was to improve early protection against polio and strengthen immunity in children from developing countries, where OPV-only schedules were associated with lower than expected rates of seroconversion29. Combining OPV and IPV to broaden immunogenicity to poliovirus was subsequently evaluated in a clinical trial of 1685 infants from The Gambia, Oman, and Thailand30. A seminal finding from this study was that IPV alone failed to provide adequate protection from poliovirus shedding, while the combined regimen of OPV with IPV induced strong seroconversion and intestinal immunity as measured by a reduction in virus excreted in stool.Recommendations to assess combined OPV and IPV schedules in infants were first presented in 1987 by the Global Advisory Group of the WHO Expanded Program on Immunization37 formed the cornerstone of current efforts to evaluate the effectiveness of combined vaccine regimens in infants using new schedules of bOPV and IPV15. A central objective of these trials is to define the best strategy not only for preventing paralytic disease, but also for inducing intestinal immunity and limiting virus shedding. Using updated immunological techniques to measure polio-specific enteric antibody responses, further studies have linked the induction of intestinal immunity to the type and timing of the primary vaccine series18. When evaluated alongside concurrent data on virus shedding, these immunologic analyses have allowed a more nuanced picture to emerge of the induction and development of enteric antibody responses to bOPV and IPV regimens, and the relationship of these responses to virus shedding upon subsequent challenge with mOPV.Results from this and subsequent clinical trials13  consortium were studied to evaluate the immunogenicity of tOPV in comparison to two schedules of bOPV and IPV16. Addition of IPV to the bOPV series had no significant effect on virus shedding after challenge as compared with bOPV only schedules16. These results point to a restriction of type-specific virus shedding that is clearly associated with prior receipt of homotypic live virus (tOPV), and are consistent with early observations that induction of mucosal immunity to poliovirus in the intestine is stimulated by enteric replication of the virus38. Further, these results demonstrate the limited impact of a single dose of IPV when added after bOPV in a primary series to reduce fecal shedding following oral exposure to live poliovirus.In comparison, infants receiving a bOPV or bOPV\u2013IPV series had negligible polio type 2-specific enteric antibody on the day of challenge. Significant type 2-specific IgA and neutralizing activity developed only after challenge with mOPV2 and reached peak levels comparable to those in the tOPV group by 2 weeks40. A 2015 clinical trial conducted in Chile examined the immunogenicity of an IPV-only primary series, in comparison to IPV-bOPV schedules, in infants for whom there was no prior polio vaccine exposure11 18. Polio type-specific enteric IgA and neutralizing responses developed similarly in both vaccine groups within 2 weeks of mOPV2 challenge and restriction of virus shedding was not substantively changed in infants receiving mIPV2HD as compared to standard IPV18. These findings underscore the distinction in immunological responses to IPV between the serum and mucosal compartments19, and further suggest these differences may not be effectively overcome by increasing the dose of IPV used in a primary schedule with bOPV.In comparison, no clear benefit was found for high-dose IPV in stimulating intestinal immunity23.Taken together these studies provide compelling evidence that enhancing serum neutralization through the addition of standard, or high-dose IPV to a primary bOPV immunization series does not yield a comparable gain in intestinal immunity upon subsequent exposure to live type 2 poliovirus. Moreover, these findings support prior observations that polio-specific enteric immunity is distinct from the serum response and is a primary determinant of virus shedding18. While poliovirus type 2-specific IgD was inversely associated with viral shedding at 1 week after challenge, this response waned by 2 weeks and a stronger inverse correlation emerged between virus shedding and type 2-specific IgA. Among subjects shedding virus, levels of type 2-specific IgA1 correlated more strongly than IgA2 with both total IgA and stool neutralization, indicating that IgA1 may be the predominant isotype mediating mucosal neutralization of poliovirus in the intestine.Further insight into the intestinal antibody response emerged from the Panamanian study, which assessed polio type-specific IgA1, IgA2, IgG, IgD, and IgM levels in stool relative to virus neutralization and shedding following mOPV2 challenge18. A central message emerging from these trials in infants is that prior live vaccine (tOPV or bOPV) induces strain-specific intestinal immunity and effectively limits virus replication on oral challenge16. Further addition of IPV (either standard or high dose) to a bOPV primary series has limited impact on the induction of enteric antibodies or virus shedding. This observation falls within the scope of a recent meta-analysis of serum and mucosal responses to different poliovirus vaccine regimens, which found no evidence of increased intestinal immunity to type 2 virus associated with the addition of IPV to a bOPV schedule46.Collectively, this series of clinical and immunologic studies in Latin American infants demonstrates induction of polio type-specific enteric IgA and virus neutralizing activity on mOPV2 challenge in infants receiving either bOPV or bOPV\u2013IPV as a primary series. A highly significant inverse correlation was found between the enteric mucosal responses and the amount of virus shed after challenge47. The observation that revaccination with OPV after an extended period is associated with immunologic boosting supports the concept that intestinal immunity wanes over time48. Indeed, studies by Grassly and colleagues have shown that protection against virus replication in children receiving OPV partially wanes within a year of initial vaccination, and may be incomplete even after multiple vaccine doses49.Fewer studies have examined mucosal immunity to poliovirus in older children and adults for whom the interval between the primary vaccine series and subsequent exposure to live virus may be considerably longer. Analyses of fecal IgA responses in older children show poor responses among those immunized with OPV in infancy, and challenged with live virus 9 years later as compared to infants vaccinated with OPV twice within an interval of 6 weeks49. Studies by Jafari et al.44 show that fecal shedding of poliovirus in children with prior IPV occurs in a significantly higher proportion of older children (10 years of age) as compared to those 6 and 11 months at the time of bOPV challenge. Persistent virus shedding on OPV challenge has also been shown in an early study of adolescent volunteers with prior exposure to IPV or OPV in childhood50. Efforts at boosting intestinal immunity with a single dose of IPV appear to be more effective in children primed with OPV on average 7 months prior to the IPV boost31 as compared to serial administration of OPV and IPV as a primary series33, providing further evidence that intestinal immunity wanes after primary immunization and may be boosted by a subsequent later exposure to IPV31.That intestinal immunity to poliovirus diminishes with age is supported by age-related studies in older children (1\u20134 years) showing that the odds of virus excretion increase significantly with the time since last vaccine exposureTogether these findings support the concept that intestinal immunity to live poliovirus may either fail to develop, or progressively diminish over time in older children and adolescents leading to an increased likelihood of virus excretion upon oral re-exposure to live virus. This suggests that in the absence of additional vaccine doses, mucosal immunity capable of restricting poliovirus replication in the intestine diminishes after the primary childhood series, creating an immunological gap in older children, adolescents and adults.51  who had received up to four doses of IPV in accordance with the recommended schedule for pediatric immunizations were challenged with a dose of mOPV2 at study entry\u20135 years 53. Although these comparisons involve different populations of differing ages, one conclusion that can be reached is that initial receipt of IPV in infancy may lead to greater shedding after an OPV challenge in older children. This has profound programmatic implications for polio eradication, and may also be an important insight into the nature of immune control of poliovirus replication in the intestine. While well-immunized IPV populations have controlled poliomyelitis and, for the most part poliovirus transmission, evidence of increased virus shedding in IPV-immunized older children following oral exposure to live virus may be significant in terms of potential enhancement of silent wild-type or VDPV circulation, particularly in geographic areas of low vaccine coverage.This observation in IPV-immunized children is in contrast to responses seen in vaccine-na\u00efve children, for whom virus shedding is markedly diminished both in percent shedding and in mean titer shed with the second dose of the same strain of OPV17, these results in older children suggest an age-related defect in enteric mucosal immunity to poliovirus associated with an increased interval between immunization and live virus challenge.The relative absence of detectable enteric antibody responses to live poliovirus in IPV-immunized children as young as 1\u20135 years of age is consistent with suboptimal induction of intestinal immunity in this age range. As compared to findings in IPV-immunized infants, in which mucosal antibody responses in stool increased rapidly following OPV challenge55  at study entry56 Fig.\u00a0. DespiteIn summarizing data on intestinal immunity from global clinical trials of bOPV and IPV regimens Fig.\u00a0 clear di18.When considered together, these findings from multiple clinical trials suggest that, unlike infants, older children and adults may be less able to mount mucosal IgA responses to poliovirus in the intestine, despite enteric replication of the virus and strong type-specific serum antibody boosts. This observation raises questions as to whether induction of intestinal immunity to poliovirus may be impaired or absent in adults, a finding that is in marked contrast to current evidence from infant studies18, making it less likely that variation in laboratory methods accounts for the observed differences in antibody responses. A decline in intestinal immunity may also reflect age-related decreases in enteric IgA produced in older children and adults, which may impact the overall neutralization potential of stool samples. While total IgA does decline with age59, it is readily detectable in stool from adult subjects and correction of polio type-specific responses to reflect total IgA concentration in stool has not been found to change the overall findings .The lack of detectable enteric antibody responses to OPV in older children and adults may be attributed to a number of possible factors, including study-related differences in sample size, collection methods, or changes in the performance of laboratory assays used to quantify mucosal immunity. In several recent studies, assessment of enteric responses is substantiated by inclusion of data from two unique laboratory assays that quantify distinct immune variables  and that are highly correlated with each other60.Likewise, it is possible that proteolytic degradation of IgA may occur during longer stool transit times in older individuals. However, experiments to evaluate the impact of prolonged incubation of neutralization-positive samples with stool from children and adults indicate that this is not a significant contributing factor . Decreased enteric IgA in older children and adults may also reflect physiologic changes that facilitate virus replication in localized areas of the intestine that are distinct from those typically associated with antigen-stimulated IgA secretion . Alternatively, lower levels of total IgA in stool may stem from natural age-related involution of the adenoids, tonsils, and Peyer\u2019s patches\u2014all primary sites of poliovirus replication60, and the same anatomic sites being responsible for induction and expression of mucosal IgA62.The underlying question of why infants respond with robust mucosal antibody responses to OPV in the intestine, and why these responses wane with age remains unanswered and has clear implications for the global polio eradication effort. The assumption that IgA-mediated mucosal immunity is critical for control of enteric poliovirus replication is strongly reinforced by observations of the striking parallels between the sites of primary poliovirus replication in epithelial cells of the intestine, and in tissues associated with the mucosal immune system 64. Production of endogenous IgA in the intestine commences during the first weeks of life and is associated with physiologic tissue maturation, immune activation, and the development of immunological tolerance to a wide range of orally ingested antigens64.While our current understanding of the maturation of the mucosal immunologic landscape in infants is incomplete, it is likely that factors associated with early immune regulation of polio-specific IgA in infancy play a significant role in determining the induction and maintenance of mucosal responses to the virus later in life. Indeed, administration of poliovirus vaccines during routine pediatric schedules generally coincides with a period of dynamic immunological development in infancy69. Immune responses to commensal microbes are directed toward establishing tolerance, limiting inflammation, and maintaining intestinal homeostasis71. However, early exposures to pathogenic microbes and antigens through infection or immunization concurrently shape the immunologic repertoire and establish critical effector memory responses72.Importantly, microbial colonization of mucosal sites, which begins largely at birth, is a driving factor in shaping early innate and adaptive immune responses to both non-pathogenic and pathogenic organisms75. Microbe-laden DC are restricted to the mucosal compartment by mesenteric lymph nodes, providing a level of protection against systemic infiltration of pathogens into the body76.These responses are orchestrated within the highly adaptive microenvironment of the intestinal mucosa. Phagocytic macrophages and dendritic cells (DC), abundant in the lamina propria, continuously sample the luminal microbiota and effectively remove bacteria and pathogens that breach the epithelial barrier77. In contrast, mucosal exposure to microbiota elicits a more restricted response, primarily to microbial surface antigens and characterized by a more limited IgA repertoire, which rapidly declines in the absence of repeated antigenic exposure77. Moreover, while intestinal memory IgA responses increase after successive antigen exposures, they do not appear to show the synergistic increase typical of a systemic prime-boost response78.The interplay of host-microbe mutualism is further refined to promote distinct adaptive immune responses in systemic and mucosal compartments. Systemic exposure to a range of microbial taxa leads to induction of a diverse antibody repertoire dominated by IgG and designed to prevent lethal microbial sepsis17. Conversely, OPV administered alone or in combination with IPV stimulates both serum and intestinal antibody responses, the latter dominated by enteric IgA. Recent studies demonstrate the influence of the intestinal microbiota on the magnitude of the enteric IgA antibody response to combined regimens of IPV and bOPV in infants, suggesting not only the presence but the composition of the microbiota shape the adaptive response to poliovirus in the intestine79.This distinction is evident in the observed differences in antibody responses to systemic or orally delivered poliovirus vaccines in infants. Notably, subcutaneous or intramuscular injection of IPV elicits high-titered, serum IgG responses that are boosted by successive doses, but with little to no generation of intestinal IgA77. In germ-free mice, transitory exposure to a non-replicating microbe within the intestine requires a dose several orders of magnitude higher than that of a systemic exposure to reshape the antibody repertoire77. It is possible then that failure to develop a strong intestinal IgA response to OPV challenge in older children and adults may reflect a sub-threshold level of antigenic exposure, due to significant microbial competition in the intestine or the transient nature of antigenic exposure conferred by a single challenge dose of live, attenuated OPV.Induction of mucosal IgA is further restricted by a higher required threshold for antigenic priming as compared to a systemic response27 and rotavirus81 vaccines in developing country settings. Data on enteric immunity to poliovirus vaccines from several recent clinical trials is uniform across many countries18, although it does not reflect experience in some of the countries where OPV performance is diminished28. Parker and colleagues have postulated that interference with the induction of mucosal immunity to oral vaccines may be due to altered microbial populations in the gut, nutritional deficiencies or epigenetic factors that may preferentially affect children from low-income countries82. Impaired immunogenicity of OPV in children aged 6\u201311 months has been shown to correlate with recent infection with non-polio enteroviruses83. This observation supports a 2014 meta-analysis showing a consistent negative impact of concurrent infection with enteropathogens on OPV responses84, and underscores the potential impact of microbial inference in reducing induction of polio-specific IgA in the intestine.Other environmental factors and host-related changes in enteric immunity may also play a role in modulating IgA responses to poliovirus vaccines in the intestine. Previous studies have noted impaired antibody responses to oral polio88. While data from human studies is more limited, comparisons with murine models suggest the salient features of the gut mucosal immune system, and the functional outcomes needed to respond and adapt to luminal microbiota and protect against infection, are conserved between these species89.Cell-mediated immunity to poliovirus in the intestine is much less well understood than antibody-mediated immunity in part, due to difficulties in obtaining adequate primary tissues and cells from this site in young children. Many of the detailed mechanisms of cell-mediated induction of IgA have been explored in animal models, and presented in comprehensive reviews90. Subsequent signals from CD4+ T follicular helper (TFH) and T regulatory (Treg) cells in the germinal centers of Peyer\u2019s patches control B cell responses in an antigen-specific manner92, and provide signals that promote the switch to IgA-producing plasma cells90. IgA+ plasmablasts enter the circulation and subsequently home back to the intestine, where they take up residence in the lamina propria and constitute a primary effector arm of enteric immunity91.In general, induction of antigen-specific IgA within the intestinal mucosa occurs in highly specialized germinal centers in Peyer\u2019s patches and in isolated lymphoid follicles. Interaction of B cells with DC in the subepithelial dome of Peyer\u2019s patches dictates the early stages of IgA induction93. The rate of IgA transport across the mucosal epithelium is influenced in the lamina propria by Th17 cells that produce IL-17 in response to co-stimulation with cytokines97. Th17 cells contribute to maintaining intestinal homeostasis to commensal microbes via IL-17 induction of pIgR expression, thereby regulating the rate of IgA secretion into the lumen98.Transport of antigen-specific IgA from the lamina propria through the epithelial layer occurs by interaction with polymeric Ig receptors (pIgR), which mediate transfer of IgA and help stabilize the structure of the secreted dimeric IgA molecule94. It is puzzling then why older children and adults appear to lose the ability to mount a polio-specific IgA response in the intestine upon oral challenge with live poliovirus. The loss of detectable enteric IgA to OPV observed with increasing age raises questions, as to whether exposure to poliovirus vaccines in infancy may induce antigen-specific mucosal immune suppression or tolerance in the gastrointestinal tract99. As the gut is the primary site of exposure to the majority of foreign antigens early in life, mechanisms geared towards suppression of excessive immunologic reactivity and inflammation play a critical role in establishing and maintaining intestinal homeostasis70.Maintenance of immune homeostasis in the intestine is critically dependent on constant adaptation of cell-mediated immune responses that regulate the quantity and specificity of secreted IgA103. This suppressive effect could be adoptively transferred by a cellular fraction, presumed to be a suppressor T cell population103. Whether a similar phenomenon occurs in the context of parenteral administration of IPV in infancy remains a hypothesis to explain the lack of polio-specific enteric IgA responses observed in older children and adults with a history of childhood IPV.Several possible immunologic barriers may arise over time in the intestine to reduce or prevent IgA induction including inadequate cell-mediated support for IgA production or active suppression of enteric IgA induced by vaccine antigens. The latter concept was first demonstrated over 40 years ago in a series of studies showing that parenteral administration of cholera toxin in mice induced marked suppression of antigen-specific mucosal IgA in the intestine104 also play a critical role in IgA induction and maintenance of homeostasis to commensal microbes in the intestine107. In mice, depletion of CD4+ CD25+ Tregs significantly reduces intestinal IgA to microbial antigens, providing evidence of their essential role in regulating antibody responses to enteric microbiota92. At homeostasis, Tregs establish a tolerogenic state to commensal microbes by suppressing excessive inflammatory responses to microbial antigens and preventing gut pathology107.Tregs with the potential for suppressor activity113. In mice infected with Friend virus, Tregs suppress differentiation of germinal center B cells and plasma cells, and decrease B cell class switching through downregulation of CD68 expression, which reduces costimulation by TFH cells112. The suppressive effects of Tregs on immune responses to viral pathogens and vaccination are not universal, and distinct effects can be seen with different pathogens, at different stages of infection114 and after vaccination113, emphasizing the highly contextual nature of Treg suppressor activity.However, in animal models and adult human studies, Tregs are also implicated in suppressing B cell responses to certain viral pathogens and vaccines116 Studies by Rabe and colleagues have shown that a higher proportion of circulating Tregs during the first 18 months of life is inversely related to the fraction of T cells that subsequently express a memory phenotype later in childhood117, suggesting these cells may further influence the long-term expression of immunologic memory to vaccine antigens encountered during infancy118.Whether suppression of B cell immunity to poliovirus occurs in the intestine, and whether this is associated with the observed absence or loss of polio-specific enteric IgA in older children and adults is not known. In infants an abundance of Tregs home to the intestine in the first months of life, suggesting these cells play an essential role in shaping mucosal IgA responses to enteric microbiota120 and\u00a0can be modulated by co-administration of vaccine antigens with certain adjuvants. Of interest, the enterotoxin-based mucosal vaccine antigen LT  has been shown to induce strong antigen-specific Th17 responses and increase mucosal IgA to co-mixed antigens following parenteral or oral immunization123. Co-administration of dmLT with a dose-sparing amount of IPV in mice has been shown to promote polio-specific intestinal IgA and upregulate expression of the intestinal homing receptor \u03b14\u03b27 on trafficking T cells122. Clinical trials of dmLT co-administered with IPV in adults are ongoing and will yield valuable information on the impact of targeted modulation of cellular responses for induction of long-lived polio-specific mucosal IgA and virus neutralizing responses in the intestine.Human Tregs and Th17 cells in the intestine display a high degree of plasticityT (TRM) cell populations. TRM are found in abundance in the epithelium of barrier sites such as the skin and mucosae, where they serve as sentinels to rapidly activate broad localized immunity127. TRM play a central role in antiviral immunity through cytokine-mediated recruitment of both innate and adaptive immune cells, and by direct lysis of virally infected cells128. Unlike circulating CD8+ T-cells, TRM in the gastrointestinal tract appear to be maintained independently of cognate antigen for long periods and may serve to limit the duration of virus shedding129. Whether these cells participate in controlling poliovirus replication in the intestine is not currently known. However, ongoing studies of intestinal immunity in adults with prior history of IPV or OPV in childhood will shed light on the impact of early exposure to poliovirus antigens on the development of long-term cell-mediated memory responses able to control virus shedding later in life.In the absence of detectable enteric IgA to poliovirus in older children and adults, control of poliovirus replication in the intestine may rely in part on tissue resident memory The impact of early childhood immunization with live and inactivated polio vaccines during a period of dynamic immunologic development is likely to play a significant role in establishing functional cell-mediated memory responses capable of stimulating mucosal IgA and restricting virus replication in the intestine. Current observations of an age-related decline in enteric mucosal IgA and virus neutralizing responses to OPV, associated with sustained virus shedding, raise important questions as to the nature of immune regulation of poliovirus replication in the intestine and have clear implications for global eradication efforts.131. These studies will undoubtedly further shape our understanding of the induction and regulation of mucosal immunity to poliovirus. With an increasing number of vaccine-derived poliovirus outbreaks occurring globally, deployment of nOPV2 and ongoing clinical development of nOPV types 1 and 3 will provide critical new tools to help mitigate the risk of further seeding of vaccine-derived virulent strains into vulnerable populations, and to reduce the number of cases of polio associated with these outbreaks.Promising new data is now emerging on the safety and immunogenicity of novel type 2 oral poliovirus vaccines (nOPV2) with improved genetic stability after intestinal passage"}
+{"text": "These new techniques now have opened the door to individualized and highly specific molecular imaging in IBD in the future and pave the path to personalized medicine approaches. The quality of evidence was stated according to the Oxford Center of evidence-based medicine (March 2009). For this review a Medline search up to January 2021 was performed using the words \u201cinflammatory bowel disease,\u201d \u201culcerative colitis,\u201d \u201ccrohn's disease,\u201d \u201cchromoendoscopy,\u201d \u201chigh-definition endoscopy,\u201d \u201cconfocal laser endomicroscopy,\u201d \u201cconfocal laser microscopy,\u201d \u201cmolecular imaging,\u201d \u201cmultiphoton microscopy.\u201dHigh-definition endoscopy is one essential step in the initial diagnosis of inflammatory bowel disease (IBD) characterizing the extent and severity of inflammation, as well as discriminating ulcerative colitis (UC) from Crohn's disease (CD). Following general recommendations and national guidelines, individual risk stratification should define the appropriate surveillance strategy, biopsy protocol and frequency of endoscopies. Beside high-definition videoendoscopy the application of dyes applied via a spraying catheter is of additional diagnostic value with a higher detection rate of intraepithelial neoplasia (IEN). Virtual chromoendoscopy techniques  should not be recommended as a single surveillance strategy in IBD, although newer data suggest a higher comparability to dye-based chromoendoscopy than previously assumed. First results of oral methylene blue formulation are promising for improving the acceptance rate of classical chromoendoscopy. Confocal laser endomicroscopy (CLE) is still an experimental but highly innovative endoscopic procedure with the potential to contribute to the detection of dysplastic lesions. Molecular endoscopy in IBD has taken application of CLE to a higher level and allows topical application of labeled probes, mainly antibodies, against specific target structures expressed in the tissue to predict response or failure to biological therapies. First pre-clinical and  Confocal laser endomicroscopy (CLE) was introduced in 2006 and gave exclusive insight into the gastrointestinal tract on a cellular and subcellular level in a variety of gastrointestinal diseases. Initially, there were two independent in-vivo histology systems available on the market, the endoscope-based CLE (eCLE) by Pentax, Tokyo, Japan, and a probe-based CLE (pCLE) by Mauna Kea Technologies, Paris, France. A couple of years ago the technical support for eCLE was permanently discontinued and research activities with that specific system were restricted to a very small number of research centers with active running systems. In IBD, CLE was used for characterization and classification of inflammatory activity and mucosal healing in active disease as well as for the detection of IEN during surveillance. For example, a combination of chromoendoscopy with CLE can detect 5-fold higher rates of IEN compared with random biopsy protocols . The initial diagnosis, the determination of disease activity and surveillance are the key steps of rational disease management and include primarily an endoscopic approach to visualize and characterize the extent and severity of mucosal inflammation and to take targeted biopsies of inflamed and non-inflamed tissue areas. High-resolution or high-definition endoscopy should be the gold standard when examining IBD patients. In surveillance colonoscopy, a combination of high-definition endoscopy with classical dye-based chromoendoscopy  is of additional value to detect flat polypoid neoplastic mucosal lesions and discriminate these areas from colitis-associated pseudopolyps or other benign lesions . The exclusion or detection of intraepithelial neoplasia (IEN) is the aim of all surveillance colonoscopies in IBD to reduce the risk of malignant transformation to colorectal cancer. Although many study data showed different results this risk seems to be lower than previously assumed , level , . This exciting technique was originally designed to allow virtual histology on a cellular and subcellular level with the potential to at least partially replace classical histology. The procedure, however, is time-consuming, technically challenging and intravenous applied fluorescein is necessary for each procedure to generate high-resolution images. This and the fact that no reimbursement was provided by health care authorities restricted the running CLE systems to large research units in University centers. The acquisition of targeted biopsies became reality and a large number of clinical studies investigating a variety of gastrointestinal diseases were published between 2005 and 2012. Most of these studies characterized pre-malignant or inflammatory lesions in Barrett's esophagus , gastric lesions . Data of lesions  in UC pa lesions . However lesions ,  by a fluorescent-labeled adalimumab anti-TNF antibody showed that high numbers of mTNF-positive cells correlated with higher short-term response rates to treatment with the TNF-neutralizing antibody adalimumab. Patients with high numbers of mTNF-expressing cells demonstrated a higher probability of clinical response than patients with low numbers of mTNF+ cells (92 vs. 15%). The sensitivity, specificity and accuracy for the prediction of therapeutic responses were 92, 85, and 88%, respectively. Positive and negative predictive values were 85 and 92%  is one of the emerging innovative imaging technologies with the potential to visualize intestinal epithelial cells under normal and inflamed conditions without the addition of exogenous fluorescent dyes . The fir colitis . A futurin vivo histology method brought extensive insight and understanding of gastrointestinal mucosal pathology, its widespread use in routine endoscopy is hampered by the lack of reimbursement and additional examination time (in vivo use in an animal model. Label-free high-resolution endomicroscopy would be the logical consequence and a perfect long-term perspective for the use in patients with IBD.On the way to an individualized endoscopic approach, a large number of technical improvements are nowadays available for patients with IBD. These include mainly high-definition endoscopy with nearly comparable efficiency compared to dye-based and virtual chromoendoscopy techniques. If upcoming clinical studies with oral intake of methylene blue prior to surveillance colonoscopy become available and confirm the additional benefit, the reservations against classical dye spraying would finally come to an end. Although CLE as the most widely used ion time . HoweverAll authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "This paper examines the implications of employers' current COVID-19 protective workplace attendance policies toward older workers, potentially creating the outcomes of increased numbers of involuntary retirees and the discouraged older worker syndrome among otherwise qualified older workforce participants. How potential ageist assumptions and age discrimination under COVID-19 affect workplace decisions in reflection on the Age Discrimination in Employment Act (1967) guidelines is discussed. Older workers may remain in the workforce longer than ever before due to having healthier life expectancies. Workplace policies need to be increasingly sensitive to older employees\u2019 rights to sustain their workplace engagement . The author reviewed current unemployment trends in 2020 and emerging litigation in reflection upon general issues of COVID-19 related age discrimination in the older workers' workplace attendance decisions by employers and the historical framework of the Age Discrimination in Employment Act . The policy analysis paper presents the implications of employers' COVID-19 protective policies on older workers and how it may affect the \u201chealth\u201d of the workplace and older adults and the economy beyond the pandemic. Lastly, strategies to address an \"age-friendly\" workplace during a pandemic and post-pandemic are discussed."}
+{"text": "Melanoma-associated retinopathy (MAR) is a paraneoplastic syndrome that involves the production of autoantibodies which can cross-react with retinal epitopes leading to visual symptoms. Autoantibodies can target intracellular proteins, and only a few are directed against membrane proteins. This discrepancy in autoantibody\u2013protein target can translate into different immune responses (T-cell mediated vs B-cell mediated). Historically, treatment of MAR has focused on surgical reduction or immunosuppressive medication, mainly glucocorticoids. However, tumor resection is not relevant in metastatic melanoma in which MAR is mostly encountered. Moreover, the use of glucocorticoids can reduce the efficacy of immunotherapy. We report the first case to our knowledge with subjective resolution of visual symptoms and objective evidence of normalization of electroretinogram of MAR with undetectable autoantibodies after administration of programmed death-1 (PD-1) inhibitor (pembrolizumab) without the use of surgical reduction or systemic immunosuppression. This case highlights the potential improvement and resolution of negative autoantibody MAR with the use of PD-1 inhibitors and emphasizes the importance of multidisciplinary approach and team discussion to avoid interventions that can decrease immunotherapy-mediated anti-tumor effect. Melanoma-associated retinopathy (MAR) is a rare paraneoplastic syndrome characterized by photopsia and decreased night vision  initially with normal fundus exam followed by painless progressive vision loss with viewable retinal changes . This paThe treatment of malignant melanoma has been revolutionized since the introduction of immune checkpoint inhibitors (ICI) which have replaced chemotherapy and are now considered the standard of care for advanced and metastatic cutaneous melanoma , 3. The Treatment of MAR has been based on either cytoreduction of the primary tumor or the immunomodulation and/or immunosuppression with medications such as glucocorticoids and intravenous immunoglobulins (IVIG). Of importance, there is a concern with a growing evidence that the use of immunosuppression such as glucocorticoids might counteract the anti-tumor effect of ICI and lead to low response rates to immunotherapy especially if it is started prior to the initiation of ICI , 6. MoreWe report our multidisciplinary approach among medical oncologists and ophthalmologists that led to avoiding glucocorticoid administration prior to initiation of cancer treatment with ICI in a patient who was found to have MAR that led to the diagnosis of metastatic melanoma. Interestingly, we observed that patient\u2019s visual symptoms secondary to paraneoplastic syndrome of MAR improved after starting pembrolizumab. This was accompanied by a resolution of electroretinogram (ERG) findings . This observation provides an insight into the heterogeneous immunological etiology of MAR and warrants further investigation on the safety and efficacy of ICI in MAR subtypes .A 74-year-old Caucasian male presented to the ophthalmology clinic with complaints of vision changes. His medical history was significant for paraplegia due to spinal trauma, melanoma of the left upper arm four years prior (Stage I: T1aN0M0) with Breslow depth of 0.77\u00a0mm without significant mitotic activity or associated ulceration. An uncomplicated wide local excision was performed at that time without a sentinel lymph node biopsy. He had regular and reassuring dermatological examinations for three years after surgical excision until one year prior to presentation when he was lost to follow-up. His other medical history included atrial fibrillation and hypothyroidism, and there was no history of previous autoimmune disease.The patient described his vision changes as shimmering lights in the entire field of vision for the past 5\u00a0weeks prior to his presentation. The shimmering lights began in his right eye but eventually became bilateral and was accompanied by a decrease in night vision . The ophthalmologic history was significant for a cataract surgery in the left eye. On examination, he had cataract in the right eye with decreased bilateral visual acuity. His color vision was normal, and no field loss was detected on clinical testing by confrontation. He could not perform reliable automated perimetry since he was wheelchair bound and could not be positioned accurately during the test. The fundus examination revealed a normal optic disc without retinal pigmentary change or arterial attenuation. Optical coherence tomography (OCT) of the maculae was normal.The patient\u2019s previous history of melanoma coupled with his symptoms of nyctalopia and shimmering lights raised a concern for the possibility of melanoma-associated retinopathy (MAR). We ordered an electroretinogram (ERG) which revealed prominent reduction of b-waves, indicative of bipolar cell dysfunction\u2014a hallmark of MAR Fig.\u00a0. The patOur report describes resolution of MAR symptoms after the use of PD-1 inhibition which was demonstrated by complete resolution of visual symptoms after the second cycle of pembrolizumab and reversal of the pathogenic ERG changes related to MAR. This approach suggests the safety and efficacy of programmed death-1 inhibitors such as pembrolizumab in the treatment of both malignant melanoma and autobody negative paraneoplastic syndrome of MAR. There was a major concern of exacerbating the underlying paraneoplastic syndrome at the time of treatment initiation, but the undetectable retinal autoantibodies against intracellular proteins suggested\u00a0that the pathophysiology of MAR was likely B-cell driven. The commercially available panel of retinal autoantibodies does not include antibodies against cell membrane. Moreover, we were not able to perform another antibody test directed at transient receptor potential channel protein 1 (TPRM1) as this test was not commercially available.There is a lack of consensus regarding treatment of MAR, but it has been centered in the past on two different approaches. The first approach revolves around suppressing the immune system to decrease the immune response; however, corticosteroids have been ineffective in most cases . In addiThe treatment\u00a0paradigm of advanced non-metastatic and metastatic melanoma has shifted in the last decade from chemotherapeutic agents to targeted therapy and ICI. The 5-year survival data have demonstrated significant improvement of overall survival reaching 52% and 41% with the use of PD-1/CTLA-4 inhibitor combination (nivolumab and ipilimumab) and PD-1 inhibitor pembrolizumab, respectively , 15. HowThere have been no prospective studies to support the role of immunosuppressants such as glucocorticoids on the efficacy of ICI, and most of the evidence is derived from retrospective analysis. For example, in a retrospective study by Fuc\u00e0 et al. the early use of steroids prior to the initiation of ICI in patients with lung cancer was associated with worse outcomes including worse progression-free survival and overall survival . SimilarThe immune response implicated in the pathogenicity of paraneoplastic neurological syndromes is regarded to be humoral (B-cell mediated) for unknown reasons, and only a minority of these syndromes could be mediated by cellular immunity (T-cell response) . The B-cOur patient did not develop autoimmune uveitis, retinitis, or autoimmune orbital disease, as some patients on PD-1 inhibitors may develop neurological immune-related adverse events. Contrary to our report, Roberts et al. described a patient who was diagnosed with metastatic cutaneous melanoma and developed MAR with unanticipated fundus findings while receiving treatment with pembrolizumab . The patTherefore, further research into delineating the heterogeneity of the immunological dysfunction related to MAR is essential, as current standard of care is based on immunotherapy (ICI). It appears that the safety of ICI use in MAR depends on the immunological cellular pathophysiology (B-cell mediated vs T-cell mediated). Our observation along with previously reported cases demonstrate the discrepancy in outcomes in patients with MAR who receive ICI, which suggests the immunological heterogeneity leading to MAR and advocates for further research to understand the immunological response in this paraneoplastic syndrome. The development of clinically available antibody panels directed at intracellular and extracellular retinal antigens could aid in the\u00a0decision making on treatment approach of metastatic melanoma patients who are diagnosed with MAR and are expected to receive immunotherapy. The rare incidence of MAR and the presence of retinal antibodies in healthy individual controls pose a challenge in establishing a unified approach . LimitatIn conclusion, this is the first case, to our knowledge, to describe the resolution of autoantibody negative MAR after treatment with programmed death-1 (PD-1) inhibitor in a patient with metastatic melanoma. The possible negative impact of glucocorticoid (used to treat MAR) on ICI anti-tumor response and the potential role of ICI on the resolution of sub-types of paraneoplastic syndrome highlight the importance of multidisciplinary approach when treatment is planned. We believe patients with undetectable retinal-intracellular protein autoantibodies can be safely treated with ICI. The limitations of this study include a single patient and lack of mechanistic insight into the immunological response of MAR in this patient, which warrants further research to support our observation."}
+{"text": "Chronic visceral pain represents a major unmet clinical need with the severity of pain ranging from mild to so severe as to prevent individuals from participating in day-to-day activities and detrimentally affecting their quality of life. Although chronic visceral pain can be multifactorial with many different biological and psychological systems contributing to the onset and severity of symptoms, one of the major triggers for visceral pain is the exposure to emotional and physical stress. Chronic visceral pain that is worsened by stress is a hallmark feature of functional gastrointestinal disorders such as irritable bowel syndrome (IBS). Current pharmacological interventions for patients with chronic visceral pain generally lack efficacy and many are fraught with unwanted side effects. Cognitive behavioral therapy (CBT) has emerged as a psychotherapy that shows efficacy at ameliorating stress-induced chronic visceral pain; however, the molecular mechanisms underlying CBT remain incompletely understood. Preclinical studies in experimental models of stress-induced visceral pain employing environmental enrichment (EE) as an animal model surrogate for CBT are unraveling the mechanism by which environmental signals can lead to long-lasting changes in gene expression and behavior. Evidence suggests that EE signaling interacts with stress and nociceptive signaling. This review will (1) critically evaluate the behavioral and molecular changes that lead to chronic pain in IBS, (2) summarize the pharmacological and non-pharmacological approaches used to treat IBS patients, and (3) provide experimental evidence supporting the potential mechanisms by which CBT ameliorates stress-induced visceral pain. Irritable bowel syndrome (IBS) is a chronic gastrointestinal (GI) disorder that affects about 10\u201320% of the population of the USA . The durMost pharmacological therapies to alleviate IBS symptoms show limited efficacy and can cause unwanted side effects , 11. BehChronic visceral pain is defined as long-lasting, poorly localized pain emanating from the abdominal region , 12 and Experimental models of post-inflammatory IBS have revealed that previous inflammatory insult in the colon of rodents sensitizes afferent neurons to induce visceral hypersensitivity mediated by increased expression of nociceptive receptors including calcitonin gene-related peptide (CGRP)  and tran3 receptor antagonists that can aid in relaxing the colon and slowing lower GI motility while eluxadoline is a \u03bc-opioid receptor agonist, which decreases GI transit by reducing muscle contractions and fluid secretion in the intestine. Both alosetron and eluxadoline have also been shown to relieve abdominal pain in IBS-D patients  have been developed as the rodent analog of CBT and are used to investigate the molecular effects of behavioral interventions in rodents. EE involves exposing animals to a novel environment with sufficient physical and social stimuli to promote cognitive and physiological well-being . EE typiClinical and preclinical studies clearly show that multiple factors are involved in the pathophysiology of visceral pain which might explain why finding the ideal therapy has been elusive. Current pharmacological treatments available for IBS focus on symptom relief rather than reversing the underlying pathology. Stress, anxiety, and inflammation cause changes in the expression of genes  in brain centers critical for stress reactivity and sensory neurotransmission . These alterations ultimately potentiate stress reactivity and sensitize nociceptive afferent fibers leading to visceral hypersensitivity in IBS. Behavioral therapies including hypnotherapy and CBT have already been used extensively as effective behavioral therapies for cognitive, mood, and neuropathic pain disorders and now clinical and pre-clinical trials are showing that behavioral therapies can also ameliorate chronic visceral pain . UnfortuIn recent years, interest in CBT-based treatment has increased leading to more clinical research and understanding of CBT techniques. Other variations of CBT have been developed to ease the burden of the patients having to constantly visit the clinic for CBT sessions. Studies have shown that patients can be trained to effectively practice CBT techniques remotely. Patients who attended an initial CBT session with a physician and then had subsequent follow-ups via the telephone reported improvements in their IBS symptoms similar to patients who visited a clinician for every session . CBT sesOne caveat when interpreting clinical data from behavioral studies is the risk of over-interpretation of placebo effects. Multiple studies have shown significant effects of psychological placebos in behavioral interventions for anxiety and depression , 126. ItIn conclusion, non-pharmacological therapies have been shown to induce molecular and psychological changes that quantifiably reverse the pathophysiology of visceral pain in clinical and preclinical studies. Although more research is needed to unravel the mechanisms underlying CBT, experimental models employing EE are being used to determine the role of EE to influence gene expression . This reResearch in BG-V laboratory has grant funding from Ironwood Pharmaceuticals, Blue Therapeutics, and TEVA Pharmaceuticals.AO was the lead author in writing the review. TY used her expertise to write certain sections of the main text. BG-V mentored and supervised the team, providing critical input on the scope and topics included in the review. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Brain stimulation technology has become a viable modality of reversible interventions in the effective treatment of many neurological and psychiatric disorders. It is aimed to restore brain dysfunction by the targeted delivery of specific electronic signal within or outside the brain to modulate neural activity on local and circuit levels. Development of therapeutic approaches with brain stimulation goes in tandem with the use of neuroimaging methodology in every step of the way. Indeed, multimodality neuroimaging tools have played important roles in target identification, neurosurgical planning, placement of stimulators and post-operative confirmation. They have also been indispensable in pre-treatment screen to identify potential responders and in post-treatment to assess the modulation of brain circuitry in relation to clinical outcome measures. Studies in patients to date have elucidated novel neurobiological mechanisms underlying the neuropathogenesis, action of stimulations, brain responses and therapeutic efficacy. In this article, we review some applications of deep brain stimulation for the treatment of several diseases in the field of neurology and psychiatry. We highlight how the synergistic combination of brain stimulation and neuroimaging technology is posed to accelerate the development of symptomatic therapies and bring revolutionary advances in the domain of bioelectronic medicine. Functional and structural brain imaging modalities and related analytical techniques have become the cornerstone of modern neurosciences and revolutionized translational medicine in neurological and psychiatric disorders. Multi-tracer positron emission tomography (PET) or single photon emission tomography (SPECT) permits not only molecular imaging of neurotransmitters, neuroreceptors and protein aggregates, but also precise mapping of brain glucose metabolism cerebral blow flow (CBF). Non-invasive multi-spectral magnetic resonance imaging (MRI) allows for high resolution visualization and measurement of macrostructural brain anatomy, microstructural integrity with diffusion tensor imaging (DTI), CBF with arterial spin label (ASL) and blood-oxygen-level-dependent (BOLD) neural activity with rest-state functional MRI (rsfMRI). Brain anatomy is also frequently evaluated clinically with computerized tomography (CT). While direct molecular imaging modality with PET/SPECT is more specific in describing regional neuropathogenesis and confirming disease diagnosis from the objective basis of neurochemistry, it is costly in general and only available in specialty medical centers. On the other hand, indirect imaging modality is more economical and easily accessible, and able to define specific, widely-distributed brain networks and pathways associated with each disorder. The latter is concerned primarily with brain metabolism or perfusion with PET/SPECT and multiple anatomical or functional markers with MRI. Such information is highly important in facilitating early differential diagnosis, monitoring disease progression, assessing treatment effects and predicting functional recovery of novel experimental therapies.Neuromodulation therapy has been a central technique in the non-pharmacological treatments of medically refractory patients with a variety of neurological and psychiatric disorders. There are two general classes of intervention based on deep brain stimulation (DBS) or non-invasive brain stimulation (NIBS). The effectiveness of brain stimulation strategy is dependent critically upon rigorous neuroimaging studies to help select neuroanatomical targets, screen trial participants, and evaluate postoperative safety issues and brain correlates in response to functional restorative therapies. Neuroimaging of large-scale brain networks can help clinicians to optimize target selection and improve the clinical efficacy of NIBS in neuropsychiatric diseases  circuits. DBS at many different deep nuclei structures has been most successful in moderate to advanced patients with Parkinson\u2019s disease (PD) for whom available medications are no longer effective  but higher in the STN than in the Vim DBS group for PDRP (p\u00a0<\u20090.01). Treatment-mediated changes (ON\u2013OFF) in network activity in the same Vim and STN DBS patients and 14 test-retest PD control subjects . Compared with the test-retest PD group, PDTP network activity declined in both DBS groups  with greater PDTP modulation with Vim than with STN DBS (p\u00a0<\u20090.05). Conversely, PDRP expression were reduced with STN DBS (p\u00a0<\u20090.05) but not with Vim DBS. These studies demonstrated that differential effects of novel antiparkinsonian interventions on different motor features of PD can be evaluated objectively by changes in activity of specific metabolic brain networks.We have investigated differences in brain network modulation by ventral intermediate (Vim) thalamic and STN DBS in patients with PD using PDTP and PDRP  to different forms of dementia as late-stage manifestations. In the following section we cover some applications of DBS in the treatment of dementia resulting from PD and AD.PD dementia (PDD) and dementia of Lewy bodies (DLB) have been described in the literature of parkinsonism depending on the clinical diagnostic criteria. Bilateral DBS of the nucleus basalis of Meynert (NBM) at low frequency has been proposed as a promising therapy for patients with dementia given that this nucleus, populated with abundant cholinergic neurons, is a key relay structure associated with dysfunctional brain circuits of memory and cognition  is the most common form of neurodegenerative dementia affecting principally elder populations across the world. Of note, MCI represents a high-risk category of prodromal AD given that it falls into intermediate clinical stages between healthy aging and the onset of dementia. The severity of the disease is evaluated quantitatively by many clinical dementia rating scales such as the Alzheimer\u2019s Disease Assessment Scale \u2013 Cognitive subscale 13 (ADAS-Cog 13). There is strong evidence for central involvement of widespread brain networks behind memory loss and cognitive dysfunction in AD, but only limited options are available for viable medical treatments. NBM and fornix in the medial forebrain have been explored as potential targets of choice for neurosurgical interventions due to their prominent roles in cholinergic systems  and the Hamilton Depression Rating Scale (HDRS).Obsessive-compulsive disorder (OCD) is one of prevalent psychiatric diseases with abnormal functional and structural substrates involving the CSPTC brain circuitry. Approximately 10% of OCD patients are refractory to first-line treatment and need neurosurgical interventions such as ablative lesioning or DBS. Several structures including ventral capsule/ventral striatum (VC/VS), ventral anterior limb of the internal capsule (ALIC), nucleus accumbens (NAc) and anteromedial STN are effective targets for severe treatment-refractory OCD based on open-label trials  in early 2008 for the treatment of refractory OCD, global efforts have begun to focus on DBS , with anteromedial STN projected mainly to the lateral OFC, dorsal ACC, and DLPFC  have emerged as a viable form of neuromodulation therapies  undergoing VNS Table . An openVNS is also one of major brain stimulation modalities to treat medically refractory epilepsy but with highly variable rates of responses in both adults and children (Foit et al., Other imaging modalities have also been employed to select suitable candidates before initiating VNS therapy. One study acquired preoperative rsfMRI data in 21 children with epilepsy who were mostly treated for at least 12\u2009months with VNS (Ibrahim et al., In summary, robust changes in specific pathways and associated connectivity revealed by multimodal neuroimaging methods further support the notion that VNS is able to bring symptomatic relief by modulating distinct brain networks underlying these disorders. In particular these multi-institutional studies demonstrate the power of connectome in providing new insights into the mechanism of action for VNS. The novel classification algorithms based on neuroimaging data are highly accurate in predicting treatment responses in individuals and prevent some patients from participating in invasive and costly VNS procedures.Brain stimulation has been an effective option in treating a variety of neurodegenerative and neuropsychiatric disorders with deep and peripheral brain stimulation (Graat et al., There have been multiple obstacles in translating promising therapeutic solutions from preclinical to clinical arenas in neurological disorders. Firstly, different functional biomarkers were used for the mechanistic assessment of efficacy in light of inevitable inter-species differences. This situation could be overcome by developing in animal models viable imaging biomarkers that have proven effective in patient populations for use in preclinical trial of novel therapeutics. A primary example had been the work with FDG PET on metabolic brain networks in non-human primate models of experimental parkinsonism undergoing striatal dopamine cell implantation (Ma et al., The last decade has witnessed the development and clinical validation of large-scale metabolic brain networks involving widely-distributed functional neuroanatomical structures. This was especially true with FDG PET in patients with PD and atypical PD such as multiple system atrophy, progressive supranuclear palsy and cortico-basal degeneration (Teune et al., Studies with FDG PET had also reported robust metabolic brain networks associated specifically with cognitive dysfunction in PD (Meles et al., Recent studies in clinical trials suggest a need for early-interventions to delay onset or slow down progression of the disease. Work is currently under way to develop DBS as potential neuroprotective therapies to intervene early in the disease course (McKinnon et al., Multimodality neuroimaging techniques have accelerated the pace of development and evaluation of stimulation-based therapeutics by using various analytical approaches showcased in this review. To this end we have cited many examples demonstrating the unique advantages of multimodal neuroimaging data. It is known that anatomical imaging is indispensable for target identification and neurosurgery while functional imaging is mostly useful for probing brain responses in relation to clinical outcome measures Table . In geneOne interesting development in the field of molecular imaging is the availability of PET radioligands that are specific to microglial activation. This has been used successfully to detect neuroinflammation in cortical and subcortical regions in intervention studies and neurological disorders such as PD, AD and epilepsy (Gershen et al., One of the most revolutionary areas in neuroimaging research that drive the development of DBS-based therapeutics is the recent applications of human connectome and associated software tools based on DTI and rsfMRI data (Coenen et al., A number of internal and external brain stimulation modalities have been approved by FDA for providing symptomatic relief in many neurological and psychiatric disorders. This mode of intervention is most effective when combined with prevalent pharmacotherapy without major complications but generally unable to halt progression of the underlying disease. There is still only a limited number of randomized, double-blind and placebo-controlled trials of DBS over long-term despite proven clinical efficacy in many trials over short-term. Multimodal neuroimaging methodology has successfully guided the development this fledgling field from the beginning, demonstrated its translational potential and brought critical insights on mechanisms of action. This is achieved by revealing specific functional neuroanatomical substrates associated with each disorder, optimizing neurosurgical procedures, tailoring stimulation paradigms, identifying clinical responders and detecting modulation of brain function on regional and network levels in human trials. There is still a urgent need to develop and cross-validate robust neuroimaging markers and diagnostic algorithms for use in multi-center clinical trials both nationally and internationally. Applications of such maturing and innovative techniques will continue to play pivotal and integral roles in further validating and advancing this revolutionary field of bioelectronic medicine."}
+{"text": "Skilled nursing facilities (SNFs) are on the front lines of changing policies regarding the COVID-19 pandemic. The most recent development is a potential vaccine mandate for staff working in SNFs. We use ongoing findings from 130 of 160 in-depth, semi-structured interviews in progress with administrators at 40 SNFs in eight diverse healthcare markets across the United States to understand the current landscape of COVID-19 in SNFs. Four repeated interviews at 3-month intervals provide a unique longitudinal perspective on the impact of COVID-19 and SNFs\u2019 response to vaccinations, including the vaccine mandate. Rigorous thematic analysis reveals insights into administrator responses and creative approaches to address vaccine hesitancy, and future expectations for SNF operations in light of the vaccine and the mandate. Administrators express cautious hope that the vaccine will allow SNFs to return to a new normal of daily life for residents in terms of family visitations, communal dining, and resident activities. Overriding questions include how to overcome persistent vaccine hesitancy from SNF staff who cite fear of side effects despite education initiatives and how to stem staff retirement or transition to other healthcare settings. SNFs represent a microcosm of the country\u2019s concerns as a whole. Insight into the evolving and complex dynamics shed important light on national trends and help provide solutions for moving forward. Findings from this study have implications for policymakers and SNF leadership as they consider ways to promote vaccination and retain staff amid vaccine mandates."}
+{"text": "The advent of spectral-domain optical coherence tomography has played a transformative role in posterior segment imaging of the eye. Traditionally, images of the optic nerve head and the peripapillary area have been used to evaluate the structural changes associated with glaucoma. Recently, there is growing evidence in the literature supporting the use of macular spectral-domain optical coherence tomography as a complementary tool for clinical evaluation and research purposes in glaucoma. Containing more than 50% of retinal ganglion cells in a multilayered pattern, macula is shown to be affected even at the earliest stages of glaucomatous structural damage. Risk assessment for glaucoma progression, earlier detection of glaucomatous structural damage, monitoring of glaucoma especially in advanced cases, and glaucoma evaluation in certain ocular conditions including eyes with high myopia, positive history of disc hemorrhage, and certain optic disc phenotypes are specific domains where macular imaging yields complementary information compared to optic nerve head and peripapillary evaluation using optical coherence tomography. Moreover, the development of artificial intelligence models in data analysis has enabled a tremendous opportunity to create an integrated representation of structural and functional alterations observed in glaucoma. In this study, we aimed at providing a brief review of the main clinical applications and future potential utility of macular spectral-domain optical coherence tomography in glaucoma. Importantly, glaucomatous damage to the macular area may happen early in the disease course and such damage can be underestimated or even missed using common clinical paradigm. Also, evaluating glaucoma progression especially at the advanced stage where optic nerve head (ONH) and circumpapillary retinal nerve fiber layer (cpRNFL) measurements have reached to an apparent floor is limited by the current common clinical paradigm. Another challenge happens in the evaluation of glaucoma patients with high myopia where the OCT segmentation algorithms are more prone to errors at the ONH area as a result of anatomical alterations such as peripapillary atrophy, ONH tilt, and stretching of the cpRNFL. Macular OCT imaging with high resolution scans of different layers can be a useful adjunct to common clinical paradigm in these scenarios. Moreover, the application of artificial intelligence (AI) techniques to analyze the big data obtained from these high-resolution images shows promise to improve the currently available diagnostic modalities and structure\u2013function relationships in glaucoma.Glaucoma, characterized by progressive loss of retinal ganglion cells (RGCs) and their axons accompanied by concomitant characteristic visual field (VF) damage, is globally a leading cause of irreversible blindness. Potential damage to this area leads to impairments in the central VF which is associated with a dramatic decline on the functional status in glaucoma patients. Moreover, macular evaluation in glaucoma has recently regained a specific focus of interest based on the possibility of early involvement in the disease process. New SD-OCT post acquisitional algorithms provide automated segmentation of different layers of macular area that focuses on interest in glaucoma evaluation and monitoring including macular retinal nerve fiber layer (mRNFL), ganglion cell layer (GCL), ganglion cell/inner plexiform layer (GC/IPL), and ganglion cell complex (GCC). Consequently, the utility of these SD-OCT-derived macular parameters for glaucoma detection and monitoring of disease progression have been shown in many previous studies. In this perspective, we aim at providing more insight on the potential utility of SD-OCT macular imaging in glaucoma practice.Glaucomatous damage to the macular area that contains around 50% of retinal RGCs in a multilayered fashion has been reported for a long time using histological studies.Cirrus HD-OCT  is one of the instruments that provides high macular images using SD-OCT technology [Figure 1A]. The Cirrus HD-OCT performs volumetric scan  is another SD-OCT imaging modality that is capable of performing a 3-D volumetric scan of the macula over a 7mm square that is centered 0.75 mm temporally to the fovea. In the printout, it displays average, superior, and inferior GCC  measurements [Figure 1B]. Moreover, two color-coded maps are provided in the software output that display the absolute GCC measurements and GCC deviation patterns based on the age-adjusted normalized database of the software. Cross-sectional high-resolution B-scans are also shown for further structural evaluation and detection of possible image artifacts. [Figure 1C].Spectralis OCT (Heidelberg Engineering GmbH) instrument uses Posterior Pole Analysis  algorithm to capture macular images composed of 61 distinct horizontal B-scans (X768 A-scans) that are aligned in parallel to Bruch's membrane opening (BMO)-fovea axis. Each horizontal B-scan is repeated 9\u201311 times and averaged to decrease speckle noise. The latest software (Glaucoma Module Premium Edition) provides automated segmentation of the layers of interest. The output displays an 8  [Figure 1D].There are multiple Topcon 3D-OCT  instruments of different generations including 3D-OCT 1000, 3D-OCT 2000, and a newer swept-source OCT (DRI OCT-1) device. Topcon 3D-OCT measures a 6 ,23,24,25 which is mostly represented using the Area Under the Receiver Operating Characteristic curve (AUROC). Hence, attempts have been made to evaluate the diagnostic accuracy of macular OCT parameters and compare their performance to those of ONH and cpRNFL thickness at earlier (pre-perimetric and mild perimetric) stages of glaucoma. Their findings reveal excellent and comparable diagnostic performance of macular and cpRNFL parameters in early glaucoma.,32,33,34 In one of these studies, Kim et al found inferotemporal GCIPL as the macular parameter with the highest diagnostic performance (AUROC = 0.82) comparable to those of best parameters of RNFL  and ONH . Other studies have reported comparable diagnostic performances of macular GCIPL and cpRNFL deviation maps in the detection of pre-perimetric glaucoma and good performance of macular GCA maps in the detection of early glaucoma  and early perimetric glaucoma (AUROC = 0.96). Likewise, eyes with optic disc hemorrhage have been associated with more degree of central macular involvement and parafoveal scotoma. In a study by Liu et al, GCIPL showed higher proportional rates of thinning and greater association with functional progression compared to cpRNFL. Accordingly, macular structural evaluation using OCT can be tailored to the individual patients based on the optic disc appearance and this has the potential to enhance the diagnosis and management of early glaucoma.The association between distinct glaucomatous optic disc appearance and the presence of central VF defects has been a recent focus of interest. Ekici and collaborators demonstrated that early macular damage in glaucoma patients tends to happen more in optic discs with focal ischemic and myopic phenotypes compared to those with generalized cup enlargement phenotype.,40 Bowd and collaborators defined a region of interest approach to estimate the measurement floors of optic disc and macular parameters in a longitudinal cohort of moderate to advanced glaucoma patients  had a significantly faster rate of progression in highly advanced glaucoma patients .Monitoring of advanced glaucoma is another challenging task in clinical practice where VF tests show increased variability. Evaluating structural change alongside functional performance can be a useful adjunct if the measurements are reproducible, demonstrate acceptable global and regional structure\u2013function relationship, and fall within the dynamic range of variability. The concept of measurement floor points to another limitation in the evaluation of advanced glaucoma. It is ascribed to a level beyond which the structural measurements no longer show a decremental pattern with worsening of the disease and is believed to represent the thickness of the remining non-neural tissues. Despite that the dynamic range for cpRNFL extends to \u20138 to \u201310 dB MD, macular OCT reaches measurement floor at more advanced glaucomatous damage.,45 This recommends macular measurements like GCC and GCIPL thickness as possible biomarkers for the evaluation of advanced glaucoma; however, it must be kept in mind that accurate segmentation of different macular layers becomes more challenging with worsening of the disease.In addition, macular OCT measurements have shown high reproducibility in advanced disease, good correlation with VF sensitivity measures, and preserved dynamic range at a stage when the reliability of VF tests decline. A small number of studies have shown that the variability of macular measurements does not significantly increase as the disease gets worse. We know that myopia affects the patterns of RNFL distribution measured by the SD-OCT instruments resulting in temporal displacement of RNFL peaks on thickness plots with possible influence on the diagnostic performance of OCT measurements. Therefore, the so-called \u201cred disease\u201d is not uncommon when clinicians evaluate ONH repots in these patients [Figure 2A]. This false positive in cpRNFL color code is especially common in inferior quadrants. In addition, the morphology of the ONH might be altered in highly myopic patients as a result of ONH tilt and the presence of peripapillary atrophy. These anatomical changes may lead to OCT artifacts and potentially affect the performance of segmentation algorithms especially in the ONH due to a more complex anatomy compared to the macula.,51 In the same line, investigators have shown the superiority of macular over ONH parameters for the diagnosis of glaucoma in highly myopic eyes;,54,55,56 although, there are some reports showing a comparable performance between the measurements of these two areas.,58,59,60 Inferotemporal GCIPL thickness is the best macular parameter to detect glaucomatous damage in highly myopic eyes especially at the pre-perimetric stage  [Figure 2B]. Kim and colleagues studied Asian high myopic patients and demonstrated an excellent diagnostic accuracy for GCIPL hemifield test to detect glaucomatous damage (AUROC = 0.94). Hence, the presence of temporal horizontal raphe on GCIPL thickness map in high myopic eyes may serve as a useful diagnostic clue to detect glaucoma.Evaluation of glaucoma in myopic eyes is another area where macular images may yield additional benefit compared to ONH images. Evaluation and diagnosis of glaucoma in highly myopic eyes is challenging. It has been shown that ONH parameters have a worse performance in the detection of glaucoma in highly myopic eyes compared to non-highly myopic eyes while GCC's performance remains the same.,62 This highlights the role of earlier disease detection and risk stratification of patients according to the future rates of glaucoma progression. Clinical parameters that are associated with prognostic utility in terms of future glaucoma progression are age, the level and fluctuation of intraocular pressure, central corneal thickness, disc hemorrhage, and the diagnosis of pseudoexfoliative glaucoma.,69,70,71 Certain high risk groups may not only benefit from earlier intervention, but also require closer follow-up appointments and diagnostic tests for the evaluation of disease progression. Macular OCT imaging can be a useful modality in some of these patients. Recently, Shukla and colleagues showed that the presence of disc hemorrhage is associated with more severe damage on 10-2 VF test and faster rate of central VF progression. Hence, this subgroup of patients may benefit from regular macular OCT monitoring for earlier detection of glaucoma progression. Another study showed that the presence of temporal raphe sign on baseline macular GCIPL deviation maps of elderly patients with enlarged vertical cup-to-disc ratio is associated with faster progression to normal tension glaucoma. In addition to the aforementioned clinical settings, it has been shown that evaluating macular structure using OCT can further enhance the performance of prognostic models and consequently improve our understanding of glaucoma progression. Anraku and associates evaluated the performance of different baseline structural (macular and cpRNFL OCT) and functional parameters in a cohort of early glaucoma eyes for the detection of future VF progression. The cohort was classified into two groups of slow  is the best single predictor for subsequent glaucoma conversion in pre-perimetric glaucoma patients and for VF progression in patients with established glaucoma. In the first study, they found that eyes with abnormal or borderline GCC\u2013FLV have a four-fold increase in the risk of future glaucoma conversion over a six-year period. In the second study, they reported that abnormal GCC\u2013FLV at baseline leads to a triple increase in the risk of future VF progression based on an average 3.7 years follow-up of 277 eyes with established glaucoma and average baseline VF MD of \u20134.8 dB. Hou et al evaluated the temporal relationship between progressive GCIPL thinning, cpRNFL thinning, and VF progression in a cohort of patients with primary open-angle glaucoma with a follow-up duration of more than five years. They found that progressive GCIPL and cpRNFL thinning are mutually predictive and both are indicative of VF progression. They suggested that integrating macular and cpRNFL parameters may probably lead to earlier detection of disease progression in glaucoma patients.As glaucomatous VF damage is generally irreversible, early intervention is required to prevent further functional deterioration and potential blindness. and unsupervised identification of different patterns that exist in large datasets of images. A widespread use of different imaging modalities in ophthalmology research and clinical practice makes this medical subspecialty a major area for the implementation of these novel algorithms to assist in diagnosis and improve the currently used image analysis techniques. A great proportion of publications on AI methods in glaucoma have focused on the detection of the disease using different inputs like fundus and OCT images. Asaoka and colleagues developed and validated a deep learning model to accurately (AUROC = 93.7%) detect early open-angle glaucoma  with a relatively well preserved performance among eyes with different degrees of myopia. Development of deep learning models to evaluate the details of structure\u2013function relationship has been another focus of AI investigations in glaucoma. These models have shown a high accuracy to extract and use the relevant information obtained from macular volumetric OCT scans and provide a corresponding simulation of central VF in glaucoma patients.,83,84 Moreover, Nouri-Mahdavi et al in a recent study showed that VF progression in moderate to advance glaucoma can be partly predicted using combined OCT measurements of peripapillary and macular areas. Of note, they developed and compared separate models using macular or peripapillary measurements and showed that macular models performed better than peripapillary models to detect VF progression. This finding highlights the potential of macular OCT in monitoring patients with moderate to advanced glaucoma. Hopefully, by further refining these AI approaches, automated precise systems for the detection and monitoring of disease progression in glaucoma will become available in the future.In the recent years, the applications of AI in general (and deep learning networks in particular) into medicine has led to the introduction of numerous automated diagnostic modalities. AI techniques have many implications in machine vision tasks including image classification with the performance sometimes higher than that of humansWhile it is common clinical practice to obtain an OCT scan of the disc, many clinicians do not routinely obtain a scan of the macular region for patients with glaucoma or suspected glaucoma. As previously discussed, macula SD-OCT has been helpful for the earlier detection of glaucoma \u2013 particularly in eyes with certain ONH phenotypes, eyes with DH, and myopic eyes. For example, Figure 3 shows a case in which the cpRNFL report appears normal, while the macula scan shows apparent GCIPL thinning. Macula scans may also serve as a clue for clinicians for the presence of parafoveal scotoma, which should receive attention and be further evaluated with a 10-2 VF test. In addition, macula scans play an important role in monitoring eyes with advanced disease, as they may help clinicians identify disease progression and decide to escalate treatment. Consequently, one may ask, \u201cWhen do you perform an OCT scan of the macula?\u201d Although macula scans can be selectively ordered for those patients who may be most likely to benefit from it (as discussed earlier), obtaining OCT scans is so efficient today that many experts recommend routinely performing both disc and macula scans for all patients with glaucoma and suspected glaucoma, thus have a comprehensive glaucoma assessment of the patients. Moreover, any retinal diseases involving macular areas such as the epiretinal membrane, age-related macular degeneration, or macular edema can affect macular GCIPL thickness and reducing performance of the macula scans for detection of glaucoma. Similarly, macula scans are not helpful for detection of glaucoma in eyes with myopic myopathy. Even in eyes without maculopathy, abnormal diagnostic classifications on GCIPL map can be seen in up to 40% of myopic eyes with diffuse, circular pattern being the predominant form. In addition, macular measurements obtained by different OCT devices are not interchangeable despite showing a fair degree of correlation. Finally, it has to be mentioned that glaucomatous damage with a high angular distance from the BMO\u2013fovea axis may fall out of the measurement territory of macular OCT images depending on the OCT instrument and software and consequently not be identifiable on the deviation maps. Clinicians need to be aware of this issue and take it into consideration.,32Like every other imaging modality, there are some limitations in the use macular OCT for glaucoma practice and research that clinicians need to consider. First, GCIPL analysis with the SD-OCT may be complicated by coexisting macular pathology and scan artifacts. Most currently available data on macular OCT in glaucoma are obtained from studies that have excluded eyes with other macular pathologies and also poor quality images like those with artifacts and lower signal strength. Thus, one needs to expect higher variability of macular measurements in real world scenarios. The presence of age-related macular pathologies and drusen may disrupt the correct segmentation of the macular layers that are important in the diagnosis and monitoring of glaucoma patients especially in the elderly. Recent studies using GCIPL analysis have excluded up to 6% of scans due to machine segmentation or acquisition error.Macular OCT is a useful imaging modality in glaucoma management and research. It provides complementary information to the conventionally used modalities by glaucoma specialists especially in the evaluation of patients with early macular damage and/or high myopia and monitoring of the advanced disease. With the development and widespread use of AI techniques in medicine, macular OCT information can be integrated with the information obtained from optic disc OCT and VF assessment to provide a more comprehensive picture of the true nature of glaucomatous damage and progression. This will definitely enhance the quality of medical care and research in the future.This study was supported by the UC Tobacco Related Disease Research Program Grant T31IP1511.There are no conflicts of interest."}
+{"text": "Editorial on the Research TopicToxic Plant Proteins as Experimental Drugs for Human PathologiesSince the ancient times, plants extracts have been largely used in traditional and folk medicine .The type 2 Riproximin, purified from Adenia stenodactyla. The anti-tumor effects of stenodactylin were demonstrated on acute myeloid leukemia cells. Genome-wide gene expression microarray analysis revealed early changes in the expression of genes involved in the regulation of cell death, inflammation and stress response. The early response to stenodactylin treatment was proven to involve inflammatory and apoptotic signaling compatible with the activation of multiple cell death pathways .Stenodactylin is a highly toxic type 2 RIP purified from the caudex of Momordica balsamina, was combined with some anticancer flavonoids such as naringenin, quercetin and naringin. The treatment with flavonoids plus balsamin reduced HepG2 and MCF-7 cell viability and increased the activation of caspases and induced apoptosis. Balsamin combined with flavonoids also activated endoplasmic reticulum stress\u2013mediated apoptosis in liver and breast cancer cells .The type 1 RIP balsamin, from di Leandro et al.).A novel suicide gene therapy approach was tested in glioblastoma multiforme cells. The gene coding for saporin was driven intracellularly by a glioma-specific aptamer recognizing the surface antigen nucleolin, efficiently inducing target cell death. Cells that do not expose nucleolin on cell surface, used as control, remained unaffected. Suicide gene therapy was not observed when the inactive saporin mutant DNA was used .Podophyllotoxin is a plant derivative that has demonstrated an antitumor effect on triple-negative breast cancer cells by inhibiting cell migration and invasion and inducing apoptosis. The Gene Set Enrichment Analysis showed that the expression of some genes often associated with a poor prognosis in breast cancer  in the cell cycle is inhibited by regulating P53 by podophyllotoxin in triple-negative breast cancer cells  of action of these toxins may improve pharmacological strategies to achieve higher specificity and potency in targeting and destroying cancer cells."}
+{"text": "Objectives: This study examines how successful aging discourse manifests through physical and social participation among members of a self-organized mall walkers club. There is a paucity of research investigating successful aging in situ and theorizing the relationship between successful aging discourse and community participation. I draw on symbolic boundaries\u2014a concept from cultural sociology\u2014as a way to make sense of what mall walkers say and do. Methods: I draw on data from 15 months of participant observations and interviews of mall walkers, all of whom are over 65 and predominantly Caribbean-Canadian women Results: I identify three common boundaries: personal, interpersonal, and community, that mall walkers draw on to challenge narratives of decline and internalize dimensions of successful aging. Discussion: These findings uncover the ways members in a self-organized community reinforce boundaries that highlight how certain dimensions of successful aging as something to be proud of and desirable. This article contributes to research on intersubjective experiences of aging by revealing how successful aging is rooted in community participation, rather than individual achievement."}
+{"text": "Teaching point: Age-related variability in endochondral ossification of the femoral condyles in children is a normal variant of skeletal maturation and should not be misdiagnosed as osteochondritis dissecans or any other epiphyseal abnormality. A 9-year-old boy was referred to the accident and emergency department. He had sustained an acute left knee injury with severe pain and restriction of movement. No previous medical history was known.Figure 1, asterisk) without any evident fracture. Irregular epiphyseal outline at the posterior aspect of both femoral condyles was also noted .Lateral radiograph of the right knee demonstrated a large joint effusion  with widening of the growth plate .MRI of the right knee \u2013 proton density (PD) and fat suppressed proton density (FS-PD) \u2013 were obtained to evaluate for radiographically occult fractures and meniscal or ligamentous injury. MRI evidenced a Salter-Harris type III fracture  representing incomplete epiphyseal bone formation \u2013 a normal variant. The defects at the more cranial aspect of the lateral femoral condyle showed a more advanced stage of ossification , while the defects at the more caudal aspect of the femoral condyle showed a more spiculated and early ossification . Note the intact overlying cartilage and the absence of bone marrow oedema.Additionally, ill-defined defects in the posterior third of both femoral condyles were present  than in girls (mean age of 6 years old) . EventuaIrregular epiphyseal ossification of the femur is often bilateral and typically located at the posterior aspect of the femoral condyle. This variant can also be seen in other bones, such as the trochlea of the elbow and the tarsal navicular. When unilateral, osteochondritis dissecans or a fracture are the main pitfalls for misdiagnosis \u2013 lack of adjacent bone marrow oedema and intact overlying cartilage are key differentiating features on MRI. It is important to correctly recognise this normal morphologic variability and distinguish it from pathological epiphyseal disease, which may lead to incorrect treatment and unnecessary follow-up investigations."}
+{"text": "Clinical publications show consistently that headache is a common symptom in the coronavirus disease of 2019 (COVID-19). Several studies specifically investigated headache symptomatology and associated features in patients with COVID-19. The headache is frequently debilitating with manifold characters including migraine-like characteristics. Studies suggested that COVID-19 patients with headache vs. those without headache are more likely to have anosmia. We present a pathophysiological hypothesis which may explain this phenomenon, discuss current hypotheses about how the coronavirus SARS-CoV-2 enters the central nervous system and suggest that activation of the trigeminal nerve may contribute to both headache and anosmia in COVID-19. Headache is a frequently described initial symptom of COVID-19 (1). The headache is mostly bilateral though it frequently has a migraine-like phenotype and lasts longer than two days in most cases ,3. RemarThese hypotheses give rise to two principal questions. The first question is: how does the virus penetrate the brain and how it is transported? There are two possible routes for the direct passage of peptides from the nose to the brain, namely an intraneuronal pathway using the axonal transport, and an extraneural pathway through intercellular clefts in the olfactory epithelium directly connected with the subarachnoid space . Large mThe second principal question is, why SARS-CoV-2 causes a loss of function (anosmia) in the olfactory system but a gain of function (headache) in the trigeminal system; and furthermore, are both these phenomena interconnected? Most of the trigeminal afferents innervating the nasal mucosa are nociceptors expressing transient receptor potential (TRP) cation channels of the type TRPV1, which may be activated by chemical compounds like capsaicin. Inflammatory responses caused by SARS-CoV-2 with a massive increase of cytokines in the nasal mucosa, particularly high TNF-\u03b1 levels , may indIn rodents as well as humans, the afferent fibres from the nasal mucosa reach the anterior cranial fossa via the ethmoid nerve and travel in the dura mater to the trigeminal ganglion . Activat31However, the loss in olfactory function may not only be explained by the damage of the olfactory epithelium  but alsoIn conclusion, the frequent association of headache and anosmia in COVID-19 may originate with inflammatory responses in the nasal mucosa but probably also requires the activation of meningeal nociceptors. SARS-CoV-2 may penetrate the cribriform plate to affect the meninges around the olfactory bulb. Although this is still a hypothesis that should be further investigated, CGRP released from activated trigeminal afferents may therefore contribute to suppress the olfactory functions in the nasal mucosa and the olfactory bulb in those patients experiencing simultaneously headache and anosmia"}
+{"text": "Significance: Common-path interferometers have the advantage of producing ultrastable interferometric fringes compared with conventional interferometers, such as Michelson or Mach\u2013Zehnder that are sensitive to environmental instabilities. Isolating interferometric measurements from mechanical disturbances is important in biodynamic imaging because Doppler spectroscopy of intracellular dynamics requires extreme stability for phase-sensitive interferometric detection to capture fluctuation frequencies down to 10\u00a0mHz.Aim: The aim of this study was to demonstrate that Doppler spectra produced from a common-path interferometer using a grating and a spatial filter (SF) are comparable to, and more stable than, spectra from conventional biodynamic imaging.Approach: A common-path interferometer using a holographic diffraction grating and an SF was employed with a low-coherence source. Simulations evaluated the spatial resolution. DLD-1 (human colon adenocarcinoma) spheroids were used as living target tissue samples. Power spectra under external vibrations and drug-response spectrograms were compared between common-path and Fourier-domain holographic systems.Results: The common-path holography configuration shows enhanced interferometric stability against mechanical vibrations through common-mode rejection while maintaining sensitivity to Doppler frequency fluctuations caused by intracellular motions.Conclusions: A common-path interferometer using a grating and an SF can provide enhanced interferometric stability in tissue-dynamics spectroscopy for drug screening assays. An example of target image reconstructions using CDH is shown in Simulations were performed using Eq.\u00a0(5) to estimate the optimal size of the reference aperture by measuring the modulation transfer function (MTF). The MTF of an imaging system is defined as the output modulation, The reconstructed image for the large reference aperture (100% size ratio) is the autocorrelation of the object image and has no phase information. However, a reference aperture with a smaller diameter at the image plane IP2 acts like a pin hole that makes the reference wave at the FP2 more similar to a plane wave, increasing the spatial resolution, as shown in the graph in We used living DLD-1 (human colon adenocarcinoma) spheroids as a target tissue sample to validate that the CDH system is more stable to external vibrations and more sensitive to biological movements than the noncommon-path FDH system. Tumor spheroids were cultured in a rotating bioreactor for 7\u2013to 14 days until 300 to Fluctuation power spectra are acquired by performing temporal FFTs of the time series of multiple reconstructions performed at the specified frame rate as shown in To validate that the CDH system is an effective modality for TDS, tissue-response spectrograms tracking time changes in intracellular dynamics in response to drug perturbations were acquired in both FDH and CDH modes as shown in Spectrograms for the negative control in FDH and CDH modes show relatively small response typically seen in continuously proliferating tissue samples, with minor changes over time. The average spectrograms in response to iodoacetate in FDH mode indicates an overall inhibition of cellular activity. In CDH mode, the tissue-response is close to that of FDH mode except for the stronger redshift in CDH at low frequencies. The response to nocodazole showed enhanced low and high frequencies and suppression at mid-frequencies with minor differences between the FDH and CDH modes. The response to paclitaxel closely matches that of nocodazole, except for a weaker response. Therefore, tissue responses to drugs are functionally equivalent between the CDH and FDH modes, whereas the CDH system has the added advantage of stability against environmental influences and may have more flexibility than the FDH system in point-of-care applications despite its lower resolution.\u2013Achieving enhanced interferometric stability using this common-path holography configuration required several trade-offs on biodynamic performance. For instance, the common-path system trades off spatial resolution against holographic fringe contrast on the camera. For the application of imaging tumor spheroids, nominal performance is achieved by limiting the reference aperture to 20% of the image aperture that limits the imaging resolution to"}
+{"text": "Cellular stress is a fundamental component of age-associated disease. Cells experience many forms of stress , and as we age the burden of stress and resulting damage increases while our cells\u2019 ability to deal with the consequences becomes diminished due to dysregulation of cellular stress response pathways. By understanding how cells respond to stress we aim to slow age-associated deterioration and develop treatment targets for age-associated disease. The majority of past work has focused on understanding responses to individual stressors. In contrast, how pathology and stress responses differ in the presence of multiple stressors is relatively unknown; we investigate that here. We cultured worms on agar plates with different combinations of arsenic, copper, and DTT  stress, respectively) at doses that result in 20% lifespan reduction individually and measured the effect on lifespan. We found that arsenic/copper and arsenic/DTT combinations created additive lifespan reductions while the copper/DTT combination created an antagonistic lifespan reduction when compared to controls (p<0.05). This antagonistic toxicity suggests an interaction either between the mechanisms of toxicity or the cellular response to copper and DTT. We are now evaluating the impact of copper and DTT individually and in combination on unfolded protein and heavy metal response pathways to understand the underlying mechanism of the interaction. Additionally, we are continuing to screen stressors to identify combinations that cause non-additive (synergistic or antagonistic) toxicity to build a comprehensive model of the genetic stress response network in C. elegans."}
+{"text": "Racial and ethnic minority older adults\u2014especially non-Latino Black and Latino older adults\u2014continue to have a higher prevalence of dementia with longer delays in formal diagnosis compared to non-Latino Whites. Few studies have estimated racial/ethnic differences in trajectories of dementia onset using nationally representative data with representation from the three largest racial/ethnic groups in the U.S.: non-Latino White, non-Latino Black, and Latino older adults. Additionally, given the delays in formal diagnosis we rely on a measure of probable dementia that takes into account both formal diagnosis and cognitive function. Data from the National Health and Aging Trend Study  reveals three trajectories of dementia onset  and we find that Latino and Black older adults are at greater risk for early dementia onset compared to non-Latino Whites. Our next step is to explore the role of social function for dementia disparities."}
+{"text": "Older adults in rural communities have access, isolation, and technology barriers to healthcare that are exacerbated by the COVID- 19 pandemic. A shortage of healthcare professionals combined with limited resources and poor broadband access have limited their ability to benefit from telehealth. The pandemic has further worsened isolation in rural communities. This Age-Friendly Care, PA pilot study uses community health workers (CHW) as a bridge to connect isolated and underserved older adults with their healthcare team. The CHWs facilitate access to telehealth provided by a Federally Qualified Health Center (FQHC), and also provide \u201ccheck-ins\u2019 to housebound patients. The focus of the intervention is CHW delivered facilitation of telehealth and other supports to better manage their healthcare needs. We will describe the co-design of the project and discuss lessons learned in attempting to bridge the digital divide for rural older adults during and after the pandemic."}
+{"text": "Twenty-three participants ranging in age from 80-102 years living on remote islands in the Pacific Northwest, USA reported the privileges of their current years. The aim of the study was to explore lived bodily experience and its impact on social exclusion. Participants utilized a unique visual methodology by photographing their experiences which highlighted daily life. While acknowledging that their years \u2018before\u2019 were different, and that life going forward may present unwelcome challenges, life in the now brought new joys and self-determination, despite various bodily compromises. Their perceptions of their bodies defied the dominant narrative of decline. These important findings warrant further investigation of the ways in which this emerging cohort views the challenges of aging bodies and their ability to remain socially connected. The role the dominant narrative of decline plays in their lives may prove to misdirect supports."}
+{"text": "Anticancer therapies can impact female ovarian reserve and reproductive potential beyond possible perturbation in ovarian function.Several studies have reported the gonadotoxicity of the most commonly used chemotherapy regimens in premenopausal women with breast cancer using both amenorrhea rates and AMH levels following its administration as the definition of treatment-related POI .2Table\u00a01,The highest gonadotoxic risk in breast cancer is associated with the use of the alkylating agent cyclophosphamide and its dose.,In premenopausal women with hormone receptor-positive breast cancer, endocrine therapy use for 5-10 years can indirectly affect the ovarian reserve and fertility potential through aging.,Limited evidence exists on the gonadotoxicity of targeted therapies and no data exist on immune checkpoint inhibitors. A potential negative effect of bevacizumab cannot be excluded, while the anti-human epidermal growth factor receptor 2 agents trastuzumab, lapatinib and T-DM1 appear to be safe for the ovaries.Collecting prospective information about the functional and endocrinological impact of modern anticancer therapies on women\u2019s gonadal reserve and reproductive outcomes should become a crucial and vital component of drug development.,BRCA genes, may negatively impact ovarian reserve and performance of fertility preservation strategies, but data are too limited and controversial to conclude about a potential increased risk of treatment-related POI in these patients.,Age at diagnosis is the most important patient-related factor to be considered when estimating the risk of gonadotoxicity with the proposed treatment.,,Cryopreservation of oocytes and/or embryos is a standard strategy for fertility preservation and the first option to discuss with all women whenever the ovarian reserve is adequate, a vaginal ultrasound is possible and at least 2 weeks are available before starting anticancer therapy.,BRCA pathogenic variants.BRCA-mutated breast cancer patients.The success of this strategy is strongly dependent on the number of mature oocytes collected after ovarian stimulation, which is directly linked with the age of the patient and her ovarian reserve at diagnosis.,,Safety concerns have been raised with the use of ovarian stimulation for approximately 2 weeks in women newly diagnosed with breast cancer and particularly in those with hormone receptor-positive disease.,,Ovarian tissue cryopreservation is an alternative approach to preserve fertility (and ovarian function) when oocyte/embryo cryopreservation is not feasible.,,There are two crucial factors for the success of ovarian tissue cryopreservation: the expertise of the laboratory in cryopreserving the tissue and the age of the patient at the time of the procedure. With a \u2018hub and spoke\u2019 model, regional networks should be implemented to optimize the success of this strategy, with the possibility to carry out the surgery locally while referring the tissue to a central experienced facility for cryostorage.,,BRCA pathogenic variants). Limited evidence is available in this setting.per se, although specific considerations are needed including the choice of the transplantation site.,In terms of safety, the risks and complications related to the procedure are low in women without contraindication to surgery/anaesthesia.,,In premenopausal breast cancer patients, medical gonadoprotection obtained by administering gonadotropin-releasing hormone agonist (GnRHa) during chemotherapy is standard strategy for ovarian function preservation.A large meta-analysis based on individual patient-level data from 873 patients randomized in five major breast cancer trials reported the efficacy and safety of this strategy.,Concurrent use of GnRHa during chemotherapy was shown to be safe with similar disease-free survival  and overall survival  in patients treated with or without pharmacological ovarian suppression during cytotoxic therapy. The safety of this strategy was observed irrespective of hormone receptor status.Breast cancer survivors have a significantly reduced likelihood of having a subsequent pregnancy compared with the general population, with an estimated 60% lower prevalence .These concerns have been recently dispelled by a large systematic review and meta-analysis.In terms of patients\u2019 prognosis, no detrimental effect of pregnancy after breast cancer was shown, even when correcting for the potential guarantee-time bias . Patients with a post-treatment pregnancy showed a better disease-free survival  and overall survival  compared with women with breast cancer without subsequent pregnancy. The safety of pregnancy was observed irrespective of patient, tumor, treatment characteristics, timing and outcome of pregnancy.,NCT02308085) has recently completed accrual and will report on the safety of a temporary interruption of adjuvant endocrine therapy to attempt pregnancy in women with hormone receptor-positive breast cancer.Based on the reassuring growing body of knowledge on the topic, pregnancy in women with a prior history of breast cancer should not be discouraged following proper treatment and follow-up.,,Nowadays, giving hope for a family after cancer diagnosis and treatment should be considered a crucial ambition in cancer care.Building a strong oncofertility network within or outside the cancer center is the first crucial step to accomplish for allowing a proper path to all patients in this setting . NotablyDespite many studies have been carried out over the past years in this field, additional prospective research efforts are needed to further improve and ensure optimal oncofertility care in young women with early breast cancer."}
+{"text": "This research explores the emotional health of home care workers (HCWs) during the coronavirus pandemic. In-depth, qualitative interviews were conducted with 17 home care workers in the fall of 2020. Thematic analysis revealed important connections between emotional health and success on the job. Perception of time and appreciation emerged as key elements that impacted emotional health. HCWs expressed the pressure to perform as usual while simultaneously taking on extra tasks as distracting from direct client care and reinforcing a task-oriented care approach. As a result of these tensions, HCWs experienced a loss of appreciation by the client, who prioritized personal safety and a \u201cget in and get out\u201d attitude, leaving the HCW feeling less fulfilled in their work. Implications of this research highlight the importance of HCW emotional health needs when retaining HCWs as valuable members of the long-term care workforce is paramount."}
+{"text": "To the Editor,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has cast a shadow on all cancer screening programs; millions of screening appointments were canceled due to the pandemic and resulting in depriving the population from a vital healthcare service that could save lives. One study in the USA reported a drastic drop in the screenings for breast, colon, and cervical cancer by 94%, 86%, and 94% respectively between January 2020 and April 2020 . In JapaHepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related mortality in the world . The mosEgypt has the second highest incidence rate of HCC in the world with an age-standardized rate (ASR) of 32.2 .HCC is clinically silent in most patients until late stages and diagnosis could be challenging. Patients with tumors of a size of 2 cm or less could theoretically benefit from all treatment options while those with larger tumors or extra-hepatic spread have limited options and suffer worse prognosis. Screening for HCC in high-risk individuals was started in the 1980s in order to early detect the tumor and possibly improve the outcomes . The mosThe benefits of HCC surveillance programs were well established in 2004 when a randomized clinical trial conducted in China revealed that biannual screening using AFP and ultrasonography had reduced HCC mortality by 37% . MoreoveAlthough Egypt has a heavy burden of liver cirrhosis and HCC, most of the government's attention is directed to HCV screening and eradication; a great success was achieved during the national campaign of HCV screening and eradication in 2018 and the country is moving steadily toward the elimination target . HoweverIn Egypt, the weak HCC surveillance system is expected to be severed due to the pandemic. Over 300 public hospitals were turned into isolation centers for SARS-CoV-2 patients including many tropical medicine hospitals and some cancer and liver institutes . The exaWith a staggering 200\u2013400% increase in the relative incidence of breast cancer in Egypt between the years 1990 and 2017\u2014an increase that was only surpassed by the Kingdom of Saudi Arabia\u2014the deadly cancer has declared itself a challenging public health problem that needs urgent intervention . The surIn Africa, the continent with the highest breast cancer mortality rates, the situation is becoming increasingly challenging . The rapBreast cancer is the most expensive cancer to treat ; this ecDespite the initial success of the national campaign of breast cancer screening, the campaign was severed as the pandemic took over. Many hospitals that were participating in the campaign were turned into isolation centers for SARS-CoV-2 patients. Moreover, the understaffing that happened in other non-isolation hospitals affected the service in the outpatient clinics where women are supposed to be checked annually for breast cancer. Another important factor that markedly influenced breast cancer screening during the pandemic is the fear of getting infected with SARS-CoV-2 while doing the annual breast check in the hospital.There is no doubt Egypt needs to adopt new efficient strategies for cancer screening, but for now, we should aim to restore our pandemic-exhausted system first. The first step toward restoring the normal capacity of the healthcare system is to speed up the vaccination process. Unfortunately, Egypt has been performing poorly regarding the SARS-CoV-2 vaccination with only 164,534 doses administrated by April 2021 . This we"}
+{"text": "In delayed or neglected cases of flexor tendon injury, reconstruction of flexor digitorum profundus (FDP) is usually performed using free tendon graft due to the retraction of tendon ends and shortening of the tendon. Flexor digitorum superficialis (FDS), palmaris longus or plantaris tendons can be used as a free tendon graft [1\u20133].This is a case report of female patient 17 years old with neglected cut of her left Ring finger's FDP and FDS tendons zone II with suspected concomitant digital nerve injury, the injury was neglected for 10 years in the patient's non-dominant hand.Upon exploration unusual finding of spontaneous healing of the proximal stumps of FDS and FDP tendons raised the idea of doing the repair one stage without free graft by using pedicled intra-synovial graft from the sublimis tendon to reconstruct the FDP tendon.The patient after 4 months follow-up and after completion of the physiotherapy program regained the ability to actively flex her finger to near full flexion with improved function and cosmesis.Delayed flexor tendon reconstruction in neglected cases is still offering good results even after long periods of delay provided that the finger's joints are still supple and mobile. \u2022In neglected cases of flexor tendon injury, reconstruction of FDP tendon is usually performed using free tendon graft.\u2022The presence of two repair sites with free graft in between carries the risk of rupture or adhesion formation around the tendon graft.\u2022In this case report we succeed in doing the repair one stage without free graft.We used pedicled intra-synovial graft from the sublimis tendon to reconstruct the FDP tendon. Paneva-Holevich has modified a technique for staged flexor tendon reconstruction by using pedicled intra-synovial graft from sublimes tendon which offers less incidence of adhesions if compared to the free tendon graft ,6,7.In our case report we did one stage surgery using pedicled intra-synovial graft from sublimes tendon after spontaneous healing of the proximal stumps of FDP and FDS tendons.The author has nothing to disclose. No funding was received for this article.Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request."}
+{"text": "Fluorescent-guided surgery (FGS) is an intra-operative imaging modality with a potentially broad application and range of clinical utility. It provides an additional visual dimension to white light and represents an extension of pre-operative radiological investigations with real-time imaging during an operation . The main clinical usage relates to lymphatic mapping or evaluation of blood flow in the context of tissue perfusion . In addiIndocyanine green (ICG) is the most commonly used fluorophore that is considered clinically safe and has exclusive FDA approval . These nThis series of research papers discusses current applications of FGS surgery and strategies for widening clinical usage of this technology during both conventional and minimally invasive surgery. A shared principle is the visual augmentation of molecular feedback that provides an adjunct to tactile feedback in open surgery and compensates for lack of this with laparoscopic or robotic procedures.Nakamura and colleagues report on a medical imaging projection system (MIPS) that provides a continuous real-time projection of fluorescence mapping onto the surgical field and overcomes the problem of periodic dimming of theatre lights. This novel system avoids the need to shift visual focus from direct viewing of the surgical field under white light to the TV monitor. Initial studies revealed comparable nodal identification rates to standard NIR methodology but relatively low node positivity rate  agents, such as peptides or small molecules that retain a high receptor affinity but possess an improved pharmacokinetic profile. Six LMW agents are discussed that can potentially improve intra-operative visualization and identify foci of tumor that would otherwise have been undetected (PPV 90 \u2013 95%)  . Apart fThere are some important challenges for receptor-targeted FGS before adoption into routine clinical practice; these include uncertainties in optimum quantitative evaluation of drug performance parameters along with confounding imaging factors. Furthermore, most commercial FGS devices have been optimized for ICG imaging in terms of spectral and sensitivity requirements and these may differ for tumor-specific probes and other fluorescent bio-conjugates. Development of newer cancer markers must ensure the presence of high affinity targeting motifs to guarantee high tumor selectivity and minimize non-specific interactions within normal tissues. This may be facilitated by a net-neutral charge that will promote elimination from non-malignant tissue .Kaibori and colleagues review the clinical application of NIR fluorescence imaging for hepatic resection in liver surgery. These authors have developed a novel nanoparticle incorporating ICG as a signaling agent that is biocompatible and can potentially assess hepatic anatomy and function as well as acting as a therapeutic agent for drug delivery . The ICG lactosome relies on increased vascular permeability of cancerous tissues that retain these particles to permit FGS with tumor demarcation or anti-tumor effect of a therapeutic molecule that uses the lactosome as a carrier. Fluorescence imaging with either ICG or the porphyrin precursor (5-aminolevulinic acid (5-ALA) can improve accuracy through real-time visualization of hepatic tissue during surgery. Furthermore, ICG fluorescence can detect fibrosis within non-cancerous liver parenchyma and indicate severity. ICG has a higher sensitivity for detection of smaller tumors near the surface of the liver, although is associated with lower levels of specificity; by contrast, 5-ALA imaging showed a lower sensitivity but a higher specificity. Optimum imaging of superficial liver tumors might eventually be achieved through use of a combination of ICG and 5-ALA that employs the concept of multi-wavelength fluorescence imaging; the latter can be applied to other scenarios including imaging for SLN biopsy  delineate segments and sub-segments during laparoscopic surgery in both cirrhotic and non-fibrotic livers, but careful planning is essential with appropriate simulation and selection of fluorescent imaging method .Luo and colleagues have examined the role of ICG fluorescence angiography (ICG-FA) in prevention of major anastomotic leakage after minimally invasive surgery (MIS) for a range of esophageal malignancies. This relies on use of intra-operative fluorescent imaging to assess perfusion of the gastric conduit prior to definitive anastomosis. ICG-FA might allow more accurate and objective evaluation of blood flow in the anastomotic zone without reliance on visual inspection and detection of vascular pulsation or peristalsis. Larger studies with standardized surgical techniques are required to confirm these benefits of ICG-FA in terms of reducing anastomotic leakage (There are several important applications of fluorescence imaging in surgical oncology not directly related to tumor location and adequacy of resection, but nonetheless can improve clinical outcomes for patients.  leakage , 19.A number of vendors now supply laparoscopic systems that incorporate an NIR imaging options an example being integration of the firefly camera in the da Vinci robotic platform. Moreover, technologies for dynamic visualization of the gastric conduit are now available and provide more reliable information on adequacy of perfusion. Hence employment of real time intra-operative evaluation may reduce the frequency and severity of surgical complications, although the majority of anastomotic leaks do not lead to secondary surgery.Original draft preparation: JB. Review and editing: FL and TS. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Cellular reprogramming has rapidly become a promising methodology to generate new cardiomyocytes from non-cardiomyocyte cell types. Using the transient expression of OSKM factors, Chen et al. demonstrate a unique reprogramming strategy involving the modulation of the resident adult cardiomyocyte identity to an immature proliferative state . This OSKM-mediated reversion results in the adoption by adult murine cardiomyocytes of a transcriptional profile similar to cardiomyocytes found in developing hearts, as well as increased proliferative capacity of these reprogrammed cardiomyocytes compared to mature cardiomyocytes. Furthermore, this novel approach enhances the regeneration of adult murine hearts post-myocardial injury. Although concerns and questions remain, the encouraging results of this study advance the field of cardiac regeneration by providing a new technique to generate cardiomyocytes as well as insights into cardiomyocyte dedifferentiation and its relation to proliferation. The high global prevalence of cardiac injury and disease has made finding new sources for cardiomyocytes an ever-evolving area of research. Numerous approaches to repair injured cardiac tissue have been developed and range from bioengineering-focused therapies, to stem cell-based strategies, to direct manipulation of cell signaling pathways. The ultimate goal for these methodologies is to generate new cardiomyocytes and/or replace damaged ones with the aim of improving heart function. Direct and indirect (via iPSC route) reprogramming-based methods are attractive options for generating new cardiomyocytes from non-cardiomyocyte cell types and have shown promise as potential therapeutic tools for heart regeneration  in murine cardiomyocytes, and investigate whether this reversion process allows resident cardiomyocytes to proliferate post-myocardial infarction (Chen\u00a0et. al Investigation of the different intermediary states resulting from OSKM factor-mediated reversible reprogramming would provide exciting insights into the molecular mechanisms behind this de-differentiation process as well as how the OSKM factors guide cardiomyocytes to regain their proliferation capabilities. Single cell genomics has allowed for the visualization of the heterogeneity of reprogrammed cells in other reprogramming methodologies and has shown the presence of multiple intermediary states between the starting cell type and final identity (Stone et al.\u00a0This study also raises an interesting question on what should be the desired end product of cardiomyocyte reprogramming for cardiac regeneration. While other reprogramming strategies seek to create mature cardiomyocytes to replace damaged ones, this study seeks to obtain an earlier stage of cardiomyocyte identity which may result in increased proliferation potential at the expense of losing key functional attributes. This may explain why this technique yields new cardiomyocytes but does not result in significant improvement of cardiac function after myocardial infarction. What is necessary and not for a reprogrammed cardiomyocyte to remain a cardiomyocyte in both identity and function is a topic that warrants further evaluation as new regenerative techniques are added to the toolbox. Along the same lines, it would be interesting to see if this OSKM-mediated reversion is cardiomyocyte-specific or if the approach can be used to generate other cell types such as neurons or hepatocytes. Because this de-differentiation reprogramming is unique from other reprogramming techniques in its use of generic reprogramming genes rather than cell-type specific genes, it would be intriguing to assess whether this transition to a proliferative immature state is unique to cardiomyocytes.Another potential impact of this study is the ability to identify signaling pathways and genes that regulate the acquisition and silencing of the regenerative properties of immature cardiomyocytes. These genetic targets could be future focal points for manipulation in adult cardiomyocytes in order to increase their proliferation potential. Previous studies have shown that more targeted approaches for increasing adult cardiomyocyte proliferation have therapeutic promise. Several research groups have shown that members of the cyclin family of proteins are promising candidates\u00a0(Mohamed et al.\u00a0While there remains some interesting questions regarding this reversible OSKM-mediated reprogramming, this study provides foundational knowledge on the potential uses and limits of OSKM factors to modulate adult cardiomyocyte identity and achieve more regenerative cardiac tissue. OSKM-mediated identity reversion may, in the end, be a too powerful or non-specific methodology to modulate the maturation of cardiomyocytes, but the molecular pathways affected by this approach may ultimately be the key to unlocking the regenerative potential of adult cardiomyocytes and regenerating injured hearts"}
+{"text": "In particular, 40% of patients with non-small cell lung cancer develop brain metastasis. As systemic therapies for the treatment of non-small cell lung cancer become increasingly effective at controlling primary disease, patients are ironically succumbing to their brain metastases. This highlights a large unmet need to develop novel targeted therapies for the treatment of lung-to-brain metastases (LBM). We hypothesize that an in vivo imaging to track the progression of lung tumor and brain metastases.To do this, we developed a patient-derived xenograft (PDX) mouse model of LBM using patient lung cancer cell lines. This PDX model of LBM enables the use of fluorescent and bioluminescent in vivo genome-wide CRISPR activation screening to identify novel drivers of LBM. We will derive candidate genes through mouse brain and lung tissue sequencing after mice reach endpoint.We have performed an This platform will lead to potential therapeutic targets to prevent the formation of LBM and prolong the survival of patients with non-small cell lung cancer.in vivo CRISPR activation screen searching for drivers of LBM using a PDX animal model. This study can provide a framework to gain a deeper understanding of the regulators of BM formation which will hopefully lead to targeted drug discovery.To the best of our knowledge, this is the first genome-wide"}
+{"text": "Caregivers engage in myriad tasks from household help to complex medical care. However, little information is available on how caregivers experience individual tasks \u2013 particularly key end-of-life tasks such as managing breathing problems or patients' sadness and anxiety. The purpose of this study was therefore to assess task difficulty. Using data from the National Health and Aging Trends Survey and the National Survey on Caregivers (2015-2017), we assessed eleven caregiving tasks in 241 primary caregivers of care recipients in their last month of life. A latent cluster analysis revealed three key clusters: 1) pervasive difficulties, in which caregivers reported difficulty across most or all of the tasks; 2) minimal difficulties; and 3) emotional management difficulties, in which caregivers reported difficulty with managing sadness and anxiety and lower levels of difficulty on the other tasks. Weighted frequency analyses revealed that caregivers in the pervasive difficulties cluster were most likely to be filial caregivers  or co-residing with the care recipient . Caregivers identified as having pervasive difficulties were also more likely to report providing intensive care, more than 100 hours per week . Care recipient condition was not associated with cluster membership. The findings highlight the need to consider caregiver coping at the task-level and have implications for understanding unmet needs. Future research will assess predictors of cluster membership and how task difficulties are associated with symptoms and well-being outcomes."}
+{"text": "Despite a free access to public health services policy in most sub-Saharan African countries, households still contribute to total health expenditures through out-of-pocket expenditures. This reliance on out-of-pocket expenditures places households at a risk of catastrophic health expenditures and impoverishment. This study examined the incidence of catastrophic health expenditures, impoverishing effects of out-of-pocket expenditures on households and factors associated with catastrophic expenditures in Malawi.We conducted a secondary analysis of the most recent nationally representative integrated household survey conducted by the National Statistical Office between April 2016 to 2017 in Malawi with a sample size of 12447 households. Catastrophic health expenditures were estimated based on household annual nonfood expenditures and total household annual expenditures. We estimated incidence of catastrophic health expenditures as the proportion of households whose out-of-pocket expenditures exceed 40% threshold level of non-food expenditures and 10% of total annual expenditures. Impoverishing effect of out-of-pocket health expenditures on households was estimated as the difference between poverty head count before and after accounting for household health payments. We used a multilevel binary logistic regression model to assess factors associated with catastrophic health expenditures.A total of 167 households (1.37%) incurred catastrophic health expenditures. These households on average spend over 52% of household nonfood expenditures on health care. 1.6% of Malawians are impoverished due to out-of-pocket health expenditures. Visiting a religious health facility , hospitalization , larger household size , higher socioeconomic status , living in central region  and rural areas  increased the odds of incurring catastrophic expenditures.The risk of catastrophic health expenditures and impoverishment persists in Malawi. This calls for government to improve the challenges faced by the free public health services and design better prepayment mechanisms to protect more vulnerable groups of the population from the burden of out-of-pocket payments. The goal of health care financing system is to protect households from the financial risk due illnesses. This goal is well articulated in the world health organization 2010 report as the Universal Health Coverage (UHC) goal . Such reCatastrophic health expenditures (CHEs) occur when out-of-pocket health payment as a share of household\u2019s income or capacity to pay exceeds a predetermined threshold level . CHE pusMalawian health system is mainly publicly financed through tax revenues and receives substantial funding from external donors . A minimWhile access to health services in public facilities is free at point of use, households still contribute to total health expenditure through out-of-pocket payments in Malawi. Two main factors could explain this phenomenon. Firstly, the health system face many bottlenecks such as shortage of drugs, skilled medical personnel, poor quality of services and inaccessibility of facilities . These bAccording to previous studies, out-of-pocket health payments expose households to the risk of CHEs and impoverishment ,16\u201321. TThis study is a secondary analysis of data from a nationally representative integrated household survey (IHS4) conducted between April 2016 to April 2017 by the National Statistics office of Malawi . The IHSEthical clearance for this secondary reanalysis was obtained from National Committee on Research in the Social Sciences and Humanities (NCRSH) reference No. P.10/19/434. The National Statistical Office of Malawi enumerators obtained verbal informed consent from the participants and this was recorded on the questionnaire and upon agreement to participate the enumerator proceeded with the interview.To assess catastrophic health expenditures we used measures proposed by Wagstaff and Doorslaer . WagstafE is defined as  ,25.Therefore, average catastrophic payment overshoot was estimated as ,25:OcatIn this study households incurred CHEs if out-of-pocket health expenditures as a share of household\u2019s capacity to pay exceed 40%, where household\u2019s capacity to pay was defined as annual household consumption expenditures remaining after food expenditures . The choImpoverishment due to out-of-pocket payments occurs when non poor households become poor after paying for health services . To assePL denotes the poverty line and xi is the total annual household consumption expenditure per capita for household i; as the individual household i poverty before out-of-pocket health payments. Then the average pre-payment poverty headcount was estimated as [i as Suppose we define mated as ,25:Hpovmated as ,25:GpovWhere N is the sample size. The normalized poverty gap before health payments was estimated as:We obtained similar measures for the post payment poverty head count and gap after subtracting total annual household\u2019s out-of-pocket expenditure per capita from total annual household\u2019s consumption expenditure per capita and replacing the superscripts in Eqs The difference between the corresponding post and pre poverty measures gives the impoverishing effects of out-of-pocket health payments on households. For example, we estimated the impoverishing effects of out-of-pocket payments on poverty head count and gap using the differences:A multilevel binary logistic regression was used to assess the factors associated with catastrophic health expenditures. This regression was used to account for the nested structure of the survey data where households are nested in districts and to ensure correct estimation of standard errors and statistical inference of the model parameters. This binary regression was also used to account for our main outcome variable which takes the value of 1 if a household incurred catastrophic health expenditure and zero otherwise. We estimated two models; model 1 was estimated with CHEs defined based on 40% of household nonfood consumption expenditures and model 2 with CHEs based on 10% of household total consumption expenditures.Multilevel binary logistic regression model. Let Yij be the outcome of catastrophic health expenditures for the ith household in jth district, \u03c0ij be the probability of incurring catastrophic health expenditures and xij be some household level covariates. We assume Yij follows a binomial distribution, i.e. Yij~Bin. Then, the probability of incurring catastrophic health expenditures \u03c0ij is modelled using a logit link function and the random intercept model is specified as:\u03b2 is a vector of fixed effects regression coefficients of the corresponding household level covariates xij and uj is the district level random effects term which captures the unobserved district level effects. The district level random effects term is assumed to be normally distributed with mean of zero i.e. Where We included as covariates those factors identified in previous literature as determinants of catastrophic health expenditures ,16\u201321. TMore households (32.12%) from the fourth income group and 30.63% of the households from rural reported illnesses in the past two weeks preceding the survey as shown in The incidence of catastrophic health expenditures varied by socio-economic status, location of the household, type of health facility and type of health service utilized as shown in This study assessed the incidence of catastrophic health expenditures, its determinants and the impoverishing effects of out-of-pocket health expenditures using the most recent Malawi fourth integrated household survey. Our study shows that out-of-pocket health expenditures are regressive as poorer households bear more financial burden relative to their income than richer households in Malawi. This study also shows that CHEs and impoverishment appear to have increased by 37% and 60% respectively since the last integrated household survey in 2010/11 . This inThe low levels of overall incidence of catastrophic health expenditures may not necessarily mean high levels of financial protection considering the fact that the Malawian health care financing system is not as well developed as other sub-Saharan African countries such as Kenya, Rwanda, Tanzania and Ghana  with higWe found that rural households incur high incidence of CHEs and are at an increased risk of CHEs as reported by other authors ,28,32,39Our finding that hospitalizations increased the incidence of catastrophic health expenditures is consistent with findings from other studies ,21,41,42The result that having the nearest medical doctor based at a religious health facility increased the odds of incurring CHEs than government facility is intuitive in the Malawian context. Religious health facilities charge user fees at point of use this implies households that access care at religious facilities are burdened with higher out-of-pocket payments. This finding corroborates with findings from Kenya . For exaThe study has some limitations. Firstly, the study used self-reported data on consumption expenditures and illnesses which is prone to recall bias which can lead to underreporting as also observed by other authors. This limitation would underestimate the incidence of catastrophic health expenditures and impoverishing effects of out-of-pocket expenditures on households. Secondly, use of cross-sectional data prevents causal interpretation of the relationship between catastrophic health payments and its associated factors. Thirdly, data on total health expenditures were annualized this could lead to overestimating of total health spending as we assume the same rate of monthly health expenditures over time. Despite these limitations, our study makes use of a multilevel logistic regression model to assess factors associated with incidence of CHEs which highlighted variations by districts. In addition, the study assessed the incidence of CHEs, the impoverishing impact of out-of-pocket health payments on households using the most recent available data which is important for monitoring financial protection.Our results are important for monitoring the incidence of catastrophic expenditures and impoverishing effects of out-of-pocket health expenditures in Malawi consequently progress towards achieving Universal Health Coverage. Despite a free public health care policy, our findings suggest that the incidence of catastrophic health expenditures and impoverishment effect of out-of-pocket health expenditure has increased compared to a previous study using similar data. Our finding that rural households face high incidence of catastrophic payments reflects challenges faced by free public health facilities in providing much needed care to households considering that majority of rural population access free public health services. This finding calls for government to improve the challenges faced by free public health services to protect majority rural poor from the financial risk of out-of-pocket payments. This study also shows that access to medical doctors from religious health facilities, living in rural areas and hospitalizations increased the odds of incurring catastrophic payments. There is a need for government to establish more equitable health financing mechanisms such as a mandatory national health insurance scheme or a health fund and expand the innovative financing mechanism of Service Level Agreements with mission health facilities. This will ensure that the identified vulnerable groups of the population are protected from financial hardship due to out-of-pocket payments."}
+{"text": "Regeneration of peripheral nerves after repair is incomplete. Painful microneuromas may form at the site of an appropriately performed primary microsurgical nerve repair leading to a persistent Tinel\u2019s sign and hypersensitivity in that location. Here, we describe an autologous option using a free muscle-derived nerve wrap with the intent to capture axonal escape at the site of primary nerve coaptation. We demonstrate this technique on a patient undergoing primary nerve repair of a laceration to the superficial branch of the radial nerve using extensor digitorum communis muscle as a donor graft. This has become our preferred technique over commercially available nerve wraps as the muscle wrap is autologous, not limited by cost, and has the potential to limit microneuroma formation at the coaptation site. Peripheral nerve injuries are common and diagnosed between 1% and 5% of patients treated for traumatic injuries .\u00a0This deCommercial nerve wraps can be used as an adjunct to primary repair and are intended to decrease perineural scarring and improve distal axon regeneration resulting in better distal functional recovery ,5. HowevModern treatments for prevention of clinically apparent neuroma formation redirect a proximal nerve after transection into a segment of denervated muscle or dermis to prevent further aberrant growth -8. CreatBased on the well-studied benefits of RPNI combined with the need for an autologous nerve wrap option came the rationale for using free muscle-derived grafts at the time of nerve repair. Here, we present the biologic autologous muscle-derived nerve (BAM)-wrap\u00a0intended for use at the time of nerve repair when donor muscle is available within the surgical field. This technique can stabilize and prevent tension at the repair and may limit painful and hypersensitive microneuromas by drawing on the effectiveness of RPNIs for the prevention of neuroma formation.IndicationsThe BAM-wrap can be employed both in acute repair of a traumatic nerve injury and in allo- or autograft-based reconstruction whenever a donor muscle is available in the surgical field. The clinical objective of this procedure is to capture misdirected axons at each coaptation site thereby preventing microneuroma formation and neuropathic hypersensitivity. Secondarily, this wrap directly prevents tension at the repair site and may behave in a similar fashion to commercially available nerve wraps by inhibiting perineural scarring and optimizing the environment for axonal regeneration .Surgical techniqueThe affected nerve is trimmed to healthy edges and repaired in a tension-free epineural fashion. A free muscle graft is then harvested from a healthy donor muscle within the surgical field Figure . We haveThe graft is sutured into a cuff around the coaptation site with a 7-0 nylon suture. Three sutures are sufficient to maximize contact between the graft and the repaired nerve. The proximal and distal sutures are passed through epineurium to maintain the position of the graft and prevent tension on the coaptation Figure , Video 1The BAM-wrap has become our preferred supplement to nerve repairs with the goals of preventing tension or stress on the repair, maximizing the return of function, and limiting the development of postoperative neuropathic pain. We have used this technique in upper and lower extremities in the setting of acute primary repairs after trauma, after resection of neuromas-in-continuity, and combined with targeted muscle reinnervation (TMR) after resection of symptomatic end-neuromas Figures , 4. We iThe known benefits of forming a regenerative peripheral nerve interface to prevent neuroma pain and augmenting a coaptation with a nerve wrap together make this technique a straightforward, cost-effective, and readily available adjunct to primary nerve repair. The regular use of a muscle wrap may augment primary nerve repair by directly preventing tension on the repair and limiting post-operative pain through targeted redirection of aberrant nerve growth."}
+{"text": "Decades of research have the beneficial effects of marital support and the detrimental consequences of marital strain on health and well-being. However, we know relatively less about how circumstances in childhood\u2014a key developmental period of the life course\u2014influence the relational structure in which later life is embedded and any implications this may hold for well-being. We integrate the life course perspective with the stress process model to offer a framework for how childhood conditions  moderate the relationship between marital support/strain and subjective well-being in older adulthood in potentially different ways for men and women. The consequences of marital strain may be more severe and the benefits of marital support may not be as strongly felt for those adults who experienced greater adversity during childhood. Drawing on longitudinal data from Waves 2 (2010-2011) and 3 (2015-2016) of the NSHAP project , results from lagged dependent variable models suggest that marital support buffers the effect of not living with both parents in childhood on subjective well-being for men. Meanwhile, women raised in families that experienced financial hardship reported lower subjective well-being in the context of marital strain in later life. No significant interaction effects were obtained for childhood happiness. Taken together, our findings suggest that adverse experiences in childhood can be scarring, particularly in the context of strained intimate relationships. However, a supportive marriage can, in some cases, offset the effects of childhood hardship on subjective well-being in later life."}
+{"text": "This presentation describes how we plan to address the challenges of testing an evidence-based caregiver program in a real-world setting without the infrastructure and personal contact of a typical RCT. Instead of screening participants for eligibility, clinic staff will pre-identify participants whom clinicians then confirm. Each clinic will include Tele-Savvy as standard of care; we will thus be able to obtain IRB approval for a waiver of consent. By securing agreement from each clinic to incorporate a small set of standard instruments  into their standard operating procedure of routinely collecting caregiver data gathering, we will be able to eliminate the need for a central research staff to conduct baseline and follow-up interviews and will, instead, collect key outcome data through the electronic health record. Instead of in person training of Tele-Savvy facilitators, we will rely on an online training program and facilitator manuals."}
+{"text": "Introduction The COVID-19 pandemic brought about seismic change for dentistry including the direction to provide remote advice and prescribe analgesia and antimicrobials. The possibilities for care have widened, but the impact of both restrictions and remobilisation on antibiotic prescribing is not known.Aims To report the impact of COVID-19 restrictions and remobilisation on dental antibiotic prescriptions and explore dentists' intentions and attitudes towards antibiotic prescribing.Design and setting Public Health Scotland national prescribing and claims data are reported alongside an online survey of Scottish general and public health service dentists including closed and open-ended questions.Results Antibiotic prescribing rose by 49% following the suspension of routine dental care, to a peak of 34,993 antibiotics (July 2020). The data also show that since the remobilisation of NHS dental care, antibiotic prescribing remains raised at levels around 28% higher than pre-pandemic. The survey highlights dentists' frustrations and concerns about this increased use of antibiotics. Most dentists intend to reduce their prescribing; however, significant challenges to this being realised were raised.Conclusions The previous success within dentistry to protect against the development of antimicrobial resistance has suffered a knock-back during the pandemic. A renewed focus on reducing unnecessary antibiotics within dentistry is required but, crucially, needs to be approached sensitively alongside the current backdrop of challenges within the service.Zusatzmaterial online: Zu diesem Beitrag sind unter 10.1038/s41415-021-3621-8 f\u00fcr autorisierte Leser zus\u00e4tzliche Dateien abrufbar. Highlights the increased antibiotic prescribing that resulted during the COVID-19 pandemic using routine national prescribing and claims data.Highlights that antibiotic use remains at a higher level despite the remobilisation of NHS dentistry.Details the results of a national survey of Scottish general and public dentists reporting ongoing challenges.Reports that dentists are aware they are prescribing at higher levels, are frustrated and concerned by this, and wish to reduce this but are facing challenges to do so.Zusatzmaterial online: Zu diesem Beitrag sind unter 10.1038/s41415-021-3621-8 f\u00fcr autorisierte Leser zus\u00e4tzliche Dateien abrufbar. There is emerging evidence to suggest that the pandemic has had an impact on antibiotic prescribing. A recent study4 highlighted that in the early months of the pandemic in England (April-July 2020), dental antibiotic prescribing was 25% higher compared with the same months in 2019.The efforts to control antimicrobial resistance through reducing the unnecessary exposure to antibiotics have seen some success in recent years. Total antibiotic use in Scotland decreased by 7.6% from 2015-2019, and over the same time period, the use in primary care decreased by 9.1% to the lowest figure since 1993.5 and NHS England announced the suspension and deferment of all routine, non-urgent dental care on 25 March 2020.6 During the suspension of routine dental care, Scottish practices were instructed to operate on an 'advice, analgesia, anti-microbial' basis with the rationale stated as 'where an extraction is not indicated an anti-microbial will provide relief until the tooth can be opened and drained by an urgent dental care team'.5 Patients with dental care concerns were remotely triaged by practices and those with an urgent need that could not wait were directed to the designated urgent dental care centre for the area. In England, the Office of the Chief Dental Officer (CDO) produced similar advice: dentists should not provide routine care; should offer telephone triage and advice, giving prescriptions where necessary; and should refer patients requiring active emergency treatment to regional urgent care centres. These arrangements stayed in place during the three-phase remobilisation of NHS dental services, with a return to emergency-only General Dental Services care in Scotland from 22 June 2020, routine non-aerosol generating procedures (AGPs) returning from 13 July 2020 and AGPs for urgent dental care only returning from 17 August 2020.7 The full range of NHS dental treatments (including AGPs for routine care) could not be provided until November 2020.8 On 21 June 2021, the CDO for Scotland wrote to the profession in response to recommendations raised by the Scottish Antibiotic Prescribing Group to emphasise that the first-line management of acute dental conditions should revert to clinical management rather than antibiotic prescribing.9The early months of the COVID-19 pandemic brought severe curtailment to the delivery of dental care within the UK. In Scotland, the Chief Dental Officer (CDO) wrote to all practices announcing the suspension of routine dental care on 23 March 2020It is not currently known what the impact of COVID-19 and the remobilisation of NHS dentistry has had on the levels of antibiotic prescribing, nor is it known whether the increased dental antibiotic prescribing figures seen in England is reflected in the data for the rest of the UK. Furthermore, the prescribing data only provide part of the picture and there is a need to hear from dentists themselves about the experiences and feelings that lie behind the antibiotic prescribing figures. This paper reports on an exploration of the Scottish data to report the impact of COVID-19 and remobilisation on dental antibiotic prescriptions, and the results of a national questionnaire of General Dental Services and Public Dental Services dentists in Scotland exploring dentists' intentions and attitudes towards antibiotic prescribing.We used Prescribing Information System for Scotland (PRISMS) data to obtain overall NHS antibiotic prescriptions and Management Information Dental Accounting System (MIDAS) data to obtain the total number of NHS claims. Both databases are held by Public Health Scotland. Data in PRISMS are identified by list number, which is a unique identifier of a dentist in a given dental practice. Antibiotic prescription data comprise all antibiotic items  prescribed by primary care dentists in Scotland and dispensed in community pharmacy. We calculated percentages of change between pre-pandemic levels of antibiotic prescription (January 2019) and post-pandemic levels by using a standard proportion calculation; that is, (prescriptions [post-pandemic] minus prescriptions [pre-pandemic] divided by prescriptions [pre-pandemic]). Claims data comprise course of treatment claims and non-course of treatment claims; for example, patient registrations. Data were included from January 2019 to May 2021. Prescribing rates were calculated as the total national number of antibiotic items prescribed by primary care dentists in Scotland per month divided by the total national number of claims in Scotland in the same month and multiplied by 100. They are presented with descriptive statistics - average (mean), standard deviation (SD) and range (minimum-maximum).Ethical review of the survey was completed by University of Aberdeen Research Governance on 30 September 2020 which classed this project as service evaluation. The project was registered with the Quality Improvement and Assurance Team (Project ID 5196) on 7 December 2020.10,11 The questionnaire was piloted with six dentists  who provided feedback to improve clarity of questions and to ensure response options were appropriate for both General Dental Services (GDS) and Public Dental Services (PDS) respondents. Within the questionnaire, the term 'lockdown' was defined as the period of March 2020 when routine dental care was suspended.The questionnaire included both open- and closed-ended questions. Items in the questionnaire were developed based on previous qualitative research exploring dental antibiotic prescribing.E-mails inviting dentists to complete the survey were sent via the NHS Education for Scotland Portal on 8 December 2020. One reminder e-mail was sent on 7 January 2021.www.openepi.com/).To achieve a precision of 5% with over 95% power to estimate the proportion of dentists that have 1) increased their prescribing during the pandemic or 2) intend to decrease their prescribing in the future, we required 300 responses. This assumes a population of 4,500 dentists in Scotland and an expected prevalence of 80% or above for each outcome. This calculation was done using OpenEpi, version 3, open source calculator  highlight the proportion of patients being treated who were prescribed antibiotics. The average monthly rate of antibiotic prescriptions per 100 claims pre-pandemic (January 2019-March 2020) was 5.4 antibiotics per 100 claims . This increased markedly to an average monthly rate of 148.7 antibiotics per 100 claims  during the period of most intense restrictions to service (April-August 2020). Rates then reduced to 17.7 antibiotics per 100 claims  during the remobilisation period (September-November 2020). However, data for the period December 2020-May 2021 highlight that prescribing rates have not reduced to pre-pandemic levels, with an average of 17.3 antibiotics per 100 claims .Responses were obtained from 311 dentists, of whom 278 (89%) were from GDS and 32 (10%) were working in PDS (one respondent did not declare). All health boards within Scotland except Shetland returned at least one response (see online supplementary information) and the distribution of dentists across health boards in our sample is similar to the distribution of GDS dentists in Scotland. The majority of respondents provided NHS dental services for the whole, main or equal proportion of their practice time (n = 267), with 44 providing whole or mostly private provision. (participant 191); 'we should never have prevented dental services' (participant 246); 'practices should never have been told to close and extractions should have continued throughout the pandemic. I am still unaware of any evidence to show this would have been unsafe' (participant 307).Frustration was expressed in the open responses about the restrictions, guidance and policies brought into effect during the pandemic: 'there was no good reason for practices to be closed'Harms caused by the impact of the restrictions on treatments were raised, including 'a loss of satisfaction and trust in dental care for these patients' (participant 143); 'the huge backlog of patients, the extreme reduction in capacity within the GDS [...] severe deterioration in the nation's dental health and an uptick in patients attending emergency departments and their GPs due to completely unavoidable lack of access to their dentist. Complaints are going to skyrocket' (participant 190).Deterioration to patients' dental health was mentioned as a concern alongside frustration about being prevented from effectively helping patients in need: 'it was wrong [prescribing antibiotics for pulpits] and felt wrong, it was a bad time not being able to help people in pain' (participant 246).Comments also suggested a loss of trust in regulatory bodies and in guidance, and a loss of professional autonomy: 'we are health professionals who have been treated like little children. I feel strongly about this. A wholly negative experience' (participant 209).Links were made by respondents between the changes to delivery of dental care and an increased use of antibiotics: 'first we are to reduce prescribing and then we are prevented from looking after our patients and asked to hand them out like sweeties' (participant 209); 'antibiotics should never have been used as a substitute for treatment [...] it should not have been forced upon us during lockdown' (participant 219). Respondents commented on their feelings that antibiotic prescribing had increased during COVID-19: 'I was shocked by the amount of antibiotics I prescribed over lockdown. All necessary because I couldn't see the patients face-to-face to treat them properly' (participant 100).The vast majority of respondents reported they had increased their antibiotic prescription slightly or greatly during the suspension of face-to-face care in March 2020  and the emergency-only GDS care in June 2020  compared to pre-COVID, as shown in Comments were also made about prescribing antibiotics counter to clinical assessment of need during COVID-19 to permit patients to access urgent treatment: 'urgent dental care centres during lockdown were declining patients if they haven't taken at least one course of antibiotics. You can understand how ridiculous this looks to patients' and dentists' eyes' (participant 272). This happened even when their clinical judgement was that it would not be of benefit: 'we were given no option but to Px [prescribe] ABs [antibiotics] even when we knew it would do no good' (participant 314). These comments are reflected in the quantitative responses where 84% (n = 262) of respondents were unsure, disagreed, or strongly disagreed that prescribing antibiotics when no other treatment is possible will effectively solve or manage the patient's condition. Most respondents  agreed or strongly agreed that prescribing antibiotics when no other treatment is possible goes against their views of best practice .Table 1 Reports were also shared of prescribing antibiotics as a means of providing some level of care when nothing else was possible: 'Antibiotics were often prescribed in lockdown when the symptoms were not indicative that antibiotics would have any effect just because \"you had to do something\"' (participant 57).There were strong feelings expressed such as: 'I felt terrible giving patients antibiotics that I knew were unlikely to help' (participant 311); 'the way antibiotics was [sic] prescribed by the hubs (and some GDPs) during lockdown was verging on criminal' (participant 287); and 'patients were having 5+ courses of antibiotics as no access to dentistry. Totally disgraceful' (participant 294).Further quantitative responses related to attitudes to prescribing antibiotics are presented in Some of the respondents reflected that antibiotic prescribing was already returning to a reduced pre-COVID-19 level: 'during lockdown was difficult [...] prescribing them [antibiotics] for 3 months when I knew this was not the ideal treatment was counter productive and I am very happy not to be in that situation anymore' (participant 49); 'Luckily being able to carry out treatments has ensured a decrease in prescribing already' (participant 279).However, for others, the picture has not yet changed and antibiotic prescribing remains at a higher level: 'I think we can't expect antibiotic prescription to reduce until we are working with less restrictions' (participant 275); 'how can we reduce the antibiotic prescribing with only enough PPE and time to see 5 AGPs a day if patients are in pain?' (participant 84). As well as the restrictions on AGP appointments, PPE and time, references were also made to the impact of the backlog and increased waiting lists, and the lack of dentists with face-fitted masks.When asked to quantitatively rate their intentions and expectations about antibiotic prescribing, the vast majority of respondents (80%) intend to decrease their prescriptions and 80% expect antibiotic prescribing to reduce in dentistry overall.Concerns were expressed by respondents that patients will have greater expectations for antibiotics post-COVID-19: 'Many patients are now happier to have antibiotics over treatment and expect things to be as they were in lockdown' (participant 183); 'Over the last number of years I feel the profession on the whole has been trying to reduce antibiotic prescriptions and instead using local measures to deal with the cause of the infection. We have been slowly changing public perception that antibiotics aren't always necessary or indicated and they're slowly accepting this. During COVID we have done the exact opposite of this and have only been prescribing antibiotics in a lot of cases and have undone years of hard work. I feel this has set us back a lot in terms of patient expectation' (participant 329). Furthermore, 42% (n = 132) of respondents agreed that prescribing antibiotics when no other treatment is possible preserves a good patient/dentist relationship. Around the same proportion  agreed that not providing antibiotics is likely to cause conflict .Comments also described the role of patients in terms of directly requesting antibiotics and refusing treatments so that antibiotics are the only route left: 'when a patient doesn't want a tooth out but they can't have rct [root canal treatment] for a weeks [sic] what other option is there?' (participant 316); 'patients think antibiotics are the golden nugget that will fix their pain and don't understand it will only temporarily take down the infection. Pts [patients] think Abs [antibiotics] will solve all their emergency issues and ask blatantly for them. Patients have boxes of Abs [antibiotics] lying in drawers at home [...] It's an absolute wild west out there when it comes to antibiotics' (participant 255).The vast majority of participants  agreed or strongly agreed that responsible use of antibiotics is important within dentistry . Only a 4 This study also provides further insight that higher levels of prescribing persist even with the remobilisation of NHS treatment (June to November 2020). Dentists report feeling compelled to 'do something' for patients and that prescribing antibiotics satisfied this need to provide some level of care during the COVID-19 restrictions when treatment options were so limited.This paper combines data from mixed sources to provide a unique insight into how the pandemic has impacted dentists' prescribing behaviour, perceptions and experiences. The data reported in this study from the national routine prescribing datasets show that dental antibiotic prescribing rose significantly in Scotland during the COVID-19 pandemic, echoing the picture reported during the early months of the pandemic in England.12 around the anticipated backlog of treatments and patients needing care suggests that there is a clear need to help support practices to manage this alongside the remobilisation of care. Furthermore, there has, as yet, been no real change in how dentists can deliver care with social distancing measures, PPE and fallow time restrictions remaining in place.Dentists are aware that they are prescribing antibiotics at higher levels and report feeling frustrated about prescribing antibiotics against their clinical judgement. They expressed concerns about the future impact of this increased antibiotic prescribing and most respondents reported an intention to reduce their antibiotic prescribing in the future. However, significant challenges were reported to reducing prescribing in the context of ongoing restrictions to the numbers of patients that can be seen and the large backlog of patients needing attention. The anxiety shared in this study, and others,12 highlighting that dentists would struggle with not providing a service to patients during the pandemic, seeing this as an integral part of their identity as a healthcare professional. Dentists in this study reported that prescribing antibiotics satisfied this 'need to do something', despite the fact antibiotics are unlikely to resolve much dental pain. This strong sense of duty to act may also be, in part, driven by concerns about the medico-legal consequences of withholding care. The potential legal consequences of not providing care when patients are clearly in need and may come to harm if not treated is a concern for UK dentists.13Dentists expressed feeling a strong sense of duty to act rather than leave patients in pain waiting with no treatment. This resonates with previous work,14 We would encourage the global dental community to reflect on lessons learned from this approach and come together to prepare for the next pandemic.Furthermore, going from the established guidance on management of acute dental problems to the advice, analgesia, antimicrobial (AAA) approach during the pandemic may also raise medico-legal concerns. Indeed, most dentists in this study agreed that prescribing antibiotics just because no other treatment is available goes against best practice. The move to AAA during the restrictions to dental services was not only applied within the UK but formed part of World Health Organisation global guidance.There are some strengths and limitations of this study to note. The data in this paper reflect the picture of antibiotic prescribing in Scotland only and generalisability beyond this context is uncertain. However, the use of routinely collected datasets to provide granular antibiotic prescribing data is a major strength which would not be possible in all countries. The claims data that have been used to calculate the proportions of patients being seen who received antibiotics may result in a degree of over-estimation of prescribing rates per claims, as submissions of claims may have been disrupted during the pandemic. Although the prescribing rates per claims figures should be interpreted with caution, the clear increase and sustained rise observed in the total number of antibiotic items comes at a time when the number of patients being seen was dramatically reduced.15 demonstrates the pandemic-related mental health burden within dentistry, with 27% of survey respondents reporting significant depressive symptoms and 55% reporting emotional exhaustion. The pressures and mental health impacts being faced within dentistry are likely to be a persisting challenge going forward, and renewed focus on mental health awareness and support within dentistry is apparent in recent initiatives.16,17The results reported in this paper suggest that a renewed focus on optimisation and reduction of antibiotic prescribing is warranted within dentistry but, crucially, this needs to be framed sensitively in what continues to be challenging times for dentistry. Alongside the frustrations expressed about the restrictions to service, loss of professional autonomy and loss of trust in regulatory bodies reported in this study, there is also the mental health impact which makes sensitive framing so critical. Recent research11 but also raising concerns about the potential for greater future demand following the widespread use of antibiotics during the pandemic. However, recent research18 examining Twitter communications about dental health and care during the pandemic suggested that the overuse of antibiotics and antimicrobial resistance was a concern to the general public too. These findings suggest that initiatives that target dentist-patient treatment discussions and decision-making may be indicated.The dentists in this study also highlighted the influential role patients can play in antibiotic prescribing, resonating with previous work19 highlights the increasing impact dentistry has within primary care antibiotic prescribing. In the six months before the pandemic restrictions of March 2020, on average, 7% of the total primary care antibiotic prescribing was within dentistry; however, in the six months from April-September 2020, this had increased to 12%. This represents an increase from dentists prescribing 1 in every 14 antibiotics in primary care to prescribing 1 in every 9 antibiotics. This further supports a renewed focus on antibiotic optimisation within dentistry and there are successful evidence-based initiatives that have been shown to help. Providing dentists with personalised prescribing feedback reports, alongside a short actionable message based on behaviour change theory, successfully reduced antibiotic prescribing rates.20 A novel initiative to examine whether the addition of in-practice training support to these feedback reports is currently underway to see if this brings about further reductions in antibiotic prescribing.21 The in-practice training support element may help dental practices to find a way to move forward with reducing dental antibiotic prescriptions in the current and future post-COVID-19 dental care landscape.Most dentists in this study felt that reducing antibiotic prescribing is very important and recent exploration of the Public Health Scotland prescribing in the community datasetsThe previous success within dentistry to protect against the development of antimicrobial resistance has suffered a knock-back during the pandemic. Antibiotic prescribing rose significantly in dentistry during the COVID-19 pandemic and prescribing continues at a higher level than pre-pandemic. A renewed focus on reducing unnecessary antibiotics is required but dentists report ongoing challenges that may stymie prescribing levels falling. Efforts to help support reducing dental prescribing need renewed focus alongside careful tailoring and sensitive framing for what continues to be a difficult new landscape for dentistry.Supplementary Table 1 (PDF 727KB)"}
+{"text": "There is debate whether human atrial fibrillation is driven by focal drivers or multiwavelet reentry. We propose that the changing activation sequences surrounding a focal driver can at times self-sustain in the absence of that driver. Further, the relationship between focal drivers and surrounding chaotic activation is bidirectional; focal drivers can generate chaotic activation, which may affect the dynamics of focal drivers.In a propagation model, we generated tissues that support structural micro-reentry and moving functional reentrant circuits. We qualitatively assessed (1) the tissue\u2019s ability to support self-sustaining fibrillation after elimination of the focal driver, (2) the impact that structural-reentrant substrate has on the duration of fibrillation, the impact that micro-reentrant (3) frequency, (4) excitable gap, and (5) exposure to surrounding fibrillation have on micro-reentry in the setting of chaotic activation, and finally the likelihood fibrillation will end in structural reentry based on (6) the distance between and (7) the relative lengths of an ablated tissue\u2019s inner and outer boundaries. We found (1) focal drivers produced chaotic activation when waves encountered heterogeneous refractoriness; chaotic activation could then repeatedly initiate and terminate micro-reentry. Perpetuation of fibrillation following elimination of micro-reentry was predicted by tissue properties. (2) Duration of fibrillation was increased by the presence of a structural micro-reentrant substrate only when surrounding tissue had a low propensity to support self-sustaining chaotic activation. Likelihood of micro-reentry around the structural reentrant substrate increased as (3) the frequency of structural reentry increased relative to the frequency of fibrillation in the surrounding tissue, (4) the excitable gap of micro-reentry increased, and (5) the exposure of the structural circuit to the surrounding tissue decreased. Likelihood of organized tachycardia following termination of fibrillation increased with (6) decreasing distance and (7) disparity of size between focal obstacle and external boundary.Focal drivers such as structural micro-reentry and the chaotic activation they produce are continuously interacting with one another. In order to accurately describe cardiac tissue\u2019s propensity to support fibrillation, the relative characteristics of both stationary and moving drivers must be taken into account. When the cardiac arrhythmia atrial fibrillation was first identified more than 100 years ago , it was We postulated that what is often described as fibrillatory conduction could under some circumstances represent moving functional reentry and as such could sustain in the absence of a focal driver. Furthermore, if MWR and FD can coexist it is possible that the chaotic waves surrounding a focal driver might interact with that driver and have implications for the duration of episodes of fibrillation.In the present study, we examine structural micro-reentry as a focal driver of fibrillation and use a computational model of propagation to qualitatively study the ability of chaotic activation to sustain after driver elimination, the interactions between these chaotically propagating waves and the spatially fixed structural reentrant substrate, and the impact that these interactions have on the overall duration of fibrillation. We also examined the likelihood that fibrillation will organize into atrial trachycardia after focal ablation.2 of cardiac tissue) undergo action potentials when they receive current sufficient to perturb their potential from rest (Vrest) to above a defined threshold (Vthresh). Action potentials cause the cell voltage to increase toward peak potential (Vpeak) after which it gradually returns to Vrest over a period of time, the action potential duration (APD). While the voltage is above Vthresh the cell is refractory to new stimuli. Cells transmit current to their adjacent neighbors, increasing the voltage of each neighbor with a time constant equal to the product of the cell-cell ohmic resistance (R) and the electric charge capacitance of the neighboring cell (C). This design results in appropriate source-sink behavior in which curved waves propagate more slowly than planar waves, and beyond a critical curvature propagation fails due to source-sink mismatch, creating rotation around an unexcited core.In the following experiments, we made use of a previously described computational model of electrical propagation in cardiac tissue , 2012. Oscar) was surrounded by a 1 mm thick protective partial annulus with larger radius (rbarrier) such that a tract of excitable cells between the two provided the substrate for a reentrant circuit, and an open portion of the protective annulus [defined by the angle of exposure (\u03b8exposure)] exposed the circuit to the surrounding cardiac tissue. Micro-reentry could be initiated by appropriately timed programmed stimulation to produce unidirectional block adjacent to the central scar. Structural micro-reentry could then be terminated by focal ablation of the excitable tract between rscar and rbarrier . The mean APD of individual monolayers was varied between 65 and 200 ms in 5 ms increments, each with \u00b110 ms of homogeneously distributed random variation. These parameter ranges were purposely selected to produce episodes of chaotic activation lasting between 0 and 10,000 s in the simulated tissues. In each monolayer, we initiated 500 unique episodes of structural reentry around the central obstacle. One second after initiation, structural reentry was eliminated by ablation. We then measured the mean duration of residual fibrillation in the surrounding monolayer . These values were compared to predictions made using the fibrillogenicity index (Eq. 1), a previously described metric of cardiac tissue\u2019s propensity to support multi-wavelet reentry . In these monolayers, the APDs of the central region  and the surrounding monolayer  were varied independently (both with \u00b110 ms of homogeneously distributed random variation). We tested the likelihood of structural micro-reentry in three separate experiments. In the first  of 5 ms was used.In each of the above experimental monolayer set-ups, we created 50 episodes of MWR by high frequency burst pacing (100 Hz) for 10 s from a virtual electrode positioned far from the central scar. The mean proportion of time in which structural micro-reentry and MWR coexisted was measured for the 10 s period of MWR. Structural reentry was declared present when all cells directly adjacent to the central obstacle were found to be simultaneously undergoing periodic excitation, as defined by Eq. 2. In this case, a threshold for periodic behavior  as a function of both the distance between, and the relative sizes, of the central scar e.g.,  and the In our first simulation of structural micro-reentry  depended upon the relative frequencies of the micro-reentry and MWR . We found that the probability of MWR converting to \u201catrial\u201d tachycardia decreased linearly with increasing distance , if circuits are not completed, activation is passive and driven, requiring a driver. As we have previously explored , MWR falIn the present study, we have explored a number of different aspects of the relationship between stationary drivers  and moving drivers (MWR) when they coexist during fibrillation. This relationship has traditionally been viewed as one sided; focal drivers act upon the surrounding excitable tissue to generate shifting conduction block and varying activation patterns . We founIn the presence of both a scar substrate for reentry and surrounding cardiac tissue with sufficient propensity to fibrillate, structural and moving functional reentry coexisted and together drove fibrillation . We founOne of the well-known complications associated with focal ablation of atrial fibrillation is the induction of atrial tachycardia . HoweverThus, properties which affect the likelihood of wave ends anchoring to separate boundaries affect the likelihood of atrial tachycardia. Boundaries that are further apart from one another or are more disproportionate in size reduce the probability of a single wave having wave ends anchored on opposite boundaries.in silico studies however, we cannot consider the concepts we present here to be confirmed. Our conclusions require validation in a biological setting, ultimately humans. Nonetheless, our findings provide a set of testable predictions that can guide the design of future experimental study.Our goal in this series of experiments was to establish the theoretical principles that define interactions between stationary and moving drivers of fibrillation. In particular, we were interested in defining qualitative relationships between emergent behaviors  and tissue properties . The computer model of propagation we selected for this study is therefore ideal, since its low computational burden allows for both direct visualization of electrical activity and exhaustive search of the parameter landscape. As with all Several recent modeling studies  have higThere is an enormous amount of complexity involved in human atrial fibrillation that was not captured by the simplistic model we used in this study. Our intention was not to determine what does happen in human AF but rather what can happen when a generic stationary driver is surrounded by tissue capable of supporting moving functional reentrant circuits. The use of a simplistic model allowed us to test long episodes of fibrillation, in tissues with a wide range of parameters and with multiple episodes of fibrillation in each tissue. Our results therefore speak more to how focal drivers and fibrillation can interact and how some physiologic features affect those interactions; the exact numerical values of our results cannot be directly extrapolated to human AF. The actual behavior in any individual AF patient will be determined by the extremely complex interactions between that patient\u2019s electrical properties and tissue architecture; our data provides a framework for understanding the complex propagation that emerges.In this study, we used a computational model to examine the interplay between spatially stable structural micro-reentry and the surrounding cardiac tissue during fibrillation. Focal drivers could initiate fibrillation via wave break in the setting of heterogeneous refractoriness of the surrounding cardiac tissue, and chaotic activation could both initiate and terminate structural micro-reentry via well-timed collisions between waves of excitation. The degree to which a focal driver and the surrounding chaotic activation interact depended on the relative characteristics of the structural and functional reentrant substrates. In order to accurately describe cardiac tissue\u2019s propensity to support fibrillation, the relationship between stationary and moving drivers must be taken into account.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation, to any qualified researcher.PS: study design, data analysis, and writing. RC: study design, data acquisition, data analysis, and writing. BB and OB: data analysis. All authors contributed to the article and approved the submitted version.PS received consulting fees from Biosense Webster and Medtronic. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Serious questions have arisen surrounding the safety of undertaking major complex (cancer) surgery during the current pandemic. Are patients at significant risk of acquiring COVID-19, which may lead to devastating outcomes in the perioperative period?A prospective multi-center study was undertaken in nine high-volume European surgical centers serving regions heavily affected by COVID-19.Updated guidance is required concerning minimum precautions that should be exercised to facilitate the safe continuation of complex major surgical programs. Prospective and transparent reporting of all perioperative outcomes is required by other groups to provide continued reassurance that our findings are generalizable in other regions and in differing periods during the pandemic. Reassurance must be provided to patients and their carers that complex surgical management is being safely delivered and that they should not avoid attending the hospital for life-saving treatment."}
+{"text": "The COVID-19 pandemic prompted an urgent reconsideration of space and place within congregate housing. Research has only underscored the need for health-promoting physical alterations to residential environments , but also generated lasting questions about the relationships between congregate environments and their residents, visitors, and workforce \u2014among them, what ways can environments be negotiated to reduce risk ? How can environments enact care for formal caregivers ? Who might be challenged by this care which may question the dangers associated with proximity ? This symposium focuses on the ways stakeholders within congregate housing observed, related to, and negotiated changes to space and place during the pandemic. Paper 1 presents an organizational case study investigating provider perspectives of how housing and healthcare responses to COVID have shaped palliative care with unhoused patients during the pandemic. Paper 2 highlights the collaborative work of a multi-sector coalition working to address timely needs of residents in low-income senior buildings. Paper 3 reflects on the formation of a cross-national senior housing network and the interdisciplinary exchange of best practices and policy recommendations that emerged. The collective findings of these papers challenge previous notions of care in congregate environments, illuminate how provider networks respond to crises and share emergent knowledge, and consider how institutional decisions about the pandemic have re-placed and re-spaced provider and patient experiences. This symposium offers observations and strategies that may assist in envisioning successful congregate care during COVID-19 and beyond."}
+{"text": "Molecular chaperone networks fulfill complex roles in protein homeostasis and are essential for maintaining cell health. Hsp40s (commonly referred to as J-proteins) have critical roles in development and are associated with a variety of human diseases, yet little is known regarding the J-proteins with respect to the post-transcriptional mechanisms that regulate their expression. With relatively small alterations in their abundance and stoichiometry altering their activity, post-transcriptional regulation potentially has significant impact on the functions of J-proteins. MicroRNAs (miRNAs) are a large group of non-coding RNAs that form a complex regulatory network impacting gene expression. Here we review and investigate the current knowledge and potential intersection of miRNA regulatory networks with the J-Protein chaperone network. Analysis of datasets from the current version of TargetScan revealed a great number of predicted microRNAs targeting J-proteins compared to the limited reports of interactions to date. There are likely unstudied regulatory interactions that influence chaperone biology contained within our analysis. We go on to present some criteria for prioritizing candidate interactions including potential cooperative targeting of J-Proteins by multiple miRNAs. In summary, we offer a view on the scope of regulation of J-Proteins through miRNAs with the aim of guiding future investigations by identifying key regulatory nodes within these two complex cellular networks. MicroRNA (miRNA) networks of gene regulation and molecular chaperone networks both consist of complex webs of interactions with broad implications in shaping the proteome. In both networks, the activity of individual molecules impacts many target or client molecules, resulting in broad regulation of protein homeostasis (proteostasis)  of a broad subset of chaperone gene targets during stress conditions such as heat shock  which identifies predicted canonical mRNA target sequences with 7\u20138 nt stretches of complementarity to the miRNA seed sequence (Agarwal et al., To obtain a more global perspective on the potential miRNA network of interactions on the J-Proteins we performed an Within the context of miRNA target prediction, both evolutionary conservation aspects of the miRNAs themselves and particular putative miRNA target sequences within a mRNA exist. With respect to our analysis, there are miRNAs and miRNA families that are broadly conserved among vertebrates and miRNAs conserved among mammals Bartel, . While tAn initial analysis for putative miRNA targets of the J-protein family with cumulative context scores of \u2264\u22120.1 (Agarwal et al., The specific predicted conserved target interactions for all the J-Protein members by broadly conserved miRNAs or those conserved among mammals are shown in Despite the large number of predicted potential interactions, many predicted conserved miRNA target sequences are known to not significantly regulate expression levels of their targets in cells (Baek et al., The degree of regulation of mRNAs by miRNAs depends on the identities and abundance of the particular miRNAs in the cell, the number of target mRNA sites in a cell, as well as the specific binding efficacy for a given miRNA target site. For each given miRNA:mRNA interaction, the regulation is typically modest with repression being <50% (Baek et al., Complex patterns of miRNA expression exist in different cell and tissue types (Landgraf et al., The potential for multiple different miRNAs targeting the same J-Protein is summarized in To query the potential for cooperative interactions between the predicted miRNA target sequences in the 3' UTRs of the J-protein mRNAs, target sequences within 8\u201340 nts of each other were identified. Perhaps as a result of the enormous inherent complexities of both the chaperone networks and miRNA regulatory networks, there has been relatively little reported work validating their intersection of regulation. Our analysis offers starting points for the exploration of miRNA and J-protein interactions. With the reported linkages and interest in both miRNAs and J-proteins in human diseases such as neurodegeneration and cancer, there are ample possibilities that we have outlined for future investigations into the interplay of these systems.LB: drafted the manuscript and collected literature and data. RF: data analysis and edited the manuscript. SAM: designed the content of the article and edited the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Cardiff CASC Training (CCT) has provided structured and formal training for the CASC exam for Wales trainees since 2012, in conjunction with Wales Deanery. For the past 8 years CCT has delivered face-to-face mock CASC exams and received excellent feedback from candidates and examiners, in addition to an extremely positive outcome of improvement in CASC pass rate for candidates.Due to the current COVID-19 pandemic restrictions delivery of the mock CASC examination had to be adapted with the aim of running it remotely via an online platform.The examinations were run online via Zoom due to its ease of use, including the ability to screen share candidate instructions and assign participants in to breakout rooms. One lead exam coordinator manually rotated candidates around the circuit of 16 stations.A total of 16 candidates sat the mock exam over two separate sittings. Written feedback was obtained from candidates and examiners. Limitations identified during the initial sitting included high logistical workload for the lead exam co-ordinator and Zoom not being supported by all hospital computer internet browsers, these issues were addressed prior to the second sitting. Feedback from candidates regarding the overall experience of the online exams ranged from 'extremely effective\u2019 to \u2018very effective\u2019, this is in line with feedback obtained following previous face-to-face mock exam events CCT has run.Although online learning may feel very different to the face-to-face interactions we are all used to we are in an era where adaption is necessary. These online mock CASC examinations have been a success and are also in keeping with how the real CASC examination is currently being run by the Royal College of Psychiatrists. CCT are running a further online mock examination to support the next cohort of candidates through their CASC exam in this particularly challenging time."}
+{"text": "Nearly 30% of China\u2019s workforce consists of China\u2019s rural-to-urban migrant workers, accounting for nearly 300 million of China\u2019s population. Even though they have gained freedom of movement since the 1980s, they still have no access to healthcare in urban areas where they work. This study utilizes a mixed method of a survey with a sample of migrant workers from three Chinese emigration provinces (n=817) in 2018 and follow-up interviews with 30 migrant workers in 2020 to examine factors of migration experience affecting migrant worker\u2019s health and healthcare. Using binary logistic regression, we found that migrant workers\u2019 longer work experience is correlated with poorer self-rated health, their better financial status and level of hopefulness towards the future are positively correlated to self-rated health. Qualitative findings shed light on the cumulative effect of the length of work experience and fear of medical cost on migrant workers\u2019 declining health. The lack of portability in health insurance and different reimbursement rates in health care access are structural barriers in health-seeking behaviors among migrant workers. Policy implications are presented in the global context of social rights and freedom of movement."}
+{"text": "The formation of long-term memory requires activity-dependent gene expression and protein translation, which allow the neurons to dynamically adjust their synaptic strength during learning . One of de novo gene expression, both mRNAs and non-coding RNAs (ncRNAs)  undergo further processing, including splicing, polyadenylation and nuclear export to ensure their proper expression, localization or translational control in neurons. Together the cross-talk between transcription factors and epigenetic modifiers play an important role in driving neuronal plasticity and long-term memory formation. However, the molecular mechanisms controlling both epigenetic and epitranscriptomic regulation remain largely unknown. In addition, molecular aberrations in these regulatory pathways are thought to contribute to various kinds of learning disability and memory deficits. This special topic covers a series of original research and review articles that further our knowledge about the genetic, epigenetic and epitranscriptomic mechanisms associated with learning and memory in health and disease.The traditional view of nature  versus nurture  as two separate entities has been challenged over the past two decades by evidence of a direct and dynamic relationship between genes and environmental stimuli . EpigeneZhang et al., explored the impact of three major high-risk AD genes  on function connectivity in healthy middle-aged adults. They found that both CLU and ABCA7 might interact to regulate the functional connectivity of the medial prefrontal and posterior cingulate cortices and that APOE\u03b54 might also interact with ABCA7 and CLU in middle-aged carriers to affect functional output and disease severity. While this paper focuses on DNA regulation, a complementary review paper by Wei et al., focuses on RNA regulation. This paper investigates the impairment of non-coding microRNAs  in AD pathogenesis and their potential to serve as biomarkers of disease progression. In addition, Wang et al., investigated the role of noncoding circular RNAs (cirRNAs), which have also been shown to play a role in learning and memory and neurological disorders such as AD and Down Syndrome. In this study, hippocampal fetal tissue from Down Syndrome patients was used to quantify circRNA-miRNA-mRNA competing endogenous RNA (ceRNA) regulatory networks. The authors identified several alterations in pathways associated with synaptic plasticity and learning and memory. This work suggests a potential role for noncoding RNAs, such as circRNAs, in neural signaling transfer might play an underlying role in disease progression.Alzheimer\u2019s disease (AD) is a neurodegenerative disorder which presents with memory deficits as well as complex genetic characteristics. Accumulating evidence suggests that both epigenetic and epitranscriptomics may play important roles in cognitive disorders like AD, yet how they contribute to the epidemiology of the disorder is not well understood. In an effort to gain better insight into the relationship between key AD-risk genes and cognitive severity Dell\u2019Orco et al. and colleagues. Here the investigators examine the interaction of the RNA binding protein (RBP) HuD  with circRNAs. After previously characterizing that HuD interacts with circHomer1a, the authors went on in the current work to demonstrate that HuD also binds to 226 other genes involved in neuronal differentiation, synapse formation and learning and memory. Together, HuD binds to and regulates the levels of multiple circRNAs to ensure changes in HuD-regulated ceRNA networks to modulate synaptic plasticity. Finally, regulation of mRNA splicing by RBPs can also affect synaptic plasticity and disease progression in the brain. In a review by Gallo et al. and collogues, Apolipoprotein E receptor 2 (apoER2), a type I transmembrane protein of the low-density lipoprotein receptor family known to regulate learning and memory in the adult brain regulation is discussed. ApoER2 has several known isoforms whose splice variants are cell type specific. A deeper understanding on the effects of RBPs on alternative splicing and the epigenetic factors modulating RBPs themselves is still needed to further understand the contribution of specific regulatory pathways. In the future it will be critical to link different DNA and RNA regulatory pathways to both learning and memory paradigms and disease pathogenesis. In order to do so, a thorough understanding is needed of how these different signaling components work together with environmental influences to shape brain plasticity and store long-term memories.Understanding how these circRNAs might be regulated in response to learning and memory paradigms can be gleamed from"}
+{"text": "Racial and ethnic minority older adults\u2014especially non-Latino Black and Latino older adults\u2014continue to have a higher prevalence of dementia with longer delays in formal diagnosis compared to non-Latino Whites. Few studies have estimated racial/ethnic differences in trajectories of dementia onset using nationally representative data with representation from the three largest racial/ethnic groups in the U.S.: non-Latino White, non-Latino Black, and Latino older adults. Additionally, given the delays in formal diagnosis we rely on a measure of probable dementia that takes into account both formal diagnosis and cognitive function. Data from the National Health and Aging Trend Study  reveals three trajectories of dementia onset  and we find that Latino and Black older adults are at greater risk for early dementia onset compared to non-Latino Whites. Our next step is to explore the role of social function for dementia disparities."}
+{"text": "Individuals higher in depressive symptoms commonly present with neuropsychological deficits including poorer memory performance. Sense of purpose in life, a component of psychological well-being, has been shown to promote resilience to cognitive impairment in older adulthood, but it is unclear whether it may also protect against cognitive deficits associated with higher depressive symptoms. This study examined whether purpose in life moderated the effect of depressive symptoms on cognitive functioning in a large longitudinal study of 4599 American older adults  across a 12-year follow-up period. Depressive symptomatology was assessed at each wave using the 8-item Center for Epidemiologic Studies Depression Scale. Multilevel models assessed the influence of depressive symptoms and the interaction with sense of purpose in life on changes in word recall and mental status. Higher depressive symptoms were associated with poorer recall at baseline, but not rate of change over time. A negative interaction was observed between sense of purpose in life and depressive symptoms such that individuals higher in purpose experienced a less negative impact of depressive symptoms on word recall. No significant interaction of sense of purpose and depressive symptoms was observed on mental status. Having a sense of purpose in life may help protect older adults from memory deficits associated with higher depressive symptoms. The present findings underscore the potential for sense of purpose to promote cognitive reserve in older adulthood, allowing individuals to maintain cognitive performance in the face of accruing neuropsychological challenges."}
+{"text": "The management of anxiety and distress in patients with cancer is stressful for the oncology clinicians who treat them . UnfortuIn addition to the usual stresses of having cancer, the COVID-19 pandemic has altered the usual delivery of cancer care making every encounter with a medical facility fraught with danger, increasing the sense of isolation and loneliness that patients feel during this pandemic . This isConsult-liaison psychiatry tends to focus more on psychiatric consultations than on liaison activities . HistoriThe stresses of oncology practice and the management of cancer-related distress and anxiety may be co-managed to some extent by the liaison activity of conducting in-person or virtual Balint groups, which may be led by CL psychiatrists or other trained mental health professionals with specific Balint group training .The \u2018Balint\u2019 group was created in the 1950 by the English psychoanalysis Enid Balint and is used around the world to help other physicians outside of mental health with the stresses of difficult patients and/or medical situations . The guiIncorporating \u2018Balint\u2019 group training and experiences is consistent with the tenants of patient-centered medicine . EvidencOncologists and other cancer clinicians outside of mental-health have limited training on interpersonal communication, doctor-patient relationship, transference/countertransference and limited supervision on effectively dealing with difficult or personality disordered patients. In general, patients who are reluctant to receive psychosocial services use their primary medical provider as a surrogate support for mental healthcare ,30. ThisAlongside a global pandemic is the ongoing epidemic of physician distress and burnout . While t\u2018Balint\u2019 groups for oncology clinicians who are in training or experienced have demonstrated feasibility and draw upon common principles that enhance the doctor-patient relationship and the wellbeing of clinicians . The tra"}
+{"text": "Conservation Physiology (Danaus plexippus) released in the wild with radio-transmitters were able to orient southwards during fall migration. In contrast, monarchs reared under the same conditions but flown in a flight simulator did not show a strong tendency towards southward migration. Davis (2021) raised three main concerns related to (i) the orientation of monarch butterflies during fall migration, (ii) the lack of a control group and (iii) the potential negative impact of the devices used in both orientation tests. We address each of these issues below.We thank Davis (2021) for their comments on our recent paper in Davis (2021) points out that, while that evidence suggests the eastern North American population of monarch butterflies follows a southwest trajectory during fall migration  expressed concern that a control group of wild-caught monarch butterflies was not radio tracked at the same time as captive-reared monarchs. This is a fair point and something we already addressed in We agree with Davis (2021) that the use of radio transmitters may cause deleterious effects on animals and that unexpected behavioural responses during radio tracking are most often attributed to the weight and attachment of devices . The tagThe procedures for attaching the radio transmitters and the tungsten rod to tether monarchs in the flight simulator could impact monarch flight. However, all efforts were made to ensure that monarchs had a full range of motion and showed characteristic patterns of flight (i.e. strong flapping with intermittent gliding). Though it is possible that methods used to secure the tungsten rod could result in reduced survival (Experimental approaches offer a unique opportunity to gain insight into the mechanisms driving variation in migration success, yet few studies have combined laboratory and field techniques ("}
+{"text": "Complex tricuspid valve repair techniques that avoid the use of prosthetic material carry the potential for improved long-term outcomes.293.See Article page Consider the \u201cpull the goalie\u201d scenario confronted by this Cliniques Universitaires Saint-Luc team in delivering such a spectacular victory for this unfortunate young man.,But even as we admire the masterful techniques on display in the accompanying video, we are left wondering if further innovation in the management of tricuspid valve endocarditis could swing the odds so heavily in favor of long-term survival as to make these sorts of clever solutions seem unnecessary. To that end, a number of technology solutions are already on the horizon. Traditional indications for urgent surgery include large persistent vegetations, right heart failure in the setting of severe tricuspid regurgitation, and recurrent pulmonary emboli."}
+{"text": "Teaching Point: The advantages of CT over other imaging techniques for the diagnosis of acute appendicitis in adults include the ability to identify foreign bodies that may be involved. Contrast-enhanced computed tomography (CT) with sagittal , axial  and volume rendering (VR)  views revealed perforated retrocecal appendicitis (white arrow) with an abscess . An intraluminal metallic foreign body with the typical shape of a hemostatic clip was found . Review of the medical data revealed that the patient had undergone a colonoscopy six weeks previously with a somewhat hemorrhagic resection of a polyp of the cecum requiring two hemostatic clips . One of these had migrated in the appendix causing its perforation. Surgical dissection of the parietal abscess  found the clip  and was completed by radical appendicectomy.A 65-year-old woman was admitted with pain in the right iliac fossa for three days. Laboratory tests showed elevated C-Reactive Protein  and white blood cell count  but also to identify foreign bodies."}
+{"text": "Aging is a progressive physiological degeneration and represents the most important risk factor for the development of multiple human neurodegenerative disorders . Therefoin situ in human brain specimens.In recent years, new strategies for targeting senescent cells have been developed to alleviate the systemic detrimental effects that arise from these cells. Some of these therapies are within the family of so-called senotherapeutics: drugs that either selectively eliminate senescent cells (senolytics) or that effectively suppress the senescence-associated secretory phenotype (SASP) responsible for driving chronic inflammation during aging (senomorphics). Until recently, their impact in the central nervous system had mostly been tested in mice where a number of studies have shown that senescent oligodendrocyte precursor cells, astrocytes and microglia are responsible for neurodegenerative phenotypes in mouse models of Alzheimer\u2019s disease , tau-deppost mortem evaluation.Brain organoids (BOs) have become a valuable model platform for human brain disease modelling as they accurately model complex neuronal networks and to an extent recapitulate the cell diversity of the human brain . This inATM) gene, is a premature aging syndrome that in many aspects recapitulates human brain aging [Ataxia-Telangiectasia (A-T), a genome instability disorder caused by biallelic mutations in the ataxia-telangiectasia mutated (in aging . In a rein aging . As compin aging . This obin aging . Furtherin aging .The clinical significance of chronic inflammation and the impact of aging in driving disease progression - such as neurodegeneration - in the central nervous system of the aging population has to date remained largely unresolved. It is now acknowledged that improved understanding of the mechanisms that drive aging hallmarks can lead to the identification of novel therapeutic targets. This is an area where human BO models have the potential to exponentially expand the area of human brain aging. It is therefore conceivable that high throughput testing in BOs of known senotherapeutic and novel compounds may be used in the future to study mechanisms of aging as well as their capacity to alleviate multiple brain aging phenotypes."}
+{"text": "There is an unmet need for the treatment of hydrocephalus in Tanzania. Thousands of newborns each year in the region are affected by this condition and access to care remains a challenge. While treatment options like cerebrospinal fluid diversion through ventriculo-peritoneal shunting are within the skill set of general surgeons, the potential complications represent an additional challenge. We present a 10-month-old Tanzanian female who developed bilateral-subdural hematomas after insertion of a ventriculoperitoneal shunt. Surgical Intensive Care Services (SICU) are capped at 8 beds and usually run at capacity thus several ICU candidates are often rejected due to lack of space.2 Shunt failure is a life-threatening emergency and thus access to emergency neurosurgical care is very vital.Patients presenting with Congenital Hydrocephalus are exclusively managed by insertion of a VP shunt. While it is a relatively simple procedure, failure rates within the first year of up to 25% have been reported.4 It's occurrence in SSA following VP shunt insertions in paediatric populations is unreported to the best of our knowledge. We present a case report of a 10-month-old Tanzanian female who presented with a bilateral subdural collections 2 months after insertion of a VP shunt system.The collection of a subdural hematoma following drainage of Cerebro-Spinal Fluid (CSF) via VP shunt insertions has been studied mainly in adult patients presenting with normal pressure hydrocephalus.5) and a ventricular index of 42%. The mother reported that despite regular pumping of the shunt, the bulging did not subside. She denied any history of convulsions, vomiting, high-pitched cry or fevers.A 10-month-old Tanzanian female presented to our centre with a 1-week history of progressively worsening bulging of her anterior fontanelle. Her past medical history was suggestive of congenital hydro-cephalus and insertion of a VP shunt when the child was 8 months old; 2 months prior to the current presentation. Before the shunt insertion, she had a head circumference of 51 centimetres . There was no neck stiffness, no opisthotonos posturing and the tone of the limbs was normal. Sunset phenomenon of the eyes was not observed and the cardiovascular, abdominal, musculoskeletal and genitourinary examination was otherwise normal.Upon initial examination, an active child was observed with hemodynamically stable vitals. The anterior and posterior fontanelles were tense and bulging, with the edges of the sagittal sutures wide apart. The occipitofrontal circumference was 52 centimetres- scan of the head demonstrated a bilateral acute-on-chronic subdural hematoma with the shunt system in situ .The child was initiated on acetazolamide and planned for bilateral decompression burr hole surgery to allow for drainage of the hematoma. Intraoperatively, one burr hole was made on each side and a total of 200 millilitres of haemolysed blood was evacuated. The intraoperative-course was stable and the child recovered well from anaesthesia with neurological examination post-surgery conforming with pre-operative findings. The child was nursed in General Surgical Ward with a stable progress over 48 hours post-surgery. We would ideally have preferred post-op care in a High Care Unit. However, such services are not available at our hospital due to limited resources.Unfortunately, on day 3, there was a sudden deterioration of the child's status while in the ward from an undetermined cause. Cardiopulmonary resuscitation was immediately initiated by the General Surgical Ward team, however it was unsuccessful and the child succumbed.The child's rapid deterioration may have been due to various conditions. Possibilities considered by the treating team were; raised intracranial pressures secondary to subdural recollections with subsequent herniation or a seizure complicated by aspiration and hypoxia. Due to the family's preferences, a post-mortem was not conducted and an exact cause of death could not be identified.We present a 10-month-old child with congenital hydro-cephalus who developed a relatively uncommon complication following insertion of a VP shunt.VP shunting is a procedure for diverting Cerebro-Spinal Fluid (CSF) to a compartment in the body which has absorptive capacity. It involves subcutaneous tunnelling of a catheter from the scalp to the abdomen in a sterile fashion, securing the proximal tip to a ventricular catheter and burying the distal tip under direct vision in the peritoneal cavity. The CSF flow towards the distal end is absorbed in the distal cavity thus resulting in lowered intracranial pressure with values closer to normal.6 It is a complication linked to high opening pressures of the CSF likely leading to drainage of large volumes of CSF during shunt insertion and subsequent high-volume drainage.6In patients with idiopathic normal pressure hydrocephalus, it is proposed that the collection of subdural blood is most likely due to the sudden decrease in intracranial pressure following drainage which allows the brain matter to fall away from the calvarium.7 There are no exact figures describing the burden of congenital hydrocephalus and associated treatment complications within SSA. It is largely from data extrapolated from centres within the region managing this condition that estimates have been put forward.8Studies in high and middle-income countries have reported variable rates (11 to 25%) of shunt complications during the first year post-surgery.9 These figures highlight the need to manage this condition in a timely and appropriate manner while also anticipating possible complications.Warf et al.'s work defined the economic burden of congenital hydrocephalus in infants in SSA; they determined that the long-term benefit of managing hydrocephalus in infants for one-year can amount up to $56 billion.11 Subdural hematoma collection following shunt insertion has largely been reported in patients who Various complications following VP shunting are reported in literature including shunt obstruction, shunt migration, bowel perforation, abdominal pseudocyst formation and infection.11 Subdural hematoma collection following shunt insertion has largely been reported in patients who were shunted for idiopathic normal pressure hydrocephalus with an incidence of 10% over 12 years in a Swedish study.3Various complications following VP shunting are reported in literature including shunt obstruction, shunt migration, bowel perforation, abdominal pseudocyst formation and infection.12 Subdural hematoma collection following ventriculoperitoneal shunting for congenital hydrocephalus has not been commonly reported in literature.Illingworth's series of patients who developed subdural hematomas after drainage of a hydrocephalus had all been managed by a ventriculocaval shunt.The lack of neurosurgical services at our centre - the Northern Zone Referral Hospital in Tanzania - has required general surgeons to develop proficiency in the insertion of VP shunts for patients with hydrocephalus. Investment in neurosurgical services and expertise in our region will contribute towards lessening the incidence of complications in patients post VP shunt placement. Currently, at our centre, this condition is managed entirely by general surgeons and it is the most common procedure in children under 6 months of age. Before discharge from hospital care, mothers and caregivers are counselled on the signs of increased intra-cranial pressure as well as techniques of pumping the shunt system to allow for adequate drainage.It is clear that the allocation of human and financial capital to the health care systems in SSA is required for addressing the burden of hydrocephalus in the paediatric population and investing in access to neurosurgery care for these patients.Infant hydrocephalus in Tanzania represents a major Public Health challenge. The gap in adequate short and long-term post-operative care and follow-up also needs to be addressed to minimise morbidity and mortality. There is an un-met need for care resulting in immense loss of Disability Adjusted Life Years. While management is possible even by personnel who are not specialised in neurosurgery, the possibility of complications following VP shunt insertion should always be acknowledged."}
+{"text": "The disabilities of the arm, shoulder and hand (DASH) is a commonly used region-specific patient-reported outcome measure (PROM) that quantify upper extremity function (activity limitation) and symptoms. Current evidence suggests that measurement properties of the adapted versions of the DASH are not sufficiently examined. The Arabic DASH has evidence supporting its internal consistency, test\u2013retest reliability, construct validity and responsiveness. On the other hand, the validity of the assumed unidimensionality of the Arabic DASH has not been examined previously. The aim of this study was to examine the structural validity of the Arabic DASH in patients with upper extremity musculoskeletal disorders using Rasch measurement model.Patients with upper extremity musculoskeletal disorders were recruited and were asked to complete the Arabic DASH at their initial visit to physical therapy departments. The overall fit of the Arabic DASH to the requirement of the Rasch measurement model was examined using chi-square statistics for item-trait interaction, mean item and person fit residuals. The fit of individual items, thresholds ordering, local dependency, differential item functioning (DIF), and unidimensionality using the t-test approach were also examined.2\u2009=\u2009179.04, p\u2009<\u20090.001) with major breach of local item independence and a pattern of high residual correlations among the activity-related items and among the impairment-related items. Combining items into activity-limitation and impairment testlets accommodated the local dependency and led to satisfactory fit of the Arabic DASH to the requirement of the Rasch measurement model .The Arabic DASH did not fit the Rasch measurement model initially (\u03c7Rasch measurement model supports the structural validity of the Arabic DASH as a unidimensional measure after the accommodation of local dependency. The disabilities of the arm, shoulder and hand (DASH) is a commonly used region-specific patient-reported outcome measure (PROM) that quantify upper extremity function (activity limitation) and symptoms . Early eThe measurement properties of the Arabic version of the DASH has only been tested in one single study . AlotaibThe consensus-based standards for the selection of health measurement instruments (COSMIN) defines structural validity as \u201cthe degree to which the scores of a health-related patient-reported outcomes instrument are an adequate reflection of the dimensionality of the construct to be measured\u201d . EstabliIn addition to the unestablished dimensionality of the Arabic DASH, no prior studies examined the validity of the Arabic DASH 5 response categories, and whether the scale items function in a similar manner among subgroups of patients with different characteristics (measurement invariance). In contrast to classical test theory methods, Rasch measurement model provide unique opportunity to examine the Arabic DASH structural validity and to examine the validity of the rating scale and also to examine its measurement invariance across important clinical characteristics \u201322. TherParticipants in the current study were recruited from two outpatient physical therapy departments in Riyadh city using convenience sampling. Patients with upper extremity musculoskeletal disorders were recruited if they were 18\u00a0years of age or older. Potential participants were excluded if they were unable to read or understand Arabic language, or if they had any neurological disorder. Participants were also excluded if they had spinal surgery or disorder, cardiopulmonary disorder, or neurological disorder that were perceived by the patients as functionally limiting. Ethical approval for the study was obtained from the ethical committees at the participating institutes. Participants signed informed consent forms prior to participation. Two licensed physical therapists and one licensed occupational therapists with cumulative clinical experience of 20\u00a0years collected the data.Participants were asked to complete the Arabic DASH during their initial visit to the physical therapy department where they were seeking care for their upper extremity disorders. The Arabic DASH is 30-item region-specific PROM. Each item was scored on 1  to 5  scale . Items rPartial credit model  was usedThe required sample size was determined based on the COSMIN guidelines . A samplOne hundred and nine participants with upper extremity disorders were enrolled Table  Table 22. Fifty Initially, Rasch analysis suggested that the Arabic DASH deviates from the Rasch measurement model as indicated by the significant chi-square statistics for item-trait interaction and the high standard deviations for item and person fit residuals Table . The iniAfter removing the misfitting patients in the second run, the Arabic DASH still did not satisfy the requirement of the Rasch measurement model showing significant chi-square statistics for item-trait interaction and its unidimensionality was not supported Table . At this2\u2009=\u20092.55, p\u2009=\u20090.280)   was the only item that had missing responses (no response). In the Arabic DASH, item 21  was the only item that was labeled as an optional item which might explain why only this item had missing responses. Given that item 21 cover sensitive issue , cultural factors might have also contributed to some missing responses to this item. The optional nature of the item and the high missing rate led to the removal of the item 21  before conducting Rasch analysis in the current study.After removing misfitting patients, Items 30 (confidence), 26 (tingling), and 29 (sleep) were misfitting based on their fit residuals and chi-square statistics. This indicate that the behavior of these items did not follow the expectation of the Rasch measurement model. The non-conformity of these items to the Rasch measurement model suggests that these items do not belong to the major underlying trait measured by the majority of the scale items, upper extremity activity limitation. The violation of local item independence observed in the current study might have driven these items to deviate from the measurement model . AlthougProper functioning of the scale response categories manifest as ordered coverage of the underlying continuum by the response categories where each response category becomes the most probable option in part of the continuum Fig.\u00a0. Under tThe Arabic DASH has major violation of local item independence indicating response dependency and multidimensionality , 33. TheSimilar to the residual correlation observed between activity-related items, impairment-related items also exhibited high residual correlation. This pattern of residual correlation might be an indicator of multidimensionality where these items represent an impairment-related dimension. Additionally, similar content might also explain some of the residual correlations among impairment-related items. Items 24 (pain), 25 (pain during activity), and 29 (sleep) for example inquire about pain severity and pain-related sleep difficulty. This enquiry about the same impairment might constitute the shared concept that lead to the high residual correlation even after the removal of the major underlying factor. Consistent with our findings, DASH has been reported to violate the requirement of local item independence. A pattern of high residual correlation similar to ours where activity-related item group together while impairment-related items group together has been reported in patients with various upper extremity musculoskeletal disorders , 36, 37.Rasch measurement model is a unidimensional model where the probability of being able to perform an activity is only governed by a single factor that is the person ability (level of upper extremity function possessed by the patient). We believe that the major breach of local item independence was the main reason explaining why the Arabic DASH did not satisfy the requirement of unidimensionality initially. After the accommodation of the local dependency by the creation of activity limitation and impairment testlets, The Arabic DASH satisfied the requirement of unidimensionality as suggested by the principal component analysis of residuals followed by the t-test , 33. AltThe Arabic DASH items seems to have no uniform or non-uniform DIF by age, sex, surgical status, or affected side. This suggests that the scale items behave in a similar manner regardless of the patient characteristics and that items were not biased to any of the levels of these characteristics . The lack of uniform and non-uniform DIF was also observed in the current study at the level of testlets suggesting that the testlets also are invariant to patients\u2019 characteristics. These measurement invariance results of the Arabic DASH at the item level and at the testlet level should be interpreted with caution giving the limited number of participants in each subgroup  and a foThis study represents the first attempt to examine the structural validity  of the Arabic DASH. Rasch measurement model pointed to areas of dysfunction in the behavior of the Arabic DASH items mainly local dependency between items that could not have been determined using classical test theory methods. The accommodation of the local dependency between items improved the internal structure of the Arabic DASH resulting in an interval-level unidimensional measure of upper extremity function. The results of this study would help in guiding future modifications of the scale aiming to improve its validity. Although the sample size used in the current is adequate for conducting Rasch analysis , it is aRasch measurement model supports the validity of the Arabic DASH as a unidimensional measure of upper extremity activity limitation and impairment after accommodating for local dependency between items. The total Arabic DASH score can be used in clinical practice and for research purposes to reflect the level of upper extremity activity limitation and impairment in patients with upper extremity musculoskeletal disorders."}
+{"text": "Residents of long-term care (LTC) facilities  have historically been vulnerable to feelings of loneliness and social isolation. Due to the COVID-19 pandemic, LTC facilities were required to restrict public access in March 2020. LTC communities were not prepared for the residents\u2019 increased socioemotional needs which arose because of the mandated facility lockdown. This study investigated ICT use in LTC facilities and how ICTs are being used by residents since the onset of the COVID19 pandemic. Seventy LTC administrators in South Carolina (12 nursing homes and 58 assisted living facilities) completed an online survey exploring ICT access and use in LTC facilities and whether access and use changed as a result of COVID-19. Administrators from fifty-three percent of LTC facilities reported purchasing ICTs for their residents to use for communicating with family members and telehealth since the onset of COVID-19. LTC administrators reported that using the ICTs helped residents to socialize more frequently and feel more socially connected to their family members, friends and/or other residents. Barriers to ICT use included staff not having time to assist residents with technology, broken technology, and residents not wanting to share technology. LTC facilities were not adequately prepared to support the socioemotional needs of their residents in the event of a federally mandated facility lockdown. Future research should investigate the ICTs available for residents\u2019 use in a national sample of LTC facilities and how LTC administrators adapted the ICTs available as a result of their experiences with COVID-19."}
+{"text": "Since the declaration of COVID-19 by the World Health Organisation (WHO) as a global pandemic on 11th March 2020, the number of deaths continue to increase worldwide. Reports on its pathologic manifestations have been published with very few from the Sub-Saharan African region. This article reports autopsies on COVID-19 patients from the Ga-East and the 37 Military Hospitals to provide pathological evidence for better understanding of COVID-19 in Ghana.Under conditions required for carrying out autopsies on bodies infected with category three infectious agents, with few modifications, complete autopsies were performed on twenty patients with ante-mortem and/or postmortem RT -PCR confirmed positive COVID-19 results, between April and June, 2020.There were equal proportion of males and females. Thirteen (65%) of the patients were 55years or older with the same percentage (65%) having Type II diabetes and/or hypertension. The most significant pathological feature found at autopsy was diffuse alveolar damage. Seventy per cent (14/20) had associated thromboemboli in the lungs, kidneys and the heart. Forty per cent (6/15) of the patients that had negative results for COVID-19 by the nasopharyngeal swab test before death had positive results during postmortem using bronchopulmonary specimen. At autopsy all patients were identified to have pre-existing medical conditions.Diffuse alveolar damage was a key pathological feature of deaths caused by COVID-19 in all cases studied with hypertension and diabetes mellitus being major risk factors. Individuals without co-morbidities were less likely to die or suffer severe disease from SARS-CoV-2None declared Pathological findings in the gastrointestinal tract have been reported to include segmental dilatation and stenosis of the small intestine.14Our objective was to present the histopathological findings following autopsy of 20 COVID-19 patients at the Ga-East Municipal and the 37 Military Hospitals in Accra, Ghana. We provide pathological evidence for better understanding and improved management of COVID-19 patients in Ghana.Ethical clearance with reference number 37MH-IRB IPN/MAST/402/2020 was received from the Institutional Review Board of the 37 Military Hospital. With few modifications to conditions required for carrying out autopsies on bodies infected with category three infectious agents, complete autopsies were performed between April 2020 and June, 2020, on twenty patients with either an RT-PCR confirmed positive COVID-19 results, or presumed cases but with a positive RT-PCR at autopsy. Post-mortems were performed (on average 2 days after death) following WHO guidelines for Infection Prevention and Control for the safe management of a dead body in the context of COVID-19.9/L). She later developed respiratory distress. Almost all the patients had co-morbid conditions. Details of patients' clinical presentation are summarized in Table 1Twenty patients of age between 20 years and 79 years who tested positive for COVID-19 prior to or after death are presented. There was equal proportion of males and females. Thirteen (65%) of our patients were 55years or older with the same percentage (65%) having Type II Diabetes Mellitus (DM) and/or hypertension (HPT). Most of these patients presented with respiratory symptoms of varying severity with decreased saturation on intranasal oxygen  involving both the larger and smaller pulmonary artery branches of the lungs in some patients  in keeping with hypertensive heart disease. There was an isolated case of a patient with an atrial myxoma (Case 12) who had a friable soft gelatinous mass measuring 45x30mm attached to the anterior wall of the left atrium, 12mm above the annulus of the anterior leaflet of the mitral valve. This was consistent with the antemortem clinical diagnosis. Again, this patient had isolated dilatation of all the chambers of the heart except the left ventricular chamber. In this patient and another (Case 14), there were areas of scaring in the left ventricle suggestive of previous myocardial infarction.The liver was heavy and showed fatty change in most patients. In general, however the liver was moderate to severely congested in all patients though no other significant pathology was found except in a pregnant patient who had a subcapsular bleed (Case 4).The kidneys showed no significant changes in most patients except one in whom the kidneys were small in size and showed coarsely granular subcapsular surface (Case 7). There was a patient with an adrenal adenoma (Case 19) and another with a cystic mass in the brain (Case 5) but no other patient had any significant findings in the brain. There were no other significant findings in any other organs.The most significant findings on histopathological examination were respiratory, in agreement with the gross findings. Sections from patients' lungs showed severe edema within the lungs , sometimOther organs such as the heart in Case 1 showed thickened myocytes and a thrombus within a coronary vessel but without evidence of an infarct . There wSignificant histological findings in the liver included severe macrovesicular steatosis of the hepatocytes with moderate mononuclear inflammatory cell infiltrates in the portal tracts.Our experience revealed that prior to autopsy, most bodies were sub-optimally preserved. This was due to delays in removing bodies to the autopsy suite because there were protocols in place that needed to be followed in order to avoid spread of the infection. The very warm, humid environmental conditions at that time of the year also contributed to the rapid deterioration of some of the bodies. In addition, all the bodies needed to be sprayed with chlorine as a disinfection practice stipulated by the accepted protocols for managing deaths from COVID-19. In order to obtain the best results from histopathological examination however, bodies and thus internal organs needed to be well preserved. It therefore took between 9 and18 hours before the bodies were put into the fridge. Then again, the autopsies had to be done in a timely manner while observing laid down autopsy protocols for carrying out autopsies on category-3 and 4 infectious organisms such as SARS-CoV-2. To achieve this, bodies of deceased patients had to be removed in a timely fashion to the COVID-19 theatre in the autopsy suite for examination.In relation to category 3 and 4 infectious organisms, there is currently no working, completely well-equipped autopsy suite in Ghana for carrying out such autopsies. The structural design of our autopsy suites lacks the negative pressure systems with filters recommended by the WHO.There was equal proportion of males and females in the cases presented. Thirteen 65%) of the cases were 55 years or older, a finding that is consistent with worldwide reports on COVID-19 deaths which consistently report deaths in older people who also tend to live with comorbidities.% of the Forty percent 6/15) of our cases that had the nasopharyngeal swab test before death had negative results for COVID-19 but had positive results at post-mortem. This is consistent with earlier reports that broncho-alveolar lavage specimen is more sensitive than the nasopharyngeal swab. of our cSevere COVID-19 disease is characterized histopathologically by DAD with deposition of HMs that result in diffusion-perfusion mismatch in the lung characterized clinically by Acute Respiratory Distress Syndrome (ARDS) in which there is respiratory hypoxemia that is refractory to oxygen.5Additional pathological features that have been reported in the lung include reactive hyperplasia limited to some type-II pneumocytes and patchy inflammatory changes with scattered multinucleated giant cells.A number of our patients had pulmonary thromboemboli within both the major pulmonary artery branches and smaller pulmonary artery branches (70%). The role of stasis, endotheliitis and other factors that affect susceptibility to thrombosis in relation to COVID-19 infection needs to be properly studied in order to understand the causal role played by COVID-19 infection. However, the prominent role of endotheliitis in COVID-19 infection related thrombosis has been reported with suggestions that infection with SARS-CoV-2 results in endotheliitis in several organs from their involvement by the virus and as part of the host inflammatory response. It is believed that a strategy that targets endotheliitis in susceptible patients is likely to improve survival in such patients.Pathological features in other organs including the liver and heart were less significant with mostly a confirmation of pre-existing hypertensive heart disease or fatty liver as in other reports.The majority of the patients autopsied had pre-existing medical conditions with the commonest being HPT and DM. The most significant pathological feature of the patients who died of COVID-19 was DAD. A management approach that recognizes early onset ARDS/DAD and aggressively treats or prevents further damage to the lung may improve the survival of patients."}
+{"text": "Marinaccio and colleagues are applauded for providing valuable data on the risk of acquiring COVID-19 due to exposure in the workplace in Italy.Although this number is much lower compared to claims received in Italy reported by the Italian Workers\u2019 Compensation Authority, in the Netherlands, COVID-19 was the 2nd most common occupational disease reported from March-September , exceed only by mental illness 42%). Musculoskeletal disorders accounted for 19%. This percentage is consistent with their estimate of 30% of reported occupational COVID-19 cases in the working age. Most Dutch occupational COVID-19 cases were reported within the nurse and caring homes  and hospitals , which is in line with the 70% reported for healthcare workers in Ontario Canada.2%. MuscuBoth approaches in assessment and reporting of occupational COVID-19 cases have own (dis)advantages. Compensation claim data may be biassed by the financial need of a workerRecording of occupational diseases is of additional value in developing preventive measures in the workplace. To enable comparison of notification approaches used in different countries, harmonisation of epidemiological surveillance systems and case definitions such as currently done by the OMEGA-NET initiative"}
+{"text": "Arora et al.; Foster; Speziale and Pietrocola), serine rich repeat proteins , antigen I/II proteins , NEAT motif containing proteins  and streptococcal fimbriae/pili .The surfaces of Gram-positive bacterial cells are decorated with a diverse array of proteins including a large group that are covalently anchored to peptidoglycan by sortases. Several types of sortase-anchored proteins can be differentiated on the basis of their structures. Notable examples reviewed in this special topic include MSCRAMMs . Lipoproteins are anchored to the outer surface of the cytoplasmic membrane via membrane lipids . Other non-covalently anchored surface proteins including moonlighting cytoplasmic proteins and extracellular vesicles are not reviewed here.Many proteins that are located of the surface of Gram-positive pathogens and not anchored covalently. Staphylococcus aureus , surface proteins of Staphylococcus epidermidis (Foster) and pili of Streptococcus pneumoniae and Streptococcus pyogenes . Others describe protein families spanning different species/genera including proteins related to the biofilm associated protein BAP of S. aureus , polymer adhesion domain containing proteins  and collagen binding proteins .Some articles review specific protein types drawn from a single species for example fibronectin binding proteins (FnBP) of Pickering and Fitzgerald).An emerging theme is that a single protein can often carry out multiple functions. Proteins that are exposed on the surface of bacterial cells are in direct contact with the host and are subjected to selective pressure to perform functions related to colonization of host tissues and evasion of host defenses. The repertoire of proteins is limited so many have evolved to adopt multiple roles. Amino acid sequence variation can help explain niche and host specialization and why some murine models of infection are limited . An important recent discovery is that binding of MSCRAMMs to their ligands is strengthened by shear forces to the extent that the force required for separation is equivalent to that required to break a covalent bond (Dufr\u00eane and Viljoen). This is reminiscent of catch bonds of pili of uropathogenic Escherichia coli binding the urinary tract epithelium.The defining structural feature of MSCRAMM family is two adjacent IgG-like folded domains that bind ligands by the dock lock latch (DLL) or collagen hug mechanisms . The A domain also binds plasminogen and histones by non-DLL mechanisms and engages in homophilic interactions that promote biofilm formation. These ancillary functions contribute to pathogenesis and immune evasion. The C-terminal repeat region forms an unfolded flexible stalk that engages fibronectin by a tandem \u03b2-zipper mechanism.The N-terminal A domains of FnBPs of S. aureus that bind collagens by the shear force-enhanced collagen hug mechanism and a subset of M proteins of S. pyogenes including those that carry the peptide associated with rheumatic fever in their N-terminal hypervariable domain . There are three other less well-defined groups including the V region PAD of streptococcal antigen I/II proteins .The ability to bind collagens is an important feature of many Gram-positive bacterial pathogens. There are two well-known structural classes of collagen binding protein namely the MSCRAMM proteins related to CNA of J\u00e4rv\u00e5 et al.). PADs have been classified into groups based on structural similarities and functions. PADs can bind a diverse array of carbohydrate ligands such as glucans and dextrans, lipoteichoic acids and DNA. They can promote adhesion, cell aggregation, and plasmid conjugation. The ligand binding domain V of the antigen I/ll proteins of oral streptococci are class II PADs that binds protein ligands such as collagen and fibrinogen, promotes adhesion to the surface of epithelial and endothelial cells, and stimulates cellular aggregation and biofilm formation .A structural motif that is widespread among surface proteins has herein been named the polymer adhesin domain (PAD) . It has recently been recognized that the cell-cell aggregation and the accumulation phases involve surface proteins forming amyloid fibers in the biofilm matrix. This occurs with the BAP protein of S. aureus , the accumulation associated protein Aap of S. epidermidis (Foster) and the SraP protein of Streptococcus mutans .Surface proteins are involved in both the primary attachment and accumulation phases of biofilm formation .Some Gram-positive pathogens express filamentous surface appendages called fimbriae/pili that are assembled and anchored to the cell surface by sortases. As pili are extruded from the bacterial cell subunits are covalently linked to each other by sortase-catalyzed isopeptide bonds. Structural analysis of pilins revealed intramolecular isopeptide bonds. P1 pili of S. pyogenes pili are responsible for the T serotyping scheme. These diverse pili can be categorized into nine different forms based upon heterogeneity of the encoding loci and sequence differences (Nakata and Kreikemeyer). Pili contribute to tropism for the skin or the nasopharynx. This is supported by enhanced expression at temperatures below 37\u00b0C that occur at these superficial niches. A novel feature of one of the minor pilins is to harpoon host ligands by formation of covalent thioester bonds.Antigenic differences in Chan et al.). The variable binding region (BR) is sandwiched between serine rich regions at the N-terminus and the longer C-terminal region. The BR of the Srr1 protein of Streptococcus agalactiae comprises an MSCRAMM motif that binds fibrinogen and keratin by DLL and contributes to adhesion to endothelial cells and vaginal epithelial cells promoting endocarditis and vaginal colonization, respectively. Both Srr1/2 and PsrP of S. pneumoniae play important roles in the transition from the commensal carriage state to invasive infection.Several species of streptococci express large serine rich repeat proteins that are heavily glycosylated by cognate glycosyltransferases (S. aureus and Staphylococcus lugdunensis encode iron regulated surface determinant (Isd) systems characterized by surface anchored proteins with NEAT motifs . These bind hemoglobin (Hb) and extract bound heme by forcing conformational changes in Hb. It is postulated that Isd proteins form protein wires that relay heme from the cell surface though the peptidoglycan to the membrane transporter.Pathogenic bacteria need a source of iron when growing in the host in order to overcome nutritional immunity. Nguyen et al.). The protein parts assist in nutrient acquisition, have chaperone activity, promote invasion of host cells and conjugation. When released from the bacterium the lipid moiety activates TLR2 pathways in host cells triggering inflammatory responses.The special topic also considers some non-covalently anchored surface proteins. All Gram-positive pathogens express lipoproteins that perform a multiplicity of functions (Ravi and Fioravanti). This includes localizing conserved domains involved in S-layer assembly and folds that promote attachment to cell surface polysaccharides. S-layer proteins are excellent candidates for future translational studies in diagnostics, therapeutics and vaccines.Recent structural studies provide insights into the S-layer and S-layer associated proteins . Staphylococcal IsdB proteins have a higher affinity for human hemoglobin than for the mouse protein which compromizes the study of virulence in murine infection models. Host specificity is also conferred by MSCRAMMs binding to the variable \u03b1-chain of fibrinogen (Fg). The ClfB protein of S. aureus binds to a human specific sequence and has very low affinity for canine Fg. In contrast the SpsL protein of Staphylococcus pseudintermedius binds strongly to the canine Fg \u03b1-chain and weakly to the human version. By manipulating a key adhesin/invasin-ligand interaction it is possible to create infection models that more closely resemble the human disease. Internalin A (InlA) binding to E-cadherin is key to invasion of the intestinal epithelium by Listeria monocytogenes. Transgenic mice expressing human E cadherin in the intestinal epithelia could be infected orally whereas wild-type mice are resistant. Conversely by altering residues in InlA to strengthen binding to murine E-cadherin it was possible to \u201cmurinize\u201d the pathogen.Surface proteins can confer specialization for different hosts as well as colonization of specific niches within the host (In conclusion this special topic provides a comprehensive and up-to-date summary of many important aspects of proteins that are located on the surfaces of Gram-positive bacterial pathogens and provides a useful starting point for anyone who wishes to obtain an overview of this important topic.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Eukaryotic cells are characterized by their exquisite compartmentalization resulting from a cornucopia of membrane-bound organelles. Each of these compartments hosts a flurry of biochemical reactions and supports biological functions such as genome storage, membrane protein and lipid biosynthesis/degradation and ATP synthesis, all essential to cellular life. Acting as hubs for the transfer of matter and signals between organelles and throughout the cell, membrane contacts sites (MCSs), sites of close apposition between membranes from different organelles, are essential to cellular homeostasis. One of the now well-acknowledged function of MCSs involves the non-vesicular trafficking of lipids; its characterization answered one long-standing question of eukaryotic cell biology revealing how some organelles receive and distribute their membrane lipids in absence of vesicular trafficking. The endoplasmic reticulum (ER) in synergy with the mitochondria, stands as the nexus for the biosynthesis and distribution of phospholipids (PLs) throughout the cell by contacting nearly all other organelle types. MCSs create and maintain lipid fluxes and gradients essential to the functional asymmetry and polarity of biological membranes throughout the cell. Membrane apposition is mediated by proteinaceous tethers some of which function as lipid transfer proteins (LTPs). We summarize here the current state of mechanistic knowledge of some of the major classes of LTPs and tethers based on the available atomic to near-atomic resolution structures of several \u201cmodel\u201d MCSs from yeast but also in Metazoans; we describe different models of lipid transfer at MCSs and analyze the determinants of their specificity and directionality. Each of these systems illustrate fundamental principles and mechanisms for the non-vesicular exchange of lipids between eukaryotic membrane-bound organelles essential to a wide range of cellular processes such as at PL biosynthesis and distribution, lipid storage, autophagy and organelle biogenesis. The CO2 biomass . While cIn 2013, the Nobel prize in Physiology or Medicine was awarded for \u201cthe discoveries of machineries regulating vesicle traffic, a major transport system in our cells.\u201d The Rothman, S\u00fcdhof and Schmekan groups characterized the molecular machineries and mechanisms for the energy-dependent vectorial transport of macromolecules between membrane-enclosed organelles through their encapsulation into small membranous vesicles. Their work proved the hypothesis originally posited by the 1974 Nobel laureate George Emil Palade . While vsans\u201d vesicles is assisted or catalyzed by proteins and protein complexes that function as exchange factors between heterotypic membranes. MCSs in yeast and human cells have been extensively imaged in vivo to characterize their morphology, size, cellular repartition and dynamics , have emerged as major platforms for the exchange of lipids and other molecules and signals  within the eukaryotic cell but also the regulation of many other complex biological pathways . This trdynamics ; they cadynamics . The ave in vivo  in yeast in vivo .In the eukaryotic cell, making and distributing PLs requires sharing. As a central player in the biosynthesis of lipids and membrane proteins, the ER contacts virtually all other organelles from mitochondria, Golgi to lipid droplets (LDs), vacuole/lysosome and endosomes. Lipids and in particular PLs are important to many aspects of cellular life. They are the main components of biological membranes defining the very boundaries of cells and their organelles where their physicochemical properties determine the fluidity, plasticity/rigidity, permeability and shape/curvature of these membranes. They also serve as energy stores  or signaling molecules . While some of them are consumed for the purpose of fueling and maintaining cellular energetics, lipids also play essential regulatory roles by affecting the structure and function of membrane proteins ; for exaProtein Data Bank (www.rcsb.org) and the Unified Data Resource for 3D-EM (www.emdataresource.org) and are referenced with their identifiers throughout this review.Organelle membranes have very distinct lipid compositions  as a resTakeout and BPI/CETP subgroups. Takeout and similar proteins such as the Juvenile Hormone Binding Protein (JHBP) serve as hydrophobic ligand carriers in the hemolymph of insects  proteins, mammalian OxySterol Binding Protein (OSBP) and Oxysterol-binding Related Proteins (ORP) proteins form another large LTP protein family . At leasAlthough not all LTPs are present at MCSs they all function by extracting/releasing lipids from and into membranes and shielding them from the aqueous phase by burying them in their protein core during the transfer step between the donor and acceptor organelles. The structural diversity of LTPs also translate into a certain diversity of their mechanisms of action. Mechanisms of non-vesicular transfer of lipids by LTPs roughly fall into three classes simplistically described in Others LTPs are tubular-shaped  with a hydrophobic tunnel seemingly suited for the channeling of lipids from one end to the other by lipid sliding . PLs beaprotein bridges or tunnels such as Vps13 and Atg2 that will be discussed in -tethers are much larger  and elongated (\u223c200\u2013400\u00c5) proteins: Their lipid transfer domains extend beyond their small lipid-binding signature Chorein-N motif  mitochondrial shuttle illustrates the basic principles for how a soluble LTP confined between two closely apposed membranes at a MCS can function as a \u201csimple\u201d shuttle without the need of being physically tethered to one or both membranes to promote efficient vectorial transfer of a PL along its concentration gradient. Ups1 is the LTP subunit while Mdm35 is a regulatory subunit controlling mitochondrial import of Ups1, its sensitivity to proteolytic degradation and its affinity towards membranes during the PA transfer cycle . A seconWhile the vectorial efficient transfer of PA by a soluble LTP such as Ups1/Mdm35 operating in the constrained and \u201cclosed\u201d MIMS compartment is simple to conceptualize, other shuttle systems working in the context of more \u201copen\u201d MCSs in the cytosol function with equal efficiency but use tethering to localize and target the transfer process to a specific MCS. Several variations of the simple direct diffusion LTP model exist: The LTP domain is directly tethered to one or both membranes at the MCS, one or several membrane-associated adaptor(s) can tether the LTP domain to the MCS and combinations of these two models have also been observed ; adaptorThe role of mitochondria-associated membranes in lipid trafficking in yeast (and later in metazoans) has been described several decades ago . Since tin vitro . So far, the mechanistic importance and roles of the two-fold symmetry displayed within the Mdm12-Mmm1 tetramer remain unclear.SMP domains are exclusively associated with MCSs ; howeverin vitro  while the two dimerized SMP domains shuttle glycerophospholipids between ER to PM along their concentration gradients. Based on these biophysical and structural data, it is thought that E-SYTs transfer lipids using an extraction-sliding-diffusion-release model where linker lengths and protein dimensions provide the necessary conformational freedom but preclude a transfer by direct bridging of the two organelles by the dimer of tubular SMP domains  validate the presence of the SMP fold in Mdm34. In vitro biochemical studies , in regulating the number of ERMES foci  . In yeas unknown . Lastly, unknown . These oDrosophila and human Miro  in Metazoans . This reman Miro  provide man Miro   and the interaction with membrane-specific adaptor proteins binding at the C-terminal and N-terminal ends of the protein     .Chaetomium thermophilum Vps13  transport system (Lpt)   and the em (Lpt)  span theem (Lpt) . Transpoem (Lpt)  that ensem (Lpt) .de novo from the ER through protein-assisted desorption of lipids to form a separate oil phase in the aqueous cytoplasm. Phase transition in microdomains of the ER membrane are essential to the nucleation and growth of LDs. LD-organelle contact sites have distinctives features that set them apart from all other MCSs where proteinaceous tethers appose membranes but prevent their fusion. This is not the case for MCSs with LDs, in particular at the biogenesis stage, where the two membranes  bilayer(s) like all other eukaryotic organelles. The main function of LDs is to serve as storage compartment for fatty acids. Neutral lipids  and sterol-esters (SEs)) stored in LDs are used for energy and membrane biogenesis when fatty acids are mobilized either by lipolysis or lipophagy of LDs in yeast . LDs are bridges .and organismal levels. Seipins regulate ER-LD contacts and growth by stabilizing ER-LD contacts and facilitating the incorporation of proteins (lipid biosynthetic enzymes) and lipids into the growing LDs (Drosophila melanogaster (Dm) (Homo sapiens (Hs)  with dramatic consequences on health. Thus, seipin regulates lipid storage at the cellular wing LDs . The cryter (Dm)  and Homoens (Hs)  were theens (Hs) ; the domens (Hs) . The cryens (Hs) . The C2-l chains  suggestiA general model has emerged explaining the role of seipins in LD biogenesis at ER-LD contacts . BiosyntLDs do not constitute \u201cdead ends\u201d; following their formation at and separation from the ER membrane they establish many additional contacts with other organelles such as mitochondria, peroxisomes, lysosomes (vacuoles) and other LDs . In starin vitro systems with liposomes used as donor and acceptors of fluorescent lipids to monitor their LTP-mediated transfer either by dequenching or quenching of fluorescence; liposome flotation has also been used to characterize the affinity of LTP for membranes of specific compositions. Studies of the SMP domains of E-SYT2 , or ion-gradients  generating membrane potentials. Such transporters are opposed to channels that \u201conly\u201d facilitate the movement of molecules along an existing concentration gradient . Thus, transporters can function against concentration gradients while channels cannot . In moleTwo classes of integral membrane proteins participate in the transfer of lipids from one leaflet to another within the same membrane: scramblases and flippases/floppases. Technically they are not considered as lipid \u201ctransfer\u201d proteins as they do not shuttle lipids across an aqueous space between membranes. Their functional importance is considerable as they abolish  or establish  membrane asymmetry and contribute to lipid fluxes (in particular PS) at MCSs and within the cell through the formation of gradients between leaflets within a membrane and thus support the formation of lateral nanodomains not only within the membrane but also within leaflets  Figures. FlippasScramblases equilibrate lipid distributions between leaflets and thus dissipate lipid asymmetry in membranes; they are ATP-independent and follow energy potential gradients associated with a simple chemical concentration gradient or the membrane electric potential (resulting from charge distributions) . The firCompared to scramblases that facilitate lipid movements at rates of \u223c10,000 lipids/sec, flippases are much slower (\u223c2\u201325 lipids/sec) ; this isirreversible hydrolysis into PI by the ER-associated phosphatase Sac1 sets the directionality of these two cycles. OSBP has a higher affinity towards PI4P than the sterol so exchange of sterol for PI4P is facilitated at the Golgi; once the PI4P is shuttled to the ER, its hydrolysis acts as an energy sink, irreversibly driving this branch of the cycle. This counter-exchange mechanism is remarkable as it enables transport of cholesterol from the ER to enrich the Golgi. These latter examples underline the importance and complementarity of LTPs next to vesicular trafficking as LTPs by transferring lipids against their concentration gradients can counteract lipid homogenization resulting from vesicular traffic  thus lowering the activation energy associated with lipid desorption and transfer to the LTP core.In lipid exchange mediated by \u201cbasket\u201d-shaped LTPs that shuttle lipids back and forth by diffusion or tethered diffusion, the rate-limiting step for the transfer of a lipid from one membrane to another is the extraction or desorption from the membrane itself rather than the LTP-assisted transport . SpontanRedundant yet slow and insufficient? When a lot is not enough. Based mostly on in vitro reconstitution studies and measurements, at the single protein molecule level these systems appear quite slow (\u223c1 lipid/sec at best) and likely involved in local adjustment/tweaking of the lipid composition of membranes. For example, in vitro, Osh4 transports sterol or PI4P (in absence of their counterpart) at rates \u223c 2 lipids/min; however, when both two lipids are present, Osh4 counter-exchanges them at rates of \u223c 20 lipids/min (in vitro or in vivo) have to be considered. In the case of ERMES and lipid exchange at yeast mitochondria-associated membranes, Petrungaro and Kornmann attempt to address these discrepancies (\u223c500 fold difference) to reconcile Biology with the apparent insufficiency of measured lipid fluxes , \u201cmetabolic\u201d diseases  and cancer  in proteins in the formation of membrane-less organelles in the introduction; this theme in Biology has received more attention in the recent years. IDRs in soluble or membrane-bound proteins might also play a role in controlling protein segregation, dynamics and orientation in or near crowded membrane environments. A N-terminal 90-residue long IDR in OSBP controls the orientation and dynamics of OSBP at ER-to-Golgi MCSs  and prevand protein-RNA association drive PB formation through LLPS. The proteinaceous machinery that controls PB assembly and partitioning from the cytoplasm is conserved between yeast and humans  and other advanced cellular imaging methods improving resolution and sensitivity in the last decade, more complex MCSs with their associated tethers, LTPs and scaffolding regulatory factors will become tractable targets for structural and cell biologists, promising further insights into the architecture of the eukaryotic organelle network and a better understanding of diseases linked to dysfunctional MCSs."}
+{"text": "In disease states, mesothelial cells are exposed to variable osmotic conditions, with high osmotic stress exerted by peritoneal dialysis (PD) fluids. They contain unphysiologically high concentrations of glucose and result in major peritoneal membrane transformation and PD function loss. The effects of isotonic entry of urea and myo-inositol in hypertonic (380 mOsm/kg) medium on the cell volume of primary cultures of rat peritoneal mesothelial cells and rat kidney outer medullary collecting duct (OMCD) principal cells were studied. In hypertonic medium, rat peritoneal mesothelial cells activated a different mechanism of cell volume regulation in the presence of isotonic urea (100 mM) in comparison to rat kidney OMCD principal cells. In kidney OMCD cells inflow of urea into the shrunken cell results in restoration of cell volume. In the shrunken peritoneal mesothelial cells, isotonic urea inflow caused a small volume increase and activated regulatory volume decrease (RVD). Isotonic myo-inositol activated RVD in hypertonic medium in both cell types. Isotonic application of both osmolytes caused a sharp increase of intracellular calcium both in peritoneal mesothelial cells and in kidney OMCD principal cells. In conclusion, peritoneal mesothelial cells exhibit RVD mechanisms when challenged with myo-inositol and urea under hyperosmolar isotonic switch from mannitol through involvement of calcium-dependent control. Myo-inositol effects were identical with the ones in OMCD principal cells whereas urea effects in OMCD principal cells led to no RVD induction. The maintenance of a constant cell volume in the face of extracellular and intracellular osmotic perturbations is an issue faced mainly by epithelial cells. Most cells respond to osmotic challenges by activating specific membrane transport processes that serve to return cell volume to its normal, initial value ,2. These2O), principal cells are the major cell population of the collecting ducts and are critical in mediating the fine tuning of urine solute and water concentrations i) during regulatory volume changes were assessed using the fluorescent probe Fluo4. Every tonicity change in the extracellular medium in our experiments disturbed the cell volume. In these instances, spikes of [Ca2+]i were observed as the cells were challenged by hypertonic medium that contained mannitol, or when the mannitol content of the medium was changed for either myo-inositol or urea with the same osmotic concentration. In the experiments with synchronized fluorescence profiles of calcein and Fluo-4, the concurrent changes in cell volume  and [Ca2+]i (Fluo-4) could be seen, demonstrating that the peaks of calcium correspond to the cell volume changes  or RVI (in case of cell shrinkage) . These mPD treatment is based on the infusion of glucose rich, hyperosmolar PD fluids in the peritoneal cavity in order to remove excess water together with ions and metabolic byproducts (such as urea). In this setting the peritoneal mesothelial cells are chronically exposed to fluctuating but persistently hyperosmolar conditions, a key factor of mesothelial cell degradation. Nonetheless their cell volume regulation properties have scarcely been studied. Under hyperosmolar stress MeT-5A mesothelial cells have lower water permeability than principal OMCD cells, mediated mainly by AQP1 function .We now demonstrate that parietal peritoneal mesothelial cells have urea and myo-inositol permeability, but at lower rates than principal OMCD cells. In both cell types the entry of urea is faster than that of myo-inositol and in both cell types myo-inositol gradients caused cell swelling and induced RVD. In contrast, urea induced similar reactions in peritoneal mesothelial cells, while the RVD response was absent in the principal OMCD cells, since they underwent a swelling process that allowed them to recover to their initial volume. The transport mechanism of urea in the principal OMCD cells is not well understood and it is not clear why RVD activation was not achieved, but it may be due to the fact that these cells are physiologically exposed to high urea concentrations and may have developed adaptative protection mechanisms that are not present in cells such as mesothelial cells.Another finding of interest is the comparable intracellular calcium response to the isotonic switch of osmolytes in both cell types. The short intracellular calcium spikes were similar. They reflect activation of calcium-dependent processes including some control cell permeability and cell volume regulation . This fiMyo-inositol intracellular concentrations increased progressively in mesothelial cells in response to hypertonic stress, similar to PD conditions. At the molecular level this occurs by increasing the levels and activity of the sodium/myo-inositol cotransporter . The higWe provide the first evidence that peritoneal mesothelial cells under isotonic switching in hyperosmolar conditions exhibit significant RVD reactions in response both in the case of myo-inositol and urea. Myo-inositol effects were identical with the ones in OMCD principal cells, whereas urea effects in OMCD principal cells led to no RVD induction. Future studies should aim at identifying the molecular counterparts of these fast processes and the translational potential of these findings in disease settings and treatments such as PD."}
+{"text": "Cognitive decline is a precursor to cognitive impairment and dementia. Recent research suggests that cognitive decline may begin earlier in the life course for Blacks and that Black-white disparities in cognitive function emerge in midlife. Disproportionate exposure to chronic and acute stressors during mid-life may explain Black-white differences in trajectories of cognitive function over time. In this study we use data from approximately 3,700 Black and white respondents age 51-64 from the Health and Retirement Study to examine race differences in cognitive decline and the role mid-life stress exposure play in these differences. Initial findings suggest that mid-life Blacks have lower levels of cognitive function, but their rates of cognitive decline do not differ significantly from mid-life whites. Financial strain and everyday experiences of discrimination are inversely associated with cognitive decline and only partially explain differences in cognitive decline between mid-life Blacks and whites."}
+{"text": "The rapid growth of the off-the-shelf smart speakers (such as Amazon Alexa and Google Home), also called Conversational Agents (CAs), creates potential to deliver everyday life support to users at home . Literature demonstrated the technology acceptance of CAs among older adults (including novice users) given the low barriers to use CAs. The natural conversations among CAs and users enable the opportunities to build deeper understandings about a topic through theory-driven guided dialogues. Our study has designed the metacognition strategies in the guided dialogues of CAs to support informal self-regulated learning of health information among older adults. The study has shown the feasibility and acceptance of CAs to help older adults learn new health information on their own through these guided dialogues. Additional analyses on the feasibilities to implement different metacognitive strategies in guided dialogues in the off-the-shelf CAs were also conducted."}
+{"text": "Skilled nursing facilities (SNFs) are on the front lines of changing policies regarding the COVID-19 pandemic. The most recent development is a potential vaccine mandate for staff working in SNFs. We use ongoing findings from 130 of 160 in-depth, semi-structured interviews in progress with administrators at 40 SNFs in eight diverse healthcare markets across the United States to understand the current landscape of COVID-19 in SNFs. Four repeated interviews at 3-month intervals provide a unique longitudinal perspective on the impact of COVID-19 and SNFs\u2019 response to vaccinations, including the vaccine mandate. Rigorous thematic analysis reveals insights into administrator responses and creative approaches to address vaccine hesitancy, and future expectations for SNF operations in light of the vaccine and the mandate. Administrators express cautious hope that the vaccine will allow SNFs to return to a new normal of daily life for residents in terms of family visitations, communal dining, and resident activities. Overriding questions include how to overcome persistent vaccine hesitancy from SNF staff who cite fear of side effects despite education initiatives and how to stem staff retirement or transition to other healthcare settings. SNFs represent a microcosm of the country\u2019s concerns as a whole. Insight into the evolving and complex dynamics shed important light on national trends and help provide solutions for moving forward. Findings from this study have implications for policymakers and SNF leadership as they consider ways to promote vaccination and retain staff amid vaccine mandates."}
+{"text": "We describe a unique case of bilateral acquired vitelliform lesions in a 67-year-old-female with pachychoroid associated with subretinal fluid in the right eye (OD) and a nonexudative choroidal neovascular membrane (CNVM) in the left eye (OS). Multimodal imaging performed at baseline and over the ensuing two years showed an increase in the OS vitelliform lesions with a concurrent transformation of quiescent CNVM to an exudative form. Further studies are warranted to gain better insight into the etiopathogenesis of these vitelliform lesions in pachychoroid and their potential role in instigating CNVM activation. Acquired vitelliform lesions (AVL) are a focal or multifocal subretinal accumulation of autofluorescent material reported in various dystrophic, degenerative, paraneoplastic, toxic, and vitreoretinal interface disorders involving the macula . The natA 67-year-old lady with a history of hypertension, dyslipidemia, and ischemic heart disease presented to us with complaints of diminution of vision in the right eye for 1.5 years. Her best-corrected visual acuity (BCVA) was 20/40 in the right eye (OD) and 20/20 in the left eye (OS). OU anterior segment was normal. Fundus examination showed patterned retinal pigment epithelial (RPE) alterations in OD and nonspecific RPE changes in OS, seen better on multicolor imaging Figures . VitelliSerial infrared reflectance IR;  and SD-OThe purpose of this case report was to highlight the conversion of quiescent PNV to an exudative network with progressive deposition of AVL. We also illustrate the role of OCTA in detecting quiescent networks that are likely to be missed on dye-based angiography and for their periodic noninvasive monitoring. Additionally, intravitreal ranibizumab monotherapy can be successfully used to treat PNV in the presence of AVL.In the current case, there was presence of bilateral pachychoroidopathy with AVL deposition. One eye showed spontaneous resolution of the deposits while the other eye having PNV demonstrated recurrent deposition with the onset of exudation. Freund et al. had reported features of AVL eyes demonstrating the natural history and imaging characteristics of these lesions . 2.2% ofWe believe that in pachychoroid eyes, the dilated outer choroidal vessels with a resultant choriocapillaris compression led to a primary RPE dysfunction. This can alter the physiological homeostasis of the RPE and neurosensory retina causing poor phagocytosis of the shed outer segments that can accumulate over time as the vitelliform lesions. Spontaneous resolution may occur when there has been sufficient photoreceptor loss to allow for the normal mechanisms of photoreceptor outer segment turnover to \u201ccatch up,\u201d whereby RPE phagocytosis of the abnormal subretinal material may occur . This phAlthough many eyes having primary pattern dystrophy with vitelliform deposits are misdiagnosed as age-related macular degeneration (AMD), central serous chorioretinopathy (CSCR), or nonspecific RPE changes , the conIn conclusion, our case highlights the presence of vitelliform lesions in pachychoroid eyes. We noted the transformation of a subclinical PNV to an exudative one with progressive deposition of vitelliform lesions. To the best of our knowledge, this is the first case report to describe the simultaneous occurrence of these two pathologies, namely, PNV and AVL. More research is needed to ascertain whether the simultaneous occurrence of these two pathologies is linked to each other or is a mere coincidence."}
+{"text": "Our recent GWAS of a composite measure of physiological dysregulation (PD) in the Long Life Family Study (LLFS) found that the top genes associated with age-related changes in PD are involved in biological pathways relevant to maintaining neural networks and brain resilience. In our prior work, PD itself was linked to resilience-related traits. Alzheimer\u2019s disease (AD) is a heterogeneous trait and it may involve an accelerated decline in resilience with age as a contributing factor. We proposed that genes associated with aging-changes in PD and brain resilience may contribute to AD risk. We investigated interactions between SNPs in such candidate genes with AD in LLFS and Health and Retirement Study (HRS). Our analysis revealed significant interactions between SNPs in UNC5C and other genes with AD, in both LLFS and HRS. These findings support roles of genetic interactions with UNC5C gene  in AD."}
+{"text": "Left bundle branch block (LBBB) is an uncommon complication of myocardial perfusion imaging using Regadenoson, a vasodilatory agent. The mechanism is poorly understood at this time but could be related to ongoing ischemia. The use of a Regadenoson with the subsequent occurrence of LBBB could be a predictor of coronary artery disease or conduction abnormalities and should be understood by the physician to diagnose and risk stratify patients undergoing myocardial perfusion imaging properly. Myocardial perfusion imaging (MPI) stress test is performed using exercise or vasodilatory agents such as dipyridamole (a vasodilatory agent which achieves vasodilation through the activity of adenosine deaminase and phosphodiesterase) or Regadenoson . Regadenoson is also known to cause significantly higher peak, absolute and relative heart rates than dipyridamole during MPI. The incidence of exercise stress test-induced left bundle branch block (LBBB) is rare and reportedly occurs in approximately 0.5-1% of all patients undergoing exercise testing [We present a 56-year-old Caucasian male with a past medical history of hypertension and hyperlipidemia presenting with a one-month history of atypical chest pain. The patient specified that the pain was a burning sensation along the right side of the chest without aggravating or alleviating factors. The patient admitted to numbness and tingling of his right hand in an ulnar nerve distribution and denied shortness of breath. His social history was remarkable for chewing tobacco for over 50 years and a strong family history of myocardial infarction, stating his mother had two heart attacks before the age of 45.\u00a0With a baseline heart rate of 84, the patient subsequently underwent treadmill exercise stress testing and was found to have new-onset LBBB Figure  at a heaThe presence of LBBB on a resting electrocardiogram (ECG) and at low work levels on a stress test essentially exclude exercise-induced LBBB . EI-LBBBWhen LBBB occurs, it may produce a partially reversible or fixed septal defect on perfusion imaging . This peSome studies have documented a strong association between stress-induced LBBB and coronary artery disease (CAD) or heart failure . Such paLBBB is an uncommon complication of Regadenoson stress tests and should be recognized as it may predict the presence of CAD and the probability of permanent LBBB and conduction abnormalities. When this occurs, patients may benefit from CA to rule out existing CAD."}
+{"text": "OBJECTIVES/GOALS: The objectives are to assess the impact of cumulative grief on the development of Compassion Fatigue (CF) and Burnout Syndrome (BS) in HCPs who care for dying children. We will also evaluate the relationship between CF and cortisol patterns in HCPs. METHODS/STUDY POPULATION: Cross-sectional study to be conducted in a Pediatric Hospital in Puerto Rico. A sample of 50 pediatric nurses will be selected to collect the data to evaluate the occurrence of CF and BS among HCP caring for children during end of life (EoL). Study subjects will include nurses who care for dying children in the Intensive Care Units and Oncology ward. Nurses working in the pediatric ward will be included as the control group. Three validated instruments (Spanish Version) will be administered . Cortisol samples in saliva and hair will also be taken to determine levels in these HCPs. RESULTS/ANTICIPATED RESULTS: Our expected outcome is that CF and BS will be more frequent in HCPs caring for children during EoL compared with controls and that EoL nurses will have higher scores on CF scale and more frequent dysregulated cortisol patterns. DISCUSSION/SIGNIFICANCE OF IMPACT: Understanding how HCPs cope with grief caused by child death and the occurrence of CF and BO in our hispanic population allowing us to develop support strategies based on the specific HCPs needs. This knowledge will help improve HCPs\u2019 well-being and may diminish the physiologic impact on cortisol."}
+{"text": "Actin cytoskeletal dynamics drive cellular shape changes, linking numerous cell functions to physiological and pathological cues. Mutations in actin regulators that are differentially expressed or enriched in immune cells cause severe human diseases known as primary immunodeficiencies underscoring the importance of efficienct actin remodeling in immune cell homeostasis. Here we discuss recent findings on how immune cells sense the mechanical properties of their environement. Moreover, while the organization and biochemical regulation of cytoplasmic actin have been extensively studied, nuclear actin reorganization is a rapidly emerging field that has only begun to be explored in immune cells. Based on the critical and multifaceted contributions of cytoplasmic actin in immune cell functionality, nuclear actin regulation is anticipated to have a large impact on our understanding of immune cell development and functionality. The immune system is tasked with detecting and responding to harmful non-self and self- molecules through the cooperative action of different cells. Immune cells are among the most motile cells in the body which enables the rapid communication between leukocytes specialized in gathering information about pathogens and altered self with other leukocytes specialized in mounting effector responses in lymphoid organs as well as the delivery of these cells to the sites of inflammation. Thus, leukocytes continually change shape to adapt to their environment but also to communicate with other cells. For instance, at sites of infection chemokine and selectin receptors on the surface of circulating immune cells are engaged by factors released from the endothelial cells lining the capillaries. This causes leukocytes such as neutrophils and lymphocytes to roll on the activated endothelium and trigger outside-in activation of integrin molecules which stimulates the immune cells to slow down and stop . The immDefense against non-self pathogens is intuitively seek and destroy. Paradoxically, however, this same detection machinery is used to distinguish harmless non-self pathogens such as commensal bacteria leading to tolerance. Recent studies of have established the importance of immune cells\u2019 ability to sense the mechanical properties of their environment and a role for such mechanosenstion in fine-tuning the strength and outcome of immune cells\u2019 interactions with the environment and between cells . MoreoveImmune cells uniquely face the challenge of requiring a single cell or its lineage to have plastic differentiation potential, migrate and adapt to diverse environments . Here, wL270P and WASpI294T and increased activity of MRTF-A/MKL1 have further increased the understanding of actin regulators in the hematopoietic lineage cells  in which patients suffer from severe immunodeficiency caused by loss-of-function mutations in the hematopoietic specific WAS protein (WASp). WASp gave the name to the WASp family of actin promoting factors also containing the ubiquitously expressed neural WASp (N-WASp), the WASp-family verprolin-homologous protein/suppressor of the cyclic AMP receptor (WAVE/SCAR), WASp and SCAR homolog (WASH), and WASp homolog associated with actin, membranes, and microtubules (WHAMM) . The actge cells . Studiesmechanopresentation- the mechanical stimuli is presented to the cells, (2) mechanoreception- the ligand is engaged by the mechanoreceptor at the cell surface, (3) mechanotransmission- the signal propagates away from the ligand/receptor binding site and, (4) mechanotransduction- the mechanical stimuli is converted into a biochemical signal.Cells are exposed to normative and shear mechanical forces from their microenvironment. The complex interplay between such mechanical stresses and cellular behavior were brought to the forefront by pioneering observations that compliance or rigidity of a substrate that presents collagen affects the adherence and motility of differentiated epithelial and fibroblastic cells  and mesein vitro differentiation has been shown to negatively regulate the expression of C-type lectins, \u03b22 integrins as well as podosome formation leading to decreased antigen uptake . Using BMDCs from murine models of WASp, Fascin or HS1 deficiency, a role for WASp expression in this maturation response was also shown. Surprisingly, this study revealed that DC stiffness lowers the activation threshold for CD4 but not CD8 T cells  are expressed. Hematopoietic stem cells use this route to home and migrate into the bone marrow. the flow . Effectothe flow . Neutropthe flow . Marginathe flow . This shMechanoreception by the cell is mediated by cell surface receptors and ion channels and transmitted from these receptors by force induced conformational changes or alteration of receptor-ligand bond properties [reviewed in Mechanotransduction is the translation of mechanical stimuli sensed by the mechanoreceptor into biochemical signals which activates signaling pathways inside the cell via cytoskeletal remodeling. In a wide range of cells, the Ras homology gene family, member A (RhoA) pathway is activated in response to forces particularly downstream of integrin signalling and has been extensively studied in this context as it regulates both actin cytoskeletal changes and myosin contractility. When tension is applied, for instance, on \u03b15\u03b21 integrins, it promotes the binding of the fibronectin synergy motif leading to the activation of focal adhesion kinase (FAK)  and the Dysregulation of Rho GTPases is associated with cell transformation and immunodeficiency . RhoA isThe nucleus can sense mechanical stimuli from the environment through biochemical signal transduction from mechanoresponsive cell surface receptors resulting in nucleo-cytoplasmic shuttling of mechanoresponsive biochemical cues  or more The Myocardin Related Transcription Factor A (MRTF-A), also known as Megakaryoblastic leukemia 1 protein (MKL1) , is prob\u221716 resulting in the absence of MRTF-A in patient cells and severe migratory defects in patient\u2019s neutrophils (A homozygous nonsense mutation p.K723X in MRTF-A leading to a strongly reduced expression of the protein has been described in a patient presenting with severe immunodeficiency . The pattrophils .Another important pathway for mechanotransduction into the nucleus is the Hippo pathway that activates transcription by Yes-associated protein (YAP) and its paralog WW Domain-Containing Transcription Regulator Protein1 (WWTR1/TAZ) proteins . YAP andWhile there is increasing evidence for the role of the Hippo pathway in immune cells , the speApproaches for quantitatively studying the mechanical properties of the nucleus and for determining the relevance of various biomolecules in mechanotransduction have included nuclear deformation in response to controlled presentation of force at the plasma membrane and nuclear positioning during migration . During The LINC complex is composed of outer nuclear envelop membrane protein Nesprin containing the KASH  domain. The KASH domain interacts directly with inner nuclear envelop membrane SUN  proteins, that are anchored to the nucleoskeleton by interactions with the carboxyl terminus of Lamin A . VariousSomatic cells express Lamin A/C and Lamin B1 and B2. Genetic disorders that result in altered Lamin A expression or duplication of Lamin B result in human diseases and are collectively termed laminopathies . These din vitro. The preferred Treg cell differentiation of Lamin A deficient T cells was further confirmed using an in vivo model for inflammatory bowel disease in which Lamin A deficient T cells were protected from disease development  complex being the most studied . Out of In most of the remodeling complexes, actin serves in its monomeric state, often bound to different actin-related proteins . StudyinIn haematopoietic stem cells, WASH associates with the nucleosome remodeling factor (NURF) complex in the nucleus where the NURF complex binds to the promoter of the c-Myc gene, necessary for haematopoietic stem cell differentiation . The nucThe final stage of cell division, cytokinesis, is tightly coordinated during chromosome segregation and dependent on actin polymerization and depolymerization. At the terminal stage of cytokinesis, the daughter cells are connected by a thin cytoplasmic canal, the cytokinetic intercellular bridge, that is eventually cut in a complex process called abscission . In respThe importance of the abscission/NoCut checkpoint becomes apparent during cell transformation. Cancer cell genomes can contain multiple chromosomal rearrangements. During cell transformation to cancer cells, faulty metaphase progression can lead to presence of chromosomes in the cytokinetic intercellular bridge . ChromosElevated actin polymerization during mitosis is associated with genomic instability and cell transformation. Gain-of-function mutations of WASp in X-linked neutropenia patients lead to increased F-actin that abnormally localize around the mitotic spindle and chromosomes during their alignment and separation, and during anaphase accumulates within the cleavage furrow around the spindle midzone . This rein vitro and in vivo (Elevated F-actin in the cytoplasm is associated with increased cell viscosity leading to activation of mechanosensors such as Aurora A and B during mitosis. Aurora A and Aurora B jointly coordinate chromosome segregation and anaphase microtubule dynamics . Aurora  in vivo . On the  in vivo  and resc in vivo . Cells e in vivo . Increas in vivo . TogetheR62D-NLS mutant or the actin exporter exportin-6 results in a decreased volume of the daughter cell nuclei as well as an increase in chromatin compaction at mitotic exit (During mitotic exit, the nuclear volume of the two daughter cells is expanding in a process dependent on dynamic assembly of nuclear actin filaments enabling chromatin decondensation. Interfering with the polymerization-competent nuclear actin pool by overexpression of the non-polymerizable actintic exit . The postic exit . The nuctic exit . DepletiThe rapid development of biophysical and bioimaging tools to probe cell mechanics has enabled the study of mechanical properties in immune cells [reviewed in Understanding immune cell mechanosensing and nuclear actin function is likely to have direct clinical implications. Efforts using whole genome sequencing have revealed an increasing number of diseases caused by mutations in actin regulators. This subgroup of primary immunodeficiency diseases called actinopathies provide a unique opportunity to understand how deficiency in a specific actin regulator affects immune cells . The stuJR, MS, and TV wrote the manuscript. JR, MS, TV, PP, and LW edited the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "A growing literature seeks to understand the relationship between the experience of work and important later-life outcomes. Rich longitudinal measurement of both sides of this equation in datasets such as the Health and Retirement Study (HRS) have made this research possible. These data take the form of self-reported experiences of work . Increasingly, researchers are looking to add potentially complementary information on the work environment available in the Occupational Information Network (O*NET) database through a linkage using occupation and industry codes in the survey data. The session talks will describe research conducted using O*NET linked with HRS data as well as ongoing work to create a new data resource that will allow other researchers to undertake research with O*NET-HRS linked data. Each presentation will include some discussion of both the value and limits of using the linkage to O*NET. Carpenter will provide a detailed description a new project linking the 2019 O*NET data to the HRS for public use.This presentation explains the types of variables that will be made available in the O*NET-HRS occupation project and will provide examples for how the measures can be used in longitudinal HRS studies. Using O*NET-HRS linked data, Carr will present on work examining the role of preretirement job complexity in alternative retirement paths and cognitive performance. Helppie-McFall will used the linked data to discuss the role of mismatch between demands of work and workers\u2019 ability to meet those demands in retirement decisions."}
+{"text": "The differential diagnosis for a wide complex tachycardia includes all causes of supraventricular tachycardia (SVT) with bundle branch block or all causes of SVT with antegrade pre-excitation by bystander involvement of any accessory pathways, myocardial or bundle brunch ventricular tachycardia, and antidromic (atriofascicular or nodofascicular/nodoventricular) and other pre-excited reciprocating tachycardias. We present a case of wide complex QRS tachycardia with a left bundle branch block QRS morphology. A second wide complex QRS tachycardia with a QS pattern with a descending limb notching in lead V1 developed soon after . Later, a transient third wide complex QRS tachycardia was also observed. What is the mechanism of these tachycardias?A 45-year-old woman with recurrent wide complex QRS tachycardia was admitted to our hospital for an electrophysiological study. Echocardiography showed no structural abnormality; however, cardiac magnetic resonance imaging reported a patchy distribution of cardiac late gadolinium enhancement in the periaortic region. She had a clinically documented episode of wide complex QRS tachycardia with a left bundle branch block QRS morphology. During the electrophysiological study, the fragmented signals were seen on the His electrogram during tachycardia 2 Isolated periaortic substrates should also be suspected in patients with nonischemic cardiomyopathy with minimally depressed left ventricular ejection fraction without an overt scar or wall motion abnormalities presenting with VT with an inferior axis.3 Therefore, distinguishing between an antegrade His and a retrograde His is a critical step in the interpretation of wide complex QRS tachycardia cases.4 Antegrade activation suggests that the mechanism of the wide complex QRS tachycardia is a supraventricular tachycardia with aberrancy, whereas retrograde activation is consistent with either VT or antidromic tachycardias, including atriofascicular or nodofascicular/nodoventricular reentrant tachycardias.4 The dissociation of antegrade His signals from the ongoing tachycardia excluded the nodofascicular/nodoventricular or bundle branch participation in the current case . Furthermore, Figure 1 demonstrated a continuation of the tachycardia despite atrioventricular dissociation. This provided proof that the atrium was not necessary to sustain the tachycardia and ruled out the participation of accessory pathways.5 The principal unique maneuver in the differential diagnosis of the wide complex QRS tachycardia is the placement of sensed premature atrial extrasystole during the tachycardia, the pacing of the atrium faster than the tachycardia to entrain the tachycardia, and then the analysis of the return beats after cessation of pacing.6 In the current case, both early and late atrial extrasystoles did not affect the morphology and cycle length of the ventricular electrograms during tachycardias.8 Comparison of the QRS complexes between the tachycardia and those in sinus rhythm is also helpful as a QRS complex that is narrower during wide complex QRS tachycardia than during sinus rhythm establishes the diagnosis of VT .11The differential diagnosis for a wide complex QRS tachycardia includes all causes of supraventricular tachycardias with a bundle branch block, or all causes of supraventricular tachycardias with an antegrade preexcitation by bystander involvement of any accessory pathways, myocardial or bundle branch ventricular tachycardias (VTs), and antidromic (atriofascicular or nodofascicular/nodoventricular) and other pre-excited reciprocating tachycardias.. However, the first tachycardia converted to a second tachycardia without the completion of activation mapping. According to the characteristics of a QS pattern with a notch on the descending limb in lead V1 , the second VT was initially considered to be arising from the commissure between the left and right coronary cusps (L-RCC).14 We continued the mapping from the aortic cusps and detected the earliest ventricular activation with fractionated signals in the L-RCC region . Interestingly, this place was also the earliest ventricular activation point for the first wide complex QRS tachycardia . A third VT  was also seen, but it was infrequent. Pace-mapping from the L-RCC region with high and low voltages17 showed similar QRS morphologies with all three VTs and short and long stimuli (S) to QRS intervals, with most of them suggesting direct capture , and the capture via an insulated myocardial fiber across the ventricular outflow septum  . Therefore, all these three wide complex QRS tachycardias were thought to originate from the L-RCC with three breakout sites  compared to the localized reentry confined to this anatomically challenging region,20 suggesting the existence of preferential conduction from the L-RCC commissure to both the right and left outflow tracts. The first radiofrequency lesion below the L-RCC was suppressed transiently , but the application from near-field potentials taken above the L-RCC  terminated the tachycardia. Burst pacing and isoproterenol failed to elicit any further tachycardia. The other clinical VT was also no longer seen. This was a simple tracing, with multiple findings that instructively show the importance of both preferential conduction and the pacing threshold to define preferential conduction routes in the identification of successful ablation points.We started mapping from the right ventricular outflow tract due to the delayed QRS transition in the precordial leads"}
+{"text": "Mounting evidence that early life adversity (ELA) exposures confer risk for cardiometabolic disease over the lifespan motivated this narrative review to examine parenting quality as a potential intervention target to reduce ELA exposures or mitigate their impact as a way of reducing or preventing cardiometabolic disease. We describe findings from the limited number of family-based intervention studies in ELA-exposed children that have tested parenting impacts on cardiometabolic health outcomes. We then describe the implications of this work and make recommendations for future research that will move this field forward. Mounting evidence points to the toxic role of early life adversity (ELA) exposures such as family turmoil, stressful or traumatic events, and contextual stressors  in shaping cardiometabolic risk over the lifespan. In this context, it is imperative that we build our knowledge of potential interventions to either target the reduction of ELA exposures or to mitigate their impact as a means of reducing or preventing cardiometabolic disease. Given the large number of ELA exposures that have been identified as well as the intractable nature of their effects, much work remains to identify the type and delivery of interventions that would be most effective. In this narrative review, we examine the early emergence of cardiometabolic risk in childhood and the evidence relating ELA exposures to cardiometabolic health over the lifespan. We then provide a conceptual framework using attachment theory to highlight the potential role of parenting quality in mitigating ELA impacts on cardiometabolic health. Finally, we describe findings from the limited number of family-based intervention studies among ELA-exposed children that have tested parenting effects on cardiometabolic health outcomes and make recommendations for future research to move this field forward.Risk for adulthood cardiometabolic disease begins early in life  attachment relationships exhibit poor self-regulation, including maladaptive coping strategies in response to feelings of distress that paradoxically result in unresolved or further distress   study of vulnerable, low-income families, mothers and their children (11 years old) were randomized to a multifaceted family-based intervention versus control condition in which only the study assessments were administered  due to an identified risk in the home  were randomized to receive the Attachment and Biobehavioral Catch-up (ABC) intervention vs. control condition in which educational materials about child development were delivered . There is immense untapped potential in existing evidence-based parenting interventions that have already been developed to enhance outcomes in areas of child socioemotional well-being and parent-child relationships. These same interventions should be re-examined in relation to child health outcomes. Some examples of established parenting interventions include the ABC intervention mentioned above  program or other established home-visiting programs. MIECHV, described here to illustrate this potential, started in 2010 as a provision within the Affordable Care Act to provide states with resources for home visiting. Seventy-five percent of funds to the states are required to go to evidence-based home visiting programs. Currently, there are 18 programs listed as evidence-based (\u201cUS Department of Health and Human Services, Home Visiting Evidence of EffectivenessIn response to mounting evidence that ELA exposures confer risk for cardiometabolic disease, starting even in early childhood, we highlighted the role of parenting as a potential focus of intervention for the reduction of ELA exposures or their mitigation as a way of reducing or preventing cardiometabolic disease. Among the limited number of family-based intervention studies that examined cardiometabolic health outcomes in ELA-exposed children, significant intervention effects on health outcomes were mediated by improvements in parenting behaviors specifically, confirming the key role of parenting. These findings raise the profile of existing evidence-based parenting interventions that have primarily focused on child socioemotional and behavioral outcomes by identifying the opportunity to test these interventions in relation to child cardiometabolic health. Moreover, existing parenting interventions, if found to also benefit child health, have the potential for broad dissemination through home-visiting mechanisms such as the federally funded MIECHV program, making it plausible to reach the most vulnerable families in whom ELA exposures and cardiometabolic risk factors are disproportionately prevalent.MB developed the study concept and drafted the manuscript. SS and CB-L provided critical revisions. All authors read and approved the final version of the manuscript for submission.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The COVID-19 pandemic has exposed the fragile state of patient involvement in research. The involvement of the most vulnerable population (older people with dementia) in research was even more challenging. This presentation outlines challenges my research team encountered in patient-led projects (older people with dementia) and describes how we found creative strategies to set up and complete research during the time of pandemic. I will describe how the team applied collaborative participatory principles to engage a team with diverse backgrounds in the lockdown time to maintain research progress. Patient partners in my research team actively led recruitment, research planning and decision-making, team analysis and knowledge exchange. University students in our research team helped to make technology easy to use for our patient partners. The friendly, flexible and accessible exchange between students and patient partners reinforced the importance of a respectful relational approach in patient-oriented research."}
+{"text": "Online health communities (OHCs) have emerged as the leading venues for behavior change and health-related information seeking. The soul and success of these digital platforms lie in their ability to foster social togetherness and a sense of community by providing personalized support. However, we have a minimal understanding of how conversational posts in these settings lead to collaborative societies and ultimately result in positive health changes through social influence.Our objective is to develop a content-specific and intent-sensitive methodological framework for analyzing peer interactions in OHCs.We developed and applied a mixed-methods approach to understand the manifestation of expressions in peer interactions in OHCs. We applied our approach to describe online social dialogue in the context of two online communities, QuitNet (QN) and the American Diabetes Association (ADA) support community. A total of 3011 randomly selected peer interactions  were analyzed. Specifically, we conducted thematic analysis to characterize communication content and linguistic expressions (speech acts) embedded within the two data sets. We also developed an empirical user persona based on their engagement levels and behavior profiles. Further, we examined the association between speech acts and communication themes across observed tiers of user engagement and self-reported behavior profiles using the chi-square test or the Fisher test.P<.05) with 9 speech acts from a total of 10 speech acts  within the QN community. Only four speech acts  were significantly associated (P<.05) with the social support theme in the ADA community. The speech acts were also significantly associated with the users\u2019 abstinence status within the QN community and with the users\u2019 lifestyle status within the ADA community (P<.05).Although social support, the most prevalent communication theme in both communities, was expressed in several subtle manners, the prevalence of emotions was higher in the tobacco cessation community and assertions were higher in the diabetes self-management (DSM) community. Specific communication theme-speech act relationships were revealed, such as the social support theme was significantly associated (Such an overlay of communication intent implicit in online peer interactions alongside content-specific theory-linked characterizations of social media discourse can inform the development of effective digital health technologies in the field of health promotion and behavior change. Our analysis revealed a rich gradient of expressions across a standardized thematic vocabulary, with a distinct variation in emotional and informational needs, depending on the behavioral and disease management profiles within and across the communities. This signifies the need and opportunities for coupling pragmatic messaging in digital therapeutics and care management pathways for personalized support. Lifestyle risk factors, such as tobacco use, poor diet, and physical inactivity, play an essential role in chronic disease management . These hOnline health communities (OHCs) have gained popularity as venues for behavior change -17. ThesIn this paper, using the concepts drawn from pragmatics , we focuAlthough the majority of earlier works using pragmatics are in the general domain, in this paper we propose a methodological framework using speech act theory -29 and a(1) How are communication content and intent expressed in OHCs for behavior change and chronic disease management?(2) How is communication intent associated with self-reported user behavior and observed user engagement in an OHC?The proposed research was conducted in the context of two different OHCs: one for tobacco cessation and another for DSM.QuitNet (QN) is one of the largest OHCs promoting tobacco cessation amongst its users [ts users . The usets users . The datAmerican Diabetes Association (ADA) support community is an online support group for individuals who have diabetes  to engage with their peers as well as their caregivers [The regivers . The comBased on our prior research that focused on the qualitative analysis of digital communication from these OHCs ,39, we eWe conducted an in-depth qualitative analysis, in which we used directed content analysis  and discYES Cravings will go away!!! It\u2019s hard to believe, I didn't believe it either, but figured a zillion people here said they would and they were right!!! Just hang in, tough it out, stick head in freezer and breath deep and whatever you do, if any chance of slipping might creep up remember the 3 post rule!! Again, the Cravings are going to stop, it\u2019s going to be ok, I promise!!!cravings where the user who has posted the message is providing advice on how to deal with cravings and is providing specific instructions to the other user in the form of social support (communication theme) as to how they can deal with this issue. The user used a directive speech act, where the intention was to get one\u2019s peer to remember the three-post rule, where the user is encouraged to make a post if they are craving for a smoke and wait for at least three responses. The user also used an assertive speech act, where the user talked about their beliefs associated with cravings, such as \u201cCravings are going to stop.\u201dThis message has embodied an overarching theme of Communication themes and speech act codes were not mutually exclusive and may relate to multiple codes. Two independent researchers were involved in the coding process. Each coder used a qualitative coding schema to independently assign communication theme and speech act categories to a subset of messages by performing line-by-line analysis of every message using directed content analysis techniques . Each meWe manually developed an empirical user persona based on users\u2019 engagement levels and behavior profiles. We also reported their self-reported smoking status by manually analyzing the messages, leveraging the fact that QN community users tend to specify the number of days since they last smoked in their message postings as a form of tradition. From these data, we estimated the user abstinence status for a subset of users (n=254) and identified users as falling into one of the following categories: abstinent (status 1), non-abstinent (status 0), relapsed (status 1 to status 0), users who started their quit recently (status 0 to status 1), and users with no self-reported smoking status.Further, we constructed a DSM behavior persona for a subset of users  based on their self-reported forum signature and classified them as follows based on their DSM strategies and diagnostic features: (1) medication versus nonmedication users\u2014the users were differentiated based on whether they managed their diabetes with the help of medications, such as metformin (Glucophage) or insulin, from those who did not use any medications for self-management or had no mention of medication use in their self-reported signatures; (2) users with newly diagnosed T2DM versus users with advanced T2DM\u2014the users were differentiated based on whether they had a diagnosis of diabetes for less than 4 years (2017 or onward) from those that had had a diagnosis of diabetes for over 4 years (earlier than 2017); and (3) incorporation of lifestyle changes versus no incorporation of lifestyle changes\u2014the users were differentiated based on whether they had incorporated lifestyle changes, such as low-carb diets or exercise, into their daily routines from those who did not incorporate such changes or had no such mentions in their self-reported signatures.V to assess their correlation strengths. All statistical analyses were performed using the R programming language (using the stats package), and the significance level was P<.05.Further, the associations among user behavior and engagement profiles with speech acts and communication themes were evaluated by statistical analysis approaches, such as the chi-square test or the Fisher test, depending on the sample size. We also used the Cramer The qualitative analysis of the 3011 messages exchanged by QN and ADA community users provided insights into the nature of the thematic interest of the community users and the variance in the expression of intentions among them  and 3.traditions were quite popular in the QN community, such as bonfires, which is a virtual event in which users bring their unsmoked cigarettes and throw them into the fire, sharing stats with one another in the form of the number of days since they last smoked and celebratory exchanges upon meeting certain milestones, or pledges, which is a ritual in which users extend their hand to other community users to stay committed to abstinence. Messages describing incentives to not smoke (teachable moments), such as improved quality of life , better perception of everyday moments , reduction in health risks , were also common in the QN community. The QN community users also posted messages seeking help to fight cravings or making a confession to others about their relapse or obstacles that uninspired users to stay quit. Pharmacotherapy options in the form of gums and patches that helped users stay away from tobacco were also commonly discussed to help those struggling in staying quit.Community-driven pharmacotherapy). Anxiety issues or the inability to manage blood glucose levels within the desired range were the most commonly expressed obstacles among ADA community users (obstacles). The ADA community users also shared their progress via objective metrics, such as improved A1c values and adherence to healthy diets. Patient-reported outcomes were shared by ADA community users, such as higher blood glucose readings caused by beta-blockers.In the ADA community, medication-related conversations centering around the use of insulin (Lantus), metformin, etc, were quite prevalent . Similarly, stance and statement speech acts, for example, were often prevalent in the discussions outlining motivations to quit smoking (teachable moments). Declarative and directive speech acts, for example, were often used in the context of a user\u2019s progress with smoking cessation. The strength of association was highest for the desire speech act within the social support theme (Cramer V=.26), followed by the directive speech act within the social support theme (Cramer V=.20) and the declarative speech act within the traditions theme (Cramer V=.15); see The associations between all categories of speech acts and the five most prevalent categories of communication themes within the QN and ADA communities are shown in assertion speech act was mostly used in the context of a user\u2019s readiness to manage lifestyle behaviors that influence diabetes. The commissive speech act was often prevalent within the social support, readiness, and teachable moments communication themes. Messages conveying the user\u2019s experiences with hurdles (teachable moments) often contained expressive and stance speech acts. The social support theme often had higher prevalence of the emotion, expressive, and stance speech acts  and expressive (18%) speech acts compared to high- or medium-engagement users, which indicates that low-engagement users are willing to incorporate behavior change but somehow need more motivation to engage with other users of the community who have successfully quit. Emotion (37%) and declarative (28%) speech acts were more frequently expressed by high-engagement users compared to other engagement levels, showing how active users in the QN community play an essential role in providing emotional support to other users in this community. Statistical analysis showed that there is a significant association (P<.05) between the overall expression of speech acts and user engagement levels based on the counts of messages expressing different speech acts exchanged by individual user groups, while the overall strength of association is weak (Cramer V=.07). Post hoc analysis revealed that there is a significant association (P<.05) between the assertion, declarative, question, and statement speech acts and the user engagement levels in the QN community (see nity see .desire (6%) and declarative (17%) speech acts to a greater extent compared to other engagement levels. The high-engagement users of the ADA community provided directives (29%) to other users compared to other engagement levels, which indicates that these users might be able to appropriately guide other community users per users\u2019 concerns. High-engagement users within the ADA community were also quite opinionated as they expressed high levels of stance (22%). Statistical analysis showed that there is a significant association (P<.05) between the overall expression of speech acts and user engagement levels, while the overall strength of association is weak (Cramer V=.13). Post hoc analysis revealed that there is a significant association (P<.05) between the commissive, declarative, directive, and stance speech acts and the user engagement levels in the ADA community  and expressive (19%) speech acts. The other commonly occurring speech acts among abstinent users were assertion (18%), directive (17%), and statement (17%). The most highly prevalent speech act among non-abstinent users was directive (21%), and they also expressed themselves with the commissive (17%) and declarative (13%) speech acts through promises to themselves or the community. The other commonly occurring speech acts among non-abstinent users were emotion (13%) and statement (12%). The stance speech act was only expressed by abstinent users and had low prevalence (2%). The prevalence of the desire speech act was comparable across QN community users per their abstinence status\u20144% for abstinent users and 5% for non-abstinent users.The distribution of different speech acts by the percentage of messages exchanged per the QN community user\u2019s abstinence status is shown in assertion  and statement (both 38%). The other commonly occurring speech acts among medication and nonmedication users were directive , stance , and question . Regarding the distribution of different speech acts by the percentage of messages exchanged per ADA community users\u2019 diagnosis status  and statement . The newly diagnosed T2DM users had a higher prevalence of the stance (25%) speech act, while advanced T2DM users had a higher prevalence of the directive (29%) speech act. The users who incorporated lifestyle changes provided directives (29%) to others and also shared their health practices through the use of statements (40%). The users who incorporated lifestyle changes had a high prevalence of the assertion (54%), question (21%), and stance (26%) speech acts in their peer interactions compared with users who had not incorporated lifestyle changes  association between the expression of speech acts and abstinence status in the QN community. Similarly, there was a statistically significant (P=.03) association between the prevalence of various communication themes and abstinence status in the QN community. There was a statistically significant (P=.007) association between the expression of speech acts and lifestyle change status in the ADA community. This significance was also noted in the prevalence of communication themes and lifestyle change status within the ADA community (P=.001). The relationship strength between speech acts and abstinent status (Cramer V=.22) and between speech acts and lifestyle change status (Cramer V=.12) was weak. There was no significant relationship between the expression of speech acts and the ADA community users\u2019 medication or diagnosis status. Further analysis is required to identify the specific categories of speech acts that might contribute to these significant relationships.commissive speech acts formed only a small fraction of the discussion. Although we used the 10 categories of speech acts from Searle's taxonomy of speech acts, other studies have focused on only stance-taking intentions of complaining or disagreeing [self-praise speech act to understand how this speech act instills positive values among the smoking cessation community users [Our study focused on analyzing the speech acts embedded within the user communications in OHCs using the mixed-methods approach in order to gain an understanding of the factors contributing toward behavior change in the context of two health care domains, tobacco cessation and diabetes self-management (DSM). The study of communication intent to understand and model health-related user communications is not without precedent. For example, earlier research used a similar pragmatics-based discourse analytic framework to investigate the expression of empathy within a T2DM Facebook support group and found that empathy may be expressed and perceived differently depending on the user\u2019s perspectives . Similaragreeing  or relatty users . Howevercommissive statement  logically follows. Existing tobacco cessation interventions oftentimes target an individual\u2019s readiness based on their stage of behavior change  and havf change ,57. In adesire speech act in their communication with peers, reflecting on their needs to fulfill their self-management goals. However, most ADA community users with high engagement had a high prevalence of the directive speech act, which may reflect their ability to provide guidance to their peers, thus emphasizing the role of peer mentors and patient expertise [Significant associations between speech acts, communication themes, and user engagement within the two OHCs also suggest variances in preferred methods of expression and peer discussions, depending on the engagement levels of users. It is also interesting to note that ADA community users with low engagement had a higher prevalence of the xpertise . This prxpertise , which iquestion) were significantly associated with the social support theme within the QN community. Only a few speech acts  were significantly associated with the social support theme in the ADA community. As social support is delivered within the full range of speech acts, this indicates robust use of many different subtle forms of transmission, emphasizing how the messages are formed matters. Areas of differentiation in how these ideas are shared  indicate areas where coupling pragmatic action with message content has the potential for impact. The differences observed among online communities to discuss communication themes such as traditions, obstacles, and patient-related outcomes also highlight the distinctive approaches necessary to address independent communities. Previous research has shown that smokers who receive comprehensive cessation counseling over the telephone using techniques that focus on cognitive, emotional, and coping processes tend to have increased acceptance of cravings to smoke [directive speech act was highly prevalent in the cravings theme; thus, digital behavior change interventions can benefit from incorporating such additional insights into cravings to improve message crafting and content tailoring capabilities per the user\u2019s needs.In terms of the associations between speech acts and communication themes, all of the speech acts  construction of user representations and their information needs and (2) modeling of collective social resilience and human behavior patterns in collaborative endeavors in digital settings. This deeper understanding can result in downstream technologies such as digital therapeutics and virtual coaching agents with real-time naturalistic conversational capabilities. The results of our study indicate that we can use linguistic taxonomies  in order to capture the latent needs of OHC users based on their interactions with their peers, alongside their topics of interest (communication content), which can subsequently result in more responsive and personalized digital health interventions to support behavior change. This can have implications for designing digital care management pathways for individuals and communities based on their self-reported digital behaviors and engagement preferences, thereby enabling individuals to make better choices, and support them in sustaining long-term behavior change, thus ultimately improving their quality of life.Our study is not without limitations. Although QN and ADA messages were selected at random, the relatively small and uneven sample sizes may have resulted in inaccurate representations of the overall prevalence of speech acts and thematic emphasis. However, our sample of 3011 messages using qualitative research methods is appropriate for the study objectives. Even though we used empirically sound and reliable methods for coding the peer conversations, our analysis might be limited by subjective bias in the annotation process that is inherent in human coding in qualitative research . AlthougDigital health platforms, specifically OHCs, provide unprecedented opportunities for researchers to transform into empathetic listeners of people\u2019s endeavors, from small-scale, 1-day-at-a-time to large-scale life-consuming behavior modifications. Such listening capabilities will help us glean the needs of individuals to initiate and sustain positive health changes. This paper proposes an analytical framework to enable deep social listening capabilities to uncover the unmet needs of individuals, thus laying the foundation for next-generation technology innovation efforts. Our efforts to overlay the communication intent implicit in peer interactions alongside content-specific theory-linked characterizations of social media discourse have provided insights into topic diversity and latent interactions of users within these topics. Such content-specific and intent-sensitive methodological framework can inform the development of cognitively enabled big data analytics and machine learning models that better harvest the digital footprint of social media users."}
+{"text": "Specimens from 45 patients with previously-untreated non-small cell lung cancer (NSCLC) were tested for in vitro chemosensitivity to ten drugs utilising the DiSC assay, which measures cell kill in the total (largely non-dividing) tumour cell population. Thirty-five assays were successful and 25 patients with advanced disease subsequently received chemotherapy with the 'best' three drugs selected by the assay. Six patients were Karnofsky performance status 60 or less and the median pretreatment weight loss was 8.5%. Nine patients had a partial response  and the median survival of all patients was 202 days. Specimens from responding patients were significantly more sensitive in the assay to drugs in general  and to the drugs used in treatment than were specimens from non-responding patients. In vitro drug resistance differences between responding and non-responding patients were of greater significance than were differences between other clinical and laboratory measurements. Assay results classified patients into two cohorts, having relatively high and low probabilities of responding to chemotherapy. Assay results also identified patient cohorts with above average and below average durations of survival. Five patients (20%) were found to have tumours with extreme drug resistance (EDR), defined as assay results for the average of all ten tested drugs falling greater than one standard deviation more resistant than the median for all tumours assayed, and none of these patients with EDR responded to chemotherapy."}
+{"text": "Late relapses of testicular germ cell tumor are uncommon. We report a case of cervical mature teratoma appeared 17 years after treatment of testicular teratocarcinoma.A 20- year- old patient underwent left sided orchiectomy followed by systemic therapy and retroperitoneal residual mass resection in 1989. He remained in complete remission for 200 months. In 2005 a huge left supraclavicular neck mass with extension to anterior mediastinum appeared. Radical surgical resection of the mass was performed and pathologic examination revealed mature teratoma.This is one of the longest long-term reported intervals of a mature teratoma after treatment of a testicular nonseminoma germ cell tumor. This case emphasizes the necessity for follow up of testicular cancer throughout the patient's life. The prognosis for nonseminomatous germ cell tumor (NSGCT) of the testis has been dramatically improved by using a treatment protocol of cisplatin-based chemotherapy followed by surgical resection of residual tumor mass. The complete response rate of disseminated germ cell tumor with this protocol is between 70%\u201380%.Most patients who relapse do so within the first year of therapy. Late relapse is defined as recurrence after a relapse- free interval of more than two years after completion of primary treatment . The cumThe incidence of late relapse after cisplatin based chemotherapy of germ cell tumor is related to initial tumor burden and patients with bulky retroperitoneal disease appear to be at an increased risk of late relapse. As tumor markers do not rise in one quarter of late relapses, they should undergo CT scans at annual follow-up evaluations. In the remaining patients, history, physical examination, tumor markers and chest X-ray may allow to detect the majority of late asymptomatic relapses .Herein we report a case of late relapse of a bulky teratocarcinoma, 17 years after completion of treatment as a mature teratoma of the neck and upper thorax.A 36 year-old man was admitted to our hospital with chief complaint of left sided neck mass. He had a history of left orchiectomy in 1988 in another center because of testicular teratocarcinoma. At that time he was referred to our center because of huge retroperitoneal mass medial to the left kidney Figure . The othGerm cell tumours, which are in complete remission two years after treatments have a high probability of cure and reports of late relapse, are rare 1.3%\u20136.2%) [% [2-6]. The possible mechanisms of development of a late relapse in germ cell tumors include the followings: malignant degeneration of mature teratoma to germinal malignancy, growth of an occult testicular tumor not eliminated by chemotherapy, development of a second primary germinal malignancy, persistent microscopic viable tumor with an atypical less aggressive biologic behaviour .Patient with bulky retroperitoneal disease and patient found to have teratoma following cisplatin-based chemotherapy appear to be at an increased risk of late relapse. Of 51 patients with mature teratoma in resected retroperitoneal residual tumor masses after chemotherapy, 9 patients (17.6%) relapsed. In five patients (9.8 %) relapse resulted from growing mature teratoma [Teratoma is a chemo resistant, nonseminomatous germ cell tumor composed of somatic cell type from two or more germ layers and is derived from a toti potential, malignant precursor cell . Although teratoma is a benign tumor but its biologic potential is unpredictable and it should be resected completely because it may grow and become unresectable.Disease free survival following resection of teratoma is related to completeness of resection; therefore, there are significant advantages to surgery with low volume disease. Moreover, there is the risk of malignant transformation of teratoma to carcinoma or sarcoma , so unreHerein we report a case of late relapse in the left side of neck 17 years after treatment of left testicular teratocarcinoma. The incidence of cervical metastasis in testicular germ cell tumor is about 5% . In germWhereas chemotherapy has only minor curative potential in the treatment of late relapse, patient with localized resectable disease can be cured. Modified neck dissection has a demonstrated valuable role in the treatment of metastatic non-seminomatus germ cell tumours .Our patient has been well with no evidence of disease after resection of cervical mature teratoma until the date of last follow-up (October 2006). However, continued close follow-up of this case is necessary because the large tumor burden of teratoma is a significant adverse factor predictive for further relapse . In our This case emphasizes the necessity of annual follow-up evaluation of testicular germ cell cancer patient through their life, in order to detect the majority of late relapse at an asymptomatic phase.The author(s) declare that they have no competing interest.RO carried out the surgery and drafted the manuscript.MA assisted in operation and participated in drafting the manuscript.All authors read and approved the final manuscript."}
+{"text": "Previous reports have indicated that reconstituted basement membrane (matrigel), when co-injected with either established or primary human tumour cells, can improve the growth of subcutaneous xenografts in nude mice. The human adenocarcinoma cell lines A549, SW480, and WiDr, and the human fibrosarcoma cell line HT1080scc2 exhibit varying degrees of tumourigenicity in nude mice. All these lines showed increased tumorigenicity and/or growth rate, together with a change towards a more differentiated tissue morphology, when co-injected with matrigel into nude mice. Experiments using A549 cell line have indicated that the effect of matrigel is concentration-dependent and that increased growth rate is not maintained when xenografts grown with matrigel are passaged into further mice. These results strongly suggest that increased tumour growth results from the improved growth conditions afforded by matrigel, rather than from the selection of subpopulations of the most tumourigenic cells. Increased growth of intracaecal tumours arising from the co-injection of SW480 cells with matrigel, indicate a possible use for matrigel in the development of more relevant animal models using the orthotopic site. Purified laminin significantly increased the growth of sc tumours resultant from co-injection with either WiDr or A549 cells, whereas collagen IV or laminin with entactin showed no such effect. A role for free laminin in the stimulation of cell growth in the absence of an intact basement membrane is discussed."}
+{"text": "Enormous effort has been devoted to the development of a vaccine against human immunodeficiency virus (HIV). But it is proving to be an unprecedented challenge to create an effective vaccine mainly due to the high genetic variability of the virus and the necessity of cytotoxic T lymphocytes (CTL) for containing the infection. Currently pursued vaccine strategies appear to induce CTL in nonhuman primate models but in the early clinical trials, these strategies fail to fully control the viral infection. New strategies that can cover the vast genetic diversity of HIV are needed for the development of a potent vaccine. In just over two decades the virus has killed more than 20 million humans and infected over 42 million people globally with the latest yearly infection rate of over 6 million [Since it was first reported in 1981, the disease has been misrepresented in mass-media as gay scourge, drug-user's Black Death, a punishment on sinful, etc. The list of stigma goes on mainly due to the unique biology of the causative agent which spreads both venereally and by contaminated blood products. The disease is caused by a retrovirus of the Lentivirus genus under the name of Human Immunodeficiency Virus (HIV-1). Once in the human body, the virus replicates mainly in CD4In its 2004 report, the AIDS Vaccine Advocacy Coalition (AVAC) documented that there will not be a safe and effective vaccine in 2007 and that we need to \"focus on the long haul and set an agenda for sustained and sustainable action that stretches well beyond 2007\" [With a genome of approximately nine thousand nucleotides, HIV-1 has packaged the necessary information in overlapping open reading frames to encode 15 proteins from multiply-spliced mRNAs  and, thus progressively destroy the body's ability to fight opportunistic infections and certain cancers resulting in AIDS and finally death in 7 to 10 years.Additionally, the replication machinery of the virus is so inaccurate that it generates new mutants for virtually every virion produced in an infected individual, thus, creating a myriad of new and unique viral particles every day . A high The evolution of HIV is also believed to be the result of genetic heterogeneity. A large number of lentiviruses exist in African nonhuman primates as apathogenic species-restricted simian immunodeficiency viruses (SIV) . Wild poin vivo and in vitro observations: the emergence of HIV-specific CD8+ CTL responses coincides with the initial containment of viral replication in acute infections [in vitro replication of HIV-1 in CD4+ lymphocytes can be inhibited by CD8+ lymphocytes possibly through direct cytotoxicity and other soluble factors including beta chemokines [+ lymphocytes in controlling HIV replication came from animal models. Monkeys depleted of CD8+ lymphocytes by administering anti-CD8 monoclonal antibodies were unable to control viral replication upon infection with SIV. These animals died of AIDS-like disease with an accelerated course [As mentioned above, a potent defense against HIV would require both arms of the immune system: humoral and cellular immunity. The protective role of HIV-neutralizing antibodies in natural infection seems to be insufficient since such antibodies are detected only after several weeks of initial containment of virus replication. Moreover, only low titers of neutralizing antibody are detected in HIV-1 infected individuals. Cellular immune responses seem to have a dominant role in HIV-1 containment as evidenced by several fections ; in vitremokines ,11. The d course .Mutations have been shown to help HIV escape recognition by CTL . Escape Traditional strategies for vaccination such as attenuated- or inactivated-viruses, passive immunization and purified or recombinant proteins Figure  safely pet al. [In SIV-macaque models, gene-deleted SIV known to be pathogenically attenuated were found to cause disease in monkeys  and the et al.  evaluateet al. . The faiLive recombinant viral and bacterial vectors and plasmid DNA have been explored as novel approaches for delivering HIV proteins as immunogens Figure . ResultsGenes of HIV and SIV have also been expressed in microorganisms that have a proven record of being safe and effective live-attenuated vaccines. A long list of such live recombinant vectors includes attenuated vaccinia and other pox-, alpha-, adeno- and measles viruses, attenuated mycobacterium Bacille Calmette-Guerin, Salmonella, Shigella and others. Since several of such vectors are replication competent, expression of HIV proteins from them is expected to induce CTL. Many of the vaccine studies combine various approaches in a prime-boost fashion for avoiding immune responses to the vectors. Results of several animal studies using these modalities have been encouraging, but observations in early phase clinical trials in humans have not been promising. Some of the trials were stopped at various stages owing to adverse reactions to the delivering vector or the inability of the expressed immunogen to cover genetically diverse isolates prevalent in the geographical areas. Nevertheless, the outcome of several ongoing clinical trials is expected to deliver the good news about safe vaccine delivery vectors and, if possible, an effective vaccine against a particular strain of HIV-1 .in vitro antigen-pulsed dendritic cells (DC) upon re-injection show improvement in cellular immune responses against the same HIV-1 strain [ex vivo loading of DC seems an exciting avenue for individualized therapeutic intervention, the financial cost of such an approach makes it unattractive endeavor for a prophylactic vaccine in developing countries.In anther approach, 1 strain . This apLately, several neutralizing monoclonal antibodies have been reported . The neuThe accumulated experience in vaccine development against HIV highlights the challenge in devising an immunogen that can mount a potent immune response against the continuously arising viral variants and the AIDS epidemic. Using geographically prevalent strains or consensus sequences have so far been the strategies for developing vaccines against antigenic variants of HIV-1 . Lately,nef in order to weaken the virus. Several investigators have been pursuing the tetracycline/doxycycline-controlled transcriptional regulator (tetO/tTA or tetO/rtTA) systems [in vitro or in vivo. Since the system has also been shown to have background expression [in vivo utilization would require enhanced transcriptional control. More stringency could be added to the system by combining it with the tetO silencer (tTS) that would abrogate the background expression or leakiness [in vitro and later in animals using SIV as a model. The major concerns over this approach would be recombination between the multiple genomes of HIV resulting in pathogenic variants. Moreover, if such viruses capture the cellular promoter/enhancer elements, the conditional replication control would be lost resulting in a pathogenic virus.Easier said than done, one can think of utilizing the error-prone replication machinery of HIV to generate potential immunogens that would represent all the variants. In this strategy, one would first replace the transcription-transactivator Tat/TAR axis of HIV with controllable transcription regulators and take out other non-structural protein genes such as  systems ,29. Thispression , its in eakiness . The HIVin compu by digitally generating sequences of HIV through combining all the possible substitutions at each nucleotide position. The putative immunogens from such sequence combinations would be identified by digitally matching them to the three-dimensional structures of the human MHC molecules (HLA) for the feasibility of CTL epitopes presentable to the immune system. These epitopes would be screened for their relevance to generate CTL in vitro against the prevalent HIV strains. A cocktail of such epitopes would be delivered using live-vectors or primed-DC for generating protective immune responses against the genetic variants. Similarly, putative neutralizing antibody inducing epitopes can also be generated utilizing the information on antigen-binding sites of neutralizing antibodies. These designer cocktails can be readjusted through the digital data-base of prevalent variant viral sequences. Studies on representative or \"immunogenic consensus sequence\" epitopes from multiple viral variants using computer-driven methods are already underway [in compu, and the optimal delivery vehicles needed for the cocktails. With the latest pledge from Microsoft\u00ae for helping investigators to devise strategies against HIV [Alternatively, one can utilize the knowledge of human genome and HIV sequences for creating \"swarm or quasi-species\" underway . The majinst HIV , the necA tremendous amount of economic and intellectual effort has already been invested in the pursuit of a vaccine against HIV. The unique biology of HIV replication and high rate of mutations have made it harder than initially believed to come up with a preventive measure against AIDS. With the technological advancements and concerted efforts from the policy makers and investigators, it seems not far when a preventive vaccine would be available against HIV.AIDS Acquired immunodeficiency syndromeAVAC AIDS Vaccine Advocacy CoalitionCTL Cytotoxic T lymphocytesDC Dendritic cellsHIV Human immunodeficiency virusHIV-1 Human immunodeficiency virus subtype 1HLA Human leukocyte antigenMHC Major histocompatibility complexSIV Simian immunodeficiency virusrtTA reverse tetracycline-controlled transcriptional activatortetO tetracycline responsive operator sequencestTA tetracycline-controlled transcriptional activatortTS tetracycline-controlled transcriptional silencerThe author(s) declare that they have no competing interests."}
+{"text": "We have recently reported the activation of a new oncogene in human papillary thyroid carcinomas. This oncogene, named PTC, is a novel rearranged version of the ret proto-oncogene. In fact PTC is the product of the fusion of the tyrosine kinase domain of the ret proto-oncogene with the 5'-terminal region of another gene that we have named H4. The ret proto-oncogene shows a pattern of expression restricted to neuroendocrine tissue. Its fusion with H4 allows the expression of the activated form in thyroid papillary carcinomas. Therefore the detection of ret transcripts is a tool to investigate ret activation in thyroid neoplasms. Here we show the detection by in situ hybridisation, of activated ret transcripts in human thyroid papillary neoplasms that were positive for PTC activation by Southern blot analysis. We did not find any ret transcripts in papillary carcinomas negative for PTC activation, nor in normal thyroid and in non-papillary thyroid neoplasias."}
+{"text": "Although EGF receptor expression is generally elevated in human lung squamous carcinoma, the biological significance of this phenomenon and the role of EGF and TGF-alpha in this disease are poorly understood. We have investigated three human lung squamous carcinoma cell lines  and have shown, using an antibody (EGFR1) directed against the EGF receptor, that the majority of cells in all three lines express the EGF receptor. Using a ligand binding assay, Scatchard analysis indicated high concentrations  of a single low affinity binding site (Kd = 3-5 nM) within these lines. Addition of EGF or TGF-alpha at concentrations greater than 0.1 nM resulted in growth inhibition of all three lines and this was associated with an accumulation of cells in the G2/M phase of the cell cycle. Growth inhibitory effects were not explained by an enhancement of cellular differentiation as monitored by involucrin expression and the ability to form cornified envelopes. While the presence of EGF could not be detected in medium conditioned by the NX002 cell line, mRNA for TGF-alpha was detected in all three lines suggesting the possibility of an autocrine loop. These results together with reports of growth inhibition by EGF and TGF-alpha in other systems suggest that EGF and similar molecules might have a growth regulatory role in lung cancer cells and modulation of such may have therapeutic potential."}
+{"text": "Zinc phthalocyanine substituted with four hydroxyl groups attached to the macrocycle, either directly or via spacer chains of three or six carbon atoms, were tested for their photodynamic ability to inactivate Chinese hamster lung fibroblasts (line V-79) in vitro, and to induce regression of EMT-6 tumours grown subcutaneously in Balb/c mice. Their potential to inflict direct cell killing during photodynamic therapy was investigated by examining vascular stasis immediately following photoirradiation using fluorescein as a marker, and also by an in vivo/in vitro EMT-6 cell survival assay. Both of the tetraalkylhydroxy substituted zinc phthalocyanines are effective photodynamic sensitisers in vivo with the tetrapropylhydroxy compound exhibiting about twice the activity of the tetrahexylhydroxy analogue. The differences in activities were accentuated in vitro, the tetrapropylhydroxy compound was two orders of magnitude more potent than the tetrahexylhydroxy analogue in photoinactivating V-79 cells. The tetrahydroxy compound lacking spacer chains failed to exhibit photodynamic activity in either system. Tumour response with the active compounds was preceded by vascular stasis immediate following irradiation which suggests, together with the absence of activity in the in vivo/in vitro assay, that tumour regression involves an indirect response to the photodynamic action rather than direct cell killing. These data demonstrate the importance of the spatial orientation of functional groups around the macrocycle of photosensitisers for their efficacy in the photodynamic therapy of cancer."}
+{"text": "Epidermal tumourigenesis can be achieved in rodents by the application of a single subthreshold dose of a carcinogen (initiation) followed by repeated applications of a tumour promoter such as 12-0-tetradecanoyl phorbol, 13-acetate (TPA). TPA induces terminal differentiation in the majority of epidermal keratinocytes in vitro. However, transformed keratinocytes respond weakly to this terminal differentiation signal, and it is suggested that this property allows initiated cells and their progeny to obtain a selective advantage over their normal counterparts during promotion of papilloma formation by TPA. New data are reviewed which suggest that a putative wound hormone TGF-beta has similar differential effects on normal and transformed epithelial cells to those of TPA. It is proposed that the release of TGF-beta from platelets following deep skin wounding may be an explanation as to why wounding is a promoting stimulus but milder forms of epidermal injury are not. Weakly promoting hyperplasiogenic agents are also discussed within the context of a selection theory of tumour promotion."}
+{"text": "MicroRNAs (miRNAs) are a new class of 18\u201323 nucleotide long non-coding RNAs that play critical roles in a wide spectrum of biological processes. Recent reports also throw light into the role of microRNAs as critical effectors in the intricate host-pathogen interaction networks. Evidence suggests that both virus and hosts encode microRNAs. The exclusive dependence of viruses on the host cellular machinery for their propagation and survival also make them highly susceptible to the vagaries of the cellular environment like small RNA mediated interference. It also gives the virus an opportunity to fight and/or modulate the host to suite its needs. Thus the range of interactions possible through miRNA-mRNA cross-talk at the host-pathogen interface is large. These interactions can be further fine-tuned in the host by changes in gene expression, mutations and polymorphisms. In the pathogen, the high rate of mutations adds to the complexity of the interaction network. Though evidence regarding microRNA mediated cross-talk in viral infections is just emerging, it offers an immense opportunity not only to understand the intricacies of host-pathogen interactions, and possible explanations to viral tropism, latency and oncogenesis, but also to develop novel biomarkers and therapeutics. MicroRNAs (miRNAs) are small RNA molecules which have recently gained widespread attention as critical regulators in complex gene regulatory networks in eukaryotes. These small RNA, processed from non-coding regions of the genome into 18\u201323 nucleotide long single stranded RNA, have been shown to regulate translation of messenger RNA (mRNA) by binding to it and effecting target cleavage or translational block depending on the extent of sequence complementarity with the target [MicroRNA mediated regulation has been lately shown to encompass a wide spectrum of host biological processes ranging from growth and development to oncogenesis -5. RecenMicroRNAs have recently been implicated in the intricate cross-talk between the host and the pathogen  in viralCaenorhabditis elegans [MicroRNAs were initially discovered in 1993, in a genetic screen for mutants that disrupt the timing of post-embryonic development in the nematode  elegans , and wasMicroRNAs have been classically thought to be transcribed from intergenic regions, but recent large-scale genome-wide cloning experiments  have shoMicroRNAs are transcribed by RNA Polymerase II as primary microRNAs (pri-miRNAs) which range from hundreds to thousands of nucleotides in length and resemble protein-coding transcripts in that they are poly-adenylated and capped . These pThe mechanism of action of microRNAs is considered to be by two modes \u2013 translational repression and target degradation. The former is common in mammalian systems while the latter is found predominantly in plants. The basic difference in the two mechanisms is thought to be primarily governed by the levels of complementarity between microRNAs and their target transcripts. Perfect or near perfect complementarity as is common in plant microRNAs and in a small class of eukaryotic microRNAs causes target cleavage and degradation , analogoIn fact, one microRNA can have binding sites in multiple targets  and one target can be repressed by multiple microRNAs (multiplicity and co-operativity) . Moreovevide infra). A recent report by Bhattacharyya et al suggests that microRNA mediated mechanism of post-transcriptional repression of gene expression is indeed reversible [Recent evidence suggests that microRNAs can also regulate protein expression through non-classical ways. Genome-wide expression analysis of microRNA targets have shown to decrease the transcript levels . But wheversible , suggestde novo prediction of microRNA still remains a challenging task. This is especially important in the case of viruses as viral microRNAs do not share close homology even in the same class. We hope the prediction algorithms will improve with a better understanding of the sequence and structural components of precursor hairpins involved in microRNA biogenesis [de novo method (unpublished results) for microRNA prediction in viruses based on Support Vector Machines, rationalizing that virus encoded microRNA precursor hairpins would share the sequence and structure features with that of host as they share the same microRNA processing machinery. The algorithms for microRNA target prediction also have been significantly improved from first-generation algorithms which rely on sequence complementarity rules, thermodynamic stability and conservation [Computational predictions have been the mainstay for discovery of microRNAs and their targets. The algorithms for microRNA prediction range from custom-made programs to search for hairpin loops and energetic stability to advanced algorithms employing machine learning approaches -25. Evenogenesis . We haveervation ,27,28 byervation .Viruses are obligate intracellular parasites and use the cellular machinery for their survival and replication. The success of the virus essentially depends on its ability to effectively and efficiently use the host machinery to propagate itself. This dependence on the host also makes it susceptible to the host gene-regulatory mechanisms. Though the gene regulatory mechanisms involving both host and viral proteins have been extensively studied, data on small RNA mediated gene regulation in viral infections is just emerging. Interestingly, it seems that the cellular microRNAs, in addition to their normal regulatory roles in cellular gene expression also double up as fortuitous agents that target foreign nucleic acids, as in the case of viruses. The inventory of microRNAs encoded differs between cell types, and thus may contribute to the tissue tropism of viruses. Some of these are elaborated in the subsequent sections.et al [Lecellier et al , for thenef. The targets were found to be highly conserved in all of the viral clade sequences with the exception of clade O. The fact that defective nef is well known to be associated with a long term non-progressor state led us to speculate that the levels of the cellular microRNAs would be a decisive factor in determining the progression of the disease. The targets have been experimentally validated (unpublished results) by cloning the target site in the 3'UTR of Green Fluorescent Protein (GFP) reporter gene. Analysis of previously reported microarray data [We have earlier shown , using rray data  of theseray data  . Two human encoded microRNAs mir-507 and mir-136 had potential binding sites in Polymerase B2 (PB2) and Hemagglutinin (HA) genes respectively. The target regions in the respective genes were not only found to be conserved across different viral strains, but were also found to fall in highly accessible regions of the predicted target RNA structure. Moreover, analysis of previously reported  microarrBoth the genes PB2 and HA are known to be critical for the pathogenicity of the virus. While HA is the surface glycoprotein involved in direct binding of the virus to the cell surface, HA in the H5N1 subtype carries a polybasic site, cleavage at which, by cellular proteases is an essential step in establishing infection. PB2 is one of the three components of the Ribonucleoprotein which is responsible for RNA replication and transcription. Recent evidence, from recombinant viruses generated by combinations of murine and avian viruses identified PB2 as one of the two genes associated with virulence. The polymerase activity was directly correlated with the high virulence of the murine strain in their cognate host . Anotheret al [Jopling et al  reportedInterestingly viruses have also evolved to evade RNAi by a variety of strategies. The suppressors of antiviral RNAi is better understood in plant viruses. To counteract the small RNA mediated interference, viruses express suppressors that interfere with microRNA as well as siRNA pathways . The virThe interest in discovering novel microRNA candidates using both computational tools and experimental validation of the predicted candidates have shown that viruses also encode microRNAs  latency associated transcript (LAT) encodes for a microRNA which target critical genes of the apoptosis pathway [Of late, Cui V genome . Subsequ pathway  includinSuch a mechanism could operate in other related herpes viruses like Epstein-Barr virus, which not only causes latent infection, but also associated with a wide spectrum of neoplasms in humans including Burkitts lymphoma and nasopharyngeal carcinoma. It is all the more probable that oncogenic herpes viruses like EBV and KSHV encoded microRNAs can target critical genes involved in oncogenesis. This is especially so in the case of EBV encoded microRNAs as they have been shown to be differentially expressed in different phases of the viral life . Our anaet al, using a combinatorial approach incorporating both computational prediction and experimental validation demonstrated the possibility that a virus-encoded microRNA could auto-regulate itself. A nef derived microRNA could down regulate nef expression in vitro suggesting that it could be a mechanism of maintaining low viremia in Long term non-progressor (LTNP) states [nef derived microRNA also suppress transcription [Omoto ) states . This ficription  by reducIn yet another instance, a virus encoded microRNA, is effectively used by the virus to tune down a set of genes and thereby evade cytotoxic T cell response . Simian Recently microRNA expression profiles have been analyzed for viral infections like HIV . MicroRNMicroRNAs and anti-microRNA oligonucleotides (AMOs) have been proposed as novel therapeutics ,56. ReceMicroRNAs are promising candidates for developing novel bio-therapeutics against viruses, as it requires only partial complementarity unlike siRNAs and thus can tackle the high rate of mutations in viruses better than siRNAs. Initial experiments creating microRNAs based on siRNA design rules have shown promising results . Our groWith evidence demonstrating that both host encoded and virus encoded microRNAs interact with host and virus transcripts respectively, in addition to their roles in regulating their own transcripts warrants a comprehensive analysis of host and virus microRNAs and their targets to elucidate a holistic picture of microRNA mediated host-virus interaction model Figure . The cha"}
+{"text": "Small cell lung cancer (SCLC) is treated primarily with combination chemotherapy. Despite high initial response rates, most patients eventually die with drug resistant disease. In some tumours, resistance to multiple chemotherapeutic agents is attributed to overexpression of P-glycoprotein (P-gp). However, this does not appear to be a frequent occurrence in drug resistant SCLC. Increased levels of glutathione (GSH) and related enzymes may play a role in resistance to alkylating agents as well as natural product drugs. We measured levels of GSH, glutathione S-transferase (GST), glutathione reductase (GSH Red), glutathione peroxidase (GSH Px), and gamma-glutamyl transpeptidase (gamma-GT) in a panel of 20 SCLC cell lines. Most of these lines were established from patients treated at this centre. Each cell line had a characteristic and reproducible profile of GSH and related enzyme levels. Immunoblot analysis indicated that the predominant GST in the cell lines was the anionic pi isoenzyme. The relative sensitivity of each of these cell lines to 16 different chemotherapeutic agents was measured using a modified MTT assay. Spearman rank correlation analysis was used to determine the relationships between the relative chemosensitivity of these cell lines and the levels of GSH and related enzymes. The number of positive correlations was no greater than expected by chance alone. Furthermore, there was no correlation with the treatment history of the patients from whom the cell lines were derived. These data suggest that alterations in glutathione metabolism do not play a major role in resistance to chemotherapeutic agents in these human SCLC cell lines."}
+{"text": "Understanding the regulatory processes that coordinate the cascade of gene expression leading to male gamete development has proven challenging. Research has been hindered in part by an incomplete picture of the regulatory elements that are both characteristic of and distinctive to the broad population of spermatogenically expressed genes.K-SPMM, a database of murine Spermatogenic Promoters Modules and Motifs, has been developed as a web-based resource for the comparative analysis of promoter regions and their constituent elements in developing male germ cells. The system contains data on 7,551 genes and 11,715 putative promoter regions in Sertoli cells, spermatogonia, spermatocytes and spermatids. K-SPMM provides a detailed portrait of promoter site components, ranging from broad distributions of transcription factor binding sites to graphical illustrations of dimeric modules with respect to individual transcription start sites. Binding sites are identified through their similarities to position weight matrices catalogued in either the JASPAR or the TRANSFAC transcription factor archives. A flexible search function allows sub-populations of promoters to be identified on the basis of their presence in any of the four cell-types, their association with a list of genes or their component transcription-factor families.This system can now be used independently or in conjunction with other databases of gene expression as a powerful aid to research networks of co-regulation. We illustrate this with respect to the spermiogenically active protamine locus in which binding sites are predicted that align well with biologically foot-printed protein binding domains. K-Means and hierarchical clustering analyses are increasingly used in microarray studies to reveal correlated expression between groups of genes. Through time-series experiments, regimes of co-expression and regulatory cascades have been described. Nonetheless, determining the mechanistic relationship underlying co-regulation has not been trivial. The subtle interplay of systems controlling expression makes hidden variable models attractive to the analyst but ultimately problematic for the biologist seeking verifiable pathways. Studies of co-regulation have been most effective in bridging this gap when gene expression data has been used in conjunction with data describing transcription factor specificity. The approach allows the agents and outcomes of regulation to be explicitly connected .Transcriptional mechanisms regulating expression are currently thought to include binary differentiating systems that potentiate chromatin for transcription as well as a scalar mechanism that determines the extent and products of expression. The binding of transcription factors within critically defined promoter regions is thought to be a class of scalar regulation that initiates transcription only after binary control mechanisms have potentiated the chromatin locus . ReverseKrawetz-Lab database of Spermatogenic Promoters Modules &Motifs), provides online access to a suite of promoter structure-based analytical tools. This employs a database of known transcriptional control elements as an in-silico discovery tool that is targeted to the promoter regions of a set of testes expressed genes that regulate male germ cell differentiation.The differentiation of cells in the testes occurs continuously in adult mice through the serial interplay of gene expression that affects approximately one third of the genome. This includes an estimated 4% of genes that are uniquely expressed during spermatogenesis . Spermatth, 2005. The libraries, representing four major cell-types found within the testes, were selected as follows: Sertoli , spermatogonia , spermatocytes  and spermatids (lib#-6786). Their respective promoter sequences were downloaded from mm5 genome build of DBTSS, the DataBase of Transcription Start Sites [K-SPMM databases. These databases describe murine promoter location, Transcription Factor Binding Site (TFBS) distribution and the location of putative homo or heterodymeric transcription-factor modules. This data was enhanced with a per-base conservation score relative to four vertebrate genomes hg17, rn3, canFam1 and galGal2 obtained from the UCSC archive of phastCons scores [A dataset of spermatogenically active genes was gathered from nine NCBI published cDNA libraries  and acceThe promoter location database contains the many-to-one mapping of 11,715 potential promoter regions with the 7,551 genes in the cDNA libraries. Each DBTSS promoter sequence contains a 1 kb upstream sequence from each Transcription Start Site (TSS) described. Analysis of the 200 bp sequence downstream from TSS is available as an optional element. Annotation of the genes associated with each promoter was extracted from NIH DAVID 2.1 . The TFBTranscription factor binding sites were then refined and combined on the basis of distance metrics . This idThe system is executed as a JSP application within a Jakarta Tomcat framework with SQL queries directed to a local MySQL database.As shown in Fig. The response of the genome to spermatogenic differentiation is global, affecting the expression of approximately one third of its genes. Many of these genes are expressed as tissue specific isoforms  or are drm1 & Prm2) required for the successful repackaging of nuclear DNA into the spermatozoon nucleus as well as one of the condensation enabling genes (Tnp2). The coordinate regulation of this locus has been widely investigated [The protamine locus provides a key example of a gene cluster that is active in the latter spermiogenic phase of spermatogenesis. It contains both protamine genes  overlapping on opposite strands and paired with a third YY1 site located 20 bp further upstream. This places all three YY1 elements within the 113 bp upstream region required for Prm1 expression [In the 200 bp upstream region of Ppression , with thpression . Transfa117 and interaction with CBP, the ubiquitous CREB-Binding Protein co-activator. By contrast, the transcriptional activity of CREM in testes is controlled through its interaction with ACT, the tissue-specific Activator of CREM in Testis [CREM, the cAMP Response Element Modulator that directly binds to CRE, has been widely implicated for its role in spermiogenesis. CREM deficient mice arrest spermatogenesis at the early round spermatid stage , with thn Testis ,37 that n Testis . Interesn Testis  and in cn Testis  but thesTogether these results show that the use of transcription factor colocalization in conjunction with conservation as implemented in the K-SPMM promoter discovery tool yield potential sites of transcription factor binding that are biologically well validated. In testing the system, we noted the presence of the YY1 response element in the upstream regions of all three genes in the protamine domain that has been associated with a sterol response element binding protein that regulates proacrosin, another haploid expressed gene. . The devDatabase of Transcription Start Sites [DBTSS The rt Sites JASPAR An open source database of transcription factor DNA-binding preferences Krawetz-Lab database of Spermatogenic Promoters Modules &Motifs [K-SPMM  &Motifs NIH DAVID National Institute of Health DAVID Gene Annotation system Position Weight MatrixPWM Transcription Factor Binding SiteTFBS Transcription Factor Database [Transfac The Database Transcription Start SiteTSS UCSC Genome Browser University of California Genome Browser YL developed the final version of the JSP codebase and constructed the SQL database. AEP coordinated the bioinformatic investigation leading to the data used in the system. GCO provided biological context and guidance during the initial phase of system development. SAK originated the concept and supervised its design and implementation. The manuscript was drafted by AEP and SAK with the input and approval of all authors."}
+{"text": "The physiology of the multidrug transporter P-glycoprotein (Pgp) is still poorly understood. We now show evidence that cell lines with a high expression of Pgp display a reduced accumulation of cortisol and an ATP-dependent outward transport of the hormone. Cortisol efflux from Pgp negative cells does not have such an active component. Further we show that the steroid hormones cortisol, testosterone, and progesterone cause an immediate, dose-dependent increase of daunorubicin accumulation in Pgp overexpressing cells. These effects are particularly apparent for the more lipophilic steroids. These results demonstrate that Pgp may function as a transporter for cortisol and suggest a physiological role of the protein in steroid handling by organs such as the adrenal."}
+{"text": "Flavone acetic acid (FAA) is a synthetic flavonoid with dramatic pre-clinical anti-tumour activity involving a vascular component in its mechanism but no clinical effects have been seen to date. As FAA also has immunomodulatory activity, immunological factors might explain differences in activity between mouse and man. This study examines the influence of host immune status on the anti-tumour activity of FAA. Two human colon tumour xenografts  fail to respond to FAA in nude mice. The lack of activity of FAA against HT-29 xenografts cannot be explained on the basis of limited drug bioavailability as achievable plasma, and tumour levels of FAA are similar to those seen in sensitive murine colon tumours. The immune status of the host also influences the activity of FAA against two transplantable tumours of the mouse colon. Both these tumours are highly responsive to FAA in their normal NMRI hosts, but neither tumours exhibited significant growth delay in thymectomised NMRI or nude hosts. Histological examination of treated tumours revealed significant areas of haemorrhagic necrosis in all three hosts. These data suggest a clear immunological component in the mechanism of action of FAA which is separate from the previously described haemorrhagic necrosis."}
+{"text": "Several splicing variants of hTERT have been described whose regulated expression contributes to the control of telomerase activity. Knowledge of the different hTERT mRNA isoforms and the ability to distinguish between them is an important issue when evaluating telomerase expression.Human telomerase reverse transcriptase (hTERT) is a key component for synthesis and maintenance of telomeres on chromosome ends and is required for the continued proliferation of cells. Estimation of hTERT clones individually for differences in DNA sequence. This made possible the identification of novel alternatively spliced sites as well as analysis of their frequency and mutual correlation in mRNA isoforms. Ten different alternatively spliced sites were detected, of which six were novel sites resulting from alternative splicing of intron 2 or 14. The majority of hTERT cDNA clones from normal and tumour lung and colon tissues encoded truncated proteins ending close after exon 2 or 6.By establishing cDNA-clone panels from lung and colon tissues, we could map hTERT expression.The increased complexity in telomerase expression revealed here has implications for our understanding of telomerase regulation and for the choice of suitable methods for addressing  The ends of eukaryotic chromosomes are usually capped by telomeres which consist of repeated copies of a short DNA sequence and several associated proteins [reviewed in ]. The tehTERT correlates well with telomerase activity and seems to be the rate-limiting factor for telomerase activity in human cells . TelhTERT cDNA. The situation with over-amplification of the deletion ASPS Del-e11 . It is possible that these clones have originated from nuclear mRNA in which intron 14 is retained because of incomplete processing.In addition to being a tool for detecting sequence differences, the panels of cDNA clones may also be used to address quantitative relationships and mutual correlation of ASPSs in mRNA isoforms. Since the PCR amplicon used to generate RT-PCR cDNA clones is rather large, the differences in size between the different isoforms due to insertions/deletions becomes comparatively smaller. This may promote a more equal amplification rate of the different isoforms being co-amplified in the PCR reaction, compared to PCR covering smaller sub-regions of the 11 Table  may serv11 Table  is not sRT Table , several+ mRNA and it is reasonable to assume that the corresponding mRNA isoforms are processed by the translation machinery with similar efficiency as the normal full-length isoform. If not, specific mechanisms must exist that can recognize the different internal insertions/deletions in these mRNAs and suppress transport/translation. Thus, the expected frequency of a particular protein isoform  depends in part on the frequency of the corresponding ASPS in mRNA, but also on the presence of additional ASPSs located further upstream. Since the majority of hTERT transcripts in lung and colon tissues contained two or more ASPSs, ASPSs located downstream (and in particular 3' to exon 8) are rarely continuous with the ORF  are similar in size to normal full-length. It would require a method with perfect one-nucleotide resolution for fragments above 2 kbp and an acceptable quantitative read-out. One solution to these problems is to map long PCR products (or cDNA clones) covering all ASPSs on individual basis as shown in Figure RT-PCR analysis of a sub-region in Del-e6 1\u20136 and DelhTERT ASPSs [hTERT mRNA. In the present study, by analysing a modest number of RT-PCR-generated cDNA clones from two different human tissues, six novel ASPSs were identified of which two represented dominating hTERT isoforms. A better understanding of hTERT mRNA processing and its implications for telomerase regulation will require more studies on human primary tissues, including those that are low or negative for telomerase activity. It is also necessary to use methods that do not discriminate between mRNA isoforms based on size, as opposed to PCR, since ASPSs may involve intronic insertions of considerable length. Detailed knowledge of the different hTERT isoforms present in human tissues and the ability to distinguish between them is required to obtain a proper understanding of telomerase function and regulation, and may identify hTERT sequences suitable for targeted cancer immuno therapy.Previous work addressing identification of RT ASPSs ,14,15 ha+ mRNA was isolated and double-selected from total RNA using the GenoPrep Direct mRNA kit  and cDNA synthesis was performed by using the StrataScript Reverse Transcriptase  with oligo(dT) priming as described by the manufacturer.Lung and colon tumour/adjacent tissue matched pair cDNA samples A-E were obtained from Clontech . Additional tissue samples were removed by surgery  and stored in RNAlater (Sigma-Aldrich) for preservation of RNA. The samples were homogenized in Trizol Reagent  using the Ultra-Turrax T8 homogenizer  and total RNA was isolated and purified according to the Trizol Reagent manual. Poly(A)hTERT gene was produced in two consecutive PCR reactions using two primers . Following transfection of E. coli DH10B and growth on LA-amp, colonies were picked at random for production of plasmid DNA .PCR fragments encompassing intron positions 2\u201315 in the hTERT RT-PCR plasmid clones were screened for the presence of ASPSs by running PCR with a panel of 6-fam-labelled primer pairs . Clones that contained insertions and/or deletions compared to normal full-length hTERT cDNA were sequenced through the relevant region using the MegaBACE sequencing system (Amersham).Individual rs Table  coveringhTERT ASPSs by performing two consecutive PCR reactions with a panel of 6-fam-labelled primer pairs  with 10% vol/vol of the first PCR as template, 20 cycles of PCR and other parameters as described for the first PCR. The products were analysed with the MegaBACE 1000 capillary electrophoresis unit.cDNA samples were screened for the presence of rs Table  coveringSSL carried out the design of the study, most of the experiments and drafted the manuscript. EF carried out molecular biology studies. GG participated in the coordination and revising of the manuscript. All authors read and approved the final manuscript."}
+{"text": "A novel therapy for improving selectivity in cancer chemotherapy aims to modify distribution of a cytotoxic drug by generating it selectively at tumour sites. In this approach an antibody-enzyme conjugate is allowed to localise at the tumour sites before injecting a prodrug which is converted to an active drug specifically by the targeted enzyme in the conjugate. We present here pharmacokinetic studies on the prodrug 4-(bis (2-chloroethyl) amino) benzoyl-L-glutamic acid and its activated derivative, benzoic acid mustard. The glutamic acid is cleaved from the prodrug to form the active drug by carboxypeptidase G2 (CPG2), an enzyme from Pseudomonas sp., which is not found in mammalian cells. The prodrug and its parent active drug were rapidly distributed in plasma and tissues after administration of prodrug or active drug  to mice bearing human choriocarcinoma xenografts. Prodrug and active drug both followed a two-compartment kinetic model. Prodrug was eliminated more rapidly  than active drug . Conversion of the prodrug to the activated parent drug was detected within 5 min of administration to mice which had previously received a F(ab')2-anti-human chorionic gonadotrophin antibody (W14A) conjugated to the enzyme, CPG2 . Tumour was the only tissue that activated all the prodrug reaching the site. It contained the highest concentration of targeted enzyme conjugate capable of catalysing the reaction of prodrug to drug. Plasma and other tissues were also capable of activating the prodrug but active drug production was limited by the amount of enzyme present. The active drug measured in plasma and tissues other than tumour was attributable to residual antibody-enzyme conjugate at non-tumour sites. Low levels of conjugate in tissues and plasma militate against the advantage of tumour localised enzyme therefore necessitating removal of non-localised enzyme."}
+{"text": "Although animals bearing the MAC16 colon adenocarcinoma showed progressive weight loss, the average food consumption  did not differ from non tumour-bearing controls , while animals bearing a related colon adenocarcinoma, MAC13, which had no effect on body weight had a significantly (P less than 0.01) elevated food intake  above controls. Weight loss in animals bearing the MAC16 tumour was associated with a significant reduction in the percentage contribution of the kidneys, colon and epididymal fat pads to the total body weight. Although loss of body fat occurred only in the MAC16 model, both tumours were capable of synthesising lipids from glucose both in vitro and in vivo at the same rate. In addition both tumours increased the rate of lipogenesis from glucose in kidney, liver and epididymal fat pads of the host. Lipogenesis from glucose would be expected to result in a loss of utilisable carbohydrate energy and thus would be expected to increase the overall energy requirements in the tumour-bearing state leading to catabolism of host body tissues if the energy intake is not increased."}
+{"text": "These often feature polymerase III (pol. III) promoters of either mouse or human origin.The use of small interfering RNA (siRNA) molecules in animals to achieve double-stranded RNA-mediated interference (RNAi) has recently emerged as a powerful method of sequence-specific gene knockdown. As DNA-based expression of short hairpin RNA (shRNA) for RNAi may offer some advantages over chemical and To develop a shRNA expression vector specifically for bovine RNAi applications, we identified and characterised a novel bovine U6 small nuclear RNA (snRNA) promoter from bovine sequence data. This promoter is the putative bovine homologue of the human U6-8 snRNA promoter, and features a number of functional sequence elements that are characteristic of these types of pol. III promoters. A PCR based cloning strategy was used to incorporate this promoter sequence into plasmid vectors along with shRNA sequences for RNAi. The promoter was then used to express shRNAs, which resulted in the efficient knockdown of an exogenous reporter gene and an endogenous bovine gene.We have mined data from the bovine genome sequencing project to identify a functional bovine U6 promoter and used the promoter sequence to construct a shRNA expression vector. The use of this native bovine promoter in shRNA expression is an important component of our future development of RNAi therapeutic and transgenic applications in bovine species. Caenorhabditis elegans, has been used to determine gene function  ATP using a mirVana Probe & Marker Kit (Ambion) and hybridised to the enriched RNAs using the mirVana miRNA Detection Kit (Ambion). The RNA fragments were then separated by electrophoresis on a 15% denaturing polyacrylamide/ 8 M Urea gel and detected by autoradiography.Detection of EGFP shRNAs was carried by out using an RNAse protection assay on extracts enriched for small RNAs isolated from transfected Vero cells using a LSL carried out all experiments and drafted the manuscript. TJD, RJM and MM participated in design and coordination of the research and revision of the manuscript. BPD and SM helped with bioinformatics and revision of the manuscript. All authors read and approved the final manuscript."}
+{"text": "An analysis has been made of the relationship between neuron specific enolase (NSE) in serum and immunohistochemically identified occurrence of NSE in the primary tumour in 56 patients with small cell lung cancer (SCLC). Patients were referred to the Finsen Institute for treatment during a period of 18 months. Forty-six tumours (82%) were NSE positive. To compare this staining with the occurrence of NSE in serum, a histological staining index (HSI) was established by semiquantitative gradation of the staining. No significant differences were found between distribution of serum NSE values in different HSI categories, and a high ranking in HSI was not associated with a high level of serum NSE. Both univariate and multivariate analysis selected serum NSE and not HSI as the most influential prognostic factor in SCLC."}
+{"text": "The effect on normal skin of combined modality treatment with 300 kV X-rays and photodynamic therapy (PDT) using the photosensitising drug meso-tetra (sulphonatophenyl) porphine (TPPS) was studied using the mouse tail necrosis assay. Prior treatment with a tolerance dose of PDT produced a significant increase in the probability of necrosis following graded doses of ionising radiation. A tolerance dose of X-rays administered prior to graded doses of PDT also produced a significant rise in the necrosis rate. TPPS appeared to have a radiosensitising effect but, as the animals were kept in subdued light, the low dose of PDT they therefore received may provide an alternative explanation. The effect of prolonging the interval between the modalities on the necrosis rate did not appear to be related to the time course of either the changes in blood flow produced by each modality, measured by xenon clearance studies or the development of the skin reaction following X-ray irradiation."}
+{"text": "The most recent treatment option of medically refractory heart failure includes cardiac resynchronization therapy (CRT) by biventricular pacing in selected patients in NYHA functional class III or IV heart failure. The widely used marker to indicate left ventricular (LV) asynchrony has been the surface ECG, but seems not to be a sufficient marker of the mechanical events within the LV and prediction of clinical response. This review presents an overview of techniques for identification of left ventricular intra- and interventricular asynchrony. Both manuscripts for electrical and mechanical asynchrony are reviewed, partly predicting response to CRT. In summary there is still no gold standard for assessment of LV asynchrony for CRT, but both traditional and new echocardiographic methods have shown asynchronous LV contraction in heart failure patients, and resynchronized LV contraction during CRT and should be implemented as additional methods for selecting patients to CRT. The most recent treatment option of medically refractory heart failure includes cardiac resynchronization therapy (CRT) by biventricular pacing in selected patients in NYHA functional class III or IV heart failure (HF) caused by idiopathic dilated (DCM) or ischemic cardiomyopathy, with QRS duration \u2265 130 milliseconds, left ventricular (LV) end-diastolic diameter \u2265 55 mm, and ejection fraction \u2264 35% . HoweverThe acute improvement of LV performance by CRT was demonstrated by reduction of capillary wedge pressure and an improvement in peak dp/dt without increase in myocardial oxygen consumption -14. LongThe main focus of this manuscript is to review LV asynchrony, and to present an overview of techniques for identification of left ventricular intraventricular and interventricular asynchrony.The widely used marker to indicate LV asynchrony has been the surface ECG. The rational for that, is that the electrical delayed stimulation may lead to a mechanical delay of the respective LV areas. In LBBB the lateral free wall is activated later than the interventricular septum and thus leads to a delayed contraction of LV free wall. This surrogate marker represented by LBBB is one of the criteria indicating implantation of CRT . It is sIn 29 patients Alonso et al showed that reducing the QRS duration by CRT correlated to a positive clinical response suggesting a hemodynamic improvement associated with narrowing of QRS indicating reduction of the mechanical asynchrony of LV contraction. The study concluded even that the optimal placement for hemodynamic LV improvement of the right and LV leads would be those sites that could induce the greatest shortening of QRS duration . HoweverAn additional method to elucidate the intraventricular activation pattern in HF patients eligible for CRT is electroanatomical activation mapping.  In 26 patients Peichl et al. showed that the surface ECG is of limited value to describe the complex conduction disturbance of the LV . They foAlso Yu et al. showed that endocardial electrical LV activation sequences was variable among 7 HF patients with LBBB . LambiasAsynchronous contraction of LV was demonstrated in patients with DCM with intraventricular conduction delay by Curry et al., who used MRI . MRI is  By using gated equilibrium radionuclide angiography and Fourier phase analyses Fauchier et al. demonstrated in 103 patients  with DCM that QRS duration was related to both interventricular and intraventricular asynchrony . FurtherAnother radionuclide angioscintigraphy study by Toussaint JF et al.  in 21 patients showed that resynchronization by CRT between LV apex and base which persisted up to 12 months was also associated with a persisting improvement in LV systolic function . The samKerwin et al. used gated blood pool scintigraphy in 13 patients to demonstrate asynchronous contraction of LV and to show the resynchronizing effect of CRT . DCM witEchocardiography is an essential method to diagnose HF and is also used to evaluate the effect of treatment to improve cardiac performance. The echocardiographic measurement of LV fractional shortening by M-mode and EF measured from two-dimensional images by using Simpsons method in accordance with the recommendations of the American Society of Echocardiography Committee, are widely used parameters for cardiac evaluation . An addi150 ms  predicted response to CRT in terms of > 15 % reduction of left ventricular end-systolic volume index in 79% of the patients. The authors demonstrated the prediction of reverse remodelling by septal-to-posterior wall motion delay to be more precise than the QRS duration (accuracy 85% vs. 65%) Using the septal-to-posterior wall motion delay in M-mode recordings from the parasternal short axis view Pitzalis et al. demonstrated in 20 patients that a septal-to-posterior wall motion delay  of  \u2265 130 ms and QRS duration   \u2265. The samThe septal-to-posterior wall motion delay in M-mode recordings can also be examined in the parastrenal long axis view and a decrease of the posterior delay during CRT can be shown .The measurement of interventricular electromechanical delay using pulsed Doppler imaging was examined by Rouleau  et al in 35 patients with DCM . A QRS wVarious echocardiographic parameters of ventricular asynchrony were examined by Bordachar et. al in 41 patients undergoing CRT. Changes in interventricular asynchrony, defined as the difference between the aortic and pulmonary pre-ejection delays and determined as the time from the onset of the QRS complex to the beginning of each respective systolic ejection by pulsed wave Doppler imaging were not correlated with changes in cardiac output, whereas several TVI modalities could confirm high correlation with hemodynamic changes .The use of pulsed tissue velocity Doppler imaging by Ansalone et al in 21 non ischemic patients receiving CRT demonstrated a reduction of asynchronous contraction of LV basal segments. After CRT, LV performance improved significantly in patients with better LV resynchronization evaluated by TVI, whereas the QRS narrowing was not predictive of this functional improvement .The effect of inflow based AV optimization adopted from use in DDD pacing  showed iFunctional mitral regurgitation is reduced by CRT in patients with HF and LBBB shown in 24 patients by Breithardt et al, explained by a more coordinated LV contraction and due to the increased closing force (left ventricular systolic pressure rise) .A new echocardiographic method based on contrast variability imaging was used in 10 patients by Kawaguchi et al. to quantify asynchrony and magnitude of resynchronization achieved by CRT . The metA semiautomatic border detection method based on the fact that each region of the ventricular endocardial wall undergoes a periodic cycle of inward and outward displacement was performed in 34 patients by Breithardt et al. The authors showed a septal-lateral resynchronization during CRT by using this echocardiographic phase analysis of radial endocardial wall motion predicting an acute hemodynamic response (dp/dt) .Three dimensional (3 D) echocardiography has been used by Kim et al. to document hemodynamic improvement by CRT  and additionally to identify LV segments with asynchrony . The latThe excellent time resolution of c-TVI by using a postprocessing procedure is used in several studies to demonstrate the regional time aspect of LV contraction. In addition to the high time resolution another main advantage of c-TVI method is the possibility of comparing the contraction pattern of different LV regions simultaneously from the recording. Synchronicity of LV contraction pattern in the structurally normal heart is demonstrated  and compared to HF patients with bundle brunch block  showing a significant asynchrony within the LV in the HF patients ,47. FigComparing surface ECG with the mechanical contraction pattern in HF patients showed that neither QRS duration nor QRS pattern predicts the mechanical asynchrony. Even HF patients with normal QRS width can have significant LV asynchronous contraction ,49. The Using c-TVI has shown resynchronization during CRT, both as measurement of regional contraction timed to the QRS complex  by Yu et al. and measured as an absolute resynchronization of the contraction of LV septum and the lateral free wall by Schuster et al. and by Bax et al -54. One The measurement of LV segment shortening or lengthening (strain) is also used to demonstrate resynchronization during CRT, but the more angle dependency of strain compared to TVI allows only the measurement of relative resynchronization because of the fact that the different regions have to be examined in separate recordings. However a resynchronization effect by CRT is shown using the strain method by Breithardt et al .The above mentioned manuscripts deal partly with concordance or disconcordance of electrical and mechanical markers of asynchrony. Despite the findings of angioscintigraphic asynchrony related to the QRS complex , in summ"}
+{"text": "The primary aims of this study were purification and molecular cloning of a putative retrovirus designated human mammary tumour virus (HMTV). However, our preliminary unpublished data of negative reverse transcriptase (RT) activity in ostensibly 'infected' cells led us to re-examine the evidence for this virus; namely multinucleate giant cell (MNGC) formation and RT activity in cultured blood monocytes from breast cancer patients versus benign breast tumour and normal control subjects. MNGCs from by fusion of monocytes and we estimated the total number of cell fusions which had occurred after 10 days of culture in vitro by counting cells with two, three, four and five or more nuclei (n) and by measuring the density of adherent mononuclear cells for each subject studied. We found no clear-cut difference in MNGC formation between the three subject groups. Moreover, a substantial number of cultures, encompassing the three groups, showed far more MNGCs per 10(5) monocytes than previously reported. Various parametric and nonparametric statistical analyses were performed on the multinucleate cell data and only one parametric test, which utilised the density of monolayers as a co-variate, showed a statistically significant difference at the 5% level between the breast cancer and the normal subject groups. We observed marked subject-to-subject variation in multinucleate cell formation and we suggest that the evidence for a difference between the breast cancer and the normal groups is marginal. Further, MNGC formation by breast cancer monocytes may not be attributed to the presence of a retrovirus since 5'-Azacytidine (AZA), an agent known to stimulate replication of latent retroviruses showed no effect on the MNGC formation. In addition, culture supernatants from the three groups were assayed for RT activity and no test sample gave a significant signal above background. Preliminary transmission electron microscopy analysis failed to identify viral particles in MNGCs."}
+{"text": "The design of clinical trials of interventions aimed at reducing mortality in patients with severe sepsis assumes that the relative treatment effect of the intervention is independent of the patients' risk for death. We reviewed published data from phase III clinical studies of severe sepsis to determine whether a relationship exists between risk for death and the relative benefit of the investigational agent. Such an interaction might warrant a change in the assumptions that underlie current trial designs.We conducted a systematic review of published phase III, randomized, placebo-controlled trials in adult patients with sepsis, severe sepsis, or septic shock up to November 2004. All studies enrolled patients with known or suspected infection, evidence of a systemic response to the infection, and one or more organ dysfunctions resulting from the systemic response.Twenty-two publications, investigating 17 molecular entities, fulfilled criteria for phase III or equivalent studies aimed at reducing mortality in adult patients with severe sepsis or septic shock. Three studies achieved the prospectively defined primary end-point of a statistically significant reduction in 28-day all-cause mortality. The control group mortality rates for these studies were 31%, 43% and 61%, indicating that the beneficial effects of adjunct therapies could be demonstrated over a wide range of illness severity. Analysis of subgroup data from failed studies provided no evidence that the efficacy of the therapeutics being investigated varied by baseline placebo mortality rates. Among all studies, interventions with anticoagulant activity or anti-inflammatory activity did not appear to be harmful in patients with evidence of less coagulopathy or less inflammation.Our review of published clinical data does not support the hypothesis that mortality risk of the population studied alters the relative treatment effect associated with anti-inflammatory or other agents used to treat severe sepsis. Clinical studies in severe sepsis should continue to enroll patients over a wide range of disease severity, as long as patients enrolled have evidence of sepsis-induced organ dysfunction(s), patients are at an appreciable risk for death (e.g. as evidenced by admission to an intensive care unit), and the potential for benefit outweighs the potential for harm. The development of agents aimed at reducing mortality from severe sepsis has been predicated on the hypothesis that death results from sepsis-induced organ dysfunction, the latter being the consequence of an excessive or uncontrolled host response to the infection -3. Fundapost hoc analyses of successful and failed clinical trials in patients with severe sepsis [Recent publications -8 have ce sepsis . Howevere sepsis  failed tWe therefore undertook a systematic review of all published phase III, randomized, controlled clinical trials in adult patients with severe sepsis or septic shock to determine whether there were data supporting the hypothesis that biologic modifiers might be associated with qualitative treatment effects dependent on disease severity . Understanding whether data from prior clinical trials suggest that these agents might produce differential effects on survival depending on a patient's severity of illness is important in designing future trials of newer agents in severe sepsis. We report the lack of any such data and discuss the advantages and disadvantages of current trial designs in severe sepsis.Publications of randomized, placebo-controlled phase III or phase III equivalent studies that tested the effects of specific pharmaceutical interventions aimed at improving survival from severe sepsis were identified by a search of the PubMed database. The following search terms were used, each with restrictions for human studies and randomized controlled trials: sepsis and mortality, and severe sepsis and mortality. An additional check of the PubMed database was conducted using the search terms sepsis or severe sepsis, with restrictions for human studies and meta-analysis. Reference lists from these latter publications were cross-checked against the original search results to identify any additional reports. The PubMed database was searched multiple times throughout the preparation of this manuscript. The final search was conducted on 29 November 2004.Studies were included in this analysis if they met the following criteria: randomized, double blind, placebo controlled clinical trial; enrollment of adult patients who met the diagnosis of severe sepsis or septic shock; assessment of 28- to 30-day all-cause mortality as the primary outcome; and adequate power (\u2265 80%) to detect statistically significant improvements in the primary outcome at the two-sided alpha of 0.05. Studies that compared more than one active therapy arm with placebo were required to include an intent to adjust statistically for two or more comparisons (e.g. Bonferroni procedure) . LikewisSevere sepsis was defined in all studies as follows: the presence of known or suspected infection; evidence of a systemic response to infection ; and one or more organ dysfunctions resulting directly from the systemic response to infection . Septic shock was defined as the presence of either hypotension (absolute or relative) or the need for vasopressor support to maintain adequate perfusion and evidence of end-organ hypoperfusion.The primary end-point of 28-day all-cause mortality was extracted from all studies with no adjustment for imbalance in baseline characteristics between patient treatment groups. Quantitative assessments of outcome at 28 days for subgroups defined by baseline measures of disease severity were also extracted. These subpopulations included groups defined by Simplified Acute Physiology Score , Acute PData pertaining to the safety of the intervention was also extracted. In particular, the incidence of any post-treatment infectious complications was specifically sought.Mortality rates were extracted from publications. Some reports included the total number of patients within severity classes but did not include per treatment sample sizes within severity groups. In these instances, calculations of placebo and treatment sample sizes per groups assumed that patients were evenly divided between treatment groups. The information extracted was used in a logistic regression to determine whether there was a significant interaction between treatment and severity after adjusting for overall treatment and severity effects. One severity classification was selected per study. If multiple severity classes were reported, priority was attributed in the following order: predicted risk for death; APACHE II; shock versus no shock; and remaining available severity measure. Analyses were performed using SAS version 8.02 software .n = 43), non-phase III studies of biologic response modifiers in severe sepsis (n = 158), antibiotic studies in severe sepsis (n = 76), nonantibiotic, nonbiologic response modifier studies in severe sepsis (n = 41), and unrelated studies (n = 335). A total of 110 unique reports were identified using the search terms sepsis or severe sepsis and restricted to meta-analyses of human studies, of which nine were specific to severe sepsis. From the initial publication list and review of the references from identified meta-analyses, 22 reports, investigating 17 molecular entities, fulfilled criteria for phase III or equivalent studies aimed at reducing mortality in adult patients with severe sepsis or septic shock , neither treatment (P = 0.32) nor an interaction between treatment and severity of illness (P = 0.70) was significantly related to mortality. For failed studies reporting survival data for subgroups defined by baseline measures of disease severity, four demonstrated lower mortality in the active treatment arm in subgroups with lower severity of illness. These were the studies by Opal and coworkers in 2004 [Figure  in 2004 , Abraham in 2004 , Greenma in 2004  and Abra in 2004  , better outcomes were observed in higher severity subgroups defined by APACHE II scoring and in lower severity subgroups defined by biologic markers of disease severity (i.e. IL-6 level and prothrombin time) . For patAmong all studies, interventions with anticoagulant activity or anti-inflammatory activity did not appear to be harmful in patients with evidence of less coagulopathy (as assessed by coagulation tests) or less inflammation (as assessed by IL-6 levels). Three studies of medications with anticoagulant properties were reported ,29,35. FTable Recent publications and editorials have suggested that one possible explanation for the discordance between the preclinical efficacy and subsequent clinical failures of many therapeutics investigated in severe sepsis is that these therapies might be expected to reduce mortality only in the most severely ill patients or those patients at highest risk for death -8. ImpliTwenty-two publications investigating 17 different pharmacotherapeutic agents targeting the host response to infection were identified. Only phase III studies were included to reduce potential noise related to small sample size and multiple dosing regimens. Three studies met their prospectively defined end-point. The control mortality rates range between 31% and 61%, indicating that the beneficial effects of adjunct therapies could be demonstrated over a wide range of illness severity. For failed trials, lower control mortality rates did not appear to be an explanation for possible failures Fig. .The first phase III study of IL-1ra has frequently been cited as evidence for the existence of a differential effect of treatment based on disease severity ,32. In tAdditionally, interventions with anticoagulant activity or anti-inflammatory activity did not appear to be harmful in patients with evidence of less coagulopathy (as assessed by coagulation tests) or less inflammation (as assessed by IL-6 levels). Almost all investigated therapeutics had some reported anti-inflammatory effects. However, in the three studies that reported outcomes by baseline IL-6 levels ,36,37 thReview of the safety data from each of the published studies indicates that the current reporting system for adverse events appears to be adequate in capturing potential toxicities associated with these therapies. An increased risk for bleeding complications was noted for antithrombin III, tissue factor pathway inhibitor, and drotrecogin alfa (activated), which is consistent with their anticoagulant properties. Multiple studies investigating murine-based antibodies documented allergic and anaphylactic reactions associated with therapy. Antibody formation was also documented. The nitric oxide synthase inhibitor study, in which statistically higher mortality was observed in the active treatment arm, reported a higher incidence of cardiovascular related deaths in the active treatment arm. No study reported adverse events that might be considered related to inhibition of the host response to infection. However, in the study conducted by Bone and coworkers  of high Interactions between treatment and disease severity can be generally classified into two major categories: quantitative interactions, in which the relative benefit of a drug may be less in less severe disease; and qualitative interactions, in which the drug is truly beneficial at one level of severity and truly detrimental at another. For quantitative interactions a more favorable benefit:risk ratio might exist for patients with more severe disease, assuming that the absolute benefit of therapy is greater for more severely ill patients and that the absolute risk of therapy is uniformly distributed across disease severities. This type of interaction is not uncommon, and physicians and other health care providers commonly weigh the benefits and risks associated with all medicines before administration. Drotrecogin alfa (activated) may exhibit a quantitative interaction particularly from a risk:benefit perspective, because absolute reductions in mortality are larger for populations at higher risk for death whereas the bleeding complications of therapy appear to be independent of disease severity. As a consequence, many regulatory agencies limited the use of drotrecogin alfa (activated) to patients with severe sepsis at higher risk of death ,39.Qualitative interactions, on the other hand, are probably rare . This tyUnderstanding whether data from prior clinical trials suggest that these agents might produce differential effects on survival depending on a patient's severity of illness is important in designing future trials of newer agents in severe sepsis. If present, such a qualitative interaction could warrant a change in the design of phase III trials that currently enroll patients with severe sepsis over a wide range of disease severity (e.g. one to five organ dysfunctions) and predicted risk for death . Additionally, current recommendations for the treatment of severe sepsis assume, to some degree, the absence of interactions between treatment and disease severity. For example, intensive insulin therapy was demonstrated to reduce mortality in a population of nonseptic patients at very low risk for death . Intensiper se, because a similar outcome was not observed in medical patients with a single organ dysfunction. Other potential confounders might include difficulty in making a diagnosis of severe sepsis in postoperative patients with a single organ dysfunction, a delay in treatment of these patients because of the requirement to delay therapy for 12 hours after surgery, and a higher risk for bleeding complications. This adverse finding prompted revision of the product label for drotrecogin alfa (activated) [The lack of evidence for a qualitative interaction between treatment and severity does not preclude that such an interaction may indeed exist. The recently completed study of drotrecogin alfa (activated) in patients with severe sepsis at lower risk of death (ADDRESS)  was stoptivated) ,39.The observations from the ADDRESS study  underscopost hoc subgroups is also biased because those subgroups reported in publications of negative trials may represent those in which a beneficial treatment effect was observed in at least one stratum, leaving an unfavorable effect in the complementary strata. The study of HA-1A was included in this analysis despite concerns over the statistical rigor of the study because the intent of the present analysis was not to demonstrate that any therapy was or was not effective but to determine whether evidence supporting an interaction between treatment and disease severity exists amongst published clinical data. A follow-up study of HA-1A in a similar population of patients with severe sepsis was stopped because of futility [There are multiple limitations to the above analyses. As with any analysis based on literature review, there is always a concern regarding publication bias. Furthermore, analyses based on futility . The folA review of published clinical data does not support the hypothesis that there is a qualitative interaction between treatment and severity associated with anti-inflammatory or other agents used to treat severe sepsis. Clinical studies in severe sepsis should continue to enroll patients over a wide range of disease severity and risk for death, as long as patients enrolled have evidence of sepsis-induced organ dysfunction(s), patients are at an appreciable risk for death (e.g. as evidenced by admission to an intensive care unit), and the potential for benefit outweighs any potential for harm.\u2022 \tSevere sepsis trials assume that the relative treatment effect of an intervention is independent of the patients' risk for death.\u2022 \tThree studies met the prospectively defined primary end-point of a statistically significant reduction in 28-day all-cause mortality.\u2022 \tThe lack of demonstrated efficacy in the negative studies is not due to enrollment of less severe or more severely ill patients.\u2022 \tInterventions with anticoagulant activity or anti-inflammatory activity did not appear to be harmful in patients with evidence of less coagulopathy or inflammation.\u2022 \tClinical studies in severe sepsis should continue to enroll patients over a wide range of disease severity.APACHE = Acute Physiology and Chronic Health Evaluation; IL = interleukin; IL-1ra = IL-1 receptor antagonist.All authors are employees and shareholders of Eli Lilly and Company, who hold a patent in activated protein C.WM conceived the design and methods of this study and drafted the manuscript. DN performed all statistical analyses and participated in manuscript preparation. MW helped perform literature review and drafted/edited the manuscript. RG helped perform literature review and drafting of manuscript. JJ helped perform literature review and drafting of manuscript. AS assisted DN with statistical analyses and drafting of manuscript. All authors read and approved the final manuscript."}
+{"text": "Cells from V79 multicell spheroids must be exposed to approximately 50 times more etoposide than exponentially growing monolayers in order to produce the same amount of cell killing. A part of this difference in sensitivity is readily explained by the decrease in growth fraction of large spheroids, and by the protection afforded by nutrient deprivation which also reduces cellular ATP. However, cells composing the outer 10% of large (approximately 600 microns diameter) V79 spheroids, although actively cycling, were still ten times more resistant to etoposide than exponentially growing monolayers, regardless of whether cells were exposed in situ in spheroids or dispersed by trypsin immediately prior to exposure to the drug. Four cell doublings (48 h) as monolayers were required before the outer cells of spheroids regained drug sensitivity equivalent to that of exponentially growing monolayers. No differences in uptake/efflux of 3H-etoposide or in levels of p-glycoprotein were observed between monolayers and the outer cells of spheroids. In addition, topoisomerase II protein measured by immunoblotting and topoisomerase II activity measured by decatenation of kinetoplast DNA were not reduced in the outer cells of spheroids compared to monolayers. DNA strand breakage measured in individual cells using the DNA precipitation and comet assays correlated well with cell killing with one exception: DNA damage was not affected when cells were incubated with etoposide in phosphate-buffered saline, although the etoposide concentration required to produce a given amount of cell killing was increased approximately 7-fold compared to cells incubated with the drug in complete medium. These results indicate that etoposide toxicity towards V79 spheroids is influenced not only by proliferative status of the cells but also by factors which may include DNA packaging and the growth environment of the cell prior to and during treatment."}
+{"text": "The most prominent cellular changes in heat-shock response are induction of HSPs synthesis and reorganisation of cytoskeleton. Vincristine was used as a tool to evaluate the integrity of microtubules in 9L rat brain tumour cells recovering from heat-shock treatment. Cells treated at 45 degrees C for 15 min and recovered under normal growing condition became resistant to vincristine-inflicted cytotoxicity and microtubule destruction. Among all HSPs, the level of HSP70 and the degree of vincristine resistance are best correlated. HSP70 and tubulin were found to be associated with each other as they were co-immunoprecipitated by either anti-HSP70 or anti-beta-tubulin monoclonal antibody. The current studies establish for the first time that HSP70 can complex with tubulin in cells and this association may stabilise the organisation of microtubules thus protect the heat-treated cells from vincristine damage. These findings are noteworthy in combining hyperthermia and chemotherapy in the management of malignant diseases."}
+{"text": "Photodynamic therapy (PDT) is efficacious in the treatment of small malignant lesions when all cells in the tumour receive sufficient drug, oxygen and light to induce a photodynamic effect capable of complete cytotoxicity. In large tumours, only partial effectiveness is observed presumably because of insufficient light penetration into the tissue. The heterogeneity of the metabolic response in mammary tumours following PDT has been followed in vivo using localised phosphorus NMR spectroscopy. Alterations in nucleoside triphosphates (NTP), inorganic phosphate (Pi) and pH within localised regions of the tumour were monitored over 24-48 h following PDT irradiation of the tumour. Reduction of NTP and increases in Pi were observed at 4-6 h after PDT irradiation in all regions of treated tumours. The uppermost regions of the tumours (those nearest the skin surface and exposed to the greatest light fluence) displayed the greatest and most prolonged reduction of NTP and concomitant increase in Pi resulting in necrosis. The metabolite concentrations in tumour regions located towards the base of the tumour returned a near pre-treatment levels by 24-48 h after irradiation. The ability to follow heterogeneous metabolic responses in situ provides one means to assess the degree of metabolic inhibition which subsequently leads to tumour necrosis."}
+{"text": "High levels of neurotensin-like immunoreactivity were found in human small cell lung carcinoma lines. No immunoreactivity was present in non-small cell carcinoma lines and only low amounts in postmortem human lung tissue. The immunoreactive material co-eluted with synthetic neurotensin on two different chromatographic systems. No evidence was obtained for the presence of specific neurotensin binding sites in any of the small cell carcinoma lines examined. The results suggest that small lung cell carcinoma lines may be useful for studying the biosynthesis of human neurotensin."}
+{"text": "A case-control study on cancers of the oral cavity was conducted by utilising data from the population based cancer registry. Bangalore, India. Three hundred and forty-eight cases of cancers of the oral cavity (excluding base tongue) were age and sex matched with controls from the same residential area but with no evidence of cancer. The relative risk due to pan tobacco chewing was elevated in both males and females, being appreciably higher in the latter . A statistically significant (linear test for trend P less than 0.001) dose response based on years, times per day and period of time chewed was seen. Any smoking (cigarette or bidi or both) had only slightly elevated risk of developing oral cancer, whereas a history of alcohol drinking or inhalation of snuff did not influence the risk. A new finding of our study was the markedly elevated risk of oral cancer in persons consuming ragi  in comparison to those not consuming ragi as staple cereal in their diet. There also appeared to be some interaction between ragi consumption and tobacco chewing with substantially higher relative risks in those who pursued both habits compared to those who gave a history of either."}
+{"text": "Autonomic nervous system plays an integral role in homeostasis. Autonomic modulation can frequently be altered in patients with cardiac disorders as well as in patients with other critical illnesses or injuries. Assessment of heart rate variability is based on analysis of consecutive normal R-R intervals and may provide quantitative information on the modulation of cardiac vagal and sympathetic nerve input. The hypothesis that depressed heart rate variability may occur over a broad range of illness and injury, and may inversely correlated with disease severity and outcome has been tested in various clinical settings over the last decade. This article reviews recent literature concerning the potential clinical implications and limitations of heart rate variability assessment in general medicine. Autonomic nervous system plays an integral role in many aspects of homeostasis, and it is affected by a wide variety of pathophysiologic conditions. Assessment of heart rate variability (HRV) is based on the analysis of consecutive sinus rhythm R-R intervals and may provide quantitative information about the modulation of cardiac vagal and sympathetic nerve activities. HRV measurements can be derived from short-term (2 to 5 minutes) or long-term ECG recordings (24 to 48 hours). It can be quantified in a number of ways but techniques of conventional time domain  and frequency domain measurements  remain predominantly utilised . Recentl Autonomic nervous system plays a central role in the maintenance of hemodynamic stability. Cardiac autonomic dysfunction may result in serious complications, such as malignant cardiac arrhythmias and/or sudden cardiac death. The analysis of HRV has been widely explored in cardiac research during last decades. HRV has been recognised as a powerful risk stratifier for adverse cardiac events in patients surviving myocardial infarction and for identifying patients with diabetic neuropathy. HRV is affected by a number of physiological and pathological conditions. Significantly altered HRV can be found not only in cardiac diseases but also in a wide variety of pathophysiologic disorders characterised by neurohumoral activation . Physiologic systems constantly change over time and respond to stimuli. Physiologic systems of young healthy subjects exhibit marked physiological signal variability and complexity, while aging or diseased systems show a loss of variability, decreased complexity, and increased regularity . The losAutonomic dysfunction is frequently seen in cardiac disorders or other diseases including those requiring admission to intensive care unit such as myocardial infarction ,8, multiA general consensus of a practical use of HRV has been reached in the setting of myocardial infarction. Depressed HRV indicates increased risk of malignant arrhythmias and of mortality after acute myocardial infarction and the prognostic value of time and geometric parameters of HRV has been consistently confirmed . Carney A number of recent studies confirmed that HRV was significantly depressed in patients with decompensated heart failure and assessment of HRV could be used to identify heart failure patients with poor prognosis ,23-25. BMore recent report from ATRAMI confirmed the predictive value of HRV for life-threatening arrhythmias in patients after myocardial infarction . HRV  analysis of HRV have been applied to evaluate autonomic modulation and cardiovascular function in patients after cardiovascular surgery -40. SteiAbout two decades ago, Lowensohn tested whether or not the characteristics of the adult heart rate reflected the condition of the central nervous system as they appear to characterise it in the fetus. They found that the normal cyclic changes in heart rate were reduced in the presence of severe brain damage. HRV decreased rapidly when intracranial pressure rose, and the rate of return of variability reflected the subsequent state of neuronal function, even when intracranial pressure was restored to normal. Thus, it appears in this limited setting that HRV may reflect the functional state of the central nervous system . Power s Meglic et al assessed HRV by power spectra analysis in 14 patients with acute brainstem stroke. Transient dysfunction of autonomic nervous system was found in patients with acute medullary stroke (n=6) in contrast to those with non-medullary (n=8) brainstem stroke . HoweverFlachenecker et al conducted serial studies in patients with Guillain-Barre syndrome and found that the sympathovagal balance shifted to sympathetic predominance at the height of the disease -47. The Cardiac autonomic dysfunction is associated with mortality in patients with end-stage renal disease. Cashion et al evaluated the value of HRV analysis in 278 patients with end-stage renal disease to identify those at high risk of sudden cardiac death. They showed that end-stage renal disease patients, particularly diabetics, had a compromised autonomic function. Although they suggest that 24-hour time domain measure of the HRV held the promise of identifying patients at increased risk of death, this study contained only 5 patients with sudden cardiac death . In patiGodin et al prospectively studied the relation between human endotoxemia to loss of the physiologic beat-to-beat variability of heart rate. They found that endotoxin administration was associated with loss of the variability by all measures of HRV in healthy volunteers . Later fIt was hypothesised that septic shock resulted in an uncoupling of organ system interconnectivity and that the uncoupling phenomenon could be quantified as a loss in HRV . GoldsteAs early as in 1965, Hon and Lee noted that fetal distress was preceded by alterations in the beat-to-beat intervals before any appreciable changes occurred in heart rate itself . More reA number of recent studies showed that altered HRV was found in other patients populations including Parkinson disease , sleep aThe expansion of heart rate variability analysis has been facilitated by the remarkable development of computer sciences and digital signal processing during the last decades. The prognostic value of time and geometric parameters of HRV has been consistently confirmed. It seems encouraging that HRV analysis may provide additional diagnostic and prognostic information within the context of multiple confounding factors, which are associated with various pathophysiologic conditions. It has been known that both linear and non-linear components of HRV may be significantly altered in critically ill patients . The newHRV analysis is a recognised tool for the estimation of cardiac autonomic modulations. Reduced HRV is a powerful and independent predictor of an adverse prognosis in patients with cardiac disease. It has a potential to become a non-invasive diagnostic and prognostic index in clinical practice, particularly in patients with post myocardial infarction and diabetic neuropathy. Although assessment of HRV in other clinical settings seems to be helpful and promising, substantial number of further prospective studies in larger population are needed to evaluate the validity of HRV in general medicine."}
+{"text": "Intratumoral induction of tumour necrosis factor (TNF) by administration of Bordetella pertussis vaccine (BPV) as compared with that by the agent OK-432 was investigated in mice. Two hours after such administration tumour tissues tested were resected from the mice, homogenised, and the TNF activities in the homogenate were assayed using a L-929 fibroblast assay. Intravenous injection of BPV into mice bearing the MM46 carcinoma resulted in a greater concentration of TNF in the tumour homogenate than in the serum. With OK-432, however, there was a greater concentration of TNF in the serum than in the tumour homogenates. A high level of intratumoral TNF induction by BPV was also observed in mice bearing Meth A fibrosarcoma or Lewis lung carcinoma. The therapeutic effect against the Meth A fibrosarcoma was in parallel with the intratumoral TNF activity. Intratumoral TNF activity is therefore believed to be a good index of therapeutic effect."}
+{"text": "The in vitro clonogenicity of 25 human tumours was compared in two simple two layer culture systems, agar/agar and liquid medium/agar. There was a strong correlation between the values for clonogenicity obtained in each system. A linear relationship between cells plated and colonies formed was found in both systems. Radiation survival in the liquid culture system was essentially log linear with a small initial shoulder confirming that we were not simply counting clumps. We present a simple method of assessing the self-renewal capability of the clonogenic cells of human solid tumours, based on the liquid/agar two-layer system, which we have used to compare secondary plating efficiency and colony size analysis as measures of self renewal in human transitional cell carcinoma of the bladder."}
+{"text": "Comparison of data produced on different microarray platforms often shows surprising discordance. It is not clear whether this discrepancy is caused by noisy data or by improper probe matching between platforms. We investigated whether the significant level of inconsistency between results produced by alternative gene expression microarray platforms could be reduced by stringent sequence matching of microarray probes. We mapped the short oligo probes of the Affymetrix platform onto cDNA clones of the Stanford microarray platform. Affymetrix probes were reassigned to redefined probe sets if they mapped to the same cDNA clone sequence, regardless of the original manufacturer-defined grouping. The NCI-60 gene expression profiles produced by Affymetrix HuFL platform were recalculated using these redefined probe sets and compared to previously published cDNA measurements of the same panel of RNA samples.The redefined probe sets displayed a substantially higher level of cross-platform consistency at the level of gene correlation, cell line correlation and unsupervised hierarchical clustering. The same strategy allowed an almost complete correspondence of breast cancer subtype classification between Affymetrix gene chip and cDNA microarray derived gene expression data, and gave an increased level of similarity between normal lung derived gene expression profiles using the two technologies. In total, two Affymetrix gene-chip platforms were remapped to three cDNA platforms in the various cross-platform analyses, resulting in improved concordance in each case.We have shown that probes which target overlapping transcript sequence regions on cDNA microarrays and Affymetrix gene-chips exhibit a greater level of concordance than the corresponding Unigene or sequence matched features. This method will be useful for the integrated analysis of gene expression data generated by multiple disparate measurement platforms. The first years of microarray analysis of human cancer samples produced several promising results, introducing complex gene expression profiles for diagnostics and predicting disease outcome . HoweverOne of the difficulties in the cross platform comparison of microarray data is to ascertain that probes on the various platforms aimed at the same gene do in fact quantify the same mRNA transcript. The various strategies to match probes between different platforms can be constrained by the amount of information provided by the manufacturers of the given microarray. Initially, actual probe sequence information was not released; therefore, probe matching could be based only on gene identifiers such as the Unigene ID. This strategy is known to produce a significant number of incorrect pairings . As partIn a recent study, we compared several Affymetrix platforms (for which probe sequence information was available) to the Agilent Human 1 cDNA microarray platform . Probe sIn contrast to the Agilent probes, short sequences from both the 5' and 3' ends are generally available for clones on Stanford cDNA microarrays. Using these sequences to infer the complete clone sequence, we show that the level of probe sequence overlap is highly related to the gene expression concordance between the Affymetrix and cDNA microarray platforms. Eliminating non-overlapping probes allowed us to extract more consistent results from cancer associated gene expression data produced by different platforms and in different institutions.Depending on availability or the set of genes to be quantified, large scale gene expression profiling studies have used different versions of chips of a given microarray platform. For the data sets analyzed in this study two types of Affymetrix chips were used: the HuFL oligo chips and the U95Av2 chips. These contain 20 and 16 oligo probes per probe set, respectively. For the cDNA microarray studies, the pool of actual clones shows a very high level of diversity between various studies. Therefore, the exact number of overlapping probes depended on both the specific generation of Affymetrix platform and the set of cDNA clones to which it was mapped. A summary of these data is listed in Table Because cDNA microarray measurements are typically reported as the log ratio of an experimental (Cy5) and control (Cy3) channel, direct comparison with single-channel Affymetrix data required that one of the two data sources be converted to a scale compatible with the other. Because the spot-size on robotically spotted cDNA microarrays can vary substantially, considering only the experimental channel would have given expression measurements prone to probe-quantity artifacts. On the other hand, without direct measurement on the Affymetrix platform of the control RNA used in the cDNA hybridization, it was impossible to replicate exactly the reference response level of each measurement feature.We attempted to address this difficulty by assuming that the reference RNA batches chosen for each cDNA hybridization uniformly reflect the diversity of experimental transcript populations and therefore that the mean of a gene's measured expression level across all experiments may serve as a reference for the normalization of Affymetrix data (methods). We verified that the mean expression measured by each Affymetrix array did not vary substantially (max- min < 0.25).The NCI-60 cell line panel consists of sixty well characterized human tumor cell lines derived from patients with leukaemia, melanoma, and lung, colon, central nervous system, ovarian, renal, breast and prostate cancers. This cell line panel has been developed by the Developmental Therapeutics Program of the National Cancer Institute and routinely used to screen potential anticancer drugs .The gene expression profiles of the NCI-60 cell line panel measured by cDNA microarray and by Affymetrix HuFL oligo chips constitutes a unique data source. To the best of our knowledge, it is the only publicly available dataset in which replicates of a large number of diverse RNA samples have been quantified by these two microarray platforms. Affymetrix microarray probe sets were classified based on their shared sequence identity across the two platforms.Since the actual number of overlapping probes can be between 0 and 20, a large number of potential stratification schemes can be implemented. However, for a clear presentation of results we chose to compare the following classes representing different levels of shared identity: a) Affymetrix probe sets that share a Unigene ID with a cDNA clone. (termed Shared Unigene probes) b) Affymetrix probe sets containing probes that could be sequence-matched to the same transcript sequence as the cDNA clone, but for which no Affymetrix probe actually overlaps the cDNA clone sequence (termed Shared Transcript probes); c) Affymetrix probe sets with 1 to 10 probes sequence overlapping with the cDNA clone ; d) Affymetrix probe sets with 20  probes sequence overlapping with the cDNA clone (termed Completely Overlapping probes); e) alt-CDF or \"redefined probe sets\" for which all probes across the entire array that matched to a given cDNA clone insert were used to define a new derivative probe set. This new probe set may contain only a subset (even a single probe) of an original probe set; in other cases probes across several original probe sets were joined into the new derivative probe set  We removed genes from the cDNA dataset with standard deviations below 0.265, (representing the 50th percentile of standard deviation in the full cDNA dataset.) Matched gene and cell-line concordance was then assessed as described using the genes remaining in both datasets  Alternatively, the redefined probe sets may contain spurious probes in cases where a false-positive clone sequence prediction led to the combination of several Affymetrix-defined probe sets. In any case, the ~4-fold increase in the number of mapped genes available through redefined probe sets may offset the small reduction in concordance.Highly correlated genes are expected to produce a more reproducible unsupervised classification of the cell lines than that derived from a larger pool of genes with less correlation. This can be evaluated in several ways. For example, the hierarchical classification trees derived from the Affymetrix gene chip and cDNA microarray based measurements can be visually compared. Improved reproducibility of classification is indicated by the fact that more cell lines show similar or identical classification on the two hierarchical trees fig .Encouraged by our initial success, we merged the Affymetrix and cDNA microarray based gene expression profiles and hierarchically clustered the composite data set. More consistent measurements of gene expression across the two platforms would result in a greater number of instances in which the measurements of the same cell-line cluster together. In addition, co-clustering of cell lines of similar origin also provides circumstantial evidence that the gene expression profiles accurately reflect a certain tumor subtype.Indeed, hierarchical clustering of the combined datasets resulted in a greater number of matched cell-lines clustering together when only sequence-overlapping measurements were used fig . The majWe were somewhat disconcerted by the fact that some of the cell lines showed a completely different localization on the two hierarchical trees. For example, the colon cancer cell line HT-29 clusters together with other colon cancer cell lines on the cDNA microarray derived tree but it is placed in a different cluster on the Affymetrix gene chip based classification tree fig . An obvi in vitro cell lines. Therefore, we needed to rely on \"indirect\" measures of cross-platform consistency, such as classification reproducibility.We were seeking further confirmation for our method using gene expression profiles derived from various human tissue samples. These data sets do not allow highly controlled side-by-side comparisons such as the above presented analysis using Namely, we investigated whether sequence matching of probes would enable us to reproduce the classification of primary breast tumor derived gene expression profiles produced by different microarray platforms.A breast-cancer subtype classifier was derived from a cohort of patients profiled on cDNA microarrays . This cla priori for novel cancer subtypes, we focused our attention on a subtype where gene expression profiles associated with an independent immunohistochemical marker: Her-2 / erbB2 status. Significantly, the classification based on 'redefined probe sets' contains a larger and more coherent ERBB2+ subtype cluster than that based on shared Unigene identifier. The validity of this cluster was substantiated by the immunohistochemical assessment of Her-2 status (available only for the Santorini cohort); all of the tested samples in this cluster stained positive for Her-2 amplification.Furthermore, we compared the transfer of the cDNA-based classifier  to two aFinally, we evaluated our sequence-overlap probe set redefinition method on a third cDNA platform. In this case, we evaluated the cross-platform similarity of normal lung samples profiled on cDNA microarrays  and AffyDespite the fact that all microarray technologies are based on the same basic principle of complementary hybridization, various probe selection strategies aim to achieve optimal probe performance given the technological constraints using fundamentally different strategies. In order to be able to plan long-term microarray based experimental strategies, end users have hoped either for a clearly superior technology to emerge, perhaps supported by a large number of independent validations, or for a high level of cross-platform consistency when the same type of RNA is expression profiled on different platforms. The latter being true would mitigate the risk of committing to a less accurate technology. Unfortunately, this hope has not been fulfilled yet. The limited number of independent validations published so far suggested a similar level of accuracy, or lack thereof, for the most widely used platforms -15, and sine qua non of accurate microarray measurements but by itself will not validate the technology.Cross platform consistency is an imperfect tool with which to validate microarray platforms. Lack of consistency can be caused by the inferior performance of either one or both platforms, without clear indication of their relative merit. On the other hand, highly similar results across platforms could be simply caused by consistent cross-hybridization patterns without either platform measuring the true level of expression. Nevertheless, a high level of cross platform consistency is desirable. If both platforms perform accurate measurements then cross platform consistency will automatically follow. In other words, cross platform consistency is the Cross platform inconsistencies can be caused by at least two major factors: a) significant differences in noise structure between technologies; b) differential hybridization of homologous probes designed to measure the same gene on various platforms. It has been shown that the most consistent results across different versions of the Affymetrix DNA chips are provided by identical probes . Probes There are only a few publicly-available data sets that allow comprehensive cross platform comparison of a relatively large number of RNA samples with ample probe sequence information available. The most widely studied of these is the gene expression profiling of the NCI-60 cell line panel produced by the Affymetrix and cDNA microarray technologies ,16,18-20These two data sets showed an alarming level of inconsistencies in an early study when microarray probes, due to the lack of available probe sequence information, were matched across platforms by Unigene IDs . A higheWe have shown that probes which target overlapping transcript sequence regions on cDNA microarrays and Affymetrix gene-chips exhibit a greater level of concordance than the corresponding Unigene or sequence matched features. Despite these promising results, we should remain aware of the limitations of this method. Microarray signals are a composite of three factors: 1) true signal from the targeted gene, 2) cross-hybridization with other genes, and 3) random noise. The stringent sequence matching applied in this paper increases the consistency of the first two factors across the platforms. However, it does not allow for an easy deconvolution i.e. whether the higher level of observed cross-platform consistency is due to measurement of only the true signal or to reproduction of the cross hybridization pattern. This determination will require further studies underway in our laboratory.Finally, the assumption that reference mRNA batches used in cDNA hybridizations reflect the full level of diversity in a target experimental mRNA population is imperfect. Without access to measurements of this mRNA on the experimental platform of interest, it is impossible to replicate exactly the normalization inherent in a cDNA log ratio. It is therefore important that the origin of the reference mRNA sample be kept prominently in mind when considering the results of any cDNA microarray experiment.For a given cDNA clone, all corresponding read sequences were extracted from dbEST . When boFor a given Affymetrix platform, all probe sequences as obtained from Affymetrix were matched against the Acembly transcript database. Only exact matches were retained. Based on these results, we determined the number of Affymetrix probes in each probe set that overlapped each predicted clone sequence.In addition to assessing the extent of whole probe set-level overlap with the clone sequence, we also constructed alternative groupings of Affymetrix probes for each platform. These redefined probe sets comprised all Affymetrix probes that overlapped the corresponding cDNA clone, whether or not those probes were intended to be a single probe set by the manufacturer. In some cases, these probes spanned several of the probe sets as defined by Affymetrix table . We thenAll raw Affymetrix probe-level measurements were first transformed into log expression measures using RMA . These eNormalized cDNA microarray expression data for the NCI-60 cell lines was obtained from a previous study . The refIn addition to sequence-overlap methods of matching measurements across the platforms, we also assessed the weaker criterion of matching probes by Unigene identifiers (build #175). Unigene clusters corresponding to each probe set were obtained from Affymetrix (annotation downloaded September 2004.) Clones on the cDNA microarray were assigned to a Unigene cluster if that cluster included an entry annotated as a read sequence for the clone's IMAGE identifier.Concordance was assessed by computing the Pearson correlation coefficient between matched-pairs of both genes and cell-lines across the two platforms. Genes were excluded if more than 50 of the cDNA measurements for that gene were missing. We also computed the average-linkage Pearson correlation hierarchical clustering of the combined datasets using both the Unigene and sequence-overlap mappings.Previously described cDNA microarray expression measurements from a cohort of breast cancer patients were obtained for an 'intrinsic' gene set used to classify tumor subtypes . The oriRaw Affymetrix HG-U95Av2 CEL files were obtained for 199 samples from two additional cohorts of breast cancer patients profiled in previous studies  and normcDNA microarray data profiling of 5 normal lung samples was obtained from a previous study of lung cancer . The oriSLC participated in conceiving the study, carried out most of the analyses and prepared the manuscript, ACE participated in conceiving the study, carried out parts of the analyses and prepared the manuscript, BHM participated in the experimental design, ISK participated in conceiving the study and preparing the manuscript, ZS originated and conceived the study and prepared the manuscript.ZIP of 4 files allowing the remapping Affymetrix probe-sets described in this manuscript. These files can be used with the \"altcdfenvs\" package in Bioconductor to implement the redefinition of probe-sets based on sequence-matching with each of the 4 cDNA datasets described.Click here for file"}
+{"text": "Tamoxifen has been implicated as a risk factor for venous thrombosis in advanced breast cancer although the evidence for increased arterial or venous thrombosis with tamoxifen in early breast cancer is less clear. The effect of tamoxifen on haemostasis, and thereby possible thromboembolic risk, was investigated in normal women enrolled in a placebo controlled trial of tamoxifen as a chemopreventative agent for breast cancer. There was an initial reduction in fibrinogen levels in all women on tamoxifen over the first year of follow-up and a marginal reduction in antithrombin III and Protein S in postmenopausal women at 6 months. There were no changes in cross linked fibrinogen degradation products or Protein C for pre or post-menopausal women. There was no increase in the incidence of thromboembolic events on tamoxifen. This study demonstrates that tamoxifen has only marginal effects on factors involved in haemostasis reported to affect the incidence of arterial or venous thromboembolic disease. The follow-up time is relatively short (maximum 36 months) and careful long term follow-up is necessary to detect clinically significant morbidity."}
+{"text": "Monoclonal antibody (McAb) Po66 has been obtained by immunisation of mice against a human lung squamous cell carcinoma. The in vitro reactivity of the antibody with cancer cells and its ability to localise in human lung cancer xenografts growing in nude mice have been reported earlier. Presented here is the first clinical evaluation of the antibody for scintigraphic detection of tumours. Thirty-three patients with histologically confirmed primary non-small cell lung carcinoma were investigated. Twenty-seven of them were explored at the preoperative stage and six at 6 months after surgery. Biodistribution results were obtained from seven operated patients by combining injections of 131I-radiolabelled Po66 and of 125I-labelled unrelated immunoglobulin. The localisation index was three times higher for this specific antibody. Immunoscintigraphy detected 78% of primary tumours and 100% of recurrences. In this short series of patients, immunoscintigraphy proved helpful in the assessment of tumour spread in four patients by visualising localisations in the mediastinum or the contralateral lung which the CT scan had failed to demonstrate. Immunoscintigraphy was also more efficient than plain chest X-ray for the detection of local tumour recurrences."}
+{"text": "Mixtures of drug-resistant and drug-sensitive tumour cells growing in 3-dimensional boluses in collagen gel matrix are shown to be effectively coupled so that the response of the mixture is significantly influenced by a subpopulation making up only 1% of the total cells."}
+{"text": "To examine the hypothesis that radiotherapy for breast cancer can cause myocardial infarction, cause-specific mortality by laterality of the primary tumour was analysed among 54,617 breast cancer patients reported to the Swedish Cancer Registry during 1970-1985. The rationale was that radiotherapy for a left-sided breast cancer invariably results in higher doses of radiation to the myocardium than a similar treatment given for a right-sided tumour whereas other possible risk factors for cardiovascular disease probably are unrelated to the laterality of the tumour. The median follow-up was 9 years (range 1-17 years). Patients with left-sided tumours were found to have a higher mortality due to myocardial infarction than patients with right-sided tumours (P less than 0.01) but there was no difference in regard to total intercurrent mortality. Further analyses of individual radiotherapy studies are warranted to quantify the excess risk associated with radiation and to study the significance of the type of radiation, portal arrangements, total dose and fractionation. It seems reasonable to assume that adverse effects of radiation are dose-related and may thus be minimised or prevented by the use of appropriate treatment techniques."}
+{"text": "Single nucleotide polymorphisms (SNPs) represent the most abundant type of DNA variation in the vertebrate genome, and their applications as genetic markers in numerous studies of molecular ecology and conservation of natural populations are emerging. Recent large-scale sequencing projects in several fish species have provided a vast amount of data in public databases, which can be utilized in novel SNP discovery in salmonids. However, the suggested duplicated nature of the salmonid genome may hamper SNP characterization if the primers designed in conserved gene regions amplify multiple loci.Salmo salar) and other salmonids. A total of 69 loci with differing priming strategies were screened in S. salar, and 27 of these produced ~13 kb of high-quality sequence data consisting of 19 SNPs or indels (one per 680 bp). The SNP frequency and the overall nucleotide diversity (3.99 \u00d7 10-4) in S. salar was lower than reported in a majority of other organisms, which may suggest a relative young population history for Atlantic salmon. A subset of primers used in cross-species analyses revealed considerable variation in the SNP frequencies and nucleotide diversities in other salmonids.Here we introduce a new intron-primed exon-crossing (IPEC) method in an attempt to overcome this duplication problem, and also evaluate different priming methods for SNP discovery in Atlantic salmon (Sequencing success was significantly higher with the new IPEC primers; thus the total number of loci to screen in order to identify one potential polymorphic site was six times less with this new strategy. Given that duplication may hamper SNP discovery in some species, the IPEC method reported here is an alternative way of identifying novel polymorphisms in such cases. The diversification of the variety of molecular markers available has been an important development in the field of genetics over the past two decades , with onet al. ], where K is the number of observed polymorphic sites, L is the total length of the sequence (in bp) and n is the total number of chromosomes screened. The formula corrects for different sequence lengths and variation in the number of gene copies analysed . Data provides detailed information of the observed polymorphic sites in the analyzed loci.Details of the polymorphic sites detected at the sequenced fragments in fifteen Atlantic salmon populations. Overlapping fragments from the same gene have been combined as one index. Population abbreviations are given in Figure Click here for file"}
+{"text": "Sentinel lymph node biopsy (SLNB) is a simple technique that uses subdermal or peri-tumoral injection of vital blue dye and/or radioactive isotope to identify the first lymph node(s) draining the primary tumor. It has been shown to accurately predict axillary node status in patients with clinically node negative breast cancer. The SLNB is emerging as a new standard of care in patients with early breast cancer. However, the use of methylene blue (MB) dye can be associated with a number of local complications due to its tissue reactive properties. We report a rare case of skin and fat necrosis followed by a dry gangrene of the skin in a female patient with breast cancer who underwent SLNB localization using peri-tumoral injection of MB dye in another institution. This case and literature review suggest that the use of MB dye for SLNB identification should be avoided and replaced with alternative types of blue dye such as Patent Blue V preferably in conjunction with a radioactive isotope tracer. Sentinel lymph node biopsy (SLNB) is emerging as a new standard in the treatment of patients with operable breast cancer. It is a simple technique that uses subdermal or peri-tumoral injection of vital blue dye and/or radioactive isotope to identify the first lymph node(s) draining the primary tumor. SLNB is a reliable and minimally invasive procedure, which accurately predicts axillary node status in patients with clinically node negative breast cancer . LocalizWe report a rare case of severe skin and fat necrosis secondary to the injection of methylene blue dye in a patient with T1 breast cancer. This complication occurred in a different institution.A postmenopausal woman was referred to the senior author (KM) following breast conserving surgery for 17 mm invasive ductal carcinoma of the right breast. Localization of the sentinel lymph node was performed using the dual localization technique. Intradermal injection of technetium-labled sulphur colloid was performed over the tumour site. The following day, the patient had the MB dye injected in the peritumoral area. The operation was uneventful.Three days post operatively and upon removal of the wound dressing, the lateral aspect of the breast skin exhibited a rectangular erythematous violaceous surface which developed into a dry gangrenous area a few days later Figure . We beliThe technique of blue dye mapping was first described for breast cancer by Giuliano et al . IsosulfIn our reported case, severe skin and fat necrosis complicated the peri-tumoral injection of methylene blue dye; This might be due to that methylene blue dye may induce an early foreign body-type reaction characterized by ischemic ulceration, fibrinoid necrosis with eosinophilic infiltration .Therefore, we recommend the use of Patent Blue V dye instead of MB for SLNB localization in patients with breast cancer in order to avoid such significant complications which may delay subsequent treatment. Patent Blue dye has been reported to cause minor local complications in form of long-term discoloring of the skin at the site of injection . AlthougIn conclusion, the use of MB dye for SLNB identification should be avoided and replace with alternative types of blue dye such as Patent Blue V preferably in conjunction with a radioactive isotope tracer."}
+{"text": "Growth of cells in vitro in the presence of fatty acids can alter the membrane composition and hence fluidity and permeability. Exposure of both doxorubicin (2780AD) and cisplatin (2780CP) resistant human ovarian cell lines to non-toxic concentrations of polyunsaturated fatty acids (gamma-linolenic acid and eicosapentaenoic acid) either before or during exposure to the cytotoxic drug did not modulate drug sensitivity. However, the fatty acids were toxic in their own right. Whilst the ovarian cell lines 2780AD and 2780CP showed a small degree of cross resistance to both fatty acids the doxorubicin resistant breast cell line MCF7/Adr was slightly more sensitive than MCF7. When the interactions between the polyunsaturated fatty acids and cytotoxic drugs were analysed by the isobologram method the toxicities were shown to be additive. The combination of polyunsaturated fatty acids and cytotoxic drugs may have clinical potential provided that the normal tissue toxicities of the two treatments are not additive."}
+{"text": "Pleural effusion fluid obtained from eleven patients with metastatic spread to the pleura was screened for the ability to cause the dispersal--'scattering'--of MDCK colonies in vitro. Four of these samples proved to be positive using this assay. Of these two had titres high enough to warrant further purification on a cation exchange Mono S column. Active material from both lung samples, eluted at the same positions as factor from cultured human lung fibroblasts (MRC-5) and human placenta but in a slightly different position to murine scatter factor. In both cases the semi-purified active agent was identified as hepatocyte growth factor/scatter factor (HGF/SF) using an ELISA detection system specific for human HGF/SF. This is the first report identifying the presence of significant amounts of HGF/SF in the pleura of patients where malignant spread has occurred."}
+{"text": "Six human melanoma xenograft lines grown s.c. in BALB/c-nu/nu mice were subjected to 31P-nuclear magnetic resonance (31P-NMR) spectroscopy in vivo. The following resonances were detected: phosphomonoesters (PME), inorganic phosphate (Pi), phosphodiesters (PDE), phosphocreatine (PCr) and nucleoside triphosphate gamma, alpha and beta . The main purpose of the work was to search for possible relationships between 31P-NMR resonance ratios and tumour pH on the one hand and blood supply per viable tumour cell on the other. The latter parameter was measured by using the 86Rb uptake method. Tumour bioenergetic status [the (PCr + NTP beta)/Pi resonance ratio], tumour pH and blood supply per viable tumour cell decreased with increasing tumour volume for five of the six xenograft lines. The decrease in tumour bioenergetic status was due to a decrease in the (PCr + NTP beta)/total resonance ratio as well as an increase in the Pi/total resonance ratio. The decrease in the (PCr + NTP beta)/total resonance ratio was mainly a consequence of a decrease in the PCr/total resonance ratio for two lines and mainly a consequence of a decrease in the NTP beta/total resonance ratio for three lines. The magnitude of the decrease in the (PCr + NTP beta)/total resonance ratio and the magnitude of the decrease in tumour pH were correlated to the magnitude of the decrease in blood supply per viable tumour cell. Tumour pH decreased with decreasing tumour bioenergetic status, and the magnitude of this decrease was larger for the tumour lines showing a high than for those showing a low blood supply per viable tumour cell. No correlations across the tumour lines were found between tumour pH and tumour bioenergetic status or any other resonance ratio on the one hand and blood supply per viable tumour cell on the other. The differences in the 31P-NMR spectrum between the tumour lines were probably caused by differences in the intrinsic biochemical properties of the tumour cells rather than by the differences in blood supply per viable tumour cell. Biochemical properties of particular importance included rate of respiration, glycolytic capacity and tolerance to hypoxic stress. On the other hand, tumour bioenergetic status and tumour pH were correlated to blood supply per viable tumour cell within individual tumour lines. These observations suggest that 31P-NMR spectroscopy may be developed to be a clinically useful method for monitoring tumour blood supply and parameters related to tumour blood supply during and after physiological intervention and tumour treatment. However, clinically useful parameters for prediction of tumour treatment resistance caused by insufficient blood supply can probably not be derived from a single 31P-NMR spectrum since correlations across tumour lines were not detected; additional information is needed."}
+{"text": "In 1977, a flurry of papers ushered in a radical new concept in molecular biology\u2014the idea of RNA splicing. It had been known for some years that the information for building organisms is stored as DNA sequences, which are transcribed into messenger RNAs (mRNAs) before translation into proteins. Although it had been established that the DNA and mRNA sequences line up exactly in bacteria, molecular biologists began to suspect in the mid-1970s that the genomes of eukaryotes (organisms with nuclei) are organized somewhat differently. Eukaryotic genes, it turns out, are encoded in small sections scattered over enormous distances of DNA. To make proteins from these \u201csplit genes,\u201d the whole length of DNA is transcribed into pre-mRNA and then converted into mRNA by spliceosomes\u2014molecular machines that remove the non-coding pieces of RNA (the introns) and splice together the protein-coding pieces (the exons).One important consequence of RNA splicing is that one gene can produce several different mRNA variations, or isoforms, simply by stitching together different combinations of exons. For example, a single gene in vertebrates encodes calcitonin  and calcitonin-gene-related peptide (a neuropeptide). Alternative splicing also contributes to human disease\u2014for instance, the selection of different splice sites generates aberrant ratios of mRNA isoforms in several neurological diseases.But how are these alternative splice sites selected? One popular model proposes that alternative splicing in mammalian cells is largely controlled by binding of general splicing factors to pre-mRNA molecules during the formation of the spliceosome. The spliceosome contains many of these factors, including a class of proteins called SR proteins, which contain one or two RNA-binding domains and a protein\u2013protein interaction domain that is rich in serine and arginine amino acids. An important prediction of the combinatorial model for control of alternative splicing is that alternatively spliced transcripts will recruit different combinations of pre-mRNA splicing factors in vivo. New data from Mabon and Misteli support this prediction.tau gene is included or excluded from tau mRNA with roughly equal probability during pre-mRNA splicing; in people with a rare Parkinsonism-like neurological disorder, mutations near one end of exon 10 result in its predominant inclusion. The researchers, therefore, examined cell lines carrying tau genes with and without a mutation of this type to change the ratios of mRNA transcripts including or excluding exon 10. Their results show that a subset of SR protein splicing factors is efficiently recruited to tau transcription sites that produce exon 10\u2013containing mRNA, but less efficiently recruited to transcription sites where exon 10 is excluded.Pre-mRNA splicing factors accumulate at sites of active transcription, and splicing and can be detected and quantified in individual living cells by tagging the splicing factors with fluorescently labeled antibodies. So, to see whether different factors accumulate at alternatively spliced transcripts, the researchers developed stable cell lines carrying versions of the gene encoding a protein called tau designed to splice in different ways. In healthy people, exon 10 of the Jane BradburyThese results provide the first in vivo evidence for the differential association of pre-mRNA splicing factors with alternatively spliced transcripts, and support a combinatorial mechanism for spliceosome formation. Exactly which splicing factors are recruited to each spliceosome would depend on both the concentration of each factor in individual cell types and the regulatory elements present in each pre-mRNA. The combinatorial mechanism for the control of alternative splicing, the authors suggest, could allow cells to adjust splicing outcome (and consequently which proteins they express) rapidly in response to intracellular or extracellular cues, as well as contributing to the generation of protein diversity. \u2014"}
+{"text": "Homocysteine is an independent risk factor for cardiovascular diseases. It is also known to be associated with a variety of complex disorders. While there are a large number of independent studies implicating homocysteine in isolated pathways, the mechanism of homocysteine induced adverse effects are not clear. Homocysteine-induced modulation of gene expression through alteration of methylation status or by hitherto unknown mechanisms is predicted to lead to several pathological conditions either directly or indirectly. In the present manuscript, using literature mining approach, we have identified the genes that are modulated directly or indirectly by an elevated level of homocysteine. These genes were then placed in appropriate pathways in an attempt to understand the molecular basis of homocysteine induced complex disorders and to provide a resource for selection of genes for polymorphism screening and analysis of mutations as well as epigenetic modifications in relation to hyperhomocysteinemia. We have identified 135 genes in 1137 abstracts that either modulate the levels of homocysteine or are modulated by elevated levels of homocysteine. Mapping the genes to their respective pathways revealed that an elevated level of homocysteine leads to the atherosclerosis either by directly affecting lipid metabolism and transport or via oxidative stress and/or Endoplasmic Reticulum (ER) stress. Elevated levels of homocysteine also decreases the bioavailability of nitric oxide and modulates the levels of other metabolites including S-adenosyl methionine and S-adenosyl homocysteine which may result in cardiovascular or neurological disorders. The ER stress emerges as the common pathway that relates to apoptosis, atherosclerosis and neurological disorders and is modulated by levels of homocysteine. The comprehensive network collated has lead to the identification of genes that are modulated by homocysteine indicating that homocysteine exerts its effect not only through modulating the substrate levels for various catalytic processes but also through regulation of expression of genes involved in complex diseases. Elevated levels of homocysteine (hyperhomocysteinemia) has been implicated as an independent risk factor for cardiovascular disease ,2 and isAlthough hyperhomocysteinemia has been associated with several diseases, the mechanism of homocysteine-induced deleterious effects is not fully elucidated. Prominent among the various mechanism proposed for the harmful effects of homocysteine is its ability to modulate the expression of certain genes that may either directly or indirectly lead to several pathological conditions . HomocysWe manually screened all the abstracts from PUBMED, NCBI (up to November 2004) that contained the keywords \"homocysteine\" and \"gene\". The genes that are associated with homocysteine could be classified into two broad groups: (i) Genes that are modulated in response to elevated homocysteine levels Table . Modulat2O2), thereby generating oxidative stress [One of the mechanisms proposed for the deleterious effects of homocysteine is its ability to generate reactive oxygen species thereby producing oxidative stress Figure . It is ge stress . Howevere stress  and althe stress . Therefoe stress  and catae stress . Homocyse stress . Nonaka e stress  reportedHyperhomocysteinemia has also been reported to be associated albeit indirectly with hypoxic conditions. Supporting this is the expression of Cap43 [that codes for a 43 kDa protein associated with hypoxia in endothelial cells (EC)] in cells treated with homocysteine. Hypoxia in alveoli leads to damage of capillary wall, a condition predisposing for atherosclerosis. Furthermore, it has also been shown that there is a decrease in the MAT1A transcription and mRNA stability in cultured hepatocytes exposed to hypoxic conditions .-) [- and its oxidation results in formation of trihydrobiopterin radical (BH3\u2022) and consequently decrease NO production [Elevated levels of homocysteine have been reported to decrease the bioavailability of endothelial nitric oxide. Under normal condition Nitric oxide (NO) exerts anti-atherosclerotic effect through various mechanisms Table . The NO -) -27. Furtoduction ,29. ThusAnother potential mechanism for the decreased bioavailability of NO in hyperhomocysteinemic states is the increased generation of asymmetric dimethylarginine (ADMA), an analogue of L-arginine, which is a competitive inhibitor of eNOS . ADMA alFurthermore, one of the mechanisms proposed for the anti-thrombotic effect of NO is its ability to inhibit the expression of the prothrombotic protein PAI-1. It has also been shown that NO released from activated platelets inhibits the recruitment of platelets to the growing thrombus . Thus de2O2 & other lipid peroxides due to decreased activity of intracellular antioxidant enzymes. Furthermore, decreased bioavailability of nitric oxide may lead to the increased expression of pro-inflammatory cytokines and PAI which can potentially lead to cardiovascular diseases.Intracellular oxidative stress may be either due to excessive generation of reactive oxygen species or to decreased ability of cells to scavenge the reactive oxygen species leading to its accumulation. We propose that homocysteine-induced oxidative stress is primarily due to the decreased ability of the cells to detoxify HThe major process linking levels of homocysteine with apoptosis and inflammatory pathway is the Endoplasmic Reticulum (ER) stress  that regulate gene expression via phosphorylation and activation of transcription factors such as c-JUN. The activation of JNK is mediated by TNF receptor-associated factor-2 (TRAF2), which transduce signals from IREs that act as stress sensors and initiates UPR . TRAF2 aExpression of c-myc sensitizes cells to a wide range of pro-apoptotic insults that include DNA damage, hypoxia and nutrient deprivation . Homocysteine induces the expression of sterol regulatory element binding protein-1  in appropriate pathway, we show that elevated levels of homocysteine cause the up regulation of ER stress proteins resulting in apoptosis. Homocysteine might also mediate apoptosis via P53 mediated pathway or by inhibition of methyl transferases like ICMT. Furthermore, ER stress also leads to altered lipid metabolism which may lead to cardiovascular disorders. Thus, homocysteine-induced ER stress emerges as the common pathway that relates to apoptosis and atherosclerosis. In this context it needs to be mentioned that homocysteine can potentially cleave critical protein disulfide bonds resulting in the alteration of structure and/or function of the protein -64. It cDuring vascular injury, tissue factor, an integral membrane glycoprotein that is tightly associated with phospholipids, form a complex (1:1) with factor VII thereby initiating the coagulation cascade Figure . HomocysThus, it can be perceived that elevated homocysteine levels will lead to prothrombotic state by enhancing the pro-coagulant pathway and/or suppressing the anticoagulant pathways.Atherosclerosis is a chronic inflammatory disease of the artery, in which deposits of fatty substances, cholesterol, cellular waste products, calcium and other substances build up in endothelial layer of artery . Apart fHomocysteine plays an important role in cholesterol biosynthesis by inducing the transcription as well as translation of 3-hydroxy-3- methylglutaryl coenzyme A reductase (HMGCR), the rate-limiting enzyme in the cholesterol biosynthesis  both at the transcription and translation level presumably via PKC activation , figure . It is sHomocysteine is known to down regulate the expression of peroxisome proliferators-activated receptors (PPARs) that are redox sensitive transcription factors in the vasculature belonging to the ligand-activated nuclear receptor family    which isIncreasing evidence suggests the role of hyperhomocysteinemia in the underlying pathophysiological mechanism of the increased vascular risk development of coronary artery disease in patients with T2DM (Type 2 Diabetes Mellitus). The mechanisms by which homocysteine promotes this and exerts its detrimental effects may relate to induction of endothelial dysfunction and/or chronic inflammation Figure . AssociaHypertension is a risk factor for cardiovascular disease, and experimental evidence supports a role of renin-angiotensin system in contributing to pathogenesis of atherosclerosis , Figure . UntreatHomocysteine up regulates the synthesis and accumulation of SMC collagen  Figure 5,104 ExtrApart from collagen, homocysteine induces matrix metalloproteinases. Remodeling of extra-cellular matrix of the arterial wall by inducing elastolysis via activation of metalloproteinases in response to elevated levels of homocysteine is shown by studies in animal models. Chaussalet et al  showed tElevated levels of homocysteine have been associated with Alzheimer disease Figure . A charaAD patients have elevated levels of homocysteine and decreased levels of SAM. This is believed to alter the DNA methylation status and hence gene expression in AD patients. This hypothesis is supported by the observation that SAM when added to human neuroblastoma SK-N-SH cells in culture, down-regulates expression of PS I gene coding for presenilin, a key factor for A\u03b2 formation in AD due to methylation of its promoter . SimilarHomocysteine acts as an agonist and a partial antagonist at the glutamate binding site of the NMDA and the glycine-binding site of the receptor respectively. Under physiological conditions, when the concentration of glycine is normal, the neurotoxicity of homocysteine is observed at a very high concentration (millimolar range). However, under pathological conditions, such as in stroke or trauma where glycine levels in the brain is elevated, neurotoxicity of homocysteine is observed even at very low concentrations of homocysteine (10\u2013100 \u03bcM) as the neurotoxic attributes of homocysteine exceeds its protective activity . Under pThus, we propose that homocysteine either by inducing oxidative stress or ER stress might lead to apoptosis which in turn may result in neurological disorders. Alternatively homocysteine might act on glutamate receptors triggering a cascade of events that might result in the disease.Quantitative differences in the activity and availability of enzymes involved in regulation of homocysteine levels directly or indirectly are important in regulating the levels of homocysteine and hence phenotype of complex diseases. The factors that contribute to quantitative variation between individuals are repeat and single nucleotide polymorphism at the genetic level and epigenetic modifications. There are several attempts to analyze polymorphism in genes related to homocysteine pathway. A similar analysis of polymorphism in genes that are part of the interlinked network would be necessary to understand the implications of plasma homocysteine levels on predisposition and manifestation of complex diseases.Polymorphisms in the genes involved in the methionine and the folate cycles and the transsulfuration pathway Figure  are corrTrascobalamin II (TCN II) facilitates the transport of the vitamin B12 to various tissues. Genetic variations in TCNII gene such as Pro259Arg significantly decrease holo- TCNII or holo-TCNII concentrations . Karin ePolymorphism in genes is population dependent. Thus, it might be important to study the status of all these polymorphism in different cohorts to evaluate the importance of each of these polymorphisms with respect to hyperhomocysteinemia.The challenges of understanding the molecular etiology of complex diseases is in designing a comprehensive analysis of genetic and epigenetic factors that contribute to quantitative differences in the levels of proteins coded by genes in pathways relevant the disease phenotype. The source of data to derive a rational list of genes for analysis is the literature where interactions and functional relationships between individual gene products have been elucidated. The present study is aimed at generating a resource for selection of genes for polymorphism screening and analysis of mutations as well as epigenetic modification in relation to hyperhomocysteinemia.We have compiled a gene-list for researchers interested in deciphering the molecular basis of the role of homocysteine as an independent risk factor in cardiovascular diseases and other complex diseases. Among the variety of pathways that are modulated directly or indirectly by the levels of homocysteine, endoplasmic reticulum stress or ER stress emerges as a common pathway affecting different complex diseases. The data compiled here would assist the selection of genes for analysis based on the disease of interest and/or pathways of interest. Presently we are using the gene list for population specific frequency of known SNP and for discovery of new SNP.It is noted that the levels of Homocysteine may be closely linked to epigenetic effects both as post-replication and post-translation modification. Methylation of histones plays an important role in chromatin remodeling and maintenance of the remodeled state through mitosis. With reference to post-replication modification of CpG sequences homocysteine pathway can function as a auto-regulatory process with reference to methylation of 5'upstream sequences of genes central to its own metabolism: while it can also influence the expression of other genes by regulation of levels of SAM for methylation of 5' upstream sequences. Thus a pathway related analysis of SNP as well as variation at epigenetic level is necessary for complete understanding of the molecular mechanisms relating homocysteine levels and complex disorders.B2: Vitamin B2 ; B12: Vitamin B12; 5f-THF:5-formyltetrahydrofolate; 5,10-CH2-THF: 5,10-methylenetetrahydrofolate; 5-CH3THF: 5-methyltetrahydrofolate; dUMP: Uridine -5-prime monophosphate; dUTMP: Tymidine -5-prime monophosphate; DMG: Dimethylglycine; DMGDH: Dimethylglycine Dehydrogenase; M+: Metal catalysed; ERKP: Phophorylation of Extracellular signal regulated kinase; eIF-2\u03b1 : Eukaryote initiation factor 2 \u03b1 ; CHOP : C/EBP-homologous protein; PERK: PKR-like endoplasmic reticulum eIF2alpha kinase; CEBPB: CCAAT/enhancer -binding protein alpha; EGR1: Early growth response 1;CCND1: Cyclin D1; IL6R: Interleukin 6 receptor; LEP: Leptin; LEPR: Leptin receptor; PTX3: Pentraxin 3; STAT3: Signal Transducer And Activator Of Transcription 3 TNFRSF1B: Tumor Necrosis Factor Receptor Member 1A; PLA2: Phospholipase A2; LOX: Lipoxygenase; COX; Cycloxygenase; PS: Phosphatidyl Serine; PARP; Poly-ADP-ribosome polymerase"}
+{"text": "A system was designed to allow imaging of control and drug treated multicellular spheroids with a high frequency backscatter ultrasound microscope. It allowed imaging of individual spheroids under good growth conditions. Since little data were available on cellular toxicity of ultrasound at these high frequencies (80 MHz), studies were undertaken to evaluate effects on cell survival, using a colony forming assay. No toxicity was observed on cell monolayers subjected to pulsed ultrasound at the intensities used for imaging experiments. Spheroids were also subjected to pulsed ultrasound and no growth delay was observed when exposed spheroids were compared with mock-exposed spheroids. Imaging studies were performed and pictures of untreated spheroids were obtained in which the necrotic and viable regions are clearly distinguishable. When the hypoxic cell cytotoxin 1-methyl-2-nitroimidazole (INO2) was added to the spheroid, dramatic changes were observed in the backscatter signal. The interior viable cells of the spheroid were selectively affected. Changes in the backscatter signal were also observed when the reduction product 1-methyl-2-nitrosoimidazole (INO) was added to spheroids. With INO however, the changes were located at the periphery of the spheroid, presumably due to the high reactivity of INO which limits diffusion of the drug into the spheroid. The present work demonstrates the potential usefulness of ultrasound backscatter microscopy in following the action of selected drugs in this in vitro tumour model."}
+{"text": "The potential for a pharmacokinetic interaction between epirubicin and the second-generation multidrug resistance modulating agent D-verapamil (DVPM) has been investigated in six patients with advanced colorectal cancer. Our results indicate that a significant interaction takes place. Enhanced distribution of epirubicin from the serum and altered disposition might, in fact, explain the increased level of myelotoxicity in this pilot as well as in other clinical phase II studies involving DVPM."}
+{"text": "A prospective, consecutive study of the aetiology of treatment-associated diarrhoea was conducted in 25 patients with disseminated germ cell cancer treated with intensive chemotherapy. Clostridium difficile was isolated in 45% of the diarrhoea episodes, which makes this species the most important bacterial pathogen in the development of clinically significant diarrhoea in this group of immunocompromised patients."}
+{"text": "A specific two-site ELISA for human epidermal growth factor (hEGF) has been used to measure urinary hEGF/creatinine ratios in 30 normal subjects, 30 hospital in-patients with breast cancer and 30 hospital in-patients with colonic or rectal cancer. There was no significant difference between patients with breast cancer and controls. Although a statistically significant difference between patients with colorectal cancer and controls was observed, the biological significance of this observation is doubtful. No clear effect of the presence of breast or colorectal carcinoma on the urinary excretion of hEGF has been observed."}
+{"text": "Brugada syndrome is an arrhythmogenic disease characterized by an ECG pattern of coved-type ST segment elevation in the right precordial leads and an increased risk of sudden cardiac death (SCD) as a result of polymorphic ventricular tachyarrhythmia or ventricular fibrillation (VF). Data from large patient studies and a meta-analysis of previous reports have shown that patients with a history of syncope or SCD and a spontaneous type 1 Brugada type ECG are at high risk for SCD. However, risk stratification of asymptomatic patients with Brugada type ECG is still a challenge. In particular, the use of electrophysiological study (EPS) for risk stratification remains controversial. Although some investigators have reported the possibility of use of EPS for distinguishing between high- and low-risk patients with Brugada type ECG, no precise predictor of risk for SCD in asymptomatic patients has yet been determined. The approach to treatment of these patients is thus still unclear. Large clinical prospective studies with uniform diagnostic criteria and protocols for EPS as well as extended follow-up periods of over ten years are required for prediction of SCD. Since its description in 1992 . On the Some reports have noted the natural history of asymptomatic patients with Brugada type ECG. Data from the largest patient series have shown that 8% of patients without previous cardiac arrest had SCD or documented ventricular fibrillation during a mean follow-up of 24 months -9. EckarThese findings suggest that, although the risk of SCD in sporadic asymptomatic patients may be much lower, a spontaneously abnormal type 1 Brugada ECG might be a predictor for SCD in these patients.Recent studies have suggested that combined noninvasive ECG markers may be helpful in risk stratification. Atarashi et al. reported the feasibility of risk stratification using the width of the S wave and ST segment elevation magnitude in the right precordial leads on surface ECG . Some reThe predictive value of inducibility of sustained ventricular arrhythmias during EPS is still controversial. Although Brugada et al. have supported the value of EPS based on the results for the largest series of patients , two othCurrently, implantation of an ICD is the only effective treatment for this syndrome. However, various other treatments have been attempted to prevent SCD. Quinidine has been shown to be effective for prevention of SCD -20. TediFor symptomatic patients with type 1 Brugada ECG (either spontaneously or after sodium channel blockade), ICD implantation is recommended in the report of the second consensus conference . With reThere has been some lack of uniformity in the diagnostic criteria and protocols for EPS, and follow-up periods have been limited. Large clinical prospective studies with uniform diagnostic criteria and protocols for EPS as well as extended follow-up periods of over ten years are required for prediction risk of SCD in asymptomatic patients with Brugada syndrome."}
+{"text": "Ab initio gene predictions in a genome are based on a priori knowledge of species-specific features of genes. The training of ab initio gene finders is based on the definition of a data-set of gene models. To accomplish this task the common approach is to align species-specific full length cDNA and EST sequences along the genomic sequences in order to define exon/intron structure of mRNA coding genes.The structure annotation of a genome is based either on GeneModelEST is the software here proposed for defining a data-set of candidate gene models using exclusively evidence derived from cDNA/EST sequences.GeneModelEST requires the genome coordinates of the spliced-alignments of ESTs and of contigs (tentative consensus sequences) generated by an EST clustering/assembling procedure to be formatted in a General Feature Format (GFF) standard file. Moreover, the alignments of the contigs versus a protein database are required as an NCBI BLAST formatted report file.The GeneModelEST analysis aims to i) evaluate each exon as defined from contig spliced alignments onto the genome sequence; ii) classify the contigs according to quality levels in order to select candidate gene models; iii) assign to the candidate gene models preliminary functional annotations.Solanum lycopersicum, whose genome sequencing is an ongoing effort by the International Tomato Genome Sequencing Consortium.We discuss the application of the proposed methodology to build a data-set of gene models of ab initio gene finders and/or as a reference gene list for a human curated annotation.The contig classification procedure used by GeneModelEST supports the detection of candidate gene models, the identification of potential alternative transcripts and it is useful to filter out ambiguous information. An automated procedure, such as the one proposed here, is fundamental to support large scale analysis in order to provide species-specific gene models, that could be useful as a training data-set for  It requires a Perl interpreter version greater than 5.8.*.N. D'Agostino and A. Traini contributed equally to this work."}
+{"text": "We have recently used two-dimensional DNA typing to detect genetic alterations in breast tumours. This method, which is based on size separation in neutral gels and sequence separation in denaturing gradient gels followed by hybridisation analysis with mini- and microsatellite core probes, allows the simultaneous analysis of hundreds of allelic fragments in a very short time. Here we demonstrate the potency of this method for total genome scanning of the tumour genome by analysing a small series of breast cancers. Comparison of tumour and normal DNA from ten breast cancer patients, using two-dimensional DNA typing with four core probes, revealed a considerable number of genomic alterations. In contrast, with Southern blot analysis only a few alterations were observed using the same probes. Most of the changes observed (74%) were deletions (absence of spots in the tumour) while 20% corresponded to amplifications (spots of higher intensity in the tumour) and 5% were new spots (gains). About 10% of the genomic changes detected appeared to occur in the tumours of more than one patient."}
+{"text": "Manipulation of hepatic blood flow may improve drug delivery to hepatic tumour. Somatostatin and its long acting analogues are known to elicit effects upon hepatic and splanchnic blood flow in experimental animals and patients with portal hypertension. This study investigates the effects of SMS 201-995 (sandostatin) infusion on hepatic, splanchnic and tumour blood flow in an experimental model of liver metastases. Hepatic tumour was induced by the intraportal inoculation of 10(6) HSN sarcoma cells and blood flow measured using the dual reference microsphere method before and after infusion of SMS 201-995. There was a significant decrease in hepatic arterial flow and a significant increase in the tumour:liver blood flow ratio associated with a marked reduction in blood flow to normal hepatic parenchyma. Portal venous inflow and tumour blood flow were not significantly affected. SMS 201-995 infusion may lead to preferential delivery of concomitantly injected cytotoxic drugs to hepatic tumour. In addition, the reduction in growth of hepatic tumour may be due to a reduction in nutritive, arterial blood flow to hepatic tumour."}
+{"text": "In previous pharmacologic studies, the native fluorescent properties of doxorubicin (DOX) have been utilised to visualise tissue and cellular drug distribution. Such distribution studies provide valuable additional information to that obtained by measuring tissue drug concentration alone. An alternative immunocytochemical method of drug localisation using a rabbit immunoadsorbed antiserum to DOX and silver-enhanced gold-labelled second antibodies has been used to achieve visualisation of DOX in normal and malignant tissues from drug-treated animals and patients, and in human tumour cell lines treated in vitro. Non-specific staining in untreated tissues or in controls stained without primary antibody was minimal. Widespread dark brown to black specific immunostaining was observed in the normal tissues of drug-treated animals and in rat sarcoma and in the mouse EMT6 mammary tumour. In human breast tumour biopsy samples obtained at surgery 1 h following a 25 mg intravenous dose of DOX, considerable variation in drug distribution was observed which appeared to be related to drug concentration. Both nuclear and membrane staining was apparent; the latter was especially noticeable in human tumour cells grown in the presence of DOX at concentrations greater than 0.92 microM. Immunolocalisation using silver enhanced gold-labelled reagents provides an additional technique to study cell and organ specific differences in drug uptake and distribution."}
+{"text": "The oestrogen receptor (ER) is considered to be an essential component of the mechanism of response of a breast tumour to endocrine therapy, but ER measurements have proved to have only modest predictive value. In the present study, we have examined ER status by both immunocytochemical assay (ER-ICA) on a fine needle aspirate and by radioligand-binding assay (DCC) on an excised portion of tumour. There was a correlation between the ER level detected by the two assays . Each assay showed an increasing proportion of ER+ve results with increasing patient age. In the case of ER+ve tissues only, while ER concentration by DCC assay increased steadily with age , the ER-ICA assay revealed that, staining intensity increased with age  but the percentage of cells stained did not . It is concluded that increasing endocrine responsiveness with advancing age could reflect the increasing proportion of ER+ve tumours with increased levels of ER per cell (as indicated by staining intensity) rather than increasing proportion of ER+ve cells."}
+{"text": "Patient-ventilator synchrony is a major concern in critical care and is influenced by phasic lung-volume feedback control of the respiratory rhythm. Routine clinical application of positive end-expiratory pressure (PEEP) introduces a tonic input which, if unopposed, might disrupt respiratory-ventilator entrainment through sustained activation of the vagally-mediated Hering-Breuer reflex. We suggest that this potential adverse effect may be averted by two differentiator forms of nonassociative learning (habituation and desensitization) of the Hering-Breuer reflex via pontomedullary pathways.We tested these hypotheses in 17 urethane-anesthetized adult Sprague-Dawley rats under controlled mechanical ventilation. Without PEEP, phrenic discharge was entrained 1\u22361 to the ventilator rhythm. Application of PEEP momentarily dampened the entrainment to higher ratios but this effect was gradually adapted by nonassociative learning. Bilateral electrolytic lesions of the pneumotaxic center weakened the adaptation to PEEP, whereas sustained stimulation of the pneumotaxic center weakened the entrainment independent of PEEP. In all cases, entrainment was abolished after vagotomy.Our results demonstrate an important functional role for pneumotaxic desensitization and extra-pontine habituation of the Hering-Breuer reflex elicited by lung inflation: acting as buffers or high-pass filters against tonic vagal volume input, these differentiator forms of nonassociative learning help to restore respiratory-ventilator entrainment in the face of PEEP. Such central sites-specific habituation and desensitization of the Hering-Breuer reflex provide a useful experimental model of nonassociative learning in mammals that is of particular significance in understanding respiratory rhythmogenesis and coupled-oscillator entrainment mechanisms, and in the clinical management of mechanical ventilation in respiratory failure. Mechanically ventilated patients in critical care who are unable to entrain their respiratory activity to the ventilator rhythm and fight the ventilator instead often require sedation or even paralysis in order to avoid lung injury and improve pulmonary ventilation The rising popularity of patient-triggered assisted ventilation is premised on the general belief that patient-ventilator synchrony is difficult if not impossible with controlled (non-patient triggered) mechanical ventilation. On the contrary, many studies in anesthetized animals or awake or sleeping humans have shown that periodic lung inflation during controlled mechanical ventilation may entrain the respiratory rhythm to the ventilation frequency or some sub-harmonics close to the intrinsic respiratory frequency The effects of extrinsic and intrinsic PEEP on respiratory-ventilator entrainment during controlled mechanical ventilation are less clear. If such entrainment is indeed mediated by phasic vagal volume input as predicted by theory These recent revelations raise the intriguing possibility that vital physiological functions such as reflex modulation of the mammalian respiratory rhythm during controlled mechanical ventilation could be subject to nonassociative learning, a basic behavioral paradigm which has been widely studied in invertebrate animal models such as Aplysia or C. elegans and in certain cognitive functions such as the acoustic startle response in mammals [for review, see All experimental protocols were reviewed and approved by the MIT Committee on Animal Care in accordance with published guidelines.Experiments were performed on 17 urethane-anesthetized male Sprague-Dawley rats (300\u2013350 g). The general procedures for animal surgery and anesthesia, mechanical ventilation and PEEP, cardiorespiratory/body temperature monitoring and phrenic nerve recording, etc. are as described previously The pneumotaxic center in the rat dorsolateral pons is as defined in At the end of the experiment, the animal was killed with overdose of urethane (2 g/kg) and perfused with 0.05 M PBS and 4% paraformaldehyde. The brainstem was removed, post-fixed in 4% paraformaldehyde for 7 days, and cut into 80-\u00b5m sections with a vibratome. The actual loci of lesions were examined histologically. Data were discarded if the lesions were outside the dorsolateral pons.Application of PEEP abruptly switched the entrainment to 1\u22362. Phrenic activity remained phase-locked to the inflation phase every other ventilator cycle , unilateral electrical stimulation at the dorsolateral pons initially decreased the amplitude of phrenic discharge by>50% without affecting the respiratory entrainment  and significant prolongation of expiratory duration, both effects adapting gradually as the stimulation continued  as reporOur results confirmed previous findings that controlled mechanical ventilation at a suitable frequency could entrain respiratory activity 1\u22361 in animals with intact vagi but not after vagotomy In a recent study in anesthetized, vagi-intact animals after acid-induced lung injury, the application of PEEP was found to promote phasic respiratory activity during neurally-adjusted ventilatory assist In contrast, the present study showed that in animals with normal lungs respiratory entrainment to mechanical ventilation was dampened by PEEP, most probably via corresponding activation of the Hering-Breuer inflation reflex and consequent slowing of the respiratory rhythm. This is indicated by the following observations: a) the decrease of entrainment during PEEP was transient and with a similar time course as the reported central adaptation of the Hering-Breuer reflex during sustained lung inflation Importantly, our results showed that this acute adverse effect of PEEP was effectively negated by nonassociative learning acting as a high-pass filter or buffer for the tonic input. This was accomplished in part through desensitization of the pneumotaxic center, but also through extra-pontine mechanisms\u2013such as habituation of the primary pathway for vagal lung volume input The important role of the pons in modulating respiratory-ventilator entrainment is also demonstrated by the dampening of entrainment during pontine stimulation. The initial inhibition and adaptation of the phrenic discharge (before the entrainment bifurcated from 1\u22361 to higher ratios) during unilateral pontine stimulation in vagi-intact animals are intriguing and are in sharp contrast to the Hering-Breuer reflex-like respiratory response and adaptation to the same stimuli after vagotomy. These salient effects indicate the existence of complex adaptive processes at the right and left pneumotaxic center whereby ipsilateral and contralateral vagal and pontine inputs are integrated bilaterally in modulating the respiratory rhythm.Entrainment is an important physiologic phenomenon of potential clinical significance in that it allows the spontaneous (barring voluntary) respiratory rhythm to synchronize with the ventilator naturally without any external triggering device necessary. This potent effect has not been fully exploited in current assist/support-mode ventilators that rely on patient triggering, and deserves further investigation particularly in cases where the latter is not feasible or beneficial Although the important role of phasic lung volume input in mediating respiratory-ventilator entrainment is well established, the efficacy of the Hering-Breuer reflex in humans remains controversial. It has been suggested that acute lung inflation or elevation of end-expiratory lung volume or local anesthetic blockade of the vagi has little or no immediate effect on the respiratory rhythm in awake or sleeping humans Although the important role of the pneumotaxic center in averting apneustic breathing has been extensively documented in vagotomized animals since the discovery of this brainstem structure over eight decades ago"}
+{"text": "Plasmodium falciparum sequesters in vital organs, and this is also the species responsible for the vast majority of malaria-related deaths. Autopsy studies of fatal malaria cases show convincing correlations between extent of sequestration in the brain and coma as a presenting symptom [We are grateful for Ian Clark's suggestions  in resposymptom . Direct symptom . Both ar"}
+{"text": "The mutagenic activity of razoxane (ICRF 159) was studied using the Salmonella/microsome assay and rodent bone-marrow micronucleus and metaphase assays. Razoxane (up to 5000 micrograms/plate) did not cause an increase in the mutation frequency in the Salmonella/microsome assay. In the mouse micronucleus assay razoxane (200 and 400 mg kg-1 i.p.) was cytotoxic to the bone marrow cells  but an increase in micronucleated polychromatic erythrocytes was observed in razoxane dosed animals . In the Chinese hamster metaphase assay razoxane  induced abnormal chromosome condensation and an increase in structural chromosome aberrations  as well as an increase in the number of polypoid cells . The mutagenic effect of razoxane was restricted to eukaryotic organisms and was associated with specific chromosomal changes."}
+{"text": "Ion transport is essential for maintenance of transmembranous and transcellular electric potential, fluid transport and cellular volume. Disturbance of ion transport has been associated with cellular dysfunction, intra and extracellular edema and abnormalities of epithelial surface liquid volume. There is increasing evidence that conditions characterized by an intense local or systemic inflammatory response are associated with abnormal ion transport. This abnormal ion transport has been involved in the pathogenesis of conditions like hypovolemia due to fluid losses, hyponatremia and hypokalemia in diarrhoeal diseases, electrolyte abnormalites in pyelonephritis of early infancy, septicemia induced pulmonary edema, and in hypersecretion and edema induced by inflammatory reactions of the mucosa of the upper respiratory tract. Components of membranous ion transport systems, which have been shown to undergo a change in function during an inflammatory response include the sodium potassium ATPase, the epithelial sodium channel, the Cystic Fibrosis Transmembrane Conductance Regulator and calcium activated chloride channels and the sodium potassium chloride co-transporter. Inflammatory mediators, which influence ion transport are tumor necrosis factor, gamma interferon, interleukins, transforming growth factor, leukotrienes and bradykinin. They trigger the release of specific messengers like prostaglandins, nitric oxide and histamine which alter ion transport system function through specific receptors, intracellular second messengers and protein kinases. This review summarizes data on in vivo measurements of changes in ion transport in acute inflammatory conditions and in vitro studies, which have explored the underlying mechanisms. Potential interventions directed at a correction of the observed abnormalities are discussed. The main mechanisms for ion transport in the single cell as well as through epithelial cell layers involve for sodium the epithelial sodium channel [ENaC], which allows passive influx of Na+ into the cell through the apical membrane and the sodium potassium ATPase [Na/K ATPase], which moves Na+ actively out and K+ into the cell in blood cells and the basolateral membrane of epithelial cells  and EMBASE [1975 to present]. The reference lists of relevant articles were also scanned.Reports on changes of Na/K ATPase function in skeletal muscle in endotoxemia in human and animal experiments  were excNasal potential difference measurements involve the in vivo measurement of a potential difference [voltage] between a cutaneous or intravenous electrode and a fluid perfused electrode in contact to the respiratory epithelium under the inferior turbinate of the nose. The potential measured represents the end result of ion transport processes, which are dominated by sodium transport. On change of the perfusion fluid to an amiloride [ENaC blocker] containing fluid the resulting depolarization is equivalent to the contribution of ENaC function to the potential. A perfusion with a low chloride or chloride free solution plus amiloride following this measurement will activate chloride channels in a normal respiratory epithelium and result in a hyperpolarisation which represents the ability of the epithelium to secrete chloride and is thus a measure of chloride channel function.sc] measurement the charge flow per time through the epithelium [between the two chamber halves] when the epithelium is short-circuited, i.e. the voltage clamped to 0 mV, is measured. Ion channel function is analyzed by measurement of current or voltage changes in response to blockers and stimulators of ion channel function. Amiloride is used to block sodium channels and forskolin, a stimulator of the adenylate cyclase, which activates CFTR mediated chloride secretion through increase in intracellular cAMP, is used to test CFTR function.In the Ussing chamber an epithelium is inserted between two fluid filled chamber halves, which contain electrodes for stimulation and measurement of current and voltage. In the short circuit current  or ionomycin [a calcium ionophore used to stimulate calcium activated chloride channels] is measured. The radioactivity in the cells at a defined point in time is calculated as the sum of radioactivities released in subsequent efflux samples and the radioactivity in the cells at the end of the experiment. The studies are then conducted with the inhibitor of the outwardly rectifying chloride channel [ORCC] DIDS  and the inhibitor of both CFTR and the ORCC DPC (diphenylamine-2-carboxylic acid or N-phenylanthranilic acid). From the difference in activity is then the activity of CFTR calculated.After incubation of cells with the chloride analogue + into cells over time. The uptake study involves interruption of the uptake at defined time points after which the radioactivity of the cell population is measured with a gamma counter. The Na/K ATPase mediated uptake is measured by conducting the measurements with and without addition of ouabain, a specific inhibitor of the Na/K ATPase.Rubidium flux studies measure the activity of the Na/K ATPase. This is achieved in vitro by measuring the Na/K ATPase mediated uptake of a potassium analogue, the gamma radiation emitting isotope Rubidium 86In patients with pollen allergy the nasal potential difference, which is a representation of nasal mucosal sodium transport was reduced in the pollen season compared to controls. Amiloride sensitive nasal potential difference, which reflects nasal epithelial sodium channel function was found to be significantly decreased after allergen challenge . This suIn vivo studies of ion transport in humans with systemic inflammatory response syndrome and pulmonary edema found evidence of a systemic reduction in epithelial sodium and chloride transport ,11. The The CFTR dysfunction may have been related to the Na/K ATPase dysfunction and previous studies have demonstrated a reduction of function of the Na/K ATPase in red blood cells, muscle and liver of patients with septicemia ,13. Inhi4 prostanoid receptors and subsequently to a reduction of PGE2 induced cAMP production. Reduced intracellular cAMP levels then lead to a reduction in cAMP dependent CFTR function [See figure IL-1beta was found to antagonize the effects of prostaglandin E2 [PGE2] which stimulated chloride transport in canine tracheal epithelium and in Calu-3 bronchial epithelial cells by inducing excess production of PGE2. This lead to a down regulation of EPMore recently it has been recognized that the lipoxygenase product leukotriene D4 increases alveolar epithelial sodium transport and fluid clearance by activation of the lung Na/K ATPase .Previous investigations into the influence of inflammatory mediators on respiratory epithelial chloride transport in vitro have demonstrated that PGE2 released in response to bradykinin , eosinopA new pathway for prostaglandin E2 release and stimulation of respiratory epithelial chloride secretion has been revealed recently: Activated mast cells can by secretion of tryptase stimulate protease activated receptors type 2 [PAR2] in airway epithelial cells . PAR2 arProlonged exposure of alveolar epithelial cells to TNF alpha by in vitro incubation [24hours], a condition which is known to change the physiological properties of alveolar epithelial cells significantly  seemed t+ channel as measured in short circuit current experiments  and noninfective [ulcerative colitis and Crohn's disease] types of inflammatory diarrhoea has recently been clarified. All forms of inflammatory diarrhoea are associated with hypersecretion of chloride into the gut lumen by activation of CFTR at the apical membrane of colonocytes drawing water with it by osmotic effects. Activated CFTR can inhibit ENaC  required comounting with TNF stimulated jejunal fibroblasts to generate an increased short circuit current, which was sensitive to PGE2 inhibition. This indicated that fibroblasts may also be involved in changes in epithelial ion transport in inflammatory bowel disease ,62. PGE2-secretion by stimulation of CFTR through cGMP-regulated protein kinase G type II  exposure also CFTR protein on the cell surface. This process seemed to reduce the chloride current . Other cA dichotomous effect on CFTR expression was noted for Interleukin 1beta. It upregulated CFTR mRNA levels at a dose of 0.25 ng/ml and inhibited CFTR mRNA and protein expression at higher doses [1 ng/ml] in T 84 cells . This cyIFN gamma reduced Na/K/2Cl-cotransporter and Na/K ATPase expression without altering CFTR levels in T84 intestinal epithelial cells . Another+ -glucose cotransport found in the chronically inflamed rabbit ileum for which these basolateral pumps are essential for creating a sodium gradient -hydroxyeicosatetraenoic acid .The effect of nitric oxide on ion transport in the nephron has been reviewed recently . One groIn vivo studies have demonstrated that bradykinin is another potent natriuretic agent. This effect is mediated by inhibition of ENaC and Na/K ATPase activity possibly mediated by an increase in intracellular calcium and/or pH. Bradykinin seemed to counteract the stimulatory effect of Angiotensin -7 on theIL 1beta inhibited protein expression of Na/K ATPase in medullary and cortical rat kidney cells and this effect was mediated by the extracellular signal regulated protein kinase pathway which activated the nuclear factor NF-kappaB, thus leading to increased cycloxyenase-2 [COX-2] expression and PGE2 release. PGE2 in turn inhibited NF-kappaB and reduced the protein expression of Na/K ATPase . AnotherAn increase in expression of apical amiloride-blockable Na+ channels was observed in a distal nephron cell line [A6] not after short [3\u20136min] but prolonged [10\u201350min] stimulation with PGE2. Short stimulation resulted in a reduced opening probability of sodium channels . PGE2 alVery little data are available for influence of cytokines on renal chloride transport. TGF beta1 was found to lead to perinuclear accumulation of CFTR protein and reduced chloride secretory responses to cAMP stimulating agents . BradykiBefore considering interventions in the pathophysiological processes leading to changes in ion transport in inflammatory conditions, the physiological effect of a change in ion transporter function on inflammatory mediators needs to be considered. In vitro studies have investigated the effects of CFTR dysfunction in cystic fibrosis [CFTR mutation] patients on cytokine secretion in white blood cell and respiratory epithelial cell populations. Experiments revealed that blood mononuclear cells and lymphocytes with CFTR dysfunction exhibited a reduced potential for secretion of the cytokines IL-10 and IFN gamma ,116. TheThese findings of changes in inflammatory mediator production related to CFTR dysfunction demonstrate that therapeutic modifications of ion transport abnormalities explained below may have an impact on the physiology of inflammatory processes.Interventions which modify ion transport in inflammatory disease can be directed at a reduction of production or activity of cytokines, their messengers like prostaglandins and nitric oxide and ion channels directly or through second messengers. Interference with the cytokine or chemokine network could interfer with their beneficial effects.To overcome this a synthetic peptide [tip peptide] mimicking the lectine like domain of TNF has been constructed and was found to increase edema absorption . TopicalThe beta-agonist isoprenaline has been shown to reverse chloride channel dysfunction in nasal respiratory epithelium in meningococcal septicemia related pulmonary edema in vivo [see figure In the lung beta-agonists and dopamine have also been shown to improve sodium and the associated fluid transport in pulmonary oedema ,129. ThiOther hormones able to upregulate Na/K ATPase levels in cell membranes are glucocorticoids, insulin and thyroid hormones ,131 but Changes in ion transport were associated with inflammation due to allergy, auto-immune disease and infection. This means that not the etiological agents but mediators of inflammation, which are found in all types of inflammatory disease are involved in the changes in ion transport.In respiratory tract, gut and kidneys pro-inflammatory cytokines are involved in down regulation of sodium transport. This down regulation affects not only protein function but also gene expression of ENaC and/or Na/K ATPase. This effect on function and gene expression is mediated by PGE2 and/or NO [See table This review reveals the need for more research into most aspects of the interaction of pro-and anti-inflammatory mediators and ion transport systems. Table The relative importance of each of the numerous inflammatory mediators involved in regulation of ion transport needs to be clarified for each type of ion transport system and the various organsystem by comparative studies. This will facilitate the therapeutic targeting of the most important pathophysiological processes. Topical therapies in the colon and lungs may be able to deliver agents counteracting undesirable effects of inflammatory mediators on epithelial ion transport without systemic side effects. This may lead to supportive therapies directed specifically at a correction or prevention of the abnormal fluid and electrolyte shifts found in inflammatory diseases affecting these organ systems.cAMP Cyclic adenosine monophosphatecGMP Cyclic guanosine monophosphateCaCC Calcium activated chloride channelCFTR Cystic fibrosis transmembrane conductance regulatorCOX-2 Cyclooxygenase-2EGF Epithelial cell growth factorENaC Epithelial sodium channelIFNg Interferon gammaIL InterleukinNa/K ATPase Sodium potassium adenosine triphosphataseNO Nitric oxidePAR2 proteinase activated receptor type 2PGE2 Prostaglandin E2PK Protein kinaseRANTES Regulated upon activation, normal T-cell expressed and secretedRb RubidiumTGF Transforming growth factorTNF Tumor necrosis factor alphaTNFR Tumor necrosis factor receptorThe author(s) declares that he has no competing interests.The author was the only person involved in the production of this review."}
+{"text": "The perfusion characteristics of the P22 carcinosarcoma were investigated in tissue-isolated tumour preparations in the ovarian and inguinal fat pads of BD9 rats. Tumours were perfused with a physiological buffer of known viscosity and changes in perfusion pressure were recorded at different perfusion rates in an ex vivo system. At perfusion pressures exceeding 30-40 mmHg tumour flow rate was directly proportional to the perfusion pressure in all tumours, indicating a constant resistance to flow. An apparent positive pressure difference across the tumour vasculature of 20-30 mmHg occurred under conditions of zero flow in either site. At low perfusion pressures, the flow resistance increased sharply due to increases in the geometric resistance of the tumours. These findings are in accord with previously published data. Geometric resistance increased with tumour volume in both sites and was approximately five times greater in the inguinal tumours than it was in the ovarian tumours, on a weight to weight basis. The dependence of tumour geometric resistance on perfusion pressure differs from the situation in normal tissues and may provide a means of manipulating the tumour microcirculation to the exclusion of the systemic blood supply. The dependence of geometric resistance on tumour site may partly explain why tumours located in different sites respond differently to various forms of therapy."}
+{"text": "Escherichia coli and Salmonella enterica, in both of which details of histidine biosynthesis appear to be identical. In these two enterobacteria the pathway is unbranched, includes a number of unusual reactions, and consists of nine intermediates; his genes are arranged in a compact operon (hisGDC [NB]HAF [IE]), with three of them  coding for bifunctional enzymes. We performed a detailed analysis of his gene fusions in available genomes to understand the role of gene fusions in shaping this pathway.Histidine biosynthesis is one of the best characterized anabolic pathways. There is a large body of genetic and biochemical information available, including operon structure, gene expression, and increasingly larger sequence databases. For over forty years this pathway has been the subject of extensive studies, mainly in The analysis of HisA structures revealed that several gene elongation events are at the root of this protein family: internal duplication have been identified by structural superposition of the modules composing the TIM-barrel protein.his gene fusions happened in distinct taxonomic lineages; hisNB originated within \u03b3-proteobacteria and after its appearance it was transferred to Campylobacter species (\u03b5-proteobacteria) and to some Bacteria belonging to the CFB group. The transfer involved the entire his operon. The hisIE gene fusion was found in several taxonomic lineages and our results suggest that it probably happened several times in distinct lineages.Several hisIE and hisD genes (HIS4) and hisH and hisF genes (HIS7) took place in the Eukarya domain; the latter has been transferred to some \u03b4-proteobacteria.Gene fusions involving Gene duplication is the most widely known mechanism responsible for the origin and evolution of metabolic pathways; however, several other mechanisms might concur in the process of pathway assembly and gene fusion appeared to be one of the most important and common. Escherichia coli and Salmonella enterica, including operon structure, gene expression, and growing sequence data [his genes are arranged in a compact operon (hisGDC [NB]HAF [IE]), with three of them  coding for bifunctional enzymes  synthase, a heterodimeric protein composed by one subunit each of the hisH and hisF products -5-aminoimidazole-4-carboxamide ribonucleotide (ProFAR) isomerase and a cyclase, respectively, which catalyze two central and sequential reactions (the fourth and fifth ones) of the pathway  to the ancestral hisA gene, which in turn underwent a duplication that gave rise to the ancestor of hisF , where b is a residue found in in column I and f its frequency in I and the summation extends over all residues in column I.Click here for filePairwise identity values within HIS4 domains. Identity values for the pairwise comparison of the different domains composing HIS4 proteins .Click here for fileIdentifiers of sequences used in this work.Click here for file"}
+{"text": "There are important interactions between prostatic tumours and bone. This study was designed to examine whether prostatic tissue can express bone inductive factors, in particular, the Bone Morphogenetic Proteins (BMPs). The polymerase chain reaction (PCR) has been used to screen for the expression of BMPs one to six in the prostatic tissue of patients with benign prostatic hyperplasia (BPH), non-metastatic prostatic adenocarcinoma and metastatic prostatic adenocarcinoma. BMPs were expressed in both benign and malignant prostate tissue and in the prostate tumour cell lines, PC3 and DU145. BMPs were also expressed in ocular melanoma tissue, a tissue which rarely metastasizes to bone. BMP-6 expression was detected in the prostate tissue of over 50% of patients with clinically defined metastatic prostate adenocarcinoma, but was not detected in non-metastatic or benign prostate samples or in ocular melanoma tissue. These findings suggest that the BMPs may play a role in the osteoinductive activity of prostate metastases and that the pattern of expression of BMPs may be important in the pathogenesis of osteoblastic metastases associated with prostate adenocarcinoma."}
+{"text": "Pulmonary rehabilitation programs have been shown to increase functional exercise capacity and quality of life in COPD patients. However, following the completion of pulmonary rehabilitation the benefits begin to decline unless the program is of longer duration or ongoing maintenance exercise is followed. Therefore, the aim of this study is to determine if supervised, weekly, hospital-based exercise compared to home exercise will maintain the benefits gained from an eight-week pulmonary rehabilitation program in COPD subjects to twelve months.Following completion of an eight-week pulmonary rehabilitation program, COPD subjects will be recruited and randomised  into either the maintenance exercise group  or the control group (unsupervised home exercise) and followed for twelve months. Measurements will be taken at baseline (post an eight-week pulmonary rehabilitation program), three, six and twelve months. The exercise measurements will include two six-minute walk tests, two incremental shuttle walk tests, and two endurance shuttle walk tests. Oxygen saturation, heart rate and dyspnoea will be monitored during all these tests. Quality of life will be measured using the St George's Respiratory Questionnaire and the Hospital Anxiety and Depression Scale. Participants will be excluded if they require supplemental oxygen or have neurological or musculoskeletal co-morbidities that will prevent them from exercising independently.Pulmonary rehabilitation plays an important part in the management of COPD and the results from this study will help determine if supervised, weekly, hospital-based exercise can successfully maintain functional exercise capacity and quality of life following an eight-week pulmonary rehabilitation program in COPD subjects in Australia. Chronic Obstructive Pulmonary Disease (COPD) is the fourth leading cause of death in Australian males, the sixth leading cause of death in females  and resuPulmonary Rehabilitation is a multi-disciplinary approach to the management of patients with respiratory disease. The program is individually tailored to the needs of the patient, combining exercise, self-management education and psychosocial support . PulmonaFollowing pulmonary rehabilitation, benefits in terms of functional exercise capacity and quality of life are maintained for up to nine months -8. HowevThe aim of the study is to determine if supervised, weekly exercise following an eight-week pulmonary rehabilitation program will maintain the benefits to twelve months.This study will be a prospective, randomised controlled trial in participants diagnosed with COPD. Participants will be recruited consecutively on completion of an eight-week pulmonary rehabilitation program and randomised into either a maintenance exercise group (ME) or a control group and followed for 12 months. Randomisation will be by computerised random number generation in concealed envelopes prepared by an investigator not involved in subject testing or training. The chief investigator will conduct both testing and training so will be aware of group allocation.Participants will be excluded if they have experienced an exacerbation of COPD in the previous month, if they require supplemental oxygen, or if they have co-morbidities such as severe cardiovascular, neurological or musculoskeletal conditions that will prevent them performing functional exercise tests. The flow of participants through the study will reflect the recommendations from the Consolidated Standards of Reporting Trials (CONSORT) statement , and is Participants randomised to the ME group will attend hospital-based pulmonary rehabilitation once a week for supervised exercise training and will also be asked to follow an unsupervised home exercise program on four other days a week. The hospital-based program will be individually designed and supervised by a qualified physiotherapist and will consist of lower limb and upper limb exercise Table  similar Participants randomised to the control group will follow standard care and be asked to follow an unsupervised home exercise program on five days per week which will consist of 30 minutes of walking, unsupported arm exercises  and loweAll outcome measures will be recorded at baseline, three, six and 12 months post pulmonary rehabilitation  Six-minute walk test (6MWT) . This teb) Incremental shuttle walk test (ISWT) . This tec) Endurance shuttle walk test (ESWT) . This teBefore and immediately after each walk test the following measurements will be recorded a) oxygen saturation and heart rate using a portable saturation monitor ; b) dyspnoea using the Borg Scale category ratio 0\u201310 scale . The 6MW2. Quality of life will be measured by:a) St George's Respiratory Questionnaire (SGRQ) . This isb) Hospital Anxiety and Depression Scale (HADS) . The HAD3. Lung function will be measured by:1) and forced vital capacity (FVC) will be measured using a mass flow sensor . The spirometer will be calibrated immediately before each test using a three litre-calibrating syringe. The highest value for FEV1 and FVC after three reproducible trials will be recorded and compared to predicted normal values [a) Spirometry. This will be performed in accordance with American Thoracic Society standards . Forced l values .b) Lung Volumes. These will be performed in accordance with American Thoracic Society standards  using a For all outcome measures, the mean difference between the ME group and the control group in the change from baseline to 12 months will be determined and the significance of these mean differences will be tested by repeated measures ANOVA. Significance will be set at p < 0.05. Intention to treat analysis will be used.The sample size calculation is based on functional walking capacity as this is the major outcome of the study. Redelmeier and colleagues  have repThe primary aim of the study is to determine if a once a week supervised, hospital-based exercise plus a home exercise program will maintain functional exercise capacity and quality of life in COPD subjects compared to standard care of unsupervised home exercise, twelve months following the completion of pulmonary rehabilitation. We hypothesize that exercise capacity and quality of life will be better maintained in the ME group compared to the control group.Pulmonary rehabilitation programs consisting of exercise and education have been shown to improve functional exercise capacity and quality of life . BenefitThis study may have a significant impact on the delivery of health care to people with COPD. If it is shown that supervised maintenance exercise programs ensure the benefits of pulmonary rehabilitation are retained, in terms of exercise capacity and quality of life, then such programs should be routinely instituted.The author(s) declare that they have no competing interests.LMS, JAA and ZJM all contributed to the design of the study, the preparation of the manuscript, and have read and approved the final manuscript.The pre-publication history for this paper can be accessed here:"}
+{"text": "The influence on heat sensitivity of interactions between HT29 human colon adenocarcinoma cells grown in two- or three-dimensional contact was investigated. No evidence for intercellular cooperation affecting cellular sensitivity to hyperthermia was found. Cells grown in monolayer were found to be more heat sensitive than those in aggregates, probably due to the different physical properties of the membrane of flat cells attached to the substratum. Cell-cell contact appears to affect the heat sensitivity of HT29 cells possibly by means of inducing arrest in a heat resistant phase of the cell cycle."}
+{"text": "A recent commentary stirred intense controversy over the status of anti-cancer immunotherapy. The commentary suggested moving beyond current anti-cancer vaccines since active-specific immunization failed to match expectations toward a more aggressive approach involving the adoptive transfer of in vitro expanded tumor antigen-specific T cells. Although the same authors clarified their position in response to others' rebuttal more discussion needs to be devoted to the current status of T cell-based anti-cancer therapy. The accompanying publications review the status of adoptive transfer of cancer vaccines on one hand and active-specific immunization on the other. Hopefully, reading these articles will offer a balanced view of the current status of antigen-specific ant-cancer therapies and suggest future strategies to foster unified efforts to complement either approach with the other according to specific biological principles. A recent commentary stirred intense controversy over the status of anti-cancer immunotherapy. The commentary suggested moving beyond current anti-cancer vaccines since active-specific immunization failed to match expectations . Althougin vivo that are rarely sufficient to induced cancer regression [ex vivo activated T cells and appears to be associated with enhanced clinical response rates at least in the subgroup of patients in which successful expansion is possible [ex vivo manipulation or in vivo conditions in different patients may differentially influence T cell persistence and, possibly, function. Interestingly, however, T cell persistence in itself does not clearly explain therapeutic effectiveness since other ex vivo expansion protocols are associated with long term persistence of adoptively transferred T cells which is not associated as tightly with tumor regression as discussed by the accompanying Yee's manuscript. In between these two extreme treatment modalities lies the combination of active-specific immunization with the systemic administration of interleukin-2 that has been associated with intermediate clinical response rates [in vivo activation as an alternative to the ex vivo activation utilized for adoptive transfer. It is, therefore, our conclusion that the dichotomy between the two strategies is quite arbitrary and is merely symptomatic of our limited understanding of the requirement for effective T cell localization and activation in target tissues [In the commentary the adoptive transfer of tumor antigens-specific T cells was promoted in alternative to active-specific immunization as if the two modalities were distinct biological entities rather than two extreme manifestations of the same phenomenon . In factgression . We havegression . In partgression . Adoptivpossible ,8. Interpossible . This fise rates . Althoug tissues .mea culpa for our failure to pay enough attention to the process of immunization at the systemic as well as at the tumor level [The surprising conclusion that anti-cancer immunization failed to yield the results anticipated by pre-clinical and early clinical studies ,10-12 maor level . In fairor level . We haveor level -16.In the accompanying Point-Counter Point series published in the Journal of Translational Medicine Craig Slingluff and Cassian Yee engage in a balanced discussion over the advantages and disadvantages of active specific immunization on one side and adoptive transfer of tumor antigen-specific T cells on the other. Future opportunities are presented with special emphasis on the complementarily and biological similarity of the two approaches. It is hoped that lessons learned from either approach will enable better design of future clinical studies combining the simplicity and safety of active-specific immunization with the power of adoptive immune therapy."}
+{"text": "Although the bone's capability of dental implant osseointegration has clinically been utilised as early as in the Gallo-Roman population, the specific mechanisms for the emergence and maintenance of peri-implant bone under functional load have not been identified. Here we show that under immediate loading of specially designed dental implants with masticatory loads, osseointegration is rapidly achieved.We examined the bone reaction around non- and immediately loaded dental implants inserted in the mandible of mature minipigs during the presently assumed time for osseointegration. We used threaded conical titanium implants containing a titanium2+ oxide surface, allowing direct bone contact after insertion. The external geometry was designed according to finite element analysis: the calculation showed that physiological amplitudes of strain  generated through mastication were homogenously distributed in peri-implant bone. The strain-energy density (SED) rate under assessment of a 1 Hz loading cycle was 150 Jm-3 s-1, peak dislocations were lower then nm.Bone was in direct contact to the implant surface (bone/implant contact rate 90%) from day one of implant insertion, as quantified by undecalcified histological sections. This effect was substantiated by ultrastructural analysis of intimate osteoblast attachment and mature collagen mineralisation at the titanium surface. We detected no loss in the intimate bone/implant bond during the experimental period of either control or experimental animals, indicating that immediate load had no adverse effect on bone structure in peri-implant bone.In terms of clinical relevance, the load related bone reaction at the implant interface may in combination with substrate effects be responsible for an immediate osseointegration state. Although the bone's capability of dental implant osseointegration has clinically been utilised as early as in the Gallo-Roman population , the speOsseointegration is defined as a direct and stable anchorage of an implant by the formation of bony tissue without growth of fibrous tissue at the bone-implant interface . A defin2+ oxide surface, allowing direct bone contact after insertion. The external geometry was designed according to finite element analysis: the calculation showed that physiological amplitudes of strain  generated through mastication were homogenously distributed in peri-implant bone  is reque Figure . The strBone was in direct contact to the implant surface (bone/implant contact rate 90%) from day one of implant insertion, as quantified by undecalcified histological sections Figure . This efBone response on an implant surface depends on the reaction of cells and matrix towards the material surface as well as to the mechanical constraints in the vincinity of the implant. The maintenance of bone and its adaptation to external loads is based on a complex strain driven regulatory process of cells and matrix components ,6. OutsiUsing an atomic force microscope, a molecular mechanistic origin for the remarkably fast recovery of toughness after bone deformation was found, when deformation of less then 50 nm at the surface of multivalent ions (as in the case of Ti-oxide) is present . Our undThe author(s) declare that they have no competing interests.UJ designed the study, searched the database, extracted the data. AB helped with the study design and analysis. HPW had analysis the histological probes and UJ developed the implant design."}
+{"text": "Four patients with chronic lymphocytic leukaemia were treated by one or more infusions of polyclonal antibody specific for the immunoglobulin idiotype expressed on their leukaemic cells. The antibody was in the form of IgG from sheep antiserum. Three of the 4 cases showed a significant fall in blood lymphocyte count. On one occasion most of the residual circulating lymphocytes were apparently dead. However on all occasions the cell counts rebounded to near pre-infusion levels within one week. Viable lymphocytes recovered from the blood after infusion always showed evidence of antigenic modulation: a diminished level of surface idiotype in a patched distribution, with an accompanying refractoriness to lysis by anti-idiotype plus complement. When cultured in vitro blood lymphocytes from three of the four patients revealed an appreciable export of idiotypic Ig. These 3 patients showed plasma levels of idiotypic Ig up to 400 micrograms ml-1, reduced by plasma exchange prior to infusion. The fourth patient had a level of less than 4 micrograms ml-1, and was the only one in whom free antibody could be found in the plasma after infusion. These cases demonstrate two major factors which thwart antibody attack on leukaemic cells--extracellular antigen and antigenic modulation--as well as problems relating to sparseness of surface antigen, recruitment of effectors, and exhaustion of effectors."}
+{"text": "This is far from an exact science, and often results in clinicians oversimplifying the complexity of the underlying pathophysiology. In a time-pressured clinical environment, clinicians use intuitive decision-making to make fast and impulsive judgments that often attribute a patient's complaint to a single common phenotype leading to a \u2018one-size-fits-all\u2019 approach to treatment. This population-approach to myocardial infarction has yielded better use of evidence-based therapies and promotion of lifestyle modifications to dramatically reduce early deaths from myocardial infarction over the past two decades. However, many patients fail to benefit from the widely advocated successes of a \u2018one-size-fits-all\u2019 approach either by sustaining harm from treatment or by remaining at increased risk of recurrent cardiovascular events despite optimal therapeutic interventions . Of noteTo influence long-term outcomes, a more considered and logical approach is required. Precision medicine requires taking account of the heterogeneity of disease and an individual's variable response to treatment. A detailed insight into the biological continuum of disease will help unravel the complexity of why some individuals gain significant benefits from interventions whereas others do not. Whereas current strategies in coronary artery disease have focused on population-derived evidence-based therapies, precision medicine seeks to understand an individual's unique biological network using \u2018omics\u2019  to stratify treatment. The life-threatening complications that afflict individuals following an acute myocardial infarction despite optimal medical therapy are commonly referred to as the concept of residual risk.The multinational INTERHEART study demonstrated that nine modifiable risk factors account for over 90% of an individual's future cardiovascular risk . SuboptiWhile cardiovascular imaging techniques are not a therapeutic tool in themselves, the information obtained can influence downstream management by confirming a diagnosis and better selecting the prescription of treatment to reduce the complications of cardiovascular disease. Despite the ubiquitous use of imaging in cardiovascular medicine, until recently no randomized clinical trials have evaluated whether incorporating an imaging technique into a treatment pathway actually improves the care of patients. The first trial to do so was the SCOT-HEART trial published in 2015, which sought to ascertain the impact of computed tomography coronary angiography in the diagnosis and management of patients with stable chest pain due to suspected coronary artery disease in an outpatient clinic setting . It founThis trial exemplifies that even in a clinical setting where evidence-based practice is already in place, significant improvements can be achieved by adopting a more precise approach to the classification of coronary artery disease.in vivo. Advances in hybrid cardiovascular imaging with the emergence of positron-emission tomography\u2013computed tomography have allowed investigators to visualize disease activity at the molecular level within specific vascular territories. The ability to directly observe a pathophysiological process in vivo using molecular imaging has transformed oncological practice where precision medicine plays an integral role in the detection of malignancy and evaluation of response to treatment. Translation of this imaging technique into the field of coronary imaging has been facilitated with technological improvements in scanner resolution and ECG-gated acquisition. Precision medicine using positron-emission tomography is a different concept from an \u2018omics\u2019 approach to categorizing disease. A strength of recent cardiovascular genetic studies is the observation that genetic polymorphisms significantly influence the pharmacodynamics of drug therapy. The inheritability of these polymorphisms therefore allows for pre-emptive screening to mitigate against adverse responses to drug therapy. However, partly due to the complex and multifactorial nature of coronary atherosclerosis, candidate gene association studies have delivered widely conflicting results for predicting risk of recurrent myocardial infarction. For instance, whereas genetic variants associated with Chromosome 9p21 were strongly associated with the first myocardial infarction, they did not stratify individuals at risk of further cardiac events [in vivo molecular targets of active atherosclerosis.Attention is now focused on identifying the pathophysiology of coronary artery disease Molecular targets of inflammation in the coronary and carotid arteries can be detected using 2-18F]-Fluoro-2-deoxy-D-glucose imaging . This moF-Fluoro-in vivo using molecular imaging is an enticing way of delivering precision cardiovascular medicine.Considerable interest now centers on identifying these areas of activity in patients with myocardial infarction to evaluate whether secondary prevention can be better stratified to those at high-risk of recurrent cardiovascular events. This is the key research question for the ongoing prospective observational PRE18FFIR study (NCT02278211). The ability to provide a detailed phenotype of the activity and progression of pathophysiology"}
+{"text": "Burkholderia glumae BGR1, we mutated the gltI gene encoding a periplasmic substrate binding protein of a glutamate transport system to abolish glutamate uptake, and monitored the growth of the gltI null mutant in Luria-Bertani medium. We found that the gltI null mutant showed a slower growth rate than the wild-type strain and experienced hyperosmotic stress resulting in water loss from the cytoplasm in stationary phase. When the incubation time was extended, the mutant population collapsed due to the hyperosmotic stress. The gltI null mutant exhibited loss of adaptability under both hypoosmotic and hyperosmotic stresses. The growth rate of the gltI null mutant was restored to the level of wild-type growth by exogenous addition of glycine betaine to the culture medium, indicating that glycine betaine is a compatible solute in B. glumae. These results indicate that glutamate uptake from the environment plays a key role in osmoregulation in B. glumae.Bacteria exhibit an optimal growth rate in culture media with sufficient nutrients at an optimal temperature and pH. In addition, the concentration of solutes plays a critical role in bacterial growth and survival. Glutamate is known to be a major anionic solute involved in osmoregulation and the bacterial cell\u2019s response to changes in solute concentration. To determine how glutamate uptake is involved in osmoregulation in the rice bacterial pathogen  N-acetylated amino acids), and sugars   (C) with various concentrations of glycine betaine as a compatible solute in Luria-Bertani (LB) media. Error bars indicate the standard error ranges of triplicate experiments.Growth of the (PDF)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file."}
+{"text": "Preterm infants \u2264 35 weeks' gestational age (GA), and children \u2264 24 months of age with bronchopulmonary dysplasia (BPD) or hemodynamically significant congenital heart disease (hsCHD) are at high risk for developing severe respiratory syncytial virus (RSV) disease. In 3 previous randomized, placebo-controlled trials, palivizumab efficacy varied significantly based on these underlying conditions, and trial enrollment was not proportional to condition prevalence. This analysis provides the first estimate of the population-weighted efficacy of palivizumab in high-risk children, adjusting for condition prevalence. Palivizumab efficacy by high-risk condition was obtained from the clinical trials. The annual number of US children with each condition was obtained from the 2010 Centers for Disease Control and Prevention (CDC) natality statistics and the medical literature. Data from specialty pharmacies in the US palivizumab distribution network were used to estimate the population for each condition receiving at least 1 dose in the outpatient setting in 2012\u20132013. The weighted efficacy estimate was derived by summing the products of the condition-specific relative risk reductions and the relative frequency of each condition among those receiving palivizumab. The US population-weighted efficacy estimate for those receiving palivizumab was 68%. Due to the low prevalence of BPD and hsCHD and the higher efficacy observed in preterm infants without BPD or CHD, the population-weighted estimate of palivizumab efficacy is higher than the overall 45\u201355% efficacy observed in initial clinical trials. Consistent with 2012 American Academy of Pediatrics RSV prophylaxis recommendations, a low proportion of preterm infants 32\u201335 weeks' gestational age receive palivizumab. BPDbronchopulmonary dysplasiaCDCCenters for Disease Control and PreventionCHDcongenital heart diseaseFDAUS Food and Drug AdministrationGAgestational agehsCHDhemodynamically significant congenital heart diseaseRSVrespiratory syncytial virusRSVHrespiratory syncytial virus-related hospitalizationRespiratory syncytial virus (RSV), an important pathogen of infants and young children, is the most common cause of bronchiolitis and pneumonia worldwide.Palivizumab is a humanized monoclonal antibody indicated for the prevention of serious lower respiratory tract disease in these high-risk populations.This analysis provides the first estimate of the population-weighted efficacy of palivizumab in US children at high risk for severe RSV disease, adjusting for condition prevalence.Palivizumab efficacy by specific high-risk condition  was obtained from the results of the following 3 clinical trials.The annual number of US infants with prematurity by GA subgroup was obtained from the 2010 Centers for Disease Control and Prevention (CDC) natality statistics.Data from specialty pharmacies in the US palivizumab distribution network were used to estimate the population for each condition receiving \u2265 1 dose of palivizumab in the outpatient setting in 2012\u20132013. The weighted efficacy estimate was derived by summing the products of the condition-specific relative risk reductions from the clinical trials (The estimated total US population eligible to receive palivizumab and the estimated population receiving at least one dose of palivizumab in the outpatient setting by underlying condition is shown in Compared with placebo, the relative risk reduction in RSVH with palivizumab was greater in preterm infants without BPD or CHD than in children with BPD or moderate/severe CHD (Because of the low prevalence of BPD and hsCHD and the higher efficacy observed in preterm infants without BPD or CHD, the population-weighted estimate of palivizumab efficacy is approximately 70%, which is higher than the overall 45\u201355% efficacy observed in the initial clinical trials. Previous studies have demonstrated the efficacy of palivizumab in helping to prevent hospitalizations due to severe RSV disease.Based on the 2012 AAP guidelines, RSV prophylaxis is recommended throughout the RSV season for all infants born at <32 wk GA.A strength of this analysis is that it included data from 3 randomized, double-blind, placebo-controlled trials. Limitations include assumptions inherent in modeled projections and the fact that no distribution data were available for hospital utilization of palivizumab. However, hospital utilization represents a small fraction of palivizumab use as eligible infants would only receive their initial dose before discharge from the birth hospitalization during the RSV season.In conclusion, this analysis estimates the population-weighted efficacy of palivizumab in reducing RSVH at approximately 70%, which is higher than the overall 45\u201355% efficacy observed in initial clinical trials. The proportion of children receiving palivizumab on an annual basis is substantially lower relative to the total population that is eligible to receive it."}
+{"text": "Colorectal cancer (CRC) is one of the most common cancers in the western world. Early screening and detection could be highly preventative and therefore reduce mortality. Tight junctions (TJ) are well known for their function in controlling paracellular traffic of ions and molecules. It has become increasingly evident that TJs play a crucial role in maintaining cell-cell integrity, and the loss of cell junctional sealing could involve itself in the processes of carcinoma and cancer metastasis. If correlations between altered TJ proteins and CRC presence or invasiveness could be established, they may serve as important markers and guidelines for prophylactic and prognostic purposes, along with other screening methods. This review will present recent data from clinical and animal studies showing how altered TJ protein expression is a feature of certain CRCs. The up-regulation of claudin-1 in many CRCs is especially noteworthy. The focus of this article is simply on the association \u2013 however imperfect \u2013 between CRC and the major TJ transmembrane barrier proteins, namely claudins and occludin. Any causal relationship between TJ protein change and neoplasia remains conclusively unproven at present."}
+{"text": "Pervious randomized studies have demonstrated survival benefit in favor of tyrosine kinase inhibitors (TKIs) compared to cytokines in metastatic clear cell renal cell carcinoma (RCC). However, the role of TKIs for treating brain metastasis from RCC remains unknown. Previous studies have reported possible activity of sunitinib and sorafenib in RCC patients with brain metastasis. We report on patient with metastatic RCC who responded to first-line sunitinib but then progressed with multiple brain metastasis, but with controlled extra-cranial metastatic disease. The patient was treated with whole-brain palliative radiotherapy followed by treatment schedule of pazopanib at standard dose of 800 mg/day which was associated with a response in brain metastasis. Subsequently, she was re-challenged at reduced dose of 600 mg/day and developed further response in metastatic brain lesions. She lived for more than 3 years from initial diagnosis of brain metastasis. This is the first case report of sequential TKI therapy for treating metastatic RCC with brain metastasis and supports the probable use of pazopanib as potent TKI for treating patients with cerebral metastasis. The development of brain metastases has been reported in 10-25% of patients with renal cell carcinoma (RCC) with an average interval of approximately 17 months from original diagnosis and development of extra-cranial metastasis . In contWe report on a case with metastatic RCC who developed response to first-line TKI therapy with sunitinib, but then progressed with development of multiple brain metastases. The patient was treated with WBRT and re-challenged with further TKI (pazopanib) that induced a partial response and regression of brain metastasis. The patient had unusually prolonged survival of 3 years from diagnosis of brain metastasis.A 73-year-old Caucasian female presented in January 2009 with a large 9 \u00d7 8 cm tumor involving the left kidney. She underwent a left radical nephrectomy and post-operative histology showed presence of typical clear cell carcinoma of kidney (Fuhrman grade 3) with involvement of renal vein with pathological staging of T3aN0 (TNM version-7) completely excised RCC. She did not receive any adjuvant therapy. She relapsed in February 2010 when a routine surveillance CT scan demonstrated metastatic lesion in the upper lobe of right lung with associated mediastinal and hilar lymphadenopathy. She was asymptomatic with WHO performance status of one and the hematological and biochemical profile was normal. She was classified as favorable risk based on the Memorian Sloan Kettering Cancer Center prognostic stratification model. She commenced TKI therapy sunitinib at dose of 50 mg/day based on 4 weeks \u201con\u201d and 2 weeks \u201coff\u201d schedule. She underwent staging CT scan in September 2010 that demonstrated complete response in hilar lymphadenopathy and more than 50% reduction in size of lung metastasis . She conIn June 2011 a follow-up CT showed small volume lung metastasis and stable appearances of brain metastasis. There was an improvement in her clinical condition and performance status (WHO grade 1-2), but she had commenced therapeutic anticoagulation with low-molecular weight heparin in view of below-knee deep vein thrombosis and pulmonary embolism. In view of reappearance of lung metastasis, she was commenced on pazopanib 800 mg/day that she tolerated well with no significant toxicities. She underwent repeat imaging 3 months later that showed an improvement in lung metastasis and also response in the brain metastasis . She conThe management of RCC was revolutionized following the results from a pivotal phase III study published in 2007 demonstrating the effectiveness of TKI therapy with sunitinib improving survival outcomes compared to cytokines . More reBoth sunitinib and pazopanib are small molecular TKIs with similar mechanisms of action and induce blockade of vascular endothelial growth factor (VEGF) types 1 through 3, platelet-derived growth factor (PDGF-\u03b1 and PDGF-\u03b2), KIT, Fms-like tyrosine kinase-3 (FLT3), and colony-stimulating factor-1 pathways. There are pre-clinical data from animal studies that both sunitinib and pazopanib cross the blood-brain barrier (BBB) . In miceThere is limited evidence on the role of TKIs in the treatment of metastatic RCC with brain metastasis. All the pivotal phase III studies have excluded patients with brain metastasis. However, TKIs may have activity in treatment of brain metastasis as indicated by several case reports of response after exposure to sunitinib . In an eThis case report is unique as the patient progressed on initial TKI therapy with sunitinib, but responded to further sequential TKI inhibition with pazopanib. There is some evidence on possibility of objective responses with sequential VEGF TKI inhibition , but thiThe clinical history of our case and the response in brain metastasis observed with pazopanib raises some extremely important and pertinent questions. Does the development of brain metastasis on TKI therapy in the presence of response in extra-cranial sites of metastatic disease be truly characterized as TKI failure, and what is the best therapeutic approach for these patients? It is more than likely that the development of brain metastasis in this situation represents inability of drug to cross the BBB, rather than representing loss of drug activity. Therefore, appropriate treatment of brain metastasis followed by re-challenge schedule of TKI appears to be a reasonable therapeutic paradigm to follow in these circumstances.In our patient MRI showed multiple small brain metastasis and therefore patient received WBRT compared to surgery or SRS therapy. We decided to treat the patient with pazopanib given the favorable tolerance profile of the drug as the patient had experienced significant fatigue following completion of radiotherapy. It remains unknown whether the response to pazopanib may have been influenced by WBRT with its complex modulation of blood brain permeability, and whether re-challenging the patient with sunitinib may have induced a similar response. Does the response in brain metastasis induced by pazopanib in a patient progressing on sunitinib imply that pazopanib may be a more effective agent for treating brain metastasis? In contrast to sunitinib and sorafenib, there is no definite evidence on the possible activity of pazopanib in metastatic RCC with brain metastasis. We searched the literature and could identify only one report on pazopanib-induced response in brain metastasis in metastatic renal cancer. The report described a patient with papillary variant of RCC with multiple brain metastasis who was treated with WBRT followed by multiple lines of systemic therapy. Patient was treated with sunitinib, everolimus, standard-dose pazopanib (800 mg/day), sorafenib, and high-dose pazopanib (1 g/day). Patient was developing progressive brain lesions on standard-dose pazopanib which responded when the dose was escalated to 1 g/day. The patient had survival of 23 months from diagnosis of brain metastasis. The authors hypothesized that there may be a dose-response relationship with probable superior penetration of BBB with the increased dosage of pazopanib that reinforces the principles and importance of drug titration with targeted therapy . In contIn summary, this is the first case report of activity of pazopanib in brain metastasis arising from conventional renal clear-cell carcinoma. This report demonstrates robust and sustained activity of pazopanib for treating brain metastasis in metastatic RCC arising on background of progression on first-line sunitinib. This report highlights that sequential TKI inhibition may be an appropriate therapeutic strategy to adopt in patient with brain metastasis. There should be further research in the role of pazopanib for treating brain metastasis in metastatic renal cancer."}
+{"text": "A 29-year-old man admitted to a psychiatric unit was successfully treated for a paranoid psychosis with trifluoperazine. Following reduction of neuroleptic dosage and addition of paroxetine he developed severe extra-pyramidal side effects. These remitted after withdrawal of medication and did not recur following recommencement of trifluoperazine. This is the first report of such a side effect associated with paroxetine use in man."}
+{"text": "Transcranial direct current stimulation (tDCS) has been shown to enhance cognitive performance on a variety of tasks. It is hypothesized that tDCS enhances performance by affecting task related cortical excitability changes in networks underlying or connected to the site of stimulation facilitating long term potentiation. However, many recent studies have called into question the reliability and efficacy of tDCS to induce modulatory changes in brain activity. In this study, our goal is to investigate the individual differences in tDCS induced modulatory effects on brain activity related to the degree of enhancement in performance, providing insight into this lack of reliability. In accomplishing this goal, we used functional magnetic resonance imaging (fMRI) concurrently with tDCS stimulation  using a visual search task simulating real world conditions. The experiment consisted of three fMRI sessions: pre-training (no performance feedback), training , and post-training (no performance feedback). The right posterior parietal cortex was selected as the site of anodal tDCS based on its known role in visual search and spatial attention processing. Our results identified a region in the right precentral gyrus, known to be involved with visual spatial attention and orienting, that showed tDCS induced task related changes in cortical excitability that were associated with individual differences in improved performance. This same region showed greater activity during the training session for target feedback of incorrect (target-error feedback) over correct trials for the tDCS stim over sham group indicating greater attention to target features during training feedback when trials were incorrect. These results give important insight into the nature of neural excitability induced by tDCS as it relates to variability in individual differences in improved performance shedding some light the apparent lack of reliability found in tDCS research. The passing of low intensity electric current through the scalp to underlying brain tissue by transcranial direct current stimulation (tDCS) has been used extensively in both research and clinical settings to improve performance and learning on various perceptual, motor, and cognitive tasks as well as for treatment of various mental and neurological disorders \u20135. TDCS To better understand the underlying effects that tDCS has on the brain several studies have been conducted using tDCS in conjunction with non-invasive brain recording such as electroencephalography EEG \u201328, magnIn an attempt to better understand whether apparent discrepancies in the effectiveness of tDCS is related to individual differences in its induced neural modulation, we investigated both the after-effects of tDCS as well as the concurrent effects during task training using simultaneous fMRI-tDCS. For this study, we employed a visual search task that simulates real world conditions. Participants were to identify the presence or absence of a specific red truck amongst distractors in an urban environment through a simulated unmanned aerial vehicle (UAV) video-feed. We selected the right posterior parietal cortex rPPC as our site of anodal stimulation based on previous behavioral tDCS studies that have shown that stimulation of this region results in performance changes on a variety of spatial attention tasks related to visual search \u201355.Visual search is intimately related to both bottom-up  and top-down  processes as they interact to reorient attention to behaviorally relevant stimuli , 57. TheIt has been previously posited that on complex visual perceptual detection tasks, such as visual search, tDCS enhances learning mechanisms through an improvement in attention , which iTowards the comprehensive understanding of the specific induced modulation that tDCS has on brain activity during learning and performance of a complex visual search task, we devised an integrative experimental design that enables us to investigate: individual differences in neural after-effects of tDCS as related to variable facilitation in behavioral performance, and the specific concurrent neural effects of tDCS on brain processes related to complex perceptual learning. We used error feedback training, in which visual and auditory feedback indicating the true target is presented following each response. This scheme facilitates subjects to acquire relevant target features and allows us to focus on brain activity during the time period where the greatest amount of learning is expected to take place. The primary goals of the experiment are the following: 1. To determine individual differences in behaviorally related changes in brain activity post- relative to pre-training that is specific to the tDCS stim over the sham group. This is accomplished by correlating differential brain activity from post- relative to pre- training with each individual\u2019s improvement in visual search performance after training and comparing this correlation between real and sham tDCS. Consistent with the hypothesis of tDCS-induced excitability leading to LTP, it is predicted that specific effects of tDCS will be seen in the form of a positive relationship between improvement in behavioral performance and increased brain activity in the rPPC (site of stimulation) and/or in related brain regions involved with visual search. In other words, individuals in the tDCS stim group who display larger increases in brain activity will also have larger improvements in visual search performance following training compared to the tDCS sham group. These results would suggest that tDCS stimulation is enhancing learning selectively for the tDCS stim group. Conversely, we may also see a reduction in activity in brain regions involved with visual search with improvement in behavioral performance for the tDCS stim group over the tDCS sham group reflecting more efficient processing .The participants consisted of 28 Japanese adults  aged 18\u201325 years (mean = 20.7) from Osaka University. Participants were screened and excluded for having a history of head injuries or concussions, current or previous history of mental, neurological, alcohol or drug abuse disorders, or current medication affecting central nervous system function. Subjects without normal vision were given MRI compatible glasses to correct their vision to normal before the study was conducted and all subjects were right-handed. Participants were randomly assigned to the real tDCS (which will be referred to as the \u201cstim group\u201d from this point forward) or sham group. There were 14 individuals  in the tDCS stim group (mean age = 22.1 years) and 14 individuals  in the tDCS sham group (mean age = 21.3 years). Several subjects were not included in this study as a result of pressure pain caused by the tight fit of the headphone within the head coil or below chance performance on the post-training session. In the tDCS stim group there were originally 18 subjects and 4 were removed from the study. For the sham group, there were originally 17 subjects and 3 were removed from the study. Subjects gave written informed consent. The experimental procedures were approved by the National Institute of Information and Communications Technology NICT Human Subject Review Committee and were carried out in accordance with the principles expressed in the WMA Declaration of Helsinki. The person giving the instructions was blind with regard to the group membership of the participant. Therefore, this is a double-blind study.A high-fidelity battlefield simulator and training platform, Virtual Battlespace 2 (VBS2), was used to program the UAV visual search task. Participants viewed a 3D virtual Middle Eastern urban environment on a monitor from the perspective of a video feed from an MQ-9 Predator unmanned aerial vehicle. In each trial, the UAV camera was locked to the central point of the area to be surveyed as the UAV loitered in a circular path around this point. The goal of the task was based on a search and rescue mission that required participants to locate a red pickup truck located in the search area amongst buildings and other similar looking distractor vehicles. In each trial, there were 5 non-moving vehicles distributed throughout the search area, one of which could be the red truck . These vAll distractor vehicles in this task were chosen to share one particular feature with the target vehicle, which is the color red ; 2. Response time for hit and correct rejection trials (RT HT&CR Search); 3. Response time for target present trials ; 4. Response time to target for target present trials . The \u201cRT TP trials Search\u201d and \u201cRT TP trials Target\u201d measures were only analyzed for the training session to correspond with an fMRI analysis looking at the effects of feedback  as visual target feedback only occurred in the training session and on target present trials. All measures  were analyzed using between subjects t-tests (stim vs. sham) to identify any significant differences. This was done for each session as well as for gain scores from the pre-training session to the post-training session.All 3 sessions were conducted within a Siemens 3T Trio Scanner using a 32-channel head coil at the Center for Information and Neural Networks NICT Osaka University. The functional T2* weighted images were acquired using a gradient echo-planar imaging EPI sequence with a repetition time of 2 seconds (TR = 2). Each scan consisted of 30 interleaved axial slices (3x3x4mm) covering the brain and cerebellum. For sessions 1 and 3, 454 scans (~15 minutes) were taken for each session. For session 2 approximately 475 scans (~16 minutes) were taken that varied depending on the participant\u2019s response time on the feedback trials. An additional 150 scans (5 minutes) measuring resting-state activity were collected after each experimental session. The analysis and results of the resting state activity are presented in a separate study . Images Fixed effect SPM analyses were conducted for each subject. These analyses consisted of the following:This contrast was designed to determine differences in brain activity after relative to before training. The rest condition was used to ensure that differential activity post- relative to pre-training was not related to session effects, including unspecific tDCS effects. The same visual search task was used for pre- and post-training and therefore the conditions were matched for both visual input and motor output. The goal of this analysis was to determine brain activity showing task-related changes after training and active stimulation.The contrast of post- relative to pre-training for the visual search trials compared to the rest trials (post-training relative to rest minus pre-training relative to rest) ; Target feedback trials with no response or incorrect hits; All target absent trials. Contrasts were not conducted amongst these conditions so they can be thought of as regressors of non-interest extracting extraneous brain activity not related to target feedback processing. The contrast of target feedback incorrect versus correct trials was designed to specifically focus on activity related to training that is matched for visual input and motor output. Additionally, any unspecific effect due solely to tDCS should be cancelled-out as there is stimulation in both the incorrect and correct trials.The contrast of target feedback for incorrect trials relative to target feedback for correct trials. This contrast was from data collected during the second session in which subjects were trained on the visual search task during real stimulation or sham stimulation See  was giveWe conducted between subjects random-effects analyses (between subjects t-tests) using change in behavioral performance as a covariate of interest to determine performance related brain activity post- relative to pre-training that differs between the tDCS stim and sham groups. This was accomplished by using percent correct change in performance on the visual search task as a covariate of interest in the between subjects analysis of the contrast of post-training relative to rest minus pre-training relative to rest. The use of covariates allows us to investigate how the performance change (post-pre) of each subject is related to the change in overall activity on the visual search task (post-pre). Performance related brain activity specific to tDCS could be determined by comparing the stim group to the sham group. Essentially, we can determine why tDCS worked to increase performance for some subjects in the stim group and not for others. The use of covariates and the contrast of the stim vs sham group allow us to distinguish tDCS effects on performance rather than general learning effects resulting from training. Analyses were also conducted for the sham over the stim group.Between subjects random-effects analyses were also conducted to determine differences in brain activity between the tDCS stim and sham groups during training. The contrast of stim over sham was conducted to determine differential brain activity between the two groups during the training session specifically related to target-error feedback for incorrect over correct trials that is hypothesized to be modulated as a result of tDCS stimulation. Analyses were also conducted for the sham over the stim group as well. Because it was later found that there was a significant difference in hit rate between the tDCS stim and sham groups in the training session we conducted an additional analysis using hit rate as a regressor of interest for the same target-error feedback contrast of stim relative to sham. The results of this contrast using a lenient threshold of p < 0.05 uncorrected was used as an exclusive mask for the primary analyses described above to ensure that the results were not due to differences in hit rate between stim and sham groups.Correction for multiple comparisons (p < 0.05) across the entire brain was carried out using Monte-Carlo simulation of the brain volume to define a voxel contiguity threshold at an uncorrected significance level of p < 0.005 using the AFNI  3dClustSBecause we only included trials in which responses were given, it is possible that the number of trials between groups may differ and confound the brain imaging results. Analyses were conducted to ensure that there were no between group differences with regard to the number of trials included for each contrast of interest. For the target-error feedback contrast no significant differences  in the number of trials were present between the tDCS stim  and sham  groups. For the post- relative to pre-training contrast there were no significant differences for the following: 1. The post-training session  between the tDCS stim  and sham  groups. 2. The pre-training session  between the tDCS stim  and sham  groups. And 3. The difference in the number of trials included for the post- minus the pre-training session  between the tDCS stim  and sham  groups. Based on these results it is unlikely that the difference in the number of trials between the groups for the various contrasts confounded the brain imaging results.TDCS was applied using a NeuroConn DC-Stimulator MR, which is a certified MRI compatible device, which allows for DC stimulation during magnetic resonance imaging. Conductive paste was applied to two (5.3 x 7.2 cm) rectangular-shaped MRI compatible rubber electrodes that were attached to the participant. The anode was placed over the right P4 ) according to the 10\u201320 International EEG System and held in place using a padded headband. The cathode was placed contralateral on the back half way between the shoulder and neck (trapezius muscle) that was held in place by the conductive paste and the weight of the participant as they lay in the supine position in the MRI scanner. An extracranial reference electrode placement was used to avoid any confounding effects on brain activity due to current density beneath the cathode .Participants in the real stimulation group received 1mA current (maximum current dosage achievable with our MRI compatible tDCS unit) for a total of 30 minutes during the training session. Stimulation was started 5 minutes before the training began in order to ensure that the full modulatory effect of tDCS was active during task performance. The 30 minutes duration was sufficient time such that stimulation was always present during the task as well as during the acquisition of resting state activity used for a separate study . ParticiThe between subjects t-test results for all dependent measures for the training session are given in The t-test results for the pre-training session, the post-training session, and the post- minus the pre-training session are given in The brain imaging results for all the contrasts of interest are reported in Figs The random effects analysis investigated individual performance related activity for the contrast of visual search post- versus pre-training relative to the baseline rest condition, where each subject\u2019s differential percent correct improvement for post- minus pre-training was used as a covariate of interest. Significant differential activity correcting for multiple comparisons for the stim group over the sham group is given in For the sham over stim analysis there was a significant cluster of activity correcting for multiple comparisons within the left and right calcarine sulcus, lingual gyrus, and inferior occipital gyrus See . The linThe results of the random effects analysis for the contrast of target feedback incorrect trials relative to target feedback correct trials for the tDCS stim group over the sham group are presented in To determine brain regions that are selectively modulated by tDCS that are related to training and individual differences in the improvement in performance on the visual search task, the overlap in brain regions found to be significant in the two analyses reported above was assessed. The results for the overlap in activity present for the stim over sham groups for these two analyses are given in The results of this study elucidate potential neural modulatory mechanisms involved with task related individual differences in performance induced by tDCS. In accordance with the goals of this research, significant task related differences in brain activity between the stim and sham groups were identified. Specifically, a right hemisphere region on the border of the pre- and post-central gyrus including the somatosensory cortex, premotor cortex, and primary motor cortex were found to show the following: 1. Individual differences in behaviorally related enhancement in activity post- relative to pre-training for the tDCS stim over the sham group See . The degIndividual differences in the extent to which tDCS affects learning is supported by the significant positive correlation between post-training brain activity in the precentral gyrus and behavioral performance . In otheAnother interesting finding of our study was the apparent decrease in improvement related activity in visual areas including human occipital cortex visual processing areas V3 and V4 as a result of tDCS stimulation See . These aIn support of our hypothesis that tDCS modulates attentional processes during visual search training, previous research has shown that the same region in the pre- and post-central gyrus that we found to show overlap in all of our analyses see  is involIt is also interesting to point out that this region in the pre- and post-central gyrus found to overlap in all our analyses also shows greater resting state activity as measured by fractional amplitude of low frequency fluctuations for the stim over the sham group during concurrent tDCS stimulation . AdditioAs with all brain imaging studies, there are many potential limitations and confounds that need to be addressed. One potential limitation of this study is that the changes we see in BOLD response may not be a result of changes in task-relevant neural activity, but rather may be a result of changes in cerebral perfusion or noise induced by tDCS . Previous studies using concurrent tDCS and fMRI have suggested that tDCS induced distortions on fMRI signal-to-noise ratio SNR are minimal , 82. In An additional confound that we did not test was whether the radio frequency and gradients associated with fMRI EPI scanning influences the tDCS current. The NeuroConn DC-Stimulator MR that we used for this experiment includes an RF filter module with MRI compatible cables and electrodes. These components help to prevent effects of RF on tDCS current. In addition, we avoided cable loop formation in the setup that may result in gradient induced currents. Furthermore, the fMRI compatible cables used for tDCS had a high resistance (5k\u03a9), which should also decrease the induced current avoiding potential effects of MRI on tDCS. Although we do not believe it to be the case, since we did not measure the current during stimulation, we cannot rule out the possibility that the tDCS current could have been reduced or modulated such that its enhancement effects on behavior were diminished.The main purpose of this study was to identify tDCS induced brain activity associated with individual differences in enhancement of behavioral performance that may shed light on the growing number of studies disputing the reliability of tDCS. This was accomplished by using an fMRI-compatible tDCS device that allowed us to concurrently apply DC stimulation while measuring brain activity during visual search training and performance. A cluster was identified during target-error feedback in a brain region believed to contain the FEFs that is a major node in the top-down attention network. This suggests an active effect of tDCS on task-relevant networks during training. In addition, we identified a significant relationship between individual differences in visual search improvement and brain activity following the training session (after-effects) in the same attentional brain region for the real stimulation group that did not exist for the sham stimulation group despite not observing differences in behavioral performance at the group level. Specifically, individuals who had greater increases in visual search performance also displayed increased brain activity in the FEFs. This individual difference in the increase in activity during and after stimulation within task-relevant networks in areas not directly beneath the electrode is consistent with long-range tDCS induced LTP-like mechanism resulting in synaptic strengthening within these networks. Furthermore, the decrease in activity in visual areas with greater individual differences in improvement of visual search performance may represent more efficient processing resulting from processing in the FEF. Our findings together suggest that the apparent lack of reliability found in tDCS research in healthy adults may result from individual differences in the efficacy to which tDCS can induce long-term modulation of processing seen in after-effects in relation to enhanced task performance. The behavioral and fMRI data used for the results of this study are available as supplementary data S1 File(ZIP)Click here for additional data file."}
+{"text": "Genomic instability, a hallmark of almost all cancers, originates from the combined effects of a deregulated DNA damage response, DNA repair defects, and a failure of cell-cycle checkpoints before the damaged DNA is propagated to daughter cells . AlteratRecent evidence shows that elevated homologous recombination (HR) activity is a key mediator of genomic instability in MM. Increased HR activity results in an increased burden of mutations and the continued accumulation of genetic alterations, thereby leading to drug-resistant MM phenotypes and disease progression . AlthougPost-transcriptional RNA processing adds another layer of complexity to the maintenance of genomic stability in MM. RNA processing includes the concerted modification of the splicing patterns of transcripts involved in the repair of DNA damage and those involved in the regulation of genomic stability, which occurs in reponse to genotoxic stresses . The altThe potential to therapeutically target aberrant RBP activities has been illustrated by our recent studies, which show that highly genomically unstable and aggressive MMs carrying the 1q21 amplification have acquired dependency on the 1q21 amplification\u2013induced overexpression of the RBP interleukin enhancer binding factor 2 (ILF2) . ILF2 isFurther dissecting the altered function of RBPs and RBP-associated RNAs in response to DNA damage will provide a deeper insight into the mechanisms driving genomic instability in MM and lead to the identification of selective vulnerabilities that can be used to target highly genomically unstable cancers Figure ."}
+{"text": "ESR1 and ESR2. These bind to DNA and modulate the expression of target genes. Identification of estrogen target genes is greatly facilitated by the use of transcriptomic methods, such as RNA-seq and expression microarrays, and chromatin immunoprecipitation with massively parallel sequencing (ChIP-seq). Combining transcriptomic and ChIP-seq data enables a distinction to be drawn between direct and indirect estrogen target genes. This chapter discusses some methods of identifying estrogen target genes that do not require any expertise in programming languages or complex bioinformatics.Estrogen is a steroid hormone that plays critical roles in a myriad of intracellular pathways. The expression of many genes is regulated through the steroid hormone receptors  ESR1 and ESR2, the nuclear receptors through which estrogen exerts much of its effect . It. ItConveConsiderations for experimental design: Replicates are essential for ChIP-seq and transcriptomic analysis when attempting to distinguish biologically meaningful variation from noise. As mentioned in the introduction, if using stimulation with estrogen or an estrogen receptor agonist, it is vital to decide on the time scale of stimulation to ensure that the correct cross section of binding and transcriptomic changes are sampled.Limitations of current bioinformatic methods: There are several important limitations to consider when interpreting lists of direct gene targets. The output is only as good as the data input into the model in the first place. This can be an issue particularly for ChIP-seq datasets, which are noisy and frequently irreproducible in the main between different studies nominally using the same material and methods [ methods . However methods . Another methods . Methods methods .Further functional annotation of direct gene targets: As mentioned above, many of the thresholds used are rather arbitrary and so it can be informative to include other forms of functional annotation to hone down a list of potential gene targets to ones of higher confidence. ESR1 binding sites are more likely to be consistent between different ChIP datasets if they possess a classical ESR1 recognition motif or are located in a region of open chromatin (as assessed by DNase-seq) [ase-seq) . BETA wiase-seq) . There iase-seq) ."}
+{"text": "Likewise, Reelin is important for the orientation and maintenance of the leading processes of migrating neurons since they are misoriented in the developing reeler cortex, as are the apical dendrites of pyramidal cells in the mature mutant. Reelin-induced phosphorylation of cofilin, an actin-associated protein, is crucial since pyramidal neurons transfected by in utero electroporation (IUE) with a non-phosphorylatable form of cofilin (cofilinS3A) show severe migration defects reminiscent of those in the reeler mutant. Remarkably, migration of neurons in the cortex of reeler mice was partially rescued by transfecting them with LIM kinase 1 (LIMK1), the kinase that induces phosphorylation of cofilin at serine3, or with a pseudo-phosphorylated cofilin mutant (cofilinS3E). Together these results indicate that Reelin-induced phosphorylation of cofilin is an important component in the orientation and directed migration of cortical neurons and in their correct lamination.Neurons are highly polarized cells. They give rise to several dendrites but only one axon. In addition, many neurons show a preferred orientation. For example, pyramidal neurons of the cerebral cortex extend their apical dendrites toward the cortical surface while their axons run in opposite direction toward the white matter. This characteristic orientation reflects the migratory trajectory of a pyramidal cell during cortical development: the leading process  extends toward the marginal zone (MZ) and the trailing process (the future axon) toward the intermediate zone (IZ) while the cells migrate radially to reach their destination in the cortical plate (CP). In this review article, we summarize the function of Reelin, an extracellular matrix protein synthesized by Cajal-Retzius cells in the MZ, in the development of the characteristic orientation of the leading processes running perpendicular to the cortical surface. Reelin promotes migration toward the cortical surface since late-generated cortical neurons in the  The student of the mammalian cerebral cortex is impressed by two phenomena pointing to a well-ordered, non-random structural organization. First, there is the arrangement of cortical neurons in layers as seen in Nissl-stained sections or in sections immunostained using layer specific markers. Second, there is an almost uniform vertical orientation of the vast majority of cortical neurons. This is nicely seen when cortical neurons are impregnated using the Golgi method which stains the cells with their axonal and dendritic processes Golgi, . The verFrom a cell biological point of view numerous questions arise after this short description of cortical organization. Numerous researchers have dealt intensely with these questions during the last decades. In a landmark article, Berry and Rogers  describeDevelopmental studies in various species and more recently real-time microscopy of migrating neurons in the cortex have contributed much to our understanding of the journey of late-generated neurons through the layers of their predecessors  and very low-density lipoprotein receptor (VLDLR), showed a We previously found that Reelin induces phosphorylation (activation) of LIM kinase 1 (LIMK1), a kinase that in turn induces phosphorylation of cofilin  experiments  revealed a significant migration defect of the transfected cells, which remained near their site of origin in the subventricular zone (SVZ)\u2014very much reminiscent of the reeler phenotype. Neurons transfected with a pseudophosphorylated form (cofilinS3E) also showed a migration defect. Remarkably, transfection of reeler embryos with LIMK1 seemingly forced the phosphorylation of cofilin in these animals and resulted in a partial rescue of the migration defect in reeler, as did transfection with pseudophosphorylated cofilinS3E. These results on GFP-expressing neurons were obtained by IUE on embryonic day (E) 14.5, sacrificing the embryos on E17.5 and counterstaining sections of the cortex for propidium iodide /SVZ to the deep cortical layers. As already pointed out, late-generated cortical neurons destined to superficial layers have to migrate for longer distances. This holds particularly true since the cortical plate (CP) and the intermediate zone (IZ) have become thicker at later developmental stages due to the continuous arrival of numerous neurons and the development of their dendritic and axonal processes. In order to traverse these larger distances successfully, late-generated neurons migrate along radial glial fibers, which span out between the ventricle and the pial surface, serving as a guiding scaffold for migrating cells Rakic, . Is Reelin vivo, they were found to branch as soon as they reached the Reelin-containing MZ -positive processes of radial glial cells studied in a stripe choice assay with Reelin-containing stripes next to control stripes, started to branch as soon as they reached the Reelin stripes  and more often in embryos transfected with cofilinS3E. These findings in particular underscore the significant role of Reelin-induced cofilin phosphorylation for the orientation of the leading process and directed migration of cortical neurons. Indeed, we have previously shown that the phosphorylated form of cofilin is much enriched in and near the MZ (Chai et al., reeler embryos with pseudophosphorylated cofilinS3E or LIMK1 partially rescued orientation of the leading processes and the migration defect in reeler. In order to study the migratory behavior of the living cells in some detail, IUE with the various constructs was performed on E 14.5 and slice cultures of neocortex were prepared 3 days later, when many neurons destined to superficial layers were migrating (Figure Since radial glial cells are precursors of neurons, we hypothesized that also the leading processes of neurons would start to branch upon arrival at the MZ. Indeed, the leading processes gave rise to branches precisely upon arrival at the Reelin-containing MZ Figure . In the  cofilinSA and morS3Acofilin and cofilinS3E and to observe partial rescue of the reeler phenotype following transfection with LIMK1\u2014although many other molecular players such as molecules of the tubulin cytoskeleton (e.g., Meseke et al., We were impressed to find such significant migration defects when transfecting wild-type embryos with MF developed the concept of this review article and wrote the manuscript. SZ, SW and XC performed the majority of the experiments reviewed in this article and contributed to manuscript writing and editing.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The size of the resistance arteries limits the capacity to examine changes in protein phosphorylation/expression levels associated with ROK signaling. A highly sensitive biochemical detection approach was beneficial in examining the role of ROK in different force generation mechanisms along the course of myogenic constriction. In this mini review, we summarize recent results showing direct evidence for the contribution of ROK in development of myogenic response at the level of mechanotransduction, myosin light chain phosphatase inhibition and dynamic actin cytoskeleton reorganization. We will also present evidence that alterations in ROK signaling could underlie the progressive loss in myogenic response in a rat model of type 2 diabetes.The myogenic response is an inherent property of resistance arteries that warrants a relatively constant blood flow in response to changes in perfusion pressure and protect delicate organs from vascular insufficiencies and excessive blood flow. This fundamental phenomenon has been extensively studied aiming to elucidate the underlying mechanisms triggering smooth muscle contraction in response to intraluminal pressure elevation, particularly, Rho-associated kinase (ROK)-mediated Ca Over 100 years ago, Pressure-induced tone is crucial for various aspects of the cardiovascular homeostasis. The sum of effects of endothelial activation by blood flow, sympathetic neuronal control, and humoral factors modulates the myogenic response and sets the peripheral vascular resistance and thus contributes to blood pressure regulation. Moreover, the arteriolar myogenic response tightly regulates the capillary hydrostatic pressure against fluctuations in systemic pressures thus, stabilizing capillary flow and shielding downstream structures from the damaging effects of high intravascular pressure . Thus, aAdvances in the study of myogenic tone over the last two decades unfolded the crucial role of Rho-associated kinase (ROK) in the myogenic response of resistance arteries. In this mini review, we will focus on the role of ROK in myogenic constriction in health and disease condition, specifically type 2 diabetes. We will provide a summary of our findings pertaining to the direct detection of ROK phosphorylated protein targets in the context of myogenic constriction using a highly sensitive western blotting detection technique.Figure 1).The cascade of events between the initial pressure rise and the increased force generation was subject to extensive study. Numerous studies utilized various experimental techniques to offer models and explanations of the molecular processes involved in pressure sensation and signal transduction to force-production mechanisms involving cross-bridge cycling and cytoskeletal reorganization. A widely accepted model of smooth muscle contraction involves an increase in the cytosolic calcium levels, which, via the stimulation of calcium and calmodulin-dependent kinase, activates myosin light chain kinase (MLCK) with the subsequent phosphorylation of the 20 kD regulatory light chain of myosin (LC20) leading to increased actin/myosin interaction followed by cross-bridge cycling and cell shortening . Integrins are heterodimeric transmembrane proteins that form a unique link between the smooth muscle cytoskeleton and extracellular matrix that is suitable for bi-directional signal transfer . One accOn the other hand, the assumption that a stretch-activated cation channels, such as transient receptor potential (TRP) channels and the epithelial sodium channels, act as a mechanosensor becomes reasonable given the fact that an early event in the cascade culminating in the arterial myogenic contractility in response to increased intraluminal pressure is smooth muscle membrane depolarization . Yet, reSeveral lines of evidence suggested that calcium-mediated MLCK activation and LC20 phosphorylation cannot be the only mechanism underlying force generation during the myogenic response. Studies employing ratiometric calcium dyes (Fura-2) to determine changes in the concentration of intracellular calcium in the pressure range eliciting the myogenic response demonstrated little to no change in calcium levels with increasing pressure. In 1997, D\u2019Angelo and colleagues showed that despite the differences in the magnitude of myogenic constriction produced by different intravascular pressure levels, there were no differences detected in the steady state intracellular calcium concentration . In 2002As mentioned earlier, not only was ROK reported to initiate smooth muscle depolarization during myogenic constriction , it was de novo actin polymerization in response to pressure increases. This was later supported by qualitative evidence showing that F-actin content increased in response to intraluminal pressure elevation  ROK-mediated sensitization vs. inhibition of a pressure-evoked ROK activity . SeveralFigure 1. Using the high-sensitivity three-step detection method, a graded increase in MYPT1 phosphorylation was evident. These findings implicated MYPT1 phosphorylation at T855 as the more likely site for regulation of MLCP activity in the context of pressure-induced contraction whereby myogenic constriction associated with step increases in intraluminal pressure from 20 mmHg to 60 and 100 mmHg was associated with an increase only in T855 phosphorylation. A corresponding gradual increase in LC20 phosphorylation was also observed and both increases were sensitive to pharmacological inhibition of ROK. No change in T697 phosphorylation was recorded in the pressure range of 60\u2013120 mmHg and this observation was consistent in both rat cerebral and skeletal muscle arterioles. Interestingly, vessels segments from these vascular beds showed significant basal (low pressure) levels of MYPT1 phosphorylation at both sites, with only T855 phosphorylation being sensitive to ROK inhibition  at Y397 and Src family kinase (SFK) at Y416 was identified as an early and essential event for the development of myogenic constriction . A pressSeveral issues remain to be clarified by future research. The calcium dependence of the integrin-mediated FAK and SFK signaling needs to be examined. This might explain the obligate dependence of the myogenic response on calcium despite the demonstrated involvement of ROK-mediated calcium-independent pathways. In addition, several observations indicate that different force generation mechanisms are not necessarily simultaneously activated at all pressure ranges, though all appear to involve ROK activity. Whether this effect is due to a limited effective range, e.g., LC20 phosphorylation reaching a maximum level, or selective activation by disparate mechanotransduction pathways remains to be determined. As well, GPCRs remain a viable alternative pathway for mechanotransduction to ROK in need for validation with direct molecular evidence in the context of myogenic constriction.Given the crucial physiological role of the myogenic response in cardiovascular homeostasis, it is predictable that dysfunctional myogenic regulation of arterial diameter will be associated with multiple vascular pathologies. Specifically, enhanced basal myogenic tone may preclude the vasodilatory response of resistance arteries in periods of high metabolic activity and oxygen demand. The reduced arterial diameter would be expected to restrict blood flow to the organ increasing the risk of ischemia. These microvascular changes could provide the starting point for further more permanent alterations in the micro/macro-vasculature . AbnormaFigure 2. Enhanced ROK activity rather than its level of expression was a common defect that has been characterized in most of the vascular beds of prediabetic and diabetic animal models exhibiting augmented contractile responses to agonists  ROK-dependent inhibition of MLCP; and (iii) ROK dependent dynamic actin cytoskeleton reorganization. It is now evident that the relative contribution of the three mechanisms during myogenic constriction is contingent on the intravascular pressure sensed by the mechanosensors in the vascular wall, yet all three share an obligate reliance on ROK activity. Moreover, the observed dysfunctional myogenic response in a type 2 diabetic rat model appeared to reflect an altered ROK activity. Delineating these alterations in type 2 diabetes and other vascular disorders will lead the search for new targets that could be clinically exploited in the future to alleviate the progression of cardiovascular diseases.In conclusion, three major mechanisms have been well characterized to underlie myogenic constriction including (i) CaAE-Y and KA-E have participated in reviewing the literature, summarizing the results, and writing the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In previous work we used diffusion tensor spectroscopy (DTS) to identify abnormal diffusion of the neuron-specific metabolite NAA in frontal white matter in patients with chronic schizophrenia in the absence of abnormalities in the diffusion of cell-type non-specific metabolites Cr and Cho.DTS relies on the same principles as DTI, but the diffusion characteristics of metabolites are probed, instead of those of water. Since brain metabolites are concentrated in specific cellular and sub-cellular compartments, their diffusion reflects the local geometry of these compartments. We have implemented a DTS approach at a 4 Tesla Varian MRI scanner .We have now collected similar data from first episode psychosis patients and matched healthy controls. We find that NAA diffusion is normal in the frontal PFC in first episode patients, but Cr and Cho diffusion is abnormal.Taken together, our studies suggest white matter abnormalities in non-neuronal elements in early phases of schizophrenia which are followed by neuronal damage in chronic disease."}
+{"text": "Overall Abstract: Converging behavioural and neuroimaging evidence indicates that an inability to regulate behaviour by working memory (WM) is a core feature of people with schizophrenia (PSZ) which significantly influences their level of recovery. WM dysfunction has also gained interest as a target of cognitive enhancement interventions and as an intermediate phenotype in the study of the genetic architecture of schizophrenia. These translational strategies critically depend upon a clear understanding of the underlying cognitive and neurophysiological disturbances. The aim of the symposium is to highlight current approaches to identify the pathophysiological mechanisms underlying WM deficits on both the microcircuit and the systems level.M. Ichinose will report cognitive modelling data showing that PSZ have elevated internal noise during perceptual processing, which was inversely correlated with WM precision. This indicates that \u2018noisy\u2019 perception contribute to impairments in WM and other cognitive domains.R. Bittner will present behavioural data from PSZ and imaging genetics fMRI data from a large cohort of healthy participants. The results of these studies indicate, that specific impairments in bottom-up attentional processes associated with genetic risk contribute to the dysfunction of working memory encoding in schizophrenia.A. Anticevic will present computational microcircuit models, resting state fMRI data and fMRI data using ketamine which provide evidence for a disturbed excitation-inhibition (E-I) balance and resulting in large scale dysconnectivity in schizophrenia in the context of working memory and other cognitive processes.The research presented in this symposium integrates computational, neuroanatomical, electrophysiological, pharmacological, genetic, behavioural and neuroimaging methods to connect pathophysiological mechanisms at the microcircuit level such as increased neuronal noise and an abnormal E-I balance to disturbances in large scale brain networks at the systems level and to behavioral impairment. Such an integrative approach promises to yield new insights into the pathophysiology of cognitive dysfunction in schizophrenia."}
+{"text": "Although technically challenging, the development of reliable methods for in vivo measurement of ACD and EtOH is of paramount importance to solve the \u201cpuzzle of acetaldehyde as a neuroactive agent.\u201d In this short review we discuss the recent advances on brain EtOH pharmacokinetic and state-of-the-art available techniques that could be used for in vivo detect EtOH and ACD both non-invasively (magnetic resonance spectroscopy), and invasively . Among the different in vivo sampling techniques described, particular emphasis is paid to the field of enzyme-based amperometric biosensors. Biosensors have gained much attention in recent years for their ability to online monitor biological signals in vivo, and several micro- and nano-structured devices have been successfully used for in vivo studies. Owing to their high temporal and spatial resolution, biosensors could provide the adequate technology for studying in vivo EtOH pharmacokinetic.Over the last 20 years researchers have explored the postulated role of acetaldehyde (ACD) as a mediator of some of the actions of ethanol (EtOH) in the central nervous system (CNS). However, efforts have been hampered mainly by the difficulty of directly measuring  Acetaldehyde (ACD) is a naturally occurring compound, found in several fruits and vegetables as well as in tobacco smoke and fermented alcoholic beverages .In the last decades many attempts have been made to quantify brain EtOH and ACD, in order to correlate their concentrations with behavior . So far in vivo EtOH and ACD study.In this brief review we offer an overview of the recent advances on brain EtOH pharmacokinetic and discuss the state-of-the-art of available techniques for in situ synthesis has been long postulated as a plausible source of brain ACD  and is found in highest amount in the liver. However, since ADH is not uniformly expressed in the brain tissue, its real contribution to local ACD levels in discrete brain areas could have been underestimated and may deserve more detailed evaluation .in vivo study on EtOH-induced locomotion  mice, suggest that CYP2E1 function may be linked to catalase-mediated EtOH oxidation by increasing the availability of H2O2  administration impair the acquisition of operant EtOH self-administration in the rat . Howeverin vivo studying the involvement of catalase in brain ACD formation is based on the use of lentiviral vectors coding for an anticatalase shRNA (RNAi precursor), which allows for efficient (up to 75%) inhibition of catalase activity  is a non-invasive analytical technique used to provide a measure of hemistry . In vivodetected , MRS has animals . Howeveretection . Therefo13C-labeled EtOH administration , allowing the analysis of several molecules in cerebro spinal fluid (CSF) based on their diffusion across a semi-permeable membrane -based analytical methods are largely employed in microdialysis studies . With reGas chromatography (GC) is an efficient analytical technique for separating volatile species in complex samples, and several GC-based protocols have been developed for the detection of EtOH and ACD in biological matrices.Several detector types can be used in conjunction with GC for EtOH and ACD detection; the most efficient protocols available have been developed mainly using mass spectrometry (GC\u2013MS)  or flameGas chromatography with headspace extraction and mass spectrometry or flame ionization detection is the most reliable and sensitive technique available for EtOH and ACD detection in microdialysates . Indeed,A new fluorimetry-based analytical method for EtOH and ACD has been recently published . AlthougA biosensor can be defined as \u201ca self-contained analytical device that combines a biological component with a physicochemical device for the detection of an analyte of biological importance\u201d . Biosensin vivo brain monitoring  are increasingly employed in nitoring . In factnitoring . Anothernitoring .Amperometric enzyme-based biosensors are mainly based on enzymes that belong to two classes: oxidases and dehydrogenases; in their most common implementation the enzyme is linked on the transducer surface and the output signal is generated by measuring the electroactive by-products of enzymatic reaction.In recent years several AEBs for EtOH detection have been developed, based on both alcohol oxidase (AOx) or dehydrogenase (ADH).2) as the electron acceptor and flavin-adenine dinucleotide (FAD) as cofactor (reactions 2 and 3).Alcohol oxidase catalyzes the oxidation of aliphatic, low molecular weight alcohols to their respective aldehydes using molecular oxygen (O2O2 poses a problem of Faradaic interference due to the presence of other compounds (such as ascorbic acid and uric acid) physiologically present in high concentrations in the CSF, which are also oxidized at the same potential . However, the high anodic potential needed to oxidize Hotential . The use signals .+/HRP- redox couple (reaction 5) is used as the sensing scheme at the transducer surface of AOx/HRP-based AEBs.The HRPAlcohol dehydrogenase catalyzes the reversible oxidation of primary aliphatic and aromatic alcohols using nicotinamide-adenine dinucleotide (NAD) as cofactor (reaction 6).+/NADH redox couple (reaction 7) as the sensing scheme at the transducer surface of ADH-based AEBs  into acetate using NAD as cofactor (reaction 8).The ALDH-catalyzed reaction is monitored by using the NAD+/NADH redox couple (reaction 9) as the sensing scheme at the transducer surface of ALDH-based AEBs .in vitro, with high time resolution and substrate specificity  ACD analysis. Its invasiveness together with the low temporal resolution, and the necessity of complex analytical procedures, represent the most important problems.Brain microdialysis is a well-known sampling technique for in vivo study of neurochemistry. When compared to microdialysis the main advantages of AEBs are represented by their reduced invasiveness, high time resolution, and the possibility to detect analytes which cannot be studied with microdialysis. In the case of EtOH monitoring, AOX-based AEBs have proved to be capable of in vitro and in vivo detecting concentrations of EtOH in the \u03bcM range. ALDH-based ACD AEBs have not been applied for in vivo ACD detection yet, however in vitro data strongly suggest that these devices may represent the most promising opportunity for in vivo brain ACD detection.Biosensors are the emerging tool for the preclinical PE: performed literature analysis and data collection, wrote manuscript and acted as corresponding author. MD: supervised development of work, helped in data interpretation and manuscript evaluation and editing.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Previous studies have shown that, in electroencephalography (EEG) and magnetoencephalography (MEG), cortical oscillations in specific frequency bands  are functionally related to cognitive processing and behavior, and that abnormal patterns correlate with pathophysiological processes of neuropsychiatric disorders. Although these results have provided useful insights for neural communication in the human brain, they appeared to be highly speculative based on the level of EEG and MEG analyses performed . The development of new analysis methods for EEG and MEG signals has allowed researchers to depict the information code of brain networks, by precisely localizing sources of oscillatory activity related to brain functions or pathological processes. However, this kind of approach, characterizing brain activity purely in terms of anatomically segregated responses, is not sufficient to explain the pathophysiology of complex neuropsychiatric disorders or the mechanisms underlying cognitive functions.Recent advances in the neuroimaging field areas allow us to visualize the aggregate of neural connections at the macroscopic level within the brain, the so-called \u201cconnectome.\u201d In order to promote the development of the neurophysiological investigation of connectome of brain oscillations, this e-book aims at bringing together contributions from researchers in basic and clinical neuroscience using EEG and MEG connectome analysis. The most important focal point will be to address the functional roles of connectome of brain oscillations in contributing to understandings of higher cognitive processes in normal subjects and pathophysiology of psychiatric diseases.Pascual-Marqui et al. who founded LORETA himself, presented namely the \u201cisolated effective coherence\u201d (iCoh) obtained from eLORETA, which consists of estimating the partial coherence under a multivariate autoregressive model, followed by setting all irrelevant associations to zero, other than the particular directional association of interest. They elucidated the direct directed connection of alpha activity from the posterior cingulate to all other regions during eyes closed and theta-alpha activity from the anterior cingulate to other frontal regions during eyes open in human brain. Aoki et al. applied eLORETA-ICA analysis to resting-state EEG data in 80 healthy subjects using five frequency bands  and found five resting-state-independent-networks in alpha, beta and gamma frequency bands. Thatcher et al. analyzed the phase shift and lock duration of 3-dimensional current sources in 14 Brodmann areas located in the DMN using LORETA in the delta frequency band by using the Hilbert transform between all pairs of Brodmann areas. By depicting an inverse relation of phase shift and lock durations in an exponential way with distance between Brodmann areas, they showed a tremendous view of anatomical hubs in the brain behave like a \u201cshutter\u201d that opens and closes at specific durations as nodes of brain network. These cutting-edge methodologies were often applied in the recent publications and cited almost 60 times in these four years in total.The included papers can be roughly divided into three groups as follows: the first group of papers both tried to expand the boundaries of brain connectome analysis by applying new statistic solvers on exact low resolution electromagnetic tomography (eLORETA) analysis of EEG. Sugata et al. analyzed the correlation coefficient between performance of neural decoding and functional connectivity over the whole brain using. They suggest that use of the strength of functional connectivity between M1 and motor association areas has the potential to improve the performance of BMIs to perform real and imagined movements. Asakawa et al. evaluated the effect of different anxiety states on information processing as measured by EEG using emotional stimuli on a smartphone. They found that the propagation speed of the low anxiety group at the medial coronal for resting stimuli for all time segments was higher than those of high anxiety group and suggested that neural information processes concerning emotional stimuli differ based on current anxiety state. Ishii et al. used spatially filtered MEG and permutation analysis to precisely localize cortical generators of the magnetic counterpart of frontal midline theta rhythm (Fm\u03b8) and found the dorsal anterior cingulate and adjacent medial prefrontal cortex as the generetors of Fm\u03b8 and gamma event-related synchronization in right parietal regions subserving basic numerical processing and number-based spatial attention. They suggested that these multiple oscillatory activities might interact each other to proceed these cognitive tasks in the brain. Leiken et al. reported high-frequency brain signals in the developing brain using time-frequency analysis along with beamforming methods on MEG data. They suggested that the developing brain generates high-frequency signals that can be detected with the non-invasive technique of MEG. These studies showed several type of connectivity among certain brain areas in multiple frequency bands such as theta, alpha, beta, gamma bands related to various types of cognitive process and behavior.The application of these connectivity analysis for basic cognitive studies was described in the following papers\u2014the focus of the second group. To examine the relationship between functional connectivity and performance of brain-machine interfaces (BMIs), Ibanez et al. assessing the combination of basal resting state influences together with the ongoing activity during a task and its evoked neural response to characterize brain dynamics changes related to preclinical Alzheimer's disease and the review article from Miki and Kakigi introducing their own three studies that focused on facial movements.The third group contains the new research proposal from In summary, this ebook presented novel methodologies and various applications of neurophysiological connectome analysis. As a result, these papers were cited more than 120 times in these 4 years in total and threw light and impact on new directions for investigating the connectome of human brain.RI and LC discussed about this research topic and wrote the manuscript. RP-M, JX, and WG gave significant advise and helped the editing the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Overall Abstract: The recognition that attenuated clinical symptoms and impaired functioning often precede the onset of psychotic disorders has led to potentially transformative early intervention strategies which could benefit individuals during the prodromal phase through clinical intervention. However, these efforts could present a double-edged sword whereby on one hand earlier treatment could improve symptoms and facilitate recovery, but on the other hand, it could also increase labeling and associated stigma. This set of presentations draws from a diverse set of countries and researcher backgrounds, including peer perspectives to enhance recovery. Our panelists present novel data to address the potential challenges of early intervention strategies and how a better understanding of the stigmatising beliefs and experiences among individuals during the earliest signs of psychotic disorder could improve early intervention efforts.Two presentations use new perspectives to evaluate the perceptions and impact of stigma among prospective cohorts of young people at elevated risk for psychosis. Lawrence Yang uses one of the largest known cohorts of clinical high-risk young people from a multi-site study in the USA to assess the impact of two types of stigma: stigma associated with symptoms and and stigma associated with labelling of the \u2018high-risk for psychosis\u2019 identification. Sara Evans-Lacko uses two unique prospective community cohorts of young people enriched for risk of psychotic disorder from Brazil and the UK and investigates the levels of personal stigma and mental health literacy in relation to psychosis among young people with and without high risk of developing psychotic disorder. She will then present new data on how this relates to intended help-seeking and actual mental health service use among those at-risk for psychotic disorder. Utilizing a different perspective based on changing medical terminology for at-risk states, Danny Koren explores the attributions made by individuals in the general population and mental health professionals when applying \u2018attenuated pathology\u2019 versus \u2018compromised health\u2019 labels to refer to at-risk psychosis states."}
+{"text": "The ketogenic diet is a metabolic therapy used to treat epilepsy in adults and children for nearly 100 years; it can reduce or eliminate even severe or refractory seizures. New insights into its underlying mechanisms have been revealed by diverse types of electrophysiological recordings in hippocampal slices. Here we review these reports and their relevant mechanistic findings. We acknowledge that a major difficulty in using hippocampal slices is the inability to reproduce precisely the in vivo condition of ketogenic diet feeding in any in vitro preparation, and progress has been made in this in vivo/in vitro transition. Thus far at least three different approaches are reported to reproduce relevant diet effects in the hippocampal slices: (1) direct application of ketone bodies; (2) mimicking the ketogenic diet condition during a whole-cell patch-clamp technique; and (3) reduced glucose incubation of hippocampal slices from ketogenic diet\u2013fed animals. Significant results have been found with each of these methods and provide options for further study into short- and long-term mechanisms including Adenosine triphosphate (ATP)-sensitive potassium (KATP) channels, vesicular glutamate transporter (VGLUT), pannexin channels and adenosine receptors underlying ketogenic diet and other forms of metabolic therapy.The hippocampus is prone to epileptic seizures and is a key brain region and experimental platform for investigating mechanisms associated with the abnormal neuronal excitability that characterizes a seizure. Accordingly, the hippocampal slice is a common  The hippocampus is well-known as a brain area involved in learning and memory and also as the key region underlying the form of epilepsy known as mesial temporal lobe epilepsy. The temporal lobe refers to the ventrolateral middle part of cerebral cortex and abnormal neuronal discharge or a lesion affecting this lobe causes seizures Gastaut, . There aThe basic structure of hippocampus is simple. It includes principal cells  and surrounding interneurons. The principal cells form an excitatory circuit which is modulated by inhibitory interneurons. Notably, CA3 pyramidal neurons are connected to each other by excitatory recurrent collaterals. Thus, the hippocampal circuit is regulated by a balance between excitation from recurrent collaterals and inhibition from interneurons. When the balance collapses, the hippocampal circuit becomes hyper excitable and susceptible to seizures. Therefore, atrophy in the hippocampus is thought to be one of the main focuses of mesial temporal lobe epilepsy and excision of hippocampal sclerosis with selective amygdalohippocampectomy successfully improves ~70% of surgical patients  Ease of use and tissue access: acute brain slices must be maintained by perfusion with oxygenated artificial cerebrospinal fluid . All of these studies concluded that ketone bodies do not directly affect synaptic transmission, seizure-like activity or LTP in the rat hippocampal slice.A number of studies found negative results. Thio et al.  reportedin vivo  channels, which contribute to the slow afterhyperpolarization after action potential bursts to modulate spontaneous firing, suggesting that direct ketone body-mediated opening of KATP channels in dentate granule neurons may act as a seizure gate in the hippocampus. Similar results were reported from neurons of the substantia nigra in coronal midbrain slices of rats and mice from same laboratory  lacking voltage-gated potassium (Kv1.1) channels, which is thought be a model for several types of epilepsy including human temporal lobe epilepsy. Extracellular multielectrode array recordings showed spontaneous seizure-like events in organotypic hippocampal slice cultures from Kcna1-null mice. The application of ketone bodies for 2 weeks attenuated the seizure-like events in the mutant tissue. They also applied 5 mM \u03b2HB in vivo using subcutaneously implanted osmotic minipumps to Kcna1-null mice and reported that administration of this ketone body reduced the number of seizures , but trickier to change the intracellular milieu. The whole-cell patch clamp technique is one of the methods for recording a single cell  with subsequent opening of KATP channels. Opening of these potassium channels caused hyperpolarization and reduced excitability. These results indicate that mimicking the ketogenic diet condition with increased ATP and reduced glucose reduces excitability in hippocampal CA3 pyramidal neurons with autocrine modulation via adenosine A1R, and this might be a one of the key mechanisms of the anticonvulsant effects of the ketogenic diet in vivo  of the ketogenic diet is a stable, mild hypoglycemia in humans  treatment for 11\u201315 days. Mossy fiber-CA3 dendritic field potential slopes and fiber volley amplitudes of mossy fiber were not significantly different between slices from control diet-fed and ketogenic diet-fed Knca1-null mice, however ketogenic diet increased paired-pulse facilitation ratios and the half maximal stimulation intensities of field potential slope which are decreased by Kv1.1 knock out. They suggested that the improvement of mitochondria function by ketogenic diet might restore the hyperexcitability of CA3 neurons in Knca1-null mice and decrease seizure-like events (Simeone et al., 1R antagonist and did not occur in slices from adenosine A1R knock-out mice. Antagonism of KATP channels or pannexin-1 channels inhibited the ketogenic diet-induced suppression of bicuculline-induced bursting. These results suggest that ketogenic diet causes antiseizure effects through a pannexin-1 channel-adenosine A1R-KATP channel autocrine pathway (Figure A third approach is possibly the most direct and useful way for investigating mechanisms of ketogenic diet because it uses acute hippocampal slices from ketogenic diet-fed animals Figure . In patiy Figure , the samy Figure .These studies used acute hippocampal slices from ketogenic diet-fed rodents successfully to elucidate altered neuronal activity underlying this treatment. Interestingly, reducing extracellular glucose concentration is thought be one of the most important points for reproducing the effects of ketogenic diet in this approach. Synaptic transmission in hippocampal slices from ketogenic diet-fed rodents were not different from slices from control diet-fed rodents when extracellular glucose concentration in artificial cerebrospinal fluid is standard in all three reports [however, evidence is mounting that this standard glucose concentration for acute brain slices is higher than physiological brain glucose levels (Shram et al., ATP opening, activation of adenosine receptors, and ATP release from pannexin channels. Complementary in vivo work has provided additional evidence for some of these mechanisms (Masino et al., in vitro such as ketone application, reduced extracellular glucose and increased intracellular ATP, and this requirement may explain the lack of a standardized protocol and a robust literature in this area. Finally, electrophysiology in slices is not a direct measurement of the in vivo anticonvulsant effects of ketogenic diet, and a combination of both in vivo and in vitro recordings is the best approach to provide further insight into the key anticonvulsant mechanisms underlying ketogenic diet and other metabolic therapies.Here we describe three approaches for researching anticonvulsant mechanisms of ketogenic diets by using electrophysiological recording from hippocampal slices. The usefulness of hippocampal slices is that it is easy to elucidate the details of neuronal modulation by ketogenic diet as shown in Figure MK, DNR and SAM wrote the article.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "A massive bleeding from the right ear, the nose and from the mouth occurred in a 46-year-old female after ambulatory myringotomy was performed in order to treat symptoms mimicking a persisting middle ear effusion with conductive hearing loss. The patient was directly admitted to our intensive care unit. The bleeding continued until the blood pressure was lowered to normal and the patient was positioned in an upright position. Otoscopy showed a pulsatile bleeding through a perforation of the tympanic membrane. Endoscopy of the epipharynx showed fresh blood coming from the eustachian tube. MRI (Panel A) and angiography (Panel B) showed an aberrant internal carotid artery on the right side in the petrousal part with a thorn-like protrusion at the side of injury followed by a decreased vessel-diameter directly below the injury . No coincidental aneurysm or vascularised tumor were found. An aberrant internal carotid artery in the middle ear is rare. Without prior diagnosis routine myringotomy can cause life-threatening situations. If a bluish-red formation behind the tympanic membrane is seen combined with the symptoms of pulsatile tinnitus and conductive hearing loss, a vascular malformation in the middle ear should be suspected and imaging of the temporal bone should precede any intervention. To avoid puncture of aberrant vessels in the middle ear, a paracentesis should in suspicious cases rather be performed with a sickle knife especially and not with a lancet."}
+{"text": "Recently, single-particle experiments have been used to provide measurements of details not available in the bulk assays. Here we focus our discussion on the key dynamical aspects of fusion protein structure, along with some of the experimental and computational techniques presently being used to investigate viral-mediated membrane fusion.Enveloped viruses commonly employ membrane fusion during cell penetration in order to deliver their genetic material across the cell boundary. Large conformational changes in the proteins embedded in the viral membrane play a fundamental role in the membrane fusion process. Despite the tremendously wide variety of viruses that contain membranes, it appears that they all contain membrane fusion protein machinery with a remarkably conserved mechanism of action. Much of our current biochemical understanding of viral membrane fusion has been derived from high-resolution structural studies and solution-based"}
+{"text": "Schizophrenia is thought to be a heterogeneous disorder and evidences reflect categorically distinct subtypes according to the antipsychotic treatment response. Altered frontostriatal functional connectivity (FC) in schizophrenia and its correlation with antipsychotic treatment response also suggests divergence of underlying pathophysiologic mechanism. Meanwhile, the observations that prefrontal activity correlates with striatal dopaminergic function, leads to the hypothesis that the disrupted frontostriatal FC would be related with altered dopaminergic pathway in schizophrenia. The aim of this study was to investigate the relationship between frontostriatal FC and striatal dopaminergic activity in patients with schizophrenia according to the responsiveness to first-line antipsychotic drug.24 symptomatically stable schizophrenia patients were recruited from Seoul National University Hospital, 12 of which responded to first-line antipsychotic drugs (first-line AP group) and 12 stable under clozapine (clozapine group), along with 12 matched health controls. All participants underwent resting-state functional MRI and [F18]DOPA positron emission tomography.There were no significant difference in the total PANSS score between the first-line AP group and the clozapine group . Voxel-based analysis found significant negative correlation between frontal FC to the left associative striatum and the kicer in the corresponding region was found in first-line AP group but not in clozapine group or healthy control. Additional region of interest analysis confirmed the result .Different patterns of relationship between striatal dopamine capacity and frontostriatal FC observed in this study indicates different pathophysiology underlying schizophrenia according to antipsychotics treatment-responsiveness. Results should be reconfirmed in prospective manner with larger sample size in future studies."}
+{"text": "Fiber matrices composed of PLLA and COLI in different ratios were characterized with respect to their morphology, as well as their ability to promote growth of human mesenchymal stem cells (hMSC) over a period of 22 days. Furthermore, the course of differentiation was analyzed by gene expression of alkaline phosphatase (ALP), osteocalcin (OC), and COLI. The PLLA-COLI blend nanofibers presented themselves with a relatively smooth surface. They were more hydrophilic as compared to PLLA nanofibers alone and formed a gel-like structure with a stable nanofiber backbone when incubated in aqueous solutions. We examined nanofibers composed of different PLLA and COLI ratios. A composition of 4:1 ratio of PLLA:COLI showed the best results. When hMSC were cultured on the PLLA-COLI nanofiber blend, growth as well as osteoblast differentiation  was enhanced when compared to PLLA nanofibers alone. Therefore, the blending of PLLA with COLI might be a suitable tool to enhance PLLA nanofibers with respect to bone tissue engineering.The aim of this study was to enhance synthetic poly(L-lactic acid) (PLLA) nanofibers by blending with collagen I (COLI) in order to improve their ability to promote growth and osteogenic differentiation of stem cells"}
+{"text": "Optic Neuritis (ON) has been associated to both parvocellular dysfunction and to an alteration of the magnocellular pathway. After objective visual field and acuity recovery, ON patients may complain about their vision suggesting a residual subclinical deficit. To better characterize visual abnormalities, 8 patients recovering from a first ON episode as well as 16 healthy controls performed a simple detection task and a more complex categorization task of images presented in low spatial frequencies (to target the magnocellular system) or in high spatial frequencies (to target the parvocellular system) or of non-filtered images. When completing the tasks with their (previously) pathologic eye, optic neuritis patients showed lower accuracy compared to controls or to their healthy eye for low spatial frequency images only. Conjointly, the longest reaction times were observed with the previously pathologic eye regardless the type of images and to a greater extent in the categorization task than in the detection task. Such data suggest two distinct, although associated, types of residual dysfunction in ON: a magnocellular pathway alteration and a more general (magno and parvocellular) visual dysfunction that could implicate the cognitive levels of visual processing."}
+{"text": "We present a case of a 22-year-old female with a history of intravenous drug abuse and homelessness presenting with four days of vomiting and abdominal pain. She noted significant weight loss in the preceding weeks; this was surmised to be secondary to increased drug usage. Examination revealed a diffusely tender but non-peritoneal abdomen. Computed tomography (CT) demonstrated duodenal obstruction with findings consistent with superior mesenteric artery (SMA) syndrome, which presents as high intestinal obstruction. While SMA syndrome can present due to medical conditions such as achalasia, it may also be seen in malnutrition related to substance abuse.Symptoms are caused by duodenal compression by the narrow angle of the SMA pressing against the posterior structures. The narrow angle of the SMA is due to lack of fat surrounding the vessel."}
+{"text": "During the secretory phase of their life-cycle, ameloblasts are highly specialized secretory cells whose role is to elaborate an extracellular matrix that ultimately confers both form and function to dental enamel, the most highly mineralized of all mammalian tissues. In common with many other \u201cprofessional\u201d secretory cells, ameloblasts employ the unfolded protein response (UPR) to help them cope with the large secretory cargo of extracellular matrix proteins transiting their ER (endoplasmic reticulum)/Golgi complex and so minimize ER stress. However, the UPR is a double-edged sword, and, in cases where ER stress is severe and prolonged, the UPR switches from pro-survival to pro-apoptotic mode. The purpose of this review is to consider the role of the ameloblast UPR in the biology and pathology of amelogenesis; specifically in respect of amelogenesis imperfecta (AI) and fluorosis. Some forms of AI appear to correspond to classic proteopathies, where pathological intra-cellular accumulations of protein tip the UPR toward apoptosis. Fluorosis also involves the UPR and, while not of itself a classic proteopathic disease, shares some common elements through the involvement of the UPR. The possibility of therapeutic intervention by pharmacological modulation of the UPR in AI and fluorosis is also discussed. AMELX/Y in humans; Amelx in rodents)  on to the pre-existing dentine surface by columnar secretory ameloblasts. The enamel matrix is overwhelmingly (>90%) composed of proteins derived by extracellular proteolysis of alternatively spliced products of the amelogenin gene  which are interspersed with inter-prismatic enamel crystals that together delineate the enamel ultrastructure; a process directed by the ameloblasts' specialized Tomes' process from which the secretory cargo is elaborated Smith, . The funThe functional importance of the enamel matrix proteins in amelogenesis is evidenced by the effects of mutations in their respective genes on the enamel phenotype, which can result in amelogenesis imperfecta (AI), characterized by biomineralization defects of enamel   that direct the folding of nascent polypeptides to maximize the probability that a nascent protein attains its correct functional 3-dimensional conformation. In addition, oxidoreducatase enzymes ensure that disulphide bond formation is regulated to inhibit random disulphide bond formation that if allowed could result in mis-folding. However, the molecular policing mechanisms that prevent protein mis-folding can fail. In this case, the protein may be permitted to access and become trapped in some low-energy state with a conformation that may not be biologically active or in some cases may promote pathological intracellular protein aggregation or be frankly cytotoxic Dobson, . Up to 3Activation of the trans-ER membrane sensors triggers an integrated signaling pathway that initially attempts to restore ER homeostasis by: (i) reducing the secretory load, (ii) increasing the folding capacity of the ER by up-regulating chaperone expression and increasing ER volume, and (iii) increasing ER-associated protein degradation (ERAD) . IRE1 endoribonuclease activity can be used to manipulate the UPR response by finely controlling the degradation of specific target mRNAs  are affected by genetic mutations and generate even more intense levels of ER stress. The net effects of the UPR in the presence of an enamel protein mutation may be relatively mild  or more severe . The next section will review the evidence that mutations in enamel matrix proteins can indeed cause AI driven by ER stress.Classically, AI has been approached from the perspective that mutations in genes encoding for secreted enamel matrix proteins would impact on protein functionality and behavior within the extracellular matrix itself. For example, studies have shown that certain AMELX mutations can affect amelogenin self-assembly  mutation  and human ENAMp.(L31R) mutations have also been associated with ameloblast ER stress  (there is no AMELY transcript in rodents) closely phenocopies mice heterozygous for Enamp.(S55I).The first evidence that ER stress could drive AI came from detailed phenotyping of a mouse model exhibiting an Amelxp.(Y64H) and Enamp.(S55I) animals showed a clear upregulation of markers indicative of ER stress and an activated UPR . During the early secretion stage, ameloblasts in affected mice were present as an ordered monolayer characteristic of WT animals and produced a structurally normal inner layer of enamel. However, in the later stages of secretion, the ameloblast monolayer became more disorganized, coincident with the loss of normal prismatic structure. These observations were interpreted in terms of the UPR initially acting in pro-survival mode, which maintained a functional ameloblast monolayer and allowed the cells to produce a structurally normal initial layer of enamel in both mutant genotypes. However, as the UPR signal evolved, ameloblasts from female mice expressing the Amelxp.(Y64H)  were directed toward apoptosis as evidenced by increased Chop expression, which severely disrupted the ameloblast monolayer leading to the production of structurally abnormal enamel. In contrast, Chop expression in enamel organs from mice heterozygous for Enamp.(S55I) remained at WT levels and it was assumed that the evolving UPR in these animals was up-regulated but failed to reach the tipping point required to trigger apoptosis. Nevertheless, the response was evidently sufficient to compromise the integrity of the ameloblast monolayer which resulted in the production of a structurally abnormal outer layer of enamel. This section is summarized in Figure Incisor enamel from heterozygous mice of both genotypes revealed an unusual phenotype in which the first 30\u201350 \u03bcm of initially secreted incisor enamel  exhibited the decussating prismatic structure characteristic of WT rodent incisor enamel but this was overlaid with subsequently secreted, structurally abnormal, aprismatic enamel  mutation and mice homozygous for Enamp.(S55I) exhibited increased expression of the pro-apoptotic transcription factor Chop compared to WT animals. Animals of both mutant genotypes did not produce a recognizable enamel layer. The failure to produce any enamel may have been related to the fact that the UPR evolved more quickly away from a pro-survival mode. However, another possibility is that insufficient mutated AMELX or ENAM molecules were secreted into the matrix to support amelogenesis and even if they were, the mutation could have impacted on their extracellular function.Secretory stage ameloblasts in hemizygous male mice carrying the Amelx and Enam genes? We can only assume that if the ER stress reaches a critical intensity, the UPR can circumvent the \u201cprotection\u201d provided by IGF-1 receptor signaling. The details of how this can be achieved are unclear but it may be simply due to the significant increase in Chop expression in the presence of a mutation that overcomes the anti-apoptotic effects of IGF-1 receptor signaling.What about the anti-apoptotic role of IGF-1 in these animals, which should be unaffected by mutations in the Amelxp.(Y64H) and Enamp.(S55I) described above. A similar enamel phenotype was recently described in teeth obtained from an AI patient heterozygous for an ENAMp.(L31R) mutation. The mature enamel phenotype from the patient's exfoliated teeth exhibited the same layer of structurally normal inner enamel overlaid by a subsequently secreted, structurally abnormal enamel outer layer , Xbp-1, and Chop expression in the LS8 ameloblast cell line  by inhibiting free radical scavenging systems such as those based on glutathione peroxidase and superoxide dismutase Chlubek, . ROS areOnce activated, how does the UPR actually effect extracellular events in the maturation stage enamel matrix under fluorotic conditions? Fluorosis is associated with enamel hypomineralization and abnormal retention of secretory stage matrix proteins in maturation stage enamel, where they could then inhibit secondary crystal growth , partially corrected the situation. A child homozygous for the BSEPp.T1210P mutation was treated with oral 4-PB with a subsequent improvement in liver function and partial restoration of biliary bile acid secretion. In this case, it appeared that 4-PB restored the trafficking of the mutated bile salt export pump to the canalicular membrane, where, despite the mutation, it was still functional to some degree. Restoring ER trafficking in this case allowed the mutated protein to escape the ERAD system  mutation were fed 4-PB in their diet. A dramatic rescue of the AI phenotype resulted . This presumably allowed the remaining ameloblasts expressing WT AMELX to complete amelogenesis. It is possible that AMELX synthesis and secretion was increased in the unaffected ameloblasts and that this compensated for the fact that only half the ameloblasts were secreting matrix.Despite this, the specific cellular response to 4-PB depends on cell context. For example, 4-PB can be pro-apoptotic in myeloid leukemia cells  mutation. However, restoring a stalled secretory pathway or inhibiting the pro-apoptotic actions of the UPR will not rescue the phenotype if the mutated protein in question is dysfunctional when it is secreted into the extracellular matrix.It is currently unknown whether or not 4-PB treatment can rescue the enamel phenotype in cases of AI other than that in female mice heterozygous for the The suggestion that 4-PB is anti-apoptotic in stressed ameloblasts is further supported by the report that apoptosis triggered by exposure to fluoride in an ameloblast-derived cell line was inhibited by 4-PB, resulting in an anti-apoptotic BCL2/BAX ratio  proves the principle that AI driven by ER stress and a pro-apoptotic UPR can be treated therapeutically with 4-PB. 4-PB is an approved therapeutic for urea cycle disorders. Acting as an excretable ammonium scavenger, 4-PB is administered orally in high doses from birth. However, 4-PB is contraindicated during pregnancy and so its therapeutic value would be restricted to protecting those permanent teeth whose enamel begins to mineralize after birth.The phenotypic rescue of female mice heterozygous for Clearly, more research is required using relevant mouse models to establish how common ER stress is as an etiological factor in human AI and how appropriate is targeting ER stress and the UPR as a treatment option. There are numerous other compounds under investigation for their therapeutic potential in terms of influencing folding of mutated proteins, inhibiting aggregation of mutated proteins and modulating the UPR. (Schonthal, In summary, ER stress and the UPR play an important role in maintaining ameloblast function and proteostasis under high secretory load during amelogenesis. We also know that it plays a role in the etiology of enamel pathology, and that, at least in some cases, AI can now be added to the growing list of proteopathic diseases. Proteopathies include several of the major diseases of our age and there is intense research underway to identify compounds of therapeutic value. It is an exciting possibility that anti-proteopathic drugs may provide an effective treatment option in amenable cases of AI. Fluorosis is not a classic proteopathic disease but the etiological involvement of the UPR raises the possibility that drugs that can modulate the UPR, or control the oxidative stress triggering the UPR, may be of therapeutic value in areas where fluorosis is endemic.SB, MB, MD, and JK contributed to the writing of the manuscript and its final approval. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The rotational motion of the Left Ventricle (LV) is a valuable measure in assessment of cardiac mechanics and can be estimated best through radial tagging. For practical quantitative application of this newly developed sequence, corresponding analyzing tools need to be developed. In this study, we presented a processing method based on peak-combination Harmonic Phase (HARP) approach to obtain displacement fields in polar coordinate.Short-axis human heart images with radial tagging pattern were acquired using a radial k-space sampling scheme. The data consisted of 19 cardiac frames obtained in a single breath-hold of 12 seconds duration. We exploited a Polar Fourier Transform for the reconstruction and processing of polar images. The method is based on two angularly Fourier Transforms separated by a Hankel-transform in the radial direction. Figure The outcome of this procedure for a sample radial tagging image, which has been transferred to polar coordinate system during PFT, is shown in the second row of figure HARP method for 1-1 SPAMM has a dual version in the Radial tagging in which the spectral peaks are replaced with the highlighted lines after the first angular FFT. Therefore, the same advantages one may expect from HARP in conventional tagging is transferred to radial tagging, if we use PFT in image reconstruction. It should be further noted that the rotational motion can be directly measured in the polar rather than Cartesian coordinates."}
+{"text": "The United States Food and Drug Administration (FDA) recommends that drugs that exert a pro-cognitive effect should be accompanied by measurable improvements in \u2018real-world\u2019 functioning. Patients with schizophrenia typically exhibit substantial impairments across a wide range of cognitive domains, representing an important target for therapeutic intervention. This has led to the development of several instruments specifically for use in this population that seek to capture the subjective experience and impact of cognitive dysfunction on daily living for use as co-primary endpoints in clinical trials. However, it remains unclear to what extent these accurately reflect objective cognitive performance.We conducted a secondary analysis of data from 413 patients with schizophrenia who participated in a multi-national randomized, double-blind, placebo-controlled trial. During the trial, participants completed two different neurocognitive test batteries, the Cambridge Neuropsychological Test Automated Battery (CANTAB) and the MATRICS Consensus Cognitive Battery (MCCB). They also completed two measures of subjective cognitive performance, the Schizophrenia Cognition Rating Scale (SCoRS) and the Patient Reported Experience of Cognitive Impairment in Schizophrenia (PRECIS). The severity of patient\u2019s symptoms was also assessed at each time point using the Positive and Negative Syndrome Scale (PANSS). All assessments were conducted at baseline and at a 12-week follow-up assessment (end of treatment). We examined the associations between these variables using correlational and multivariable linear regression analyses.Scores on each of the subjective measures of cognition were weakly correlated in the expected direction with objective measures of cognitive performance across both the CANTAB and MCCB tasks. Scores on each of the subjective cognition measures were more strongly associated with severity of symptoms as assessed using the PANSS. Multivariable regression analyses suggested that clinical symptoms accounted for significantly greater variance in subjective cognition scores than either objective cognitive performance or demographic factors.Subjective appraisals of cognition are poor predictors of objective cognitive performance in patients with schizophrenia. The burden reported by patients on these instruments appears to be more closely associated with the severity of their clinical symptoms. This has important implications for the use of these measures as co-primary endpoints in clinical trials assessing pro-cognitive drug effects."}
+{"text": "Cardiovascular magnetic resonance (CMR) imaging has long been used to calculate the ejection fraction (EF) of the left ventricle (LV) and more recently to calculate the ventricular-vascular-coupling (VVC) ratio, both entirely measured within the LV. Here we seek to demonstrate the role of blood transmission efficiency measure within the aorta.To establish the nature of the linkage between aortic vascular ejection efficiency (VEE) and LV EF and VVC which may prove useful for predicting future LVEF decline.Vascular ejection efficiency (VEE) is proportional to the dimensionless ratio of aortic diameter to wavelength of the transmitted blood pulse. The wavelength of ejected blood is proportional to blood wave velocity divided by blood wave frequency measured using phase velocity mapping (PVM) applied to the ascending aorta. Left ventricular function and aortic PVM data were retrospectively obtained in 118 patients who underwent CMR scanning as a clinical routine. The LV end-diastolic and end-systolic volumes were measured using manually drawn contours for a contiguous stack of LV slices. The aortic area was measured from the PVM images along with the average velocity, taken as a measure of blood wave velocity (not to be confused with the more common pulse wave velocity), the end-systolic time was taken as the pulse length and aortic area instead of diameter to yield the VEE index:VEE = Aortic Area \u00d7 End systolic time / Average blood velocityThe VEE was calculated and plotted against the ventricular measures of EF and VVC.In the plots of EF vs. VEE patients stratified into three regions, Figure We show that vascular ejection efficiency (VEE) measured in the aorta relates to LV EF measured in the ventricle via a series of power relationships, which accommodates the precipitous decline in EF at the lower levels of VEE. VEE may permit more effective risk-stratification and early detection for patients who are near an abrupt decline in LV systolic function. To date, predictive modeling for predicting precipitous declines in cardiac function is not in existence."}
+{"text": "Introduction:The necessity for complex and multidisciplinary approach of \u201cborder\u201d surgical pathology has unanimously been agreed upon for such a long period of time, its advantages becoming even more obvious in rare, particular cases.Patients and methods:We report the case of a 39 year-old man diagnosed with lymphangiomatosis back in his childhood. He is admitted with a giant pseudotumoral scrotal mass presenting an important scrotal enlargement (40/35 cm).Physical examination, blood tests, ultrasound, IVP, abdominal and chest CT, psychiatric and plastic surgery evaluation established the diagnosis: peno-scrotal lymphedema with gigantic hydrocele and depressive disorder. Taking into account the important enlargement of the scrotum associated with the alteration of the local skin, we decided to form a mixed surgical team: urology - plastic and reconstructive surgery.We performed bilateral surgical therapy of hydrocele with partial excision and eversion of sac edges, excision of peno-scrotal skin and subcutaneous tissue surplus. At the end we made a reconstruction by using a partial-thickness graft from the normal skin of the left thigh.Results:Spinal anaesthesia was sufficient in order to perform a qualitative complex surgery. Intra and postoperative course was uneventful with minimal blood loss.Conclusion:Rare cases like this one clearly reveal the advantages of a multidisciplinary surgical team by combining usual surgical procedures from different specialities that could lead to spectacular results. Lymphedema is an abnormal collection of protein-rich fluid in the interstitium and, regardless of etiology, is caused by inadequate lymphatic drainage leading to a chronic inflammatory process of hypertrophy and hyperplasia of connective tissue.Peno-scrotal lymphedema is a condition which leads to the progressive enlargement of the scrotum and penis causing significant psychical discomfort for patients, making both sexual intercourse and urination act difficult or even impossible, impairing movement and proper hygiene of the perineal region.The lymphedema is classified into primary, idiopathic - when it is caused by lymphatic malformation and could be congenital (Milroy disease), lymphedema praecox , and lymphedema tarda (after 35 years old).Wuchereria bancrofti warm (that causes filariosis) transmitted by mosquito bites migrate to the lymphatic tissue of the scrotal region causing lymphedema [1].Secondary lymphedema is due to an acquired obstruction and most frequently is the result of a parasite spreading disease \u2013 filariosis. The larvae of But the second type of lymphedema can result out of inflammatory or infectious diseases such as lymphogranulomatosis, tuberculosis or bacterial cellulitis.The most common etiologic malignancy is the prostate cancer with metastases inguinal lymph nodes.1], [2], [4].Surgical procedures, especially inguinal lymphadenectomy and radiation therapy in the pelvic region, can also be important causes. Literature mentions only one case of peno-scrotal lymphedema after complicated circumcision .The peno-scrotal lymphedema secondary to silicon subcutaneous or intradermic penian self injection is also described .Surgical treatment based on the restoration of lymphatic drainage with different anastomoses is not used anymore due to poor results [5].The excision of all the affected penile skin and subcutaneous tissue is a fundamental principle for an uneventful postoperative evolution and good plastic results ,[8].The coverage of the penile shaft with split-thickness skin graft is the optimal choice due to its very impressive cosmetic results. In the same time, the use of flaps could affect tactile sensitivity and erection, so, this technique has lost its supporters over time [The plastic surgery result is impressive when it is seen through the eyes of a patient with better mental status and recovered self-esteem."}
+{"text": "The article by Ballesteros and colleagues provides a fresh approach to the cognitive neuroscience of aging with a central focus on enhancement of cognitive functions by a video game training in normal healthy elderly.In the Twenty-first century the interest of researchers on beneficial effects of various cognitive therapies in amelioration of the mental power in elderly has grown rapidly with the increasing population of older people and it is the topic of many scientific papers, meta-analyses and review articles. As aging triggers progressive loss in multiple cognitive systems  and simulation strategy games (active controls). Transfer of video-game gains is studied with two selective attention  and two working memory tasks (Corsi blocks and N-back), considering self-report data on motivation, engagement and expectations in two compared groups. The main finding is that the Lumosity did not result in greater cognitive improvements than the intervention based on simulation games. Thus, video-game training provides modest benefits for untrained cognitive tasks.I would like to express some methodological comments on this experimentation raised also in my review of this study. These comments may be important for future neurorehabilitation studies.vs. after the intervention, in this study in ca. 12 weeks). In my opinion such effect cannot be avoided, even using the alternative test versions because of memorized task items or a strategy learning. The other influences may be caused by subjects' participation in the training protocol. Therefore, such extra control group allows to control for these nonspecific influences. Without the convincing control conditions any conclusion on training-related improvement may be misleading, because a contribution of nonspecific factors may be reflected even in the marginal improvements, as reported here.First, in training studies the inclusion of the non-active (passive) control group seems necessary, however, it is missing in the study by Ballesteros et al. It creates some methodological imbalance and may lead to unclear conclusions. Such extra passive controls should be tested twice in a time distance corresponding to the intervention duration. It provides evidence on possible changes in cognitive performance caused by the measurement repeated twice in a relatively short time  or a possibility of distant gains resulting from accumulation of neuroplastic changes in the brain. Without the follow-up assessment one cannot conclude whether the obtained intervention-related benefits  are transient or more stable, thus, based probably on reorganization within the neural network.The most important issue concerns the discussion and interpretation of data which focus on the behavioral level only and neglect any explanation on underlying mechanisms. A challenging problem in cognitive training studies is to define the neural mechanisms (or processes) that could account for training-related changes. Despite the statement that in elderly the application of non-action video games may influence modestly selective attention and working memory, one should agree that it influences the underlying neural network because the training-related gains are rooted in neuroplastic reorganization within the brain. Such approach is often ignored among researchers, leading to difficulties in understanding why the training-related changes may be expected.What neural mechanisms (or processes) may underlie the training-related benefits? One candidate indicated in Ballesteros's paper are executive functions that are high demand meta-cognitive processes that guide the optimization of goal-oriented behaviors (Etnier and Chang, An important question arising from this study is: A number of literature studies have indicated the patterning in time as one of characteristic features of human cognition because many mental functions are rooted in the exact temporal template P\u00f6ppel, . The idetiming-cognition,\u201d indicating correlations between the efficiency of temporal resolution and executive functions (Nowak et al., In our previous report we extended the relation \u201cOn a basis of these evidence one could reinterpret the merits of this paper. Age-related disruption of timing leads to declined cognition. Playing of video-games influences cognitive and executive functions because it might enhance the temporal resolution of the system. As a researcher in the field of timing, I am on the opinion that studies focused on cognitive skills in isolation, without any analysis of neural substrates cannot give a complete picture of the mental power in elderly brains.The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Epithelial ovarian cancer (EOC) is the commonest cause of gynecological cancer-related death; it is usually diagnosed at late stages when it is widely spread into the peritoneal cavity. Standard care remains surgery followed by platinum-based chemotherapy and despite a good response rate to front-line treatment, most of the patients eventually develop an incurable state of platinum-resistant disease . This unIn the era of next generation sequencing, to provide information on tumor progression and relapse, we decided to rely on the importance of expression studies, in particular on the non coding area of the genome. Indeed, we have focused our attention to microRNAs (miRNAs), short (21-25 nucleotides) non coding RNA that regulate the expression of about 60% of genes and whose hairpin structure makes them particularly resistant to degradation and stable in cells and in body fluids and therefore attractive candidates as cancer biomarkers [By using 3 retrospective cohorts including 894 EOC cases, which is the largest collection so far analyzed for miRNA expression, we derived a robust 35 miRNAbased predictor of EOC risk of relapse (MiROvaR) [Our effort to globally analyze 894 EOC samples for miRNA expression profile has implicated the need for an accurate data pre-processing to allow the best comparison among the different platforms and chip arrays used to obtained the analyzed profiles. After data filtering and miRNAs re-annotation, we obtained a list of 385 unique miRNAs shared among the platforms from which the 35 miRNA-based predictor of EOC risk of relapse was developed  and invoBeyond standard clinical parameters , there are few factors able to support clinicians in identifying those EOC patients who would indeed benefit from alternative therapeutic modalities.This study, showing that the prognostic role of MiROvaR can be shared across different histological subtypes, represent an important step forward in highlighting the role of miRNAs as biomarkers in EOC and warrant a further prospective validation for MiROvaR entering into clinical practice. Concerning its applicability, the subgroup of advanced stage EOC patients with a very unfavorable prognosis identified by MiROvaR might be candidated to more aggressive strategies (addition of bevacizumab and/or maintenance treatment in first line therapy). On the other hand, if applied to early stages EOC patients MiROvaR can help in identifying those patients who could really benefit from chemotherapy, sparing low risk patients from over-treatment."}
+{"text": "Xyrichthys novacula). Using underwater-video recording, we firstly document a fast and high exploitation rate of about 60% of the adult population removed in just few days after the opening of the season. Subsequently, we tagged a sample of individuals with acoustic transmitters and studied whether behavioral traits were significant predictors of the vulnerability to angling. Tagged individuals revealed repeatable behaviors in several home range-related traits, suggesting the presence of spatial behavioral types. The individuals surviving the experimental fishery showed only localized and low-intensity movement patterns. Our study provides new insights for understanding the harvesting pressures and selective properties acting on behavioral traits of recreational fishing. Many fish stocks around the globe are today predominantly exploited by recreational fisheries. The fisheries-induced change in fish behavior described here may be therefore widespread, and has the potential to alter food-webs, profitability of the fisheries and to affect stock assessment by eroding catchability in the long-term.Harvesting of wild-living animals is often intensive and may selectively target heritable behavioral traits. We studied the exploitation dynamics and the vulnerability consequences of individual heterogeneity in movement-related behaviors in free-ranging pearly razorfish ( Humans exploit wild-living animals by way of fishing and hunting since the origin of our species6In addition to the extraction of biomass, exploitation affects fish populations also by way of trait-selective harvesting1013Vulnerability is a complex process in recreational fisheries. Behavioral traits have been suggested to play a major role, either due to selection directly acting on such traits or due to indirect selection responses emerging from correlation with life-history traits192325in situ23Fig. 12031With the development of fine-scale aquatic telemetry and the development of novel statistical tools applied to movement data such as state-space models (SSM), ecologists have now a powerful tool for studying individual behavioral heterogeneity Cervus elaphus and pheasants, Phasianus colchicus that exhibit large home ranges, other recent work23Gadus morhua and the European lobster, Homarus gammarus, respectively. Simulation models have also shown the specific spatial patterns of harvesting by humans shapes the consistency and direction of selection gradients on home rangesHarvested animals in systems where encounters with the human predator mainly determines the probability of capture are expected to display smaller home range areas and reduced exploration rates in response to exploitation in agreement with the recently proposed \u201ctimidity syndrome\u201d28Xyrichtys novacula  using a before-after-impact-control (BACI) design based on underwater video cameras. Second, we used a novel SSM model applied to acoustic tracking data and investigated the individual heterogeneity in behavior and whether the home range behavior shown by individual fish was repeatable, hence representing a personality traitThe objectives of our work were two-fold. First, we sought to estimate the exploitation rate induced by recreational anglers on pearly razorfish nMax as proxy of abundance of pearly razorfish demonstrated a significant (p\u2009<\u20090.05) interaction effect of area (no-take vs. exploited)\u2009\u00d7\u2009period . Overall, the acoustic tracking revealed strong among-individual differences in both mechanistic descriptors of home range suggesting high individual heterogeneity in home range behavior in our tagged sample of pearly razorfish. Radius and k were uncorrelated and therefore provided independent measures of the intensity (k) and spatial extent (radius) of the home range behavior  to assess the consistency of individual heterogeneity in home range behavior over time in the five chosen daily-based behavioral traits were generally high  and longitude  of the center of the activity to be highly repeatable in both study years, with R values close to 1. This indicated strong among-individual differences in the location of the center of the home range and in activity over the study periods in both years (2) was also repeatable, although values were slightly lower for the fish tagged in 2013 in relation to the 95% KUD: 50% KUD  and 95% KUD . These results again indicated consistent differences in the spatial extent of the activity spaces across the two tracking periods . These results overall suggested that the specific home range behavior shown by individual pearly razorfish can be interpreted as a repeatable behavioral trait, either being an outcome of personality or in the case of swimming activity a personality trait per se, thus demonstrating the existence of spatial behavioral types  were harvested during a monitoring period of just 9 days after the opening of the harvesting season. After the AIC-reduction of the Cox model  were negative in all cases, collectively suggesting a reduced space use and smaller activity levels of the remaining individuals of our tagged sample after the harvesting peak. Specifically, S\u03bc was estimated as \u22121.43 for the parameter radius and \u22120.52 for the parameter exploration tendency k. Hence, selection by fishing was more strongly acting on the spatial extent compared to selection on exploration tendency. S\u03bc for the latitude and longitude of the center of the home range were also negative with values of \u22120.16 and \u22120.32, respectively. These findings collectively indicated recreational fishing-induced could favor selection towards individuals characterized by small home range and reduced exploration intensity with small swimming speeds.The trait-specific mean-standardized selection gradients  that were higher than those reported in previous telemetry studies in the wild23Rs values were overestimated due to the limitations in the duration of tracking and the potential temporal autocorrelation of the behaviors measured at daily scalesRs. However, a meta-analysis on animal personality reported average R of 0.37 among 98 species across several taxa23We specifically have found that movement parameters characterizing the extension of the home range and the exploration rate were the only predictors of the survivorship of the tracked individuals after the opening of the fishery. Collectively, individuals with small foraging areas and exploration rates and with low average swimming speeds survived the harvesting season. This pattern was consistent across the two years and independent of size/gender. Moreover, we found high repeatability of the daily home range-related behaviors. There is growing evidence about consistent  individual heterogeneity in behavioral traits leading to personality traits that form behavioral typesk) were more quickly harvested from the fishery, generating an estimate of a negative selection gradient on k, in agreement with our previous theoretical workradius and k was found to be high compared with published values for a range of traits under natural selection, despite our sample being biased towards angled fishWe concluded from our previous simulation workMicropterus salmoides protected from fishing also shows that exploited bass are more timid, which could have been caused by both evolution and learning similar to the case in pearly razorfishA recent meta-analysis suggests that about 52% behavioral variation across taxa is attributable to additive genetic variationMethods were carried out in accordance with approved guidelines. Specifically, all experimental protocols, including fish capturing and tagging, were approved by the authority responsible for marine natural resources of the study area , through a permit to the CONFLICT Project (ref: CGL2008-00958) and to the REC2 Project (ref: CTM2011-23835).We studied the pearly razorfish population harvested in a local fishery located in the Balearic Islands . The peanMax as proxy of real abundance, which is defined as the maximum number of individuals observed in a single frame during the viewing intervalnMAX was regressed on the interaction effect (the effect if interest) of site (no-take vs. exploited)\u2009\u00d7\u2009period (before vs. after) with sampling site ID considered as random effect (over-dispersion was checked). We discarded spatial pseudo-replication of the sampling points by fitting the univariate Moran\u2019s I autocorrelation. The estimated interaction effect was then used to calculate the exploitation rate while controlling for the environmental-related changes in the abundance by comparing exploited and control (baseline) sites.We randomly defined 49 sampling points within the MPA of Palma Bay (n\u2009=\u200911 in ntMPA and n\u2009=\u200938 in the pMPA) . We usedradius) in meters as a surrogate of the total foraging area and activity space, the harmonic force (exploration rate k in min\u22121) that represents how strongly a fish is attracted toward the center of its home range, i.e., how fast and intense the home range is explored, and the latitude and longitude of the center of the home range. radius and k affects the fish trajectory and the average daily swimming speed.We used the mechanistic approach proposed by ref. radius, k, latitude and longitude) at the individual level. Three Markov chain Monte Carlo (MCMC) were run assuming minimal prior knowledgeTo feed the SSM with field data, we carried out a standard acoustic tracking experiment in the study area . In AuguR) assesses the degree of consistency of behaviors shown by individuals over timeR represents the phenotypic variation attributable to individual heterogeneity and is often used to characterized animal personalities; it can be estimated as:The repeatability score  using the 95% and 50% KUD in the same way as ref. R was computed following MCMCglmm of the R-packageOur mechanistic approach to the home range behavior summarized the behavior of fish in relation to four movement parameters, which was useful for testing our vulnerability hypothesis. However, this approach did not provide repeated measures for studying how consistent and repeatable the four behaviors were over time. To obtain alternative repeated measures and estimate To examine whether home range behavior and other traits  were correlated with vulnerability , a survival model was fitted to the survivorship data of the tagged fish. Survival of each tagged fish was evaluated across/during the intensive harvesting period of 9 days, which covered the first two weekends after the opening of the fishery that concentrated most of the fishing pressure of the year according to the effort dynamics of the fishery see . Moreovesurvival library of the R-package. The full model included the individual mechanistic movement-related behavioral traits , the study year, gender and all of the second order interaction with gender. Fish length was strongly correlated with gender as the pearly razorfish is a protogynous hermaphrodite, and we selected gender to be incorporated in the Cox model. The coefficients of the Cox regression were estimated for the minimally adequate model ranked by the Akaike information criterion (AIC). The predicted survivorship probabilities over the exploitation phase were plotted using the function survfit of the R-package for significant effects.We fitted a Cox- regression model to the binary (harvested or not) and continuous  response data using the S\u03bc) acting on each movement trait according to ref. We calculated the mean-standardized selection gradient .Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations."}
+{"text": "The dorsal-metacarpal-artery (DMCA) flap in its standard or extended version is considered as the working horse to cover dorsal soft tissue finger defects with exposed extensor tendon or bone. We hereby present a clinical case of an 80-year-old male patient who is right-handed and sustained a soft tissue defect of the proximal dorsal aspect of his left 5th finger and the postoperative outcome employing a modified transposition flap. The double-pedicled DMCA flap (dpDMCA flap) of the hand poses in adequate clinical scenarios a comparably fast and safe solution to cover dorsal finger defects extending just distal to the PIP joint. To the best of our knowledge, this is the first report of a DMCA-based flap with a double pedicle to cover soft tissue defects at the dorsum of the hand.Level of Evidence: Level V, therapeutic study. The dorsal-metacarpal-artery (DMCA) flap in its standard or extended version is considered as the working horse to cover dorsal soft tissue finger defects with exposed extensor tendon or bone. The vascular supply of the DMCA flap is since its first description , 2 and iWe present a case of an 80-year-old male patient with a traumatic laceration of his left pinky with intact extensor apparatus Fig. , which wSince the first description of the DMCA flap in 1990  and its The variety of other options to reconstruct defects with DMCA-derived flaps are vast and were often tailored to the patients\u2019 need. Reversed DMCA flaps can be harvested as fasciocutanous flaps, adipofascial flaps, digitometacarpal with an extended retrogade pedicle , or as cIn this selected patient, we could demonstrate that our modified DMCA-derived transposition flap can serve as a useful adjunct to the aforementioned range of DMCA-modifications. The advantage of this procedure is a comparably short operating time  and a common recovery time for standard DMCA flaps (approx. 2\u00a0months). The patient was satisfied with the cosmetic outcome and functional restoration and no further treatment was desired or mandatory. Considering the flexion contracture, the patients\u2019 first priority was to use his bicycle again and therefore denied any surgical suggestions such as teno-artholysis.This double-pedicled flap may further be an option to develop other locoregional flaps to reconstruct more extensive soft tissue defects of the hand. We consider this combined flap of the dorsal aspect of the hand as a useful addition to the armamentarium of reconstructive options in selected cases but with presenting only one clinical case more patients with longer follow-up are required to confirm our findings."}
+{"text": "The neuroteratogenic nature of Zika Virus (ZIKV) infection has converted what would have been a tropical disease into a global threat. Zika is transmitted vertically via infected placental cells especially in the first and second trimesters. In the developing central nervous system (CNS), ZIKV can infect and induce apoptosis of neural progenitor cells subsequently causing microcephaly as well as other neuronal complications in infants. Its ability to infect multiple cell types  and increased environmental stability as compared to other flaviviruses (FVs) has broadened the transmission routes for ZIKV infection from vector-mediated to transmitted via body fluids. To further complicate the matters, it is genetically similar (about 40%) with the four serotypes of dengue virus (DENV), so much so that it can almost be called a fifth DENV serotype. This homology poses the risk of causing cross-reactive immune responses and subsequent antibody-dependent enhancement (ADE) of infection in case of secondary infections or for immunized individuals. All of these factors complicate the development of a single preventive vaccine candidate or a pharmacological intervention that will completely eliminate or cure ZIKV infection. We discuss all of these factors in detail in this review and conclude that a combinatorial approach including immunization and treatment might prove to be the winning strategy. Multiple reports have now confirmed that Zika virus (ZIKV) is a neuroteratogenic pathogen and is the causative agent of microcephaly and other developmental anomalies of the central nervous system (CNS) in children born to infected mothers  , yellow fever virus (YFV), and encephalitic viruses, like West Nile virus (WNV), Japanese encephalitis virus (JEV), and now ZIKV. Other than prenatal death  of ZIKV-associated severe thrombocytopenia and subcutaneous hematomas   pursuing different strategies in parallel. Approaches used include live-attenuated virus, nucleic acid based, live vectors, subunit vaccines, and nanoparticles WHO . In JuneThe recently licensed DENV vaccine is partially successful and can be used only in a certain population (aged 9\u201345\u00a0years) living in highly endemic areas WHO . Unlike Barba-Spaeth and coworkers identified structural details of a quaternary epitope in DENV known as envelope dimer epitope (EDE) formed at the interface of two enveloped monomers, 90 of which are arranged in icosahedral symmetry into the DENV glycoprotein shell. Antibodies targeting this region can be divided into two categories: EDE1, which is not sensitive to glycosylation at the Asn153 residue and EDE2, which requires the N-linked glycan at Asn153. They found that antibodies targeting EDE1, especially C8 and C10, efficiently neutralized ZIKV, while other antibodies targeting the fusion loop epitope were just cross-reactive (Barba-Spaeth et al. convalescent sera from patients with DENV infection and showed that while some anti-DENV antibodies confer neutralization of ZIKV infection, most antibodies caused ADE (Priyamvada et al. Swanstrom et al. confirmed the neutralizing potential of these two antibodies in human monocytic cell line, U937-DC-SIGN, and Vero cells (Swanstrom et al. Prevention of mother to fetus transmission via the use of an entry inhibitor would be the ideal solution to avoid cortical complications in the infants. Recent reports suggest that Axl is the primary entry receptor used by ZIKV in neuronal as well as skin cells (Hamel et al. Repurposing of FDA-approved drugs to identify anti-ZIKV compounds is an advantageous strategy that has proven successful in case of other infections such as Ebola and hepatitis C virus (He et al. Prevent ADE for ZIKV infection in DENV-immune individuals and vice versa.Not increase the chances of developing/worsening GBS, which means that the use of live-attenuated vaccines may be ruled out until the cause of GBS is identified.Safe for use in pregnant population and immune-compromised individuals especially because persons with immunosuppression or autoimmune disorders are at a higher risk of developing severe disease (Azevedo et al. Keep in consideration the broader tropism as well as increased stability of the ZIKV and its effect on the different modes of transmission.ZIKV infection is spreading across the globe at an alarming pace not only in vector-prevalent areas but also to other countries like USA, because of a wider range of routes of transmission. What started as yet another tropical disease has ended up being a much more serious threat because of its association with neurologic complications. Based on our knowledge so far, an ideal ZIKV prophylactic or therapeutic agent will be required to satisfy various criteria such as,While development of a preventive vaccine candidate is extremely important, it is also necessary to focus attention on identifying pharmacological agents that can either prevent/reduce mother to infant transmission or confer neuroprotection in the presence of viral burden. Considering these multiple factors, it seems likely that a combination of these two approaches will be the most successful in eradicating this global threat."}
+{"text": "Frontal cortical deficits have repeatedly been shown to be relevant in the development of psychiatric disorders and are supposed to evoke characteristic psychiatric and cognitive symptoms in schizophrenia. It is assumed that plasticity and connectivity impairments following non-invasive brain stimulation, which are observed as common patterns in the motor system of schizophrenic patients, are as well present in frontal cortical areas and cause the mentioned dysfunctions. Until now experimental evidence is lacking substantiating that this hypothesis is correct and both cortical regions show similar patterns of deficits. Hence, this study aimed to assess the plasticity and connectivity in the frontal cortex of schizophrenia patients.We applied anodal transcranial direct current stimulation (a-tDCS) to evoke long-term potentiation (LTP)-like plasticity in the dorsolateral prefrontal cortex (DLPFC). This non-invasive brain stimulation has been demonstrated to evoke plasticity in frontal cortical regions. As tDCS modulates cortical activity we employed electroencephalography (EEG) measurements to trace potential deficits in patients with schizophrenia compared to healthy participants. In total 20 schizophrenia patients and 20 age, gender and handedness matched healthy controls received 13Min of a-tDCS (1mA). EEG was measured before and after plasticity induction (up to 50 minutes) to record neuronal changes in excitability and plasticity.First analyses obtained a significant EEG alpha-activity change after LTP application in the frontal cortex of schizophrenia patients. This effect remained stable up to 50 minutes following a-tDCS stimulation.We were able to show for the first time that anodal tDCS is capable of inducing stable EEG alpha-activity changes in the frontal cortex of schizophrenia patients. Future analyses will focus on differences to healthy participants, which we hypothesize to show similar but stronger patterns of activity changes after a-tDCS stimulation."}
+{"text": "Resonant propagating waves created on the surface of a dielectric multilayer stack, called Bloch surface waves (BSW), can be designed for high sensitivity monitoring of the adjacent refractive index as an alternative platform to the metal-based surface plasmon resonance (SPR) sensing. The resonant wavelength and polarization can be designed by engineering of the dielectric layers unlike the fixed resonance of SPR, while the wide bandwidth low loss of dielectrics permits sharper resonances, longer propagation lengths and thus their use in waveguiding devices. The transparency of the dielectrics allows the excitation and monitoring of surface-bound fluorescent molecules. We review the recent developments in this technology. We show the advantages that can be obtained by using high index contrast layered structures. Operating at 1550\u00a0nm wavelengths will allow the BSW sensors to be implemented in the silicon photonics platform where active waveguiding can be used in the realization of compact planar integrated circuits for multi-parameter sensing."}
+{"text": "Gene transfer through retrograde axonal transport of viral vectors offers a substantial advantage for analyzing roles of specific neuronal pathways or cell types forming complex neural networks. This genetic approach may also be useful in gene therapy trials by enabling delivery of transgenes into a target brain region distant from the injection site of the vectors. Pseudotyping of a lentiviral vector based on human immunodeficiency virus type 1 (HIV-1) with various fusion envelope glycoproteins composed of different combinations of rabies virus glycoprotein (RV-G) and vesicular stomatitis virus glycoprotein (VSV-G) enhances the efficiency of retrograde gene transfer in both rodent and nonhuman primate brains. The most recently developed lentiviral vector is a pseudotype with fusion glycoprotein type E (FuG-E), which demonstrates highly efficient retrograde gene transfer in the brain. The FuG-E\u2013pseudotyped vector permits powerful experimental strategies for more precisely investigating the mechanisms underlying various brain functions. It also contributes to the development of new gene therapy approaches for neurodegenerative disorders, such as Parkinson\u2019s disease, by delivering genes required for survival and protection into specific neuronal populations. In this review article, we report the properties of the FuG-E\u2013pseudotyped vector, and we describe the application of the vector to neural circuit analysis and the potential use of the FuG-E vector in gene therapy for Parkinson\u2019s disease. To understand the mechanisms underlying brain functions controlled through complex neural networks, an analysis of the functions of specific neuronal pathways and cell types forming these complex networks is necessary. Recently, we developed a novel lentiviral vector\u2013mediated retrograde gene transfer system that enables analysis of a specific neuronal pathway in the central nervous system \u2013based lentiviral vector has been the most commonly used for experimental studies. The HIV-1\u2013based lentiviral vector is a valuable tool for gene therapy trials because it is able to transduce nondividing cells as well as dividing cells, in contrast to other retroviral vectors  during testing of various glycoproteins, with a shift in the junction between RV-G and VSV-G sequences  is well known to spread transsynaptically in the retrograde direction in the central nervous system Ugolini, . A recomSome serotypes of AAV vectors transfer foreign genes in a retrograde fashion in the central nervous system (Masamizu et al., The FuG-E\u2013pseudotyped vector has provided a useful gene engineering tool for experimental studies of neural circuit functions (for review see Kobayashi et al., Parkinson\u2019s disease is a neurodegenerative disorder characterized by progressive loss of nigrostriatal dopaminergic neurons; the loss of these neurons induces motor dysfunctions Fahn, . VariousGene transduction via viral vectors offers great advantages in genetic manipulation of neural circuit functions in diverse animal models, including rodents and nonhuman primates. We have developed novel types of lentiviral vectors, the HiRet and NeuRet vectors, which display HiRet in the central nervous system. These viral vectors enable analysis of the roles of specific neuronal pathways or signaling molecules with critical functions in complex neural circuits. Viral vector\u2013mediated retrograde gene delivery is a particularly important genetic technology in nonhuman primates because conventional transgenic approaches generally used for mice are hardly applicable to monkeys. Notably, the NeuRet vector possesses a unique characteristic in that it scarcely transduces dividing glial and neural stem/progenitor cells around the injection site. This property of the NeuRet vector is essential for genetic treatment of neurodegenerative diseases because viral vector integration into dividing cells may increase the risk of tumorigenesis in the brain. The NeuRet vector permits reducing the risk of tumorigenesis by suppressing gene delivery into glial and neural stem/progenitor cells. The NeuRet vector exhibits efficient retrograde gene transfer into the nigrostriatal pathway in primates, and the FuG-E vector has remarkably higher gene transfer efficiency in this pathway than the FuG-C vector. The FuG-E vector possessing these advantageous characteristics could contribute to the development of novel primate models for Parkinson\u2019s disease. Furthermore, the FuG-E vector may provide promising approaches to gene therapy for Parkinson\u2019s disease by delivering genes required for neuronal survival and protection into nigrostriatal dopaminergic neurons.All experiments were performed in accordance with the guidelines of the National Institutes of Health, and were approved by the Animal Research Committee of Fukushima Medical University for rodents and the Animal Welfare and Animal Care Committee of the Primate Research Institute, Kyoto University for monkeys. We made all efforts to minimize the number of animals used and their suffering.KeK wrote the present manuscript; KI, ST and SK designed figures; MT and KaK critically read and edited the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Hordeum vulgare L.) breeding programs. Fine adjustment of heading date is important for understanding other developmental traits such as leaf area, plant height, tillering, and grain number  is the most accurate and widely accepted way to present the actual required time to reach that stage  is one of the central regulators for heading date in barley as a long-day (LD) crop. Ppd-H1 encodes a component of the photoperiod pathway and the dominant alleles promote time to heading  acts as suppressor heading in barley plants that have not been exposed to vernalization -CO-FT, is also active in barley  genes control heading time and phase transition; but are poorly understood until now. Even though, dozens of heading date QTLs distributed over seven barley chromosomes have been detected using segregating populations (Esparza Mart\u00ednez and Foster, EARLY FLOWERING 3 (HvELF3/eps1; Faure et al., CENTRORADIALIS (HvCEN/eps2; Comadran et al., LUX ARRHYTHMO/PHYTOCLOCK 1 (HvLUX/PCL1/eps3; Campoli et al., PHYTOCHROME C (HvPHY-C/eps5; Nishida et al., In the last decade, extensive progress has been made in order to understand the genetic and molecular regulation of heading date in barley. Since several sophisticated next-generation sequencing or genetics approaches are now available to better analyze and understand the underlying molecular mechanisms of developmental traits, defining the correct developmental stage is very critical for understanding the molecular-genetic basis and biological pathways.The previous genetic studies found that pre-heading phases are partially independent and are under different genetic control compared to stage/phase-specific QTLs or genetic mechanisms regulating heading stage in barley (Borras-Gelonch et al., The investigations conducted so far on heading date clearly show that it is a key developmental stage for improving yield and adaptation. This article is intended to emphasize the importance of an accurate heading date definition in spring barley that in turn determines stage-specific genetic factors. Therefore, a clear morphological definition of heading date is key for further molecular and genetic analyses such as QTL/gene detection in addition to transcriptome and expression analyses. We put valuable inputs forward that will greatly help the scientific community working in this field.The authors confirmed their contribution of this work and prepared it for publication. AA formulated the idea. AA and TS wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer PMAK and handling Editor declared their shared affiliation, and the handling Editor states that the process met the standards of a fair and objective review."}
+{"text": "Corrigendum to: Differential effects of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 on atherosclerosis and monocyte/macrophage invasion Dr. Jackson has asked for his name to be removed. He contributed to elements of the reported studies during the initial submission but he did not contribute to the revision and the final manuscript was submitted without his formal approval. This has now been corrected online via post-production correction."}
+{"text": "Shape-memory polymers (SMPs) are a new class of smart materials, which have the capability to change from a temporary shape \u2018A\u2019 to a memorized permanent shape \u2018B\u2019 upon application of an external stimulus. In recent years, SMPs have attracted much attention from basic and fundamental research to industrial and practical applications due to the cheap and efficient alternative to well-known metallic shape-memory alloys. Since the shape-memory effect in SMPs is not related to a specific material property of single polymers, the control of nanoarchitecture of polymer networks is particularly important for the smart functions of SMPs. Such nanoarchitectonic approaches have enabled us to further create shape-memory surfaces (SMSs) with tunable surface topography at nano scale. The present review aims to bring together the exciting design of SMSs and the ever-expanding range of their uses as tools to control cell functions. The goal for these endeavors is to mimic the surrounding mechanical cues of extracellular environments which have been considered as critical parameters in cell fate determination. The untapped potential of SMSs makes them one of the most exciting interfaces of materials science and cell mechanobiology. In. InTm = lignment . HolograThese dynamic changes in nanotopography created on PCL substrate can also influence the intracellular localization of YAP/TAZ in cardiac progenitor cells . YAP and3.3.Although a thermally induced shape-memory effect can be achieved by an increase in temperature, shape-memory activation by remote light irradiation could lead to a variety of potential biomedical or other applications. From this regard, we have recently demonstrated the light-induced shape-memory transitions of nanopatterns using gold nanorods (AuNR)-embedded PCL films . AuNRs h4.As described above, cell responsiveness to their surrounding mechanical cues  has been an active research subject. Although our understanding of biochemical and physicochemical cues in the cellular microenvironment has been constantly improved, these sophisticated hierarchical interactions have often been overlooked when experiments were conducted in the context of static system. In this regards, SMPs or SMSs are becoming one of the most powerful tools available to lead to a new generation of dynamic systems that are capable of responding to external stimuli or cellular signals with spatial precision. From the numerous investigations described herein and elsewhere, it is clear that dynamically tunable materials play a critical role in regulating cell behavior. Scientists should now be able to take full advantage of SMPs or SMSs to gain additional insight into fundamental mechanisms driving cell behavior. New developments of independent, dynamic regulation of multiple parameters during tissue formation are desired. In addition, development of dynamic materials capable of incorporating a wide range of biologically relevant molecules has the potential to provide useful therapeutic benefits because it has been difficult for conventional technologies to produce highly-organized constructs with tunable properties. Since an ongoing challenge is to control stem cell differentiation, novel nanoatchitectonics-based strategies for substrate design will facilitate the creation of new classes of dynamic substrates in the future."}
+{"text": "The correct version can be found in this Erratum:In the original publication  is an inIncorrect version:decrease of basal IC rather than a modification of dynamic hyperinflation during exercise. The efficacy in terms of endurance time seems higher in studies which enrolled patients with hyperinflation, with a similar efficacy on walking or cycling.Conclusions: Long-acting bronchodilators improve exercise capacity in COPD. The main effect of long-acting bronchodilators seems to be a Correct versionincrease of basal IC rather than a modification of dynamic hyperinflation during exercise. The efficacy in terms of endurance time seems higher in studies which enrolled patients with hyperinflation, with a similar efficacy on walking or cycling.Conclusions: Long-acting bronchodilators improve exercise capacity in COPD. The main effect of long-acting bronchodilators seems to be an"}
+{"text": "Since the mid-1980s magnetic resonance imaging (MRI) has been investigated as a non- or minimally invasive tool to probe kidney allograft function. Despite this long-standing interest, MRI still plays a subordinate role in daily practice of transplantation nephrology. With the introduction of new functional MRI techniques, administration of exogenous gadolinium-based contrast agents has often become unnecessary and true non-invasive assessment of allograft function has become possible. This raises the question why application of MRI in the follow-up of kidney transplantation remains restricted, despite promising results. Current literature on kidney allograft MRI is mainly focused on assessment of (sub) acute kidney injury after transplantation. The aim of this review is to survey whether MRI can provide valuable diagnostic information beyond 1 year after kidney transplantation from a mechanistic point of view. The driving force behind chronic allograft nephropathy is believed to be chronic hypoxia. Based on this, techniques that visualize kidney perfusion and oxygenation, scarring, and parenchymal inflammation deserve special interest. We propose that functional MRI mechanistically provides tools for diagnostic work-up in long-term follow-up of kidney allografts. A rise in serum creatinine concentration (SCr) is often the first sign of kidney allograft dysfunction. It is only observed if considerable damage has occurred in the allograft, from which it follows that initial damage develops subclinically   physiological processes in the kidney potentially relevant for kidney allograft follow-up have been visualized with non-contrast enhanced  MRI to date Table . The chrThe essence of the chronic hypoxia theory is shown in Figure Thus far, the focus of interest has been on non-invasive diagnosis of the cause of acute allograft dysfunction. In this setting, non-functional MRI techniques possess unique qualities to assess morphologic abnormalities such as urinary obstruction  can also explain the decrease in Since the introduction of BOLD MRI in nephrology various researchers have investigated this technique in kidney transplant recipients  over 2 years follow-up  compared to corrected baseline GFR, these results suggest a role for disturbed oxygen balance in development of subclinical chronic damage. Continuous follow-up of these patients beyond 2 years would be interesting to further test this hypothesis. In contrast, results with BOLD MRI in CKD are inconsistent with the above, since most studies demonstrate no difference in CAs mentioned, experience in the chronic phase post-transplantation is very limited. Djamali et al. investigated It follows from these studies that the relationship between BOLD parameters and kidney function in kidney allografts is not fully understood. Confusingly, decreased values for 1 decay during the delay time. Combining this with a similar image acquired without applying the label, allows for renal cortical perfusion to be assessed  between the two techniques was found in a small study in which total kidney blood flow was determined in 19 healthy volunteers  is used for mapping of arterial blood flow and cortical perfusion at capillary level. In ASL, spins are labeled in the arterial phase  compared to baseline. According to Figure P < 0.05).Three studies in kidney transplantation patients have demonstrated a good correlation between kidney function and cortical perfusion as assessed with ASL Table  Lanzman, 2014 Thr = 0.73) with relative kidney perfusion as determined with ASL  measures the diffusion of water molecules in tissue. Since water motion in tissue is restricted, its diffusion constant differs from that of free water and is therefore described with the apparent diffusion coefficient (ADC). Applying a diffusion weighting  causes loss of signal which is proportional to the ADC and can be modeled using a mono-exponential function. Seven studies investigated mono-exponential DWI in kidney transplantation patients Table  Thoeny  Next to Another way of describing the signal measured with DWI is the tensor model, also known as Diffusion tensor imaging (DTI). Diffusion of water within a compartment such as a blood vessel or tubule is restricted to a specific direction by boundaries of the compartment. This phenomenon is known as anisotropy. If DWI is performed in at least six unique directions it becomes possible to describe the anisotropic diffusion using the diffusion tensor from which a quantitative measure of anisotropy can be derived, e.g., the fractional anisotropy (FA). Data can be displayed more sophisticatedly by showing intervoxal connectivity, which is called tractography. In tractography in each voxel the primary diffusion direction is identified and described by a vector     for prediction of lupus nephritis , since these particles diffuse into extravascular space quickly after infusion and are then taken up by macrophages  to cortical macrophage infiltration  in kidney biopsies was demonstrated by Sent\u00eds et al., who found that the GMC is predictive of death-censored graft failure up to 500 days after biopsy  is feasible and reliable for the assessment of kidney stiffness clinical kidney disease. In the future MRI could become feasible as a screening tool in long-term follow-up of kidney allografts. Longitudinal information on active inflammation and existing fibrosis, a combination that was identified as a strong predictor for allograft loss Haas,  could beAdmittedly, progress made in the past decade toward clinical implementation is not satisfying. This may be partially explained by the fear of nephrogenic systemic fibrosis due to GBCAs. It should therefore be stressed that with current technology administration of GBCAs has become unnecessary in many cases. Awareness of the potential of functional MRI in long-term follow-up of kidney transplantation patients among nephrologists is warranted  [grant number 150KK119]. The Dutch Kidney Foundation had no role in deciding on the study design, or in the collection, analysis, and interpretation of data; neither has this funder contributed to writing the article nor to making the decision to submit the article for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Acute myeloid leukemia (AML) is a heterogeneous disease. One reason for the heterogeneity may originate from inter-individual differences in the responses of leukemic cells to endogenous cytokines. On the basis of mathematical modeling, computer simulations and patient data, we have provided evidence that cytokine-independent leukemic cell proliferation may be linked to early relapses and poor overall survival. Depending whether the model of cytokine-dependent or cytokine-independent leukemic cell proliferation fits to the clinical data, patients can be assigned to two groups that differ significantly with respect to overall survival. The modeling approach further enables us to identify parameter constellations that can explain unexpected responses of some patients to external cytokines such as blast crisis or remission without chemotherapy. Acute myeloid leukemias (AML) comprise a heterogeneous group of malignant diseases. Since major clinical symptoms originate from impairment of healthy blood cell production, it is important to understand how leukemic cells interfere with healthy hematopoiesis. Clinical and genetic observations reveal a strong heterogeneity among individual patients. One reason for the observed heterogeneity may be differences in cytokine dependence of leukemic cells, i.e., cells of some patients require cytokines to expand (cytokine-dependent leukemic cells) whereas others exhibit autonomous (cytokine-independent) growth.2. Similarly, in vitro studies imply that leukemic cells of some patients exhibit autonomous growth in cell cultures whereas others require cytokines to expand5. The correlation between cytokine-dependence in cell culture and patient survival suggests that cytokine dependence of leukemic cells may be a clinically meaningful parameter5. However, it can depend on the culture conditions whether a leukemia sample exhibits autonomous growth or not3. Clinical trials also suggest that cytokine dependence of leukemic cells differs between patients. In principle, exogenous cytokine administration could recruit cytokine-dependent leukemic cells into cell cycle and thus increase efficacy of S-phase specific cytotoxic drugs3. However, clinical trials show that this approach, also referred to as \u201cpriming\u201d, works in some but not in all patients. Some trials report an improved rate of complete remission, disease free survival and rarely also overall survival after priming6, whereas others report no effect9. A direct measurement of the increase of blasts in S-phase after cytokine administration confirms this heterogeneity10. More detailed studies suggest that the impact of priming may depend on the patient subgroups defined e.g., by risk scores14.The idea that cytokine dependence of leukemic cells differs between patients is supported by experimental results. Xenotransplantation assays reveal that some leukemia samples exclusively engraft in mice transgenic for human cytokines and not in standard NSG mice6. In this context the question arises whether cytokines could potentially stimulate leukemic cells that survived therapy and trigger relapse. Although studies in AML patients suggest that leukemic cells can be recruited into cell cycle in response to administered cytokines15, multiple clinical trials imply that supportive cytokine treatment has no negative effects on relapse free survival6. Nevertheless, there exist trials and case reports stating that in some patients administration of cytokines or their analogues increases leukemic cell load or reduces relapse free survival18. Different genetic hits accounting for that have been identified so far20. On the other hand, there exist reports of patients achieving complete remission solely by cytokine administration without chemotherapy24. Both phenomena, negative and positive impact of cytokines on leukemic cell load, are so far not well understood.Cytokine administration has become a widely used supportive strategy to prevent chemotherapy-related neutropeniaThe aim of this work is to study if cytokine dependence of leukemic cells has an impact on the clinical course of the disease. For this purpose, we compare disease dynamics in case of cytokine-dependent (i.e. leukemic cells require endogenous cytokines to expand) and cytokine-independent (i.e. leukemic cells can expand in absence of endogenous cytokines) AMLs using mathematical models. We focus on the following questions: (i) How does time evolution of blasts differ in mathematical models of cytokine-dependent and cytokine-independent AML? (ii) Does it have a prognostic impact if patient data fits to the model of cytokine-dependent or to the model of cytokine-independent AML? (iii) Which cell parameters determine whether cytokine administration may have negative, neutral or positive effects on the leukemic cell load?24.To approach these questions, we develop new mathematical models of cytokine-dependent and cytokine-independent AML and apply them to patient data showing time changes of bone marrow blast counts between first remission and relapse. Comparing the two models we identify key dynamic features that may help to distinguish between both scenarios. Model-based patient data analysis suggests that the overall survival may depend on the type of regulatory feedback governing cancer stem cell behavior and that it could be significantly worse in case of cytokine-independent AML. Mathematical models provide potential explanations for unexpected responses of patients to cytokines described in literature26. Studies from literature demonstrate that mathematical modeling is a suitable approach to investigate the dynamics of cancer cells subjected to regulatory feedbacks or treatment interventions30. Especially in case of ambiguous experimental results or in systems where the observables strongly depend on experimental conditions, a model-based interpretation of patient data can provide additional insights.Mathematical models are a useful tool to understand processes that cannot be manipulated or measured experimentally. They allow rigorous comparison of different hypothetical scenarios and estimation of unknown parameterset al.31 and applied to data from AML patients25. Both models are an extension of a model of hematopoiesis32, which has been validated on the basis of patient data and applied to clinical questions35.The interaction of healthy and leukemic cells by cytokine feedbacks and consumption of environmental resources, such as niche spaces, makes it necessary to model both healthy and leukemic cells. To study the potential impact of these interactions on the clinical course of the disease our models incorporate two different modes of feedback, namely cytokine-dependent leukemic cells and cytokine-independent leukemic cells. Cytokine-dependent leukemic cells expand only in presence of cytokines, whereas cytokine-independent (autonomous) leukemic cells have the ability to expand without cytokine stimulation. In this work we develop a new mathematical model for cytokine-independent leukemic cells and compare it to a model of cytokine-dependent leukemic cells proposed by Stiehl 36. Since acute myeloid leukemia (AML) is a disease of the myeloid lineage, our models focus on the granulopoietic branch of the hematopoietic system. A complex network of cytokine signals adjusts cell production to the need of the organism36. Time evolution of the non-linear cytokine feedback in the models are inspired by G-CSF, the main cytokine of granulopoiesis36, and were proposed by Marciniak-Czochra et al.32. It has been reported that cytokine concentration influences properties of stem cells37 and more mature cells36, we therefore assume in the model that feedback signals act on all mitotic cell compartments.In the following we introduce the biological system underlying our models. In a multi-step process, the hematopoietic stem cell (HSC) population gives rise to all types of mature blood cells39. To investigate the potential impact of leukemic cell cytokine dependence on disease dynamics we consider two models, which are summarized in Fig.\u00a0In case of AML the leukemic cell population shows a similar hierarchical organization as the hematopoietic system with the leukemic stem cell  population at the top of the hierarchy40. (2) Leukemic cells of some patients expand only in the presence of cytokines and engraft only in mice transgenic for human cytokines5. (3) Cytokine administration in some AML patients recruits leukemic cells into S-phase15. Since hematopoietic and leukemic cells absorb and degrade cytokine molecules by receptor-mediated endocytosis, the two cell lineages interact through competition for the cytokine40.In Model 1 (cytokine-dependent AML), it is assumed that leukemic cells depend on the same endogenous cytokines as healthy hematopoietic cells. This assumption is justified by the following biological findings: (1) Leukemic cells express the same cytokine receptors as hematopoietic cells42. The cytokine-independent leukemic cell growth is then limited by a competition for the bone marrow space that results in an increased cellular degradation due to overcrowded bone marrow space. It is modeled by a feedback loop in death rates depending on the total immature cell population. A model assuming increased cell differentiation in case of marrow overcrowding leads to similar results. These assumptions are justified by the following evidence: (1) Different mechanisms of cytokine-independent leukemic cell expansion have been identified. One mechanism is autocrine sinalling where leukemic cells express the hematopoietic cytokines required for their survival. The cytokine expression profile of leukemic cells shows high inter-individual variability44 and includes multiple growth factors such as GM-CSF46, G-CSF43, M-CSF47, and IL-148. Secretion of these factors together with expression of the corresponding receptors leads to activation of the leukemic cells47. Another mechanism of factor-independent growth is constitutive activation of key signaling components due to mutations such as JAK/STAT or MAP-Kinase42. (2) Markers for cell death such as LDH, are increased in bloodstream of leukemic patients50 and enhanced cell death is observed in marrow samples of many patients51. The increased cell death is included in Model 2. Several mechanisms for spatial competition have been described such as (i) physical stress owing to overcrowding leading to extinction of cells52, (ii) competition for a limited niche surface expressing certain receptors (contact molecules) necessary for survival of healthy and leukemic cells and apoptosis or differentiation occurring, if no contacts to these molecules can be established53.Model 2 (cytokine-independent AML) is based on the evidence that in some patients malignant cells are autonomous with respect to physiological hematopoietic growth factorsThe latter niche competition mechanism is also valid for the cytokine-dependent AML in case of overcrowded bone marrow. Therefore, we include it also in the Model 1. As shown by numerical simulations this mechanism is relevant in Model 1 only under external cytokine stimulation. In absence of external cytokine stimulation, the feedback mechanism prevents significant overcrowding of the bone marrow space in cytokine-dependent AMLs.25.Both considered models include one leukemic cell lineage and one healthy cell lineage. Dynamics of the different healthy and leukemic cell types are given by ordinary differential equations. We assume that each lineage can be described by 2 compartments: dividing cells (including stem cells and progenitors) and post-mitotic cells. The resulting four-compartment model architecture is based on a simplified description of the multi-stages differentiation process, which reduces the complexity of the differentiation process to focus on mechanisms and effects of competition between different cell lines. The previous studies showed that reduction of the number of compartments do not change the behavior of the model after the modification of the parameters corresponding to the new interpretation of the compartmentsProliferation rate, describing the number\u00a0of cell divisions per unit of time.Fraction of self-renewal, describing the fraction of progeny cells returning to the compartment occupied by the parent cells that gave rise to them. On the basis of our earlier work and on compatibility with clinical data35, we assume that the fraction of self-renewal is regulated by feedback signaling. The fraction of self-renewal assigned to non-stem cells is a measure of the average number of cell divisions performed before a cell differentiates under homeostatic conditions33.Death rate, describing the fraction of cells dying per unit of time. For simplicity, we assume that under physiological conditions dividing cells do not die and non-dividing cells die at constant rates.Each cell type is characterized by the following cell parameters, which are summarized in Fig.\u00a035, have shown that additional regulation of proliferation rates has little impact on model dynamics. A system with a regulation of proliferation rates but constant self-renewal /differentiation is insufficient to explain hematopoietic reconstitution35. The simulations depicted in Supplemental Fig.\u00a035 and in leukemias25.The effects of cytokines on hematopoietic and leukemic cells are complex. In our models, we assume that cytokines regulate the ratio of self-renewing versus differentiating cells. We neglect the impact of cytokines on the proliferation rates. Our previous quantitative modeling works, see referenceseffective growth rate of a mitotic cell population. It describes how many mitotic cells are generated per unit of time, see Fig.\u00a0For analysis of the model dynamics, we define also the 34 (based on model fitting to data of hematopoietic reconstitution) and are assumed to be the same for all patients. Leukemic cell properties  and parameters describing interaction of leukemic and healthy cells  are considered to be patient specific. We use the least square method to fit the model to the patient data. The purpose of the parameter fitting is to determine which of the two models are able to capture the individual dynamics of a given patient. During the fitting procedure we restrict patient-specific parameters to biologically plausible ranges: (i) The leukemic cell proliferation rates can vary between one division per two years and one division per day. The latter is considered the upper bound taking into account the DNA replication time of a eukaryotic cell54. (ii) Leukemic cell self-renewal may vary between zero and one. (iii) Blast half-life is chosen between 25% and 100% of leukocyte half-life, motivated by literature55. More details are provided in Section 3.2 of the Supplement.Simulations have been performed using standard ODE-solvers in MATLAB . We start simulations with equilibrium cell counts in the hematopoietic lineage and a small number of LSC (1 per kg of body weight), mimicking the appearance of LSC due to a mutation or survival of LSC after therapy. Parameters describing the healthy cells  are taken from the previous workTo decide which of the models fits to the data of a given patient better, we find the best fit for each of the two models and calculate the RMSE (root mean square deviation) for each model. If RMSE for Model 1 is 5% larger than that for Model 2, we conclude that Model 2 fits the data better than Model 1 and vice versa. The results are robust with respect to these choices.We use bone marrow aspiration data from patients participating in clinical trials at the University Hospital of Heidelberg . Written consent for usage of clinical data for scientific purposes was obtained from each patient. We consider the data of 41 randomly chosen patients. Patients meet the following criteria: (i) at least one documented relapse of the disease in the bone marrow, (ii) achievement of complete hematological remission after treatment of primary diagnosis, (iii) successful bone marrow examination at relapse, and (iv) documented date of death or patients were still alive at the day of data collection. Criterion (iv) limited the number of considered patients.56. In all considered cases, the test yields significant results (p\u2009<\u20090.05).Survival distributions of different patient groups are compared using standard Kaplan-Meier survival analysisAll data analyzed in this study are included in this article, its supplementary information and in the cited references.35. For details see section \u201cMethods and Model Description\u201d and Sections 1 and 3 of the Supplement.To study how the dependence of leukemic cells on endogenous cytokines can impact on the clinical course of AML, we introduce two different mathematical models. In one model leukemic cells need endogenous cytokines to expand (cytokine-dependent AML) whereas in the other model leukemic cells can expand independently of endogenous cytokines (cytokine-independent AML). The models are summarized in Fig.\u00a054. We then measure the time span from origin of one LSC per kg of body weight to a marrow blast fraction of 10% for different LSC self-renewal fractions, see Fig.\u00a0We perform numerical simulations to compare blast expansion rates in the models of cytokine-dependent and cytokine-independent (autonomous) leukemic cells. To simulate the fastest possible expansion of leukemic cells, we set their proliferation rate to one division per day, which is an upper boundTo check whether the observed clinical courses are covered by our models, we fit both models to patient blast counts between complete remission (CR) and relapse, see Fig.\u00a0\u22123, Fig.\u00a05 and also with the finding that in some trials patient subgroups with unfavorable risk do not respond to cytokine priming before chemotherapy12.We ask whether cytokine-dependence of leukemic cells can have impacts on patient prognosis. For this purpose, we compared overall survival of patients compatible only with the model of cytokine-independent AML  to patients compatible with the model of cytokine-dependent AML . Survival analysis yields a significantly longer overall survival for group 1  leukemic and healthy cells compete for endogenous cytokines, which they require for expansion. In Scenario 2 (cytokine-independent AML) leukemic cells expand independently of cytokines but cells compete for the bone marrow space and die in case of overcrowding. Both scenarios are supported by experimental evidence57. This finding suggests that a better understanding of the disease mechanisms could allow to derive clinical strategies that support healthy hematopoiesis and reduce expansion of leukemic cells.Unlike many previous models, the models considered in this work explicitly include dynamics of healthy cells. Animal experiments show that hematopoietic stem cells isolated from leukemic organisms can lead to normal hematopoiesis if transplanted to a non-leukemic hostThe proposed mathematical models provide criteria that might allow discrimination between cytokine-dependent and cytokine-independent AMLs. Our results suggest that rapid leukemic cell expansion and early relapses may be typical for cytokine-independent AML. The models suggest that if time between complete remission and 10% marrow blasts at relapse is shorter than 200 days, only the model of cytokine-independent AML is able to explain the dynamics.5.Fitting of the developed models to patient blast counts between complete remission and relapse demonstrates that patients compatible only with the model of cytokine-independent AML have a significantly poorer overall survival compared to patients compatible with the model of cytokine-dependent AML. This observation is in line with data from cell culture studies showing that autonomous cell growth is correlated with a poor prognosis6. Although considered safe in general, there exist multiple reports of patients showing unexpected increase or reduction of the leukemic cell burden after cytokine administration. Increasing leukemic cell counts can be explained by cytokine-mediated blast expansion16, whereas decreasing leukemic cell counts result from stimulation of hematopoiesis and out-competition of leukemic clones21. Our modeling approach suggests the effective growth rate of leukemic and hematopoietic mitotic/stem cells as a crucial parameter to understand divergent reaction of patients to cytokine administration. The effective growth rate of a cell population describes how many cells of that population are produced per unit of time. It can potentially be estimated based on mathematical models. In our model simulations cytokine stimulation can induce complete remissions even in cytokine-dependent AML provided the effective growth rate of mitotic leukemic cells is smaller than that of mitotic hematopoietic cells (note that an effective growth rate of leukemic cells larger than zero is necessary and sufficient for their expansion). This scenario is in line with multiple clinical observations24. If the effective growth rate of leukemic cells is higher compared to hematopoietic cells, cytokine administration can result in blast expansion as it has been clinically observed16.Another important difference between the models lies in the reaction of the patient to external cytokine administration. Cytokine administration is a commonly used treatment strategy to increase healthy cell counts and to reduce complications of chemotherapy23. The observation that a given treatment can be beneficial in some patients and harmful in others demonstrates the need to distinguish between the regulation modes present in different patients. The criteria developed in this work can be helpful for this task.Similarly, leukemic cell load can be temporarily reduced in the model of cytokine-independent AML if the effective growth rate of hematopoietic cells is larger than that of leukemic cells. Nevertheless, this reduction is less efficient compared to the case of cytokine-dependent AML, since remaining leukemic cells expand fast. Model dynamics in this case also fit to clinical reportsThe models considered in this manuscript describe two opposite extremes of a continuum, namely cytokine-dependence and cytokine-independence. However, more complex dynamics may emerge in more complex scenarios, e.g., in scenarios where leukemic cells are not fully independent of cytokines but they need less stimulation than their benign counterparts or leukemic cells are less sensitive to cytokine stimulation than healthy cells. These scenarios can be included in future versions of the presented modeling framework.3. Another possibility is assessment of cell surface receptors, however experimental data suggest that presence of growth factor receptors not automatically implies response of cells to these factors58. Further complications arise from evidence suggesting that hematopoietic growth factors can interact with their receptors inside the cell, which would imply that autocrine loops not necessarily depend on surface receptor expression59.From an experimental point of view, it is challenging to decide if leukemic cells depend on cytokines or not. One possibility is to study if leukemic cells show autonomous growth in cell cultures. However, the readout can depend on the culture conditions60. A multi-clonal version of the model of cytokine-dependent leukemia with stochastic mutation acquisition can be found in reference60. These extensions allow to study the impact of leukemic cell parameters on clonal evolution in absence and presence of therapy60. If the frequencies of different leukemic clones at multiple time-points are available for individual patients, the analysis presented in this work can be applied to compare cell properties of different clones. However, such data is not available in clinical routine so far.As previously shown our models can be generalized to a multi-clonal setting, see refsOur mathematical modeling approach allows to assign patients to different risk groups based on time evolution of their individual blast counts. This strategy is complementary to the clinically used risk stratifications which rely mostly on genetic hits. In the future this approach could be used to identify patients with adverse and beneficial response to exogenous cytokines and to improve risk stratification approaches.Our results support the hypothesis that cytokine-dependence of leukemic cells impacts on the course of the disease. Fitting the models to data of individual patients suggests differences in the response of AML cells to cytokines. The models propose a distinction between patients with cytokine-dependent and cytokine-independent AML cell dynamics which leads to significant differences in patients\u2019 prognosis. The modeling insights suggest that this topic may be of clinical relevance and merits further investigation.Supplementary Information"}
+{"text": "AR-mediated) synapses in a sub-group of cells that constitutes a memory-pattern selectively amplifies this memory. Here we confirm the cellular basis of this model by validating its major predictions in four sets of experiments, and demonstrate its induction via a whole-cell transduction mechanism. Subsequently, using theory and simulations, we show that this whole-cell two-fold increase of all inhibitory and excitatory synapses functions as an instantaneous and multiplicative amplifier of the neurons\u2019 spiking. The amplification mechanism acts through multiplication of the net synaptic current, where it scales both the average and the standard deviation of the current. In the excitation-inhibition balance regime, this scaling creates a linear multiplicative amplifier of the cell\u2019s spiking response. Moreover, the direct scaling of the synaptic input enables the amplification of the spiking response to be synchronized with rapid changes in synaptic input, and to be independent of previous spiking activity. These traits enable instantaneous real-time amplification during brief elevations of excitatory synaptic input. Furthermore, the multiplicative nature of the amplifier ensures that the net effect of the amplification is large mainly when the synaptic input is mostly excitatory. When induced on all cells that comprise a memory-pattern, these whole-cell modifications enable a substantial instantaneous amplification of the memory-pattern when the memory is activated. The amplification mechanism is induced by CaMKII dependent phosphorylation that doubles the conductance of all GABAA and AMPA receptors in a subset of neurons. This whole-cell transduction mechanism enables both long-term induction of memory amplification when necessary and extinction when not further required.Intense spiking response of a memory-pattern is believed to play a crucial role both in normal learning and pathology, where it can create biased behavior. We recently proposed a novel model for memory amplification where the simultaneous two-fold increase of all excitatory (AMPAR-mediated) and inhibitory (GABA all inhibitory and all excitatory synapses in the cell and is induced by whole-cell phosphorylation of all inhibitory and excitatory synaptic receptors in a subset of cells, via a process that is distinct from memory formation. Computationally, the inherent scaling of both excitation and inhibition yields a robust and stable amplifier of the neuron\u2019s response. When such an amplifier is induced in a set of cells that compose a memory-pattern, it can selectively amplify the response of this memory. The memory amplification mechanism is independent from associative learning. Thus, while associative learning forms a memory that encodes new associations, the amplification mechanism can promote an already formed memory to a dominant memory.Amplifying the strength of a neuronal assembly that underlies a behavioral choice can lead to a particularly long lasting dominant memory. We report experimental and theoretical evidence for a long-term mechanism that amplifies the response of a neuronal assembly which we termed \u201cmemory amplification mechanism\u201d. The amplification mechanism is mediated by doubling the strength of  Traditionally, increased synaptic response is believed to reflect activity dependent synaptic plasticity, in which the association between different inputs is strengthened through synaptic-specific potentiation. We have previously shown that acquiring the skill to perform in a particularly difficult olfactory-discrimination task \u20134 resultall AMPA and GABAA receptors double their strength through a whole-cell two-fold increase of their single channel conductance. This process results in a two-fold increase in the strength of all excitatory and inhibitory synapses in the cell : Whole cell recordings of spontaneous events where done in the presence of 1 \u03bcM tetrodotoxin and were performed 10\u201315 min after membrane rupture and lasted for up to 45\u201350 min. Miniature excitatory post-synaptic currents (mEPSCs) were recorded at holding potential of \u221280 mV causing miniature inhibitory synaptic events to be exceedingly small due to the small driving force and leaving most voltage-dependent channels closed and NMDA receptors seldom activated. To record GABACaMKII blockers: the CaMKII inhibitor KN93 (10 \u03bcM) and the CaMKII cell-penetrating peptide inhibitor, tatCN21  were used in order to inhibit the active state of CaMKII.\u03c32) after subtraction of the background variance Estimate of the average single channel current and the average number of active channels were obtained using a peak-scaled non-stationary fluctuation analysis (NSFA) of synaptic events . The NSFOnly cells in which the fitting of the equation yielded an R>0.85 were incorporated in the analysis.a, given that a fraction x of the events was affected by the blocker then the blocker effect y should be calculated as follows:Under the assumption of a model in which the blocker effect (averaged events amplitude before the blocker divided by the averaged events amplitude after the blocker) on the event amplitude is a division by a factor of x) asSome algebra enables as to calculate the fraction of the events that was modified by the blocker ; transient inactivating gK(A); In addition we included currents that participate in spike adaptation: muscarinic receptor suppressed potassium conductance gK (M); slow calcium dependent potassium conductance gK (AHP). For the activation of the gK (AHP) we implemented a high threshold non- inactivating calcium conductance gCa(H) and calcium homeostasis mechanism. [Ca]i was elevated by the calcium current and decayed due to calcium homeostasis mechanisms according to the following equation:i removal.The whole-cell balanced amplification mechanism acts directly through modulation of the synaptic strength and is only indirectly dependent on intrinsic excitability. In this paper we aimed to understand the functional outcome of this mechanism and not address its quantitative effect on spike frequency. Therefore we did not do extensive modeling of the cell\u2019s intrinsic properties. We modeled a regular spiking pyramidal cell that exhibits moderate adaptation . We inclNa; gK) were located in the soma whereas the currents that underlie the after- hyperpolarization and the calcium current (gk(M); gca(H); gk(AHP)) were located in the proximal apical dendrite.The equation describing muscarinic conductance was taken from ; the equThe response of the cell to a step current was similar to the responses of cells as recorded in the piriform cortex, both in the characterization of action potential and their firing frequency adaptation Click here for additional data file.S2 Text(DOCX)Click here for additional data file."}
+{"text": "People with schizophrenia demonstrate deficits in insight and the ability to self-evaluate their functioning. Research about patients\u2019 ability to recognize their psychotic symptoms is well established, but recent findings show that there are still unexplored fields regarding how patients perceive their level of functioning A previous study showed that patients who overestimate their functioning, also consistently get high scores in interview-based assessment regarding real-world functional performance. The possible consequences of patients\u2019 ability to correctly estimate their function need to be further investigated. The aim of the present study was to examine how the perception of one\u2019s own capacity relate to symptoms in patients with schizophrenia spectrum disorders.Data collection took place within the ongoing project Clinical Long-term Investigation of Psychosis in Sweden (CLIPS), which examines psychiatric outpatients. In this study, 222 patients with schizophrenia participated. They were divided into four groups based on their results on the UPSA-B and their self-perceived function; two groups with ordinary function (accurate estimators and under -estimators) and two groups with low function (accurate estimators and over-estimators). The groups were compared regarding psychiatric symptoms, examined using the Positive and Negative Syndrome Scale (PANSS). Non-parametric statistics were used to analyze differences in their symptoms.There were statistically significant differences in the total score of PANSS across the four groups of function. The following analyses showed significant differences in the negative and general domain. Results from the post hoc examination revealed identical patterns in these two symptom domains. The group with Low function accurate estimators have significantly more severe symptoms compared to the other three groups.The result in the present study showed that patients with low function who overestimate their function have less or the same level of symptoms as patients in the two groups with ordinary functioning. In further studies it is important to investigate if this actually is a result of lower symptom level or if it is due to the impaired insight. This is important since the result in the present study mirror previous results where patients who overestimate a low function also, by clinicians, will be perceived as patients with a higher capacity and less difficulties."}
+{"text": "Vertically aligned ZnO nanowires with high aspect ratio were prepared by chemical vapor deposition on Si substrate, which had been catalyzed by the polar plane in [0001] direction of ZnO nanorods prepared by the hydrothermal method. Morphology and structure characterizations showed that the as-grown nanowires had the single-crystal hexagonal wurtzite structure with a [0001] growth direction. Energy Dispersive X-ray (EDX) measurement indicated the as-grown ZnO nanowires had a good deal of oxygen vacancies owing to the high operation temperature. Temperature-dependent photoluminescence measurement revealed that the peak of near-band-edge emission shifted from 380 to 387 nm with the increase of temperature from 150 to 300 K. The high intensity of the green peak at 525 nm highlighted the potential application in visible light emitting diodes. The selThe black curve of The top views of ZnO samples prepared by HM and self-catalytic CVD with HM pretreament are presented in 2. The ZnO NRs with high c-axis preferred orientation restrict the nucleation position and prevent the growth direction of the ZnO NWs from other polar surface like The EDX spectrum of the ZnO NWs grown by the CVD with HM pretreatment have been measured. Igreen and IUV turns out that numerous ionized oxygen vacancies exit in NWs, which is consistent with the result of EDX. High intensity of GL and width reveal the potential application in visible light emitting diodes  crystallographic orientation. This synthesis method offers a way to prepare ultralong single crystal NWs with the spontaneous polarization just like the synthesis method of the multilayer thin films by Sol-gel. The temperature-dependent PL measurement suggested that the self-assembled ZnO NWs had many deep level defects such as singly ionized oxygen vacancies, since the GL presented in the PL spectrum."}
+{"text": "I enjoyed reading the interesting article by Wu et al. In recent years, the term fibrotic atriocardiomyopathy (FACM) has been proposed to define the atrial remodeling process resulting in atrial myocyte abnormalities and causing fibrosis in patients with lone AF In conclusion, serum MMP-9 levels may significantly predict the success rate of catheter ablation therapy in patients with persistent AF, probably by indicating the extent of LA fibrosis. However, additional non-invasive or invasive measures should be used in conjunction with this biomarker to predict the success rate of catheter ablation for the treatment of persistent AF."}
+{"text": "Olfactory dysfunction has repeatedly been observed in individuals diagnosed with schizophrenia. The most stable and consistent finding on the behavioral level is that of smell identification deficits. However, the nature of olfactory identification abnormalities seems to extend to structural abnormalities in the underlying neurobiology of the olfactory system. Furthermore, smell identification deficits are also documented in first-episode patients and non-psychotic first-degree relatives of schizophrenia patients. Family members of schizophrenia patients also show structural abnormalities of the olfactory system, suggesting that these may serve as an endophenotype for the development of schizophrenia.Only a few studies examined the olfactory identification ability in adolescents at-risk for schizophrenia and suggested smell identification deficits as a risk marker for schizophrenia. These studies included adolescents at clinical as well as at genetic risk for schizophrenia. None of these studies focused on children at genetic risk for schizophrenia. Therefore, we investigated the olfactory identification ability in children of parents with schizophrenia in comparison to children of parents without a psychotic disorder. As we are also interested in the specificity of the olfactory impairments to schizophrenia, we included children of parents with bipolar disorder. We hypothesize that children at genetic risk for schizophrenia would have the most severe smell identification deficits and that children of bipolar disorder patients would have less severe deficits than the at-risk for schizophrenia group but more severe than the group of children without a psychotic parent.Participants - The olfactory identification ability was assessed in 202 children of schizophrenia patients  in relation to that of 200 children of parents without a psychotic disorder (\u2018controls\u2019). In addition, we also assessed the B-SIT in 120 children of bipolar disorder patients . All children were 7 years of age at the time of assessment and they were part of the Danish High Risk and Resilience Study \u2013 VIA7.Brief Smell Identification Test - The Brief Smell Identification Test (B-SIT) contains 12 items that need to be scratched and sniffed. The test has excellent reliability (> 0.80) and demonstrates agreement for abnormal olfaction comparing B-SIT with the San Diego Odor Identification Test (SDOIT). A maximum score of 12 reflects intact olfactory identification functioning. B-SIT has been conducted in patients with neurodegenerative disorders (Parkinson\u2019s disease and Alzheimer\u2019s disease) and can be used for individuals above 5 years of age.Statistics - We will use analysis of covariance (ANCOVA) for analysis of the B-SIT total scores with \u2018diagnosis of parent\u2019 as the independent variable and age and sex as covariates for the three groups.Analyses will be performed within the next 3 months so can be presented in April 2018.Conclusion and discussion cannot be drawn at this time."}
+{"text": "Cognitive Adaptation Training (CAT) has consistently demonstrated effectiveness in enhancing community functioning in clinical trials of its 9-month application by a specialist. This is a compelling development in the field as clinicians struggle to support gains in independent functioning among patients with schizophrenia. However, outreach interventions delivered by specialists are difficult to support in many contexts where investment in mental health care is insufficient for population needs. This presentation will describe research and implementation efforts that support the delivery of CAT in routine clinical practice.This program of work began with a feasibility study of a modified version of CAT. CAT was modified to decrease the duration of specialist-delivered CAT to 4 months, with the intervention subsequently supported by the individual\u2019s case manager who received rudimentary training and could consult specialists. Twenty-three people with schizophrenia participated in this study of symptom and functional outcomes, evaluating improvements after 4 months of CAT specialist intervention and after an additional 5 months of case manager support. Also described briefly will be (i) preliminary findings from a superiority randomized controlled trial of modified CAT in an early intervention population comparing CAT (n=25) with Action Based Cognitive Remediation (n=23) and (ii) efforts to build out CAT implementation in a tertiary facility enabled through the above clinical trial resources.Analysis of feasibility study findings revealed significant improvements in adaptive functioning, psychiatric symptomatology, and goal attainment that were maintained throughout case management follow-up. Effect sizes for the specialist delivered period ranged from .33 (negative symptoms) to 2.01  with a modest decline in the follow-up period with community functioning remaining at ES=.66. Improvement in the large effect size range was also observed in community functioning in the trial of modified CAT in early intervention. In this period over 70 allied health clinicians were intensively training in CAT locally and regionally and a community of practice was established. These impacts were further extended through the development of an open-access CAT guide for families that can be used independently or with clinician support.This study supports a model for extending the accessibility of CAT in settings that might not otherwise sustain the intervention as it was originally designed. Functional impacts similar to the original clinical trials were observed in a briefer period of specialist delivered CAT and show the promise of being largely sustained over an indefinite period by rudimentary-trained case managers in a consultation model. This observation would appear to apply to both early intervention and general schizophrenia populations. Additionally, this program of work has demonstrated how research-practice synergies can foster implementation that can be sustained after initial research investments."}
+{"text": "Analysis of scab samples collected from poultry during outbreaks of fowlpox in Mozambique in 2016 revealed the presence of clade E avipoxviruses. Infected poultry were from flocks that had been vaccinated against fowlpox virus. These findings require urgent reevaluation of the vaccine formula and control strategies in this country. Avipoxvirus in the Chordopoxvirinae subfamily of the family Poxviridae. These viruses cause disease in a large number of bird species and are generally named after the species from which the virus was first isolated and characterized  and the DNA polymerase, which are both highly conserved among poxviruses ; and pronounced ulcerations on the interdigit space. Different color tones and irregular wrinkled shells were also observed on eggs.The 16 scab samples were positive for FPV P4b gene following PCR amplification with specific primers ; the ampTKPV-HU1124/2011 was isolated from a flock of turkeys vaccinated with a commercial vaccine for FPV, and FPV-MOZ-608/2016 and FPV-MOZ-980/2016 were also obtained from vaccinated chickens. The laying pullets imported from South Africa had already been vaccinated for FPV on day 1 with the commercial fowlpox-vectored infectious laryngotracheitis vaccine and day 17 with the fowlpox-vectored infectious laryngotracheitis/avian encephalomyelitis vaccine. Our data suggest a possible failure of the vaccine to protect against clade E viruses, similar to what has been reported previously for TKPV-HU1124/2011 (The identification of a clade E avipoxvirus in Mozambique requires further investigation to clarify how a virus that has only been reported once found its way to this country. Because the chickens in both infected flocks were purchased from the same pullet reseller who had (for both flocks) imported the birds from South Africa, it is likely that the source of infection was the same. However, the specific source has not been identified. FPVs are known to infect >230 species of wild birds, many of which are migratory (Resolution of the full genome of these viruses might provide hints to their origin. The presence of fowlpox disease in birds vaccinated against FPV requires urgent reevaluation of the vaccine formula and control strategies in Mozambique.Description of the methods used for DNA isolation and PCR amplification and sequencing of the 4b core-like protein and DNA polymerase gene fragments of avipoxviruses, Mozambique."}
+{"text": "Epigenetics is hypothesized to mediate the interplay between genes and environment leading to the onset of psychosisWe performed a longitudinal prospective study of genomic DNA methylation during psychotic transition in help-seeking young individuals referred to a specialized outpatient unit for early detection of psychosis and enrolled in a 1-year follow-up (n=39). We used Infinium HumanMethylation450 BeadChip array after bisulfite conversion and analyzed longitudinal variations in methylation at 411947 cytosine\u2013phosphate\u2013guanine (CpG) sites.We observed that conversion to psychosis was not associated with a global change in methylation and there was no individual CpG significantly associated with psychotic transition. By contrast, we found that conversion to psychosis was associated with specific methylation changes in genes involved in axon guidance, as well as genes of the IL-17 pathway and the glutathione-S-transferase family.Alterations in oxidative stress regulation, axon guidance and in inflammatory pathways could represent multiple theaters for the disruption in homeostasis that accompanies the emergence of full-blown psychosis."}
+{"text": "Since circulating tumor cells (CTCs) are tumor cells which are found in the blood of cancer patients, CTCs are potential tumor markers, so a rapid isolation of CTCs is desirable for clinical applications. In this paper, a three-dimensional polystyrene (PS) microfiber fabric with vacuum aspiration system was developed for capturing CTCs within a short time. Various microfiber fabrics with different diameters were prepared by the electrospinning method and optimized for contact frequency with cells. Vacuum aspiration utilizing these microfiber fabrics could filter all cells within seconds without mechanical damage. The microfiber fabric with immobilized anti-EpCAM antibodies was able to specifically capture MCF-7 cells that express EpCAM on their surfaces. The specificity of the system was confirmed by monitoring the ability to isolate MCF-7 cells from a mixture containing CCRF-CEM cells that do not express EpCAM. Furthermore, the selective capture ability of the microfiber was retained even when the microfiber was exposed to the whole blood of pigs spiked with MCF-7 cells. The specific cell capture ratio of the vacuum aspiration system utilizing microfiber fabric could be improved by increasing the thickness of the microfiber fabric through electrospinning time."}
+{"text": "Spectral results suggest the formation of polymer, through C\u2013C and C\u2013O\u2013C coupling of the phenylene and oxyphenylene. The relationship between the structures and photophysical properties of azine and polyazine was studied. Both azine and polyazine show, aggregation induced emission with increase in concentration in DMSO solution. The single crystal structure of azine suggesting the various inter and intra molecular interactions rigidify the conformation and locked the intramolecular rotations of the phenyl rings in the molecule. The inhibition of intramolecular rotation, J- aggregation and increase of conjugation impart the fluorescence in aggregated state. Additionally, the electronic properties namely orbital energies and resulting energy gap calculated theoretically by density functional theory (DFT).An azine monomer 4-hydroxy-3-methoxybenzaldehyde azine was synthesized by refluxing with ethanolic solution of vanillin with hydrazine hydrate. It was then converted into polyazine by oxidative polymerization. The structure of azine and polyazine was characterized by FT-IR, UV\u2013visible,  AlthoughThis aggregation caused quenching (ACQ)  effect hIn this background two unusual phenomena exactly opposite to ACQ are aggregation induced emission (AIE)  and aggrI2 to form iodonium complexes. PAZs contain a diamine linkage could be used to chelate transition metal ions. This could serve a dual purpose: to restrict rotations and to provide a method to influence the electronic structure of the polymer by varying the charge or bonding properties of the chelated metal complex. PAZs are potentially very suitable class of semiconducting materials for organic thin film transistors..Supplemental data for this article can be accessed here [No potential conflict of interest was reported by the authors.Click here for additional data file."}
+{"text": "This special issue is the second annual special issue of Intelligent Informatics in Translational Medicine (IITM). Only seven papers were published in this special issue after rigorous reviewing processes, of which four papers were selected from the 10th International Conference on Systems Biology (ISB 2016) organized by Computational Systems Biology Society of ORSC (China) in August 2016.In 2013, we have launched the first special issue with high-quality original research articles, and the title of the special issue was named as Intelligent Informatics in Biomedicine. Most of the published papers were recommended by the International Workshop on Intelligent Informatics in Biology and Medicine (IIBM). In order to extend the scope of research areas and continue this fruitful discussion, we renamed the special issue as the new title of Intelligent Informatics in Translational Medicine (IITM) in 2014 and organized this special issue as a series edition for discovering more biological insights from genomics data or any medical big data. This special issue focuses on the challenges and solutions for information processes with an emphasis on forthcoming high throughput technology and systems biomedicine.Advances in information technologies are facilitating and accelerating research on molecular biology and medicine. Especially in the precision-medicine era, the increasing complexity and volume of biological data mean that more sophisticated computational techniques are urgently required. Such methods must be able to support new sensing techniques that are being developed to improve the quality of healthcare and medicine. The use of artificial intelligence, machine learning, and data mining can potentially play a significant role in addressing these important challenges. We hope the published series special issue will provide an opportunity for academic and industry professionals to discuss the latest issues and progress in the area of biomedicine.The current special issue aims to combine intelligent informatics and bioinformatics on diseases and translation medicine, and these collected papers address the data-analytical method design, algorithm development, mathematical modeling, and computational simulation techniques to the translational medical applications.X. Jiang et al. in their article entitled \u201cDifferentially Coexpressed Disease Gene Identification Based on Gene Coexpression Network\u201d designed a novel framework to identify disease-related genes and developed a differentially coexpressed disease-related gene identification method based on gene coexpression network to screen differentially coexpressed genes. They constructed phase-specific gene coexpression network using time-series gene expression data and defined the conception of differential coexpression of genes in coexpression network. They also designed two metrics to measure the value of gene differential coexpression according to the change of local topological structures between different phase-specific networks. At last, they performed meta-analysis of gene differential coexpression based on a rank-product approach. Their experimental results have shown the feasibility and effectiveness of such a gene coexpression network and the superior performance over other popular disease-related gene selection approaches.Y. Su et al. described that oncolytic virus is a kind of tumor killer virus which can infect and lyse cancer cells and spread through the tumor, while leaving normal cells largely unharmed. We know that appropriate mathematical models could help biologists to understand the tumor-virus dynamics and find better treatment strategies. The authors proposed a new mathematical model of tumor therapy with oncolytic virus and MEK inhibitor. Due to mitogen-activated protein kinase providing greater oncolytic virus infection into cancer cells and limiting the replication of the virus, in order to provide the best dosage of MEK inhibitors and balance the positive and negative effects of the inhibitors, authors proposed an optimal control strategy regarding the inhibitor. Simulations have shown that the optimal control indeed possessed better control effects than constant control under the same initial conditions.F-score measurement.C. Quan et al. proposed a multichannel convolutional neural network for automated biomedical relation extraction. The proposed model provides two contributions: it enables the fusion of multiple versions in word embedding and the need for manual feature engineering can be obviated by automated feature learning with convolutional neural network. The authors have evaluated the proposed model on two biomedical relation extraction tasks including drug-drug interaction extraction and protein-protein interaction extraction. For conducting several experimental trials on benchmark testing datasets, the proposed system outperformed the standard SVM based systems within a range from 2.7% to 5.6% on  Salmonella Typhi-Specific Genes as Markers for Diagnosis of Typhoid Fever Using Single-Gene Target PCR Assays\u201d identified new markers to detect the Salmonella Typhi pathogen and developed sensitive and specific diagnostic tests in this study. Based on genomic comparison of Salmonella Typhi with other enteric pathogens, there are six Salmonella Typhi genes found to be specific, and corresponding PCR assays for each target gene were developed to verify their specificity and sensitivity in vitro. The experimental results showed that 5 genes selected from the 6 candidate genes could be demonstrated with perfect verification results (100% sensitivity and 100% specificity), and these genes could be applied as important biomarkers for diagnosis of typhoid fever through single-gene target PCR-assays.Y. X. Goay et al. in their article entitled \u201cIdentification of Five NovelN. Yu et al. proposed a single-trial sparse representation-based approach for visual evoked potential (VEP) extraction. Sparse representation is a powerful tool in signal denoising, and visual evoked potentials have been proven to have strong sparsity over an appropriate dictionary. The authors presented such a novel sparse representation-based approach to solving the extraction problem. Three stages were proposed in their article: utilizing the previous electroencephalogram (EEG) data to identify the parameters of the EEG autoregressive (AR) model; applying sparse representation to model the VEPs in the autoregressive-moving average model; calculating the sparse coefficients and deriving VEPs by using the AR model. The proposed method was verified and compared by employing synthetic and real data against different existing methods, and the evaluation demonstrates that their proposed method can well preserve the details of the VEPs for latency estimation, even in low SNR environments.B. Tang developed a toolkit META2 for DNA methylation annotation and analysis. The tool performs integrative analysis on differentially methylated loci and regions through deep mining and statistical comparison methods. The author examined the association within differentially methylated CpG and differentially methylated region candidates regarding counts and region lengths and identified major transition zones as clues for inferring statistically significant regions. The developed tool can provide a comprehensive analysis approach for epigenetic research and clinical study.Y. Li et al. constructed a multilevel evolutionary structure for avian influenza virus system based on considering both hemagglutinin and neuraminidase protein fragments. An optimization model was established to determine the rational granularity of the virus system for exploring the intrinsic relationship among the subtypes based on the fuzzy hierarchical evaluation index. To reduce the systematic and computational complexity of the proposed algorithm, the granular signatures of virus system were identified based on the coarse-grained idea. The proposed system can effectively identify the virus signatures and reflect the whole avian influenza virus system, which indicates that the proposed method provides an alternative mechanism to perform new virus subtyping comparison and functional prediction."}
+{"text": "Extracellular nicotinate was depleted and metabolites of the deamidated salvage pathway were reduced but intracellular NAD+ and nicotinamide were nevertheless maintained. However, sirtuin 1 was downregulated and so the accumulation of NMN and NR was best explained by reduced flux through the amidated arm of the NAD+ salvage pathway due to reduced sirtuin activity. PEsen cells also showed evidence of increased redox homeostasis and upregulated pathways used to generate energy and cellular membranes; these included nucleotide catabolism, membrane lipid breakdown and increased creatine metabolism. Thus PEsen cells upregulate several different pathways to sustain their survival which may serve as pharmacological targets for the elimination of senescent cells in age-related disease.Cellular senescence occurs by proliferative exhaustion (PEsen) or following multiple cellular stresses but had not previously been subject to detailed metabolomic analysis. Therefore, we compared PEsen fibroblasts with proliferating and transiently growth arrested controls using a combination of different mass spectroscopy techniques. PEsen cells showed many specific alterations in both the NAD+  Senescent cells accumulate in a variety of pathologies235834141516There is accumulating evidence demonstrating the regulation of senescence and the SASP by metabolic enzymes7181920in vivo23We have established that PEsen fibroblasts modify their extracellular metabolites in a manner that overlaps considerably with that of the same cells induced to senesce by irreparable DNA damage and the metabolic profile of ageing humans We now report that PEsen fibroblasts display further intracellular specific metabolic changes, independently of growth arrest, which although complex and numerous, would conventionally be expected to generate alternative energy sources or otherwise protect the cells against oxidative damage and support cell survival. In particular, PEsen cells maintained NAD+ and nicotinamide levels despite showing no increase in the rate-limiting enzymes for their production and greatly suppressed sirtuin levels. However, there was evidence of increased nicotinamide turnover suggesting that compensatory mechanisms are activated in senescent cells. Such mechanisms may offer targets for the development of senolytic drugs in the future.The NHOF-1 oral fibroblast line has been characterised previously23Principal component analysis (PCA) is a mathematical procedure that uses an orthogonal transformation to convert a set of observations of possibly correlated variables into a set of values of linearly uncorrelated variables called principle components. PCA revealed a distinct separation between conditions in cell pellet samples  that may+9-HODE and 4-hydroxy-nonenal-glutathione  accumulated in PEsen cells, although they also accumulated in confluent cells as well  and nicotinamide riboside (NR)+ precursor that is converted to NMN by specific NR kinases (NRK) and as NAD+ levels were not significantly depleted in PEsen cells  and from nicotinic acid by the enzyme nicotinamide phosphoribosyltransferase (NAMPT) to produce NADen cells  this sugcleotide  appears cleotide  is deplecleotide , the brecleotide  and althTo investigate the NAD salvage pathway  in more Multiple purine and pyrimidine degradation products including 3-uriedoproprionateSeveral lipids were altered within PEsen cells relative to the controls  and the The phospholipid catabolite glycerol 3-phosphate was specifically elevated in PEsen cells compared to the controls  and thisSeveral amino acids accumulated in PEsen cells when compared to growing and growth-arrested controls, including alanine, creatinine, creatine phosphate and several N-acetylated or -methylated amino acids, whereas other N-acetylated amino acids were depleted  and the Several other metabolites of uncertain significance specifically accumulated in PEsen cells when compared with both the growing and growth-arrested controls ; these iAs PEsen intracellular metabolism had not been studied previously in detail we conducted an unbiased metabolic screen of these cells to identify metabolites that were altered when compared not only to young growing cells but also to cells growth-arrested by two independent methods and we report here only metabolites that were specific to senescence. These alterations were still very numerous and although we have yet to conduct flux experiments to identify the rate limiting steps in the various metabolic pathways but with this caveat our data suggests that senescent cells activate pathways that may aid their survival against a background of considerable cellular dysfunction.de novo glutathione synthesis. The reduced gamma-glutamyl amino acid levels in PEsen cells could arise from decreased import and catabolism but 5-oxoproline levels did not differ between PEsen cells and the controls. Therefore, reduced cysteinylglycine levels (particularly in PEsen cells) may suggest a decline in GGT activity and/or expression. We previously reported that PEsen cells exhibited a strong trend for reduced levels of cysteine compared to growing, confluent, and quiescent counterparts+9-HODE and 4-hydroxy-nonenal-glutathione  accumulated in PEsen cells, although they also accumulated in confluent cells as well. Finally, the non-significant trend for low levels of alpha-tocopherol in PEsen cells compared to the controls may suggest antioxidant depletion to restore redox homeostasis but this did not reach statistical significance. In addition, we have previously reported an increase in metabolites of the pentose phosphate pathway (PPP)WAF that are the features of senescent cells established by DNA damageWe previously reported that PEsen cells show evidence of increased glycolysis and pentose phosphate pathway metabolism7de novo pathway and/or the salvage pathway may have a role in the generation of NAD+ to meet the energy demands of PEsen cells in the absence of effective oxidative phosphorylation and this is consistent with the decline in TCA metabolism. However, NADH levels were not maintained in PEsen cells or indeed the cell cycle arrested controls arguing against this hypothesis. We have previously reported that kynurenine is elevated both intracellularly and extracellularly in PEsen fibroblasts compared to controlsde novo pathway from tryptophan. NAD+ levels are maintained in PEsen cells but not NADH levels suggesting that NAD+ levels may contribute to PEsen biology by a mechanism other than energy production. NAD+ is also a co-enzyme that in particular, regulates the family of deacetylases known as the sirtuins (SIRTs) that have multiple anti-senescence functionsOur results also suggest that the kynurenine The main sources of NAD+ within the cell are the salvage pathways from the two forms of vitamin B3, namely nicotinate and nicotinamide. Nicotinate can be converted to NAD+ from nicotinate mononucleotide involving the enzymes NMNAT and NADS via the deamidated routede novo and salvage pathways. Although our analysis of NAD+ metabolism is by no means complete, our data is consistent with the hypothesis that PEsen cells sustain nicotinamide and NAD+ levels by as yet undetermined mechanisms to compensate for the loss of SIRT and NMNAT activity which in turn, may explain the accumulation of NMN and NR.The maintenance of NAD+, nicotinamide and in PEsen cells is consistent with the retention of some SIRT activity in PEsen cells, although several enzymes can contribute to the production of nicotinamide from NAD+The accumulation of multiple purine and pyrimidine degradation products may contribute to and be indicative of altered redox homeostasis (discussed above) as the generation of xanthine is accompanied by the production of hydrogen peroxide, while allantoin is produced through non-enzymatic oxidation in human cells. Purine and pyrimidine nucleoside mono- and some di- and tri-phosphates were specifically depleted in PEsen cells when compared to the controls, as was adenine. Interestingly, published studies in other cell types suggest that the suppression of nucleotide metabolism underlies the maintenance of OIS18We observed elevated levels of PGE2 in PEsen cells which have been reported to both accompany senescence and promote features of the phenotype34The phospholipid catabolite glycerol 3-phosphate was specifically elevated in PEsen cells and may highlight increased membrane degradation that may provide lipid substrates for the maintenance of energy metabolism and this is consistent with other reports in the literature3940Both creatine and creatine phosphate were elevated in PEsen cells. Creatine can serve as a phosphate energy store and this may therefore reflect a difference in energy storage and/or availability in these cells and this increased phosphate store may support cell survival. Creatine metabolites may potentially arise from decreased energy utilization as opposed to generation in confluent and PEsen cells, although this was more marked in PEsen cells. Thus, differences in creatine metabolism in PEsen cells may highlight altered energy storage and utilization in these cells. Alanine increased in PEsen cells and could either be an indication of increased oxidative stress and/or increased glycolysis through the alanine-glucose cyclein vitro. There are also differences between liver and muscle in methionine metabolism43We have recently reported that the extracellular senescence metabolome (ESM) of cultured human PEsen fibroblasts shows considerable overlap with that of human serum ageing biomarkersThe long-lived Ames Dwarf mouse has been reported to sustain better mitochondrial function and shows reduced insulin signalling and atypical methionine metabolismin vivo. Kynurenine can also be neuroprotective if metabolised to kynurenic acid but also has the potential to mediate deleterious effects as its metabolism in the liver can lead to the generation of metabolites such as 3-hydroxykynurenine that can cross the blood-brain barrier and contribute to neurodegeneration46474927in vitro and perhaps in vivo possess properties normally associated with anti-ageing strategies. NAMPT levels are reduced in the neuronal stem/progenitor cells of the hippocampus with ageingin vitroin vivo should they evade the immune system3In addition to their association with ageing several of the metabolic pathways described above are associated with other diseases and processes. Kynurenine can activate the immune system that could perhaps lead to the clearance of PEsen cells Although the metabolic profile of established PEsen cells is superficially complex there are two conclusions that are consistent with a large amount of the data. Firstly, PEsen cells appear to activate the same mechanisms that delay the initiation of senescence; a shift from oxidative phosphorylation towards glycolysis and the pentose phosphate pathway to reduce the production of ROS142/90% air and subcultured once weekly at a density of 1\u2009\u00d7\u2009105 cells per 9\u2009cm plate to prohibit confluence. Mean population doublings (MPDs) were calculated as described previously23The NHOF-1 oral fibroblast line its characterisation and the culture methods have been described previously23Cell pellets were collected from growing, quiescent, confluent and PEsen NHOF-1 cells essentially as describedThe details of the metabolomics analysis have been published previously, including sample preparation, instrumentation, conditions for mass spectrometry , peak data reduction, and assignment of peaks to known chemical entities by comparison to metabolite library entries of purified standards, has been previously describedWestern blotting was carried out as described previouslyT-test was used to identify biochemicals that differed significantly between experimental groups and in some instances one way analysis of variance (ANOVA) and Tukeys post hoc test were used. Pathways were assigned for each metabolite, allowing examination of overrepresented pathways. Principal component analysis was utilized to determine the metabolites that differed between the four experimental groupsT tests were carried out on log-transformed data to compare relative biochemical concentrations between experimental groups. False discovery rate (FDR) was estimated using q values to account for multiple comparisons.A two-sample How to cite this article: James, E. L. et al. Replicatively senescent human fibroblasts reveal a distinct intracellular metabolic profile with alterations in NAD+ and nicotinamide metabolism. Sci. Rep.6, 38489; doi: 10.1038/srep38489 (2016).Publisher\u2019s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations."}
+{"text": "Acquired von Willebrand syndrome (AVWS) is a rare clinical condition characterised by prolonged bleeding time and decreased levels of factor VIII and von Willebrand factor. It has been reported to occur in patients with severe aortic stenosis and other cardiac conditions associated with high shear stress, such as para-valvar leaks after prosthetic valve replacement surgery. First reported decades ago, the mechanism was initially unclear but it has now become known. In this issue, Binneto\u011flu and colleagues (page 222) report on a prospective series of children with aortic and pulmonary stenosis, and describe the frequency of occurrence and underlying pathophysiology.There is general agreement on the considerable variation in the prevalence of various cardiac diseases among the different ethnic groups in Africa and there may also be differences in the manner in which the diseases express themselves. There is less clarity about the contributions of intrinsic \u2018genetic\u2019 differences to that variability compared to acquired or environmental factors. Sirtuin 1 (SIRT1) has been identified as a candidate molecule affecting the epigenetic mechanisms of cardiovascular disease (CVD). Previous studies have shown that some SIRT1 singlenucleotide polymorphisms (SNPs) are associated with body mass index, diabetes, blood pressure, cholesterol metabolism and coronary artery calcification. An investigation conducted by Ramkaran and co-workers (page 213) in young South African Indians with coronary disease concluded that SNP variant alleles occurred more frequently in South African Indians than in black South Africans. The study is not large enough to definitively assess whether these variants may serve as risk factors that contribute to Indians developing early-onset CVD but the results are intriguing and warrant further investigation.Technological advances in many aspects of the management of CVD continue to amaze those of us who have been privileged to witness their evolution and development. Left ventricular assist devices (LVADs) and two- and three-dimensional echocardiography were the stuff of dreams when many of us were training but now are part of routine care in some parts of the world. Demirozu and co-workers (page 208) elegantly demonstrate how the use of advanced imaging techniques of echocardiography can be used to fine-tune the functioning of LVADs.Intravascular stenting was equally unthinkable only a few decades ago but has now revolutionised much of the management of CVD. The way in which a new generation of biodegradable stents promises to advance this area even further is described by Tiryakioglu et al. (page 238).Cardiologists and physicians trained in an era prior to the introduction of the technological advances mentioned above will be pleased to see that the old stalwart, electrocardiography (ECG) continues to be widely used. Some consider it does not receive the recognition it deserves as a cheap, non-invasive adjunct to the clinical examination. A cross-sectional study carried out on adults in Nigeria examined the ECGs of 100 HIV-infected patients on highly active anti-retroviral therapy (HAART), 100 HIV-infected HAART-na\u00efve patients and 100 HIV-negative controls . The clinical relevance of these findings and that of similar findings reported by others and discussed by the authors, remains unclear and requires long-term follow up studies accompanied by imaging, either by echocardiography or perhaps more helpfully, by cardiac magnetic resonance imaging."}
+{"text": "Our perception of the world is remarkably stable despite of distorted retinal input due to frequent eye movements. It is considered that the brain uses corollary discharge, efference copies of signals sent from motor to visual regions, to compensate for distortions and stabilize visual perception. In this study, we tested whether patients with Alzheimer\u2019s disease (AD) have impaired corollary discharge functions as evidenced by reduced compensation during the perception of optic flow that mimics self-motion in the environment. We asked a group of early-stage AD patients and age-matched healthy controls to indicate the perceived direction of self-motion based on optic flow while tracking a moving target with smooth pursuit eye movement, or keeping eye fixation at a stationary target. We first replicated the previous findings that healthy participants were able to compensate for distorted optic flow in the presence of eye movements, as indicated by similar performance of self-motion perception between pursuit and fixation conditions. In stark contrast, AD patients showed impaired self-motion perception when the optic flow was distorted by eye movements. Our results suggest that early-stage AD pathology is associated with disrupted eye movement compensation during self-motion perception. At the behavioral level, it has been shown that AD patients have poor performance in spatial navigation tasks3 and impaired perception of optic flow that mimics self-motion in the environment5. Comparing to healthy elderly individuals, AD patients possess elevated optic flow thresholds6 and are worse at perceiving and steering in the direction of self-motion based on the pattern of optic flows7. Consistent with these behavioral deficiencies, imaging studies have revealed that AD patients have noticeable atrophy in the superior parietal lobules9 and they show reduced activations in dorsal visual stream areas that are implicated in visuosptial processing12. There is also evidence that AD patients have impaired ability to bind distinct visual features of a stimulus  in a sensory integration task, implicating that AD pathology might be associated with declined cross-cortical connectivity in the cerebral cortex14.In addition to the progressive loss of memory and cognitive functions, patients with Alzheimer\u2019s disease (AD) at the early stage often exhibit declined visuospatial capabilities16. Corollary discharge is an integral part of cortical functions that allow the brain to monitor its own actions17  and compensate for visual distortions to achieve perceptual stability in the presence of eye movements21. There is growing evidence that corollary discharge functions might have failed in several clinical populations leading to neurologic symptoms22 and delusional experiences such as auditory hallucination23, mirror-touch synaesthete24, and schizophrenic disorders25. Up to date, there is little evidence of corollary discharge dysfunctions in AD pathology in the literature.Corollary discharge, one special form of functional connectivity among cortical regions, is often referred to as efference copies of motor command signals sent from motor to sensory areas that are used to predict the sensory consequence of an impending movement26. Nevertheless, previous findings have shown that healthy human observers barely experience a twisted visual representation28, owing to pursuit compensation mechanisms which are widely believed to rely on corollary discharge signals sent from pursuit areas to visual areas to cancel the distortion30 . In this study we will exploit the pursuit compensation effects to examine the potential dysfunction of corollary discharge in AD patients. To this end, we will compare the performance of optic flow perception between a group of AD patients and age-matched healthy elder participants, under the condition of either smooth pursuit eye movements or pure fixations.The purpose of this study is to address whether deficits in corollary discharge functions are present in patients at the early stage of AD. We will assess the influence of eye movements on optic flow perception in AD patients. Eye rotations during pursuit eye movement distort the optic flow by adding a rotational component to it32; and (2) According to the assessment of the Mini-Mental State Exam (MMSE)33, they had a MMSE score less than 25 but larger than 18, hence classified as mild cognitive impairment patients. The second group involved 15 age- and sex- matched healthy elderly, most of whom were the spouse or relatives of AD patients tested in the current study. All participants had passed the ophthalmologic exams to be free of other neurologic, ophthalmologic, or psychiatric illnesses. All participants had given informed consent for their participation in the current study prior to the experimentation. All the experiments were performed in accordance with the guidelines and regulations approved by the Ethics Committee of Liaocheng People\u2019s Hospital, China.Two groups of participants took part in the current study. The first group consisted of 15 early-stage AD patients who were selected based on two criteria: (1) They had to met the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer\u2019s Disease and Related Disorders Association criteria for the diagnosis of AD35 to generate the visual optic flow and design the control of experimental flow as described below. The optic flow was made of a cloud of moving dots, consisted of 2000 white dots (each 0.2\u2009deg in diameter) on a black background (0.7\u2009cd/m2) and distributed in a virtual trapezoidal volume. Dots moving outside the trapezoidal volume were randomly assigned to locations on the furthest base as the new starting locations. The speed and luminance gradients of moving dots within this column resemble the visual experience of forward translation in the environment at a speed of 2.5\u2009m/s. Specifically, the focus of expansion (FOE) in the optic flow corresponds to the direction of self-motion, which was interleaved from trial to trial along an imaginary horizontal line, locating at one of the six possible positions , relative to the straight ahead direction (\u201cdead ahead\u2019).Subjects seated in a dimly lit room. They rested their chins on a chinrest which helps to stabilize head position. They faced a CRT monitor  which was 57\u2009cm away from the chinrest. We used the Psychophysical ToolboxEach trial begun with an initial ocular fixation at the cross (+) for 500 ms. Then the optic flow was presented for 1000 ms, and after a fixed delay of another 500 ms following optic flow offset, participants were required to report the perceived self-motion direction (either left or right relative to the straight ahead direction) by means of keyboard presses  was the proportion of rightward choice. Of the parameters derived from the fitted function, \u03bc represented the FOE angle at which the subjects show equal left/right choice probability and was defined as the point of subjective equality (PSE), also known as the perceptual bias. The scaling factor \u03c3 (sigma) was inversely related to the slope of the psychometric function and was an index of perceptual sensitivity.All data analysis was performed with custom-made MatLab scripts . To quantitatively characterize the performance of optic flow perception, we fitted a logistic function to the psychometric curve obtained for each subject. The logistic function was formulated as the following:28. In sharp contrast, eye movements affected the perception of self-motion in AD participants . In contrast, the perceptual biases in the fixation condition were both very low  and they were not statistically different between groups . Meanwhile, analysis of sigma also showed a similar pattern of results . When there was no pursuit movement (fixation condition), mean sigma became statistically indistinguishable between groups .To quantitatively characterize these effects, we fitted a logistic function to the psychometric data and we did this for each task condition and for each observer, before we average them across participants (see Methods). Of the derived parameters, the absolute value of point of subjective equality (PSE) denotes the magnitude of perceptual bias whereas sigma measures the perceptual sensitivity. Figure\u00a0lts Fig.\u00a0. AD patiTo sum it up, our results revealed that AD patients possessed larger biases and weaker sensitivity during the perception of distorted optic flow in the presence of eye movements, comparing to healthy elderly participants. When there was no distortion in the optic flow (fixation condition), self-motion judgments were not different between groups.The current study revealed that AD pathology is associated with disrupted eye movement compensation during the perception of optic flow. We showed that both the sensitivity and bias of optic flow perception were impaired in AD patients in the presence of pursuit eye movement. However, AD patients did not exhibit deficits in the perception of optic flow when there was no eye movement. These findings add to the notion that non-cognitive impairments, such as sensory and motor dysfunctions, are increasingly evident in early-stage AD patients.9. Most previous studies focused primarily on the perception of optic flow during ocular fixation (without eye movements), that is, no corollary discharge is involved. For example, studies from Duffy laboratory report that AD patients show elevated optic flow coherence thresholds during passive viewing36. Here we examined optic flow perception in AD patients in the presence of pursuit eye movements as well as during passive viewing (fixation condition). By comparing results across participant groups and task conditions, we can infer if corollary discharge of pursuit compensation during optic flow perception is intact in AD patients. To our knowledge, this is the first study that links corollary discharge dysfunction to AD pathology. We showed that AD patients exhibited impaired pursuit compensation during optic flow perception as comparing to healthy controls. In contrast, the performance of optic flow perception (both bias and selectivity) in the passive viewing condition  did not differ between groups. This ruled out a general decline of low level processing as the explanation for the observed results. Instead, the between-group difference in the optic flow perception was specific to eye movement compensations . It should be noted that, our results of similar self-motion performance between AD patients and healthy controls during passive viewing are seemingly contradictory with previous studies showing that AD is associated with elevated optic flow threshold36. However, this difference may well be explained by the methodological differences between studies. More precisely, the previous studies varied the coherence levels of optic flow (by adding randomly-moving dots) and took the coherence threshold as a measure of perceptual capability. In contrast, in the current study we did not incorporate visual noise into the optic flow. Instead, we varied the angle of optic flow to obtain the psychometrical performance. To what extent the perceptual performance based on these two different measures are related is still unknown.Optic flow perception is one commonly used perceptual task in AD researchThere is a possibility that between-group difference of optic flow perception in pursuit conditions was a consequence of differences in the qualities of pursuit movements per se. This explanation is also compatible with the apparent lack of between-group difference in fixation trials. Since we did not conduct simultaneous eye-tracking to monitor gaze positions in parallel to the psychophysical measurements, we cannot completely exclude this possibility. More-carefully designed experiments are needed to better determine the nature of these compensation differences. Another limitation of the current study is that, due to a lack of sufficient variability in MMSE scores, we could not know whether the amounts of pursuit compensation impairment are correlated with the severity of AD pathologies. Future studies should recruit more AD patients with larger MMSE variability (from early to late stages) to explore the correlative relationships between compensation deficits and AD pathology.37. Neurons in these two areas received not only visual information about the optic flow40 but also extra-retinal information including signals related to pursuit eye movements43. Single-unit neurophysiologic studies in monkeys have shown that neural responses in MSTd and VIP are stable despite of distorted retinal optic flow in the presence of eye movements46, indicating the involvement of these two areas in movement compensation. Our results of impaired pursuit compensation during optic flow perception in AD patients suggest that AD pathology is probably associated with the progressive cell death and/or synaptic loss in these two parietal areas. However, this does not exclude the possibility of structural and functional alterations of cerebral white matter in AD, as the integrity of white matter is also pivotal for normal brain functions48. Further studies with animal models of AD are needed to advance our understanding of its underlying cortical and white matter pathology and to explore the relevance of eye movement compensation deficits in AD.The current study has implications on the cortical dysfunctions in AD pathology. Optic flow is generally believed to be processed by the dorsal subdivision of medial superior temporal area (MSTd) and ventral intraparietal area (VIP)"}
+{"text": "Steroidogenic Acute Regulatory protein (StAR). StAR plays an essential role in steroidogenesis- it controls the hormone-dependent movement of cholesterol across the mitochondrial membranes. Currently StAR's mechanism of action remains a major unanswered question in the field. However, some insight may be gained from understanding the mechanism(s) controlling the PKA-dependent phosphorylation of StAR at S194/195 (mouse/human StAR), a modification that is required for function. This mini-review provides a background on StAR's biology with a focus on StAR phosphorylation. The model for StAR translation and phosphorylation at the outer mitochondrial membrane, the location for StAR function, is presented to highlight a unifying theme emerging from diverse studies.Adrenocorticotropin hormone (ACTH) produced by the anterior pituitary stimulates glucocorticoid synthesis by the adrenal cortex. The first step in glucocorticoid synthesis is the delivery of cholesterol to the mitochondrial matrix where the first enzymatic reaction in the steroid hormone biosynthetic pathway occurs. A key response of adrenal cells to ACTH is activation of the cAMP-protein kinase A (PKA) signaling pathway. PKA activation results in an acute increase in expression and function of the  Furthermore, this factor needed to fulfill the following criteria: be newly synthesized upon hormonal stimulation in a time- and dose-dependent manner, be localized at the mitochondria, and have a short-half  fulfills the criteria for the acute regulator of steroidogenesis.The study of steroid hormone production has origins in work on adrenocorticotropin hormone (ACTH)-stimulated adrenal steroid synthesis  were identified in patients with congenital lipoid adrenal hyperplasia (lipoid CAH), a disorder marked by a lack of adrenal and gonadal steroidogenesis due to the inability to move cholesterol into the mitochondria [ pp37, pp32, and pp30 that appeared in rat adrenal after ACTH stimulation  was functional in cell-based assays, indicated that mitochondrial import was not required for function. However, the targeting of StAR to mitochondria may be important for efficient cholesterol transfer and steroid production in vitro assays  triggers cholesterol transfer  complex that function with the pore-forming TOM40 complex to control protein import into mitochondria  and that the AKAP1-StAR mRNA association contributes to translation efficiency. The model that AKAP1 localizes PKAR2 at the OMM provides a platform for localized phosphorylation of StAR  as components of a StAR-containing complex (Bose et al., \u2212/\u2212 mice present with mitochondrial alterations in a strain-dependent manner. Loss of VDAC2 results in embryonic lethality (Anflous et al., The prevailing concept is that StAR phosphorylation influences key interactions with OMM proteins that promote cholesterol transfer. The challenge is that several StAR-interacting complexes at the OMM have been proposed yet the identity of the functional StAR cholesterol transfer complex remains to be validated (Bose et al., In summary, ACTH action on StAR biology requires an immediate response to hormone stimulation, which is seen in a rapid increase in StAR transcription. StAR translation, phosphorylation, and mitochondrial import are likely coordinated processes, but the mechanisms regulating these steps are lacking. Nevertheless, the work over the past decade supports a model for localized translation at the mitochondria. One proposed scenario is the newly transcribed StAR mRNA binds AKAP1 through 3\u2032UTR-driven interactions localizing the mRNA to the mitochondria where it is bound by ribosomes and translated Figure , 2002, aBC reviewed the literature, generated the figure, and wrote the mini-review.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The human treponematoses comprise venereal syphilis and the three non-venereal or endemic treponematoses yaws, bejel, and pinta. Serological assays remain the most common diagnostic method for all treponemal infections.Point-of-care tests (POCTs) for syphilis and yaws allow testing without further development of infrastructure in populations where routine laboratory facilities are not available. Alongside the test\u2019s performance characteristics assessed through diagnostic evaluation, it is important to consider broader issues when rolling out a POCT. Experience with malaria POCT roll-out in sub-Saharan Africa has demonstrated that both healthcare worker and patient beliefs may play a major role in shaping the real-world use of POCTs. We conducted a qualitative study evaluating healthcare worker and patient perceptions of using a syphilis/yaws POCT in clinics in the East Malaita region of Malaita province in the Solomon Islands. Prior to the study serology was only routinely available at the local district hospital.The POCT was deployed in the outpatient and ante-natal departments of a district hospital and four rural health clinics served by the hospital. Each site was provided with training and an SOP on the performance, interpretation and recording of results. Treatment for those testing positive was provided, in line with Solomon Islands Ministry of Health and Medical Services\u2019 guidelines for syphilis and yaws respectively. Alongside the implementation of the POCT we facilitated semi-structured interviews with both nurses and patients to explore individuals\u2019 experiences and beliefs in relation to use of the POCT.Four main themes emerged in the interviews: 1) training and ease of performing the test; 2) time taken and ability to fit the test into a clinical workflow; 3) perceived reliability and trustworthiness of the test; and 4) level of the health care system the test was most usefully deployed. Many healthcare workers related their experience with the POCT to their experience using similar tests for malaria. Although the test was considered to take a relatively long time to perform the benefits of improved access to testing were considered positive by most healthcare workers. Qualitative data is needed to help inform better training packages to support the implementation of POCT in low-resource settings. Syphilis and yaws are closely related bacterial infections. In many countries where the diseases are found there is limited access to diagnostic testing. Recently a point of care test for both diseases has been developed. In the current study we evaluated the experience of healthcare workers and patients in using the test in the Solomon Islands. Both healthcare workers and patients valued the improved access to testing that provided by the point of care test. Experience of healthcare workers in using similar tests for other diseases, such as malaria, had both positive and negative impacts on their beliefs about the syphilis and yaws test. Treponema pallidum subsp. pallidum, remains an important cause of both morbidity and mortality worldwide and remains one of the major preventable causes of stillbirth globally [The human treponematoses comprise venereal syphilis and the three non-venereal or endemic treponematoses yaws, bejel, and pinta. Syphiliglobally . Stillbiglobally ,4; this globally , but accglobally ,7.T. p. subsp. pertenue is the most common of the endemic treponematoses[T. p. subsp. pallidum, yaws is transmitted by non-sexual skin to skin contact affects children living in poor, rural communities in the tropics, where the ambient humidity is high[Yaws, caused by nematoses. Althougy is high. In 2012y is high,10. The y is high, and wouTreponema pallidum particle agglutination assay (TPPA), combined with a non-treponemal test, such as the Rapid Plasma Reagin (RPR) assay. Treponemal tests are highly specific but generally remain positive for life following infection. Non-treponemal tests are less specific but reflect disease activity more accurately, and their titres fall following successful treatment. Testing therefore requires both assays to give an interpretable result.Serological assays remain the most common diagnostic method for all treponemal infections. Importantly, none of the currently available assays is able to differentiate between infection with syphilis and infection with any of the endemic treponematoses. StandarWhilst traditional serological tests are relatively straightforward to perform, they require a cold chain and electricity, denying access to testing to those living in many remote communities. Point-of-care tests (POCTs) allow testing without further development of infrastructure in populations where routine laboratory facilities are not available. A large number of syphilis POCTs meeting the ASSURED criteria have beeA single commercially available test, the Dual Path Platform (DPP-POCT) Syphilis Screen and Confirm test kit  provides both a \u201ctreponemal\u201d result  and a \u201cnon-treponemal\u201d result , and canAlongside the test\u2019s performance characteristics assessed through diagnostic evaluation, it is important to consider broader issues when rolling out a POCT. Adequate training and quality control (QC) steps must be developed, and both health-care workers and patients may require additional education about the role of POCTs in making a diagnosis. Experience with malaria POCT roll-out in sub-Saharan Africa has demonstrated that both healthcare worker and patient beliefs significantly influence the utilisation and interpretation of POCTs and may play a major role in shaping their use in real-world settings,21.The Solomon Islands reports the third most cases of yaws in the world annually, after GThe study was at Atoifi Adventist Hospital (AAH), Uru Harbour, the local referral hospital for the eastern region of Malaita Province. Addition healthcare services are provided in the Province by a number of nurse aid posts and rural health clinics. Serological testing for syphilis and yaws is available in this catchment area but requires venepuncture and delivery of the blood sample to AAH or for the patient to travel to the hospital for venepuncture. In many remote communities this may require travelling for more than eight hours to have blood taken.DPP-POCT kits were purchased from Chembio for use in the study. The DPP-POCT combines both a treponemal and a non-treponemal line. A finger prick blood sample is collected and placed with buffer into the first well on the POCT. The test is allowed to run for five minutes before additional buffer is added to the second well on the POCT. The test is allowed to run for a further 10\u201315 minutes before the results are read. Tests were purchased by the London School of Hygiene & Tropical Medicine. Test kits and equipment required to perform the DPP-POCT were provided to all clinics for the duration of the study.The DPP-POCT was deployed in three settings: the outpatient department of AAH, the antenatal clinic of AAH and four rural health clinics accessible to AAH only by walking or canoe. Clinical care in each of these settings is provided by registered nurses. The rural clinics all provide antenatal care as well as general outpatient care including seeing patients with yaws. Members of the study team visited each location and provided a one-day training package to staff members on the use of the DPP-POCT. Each location was also provided with a standardised protocol for performance, interpretation and recording of results. Briefly this protocol included collection of a finger-prick blood samples followed by performance and interpretation of the assay in line with manufacturer\u2019s instructions. Treatment for those testing positive was provided, in line with Solomon Islands Ministry of Health and Medical Services\u2019 guidelines for syphilis and yaws respectively.We facilitated semi-structured interviews with both health care workers and patients to explore individuals\u2019 experiences and beliefs in relation to the DPP-POCT. Participants were selected using convenience sampling of health-care workers at each facility who reported having used the DPP-POCT. The interviews covered experience of training, positive and negative experiences of performing the test, perceptions of reliability of the test and what level of the healthcare system that individuals believed the test should be available at. For health care workers interviews were performed by researchers with training and previous experience in qualitative research in the Solomon Islands. We performed interviews at each clinical location one and six months after the rollout of the POCT aiming to interview each healthcare worker in each clinical settings. At six months, we used convenience sampling to additionally interview patients attending clinics about their experience of being tested using the POCT. All interviews were undertaken in either Kwaio  or Pijin (the lingua-franca of the Solomon Islands). Interviews were digitally recorded and then transcribed for analysis by a member of the study team (TE).As this was a qualitative study, no formal sample size calculation was undertaken. In each setting purposive sampling of health workers was used to select participants. In each clinical setting only one cadre of staff was available, either nurses in rural clinics and the AAH outpatient department and midwives in the AAH ANC department. We aimed to perform multiple interviews at each clinic and at each time point to ensure a full range of views and experience of the DPP-POCT were obtained until we reached saturation.Immersion in the data was achieved by verbatim transcribing of the interviews and repeated reading of interview transcripts prior to their analysis. We used thematic analysis to identify common themes or stands in healthcare worker and patient experiences.The study was approved by the ethics committees of the Atoifi Adventist Hospital, the Solomon Islands Ministry of Health and Medical Services, and the London School of Hygiene & Tropical Medicine. Individuals undergoing testing with the DPP-POCT and individuals participating in interviews provided written informed consent. Where a DPP-POCT was performed on a child we obtained written consent from their parent or guardian and additionally obtained verbal assent from the child.Over the study period approximately 500 DPP-POCTs were used across the study sites. We interviewed a total of 20 health care workers, 12 at the one month time point post training and a further eight healthcare workers at the six month time point post training. We additionally interviewed four patients who had been tested using the DPP-POCT.As a result of the thematic analysis we identified four main themes: 1) training and ease of performing the test; 2) time taken and ability to fit the test into a clinical workflow; 3) perceived reliability and trustworthiness of the test; and 4) level of the health care system the test was most usefully deployed.\u201cbikos hemi similar wetim RDT blo malaria \u201d. The majority of healthcare workers reported that the test was relatively easy to perform but several noted that it was possible to make mistakes with both the timing and volume of buffer resulting in errors in the testAll but two healthcare workers interviewed (18/20) had received training in the use of the DPP-POCT from members of the study team at the time of the DPP-POCT pilot. All healthcare workers reported that they were already familiar with POCTs for malaria and that this helped them conduct the DPP-POCT;; \u201chia test kit ia bae hem onle problem, if mi makem mistake lo namba of pufs mi duim mistake lo hem, or taeming blo mi hem no accurate hem nao bae mi save westim kit blo mi yia (the only problem is if you make a mistake with the number of drops or the timing the test isn\u2019t accurate and is wasted) \u201dwan nogud samting lo saed lo staff nomoa, lo saet lo withdrawal lo blud. Hem nomoa hem lelbet danger fo saed lo staff\u201d .One healthcare worker explained the withdrawal of the blood for the test was sometimes difficult; \u201cSeveral nurses (4/20) reported that the DPP-POCT took a relatively long time to deliver a result and that this could disrupt workflow in a clinical environment. One health care worker explained,\u201cLelebet part hemi nogud nomoa lelebet taeming wea iu tekem fo redim resolt; wea hem rekwaerim 20\u201325 minutes fo iu redim resolt yia.  \u201dDespite this delay, healthcare workers at both AAH and the clinics reported that the time taken for the test compared favourably with having to wait a week for a result to come back from the hospital laboratory, or the time it would take patients to reach facilities where standard laboratory tests could be performed. A health care worker from AAH stated that previously,\u201clast taem ia, bae mifala givim go lo lab afta wan wik na bifo mifala resivim resolt (before when we have the sample to the lab we had to wait a week to receive the result)\u201d \u201d.A rural healthcare worker explained\u201c15 minutes ia hem sort taem ia compared lo oketa test before wea laek lo siteton lo hia samfala lo oketa like antenatal mothers oketa hev to walk fo 3,4,5 hours ia fo casim facilitI  \u201dMost nurses (16/20) reported confidence in the results of the DPP-POCT and that this had been reinforced by concordance between POCT and laboratory tests. Two nurses highlighted the experience of discordant results between laboratory and POCT testing as impacting their confidence in the test. One healthcare worker stated,\u201cwea oketa test fo syphilis so taem diswan hem confirm positive and mefala sendim blud ah same resolt hem araef, so that\u2019s how mi garem trust det diswan ah hem confirm test. \u201d\u201cwanfala patient na taem mefa checkim lo RDT hem negativ but den mefala cross check lo down hem reactive na blud blo hem so hem na mifala stat kwestion about diss test (One patient was negative on the RDT but reactive on the blood which makes me question the test) \u201dAnother healthcare worker at a different clinic explained, Parallels were also drawn between the experience of RDTs for malaria and the DPP-POCT. Two nurses invoked previous experience of discordant results between the POCT used for malaria and microscopic diagnosis of malaria, and reported that this made them worry, by analogy, if the DPP-POCT was accurate.\u201cLo malaria kit if malaria wea hem 1 plus disfala RDT blo malaria yia hemi no readim yia..Bae olwes givim mifala negatif ansa.But sapos mi givim go lo microscopist bae hemi say 1 plus. So det wan ia nao hemi givim mi daot lo disfala syphilis becos hemi no givim mi how seriousness nao disfala diseses.  \u201d\u201cbikos lab hem farawe from mifala. So hem barava best ples na ia. (The lab is far away from us. So here (clinic) is the best place) \u201d. Another rural health worker explained,All health care workers (20/20) reported that providing access to testing at the clinic level was a strength of the POCT. Lack of access to laboratory facilities due to the distance from the hospital was seen as a significant challenge in terms of logistics, time and costs. POCT addressed these challenges by providing access to testing at a lower level of the health care system. One nurse stated \u201cHem nao ekspensif fo olketa mama fo cum daon lo hospital fo usem test ia. Iumi save duim noma lo olketa rural clinics  to have the test. Lets do the test at all of the rural clinics .Patients reported that improving access to testing at the clinic level was beneficial due to the delays involved in travelling to hospitals for testing. One patient explained,\u201csendem go lo hospital o sendem go lo olketa nara place testim kam olketa blud ia ating bae hem lelebet slo to so ating hem gud na for okelta makem lo hia nomoa  .The costs of getting to the hospital was also a concern expressed by for health workers.In this study we provide the first real-world evaluation of the acceptability of the DPP-POCT in routine health care settings, in a country co-endemic for yaws and syphilis. Whilst a number of evaluations have been conducted of the analytic performance of the DPP-POCT,18,19, nThe majority of nurses reported a high level of trust in the test, and both patients and nurses recognised the benefits of making diagnostic testing available in primary health facilities without recourse to a hospital laboratory. The test was generally reported to be easy to perform based on the training received in the study and despite the relatively long time required to obtain a result, nurses reported the test could be integrated into clinical workflows. Previous studies of the roll-out of rapid syphilis tests in other settings have also demonstrated an overall high level of acceptability and feasibility . In lineIn the current study, many health care workers drew parallels between their experience of the DPP-POCT and their previous experience with malaria RDTs. Whilst familiarity with RDTs was clearly advantageous, it also highlighted how lack of confidence in one test kit could affect the roll-out of a second, unrelated, test kit. Adoption of RDTs for the diagnosis of malaria has not always translated into anticipated reductions in the number of patients treated for malaria in the real world. StudiesThere are a number of limitations to this study. Firstly, we focused on a relatively small number of clinics over a fairly limited timeframe. This reduced our ability to consider the impact of broader health systems factors that may influence the feasibility of rolling out the DPP-POCT. Previous studies on syphilis RDTs have highlighted the importance of supply chain and quality control monitoring systems in maintaining long term effectiveness of RDT scale-up at a national level. These cThis is the first study to assess the acceptability of rolling out the DPP-POCT in a routine health care setting. We highlight the potential added value to both patient and healthcare workers that can be provided by positioning these tests at the primary health care level. Longer term and larger evaluations of DPP-POCT would be valuable to assess the impact and cost-effectiveness of scaling up access to the DPP-POCT on the management of syphilis and yaws.S1 Checklist(DOCX)Click here for additional data file."}
+{"text": "BCAAs have been initially shown to increase muscle mass and have also been implicated in the limitation of structural and metabolic alterations associated with exercise damage. This systematic review provides a comprehensive analysis of the literature regarding the beneficial effects of BCAAs supplementation within the context of exercise-induced muscle damage or muscle injury. The potential benefit of a BCAAs supplementation was also analyzed according to the supplementation strategy\u2014amount of BCAAs, frequency and duration of the supplementation\u2014and the extent of muscle damage. The review protocol was registered prospectively with Prospective Register for Systematic Reviews (registration number CRD42017073006) and followed Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. Literature search was performed from the date of commencement until August 2017 using four online databases . Original research articles: (i) written in English; (ii) describing experiments performed in Humans who received at least one oral BCAAs supplementation composed of leucine, isoleucine and valine mixture only as a nutritional strategy and (iii) reporting a follow-up of at least one day after exercise-induced muscle damage, were included in the systematic review analysis. Quality assessment was undertaken independently using the Quality Criteria Checklist for Primary Research. Changes in indirect markers of muscle damage were considered as primary outcome measures. Secondary outcome measures were the extent of change in indirect markers of muscle damage. In total, 11 studies were included in the analysis. A high heterogeneity was found regarding the different outcomes of these studies. The risk of bias was moderate considering the quality ratings were positive for six and neutral for three. Although a small number of studies were included, BCAAs supplementation can be efficacious on outcomes of exercise-induced muscle damage, as long as the extent of muscle damage was low-to-moderate, the supplementation strategy combined a high daily BCAAs intake (>200 mg kg In a recent report entitled \u201cProtein Ingredients Market by Source , Application , and Region\u2014Forecast to 2022\u201d, the market for protein ingredients was projected to reach 58.49 billion dollars by 2022 . Indeed, Olympic as well as college athletes and many people exercising in gyms regularly use supplements with amino acids representing 10\u201320% of these nutritional strategies ,4. BrancBCAAs are important precursors of tricarboxylic acid (TCA) cycle intermediates via acetyl-CoA and Succinyl-CoA  and can Taking into account all the physiological mechanisms linked to BCAAs intake and that BCAAs are mainly metabolized in skeletal muscle , whereasThe aim of this systematic review was to objectively describe the effects of BCAAs supplementation on indirect markers of muscle damage considering studies reporting clinical trials  involving healthy subjects supplemented with BCAAs only. Potential confounding factors were determined relating to the extent of muscle damage  and the supplementation strategy .This systematic review provides a comprehensive analysis of the literature regarding the assumption that BCAAs supplementation can alleviate alterations of skeletal muscle function acting on exercise-induced muscle damage or muscle injury. Recommendations on the most efficient nutritional strategy to minimize consequences of damage induced by exercise on muscle function are highlighted.The pre-defined review protocol was registered prospectively with Prospective Register for Systematic Reviews (PROSPERO\u2014registration number: CRD42017073006). This systematic review was completed in accordance with the recommendations of the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines .Criteria for study inclusion were chosen using the Population-Intervention-Comparator-Outcomes-Study design (PICOS) format . ArticleThe computerized literature search was performed from date of commencement until August 2017 using four online databases: Medline (PubMed), Cochrane library, Web of Science and ScienceDirect; a supplementary Google Scholar search was also undertaken. The key words used to find relevant papers were: (\u201cmuscle damage\u201d OR \u201cmuscle injury\u201d OR \u201cexercise-induced muscle damage\u201d OR EIMD) AND . The reference sections of all identified articles were also examined.Data related to participants , experimental design , exercise , outcome measures  and supplementation strategy  were extracted. The quality of selected studies  were rated using the Quality Criteria Checklist for Primary Research  to limitA greater emphasis was placed on findings from studies achieving high-quality ratings. Significant effects described in the included studies were extracted to quantify outcomes associated with the damaging exercise and the BCAAs supplementation. Rating criteria were created according to the supplementation strategy and the extent of muscle damage . Due to We initially identified two thousand one hundred and thirty-three papers from databases and internet searches and included 11 studies in the present systematic review according to the 4-phase flow diagram described in The included studies were trials with numbers of subjects ranging from 9 to 30 and were conducted in the last 20 years . We idenThe majority of studies included in the systematic review were rated as positive (55%). Neutral (27%) and negative (18%) qualities were reported for the other studies  for multMoreover, the supplementation strategy and the extent of EIMD were considered as cofounding parameters to objectively assess the effects of BCAAs on muscle damage outcomes.Duration, frequency and daily amount of BCAAs was rated . More thThe damage extent was generally low in the included studies. It is noteworthy that a few studies reported discordant changes in muscle performance and CK/LDH measurements ,40 as a The positive effects of BCAAs supplementation on EIMD outcomes are reported in \u22121 day\u22121) in a context of low-to-moderate muscle damage extent [Considering the studies with positive and neutral quality rating, the benefits of BCAAs supplementation was mostly observed when the supplementation strategy included a high amount of BCAAs intake  of EIMD. Throughout this systematic review, we identified that BCAAs can alleviate outcomes of EIMD for specific conditions regarding the extent of muscle damage and the supplementation strategy. Potential benefits of BCAAs supplementation can actually be obtained for low-to-moderate extent of muscle damage and considering a supplementation strategy that includes high daily BCAAs intake over a long period of time  and especially before the damaging exercise period.Previous systematic reviews have reported positive chronic effects of protein supplementation on muscle mass, strength and power . The corA first confounding factor for the assessment of BCAAs supplementation was the extent of muscle tissue alteration reported in the included studies. These alterations and the corresponding extent were estimated and rated from changes in indirect markers of muscle damage including decreased muscle performance and increased amount of blood markers . As reported previously, the maximal voluntary contraction (MVC) loss is currently considered as the most reliable indicator of muscle injury  as compaMuscle soreness is a subjective outcome of EIMD ,47 givenPutting aside these methodological considerations, positive effects of BCAAs supplementation have been mainly reported for low-to-moderate muscle damage induced by exercise. For larger muscle alterations, which have been reported in two studies ,35, no s\u22121 day\u22121) over a long period of time [\u22121 day\u22121) during a moderate supplementation duration  was not enough to produce benefits on EIMD indirect markers [In the present review, we considered three criteria  in order to more accurately assess the BCAAs supplementation strategies reported in the selected studies. A high frequency of BCAAs intake  was used over the whole set of studies demonstrating benefits regarding EIMD. In addition, the daily amount of BCAAs and the supplementation duration seem to be important factors. Positive effects of BCAAs supplementation were mainly obtained for a high daily amount of BCAAs intake  of both the control and supplemented groups. Overall, this systematic review suggests that a BCAAs supplementation strategy with daily intake larger than 200 mg kg\u22121 day\u22121, duration longer than 10 days starting at least 7 days before the damaging exercise would be effective to limit muscle damage resulting from exercise. On that basis, one can expect a peak force loss of less than 15% and/or an increase in plasma/serum CK peaking at one day following the damaging exercise. However, further placebo-controlled randomized clinical trials would be needed to support the beneficial effects of this strategy. In addition, it might be of interest to assay the effects of other nutritional strategies for which BCAAs could be combined with taurine [In summary, the efficacy of a nutritional strategy based on BCAAs supplementation and aimed at reducing/preventing muscle damage resulting from high-intensity exercise seems to be poor. Among the studies selected in the present review, only one rated as positive regarding the quality of reported beneficial effects . However taurine  or other taurine  and for As a take home message, there is no direct evidence of positive effects of BCAAs on muscle damage. However, in specific conditions, BCAAs supplementation seems to diminish the outcomes of EIMD. It would be of interest to further support these findings on the basis of imaging investigations."}
+{"text": "The South African Heart Association (SA Heart) together with two of its special-interest groups, the South African Society of Cardiovascular Intervention (SASCI) and the Society of Cardiothoracic Surgeons in South Africa (SCTSSA), represent the scientific, educational and professional interests of South African cardiac specialists, with a combined membership of over 200 members. These two interest groups exclusively represent practicing cardiologists and cardiothoracic surgeons in South Africa. SASCI and SCTSSA are dedicated to maintaining the highest standards of specialist practice and the highest quality of patient care. As a result, SASCI and SCTSSA seek to serve as a knowledge resource for patients and funders in matters related to new technology used in the cardiac interventional and surgical disciplines.The introduction of new technology is a constant in modern medicine. While authorities in the United States of America (USA) and European Union, such as the Food and Drug Administration (FDA) and Conformit\u00e9 Europ\u00e9ene (CE), provide regulatory clearance on safety and effectiveness, practicing medical practitioners require scientific evidence on net health outcomes before offering new procedures to their patients. In addition, to meet clinical expectations of practicing specialists, new technology must stay consistent with fundamental medical and surgical principles.Transcatheter aortic valve implantation (TAVI) is considered a feasible technique, which may be used as an alternative to standard surgical aortic valve replacement in selected cases. The procedure is performed on the beating heart without the need for a sternotomy or cardiopulmonary bypass. There are currently two devices available in South Africa that are CE-marked and approved by the FDA. The procedure may be performed via the transfemoral, transsubclavian and transapical approaches or via a mini-sternotomy (transaortic approach).SA Heart and the respective boards of the SASCI and SCTSSA by consensus hereby adopt the TAVI procedure for aortic stenosis in line with the principles of evidence-based medicine after considering the most recent published evidence and the various multinational society position statements and guidelines concerning TAVI.This consensus guideline considers all the literature reviewed, including the 2014 American Heart Association/American College of Cardiology guideline for the management of patients with valvular heart disease, the 2012 European Society of Cardiology/European Association for Cardiothoracic Surgery guidelines on the management of valvular heart disease, and the updated standardised endpoint definitions for TAVI [as per the Valve Academic Research Consortium-2 (VARC-2) consensus document].3Members of the SA Heart Association, SASCI and SCTSSA with experience in the technique and knowledge of the TAVI literature have agreed to the following consensus statement:The performance of TAVI, ab initio, should be restricted to a limited number of high-volume centres, which have both cardiology and cardiac surgery departments on site, with expertise in structural heart disease intervention and high-risk valvular surgery. Interventional cardiologists should be experienced in catheter-based valvular interventions and peripheral access using large devices. Cardiac surgeons should be experienced in valve surgery and the management of complex cases. It is recommended that all TAVI teams aim to perform more than 10 implants per year.TAVI should currently be reserved for patients who, after evaluation by a multidisciplinary heart team (MDT) are found to have a risk/benefit ratio favouring TAVI rather than open-heart surgery. The heart team should at least include a cardiologist, cardiac surgeon and imaging specialist. Its composition is however dynamic and can also include a cardiac anaesthetist, geriatrician and neurologist as well as other members as the MDT sees fit.Patients should be screened into a TAVI programme by a MDT (as defined above) and not by an individual specialist.Formal training of the implanting team should include:didactic theoretical trainingsimulator training where availablea visit to an experienced centre to observe TAVI casessupport for the initial cases at any site by a proctor until the proctor has certified the centre to be independent.Proof of severe symptomatic aortic valve stenosis.Patient evaluation by a MDT.TAVI is recommended in patients who are, according to the MDT heart team, considered to be unsuitable for conventional surgery because of severe co-morbidities. These include:Possible procedure-specific impediment, for example:porcelain aorta or severely atherosclerotic aortahostile chestpatent coronary artery bypass grafts crossing the midline and/or adherent to the posterior table of the sterumORFrailty. In the absence of validated frailty scores, this remains the opinion of an experienced physician. We recommend that it is the opinion of at least two physicians of which one should be a cardiac surgeon experienced in aortic valve replacement surgeryORMajor organ compromise of two or more organ systems. Examples include:cardiac: severe left or right ventricular dysfunction, severe pulmonary hypertensionpulmonary dysfunction (FEV1 or DLCO2 < 50% predicted)central nervous system dysfunction gastro-intestinal dysfunction liver cirrhosis, variceal bleeding.TAVI is recommended in patients who are, according to the MDT, considered to be at high risk for conventional surgery. In line with other guidelines, the evaluation of surgical risk should rely on the clinical judgement of an MDT rather than quantitative risk scores as these have not been well validated in this population. These risk scores may be used in addition, with cut-off values of an STS (Society of Thoracic Surgeons) risk score > 4 or a log EuroSCORE > 20 recommended. It must be emphasised that risk scores should not be used in isolation to determine whether a patient qualifies to undergo a TAVI procedure. Growing evidence supports the efficacy of TAVI in \u2018intermediate-risk group\u2019 patients.Absence of an MDT heart team and no cardiac surgery on site.Patients whose life expectancy is less than one year.Clinical improvement in quality of life after TAVI limited by co-morbidities. This may be especially relevant if the indication for TAVI is major organ compromise, as outlined above.Anatomical factorsinadequate annulus sizeactive endocarditisinadequate access site.Significant other valve lesions or coronary artery disease that requires additional valve or coronary artery bypass surgery.Relative contra-indicationsleft ventricular ejection fraction (LVEF) < 20%haemodynamic instability.The centre should be sufficiently equipped to perform transcatheter procedures safely.3Minimum infrastructure requirements include:The ability to set up an MDT (as outlined above)Immediate availability of transthoracic and transoesophageal echocardiography.Availability of a dedicated cardiac catheterisation laboratory or hybrid theatre [a theatre with mobile fluoroscopy (\u2018C\u2019-arm) screening facilities is generally not appropriate for TAVI procedures].Computed tomography (CT) scanning facilities.Immediate availability of perfusion services in case emergency cardiopulmonary bypass  becomes necessary.On-site availability of a surgical recovery area and intensive care with staff experienced in looking after patients following surgical aortic valve replacement.Facilities for immediate renal support if necessary.Immediate access to vascular surgery and interventional radiology to deal with peripheral vascular complications.The above requirements will mean that this procedure should only be performed in a unit currently carrying out surgical aortic valve replacement."}
+{"text": "The occurrence of high rates of somatic mutations in cancer is believed to correspond to increased frequency of neo-epitope formation and tumor immunogenicity. Thus, classification of patients with cancer according to degree a somatic hyper-mutational status could be proposed as a predictive biomarker of responsiveness to immunotherapy with immune checkpoint inhibitors. Here, we discuss the suitable and reliable tests easily adoptable in clinical practice to assess somatic mutational status in patients with advanced cancer. Recently, the load of non-synonymous sequence variants has been significantly associated with clinical benefit from treatment of patients with cancer with immune checkpoint inhibitors In particular, cancer types associated with chronic exposure to external mutagens  or constitutive impairment in genomic integrity (i.e. defective DNA repair mechanisms in a subset of colon cancer) have been reported to preferentially respond to immune checkpoint inhibitors \u20134. In thAlthough qualitative mutation data on somatic cancer samples are still limited, research efforts aim at defining whether the increased load of the non-synonymous sequence variants may follow distinct mutational patterns or rather represent the consequence of the accumulation of mutations in specific pathways , 7. DeteWhile in the future NGS may cross the threshold of clinical application, what can be done in the meanwhile?The following pressing question arises: does a reliable and simple diagnostic test exist ready for use in clinical practice for the assessment of a somatic mutational status?To date, only the selective identification of patients carrying tumors with genomic instability is practically achievable. The occurrence of alterations impairing the mechanisms involved in maintenance of the genome integrity may induce progressive accumulation of genetic DNA errors and provide a selective advantage for cancer cells during malignant evolution. It has been long known that tumors with non-functional DNA mismatch repair (MMR) present with a higher tendency to bear DNA genomic errors and display a pattern of genomic instability . An effiConsidering recent results about the efficacy of the PD-1 inhibitors according to the microsatellite status, the response rate in the MMR proficient colorectal cancer (CRC) and non-CRC cohorts was overall 1% (1/79), with a disease control rate of 13% (10/79) , 12\u201315. Genetic  or epigenetic  inactivation of both alleles of the MMR genes leads to MSI at somatic level. The MMR system is composed of 6 MMR genes and their encoded proteins , though inactivation of MLH1 and MSH2 account for over 85% of MSI cases .A correlation between presence of MSI and abnormal MMR gene expression has been widely reported \u201319, stroBAT-25 and BAT-26) and three dinucleotide repeats  . In both cases, the PCR products are separated by capillary electrophoresis using an automated sequencer  and the output data analyzed with specific software  to determine MSI status. The PCR-based multiplex assay is also relatively inexpensive (less than 50 euros per patient\u2019s classification) as compared to the four-five fold higher costs of developing NGS-based methodologies.Collating these findings, it becomes evident that MSI might be considered the only reliable marker of replication errors in human cancers and that a well-conducted microsatellite analysis may yield an accurate detection of genetic instability. MSI testing by polymerase chain reaction (PCR) is considered the gold standard allowing the identification of abnormalities even in the setting of non-truncating protein mutations. For this purpose, a recommended reference panel by the National Cancer Institute (Bethesda panel assay) exists and comprises two mononucleotide repeats (While waiting for the application in clinical practice of NGS technology, the standardization of screening approaches based on unique microsatellite panels will improve the classification of genetic instability. This might represent an opportunity to select more homogeneous subsets of unstable patients with a higher mutational load allowing a more accurate assessment of the predictive role of increased mutation rates."}
+{"text": "GLS knockdown had no effect on growth and metabolite levels in non-TNBC cell lines. We rescued the anti-tumor effect of GLS knockdown using shRNA resistant cDNAs encoding both GLS isoforms and by addition of an \u03b1-ketoglutarate (\u03b1KG) analog thus confirming the critical role of GLS in TNBC. Pharmacological inhibition of GLS with the small molecule inhibitor CB-839 reduced cell growth and led to a decrease in mammalian target of rapamycin (mTOR) activity and an increase in the stress response pathway driven by activating transcription factor 4 (ATF4). Finally, we found that GLS inhibition synergizes with mTOR inhibition, which introduces the possibility of a novel therapeutic strategy for TNBC. Our study revealed that GLS is essential for the survival of TNBC with a deregulated glutaminolysis pathway. The synergistic activity of GLS and mTOR inhibitors in TNBC cell lines suggests therapeutic potential of this combination for the treatment of vulnerable subpopulations of TNBC.Tumor cells display fundamental changes in metabolism and nutrient uptake in order to utilize additional nutrient sources to meet their enhanced bioenergetic requirements. Glutamine (Gln) is one such nutrient that is rapidly taken up by tumor cells to fulfill this increased metabolic demand. A vital step in the catabolism of glutamine is its conversion to glutamate by the mitochondrial enzyme glutaminase (GLS). This study has identified GLS a potential therapeutic target in breast cancer, specifically in the basal subtype that exhibits a deregulated glutaminolysis pathway. Using inducible shRNA mediated gene knockdown, we discovered that loss of GLS function in triple-negative breast cancer (TNBC) cell lines with a deregulated glutaminolysis pathway led to profound tumor growth inhibition  GLS and GLS2, encode distinct forms of glutaminases. The KGA and GAC isoforms generated by alternative splicing are derived from the GLS gene and share an identical N-terminus and catalytic domain but have distinct C-termini of unknown function  glucose or [U13- C5] glutamine and determined the incorporation of each tracer into the TCA cycle upon GLS knockdown. A schematic of the tracer carbons through the first round of the TCA cycle is illustrated in To investigate the contribution of glutamine towards intermediary metabolism, we incubated GLS dependent cells MDA-MB-231 and SUM-159PT with either [Uin vitro, we tested whether GLS was essential for in vivo growth of these cell lines as tumor xenografts. Consistent with our in vitro results, doxycycline induced GLS knockdown led to profound tumor growth inhibition in vivo. GLS knockdown with sh1 and sh2 significantly reduced growth of MDA-MB-231 tumors and led to regression of SUM-159PT tumors  and SUM-159PT (\u0394T/\u0394C~69%) tumor xenografts. Although unexpected based on the phenotypes observed upon GLS knockdown with shRNA, the results do agree with the limited single agent anti-tumor activity of CB-839 reported in the literature [in vivo can perhaps be explained by the suboptimal pharmacokinetic properties of this compound in experimental models of cancer.Based on our findings terature . This moFor cells that are highly dependent on glutamine as a major source of carbon and nitrogen for growth and survival, GLS knockdown or inhibition will likely imitate conditions of amino acid starvation and subsequently lead to activation of the ISR pathway and inhibition of the mTOR pathway. The mTOR pathway is a central regulator of cellular metabolism that promotes growth in response to nutrient availability . The mTOOur work has clearly demonstrated that cell lines representing basal breast cancer subtype are highly sensitive to glutaminolysis inhibition that results in a profound decrease in TCA cycle intermediates and glutamine derived amino acids. Our analysis of the cellular responses to either GLS knockdown or pharmacological inhibition has identified potential PD markers and provides a molecular basis for combining GLS and mTOR inhibitors as a novel therapeutic strategy for treating basal breast cancers.S1 Checklist(PDF)Click here for additional data file."}
+{"text": "To the Editor:Recent laboratory research reported that in vitro hypo-oxygenation (hypoxia) can result in permeability changes of the blood brain barrier (BBB) . Such chIt has been shown that endotoxin itself can damage the BBB resulting in changes of permeability . FurtherEscherichia coli (a Gram-negative bacterium) in the gut to the blood, resulting in reduced levels of LPS binding protein (in the blood), suggesting the occurrence of increased cytokine levels  . Patiente levels . LPS froHao et al indicated that the density of occludin and trans-endothelial electrical resistance were both reduced during hypoxic events as compared to controls . An evenHypoxia can occur in cases of sepsis with a high release of endotoxin in the blood, creating a greater risk for developing parkinsonism and dementia in septic survivors . The rolIt should be noted that a recent epidemiological publication evaluating endotoxin exposure did not find a relationship of this agent with PD . Rather,Based on the information provided by Hao et al , we woul"}
+{"text": "Secondary osseous involvement in lymphoma is more common compared to primary bone lymphoma. The finding of osseous lesion can be incidentally discovered during the course of the disease. However, osseous metastases are infrequently silent. Detection of osseous metastases is crucial for accurate staging and optimal treatment planning of lymphoma. The aim of imaging is to identify the presence and extent of osseous disease and to assess for possible complications such as pathological fracture of the load-bearing bones and cord compression if the lesion is spinal. We are presenting two patients with treated lymphoma who were in complete remission. On routine follow-up contrast enhanced CT, there were new osteoblastic lesions in the spine worrisome for metastases. Additional studies were performed for further evaluation of both of them which did not demonstrate any corresponding suspicious osseous lesion. The patients have a prior history of chronic venous occlusive thrombosis that resulted in collaterals formation. Contrast enhancement of the vertebral body marrow secondary to collaterals formation and venous flow through the vertebral venous plexus can mimic the appearance of spinal osteoblastic metastases. Approximately 16% of lymphoma patients will eventually have osseous involvement . The ossOsseous metastases can cause significant morbidity as a result of pathologic fracture and spinal cord compression , 4.A 54-year-old male with Hodgkin lymphoma, who was in complete remission, had several new osteoblastic spinal lesions on routine follow-up contrast enhanced CT of the neck  which weThe patient has a history of left innominate and left subclavian veins chronic occlusive thrombosis in addition to a partially occlusive thrombosis of the left internal jugular and left axillary veins. The routine follow-up contrast enhanced CT of the neck demonstrated at least partial occlusion of the proximal left subclavian vein with numerous collaterals in the left shoulder and left upper back region.The lack of uptake on bone scan and FGD PET along with disappearance of lesions on the non-contrast enhanced CT portion of the PET/CT  implies A 22-year-old male with non-Hodgkin lymphoma, who was in complete remission, had a new osteoblastic lesion at the T5 vertebral body on routine follow-up contrast enhanced CT of the chest  which waThe patient has a history of chronic occlusive thrombosis of bilateral brachiocephalic and left subclavian veins which was demonstrated on contrast enhanced CT of the chest.Again the lack of uptake on bone scan along with disappearance of lesion on the non-contrast enhanced CT portion of the SPECT/CT  implies The apparent osteoblastic lesions on both contrast enhanced CTs were merely marrow enhancement of the vertebral bodies. In the presence of chronic subclavian vein occlusion, collaterals often form and may result in venous flow through the vertebral venous plexus after contrast administration.Contrast enhancement of the vertebral body marrow secondary to venous flow through the vertebral venous plexus can mimic the appearance of spinal osteoblastic metastases. Therefore, focal contrast enhancement of a vertebral body should be considered as a mimicker of an osteoblastic lesion on contrast enhanced CT in the presence of significant chronic venous occlusion and collaterals formation."}
+{"text": "Sc) in the brain. PrPSc accumulation in the endoplasmic reticulum (ER) result in a dysregulated calcium (Ca2+) homeostasis and subsequent initiation of unfolded protein response (UPR) leading to neuronal dysfunction and apoptosis. The molecular mechanisms for the transition between adaptation to ER stress and ER stress-induced apoptosis are still unclear. Mitogen-activated protein kinases (MAPKs) are serine/threonine protein kinases that rule the signaling of many extracellular stimuli from plasma membrane to the nucleus. However the identification of numerous points of cross talk between the UPR and MAPK signaling pathways may contribute to our understanding of the consequences of ER stress in prion diseases. Indeed the MAPK signaling network is known to regulate cell cycle progression and cell survival or death responses following a variety of stresses including misfolded protein response stress. In this article, we review the UPR signaling in prion diseases and discuss the triad of MAPK signaling pathways. We also describe the role played by MAPK signaling cascades in Alzheimer\u2019s (AD) and Parkinson\u2019s disease (PD). We will also overview the mechanisms of cell death and the role of MAPK signaling in prion disease progression and highlight potential avenues for therapeutic intervention.Prion diseases are neurodegenerative pathologies characterized by the accumulation of a protease-resistant form of the cellular prion protein named prion protein scrapie (PrP Sc  are a group of fatal neurodegenerative disorders affecting both humans and animals. Major animals TSEs include bovine spongiform encephalopathies (BSE) in cattle, scrapie in sheep and goats and chronic wasting disease in elk and deer. Human TSEs include Creutzfeldt-Jakob disease (CJD), Gerstman-Str\u00e4ussler-Scheinker syndrome (GSS), Fatal Familial Insomnia (FFI) and kuru  is a multifunctional organelle responsible for folding and processing of secretory and transmembrane proteins. Balanced protein load and folding capacity are two important factors for correct protein folding and processing in the ER. Under pathological conditions this balance between folding load and capacity is disrupted and misfolded/unfolded proteins are accumulated that subsequently initiates ER stress  and the p38 kinases. The widely accepted perception that exists about these MAPKs is that JNK/SAPK (stress-activated protein kinase) and p38 MAPK help in promoting cell death in face of chronic stress stimuli, while ERK1/2 opposes cell death signaling cascades , Parkinson\u2019s disease (PD) and prion diseases  and prion diseases have harmful effects on humans and animals due to lack of effective therapeutic strategies and presymptomatic diagnostic tools. Thus there is a need of novel therapeutic intervention strategies to control these diseases. Here in this review article, we will focus on the role of UPR and MAPK signaling cascades in neurodegenerative diseases with special focus on prion diseases.c to PrPSc is the hallmark of all TSEs . The general decline in several synaptic proteins levels during infection was proposed to be a key trigger for neurodegeneration  reversing the translational repression of the synaptic proteins is a valid therapeutic strategy for prion disease.The main purpose of the PERK pathway signaling cascade is to relieve the ER stress by reducing the amount of proteins entering the ER  and the p38 family of kinases (p38 MAPKs). They are activated through three-tier kinase signaling mechanism. As mentioned above, the MAPK subgroups are activated upon phosphorylation via the dual threonine/tyrosine motif in their activation loop: ERK1/2 with glutamine (Glu), proline (Pro) and glycine (Gly) embedded between threonine/tyrosine motif (Thr-Glu-Tyr), JNK (Thr-Pro-Tyr), and p38 (Thr-Gly-Tyr). There are a variety of selected MAP kinase kinases (MKKs) which phosphorylate these threonine/tyrosine motifs. The MKKs are in turn activated via the phosphorylation of a number of MAP kinase kinase kinases (MKKKs). The intricate mechanisms of biological outcomes of MAPK signaling are dependent on several factors including the sub-cellular localization of the MAPK signaling (determined by the amount of misfolded proteins and scaffolding proteins). In addition, the magnitude and duration of MAPK pathways activation and the effect of other signaling pathways such as UPR on MAPK pathways determines cell fate  through the regulation of the BCL2 family members  treatment Coffey, . There aThe p38 MAPKs activation has been observed in response to a variety of inflammatory cellular stresses such as hyperosmolarity, arsenite or taxol and pro-inflammatory cytokines released in response to activated microglia due to the accumulation of misfolded proteins  misfolds and transform to prion protein scrapie (PrPSc). There is an increase in the \u03b2- sheet content and a corresponding decrease in \u03b1-helices . But there are several cases where ERK1/2 can be apoptotic . The mechanism of MAPK signaling requires further molecular research to determine whether MAPK-dependent signaling can promote cell proliferation, survival or cell death. Scientists are agreed on the analogy with the other investigations that the response to ER stress could prove crucial in reflecting the differences in the duration of signaling, magnitude of signaling, relationship with other signaling pathways and to some extent cell type-specific expression of MAPK cascades. Although there are still several challenges in understanding the role of MAPK signaling and ER stress in prion diseases there are cases where there are indications that therapeutics to manipulate both UPR and MAPK signaling could be advantageous. To date studies on prion disease in vivo models or in vitro models none has focused on inhibiting UPR and MAPK pathways simultaneously. Moreno et al.\u2019s  reversed caspase mediated cell death in prion disease cell model -ASK signaling or due to the Caet al.\u2019s  work on et al.\u2019s , 2013. OIt is clear from previous investigations that useful therapeutic investigation for all the major misfolding diseases such as AD, PD, HD and TSEs should be focused on targeting either the misfolded proteins directly or indirectly by targeting the subsequent downstream signaling pathways. These pathways are initiated in response to the ER stress due to accumulation of the pathogenic proteins. UPR and MAPK pathways need further molecular research to exactly pinpoint the signaling cascades that are activated in response to the accumulation of prion protein in TSEs. In addition, focusing on the UPR and MAPK pathways simultaneously might be a good idea as all the previous research conducted on prion diseases was focused solely either on UPR inhibition or MAPK inhibition individually. Modern molecular level pharmacological research has contributed significantly towards achieving the goal of inhibiting MAPK pathways. Currently all available inhibitors in the market can only target any one of the arms of MAPK pathways. By contrast to other arms of MAPK pathways, many p38 MAPK inhibitors are available such as PH-797804, BIRB 796, VX-702, SB 239063, SB202190, SCIO 469, and BMS 582949. ERK1/2 pathway inhibitors available are PD98059, BVD-523 and U0126. JNK pathway inhibitor commonly used in research is SP600125. On the other hand there are very few inhibitors available to target the UPR signaling cascades. That means simultaneous targeting of UPR and MAPK pathways via inhibitors may be difficult. But Modern scientific tools such as gene manipulation techniques  can be adopted to target UPR and MAPK pathways simultaneously in protein misfolding neurodegenerative diseases to achieve the goal of stress free environment within the nervous cell.SZAS wrote the manuscript, DZ gave the idea, TH helped in figures and LY critically reviewed the manuscript before final submission.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Overall Abstract: Evidence is accumulating that core features of schizophrenia (SCH) may arise from a fundamental disturbance in the cellular balance of excitation and inhibition  within neural circuitry. In the symposium, we will provide a comprehensive overview of E-I balance alterations in SCH with evidence from preclinical models and in vivo measurements investigating potential neurobiological mechanisms underlying these dysfunctions as well as interventions that remedy these disturbances.Takao Hensch will summarize findings on critical period plasticity and its potential role in vulnerability to schizophrenia. He will present new preclinical data on the destabilizing consequences of enhanced gamma oscillations, which reversibly prolong juvenile forms of brain plasticity by redox imbalance.Jan-Harry Cabungcal will address the role of redox dysregulation and oxidative stress in the pathophysiology of schizophrenia. He will present recent data on the relationship of deficits of the perineuronal net and oxidative stress in the anterior cingulate cortex, and evidence that redox dysregulation can be targeted with antioxidants/redox regulators across animal models.Lawrence Kegeles will present simultaneous EEG and proton MRS measurements of glutamate and GABA during ketamine administration in healthy young adults. These data will be compared with the same modalities acquired in individuals at clinical high risk and patients with SCH, showing disturbed delta and gamma band power and altered E-I balance despite homeostatic rebalancing of glutamate and GABA.Peter Uhlhaas will summarize evidence from EEG/MEG data examining the potential role of neural oscillations in the pathophysiology of schizophrenia. He will show that alterations in gamma-band oscillations are present prior to the onset of schizophrenia in at-risk individuals and related to aberrant E-I balance parameters revealed by MRS-measured levels of GABA and glutamate. Developmental data on the maturation of neural oscillations suggests that the transition from adolescence to adulthood is a sensitive period for modifications in neuronal dynamics that could potentially explain the manifestation of psychosis during this period."}
+{"text": "The enhancement of cognitive function in healthy subjects by medication, training or intervention yields increasing political, social and ethical attention. In this paper facilitatory effects of single-pulse TMS and repetitive TMS on a simple picture naming task are presented. A significant shortening of picture naming latencies was observed after single-pulse TMS over Wernicke's area. The accuracy of the response was not affected by this speed effect. After TMS over the dominant motor cortex or over the non-dominant temporal lobe, however, no facilitation of picture naming was observed. In the rTMS experiments only rTMS of Wernicke\u2019s area had an impact on picture naming latencies resulting in a shortening of naming latencies without affecting the accuracy of the response. rTMS over the visual cortex, Broca's area or over the corresponding sites in the non-dominant hemisphere had no effect. Single-pulse TMS is able to facilitate lexical processes due to a general preactivation of language-related neuronal networks when delivered over Wernicke's area. Repetitive transcranial magnetic stimulation over Wernicke\u2019s area also leads to a brief facilitation of picture naming possibly by shortening linguistic processing time. Whether TMS or rTMS can be used to aid linguistic therapy in the rehabilitation phase of aphasic patients should be subject of further investigations."}
+{"text": "Overall Abstract: Schizophrenia is associated with a reduced life expectancy of 15\u201320 years due to a high prevalence of cardiovascular disease and metabolic syndrome. Unhealthy lifestyles and pharmacological side effects have been suggested to be a major cause of excess mortality rates in patients with psychotic disorders. However, abnormal glucose homeostasis, hyperinsulinemia and accumulation of visceral fat are already detected in drug-na\u00efve first episode psychosis (FEP) patients, independently of obesity.The aim of this symposium is to present the latest research on the theme of metabolic co-morbidities in psychotic disorders. Preliminary and published data from the symposium speakers suggests that FEP is associated with altered composition of gut microbiota, inflammation and lipid dysregulation including changes in the endocannabinoid system in the central nervous system. The studies presented in this symposium may offer new insights into the gut-brain axis in psychotic disorders as well as provide new evidence on the role of lipids as a potential underlying link between the aetiology of psychosis and the associated metabolic disturbances.All four speakers are principal investigators in the European FP7 project METSY, which aims to identify and evaluate multi-modal peripheral and neuroimaging markers that can predict and monitor psychotic and metabolic symptoms, with specific focus on metabolic co-morbidities in psychotic disorders.Oliver Howes will first introduce the topic, based on his recent meta-analysis  as well as present his recent research on neuroimaging of the endocannabinoid system in FEP.Jaana Suvisaari will present her recent research on gut microbiome and inflammation in FEP. The findings so far suggest that FEP patients have specifically altered gut microbiome composition and increased levels of inflammation.Tuulia Hy\u00f6tyl\u00e4inen will introduce the field of metabolomics in psychosis research and discuss the latest findings from at-risk mental state individuals and FEP patients. Recently published findings suggest that FEP patients who later rapidly gain weight are characterised by increased markers of liver fat at the baseline.Jarmo Hietala will present neuroimaging studies of the endocannabinoid system using PET and the [18F]FMPEP-d2 tracer, a CB1R radioligand. These studies suggest a major sex difference in the brain CB1 receptor system as well as clear evidence for a dysregulated endocannabinoid system in first-episode psychosis.Given the endocannabinoid system in the periphery promotes the development of fatty liver, the presented work together suggests that the endocannabinoid system may be the underlying link between the psychosis and the associated metabolic disturbances. This intriguing possibility with potential diagnostic and therapeutic implications will be discussed by the presenters. The discussant Matej Oresic is the coordinator of the METSY project."}
+{"text": "Proteasome inhibitors have distinct properties and the biochemical consequences of suppressing ubiquitin E1 enzymes and the proteasome differ. We compared the effects of the proteasome inhibitors bortezomib, ixazomib and carfilzomib and the ubiquitin E1 enzyme inhibitor MLN7243/TAK-243 on cell viability and cell death in normal keratinocytes and cutaneous squamous cell carcinoma (cSCC) cell lines. The effects of both a pulse of treatment and more extended incubation were investigated. This is relevant to directly-delivered therapy  where the time of exposure can be controlled and a short exposure may better reflect systemically-delivered inhibitor pharmacokinetics. These agents can selectively kill cSCC cells but there are variations in the pattern of cSCC cell line sensitivity/resistance. Variations in the responses to proteasome inhibitors are associated with differences in the specificity of the inhibitors for the three proteolytic activities of the proteasome. There is greater selectivity for killing cSCC cells compared to normal keratinocytes with a pulse of proteasome inhibitor treatment than with a more extended exposure. We provide evidence that c-MYC-dependent NOXA upregulation confers susceptibility to a short incubation with proteasome inhibitors by priming cSCC cells for rapid BAK-dependent death. We observed that bortezomib-resistant cSCC cells can be sensitive to MLN7243-induced death. Low expression of the ubiquitin E1 UBA1/UBE1 participates in conferring susceptibility to MLN7243 by increasing sensitivity to MLN7243-mediated attenuation of ubiquitination. This study supports further investigation of the potential of proteasome and ubiquitin E1 inhibition for cSCC therapy. Direct delivery of inhibitors could facilitate adequate exposure of skin cancers. Cutaneous squamous cell carcinoma (cSCC) causes significant mortality and morbidity in the general population . In addiUbiquitination regulates protein stability, activity, association and localization , 7. ThisThe proteasome inhibitor bortezomib has been widely used to treat patients with multiple myeloma. Two additional proteasome inhibitors: ixazomib and carfilzomib have recently been approved for multiple myeloma therapy. These agents differ in their affinity for inhibition of the individual proteolytic activities of the proteasome and/or in their reversibility. The importance of these differences in influencing the therapeutic efficacy of these inhibitors is not fully understood. At low concentrations all of these compounds inhibit the chymotrypsin-like activity of the proteasome. Bortezomib and ixazomib inhibit the caspase-like activity at moderately high concentrations and the trypsin-like activity at high concentrations . ModeratAn alternative way of targeting the core ubiquitin-proteasome system is to inhibit the ubiquitin E1 enzymes . BlockinThe therapeutic potential for cSCC of targeting the ubiquitin-proteasome system has not been adequately explored. Furthermore, the anti-tumour activity and the degree of tumour selectivity of proteasome and ubiquitin E1 inhibition have not been compared for any cancer type. It is common in pre-clinical investigations to determine the effect of extended exposure to proteasome inhibitors on the viability of cultured cells. It is relevant for directly-delivered therapy to assess the effects of different times of tumour treatment. It may also better model systemically-delivered inhibitor pharmacokinetics to investigate the consequences of a shorter pulse of inhibitor treatment -24, 39. We investigated whether there were differences in responses to the proteasome inhibitors bortezomib, ixazomib and carfilzomib and the ubiquitin E1 inhibitor MLN7243. The effects of these agents were assessed in untransformed normal keratinocytes from an RDEB patient (RDEBK), normal human keratinocytes (NHK) and eight cSCC-derived cell lines. cSCCs arise from the malignant transformation of keratinocytes in the epidermis. Keratinocytes constitute over 90% of cells within this layer of the skin. It is consequently appropriate to include keratinocytes in the study as the cell of cSCC origin and a major normal cell type that would be exposed to locally-delivered therapy. Measurement of the proteolytic activities of the proteasome verified target suppression by proteasome inhibitors Figure . In addiClonogenic assays indicated that a 6 to 8-hour treatment with the inhibitors was required for efficient anti-cSCC activity . To compWith continuous exposure to bortezomib there was little selectivity for cSCC compared to untransformed keratinocytes Figure . HoweverThe general pattern of ixazomib susceptibility in normal keratinocytes and representative cSCC cell lines was similar to that of bortezomib . Under tCarfilzomib was more generally selective for killing cSCC cells compared to normal keratinocytes than the other agents tested Figure . The cSCThe ubiquitin E1 inhibitor MLN7243 selectively killed a subset of cSCC lines . In bortezomib-sensitive SCCRDEB4 and SCCIC1 cells siRNA-mediated depletion of c-MYC and the pro-apoptotic proteins NOXA and BAK was found to attenuate cell death in response to a pulse of bortezomib Figure . BAK is Basal expression of c-MYC and NOXA was low in bortezomib-resistant normal keratinocytes and SCCIC1Met cells and BAK levels were low in the bortezomib-resistant SCCRDEBMet cell line Figure . Low expc-MYC/NOXA/BAK also contribute to promoting rapid cell death in response to a pulse of carfilzomib treatment in bortezomib-sensitive cSCC cells . In carfTo identify determinants of sensitivity to MLN7243 the protein expression of the ubiquitin E1 UBA1 was compared in the panel of cells used in this study Figure . Two majKnockdown of UBA1 did not greatly alter the pattern of bulk high molecular weight ubiquitin conjugates in cSCC cells, even in the SCCRDEBMet line which expresses the lowest endogenous levels of the E1 Figure . In addiWe compared the effects in normal keratinocytes and cSCC cell lines of a long and short treatment with proteasome inhibitors and the ubiquitin E1 inhibitor MLN7243. We show that a pulse of proteasome inhibitor exposure results in greater selectivity for killing cSCC cells than a more extended exposure. In sensitive cSCC cell lines a pulse of bortezomib treatment gives the highest level of selectivity compared to normal keratinocytes but some cSCC cell lines are bortezomib-resistant. These bortezomib-resistant tumour cells can be sensitive to MLN7243. Carfilzomib is more generally cSCC selective than bortezomib or MLN7243. We provide evidence that c-MYC, NOXA and BAK are determinants of susceptibility to a pulse of proteasome inhibition and that low UBA1 expression confers susceptibility to MLN7243.This study indicates that the cSCC selectivity of a pulse of proteasome inhibitor exposure is related to a differential dependency for survival of sensitive cSCC cells and normal keratinocytes on the proteolytic activities of the proteasome. For example, killing of the most bortezomib-sensitive cSCC cell lines by a short treatment with bortezomib occurs at inhibitor concentrations that markedly attenuate the chymotrypsin and caspase-like activities but only modestly inhibit the trypsin-like activity. In normal keratinocytes death is associated with inhibition of all three activities at high bortezomib concentrations. This suggests that the window of selectivity for cSCC cells compared to normal keratinocytes can be determined by the specificity of inhibitors for the activities of the proteasome. For instance, a small molecule which inhibits the chymotrypsin and caspase-like activities without substantially inhibiting the trypsin-like activity may show even greater selectivity for sensitive cSCC cells than bortezomib. These results are consistent with the previous finding that inhibition of different individual proteolytic activities and combinations of proteolytic activities of the proteasome results in distinct degrees of interference with protein degradation , 16. TheWe observed that concentrations of bortezomib and carfilzomib that kill cSCC cell lines have divergent effects on the proteolytic activities of the proteasome. Variations in the extent to which cellular pathways are affected due to these differences in proteasome inhibition may underlie the greater cSCC selectivity of continuous exposure to carfilzomib and the ability of a pulse of carfilzomib to kill cSCC cells resistant to a short treatment with bortezomib. Consistent with this, our study indicates that a pulse of carfilzomib can induce cell death by different mechanisms in bortezomib-resistant and bortezomib-sensitive cells. Differences in the mechanisms through which distinct proteasome inhibitors kill cells have been observed previously .NOXA transcription. Upregulation of basal NOXA mRNA expression by elevated c-MYC could contribute to fast protein accumulation upon inhibition of the proteasomal degradation of NOXA. Proteasome inhibition also increases c-MYC transcriptional activity towards the NOXA gene [c-MYC, NOXA and BAK promote cell death in response to an extended exposure to bortezomib in a number of cancer types , 62, 63.OXA gene , 57, 68.The pattern of sensitivity of cSCC cells to ubiquitin E1 inhibition is different from proteasome inhibitors. The two cSCC cell lines most resistant to a pulse of bortezomib are among the most sensitive to MLN7243-induced cell death. We observed that low expression of both UBA1A and B isoforms is associated with MLN7243 sensitivity and high expression of UBA1A with MLN7243 resistance. Furthermore, knockdown of UBA1A and B confers MLN7243 sensitivity to resistant cSCC cells. MLN7243-induced cell death is associated with a reduction in the level of ubiquitin conjugates. A lower concentration of MLN7243 is required to diminish ubiquitination in cSCC cells with low UBA1 expression. UBA1 protein levels may thus provide a marker for tumour sensitivity to MLN7243. It would be of great interest to determine the mechanisms responsible for the observed differences in UBA1A and B expression. A better understanding of how levels of UBA1 isoforms are regulated could lead to the development of therapeutic interventions that modulate their expression. This may provide a means to enhance tumour sensitivity or increase the resistance of normal cells to MLN7243. UBA1 and UBA6 are both inhibited by MLN7243. While our study supports a pre-eminent role of UBA1 in determining the sensitivity of cSCC cells to MLN7243 under some circumstances suppression of UBA6 could contribute to the anti-tumour activity of this inhibitor. UBA6 can play a non-redundant role in maintaining cell viability , 69.A high degree of E1 suppression is required to reduce bulk high molecular weight ubiquitin conjugates in the cSCC cell lines examined. This indicates that the ubiquitin E1s are not normally rate-limiting for these ubiquitination events. This is consistent with previous studies . UBA1 isThis study indicates that there is therapeutic potential for proteasome and UBA1 inhibition for cSCC. Future work could initially be aimed at developing direct delivery of inhibitors to tumours. This would overcome limitations of systemic delivery and allow optimal exposure of cSCCs. Effective directly-delivered therapy would be of benefit to cSCC patients and it would inform systemic therapy for treating cSCC and other solid tumours.2 in a humidified atmosphere in keratinocyte medium containing 10% serum and growth factors [Normal keratinocytes (NHK and RDEBK) and cSCC cell lines were isolated and maintained as described , 72. Cel factors . cSCC ce factors . SCCIC1/Inhibitors were dissolved in DMSO (20 to 50 mM stocks). Unless otherwise indicated cells were treated with inhibitors 16 to 24 hours after plating. Compounds used in this study were: bortezomib , carfilzomib , ixazomib (S2180: Selleckchem) and MLN7243 .Dharmacon ON-TARGETplus modified siRNAs  were used in this work and are listed in Cells were seeded into 96 well plates and live cell number and cell death were analysed according to the manufacturers\u2019 instructions with an IncuCyte ZOOM real-time imager  using the CellTox Green Cytotoxicity Assay . Relative EC50 values were determined using GraphPad Prism . For clonogenic assays cells were seeded into six well plates. Inhibitors were added for the indicated times and then cells were maintained in drug-free medium for up to 2 weeks to allow colony formation. Colonies were fixed in 10% methanol, 10% acetic acid and stained with crystal violet.The statistical significance of differences between two groups (control and targeting siRNA) was determined using a one tailed T-test.The three proteolytic activities of the proteasome were measured in parallel in cells seeded in 96 well plates using the Cell-Based Proteasome-Glo Assay (G1180: Promega). Medium from wells containing no cells was used as a blank.The primary antibodies used are listed in"}
+{"text": "Epilepsy is a group of neurological syndromes characterized by the occurrence of recurrent spontaneous seizures . These aEpileptogenesis is associated with large-scale changes in protein expression which contribute to hyperexcitability-promoting alterations in neuronal networks and synaptic transmission . While mThe ubiquitin proteasome system (UPS) is highly conserved among different species and is the principal intracellular pathway leading to the clearance of short-lived, aberrant and/or misfolded proteins. The UPS consists of two separate steps including protein labeling via polyubiquitination and the subsequent degradation of polyubiquitinated proteins by the proteasome . An impaPrevious studies suggest UPS function is also altered in epilepsy and there is in vitro evidence that increased neuronal activity interferes with a correct functioning of the proteasome . The immThere was another notable observation in our study. UPS impairment was first evident in the principal excitatory neurons of the hippocampus. However, UPS inhibition emerged in astrocytes at later stages . We do nSeveral conclusions can be drawn from our studies. (1) An impairment of the UPS possibly contributes to changes in the proteome following seizures and during epilepsy. (ii) UPS inhibition is dependent on cell type and brain area affected. (iii) UPS inhibition may be beneficial at a certain range, (iv) seizures are a frequent co-morbidity among other brain diseases, therefore the observed UPS impairment in these diseases might be in part due to increased hyperexcitability states, and (v), finally, the identification of proteins showing a reduction in their UPS-dependent degradation during seizures might lead to the discovery of new drug targets for epilepsy.Our findings represent key steps in identifying the exact role the UPS carries out during seizures and epilepsy and helps point toward UPS-targeting drugs as potential novel treatments for epilepsy. Several unanswered questions remain, critical to further determine the therapeutic potential of UPS interference during epilepsy.What are the molecules that accumulate during UPS inhibition after seizures and do these differ between acute and chronic stages? Second, proteasome inhibition was only effective at a specific dose. What is the exact dose window to protect the brain and when does it become neurotoxic? Last, does proteasome inhibition benefit or harm the epileptic brain?In conclusion, inhibition of proteasome function may constitute an endogenous protective mechanism in the setting of prolonged seizures. While it is unlikely that UPS-interfering drugs will be used in the future to treat epilepsy, identifying proteins which are regulated by the proteasome during seizures may represent new drug targets to protect the brain from seizure-induced damage."}
+{"text": "Here, we analyzed a Xenopus model of conversion of melanocytes to a metastatic-like phenotype only previously observed in an all-or-none manner. Prior in vivo genetic and pharmacological experiments showed that individual animals either fully convert or remain normal, at some characteristic frequency after a given perturbation. We developed a Machine Learning method which inferred a model explaining this complex, stochastic all-or-none dataset. We then used this model to ask how a new phenotype could be generated: animals in which only some of the melanocytes converted. Systematically performing in silico perturbations, the model predicted that a combination of altanserin (5HTR2 inhibitor), reserpine (VMAT inhibitor), and VP16-XlCreb1 (constitutively active CREB) would break the all-or-none concordance. Remarkably, applying the predicted combination of three reagents in vivo revealed precisely the expected novel outcome, resulting in partial conversion of melanocytes within individuals. This work demonstrates the capability of automated analysis of dynamic models of signaling networks to discover novel phenotypes and predictively identify specific manipulations that can reach them.Progress in regenerative medicine requires reverse-engineering cellular control networks to infer perturbations with desired systems-level outcomes. Such dynamic models allow phenotypic predictions for novel perturbations to be rapidly assessed  One of the key areas in which artificial intelligence and the information sciences can contribute to biology is by helping human scientists understand cellular behavior in the context of a complex organism1345678Xenopus embryos, so-called instructor cells, results in a metastatic-like conversion of normal melanocytes2223The coordination of cellular behavior towards the anatomical needs of the host organism, and away from tumorigenesis, is achieved in part via bioelectrical communication among many cell types131415161718Xenopus depolarizes cells bearing the GlyR channel20in vivo). Each animal is either fully covered with the ectopic, highly-arborized melanocytes, or it looks completely normal , the incidence of conversion from a depolarization treatment  or a completely converted phenotype  (We employed a stochastic model of the regulation of melanocyte conversion in vessels) . Interesin silico all possible experiments involving the application of up to three reagents, for a total of 576 different experiments, each repeated 100 times. in vivo. The results show that all except one experiment (red arrow) are below the 0.1 threshold to an extreme phenotype . The experiment above the 0.1 threshold indicates an intermediate phenotype between the previously observed wild-type normal pigmentation and the converted phenotype . This phenotype is predicted by the inferred model to result from a combined application of altanserin (an R2 inhibitor), reserpine (a VMAT inhibitor), and VP16-XlCreb1 (constitutively active CREB).We then performed in silico the dynamic characteristics of the predicted partially converted phenotype with the inferred model using the combined application of the drugs altanserin and reserpine, and constitutively active CREB. We first investigated in vivoThe \u201cpartially converted\u201d attractor (green dot) was not observed in any previous simulation or experiment The effects of the three reagents in the treatment can be observed in the temporal dynamics of the level of conversion and pathway components targeted by the drugs . Embryosin vivo the newly discovered combination of reagents. Control embryos exposed to vehicle alone were 99% normal 21not due to mosaic expression of the CREB construct, as injected alone, in one cell of the 32-cell stage embryos as above, causes an incidence of ~45% complete conversion. The model predicted the wild-type phenotype within 1% (24% in vivo vs 25% in silico), yet it aggregated the partially and fully converted phenotypes observed in vivo  into a single partial phenotype . This difference in the frequency of partial and fully converted phenotypes between the in silico and in vivo results may be explained by the lack of time information in the training dataset and the observed dynamics of the system  changes of the phenotypes predicted by the model. Indeed, the training dataset does not contain any time information, and hence the current system does not yet capture realistic timing, which would allow a finer-course analysis of trajectories and comparison with in vivo results; in future work we will extend this platform to include time-series data, so that these transient phenotypes can be better investigated.We validated these predictions e system  and 4. Iin vivo.Identification of interventions that alter system-level physiology or pattern formation is a crucial nascent field with many implications for biomedicine32Xenopus embryos were maintained according to standard protocolsXenopus embryos were staged according to Nieuwkoop and FaberXenopus embryos were approved by the Institutional Animal Care and Use Committees (IACUC) and Tufts University Department of Laboratory Animal Medicine under protocol M2014-79. All experiments were performed in accordance with relevant guidelines and regulations. Although we have not observed light to make any difference to the converted phenotype, all groups were subjected to the same light conditions.Embryos were injected with mRNA encoding constitutively active CREB  represents a Gaussian random noise of zero mean):The following set of differential equations, including all the kinetic parameters, define the complete model : either normal (pigmentation level 0) or high level (pigmentation level 1) of melanocyte conversion, never an intermediate level as described in ref. This set of equations (defined in the model) together with a set of initial conditions of the signaling products (defined in the model) and the drugs (defined in the experiment) form an initial value problem which is then numerically solved until reaching a steady state. Due to the stochastic nature of the equations, different runs with the same initial conditions (same experiment) can result in different phenotypic outcomes (level of melanocyte conversion) as observed in silico with the model and in vivo with Xenopus experiments, we defined a distance metric for simulated phenotypes obtained with the model. The metric quantifies the level of intermediate conversion obtained in a set of resultant in silico phenotypes simulated with the model for a specific experiment (combination of reagents). The distance metric is defined with the following equation:To discover phenotypes different from the two extreme levels of conversion  previously observed d(E) is the mean distance of experiment E (a combination of reagents) when simulated 100 times with the model and resulting in phenotypes with level of conversion pi .where How to cite this article: Lobo, D. et al. Discovering novel phenotypes with automatically inferred dynamic models: a partial melanocyte conversion in Xenopus. Sci. Rep.7, 41339; doi: 10.1038/srep41339 (2017).Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations."}
+{"text": "A patient who suffered a transient global amnesia (TGA) attack underwent regional cerebral blood flow (rCBF) SPECT imaging and neuropsychological testing in the acute phase, after one month and after one year. Neuropsychological testing in the acute phase showed a pattern of anterograde and retrograde amnesia, whereas memory was within age normal limits at follow up. SPECT data were analysed with a within subject comparison and also compared with those of a group of healthy controls. Within subject comparison between the one month follow up and the acute phase detected increases in rCBF in the hippocampus bilaterally; further rCBF increases in the right hippocampus were detected after one year. Compared to controls, significant hypoperfusion was found in the right precentral, cingulate and medial frontal gyri in the acute phase; after one month significant hypoperfusion was detected in the right precentral and cingulate gyri and the left postcentral gyrus; after one year no significant hypoperfusion appeared. The restoration of memory was paralleled by rCBF increases in the hippocampus and fronto-limbic-parietal cortex; after one year neither significant rCBF differences nor cognitive deficits were detectable. In conclusion, these data indicate that TGA had no long lasting cognitive and neural alterations in this patient."}
+{"text": "To challenge and refine these models using a structure-based approach we set out to investigate how human cathelicidin (LL-37) and dermcidin (DCD) interact with membranes. Both peptides are \u03b1-helical and their structures have been solved at atomic resolution. DCD assembles in solution into a hexameric pre-channel complex before the actual membrane targeting and integration step can occur, and the complex follows a deviation of the barrel stave model. LL-37 interacts with lipids and shows the formation of oligomers generating fibril-like supramolecular structures on membranes. LL-37 further assembles into transmembrane pores with yet unknown structure expressing a deviation of the toroidal pore model. Both of their specific targeting mechanisms will be discussed in the context of the \u201cold\u201d models propagated in the literature.Mammals protect themselves from inflammation triggered by microorganisms through secretion of antimicrobial peptides (AMPs). One mechanism by which AMPs kill bacterial cells is perforating their membranes. Membrane interactions and pore formation were investigated for \u03b1-helical AMPs leading to the formulation of three basic mechanistic models: the barrel stave, toroidal, and carpet model. One major drawback of these models is their simplicity. They do not reflect the real  Antimicrobial peptides evolved during an early stage of the mammalian evolution and represent ancient molecules optimized through their co-evolution with bacteria . In the absence of detergents, LL-37 forms an anti-parallel dimer similar to the structure of magainin, mellitin, or the antiparallel dimer of DCD Figure . One of Which model mechanism comes closest to the most recent Figure  LL-37 dain vivo in the context of bacterial cell walls are even more complex, and future work needs to initiate studies on the direct interactions of AMPs with the bacterial cell.The growing number of AMPs from many sources forms a solid basis for the development of new antibiotics. This process can be enhanced once their individual mechanisms of action are understood in more detail. Here we show that for two human AMPs their membrane interactions are sophisticated multi-step pathways which deviate from the three simple model mechanisms. Although, our own work has mainly delivered indirect insights based on AMP interactions with detergents and lipids it creates significant improvement of our understanding how DCD and LL-37 target artificial membranes. Together these data represent one critical step forward toward their full mechanistic understanding. However, there is no doubt that true mechanisms Why has the long DCD channel version, with physical dimensions significantly longer than required for spanning an average membrane thickness been retained?How a negatively charged peptide like DCD would interact with an outermost LPS or LTA leaflet layer and how would it pass this layer?What is the mechanism by which DCD is translocated over the cell wall of Gram-negative bacteria?DCD and LL-37 are only two selected examples of AMPs, and such do not represent the broadness of mechanisms of how AMPs perturb bacterial membranes. In spite of their improved understanding, general questions remain unanswered e.g.:How this peptide interacts with LPS and LTA, and if these molecules are extracted from the membrane to gain access to the cell?What is the reason for fiber formation of LL-37 and other AMPs on artificial membranes, and are these fibers also formed on natural membranes?in vivo.Finally, it will be important to test if the detergent binding sites we see in our structures actually resemble lipid binding sites The ultimate step of LL-37 forming pores in membranes and the putative involvement of lipids remains to be shown.LL-37 activity and killing mechanisms also harbors many secrets e.g.:All authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "A recent study analyzed the variation in firing rates among neurons of the monkey brain in response to a large set of humanoid face images  psychometric face identity space, testing neurons with monotonic response profiles, but at no point establishes a null hypothesis; i.e., what conditions or stimulus manipulations would result in poor decoding/encoding performance? If another linear space was created via the same process but with round fruits as the input images rather than faces, would we expect a different pattern of responses from face-selective neurons? Is a different pattern even possible when using such a high-dimensional space? Why would face identity decoding benefit from pooling neurons' responses across two monkey brains?Variations in the firing rate of face-selective neurons to images of different individual faces has long been reported in the monkey infero-temporal (IT) cortex, with population coding proposed as a mechanism for the recognition of individual faces  to reach above chance performance at discriminating individual conspecific faces (Parr et al., If monkeys lack human-like expertise at individual face recognition, why would variations in single neuron spike rates in their brain successfully decode human faces? This issue concerns both the limitations of anatomico-functional brain homologies across species, and the interpretation of a classifier performance. In humans, the cortical face network is primarily located in the ventral occipito-temporal cortex (VOTC; Rossion et al., In summary, the recently reported study (Chang and Tsao, All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "We report the case of a 23-year-old male who suffered localised testicular infarction and rupture following blunt trauma. This pathology is rare after blunt trauma and has not been previously described in literature. The appearance on ultrasound resembled malignancy, necessitating orchidectomy. An overview of the pathology of testicular trauma as well as its management is given with particular emphasis on the use diagnostic ultrasound in testicular trauma."}
+{"text": "This image based series comprises of a quiz pertaining to the identification of salient anatomical structures expected to be seen at a given level on the computed tomography (CT) followed by examples of multiple representative pathologies that can be seen at the same level in a routine clinical setting. It is expected that this will improve confidence of nuclear physicians in interpretation of the CT component of the single photon emission computed tomography (SPECT) and positron emission tomography (PET) studies. POINTS TO REMEMBERth/5th intervertebral disk space.- Tracheal bifurcation (carina) is an important landmark in sectional imaging of the chest and is approximately at the level of 4- Main pulmonary trunk bifurcates into the right and left pulmonary arteries at this level with right artery larger than the left.- Ascending and descending thoracic aorta, oesophagus and superior vena cava are the other structures that are always seen at this level.AnswerThe image is just below the level of tracheal bifurcation (carina) which anatomically corresponds to the level of T4/T5 intervertebral disc space posteriorly and manubriosternal junction .A: Ascending aortaB: Main pulmonary trunkC: Descending thoracic aortaD: Superior vena cavaE: Left main bronchusF: Left pulmonary arteryG: SternumH: Rib"}
+{"text": "The aim of this report is to identify the radiological findings of unilateral tuberculous lung destruction (UTLD).Thirteen patients with (UTLD) were reviewed from 1999 to 2014. Only patients with radiological evidence of absence of pulmonary parenchyma preserved were included. Clinical and demographic data were obtained and radiological studies (chest radiograph and CT) were retrospectively reviewed.The left lung was more commonly involved (85%). The following radiological findings were found in all cases: a decrease in the diameter of the pulmonary vessels of the affected lung, herniation of the contralateral lung and hypertrophy of the ribs and/or thickening of extrapleural fat. Two radiological patterns were identified: UTLD with cystic bronchiectasis (85%) and UTLD without residual cystic bronchiectasis (15%). Forty-six per cent of cases had respiratory infection symptoms with presence of air-fluid levels in the affected lung as the most common finding in these patients.Total unilateral post-tuberculous lung destruction is an irreversible complication with the following main radiological features: predominantly left-sided location, decreases in the diameter of the ipsilateral pulmonary vessels, herniation of the contralateral lung and hypertrophy of the ribs and/or thickening of extrapleural fat.Unilateral tuberculous lung destruction is an irreversible complication of tuberculosis.\u2022 Left-side predominance and herniation of the contralateral lung are characteristic.\u2022 Decreased diameter of the ipsilateral pulmonary vessels occurred in all patients.\u2022 The pattern with residual cystic bronchiectasis is the most frequent.\u2022 Superimposed non-tuberculous infections may affect the destroyed lung.\u2022  Tuberculosis (TB) remains one of the world\u2019s deadliest communicable diseases. In 2014, an estimated 9.6 million people developed TB and 1.5 million died from the disease  andIn this report, we present a review of 13 patients with UTLD secondary to TB attended in our centre, with the aim of describing the radiological findings in radiograph and chest CT of this late and uncommon complication of TB.TUTLD is a late complication that requires years to develop; so it is difficult to estimate the influence of other superimposed nontuberculosus infections and to assemble a large sample or perform a prospective study with significant data. However, for this review article we were able to collect these cases to discuss the typical findings of UTLD against the background of findings in patients of our own department. This instructive patient sample was not obtained from a database containing all tuberculosis cases occurring in the study period; therefore the incidence of this complication in our setting will not be discussed in detail.Among the 13 patients comprising the series, there was a male predominance  and the age range was 27 to 83\u00a0years (mean 55\u00a0years). All the patients were diagnosed with chest tuberculosis during childhood or youth. Two patients were from countries with a higher incidence of TB than Spain [Regarding symptomatology in these patients, most of them presented with dyspnoea or a respiratory infection event. One patient showed self-limited haemoptysis probably related to the existence of bronchiectasis.With regard to the anti-TB treatment received, it was not collected in the clinical records of five patients and available for the nine patients remaining. Three patients were treated with collapse therapy, which could have promoted the lung destruction. Tuberculous reactivation was treated with medical treatment in one patient. The remaining five patients  were treated with anti-TB drugs with tuberculous reactivation in one case treated again with drugs.Four patients were diagnosed with chronic obstructive pulmonary disease (COPD) . The relationship between TB and COPD is well recognised and can increase with age . The meaPA chest X-ray showed diffuse opacity of a whole hemithorax with severe ipsilateral mediastinal deviation, mimicking an almost complete lung collapse, in one case. The remaining 12 patients presented with a small hemithorax with aireated lung secondary to contralateral lung herniation and/or cystic bronchiectasis or cavitated lesions. Lateral projection showed retrosternal hyperclarity in all patients in relation to the existence of lung herniation contralateral to the UTLD.On retrospective review of the CT, the patients were classifiable in two main patterns: unilateral lung destruction with residual cystic bronchiectasis 11/13, 85%) , Streptococcus pneumoniae  and Haemophilus influenzae .Six patients  had symptoms consistent with respiratory infection (fever and expectoration), and four showed the following radiographic findings: pulmonary air-fluid levels , pulmonary air-fluid levels and mucus impaction  Fig.\u00a0 and centPseudomonas aeruginosa, Streptococcus pneumoniae, and Haemophilus influenza) are consistent with the findings from a prospective study in hospitalised patients with acute COPD exacerbations [Tuberculosis infection tends to be inactive in cases of lung destruction, making the diagnosis more difficult. The microbiological study of secretions often shows other microorganisms , which mrbations  and simirbations . All COPrbations .In patients treated in our hospital, we observed two radiological patterns: unilateral destruction with cystic bronchiectasis and unilateral destruction without cystic bronchiectasis. All patients with superinfections signs had the total destruction with cystic bronchiectasis pattern. Therefore, the pattern of lung destruction with cystic bronchiectasis is associated with the highest risk of superinfection.The contralateral lung in post-tuberculous lung destruction showed residual lesions, such as bronchiectasis Fig.\u00a0, bronchiThe diagnosis of this entity is straightforward if the previous history of TB is clear and well documented on clinical records. When radiological findings consistent with lung destruction are seen, we should consider any granulomatous disease. Similar features can be observed in some types of mycosis, although the fibrosis and mediastinal displacement are never as severe as in TB . The difSeveral papers in the medical literature describe surgical treatment of the UTLD by means of pneumonectomy in certain cases, though this treatment is considered high risk , 22\u201324. In our daily practice all patients were incidentally diagnosed as a consequence of signs and symptoms of respiratory infection or dyspnoea. Due to the appearance of infections in these patients an imaging examination may be necessary for the diagnosis.In conclusion, UTLD is an irreversible complication of pulmonary TB that presents with characteristic radiological findings: unilateral volume loss predominantly in the left lung, decreased diameter of the ipsilateral main pulmonary artery and pulmonary veins, and herniation of the contralateral pulmonary parenchyma. The pattern with residual cystic bronchiectasis is the most frequent. Usually the tuberculous infection is inactive, although associated non-tuberculosis infection may develop and affect the destroyed lung. Therefore, a correct diagnosis and radiological follow-up are very important in these patients."}
+{"text": "The increasing adoption of clinical whole-genome resequencing (WGS) demands for highly accurate and reproducible variant calling (VC) methods. The observed discordance between state-of-the-art VC pipelines, however, indicates that the current practice still suffers from non-negligible numbers of false positive and negative SNV and INDEL calls that were shown to be enriched among discordant calls but also in genomic regions with low sequence complexity.Here, we describe our method ReliableGenome (RG) for partitioning genomes into high and low concordance regions with respect to a set of surveyed VC pipelines. Our method combines call sets derived by multiple pipelines from arbitrary numbers of datasets and interpolates expected concordance for genomic regions without data. By applying RG to 219 deep human WGS datasets, we demonstrate that VC concordance depends predominantly on genomic context rather than the actual sequencing data which manifests in high recurrence of regions that can/cannot be reliably genotyped by a single method. This enables the application of pre-computed regions to other data created with comparable sequencing technology and software. RG outperforms comparable efforts in predicting VC concordance and false positive calls in low-concordance regions which underlines its usefulness for variant filtering, annotation and prioritization. RG allows focusing resource-intensive algorithms  on the smaller, discordant share of the genome (20\u201330%) which might result in increased overall accuracy at reasonable costs. Our method and analysis of discordant calls may further be useful for development, benchmarking and optimization of VC algorithms and for the relative comparison of call sets between different studies/pipelines.https://github.com/popitsch/wtchg-rg/.RG was implemented in Java, source code and binaries are freely available for non-commercial use at Bioinformatics online. Whole-genome resequencing (WGS) allows researchers to address a broad range of clinical and research questions at comparably low costs and with short turnaround times. For these reasons it is quickly becoming a central tool for genomic medicine and the accurate calling of small variants  from WGS data plays a central role in most analyses. The currently observed amount of discordant variant calls between different state-of-the-art variant calling (VC) pipelines, however, indicates that the current practice still suffers from non-negligible numbers of false positives and negatives .It was shown that false positives and negatives are strongly enriched among calls that are discordant between different VC pipelines as these are often a consequence of imperfect data interpretation by the applied bioinformatics pipelines .a priori saves the effort of analysing every WGS dataset with multiple pipelines. Instead, one may either consider only the (reliable) calls in concordant regions for downstream analysis or alternatively concentrate additional efforts  solely on the small discordant fraction of the genome, thereby significantly reducing analysis and validation costs and times. Additionally, comparisons between datasets/studies would become easier and more reproducible if restricted only to variants in concordant regions. Above all, however, it would allow us to study recurrent regions of discordance in greater detail with the ultimate goal of uncovering the underlying causes for VC artefacts therein  if the called genotypes did not match or if some call sets l bases up-and downstream overlap between the different call sets, cf. l\u2009=\u20095 in this study.For each such position we compare all called genotypes (in the VCF GT field) and write a merged variant call to a new joined VCF file iJ are the input to the second stage of our algorithm that calculates a concordance score ps for each polymorphic position p in the input call sets The joined call sets iJ at this genomic position p and kp from the ordered set of all polymorphic positions in x\u2009=\u20091000 in this study). If the upstream polymorphic position kp, otherwise we interpolate between kp with the score ct and dt respectively. A more detailed description of the individual algorithmic steps and their implementation is given in the Supplement. We evaluated our approach by calculating a set of concordant regions from N\u2009=\u2009219 WGS datasets that were subjected to M\u2009=\u20093 different VC pipelines using samtools  of concordant and discordant regions that covers the whole genome.In a subsequent step, the concordance scores for all other genomic position  and then calculated an alternative genomic partition from 34 independent WGS datasets that were used as ground truth set in this experiment. These 34 datasets were mapped with a different read mapper but variants were called using the same VC pipelines as for the RG set (see Supplement for more details). We then measured how well we could predict concordant/discordant variant calls in these data using our genomic partition RG as well as four comparable sets of genomic regions that were proposed for filtering variants, namely the \u2018reliable regions\u2019 from the Genome-In-A-Bottle project , a set of low-complexity regions that was recently suggested for variant filtering . We also derived a set LCR100 by extending each low complexity region in LCR by 100bp upstream and downstream and a set RG-UM75 that combines the two respective partitions. We furthermore created two derived genomic partitions (RG-LCR-HD and RG-LCR100-HD) from our RG set by excluding all LCR or LCR100 regions and all genomic windows that showed high density (HD) of discordant calls. For this, we iterated over all variant calls in our 219 WGS datasets and counted the number of (stretches of) discordant calls that were interrupted by (stretches of) concordant calls within a genomic window that started 1000 bp upstream and ended 1000 bp downstream of the respective call. We then created a genomic partition by merging all such genomic windows that contained at least 10 such counts (see Supplement for further details). The respective genomic coverages of all used genomic partitions are depicted in In the second evaluation experiment, we tried to measure how robustly we can apply a pre-calculated genomic partition to a different cohort and compared the results to similar approaches. For this, we first calculated a genome-wide genomic partition from all 219 WGS datasets mentioned above  than most other approaches  and negative prediction value (NPV) in ches cf. .RG-derived partitions clearly outperform all other partitions in this evaluation, reaching LCR, HD and/or UM75 regions are subtracted.In our final evaluation experiment, we measured the performance of our genomic partition for predicting potential false positives/sequence artefacts. Following along the lines of Finally, we comprehensively analysed all variant positions that we found in the 219 WGS datasets by calculating various statistics and present the results in the Supplement. Although germline variant calling is considered a solved problem by many, researchers still observe low overlap between different state-of-the-art VC pipelines and tools. This discordance between different methods not only hinders data comparison, integration and reproducibility; it also indicates non-negligible numbers of false positives and negatives that are introduced due to differing interpretation of sequencing data by current VC pipelines. This stands in contrast to the increasing demands for highly accurate and reproducible VC sets from WGS experiments, in particular in clinical environments . With WGa priori calculation of genomic partitions with high variant calling concordance that can then readily be applied to additional data analysed by the same pipeline. Our method differs from comparable previous efforts in that it incorporates data from many different WGS datasets, thereby capturing more of the data\u2019s variance. It is applicable to arbitrary variant sets  and can thus be used to calculate high-concordance regions in a large range of scenarios. Our evaluation confirmed that our classifier improves with more training data which means that we can expect even higher accuracies when applying RG to larger cohorts such as the recently sequenced set of 10,000 human genomes  and also on the data itself. However, as shown in this study, the influence of the actual sequencing data is much smaller than we initially expected. Also, although not thoroughly evaluated in this study, we found evidence that our genomic partition is quite robust with respect to slightly differing VC pipelines. Experiments 2 and 3 demonstrate that a partition that was derived from a different cohort can be used to accurately predict regions of discordance/unreliable VC in data that were created using different read mapping and variant calling algorithms. This may render RG a useful tool for the comparison and integration of data from different studies that was analysed using various bioinformatic pipelines or even sequencing technologies. Besides applying the same RG partition on data from multiple cohorts, one could also easily intersect RG partitions calculated from the individual cohort data to calculate shared regions of concordance.Genomic partitions such as the one presented in this study allow us to focus on the \u2018hard to call\u2019 fraction of the genome where current VC algorithms are often in disagreement and where false positives and negatives accumulate. This enables the concentration of available resources on the small part of the genome that cannot be confidently genotyped by a single method, e.g. by applying computationally intensive consensus calling algorithms that do not scale to the whole genome  and location-dependent  features. The supplemental analysis of our genomic partition shows that quality values work well yet are not perfect for separating concordant and discordant calls. As we and others showed that false positives are strongly enriched among discordant calls, we conclude that current variant quality values are also limited in filtering those. Augmenting the location-dependent features that are already considered by current quality value calculations, we identified/confirmed several cohort-wide properties  that seem to differ substantially between concordant and discordant variant calls. These features show considerable variance among datasets and neither feature alone seems sufficient for the accurate prediction of concordant of discordant calls. Our method captures this variance by integrating the decisions from multiple algorithms across multiple datasets, and in this regard it is not surprising that it substantially outperforms previous works that were derived from single datasets  or single sequence-dependent features (LCR).Our findings are consistent with previously reported causes for artefacts such as PCR errors, alignment errors in repetitive regions and around INDELs but also the incompleteness of the used reference genome. Actually we expect the fraction of discordant regions to decrease when using the latest version of the human reference genome which would reduce the number of artefacts stemming from copy number variations (CNV) or missing paraloguous sequences, cf. Unannotated copy number variations (CNVs) are another likely source of discordant variants. The used UM75 partition was created by integrating regions of low read mapability and/or low sequence complexity with regions that are enriched with \u2018aberrant\u2019 variant calls. The latter were computed by clustering regions with negative inbreeding coefficients in 1000 Genomes Project phase III data (see Supplement for details). By doing this, UM75 excludes regions that are likely mis-assembled in the human reference genome or are enriched with common CNVs in the 1000G data. Such regions are likely to harbour many false-positives in the experiment 3 data  and UM75 thus complements our genomic partition well as demonstrated by the good results when combining both sets.In this work we presented a first straight-forward method for calculating genomic partitions that are likely to harbour concordant/discordant variant calls in WGS resequencing experiments when applying different VC pipelines. Our method can be applied to arbitrary VC pipelines and the resulting genomic partitions can be used for variant filtering, annotation and prioritization or for focusing computational resources on hard-to-analyse regions of the genome. It may further be useful for the development, benchmarking and optimization of VC algorithms and pipelines with the goal of improving their accuracy and for the relative comparison of VC results across different studies and pipelines. A limitation of the current study is that it was conducted only with deep WGS data from a single sequencing technology and it is yet unclear whether the results are reproducible with other kinds of sequencing data.Possible future work includes the investigation of this matter, the comparison of somatic variant callers (that show even less concordance in current studies, cf. Supplementary DataClick here for additional data file."}
+{"text": "This review will provide a brief overview of the development of the Fv fragment and provide a summary of recent studies using Fv to deliver therapeutic peptides and proteins  to cells.Protein therapy refers to the direct delivery of therapeutic proteins to cells and tissues with the goal of ameliorating or modifying a disease process. Current techniques for delivering proteins across cell membranes include taking advantage of receptor-mediated endocytosis or using protein transduction domains that penetrate directly into cells. The most commonly used protein transduction domains are small cell-penetrating peptides derived from such proteins as the HIV-1 Tat protein. A novel protein transduction domain developed as the single chain fragment (Fv) of a murine anti-DNA autoantibody, mAb 3E10, has recently been developed and used to deliver biologically active proteins to living cells"}
+{"text": "The underlying mechanisms in the development of diabetic nephropathy are currently unclear and likely consist of a series of dynamic events from the early to late stages of the disease. Diabetic nephropathy is currently without curative treatments and it is acknowledged that even the earliest clinical manifestation of nephropathy is preceded by an established morphological renal injury that is in turn preceded by functional and metabolic alterations. An early manifestation of the diabetic kidney is the development of kidney hypoxia that has been acknowledged as a common pathway to nephropathy. There have been reports of altered mitochondrial function in the diabetic kidney such as altered mitophagy, mitochondrial dynamics, uncoupling, and cellular signaling through hypoxia inducible factors and AMP-kinase. These factors are also likely to be intertwined in a complex manner. In this review, we discuss how these pathways are connected to mitochondrial production of reactive oxygen species (ROS) and how they may relate to the development of kidney hypoxia in diabetic nephropathy. From available literature, it is evident that early correction and/or prevention of mitochondrial dysfunction may be pivotal in the prevention and treatment of diabetic nephropathy. Diabetic nephropathy accounts for ~45% of cases with end-stage renal disease  production.+ positively correlates with ROS production in this segment  and reduction grade of the electron transport chain in proximal tubules , the transferring of electrons from complex I to IV is coupled to translocation of protons to the intermembrane space, creating a membrane potential that is utilized by the ATP-synthase to produce ATP. Under normal conditions, ~0.1\u20130.2% of mitochondrial oxygen consumption is due to production of ROS  by Dugan et al. observed decreased superoxide production in intact kidneys of type 1 diabetic mice compared to control mice, also supported by electron paramagnetic resonance data in whole kidney homogenates. The reduced superoxide production was accompanied by hyper-phosphorylation of pyruvate dehydrogenase that contributes to deactivation of the enzyme. This leads to reduced conversion of pyruvate to acetyl coenzyme A and therefore reduced equivalents to the ETS that can reduce oxygen. The AMP-kinase (AMPK) activator 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) restored the observed effects and the authors proposed a feed-forward cycle in which decreased AMPK activity would decrease mitochondrial biogenesis via peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1\u03b1), a cycle that would be initiated and maintained through decreased mitochondrial ROS production  caused increased proton leak with a functionally intact electron transport chain (Galloway et al., The development of diabetic nephropathy is likely to represent a series of dynamic events. Many studies report altered mitochondrial function in the diabetic kidney. These alterations include altered mitophagy, mitochondrial dynamics, mitochondrial uncoupling, and signaling through AMPK and HIF. Herein, we have discussed how these pathways may relate to mitochondrial ROS production in the diabetic kidney. In experimental models, correcting mitochondrial ROS production reduces albuminuria in diabetic mice (Sourris et al., Many of the discussed factors are intertwined in a complex manner, making it very difficult to highlight a specific mechanism in the diabetic kidney. Partly underlying the difficulty of highlighting a specific mechanism is the functional heterogeneity of the kidney. Different segments have different function and surrounding oxygen levels, different levels of the discussed cellular pathways and different sources and levels of ROS production. However, from available literature it seems clear that mitochondrial ROS production may be a joint mechanism. The resulting effects on mitochondrial and cellular pathways affecting oxygen metabolism may play an important role in the development of diabetic nephropathy. For a schematic summary, see Figure TS and MFP both wrote manuscript, viewed the content critically and approved the final submitted version.MFP is supported by the Wenner-Gren Foundations.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "COPD and asthma are important chronic inflammatory disorders with a high associated morbidity. Much research has concentrated on the role of inflammatory cells, such as the neutrophil, in these diseases, but relatively little focus has been given to the endothelial tissue, through which inflammatory cells must transmigrate to reach the lung parenchyma and cause damage. There is evidence that there is an abnormal amount of endothelial tissue in COPD and asthma and that this tissue and its\u2019 progenitor cells behave in a dysfunctional manner. This article reviews the evidence of the involvement of pulmonary endothelium in COPD and asthma and potential treatment options for this. Chronic obstructive pulmonary disease (COPD) is an important smoking related condition with 10.1% prevalence (with Forced expiratory volume in one second (FEV1)\u2009<\u200980%) in adults over 40 years worldwide . COPD isAsthma is a chronic respiratory condition characterised by variable airflow obstruction and airway hyper-responsiveness (AHR) in the presence of typical symptoms such as wheeze or cough . ApproxiBoth asthma and COPD are disorders associated with increased inflammation , 8. Ther2 [The pulmonary vasculature is critical to gas exchange in the lung, with a total pulmonary vascular surface area of 90m2 . Endothe2 . Finally2 , 13. A dTransendothelial migration (TEM) is a mechanism by which the endothelium may play a role in asthma or COPD. Neutrophils play an important role in the inflammatory response in COPD . In ordeTEM appears to be upregulated in COPD and macrophage-1 antigen (MAC-1), a protein involved in TEM is upregulated in neutrophils from COPD patients . MAC-1 bTEM also appears to be of importance in asthma. For example, mice deficient in cell adhesion molecules L-selectin and ICAM-1 show a reduced influx of inflammatory cells into the lung and a reduction in AHR on exposure to an ovalbumin challenge . In addiThe absolute level of adhesion molecules may not be the only factor of importance in TEM in asthma. Different alleles of adhesion molecules may predispose to asthma. For example the PECAM-1  125 Val/leu polymorphism is more frequent in asthma patients in comparison with controls .In addition to inflammation and endothelial dysfunction, another possible mechanism of increased TEM in asthma is upregulation of chemokines. Endothelial cells in asthma appear to increase production of chemokines to attract and activate circulating eosinophils. For example, Eotaxin messenger ribonucleic acid (mRNA) expression is increased in endothelial cells from bronchial biopsy specimens in asthmatic patients and levels are associated with AHR . PulmonaIn summary, TEM appears to be upregulated in obstructive lung diseases and an increase in endothelial adhesion molecules is seen in both COPD and asthma. This is likely to play a role in the increased influx of inflammatory cells seen in both conditions and therefore may be important in the development of inflammation and the pathogenesis of obstructive lung disease.Apoptosis (programmed cell death) is a highly ordered process which eliminates damaged or unwanted cells . In the Animal studies provide support for apoptosis of endothelial cells resulting in emphysema. For example, it is possible to induce emphysema in rodents by deliberately causing endothelial apoptosis by blockade of vascular endothelial growth factor (VEGF) . When thIn addition to VEGF other mechanisms have been proposed for the development of endothelial apoptosis in COPD patients. For example, Noe et al. demonstrated that Cystic Fibrosis Transmembrane Regulator (CFTR) in human pulmonary endothelial cells was required for stress-induced apoptosis. CFTR inhibition resulted in the attenuation of endothelial apoptosis in response to treatment of cells with staurosporine or hydrogen peroxide . Alpha-1Whole lung gene expression studies which have demonstrated that gene expression appears to differ between emphysematous tissue and normal lung have shown that angiogenesis-related genes are down-regulated in emphysema. Also, SERPINF1 (an antiprotease) was elevated in severe emphysema and this acts as an angiogenesis inhibitor by inducing endothelial cell apoptosis . TherefoIn conclusion, vascular atrophy due to endothelial apoptosis may contribute to the destruction of alveoli and consequently the development of emphysema. It may therefore be an important mechanism of COPD pathogenesis in this subgroup of patients.Senescent cells are unable to progress through the cell cycle and divide, but remain metabolically active . SenesceA reduction in endothelium in patients with emphysema may be caused by reduced levels of Vascular Endothelial Growth Factor (VEGF) . VEGF isInterestingly, similar studies looking at the expression of HIF-1\u03b1 and VEGF in patients with chronic bronchitis (rather than emphysema) have shown HIF-1\u03b1 and VEGF are increased in this patient group . This suThere is also evidence that vasculature may be altered in the airways of patients with COPD, in addition to their peripheral lung tissue \u2013 several groups have shown an increased vascular area in the airways of patients with COPD , 53. It Patients with asthma also demonstrate increased VEGF expression in a similar way to chronic bronchitis patients. For example, VEGF mRNA levels are increased in endobronchial biopsies in patients with asthma in comparison to normal controls . VEGF isAgain, in a similar way to chronic bronchitis, patients with asthma have increased vasculature in their airways which might be important in the development of airway narrowing . BronchiIn addition to altered levels of endothelium in patients with COPD, the endothelium appears to behave in a dysfunctional manner. Endothelial dysfunction is defined as disturbed endothelial dependent vasodilatation. It results in a breakdown of the microvascular endothelial barrier and loss of the anti-adhesive and anti-thrombotic functions of the endothelium . Animal Endothelial dysfunction was previously measured by arterial catheterization to identify the response of the artery to acetylcholine. Patients with endothelial dysfunction respond with vasoconstriction rather than vasodilatation as expected . HoweverIn addition to FMD endothelial dysfunction can also be measured by serum markers. For example, one can look at the blood level of von Willebrand factor (vWF) as an indication of endothelial dysfunction . This isNitric oxide (NO) is reduced in endothelial dysfunction due to a reduction in production and/or inactivation of NO synthase by ROS . Maricic123I-metaiodobenzylguanidine (123I-MIBG) is an analogue of guanethidine and is actively taken up and metabolized by the lungs through a sodium-dependent channel into the pulmonary endothelium. Therefore, scintigraphic analysis of 123I-MIBG in the lungs can be used to provide information on how well the pulmonary endothelium is functioning. The washout rate of 123I-MIBG is reduced in COPD patients suggesting injury to the microvascular pulmonary endothelium. Interestingly 123I-MIBG washout rate was also correlates with the severity of COPD (using FEV1 and DLCO) providing further support for endothelial damage underlying COPD development [elopment .Finally, endothelial dysfunction of the airways can be measured specifically using airway blood flow (Qaw) measurements which should increase in response to inhaled albuterol. Patients with COPD have reduced response to albuterol suggesting endothelial dysfunction in their airways. The responsiveness to albuterol does increase after exposure of fluticasone/salmeterol for 4\u20136 weeks suggesting that current inhaled therapy might help improve underlying endothelial dysfunction .It is known that the prevalence of cardiovascular disease in patients with COPD is greater than controls. The risk of cardiovascular mortality also appears to be increased in COPD patients . It is nThe evidence for endothelial dysfunction in asthma is not as great as that in COPD. However, one study has demonstrated that asthma patients have reduced FMD levels in comparison to controls . FMD wasQaw is increased in patients with asthma which is likely related to the increased vascularity seen in the airways in asthma \u201395. HoweEndothelial progenitor cells (EPCs) act to repair endothelial injury and replace dysfunctional endothelium after being mobilized from the bone marrow to circulating blood . TherefoThere is also evidence that EPCs do not function normally in patients with COPD. EPCs isolated from COPD patients had reduced proliferation rates and formed fewer clusters in vitro compared to control patients. EPCs from COPD patients had reduced chemotaxis levels and were less able to form tubular structures (in Matrigel angiogenesis studies) than control EPCs suggesting that their ability to repair endothelium was reduced. Expression of platelet/endothelial cell adhesion molecule-1 (PECAM-1), an adhesion molecule necessary for endothelial migration and junctional integrity on the surface of EPCs was also reduced in COPD patients further suggesting their dysfunctional nature. This was supported in animal studies by the same group who showed that fewer EPCs from COPD patients attached to injured arterial intima in mice compared to controls . Human sIn contrast to COPD EPCs appear to be upregulated in patients with asthma . EPCs deSmoking is known to have widespread effects on the microcirculation and may result in microvascular disease in various organs such as the eye, heart and kidney . It has Angiopoietins and their receptors (Tie-1 and Tie-2) are involved in the late phases of angiogenesis. Angiopoietin 1 (Ang-1) is proangiogenic and acts in the development of vascular networks . Ang-2 aAngiopoietins also appear to play a role in asthma. Levels of both Ang-1 and Ang-2 in sputum are increased in stable asthmatic patients in comparison to controls. Smoking also increased angiopoietin levels in the asthma group . AngiopoIn conclusion, the endothelium appears to behave in an abnormal fashion in COPD and asthma. Multiple pathways involving the endothelium may have importance in both conditions. In some cases such as TEM, pathways appear to behave in a similar fashion in COPD and asthma. However, other pathways behave differently depending on the phenotype of the patient. For example, increased angiogenesis in asthma/chronic bronchitis and decreased angiogenesis in emphysema. A summary of the mechanisms involved in endothelial dysfunction in COPD and asthma can be seen in Fig.\u00a0Endothelial dysfunction may be a result of the increased levels of oxidative stress seen in COPD. Patients with COPD and low levels of FMD show improvements in FMD when given anti-oxidants . The RhoAs systemic inflammation is increased in COPD patients studies have been performed to investigate whether the level of inflammation seen in these patients is related to endothelial dysfunction. Eickhoff et al. demonstrated that FMD was associated with C-reactive protein and leukocyte levels suggesting an underlying association between inflammation and endothelial dysfunction . HoweverInsulin resistance may also have a role in the development of endothelial dysfunction in patients with COPD. One study followed up COPD patients over the course of a year. During this time FMD decreased and fasting blood glucose increased. FMD was significantly negatively correlated with fasting blood glucose suggesting that patients with worse glucose control also had worse endothelial function . InteresThere is a lack of evidence for why patients with asthma might develop endothelial dysfunction. However, one study demonstrated that vascularity in bronchial biopsy specimens was reduced in asthma patients after a 6 month course of inhaled corticosteroids (ICS) . This suMany of the above pathways have potential treatments associated with them. For example, as above, patients with COPD and reduced FMD have shown improvement in FMD with the use of anti-oxidants . Ginkgo It is possible that some of the treatments already available for COPD might be able to improve endothelial functioning. For example, one study observing endothelial function in COPD patients demonstrated that patients with improved 6MWT scores had improved FMD levels . TherefoOther studies have focused on treating the increased levels of endothelial apoptosis seen in patients with emphysema. For example, one study demonstrated that CSE induced apoptosis and decreased prostacyclin synthase levels in human umbilical vein endothelial cells (HUVECs) in vitro . ProstacAs previously mentioned, targeting the inflammation seen in asthma using ICS can reduce VEGF expression and airway vascularity , 132. AnAnother potential treatment option is to target EPCs in asthma. When a chemokine receptor antagonist (AMD3100) was given to mice sensitized to ovalbumin airway pulmonary EPCs, eosinophil accumulation, vascularity and AHR was reduced . HoweverFinally, reducing TEM may be another treatment option for patients with asthma. Theophylline (a methylxanthine drug with bronchodilator and anti-inflammatory properties) was added to HUVECs in vitro. This reduced adhesion of eosinophils to the HUVECs and also reduced the expression of endothelial adhesion molecules such as ICAM-1 . This suPulmonary endothelium in asthma and COPD patients appears to be altered in comparison to control subjects. There is evidence that in some COPD patients with the subtype of emphysema apoptosis of the endothelium may result in alveolar destruction and reduced gas transfer. In patients with asthma or chronic bronchitis increased VEGF and vascular remodelling in the airways may have a more important role. The endothelium also behaves in a dysfunctional manner in COPD and endothelial progenitor cells appear to be less effective at repairing the damaged and dysfunctional endothelial tissue. There is some evidence that endothelial dysfunction also occurs in asthma and endothelial progenitor cells are upregulated in these patients.Multiple mechanisms such as inflammation may explain the underlying alteration in the endothelium in these patients and some already existing treatments could target these mechanisms and improve underlying endothelial function. Very few studies looking into treatment of endothelial dysfunction in COPD and asthma exist and more work is required to evaluate whether or not mechanisms of endothelial dysfunction researched in vitro will lead to promising treatment strategies in COPD and asthma."}
+{"text": "Developmental plasticity \u2013 the concept that adaptation to changing and unfavorable environmental conditions are possible but may come at the price of compromised health potentials \u2013 has evolutionary grounding as it facilitates survival but dissents with fundamental evolutionary principles in that it may advance the lesser fit. It is an important cornerstone of the Developmental Origins of Health and Disease (DOHaD). Unlike evolutionary adaptation developmental plasticity may be short-lived and restricted to one or few generations and inheritance is uncertain. Potential mechanisms include epigenetic modifications adopted in utero which may not transmit to the next generation; future insights may allow adjustments of the outcomes of developmental plasticity.  The evoet al.  demarcatThe concept of developmental plasticity has been embraced by the followers of the Barker-hypothesis  as a suitable model for epidemiologic observations linking the intrauterine environment to later life health . This coPlasticity of an organism is assumed greatest at conception and to dwindle thereafter . With inin utero, and the intrauterine environment will imprint its marks on the epigenetic signature. The stability of such marks throughout the lifecourse remains unclear, and potential reversibility would allow corrections of plasticity-misdirected prospects. Although DNA methylation, chromatic structure, histone modification and miRNA activity are malleable, the complexity of this delicate and intertwined epigenetic architecture has not been disassembled. What has emerged, however, is that all components are impressionable by the environment and in particular DNA methylation may offer stable, long-lasting profiles that may affect disease propensity [While genetic traits favored by natural selection slowly evolve over large time-intervals\u2014reacting to environmental variations\u2014developmental plasticity or the thrifty phenotype allows short-term responses to the environment without genome alterations. The mechanisms allowing such immediate defense are poorly understood and a current focus of DOHaD research. The concept of plasticity\u2013phenotypic accommodation in the absence of genetic change-aligns with epigenetic principles: the propensity of phenotypic modification without genetic change. Indeed, epigenetic mechanisms represent a likely explanation for much of the DOHaD phenomena. Most of the epigenetic code is determined opensity . Is developmental plasticity a survival plan gone awry? Evolutionary interests should not support survival of the unfit. The concepts, however, may be less divergent than apparent. Evolution fosters multi-generational adaptation to the ever-changing environment to secure long-term survival of the genetic lineage, whereas developmental plasticity allows short-term tolerance possibly to avoid instant extinction within the same generation\u2014at the cost of inferior health. A big unknown is whether passing the newly acquired traits and \u2018quick fix\u2019 to the next generation is part of that master plan. Do they offer a survival advantage to the offspring? If epigenetics is indeed the underlying mechanistic tool inheritance may not be the intention. A double-layer of epigenetic erasure, two distinct demethylation cycles\u2014one prior to and one subsequent to conception\u2014aims to ensure the deterrence of passing any methylation marks to the next generation . TransgeWith much exploration ongoing in this field, our cursory understanding of these complex but fundamental processes will be much enriched and may stipulate unknown prospects for prevention.Conflict of interest: None declared."}
+{"text": "The precise control of physical properties of growing tissues is crucial for plant morphogenesis. Sahaf and Sharon (pages 5509\u20135515 in this issue) examined the mechanics of the expanding leaf and showed that plant tissues respond to stress by changing their mechanical properties. A new method is proposed to distinguish reversible and irreversible tissue deformation, an important step in understanding the physics of a growing cell wall. Leaf blades could hold the key to understanding how plants regulate their growth in different directions.plastic) deformation of their stiff cell wall under tension. The cell wall is a complex hydrated gel composed mainly of pectins and hemicellulose reinforced by stiff cellulose microfibrils. Different models of plant cell wall structure agree on the load-bearing role of cellulose, but the mechanical function of other wall components remains unclear  differs from the resultant growth, i.e. the only expansion we can actually observe  results in fast tissue stretching (white bar) in the direction of applied load and tissue contraction (red bar) in the perpendicular orientation due to the Poisson effect (A). Growth under constant load is first oriented along the applied force (B) and then becomes isotropic (C) as in the non-stretched side (left). Releasing load causes growth reorientation, which becomes perpendicular to the previously applied force (D) and turns back to isotropy only after several hours (E). Before loading, leaf tissue is equally elastic in both orientations. Prolonged load leads to tissue stiffening parallel to, and softening perpendicular to, the applied force (F).What changes in mechanical properties underlie this coping mechanism? A possible candidate would be modifications in elasticity (reversible deformation of the tissue). The link between elasticity and growth is still unclear and even controversial , althougA static load (red curve) can be used over long periods of time to mimic the effects of tissue stresses and study the plastic deformation (green curve) of the leaf blade (A). At first the tissue exhibits a fast linear deformation that is mainly reversible  and later slowly creeps (plastic or irreversible deformation) until reaching a steady growth rate. On a smaller timescale, visco-elasticity is measured by applying an oscillating force (red curve) to the tissue (B). Loading cycles occur sufficiently fast such that creep does not take place and the amplitude of deformation (green curve) stays constant. The curve\u2019s slope reflects tissue elasticity, while the time shift between curves indicates viscous relaxation. The technique used by Sharon and Sahaf probes tissue elasticity by adding mechanical stress to those already existing. Measuring cell deformation upon osmotic treatments, on the other hand, gives an insight into cellular elasticity at different levels of turgor-based mechanical stress (Sahaf and Sharon show that in the leaf blade changes in plastic behavior induced by stress do correlate with modifications in visco-elastic properties. They observe a clear increase in stiffness along the direction of imposed stretch. This behavior is in accordance with previous findings that cortical microtubules orient according to the direction of maximal stress, guiding the deposition of new cellulose microfibrils , the aliSeveral scenarios explaining blade softening in the direction perpendicular to applied stress could be investigated. The primary cell wall exhibits a polylamelate structure in which cellulose microfibril orientation in-between successive layers can vary abruptly . It is cLeaves also provide an interesting system for exploring subcellular mechanical regulation of growth. In Arabidopsis, despite a relatively uniform expansion of leaves at the tissue scale , puzzle-Despite renewed interest in plant mechanics, fundamental questions regarding growth regulation still need to be answered. Because they cannot be observed directly, the different kinds of mechanical stresses driving cell expansion have often been omitted, leading to apparent discrepancies between the observed growth and cell wall structure . Using t"}
+{"text": "Moral Reconation Therapy (MRT) is a cognitive-behavioral intervention aimed at reducing risk for criminal recidivism by restructuring antisocial attitudes and cognitions . MRT has empirical support for reducing risk for criminal recidivism among civilian offenders. Recently, a version of MRT was developed for military veterans; however, no randomized controlled trials (RCT) have been conducted with the veteran-specific protocol, and the effectiveness and implementation potential of MRT outside of correctional settings has not been established.Using a Hybrid Type 1 RCT design, this study will test the effectiveness of MRT to reduce risk for criminal recidivism and improve health-related outcomes among justice-involved veterans entering mental health residential treatment at three US Veterans Health Administration (VHA) Medical Centers. Upon admission to the treatment program, justice-involved veterans will complete a baseline assessment, be randomized to usual care (UC) or UC\u2009+\u2009MRT, and be followed 6 and 12\u00a0months post-baseline. A process evaluation will also be conducted to identify barriers and facilitators to implementation of MRT in residential treatment.The primary aim of this study is to evaluate the effectiveness of MRT with justice-involved veterans. If MRT proves effective in this trial, the findings can provide large healthcare systems that serve veterans with an evidence-based intervention for addressing criminogenic thinking among justice-involved adults, as well as guidance on how to facilitate future implementation of MRT in non-correctional settings.NCT02524171).This trial is funded by the VA Health Services Research & Development Program (IIR 14\u2013081) and is registered with ClinicalTrials.gov (ID:  Among criminal offenders, two-thirds will recidivate  within 3 years from their release . Criminacriminogenic thinking \u2013 are the risk factors most strongly associated with criminal recidivism  , and Timex [ASI] , mental pression , and thepression ), housin System) , and empinterpersonal functioning  to test whether scores on these indices at baseline moderate MRT\u2019s direct effects on outcomes. The ASI Legal Status module will also be used to measure criminal recidivism during the follow-up period.In order to test whether the effects of MRT on reduced recidivism risk and better health-related outcomes are mediated in part by greater likelihood of completing the mental health residential treatment program and utilizing substance use disorder/mental health continuing care services, we will also collect data on service utilization (via patients VHA administrative records) and mutual-help group attendance (via the Alcoholics Anonymous Interview ). In ordProblems ) and antsociates  and the sociates ) to test Measure  and crimReach (how to reach the target population with the intervention); Effectiveness (how to know the intervention is effective); Adoption ; Implementation (fidelity and consistency of an intervention\u2019s delivery); and Maintenance (sustainability of an intervention in the long-term). The RE-AIM Planning Tool will be modified to ask questions of providers and patients within these domains regarding key issues that should be considered when planning to implement MRT in mental health residential treatment across VHA.The RE-AIM  Planning Tool  will be Intent-to-treat analyses will be conducted. The primary and secondary outcomes will be measured at all three time-points. Therefore, we will use generalized linear mixed model (GLMM) regressions to compare the UC and MRT conditions on these outcomes. These models take into account that the repeated measures across time points are clustered within each individual by treating time as a single repeated factor. GLMMs also have the advantages of being able to use all available data (under the assumption that data are missing at random) and being able to accommodate different conditional distributions for outcome variables . We will also examine these outcomes as a function of MRT dose . To test mediation, we will conduct GLMM regressions following the approach of Mackinnon and Fairchild , which wThe de-identified audio-files of the staff and patient interviews will be transcribed. The interview transcripts will then be will be analyzed using template analysis to identify common themes in textual data . This apClinicalTrials.gov (ID: NCT02524171). Prospective participants will be told that they may withdraw from the study at any time and refrain from answering specific questions, and that all information will be confidential and used only for the purposes of the research study. Prospective participants will also be told that any withdrawal from the study on their part or on the part of the investigators will not affect the standard care that the participant is receiving in the residential treatment program or any other healthcare from the VHA to which the participant is entitled.This study was reviewed and approved by the VA\u2019s Central IRB (Study #15\u201304) and registered with The primary aim of this hybrid trial is to evaluate the efficacy of MRT with justice-involved veterans using the new veteran-specific protocol of this intervention . AnotherRecent work by Blonigen and colleagues  highlighThis hybrid trial represents the first attempt to systematically evaluate the effectiveness of MRT with justice-involved veterans and the implementation potential of this intervention in a large, integrated healthcare setting. The potential impact of this work is underscored by the extensive criminal histories of veterans treated in mental health residential treatment programs in VHA  and the"}
+{"text": "The human brain is complex at every level, from the scale of single neurons to microcircuits and large neuronal networks. Although this complexity is well known and studied in neuroscience, few tools or concepts of complex analysis have been transferred to the clinic yet. In the case of the basal ganglia, there has been much debate about the necessity to include nonlinear concepts into pathophysiology models .Current theories of the basal ganglia are not always consistent with clinical and experimental observations. New models need to be built based on advances in the fields of complexity, chaos and non-linear systems .A new model emphasizes the role of cognition in motor control, showing that freezing of gait can result from increased risk sensitivity in patients with Parkinson's disease (PD) .Action selection concepts and pharmacokinetics combined in a mixed modeling approach can be used to study how dopamine affects a motor task at different stages of PD .The basal ganglia together with the cerebellum and prefrontal cortical areas play a role in time processing, which is altered in movement disorders and affects both motor and cognitive performance .Dopamine signaling influences the level of physical activity. Chronic exposure to obesogenic diets cause striatal dopamine dysfunction, which might be related to the difficulty of people with obesity to increase their physical activity .Local field potentials (LFP) observations in patients with PD show that the subthalamic nuclei (STNs) are bilaterally involved in voluntary muscle contraction and relaxation, with characteristic activity in the theta (4\u20137 Hz), beta (14\u201335 Hz), and gamma bands (40\u2013100 Hz) .Accumulation of alpha-synuclein (\u03b1Syn) in Lewy bodies and Lewy neurites characterizes the progression of Parkinson's disease. The discovery of cell-to-cell propagation of \u03b1Syn opens new therapeutic avenues for the treatment of PD and related disorders Huntington's disease (HD) is considered as a paradigm of epigenetic dysregulation. Cell-type specific techniques and 3D-based methods can be used to advance knowledge in the context of brain region vulnerability in neuordegenerative diseases, leading to the design of new therapeutic targets (Bunner and Rebec).Dysregulation of glutamate in the corticostriatal pathway is implicated in HD. Alterations of dopamine, a modulator of glutamatergic activation, also plays a role in deficits of neuronal communication throughout the basal ganglia in HD Apathy is a cardinal symptom of PD, but its pathophysiology is poorly understood. A new animal model (VMAT2 deficient mice) shows an apathetic-like phenotype that might be independent of depressive-like symptoms. This is a step forward to study the biological substrates of apathy in PD. .A study based on electroencephalograms (EEG) of PD patients and aged-matched healthy individuals shows that pharmacologic treatment helps maintaining long-term action-outcome representations in PD patients, but not the initial experience of action-effect (Nanni and Andres).The temporal structure function is a robust and simple to compute tool for the analysis of neuronal activity, which helps identifying random, oscillatory and non-linear behavior in the dynamics of single neurons. This technique can be used to quantify complex neuronal activity in healthy and PD neurons .A new cost-effective screening protocol for parkinsonism based on combined objective and subjective monitoring of balance using a game industry balance board might be a strategy for PD screening in communities with limited access to healthcare .Bicycling ability remains preserved in PD patients who suffer freezing of gait, but the neural mechanisms underlying this observation are not known. A new experimental setup allows to investigate this phenomenon, combining recording of basal ganglia LFP and scalp EEG in PD patients while bicycling, walking or performing other motor tasks .Disparate patterns of subcortical degeneration evidenced by automated volumetric magnetic resonance imaging can explain some differences in symptoms between PD clinical subtypes, such as gait disturbances and cognitive functions. This finding may help to design personalized therapeutic approaches in the future .Quantification of specific functional deficits of gait could provide a basis for locating the source and extent of neurological damage in PD, aiding clinical decision-making for individualizing therapies .A new method uses intraoperative stimulation test data to identify optimal implant position of DBS leads by relating electric field simulations to patient/specific anatomy and the clinical effects of stimulation as measured by accelerometry .A new study based on near-infrared spectroscopy (NIRS) in PD patients concludes that therapeutic DBS promotes neuronal network remodeling in the prefrontal cortex .Impulsivity is related to an abnormally fast reaction time in high conflict situations, which is high under DBS of the STN. In a computational model, reaction time can be controlled varying the DBS electrode position within the STN and causing antidromic activation of the globus pallidus externa (GPe) (The results published in this topic promise great advancements in coming years in the field of basal ganglia pathophysiology and related disorders.DA, MM, and OD are responsible for the full content of this article.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Homonymous hemianopia (HH) is the most common cortical visual impairment leading to blindness in the contralateral hemifield. It is associated with many inconveniences and daily restrictions such as exploration and visual orientation difficulties. However, patients with HH can preserve the remarkable ability to unconsciously perceive visual stimuli presented in their blindfield, a phenomenon known as blindsight. Unfortunately, the nature of this captivating residual ability is still misunderstood and the rehabilitation strategies in terms of visual training have been insufficiently exploited. This article discusses type I and type II blindsight in a neuronal framework of altered global workspace, resulting from inefficient perception, attention and conscious networks. To enhance synchronization and create global availability for residual abilities to reach visual consciousness, rehabilitation tools need to stimulate subcortical extrastriate pathways through V5/MT. Multisensory bottom-up compensation combined with top-down restitution training could target pre-existing and new neuronal mechanisms to recreate a framework for potential functionality. Normal vision in humans is primarily mediated by the geniculo-striate pathway where the visual information is processed in a hierarchical order via the retina, the lateral geniculate nucleus (LGN) and the striate cortex. Once the primary characteristics of visual information are processed, visual connections are sent to the parietal cortex involved in spatial attention and action  and to the temporal cortex involved in recognition and identification . Following post-chiasmatic lesions inducing an alteration in the geniculo-striate pathway, a contralateral cortical blindness (CB) occurs, either as a result of a neurophysiologic disorder requiring surgical interventions of V1, or mainly subsequent to a stroke affecting the posterior visual cortex , and what is measured objectively, i.e., the rate of correct answers in the two-alternative forced-choice paradigm is above the chance level. The first extended precepts of the phenomenon are described from the results obtained on GY who had a trauma affecting the striate cortex at a young age  or not optimal synchronization (blindsight type II) between the perception, attention and conscious networks.Alternative visual abilities consist of an abnormal degraded vision which is qualitatively different from normal vision but is associated with visual awareness mediated by secondary visual pathways that can\u2019t be explained by the activity of the striate cortex.The idea is to understand how we can pass from blindsight type I, to blindsight type II to an alternative visual ability. In other terms how can we pass from a state of no awareness to a state of awareness and finally to visual awareness by stimulating secondary visual pathways?The geniculo-extrastriate pathway is a perfect candidate to our altered perception workspace. Its existence implies that V1 lesions do not lead to a complete degeneration of the LGN, and that koniocellular projections are sent to the secondary extrastriate regions, such as MT  in blindsight is strongly corroborated with behavioral data. More specifically, the physical parameters of stimuli inducing blindsight correspond specifically to the inherent characteristics of the SC neurons (Leh et al., We hypothesize that consciousness and moreover visual consciousness is mediated by multiple workspaces interacting together. Conscious processors can be mediated by interactions of the fronto-parietal and prefrontal network Zeman,  with higThis section reports the estimated tools to promote plasticity following a CB and increase potential recovery of functional vision. First, future researches should emphasize the importance of stimulating visual pathways in the subacute period following the lesion (Alber et al., It has been demonstrated that subsequent to a striate lesion, reorganization of the cerebral cortex in favor of the intact hemisphere induces V5/MT of the ipsilateral hemifield to project to V5/MT of the contralateral hemifield after stimulation of the blind field (Bridge et al., Reorganization following audio-visual stimulations allows a decrease of the ipsilesional attentional bias showed by a reduction in P300 amplitude (Dundon et al., Restitution techniques are effective if they aim typical visual attributes training specific to blindsight to expand over a large spectrum of visual characteristics and functions. For example, a transfer of information can be achieved by presenting simultaneous and diversified stimulations in the blindfield accompanied by temporal and spatial cues (Kentridge et al., Audio-Visual Scanning Training could allow feedforward interactions between the SC and V5/MT (Dundon et al., The problem is to know how visual therapies can target residual visual abilities when neurophysiological correlates are so divergent between patients. Can we really use what we know of blindsight to develop rehabilitation tools? Our review explains how combined rehabilitation tools using visual training can enhance blindsight by targeting an inefficient global framework. Blindsight, defined as an unconscious residual visual ability, can come with or without awareness, but except in rare cases, doesn\u2019t elicit visual awareness (Balsdon and Azzopardi, FL and VH: equal contribution for the literature search and article preparation.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "An 85-year-old woman presented to the emergency department (ED) with altered mental status. She appeared to be in shock with a distended abdomen. A point-of-care (POC) echocardiogram using a 4 Mhz phased array transducer revealed a large anechoic mass posterior to the left atrium concerning for an aneurysm of the descending thoracic aorta (DTA). , Video HThe detection of hiatal hernia on echocardiography has been described in the cardiology literature;When suspicious for a hiatal hernia on echocardiography, be certain to visualize the object of interest in at least two windows. The inner lining of the structure should be thick 6\u201313mm) and resemble stomach mucosa with the presence of microbubbles.mm and re4In conclusion, a posterior anechoic mass seen on the PLAX view on POC echocardiography can be mistaken for a DTA aneurysm, but may be accurately diagnosed as an hiatal hernia if it has a thick inner lining resembling stomach mucosa and contains microbubbles.What do we already know about this clinical entity?Emergency physicians rely on point-of-care echocardiography for rapid detection of critical diagnoses such as aortic aneurysms and dissections.What is the major impact of the image(s)?A hiatal hernia may be distinguished from an aortic aneurysm on ultrasound by the presence of microbubbles and a thick inner lining resembling stomach mucosa.How might this improve emergency medicine practice?By recognizing mimics of life-threatening conditions on ultrasound, emergency physicians can better expedite patient care and resource utilization."}
+{"text": "A characteristic feature of liver cirrhosis is the accumulation of large amounts of connective tissue with the prevailing content of type I collagen. Elastin is a minor connective tissue component in normal liver but it is actively synthesized by hepatic stellate cells and portal fibroblasts in diseased liver. The accumulation of elastic fibers in later stages of liver fibrosis may contribute to the decreasing reversibility of the disease with advancing time. Elastin is formed by polymerization of tropoelastin monomers. It is an amorphous protein highly resistant to the action of proteases that forms the core of elastic fibers. Microfibrils surrounding the core are composed of fibrillins that bind a number of proteins involved in fiber formation. They include microfibril-associated glycoproteins (MAGPs), microfibrillar-associated proteins (MFAPs) and fibulins. Lysyl oxidase (LOX) and lysyl oxidase-like proteins (LOXLs) are responsible for tropoelastin cross-linking and polymerization. TGF-\u03b2 complexes attached to microfibrils release this cytokine and influence the behavior of the cells in the neighborhood. The role of TGF-\u03b2 as the main profibrotic cytokine in the liver is well-known and the release of the cytokines of TGF-\u03b2 superfamily from their storage in elastic fibers may affect the course of fibrosis. Elastic fibers are often studied in the tissues where they provide elasticity and resilience but their role is no longer viewed as purely mechanical. Tropoelastin, elastin polymer and elastin peptides resulting from partial elastin degradation influence fibroblastic and inflammatory cells as well as angiogenesis. A similar role may be performed by elastin in the liver. This article reviews the results of the research of liver elastic fibers on the background of the present knowledge of elastin biochemistry and physiology. The regulation of liver elastin synthesis and degradation may be important for the outcome of liver fibrosis. Elastin is the most stable protein of the extracellular matrix (ECM) which is composed of collagen, glycoproteins, glycosaminoglycans and proteoglycans  possessing a molecular weight of about 72 kDa. TE is a single gene protein encoded by 36 exons that persist in many animal species. Exons 34 and 35 were lost during the evolution of human TE. Seven other exons may be alternatively spliced reflecting elastin function in different tissues  which is an enzymatically inactive variant of \u03b2-galactosidase. EBP functions as a 67 kDa chaperone that prevents intracellular TE aggregation and protects TE from proteolytic degradation. TE is packaged into secretory vesicles in Golgi apparatus  isolated from liver biopsies express all components forming the large latent complex of TGF-\u03b2: four LTBP isoforms and their splice variants, LAP and three TGF-\u03b2 isoforms, suggesting the importance of TGF-\u03b2 activity in diseased liver  family  attach to fibrillin. Their molecular weight is small, about 25 kDa. MAGP-1 binds TE and members of TGF-\u03b2 and BMP family. It may modify TGF\u03b2 signaling and tissue homeostasis  and fibulin-2 (200 kDa), and proteins much smaller, fibulin-3, -4, and -5 (50\u201360 kDa). Their characteristic feature is the presence of calcium-binding epidermal growth factor-like (cbEGF) domains and the fibulin-type C-terminal region. All of them bind TE but they have different roles in elastic fibers formation  is involved in crosslinking both collagen and elastin. Fibulin-4 interacts with lysyl oxidase (LOX) propetide, tethers LOX to TE and facilitates elastin crosslinking  circulate in the blood sera of healthy individuals  die from occlusive fibrocellular pathology caused by subendothelial proliferation and accumulation of vascular SMCs in early neonatal life. SMCs isolated from newborn Eln\u2212/\u2212 pups proliferate at a much higher rate than Eln+/+ cells. Eln\u2212/\u2212 SMCs show a remarkable paucity of actin stress fibers that can be reversed by recombinant TE treatment. TE inhibits SMC migration and proliferation in culture . However, this is not their only function. The regulatory role of TE, elastin polymer and products of elastin degradation have become prominent in recent years  and other peptides containing GXXPG sequence where X is a hydrophobic amino acid. These peptides are biologically active (Almine et al., Fragments of ECM including elastin are chemotactic for monocytes and polymorphonuclear leucocytes (Hauck et al., Elastin hydrolysate and EP stimulate the proliferation of fibroblasts and SMC (Chatron-Colliet et al., Elastin that accumulates in the liver with advancing fibrosis can be used to diagnose the disease. Magnetic resonance with an elastin-specific contrast agent containing gadolinium may be used as a noninvasive diagnostic technique (Ehling et al., ECM markers, degraded collagen III, collagen V and elastin, correlate with galactose elimination capacity and with the degree of portal hypertension (Leeming et al., The formation of fibrotic septa is regarded as a negative outcome of liver diseases. Elastic fibers contribute to the stability of the septa. All aspects of the presence of elastic fibers in the liver are not known, however. The synthesis of individual components of elastic fibers in the liver and their assembly is likely to follow the general pattern of elastic fibers formation in the organism. The knowledge of the regulation of elastogenesis obtained in the studies done in other organs may provide a useful inspiration for the study of elastogenesis in the liver. The emerging regulatory role of fibulins is an example. The research done in human cells should be given a priority because of the differences in the splicing of the primary TE gene transcript in various animal species. Elastin and other components of elastic fibers may also be useful as diagnostic tools in hepatology.The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer PK and handling Editor declared their shared affiliation, and the handling Editor states that the process nevertheless met the standards of a fair and objective review."}
+{"text": "Social inequalities in UK educational outcomes continue to persist despite improvements in recent years. However, studies that examine these inequalities fail to account for differences in prior cognitive ability. We seek to determine the influence of cognitive ability on educational outcomes and the extent of socio-economic disparities in education across a wide range of indicators while accounting for cognitive ability. Social inequalities exist whereby children from disadvantaged backgrounds systematically underperform compared to their advantaged peers regardless of cognitive ability; high ability children from disadvantaged backgrounds are disproportionately less likely to attain good grades compared to children from advantaged backgrounds. In addition, school effects operate to add to this inequality as children in fee-paying secondary schools outperform their state secondary school counterparts regardless of ability. Future UK policies should focus on reducing social inequality in education to ensure that all children are offered the same life chances regardless of background. Social inequalities in education have long been documented in great detail in many modern societies, with social forces acting directly to increase or maintain them through lack of material resources or non-alleviation of developmental problems McLoyd, , or indiThis paper concerns just the UK but its findings may be more widely applicable. In the UK children from the most deprived quintile of families are 3 times less likely to achieve highly in both Maths and English at age 7 compared to those from the least deprived quintile, rising to three and a half times less likely at age 11, and over 4 times less likely when they finish school at age 16 .Participants were children from the Avon Longitudinal Study of Parents and Children (ALSPAC). Pregnant women were eligible to enrol if they had an expected date of delivery between April 1991 and December 1992 and were resident in the (former) Avon Health Authority area in South West England . FigureA range of exposure variables were tested to examine the relationship between different aspects of family social status and educational attainment. These include highest maternal education at pregnancy (categorised as certificate of secondary education (CSE)/none/Vocational, O-level [exams taken at completion of compulsory school attendance], A-level [exams taken in post-compulsory schooling at age 18], and university degree or above); a family adversity index measuring multiple aspects of household deprivation ; highest parental Social Class based on Occupation  and II  were combined together, and IV (Partly skilled occupations) and V (Unskilled occupations) combined); and income reported by mothers at age 7 and mothers\u2019 partner at age 11.Educational attainment data was taken from the UK National Pupil Database (NPD) at Key Stage 4 (GCSE) examinations and Key Stage 5 (A-level) then linked to ALSPAC children whom had given consent for data linkage. GCSE examinations are sat during the 11th year of compulsory schooling when children are aged 15/16 (years 2007\u20132009 for the ALSPAC cohort) and A-levels are sat during the second year of post-compulsory schooling when children are aged 17/18 (years 2009\u20132011 for the ALSPAC cohort). We used Maths and English at GCSE as these are the two core subjects most widely required for participation in further education and the labour market. . Due to the wide range of subjects available at A-level and the resulting data confidentiality issues, A-level subject grades were averaged then grouped into categories representing different grade combinations .Cognitive ability was assessed at the age eight clinic visit using the Wechsler Intelligence Scale for Children (WISC) to assess cognitive function from verbal, performance, and digit span tests  from differing socio-economic backgrounds. These are complemented by results from a multivariate regression analysis on the full sample (we omit income at 11 due to sample size issues). Lastly we demonstrate attainment differences between children attending state and fee-paying schools. All statistical analyses were performed using STATA v 13 .There has been considerable recent debate over the statistical phenomenon of regression towards the mean (RTM) when modelling the progress trajectories of high attaining, socio-economically disadvantaged groups. Jerrim and Vignoles  point oun\u2009=\u20091951; 48.18%) of participants attained a B or above in Maths and just over half  attained a B or above in English. Gender differences were observed for English  but not Maths   as an instrument for cognitive ability at age eight. The second utilises an error in variables regression analysis which allows results to be tested with varying levels of variable reliability. The results of these analyses, presented and discussed in more detail in the Supplementary material indicate that our main results are robust to WISC measurement error. Further additional analyses were conducted to determine if our results could be influenced by differences in maternal cognitive ability (n\u2009=\u20091676) . Results show that maternal cognitive ability strongly predicts child educational outcomes and remains even after adjustment for child cognitive ability and it is therefore possible that our results may be influenced in part by the endogenous link between certain SEP measures and maternal cognitive ability.Given concerns of measurement error we ran two additional sets of analyses which are presented in the Supplementary material (Tables S8 and S9). The first of these utilises an instrumental variables approach and uses cognitive ability measured at age four for a small subsample of ALSPAC participants (The easiest way to see the effect of school type is to compare the progress of children attending different types of school establishment. These findings indicate considerable social inequality in educational attainment in the UK even after accounting for child cognitive ability. There is evidence that high ability children who come from more socio-economically deprived family backgrounds are less likely to fulfil their cognitive potential regarding GCSE attainment by up to a factor of 1.6 and A-level attainment by up to a factor of 7.8. Here \u2018cognitive potential\u2019 means what educational attainment we would have expected of a similar child who scored as well at age eight but came from a socio-economically better off home. Maternal education remained the strongest determinant of social inequalities in attainment among high ability children at both GCSE and A-level, followed by family income. Our results remain when considering a wide range of indicators of SEP together and conform to previous findings that non-deprived, high achieving students in the UK are more likely to maintain high levels in education than deprived, high achieving students (Crawford et al., Our findings that students at fee-paying secondary schools perform better, especially if they performed poorly at age eight, as compared to those at non-selective state secondary schools is consistent with recent research on a large, nationally representative cohort of UK children (Crawford et al., The data presented suggest that it would be more socially equitable if resources for children from disadvantaged backgrounds were improved in order to bring their outcomes in line with those of children from more advantaged backgrounds (Blau & Currie, Our use of educational linkage data meant that school type data and grade outcomes were accurate and not subject to reporting bias. The use of the clinically assessed WISC test provided accurate measures of children's cognitive ability at age eight, and due to the timing of the test before subject-specific teaching at secondary school (Deary et al., Differences exist in mean cognitive ability between groups of children by educational attainment at age sixteen and eighteen whereby higher attaining groups have higher mean cognitive ability. However social inequalities in educational ability persist above this relationship; low SEP children systematically underperform their high SEP peers regardless of cognitive ability. In addition to family background characteristics school effects operate to add to this inequality as children in fee-paying secondary schools outperform their state secondary school counterparts regardless of ability.Click here for additional data file."}
+{"text": "It is well established that spontaneous activity in the developing mammalian brain plays a fundamental role in setting up the precise connectivity found in mature sensory circuits. Experiments that produce abnormal activity or that systematically alter neural firing patterns during periods of circuit development strongly suggest that the specific patterns and the degree of correlation in firing may contribute in an instructive manner to circuit refinement. In fish and amphibians, unlike amniotic vertebrates, sensory input directly drives patterned activity during the period of initial projection outgrowth and innervation. Experiments combining sensory stimulation with live imaging, which can be performed non-invasively in these simple vertebrate models, have provided important insights into the mechanisms by which neurons read out and respond to activity patterns. This article reviews the classic and recent literature on spontaneous and evoked activity-dependent circuit refinement in sensory systems and formalizes a set of mechanistic rules for the transformation of patterned activity into accurate neuronal connectivity in the developing brain. Moreover, unlike mammals, these animals rely extensively on vision for survival from very early developmental stages, and use this same visual information to direct circuit refinement.In this review article, we propose a detailed set of cellular rules that govern activity-dependent circuit refinement. This list of rules synthesizes what has been learned in the extensive experimental literature on the development of the visual system, with a strong emphasis on data obtained from live imaging of the retinotectal projection in fish and frogs. Because of their external development and largely translucent bodies, permitting high-resolution in vivo imaging that reveal fundamental details about how activity-dependent structural and functional refinement takes place. The refinement of the retinotectal circuit achieves a remarkably accurate retinotopic representation that contributes to effective visual processing and ultimately to the generation of visually-guided behaviors. Here, we define refinement as the process of establishing precise anatomical wiring , which allows for the optimal function of neural circuits in the animal.While molecular guidance cues are critical for establishing the initial crude topographic projections from the eye to the brain, even greater precision of neuronal maps is achieved through the involvement of activity-dependent mechanisms. Because neighboring retinal ganglion cells (RGCs) in the eye are more likely to exhibit temporal correlation in their firing patterns than distantly separated RGCs, the pattern of firing of action potentials in the developing visual system contains important information about the relative position of the RGC somata in the retina. The system therefore is able to use patterned neural activity in RGCs to instruct the orderly mapping of their axons onto postsynaptic partners in the optic tectum. This results in a more precise map of the retina onto the optic tectum. This review article will discuss classic studies and more recent experimental insights from In fish and frogs the RGCs project to at least 10 distinct tectal and pretectal arborization fields believed to mediate important behavioral responses such as eye movements and prey capture  and therefore the rules that control retinotectal refinement may be fundamentally different, or manifest themselves differently, during later refinement events.We begin by outlining a list of fundamental mechanistic events that the experimental evidence indicates are likely to occur during retinotectal map refinement. Each of these is elaborated in greater detail below.Molecular guidance cues provide information for coarse axonal targeting.Inputs compete for available synaptic target space.Axonal and dendritic arbors are highly dynamic, even after seemingly mature morphology is attained.(a) Synchronous firing stabilizes synapses and prolongs branch lifetimes while actively suppressing branch dynamics via N-methyl D-aspartate receptor (NMDAR)-dependent retrograde signaling (Hebbian mechanisms).(b) Asynchronous activity weakens synapses (LTD) and actively promotes axonal branch dynamics, including addition and elongation, as well as branch elimination (Stentian mechanisms).Patterned neuronal activity provides instructive cues that help refine inputs:5. In the absence of sensory input, correlated spontaneous firing provides surrogate patterned activity.6. New axonal branch tips emerge near existing synapses.7. Stronger synapses help stabilize the axons and dendrites on which they form (Synaptotropism).8. Homeostatic mechanisms help maintain the overall level of functional synaptic input to the target.The classic experiments of Sperry  studyingConcrete support for this model came initially with the identification of a candidate molecular activity expressed in membranes isolated from posterior optic tectal cells that could serve as one of Sperry\u2019s tags  throughout the eye  and depression (tLTD) in vivo , and trafficking of \u03b1-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid type glutamate receptors (AMPARs) to the synapse  almost certainly requires retrograde signaling, as the correlation detection is most likely performed by NMDAR activation in postsynaptic neurons. At the level of single axon branch dynamics, time-lapse imaging of Xenopus tadpoles is almost purely contralateral, in the occasional animal one or two individual RGC axons can be found to project by accident to the ipsilateral optic tectum  and dramatic upregulation of new branch additions and a significant increase in branch tip elongation compared with axon dynamics during a preceding period of darkness. Elimination of branch tips was also enhanced, indicating that rather than producing a larger arbor, asynchronous stimulation makes the axon more dynamic and exploratory. Thus, asynchronous visual stimulation produced an enhancement in growth and dynamics akin to the effects of NMDAR blockade. This makes sense as it is unlikely that the lone ipsilateral axon would by itself be able to drive sufficient depolarization of the postsynaptic tectal cell to permit Ca2+ flux through NMDARs. Consistent with this notion, addition of MK801 to block NMDARs did not prevent the increased rate of branch additions in response to asynchronous stimulation. It is therefore possible that the source of the branch promoting signal may not be postsynaptic in origin, but could, for example be released by surrounding glial cells or come directly from nearby axon terminals.In contrast, synchronous stimulation of the two eyes resulted in a rapid decrease in the rate of branch additions to levels seen in darkness. This decrease in branch dynamic behavior was completely prevented in the presence of MK801, or if tetanus toxin was expressed in the ipsilateral axon to render it incapable of releasing neurotransmitter, indicating that the activation of postsynaptic NMDARs likely leads to the release of a retrograde branch suppressing factor. In addition, branches that did form during synchronous stimulation had longer lifetimes on average that those that emerged during periods of asynchronous stimulation, indicating that they were more stable overall.This experimental protocol tests the full range of growth responses that patterned activity might be able to induce, as it creates a set of extreme differences in firing correlation with synchronous stimulation resembling the conditions that might be produced by strobe rearing where all inputs are artificially correlated, and asynchronous stimulation creating a set of correlations that might only be found if the RGC were to ramify in an entirely inappropriate part of the tectum or what occurs in the dually innervated tectum. In the normal process of activity-dependent developmental refinement a typical axon might be expected to experience a more modest range of local correlation and asynchrony that would lead to a slight upregulation of exploratory branching and synapse disassembly on those branches that extend away from the proper termination zone (promoting them to keep growing until they land in more welcoming territory), and a stabilization and synaptic strengthening on those branches that extend into the appropriate part of the map where inputs with similar activity patterns converge (promoting consolidation and further synaptogenesis at this site). Figure in utero, which leads to a general deprivation of visual experience during the time when visual circuit refinement takes place. It is reasonable to speculate that spontaneous activity in the retina may have arisen as an evolutionary adaptation to provide replacement patterns in amniotes of neuronal activity that lower vertebrates are able to experience by visually interacting with their surrounding environment after hatching. The first evidence for locally correlated spontaneous activity in the fetal retinal came from extracellular retinal recordings made in rat pups while still attached to the uterus via the umbilical cord  in mice results in abnormal retinal waves with impaired spatiotemporal properties  in which \u03b22-nAChR expression was conditionally deleted specifically in the retina  signaling. These authors made the important observation that new axonal branch tips almost always emerged from GFP-VAMP2 positive puncta, a finding that was later confirmed using a better targeted synaptic marker, synaptophysin-GFP . The blu mutation disrupts vglut2a, encoding a vesicular glutamate transporter homologous to the mammalian VGLUT2  amplitudes in tectal neurons, suggesting a reduction in glutamate concentration per vesicle. Interestingly, mEPSC frequency in mutant animals is increased, consistent with a higher probability of glutamate vesicle release or with upregulation in the number of release sites. These observations allude to a compensatory mechanism that helps normalize glutamatergic transmission in these animals. In accordance with this homeostatic regulation, the RGC arbors in the blu mutant zebrafish are larger, spanning a greater area of the optic tectum and tectal neurons exhibit larger receptive fields. In tectal blu animals neurotrophin-3 (NT-3) protein levels are upregulated in the optic tectum, suggesting that it could act as a homeostatic retrograde signal through TrkC receptor promoting axonal branch elaboration (Auer et al., Further evidence for homeostatic regulation of the retinotectal circuit during development was obtained using zebrafish Thanks to many decades of experimentation on retinotectal development in models ranging from fish to mammals, in conjunction with modern technology permitting live imaging of developing axons in the intact animal, we now have a much clearer understanding of the mechanisms that regulate the developmental fine-tuning of the retinotectal map. The decisions faced by a growing retinotectal axon are summarized in the form of a flow chart in Figure This article was written jointly by EK and ESR in consultation with MM. Figures were made by EK and MM.EK holds a Jeanne-Timmins Costello Fellowship from the Montreal Neurological Institute. MM holds a Human Frontiers Fellowship. ESR holds a Fonds de Recherche du Qu\u00e9bec - Sant\u00e9 Research Chair.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "According to a number of high quality studies intrauterine insemination (IUI) with homologous semen should be the first choice treatment in case of unexplained and moderate male factor subfertility. IVF and ICSI are clearly over-used in this selected group of infertile couples.The limited value of IUI in infertility treatment as mentioned in the 2013 NICE guidelines was surely a premature statement and should be adapted to the actual literature.More evidence-based data are becoming available on different variables influencing the success rates after IUI. It can be expected that these findings may lead to a better understanding and use of IUI in the near future. Assisted reproductive technologies (ART) are considered as an established therapy for the treatment of infertility in a multitude of clinical conditions. It embraces a wide scope of techniques of which intrauterine insemination (IUI), in-vitro fertilization (IVF) and intra-cytoplasmic sperm injection (ICSI) are most popular.Because IUI is a simple and non-invasive technique it can be performed without expensive infrastructure with a reasonable success rate within three or four cycles. It is a safe and easy treatment with minimal risks and monitoring. Subsequently IUI has a good couple compliancy (low drop-out rate) and a very low risk for complications such as OHSS (ovarian hyperstimulation syndrome).Nevertheless, the use of IUI as a first-line treatment in case of unexplained and mild/moderate male infertility remained very controversial until very recently. This was due to a lack of prospective randomized trials and large prospective cohort studies caused by the low budget linked to IUI when compared to the budget associated with other methods of assisted reproduction such as IVF and ICSI. Large multicentre trials organised by the pharmaceutical industry are not available in the IUI scene.Based on the results of an ESHRE workshop in 2009 IUI was considered to be a poor substitute for IVF and associated with a significant rate of high-order multiple births. The recommendations were made in the absence of proper trials and absent live birth data . It was The NICE guidelines  recommenSince then, a number of excellent randomized trials have been published supporting the value of IUI. In a multicentre randomised non-inferiority trial in the Netherlands, the effectiveness of IVF with single embryo transfer or IVF in a modified natural cycle was compared with the effectiveness of IUI-OS (ovarian stimulation) with a healthy live birth as the main outcome parameter . IUI-OS On the occasion of the annual meeting of ESHRE (European Society of Human Reproduction and Embryology) in Geneva, July 2017, the results of two randomized controlled trials (RCT) on IUI and unexplained infertility were presented. Cindy Farquhar showed the results of an RCT in which 201 couples with 3-4 years unexplained infertility were randomised to receive three cycles of IUI or expectant management (Farquhar et al., According to the above mentioned studies it\u2019s obvious that we are over-using IVF to treat unexplained infertility. Anno 2018 evidence-based data clearly indicate that promoting IVF and ICSI to result in pregnancy \u201cas quick as possible\u201d ignores the advantages of IUI completely in case of unexplained and mild male factor infertility."}
+{"text": "Chromosome aneuploidies generate genetic diversity and subclonal heterogeneity in the progression of human cancers. In multiple myeloma (MM), there is consensus that chromosomal aneuploidies involve two primary numerical subgroups with different prognostic significance . The larRecently we described a new numerical subgroup composed of hyperhaploid karyotypes with a range of 30-33 chromosomes [In clinical series of MM hyperhaploidy appears to be a rare numerical subgroup, or at least is rarely reported, which may be due in part to the difficulty in detecting hyperhaploid clones using current interphase FISH (iFISH) probe panels for MM. Our findings suggest that an unknown number of patients with hypotriploid or near triploid clones passed through a hyperhaploid stage without detection, and that the double chromosome number in the near triploid clones can become dominant and mask the presence of a hyperhaploid origin. Of clinical significance is the observation that the reduplication of chromosomes in the hyperhaploid clones leading to hypotriploid subclones results in these clones being masked to detection by the commonly used iFISH probes panels.In the analysis of aneuploidy patterns in cancer by single nucleotide polymorphism arrays, it has been found that most copy number aberrations (CNAs) involve almost exactly the length of a whole chromosome or chromosome arm (arm-level) or are very short  amplifications and deletions . InteresInterestingly, hyperhaploid clones are inherently monosomic for whole-chromosomes or chromosome arms harboring adverse cytogenetic lesions in MM including 17p, 1p, 13q, and 16q  and may Cytogenetic risk stratification by the International Myeloma Working Group relating to aneuploidy states that non-hyperdiploid karyotypes are considered a high-risk cytogenetic marker. We have reported the prognosis of patients with hyperhaploid karyotypes are significantly worse than patients with both hyperdiploid and hypodiploid karyotypes. Finally, when outcomes are compared in terms of the international staging system (ISS) and gene expression profiling (GEP), hyperhaploid patients have very adverse risk profiles, similar to patients with ISS stage III and GEP70 high-risk."}
+{"text": "Asthenozoospermia is considered as a common cause of male infertility and characterized by reduced sperm motility. However, the molecular mechanism that impairs sperm motility remains unknown in most cases. In the present review, we briefly reviewed the proteome of spermatozoa and seminal plasma in asthenozoospermia and considered post-translational modifications in spermatozoa of asthenozoospermia. The reduction of sperm motility in asthenozoospermic patients had been attributed to factors, for instance, energy metabolism dysfunction or structural defects in the sperm-tail protein components and the differential proteins potentially involved in sperm motility such as COX6B, ODF, TUBB2B were described. Comparative proteomic analysis open a window to discover the potential pathogenic mechanisms of asthenozoospermia and the biomarkers with clinical significance. Infertility is defined as the lack of ability to achieve a clinical pregnancy after one year or more of unprotected and well-timed intercourse with the same partner . It is eProteomic approaches, such as two-dimensional (2D) polyacrylamide gel electrophoresis, mass spectrometry (MS), matrix-assisted laser desorption ionization time of flight (MALDI-TOF) and isobaric tags for relative and absolute quantitation (iTRAQ) could be useful in identifying a wide range of the proteins responsible for diagnosis of sperm dysfunctions and the regulatory mechanism of male fertility \u201317 , associated with the production of ATP in distal regions of the flagellum , 26, hadSperm is a highly polarized cell and its motility is fully dependent on flagellum. The ability of sperm to move forward is crucial for the successful fertilization of an egg . The redTubulin is known to play a key role in the formation of microtubules of flagellum. TUBB2C is a major cytoskeletal protein present in the head and flagellum of spermatozoa and existed actual influences on sperm motility , 39. TUBHSP family proteins are stress response proteins which protect the cell against oxidative stress and pathological changes . HSPA9 iSiva et al.  employedProteasomes have been detected in sperm from various species and the major function of proteasome is to degrade nuclear and cytosolic ubiquitinated proteins \u201349. Its Mart\u0131\u2019nez-Heredia et al.  comparedPIP is a 17-kDa glycoprotein present in human seminal plasma. Its aspartyl-proteinase nature suggests its specificity to fibronectin that is one of the major protein constituents of the seminal coagulum \u201355, whic2D electrophoresis MALDI-TOF analysis was performed to compare sperm protein composition in asthenozoospermic patients with that of normozoospermic samples , 56. SixTen differentially expressed proteins involved in the regulation of sperm motility were identified by Zhao et al. and these proteins were distributed into three categories: metabolic enzymes, tructure-associated proteins and other functional proteins . ContrarPost-translational modifications especially phosphorylation play an important role in sperm motility and protein phosphorylation is reported to be a prerequisite for spermatozoa to fertilize an egg. Chan et al.  performeSeminal plasma is a mixture of secretions from the testis, epididymis and several male accessory glands and a growing number of seminal plasma proteins have been shown to be related with sperm motility. To further explore the impact of post-testicular processes on sperm motility, seminal plasma proteins from asthenozoospermia individuals and healthy men were collected and analyzed by LC-MS/MS. 101 differentially expressed proteins were identifed and Chain A, Human Dj-1 with sulfinic acid (DJ-1) was the most downregulated protein in the seminal plasma of asthenozoospermic patients. Most of these proteins enriched in the hydrolase activity, catalytic activity and enzyme regulator activity. In addition, the levels of reactive oxygen species (ROS) were higher in asthenozoospermia men and these data suggest that downregulation of the DJ-1 protein could lead to increased oxidative stress for spermatozoa which would influence the quality of the semen and sperm motility . SaraswaIn this review, we have compared data of proteome studies from asthenozoospermic men and normal individuals that evaluated the protein profile that controls infertility. Studies compiled in this work would contribute appreciably to the presently limited information available about molecular mechanism underlying sperm motility. There is a need to extend these studies to get a consistent view on the specific proteins involved in asthenozoospermia and their characterization could merit further investigation on sperm motility-related infertility. Ultimately, these findings will contribute towards the development of novel diagnostic markers of male infertility."}
+{"text": "According to embodied cognition accounts, viewing others\u2019 facial emotion can elicit the respective emotion representation in observers which entails simulations of sensory, motor, and contextual experiences. In line with that, published research found viewing others\u2019 facial emotion to elicit automatic matched facial muscle activation, which was further found to facilitate emotion recognition. Perhaps making congruent facial muscle activity explicit produces an even greater recognition advantage. If there is conflicting sensory information, i.e., incongruent facial muscle activity, this might impede recognition. The effects of actively manipulating facial muscle activity on facial emotion recognition from videos were investigated across three experimental conditions: (a) explicit imitation of viewed facial emotional expressions (stimulus-congruent condition), (b) pen-holding with the lips (stimulus-incongruent condition), and (c) passive viewing (control condition). It was hypothesised that (1) experimental condition (a) and (b) result in greater facial muscle activity than (c), (2) experimental condition (a) increases emotion recognition accuracy from others\u2019 faces compared to (c), (3) experimental condition (b) lowers recognition accuracy for expressions with a salient facial feature in the lower, but not the upper face area, compared to (c). Participants  underwent a facial emotion recognition experiment (ADFES-BIV) while electromyography (EMG) was recorded from five facial muscle sites. The experimental conditions\u2019 order was counter-balanced. Pen-holding caused stimulus-incongruent facial muscle activity for expressions with facial feature saliency in the lower face region, which reduced recognition of lower face region emotions. Explicit imitation caused stimulus-congruent facial muscle activity without modulating recognition. Methodological implications are discussed. Embodied cognition accounts postulate that there are interrelations between bodily actions  and cognitions. When we acquire memory, we store all information of the specific situation  together in a representation of the situation also containing embodiments . When weSupport for the idea that stimulus-congruent facial muscle activation facilitates facial emotion recognition comes from a study investigating the effects of actively manipulating facial movements in observers on facial emotion recognition in others. Another explanation for diminished recognition accuracy when participants\u2019 facial movements are actively manipulated  is that active manipulations themselves induce muscle feedback. Considering what is known from the literature on embodied cognition, it should be noted that such facial muscle feedback itself can have an effect on social processes such as facial emotion recognition. When mouth movement is actively manipulated, the activation in the observer\u2019s face does not align with the activation in the observed expression, instead of being stimulus-congruent as during facial mimicry. This conflicting facial muscle activation could be causing interference during the decoding of the expression leading to decreased recognition accuracy. However, if automatic stimulus-congruent facial muscle feedback in observers  facilitates facial emotion recognition, it is plausible that more intense and deliberate muscle activation could facilitate decoding of the observed facial expression of emotion even further . This assumption is supported by the results of a study by A study considering these factors was conducted by Published research has included either an explicit imitation condition or a condition where participants held a pen in their mouth, alongside a condition without any facial movement manipulation. Much of the previous research testing the effects of facial muscle manipulations on emotion recognition ability has used either static images or morphed image sequences, which are limited in ecological validity compared to other types of stimuli. Many previous studies have only used a limited number of basic emotion categories, along only two or three muscle sites in the face to measure muscle activity, which limits the measures about emotion processing and activity in the face. The present study is the first report the authors are aware of to include all three experimental conditions in one experiment to assess how facial emotion recognition is affected by explicit facial muscle activation: (1) an Explicit Imitation condition where participants were told to exactly imitate the expressions they saw while they viewed video stimuli of others displaying various emotional expressions, (2) a Pen-Holding condition where participants held a pen tightly with the lips of their mouth while they watched the videos, and (3) a Passive Viewing control condition where participants just passively viewed the videos. The present study also increased the number of emotion categories included  and measured EMG from five different muscle sites .The aim of the present study was to induce explicit facial muscle activation and to investigate the effects of actively manipulating facial muscle activity to being stimulus-congruent and stimulus-incongruent on subsequent facial emotion recognition accuracy based on more ecologically valid stimuli. There were three hypotheses: (1) Enhanced facial muscle activity throughout the face was expected to result from the Explicit Imitation condition, and in the muscles of the lower face region from the Pen-Holding condition, compared to the Passive Viewing control condition. (2) It was hypothesised that enhanced congruency of facial muscle activity between the stimuli and observers (Explicit Imitation condition) would facilitate recognition of emotion compared to the Passive Viewing control condition. (3) It was further hypothesised that the Pen-Holding condition would induce stimulus-incongruent facial muscle activity in observers\u2019 mouth region, resulting in poorer recognition of facial emotional expressions with salient facial features in the lower face region compared to the Passive Viewing control condition.SD = 3.6) were recruited through Campus advertising at the University of Bath and represented both Humanities and Science Departments (54 from Humanities and 32 from Sciences). Technical equipment failure resulted in the loss of data for two participants, resulting in a final sample of 84 participants . Based on a power analyses using G\u2217Power (t-tests), a sample size of 84 retrieves 0.78 power with an alpha level of 5% and a small effect size of dz = 0.3. The majority of participants in the final sample were undergraduate students (n = 82), with one participant enrolled in a Master\u2019s Programme and another in a Ph.D. Programme. Two participants reported about a diagnosis of Major Depression and one participant reported about a diagnosis of an Anxiety Disorder. These participants reported to be on medication and not to experience any symptoms of their mental disorders at the time of participation. Thus, these participants were included in the analyses1. All participants had normal or corrected-to-normal vision. Ethical approval for the current study was granted by the Psychology Ethics Committee at the University of Bath.A total of 86 university students  and EMG110C units for each of the five facial muscle sites  were used for recording of the EMG data. Pairs of shielded surface silver\u2013silver chloride (Ag\u2013AgCl) electrodes (EL254S) filled with conductive gel  and with a contact area of 4mm diameter were used. The EMG signal was amplified by 2000 and online bandpass filtering of 10 Hz and 500 Hz was applied. Grounding was achieved through the VIN- of the TSD203 (GSR), the data of which is not reported in this paper. The sampling rate was 1000 Hz throughout the experiment.Participants were tested in a quiet testing laboratory at the University of Bath, and written consent was obtained prior to study participation. Participants were seated approximately 60 cm from the PC monitor. Before EMG electrode attachment, participants\u2019 faces were cleaned with alcohol swabs. The 10 face EMG electrodes were then placed in pairs over the respective muscle sites on the left side of the face, which was done according to the guidelines by There were 90 trials within each of the three different conditions in the facial emotion recognition experiment: (1) Explicit Imitation, (2) Pen-Holding, and (3) Passive Viewing control condition. During the Explicit Imitation condition, participants were instructed to exactly imitate the facial expressions they observed in the videos  as soon as they perceived them. For the Pen-Holding condition, participants were told to hold a pen tightly with their lips, with one end of the pen sticking straight out of their mouth, with pressure applied by the lips (but not the teeth). This manipulation aimed to actively induce facial muscle activity, which also would be incongruent with the emotional expressions included in the study with facial feature saliency in the lower part of the face. The experimenter demonstrated to each participant how the pen was to be held in the mouth, and only after the experimenter was satisfied with the pen-holding technique, the experiment was started. The instruction for the Passive Viewing control condition was to simply watch the videos. Each trial started with a blank screen presented for 500 ms, which was followed by a fixation cross for 500 ms appearing in the centre of the screen. Immediately after the disappearance of the cross the stimulus appeared, followed by a blank screen for 500 ms before the answer screen appeared. The methods used for the facial emotion recognition task were the same as those reported in a previous study using the stimulus set and task . The ansFigure 1 displays the raw data of two selected participants across the whole experiment. Visually comparing the activity in the Passive Viewing control condition from Figures 1A,B clearly shows that the participant from Figure 1B explicitly imitated in the Passive Viewing control condition. The EMG activity of this participant was, for many trials, as intense in the Passive Viewing control condition as in the Explicit Imitation condition, whereas it should have been similar to the corrugator and frontalis channel during the pen-holding. Eighteen participants were subsequently identified to have shown explicit imitation in conditions other than the Explicit Imitation condition. Looking through the raw EMG data, a further two participants were identified who did not show constant elevated EMG activity in the muscles of the lower part of the face in the Pen-Holding condition, consistent with tightly holding a pen in their mouth . Another participant misunderstood the instructions and did the Explicit Imitation condition twice, so no data on the Passive Viewing control condition exists for this participant. Consequently, the EMG data of these participants for the experimental conditions where the instructions were not fully complied with were excluded from EMG data analyses. The same approach was taken for the accuracy of response data. In addition, there were errors for recording EMG from certain muscles for some participants, which meant the EMG data for some participants was not complete. Again, these participants were still included, but the EMG data of the muscles where problems occurred were excluded from the EMG data analyses. The resulting sample sizes per muscle in each analysis are reported in the respective results section. Participants were not fully excluded from analyses in order to retain enough power for the analyses.Several participants (who did not undergo the Explicit Imitation condition as last condition) verbally self-reported after the testing session that they were unable to stop themselves from imitating the observed facial expressions in subsequent conditions. Thus, the raw EMG data of all participants was visually inspected at trial level to identify participants whose EMG activity pattern suggested explicit imitation in other experimental conditions. Imitative activity on a trial basis during the Passive Viewing control condition was clearly visible in the raw data. The Autonomic Nervous System Laboratory 2.6 ANSLAB;  was usedWhen participants complete a task consisting of many trials or repeatedly do conditions of a new task, this produces learning effects and the participant\u2019s performance will improve over time. t-tests to test for a significant increase in accuracy of response over the course of the experiment. The alpha-level of 5% was Bonferroni-corrected to account for multiple comparisons; the resulting p-values were compared to a p-value of 0.025 (p = 0.05/2) for significance determination. The within-task improvements analysis was conducted on a sample of N = 83 . Cohen\u2019s d is presented as effect size measure. If the results show significant increase in accuracy of response from the first to the second and to the third Block, then this has important implications for the analyses. That is, between-subject analyses with only the first experimental condition each participant completed will be necessary instead of the planned within-subject analyses.To test for within-task improvements, the individual consecutive trials of the facial emotion recognition task were split into three equal \u2018blocks,\u2019 and accuracy of response was calculated for each block in order of their presentation for each participant . Then, difference scores were calculated between the accuracy of response from the first and second block and between the second and third block. The two resulting difference scores were tested for a significant change using one-sample t-tests showed that there was a significant increase in accuracy of response for participants from the first to the second Block , and from the second to the third Block . Since accuracy scores increased significantly over the course of the experiment, between-subject analyses needed to be conducted to test the hypotheses of the current study. . Due to the right-skewed nature of the EMG data, gamma distribution and log link function were specified in the conducted analyses. Pairwise comparisons were used to follow up significant main effects of Experimental Condition. Due to the necessary data eliminations described in Section \u201cEMG Data Preparation,\u201d the sample sizes for the EMG data per experimental condition varied. The resulting zygomaticus muscle showed a significant main effect of Experimental Condition ; see Figure 2. Pairwise comparisons showed that the EMG activity in the zygomaticus was significantly higher in the Explicit Imitation condition  than in the Passive Viewing control condition , but was not significantly different from the Pen-Holding condition . The EMG activity in the zygomaticus during the Pen-Holding condition was significantly higher than during the Passive Viewing control condition (p < 0.001).Generalised linear model results for the EMG activity in the depressor muscle showed a significant main effect of Experimental Condition ; see Figure 2. Pairwise comparisons showed that the EMG activity in the depressor was significantly lower in the Explicit Imitation condition  than in the Pen-Holding condition  and significantly higher in the Explicit Imitation condition than in the Passive Viewing control condition . The EMG activity in the depressor during the Pen-Holding condition was significantly higher than during the Passive Viewing control condition (p < 0.001).Generalised linear model results for the EMG activity in the levator showed a significant main effect of Experimental Condition ; see Figure 2. Pairwise comparisons showed that the EMG activity in the levator was significantly lower in the Explicit Imitation condition  than in the Pen-Holding condition  and significantly higher in the Explicit Imitation condition than in the Passive Viewing control condition . The EMG activity in the levator during the Pen-Holding condition was significantly higher than during the Passive Viewing control condition (p < 0.001).Generalised linear model results for the EMG activity in the corrugator showed a significant main effect of Experimental Condition ; see Figure 2. Pairwise comparisons showed that the EMG activity in the corrugator was significantly higher in the Explicit Imitation condition  than in the Passive Viewing control condition  and the Pen-Holding condition . The EMG activity in the corrugator during the Pen-Holding condition was not significantly different than during the Passive Viewing control condition (p = 0.466).Generalised linear model results for the EMG activity in the frontalis showed a significant main effect of Experimental Condition ; see Figure 2. Pairwise comparisons showed that the EMG activity in the frontalis was significantly higher in the Explicit Imitation condition  than in the Pen-Holding condition  and the Passive Viewing control condition . The EMG activity in the frontalis during the Pen-Holding condition was not significantly different from the Passive Viewing control condition (p = 0.125).Generalised linear model results for the EMG activity in the Since it was hypothesised that the pen-holding would affect recognition of emotional expressions with facial feature saliency in the lower part of the face but not the upper part of the face, respective variables for the recognition scores were created. The \u2018lower face saliency\u2019 variable included accuracy scores for disgust, happiness, embarrassment, contempt, and pride. The \u2018upper face saliency\u2019 variable included accuracy scores for anger, fear, sadness, and surprise. This categorisation was based on the location of the facial features that are characteristic for each expression (and the number thereof) in the face stimulus set used; a table listing all facial features per emotion category is printed in n = 28 for the Passive Viewing control condition  and the Explicit Imitation condition . The sample size was 26  for the Pen-Holding condition. Three comparisons were conducted using independent samples t-tests to test the hypotheses of the current study. The accuracy scores of the variable \u2018all emotion categories\u2019 from the Explicit Imitation condition were compared to the accuracy scores from the Passive Viewing control condition to test whether enhanced stimulus-congruent facial muscle activation facilitated recognition. To test whether stimulus-incongruent facial muscle activation impeded recognition, the accuracy scores of the variables \u2018lower face saliency\u2019 and \u2018upper face saliency\u2019 from the Pen-Holding were compared to the Passive Viewing control condition. The alpha-level of 5% was Bonferroni-corrected to account for multiple comparisons. The resulting p-values were compared to a p-value of 0.017 (p = 0.05/3) for significance determination. Cohen\u2019s d is presented as effect size measure.Only the first experimental condition a participant underwent was included in the between-subject analyses, as the first condition naturally could not have been influenced by former instructions. This between-subject approach decreased the sample size to t-test comparing accuracy of response across \u2018all emotion categories\u2019 included in the task from the Explicit Imitation condition  to the Passive Viewing control condition  showed no significant difference between the two experimental conditions ; see Figure 3A.The independent samples t-tests showed that the accuracy rates were significantly higher in the Passive Viewing control condition  than in the Pen-Holding condition  = 2.53, p = 0.014) with a medium to large effect size (Cohen\u2019s d = 0.688); see Figure 3B.Comparing the accuracy rates of the \u2018lower face saliency\u2019 emotion category using independent samples t-tests showed that the accuracy rates from the Passive Viewing control condition  were not significantly different from the Pen-Holding condition ; see Figure 3C.Comparing the accuracy rates of the \u2018upper face saliency\u2019 emotion category using independent samples The current study investigated the effects of active facial muscle manipulations in observers on their ability to recognise emotions from others\u2019 faces. Results showed that facial muscle manipulations effectively changed observers\u2019 facial muscle activity. Holding a pen in the mouth increased the activity of facial muscles in the lower face region compared to a control condition with no facial movement manipulation, while explicit imitation of observed facial emotion produced enhanced facial muscle activity across the face compared to the control condition. In line with the facial muscle manipulation, holding a pen in the mouth was found to produce lower accuracy for recognising facial displays of emotion when the most salient facial feature was in the lower face region compared to passively viewing emotional expressions. In contrast, explicitly imitating the emotional expression seen in others did not result in greater recognition of these emotional expressions compared to passive viewing of the videos. The current findings provide support for embodied cognition accounts, but only when the experimental condition involved stimulus-incongruent facial muscle activity while observing emotional expressions in others, and not when the condition involved stimulus-congruent facial muscle activity. The methodological implications for investigations like the current research with a within-subject study design are discussed.Based on embodied cognition accounts, it was hypothesised that explicit facial muscle activity that is congruent with the observed facial expression would increase recognition rates compared to passive viewing. While explicitly imitating the perceived facial expressions of emotion by others in videos resulted in higher facial muscle activity compared to when they passively viewed the facial expressions, results showed the explicit imitation of others emotions had no facilitating effect on facial emotion recognition. These results are in line with those by As expected, holding a pen in the mouth caused increased EMG activity in the muscles of the lower face region, especially the depressor muscle. Further in line with the predictions, accuracy scores were significantly lower in the Pen-Holding condition compared to the Passive Viewing control condition when recognising emotional expressions with feature saliency in the lower face region. Effects for mouth movement manipulations on recognition of emotions with saliency in the lower face region are in line with previous studies. For example, disgust and happiness recognition are impaired when mouth movements are manipulated with a pen compared to passive viewing without facial movement manipulation . For botAn alternative interpretation is that facial muscle activations, as achieved through pen-holding, induce facial muscle feedback that is incongruent with the muscle activation underlying the observed facial expression. Since embodiments also include the typical facial expressions of emotions, it was proposed that facial muscle feedback in an observer that is in conflict with the perceived visual information might hamper recognition . StimuluThe Explicit Imitation condition and the Pen-Holding condition required additional action from the participants as opposed to the Passive Viewing condition. It could be argued that the results from the current study are based on the additional cognitive load the experimental conditions imposed rather than specific effects of the manipulations. However, The current study manipulated the muscles of the lower face region, but not the muscles of the upper face region. Future research should systematically test the effects of stimulus-incongruent muscle activity across the entire face on facial emotion recognition. Researchers have attempted to fix facial muscles in the upper face region by instructing participants to perform certain facial movements e.g., . It is lResults from the within-subject analyses of the current study showed that the accuracy rates from the Pen-Holding condition were comparable to the Passive Viewing control condition, against the expectation for the emotions with saliency in the lower face region. This finding can, however, be explained by a combination of two occurrences. The first occurrence was the necessary data eliminations, which lead to uneven numbers of participants for the six versions of the experiment. More participants underwent the Passive Viewing control condition first in the experiment sequence than last, while the number of participants per order in the Pen-Holding condition was similar. The second occurrence was the increase in recognition accuracy over the course of the experiment producing higher recognition rates in the last experimental condition a participant underwent. Combining these two occurrences resulted in lower mean accuracy scores for the Passive Viewing control condition, making the mean similar to the mean from the Pen-Holding condition instead of higher. The small albeit non-significant increase in facial emotion recognition when explicitly imitating observed facial expressions compared to the Passive Viewing control condition from the current study can also be explained by the combination of necessary data eliminations and an increase in recognition accuracy over the course of the experiment, as most participants included in the analyses underwent the Explicit Imitation condition last in the experiment. Consequently, theoretical interpretation of the findings from the within-subject analyses of the current study is problematic.The advantage of a within-subject design is usually that the found effects are the result of the experimental manipulations and not due to potential differences between samples as can be the case in between-subject designs, thereby reducing the error variance. However, the instruction to explicitly imitate the observed facial expressions turned out to have a lasting effect on more than a few participants in the current study. Those participants showed a similar pattern of facial muscle activation in the Pen-Holding condition and Passive Viewing control condition as during the Explicit Imitation condition when the Explicit Imitation condition preceded these conditions. This occurrence indicates that explicit imitation was carried out in the other experimental conditions as well (and led to data loss in the current study). This occurrence is very important to consider for researchers who are intending to conduct research similar to the current study. To avoid data eliminations and potential resulting data confounding effects (see next paragraph), it is advisable to apply a between-subject design. Nonetheless, the instruction to explicitly imitate facial emotional expressions having such a long-lasting effect constitutes an interesting finding in itself. The question why some people automatically keep imitating expressions against the task instructions should gain further attention in future research of this type. Example research questions to address could be: Are these individuals more likely to experience emotion contagion? Do those individuals possess higher empathy?Further noteworthy is the continuous increase in accuracy of response over the course of the experiment in the current study, independent of the instructions given to participants for the various experimental conditions. The resulting methodological implication is the importance to balance the order of presentation of the experimental conditions when using a within-subject design (as done with the current study) or to apply a between-subject design. The latter option is recommendable when it is likely that unequal amounts of participants will be excluded per order of experimental condition. Nonetheless, that accuracy rates do increase even without the explicit feedback about the correctness of the response is interesting. It indicates some sort of underlying learning processes and it is possible that focussing attention on decoding of facial emotion also outside the laboratory in everyday social interactions might lead to improvements in facial emotion recognition, which could be particularly relevant for clinical populations with impairments in facial emotion recognition.Taken together, the current study showed that explicit stimulus-incongruent facial muscle activations in observers hamper recognition compared to passively viewing expressions. It was further demonstrated that explicit stimulus-congruent facial muscle activation does not lead to a facial emotion recognition advantage compared to passively viewing expressions. This latter finding is peculiar since awareness was added to the stimulus-congruent facial muscle activations and the facial muscle activation was explicit . Nonetheless, the results from the current study imply that stimulus-congruent facial muscle activations in observers have no facilitating effect on facial emotion recognition and that only stimulus-incongruent facial muscle activations hamper recognition. Given that observing facial emotion might elicit an emotion representation, incongruency between an observed emotion and the facial activity in the observer\u2019s face might disrupt the encoding process due to the embodiment of facial emotional expressions, in line with embodied cognition accounts of emotion.This study was carried out in accordance with the recommendations of the University of Bath Psychology Ethics Committee with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the University of Bath Psychology Ethics Committee.TW conceptualised, designed, and carried out the study. MB, CA, and MoP supervised TW. MiP and TW prepared the data for analyses. MoP provided the means for data preparation. TW analysed the data and interpreted the results. TW wrote the manuscript. All authors edited the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Several large copy number variants (CNVs) in the genomic sequence are strongly associated with schizophrenia. These loci are important objects of study in their own right as well as enticing points of entry for the better understanding of the molecular etiology of schizophrenia. However, most of the schizophrenia-associated large CNVs are larger than one million base pairs and affect up to several dozen genes, presenting a complex challenge for research aiming to determine how these sequence variants are connected on the molecular level to the phenotype.We have established iPSC based tissue culture models for three of the major schizophrenia associated large CNVs, on chromosomes 22q11 (deletion), 15q13 (deletion) and 16p11 (deletion or duplication). We create neuronal cells with the defined genotypes using either direct induction into the neuronal state , by slower differentiation via neuronal precursor cells (NPCs) or by generating 3D cultures of cortical spheroids. We then assay the molecular effects of the large CNVs along the trajectory of differentiation by using RNA-Seq (transcriptome), ATAC-Seq (chromatin state) and SeqCap-Epi (DNA-methylation patterns). We also carry out single-cell RNA-Seq analysis using the drop-Seq approach.We detect common effects across the large CNVs as well as locus-specific phenomena. For the most part genes within the CNV boundaries will change their expression patterns in concordance with their new copy number, with notable exceptions. Transcriptome-wide there is a network effect where several hundred genes are differentially expressed, including genes already identified as candidate genes for schizophrenia. Epigenomic states are affected, again most often not only in or nearby the boundaries of the large CNVs but epigenome-wide. Integrative analysis across the layers of molecular signals shows partial concordance as well as a degree of changes in signal being \u2018offset\u2019 between the levels, potentially owing to the dynamic differentiation state of the model system.Neuronal tissue culture models based on iPSCs with defined large CNVs strongly associated with Schizophrenia allow for an analysis of the effects of such structural genomic sequence changes in disease-relevant cellular differentiation states. Application of cutting edge genomics and epigenomics assays and integrative data analysis reveals incomplete transcriptional dosage compensation of the genes within the large CNVs as well as transcriptome-wide network effects. Furthermore, there are epigenomic effects in the form of altered chromatin states that may to some extent mediate the gene expression changes. Differences between the large CNV loci as well as potential points of convergence will be discussed."}
+{"text": "We present a brief review of the microstructures and mechanical properties of selected metallic alloys processed by additive manufacturing (AM). Three different alloys, covering a large range of technology readiness levels, are selected to illustrate particular microstructural features developed by AM and clarify the engineering paradigm relating process\u2013microstructure\u2013property. With Ti-6Al-4V the emphasis is placed on the formation of metallurgical defects and microstructures induced by AM and their role on mechanical properties. The effects of the large in-built dislocation density, surface roughness and build atmosphere on mechanical and damage properties are discussed using steels. The impact of rapid solidification inherent to AM on phase selection is highlighted for high-entropy alloys. Using property maps, published mechanical properties of additive manufactured alloys are graphically summarized and compared to conventionally processed counterparts.  The SEBM process is similar to SLM with the difference that an electron beam is used instead of the laser to preheat and fuse the powder bed layers in a vacuum chamber ."}
+{"text": "Retinoblastoma is rare tumor of the retina caused by the homozygous loss of the Retinoblastoma 1 tumor suppressor gene (RB1). Loss of the RB1 protein, pRB, results in de-regulated activity of the E2F transcription factors, chromatin changes and developmental defects leading to tumor development. Extensive microarray profiles of these tumors have enabled the identification of genes sensitive to pRB disruption, however, this technology has a number of limitations in the RNA profiles that they generate. The advent of RNA-sequencing has enabled the global profiling of all of the RNA within the cell including both coding and non-coding features and the detection of aberrant RNA processing events. In this perspective, we focus on discussing how RNA-sequencing of rare Retinoblastoma tumors will build on existing data and open up new area\u2019s to improve our understanding of the biology of these tumors. In particular, we discuss how the RB-research field may be to use this data to determine how RB1 loss results in the expression of; non-coding RNAs, causes aberrant RNA processing events and how a deeper analysis of metabolic RNA changes can be utilized to model tumor specific shifts in metabolism. Each section discusses new opportunities and challenges associated with these types of analyses and aims to provide an honest assessment of how understanding these different processes may contribute to the treatment of Retinoblastoma. Rb1: gene, pRB: protein) gene and the E2 promoter binding Factors (E2Fs) function to control both of these pathways  cells as the major cells of origin of Retinoblastoma . High reFigure 1).Pioneering studies into the transcriptome of Retinoblastoma tumors using microarrays have provided critical foundations for our understanding of the disease. The advent of new and unbiased profiling of the RNA content of cells by RNA-sequencing (RNA-seq) significantly increases the resolution of the RNA measurements and can be expanded to include non-coding expression and detection of rare RNA fusion products. RNA-seq provides enhanced transcriptomic profiling by directly sequencing the RNA or DNA copies of the RNA and comparing it to the genome rather than relying on probe detection on traditional microarrays. This technology therefore circumvents the need to test RNA on pre-determined gene sets and can interrogate the entire transcriptome. RNA-seq platforms can measure all the RNA of cells, however, require the removal of very abundant RNA species within the cells that do not contribute to the transcriptome including ribosomal RNA (rRNA) and transfer RNA (tRNA). This critical experimental step depletes these specific RNA species from the cellular pool of RNA before library preparation and increases the overall coverage and depth of RNA-seq reads on the remaining genes. Currently RNA-seq datasets of Retinoblastoma tumors and normal controls have not been published, however, several independent teams are known to be working to generate these exciting datasets. In this perspective, we discuss three exciting opportunities that RNA-seq datasets of Retinoblastoma tumor may provide to the research community . E2F1-3 are potent inducers of transcription and in particular genes required for cell cycle progression and apoptosis, however, very little is known about how these factors control LINC-RNA expression. Preliminary studies from cell lines mapping activator E2F-mediated regulation of LINCs have suggested that a significant number of these RNAs may show transcriptional changes upon RB-loss via both direct and in-direct mechanisms . In addiin vitro or in model organisms changes the LINC expression profile is limited, determining how RB1 homozygote mutation affects LINC levels in a complex and developmentally disorganized Retinoblastoma tumor represents a real challenge. With the development of RNA-sequencing that unbiasedly measures the levels of RNA in cells without the need to purify polyadenylated mRNAs or have probes designed against the transcriptome we can now, for the first time, interrogate the entire transcriptome of these tumors. This new approach will enable the development of Retinoblastoma specific LINC-RNA profiles and may generate clinically predictive biomarkers for identifying patients likely to develop secondary tumors. However, significant technical challenges have arisen in other tumor types when profiling LINC-RNAs. These are generally due to the lower expression levels of most LINC-RNAs compared to coding mRNAs and the high variability between patients. RNA-seq reads at the lower end of the runs tend to have greater signal to noise levels than better expressed mRNAs which can make generating predictive LINC profiles from small numbers of tumors difficult. This is a potential issue in Retinoblastoma studies as these tumors are rare and both normal control and tumor cohort size tends to be smaller than for more common adult malignancies.Given that our understanding of how RB1 loss Figure 2). Profiling Retinoblastoma by RNA-seq technology will help fill some of the gaps in our knowledge and provide new insights into how RB1-loss may change the LINC-RNA transcriptome of these aggressive tumors but also to those in more genetically complex adult tumors.Although there are currently significant gaps in our understanding of how RB1 and the E2F pathway modulate the expression of the LINC-RNA transcriptome in cells and in tumors there seems to be little doubt that expanding our knowledge about how RB1-loss changes the entire transcriptome is an exciting and clinically relevant question . Such events would normally be excluded or undetectable with traditional microarray technology. Finding and mapping these rare events is an area of growing interest as the aberrant proteins are potential neo-antigens which can be recognized by the patients\u2019 immune system. A number of groups have highlighted the utility of these \u201cabnormal\u201d products for the clearance of tumors, although as yet not in Retinoblastoma, to immunotherapy. This is an emerging clinical avenue and in particular could have significant advantages in the treatment of Retinoblastoma as it would reduce the exposure of pediatric patients to developmentally harmful chemotoxic treatments. The detection and mapping of these events is possible with deep RNA-seq coverage and may provide insights into how splicing and/or RNA metabolism is changed in Retinoblastoma tumors.In addition to the documentation of LINC-RNA and other non-coding RNA changes caused by RB1 loss, RNA-seq also enables the measurement and identification of novel or fusion RNAs in samples. The pRB protein has important roles in modulating genomic integrity and stability and loss of pRB has been shown to contribute to accelerated genome manipulations and enhanced drug sensitivity. RNA-seq of Retinoblastoma tumors may also enable the identification of novel RNA species caused by genomic rearrangements or aberrant RNA processing events . This approach has previously been employed to assay model organisms, tissue and drug treatment network maps . One limMicroarray profiling of Retinoblastoma tumors has been instrumental in identifying the aberrant pathways driving the growth and invasion of the tumors. These approaches have really built an immense foundation that has enabled the Retinoblastoma research field to test and develop new ways to therapeutically target these tumors. This technology, that has served us so well, has a number of limitations that can be largely circumvented by the use of RNA-sequencing. In particular, RNA-seq measures both coding and non-coding RNAs changes which may be invaluable to understanding the biology of these tumors but also in helping to stratify patients into different treatment outcome or relapse groups. Collectively, this tool enables us to interrogate the biology sustaining Retinoblastoma tumor growth and may led to discovery of new therapeutic approaches to treat these patients.The protocol was approved by institutional review board on Ethical practices for research at Sankara Nethralaya.SE and WM contributed to the conception, preparation, and revision of the manuscript. SR built the figures. All of the authors approved and agreed on the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Homocysteine (Hcy) is a toxic, sulfur-containing intermediate of methionine metabolism. Hyperhomocysteinemia (hHcy), as a consequence of impaired Hcy metabolism or defects in crucial co-factors that participate in its recycling, is assumed as an independent human stroke risk factor. Neural cells are sensitive to prolonged hHcy treatment, because Hcy cannot be metabolized either by the transsulfuration pathway or by the folate/vitamin B12 independent remethylation pathway. Its detrimental effect after ischemia-induced damage includes accumulation of reactive oxygen species (ROS) and posttranslational modifications of proteins via homocysteinylation and thiolation. Ischemic preconditioning (IPC) is an adaptive response of the CNS to sub-lethal ischemia, which elevates tissues tolerance to subsequent ischemia. The main focus of this review is on the recent data on homocysteine metabolism and mechanisms of its neurotoxicity. In this context, the review documents an increased oxidative stress and functional modification of enzymes involved in redox balance in experimentally induced hyperhomocysteinemia. It also gives an interpretation whether hyperhomocysteinemia alone or in combination with IPC affects the ischemia-induced neurodegenerative changes as well as intracellular signaling. Studies document that hHcy alone significantly increased Fluoro-Jade C- and TUNEL-positive cell neurodegeneration in the rat hippocampus as well as in the cortex. IPC, even if combined with hHcy, could still preserve the neuronal tissue from the lethal ischemic effects. This review also describes the changes in the mitogen-activated protein kinase (MAPK) protein pathways following ischemic injury and IPC. These studies provide evidence for the interplay and tight integration between ERK and p38 MAPK signaling mechanisms in response to the hHcy and also in association of hHcy with ischemia/IPC challenge in the rat brain. Further investigations of the protective factors leading to ischemic tolerance and recognition of the co-morbid risk factors would result in development of new avenues for exploration of novel therapeutics against ischemia and stroke. These mechanisms can also be artificially induced by various approaches resulting in the protective state known as ischemic tolerance  is an intermediate sulfhydryl- containing amino acid derived from methionine. It has been proved to be toxic for neuronal and vascular endothelial cells Figure . In humaHomocysteine is metabolized from methionine by three independent alternative pathways:re-methylation,transmethylation to methionine,trans-sulfuration to cysteine.Though mutations or polymorphisms in the key genes encoding enzymes of Hcy metabolic pathways have been well elucidated in cardiovascular disorders and also in stroke, the epigenetic mechanisms, such as DNA methylation, chromatin remodeling, RNA editing, noncoding RNAs (ncRNAs) and microRNAs (miRNAs) are now involved in the ethiology of stroke  we observed significant cell death which allowed us to suggest that Hcy-induced impairment of neuronal functions with damage to the glial cells might contribute to the etiopathogenesis of neurological disorders associated with hHcy  epithelial cells via a specific saturable receptor in addition to simple diffusion , intermediate (for concentrations of 31\u2013100 \u03bcmol/l) and severe (for concentrations higher than 100 \u03bcmol/l) which is also manifested with clinical symptoms of homocystinuria  and ionotropic (AMPA) receptors, as well as for N-methyl-D-aspartate receptor (NMDA)  formed in redox reactions involving the thiol group of Hcy was responsible for the toxicity of this compound. The major drawback of this hypothesis was that Cys (which is a common amino acid) is not a risk factor for vascular diseases, despite its up to 30-fold higher concentration than Hcy -dependent generation of the superoxide anion via uncoupling of endothelial NOS (eNOS),disruption of extracellular superoxide dismutase from endothelial surfaces, andactivation of NADPH oxidases.Moreover production of a strong oxidant peroxynitrite activates tyrosine nitration and results in modifications of protein function and cellular dysfunction  stress  comparing to normal individuals  activity in cortical mitochondria in the hHcy model in rats. This enzyme belongs to the first line of cellular defense against oxidative injury and has been observed to be diminished in the hHcy group compared to the control group. These results are consonant with very recent experiments of Longoni et al.  complex II, and inhibits the ETC complex IV activity /PI cells but did not induce GFAP(+)/PI cells. Calcitriol prevented these alterations likely by increasing the level of the vitamin D receptor. These findings suggest that calcitriol treatment may be one of the therapeutic strategies against cerebral complications caused by Hcy.Similarly, results from hHcy experiments  release into the extracellular fluid. Hcy increased the LDH release suggesting an aggravated tissue injury caused by hypoxic/ischemic conditions  initiated morphological degenerative alteration and also affected considerably the expression of the MAPKs pathways by massive activation of MAPK/p-p38 with a maximum at 24 h after reperfusion  in patients with cerebral stroke through apoptosis. Ischemic insults activates migration of EPCs from bone marrow to repair damaged sites either through direct incorporation of EPCs or by repopulating mature endothelial cells. Increased level of Hcy mediates toxicity to EPC due to apoptosis involving caspase-8, cytochrome c release, and caspase-3 activation and thus making reduction of EPC numbers  are implicated in these processes. As a result, its might lead to hypermethylation of the genomic DNA and silencing of functional genes \u2014associated enzyme, Hcy \u2013thiolactonase/paraoxonase 1 (PON1)  and/or exogenous factors (dietary deficiency of folate and vitamins) and may be involved in hHcy pathogenesis. Thus, revealing many factors that may affect the methyl balance and understanding the pathophysiology of diseases from \u201cmethylation point of view\u201d still remain a great challenge. Advanced studies are needed to understand whether and how changes in DNA methylation patterns, global and gene specific are associated with elevated levels of Hcy in the context to diseases and risk factors, such as oxidative stress, aging and exposure to drugs.In this review we made an attempt to summarize and also emphasizes the results of novel experimental paradigm which combines only hHcy conditions  and together with the ischemic insult and preconditioning maneuvers. Induction of hHCy alone leads to progressive neuronal cell death and morphological changes in the hippocampus and cerebral cortex in the rats. Ischemic reperfusion injury activates degeneration processes and de-regulates intracellular signaling which are aggravated under hHcy conditions.The preischemic maneuver (preconditioning) evolves the state of ischemic tolerance manifested by the attenuated extent of neuronal degeneration as well as the intracellular signaling involved in the tolerance phenomenon. Combination of preconditioning with the hHcy retains the integrity of the majority of hippocampal neurons and also stimulates recovery of the expression rate of both the SPCA1 mRNA and the protein. Preconditioning even if combined with hHCy could still preserve the neuronal tissue from the lethal ischemic effect. The studies also emphasize the opposing effects of MAPK/ERK and MAPK/p38 signaling pathway on cell survival and cell death in the condition of preconditioned hHcy ischemia in the rat model of human stroke. The increased prevalence of hHcy in the population and crucial role of elevated Hcy levels in pathogenesis of different diseases, make this amino acid as an interesting target for future research.In the human brain pathology, IPC is hardly suitable as a preventative measure in the predispose cerebrovascular patients. However, it could be used as a precaution against secondary stroke following medical procedures such as aneurysm repair or cardiac surgery. From the clinical point of view, use of preischemia/preconditioning challenge may bring some complications (Dirnagl et al., Further investigations of the protective factors leading to ischemic tolerance and recognition of the co-morbid risk factors would result in development avenues for exploring novel therapeutics against ischemia and stroke. Usefulness and validity of Hcy as a biomarker of some diseases is another research challenge.All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The past decade has seen considerable excitement in the use of biological therapies in treating neoplastic disease. In particular, cancer immunotherapy and oncolytic virotherapy have emerged as two frontrunners in this regard with the first FDA approvals for agents in both categories being obtained in the last 5 years. It is becoming increasingly apparent that these two approaches are not mutually exclusive and that much of the therapeutic benefit obtained from the use of oncolytic viruses (OVs) is in fact the result of their immunotherapeutic function. Indeed, OVs have been shown to recruit and activate an antitumor immune response and much of the current work in this field centers around increasing this activity through strategies such as engineering genes for immunomodulators into OV backbones. Because of their broad immunostimulatory functions, OVs can also be rationally combined with a variety of other immunotherapeutic approaches including cancer vaccination strategies, adoptive cell transfer and checkpoint blockade. Therefore, while they are important therapeutics in their own right, the true power of OVs may lie in their ability to enhance the effectiveness of a wide range of immunotherapies. The plethora of side effects associated with current standard of care treatments for cancer stem from their limited ability to consistently distinguish between healthy and diseased tissue. While the development of targeted therapies has sought to overcome this issue, these strategies often fall prey to either acquired or intrinsic resistance in tumors which are by nature heterogeneous and highly mutable . BiologiWhile advances in the fields of cancer immunotherapy and oncolytic virotherapy have ushered in a new era of promise, these treatments are not successful for all patients. For example, in a clinical trial using Imlygic in patients with advanced melanoma the durable response rate was 16% compared to 2% when treated with GM-CSF alone . SimilarIt is becoming increasingly accepted that oncolytic viruses (OVs) function as immunotherapeutic agents  and thusThe therapeutic benefit of viral infection in cancer therapy was first described over a century ago  and seveThe tropism of many viruses for cancerous tissue is not surprising given the highly proliferative nature and immune dysregulation associated with oncogenic transformation and tumor establishment . Indeed,Rhabdoviridae family, have been lauded as ideal oncolytic agents. This is partially due to their low pathogenicity and established immunity in human populations as well as the relative ease with which they can be genetically engineered [While the natural propensity of OVs to infect and lyse cancer cells provides a useful backbone off which to build, efforts to enhance the cancer-selectivity of OVs through genetic engineering have enabled much of the recent progress in the field . This spgineered . The matgineered . Deletiogineered ,21.While early interest in the field of oncolytic virotherapy revolved around the cancer-specific lytic (direct killing) ability of these agents, the first wave of clinical trials were widely regarded as disappointing . AdenoviIt is well documented that viral infection of a tissue stimulates the recruitment and activation of the immune system leading to elimination of infected cells and protection or immunopathology . The immImmune activation in the context of tissue infection can be viewed as occurring through two complementary mechanisms, pathogen associated molecular patterns (PAMPs) and danger associated molecular patterns (DAMPs). PAMPs represent broadly expressed constituents of different classes of microbes which can be detected by invariant pattern recognition receptors (PRRs) on innate immune cells. This allows the immune system to recognize \u201cinfectious non-self\u201d ,34. The OV infection also serves to enhance the repertoire of tumor-associated antigens (TAA) to which an immune response can be mounted. Signals derived from virally infected cells can promote cross-presentation of endocytosed antigens by DCs and thereby generate a CD8 T-cell response ,49. In aWhile activation is a crucial component of the OV-mediated immune response, the trafficking of additional immune cells to the tumor also represents a potent mechanism of oncolytic virus immunotherapy. Chemokines and cytokines are the immune system\u2019s signals for cell recruitment to a site of infection. OVs are demonstrably capable of inducing the expression of these signals within the tumor as well as their receptors on relevant immune cells. VSV and VacV infection of tumors has been shown to result in the production of the pro-inflammatory chemokines CXCL1 and CXCL5 which mediate neutrophil recruitment and enhanced therapeutic outcome . Gujar eDespite increasing evidence that much of the therapeutic benefit observed by OVs is the result of their orchestration of an antitumor immune response, when administered as monotherapies, OVs have yet to consistently demonstrate the desired clinical outcome. Though the existence of an OV-mediated immune stimulation is well documented, it appears that this alone is insufficient to produce reliable cures in the clinic. However, in understanding the strengths and weaknesses of the OV-induced immune response, one can begin to rationally combine these agents with a variety of other immunotherapies in order to play to the strengths and compensate for the weaknesses of either approach alone. This endeavour has met with early success across virtually all forms of immunotherapy and much of the most promising preclinical and clinical data using OVs comes from such strategies.Given that a key mechanism of OV therapy involves the induction of a cancer-targeted immune response but that this response is typically insufficient to mediate durable remission, a logical next step involves the genetic modification of OVs to enhance their immunostimulatory ability. To this end a plethora of cytokine-engineered OVs have been generated with the goal of further enhancing immune recruitment and activation beyond what is achieved by any OV naturally . CytokinOne of the most commonly used cytokines in OV backbones has been the granulocyte macrophage colony stimulating factor (GM-CSF) . GM-CSF A variety of other cytokines have been engineered into OV backbones in efforts to increase immune activation. IL-2 has been shown to enhance a T-cell response in animal models of cancer but its\u2019 systemic application has come with a plethora of toxicities . In a scAnother immune activating group of cytokines are the interferons (IFNs). Though accompanied by significant clinical side effects, systemic IFN-\u03b1 administration has been used directly as a treatment for a variety of malignancies. In addition to direct antiproliferative effects on tumors, it also has immune activating properties in terms of MHC I upregulation and direct effects on cells of the immune system such as macrophages and NK cells ,68. In aA plethora of other immunostimulatory cytokines have been engineered into various OV backbones, a comprehensive list of which can be found in . AnotherAs demonstrated above, strategies aimed at increasing the immunostimulatory potential of OVs clearly produce therapeutic benefits but have yet to achieve the sought after durable remissions. Therefore, evidence for the augmented effect of combining these agents with other therapies such as cancer vaccines  is encouThe description of TAAs as potentially cancer-specific targets  spawned From a conceptual standpoint, OVs have the potential to address several of these criteria and thus synergize with a variety of these vaccination approaches. The anti-cancer immune response elicited by OVs upon infection and induction of immunogenic cell death within the tumor has been termed in situ vaccination . In thisThe natural vaccinating propensity of OVs can also be enhanced through further manipulation of the viruses. For example, Lemay et al. demonstrated that infecting an irradiated cancer cell vaccine with oncolytic VSV prior to its administration led to an improved therapeutic outcome when compared to the cell vaccine alone; an effect which the authors attributed to the adjuvant effects of the virus. Indeed, vaccine-mediated protection was enhanced when the virus was engineered to express GM-CSF and was mediated through improved activation of DCs and a concomitant increase in T and NK cell responses . In anotOne strategy to direct the vaccinating effect of OVs has been to generate recombinant OVs which encode a tumor-associated antigen in the viral genome, termed oncolytic virus vaccine (OVV). This provides the induced immune response with a defined target as opposed to relying on the release of antigens upon tumor cell lysis. For example, expression of HY  by VacV has been used in conjunction with a VacV expressing GM-CSF to induce a T-cell response against this target antigen . DespiteIn order to circumvent the antiviral immune response and achieve a robust antitumor response in the context of OV vaccination, a heterologous prime-boost strategy has been taken . In thisEFF) targeting hDCT was still underway [+ DCs and presented to central memory T cells (TCM) that are also located within B cell follicles. Since effector T-cells cannot traffic through follicular regions , prolonged antigen production and presentation by follicular APCs is secured [hDCT-expressing Maraba MG1 was also demonstrated to be a strong boosting vector, producing higher levels of activated CD8+ T-cells than did VSV boosting. Interestingly, Maraba MG1-hDCT had improved boost at shorter intervals and required intravenous administration to provide its\u2019 full effect . This waunderway . Subsequunderway  have sho secured . This un secured .The use of heterologous prime-boost protocols has clearly demonstrated the potential of oncolytic vaccines to recruit and expand a pre-existing (primed) anti-tumor response ,90. PrimOne way to ensure the presence of a robust pre-existing antitumor T-cell response would be to directly transfer primed T-cells into the patient. Adoptive cell therapy (ACT) as it is known, involves the administration of ex vivo cultured cancer targeted T-cells to mediate cancer killing. These T-cells can be inherently TAA-specific lymphocytes isolated from a patient\u2019s tumor or enriched from peripheral blood monocytes (PBMCs). They can also be cells that have been artificially reprogramed for cancer targeting through various recombinant DNA technologies ,99. SuchCM) will traffic to secondary lymphoid organs upon adoptive transfer but could theoretically be driven to proliferate and subsequently recruited to the tumor through boosting with an OVV, just as previously described in the prime-boost therapy platform [Another major difficulty faced in the effective clinical use of ACT has been the poor persistence of cells following transfer . While iplatform . Becauseplatform ,109. In platform  or virusplatform  or CAR [platform ,109  and programmed death ligand 1 (PDL-1) represent T-cell expressed checkpoint receptors extensively studied for their role in tumor immunosuppression ,116,117.Immune checkpoint blockade is a strategy to target and block these immunoregulatory mechanisms with the use of antibodies in order to \u2018release the brake\u2019 on the immune response to TAAs . ExampleSeveral proof of principle examples of the potency of a combined OV-checkpoint blockade therapy are now emerging. For example, Zamarin et al. demonstrated in mouse models that a combination of oncolytic NDV and anti-CTLA4 could cure the majority of animals while NDV alone was effective in only 10% of mice. Interestingly, this strategy could induce an immune response against both virally injected and uninfected tumors, though this effect was impeded in tumors that were antigenically distinct. These effects were CD8+ T-cell, NK cell and type I IFN-dependent but independent of oncolysis . Rojas eThus the combination of oncolytic viruses and checkpoint blockades has demonstrated significant promise in enhancing the efficacy of either therapy alone. However, such an approach does not exclude the combination with other forms of immunotherapy. For example, alleviation of checkpoint induced immune suppression could prove beneficial in the context of the prime boost or ACT + OVV strategies previously discussed. While these combinations could bring a new level of potency to these approaches, such endeavours should be undertaken with care as the alleviation of immune checkpoints through checkpoint blockade is largely non-specific  in its cAs it becomes increasingly clear that a large portion of the efficacy of OV therapy stems from its modulation of an antitumor immune response, it is likely that efforts in the field will increasingly focus on harnessing this potential. While this can and should be undertaken in a variety of different ways, including further engineering of these vectors, recent experience clearly illustrates the potential of such approaches to synergize with other immunotherapeutic strategies. Given the broad spectrum of available OVs and the ease with which these agents can be further engineered for specific needs, they provide unparalleled potential and versatility as tools. As combinational agents, they offer the potential to play to the strengths and compensate for the weaknesses of other immunotherapeutic strategies, illustrating true synergy. Viewed in such a context, OVs can represent a foundation on which diverse therapeutic strategies can be rationally built in order to address the highly heterogeneous disease that is cancer."}
+{"text": "This highly conserved catalyst has an almost universal propensity to non-productively interact with its substrate ribulose 1,5-bisphosphate, leading to the formation of dead-end inhibited complexes. In diverse autotrophic organisms this tendency has been counteracted by the recruitment of dedicated AAA+ (ATPases associated with various cellular activities) proteins that all use the energy of ATP hydrolysis to remodel inhibited Rubisco active sites leading to release of the inhibitor. Three evolutionarily distinct classes of these Rubisco activases (Rcas) have been discovered so far. Green and red-type Rca are mostly found in photosynthetic eukaryotes of the green and red plastid lineage respectively, whereas CbbQO is associated with chemoautotrophic bacteria. Ongoing mechanistic studies are elucidating how the various motors are utilizing both similar and contrasting strategies to ultimately perform their common function of cracking the inhibited Rubisco active site. The best studied mechanism utilized by red-type Rca appears to involve transient threading of the Rubisco large subunit C-terminal peptide, reminiscent of the action performed by Clp proteases. As well as providing a fascinating example of convergent molecular evolution, Rca proteins can be considered promising crop-improvement targets. Approaches aiming to replace Rubisco in plants with improved enzymes will need to ensure the presence of a compatible Rca protein. The thermolability of the Rca protein found in crop plants provides an opportunity to fortify photosynthesis against high temperature stress. Photosynthesis also appears to be limited by Rca when light conditions are fluctuating. Synthetic biology strategies aiming to enhance the autotrophic CO A Mg2+ ion is then bound to complete the activation process, forming the holoenzyme termed ECM  already possesses all of the features required to bind the substrate RuBP, the active site will close when it encounters the substrate  have now been identified , is always found in an operon with the red-type (Form IC) Rubisco encoding genes in mixotrophic proteobacteria  that are encoded by the same genome  and Lys-33 on the opposite subunit. These residues are conserved in many Form II enzymes, and the interaction may thus be part of an alternative Loop 6 locking mechanism. Another important feature of active site closure concerns a 2\u00b0 rotation of the N-terminal domain, resulting in a reduced distance between the phosphate binding sites of the active site . Mutagenesis of this motif strongly impaired the ability of the target Rubiscos to be activated by their activases, drawing a strong mechanistic parallel to the pore-loop threading red-type Rcas  primary sequence identity of the Form I and Form II Rubisco large subunits, the C-termini of those enzymes encoded in 0% primarcbbQ gene possesses a von Willebrand factor A (VWA) domain at its C-terminus . In particular the rapid development of CRISPR-Cas9 technology will facilitate this process further  systems  and the Ministry of Education of Singapore (MOE2013-T2-2-089).The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "High-pressure torsion (HPT) is widely used as a severe plastic deformation technique to create ultrafine-grained structures with promising mechanical and functional properties. Since 2007, the method has been employed to enhance the hydrogenation kinetics in different Mg-based hydrogen storage materials. Recent studies showed that the method is effective not only for increasing the hydrogenation kinetics but also for improving the hydrogenation activity, for enhancing the air resistivity and more importantly for synthesizing new nanostructured hydrogen storage materials with high densities of lattice defects. This manuscript reviews some major findings on the impact of HPT process on the hydrogen storage performance of different titanium-based and magnesium-based materials."}
+{"text": "This paper provides an overview on our recent investigations on the consolidation of hierarchy-structured nanopowder agglomerates and related applications to net-shaping nanopowder materials. Understanding the nanopowder agglomerate sintering (NAS) process is essential to processing of net-shaped nanopowder materials and components with small and complex shape. The key concept of the NAS process is to enhance material transport through controlling the powder interface volume of nanopowder agglomerates. Based upon this concept, we have suggested a new idea of full density processing for fabricating micro-powder injection molded part using metal nanopowder agglomerates produced by hydrogen reduction of metal oxide powders. Studies on the full density sintering of die compacted- and powder injection molded iron base nano-agglomerate powders are introduced and discussed in terms of densification process and microstructure. The potential application of nanoscale materials as novel structural or functional engineering materials largely depends on the consolidation of powders into bulk nanoscale solids. In general, pressure-assisted sintering is known to be adequate for both reaching full density and preventing grain growth . Besideset al. [It was reported that Fe base nanopowder compacts underwent the densification process strongly depending on the state of powder agglomeration . The conet al. ,4,5 suggThe key concept of the NAS process is based on the optimization of structure design and full density processing of nanopowder into nanostructured micro-components. The kinetics of this process is found to be controlled by material transport through hierarchical interface structures of nanopowder agglomerates ,6,7. Froi.e., hierarchical interfaces in nanopowders. Moreover, based on this processing concept, Lee and his coworkers [This experimental finding provides a breakthrough for processing full density nanopowders by optimal design of the agglomerate structure, oworkers ,4,5 fabroworkers .In this paper we review our recent investigations on the consolidation of hierarchy-structured nanopowder agglomerates in terms of the densification process and microstructural development and also introduce on their application studies for processing a net-shaped Fe base nanopowder parts using PIM technology and pressureless sintering. In addition, current research on low-temperature PIM using hierarchy-structured micro-nano powder feedstock is briefly addressed.Regarding the other method for making PIM feedstock, the mixing process of Fe\u2013Ni nanopowder and binder material for preparing the PIM feedstock turned out to be effective for uniform and isotropic sintering process, resulting in homogeneous microstructure . As depiThe key issue for the application of nanopowder to engineering parts is how to consolidate the powder into the sintered part with full density and nano-grained microstructures, especially by pressureless sintering . As descNano grain boundary diffusivity was calculated to be similar to that for coarse-grained materials . This fa\u03d5 is the ratio of the heating rate, T is temperature, R is gas constant, Y is the identical value of shrinkage and Q is activation energy for densification [In order to examine the role of agglomerate boundary of hierarchical structured nanopowder in sintering kinetics, densification kinetics for Fe\u20138 wt % Ni nanopowder agglomerate compacts with different agglomerate size of 5 and 500 \u03bcm was investigated in terms of the activation energy for densification process . The parfication .Both agglomerate powders were virtually identical, only differing in the agglomerate size. To eliminate inter-agglomerate pores, both powders were equally compacted to 72% of theoretical density (T.D.) with compacting pressure of 1.2 GPa.i.e., enlarging the agglomerate boundary volume, which provides faster diffusion path [ion path .The inverse behavior in the densification processes for two different agglomerate sizes can be explained in terms of powder packing structure and pore structure. Regardless of the same porosity in two compacts, the small agglomerate sample forms a higher volume fraction of inter-agglomerate boundary rather than that of intra-agglomerate boundary. Therefore, the 5 \u03bcm agglomerate can have much higher volume of atom diffusion path for rapid material transport for densification than the large agglomerate sample. However, in terms of driving force for sintering, which can be expressed as sintering reaction site, rather such large volume of the agglomerate boundary plays a negative role in sintering of nanopowder which limitedly proceeds within the agglomerates. Initially dominant sintering takes place first in the agglomerate, then followed by sintering between neighbored large powders as locally full densified agglomerate powder. At this point when the neighboring sintered agglomerate powders start to sinter together or neighboring nanopowders near the boundaries sinter we can expect further continuous densification process in the sample leading to eventually inverse densification in later stage of sintering.An evidence of agglomerate boundary acting as effective diffusion path for densification process is confirmed by microstructure observation. First, in case of the large agglomerate sample in Apart from the large agglomerate sample, the small agglomerate powder compact shows a different microstructural development as seen in Accordingly, sintering of the 5 \u03bcm agglomerate Fe\u2013Ni nanopowder compact is thought to proceed by two competing sintering processes; one is the sintering of nanopowder within the agglomerates and the other is that of agglomerates. The latter process can only take place when the particles neighboring in boundaries have sufficient driving force for further continuous sintering process. For this reason the small agglomerate sample might undergo slow densification in early stage of sintering due to the hindering effect of the agglomerate boundary and then gradual higher densification at such critical point as described. TEM micrograph of the 5 \u03bcm agglomerate sample d clearlyIn order to check the applicability of the NAS process to net-shaping of nanopowders small double gear component as well as die compact sample was fabricated by die compaction and powder injection molding of Fe base nanopowder and Fe micro-nano powder feedstock of which agglomerate size was optimized by wet-milling and powder injection molding.m (melting point) of Fe. In particular, it should be noted that the densification in isothermal sintering reaches near full density in the range of 96.5% to 99.2%. This indicates that the isothermal sintering process in this study corresponds to final stage of sintering [As seen in intering .Final stage of sintering process is shown in the results of SEM-EBSD (electronback scatter diffraction) of v) was measured after various sintering times and summarized in v of 210 at 0 h to Hv of 160 at 4 h. However, these values are higher than the values for conventional PM  steel parts containing carbon content. This remarkable strengthening effect of the pure Fe nanopowder without the presence of carbon is well interpreted in terms of grain refinement effect. It is interesting that no drastic grain growth takes place during isothermal sintering at 700 \u00b0C. As depicted in Such hierarchical microstructures can be illustrated more clearly by EBSD-images . Figure Recently the authors found that the nano-agglomerate powder can be effectively used for optimal feedstock for micro-PIM in combination with micron powders ,28. ThesThe formation of strong nanopowder bridges during debinding indicates that using high density organic binders with high viscosity is no longer necessary. Instead, some binder materials with lower viscosity and melting temperature can be utilized without any problems in the debinding process. This argument is strongly supported by the result of the green strength measurements by using a compression test . Figure In this paper we reviewed our recent investigations on the consolidation of hierarchy-structured Fe base nanopowder agglomerates in terms of the densification process and microstructure and also introduced on their application studies for processing a net-shaped parts. Understanding NAS process is essential to processing of net-shaped nanopowder materials and components with small and complex shape. The key concept of NAS process is to enhance material transport through controlling the powder interface volume of nanopowder agglomerates. We found that the enhanced sintering effect at low temperature is an evidence of NAS process which is basically driven by the densification process along hierarchical boundaries consisting of two high diffusivity paths of agglomerate- and nano-grain boundaries. This experimental evidence provides a new idea of full density processing for fabricating micro-PIM part using metal nanopowder agglomerates. It is concluded that the optimization of agglomerate size control of nanopowder is a breakthrough for processing of net-shaped Fe base nanopowder materials."}
+{"text": "Increasing resistance to current anti-malarial therapies requires a renewed effort in searching for alternative therapies to combat this challenge, and combination therapy is the preferred approach to address this. The present study confirms the anti-plasmodial effects of two compounds, cryptolepine and xylopic acid and the relationship that exists in their combined administration determined.\u22121) and xylopic acid (XA)  was evaluated in Plasmodium berghei-infected male mice after a 6-day drug treatment. The respective doses which produced 50% chemosuppression (ED50) was determined by iterative fitting of the log-dose responses of both drugs. CYP and XA were then co-administered in a fixed dose combination of their ED50s (1:1) as well as different fractions of these combinations  to find the experimental ED50 (Zexp). The nature of interaction between cryptolepine and xylopic acid was determined by constructing an isobologram to compare the Zexp with the theoretical ED50 (Zadd). Additionally, the effect of cryptolepine/xylopic acid co-administration on vital organs associated with malarial parasiticidal action was assessed.Anti-plasmodial effect of cryptolepine (CYP)  below the additive isobole indicating that co-administration of cryptolepine and xylopic acid yielded a synergistic anti-plasmodial effect. This observed synergistic antiplasmodial effect did not have any significant deleterious effect on the kidney, liver and spleen. However, the testis were affected at high doses.The ZThe co-administration of cryptolepine and xylopic acid produces synergistic anti-malarial effect with minimal toxicity. Every 2\u00a0min a child dies due to malaria in sub-Saharan Africa. It is estimated that 88% of the cases and 90% of the malaria deaths reported in 2015 were in the WHO Africa region while most deaths (70%) were in children under 5\u00a0years of age -treated mice appeared normal but with dilation and congestion of blood vessels while CYP/XA (0.93\u2009+\u20090.63\u00a0mg\u00a0kg\u22121) [ED50(CYP\u2009+\u2009XA)/32]-treated mice showed increased capsular space of renal corpuscles with atrophy of glomerulus and vacuolation of cuboidal cells especially near the periphery of the cortex /16 and ED50(CYP\u2009+\u2009XA)/32 treated animals showed signs of high regeneration. Fatty changes were observable mostly within hepatocytes around the central vein. Haemosiderosis and Kupffer cell hyperplasia were mildly observed in the vehicle-treated mice and ED50(CYP/XA)/16-treated mice -treated mice however exhibited some cytotoxic activity due to cleared matured spermatozoa and germ cells in the seminiferous tubules  and the theoretical Zadd of the co-administered drug thus indicating synergism of the anti-malarial effects of the two drug candidates. With an interaction index of 0.2041 which is far less than 1 this is a confirmation of supra-additive or synergistic interaction [To ascertain the improved or enhanced antiplasmodial efficacy and potency of cryptolepine and xylopic acid in mice, isobolographic analysis was performed on the two drug candidates. The co-administration of cryptolepine and xylopic acid resulted in significant antiplasmodial activity compared to the vehicle treated animals. The isobologram showed the Zeraction  between The mechanism of anti-malarial action for the co-administered drug is not immediately clear from the present study as both molecules may have acted via their individual respective mechanisms to produce the antiplasmodial synergism or via novel pathway by the admixture.Cryptolepine exerts its anti-malarial effect by intercalating with the DNA of the Plasmodium parasite in GC-rich sequences thus inhibiting DNA synthesis and stabilizing the topoisomerase II-DNA covalent complex , 20. AltXylopia aethiopica and Cryptolepis sanquinolenta to treat malaria. The beneficial or detrimental effect of XA/CYP in diseased person may differ from a healthy individual. The potential toxicity of the CYP\u2009+\u2009XA combination was then evaluated by assessing the integrity of various structures involved in the general malarial parasiticidal action, detoxification and eventually, possible elimination of the test drug in the host. From the study, all the various dose combinations of the cryptolepine/xylopic acid significantly prevented loss of body weight in conformity with previous studies using other medicinal plant products and active drug candidates [Healthy individuals can relatively detoxify chemicals/drugs when ingested compared to an immune compromised individual. This study tried to determine the potential toxic or ameliorative effects of CYP/XA combinations when malaria infected patients ingest these plant-derived molecules in attempt to treat the infections. It is a common traditional practice in Africa where patients combine ndidates , 25. Losndidates . The losndidates . An ideaDuring malaria infection, matured merozoites exit the hepatocyte by exocytosis and induce spontaneous necrosis of the affected liver cells in man. Again, the utilization of glucose by Plasmodium and the resulting formation of lactic acid with the consequential release of free radicals into the extracellular compartment of the liver cause bleb of the hepatocyte plasma membrane. In the liver sections observed, the absence of Kupffer cell hyperplasia and haemosiderosis in the CYP/XA-treated groups other than the lowest combination dose could partly be due to the significant reduction of parasitaemia by the treatment regimen.P. berghei infection and subsequently storing the iron they contain apparently showed no loss of cellular architecture. Apart from the lowest dose, all the other treatment doses of the CYP\u2009+\u2009XA combination treatment showed mild reduction of these pathologies caused by the P. berghei parasite in the tissues of the spleen compared to the vehicle-treated mice. Histological analysis of the kidney showed that the cryptolepine\u2013xylopic acid combination drug was unable to restore the damage caused by the infiltration of perivascular interstitial mononuclear cells which are located between tubules of the nephron.The spleen which is the site for the breakdown of worn-out red blood cells in Histopathological analysis of the testes of animals treated with the lowest dose of CYP\u2009+\u2009XA showed normal morphological appearance with seminiferous tubules with all the various stages of spermatogenesis. Anti-androgenic and spermatotoxicity of both cryptolepine and xylopic acid have been previously suggested at higher doses , 28 and Results from this study confirms the antiplasmodial effects of cryptolepine and xylopic acid and further demonstrate that co-administration of the two drug candidates exhibit a synergistic interaction with minimal toxicological effects in the testes during malaria infections in rats at relatively higher doses. Further detailed toxicity studies using animal models and human tissues to enable the possible use of these drugs in human populations is recommended."}
+{"text": "Yellow fever vaccine  is a live, attenuated virus vaccine recommended for persons aged \u22659 months who are traveling to or living in areas with risk for yellow fever virus transmission  and released. The error was reported to the Vaccine Adverse Event Reporting System (VAERS)  used in mass vaccination campaigns (Most reports did not involve an adverse event, but the error was costly in terms of follow-up medical evaluation and vaccine waste. Vaccine providers should follow the instructions provided with YF-VAX; preventive measures such as more distinctive packaging and in-service training in clinics that stock both the single and multidose vials might be helpful."}
+{"text": "Starting from primary sources of normal human cells, it is now possible to reproducibly generate several types of malignant cell populations. Powerful methods for clonally tracking and manipulating their appearance and progression in serially transplanted immunodeficient mice are also in place. These developments circumvent historic drawbacks inherent in analyses of cancers produced in model organisms, established human malignant cell lines, or highly heterogeneous patient samples. In this review, we survey the advantages, contributions and limitations of current  de novo tumorigenesis protocols to be applied to human cells and the insights derived from them to date, as well as the exciting and relevant technical developments anticipated to extend even further the utility of these strategies.A better understanding of the earliest stages of human cancer formation can enable future improvements in early detection, diagnosis and treatment. In this review, the authors summarize the methods enabling  Indeed, by the time they are detected, most will already consist of millions, if not trillions, of cells exhibiting many abnormal featuresde novo tumorigenesis experiments that are driving new concepts relevant to this rapidly evolving topic. When coupled with unbiased DNA barcoding, reprogramming, and CRISPR/Cas9 technologies, these methods hold promise for obtaining further insights into the different stages of development of malignant human cell populations with unprecedented precision and clinical relevance.Here, we first review the background of information on which current understanding of the process of human oncogenesis has been founded. This is then followed by a review of newer developments and findings emanating from \u22128 mutations per nucleotide per cell generation in human cells)5678The concept that almost all human tumours represent aberrant clonal outgrowths is well establishedModern sequencing data has now revealed the enormous heterogeneity that exists within the genomes of malignant populations111314161718Most of our knowledge of the process of oncogenesis in human tissues has been derived historically from 3 different types of investigation: (i) genomic analyses of cells obtained from patients at different times during the development and evolution of their cancer with retrospective inferences drawn from the spectrum and prevalence of sequence changes (best determined at the single cell level)212223252728Although, mutations do not occur randomly3132BCR-ABL1+) cells as shown by their unique capacity for prolonged CML cell output both in vitro and in vivo34233839404143In the human hematopoietic system, this concept has been most strongly supported by genomic analyses of cells from patients with chronic myeloid leukemia (CML). This leukemia is unusual in that it is typically diagnosed at an early stage (referred to as chronic phase). Although the clone can already be huge , the process of differentiation is minimally perturbed and hence most of the cells are actually highly differentiated, short-lived mature blood cells, indistinguishable from their normal counterparts. Cell production within the chronic phase clone, in fact, largely mirrors the normal process of adult human hematopoiesis and is likewise sustained by a phenotypically similar and rare subset of multi-potent self-renewing CML (The restriction of transplantable tumour-initiating ability (in immunodeficient mice) to a rare, prospectively separable subset of malignant human cell populations was first demonstrated in human AML49505152However, in other human cancers, like melanoma555657Mouse models have been valuable for analysing early oncogenic events because of the ease with which their genomes can be genetically manipulated in defined manners and times. This has made it possible to interrogate many specific molecular, cellular and tissue-specific characteristics associated with inherited and somatically acquired mutations in humans that have been inferred to play a role in their transformation. There are, however, numerous physiological differences between mice and humans that limit the utility of this approach to provide insights into mechanisms operative in humans. Of particular note in this regard is the apparent ease with which mouse cells can be transformed, in contrast to their human counterpartsMouse models have been particularly helpful in tracing the clonal origin of normal and transformed cells in various tissues. This type of experiment typically takes advantage of a known lineage-specific gene promoter to transgenically engineer the expression of an oncogene exclusively in the cell types in which that promoter is active. This strategy can thus be used to track subsequent changes in predefined cell types before the formation of a detectable tumour. In addition, this strategy has been useful for identifying the origin of any malignant populations ultimately obtained and demonstrating different properties in the tumours thus generated27606162+PR+) and ER\u2212PR\u2212 tumours from mouse basal and luminal cells engineered separately to express PIK3CA(H1047R), thereby creating models that appear to mirror analogous phenotypes of human breast cancer64in vitro and in vivo67PIK3CA expression and p53 deletion6465BRCA1/PTEN/p53 depletion in mouse mammary cellsFor example, in the adult mammary gland, the specificity of expression of different types of cytokeratins associated with either basal or luminal mammary epithelial cells has enabled tumours derived from these different cell types to be produced and compared. These include the production of estrogen receptor-positive and progesterone receptor-positive  genes would be different from that characteristic of tumours caused by mutations in the corresponding endogenous genes. The different epigenetic mechanisms regulating their expression in the two different sites would be expected to contribute to the types, or at least speed, of the phenotypic changes induced. Furthermore, interactions of spontaneously arising mutant human cells within their native microenvironments, as well as intrinsic aspects of the process of normal tissue control, may not be well modelled in the mouse. On the other hand, transgenic mouse models offer the advantage that they can now be readily engineered to regulate not only the lineage, but also the level, timing and duration of expression of genes of interest that have been introduced into the germ line.KRAS(G12D) gene enabling the genesis of lung cancer, thymic lymphoma, and aberrant intestinal crypt foci to be created and studied8384Mouse knock-in (KI) protocols now enable some of the short-comings of historic transgenic models to be addressed. These involve the use of homologous recombination to replace endogenous genes in mouse embryonic stem cells with candidate oncogenic mutant alleles and subsequent introduction of the selected cells into the mouse germ line. KI mice have thus been generated to explore the function of Kit mutations in gastrointestinal stromal tumours, the role of TP53 in Li-Fraumeni syndrome tumours and for recapitulating familial cancers. This technique has also been further adapted to induce spontaneous expression of the oncogenic MYCEGFRNicastrinERBB2 , CCND1, PIK3CA and KRAS(G12V)SV40 plus KRAS(G12V)KRAS(G12D) alonede novo leukaemogenesis using primitive (CD34+) subsets of hematopoietic cells isolated from human cord blood is also accruing. In this case, examples of genes whose vector-mediated forced overexpression in normal cells have produced overt leukaemic populations in immunodeficient mice include cDNAs for MLL-AF9 (refs MLL-AF4 (ref. MN1 plus NUP98HOXD13 (ref. BCR-ABL plus a dominant-negative form of IKAROSMYC plus BCLMLL) gene is rearranged and fuses with multiple partner genes in both spontaneously arising human AML and acute lymphoid leukemia (ALL), but the MLL-AF9 fusion oncogene is associated almost exclusively with AML in humansMLL-AF9 in normal cord blood cells produced ALL in transplanted Non-obese diabetic-Scid (NOD-SCID) hosts, but AML in NOD-SCID mice that had been engineered to express three human growth factors. This result illustrates the ability of external factors to dictate the phenotype of the malignant cells produced and further underscores the fallacy in assuming the predominant cell type necessarily reflects the cell of origin or the specific oncogene driving the tumorigenic state. The MN1-NUP98HOXD13 model also serves to illustrate the difference between effects obtained in analogous mouse and human target cells. In mouse cells, MN1 alone was sufficient to induce a myeloid leukaemia, whereas in human cord blood cells it induced only a transient myeloproliferation. Only when an activated HOX gene , was also introduced was a serially transplantable AML obtained in the human cells.Examples of AF9 refs , 109, MLAF4 ref. , MN1 pluD13 ref. , BCR-ABLde novo human tumours whose characteristics are heavily influenced by factors beyond the cell of origin, or the genetic alterations used.These studies demonstrate some of the unique aspects of tumorigenesis in primary human cells that are not well predicted by mouse models. They also provide examples of experimentally generated Most studies attempting to analyse the subclonal diversity of malignant human populations that arise in patients have relied on retrospective inferences derived from analyses of the genomic or phenotypic characterization of primary samples and/or changes incurred in serial transplants of these cells in immunodeficient mouse hosts23114115116117in vivo. The LDA approach has been extensively applied to a number of primary human tumour types that can engraft immunodeficient mice. These include malignant populations that arise in the human brain47485445125126127single tumorigenic cells, the transplants must be initiated with cell numbers that produce tumours at a frequency of less than one in three mice. The large numbers of mice required to obtain clonal data can thus become rapidly prohibitively expensive, if not impractical, particularly when clonal outputs may vary quantitatively as well as phenotypically and dynamically within and between different primary tumours being assessed.Limiting dilution analysis (LDA) and vector-based tracking of clonogenic cells offer powerful approaches to quantify malignant cells with proliferative potential The use of massively parallel DNA sequencing has improved the sensitivity and efficiency of vector insert analysis to identify clones based on their semi-random integration sites109131132133134135136Application of these protocols has revealed complex clonal dynamics in human tumours derived from serially passaged cellsin vitro of cells derived directly from human tumours139140Technological advances are well known to be the drivers of new information. Nowhere is this more relevant than to current issues of interest in the general arena of biomedicine. In the field of human cell oncogenesis, three technologies are of particular relevance: organoid cultures, reprogramming and CRISPR/Cas9. Organoid culture systems are allowing more faithful tissue development to be generated from primitive normal cells and are showing promise for supporting the expansion in vivo counterparts will facilitate the modelling of human disorders, performing drug screens, and the creation in vitro of replacement tissues and/or organs. Methods combining directed differentiation of cells in culture systems that promote organoid formation are being developed for many complex tissues such as the liver, kidney, intestine, eye, and brain, to name a fewin vivo, better spatial organization of cell types than is achieved in 2D in vitro systems and improved mimicry of in vivo cell behaviour, potential for larger scale testing of variables and drug effects, and reduced ethical concerns and costs associated with animal xenograft experiments.This term refers to 3D structures generated in suspension cultures under conditions where 2D growth of attached cells is blocked or prevented (either by suspending the cells in a semi-solid medium-like matrigel or the use of a culture container that prevents cell attachment). The generation of 3D organoids to engineer tissues that are histologically and functionally more similar to their iPSC technology offers a novel method of capturing the genomic state of single cells from almost any source, including transformed cells. However, this comes at the cost of losing the malignant phenotype of the original cells from which each iPSC clone is derived. Nevertheless, from the limited experience where it has been applied to the study of cancer to date, it appears that at least some properties of the malignant cells of origin may be reactivated by stimulating the iPSCs to differentiate back into the lineage or tissue from which the malignant cells arose and may then also be used for drug screening143BCR-ABL1 fusion gene145146MLLp53 gene is mutatediPSCs have been derived from human chronic phase CML cells with documented retention and expression of the signature The CRISPR/Cas9 technology originates from type II CRISPR-Cas systems that evolved to provide bacteria with a form of adaptive immunity to viruses and plasmids. The CRISPR-associated Cas9 protein is an endonuclease that introduces a site-specific double-strand break (DSB) into DNA. The ability of CRISPR/Cas9 to introduce DSBs at defined positions using a guide RNA can also be used to generate human cell lines and primary cells bearing chromosomal translocations resembling those described in human cancers . Example161163in vivo setting. Together with improvements in lentiviral design and production, and methods to isolate and purify normal viable human cells, these advances are now enabling a growing number of de novo models of human tumorigenesis to be developed. The use of DNA barcoding of the initial cells is now also providing a tractable method to analyse the clonal composition and dynamics of the malignant cells generated and should provide a powerful approach to examine therapeutic effects in the future. These approaches coupled with emerging methods to modify and regulate cell behaviour even more precisely herald a new era of improved understanding of the complex processes of human tumorigenesis.Recreating the process of human tumorigenesis in naive human cells has been a challenging frontier not anticipated by the historically contrasting ease of achieving this outcome in mouse cells. However, several major developments are now changing this picture. One has been the generation of long-lived mice in which multiple components of the innate and acquired immune system have been suppressed. This advance now allows transformed human cells to grow and evolve into fully malignant populations in an How to cite this article: Balani, S. et al. Modeling the process of human tumorigenesis. Nat. Commun.8, 15422 doi: 10.1038/ncomms15422 (2017).Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations."}
+{"text": "Single cell imaging mass spectrometry opens up a complete new perspective for strategies in toxicological risk assessment and drug discovery. In particular, time-of-flight secondary ion mass spectrometry (ToF-SIMS) with its high spatial and depth resolution is becoming part of the imaging mass spectrometry toolbox used for single cell analysis. Recent instrumentation advancements in combination with newly developed cluster ion guns allow 3-dimensional reconstruction of single cells together with a spatially resolved compound location and quantification on nanoscale depth level. The exact location and quantification of a single compound or even of a set of compounds is no longer restricted to the two dimensional space within single cells, but is available for voxels, a cube-sized 3-dimensional space, rather than pixels. The information gathered from one voxel is further analysed using multivariate statistical methodology like maximum autocorrelation factors to co-locate the compounds of interest within intracellular organelles like nucleus, mitochondria or golgi apparatus. Furthermore, the cell membrane may be resolved, including adhering compounds and potential changes of the lipid patterns. The generated information can be used further for a first evaluation of intracellular target specifity of new drug candidates or for the toxicological risk assessment of environmental chemicals and their intracellular metabolites. Additionally, single cell lipidomics and metabolomics enable for the first time an in-depth understanding of the activation or inhibition of cellular biosynthesis and signalling pathways. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) in combination with stable isotope labelling and a range of new cluster ion beams for depth profiling has established the opportunity for exact identification and quantification of substances on a cellular and subcellular level. This allows for the first time single cell analysis in combination with a full 3-dimensional reconstruction to assess the metabolite distribution pattern. Single cell imaging can also mirror the intracellular distribution of cell specific biomolecules. These may be synthesised either by the target cells themselves or in specific tissues or organs from where they are subsequently transported to their respective destinations. Subsequently to their uptake, the biomolecules may either be stored in cell-specific organelles or further metabolised. Reaction products are used either specifically at their site of origin or transported out of the cell again and delivered to other targets. This is achieved by a complex framework of cellular intake, uptake and segregation which can be observed not only in tissues but also in single cells. Different single cells in a tissue or organ may represent either different metabolic states or may participate in different metabolic frameworks. This may include a specific up- or down-regulation of toxicological relevant signalling pathways. Even in complex tissues single cell analysis is of paramount interest in toxicological research, especially with respect to the identification of the early onset biomarkers of diseases such as cancer. The gathered information can also be used for drug discovery and is further instrumental in the assessment and prediction of possible drug and its metabolites\u2019 distributions as well as of the fate and metabolism of environmental chemicals and their associated toxicity.in vitro or in tissue sections according to their physiological state.Conservation of the native status and distribution of all biomolecules is the most important prerequisite for single cell analysis. To achieve this, a plunge freezing methodology is used commonly , where t60+  with a nanoscale spot size, where the ion beam can be used in continuous mode simultaneously etching and imaging + and 784.6 [M+K]+, their high mass ions at m/z 709.5 and 725.5 and the phosphatidylcholine headgroup at m/z 184 were observed. The summarised total contribution of these phosphatidylcholine-derived peaks shows a heterogeneous distribution of the substance on the neuron. As the dominant phospholipid of the neuron surface, phosphatidylcholine is a precursor of the platelet-activating factor which is involved in regulation of inflammation [For the first time a 3-dimensional reconstruction of a single cell, a  reality . The outtrometry . It was ammation . Alyssum lesbiacum was investigated [The localisation of nickel in the accumulator plant stigated . An accuLipidomics comprises the analysis and quantification of cellular lipids to gain information about differences of membrane compositions as well as on the metabolic state of body liquids, tissues and even single cells. The revealed information may be used afterwards not only for the diagnosis of various diseases like cancer, Alzheimer\u2019s disease, and diabetes but also for the assessment of early onset disease biomarkers and drug treatment success. Analysis and comparison of single cells\u2019 lipid profiles provides insight into specific metabolic states in contrast to conventional lipidomics dealing with cell colonies, tissues or even whole organs. Within a cell colony or a tissue section specific cells may have their own lipid profiles indicating not only the state of the single cell in respect to its signalling status or metabolic state, but also hinting about hot spot regions, where cells develop individual responses to environmental chemicals like apoptosis or tumour formation. Analysing and characterising lipid profiles from single cells therefore enables sensitive detection of aberrant lipid profiles as markers for early disease development, which might be overlooked due to their small concentrations with conventional lipidomics. This advantage of single cell analysis may enable for very early diagnosis of diseases like cancer or Alzheimer\u2019s disease. Lipidomics analysis requires recording of the multitude of lipids present in cells, such as steroids, lipoproteins, phospholipids, sphingolipids, glycerides and fatty acids. Phospho- and sphingolipids constitute the essential biomolecules of cell membranes whilst glycolipids are the key molecules in cell recognition and also immunological processes. The high number of analysed compounds is resulting in the generation of huge data sets. Therefore lipidomics studies require significant statistical data interpretation involving multivariate data analysis like principal component or discriminant analysis.ToF-SIMS analysis in combination with multivariate statistical analysis was used to differentiate between mouse fibroblasts and rat oesophageal epithelial cells in heterogeneous cultures . For thi13C, 15N or 10B) were added to the culture medium. Simultaneous incubation of PC12 cells with phosphatidylcholine resulted in a decrease of exocytosis, whilst the cultivation with phosphatidyl ethanolamines resulted in an increased exocytosis rate [Rat derived neuronal PC12 cells that communicate via exocytosis were shown to express a time-dependent uptake of stable isotope-labelled phospholipids. Biomolecules labelled with stable isotopes . The ratio of intensity observed for palmitoleic acid, m/z 253.2, was determined with 43.2% between human breast cancer stem cells and non-stem cancer cells. Neither further differences in fatty acid composition nor specific membrane structures were observed. The study may give hints for cancer therapy and represents an example for the application of FACS and ToF-SIMS for imaging of cellular membrane components .Lipidomics linked to imaging mass spectrometry for single cell analysis is further representing a suitable tool for investigation of potential penetration mechanisms of cosmetic ingredients related to their fate and potential toxicity. ToF-SIMS analysis was used to localise commonly applied susbtances in the dermis and in the stratum corneum, representing the major part of the skin barrier consisting mainly of corneocytes and extracellular lipid matrix . The stuMolecular imaging offers a new perspective for the 3-dimensional analysis of cellular substructures on a microscale, envisioning the possibility not only to look at cellular compartments but also at the biomolecules associated with each compartment and its metabolic flux. With the advent of cluster ion guns and the possibility for 3-dimensional, mass spectrometry-based chemical imaging, especially ToF-SIMS and magnetic sector field SIMS are very well suited for that purpose. Three-dimensional reconstruction of subcellular structures like the nucleus or the mitochondria with full chemical distribution patterns including exact quantification will allow new insights in cellular uptake processes and in the regulation of signalling pathways. The identification of possible metabolic compartments may shed further light on regulation, transport and metabolism of chemicals and drugs. Especially for pharmaceuticals, the uptake rate and intracellular 3-dimensional distribution of the active ingredient are of paramount interest. Ideally the pharmaceutical acts not only organ specific and within the target organ, e.g., tumour cell specific, but can also target specific intracellular compartments for enhanced drug performance. By this a significant reduction of active ingredient and negative side effects, caused by non-target supply will be achievable. This might allow the further development of personalised medicine and drug treatment regimens. For environmental chemicals molecular imaging offers the opportunity to investigate barrier penetration and cellular uptake mechanisms. To date, such information is missing to a large extent, especially considering the multitude of potential impurities in consumer products such as mineral oils and polycyclic aromatic hydrocarbons.Furthermore, early changes associated with toxic effects, not visible on tissue or organ level, may be revealed by analysis of 3-dimensional distribution patterns of externally added compounds and metabolites in single cells. Environmental chemicals are predominantly compounds that cannot be biosynthesised by the living organism itself and therefore require cell-specific detoxification before excretion can occur. Such mechanisms may be activated only after the substances enter a specific single cell or have reached a certain intracellular concentration. This threshold may differ between organ tissues and single cells, resulting in different activation of specific metabolic and signalling pathways. Therefore different cells from a population may show an individual response according to their chemical load, which impacts on signalling patterns as well as enzyme and metabolite configurations. With the still necessary improvements, in particular regarding spatial resolution and sensitivity on biological samples, mass spectral imaging has the potential to discover such communication networks in order to facilitate toxicological risk assessment of chemicals originating from environmental sources and consumer products."}
+{"text": "Each patient received also a cognitive assessment using a battery of neuropsychological tests specific to cognitive deficits in MS.The disturbance of cortical communication has been hypothesized as an important factor in the appearance of cognitive impairment in (MS). Cortical communication is quantified here in control subjects and patients with relapsing-remitting multiple sclerosis (RRMS) on the basis of mean coherence in the No difference was observed for the coherence indices whereas inter-hemispheric and right hemisphere mutual information is significantly lower in patients with MS than in control subjects. Moreover, inter-hemispheric mutual information decrease significantly with illness duration and right mutual information differentiate cognitively deficient and non-deficient patients.Mutual information allows to quantify the cortical communication in patients with RRMS and is related to clinical characteristics.Cortical communication quantified in a resting state might be a potential marker for the neurological damage induced by RRMS."}
+{"text": "Joint loads were predicted by optimally scaling the magnitude of four unit loads  to analyse the parameter sensitivity of the joint load predictions at one proximal femur and (2) to assess the plausibility of the results by comparing load predictions of ten proximal femora to in vivo hip joint forces measured with instrumented prostheses (available from  Knowledge of physiological bone loading conditions is highly relevant for medical applications such as predicting patient specific fracture risk  to conduct a systematic investigation of the parameter sensitivity of micro-FE-based joint load predictions on one human proximal femur and (2) to assess the plausibility of the results by comparing the predicted joint load vectors (i.e. magnitude and direction) of ten proximal femora to hip joint loads measured in vivo  of the distribution of the mechanical stimuli mentclass2pt{minimParameter sensitivity of the joint load predictions was analysed by comparing the results of one specimen with a set of reference parameters  or distributed following an ellipsoidal (Hertzian) pressure distribution (\u201cvariation 2\u201d) Table\u00a0. AdditioThe algorithms robustness was investigated by increasing the number of unit loads, shifting the location where unit loads were applied, reducing the size of the region of interest (ROI) of the SEDs included in the optimization, and varying the remodelling equilibrium stimulus, as shown in Table\u00a0entclass1pt{minimaPeak and mean vectors of the joint load predictions were evaluated for the parameter sensitivity analysis. Mean vectors were defined as the sum of the scaled resultant force vectors of each load case divided by the number of load cases. Mean vectors were used as an output variable to quantify differences in the load predictions, irrespective of changes in the number and/or location of unit loads. Additionally, unit load case-specific force magnitudes were compared qualitatively.www.orthoload.com, dataset \u201cStandard Loads Hip Joint\u201d). Data selection and processing are described in the following sections.The plausibility of the joint load prediction results was assessed by comparing load prediction results from all ten femora (as described in Sect.\u00a0In the study by Bergmann et\u00a0al. , hip joiSubject-specific in vivo peak loads were compared to the peak load vectors obtained from the micro-FE-based load prediction. Peak load directions were quantitatively compared based on the angles of the force vectors with respect to the vertical axis in the frontal plane. Additionally, the range of force directions predicted by the FE models was compared to the full range of force directions measured in vivo.Load magnitude scaling factors entclass1pt{minimaFigure\u00a0The predicted peak joint load vector in the reference specimen was inclined by The mean joint load vector in the reference specimen was inclined by Figure\u00a0The in vivo range of resultant force vectors was confined to inclinations of magnitudes of the load predictions have to be interpreted with caution considering their sensitivity to parameters associated with high uncertainty such as bone material properties and remodelling equilibrium stimulus.The goal of this study was to investigate the parameter sensitivity and plausibility of micro-FE-based prediction of joint loads. A comparison with in vivo loading data of the hip joint showed that peak load predictions were plausible in terms of both load magnitude and direction. However, particularly the magnitude might be biased by the selection of bone material properties and equilibrium stimulus, predicted directions of both peak and mean vectors were less sensitive to variations in these parameter. Also, other potential sources of influence such as the cartilage elasticity, ROI of SEDs used in the optimization, and load distribution were shown to have a limited effect on both the load directions and magnitudes. Overall, our results suggest that micro-FE-based load predictions are potentially robust enough to compare dominant joint loads between different bones using the same set of parameters, and that predicted directions of loads are robust even when parameters vary. However, absolute values of load magnitudes should be interpreted with caution until validated parameters are available.The results of the parameter sensitivity analysis highlight many important factors to be considered when utilizing and interpreting micro-FE-based load prediction following Christen et\u00a0al. . First, The comparison of joint load predictions of the full sample with the in vivo hip joint load data (Bergmann et\u00a0al. Several limitations of this study remain to be mentioned. First, micro-FE predictions were performed on specimens obtained from elderly donors (age Overall, the results of this study suggest that micro-FE-based joint load predictions deliver plausible estimates of the most dominant loading experienced by a given bone structure. Load predictions are potentially robust enough to perform inter-subject or inter-species comparisons of joint loads, but absolute values should be interpreted with caution considering both parameter sensitivity and many limitations inherent to the load estimation algorithm."}
+{"text": "Pina and Pinb) genes control grain texture or hardness in wheat. Wild-type/soft alleles lead to softer grain while a mutation in one or both of these genes results in a hard grain. Variation in hardness in genotypes with identical Pin alleles (wild-type or mutant) is known but the molecular basis of this is not known. We now report the identification of wheat genotypes with hard grain texture and wild-type/soft Pin alleles indicating that hardness in wheat may be controlled by factors other than mutations in the coding region of the Pin genes. RNA-Seq analysis was used to determine the variation in the transcriptome of developing grains of thirty three diverse wheat genotypes including hard (mutant Pin) and soft (wild type) and those that were hard without having Pin mutations. This defined the role of pin gene expression and identified other candidate genes associated with hardness. Pina was not expressed in hard wheat with a mutation in the Pina gene. The ratio of Pina to Pinb expression was generally lower in the hard non mutant genotypes. Hardness may be associated with differences in Pin expression and other factors and is not simply associated with mutations in the PIN protein coding sequences.Puroindoline ( Puroindoline (Pin) genes, Pina and Pinb, which are part of only the D sub-genome and located on chromosome 5 at the Hardness (Ha) locus. Grain softness protein -1 (GSP-1), another gene tightly linked to the Pin genes on the Ha locus, was initially thought to be associated with grain hardness but later reports indicated otherwise wheat bre database. HoweverPina in comparisons between soft vs HPAM and HNM vs HPAM supports the vital role of Pina in controlling grain hardness. However, Pina or Pinb was not identified as a differentially expressed gene in comparison of the soft vs HNM group. This indicates that although grain hardness is greatly influenced by mutation in the Pin genes, other factors may also be involved in control of this trait. In the genes which were differentially expressed between soft+HNM group and HPAM+HPBM group it was observed that most of the genes were down-regulated in hard wheats (HPAM+HPBM). This down-regulation of gene expression could be the influence of grain hardness or it may contribute to the grain hardness. No annotation was available for some of the significant DEGs. None of the other annotated DEGs identified in different comparisons has been previously reported to be associated with wheat grain hardness. Further study is required to determine the role of candidate genes identified in this study. Up-regulation of glutenins and gliadins   [st (53%) . Higher -mutants . This obr 30 DPA . Generaln, Meyer  reportedn, Meyer . Hard grSA test) . HoweverPinb expression was observed in Pina-mutants (HPAM) compared to other groups , when transformed with wild type Pin-a or\u2013b alleles produces soft grains. However, lines transformed with Pinb-D1a were softer than the lines transformed with Pina-D1a and in addition there was no correlation with levels of PIN expression and hardness. This demonstrates that excessive expression of one wild type Pin allele does not compensate for another mutant Pin allele and also indicated that PINA and PINB act together. Comparable levels of Pina and Pinb expression in some non-mutants and Pinb-mutants suggests that mutation in the Pin-b gene does not necessarily alter the expression levels of Pin genes. A study by Gasparis, Orczyk [Pin genes also reported that puroindoline transcript abundance or protein content is not altered by mutation. However, mutation may interfere with PIN protein functionality and stability. Greater association of Pin transcripts at 14 DPA with grain hardness is most likely due to the abundance of transcripts whereas less association at 30 DPA is most likely due to reduced gene expression. The total gene expression process starts to slow down as the seed proceeds towards maturity [A slightly lower r groups . Likewismutation . Amorosomutation  suggestegi, Hogg  reportedgi, Hogg  showed t, Orczyk  using RNmaturity .Pin genes may explain differences in expression levels of Pin genes. Mutations in these regions are likely to affect gene expression levels. Further understanding of grain hardness may allow selection of specific levels of gene expression to breed for specific level of grain hardness and not just for broader classes of hardness. A more complete understanding of the regulatory sequences at these loci may allow a more complete explanation of genetic variation in hardness in wheat and allow reliable selection for hardness based upon sequence specific markers.Study of 5\u2019 and the 3\u2019 sequences of the Pin alleles is explained by higher expression of Pinb than Pina. Puroindoline genes still remain the major determinants of grain hardness. Expression of Pin genes at earlier stages of grain development determines grain hardness. Variation in grain hardness (SKCS HI) among the different genotypes within a particular class of hardness couldn\u2019t be explained by patterns of Pina and Pinb expression. Several statistically significant differentially expressed genes were identified between soft wheats and hard wheats. Further investigation of these genes may provide more understanding of wheat grain hardness.Results of this study show that grain hardness in some wheat genotypes containing wild type S1 TableDifferentiallyexpressed genes identified between the HNM group and the HPAM group (1a), the HPBM group (1b) and common DEGs (1c).(DOC)Click here for additional data file.S2 Table(DOC)Click here for additional data file.S3 TableDuplicates were grown in a glasshouse and analysed to exmine reprodctibility of expression patterns. (DOC)Click here for additional data file."}
+{"text": "Venous thromboembolism (VTE), which constitutes pulmonary embolism and deep vein thrombosis, is a common disorder associated with significant morbidity and mortality. Landmark trials have shown that direct oral anticoagulants (DOACs) are as effective as conventional anticoagulation with vitamin K antagonists (VKA) in prevention of VTE recurrence and associated with less bleeding. This has paved the way for the recently published guidelines to change their recommendations in favor of DOACs in acute and long-term treatment of VTE in patients without cancer. The recommended treatment of VTE in cancer patients remains low-molecular-weight heparin. The initial management of pulmonary embolism (PE) should be directed based on established risk stratification scores. Thrombolysis is an available option for patients with hemodynamically significant PE. Recent data suggests that low-risk patients with acute PE can safely be treated as outpatients if home circumstances are adequate. There is lack of support for use of inferior vena cava filters in patients on anticoagulation. This review describes the acute, long-term, and extended treatment of VTE and recent evidence on the management of sub-segmental PE. Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is one of the most common cardiovascular diseases occurring for the first time in about 1 in 1000 people . Its incThe initial management of patients with a PE should be based on risk stratification of the patient into low, intermediate, or high risk for 30-day mortality based on established risk scores such as pulmonary embolism severity index (PESI) or its simplified version (simplified PESI) , 10. LowAnticoagulants are the mainstay treatment of VTE and are given in three phases of acute, long-term (in the first 3\u00a0months), and extended treatment . For manThe aim of this review is to (1) describe the initial management of patients with acute PE including the role of thrombolytic agents in hemodynamically unstable patients and at the other extreme outpatient management of low risk patients, (2) summarize the evidence on acute, long-term, and extended treatment of VTE comparing DOACs versus VKA, and (3) review the recent data on the management of sub-segmental PE and the lack of support for use of inferior vena cava filters in patients on anticoagulation.Anticoagulant therapy alone is recommended over thrombolysis for most patients with an acute DVT with exception for those with extensive iliofemoral or proximal DVT at high risk of limb ischemia , 21. ThrSystemic thrombolysis is a widely accepted treatment for PE in patients with persistent hypotension  and not at high risk of bleeding , 21. TheCDT may be used in patients with acute PE at increased risk of bleeding as a lower dose of a thrombolytic agent is infused directly into the pulmonary artery via a catheter . CDT is Home therapy is commonly employed for patients with an acute DVT in clinical practice with a few exceptions. Several randomized controlled trials and meta-analyses, which have compared home therapy with LMWH versus inpatient therapy with intravenous unfractionated heparin, suggest that outpatient therapy is safe and feasible in most patients with acute DVT \u201336. OutpThe outpatient treatment of acute PE is suggested with grade 2B evidence in the most recent ACCP guidelines in low-risk patients with adequate home circumstances . The decFour DOACs including dabigatran, rivaroxaban, apixaban, and edoxaban were compared with conventional therapy in the RE-COVER I and II, EINSTEIN-DVT and PE, AMPLIFY, and Hokusai-VTE trials, respectively \u201320. The The major society guidelines including the ACCP, American Society of Clinical Oncology, and the National Comprehensive Cancer Network recommend use of LMWH for treatment of VTE in cancer patients , 40, 41.There are no published randomized trials that a priori have compared DOACs with VKA or LMWH for treatment of VTE in cancer patients. A meta-analysis of the subsets with DVT and cancer totaling 1132 patients in the six trials that compared DOACs versus VKA \u201320 has bExtended anticoagulation can be employed in patients with unprovoked VTE to reduce the risk of recurrent VTE if the benefit/risk ratio favors continuation of anticoagulation while taking into account patient\u2019s risk of bleeding. All DOACs except for edoxaban have been compared with placebo in randomized trials for extended secondary VTE prevention beyond the initial three months of anticoagulation , 50, 51.Dabigatran is the only DOAC that has been compared with warfarin for extended VTE prevention in the RE-MEDY trial . DabigatAspirin has been also evaluated in secondary VTE prevention in patients with first unprovoked VTE who have completed anticoagulant treatment. In this setting, randomized trials and a meta-analysis reported a 30\u00a0% reduction in rates of recurrent VTE compared to placebo or observation \u201355. The The increase in utilization of a highly sensitive computed tomography pulmonary angiography (CTPA) has led to detection of incidental asymptomatic PE or small sub-segmental PE . WhetherInferior vena cava (IVC) filters are typically used in patients with an acute VTE and an absolute contraindication to anticoagulation  . The IVCVTE is a major cause of morbidity and mortality. DOACs are suggested over VKA for acute and long-term treatment of VTE in patients without cancer, as they have been shown to be as effective as VKA in reducing VTE recurrence and associated with significantly less major bleeding. Future studies are needed to assess their safety and efficacy in outpatient treatment of acute VTE. LMWH is the current standard of care for treatment of VTE in cancer patients. Randomized trials are ongoing to examine the non-inferiority of DOACs versus LMWH in cancer patients. Lastly, it is currently unclear whether or not to treat patients with SSPE and no proximal DVT; future prospective studies are needed to examine different management strategies in this patient group."}
+{"text": "The importance of hydrogen bonding, a relatively strong intermolecular force of attraction between molecules in biological systems, is discussed in the respect of P450 substrate affinity towards one or more of the human P450 enzymes that are generally associated with drug and other xenobiotic metabolism. It is shown that calculation of hydrogen bond distances and energies based on simple empirical relationships provide values that agree closely with experimental findings. It is thus possible to estimate the hydrogen bond contribution to P450 enzyme-substrate binding affinity based on modelled interactions and by use of these relatively simple formulae, particularly when employed in conjunction with substrate-lipophilicity relationships."}
+{"text": "This paper describes a logatome discrimination test for the assessment of speech perception in cochlear implant users (CI users), based on a multilingual speech database, the Oldenburg Logatome Corpus, which was originally recorded for the comparison of human and automated speech recognition. The logatome discrimination task is based on the presentation of 100 logatome pairs  with balanced representations of alternating \u201cvowel-replacement\u201d and \u201cconsonant-replacement\u201d paradigms in order to assess phoneme confusions. Thirteen adult normal hearing listeners and eight adult CI users, including both good and poor performers, were included in the study and completed the test after their speech intelligibility abilities were evaluated with an established sentence test in noise. Furthermore, the discrimination abilities were measured electrophysiologically by recording the mismatch negativity (MMN) as a component of auditory event-related potentials. The results show a clear MMN response only for normal hearing listeners and CI users with good performance, correlating with their logatome discrimination abilities. Higher discrimination scores for vowel-replacement paradigms than for the consonant-replacement paradigms were found. We conclude that the logatome discrimination test is well suited to monitor the speech perception skills of CI users. Due to the large number of available spoken logatome items, the Oldenburg Logatome Corpus appears to provide a useful and powerful basis for further development of speech perception tests for CI users."}
+{"text": "It is essential the existence of suitable preclinical models to elucidate the molecular mechanism of a disease and to test potential drugs and therapies. One of the major problems to discover new pharmacological therapies in Parkinson's disease is the lack of suitable preclinical model. This explains why L-dopa is still the most effective drug despite the severe side effects observed after 4-6 years of treatment. There is a long list of clinical studies failed despite being based on robust preclinical results obtained with exogenous neurotoxins as preclinical model. The use of preclinical models based on exogenous neurotoxins  or rotenone) is an important problem to translate successful results to clinical studies and new therapies in Parkinson's disease [Recently, we published that aminochrome can be used as a new preclinical model for Parkinson's disease. The unilateral injection of aminochrome in the striatum induces contralateral behavior without significant loss of dopaminergic neurons accompanied with a significant decrease in dopamine release and a significant increase in GABA levels, generating an imbalance of neurotransmitters in the basal ganglia. Aminochrome induces mitochondrial dysfunction resulting in a significant decrease in ATP level, explaining the significant decrease in the amount of synaptic vesicles in the terminals and a decrease in dopamine release since both axonal transport of vesicles for neurotransmission and dopamine release require ATP .Aminochrome is an o-quinone formed during dopamine oxidation to neuromelanin in dopaminergic neurons containing neuromelanin. It has been demonstrated that aminochrome induces mitochondrial dysfunction, generation of neurotoxic oligomers of alpha-synuclein, protein degradation dysfunction of both proteasomal and lysosomal systems, oxidative and endoplasmic reticulum stress  aminochrome is formed inside of dopaminergic neurons containing neuromelanin lost during the disease; (ii) aminochrome triggers mitochondria dysfunction, formation of alpha-synuclein neurotoxic oligomers, protein degradation dysfunction, oxidative stress and endoplasmic reticulum stress."}
+{"text": "Genomic-scale sequence alignments are increasingly used to infer phylogenies in order to better understand the processes and patterns of evolution. Different partitions within these new alignments  often favor hundreds if not thousands of competing phylogenies. Summarizing and comparing phylogenies obtained from multi-source data sets using current consensus tree methods discards valuable information and can disguise potential methodological problems. Discovery of efficient and accurate dimensionality reduction methods used to display at once in 2- or 3- dimensions the relationship among these competing phylogenies will help practitioners diagnose the limits of current evolutionary models and potential problems with phylogenetic reconstruction methods when analyzing large multi-source data sets. We introduce several dimensionality reduction methods to visualize in 2- and 3-dimensions the relationship among competing phylogenies obtained from gene partitions found in three mid- to large-size mitochondrial genome alignments. We test the performance of these dimensionality reduction methods by applying several goodness-of-fit measures. The intrinsic dimensionality of each data set is also estimated to determine whether projections in 2- and 3-dimensions can be expected to reveal meaningful relationships among trees from different data partitions. Several new approaches to aid in the comparison of different phylogenetic landscapes are presented.Curvilinear Components Analysis (CCA) and a stochastic gradient decent (SGD) optimization method give the best representation of the original tree-to-tree distance matrix for each of the three- mitochondrial genome alignments and greatly outperformed the method currently used to visualize tree landscapes. The CCA\u2009+\u2009SGD method converged at least as fast as previously applied methods for visualizing tree landscapes. We demonstrate for all three mtDNA alignments that 3D projections significantly increase the fit between the tree-to-tree distances and can facilitate the interpretation of the relationship among phylogenetic trees.We demonstrate that the choice of dimensionality reduction method can significantly influence the spatial relationship among a large set of competing phylogenetic trees. We highlight the importance of selecting a dimensionality reduction method to visualize large multi-locus phylogenetic landscapes and demonstrate that 3D projections of mitochondrial tree landscapes better capture the relationship among the trees being compared.The online version of this article (doi:10.1186/s12859-017-1479-1) contains supplementary material, which is available to authorized users. The rapid increase in the availability of genomic-scale multiple sequence alignments covering diverse sets of taxa offers new and exciting opportunities for those seeking to understand the processes and patterns of molecular evolution and brings us a step closer to solving such grand challenges as assembling a Tree of Life. In practice however, regions  of large multi-source data sets seldom support a single phylogenetic tree. More often than not, we are left to sort through hundreds if not thousands of competing phylogenies. Different data partitions may support different phylogenies because reconstruction methods sometimes fail to adequately accommodate process heterogeneous underlying data partitions found within an alignment \u20134 or becTo date, the typical approach used to summarize a set of phylogenetic trees is to create a single consensus tree from the set of competing trees, in which the vertices of the consensus tree are only retained if they are shared by a majority of the trees contained within the set of candidate trees. Phylogenetic network  and maxiMotivated by the inherent limitations of the consensus tree approach, Amenta and Klinger  applied While the aforementioned authors did an excellent job demonstrating the utility of this new approach, they did not specifically address some key methodological questions specifically related to mapping high-dimensional data, in this case tree-to-tree distance, into a lower dimension for visualization. In this study we specifically address some of these unanswered questions by applying several Nonlinear Dimensionality Reduction (NLDR)  methods In addition, we estimate the intrinsic dimensionality of large collections of mtDNA gene trees in order to better understand whether viewing the relationship among phylogenetic trees in 3D is warranted. Finally, we introduce ways to compare projections obtained from unrelated alignments so that we might better understand the biological processes and methodological biases associated with the inference of phylogenetic trees. Correctly characterizing phylogenetic tree-space by dimensionality reduction methods is critical if this approach is to be of value as an interpretive or a diagnostic tool for detecting problems with substitution models or tree searching strategies.Aligned whole mitochondrial DNA (mtDNA) genomes were obtained from three published studies representing Fishes (90 sequences) , MammalsPhylogenetic analyses as described above were also performed on a test data set consisting of 15 partitions equal in size to the original gene partitions found in the Salamander data set. The 15 test partitions were composed of characters  selected at random but in proportion to their occurrence in the original Salamander mtDNA genome alignment. Therefore, the partitions within the newly compiled test data set only differ from one another by sampling error and by size . The test data set was intended to serve as a null data set in which any patterns observed in subsequent NLDR projections could only have resulted from sampling error and the size of data partitions.A set of trees was compiled for each of the three multiple sequence alignments by taking the union of the bootstrap trees obtained from the analyses of the 15 individual gene partitions  a stress function, which is an objective function used to evaluate embeddings of the RF-distances in lower dimensions, and 2) an algorithm used to optimize the stress function. The stress functions are Normalized stress , KruskalWhen implementing each pairing of stress function and optimization algorithm, efficiencies specific to the pair were exploited. The details of stress functions, optimization algorithms, and implementation considerations are presented in the Additional file The number of bootstrap trees  representing each gene partition varied from between 103 and 1559 (Table\u00a0Not only are more trees retained by bootstrap analyses of shorter gene partitions, but the mean RF-distance among trees from shorter partitions is generally greater then the mean RF-distances among bootstrap trees from longer gene partitions Fig.\u00a0. This reThe bootstrap analysis, as applied in phylogenetics, uses randomly selected columns from the original multiple sequence alignment to generate new character matrices, which are then used to infer optimal tree topologies . If all,We used four different methods to estimate the intrinsic dimensionality of each of the three tree-to-tree distance matrices generated from the concatenated bootstrap analyses. Our estimates of the intrinsic dimensionality for each data set varied from between 3 to 15-dimensions Table\u00a0. These eIn order to better understand the effect of each constituent component of the NLDR analysis, the results from 14 of the 16 combinations of cost functions and optimization algorithms were evaluated. The combination of Majorization with CCA and Gauss-Seidel with CCA were not included for the reasons discussed in the Additional file All of the NLDR analyses that we evaluated took between four and 230\u00a0min to converge on local minima Fig.\u00a0. Our resTime to convergence is only useful in light of how well each of the optimization algorithms is able to minimize their respective cost functions. For example, majorization took the longest time to minimize the Kruskal-1 cost function among all the other optimization algorithms that we compared Fig.\u00a0; howeverWe evaluated the relative performance of each cost function using three measures of goodness of fit. These measures provide a common objective function that can be used to evaluate how well each projection preserves the relationship among the bootstrap trees as suggested by the original RF-distances. We chose to evaluate the projections with the lowest stress value for each cost function no matter which optimization algorithm was used to obtain it. In this way we restricted our comparisons to the best representation of the cost function given the optimization algorithms that were included in this analysis. According to both the 1-NN  and TrusThe choice of cost function and optimization algorithm used to project the RF-distances in 2 and 3D space significantly impacts the visual interpretation of the projected RF-distances. More importantly, it was not necessary to visually compare extreme cases to detect these differences. For example, Fig.\u00a0While the choice of optimization algorithm and cost function make a noticeable difference in the projection of mtDNA distances, different initial conditions for a given method are difficult to discern. For example, Fig.\u00a0Hillis et al.  did a thCorrectly characterizing phylogenetic tree-space by dimensionality reduction methods is critical if this approach is to be of value as an interpretive or a diagnostic tool for large sets of trees obtained from whole genomes or from multi-gene data sets. We found that different dimensionality reduction methods can significantly influence the appearance, and hence interpretation of 2- and 3-D projections of tree-to-tree distances. In particular, among the cost functions and optimization algorithms that we evaluated, we found that CCA and the SGD method gave the best representation of the original tree-to-tree distances as indicated by the trustworthiness and continuity metrics. We also demonstrate by using several different estimates that the intrinsic dimensionality of three mtDNA tree-to-tree distance matrices is greater than two, and therefore using 3D to view these data is warranted in order to minimize distortions related to projecting high dimensionality data into a lower dimension. Tree landscapes obtained from analyses of alignments composed of very different sets of taxa but similar data partitions share some striking similarities. These similarities are easiest to observe when outliers are removed and related points are covered by a convex hull. The results obtained in this study establish that the choice of NLDR method can significantly influence our interpretation of tree landscapes. Perhaps more importantly, this work establishes the necessary framework for the application NLDR to be used in the evaluation of tree reconstruction methods, nucleotide substitution models, and other tree-to-tree distance matrices [e.g., Nearest Neighbor Interchange , Quartet"}
+{"text": "Central nerve terminals contain a limited number of synaptic vesicles (SVs) which mediate the essential process of neurotransmitter release during their activity-dependent fusion. The rapid and accurate formation of new SVs with the appropriate cargo is essential to maintain neurotransmission in mammalian brain. Generating SVs containing the correct SV cargo with the appropriate stoichiometry is a significant challenge, especially when multiple modes of endocytosis exist in central nerve terminals, which occur at different locations within the nerve terminals. These endocytosis modes include ultrafast endocytosis, clathrin-mediated endocytosis (CME) and activity-dependent bulk endocytosis (ADBE) which are triggered by specific patterns of neuronal activity. This review article will assess the evidence for the role of classical adaptor protein complexes in SV retrieval, discuss the role of monomeric adaptors and how interactions between specific SV cargoes can facilitate retrieval. In addition it will consider the evidence for preassembled plasma membrane cargo complexes and their role in facilitating these endocytosis modes. Finally it will present a unifying model for cargo retrieval at the presynapse, which integrates endocytosis modes in time and space. The basis of neuronal communication in mammalian brain is the activity-dependent release of chemical neurotransmitter from the presynapse . This event is triggered by action potential-driven calcium influx, resulting in the fusion of neurotransmitter-containing synaptic vesicles (SVs). The pool of SVs that are available for fusion at any one time is highly limited (between 200\u2013400) inside a typical small central nerve terminal  at the plasma membrane and stabilized by both cargo binding . AP-2 is a cytoplasmic heterotetrameric complex formed from four separate polypeptides named adaptins  protein synaptobrevin II (sybII). This suggests that other clustering and retrieval mechanisms must occur at nerve terminals to ensure accurate SV cargo retrieval. The helical SNARE motif of sybII is essential for SV fusion when complexed with the plasma membrane proteins syntaxin and SNAP-25 . Syt-1 is essential for coupling of calcium influx to SV fusion, with calcium binding to its C2 domains resulting in synchronous neurotransmitter release on action potential stimulation .The first iTRAP identified was the abundant transmembrane SV cargo synaptophysin. Early studies which examined the effect of genomic deletion of the synaptophysin gene revealed that its absence had no apparent effect on either neurotransmitter release or presynaptic morphology , which ensures the accurate clustering and retrieval of Syt-1. SV2A interacts with the C2B domain of Syt-1 via its N-terminus , with the endocytosis mode utilized determined by the intensity of stimulation encountered.The adaptor protein complex AP-2 clusters SV cargo on the plasma membrane and this action aids the recruitment of clathrin  directly from the nerve terminal peri-active zone within 100 ms of action potential stimulation . Removal of the fluorescent moiety from the plasma membrane population of sybII-pHluorin revealed that the reporter deposited on the cell surface during neuronal activity was not the same as the reporter that was retrieved by endocytosis , whereas the ongoing destruction of this phospholipid to make the lipid composition more \u201cendosomal\u201d  whereas others  display expression levels of up to 50% of total  preparing the readily retrievable pool for the next cycle of activity  ADBE-specific cargo at sites selective for ADBE Figure . The locMAC conceived and wrote the manuscript.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In a Perspective, James Topham and Marco Marra discuss progress in the use of genomic information to guide cancer treatment. Cancer is a complex genetic disease often associated with the accumulation of somatic DNA alterations . Genes tTargeted treatments have become a major modality in the treatment of cancer and can offer advantages to the patient over standard chemotherapy alone ,6. HowevHER2 copy number amplifications in ~30% of patients, noting that overexpression of HER2 was associated with poor prognosis [HER2-expressing tumor cells. The success of clinical trials investigating the use of trastuzumab in the treatment of HER2-positive breast cancers has resulted in routine screening for HER2 amplifications in the management of breast cancer patients [BCR\u2013ABL fusion [BCR\u2013ABL fusion transcripts thus became routine in the use of imatinib for CML patients [The first assays to screen cancer patients for somatic alterations targetable by drugs were based on detection of single gene alterations . For exarognosis . Trastuzpatients . Anotherpatients . ImatiniL fusion . Screenipatients .Continued discovery of recurrent driver alterations in different cancers, concomitant with further development of targeted drugs, eventually generated an impetus for the construction of multiplexed assays to detect multiple genomic alterations in cancer patients. Extending from single-gene-based assays, panel sequencing offered the opportunity to discover genomic alterations in tumors that were not known to harbor such alterations. Early applications of multi-gene assays aimed at guiding cancer treatment focused on a small number of genes directly associated with targeted agents, including examples such as a panel capable of detecting 41 alterations in 9 genes relevant in lung cancer , as wellInvestigations into the feasibility and efficacy of applying panel sequencing techniques to large populations of patients with advanced cancer are ongoing and include trials such as NCI-MATCH  , TAPUR  approaches, which are now being explored and offer the substantial advantage of comprehensive detection of genomic alterations that elude detection using panel sequencing. Among the first demonstrations of the use of WGS technology to guide treatment decision-making in cancer was a case of late-stage, metastatic adenocarcinoma of the tongue . IntegraComplicating the application of precision approaches to guide cancer treatment are results from detailed investigations into the clonal landscapes of tumors, which have revealed the dynamic nature of cancers resulting from evolution in response to selective pressures . Consequ"}
+{"text": "An 11-year-old boy presented to the emergency department (ED) with sudden onset severe atraumatic right testicular pain, associated with nausea and vomiting. On examination, the patient exhibited a slight horizontal lie of the right testicle as well as an absent cremasteric reflex on the right. Urology was emergently consulted. Though vascular flow was noted bilaterally on spectral Doppler , the patTesticular torsion with whirlpool sign: Testicular torsion occurs when twisting of the spermatic cord results in a subsequent loss of blood supply to the ipsilateral testicle. Testicular torsion is primarily a pediatric problem, with a bimodal age distribution of the first year of life and early adolescence. Evaluation of testicular flow by color and spectral Doppler is the primary method of diagnosis.CPC-EM CapsuleWhat do we already know about this clinical entity?The whirlpool sign is an important diagnostic marker in the evaluation of suspected testicular torsion by point- of-care ultrasound.What is the major impact of the image(s)?The whirlpool sign is a characteristic sonographic finding indicative of testicular torsion.How might this improve emergency medicine practice?Visualization of the whirlpool sign allows confident diagnosis of testicular torsion."}
+{"text": "Alzheimer\u2019s disease (AD) is the most common form of dementia in old age, and is characterized by prominent impairment of episodic memory. Recent functional imaging studies in AD have demonstrated alterations in a distributed network of brain regions supporting memory function, including regions of the default mode network. Previous positron emission tomography studies of older individuals at risk for AD have revealed hypometabolism of association cortical regions similar to the metabolic abnormalities seen in AD patients. In recent functional magnetic resonance imaging (fMRI) studies of AD, corresponding brain default mode regions have also been found to demonstrate an abnormal fMRI task-induced deactivation response pattern. That is, the relative decreases in fMRI signal normally observed in the default mode regions in healthy subjects performing a cognitive task are not seen in AD patients, or may even be reversed to a paradoxical activation response. Our recent studies have revealed alterations in the pattern of deactivation also in elderly individuals at risk for AD by virtue of their APOE e4 genotype, or evidence of mild cognitive impairment (MCI). In agreement with recent reports from other groups, these studies demonstrate that the pattern of fMRI task-induced deactivation is progressively disrupted along the continuum from normal aging to MCI and to clinical AD and more impaired in e4 carriers compared to non-carriers. These findings will be discussed in the context of current literature regarding functional imaging of the default network in AD and at-risk populations."}
+{"text": "The viral replication cycle presents viruses with a series of logistical challenges: To be successful, the virus must synthesize new copies of its genetic material, induce the cell to translate its genome into protein, and coordinate the host and viral factors required to assemble new virus particles. Much of this occurs at intracellular membranes, and lipid bilayers are expected to both play a central role in organizing the molecular machinery required for each stage of virion biogenesis and provide a structural foundation for particle assembly. These functions are prominently exploited by viruses with single-strand, positive-sense RNA genomes, which dramatically remodel intracellular membranes to form specialized replication complexes (RC) in the cytoplasm of infected cells . While tAmong the major contributors to the positive-strand RNA virus global disease burden are the flaviviruses, a genus of enveloped viruses that includes Yellow fever virus (YFV), Zika virus (ZIKV), Dengue virus (DENV), and West Nile virus (WNV) and is closely related to Hepatitis C virus (HCV) . DespiteFlavivirus particles are internalized through receptor-mediated endocytosis, followed by pH-mediated fusion, uncoating, and release of the RNA genome from the endosome into the host cytoplasm. This strand of positive-sense RNA is translated by host ribosomes to a single polyprotein, which is cleaved by cellular and viral proteases into three structural  and seven nonstructural (NS) proteins that form the genomic replication machinery. A combination of membrane-associated NS proteins and co-opted host factors then collaborate to bend the surrounding endoplasmic reticulum (ER) membrane into clusters of invaginated vesicles (Ve) connected to the cytosol by a single pore \u20136 Fig 1Fig 1. A Inducing the negative membrane curvature required for vesicle formation is a thermodynamically unfavorable process . To loweSimilar results have been shown for phosphatidylcholine (PC), a second lipid class strongly enriched during flavivirus infection \u201322. RemaIn concert with changes in structure and lipid makeup, the ER undergoes significant expansion during flavivirus infection . This grFatty acid synthesis is regulated by sterol regulatory element-binding proteins (SREBPs), a family of membrane-bound transcription factors also responsible for controlling cholesterol biosynthesis . AlthougMounting evidence suggests that different flaviviruses have different cellular and tissue tropisms with distinctive disease pathology. Although the exact determinants of differential flavivirus tropism are unknown, the lipid microenvironment of the tissue may have a critical role in this process. For instance, it is now well established that ZIKV crosses the human fetal\u2013placental barrier to infect the developing central nervous system to cause microcephaly . ZIKV inAn important process involved in the regulation of lipid metabolism that is affected by ZIKV and possibly by other flaviviruses is the Akt\u2013mTOR signaling pathway . ZIKV reRecent advances in the fields of genomics and proteomics have transformed our understanding of health and diseases. Despite the latest improvements in analytical approaches\u2014in particular, liquid chromatography and mass spectrometry\u2014the field of lipids lacks a corresponding advancement of knowledge in host\u2013pathogen interactions. Due to the complexity of lipids and the absence of robust tools, manipulation of lipid composition in a controlled manner remains an experimental challenge. A combination of recently developed lipid tools such as the bi- and trifunctional lipid probes would provide the means to monitor the spatial and temporal distribution of cellular lipids during infection . Combine"}
+{"text": "This report details the use of zygomatic oncology osseointegrated implants to support and retain a maxillary obturator in a 13-year-old male patient who underwent a right-sided hemi-maxillectomy (Brown Class 2b)  for a myxoid spindle cell carcinoma. At the time of maxillary resection, two zygomatic oncology implants were inserted into the right zygomatic body and subsequently utilised to provide in-defect support and retention for a bar-retained maxillary acrylic obturator prosthesis, which restored the patient\u2019s aesthetics and function to a very high level. Close follow-up over 2\u00a0years demonstrated ongoing excellent function and disease control with no deleterious effects on facial or dento-alveolar growth clinically. This is the first clinical report of its kind in the published literature detailing the use of a zygomatic implant-retained obturator in a paediatric patient. Maxillary defects of acquired  or congeAn obturator is a custom-made denture prosthesis that is used to close the communication with the antrum/nose in order to allow satisfactory mastication and speech. In the dentate patient, maxillary obturator prostheses may be retained by the natural dentition together with the engagement of undercuts within the maxillary defect itself. The use of osseointegrated implants to assist with the retention of a maxillary obturator has been reported ; utilisiThe characteristics of a good obturator will improve swallowing, speech function, minimise nasal fluid leakage from the antrum and nasal spaces, restore facial aesthetics including the teeth and facilitate masticatory function and speech. A surgical obturator can be provided at the time of surgery to facilitate function and haemostasis in the immediate post-operative period, and this can subsequently be replaced with a more definitive prosthesis once the maxillary defect has healed to a more stable condition.To date, no literature exists on the fabrication of an implant-retained maxillary obturator for a paediatric patient, and this case presentation describes the use of zygomatic oncology implants together with the rationale for their use in a paediatric patient.A medically fit and well 13-year 11-month-old male was referred to the oral and maxillofacial surgery department at Alder Hey Children\u2019s Hospital in Liverpool in regard to an intra-oral swelling of the right palatal region Fig.\u00a0. An inciFurther investigations undertaken to stage the tumour included a repeat CT scan which presented no evidence of significant bony involvement or erosion. An MRI scan showed no significant asymmetry or signal abnormality in the region of the hard palate, and there was no evidence of loco-regional metastasis of this tumour.Following a discussion of the craniofacial multidisciplinary team and numerous paediatric pathologists, a diagnosis of intermediate-grade sarcoma of the oral mucosa and hard palate was re-affirmed. A partial right-sided maxillectomy was planned to gain adequate tumour clearance, and prior to surgery, the patient attended for dental impressions and counselling regarding the procedures involved, together with instructions regarding the obturator prosthesis.A low-level right-sided standard hemi-maxillectomy was carried out via an intra-oral approach with preservation of the pterygoid plates (December 2013). The anterior alveolar cut was undertaken through the right lateral incisor socket following the extraction of this tooth in order to maximise the bone support on the maxillary central incisor abutment tooth. The residual zygomatic body on the right side was exposed, and two 37-mm zygomatic oncology implants  , a definitive implant bar-retained maxillary obturator was fitted utilising precision attachments  Figs.\u00a0 and 6. TThe paediatric population rarely suffer malignant disease of the oral cavity requiring any form of maxillectomy, and there is little published evidence around the rehabilitation and restorative management of children undergoing such procedures. The seemingly most common approach for a limited low-level maxillary resection in a child would be to consider resection and simple prosthetic obturation as this allows relatively simple management of the tumour from a surgical point of view as well as immediate functional and aesthetic rehabilitation with a prosthesis. It also allows for full histopathological examination of the resected specimen to ensure complete resection of the tumour before committing the patient to any form of complex surgical reconstruction which could be planned at a later date should the patient wish. The delivery of a maxillary obturator improves quality of life significantly by primarily restoring aesthetic and functional modalities. It also serves as a purpose to allow correct phonation of speech, prevent nasal discharge of masticatory contents and facilitate swallowing. The aesthetic and psychological benefits of facial restoration are paramount in a child undergoing such a procedure. The use of microvascular reconstruction techniques have allowed for autogenous tissue reconstruction of maxillary defects with either soft or hard tissue. The use of a soft-tissue-only reconstruction such as a radial forearm flap in this clinical situation would prevent successful dental rehabilitation as the soft tissue flap provides no support for the dental prosthesis and, apart from the separation of the oral and nasal cavities, provides no advantage for the patient. The use of a composite-bone-containing flap such as the fibula flap has the potential to provide oro-nasal separation as well as bone to support an implant-retained prosthesis, and with the latest digital technologies, this can be provided rapidly in carefully selected cases , althougThe difficulty of restoration with a maxillary obturator prosthesis depends on the extent of the surgical resection, with the acceptance that resections with an increasing horizontal component provide a much greater prosthodontic challenge. The number of remaining teeth is a key component in conventional obturator design  with theIn a paediatric patient, the development and subsequent growth of facial skeleton is an added concern, although by age 13/14, the major mid-face growth will be largely completed . CertainThe use of modified zygomatic implants Fig.\u00a0 allows iThe evidence for loading zygomatic implants immediately is very clear in the literature  in a croThe use of zygomatic implants to supplement the stability and retention of the maxillary obturator in this case has improved the function of the prosthesis and provided for a very high-quality rehabilitation for the patient reported with no evidence of disruption to facial growth in the 22\u00a0months following surgery."}
+{"text": "Malaria remains a major cause of mortality across the world, but particularly in sub-Saharan Africa. WHO-sponsored World Malaria Day activity has helped to improve education and has contributed to a reduction in mortality globally in the past decade. However, much needs to be done still in Africa. We report on a World Malaria Day scheme in three primary Healthcare Facilities in and around the Abuja Federal Capital Territory in Nigeria in 2017. Activity included educational talks to pregnant women and nursing mothers of young children, with malarial testing, distribution of free mosquito nets and also medical treatment if needed. We found a large clinical over-diagnosis of malaria with simple fevers of any cause being reported as malaria. None of these cases were found to be due to malaria on formal malarial testing. We conclude that efforts should continue into education and prevention of malaria with insecticide-impregnated mosquito nets a key factor. However, over-diagnosis of malaria and the use of unnecessary antimalarial treatment may lead to parasite resistance to antimalarial treatment, morbidity from drug side-effects and potential mortality from not receiving the right treatment for other febrile illnesses. We recommend that malarial testing, particularly with simple blood film microscopy is implemented more widely across Africa, as it is simple to perform and allows effective management plans to be drawn up for individual patients. Malaria is a preventable and curable/treatable illness transmitted by infected female Anopheles mosquitoes. According to the World Health Organization (WHO), in 2015, 91 countries and areas had ongoing malaria transmission [Excellence and Friends Management Care Centre (EFMC) partnered with the Center for Family Health Initiative (CFHI) in Abuja in the implementation of free medical services to pregnant and nursing women, and children under the age of 5 yrs living in and around the Nigerian capital city. Mosquito nets and rapid diagnostic kits were provide by EFMC, CFHI and the Nigerian National Malaria Elimination Program (NMEP). Following several preparatory meetings, three sites-Kagini, Gwagwa and Idu-Karmo Primary Health Care Centers were purposefully selected . CriteriA total of 117 women (pregnant women and nursing mothers) were enrolled with free medical services at the three centers-Kagini (40), Gwagwa (42) and Idu-Karmo (35) Primary Health Care Centers Health talks: The program began with a health talk upon the arrival of the project team at the designated facility. In most facilities, the beneficiaries, made up of women and children, were already seated in anticipation of the proposed medical services. Health talks on healthy living, malaria symptoms, preventive strategies including use of ITNs, indoor residual sprays and malaria chemoprophylaxis for the vulnerable population were undertaken; and management of fevers were presented to the participants by qualified healthcare workers. Strategies to prevent malaria infection by reducing mosquito bites were highlighted including through the use of mosquito nets. Attendees were encouraged to prevent malaria by embracing the use of treated mosquito nets and maintaining them appropriately. Participants were also advised to maintain clean environments devoid of breeding grounds for mosquitoes. Several questions on how to effectively use mosquito nets where posed by attendees and responded to by the project management team Malaria diagnosis and ITN distribution: Free malaria tests were conducted using rapid test kits (One Step Malaria P.f HRH -II Antigen Rapid TEST One Step Malaria P.f HRH-II Antigen Rapid TEST [pid TEST  for 79 (Outcome of malaria testing: None of the women and children tested was identified to have malaria from the test. This is despite the fact that they had clinical symptoms similar to malaria like fever.Responses from beneficiaries: Beneficiaries were excited about the services and knowledge acquired on how to prevent malaria. The beneficiaries also took turns to show their appreciation in their local languages from several ethnic groups of Nigeria. In the words of some of the beneficiaries: \u201cWe are glad for the knowledge acquired today, the free test and free net. Thank God someone remembered us in recession\u201d LE \u201cWhat happened today is a good thing. I have leant how I can protect my family\u201d MU \u201cWe give God thanks for the good works of EFMC\u201d RA.World Malaria Days are dedicated days designed to help improve awareness of the impact of malaria, prevention strategies and treatment options available in the communities. Our activity showed that not all malaria-like fevers in malaria-endemic regions like Nigeria are as a result of malaria , 4. TherAs clinical diagnosis has very low sensitivity and specificity due to the nonspecific nature of the symptoms and signs of malaria, this informed the development of the current malaria treatment guidelines that emphasized parasitic diagnosis rather than clinical diagnoses -12. TherThe impact of the knowledge shared and rapid test carried out was evident during the field work. As severe malaria is clinically similar to other severe febrile illnesses and in endemic areas, parasitological confirmation of parasitaemia is often unavailable or unreliable, false-positive malaria microscopy is therefore very common. This most time results in wrong focus on malaria with resultant unnecessary antimalaria treatment and failure to address other life-threatening conditions . Over diThe authors declare no competing interests."}
+{"text": "Bilateral hydronephrosis secondary to urinary obstruction leads to a buildup of back pressure in the urinary tract and may lead to impairment of renal function. We present a case of a 57-year-old male with a history of alcoholic liver cirrhosis, who presented with tense ascites and acute renal failure. Bilateral hydronephrosis was seen on abdominal ultrasound. Multiple large-volume paracenteses resulted in resolution of hydronephrosis and prompt improvement in renal function."}
+{"text": "Viatra reactive transformation framework. We demonstrate the feasibility of our approach with two case studies: one in an advanced model engineering workflow; and one in the context of on-the-fly gesture recognition.Streaming model transformations represent a novel class of transformations to manipulate models whose elements are continuously produced or modified in high volume and with rapid rate of change. Executing streaming transformations requires efficient techniques to recognize activated transformation rules over a live model and a potentially infinite stream of events. In this paper, we propose foundations of streaming model transformations by innovatively integrating incremental model query, complex event processing (CEP) and reactive (event-driven) transformation techniques. Complex event processing allows to identify relevant patterns and sequences of events over an event stream. Our approach enables event streams to include model change events which are automatically and continuously populated by incremental model queries. Furthermore, a reactive rule engine carries out transformations on identified complex event patterns. We provide an integrated domain-specific language with precise semantics for capturing complex event patterns and streaming transformations together with an execution engine, all of which is now part of the  Live models in smart cyber-physical systems Smart Cyber-Physical Systems Future wour works  gives a We plan to further investigate the execution formalisms suitable for event processing. Apart from the widely used DFA- and NFA-based approaches, DEVS  can be cunderlying consistency algebra which the tolerance rules conform to and which facilitates the automated extraction of such rules.As mentioned in Sect.\u00a0visual debugger for observing the runtime behavior of event patterns at run-time. The thorough performance assessment of the framework is an ongoing work for which we use the Linear Road benchmark ..visual d"}
+{"text": "Active shape models (ASM) showed to have potential for segmenting the right ventricle (RV) in CMR images. Nevertheless, the large variability and complexity of the RV shape do not allow for concisely capturing all possible shape variations among different patients and anatomical cross-sections. Noticeably, the latter increases the number of iterations required to converge to a proper solution and reduces the segmentation accuracy.In this work, a new ASM framework has been developed for efficiently modeling the RV shape in short-axis CMR images. In this framework, the RV contour is split into two simpler segments, septal and free wall, whose shape variations are independently modeled using two separate  ASM models Figure Table 1 shows the mean \u00b1 SD errors between the contours produced by the proposed and conventional ASM models with respect to manually delineated contours at the three different cross-sectional slices. As can be seen in Table 1, the performance of the proposed ASM framework is better than that of the conventional ASM model. This is evident by the lower value of the Mean Absolute Distance (MAD) and Hausdorf measures and higher value of the Dice index. Figure The developed double-ASM RV segmentation technique outperforms the conventional ASM framework and can efficiently model complex RV shape variation with more accuracy in less iteration steps. Although the proposed framework extracts only the RV endocardium, the epicardium can be segmented through dilating the endocardium contour."}
+{"text": "Such kind of plasticity can be induced by different STDP paradigms with multiple repeat numbers and stimulation patterns. They subsequently recruit or activate different molecular pathways and neuromodulators for induction and expression of STDP. Dopamine (DA) and brain-derived neurotrophic factor (BDNF) have been recently shown to be important modulators for hippocampal STDP at Schaffer collateral (SC)-CA1 synapses and are activated exclusively by distinguishable STDP paradigms. Distinct types of parallel synaptic plasticity in a given neuron depend on specific subcellular molecular prerequisites. Since the basal and apical dendrites of CA1 pyramidal neurons are known to be heterogeneous, and distance-dependent dendritic gradients for specific receptors and ion channels are described, the dendrites might provide domain specific locations for multiple types of synaptic plasticity in the same neuron. In addition to the distinct signaling and expression mechanisms of various types of LTP and LTD, activation of these different types of plasticity might depend on background brain activity states. In this article, we will discuss some ideas why multiple forms of synaptic plasticity can simultaneously and independently coexist and can contribute so effectively to increasing the efficacy of memory storage and processing capacity of the brain. We hypothesize that resolving the subcellular location of t-LTP and t-LTD mechanisms that are regulated by distinct neuromodulator systems will be essential to reach a more cohesive understanding of synaptic plasticity in memory formation.Understanding learning and memory mechanisms is an important goal in neuroscience. To gain insights into the underlying cellular mechanisms for memory formation, synaptic plasticity processes are studied with various techniques in different brain regions. A valid model to scrutinize different ways to enhance or decrease synaptic transmission is recording of long-term potentiation (LTP) or long-term depression (LTD). At the single cell level, spike timing-dependent plasticity (STDP) protocols have emerged as a powerful tool to investigate synaptic plasticity with stimulation paradigms that also likely occur during memory formation  Furthermore, many LTP/LTD results are obtained from recordings that average synaptic responses of groups of neurons rather than looking at the level of single cells. While responses from groups of neurons might provide a better insight into synaptic changes at the network level, recordings at the single cell level allow investigating synaptic function with sufficient spatial resolution to disentangle subcellular and molecular differences of synaptic plasticity in the same neuron. We hypothesize that the location of a synaptic input onto a postsynaptic neuron along its dendritic tree decides about the direction , the magnitude, and the expression mechanism of the synaptic modification that is induced. This decision is regulated by the local neuromodulatory microenvironment , acetylcholine (ACh) and BDNF) in the vicinity of the synaptically activated dendritic location  come into play. Active backpropagation of sodium-dependent action potential (AP) into dendrites -LTP or t-LTD that are induced by STDP protocols have been observed in response to various protocols and in different circuits and brain areas  is dependent on DA signaling via D1 receptor activation  can be induced independently and subsequently at a given subset of SC-CA1 synapses Figure . WhetherNeuromodulators can affect\u2014among other things\u2014neuronal excitability (AP firing and propagation properties), transmitter release, morphology  and molecular outfit of synaptic structures. Importantly, neuromodulatory transmitters like ACh, DA and NA can shape the backpropagation of APs or calcium spikes in the dendrites by different G-protein induced actions , as well as firing mode and firing rates of these cells can enhance or multiply the versatility of neuromodulatory mechanisms for memory encoding  the main locus of expression of early LTP diverges. Postsynaptic expression seems to be the most plausible mechanism for early LTP at SC-CA1 synapses, while at MF-CA3 synapses, presynaptic expression takes place  and basal dendrites of CA1 pyramidal neurons are the main target regions of the presynaptic SCs in the CA1 area  contain NMDARs, while perforated synapses  show additionally a distance-dependent increase in the expression level of AMPARs from proximal to distal regions  sets the stage for the mechanism of LTP expression that can take place at this spine, thus representing another cellular process that decides which type of plasticity can be brought about at this very location.A synapse specific microenvironment for t-LTP expression is also likely to be created by the differential availability of BDNF/TrkB signaling at individual synapses. Postsynaptically mediated BDNF-dependent types of t-LTP are presumably expressed at specific dendritic sites, where BDNF is synthesized or delivered  in dendrites is likely to erase (some of the) bAPs. This has almost certainly more dramatic consequences for weaker (1:1 stimulation) than stronger (1:4) STDP paradigms. Whether repeat number, pairing frequency or pattern of postsynaptic bursts in STDP paradigms is the strongest determining factor remains to be tested. However, it seems plausible that more robust stimulations might be suited to overcome any attenuation of bAPs in dendrites , STDP induction is heavily dependent on successful backpropagation of APs. In this respect it seems reasonable to assume that factors regulating this backpropagation are likely to facilitate synaptic plasticity in more distal parts of the apical and basal dendrites of the CA1 area  vs. deep CA1 pyramidal neurons (close to Stratum radiatum) were already described by Lorente de N\u00f3  and coulin vitro are crucial to understand hippocampal memory formation in vivo, remains a challenging question to be tackled by future experiments.The heterogeneity of apical and basal dendrites and the described somato-dendritic gradients of receptors, transmitter release probabilities and ion channels might be important for the location specific activation of distinct synapses to allow independent coexistence of multiple types of t-LTP in the same individual neuron. Furthermore recent studies suggest functional differences of deep and superficial CA1 pyramidal neurons, which might underlie different and coexisting mechanisms of synaptic plasticity. Whether the subtle changes in induction paradigms that lead to differential success of t-LTP along the dendritic tree of a CA1 pyramidal neuron 3) anchored to the dendritic shaft by the spine neck  differentially affect AMPAR conductance at the potentiated synaptic sites. Synaptic plasticity induced with the 1:4 rhythm significantly increased the AMPAR mediated currents due to enhanced trafficking of GluA1 subunit containing receptors, whereas for the 1:1 paradigm synaptic AMPAR conductances remained unaffected  along CA1 dendrites that might be susceptible to undergo t-LTP in response to divergent STDP protocols (associative or input-specific synaptic plasticity; compare e.g., Buonomano and Merzenich, Taken together these additional heterosynaptic effects of synaptic plasticity that are induced by STDP paradigms might lead to even more and sophisticated ways to strengthen or weaken synapse function as cellular correlate for learning and memory.in vivo.Summarizing and collecting evidence of published and our own unpublished data, we think that synaptic plasticity at SC CA1 synapses has multiple facets and mechanisms. The magnitude of t-LTP and the locus of t-LTP expression depend on dendrite subtype, spine structure and location, location of synapses at proximal vs. distal dendrites, effective neuromodulation and background brain activity. Furthermore, we believe that the different mechanisms for encoding or processing memory can coexist simultaneous and independently at the same subset of synapses. However, so far we have just begun to understand how these processes interact at the cellular level and can only speculate how they might be involved in learning and memory in vitro data reviewed in this article might contribute to memory formation in vivo.Clearly, a plethora of new experiments will be required to translate how the EE and VL designed the outline of the article. EE, EC-P and VL wrote the text. EE and VL prepared the figures.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Severe combined immunodeficiencies (SCID) are a group of hereditary diseases mainly characterized by T-cell lymphopenia. These diseases are recognized as pediatric emergencies due to their high morbidity and mortality. Data suggest that more than 90% of children with an early diagnosis of SCID who are able to receive a bone marrow transplant before the age of four survive. Of those receiving treatment after four years of age, only 50% survive. This data indicate that early diagnosis is critical.Neonatal screening done by quantifying T-cell receptor excision circles (TRECs) allows for the diagnosis of severe immunodeficiencies in the immediate postnatal period. The sensitivity of neonatal diagnosis of typical severe combined immunodeficiencies using the TREC count is around 100% and depends on the establishment of a baseline for the minimum number of TRECs considered normal in subjects without severe combined immunodeficiency. Adapting an algorithm for preterm infants/children with signs and symptoms of immunodeficiency greatly reduces the number of false positives. By adding on the evaluation of the kappa-deleting recombination excision circles (KRECs), which are present in cell differentiation, there is a gain in the diagnosis of some B-lymphocyte deficiencies, that have a greater incidence than the severe combined immunodeficiencies.Revista Paulista de Pediatria, \u201cNeonatal Screening of Severe Combined Immunodeficiencies by TRECs and KRECs: Second Pilot Study in Brazil,\u201d by Kanegae, Barreiros et al.,The study presented in this issue of the"}
+{"text": "Repetitive transcranial magnetic stimulation (rTMS) applied to the left frontal lobe is discussed to be a promising add-on treatment for negative symptoms in schizophrenia. The Positive and Negative Syndrome Scale (PANSS) has been used as outcome parameter in several previous rTMS trials, but studies focusing on PANSS factor analyses are lacking.For this purpose, we used the available PANSS data of the \u2018rTMS for the Treatment of Negative Symptoms in Schizophrenia\u2019 (RESIS) trial to calculate different literature-based PANSS factors and to re-evaluate the impact of rTMS on negative symptoms in this trial.In an exploratory re-analysis of published data from the RESIS study , we tested the impact of rTMS applied to the left dorsolateral prefrontal cortex on two PANSS factors for negative symptoms in psychotic disorders as well as on a PANSS five-factor consensus model intending to show that active rTMS treatment improves PANSS negative symptom subscores.In accordance to the original analysis, all PANSS factors showed an improvement over time in the active and, to a considerable extent, also in the sham rTMS group. However, comparing the data before and directly after the rTMS intervention, the PANSS excitement factor improved in the active rTMS group significantly more than in the sham group, but this finding did not persist if follow-up data were taken into account. These additional analyses extend the previously reported RESIS trial results showing unspecific improvements in the PANSS positive subscale in the active rTMS group.Our PANSS factor-based approach to investigate the impact of prefrontal rTMS on different negative symptom domains confirmed no overall beneficial effect of the active compared to sham rTMS.This secondary analysis of the RESIS trials has several limitations. First of all, the analysis of the primary endpoint was negative [24] and all subsequent secondary analyses showing a positive effect of the intervention (here: change in PANSS excitement factor) are of limited statistical power and therefore subject to uncertainty. On the other hand, our analyses confirm the negative finding of the original publication extends this finding to a broader negative symptom definition. Moreover, the new analysis provides a possible, but hypothetical explanation for the previously described effect of active rTMS on PANSS positive subscale. Of course, many other PANSS factor models are available and in pharmacological research the Marder factors  have particular significance. However, the here used five-factor consensus model [21] includes the Marder factor results and our negative symptom factors overlaps with those factors. Another limitation is that it may be possible that our sham stimulation (coil tilted over one wing at an angle of 45\u00b0[24]) may still have been slightly biologically active as discussed elsewhere [24]."}
+{"text": "Rivaroxaban, an oral direct factor Xa inhibitor, is one of the non-vitamin K antagonist anticoagulants and has been approved for various thrombotic diseases. Here we present a patient who developed leukocytoclastic vasculitis (LCV) associated with rivaroxaban as a rare non-bleeding side effect.th month of Pozzi protocol [A 28-year-old man who was being treated with diltiazem (60 mg/day) and oral methylprednisolone  (6protocol ) for IgALCV is associated with the deposition of the immune complex in small vessels that brings about loss of vessel wall integrity and extravasation of erythrocytes by immune response resulting in purpura. Although drugs and infections are the most common etiologies for LCV, idiopathic forms of the disease account for approximately half of all cases . ConnectThere is only one similar report in the literature, from Chaaya et al., in which they presented a 68-year-old male patient with multiple comorbidities who developed signs of LCV after 7 days of rivaroxaban treatment due to deep venous thrombosis . In thatIn conclusion, this report is the second case of rivaroxaban-associated LCV in the literature and this adverse event should be included in the list of significant adverse reactions to rivaroxaban.All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional research committee and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards."}
+{"text": "Considering high burden of violence against healthcare workers in Pakistan APPNA Institute of Public Health developed a training to prevent reactive violence among healthcare providers. The purpose of this training was to equip healthcare providers with skills essential to control aggressive behaviors and prevent verbal and non-verbal violence in workplace settings. This study assesses the effectiveness of training in prevention, de-escalation and management of violence in healthcare settings.A quasi-experimental study was conducted in October, 2016 using mixed method concurrent embedded design. The study assessed effectiveness of de-escalation trainings among health care providers working in emergency and gynecology and obstetrics departments of two teaching hospitals in Karachi. Quantitative assessment was done through structured interviews and qualitative through Focus Group Discussions. Healthcare providers` confidence in coping with patient aggression was also measured using a standard validated tool\u201d.The overall self-perceived mean score of Confidence in Coping with Patient Aggression Instrument \u201c(CCPAI)\u201d scale was significantly higher in intervention group  as compared to control group  (p<0.001). No statistically significant difference was observed between intervention and control groups with regard to frequency of violence faced by HCPs post training and major perpetrators of violence..De-escalation of violence training was effective in improving confidence of healthcare providers in coping with patient aggression. Violence against Health Care Providers (HCPs) is a major problem in both developed and developing countries. Fear of violence affects the performance of HCPs and decreases their responsiveness to healthcare needs of the patients especially in emergency settings.5Situation in Pakistan is dismal as hundreds of HCPs have been killed in the last decade as a result of terrorism, crime, sectarian divide and extremist elements in the society.Evidence from various parts of the world supports the effective role of trainings for de-escalation of violence for HCPs. These trainings helped in reducing impact and frequency of violence and improved patient-providers` interactions in healthcare settings.The content of the four hours de-escalation training comprised of four modules which are:Understanding Violence and Stress, .Escalation and De-escalation of violence .Management of Post-Traumatic Stress Disorder (includes strategies for managing PTSD).Patient-Communication Protocol .Training included varied teaching methodologies including brainstorming, videos based on scenarios and role plays on doctor-patient interactions which may potentially cause reactive violence. Master trainers from AIPH conducted those trainings in the public sector tertiary care hospital of Karachi which were the intervention site.This study aimed to assess the effectiveness of training for prevention and de-escalation of violence by HCP\u2019s after four months. The ultimate aim was to scale-up this intervention if results showed better skills of the trained HCPs in de-escalation of violence.This Quasi-experimental study using mixed methods Concurrent Embedded design was conducted in October, 2016. The study was conducted among health care providers currently working in Emergency, Gynecology & Obstetrics, Medicine & Allied and Surgery and Allied departments of two tertiary care teaching hospitals of Karachi. The assessment was conducted simultaneously after four months of de-escalation training at the intervention hospital and a control hospital of similar scale where trainings were not conducted.The Quantitative assessment was done through a structured questionnaire. Study participants for intervention group were randomly selected from a list of 147 healthcare providers (HCPs) who had received des-escalation trainings at intervention hospital while controls were selected from the hospital where trainings were not conducted. The HCPs at intervention hospital that were not working at the time of data collection were excluded from the study. With an assumption of overall 20% reduction in the frequency of violence faced by all trained healthcare providers in intervention group as compared to control arm at 5% level of significance and a power of 80% the minimum sample size of 154 was obtained i.e. 77 in each group.Participants from each study site were selected using non-probability convenience sampling technique. For control arm, healthcare providers from emergency and other departments who had been working in these settings for at least past four months were approached. Data was collected by trained data collectors using structured questionnaire to collect information regarding frequency, types and reasons of violence in control and intervention groups. Confidence levels of HCPs in dealing with agitated patients was measured using a tool adapted from \u201cConfidence in Coping with Patient Aggression Instrument \u201c(CCPAI)\u201d scale.14Data was analyzed using SPSS version 20. Descriptive statistics are reported as frequencies and percentages. The intervention and control group ware compared to identify possible differences in their demographics, frequency of violence experienced and aggregate CCPAI scale scores using Chi-Square Test for categorical variables and Independent T-test for quantitative variables.For Qualitative study two Focus Group Discussions (FGDs) at each site  were conducted with doctors and nurses working in emergency and other relevant departments by authors of this paper. Each FGD was recorded and transcribed in Urdu and later translated into English. The data was analyzed using thematic content analysis. Both \u2018manifest content\u2019  and \u2018latent content\u2019 (underlying meaning) of the text was analyzed.Quantitative data was collected from 141 HCPs including: 71 from intervention and 70 from control hospital. The FGDs included a total of 30 participants (14 in intervention and 16 in control arm).The study participants in intervention and control hospitals were comparable as no statistically significant differences were found between them for socio-demographic variables. The departmental affiliations varied significantly  .There were no statistically significant differences regarding frequency of experiencing or witnessing any kind of violence at work and types of major perpetrators of violence in the last four months.. The healthcare providers of the intervention hospital had higher average scores on CCPAI scale  as compared to control  (p<0.001) .The proportion of self perceived confidence was significantly higher for eight out of ten items in intervention group that received training on de-escalation of violence as compared to control .For qualitative data analysis coding of transcripts was done by two independent researchers and consensus was reached on three themes including recall of training content, positive experiences and recommendations.HCPs in intervention group were able to recall contents from training modules mainly related to communication and de-escalation; however majority was not able to recall strategies for management of Post Traumatic Stress Disorder (PTSD). When asked about PTSD module, HCP\u2019s at intervention hospital said, i) \u201cNobody has experienced this kind of disorder; perhaps we have not applied it that is why we have forgotten it\u201d, ii) \u201cWe get over stress very quickly realizing that some form of violence is inevitable in our field.\u201dHCPs at the intervention group acknowledged that training helped them control their temperament in a challenging environment and also enabled them to effectively practice active listening and empathy. One of the HCP mentioned that, \u201cI learnt how to respond to different behaviors of patients and maintain composure\u201d. They also felt that their counseling practices have improved and they felt more confident communicating with patients and avoid lengthy altercation and possible violence.The control group said that they lack confidence in dealing with aggression, one HCP said, \u201cRunning away is the best option\u201d. HCPs in control group managed aggression and violence by applying self learnt strategies including counseling of patient, maintaining silence when abused, and agreeing with perpetrators to control violence. HCP\u2019s, in control group strongly emphasized the need of training for coping with aggression and violence at work . The traThe participants from both groups strongly recommended that de-escalation trainings must be institutionalized and included as part of medical and nursing curricula at undergraduate level.The participants from both groups also recommended periodic refreshers for HCPs in practice.Both groups suggested that training should be conducted in short sessions of one or two hours as attending a four hours are difficult to manage within their busy work schedules.\u201cDefinitely communication by healthcare provider matters a lot but equally important is societal behavior towards healthcare providers\u201dHCPs in both groups also emphasized the need of raising public awareness on respecting HCPs a doctor said: This is the first study of its kind in Pakistan which attempted to assess the effectiveness of trainings for de-escalating and managing violence in healthcare settings. We found that HCPs in intervention group had higher perceived confidence levels and coping skills to deal with aggression when compared with the control group. We did not find any statistically significant differences in the frequency of patient aggression faced by HCPs in intervention and control groups. These finding are consistent with findings reported by a systemic review published in 2015 which included studies published between January 2000 and September 2011. The systematic Review of 9 studies reported improved confidence levels and coping skills to deal with aggression among HCPs who received des-escalation of violence trainings but no change in frequency of patient aggression incidents.17We found that HCPs in intervention group acknowledged that de-escalation training had improved their attitude and temperament towards aggression expressed by patients and their attendants. These findings are consistent with studies conducted by Grenyer and Collins.19Our results are also congruent with the study conducted in Stockholm, Sweden, which showed that violence prevention and management training can influence the HCPs attitude and can improve work place environment in healthcare settings.20We found that HCPs who had received de-escalation of violence training could recall most of the training content except the training related to PTSD. This in our opinion could be due to the perceived usefulness of training and that they may have used some of the strategies suggested in the training for de-escalation of violence. This could also explain why PTSD training module was not recalled as it may not have been utilized as much.The study participants suggested multipronged approaches to reduce incidence of violence in healthcare settings. HCPs from intervention and control groups suggested similar interventions including raising awareness regarding respect for HCPs, incorporation of violence prevention trainings in medical and nursing curricula at undergraduate level and refresher trainings for trained HCPs. These findings are in concordance with the studies done by Oostrom & Mierlo, and Lehmann et al.21The study participants also recommended regular refresher courses to maintain learning for HCPs already in practice. These recommendations are consistent with the suggestion of HCPs in previously conducted studies.24the scale of this study is limited to comparison of two tertiary care hospitals of Karachi which may not be a representative sample of all HCPs in Karachi.De-escalation training was found effective in improving confidence of healthcare providers in coping with patient aggression. There is a need to upscale and institutionalize de-escalation of violence trainings for HCPs.Ethical approval for this study was obtained from Institutional Review Board (IRB) of Jinnah Sindh Medical University and Dow University of Health Sciences. Informed consent was obtained before each interview and confidentiality of participants was ensured.LB: Conceived the idea, designed the study and the de-escalation of violence training manual, and did final edits on the manuscript.ST: Participated in coding and analysis and wrote the first draft of manuscript.SS: Participated in coding and statistical analysis, did the training on de-escalation of violence and wrote the methodology section of the manuscript.IH: Participated in data collection, coding and data analysis, also wrote the introduction section of the manuscript.MAK: Participated in data collection, training on de-escalation of violence, coding and wrote the results section.MP: Participated in conceptualizing the project and edited the last draft."}
+{"text": "After Four-chamber cine images were acquired during short breath-holds with a retrospectively gated turbo FLASH gradient-echo sequence and the longitudinal strain independently measured by two radiologists on four-chamber cine images with Trufistrain (Siemens). The hemodynamics was evaluated with right heart catheterization. The feasibility of the longitudinal strain assessed by Trufistrain. The feasibility of strain evaluated with Trufistrain were assessed with A Bland-Altman plot and correlation of strain with hemodynamics was evaluated with Spearman correlation on Medicalc and SPSSA Bland-Altman plot Figure  of the lIn this work, we demonstrated the feasibility of the longitudinal strain measurement on Cine images by Trufistrain. And the longitudinal strain correlated with PAP, CO and PVR. These suggest longitudinal strain measurement on Cine images by Trufistrain is promising to assess hemodynamics. In the future, we will analyze the correlation of longitudinal strain with myocardial function and fibrosis."}
+{"text": "The correlation between eRNA production and enhancer activity has stimulated studies on the potential role of eRNAs in transcriptional regulation. Additionally, eRNA has also served as a marker for global identification of enhancers. Here I review the brief history and fascinating properties of eRNAs.Enhancer-derived RNAs ( NGS has not only made it possible to exhaustively catalog the transcripts from coding sequences (cis-regulatory elements (CREs) such as promoters and insulators, enhancers contain binding sites\u2014DNA sequence motifs varying in length between 6\u00a0bp and 20\u00a0bp\u2014of various transcription factors (TFs) Of the ncRNA family, a latecomer and somewhat unconventional member is the enhancer-derived RNAs (eRNAs), which are transcribed at the loci of enhancers While enhancers and TFs are the primary players of gene regulation, other factors capable of chemically modifying DNA and histones are gradually being incorporated into the overall scheme of gene regulation, many of which modulate the accessibility of chromatin to allow for direct contact between TFs and enhancers cis-regulatory activity of their template enhancers\u2014that is, context-dependent, enhancer-stimulated mRNA synthesis of nearby genes\u2014indicating an intimate association between enhancer function and eRNA production Although transcription from active enhancers was reported in the early 1990\u00a0s Because the abundance of eRNAs is 19\u201334-fold lower than that of gene transcripts eRNAs are not as stable as mRNAs e.g., H2AZ) or modifications  can be applied in eRNA detection experiments To assist with the enrichment of eRNAs, chromatin immunoprecipitation (ChIP) using antibodies against histone variants  to deplete several eRNAs in human cells found evidence for a causal role of eRNAs in transcriptional activation cdkn1bcdkn1b, is largely intact A more rigorous approach to investigate the function of the eRNA is to interfere with its synthesis by inserting a polyadenylation cassette near its transcription start site, which triggers premature transcription termination. In a recent study, this approach was applied on the locus of an enhancer regulating the expression of Since the completion of the Human Genome Project, a major focus of the scientific community is to develop effective means to precisely map the estimated millions of CREs orchestrating distinct gene expression patterns of each cell type and developmental stage e.g., JQ1) Indeed, thousands of enhancers have been identified through analyzing the transcripts from non-coding sequences, which exhibit excellent overlap with the enhancer maps generated by histone mark ChIP-seq e.g., in clinical settings) As the cost of high-throughput sequencing rapidly decreases, protocols allowing for accurate determination of eRNAs become more feasible over time. Given that RNA-seq is now routinely used in genomic characterization of cells and tissues, using eRNAs to predict enhancer activity can obviate the need for additional experiments to identify enhancers. This is an advantage over other enhancer mapping techniques such as ChIP-seq, DNase-seq, and assay for transposase-accessible chromatin (ATAC)-seq, all of which use protocols different from RNA-seq. Thus, eRNA analysis may be especially useful in situations where specimen supply is limited  and mutations that appear to be enriched in putative enhancer elements Finally, the growing need to decipher the epigenome in both normal and disease tissues is expected to demand ever more sensitive and comprehensive methodologies to characterize enhancers in various cellular contexts. Notably, the past decade has seen the documentation of a plethora of disease-associated genetic variants (The author declares no competing interests."}
+{"text": "Introduction: Unstable posterior pelvic ring injuries are best treated with operative methods due to better post-op functional score. Our patient cohort was involved in heavy manual laboring frequently required ground level work in their activities of daily living. There are very few outcome studies dealing exclusively with such patients.Materials & Methods: Forty one patients who were treated with percutaneous sacroiliac screw fixation under fluoroscopic guidance and were followed-up for at least one year were analyzed retrospectively for functional outcome using the Majeed score.Results: Twenty one (51.22%) and thirteen (31.70%) patients were found to be in excellent and good categories respectively and majority of the patients (thirty/73.17%) were able to return to their original occupation with or without minor adjustments.Conclusion: Percutaneous ilio-sacral screw fixation for posterior pelvic unstable injuries is an acceptable mode of treatment in patients involved in heavy manual laboring. Percutaneous screw fixation for PPR injuries has been shown to provide good biomechanical stability & functional outcome and is a good compromise between non-operative management having risk of residual disability in unstable injuries and open procedures having risk of infections due to excessive soft tissue stripping3. Though there are proponents of each of them, there have been very few studies focusing exclusively on the outcome of the percutaneous screw fixation in the rural populations of developing countries where unlike the Western countries, squatting, sitting cross-legged and frequent forward bending are an important component of activities of daily living and majority of the population is involved in some form of heavy manual laboring.Posterior pelvic ring (PPR) injuries are serious injuries with high rates of mortality and morbidity due to other associated injuries and due to the pelvic trauma itself. Three modes of treatment have been advocated for PPR disruptions; viz. non-operative, open reduction & fixation and percutaneous screw fixationA retrospective study of forty-nine consecutive patients was conducted at the authors\u2019 institute, which is a medical college hospital and a level I trauma center in India in patients with unstable pelvic ring injuries who were treated with percutaneous ilio-sacral screw fixation in the intervening period between June 2007 to May 2014.Ethics- The study design was reviewed and approved by the Departmental & Institutional Ethics and Review Board. Informed consent was taken in all patients for use of their clinical data/imaging and for subsequent follow-up examinations and radiology.Study Design- It was a retrospective analysis in which all the patients meeting the inclusion criteria and consenting to be included in the study were considered.Traumatic unstable posterior pelvic injury based on Young-Burgess classification system Skeletally matureMinimum one year of follow-up at the time of study after the surgeryOccupation involving heavy manual laboring and ground-level activitiesInclusion Criteria-Injuries which needed open reduction, either primarily or in the follow-up period for revisionSkeletally immatureAssociated acetabular injuriesConcomitant long bone fractures of lower limbSpinal cord injuriesExclusion criteria-Forty nine patients  were fit4. Anterior fixation, if needed, was done in supine position was done later. No intraoperative electro diagnostic studies for potential nerve damage were done. For PPJ fixation the guide wire for the screw was placed below the iliac-cortical density at the posterior cortex of the sacral body in the lateral fluoroscopic view. Then the outlet view was taken to direct the guide wire in a cephalad direction above the S1 foramen towards the superior endplate. Finally the inlet view was taken to make sure that the trajectory is directed towards sacral promontory. The guidewire was advanced till it just crossed the midline. A screw was then inserted over it using a stab incision6. The reader is referred to the pre-operative and intra-operative fluoroscopic images in the adjoining figures for better clarification  patient had tingling in the posterior part of thigh, which resolved on its own in eight weeks. There were no cases of motor nerve damage, vascular/ureteral injury, sexual dysfunction, or deaths related to the surgical procedure. The mean Majeed functional score for individual components is tabulated as follows: . Thirty 2. All patients were routinely discharged after forty eight hours which firstly reduces the patient load at the institutes like ours which has very high patient load and secondly reduces the financial burden on the patients and their families, majority of whom are from lower socioeconomic background. Compared to conservative and open procedures, we feel the patients had better pain relief probably due to early pelvic stabilization, minimal instrumentation and less soft tissue trauma7.The unique advantage of percutaneous ilio-sacral screw fixation is simplicity of the procedure with minimal blood loss, less indoor time and minimal cost2.Conservative management is a poor choice especially in our case cohort because majority of them were daily-wage workers & laborers. The time for recovery for conservative method has been shown to be greater than operative methods in many studies and also the functional outcome in the former is poorer as compared to the later8.The open reduction though might give an anatomical reduction and maybe a greater strength to fixation, incase plates were used; the technique is not without complications. There is blood loss, an increased risk of infection and increased cost due to increased operative time9.Though percutaneous technique is relatively blind and logically it may be felt that there might be greater instance of iatrogenic injury, no such complications occurred in our series. This may be attributed to strict adherence to the intraoperative fluoroscopic bony landmarks for screw placements10. Majority of our patients (82.92%) were in excellent or good category, which is in sync with other studies in these types of injuries13. Again this can be attributed to strict adherence to the inclusion criteria. We had a very low threshold for abandoning the procedure and opting for open reduction incase of non-satisfactory joint reduction.Majeed functional score and pelvic grade score is the most widely used scoring system for the SIJ injuriesThough Majeed functional score covers majority of the activities involving usage of SIJ, the score falls short in assessing certain activities which are considered essential in many developing and under-developed countries- squatting, sitting cross legged and forward bending (prayer/namaz position). These are the very activities, which were of importance in our cohort of patients, majority of whom were manual laborers and belonging to low socio-economic strata ,3B,3C. TThe major limitation of the study is its small sample size (because of the rarity of the injury pattern). The validation of the Majeed score in the patient cohort as ours will need larger study population ideally involving multiple centers. Also there was no control group or any comparison with other modality of treatment to test the utility of the score and the outcome for percutaneous screw fixation in unstable SIJ injuries in them.To conclude, it can be said that percutaneous screw fixation of unstable PPR injuries in patients requiring squatting, sitting cross-legged and forward bending (prayer/namaz position) and involved in heavy manual laboring can give satisfactory result."}
+{"text": "At present, there is still little information on nitrogen (N) accumulation in forests contrasting with the crucial importance of N in forest ecosystems. This work analyzes the N bioaccumulation in mosses from forested areas from Lower Saxony and North Rhine-Westphalia , the Weser Ems Region (part of Lower Saxony), and the Euro Region Nissa . The studies involved samples collected from 190 sites between 1998 and 2005. Different spatial scales and regional differences in land use were chosen to assess the factors affecting N bioaccumulation in forested areas. A continuous reduction of N bioaccumulation was found from Lower Saxony (a region where agriculture is most predominant) to North Rhine-Westphalia (mostly urban). The Weser Ems Region  showed a higher N concentration in mosses than the Euroregion Nissa . Statistical analyses performed at the different spatial scales revealed that the areas showing greater agricultural and livestock spatial densities favor N bioaccumulation in mosses. N concentration in mosses was moderately correlated with the N concentration in the leaves and needles of the surrounding trees. No significant relationships were found regarding the crown density of forest trees or N deposition estimations from a combination of atmospheric models and deposition measurements."}
+{"text": "The last 5 years\u2019 studies using next-generation sequencing provided evidences that many types of solid tumors present spatial and temporal genetic heterogeneity and are composed of multiple populations of genetically distinct subclones that evolve over time following a pattern of branched evolution. The evolutionary nature of cancer has been proposed as the major contributor to drug resistance and treatment failure. In this review, we present the current state of knowledge about the clonal evolution of high-grade serous ovarian cancer and discuss the challenge that clonal evolution poses for efforts to achieve an optimal cancer control.A systemic search of peer-reviewed articles published between August 2007 and October 2016 was performed using PUBMED and Google Scholar database.Recent studies using next-generation sequencing have allowed us to look inside the evolutionary nature of high-grade serous ovarian cancer, which in the light of current evidence can explain the relapsing course of the disease frequently observed in the clinical practice. Since only minimal improvement in the survival of patients treated with standard therapy has been observed in the last decade, novel molecular targeted therapies are of great interest in high-grade serous ovarian cancer. However, both spatial and temporal intratumoral genetic heterogeneity is a major challenge for personalized medicine, and greater knowledge of the molecular rules that drive tumor evolution through space and time is required to achieve a long-term clinical benefit from personalized therapy. High-grade serous ovarian cancer (HGSOC), the most common and aggressive form of the epithelial ovarian cancer (EOC), remains the leading cause of cancer-related death among all gynecological cancers in the developed parts of the world , 2.The majority of cases show a significant, but transient response to standard therapy including debulking surgery followed by platinum-based chemotherapy, and the development of resistance is almost permanently inscribed in the clinical course of the disease . TherefoThe last 5\u00a0years\u2019 studies using next-generation sequencing provided evidences that many types of solid tumors present spatial and temporal genetic heterogeneity and are composed of multiple populations of genetically distinct subclones that evolve over time following a pattern of branched evolution in a similar manner to the Darwinian evolution of species \u20139. This In this review, we present the current state of knowledge about the clonal evolution (CE) of HGSOC and discuss the challenge that CE poses for efforts to achieve an optimal cancer control.Large-scale genomic analyses demonstrated that HGSOC exhibits a high degree of genomic instability (GI) arising as a result of DNA repair defects caused mainly by TP53 mutations and homologous recombination (HR) deficiency, occurring in 96% and almost 50% of cases, respectively , 12. DurTo investigate clonal heterogeneity in HGSOC, Bashashati et al. obtained 29 spatially separated samples from 5 patients with newly diagnosed stage III\u2013IV HGSOC . Exome sThe results reported by Hoogstrat et al.  highlighStudies showed a rather consistent picture of HGSOC as a dynamic entity composed of multiple populations of genetically and phenotypically distinct subclones evolving from a single ancestral clone following patient-specific patterns of branched evolution , 25\u201327. It appears that in an advanced-stage HGSOC the presence of extensive phenotypic diversity as well as noticable differences in chemosensivity between cancer cells isolated from different tumor deposits  can be iThe coexistence of genetically dissimilar subclones widespread within the three-dimensional (3D) tumor space can lead to interclonal interactions which are not limited, however, to a simple competition for space and resources during ongoing selection , 38\u201340. The emergence of treatment resistance followed by initial response to standard therapy resulting in tumor relapse remains a main clinical problem in the management of most HGSOC cases reducing the possibility to cure the advanced-stage disease , 45.For heterogeneous tumor cell population, cancer therapy constitutes a selection pressure widely affecting the patterns of tumor evolution . Beyond HGSOC evolution over the course of treatment have been analyzed in several studies. Recently, paired tumor samples taken before and after first line of platinum-based chemotherapy have been compared using whole-exome sequencing (WES) and single nucleotide polymorphism profiling . While oBranched CE in the progression of HGSOC from primary to reccurent disease has also been indicated by a case study using WES and comparative genome hybridisation to compare samples taken during debulking surgery first at initial diagnosis and second at disease relapse after treatment with platinum-based chemotherapy in combination with bevacizumab . Only 42Studies provided consistent evidence that HGSOC continues evolution during the course of treatment following highly individual patterns of CE , 54\u201356. All studies that have monitored HGSOC evolution over the course of treatment consistently suggest that tumor relapse originates from drug-resistant subclone/s originally present in the primary tumor that expand under selective pressure of therapeutic intervention , 54\u201356. The fact that in all cases adjuvant chemotherapy failed to destroy resistant subclones , 54\u201356 hAdvances in sequencing techniques have allowed us to look into the evolutionary nature of HGSOC, which in the light of current evidences can explain the relapsing course of the disease observed in clinical practice. Since only minimal improvement in the survival of patients treated with standard therapy has been observed in the last decade, novel molecular targeted therapies are of great interest in HGSOC . HoweverSince growing amount of evidence suggests that HGSOC relapse arises from outgrowth of pre-existing drug-resistant subclonal populations, further integrative genomic and phenotypic analyses using precise sequencing techniques should be carried out to define the molecular and genotypic signatures of resistant subclones. These data, respectively cataloged, could be used to evaluate the differences in the resistance patterns between individual patients and also could serve as a starting point for the design of novel therapeutic strategies. Further pre-clinical studies should give answer to a number of intriguing questions: (1) when do resistant subclones arise during the HGSOC evolution? (2) Whether they are distributed randomly or stochastically within the primary tumor? (3) What types of functional relationships do link them with dominant clones and surrounding non-malignant cells? (4) What is the role of microenvironmental niches in their selection or storage? (5) Whether their genotypes or phenotypes have a decisive influence on their positive selection? (6) Whether they are able to lead to recurrence autonomously or need support from the surrounding cells?Personalized medicine requires tools to provide precise data on the subclonal composition of a patient\u2019s tumor at the time of diagnosis, and which will also allow for regular tracking of its changes in relation to the therapeutic intervention . With thAlthough existing evidences suggest that HGSOC displays highly individual patterns of CE, they are based on a relatively small number of cases. Therefore, further genomic analyses on representative groups of cases at different clinical stages should assess to what extent patterns of evolution are reproducible between patients and to what extent they are predictable in individual patients.Heterogeneity is a hallmark of HGSOC. It must, therefore, be taken into account during efforts to improve efficiency of standard therapy, as well as during design of novel personalized therapeutic strategies."}
+{"text": "We present evidence from previous works in both rodents and humans of the importance of these cell types  in neurological disease and highlight new hiPSC-based models that have sought to explore these relationships in vitro. Lastly, we summarize efforts toward conducting high-throughput screening experiments with hiPSCs and propose methods by which new screening platforms could be designed to better capture complex relationships between neural cell populations in health and disease.Current applications of human induced pluripotent stem cell (hiPSC) technologies in patient-specific models of neurodegenerative and neuropsychiatric disorders tend to focus on neuronal phenotypes. Here, we review recent efforts toward advancing hiPSCs toward non-neuronal cell types of the central nervous system (CNS) and highlight their potential use for the development of more complex  Their great self-renewal and wide differentiation capacity, coupled with the relative ease of producing patient-specific hiPSCs harboring genetic variations implicated in disease, makes possible the generation of large quantities of diverse cell types in a controlled and iterative manner, ideal for high throughput screens to discover and evaluate the efficacy and safety of novel therapeutics  from hiPSCs now presents an exciting opportunity to explore how these various cell types interact with one another in a controlled manner. In this review, we briefly overview current advances toward generating the major neural cell types\u2014neurons, astrocytes, oligodendrocytes and microglia\u2014using stem cell technologies. Further, we highlight recent advancements in understanding non-neuron cell-autonomous effects in the pathology of three representative neuropsychiatric disorders\u2014Amyotrophic Lateral Sclerosis (ALS), schizophrenia and Rett Syndrome\u2014both The lack of live patient neural tissue, combined with the limitations of post-mortem brain tissue, has spurred efforts to find new methods of models of CNS diseases. Stem cell based technologies, particularly the ability to reprogram induced pluripotent stem cells (hiPSCs), presents a powerful opportunity to create scalable, easily perturbed platforms to study how various genetic abnormalities implicated in disease manifest in altered neural cell function. There exist two general strategies for the creation of neurons using hiPSC-based technologies, directed differentiation and induction, each having advantages and disadvantages that Should be carefully considered when developing an appropriate platform for drug development.in vivo. Neuronal differentiation protocols typically proceed via a neural progenitor cell (NPC) intermediate, a population of cells with the capacity to self-renew and to generate both neurons and glia. The application of a variety of mitogens can confer different positional identities and enrich for specific subtypes of neural cells. For a more in depth review of these differentiation methods and their developmental basis, an excellent review has been published elsewhere , achaetescute homolog 1 (ASCL1) and myelin transcriptional factor1-like protein (MYT1L)\u2014in mouse or human fibroblasts     , the populations produced tend to include large numbers of fibroblast-like contaminants and the absolute number of neurons that can be generated is less, reflecting the more limited replicative capacity of fibroblasts. A compromise of inducing neurons directly from hiPSCs promises a larger number of rapidly maturing neurons and may grow more common as subtype-specific induction methodologies become more refined.in vitro are being uncovered  and either Nkx6.2  lead to a dominant, inherited form of ALS  displayed degenerative symptoms and pathology consistent with ALS  and non-volumetric diffusion tensor imaging (DTI) of post-mortem tissue have revealed abnormalities in white matter on a macro and microstructure level respectively  are perturbed in schizophrenia. Critically, the relevance of these post-mortem observations is clouded by the fact that antipsychotic treatments may impact astrocyte levels and/or function in the CNS, as these cells express dopamine receptors , though other genetic variations account for a minority of cases. MECP2 encodes the regulatory protein MeCP2, which binds to methylated DNA to regulate transcription of a number of genes (Amir et al., Rett Syndrome is a rare X-linked neurodevelopmental disorder affecting the gray matter of the brain, primarily in female patients, and characterized by an initial period of normal development during early infancy followed by a sudden attenuation of developmental growth and the loss a number of motor and language skills (Hagberg et al., MECP2 mutations in neurons has been well-examined in a variety of studies (Marchetto et al., MECP2 also exerts its effect through non-cell autonomous events involving astrocytes. MeCP2 deficiency in astrocytes causes significant abnormalities in cytokine production and neuronal dendritic induction that could impact neurodevelopment in mice (Maezawa et al., MECP2 preferentially in astrocytes restores normal neuronal dendritic morphology, improves locomotion and anxiety, and rescues respiratory symptoms in a mouse model of Rett syndrome (Lioy et al., The role of in vivo.While the role of astrocytes in non-cell autonomous effects on neuronal function in Rett syndrome is well-established in mice, it was unclear whether the same effects held true in a human context. Two recent studies using Rett syndrome patient-derived hiPSCs have now not only confirmed that astrocyte role in Rett Syndrome, but also identified molecular targets involved in astrocyte-mediated neuronal deficits. Astrocytes derived from patient-specific hiPSCs recapitulate the negative effects on neuronal morphology observed in mouse studies, an effect that can again be reproduced using only conditioned media (Williams et al., in vitro and in vivo mouse models. Selective correction of Rett syndrome microglia with wild type microglia using a Cre-Lox based system in mice produced an improvement of symptoms, one that could be reversed using annexin IV, suggesting that microglia-mediated phagocytosis is a key mechanism of Rett syndrome pathology (Derecki et al., MECP2 deletion are significantly smaller than their wild type counterparts (Muffat et al., Microglia have also been implicated in Rett syndrome pathology through a variety of Altogether, while Rett syndrome is arguably the first autism spectrum disorder to be convincingly linked to aberrant astrocyte and microglial function, there is no reason to suspect that other forms of autism will not soon be associated with neuron non-cell autonomous effects as well. Complex genetic neuropsychiatric disorders, from ALS to schizophrenia to Rett Syndrome, may in fact represent a convergence of clinical phenotypes arising through a diverse range of genetic and cellular mechanism, suggesting that a \u201cpersonalized\u201d or genotype-dependent understanding of disease mechanisms may be critical for properly matching patients with appropriate therapeutics.The development of new pharmaceutical treatments for neuropsychiatric diseases has been severely hampered by the poor availability of preclinical models that adequately capture the complex pathophysiology of these disorders. It has been difficult to translate the success of the high throughput drug screens used to identify novel targets and lead structures for therapeutics in other fields to neuroscience. Moving forward, we hope that this will be addressed by this new ability to create disease specific, patient-derived hiPSC lines, which serve as genetically relevant models that are scalable and easily perturbed through genetic and chemical approaches. Importantly, the ability to create and bank large stores of hiPSC-derived cells will permit repeated experiments across genetically isogenic human cell types, hopefully improving reproducibility. As advancements in high content imaging technologies develop alongside hiPSC technology, this integrated approach may help identify new therapeutic targets for drug development and advance our understanding of genotype-phenotype correlations in neuropsychiatric disease in ways that were not previously possible. This approach is of particular importance for complex genetic diseases such as schizophrenia and autism, where simplistic knock in models fail to accurately capture each patient's complex and potentially unique genetic background.Pluripotent stem cell based screens have shown notable recent successes in the context of neuropsychiatric disease, reviewed elsewhere (Haggarty and Perlis, While the screens outlined above are unique in their methods and targets of interest, they are unified in their focus on a single cell type, limiting their relevance to the physiological context. With advancements in hiPSC differentiation protocols now encompassing many different neural cell types, we hope that future screening experiments will combine several distinct pre-differentiated cell types. Such a proof-of concept screen was conducted using Nestin-positive progenitor cells that were differentiated into neurons and/or astrocytes, cultured both in isolation and together (Efthymiou et al., A number of coculture platforms have been developed for the study of neurological disease, shedding light on the interactions that occur between neural cell types (excellently reviewed by Meyer and Kaspar, New advances in the field of stem cell biology and reprogramming are allowing for the creation of once inaccessible neural cell types, improving our ability to model complex neuropsychiatric and neurodegenerative diseases in ways not previously possible. The development of these models has begun to shed light on important interactions between neural cell-types in the context of human disease pathology. As the importance of these non-cell autonomous effects becomes increasingly clear, drug discovery platforms that pair new stem cell technologies with high throughput assays and high content imaging software capable of analyzing individual cell populations within a heterogenous pool may be an invaluable resource for the development of new therapies for these complex disorders.DG and KB: wrote the manuscript; JG: prepared Figure The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer LJ and handling Editor declared their shared affiliation."}
+{"text": "Xanthogranulomatous pyelonephritis (XGP) is a chronic inflammatory process that results in replacement of renal and/or perirenal tissue with a diffuse infiltrate of inflammatory cells referred to as xanthoma cells. We present a case of a 49-year-old man with an incidentally discovered renal mass with inferior vena cava (IVC) thrombus, who was found intraoperatively to have a significant inflammatory process involving the posterior wall of his IVC and right renal vein consistent with XGP surrounding a focus of clear cell renal cell carcinoma in the midportion of his right kidney."}
+{"text": "The potential mechanisms underlying diastolic dysfunction and heart failure caused by these cTnI C-terminal mutations are discussed as well. Furthermore, calcium desensitizing in correction of impaired relaxation in myocardial cells due to cTnI mutations is discussed. Finally, we describe a model of translational study, i.e., from bedside to bench and from bench to bedside. These studies may enrich our understanding of the mechanism underlying inherited cardiomyopathies and provide the clues to search for target-oriented medication aiming at the treatment of diastolic dysfunction and heart failure.Cardiac troponin I (cTnI) plays a critical role in regulation of cardiac function. Studies have shown that the deficiency of cTnI or mutations in cTnI (particularly in the C-terminus of cTnI) results in diastolic dysfunction (impaired relaxation) due to an increased myofibril sensitivity to calcium. The first clinical study revealing the association between restrictive cardiomyopathy (RCM) with cardiac troponin mutations was reported in 2003. In order to illustrate the mechanisms underlying the cTnI mutation caused cardiomyopathy, we have generated a cTnI gene knockout mouse model and transgenic mouse lines with the reported point mutations in cTnI C-terminus. In this paper, we summarize our studies using these animal models from our laboratory and the other  The former contains mainly myosin and myosin bind C-protein and the latter contains actin and troponin-tropomyosin complex. The so called cross-bridge formation between the thin filament actin and the thick filament myosin determines the filament movement, i.e., muscle contraction and relaxation. Whereas, the troponin complex plays an important role in regulation of the filament movement. Troponin complex consists of three subunit proteins: Troponin C (TnC), troponin T (TnT), and troponin I (TnI). Among them, TnC is a Ca2+ concentration results in an enhanced cardiac contractility whereas the decreased Ca2+ concentration can reduce the cardiac contractility. The concentration of intracellular Ca2+ is regulated by various calcium handling proteins in myocardium, such as Ca2+ channel receptors, the SERCA2a calcium ATPase pump, phospholamban, etc. , dilated cardiomyopathy (DCM), and restrictive cardiomyopathy (RCM)  was in 2003  modeling human RCM mutation cTnI R192H (cTnI R193H in mouse sequence) in the heart. In addition, our laboratory has created another TG mouse line containing the RCM cTnI K178E mutation reported by Mogensen et al.  mice  expressing human RCM mutation cTnI R192H (cTnI R193H in mouse sequence) in the heart. Histological examination confirms that cTnI193His mice do not show cardiac hypertrophy or ventricular dilation. The general morphology of the ventricles from these mice is similar to that of a wild type heart. However, the enlargement of bi-atria, both right and left atria, is very dramatic, which is similar to that in human RCM patients carrying cTnI R192H mutation. Functional measurements on these mice indicate a diastolic dysfunction in the early stage and a diastolic heart failure in the late stage  that expresses the cTnI with N-terminal deleted in the heart, we discovered that the hyposensitivity caused by cTnI-ND favored a general balance of myofibril sensitivity to calcium in the heart and reversed the diastolic dysfunction and rescued RCM phenotype  may alter myofilament sensitivity to Ca2+ via their inhibitory effect on actomyosin cross-bridge formation -epigallocatechin-3-gallate (EGCg) has Ca2+ desensitizing abilities via its interaction with cTnC (Liou et al., 2+ by forming a ternary complex with the C-terminal domain of troponin C and the anchoring region of cTnI (Liou et al., 2+ is reduced as a result which facilitates cardiac relaxation (Liou et al., 2+ hypersensitivity and diastolic dysfunction has been demonstrated in a HCM mouse model confirming the therapeutic potential of that compound for diastolic dysfunction (Tadano et al., Increased Ca193His RCM mice (Li et al., In our recent study, we have reported that diastolic dysfunction is corrected in RCM mice after the treatment of EGCg for 3months, suggesting that desensitizer catechin extracted from green tea is helpful in correcting impaired relaxation caused by calcium hypersensitivity in cTnICardiac troponin plays a critical role in cardiac contraction and relaxation. cTnI deficiency or mutations are associated with RCM characterized with a diastolic dysfunction. The discovery of sarcomeric protein mutations responsible for the development of the disease helps in identifying the etiology of RCM and allows for the screening of potential RCM patients. These measures may facilitate early diagnostic of the disease and proper monitoring and management of RCM patients. It also paves the way for the development of transgenic animals with the RCM phenotype which will contribute greatly to a better understanding and characterization of the disease. In fact, RCM transgenic animals may provide a link in the translational study which is from bedside to bench and from bench to bedside. They will also be very useful for the trial of potential drugs or devices designed to correct the diastolic dysfunction associated with RCM. The lack of effective treatments and the unavailability of drugs that selectively correct the diastolic dysfunction of the restricted heart, make the development of new pharmacological agents an urgent necessity. Desensitizing green tea extract catechin has been proved to be useful in correcting hypersensitivity and reversing diastolic dysfunction both in RCM animal studies and in reconstitute myofilament assays using a cTnI with a point mutation from HCM patient. It seems promising to apply desensitizing green tea extract catechin in correcting impaired relaxation in RCM patients caused by troponin mutations.XL, DP, JZ, CN, WS, and XH participated in paper writing and LZ, JQ, and JT participated in patient sample collection and genotyping measurements.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Post-stroke depression (PSD) is a neuropsychiatric affective disorder that can develop after stroke. Patients with PSD show poorer functional and recovery outcomes than patients with stroke who do not suffer from depression. The risk of suicide is also higher in patients with PSD. PSD appears to be associated with complex pathophysiological mechanisms involving both psychological and psychiatric problems that are associated with functional deficits and neurochemical changes secondary to brain damage. Transcranial magnetic stimulation (TMS) is a non-invasive way to investigate cortical excitability via magnetic stimulation of the brain. TMS is currently a valuable tool that can help us understand the pathophysiology of PSD. Although repetitive TMS (rTMS) is an effective treatment for patients with PSD, its mechanism of action remains unknown. Here, we review the known mechanisms underlying rTMS as a tool for better understanding PSD pathophysiology. It should be helpful when considering using rTMS as a therapeutic strategy for PSD. Stroke is the most common cause of adult disability in developing countries  was approved for the treatment of major depression in the USA  is an important neurotrophic factor that is distributed extensively in the central nervous system. BDNF is crucial for the survival, growth and maintenance of neurons within brain circuits that control emotion and cognition  or high- (50 Hz) frequency paradigms. This method is now often used to visualize neuronal activation of the cortex and cortical networks during different types of stimulation , protein kinase C (PKC) and glutamate receptor 2 (GluR2). These findings suggested that rTMS could act on the rat cerebellar cortex to induce LTD-related neuroplasticity  values and increase left frontal lobe activation  receptor/N-methyl-D-aspartate (NMDA) receptor expression , actions on the neuroendocrine system, neuroprotection via reduced oxidative stress and inflammation, and changes in neurotrophin expression. These molecular effects may modify the intrinsic and extrinsic electrophysiological properties of neurons and reprogram the expression of excitatory and inhibitory neurotransmitters and their cognate receptors, which lead to long-lasting synaptic plasticity-related changes similar to LTP and LTD , has been shown to produce similar if not greater effects on brain activity than standard rTMS  over the left DLPFC and 1000 rTMS pulses (1 Hz at 80%\u2013100% of rMT) over the right DLPFC for 10 days to treat depression after stroke. Understanding the how rTMS affects PSD should help the development of new and more effective treatments, and the mechanism should be further studied to provide a strong theoretical basis for clinical application.Recently, researchers have explored the mechanisms underlying rTMS therapy using a variety of methods. Neuroimaging, including PET and functional magnetic resonance imaging, have been used to learn about the remote effects of TMS on the brain (Hallett et al., XD and GY wrote the manuscript. ZL, WY and RC provided the critical revisions. All authors approved the final version of the manuscript for submission.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The recent observation of interviral recombination between members of two distinct classes of DNA viruses has opened the gates to a new field of human disease development. In all cases studied thus far interviral recombination is a rare event that requires special circumstances for intracellular interaction of participating viral genomes. The rarity and special requirements do not detract from the potential clinical significance of resulting recombinants, as exemplified by recombination between JC viral and Epstein-Barr viral genomes. This significance depends largely upon the mechanisms of recombination that would generate specific forms of recombinant viral genomes. At this time little is known regarding mechanisms of interviral recombination. DNA break-induced replication seems presently to be a highly plausible means of initiating formation of different, potentially active recombination products. Generalizing interviral recombination to a variety of viruses will open a fertile field for discovery as multiple diseases of mysterious etiology are investigated. At first consideration the observation that the distinct human viruses, JC virus (JCV) and Epstein-Barr virus (EBV) can undergo interviral recombination  may seemAssessment of important aspects of the clinical significance of interviral recombination requires understanding of the mechanisms underlying this process. Elucidating such recombination mechanisms will address three major questions concerning significance. First, when two DNA viruses recombine, can one virus incorporate the complete genome of the second virus? This is of particular importance regarding circular viruses, and can be illustrated using the example of JCV and EBV. JCV is a small polyomavirus, with double-stranded DNA of approximately 5 kb, that replicates in circular form initiated from a single origin of replication located in its control region (NCCR). EBV is a very large gamma-herpes virus of about 180 kb that can replicate as circular episomes initiated from its latent ori P. A speculative model describing the structural interaction of these two viral genomes is presented in A plausible mechanism that would explain all aspects of the type of JCV-EBV recombination thus far observed has yet to be proposed or tested. There are three sequences in the JCV NCCR that bear significant homology to any sequences in the entire EBV genome. These homologies are all at sites in the NCCR that are rearranged in the forms of JCV found in the demyelinating disease, PML . These hAs one considers interviral recombination in general, certain of the clinical implications described for JCV-EBV recombination are further clarified. One can use JCV-EBV interviral recombination as an example to generalize such recombination between different human viruses. As discussed, JCV-EBV recombination requires special circumstances, and it is likely that recombination among different viruses will require special circumstances as well. It is likely, therefore, that all or nearly all interviral recombination events are rare. Can such rare events be of great significance? They may be so. The JCV-EBV recombination described above involves latent EBV in which genes necessary for productive activation have been disabled . We haveThere are several diseases, the etiology of which may now be assessed in terms of interviral recombination. Recombination between HIV-1 and HIV-2 has been demonstrated after coinfection with genetically modified viruses and has not thus far been shown in an infected population. Although its consequences cannot be assessed, they are potentially intriguing because each virus may influence cell entry of the other and because these viruses differ in propensities for pathology in AIDS. JCV-EBV recombination has been shown in immunosuppressed individuals . JCV mus"}
+{"text": "Motor learning consists of the ability to improve motor actions through practice playing a major role in the acquisition of skills required for high-performance sports or motor function recovery after brain lesions. During the last decades, it has been reported that transcranial direct-current stimulation (tDCS), consisting in applying weak direct current through the scalp, is able of inducing polarity-specific changes in the excitability of cortical neurons. This low-cost, painless and well-tolerated portable technique has found a wide-spread use in the motor learning domain where it has been successfully applied to enhance motor learning in healthy individuals and for motor recovery after brain lesion as well as in pathological states associated to motor deficits. The main objective of this mini-review is to offer an integrative view about the potential use of tDCS for human motor learning modulation. Furthermore, we introduce the basic mechanisms underlying immediate and long-term effects associated to tDCS along with important considerations about its limitations and progression in recent years."}
+{"text": "Diffusion tensor imaging enables the study of cardiac microstructure in vivo, including its changes through the cardiac cycle. The left ventricle consists of myocytes with opposing helical arrangements in the epi- and endocardium. Histology shows that these myocytes are arranged into small laminar \"sheetlet\" structures, separated by shear layers which allow the sheetlets to move and reorient relative to each other during myocardial contraction. While the direction of the first eigenvector of the cardiac diffusion tensor indicates the average direction of the myocytes in a voxel, the second eigenvector appears to indicate the mean orientation of the sheetlets (1). Recent work has demonstrated that there are differences between the motion of these sheetlets between healthy volunteers and patients with hypertrophic cardiomyopathy (2). In order to facilitate comparison of sheetlet orientations in disease between different centres, the aim of this study was to test the intercentre reproducibility of the second eigenvector orientation.Ten healthy volunteers were scanned at two centres using a stimulated echo cardiac diffusion tensor sequence (3) on different models of 3T MRI scanner. The two centres calculated the second eigenvector angle (E2A) for each volunteer in both systole and diastole in a single mid-ventricular slice using scripts written independently in Matlab . The mean magnitude of E2A (denoted |E2A|) was calculated over similarly drawn (3) ROIs covering the left ventricle to produce a single number for each subject in systole and diastole. Bland-Altman analysis was carried out on the values for each centre, and statistical significance of differences tested using a paired t-test. The mean intrasubject, intercentre coefficient of variance was calculated.Example maps for one of the volunteers are shown in Figure In healthy volunteers, it is possible to obtain consistent evaluations of the second eigenvector angle, a measure of the myocardial sheetlet orientation, at two different centres running equivalent stimulated echo cardiac diffusion tensor sequences."}
+{"text": "Uterine arteriovenous fistulas are rare and acquired causes of life-threatening vaginal bleeding. They usually present with intermittent menometrorrhagia in young patients in childbearing age with history of gynecological procedures on uterus. Traditional management is hysterectomy; endovascular embolization represents nowadays an alternative strategy for patients wishing to preserve fertility. Here, the endovascular approach to a 29-year-old woman affected by severe menometrorrhagia caused by a uterine arteriovenous fistula with a concomitant pelvic varicocele is reported; a bilateral uterine arteries embolization with Onyx-18  has successfully resolved the fistula with clinical success. A uterine arteriovenous fistula (AVF) is a rare acquired cause of life-threatening vaginal bleeding; it may be the result of trauma or surgical intervention or may be acquired in the setting of a preexisting pathologic uterine process .Here, the endovascular approach to a 29-year-old woman affected by severe menometrorrhagia caused by an AVF with a concomitant pelvic varicocele is reported; the lesion has been resolved with a bilateral uterine arteries embolization (UAE) by Onyx-18  injection.A 29-year-old woman presented with severe vaginal bleeding in emergency room with a value of 7\u2009g/dl of hemoglobin.She reported episodes of severe menometrorrhagia during the previous 4 months.Her clinical history presented multiple interventions on the uterus: a hysteroscopic ablation 5 years previously to remove a pedunculated lesion , a successful pregnancy with cesarean During the hospital stay, she underwent a suprapubic ultrasound (US) examination revealing a high flow vascular lesion involving the uterine wall; a contrast-enhanced Magnetic Resonance (MR) Figures  showed mThe beta human Chorionic Gonadotropin (hCG) test was negative.According to laboratory and radiological data, considering even the previous multiple uterine interventions, the diagnosis of uterine AVF was proposed.Because of the young age of the patient and the will of future pregnancies, conventional surgery consisting of hysterectomy was avoided and a conservative endovascular approach was considered as first option.The patient underwent a bilateral superselective UAE ; the proBased on the diagnostic angiograms, the embolization of both uterine arteries was planned during the same session.The most distal portion of the uterine arteries was superselectively reached with a microcatheter using a coaxial technique; the 5Fr catheter was positioned at the origin of the uterine artery and the microcatheter was advanced distally over the horizontal segment of the uterine artery; the diagnostic angiogram showed the venous outflow directly communicating with arterious inflow, confirming the fistula diagnosis.The embolization was performed using a definitive liquid agent (Onyx-18) Figures ; first, The final angiographic control  showed cThe patient was monitored for 5 days with nonsteroid anti-inflammatory medication because of a mild postembolization syndrome and then was dismissed.The MR follow-up after 30 days showed resolution of the fistula with consequent disappearance of the varicocele; uterine vascularization was preserved without signs of necrosis .No other episodes of menometrorrhagia occurred during the 3-month clinical follow-up and the period returned to normal 1 month after embolization.Uterine arteriovenous malformations can be congenital or acquired; the latter are named AVFs and are more common than congenital lesions that on the other hand should be properly named as arteriovenous malformations (AVM) .The correct diagnosis of uterine AVF is based on negative hCG test and imaging of abnormal uterine vascular network with tortuous and serpiginous vessels . ClinicaThe traditional treatment is hysterectomy ; howeverThe first conservative treatment for uterine AVF has been reported in 1982 ; since tAs for AVF or AVM from other body districts, it is crucial to recognize and embolize all the arterious feeders; typically uterine AVFs do not present with extrauterine involvement and are fed only by uterine arteries .The technical success should always be related to the clinical success because AVF frequently relapses ; therefoThe risk of uterine necrosis should be considered after definitive UAE; however, the vascularization is usually supplied by the wide uterine collaterals network, as ovarian, spinal, epigastric, and hypogastric arterial branches .Different embolizing agents, as coils, Spongel, particles, and glue alone or in combination, have been proposed \u201310; overOnly one paper  recentlyThere is no consensus about the best embolizing agent and there are also no technical guidelines because uterine AVF is a rare entity; however, endovascular conservative management should be considered as an alternative to hysterectomy in order to preserve fertility in young women wishing for future pregnancies."}
+{"text": "In our review, we discuss the various subtypes of tumor antigens with a focus on neoantigens and their potential in cancer immunotherapy. We will describe the current methods and techniques of detection as well as the structural requirements for neoantigens that are needed for their recognition by T cells and for tumor destruction. To assess the clinical potential of neoantigens, we will discuss their occurrence and functional relevance in spontaneous and hereditary cancers and their prognostic and predictive value. We will present in detail the existing immunotherapeutic options that exploit the neoantigen burden of tumors encompassing both preclinical efforts that provided convincing technological proof-of-concept and the current clinical studies confirming the potential of neoantigen-directed immunotherapies.During their development and progression tumors acquire numerous mutations that, when translated into proteins give rise to neoantigens that can be recognized by T cells. Initially, neoantigens were not recognized as preferred targets for cancer immunotherapy due to their enormous diversity and the therefore limited options to develop \u201cone fits all\u201d pharmacologic solutions. In recent years, the experience obtained in clinical trials demonstrating a predictive role of neoantigens in checkpoint inhibition has changed our view on the clinical potential of neoantigens in cancer immunotherapy. Technological advances such as sequencing of whole cancer genomes, the development of reliable algorithms for epitope prediction, and an increasing number of immunotherapeutic options now facilitate the development of personalized tumor therapies directly targeting a patient\u2019s neoantigenic burden. Preclinical studies in mice that support the excellent therapeutic potential of neoantigen-directed immunotherapies have provided blueprints on how this methodology can be translated into clinical applications in humans. Consistently, very recent clinical studies on personalized vaccinations targeting  Designing tumor therapies which effectively destroy tumors but spare healthy tissues is considered the Holy Grail in clinical oncology. Conventional chemotherapies target tumors but also dividing cells in healthy organs and are therefore frequently associated with significant toxicity. Promising antitumor activity without detrimental side effects, the advent of targeted therapies as a novel class of more tumor-selective oncology drugs initially raised a lot of enthusiasm. Indeed, such targeted therapies led to remarkable remissions in hematologic malignancies as observed with the introduction of imatinib for the treatment of chronic myeloid leukemia . In mostFor more than a century, immunotherapy has been postulated at times as a promising alternative to conventional cancer therapy although clinical proof of its therapeutic efficacy in large patient cohorts was lacking. The perception of immunotherapy as an alternative therapeutic means was mainly driven by case reports of immune-mediated tumor control in cancer patients. Upon occasional observations of tumor regressions in patients in the context of erysipela and high fever, it was William Coley who in late nineteenth century inoculated sarcomas with bacteria . Since tin vitro cultivation of antitumoral cytotoxic T lymphocytes, T cells were suggested as the major effector cell population that specifically responds to tumor antigens in humans  provided evidence of clinical efficacy the gain in median survival was, similar to the advances achieved with targeted therapies, rather modest without evidence for long-term progression-free survival .Surprisingly, it was a generic approach of T cell stimulation that finally succeeded and initiated the recent success story of cancer immunotherapy. Instead of eliciting a target-antigen-directed immune response in the context of a cancer vaccine, the pharmacologic interference with inhibitory immune checkpoints such as CTLA-4 or the PD-1/PD-L1 axis restored cytotoxicity of preexisting, exhausted cancer-specific T cells. It has to be pointed out that these therapies for the first time in clinical oncology resulted in long-term remissions in advanced cancers , 23 thatThe initial discovery of the interaction between tumor and immune cells was followed by intensive research to identify the target antigens that were recognized by the adaptive immune system. In 1989, a cell surface glycoprotein of the mucin family, MUC1, which is expressed in tumors in an aberrantly glycosylated form, was described as a tumor antigen that can be recognized by cytotoxic T cells . The melA highly promising class of tumor antigens are tumor-specific antigens (TSAs). These proteins are not encoded in the normal genome and encompass antigens derived from viral oncogenic proteins  or from proteins that are the result of somatic mutations or gene rearrangements. Whereas the presence of virus-derived proteins is mostly limited to tumors originating from a viral infection process, tumors in general acquire mutations during carcinogenesis and progression, resulting in altered proteins that may serve as neoantigens . NeoantiDepending on the position of the mutated amino acid in the sequence of the MHC-bound peptide the non-synonymous mutations differentially impact the quality of the neoantigen. While mutations in anchor positions primarily affect peptide affinity, mutations outside the anchor positions preferentially influence the interaction of the peptide/MHC complex with the TCR. As a consequence, mutations in anchor positions potentially create high affinity epitopes while mutations in the TCR-interacting positions may lead to the recognition of naive T cells which specifically recognize the mutated neoepitope.ex vivo expanded TILs that had been adoptively transferred in melanoma patients who subsequently experienced a complete tumor regression -R24C mutation in melanoma patients as a neoantigen that was a target of CTL responses . This mugression . TogetheAccording to the results of high throughput cancer genome sequencing it has been firmly established by now that all tumors contain a significant number of somatic mutations . HoweverAs a consequence of the mostly private nature of neoantigens, potential neoantigen targets can only be identified after analysis of a tumor mutanome by means of whole exome and/or next generation RNA sequencing , 43. DepOf the vast number of non-synonymous mutations detected in tumors only a tiny fraction may be suited for tumor treatment. To enhance the chances for successful immunotherapy a number of critical features of neoantigens have been described that impact on their quality as immunotherapeutic target.As one of the more simple requirements, the target antigen has to be expressed inside the tumor cells. Following transcription from genomic DNA into mRNA, the non-synonymous mutations are translated into the corresponding mutated proteins. Since most studies targeting tumor neoantigens perform next generation mRNA sequencing, mRNA quantity has been used most frequently as a surrogate marker for target gene expression although direct protein measurement is likely to be more accurate. Nevertheless, studies have supported the notion that higher mRNA quantites correlate with both protein quantity and the number of peptide/MHC complexes presented on the tumor cell surface . This coin silico prediction of neoepitope affinity for a given MHC molecule  are available that allow accurate prediction of peptide affinity for a neoepitope if the binding properties of the MHC allele are sufficiently characterized . Althougestioned  the in sTo generate neoantigen-specific adaptive immune responses the peptide\u2013MHC complexes must be presented on the surface of antigen-presenting cells and interact with neoepitope-specific T cells. In endogenous tumor-specific immune responses, tumor cells undergoing cell death are taken up by dendritic cells which then process endocytosed neoantigens and present the class II neoepitopes on their MHC class II molecules. In parallel, MHC class I neoepitopes are presented on DCs by cross-presentation, a process by which endocytosed proteins after proteasomal cleavage gain access to MHC class I molecules inside the endoplasmatic reticulum . This duFor vaccinations with soluble, short peptides containing MHC class I epitopes  or MHC class II epitopes the exogenously administered peptides have to compete with endogenous MHC class I and class II peptides that are already present on antigen-presenting cells. If the neoepitopes are of higher affinity than the endogenous MHC class I, they are able to replace the endogenous peptides directly on the APC surface. For vaccinations in the form of DNA, RNA, or polypeptides/proteins, the target antigen must undergo cross-presentation since these antigen carriers are usually taken up and endocytosed by antigen-presenting cells, thus underlying the same restrictions mentioned above for the endogenous tumor cell-specific T cells responses.de novo\u201d antigens it has been postulated that neoantigen-specific T cells are not subject to central tolerance. As a consequence, neoantigen-specific T cells may not only be of higher functional avidity but may also be more abundant than T cells recognizing autoantigens.To elicit robust immune responses, the neopeptide\u2013MHC complexes must form an immunological synapse with TCRs on either CD4 or CD8 T cells. Since neoantigens represent \u201cCurrently, the methodology for the detection of naive neoantigen-specific T cells in peripheral blood is limited, both in preclinical models and in humans. As an alternative, the number of potentially neoantigen-responsive T cells has been assessed by selective screening of PD-1 expressing, circulating CD8 T cells for their potential to recognize neoantigens . HoweverHowever, these methods have a number of caveats to consider. First, detectable neoantigen-specific T cells in patients are likely to be antigen-experienced and more terminally differentiated . It is uin vivo.Once the neopeptide is sufficiently expressed on MHC and the MHC/peptide/TCR synapse is formed  the robustness of the ensuing immune response is dependent on additional costimulation  and secretion of immunostimulatory cytokines such as IFN\u03b1 and IL-12  . Since tin vivo may take much longer than the same process in vitro, possibly requiring multiple consecutive hits from cytotoxic T cells ]. As a consequence, whole exome analyses of tumor samples from patients with Lynch syndrome have revealed a number of recurrent frameshift mutations in genes with microsatellite sequences. Similar to the reported genetic alterations in sporadic tumors some of these frameshift mutations presumably target genes involved in tumor development, particularly genes with tumor-suppressor function including TGFBR2, BAX , 66, CRTAs a potential caveat, the large mutational burden in patients with mismatch repair deficiencies seems to greatly accelerate the formation of immune escape variants. In patients with MSI-tumors, defects in antigen presentation have been detected in MHC molecules and in molecules associated with MHC expression at high frequencies . These MMicrosatellite instable tumors are increasingly recognized as a subset of tumors with distinct prognostic and predictive features. In patients with colorectal cancers, MSI tumors are overrepresented in early stage cancers but underrepresented in metastatic disease. This feature of MSI tumors has been attributed to the presence of high numbers of immune cells in MSI tumor specimens which may limit local tumor recurrence and systemic spread. Patients with MSI-H colorectal cancers UICC stage II have been shown to have a favorable prognosis compared to patients with MSI-L or microsatellite stable (MSS) tumors , 76, depThe better prognosis of patients with MSI tumors has a direct impact on the treatment of this patient population after tumor resection. Owing to the lower frequency of local recurrence and systemic spread after resection, adjuvant therapy for UICC stage II MSI colon cancer is not recommended. For UICC stage III patients, the usefulness of adjuvant therapy in MSI patients is still a matter of debate, with some studies arguing in favor of adjuvant therapy  and otheMore recently, the clinical success of checkpoint inhibitors in melanoma patients has revealed an additional predictive role of the mutational load in patients treated with either anti-PD-1 or anti-CTLA-4 antibodies \u201384. ThesThe notion that neoantigen-specific T cell responses are involved in tumor growth control in patients raised significant interest in identifying specific neoantigens as suitable targets to facilitate the design of tumor-directed vaccines. A particularly attractive kind of neoantigens are those that represent relevant mutation in tumor driver genes. It has been widely assumed that immunotherapies targeting noepitopes originating from oncogenic driver mutations may induce antitumor responses in a most effective manner since they are most likely essential for tumor survival and are homogenously expressed throughout the tumor tissue. Consequently, investigations initially focused on neoepitopes derived from well-known mutations in prominent oncogenes such as KRAS mutated at codon 12, or mutated p53 , 93. An Although the abovementioned mutations represent rather frequent genetic events the abundance of shared neoepitopes is significantly reduced by the huge HLA diversity rather low and inter-individual overlap is limited. The feasibility to develop broadly applicable vaccines has been recently estimated by a genomic analysis and epitope prediction of more than 63,000 tumors across multiple tumor entities and for the most common HLA A/B subtypes . Hypothein silico and algorithms are available that help to predict neoepitopes. These technologies therefore promise to achieve the identification of suitable neoepitope candidates for patient-specific immunotherapy within acceptable time, being one of the most critical requirement for patients with progressive tumor growth. The correlation of therapeutic efficacy of checkpoint inhibitors and the neoantigenic load clearly demonstrated that neoepitopes could play a prominent role also in more target-selective approaches of cancer immunotherapy. Several preclinical studies developed and simulated workflows including tumor exome mining and neoepitope prediction, eventually followed by methods to confirm truely immunogenic neoepitopes within the predicted pool, aiming at the development of a personalized immunotherapy. Just recently, the first results from clinical studies which applied these preclinically established methods to real-life therapeutic settings in humans have been reported. The promising clinical results will be described in more detail in the following subchapters. Furthermore, the full spectrum of immunotherapies targeting neoantigens in cancer patients is summarized in Figure Several technological advances in parallel opened up new avenues for the discovery of neoantigens and their potential use as target antigens in cancer immunotherapy. Next generation sequencing facilitated the exploitation of whole tumor exomes and revealed that in all tumors the mutated genome encodes for a variable but significant number of non-synonymous mutations and thus potential neoantigenic epitopes . FurtherAntagonizing coinhibitory molecules has shown great success in treatment of some cancer entities even at advanced stage , 23. Cheb epitopes of mutated Reps1 and Adpgk, and the H-2Kb epitope of Dpagt1. Remarkably, vaccinations with peptides predicted by this combined in silico prediction/mass spectrometry approach yielded therapeutically active T cell responses thus impressively confirming its excellent accuracy. Central aims of these strategies were not only to show the feasibility of in silico prediction of neoepitopes within acceptable time but also to demonstrate the accuracy and reliability of the chosen in silico approach in identifying immunogenic neoepitopes. Mass spectrometry was a first powerful analytical step to narrow down the number of therapeutically relevant neoepitodes with an additional validation step. However, the more stringent the selection criteria are in silico or in vivo, the higher the risk to omit relevant neoepitope candidates for targeted therapies. As an example, the nature of the chosen immunotherapy may impact on the quality of neoepitope responses as Gubin et al. demonstrated in their study when showing treatment-specific transcriptional alterations in neoepitope-specific CD8 T cells after CTLA-4, or PD-1 checkpoint inhibition, respectively . In CARs, the ligand for the molecular target is usually a single chain variable fragment (scFv) derived from a target-binding antibody. The use of CARs circumvents some problems associated with the use of TCR transfer such as mixed chimerism, unwanted off-target specificities and MHC downregulation in target cells. Posey et al. have developed a CAR that recognizes the tumor-specific glycoform of MUC1, a TSA already described in the introduction . Anti-MUde novo neoantigen-specific responses with diverse TCR usage . To enhance the efficacy of the vaccine and to break local immunotolerance, checkpoint inhibitors have already been used either in combination or after neoantigen vaccination, resulting in complete tumor regression in a number of treated patients . The comThe emergence of tumor subclones devoid of MHC class I expression represents the most challenging resistance mechanism to vaccines so far. Allelic loss of MHC molecules prevents recognition of the tumor cells by CD8 T cells and, in some cases, even CD4 T cells. In contrast, downregulation of MHC molecules can be counteracted by small molecules such as cobimetinib which is currently under clinical investigation in combination with the PD-L1 targeting antibody atezolizumab for the treatment of colorectal cancer . A critical question to be considered in the design of vaccines is whether MHC-negative tumor clones are already present at the beginning of the vaccination or if the resistant clones emerge during vaccination. If resistant clones emerge during vaccination, then vaccination should be designed to inflict maximum damage in a short period of time to avoid the equilibrium and the escape phase of the tumor-immune cell interaction. According to this hypothesis, an ideal vaccination regimen would consist of a limited number of vaccinations with a maximized magnitude of the ensuing T cell response (\u201chit hard and early\u201d). Even in the case that MHC-negative tumor subclones are already present at the beginning of the vaccination, a \u201chit hard and early\u201d vaccination might have advantages since high magnitude immune responses may favor the influx of natural killer cells which preferentially recognize and eliminate MHC-negative tumor cells. MHC-negative tumor cells should be preferred targets of natural killer cells. Consequently, it should be considered to combine neoantigen-directed immunotherapy with systemic NK cell activators. In preclinical studies, antibodies targeting NK cell checkpoints, such as CD96 have demonstrated the ability to control metastasis . In addiIn summary, the advent of novel therapies targeting neoantigens will revolutionize the treatment of cancer patients in the decades to come by fulfilling the promise of a personalized, individual treatment. Vaccinations are ideally suited for combination therapies, particularly in combination with checkpoint inhibitors, but also in combination with surgery, radiation therapy, chemotherapy, and locoregional and locally ablative procedures.TW and FK planned the manuscript and wrote sections of the manuscript. Both authors read and approved the submitted version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Somatosensory input is known to be essential for postural control. The present study examined the effects on postural sway of sensory input delivered via transcutaneous electrical nerve stimulation (TENS) applied to the knees during stance. Electrodes from a dual-channel portable TENS unit were adhered to the skin overlying the lateral and medial aspect of both knees of 20 young healthy volunteers . Postural sway parameters were obtained during static bipedal stance with an AMTI force platform. Four stimulation conditions were tested with eyes open and with eyes closed: no TENS; TENS applied bilaterally; and TENS applied to either the right or the left knee. Participants underwent two eight-trial blocks, with each trial lasting 30 seconds. The order of conditions was randomized for each participant. Stimulation consisted of a biphasic symmetrical stimulus delivered at the sensory detection level, with a pulse duration of 200\u03bcsec and a pulse frequency of 100Hz. The application of TENS induced significant reductions in mean sway velocity and in the medio-lateral dispersion of the center of pressure, with no corresponding effect on the anterior-posterior dispersion. These findings suggest that electrical stimulation delivered at the sensory detection level to the lateral aspects of the knees may be effective in improving balance control, and that this effect may be directionally specific."}
+{"text": "Different molecular therapies like the EGFR-inhibiting antibody cetuximab have come into clinical practice. Cetuximab is EMEA-approved for metastatic colorectal cancer and advanced squamous-cell head and neck cancer. Administration is said to be safe and well tolerated with common, usually mild dermatologic side effects.en-bloc oesophagectomy was performed. Few days later the patient died due to gas exchange dysfunction and circulation instability after a previously unseen combination of drain-erosion of the stomach with subsequent pleurisy and air leak of the left main bronchus.We present the case of a patient with fatal complications after oesophagectomy and neoadjuvant chemotherapy including cetuximab for squamous-cell esophageal cancer. A transthoracic So far we have never observed this fatal combination of drain erosion of the stomach with fibrinous pleurisy and unmanageable progressive tracheal defect before. The role of cetuximab in the multifactorial aetiology of damages of stomach and trachea after oesophagectomy remains unclear since we are not able to link the complication directly to cetuximab or definitely exclude it as a sole surgical complication. Clinicians should be aware of the possibility of fatal side effects and careful recording of all complications is necessary in ongoing and planned studies to obtain more evidence about safety and tolerance of targeted therapies. Oesophageal cancer represents the sixth leading cause of cancer-related death in the world. Despite recent advances in surgical critical care medicine and combined modality therapies 5-year overall survival rates 10\u201314%) are unsatisfactorily low 0\u201314% are. Next toIn the last decade different molecular therapies have changed the field of research, trying to inhibit or modulate targets of signal transduction pathways. One of those that made it into clinical practice is the epidermal growth-factor receptor (EGFR) inhibiting chimeric antibody cetuximab . This monoclonal antibody blocks EGF and TGF-\u03b1 binding to the extracellular domain of EGFR, which results in cell-growth inhibition, induction of apoptosis and decreased production of EGF .Cetuximab is EMEA-approved for second line treatment of EGFR-expressing metastatic colorectal cancer refractory to irinotecan-based chemotherapy and locally advanced squamous-cell head and neck cancer with concomitant radiotherapy. Many solid tumors including esophageal cancer overexpress EGFR, predicting poor survival, poor response to therapy as well as higher probability for disease progression and resistance to therapy -10. ThisGenerally EGFR-antibodies  or EGFR tyrosine kinase inhibitors  are said to be safe and well tolerated without systemic side-effects of chemotherapy. Common dermatologic side effects of cetuximab in a considerable number of patients are acneiform eruptions, xerosis, eczema, fissures, teleangiectasia, hyperpigmentation, hair changes and paronychia . More seIn this report we present a case report with fatal postoperative complications after neoadjuvant chemotherapy including cetuximab for squamous-cell esophageal cancer and discussion of the literature.A 52-year old man was diagnosed with squamous-cell esophageal cancer of the lower third. Pretherapeutical investigations included endoscopical biopsy, CT scan, endosonography and mediastinoscopy with lymph-node biopsy. These investigations showed a locally advanced stage T4N1 cancer.2 and 5-FU 1000 mg per m2. After the first chemotherapy cycle the patient developed grade 3 mucositis and esophagitis combined with an infection of the port-a-cath system, which had to be removed. This intense toxicity gave us reason to search for a dihydropyrimidin-dehydrogenase-deficiency. The result of the genetic testing was negative. Because of the toxic esophagitis and mucositis the patient refused to undergo the planned radiotherapy. From the second cycle continous 5-FU was replaced by oral capecitabine because of the port-a-cath infection and cetuximab was added as an alternative to radiotherapy after informed consent in a compassionate use setting. The EGFR-testing had shown a strong overexpression in all tumor cells. The treatment consisted of an intravenous standard loading dose of 400 mg per m2 after administration of diphenhydramine and ranitidine and continued with 250 mg per m2 once weekly for four weeks. After five weeks the patient developed disseminated pustules with generalized deeply infiltrated erythematous plaques highly indicative for a severe acute generalized exanthematic pustulosis (AGEP) as shown in figure The patient was scheduled for two cycles of neoadjuvant radiochemotherapy with cisplatin 100 mg per men bloc oesophagectomy five weeks after the last cetuximab application. Replacement of the esophagus was performed with an orthotopic gastric tube and cervical esophago-gastrostomy. On the third postoperative day a leakage from the right thoracic drain was observed and the following immediate revision operation showed an erosion of the stomach, which was most likely caused by a thoracic drain positioned in the vicinity of the gastric tube. The anastomosis 3 cm above the defect was completely intact with macroscopic sufficient blood circulation. Because of an additional fibrinous pleurisy we had to conduct a disconnection esophagostomy, catheter-gastrostomy and -jejunostomy for early enteral feeding. After four days the patient developed an airleak of the left main bronchus just below the tracheal bifurcation. At the time of the first bronchoscopy we found a 5 mm ulcer where the tracheal tube cuff was located during the operation until extubation on the first postoperative day. Within four days the defect's size increased by fourfold as shown in figure Reevaluation showed nearly no remission of the tumor as well as stable disease in the suspect lymph nodes. Because of lack of response and the intense toxicity the patient wanted to stop the neoadjuvant therapy and proceeded to transthoracic en bloc transthoracic oesophagectomy with paraesophageal, paratracheal, aorto-pulmonary and paracardial lymphadenectomy including lymph nodes of the splenic, hepatic and celiac arteries followed by cervical esophagogastrostomy under general anesthesia with separate intubation. The operation time was 4.5 hours and the blood loss approximately 600 ml. The reoperation consisted of a disconnection esophagostomy, catheter-gastrostomy and -jejunostomy. The tracheal leakage was treated by a 12 French Dumont silicone stent.The patient's squamous-cell esophageal cancer of the lower third (35 \u2013 38 cm from incisor teeth) was treated by Histologic tumor studies were done by haematology and eosin staining and EGFR-overexpression was measured by EGFR Pharm Dx kit K 1494 (Dako Cytomation).The oesophageal tumour was staged as ypT3 N1(9/25) MX R0 on final pathology. After reoperation the histologic examination of the resected specimen revealed extensive ischemic necrosis of the gastric mucosa with erosions and microabscesses, oedematous submucosa and the muscular and serosal layer next to the defect in good order.The autopsy showed massive fibrinous pleurisy, mediastinitis, left-sided bronchitis and bronchopneumonia in addition to the 2 cm tracheal defect of the membranous part of the left main bronchus. Histological complete tracheal wall destruction was observed with fibrin, necrotic areas and focal formation of granulation tissue without evidence of residual tumour figure .So far we have never observed this fatal combination of drain erosion of the stomach with fibrinous pleurisy and unmanageable progressive tracheal defect. Tracheal fistulae with airleaks are rare but life threatening complications after esophageal resections one to thirty days after oesophagectomy. The reported incidence of tracheal lesions is about 4 percent and about a third of the patients dies during the postoperative course, mostly because of unhealed lesions at the bifurcation or in the left main stem bronchus . IschemiPreoperative radiochemotherapy predisposed to this complication significantly and also in our patient neoadjuvant chemotherapy including cetuximab was administered. In the interdisciplinary tumorboard review a multifactorial event was discussed with cetuximab possibly playing a role. Other predisposing factors such as tracheal ischemia after extended mediastinal lymphadenectomy and damage of the membranous part after perforation of the stomach with subsequent mediastinitis have certainly contributed to the lethal outcome.Since the reassessment of EGFR-expression in the gastric and tracheal tissue was not possible one can only speculate about a possible contribution of cetuximab in addition to surgical complications after extensive lymphadenectomy.et al., described the important role of EGF in restitution of gastric mucosae in guinea pigs, that was significantly inhibited by an anti-EGFR antibody [et al., demonstrated that EGF inhibits acid secretion, exerts a trophic effect on gastroduodenal mucosa, protects gastric mucosa against injury, mediates mucosal adaptation and accelerates gastroduodenal ulcer healing by stimulating cell migration and proliferation [Yanaka antibody . Tarnawsferation . Regardiferation  and seveferation .et al., hypothesised that EGFR ligands and other growth factors mediate bronchial epithelial repair in sheep [et al., demonstrated in human airway epithelial cells that EGF induced epithelial repair via cell migration after mechanical injury [et al., showed that EGF-promoted wound closure in airway epithelial cells was retarded by a selective EGFR tyrosine kinase inhibitor (AG 1478) [Considering the bronchial system Barrow in sheep . White el injury . PuddicoAG 1478) . These pAG 1478) .th to 6th leading cause of death in the US causing 106.000 fatalities per year [et al., have demonstrated that voluntary reporting identifies only about 6% of ADRs in the clinical routine and improvement is essential [Adverse drug reactions are suspected to be the 4per year  althoughper year . Cullen ssential . Linkingssential . The totssential .et al., found tracheal complications in 4% after 785 esophagectomies  [et al., found no evidence that induction therapy adversely influences the incidence of postoperative morbidity or mortality after oesophagectomy in 155 patients [The role of cetuximab in ischemic damages of the stomach and trachea after ooesophagectomy is unclear. While Bartels y alone) . Kelley patients .Preclinical evidence exists for a possible correlation between EGFR-antibody therapy and impaired EGFR-mediated repair mechanisms in gastric and airway epithelial cells. The widespread, in general safe and well-tolerated use of cetuximab in metastatic colorectal and locally advanced squamous-cell head and neck cancer has to lead to further investigations in neoadjuvant settings also in other cancers such as esophageal cancer. In our patient with severe postoperative complications the etiology of this complication is likely to have been multifactorial, with cetuximab possibly playing a role. Although the suspected increase of risk for complications after oesophagectomy needs to be confirmed in prospective trials before final conclusions can be made, clinicians should be aware of the possibility of these side effects. Careful recording of all complications is necessary in ongoing and planned studies to obtain more evidence about safety and tolerance of targeted therapies since these new biologic agents may be not as safe as we have initially assumed.The author(s) declare that they have no competing interests.KM & HA Conception and design, writing of manuscriptWE, OF: Help in preparation of draft and editing of manuscript, data analysis and interpretation.AK, CP, TM: Managed the case and helped in preparation of draftKM, LA, TM: Collection and assembly of dataAll authors read and approved final manuscript for publication."}
+{"text": "The effect of serial passage in immune-deprived mice on certain biological and biochemical parameters has been studied in a series of 6 human colorectal tumour xenografts. Histological integrity is maintained for up to 10 serial passages, together with production of epithelial mucins and carcinoembryonic antigen. Passaged tumours retain human lactate dehydrogenase and glucose-6-phosphate dehydrogenase isoenzyme patterns and a human chromosome constitution. The induction of a murine tumour has been identified in this system, and the importance of routine checks for the presence of human tissue during serial passage is stressed."}
+{"text": "National Quality Forum (NQF) refers to these events as \"serious reportable events\" in all of their definitions and references. In this editorial, we use the popular - but likely improper - term \"never events\" as it further illustrates the public's perception of adverse occurrences. Although the preferred terminology reverts to \"serious reportable events\", this definition may be unlikely be given the prevalence of the viscerally moving term \"never event.\"Despite the widespread usage of the term \"never events,\" the Centers for Medicare and Medicaid Services (CMS) have deemed as \"non-reimbursable serious hospital-acquired conditions\".Further confusion persists about the definition of \"never events\" as they relate to either (1) conditions listed as \"serious reportable events\" by the NQF, in contrast to (2) conditions defined by the http://www.qualityforum.org. In 2002, the NQF published a first report which defined 27 so-called \"serious reportable events\" in healthcare. These encompass serious adverse events occurring in hospitals that are largely preventable and of concern to both the public and to healthcare providers. One additional event was added to the updated report in 2006, leading to a total 28 \"never events\" defined by the NQF  can be consistently and effectively prevented through the application of evidence-based guidelines. (...) Their inclusion may have unintended consequences that may cause greater harm than the falls that the initiative is meant to prevent\" [A recent editorial in the misguided. Accordiprevent\" .\"Falls are often the result not of medical errors but of disease, impairments, and appropriate uses of medications and other treatments. Falls and injuries can occur even when hospitals provide the best possible care\" [Unintended consequences are likely to include a decrease in mobility, increase in use of physical restraints, and a tendency to focus on measures including new prevention devices. These measures can cause reallocation of resources from areas that might have greater impacts on patient safety. According to the editorial, le care\" .American Academy of Orthopaedic Surgeons (AAOS) to recommend different prophylaxis regimens compared to the evidence-based guidelines published by the American College of Chest Physicians (ACCP)[It is known that certain orthopaedic procedures can result in the hospital-acquired conditions of postoperative infections and thromboembolic events. Neither complication can ever be completely prevented. Arguments also exist that vigorous thromboprophylaxis in certain orthopaedic procedures can lead to an increased risk of delayed bleeding, wound healing problems, and postoperative infections. This notion has led the ns (ACCP).We strongly feel that there is a need to officially clarify that falls, postoperative infections, and thromboembolic events are \"non-reimbursable serious hospital-acquired conditions\", but not \"never events\". Efforts certainly must be made to reduce either complication as much as possible via evidence-based assessment and treatment. Documentation of the informed consent process, and the risk/benefit analysis underlying the clinical decision making processes are critical to patient understanding of potential complications and our ability to defend the care provided in the medicolegal setting.Strategies to improve the defensibility of care where appropriate, particularly those falling under the non-preventable adverse events list include:\u2022 Pretreatment or pre-hospital documentation of underlying pre-existing conditions, particularly those involving infections, pressure sores, altered mental status, hyper-/hypoglycemia, and patients at high risk for venous thromboembolism.\u2022 Hospital outcomes data with identification of care improvements directed at those complications - particularly hospital-acquired infections.\u2022 Standardized and universally followed approaches to reduce wrong site/wrong patient surgery.\u2022 Culture-changing training around communication, assertiveness, team training, and the use of briefings and debriefings, particularly in high-acuity patient care areas.\u2022 The use of surgical checklists.\u2022 Understanding and using clear language in policies and publications of the difference between the NQF \"never events\" and the CMS \"non-reimbursable serious hospital-acquired conditions\" to avoid claims of negligence.\"Never events\" and non-reimbursable adverse events are framed in the negative and likely carry some \"extra psychological charge\", as mentioned above. Our concept of the \"always events\" represents a positive affirming behavior that can motivate us to improve patient safety and promote better outcomes. Some basic examples of \"always events\" include:\u2022 Including patient identification by more than one source.\u2022 Mandatory \"readbacks\" of verbal orders for high-alert medications.\u2022 Disclosure of adverse outcomes and transparency with patients and families.\u2022 Medication error reduction strategies.\u2022 Surgical time-out.\u2022 Anesthesia monitoring that is appropriate for the level of sedation.\u2022 Tracking of critical imaging, lab and pathology results.\u2022 Making critical information available at handoffs or transitions in care.Standardization and validation of \"always events\" may represent the basis for a positive long-term culture of patient safety to be passed on to the next generation of health care providers.Colorado Physician Insurance Company (COPIC). The author declares no other competing interests with regard to this manuscript.Both authors are affiliated with the Both authors contributed equally in the design and writing of this editorial."}
+{"text": "The present study was conducted to determine how long hyperplastic polyps (HPs) and fundicgland hyperplastic polyps (FGPs) should be endoscopically followed up. Our findings showedthat in the case of FGPs, yearly endoscopy is not required and it is sufficient to repeat X-rayand compare films with those obtained in the previous year. In contrast, yearly follow-up byendoscopy is necessary in the case of HPs."}
+{"text": "Large fluctuations in glutathione content were observed on a daily basis using the Tietze enzyme recycling assay in a panel of six human cell lines of varying radiosensitivity. Glutathione content tended to increase to a maximum during exponential cell proliferation, and then decreased at different rates as the cells approached plateau phase. By reference to high-performance liquid chromatography and flow cytometry of the fluorescent bimane derivative we were able to verify that these changes were real. However, the Tietze assay was occasionally unable to detect glutathione in two of our cell lines (MGH-U1 and AT5BIVA), although the other methods indicated its presence. The existence of an inhibitory activity responsible for these anomalies was confirmed through spiking our samples with known amounts of glutathione. We were unable to detect a direct relationship between cellular glutathione concentration and aerobic radiosensitivity in our panel of cell lines."}
+{"text": "A report of the meeting \"Challenges in experimental data integration within genome-scale metabolic models\", Institut Henri Poincar\u00e9, Paris, October 10-11 2009, organized by the CNRS-MPG joint program in Systems Biology. Instances of such methods were presented by Maranas, who developed with his colleagues novel algorithms including GapFill and GapFind [While the number of fully sequenced genomes continues to grow at an exponential rate, the number of published reconstructions of metabolic models  is drama GapFind  to fill S. cerevisiae from the Charlie Boone Lab [in silico enumeration of all lethal gene pairs, triplets and quartets using FBA is computationally intractable for any genome-scale metabolic model; instead, Maranas presented a heuristic method based on a bi-level optimization approach which improves considerably the computational time to obtain lethal triplets and quartets  as candidates for further assessment of the genetic interactions predicted by the model [While single gene-deletion mutants are considered a prominent source of data for assessing the quality of reconstructed models, datasets including the phenotypes of double gene-deletion mutants appeared recently. Bal\u00e1zs Papp  presented unpublished results where such a dataset obtained in yeast oone Lab  was usedhe model .Tomer Shlomi  also showed that reconstructing a model may involve further challenges, pertaining for instance to the proper account of cellular compartments in absence of prior knowledge of enzyme localization. In particular, he presented a novel algorithm to predict sub-cellular localization of enzymes based on their embedding metabolic network, relying on a parsimony principle which minimizes the number of cross-membrane metabolite transporters .in silico and in vivo single mutant growth phenotypes by suitably modifying the static biomass composition under different environmental conditions. Shlomi presented a method, Metabolite-dilution FBA (MD-FBA), which systematically accounts for the growth demand of synthesizing all intermediate metabolites required for balancing their growth dilution, leading to improved metabolic phenotype predictions [While the static composition of the biomass as a component of a metabolic model is known to influence the results of FBA predictions, little had been proposed to date in order to overcome this limitation of the framework. Maranas presented the GrowMatch  method tdictions .13C labeling experiments followed by nuclear magnetic resonance (NMR) or mass spectrometry (MS) analysis have generated experimental data for a number of intracellular fluxes and metabolite concentrations [Condition-dependent refinements of metabolic models can also be fed by further experimental observations. Recently, trations . Such extrations  which syS. cerevisiae and Lactobacilli where the two maximizations are not equivalent. He compared the two cases with the experimentally observed solution corresponding to maximization of rate [Another criticism often addressed to FBA pertains to the use of an optimality principle to obtain a single biologically relevant flux distribution. Stefan Schuster  emphasized that FBA predicts a flux distribution that strictly maximizes biomass yield rather than biomass flux or growth rate. Although, in most situations, maximization of rate and yield give equivalent solutions, Schuster presented interesting examples in  of rate . In cont of rate  cannot b of rate  closely The reconstruction of metabolic networks for several organisms spread across the tree of life and that thrive in diverse habitats has enabled investigations aimed at understanding the role of the environment in determining the structure of metabolic networks of different organisms. Oliver Ebenh\u00f6h  presented a simple heuristic based on the principle of forward propagation called network expansion  which usBuchnera aphidicola receives from its host.Marie-France Sagot  presented ongoing work in her group to improve the network expansion algorithm by appropriately differentiating self-regenerating metabolites   from nutE. coli metabolic network, Martin and colleagues showed that the E. coli network is atypically robust to mutations.Several studies in the past have been focused towards understanding the relation between structure and function of metabolic networks. However, little is known about the variation in reaction content of the different possible metabolic networks having the same phenotype. Olivier Martin  presented a new method based on Markov Chain Monte Carlo (MCMC) sampling which can be used to uniformly sample the space of metabolic networks with a given phenotype and fixed number of reactions in a global reaction set . Using tE. coli was identified. Modeling this process allowed him to further characterize qualitatively different regimes.While the investigation of statistically overrepresented motifs in gene regulatory networks has resulted in the identification of qualitative features of the associated dynamics , similarAs an alternative to traditional optimization-based predictions, Daniela Calvetti  presented a probabilistic extension of both kinetic and steady state models of metabolism that she introduced with her colleague E. Somersalo . RelyingWolfram Liebermeister  presented various methods leveraging such mathematical theories to integrate experimental data within metabolic models. He provided the audience with a thorough review of the methods he developed with his colleagues to induce quantitative relationships between enzyme levels, metabolite concentrations and metabolic fluxes, while properly accounting for physical laws and allosteric regulation ,23. EmphAlthough the detailed modelling of human metabolism was initiated almost ten years ago, to date it has been restricted to specific cell-types and organelles. In parallel, comprehensive datasets of the genes involved and biochemical activities in human cells have been gathered, allowing Duarte and colleagues to publish the first global map of human metabolism in 2007 . BuildinKiran Patil  tackled the challenge of modeling several other metabolic processes in humans. He specifically investigated the metabolic and regulatory underpinnings of diabetes, combining the knowledge on regulatory and metabolic mechanisms to pinpoint biomarkers of diabetes with the help of several case-studies pertaining to this particular disease. An analysis of the enrichment in binding sites of transcription factors in upstream regions of the enzymatic genes relevant to this study allowed him to uncover the potential of various transcription factors as drug targets .The authors declare that they have no competing interests.All authors contributed equally to this manuscript. All authors have read and approved the manuscript."}
+{"text": "BMC Medicine provides preliminary evidence that baseline phosphorylated extracellular signaling-regulated kinase (pERK) may be a relevant marker to reflect the level of constitutive activation of the RAF/mitogen-activated protein kinase kinase (MEK)/ERK signaling pathway and has the potential value in predicting response to sorafenib. The clinical data from the initial single arm phase II study and preliminary report from the randomized phase III study also suggest the correlation of baseline archived tumor pERK levels and time to tumor progression in HCC patients. Whether baseline pERK will prove to be a useful predictive biomarker of response and clinical benefits for sorafenib in HCC will need to be validated in future large prospective studies.The approval of sorafenib and active development of many other molecularly targeted agents in hepatocellular carcinoma (HCC) have presented a challenge to understand the mechanism of action of sorafenib and identify predictive biomarkers to select patients more likely to benefit from sorafenib. The preclinical study by Zhang and celleagues published this month in  P < 0.001). The median TTP was 5.5 months in the sorafenib group and 2.8 months in the placebo group (P < 0.001). In a subsequent randomized phase III study conducted in Asia, sorafenib also demonstrated a longer OS and TTP in patients with advanced HCC [BMC Medicine, Zhang and colleagues report their study assessing the potential role of phosphorylated extracellular signaling-regulated kinase (pERK) as a predictive marker in a preclinical HCC model [In 2007, Llovet and colleagues first reported the results of the international, phase III, placebo-controlled Sorafenib HCC Assessment Randomized Protocol (SHARP) trial, which demonstrated a longer overall survival (OS) time and time to tumor progression (TTP) compared to placebo in patients with advanced hepatocellular carcinoma (HCC) . As showCC model .in vivo [Sorafenib is an oral multikinase inhibitor that targets tumor cell proliferation and tumor angiogenesis by inhibiting the serine/threonine kinases Raf-1 and B-Raf through the canonical Raf/mitogen-activated protein kinase/extracellular signal-regulated kinase (RAF/mitogen-activated protein kinase kinase (MEK)/ERK) signaling pathway and the receptor tyrosine kinases (RTK) of vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3 and platelet-derived growth factor receptor (PDGFR)\u03b1 and \u03b2 and stem cell factor receptor (KIT) ,5. Humanin vivo . Unlike in vivo . Howeverin vivo ,10. In ain vivo . SorafenBMC Medicine, Zhang and colleagues provided evidence to support the notion that pERK might be a useful predictive marker in preclinical HCC model [185 followed by Thr183 [et al. assessed the pERK expression by immunocytochemical quantification and found that basal pERK levels increased stepwise in these cell lines in accordance with their metastatic potential. Sorafenib inhibited ERK phosphorylation in a dose-dependent manner in these cell lines at a concentration between 5 and 20 \u03bcM and the degree of inhibition correlated with their basal pERK expression level. They further demonstrated that the effects of sorafenib on cell proliferation correlated significantly with basal pERK levels. To explore if this correlation was linked to pERK, the authors showed that by reducing the basal ERK phosphorylation level in MHCC97-H with U0126, a selective inhibitor of MEK1/2, they could render these cells less sensitive to sorafenib-mediated growth inhibition. These preclinical findings lend support to the initial report from the phase II study of sorafenib in advanced HCC, in which 33 out of 137 enrolled patients had pretreatment archived tumor tissue available for pERK staining and correlative analyses. In the majority of tumor samples, staining was generally most intense within the nucleus of tumor cells and there was a significant difference in TTP between patients with higher tumor cell pERK staining intensity, versus those with lower intensity [The successful clinical development of sorafenib in HCC and the improved understanding of the mechanism of action of sorafenib have raised several critical questions. What are the potential mechanisms of action that lead to the sorafenib-mediated clinical benefits? Is this due to the VEGFR blockage, inhibition of RAF/MEK/ERK signaling pathway, or off target effects? What are the molecular and clinical predictors of benefits of sorafenib in HCC? In an article published this month in CC model . RAF/MEKCC model . The MEKy Thr183 . Therefoy Thr183 . The keyntensity .in vitro results, much has to be done before pERK evaluation will become a useful biomarker. Future mechanistic study should assess the link of perturbing pERK pathway in each cell line with drug sensitivity. In addition, the expression of other signaling molecules should be evaluated to make certain that the sensitivity to sorafenib is indeed dependent on pERK expression. The clinical evidence to support the use of pERK as a predictive marker for sorafenib in HCC is also preliminary. Future studies should evaluate pERK expression in large numbers of patients and determine if this biomarker has predictive or prognostic value.Is the evidence strong enough to support the use of pERK as a predictive biomarker for sorafenib in HCC? Although this is an intuitive biomarker candidate for sorafenib, and the study of Zhang and colleagues provides promising Identification of potential predictive and surrogate markers in patients receiving sorafenib and other targeted agents remains an area of active investigation. In a preliminary presentation at the American Association for the Study of Liver Diseases (ASSLD) meeting in 2008, Llovet and colleagues reported the early results of assessing potential useful predictive biomarkers in the SHARP study . They foet al. provides additional evidence that baseline pERK may be a relevant marker to reflect the level of constitutive activation of the RAF/MEK/ERK signaling pathway and has the potential value in predicting response to sorafenib. The clinical data on the correlation of pERK and TTP is interesting, but preliminary. Whether baseline pERK will prove to be a useful predictive biomarker of response and clinical benefits for sorafenib in HCC will need to be validated in future large prospective studies.In conclusion, the study by Zhang AZ works in an advisory role for Bayer and Genentech.The pre-publication history for this paper can be accessed here:"}
+{"text": "This combined approach was applied to investigate the hypertensive side effect of the cholesteryl ester transfer protein inhibitor torcetrapib in the context of human renal function. A metabolic kidney model was generated in which to simulate drug treatment. Causal drug off-targets were predicted that have previously been observed to impact renal function in gene-deficient patients and may play a role in the adverse side effects observed in clinical trials. Genetic risk factors for drug treatment were also predicted that correspond to both characterized and unknown renal metabolic disorders as well as cryptic genetic deficiencies that are not expected to exhibit a renal disorder phenotype except under drug treatment. This study represents a novel integration of structural and systems biology and a first step towards computational systems medicine. The methodology introduced herein has important implications for drug development and personalized medicine.Recent advances in structural bioinformatics have enabled the prediction of protein-drug off-targets based on their ligand binding sites. Concurrent developments in systems biology allow for prediction of the functional effects of system perturbations using large-scale network models. Integration of these two capabilities provides a framework for evaluating metabolic drug response phenotypes  Pharmaceutical science is only beginning to scratch the surface on the exact mechanisms of drug action that lead to a drug's breadth of patient responses, both intended and side effects. Decades of clinical trials, molecular studies, and more recent computational analysis have sought to characterize the interactions between a drug and the cell's molecular machinery. We have devised an integrated computational approach to assess how a drug may affect a particular system, in our study the metabolism of the human kidney, and its capacity for filtration of the contents of the blood. We applied this approach to retrospectively investigate potential causal drug targets leading to increased blood pressure in participants of clinical trials for the drug torcetrapib in an effort to display how our approach could be directly useful in the drug development process. Our results suggest specific metabolic enzymes that may be directly responsible for the side effect. The drug screening framework we have developed could be used to link adverse side effects to particular drug targets, discover new uses for old drugs, identify biomarkers for metabolic disease and drug response, and suggest genetic or dietary risk factors to help guide personalized patient care. Despite the advantages gained from drug therapy in medicine, drug development has historically presented an expensive and frequently perplexing challenge for researchers. Identifying useful drug targets for treating disease and matching them to chemical compounds that can elicit the desired effect through drug-target interaction has been the paradigm for the drug development process in the era of molecular medicine. However, this approach has yielded many failed drug treatments and an incomplete understanding of the consequences of treatments for human health, even with drugs that have made it to market and been prescribed for decades. Two major contributing factors that confound individual molecular target-based drug discovery are drug off-target binding and the lack of systems-level understanding of drug response The growing wealth of omics data offers a valuable opportunity for novel approaches in systems medicine but also presents significant challenges for data integration M. tuberculosisS. aureusH. pylori, and E. coliin silico drug studies. Integrating these structural bioinformatics and human system modeling techniques for application in drug development represents a first computational step into the era of systems medicine. As an example of this integrative approach, the results of protein off-target prediction for the drug torcetrapib Biological systems exhibit redundant pathways and synergistic effects conferring a robustness of phenotype when confronted with external stimuli. As a result, multi-target drugs are generally more clinically efficacious than single-target drugs. These facts highlight the critical importance of studying polypharmacology in a systems level context CETP inhibitors are intended to treat patients at risk for atherosclerosis and other cardiovascular diseases by raising high-density lipoprotein cholesterol (HDL-C) and lowering low-density lipoprotein cholesterol (LDL-C) The predicted torcetrapib off-targets include many metabolic enzymes and metabolite transport proteins. Although there are several mechanisms involved in regulating blood pressure that may be responsible for the hypertensive side effect, one possible mode is the renal regulation of blood pressure via metabolite reabsorption and secretion. The kidneys are the primary organs that filter the blood and therefore are strong contributors to maintaining a normotensive state even independent of RAAS function. Thus a model of renal metabolism was developed as the system context in which to analyze torcetrapib off-targets and predict drug response phenotypes. The two best-supported causal off-targets predicted in this study are prostaglandin I2 synthase (PTGIS), due to decreased capacity for renal prostaglandin I2 (PGI2) secretion, and acyl-CoA oxidase 1 (ACOX1), due to decreased capacity for renal citrate and amino acid reabsorption. Four other predicted off-targets are also predicted to impact amino acid, glucose, citrate, or bicarbonate reabsorption. As well, the model predicts no effect on renal reabsorption or secretion for a number of other predicted off-target metabolic proteins.The goal of this study is not only to provide new insight into the torcetrapib problem but also to reveal the theoretical implications that this computational systems medicine platform has for drug development and personalized medicine. Characterizing the influence that genetic variation has in determining drug response phenotypes has been recognized as a crucial goal for the future of drug development Although many of the predictions generated by this approach are supported by clinical and other experimental evidence that describe the impact of loss of function for predicted causal off-targets and genetic deficiencies, the full set of exact metabolic mechanisms of drug action predicted by our model remain to be completely validated. While this is seen as a limitation of this study, it also offers a number of opportunities to experimentally evaluate promising hypotheses that, if validated, will lead to significant advancements in developing CETP inhibitors for treatment and novel insight into certain renal disorders.The approach for context-specific organ modeling proposed in this study see  yielded The kidney model included 336 explicitly predicted active metabolic genes  that metThe active reactions in the model reflect both the possible pathways by which the kidney can achieve the specified renal objectives as well as other functions supported by the gene expression data. The model included 1587 active reactions , excludiThe integrative framework adopted for predicting causal drug targets associated with response phenotypes employed both structural bioinformatics tools as well as modeling techniques of systems biology see . The worThe renal response phenotypes for inhibition of two of the predicted drug off-targets were supported by existing scientific literature. Simulated PTGIS inhibition completely precluded PGI2 secretion. Based on the relation of renal PGI2 secretion to blood pressure see , this inTwo predicted causal CETP inhibitor off-targets, PTGIS and ACOX1, exhibited notable binding affinity differences when comparing docking results for their endogenous substrates to those for the three CETP inhibitors . The meaSimilar to the use of the model to test inhibitory effects on drug targets, the model was also used to predict genetic deficiencies that lead to renal disorders and drug off-targets that act synergistically with genetic deficiencies. Simulated gene knockouts predicted to impact renal objective functions are displayed in Some renal disorders were only predicted in the gene-deficient models in combination with drug treatment, not in the untreated gene-deficient models or in the normal drug-treated model, and are referred to in this study as cryptic genetic risk factors. Five such gene deficiencies were predicted see . A defic\u221222. This observation is especially notable since the reduced kidney model was not a global model of kidney metabolism, and the result suggests the relative importance of the renal functions captured by our model within the context of total kidney gene activity.Multiple evaluations were performed to analyze and validate the content of the reduced kidney model. The reduced kidney model effectively predicted activity of significantly expressed metabolic genes. The ability of our modeling approach to correctly and robustly predict activity of highly expressing genes was evaluated by a five-fold cross validation see . Our appWe compared the metabolic gene activity predictions from the reduced kidney model to the set of significantly expressed genes as well as to a proteomic dataset derived from normal, healthy human kidney glomerulus tissue et al  analysis based on not only the abovementioned clinical validations of our gene-deficient phenotype predictions but based on the entire set of such known clinical phenotypes that could potentially have been investigated using our model see . The shaable see , we alsoIn order to assess the effects of some of the critical assumptions made in the model development and simulation procedures, we performed sensitivity analysis with respect to the predicted renal disorder phenotypes.First, we compared the predictive capability of our reduced kidney model to that of the original, unconstrained human Recon1 metabolic network. The same approach to simulating renal disorder states was employed using both models see . We simuSecond, we investigated the sensitivity of our drug off-target response phenotype predictions to the variability of two important parameters used in our simulations, the system boundary flux constraint, set as equal fractions of the upper bound on renal objective fluxes see , and theThe system boundary flux constraint was imposed upon demand and exchange reactions other than those optimized during a given simulation. By default we set this constraint assuming that all allowed boundary fluxes can carry an equal fraction of the potential maximum renal objective flux. This assumption was made to allow all pathways that could possibly contribute to the objective to be used simultaneously in the optimal flux state, providing the most flexible state while maintaining maximum sensitivity of our model to additional system perturbations such as gene deficiencies or drug effects. This approach was unbiased in that it did not favor any possible pathway over another in achieving a set objective without imposing additional constraints, which may not always reflect biological reality but was the most conservative assumption in the absence of additional experimental data required to more precisely set these flux constraints. In our sensitivity analysis, we varied this parameter between 0 and 1000 flux units, the absolute lower and upper magnitudes possible in our model, and repeated the simulations of drug off-target effects. The result of this analysis  was captIt is clear from We similarly analyzed the sensitivity of our predictions to changes in the degree of enzyme inhibition assumed to follow from drug treatment . For theA novel approach for making functional predictions of drug response phenotypes has been introduced that integrates techniques of both structural bioinformatics and systems biology. Although the current study focused on a specific metabolic system, the general methodology excluding techniques particular to metabolic modeling are extensible to other systems such as signaling or transcriptional regulation. Non-metabolic protein drug off-targets are predictable using the same structural analysis tools, and many such off-targets have indeed been predicted as well for CETP inhibitors et al, when integrated with multiple omics datasets, can lead to more biologically realistic models. It is also of critical importance to include context-specific metabolic objective functions in the model development process in order to yield a fully functional and predictive model, as is evident from the functional comparisons of models performed in this study.The context-specific organ metabolic modeling strategy employed in this study represents an improvement upon previous efforts in this realm. Model development algorithms such as GIMME As an early effort at modeling such a context-specific metabolic system it is important to discuss the limitations of our model. Although the functional validations presented here are compelling, currently available clinical data only permits the assessment of a subset of the predictions possible in the model. Also, the functional portion of the model, the reduced kidney model, does not and is not intended to represent a global model of kidney metabolism but only the specific renal functions studied in this work. As such, our model does not fully resolve of complexity of the human kidney. The human kidney fulfills a number of functions not studied here and is a spatially distributed system across multiple distinct tissue types. Here we have summarily replaced the various kidney sub-tissues with a single, net system model. Because we integrated expression data with curated renal functions that operate across multiple kidney tissues, it is likely that our model approximates a superset of the metabolic pathways supporting these functions. Although we have made several simplifying assumptions in the model development process, even the current level of model validation suggests that the gene and reaction content of the model is fairly accurate and that simulations in this model indeed hold predictive capability.The simulation approach taken, optimization of a linear objective function, does not fully capture the full physiological role of the kidney. The goal of these simulations was to determine drug-target effects that may limit the capacity of the kidney to move towards a homeostatic nominal state from a state of high blood pressure, thereby decreasing the capacity of the kidney to lower blood pressure. This strategy is appropriate for the goals of the current study but would not be appropriate to simulate all physiological states of interest in the kidney. On a related note, the choice to define a disorder state based on the ratio of perturbed to unperturbed maximum achievable renal objective flux demonstrates a difference in the capacity of the renal function and not necessarily a precise flux state. Therefore this strategy too is not appropriate for modeling all physiological states.The predictions made for CETP inhibitors in this study serve as illustrative examples of many important implications that this approach has for drug development and personalized medicine. Predicted causal off-targets for renal metabolic disorders related to blood pressure may be responsible in part or full for the clinically observed hypertensive side effect of torcetrapib. The evidence resulting from this study suggests that PTGIS and ACOX1 are both potential causal torcetrapib off-targets, the inhibition of which may explain the side effect of hypertension. In addition, AK3L1, HAO2, MT-COI, and UQCRC1 may also play a role in this side effect as we have predicted, although our docking trials did not suggest that they are bound as strongly by torcetrapib. The specific predicted deficiencies in renal function associated with the drug off-targets can serve as biomarkers to be measured in patients participating in clinical trials. A positive correlation of these biomarkers with side effects would lend support to the predictions of this study and confirm these biomarkers as risk indicators in future patient treatment. It is important to note that although these predictions comprise the basis for a renal filtration and secretion-based hypothesis explaining the hypertensive side effect of torcetrapib, these results do not refute the hypothesis based on a RAAS-mediated mechanism. These two hypotheses are not mutually exclusive and could potentially contribute alternatively or synergistically to the clinically observed side effects. This possibility illustrates the major tenet for systems biology: studying a single protein or even a single pathway is not necessarily sufficient to explain complex biological phenomena.Aside from the confirmation that some of our predicted off-targets are known to be involved in renal disorders, we do not currently present direct experimental verification that torcetrapib binds and inhibits the predicted targets and that this inhibition leads to the predicted response phenotypes. Although this would be the obvious next step, a retrospective validation is currently hampered by the availability of the drug and the nature of the phenotypes both predicted and known. Ideally, relevant physiological studies would be carried out during actual clinical trials, when a method such as ours would be most useful, in preclinical and clinical phases of drug development.The extended structural analysis of causal drug off-targets to identify differential binding affinities for endogenous substrates and drug molecules suggests possible differences in drug response phenotypes across the CETP inhibitors tested. The results suggest that anacetrapib may potentially lead to a similar response phenotype to that of torcetrapib, while JTT-705 may not carry the same adverse effect, at least with respect to the off-targets detailed in this study. This particular type of analysis may aid in differentiating between likely response phenotypes expected for chemically and functionally similar drugs. Results of the computational pipeline for interaction prediction between proteins and CETP inhibitors employed in this study, SMAP and docking, have yet to be confirmed experimentally. Although we are currently unable to provide direct experimental evidence for the off-target interaction predictions for this class of drugs, multiple recent studies have shown experimental support for the general efficacy of this approach for interaction prediction The predicted renal metabolic disorders with a genetic basis suggest classes of individuals in which treatment with CETP inhibitors may pose a higher risk for adverse side effects. These predictions suggest a likely relationship between participants in torcetrapib clinical trials exhibiting symptoms of these disorders and the observed adverse side effects. The concept of cryptic genetic risk factors for drug treatment introduced in this study suggests a novel approach to personalized medicine. Should polymorphisms within these genes be clinically linked to side effects of drug treatment, the result would comprise a basis for genetic screening to assess the risk of drug treatment for future patients. Given that these cryptic risk factors are not expected to elicit the predicted abnormal phenotypes in the absence of drug treatment, identification of causal polymorphisms through association studies could only occur during clinical phase when a sufficient number of patients could be observed to gain the statistical power needed to draw significant correlations.in silico drug testing could become an indispensible tool during the pre-clinical and clinical phases of new drug development for studying the nature of adverse side effects. In addition, this platform holds obvious potential for analyzing drug efficacy in general and identification of potential beneficent drug side effects that may be useful for drug repositioning and could also be easily adapted for studying combinatorial drug treatment. For a failed drug like torcetrapib, results from this approach could reinitiate the drug development process, providing new insight to help target patients who could benefit from the treatment without the risk of serious adverse side effects.As illustrated above, this approach for The binding site for CETP inhibitors on the CETP structure and the predicted off-target binding sites for this class of drug across the proteome were assumed to be as previously predicted using the SMAP program http://www.pdb.org) corresponding to human metabolic proteins included in Recon1, downloaded from the BiGG database, to their respective gene identifiers as represented in Recon1. The BiGG database requires registration and a password, which can be requested by visiting (http://bigg.ucsd.edu/bigg/home.pl). The UniProt ID mapping tool (http://www.uniprot.org/) was used to map PDB structures corresponding to human proteins to gene identifiers linked to metabolic reactions in Recon1 accounting for all predicted human metabolic protein drug off-targets. All non-human predicted metabolic protein drug off-targets were mapped to their human orthologs using the Basic Local Alignment Search Tool (BLAST) http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene) with respect to predicted drug targets, leading to the reannotation of three Recon 1 GPRs. The overall result of this mapping was that 97 metabolic reactions in Recon1 were linked to 41 predicted CETP inhibitor off-targets.In order to integrate the result of drug off-target predictions with the metabolic network, it was necessary to first map all PDB structures (http://www.pdb.org) and catalytic sites from the Catalytic Site Atlas (http://www.ebi.ac.uk/thornton-srv/databases/CSA/). Ligand-binding sites were defined as amino acid residues lying within 4.5 \u00c5 from atoms of the ligand. Drug-binding sites were defined as residues aligned with the cholesteryl ester binding sites on the CETP structure using SMAP. Overlap between endogenous ligand-binding sites and drug-binding sites was defined by a sharing of any amino acid residues between the sites. The function of predicted drug targets present in Recon1 with at least a partial such overlap was considered to be competitively inhibitable by the drug.The metabolic enzymes predicted as CETP inhibitor off-targets using SMAP were evaluated to determine potential enzymatic inhibition by the drug. The predicted drug-binding sites of the putative off-targets were compared to endogenous ligand-binding sites from existing PDB protein-ligand complex structures  were excluded from docking trials due to size or structural challenges prohibiting a useful docking result for the purposes of binding affinity predictions. All protein structures used in this study were downloaded from the PDB (http://www.pdb.org). Three-dimensional structures for endogenous enzyme substrates were downloaded directly from the PDB if available. If the PDB ligand structure did not exist or was non-functional for docking, the structure was searched for in PubChem (http://pubchem.ncbi.nlm.nih.gov/). The subsequently downloaded SDF file was converted to PDB format using the ChemAxon web applet available at the PDB website (http://www.rcsb.org/pdb/ligand/chemAdvSearch.do). If the three-dimensional ligand structure could not be found in PubChem, the two-dimensional structure was derived from the canonical SMILES http://www.chemaxon.com/marvin/sketch/index.jsp). The three-dimensional structures for glycolipids were derived from their KEGG glycan structures (http://www.genome.jp/kegg/glycan/) using SWEET-II (http://www.glycosciences.de/spec/sweet2/doc/index.php).Enzyme substrates were identified from Recon1 reaction formulas. Certain molecules (HProtein structures were pre-processed for docking using AutoDockTools (ADT) version 1.5.2 Docking was performed using AutoDock Vina http://bigg.ucsd.edu/bigg/home.pl), by performing flux balance analysis (FBA) on the fully unconstrained network optimizing for the given function. Those functions compatible with Recon1 were those that could achieve a positive flux and are summarized in As the preliminary step in modeling human renal function, the scientific literature was reviewed to compile a list of specific metabolic functions of the kidney, with a focus on functions implicated as determinants of blood pressure. This list includes a number of renal reabsorptions and secretions. Each function in this list was tested for compatibility with Recon1, downloaded from the BiGG database  A preliminary model was created by imposing kidney-specific exchange flux constraints representing the metabolic exchanges the kidney carries out with the blood and urine. The preliminary model was initialized by loading Recon1 into the COBRA Toolbox http://www.hmdb.ca/) was queried to derive further evidence in support of allowable exchange fluxes for the kidney. All 407 exchange metabolites in the preliminary model were searched in HMDB for experimental detection in specific biofluids and tissues. Those metabolites detected both in the blood and kidney tissue were assumed to be freely exchangeable in the kidney model, leading to 78 more explicitly unconstrained exchanges beyond what was derived from basic and curated kidney-specific metabolic functions. This assumption is based on the kidney's physiological role of filtering the blood and the observation that if both the blood and kidney contain a metabolite, it must either be exchanged between the two or synthesized separately in both. In the former case, this data provides evidence of that exchange. In the later case, although the model might allow a biologically unrealistic exchange, because the metabolite exists in both blood and kidney, the impact on simulations using the resulting model should be merely quantitative in terms of the maximum renal objective fluxes achievable by the unperturbed model. The integration of gene expression data in the model development process described below should reduce the propensity for biologically unsound metabolic pathway activation that could follow from precursors introduced by any biologically unsound exchanges. Those metabolites detected both in the urine and kidney were assumed to be possible excretions, and exchange constraints were set accordingly. Excretions determined utilizing the urine metabolomics data mostly showed redundancy in determining exchange constraints with exchanges determined using blood data or literature curation with the exception of 4 additional metabolites. The remaining 276 exchange fluxes for which no evidence was found to support were tentatively constrained to 0 flux units.The Human Metabolomics Database (HMDB) , accession GSE803. The two background-subtracted datasets were first normalized using a global normalization factor equal to the sum of probe intensities from the first dataset divided by the sum of probe intensities from the second dataset to account for any systematic differences in procedure between the two experiments. The resulting data were then normalized using the Lowess method Two gene expression microarray dataset for normal, healthy kidney tissue The gene-protein-reaction associations (GPRs) in Recon1 use Entrez Gene IDs to annotate reactions in the network. To map the data from the AffyHG-U95 chips to Recon1, all genes included in Recon1 were mapped to corresponding AffyHG-U95 probesets using Bioconductor Finally, a significant expression threshold was established for subsequent use in the GIMME algorithm. This was done by fitting the normalized gene expression data to a Gaussian distribution, estimating the mean and standard deviation of this distribution, and calculating p-values associated with each data point by subtracting the cumulative distribution function from one. The normalized data value corresponding to the p-value closest to but not exceeding 0.05 was chosen as the significance threshold; this resulted in a threshold of 991.3698 for the normalized expression data.To integrate the renal objective function and kidney gene expression data with the preliminary model to derive a functional kidney model, the GIMME algorithm Gene activity predictions made when deriving the metabolic kidney model were compared to the set of expressed genes with normalized expression values above the significance threshold described above. Activity predictions were also validated against a comprehensive proteomics dataset from normal human kidney glomerulus tissue To evaluate the modeling approach used in this study, a five-fold cross validation was performed in which the data corresponding to the most highly expressed 20% of network-associated genes were excluded before deriving the kidney model. The ability of each approach to correctly predict the activity of these most highly expressed 20% of genes was measured from the overlap of predictions with the highly expressed gene set assuming a hypergeometric distribution, and the resulting probability was Bonferroni-adjusted.All predicted metabolic protein drug off-targets were tested in the kidney model to assess the drug response phenotype caused by inhibitory effects in this system. Inhibition of metabolic proteins by the drug was modeled by constraining corresponding reactions catalyzed by drug targets to 0 flux units. Simulations of the consequences of these drug effects were performed using FBA as implemented in the COBRA Toolbox Single gene deficiencies were also simulated in the kidney model to assess their effects on renal function and their potential as risk factors for treatment with CETP inhibitors. Each of the genes annotated to reactions in Recon1 was knocked-out of the kidney model and simulations were run using the gene-deficient kidney model both with and without drug treatment to assess effects on each individual renal reabsorption and secretion.http://www.ncbi.nlm.nih.gov/omim/).Drug response and metabolic disorder phenotypes were assessed by taking the ratio of maximum gene-deficient, untreated renal function flux to maximum normal, untreated renal function flux. A ratio of less than unity indicates a deleterious phenotype. Predicted metabolic disorder phenotypes were validated against previous clinical studies as represented in the Online Mendelian Inheritance in Man (OMIM) database  by searching for all metabolic disorders related to renal reabsorptions or secretions that are associated with deficiencies in genes included in the reduced kidney model. The resulting list of disorders was manually curated using literature references to identify precisely which metabolic renal reabsorptions and secretions were impacted. These included not only those renal functions captured in Benchmark data was collected from the OMIM database (Dataset S1Reduced kidney model.(0.50 MB XML)Click here for additional data file.Figure S1Genetic deficiencies causing renal metabolic disorders. Elements of the color matrix represent the percent of the maximum normal, untreated renal objective flux achievable by the drug-treated gene-deficient kidney model. The x-axis corresponds to individual renal objective functions, and the y-axis corresponds to the individual gene deficiencies represented by their official gene symbols. Metabolite abbreviations are defined in (0.53 MB TIF)Click here for additional data file.Figure S2Genetic deficiencies causing renal metabolic disorders (continued).(0.48 MB TIF)Click here for additional data file.Figure S3ROC curves for gene-deficient phenotype prediction. The blue line represents the analysis of the predictions of the model simulations presented in this study. The red lines represent the analysis of 100 different permutation trials. The dashed black line is the line y\u200a=\u200ax.(0.11 MB TIF)Click here for additional data file.Figure S4System boundary flux constraint sensitivity. Only those drug targets and renal functions are shown for which a deficient phenotype was predicted. The x-axis is in units of flux. The black star represents the base case which is presented as our primary result.(0.77 MB TIF)Click here for additional data file.Figure S5Degree of drug-induced inhibition sensitivity. Only those drug targets and renal functions are shown for which a deficient phenotype was predicted. The x-axis values correspond to the fraction of maximal enzymatic flux achievable in the untreated simulation, which represents the constraint placed on associated reactions for each simulation. The black star represents the base case which is presented as our primary result.(0.93 MB TIF)Click here for additional data file.Table S1Kidney gene activity predictions. A one indicates that the given gene satisfies the criterion corresponding to that column.(0.15 MB XLS)Click here for additional data file.Table S2Kidney reaction activity predictions. Reactions with at least one non-zero flux bound are predicted active in the kidney model. All other reactions are predicted inactive in the kidney model.(0.74 MB XLS)Click here for additional data file.Table S3Metabolic protein drug target predictions. All predicted metabolic protein targets for CETP inhibitors were subject to multiple levels of analysis to determine their possible causal role in adverse drug response phenotypes. An x indicates a positive result with respect to column labels representing each level of analysis. The proteins are sorted by the number of analyses suggesting a causal role.(0.03 MB XLS)Click here for additional data file.Table S4Summary and validation of gene deficiencies causing renal metabolic disorders. The complete list of gene deficiencies predicted to cause renal metabolic disorders is presented. Specific impacted renal secretions and reabsorptions are also displayed using metabolite abbreviations as represented in Recon1. Clinically observed phenotypes validating the association of these genetic deficiencies with predicted metabolic renal disorders found in the OMIM database and literature are noted. These validated predictions are listed first in the table, and the remaining predictions are sorted by the type of renal disorders caused by the gene deficiencies in simulation.(0.05 MB XLS)Click here for additional data file.Table S5Clinical gene-deficient renal disorder benchmark data. The set of clinically-observed gene-deficient renal metabolic disorder phenotypes collected from the OMIM database are presented that were used to perform AROC analysis. Clinical positives are observed disorder phenotypes with respect to specific metabolite reabsorptions or secretions associated with a gene deficiency, and clinical negatives are disorder phenotypes that were clinically confirmed not to occur in association with a gene deficiency.(0.03 MB XLS)Click here for additional data file."}
+{"text": "This paper presents a modular approach to motion control using a microconlroller-based stepper motor driver. As an application of the driver, an inexpensive and portable one-dimensional robot was built to automate an existing experimental setup for measurement of adsorption isotherms using the McBain-Bakr technique. Automatic recording of position versus time yields data for the sludy of adsorption/desorption dynamics."}
+{"text": "Resistance can be induced in the syngeneic host (August rats) to a myelogeneous leukaemia of spontaneous origin, called SAL, by immunization with allogeneic cells derived form both normal and malignant tissues obtained from the Hooded rat strain. Serological experiments support the conclusion that the antigen involved-referred to as \"Ho-SAL\"-has the properties of a tumour specific transplantation-type antigen for SAL cells but is a widely expressed alloantigen found in both normal and malignant cells derived from Hooded rats. Antisera to it can be raised in Wistar rats."}
+{"text": "Successful detection of apoptosis ex vivo requires the recognition of the initial phase of this process, because at a later stage the cells may not remain any longer in the circulation. We measured quantitatively the amount of early apoptotic peripheral blood lymphocytes directly ex vivo in HIV-1 infected patients using a recently described flow cytometric assay. With this method we observed in an unselected heterogenous group of twelve HIV-infected individuals a median percentage of apoptotic lymphocytes to be significantly higher than in ten healthy controls. To the best of our knowledge this is the first report of ex vivo observed increased apoptosis of peripheral blood lymphocytes in HIV-infected persons.In HIV-1 infection the ongoing depletion of CD4+ T-lymphocytes is believed, to a large extent, to be due to apoptosis. Until now quantitative information about"}
+{"text": "After Hurricane Katrina, the number of reported cases of West Nile neuroinvasive disease (WNND) sharply increased in the hurricane-affected regions of Louisiana and Mississippi. In 2006, a >2-fold increase in WNND incidence was observed in the hurricane-affected areas than in previous years. Hurricane Katrina devastated portions of Louisiana and Mississippi on August 29, 2005. Previous reports of West Nile neuroinvasive disease (WNND) in this area after this hurricane did not examine any statewide increases in 2005 (We used WNV human case data for Louisiana and Mississippi from the Centers for Disease Control and Prevention (CDC)  in the 8-parish region affected by the storm. In the 3 weeks after the storm (CDC weeks 35\u201337), 11 WNND cases were reported in the affected region . This inA similar pattern was observed in Mississippi. In the 3 weeks after landfall, the affected region showed an increase from 0 to 10 WNND cases; the unaffected region of Mississippi showed only a minor increase in cases during the same periods (8 cases before and 10 cases after the storm).To assess potential long-term effects of Hurricane Katrina on WNND incidence, we compared incidence rates of WNND for both states during 2006 with rates during the 4 years preceding the storm (2002\u20132005). Because the hurricane-affected region experienced population displacement, we used special population estimates from the US Census Bureau for rate estimations for 2006  . IncidenOur evidence demonstrates that areas directly affected by Hurricane Katrina experienced increases in WNND cases after the storm compared with before the storm. Analyses of the immediate period after the storm indicate that the observed increase was unique both in time and to the affected region. WNND incidence in 2006 equaled or exceeded the incidence rates in both states during the 2002 epidemic. Because WNND complications are seen in \u22481% of WNV infections (Because our study is based on surveillance data, confounding factors that may bias our analysis should be considered. Although Lehman et al. (The immediate increase in cases may be attributed to increased human exposure to mosquitoes. Tens of thousands of persons in the hurricane-affected region were living in damaged housing or were waiting outside for days to be evacuated. The sudden decrease in WNND cases in the hurricane-affected areas 3 weeks after landfall could be attributed to reduced human exposure caused by eventual evacuation and aerial application of insecticides (Hurricane Katrina was the first major tropical cyclone to make landfall in a large metropolitan area since the 1999 introduction of WNV into the United States. The scale of hurricane damage, especially to residences, may have contributed to increases in WNND. We recommend a region-specific, short- and long-term analysis of arboviral disease to accurately assess the public health effect of natural disasters. Prepositioning mosquito control assets and continuing to provide enhanced emergency assistance for surveillance and control could aid in inhibition of mosquito-transmitted diseases during the immediate period after a hurricane and throughout an extended recovery period."}
+{"text": "A cell-free plasmid reactivation assay was used to determine the fidelity of DNA double-strand break (DSB) repair in a panel of eight DSB repair-proficient human tumour cell lines. Nuclear protein extracts derived from radiosensitive tumour cells were less capable of correctly rejoining EcoRI-induced DSBs than were similar extracts from radioresistant tumour cells. Linear regression analysis suggests that there was a significant  correlation between the fidelity of DSB rejoining and the SF2 values of the cell lines studied. This cell-free assay is clearly sensitive to differences in the nuclear protein composition that reflect the clinically relevant radiosensitivity of these cell lines. The fact that our cell-free assay yielded similar results to previous studies that used intracellular plasmid reactivation assays suggests that those differences in DSB mis-rejoining frequencies in radiosensitive and radioresistant cell lines may be due to inherent differences in nuclear protein composition and are not directly attributable to differences in proliferation rates between cell lines. The underlying cause for this association between DSB mis-rejoining frequencies and radiosensitivity is presently unknown, however restriction endonuclease mapping and polymerase chain reaction (PCR) amplification analysis revealed that approximately 40% of the mis-rejoined DSBs arose as a result of the deletion of between 40 and 440 base pairs. These data raise the possibility that the radiosensitivity of DSB repair-proficient human tumour cell lines may be partly determined by the predisposition of these cell lines to activate non-conservative DSB rejoining pathways."}
+{"text": "The Cavitron Ultrasonic Surgical Aspirator (CUSA) may be used to remove mucosa of organs of thegastro-intestinal tract. A histological analysis was performed on gallbladders treated with aCUSA-mucosectomy to assess the extent and degree of mucosectomy and to evaluate parietal damage.The histological studies performed on three specimens of chronic cholecystitis revealed a completemucosectomy except in areas where Rokitansky-Aschof sinuses were present. There was no evidence ofparietal damage. The CUSA may be used to remove the mucosa of gallbladders without injury to otherlayers, and may have a potential application in procedures such as mucosal cholecystectomy."}
+{"text": "Data on survival endpoints are usually summarised using either hazard ratio, cumulative number of events, or median survival statistics. Network meta-analysis, an extension of traditional pairwise meta-analysis, is typically based on a single statistic. In this case, studies which do not report the chosen statistic are excluded from the analysis which may introduce bias.In this paper we present a tutorial illustrating how network meta-analyses of survival endpoints can combine count and hazard ratio statistics in a single analysis on the hazard ratio scale. We also describe methods for accounting for the correlations in relative treatment effects (such as hazard ratios) that arise in trials with more than two arms. Combination of count and hazard ratio data in a single analysis is achieved by estimating the cumulative hazard for each trial arm reporting count data. Correlation in relative treatment effects in multi-arm trials is preserved by converting the relative treatment effect estimates (the hazard ratios) to arm-specific outcomes (hazards).A worked example of an analysis of mortality data in chronic obstructive pulmonary disease (COPD) is used to illustrate the methods. The data set and WinBUGS code for fixed and random effects models are provided.By incorporating all data presentations in a single analysis, we avoid the potential selection bias associated with conducting an analysis for a single statistic and the potential difficulties of interpretation, misleading results and loss of available treatment comparisons associated with conducting separate analyses for different summary statistics."}
+{"text": "The potential for the modification of the pharmacokinetics of doxorubicin (DOX) concurrently administered with high-dose verapamil (VER) has been investigated in 17 patients with advanced neoplasms refractory to drugs belonging to the multidrug resistance spectrum. Steady-state concentration of DOX, systemic clearance and urinary excretion were analysed. No significant difference was found between the kinetic parameters estimated for DOX at different levels of VER and those reported for doxorubicin as single agent. It can be concluded that VER does not appear to modify DOX kinetics."}
+{"text": "The diagnosis and follow-up of patients with bladder cancer rely on invasive procedures (cystoscopy with biopsy). Polymerase chain reaction (PCR)-based technologies may allow the sensitive detection of cancer-related genetic mutations in exfoliated tumour material, potentially allowing the development of less invasive techniques. This pilot study investigated the feasibility of detecting mutations in exons 5\u20138 of the p53 gene using single-stranded conformational polymorphism (SSCP) analysis in bladder-washing specimens from patients with bladder cancer. Bladder-washing samples (31) were collected from patients (27) with bladder cancer. An abnormal additional SSCP band was detected in five samples from five different patients suggesting the presence of a p53 mutation. In all five cases the same abnormal SSCP pattern was demonstrated in samples of the corresponding bladder tumour. In one case bladder washings were available from the same patient on two separate occasions with one washing demonstrating a mutation and the other not. In two further cases a mutation was demonstrated in the bladder tumour but not in the corresponding washing. It is concluded that it is possible to detect and characterize p53 mutations in bladder-washing samples from patients with bladder cancer. Improved sensitivity in detecting mutations in a sample containing a mixture of normal and malignant cells may lead to the clinical applicability of molecular methods of disease monitoring. \u00a9 2000 Cancer Research Campaign"}
+{"text": "Case-control studies and outbreak investigations are the major epidemiological tools for providing detailed information on enteric disease sources and risk factors, but these investigations can be constrained by cost and logistics.We explored the advantages and disadvantages of comparing risk factors for enteric diseases using the case-case method. The main issues are illustrated with an analysis of routine notification data on enteric diseases for 2006 collected by New Zealand's national surveillance system.Our analyses of aggregated New Zealand surveillance data found that the associations (crude odds ratios) for risk factors of enteric disease were fairly consistent with findings from local case-control studies and outbreak investigations, adding support for the use of the case-case analytical approach. Despite various inherent limitations, such an approach has the potential to contribute to the monitoring of risk factor trends for enteric diseases. Nevertheless, using the case-case method for analysis of routine surveillance data may need to be accompanied by: (i) reduction of potential selection and information biases by improving the quality of the surveillance data; and (ii) reduction of confounding by conducting more sophisticated analyses based on individual-level data.Case-case analyses of enteric diseases using routine surveillance data might be a useful low-cost means to study trends in enteric disease sources and inform control measures. If used, it should probably supplement rather than replace outbreak investigations and case-control studies. Furthermore, it could be enhanced by utilising high quality individual-level data provided by nationally-representative sentinel sites for enteric disease surveillance. In most developed countries, information on enteric disease epidemiology comes from a range of routine sources, outbreak investigations and case-control studies conducted outside of the context of an outbreak. The most accessible information comes from routine compilations of pathogen-specific surveillance data. This source usually provides important information on demographic, temporal and geographic trends and can be used both to identify potential outbreaks and to monitor trends that may suggest potential exposure sources. Maintaining and analysing these data are a routine part of infectious disease surveillance. Outbreak investigations are a necessary extension of public health surveillance and are particularly critical where the source of an outbreak is not well established. However, risk factors and sources of disease identified in the context of an outbreak may not always reflect the major transmission pathways for the disease agent in the general population. Case-control studies aiming to investigate risk factors and sources of disease outside of outbreaks may be the best way to characterise transmission pathways for the disease within populations and for sporadic (non-outbreak) cases. However, such studies are expensive, and go beyond the capacity of many public health agencies.For example, in the country we are most familiar with , case-control studies have proved useful in identifying risk factors for sporadic enteric infections including campylobacteriosis -5, giardA potentially less expensive analytic approach, that may be less susceptible to recall bias, is the case-case method. This is a variant of the case-control design that was first described in the 1980s when applied to cancer epidemiology . In infeWe explored the advantages and disadvantages of the case-case method for studying risk factors for enteric diseases using routine surveillance data, through comparisons with other studies (mainly case-control studies). Domains that were considered on the basis of our understanding of the enteric disease epidemiological literature were: (i) selection bias among cases; (ii) selection bias among controls (or comparison cases in this instance); (iii) information and recall bias; (iv) confounding; and (v) lack of detail of exposures.A worked example of case-case analyses for risk factor comparisons used the routine national notification data on enteric diseases for New Zealand in 2006. These data are collected by the public health services of District Health Boards and published by the Institute of Environmental Science and Research Ltd (ESR), a national disease surveillance and reference laboratory organisation . CompariNotification data in New Zealand come from medical practitioners who are legally required to report \"notifiable diseases\" to their local Medical Officer of Health. Some laboratories have also provided this information to health authorities on a voluntary basis . Standardised forms used for enteric disease notifications include risk factor questions and these are usually completed by public health staff interviewing cases over the telephone. However, due to resource constraints, this risk factor collection is far from complete (see Table The results for the nine risk factors for which data are routinely collected are detailed in Table Significantly elevated crude odds ratios were apparent for overseas travel and shigellosis (OR = 24), giardiasis (OR = 5.6) and salmonellosis (OR = 3.7). Elevated crude OR were also evident for consumption of untreated drinking water for giardiasis (OR = 2.9), cryptosporidiosis (OR = 2.7) and salmonellosis (OR = 1.3). For the latter three diseases, this pattern was also evident for contact with recreational water (as it was for shigellosis as well).Contact with farm animals and contact with sick animals were apparent risk factors for cryptosporidiosis (OR = 2.8 and OR = 7.1 respectively). For contact with symptomatic people all diseases except yersiniosis had elevated OR. This pattern also held for contact with confirmed cases . Contact with human faecal matter had elevated OR for all diseases except salmonellosis and shigellosis.There were some diseases where the OR were significantly lower than for the reference disease of campylobacteriosis. That pattern was seen for all the diseases, except shigellosis, for consumption of food from a food premise; and for both salmonellosis and shigellosis for contact with farm animals. These findings may suggest that these risk factors are significantly more important for campylobacteriosis than for these other diseases in the New Zealand context.Our comparative analyses of enteric disease risk factors using the case-case method and routine surveillance data identified some important limitations with this approach. These limitations are illustrated with examples drawn from New Zealand's infectious diseases surveillance systems:A possible selection bias is that risk factor exposures among the study cases may be atypical because the cases are not representative of all cases in the population . For exSimilar selection bias may also occur in case-control studies which use notified or laboratory-confirmed cases. Arguably, there is greater potential for selection bias with case-control studies where cases are derived from notifications but where controls are recruited from a difference source .A specific limitation of case-case analysis is that the estimated strength of the exposure-disease association is strongly influenced by the level of exposure reported by the comparison cases. If the exposure was a protective factor for the comparison cases (those with the reference disease), then this analysis would tend to over-estimate the strength of association. By contrast, if the exposure is also a risk factor for the reference disease, then this type of case-case analysis will under-estimate the strength of the association. Changes in the pattern of exposure among the comparison cases could result in spurious changes to the estimated exposure-disease association, and this possible explanation should be considered where associations change over time. However, given that the exposures reported for these diseases are all well-established risk factors for most enteric diseases, results from this risk factor comparative analysis will tend to be conservative . Examples of this are the results for \"overseas travel\" and for \"food consumption from a food premise\" Table  where thInformation biases may occur in a case-case analysis due to biased investigator data collection or respondent recall of exposure. The systems for collecting risk factor information from cases of notifiable enteric diseases are often heterogeneous, particularly in countries where health systems vary at district or regional levels. For example, in New Zealand information collection can involve interviews by communicable disease clerks, health protection officers or even self-completion of printed questionnaires by cases. Both case investigators and cases are usually aware of the specific enteric disease diagnosis when risk factor data are being collected. Information bias may therefore occur as some of these risk factors may be well known by case investigators and cases themselves . This situation could result in improved or even false recall of exposure to specific well-known risk factors or to exposures which are widely viewed as risk factors for enteric infections, increasing the observed association with the disease. However, as for case-case studies, case-control studies are also likely to be affected by such recall biases. Indeed, recall bias is likely to be a larger problem for case-control analyses involving community controls, as such controls will not have had a gastro-intestinal infection to stimulate recall of known or suspected causes of these diseases.There are numerous potential confounders in any case-case analysis using aggregated routinely collected enteric disease surveillance data . These effects may be reduced through using comparison cases with other laboratory-confirmed enteric infections, though this is certainly not guaranteed. Appropriate adjustment for these potential confounders using individual data may well be worthwhile once improvements in surveillance data quality are made . Consequently, the findings do not provide a particularly strong basis for taking specific public health action to reduce exposures to these sources. This limitation could be reduced by improved data collection with greater detail, specificity and completeness of the exposure data. This expansion could extend to a \"shotgun\" type questionnaire to provide a tool for rapid hypothesis generation for use in outbreak situations . The obvious trade-off would be the additional time and resources required to obtain detailed exposure history information. As noted later in the Discussion Section, this extension could be facilitated through the use of sentinel data collection sites.The scope of specific exposures recorded in routine surveillance data is always going to be restricted and in the New Zealand example it was limited to just nine. Furthermore, some of these risk factors were quite broad in nature  cryptosporidiosis and shigellosis. Also, by being easier to undertake, these case-case analyses may be more readily made a routine part of ongoing national surveillance activities. Indeed, community controls for case-control studies are becoming very difficult and expensive to obtain due to the low participation rate from telephone recruitment methods .E. coli [A further relative advantage of the case-case approach could be timeliness as the analyses can use already collected case data. This requirement is particularly important in some rapidly evolving outbreaks, such as may occur where a widely distributed food is contaminated with a serious disease causing agent such as verotoxigenic E. coli . ControlFor the worked example using New Zealand surveillance data it is apparent that the associations are fairly consistent with other published New Zealand evidence about risk factors for specific enteric diseases eg:\u2022 Overseas travel and shigellosis based on an outbreak investigation  and also\u2022 Drinking water and giardiasis based on case-control studies -9 and al\u2022 Contact with farm animals and cryptosporidiosis based on an outbreak investigation . Of note\u2022 Contact with confirmed cases and giardiasis has not been specifically assessed in previous New Zealand studies but the risk associated with human waste exposure is well documented for this country based on case-control studies ,9,35 whiThe finding that there were some diseases with an OR that was statistically significantly lower than for the reference disease of campylobacteriosis was also not surprising. That is because there is good evidence from many studies that contaminated food  is an important risk factor for campylobacteriosis in New Zealand ,36.The findings therefore suggest that case-case analysis using routine data may provide supplementary information on risk factors for enteric diseases. Repeated over time, this approach could potentially provide further information on progress with disease prevention interventions . But interpreting apparent trends for an enteric disease would need a lot of additional contextual information, including changes in exposure experienced by the comparison cases with the reference disease(s).Results Section.It is also conceivable that these case-case analyses could identify newly emerging risk factors if repeated periodically  and act as a trigger for more in-depth investigations. Nevertheless, we would argue against any of these routine uses of such case-case analyses with current New Zealand data until further work is done to assess the importance of the biases detailed in the Results Section, we recommend that countries wishing to undertake supplementary case-case analyses with routine enteric disease surveillance data ensure that they have high quality data collection processes. For New Zealand, this would mean reducing the large proportions of \"unknowns\" as listed in Table Given the considerations detailed in the preceding Sentinel surveillance is \"surveillance based on selected population samples chosen to represent the relevant experiences of particular groups\" . This apWe are not aware of New Zealand examples of sentinel surveillance where additional exposure or risk factor information is collected on a sample of cases on an ongoing basis. However, there are several diseases where considerable risk factor/exposure data are collected on all cases, with HIV/AIDS being probably the best example . SimilarDeveloping sentinel surveillance system for gastrointestinal illness could reduce most of the limitations of case-case analyses described above (the one exception being selection bias among comparison cases). Sentinel surveillance could reduce selection bias among cases by putting greater effort into obtaining faecal specimens from patients presenting with gastroenteritis. Information/recall biases could be reduced by shortening the time delay before interviewing cases . Confounding could be reduced by collecting more complete data from cases allowing for adjusted analyses of individual level data. Lack of detail of exposures could be reduced through the use of highly detailed questionnaires covering important disease sources (the \"shotgun\" type questionnaires referred to above).Some of the extra cost of running these sites could be offset by a reduced need for collecting routine risk factor data in the non-sentinel areas . If sentinel sites were appropriately resourced then they could also run case-control studies, case-case studies (between strains) and case-crossover studies that would allow direct comparisons with the cruder case-case method used here. For case-control studies the controls could possibly be selected from the general practices involved in notifying the cases (given the difficulty in recruiting community controls in many developed countries). This approach could provide an established population of controls to facilitation rapid outbreak investigation ie a \"control bank\" ,43.Despite various inherent limitations, case-case analyses using routine surveillance data have the potential to supplement other studies to assist in monitoring risk factor trends for enteric diseases. They may also help with monitoring the impact of interventions and could potentially provide a base for rapid outbreak investigations. Nevertheless, adopting this approach may need to be accompanied by moves to: (i) reduce potential selection and information biases by improving the quality of the surveillance data; and (ii) reduce confounding by undertaking more sophisticated analyses of individual data. These improvements could be facilitated by establishing high quality sentinel sites for enteric disease surveillance. For the particular New Zealand data studied, it was apparent that the case-case analyses of enteric diseases data produced information that was consistent with findings from local case-control studies and outbreak investigations. That observation adds support for the use of this type of case-case analysis for investigating sources and studying the impact of control measures for enteric diseases.The lead author (NW) has previously undertaken contract work in 2005 for the government agency involved in foodborne disease control (the NZ Food Safety Authority). The other authors declare that they have no competing interests.NW was responsible for data collation and analysis. All authors were involved in interpreting the results and drafting various versions of the article. All authors read and approved the final manuscript."}
+{"text": "TRALI is considered a serious hazard among immune complications             of blood transfusion and its occurrence is admitted to be globally underestimated.             Each type of blood product is likely to cause TRALI. We report here on two             consecutive observations of TRALI caused by red blood cell concentrates, in             which anti-HLA class I and class II antibodies resulting from post-gravitational             allo-immunization were evidenced in donors. HLA class I and II antigenic             community between recipients and donors' husbands were found and strong              reacting IgG antibodies directed at several of those common antigens were              detected in the donors' serum. Both donors had more than 3 pregnancies, raising              the issue of             blood donor selection or of plasma reduction for cellular products."}
+{"text": "Hfq is a bacterial protein involved in several aspects of nucleic acid transactions, but one of its best-characterized functions is to affect the post-transcriptional regulation of mRNA by virtue of its interactions with stress-related small regulatory (sRNA).By using cellular imaging based on the metallothionein clonable tag for electron microscopy, we demonstrate here that in addition to its localization in the cytoplasm and in the nucleoid, a significant amount of Hfq protein is located at the cell periphery. Simultaneous immunogold detection of specific markers strongly suggests that peripheral Hfq is close to the bacterial membrane. Because sRNAs regulate the synthesis of several membrane proteins, our result implies that the sRNA- and Hfq-dependent translational regulation of these proteins takes place in the cytoplasmic region underlying the membrane.This finding supports the proposal that RNA processing and translational machineries dedicated to membrane protein translation may often be located in close proximity to the membrane of the bacterial cell. Hfq is an abundant and phylogenetically conserved bacterial protein involved in several aspects of nucleic acid transactions. One of its best-characterized functions is to affect the post-transcriptional regulation of mRNA translation by virtue of its interactions with small regulatory noncoding RNAs (sRNAs). The identification of these sRNAs in bacteria has recently increased dramatically and a number of studies showed that they contribute to the responses to stress conditions such as oxidative-, envelope- or osmotic stress ; mouse anti-MT monoclonal antibody purchased from Abcam . Secondary antibodies conjugated with 10 or 15 nm colloidal gold particles were provided by BBInternational . Immunolabeling of ultra-thin sections was performed following procedures previously described in detail Cryosections were obtained in a ultracryomicrotome (Leica EM FCS) operating at \u2212120\u00b0C by the standard Tokuyasu method and processed for immunogold labeling as described earlier"}
+{"text": "Selective internal radiation therapy (SIR therapy) is a technique whereby metastatic liver cancer is irradiated by embolising microspheres containing the radionuclide yttrium-90 into the hepatic arterial circulation. To date this technique has not been used as an adjuvant therapy, but rather to treat established metastases in the liver. This study evaluated the use of two intrahepatic radiation doses delivered on radioactive microspheres for the treatment of small, growing micrometastases. Three groups of five rats were each inoculated with tumour spheroids into the portal vein. The resultant liver micrometastases were treated with either 10 or 20 MBq of yttrium-90 microspheres or a sham dose of non-radioactive microspheres injected into the portal vein 2 days following tumour inoculation. The livers of each animal were examined for the presence of metastases after a further 21 days and liver function tests were performed. At the time of sacrifice there was no obvious normal liver damage in any of the rats treated with microspheres. The livers of the sham-treated animals contained extensive signs of tumour deposition. A mean of 34 tumours were taken from the livers of each of the sham-treated animals, whereas only a single tumour was found in one animal treated with 10 MBq of yttrium and eight small tumours from two animals treated with 20 MBq. Liver function tests demonstrated a significant short-term increase in alkaline phosphatase levels in the radiation-treated animals compared with shams, but there were no other indications of any effects on liver function. These results indicate a potential role for SIR therapy in an adjuvant setting with colorectal cancer."}
+{"text": "An enzyme-linked immunosorbent assay (ELISA) was developed in which a tumour-specific component of human squamous-cell carcinoma of the lung could be readily detected using an absorbed rabbit antiserum. This antiserum did not react with equivalent preparations made from pooled normal lung tissue. In a study using the coded sera from normal individuals and preoperative patients subsequently shown to have Stage I bronchogenic carcinoma of various histological types, we found that the patients' sera effectively inhibited the reaction between the rabbit antiserum and the partially purified tumour antigen, whereas the serum from normal individuals did not."}
+{"text": "Other sarcomas at the same anatomic sites were also studied. Controls were females diagnosed with cancers other than sarcoma during the same time period (n = 266 444). Cases and controls were then compared with respect to history of a prior invasive epithelial breast cancer. A history of breast cancer increased the risk of upper extremity angiosarcoma by more than 59-fold . A strong increase in risk after breast cancer was also observed for angiosarcoma of the chest and breast  and for other sarcomas of the chest and breast . \u00a9 1999 Cancer Research CampaignLymphangiosarcoma of the upper extremity is a rare and aggressive tumour reported to occur following post-mastectomy lymphoedema (Stewart\u2013Treves syndrome). Haemangiosarcoma, a related rare tumour, has occasionally been reported to occur in the breast following irradiation. We conducted a case-control study using the University of Southern California-Cancer Surveillance Program, the population-based cancer registry for Los Angeles County, to evaluate the relationship between invasive female breast cancer and subsequent upper extremity or chest lymphangiosarcoma and haemangiosarcoma together referred to as angiosarcoma. Cases were females diagnosed between 1972 and 1995 with angiosarcoma of the upper extremity ("}
+{"text": "Polyclonal antibodies have been raised in rabbits to a haemocyanin adduct of a reductively-activated, fluorinated analogue of misonidazole. Fluorescence immunohistochemical studies show that the polyclonal antibodies bind to spheroid sections and tumour sections in patterns similar to those revealed by autoradiographic studies with a tritium-labelled derivative of the fluorinated misonidazole analogue."}
+{"text": "We describe ten patients with a clinical diagnosis of primary progressive aphasia (PPA)  who developed abnormal laughter-like vocalisations in the context of progressive speech output impairment leading to mutism. Failure of speech output was accompanied by increasing frequency of the abnormal vocalisations until ultimately they constituted the patient's only extended utterance. The laughter-like vocalisations did not show contextual sensitivity but occurred as an automatic vocal output that replaced speech. Acoustic analysis of the vocalisations in two patients revealed abnormal motor features including variable note duration and inter-note interval, loss of temporal symmetry of laugh notes and loss of the normal decrescendo. Abnormal laughter-like vocalisations may be a hallmark of a subgroup in the PPA spectrum with impaired control and production of nonverbal vocal behaviour due to disruption of fronto-temporal networks mediating vocalisation. Three canonical clinical syndromes have been described: progressive non-fluent aphasia (PNFA) where there is impairment of articulation (commonly an apraxia of speech) and agrammatism; semantic dementia (SD) where there is progressive breakdown of conceptual knowledge; and the logopenic or phonological variant of PPA (LPA) where there is a decreased speech rate with word-finding pauses and anomia Here we describe a group of patients with progressive aphasia who exhibited abnormal laughter-like vocalisation (LLV) that increasingly replaced speech as the disease evolved, until ultimately LLV was the only extended utterance produced by these patients.2In the period between 1996 and 2007, ten patients were ascertained via the Specialist Cognitive Disorders Clinic of the National Hospital for Neurology and Neurosurgery with a clinical syndrome of reduced speech output accompanied by excessive LLV. All patients fulfilled consensus criteria for PPA or FTLD at presentation During the period these cases were ascertained, a total of 210 patients with a diagnosis of PPA presented to the clinic. Based on this series, the estimated prevalence of LLV in PPA is therefore of the order of 10/210 or 5%. This may be an underestimate as many patients were not followed as their disease progressed. Over the same time period, no patients attending the clinic with an alternative neurodegenerative diagnosis  exhibited LLV, suggesting that the prevalence of the syndrome in other degenerative diseases (though undefined) is very low.3Normal laughter has a characteristic acoustic signature and quantitative data are available We analysed recorded samples of LLV from two patients in this series (Cases 2 and 5) using an acoustic software package PRAAT, . Both paTo further assess the specificity of the syndrome, we analysed random samples of laughter from two female patients with a diagnosis of a neurodegenerative dementia  who did not have the clinical syndrome of abnormal laughter. Qualitatively, laughter in these patients tended to occur in conversational pauses and was broadly appropriate to social or emotional context (though the patient with bvFTD laughed in the context of fatuous humour). Quantitative analysis  revealed4Here we have characterised a syndrome of abnormal laughter-like vocal output accompanying mutism in a series of patients with PPA. While LLV frequently occurred in a conversational setting, it was not modulated by conversational pauses or other cues and there was no evidence the patients recognised their own laughter as abnormal. LLV was not associated with features of corticobulbar dysfunction or with abnormal crying or other overt emotional displays, suggesting the LLV syndrome is pathophysiologically distinct from the pathological laughter that frequently accompanies diseases with involvement of the corticobulbar tracts. While other behavioural changes did develop in a majority of cases, this was not inevitable . Taken tThe abnormal LLV syndrome we have characterised is also unlike other forms of pathological laughter in neurological disease. Pathological laughter can be defined as involuntary laughter in the absence of a congruent emotion, and has a variety of disease associations Although laughter has attracted the attention of clinicians and scientists for many years Based on the clinical and acoustic and evidence presented here, we propose that some patients with PPA develop abnormal LLV as a specific functional derangement of fronto-temporal networks for the regulation and production of nonverbal vocalisations. Highly organised behaviours such as laughter are mediated by distributed cerebral networks"}
+{"text": "Similar cells (in terms of size and sensitivity to anti-theta serum) were detected in both assays. However, while lymphoid cells from animals at all stages post-MSV infection were active in protecting irradiated mice from the lethal effect of induction of MSV sarcomata, cells from animals at early stages post-MSV infection (when the tumour was in a progressive phase of growth) were not active in the in vitro assay. By manipulation of the in vivo assay conditions a situation was observed in which cells from \u201cprogressor animals\u201d were able to suppress both the in vitro and in vivo activity of regressor lymphoid cells. The potential physiological role of this cell type is disussed.A comparison was made between the cells responsible for demonstrable activity against MSV antigens, using both"}
+{"text": "Both obesity and over-expression of HER II are associated with poor prognosis of breast cancer. In vitro experiments suggest that anti-tumour activity of the anti-obesity drug Orlistat is likely to be due to transcriptional suppression of HER II expression. The overexpression of HER II is also positively correlated with other markers of prognosis of breast cancer such as cathepsin expression.The hypothesis we tested was that the obese women with breast cancer might over-express HER II more often than their lean counterparts to account for the poor prognosis.One hundred consecutive patients were included in this study. Their body mass indexes were correlated with overexpression of HER II.There was also no association between oestrogen or progesterone receptor positivity and obesity or HER II over expression in premenopausal or post-menopausal women with breast cancer.The present study demonstrated that the poor outcome of breast cancer in obese patients is not due to over expression of HER II. Obesity leads to poor prognosis in women diagnosed with breast cancer even in early stage disease as shown in systematic literature reviews, several large-scale cohort studies and critical reviews such as the Nurse's Health study and cancer prevention study II -9. The wRecent in vitro experiments suggest that anti-obesity agents Orlistat may have anti-tumour activity which is likely to be due to transcriptional suppression of HER II expression . OrlistaOver-expression of HER II is also associated with a poor prognosis of breast cancer as HER II over-expression playS an important role in the development, aggressive behaviour of breast cancer. Overexpression of HER II has been associated with other markers of poor prognosis of breast cancer such as cathepsin D .The hypothesis we tested was that the obese women with breast cancer over-express HER II more often than their lean counterparts to account for the poor prognosis in obese women.One hundred consecutive patients were included in this study. Their height, weight and body mass index were correlated with overexpression of HER II.\u00ae. The borderline cases were tested with fluorescence in situ hybridisation (Abbott Path Vision)\u00ae.The criteria of HER II over expression were used as per Pan Birmingham Protocol. The HER II over expression was measured by immunohistochemistry (DAKO)Using the chi(2)-test, relationships were determined between marker labelling and histological type of cancer, tumour grade, tumour size, axillary lymph node status and age of patient. A p value below 0.05 was considered significant.2 there is no significant trend in the proportions who are HER positive or negative within these categories Figure All results are summarised in table Obesity is associated with poor prognosis of breast cancer. The exact mechanism by which obesity affects the outcome of breast cancer is not fully understood. HER II overexpression is associated with poor prognosis of breast caner. The present study demonstrated that the poor outcome of breast cancer in obese patients was not due to overexpression of HER II. The present study is in concordance with another small-scale study that showed no association obesity and erbB-2 expression without the use of Fluorescence in-situ hybridisation (FISH) . The preThe relationship between obesity and steroid hormone receptors is complex and controversial. Several relationships have been reported and refuted. Our study is in concordance with other reports, which show no reliable association between steroid hormone receptor and obesity in breast cancer patients."}
+{"text": "In France, there are 35\u2009000 new cases of breast cancer each year. There are various areas where clinical research is active, including benign tumours and risk factors for malignant transformation, biological evolution of normal and cancerous cells, prevention, screening, diagnosis, therapeutic strategies, rehabilitation and maintenance of quality of life.in situ carcinomas have not been included (these will be covered in a specific document). In addition, breast cancer with a genetic predisposition (BRCAX) will not be specifically covered in this document.This document concerns the diagnosis and therapeutic management of nonmetastatic breast cancer, and does not cover screening or prevention. This is a summary of an update  project, which started in 1993, involves a collaboration between the Federation of French Cancer Centres (FNCLCC), the 20 French Regional Cancer Centres, several French public university and general hospitals, private clinics and cancer-learned societies. The main objective of the SOR project is to develop clinical practice guidelines which can be used to improve the quality of health care and outcomes for cancer patients. The methodology is based on a literature review, followed by critical appraisal by a multidisciplinary group of experts to produce draft guidelines which are then validated by specialists in cancer-care delivery. The details of the methodology used for developing these SOR have been described previously  provided a complementary updated bibliographic search (1999 to October 2000). After selection and critical appraisal of these articles, the members of the working group drafted the SORs.A multidisciplinary working group was set up by the FNCLCC. References to pertinent articles were identified by the global bibliographic monitoring process of MEDLINE, set up in 1996 and by specific searches in other databases such as Standards\u2019 identify clinical situations for which there exist strong indications or contraindications for a particular intervention and \u2018Options\u2019 identify situations for which there are several alternatives, none of which have shown clear superiority over the others  and a French summary version , can be complemented by other views and by ultrasonography (standard). The equipment used for mammography should undergo regular quality control (standard). To confirm the diagnosis, additional views and enlargements may be necessary (option).Specific imaging is not indicated in the examination of lymphadenopathy. Standard reporting of mammograms should be used in which the stated diagnosis is based on the mammographic features suspicious of malignancy using the American College of Radiology classification (recommendation).The diagnostic findings should be discussed by a multidisciplinary team. When the level of suspicion from imaging justifies histological verification, this should be done using interventional breast diagnostic techniques in an outpatient setting under a local anaesthetic.The diagnosis of malignancy can be obtained from cytology (fine-needle aspiration) or tissue sample (core biopsy), whereas the diagnosis of an invasive carcinoma can only be made from a biopsy sample (standard).in situ, lobular carcinoma in situ and atypical hyperplasia from a needle biopsy sample should always be reconfirmed using a sample obtained by surgical excision . Regular assessment of the diagnostic performance of image-guided biopsy systems is recommended .The histological diagnosis of impalpable lesions should be compared with the diagnostic hypotheses generated from diagnostic imaging (recommendation). The diagnosis of ductal carcinoma Examination of frozen sections is not indicated for isolated clusters of microcalcification or for a tumour measuring less than 10\u2009mm (standard). It is indicated in other cases where it is likely to modify the surgical plan (standard). This examination should not jeopardise the quality of the excised sample and therefore the reliability of the final histological diagnosis (standard).the size of the malignant lesion(s) (in mm);the histological type;the histological grade (specifying the grading system used);in situ (DCIS);the percentage of any ductal carcinoma the presence of peritumoral vascular invasion;the status of the surgical margins, including that of all additional excised samples.The standard histological report should mention the findings from the diagnostic work-up and all factors necessary for establishing the prognosis:For an invasive tumour, the measurement of the infiltrating component should be given, including data from macroscopic and microscopic examinations (recommendation). The overall size of the lesions  can be documented .If there is intraductal carcinoma only, the size of the lesions should be assessed by combining the findings from the radiological and histopathological examinations (recommendation). If this assessment is difficult , the number of \u2018positive\u2019 sections out of the total number of sections examined should be stated .the distance (in mm) between all malignant foci and the nearest excision margin ;the nature of the tumour lesion  nearest to the surgical margin.The quality of the excised sample is defined by two criteria (recommendation):In cases where the surgical margin is invaded by tumour, the extent of this should be specified .the sites and number of malignant lesions;the size of the malignant lesions (in mm);the histological type of the tumour;the histological grade (specifying the grading system used);the percentage of DCIS, if present;the presence of peritumoral vascular invasion;the presence of extension into the nipple ;the presence if any of cutaneous or pectoralis major fasciomuscular involvement.The standard histological report for a mastectomy sample should state the details of the diagnostic work-up and those factors required to establish the prognosis:For an invasive tumour, the extent of the invasive component should be given, integrating data from macroscopic and microscopic examinations (recommendation). The overall extent of the lesions  can be documented .If there is intraductal carcinoma only, the size of the lesions should be assessed by integrating the data from radiological and microscopic examinations (recommendation). If this assessment is difficult , the number of \u2018positive\u2019 sections out of the total number of sections examined should be given .All lymph nodes removed by axillary dissection should undergo full histological examination using a series of macroscopic sections (standard).the number of lymph nodes examined;the number of metastatic lymph nodes, including the presence of micrometastases and if a sentinel node biopsy was performed before axillary dissection (standard);the number of metastatic lymph nodes with capsular rupture.The standard histological report for the samples from axillary dissection should specify:Optimal quality for axillary examination requires sampling from at least 10 lymph nodes . This is usually achieved by a level I/II axillary dissection . Surgical guide marks should be made to orientate the sample, at least at one end (standard). The technique of sentinel node biopsy may avoid axillary dissection in 85\u201390% of patients without lymph node involvement (level of evidence: B1), but cannot be recommended until the results of ongoing studies are available . This technique requires input from a multidisciplinary team experienced in the area .in situ carcinomas (standard). The coding of lesions can be performed using the CIMO/SNOMED system (WHO classification) and/or the ADICAP system (French classification) (option).The standard histological classification of breast cancer is that developed by the World Health Organisation (WHO) (standard). The standard for histo-prognostic grading is that developed by Elston and Ellis (standard). This is applicable to all invasive cancers with the exception of medullary carcinomas and in situ carcinomas (standard).There is no indication to undertake a metastatic screening before the confirmation of a diagnosis of an invasive carcinoma (standard). This is also true for If a mastectomy is planned, a metastatic screening should be performed prior to surgery to avoid unnecessary surgery in women who already have metastatic disease, even if the probability is low (recommendation). In the absence of symptoms, a metastatic screening should only be performed after evaluation of the metastatic risk factors (see section on Prognostic factors) (recommendation). Assays of CA 15.3 and other tumour markers should not be done during the initial work-up because of their low sensitivity . At a more advanced stage of disease, they are often elevated but have no diagnostic value. Tumour markers can sometimes be used as a reference when poor prognostic factors are present (option). No study has shown an independent prognostic value for tumour markers. Nonspecific markers, such as CA 125, CA19-9 and TPA, should not be assayed (standard).It is essential to perform a clinical examination of the axillary region even though it is imprecise . Lymph node involvement generally progresses towards the apex of the axilla . Tumour size is the principal risk factor for lymph node involvement . Histologically confirmed axillary involvement, tumour size and young age are the main predictive factors for internal mammary node involvement . The influence of the tumour site is controversial.in situ component associated with the invasive component, high-grade tumour, the presence of peritumoral vascular invasion and inappropriate treatment.The most important clinical factors are young age (under 35 or 40 years old) and premenopausal status. The most important histological factors are: positive excision margins and the presence of an extensive ductal The most important clinical factors are young age (under 35 or 40 years old), tumour size and axillary node involvement. The histological factors with the strongest prognostic value are tumour size, histologically confirmed node involvement, the number of axillary nodes involved (\u2a7e4), a high-grade tumour and positive excision margins. The presence of peritumoral vascular invasion is also a predictive factor for metastatic disease.Hormone receptor status should be determined in all cases of invasive disease (standard), using either a biochemical or immunohistochemical method (standard). The analysis for overexpression of c-erbB-2 should not be performed on a routine basis (standard). The predictive factors for response to chemotherapy, including c-erbB-2, are in the process of being evaluated. Cellular proliferation should be assessed in all infiltrating tumours, using either the mitotic index, S phase fraction measurement or Ki67 immunohistochemical assay . Quality control is mandatory in all laboratories irrespective of the prognostic test performed (standard).Irrespective of the surgical technique used, tumour excision should be complete with negative margins and should be adapted to the tumour size and the breast volume (standard). The optimal size of excision to ensure negative margins has not been defined (standard).When breast-conserving surgery is to be undertaken, the aesthetic result should be acceptable to the patient (standard). Central tumours can be treated in a conservative manner if excision is complete (sometimes requiring excision of the nipple\u2013areolar complex) (option).Modified radical mastectomy is equivalent to radical mastectomy in terms of local control and survival (standard). Breast-conserving treatments with lumpectomy followed by radiotherapy are equivalent to mastectomy in terms of local recurrence and survival . Subcutaneous mastectomy should not be considered for invasive or noninvasive breast cancer .There appears to be no technique available to assess the risk of sequelae (particularly lymphoedema) following surgery to this anatomically complex and strategic area where several different lymphatic regions converge . Early physiotherapy for the shoulder and the thoracic wall is by far the most significant preventative treatment. Informing patients of the best means of prevention remains the best means of preventing lymphoedema. Lymphatic drainage is not indicated as a preventative measure (recommendation).Radiotherapy reduces the risk of mortality due to breast cancer . However, it may increase the risk of long-term cardiovascular mortality if an inappropriate technique is used. Breast, chest wall or lymph node irradiation should be performed with caution, with the aim of limiting the irradiation of healthy tissue, while satisfying quality assurance criteria (standard). The dose prescription is standardised ) .After breast-conserving surgery, breast radiotherapy should always be performed, using a minimum dose of 50\u2009Gy in 25 fractions . Breast irradiation after breast-conserving surgery significantly reduces the risk of local recurrence irrespective of the initial disease stage . In women under 50 years old, a boost should be administered routinely to the tumour bed even when the margins are clear . Guidelines from an expert committee of the French Society of Oncological Radiotherapy  cover thIrradiation of the internal mammary lymph nodes is indicated in all cases of axillary lymph node involvement  and when the tumour is medial or central . Irradiation of the infra- and supraclavicular lymph nodes is indicated in the presence of axillary lymph node involvement . The omission of lymph node irradiation, as defined above, is only justified in the setting of a randomised clinical trial .The choice of immediate breast reconstruction should not jeopardise the optimal use of locoregional radiotherapy and systemic treatment (recommendation). After axillary dissection, radiotherapy to the axilla should be avoided as much as possible because of the increased risk of locoregional complications .Anthracycline-containing polychemotherapy is currently the most commonly used regimen in France and is more efficacious than the CMF regimen: cyclophosphamide, methotrexate and fluorouracil (5-FU) . This is supported by the conclusions from the NIH consensus conference .Adjuvant chemotherapy improves progression-free survival and overall survival in patients with node-positive breast cancer and in certain patients without node involvement. Premenopausal women seem to benefit more than menopausal women.Doxorubicin, epirubicin, 5-FU, cyclophosphamide and methotrexate used in combination every 3\u20134 weeks, with a maximum of six cycles, is the reference treatment. The optimal number of cycles (four to six cycles) is unknown. Chemotherapy should be started promptly. The efficacy of perioperative chemotherapy has not been clearly proved, and should only be undertaken in the setting of a randomised clinical trial. High-dose chemotherapy, with or without stem cell infusion, is under evaluation and cannot be considered as a therapeutic standard. The optimal dose for epirubicin remains to be determined. Taxanes have not yet been shown to offer any benefit as adjuvant or neoadjuvant treatment.Induction or neoadjuvant chemotherapy is an option in operable breast cancer where first-line breast-conserving surgery is not possible, in the absence of multifocal lesions, and where the patient would prefer breast conservation (option). Compared with adjuvant therapy, induction or neoadjuvant therapy has no effect on survival but has been shown to avoid mastectomy in more than 50% of women. The risk of local recurrence is higher than with a primary mastectomy and the possibility of breast-conserving surgery is reduced. After neoadjuvant chemotherapy, locoregional treatment should be performed in the same manner as that used for first-line locoregional treatment (standard).In premenopausal women, the combination of hormone therapy with adjuvant chemotherapy does not lead to a significant improvement in global survival or progression-free survival. This may be due to the low number of young women treated with tamoxifen and/or the lack of stratification for hormone receptor status in previous studies . However, the practice was recommended in November 2000 by the NIH consensus conference .\u22121 . Patients treated with tamoxifen should have regular gynaecological clinical examinations . Additional examinations are not necessary in the absence of symptoms.Treatment with adjuvant tamoxifen is beneficial, despite its side effects, irrespective of the patients\u2019 age, if the tumour expresses oestrogen receptors . Tamoxifen should not be prescribed to women with tumours that do not express oestrogen receptors . The optimal duration for adjuvant hormone therapy with tamoxifen is 5 years at a dose of 20\u2009mg\u2009dayNeoadjuvant treatment with antioestrogens can be used in elderly women with slowly evolving hormone-sensitive tumours . This should be followed when possible by optimal locoregional treatment . At present, antioestrogens cannot be considered as standard neoadjuvant treatment for initially operable tumours.suppression of ovarian function in women with ovarian activity and/or as an antioestrogen,antioestrogenic therapy in postmenopausal women.Hormone therapy can be administered for different reasons, depending on the patients\u2019 age:In postmenopausal women, the combination of chemotherapy with an antioestrogen significantly improves progression-free survival and overall survival . The ratio of efficacy  and risk (toxicity) should be considered when taking the decision to prescribe this combination. The efficacy/risk ratio favours treatment in women with major metastatic risk factors .Other hormone therapy  should not be considered as adjuvant treatments except in the setting of a randomised clinical trial (standard).transverse rectus abdominis myocutaneous) pedicle flaps and microanastomosed free flaps (option).When mastectomy is necessary to obtain local control and the patient would prefer immediate breast reconstruction, multidisciplinary consultation is essential to assess the need for locoregional (irradiation) or systemic (chemotherapy or hormone therapy) treatment. Breast reconstruction is not a cancer treatment but is an integral component of breast cancer care (standard). It can be performed immediately or be delayed, but should never interfere with the administration of other treatments (chemotherapy and/or radiotherapy) (standard). Poor prognosis is not a contraindication for breast reconstruction (standard). However, the patient's performance status and/or a high risk of recurrence of the disease can be relative contraindications (standard). The patient should participate in the final decision (standard). There are three main techniques for reconstruction: submuscular inplant, latissimus dorsi flap or TRAM . Painful scarring (leading to limited mobility of the arm/shoulder) and lymphoedema are the most frequently observed complications after surgery. The aesthetic result depends on the quality of the surgery and radiotherapy technique (standard). Aesthetic problems do not occur following chemotherapy alone, but are observed when chemotherapy is used concomitantly with radiotherapy (standard). Visual analogue scales of well being are useful for assessing quality of life. Fatigue has a significant impact on quality of life and can be related to treatment and/or a depressive reaction. This should always be taken into consideration by the physician and its importance should not be underrated. Questionnaires exist for assessing fatigue and quality of life (standard).Surgery and/or radiotherapy are used for the locoregional control of the disease.in situ is not covered in this document. The therapeutic management of impalpable tumours is often a stepwise process guided by the histological results of the previous intervention. The patient should be informed right from the start about the risks associated with repeated interventions.First decisional step : There is no specific data concerning the risk of progression of microinvasive cancers. The recommendations are the same as those proposed for invasive cancers : Modified radical mastectomy followed by immediate breast reconstruction should be offered (standard).\u2013 Clear margins and no residual microcalcifications: The breast should be irradiated (standard). Modified radical mastectomy can be considered if the patient refuses conservative treatment (option). Axillary dissection or axillary radiotherapy may also be performed (option). In the absence of known risk factors for metastatic recurrence, adjuvant systemic treatment should not be given .\u2013 Involved margins and/or residual microcalcifications: Mastectomy is the standard treatment (standard). Re-excision and breast radiotherapy, or axillary dissection and radiotherapy can be performed (option). If re-excision does not provide clear margins, mastectomy should be performed (standard).\u2013 \u25cb  cancers .\u2013 ExtenInvasive cancer . In the event of lymph node invasion, radiotherapy to the chest wall and lymph nodes  should be performed (standard).\u2013 Clear margins and/or absence of residual microcalcifications: The standard procedure is axillary dissection and breast radiotherapy (standard). If the patient presents with lymph node involvement, this should be followed by lymph node irradiation  (standard). It is also possible to irradiate the lymph nodes without axillary surgery (option).\u2013 Invaded margins and/or presence of residual microcalcifications: Modified radical mastectomy should be performed (standard). In the event of lymph node involvement, this should be followed by the chest wall and lymph nodes  irradiation (standard). Re-excision combined with axillary dissection, followed by breast radiotherapy can be undertaken. Breast radiotherapy with a boost to the tumour bed can also be considered (option).\u2013 \u25cb e cancer :\u2013 ExtenThe therapeutic strategy for ductal carcinomas A single palpable localised tumour can be completely excised with a wide margin . The standard procedure is to undertake re-excision and breast radiotherapy (standard). This should be followed by a boost to the tumour bed if the patient is under 50 years old (standard) or has other risk factors (option).If a boost to the tumour bed and/or re-excision is performed, the aesthetic result should be satisfactory . If the patient refuses re-excision, breast radiotherapy with a boost to the tumour bed can be considered (option). Modified radical mastectomy can also be considered (option).\u2013 When re-excision is impossible . Modified radical mastectomy should be performed (standard). Immediate breast reconstruction can be considered if there are no other risk factors for locoregional recurrence and/or this does not prejudice the administration of additional treatment (option).\u2013 .\u25cb Positive excision margins .Third decision step .\u2013 Central and/or medial tumour\u2003The internal mammary chain should be irradiated (standard). Infra- and supraclavicular radiotherapy can also be considered (option). Nodal irradiation for low-risk tumours is not recommended, and is currently under evaluation.\u2013 Irrespective of the tumour localisation, axillary radiotherapy should not be performed in the absence of histologically proven nodal involvement .\u2013 \u25cb Presence of axillary node involvement: Screen for distant metastases (standard) and irradiate infra- and supraclavicular plus internal mammary nodes (standard). If extensive nodal involvement is present, the whole of the axillary region can be irradiated (option). Radiotherapy should only be omitted in the setting of a randomised clinical trial (option).\u25cb First decision step: A metastatic screen should be undertaken (standard) .\u25cb Presence of risk factors for local recurrence: Chest wall radiotherapy is indicated (standard).\u25cb Third decision step  for oestrogen receptors (option)  . Clinical follow-up should then be repeated every 6 months for 5 years and then yearly for 10 years (standard). Routine follow-up should be continued after 10 years, but the timing can be adjusted depending on the risk of local recurrence (option). An annual mammogram should be performed starting 6 months after treatment (standard).Routine clinical examination forms the basis of follow-up for the thoracic wall and the lymph node areas after treatment for breast cancer.Clinical examination and a mammogram should be performed at the same frequency as above for the follow-up of the conserved breast .History taking and clinical examination form the basis of follow-up (standard). In the absence of symptoms or signs, a routine screen for metastases is not indicated . If a metastasis is found, the patient should undergo a full work-up . The frequency of general clinical follow-up is the same as that for locoregional follow-up .Rehabilitation should start before treatment with clear specific information about possible post-treatment complications and how they can be prevented and/or managed (standard). Functional problems of arm or shoulder movement require early physiotherapy (standard). Lymphoedema can be treated with physical methods and systemic therapy (recommendation). Coumarin is no longer indicated because of its toxicity and lack of efficacy (standard).To avoid weight gain, dietary advice should be provided routinely (recommendation). Sexual problems should be evaluated and treated (recommendation). The need for contraception and family planning advice should be discussed individually taking into consideration each patient's preference (recommendation).Hormone replacement treatment for postmenopausal symptoms should not be prescribed after treatment for breast cancer, except in specific cases. The prescription of hormone replacement treatment after breast cancer is being evaluated prospectively. Nonhormonal treatments exist for the various symptoms (recommendation).Psychological support may well be required at some stage during the management process (option). Social support, to strengthen the psychological support, should be provided routinely to help patients and their families (option). Patient rehabilitation groups can contribute to the psychosocial support of patients (option).Local recurrence should be treated with surgery. Radiotherapy should not be considered except in specific cases (standard). The standard treatment is a simple total mastectomy (standard). Immediate reconstruction can be considered (option). If oestrogen receptors are present, additional hormone therapy is recommended (recommendation).Breast-conserving surgery can only be considered if the patient refuses mastectomy or if mastectomy is technically impossible. In this case, the patient should be informed of the high risk of recurrent disease (recommendation). As the efficacy of additional chemotherapy is unknown, this should only be considered in the setting of a randomised clinical trial .There is no standard (standard). Chemotherapy can be considered, followed if possible, by local treatment that may or may not be curative (options). Local treatment (surgery and/or radiotherapy) for symptom control can also be considered (option).Chemotherapy is appropriate for an inflammatory recurrence. Radiotherapy can be considered if there are contraindications for chemotherapy (option). When possible, mastectomy should be performed for a locally advanced recurrence (option). If this is not possible, chemotherapy or radiotherapy should be given with the aim of making the lesion operable (option). Irrespective of the treatments administered, the indications for additional medical treatment will be the same as those for potentially curable isolated recurrences ."}
+{"text": "Stimulation of CFE by CS occurred in adrenalectomized rats but was inhibited by treatment of rats with an anti-inflammatory steroid, dexamethasone. CFE was stimulated by CS in tumour immunized rats; the inflammatory state did not prevent the expression of immunity but \u201crescued\u201d a proportion (approximately 20%) of the injected tumour cells from immunodestruction in the lungs. A higher proportion of tumours grew in the paws of rats when a small number of W-256 cells were injected interdigitally into the acute inflammatory swellings produced by the local injection of paws with LH or CS.Acute inflammatory reactions were induced in rats by the intravenous injection of cellulose sulphate (CS) or an extract of normal rat lung homogenate (LH), or by intraperitoneal injections of Compound 48/80. These treatments greatly increased survival and clonogenic growth in the lungs of rats of intravenously injected allogeneic W-256 and Y-P388 tumour cells. Increase in the dose of intravenously injected CS caused a logarithmic increase in colony forming efficiency (CFE) of tumour cells in the lungs. CFE was not stimulated by the intravenous injection of rats with pharmacological mediators of inflammation (histamine, 5-hydroxytryptamine, bradykinin and prostaglandins PGECS is a \u201csynthetic heparin\u201d which causes marked prolongation of blood clotting time and also increases fibrinolytic activity of the blood. Anticoagulant treatment of rats with heparin did not affect CFE. Thus, there was no direct correlation between blood clotting time and CFE of blood borne tumour cells in the rat.The mechanisms which may be responsible for the nonspecific growth promoting effects of inflammatory reactions induced by various types of tissue injury on tumour induction and growth are discussed."}
+{"text": "Brain metastases are a common complication of non-small-cell lung cancer (NSCLC). The role of chemotherapy in the treatment of brain metastases has not been clearly defined. Emerging case reports of patients with recurrent NSCLC treated as part of the Expanded Access Programme reveal that gefitinib  has clinical activity in some patients with brain metastases. Here, we describe a number of case studies documenting the response of patients with brain metastases to treatment with gefitinib. Many of these patients had quality-of-life benefits with improvement of neurological and systemic symptoms; some had a partial response of their brain metastases and even complete responses have been seen in a few patients. One case report also describes a durable long-term response with concurrent treatment with gefitinib and radiotherapy. Such results call for larger trials designed to evaluate and define the role of gefitinib in the treatment of brain metastases in NSCLC patients, either as a single agent or in combination with radiation therapy. Brain metastases are a common complication for patients with non-small-cell lung cancer (NSCLC) and a significant cause of morbidity and mortality. Radiotherapy remains the mainstay of treatment for brain metastases; however, patients treated with whole-brain radiation still have a poor prognosis with a median survival of only 3\u20134 months  and 105% (P<0.001), respectively. The preliminary results of a Phase II study also show modest activity of gefitinib in patients with recurrent glioblastoma  is an orally active, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that blocks signal transduction pathways implicated in the proliferation and survival of cancer cells. High levels of EGFR are frequently found in malignant primary brain tumours  have described promising activity in patients with brain metastases. Here, we accumulate these results and discuss the possible implications and future directions.The case reports of patients with brain metastases secondary to NSCLC treated with gefitinib as part of the compassionate-use programme have recently been reported as published case studies . In this case study, a 55-year-old male exsmoker with stage IV NSCLC and multiple pulmonary (lymphangitic) metastases developed multiple brain metastases  after receiving treatment with gefitinib for >1 year  . Of these, three patients had a complete response, 10 a partial response, eight had stable disease and four patients had progression of their brain metastases. In all of these case reports, treatment with gefitinib appears to have been well tolerated. Any reported adverse events are consistent with the adverse-event profile of gefitinib established in Phase II trials in patients with advanced NSCLC , an opinion also expressed by P450 3A isoenzymes, including CYP 3A4, which has been identified as the isoenzyme primarily involved in the metabolism of gefitinib. Therefore, coadministration of dexamethasone may lead to increased metabolism of gefitinib, with consequently lower plasma concentrations and potentially reduced efficacy. In addition, such studies would need to use standardised patient staging to identify and monitor asymptomatic as well as symptomatic brain metastases.A consideration for such future studies in patients with brain metastases is the optimum dose of gefitinib if dexamethasone is also being administered. Dexamethasone is an inducer of cytochrome in vitro and in vivo (A number of preclinical studies support the combined use of radiotherapy and gefitinib as a strategy for cancer treatment (In summary, a number of case reports suggest activity of gefitinib against brain metastases secondary to advanced NSCLC. Larger trials are needed to validate these findings and further investigate the potential of combined gefitinib and radiotherapy treatment."}
+{"text": "Epidermal growth factor (EGF) receptor expression in 31 primary human bladder tumours was quantitated using both structural and functional assays and the EGF receptor gene in the same tumours was analyzed by Southern blot analysis. Immunocytochemical studies using the EGFR1 monoclonal antibody (Mab) showed a significant correlation between EGF receptor levels and the stage and grade of the tumours. Autophosphorylation assays employed to evaluate the receptor's tyrosine kinase activity gave results which in general were consistent with the immunocytochemical data. Using internally controlled immunocytochemical studies with two Mabs and Southern blot analysis of DNA isolated from the tumours, no evidence was obtained for the production of truncated receptors similar to those encoded by the v-erb-B oncogene. Gene amplification was not found in any of the superficial tumours, but one invasive tumour with high EGF receptor expression had an 8-10 fold amplification of the EGF receptor gene. The EGF receptor isolated from this tumour showed a normal pattern of tyrosine phosphorylation at all three major autophosphorylation sites. Our detailed study is consistent with the correlation previously found between EGF receptor expression and stage and grade of bladder tumours, and suggests that at this level of analysis EGF receptors in bladder tumours are not abnormal in structure or size, autophosphorylation activity, or gene structure."}
+{"text": "Many health care practitioners use a variety of hands-on treatments to improve symptoms and disablement in patients with musculoskeletal pathology.Research to date indirectly suggests a potentially broad effect of manual therapy on the neuromotor processing of functional behavior within the supraspinal central nervous system (CNS) in a manner that may be independent of modification at the level of local spinal circuits. However, the effect of treatment speed, as well as the specific mechanism and locus of CNS changes, remain unclear.We developed a placebo-controlled, randomized study to test the hypothesis that manual therapy procedures directed to the talocrural joint in individuals with post-acute ankle sprain induce a change in corticospinal excitability that is relevant to improve the performance of lower extremity functional behavior.This study is designed to identify potential neuromotor changes associated with manual therapy procedures directed to the appendicular skeleton, compare the relative effect of treatment speed on potential neuromotor effects of manual therapy procedures, and determine the behavioral relevance of potential neuromotor effects of manual therapy procedures. identifier NCT00847769. Many health care practitioners use a variety of hands-on treatments to improve symptoms and disablement in patients with musculoskeletal pathology. Often, these manual procedures purport to target specific musculoskeletal structures, such as joints, muscles, or fascia. Procedures that historically have been relevant to joint structures may be placed on a continuum of speed and amplitude. Mounting scientific evidence supports statistically significant and clinically important benefits of manual therapy in subgroups of patients with various forms of musculoskeletal disablement affecting the axial region -3 and apVarious central and spinal sensorimotor mechanisms of manual therapy procedures recently have been investigated. Inhibition of the Hoffman reflex following spinal manipulation and increased lower extremity muscle strength have been observed following manual therapy directed to the lumbopelvic region in several studies. -14 ManuaTaken together, these results suggest a potentially broad effect of manual therapy on the neuromotor processing of functional behavior within the supraspinal CNS in a manner that may be independent of modification at the level of local spinal circuits. However, several important limitations of existing studies continue to constrain our collective understanding of the CNS changes associated with the clinical effects of manual therapy in patients with musculoskeletal disablement. The use of non-disabled volunteers in the majority of existing research to date may provide limited information regarding the specific effects of mobilization and manipulation in patients with disablement due to pain and weakness. The use of spinal manual therapy as a subject of study potentially jeopardizes the specificity of conclusions that can be drawn, since spinal manipulation is poorly localized even in skilled and experienced practitioners. The abseOne promising research design for determining the underlying neural mechanism associated with manual therapy involves the talocrural joint. There are a number of advantages for using the talocrural joint as an experimental preparation for studying the neurophysiological effects of manual therapy procedures. These include (i) the relatively large size of the talocrural joint, (ii) the relatively large size of the muscle groups crossing this joint, and (iii) the talocrural joint is subject to a prevalent injury that may be identified on the basis of a simple history and clinical examination. The large size of the talocrural joint suggests manual therapy procedures may be more specifically directed to this region than a smaller joint of the spine. The relatively large size of the muscles crossing the talocrural joint provide for easily reproducible recording sites for transcranial magnetic stimulation with electromyographic recording (TMS/EMG). Valid and reliable behavioral measurements for talocrural joint range of motion and lower extremity functional behavior exist. These measurements will allow for empirical examination of the relationship between short-term CNS neuroplasticity and the changes in functional behavior that have been elucidated by clinical studies.The purpose of this paper is to describe methodology for using the talocrural joint as an experimental preparation to study the neuroplastic CNS changes associated with mobilization and manipulation. The specific aims of this study are to (1) determine the same-day test-retest reliability of TMS/EMG in individuals with post-acute ankle sprains, (2) quantify corticospinal excitability in individuals with post-acute ankle sprains receiving HVLA ankle manual therapy, slow ankle manual therapy, and control intervention; and (3) relate changes in corticospinal excitability in individuals with post-acute ankle sprains receiving HVLA ankle manual therapy, slow ankle manual therapy, and control intervention to short-term changes in lower extremity function.Subjects with post-acute ankle sprains (n = 27) will be enrolled into the study. Inclusion criteria include (i) subject age between 18\u201360 years, (ii) onset of ankle sprain at least 2 weeks prior to enrollment, (iii) Foot and Ankle Ability Measure Activity of Daily Living subscale score >20%, and (iv) ankle dorsiflexion range of motion limitation greater than 2 standard deviations from published values. ExclusioA total of 27 subjects will be recruited for this study (n = 9 per group). This sample size will provide >80% statistical power to detect differences in lateral star balance excursion performance based on an effect size d = 1.47 from Hale and colleagues[Subjects each begin with pre-intervention TMS measures (motor thresholds and input-output curves), ankle range of motion (ROM) tests, and lower extremity functional behavior tests. Each pre-intervention measurement will be taken a total of 2 times with a 30 minute rest break between measurements. Subjects will then be randomized into 1 of 3 comparison groups, each to receive a different manual therapy intervention. Immediately following the intervention, subjects will receive post-intervention TMS measures, ankle ROM tests, and lower extremity functional behavior tests, identical to the pre-intervention assessments.All subjects who meet the inclusion and exclusion criteria will be eligible for participation Figure . PotentiAfter informed consent is obtained, subjects will receive pre-intervention testing. Pre-intervention testing will include:2) will be used to carry out all TMS studies. A Double Cone 110-millimetre (mm) coil that provides sufficient depth of penetration to reliably stimulate cortical representation of ankle musculature will be used in this study. Subjects from each intervention group will undergo TMS testing both pre- and post-intervention. The primary motor cortex of the hemisphere contralateral to the impaired ankle will be tested. The pre-intervention session will consist of (i) identifying optimal coil position ('hot spot') and motor threshold (MT) for the target leg muscles , (ii) conducting input-output (IO) curve studies of both muscles, (iii) input-output curve studies will be conducted both with the muscles at rest and with the muscles pre-activated (active contraction condition). The pre-activated condition is required to generate cortical silent period data.A single-pulse magnetic stimulator  samples beginning 100 ms before TMS onset . For the active contraction condition the subject will be asked to perform maximal dorsiflexion and maximal plantarflexion against a load cell, with care taken to minimize contribution from other muscle groups at the thigh or pelvis. The largest of three attempts is taken as the maximum voluntary contraction force (MVC).To determine optimal TMS coil location and orientation, TMS pulses are delivered while the subject contracts the ankle musculature and at an inter-stimulus interval of 5\u201310 seconds. The coil is initially placed at the vertex and the optimal scalp position for TMS ('hot spot') is determined by moving the coil a few centimetres (cm) in each direction from this position and observing the site at which the largest motor evoked potential (MEP) is produced at supra-threshold intensities. The initial muscle contraction serves to facilitate induction of MEPs and is used to aid in finding the motor hot spot.Brainsight\u2122 Frameless is a stereotactic image guidance system that will facilitate the positioning of the TMS coil over a subject's brain Figure . With BrMT is defined as the lowest TMS intensity required to elicit a small, clearly discernable MEP at least 50% of the time . Within a given individual, MT is stable across TMS sessions which assures that suprathreshold TMS intensities expressed as a percentage of MT can be reliably compared between TMS sessions.The following procedure for determining active MT will apply for testing the tibialis anterior and gastrocnemius. Active contraction corticomotor excitability data will be collected with the muscles at 10% of the subject's MVC. The coil is oriented and positioned with the handle of the coil pointing backward to induce posterior to anterior current flow across the primary motor cortex. For determination of active MT, the subject makes a steady, minimal background contraction against a load cell (10% of MVC) with the help of audiovisual feedback. TMS pulses are delivered while the subject contracts and at an inter-stimulus interval of 5\u201310 seconds. The coil is initially placed at the vertex. Optimal coil location for TMS ('hot spot') is determined by moving the coil a few cm in each direction from this position and observing the site at which the largest MEP is produced at supra-threshold intensities. This optimal coil location is then marked on the 3D MRI using Brainsight and the coil is fixed at this location on the scalp using a clamp and external support. TMS intensity is then decreased by 1\u20132% intervals. TMS MT for the muscle is the TMS intensity where at least 5 of 10 responses generate peak-to-peak MEP amplitudes of at least 50 \u03bcV for the resting condition and 100 \u03bcV for the active contraction condition. Alterations in corticomotor system excitability will be assessed as changes in MEP and cortical silent period duration (CSP) input-output curve characteristics between pre- and post-intervention time points for the three groups. TMS intensities for this study will be expressed as a percentage of MT.Input-output (IO) curves will be generated by keeping the TMS coil at its optimal hotspot and varying TMS intensity  at 5% intervals from 95% (subthreshold) to 140% (suprathreshold) of MT. At all intensities, 8 single-pulse TMS stimuli will be delivered under each of 2 conditions: (i) at rest and (ii) simultaneous with an active contraction of the muscle (5\u201310 seconds between stimuli). The order of TMS intensities will be varied randomly.Silent period durations depend largely on the intensity of the TMS stimulus delivered over the 'hot spot' of a pre-activated target muscle. The active muscle contraction condition will be standardized by (i) using audio-visual feedback provided to the subject for consistent levels of muscle contraction (10% MVC) and (ii) triggering TMS discharge when EMG activation is maintained at 10% MVC. As such, CSP durations will be obtained during IO curve studies. At each trial, the duration of the silent period will be calculated as the time between (i) when rectified EMG activity drops below average pre-TMS EMG activity (10% MVC) and (ii) when rectified EMG activity rises above that average pre-TMS EMG activity.max, the plateau of the relation, (ii) the stimulus intensity (S50) required to obtain a response 50% of the maximum, (iii) and the maximum slope parameter.The relationship between the size of the MEP and the duration of the silent period versus stimulus intensity can be illustrated as a sigmoidal shape. As such, measured characteristics of the IO curve will be extracted using the Boltzmann sigmoidal function to fit the data points by the Levenberg-Marquard nonlinear least-mean-squares algorithm. The BoltIn order to determine whether potential changes in TMS-assessed corticospinal excitability pre- and post-intervention are spinally and/or centrally mediated the Hoffmann (H) reflex will be performed. The H reflex is considered the electrical analogue of the tendon stretch reflex. Since it bypasses the effects of gamma motoneurons and muscle spindle discharge, it can be used as a method for assessing spinal reflex excitability in intact human subjects before and after intervention. The H-reSubjects are positioned prone with the leg to mid thigh exposed. The active electrode is placed 1/3 of the distance up from the intermalleolar line to the popliteal fossa . The reference electrode is located midline of the Achilles tendon. The skin will be marked in order to decrease the variability of pre-post testing electrode placement. The ground is placed between the stimulator and electrodes  and the amplifier is positioned at the hip away from electrodes.Stimulation will be at the popliteal fossa with the top prong (cathode) placed in the middle of the fossa and superior to the bottom prong. The \"Positive\" end of the stimulator (anode) is positioned inferiorly toward the ankle. The arrow on the stimulator points in the direction of the current flow. In this case, we want the current flowing proximally toward spine. With the pulse width for stimulation set at 1 ms, stimulation is started at a low intensity. Intensity is increased in 1 milliampere (mA) increments. The stimulator delivers pulses at regular intervals (pulse width = 1000 ms) to the Ia afferents. Intensity is gradually increased until an H wave appears. At this point, intensity is increased at 1\u20132 mA per discharge until the H wave reaches maximum, starts to decrease and the M-wave appears. Intensity is now increased in larger increments (5\u201310 mA) until the H wave completely disappears and the M-wave reaches a maximum.Following the second TMS MT measurement, all subjects will receive 2 different ankle ROM measurements. In the first measurement, subjects will lay prone on a padded table. A single blinded and standardized examiner will measure ankle dorsiflexion ROM with the knee fully extended and then flexed to 90 degrees using a 15.24 cm goniometer in a standard manner. This meaFollowing the ankle ROM tests, all subjects will receive a measurement of lower extremity functional behavior involving a star balance excursion test (SBET) conducted on a single limb. The SBET is a clinical test of dynamic balance. SubjectsSubjects will be randomized into 3 groups after pre-participation screening is completed, informed consent is obtained, and baseline measures are recorded. The first group (n = 9) will receive an HVLA procedure directed to the talocrural joint  software tool for analysis of time-series data (dataWizard). Each TSBET measurements will be indexed to lower limb length as measured from anterior superior iliac spine to medial malleolus prior to data analysis. Two-sample t-tests with appropriate correction will be used to determine the statistical significance of differences in pre- and post-intervention ankle DF ROM, SEBT performance, and MEP/CSP data. Test-retest reliability and minimum detectable change will be determined for the 2 baseline measurements of MEP/CSP data.,38 PearsFor all TMS, ROM, and lower extremity functional behaviour variables, two-factor multivariate analysis of variance with repeated measures for time will be used to determine the effects of repeated baseline testing and the intervention under study on SBET performance and ankle ROM measurements. Significant main effects will be reported if there are no significant interactions. If significant interactions are found, then one-way analysis of variance will be completed for each variable. Post-hoc testing will be performed as necessary with appropriate correction to determine the significance of pairwise comparisons. Pearson correlations with appropriate statistical correction will be used to test the significance of associations among ankle DF ROM, SBET measurement, and TMS/EMG variables within subjects.This study protocol describes one of the first reported feasible study methodologies to date that is designed to identify potential neuromotor changes associated with manual therapy procedures directed to the appendicular skeleton. We believe the large muscles associated with the talocrural joint and ability to localize the procedure to the talocrural joint will better elucidate potential neuromotor effects of manual therapy procedures than the studies to date that have focused on spinal procedures. Further, we will be able to compare the relative effect of treatment speed on potential neuromotor effects of manual therapy procedures in the context of a controlled study. Also, this study will provide the ability to make inferences regarding the functional relevance of changes in corticospinal excitability through the use of measurements of lower extremity range of motion and functional behavior. These characteristics will allow this study's data to further our understanding of appropriate clinical management of individuals with many forms of musculoskeletal dysfunction.The authors declare that they have no competing interests.BEF, TED, KK, and AW contributed to the design of this study protocol. TE Davenport provided research funding.The pre-publication history for this paper can be accessed here:"}
+{"text": "The accumulation of mutant protein is a common feature of neurodegenerative disease. In Huntington's disease, a polyglutamine expansion in the huntingtin protein triggers neuronal toxicity. Accompanying neuronal death, mutant huntingtin aggregates in large macromolecular structures called inclusion bodies. The function of the machinery for intracellular protein degradation is linked to huntingtin toxicity and components of this machinery colocalize with inclusion bodies. An increasing body of evidence implicates the ubiquitin-proteasome pathway in the failure of cells to degrade mutant huntingtin. A number of potential mechanisms that link compromised ubiquitin-proteasome pathway function and neurodegeneration have been proposed and may offer opportunities for therapeutic intervention."}
+{"text": "Four human cell lines derived from malignant gliomas were immunohistochemically examined for their content of estramustine-binding protein (EMBP). EMBP was detected in a large amount in all glioma cells during the entire cell cycle. EMBP has previously been demonstrated to be the major receptor protein in prostatic cancers for the cytostatic drug estramustine-phosphate (EMP). EMP caused a dose-dependent inhibition of exponentially growing cells by increasing the number of cells in G2/M stage of the cell cycle as monitored by flow cytofluorometry. The effect may be coupled to arrest of the glioma cells at metaphase. The presence of EMBP may suggest a selective binding and effect of EMP in glioma cells."}
+{"text": "Infection of long-term BDF1 marrow cultures with Friend leukaemia virus complex (FLV) induced transformed cells with myelomonocytic characteristics, which were isolated only 14 days after the viral infection. Criteria for transformation were growth in suspension cultures and high plating efficiency in agar. The lymphatic leukaemia virus (LLV) replicates in these suspension cultures, but the spleen focus-forming virus (SFFV) component of the FLV complex has not been detected. Injection of the transformed cells into syngeneic neonatal or adult mice leads to the development of leukaemia which can be demonstrated to be of donor origin by the presence of two metacentric marker chromosomes which are also seen in the cultured cells."}
+{"text": "The effects of a single intramuscular iron dose, 10mg, to pregnant rats on Day of pregnancy, on theoutcome of pregnancy, with respect to foetal weight and mother\u2019s immune function has been investigated.Despite significantly elevated hepatic iron stores after iron supplementation in pregnant rats this had nosignificant effect upon blood haemoglobin or transferrin saturation levels. However the mean weight of thefoetuses at Day 20-21 was significantly lower than that of the non-supplemented pregnant rats. Ironsupplements significantly increased the activity of NADPH oxidase in the maternal alveolar macrophages,the primary event in the formation of the phagolysosome to combat invading organisms. However induciblenitric oxide synthase activity was significantly reduced in these macrophages as shown by decreases in LPSinducedand LPS+IFN\u03b3-induced NOS activation. Iron supplementation to rats of normal iron status at thecommencement of pregnancy did not show any beneficial effects to either the foetus or the mother."}
+{"text": "Neutrophil function has been assessed in 62 patients with lymphoreticular malignancy by means of the NBT test and an in vitro micro-organism killing technique. Normal or enhanced phagocytosis was found, the greatest enhancement being found in patients with disseminated disease (in the absence of infections). Candicidal capacity alone was depressed in 7 patients but 4 of these showed depressed cell-mediated immunity to Candida antigen. Splenectomy, radiotherapy and chemotherapy did not alter phagocytic function."}
+{"text": "In a recent paper written by Hilbe et al , the nature and specificity of the prion protein deposition in the kidney of feline species affected with feline spongiform encephalopathy (FSE) were clearly considered doubtful. This article was brought to our attention because we published several years ago an immunodetection of abnormal prion protein in the kidney of a cheetah affected with FSE. At this time we were convinced of its specificity but without having all the possibilities to demonstrate it. As previously published by another group, the presence of abnormal prion protein in some renal glomeruli in domestic cats affected with FSE is indeed generally considered as doubtful mainly because of low intensity detected in this organ and because control kidneys from safe animals present also a weak prion immunolabelling. Here we come back on these studies and thought it would be helpful to relay our last data to the readers of BMC Vet res for future reference on this subject.Here we come back on our material as it is possible to study and demonstrate the specificity of prion immunodetection using the PET-Blot method (Paraffin Embedded Tissue - Blot). It is admitted that this method allows detecting the Proteinase K (PK) resistant form of the abnormal prion protein (PrPres) without any confusion with unspecific immunoreaction. We re-analysed the kidney tissue versus adrenal gland and brain samples from the same cheetah affected with TSE using this PET-Blot method. The PET-Blot analysis revealed specific PrPres detection within the brain, adrenal gland and some glomeruli of the kidney, with a complete identicalness compared to our previous detection using immunohistochemistry. In conclusion, these new data enable us to confirm with assurance the presence of specific abnormal prion protein in the adrenal gland and in the kidney of the cheetah affected with FSE. It also emphasizes the usefulness for the re-examination of any available tissue blocks with the PET-Blot method as a sensitive complementary tool in case of doubtful PrP IHC results. In a recent article relating to feline spongiform encephalopathy (FSE) in cats, the authors described the distribution of abnormal prion protein in different tissues detected using immunohistochemistry (IHC) method . They deInterestingly, we also reported in a previous work  the accuin situ the resistant form of abnormal PrP (PrPres), after digestion with high concentration of proteinase K (PK), the PET-blot method was also used as previously described [res) would be detectable. Membranes were treated with guanidine isothiocyanate , then thoroughly washed in TBST. Immunodetection was performed after pre-incubation in blocking solution (skimmed milk diluted at 0.2% in TBST). The monoclonal antibody used was SAF84 (1/2500) for a night at room temperature. A phosphatase alkaline coupled anti-mouse antibody was used as secondary antibody . Before revelation, the pH was adjusted to 9 by incubating membranes in NTM buffer . Finally NBT/BCIP was used to visualize the reaction product (dark-blue deposits). PET-blot membranes were assessed using a stereo-microscope  coupled to an image analysis workstation Explora Nova, La Rochelle, France. Immunohistochemical detection of the pathological form of the prion protein (PrPd for disease-related) was performed using the SAF84 monoclonal antibody as published previously [d was revealed using DAB intensified with chloride nickel giving dark deposits. The absence of detection of PrPres in the obex of scrapie-free sheep combined with the presence of PrPres seen in the obex of the scrapied sheep allowed to validate the PET-Blot procedure (data not shown).The tissue samples were the same as those used in our previous study in which the tissue preparation is described in detail . To visuescribed . Brain sThe abnormal form of prion protein characterized by its resistance to PK digestion was detected with high intensity in each sample analysed. When compared to our IHC results  we clearThese new results enable us to confirm confidently the presence of specific abnormal prion protein in the adrenal gland and in the kidney of the cheetah affected with FSE. This question is important because it becomes evidenced that urine may sustain transmission of certain forms of the transmissible spongiform encephalopathy (TSE) diseases, such as hamsters carrying infectious particles. More recently the kidney was found to accumulate abnormal PrP in other species too such as sheep ,18, and The present study shows that the use of the PET-blot method would have been very interesting to test to clarify the presence of prion in the kidney of affected cats with FSE as well as in controls. This approach could have also a great interest in the characterization of the PrP staining observed in the adrenal gland. In the study of Hilbe et al , the adrFinally, the data reported here demonstrate the specificity of the detection of abnormal prion protein in the kidney as well as in adrenal gland in cheetah affected with FSE. It also emphasizes the need for the re-examination of available tissue blocks with the PET-Blot method as a sensitive complementary tool in case of doubtful PrP IHC results.AB conceived and designed the study, SL performed the PET-Blot experiments, AB and SL analyzed the data and wrote the paper. TB had overall responsibility as head unit. All co-authors have read and approved the final manuscript."}
+{"text": "Five high-grade (3 grade III and 2 grade IV) astrocytoma tumour cell populations were treated with a preparation of Human Leukocyte Interferon either in monolayer cell culture or as multicellular spheroids in vitro or as xenografts growing in immune-deprived mice in vivo. A moderate and transient sensitivity was seen in one grade III tumour when tested in both of the in vitro assays, but no inhibition of growth was seen in vivo. Two tumours which were apparently resistant to Interferon treatment responded to orthodox chemotherapy. When used in conjunction with BCNU, Interferon was not effective in prolonging delay in tumour growth. It is concluded that Interferon is unlikely to be an effective agent in the treatment of malignant brain tumours."}
+{"text": "These studies demonstrate that changes in vascular functionin the STZ-induced diabetic rat precede theslowing of motor nerve conduction velocity (MNCV)and are accompanied by an increase in superoxidelevels in arterioles that provide circulation to theregion of the sciatic nerve.Diabetes mellitus produces marked abnormalities inmotor nerve conduction, but the mechanism is notclear. In the present study we hypothesized that inthe streptozotocin (STZ)-induced diabetic rat impairedvasodilator function in arterioles that providecirculation to the region of the sciatic nerve isassociated with reduced endoneural blood flow(EBF) and that these defects precede slowing ofmotor nerve conduction velocity, and thereby maycontribute to nerve dysfunction. As early as threedays after the induction of diabetes endoneuralblood flow was reduced in the STZ-induced diabeticrat. Furthermore, after 1 week of diabetes acetylcholine-induced vasodilation was found to be impaired.This was accompanied by an increase in the superoxidelevel in arterioles that provide circulation tothe region of the sciatic nerve as well as changes inthe level of other markers of oxidative stressincluding an increase in serum levels of thiobarbituricacid reactive substances and a decrease in lensglutathione level. In contrast to the vascular relatedchanges that occur within 1 week of diabetes, motornerve conduction velocity and sciatic nerve Na"}
+{"text": "Plasmodium blood-stage merozoites, liver-stage merozoites and mosquito midgut sporozoites relies on protease activity, so the enzymes involved have potential as antimalarial drug targets. This review examines the role of parasite proteases in egress, in the light of current knowledge of the mechanics of the process. Proteases implicated in egress include the cytoskeleton-degrading malarial proteases falcipain-2 and plasmepsin II, plus a family of putative papain-like proteases called SERA. Recent revelations have shown that activation of the SERA proteases may be triggered by regulated secretion of a subtilisin-like serine protease called SUB1. These findings are discussed in the context of the potential for development of new chemotherapeutics targeting this stage in the parasite's life cycle.Malaria is a scourge of large swathes of the globe, stressing the need for a continuing effort to better understand the biology of its aetiological agent. Like all pathogens of the phylum Apicomplexa, the malaria parasite spends part of its life inside a host cell or cyst. It eventually needs to escape (egress) from this protective environment to progress through its life cycle. Egress of  Plasmodium, the causative agent of malaria, is no exception. At different points in its life cycle the parasite finds itself residing within either an oocyst on the basal side of the female Anopheline mosquito mid gut wall, a vertebrate hepatocyte (or fibroblast) or a red blood cell (RBC). In the latter two cases the parasite is not free within the host cell cytosol, but lies within a membrane-bound parasitophorous vacuole (PV). Following a period of repeated mitotic replication \u2013 the length and extent of which varies considerably depending on species and life cycle stage \u2013 the parasite exits from the host cell in a process known as egress. Many details of how the parasite makes its escape are obscure, but the accumulated evidence indicates an important role for parasite proteolytic enzymes. This review aims to critically summarize this evidence in the expectation that it may provide plausible future strategies in the search for improved control of malaria and other pathologies caused by apicomplexan parasites. As a full appraisal of the molecular role of proteases in egress cannot logically be considered in isolation from the ultrastructural and physicomechanical aspects of the process, this article comprises three sections: first, it briefly reviews what is known about the mechanics of malaria parasite egress; second, it examines the biochemical and genetic evidence implicating proteases in egress; and finally it attempts to draw these together into a collective model of how egress may be regulated and targeted. Throughout, the main focus is on egress of Plasmodium falciparum merozoites from the blood-stage schizont, because of its particular significance for chemotherapeutic control of severe clinical malaria and because the majority of experimental work on egress has been on this developmental stage.All apicomplexan pathogens spend part of their life cycles within the confines of a host cell or cyst. in vitro blood-stage egress and events leading up to it in live parasites has been performed in the avian parasite Plasmodium lophurae  either exclusively in the PV lumen or in the RBC cytosol. Irrespective of its previous location, the GFP marker was observed to relocalize to fill the entire infected cell late in schizogony -based ultrastructural analyses cannot detect subtle time-dependent effects, but they have a place in investigating the mechanistic basis of egress. Both in vivo or HepG2 cells infected in vitro with GFP-expressing transgenic clones of the rodent malaria Plasmodium berghei eventually round up, detach from neighbouring cells and die. This is concomitant with disappearance of the PVM and release of the mature merozoites into the host cell cytosol , revealed defects in the proteolytic processing and shedding of a range of parasite proteins, including fragments of a major schizont surface protein now known as merozoite surface protein-1 (MSP1). Shortly after this study, P. falciparum schizont rupture, concomitantly interfering with the proteolytic processing of an abundant PV protein called P126 (now known as SERA5 \u2013 see below). Examination by EM of the stalled schizonts showed that, whereas rupture of the RBC membrane was prevented by the leupeptin treatment, disintegration of the PVM had taken place, releasing the mature merozoites into the residual cytoplasm of the host cell. This important finding provided the first evidence that rupture of the PVM and RBC membranes is differentially sensitive to protease inhibitors. Several more recent studies have built on that work. P. berghei-infected HepG2 cells, found that treatment of the cells with E64 blocked egress and clearly prevented the PVM degradation that usually precedes egress in this system.Whatever the physicomechanical details of egress and the temporal sequence of PVM and host cell membrane rupture, all except perhaps the fusion model invoke a requirement for generalized destabilization of the two membranes and host cell cytoskeleton to allow their eventual disruption. This notion has encouraged a search for parasite-derived molecular mediators of egress. The earliest documented evidence suggesting protease involvement in egress came from a series of studies indicating effects on egress and RBC invasion by It will be evident that the above studies reach sometimes conflicting conclusions, although much of the contrary data (e.g. the different effects of leupeptin in different studies) could in part be a result of experimental variables such as different culture conditions and differences in the age of the RBC used in the cultures. Notwithstanding this, at least three common threads can be drawn from the accumulated data. These are: that breakdown of the PVM and host cell membrane are differentially regulated; that both events are protease-dependent; and that PVM rupture is an E64-sensitive process. Given the high specificity of E64 for cysteine proteases, this strongly implicates one or more cysteine proteases in PVM rupture, and at least one additional distinct activity in host cell membrane rupture. What are the likely identities of the responsible proteases, and how are their activities regulated?P. falciparum aspartic proteases \u2013 plasmepsins I, II, III  and IV, plus three papain-like cysteine proteases called falcipain-2, -2\u2032 and -3 \u2013 have been implicated in haemoglobin digestion. Digestion takes place within an acidic digestive vacuole . As expected, the knockout lines exhibited no phenotype during blood-stage growth and the early stages of sporogony, but the resulting midgut sporozoites failed to egress from oocysts. Phase microscopic examination of the ecp1(\u2212) oocysts showed that the trapped sporozoites moved in a continuous circular motion inside the intact oocysts, in contrast to mature wild-type oocyst sporozoites which adopted a radially oriented, mostly motionless state within the oocysts. Mechanical dissection of the ecp1(\u2212) oocysts showed that the freed sporozoites possessed normal gliding motility but were completely non-infectious when mechanically transmitted to mice, in contrast to wild-type oocyst sporozoites which were infectious . The oocyst wall is a two-layered structure, with an inner wall of parasite origin and an outer, thicker wall derived from the basal lamina of the insect midgut epithelium. Further examination of the ecp1(\u2212) oocysts showed that they were structurally different from wild-type oocysts, being refractory to permeabilization with saponin. Although the subcellular site of expression of ECP1 was not determined, and ECP1 has not been demonstrated to possess protease activity, the authors speculated that it might play a role in degradation of the inner wall of the oocyst at egress. Consistent with this, comparison by Western blot of ecp1(\u2212) and wild-type oocysts detected a difference in the pattern of proteolytic processing of the circumsporozoite protein (CSP), a dominant component of the inner oocyst wall.The full power of reverse genetics was demonstrated by a beautiful study on the role of a different putative protease in egress of midgut sporozoites from oocysts in the mosquito vector. In an investigation of genes previously shown to be upregulated during P. falciparum orthologue of ecp1, called SERA8, belongs to a family of nine genes, eight of which (SERA1\u20138) are disposed in a tandem head-to-tail array on chromosome 2, while SERA9 is on chromosome 9. All the SERA gene products share a central relatively conserved papain-like domain as well as N- and C-terminal regions that contain a number of conserved Cys residues  responsible, Most proteases are synthesized as inactive zymogens that are converted to their active forms by proteolytic cleavage, either in an autocatalytic intramolecular manner or Plasmodium species examined, and the above findings indicate it is a \u2018druggable\u2019 target. Interestingly, SERA orthologues were detected in a recent proteomic analysis of liver-stage schizonts (These findings have been greatly clarified by a recent study in which processing of SERA5 was shown to be mediated by a subtilisin-like serine protease called PfSUB1. Previous work had shown that this protease is expressed in a membrane-associated form in schizont stages, and had partly characterized its substrate preference and inhibitor profile using recombinant PfSUB1 (activation event then could conversion of P56 to P50 represent a subsequent inactivation step or other functional modification associated with RBC membrane rupture? This is just one more unanswered question regarding this intriguing proteolytic pathway. Identification of the cysteine protease responsible would be a first step in addressing it.Why is SERA5 P56 truncated to P50 following the PfSUB1 processing step? The fact that this is blocked by leupeptin under conditions where RBC membrane rupture is prevented (Leishmania use pore-forming proteins or phospholipases for egress, and Chlamydia egress is a two-stage process in which the first step, breakdown of the intracellular inclusion vacuole, is cysteine protease-dependent (Toxoplasma gondii. It is likely that future advances in these areas will shed useful light on malarial egress.Many questions about malarial egress remain unresolved, not least the fundamental issue of how proteases can promote destabilization of the PVM and RBC membranes. Simplistically, two broad mechanisms of protease action may be imagined; proteases may act as indirect regulators of egress by activating distinct effector proteins or signal transduction pathways. Alternatively, proteases may directly mediate the membrane and cytoskeletal destabilization presumably required for egress, by hydrolysis of integral membrane or cytoskeletal proteins as described above for plasmepsin II and falcipain-2. Other obligate intracellular pathogens may provide clues: several intracellular bacteria and ependent ; 2008. RIn conclusion, the present indications are that egress of different life cycle stages the malaria parasite involves mechanistically conserved pathways and the action of at least three essential proteases in the vertebrate host. Arguably, all these represent viable future targets for drugs designed to interfere with the critical step in the parasite life cycle. The task now is to enhance our understanding of this pathway and exploit it in new approaches to malaria control."}
+{"text": "Survival analyses of patients with cancer of the cervix uteri, corpus uteri or ovary registered at Cambridge in 1960-1979 show that, although the long-term survivors had mortality rates similar to those of a normal age-matched population and might therefore be considered 'statistically cured', their risk of dying from their original cancer was still much higher than normal. Death rates from other cancers were slightly increased in cervix patients but not in corpus and ovary. At all three sites there was no evidence that deaths from non-malignant causes were increased. Only in cancer of the ovary was survival significantly better for patients registered in 1970-1979 than for patients registered in 1960-1969."}
+{"text": "A trend showing a reduction in glutathione peroxidaseactivities was demonstrated with aging ; however, this trend was not found in diabetic subjects. The results indicate a possibleimbalance in the antioxidant system in erythrocytes of aging adult women, which is even more pronounced in casesof type II diabetes. This study may indicate possible therapeutictreatment or preventive measures to limit oxidativedamage and reduce complications of diabetes.It is widely believed that oxidative stress plays an importantrole in the pathogenesis of type II diabetes. The presentstudy was undertaken to examine the functioning of two antioxidantscavenger enzymes, superoxide dismutase (SOD)and glutathione peroxidase (GSH-Px), in erythrocytes in apopulation of healthy aging adult women compared witha similar population with type II diabetes. Blood sampleswere examined from 42 female adult healthy subjects atdifferent ages and from 59 female patients with type II diabetes.A significant increase in SOD activities was correlatedwith aging in erythrocytes of the healthy control subjects("}
+{"text": "The cumulative expression of p53 protein is significantly associated with increasing proliferation activity. Evaluation of apoptosis in pre-treatment specimens may have potential utility in predicting the efficacy of treatment. Assessment of the tumours proliferation activity by Ki-67 expression might identify patients who are at risk of developing metastastic disease. \u00a9 2001 Cancer Research Campaign http://www.bjcancer.comThe use of neoadjuvant chemoradiotherapy prior to surgery in the treatment of oesophageal adenocarcinoma has increased in recent years, and up to 25% of patients will have a complete pathological response to the neoadjuvant therapy. Many patients will not respond, however, and the knowledge of molecular factors predicting response or resistance to chemoradiotherapy is required to enhance treatment results. An understanding of apoptosis and cell proliferation may be relevant and this study focused on apoptotic indices and cell-cycle related  protein expression in a cohort of 42 patients with primary oesophageal adenocarcinoma. We documented that apoptosis occurs among viable (proliferating) tumour cells in all adenocarcinoma cases examined in this study. Pre-operative chemoradiotherapy significantly increased apoptosis and significantly decreased cell proliferation (estimated by Ki-67 expression). Immunohistochemically detected"}
+{"text": "Skin toxicity is a common side-effect of treatment with imatinib mesylate  in advanced gastrointestinalstromal tumours (GIST) and chronic myeloid leukaemia. The optimal duration of treatment with imatinib mesylate inGIST has not yet been established, as durable remissions have been observed in patients. It is, therefore, important todevelop strategies to deal with common side-effects of what may be a long-term treatment. Here we report the case of apatient with advanced GIST who developed a cutaneous drug reaction secondary to imatinib mesylate and the variousmanagement options that may be employed depending upon the severity of the toxicity. The case and literature arediscussed."}
+{"text": "The effect of mitomycin C on two human ovarian cancer cell lines was measured during several exposure times and concentrations using the Human Tumour Colony-forming Assay (HTCA). Changes in exposure time and concentration resulted in considerable differences in tumour cell survival. It is concluded that several exposure times and concentrations are necessary for in vitro sensitivity testing. We suggest alternative criteria derived from pharmacokinetic data in patients instead of one-tenth of the peak plasma level which is the usual practice."}
+{"text": "The oestrogen receptor (RE) status of the primary tumour has been assessed in 466 of a consecutive series of 550 patients with primary operable breast cancer. All patients were followed up (without treatment) until the development of recurrence or metastases. Distant metastases have so far occurred in 124 patients and 82 have had symptomatic local or regional recurrence. A significant correlation exists between the RE status of the primary tumour and subsequent patterns of metastasis. Symptomatic metastases to regional lymph nodes are more common with RE- cancers. There is no significant difference in either time of onset or total incidence of distant metastases between patients with RE+ and RE- tumours. Distribution of distant metastases is influenced by RE status: RE+ tumours tend to recur in bone, RE- tumours show affinity for viscera."}
+{"text": "Radiolabelled meta-iodobenzylguanidine (mIBG) currently provides one of the most promising options for targeted radiotherapy of neuroblastoma. No means currently exists for prediction of mIBG uptake in tumour cells of individual patients other than semiquantitative inferences from diagnostic scanning which depend on the continued existence of a macroscopic tumour mass. A biological rapid assay which could be applied at initial biopsy would be invaluable in selecting patients for therapeutic strategies which incorporate radiolabelled mIBG. We have assessed the expression of the noradrenaline transporter gene in six human neuroblastoma cell lines and in three non-neural crest-derived cell lines using reverse transcription followed by the polymerase chain reaction. Transcription of this gene was observed in five out of six neuroblastoma cell lines but in none of the control cells. A highly significant correlation was established (P < 0.01) between gene expression and active cellular accumulation of mIBG. It is suggested that semiquantitative evaluation of noradrenaline transporter gene transcripts may be predictive of mIBG uptake by tumours in vivo."}
+{"text": "We are reporting a case of bilateral Fuchs\u2019 heterochromic iridocyclitis with chikungunya virus infection in the left eye. A 20-year-old female was presented with a past history of fever suggestive of chikungunya with bilateral Fuchs\u2019 heterochromic iridocyclitis and complicated cataract. She had a tripod dendritic pattern of keratic precipitates by confocal microscopy in the left eye with a stippled pattern of keratic precipitates in both eyes. The real-time polymerase chain reaction (RT-PCR) assay in the aqueous humor detected 98 copies/ml of chikungunya virus RNA. The patient underwent clear corneal phacoemulsification with in-the-bag intraocular lens implantation in the left eye with a good visual outcome. This is the first report where the presence of chikungunya virus RNA has been associated with a case of bilateral Fuchs\u2019 heterochromic iridocyclitis. Fuchs\u2019 heterochromic iridocyclitis is a specific form of uveitis. Earlier studies suggest its association with infectious agents like toxoplasmosis, toxocariA 20-year-old female of Indian origin presented with the complaint of decreased vision in the left eye since 2 weeks. One week prior to the onset of ocular symptoms, the patient had fever lasting for 3 days suggestive of chikungunya fever. Her ocular history was negative for trauma and previous inflammation. Her old investigational reports ordered by the physician revealed positive serum anti-rubella virus IgG (153 IU/ml), and serum toxoplasma, cytomegalovirus, and herpes simplex virus antibodies were negative. Her best corrected visual acuity was 20/30 in the right eye and counting finger close to face in the left eye. Intraocular pressure was normal in both the eyes. Slit-lamp biomicroscopy in the right eye demonstrated fine-to-medium-sized keratic precipitates, flare+, cells+, stromal atrophy of the iris , nodulesDiagnosis of bilateral Fuchs\u2019 heterochromic iridocyclitis with a complicated cataract was made probably of viral origin. A sample of aqueous humor (AH) was drawn through a paracentesis at the beginning of the cataract surgery for RT-PCR and the anterior capsule was removed during the capsulorrhexis in the left eye for histopathological examination.Reverse transcriptase PCR for rubella virus on the AH was carried out using primers and protocols as described earlier found toChikungunya is a single-stranded RNA virus. It can cause conjunctivitis, iridocyclitis, episcler6et al.[Confocal microscopy of keratic precipitates in Fuchs\u2019 heterochromic iridocyclitis are globular keratic precipitates, infiltrating and dendritiform, stippled, and cruciform as described by Kanavi et al.et al. whereas the tripod dendritic pattern of keratic precipitates was noted in the left eye by confocal microscopy. We had an epidemic of chikungunya. The patient had fever suggestive of chikungunya which made us do the RT-PCR for chikungunya in the aqueous humor at the time of cataract surgery. The presence of chikungunya RNA virus in the AH of Fuchs\u2019 heterochromic iridocyclitis suggests that chikungunya virus infection is present in a case of Fuchs\u2019 heterochromic iridocyclitis, although it is not clear if the chikungunya virus was the initiator of the disease or a coincidental finding. This association reinforces the theory based on the putative role of an infectious agent associated with different forms of Fuchs\u2019 heterochromic iridocyclitis. To the best of our knowledge, this is the first report where the presence of chikungunya virus RNA has been demonstrated in the case of Fuchs\u2019 heterochromic iridocyclitis.The stippled pattern of keratic precipitates in both eyes was present which is similar to that reported by Kanavi"}
+{"text": "This Phase 3 multicenter randomized trial comparedManagement of advanced renal-cell carcinoma (RCC) has made considerable progress in recent years and new emerging strategies are being developed. As distant metastases develop in about one-third of patients with RCC and most of these cases cannot be cured surgically, other options play an important role. Sunitinib, sorafenib and bevacluzimab have been proven to have efficacy in this scenario. Both temThe combination of temsirolimus plus interferon did not improve overall survival. This could be due to greater adverse effects resulting in more delays and reductions in treatment and lower mean dose intensity of temsirolimus (10.9mg vs. 23.1mg per week). Patients with extensive and rapidly progressive disease may be less able to tolerate treatment and may have tumors that are inherently more resistant to therapy. Accordingly, the moderate efficacy of temsirolimus in advanced disease suggests that the drug might benefit patients with less extensive metastatic renal-cell carcinoma. The results of this trial point to mTOR as a target for cancer treatment and the possibility of using temsirolimus as first-line treatment for metastatic renal-cell carcinoma."}
+{"text": "In some clinical situations the endogenous production of glutamine may be insufficient to maintain optimal tissue structure and function such that glutamine becomes a conditionally essential amino acid. Studies in laboratory animals have demonstrated that glutamine supplementation can reduce the incidence and severity of cytotoxic-induced mucositis. This study examined the role of oral glutamine supplementation in the management of mucositis caused by 5-fluorouracil (5-FU) and folinic acid. Twenty-eight patients with gastrointestinal cancers were randomised to receive 16 g of glutamine per day for 8 days, or placebo, in a randomised double-blind trial before crossing over to the alternative supplement during the second treatment cycle. The supplement was well tolerated with no apparent adverse effects, but failed to have any significant effect on oral mucositis assessed by the patients or investigator. The possible reasons for this apparent lack of benefit are discussed."}
+{"text": "Human perception of ambiguous sensory signals is biased by prior experiences. It is not known how such prior information is encoded, retrieved and combined with sensory information by neurons. Previous authors have suggested dynamic encoding mechanisms for prior information, whereby top-down modulation of firing patterns on a trial-by-trial basis creates short-term representations of priors. Although such a mechanism may well account for perceptual bias arising in the short-term, it does not account for the often irreversible and robust changes in perception that result from long-term, developmental experience. Based on the finding that more frequently experienced stimuli gain greater representations in sensory cortices during development, we reasoned that prior information could be stored in the size of cortical sensory representations. For the case of auditory perception, we use a computational model to show that prior information about sound frequency distributions may be stored in the size of primary auditory cortex frequency representations, read-out by elevated baseline activity in all neurons and combined with sensory-evoked activity to generate a percept that conforms to Bayesian integration theory. Our results suggest an alternative neural mechanism for experience-induced long-term perceptual bias in the context of auditory perception. They make the testable prediction that the extent of such perceptual prior bias is modulated by both the degree of cortical reorganization and the magnitude of spontaneous activity in primary auditory cortex. Given that cortical over-representation of frequently experienced stimuli, as well as perceptual bias towards such stimuli is a common phenomenon across sensory modalities, our model may generalize to sensory perception, rather than being specific to auditory perception. Natural stimuli are variable and often mixed with noise. Our perception of these stimuli is thus derived from ambiguous sensory inputs. Psychophysical experiments in humans and primates indicate that this ambiguity is partly compensated for by incorporating information about the probabilities of previously experienced stimuli directly into the percept in a Bayesian manner Previous theoretical investigations of Bayesian inference were often based on homogeneous stimulus representations\u2014i.e., all possible values of stimulus parameters are evenly represented Although such a mechanism of dynamic prior information encoding and integration may underlie perceptual bias arising in the short-term and in a context-dependent manner Cortical stimulus representations are not homogeneous. Sensory experience during early development results in robust changes in primary cortical sensory representations that persist into adulthood. A very consistent finding is that more frequently experienced stimuli gain greater representations in primary sensory cortices We modeled primary auditory cortex (AI) frequency representations with 800 independent Poisson-firing neurons. The parameters of the model were chosen based on properties of the primary auditory cortical neurons documented in the literature and our unpublished results. In particular, our experimental finding that the firing rates of neurons in auditory cortex exhibit significant variability, with a mean Fano factor value of 0.98+/\u22120.21 To replicate frequency representations seen in AI of na\u00efve animals and animals with extensive prior experience of a specific tone (7 kHz) We modeled auditory perception by decoding the simulated population response to an input frequency using the maximum-likelihood decoding method Modeling Bayesian integration. According to Bayesian integration theory, frequency perception depends both on prior-based expectation and sensory input We therefore modeled Bayesian integration of sensory input and prior-based expectation by calculating the stimulus likelihood function derived from the linear superposition of stimulus-evoked activity and elevated spontaneous activity ( and )Fig. 2c.We first examined model auditory perception with normal levels of baseline activity for both the na\u00efve and 7kHz-over-represented model AIs. The maximum likelihood estimate or \u2018percept\u2019 converged at the input frequency for both na\u00efve and 7kHz-over-represented model AIs  It has recently been shown that Bayesian integration of probability distributions represented in neuronal population codes such as the one used in our model may be achieved by simple summation of population activities The relative decoding variability at the over-represented frequency range behaves differently with and without the elevated baseline activity. With an increased baseline, although overall variability is increased, it is relatively lower for the over-represented frequencies than for the neighboring frequencies Fig. 3d.Some parameters of the model AI, such as the total number of neurons and the magnitude of the elevated spontaneous firing rate, were arbitrarily chosen. We therefore systematically varied these parameters to explore their influence on the observed characteristic perceptual shift Fig. 4. non-selective increase in the activity of all neurons in primary auditory cortex. In the model, the same cortical circuit performs both the encoding and integration of the prior. The increase in overall activity could be driven by a general top-down signal without specific prior information.Earlier studies have suggested that dynamic prior information may be encoded by the activity of a subset of primary cortical neurons in a homogeneous representational system. The specific pattern of activity is driven by inputs outside of primary sensory cortex that carry prior information derived from high-level inference. Thus the encoding of the prior is separate from its integration with sensory information and must be mediated by different neural circuits. The specific brain substrates and mechanisms for prior encoding and retrieval are unknown. The present study considered the possibility of storing long-term prior information in the size of sensory representations. A novel finding is that in the context of auditory perception, long-term priors about sound frequency distributions can be retrieved by In order for optimal Bayesian integration of prior and sensory information to occur, our model requires that the relative contributions of prior-related and sensory-evoked activity be modulated by task conditions on a trial-by-trial basis. In other words, although the prior is long-term, optimal Bayesian inference requires that the extent to which it used in generating a sensory percept depend on task demand and stimulus uncertainty. Our simulation shows that this could be accomplished by changing overall levels of activity. Higher levels of overall activity increase the contribution of prior information to sensory perception and increase prior bias. Thus our results suggest that in situations where auditory input is ambiguous, the overall level of activity in all primary auditory cortex neurons should increase. Although dynamic prior encoding also calls for a higher level of prior-related activity when the sensory input is ambiguous, such activity occurs only in a subset of neurons.Elevated neuronal activity is not the only way that a prior stored in the size of sensory representations could be read out. Another possibility, recently proposed in unpublished work Different levels of intrinsic, \u201cbaseline\u201d activity in primary sensory cortices have been shown to profoundly influence neuronal responses to sensory stimuli Maximum-likelihood estimation is an unbiased feature decoding method. With a sufficient number of neurons, as well as the knowledge of which part of the neuronal activity is due to the input stimulus, its decoding result always converges on the input stimulus Fig. 3. ). Thus, stimulus-decoding performance is decreased. However, the increase in spontaneous activity in our model is caused by task demand when the sensory input is ambiguous, and cannot be resolved by simple  stimulus decoding. It enables integration of prior information to optimally resolve stimulus ambiguity. Furthermore, decoding variability decreases rapidly when more neurons are included in the model  percepts of ambiguous stimuli are biased toward stimuli with larger sensory representations; 2) ambiguous sensory input leads to a"}
+{"text": "CD4+ T cells. The mechanisms underlying low viral load persistence, slow decay of the latent reservoir, and intermittent viral blips are not fully characterized. The quantitative contributions of residual viral replication to viral and the latent reservoir persistence remain unclear. In this paper, we probe these issues by developing a mathematical model that considers latently infected cell activation in response to stochastic antigenic stimulation. We demonstrate that programmed expansion and contraction of latently infected cells upon immune activation can generate both low-level persistent viremia and intermittent viral blips. Also, a small fraction of activated T cells revert to latency, providing a potential to replenish the latent reservoir. By this means, occasional activation of latently infected cells can explain the variable decay characteristics of the latent reservoir observed in different clinical studies. Finally, we propose a phenomenological model that includes a logistic term representing homeostatic proliferation of latently infected cells. The model is simple but can robustly generate the multiphasic viral decline seen after initiation of therapy, as well as low-level persistent viremia and intermittent HIV-1 blips. Using these models, we provide a quantitative and integrated prospective into the long-term dynamics of HIV-1 and the latent reservoir in the setting of potent antiretroviral therapy.Although potent combination therapy is usually able to suppress plasma viral loads in HIV-1 patients to below the detection limit of conventional clinical assays, a low level of viremia frequently can be detected in plasma by more sensitive assays. Additionally, many patients experience transient episodes of viremia above the detection limit, termed viral blips, even after being on highly suppressive therapy for many years. An obstacle to viral eradication is the persistence of a latent reservoir for HIV-1 in resting memory  CD4+ T cells and persists in patients on potent treatment for a long time. These latently infected cells decay slowly, but can produce new virions when activated by relevant antigens. Many patients experience transient episodes of viremia, or blips, even though they have \u201cundetectable\u201d plasma viral loads for many years. Here, we develop a new mathematical model describing latently infected cell activation upon random antigenic stimulation. Using the model, we show that programmed expansion and contraction of latently infected cells upon activation can generate both low viral load persistence and viral blips. Occasional replenishment of the latent reservoir may explain the different decay kinetics of the reservoir observed in clinical practice. We also show that a model with homeostatic proliferation of latently infected cells can explain persistence of low-level virus, stability of the latent reservoir, and emergence of viral blips. These results provide novel insights into the long-term virus dynamics and could have implications for the treatment of HIV-1 infection.Current combination therapy can suppress viral loads in HIV-1-infected individuals to below the detection limit of standard commercial assays. However, it cannot eradicate the virus from patients. HIV-1 can generally be identified in resting memory  Following initiation of highly active antiretroviral therapy (HAART) the plasma viral load declines with a rapid first phase, followed by a slower second phase . After sAnother line of evidence for HIV-1 persistence is the observation of transient episodes of viremia (\u201cblips\u201d) above the detection limit in patients on HAART  [7],[23]The management of HIV-1 infection requires a further understanding of the mechanisms underlying low viral load persistence, stability of the latent reservoir, and occurrence of intermittent viral blips, as well as the relationships between them. We approach this through mathematical modeling. Many models, as surveyed in In this paper, we further study latently infected cell activation in response to antigenic stimulation by extending the models in A basic model of latent cell activation was initially developed to examine the cell populations contributing to the second-phase viral decline after administration of both reverse transcriptase (RT) and protease inhibitors There is only one positive steady state viral load of Eq. (1):Both  T cells . We inveLet As suggested by We employ a basic \u201con-off\u201d model, which has previously been used to describe the in vitro and in vivo compared with Although We choose the overall drug efficacy Since we are interested in the dynamics of the third-phase viral decline during treatment, we choose the initial viral load to be Homann et al. A recent experimental study by Chomont et al. We choose a small base value for the transition rate, In order to maintain the latent cell pool during potent drug therapy, we choose the proliferation rate The carrying capacity  of latently infected cells during therapy is unknown. Assuming The simulation with an initial T cell count in vivo, the duration of antigen exposure, as well as whether T cell proliferation continues in the absence of further antigenic stimulation Numerical simulations of model (4) show that programmed expansion and contraction of latently infected cells upon occasional antigenic stimulation can robustly generate intermittent viral blips with reasonable amplitude and duration, without seriously depleting the latent reservoir . We assude novo infection of susceptible T cells is maximally inhibited by potent antiretroviral drugs and productively infected cells have a fast turnover rate. However, if the activation induces a substantial proliferation of activated latently infected cells, it can simultaneously reseed the latent reservoir as a small fraction of activated cells revert to the resting state in the formation of memory T cells. To what extent the activation replenishes the latent cell pool depends heavily on the proliferative potential of activated cells, i.e., how many daughter cells are derived from the activation of latently infected cells. In An interesting result is that the amplitude of viral blips is inversely correlated with the decay of the latent reservoir. Based on model (4), viral blips originate from activation of latently infected cells into the productive class. It was initially thought that this activation would deplete the latent reservoir quickly in HAART-treated patients because We ran stochastic simulations of the model 30 times, recorded the number and amplitudes of viral blips, and calculated the half-life of the decay of the latent reservoir based on the change in the latent reservoir size in 300 days. The summary statistics on our simulations is given in The fraction of resting latently infected cells that are activated by antigenic stimulation remains largely unknown. Due to the heterogeneity of latently infected cells with respect to the antigens they respond to, it is likely that a very small fraction of latently infected cells are activated by a particular antigen. We tested model predictions (Eq. (4)) with different activation rates on rate  B. When In addition to changing the proliferation rate In summary, occasional activation of latently infected cells upon stochastic antigen encounter is able to produce a large quantity of activated T cells temporarily, and thereby generate intermittent viral blips. The blip amplitude/frequency is inversely correlated with the decay of the latent reservoir. Using different potentials of activated T cells to divide during the initial clonal expansion phase or different duration or frequency of antigenic stimulation enables us to generate the different decay characteristics of the latent reservoir observed in different clinical studies We have assumed a density-dependent mortality rate for productively infected cells in the model given by Eq. (4) in order to maintain a low steady state viral load when antigen is absent. The reason that viral loads decrease very quickly in the absence of activation in this model is that activated cells decline quickly to an extremely low level during the contraction phase, with not enough cells entering the productive stage. Even when we choose a smaller death rate of activated cells, for example, A) B) C) A) there is almost no decay; (B) the latent reservoir decays at a very slow rate; (C) the reservoir decays at a faster rate. The decay of the latent reservoir is inversely correlated with the amplitude or frequency of viral blips. The viral load does not decline to an unreasonably low level in the absence of antigenic stimulation. This low-level viremia is primarily maintained by a small number of activated cells that transition into the productive class during the second slower contraction phase. However, the absence of antigenic stimulation over a long time  will deplete activated cells, and the viral load will decrease to an extremely low level  homeostatic proliferation of The homeostasis model can robustly describe the multiphasic viral decline following initiation of combination antiretroviral treatment, and maintain both low-level persistent viremia and the latent reservoir during therapy. rd phase A and 9Bed cells D and 9EWe also plot the level of latently infected cells and viral load with different  latency G and 9Hefficacy J and 9Koir size G and 9Heservoir J, althoeservoir K. In ouWe further examine the relative contributions to the latent reservoir persistence from ongoing viral replication and latently infected cell proliferation  B) C) The model with homeostatic proliferation of latently infected cells can also generate viral blips given intermittent bursts of activation of latently infected cells  In many mathematical models, the steady state viral load is very sensitive to small changes of drug efficacy and thus they cannot robustly describe the low viral load persistence during HAART Our model can robustly maintain the stability of the latent reservoir and meanwhile generate viral blips with reasonable duration and amplitude in infected individuals in the setting of HAART. We hypothesize that latently infected cells act similar to other memory cells and experience programmed proliferation and contraction upon antigenic stimulation by their recall antigens. During the response, a portion of activated latently infected cells transition into the productive class and generate viral blips. In the meanwhile, a small fraction of activated cells revert back to the resting state, providing a potential to replenish the latent reservoir. An interesting result is that this model can reconcile the divergent estimates of the decay rate of the latent reservoir in the literature. The half-life of the reservoir decay is largely determined by the frequency and duration of antigenic stimulation and by how many times the resultant activated latently infected cells proliferate during the latent cell response. In addition, we observe that assuming activated T cells remain at a low level after the rapid contraction phase ) can maintain a low level of viremia. This suggests that latently infected cell activation solely can maintain low-level viremic persistence and produce intermittent viral blips simultaneously, with the latent reservoir occasionally replenished. Model simulations show that the levels of persistent viremia and latently infected cells are not correlated with HAART potency, which suggests that low viral load persistence and the stability of the latent reservoir need not arise from ongoing active replication during HAART.The conclusion that ongoing viral replication is a minor factor contributing to viral and the latent reservoir persistence is consistent with the results of recent studies Motivated by the observation that latently infected cells have the potential to renew themselves when stimulated by their previously encountered antigens, a much simpler phenomenological model with homeostatic proliferation of latently infected cells was proposed to study viral persistence and HIV-1 blips. The idea that the stability of the latent reservoir can be maintained by homeostatic proliferation of latently infected cells is also supported by a very recent experimental study Considering that the latent reservoir consists of heterogeneous mixture of latently infected T-cell clones that respond differently to different antigens, our models can be generalized to account for the heterogeneity of latently infected cells. For example, we can extend the homeostasis model by including multiple subpopulations of latently infected cells, with each subpopulation having a different transition rate Given that the latent reservoir has been identified as a major barrier to virus eradication with current combination therapy Unfortunately, as viral levels are driven down, say below 1 RNA copy/mL, and latently infected cells become rare, it becomes impossible to follow the dynamics of these populations. Therefore, we must rely on mathematical models to make inferences about the end game in viral eradication. Here we have presented a set of models that agree with much of our knowledge about low-level viral persistence, the latent reservoir, and viral blips. Direct experimental tests of these models would involve the examination of the latently infected cell response when cells are activated by specific antigens. In addition, all of our models suggest that there is an inverse relationship between the decay of the latent reservoir and the frequency (or amplitude) of viral blips. Thus, more accurate and frequent data on the latent reservoir size, the number of viral blips and their amplitudes also can be used to test our models."}
+{"text": "Unique and uncommon BamHI allelic restriction fragments of the Ha-ras locus have been reported in the genomes of patients with cancer and of three affected members of a familial melanoma kindred . Analysis of the BamHI and Msp/HpaII restriction fragments of peripheral blood leucocyte DNA from the members of two families with hereditary melanoma (HM)/familial dysplastic naevus syndrome (DNS) revealed that the only Ha-ras allele common to four affected members of one kindred and two from a second kindred, was the 6.7kb allele which is found in 66% of the normal population. This allele was found equally in affected and non-affected family members, and in one affected case was inherited from an unaffected homozygous parent. It was absent in two affected sisters in a third kindred. In the first kindred the karyotype of all three melanoma sufferers was 46XX 9qh+, while six unaffected members had a normal karyotype. BamHI polymorphism of the Ha-ras gene does not identify the affected members in the HM/DNS families studied."}
+{"text": "We have studied a remarkable family with seven cases of malignant lymphoma extending through three generations wherein five sisters and their mother had histopathologically documented non-Hodgkin's lymphoma, while a granddaughter had Hodgkin's disease. An immunological study of three lymphoma survivors, nine of their first degree relatives, and four spouse controls was undertaken. Significant findings consisted of a depressed serum IgG3 level in four of the nine first-degree relatives; in two of these four, lymphocyte stimulation by both pokeweed mitogen and concanavalin A were significantly depressed. The subtle immunological abnormalities present in this kindred may be associated with the pathogenesis of the lymphomas."}
+{"text": "The recent rapid accumulation of sequence resources of various crop species ensures an improvement in the genetics approach, including quantitative trait loci (QTL) analysis as well as the holistic population analysis and association mapping of natural variations. Because the tribe Triticeae includes important cereals such as wheat and barley, integration of information on the genetic markers in these crops should effectively accelerate map-based genetic studies on Triticeae species and lead to the discovery of key loci involved in plant productivity, which can contribute to sustainable food production. Therefore, informatics applications and a semantic knowledgebase of genome-wide markers are required for the integration of information on and further development of genetic markers in wheat and barley in order to advance conventional marker-assisted genetic analyses and population genomics of Triticeae species.The Triticeae mapped expressed sequence tag (EST) database (TriMEDB) provides information, along with various annotations, regarding mapped cDNA markers that are related to barley and their homologues in wheat. The current version of TriMEDB provides map-location data for barley and wheat ESTs that were retrieved from 3 published barley linkage maps  and 1 diploid wheat map. These data were imported to CMap to allow the visualization of the map positions of the ESTs and interrelationships of these ESTs with public gene models and representative cDNA sequences. The retrieved cDNA sequences corresponding to each EST marker were assigned to the rice genome to predict an exon-intron structure. Furthermore, to generate a unique set of EST markers in Triticeae plants among the public domain, 3472 markers were assembled to form 2737 unique marker groups as contigs. These contigs were applied for pairwise comparison among linkage maps obtained from different EST map resources.TriMEDB provides information regarding transcribed genetic markers and functions as a semantic knowledgebase offering an informatics facility for the acceleration of QTL analysis and for population genetics studies of Triticeae. Accumulation and saturation of available genetic markers directly contribute to advances in marker-assisted genetic studies with a wide range of applications. Genetic markers designed to extensively cover a genome permit not only the detection and identification of individual genes associated with complex traits by quantitative trait loci (QTL) analysis but also the exploration of genetic diversity and population structure with regard to natural variations -3. The rTriticum aestivum L.) and barley (Hordeum vulgare L.). It is necessary to accumulate and saturate the available markers and to design a core marker set for efficient map-based research in order to discover the key loci associated with phenotypic changes that occur in different varieties of these crops and are involved in productivity. These efforts will contribute to sustainable food production through the application of molecular breeding. Expressed sequence tags (ESTs) of common wheat and barley have been collected on a large scale in order to establish a comprehensive sequence resource for gene discovery and a reliable database of gene expression [Triticum monococcum L.) was constructed using transferable markers derived from barley ESTs [The tribe Triticeae includes important crops such as wheat  and 1 doubled haploid (DH) populations, in order to integrate and extend the use of previously known QTLs and phenotypes for the evaluation of diverse germplasms. Consequently, conserved QTLs among populations and coincident QTLs have been identified using consensus marker intervals . More reThus, the integration of the available cDNA markers into a semantic knowledgebase that can provide various annotations and generate a unified set of identical markers would definitely be useful for improving the genome-wide map-based approaches. Herein, we report the Triticeae mapped EST database (TriMEDB) \u2013 a database providing information on the mapped cDNA markers in barley, along with various annotations, and their homologues in wheat. The current version of TriMEDB contains 2737 unique cDNAs mapped onto linkage maps, and the results of queried data are displayed on the web interface.et al. (2007). These PCR markers were used to detect the corresponding sequences in the wheat and barley EST sets in dbEST (GenBank EST release #163.0). The longest ESTs found by this search for each PCR primer were analysed further by studying the cDNA sequence corresponding to each primer pair.The current version of TriMEDB provides information regarding barley and wheat ESTs and their map location data retrieved from 3 published barley linkage maps and 1 diploid wheat map. This information can be imported to CMap  and used-200. Marker sequences that were homologous between barley and wheat were identified using BLASTN similarity searches against each sequence resource with a threshold e value of <1e \u00d7 10-130.Nucleotide sequences of the mapped EST markers were obtained from each cDNA database that provides representative sequences of clustered or assembled cDNA. For this purpose, PCR primer sequences and amplified marker sequences were searched for NCBI UniGene , TIGR GeTo generate a unique EST marker set for the tribe Triticeae, 3472 ESTs derived from 4 maps were assembled using CAP3  with def-20 against the rice genome sequence of The International Rice Genome Sequencing Project (IRGSP) ver. 4.0 obtained from the Rice Annotation Project Database (RAP-DB) [To identify the homologous counterparts of the rice gene for each barley EST marker and to predict an exon-intron structure based on the rice homologous sequences, a homology search was performed using BLASTN with a threshold e value of <1e \u00d7 10(RAP-DB)  with def(RAP-DB) .The database is implemented in MySQL and Perl CGI scripts and the web interface runs on the Apache Web server. CMap is implemented to visualize the linkage maps. Generic Genome Browser is implemented to display the exon-intron structure of the cDNAs of each marker and to compare the ESTs with the rice homologous sequences and the annotated rice genome obtained from RAP-DB.A user can search the EST markers in barley and diploid wheat by using 2 different queries: a marker name and a chromosome name Fig. . Each ofThe assembled marker search page provides an interface to retrieve 2737 unique marker groups derived from the CAP3 assembly for a total of 3472 markers. As shown in Fig. Accumulation of information pertaining to the genetic markers in barley and wheat and integration of various annotations related to these markers into a semantic knowledgebase have been effective in facilitating the map-based approach for Triticeae genomics. Our assembly that unifies the mapped EST markers currently available for barley and wheat has already been used to map more than 2700 cDNAs to homoeologous chromosomes of barley and wheat. These unique markers would be considered initial candidates with regard to polymorphisms that can be used for generating linkage maps by using a novel mapping populations that may in turn be used for QTL analysis. These unique markers would be shared by barley and wheat. Because the predicted exon-intron structures and the information on the rice genome should also be useful in designing PCR primers to amplify suitable introns for polymorphism discovery, they should also benefit the effective throughput genome mapping of Triticeae .Genetic markers are provided by several database resources, which have a web interface to allow the users to browse genetic linkage maps. GrainGenes is a popular site for Triticeae genomics; it also provides genetic markers and linkage map data on wheat, barley, rye, and oat . GrameneSupplemental Figure. S1 in Additional File Furthermore, the derived marker groups may be applicable as a set of core markers for high-throughput genotyping of natural variation in order to display the population structure of Triticeae plants. Domestication and adaptation have lead to the expansion of the area of cultivation of wheat and barley . TriMEDBTherefore, TriMEDB is particularly useful for both conventional map-based analyses, such as QTL analysis and association mapping, and evolutionary population genomics studies that will facilitate the molecular breeding of Triticeae plants.Project name: TriMEDB: Triticeae Mapped EST DatabaseProject home page:Operating system: Platform independentProgramming language: PerlOther requirements: NoneLicense: None requiredAny restrictions to use by non-academicians: NoneKM designed the project, performed data analysis, assisted in the designing of the database, and drafted the manuscript. DS also designed the project and analysed the published genetic maps. TY performed data analysis and assisted in the designing of the web interface and the database. TS performed database system administration. KS served as the principal investigator of the project. All authors have contributed to the writing of the manuscript and have read and approved the final submitted version.Supplemental Figure S1 is a schematic presentation of the map-based analyses and the use of TriMEDB. Supplemental Figure S2 is a schematic presentation of the database structure of TriMEDB.Click here for file"}
+{"text": "The plasminogen activation cascade is involved in carcinogenesis, invasion and metastasis. In this study plasminogen activators and their type 1 inhibitor were evaluated in colonic tissue from 19 patients with familial adenomatous polyposis coli, an inherited disorder characterised by the presence of thousands of adenomatous polyps in the colorectum which predispose to colorectal cancer. The conversion of normal-appearing colonic mucosa to neoplastic tissue in these patients was associated with an increase in urokinase-type plasminogen activator and plasminogen activator inhibitor type 1, accompanied by a decreased level of tissue-type plasminogen activator. These observations are essentially similar to those found in solitary adenomas and carcinomas of the colon, and illustrate the uniform involvement of the plasminogen activation system in colorectal carcinogenesis."}
+{"text": "The surviving fraction (SF) of Chinese hamster cells and HeLa cells after treatment with a range of Adriamycin concentrations and exposure times was determined. The cytostatic effect was proportional to the product of extracellular drug concentration (c) and exposure time (t) according to the equation: SF=e-ktc. By determining the intracellular drug concentration at various exposures, it could be shown that absorbed dose is not proportional to exposure dose."}
+{"text": "Epidermal growth factor receptor (EGFR) overexpression has been associated frequently with squamous cell carcinomas (SCC) and SCC cell lines. In most cases the level of EGFR on the tumours from which the cell lines were derived has not been determined, nor have EGFR levels been determined for xenograft tumours from the cell lines. In this study we determined EGFR expression on a new series of head and neck SCC (SCCHN)-derived cell lines, which were obtained from tumours representing a spectrum of malignant progression, and two cell strains derived from erythroplakia premalignant lesions. The level of EGFR on cell lines was determined by [125I]EGF competitive binding assays. EGFR levels on some of the original tumours and xenografts of the cell lines were determined on cryosections by a competitive binding assay based on [125I]EGFR1, an EGFR-specific monoclonal antibody. EGFR expression on the tumour cryosections was compared with expression on cryosections of skin and buccal mucosa. Eight of the ten tumour cell lines had elevated EGFR. Two of the tumour-derived cell lines and the two erythroplakia-derived cell strains expressed EGFR at levels similar to that detected on normal keratinocytes in tissue culture. Only two of the tumours overexpressed EGFR when compared with normal tissue. The other tumours had levels similar to that detected on the basal layers of skin or buccal mucosa. The xenografts expressed EGFR, as did the original tumours, even though they were derived from cell lines that displayed significant overexpression of EGFR. This study suggests that most tumours have a latent potential to overexpress EGFR which is realised in tissue culture."}
+{"text": "A mail survey among 970 physicians from different specialties was carried out in Italy to learn about factors that influence physicians' decision-making for patients with early breast cancer. Ninety percent of respondents were in favour of a conservative procedure for the surgical treatment of a 35-year-old patient with primary tumour smaller than two centimeters. The same preference was also expressed by 66% of doctors for a 60-year-old patient with similar disease. Most physicians (78%) favoured the use of adjuvant chemotherapy for premenopausal node-positive women. Preferences for the treatment of post-menopausal patients were divided among those in favour of endocrine therapy (51%), chemotherapy (32%), the combination of the two (7%) or no further treatment after surgery (8%). Several factors appeared to relate to therapeutic preferences. Each physician's specialty was the single most important factor associated with the preference for surgical treatment together with the attitude towards patients' involvement in decision-making which, however, was statistically significant only for the older patient. Analysis of predictors of preferences for adjuvant therapy showed that specialty and hospital size were associated with choosing chemotherapy for a premenopausal woman, and specialty and physician's sex with the indication of endocrine treatment in a postmenopausal patient. Our study documents that the application of research results depends on many factors, some of which have a sound scientific basis while others reflect highly personal opinions and the influence of the practice environment."}
+{"text": "Germ cell tumours tend to affect young adults and with advanced treatments achieve more than 90% cure rates. Over the years cisplatin has significantly improved the relapse free survival in these patients, hence forming an essential component of chemotherapy regimes. But, the thrombo-embolic complications suffered with cisplatin significantly affect the quality of life in these young patients.We describe a young adult who suffered a potentially fatal cerebral and pulmonary vascular insult on completing first cycle of cisplatin-based chemotherapy for a non-seminomatous germ cell tumour. Venous and arterial thrombo-embolism was the mechanism of injury and was promptly managed surgically and medically including neuro-rehabilitation. Thrombo-embolism is a known vascular toxicity associated with germ cell tumours, amongst which VTE (Venous Thrombo-embolism) continues to share the highest proportion. Amongst thrombotic complications, arterial thrombosis is a rare complication of chemotherapy for testicular tumours and especially in those lacking any risk factors. Herein we describe an unusual and unfortunate case of NSGCT (Nonseminomatous germ cell tumour) who suffered an extensive internal carotid artery thrombosis and saddle pulmonary embolism after BEP  regime of chemotherapy.A 36 year old previously fit and healthy non-smoker Caucasian male underwent left orchidectomy for a testicular tumour Fig.  with AFPThe overall recovery suffered another insult by an extensive saddle pulmonary embolus for which he was anticoagulated again, only this time with warfarin. The patient's neurological state showed signs of improvement in terms of speech, motor power and sensations on right upper (power 3/5) and lower limbs (power 5/5). But two months later he demonstrated seizure activity which on MRI (magnetic resonance imaging) scan confirmed haemorrhagic transformation in the large maturing previous infarct in left middle cerebral artery territory, which was effectively controlled by anti-epileptics. He later completed his second cycle of BEP regime and a surveillance CT scan showed shrinkage of common iliac lymph node to only 7 mm and the pulmonary nodule of 4 mm. Tumour markers were normal and the plan was to continue with scheduled three monthly CT scans.Cisplatin based chemotherapy as in BEP regime is considered to be highly effective in GCT, but its associated vascular complications include not only venous but also arterial thrombosis and/or hemorrhages -6 with tOur case suffered thrombosis of the carotid system on the day of finishing his first cycle of BEP chemotherapy, although the diagnosis of ischaemic stroke was delayed by a few hours due to the normal appearance of the immediate CT scan and hence, thought was directed towards a possibility of encephalitis secondary to chemotherapy induced immunosuppression. However the co-relation of history and clinical findings led to the early discovery of thrombosis of the carotid system on further investigations. It is difficult to demonstrate that early institution of active anticoagulation and emergency thrombo-embolectomy dictated his good neurologic recovery. However emergency surgery removed the thrombus from the left carotid system to a fairly good extent and the immediate active anticoagulation played a significant role to maintain the patency of blood-flow to the cerebral circulation.Pretnar et al  describeA retrospective analysis  of patieIt has been demonstrated that liver metastasis, low magnesium, high dose of corticosteroids pose an additional risk of thrombo-embolic complications in germ cell tumour patients receiving chemotherapy . Our patOur case was unique and unfortunate in suffering from both an extensive arterial thrombosis and venous embolism a few days apart with no risk factors and a negative family history and a negative cranial CT on admission.Since the introduction of cisplatin based chemotherapy in 1970s, patients have benefited from longer disease free survival and better cure rates for any adult malignancy . The 5-yWith our experience from this particular case we cannot emphasis enough the importance of history and clinical findings and their mutual co-relation to dictate the diagnosis with the subsequent aide of most appropriate set of investigations. Given the incidence of germ cell tumours in young patients and the high cure rates, patients stay disease free for a long time. Therefore prevention and early recognition of adverse effects of treatment is of paramount importance as it dictates the quality of life of these young patients.Written consent was obtained from the patient's next of kin for publication of this case report and accompanying images.Full anonymity of our case is maintained in the case report and accompanying images.The authors declare that they have no competing interests.JND was the operating vascular surgeon for the patient.RB was the vascular surgical trainee involved in the clinical management of patient, collecting the information and editing it for submission.DC was the oncologist involved in the care of our patient."}
+{"text": "The soluble oestrogen-receptor content of common breast tumours has been measured by 5 different laboratories, each using their own assay procedure. Good agreement was achieved on whether a sample was positive or negative for oestrogen receptor. Qualitative differences between laboratories could be explained by differences in thiol-reagent content of assay medium and by the method of homogenization. Recommendations are made on some of the factors involved in the routine assay of receptors in breast tumours."}
+{"text": "There was no effect of an absence of OPN on the ability of the cells to undergo immortalization or to form morphologically transformed foci following ras transfection. Wildtype and OPN-deficient cell lines were established from such foci, and lines with similar ras mRNA levels selected for further analysis. Ras -transformed cell lines from both wildtype and OPN-deficient mice could form colonies in soft agar indicating that this process can occur in the absence of OPN. However, the ability of the OPN-deficient cell lines to form colonies was reduced as compared to wildtype cell lines. Tumorigenesis in syngeneic and nude mice was assessed for a subset of cell lines that formed colonies efficiently in soft agar. Cell lines unable to make OPN formed tumors in these mice much more slowly than wildtype cells, despite similar growth of the cells on plastic and in soft agar. Taken together, these results indicate that maximal transformation by ras requires OPN expression, and implicate increased OPN expression as an important effector of the transforming activity of the ras oncogene. \u00a9 2000 Cancer Research CampaignThe secreted phosphoprotein osteopontin (OPN) is strongly associated with the process of neoplastic transformation, based both on its pattern of expression in vivo and in vitro and on functional analyses. We have used 3T3 cells derived from wildtype and OPN-deficient mice and transformed by transfection with oncogenic"}
+{"text": "The life span of C57/Bl mice inoculated with Lewis lung carcinoma cells was prolonged if the mice were pre-immunized with membranes from these cells infected in vitro with influenza virus. Likewise, BALB/c mice were protected against the malignant tumour WEHI-11 by prior immunization with extracts of cultured WEHI-11 cells which had been infected with influenza virus or Semiliki Forest virus (SFV). Partially purified SFV grown in WEHI-11 cells also protected mice from cancer grafts but neither highly purified SFV nor the glycoprotein from the envelope of this virus protected the mice. It is concluded that SFV-induced immunopotentiation against cancer is not due to covalent linkage of tumour specific transplantation antigen (TSTA) to viral envelope protein but more probably is due to the apposition of viral glycoprotein and cellular TSTA in the plasma membrane of the cancer cell."}
+{"text": "Two north Indian siblings, an 11-year-old sister and an eight-year-old brother born to non-consanguineous parents and with a negative family history, presented with severe atopic eczema and abnormal scalp hair from the first year of life . The haiEpiluminescence microscopy and light microscopy of the hair shafts was normal. Polarized microscopy showed alternating dark and light bands arranged parallel to the long axis of the hair shaft .The spangled appearance of hair under reflected light with alternate parallel banding under polarized microscopy favors the diagnosis of pili annulati. Association with atopy has not been reported in the literature according to my knowledge.Pili annulati is an extremely rare non-fragile hair shaft disorder characterized by banding leading to spangled hair. It is an autosomal dominant condition with a recently identified genetic locus on Chromosome 12.[An inherent defect in the hair shaft leads to formation of air-filled cavities within the cortex that lie parallel to the long axis of the hair. These arPili annulati has to be differentiated from pseudo pili annulati which is sometimes the feature of normal hair due to an optical illusion caused by partial twisting. Pili annulati differs from trichothiodystrophy which shows alternating light and dark bands arranged perpendicular to the long axis of the hair shaft resembling tiger's tail .Pili annulati is rarely associated with woolly hair, anhidrotic ectodermal dysplasia, blue nevPili annulati does not resolve spontaneously or improve with age. Since hairs are non-fragile no treatment is required."}
+{"text": "A malignant invasive fibrosarcoma in hamsters and a malignant mammary carcinoma in mice were each challenged with the broad spectrum proteinase inhibitor aprotinin (Trasylol). In both tumour systems, significant anti-tumour effects of aprotinin were observed. Variations in the site and dosage of aprotinin application were made in an attempt to improve the chemotherapeutic response."}
+{"text": "Tirapazamine (TPZ) is a new anticancer drug that is activated specifically at the low oxygen level typically found in solid tumours. It exhibits preferential cytotoxicity towards hypoxic cells and has been shown in preclinical studies with transplanted tumours and in phase II and III clinical trials to potentiate the anti-tumour efficacy of cisplatin without increasing its systemic toxicity. At present, the mechanism for this potentiation is unknown. Here we show that there is a schedule-dependent enhancement of cisplatin cytotoxicity by TPZ for cells in vitro that is similar to that seen with transplanted murine tumours. This cisplatin potentiation depends on the TPZ exposure being at oxygen concentrations below 1%, which are typical of many cells in tumours but not in normal tissues. Also, the interaction between TPZ and cisplatin does not occur in cells mutant in ERCC4, a protein essential for repair of DNA interstrand cross-links. Incubation of the cells with TPZ under hypoxia prior to cisplatin treatment increases cisplatin-induced DNA interstrand cross-links with kinetics suggesting that TPZ inhibits or delays repair of the DNA cross-links. In conclusion, we show that the tumour-specific potentiation of cisplatin cytotoxicity is likely the result of an interaction between TPZ and cisplatin at the cellular level that requires the low oxygen levels typical of those in solid tumours. The mechanism of the interaction appears to be through a potentiation of cisplatin-induced DNA interstrand cross-links, possibly as a result of a diminished or delayed repair of these lesions \u00a9 1999 Cancer Research Campaign"}
+{"text": "A number of men with malignant lymphoma of the histiocytic type and previous exposure to phenoxy acids or chlorophenols were observed and reported in 1979. A matched case-control study has therefore been performed with cases of malignant lymphoma (Hodgkin's disease and non-Hodgkin lymphoma). This study included 169 cases and 338 controls. The results indicate that exposure to phenoxy acids, chlorophenols, and organic solvents may be a causative factor in malignant lymphoma. Combined exposure of these chemicals seemed to increase the risk. Exposure to various other agents was not obviously different in cases and in controls."}
+{"text": "Primary small intestinal liposarcomas originating in the small bowel are uncommon with a generally poor prognosis due to the advanced stage at the time of diagnosis. We describe a case of primary small bowel dedifferentiated liposarcoma presenting as a solid mass in the right iliac fossa. The current case is unusual as the tumour seemingly originated from the bowel and the well-differentiated component was seen extensively infiltrating the bowel wall including the small bowel submucosa. Primary small intestinal malignant mesenchymal tumours are uncommon, and liposarcomas originating in the small bowel are extraordinarily rare . The earA 59-year-old gentleman presented with a history of right iliac fossa mass. The CT scan showed a solid mass not obviously attached to the small or large bowel and had a possible fatty component at the edge . The bioHistology showed the lesion to be composed of well-differentiated liposarcoma  with abrupt transition to areas with an extensive dedifferentiated component. The well-differentiated areas were represented by adipose tissue in which atypical adipocytes and lipoblasts were easily identifiable Figures . The dedThe tumour appeared to originate from the bowel and the well-differentiated component was seen extensively infiltrating the bowel wall including the small bowel submucosa. Critical examination of sections taken from the bowel wall well away from macroscopic tumour showed well-differentiated liposarcoma infiltrating along the submucosa. Furthermore well-differentiated liposarcoma was present at the resection margins Figures  despite Dedifferentiated liposarcoma (DDLPS) is a term first introduced by Evans in 1979  to descrThe nomenclature of the low-grade component of these tumours has been the subject of much confusion in the literature: the original terms \u201catypical lipoma\u201d and \u201cwell differentiated liposarcoma\u201d (WDLPS) pertain to homologous tumours arising in either the superficial or deep tissues, respectively. It was subsequently recognised that atypical lipomas and WDLPS have no metastatic potential without dedifferentiation and thus the nomenclature of these tumours was standardised in the WHO 2002 classification of soft tissue tumours. Currently all these lesions are termed atypical lipomatous tumours (ALTs) except when arising within the retroperitoneum or mediastinum. The term WDLPS was retained in these latter cases to emphasize that lesions at these particular sites are very difficult to eradicate, have a high rate of dedifferentiation, and often prove fatal. The risk of dedifferentiation occurring in ALT/WDLPS is higher in deep-seated tumours, particularly in the retroperitoneum (2/3 cases), and is probably a time-dependent phenomenon . DediffeHistologically, dedifferentiated liposarcoma is defined by the association of atypical lipomatous tumour/well-differentiated liposarcoma areas and a non-lipogenic high grade sarcoma, usually with an abrupt transition between the two components. Dedifferentiated areas exhibit a wide morphological spectrum. Most cases show areas of high-grade sarcoma resembling pleomorphic undifferentiated sarcoma or myxofibrosarcoma. In about five to 10% of cases, the dedifferentiated component shows divergent differentiation with a myogenic or osteochondrosarcomatous element. The genomic profile of DDLPS mirrors those of ALT and WDLPS, all of which show, on cytogenetic analysis, ring and giant chromosomes composed of amplified sequences of the 12q13-14 chromosome region. This amplicon is mainly composed of the MDM2 and CDK4 genes . AmplifiThe most important prognostic factor in DDLPS is location with poor prognosis for retroperitoneal tumours, largely related to difficulty in achieving complete clearance of the tumour. Histological grade is not of prognostic value , 7. The In summary we have presented a very unusual case of dedifferentiated liposarcoma of the small bowel with myogenic divergent differentiation and extensive involvement of the small bowel submucosa. The case illustrates the particular point that this form of tumour may be much more highly infiltrative and extensive than apparent clinically and radiologically. This may go some way to explain the extremely high recurrence rates of these tumours, particularly in the abdominal cavity."}
+{"text": "N-methyl-d-aspartate and \u03b1-amino-3-hydroxy-5-methylisoxazole-4-propionate postsynaptic currents, whereas other studies have highlighted the possible contribution of the neuromodulator acetylcholine. This review summarizes some recent modelling and experimental studies investigating mechanisms of attention in sensory areas and discusses possibilities of how glutamatergic and cholinergic systems could contribute to increased processing abilities at the cellular and network level during states of top-down attention.Attention is a rich psychological and neurobiological construct that influences almost all aspects of cognitive behaviour. It enables enhanced processing of behaviourally relevant stimuli at the expense of irrelevant stimuli. At the cellular level, rhythmic synchronization at local and long-range spatial scales complements the attention-induced firing rate changes of neurons. The former is hypothesized to enable efficient communication between neuronal ensembles tuned to spatial and featural aspects of the attended stimulus. Recent modelling studies suggest that the rhythmic synchronization in the gamma range may be mediated by a fine balance between  Attention is necessary for all cognitive tasks, tasks that in their most simple form require stimulus selection, response selection and performance monitoring. It serves to tune out irrelevant information, enhance perceptual abilities and increase our readiness to respond appropriately. This is achieved by increased sensory representation of the attended objects at the neuronal level, which has been demonstrated for most visual cortical areas by means of single-unit recordings in macaque monkeys .To understand how attention is implemented in the brain it is important to distinguish the control signals responsible for the generation and maintenance of attention (which originate in higher \u2018source\u2019 areas) from their effect on sensory processing and perception (which are visible in sensory areas as described in some detail below). Studies in humans and macaque monkeys have demonstrated that the control signals are mediated and maintained within circumscribed networks of the parietal and frontal cortex , \u03b1-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) and \u03b3-aminobutyric acid receptor dynamics  have been found in most species and brain areas investigated, including the visual cortex  and atteAMPA and gNMDA). An increase of gAMPA and a decrease of gNMDA allowed the pyramidal-to-interneuron loop interactions to oscillate more strongly and resulted in increased gamma activity. Within this network it was possible to adjust the conductances of AMPA and NMDA receptors (and thus the excitation/inhibition recurrent cycle) such that the network only showed gamma oscillations during stimulus presentation. Interestingly, these changes in the AMPA and NMDA receptor conductance of the network also determined whether attentional bias affected the rates more strongly or had a larger effect on the gamma synchronization  This narrow range of gAMPA:gNMDA conductance ratios generated the overall fastest neuronal RTs. (ii) It generated the largest RT differences between the attended and unattended pool. (iii) It allowed attention to strongly increase gamma modulations. (iv) Neuronal RTs inversely correlated with the attentional modulation in the gamma band, i.e. stronger attentional gamma band modulation led to shorter neuronal RTs. Thus, in-vivo  has a reduced influence on perception. In these studies attention served to reduce the influence of behaviourally irrelevant contextual stimuli  or serveA direct test of the proposal that ACh is part of the machinery of attentional modulation in visual cortex has been performed recently  and affeAMPA:gNMDA  will abolish attention-induced changes in gamma power as predicted by The data reviewed so far demonstrate that attention affects firing rates and neuronal synchrony in different cortical areas. Modelling work suggests that these two effects are complementary mechanisms. Attention-induced increases of gamma synchrony seem to depend on a finely tuned balance of NMDA/AMPA receptor activation. Attention-induced firing rate changes in V1 depend on cholinergic activation of muscarinic receptors. Intriguingly, increased cortical synchrony in the gamma band range can also be induced by stimulation of the mesencephalic reticular formation . Moreovein-vitro, in-vivo and in-silico approaches need to be integrated.The possible contribution of NMDA receptors to the attention-mediated increase in gamma oscillation is intriguing, as cognitive disorders are often associated with abnormal neural synchronization  and in sThere is additional evidence suggesting that NMDA receptors play a \u2018special\u2019 role in attention. A striking similarity exists between changes in neuronal gain that are induced by direct NMDA application and those induced by selective attention  has beenIt may also be interesting to determine the effects of NMDA receptor blockade on the frequency and overall strengths of gamma oscillations in the absence of attentional manipulations. In a pyramidal/interneuron network the frequency of oscillations is determined by the rise and decay time of the inhibitory and excitatory postsynaptic potentials . Faster 2+-dependent afterhyperpolarization adaptation. Parametric manipulation of these parameters in the model may reveal how each parameter contributes to attentional amplification and suppression in the biased competition network, and to what extent these changes are rate or synchrony based. If successful, the effect of cholinergic receptor agonist and antagonist on attention-mediated biased competition in V4 could be explored experimentally, in conjunction with possible NMDA receptor mechanism interactions.The same theoretical and computational framework that has been used to study the contribution of NMDA and AMPA receptors can be extended for a detailed study of the modulatory effects of ACh in attention. Here it will be of interest to explore how ACh could mediate biased competition in a two-area network. It is likely that this will involve modifying the strength of the recurrent connections, strength of the feedforward  input and level of Cain-vitro studies showed that persistent memory-related activity in the entorhinal cortex depends on muscarinic receptor mechanisms , and to explore how these are related in terms of their dependence on cholinergic and NMDA mechanisms. Modelling suggests that persistent mnemonic activity can be mediated by synaptic reverberations in recurrent circuits enabled by NMDA receptors , whereasThe questions outlined in this review, although challenging, can now be addressed directly in task-performing monkeys. Such experiments will provide specific insights into the mechanisms of attention. The approaches are ideally informed by detailed model predictions but ultimately these are empirical questions that have to be tested experimentally. It is unlikely that all open questions can be resolved by probing attentional modulations in a single cortical area, as different areas show differences regarding neuromodulator receptor distributions . Ultimat"}
+{"text": "Drosophila, each sensory organ precursor cell (SOP) divides asymmetrically to produce an anterior pIIb and a posterior pIIa cell. The Par6-aPKC complex localizes at the posterior pole of dividing SOPs and directs the actin-dependent localization of the cell fate determinants Numb, Partner of Numb (Pon) and Neuralized at the opposite pole. The plasma membrane lipid phosphatidylinositol -bisphosphate (PIP2) regulates the plasma membrane localization and activity of various proteins, including several actin regulators, thereby modulating actin-based processes. Here, we have examined the distribution of PIP2 and of the PIP2-producing kinase Skittles (Sktl) in mitotic SOPs. Our analysis indicates that both Sktl and PIP2 reporters are uniformly distributed in mitotic SOPs. In the course of this study, we have observed that overexpression of full-length Pon or its localization domain (LD) fused to the Red Fluorescent Protein (RFP::PonLD) results in asymmetric distribution of Sktl and PIP2 reporters in dividing SOPs. Our observation that Pon overexpression alters polar protein distribution is relevant because RFP::PonLD is often used as a polarity marker in dividing progenitors.Unequal segregation of cell fate determinants at mitosis is a conserved mechanism whereby cell fate diversity can be generated during development. In  Ontogenesis of complex multicellular organisms involves the generation of different cell types. One mechanism by which cell fate diversity can be achieved is asymmetric cell division. During asymmetric cell division, progenitor cell polarity directs the orientation of the mitotic spindle and the asymmetric localization of cell fate regulators, thereby ensuring unequal segregation of these regulators Drosophila is composed of four different cells. These cells originate from a single sensory organ precursor cell (SOP) via a fixed lineage comprising four stereotyped asymmetric cell divisions Each mechanosensory bristle located on the notum of By analogy with the role of atypical Protein Kinase C (aPKC) in neuroblasts Drosophila genome encodes three predicted PIP5KIs: PIP5K59B, CG17471 and skittles (sktl)sktl gene has been shown to play a critical role in PIP2 synthesis in the oocyte . Interestingly, the sktl gene appears to be expressed in SOPs Phosphatidylinositol 4,5-bisphosphate (PIP2) is a phospholipid present at the inner leaflet of the plasma membrane that has a wide range of proposed functions Drosophila Liquid facets (Lqf) LD) LD, PH::GFP was found to localize at the cell cortex and appeared to be slightly enriched at the posterior cortex , two proteins that colocalize with Pon at the anterior cortex of dividing SOPs To test whether the activity seen with the C-terminal LD domain of Pon indeed reveals a novel activity of Pon, a tagged version of full-length Pon was overexpressed in dividing SOPs. While expression of Pon did not detectably alter the localization of PH::GFP  or ENTH: compare  and 3A,BLD expression in SOPs . Sktl was detected at the apical cell cortex of all cells in the notum. We did not detect an increased accumulation of Sktl in SOPs. Sktl was found to accumulate uniformly at the cell cortex in dividing SOPs .We have shown that PIP2 and the PIP2-producing kinase Sktl are distributed at the cortex of dividing SOPs with no asymmetry within the plane of the epithelium. Whether PIP2 and Sktl regulate SOP polarization and/or polar localization of cell fate determinants in dividing SOPs remains to be further studied. Of note, we have not been able to analyze the phenotypes associated with a loss of We have also shown that overexpression of Pon can alter the spatial distribution of PIP2 binding proteins and of endogenous Sktl in dividing SOPs. This unexpected observation raises at least two questions and should also serve as a note of caution for studies using Pon as a marker of polarity.Multiple mechanisms may explain how Pon overexpression alters the distribution of Sktl. One hypothesis is that both proteins compete for transport machinery components and/or cortical anchoring sites. Endogenous Pon would not affect the transport and/or anchoring of Sktl but overexpression of Pon could saturate the system. Also, the posterior pole accumulation of the PIP2-binding proteins PH::GFP and ENTH::GFP in Pon-overexpressing cells can be interpreted to suggest that overexpression of Pon results either in lower PIP2 concentration at the anterior pole or in higher concentration of competing PIP2-interacting proteins. It would also be interesting to examine whether the localization of the PIP2-producing kinase is itself regulated by PIP2 levels.How may endogenous Pon regulate protein distribution at the cortex of asymmetrically dividing progenitors? A known function of Pon is to recruit Numb, most likely via direct protein-protein interaction LD alter the distribution of both PIP2 reporters and Sktl is relevant since both RFP::PonLD and GFP::PonLD have often been used to study asymmetric cell division of neural precursor cells in Drosophila [see: LD-expressing cells is likely to cause subtle deviations from the wild-type, our observation should serve as a note of caution when interpreting studies that use RFP::PonLD as a marker.Finally, our observation that Pon and RFP::Ponila see:  includinP72Gal4 ts transgene: ENTH::GFP LDThe following transgenes were expressed using neurLive GFP imaging was carried out as described in Pupal nota were dissected from staged pupae and processed as previously described"}
+{"text": "Using RNA extracted from human tumour samples removed during surgery, we have analysed expression of mRNA for parathyroid hormone-related protein (PTHrP) and for the PTH/PTHrP receptor by RT-PCR in a panel of human breast and colon tumours. All but 1 of 18 breast tumour samples expressed PTHrP, whereas receptor expression was detected in 11 of these. Expression of the PTH/PTHrP receptor was found in three out of four metastatic lesions, including one sample in which no receptor was detected in the primary tumour. PTHrP expression was also detected in five colon tumours, and receptor expression detected in two of these. These results demonstrate that PTHrP and the PTHrP receptor are also co-expressed in breast tumours in vivo and provide further evidence that PTHrP may be an important autocrine/paracrine growth factor in breast cancer."}
+{"text": "A common characteristic of cancer cells is unrestrained cell division. This may be caused by mutational changes in genes coding for components of cell cycle-controlling networks. Alterations in genes involved in G1 checkpoint control have been registered in many human tumours, and investigations from several laboratories show that such alterations, taken together, are the most frequent changes detected in cancer cells. The present paper describes mutational analysis by polymerase chain reaction-single-strand conformation polymorphism (PCR/SSCP) and nucleotide sequence analysis of the genes coding for the p15, p53 and N-ras proteins in 26 metastases from 25 melanoma patients. The registered mutation frequencies add together with previously registered mutations in p16 in the same patient samples to a substantial total frequency of 44% of patients with mutation in at least one of the investigated genes. These results show the occurrence of heterogeneous defects among components of the cell cycle controlling machinery in a human melanoma tumour sample collection and demonstrate that the total frequency of detected alterations increases with the number of cell cycle controlling genes included in the screening panel."}
+{"text": "Given escalating rates of chronic disease, broad-reach and cost-effective interventions to increase physical activity and improve dietary intake are needed. The cost-effectiveness of a Telephone Counselling intervention to improve physical activity and diet, targeting adults with established chronic diseases in a low socio-economic area of a major Australian city was examined.A cost-effectiveness modelling study using data collected between February 2005 and November 2007 from a cluster-randomised trial that compared Telephone Counselling with a \u201cUsual Care\u201d (brief intervention) alternative. Economic outcomes were assessed using a state-transition Markov model, which predicted the progress of participants through five health states relating to physical activity and dietary improvement, for ten years after recruitment. The costs and health benefits of Telephone Counselling, Usual Care and an existing practice  group were compared. Telephone Counselling compared to Usual Care was not cost-effective . However, the Usual Care group did not represent existing practice and is not a useful comparator for decision making. Comparing Telephone Counselling outcomes to existing practice , the intervention was found to be cost-effective . Usual Care (brief intervention) compared to existing practice  was also cost-effective .This modelling study shows that a decision to adopt a Telephone Counselling program over existing practice  is likely to be cost-effective. Choosing the \u2018Usual Care\u2019 brief intervention over existing practice  shows a lower cost per quality adjusted life year, but the lack of supporting evidence for efficacy or sustainability is an important consideration for decision makers. The economics of behavioural approaches to improving health must be made explicit if decision makers are to be convinced that allocating resources toward such programs is worthwhile.ACTRN012607000195459This paper uses data collected in a previous clinical trial registered at the Australian Clinical Trials Registry, Australian New Zealand Clinical Trials Registry: Anzcrt.org.au  Non-communicable diseases are projected to cause over three-quarters of deaths in 2030 In Australia, it has been estimated that for every 1% increase in the proportion of the population that becomes physically active, 100 deaths from coronary heart disease could be avoided, and $7.2 million in overall direct health care costs could be saved Despite this evidence, a significant gap in the translation of research-into-practice remains, with only a small proportion of effective interventions adopted. Reasons for this might include a lack of dissemination research Reviews of cost-effectiveness studies on health behavior change interventions have identified significant gaps in knowledge. Dalziel et al. There exists an evidence base for the efficacy of telephone-delivered interventions for physical activity and dietary behaviour change A cluster-randomized trial of a telephone counselling intervention for physical activity and diet was conducted among adults from a low socio-economic community in Australia Participants were randomised to Telephone Counselling (n\u200a=\u200a228) or Usual Care (n\u200a=\u200a206). Participants in the Telephone Counselling group received a 12-month intervention involving 18 telephone calls from trained counsellors. The intervention schedule was adapted from the work of King and colleagues to facilitate initiation and then maintenance of behaviour change All costs are reported in 2008 Australian dollars. The cost of delivering the Telephone Counselling intervention and the Usual Care alternative were measured during the primary trial. Single-use items such as workbooks and mail-outs were attributed to participants. The jointly used resources of telephone counsellor time, fixed overheads and the staff costs of managing the program were allocated to participants on the basis of the number and duration of calls. All costs incurred were allocated across successful contacts. The dollar costs of input factors were obtained by a review of local market prices. The participant use of health care services between baseline and 12 months were self-reported and collected by validated questionnaire Diet and physical activity outcomes of the trial were assessed using telephone interviews at baseline, 4-months and 12-months. Validated instruments used in Australian population health surveys were employed Risk of death was based on the estimated future mortality risks of the subjects in the trial. Self-reported data were collected on age, sex, body mass index, cigarette smoking status, history of diabetes mellitus or cardiovascular events, hypertension and hypercholesterolemia. The latter two were converted to systolic blood pressure and total serum cholesterol by imputing the age and sex-specific average values Cost-effectiveness was assessed using a state-transition Markov model, which predicted the progress of participants through five health states for ten years after recruitment. The structure of the model is shown in The first comparison, which is based on the cluster randomised trial, is Telephone Counselling vs. Usual Care. Comparison groups in randomised trials are often inappropriate comparators for cost-effectiveness analyses and decision making The model shown in The probability an intervention was cost-effective vs. the relevant comparator was estimated by taking 2,000 random re-samples from the probability distributions for parameters; and then counting the number of times the monetary net benefit statistic was positive over the total number of re-samples The costs of delivering the Telephone Counselling intervention were estimated to be $570 for the first year and $410 per year for all subsequent years up to year 10. The costs of delivering Usual Care were estimated to be $134 per year for all 10 years. Plots that show membership of the Markov health states for Telephone Counselling, Usual Care and existing practice alternative  over time are included in The means and 95% Bayesian credible intervals of incremental cost (\u0394C) and QALY (\u0394E) outcomes for all comparisons are included in There are no published studies that describe the economics of changing health behaviour in the Australian setting and few published internationally which evaluate the use of telephone-delivered interventions, despite evidence for the effectiveness of this modality The comparison arising from the cluster-randomised controlled trial is whether to adopt Telephone Counselling over Usual Care, but this choice is unlikely to be relevant to decision makers. The Usual Care \u2018control\u2019 group did not approximate existing practice, which decision makers might prefer to use as the comparator for alternate programmes. The Usual Care group underwent extensive health behaviour assessment as part of their trial participation, and to minimise attrition and comply with ethical standards, they received behavioural feedback and generic print materials. Improvements among the Usual Care participants may have arisen as a result of their participation in assessment A useful comparison for decision-making is between Telephone Counselling and existing practice . The findings from this comparison show a decision to adopt Telephone Counselling over existing practice  is cost-effective given current information. For full transparency, the brief intervention of Usual Care was compared with existing practice ; this revealed the lowest incremental cost-effectiveness ratio  and highOther economic analyses of physical activity and diet behaviour change programs show evidence for cost-effectiveness. Cobiac et al. This modelling study has strengths and weaknesses. Predicting the health behaviours of participants for ten years after recruitment has an advantage over trial-based evaluations that only capture events that happen during the period of data collection Risk of death was not reduced in the model when participants adhered to the good health behaviour. There is evidence that improving physical activity and diet reduce risk of premature death"}
+{"text": "The concentrations of IgG in acidic and 3MKCl eluates of resected colonic carcinomas and adjacent normal tissue were determined by radioimmunoassay. The mean concentration of IgG was significantly higher in both acidic and KCl eluates of primary Dukes Stage C tumours than Dukes Stage A tumours. These results provide direct evidence for increased fixation of IgG in vivo by human colonic cancers which had metastasized. Our results also raise the possibility that IgG is more tightly bound to the Stage C tumours. It is likely that this tumour-associated Ig represents antibody to tumour antigens or antigen-antibody complexes, bound to Fc receptors in the tumour."}
+{"text": "This approach could both reduce the need for animal testing and speed up the regulatory process.Government agencies rely on toxicity data to help make key regulatory decisions on pesticides and other chemicals in the environment. But thousands of chemicals, including many currently in commerce, have yet to be tested for potential toxicity and impact on human diseases. Such testing can be time-consuming and expensive; a full set of regulatory tests for a single chemical may use thousands of animals and cost millions of dollars. To help address this large backlog of untested chemicals, the U.S. Environmental Protection Agency (EPA) recently completed the first phase of its large-scale ToxCast\u2122 program, which looks at the potential for combining faster and less expensive in vitro assays for understanding the types of molecular and pathway perturbations caused by chemical exposures and computer-based prioritization models for in vivo toxicity. In phase I, researchers chose 309 chemicals for which toxicity data were already available. Using 467 in vitro assays across 9 technologies, including high-throughput cell-free assays and cell-based assays in multiple human primary cells and cell lines, they investigated a broad spectrum of chemical activities at the molecular and pathway levels. Matching these in vitro results with existing data helped researchers build initial prioritization models for predicting toxicity of similar but untested chemicals.The ToxCast program evaluates the use of in vitro high-throughput data can help predict mechanisms of action for many other well-studied chemicals and indicate which other biological pathways may also be activated. This will lay the groundwork for screening untested chemicals and provide vital guidance for future testing.This process also provided information on underlying mechanisms of toxicity, which are difficult to investigate directly using animal models. Using human cells or human cell constituents allowed researchers to measure the effects of chemicals on toxicity pathways that may be relevant to human disease. Based on the phase I examples, the ToxCast researchers feel confident that in vitro testing can help predict human toxicity. Phase II could be completed over the next several years.The authors hope molecular and computational models will help better guide targeted testing of environmental contaminants but caution that building this new paradigm will itself take time and require input from multiple government organizations. They are launching a second phase of ToxCast to expand on and further confirm that"}
+{"text": "An international conference on mobile DNA was held 24-28 April 2010 in Montreal, Canada. Sponsored by the American Society for Microbiology, the conference's goal was to bring together researchers from around the world who study transposition in diverse organisms using multiple experimental approaches. The meeting drew over 190 attendees and most contributed through poster presentations, invited talks and short talks selected from poster abstracts. The talks were organized into eight scientific sessions, which ranged in topic from the evolutionary dynamics of mobile genetic elements to transposition reaction mechanisms. Here we present highlights from the platform sessions with a focus on talks presented by the invited speakers. The meeting was launched with a Keynote Address by Frederic Bushman . Bushman summarized the extensive work his laboratory has conducted over the past several years to better understand mechanisms of retroviral integration. The Bushman laboratory pioneered the use of high throughput sequencing methods to map large numbers of retrovirus insertion sites. Bushman described how this approach revealed a preference for HIV to integrate into transcription units and the features of transcriptionally active chromatin that characterize these preferred sites. The relevance of this work was brought home when Bushman discussed integration patterns in the genomes of patients who received retroviral gene therapy. A better mechanistic understanding of how integration sites are selected should lead to better therapeutic approaches and limit the mutagenic outcome that caused leukemia in some of these patients.Over the past several years, mobile DNA has progressively moved from second fiddle to centre stage in the field of genome evolution. The 'genome evolution' session highlighted the intricate and intertwined evolutionary trajectories of parasitic elements and their host genomes. Presenters and audience alike were amazed by the omnipresence and bewildering diversity of mobile DNA as they swung from one branch of the tree of life to another .Although viruses are found virtually everywhere on the planet, it is in the oceans that their abundance and extraordinary diversity is the most impressive, as Curtis Suttle  explained. He argued that viruses should be viewed both as an essential component of the ecosystem and as a threat to cellular organisms.A flurry of talks by Mark Batzer , Brandon Gaut , Pierre Capy  and Richard Cordaux  presented the results of empirical and theoretical studies, showing how adaptive processes  as well as non-adaptive processes  and life history traits of the host species  have helped to shape the diverse genome landscapes adorned by transposons.Drosophila population genomics to uncover a set of rare transposon insertions likely to be involved in the flies' adaptation to temperate climates. Another approach presented by C\u00e9dric Feschotte , which relies on multi-species genome alignments to demarcate evolutionarily conserved and likely functional elements, revealed thousands of primate-specific conserved non-coding sequences derived from transposable elements. Another mode of transposon domestication, whereby the transposition enzymes themselves are co-opted for host genome function, was illustrated by Irina Arkhipova . She discovered an intriguing group of reverse transcriptases in fungi that apparently serve an, as yet, uncharacterized cellular function. Brian Higgins , provided evidence for the involvement of transposases in programmed genome rearrangement in the ciliate Oxytricha.Another group of presentations focused on the involvement of mobile elements in the function of the genome. Josefa Gonzalez  drew on the power of The genome diversification session contained an eclectic collection of talks on widely differing systems and organisms, unified by a common theme. Marjorie Oettinger  discussed V(D)J recombination, the DNA rearrangement process that generates a highly assorted collection of immunoglobulin molecules. She reported data on a new regulatory mechanism for V(D)J shuffling. The C-terminus of the recombination-activating gene 2 (RAG2) protein (one of the recombinase subunits) preferentially recognizes histone H3 that is dimethylated at Arg2 and trimethylated at Lys4, and methylation increases V(D)J recombination. Another layer of regulation may be contributed by chromatin accessibility modulated by the DNA binding protein CCCTC-binding factor, whose expression is regulated by an extracellular signal.Paramecium  and Alexander Vogt on Tetrahymena (Austrian Academy of Science). During the sexual development of these organisms a new macronucleus is derived from the germline which involves a process referred to as DNA elimination. During this process a large number of internal eliminated sequences (IESs) are removed. Both groups have shown that this process is driven by a domesticated piggyBac transposase in Paramecium and Tetrahymena, providing yet another example of a domesticated transposase with an important function. The domesticated transposase localizes to the new developing macronucleus in both organisms. The CNRS group has also highlighted a role for DNA ligase IV/XRCC in completing the DNA elimination reaction.Genome diversification in ciliated protozoans was also a focal point of the session, with talks by Mireille Betermier on Trypanosoma brucei results in a 200-fold increase in VSG recombination. Moreover, naturally occurring DSBs were detected upstream of the expression locus, suggesting that DSBs may be the trigger that initiates the DNA rearrangements underlying antigenic switching. The mechanism of DNA switching at the vlsE locus in Borrelia burgdorferi is being studied in the laboratory of George Chaconas . He reported that, out of the 14 genes identified in antigenic switching in Neisseria, only the ruvAB function is required in B. burgdorferi. The lack of a requirement for recA and other recombination/repair functions may be explained by the observed ability of DNA sequences in the vls locus to promote synapsis and template strand switching by DNA polymerase to generate recombinant DNA molecules. These findings suggest an unusual DNA-driven mechanism for antigenic switching that reduces protein involvement in the recombination process at the antigenic variation locus in this organism.Other examples of a genome diversification process are the DNA rearrangements underlying changes in surface proteins (antigenic variation) by which pathogens escape immunosurveillance in the host. Nina Papavasiliou  reported that induction of a double-stranded break (DSB) contiguous to the expressed variant surface glycoprotein (VSG) gene of A very unusual mechanism of genome diversification was discussed by Jeff F. Miller . Diversity-generating retroelements (DGRs) are found in bacteria and phage, including human pathogens. These elements direct nucleotide substitutions (A to any base) within specific regions in protein coding sequences in target genes through a mutagenic homing pathway. The results are a constellation of diversified proteins with altered properties. Such sequence scrambling can offer a selective advantage for protein optimization through diversification, particularly in surface receptor proteins. The non-proliferative copy-and-replace mechanism involves integration of diversified complimentary DNA (cDNA) copies generated by the DGR-encoded reverse transcriptase.in vitro high-resolution crystallographic dissection of transposase architecture to an in vivo analysis of the roles of host proteins in transposition. They provided answers to some long-standing issues in the field and also provided exciting new topics to be explored.The very interesting talks in the 'DNA transposons' session ranged from an Mos1 transposase bound to DNA. Notably, the configuration of the Mos1 transposon ends is quite distinct from that of Tn5, the only other DNA-transposase co-crystal. In Mos1, the two transposon ends are positioned in parallel in the active sites of the transposase dimer as opposed to the anti-parallel alignment in Tn5.Fred Dyda  discussed the known structures of DNA transposases and retroviral integrases of the DDE type. He emphasized that, while we do know the structure of several such enzymes, many more transposable elements have been bioinformatically described for which there has been no experimental work. Will all these other elements fit the DDE paradigm and transpose using similar chemical steps? Julia Richardson  presented her structure of the Mos1 that support the view that the active transposase form is indeed a dimer but that a single protomer bound to each end carries out a double strand break - that is, cleaves both the 5' and 3' strands at each end. However, it remains to be determined how a single protomer can promote cleavage of both DNA strands. Rasika Harshey  provided a key insight into a long-standing issue in Mu transposition of how donor site DNA that contains the 5' ends of the transposon is cleaved upon integration into the bacterial chromosome to form the Mu lysogen. She has identified a 5' end endonuclease activity in the Mu transposase that performs the 3' end cleavage and target-joining steps.Several talks focused on how cleavage at the transposon ends occurs. Corentin Claeys Bouuaert  reported experiments also using Tn7 TnsE protein interacts with the bacterial processivity factor and is thus recruited preferentially to replicating DNA. Nancy Craig  presented work demonstrating that, in a heterologous Saccharomyces cerevisiae system, the favoured chromosomal targets of the insect hAT element Hermes are nucleosome-free regions.Two other talks dealt with how transposon target sites are found. Joe Peters  discussed his findings that the The session on non-LTR retrotransposons and group II introns illustrated both the continued activity of these elements in altering the human genome and the remarkable diversity of regulatory mechanisms of the various non-LTR elements. Talks by Haig Kazazian  and John Moran  described new approaches to detect the remarkable level of ongoing L1 activity in the human genome. The Kazazian talk utilized a polymerase chain reaction (PCR)-based approach combined with next generation sequencing to look at L1 diversity in 25 different human genomes. He found that there were typically about 285 L1 inserts which were polymorphic between any two different individuals and approximately 10,000 such polymorphisms among the 25 individuals surveyed.The Moran study utilized a paired-end sequencing procedure on fosmids from different individuals that allowed identification of full-length and, therefore, potentially active elements in six geographically distinct individuals. This approach avoids the use of PCR which aided in testing the retrotransposition potential of these elements, and they found that highly active elements are much more common in the genome than previously predicted.The L1 talks were rounded out by Elena Khazina , who presented an elegant model of L1 open reading frame (ORF)1p function based on crystal structure determination at the 1.4 angstrom level. She found a strikingly flexible structure between the required RNA recognition motif (RRM) and C-terminal (CTD) domain that suggests a need for a dynamic structure in functional ORF1p. Tom Eickbush  pushed his studies on the target-primed reverse transcription of insect R2 elements to a new level by demonstrating that their processing from the ribosomal transcripts in which they are initially made is the result of a conserved ribozyme domain that specifically cleaves at the 5' end of the functional R2 RNA.There were two talks on SINEs from Prescott Deininger  and Jean-Marc Deragon . Deininger summarized the structural features of human Alu elements that combine to silence all but the most recent Alu inserts. Variations in the A-tail led to the most rapid decline of activity with damage to the 3' end of the A-tail being most disruptive. These rules helped identify the most likely source element for an Alu insertion causing cystic fibrosis. Deragon described more diverse groups of short interspersed nuclear elements (SINEs) found in maize with a particular emphasis on SINE families that end in runs of T residues rather than As. The polythymine (polyT) end on these element families is not consistent with the classical target primed reverse transcription (TPRT) mechanism and suggests the need for an as yet unknown variation on the normal priming mechanism.Marlene Belfort  spoke about group II introns, which are self-splicing RNAs found principally in prokaryotes and archaea. Group II introns are hypothesized to be precursors to eukaryotic spliceosomal introns. However, they are not found in eukaryotic nuclear DNA. By introducing a bacterial group II intron into the yeast genome, Belfort's group found that the intron is spliced effectively but the RNA is subject to nonsense-mediated mRNA decay and is poorly translated. This suggests a hostile eukaryotic genome may have promoted intron loss and the evolution of a protein-dependent splicing apparatus.Kluyveromyces lactis to the exogenous HIV retrovirus that infects human cells.The talks in the 'host-element interactions' session revealed the ever-expanding diversity of mechanisms by which host-element crosstalk reflects developmental changes in the organism and influences genome structure. Each talk focused on different host-element relationships, ranging from the highly domesticated a3 DNA transposon of the yeast, K. lactis a3 mating-type (MAT) gene is a transposon that is excised from the chromosome as a circular DNA molecule. The \u03b13-encoded protein contains a DDE motif that is conserved among transposases and is essential for the excision event and for mating type switching. Mobilization of the \u03b13 transposon results in a chromosome break. Formation of the chromosome break induces the introduction of a-cell-specific information from another chromosomal locus, completing the switch from MAT\u03b1 to MATa. Excision circle formation, and therefore mating-type switching, requires the host Mts1 protein which, in turn, is regulated by the nutrient-sensing RAS/cyclic adenosine monophosphate (cAMP) pathway, thereby linking this transposon-mediated mating type switch to nutrient availability.Stefan \u00c5str\u00f6m  presented evidence that the S. cerevisiae is not as domesticated. However, its mobility is regulated by environmental stresses through host cell signalling pathways and it facilitates chromosomal rearrangements, retrogene formation and telomere elongation in the absence of telomerase. Therefore, it is not surprising that Ty1 retrotransposition relies heavily on the host to carry out basic replication steps, such as Ty1 RNA packaging into virus-like particles. Joan Curcio  reported that packaging of Ty1 RNA requires the host 5' to 3' mRNA degradation pathways. Ty1 RNA is sequestered from translation in high molecular weight particles, and Ty1 Gag localizes to mRNA processing bodies, where the 5' to 3' mRNA degradation machinery is concentrated. Curcio speculated that Ty1 RNA packaging might be associated with the host mRNA degradation machinery to exclude cellular mRNAs from Ty1 virus-like particles.By comparison to the a3 transposon, the Ty1 retrotransposon of MuDR elements of maize. He revealed a surprising loss of epigenetic control of MuDR expression in leaves that are undergoing a transition from juvenile to adult. Lisch speculates that there is a close relationship between the transition to reproductive maturity and mechanisms for transposon recognition and silencing.Transposable element activity is frequently held in check by the activity of a nuclear immune system that silences potentially dangerous repetitive DNA. Damon Lisch  talked about regulated expression of the How does the intimate host-element relationship begin? Sarah Schaack  presented recent findings that address this question. Transposable element families in a blood-sucking triatomine bug are almost identical to those found in the genomes of a variety of phylogenetically diverse animals that are related by their geographic distribution and by being hosts to the triatomine bug. The findings by Schaack and colleagues highlight the central role that parasites may play in introducing transposable elements (TEs) from one animal species to another by horizontal transfer. The subsequent expansion of horizontally transferred TEs is likely to impact the structure of the host genome.Alan Engelman  rounded off the session by discussing the idea of exploiting the host-element relationship. The lentiviral integrase binding protein, lens epithelium-derived growth factor (LEDGF) is involved in targeting HIV to active genes during integration. Altering the chromatin binding capacity of recombinant LEDGF fusion proteins redirected HIV to novel integration sites, suggesting that LEDGF fusions could one day help steer lentiviral gene therapy vectors to benign regions of the human genome. Engelman also presented a new model for the active HIV intasome nucleoprotein complex based on the recent foamy virus integrase-DNA crystal structure, which highlighted novel HIV integrase-DNA contacts.S. cerevisiae. Mapping the positions of individual integration sites revealed that Ty5 integrates specifically into regions of heterochromatin such as the mating type locus and telomeres. In order to get a comprehensive view of insertion sites throughout the genome, Voytas used ligation-mediated PCR and 454 pyrosequencing. This approach provided thousands of insertion sites and was able to show that a full 5% of the insertions occurred in euchromatin. Interestingly, the insertions in euchromatin clustered upstream of ORFs. Additional analysis revealed that Ty5 integration avoided ORFs and nucleosomes but showed an association with origins of replication.The 'LTR retrotransposon' session began with a talk by Dan Voytas  who described work from his laboratory on the LTR-retrotransposon Ty5 and its behaviour in Arabidopsis thaliana. The protein DDM1 is responsible for methylating transposon sequences. Strains lacking DDM1 exhibited very high levels of transposition of the elements ATGP3, ATCOPIA13, ATCOPIA21 and ATCOPIA93. Kakutani also described wild isolates of plants that contained recent bursts of transposition of ATCOPIA93 all of which were found in centromeres. The patterns of transposition caused by the mutation of ddm1 were similar to those in wild plants suggesting that the DDM1 system serves as an important model for the mobility of transposons in A. thaliana.DNA methylation in mammalian cells is known to repress the activity of transposable elements. Tetsuji Kakutani  described his study of DNA methylation in Schizosaccharomyces pombe integrates with a strong preference for the promoters of pol II-transcribed genes. Henry Levin  described the use of pyrosequencing to identify large numbers of Tf1 insertions. These data provided a highly reproducible measure of integration levels within each promoter of the genome. Interestingly, the bulk of Tf1 integration occurred within just 20% of all promoters. Levin also described the transposition activity of Hermes, a DNA 'cut and paste' transposon from the housefly. Hermes exhibits high levels of transposition in S. pombe and 33% of the inserts occurred within ORFs. With this system, Levin used pyrosequencing of integration in a haploid to map the essential genes of S. pombe. This approach represents a novel application of pyrosequencing for mapping essential sequences throughout the genome.The LTR-retrotransposon Tf1 of Classic site-specific recombinases from the serine family were featured in two talks. Both of these recombinases are regulated by substrate topology and are activated in the context of a larger complex that promotes a dimer-tetramer transition. Reid Johnson  detailed extensive cross-linking of Hin invertase and its host cofactor Fis, leading to a well-supported model for the full synaptic complex. Marshall Stark  described an extensive analysis of the conserved residues found in the catalytic site of Tn3 resolvase and the very surprising result that only the very C-terminal portion of the catalytic domain is required for synaptic tetramer formation.Tyrosine recombinases comprise the other 'classic' family of site-specific recombinases. CTnDOT, a conjugative transposon integrase, is an unusual example that was described by Jeff Gardner . Unlike other family members, this integrase is not deterred by mismatches within its crossover site. Sequence alignments also imply that it is missing a critical catalytic residue. However, structural modelling and biochemical experiments show that it may be replaced by another residue from a different portion of the primary sequence that could occupy the same position in the tertiary structure.in vivo, perhaps through the influence of host factors. Jaroslav Nunvar  described the genomic association of a subfamily of these transposases with bacterial repetitive extragenic palindromic (REP) elements, suggesting that REP elements may be mobilized by Y1 transposases. Finally, Phoebe Rice  presented a crystal structure of an active complex of bacteriophage Mu transposase, a DDE-family enzyme, bound to both phage ends and target DNA.Three talks focused on the IS200/605 family of 'Y1' transposases. These enzymes are a branch of the His-hydrophobic-His motif (HUH) superfamily of nucleases and are remarkable among transposases for acting on single-stranded DNA substrates and recognizing a short target sequence through DNA-DNA contacts. Mick Chandler  described how these elements target replication forks while Laure Lavatine from the Chandler laboratory presented data showing that IS608 transposase is targeted to stalled replication forks The conference was capped with a session addressing biological impacts of transposition and included talks that provided a new understanding of key transposition mechanisms as well as additional insights into how mobile elements shape the biology of their hosts.S. cerevisiae, which prefers to integrate upstream of genes transcribed by RNA polymerase III. Using high throughput DNA sequencing to analyze thousands of Ty1 integration events, Boeke provided evidence that Ty1 integrates preferentially into nucleosomes upstream of preferred targets. A clear integration hotspot was observed in the nucleosome-bound DNA, suggesting histone modifications may dictate this integration bias.Peter Cherepanov  reported on his recent and much anticipated structure of the complete foamy virus integrase bound to DNA. Cherepanov observed extensive protein-DNA and protein-protein interactions among the three structural domains of integrase. Binding of strand-transfer inhibitors displaced viral DNA from the active site and the extension of these studies should aid in the development of new antiretroviral drugs. Further, this work allows the structural modelling of other retroviral integrases, including HIV. Mechanisms of DNA mobility were also addressed by Alan Lambowitz . The Lambowitz group studies mobile group II introns, and work was presented describing the mechanisms that contribute to the proliferation of group II introns in thermophilic cyanobacteria. Interestingly, group II introns from thermophiles rely on elevated temperatures to help promote DNA strand separation, making it possible for them to utilize a larger number of DNA target sites through base pairing with the intron RNA. Jef Boeke  moved one step away from the transposition reaction to assess effects of chromatin on retrotransposon target site choice. Boeke's element of study was Ty1 from Arabidopsis pollen and egg development. Activation occurs in somatic companion cells that do not provide DNA to the fertilized zygote. Small RNAs corresponding to transposable elements in these somatic cells are thought to reprogram heterochromatin in the germline to silence mobile elements and preserve genome integrity in the next generation. The theme of host-element interactions was further developed by Harmit Malik . Malik described the new field of paleovirology - the study of ancient, extinct viruses and how they impact host genome evolution. The most obvious paleoviruses are the endogenous retroviruses that riddle most vertebrate genomes. Malik suggests that other paleovirus infections influenced the evolution of host defense mechanisms and thereby the repertoire of defense strategies available to combat emerging viruses.Rob Martienssen  moved the discussion further into the realm of host/element interactions. The Martienssen group has shown that otherwise silent transposable elements become activated during The tradition of a large international meeting on 'mobile DNA' will continue. In the spring of 2012, the International Congress on Transposable Elements will be held in St Malo, France. Stay tuned for more details!A: adenine; DDM1: deficient in DNA methylation 1 protein; DGR: diversity-generating retro element; DSB: double-stranded break; LEDGF: lens epithelium-derived growth factor; LTR: long terminal repeat; MAT: mating-type; mRNA: messenger RNA; ORF: open reading frame; PCR: polymerase chain reaction; REP element: repetitive extragenic palindromic element; SINE: short interspersed nuclear elements; TE: transposable element; VSG: variant surface glycoprotein gene.The authors declare that they have no competing interests."}
+{"text": "One of the challenges in the analysis of microarray data is to integrate and compare the selected  gene lists from multiple experiments for common or unique underlying biological themes. A common way to approach this problem is to extract common genes from these gene lists and then subject these genes to enrichment analysis to reveal the underlying biology. However, the capacity of this approach is largely restricted by the limited number of common genes shared by datasets from multiple experiments, which could be caused by the complexity of the biological system itself.We now introduce a new Pathway Pattern Extraction Pipeline (PPEP), which extends the existing WPS application by providing a new pathway-level comparative analysis scheme. To facilitate comparing and correlating results from different studies and sources, PPEP contains new interfaces that allow evaluation of the pathway-level enrichment patterns across multiple gene lists. As an exploratory tool, this analysis pipeline may help reveal the underlying biological themes at both the pathway and gene levels. The analysis scheme provided by PPEP begins with multiple gene lists, which may be derived from different studies in terms of the biological contexts, applied technologies, or methodologies. These lists are then subjected to pathway-level comparative analysis for extraction of pathway-level patterns. This analysis pipeline helps to explore the commonality or uniqueness of these lists at the level of pathways or biological processes from different but relevant biological systems using a combination of statistical enrichment measurements, pathway-level pattern extraction, and graphical display of the relationships of genes and their associated pathways as Gene-Term Association Networks (GTANs) within the WPS platform. As a proof of concept, we have used the new method to analyze many datasets from our collaborators as well as some public microarray datasets.This tool provides a new pathway-level analysis scheme for integrative and comparative analysis of data derived from different but relevant systems. The tool is freely available as a Pathway Pattern Extraction Pipeline implemented in our existing software package WPS, which can be obtained at  Microarray and other high throughput (HTP) technologies have exponentially increased in popularity in recent years and consequently have generated tremendous amounts of data. This data provides great opportunities for systems-level understanding of the underlying biological themes of complex experiments. As a result, a wide range of software tools that process and analyze the data using different approaches and algorithms have been developed including clustering methods  allows an integrative and comparative analysis to be performed. This provides for a deeper understanding of the underlying biology and consolidation of initial observations made from individual studies. Furthermore, the systems-oriented approach allows for additional insights from combined datasets. For example, diseases such as prostate cancer have been studied by many different groups. These data from different platforms and independent samplings provide the opportunity not only to assess the consensus of these studies and the variation levels of the patient population, but also to perform integrative analysis for signatures at both gene and pathway level.A conventional way to integrate and compare multiple experiments derived from independent research groups or even different technologies for common or unique underlying biological themes is to derive common genes amongst them before subjecting them to enrichment analysis to reveal the underlying biology. However, such an approach often encounters limitations caused by the diversity of technologies and the complexity of the biological system itself.Many of the available software tools primarily retrieve expression patterns at the individual gene level and generate a list of genes that are differentially expressed or have certain expression patterns across samples. Even the software tools that employ ORA or GSEA methods -16, usuaIt has become more and more evident that gene level signatures or classifiers that can consistently characterize different tumor types are relatively hard to validate across different studies due to the complexity of the underlying biology , experimental variation, and even the choice of data processing  and analysis methods/algorithms. This observation likely results from the fact that many complex diseases including cancers, heart disease and hypertension have been shown to be caused by mutations in multiple genes in the same or related pathways -20. WhilUsing this rationale as our motivation, we developed a high-throughput Pathway Pattern Extraction Pipeline (PPEP) within the existing pathway analysis tool WPS , to specAs a proof of concept of this exploratory tool, we have used PPEP to analyze both public microarray datasets and datasets from our collaborators. In summary, we found that this new analysis pipeline dramatically enhanced the ability of research investigators to uncover the underlying biological themes that are shared or unique among different but related systems represented by these genes lists or datasets through pathway-level comparative analysis.The first version of WholePathwayScope or WPS provides a platform for pattern extraction at the gene-level and also allows generation of gene-term association networks (GTANs) . In thisPPEP is implemented within the existing WPS software platform and runs in the WPS environment. It utilizes an enhanced WPS internal database with more species coverage  and more functional categories including GSEA gene sets, predicted transcription factor target genes, and miRNA target genes for human and mouse. The goal of PPEP is to perform pathway-level comparative analysis of underlying biology represented by multiple lists of signature genes, differential genes, or patterned genes derived from different studies, different groups, and/or even different technologies and platforms. In our current release of WPS, PPEP works side by side with our newly developed pathway-ranking method-SLEPR  forming As illustrated in Figure The generic step-by-step procedure for PPEP is described as follows Figure . First, The PPEP in WPS provides an opportunity to study the underlying common or unique biological themes among multiple gene lists derived from related but different systems or class comparisons. It can also be used to assess different datasets with the same or even different microarray platforms or HTP datasets using other technologies that measure different aspects of the biological systems. For example, one could ask what can be found in common between different studies of the same disease, since it has been found in many cases that only a few common genes are found for similar studies or for the same study but with different analysis methods ,25. HoweThe major features and functionalities of the newly developed pathway pattern extraction pipeline (PPEP) in WPS are illustrated using example data in the following section. Although only microarray data is utilized here as examples, any source of HTP data would be equally suitable for the analysis with PPEP. More examples are also provided as supplementary files.One of the major advantages of PPEP is the ability to compare the biological themes for multiple gene lists derived from different studies at the pathway-level. To provide examples of such an analysis scheme, we chose to use the prostate cancer datasets derived from different research groups and collected in the Oncomine database . This alFrom the Oncomine database, we downloaded a total of 6 microarray datasets that all specifically studied prostate cancer -32 but wConventionally, to identify the common elements between datasets from different studies, the shared differential genes can be obtained, from which the biological themes can be deduced using enrichment analysis methods ,13. It hTo compare the conventional gene-level analysis method with our pathway-level pattern extraction method implemented in the PPEP, we first used WPS gene pattern extraction feature to retrieve 52 genes, which are differentially expressed between prostate tumor and normal tissues and are commonly shared among all of the 6 datasets  described previously .We first preprocessed the data by z-score transformation of the data and then sorted the genes into individual gene lists as highly expressed genes for each corresponding sample with the criteria that the z-score was no less than 1. Finally, we subjected these gene lists to the PPEP. The goal of this analysis is to look for those biological processes that are uniquely but consistently enriched in highly expressed genes within certain types of tissues. We chose to examine those biological processes that are shared amongst in the testis-related tissues but distinct from the rest of the tissues in the dataset. We chose the subset, since there are only 5 testis-related tissues  in the dataset and testis-related biological processes are relatively unique and specific compared to other tissues. The analysis result should be easily interpreted based on their biological expectations.We set up the pathway pattern extraction template exactly as illustrated in Figure To compare the gene-level analysis with the PPEP method, we also obtained the common genes from the highly expressed gene lists of the 5 testis-related tissues and subjected them to enrichment analysis on GOBP terms. We retrieved the top 16 enriched GO terms and compared them with those 16 GO terms that were identified using PPEP. Interestingly, many of these top ranked 16 terms derived from common gene list-based approach in fact were also widely enriched in many non-testis tissues (data not shown), which is in contrast to the behavior of the 16 terms derived from the PPEP. This observation indicated that PPEP method showed a much more specific enrichment pattern in testis-related tissues than the common gene list-based approach. Similar to the case study with prostate cancer dataset described earlier, this observation indicates that the gene-level method appeared to have more difficulty to uncover the unique biological processes specific for testis-related tissues at the pathway-level compared to the PPEP method.To explore what genes are associated with the extracted testis-specific GO terms, we used the interface shown in Figure We also used our PPEP to seek common and unique biological themes in two-class comparison in another case study  ,13 or GSOur high-throughput PPEP is designed to extend this analysis scheme into a comparative analysis scheme at the pathway-level for multiple gene lists or multiple HTP datasets. It is based on the assertion that it has the potential to integrate data from different, but related studies or even from different platforms. The advantage of the method was illustrated by the case study that used 6 prostate cancer datasets from the Oncomine database described in the result section. Recently, a meta-analysis method has made great progress trying to integrate data from different platforms by means of a summary statistics-based method in combination with FDR analysis and cross-validation ,44,45. HAs shown in the first case study in the Results section, our analysis scheme with PPEP effectively uncovers many common pathway-level signatures from the 6 prostate cancer datasets. From the analysis done within each individual gene list or dataset, some of these common pathway-level signatures may not be seen as significant, since they were not ranked at the very top in the enrichment results of each individual gene list of these independent studies. However, the consistencies and patterns of pathway-level enrichment that PPEP relies on adds weight to these terms and promotes their significance so that they become significant underlying biological themes across the independent studies. In contrast, using the common differential genes of these independent studies based on gene-level consistency as the sole-source for enrichment analysis, the derived pathway-level signatures may not be able to get significant enrichment scores. This observation illustrates the advantage of PPEP compared to conventional gene-level based enrichment methods in rationale. Our other case studies described in the Results section further substantiated the increased ability of PPEP to identify meaningful biological terms associated with input sets of gene lists derived from different sources, or with different technologies.In comparison with many other gene-set based software tools, our PPEP has many unique features not found in a single application Table . Some ofWe also have evidence that our pathway pattern extraction method is more effective than the PTM-based (Pavlidis template matching) clustering method (TM4)  in uncovAs demonstrated by our case studies using our PPEP, many commonly shared biological themes can be easily captured from multiple gene lists derived from related, but different studies. The same themes are not obvious when simply looking at the common genes shared by these lists at both the gene and pathway-level. In addition, the unique biological themes, which are specific to one or more gene lists, but not to others, can be uncovered as list-specific biological processes at the pathway-level. For example, for closely related tissues such as the 5 testis-related tissues  in the case study using the GNF dataset , since tMany efforts have been made to look for biological themes using networks of associated genes. These are largely based on curated gene-gene relationships from the literature ,10. The Before describing PPEP in this manuscript, it has been widely used for analysis of many of our collaborators' data including microarray datasets, mass spectrometry data, data from a genetic screening for functional impact study of virus insertion sites in the genome, lists of genes with specific features embedded in their sequences -54, many, many54,Project name: Pathway pattern extraction pipeline (PPEP) in WPSProject home page: WPS with PPEP and corresponding databases (WPS version 2) can be downloaded from WPS homepage [homepage . The demOperating system: Microsoft Window 2000 or XPProgramming language: Microsoft Visual Basic 6Other requirements: Built on the platform of WPS [m of WPS .License: Free to academics; distributed through license agreementAny restrictions to use by non-academics: commercial license neededWPS: WholePathwayScope; ES: Enrichment Score; GTAN: Gene-Term Association Network; HTTP: High Throughput; KEGG: Kyoto Encyclopedia of Genes and Genomes; GO: Gene Ontology; GOBP: Gene Ontology: Biological Processes category; PPEP: Pathway Pattern Extraction Pipeline; ORA: Over-representation analysis; FCS: functional class scoring; GSEA: Gene Set Enrichment Analysis.MY carried out the design and implementation of the PPEP in initially developed WPS  and drafMore details of PPEP. More technical details, features, and implementations of PPEP.Click here for fileThe gene-term pairwise relation table. The gene-term pairwise relation table that was retrieved using an interface as illustrated in Figure Click here for fileThe interface of data manipulation utilities. The image file showing the interface of data manipulation utilities in WPS.Click here for fileThe interface for data scoring and lists sorting. The image file showing the interface for data scoring and lists sorting for SLEPR method [R method  availablClick here for fileCommon differential genes among all datasets. list of 52 genes that were obtained as common differential genes among all of the 6 datasets using gene pattern extraction feature in WPS in the prostate cancer case study.Click here for filecommon GSEA annotation terms among all datasets. list of 331 terms that were obtained as common GSEA annotation terms among all of the 6 datasets using pathway pattern extraction feature in PPEP of WPS in the prostate cancer case study.Click here for fileEnrichment result of GSEA annotations for the 52 common differential genes. The full enrichment result of GSEA annotations for the 52 genes that were obtained as common differential genes among all of the 6 datasets in prostate cancer case study.Click here for filePathway-level enrichment patterns of commonly enriched GSEA terms. The heatmap of pathway-level enrichment patterns of the 33 commonly enriched GSEA terms among the differential genes of 6 datasets in prostate cancer case study that are directly involved in cancer-related processes.Click here for fileComparison of results of PPEP and gene-level method for cancer-related terms. The merged table in between the 33 cancer-related terms enriched commonly in 6 datasets of prostate cancer case study and the terms that have at least one gene out of the 52-gene common gene list, which shows that only 7 of the 33 terms are enriched in 52-gene list.Click here for fileTerms that are enriched consistently in all datasets. List of the 44 GO terms derived from PPEP that are enriched consistently in the differential genes of all 6 datasets in prostate cancer case study.Click here for fileFull enrichment result of GOBP annotations for the 52 common differential genes. The full enrichment result of GOBP annotations for the 52 genes that were obtained as common differential genes among all of the 6 datasets in prostate cancer case study.Click here for filePathway-level enrichment patterns of the commonly enriched GOBP terms. The heatmap of pathway-level enrichment patterns of the 44 commonly enriched GOBP terms among the differential genes of 6 datasets in prostate cancer case study. Many of these terms are apoptosis-related.Click here for fileTranscription factor target enrichment patterns among the differential genes. The heatmap of transcription factor target enrichment patterns among the differential genes of 6 datasets in prostate cancer case study. The 6 gene lists are enriched consistently with predicted targets of the corresponding transcription factors.Click here for filemiRNA target enrichment patterns among the differential genes. The heatmap of miRNA target enrichment patterns among the differential genes of 6 datasets in prostate cancer case study. The 6 gene lists are enriched consistently with predicted targets of the corresponding miRNAs.Click here for fileKEGG pathway enrichment patterns among the differential genes. The heatmap of KEGG pathway enrichment patterns among the differential genes of 6 datasets in prostate cancer case study. At least 3 out of the 6 gene lists are enriched for the corresponding KEGG pathways in heatmap.Click here for fileData details of heatmap in Figure Click here for fileDetails of a case study in two-class comparison. detailed description of a case study of the PPEP to seek common and unique biological themes in two-class comparison.Click here for fileGOBP term enrichment patterns in class comparison of muscle vs. testis. The heatmap of GOBP term enrichment patterns in class comparison case study. The 5 GOBP terms are commonly enriched in all 4 muscle-related tissues but not in any of the testis-related tissues.Click here for fileGOBP term enrichment patterns in class comparison of testis vs. muscle. The heatmap of GOBP term enrichment patterns in class comparison case study. These GOBP terms are commonly enriched in all 5 testis-related tissues but not in any of the muscle-related tissues.Click here for fileadvantage of PPEP method over the PTM method in TM4. Slides showing the advantage of PPEP method compared to PTM clustering method in TM4 [d in TM4 .Click here for file"}
+{"text": "Human diploid fibroblasts growth normally in medium containing physiological concentrations of the naturally occurring dipeptide carnosine . These concentrations are cytotoxic to transformed and neoplastic cells lines in modified Eagle medium (MEM), whereas these cells grow vigorously in Dulbecco's modified Eagle medium (DMEM) containing carnosine. This difference is due to the presence of 1 mM sodium pyruvate in DMEM. Seven human cell lines and two rodent cell lines were tested and all are strongly inhibited by carnosine in the absence of pyruvate. Experiments with HeLa cells show that anserine is similar to carnosine, but D-carnosine and homocarnosine are without effect. Also, the non-essential amino acids alanine and glutamic acid contribute to the effect of pyruvate in preventing carnosine toxicity, and oxaloacetate and alpha-ketoglutarate can substitute for pyruvate. We have used mixtures of normal MRC-5 fibroblasts and HeLa cells to demonstrate that 20 mM carnosine can selectively eliminate the tumour cells. This has obvious implications which might be exploited in in vivo and in vitro studies. Carnosine is known to react strongly with aldehyde and keto groups of sugars by Amadori reaction, and we propose that it depletes certain glycolysis intermediates. It is well known that tumour cells are more dependent on glycolysis than normal cells. A reduction of glycolysis intermediates by carnosine may deplete their energy supply, but this effect is totally reversed by pyruvate."}
+{"text": "An originally virus-induced, non-producer tumour system has been studied in relation to humoral and cellular cytotoxic responses to transplantation and other immunization techniques. In all experimental groups cytotoxic lymphocytes (CTL) were observed either directly or after mixed culture of lymphocytes and tumour cells (MLTC). Except for C'-dependent cytotoxic antibodies in mice immunized by irradiated cells, no antibody-mediated cytotoxicity was observed. In 2 protocols (transplantation and immunization by mitomycin-treated cells) CTL in vitro were not protective. In a third protocol (immunization by irradiated cells) CTL afforded partial protection and other factors appeared to be involved. The best in vivo protection was induced by immunization consequent on early surgical removal of a small number of transplanted tumour cells. This study provides lines of evidence for the effectiveness of protection supplied by CTL in well-defined conditions. Comparison with other modes of immunization indicated that these conditions were related to the quantity and to the characteristics of antigen involved."}
+{"text": "Hepatic artery aneurysm (HAA) was diagnosed in a62-year-old man who was a poor candidate forsurgery because of severe liver cirrhosis and diabetesmellitus. Two attempts to occlude the HAA bytranscatheter embolization failed because of recanalizationof the aneurysm. Moreover, aneurysmaldilatation of the superior mesenteric artery and theleft renal artery developed and progressed. Both theliterature and the present case show that anindividual approach to treatment of extraorganicHAA should be chosen in dependantan location andanatomy of the lesion."}
+{"text": "Relative survival rates in the National Cancer Institute (NCI) 'SEER' review of cancer in the USA are fitted by a model which can be used to estimate median survival time in any calendar year. It is argued that median survival times (MSTs) are better indicators of survival than 5-year relative survival rates (RSRs), especially when survival times are short."}
+{"text": "C-type viruses were formed in heterotransplants of 5/14 human urogenital tumours which had been serially transferred in nude mice of NIH(S) background. Except for one case in which C-type particles were present in the epithelial cells as well as the connective tissue, the viruses were only found within the stroma of the heterotransplanted tumours. Peroxidase labelling with anti-mouse serum demonstrated that the connective tissue supporting the transplanted human tumours was of mouse origin. Competition radioimmunoassays demonstrated that MuLV interspecies viral protein was present in high titre in the transplanted tumour extracts and also in extracts of 2 spontaneous mouse-tumour extracts. These data suggest that endogenous viruses of the nude mice are activated by the graft, and only subsequently infect the human tumour cells and form particles."}
+{"text": "Onthe other hand, HIV-infected African patients had a population of germinal center B cells , which are generally restricted to lymph nodes and do not circulateunless the lymph node architecture is altered. The first observations could be linked to the tropicalenvironment whereas the presence of germinal center B cells may be attributable to chronic exposure toHIV as it is not observed in HIV-negative African controls and HAART treated HIV-infectedEuropeans. It may impact the management of HIV infection in countries with limited access to HIVdrugs and urges consideration for implementation of therapeutic vaccines.To better understand the pathophysiology of B cell populations\u2014the precursors of antibody secretingcells\u2014during chronic human immunodeficiency virus (HIV) infection, we examined the phenotype ofcirculating B cells in newly diagnosed Africans. We found that all African individuals displayed lowlevels of naive B cells and of memory-type CD27"}
+{"text": "Human papillomavirus (HPV) is the main risk factor for invasive cervical cancer. High risk ratios are found in cross-sectional data on HPV prevalence. The question raised is whether this present evidence is sufficient for making firm recommendations on HPV screening. A validated cervical cancer screening model was extended by adding HPV infection as a possible precursor of cervical intraepithelial neoplasia (CIN). Two widely different model quantifications were constructed so that both were compatible with the observed HPV risk ratios. One model assumed a much longer duration of HPV infection before progressing to CIN and a higher sensitivity of the HPV test than the other. In one version of the model, the calculated mortality reduction from HPV screening was higher and the (cost-)effectiveness was much better than for Pap smear screening. In the other version, outcomes were the opposite, although the cost-effectiveness of the combined HPV + cytology test was close to that of Pap smear screening. Although small follow-up studies and studies with limited strength of design suggest that HPV testing may well improve cervical cancer screening, only large longitudinal screening studies on the association between HPV infection and the development of neoplasias can give outcomes that would enable a firm conclusion to be made on the (cost-)effectiveness of HPV screening. Prospective studies should address women aged 30-60 years."}
+{"text": "A new mycoplasmal conjunctivitis was first reported in wild house finches (Carpodacus mexicanus) in early 1994. The causative agent was identified as Mycoplasma gallisepticum (MG), a nonzoonotic pathogen of poultry that had not been associated with disease in wild songbirds. Since the initial observations of affected house finches in the mid-Atlantic region, the disease has become widespread and has been reported throughout the eastern United States and Canada. By late 1995, mycoplasmal conjunctivitis had spread to an additional species, the American goldfinch (Carduelis tristis). This new disease exemplifies the rapid spread of a pathogen following introduction into a mobile wildlife population and provides lessons that may apply to emerging human diseases."}
+{"text": "Glial fibrillary acidic protein (GFA) was assayed in nerve-tumour extracts and located in these tumours by indirect immunofluorescence study. We conclude that GFA is a specific marker of both malignant and normal astrocytes. Non-astrocytic tumours  do not contain GFA. Tumours with astrocytic differentiation potential (medulloblastoma) may contain GFA. Comparison of microscopic and GFA assays leads us to conclude that GFA concentration is proportional to the amount of malignant astrocytes in the tumour and inversely proportional to the necrotic area of a tumour. Normal tissue GFA and glioblastoma GFA were found to be immunologically identical."}
+{"text": "Here, we report the case of an HIV infected patient that was treated for pneumonia with a macrolid antibiotic. The patient experienced a prolongation of the already pathologic QTc interval resulting in repeated torsades de pointes necessitating CPR and implantation of an AICD. This case exemplifies that torsades de pointes due to acquired long QT syndrome is a serious and potentially fatal complication in HIV-positive patients. Human immunodeficiency virus- (HIV-) infected individuals are at an increased risk of cardiovascular disease , 2. HereTwo days after admission the patient experienced a syncope. Since there was no palpable pulse, cardiopulmonary resuscitation was performed by the medical team for about 30 seconds after which the patient had regained consciousness. The patient was transferred to the medical intensive care unit for further observation. There was no prior history of syncope, seizures, or cardiac events. The 12-lead electrocardiogram showed QT prolongation with a corrected QT interval  of 660\u2009ms. In the following hours the patient had repeated episodes of polymorphic ventricular tachycardias that were either self-limiting or required defibrillation.Long QT syndrome is more frequent in subjects infected with HIV than in the general population and has been reported to occur in up to 29% of the hospitalized HIV-positive patients . Why lonThis case exemplifies that torsades de pointes due to acquired long QT syndrome is a serious and potentially fatal complication in HIV-positive patients. Multiple factors including antimicrobial drugs put HIV-infected patients at an increased risk for the development of acquired long QT syndrome. Physicians should therefore always maintain a high degree of clinical suspicion for the presence of long QT syndrome in patients with HIV and should be aware of the QT-prolonging side effects of drugs they prescribe for these patients."}
+{"text": "Proliferating cell nuclear antigen (PCNA) is a nuclear protein that regulates DNA synthesis by DNA polymerase delta, and is essential for DNA replication. PCNA expression level is related to the malignancy of gastric cancer cells. Seven different gastric cancer cell lines and two kinds of control cell lines were treated with antisense oligonucleotides complementary to the messenger RNA of PCNA. Treatment of each gastric cancer cell line with antisense oligonucleotides at concentration of 10-40 microM inhibited the cell growth, colony formation and PCNA protein production in a dose-dependent manner, but only affected normal cells slightly. A random sequence oligomer showed no effect. These results show that PCNA is essential for gastric cancer cell proliferation and that the use of synthetic oligonucleotides is an effective way of producing antisense-mediated changes in the behaviour of human gastric cancers."}
+{"text": "This report presents the results of a study into the effect of breast self-examination (BSE) in a large defined population within the City of Nottingham since 1979. We have examined the effect of breast self-examination in a group of patients invited to attend for education in BSE compared with a group of historical controls. No overall survival advantage has been demonstrated for the study group but within the latter group patients who had attended for instruction in BSE had a significantly better actuarial survival at 13 years than those who did not (P less than 0.001). Patients in the study group presented with significantly smaller tumours which were more likely to be of better histological grade and lymph node stage. A case-control study has demonstrated the value of attendance for BSE particularly in post-menopausal women. Although BSE is not as sensitive as mammographic screening, patients who practise it present with more favourable tumour characteristics and its value in post-menopausal women supports its use as an adjunct to mammographic screening."}
+{"text": "Over the last decade mouse models of experimental asthma proved to be a valuable tool for the investigation of mechanisms that underlie acute allergic airway inflammation and development of airway hyperresponsiveness, two of the hallmarks of human asthma. Nevertheless, these acute models fail to reflect the aspects of this chronic disease because they do not represent any signs of chronicity and airway remodelling as it is defined by subepithelial fibrosis, goblet cell hyperplasia and airway smooth muscle cell hypertrophy. Recent mouse models were successful in overcoming these limitations by using chronic allergen-challenges. These new models of chronic experimental asthma now proved as a novel tool to examine the complex interaction of infiltrating inflammatory cells and structural cells such as fibroblasts and smooth muscle cells that ultimately leads to airway remodelling and stable airflow limitation. Recent studies clearly demonstrated that T helper 2 (TH2) cells and their typical cytokines play a critical role not only in airway inflammation but also in the development of airway remodelling. Since the transcription factor GATA-3 is essential for TH2 cell development and the production of several TH2 type cytokines this intracellular molecule represents a new promising target for therapeutic intervention in asthma that might even effect airway remodelling. Allergic bronchial asthma is a chronic inflammatory disease of the airways that is characterized by allergic airway inflammation and development of airway hyperresponsiveness (AHR). Another hallmark of asthma involves various structural changes of the airway wall such as airway fibrosis and smooth muscle cell hyperplasia summarized as airway remodelling . Over thHowever, since allergic airway inflammation in these models is induced by short term exposure to the aerosolized allergen and, therefore, does not persist for longer than 10 days, these models are limited regarding the modelling of the chronic aspects of asthma, more precisely airway remodelling and its patho-physiological consequences that might result in stable airflow limitation. Furthermore, pathological aspects of experimental asthma in these acute models are reduced to the central airways. Since asthma, allergic inflammation and airway remodelling is observed in peripheral airways of asthmatic patients as well ,6 and stOver the last few years airway remodelling became a field of special interest in asthma research since it is largely resistant to medication  and is aHowever, the modelling of these chronic aspects of asthma in animals requires clear definition of airway remodelling. The pathological analysis on bronchial specimens of asthmatic patients revealed goblet cell hyperplasia of the airway epithelium, hyperplasia of the submucosal glands, thickening of the epithelial basement membrane, extracellular matrix deposition in the subepithelial layer and hypertrophy and hyperplasia of the bronchial smooth muscle cells . To reflThe actual concept of asthma pathogenesis begins with the differentiation of na\u00efve allergen-specific T-helper cells towards TH2 cells that are characterized by the expression of the transcription factor GATA-3 and production of several typical cytokines such as IL-5 that controls the activity and the survival of eosinophils. These cells represent the main effector cell type of the allergic airway inflammation and produce a variety of cytotoxic mediators and cationic proteins such as major basic protein (MBP) and eosinophil cationic protein (ECP) that ultimately lead to epithelial damage . This fuet al. report about a model of acute experimental asthma where airway eosinophilia and development of AHR seem to be disconnected [et al in a mouse model of chronic experimental asthma [science magazine. Humbles et al. used the \u0394dbl GATA mouse which is completely deficient for the eosinophil lineage due to deletion of a high affinity GATA site of the GATA-1 promotor in a mouse model of experimental asthma to demonstrate that eosinophils are not obligatory for allergen-induced lung dysfunction [We utilized our model of chronic experimental asthma to assess the effect of a novel therapeutic strategy that targets eosinophils on airway remodelling and lung function. Since the infiltration of these cells into the airways depends on interaction of the C-C chemokine receptor-3 (CCR-3) and its ligands from the eotaxin family, we antagonized this chemokine receptor by using a low molecular weight compound . To mimionnected . Similarl asthma . The disfunction . In contfunction .et al. reported the lack of goblet cell metaplasia in PHIL mice Humbles et al. clearly demonstrated that eosinophil deficient animals were protected from airway fibrosis and smooth muscle cell hyperplasia. These findings receive further support from studies that report about the profibrotic effects of eosinophils on fibroblasts in vitro[et al. [Even though both studies seem to be contradictory regarding the role of eosinophils within the development of AHR, both studies linked eosinophils to the development of airway remodelling. Whereas Lee  in vitro-30 and to[et al.  and by oet al. investigated the effect of a neutralizing anti-CD4 antibody in a mouse model of chronic experimental asthma [Besides the fact that TH2 cells induce goblet cell hyperplasia and increased mucus production in asthmatic patients by secreting IL-13 , very lil asthma . The i.pet al. were able to clearly demonstrate that ASMCs from adoptively transfered animals exhibited increased proliferation and reduced apoptosis. All the data presented in this study support the idea that airway smooth muscle remodelling, as an important feature of asthma, is driven by antigen-specific T helper cells that require direct myocyte-T cell contact.Although all these studies reported about reduced airway remodelling after abolishing CD4 positive T cells or TH2-type cytokines one could argue that all these effects might be indirect since these lowered effects were always associated with diminished airway eosinophilia. However, a study by Ramos-Barbon gave evidence that TH2 cells can directly induce airway remodelling . In contAnimal models of experimental asthma have elucidated the central role of TH2 cells and their typical cytokines in the acute inflammatory process resulting in the formation of asthma. To answer the question whether these cells are further involved in pathophysiological processes ultimately leading to airway remodelling and chronification of the disease improved models of chronic experimental asthma that are able to reflect the chronic aspects of this disease as close as possible had to be established. Recent studies used such models to demonstrate that TH2 cells play a critical role in asthma chronification especially in airway remodelling as well. Therefore, these cells still represent promising target cells for therapeutic intervention in asthmatic patients. After embryonic development the pleiotropic transcription factor GATA-3 remains to be expressed in bone marrow derived cells such as eosinophils, basophils, mast cells and especially in T cells ,36. DuriThe author declares that he has no competing interests."}
+{"text": "A case report is presented of a synovial sarcoma arising in the abdominal wall. This is the seventh such case to be reported. A brief review of the clinical and pathological features of synovial sarcoma is made.Pre-operative diagnosis of an abdominal wall synovial sarcoma is virtually impossible, but should be considered when a soft tissue swelling is found to show amorphous stippled calcification on X-ray."}
+{"text": "Penaeus japonicus (RV-PJ) infection in Kuruma shrimps. When schizophyllan was administered orally at a dose of 50 or 100 mg/kg body weight per day, the survival rates after virus challenge were significantly higher than those of the control groups. High phagocytic activities were observed in the haemocytes of the schizophyllan-fed shrimps.These results suggest that schizophyllan confers effective protection against viral infection by increasing antiviral immune responses, and that it could be used to boost immunity to virus infection in animals or in invertebrates.An oral administration of fungal polysaccharide schizophyllan has augmented protective immune responses to Sendai virus infection in mice and the rodshaped DNA virus of"}
+{"text": "High throughput applications of the reverse transcriptase quantitative PCR (RT-qPCR) for quantification of gene expression demand straightforward procedures to isolate and analyze a considerable number of DNA-free RNA samples. Published protocols are labour intensive, use toxic organic chemicals and need a DNase digestion once pure RNAs have been isolated. In addition, for some tissues, the amount of starting material may be limiting. The convenience of commercial kits is often prohibitive when handling large number of samples.Arabidopsis thaliana tissues ready for RT-qPCR applications. Simple non-toxic buffers were used for RNA isolation from Arabidopsis tissues with the exception of seeds and siliques, which required the use of organic extractions. The protocols were designed to minimize the number of steps, labour time and the amount of starting tissue to as little as 10\u201320 mg without affecting RNA quality. In both protocols genomic DNA (gDNA) can be efficiently removed from RNA samples before the final alcohol precipitation step, saving extra purification steps before cDNA synthesis. The expression kinetics of previously characterized genes confirmed the robustness of the procedures.We have established protocols to isolate DNA-free RNA from Here, we present two protocols to isolate DNA-free RNA from Arabidopsis tissues ready for RT-qPCR applications that significantly improve existing ones by reducing labour time and the use of organic extractions. Accessibility to these protocols is ensured by its simplicity and the low cost of the materials used. Reverse transcriptase quantitative PCR (RT-qPCR) is a very useful and sensitive technique to quantitate changes in gene expression. Increasing number of labs routinely use the agarose-based or/and real-time versions of the technique. A significant number of replicates are required to ensure significance of the results, which adds a high-throughput component to the RT-qPCR. These requirements impose the need to have simplified protocols to reduce labour and costs without compromising RNA integrity or yield.Arabidopsis thaliana is a model organism for plant biologists, a number of RNA extraction protocols have been developed. Although there are several commercial kits available, the cost can be prohibitive when processing large numbers of samples. Published protocols use organic extractions with toxic chemicals, which involve the use of fume hoods to diminish health risks and lengthen the procedure [Since rocedure -5. Moreorocedure  and protrocedure -3,5 largArabidopsis thaliana that address the problems mentioned above. Both protocols start with small amounts of tissue and buffer volumes to fit the SMT format, and incorporate a DNase digestion before the final purification steps.Here we report improved RNA isolation protocols for the model plant 260/A230 and A260/A280) values  and the graphs obtained after plotting RNA species versus quantity  indicated the absence of undesirable contaminants (data not shown).The protocol presented here . AtDOF31 is a DOF transcription factor (TF) with very low relative transcript abundance, whose expression cannot be detected by in situ hybridizations or by promoter::GUS fusions . Gene-specific oligonucleotides were chosen to amplify regions near the 5' end to ensure RNA integrity and cDNA synthesis efficiency and a ubiquitin gene was amplified for sample normalization. cDNA was synthesized according to [AtDOF31 expression were detected in the wild type sample and several transgenic lines with different levels of AtDOF31 overexpression relative to the control (Col-0) were identified.To demonstrate the quality of the samples and sensitivity of the protocol, RT-qPCR was performed on RNA samples isolated from Arabidopsis leaves of the Columbia-0 ecotype (wild type) and leaves of transgenic plants overexpressing rding to , diluted260/A230 and A260/A280) values  and their electropherograms indicated the absence of undesirable contaminants  is expressed predominantly in the cortex and endodermis of the embryonic axis in germinating Arabidopsis seeds [AtBME3 (At3g54810) encodes a GATA-type zinc finger TF gene whose promoter is weakly expressed only at the micropylar end of the embryonic axis during germination [AtDOF31 is significantly induced during seed germination suggesting it may be an important player in the regulation of this seed phase since it is expressed at low levels outside this process. The kinetics observed for the AtGA3ox2 and AtBME3 genes . The only tissues not amenable for the previous protocol were seeds and siliques and we streamlined and improved existing protocols that use organic extractions for RNA purification from those recalcitrant tissues. This protocol has also been successfully used in the isolation of RNAs from developing barley seeds . Altogether, our results indicate that the use of these protocols can be extended to other plant species.We have described two simplified, inexpensive and robust protocols to isolate DNA-free RNA from Arabidopsis tissues. As far as we know, all non-commercial protocols for RNA isolation from plant tissues use organic solvents during the first steps. We present here a protocol that uses two simple buffers without organic solvents that includes a 30 min DNase digestion and requires only 90 min to obtain 24 DNA-free RNA samples. Although only data from leaves is presented here, RNA from most Arabidopsis tissues can be isolated since we have successfully used it with stems, roots and flowers (data not shown) and also from different vegetative tissues of the legume model plant AtDOF31 and AtBME3 are expressed at low levels and AtBME3 mRNA has a length (1700 bp) above the average for a TF. After cDNA synthesis using oligo dT and qPCR using specific oligonucleotides annealing as far as possible from the polyA, we were able to detect and quantify the expression levels of both genes in all samples analyzed, confirming sensitivity and specificity.We determined that the RNA obtained at an intermediate step of the isolation protocol was of sufficient quality to allow DNase digestion before the final purification steps. This modification shortens the protocol and maximizes yield bypassing the need to double precipitate the RNA. RNA integrity and purity are key factors influencing cDNA synthesis and ultimately detection and accurate quantification of RNAs, especially low abundance RNAs such as those derived from many TF coding genes. Accessibility to these protocols is ensured by its simplicity and low cost of the materials used. With the increase of genomic approaches involving the manipulation of large numbers of samples, we feel these protocols will be extremely useful for plant scientists.The authors declare that they have no competing interests.LOS was responsible for experiments and supervision of this study and JVC contributed to the supervision."}
+{"text": "An ongoing outbreak of conjunctivitis in free-ranging house finches (Carpodacus mexicanus) began in 1994 in the eastern United States. Bacterial organisms identified as Mycoplasma gallisepticum (MG) were isolated from lesions of infected birds. MG was also isolated from a blue jay (Cyanocitta cristata) that contracted conjunctivitis after being housed in a cage previously occupied by house finches with conjunctivitis, and from free-ranging American goldfinches (Carduelis tristis) in North Carolina in 1996. To investigate the molecular epidemiology of this outbreak, we produced DNA fingerprints of MG isolates by random amplification of polymorphic DNA (RAPD). We compared MG isolates from songbirds examined from 1994 through 1996 in 11 states, representing three host species, with vaccine and reference strains and with contemporary MG isolates from commercial poultry. All MG isolates from songbirds had RAPD banding patterns identical to each other but different from other strains and isolates tested. These results indicate that the outbreak of MG in songbirds is caused by the same strain, which suggests a single source; the outbreak is not caused by the vaccine or reference strains analyzed; and MG infection has not been shared between songbirds and commercial poultry."}
+{"text": "A case of hantavirus pulmonary syndrome (HPS) was serologically confirmed in a critically ill patient in Santiago, Chile. The patient's clinical course had many similarities to that of other HPS patients in North and South America but was complicated by acute severe renal failure. The patient's history included self-reported urban and probable rural rodent exposure during travel in Bolivia. Comparison of a viral sequence from an acute-phase serum sample with other known hantaviruses showed that the hantavirus nucleic acid sequence from the patient was very similar to a virus recently isolated from rodents associated with HPS cases in Paraguay."}
+{"text": "Growth of transplanted rat tumours was retarded and in some cases completely suppressed when cells were injected subcutaneously in admixture with double stranded RNA (ds-RNA). This response required intimate contact between ds-RNA and tumour cells and systemic treatment with the agent failed to prevent progressive growth of a range of rat tumours. Direct cytotoxic effects of ds-RNA may contribute to tumour suppression since the compound was cytotoxic in vitro for cultured tumour cells. The involvement of host factors is suggested, however, by the in vivo tests showing variations in susceptibility to ds-RNA mediated tumour suppression similar to that previously observed with bacterial adjuvants."}
+{"text": "The effect of sodium butyrate on mouse and human melanoma cell lines was evaluated. Sodium butyrate (0.1-2mM) is shown to reduce the clonogenic potential of several melanoma cell lines. The antiproliferative effect of sodium butyrate is accompanied by a marked increase in the activity of the plasma-membrane bound enzyme gamma-glutamyl transpeptidase. Sodium butyrate treated cells acquire a well developed rough endoplasmic reticulum and accumulate fat droplets. The development of the endoplasmic reticulum is associated with a marked increase in the activity of the enzyme marker NADPH cytochrome c reductase. It is suggested that the phenotypic alterations induced by sodium butyrate may serve as markers for the action of this agent on melanoma cells and other tumours."}
+{"text": "The properties of a new tumour cell line (NB1-G) derived from human neuroblastoma by xenografting in nude rats followed by adaptation to tissue culture are described. Studies using a panel of monoclonal antibodies demonstrate the neuro-ectodermal nature of the cells and support the diagnosis of the primary tumour as neuroblastoma. Cytogenetic studies have revealed a human karyotype with several chromosomal abnormalities. Genetic analysis by in situ DNA hybridization has demonstrated the presence of multiple copies of the N-myc gene. Approximately 20-30 fold amplification of the gene is observed on Southern blot analysis. The cell line has been adapted to growth as multicellular tumour spheroids as well as monolayer culture. Radiobiological studies on spheroids show the cells to be radiosensitive with low capacity for sub-lethal damage accumulation and repair. The cell line should be useful for fundamental studies of human neuroblastoma as well as experimental therapy in vitro."}
+{"text": "We have evaluated three analytical methods for determininginorganic phosphorus in serum applied to the Technicon RA-I000analyzer: a fully enzymatic colorimetric method based on thespecific system purine nucleoside phosphorylase/xanthine oxidasecoupled to an indicator colorimetric reaction similar to the Trinderreaction; a chemical method involving the direct UV measurementof the phosphomolybdate complex; and a chemical method withreduction of the phosphomolybdate complex to molybdenum blue.Experiments were performed to assess within-run and between-dayprecision, linearity, interference and correlation. The best performancecharacteristics were shown by the enzymatic colorimetricmethod and the phosphomolybdate UV method."}
+{"text": "Estimation of DNA duplex hybridization free energy is widely used for predicting cross-hybridizations in DNA computing and microarray experiments. A number of software programs based on different methods and parametrizations are available for the theoretical estimation of duplex free energies. However, significant differences in free energy values are sometimes observed among estimations obtained with various methods, thus being difficult to decide what value is the accurate one.We present in this study a quantitative comparison of the similarities and differences among four published DNA/DNA duplex free energy calculation methods and an extended Nearest-Neighbour Model for perfect matches based on triplet interactions. The comparison was performed on a benchmark data set with 695 pairs of short oligos that we collected and manually curated from 29 publications. Sequence lengths range from 4 to 30 nucleotides and span a large GC-content percentage range. For perfect matches, we propose an extension of the Nearest-Neighbour Model that matches or exceeds the performance of the existing ones, both in terms of correlations and root mean squared errors. The proposed model was trained on experimental data with temperature, sodium and sequence concentration characteristics that span a wide range of values, thus conferring the model a higher power of generalization when used for free energy estimations of DNA duplexes under non-standard experimental conditions.Based on our preliminary results, we conclude that no statistically significant differences exist among free energy approximations obtained with 4 publicly available and widely used programs, when benchmarked against a collection of 695 pairs of short oligos collected and curated by the authors of this work based on 29 publications. The extended Nearest-Neighbour Model based on triplet interactions presented in this work is capable of performing accurate estimations of free energies for perfect match duplexes under both standard and non-standard experimental conditions and may serve as a baseline for further developments in this area of research. Predicting the stability of a DNA duplex from base sequences is a well studied problem nowadays. Nevertheless, the accuracy of DNA duplex stability predictions largely varies with sequence length, base composition and experimental conditions. The Thermodynamic Nearest-Neighbour (TNN) Model  is a stan3)). PairFold uses RNA thermodynamic parameters from the Turner Laboratory  + concentration.Click here for file"}
+{"text": "The risk of breast cancer associated with delivering a twin birth was examined in a population-based nested case-control study of nearly 4800 Swedish women with breast cancer and 47000 age-matched control subjects. All were aged less than 50 years and parous. After adjustment for age at first birth and parity, a 29% reduction in breast cancer risk was observed in mothers of twins relative to those who were not . These results provide evidence that women who bear twins are at reduced risk of breast cancer, one explanation for which may be their unusual levels of hormonal exposure."}
+{"text": "Synthetic glycolipids prepared by esterification of various sugars and sorbitol, and containing various numbers of saturated or unsaturated fatty acid residues as well as bacterial lipid A and lipopolysaccharide, were tested for mitogenicity of splenic cells of Fischer rats and Swiss mice and for the augmentation of humoral immune response against sheep red blood cells in these species. Subsequently a few of the humoral immune-response-enhancing glycolipids were compared with non-enhancers in their anti-tumour activity against 13762 rat mammary carcinoma in inbred Fischer 344 rats and Ehrlich tumour in Swiss mice. They were given systemically after tumour inoculation and intratumourally in squalene and Tween emulsion after intradermal MAC tumour development. It was observed that certain structural characteristics in glycolipids with respect to the type of sugar, the type and number of fatty-acid residues were needed for their adjuvant action of the humoral arm of the immune response. Although humoral immune-response enhancers were somewhat superior to non-enhancers in their anti-tumour activity, the correlation coefficient demonstrated a lack of significant concordance. It is concluded that glycolipids selected for their ability to augment humoral immune responses against standard antigens need not be suspect as tumour-enhancers on the grounds that they would elicit blocking antibodies in vivo against tumour-associated antigens."}
+{"text": "Data of 10,556 case-control pairs from the Oxford Survey of Childhood Cancers and related sources have shown that when cancers originate in the reticuloendothelial system (RES neoplasms) they are liable to cause loss of immunological competence before they are clinically recognizable. Since these early effects may have lethal consequences, the true prevalence of RES neoplasms is difficult to identify, especially in infection-sensitive age groups and populations with high death rates from infection. An inevitable consequence of a nuclear holocaust is a high infection death rate. Therefore, a population of A-bomb survivors is a totally unsuitable one for studying the precise nature of the association between ionizing radiation and human cancers."}
+{"text": "Genetic                        ablation of Drosophila melanogaster insulin-like peptide (DILP) and                        adipokinetic hormone-producing cells accompanied by cell biological and                        metabolic measurements have revealed functional conservation in nutrient                        sensing and the underlying signaling mechanisms between mammal and fruit                        fly.  Despite significant advances gained in understanding the                        neuroendocrine responses to nutrient changes during developmental larval                        stages, we discuss here the need for investigating glucose homeostasis in                        the post-mitotic adult stage as the result of ablation of DILP producing                        cells (IPCs).  Our recent studies demonstrate that while both constitutive                        and adult-specific partial ablation of IPCs renders those flies                        hyperglycemic and glucose intolerant, flies with adult-specific IPC ablation                        remain insulin sensitive.  Our results substantiate a role of adult IPCs in                        modulating aspects of glucose homeostasis and highlight the complexity in                        DILP action in the adult fly.                   Drosophila melanogaster insulin-like peptides (DILPs) together                        with accumulating insight into the nutrient sensing and intracellular signaling                        mechanisms in the brain neurosecretory cells in which DILPs are produced is                        revealing many important details of the neuroendocrine mechanisms that couple                        nutrition to metabolic change [Drosophila as                        an appropriate model for such studies.  In this Research Perspective, we                        highlight recent work with adult flies that both illustrates the lifelong                        employment of conserved regulatory mechanisms and demonstrates the value of the                        adult fly as a relevant system in which to study carbohydrate homeostasis and                        post-developmental onset of metabolic pathophysiologies in animals.                                The identification and characterization                        of c change .  TheseDrosophila genome contains seven dilp genes, five of which                            exhibit significant homology to mammalian insulins                            [dilps are expressed in a                            variety of tissues including the larval ventral nerve cord, larval salivary                            glands, larval midgut, ovaries, and the larval and adult brain [pars intercerebralis (PI) region of the                            protocerebrum in both larvae and adults  has been implicated in the regulation of growth,                            development, metabolism and aging in metazoans .  The   termini ,7.     Drosophila larvae                            is further evidenced by the presence of cells in the corpus cardiacum that                            produce and secrete adipokinetic hormone (AKH), which functions in glucose                            homeostasis by mobilizing stored energy reserves and raising circulating                            carbohydrate levels [The conservation of regulatory endocrine                            mechanisms controlling circulating glucose levels in e levels . The   e levels .  Hypogle levels .       Drosophila larvae                            points to the conservation of fundamental endocrine regulatory mechanisms of                            homeostatic blood sugar levels in insects [Drosophila                            larvae may possess unique metabolic specializations that are not present in                            adult flies, which have switched over from a growth phase to a largely                            post-mitotic, reproductive phase.  Evidence for the maintenance of conserved                            glucose homeostatic mechanisms throughout the Drosophila life cycle is                            accumulating, however, and we report that conditional, adult specific partial                            IPC ablation yielded a phenotype similar to that seen in larvae experiencing                            constitutive IPC ablation  show an increase in fluorescence                            when exposed to glucose and trehalose, demonstrating that these cells increase                            their intracellular Ca2+ concentration in response to the presence                            of circulating nutrients [2+                            influx triggered by the opening of the voltage gated Ca2+ channels                            as the result of closing of the ATP-sensitive KATP channels is the                            critical event in insulin release in mammalian \u03b2 cells [ATP channels in                            IPCs via in situ hybridization [IPC                            glucose sensing mechanisms also appear to be similar to that of mammalian                            \u03b2-pancreatic cells.  Adult utrients .  Ca2+  \u03b2 cells .  Thus, dization .       Drosophila                            is not only analogous to the mammalian islet cell endocrine system [The                            tissue level organization of the glucose regulatory system in e system , but the"}
+{"text": "Immunohistochemical staining for oestrogen receptor (ER) has been carried out using antibody ER ID5 on 170 women who received first-line tamoxifen treatment for evaluable metastatic breast cancer. ER status had been determined some years previously, using a ligand-binding cytosol assay. The adequacy of the tissue used for the cytosol assay was always checked by histology on an adjacent block and was deemed to be typical of the tumour overall as was the block used for immunohistochemistry. Six different methods were used to assess the degree of staining and comparisons were made to determine which method gave the most clinically relevant results. Clinical outcome was assessed both in terms of duration of response to tamoxifen determined by log-rank analysis and type of response using the chi-squared test. The ER immunohistochemical assay gave superior results compared with the cytosol assay, with all of the subjective methods of assessment of staining giving statistically significant correlations with clinical outcome. The additional contribution of progesterone receptor (PR) staining with antibody NCL PGR was also studied."}
+{"text": "Nuclear polyploidization in the livers of CF-1 mice, exposed to dieldrin , was studied up to the median time of liver tumour development (ranging from 15 to 27 months) in the respective treatment groups. In untreated controls nuclear polyploidization is characterized by a linear increase of octaploid nuclei with age. Approximately 4 months before tumour development a reduction in the tetraploid to diploid ratio is observed. Dieldrin treatment was found to enhance nuclear polyploidization in the initial phases of treatment, as expressed by a dose-dependent increase in octaploid nuclei. In 'steady-state' situations all age dependent changes in the level of polyploidization found in controls were also found in dieldrin treated mice. However, these changes occurred at an increasingly earlier age with higher dieldrin treatment levels. The decrease in the tetraploid:diploid ratio always takes place a few months before tumour development. This change in the ploidy level may thus be related to the subsequent liver tumour formation. The liver tumours themselves appear to originate from a diploid stem line, and were found to increase their degree of polyploidization during growth, eventually developing aneuploid nuclei. A comparison of nuclear polyploidization and liver tumour formation in CF-1 mouse liver for the given dietary dieldrin concentrations showed that liver tumour formation was associated with a constant level of polyploidization. Since polyploidization is an age-dependent process, these findings suggest that liver tumour formation is imminent at a constant biological age and that dieldrin may advance the biological age of CF-1 mouse liver."}
+{"text": "Hyperthermia and photoactivated hematoporphyrin derivative induce a dose-dependent reduction in the expression of the p250 surface melanoma-associated antigen on the human FME cell line. Expression of this glycoprotein antigen was quantitated by immunofluorescence flow cytometry based on the monoclonal antibody 9.2.27. Decrease in antigen expression was followed by a transient increase above the level for untreated cells, before normalization occurred about one week after treatment. These treatment-induced changes in antigen expression could partly be explained by changes in protein synthesis. This conclusion was based on the following observations: Hyperthermia and photoactivated hematoporphyrin derivative both inhibited protein synthesis. The latter increased again rapidly to rates above normal until antigen expression reached normal level, whereupon the protein synthesis rate decreased to normal. Inhibition of protein synthesis by cycloheximide 1 day after heating, prevented the recovery of antigen expression, demonstrating that protein synthesis is necessary for resumption of normal antigen expression. The changes in both antigen expression and protein synthesis were dose-dependent, and the magnitude and duration of the changes increased with increasing dose. The time courses of the changes in protein synthesis after two different treatments which both inactivated two logs of cells were almost identical, as were the time courses after two lower heat doses inactivating one log of cells. These similarities were reflected in the changes in antigen expression. At the same time as protein synthesis reached its maximum and antigen expression resumed normal level, an increase in the Golgi apparatus was observed ultrastructurally, indicating an increased synthesis rate and transportation of glycoproteins to the cell surface."}
+{"text": "Sir,We found Dr van Noord's preconceptional mitochondrial hypothesis interesting particularly in line with a recent report linking polymorphisms of two DNA base excision repair genes (XRCC1 and hOGG1) to breast cancer risk in daughters born to older mothers . MnSOD hTo test this hypothesis, we analysed the association of parental age with breast cancer risk using data from the Shanghai Breast Cancer Study (SBCS), and the results are in shown Although we collected information on whether the mother had a threatened miscarriage with the index pregnancy, too few women reported this adverse event  to provide a stable risk estimate. Other studies may have sufficient numbers of mothers to investigate this aspect of Dr van Noord's hypothesis.Dr van Noord argued that insulin-like growth factor- I (IGF-1) might be unlikely to explain the inconsistent findings on birth weight and breast cancer risk in the literature, since the link between IGF-I and breast cancer risk has been found primarily in premenopausal women, while the high birth weight-breast cancer association has been seen among pre- and postmenopausal women. A previous report from the SBCS showed that elevated levels of IGF-I were associated with an increased risk of breast cancer among all women, but the association was more pronounced among women diagnosed premenopausally and among women with a high body mass index or waist-to-hip ratio ("}
+{"text": "A comparison has been made of the weight loss produced by tumour necrosis factor (TNF) (cachectin) with that produced by a restricted food and water intake (pair-fed controls), and by mitozolomide, a drug which in toxic doses induces weight loss with a similar decrease in nutrient and water intake. When administered as two separate injections over a 24 h period (acute administration) TNF produced a dose-related weight reduction that was accompanied by and directly proportional to a decrease in both food and water intake. When administered daily by i.v. injection over a 5-day period (chronic administration) the major weight loss was found to occur during the first 24 h after injection and thereafter the weight of treated mice increased toward that of controls. Acute administration of TNF produced hypoglycaemia that was more severe than observed with either mitozolomide or in pair-fed controls, a reduction in the circulatory level of free fatty acids (FFA) and an increase in plasma triglycerides, while mitozolomide and pair-feeding had no effect on the level of blood glucose or plasma triglycerides. Body composition analysis showed a loss of adipose tissue in TNF-injected and pair-fed animals after both acute and chronic treatment. Acute administration of TNF also induced a decrease in the total body water content of treated animals which was similar to pair-fed controls. It is concluded that the weight loss produced by TNF arises from a combination of semi-starvation and a reduced water intake, and that the effect only occurred with the first administration of TNF."}
+{"text": "Anti-inflammatory corticosteroids administered to rats in high dosages before intravenous injection of allogeneic tumour cells caused 5-10 fold reductions in \u201ctake\u201d and clonogenic growth of the cells in lung and kidney and decreased growth and spread of the cells transplanted to leg muscle. Steroid therapy also reduced the effect of local irradiation of lung tissues in increasing tumour colony efficiency (CFE) in the lungs; it also tended to reduce similar effects of sublethal whole body irradiation. A non-steroidal anti-inflammatory drug, phenylbutazone, also reduced CFE in locally irradiated lungs in the rat.The results obtained indicate that corticosteroids do not stimulate the growth of implanted tumour cells by suppressing host immunity but decrease their clonogenic growth by inhibiting local inflammatory reactions to cell arrest, and similarly to local tissue damage caused by x-irradiation; it is asserted that such inflammatory reactions are growth promoting and thereby stimulate regeneration of stroma (repair) and also support survival and early growth of the tumour cell."}
+{"text": "To study heterogeneity in a cell line derived from a human bladder carcinoma (EJ), 7 clones were isolated at low passage and examined for differences in culture behaviour, ability to grow in agar and tumorigenicity in nude mice. The parent EJ line had several distinct chromosome populations (both diploid and tetraploid), grew in agar and produced tumours in nude mice. Three of the clones had pseudodiploid modes and 4 had either hypo- or hypertetraploid modes. The 7 clones had 5 marker chromosomes in common but the combination of other marker chromosomes made each clone unique. No significant difference was found between the clones in the in vitro growth rate although analysis of in vitro culture behaviour showed heterogeneity in the pattern of cell movement on plastic substratum. Three clones were composed of static cells, one clone had very mobile cells; the other clones had rates of movement intermediate between the two. Differences were also found in the packing density of the cloned cells and in the cell size. All 7 clones grew in agar but heterogeneity was seen between the clones as shown by widely varying colony-forming efficiencies (0.5-13%). One clone had a high colony-forming ability in agar but failed to produce tumours in nude mice. The other clones were tumorigenic regardless of colony-forming efficiency in agar. Specific chromosome abnormalities were found to be associated with growth in agar and tumorigenicity but not with the growth pattern or the rate of movement of the cloned cells in culture."}
+{"text": "The in vivo effects of different oral bile salts on theintestinal absorption of radiolabelled endotoxin from rats with obstructive jaundice were compared. Thein vitro and in vivo anti-endotoxic activities of bile salts related to their known detergent activities.Deoxycholic acid and its conjugates were the most effective and should be the bile salts of choice forfurther clinical evaluation in obstructive jaundice in man.Systemic endotoxaemia is associated with postoperative renal dysfunction in obstructive jaundice, andcan be prevented by the pre-operative administration of certain bile salts. In order to find the mosteffective bile salt for use in this condition, a comparison of the anti-endotoxic activities of different bilesalts was performed. Bile salts were incubated"}
+{"text": "Cutaneous larva migrans is caused by infection with hookworm larvae in tropical and sub-tropical areas. A history of recent travel to the tropics is usually elicited.A case of cutaneous larva migrans is described in which symptoms did not appear until five months after travel to Tanzania.Although the lesion of cutaneous larva migrans may appear immediately, the larvae may lie dormant for many months and presentation may therefore occur a long time after any foreign travel. An 18-year-old white British man presented with a three-day history of an intensely itchy eruption on the dorsum of his right foot. His symptoms started immediately after a long-haul flight from Britain to Australia. Five months previously he had travelled to Tanzania, where he walked barefoot on beaches. Examination revealed a typical serpiginous lesion  and a diCutaneous larva migrans is caused by infection with hookworm larvae in tropical and sub-tropical areas; a history of foreign travel and of walking barefoot on sandy soil or beaches can often be obtained . The diaAlthough the lesion of cutaneous larva migrans may appear almost immediately, this case illustrates the fact that the larvae may lie dormant for many months after infection. Presentation may therefore occur a long time after travel to the tropics. It is possible that a subsequent long-haul flight was the precipitant that awakened the larva from its dormant stage in this case."}
+{"text": "A morphological method has been developed allowing measurement of the effect on intestinal epithelia of vincristine. In routinely prepared tissue sections the proportion of mitotic events progressing beyond metaphase is counted by microscopy. When estimated over a range of doses of vincristine this post-metaphase index (PMI) can be used to compare the sensitivity of differing intact tissues. Intestinal tumours were induced in rats by chemical carcinogenesis. Administration of vincristine in the presence or absence of verapamil was performed in these tumour-bearing animals. Sections were prepared from colonic and small-bowel tumours and from normal mucosa. The results show that verapamil increases the sensitivity of the tissues studied to vincristine. A dose dependent effect of verapamil on vincristine sensitisation was demonstrated in colonic tissues. These findings indicate a shared pharmacological property between the resistance of primary tumour tissue and the multidrug-resistance phenotype."}
+{"text": "Decreased membrane rigidity is one of the characteristics of malignant cells, resulting in part from the desaturation of stearic acid into oleic acid. In this study we investigated the influence of stearic acid on tumour cell inhibition in vitro and tumour development in vivo. Stearic acid inhibited the colony-forming ability of 4 out of 5 rat and two human tumour continuous cell lines in vitro. In contrast, the colony-forming ability of rat fibroblasts was not inhibited and that of human foetal lung fibroblasts was inhibited at a higher dose than that required to inhibit human tumour cell lines. Using a model of rat mammary carcinoma induced by nitroso-methyl urea (NMU) the subcutaneous injection of stearic acid at weekly intervals prevented tumour development in 5 to 10 rats. Using iodostearic acid twice weekly, 11 of 19 rats were alive and tumour free at week 22 whilst all of 14 animals injected with NMU alone had died of tumour by the 16th week. The ratio of stearic to oleic acids in erythrocyte membranes was significantly reduced in the tumour-bearing rats, but was normal in tumour-free animals treated with stearic or iodostearic acid. These preliminary data indicate that stearic acid inhibits tumour development in rats."}
+{"text": "The increasing interest in 5-fluorouracil (5-FU) modulation and the development of new antifolates has focused attention in recent studies on the expression of the target enzyme thymidylate synthase (TS) as a determinant of drug sensitivity and resistance. Resistance to TS-directed drugs has been shown to occur in vitro and in vivo with increased expression of the enzyme (determined by enzymatic assays as well as protein and gene expression assays). Several studies have evaluated the role of TS as a prognostic indicator of clinical response to chemotherapy containing TS-directed drugs. We have used a polyclonal antibody to recombinant human TS to establish a silver-enhanced immunogold staining method to localize TS in human tumours. Human tumour cell lines with acquired resistance to TS inhibitors owing to increased levels of TS were used to confirm the specificity of immunostaining. Stained sections were evaluated by image analysis. Immunostaining in tumour sections was greatly reduced (>80%) by preabsorption of the antiserum with recombinant TS. The method was used to determine the extent of TS immunostaining in 134 primary human colorectal tumours. The results were then compared with the clinical outcome and response to chemotherapy for the treatment of subsequent metastatic disease. A wide range (approximately 100-fold) of TS immunostaining was observed in these primary tumour sections. Normal mucosal tissue levels were 5-10 times lower than those observed in the adjacent tumour tissue. The values for TS immunostaining did not correlate with clinical endpoints, such as time from diagnosis to relapse, response to chemotherapy for disseminated disease, nor with Dukes' staging. This lack of correlation may be because this group of patients was selected on the basis of their need for palliative chemotherapy and did not include patients who were cured of their disease. Also, primary tumour TS expression may not give a good indication of the TS expression in metastatic lesions. The prognostic significance of TS protein expression in primary and metastatic lesions requires further evaluation."}
+{"text": "Rubidazone, the new semi-synthetic benzol hydrazone hydrochloride derivative of dauorubicin, has proved on a molecular weight basis to be less toxic than adriamycin and similar to daunorubicin in cardiac toxicity studies in the hamster as well as in other in vivo and in vitro test systems. It has proven effectiveness against several animal tumours and human acute leukaemias. We have compared the inhibitory effect of rubidazone to that of adriamycin on P388 leukaemia and normal bone marrow colony-forming units (CFU) using the spleen colony assay system in male DBA2 mice. The efficacy ratios  in the spleen colony assay system for rubidazone and adriamycin were 7-8 and 7-5 respectively. This near identity of efficacy ratios fro rubidazone and adriamycin correlated with the results of median survival time studies in the leukaemic mice. Their dose-median survival time curves were almost parallel, having nearly identical slopes. Rubidazone's equal therapeutic index as compared to adriamycin in the spleen colony assay system together with its known decreased toxicity to cardiac muscle cells makes it an extremely promising new anthracycline derivative to study in comparison to adriamycin in human malignancies."}
+{"text": "CEA-like antigen has been detected on the surface of some melanoma cells using a rabbit antiserum raised against CEA antigen in 51Cr-release leucocyte-dependent cytotoxic-antibody (LDA) assays. The CEA antigen used for production of the antiserum was shown to be immunologically pure by immunoelectrophoresis procedures and reacted with a reference serum to CEA. The specificity of the CEA antiserum for CEA on the melanoma cells was further shown by removal of reactivity to melanoma cells after absorption on CEA affinity columns. LDA activity to CEA was also shown in a serum taken during pregnancy. No CEA LDA activity was found in several melanoma sera. These findings suggest that CEA may have biological significance in tumour rejection, and that CEA assays may be of value in monitoring disease activity in melanoma patients."}
+{"text": "A computerised self-assessment instrument was used to capture data on the distress caused by symptoms in 110 patients treated with radical radiotherapy. Patients selected symptoms from a list of 34 problems and then quantified the distress associated with each problem using a linear Analogue self assessment (LASA)-type scale. The test instrument was feasible: 90% of assessments were completed in under 14 min. There was a significant increase in tiredness and significant decrease in anxiety and worries about the family, during treatment. Menopausal symptoms and post-surgical problems were important causes of distress in the patients with breast cancer. When the area under the curve method was used to quantify distress in the patients with breast cancer, difficulty concentrating, pain and sleep disturbances emerged as significantly troublesome problems. Computerised self-assessment may have a useful role in quantifying the distress caused by treatment with radiotherapy."}
+{"text": "Prolonged interaction in vitro between C. parvum-induced adherent predominantly phagocytic rat peritoneal cells and syngeneic or xenogeneic tumour targets consistently produces marked cytotoxicity. In the presence of irradiated foetal liver cells, expression of cytotoxicity is blocked in a dose-dependent manner. The ability of liver cells to compete with tumour targets is rapidly lost after birth. Irradiated liver cells from adult donors showed no such competition with tumour cells. The in vivo growth in ascites form of rat fibrosarcoma cells of low immunogenicity is significantly enhanced by irradiated foetal liver cells administered locally shortly before or on the day of tumour-cell challenge. The findings may provide an indication as to the nature of the structures recognized as non-self by mononuclear phagocytes."}
+{"text": "There is accumulating evidence of an increased risk of familial clustering of cancer in the first-degree relatives of lung cancer probands. However, no explanation has been proposed for these epidemiological data. We reviewed 379 female non-small-cell lung cancer (NSCLC) patients to obtain their family histories of malignancy. Among them, nine female NSCLC patients with three or more relatives diagnosed with malignancy and 28 control patients without a family history of malignancy were selected to be analysed for instability at six different microsatellite loci. We observed microsatellite instability (MSI) more frequently in the patients with three or more family histories of malignancy  than the control patients . The incidence of MSI in the former was significantly higher than that in the control (P=0.011: Fisher's exact test). We detected no significant difference in clinicopathological characteristics between the cases with MSI and those without MSI, except for their family histories of cancer. Our results show that a significantly higher rate of MSI is associated with familial clustering of malignancy. MSI could be one of the underlying mechanisms for familial clustering of malignancy in female NSCLC patients."}
+{"text": "We describe a 66-year-old man who presented initially with acute cholecystitis. He was treated bycholecystostomy and biopsy of the gallbladder mucosa which revealed carcinoma of the gallbladder.Four weeks later a cholecystectomy was performed followed by resection of the common bile duct,common hepatic duct and segments IV and V of the liver and a hepaticojejunostomy. Sixteen monthslater an abdomino-perineal resection was performed for a moderately differentiated Dukes\u2032 stage Ccarcinoma of the rectum. He is alive and without evidence of recurrence seven years later. Few patientssurvive for this length of time following resection of either carcinoma of the gallbladder or rectum. Thiscase report demonstrates the value of aggressive surgical treatment in patients with early carcinoma ofthe gallbladder."}
+{"text": "Classical Hodgkin lymphoma (CHL) is a relatively uncommon B cell-derived neoplasm that presents with rare malignant cells in an abundant reactive background. The diagnosis of CHL currently relies on a combination of morphologic findings and immunohistochemical stains. With the exception of rare cases with dramatically increased malignant populations, isolation of pure viable tumor cells has not been historically possible. Recently, a reliable flow cytometric assay for direct detection and isolation of the malignant cells in this disease has been developed. This assay has proven useful diagnostically and has been clinically validated to have a very high sensitivity and nearly absolute specificity for the diagnosis of CHL in routine clinical samples. This paper describes the methodology for the flow cytometric detection of CHL in clinical samples as well as current state of evaluation of background lymphocytes as an adjunct diagnostic test. Also discussed are exciting research applications of the direct isolation of viable tumor cells in CHL. The current state of flow cytometric evaluation of nodular lymphocyte predominant Hodgkin lymphoma and T cell-rich large B cell lymphoma is also briefly discussed. With increasingly rare exceptions, diagnosis of lymphoproliferative diseases and myeloid stem cell disorders relies on a multimodal analysis in which flow cytometry plays a significant role . While aThe relatively rapid analytical time makes flow cytometry an attractive initial diagnostic modality. This analysis can guide further morphologic and molecular workup leading to savings in cost and time of the total evaluation. In many cases, the immunophenotype obtained by flow cytometry alone can be diagnostic for specific hematologic neoplasms in a correct clinical and morphologic context. Because of the ability to analyze a large number of cells, flow cytometry is ideally suited for the detection of relatively rare, antigenically distinct populations within complex cell mixtures. This ability has been successfully exploited clinically for the detection of relatively low levels of minimal residual disease (MRD) posttreatment in leukemia and multiple myeloma is now considered one of the critical modalities to monitor MRD \u20134. It alClassical Hodgkin lymphoma is a B cell neoplasm where the neoplastic population represents less than 1% and frequently less than 0.01% of the total cells . The neoThe inability to detect the HRS cells had often been attributed to their cell lysis during preparations or during the cell acquisition . As lateNormal T cells have been shown to closely associate with HRS cells in immunohistochemical sections and bind (rosette) cell lines derived from CHL tumors. Indeed, using a CHL cell line (L428), Sanders and coworkers have shown that high levels of CD54 (ICAM-1) and CD58 (LFA-3) on the HRS cell bind to LFA-1 and CD2 on the T cell . This phThis rosetting causes a significant proportion of HRS cells to fall outside the area that is usually used for recognition of individual (nonaggregated) cells in flow cytometric analysis. The HRS-T cell rosettes fall either in the area that is routinely excluded as coincident events (cell aggregates) or are located at the very edge or beyond the high end of the measurable range of forward scatter parameters set to analyze hematopoietic cells. Moreover, the interaction of HRS cells with the T cells is expected to lead to a composite immunophenotype between these two cell types. Indeed, most cases of CHL cells do demonstrate a composite, HRS-T cell immunophenotype . Disrupting interactions between HRS cells and T cells with blocking antibodies reduces rosetting by T cells leading to the expected HRS cell immunophenotype . In routine clinical practice, blocking antibodies are not necessary with most CHL cases demonstrating both rosetted and unrosetted HRS population. Furthermore, this unique feature of Hodgkin lymphomas can be diagnostically useful .Further development of a reliable method of diagnosis of classical Hodgkin lymphoma by flow cytometry has benefited from the advances in the instrumentation. Introduction of rapid digital event acquisition on the modern cytometers now allows for the routine analysis of 500,000 events or more within less than 5 minutes, bringing a population that represents 0.01% of the total white cells well within range of sensitivity of clinical cytometry. In addition, increased numbers of lasers and detectors on the modern instruments allow for simultaneous interrogation of 10 or more antigens within the same tube. This, in turn, increases confidence in identification of small populations based on multidimensional analysis of multiple antibody staining patterns on single cells . In our In a recent blinded single-center clinical validation study that included common morphologic and immunophenotypic mimics of CHL, the above flow cytometry reagent combination demonstrated an 88.7% sensitivity and 100% specificity for diagnosing CHL. Interestingly, many false negative cases were greater than 72 hours in age, possibly suggesting selective loss of HRS cells during prolonged sample storage [Flow cytometry offers several potential benefits in the diagnosis of CHL. These include: (1) increased diagnostic certainty in cases which may be equivocal or possibly negative by initial morphologic review; our study identified four such cases, which were subsequently confirmed by extensive immunohistochemical panels or tissue section morphology on a subsequent biopsy; (2) rapid turn around time (hours compared to days) required for confirmation of CHL by immunohistochemistry; and (3) significant cost savings compared to extensive immunohistochemical panels that have become common in the morphologic diagnosis of CHL.There are still several significant limitations of this testing strategy. So far, flow cytometry data has been produced by a single institution and clinical validation at other centers would be necessary before widespread adoption of this method for routine clinical use. Our initial validation of clinical testing for CHL has relied on a 9-color tube. The instruments that are required for such detection are still not widely used in most clinical cytometry laboratories. However, they are commercially available and offer multiple advantages for other clinical applications. We are now in the process of validating a six-color assay that will allow more laboratories to use the methodology. Currently, the detection of HRS cells is limited to tissue samples and has not been validated in either peripheral blood or bone marrow samples. Finally, in cases where the immunophenotype of the cells is consistent with CHL, other related neoplasms must still remain on the differential diagnosis. These include cases of so-called grey zone lymphoma with features intermediate between classical Hodgkin lymphoma and B cell lymphoma as well as other B and T cell lymphomas with HRS-like cells. In the case of grey zone lymphoma, which may present with sheet-like proliferation of HRS-like cells, an important observation is the significantly increased number of malignant cells detected by flow cytometry. In cases of other B and T cell lymphomas, routine flow cytometry panels for B and T cells are usually sufficient to exclude these possibilities. In our practice, we have encountered several such cases following initial validation. These included HRS-like cells in a case of angioimmunoblastic T cell lymphoma, that showed an HRS cell population and aberrant T cell population by flow cytometry and two cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) with HRS-like cells that both demonstrated a predominant abnormal CD5+ B cell populations in addition to HRS-cell populations. While in none of the cases did flow cytometry provide a misleading diagnosis, the occurrence of cells with HRS-like phenotype in non-Hodgkin lymphomas further highlights the necessity of morphologic and flow cytometric correlation as a part of complete clinical evaluation.A majority of the cellularity in CHL tumors is composed of an inflammatory background. Thus, it is not surprising that a significant amount of effort has been placed in developing diagnostically useful flow cytometric tests focused on evaluation of various subsets of inflammatory cells. T cells have been of particular interest because of the variety of immunophenotypically distinct subsets that can be analyzed. Some, but not all, reports note increased ratios of CD4 to CD8-positive T cells in CHL, compared to reactive lymph nodes by either flow cytometry or immunohistochemistry \u201315. An iAdditional subsets of CD4- and CD8-positive T cells showing overexpression of CD7 have recently been demonstrated in CHL . Other aThe role of this subset and its relationship to Th17 or T regulatory subsets is unclear. While prospective data on the use of these subsets in diagnostic workup of CHL has not been reported, retrospective data showed the sensitivity of approximately 70% and specificity of 90% in the data set assembled by Seegmiller and colleagues . Thus, tIn addition to clinical detection of HRS cells as an adjunct test for CHL diagnosis, flow cytometry offers a significant opportunity to advance research investigations into this poorly understood disease. Until recently, the only applicable methods for cell enrichment were laser capture microdissection of individual HRS cells from tissue sections and magnetic bead-based enrichment using anti-CD30 antibody linked beads. While laser capture microdissection allows for limited molecular analysis, it possesses multiple disadvantages compared to flow cytometric cell sorting including limiting numbers of cells that can be reasonably isolated, unpredictable levels of contamination from underlying reactive cells in the section, and the impossibility of obtaining viable tumor cells. The use of anti-CD30 antibody linked beads has also been described, but the purity of the enriched population from many cases is limiting for even molecular analysis . Flow cyWhile major strides have been made in flow cytometric detection of CHL, relatively little is known about nodular lymphocyte predominant Hodgkin lymphoma. CHL and NLPHL share similar frequency of large malignant cells in an inflammatory background, but unlike CHL, the malignant cells in NLPHL are generally negative for CD30 and CD15 and express the usual B cell-markers CD20 and CD19 as well as normal levels of panhematopoietic marker CD45 [Other clues to the diagnosis may come from analyzing the patterns of the inflammatory cell background that accompanies the tumors. A recent publication demonstrated that detection of significant proportions of CD4 and CD8 double-positive T cells may suggest a diagnosis of NLPHL by flow cytometry . This stWhile HRS cells with their distinctive immunophenotype can now be readily identified and isolated from CHL tumors, the question remains as to whether these cells represent the only malignant component or whether some other, less distinct subset of cells, may serve as a reservoir that gives rise to these cells. This question is not trivial as it may well affect development of targeted therapies for CHL, monitoring of the disease, and our understanding of its pathogenesis. A recent article has demonstrated that in patients with CHL, a rare subset of peripheral blood-based B cells carries the same clonal B cell rearrangement as HRS cells within the tumor . The autWe hypothesize that flow cytometry could also be successfully applied to prognostication of clinical outcome of Hodgkin lymphoma. Several recent studies that used either immunohistochemistry or molecular expression array profiling have demonstrated that specific patterns of the inflammatory milieu or antigen expression in HRS cells themselves correlate with prognosis in CHL. However, tissue-based antibody staining studies are very difficult to reproducibly apply in the clinic due to the at best semi-quantitative nature of staining assessment in tissue sections. We believe that most of the markers could be readily portable to a more rapid and quantitative flow cytometry-based method. In particular, expression of Bcl-2 on the HRS cells has been shown to be a marker of poor prognosis , 53. AddSimilar techniques could be applied for the assessment of the tumor microenvironment-based predictive markers. Expression of markers on various cell subsets within the microenvironment and composition of the inflammatory background have been strongly linked to CHL prognosis , 57\u201362."}
+{"text": "Here, in order to determine whether the efficacy of chemotherapy can be enhanced by changing the regimen, we evaluated the effect of the varied timing and dosage of chemotherapy in combination with androgen withdrawal on time to androgen-independent (AI) progression in the human androgen-dependent LNCaP tumour model. We first demonstrated the synergistic effect of mitoxantrone on induction of apoptosis in LNCaP cells maintained in the steroid hormone-depleted charcoal-stripped media (CSM) compared to those in the standard media. In addition, this synergy was most remarkable during the simultaneous treatment of LNCaP cells with mitoxantrone and CSM compared to the pre- or post-use of mitoxantrone with CSM. LNCaP tumour growth in athymic nude mice and their increase in serum PSA levels were significantly inhibited by the simultaneous injection of mitoxantrone with castration, compared to the administration of mitoxantrone 2 weeks before or after castration. The TUNEL staining revealed that apoptotic cell death was extensively induced in LNCaP tumours treated with simultaneous castration and mitoxantrone compared to tumours treated with the other schedules. Furthermore, nude mice bearing LNCaP tumours were injected with a total of 0.5\u2008mg mitoxantrone divided into 2, 5 and 10 days, with the most significant therapeutic effect and delayed AI progression observed in mice given injection of mitoxantrone for 2 days. These findings suggest that this might be the optimal way to perform cytotoxic chemotherapy and androgen withdrawal simultaneously in patients with advanced prostate cancer and to administer chemotherapeutic agents at high dosage within short intervals. \u00a9 2001 Cancer Research Campaign"}
+{"text": "We have correlated the morphological features of 30 human thyroid carcinomas with the cellular localisation of insulin-like growth factor 1 (IGF-1) mRNA and IGF-1 receptor peptide using in situ hybridisation with digoxigenin-labelled oligoprobes and immunohistochemistry. Four of the five follicular carcinomas studied showed a consistent, uniform, strong positivity for IGF-1 mRNA in tumour cells compared with weakly positive surrounding normal follicular tissue and negative stroma. The majority of papillary carcinomas showed weak to moderate epithelial positivity for IGF-1 mRNA and negative stroma. Immunohistochemistry for IGF-1 receptor showed moderate positivity confined to the tumour epithelial cells in both follicular and the majority of papillary carcinomas. However, in a subgroup of papillary carcinomas characterised by a diffuse stromal lymphoid infiltration (n = 5), the stromal cells showed a much stronger reactivity for IGF-1 mRNA than the tumour or background thyroid, and the tumour cells showed a uniformly high level of immunoreactivity for IGF-1 receptor. These results are compatible with the growth of the papillary carcinoma in these cases being the result of a symbiotic relationship between the stromal lymphoid cells and the tumour epithelium with the lymphoid cells responding to an antigen produced by the tumour cells and the tumour cells responding to a growth factor produced by the lymphoid infiltrate. We suggest that this mechanism may be important in other tumours regularly associated with a widespread lymphoid infiltrate."}
+{"text": "Glaucoma, the second leading cause of blindness, is characterized by changes in the optic disc and visual field defects. The elevated intraocular pressure was considered the prime factor responsible for the glaucomatous optic neuropathy involving death of retinal ganglion cells and their axons. Extensive investigations into the pathophysiology of glaucoma now reveal the role of multiple factors in the development of retinal ganglion cell death. A better understanding of the pathophysiological mechanisms involved in the onset and progression of glaucomatous optic neuropathy is crucial in the development of better therapeutic options. This review is an effort to summarize the current concepts in the pathophysiology of glaucoma so that newer therapeutic targets can be recognized.The literature available in the National Medical Library and online Pubmed search engine was used for literature review. Glaucoma, a leading cause of irreversible visual loss, is characterized by loss of retinal ganglion cells (RGC) and their axons over a period of many years. Glaucomatous optic neuropathy is characterized by changes in the optic disc and visual field defects.2 The morThe pathophysiology of glaucomatous optic neuropathy is not well understood. Whether the site of primary damage is the ganglion cell body or their axons remains fiercely debatable. Irrespective of the initial site of neuronal injury and mechanisms involved, the terminal outcome is the death of RGCs and their axons leading to irreversible visual loss. This paper presents a review of the various mechanisms involved in the development of glaucomatous optic neuropathy. The literature published during 1984 to 2006 was reviewed except for the two research papers  which were included to show that the important role of glutamate toxicity in glaucomatous optic atrophy has been suspected for a long time. All the literature reviewed was obtained from the National Medical Library and online Pubmed search engine. All articles referenced were published in English language journals.Glaucoma is a heterogeneous group of diseases and the pathophysiology of glaucoma is believed to be multifactorial. Multiple factors acting either on cell bodies or their axons are believed to lead to RGC death. According to various theories put forth, factors like elevated intraocular pressure (IOP) and vascular dysregulation primarily contribute to the initial insult during glaucomatous atrophy in the form of obstruction to axoplasmic flow within the RGC axons at the lamina cribrosa, altered optic nerve microcirculation at the level of lamina and changes in the laminar glial and connective tissue. The factors leading to secondary insult include excitotoxic damage caused by glutamate or glycine released from injured neurons and oxidative damage caused by over-production of nitric oxide (NO) and other reactive oxygen species. Whatever may be the primary and secondary factors, the end result in glaucomatous eyes is the dysfunction and death of RGCs leading to irreversible visual loss, as a result of a complex interplay of multiple factors rather than any one of them functioning individually.The characteristic change in the optic nerve head in glaucoma is a \u201ccupping\u201d of the optic disc where ganglion cell axons have been lost. The death of the axons is associated with a loss of ganglion cell bodies in the retina and ganglion cell axon terminals in the dorsal lateral geniculate body. Death of RGCs in glaucomatous human eyes and experimental animal models of glaucoma takes place by apoptosis,7 which i4The caspases, a family of cysteine aspartyl-specific proteases have emerged as the central regulators of apoptosis. These enzymes are present as inactive zymogens and once activated initiate an ordered cascade leading to proteolysis of key cytosolic and nuclear components and eventual destruction of the cell. The actiet al. have reported significant RGC death within 24 h of superior colliculus ablation in neonatal rats which was not inhibited by general or specific caspase inhibitors.[While the evidences suggest the central role of caspases in adult RGC death, there is a growing body of evidence suggesting involvement of caspase-independent pathways in RGC death under certain conditions. Spalding hibitors.Until recently it was believed that elevated IOP plays a major role in RGC apoptosis and it is also true that reduction of elevated IOP often helps in slowing down the progression of degenerative changes in glaucoma. However, among glaucoma patients only one-third to half of all glaucoma patients have elevated IOP at the initial stages.1920 On a19Elevated IOP often results from alterations in aqueous humor dynamics due to changes in trabecular meshwork leading to impaired drainage of aqueous. The trabecular meshwork has been shown to exhibit cytoskeletal changes in cells, altered 23297Cellular responses to changes in IOP, leading to apoptosis of RGCs are not well understood. A possible mechanism of RGC apoptosis seems to be related to changes in extracelluar matrix components in the retina of glaucomatous eyes in response to elevated IOP. Extensive remodeling of the ECM, including collagen I and IV, transforming growth factor-\u00df2 (TGF-\u00df2), and matrix metalloproteinase (MMP)-1 have been detected in glaucomatous eyes.\u201338 ECM iMMPs are the major matrix-degrading enzymes. In a recent study enhanced MMP-9 activity was detected in apoptotic RGCs along with decreased deposition of laminin in the RGC layer suggesting increased degradation of the ECM at the retinal site in response to exposure to elevated IOP. Laminin Growth factors and their receptors are known to regulate cellular functions, cytoskeletal organizations and components of ECM in ocular tissue. Trabecular meshwork, optic nerve astrocytes as well as lamina cribrosa cells express a wide variety of growth factors such as neurotrophin factor and TGF-\u00df2. These growth factors may play an important role by affecting the normal development and cellular functions in the trabecular meshwork as well as retina. In the retina retrograde axoplasmic transport block, as a result of elevated IOP can deprive the RGCs of the supply of brain-derived neurotrophin factor (BDNF), important for regulating cell metabolism and cell survival. Deficiency of BDNF can further lead to progression of RGC apoptosis. These efet al., have now demonstrated rapid upregulation of TNF-A in rats with experimentally induced elevated IOP and this was followed sequentially by microglial activation, loss of optic nerve oligodendrocytes, and delayed loss of RGCs.[Nakazawa  of RGCs. An upreg of RGCs. A summarClearly, elevated IOP plays a major role in RGC damage in glaucomatous eyes but therapeutic control of IOP in many patients is not sufficient to improve the visual functions and arrest the progression of the disease process.49 BesideA number of circumstantial evidences point towards an association between vascular insufficiency and glaucoma. A positive association of glaucoma has been observed with migraine51 and pe5260In a healthy eye, a constant flow of blood is required in the retina and optic nerve head so as to meet the high metabolic needs in these vital parts of the eye. To maintain a constant rate of blood flow an efficient autoregulatory mechanism operates in arteries, arterioles and capillaries over a wide range of day-to-day fluctuations in ocular perfusion pressure that is dependent on both the systemic blood pressure and IOP. These au64The molecular mechanisms leading to RGC death due to vascular dysregulation are not clearly understood. The vascular insufficiency can directly damage and cause RGC apoptosis. Upregulation of MMP-9 expression in circulating leucocytes has been observed in patients with vasospastic NTG. The upreApoptotic cell death of RGCs has also been attributed to glutamate-mediated toxicity and upon exposure to hypoxic conditions retinal cells are known to release glutamate. The aminN-methyl-D-aspartate (NMDA), kianate (KA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) receptors. The metabotropic receptors (mGluR) are G protein-linked receptors and are divided into three groups. Glutamate-induced excitotoxicity is primarily mediated by ionotropic NMDA subtype receptors.[++ and Na+ into the neurons. Glutamate-mediated neuronal toxicity is dependent on the influx of extracellular Ca+, which in turn acts as second messenger to activate downstream signaling pathways finally leading to cell death.[76Glutamate-mediated neurotransmission is via ionotropic and metabotropic receptors . The ioneceptors.75 NMDA rll death.7677 Expe death.76 In addit death.7680 Activa death.76++-permeable AMPA-KA receptors in cultured RGCs, leading to increases in Ca++ and decreased RGC survival.[Low concentrations of glutamate were found to activate Casurvival. The KA rsurvival.There is evidence that among the mGluR activation of group I mGluRs increases neuronal excitation, whereas that of group II and III reduces synaptic transmission. Therefore, group I mGluR antagonists and group II and III mGluR agonists are expected to provide neuroprotective effects.To maintain the physiological concentrations and to protect ganglion cells from excitotoxic cell death, appropriate removal of synaptic glutamate is required. Glial cells, especially the Muller cells and astrocytes, present around the synapses express the glutamate transporter which helps in clearing extracellular glutamate by transporting it to the interior of glial cells. Within tet al., reported significant decrease of retinal glutamate uptake, decreased activity of glutamine synthetase, significantly increased glutamine uptake and release and significantly increased glutaminase activity in oculohypertensive rats.[Deviations from this normal retinal glutamate/glutamine cycle have been observed in experimental models of glaucoma. In a glaucoma model of rat, Moreno ive rats. In one sive rats. A robustive rats. Furthermive rats.in vivo rat model of optic nerve ischemia.[et al., reported significantly elevated vitreal glutamate levels in glaucomatous monkeys as compared to normal monkeys.[et al., reported that there were no significant differences in vitreal glutamate concentration between vitreous from normal control eyes and glaucomatous eyes, nor was there a significant difference in the results between the analyses performed in two independent laboratories.[et al., also reported no significant changes in vitreal glutamate levels in glaucomatous monkey eyes as compared to control eyes.[et al., and even after considering all possible factors that could have influenced the measurement of glutamate levels, the exceptionally high glutamate levels reported could not be explained. The validity of results of Dreyer et al., was therefore doubtful. A probe into the charges of scientific misconduct was initiated by Harvard University officials and the author quickly admitted fabricating some of his data. A heavy punishment of a 10-year debarment from receiving federal research funds was imposed.[Some studies have suggested a correlation between elevated levels of glutamate in vitreous and apoptotic cell death in retina, however, others have reported no alterations in vitreous glutamate levels in glaucomatous eyes. Increased glutamate levels have been observed in mutant quail with a glaucoma-like disorder. Elevatedischemia. In patieischemia. Dreyer e monkeys. Later, iratories. Hare et rol eyes. In anothrol eyes. These fi imposed.In spite of the controversial issues mentioned earlier glutamate excitotoxicity seems to play an important role in neurodegenerative changes in glaucoma. However, it remains to be determined whether the glutamate excitotoxicity is an initial response to elevated pressure and ischemia or whether the secondary response due to release from dying ganglion cells plays the more critical role.Nitric oxide plays an important and beneficial role in body function when secreted in physiological quantities, however, excess production of NO has been associated with a variety of non-neurological and neurological conditions including glaucoma. NOS produces NO by oxidation of L-arginine and has been detected in three isoforms.de novo synthesis of the NOS-1 isoform in astrocytes of the lamina cribrosa have also been observed. NOS-3 is also a constitutive enzyme present in the vascular endothelial cells in the prelaminar region of the optic nerve head in normal eyes and functions as a vasodilator. In glaucomatous eyes by causing vasodilation and increasing the blood flow NOS-3 induction can provide neuroprotective effects. The role of NOS-3 present in the astrocytes of glaucomatous optic nerve heads is not clearly known.[In normal human eyes the presence of NOS-1 has been detected in scattered astrocytes throughout the optic nerve head indicating that the NOS-1 is a constitutive enzyme in certain glia and NO serves functions as a physiological mediator between astrocytes or between astrocytes and axons. In patients with glaucoma a large number of cells show NOS-1 positivity on vitreal surface, in the remnant glial cells and in the cells in lamina cribrosa within glaucomatous tissue. Increased gene expression of the mRNA and presumably ly known.et al., observed significantly elevated NO levels in the retina of rats, 35 days after laser treatment.[NOS-2 is the inducible form of the enzyme (iNOS), which produces excessive quantities of NO under diverse conditions such as exposure to cytokines and presreatment. At this reatment.The molecular mechanisms of NOS-2 induction and production of neurotoxic quantities of NO have been studied in human optic nerve astrocyte culture. Besides elevated pressure various cytokines appear to play a key role in NOS-2 induction. Exposure of optic nerve astrocytes to interferon gamma and interleukin-1\u03b2 in culture stimulates NOS-2 production within 24 h. TNF-A apThus a large body of evidence suggests that excessive quantities of NO produced by astrocytes and microglia in optic nerve head play a crucial role in the development of optic neuropathy associated with glaucoma. The excess of NO thus produced enters freely into the cells after diffusion through the local microenvironment. It is a S-transferase,[The ocular tissue is provided with a very efficient antioxidant defense mechanism, which includes reduced glutathione (GSH) and superoxide dismutase-catalase system. Ascorbic acid also has an important protective role and its high concentration has been detected in the vitreous humor, cornea, lacrimalnsferase, a decreansferase, and an insferase,Vascular dysregulation by causing ischemia and reperfusion may be the fundamental pathogenic step in inducing oxidative stress. Under ox124The results of some of the animal experiments have suggested possible benefits of antioxidants in glaucomatous optic neuropathy. In a rat model of glaucoma topical administration of a novel free radical scavenger with esterified ion chelator side groups on a methoxypolyethylene glycol backbone was found to lower IOP by 29.6%. In the same study the RGC loss in rats in response to intravitreal NMDA was also found to be reduced when NMDA was co-administered with the same novel free radical scavanger. BDNF in Glaucomatous optic neuropathy is a chronic process, which progresses over many years. Until recently, modulation of elevated IOP was the only mode of therapeutic intervention. As the glaucomatous changes continue to progress despite well-controlled IOP, development of pressure-independent and preferentially neuroprotective treatment strategies is extremely important. As the understanding of pathophysiological mechanisms involved in glaucomatous optic neuropathy has advanced tremendously, an enormous amount of research has been stimulated for the development of effective neuroprotective strategies.As a result a variety of therapeutic options have shown efficacy as neuroprotective agents in experimental studies. Besides ocular hypotensive agents the ocular blood flow enhancers such as calcium channel blockers were suggested to provide neuroprotection by improving the optic nerve head blood flow. But there were concerns as these agents reduce the systemic blood pressure and might worsen the optic nerve head ischemia by reducing the perfusion pressure. Carbonic anhydrase inhibitors are also suggested to improve the optic nerve head blood flow.A variety of agents with antiapoptotic activity have been evaluated for neuroprotective effects in experimental animal models. Both the reversible and irreversible caspase inhibitors were found to protect RGCs in axotomised rats. Erythropoietin, which promotes proliferation and differentiation of bone marrow precursor cells by inhibiting apoptosis, when given by intravitreal injection in an episcleral vessel cautery-induced rat model of glaucoma was found to increase RGC viability. However,Therapeutic interventions to alter the process of RGC degeneration have also been studied extensively. A variety of neurotrophic factors , an antioxidant (N-ace-tyl-L-cysteine), and a NOS inhibitor  have shown promising neuroprotective effects by modulating the process of RGC degeneration in experimental animals. The NMDA antagonists especially seem to hold promise in glaucoma neuroprotection. NMDA receptor antagonists have largely failed the clinical trials as they act by virtually blocking all the NMDA receptors, and physiological NMDA activity is essential for normal neuronal functions. Memantine, an adamantine derivative, has shown encouraging results as it selectively blocks the excessive receptor activation without affecting the normal receptor activity. Memantine is a noncompetitive, low-affinity, open channel blocker and blocks the receptor-associated ion channel when it is excessively open. As its off-rate is very high it does not accumulate substantially within the channel to interfere with the normal neuronal functions. Memantine is thus well tolerated and has been approved for use in Alzheimer's disease. The resuIn spite of a large number of drugs showing efficacy in animal experiments only one has progressed to the stage of clinical trial. Clearly, the concept of neuroprotective agents playing a major role in glaucoma management is still in infancy. However, a better understanding of the pathophysiological mechanisms involved in glaucoma will undoubtedly lead us to new, safe and effective glaucoma therapy.To summarize, the primary factors responsible for apoptotic cell death in glaucoma include not only elevated IOP but also vascular dysregulation, especially in people with NTG. The molecular mechanisms involved largely include glutamate excitotoxicity, increased MMP expression, TNF-alpha upregulation, increased NOS-2 expression and oxidative stress. The complex interrelationship between primary and secondary mechanisms involved in the pathophysiology of glaucoma is shown in"}
+{"text": "Morphological evidence about the curve apex suggests that the spinal cord is also affected, and a 'double pathology' is suggested. AIS is viewed as a disorder with a wide spectrum and a common neuroanatomical abnormality namely, a spinal cord of normal length but short relative to an abnormally lengthened anterior vertebral column. Neuroanatomical changes and/or abnormal neural function may be expressed only in severe cases. This asynchronous neuro-osseous growth concept is regarded as one component of a larger concept. The other component relates to the brain and cranium of AIS subjects because abnormalities have been found in brain  and skull (vault and base). The possible relevance of systemic melatonin-signaling pathway dysfunction, platelet calmodulin levels and putative vertebral vascular biology to the asynchronous neuro-osseous growth concept is discussed. A biomechanical model to test the spinal component of the concept is in hand. There is no published research on the biomechanical properties of the spinal cord for scoliosis specimens. Such research on normal spinal cords includes movements (kinematics), stress-strain responses to uniaxial loading, and anterior forces created by the stretched cord in forward flexion that may alter sagittal spinal shape during adolescent growth. The asynchronous neuro-osseous growth concept for the spine evokes controversy. Dr Chu and colleagues respond to five other concepts of pathogenesis for AIS and suggest that relative anterior spinal overgrowth and biomechanical growth modulation may also contribute to AIS pathogenesis.There is no generally accepted scientific theory for the causes of adolescent idiopathic scoliosis (AIS). As part of its mission to widen understanding of scoliosis etiology, the International Federated Body on Scoliosis Etiology (IBSE) introduced the electronic focus group (EFG) as a means of increasing debate on knowledge of important topics. This has been designated as an on-line Delphi discussion. The Statement for this debate was written by Dr WCW Chu and colleagues who examine the spinal cord to vertebral growth interaction during adolescence in scoliosis. Using the multi-planar reconstruction technique of magnetic resonance imaging they investigated the relative length of spinal cord to vertebral column including ratios in 28 girls with AIS (mainly thoracic or double major curves) and 14 age-matched normal girls. Also evaluated were cerebellar tonsillar position, somatosensory evoked potentials (SSEPs), and clinical neurological examination. In severe AIS compared with normal controls, the vertebral column is significantly longer without detectable spinal cord lengthening. They speculate that anterior spinal column overgrowth relative to a normal length spinal cord exerts a stretching tethering force between the two ends, cranially and caudally leading to the initiation and progression of thoracic AIS. They support and develop the Roth-Porter concept of  In the absence of any accepted scientific theory for the etiology of idiopathic scoliosis treatment remains pragmatic with a very incomplete scientific basis. The International Federated Body on Scoliosis Etiology (IBSE) introduced the electronic focus group (EFG) as a means of increasing debate on knowledge of important topics. The Statement written by Dr WCW Chu and colleagues is based on important spinal imaging research, neurological findings and anthropometric data already published -3, Modermultiplanar reformat magnetic resonance imaging to the spine of 28 AIS girls and 14 matched normal girls . In 164position  in AIS . theory',  stated tin vivo kinematics caused by spinal movements . ClinicWe undertook a comparative study of magnetic resonance (MR) imaging of the whole vertebral column and spinal cord in girls with adolescent idiopathic thoracic scoliosis (AIS) and age and gender matched normal subjects . The aim14 AIS girls with mild to moderate curve (<30 degrees) and 14 AIS girls with progressive curve (> 40 degrees) were compared with 14 normal girls aged 13\u201314 years. Using the multi-planar reconstruction technique, the length of the vertebral column (from tip of C2 down to the inferior end plate of L5) and the length of spinal cord (from tip of C2 down to the conus medullaris) were measured. Compared with normal controls, the vertebral column is significantly longer in severe AIS. The latter was contributed to mainly by lengthening of the thoracic segment of the vertebral column. But, the absolute spinal cord length did not show corresponding lengthening in AIS. Therefore, the ratio of cord length/vertebral length was significantly reduced in severe AIS (ratio = 0.67) compared with the normal controls (ratio = 0.72).The concept of uncoupled neuro-osseous growth has been suggested in the pathogenesis of AIS -28. AccoWe postulate that the increased prevalence of tonsillar ectopia ,34, syriThe observations relate to lengths of the vertebral column and spinal cord in two groups of so-called idiopathic scoliosis, 14 girls AIS (<30 degrees) and 14 girls AIS (>40 degrees) in comparison with 14 normal girls are good and proper. The article is very interesting.The authors present the results of a morphometric MRI study of the spine in right thoracic AIS in girls (Rcx-T-F-AS) using the multiplanar reconstruction MRI technique. It is the second of two MRI studies on thoracic AIS from that centre. Guo et al ,7 had usIn the current study , we haveDr Chu and colleaguesa) Support the concept of uncoupled neuro-osseous growth, namely that \"...longitudinal growth of the spinal cord fails to keep pace with growth of the vertebral column.\"b) Support the concept that idiopathic scoliosis is a consequence of maladaptation of the growing immature spine to a tether created by a relatively short spinal cord.c) Speculate that relative low position of the cerebellar tonsil is related to relative shortening and functional tethering of the spinal cord.d) Suggest that patients with severe scoliosis could have subclinical cord tethering.The AIS study population comprises 14 girls with mild scoliosis (<30 degrees Cobb angle) and 14 girls with severe scoliosis >40 degrees Cobb angle).a) What are the curve types?b) What is the reproducibility of measuring cerebellar tonsillar ectopia?a) The curve types are as follows: 14 girls with mild scoliosis  and the 14 girls with severe scoliosis .b) In the previous study , the intThere is controversy on methods to analyse stature and sitting height ,132. Staa) Do you have figures for corrected heights (standing and sitting) for the AIS girls with mild and severe curves?b) If not, can the corrected heights be calculated from the data generated by the multiplanar reconstruction MRI technique?a) The mean corrected standing heights for the subjects are calculated with the Bjure-Nachemson Formula . The corb) Theoretically, corrected height can be estimated by the difference between the longitudinal height of subject's body and the entire length of the vertebral column measured by multiplanar reformat MRI.neurocentral synchondroses closure with the last closure about 6\u20137 years and not the vertebral endplate physeal closure which determines the relative anterior spinal overgrowth during adolescence.Dr Chu and colleagues explain the localization of anterior column lengthening to the thoracic vertebrae by growth plate closure later than in the cervical and lumbar spines, quoting Ganey and Ogden . But thiThank you for pointing out the misinterpretation. Lord and Ogden et at  stated tAfter the CT scanning method was applied to the scoliotic spine ,137 in ta) In what respect is the multiplanar reconstruction MR method superior to the earlier morphometric radiological studies?b) Were they any important differences between the results of studied parameters obtained by the use of the two methods?a) We think the major advantage of MR method is lack of radiation when compared with CT. This is particularly important for reducing the hazard of breast cancer risk in adolescent girls.b) We have looked into the vertebral morphometry of apical vertebrae in AIS subjects and compared with normal controls  cause, they do not allow any conclusion to explain the initiating cause of the decreased sagittal wedging of the thoracic vertebrae, ie the etiology of the spinal deformity.We think that the anterior relative overgrowth of the vertebra coupled with the relative slower growth of the spinal cord produce a coupling effect manifested maximally at the apical region of the thoracic scoliosis cases as a decrease in the sagittal wedge angle. Our previous MRI morphometry of thoracic vertebrae also showed the maximum effect at the apical and adjacent vertebrae.uncoupled, or asynchronous, neuro-osseous growth hypothesis for AIS as postulated by Dr Chu and colleagues has several requirements  Appendicular skeleton \u2013 taller standing height (corrected), sitting height (corrected), arm span, sub-ischial height and body mass index.2) Vertebral column \u2013 relative overgrowth of thoracic anterior spinal column.3) Spinal cord \u2013 normal length (but shortening relative to spine).4) Tethering of cord anatomically.- low lying tonsil, Chiari I, syringomyelia.5) Tethering of cord functionally \u2013 abnormal neurology.Do you consider the vertebral and extra-spinal skeletal length overgrowth, apparently seamless, to have a common origin?We think that the vertebral and extra-spinal skeletal length overgrowth are governed by the same underlying mechanism of abnormal skeletal growth and abnormal spinal growth is a part of the whole systemic growth disturbance. We have demonstrated abnormal appendicular skeletal growth and osteopenia in AIS subjects in our previous studies ,143-147.accelerated vertebral growth in AIS subjects Dr Chu and colleagues pose two questions  Will spinal cord growth keep pace with the vertebral column growth?Is there a dual spinal pathology? Theoretical argument suggests that for uncoupled neuro-osseous growth to induce AIS a double spinal abnormality is needed, viz:2) If not, will the central nervous system be affected? normal spinal cord without evident damage.a) Vertebral growth  may stretch a b) If the cord does not stretch normally a scoliosis could be induced \u2013 through mechanisms outlined by Porter .from whatever cause?  Are the 'morphological changes of cross-sectional shape and relative position of the cord' especially in the apical region not just adaptive to the deformity c) Is the concept of asynchronous nerve root growth testable? .PCF volume be measured in relation to each of the lower position of cerebellar tonsils, tonsillar ectopia, syringomyelia, abnormal SSEPs and the scoliosis? (\"push\" hypothesis)..PCF hypoPCF hypoplasia?f) Do you relate the smaller skull vault posteriorly in AIS subjects  to PCF ha) This concept can be answered by a biomechanical model to test the biomechanical parameters of spinal cord and geometric modification of scoliotic spine. The project is now in progress.MetaMorph imaging system, we have observed that the cross-sectional shape of the cord was fairly symmetrical. Therefore the altered cross-sectional shape was unlikely related to compression force from the concavity of the spine, which should result in an asymmetrical shape of the cord  Using the c) We have not yet worked on this. Theoretically it should be feasible if a biomechanical model can be built.PCF volume is one of the objectives in our study on volumetric analysis of brain in AIS. This project is a joint collaboration with the Brain & Body Centre of Nottingham University, UK, supported by the British Scoliosis Research Foundation .d) Measurement of e) We think this is the correct approach though the supratentorial brain abnormality might only be detected by sophisticated volumetric analysis, not by conventional MR sequences.f) Yes, both posterior skull vault and posterior cranial fossa are related to endochondral ossification, which is found to be uncoupled with membranous ossification in the vertebral column of AIS subjects.congenitally hypoplastic posterior fossa: reduced length of clivus, basisphenoid, basioccipu, increased angle of tentorium and CSF flow abnormalities .c) Might any asymmetries of rib ,112, uppd) If so, how would you account for the iliac length asymmetry  associat'asynchronous' to mean the pace of the growth is now disturbed, while the word \"uncoupled\" means there is a disruption of previously coupled growth. We think 'asynchronous' is probably a more objective term because we cannot be certain whether the growth of nervous system and skeletal system were 'coupled' in AIS before the onset of the disorder.a) Our hypothesis ,2 is pro'asynchronous neuro-osseous growth'.b) We cannot be certain about the whether the nerve roots  and peric) It is possible but cannot be proved by radiological means currently. It seems that Repko et al  provide d) The iliac length asymmetry  might beuncoupled, or asynchronous, neuro-osseous growth concept would Dr Chu and colleagues respond to the following comments:In connection with their a) the view that pontine and hindbrain regions are the likely sites of primary pathology that could lead to idiopathic scoliosis ,b) speculation that a process producing left-right spinal asymmetry  together with -i) rapid spinal elongationii) brain maturation,iii) upright posture andiv) trunk movements -may contribute to the initiation and progression of AIS ,85, Mode, Mode85,c) anecdotal evidence that prolonged rest in bed halts the progress of scoliosis ,96. In oa) The asynchronous neuro-osseous growth concept accommodates Lowe's hypothesis  of pontib) Asynchronous neuro-osseous growth accommodates the left-right spinal asymmetry concept which involves osseous growth and neuromuscular co-ordination.c) We speculate that rest in bed ,96 mightuncoupled neuro-osseous growth was considered, but rejected. This was because knowledge of normal vertebral growth supports the view that the scoliosis deformity in AIS is related to longitudinal vertebral body growth rather than growth of the vertebral canal. As pathomechanism they adopted the concept of primary skeletal change affecting the sagittal plane of the spine, and in the pathogenesis they proposed a novel histogenetic hypothesis of uncoupled endochondral-membranous bone formation. The latter was viewed as part of an 'intrinsic abnormality of skeletal growth in patients with AIS which may be genetic.' The authors of the current paper state that the findings support the concept of uncoupled neuro-osseous growth in the pathogenesis of AIS .(Rcx-T-F-AS) is not just a spinal deformity but a neglected paediatric nosological entity probably with related extra-vertebral influences .Rcx-T-F-AS) may be a subset of AIS which \"....probably should not be named 'idiopathic\"'. Patients with this type of deformity comprise about 80 per cent of those referred to hospital with AIS apart from two or three small subset. How does your proposed pathogenetic hypothesis of 'asynchronous neuro-osseous growth' explain -In the response to Comment no. 31 the authors agree that right convex thoracic adolescent scoliosis in females (a) the complex of morphological and pathophysiological manifestations of Rcx-T-F-AS ,114, andb) the simultaneous 3-D vertebral translation?hypothesis of asynchronous neuro-osseous growth proposes that during the rapid puberty growth of the adolescent girls, skeletal growth is faster than spinal cord growth; therefore they are asynchronous and therefore a tether is present. As there might be a pre-existing trend of thoracic vertebral axial rotation towards the right side . The. TheNottgenesis ; c); c)Nottigenesis .widespread skeletal overgrowth, Cole .a) How do Dr Chu and colleagues account for the association between thoracic apical rotation and upper arm length asymmetry in thoracic AIS subjects ?b) How does the uncoupled, or asynchronous, neuro-osseous growth concept explain the other patterns of extra-spinal left-right skeletal length asymmetries with AIS?a) We have not looked into details of upper arm length asymmetry and thoracic apical rotation in the previous database but we will take into account the above interesting observations in our ongoing work. We speculate that all the above observations about skeletal growth asymmetry might be part of the component in the process of asynchronous neuro-osseous growth in the pathogenesis of AISb) As mentioned in the previous point, we cannot explain other patterns of extra-spinal left-right skeletal length asymmetry at the moment but we speculate that all the above observations might be part of the whole process of asynchronous neuro-osseous growth in the pathogenesis of AIS'vicious cycle' pathogenetic hypothesis requires a pre-existing scoliosis curve that initiates asymmetric muscle loading on vertebral bodies which in turn causes worsening of the scoliosis, while everything else is anatomically and physiologically normal. How does your uncoupled, or asynchronous, neuro-osseous growth concept relate to biomechanical growth modulation concept proposed by Dr Stokes?In a recent electronic focus group, Dr Stokes  addresseOur hypothesis of asynchronous neuro-osseous growth proposes that the relative short cord can lead to hypokyphosis and hence curve initiation with or without progression of the scoliosis. Therefore, it might be the starting point as well as an aggravating factor in the 'vicious cycle' hypothesis of Dr Stokes ,104.WC with her colleagues in Hong Kong, WL, B Ng, TL, KL, XG and JC wrote the Statement based on their published research findings and also the responses to each Comment, PD was the Moderator communicating electronically with all IBSE members some of whom provided the Comments, GB with PD wrote the Abstract and Background, structured the text and compiled the list of references with TJ providing them with neuroradiological expertise. All authors read and approved the final manuscript."}
+{"text": "Mechanisms of anthracycline resistance have been investigated in a B16 murine melanoma cell subline selected by continuous in vitro exposure to increasing concentrations of doxorubicin (DX). Altered drug pharmacokinetics were observed in resistant B16 cells as compared to the sensitive counterpart. In fact, cellular DX uptake - as determined by a fluorescence method - was lower in resistant than in sensitive cells. Furthermore, drug efflux rate was shown to be higher in resistant than in sensitive cells; treatment of cells with the metabolic inhibitor sodium azide decreased drug efflux rate in resistant but not in sensitive cells, suggesting the presence of an energy-dependent drug extrusion mechanism in the resistant B16 cells. However, since drug-induced cell killing did not correlate with cellular DX contents in sensitive and resistant cells, drug resistance of B16 subline could not be completely explained by the observed differences in drug pharmacokinetics. Since drug-induced DNA breaks have been related to drug cytotoxicity, DNA cleavage was also measured by alkaline elution methods. The number of DNA breaks produced by DX was decreased in resistant cells as compared to sensitive cells at the same cellular drug accumulation. The results are consistent with the view that anthracycline resistance may be multifactorial and probably arises following multiple biochemical changes."}
+{"text": "More importantly however, the fusion kinetics must indispensably exhibit positive cooperativity among these FPs, particularly for the formation of larger organelles. We compared different types of cooperativity: sequential alignment of corresponding FPs on opposite vesicle/organelles during fusion and pre-formation of FP-aggregates  prior to fusion described by Hill kinetics. This showed that the average organelle size in the system is much more sensitive to the disproportionation strength of FPs during budding if the vesicular transport system gets along with a fusion mechanism based on sequential alignments of FPs. Therefore, pre-formation of FP aggregates within the membranes prior to fusion introduce robustness with respect to organelle size. Our findings provide a plausible explanation for the evolution of a relatively large number of molecules to confer specificity on the fusion machinery compared to the relatively small number involved in the budding process. Moreover, we could speculate that a specific cooperativity which may be described by Hill kinetics (aggregates or Rab/SNARE complex formation) is suitable if maturation/identity switching of organelles play a role (bistability).Formation, degradation and renewal of cellular organelles is a dynamic process based on permanent budding, fusion and inter-organelle traffic of vesicles. These processes include many regulatory proteins such as SNAREs, Rabs and coats. Given this complex machinery, a controversially debated issue is the definition of a minimal set of generic mechanisms necessary to enable the self-organization of organelles differing in number, size and chemical composition. We present a conceptual mathematical model of dynamic organelle formation based on interacting vesicles which carry different types of fusogenic proteins (FP) playing the role of characteristic marker proteins. Our simulations (ODEs) show that a  Eukaryotic cells are composed of morphologically and functionally distinct organelles such as the nuclei, mitochondria or lysosomes. Cellular organelles differ in number, size distribution, intracellular location and chemical composition. These organelle-specific features are maintained in a dynamic process in which organelles continuously exchange their biochemical material either through the uptake and release of smaller vesicles or direct fusion and budding Notably, fusion and budding processes among vesicles and organelles involve a large machinery of auxiliary proteins. In budding, induction of membrane curvature is facilitated by so-called coat proteins as clathrin, COP-I, COP-II. Membrane receptor bind a specific repertoire of organelle proteins and thus determine the protein content of released vesicles. In fusion, surface proteins like SNAREs  are important membrane-tethering factors establishing a stable cross-link between fusing membranes. Their activation is controlled by small GTPases like Rab proteins of which more than 60 different isoforms have been identified so far de novo self-organisation of organelles by allowing inter-vesicle fusion events. Hence, including these processes in our extended model and starting with an empty vesicular system, we again ask for the necessary conditions the budding and fusion machinery have to fulfil to enable the dynamic de novo self-organisation of biochemically diverse organelles.As often in biochemistry, the sheer overwhelming molecular complexity of a cellular sub-system, e.g. signalling or metabolic pathway, makes it difficult to decipher the basic principles governing its design and dynamics. Mathematical models that deliberately refrain from the incorporation of all known molecular details but instead merge many molecular components to a few basic functional units may help to distil such principles . In our understanding, approaches based on conceptual mathematical models are quite feasible considering that the sophisticated network of molecular interactions observed in present-day cells has been developed in natural evolution with the primary goal to make fundamental processes already present in primordial cells more efficient and specific. Our modelling approach addresses two cardinal questions susceptible to computational investigation: How does the kinetics of vesicle fusion and budding determine the formation of organelles of different size and how does the kinetics of complex formation between organelle-specific fusogenic proteins (e.g. SNAREs or Rabs) influence the formation of organelles with distinct biochemical identity? A pioneering computational analysis of In this paper, development and simulation of the model comprises two subsequent steps. First, we establish a model that describes the dynamics of a system of pure lipid vesicles that are permanently synthesised and degraded and which may undergo fusion and budding processes thereby forming larger organelle-like aggregates (L-model). We demonstrate that this model is able to reproduce experimental data on changes in the size-distribution of vesicles elicited by changes of the fusion rate. Next, we extend the L-model by including two different sorts of membrane proteins affecting the fusion and budding process (LP-model). We do not model explicitly SNAREs and Rab proteins. In our model a specific active Rab together with its specific activated SNARE and other associated effectors and characteristic resident proteins form a functional unit which we call fusogenic protein (FP). Thus, such an entity represents a lumped fusogenic protein complex playing the role of an organelle specifier or marker. Thus, the dominant presence of one type of FP defines a characteristic organelle type. Rab5 and Rab7 together with their effectors (e.g. SNAREs) may be regarded as examples of such specifiers for early and late endosomes, respectively de novo generation gets lost during the formation of larger organelles assembled via permanent fusion of these vesicles if no cooperativity governs the fusion processes.Model simulations demonstrate that the formation and maintenance of specific organelles comprising significantly different distributions of the two membrane proteins require both a certain degree of disproportionation of the two proteins during the budding off of small unit size vesicles and a positive-cooperative kinetics of homotypic protein-protein interactions during membrane fusion. An initially disproportionated distribution of FPs into unit vesicles during budding or The latter finding is in line with experimental findings demonstrating the formation of a supramolecular SNARE assembly to precede membrane fusion First, we developed a simple mathematical model to describe the process of organelle formation in a system of interacting lipid vesicles which are homogeneously composed of a single type of membrane lipid. Our system is defined by 4 basic processes: (1) formation of \u201cunit vesicles\u201d  was truncated at a finite The four upper right panels show some intermediate steps in the temporary evolution of organelle sizes induced by a decrease of the parameter The model was extended by endowing the lipid membrane of the vesicles with two different types of fusogenic proteins (FP), A and B. The fusion of two vesicles How to account for the first task may be easily illustrated mathematically by considering a novel factor As demonstrated in several experimental studies To keep the model variants as simple as possible Eqn (4\u20136) take into account only homotypic pairing of FPs. In the following we will compare the three LP-model variants represented by different fusion kinetics.de novo generated unit vesicles as well as to the released unit vesicles during a budding process from larger organelles de novo formation of unit vesicles comes now in two forms: Next, we have also to specify in which proportion the two different FPs are being transferred to the Similarly, we define an A-type and a B-type budding process, each one enriching a budded unit vesicle from an organelle either in A or B. One may identify these two types of processes as coatA and coatB initiated budding events A well defined organelle with proper biochemical identity must be assembled by at least tion see . MoreoveThe complete equation system is described as follows:For a proper comparability of the three fusion kinetics with respect to the distribution of FPs within organelles we go after a similar average organelle size in each case. To ensure this we must employ if necessary an additional scaling because the impact of FPs on the fusion frequency varies substantially for the different kinetics. As a suitable reference situation in which the different kinetics are to adjusted we chose the case of fusion of two vesicles each containing equal concentrations of A and B: We performed extensive numerical simulations of the model to study the impact of the enrichment strength For comparison, organelles arising from a fusion mechanism based on cooperativity among FPs are depicted in For ring cf. . HoweverA second revealing entity is the amount of fusion events between well defined organelles differing in their biochemical identity. In this way one organelle type is absorbed by another and may not retain its identity. Such events may be interpreted as autophagy-like processes involved in selective organelle degradation. The square markers (dashed line) in Our model is conceptual and qualitative, rather than quantitative, because many of the parameters, such as the fusion and budding constants are only known very approximately. As showcases we presented simulation results for selected parameter values rather than systematically analysed all possible scopes of influencing factors. However, the characteristic distributions of organelle sizes and FPs within them do not only exist for the chosen values of the parameters, but rather show up for a wide range of values. Adopting the concept of Metabolic Control Theory de novo formation of biochemically diverse organelles. It includes vesicle generation and destruction, fusion and budding processes and two types of fusogenic proteins (FP) playing the role of identity giving marker proteins.Vesicles and organelles contain many proteins which support the fusion process. Among them are tethering factors, adaptors, GTPases and SNARE proteins. In particular corresponding SNARE proteins The simulations suggest that the interaction of homotypic FPs governed by a bi-linear mass action kinetics is not sufficient to counteract the permanent mixing of membrane components during fusion and thus does not allow the formation of organelles with sufficiently unequal protein content. This theoretical finding is supported by experiments demonstrating that the energy from a single SNARE complex might not be sufficient to overcome the full fusion energy barrier A cooperative fusion machinery ensures that two vesicles having low numbers of non-corresponding FPs are very unlikely to fuse. The simulations also suggest that the separation of organelles into biochemically distinct sub-populations (here: of A- or B-type) becomes more and more pronounced with increasing organelle size and thus should be almost perfect for real cellular organelles as lysosomes or peroxisomes. It has to be noted that this finding is independent on the initial conditions, i.e. even if the system starts with unit vesicles strongly enriched in A and B FPs, bi-linear mass action kinetics is not sufficient to generate proper organelles with segregated FPs.Our simulations have also shown that besides a cooperative fusion kinetics a certain degree of enrichment of budding vesicles with specific types of proteins must be guaranteed. Such a separation of proteins destined for transport from those destined to remain in the donor vesicle can be accomplished by coat proteins involved in the budding process. Experiments with synthetic phospholipid liposomes have demonstrated that assemblies of cytosolic coat proteins are able to direct specific v-SNAREs (Sec22p) into budding COPII vesicles Intriguingly, in case of a cooperative fusion kinetics based on successive FP pairing the impact of disproportionation of FPs during the budding process (enrichment strength) on the average organelle size was much stronger than in case of a Hill based fusion kinetics (pre-formed aggregates). To discriminate between these two conceivable modes of cooperativity further structural studies are needed. At the moment, spontaneous self-aggregation of FPs seems very likely in the light of recent experiments demonstrating in detail how cluster formation of syntaxin 1 and syntaxin 4 (Q-SNARE proteins participating in exocytosis) primarily involving the SNARE motif proceed Our finding that cooperative homotypic fusion appears to be more efficient in providing biochemically distinct organelles than disproportionating FPs during budding is in concordance with the observation that the diversity of proteins involved in vesicle fusion (e.g. SNAREs and Rabs) is much higher than that of rather unspecific coat proteins In an evolutionary context, it appears that primordial cell types getting along with relative small organelles may have organised distinct biochemical identities of them exclusively by means of a budding machinery enabling selective enrichment of membrane proteins in released vesicles. However later, when cells became more complex and organelles larger, it was essential to develop additionally a fusion mechanism based on hyper-linear cooperativity among the specific marker proteins. This transition was perhaps accompanied by a drop in the selection pressure towards the enrichment strength such that one possibly encounters nowadays a strong cooperativity in the fusion machinery in combination with weak budding enrichments of marker proteins.A further increase in complexity during evolution could have been to replace a simple type of cooperativity (pure successive paring) by an elaborated FP interplay based on already pre-formed aggregates of fusion proteins. Such a design also opens up a potential mechanism for organelle maturation and identity switching (e.g. early to late endosome) because the activation of fusion proteins and thus the critical concentration of active fusion proteins needed for the clustering process Click here for additional data file."}
+{"text": "Purpose/Results. Ionizing radiation is carcinogenic and the induction of a second malignancy is a serious potentiallong-term complication of radiotherapy. The incidence of radiation-induced sarcomas was evaluated from many largeepidemiological surveys of long-term cancer survivors reported in the literature over the past 30 years and only one casewas found for every 1000 patients irradiated.                    Discussion. Although greater numbers of cancer patients are receiving radical radiotherapy and surviving free of diseasefor longer intervals, cases of radiation-induced sarcomas are rare and should not deter patients from accepting radiotherapyas treatment for curable cancers. With improvements in the administration of radiotherapy over the past two decadeswhich are resulting in less damage to bone and soft tissues, it is likely that fewer cases of this condition will be seen inthe future. If these sarcomas are diagnosed early, long-term survival can be achieved with surgical excision and possiblyre-irradiation, as occurs in other types of sarcomas."}
+{"text": "Early age at natural menopause or bilateral ovariectomy substantially reduce a woman's lifetime risk of breast cancer. Reversible 'bilateral ovariectomy' can now in effect be achieved by 'high-dose' luteinising hormone releasing hormone (LHRH) agonists (LHRHAs). The harmful effects of such medical reversible bilateral ovariectomy, in particular the increased risks of coronary heart disease and osteoporosis, can in all likelihood be obviated by 'low-dose' oestrogen replacement therapy (ERT), specifically 0.625 mg of conjugated equine oestrogens (CEE) for 21 days in each 28-day treatment cycle, and such ERT use will only negate to a relatively small extent the beneficial effect of such bilateral ovariectomy on breast cancer risk. We calculate that such an LHRHA plus low-dose ERT regimen given to a premenopausal woman for 10 years will, in addition to being a most effective contraceptive, decrease her lifetime risk of breast cancer by more than 50%. We calculate that such a 10-year regimen will also decrease her risk of ovarian cancer by two-thirds. This regimen should leave endometrial cancer risk and bone metabolism unaltered, and may reduce the risk of heart disease. The addition of a 'low-dose' progestogen to the regimen for 12 days in each 28-day treatment cycle would be beneficial to the endometrium, but it will adversely affect risk factors for heart disease and it may significantly reduce the benefit of the regimen as regards breast cancer. A satisfactory compromise may be to add a low-dose progestogen for 12 days at less frequent intervals. Another possibility may be to deliver a progestogen solely to the endometrium with an intra-uterine device; the benefits of such a regimen would be a significant reduction in the incidence of breast, ovarian and endometrial cancer."}
+{"text": "The procoagulant activity of cells from some experimental tumours isolated in culture or in single-cell suspensions from ascitic fluid was investigated. Cells from Lewis lung carcinoma (primary and metastasis), Ehrlich carcinoma ascites and JW sarcoma ascites were able to shorten markedly the recalcification time of normal, Factor VIII- and Factor VII-deficient but not of Factor X-deficient human plasma. The same cells generated thrombin when mixed with a source of prothrombin and Factor X, absorbed bovine serum (as a source of Factor V), phospholipid and calcium chloride. Thrombin formation was not influenced by the presence of Factor VII. Cells from Sarcoma 180 ascites were completely inactive in both test systems. It is concluded that cells from some experimental tumours have the capacity to activate Coagulation Factor X directly. These findings suggest the existence of an alternative \"cellular\" pathway in the initiation of blood clotting distinct from both the intrinsic and extrinsic mechanisms."}
+{"text": "Ovarian cancer affects more than 200,000 women each year around the world. Most women are not diagnosed until the disease has already metastasized from the ovaries with a resultant poor prognosis. Ovarian cancer is associated with an overall 5 year survival of little more than 50%. The mainstay of front-line therapy is cytoreductive surgery followed by chemotherapy. Traditionally, this has been by the intravenous route only but there is more interest in the delivery of intraperitoneal chemotherapy utilizing the pharmaco-therapeutic advantage of the peritoneal barrier. Despite three large, randomized clinical trials comparing intravenous with intraperitoneal chemotherapy showing improved outcomes for those receiving at least part of their chemotherapy by the intraperitoneal route.Cisplatin has been the most active drug for the treatment of ovarian cancer for the last 4 decades and the prognosis for women with ovarian cancer can be defined by the tumor response to cisplatin. Those whose tumors are innately platinum-resistant at the time of initial treatment have a very poor prognosis. Although the majority of patients with ovarian cancer respond to front-line platinum combination chemotherapy the majority will develop disease that becomes resistant to cisplatin and will ultimately succumb to the disease.Improving the efficacy of cisplatin could have a major impact in the fight against this disease. Arsenite is an exciting agent that not only has inherent single-agent tumoricidal activity against ovarian cancer cell lines but also multiple biochemical interactions that may enhance the cytotoxicity of cisplatin including inhibition of deoxyribose nucleic acid (DNA) repair. In vitro studies suggest that arsenite may enhance the activity of cisplatin in other cell types. Arsenic trioxide is already used clinically to treat acute promyelocytic leukemia demonstrating its safety profile. Further research in ovarian cancer is warranted to define its possible role in this disease. Epithelial ovarian cancer (EOC) affects approximately 204,000 women a year worldwide and is responsible for about 125,000 deaths -6.The management of advanced EOC has evolved over the last 30 years to become a combination of initial cytoreductive surgery (CRS) followed by chemotherapy. In 1968 Munnell reported an improved survival in patients who had maximal CRS compared to partial removal or biopsy only  and overThe reason CRS is thought to be effective when combined with chemotherapy is that it removes bulky disease containing poorly-oxygenated, non-proliferating cells which are either resistant to chemotherapy now, or potentially could become resistant, and leaves small volume tumors with a higher proportion of cells in the proliferative phase making them more susceptible to chemotherapy. At one time the concept of 'optimal' residual disease at completion of initial CRS for EOC was accepted as being any nodule < 2 cm in dimension  but it iThe most active chemotherapy agents in ovarian cancer are the platinum analogues, cisplatin and carboplatin. The antitumor activity of cisplatin (cis-diamminedichloroplatinum (II)) was discovered by Rosenberg and colleagues in 1961 . InitialTaxus brevifolia [An additional class of drug, the taxanes, was discovered and came to play a role in the front-line armamentarium against EOC. In 1971 paclitaxel was identified as the active constituent of an extract of the bark of the Pacific yew tree, evifolia ,27. In eevifolia . It becaevifolia . Paclitaevifolia -32.During this time analogues of cisplatin were investigated in an effort to maintain efficacy with reduced toxicity. Carboplatin was developed by substituting a cyclobutanedicarboxylate moiety for the two chloride ligands of cisplatin. Phase I and II trials of carboplatin showed that it was much less toxic than cisplatin especially with regard to neurotoxicity, nephrotoxicity and emetogenicity whilst retaining significant chemotherapeutic activity -37. ManyFor over twenty years there has been interest in the delivery of intraperitoneal therapy for ovarian cancer in order to maximize the efficacy and reduce the toxicity. Dedrick proposed that the intraperitoneal delivery of certain chemotherapeutic agents could lead to a significant increase in peritoneal cavity drug exposure compared to that in the systemic vascular compartment . For druDespite the advances in the treatment of EOC much more effective therapy is necessary. This is exemplified by the results of Gynecologic Oncology Group protocol #172 where even in the IP/IV arm which led to median extension of survival of 16 months over patients treated only with IV therapy the recurrence rate was 65% within the period of the study. This recurrence rate is the current optimum situation in EOC.One way of improving outcome for patients with EOC is to develop novel methods of enhancing the activity of cisplatin. Ovarian cancers that are resistant to platinum therapy are either innately resistant, shown by a lack of response to front-line therapy, or develop platinum resistance during the cancer's life history. In the patient this is demonstrated by an initial response to platinum agents followed by development of platinum resistance as the cancer progresses. Most of the women die with platinum resistant disease. Methods of preventing or overcoming resistance to cisplatin thus could be extremely beneficial.Cisplatin reacts preferentially with the N7 position guanine to form a variety of monofunctional and bifunctional adducts which result in intrastrand or interstrand cross-links, effectively preventing normal DNA function ,47. PlatCisplatin accumulates within the cell by passive diffusion or facilitated transport  and the Multidrug resistance protein (MRP) is a member of a family of transport proteins that facilitates the extrusion of a variety of glutathione-coupled and unmodified drugs out of cells but over-expression of MRP alone does not confer resistance . With reInactivation may also occur by binding of the platinum drugs to metallothionein (MT) proteins. MTs are a family of sulfhydryl-rich, small molecular weight proteins that participate in heavy metal binding and detoxication. Modulation of MT levels can alter cisplatin sensitivity but the contribution of MT to clinical platinum drug resistance is unclear . In someOnce platinum-DNA adducts are formed, cells must either repair or tolerate the damage in order to survive. The capacity to repair DNA damage rapidly and efficiently plays a role in determining a tumor cell's sensitivity to platinum drugs . IncreasInhibiting DNA repair activity to enhance platinum drug sensitivity has been an active area of investigation. Agents that have been used include nucleoside analogues, such as gemcitabine, fludarabine, and cytarabine; the riboncleotide reductase inhibitor hydroxyurea; and the inhibitor of DNA polymerases alpha and gamma, aphidocolin. All interfere with the repair synthesis stage of various repair processes, including nucleotide excision repair. The potentiation of cisplatin cytotoxicity by treatment with aphidicolin has been studied extensively in human OC cell lines with variable synergism -65. The Platinum-DNA damage tolerance is a phenotype that has been observed in both cisplatin-resistant cells derived from chemotherapy-refractory patients and cells selected for primary cisplatin resistance in vitro. This phenotype may result from alterations in a variety of cellular pathways. One component of DNA damage tolerance observed in platinum-resistant cells involves loss of function of the DNA mismatch repair (MMR) system. The main function of this is to scan newly synthesized DNA and to remove mismatches that result from nucleotide incorporation errors made by the DNA polymerases . In addiArsenic in its trivalent form is an interesting agent not only with inherent tumoricidal activity  but havi\u00ae, As2O3) is now an FDA  approved chemotherapeutic for treating all-trans retinoic acid (ATRA) resistant APL [\u00ae to treat other malignancies .In vitro studies of arsenic trioxide induced cytotoxicity in human ovarian cancer cells are promising. Clinically achievable concentrations (2 \u03bcM) induced apoptosis in the platinum-resistant human ovarian cancer cell line CI80-13S and the platinum-sensitive human ovarian cancer cell line OVCAR. They also appeared to slow the growth of the cisplatin-sensitive human ovarian cancer cells GG and JAM . ArsenicArsenic trioxide may be useful in combination therapy. Polyunsaturated fatty acids appear to sensitize arsenic resistant tumor cells, including SKOV3 cells, to arsenic trioxide induced cytotoxicity and apoptosis . There aThe preliminary studies of arsenic trioxide discussed above suggest that arsenic trioxide may be useful in therapy for EOC particularly in combination chemotherapy. Consistent with this hypothesis is that preliminary studies in our laboratories suggest that arsenic trioxide in combination with hyperthermia can overcome cisplatin resistance in A2780/CP70 cells (manuscript in preparation). Clearly, further study is warranted.Despite modern standard therapy overall survival in women with ovarian cancer remains relatively poor. The most active chemotherapeutic agent remains cisplatin but ironically most patients whilst initially responding to cisplatin ultimately die with platinum-resistant disease. Arsenic is a promising agent for helping overcome platinum resistance. In addition to inherent tumoricidal activity it has multiple biochemical interactions that may enhance cisplatin cytotoxicity. Further research into this agent is needed.The authors declare that they have no competing interests.Both authors conceived the idea and jointly wrote the manuscript.C. William Helm is Associate Professor in the Division of Gynecologic Oncology at the University of Louisville and the James Graham Brown Cancer Center. His research interests include both normothermic and hyperthermic intraperitoneal chemotherapy (HIPEC) for ovarian cancer.J. Christopher States is Professor of Pharmacology and Toxicology and Distinguished University Scholar at the University of Louisville. He is an established NIH investigator and recognized expert in disruption of mitosis by arsenicals."}
+{"text": "Baseline wander elimination is considered a classical problem. In electrocardiography (ECG) signals, baseline drift can influence the accurate diagnosis of heart disease such as ischemia and arrhythmia. We present a wavelet-transform- (WT-) based search algorithm using the energy of the signal in different scales to isolate baseline wander from the ECG signal. The algorithm computes wavelet packet coefficients and then in each scale the energy of the signal is calculated. Comparison is made and the branch of the wavelet binary tree corresponding to higher energy wavelet spaces is chosen. This algorithm is tested using the data record from MIT/BIH database and excellent results are obtained."}
+{"text": "The presence of a bladder mass in a patient with inflammatory bowel disease poses a diagnosticdilemma. We present the case of a 26-year-old male with a bladder mass who had not previouslybeen diagnosed with Crohn's disease. Initial biopsies of the bladder mass were consistent with inflammatorychanges, but superficial transitional cell carcinoma could not be reliably excluded.Subsequent evaluation confirmed the presence of Crohn's disease with bladder involvement, and thepatient underwent bowel resection and partial cystectomy. Pathologic evaluation demonstratedCrohn\u2019s disease and no evidence of malignancy. Accurate differentiation of benign and malignantbladder masses in patients with inflammatory bowel disease may be difficult and requires cooperationbetween pathologists and clinicians."}
+{"text": "A comparison has been made between the ability of long-chain triglycerides (LCT) and medium-chain triglycerides (MCT) to prevent weight loss induced by the cachexia-inducing colon adenocarcinoma (MAC16) and to reduce tumour size. There was no difference in calorie consumption or nitrogen intake between the various groups. When compared with a normal control high carbohydrate, low fat diet, animals fed MCT showed a reduced weight loss and a marked reduction in tumour size. In contrast neither weight loss nor tumour size differed significantly from the controls in animals fed the LCT diet. An elevated plasma level of 3-hydroxybuturate was found only in the animals fed the MCT diets. Administration of LCT caused an increase in the plasma level of FFA, which was not observed in the MCT group. These results suggest that diets containing MCT would provide the best ketogenic regime to reverse the weight loss in cancer cachexia with a concomitant reduction in tumour size."}
+{"text": "Much lower concentrations of PpIX accumulated in primary fibroblast cultures, in immortalized fibroblast cell lines, and in immortalized fibroblasts transfected with the G418-resistance gene only. The mechanisms responsible for the increased accumulation of ALA-induced PpIX by transformed cells  therefore appear to be closely linked to the mechanisms responsible for malignant transformation. Identification of the nature of that linkage may lead to new approaches to cancer therapy. \u00a9 1999 Cancer Research CampaignAll nucleated mammalian cells synthesize protoporphyrin IX (PpIX) when exposed to exogenous 5-aminolevulinic acid (ALA). The response to exogenous ALA under standard conditions (the ALA phenotype) is characteristic for each cell type. Significantly more PpIX accumulates in malignant and premalignant cells than in the normal cells from which they were derived. A rodent fibroblast model was developed to study the mechanisms responsible for this phenomenon. Exogenous ALA induced the accumulation of substantial concentrations of PpIX in fibrosarcoma cells, and in immortalized fibroblasts transfected with the oncogene c-"}
+{"text": "Climate change is particularly pronounced in the High Arctic and a better understanding of the repercussions on ecological processes like herbivory, predation and pollination is needed. Arthropods play an important role in the high-arctic ecosystem and this role is determined by their density and activity. However, density and activity may be sensitive to separate components of climate. Earlier emergence due to advanced timing of snowmelt following climate change may expose adult arthropods to unchanged temperatures but higher levels of radiation. The capture rate of arthropods in passive open traps like pitfall trap integrates density and activity and, therefore, serves as a proxy of the magnitude of such arthropod-related ecological processes. We used arthropod pitfall trapping data and weather data from 10 seasons in high-arctic Greenland to identify climatic effects on the activity pattern of nine arthropod taxa.We were able to statistically separate the variation in capture rates into a non-linear component of capture date (density) and a linear component of weather (activity). The non-linear proxy of density always accounted for more of the variation than the linear component of weather. After accounting for the seasonal phenological development, the most important weather variable influencing the capture rate of flying arthropods was temperature, while surface-dwelling species were principally influenced by solar radiation.Consistent with previous findings, air temperature best explained variation in the activity level of flying insects. An advancement of the phenology in this group due to earlier snowmelt will make individuals appear earlier in the season, but parallel temperature increases could mean that individuals are exposed to similar temperatures. Hence, the effect of climatic changes on the activity pattern in this group may be unchanged. In contrast, we found that solar radiation is a better proxy of activity levels than air temperature in surface-dwelling arthropods. An advancement of the phenology may expose surface-dwelling arthropods to higher levels of solar radiation, which suggest that their locomotory performance is enhanced and their contribution to ecological processes is increased. The earth is undergoing climatic changes and the model predictions for the high-arctic climate are particularly dramatic . This una priori assumptions about its exact shape. We aim at elucidating broader patterns in the relation between climate and arthropod ecology, and therefore we take a higher taxon approach. We addressed the following questions: Which meteorological variable most strongly influences the locomotory performance of different taxa of flying and surface-dwelling arthropods in a high-arctic location? What is the relative influence of weather parameters and capture date on capture numbers of these taxa?Capture rates from passive traps like pitfall traps integrate arthropod density and activity levels  and ther2, SR), precipitation  and wind speed (m/s) [The data for this study was collected as part of the Zackenberg Basic monitoring programme. The sampling was carried out at Zackenberg, North-east Greenland  which is in the high-arctic climatic zone. The mean summer (June through August) temperature during the years 1996\u20132005 was 4.3\u00b0C. At Zackenberg, June, July and August include on average 85% (range: 73%\u201393%) of the annual number of days with positive average temperatures. A climate station within 600 metres from all sampling plots provided data on ambient air temperature two metres above the ground, solar radiation (W/med (m/s) . Wind sped (m/s) . We calc2) consisted of eight pitfall traps and each window trap plot consisted of two window traps [Boloria chariclea, (Schneider) and B. polaris, ), the Lycosidae by one species ) and the Linyphiidae by five species , Hilaira vexatrix, (O. P.-Cambridge), Erigone arctica (White), Erigone psychrophila, Thorell and Mecynargus borealis, (Jackson)) [Alopex lagopus, (Linneaus)), or trampled by muskoxen ), so the capture numbers in each plot were transformed to individuals caught per trap per day for each trapping period [Arthropods were monitored during 10 consecutive years 1996\u20132005) with samples from one window trap plot (plot 1) and six pitfall trap plots plot 2\u20137) collected weekly during June, July and August. All plots were operated during the period 1996\u20132005 except for plots 6 and 7 which were operated during the periods 1996\u20131998 and 1999\u20132005, respectively. Each pitfall trap plot  [Our aim was to model the concurrent influences of ambient weather and arthropod phenology on capture numbers. Since we anticipated a non-linear phenological development through each season but had no ls (GAM)  to modells (GAM)  and so ii are the log10-transformed number of individuals per trap per day, \u03b20 is the intercept and trapping date (DAY) is modelled by a spline function s(\u00b7). The term WEATHER refers to one of the four different weather variables  and was modelled as a linear continuous predictor and \u03b5i is the error term. The weather variables were calculated as daily averages for each trapping period. We repeated the model estimation for each species group (n = 9) in each plot  in each year (n = 10) with each of the weather parameters (n = 4) as linear predictors and date as a spline function (with df = 4). This resulted in a total of 500 sets of four competing models. Some taxa were only caught in small numbers in some plots in some years, and we therefore restricted our analyses to years and plots where at least 100 individuals were caught except for the Nymphalidae and the Ichneumonidae where the limit was set to 50 due to the larger size of individuals in these families. This reduced the number of sets of models to 385. We had an average of 11.5 trapping periods within each season. Although it is likely that the capture numbers were affected by several weather variables, we included only one in each model to reduce the risk of over-parameterization. Since all models with the same response variable had the same number of degrees of freedom and the same null deviance, the lowest residual deviance indicated the best fit to data. In this way, we identified for each species group for each plot for each year the weather variable that was best able to explain variation in capture numbers. A previous study [Where Yus study  separateThe GAM models identified the weather variable that resulted in the lowest residual deviance of models for each species group in each year in each plot Table . AmbientOur analyses demonstrated that the temporal variation in capture rates of high-arctic arthropods from pitfall and window traps consisted of two components indicating the effects of density and activity. By using generalized additive modelling to separate variation in capture rates, we found one component that was unimodally related to capture date and one that was a function of short-term weather fluctuations through the season. Air temperature was the most important weather variable followed by solar radiation. The influence of temperature was most pronounced on the taxa of flying arthropods like Lepidoptera and Diptera, which is consistent with previous findings . The surSpecies-specific responses may be hidden by pooling multiple species in larger taxonomic units. However, we found no bimodality in the seasonal capture of the taxa included in this study which could suggest that individual species within a taxon occurred during different parts of the season. Also, since flying and surface-dwelling arthropods responded to different components of climate, general differences in the environmental conditions experienced by these two groups may be more important than behavioural differences between species within taxa. Clearly, this higher taxon approach precludes a detailed understanding of the species-environment interactions. However, since our aim here is to elucidate broader patterns in the relation between climate and arthropod ecology, we refer to these interactions simply as arthropod-related ecological processes. It is possible that sampling with shorter time intervals would have identified a stronger influence of weather variables on activity of the arthropods. However, without increasing the number of traps this would also have reduced the sample size from each sampling and thereby reduced the statistical power of the analyses. Indeed we are confident that by using data from ten seasons we identified the most important weather variable for the activity level of each taxon.Our non-linear statistical modelling approach also made it possible to quantify the relative importance of density and activity. It has long been acknowledged that passive traps like pitfall traps provide biased estimates of density, because differences in activity levels between trapping periods are difficult to control for . It has We found that the non-linear component of the general additive models representing density explained more of the variation than did the weather variables representing locomotory performance. This indicates that the magnitude of arthropod-related ecological processes is currently more influenced by phenological changes than by short-term fluctuations in weather. However, the dynamics of the two most important weather variables (temperature and solar radiation) differed markedly across the season and therefore a change in the timing of the phenology of the species groups could also increase the importance of weather on locomotory performance. The summer peak of incoming solar radiation occurred almost two months earlier than the summer peak in average air temperature Fig. . Since tWe were able to statistically separate the variation in capture rates of high-arctic arthropods into a non-linear component of capture date (density) and a linear component of weather (activity). Consistent with previous findings, air temperature best explained variation in the activity level of flying insects. An advancement of the phenology in this group due to earlier snowmelt will make individuals appear earlier in the season, but parallel temperature increases could mean that individuals are exposed to similar temperatures. Hence, the effect of climatic changes on the activity pattern in this group may be unchanged. In contrast, we found that solar radiation is a better proxy of activity levels than air temperature in surface-dwelling arthropods. An advancement of the phenology may expose surface-dwelling arthropods to higher levels of solar radiation, which suggest that their locomotory performance is enhanced and their contribution to ecological processes is increased. Therefore, the integrated effect of climatic changes on ecological processes depends on the change in both temperature and timing of snowmelt and may vary between processes involving surface-dwelling and flying arthropods.TTH and MCF conceived the idea TTH carried out the analyses and drafted the manuscript. Both authors have read and approved the final manuscript."}
+{"text": "Unfortunately, extracts from natural sources are usually complex mixtures of compounds:: often generated in time consuming and for the most part manual processes. As quality and quantity of the provided samples play a pivotal role in the success of high-throughput screening programs this poses serious problems. In order to make samples of natural origin competitive with synthetic compound libraries, we devised a novel, automated sample preparation procedure based on solid-phase extraction (SPE). By making use of a modified Zymark RapidTrace"}
+{"text": "Decisions around what care to provide at the population  level are particularly complex, involving considerations such as feasibility, cost, and population needs in addition to scientific evidence. One example of decision-making at this \"population-policy\" level involves what screening questions and intervention guides to include on standardized provincial prenatal records. As mandatory medical reporting forms, prenatal records are potentially powerful vehicles for promoting population-wide evidence-based care. However, the extent to which Canadian prenatal records reflect best-practice recommendations for the assessment of well-known risk factors such as maternal smoking and alcohol consumption varies markedly across Canadian provinces and territories. The goal of this study is to better understand the interaction of contextual factors and research evidence on decision-making at the population-policy level, by examining the processes by which provincial prenatal records are reviewed and revised.There is a significant gap in the knowledge translation literature related to Guided by Dobrow et al.'s (2004) conceptual model for context-based evidence-based decision-making, this study will use a multiple case study design with embedded units of analysis to examine contextual factors influencing the prenatal record revision process in different Canadian provinces and territories. Data will be collected using multiple methods to construct detailed case descriptions for each province/territory. Using qualitative data analysis techniques, decision-making processes involving prenatal record content specifically related to maternal smoking and alcohol use will be compared both within and across each case, to identify key contextual factors influencing the uptake and application of research evidence by prenatal record review committees. All study participants will be required to give written informed consent prior to participating in data collection.This study will advance knowledge in the field of evidence-based decision-making by illustrating the complex interaction of contextual factors and evidence on health policy decision-making by provincial-level committees. By increasing the transparency of decision-making within provincial prenatal record committees, this study will help inform more effective strategies for enhancing the integration of best-practice evidence into prenatal records. Decision-making -4. As man-making , beggingn-making ; these mn-making .To gain an in-depth understanding of the influence of contextual factors on evidence use by provincial/territorial prenatal record review committees, this study will focus on two specific exemplars: the uptake of research evidence related to maternal smoking, and alcohol consumption during pregnancy. The scientific evidence identifying smoking and alcohol use as risk factors for adverse obstetrical outcomes is well-documented and long-standing ,9 meriti1) Describe and compare how provincial prenatal records are reviewed and updated across selected Canadian provinces;2) Identify specific contextual factors in the decision-making environment that impede or facilitate the use of research evidence during the prenatal record revision process, as well as alternative sources of evidence contributing to decision-making within provincial prenatal record committees; and3) Explore the relative impact of internal versus external contextual factors on the integration of research evidence in provincial practice policies such as the prenatal record.Four main research questions underlie these study objectives:What are the processes and who are the actors involved in developing and revising provincial prenatal records?How are decisions made about the content of provincial prenatal records related specifically to maternal smoking and prenatal alcohol?What key contextual factors influence the uptake of research evidence during the prenatal record revision process?What other factors in the decision-making environment at the provincial level may account for variations in the evidence base of prenatal records across provinces?Standardized provincial prenatal assessment forms are universally used in most provinces and territories in Canada to serve as a written health record which may be transferred from one part of the health care system to another  and provide data for routine surveillance of perinatal risk factors. The government prenatal records for each province and territory typically include a comprehensive health history form completed by health care providers at the first prenatal visit, as well as additional forms for documentation of on-going prenatal care at each subsequent encounter. By providing health care practitioners with reminders and prompts, provincial prenatal records outline the content of routine prenatal care and play a key role in guiding health professionals in what to assess and how to intervene with pregnant women. Physician reminders and prompts have been identified as one of the most effective mechanisms for transferring evidence into routine practice in preventative care . As stanDespite the potential for manipulating prenatal records to mandate evidence-based clinical care, literature examining and comparing the content and quality of Canadian prenatal records is virtually non-existent. A recent examination of Canadian prenatal records for their content related to maternal smoking found marked variation in the application of available research evidence across provinces . In the A central focus of the study of knowledge utilization in health care is to better understand why available research evidence is not readily adopted. Few studies, however, have explored precisely how research evidence is evaluated and integrated into provincial-level practice policies. This specific area of inquiry is uniquely situated between two more extensively-researched bodies of literature in the field of evidence-based decision-making: 1) the development and implementation of clinical practice guidelines (CPGs), and 2) evidence-based health policymaking. The following text addresses each of these topics in further detail.Evidence-based CPGs are increasingly viewed as important decision-making tools in the quest to improve the quality and effectiveness of health care -18. GrowThe important question of when and how CPGs should be modified and updated following their development and dissemination has received considerably less attention, although such formal practice guidelines are expected to be as evidence-based as feasible ,27. The Whereas standardized provincial prenatal records serve in essence as clinical practice guidelines, their mandatory use as part of the patient record and additional role in health surveillance adds complexity to decision-making around their content. However findings from the field of CPG development and maintenance suggest that various issues may influence decision-making around provincial prenatal content, such as the composition and dynamics of the committee responsible for reviewing and updating the prenatal records; the different sources and types of evidence considered in the decision-making process; and situational factors such as time and resources allocated to the review process.health policy is used variably in the evidence-based decision-making literature to refer to broad political actions taken by governments and other decision makers to improve the health of populations , as well as more specific clinical practice directives aimed at the population level . Our study focus falls more closely within the latter definition, which views evidence-based health policy  as the application of best current knowledge to the health needs and values of populations rather than individual patients [The second topic, evidence-based health policymaking, has been implicated in decision-making in health care. Growing demand for a return from investments in health services research has increased the need for transparency and rationalization of health policy decision-making . The terpatients .To date, studies in the area of evidence-based health care policymaking have focused largely on increasing research uptake in the policy setting by means of strengthening relationships between policy makers and researchers . Few stuFindings from the field of evidence-based health policy point to the decision-making environment at the provincial level as an important influence on what types and sources of evidence are considered in decisions around prenatal record content. An important gap that remains in the literature is the relative influence of different types or levels of contextual factors on the uptake and application of evidence in health policy decision-making. By closely examining how provincial prenatal records are reviewed and revised, this study aims to identify key contextual influences on evidence-based decision-making that can help inform strategies to increase research uptake at the population-policy level. The development of standardized provincial prenatal records offers an intriguing example of health policy decision-making, particularly as the forms function as both national practice guidelines and as a mandatory clinical documentation system. Prenatal records also address a broad scope of clinical parameters, allowing comparison of evidence integration across different content areas. To more closely examine decision-making processes within provincial prenatal record review committees, this study will focus specifically on the uptake and application of research evidence related to the prenatal assessment of maternal smoking and alcohol use.The Canadian Guide to Clinical Preventive Health Care advocates routine prenatal screening and counseling for the behavioral risk factors of both maternal smoking and alcohol use . AccordiMaternal smoking remains an important modifiable risk factor for adverse perinatal outcomes as well as for as longer-term mother and child health problems -39. HealDespite the availability of research evidence related to effective screening and interventions to reduce maternal smoking, current Canadian prenatal records vary markedly in the extent to which they incorporate these best-practice recommendations. A recent comparison of provincial and territorial prenatal records from all Canadian provinces and territories found that all the prenatal record forms included at least one question assessing maternal tobacco use at the first prenatal visit, but only two of the forms provided prompts for on-going monitoring of maternal smoking throughout the rest of pregnancy and only two included a prompt to refer smokers for specialized smoking cessation support . SeveralThe other behavioral risk factor of this study's interest is maternal alcohol use. Alcohol use during pregnancy is a significant and preventable public health issue that can result in a lifelong burden of psychological, emotional, and financial costs to the affected individuals and families -53. Preninternal decision-making context refers to the environment in which decisions are made and includes the purpose of the decision-making activity, participants' roles in the decision-making process, and the strategies used to arrive at the decision outcome . The individual participants on the prenatal record revision committees may influence the decision-making process through personal characteristics or relationships they bring to the table, as demonstrated in the previously-mentioned studies [external decision-making context refers to the provincial environment in which the decisions are applied, and involves more fixed, uncontrollable factors such as patterns of service delivery and dynamics among health professional organizations; as well as economic, regulatory and other sociopolitical features that may influence policy alternatives. Dobrow et al.'s model traces how internal and external contextual factors impact three main stages of evidence utilization: 1) introduction of evidence, that is, how evidence is identified and brought to the decision-making table; 2) interpretation of evidence, which refers to how the internal and external validity of the evidence is evaluated; and 3) application of evidence .This study of evidence-based decision-making by provincial prenatal record review committees will be guided by Dobrow et al.'s 2004) conceptual framework for \"context-based evidence-based decision-making\" [004 conce studies ,24 of hoThis framework for evidence-based decision-making is particularly useful for understanding why best-practice recommendations related to maternal smoking and alcohol consumption may have been differentially applied by provincial prenatal record review committees, as it explicitly moves the focus of inquiry beyond \"the evidence\" to specific contextual features within the broader policy environment. Dobrow et al.'s model suggests numerous propositions that may explain why some prenatal records have more detailed and evidence-based questioning of risk factors than others. For example, political pressure from provincial medical associations to minimize government control over medical practice  may act to decrease the number and specificity of prenatal record assessment questions and prompts. Conversely, provinces with more time and money allocated to the prenatal record revision process and/or greater capacity of committee members to assess the available research evidence  would be expected to have more evidenced-base prenatal records. An important question to address is how factors from both these different decision-making contexts are collectively weighed to justify health policy decisions. Because we are examining the integration of two areas of research evidence  in the prenatal record forms, our methods will allow us to decipher the relative influence of the internal and external decision-making contexts both within and across provincial prenatal record review committees, helping to identify key contextual factors influencing decision-making at the population-policy level.literal replication of findings (obtaining the same results across similar cases) and theoretical replication (obtaining different results but for predictable reasons), allowing exploration of the study's theoretical underpinnings [A multiple case study with embedded units of analysis will be used to examine and compare decision-making processes within and across provincial prenatal record review committees. The case study approach using mixed-methods is most valuable when the questions being posed require investigation of a real-life event in detail; where the focus is on \"how\" and \"why\" questions; when boundaries between phenomena and their context are not clear; and when the investigators have little control over events ,61. The pinnings . Study cpinnings .across these six provinces, in addition to comparing contextual influences on decision-making around maternal smoking vs. alcohol use questions and prompts within each of the case provinces. Other important dimensions of comparison across the selected case provinces may come to light as our case study unfolds, such as size of the province and type of organizational body responsible for maintaining the prenatal records.We purposefully selected six Canadian provinces that varied in the extent to which their prenatal record content related to maternal smoking and alcohol use was evidence-based, as reflected by questions and intervention prompts included on current prenatal records from each province and territory in Canada. We considered the extent to which the prenatal forms integrated available research evidence related to maternal smoking questions as \"weak\" if the prenatal record simply inquired about current smoking status, and \"strong\" if there were additional questions addressing issues such as previous smoking history and exposure to environmental tobacco smoke, and if the prenatal record provided for ongoing monitoring and/or prompted referral of smokers to specialized smoking cessation resources. Similarly, we considered the extent to which prenatal record content related to alcohol consumption was evidence-based to be \"weak\" if questions simply inquired about present alcohol use, and \"strong\" if the T-ACE scale also was included as part of routine prenatal assessment. Of the six provinces chosen for comparison, two had prenatal records with strong screening questions for both smoking and alcohol use; two had weak questioning related to both smoking and alcohol use; one had strong smoking questions but weaker alcohol-related questions; and one had weak assessment of maternal smoking but stronger questions related to alcohol use. The study's embedded design thus allowed for the examination of 12 separate decision-making events Multiple sources of data will be used to explore internal and external contextual factors at play during the prenatal record revision process . The priPertinent documents  will be examined  during a site visit to the provincial organizations responsible for the prenatal record review process in each of the six case provinces. When permitted, documents and records will be copied to include as part of the case study data base. The purpose of the site visits are to interview key informants, collect additional corroborating documentary data, gain a first-hand sense of the myriad actors and organizations involved in the prenatal record review process, and seek potential opportunities to directly observe decision-making processes in provinces currently engaged in prenatal record review. Due to the large volume of data to be collected and the variety of organizational settings that may need to be visited per province, each site visit will be conducted by the research associate accompanied by at least one of the study investigators. Each site visit will be scheduled over two days. Those conducting each site visit will be asked to prepare a brief report including their field notes recording their impressions and observations of the visit. This report will be shared with provincial prenatal record committee members to verify that we have provided an accurate record of decision-making processes. The research associate will be responsible for organizing a case study database for each case province, and for maintaining additional field diaries throughout the study to record observations and track events that may be of relevance to findings and analysis.Transcription of interviews and data analysis will proceed concurrently to permit follow-up of issues that might emerge from the data. Data will be transcribed and analyzed in their source language . The content of interview transcripts, documents and observations will first be analyzed descriptively to characterize the prenatal record review process for each case province, and to develop a detailed narrative of how and why decisions around prenatal record content related specifically to maternal smoking and alcohol use were arrived at. The data will then be examined using a number of qualitative data analysis techniques and the analytic categories suggested by Dobrow et al.'s conceptual model, while also building on new insights that may arise from close familiarity with the data. For example, content analysis of the data will be conducted to identify different evidentiary sources weighed in the decision-making process, as well as contextual features of the decision-making environments. Contextual factors will be coded and categorized according to their type  as well as point of impact on individual sources of evidence . New or more refined categories may be developed as needed. Data will be ordered and displayed using category matrices, graphics and frequency tables . The anaThe four tests commonly used to ensure rigor in case study designs are construct validity, internal reliability, external validity and reliability . ConstruThis study addresses an important gap in the field of evidence-based decision-making by seeking to illustrate the complex influence of contextual factors on decision-making processes within provincial-level committees. It will build on Dobrow et al.'s framework, generating knowledge about specific contextual factors that maximize the uptake of evidence in population-policy decision-making. Specifically, this study will increase the transparency of decision-making within provincial prenatal record committees and will thus help to identify effective strategies for promoting the integration of research evidence into the mandatory and widely used prenatal records. More broadly, study findings will contribute to a model of evidence-based decision-making that can be adapted to the broader contextual features of policy environments, helping inform avenues for promoting research utilization for other types of committees developing provincial tools and programs. Examples include the development of mandatory core program guidelines in Ontario ; and the development of surveillance tools for use across clinical practice settings such as injury surveillance, and patient safety monitoring tools.This proposed research directly meets the Canadian Institutes of Health Research's knowledge translation strategic direction of advancing research in the use of health-related knowledge across the various levels of decision-making in the health system. Therefore, the study results should advance our understanding of internal and external contextual factors that influence population-policy decision-making. As such, results are expected to be of interest to scientists working in the fields of knowledge translation, public and population health, and health services research.CPGs: Clinical Practice Guidelines; FASD: Fetal Alcohol Spectrum DisordersThe authors declare that they have no competing interests.All authors contributed to the conception and design of the study protocol. SS and NE drafted the protocol, with further input from all other authors. This manuscript was prepared by PM and SS. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:Ethics approval Ottawa additional file 1.  Ethics approval to study protocol from the University of Ottawa research ethics boardClick here for fileEthics approval Laurentian additional file 2.  Ethics approval to study from University of Laurentian research ethics boardClick here for fileEthics approval McGill additional file 3.  Ethics approval to study protocol from McGill University research ethics boardClick here for fileEthics approval Alberta additional file 4. Ethics approval to study protocol from University of Alberta research ethics boardClick here for fileEthics approval Calgary additional file 5.  Ethics approval to study protocol from University of Calgary research ethics boardClick here for file"}
+{"text": "Niosomes are multilamellar vesicles formed from nonionic surfactants of the alkyl or dialkyl polyglycerol ether class and cholesterol. Adriamycin has been trapped within vesicles prepared from a monoalkyl triglycerol ether and its activity compared with adriamycin solution in human lung tumour cells grown in monolayer and spheroid culture and in tumour xenografted nude mice. The activity of the encapsulated adriamycin in vitro is maintained with similar clonogenic survival curves following treatment of monolayers and identical growth delays following spheroid exposure. The pharmacokinetics of adriamycin are altered in vivo in human lung tumour-bearing nude mice, when it is administered in niosomal form. There is prolonged release of drug from the plasma compartment with significantly lower peak levels; lower peak cardiac adriamycin concentrations with a shorter tissue half-life and decreased cardiac AUC and a greater degree of hepatic metabolism to inactive 7-deoxyaglycones. The tumour peak drug level and AUC was similar irrespective of the mode of administration of adriamycin. The growth delay (i.e. the time taken for the tumour volume to double) was significantly longer for adriamycin (15 days) and niosomal adriamycin (11 days) than for control (5.8 days). It is possible that the therapeutic ratio of adriamycin could be enhanced by administration in niosomal form."}
+{"text": "P = 0.006). Reduction of the MAPK and MEK activities in colorectal tumours was also observed in adenomas. These results suggested that down-regulation of the MAPK cascade may be caused by early genetic event(s) and that it may be related to the loss of normal growth control. Although MAPK activities were down-regulated both in adenomas and carcinomas, activities of the MAPKs in carcinomas were higher than those of paired adenomas. These results suggested that MAPK activities may be increased in the adenoma-to-carcinoma sequence and that it may play a role in the tumour progression. Observation of the differential regulation of MAPK activities in colorectal tumorigeneis suggested roles for the MAPK pathway in both positive and negative controls of cell growth. \u00a9 1999 Cancer Research CampaignHyper-activation of mitogen-activated protein kinase (MAPK) has recently been reported in several human cancers and activation of MAPK in those cancers may be associated with carcinogenesis through aberrant cell proliferation. To understand the roles of the MAPK pathway in colorectal tumorigenesis, we examined the status of extracellular signal-regulated protein kinases (ERK1/2) in 21 colorectal tumour specimens and compared it with that of paired normals. The specific MAPK activities were two- to tenfold lower in 71% (15 out of 21 cases) of colorectal tumours compared to those in paired normals. The individual MAPK kinase (MEK) correlated with MAPK activities ("}
+{"text": "The proliferating cell nuclear antigen (PCNA) is required for DNA replication and DNA nucleotide excision repair. Considerable evidence points to PCNA expression being a marker of proliferation in many situations. However, while levels of PCNA are normally very low in non-cycling tissues, high levels of the protein have been observed in the normal tissues surrounding human breast and pancreatic tumours. Using two model systems we have shown that PCNA is induced in non-cycling cells by adjacent transplanted tumour cells and that this phenomenon may be mimicked by the in vivo administration of growth factors . These data suggest that tumours may elaborate factors that induce PCNA expression in nearby normal cells. PCNA induction the normal cells surrounding tumours is a direct example of the effect of tumour cells on normal surrounding tissues. This effect may prove to be a useful parameter in the analysis of tumour-host interactions."}
+{"text": "The pharmacological agent Sildenafil belongs to a class of drugs called phosphodiesterase (PDE) inhibitors. Phosphodiesterases are enzymes which catalyze the hydrolysis of cyclic nucleoside monophosphates, viz. 3'5'-cAMP (cAMP) and 3'5'-cGMP (cGMP). To date, at least 11 isoforms of PDE have been discovered.[Sildenafil and the related compounds Tadalafil and Vardenafil, are selective inhibitors of the cGMP-hydrolyzing isoform 5. PDE 5 isPhosphodiesterase 5 inhibitors can have a range of effects due to a very wide distribution of the isoform in various body tissues. Sildenafil is the drug which has been most often studied in various clinical trials. The clinically relevant effects have been noticed on the pulmonary vasculature and the smooth muscle of the corpus cavernosum (in patients with erectile dysfunction). Several studies have documented a relaxant effect on the pulmonary vascular smooth muscle with lowering of pulmonary artery pressure and pulmonary vascular resistance in patients with various forms of pulmonary hypertension.\u20135 These 2The most commonly reported side-effects of sildenafil can be attributed to vasodilation, such as flushing, nasal congestion, headache, dizziness and hypotension. Relaxation of the lower esophageal sphincter causes dyspepsia and reflux related symptoms. In combiSildenafil potentiates inhibitory effects of nitric oxide donors on ADP dependent platelet aggregation.8 Case reThe effects of Sildenafil and related compounds on pulmonary vasculature has been the focus of several recent clinical trials. Most of the studies are conducted in patients with primary pulmonary hypertension.\u201310 The fet al, reported a favorable effect on six-minute walk test, mean pulmonary artery pressure and WHO functional class in adult patients treated with Sildenafil.[et al,[Galie ldenafil. The incil.[et al, reportedet al, demonstrated a significant decrease in pulmonary vascular resistance with improvement in systemic saturation, six-minute walk distance and WHO functional class in a group of 16 symptomatic patients with Eisenmenger syndrome treated with Tadafil.[This is characterized by elevated pulmonary vascular resistance resulting in a bidirectional or right-to-left shunt though a systemic-to-pulmonary circulation connection. The pathological changes in the pulmonary vascular bed are similar to those in patients with primary pulmonary hypertension. In contr Tadafil. None of et al, in a prospective randomized trial of 16 ventilated infants early after closure of ventricular septal defect and atrioventricular septal defect reported significant reduction in pulmonary vascular resistance index when Sildenafil was used in conjunction with inhaled nitric oxide.[et al, in a prospective non-randomized trial demonstrated that intravenous Sildenafil is more effective in reducing the PVR than nitric oxide.[et al, showed that Sildenafil augments the effect of inhaled nitric oxide in postoperative pulmonary hypertensive crisis and suggested a role for Sildenafil during the phase of weaning from nitric oxide.[There are very few randomized trials on the use of Sildenafil and related drugs in post-operative pulmonary hypertension after surgery for congenital heart disease.\u201318 Stockic oxide. Sildenafic oxide. Atz et aic oxide. A recentic oxide. However,Survey on Clinical Use of Sildenafil for Post Operative Pulmonary Hypertension and Eisenmenger Syndrome:Based on the published literature in adults with primary pulmonary hypertension, there is widespread use of Sildenafil in pediatric patients with pulmonary hypertension (both idiopathic and post-operative pulmonary hypertension) and in patients with Eisenmenger syndrome. This scenario is particularly true in developing countries with limited access to drugs like Bosentan and prostaglandin analogues. Various issues related to the use of Sildenafil such as its efficacy, duration of treatment and safety have not been fully resolvedWe therefore sought the opinion of some of the leading experts in the field of pulmonary hypertension in CHD with regard to the safety and efficacy of Sildenafil in two principal settings in congenital heart disease - postoperative pulmonary hypertension and Eisenmenger syndrome. The experts were invited to join an email survey on the use of Sildenafil in these two settings. Through a pre-designed questionnaire, a set of questions were put forward and the opinion of the experts regarding each of the issues was solicited.The e-mail survey covered the following issues:Should Sildenafil be administered for early postoperative pulmonary hypertension?If so, what would be the indications and clinical conditions?What is the dosage schedule that you use?How long do you administer it? What are your criteria for stopping the medication?What adverse effects have you encountered?Postoperative pulmonary hypertension:NeverRoutinelyIn specific circumstances onlyDo you administer Sildenafil in patients with Eisenmenger syndrome? Choose one of the following:If your answer is iii, what are the specific circumstances?Are you concerned about the potential for increased flow due to falling PVR resulting in increasing shear stress on the pulmonary vasculature?What is the recommended duration of therapy?How do you follow-up these patients?Have you found Sildenafil effective in these patients?Eisenmenger syndrome:Below is a summary of the expert opinions collected from this email survey:Older patients (> 6 months) with large L-R shunts Repair of obstructed TAPVCBorderline cases of Bidirectional Glenn shunt or Fontan operation with elevated PA pressure.Weaning from nitric oxideMost of the experts agreed that there was a role for Sildenafil in the management of postoperative pulmonary hypertension. The principal settings where Sildenafil was potentially useful included:However, two experts opined that there was insufficient data at present to support the use of Sildenafil in postoperative pulmonary artery hypertension. One of them strongly felt that the drug should not be administered pending a carefully conducted double blind placebo controlled randomized study.The response to this question was variable. The dose range recommended varied from 0.5 - 5 mg/kg/day. The frequency of administration recommended was six-eight hourly. Most experts recommended starting the drug in lower dose and then increasing the dose to the maximum tolerated dose.It is believed that most of the receptors get saturated at a dose of 0.3 mg/kg and though higher doses are well tolerated, there may not be any definite advantage over the standard dose.If used in an acute setting (post-op pulmonary hypertensive crisis which settles down in a few days), it was felt that Sildenafil can be stopped after 2-3 weeks. However, if there was persistent pulmonary hypertension at the time of discharge, the drug should be continued for at least three months. Occasional older patients with persistent pulmonary hypertension after repair of large shunts may require longer duration of therapy. One expert opined that there was no rationale for continuing Sildenafil if the pulmonary hypertension was mild or moderate in an otherwise asymptomatic patient. Two-dimensional echocardiography was recommended by most for follow-up assessment of these patients to assess pulmonary hypertension.Most respondents felt that the drug was well tolerated in their personal experience. Occasional cases of systemic hypotension and headache were observed with higher doses. One expert was wary of the use of Sildenafil in patients with sepsis in view of its property of augmenting the nitric oxide pathway.Most of the survey participants agreed that Sildenafil may be administered in a symptomatic patient with Eisenmenger syndrome. The criteria for use included severe cyanosis (oxygen saturation < 75%), symptoms of hyperviscosity (Hb > 20 gm/dl) and right ventricular dysfunction.Most experts were not worried about this possibility. The explanation was that the PVR was fixed and irreversible in all these patients and hence even a slight increase in pulmonary blood flow would have only minimal effect on the already established changes in the pulmonary vasculature.The majority of participants agreed that the therapy should be continued indefinitely and perhaps lifelong. The possibility of sudden worsening of symptoms after stopping Sildenafil is known.Most of them followed-up their patients 3-6 monthly. Parameters recommended for objective evaluation of treatment efficacy included oxygen saturation at baseline and after physical activity, exercise tolerance , echocardiographic assessment of pulmonary artery pressure, time to clinical worsening and hospitalization rates. One of the experts recommended the number of hemodilution sessions needed to control hyperviscosity-related symptoms as an index of efficacy of treatment as practiced in his unit.According to some respondents, Sildenafil was effective in as many as 50% patients with improvement in functional capacity  and oxygen saturations after its use.In conclusion, the use of Sildenafil in the treatment of postoperative pulmonary hypertension and Eisenmenger syndrome is based on anecdotal reports and small observational studies. Till date, no randomized control trials have been conducted with Sildenafil in either of the settings. Though expert opinion in this survey favored the use of Sildenafil in selected patients, one should be extremely wary of supporting the widespread use of Sildenafil in unselected populations without proper case selection and monitoring. To quote one of the experts, Dr Gil Wernovsky, \"This type of investigation/new therapy should only be done in the context of a well designed, placebo controlled, blinded randomized clinical trial. It is time for pediatric cardiology to enter the 21st century medicine and not just throw new medicines at our sickest patients\"."}
+{"text": "PLoS Neglected Tropical Diseases (PLoS NTDs) provides a platform of information that links multiple scientific disciplines in the battle against the substantial public health and economic impact imposed by neglected tropical diseases (NTDs). The types of articles published in PLoS NTDs include health policy; control, elimination, and eradication programs; epidemiological and operational research; basic pathobiology, translational research, and development; development of new diagnostic tests; and many other areas of action.PLoS NTDs also reaches health care practitioners caring for individuals suffering from NTDs through the clinical symposium section. To effectively target this audience, the clinical symposium section delivers critical information in the case management of NTDs backed by the expertise and commitment of our clinician editors. Up until now, the clinical symposium section has included two types of article formats: a case-report format, and case-based learning articles that consist of a question and answer format illustrating key clinical issues in the diagnosis and management of NTDs. Both types of articles are presented in a simple format that makes them easy to apply to direct patient care with an emphasis on key learning points to provide clinical pearls or take-home points.PLoS NTDs, we are pleased to launch a new section to complement the clinical symposium section with the publication of the first Photo Quiz. Our first Photo Quiz case addresses the diagnosis and management of actinomycetoma in both resource-rich and resource-poor settings In this issue of http://www.plosntds.org/static/license.action), followed by discussion of key learning points. Upon submission of a manuscript, cases will be assessed by the editorial office and subsequently undergo a formal peer review process following the PLoS NTDs editorial review policy (http://www.plosntds.org/static/guidelines.action#overview). Submissions for the Photo Quiz section should follow the two-part format outlined in We encourage the audience of clinical practitioners to submit relevant clinical, radiographic, or microbiological images. Some examples may include images of a clinical sign characteristic of infection with a particular pathogen; radiographic images that may be identified in patients suffering from a particular NTD; electrocardiograms or echocardiograms with relevant abnormalities; or a video of the patient's clinical signs. From a laboratory/pathology perspective, we also encourage submission of pathogens identified in clinical specimens. All images will be published under the Creative Commons Attribution License (The submitter(s) should provide an initial brief presentation of a clinical case  with key clinical images, which should invite a diagnosis from the reader by posing a single-sentence question about the case.The case presentation and question should be written in a single paragraph and should be accompanied by no more than 2 images/figures (no more than 150 words).http://www.plosntds.org/static/guidelines.action#supporting.Similar to the Symposium manuscripts, authors must obtain written consent from the patient using our consent form . Consent forms are available at The answer should give the diagnosis followed by a discussion of the most relevant clinical issues .PLoS NTDs.Authors must include a box that lists 3\u20135 key learning points of the case similar to other clinical sections of No more than 10 references."}
+{"text": "Metastatic spread of some solid tumours is thought to depend upon the adhesion of tumour cells to the vascular endothelium followed by extravasation into surrounding tissues. We investigated the role of beta 1 integrins in the adhesion of the breast adenocarcinoma cell line MDA-MB-231 and the melanoma cell line RPMI-7951 to quiescent human umbilical vein endothelial cells (HUVEC) in vitro. In the course of adhesion assays, tumour cells were observed to adhere to quiescent HUVEC monolayers, particularly at endothelial cell-cell junctions. Immunohistochemistry revealed concentration of beta 1 integrin expression at these sites. Adhesion was reduced by pretreatment of either tumour cells or HUVEC with antibodies against beta 1 integrins. Simultaneous treatment of HUVECs and tumour cells with these antibodies produced an additive blocking effect, consistent with a heterotypic adhesion mechanism. Our data suggest that tumour cell and endothelial beta 1 integrins may play a crucial role in the arrest and migration of tumour cells through the vascular endothelium in the absence of endothelial 'activation'."}
+{"text": "To the Editor: Jenkins and Farrell reported an increase in the proportion of macrolide-resistant Streptococcus pneumoniae isolates in the United States  campaign, are essential to limiting selection and spread of antimicrobial drug resistance.Decreased macrolide use has led to a decrease in macrolide-resistant pneumococci. A yearly seasonal reduction in antimicrobial drug prescribing in Israel was associated with a decrease in the proportion of antimicrobial drug\u2013resistant pneumococci that caused acute otitis media ("}
+{"text": "Maximum likelihood methods provide a useful framework for inferring temporal variation in diversification rates. LASER is a package for the R programming environment that implements maximum likelihood methods based on the birth-death process to test whether diversification rates have changed over time. LASER contrasts the likelihood of phylogenetic data under models where diversification rates have changed over time to alternative models where rates have remained constant over time. Major strengths of the package include the ability to detect temporal increases in diversification rates and the inference of diversification parameters under multiple rate-variable models of diversification. The program and associated documentation are freely available from the R package archive at  Recent years have seen an explosive proliferation of DNA sequence data for molecular phylogenetic analyses and a commensurate increase in the use of these data to draw inferences about macroevolutionary processes. A particularly active area of research involves the use of molecular phylogenies to study variation in rates of species origination and extinction, both among lineages  and overLikelihood Analysis of Speciation and Extinction Rates (LASER) is a package for the R programming environment that facilitates model-based analyses of diversification rates. LASER is the first software package to implement tests for temporal variation in diversification rates using likelihood methods based on the birth-death process . LASER iLASER was written to address several limitations of existing software for analyzing the tempo of diversification. Approaches such as the gamma statistic  and survLASER fits a candidate set of rate-variable diversification models to phylogenetic data and contrasts the likelihood of the data under these models to alternatives where speciation and extinction rates have remained constant over time. The null hypothesis that diversification rates have not changed over time is tested using the statistical approach described in RC is the Akaike Information Criterion (AIC) score for the best-fit rate-constant model of diversification, and AICRV is the AIC score for the best-fit rate-variable model under consideration. Thus, a positive \u0394AICRC value suggests that the data are best approximated by a rate-variable model of diversification. Although several previous studies have used the AIC to distinguish among rate-constant and rate-variable models of diversification  methods  tree format. Likelihoods and parameter estimates can be obtained for a range of rate-variable diversification models, including logistic and exponential density-depedent models and multi-rate birth-death models. Additional functions permit batch processing of multiple phylogenies to obtain the null distribution of \u0394AICfitdAICrc computes the \u0394AICRC test statistic for a test phylogeny using arguments that specify the candidate set of rate-variable models to be considered. The null distribution of the test statistic is obtained by either simulating branching times with the function yuleSim or by importing simulated trees using the function getBtimes.batch. The latter function is particularly useful for the analysis of phylogenies with incomplete taxon sampling, because incomplete sampling can result in a spurious decline in diversification rates over time  summary <- fitdAICrc(data. bt) data.bt of the branching times for Enallagma by reading the parenthetic tree stored in enallagma.tre. The function fitdAICrc generates an object, summary, that contains the results of fitting all rate-variable and rate-constant models to the data. The observed \u0394AICRC statistic for Enallagma is 13.0372, and the best fit model is a three-parameter rate-variable model specifying a 12.5-fold increase in the speciation rate over time. The significance of the observed \u0394AICRC statistic was assessed with the following commands:The first line creates a vector null.bt <- yuleSim fitdAICrc.batch  Enallagma tree (37) under the null hypothesis of rate-constancy and stores them in object null.bt. The set of simulated phylogenies is analyzed using fitdAICrc. batch, which approximates the probability of the observed \u0394AICRC statistic under the null hypothesis. In this case, the observed \u0394AICRC statistic indicates a highly significant departure from the null hypothesis of rate-constancy (p = 0.0016; The first line simulates 5000 phylogenies with the same number of tips as the LASER fits multiple rate-variable and rate-constant models of diversification to reconstructed phylogenies using maximum likelihood. Its main strength includes the use of Monte Carlo simulation to control for elevated Type I error rates associated with likelihood-based analyses of diversification. LASER is the first available package that can detect temporal increases in diversification rates, and has considerable power to detect temporal declines in diversification rates when clades have diversified under high background extinction rates. As a freely available package for the R programming environment, it is flexible and platform-independent, and can easily be tailored to a variety of user-specific applications."}
+{"text": "Using vanadyl sulphate, sodium orthovanadate or bisoxovanadium (BMOV), Cruz TF, Morgan A, Min W  have recently demonstrated the antineoplastic effects of vanadium in mice. In this study, the antineoplastic effects of BMOV against human tumour cell lines was confirmed, and this effect was shown to depend on the prolonged exposure of the cells to the drug. We have investigated a polymeric drug delivery system for the sustained delivery of BMOV as an antineoplastic agent in mice. The objective was to design and evaluate an injectable polymer-BMOV paste that would act as a drug implant for the slow but sustained release of BMOV in the mice. In vitro studies showed that the biodegradable polymer poly (Ghlr epsilon epsilon-caprolactone) (PCL) released BMOV in a sustained manner with rates of drug release increasing with increased loading of the drug in the polymer. In vivo studies showed that PCL-BMOV paste implants produced a concentration-dependent inhibition of MDAY-D2 tumour growth via systemic drug delivery. Further in vivo studies showed that 5% BMOV-loaded PCL (containing 20% methoxypolyethylene glycol) was effective in preventing tumour regrowth of resected RIF tumour masses in mice when the PCL-BMOV paste was applied to the resected site for localized drug delivery. The results confirm the potential of vanadium as an antineoplastic agent and show that the injectable PCL-BMOV formulation releases a chemotherapeutic dose of vanadium for the systemic treatment of whole tumours as well as the localized treatment of resected RIF tumours."}
+{"text": "The development of cervical carcinoma is strongly associated with specific types of human papillomaviruses (HPVs). A role for cellular immunity in cervical disease is supported by the increased occurrence of HPV-associated lesions in immunosuppressed individuals. Upon viral infection or malignant transformation, ensuing alterations in gene expression result in the generation of novel sets of peptides which can form complexes with specific HLA class I heavy chains and beta 2-microglobulin. These are then expressed at the cell surface as potential targets for specific T cells. In this study of 100 carcinomas HLA-A and -B class I expression by the tumour cells was down-regulated at one or more alleles in at least 73% of cervical carcinomas. Interference with the transporter associated with antigen presentation (TAP), which translocates cytosolic peptides from endogenously synthesised proteins  into the lumen of the endoplasmic reticulum was found in 38% of the HLA class I down-regulated tumours. Loss of expression for common HLA class I alleles ranged from 36% to 71%, and such changes might be expected to influence specific immunogenic peptide presentation and consequent immune recognition. These results underline the importance of single as well as multiple allelic loss in cervical neoplasia and have important implications for attempts to intervene immunologically in cervical cancer."}
+{"text": "To study whether colony growth in vitro reflects the prognosis of breast cancer patients, specimens from a total number of 138 patients with primary breast carcinomas were cultivated in the Courtenay-Mills soft agar method. The plating efficiency (PE) values were related to various clinical and histopathological parameters. No significant correlation was found between colony forming ability and menopausal status, histopathology, TNM-status or steroid hormone receptor status. The crude survival of the patients was not significantly correlated to the in vitro growth of the tumours; neither was there any difference in relapse-free survival between patients whose tumours failed to grow in vitro and those having growing tumours (PE greater than 0). A multivariate survival analysis of 115 patients with primary tumours without distant metastases revealed that the PE was not a significant independent prognostic indicator, as it gave no additional prognostic information above that of node and ER status. It is concluded that routine measurement of colony formation in vitro is not warranted in the management of breast cancer."}
+{"text": "A positive but slight correlation was found between extracellular lysosomal activity and four parameters of lung lesion  protein concentration, BALF LDH and BALF alkaline phosphatase activities). All the above findings suggest that the AM release of lysosomal enzymes during HP is a factor involved, although possibly not the only one, in the pulmonary lesions appearing in this disease.Hydrolytic enzymes are the major constituents of alveolar macrophages (AM) and have been shown to be involved in many aspects of the inflammatory pulmonary response. The aim of this study was to evaluate the role of lysosomal enzymes in the acute phase of hypersensitivity pneumonitis (HPs). An experimental study on AM lysosomal enzymes of an HP-guinea-pig model was performed. The results obtained both"}
+{"text": "Primary human panceratic exocrine adenocarcinoma has been established in tissue culture and as xenografts in immune-deficient nu/nu mice. The cell line has a doubling time of 36 h and grows as a confluent monolayer together with a constant population of free-floating cells. Evidence of tumourigenicity was provided by growth on an early diploid fibroblast monolayer and in soft agar, and as solid tumours in immune-deficient nu/mu mice. Chromosome analysis of the cultured cells confirmed their tumour origin. Xenografts established from the cell line or directly from primary tumour tissue have retained a similar histology to the original tumour on serial transplantation. An electrophoretic study of exportable pancreatic digestive enzymes and a number of intracellular enzymes has shown that the cell line and xenografts maintain a human intracellular enzyme profile, but do not produce pancreatic digestive enzymes."}
+{"text": "Recent developments in the understanding of the molecular control of iron homeostasis provided novelinsights into the mechanisms responsible for normal iron balance. However in chronic anemias associatedwith iron overload, such mechanisms are no longer sufficient to offer protection from iron toxicity, and ironchelating therapy is the only method available for preventing early death caused mainly by myocardial andhepatic damage. Today, long-term deferoxamine (DFO) therapy is an integral part of the management ofthalassemia and other transfusion-dependent anemias, with a major impact on well-being and survival.However, the high cost and rigorous requirements of DFO therapy, and the significant toxicity of deferiproneunderline the need for the continued development of new and improved orally effective iron chelators.Within recent years more than one thousand candidate compounds have been screened in animal models. Themost outstanding of these compounds include deferiprone (L1); pyridoxal isonicotinoyl hydrazone (PIH) and;bishydroxy- phenyl thiazole. Deferiprone has been used extensively as a substitute for DFO in clinical trialsinvolving hundreds of patients. However, L1 treatment alone fails to achieve a negative iron balance in asubstantial proportion of subjects. Deferiprone is less effective than DFO and its potential hepatotoxicity isan issue of current controversy. A new orally effective iron chelator should not necessarily be regarded asone displacing the presently accepted and highly effective parenteral drug DFO. Rather, it could be employedto extend the scope of iron chelating strategies in a manner analogous with the combined use of medicationsin the management of other conditions such as hypertension or diabetes. Coadministration or alternating useof DFO and a suitable oral chelator may allow a decrease in dosage of both drugs and improve complianceby decreasing the demand on tedious parenteral drug administration. Combined use of DFO and L1 hasalready been shown to result in successful depletion of iron stores in patients previously failing to respond to single drug therapy, and to lead to improved compliance with treatment. It may also result in a \u201cshuttle effect\u201d between weak intracellular chelators and powerful extracellular chelators or exploit the entero-hepatic cycle to promote fecal iron excretion. All of these innovative ways of chelator usage are now awaitingevaluation in experimental models and in the clinical setting."}
+{"text": "Fibrosis is a common side-effect of radiation therapy. As a complex network of cytokines and other mediators plays a central role in the process leading to fibrosis, we used an in vivo method to measure skin collagen synthesis, taking into account the physiological conditions. We determined suction blister  fluid concentrations of types I and III procollagen propeptides, reflecting types I and III collagen synthesis, in irradiated and unirradiated skin of breast cancer patients 1-5 years after surgery and radiation therapy, hence using the patients as their own controls. The mean concentrations of the measured collagen markers were approximately two times higher in the irradiated skin than in the unirradiated contralateral breast skin. The difference slowly diminishes with time. These results indicate that abundant collagen synthesis in the irradiated skin continues several years after discontinuation of the radiation therapy, leading to fibrosis. The method outlined here offers a new in vivo perspective to study events leading to radiation fibrosis."}
+{"text": "The presence of a tumour-associated immune response in 37 patients with ovarian cancer as assessed by blastogenesis (lymphocyte transformation) evoked by ovarian cancer cell extracts, has been correlated with survival following the test. The difference in these responses is unlikely to be accounted for on the basis of general impairment of cell-mediated immuno-competence. Serum carcinoembryonic antigen (CEA) was also determined in 27 ovarian cancer patients to assess its prognostic significance. Raised CEA levels and absence of blastogenic response to tumour cell extract during relapse are associated with a worse prognosis but neither of these parameters are significant in remission. Possible applications of these findings to the clinical management of ovarian cancer patients are discussed. Serum alpha feto-protein levels measured by radioimmunoassay were not found to be raised in any of the 32 ovarian cancer patients in whom it was measured."}
+{"text": "Single nucleotide polymorphisms (SNPs) constitute an important mode of genetic variations observed in the human genome. A small fraction of SNPs, about four thousand out of the ten million, has been associated with genetic disorders and complex diseases. The present study focuses on SNPs that fall on protein domains, 3D structures that facilitate connectivity of proteins in cell signaling and metabolic pathways. We scanned the human proteome using the PROSITE web tool and identified proteins with SNP containing domains. We showed that SNPs that fall on protein domains are highly statistically enriched among SNPs linked to hereditary disorders and complex diseases. Proteins whose domains are dramatically altered by the presence of an SNP are even more likely to be present among proteins linked to hereditary disorders. Proteins with domain-altering SNPs comprise highly connected nodes in cellular pathways such as the focal adhesion, the axon guidance pathway and the autoimmune disease pathways. Statistical enrichment of domain/motif signatures in interacting protein pairs indicates extensive loss of connectivity of cell signaling pathways due to domain-altering SNPs, potentially leading to hereditary disorders. Hereditary disorders are often linked to rare mutations in the form of single nucleotide polymorphisms (SNPs) More than ten million SNPs have been identified in the human genome Current methods for discovery of SNP-phenotype association include those focusing on non-synonymous SNPs that alter functional motifs such as binding sites This study focuses on a specific subset of human genotype-disease association, namely the annotation of SNPs that alter protein domains and thus potentially break bonds between interacting proteins in cell signaling pathways In this study, we screened the human proteome for domain annotation using the PROSITE web tool The human SNP database was downloaded from the NCBI dbSNP database  The PROSITE output for each sequence was in the form of a matrix with three columns, with the columns indicating (1) the ID number of the PROSITE domain, (2) the binary value identifying the presence or absence of a domain, and (3) the PROSITE matching score (MS) if the domain was expressed as a profile (position weight matrix) rather than expressed in the form of a pattern (regular expression). The second and the third columns of the output data allowed us to identify those SNPs that either removed a domain from the protein structure or drastically altered it when compared to sequences with and without the SNPs (DA-SNPs). If the PROSITE domain was defined as a regular expression, the second column was sufficient to identify whether the domain also existed in the presence of the SNP.For those domains expressed as a profile, we checked the third column for the value of the matching score parameter of the same protein with and without the SNP. We defined a domain distortion (DD) parameter as the ratio of the difference in the matching score (due to the presence of the SNP) to the matching score of the sequence without the SNP. In our scans, DD varied from 0 to 0.3, which was the maximum domain distortion observed in our computations. Domains with DA-SNPs were defined as the sets of domains for which the sequence with SNPs no longer fits the regular expression, plus a set of profile domains with a finite DD value cut off in the presence of the SNPs.Examples of structural diagrams of proteins with DA-SNPs were obtained using the Protein Data Bank  We used statistical enrichment to identify protein signatures  most likely to be found among binding partners of the proteins containing domain-altering SNPs. We created a score matrix with rows indicating domains that can be altered by an SNP and columns indicating domains and motifs found in binding partners of proteins with domain altering SNPs. Each element of the score matrix represented the number of times a domain with an SNP was found associated with a signature  on a binding partner. The web tool ELM (2010 version) Our computations show that proteins with SNPs in one or more of its domains are significantly more likely to be associated with human disorders. Out of the 63,899 SNPs in the coding regions of proteins, 1,782 SNPs are present in the Online Mendelian Inheritance in Man (OMIM) database version 2009 Among proteins with domain SNPs, those with domain-altering SNPs are even more likely to be associated with disorder/disease. Domain-altering SNPs discovered in our PROSITE screening method consists of two subsets. The first subset consists of SNPs the sequence no longer satisfies in the regular expression for the domain. The second subset is composed of domains defined as a profile above a prescribed domain distortion (DD) parameter cutoff. An example of a domain with DA-SNP is p53. We evaluated the statistical enrichment of the domain altering SNPs in the OMIM Database as a function of the DD cutoff, as shown in Proteins with domain-altering SNPs crowd GO molecular function categories involving calcium ion binding, adenyl ribonucleotide binding, protein kinase activity, and endopeptidase activity at DD >0.10. The DD cutoff of 0.10 corresponds to 598 domain-altering SNPs present in 505 proteins. Among these proteins, 242 had at least one known binding partner in the Human Protein Reference Database (HPRD) Shown in Next, we estimated the links broken in these pathways due to domain-altering SNPs. We have determined domain-domain and domain-motif pairs (signature pairs) statistically enhanced in protein-protein interactions involving proteins with domain-altering SNPs. The results show that only a very small fraction of possible signature pairs are statistically enriched in PPIs presented in HPRD We used statistically enriched signature pairs in the estimates of links broken due to a protein expressing a domain-altering SNP. A link (transient or stable) between two proteins is assumed broken due to a domain altering SNP if the opposing protein pair contains at least one signature enriched with the SNP containing domain in the PPIs in HPRD. Shown in The protein links we estimate to be broken between a protein containing a DA-SNP and its immediate neighbors are shown in The genome wide association studies seeking a correlation between genetic makeup and complex diseases, such as cardiovascular diseases This study explores the mechanisms by which SNPs that fall into protein domains in the human genome potentially contribute to disease. Protein domains are functional units closely aligned with post-transcriptional modification (as in phosphorylation) and play important roles in establishing the connectivity of cell signaling networks via binding to upstream and downstream proteins How does an SNP with domain altering properties affect the connectivity of pathways? The key to answering this question lies in the discovery of the set of proteins that bind to proteins under consideration via the domain containing the SNP. The grammar of protein-protein interactions in terms of primary sequence and/or 3D structure is yet to be fully understood. We used a statistical enrichment approach to identify protein domains (motifs) on the opposing protein most frequently associated with the SNP-containing domain under consideration. We then assumed a bond (transient or steady) was broken whenever we came across such a signature pair among the immediate partners of the protein with a domain altering SNP. Results shown in the present study for focal adhesion and the natural killer cell mediated cytotoxicity pathways indicate extensive loss of connectivity in these cellular pathways, caused by the presence of domain altering SNPs among the proteins in these pathways. Even when we reduced the estimates of bonds broken with the use of signature pairs already known to predict protein-protein interactions, the loss of connectivity persisted at multiple cell compartments. We obtained qualitatively similar results for axon guidance and neutrophin signaling pathways altered by the presence of a domain altering SNP (not shown).In conclusion, proteins with domain-altering SNPs are statistically enriched in the list of proteins known to be associated with disease. These proteins crowd pathways associated with immunological, neurological and cardiomyopathy disorders. Protein functional groups statistically enriched with proteins with domain altering SNPs include calcium ion binding, adenyl ribonucleotide binding, protein kinase activity, endopeptidase activity, serine-type peptidase activity, DNA binding, and GTPase binding proteins.Table S1List of proteins with domain altering SNPs (DD >0.1) for which both the SNP and the protein were previously associated in the literature with a hereditary disorder or complex disease. The columns in the table present the gene symbol, the SNP ID, the name of the domain with the SNP, whether is DD violation (yes) or violation of regular expression (no), and the associated disorder/disease.(0.02 MB XLS)Click here for additional data file."}
+{"text": "Radiofrequency ablation of Cavotricuspid Isthmus-dependent Atrial Flutter (CTI AFL), a usual and safe therapeutic procedure in interventional electrophysiology with a high success rate, aiming to induce permanent block of conduction over CTI, is normally performed via the femoral access, which allows practical access to the CTI through the inferior vena cava (IVC). In rare cases of obstruction of IVC, ablation of CTI can be performed only through the superior vena cava (SVC) access.  We present a case  of typical atrial flutter that was ablated through the right subclavian/jugular veins because of  iatrogenic obstruction of the IVC due to a previously implanted thrombus  filter. Furthermore we discuss about how we resolved access-related problems of instability during catheter ablation on CTI. Radiofrequency ablation of Cavotricuspid Isthmus-dependent Atrial Flutter (CTI AFL) is a usual and safe therapeutic procedure in interventional electrophysiology with a high success rate -5. Its aIn rare cases of congenital or iatrogenic obstruction of IVC or bilateral femoral vein thrombosis, ablation of CTI can be performed only via the superior vena cava (SVC) access. We present a case of a patient with typical atrial flutter that was ablated through the right subclavian/jugular veins due to iatrogenic obstruction of the IVC by a previously implanted thrombus  filter.A 55 year-old woman was referred to our Heart Center due to AFL with fast ventricular response despite medical therapy with verapamil plus beta-blocker, causing palpitations and fatigue on moderate excercise. The patient had a history of recurrent pulmonary embolism; therefore she had been treated in another hospital with bilateral pulmonary thromb-endarterectomy, reconstruction of tricuspid valve by annuloraphy including atriotomy and implantation of an IVC filter (type \"Cordis Easy Trap\").  The  patient's resting ECG revealed saw tooth pattern in leads II, III and AVF, providing the reasonable diagnosis of typical AFL. Due to the highly symptomatic medically-uncontrolled fast ventricular response of AFL, ablation of CTI was decided and a subclavian/jugular vein access was chosen, as the presence of IVC filter made the femoral vein access impossible. After placing two 6F-sheaths in the right jugular vein and one 8F-sheath in the right subclavian vein, a 4 pole fix-curved and a 10-pole steerable diagnostic catheter were advanced through the jugular sheaths into the Coronary Sinus (CS) and the right atrium (RA). The intracardial signals were compatible with typical counterclockwise AFL  and posiSubsequently, a 4-pole 8mm-tip ablation catheter was advanced over the 8 F subclavian sheath to the ventricular margin of the CTI zone . The ablBy  connecting the two described semi-lines  we obtained the conversion of AFL to sinus rhythm . SubsequFor ablation of  typical atrial flutter, normally the femoral vein access is chosen. In case of obstruction of the IVC, the access via SVC is most common.  In literature there are only few reports about similar situations. Authors referred about cases, where the access to successful CTI ablation was chosen via the jugular access due to total cavopulmonal connection , an inteThe obstacle to the right atrium in our patient with typical flutter  was an implanted filter in the IVC for secondary prevention of pulmonary embolism which made us choose the jugular / subclavian access. The inferior access via femoral vein allows ablation of CTI by pulling the maximally angulated ablation catheter from the ventricular aspect to the edge of IVC and thus generate a certain pressure on it, leading to better contact and energy delivery.Using  the 'superior' access the catheter has to be pushed instead of being pulled against the CTI. This leads to extreme instability and finally makes the catheter fall down into IVC without ablating the important transition zone between CTI and IVC. The manoeuvre that helped us to resolve this problem after completion of the first part of ablation as described was the turn of the catheter 'upside down' making the tip look caudal towards IVC angulated against CTI. From that point we started the second 'semi-line' moving the catheter upwards finally connecting the two lines.This allowed us to apply a certain push upon the atrial aspect of CTI, gain best possible stability and finally succeed to reach a bidirectional block. In cases of typical flutter ablation with no access via IVC, the jugular / subclavian access via SVC using the described manoeuvre is a practicable and safe approach to achieve bidirectional isthmus block."}
+{"text": "Mannose in animal cells is phosphorylated by hexokinase (HK) and later isomerised by mannose phosphate isomerase (MPI) to fructose-6-P, which is incorporated in the glycolysis pathway. In this paper we report a significant decrease of MPI activity in splenic lymphoid cells from AKR/J old mice with lymphocytic leukaemia in comparison to that found in splenic lymphocytes from AKR/J non-leukaemic young mice and BALB/c young and old control mice. However, HK with mannose as substrate presents a normal activity in AKR/J leukaemic mice. This marked shortage of MPI explains the in vitro mannose toxicity found by us here in splenic lymphoid cells from AKR/J leukaemic mice. MPI activity was also decreased in peripheral blood lymphocytes from 4 out of the 6 patients studied with chronic lymphocytic leukaemia in relation to the activity found in the lymphocytes from healthy donors. The utility of analysing MPI activity in leukaemia patients and the use of mannose as an innocuous chemotherapic supporting agent in patients with decreased MPI activity is proposed."}
+{"text": "The early and late morphological changes induced in rat bladder urothelium by intravesicular administration of the alkylating agents methyl methanesulphonate (MMS) and ethyl methanesulphonate (EMS) are described. In the short-term, both compounds produced dose-related toxic damage followed by a regenerative hyperplasia of the urothelium. At any given dose-level, the effects of MMS were more severe than those of EMS. Two years after administration of multiple doses of 2.5 mg MMS or 7.5 mg EMS the majority of animals had dose-related simple urothelial hyperplasias with occasional mild dysplasia. However, in three MMS-treated animals the hyperplasias had progressed to well-differentiated transitional-cell carcinomas. No bladder neoplasms were seen in EMS-treated animals. The urothelial response of the rat to MMS and EMS is discussed with reference to the known chemical reactivity of these compounds. It is concluded that EMS is a mitogen for the urothelium and that the few carcinomas which develop following topical exposure of the bladder to MMS do not necessarily reflect any initiating potential in this compound. Rather it is argued that the results are consistent with MMS acting as a promoter in cells which have either been previously initiated or which carry a latent oncogene."}
+{"text": "In 1980 the Cancer Research Campaign launched a multi-centre breast cancer trial; aimed at repeating the Scandinavian Chemotherapy Study Group's cyclophosphamide trial, and the NATO tamoxifen study; thereby further evaluating the role of these two adjuvant regimens in patients with early breast cancer. Two thousand two hundred and thirty women were randomized into this trial between 1980 and 1985 and preliminary analyses demonstrate a significant improvement in event-free survival for both regimens. Results from this study closely parallel the two trials it set out to repeat."}
+{"text": "Thirty-six patients with bone metastases included in a trial of supportive calcitonin on the treatment response to systemic therapy were monitored by conventional radiography, conventional indicators of bone metabolism  and collagen metabolites . All patients had been on the same systemic treatment for at least 3 months at the start of the trial. There was a positive correlation between the concentrations of ICTP and PICP at baseline (Spearman's rank-order correlation coefficient rs = 0.62). Both ICTP and PICP showed statistically significant correlations to the other markers of bone metabolism (except sCa and uCa) as well as to the number of bone metastases on bone scans. Reduction in ICTP correlated significantly with the treatment response at three months (rs = - 0.57). while PICP showed a borderline negative correlation to therapy response (rs = - 0.37). Of all the biochemical parameters studied the changes in ICTP showed the best correlation with the treatment response. PICP and ICTP changes in patients with progressive disease differed significantly from those in patients with responding and stable metastases, whereas no difference was found between responders and stable patients."}
+{"text": "Cell mediated immunocompetence was measured serially in 35 patients with malignant melanoma in order to determine the effect of extent of disease and prognosis as well as the influence of BCG immunotherapy on immune reactivity. Compared with normal adult controls, statistically significant lymphopenia occurred only in patients with widespread disease. Seventeen of 21 patients with negative pre-therapy PPD skin test converted to skin test positivity. PHA blastogenesis was depressed only in patients in the pre-terminal stages of their disease using optimal mitogen concentrations for stimulation. Threshold concentrations of this mitogen more clearly demonstrated a depressed responsiveness which correlated in severity with extent of disease. PPD induced blastogenesis was normal or increased in the majority of patients; however, the degree of stimulation by PPD was less in the BCG induced convertors than in those patients who were skin test positive before BCG treatment. Comparison of the pre- and post BCG assessments reveals no significant differences except in relation to PPD conversion. We conclude that using threshold concentrations of PHA, impaired responses are regularly associated with disease beyond the regional lymph nodes. Routine assessment of lymphocyte function by these parameters did not provide information that was not available from clinical evaluation."}
+{"text": "SCF (stem cell factor) is a pleiotropic cytokine exerting its role at different stages of bone marrow development and affecting eosinophil activation, mast cells and basophil chemotaxis and survival. The aim of the study was to assess concentration of SCF and its soluble receptor c-kit (sc-kit) in peripheral blood of patients with asthma referring it to asthma severity and phenotype.The study involved 107 patients with bronchial asthma, well characterized with respect to severity and 21 healthy controls. Concentration of SCF and sc-kit in the patients serum were measured by ELISA method.Mean serum SCF level in the group of asthmatics (n = 88) was significantly higher as compared to healthy controls . The level of SCF was higher in patients with severe asthma as compared to patients with non-severe asthma  and correlated with dose of inhaled glucocorticosteroids taken by the patients to achieve asthma control . The mean sc-kit serum level did not differ between asthmatic patients and healthy controls, however the level of sc-kit in non-severe asthmatics was significantly higher as compared to patients with severe asthma and healthy controls. In asthmatic patients (n = 63) the level of sc-kit correlated positively with FEV1% predicted value  and MEF25% predicted value . The level of sc-kit inversely correlated with the dose of inhaled glucocorticosteroids taken by the patients .Serum levels of SCF and its soluble receptor c-kit seem to be reflect asthma severity suggesting a role for these molecules in asthmatic inflammation. Hemopoietic cytokines play a crucial role in the activation and survival of cells involved in asthmatic inflammation. Stem cell factor (SCF)- the c-kit ligand, although initially was described as a mast cell growth factor  appearedAs mast cells and eosinophils are key cells in the inflammatory process ongoing in the airways of patients with asthma the role of SCF in this disease has been studied. The expression of mRNA for SCF and its receptor c-kit were shown to be higher in the bronchi of patients with asthma as compared to controls  and seruAs SCF is the cytokine acting mainly in the bone marrow, we argue if the airway inflammation typical for asthma may lead to increase of the level of circulating SCF. So the aim of the study was to assess if the concentration of SCF and its soluble receptor c-kit in peripheral blood is increased in patients with asthma and if it correlates with disease severity and asthma phenotype.The study involved 107 patients with asthma and 21 controls. SCF was assessed in 88 patients with asthma: 56 patients with severe and 32 patients with non-severe asthma, and the soluble c-kit level was assessed in 63 asthmatics: 41 severe and 22 non-severe  and the control group for c-kit consisted of 15 healthy subjects  recruited from the healthy Lodz inhabitants. Both SCF and sc-kit were assessed in 44 patients and in 15 control subjects.Asthma was diagnosed based on history, clinical examination and spirometric evaluation according to GINA definition. Severe refractory asthma was diagnosed according to ATS Workshop criteria which included use of oral glucocorticosteroids, high dose of inhaled glucocorticosteroids, daily use of a controller drug or short-acting beta 2 agonists, low respiratory function and history of exacerbation . In all Spirometry was carried according to ATS standards. Respiratory function (flow-volume curve) was measured with automatic spirometer  in patients who were without short acting beta 2 agonists for at least 8 h and long acting beta 2 agonists for at least 12 hours.Blood (5 ml for serum) was collected by venipuncture, serum was separated and frozen in -20\u00b0C. The concentrations of SCF and sc-kit SCF in serum were measured by ELISA method .Pharmacia Diagnostic, Sweden). Blood eosinophila  was assessed after staining with Pappenheim's method.The level of ECP and total IgE were measured by immunoenzymatic method . Total IgE and Eosinophil Cationic Protein(ECP) were measured in serum with ImmunoCAP  was carried out. P < 0,05 was considered statistically significant. Pearson correlation coefficient was used to compare level of SCF and sc-kit with FEV1% of predicted value, MEF% of predicted value and dose of inhaled glucocorticosteroids received by the patients.Mean serum SCF level in asthmatics (n = 88) was significantly higher as compared to healthy controls . The level of SCF was higher in the group of patients with severe asthma as compared to patients with non-severe asthma   and patients not treated with oral gluccocorticosteroids  were analyzed, the SCF level was significantly higher in both groups  as compared to mild asthmatics  and healthy controls   SCF level correlated with the dose of inhaled GCS taken by the patients to achieve asthma control  Fig . SCF levThe mean serum level of sc-kit in asthmatics without regard to asthma severity (n = 63) was similar to healthy controls p > 0,05). In patients with non-severe asthma the mean sc-kit level  was higher as compared to patients with severe asthma  and to healthy controls . There was no difference between mean sc-kit level in patients with severe asthma and healthy controls  the level of sc-kit correlated positively with FEV1% of predicted value   Fig . Sc-kit There was no correlation between serum SCF and sc-kit levels in patients with asthma, control subjects and in combined group .In this study we showed that serum level of SCF is higher in patients with asthma as compared to healthy subjects and is further increased in patients with severe refractory asthma. In parallel patients with severe asthma had decreased level of serum soluble c-kit as compared to non-severe asthmatics. Despite differences between SCF levels in patients with severe and non severe asthma serum SCF did not correlate with markers of asthma severity such as FEV1% and MEF% of predicted value, however it correlated with dose of inhaled corticosteroids needed to achieve asthma control.Previous studies showed increased production of SCF in different allergic disease like asthma, allergic rhinitis and atopic dermatitis -8. ExpreAlthough the serum level of SCF in healthy controls and patients with non- severe asthma was similar, the most severe patients had significantly higher serum SCF concentration in comparison both to healthy control and non-severe asthmatics. It is noticeable that despite aggressive anti-inflammatory treatment in the group of severe asthmatics  the level of SCF was significantly increased. It has been demonstrated that at the beginning of the treatment GCS can increase the level of SCF , howeverAs in asthmatic subjects not only SCF but also its receptor c-kit can be overexpressed on inflammatory cells we measured the soluble c-kit in the serum of patients . AlthougOur observations in line with study in patients with atopic dermatitis  which shWe were not able to correlate the level of SCF with aspirin hypersensitivity or concomitant nasal polyposis, although in previous study the increased expression of SCF within the nasal polyps of patients with asthma and aspirin hypersensitivity was reported . It suggOur study demonstrated that serum levels of SCF, a pleiotropic cytokine influencing development of two major cell lines in asthmatic inflammation- mast cells and eosinophils is elevated in patients with most severe asthma and may be important in pathogenesis of airway obstruction. Furthermore it seems that physiological down regulation of this cytokine by soluble kit receptor is also impaired in patients with severe asthma, thus modifying the SCF/c-kit interaction in asthmatics subjects.The authors declare that they have no competing interests.All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:"}
+{"text": "This study was performed to determine the changes in pulmonary function in patients randomised to receive treatment with four cycles of bleomycin, etoposide and cisplatin (BEP) (27 patients) or with four cycles of etoposide and cisplatin (EP) (27 patients) for disseminated non-seminomatous testicular cancer. This enabled us to establish whether effects other than those due to bleomycin determined the detrimental effects of BEP on lung function assessments. Slow inspiratory vital capacity (VC), the transfer factor of the lungs for carbon monoxide (TLCO), the diffusing capacity of the alveolo-capillary membrane (Dm), the pulmonary capillary blood volume (Vc) and the transfer factor of the lungs for carbon monoxide per unit alveolar volume (KCO) were determined before and at 3 week intervals during chemotherapy. Both groups, similar in terms of factors that may influence pulmonary function, showed during therapy a significant decrease in TLCO compared with the pretreatment value. Only at the end of the therapy was a significant difference in TLCO between both groups observed. Dm diminished also significantly in both groups during treatment, but differences between both groups were not seen. VC and Vc decreased in patients receiving BEP but remained constant during treatment with EP. It can be concluded that the Dm, KCO, and the widely used TLCO are not suitable parameters to monitor specifically pulmonary toxicity induced by bleomycin as part of a multidrug regimen. However, VC and Vc appear to be proper lung function assessments which reflect specifically alterations induced by bleomycin."}
+{"text": "Recent studies have proved that viruses also express microRNAs, which are thought to contribute to the intricate mechanisms of host-pathogen interactions. Computational predictions have greatly accelerated the discovery of microRNAs. However, most of these widely used tools are dependent on structural features and sequence conservation which limits their use in discovering novel virus expressed microRNAs and non-conserved eukaryotic microRNAs. In this work an efficient prediction method is developed based on the hypothesis that sequence and structure features which discriminate between host microRNA precursor hairpins and pseudo microRNAs are shared by viral microRNA as they depend on host machinery for the processing of microRNA precursors. The proposed method has been found to be more efficient than recently reported  MicroRNAs are a class of small non-coding RNAs which have recently attracted widespread attention due to their critical role in a wide spectrum of biological processes in multi-cellular eukaryotes. In animals, these small RNAs are processed from hairpin-forming precursors and exported to the cytoplasm where they are further processed and incorporated into a protein complex, the RNA Induced Silencing Complex (RISC) as a ~22 nucleotide long mature miRNA. This RNA-protein complex then affects regulation of gene expression by binding to the 3'UTR of messenger RNA and thereby causing a translational block . Recent nef gene has been shown to target its own gene formation in an auto regulatory loop [Recently viruses have also been shown to express microRNAs ,5. Theseory loop ,9 which ory loop ,11, deriFurthermore, microRNAs expressed by other pathogenic viruses could also regulate host transcripts and thus play important roles in the pathogenesis of disease. Thus it is imperative to understand the entire repertoire of virus expressed microRNAs in order to unravel the mechanisms of pathogenesis of diseases caused by viruses and for designing novel therapeutic strategies against the virus .miRseeker, was used in the discovery of Drosophila expressed microRNAs [miRscan facilitated the discovery of C elegans microRNAs [ab-initio prediction of microRNAs.Computational methods  have beeicroRNAs  and miRsicroRNAs . These microRNAs  approachicroRNAs -19 as weicroRNAs ,4. WhileicroRNAs  but sharicroRNAs  This necViruses are dependent on the cellular biosynthetic machinery for the processing of microRNAs. Thus we hypothesize that sequence-structure features that differentiate true microRNA precursors from pseudo microRNA hairpins are critical for processing microRNAs. These features would be shared between host and viral microRNA precursors and thus help in the prediction of viral microRNAs. Moreover the microRNA processing mechanism is conserved across eukaryotes. This implies that sequence and structure features inherently unique or discriminative of microRNA precursors are also likely to be shared across eukaryotes.We hypothesize that our method can therefore predict microRNAs in other eukaryotic organisms as well as discover novel non-conserved microRNAs systematically missed by prediction methods which rely on evolutionary conservation of sequences.ab-initio microRNA prediction algorithms [Pan troglodytes and Mus musculus). The method does not perform better than other tools for Caenorhabditis elegans probably due to the difference in the base composition in the genome.This proposed method employs Support Vector Machine trained on sequence-structure feature elements for an efficient discrimination between microRNA precursor hairpins and pseudo microRNA hairpins. We have validated this approach for a number of known viral as well as Chimpanzee, Mouse and Worm microRNA precursors derived from public databases. We see that proposed method is more accurate than the recently reported gorithms ,23,24. Fab-initio prediction of microRNA precursors.In fact, a genome-wide analysis has been done on Herpes Simplex virus (HSV-1) and furthermore a recent independent study has experimentally validated a subset of the prediction ,11. ThesThe method is fast enough for genome-wide predictions even in larger genomes and can aid in the discovery of both novel non-conserved microRNAs and novel virus-expressed microRNAs.The models were created by taking a non overlapping random samples amounting to half of the positive and negative datasets for training and were evaluated on the remaining dataset. The process of model generation and testing is summarized in Fig andThe model which had maximum specificity was selected for further evaluation and comparison with other existing tools. We selected model with maximum specificity rather than sensitivity to cut down on false positive predictions that may arise from cross-species predictions. The performance of the best models is summarized in Table MicroRNA precursor sequences were downloaded from miRbase for three classes of human viruses with experimentally verified microRNAs, which include Epstein Barr virus (EBV), Cytomegalovirus (CMV) and Kaposi Sarcoma Herpes virus (KSHV). They had 23, 11 and 13 entries respectively. The model correctly predicted 22 out of the 23, 11 out of 13 and 10/11 of the microRNAs expressed by EBV, KSHV and CMV respectively. The comparisons of different programs are summarized in Table ab-initio microRNA prediction methods reported in literature, BayesmiRNAfind [The dataset of microRNAs expressed by viruses was tested on three newer iRNAfind , TripletiRNAfind  and mir-iRNAfind . We findWhile this manuscript was in preparation, new microRNA sequences have been reported for Herpes Simplex virus (HSV) latency associated transcript (LAT) ,11. The The results of the prediction are summarized in Table Pan troglodytes (Chimpanzee), Mus musculus (Mouse) and Caenorhabditis elegans (Worm). The number of miRNAs were 83, 341 and 115 respectively. Only experimentally validated sequences as annotated by miRbase was used for the analysis. We selected three organisms to test the efficacy of the method on datasets derived from evolutionarily distinct species. While Chimpanzee and mouse are evolutionarily closer mammals, worms are evolutionarily distant and have been used extensively for comparative genomics studies. We have compared our method with all three ab-initio prediction methods for these organisms.To validate the models, we compared our method with a recently published method employing SVM on a set of microRNA precursor sequences derived from miRbase for Average frequencies of the feature elements were compared between the positive set  and the negative set (pseudo microRNA hairpins) to derive the frequently occurring and infrequently occurring sets of features. 20 most frequent and infrequent features are plotted in Fig The finding shown in Figure ab-initio prediction of microRNA hairpins. Recently a number of ab-initio prediction methods for microRNAs have emerged, based on machine learning approaches. These include ProMiR [In the present study we demonstrate that incorporating sequence-structure triplet elements can be used for efficient e ProMiR , Bayesmie ProMiR , Triplete ProMiR  and mir-In the method proposed here, we strike a balance between sequence and structure elements by using chimeric feature elements encompassing nucleotides and their base-pairing states in the structure. We use the RBF kernel of SVM to create a function corresponding to the hyper-surface that optimally separates true and pseudo microRNA hairpins.Caenorhabditis elegans . This method could also be modified to predict microRNAs expressed by viruses with a host range by training on host-specific datasets . Further improvements can be achieved by taking other parameters like thermodynamic features [Though our method performs better than other methods reviewed for mammalian as well as virus expressed microRNA precursors, the other methods outperform our method in predicting microRNAs expressed by ns Table . This mafeatures  and posiab-initio prediction of microRNA hairpins. The algorithm is fast and efficient and can scale for genome-scale predictions not only on viral genomes, but also on much larger eukaryotic genomes.In summary we describe a novel method based on machine learning which performs better than recently reported methods for Human microRNA hairpin sequences were downloaded from miRbase (release The hairpin sequences for other eukaryotes were similarly derived from miRbase. The virus expressed microRNA hairpins for Epstein Barr virus (EBV), Cytomegalovirus (CMV), and Kaposi Sarcoma Herpes virus (KSHV) were also derived from miRbase. The two validated microRNA hairpin sequences from Herpes Simplex Virus Type I (HSV-1) were derived from the respective manuscripts ,11.We created a set of sequences of length 90 nt derived from coding regions of genes with no alternate transcripts. The coding sequences were batch downloaded from Ensembl   normalized to the total number of triplets possible for a particular sequence using in-house developed Perl scripts. RNAfold was used to determine the secondary structure of microRNA precursors.A set of about half the number of sequences in each dataset (positive and negative) was picked up randomly for training and the remainder formed the dataset for testing the model. Models were generated by creating one hundred such random samples and were evaluated simultaneously. The models were named by numbers which denoted the sample.Support Vector Machine is a supervised machine learning method for generating functions for training data and is based on statistical and optimizing theory. In the Support Vector Machine algorithm, the datasets belonging to different classes are tagged, encoded as feature vectors and are mapped onto a feature space by the kernel function, with the aim of seeking a function that defines a global hyper-plane that would optimally separate the classes of training vectors. Support Vector Machine has been popular for quite some time due to its ability to handle large datasets and large feature spaces.light. SVMlight is an implementation of the Vapnik's Support Vector Machine algorithm [light are described in [SVM was implemented using SVMlgorithm  originalribed in . The algThe implementation enables the user to define a number of parameters as well as to select from a choice of inbuilt kernel functions. We employed RBF kernel and used a grid search strategy varying combinations of penalty parameter C and the Radial Bias Function (RBF) kernel parameter \u03b3. The performance of each model was assessed based on specificity and sensitivity.Sequence structure features are known to play a critical role in microRNA processing . We emplThe feature content is calculated using the formulawhere (i) represents one of the 512 features.The method described in this paper is implemented as a web-based server SVM: Support Vector Machine; RISC: RNA Induced Silencing Complex; LAT: Latency associated transcript; EBV: Epstein Barr Virus; KSHV: Kaposi Sarcoma Herpesvirus; CMV: CytomegalovirusThe authors declare that they have no competing interests.VS formulated the idea. Data was collected by SK and resource was implemented by SK and FAA. All authors contributed to writing the manuscript."}
+{"text": "Patients with laryngeal lesions were observed and the lesions were recorded with anelectronic videoendoscope system using the PENTAX EPM-3300 video processor and thePENTAX VNL-1330 endoscope portion. The electronic videoendoscope system differsfrom the conventional fiberoptic endoscope connected to a video camera in that a smallmonochrome charge-coupled device (CCD) chip is built in the tip of the endoscope portion.The PENTAX VNL-1330 rhinolarynx endoscope portion has a tip and insertion tube ofapproximately 4mm in outer diameter to allow its introduction through the nasal passagesinto the larynx. The dynamic color images provided by this system were superior to thoseobtained by a conventional rhinolarynx flexible fiberscope connected to a video camera inboth quality and resolution of detail. This system should be useful in diagnosing laryngeallesions."}
+{"text": "With microarray technology becoming more prevalent in recent years, it is nowcommon for several laboratories to employ the same microarray technology to identifydifferentially expressed genes that are related to the same phenomenon in the samespecies. Although experimental specifics may be similar, each laboratory will typicallyproduce a slightly different list of statistically significant genes, which calls intoquestion the validity of each gene list (i.e. which list is best). A statistically-basedmeta-analytic approach to microarray analysis systematically combines results fromthe different laboratories to provide a single estimate of the degree of differentialexpression for each gene. This approach provides a more precise view of genesthat are of significant interest, while simultaneously allowing for differences betweenlaboratories. The widely-used Affymetrix oligonucleotide array and its software areof particular interest because the results are naturally suited to a meta-analysis.A simulation model based on the Affymetrix platform is developed to examine theadaptive nature of the meta-analytic approach and to illustrate the utility of suchan approach in combining microarray results across laboratories."}
+{"text": "Transforming growth factors have a wide range of biological activities related to cell proliferation and differentiation. In general TGF-alpha promotes cell proliferation while TGF-beta may stimulate or inhibit proliferation depending on the cell type and growth factor environment. Cultured human keratinocytes, skin and oral squamous cell carcinomas were analysed for the presence of transcripts and protein for the transforming growth factors alpha & beta. Both growth factors were detected in cultured keratinocytes (which have receptors for and respond to both ligands), and in medium conditioned by these cells. Additionally transcripts for TGF-alpha were found preferentially in the basal, proliferative compartment of cultured keratinocytes. Similarly both growth factors were detected in oral squamous cell carcinomas and a highly significant inverse correlation was found between the levels of TGF-alpha and the epidermal growth factor receptor in these tumours. The data for TGF-alpha are consistent with the existence of an autocrine growth control loop influencing cell proliferation in both a normal cell type and malignant epithelial tissues, a process that in keratinocytes and responsive squamous cell carcinomas could be modulated by TGF-beta."}
+{"text": "In this bioinformatics study we treat response to antiretroviral therapy as a two-body problem: response to therapy is considered to be a function of both the host and pathogen proteomes. We set out to identify potential responders based on the presence or absence of host protein and DNA motifs on the HIV proteome.The HIV viral genome mutates at a high rate and poses a significant long term health risk even in the presence of combination antiretroviral therapy. Current methods for predicting a patient's response to therapy rely on site-directed mutagenesis experiments and An alignment of thousands of HIV-1 sequences attested to extensive variation in nucleotide sequence but also showed conservation of eukaryotic short linear motifs on the protein coding regions. The reduction in viral load of patients in the Stanford HIV Drug Resistance Database exhibited a bimodal distribution after 24 weeks of antiretroviral therapy, with 2,000 copies/ml cutoff. Similarly, patients allocated into responder/non-responder categories based on consistent viral load reduction during a 24 week period showed clear separation. In both cases of phenotype identification, a set of features composed of short linear motifs in the reverse transcriptase region of HIV sequence accurately predicted a patient's response to therapy. Motifs that overlap resistance sites were highly predictive of responder identification in single drug regimens but these features lost importance in defining responders in multi-drug therapies.in vitro mutation experiments.HIV sequence mutates in a way that preferentially preserves peptide sequence motifs that are also found in the human proteome. The presence and absence of such motifs at specific regions of the HIV sequence is highly predictive of response to therapy. Some of these predictive motifs overlap with known HIV-1 resistance sites. These motifs are well established in bioinformatics databases and hence do not require identification via  HIV hIV virus . POL alsIV virus . The thiIV virus . MutatioIV virus .in vitro cultures of HIV infected immune cells have diminishing growth rates in the presence of antiretroviral therapy but eventually a resistant viral phenotype emerges [Most of the drugs that are currently used for controlling HIV infection target the three viral enzymes coded by the HIV POL gene. Antiretroviral drugs such as zidovudine (AZT), lamivudine (3TC), emtricitabine (FTC), zalcitabine (ddC), stavudine (D4T), didanosine (DDI) and nevirapine (NVP) target RT  whereas  emerges . The res emerges -16. Comb emerges -19. As a emerges .HAART therapies often reduce viral replication to undetectable levels. They decrease morbidity and mortality rates but nonetheless can be ineffective in some individuals ,22. SearIn this study, we first cluster patients into responder and non-responder categories based on viral load response to antiretroviral therapy. We then used stepwise logistic regression to differentiate responders and non-responders using linear sequence motifs common to host and viral genomes as features. We focused on viral load in the responder/non-responder classification because recent studies indicate that CD4 cell count monitoring does not accurately identify individuals with virologic failure among patients taking antiviral therapy . A novela priori information obtained via virus-specific in vitro cell assays. This type of a feature set is attractive, as it can be used to explore the drug response of viruses to antiviral therapy in the absence of extensive data on resistance mutations. Previous research on quantitative prediction of patient response to antiretroviral drugs in HIV infection [Another novel feature of our study is the treatment of drug response as a two body problem, namely that response to drugs is assumed to be affected by both the viral and host genotypes. We sought to identify linear motifs on the HIV sequence that are also found in the host and are functionally annotated: host transcription factor binding sequence motifs , miRNA bnfection -43 has eClinical annotation of more than 2,000 RT sequence samples in the Stanford HIV Drug Resistance database contained measurements of VL at six time points during the course of twenty-four week therapy. The drugs used in various single and combination therapies as well as the numbers of HIV-1 individuals taking the therapy are shown in Table The overlap between these three methods is shown in the Venn diagram in Figure Our results show that the HIV sequence, although highly variant in nucleotide sequence, expresses eukaryotic linear motifs (ELMs) that are largely conserved over hundreds of subtype B and subtype C sequences, as shown in Figure features. SWLR employs an iterative algorithm to determine which features should be included in the final logistic regression model [We used Step-Wise Logistic Regression (SWLR) to classify patients into responder or non-responder categories based on the presence or absence of ELMs, miRNA binding sites, TF binding sites, and resistance sites, collectively referred to as on model . In brieWe used SWLR in 500 iterations of training and testing at equal proportions for all responder/non-responder samples shown in Table The AUC values for all three phenotype classification methods are shown in Table The average number of regression coefficients (features) found significant over 500 training/testing iterations ranged from five to ten, depending on the drug regimens presented in Table One of the most consistent predictors of positive outcome across therapy regimens is the presence of ELM-Lig-SH3-3 Figure . This isThe two resistance sites and the ELMs that overlap them continue to be predictors of negative outcome in terms of response to subsets of antiretroviral therapies in phenotype classification based on incremental reduction of the VL  in stepwise logistic regression for 16 different combinations of antiretroviral drug regimens containing at least one drug against HIV reverse transcriptase. Responder phenotype was defined multiple ways to gain insights into drug response at 8 weeks (SD phenotype classification) and 24 weeks (BM phenotype classification) after the beginning of the therapy and somewhere in between (IR Phenotype classification). Host motifs that appear to be highly relevant to viral replication such as the transcription site binding motifs ,57 and ma priori information about how the HIV sequence would mutate in the presence of antiretroviral drugs. We were able to make accurate predictions without the resistance site information available in the literature. The input to our machine learning algorithm is simply the HIV sequence. We use publicly available bioinformatics tools to annotate these sequences with host motifs relevant to outcome. We then identify the motifs on the sequence that differentiate between responders and non-responders. These motifs can then be linked to specific viral host protein interactions and the pathways of these interactions. The promise of our approach will be fully explored with the availability of clinically annotated HIV whole genome sequences obtained at different time points during HAART therapy.Our approach to relate HIV sequence motifs to the course of infection does not require Linear binding motifs found in both the host and viral proteomes constitute a set of features highly predictive of response to therapy involving different combinations of antiretroviral drugs. Stepwise logistic regression as used here utilizes only the HIV-1 sequence and does not require annotations of resistance sites specific to various antiretroviral drugs. This study emphasizes finding sequence motifs which facilitate binding between viral and host proteins. This binding may allow the hijacking of host protein binding sites from their usual binding partners and thus alter the signalling pathways of the host cell. Our study points to competitive binding of HIV proteins to host proteins using motifs found in the host as the mechanism of interplay between the host and pathogen genotypes in dictating response to therapy. Our method is applicable to other viral infections where the viral sequence is known but resistance sites to antiviral therapies have not yet been documented. in order to get a motif expression map of the whole genome. As of 9/1/2006, this dataset consisted of 1,112 subtype B and 922 subtype C whole genome sequences, along with a smaller number of samples from other subtypes. This dataset also contained five reference sequences each for alignment of subtypes B and C.This study utilizes sequence and clinical data from two distinct sources. All whole genome HIV-1 sequences were downloaded from the Los Alamos HIV Sequence Database We used data from the Stanford HIV Drug Resistance Database  in orderWe focused on VL in the responder/non-responder classification  and exama priori-based resistance mutations. In order to evaluate the relative positions of nucleotide motifs and protein motifs on the same platform, we annotated the protein motifs back to their corresponding nucleotide positions. This could create some ambiguity since HIV has multiple overlapping reading frames. However, our clinical dataset only contained sequences from the RT region. We used a local BLASTx query [Our classification method uses the presence and absence of short linear motifs on the HIV genome. These motifs can be grouped into three basic types: eukaryotic linear motifs (ELMs), nucleotide-based motifs and Tx query  on a dat\u00ae database as of 11/14/08 [The first feature group consisted of ELM ligation sites and subcellular targeting sequences. These were identified on HIV-1 protein amino acid sequences using the ELM webserver tool . The web11/14/08 . We requ11/14/08 . For the11/14/08 . As of 111/14/08  and the 11/14/08 . Any bin11/14/08 . In orde11/14/08 .We used stepwise logistic regression (SWLR) to assess the potential of the extracted short linear sequence features along the RT sequence in differentiating between responders and non responders . SWLR waSWLR algorithm was applied to differentiate responders from non-responders in three different assignments of the phenotype for 500 iterations of 2-fold cross validation. Since the efficiency of the SWLR algorithm is sensitive to the class composition of the training data  we ensurThe authors declare that they have no competing interests.WD wrote the manuscript with AT and performed the analysis with PE. LU provided technical insight. All authors approved the final manuscript.The pre-publication history for this paper can be accessed here:Source Code. All python and MATLAB code required to produce the figures and tables shown in the manuscript. Documentation and unit-tests are provided to facilitate their usage.Click here for file"}
+{"text": "Isotretinoin was quantitated by high-pressure liquid chromatography in plasma and lung tissue. The ratios of mean area of concentration-vs-time curve (AUC) values in the lungs over mean AUCs in the plasma for isotretinoin following single or repeated aerosol exposure surpassed those determined for the oral route by factors of between two (single low-dose) and five (single high-dose). Similarly, the equivalent ratios for the maximal peak concentrations in lungs and plasma obtained after aerosol exposure consistently exceeded those seen after oral administration, suggesting that lungs were exposed to higher isotretinoin concentrations after aerosol inhalation than after oral administration of similar doses. Repeated high doses of isotretinoin by inhalation resulted in moderate loss of body weight, but microscopic investigation of ten tissues including lung and oesophagus did not detect any significant aerosol-induced damage. The results suggest that administration of isotretinoin via powder aerosol inhalation is probably superior to its application via the oral route in terms of achieving efficacious drug concentrations in the lungs. \u00a9 2000 Cancer Research CampaignRepeated oral administration of chemopreventive retinoids such as isotretinoin over extended periods of time is associated with intolerable systemic toxicity. Here isotretinoin was formulated as a powder aerosol, and its delivery to the lungs of rats was studied with the aim to explore the possibility of minimizing adverse effects associated with its oral administration. Rats received isotretinoin orally (0.5, 1 or 10 mg kg"}
+{"text": "Urethral duplication (UD) is rare congenital anomalies with varied presentation. Careful clinical evaluation of children by specialist would enhance diagnosis, adequate management and reduce occurrence of complication. We present a 12-year-old boy with chronic post circumcision ventral penile sinus that was successfully managed for urethral duplication. Urethral duplication (UD) is a rare congenital anomaly with varied clinical presentations and treatment. The embryologic development of UD is still poorly understood and theories have shown that it is due to cloaca membrane/genital tubercle and urogenital sinus anomalies.All patients should be thoroughly evaluated because of strong association with other congenital anomalies and significant surgical management challenge this may present which may lead to unpredictable outcome.3We report a case of incomplete UD in a 12-year-old boy who presented with a post-circumcision penile sinus.A 12-year-old boy who presented with recurrent sero-mucoid discharge from a wound on the ventral surface of the penis. This occurred post circumcision done at home by a \u2018nurse\u2019 on the sixth day of live because of a distal penile swelling. Pregnancy and delivery were uneventful. The wound refused to heal in spite of repeated dressings and use of antibiotics. He had good urinary stream and normal developmental milestone. No history of recurrent urinary tract infections. He was a healthy looking young boy with adequate penile size; there was an ulcer with a background sinus and serous fluid discharge from it . The ureet al.[et al.[The occurrence of UD presents a great challenge in its identification and management because of its rarity and its variants.5 A littlet al. from Niget al. describel.[et al. classifiIn spite of warnings to practitioners against circumcision in cases of congenital abnormalities of the penis especially in cases of hypospadias and epispadias, this patient had his circumcision done within the first week of live because of the abnormal swelling noticed on the ventrum of the distal penile /preputial skin which left a residual sinus. In our environment, circumcision practice is by the untrained  and junior cadre health workers usually in late childhood between 5 and 12 years when children are gathered in groups for them to be initiated into manhood.The differential diagnoses are congenital anterior urethrocutaneous fistula, excised The danger in poor demonstration of tract is the possibility of inadequate and improper preparation for surgery leaving a residual tract or damage to adjoining tissues. Paediatric urethrocystoscopy for better definition of the UD was not available at our centre. Antibiotic and wound dressing treatment are ineffective, and other treatment such as diathermocoagulation or the injection of caustic substance into the accessory duct have been condemned and abandoned. The surgIn conclusion, urethral duplication, though rare, have good prognosis if adequately managed. Pre-emptive circumcision should be avoided in patients with any penile malformation and patient should be referred to a trained surgeon."}
+{"text": "This study investigated the modulation of type I collagen gene expression in normal fibroblasts by breast tumour cells. Northern analysis of total RNA extracted from stages I, II and III breast tumour tissue revealed that collagen mRNA levels were elevated in stage I tumours compared to the adjacent normal breast tissues, whereas they were decreased in stages II and III breast tumours. This aberrant collagen gene expression was confirmed by non-radioactive RNA:RNA in situ hybridization analysis of 30 breast carcinomas which localized the production of type I collagen mRNA to the stromal fibroblasts within the vicinity of the tumour cells. In order to determine whether the tumour cells were directly responsible for this altered collagen production by the adjacent fibroblasts, breast tumour cell lines were co-cultured with normal fibroblasts for in vitro assessment of collagen and steady-state collagen RNA levels. Co-culture of tumour cells and normal fibroblasts in the same dish resulted in down-regulation of collagen mRNA and protein. Treatment of the fibroblasts with tumour-cell conditioned medium also resulted in decreased collagen protein levels but the mRNA levels, however, remained unaltered. These results suggested that the tumour cells either secrete a labile \u2018factor\u2019, or express a cell surface protein requiring direct contact with the fibroblasts, resulting in down-regulation of collagen gene expression. Modulation of the ECM is a common characteristic of invading tumour cells and usually involves increased production of collagenases by the tumour cells or stromal fibroblasts. This study showed that tumour cells were also able to modulate collagen mRNA production by stromal fibroblasts, which may facilitate tumour cell invasion and metastasis. \u00a9 1999 Cancer Research Campaign"}
+{"text": "The Quality Enhancement Research Initiative (QUERI) is a unique quality improvement program designed to connect health services researchers to Veterans Health Administration (VHA) management and operations, as well as to provide the science and initiative for making change. Through this process, QUERI stakeholders have learned that success and impact in improving healthcare quality and outcomes largely depends on coordination and collaboration among numerous VHA programs and organizations working to develop and implement evidence-based clinical policies, practices, and quality improvement strategies. This Commentary discusses some of these collaborative efforts and perceived successes in achieving common goals from the viewpoints of two closely involved VHA Operations/Support stakeholders.Series of articles documenting implementation science frameworks and tools developed by the U.S. Department of Veterans Affairs Quality Enhancement Research Initiative (QUERI).The Commentary is part of a  In 1998, the U.S. Department of Veterans Affairs (VA) created the Quality Enhancement Research Initiative (QUERI)\u2013a bold step into uncharted territory called \"implementation research,\" representing a new path toward healthcare quality improvement (QI) , the most striking feature of TIDES was the assistance provided by the research team in implementing system changes. QUERI researchers took staff step-by-step through the process of developing this program and provided education, assistance in hiring people, as well as measurement tools. This resulted in a very effective demonstration of how to appropriately implement and successfully make what was literally a profound change in the culture of how best to treat depression among veterans. A national roll-out effort is now being planned, and involves development of the close type of collaboration between QUERI researchers and operational stakeholders recognized in this commentary as essential to success .In summary, from our viewpoint as VA managerial leaders closely aligned with QUERI, there are multiple examples of how QUERI has influenced the VA healthcare system, both directly and indirectly. In addition to those noted above:\u2022 Chronic Heart Failure (CHF) QUERI reduced readmission rates for veterans with chronic heart failure by up to 10% in one VA network.\u2022 IHD-QUERI improved lipid management for veterans with ischemic heart disease that translates into a commensurate reduction of about 75 coronary events over two years in one VA network.\u2022 MH-QUERI increased the appropriate use of antipsychotics for veterans with schizophrenia that has led to a 10% decrease in costs of these drugs in one VA network.\u2022 SUD-QUERI increased access to effective opioid agonist therapy for veterans with opioid dependence by 20%.The partnership between QUERI and other VA operational offices has resulted in successful development, implementation and evaluation of various evidence-based practices across the VA healthcare system. These efforts have helped to begin institutionalization of a cycle of quality improvement that can create a visible increase in the demonstrated quality of care through the effective implementation of evidence-based practice in routine care.Because of the collaborative efforts between research and operations, we can cite several such quality improvement efforts in the diverse QUERI disease areas. To date, QUERI Centers have identified the research evidence and developed quality improvement interventions that have been implemented at VA's facility level, regional level, and even across regions. The next phase \u2013 system-wide national rollout \u2013 will be more challenging but will continue to require the collaborative efforts of many VA healthcare stakeholders.QUERI has formed, and will continue to form the collaborative relationships necessary to address this challenge. The overarching goal remains the same: To systematically implement evidence-based practice across a large integrated healthcare systemTJC and RP participated in all phases of development and revision of this manuscript. Both authors read and approved the final manuscript. The views expressed in the article are those of the authors, who are responsible for its contents, and do not necessarily represent the views of the U.S. Department of Veterans Affairs."}
+{"text": "Five out of 18 primary explants of human carcinomata obtained at operation have been grown progressively for a minimum of one month in thymectomized, x-irradiated mice reconstituted with syngeneic bone marrow and subsequently treated also with anti-thymocyte serum. All the tumours which proliferated were of gastrointestinal origin, growing locally but not metastasizing although direct invasion of the ribs occurred in one case. No implanted breast carcinomata grew in this system."}
+{"text": "Lymphangiosarcoma following breast cancer is a relatively rare entity, with around 300 cases so far reported worldwide. Affecting the long term survivors of breast cancer, lymphangiosarcoma (Stewart-Traves Syndrome) has a high mortality rate. Since lympedema following radical mastectomy or axillary clearance and radiotherapy seems to be the main predisposing factor, further research regarding modifications in the surgical technique of axillary nodes dissection as well as the development of new chemotherapeutic agents effective in lymphangiosarcoma are required. Lymphangiosarcoma following breast cancer is a rare entity. Around 300 cases have been reported worldwide since Stewart-Traves syndrome characterized by angio sarcoma of skin and soft tissue of the area after Radical Mastectomy, Radiation and Lymphedema . Its incA 74-year-old lady with a history of hypertension and known case of breast cancer presented to our clinic with a swelling of the left proximal arm for the past three years. Patient was of Punjabi by ethnicity and was a Pakistani national.She had under gone a modified radical mastectomy (MRM) 16 years ago in 1990 for infiltrating ductal carcinoma of the left breast, received 25 fractions of radiotherapy, followed by Tamoxifen for five years. The patient had a history of gradual increase in the size of the swelling upper arm and complained of non-radiating, mild to moderate pain with appearance of nodular lesions along antero medial aspect of upper arm ; that haCurrently there are 2 million breast cancer survivors in the United States alone and 20% of them suffer from Breast Cancer Related Lymphedema . AdvanceStrategies to decrease chronic lymphedema include manual and sequential pneumatic lymphatic compression ,16, periStewart-Traves syndrome is a rare entity with poor response to chemo therapy. Awareness about the pathology and its preceding sign & symptoms among both physicians and breast cancer survivors will ensure regular long term follow up resulting in an early diagnosis. Since lympedema following radical mastectomy or axillary clearance and radiotherapy seems to be the main predisposing factor, further research regarding modifications in the surgical technique of axillary nodes dissection as well as the development of new chemotherapeutic agents effective in Lymphangiosarcoma are required."}
+{"text": "Pathogens have evolved diverse strategies to maximize their transmission fitness. Here we investigate these strategies for directly transmitted pathogens using mathematical models of disease pathogenesis and transmission, modeling fitness as a function of within- and between-host pathogen dynamics. The within-host model includes realistic constraints on pathogen replication via resource depletion and cross-immunity between pathogen strains. We find three distinct types of infection emerge as maxima in the fitness landscape, each characterized by particular within-host dynamics, host population contact network structure, and transmission mode. These three infection types are associated with distinct non-overlapping ranges of levels of antigenic diversity, and well-defined patterns of within-host dynamics and between-host transmissibility. Fitness, quantified by the basic reproduction number, also falls within distinct ranges for each infection type. Every type is optimal for certain contact structures over a range of contact rates. Sexually transmitted infections and childhood diseases are identified as exemplar types for low and high contact rates, respectively. This work generates a plausible mechanistic hypothesis for the observed tradeoff between pathogen transmissibility and antigenic diversity, and shows how different classes of pathogens arise evolutionarily as fitness optima for different contact network structures and host contact rates. Infectious diseases vary widely in how they affect those who get infected and how they are transmitted. As an example, the duration of a single infection can range from days to years, while transmission can occur via the respiratory route, water or sexual contact. Measles and HIV are contrasting examples\u2014both are caused by RNA viruses, but one is a genetically diverse, lethal sexually transmitted infection (STI) while the other is a relatively mild respiratory childhood disease with low antigenic diversity. We investigate why the most transmissible respiratory diseases such as measles and rubella are antigenically static, meaning immunity is lifelong, while other diseases\u2014such as influenza, or the sexually transmitted diseases\u2014seem to trade transmissibility for the ability to generate multiple diverse strains so as to evade host immunity. We use mathematical models of disease progression and evolution within the infected host coupled with models of transmission between hosts to explore how transmission modes, host contact rates and network structure determine antigenic diversity, infectiousness and duration of infection. In doing so, we classify infections into three types\u2014measles-like , flu-like , and STI-like . There are two major principles by which pathogens avoid their elimination: escaping the host immune response via antigenic variation or immune evasion, or transmission to a new immunologically naive host. Directly transmitted pathogens which cause chronic diseases, such as many sexually transmitted infections (STIs), tend to rely more on the former, while many acute infections, for instance measles, rely more on high transmissibility. Indeed pathogens such as measles show very little antigenic diversity, with immune responses being strongly cross-reactive between strains. There are then those pathogens which have intermediate levels of both immune escape and transmissibility \u2014 such as influenza, rhinovirus and RSV (here referred to as FLIs \u2014 flu-like infections).The evolutionary success of directly transmitted pathogens can also be seen to depend on the nature, frequency and structure of contacts between hosts. Infections transmitted to a small number of hosts  via intense contact  are usually caused by pathogens of high antigenic diversity and long duration of infection, while those transmitted via casual contact  with a large number of hosts may typically have lower diversity and much shorter durations of infection. While many of the evolutionary constraints are different It is straightforward to explain the long duration of infection and consequent antigenic diversity of sexually transmitted or blood-borne infections: the frequency of relevant contacts between hosts is low, meaning infection needs to be extended to ensure the reproduction number  must be positively correlated with infectiousness. A first-pass analysis might therefore postulate that overall transmissibility  of the work presented here is that while we might expect pathogens to be able to evolve to reduce (or increase) We will show that there is a critical value of Our approach is to construct a model of within-host pathogen dynamics which incorporates adaptive host immunity and antigenic diversification. The key output from this model is how pathogen load varies through time during an infection. We then calculate the basic reproduction number, The within-host model developed here is an extension of a model studied earlier by one of us We use We do not explicitly consider how a pathogen could evolve its biological characteristics to maximize transmission fitness (i.e. the evolutionary trajectory a pathogen would take through parameter space). There are undoubtedly many constraints on the possible paths which pathogens can take The multi-strain model used extends past work The dynamics of the model is characterized by an initial period of exponential growth of the pathogen load, which eventually slows due to immune responses and resource limitations. One observes a latency period and an initial peak. Pathogen load then declines exponentially. If the trough load of a pathogen strain drops below a threshold level we assume the pathogen is eliminated from the host . However if a novel strain emerges before the seed strain goes extinct, pathogen load can recover, so long as there is sufficient resource available and cross-immunity is not too strong \u2014 leading to a second, albeit lower peak in pathogen load. Further peaks in pathogen load can occur via the same mechanism. The rate at which new strains arise is the most important determinant of the number of pathogen load peaks seen and thus the overall duration of infection. Less intuitively, this rate also determines the size of the initial peak (discussed below).Since mutation is modeled stochastically, we average over multiple realizations e.g.  of the mpathogen parameter space, in which evolutionarily favored pathogens are represented by points that are associated with maximal fitness values.We systematically calculate average pathogen load curves from the within-host model for wide ranges of two biological parameters: the antigenic mutation rate From the discussion in the introduction, we can immediately identify the cumulative pathogen load and duration of infection as epidemiologically relevant quantities. The within-host dynamics generate a tradeoff between initial peak pathogen load and antigenic diversity: high initial peak load corresponds to low diversity and vice-versa see . Long dutransmission space. The other two define properties of the contact network between hosts: the replacement rate of neighbors contact space.To calculate the reproduction number , we model a dynamic contact network in the neighborhood of one initially infected host. The profiles of pathogen load over time obtained from the within-host model then determine the infectiousness of the infected host to its neighbors.  Epidemiological dynamics are determined by 4 parameters. Two of these relate to properties of the transmission route: the infectiousness parameter We build a model cf.  incorporVarying the 4 parameters of transmission and contact space, we obtain three different classes of fitness landscapes over pathogen space \u2014 as represented by There are clear similarities between the three classes of fitness landscapes  and the Varying the infectiousness parameter  surface , while f surface ; cf. (7) surface  in whichVarying the transmission and contact space parameters more systematically, one can map out the regions of parameter space for which particular infection types are optimal . This shSo far we have assumed only the pathogen space parameters  and sexually transmitted diseases show substantial diversity. Addressing this question requires consideration of how evolvable parameters governing the natural history of infection within a host affect the transmission characteristics of a pathogen in the host population.We developed a relatively simple multi-strain model of the within-host dynamics of infection. Pathogen particle consume resource to replicate, and their replication is inhibited by a dynamically modeled immune response with two components: strain-specific immunity, and cross-immunity. Cross-immunity was assumed to be the key fitness cost of antigenic diversity within the host; the benefit is a much enhanced duration of infection (and thus transmission). Pathogens which have a low rate of generating new antigenic variants are cleared from the host much faster than those with a high rate of antigenic diversification, but also maximize the initial peak level of parasite load reached prior to clearance cf. .The second evolvable within-host parameter we considered was the within-host pathogen replication rate. Given the resource-dependent model of replication assumed, this has a more limited effect than in some models, but can set the timescale for pathogen load to initially peak and thus determine the effective latent period of the disease.At the between-host level, we assume a simple relationship between pathogen load and infectiousness which has been shown to be appropriate to model HIV transmissibility The final element we incorporate into the framework developed is contact between hosts, assumed to occur at some rate Putting these elements together, we found that optimizing reproductive fitness in this way leads to well-defined infection types A, B, C, as contact rates (and reproductive numbers) increase cf. . Type A Infection type C represents childhood diseases with the highest values of The limited antigenic diversity and short infectious periods of type C pathogens are determined by the higher infectiousness threshold and the consequent need to maximize the peak pathogen load attained early in infection. When contact rates are high, the increase in duration of infection resulting from higher rates of antigenic diversity is insufficient to compensate for the reduction in peak pathogen load (and therefore infectiousness) caused by cross-immunity being generated against multiple pathogen strains simultaneously. A single strain pathogen generating a single immune response is able to generate a larger primary infection peak \u2014 though at the cost of being unable to sustain infection further.It is encouraging to see that the classification of infection types our model predicts closely corresponds to many of the pathogen regimes identified in other work Furthermore, it is interesting to note that in the context of our model only the concept of a minimal infectiousness threshold \u2014 introduced to characterize transmission modes \u2014 is necessary to explain the findings of The key limitation of our analysis is our highly simplified treatment of between-host transmission \u2014 namely using a network-corrected reproduction number as our measure of strain fitness. Doing so assumes evolutionary competition occurring in infinite (non-evolving) host populations in infinite timescales. It would clearly be substantially more realistic to explicitly simulate the transmission process in a large host population. The computational challenges are considerable \u2014 while large-scale simulations of influenza A evolution and transmission have been undertaken However, continuing advances in computing performance mean that it may now be feasible to explicit model multiple strains evolving within hosts and being transmitted independently in a large population. Such an approach would allow exploration of the relationship between antigenic diversity (and cross-immunity) within single hosts and strain dynamics at a population level. Perhaps even more importantly, it would allow extinction processes to be properly captured, while our current approach implicitly assumes fixation probabilities to be 1 even when fitness differences are marginal. Proper representation of finite population sizes and extinction will also allow the evolutionary emergence of childhood diseases (such as measles) as a function of early urbanization to be modeled.A second limitation is that we only consider a single, highly simplified within-host model. Future work to test the sensitivity of our results to the choice of within-host model would be valuable  or hijacking the immune system (HIV) \u2014 the model only reflects tradeoffs which may have contributed to pathogens adopting the range of persistence strategies seen in nature. An interesting addition to future work would also be the incorporation of pathogen virulence A last area which is a clear priority for future research is the relationship between within-host parasite load and infectiousness. We have assumed a relationship which has some support in data , and indThe within-host dynamics are simulated by the following system of ordinary differential equations , which links pathogen replication to two inhibitors \u2014 host immunity and resource limitation. This equation quantifies the tradeoff for increasing antigenic diversity  \u2014 namely the smaller initial pathogen load peak seen in and other strains, and can thus lower the total pathogen load. This result is largely independent of model implementation and only depends on the strain-specific immune response being generated at relatively low strain-specific pathogen loads, and being sufficiently cross-reactive to slow overall growth of pathogen load.Let us consider the pathogen load dynamics soon after infection with one initial strain. Our numerical simulations have shown that the initial strain This verbal argument can be formalized. For simplicity we assume the load of the initial strain is a good approximation of the total pathogen load at the initial peak, As a consequence of resource limitation  of our between-host model, which also illustrates how the two parameters, The transmission dynamic in an initially entire susceptible contact neighborhood of one index case and fixed size, Written exclusively in terms of susceptibles (while utilizing the notion of convolution), (9) readsText S1In this appendix we present an extension of our within-host model regarding the implementation of cross-immunity. We include the acquisition of immunity from antigenically similar strains and re-calculate (0.41 MB PDF)Click here for additional data file."}
+{"text": "Acetabular fractures still are among the most challenging fractures to treat because of complex anatomy, involved surgical access to fracture sites and the relatively low incidence of these lesions. Proper evaluation and surgical planning is necessary to achieve anatomic reduction of the articular surface and stable fixation of the pelvic ring. The goal of this study was to test the feasibility of preoperative surgical planning in acetabular fractures using a new prototype planning tool based on an interactive virtual reality-style environment.7 patients ) with an acetabular fracture were prospectively included. Exclusion criterions were simple wall fractures, cases with anticipated surgical dislocation of the femoral head for joint debridement and accurate fracture reduction. According to the Letournel classification 4 cases had two column fractures, 2 cases had anterior column fractures and 1 case had a T-shaped fracture including a posterior wall fracture.The workflow included following steps: (1) Formation of a patient-specific bone model from preoperative computed tomography scans, (2) interactive virtual fracture reduction with visuo-haptic feedback, (3) virtual fracture fixation using common osteosynthesis implants and (4) measurement of implant position relative to landmarks. The surgeon manually contoured osteosynthesis plates preoperatively according to the virtually defined deformation. Screenshots including all measurements for the OR were available.The tool was validated comparing the preoperative planning and postoperative results by 3D-superimposition.Preoperative planning was feasible in all cases. In 6 of 7 cases superimposition of preoperative planning and postoperative follow-up CT showed a good to excellent correlation. In one case part of the procedure had to be changed due to impossibility of fracture reduction from an ilioinguinal approach. In 3 cases with osteopenic bone patient-specific prebent fixation plates were helpful in guiding fracture reduction. Additionally, anatomical landmark based measurements were helpful for intraoperative navigation.The presented prototype planning tool for pelvic surgery was successfully integrated in a clinical workflow to improve patient-specific preoperative planning, giving visual and haptic information about the injury and allowing a patient-specific adaptation of osteosynthesis implants to the virtually reduced pelvis. Acetabular fractures still are among the most challenging fractures to treat because of complex anatomy, involved surgical access to fracture sites and the relatively low incidence of these lesions , resultiThe ilioinguinal and the posterior Kocher-Langenbeck approaches with or without surgical hip dislocation are the most commonly used operative approaches for the treatment of pelvic and acetabular fractures -5. In 19Today high scanner speeds and diagnostic accuracy superior to other modalities has made computed tomography (CT) imaging the standard for evaluation of blunt trauma to the pelvis ,14. MultDuring the last years a few preoperative planning tools specific to acetabular fractures have been developed, leveraging advances in radiology and computer technology. Cimerman et al. reported favorable results in the preoperative planning of pelvic and acetabular fracture reduction and osteosynthesis using a commercially available tool with a mouse-based interface comparable to Computer-Aided Design (CAD) software . The surThe goal of this study was to test the feasibility of preoperative surgical planning in acetabular fractures using a new prototype planning tool based on an interactive virtual reality-style environment, including fracture reduction, fixation and measurement.From June 2007 to March 2008 7 patients  with a median age of 53 y (range: 25 to 92 y) were prospectively included Table . InclusiAll patients underwent a whole body CT scan  on the day of admission according to standardized trauma protocol. Near-isotropic axial-oriented CT images with a slice thickness of 1 mm were reconstructed using a bone kernel for sharp depiction of bone fragment edges. Data were transferred to a picture archiving and communication system .A commercially available software package  was used for semiautomatic segmentation of the pelvic bones and fracture fragments. Pelvic bone and bone fragment surfaces were extracted using the Generalized Marching Cubes algorithm , generat\u00ae Developer Kit  for haptic rendering. It runs on a commercially available personal computer running Microsoft Windows. For haptic user interaction we chose the relatively low-cost PHANTOM Omni\u00ae Haptic Device allowing for 6 degrees of freedom positional sensing (translation and rotation) as well as 3 degrees of freedom positional force feedback (only translation). In addition an implemented stereo rendering using a stereoscopic monitor  was implemented  in preparation for the fracture fixation planning done by the surgeon (M.K.). Nevertheless the surgeon was able to experiment with fracture fragment reduction to gather information about spatial relations of the fragments.In a second step the planning system allows the adaptation of appropriate osteosynthesis implants onto the reduced virtual pelvis. The user first draws a sketch of the desired plate placement directly onto the bone surface using the haptic device cursor. The system then automatically contours the tetrahedral model of a reconstruction plate of a user-selected type onto the virtual bone surface according to this sketch. Thereafter the user can place screws of different lengths either through plate holes at angles restricted by the type of implant or freely into the pelvic bone. Figure Measurements like angles and lengths in 3D space were taken in relation to specific landmarks visible or palpable on the pelvic bone during the operation. Finally a report was generated including relevant screenshots, executed measurements, type and size of osteosynthesis implants as well as bending and torsion angles of fixation plate segments in all three planes. The surgeon (M.K.) used this information to manually contour osteosynthesis implants preoperatively according to this report. Additional screenshots were exported to the PACS and loaded on a screen in the OR as necessary.Time needed for building the patient-specific models from CT datasets, for virtual fracture reduction and fixation as well as the operative time was measured. In all patients a follow-up CT was performed 2 to 4 days after surgery. Congruence of the acetabular joint surface was determined according to Matta : displacQualitative visual analysis of the accuracy of internal fixation was done by means of hybrid renderings of the postoperative CT and respective preoperative planning, after manually registering the pelvic bones into the same space. Placement of osteosynthesis implants was then compared on these renderings.According to the Letournel classification  there weThe segmentation of the fracture was the most time consuming part of the preoperative planning. Part of the segmentation had to be performed manually due to a large number of fracture fragments in 6 patients and osteopenic bone or severely impacted fragments in 3 patients. The median time needed to segment the osseous parts of an entire pelvis and to extract a surface model was 130 minutes (range 83 to 221 minutes).Compared to a standard CAD-style mouse-based user interaction the haptic device integrated in our setup allowed a more direct and intuitive manipulation of fracture fragments. Median time of 8 minutes (range 6 to 15 minutes) was measured for fracture reduction by a trained user (J.F.).A Stoppa approach combined with the first window of the ilioinguinal approach was planned and executed in five cases and an ilioinguinal approach in one case. In one case a combined Stoppa and posterior approach was planned and executed Table . The plaIn case 6 Figure , 5 and 6Special attention was given to complement conventional internal fixation with percutaneous screw fixations. For example fixation of a posterior column fracture after reduction from an anterior approach was performed, avoiding an additional posterior approach. In one case percutaneous screw fixation of the posterior column (case 3) and in three cases of the dome of the acetabulum was successfully planned and performed . In case 4 complementary screw fixation of the acetabular dome after a both column fracture was performed Figure  and 10.Prebent fixation plates were used in all cases. In four cases  with severely comminuted injuries to the pelvis this tremendously helped in guiding the fracture reduction.Comparing the postoperative follow-up CT scans to respective preoperative planning, a good correlation was found in six of seven cases. The remaining case (case 5) partially failed due to the impossibility to reduce the fracture in the planned manner.Postoperative congruence of the acetabular joint surface as determined according to Matta  in the fWe found no serious postoperative complications such as deep infections or failure of osteosynthesis implants. Analysis of functional outcome, for example occurrence of posttraumatic osteoarthritis of the hip joint, has not been included in this study because of the absence of long-term follow-up.Acetabular fractures are severe injuries, often occurring in polytrauma patients as a result of a high-energy trauma such as motor vehicle accidents or falls from a height . Less ofAnatomic reduction of the acetabulum and stable fixation are primary goals in acetabular trauma surgery. Open reduction and internal fixation with several available approaches -5,7,8 reDefinitive treatment with open reduction and internal fixation typically is performed three to five days after the injury to prevent excessive bleeding that can be found in acute pelvic surgery . This imCimerman et al. introduced a surgical planning software for pelvic and acetabular fractures with a mouse-based CAD-style interface . In contThe emphasis in designing the presented tool was not on execution of a surgical technique, but on supporting the preoperative surgical planning. The developed planning software consists of three consecutive steps: virtual fracture reduction and internal fixation using patient-specific CT data as well as measurement and documentation.The tool enabled fast and reliable virtual fracture reduction. Interactive manipulation of the fracture fragments gave the surgeon insight into their spatial relation and helped in choosing the operative approach. Citak et al. showed that virtual planning of acetabular fracture reduction helps in understanding the fracture morphology and leads to more accurate and efficient reductions .Virtual internal fixation allowed contouring models of osteosynthesis implants currently used at our hospital to the reduced pelvis. According to measured bending and torsion angles between plate segments the surgeon could bend the fixation plates preoperatively. The use of prebent fixation plates adjusted to the patient-specific anatomy and fracture pattern was found to be extremely helpful in guiding fracture reduction especially of severely comminuted acetabular injuries, pushing the fracture fragments into their anatomic position while tightening the screws.Finally the tool also supported us in planning minimally invasive percutaneous screw fixations in selected fracture patterns. Screws should be placed as perpendicular as possible to the fracture plane while maintaining a safe distance to the hip joint. To enable the most accurate application of minimally invasive planning in the operating room, different measurements like angles and lengths in 3D space were taken in relation to specific landmarks visible or palpable on the pelvic bone.In this study, the planned fracture fixation was followed completely in six cases and partially in one case with a good to satisfactory radiographic result according to Matta  in all cA first limitation of this study is the limited number of patients. Also due to the variability of injury patterns, it is difficult to make definite quantitative conclusions. This study therefore only is able to show initial experiences and a larger patient population is requested to further assess the presented tool.A second limitation is the time-consuming segmentation of the pelvic bones and fracture fragments for the generation of the patient-specific models, requiring manual refinements especially in osteopenic bone or severely impacted fractures. In this study, segmentation was performed by a radiologist but could also be performed by a trained technician or surgeon. In addition, further developments in segmentation algorithms will accelerate or even automate this task.As a final limitation, we did not simulate interfering soft tissues with the current design of the presented tool. Soft tissue structures like muscles and tendons inserting into pelvic bones, blood vessels and pelvic organs were not modelled. In reality these structures interfere with fracture reduction and narrow down the working space or can even render a desired fracture fixation impossible.In conclusion, the presented prototype software tool for surgical planning of acetabular fractures gives visual and haptic information about the injury and allows a patient-specific adaptation of osteosynthesis implants to the virtually reduced pelvis. Manual prebending of fixation plates according to the procedure plan can guide fracture reduction especially in severely comminuted injuries.In future the coupling of the presented planning tool with an intraoperative guiding system will be planned, enhancing the transfer of the surgical planning into the operating room.In addition the information of the shape of the planned plate can be exported in STL-format enabling to order a prebent plate from dedicated companies.The authors declare that they have no competing interests.JF designed the study and programmed the software. MK carried out the read-out and recruited the patients. MH participated in programming the software. BM and GS edited the manuscript and participated in the study design. TF conceived the study, participated in its design, wrote and edited the manuscript. All authors read and approved the final manuscript.Workflow. Demonstration of the entirely process, including fracture reduction and fixation.Click here for file"}
+{"text": "Treatment of arterial bifurcation lesions using drug-eluting stents (DES) is now common clinical practice and yet the mechanisms governing drug distribution in these complex morphologies are incompletely understood. It is still not evident how to efficiently determine the efficacy of local drug delivery and quantify zones of excessive drug that are harbingers of vascular toxicity and thrombosis, and areas of depletion that are associated with tissue overgrowth and luminal re-narrowing.We constructed two-phase computational models of stent-deployed arterial bifurcations simulating blood flow and drug transport to investigate the factors modulating drug distribution when the main-branch (MB) was treated using a DES. Simulations predicted extensive flow-mediated drug delivery in bifurcated vascular beds where the drug distribution patterns are heterogeneous and sensitive to relative stent position and luminal flow. A single DES in the MB coupled with large retrograde luminal flow on the lateral wall of the side-branch (SB) can provide drug deposition on the SB lumen-wall interface, except when the MB stent is downstream of the SB flow divider. In an even more dramatic fashion, the presence of the SB affects drug distribution in the stented MB. Here fluid mechanic effects play an even greater role than in the SB especially when the DES is across and downstream to the flow divider and in a manner dependent upon the Reynolds number.The flow effects on drug deposition and subsequent uptake from endovascular DES are amplified in bifurcation lesions. When only one branch is stented, a complex interplay occurs \u2013 drug deposition in the stented MB is altered by the flow divider imposed by the SB and in the SB by the presence of a DES in the MB. The use of DES in arterial bifurcations requires a complex calculus that balances vascular and stent geometry as well as luminal flow. Drug-eluting stents (DES) are now the primary choice for percutaneous coronary interventions \u2013 implanted in millions of patients Arterial drug distribution patterns become challenging to analyze if the lesion involves more than a vessel such as in the case of bifurcations. Indeed, there is no consensus on best stent placement scenario We employed three-dimensional (3D) two-phase steady-state computational models simulating the impact of luminal flow and drug transport through the solid arterial wall after drug delivery from stents deployed in straight or bifurcating arterial vessels. We quantified the spatial heterogeneity in arterial drug deposition for several scenarios of stent placement and luminal flow settings in bifurcated beds. These results provide mechanistic insights as to how drug deposition in a multi-vessel environment is concomitantly modulated by relative stent position, regional blood flow changes due to bifurcation presence, and acute local flow alterations induced by the stent itself., Movie S1). The geometry generation algorithm allowed for controlled alteration of several parameters including stent location, strut dimensions, stent-cell shape, lumen diameter to arterial tissue thickness ratio, lengths of the arterial branches, extent of stent apposition and the bifurcation angle. For the current study, equal lengths (2LS) were assumed for the proximal and distal sections of the MB from the bifurcation. The SB was constructed at an angle of MB) and thickness (TMB) for the MB were defined such that We developed a generalized and automated parametric framework for constructing physiologically realistic three dimensional computational models of single and bifurcated arterial vessels using SolidWorks (Dassault Syst\u00e8mes) (S) and diameter (DS) were fixed at A DES was placed in different regions of the MB to quantify the effects of stent positioning on arterial drug uptake and one scenario is shown in In the arterial lumen, drug transport followed advection-diffusion process asA Poiseuille parabolic velocity profile simulating constant flow condition was imposed at the luminal inlet. At the outlets of the MB and SB, the downstream flow-split was assigned based on the MB and SB outlet areas such that 14% of flow entered the SB. No-slip boundary conditions were imposed on the mural interface and the adluminal surfaces of the stent. Flux continuities of momentum and drug transport were maintained at the mural interface. In the arterial lumen, an open boundary condition for drug concentration was applied at the outlets and symmetry boundary conditions were applied at the flow centerline. An impermeable boundary condition was established at the perivascular aspects of the model vessel. Stent drug release was simulated using a Dirichlet boundary condition of unit concentration.\u22128 reduction in the mass transport residual.A finite volume solver  was utilized to perform the coupled flow and drug transport simulations. The semi-implicit method for pressure-linked equations-consistent (SIMPLEC) algorithm was used with second order spatial accuracy. A second order discretization scheme was used to solve the pressure equation and second order upwind schemes were used for the momentum Mesh dependence studies performed on the non-bifurcating arterial vessel Fig. 1A Constant flow simulations generate local recirculation zones juxtaposed to the stent which in turn act as secondary sources of drug deposition 0, there was about a 50-fold difference between the maximum and minimum drug concentration in the proximal segment of the stent. However, this ratio decreased along the stent length to almost 30-fold in the distal stent segment. These observations imply that not all regions within a stent experience the same drug exposure as convective forces modulate non-uniformity along the stent length. Flow also extends drug distribution to regions beyond the stent deployment site into the downstream segment of the vessel, where the pattern of drug imprint on the mural surface tracks precisely with the proximity of the stent surface  or across the ostium (Midstream case), respectively, as compared to the case with a stent placed in the distal segment of MB (Downstream case). These proportions gradually decrease with increase in net luminal flow as Reynolds number increases the resistance to flow into the SB.Stent positioning also modulates SB drug distribution patterns. Blood flow through all bifurcation geometries creates boundary layer separation and re-attachment on the lateral walls of the SB that pools drug and induces drug deposition. This effect is maximal when stents are placed closer to the ostium and decreases with the stent proximity to the flow divider Fig. 6A.One can now appreciate how blood flow and flow dividers affect arterial drug deposition, and especially on inter-strut drug deposition Fig. 5B Local endovascular drug delivery was long assumed to be governed by diffusion alone Bifurcation lesions are an ideal and practical clinical model of great immediate importance for examining the interplay between flow and stent-based drug delivery. Percutaneous interventions on bifurcated vessels are sub-optimal and there is no clinical consensus to their approach. Animal model systems demonstrate that flow disruptions are re-established in certain regions near the flow divider leading to adverse outcomes such as angiographically detectable restenosis patterns Fluid dynamic coupling caused by the stent and MB and/or SB vessel dilation precludes quantitative understandings of arterial drug deposition patterns using animal models, let alone in the clinical domain. A computational schema can rigorously consider all relevant determinants of arterial drug distribution, and systematically delineate the relative effects of each variable. The significance of these quantitative findings is enhanced when one can extend the lessons learned in certain domains where other modes of analyses are limited. Previous studies focusing on simplified computer models of stent-implanted arterial vessels explained that intrinsic stent design and associated freestream luminal flow modulate arterial drug distribution The principal aim of this study was to harness the power of computer modeling and focus particularly on bifurcated regimes. Here the MB patency and associated fluid mechanics were altered under specific DES intervention settings to realize a significant dependence of drug concentration levels within the SB as well as the MB. We demonstrate that coupled hemodynamic alterations due to stenting and inherent presence of a bifurcation always affect arterial drug distribution patterns. Specifically, stent struts create local obstructions to flow and pool drug locally while dilated bifurcation vessels naturally create large retrograde flow regimes that accumulate drug; these phenomena differentially modulate arterial drug distribution patterns. Overall, our physiologically realistic 3D computational model predicts that flow-mediated effects create asymmetry in drug distribution and these impressions are far more extensive in bifurcation regimes and modulated by relative stent position with respect to the arterial flow divider and the mean Reynolds number entering the bifurcated regime  is developing cost-efficient ways of determining the effectiveness of single vessel devices or complex bifurcation stents for regulatory approval. This issue of complexity is becoming all the more acute as the \u201csimple\u201d cases are covered by approvals for previously evaluated technologies Computational methodology facilitated mechanistic understandings of arterial drug distribution patterns under different settings of MB treatment. Our model paves the way forward for selective bench-top testing and animal investigation but does not yet include complexities of lesion morphology and the pulsatile nature of blood flow. Nevertheless, our previous studies Our generalized computer-assisted design strategy facilitates the creation of geometry models that can incorporate several stent designs. We presented the hemodynamic effects on drug distribution patterns using a simplified uniform-cell stent design, though our methodology is adaptable to several types of stents with variable design features. Variability in arterial drug distribution due to other geometric and morphologic aspects such as bifurcation angle, arterial taper as well as presence of a trifurcation Computational methods coupling flow and mass transfer facilitate cost-effective mechanistic insights on the phenomena governing stent-based drug delivery for complex vascular lesions. Arterial drug deposition and distribution patterns in a bifurcated regime are fascinatingly dependent on stent location as well as free stream, and local retrograde flow. Careful consideration of these insights in conjunction with relevant experimental investigation may lead to superior design and favorable stenting procedures for bifurcation lesions. Flow perturbations prevail under all possible modes of revascularization in a bifurcated milieu and therefore should be viewed in concert with relative stent position as important parameters for understanding the mechanisms governing stent-based drug delivery.Movie S1Construction of the three dimensional computer-aided design (CAD) model of a stent-deployed arterial bifurcation.(13.39 MB MPG)Click here for additional data file."}
+{"text": "The conventional approach to screen toxic substances in oils using rats takes more than six months and involves large number of animals. In this article we describe how rapid bioassay-guided screening could be used to identify toxic substances derived from vegetable oils and/or processed foods fortified with vegetable oils. The technique incorporates sequential fractionation of oils/processed foods and subsequent treatment of human cell lines that can be used in place of animal studies to determine cytotoxicity of the fractions with structural elucidation of compounds of interest determined via HPLC-MS and GC-MS. The rapid bioassay-guided screening proposed would require two weeks to test multiple fractions from oils, compared with six months if animal experiments were used to screen toxic effects. Fractionation of oil before bio-assay enhances the effectiveness of the detection of active compounds as fractionation increases the relative concentration of minor components.It has been consistently reported that vegetable oils including canola oil have a life shortening effect in Stroke-Prone Spontaneously Hypertensive Rats (SHRSP) and this toxic effect is not due to the fatty acid composition of the oil. Although it is possible that the phytosterol content or type of phytosterol present in vegetable oils may play some role in the life shortening effect observed in SHRSP rats this is still not completely resolved. Furthermore supercritical CO Fat is an important part of the diet that provides the greatest amount of energy per gram of any food. However excessive consumption of saturated fat may raise blood cholesterol levels and lead to an increased risk for coronary heart disease. Fatty acid composition of fats and oils also has a major impact on human health. Factors such as low saturated fatty acids, high unsaturated fatty acid and relatively low \u03c96/\u03c93 polyunsaturated fatty acid ratio have been associated with favourable health benefits. Among the oils available for human consumption in today's market, canola oil has the properties that would be considered as beneficial having very low saturated fats (7%), relatively high in monounsaturated fat (61%) with moderate levels (22%) of omega-6 (\u03c9-6); linoleic acid and a relatively high amount (11%) of omega-3 (\u03c93); alpha-linolenic acid. With an ever increasing use of canola oil in processed foods, fast foods and home cooked meals in countries such as Australia, Canada and Japan the amount of canola oil consumed by some individuals is much higher than in previous decades.et al. [Since 1996 a number of studies have been conducted which have compared the effects of various vegetable oils on the lifespan of Stroke-Prone Spontaneously Hypertensive Rats (SHRSP) . It has et al. ,6 added The next oil component to be investigated for a life shortening effect was plant sterols (phytosterols). SHRSP rats fed with canola oil and corn oil which contain higher amounts of natural plant sterols than other vegetable oils showed lower survival time compared to soy oil . The meaet al. [2 separation of the oil with subsequent treatment testing in SHRSP rats. This investigation only produced three crude fractions from canola oil rich in campesterol and \u03b2-sitosterol with the lesser amounts of brassicasterol and stigmasterol and failed to clearly separate the causative substances into a specific fraction and was unable to characterise the compounds responsible for life shortening of the rats.Another approach to explore toxic substance in canola oil was reported by Ohara et al.  that invet al. [While it is clear that canola oil, corn oil and olive oil have a life shortening effect in the SHRSP rat the question must be asked, is it a strain specific effect or is the consumption of these vegetable oils as the primary dietary fat source also pathogenic in other rat strains or human populations that consume large amount of one of these oils oil? When canola oil was the only dietary fat fed to normotensive Wistar Kyoto rats, the strain the SHRSP was original derived from, a significant increase in systolic blood pressure after five weeks of canola oil feeding was observed and persisted until the conclusion of the trial at week 13, compared to soybean oil fed rats . In addiet al.  reportedet al. .In human populations there is only one published incidence of canola oil being associated with the development of disease  and thisIn summary it has been consistently reported that some oils including canola oil have life shortening effects in SHRSP rats and this effect is not due to the fatty acid composition of the oil; it is possible that the phytosterol content and type of phytosterol might play some role in the life shortening effect although this is still not completely resolved. The conventional approach to screen toxic substances in vegetable oils using animal models takes more than six months and involves a large number of animals depending on the number of oil fractions to be tested. In this report we explain an alternative rapid bioassay-guided screening approach to elucidate biologically active substances in oils using human cell lines in place of animal models.Naturally produced oils are a complex mixture of non polar TAG, a large number of phyto compounds such as phenolic compounds including phenolic acids, flavonoids, tannins, sterols and oxidised TAG ,16-18. T4 human cells/well in media and incubated overnight before treatment. Each fraction would be tested at five different concentrations ranging 50-1800 \u03bcg/ml in triplicates.The conventional approach to screen toxic substances in vegetable oils using rats takes extended period of time, is a costly exercise and requires large number of animals. Fractionation produces numerous fractions according to polarity and molecular weight, and it would not be feasible to use animals to test the biologically active compounds in each fraction on such a large scale and also the production of suitable quantities of each fraction to be incorporated to the animal diet is limiting. This incites the necessity of develop an alternative approach to screen toxic substances in vegetable oils. In addition the proposed technique significantly reduces the cost and the time required to screen for toxic substances. Employing a cytotoxicity bio-assay to test five fractions would only take two weeks compared with six months if animal experiments were used to screen toxic effects. In this bio-assay, 96-well microtiter culture plates would be seeded at 1 \u00d7 10The non polar components mostly TAG of the oils can be separated from polar compounds in vegetable oils by chromatography using silica gel column ,17,20. Pvia High Performance Liquid Chromatography-Mass Spectroscopy (HPLC-MS) and/or Gas Chromatography-Mass Spectroscopy (GC-MS). The proposed approach would be able to conquer most of the constraints of the conventional rat based approach.The proposed system would carry out sequential fractionation of vegetable oils according to the polarity and molecular weight. Subsequent treatment of human cell lines would determine cytotoxicity effects of the fractions with structural elucidation of compounds of interest determined The use of canola oil by food manufactures, commercial users and consumers has increased over recent years, primarily due to the marketing image that canola oil is a healthy alternative. Since the role of phytosterols on survival time in SHRSP rats is still not completely resolved other minor compounds in dietary oils may have toxic effects on rats and humans. Even though humans absorb less plant sterols than SHRSP rats, individuals that consume increased amounts of canola oil for lengthy period may be at risk of adverse health outcomes, due to phytosterols or other oil components. Rapid screening for toxic substances responsible for the life shortening effects of canola oil in the SHRSP rat is of particular importance because it is a potentially challenging issue for canola farmers and consumers of canola oil i.e. what can be done to remove the toxic compound(s) from canola oil. Once toxic compounds have been identified further studies would be carried out to remove toxic compounds via modification to oil processing methods and would resolve existing doubts as to the safety of consuming canola oil by humans. Authors would like to emphasize that the proposed bio assay-guided screening technique is cost effective and quick method to identify supplements or extracts that are bioactive and provide an insight as the composition of the bioactive compounds(s) prior to undertaking further time consuming and expensive animal or clinical studies.(SHRSP): Stroke-Prone Spontaneously Hypertensive Rats; (SHR): spontaneously hypertensive rats; (\u03c96): omega-6; (\u03c93): omega-3; (G6PD): glucose-6-phosphate dehydrogenase; (TAG): triacylglycerols; (FFA): Free fatty acids; (DAG): diacylglycerols; (HPLC-MS): High Performance Liquid Chromatography-Mass Spectroscopy; (GC-MS): Gas Chromatography-Mass Spectroscopy.The authors declare that they have no competing interests.SR and PAL contributed equally to the manuscript and have both read and approved the final manuscript."}
+{"text": "An enzyme immobilization technique has been developed todetermine the concentration of biological compounds. This techniquehas been applied to penicillinase and urease, which are crosslinkedas very fine films directly onto the sensitive ends of pH glasselectrodes, thereby dispensing with the need of an on-line enzymereactor. The biosensor is incorporated in an FIA system within amagnetically stirred detection cell. Penicillin-V in fermentationbroth and urea in human serum samples were detected and theresults were compared with HPLC and spectrophotometricmethods. On-line measurement is achieved through the automationof this FIA system."}
+{"text": "Saccharomyces cerevisiaeDrosophila melanogaster, Caenorhabditis elegans, and human Functional genomics has demonstrated considerable success in inferring the inner working of a cell through analysis of its response to various perturbations. In recent years several technological advances have pushed gene perturbation screens to the forefront of functional genomics. Most importantly, modern technologies make it possible to probe gene function on a genome-wide scale in many model organisms and human. For example, large collections of knock-out mutants play a prominent role in the study of Another major advance is the development of rich phenotypic descriptions by imaging or measuring molecular features globally. Observed phenotypes can reveal which genes are essential for an organism, or work in a particular pathway, or have a specific cellular function. Combining high-throughput screening techniques with rich phenotypes enables researchers to observe detailed reactions to experimental perturbations on a genome-wide scale. This makes gene perturbation screens one of the most promising tools in functional genomics.Advances in the design and analysis of gene perturbation screens may have an immediate impact on many areas of biological and medical research. New screening and phenotyping techniques often directly translate into new insights in gene and protein functions. Results of perturbation screens can also reveal unexploited areas of potential therapeutic intervention. For example, a recent RNAi screen showed that some of the most critical protein kinases for the proliferation and survival of cancer cell lines are also the least studied A goal becoming more and more prominent in both experimental as well as computational research is to leverage gene perturbation screens to the identification of molecular interactions, cellular pathways, and regulatory mechanisms. Research focus is shifting from understanding the phenotypes of single proteins to understanding how proteins fulfill their function, what other proteins they interact with, and where they act in a pathway. Novel ideas on how to use perturbation screens to uncover cellular wiring diagrams can lead to a better understanding of how cellular networks are deregulated in diseases like cancer. This knowledge is indispensable for finding new drug targets to attack the drivers of a disease and not only the symptoms.This review surveys the current state-of-the-art in analyzing single gene perturbation screens from a network point of view. We describe approaches to make the step from the parts list to the wiring diagram by using phenotypes for network inference and integrating them with complementary data sources.A phenotype can be any observable characteristic of an organism. Analysis strategies strongly depend on how rich and informative phenotype descriptors are. We will call phenotypes resulting from a single reporter  low-dimensional phenotypes and the genes showing significant results hits The second part will be devoted to high-dimensional phenotyping screens, which evaluate a large number of cellular features at the same time. Observing system-wide changes promises key insights into cellular mechanisms and pathways that can not be supplied by low-dimensional screens. For example, high-dimensional phenotypes can include changes in cell morphology The distinction between low- and high-dimensional phenotypes may sound technical, but it is crucial for choosing potential analysis methods. The central difference is that high-dimensional phenotypes allow one to compute correlations and other similarity measures, which are not applicable for low-dimensional phenotypes. Another important distinction is between static phenotypes, providing a \u201csnapshot\u201d of a cell's reaction to a gene perturbation, and dynamic phenotypes showing a cell's reaction over time. We expect more and more studies in the future to produce dynamic output and in the following note explicitly which methods can be applied to dynamic phenotypes. For the biological interpretation of screening results it is very important to keep in mind which level of \u201ccellular granularity\u201d a phenotype describes: growth rates or cell morphologies are much more \u201chigh-level\u201d features of the cell than gene or protein expressions. As soon as more studies produce dynamic phenotypes on many different cellular levels, integrative analysis of interconnected phenotypes In this review we focus on single gene perturbations by knockouts The phenotypes we have discussed above allow only an indirect view on how different genes in the same process interact to achieve a particular phenotype. Cell morphology or sensitivity to stresses, for example, are global features of the cell and hard to relate directly to how individual genes contribute to them see . Gene exThis gap between observed phenotypes and underlying cellular networks is the main problem in the analysis of perturbation screens and applies to both low- and high-dimensional screens. The goal of computational analysis is to bridge this gap by inferring gene function and recovering pathways and mechanisms from observed phenotypes. The following methods address the challenge in different ways, mostly by integrating the perturbation effects and phenotypes with additional sources of information like collections of functionally related gene sets or protein-interaction networks.A simple way to link phenotypes to gene function is to test whether pathways or functional groups of genes  graph Enrichment analysis results in a list of Good data analysis asks specific questions. A hypothesis-free method can only be the very first starting point for a deeper exploration of the data. For example, all enrichment methods rely on known gene sets and cannot uncover new pathways or components. Enrichment methods treat pathways as bags of unconnected genes without considering connections within and between pathways. Thus, enrichment methods can only deliver a very crude picture of the cell. In the following we will discuss approaches to overcome some of the limitations of enrichment analysis by integrating the observed phenotypes with complementary sources of information.Another valuable source of information to interpret RNAi hits are gene and protein networks obtained either experimentally Using these complementary data sources can improve hit identification Other approaches complement genomic data with biological prior knowledge showing how \u201cinteresting\u201d hits look. Gene prioritization Most state-of-the-art analysis techniques rely on a \u201cguilt-by-association\u201d paradigm: genes with similar phenotypes will most probably have a similar biological function. This explains the prevalence of clustering techniques in analyzing high-dimensional phenotyping screens Another useful data visualization especially for transcriptional phenotypes is to build a directed (not necessarily acyclic) graph by drawing an arrow between two genes if perturbing one results in a significant expression change at the other Most approaches to infer pathway structure from experimental data rely on probabilistic graphical models. For low-dimensional phenotypes they often suffer from nonuniqueness and unidentifiability issues The model of ideal interventions contains a number of idealizations (hence the name), most importantly that manipulations only affect single genes and that perturbation strength can be controlled deterministically. The first assumption may not be true if there are off-target or compensatory effects involving other genes. The second assumption may also not hold true in realistic biological scenarios; in particular for RNAi screens where experimentalists often lack knowledge about the exact knock-down efficiency. Probabilistic generalizations of ideal interventions can be used to cope with this uncertainty High-dimensional phenotypic profiles can be mapped to given graphs and networks by finding subgraphs that are connected in the background network and at the same time show high similarity of phenotypic profiles. These approaches already exist for mapping gene expression data onto protein interaction networks Many of the approaches discussed so far\u2014like clustering or graphical models\u2014can be applied to both static \u201csnapshots\u201d as well as dynamic time-course measurements. Another approach to model specifically the dynamics of networks comes from a branch of control theory called \u201csystems identification\u201d One of the key problems in analyzing perturbation screens is that the observed phenotypes are downstream of the perturbed pathway and may not show the direct influence of one pathway component on another. A class of models explicitly addressing this problem are Nested Effects Models (NEMS) In this review we have discussed two main approaches to describe the reaction of a cell to an experimental gene perturbation: low-dimensional phenotypes measure individual reporters for cell viability or pathway activation, while high-dimensional phenotypes show global effects on cell morphology, transcriptome, or proteome. S. cerevisiae and Escherichia coli computational models very accurately predict fitness effects of gene knock-outs The focus of this review is on functionally annotating hits in a network context and reconstructing networks from high-dimensional phenotypes. In a complementary direction of research, genome-wide reconstructions of metabolic networks While single gene perturbation screens have been immensely successful in extending our knowledge of pathway components and interactions, an important limitation can be caused by compensatory effects, genetic buffering, and redundancy of cellular mechanisms and pathways Global phenotyping and pathway screening can be combined in the same study. For example, a first genome-wide screen identifies key genes representative for pathways and cellular mechanisms involved in the phenotype. In a second step the hits of the first screen could be assayed for high-dimensional molecular phenotypes to infer a pathway diagram using NEMs or other statistical approaches.In a further step preliminary pathway models could be used to plan an additional round of experimentation. Different modeling frameworks propose future experiments to most effectively refine a pathway hypothesis, e.g., Bayesian networks Iteratively integrating experimentation and computation may lead to a virtuous circle and is one of the most promising approaches to refine our understanding of the inner working of the cell."}
+{"text": "The identification of transmission of variant Creutzfeldt-Jakob disease (vCJD) by blood transfusion has prompted investigation to establish whether there has been any alteration in the vCJD agent following this route of secondary transmission. Any increase in virulence or host adaptation would require a reassessment of the risk analyses relating to the possibility of a significant secondary outbreak of vCJD. Since there are likely to be carriers of the vCJD agent in the general population, there is a potential for further infection by routes such as blood transfusion or contaminated surgical instruments.We inoculated both wild-type and transgenic mice with material from the first case of transfusion associated vCJD infection.The strain transmission properties of blood transfusion associated vCJD infection show remarkable similarities to the strain of vCJD associated with transmission from bovine spongiform encephalopathy (BSE).Although it has been hypothesized that adaptation of the BSE agent through secondary passage in humans may result in a greater risk of onward transmission due to an increased virulence of the agent for humans, our data presented here in two murine models suggest no significant alterations to transmission efficiency of the agent following human-to-human transmission of vCJD. PRNP), the same genotype as all tested vCJD cases. Variant Creutzfeldt-Jakob disease (vCJD) is an acquired form of human transmissible spongiform encephalopathy (TSE) caused by infection by the bovine spongiform encephalopathy (BSE) agent that entered the human food chain in the United Kingdom during the 1980s and early 1990s. Two further cases of vCJD linked to blood transfusion, in MM genotype individuals, have subsequently been identified through the TMER study. PRNP genotypes other than MM could be infected by the vCJD agent. All three codon 129 genotypes are now thought to be susceptible to vCJD infection following the identification of two VV genotype appendix tissues positive for vCJD associated PrP (PrPSc) in an anonymous screening study, and the successful transmission of vCJD to \u2018humanised\u2019 transgenic mice of each genotype. A fourth case, of asymptomatic infection following blood transfusion, was described in 2004 and this individual was heterozygous (MV) at codon 129. The implications of these findings are that a significant number of the UK population may be carriers of vCJD infectivity, that some of the individuals may be donating blood, and that not only those with an MM genotype may be susceptible to infection from this source. Our research in transgenic models indicates that MV and VV individuals are likely to remain in an infectious preclinical state for a significant period of time with incubation periods potentially longer than average lifespan. TSE transmission by the blood transfusion route has been investigated in a sheep model. Strain characterisation using a standard panel of inbred lines of wild-type mice originally demonstrated that BSE and vCJD agents had similar biological properties following transmission. To investigate the nature of the transmissible agent following secondary transmission from human-to-human following blood transfusion we have examined the biological properties of brain material from the first case of transfusion-associated vCJD inoculated into panels of both wild-type, and transgenic mice expressing human PrP.Clinical signs of a TSE in the transgenic mice were rare and occurred after long incubation periods (IP) as found in our previous study. The frequency of transgenic mice positive for TSE associated vacuolation was similar between the vCJD (transfusion) case and the published vCJD (BSE) case Immunocytochemical (ICC) detection of disease associated abnormal PrP in paraffin sections was also used as a method of assessing whether mice were transmission positive. There were 13/14 HuMM, 8/17 HuMV, 1/17 HuVV positive mice in the vCJD (transfusion) case, which was similar to the frequency of positives in the published vCJD (BSE) case: 11/15 HuMM, 11/13 HuMV, 1/15 HuVV mice. ICC data can be used to show variation in targeting of abnormal PrP deposition in the brain and variation in the nature of deposits. The ICC pattern in transgenic mice inoculated with the vCJD (transfusion) case matched that reported for vCJD (BSE) Sc seen in the HuMV and HuVV were too low to allow typing by this standard Western blot method.Biochemical analysis of disease-associated PrP by Western blot can discriminate between human cases of vCJD and sporadic CJD. Secondary passage of vCJD infection via blood transfusion in an MM codon 129 genotype individual results in a clinical disease phenotype and pathological characteristics that are similar to vCJD derived from BSE. There were some differences in the results of the transmission studies which deserve further comment. The incubation period in wild-type mice was relatively extended in the vCJD(transfusion) case. However, the hierarchy of incubation periods in different inbred mouse strains was unchanged and the most plausible explanation for these findings is that, rather than implicating a change in agent characteristics, the titre of infectivity was less in the brain sample from the vCJD(transfusion) case. The distribution and degree of vacuolation was identical in the RIII mice.  While thPreliminary investigation of the individuals diagnosed with vCJD following blood transfusion does not indicate a change in the neuropathological characteristics of vCJD following secondary transmission, although further studies are required to confirm this observation.The level of infectivity in peripheral tissues in secondary cases of vCJD is unknown, although spleen and a lymph node were PrP positive in the sub-clinical case linked to blood transfusion. Evidence from BSE inoculation of primates indicates similar peripheral distribution of disease associated PrP following either oral or intravenous infection. Blood transfusion appears to be a relatively efficient means of secondary transmission of vCJD. To date, there have been four such transmissions in a cohort of 28 individuals who survived at least five years following transfusion of blood derived from individuals incubating vCJD. Despite extensive exposure of the UK population to the BSE agent in the food chain, there have been a relatively limited number of primary cases of vCJD (164 in the UK) and the outbreak has been in decline since 1999/2000. An important question is why there should be a disparity in the apparent efficiency of infection between primary and secondary vCJD. Transmission is generally more efficient within species than between species which may explain this observation. Another factor is that the intravenous route of infection is very much more efficient than the oral route, as shown in experimental models. All the primary and secondary clinical cases of vCJD have occurred in individuals with a MM genotype. The sub- or pre-clinical transfusion related infection was in a codon 129 heterozygote and genotyping of positive appendix samples identified in a screening study confirmed valine homozygosity in 2 of 3 samples tested. In conclusion, transmission studies indicate that the strain characteristics of vCJD have not been significantly altered by secondary transmission through blood transfusion. This suggests that the risk of onward transmission of vCJD through other routes, for example contaminated surgical instruments, have not been increased by adaptation of the infectious agent to humans following secondary passage. However the characteristics of the infectious agent in different genetic backgrounds has not yet been defined and the prevalence of vCJD infection in the general population remains uncertain. There is need to continue to implement appropriate policies to protect against the risk of secondary transmission of vCJD until many of the remaining uncertainties are resolved.Prnp-a genotype line and VM is a Prnp-b genotype line. The transgenic mice  used in these experiments have been described previously. \u22121 dilution by the intracerebral route, for vCJD (transfusion) and vCJD (BSE). Groups of 18 transgenic mice were injected with inoculum at a higher dilution of 10\u22122 as in previous experiments more concentrated inocula had been found to be toxic to the mice. Inoculum was prepared as a homogenate in sterile saline from frozen frontal cortex ) to allow accurate comparison with previous data. Cases used for transmission were: the first blood transfusion associated case, designated here as vCJD (transfusion), and three historical vCJD cases designated here as vCJD (BSE) A, B, and C. The historical vCJD cases were not inoculated into the transgenic mice. Data from vCJD (transfusion) inoculation of the transgenic mice was compared with that already published for vCJD (BSE). Mice were inoculated as described previously. Groups of 24 wild-type mice received a 0.02 ml dose at 10Mice were housed in independently ventilated cages in a Category 3 facility, monitored daily and scored for signs of TSE disease weekly from 100 days post inoculation. Mice were culled, when clinical TSE was evident or for animal welfare reasons, by cervical dislocation and the brain bisected sagittally; one half frozen for biochemical analysis of disease-associated prion protein and the other half fixed in formalin for histology.et al. Vacuolation scoring was performed according to published protocols and lesion profiles generated."}
+{"text": "When humans are exposed to hypoxia, systemic and intracellular changes operate together to minimise hypoxic injury and restore adequate oxygenation. Emerging evidence indicates that the hypoxia-inducible factor (HIF) family of transcription factors plays a central regulatory role in these homeostatic changes at both the systemic and cellular levels. HIF was discovered through its action as the transcriptional activator of erythropoietin, and has subsequently been found to control intracellular hypoxic responses throughout the body. HIF is primarily regulated by specific prolyl hydroxylase-domain enzymes (PHDs) that initiate its degradation via the von Hippel-Lindau tumour suppressor protein (VHL). The oxygen and iron dependency of PHD activity accounts for regulation of the pathway by both cellular oxygen and iron status. Recent studies conducted in patients with rare genetic diseases have begun to uncover the wider importance of the PHD-VHL-HIF axis in systems-level human biology. These studies indicate that, in addition to regulating erythropoiesis, the system plays an important role in cardiopulmonary regulation. This article reviews our current understanding of the importance of HIF in human systems-level physiology, and is modelled around the classic physiological response to high-altitude hypoxia. EPO) expression but which is now known to be conserved in all animal species, irrespective of the presence of specialised oxygen transfer systems such as the lungs, heart, and blood  family of transcription factors, a DNA binding complex that was first defined as a regulator of erythropoietin (Epo) gene  and carbon dioxide (Pco2). Experimental investigations into the respiratory effects of high altitude hypoxia date back to Angelo Mosso's pioneering experiments in the Italian Alps in the 1890's  and removing a major by-product (carbon dioxide), and ventilation is duly influenced by changes in the arterial partial pressures of both oxygen , although under normal conditions its contribution to maintaining Pncertain . Global ncertain .EPO RNA expression with kinetics similar to that of induction by hypoxia and cobalt chloride  is mutated. Subsequent research showed that VHL binds to the HIF-\u03b1 subunit and targets it for ubiquitin-mediated proteasomal degradation by acting as the recognition component of a multiprotein ubiquitin ligase complex , studies in humans sought to modify putative HIF-dependent physiological processes by exploiting the hypoxia-mimetic effect that iron chelation has on HIF hydroxylation. In a study of 16 subjects, an 8-h infusion of DFO increased serum Epo in a dose-dependent manner but did not measurably affect ventilatory sensitivity to acute hypoxia within 24 h of commencing the infusion  that results in an amino acid change of arginine to tryptophan  was associated with polycythaemia and inappropriately normal levels of Epo. Several further EGLN1 mutations associated with polycythaemia have since been described in unrelated individuals . When iron is scarce, IRP-IRE binding promotes cellular iron uptake and prevents iron sequestration by stabilising transferrin receptor mRNA and inhibiting the translation of ferritin mRNA. In contrast, in iron-replete cells IRP1 is biochemically inactivated and IRP2 undergoes iron-dependent proteasomal degradation, resulting in reduced IRE-binding activity and opposite homeostatic effects. It is interesting to note that it has been proposed that the IRP2 degradation pathway involves an unidentified 2-oxoglutarate-dependent dioxygenase from the same family as the HIF hydroxylases . FurtherVentilatory responses to acute hypoxia are mediated by the glomus cells of the carotid body. Though the precise oxygen-sensing mechanism has yet to be determined, it is generally accepted that hypoxic inhibition of potassium channels leads to membrane depolarisation, calcium influx, release of neurotransmitters and stimulation of sensory nerves that activate the respiratory centre of the brain . A recenco2 was significantly lower in the Chuvash polycythaemia patients, indicating an altered set point for respiratory control in the direction of an elevation in pulmonary ventilation. Cardiopulmonary responses to isocapnic hypoxia were assessed using the technique of dynamic end-tidal forcing while subjects breathed on a mouthpiece system. The ventilatory response stimulated by acute hypoxia was several-fold greater in the Chuvash polycythaemia patients than in controls for both mild and moderate hypoxic stimuli. Thus, patients with Chuvash polycythaemia had both a reduced Pco2 set point for the respiratory controller and an abnormally high acute hypoxic ventilatory sensitivity, which together are characteristic of acclimatised individuals. These results strongly support the notion that HIF is involved in human ventilatory acclimatisation to hypoxia, and establish the importance of HIF in respiratory control in hypoxia-na\u00efve individuals. Such involvement of HIF is consistent with the nature of some of the genes HIF is known to activate, most notably tyrosine hydroxylase, which regulates the biosynthesis of catecholamine neurotransmitters in the rat carotid body and brainstem respiratory centre  provoked peak systolic pulmonary arterial pressures exceeding 70 mmHg in the patients, compared with less than 30 mmHg in the control group. Several HIF-activated genes are important in vasomotor regulation and may be involved in the pulmonary vascular response to hypoxia (EDN1), which is elevated in patients with Chuvash polycythaemia (In the same study of patients with Chuvash polycythaemia, a standard echocardiographic technique was used to determine pulmonary vascular tone at baseline and during exposure to hypoxia (HIF1A have been proposed to be associated with maximal oxygen consumption during exercise (HIF1A genotypes have been reported to occur more frequently in the Sherpa population of Tibet than in lowlanders (The profound physiological disturbances associated with the Chuvash mutation raise the question of whether common genetic variation within the PHD-VHL-HIF axis might also have phenotypic effects on physiological function. Such effects might explain some of the considerable inter-individual variation seen in Epo secretive (Another potential source of variation in HIF activity is iron status. Iron is an obligate cofactor in the hydroxylation reaction through which HIF is primarily regulated, and in cultured cells HIF degradation is both inhibited by iron chelation with DFO and potentiated by supraphysiological iron supplementation .Hypoxic regulation of erythropoiesis provided the paradigm through which HIF was discovered and initially investigated. Convergent discoveries in the biochemistry of oxygen sensing and in cardiopulmonary physiology have since established that the PHD-VHL-HIF axis is important in regulating both intracellular and systems-level human biology. The emerging role of HIF in systemic physiology, described here in terms of the response to high altitude, in fact translates to any clinical scenario in which hypoxia is a feature. Functional differences arising from common genetic variation or the availability of cofactors, such as iron, may therefore influence the clinical response to any such physiological or pathological disturbance."}
+{"text": "The most commonly occurring form of neonatal cholestasis is biliary atresia, representing a relative frequency of approximately 30% [Cholestatic liver disease in children occurs as a result of either an alteration in hepatocyte bile formation or disruption of bile flow out of the hepatocyte through intrahepatic bile ductules or extrahepatic bile ducts . Liver dIf left untreated cholestatic liver injury results in the development of hepatic fibrosis and ultimately may progress to cirrhosis. The precise pathophysiological mechanisms responsible for hepatic fibrogenesis in pediatric cholestatic liver disease are unknown. Hepatic stellate cells have been shown to be responsible for increased production of fibrillar collagens in a number of adult liver diseases and in experimental models of liver injury. Recent studies by our group have identified stellate cells as the principal source of type I collagen in neonatal cholestatic liver diseases such as biliary atresia  and in tThe precise mechanisms responsible for the activation of hepatic stellate cells and the subsequent development of hepatic fibrosis in pediatric cholestatic liver disease are not known. Bile duct hyperplasia appears to be an early event in the pathology of both biliary atresia and CF liver disease. It has been suggested that the biliary hyperplasia seen in bile duct-ligated rats may be due to either increased intraductal pressure  or circu1), is significantly increased in both biliary atresia [1 is responsible for the transactivation of the procollagen alpha1(I) gene in both myofibroblast-like cells and activated hepatic stellate cells in these same areas of scar tissue formation , interleukin-8, RANTES, endothelin-1 [in vitro [in vivo remains to be determined [Another key regulator of fibrogenesis is the mitogenic cytokine, platelet-derived growth factor-BB (PDGF-BB). The observation of abundant myofibroblast-like cells within the peri-biliary and scar interface regions of the acinus in both biliary atresia and CF liver disease suggests either local activation and proliferation of portal fibroblasts or recruitment of stellate cells. Therefore, we hypothesize that bile duct epithelial cells and hepatocytes at the scar interface produce mitogens and chemokines in response to biliary obstruction Figures  and 2. T PDGF-BB . While tthelin-1  (Figure in vitro  and MCP-in vitro . We proptermined .While the precise pathways involved in the initiation of hepatic fibrogenesis in neonatal cholestasis remain elusive, a number of cytokines and growth factors have been identified which contribute to the progression of injury through matrix production and recruitment of inflammatory cells. With this knowledge it may be possible to develop novel approaches for therapeutic intervention which could assist in the suppression of fibrogenesis and may potentially lead to the reduced requirement for liver transplantation."}
+{"text": "BMC Systems Biology by Vasquez et al. developed a mathematical model to assess some features of this altered metabolism. Here, we take a broader look at the regulation of energy metabolism in cancer cells, considering their anabolic as well as catabolic needs.Cancer cells have different metabolic requirements from their normal counterparts. Understanding the consequences of this differential metabolism requires a detailed understanding of glucose metabolism and its relation to energy production in cancer cells. A recent study in http://www.biomedcentral.com/1752-0509/4/58/See research article:  Cancer is a disease of uncontrolled cell growth in which cells acquire genetic alterations that allow them to proliferate outside the context of normal tissue development. In the evolution of this transformation, cells acquire mutations that confer selective advantages for the growth of the tumor. Genetic alterations in many of the known oncogenes are selected to adapt cellular metabolism to meet the requirements of rapid cell proliferation as well as autonomous growth and survival in an environment absent of contact with extracellular matrix Figure . AccumulIn a majority of tumor types, an enhanced rate of glucose uptake is observed and serves as a reasonable starting point for understanding differential metabolism in tumors. Otto Warburg's initial observation that tumors often metabolize relatively large quantities of glucose predominantly through a fermentative-like metabolism, resulting in lactate production in aerobic conditions (termed aerobic glycolysis), provided the phenomenological foundation for studying altered metabolism in cancer . Rapid pMYC and TP53 (p53) - two of the most common cancer-associated genes [Catabolic pathways involving the oxidation of material other than glucose in the Krebs cycle are also involved in cancer cell metabolism. For example, glutamine flux into the Krebs cycle has been directly observed in cancer cell lines and appears to be in part regulated by expression of ed genes -6. Addited genes . In addied genes . These aet al. [Aerobic glycolysis is considered a relatively inefficient way of producing ATP, as the alternative catabolic fate of glucose via oxidation in the Krebs cycle and donation of electrons into the electron-transport chain can generate 15 to 20 times as much ATP per unit of glucose. A recent study by Vazquez et al.  used a rFor mammalian cells, calculations suggest that most of the ATP generated is consumed in basal cellular processes such as the maintenance of concentration gradients through ion pumps and active transport using molecular motors. A simple calculation shows that biosyntheses are not a major source of ATP consumption in tumor cells . As showThe stoichiometry of glycolysis imposes chemical constraints when high fluxes of glucose occur. Consider the overall chemical equation for conversion of glucose to pyruvate via glycolysis:+. The reduction of pyruvate to lactate by lactate dehydrogenase is the most ubiquitous mechanism known for converting NADH back to NAD+, and this activity balances the very high rate of glycolysis observed in most cancer cells. Efraim Racker noted the problem of stoichiometric ADP availability and postulated that large fluxes through yet to be characterized ATP-coupled hydrolysis reactions were required to balance the cellular glucose uptake rates found in tumors. Futile cycles, more conveniently directly coupled to glycolysis, that hydrolyze ATP were believed to be required to balance high glycolytic flux [From the equation, it is clear that glycolysis is not possible without sufficient regeneration of ADP and NADtic flux . One nowtic flux . Other AAlthough aerobic glycolysis may, by virtue of stoichiometry, be necessary to support high rates of glycolysis, the advantages of this process for tumor cells are complicated to understand. Cell-autonomous effects of lactate secretion are likely to confer advantages on tumors. Lactate may enhance the invasiveness of tumor cells by disrupting normal tissue architecture as well as promoting an environment with reduced pH to evade tumor-attacking immune cells.A complementary teleology suggests that maintaining high rates of glycolysis is required to reconfigure metabolic pathway fluxes to achieve more efficient anabolic metabolism and cell-autonomous growth. One speculation is that a movement of pathway fluxes towards anabolic metabolism can arise from the effects of differential ATP hydrolysis and redox balance that originate from the demands of the stoichiometry shown in the equation above. These differential pathway fluxes are likely to be dependent on tumor type since different oncogenes are used to regulate different anabolic fluxes.Cancer cells are limited in their growth by the availability of carbon skeletons needed to produce new proteins, nucleotides and lipids . FurtherBecause of the complexity of cancer metabolism, a better understanding will ultimately require the use of mathematical models. This improved understanding will then allow intervention in the metabolic pathways responsible for tumor cell metabolism. Exploiting these tumor-specific properties presents opportunities for therapeutic intervention in tumor development. The pharmacological targeting of enzymes that regulate this restructured metabolism has recently shown some promise in preclinical studies ."}
+{"text": "One of the most sensitive hypoxia detection methods is based on the observation that binding of nitroimidazoles to cellular macromolecules occurs as a result of hypoxia-dependent bioreduction by cellular nitroreductases. Nitroimidazole-binding techniques provide measurements of hypoxia to virtually any degree of spatial resolution and with a multiplicity of techniques. This paper demonstrates hypoxia imaging using in vivo EF5 binding with detection by a fluorochrome-conjugated monoclonal antibody. We investigated these techniques in the 9L glioma tumour, in part because the exact nature of the hypoxia in this tumour system is controversial. Our results demonstrate that following intravenous injection of EF5, binding and detection using a monoclonal antibody in 9L gliomas is specific and oxygen dependent. Detection of binding using fluorescence microscopy can be performed on frozen tissues; tissue sections can be counterstained with haematoxylin and eosin for light microscopic analysis. Alternatively, the distribution of hypoxia in a tumour can be inferred by examining individual tumour cells using flow cytometric techniques. Based upon the results presented herein, the radiation-resistant phenotype of 9L epigastric tumours grown in our laboratories can be associated with the presence of hypoxic cells."}
+{"text": "Bees heterozygous at Sex Determination Locus are females, whereas bees homozygous or hemizygous are males. Little is known, however, about the regulation that links sex determination to sexual differentiation. To investigate the control of sexual development in honeybees, we analyzed the functions and the regulatory interactions of genes involved in the sex determination pathway. We show that heterozygous csd is only required to induce the female pathway, while the feminizer (fem) gene maintains this decision throughout development. By RNAi induced knockdown we show that the fem gene is essential for entire female development and that the csd gene exclusively processes the heterozygous state. Fem activity is also required to maintain the female determined pathway throughout development, which we show by mosaic structures in fem-repressed intersexuals. We use expression of Fem protein in males to demonstrate that the female maintenance mechanism is controlled by a positive feedback splicing loop in which Fem proteins mediate their own synthesis by directing female fem mRNA splicing. The csd gene is only necessary to induce this positive feedback loop in early embryogenesis by directing splicing of fem mRNAs. Finally, fem also controls the splicing of Am-doublesex transcripts encoding conserved male- and female-specific transcription factors involved in sexual differentiation. Our findings reveal how the sex determination process is realized in honeybees differing from Drosophila melanogaster.Organisms have evolved a bewildering diversity of mechanisms to generate the two sexes. The honeybee ( Apis mellifera) provides an interesting and unusual system to study, as it is governed by heterozygosity of a single locus harbouring the complementary sex determiner gene (csd), in contrast to the well-studied sex chromosome system of Drosophila melanogaster. We show that the female sex determination pathway is exclusively induced by the csd gene in early embryogenesis. Later on and throughout development this inductive signal is maintained via a positive feedback loop of the feminizer (fem) gene, in which the Fem protein mediates its own synthesis. The findings reveal how the sex determination process in honeybees is realized by the regulation and function of two genes differing from Drosophila.Sexual differentiation is a fundamental process in the animal kingdom, and different species have evolved a bewildering diversity of mechanisms to generate the two sexes in the proper proportions. Sex determination in honeybees ( Apis mellifera) is determined by the fertilization and non-fertilization of eggs Bracon hebetorIn 1845 Dzierzon reported that the sex in the honeybee (complementary sex determiner (csd) gene csd gene satisfies the criteria of a primary signal of complementary sex determination csd exists in at least 15 allelic variants that differ on average in \u223c3% of their amino acid residues csd locus csd. Females treated with csd dsRNA develop entire male gonads, whereas the treatment of males had no sex-transforming effect.The single-locus nature of complementary sex determination in honeybees was confirmed by genetic linkage analysis csd, operates to establish the sex determined state by heterozygosity. We have recently isolated the entire genomic region of SDL and identified the feminizer (fem) gene, which is the ancestral progenitor gene from which csd derived by gene duplication csd. The fem gene is required for female development as shown by the sexual transformation of the head of fem-repressed females. Fem activity is not achieved by heterozygosity. Instead, the fem pre-mRNAs are sexually processed into the productive female mode. In the current study we characterized the sex-transforming function of other candidate genes located at SDL. We then investigated the function of sex-determining genes in controlling all aspects of development. Our previous studies were restricted to the control of basic aspects of soma differentiation Drosophila the gene transformer (tra), which is the likely ortholog of the fem gene csd is a potential source of information to maintain sexual fate throughout development Disappointingly little, however, is known about the regulatory interactions and mechanisms that link sex determination to sexual differentiation. So far we have no evidence that SDL encodes another gene that, in conjunction with csd and the fem gene realizes the sex determination process throughout development.Our findings reveal how the regulation and function of the fem and csd, in sexual development have thus far been characterized csd in the establishment of the primary sex determined state. Three other genes at SDL have been previously predicted, but their involvement in sex determination is unknown. Genes GB11211 and GB13727 are located upstream of the fem gene, whereas the gene GB30480  of unknown function. We isolated 803 bases of the transcript of gene GB13727, which splits into six exons  inseminated queens and virgin queens, respectively.In our previous study we reported the full assembly of the SDL genomic region gene csd . We expl GB13727 . The samur exons . The 5\u2032 ix exons  and whicGB11211 and GB13727 genes produced individuals with unchanged gonad development . Our series of fem repression experiments induced by fem siRNAs produced 74% females whose gonads had entirely differentiated into male testes . In these experiments we injected into embryos that were derived from two inbred and three non-inbred crosses. The inbred crosses naturally produce 50% diploid male and 50% female progeny, which we identified by genotyping csd alleles. This allowed us to compare the male-transformed characters of diploid females with wild type characters of diploid males. This is of importance as characters of haploid and diploid males can differ slightly.In fem gene resulted in 74% and 85% of the females  showing all aspects of male differentiation  gene. Dsx is a transcription factor that in Drosophila controls the activity of the final target genes necessary for both male and female somatic differentiation Drosophila gene is brought about by sexually processed transcripts encoding polypeptides that have male- and female-specific domains at their carboxyl-termini. The female splice pattern is mediated by the female Tra protein Am-dsx, in the honeybee genome dsx orthologs in sexual differentiation of insects has been provided by the housefly Musca domesticaBombyx moricsd or fem siRNAs and examined the sexual expression of fem and Am-dsx mRNAs in 5th instar larvae by RT-PCR targeting fragments that corresponds to female- and male-specific mRNAs. If the activity of the gene is repressed in females, we expect to find the male mRNAs of downstream components.Our analyses have identified csd predominantly displayed fragments that correspond to male fem and Am-dsx mRNAs  encodes a protein that directs the splicing of its own transcript into the productive female mode Ceratitis capitata at the level of the sex-determining tra (Cc-tra) gene fem gene fem provides the mechanism for maintaining the female-determined state and provides a source of a female-specific signal implementing the sexual development pathway. To test our hypothesis we transiently expressed the fem gene in males by injecting fem encoding mRNAs that we synthesized in vitro. We assayed the processing of the putative target\u2014the endogenous fem mRNA\u2014by RT-PCR amplifications. This experiment shows . We conclude that fem is the target of csd that implements male or female differentiation by a productive female, or a non-productive male splice variant. The three other mRNA encoding genes of SDL are not necessary for sex determination. Our experiments do not exclude the possibility that SDL harbours a non-mRNA encoding gene (such as a microRNA), but we find no evidence for such a gene. The exclusion of other sex-determining factors at SDL suggests that complementary sex determination entirely relies on heterozygous combination of the csd gene. The primary signal of the honeybee is a switch gene that has two regulatory states, the active female and the non-active male state. We propose that induction of the female pathway through gain of csd activity is due to the presence of two Csd proteins derived from different alleles. Lack of csd activity, and thus male development, results when Csd proteins are derived from the same allele. We hypothesize that activation in females relies entirely on the binding differences of Csd's RS- and asparagine/tyrosine-enriched domains. This region harbours elevated nucleotide polymorphism and has been proposed as the allele specifying domain in our population genetics analysis Sex in the honeybee is determined by the heterozygosity and hemi/homozygosity at a single SDL. In this study we show that this genomic locus harbours five mRNA encoding genes but that only the csd has some analogy to self-incompatibility systems in plants and fungi The heterozygous activation of csd must implement sexually different activities to downstream genes. Our identification of the fem gene also allowed us to identify female-specific mRNAs fem mRNAs are required for all visible aspects of female morphology. Testes were, however, all smaller in fem-repressed females when compared with wild type diploid males or csd-repressed females. We speculate that the timing of fem and csd activity may affect differently gonad differentiation when we experimentally repress these genes. These testes form normally differentiated testicular tubules harbouring fully developed spermatids, implying that the fem gene also controls germ cell differentiation. Despite a common evolutionary origin, the tra gene of Drosophila does not dictate the sexual fate of germ cells and its function is restricted to the control of the soma In order to determine sex, the activity of heterozygous fem and Am-dsx splice patterns are operating upstream in the cascade. The Am-dsx gene, which is an ortholog of the dsx gene of Drosophila, is another component of the sex determination whose mRNA is sex-specifically processed csd controls splicing of fem pre-mRNA, and fem regulates the processing of Am-dsx pre-mRNAs  generate stably determined states implemented by the commitment given by the primary signal csd and (2) maintain the determined state throughout development. That a positive feedback would generate stable determined states throughout development is demonstrated here by the finding of mosaic structures in fem-repressed females that have male or female characters, but not an intermediate phenotype. The mosaic intersexual phenotype is consistent with previous reports on a cell-autonomous sexual differentiation mechanism in the honeybee fem positive feedback loop as being the mechanism of stable determined cells.We have used the sex-specific mRNAs as a phenotype to identify the interactions of sex-regulatory genes by assuming that genes affecting re-mRNAs . The obsfem gene . We havefem activity and as constant activity of the positive feedback loop would lock eggs into the female determined state. Our developmental profile of fem mRNA expression indicates that transcription of fem starts expression to sizable amounts of mRNA of the male type when blastoderm is formed (\u223c12 h after egg deposition). This finding implies that the sex determined state is set to the default male regulatory mode by the onset of fem transcription in early embryogenesis. The female pathway is induced in late blastoderm stage (\u223c25\u201335 h after egg deposition) when the female mRNAs in females are produced.We also explored how the female state is established and reset to the default male state in early embryogenesis. This is important, as male development is only induced in the absence of csd is required only to initiate sex-specific differentiation early in development. When we transiently repressed fem activity, we found male fem mRNAs under conditions of resumed mRNA production in late female larvae, suggesting that csd is no longer able to induce the production of female fem mRNAs. We conclude from this finding that csd can implement the female pathway only during a critical period of development. Primary signals from other organisms are also needed for only a critical developmental window when the pathway is established DrosophilaDrosophila, once the Sxl gene is activated in females by the primary signal (the X\u2236A ratio), the Sxl protein splices its own transcript into the productive female mode Drosophila utilize the same strategy in the control of the sex determined state, they employ different molecules.We also provide evidence that fem gene and the dipteran tra genes of D. melanogaster (tra) and of the medfly Ceratitis (Cc-tra) have a common evolutionary origin tra functions in DrosophilaCeratitisfem studied here allows us to infer ancestral and derived functions within the fem/tra gene family , thus producing 50% female and 50% diploid male offspring. Haploid male eggs were collected from colonies that were headed by a virgin queen. These non-mated queens were laying unfertilized male eggs induced by repeated CO2 treatments.Diploid female eggs were derived from the progenies of eight queens inseminated with semen from a single drone having a different sex allele than that of the queen. Diploid male eggs that are homozygous for http://genemachine.nhgri.nih.gov/) using the human or Drosophila model organism option and by different BLAST search strategies at NCBI (http://blast.ncbi.nlm.nih.gov/Blast.cgi). The first strand cDNA from mRNA was generated by reverse transcription with oligo dT primer (or random hexamers), and 5\u2032 and 3\u2032 ends of genes were identified by RACE experiments according to the protocol of the supplier . Sequences of transcripts were obtained from high-fidelity PCR amplifications of embryonic cDNA and at least three independent clones. Potential homologies to genes and proteins in the database were identified by BLAST analysis using the low complexity filter option. Potential domains of proteins were identified by comparing deduced amino acid sequence with the PROSITE (http://www.expasy.org/prosite/) and the PFAM (http://pfam.sanger.ac.uk/) database.Potential exons of the assembled SDL genomic sequence fem and csd siRNAs were synthesized (MWG BioTech) . siRNAs were injected at a concentration of 50\u2013100 pg per embryo. Sequences for the mock siRNAs  pH 7.2 for 3 h at room temperature, washed with SCB, postfixed with 1% osmium tetroxide in SCB, dehydrated in a graded ethanol series, and embedded in epoxy resin elongation factor 1-alpha (\u0394Cts\u200a=\u200aCtscontrol \u2212 Ctstarget). t test statistics were carried out using the SPSS 15.0 software. Amplified fragments by fem RT-PCR  and exon 3 (size \u223c400 bp) representing the female and male transcripts, respectively. The cDNAs in the profile analysis were quantified in a NanoDrop ND-1000 spectral photometer. Differences in the amount of cDNAs were adjusted prior to PCR amplifications. mRNAs (csd-UTRfem mRNA) encoding Fem proteins were generated by inserting 5\u2032 and 3\u2032 UTRs at the corresponding 5\u2032 and 3\u2032 end of the fem ORF of clone fem S2-38 csd UTR together with a translational start codon and a Myc tag encoding sequence between the ApaI und NcoI restriction sites of the pGEMT vector (Promega). The csd 3\u2032 UTR was inserted by utilizing SpeI und PstI restriction sites. The fem ORF was ligated into NcoI and SpeI resulting in the plasmid pfemcsd-UTR. The mRNA (csd-UTRfem mRNA) was generated using the RiboMax T7 RNA polymerase kit (Promega) in which the 5\u2032cap structure (Ambion) was added during RNA synthesis in order to produce 5\u2032 capped transcripts. We polyadenylated the 3\u2032 termini of the in vitro transcribed RNA by adding ATP and Yeast polyadenylation polymerase (USB), which we terminated by following standard phenol/chloroform extraction protocol. We injected 0.08 pg of csd-UTRfem mRNA into 0\u20133-h-old male embryos. Amplified fragments (fem were composed of exons 2-3-6 (size \u223c560 bp) and exons 3 (size \u223c400 bp) corresponding to the female and male transcripts, respectively.RNAi knockdowns were induced in early embryogenesis at the syncytial stage (0\u20134 h after egg deposition) in haploid and diploid males and females k siRNAs  were obtm RT-PCR  in the reriments  were comeriments  in the fragments  of endogDataset S1siRNA and oligonucleotide primer sequences.(0.03 MB DOC)Click here for additional data file."}
+{"text": "The lack of correlation between genome size and organismal complexity is understood in terms of the massive presence of repetitive and non-coding DNA. This non-coding subgenome has long been called \u201cjunk\u201d DNA. However, it might have important functions. Generation of junk DNA depends on proliferation of selfish DNA elements and on local or global DNA duplication followed by genic non-fonctionalization.Evidence from genomic analyses and experimental data indicates that Whole Genome Duplications (WGD) are often followed by a return to the diploid state, through DNA deletions and intra/interchromosomal rearrangements. We use simple theoretical models and simulations to explore how a WGD accompanied by sequence deletions might affect the dosage balance often required among several gene products involved in regulatory processes. We find that potential genomic deletions leading to changes in nuclear and cell volume might potentially perturb gene dosage balance.The potentially negative impact of DNA deletions can be buffered if deleted genic DNA is, at least temporarily, replaced by repetitive DNA so that the nuclear/cell volume remains compatible with normal living. Thus, we speculate that retention of non-functionalized non-coding DNA, and replacement of deleted DNA through proliferation of selfish elements, might help avoid dosage imbalances in cycles of polyploidization and diploidization, which are particularly frequent in plants. C-value is defined as the haploid DNA content of an organism Other authors have proposed global adaptive roles for junk DNA as scavengers of intranuclear chemical mutagens  events.Arabidopsis, rice and other organisms There is increasing evidence supporting the idea that some stoichiometric balance between and within the subunits of macromolecular complexes must be maintained to ensure their normal functioning By virtue of the nucleotypic effect of DNA, DNA deletions in a newly formed polyploid is expected to decrease nuclear and cell volumes. Assuming that such a hypothetical volumetric contraction does not alter substantially transcription levels on a per-allele basis, it would lead to an increase in the concentration of the products of genes that remain as duplicates. This might be advantageous for a subset of genes  can also upset the regulation of the latter and change their dynamics. To explore such effects we turn to the minimalist model of a mitotic clock stricto sensu, a potential volumetric contraction owing to DNA deletions might be harmful. Thus, some of the existent non-coding DNA (including repeats) may have a connection with maintaining optimal regulation of gene expression after a WGD, as previously proposed in a different context The examples above show that even if dosage balance is maintained Another outstanding biophysical effect of non-coding DNA that cannot be overlooked in a WGD process involves protein-DNA interactions . DNA binding proteins may recognize sequences that are similar to their real target sites giving rise to non-specific interactions . By virt balance . Again, The evolution of C-value in polyploids is influenced by i) the deletion of structural genes (as their transcription and translation is costly), ii) the retention of structural genes whose products are required at high doses and of balanced regulatory genes that enhance the generation of evolutionary innovation and plasticity Oryza australiensisArabidopsis allopolyploids, also display transcriptional activity, although their transposition is limited Selfish DNA proliferation has been observed during polyploidization events. For instance, the steady-state transcript levels of some retrotransposons are much higher in newly synthesized wheat amphiploids Speciation by allopolyploidization involves complex interactions between the merging genomes. After allopolyploidization, most genes tend to be expressed at mid-parental levels but for a proportion of them, the transcriptional contributions of each subgenome are not additive, that is, each sub-genome dominates with regard to the expression of a set of genes All in all, we propose that at some point in the evolution of polyploids, junk DNA, including selfish elements, may have played (or play) an adaptive role linked to global functional effects of DNA. We hope that this theoretical exploration will provide some insights into the process of genome evolution.http://www.math.pitt.edu/~bard/xpp/xpp.html). The concentration profile of TFs bound specifically to target sites as a function of different levels of non specific binding and specific binding strengths , In the above equations, all the genes involved after a Whole Genome Duplication followed by DNA reduction (WGD+Assuming doubling of the concentrations of The simulations of To calculate the effect of non specific protein-DNA binding on transcription factor activity after whole genome duplication and massive DNA deletion let us consider a transcription factor protein At equilibirum we have:Using these relations it is simple to express the concentration of specific bound TF-DNA complexes We consider now a whole genome duplication event followed by massive DNA deletions that are accompained by volumetric shrinkage. For the point of illustrating the effect of unbalance between specific and non specific binding under such events we suppose here the limit case where the the gene and specific promoter sites concentrations double, while DNA deletion leads to the same amount of non-coding DNA available for non specific biding:"}
+{"text": "The massive reemergence of diphtheria in the Newly Independent States of the former Soviet Union marked the first large-scale diphtheria epidemic in industrialized countries in 3 decades. Factors contributing to the epidemic included a large population of susceptible adults; decreased childhood immunization, which compromised what had been a well-established childhood vaccination program; suboptimal socioeconomic conditions; and high population movement. The role of a change in the predominant circulating strains of Corynebacterium diphtheriae in this epidemic remains uncertain. Massive, well-coordinated international assistance and unprecedented efforts to vaccinate adults were needed to control the epidemic."}
+{"text": "Although the mechanisms of short- and long-term potentiation of nociceptive-evoked responses are well known in the spinal cord, including central sensitization, there has been a growing body of information on such events in the cerebral cortex. In view of the importance of anterior cingulate cortex (ACC) in chronic pain conditions, this review considers neuronal plasticities in the thalamocingulate pathway that may be the earliest changes associated with such syndromes.in vivo, while high frequency stimulation potentiated the response of this current. Paired-pulse facilitation by electrical stimulation of midline, mediodorsal and intralaminar thalamic nuclei (MITN) suggesting that the MITN projection to ACC mediates the nociceptive short-term plasticity. The short-term synaptic plasticities were evaluated for different inputs in vitro where the medial thalamic and contralateral corpus callosum afferents were compared. Stimulation of the mediodorsal afferent evoked a stronger short-term synaptic plasticity and effectively transferred the bursting thalamic activity to cingulate cortex that was not true for contralateral stimulation. This short-term enhancement of synaptic transmission was mediated by polysynaptic pathways and NMDA receptors. Layer II/III neurons of the ACC express a short-term plasticity that involves glutamate and presynaptic calcium influx and is an important mechanism of the short-term plasticity.A single nociceptive electrical stimulus to the sciatic nerve induced a prominent sink current in the layer II/III of the ACC The potentiation of ACC neuronal activity induced by thalamic bursting suggest that short-term synaptic plasticities enable the processing of nociceptive information from the medial thalamus and this temporal response variability is particularly important in pain because temporal maintenance of the response supports cortical integration and memory formation related to noxious events. Moreover, these modifications of cingulate synapses appear to regulate afferent signals that may be important to the transition from acute to chronic pain conditions associated with persistent peripheral noxious stimulation. Enhanced and maintained nociceptive activities in cingulate cortex, therefore, can become adverse and it will be important to learn how to regulate such changes in thalamic firing patterns that transmit nociceptive information to ACC in early stages of chronic pain. The cingulate cortex is one of the most frequently activated regions in human pain research ,2. The tOf equal importance is the fact that anterior cingulate cortex (ACC) has been implicated in a number of human chronic pain syndromes and three studies activated pregenaul ACC. Kern et al.  stimulatNeurons communicate with each other by transmission through chemical synapses and the dynamic course of synaptic transmission is regulated by a variety of short-lasting processes. The sum of pre- and post-synaptic responses evoked by stimulation of afferent axons is often termed synaptic \"strength\" and during dynamic short-term processes it varies in a systematic manner and is dependent on the precise onset and duration of activation, i.e., tens of milliseconds to several minutes. Short-term plasticities (STP) have been described in several forms, such as paired-pulse facilitation (PPF), augmentation, post-tetanic potentiation and synaptic depression which are each distinguished by their decay kinetics .PPF is the synaptic enhancement of the second response in which the post-synaptic potential is increased up to several times the amplitude of the first potential. The enhancement of synaptic potentials can develop and decline with a time course of about 100 ms. When the response lasts for 5-10 s, it is termed synaptic augmentation and is distinguished from post-tetanic potentiation which lasts from 30 s to several minutes. Furthermore, post-tetanic potentiation is an augmentation of synaptic transmission following a train of repetitive stimuli. During the stimulation each synaptic potential increases the synaptic strength by 1-15% and the summed effect of sequential pulses can reach to a many-fold enhancement.Action potential discharges are often activated at high frequencies or in a bursting mode and it is the pattern of dynamic discharges that change with altered synaptic strength. Thus, the properties of STP that are specific to the activated synapses may determine the spiking pattern of a presynaptic cell that ultimately influences the firing of its post-synaptic neurons. Many mechanisms can lead to activity-dependent alterations in synaptic strength during neuronal high-frequency discharges. A short-term depression may result from a reduction in neurotransmitter release either by reducing the probability of release or by depleting the readily releasable pool of vesicles. A short-term facilitation may occur by repeated activations that increase the probability of neurotransmitter release, either by saturating a local calcium buffer or by increasing calcium concentration in the presynaptic terminal ,17. The Short-term synaptic plasticity appears to be a widespread in the nervous system and STP is a dominant mechanism underlying the plasticity of sensory responses in mammalian cerebral cortex. The functional relevance of the short-term synaptic depression and facilitation has been linked to habituation and sensitization, respectively. Recently, studies have extended its role in this simple form of learning and it has been suggested that STP involves signal filtering that is used in information processing. Specifically, the differential activation and integration of short-term synaptic depression and facilitation might enhance and sustain temporal filtering .At the simple reflex level in the spinal cord, the STP of inhibitory interneurons provides an intrinsic mechanism for the dynamic regulation of a reflex. At higher levels of the nervous system, such as in the cerebral cortex, STP provides a dynamic mechanism for signal processing where it may serve as a general mechanism for the short-term amplification of signals. Some evidence suggests that short-term facilitation participates in temporal coding within neuronal circuits . FurtherAll levels of pain processing in the CNS are associated with STP. Temporal enhancement of nociceptive signals throughout the nervous system provide a mechanism of amplifying one or a few signals above baseline activity over time and the thalamus and cortex have time to assess the signals in context; i.e., in the context of other visual, auditory or somatic sensory events. In the longer term, this information can be used to predict painful outcomes, establish new memories, and modify nocifensive reflexes to particular contexts.In the peripheral nervous system, nociceptors are distinct from innocuous sensory receptors in that they have a high threshold of activation. The responses of mechanoheat-sensitive nociceptor axons increase monotonically with heat stimuli ranging from 41-49\u00b0C and correlates with the pain threshold in humans . The perTrains of afferent discharges following repeated noxious inputs from nociceptors can evoke a period of facilitated transmission in dorsal horn neurons in the spinal cord. Windup is a form of STP characterized by a progressive increase in action potential output from dorsal horn neurons during a train of repetitive, C-fiber stimuli ,28. It aNociceptive information transmitted from the dorsal horn to the forebrain are encoded in lamina I and lamina V neurons with nociceptive-specific (NS) and wide dynamic range (WDR) properties. Spinal nociceptive neurons project to the reticular formation, midbrain periaqueductal grey, parabrachial nucleus, dorsal column nuclei and thalamus -33. NeurThe thalamus is the essential relay of nociceptive inputs that are transmitted from the spinal cord to cortex. The likely thalamic source of such information to anterior cingulate cortex (ACC) is from the midline, mediodorsal and intralaminar thalamic nuclei (MITN) ,38. As nThere is also evidence for plasticity in the thalamocortical system in pain patients with deafferentation as a result of amputation or spinal cord injury. This implies that neuronal activity in the thalamus gives rise to sensations perceived as originating from the missing part of the original limb. Furthermore, stimulation in such regions frequently elicits pain sensations arising from the deafferented body region .The role of the STP in nociceptive signalling in the thalamocingulate pathway is still not clear. Attempts have been made to link the short-term facilitation to synapses in this pathway and their role in temporal signal integration. The cellular mechanisms underlying these dynamic responses involve pre- and post-synaptic and circuit properties  and the Nociceptive responses are transmitted to cingulate cortex from the MITN. Thus, expression of the product of the immediate early c-fos gene is a marker of metabolic activity and c-Fos expression in the MITN is increased in rats subjected to noxious colorectal distension or electrical stimulation of hind limb C-fibers . NeuronsSeveral lines of evidence indicate that the MITN provide the primary source of nociceptive information to the ACC.First, the nociceptive response in rabbit ACC neurons occurred within 200 ms which may preclude prior processing via other cortical areas. Also, knife-cut lesions lateral or posterior to ACC that remove most cortical input to ACC do not alter the percentage of units in area 24 driven by noxious stimuli [ stimuli .Second, the MITN has similar nociceptive response properties with cingulate neurons, which suggests a functional linkage. Nociceptive ACC neurons have a broad somatotopic organization; i.e., stimulation of large parts of the body can activate a single ACC neuron. They also respond to noxious mechanical or heat stimulation on both sides of the body and can be polymodal in responding to both such stimuli. In other words, single ACC neurons do not \"know\" where on the body the stimulus is occurring and often do not \"know\" what type of stimulus is producing the pain. Electrically-evoked cutaneous nociceptive responses in the ACC are depicted in Figure Third, thalamic lidocaine injections block ACC nociceptive activity [activity .Fourth, electrolytic lesion of MITN activity abolishes nociceptive responses in ACC [s in ACC .Fifth, multichannel recordings from all layers of ACC and thalamus during tonic noxious formalin hind paw injections confirm the nociceptive thalamocingulate link. Lee et al. [e et al.  showed tOne of the problems in interpreting the source localization of field potentials is that the voltage traces reflect both local and volume conducted activities. Thus, the values of the voltage activity pattern and those of the frequency power spectrum do not reflect local activities in particular cortical layers when the voltage is considered alone. When studying the laminar distribution of spontaneous electrical rhythms with a single electrode, it is difficult to predict the location of the current source of the synaptic input because of the variability of the rhythms in amplitude, frequency, and location during successive events. The ACC is dominated by parallel-aligned pyramidal cells whose apical dendrites extend across many cortical layers. Synchronous excitation of ensembles of pyramidal cells results in a major current flow perpendicular to the cortical layers. Under the assumptions of homogeneous cortical activity and constant extracellular electrical conductivity, CSD of the current flow can be estimated from the second spatial derivative of the recorded field potentials in the axis parallel to the cortical layers . Thus thin vivo strongly indicates that AMPA/kainate glutamate receptors mediate the excitatory drive in thalamic inputs that are presynaptic to cingulate neurons [In vitro whole cell patch-clamp recordings conducted in genetically modified mice show that postsynaptic kainate receptors contribute to fast synaptic transmission in ACC pyramidal neurons [As a general rule, STP at cortical synapses strongly influences network activity -54. Unli neurons . In vitr neurons . The fun neurons . GABA is neurons . This ar neurons . On the  neurons . The pre neurons ,64,65.Thus far, it appears that stimulation of any afferent to ACC induces STP and distinct forms of short-term synaptic plasticities in the cingulate neurons have been reported in studies of electrical stimulation of callosal inputs , the layA single nociceptive electrical stimulus (10 mA) to the sciatic nerve induced a prominent sink current in the layer II/III of the ACC  inter-pulse intervals (IPIs) at 80% of the intensity that induced maximum response activity Fig. . MaximalThe tetanic stimuli used above were pulses delivered with a regular pulse sequence but action potential discharges are often activated in irregular bursting mode in physiological conditions. Thus, the properties of STP that are specific to the activated synapses may be tested in a spiking pattern that mimics the firing condition during nociceptive stimulation. We recorded unit activities in MITN which received inputs from hind paw of anesthetized rats. The burst pattern of thalamic units was analyzed under pre- and post- formalin injected conditions. Following the formalin injection in the hind paw, the increased firing rate of unit activity was regarded as nociceptive. Unit activities were collected 30 min before and one hour after the formalin injection. The increased unit activity can be expressed as increasing firing rate in the burst and the burst sequences were defined with at least 500 ms pre-burst silent period and at least 3 spikes within 300 ms post-burst period. All burst related unit activities were displayed in raster plot Fig. . Burst sin vivo in a region of MITN that was confirmed to receive a signal from the foot. The spike pattern was further confirmed to project to the ACC by the spike-triggered averaging technique. This bursting pattern of thalamic discharges can be converted to a irregular bursting stimulation pattern which was then used to evaluate the STP of ACC activity in vitro.The unit activities were recorded in vitro stimulation/recording paradigm for studying ACC discharges following burst-modelled stimulation patterns that simulate physiological responses. Thalamic bursting unit patterns obtained following formalin injection were first transformed into transistor-transistor logic pulses. These square wave pulses meet the specific requirement for the triggering of an output signal generated from a pulse generator. These triggered stimulating pulse sequences were then used to apply stimulation in the thalamus or contralateral cc and to evoke EPSPs in ACC neurons in slices. The amplitude of EPSPs evoked by the first four stimuli from different stimulation sites were measured and normalized relative to the first responses. The thalamus-evoked fourth EPSPs showed greater potentiation than that produced by contralateral cc  can illustrate the excitatory extent of the evoked responses Fig. . The maxhed Fig. .To characterize the cellular components that corresponded to the evoked extracellular field potentials, intracellular excitatory post-synaptic potentials (EPSPs) were evoked and recorded simultaneously with the field potentials. EPSPs and the second field potentials were blocked completely in the presence of CNQX (15 \u03bcM) alone or in combination with APV (30 \u03bcM). The first field potential however was not affected by the glutamate receptor antagonist Fig. .Two consecutive stimuli of identical strength were applied at an interval of 40 ms (paired-pulse stimulation). The field action potential (fAP) evoked by the first stimulus (fAP1) did not differ from that evoked by the second stimulus (fAP2) . There is a linear relationship between the fAPs and the stimulation strength applied (from 20 to 500 \u03bcA). The field post-synaptic potentials (fPSPs) of the second stimulation (fPSP2) had greater amplitude than the fPSPs evoked by first stimulation (fPSP1) . PPF was obtained with current applied in the range of 20 to 500 \u03bcA. Optimal PPF was obtained when the interpulse interval was in the range of 20-150 ms.These findings suggest that the first fAP was directly activated by stimulation without synaptic relay and the second fPSP resulted from postsynaptic excitation. Strong short-term potentiation of the fPSP of the ACC can be obtained by PPF. Thus, layer II/III neurons express an STP that is calcium dependent and involves glutamatergic transmission. To test the presynaptic mechanism of the PPF, the effects of varying external calcium concentrations and blocking calcium influx were examined.th stimulus and the depressive effect reached a steady state that lasted from the 12th to15th stimuli . To evaluate the augmentation effect after tetanus, a single test stimulus was applied at a varying delay interval (0.2~8 s) after cessation of tetanus. The maximal response  was obtained when the test stimulus was applied with a 4 s delay.The fPSP response was recorded following 25 Hz (15 pulses with 40 ms IPI) tetanic stimulation under normal calcium conditions with superimposed responses to altered stimuli. The fAP amplitude changed very little suggesting the persistence of the excitability of a pre-synaptic volley. The amplitude of the response following the first stimulus was -0.32 \u00b1 0.017 mV and was regarded as the control value. The fPSP response reached the maximal amplitude  following the second stimulus. The maximal response declined gradually in the following stimuli. There was depression of the amplitude after the 10th response to the first response) showed depression in the presence of normal and high calcium aCSF  but showed facilitation in the presence of low calcium aCSF (except at 50 Hz stimulation). The Max/control and Min/control ratios obtained during tetanus under different calcium concentrations were plotted against stimulus frequency as shown in Figure During tetanic stimulation , the second fPSP showed maximal facilitation under normal (2 mM) and high  and second response to the test stimuli (4-s 2nd)(p's < .05), but not on steady-state amplitude or normalized augmentation amplitudes (4-s 1st/fPSP1) (p's > .05). When comparing PPF ratio, one-way ANOVA indicated a significant effect of Ca2+ influx on PPF (fPSP2/fPSP1) and PPF during augmentation (fPSP2 at 4 s/fPSP1 at 4 s).The effect of low calcium concentration on fPSP amplitude may be due to a reduction of calcium influx from the extracellular space. To test this possibility, we pharmacologically reduced calcium influx by applying the calcium-channel blocker \u03c9-Conotoxin GVIA . The fPSP amplitudes were decreased following CTX application, and the maximal effect was reached within 10 min. We measured CTX effects on facilitation and response depression under tetanus only after stable control responses had been obtained. Slices were perfused in aCSF with 25 \u03bcM CTX for 5 min then returned to perfusion with normal or low calcium aCSF. One-way ANOVA indicated a significant effects CTX and low calcium on amplitude of the fPSPThe results indicated that the presynaptic calcium influx is an important mechanism that regulates the expression of the STP in the layer II/III ACC neurons. As central neurons are susceptible to strong noxious stimulation, the central sensitization of the central neurons may underlie the long-term pathophysiological changes in chronic pain. Thus, the understanding of the calcium regulation in the nociceptive pathway will be crucial in controlling the development of the central sensitization in ACC. A recent study suggested that all different forms of STP may be caused by a common mechanism, namely calcium-dependent regulation of the presynaptic calcium channels that are responsible for triggering transmitter release . It is sThe stimulus protocols applied in all preceding experiments involved consecutive pulses applied to the same synaptic pathway. This paradigm shows the effects of potentiation via single (homosynaptic) inputs. This approach, however, does not allow for the differentiation of STP generated by presynaptic and/or postsynaptic mechanisms. To identify the role of postsynaptic mechanisms, we employ a paradigm in which two separate populations of afferent axons are stimulated independently and the resulting potentiation must be due to the postsynaptic neuron rather than the afferents themselves.A two-site stimulation protocol was used in which two consecutive stimulus pulses were delivered to different axon populations in the subcortical white matter that were separated by a knife cut between the two stimulation sites as shown in Figure A receptors [A receptors during PPF may be mediated through a change in the intrinsic membrane excitability triggered by inhibitory post-synaptic, potential-induced hyperpolarization. Hyperpolarization of the neuronal membrane, induced by the GABAAinhibitory receptor system, can result in an increase in the second excitatory response during paired-pulse stimulation [Our recent studies have shown that the post-synaptic mechanism of short-term synaptic facilitation in the ACC may be mediated by postsynaptic AMPA and GABAeceptors ,83. Theseceptors ,85. Regueceptors . This meeceptors  showed tmulation ,88.The facilitation effect observed from multi-site synaptic input was smaller than that from homosynaptic inputs in the same recording area. Our spatial recordings also revealed that not all post-synaptic neurons in the recording area were facilitated by the two-site stimulation protocol. Thus, homosynaptic facilitation may play a major role in modulating information from the same synaptic inputs. On the other hand, multi-site synaptic facilitation may play a role in the convergence of information from different synaptic inputs. Multi-site synaptic interactions, such as depression and facilitation, may differ depending upon the inputs stimulated and the target neurons affected. Post-synaptic facilitation driven by multi-site synaptic inputs may represent an additional signal processing mechanism in the ACC. Both homosynaptic and multi-site synaptic facilitation effectively transfer signals and each has distinct facilitation properties which may be used to distinguish signals received from different origins.Short-term modifications in cortical synapses appear to regulate afferent signals and this regulation is likely important to the transition from acute nociceptive stimulation to chronic pain conditions associated with persistent peripheral noxious stimulation. Our studies have shown that the input-specific, short-term synaptic plasticity in the ACC can enhance signals originating in the MITN. Thus MITN discharges within a certain frequency range are amplified and effectively stimulate cingulate cortical neurons. The thalamic drive of ACC is not a stable event, but rather changes over time depending upon the nociceptive history of the organism. Our studies have shown that cingulate circuits, in addition to being facilitated by regular and repetitive impulses, can be activated by irregular bursting thalamic impulses and that the later impulses within each burst are more likely to elicit action potentials for further signal propagation.The potential role of STP in the ACC in nociceptive signaling involved in acute and chronic pain states is presented in a diagram in Figure Considerable effort has been made to understand the mechanisms underlying high-frequency bursting of thalamocortical impulses. It has been shown, for example, that initial impulses of each burst have a greatly enhanced ability to elicit cortical action potentials, and later impulses in the burst further raise the probability of eliciting spikes . Moreove+2 channels are responsible for burst spike discharges in response to visceral pain and support the idea that burst firing plays a critical role in sensory gating in the thalamus [Several groups have reported the existence of thalamic neurons in chronic pain patients that fired in a bursting pattern similar to the low-threshold calcium spike-mediated bursting activity and such firing may be the result of and/or cause of chronic pain. Recent results indicate that T-type Cathalamus . Unit stthalamus  in patiethalamus . A studythalamus  shows ththalamus . Much ofthalamus  was concThe significance of the bursting pattern found by these authors has been interpreted to occur by a mechanism attributed to intra-thalamic interactions. Jeanmonond et al. proposed that the spinal inputs to medial and lateral thalamus are excitatory, and that the excitation of each region is limited by inputs of each area to the reticular thalamic nucleus which then produces a reciprocal inhibition of the medial thalamus by the lateral thalamus and vice versa. They suggested that most injuries resulting in chronic pain tend to deprive the lateral more than medial thalamus of peripheral inputs. Thus, the lateral thalamus becomes over inhibited by a combination of loss of spinal excitatory inputs and increase of inhibitory inputs from the thalamic reticular nucleus. These combined influences produce over-inhibition of lateral thalamic cells producing low-threshold calcium spikes. This spiking activity then over activates the reticular thalamic projection back to medial thalamus which finally produces low-threshold calcium spiking in this region and so closes a self sustaining loop of over activity through inhibition. In this model calcium spike associated bursting requires the combination of excitatory amino acid antagonists with GABA agonists.Although the medial thalamic LTS bursting activity emphasizes the thalamic mechanism of chronic pain, the potential pathophysiological relevance of thalamo-cortico-thalamic reverberating and/or synchronizing loops should not be underestimated. The medial thalamus was shown to be preponderant in the genesis of rhythmic thalamic oscillations . The wid2+ permeable GluR2 subunits were found to be critical to LTP stabilization and maintenance [The STP time scale is relatively short, on the order of seconds and minutes, and thus it cannot produce entirely the processes underlying chronic pain conditions. It is crucial to note that STP plays a transitional role in transferring the nociceptive signal mediating acute traumatic injury to the formation of long lasting changes in the ACC. Long-term enhancement of synaptic transmission after peripheral injury has been demonstrated in several studies in which the potentiation of the peripherally evoked field and EPSP in the ACC lasted 90 ~120 min or longer. ,99. Thesntenance .The short-term and long-term plastic changes in the ACC may facilitate the acute nociceptive activities to become persistent. Enhanced and maintained nociceptive activities may have an adverse effect in cingulate cortex. Studies have shown that excessive activation of NMDA receptors which are the most widely and densely distributed of the glutamate receptor subtypes in the cingulate cortex, plays an important role in the pathophysiology of acute CNS injury syndromes . NMDA anThalamic T-type calcium channels are critically involved in the generation of burst firing and oscillatory behavior in synaptically interconnected relay and reticular neurons. Of particular note, CaV3.1 channels in the thalamus have been implicated in processing of noxious stimuli . The preShort-term synaptic plasticities play an important role in the processing of input signals by enhancing or filtering signals at particular frequencies. In the ACC, unlike the primary sensory cortical areas, paired-pulse facilitation is predominant. The STP features, including homo-, hetero-synaptic facilitation and augmentation, keep neuronal activity propagation within local circuits. Thus, the potentiation induced by bursting patterns of stimulation indicate that short-term synaptic plasticity in the cingulate neurons enable them to process specifically the nociceptive information relayed from the MITN. Short-term modifications in cingulate cortical synapses appear to regulate afferent signals and this is likely very important to the transition from acute nociceptive stimulation to chronic pain conditions associated with persistent peripheral noxious stimulation.Enhanced and maintained nociceptive activities in cingulate cortex may have an adverse effect. Thus, it has been suggested to use NMDA antagonists in chronic conditions like neuropathic pain. Thalamic, T-type calcium channels are critically involved in the generation of burst firing and oscillatory behavior in thalamocortical dysrhythmia. Thus, it will be particularly important to know how to regulate such changes in thalamic firing patterns that may influence the transmittal of nociceptive information to the ACC. One approach of the thalamic firing modification may be the application of calcium channel blockers.The authors declare that they have no competing interests.BAV initiated the idea and BCS drafted the manuscript. BAV revised it critically for important intellectual content; both authors read and approved the final manuscript."}
+{"text": "Complementary-DNA based amplified fragment length polymorphism (cDNA-AFLP) is a commonly used tool for assessing the genetic regulation of traits through the correlation of trait expression with cDNA expression profiles. In spite of the frequent application of this method, studies on the optimization of the cDNA-AFLP assay design are rare and have typically been taxonomically restricted. Here, we model cDNA-AFLPs on all 92 eukaryotic species for which cDNA pools are currently available, using all combinations of eight restriction enzymes standard in cDNA-AFLP screens.In silco simulations reveal that cDNA pool coverage is largely determined by the choice of individual restriction enzymes and that, through the choice of optimal enzyme combinations, coverage can be increased from <40% to 75% without changing the underlying experimental design. We find evidence of phylogenetic signal in the coverage data, which is largely mediated by organismal GC content. There is nonetheless a high degree of consistency in cDNA pool coverage for particular enzyme combinations, indicating that our recommendations should be applicable to most eukaryotic systems. We also explore the relationship between the average observed fragment number per selective AFLP-PCR reaction and the size of the underlying cDNA pool, and show how AFLP experiments can be used to estimate the number of genes expressed in a target tissue.in silico screening of cDNA-AFLPs from a broad sampling of eukaryotes provide a set of guidelines that should help to substantially increase the efficiency of future cDNA-AFLP experiments in eukaryotes. In silico simulations also suggest a novel use of cDNA-AFLP screens to determine the number of transcripts expressed in a target tissue, an application that should be invaluable as next-generation sequencing technologies are adapted for differential display.The insights gained from  Researchers interested in studying the genetic regulation of particular processes or traits must first identify the genes contributing to the phenotype, a step which can be particularly challenging in organisms for which genomic data are not yet available. Differential display methods have been commonly used to compare levels of gene expression in target tissues at various stages, allowing the identification of sets of genes whose expression patterns are significantly correlated with traits of interest .Among the available differential display methods, one increasingly popular tool is cDNA-amplified fragment length polymorphism . This mA well-designed differential display experiment should aim to sample all transcripts present in a target tissue in order to avoid biasing downstream analyses. Optimizing coverage (here defined as the fraction of sequences that appear at least once as fragments of resolvable size 50-500 bp) in an exhaustive cDNA-AFLP screen) is at the heart of designing a successful experiment. Insufficient coverage of the cDNA pool can prevent the detection of genes correlated to the trait of interest, even if gene expression differences underlie trait production. Although complete pool coverage may often not be possible in any differential display screen, the recent literature indicates that dozens to hundreds of transcript-derived fragments (TDF) correlated to traits of interest can be obtained from the successful application of cDNA-AFLP screens Table . A varie0-500 bp The absolute number of TDFs that are screened per selective amplification is determined by several factors. An increase in the number of selective base pairs will reduce the number of fragments screened per PCR, and the choice of appropriate restriction enzymes can also systematically and substantially affect the quality of a screen, due to functional or evolutionary constraints on the triplets of amino-acid coding cDNA. The total number of fragments obtained is also directly linked to the total cDNA pool size, because the presence of more (different) cDNAs provides more restriction sites, and thus a larger pool is expected to produce more fragments per PCR. It is intuitively appealing to simply maximize the number of fragments screened per PCR to minimize the workload, and in fact the first AFLP studies  suggestein silico) analysis. These in silico approaches are becoming increasingly feasible as genetic databases increase in taxonomic breadth, analytical tools are developed, and computational resources increase in power. As AFLP searches are essentially searches for particular sequence motifs, the implementation of cDNA-AFLP in silico is computationally straightforward. Each of these screened sequence motifs is composed of the recognition site of the restriction enzyme and three or fewer selective base pairs, such that analyses are restricted to searches for up to 43 \u00d7 43 = 4096 sequence motifs for a three-selective base pair experiment involving two enzymes.Complementary DNA-AFLP optimization problems can be addressed by computational  taxa [in silico analyses of cDNA-AFLPs used RefSeq sequences from curated resources, which are typically biased towards larger and more complete sequences. As this quality of data is rarely available in real-world datasets, insights gained from simulations based on these data may not be relevant for typical research projects. The effects of the raw data themselves on the outcome of the in silico optimizations have not yet been unexplored.These first ed) taxa -8, an aped) taxa . As one in silico studies, we use a taxonomically diverse eukaryotic dataset to investigate traditional cDNA-AFLP experiments sensu Bachem [To overcome the limitations of previous u Bachem . Brieflyin silico AFLP on simulated DNA and cDNA datasets to address whether cDNA-AFLP patterning in real data differs from neutral expectations.The cDNA pool coverages obtained in these global analyses are based on the execution of all possible selective PCRs, but such extensive screens are often infeasible in the laboratory. To investigate potential differences in TDF recovery during selective PCR, we simulate all possible combinations of selective PCRs for each enzyme combination and species and extract information on the number of fragments produced per selective PCR. Because the maximum number of selective amplifications is frequently limited and the selective base pairs used in amplifications are not necessarily independent of each other, we use graphical representations to identify general patterns in the performance of selective amplifications. As a comparison, we perform in silico approach provides a realistic quantitative framework for the design of future cDNA-AFLP experiments. In addition to removing the guesswork from the design of such screens for non-model organisms, our in silico approach offers a powerful means for identifying general patterns in the transcriptomes of both model- and non-model species.Our comprehensive CBI and ENSEMBL databases provided a total of 113 pools of cDNA for this study. Twenty-one species were present in both databases, providing an opportunity to investigate the potential effects of database origin on pool coverage. While the data from NCBI and ENSEMBL differed significantly in many characteristics .NConsiderable variability exists in the observed cDNA pool coverage both within and across species Table  and 3. TA larger portion of the variation in coverage can be explained by biological factors Table , of whicThe choice of the most appropriate restriction enzymes substantially increases the coverage of a given cDNA pool from less than 40% to more than 75% Table . The effAnalyzing sequence data from a group of organisms with an evolutionary history as old and diverse as that of eukaryotes allows the quantification of the effects of taxonomic substructure on cDNA pool coverage. 68 of the 92 study species could be assigned to eight major taxonomic groups  conditions. As we wish to help the experimenter in designing experiments for their own target species, our data are based on whole organism cDNA equivalents rather than tissue-specific datasets, for which available data are much more restricted. In the course of this paper we refer to \"cDNAs\" as those transcript-derived sequences obtained from the above indicated repositories.An or AFLPs  was modiatabases ,7 lack aWe simulated cDNA-AFLPs for all 28 combinations of eight different restriction enzymes for 126 pools of eukaryotic cDNA (105 species). The eight restriction enzymes used here are commonly used in AFLP screens and were used in a previous simulation study [Initial analyses revealed that a small number of cDNA datasets contained an unusually high proportion of non-ACGT nucleotides . These datasets consisted of cDNA predictions based on early drafts of genome sequences for 13 mammalian species. Owing to the preliminary nature of these genome projects, many of the predicted cDNA sequences contained extended stretches of ambiguous base pairs (\"Ns\"). As a consequence, these sequences are effectively composed of two much shorter pieces of unambiguous sequence data. Because the probability of the presence of a particular restriction site is related to the length of a sequence, this reduction of the effective average sequence length can strongly influence the predicted cDNA pool coverage. As the peculiar nature of these poor quality datasets had a strong influence on preliminary GLMs, these species were excluded from further analyses. The remaining 113 datasets included here are listed in additional files XCEL macros and a JAVA routine and imported into SAS 9.1.3. The in silico cDNA-AFLP routine, EXCEL macros, JAVA tool, and raw data sets are available upon request from the corresponding authors.Our simulations returned information for each dataset and enzyme combination in separate results files. This information was collated into summary files using Ein silico PCRs by counting fragment numbers produced for all possible combinations of selective PCRs with three selective base pairs for each dataset and restriction enzyme combination. Three selective base pairs for each selective primer allow for a maximum of 43 \u00d7 43 different primer combinations for two enzymes, and thus this most inclusive data array contains 4096 cells. Arrays for all species tested here are available in additional file Most AFLP studies use two or three selective base pairs in their selective PCRs. We produced the most inclusive arrays of selective EQUENCE MANIPULATION SUITE[in silico cDNA-AFLP data derived from Homo sapiens  were used to study the relative importance of sequence characteristics and enzyme combinations in explaining cDNA pool coverage . All covariates were standardized by mean-centering and dividing by two standard deviations to control for the influence of different scaling factors in our predictor variables, and analyses were weighted by total pool size (in bp) to control for potential differences in variance estimates. We calculated partial R-square coefficients [Mixed model analyses  and the total pool size in base pairs (bp) are indicated. Avg Seq Lgt reports on the average sequence length, % GC indicates the percentage of GC nucleotides and Non-ACGT states the proportion of ambiguous nucleotides in each pool. Coverage \u00b1 SD reports the average percent coverage obtained across all 28 combinations of 8 tested restriction enzymes. The enzyme combination that provided the deepest cDNA pool coverage is indicated for each species.Click here for fileSpecies composition of included taxonomic groups. Taxonomic groupings for the 68 eukaryotic species derived from eight taxonomic groups with three or more representatives. Tax group indicates the taxonomic group (according to NCBI Taxonomy browser). The number of sequences (N Seq), the total pool size (in base pairs), average sequence length (Avg Seq Lgt) and GC content (% GC) are shown. Average coverage (\u00b1 SD), minimum and maximum coverage, along with the enzyme combination resulting in the deepest cDNA pool coverage for each species are indicated.Click here for fileDuplicate species from ENSEMBL and NCBI databases. Duplicate species from the ENSEMBL and NCBI databases. Average sequence length (Avg Seq Lgt), organismal GC-content (% GC) and the percentage of ambiguous base pairs (% non-ACGT) are indicated. The average pool coverage per enzyme combination, along with maximum and minimum coverage values, are shown.Click here for fileInfluence of database origin on pool coverage. The influence of database origin and enzyme choice on cDNA pool coverage for the 21 species present in both databases. We accounted for variability in coverage resulting from the nesting of species within database and weighted cDNA pool coverage by the number of sequences per pool to account for variation in available sequence data. Denominator degrees of freedom were Kenward-Roger corrected. Partial R-square indicates the proportion of the variation in cDNA pool coverage which is explained by each factor/interaction [eraction .Click here for fileArrays of all selective PCRs for all species and enzyme combinations. Selective PCR arrays using three-by-three selective base pairs for all 87 NCBI and 39 ENSEMBL species included in the present study, tested on all 28 combinations of 8 restriction enzymes.Click here for file"}
+{"text": "A study has been made of the thymidine labelling index (TLI) of marrow blast cells in 201 adults with untreated acute leukaemia. There was no significant difference between the TLI in 172 patients with acute myeloblastic leukaemia and 29 patients with acute lymphoblastic leukaemia. The TLI did not correlate with the age, sex, peripheral-blood or marrow blast-cell count, or the platelet count at presentation. In neither acute myeloblastic leukaemia nor acute lymphoblastic leukaemia was there any correlation between the TLI and the response to the initial therapy, the duration of the first complete remission or survival."}
+{"text": "The effect of 17 beta-oestradiol on a \"receptor positive\" and on a \"receptor negative\" human breast carcinoma grown in nude mice was studied. Experimental growth data were used to determine the effect on tumour growth. Flow cytometric DNA analysis (FCM) performed on tumour tissue obtained by sequential fine-needle aspirations was used to estimate the effect on the cell cycle. In the receptor-positive breast carcinoma, oestradiol induced complete tumour regression and characteristic cell cycle changes. In the receptor-negative breast carcinoma, no changes in tumour growth and cell cycle distribution could be demonstrated following the treatment. The results indicate that the oestradiol-induced cell kill could be explained to some extent by the induction of polyploid cells, which eventually die. Since the cell cycle changes monitored by FCM in the receptor-positive breast carcinoma appeared prior to any reduction in the tumour size, the results suggest that FCM may prove a valuable method in the early detection of tumour response to hormone treatment in human breast cancer."}
+{"text": "As MIBG is now being incorporated into multimodal approaches to therapy, important questions arise about the appropriate scheduling and sequencing of the various agents employed. As the ability of neuroblastoma cells to actively accumulate MIBG is crucial to the success of this therapy, the effect of chemotherapeutic agents on this uptake capacity needs to be investigated. We report here our initial findings on the effect of cisplatin pretreatment on the neuroblastoma cell line SK-N-BE (2c). After treating these cells with therapeutically relevant concentrations of cisplatin (2 microM and 20 microM), a stimulation in uptake of [131I]MIBG was observed. Reverse transcription-polymerase chain reaction (RT-PCR) analysis demonstrated that this effect was due to increased expression of the noradrenaline transporter. These results suggest that appropriate scheduling of cisplatin and [131I]MIBG may lead to an increase in tumour uptake of this radiopharmaceutical with consequent increases in radiation dose to the tumour."}
+{"text": "We used Surgisis\u00ae as an alternative surgical approach to common onlay patch surgery of the urethra performed on two Caucasian patients: a 48-year-old man and a 55-year-old man.In these two case reports, we show the positive results of reconstructive surgery with Surgisis\u00ae is considered a relevant therapeutic alternative because of the shorter operation time and the preventable surgery of the buccal cavity or foreskin.Compared to buccal mucosa flap or foreskin graft surgeries for urethral reconstruction, reconstructive surgery with Surgisis Urethral strictures are defined as restrictions of the urethral lumen irrespective of length and localization. Independent of its origin, diagnosis and treatment of a urethral stricture should be carried out as early as possible in order to avoid irreversible long-term damage -2]..2].Every process affecting the urethral urothelium and the covered tissue of the cavernous body may induce scarring, which can cause urethral stricture. Internal urethrotomy using the Sachse technique is a well established surgical approach for treatment of primary strictures.Particularly for recurrent or long-segment strictures, open surgical approaches should be preferred because of the known lower relapse rate -4]. Wid. Wid4]. \u00ae) as an onlay patch .,8.\u00ae in u\u00ae appears to be a reasonable alternative to buccal mucosa flap or foreskin graft surgery in urethral reconstructive surgery. An important advantage of Surgisis\u00ae is the prevention of the additional surgery needed in order to obtain a buccal mucosa or foreskin graft. Thus postoperative morbidity and overall surgery time decrease.Application of the commercially provided implant system SurgisisSIS: small intestinal submucosa.The authors declare that they have no competing interests.Written informed consent was obtained from the patients for publication of these case reports and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.TH was involved in drafting the manuscript and in the review of the literature and in performing the clinical follow-up. HG was involved in drafting the manuscript and in the review of the literature. SH participated in the surgery and was involved in the clinical follow-up. JR participated in the surgery, was involved in the clinical follow-up and supervised this report. All authors read and approved the final draft."}
+{"text": "Therapeutic targeting of HIV latency requires an understanding of the basic mechanisms regulating viral quiescence and activation.in situ hybridization, we found that chromatin imposes silencing in a highly specific spatial and temporal pattern. We also identified several cellular factors that interact with viral RNA by a proteomic approach, pointing to post-transcriptional processes that have been greatly overlooked as mechanisms of HIV post-integrative latency.We identified several levels of transcriptional and post-transcriptional control of viral genes expression. By looking at the organization of chromatin at the site of integration by chromatin conformation capture and HIV-1 can integrate within active genes at the periphery of the nucleus, and silencing may involve repression from a peri-centromeric region in trans. Hence, a mechanism of active spatial reorganization of chromatin at the site of proviral integration may be ultimately responsible for virus silencing. Particularly relevant to flushing therapies of the viral reservoir is the observation that the silent state of an integrated provirus in a clonal population of activated lymphocytes is not homogeneous, with a small number of cells carrying a provirus embedded into heterochromatin, compared with the majority of cells where the provirus is already poised for transcription.nrb that have been previously in nuclear retention of RNA. We demonstrated that PSF/p54nrb binds nascent HIV RNA at the transcription site, but MATR3 defines a novel sub-nuclear compartment where this viral RNA is retained. Rev is able to associate with unspliced HIV RNA co-transcriptionally directing its nuclear export. These observations lead to a model for a novel cellular pathway of RNA retention that is hijacked by the virus.Proteomic analysis revealed several novel cellular factors, including PSF, MATR3 and p54Both the control imposed by the organization of the nucleus and by post-transcriptional mechanisms is relevant for the control of HIV-1 post-integrative latency."}
+{"text": "An implantation model has been used to investigate the cellular progression of chemically induced subcutaneous neoplasia in the mouse. Implantation of 3,4-benzpyrene induced persistent changes in the normal process of connective tissue formation around the implant. Light-microscope and autoradiographic studies have shown a temporal progression from aberrant filter- or muscle-associated cells through proliferative foci to large invasive sarcoma. Electron microscopy revealed that presarcomatous cell foci consisted of one of two different cell types. These were either spindle cells with ultrastructural characteristics similar to foreign-body-induced sarcoma, or cells with the ultrastructural features of rhabdomyosarcoma. The subsequent appearance of two histological groups of sarcoma that were ultrastructurally similar to the cells of the early proliferative foci indicated that both elements may progress to form tumours. However, the constituent cells of both groups of tumours displayed a broad histological and ultrastructural spectrum and the marked similarity between the undifferentiated cells of each suggested that both may have arisen from diverse differentiation of a common pluripotential cell such as the pericyte."}
+{"text": "In five multiplex reactions, 6738 sequence tagged site (STS) markers were successfully typed on the WGRH3000 panel DNA. These STSs harboured SNPs that were developed as a result of the bovine genome sequencing initiative. Typically, the most time consuming and expensive part of creating high-density radiation hybrid (RH) maps is genotyping the markers on the RH panel with conventional approaches. Using the method described in this article, we have developed a high-density whole-genome RH map with 4690 loci and a linkage map with 2701 loci, with direct comparison to the bovine whole-genome sequence assembly (Btau_2.0) in a fraction of the time it would have taken with conventional typing and genotyping methods.High-density whole-genome maps are essential for ordering genes or markers and aid in the assembly of genome sequence. To increase the density of markers on the bovine radiation hybrid map, and hence contribute to the assembly of the bovine genome sequence, an Illumina\u00ae BeadStation was used to simultaneously type large numbers of markers on the Roslin-Cambridge 3000 rad bovine\u2013hamster whole-genome radiation hybrid panel (WGRH Radiation hybrid (RH) mapping is a powerful tool that can be utilized for the production of in-depth comparative maps of single chromosomes and whole genomes. The construction of an RH map relies upon scoring the presence or absence of markers in a hybrid cell panel constructed by fusing irradiated donor cells with recipient rodent cells. Conventional methods for typing markers on RH panels rely on individual or low-complexity multiplex PCR assays for all typed markers on DNA derived from each of the cell lines in the panel, followed by agarose gel electrophoresis to detect the presence or absence of the marker in individual RH cell lines. The proportion of the DNA fragments from the donor genome that harbor any particular marker will vary between the cell lines and so signal intensity varies among the positive cells. Signal differences as well as PCR artifacts and differentiation of rodent vs. target species amplification products usually necessitates running assays in duplicate and on occasion in triplicate to confirm results.Radiation hybrid mapping in cattle was established in the late 1990s with the creation of the 5000-rad panel . Oligonucleotides were designed, synthesized and assembled into oligo pooled assays (OPA) by Illumina Inc.Information for sequences containing SNPs was obtained from public databases  panel plus hamster and bovine control DNA samples (http://www.illumina.com). Typing was carried out in five multiplex reactions which included all 6738 loci in the final assay pool. Illumina\u00aegencall software was used to manually score the presence or absence of loci across the RH panel clones. The donor bull used to construct the RH panel was either homozygous or heterozygous for each of the markers. For the homozygous markers, positive and negative clones formed two distinct clusters  or the U genotypes as absent (0). In contrast, the heterozygous markers produced four clusters  for the marker. These ambiguities were not eliminated with the high-throughput approach described here. As seen in 3000 map  to an SNP already included in the map was integrated into the map only if an available RH location, bovine BLAST hit or human BLAST hit localized the SNP to the same chromosomal region. Finally we utilized the FLIPS5 option of Of the 6738 loci included in the Illumina oligo pooled assays, 5815 (86.3%) were successfully typed and 4690 of the 5815 (80.7%) were assigned to the RH map. These rates exceeded the 62.3% success rate in our laboratory using conventional RH typing methods (data not shown). Of the 4690 markers whose RH map locations were determined, 4334 were SNPs identified as a result of the bovine whole-genome sequencing initiative. Furthermore, 2701 of these markers were included in a high-density linkage map and used to estimate recombination distance among loci and to confirm locus order produced in the RH map . At leas3000 . Linkage maps containing 2701 loci were constructed for all autosomes, and human\u2013cattle comparative maps were built. We report cR3000 locations for 4690 markers, cM location for 2701 markers and Mb positions for 1801 of the 4690 loci. This approach for high-throughput RH mapping has allowed us to rapidly assemble comprehensive maps of the bovine genome.An updated WGRHet al. personal communication) and will be used for the next assembly of the bovine genome sequence.Generally, linkage maps are conducive to the high-level ordering of loci along a chromosome with a resolution that is generally determined by the number of informative meioses. On the other hand, RH maps are often superior for fine-mapping closely linked loci (de novo RH maps from short sequences can now be accomplished rapidly and cost effectively. This strategy appears to be particularly useful for the development of high-content maps necessary for the assembly of whole-genome shotgun sequences. On the other hand, for those genomes where a sequence assembly is not likely in the near future, the approach described here may provide an effective means of generating comprehensive comparative maps. High-throughput RH mapping may contribute towards low-cost genome sequencing by coupling the methodology described here with 454 sequencing technology (The use of high-density SNP assays such as the Illumina GoldenGate or Infinium platforms harbouring as many as 64 000 loci per assay will allow typing of a whole-genome RH panel in as little as one day. Thus, the generation of"}
+{"text": "We report evidence for the secretion of a true mammalian collagenase active against Type 1 collagen, by naturally-occurring mammary tumours of the mouse and show that tumours capable of heavily colonizing the lungs secrete significantly more of this enzyme than those with low pulmonary-colonization potential, or non-neoplastic proliferating (e.g. lactating) mammary tissue. Plasminogen activator is secreted in greater quantity by tumours than by normal tissues, but there is no significant difference in the amount produced by tumours with high or low pulmonary-colonization potential. These findings correlate well with our earlier morphological observations of marked connective tissue destruction in the vicinity of invading tumours and metastatic deposits, and indicate that protease release is implicated in the mechanism of tumour spread."}
+{"text": "In addition, oral WEB 2170 treatment in dual responder primates blocked the acute influx of neutrophils into the airways as well as the associated late-phase airway obstruction occurring 6 h after antigen inhalation. In contrast, a multiple dosing regime with WEB 2170 (once a day for 7 consecutive days) failed to reduce the chronic airway inflammation (eosinophilic) and associated airway hyperresponsiveness to inhaled methacholine that is characteristic of dual responder monkeys. Thus, we conclude that the generation of PAF following antigen inhalation contributes to the development of lipid mediators, acute airway inflammation and associated late-phase airway obstruction in dual responder primates; however, PAF does not play a significant role in the maintenance of chronic airway inflammation and associated airway hyperresponsiveness in this primate model.We have examined the effects of a PAF receptor antagonist, WEB 2170, on several indices of acute and chronic airway inflammation and associated changes in lung function in a primate model of allergic asthma. A single oral administration WEB 2170 provided dose related inhibition of the release of leukotriene C"}
+{"text": "The last decade has witnessed unprecedented developments in the genetic and epigenetic analyses of solid tumours. Transcriptional and DNA copy-number studies have improved our understanding and classification of solid tumours and highlighted the patterns of genomic aberrations associated with outcome. The identification of altered transcriptional and translational silencing by microRNAs and epigenetic modification by methylation in tumours has showed a layer of additional intricacy to the regulation of gene expression in different tumour types. The advent of massive parallel sequencing has allowed whole cancer genomes to be sequenced with extraordinary speed and accuracy providing insight into the bewildering complexity of gene mutations present in solid tumours. Functional genomic studies using RNA interference-screening tools promises to improve the classification of solid tumours by probing the relevance of each gene to tumour phenotype. In this review, we discuss how these studies have contributed to solid tumour classification and why such studies are central to the future of oncology. We suggest that these developments are gradually leading to a change in emphasis of early clinical trials to a therapeutic model guided by the molecular classification of tumours. The investigation of drug efficacy later in development is beginning to rely on patient selection defined by predictive molecular criteria that complement solid tumour classification based on anatomic site. Therapeutic decision-making in oncology after surgical resection of the tumour (adjuvant treatment) is based on an assessment of the risk of tumour relapse. Risk profiling is a complex and often imprecise task that has focussed on the clinical and histopathological features of the tumour. Molecular profiling of gene expression over the last decade has shown that heterogeneity in outcome and survival in cancer can be explained, in part, by genomic variation within the primary tumour  is currently validating one such 21 gene signature by RT\u2013PCR, developed from an analysis of three breast cancer studies in 447 patients, to guide risk stratification among patients with node-negative oestrogen receptor (ER)-positive breast cancer treated with tamoxifen ,  is associated with poorer outcome in many solid tumours including breast and colon cancer  are small non-coding RNAs that negatively regulate gene expression through the inhibition of mRNA translation or the initiation of mRNA degradation. The tissue-specific expression of miRNAs has provoked intense investigation to identify whether these non-coding RNAs can reflect signatures of tumour origin, prognosis and outcome. In one of the first investigations of 217 miRNAs in 334 tumour and normal tissue samples, miRNA expression profiling segregated tumours by developmental origin and had the capacity to correctly identify the tissue of origin of poorly differentiated tumours, in contrast to an mRNA-based tissue classifier  sequencing analysis has shown recurrent mutations in isocitrate dehydrogenase 1 (IDH1) in 12% of patients (The Cancer Genome Atlas Research Network recently published data of a similar analysis in GBM-combining gene expression profiling, DNA copy-number analysis with methylation and nucleotide sequencing analysis (Classification studies in solid tumours have showed the complex heterogeneity of gene and miRNA expression that may account for the unpredictable clinical behaviour and response to therapy in solid tumours, exacerbated further by underlying tumour genomic instability. We propose a model,  whereby Clinical trials investigating activity of EGFR-directed therapies using kRAS and EGFR receptor mutation status as biomarkers of response have altered the landscape of targeted therapy use. Clinical strategies to maximise response to Her2-targeted agents in tumours with PI3KCA mutations and/or PTEN loss are being considered based on knowledge of downstream signalling pathways. The specific targeting of a distinct pattern of genomic instability is the subject of investigation in the phase II trial CINATRA discussed in this paper.Finally, although most genes are only mutated at low frequency in each tumour type, the identification of functional gene groups belonging to the same signalling pathway, may provide opportunities for therapeutic exploitation. For example, all pancreatic cancers analysed had gene alterations in the Wnt and Hedgehog signalling pathways. Therefore, although a large number of genes are mutated in solid tumours, the number of pathways through which they function is relatively small. These studies provide a compelling focus for pathway directed, rather than traditional tumour-type specific interventions."}
+{"text": "A new non-invasive method for monitoring apoptosis has been developed using high frequency (40 MHz) ultrasound imaging. Conventional ultrasound backscatter imaging techniques were used to observe apoptosis occurring in response to anticancer agents in cells in vitro, in tissues ex vivo and in live animals. The mechanism behind this ultrasonic detection was identified experimentally to be the subcellular nuclear changes, condensation followed by fragmentation, that cells undergo during apoptosis. These changes dramatically increase the high frequency ultrasound scattering efficiency of apoptotic cells over normal cells (25- to 50-fold change in intensity). The result is that areas of tissue undergoing apoptosis become much brighter in comparison to surrounding viable tissues. The results provide a framework for the possibility of using high frequency ultrasound imaging in the future to non-invasively monitor the effects of chemotherapeutic agents and other anticancer treatments in experimental animal systems and in patients. \u00a9 1999 Cancer Research Campaign"}
+{"text": "The clinical formulation of the anti-tumour agent Taxol involves the use of a mixture of ethanol and Cremophor EL. Gel electrophoresis and density-gradient ultracentrifugation were used to detect effects of Taxol infusions on serum lipoproteins. Use of the Cremophor vehicle results in a decrease in the electrophoretic mobility of serum lipoproteins along with the appearance of a lipoprotein dissociation product. These effects persist during a 24 h infusion and for at least 1.5 h afterwards, and can be reproduced in vitro using purified high-density lipoprotein (HDL) or low-density lipoprotein (LDL). In control serum, Taxol binds to albumin > HDL, but after serum is exposed to Cremophor EL in vitro or in vivo substantial binding of Taxol to the lipoprotein dissociation product(s) was observed. The latter could represent an important factor in taxol biodistribution."}
+{"text": "The molecular cytogenetic techniques of comparative genomic hybridization (CGH) and reverse in situ hybridization (REVISH) allow the entire genomes of tumours to be screened for genetic changes without the requirement for specific probes or markers. In order to define the ability of REVISH to detect and map regions of amplification associated with drug resistance, we investigated a panel of cell lines selected for resistance to doxorubicin and intrinsic sensitivity to topoisomerase II-inhibitory drugs. We have defined a modified REVISH protocol, which involves double hybridizations with genomic DNA from the test cell lines and chromosome-specific whole chromosome paints to identify the chromosomes to which the amplicons localize. Sites of amplification are then mapped by fractional length measurements (Flpter), using published genome databases. Our findings show that amplification of the topoisomerase II alpha gene is readily detected and mapped, as is amplification of the MDR and MRP loci. Interestingly, REVISH detected a new amplicon in the doxorubicin-resistant lung cancer cell line, GLC4-ADR, which mapped to chromosome 1q. REVISH is therefore ideally suited to characterize genetic changes specific for drug resistance within a background of genetic anomalies associated with tumour progression."}
+{"text": "It has been suggested that sensitivity of ovarian carcinomas to cisplatin is in part related to an endogenous folate deficiency. In this work, we investigated whether overexpression of the folate-binding protein (FBP), a receptor involved in folate transport, might be associated with cisplatin sensitivity. The results obtained on a panel of ten ovarian carcinoma cell lines that overexpress different levels of the FBP showed a statistically significant relationship between FBP overexpression and cisplatin responsiveness, with the most sensitive cell lines expressing higher FBP levels on their membrane than the less sensitive ones. The relationship was observed both in cells growing in standard medium-containing high-folate concentrations (2.3 microM) and in cells adapted to growth in low-folate (20 nM) medium. Analysis of two cisplatin-resistant cell lines derived from the cisplatin-sensitive IGROV1 ovarian carcinoma cell line indicated that resistance was associated with a significant decrease in FBP expression. However, the receptor does not appear to be directly responsible for drug sensitivity per se as different cell lines transfected with FBP cDNA did not become more sensitive to the drug. Together, the data suggest the possible predictive value of FBP in ovarian carcinoma, as higher levels of expression can be indirectly but significantly associated with increased drug sensitivity."}
+{"text": "While three countries in South Asia decided to eliminate anthroponotic visceral leishmaniasis (VL) by 2015, its control in other regions seems fraught with difficulties. Is there a scope for more effective VL control in the Americas where transmission is zoonotic? We reviewed the evidence on VL control strategies in Latin America\u2014diagnosis, treatment, veterinary interventions, vector control\u2014with respect to entomological and clinical outcomes.We searched the electronic databases of MEDLINE, LILACS, and the Cochrane Central Register of Controlled Trials, from 1960 to November 2008 and references of selected articles. Intervention trials as well as observational studies that evaluated control strategies of VL in the Americas were included. While the use of rapid diagnostic tests for VL diagnosis seems well established, there is a striking lack of evidence from clinical trials for drug therapy and few well designed intervention studies for control of vectors or canine reservoirs.Elimination of zoonotic VL in the Americas does not seem a realistic goal at this point given the lack of political commitment, gaps in scientific knowledge, and the weakness of case management and surveillance systems. Research priorities and current strategies should be reviewed with the aim of achieving better VL control. Leishmania infantum (syn. Leishmania chagasi). Humans acquire the infection through the bite of an infected sand fly. The disease is potentially lethal if untreated. VL is reported from Mexico to Argentina, with recent trends showing a rapid spread in Brazil. Control measures directed against the canine reservoir and insect vectors have been unsuccessful, and early detection and treatment of human cases remains as the most important strategy to reduce case fatality. Well-designed studies evaluating diagnosis, treatment, and prevention/control interventions are scarce. The available scientific evidence reasonably supports the use of rapid diagnostic tests for the diagnosis of human disease. Properly designed randomized controlled trials following good clinical practices are needed to inform drug policy. Routine control strategies against the canine reservoirs and insect vectors are based on weak and conflicting evidence, and vector control strategies and vaccine development should constitute research priorities.Visceral leishmaniasis is a vector-borne disease characterized by fever, spleen and liver enlargement, and low blood cell counts. In the Americas VL is zoonotic, with domestic dogs as main animal reservoirs, and is caused by the intracellular parasite  Leishmania infantum (syn. L. chagasi). VL is a zoonosis: the domestic dog is the main animal reservoir, while foxes and other wild animals play a role in sylvatic transmission Lutzomyia longipalpis, a 2 to 3 mm-long insect well adapted to the peri-domestic environment and distributed throughout Latin America L. infantum is also transmitted by Lu. cruzi in Brazil Lu. evansi in Colombia, and Venezuela L. infantum infections lead to overt clinical disease: in Brazil ratios of 8\u201318 incident asymptomatic infections to 1 incident clinical case were described Visceral leishmaniasis (VL) in Latin America is a severe systemic disease caused by an intracellular protozoon, http://apps.who.int/tools/geoserver/www/ecomp/index.html (Accessed on September 19 2009).The VL disease burden in Latin America is not exactly known because most countries lack effective surveillance systems Control of VL in the Americas has proved challenging. Early diagnosis and treatment is essential for the patient, but has limited impact on transmission if the main animal reservoir or insect vectors are not tackled In the Mediterranean region, where VL is also zoonotic with dogs playing a role as main reservoirs, human cases and canine cases are treated with antiparasitic drugs. In Europe, individual measures to protect dogs from sand fly bites using insecticides are common practices, but no public health surveillance and control interventions such as those applied in Brazil are in place L. donovani being the causative agent, a different sandfly vector (P. argentipes) and -most importantly- anthroponotic instead of zoonotic transmission, we wanted to examine whether there is a scope for VL elimination or at least improved control in the Americas. Given the heterogeneity in causative species, vector and transmission pattern, evidence on VL control tools from one region cannot be readily extrapolated to another. We report a review of the literature on the effectiveness of novel VL control tools and strategies in Latin-America structured around diagnosis of human and canine VL, treatment of human cases and control of the animal reservatoir and arthropod vectors.Recently, the governments of India, Bangladesh and Nepal launched a VL elimination initiative, aiming to reduce the annual incidence of VL to less than 1/10,000 population by 2015 The review on VL control interventions was structured around the following topics: (i) Diagnosis of human VL; (ii) Treatment of human VL; (iii) Diagnosis of canine VL; (iv) Control of the animal reservoir and vector. Diagnosis of human VL: For the PubMed search:  AND  AND \u201cAmericas\u201d [MeSH]. For the LILACS search the key-words: leishmaniasis AND visceral AND (diagnosis OR DAT OR dipstick) were used.Treatment of human VL: For the PubMed search the following key-words were used:  AND  AND \u201cAmericas\u201d [MeSH]. For the LILACS search the key-words: leishmaniasis AND visceral AND treatment were used. For the Cochrane Central Register of Controlled Trials we used the term visceral leishmaniasis because the search with the key-words and MeSH terms used for the PubMed searching failed to retrieve any paper.Diagnosis of canine VL: For the PubMed search:  AND  AND \u201cAmericas\u201d [MeSH]. For the LILACS search the key-words: canine AND leishmaniasis AND visceral AND diagnosis were used.Control of the animal reservoir and arthropod vector: for the PubMed search:  AND \u201cAmericas\u201d [MeSH] AND control. The LILACS search was performed using the term visceral leishmaniasis OR leishmaniose visceral OR leishmaniasis visceral because of the failure to retrieve any paper when using the PubMed approach.In a next step, the titles, abstracts and if necessary the full text of the studies was examined to identify relevant papers for the review. Data were extracted by one researcher directly from the full length articles to structured tables containing all the descriptive variables and relevant outcomes. The inclusion criteria, data extracted for each item and summary measures are listed below.L. donovani or L. infantum and the rK39-ICT As we have stated above, we set out to examine whether the existing control tools allow for elimination of VL in the Americas. The goal of elimination requires diagnostic and therapeutic tools that are very easy to use and can be easily decentralized. The World Health Organization now considers two \u2018rapid diagnostic tests\u2019 as appropriate for the diagnosis of VL in control programs: the Direct Agglutination Test (DAT) based on whole promastigotes of The eligibility criteria included: original studies evaluating the DAT or the rK39 immunochromatographic test (ICT); clinical visceral leishmaniasis diseases in humans as target condition; adequate reference classification; absolute numbers of true-positive, true-negative, false-positive and false-negative observations available or derivable from the data presented. Accuracy measures were summarized as sensitivity and specificity.Clinical trials including uncontrolled and retrospective studies with description of the following characteristics: intervention; case definition; follow-up schedule; therapeutic endpoints; control group; and efficacy measure defined through cure and failure proportions for each treatment.Leishmania infection and/or VL disease in domestic dogs as target condition; adequate reference classification; absolute numbers of true-positive, true-negative, false-positive and false-negative observations available or derivable from the data presented. Accuracy measures were summarized as sensitivity and specificity.Original studies evaluating any diagnostic test for canine leishmaniasis; Field trials of control measures  evaluating at least one control measure; description of the intervention under analysis; target population, sampling and randomization process; adequate case definitions for asymptomatic infection or VL; definition of outcomes related to humans, dogs or sand flies; at least one effect measure; and at least one point estimation for the magnitude of the expected effect.A Medline search generated 77 papers, and LILACS 179. After screening the titles and abstracts of those papers for evaluations of the DAT or rK39 in human VL, we retrieved eight original papers . We repoLeishmania species. However, this meta-analysis included only two studies from Latin \u2013America, both from Brazil, and both with small sample sizes. Garcez et al (1996) reported 100% sensitivity on 16 parasitologically confirmed VL cases and 98.3% specificity on a mixed group of 65 healthy endemic controls and patients with other diseases L. chagasi and IgG-IFAT) and concluded that the FD-DAT was the most efficient, with 96.6% sensitivity (n\u200a=\u200a88) and 98.1% specificity (n\u200a=\u200a105) Andrade et al (1989) were the first to report a proof-of-principle evaluation of the DAT in Brazil Delgado et al (2001) evaluated the rK39-ICT in Venezuela, reporting 87.8% sensitivity (36/41 confirmed VL) and a specificity of 100%. The lower sensitivity was attributed to the fact that the false negative sera had been kept at \u221270\u00b0 for more than 10 years What should be the diagnostic algorithms for VL for use in primary health care and in active case detection campaigns?How to assure the quality of available VL rapid diagnostic tests?How to define asymptomatic infected individuals (and how to manage them?)Leishmania co-infection in HIV/AIDS cases?How to improve clinician's awareness about the possibility of What can be the contribution of novel (molecular) parasite detection tests to clinical diagnosis?Leishmania co-infections?What is the performance of diagnostic assays in HIV-What is the performance of antibody-assays in patients from areas with sympatric circulation of parasites causing cutaneous leishmaniasis?Seventy-seven papers were retrieved from Medline/PubMed search and 11 of them were considered relevant. The LILACS database search retrieved 26 papers of which 2 were considered relevant, but 1 was already obtained from the PubMed database . FinallyRecently more \u201cuser-friendly\u201d diagnostics as the DAT and a canine version of the rK39-ICT were evaluated with good results. For the freeze-dried DAT sensitivity ranged from 85\u2013100%, specificity 89\u2013100% Sensitive antigen detection tests as PCR might become a relevant marker of infection in the future with the advantage that they can still be used in vaccinated dogs that will be serologically positive because of the vaccine. However, Quinnell et al (2001) showed in a longitudinal study of naturally infected dogs how the sensitivity of PCR was high early after infection but declined to 50% thereafter. The sensitivity of serology also varied with time, being lowest at the time of infection but clearly superior thereafter (93\u2013100%). They concluded that PCR was most useful for detection of active disease, and considered serology as more adequate for the detection of infection What is the most cost-effective diagnostic strategy for a screen-and-treat or screen-and-cull campaign? Novel screening strategies based on combined, parallel or sequential use of current available tests need to be validated.How to distinguish an antibody response due to natural infection from that produced after vaccination in dogs?What can be the contribution of novel, molecular, parasite detection tests to clinical diagnosis in dogs?What is the value of the current diagnostic tests in terms of dog infectivity for sandflies?Thirty-nine papers were retrieved from Medline/PubMed search and four of them were considered relevant. The LILACS database search retrieved 42 papers of which 24 were not available from the PubMed database. Three of those 24 studies were considered relevant, one of them, was previously identified through the PubMed search. One paper was identified through specific author's name searching in PubMed. The Cochrane Central Register of Controlled Trials search retrieved 103 trials, three of them were conducted in the Americas but all were also identified through the PubMed and LILACS searches. Finally, seven papers were included for review Three papers were excluded from further analysis, one because it was a second publication on the same trial Dietze et al (1993) reported an open-label dose-escalating trial with amphotericin B colloidal dispersion (Amphocil) in two small groups of patients who showed similar cure rate suggesting that the 7 days was as effective as the 10 days regimen What is the current standard of care for VL treatment in the Americas?What is the case for combination therapy for VL in the Americas?What is the standard of care in VL/HIV co-infection?What is the current efficacy of pentavalent antimonials, amphotericin B deoxycholate and the liposomal formulations, miltefosine and drug combinations for VL treatment in the Americas?Are there more efficacious, safer, and simpler therapeutic schemes for VL than the current ones?Can a clinical prognostic score for treatment failure be developed to identify those cases most in need for intensive care?What is the role of non-parasite targeted drugs such as immunomodulators, antibiotics and others in VL treatment?Incidence and prevalence estimates of canine VL in the Americas have been reported from several foci visceral leishmaniasis because no document was retrieved when using the PubMed approach. The LILACS search was less specific and 519 documents were retrieved; 514 documents comprised an extensive spectrum of research irrelevant for the purpose of this paper and four of the five relevant papers were already identified through the PubMed search. After reading the titles and the abstracts and hand searching reference lists for related papers, fourteen were selected for full text reading because the main subject was at least one intervention for control VL  published a retrospective \u2013non controlled- study on the impact of a combined intervention consisting of human VL case treatment, culling of seropositive dogs and insecticide spraying with DDT in 19 municipalities of the Rio Doce Valley, State of Minas Gerais, Brazil reporting the disappearance of human symptomatic cases after 15 years of application of this strategy Dietze et al (1997) reported a field trial of dog screening and culling, based on twice-yearly screening with DOT-ELISA. This trial was conducted in three rural valleys, State of Espirito Santo, Brazil, two benefiting from the intervention and one used as control. At 6-months there was a 16% reduction of seroconversion rate in dogs (36% in the intervention vs. 52% in the control group), but this difference was not significant Braga et al (1998) reported the comparison of two strategies of dog screening-and-culling: screening by ELISA was compared to IFAT as routinely recommended by the National Control Program. The main difference consisted in the lag times after blood sampling (7 days for ELISA vs. 80 days for IFAT). The trial was conducted in a rural area of Northeastern Brazil where 28 communities were systematically allocated to one of the two groups. In the ELISA arm, reduction of canine seroprevalence was higher, probably due faster dog removal plus higher sensitivity of the ELISA test Ashford et al (1998) reported a controlled intervention trial of seropositive dog removal in an endemic area of the State of Bahia, Brazil. The intervention area was subjected to screening with FAST-ELISA and removal of seropositive dogs, in the control area no intervention was carried out. A significant reduction of dog seroconversion rate in the intervention area as compared to control was observed, and a significantly lower number of VL cases reported to health facilities in the intervention area Paranhos-Silva et al (1998) report a follow- up study of several clusters of seronegative dogs in Jequi\u00e9, State of Bahia, Brazil. The initial prevalence of infection among 1681 dogs was 23.5%. After serological screening every six months for 18 months and removal of the seroconverters, the annual incidence rate of infection was 6.55 cases/100dog-years. The migration of dogs between clusters was 2.3 cases/100 dog-years. This study is relevant because as highlights the challenges posed by dog migration for any control program dealing with the canine reservoir L. donovani antigen. Follow-up evaluations were performed at 2, 7, 13 and 24 months. A significant difference in the three endpoints was observed during the trial. The overall efficacy to prevent symptomatic VL disease was 75% Da Silva et al (2000) reported a phase III vaccine field trial in seronegative dogs screened with IFAT and FML-ELISA and exposed to fucose-mannose-ligand vaccine in three subcutaneous doses at 21 day intervals. Control arm was treated with saline placebo. Endpoints were symptomatic VL or death, seroconversion rates in FML-ELISA and conversion of leishmanin skin test composed of crude Giffoni et al (2002) reported the effect of application of a 65% permethrin spot-on formulation on canine VL infection and sandfly abundance. A decrease of canine VL prevalence was observed in the intervention area compared with increased prevalence in the control area. No effect was observed on sandfly population Lu. longipalpis. A significant decrease of sandfly abundance was observed, with a residual effect of indoor spraying of 3 months. Main limitation of this study was the specific construction style of the houses: completely cemented, plastered and oil-painted walls and zinc roofs, which lowers its external validity Feliciangeli et al (2003) described a controlled trial of pyrethroid  indoor spraying every 5 month and organophosphate (fenitrothion) ultra-low volume spatial fogging around the houses twice a month for ten months in one intervention compared to one control area. The main vector captured was De Oliveira et al (2003) reported the evaluation of routine combined control measures of seropositive dog-culling and insecticide spraying during six years. The intensity of the application of control measures correlated with human VL incidence, the coverage of canine surveys, the number of canine surveyed and the number of buildings submitted to insecticide spraying Reithinger et al (2004) reported a controlled field trial to evaluate the effectiveness of insecticide impregnated collars to prevent infection detected through serological tests or DNA detection by PCR assay in one intervention compared to one control area. The authors failed to detect a significant difference between groups in the incidence of new infections but they demonstrated a significant reduction of antibody titers in the collar protected dogs. Mathematical modeling using the results obtained in this study suggests that dog collars would be a better alternative than dog culling Leishmania infection in a cohort of dogs submitted to an optimized culling strategy consisting of: (i) ELISA screening of serum samples; (ii) shortening of the time interval from serodiagnosis to removal of dogs; (iii) screening a high proportion of the dog population. They demonstrated that the incidence of canine infection remained stable through 2.5 years of observation under this strategy but the study had no control arm for comparison. A high replacement rate by susceptible puppies and already infected dogs was observed Moreira et al (2004) reported the incidence rates of canine Lu. longipalpis in households using deltamethrin-impregnated bednets compared others using untreated bed nets. The study described a 39% increase in barrier capacity of the impregnated bednets, 80% reduction in sandfly landing rates on humans and 98% increase in the 24-h sandfly mortality rates. The study was done under field conditions with a small number of observations during a very short period of exposure to the treated bednets (three days) and the residual effect was not measured. However this intervention should be explored further because it could bring an additional benefit in areas where malaria is also endemic Courtenay et al (2007) reported the barrier effect, the 24-h mortality rate and the human landing rates of Costa et al (2007) reported a randomized community intervention trial to compare the effect of four strategies on human VL, as follows: (i) spraying houses and animal pens with pyrethroid insecticide; (ii) spraying houses and eliminating seropositive dogs; (iii) combination of spraying houses and animal pens plus eliminating seropositive dogs; and (iv) spraying houses only as the reference comparator. The outcome was evaluated by measuring incidence of seroconversion in humans six months after the application of interventions. The results indicated a positive effect of canine removal on incidence of leishmanial infection in men but surprisingly, the combination of dog culling plus outdoor spraying of peridomestic animal shelters failed to demonstrate any effect. The relevance of this study is that it constitutes the first attempt to measure the effect of combined interventions on human VL incidence De Souza et al (2008) reported a randomized community intervention trial to compare the effect of (i) pyrethroid insecticide spraying; (ii) pyrethroid insecticide spraying plus culling of seropositive dogs with (iii) no intervention. The interventions were maintained for two years and outcomes were registered every year, insecticide spraying was performed every 6 months. Although a lower incidence was observed in the groups submitted to interventions and that reduction was more intense after two years, the study failed to detect statistically significant differences The summarized characteristics and main limitations of these studies are shown in What is the most cost-effective control strategy for VL?How to conduct a valid impact evaluation?Can general support measures  be targeted to VL endemic areas?What is the potential impact of current dog vaccines on transmission?What are the determinants of dog infectiousness for the sandfly vector?What are the determinants of dog susceptibility to infection?What is the efficacy of current dog vaccines to prevent disease in dogs and to reduce infectiousness for the sandfly vectors?What is the effectiveness of insecticide- impregnated dog collars to prevent human and canine infection?What is the efficacy/effectiveness of alternative vector control devices  in the prevention of VL?Leishmania transmission in human, canine and vector populations. The exact burden of disease remains largely unknown. The increasing trend of VL cases observed in Brazil and the spread of transmission to previously not affected areas raise doubts about the impact of ongoing control measures. The determinants of human infection and of symptomatic disease are also poorly understood with the exception of the nutritional status in young children.This review of evidence related to VL control in Latin America revealed that a lot of work remains to be done in order to clarify the dynamics of To diagnose VL in humans the rK39-ICT has clear advantages over the IFAT or ELISA based tests that are widely used in Latin America. The DAT assay has shown similar diagnostic performance but is not as user-friendly as the rK39. The research priorities in this field should be geared towards diagnostic accuracy studies in large prospective trials (phase-3) and to study diagnostic performance in specific groups such as HIV co-infected patients. Current treatment practice in VL in Latin-America is based on rather weak scientific evidence. It is worrisome that case fatality rates remain high and are even increasing, at least in Brazil. The lack of clinical evidence from the region is very worrying. We retrieved not a single phase-3 randomized controlled trial on VL conducted in the Americas. Nowadays, one phase-2 trial with miltefosine is ongoing and two Brazilian large randomized controlled trials with liposomal amphotericin B, amphotericin B deoxycholate and meglumine antimoniate are expected to initiate recruitment in 2009. The research priorities include well-designed clinical trials with pentavalent antimonials, amphotericin B deoxycholate and the liposomal formulations, miltefosine and drug combinations. Although the resistance to antimonials observed in India is less relevant in Latin America, drug combinations are attractive because their potential for shortening treatment schemes and reduction of toxicity. Clinical factors associated with treatment failure should be studied to contribute to the development of a prognostic score that allows early interventions to reduce case fatality rates Control interventions targeting the dog reservoir for culling/treatment require accurate assays able to detect the asymptomatic infections as well as the symptomatic dogs. Validating such tests is no easy task, as there is no adequate gold-standard for the diagnosis of asymptomatic infection. PCR-assays seem to be very attractive but estimating their accuracy and reproducibility still constitutes a research priority. Moreover, novel screening strategies based on combined, parallel or sequential use of current available tests needs to be validated. Another challenge faced in canine diagnosis is the distinction of positive serology results produced by natural infection from those induced by vaccines. The development and proper validation of tests with capacity to discriminate both phenomena are crucial to avoid interference with concomitant interventions including dog culling and vaccination in the same area. Furthermore, the study of the determinants of dog infectiousness for the sandfly vector is essential to define the best culling strategy Some of the problems with the design of the community intervention trials we reviewed are related to the lack of accurate diagnostic methods to define the relevant outcomes in the human and canine population. Furthermore, the definition of a control group is challenging because of an obvious ethical dilemma. The heterogeneity of disease transmission within the study area often generated imbalances in the baseline comparisons among groups and the random allocation process is also complex because of the mobility of the human, canine and vector population. Most of the reported community trials used a too limited number of clusters for comparison . In spite of all those limitations a relevant number of reports could be reviewed in detail, showing no strong evidence for a significant impact on VL transmission for any of the interventions reviewed. Canine culling seems to be the least acceptable intervention at community level for obvious reasons and has low efficiency due to high replacement rate of eliminated dogs with susceptible puppies Canine and human vaccine development needs to be prioritized. The dog vaccines already registered in Brazil have some protective effect against canine VL but none of them were properly evaluated as control measures against human VL The role of sylvatic and peridomestic animals such as foxes, marsupials and rodents in some relevant VL transmission scenarios deserves more specific research Last but not least, in countries such as Brazil, where the government has put the elimination of hunger as a political priority, targeted nutritional support in VL risk areas would be an interesting and probably cost-effective intervention from a societal perspective. Similarly, schemes for the improving of housing and waste management as well as other general measures involving active community participation should be encouraged Finally, the strengthening of the surveillance system capacity is essential to avoid the underreporting of human cases The elimination of zoonotic VL in Latin America is not (yet) a realistic goal taking into consideration the complexity and diversity of its transmission scenarios, the scientific knowledge gaps and the lack of adequate and properly validated interventions. Many countries perceive the burden of leishmaniasis as negligible; there is not much political support nor funding for VL control. The zoonotic nature of transmission is an additional constraint that limits the impact of the few known effective prevention and control interventions. Nonetheless we believe the improved control of VL is possible if the region builds the political will, develops a more coherent regional control policy, and invests in better case management and epidemiological surveillance systems. The implementation of a focused research agenda to support such control initiative is essential.Checklist S1PRISMA checklist.(0.07 MB DOC)Click here for additional data file."}
+{"text": "Intracellular protoporphyrin IX (PpIX) content was quantified by extraction and fluorescence spectroscopy. Cellular PpIX content did not always correlate with cell proliferation rate as measured by the doubling times of cell lines. Cellular efflux of PpIX was also investigated. In a bladder carcinoma cell line, the observed rapid efflux was not blocked by verapamil, an inhibitor of the P-glycoprotein efflux pump. These data support the view that cellular PpIX accumulation is a dynamic process that is determined by both the efflux of PpIX from the cells and enzyme activities in the haem biosynthesis pathway. Desferrioxamine , a modulator of PpIX biosynthesis, enhanced ALA-induced cellular PpIX content significantly in all carcinoma cell lines but not in non-malignant cell lines. The enhanced PpIX cellular accumulation is attributed to inhibition of ferrochelatase activity, the enzyme responsible for the conversion of PpIX to haem. PpIX-mediated cellular photodestruction following irradiation with an argon ion laser at 514.5 nm was determined by the 'MTT assay'. There appeared to be a 'threshold' effect of cellular PpIX content; cells that synthesised less than 140 ng/mg-1 protein exhibited very little phototoxic damage, while cell lines having greater than 140 ng PpIX/mg-1 protein [corrected] exhibited a consistent phototoxic response. Among the cell lines which did undergo phototoxic damage, there was not a strict correlation between PpIX cellular content and ALA-induced phototoxicity. Desferal enhanced the PpIX content and phototoxic effect in the responsive cells. Fluorescence microscopy of the ALA-treated cells revealed marked accumulation of PpIX in mitochondria (rhodamine 123 co-staining). That the primary site of phototoxic damage is also the mitochondria was confirmed by electron micrographs of cells photosensitised with ALA-induced PpIX, which showed swelling of mitochondria within minutes after irradiation while other suborganelles appeared to be unaffected. The repair or further destruction of the mitochondria was fluence and cell-type dependent. The data from this study suggest that the basis of increased ALA-induced PpIX accumulation in tumours is a combination of various aspects of the metabolic process and pharmacokinetics and that the efficacy of photodestruction of malignancy will be determined not only by the rate of PpIX synthesis but also by specific cellular and tissue characteristics."}
+{"text": "The 11-M Madrid commuter train bombings of 2004 constituted the second biggest terrorist attack to occur in Europe after Lockerbie, while the subsequent investigation became the most complex and wide-ranging forensic case in Spain. Standard short tandem repeat (STR) profiling of 600 exhibits left certain key incriminatory samples unmatched to any of the apprehended suspects. A judicial order to perform analyses of unmatched samples to differentiate European and North African ancestry became a critical part of the investigation and was instigated to help refine the search for further suspects. Although mitochondrial DNA (mtDNA) and Y-chromosome markers routinely demonstrate informative geographic differentiation, the populations compared in this analysis were known to show a proportion of shared mtDNA and Y haplotypes as a result of recent gene-flow across the western Mediterranean, while any two loci can be unrepresentative of the ancestry of an individual as a whole. We based our principal analysis on a validated 34plex autosomal ancestry-informative-marker single nucleotide polymorphism (AIM-SNP) assay to make an assignment of ancestry for DNA from seven unmatched case samples including a handprint from a bag containing undetonated explosives together with personal items recovered from various locations in Madrid associated with the suspects. To assess marker informativeness before genotyping, we predicted the probable classification success for the 34plex assay with standard error estimators for a na\u00efve Bayesian classifier using Moroccan and Spanish training sets (each n\u200a=\u200a48). Once misclassification error was found to be sufficiently low, genotyping yielded seven near-complete profiles (33 of 34 AIM-SNPs) that in four cases gave probabilities providing a clear assignment of ancestry. One of the suspects predicted to be North African by AIM-SNP analysis of DNA from a toothbrush was identified late in the investigation as Algerian in origin. The results achieved illustrate the benefit of adding specialized marker sets to provide enhanced scope and power to an already highly effective system of DNA analysis for forensic identification. STR typing was also supplemented with standard mtDNA sequence analysis of a majority of exhibits. Seven complete STR profiles, originating from five personal items together with a handprint on the handle of the bag containing the undetonated El Pozo IED, failed to match any of the suspects held at the start of the court case in February 2007. Following an order from the Presiding Judge, the seven unmatched DNA extracts became the focus of specialist genotyping to attempt assignment of ancestry. The judge's direction specified that ancestry analysis should be confined to the comparison of European with North African variability in order to differentiate these two population groups alone.On the 11th of March 2004 ten improvised explosive devices (IED) were detonated on four commuter trains entering Madrid during the morning rush hour in a coordinated attack that killed 191 people and injured 1,755. DNA analysis supporting the subsequent investigation centered on standard forensic tests: autosomal and Y-chromosome STR profiling of 226 reference samples and more than 600 exhibits. The exhibits analyzed were predominantly contact traces that included fragments of detonated IEDs, suspect vehicles, an unexploded IED found at El Pozo train station and personal items recovered from bomb assembly sites or houses used by suspects. STR analysis used AmpAs quantities of DNA remaining from the initial STR analysis were very limited, an important pre-amble to the extended genotyping was estimation of likely success in assigning ancestry, i.e. choosing the approach that gave the minimum misclassification error from amongst the different ancestry marker sets available. The loci we opted to assess to differentiate Europeans from North Africans were: autosomal AIM-SNPs based on an established 34plex assay A simple Bayesian classifier analyzing the autosomal AIM-SNPs allowed an assessment of their ability to differentiate Europeans and North Africans by cross validation of training set samples used in the likelihood calculations. This permitted a review of classification error: how many training set samples were incorrectly assigned, and classification performance: the range of probabilities observed ahead of deciding the test priorities for scant case material. The classification error estimators of sensitivity and specificity, common to genetic association studies, simply correspond in this case to European and North African classification success in an arbitrary link to each population group.Population reference samples had been voluntarily provided at a previous date by residents of the Madrid metropolitan area with Spanish or Moroccan ancestry. Buccal swabs were collected by the Comisaria General de Policia Cientifica, Madrid with written, informed consent. Donors were informed the samples would be anonymized and used to derive allele frequency data representative of their population of origin. They verbally declared the population of origin of their parents to be either wholly Spanish or Moroccan and gave signed confirmation they understood the circumstances of sample use. DNA sets were stored with numbers and population labels only, at no point were numbers assigned to names from the consent forms. The University of Santiago de Compostela ethics committee gave institutional approval for the study.Training sets were made from the population reference samples collected as described above and comprised 48 DNAs each from Spanish and Moroccans resident in Madrid.Ancestry analyses were made of DNA extracted from the following forensic exhibits:Sample 1: Contact traces recovered (by swabbing) from a razor blade collected from the ruins of the Legan\u00e9s flat occupied by a large group of suspects and subsequently destroyed by explosions triggered by the occupants.Sample 2: Contact traces recovered (by swabbing) from a handprint on the handle of a bag found at El Pozo station containing an undetonated IED.Sample 3: Buccal cells recovered (by cutting bristles) from a toothbrush collected at Legan\u00e9s.Sample 4: Contact traces recovered (by cutting) from a blanket in a house occupied by a suspect.Sample 5: Contact traces recovered (by swabbing) from a woolen hat collected in the house where the bombs were assembled.Sample 6: Contact traces recovered (by cutting) from a scarf collected in a van used by suspects to go to one of the train stations attacked. The only female DNA of the seven extracts.Sample 7: Contact traces recovered (by cutting) from the same scarf as sample 6.Estimation of likely ancestry assignment error from each marker set was based on the observed distribution of variability between Europeans and North Africans either directly, by genotyping the 34 AIM-SNPs in samples of 48 individuals each from Spain and Morocco, or indirectly by reference to reported haplotype frequencies from previous population surveys of the Y chromosome The single base extension assay conditions, multiplex details and primer sequences were as previously described in detail From the 34-SNP profiles obtained a na\u00efve Bayes classifier was used to make ancestry assignments as previously detailed i \u2026popn that maximizes the posterior probability:l,\u2026,xm) is the SNP genotype profile.The classification algorithm assigns an individual (ind) to the population from pophttp://mathgene.usc.es/snipper/) accepting custom training sets and classifying profile submissions based on a user's own choice of SNPs and populations (hyperlink: \u2018classification with a custom Excel file of populations\u2019). Assignment probabilities are given as \u2212log likelihoods to ease handling of large differences in values. Misclassification error estimation options for uploaded training sets  include re-classification , verbose or non-verbose cross validation and bootstrap error. We used re-classification and verbose cross validation error estimators to assess the classification accuracy of the 34 AIM-SNPs for the two training sets. The complete 34-SNP training set profiles are available in supporting information, Unobserved alleles default to frequency 1/(2n+1) where n is training set sample size. The above algorithm is imbedded in an open-access web portal  but is computationally demanding. In contrast, classification performance for user defined SNP sets and populations can be obtained in seconds using the web portal.In order to compare the above classifier with an established alternative system of ancestry assessment we performed STRUCTURE analysis Five of the six male DNA samples had sufficient DNA left after AIM-SNP analysis to genotype Y-chromosome SNPs. A total of 21 Y-SNPs were genotyped using 3 multiplexes . Multiplex details, primer sequences and PCR conditions are as previously detailed As the five samples tested by Madrid with Y-STRs could be allocated into Eurasian haplogroups the choice of Y-SNP multiplexes was largely dictated by these prior results. Furthermore the Y-SNP multiplexes allowed a greatly improved resolution of the most common Eurasian haplogroups found on each side of the Mediterranean. Multiplex 1 analyzes SNPs more informative for European haplogroups and Multiplex 3 those more informative for North African haplogroups. Supporting information The two mtDNA hypervariable regions, HVS-I and HVS-II were sequenced for nucleotide ranges: 16024\u201316365 and 72\u2013340, following previously described protocols Forty-eight Moroccan and Spanish individuals were originally available to us to make training sets. We also considered using a single North African population, termed Mozabite, included in the CEPH human genome diversity panel (CEPH-HGDP). The CEPH Mozabite samples were not used as these were considered to be a population much more divergent from Europe than others in this region. However training sets should ideally sample as much regional variation as possible. Therefore to reassess the original assignments made for the 11-M investigation we collected an additional 67 Spanish together with a broader North African sampling of: 97 Tunisians (three different regions), 35 Algerians and 31 Libyans with 29 CEPH Mozabite also included. The expanded training sets of 115 Spanish and 240 North Africans were then used in a fresh analysis to assign ancestry to the case profiles. The addition of extra reference populations also gave a well differentiated principal component analysis (PCA) plot based on two and three components. The PCA analysis had originally been attempted with the 48-sample training sets but the differentiation of Europeans and North Africans and case samples was not clear in some parts of the plot, notably in the middle of the two adjoining clusters.The results of the statistical assessment of the AIM-SNP classification accuracy from re-classification and cross validation are shown in Although the autosomal AIM-SNP genotyping assay amplified sub-optimal quantities of DNA, extracted mainly from contact traces on touched objects, 33 of 34 SNPs were successfully typed in all seven case samples. The SNP rs727811 was not detected in all tests performed due to problems with the extension primer that had not been corrected prior to receipt of the case material. Representative single base extension SNP genotyping profiles from four of the case samples are shown in supporting information, http://spsmart.cesga.es/snpforid.php) nInI values obtained and indicates a trend of mildly decreasing divergence between Europe and North Africa along an approximate NW to SE geographic axis in Europe. The divergence between Spanish and Moroccan samples is slightly higher than expected given the degree of shared mtDNA and Y-chromosome variability previously reported for these populations, but is in line with other divergence levels shown here by three mid-European populations from France, the French Basque region and North Italy. The Mozabites are more divergent from Europe than the Moroccans and this probably reflects lower levels of admixture with Europe since this population has a more isolated regional distribution amongst oases of the northern Sahara. Therefore the choice of a Moroccan training set to analyze differentiation between Europe and North Africa may take more account of the effects of admixture across the west Mediterranean than an initial plan to use the Mozabite sample as a training set. Finally, it has recently been inferred from analysis of X-chromosome SNPs that Moroccans are more genetically distant from other more homogenous populations of the North African Mediterranean region Due to the problem with rs727811 outlined above the training sets and their analyses excluded this SNP. Training set allele frequencies were estimated and compared with previously published data nI values are included at the bottom of In order to further assess the representativeness of the training sets we calculated divergence between the Spanish and a combined group of six CEPH-HGDP European populations . Prior to the analyses described here we had applied the same approach to analyze subjects in a drug response trial with self-declared ancestry to be \u2018European-American\u2019 or \u2018African-American\u2019. By examining the range of probabilities in both groups we were able to identify subjects showing lower than average ancestry probabilities who could therefore represent individuals with highly admixed parentage and genomic backgrounds (unpublished data). This highlights a widely recognized characteristic of self-declared ancestry: that it is not always an adequate indication of the genetic ancestry detected by a set of markers and their subsequent analysis Given the relatively straightforward framework devised for assessing population variability ahead of genotyping limited DNA, the near-complete SNP profiling of challenging case material  and the high classification probabilities obtained in four of the seven profiles, we considered the first application of autosomal AIM-SNPs to assist a major investigation to be successful. Understandably there has been continued discussion relating specifically to the origin of the handprint on the bag containing the IED, not least because possible involvement of the Basque separatist group ETA was suspected for a large part of the investigation period and a Spanish mining contractor was ultimately convicted of supplying the explosives used in the attacks. All European suspects in the case were excluded as donors of the STR profile of sample 3. While the source of the DNA remains an open question, one positive outcome of the ancestry analysis we provided has been an overhaul of procedures for handling items recovered from terrorist attacks or major crime scenes in Spain. Amongst the Presiding Judge's concluding remarks at the trial was the comment that any number of people could have handled the bag between collection from the scene and forensic analysis, since it was first thought the bag belonged to a victim.We were initially cautious in recommending the use of 34 SNPs to differentiate such closely related population groups, particularly as the groups, while occupying different regions, can be realistically considered to be members of the same Eurasian metapopulation An important observation in the combined analysis of training sets and case profiles was the generally close match of each sample's classification likelihood and their STRUCTURE cluster plot patterns indicating that each approach can aid interpretation by revealing different perspectives of the same Bayesian assessment of individual ancestry. Our classification approach provides a simple system to obtain profile-by-profile likelihoods that are more difficult to execute with STRUCTURE, while STRUCTURE can reveal patterns of group membership from the cluster plots that indicate the degree of admixture between two sets of reference populations. Therefore we would advocate use of both methods in parallel to fully assess the SNP variability of training sets and de novo samples. The use of principal component analysis provides a third way to compare the position of unknown samples with reference data. Analyzing extended training sets with PCA gave consistent patterns to those of STRUCTURE and our single profile classifier. Similarly we observed a high level of consistency between the ancestry assignments made with the original training sets and those based on expanded Spanish and more broadly based North African sampling. All the newly derived ancestry probabilities were consistent with the original values giving identical orders of magnitude and supporting the original assessments made with more limited training set sampling. The improvement in the North African cross validation probabilities underlines the importance of the widest possible sampling of regional diversity in order to properly prepare a Bayesian classifier. This is particularly important when differentiating closely related population groups that may also show high within-group variation.Finally, as the forensic genetics community becomes increasingly interested in the development of DNA tests that can assist an investigation with intelligence data supplementary to mainstream STR-based identification, it is worth emphasizing that ancestry analysis when carefully applied alongside STR profiling has the potential to yield information critical for the progress of the investigating team and their search for suspects. Though dealing with admixed populations can mean that an ancestry assignment does not necessarily allow the definition of a series of physical characteristic phenotypes normally more closely associated with ancestry such as skin, hair and eye color. Of particular interest here is the fact that a component marker of the 34plex AIM-SNP assay: rs12913832, was recently shown to be associated with blue eyes in homozygous G form, with the A allele associated with non-blue eyes Figure S1Example electropherograms of four case samples from single base extension genotyping. Solid colors depict peaks identified as extension products by reference to pre-validated mobility windows with an average range of +/\u22120.5 bp. Peaks with relatively high signal strength not shown as solid colors (notably in the green channel) represent either random signals or those outside the mobility window of each allele.(17.69 MB TIF)Click here for additional data file.Table S1http://mathgene.usc.es/snipper/analysispopfile2.html). Samples are ordered to match the LR values plotted in Excel file of 48 Spanish and 48 Moroccan 34plex training set profiles (excluding rs727811) in valid format for data input to the SNP ancestry analysis portal used ((0.28 MB XLS)Click here for additional data file.Table S2Reference allele frequencies and divergence values of 34 AIM-SNPs from Spanish and Moroccan training sets, HapMap CEU, six CEPH-HGDP European populations combined and Mozabite. SNPs listed in order of descending power of differentiation for the population comparison analyzed (i.e. training set divergence).(0.11 MB DOC)Click here for additional data file.Table S3http://mathgene.usc.es/snipper/analysispopfile2.html).Case sample genotypes and analyses. AIM-SNP profiles are provided in the required format for analysis with the training sets of (0.05 MB XLS)Click here for additional data file.Table S4Classification error estimation of extended training sets. (0.03 MB DOC)Click here for additional data file.Table S5New ancestry assignment probabilities for case profiles using modified 48-sample training sets (excluding 4 or 12 outlier Moroccan samples) and analyses using expanded Spanish and North African training sets.(0.04 MB DOC)Click here for additional data file.Table S6Classification error estimations for combinations of four autosomal AIM-SNP sets using CEPH-HGDP samples as training sets.(0.03 MB XLS)Click here for additional data file."}
+{"text": "Sir,Femur fractures are excruciating injuries that are frequently seen in patients requiring a trauma workup in the emergency room (ER) prior to definitive surgical management. These injuries are extremely painful and merit prompt attention to adequate analgesia and are considered by many as a key management aim.Femoral nerve block (FNB) can significantly decrease the acute pain of a diaphyseal or distal femoral fracture and fracture neck of femur. This analgesic modality can be administered safely in the hospital emergency department and in the prehospital settings prior to the operative intervention. Profound analgesia is obtained without the adverse effects associated with systemic intravenous analgesics . This block is also very successfully used to facilitate positioning for placement of neuraxial block in the operating room (OR).\u00ae Titan\u2122 with LHFL 38 high frequency 13-6 MHZ 38-mm linear array transducer) guided femoral nerve block prior to the operative intervention in femur fractures. We used out-of-plane needle insertion approach, by placing the insulated needle  perpendicular to the transducer and ultrasound beam to inject local anesthetic (ropivacaine hydrochloride 0.75%) solution of mere 20 ml volume. We found that out-of-plane needle insertion approach is more convenient than the in-plane approach as the latter is more time consuming for alignment of needle with the ultrasound beam, which is often not possible in emergency situations. Moreover, if needed, catheter placement is easier with out-of-plane approach for prolonged analgesic requirements.We in our institute routinely administer ultrasound (SonositeConformation of the needle placement in peripheral nerve blocks is seen by many as a vital part of the procedure. In the emergency department, the use of a nerve stimulator for femoral nerve block would result in muscular contraction that would cause increased pain and would risk fracture displacement. Ultrasound guided FNB may be considered as a safe and an effective alternative to electrical nerve stimulation. Despite having a definitive advantage of clearly locating the nerves and negating the side effects caused by the nerve stimulator, the clarity of the image obtained can be obscured due to the presence of edema and subcutaneous air leading to block failure.Patients on emergency transport are prone to extreme stress reactions in painful conditions. Preclinically administered FNB can effectively decrease pain, anxiety and heart rate after femoral trauma.Ultrasound guided FNB can be used as an effective analgesic modality in patients with femur fractures thereby reducing post-traumatic stress disorder and the adverse effects of general anesthesia. This technique may decrease the onset time, improve the quality, reduce failure rate and permit a lower dose of local anesthetic.It is recommended that ultrasound guided FNB be considered as an important standard of care for femur fractures at emergency departments and in the OR prior to operative intervention. FNB can also be considered as an option for out-of-hospital analgesia for purposes of transportation and immobilization, provided it is administered by trained healthcare providers."}
+{"text": "Phosphorylation events direct the flow of signals and metabolites along cellular protein networks. Current annotations of kinase-substrate binding events are far from complete. In this study, we scanned the entire human protein sequences using the PROSITE domain annotation tool to identify patterns of domain composition in kinases and their substrates. We identified statistically enriched pairs of strings of domains (signature pairs) in kinase-substrate couples presented in the 2006 version of the PTM database.The signature pairs enriched in kinase - substrate binding interactions turned out to be highly specific to kinase subtypes. The resulting list of signature pairs predicted kinase-substrate interactions in validation dataset not used in learning with high statistical accuracy.The method presented here produces predictions of protein phosphorylation events with high accuracy and mid-level coverage. Our method can be used in expanding the currently available drafts of cell signaling pathways and thus will be an important tool in the development of combination drug therapies targeting complex diseases. Transient interactions of proteins with other proteins, such as those that occur during phosphorylation events, comprise a fundamental element of signal processing in living cells . ProteinTransient interactions between proteins often require multiple sites of physical connection and may even require a third party protein such as an adopter protein. Catalytic phosphorylation events at active sites is facilitated either by the utilization of protein recognition modules or the adaptation of docking interactions . Recent Known annotations of domain-motif interactions on protein partners often result in the prediction of large numbers of false positives in PPI . It is aComputational prediction of PPI from primary sequences of proteins poses a number of other challenges to overcome including the noise in the training PPI data, lack of a true negative training set, as well as problems associated with 3D experimental and molecular modeling of proteins in potentially binding configurations . PPI preThe success achieved in computational association of domain signature pairs with experimentally verified PPI in these aforementioned studies prompted us to investigate signature pair/PPI association in phosphorylation events within the human proteome. We asked the question whether modular composition of proteins (kinase and their substrates), combined with a database of known PPI, could be sufficient in a statistical enrichment procedure to predict known PPI not used in the training. The choice of domains as features for predicting PPI made sense because modular composition of proteins provides insights into their interaction with up and downstream proteins in cell signaling circuits ,5.In addressing this question, we used the Post Translational Modification (PTM) database 2006 edition containing 5602 PPIs to identify statistically enriched signature pairs in kinase/substrate binding. Our ten-to-one and two-to-one learning and testing procedures produced receiver operator characteristic curves reflecting excellent accuracy in the identification of phosphorylation events. Additional verification included the use of PPI in the PTM 2009 edition and in other databases not included in PTM -24. Our The computational space in our model is large compared to other approaches focusing only on the domain annotation of proteins known to be interacting with each other. In the present study we scanned the entire proteome for domain annotation in order to develop background sets of randomly generated virtual protein pairs to be used in statistical enrichment of domains in protein subsets. Another feature specific to our method is the consideration of strings of domains as signatures for binding predictions. This assumption facilitated us to consider binding events between proteins involving multiple sets of domains. Results produced by our method achieved better PPI prediction accuracy in phosphorylation on the average than other presently available computational methods for PPI. Our study illustrates the dominance of a grammar based on interacting domain signature pairs in the language of post modification interactions between proteins in the human proteome.The learning dataset on kinase/substrate binding was downloaded from the Post Translational Modification database (PTM), version 2006 . The datDatabase of protein domains, families and functional sites named PROSITE  was downStatistical enrichment of domains in protein subgroups (target group) was performed with respect to control (background) group made of the entire protein kinase group. Domain column matrices were determined for each member of a target group and these matrices were summed up over the membership of the subgroup. Next, a set of proteins of the same number as the target group was selected randomly from the background group and the corresponding sum domain column matrix was computed. This operation was repeated 10,000 times and the p value for enrichment was computed by the fraction of times the background group had more domains of a given identity than the target group. List of domains (domain clusters) enriched in a kinase- or substrate subtype was identified as the list of signatures that are enriched in the target group, a kinase- or substrate subtype.A score matrix was constructed for selecting signature pairs strongly associated with known PPIs in tyrosine- and serine/threonine phosphorylation subgroups. Specifically we wanted to identify signature pairs (such as A-B) such that presence of signature A in protein K and signature B in protein L would predict with high confidence a PPI between K and L. For this purpose, for the known PPI interactions in the learning dataset (EPPI), we generated a score matrix whose rows and columns identified the enriched signatures in tyrosine and serine/threonine kinases  and their substrates . Each element of the matrix corresponded to the number of EPPI for which a signature pair (A-B) was present in the opposing proteins of the pair. Another score matrix for virtual PPI, VPPI (background), was generated by randomly pairing proteins from the learning dataset, in effect creating VPPI interactions equal in number to all possible protein combinations from kinase and substrate proteins in the PPI set. The p value for signature pair enrichment in a given PPI subgroup was computed using the hypergeometric test in the R Project for Statistical Computing, based on the scores summed from the learning set and the background set. The resulting signature pairs were ranked according to their p value, with the one corresponding to the lowest p value ranked highest. The highest p value used as cut-off in the analysis was p = 0.001.N VPPI events that can be generated randomly from n kinases and m kinase substrates. Among the N VPPI, M have already been annotated as EPPI. Let the signature pair A-B predict Y number of PPPI, W of which have been verified as EPPI. The hypergeometric test than tests the probability of randomly choosing at least W EPPI by selecting Y PPPI out of a possible N VPPI. Lower the p value, higher is the accuracy of the PPI prediction method presented in this study.The signature pairs thus identified via statistical enrichment, were used to predict new PPI events. A protein pair was considered as undergoing phosphorylation interaction if they expressed at least one of the signature pairs determined by the enrichment analysis. Consider a protein pair  that is associated with a statistically enriched signature pair (A-B). Assumption that the presence of A-B means the presence of a phosphorylation PPI between L and K (PPPI) may lead to false positives. The prediction accuracy was evaluated by computing the probability that the match between predicted and experimental PPI sets to have occurred randomly. Consider there are Sp) and Sensitivity (Se). Let TP, TN, FP, and FN represent, respectively, the true positives, true negatives, false positives, and false negatives determined with the use of known PPI in the predicted set. Sp and Se were defined as follows:In addition to p values, prediction accuracy was evaluated using parameters for defining accuracy and coverage: Specificity . Parameter Se is a measure of the coverage, namely the size of the PPI pool potentially predicted by A-B.The higher the value of Pr) was defined as TP/(TP + FP). Recall (Re) is the same as the sensitivity parameter Se.We also used precision and recall to evaluate the statistical enrichment of experimental PPI in our predicted PPI set. Precision . We identified the phosphorylation PPI in the HPRD and BioGrid databases as those PPI made of a kinase and a substrate partner of the same type (tyrosine or serine/threonine) as listed in Gene Ontology . For eacWe tested the accuracy of PPI predictions of the present model, with two previously published domain based methods: correlated sequence-signature markers (CSSM)  and the Our computations showed that kinases and their substrates express statistically enriched protein domains that are largely subtype specific. We scanned the human protein sequences in the NCBI database through the PROSITE web tool and identified the domains/signatures expressed on their sequences Figure . We thenNext we considered the groups of enriched domains expressed by kinases and their substrates, grouped in two major subgroups: tyrosine and serine/threonine kinase (substrates). Many of these proteins expressed more than one subtype-specific enriched domain as shown in Figure m by chance when the corresponding value in virtual PPI score matrix is n. The negative logarithms of these p values for the correlated signature pairs are shown in Figure A score matrix in our analysis has m rows and n columns with each row corresponding to one of the m enriched signatures (domains or string of domains) in a kinase category (TK or S/TK). Each column indicates one of the n enriched signatures in the corresponding substrate category (TKB or S/TKB) Figure . ElementThe signature pairs presented in additional file Approximately 75 percent of known kinase-substrate interactions occurred between proteins with at least one annotated PROSITE domain on their primary sequence. For cross validation, we used the kinase-substrate pair list in PTM 2006 and took its subset made of protein couples with both proteins expressing at least one annotated PROSITE domain. This restriction was necessary since our prediction method is based on existence of certain domain pairs (signature pairs) in interacting proteins. As described in the methods section, we used 10-fold and 2-fold cross validation in 100 iterations and generated receiver operating characteristic (ROC) curves for predicting tyrosine kinase and serine/threonine kinase interactions Figure . The fig-12 to 7*10 -7 for PPI presented in HPRD and BioGrid database whereas we had higher but still significant p values when predicting PTM 2009.Next we compared our predicted PPI set with those phosphorylation PPI sets that have not been used in our statistical enrichment processes. Three PPI databases, BioGrid, HPRD, and PTM 2009, have contained hundreds of kinase/substrate phosphorylation events as shown in Table Next we compared the experimental data shown in Table K-GIDDI simulation also yielded in higher p values than our method when compared with the human protein interactive data shown in Table Overall, our approach predicts 8837 kinase-substrate interactions from a pool of 186,715 virtual interactions and matches 2591 PPI out of the experimentally verified 4694 PPI. The p value for the match is zero and precision and recall are equal to 0.293 and 0.552, respectively. Predictions for tyrosine kinase mediated phosphorylation PPI is better in terms of precision than those PPI involving serine-theronine kinases . The two new elements in our approach consist of (a) expanding the definition of signature to strings of domains rather than a single domain and (b) the use of background composed of random pairing of kinase and substrates in the statistical processes for identifying signature pairs indicative of phosphorylation events. The first assumption is consistent with our observation that certain strings of domains are highly statistically enriched in kinase subtypes and their substrates compared to the rest of the kinase interactome. The second assumption, requirement of statistical enrichment, against highly differentiating background sets, allowed us to further reduce the set of correlated sequence signatures obtained solely on the data involving PPI. The list of signature pairs developed in the present study, when used in predicting kinase/substrate interactions in phosphorylation events, produced results that are largely matched with experimental data not used in statistical enrichments for signature identification. The p values associated with our predictions and their comparison to independent experimental data ranged from a low of 10 Thousands of human proteins have been identified as undergoing phosphorylation binding interactions in the PhosphoELM database but the identity of the kinases responsible for these phosphorylation events are yet to be quantified. Our method produced candidate kinases targeting these substrates. The resulting list turned out to be consistent with literature not yet included into the PhosphoELM database. In all cases, the partnering between the substrate and the kinase predicted in this study can serve as a guide for kinase identification studies involving known kinase substrates. Another important use of our method will be in expanding and revising existing literature on cellular pathways decorated with phosphorylation events. Such revisions will be useful in identifying the consequences of small drug interventions on a kinase in terms of its interaction with immediate neighbors. Last but not least, our observation that domains expressed by kinase proteins and their substrates are largely subtype-specific drastically reduces the upper bound for the number of experiments one has to conduct for quantifying a major subset of transient binding interactions between protein pairs associated with phosphorylation.One important disadvantage of our method is the bias toward the discovery of PPI with proteins having similar domain composition. This feature is also persistent in PPI prediction methods based on sequence homology. This tendency is observable in our prediction of new results included in PTM 2009 based on the PTM 2006 dataset. Although our match is statistically significant, the p values we get for this comparison is significantly larger than comparison with HPRD and BioGrid. It is expected that our methodology will pick up more PPI events correctly as we learn more about the protein sequence grammar that relates domain expression with protein-protein interaction patterns.Protein phosphorylation events redirect and redistribute the flow of signals and metabolites in cellular pathways. Kinases that phosphorylate multiple substrates have been favorable targets for drug development against many disease types. In this study, we developed a high throughput method that predicts potential binding partners for kinases using existing domain annotation tools and interactome databases for the human proteome. The method, when tested against independent databases, yields predictions with high statistical accuracy. Results indicate that domains expressed by any two proteins constitute a strong determinant of the potential for phosphorylation related binding interactions between them. Our expansion of the MAPK pathway using the prediction method outlined in the study presented results compatible with research literature.YL and AT conceived and developed the research plan. YL implemented the integration of algorithms and performed the computations. All authors worked on and approved the final manuscript.PROSITE domains that are statistically enriched in subtypes of kinases and substrates. Columns of the table represent domain index used in Figure Click here for fileThe list of domain-strings pairs used in predicting phosphorylation PPI with high specificity (SP > 0.91). DSIK: Domain string index for the kinase in PPI; DSIS: Domain string index for the substrate in PPI.Click here for file"}
+{"text": "Penetrating keratoplasty has been the mainstay for the treatment of blindness and is the most common form of tissue transplantation worldwide. Due to significant rates of rejection, treatment of immunological transplant reactions is of wide interest. Recently in a mouse model, the overexpression of indoeleamine 2,3 dioxigenase (IDO) was led to an extension in corneal allograft survival. L-kynurenine is a tryptophan metabolite, which may render activated T-cells apoptotic and therefore might modulate an allogenous transplant reaction. The function of L-kynurenine in the human cornea remains unclear. We analyzed the expression levels of IDO in human corneal endothelial cells (HCECs) and downstream tryptophan/kynurenine mechanisms in cell culture.An immunological activation profile was determined in proliferation assays of monocytes from healthy donors. Reversed-phase high pressure liquid chromatography (HPLC), western blot, real time polymerase chain reaction (PCR), and microarray analyses were used. The expression of IDO and immunological infiltration of rejected human corneal allografts (n=12) were analyzed by immunohistochemistry.We found IDO and an associated tryptophan/kynurenine transporter protein exchange mechanism upregulated by inflammatory cytokines in HCECs. The inhibition of T-cell proliferation might depend on rapid delivery of the tryptophan metabolite, L-kynurenine, to the local corneal environment. Microarray analysis gives evidence that the large amino acid transporter 1 (LAT1) transporter protein is responsible for this mechanism.Our data support that adequate levels of functional L-kynurenine might contribute to the maintenance of a relative immune privilege in the ocular anterior chamber, thereby contributing to the preservation of corneal allogeneic cells. Other factors such as a slow-rate of endothelial attrition (~4% a year) that are not associated with any overt rejection episodes can also confound the loss of endothelial layer function . ,36. 8,36+ T lymphocytes are selectively sensitive to IDO-mediated tryptophan deprivation [So our model must make the assumption that the tissue microenvironment that surrounds the grafted tissue is not in equilibrium with the blood and that those local concentrations of tryptophan or its cytotoxic catabolites can vary markedly from that observed in the plasma. Given that previous mouse studies  indicaterivation  in HCECsrivation .If this is functional in vivo in the human system, the mechanism delineated by our findings might have far reaching consequences for immunoregulation and for the pathogenesis of corneal graft failure. The ability of the cornea to promote immunologic unresponsiveness by deflecting the systemic immune response away from a Th1 pathway might be an integral component of the immune privilege of corneal allografts during proinflammatory environment. This may represent a novel adaptation by the anterior chamber to preserve vision by avoiding immunogenic inflammation in the effective suppression of donor antigen-reactive Th1 activity. Recently, it has also been shown that constitutive expression of CD95L on the corneal endothelium is critical to its immune privileged status by triggering apoptosis in na\u00efve alloreactive T-cells. Accordingly, when grafted to a heterotopic site and in the absence of the corneal epithelium, CD95L prevents allosensitization and renders murine endothelial cells and stroma resistant to immune destruction following allograft rejection directed at MHC alloantigens. Full thickness allogeneic corneas, however, were rejected acutely due to the overpowering epithelial immunogenicity . The preOur current human model expand the survey of the corneal immune privilege by demonstrating that effective inhibition of T-cell proliferation depends additionally on rapid delivery of the cytotoxic tryptophan metabolites (L-kynurenine) to the local environment of HCECs (following adequate upregulation of IDO).  This is likely to be the case in rejecting corneal tissue thereby comprising an in vivo mechanism of maintaining ocular immune privilege in the anterior chamber . In thisIf the human immune system utilizes IDO-producing HCECs for suppression of deleterious immune reactions as a means of active down-regulation of Th1 immune responses to alloantigenic cells introduced into the anterior chamber of the eye, then therapeutic induction of IDO, namely the possibility that IDO transfection of tissue allografts might lead to a reinforcement of this innate mechanism.  In this setting the induction of tolerance in a human transplant might be attempted. As a result, corneal rejection episodes could possibly be delayed or prevented as has already been demonstrated in murine corneal transplants . Therefo"}
+{"text": "We succeeded in viewing the image of pancreatic duct on a TV monitor as a sequentialelectronic endoscope image by connecting a converter with a charge-coupled device toan ultra-thin pancreatoscope. Spacial image processing by adaptive enhancement, usingan electronic endoscope, was studied in the pancreatoscope images of 18 cases (10 withpancreatic cancer and 8 with chronic pancreatitis). As a result, it became clear that theimages obtained in Peak 2 of adaptive enhancement are much better than the originalimages. There was an excellent effect of clearly detecting the characteristic mucosalpatterns in pancreatic cancer and chronic pancreatitis. We are convinced that thismethod would be very useful in improving the diagnostic ability of pancreatic cancerusing an ultra-thin pancreatoscope."}
+{"text": "Peripheral B-lymphocytes of 13 patients with uveal melanoma and of 5 healthy individuals were transformed with Epstein-Barr virus (EBV). The reactivity of these transformed cells with autologous or allogeneic melanoma cells and lymphocytes was measured by the enzyme-linked immunosorbent assay (ELISA). Antigens which are neither self nor common environmental antigens  were used for controls. Lymphocyte reactivity with all types of antigen was apparent both in patients with uveal melanoma and in normal controls. The response detected by the techniques available is likely to reflect antibody multispecificity leading to mis-identification of irrelevant antigens."}
+{"text": "We report a case of a 78-year-old patient with penile leiomyosarcoma, treated by radical penectomy. Two years after theoperation the patient is without evidence of local recurrence or metastatic disease.We also discuss the treatment optionsand attempt a review of the literature."}
+{"text": "Adult oncology practices are caring for a growing number of older adults with cancer. Evidence suggests that patients with cancer have higher emergency department (ED) utilization, particularly in patients 65 years of age and older and in those whose symptoms are poorly controlled. The ED is not the most appropriate nor most cost-effective option for addressing urgent care needs of patients undergoing cancer treatment. This quality improvement project is being conducted in a community medical oncology practice during usual cancer treatment education. Older adult patients starting or changing cancer treatment are presented with a zone tool (green-yellow-red) to inform decision-making at home regarding level of severity of current symptoms and recommended actions . The tool has been distributed to 28 patients with a goal of at least 30 by 9/20/19. Outcome measures include the number of ED visits in the intervention group compared to a pre-intervention sample of older adults from the same medical oncology office. Other outcome measures are acceptability of zone tool among clinical staff and patients. Preliminary data suggest suggest acceptability among staff and patients; and ease of use among clinical staff. Tracking of visits to the ED in the sample population and surveys of patients and staff are ongoing through October 2019."}
+{"text": "Defective autophagy has been linked to a vast array of human pathologies. The molecular mechanism of the autophagic machinery is well-described and has been extensively investigated. However, understanding the global organization of the autophagy system and its integration with other cellular processes remains a challenge. To this end, various bioinformatics and network biology approaches have been developed by researchers in the last few years. Recently, large-scale multi-omics approaches  have been developed and carried out specifically focusing on autophagy, and generating multi-scale data on the related components. In this review, we outline recent applications of  To maintain their homeostasis, cells require an appropriate balance between anabolism and catabolism. There are two main degradative processes for intracellular components in eukaryotic cells: autophagy and the ubiquitin-proteasome system Dikic, . WhereasIn the present review, we go through examples on the latest research in understanding autophagy mechanisms based on the analysis of a large volume of data from omics studies, and how these findings have been gathered in databases freely available to the scientific community.Autophagy is a survival mechanism greatly conserved among every eukaryotic organism. Autophagy functions essentially as an adaptive response to stress, particularly in the condition of nutrient deprivation, allowing for cell and organism survival. When nutrient resources are restricted, cells are able to break down and reprocess all sort of macromolecules including proteins, lipids, and carbohydrates which can then be reused as essential building blocks for the synthesis of new macromolecules and the production of energy  that cannot dilute their deleterious components through division. As such, autophagy facilitates the disposal of supernumerary or damaged proteins and organelles before they become toxic to the cell  microautophagy, and chaperone-mediated autophagy Figure . InitialIn chaperone-mediated autophagy (CMA), cytosolic proteins interact with the chaperone heat shock 70 kDa protein 8 (HSPA8/HSC70) via their pentapeptide KFERQ; the chaperone in turn binds to the lysosomal-associated membrane protein 2A (LAMP2A)  is a server used for the prediction of putative LIR/AIM motifs in sequences of interest using five regular expression motifs . ELM is maintained by several European groups coordinated by the Gibson group at the European Molecular Biology Laboratory (EMBL). ELM is publicly available online at the URL http://elm.eu.org.The Eukaryotic Linear Motif (ELM) resource is a database, and web server focused on short linear motifs (SLiMs)  discovery tool which allows the user to use a motif consensus to search a proteome and discover putative novel motif instances .http://autophagyregulation.org.The Autophagy Regulatory Network resource is publicly available online at the URL http://ilir.uk/model/ and http://ilir.uk/virus/, respectively.The iLIR prediction server has been used to develop two databases: the iLIR database and iLIR@viral. The iLIR database provides a list of all the putative canonical (xLIR and WxxL motifs) LIR-containing proteins identified using the iLIR resource (see before) in the proteomes of 8 model organisms, combined with a Gene Ontology (GO) term analysis  is a database that integrates sequence data curated from the literature and related to programmed cell death in eukaryotes -associated cell death database (ncRDeathDB) documents over 4,600 ncRNA-mediated programmed cell death entries  is an open-access knowledge depository which contains 836 microRNAs associated with autophagy, 197 targeted genes or proteins, and 56 diseases related to aging . Phylogenetic trees using 16S/18S rRNA were reconstructed as a reference to compare the similarity among autophagy genes in different species. Normalized symmetric tree similarity algorithm was used to measure the similarity of the constructed phylogenetic trees. The resulting analysis has revealed that the core autophagy proteins are present in most of the investigated species with the difference being a fewer number of core proteins in plants and protists. The main difference lies in the vesicle elongation, and maturation phase of the autophagy pathway wherein most plants are characterized by a lack of some of the ATG5\u2013ATG12 conjugation-related proteins. Some of the prokaryotic homologs of the core autophagy proteins were also suggested to play different roles in the process upon comparison with the eukaryotic species. For instance, ATG11 has an essential role in selective autophagy regarding the yeast organism, in contrast to Archaebacteria this protein is liable for DNA repair and reorganization of chromosomes. By collating the phylogenetic trees, the most significant similarity was found to be among proteins which are responsible for the autophagosome nucleation and ATG9 cycling. In terms of selective autophagy, the phylogenetic trees were quite different from each other. The analysis also highlighted the fact that parasitic organisms such as Entamoeba histolytica and Plasmodium yoelii which have relatively fewer ATG proteins still exhibited autophagic activity  to discover similarities and differences in terms of the various autophagy phases and the regulatory components involved. Proteome-level data from UniProt was used to identify homologous proteins involved in autophagy across species. Finally, proteins which exist in different taxa were identified with the \u201chmmsearch\u201d tool in HMMER3 (Trypanosoma and Plasmodium). According to a comprehensive computational analysis, Atg1 and genes encoding its induction complex were found to be lacking in the genomes of all the studied species. As an alternative induction of autophagy, < 20 species contained Atg6/Beclin1, in the other remaining investigated non-unikont parasites, this protein does not appear in the genome. In this case, there is no evidence which could provide a clue on how autophagy is induced in these species , and they found up-regulated autophagy in brain samples from AD patients . Based on these observations, it was suggested that the up-regulated autophagy signatures in the AD patients could be a compensatory mechanism in order to remove the accumulated protein aggregates  exposed to monocytic and granulocytic induction helped discover the relationships between autophagy and the differentiation of HSPCs. Differentially expressed genes involved in the autophagy process were inferred by combining the observed transcriptional changes and annotations/regulator information obtained from the Autophagy Database, Autophagy Regulatory Network (ARN) and Human Autophagy Database (HADb). Based on the analysis of the temporal gene expression data using a standard clustering algorithm, 22 autophagy genes were found to be significantly altered during the monocytic and granulocytic differentiation process of myeloid progenitors into monocytes and granulocytes. The results suggested that autophagy is essential to maintain the balance between different states  in myeloid cells -based proteomics is an invaluable way for studying protein-protein interactions, protein expression, subcellular localization, and post-translational modifications. Given the increased interest in the identification of new players in the regulation of autophagy, it is not surprising that MS-based proteomics approach has been widely used and has successfully contributed to advancing the knowledge on autophagy.\u2212/\u2212 MEFs has identified 66 upregulated and 48 downregulated proteins  and mass spectrometry (MS)  deficiency. Niemann-Pick disease type C (NPC) is a severe inherited lysosomal storage disorder, most often originating from the loss-of-function of NPC1. Their lipidomics analysis on lysosomes isolated using superparamagnetic iron oxide nanoparticles (SPIONs) revealed the build-up of several species of glycerophospholipids and other storage lipids in lysosomes of NPC1-deficient cells , to explain and present the hierarchy of autophagy functions in yeast. Published omics data was combined with a newly generated genetic interaction map targeted at autophagy. It contains almost 500 genes which could be related to the process of autophagy according to the literature and results from experiments. Using protein sequences and structure details, researchers revealed interactions between proteins or genes, co-expression levels and similarities between genes. The AtgO process schema was applied to human data as well which resulted in the Human Autophagy Ontology database (hAtgO) containing 1,452 genes and 1,664 terms describing autophagy based on the expression profile of genes, interactions between proteins, co-localization, etc.  which assigns genes and their encoded products with specialized ontology terms capturing the entire range of the functional hierarchy. Kramer et al. recently developed a general framework\u2014AtgO (https://cancergenome.nih.gov/), they identified the regulators of BECN1, a core autophagy component, which has an inhibitory effect on tumor formation  was used to measure small sized molecules and liquid chromatography-mass spectrometry (LS-MS) and enzymatic assays for complex molecules. Microarray analysis followed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) measured the transcriptomic level changes. Integration of metabolomics and transcriptomics data from the rosette leaves elucidated the pleiotropic effect of autophagy activity on cellular homeostasis and revealed the dependence on autophagy of various metabolic pathways. Based on the results from the transcriptomics datasets, many genes related to plant stress response were also overrepresented upon autophagy malfunction in the mutants  are a lineage of stem cells which are present in both early embryonic and adult hematopoietic organs with the capability to renew themselves and differentiate into multiple lines of blood cells. Due to the essential role of autophagy in self-renewal and differentiation in embryonic hematopoiesis, Hu et al. investigated its role in five populations of mice cells related to HSC formation during the process of mouse embryogenesis by measuring gene expression using single-cell RNA sequencing. The results from the study revealed an increase in the transcriptional level of various autophagy component encoding genes in endothelial cells which were classified as pre-HSCs. This observation was synchronous with the down-regulated Notch signaling thus suggesting that autophagic activity could play a significant role in the formation of HSCs during the gestation period  when the cell is separated from its bulk environment. On one hand, while the examination of the cell in an isolated milieu can lead to data loss, on the other hand, the cell is a dynamic structure where the molecular states will differ temporally across different sampling points. A future goal will be to improve the in vitro models, investigations on patient-derived samples are desirable since it provides researchers with the necessary basis to understanding disease mechanisms for translational purposes as well as personalizing treatments. Mart\u00ednez-Pizarro et al. investigated the role of endoplasmic reticulum (ER) stress and autophagy in fibroblasts derived samples diagnosed with homocystinuria\u2014a disease characterized by defective cysteine metabolism and manifested by neurological and behavioral anomalies. Earlier studies reported upregulated levels of reactive oxygen species and apoptotic activity in fibroblasts derived from homocystinuria patient biopsies. However, the exact mechanisms in terms of the molecular pathologies underlying the disease were not explained. In the study by Mart\u00ednez-Pizarro et al. the authors used a combination of techniques such as PCR, Western blotting, microscopy and cytosolic Ca2+ imaging followed by in vitro assays to first identify and then verify the mechanistic roles of the identified molecular mediators. Gene and protein expression profiling revealed the induction of a number of proteins related to ER stress and calcium signaling. In addition, autophagy was also found to be activated along with mitophagy-mediated degradation of modified mitochondria. Treatment with antioxidative agents inhibited autophagy suggesting that reactive oxygen species affect autophagy which otherwise would impart a protective role under homeostatic conditions  represent a group of intestinal disorders which are characterized by chronic inflammation. The most common forms of IBD are Crohn's disease (CD) and ulcerative colitis (UC): while CD affects any part of the gastrointestinal tract, UC results in inflammation in the colon and the rectum. Silverberg and colleagues collected samples from healthy and diseased patients suffering from CD or UC. They extracted RNA from peripheral blood mononuclear cells and examined the post-transcriptional regulation of autophagy. The study revealed that there are differences in miRNA expression between the healthy and diseased samples. miRNAs are small non-coding RNA molecules which bind to mRNAs thereby silencing their transcription. miRWalk 2.0 software was used to predict miRNA-mRNA interactions and thereafter with GO and pathway analysis, the dysregulated pathways were identified and analyzed. As a result, the authors observed that the most of the differentially expressed miRNAs can effect on the autophagy pathway confirm the significant effect of miRNA-mediated modulation on autophagy  strain LF82 in HeLa cells and monitoring the induction of autophagy using mCherry-LC3  and extraction of vast amount of data from automated image analysis have gained in popularity over the past decade. Indeed, High Content Analysis (HCA) allows for the unbiased quantitation of phenotypic images through the development of automated image acquisition and analysis. Most autophagy-focused HCA screenings rely on the quantitation of autophagosomes using fluorescent-tagged LC3. In order to identify new autophagy-related genes, He and colleagues used a library of cDNA to investigate the implication of 1,050 genes of unknown function in autophagy. The overexpression of the transmembrane protein TM9SF1 resulted in the accumulation of autophagosomes and general increase of the autophagy flux in HeLa cells. Silencing of TM9SF1 using si-RNA impaired starvation-induced autophagy. In addition, TM9SF1 localized to the autophagosome and lysosome, suggesting a direct implication of this protein in the autophagy process, although its molecular mechanism and function remain unclear (He et al., Giving the fact that autophagy is related to a broad range of pathologies, targeting autophagy machinery components and regulators could be an appealing alternative to classical chemotherapeutic agents. To this end, in order to fill the gap in the number of autophagy inhibitors and potential therapeutic agents, Peppard and collaborators designed a phenotypic, cell image-based assay for small molecules that affects the accumulation of autophagosomes in starved cells expressing GFP-LC3 (Peppard et al., in vitro using a Beclin-1/Bcl-2 AlphaLISA assay to measure the interaction between the two proteins. This two-step screen led to the identification of three active molecules that induce autophagy.However, stimulating autophagy may constitute a promising approach to prevent or treat some pathologies in aging-related diseases. Chiang and colleagues sought to identify new autophagy inducers that disrupt the binding between Beclin-1 and Bcl-2 (Chiang et al., Autophagy is one of life's fundamental processes. Recent research has indicated roles for autophagy in an increasing number of pathologies, from bacterial and viral infections to cancer, and more recently in neurodegenerative and other age-related diseases. The importance and significance of the autophagy process was highlight very recently with the Nobel Prize award to Prof. Yoshinori Ohsumi for his pioneering studies revealing the mechanisms of autophagy in baker's yeast 30 years ago (Tsukada and Ohsumi, A-CJ and LG wrote the manuscript with input from PS. TK and IN edited the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The nucleolus is a prominent nuclear body that is common to eukaryotes. Since the nucleolus was first described in the 1830s, its identity had remained a mystery for longer than 100 years. Major advances in understanding of the nucleolus were achieved through electron microscopic and biochemical studies in the 1960s to 1970s followed by molecular biological studies. These studies finally established the view of the nucleolus that it is a large aggregate of RNA-protein complexes associated with the rRNA gene region of chromosome DNA, serving mainly as a site of ribosome biogenesis, where pre-rRNA transcription, pre-rRNA processing, and assembly of rRNAs and ribosomal proteins (r-proteins) into ribosome subunits occur. This function of the nucleolus appears to indicate that the nucleolus plays a constitutive and essential role in fundamental cellular activities by producing ribosomes. Recent research has shown, however, that the nucleolus is more dynamic and can have more specific and wider functions.In plants, nucleolar functions have been lately implicated in developmental regulations and environmental responses from experimental evidence obtained mostly from genetic studies of nucleolus-related mutants. Detailed and comprehensive analysis of nucleolar components and molecular cytological characterization of sub-nucleolar domains have also provided new insights into functions and behaviors of the plant nucleolus. This Research Topic has collected articles concerning recent findings from the plant nucleolar research, with a primary focus on physiological and molecular links of the nucleolus to growth and development in plants.asymmetric leaves2 (as2). Kojima et al. characterized two pointed-leaf mutants, oligocellula2 (oli2) and g-patch domain protein1 (gdp1) and demonstrated that these mutations synergistically repress cell proliferation in leaf primordia and that either of them do not strongly enhance leaf abaxialization in as2. Both OLI2 and GDP1 proteins were shown to localize in the nucleolus and participate in ribosome biogenesis. These results suggest that the leaf cell proliferation defect and leaf abaxialization triggered by mutations in r-protein genes or RBF genes may be mediated by different mechanisms.In the model plant Arabidopsis, a number of mutants have been reported for genes encoding r-proteins and ribosome biogenesis factors (RBFs). Previous works showed that most of these mutants share developmental phenotypes, one of the most typical examples of which is a pointed leaf shape. Many of these mutations are also known to affect leaf polarity and cause severe leaf abaxialization in a sensitized genetic background such as ANAC082 were found to suppress growth defects and developmental abnormalities in various ribosome biogenesis-impaired mutants, which has led to the hypothesis that plants respond to nucleolar stress via a plant-unique, ANAC082-dependent signaling pathway. Ohbayashi and Sugiyama outline these studies along with their research background and introduce the concept of plant nucleolar stress response as a new face of NAC-dependent cellular stress responses.In animals, it is well known that perturbations of ribosome biogenesis in the nucleolus cause a particular type of stress called nucleolar stress  activating specific signaling pathways to induce cell cycle arrest or apoptosis. In plants, however, a corresponding stress response pathway had long been unrecognized. Very recently, loss-of-function mutations in the NAC transcription factor gene Liu and Imai present a mini-review focusing on DExD/U-box RNA helicases among RBFs, in which information about plant DExD/U-box RNA helicases with functions in ribosome biogenesis is surveyed to highlight their involvement in adaptation to environmental stresses such as high and low temperatures.Phenotypic studies of mutants impaired in genes encoding r-proteins or RBFs have also indicated important roles of the nucleolus in various environmental responses in plants. Rodriguez-Corona et al. investigated two Arabidopsis fibrillarins AtFib1 and AtFib2 and detected a novel ribonuclease activity only in AtFib2. This discovery suggests an unidentified role of plant fibrillarin.Molecular biological reexamination of nucleolar components is another trend in exploring the hidden functions of the plant nucleolus. Fibrillarin is a major conserved nucleolar protein, which localizes at the boundary between fibrillar center and fibrillar component of the nucleolus as well as in the nucleolus-related nuclear domain Cajal body and is considered to act as a methyltransferase in the initial stage of pre-rRNA processing. Notably, most of plants have two or more different fibrillarin genes. Kalinina et al. summarize a broad range of findings to depict a comprehensive view of the multifaceted functions of the nucleolus in growth, development, disease, and stress responses of plants.Fibrillarin and several other nucleolar components have been found to associate with pathogen-derived factors such as plant viral proteins, and today the role of the nucleolus in plant-pathogen interaction has become an important topic. With a special emphasis on this aspect, Montaci\u00e9 et al. carried out proteome analysis of highly purified nucleoli of Arabidopsis by mass spectrometry and identified many RBFs and also proteins non-related to ribosome biogenesis, which interestingly contain proteins of 26S proteasome. By further experiments, they demonstrated the nucleolar localization of 26S proteasome subunits and an interplay between proteasome activity and nucleolar organization.Nucleolar proteome analysis has contributed very much to our understanding of the nucleolus. Ohtani provides an overview of the current knowledge about the roles of the nucleolus and Cajal bodies in snRNA biogenesis and discusses its possible relation to plant development and environmental responses.Small nuclear ribonucleoproteins (snRNPs), complexes of proteins and a specific class of non-coding RNAs involved in RNA processing events such as pre-mRNA splicing, are contained not only in the nucleoplasm but also in the nucleolus and Cajal bodies. It is now considered that critical steps of snRNP biogenesis occur in the nucleolus and Cajal bodies. Dvo\u0159\u00e1\u010dkov\u00e1 and Fajkus present a protocol of EU labeling optimized for visualization of plant nucleoli, which is very useful for studying nucelolar behavior and activities in plant cells.Imaging techniques are nowadays essential in molecular cell biology research. Labeling of RNA with 5\u2032-ethynyl uridine (EU) is one of such techniques recently established. We hope that these articles arouse interest in expanding aspects of the nucleolar functions in plants beyond the classical view of the nucleolus and inspire new research on the nucleolus across various fields of plant science.MS wrote the draft and YM edited it. MS and YM revised the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Tele-Savvy is a 3-arm randomized controlled trial (RCT) of a psychoeducation intervention that equips family caregivers of people living with dementia with the knowledge and skills they need to provide care to their person, while also caring for themselves. This RCT is currently underway, with cohorts rotating through over a period of 12 months. The purpose of this presentation is to describe the effectiveness of Tele-Savvy (active) versus Healthy Living Intervention (attention control) or usual care (wait-list) on the caregiving experience among dementia family caregivers. We conducted semi-structured interviews with 16 caregivers at the 6 month time point and after their initial participation in either the active, attention control, or usual care groups. Interviews elicited caregivers\u2019 perceptions regarding the program\u2019s influence on their caregiving experience. Caregivers who participated in Tele-Savvy reported positive experiences such as recognizing that their experience has become more pleasurable and happier. They also shared that the program expanded their knowledge and allowed them to become patient while implementing caregiving strategies learned. Majority of caregivers who participated in the Healthy Living program indicated that nothing changed related to their caregiving experience. Half of the caregivers in the usual care group, expressed frustration and unhappiness, while the others expressed no change in their caregiving experience. Results suggest that psychoeducation caregiver interventions are meaningful and can enact positive changes in their outlook on caregiving. Thus, results of this study may guide future policies and further development of caregiver programs and interventions."}
+{"text": "Despite benefits to overall health and well-being, healthcare professionals\u2019 knowledge and research is limited in regards to older women\u2019s sexuality and intimacy desires. There are barriers that impede fulfilling these desires and lack of understanding hinders ways to address this issue, which negatively affects the well-being of older women. A sexuality and intimacy survey of 29 women between the ages of 60-86 revealed that the majority were having sex at least once a month and expressed the desire to increase the frequency of sexual encounters. These data suggests that later-life sexuality and intimacy encounters are important for some women. Recognizing these desires could prompt responses that could greatly influence the quality of life in older women. A broader public health discussion needs to occur in order to promote awareness and optimize overall well-being."}
+{"text": "Type 2 diabetes mellitus (T2DM) has been established as an important independent risk factor for aortic stenosis. T2DM patients present with a higher degree of valve calcification and left ventricular dysfunction compared to patients without diabetes. This may be due to an increase in incidence and severity of myocardial fibrosis. Currently, there is no reliable method of determining the optimal timing of intervention for a patient with asymptomatic aortic stenosis or predicting when a patient will become symptomatic. Research into serum biomarkers to predict subclinical onset and track progression of aortic stenosis is hampered by the multimodal nature of the pathological processes ultimately responsible for aortic stenosis.The aim of this study is to prove that an approach using a combination of serum biomarkers and the echocardiographic parameter global longitudinal strain (GLS) can be used to establish baseline status of fibrocalcific aortic valve disease, predict rate of progression, and quantitatively assess any regression of these processes following aortic valve replacement in patients with T2DM.Validated serum biomarkers for the separate processes of calcification, inflammation, oxidative stress and fibrosis can be used to quantify onset and rate of progression of aortic stenosis. This, in combination with the echocardiographic parameter GLS, can be compared with other objective investigations of calcification and fibrosis with the aim of developing a quick, noninvasive one-stop assessment of aortic stenosis in patients with T2DM. The serum biomarkers BNP (B-type natriuretic peptide), Gal-3 , GDF-15 (growth differentiation factor-15), sST2 (soluble suppression of tumorigenicity 2), OPG (osteoprotegerin), and microRNA 19b and 21 will be sampled from patients undergoing aortic valve replacement (with and without T2DM), patients with T2DM but without aortic valve disease and healthy volunteers. These patients will also undergo computed tomography (CT) scans for calcium scoring, magnetic resonance imaging (MRI) to quantify myocardial fibrosis, and myocardial strain imaging with speckle-tracking echocardiography. Samples of calcified native aortic valve and a biopsy of ventricular myocardium will be examined histologically to determine the quantity and distribution of calcification and fibrosis, and the secretome of these tissue samples will also be analyzed for levels of the same biomarkers as in the serum samples. All patients will be followed up with in 3 months and 12 months for repeat blood sampling, echocardiography, and CT and MRI imaging to assess disease progression or regression. The results of tissue analysis and CT and MRI scanning will be used to validate the findings of the serum biomarkers and echocardiographic assessment.Using all of the information gathered throughout the study will yield a ranking scale for use in the clinic, which will provide each patient with a fibrocalcific profile. This can then be used to recommend an optimal time for intervention.A reliable, validated set of serum biomarkers combined with an inexpensive bedside echocardiographic examination can now form the basis of a one-stop outpatient-based assessment service, which will provide an accurate risk assessment in patients with aortic stenosis at first contact.PRR1-10.2196/13186 Aortic stenosis (AS) remains the most common valvular disease in adults, with a prevalence of 5% in people over the age of 65 years . While tThe physiological narrowing of the valve which limits the outflow of blood is the end result of a complex array of cellular mechanisms that culminate in two distinct but intertwined pathological processes: calcification and fibrosis . These mAs the presence of T2DM has been shown to accelerate the progression of aortic stenosis, it is not unreasonable to conclude that patients with T2DM who develop severe aortic stenosis warranting AVR may have more advanced underlying myocardial fibrosis. This may not be amenable to the beneficial phenomenon of reverse-remodeling following replacement of the valve; such T2DM patients may benefit from early AVR. A reliable strategy of tracking the cadence of disease progression and susceptibility to reverse-remodeling is therefore necessary, as this would optimize timing of surgery for high-risk patients. We hypothesize that a method utilizing biomarkers for the tracking of underlying cellular processes culminating in aortic stenosis shows promise in achieving this.The identification of a specific serum biomarker which can provide both an insight to the static state of a pathological process and track its progression (and subsequent regression following appropriate intervention) has proved challenging. This is due to the multimodal nature of the mechanisms which ultimately culminate in stiffening of the aortic valve. However, as a result of various studies of calcification and fibrosis in the heart, there is consensus that four core subprocesses are synergistically responsible in achieving the endpoint of aortic stenosis: valve mineralization , local inflammation, oxidative stress and ventricular fibrosis . Within sST2 (soluble suppression of tumorigenicity 2) is a member of the IL1 (interleukin-1) receptor family and is a marker of ventricular remodeling. sST2 levels increase with myocardial stress and have been demonstrated to correlate quantitatively with myocardial ischemia and heart failure. It is of particular use as it correlates with echocardiographic assessment of diastolic dysfunction and has been demonstrated to correlate with heralding the onset of new symptoms in previously asymptomatic aortic stenosis patients. High levels of sST2 are an independent predictor of mortality following aortic valve replacement surgery .Gal-3  is a beta-galactoside-binding lectin and a marker of inflammation and fibrosis of the myocardium, but it is also responsible for other processes such as regulating T-cell function and apoptosis. Gal-3 has a limited role in predicting progression of ventricular stiffening as it is also upregulated in other conditions such as renal dysfunction. However, when considered in tandem with BNP, it has shown to have significant predictive properties in the progression of heart failure .The microRNAs 21 and 19b are specific small RNAs that are 19-25 nucleotides long which are postulated to regulate gene expression related to various cellular mechanisms underpinning cardiovascular function. Although assessment of these micro-RNAs is still in early stages, microRNA-21 has shown good correlation with myocardial fibrosis. MicroRNA-19b has shown promise in determining increased myocardial collagen cross-linking in patients with aortic stenosis .GDF-15 (growth differentiation factor-15) is a stress-responsive cytokine that is sensitive to inflammatory changes and apoptosis. It is abundant in cardiomyocytes, adipocytes and macrophages and has demonstrated good predictive value in heart failure, vascular calcification and endothelial dysfunction. Like Gal-3, it is upregulated in renal dysfunction and additionally in obesity and insulin-resistant states such as diabetes. Although recent work has established GDF-15 as a useful prognostic and diagnostic marker of cardiometabolic disease in patients with diabetes, reference ranges correlating to severity have not yet been established [OPG (osteoprotegerin) is a member of the tumor necrosis factor receptor family and is expressed in early arteriosclerotic lesions and vascular smooth muscle cells. It has an important role in neocalcification, acting as a decoy receptor by binding to the RANKL (receptor activator kappa-B ligand) nuclear factor and inhibiting the receptor activity of RANK (receptor-activated kappa-B). This thus inhibits osteoclastic activity, which ultimately leads to calcification. Modulation of this pathway by the action of anti-Ghrelin antibodies suppressing OPG expression is of particular interest in seceding calcification .Speckle-tracing echocardiography is a relatively novel echocardiographic technique which has been shown to be more sensitive than conventional assessments of ejection fraction (EF) in the assessment of minute, regional wall motion abnormalities (RWMA) and left ventricular function. It correlates well with the presence and magnitude of myocardial fibrosis when compared alongside cardiac magnetic resonance, as assessed through T1-mapping and late gadolinium enhancement as quantification techniques. This noninvasive imaging modality can serve as an additional functional marker alongside the serum biomarkers mentioned above in the assessment of severity of aortic calcification and in the evaluation of reverse-remodeling postoperatively .Healthy volunteers and patients with milder, asymptomatic forms of the disease will be recruited from outpatient cardiology surveillance clinics to undergo serum biomarker sampling and strain echocardiograms. They will then undergo CT and MRI scans to investigate the relevance of these markers against objective imaging findings. This will enable the establishment of baseline levels in healthy volunteers and grading of the markers in mild, moderate and severe forms of disease.Finally, postoperative patients will be followed up with in 3 months and 12 months following surgery where they will once again undergo serum biomarker sampling and strain echocardiography to assess for evidence of reverse-remodeling. Again, CT scans for calcium scoring and MRI scans will be repeated to validate the significance of any downregulation of these biomarkers.The combination of biomarker and echocardiographic data encompassing the entire spectrum of the disease from healthy volunteers to patients with severe disease as well as disease monitoring in postoperative patients will yield a ranking scale for use in the clinic. This scale, once validated for reproducibility in an appropriately powered study, will provide each patient with a fibrocalcific profile which can then be used to recommend an optimal time for intervention.Enrollment has not commenced for this study. Ethical approval was obtained from South Central - Hampshire A Research Ethics Committee . Funding was obtained from the Wessex Heart Surgery Charitable Fund (registered charity #1051543).A reliable, validated set of serum biomarkers combined with an inexpensive bedside echocardiographic examination can now form the basis of a one-stop outpatient-based assessment service in providing an accurate risk assessment in patients with AS at first contact. In patients with diabetes, the role of such a service can be expanded to an essential screening service given the less favorable prognosis of aortic stenosis in this demographic."}
+{"text": "Isolated dislocations of the scaphoid are extremely uncommon injuries and are often associated with significant ligamentous failures. Since scaphoid dislocations typically present with associated carpal fractures, few cases of isolated dislocations of the scaphoid exist in the literature. The proposed treatment options in the literature range from closed reduction and casting to open reduction and internal fixation. We present the case of a 41-year-old male with an isolated scaphoid dislocation in whom open reduction and internal fixation was performed with K-wires. At five months follow-up, the patient had returned to work and all desired activities. Isolated scaphoid dislocations are extremely rare injuries and only individual case reports have been published in the current literature. In 1930, Higgs  classifiThe exact mechanism of the injury is unknown; however, previous reports have suggested that high-energy motor vehicle accidents with forced wrist dorsiflexion of the hand in ulnar deviation may result in the scaphoid leaving its fossa . Of the This case report details our experience in treating an isolated scaphoid dislocation in a 41-year-old man following a motorcycle accident. Open reduction with K-wire fixation was performed after a failed closed reduction in the emergency department. Since few case reports exist in the literature and present varying strategies, our case report may be a valuable resource for future diagnosis and treatment of similar injuries.A 41-year-old man presented to the emergency department following an automotive accident where he was thrown from his motorcycle traveling approximately 35\u2009mph. The patient denied loss-of-consciousness and chiefly complained of left wrist pain at presentation with exam demonstrating tenderness and swelling. Radiographs  revealedSubstantial force is required to disrupt the scaphoid from its fossa which more commonly fractures the radial styloid or the scaphoid waist . As a reThe severity of the injury is largely dependent on the number of ligaments disrupted and it is postulated that the order of ligamentous failure begins with the radioscaphocapitate and scapholunate ligaments followed by the radiolunate and scaphotrapezial ligaments . IsolateChloros et al. created an algorithm for treating isolated carpal dislocations . They reOccasionally, the diagnosis of isolated scaphoid dislocations may be missed; however, standard radiographs were sufficient to diagnose in this case . Few comIsolated scaphoid dislocations are uncommon injuries and frequently missed. The prognosis of isolated dislocations of the scaphoid is typically good when treated early and appropriately. Open reduction and percutaneous pinning is a sufficient and effective treatment for isolated scaphoid dislocations, especially in complex cases and secondary dislocations following failed closed reduction. Complications are uncommon, and most patients will return to their previous activities following proper treatment."}
+{"text": "An estuary is a dynamic environment where marine and fluvial processes meet to form complex and transient morphology. The estuary morphology is largely determined by net sediment transport by two-way tidal flows, but the hydrodynamics also depends on the morphology of the tidal channels. The estuary inherently accommodates cyclic processes that are internally generated through hydro-morphodynamic interactions. In addition, the estuary evolves in response to changes in external forces by natural and anthropogenic factors. Morphological changes under the different controls often hinder the comprehension of the evolutionary processes of estuaries. Here we explored morphological changes in the Sittang River estuary, Myanmar, which has great morphological dynamism from extreme tidal energy and large sediment inputs, through field surveys and satellite imagery analysis. We identify an autocyclic process in a sedimentary system driving large-scale channel migration in decadal to multidecadal cycles. We show that drastic changes of the estuary morphology occasionally occur with rapid bank erosion through modulation of the cyclic channel migration under conflicting tidal and fluvial forces. This extreme case with minimal human intervention highlights channel migration as a key process in morphological evolution of tide-dominated estuaries undergoing active infilling. The estuary progrades seawards if the sedimentation rate overcomes a relative sea-level rise due to climatic and/or tectonic forces. The estuary evolution, however, does not proceed monotonically, as various factors affect the sedimentary system5. Besides natural and anthropogenic effects to change external boundary conditions, the blind-channel system would evolve through simultaneous adjustment of morphology and sediment movements9.Tide-dominated estuaries are subject to a long-term process of infilling with fluvial sediments from rivers and with marine sediments brought by asymmetric tides. Hydro-morphodynamic processes shape the supplied sediments into common landscapes: an upper channel of fluvial dominance, a central basin of high tidal energy and a funnelling basin in the lower reach. The central basin comprises blind tidal channels loosely bounded by mudflats on both sides and tidal bars in the middle, among which a main channel connects to the upper channel through a transitional segment. A tight meander usually forms in the transitional segment where the tidal force competes with the fluvial force12. The flood and ebb channels are evasive with each other and are usually separated by tidal bars. Previous studies suggested that flood/ebb dominance varies with channel cross-section which affects the frictional damping of two-way flows14: Flood dominance characterises wide, shallow channels and ebb dominance characterises deep channels with high tidal flats. A loosely-bound channel system has a highly transient nature with formation, migration and filling of individual channels in contrast to the slow dynamics of emergent tidal channels bounded by consolidated sediments16. Continuous sediment input alters a channel cross-section to become ebb-dominant with built-up tidal flats. The resulting loss of sediment by ebb flows returns the channel cross-section to be flood-dominant. An estuary, therefore, is conjectured to balance the sediment input and output through cyclic changes in the channel system7. Recent experimental studies using a novel facility suggested the possibility of dynamic equilibrium with cyclic channel migration under steady tidal forcing19. However, long-term observations of subaqueous processes are limited, and the cyclic channel migration in natural tidal basins has not been well documented. A case with large-scale morphological changes and minimal human intervention can provide insights into these elusive processes.The blind-channel system consists of ebb and flood channels that are distinguished by a dominant direction of sediment transport20. The semidiurnal tides coming from the Indian Ocean have large amplitude in shallow areas of the Andaman Sea21 and further intensify into the gulf due to strong funneling effect. The tidal range inside the gulf varies from 3\u2009m to 7\u2009m over the course of spring-neap cycles22. Three major rivers\u2014the Ayeyarwady, Sittang and Salween\u2014supply a large amount of fluvial sediments into the ocean  analysis to the coastline dataset for the years 1987 to 2017, during all of which high-quality satellite images were available Fig.\u00a0. We decoThe rapid shift of the transitional segment in the early 2000s appears to have been a turning point for morphological changes in the estuary. The subsequent satellite images depict a westward shift of the channel migration with increasing amplitude Fig.\u00a0. The rec34. Another peculiar feature of this estuary is presence of large sediment sources on the sea side, originated from the Ayeyarwady and Salween. The continuous sediment supply is likely to support the fast bank accretion on the opposite side of the bank erosion. Further studies will be required to address this issue with sufficient data support.This study highlighted the cyclic channel migration as a key process in estuary evolution, which triggers alternating erosion and accretion on opposing sides of the estuary in decadal to bidecadal cycles. The cyclic channel migration occurs through the mutually evasive evolution of ebb and flood channels, but the cause of the cyclicity remains unclear as to why this estuary has the tremendous cycle that others do not. The asymmetric tides of large amplitude may be a key factor, which possibly lead to the distinct roles of flood and ebb flows on estuary morphology and thereby maintain the cyclicity of the channel system. However, other estuaries in similar tidal settings, such as Qiantang estuary in China, do not exhibit an obvious cycleThe estuary yields an equilibrium state with the channel migration cycle through which residual sediment transport in and out of the estuary is roughly balanced. However, the channel migration is occasionally modulated by morphological changes in the transitional segment under a mixed tidal\u2013fluvial control. The pivotal segment probably evolves in an irregular cycle between a cuspate and tight meander with a changing balance of tidal and fluvial forces. This multi-decadal cycle can also be viewed as the depositional-erosional cycle of estuary evolution. Both the upper channel and the central basin are filled with a tight meander, while active channel migration sweeps sediments out from the central basin with a cuspate meander. The estuary infilling likely proceeds with the downshift of the transitional segment through the destruction and creation of tight meanders.We produced the coastline dataset from Landsat satellite imagery from the years 1973 to 1978 and 1987 to 2017. Cloud-free satellite images of the estuary in November to December were obtained using Earth Explorer by the U.S. Geological Survey. We extracted vegetation lines on both sides of the estuary neglecting lower mudflats and small-scale morphological features such as narrow creeks and isolated tidal bars, which vary on a short time scale. The detection error was found to be within a few hundred meters when it was evaluated on some stable portions of coastline. A major uncertainty arises from an ambiguity of coastline definition in a depositional phase. Coastlines under the definition above occasionally move a few kilometers seaward over one year when an extensive mud flat rises above the high water level. Therefore, the bank accretion process is more or less represented by step-like changes on the time axis. This poses an uncertainty for an instantaneous estuary planform when the boundary is not clear. Nevertheless, we could capture global trends of the estuary evolution with low-order EOF variances, since local changes associated with the uncertainty are decomposed into higher-order EOF variances.35. The survey period of the latter old map was not given; we assumed it to have been the mid 19th century. Supplementary Fig.\u00a0The two additional coastlines in the 1940s and the 19th century were derived from two old maps: a 1:250,000-scale map by the US Army Corps of Engineers  based on surveys from 1944\u201345 and a topographic map of Lower Sittang Valley that appeared in an 1876 geography book36. Coastline displacements were not demeaned prior to the EOF deconstruction, and thus, the first-mode variance represents the mean coastline which resembles the statistical mean37. The base coastline was created by averaging the first-mode coastlines over the entire period, and the second- and third-mode variances were displayed from it in Fig.\u00a0For the EOF analysis, we introduced a longitudinal coordinate along the estuary axis and resampled the coastline data on the west and east as displacements from the axis at 30\u2009m intervals. Then, we stored the 31-year dataset on each side of the estuary in a matrix arranging each coastline into a row vector and deconstructed it into orthogonal components by the eigenvalue expansion. The EOF deconstruction was implemented independently for the two sides with a simple Matlab algorithmWe measured the water surface, flow velocity and bank displacement over tidal cycles in the field surveys. The water-level measurement was performed with a bottom pressure sensor fixed on a muddy bed by a wooden pile during low tides. The sensor was collected after one day since the bank retreated quickly over tidal cycles. The bottom pressure sensor captured water-surface variation over a full tidal cycle, although short data breaks occurred due to sensor exposure during low tide and oscillations by turbulent flows during flood tide in the dry-season data. Flow-velocity measurement was done by tracking floating objects away from the bank where flows were not directly affected by bank-generated vortices. For the bank-line measurement, we took orthogonal images of the bank line with ground-control points using an UAV and detected the bank lines from the rectified aerial images.Supplementary FiguresTidal bore arrival at the survey siteRapid bank erosion in a cantilever failure modeSequential satellite images of the Sittang River estuary from 1987 to 2017. Landsat imagery courtesy of NASA Goddard Space Flight Center and U.S. Geological Survey."}
+{"text": "Tumor heterogeneity is the major cause of failure in cancer prognosis and prediction. Accurately detecting heterogeneity for the development of biomarkers and the detection of the clones resistant to therapy is one of the main goals of contemporary medicine. Metastases belong to the natural history of cancer. The present review gives an overview on the origin of tumor heterogeneity. Recent progress has made it possible to isolate and characterize circulating tumor cells (CTCs), which are the drivers of the disease between the primary sites and metastatic foci. The most recent methods for characterizing CTCs are summarized and we discuss the power of CTC profiling for analyzing tumor heterogeneity in early and advanced diseases. Anyone who has observed a tumor section under a microscope is familiar with the significant heterogeneity of the tumor mass. Within a single tumor mass, several foci with various, specific histological features can cohabit Figure . In addiThe evolution in good clinical practices (e.g. needle biopsies) has recently led to a significant decrease in the amount of biological material available for molecular investigations. A biopsy cannot reflect and illustrate spatial tumor heterogeneity and should be considered as a partial photograph of the tumor mass at a given time. The follow-up of the dynamic process requires repeated sampling carried out using low invasive methods and should be as representative as possible of the tumor mass. Repeated biopsies are ethically non-acceptable and sometimes unrealistic for high-risk localizations of metastatic foci (e.g. the spine). The establishment of metastatic disease is directly related to the migration of cancer cells called circulating tumor cells (CTCs) into the blood and/or lymphatic circulation, plus their ability to reach distant organs TP53, Rb) lead to the formation of neoplastic foci characterized at the early stage by monoclonal expansions of mutated cells. This type of mutation results in genomic instabilities characterized by a high sensitivity to chromosome breakages and consequently a new series of mutations, deletions, and amplifications Cancer is characterized by the development and growth of abnormal cell populations . As DNA is the only cell component that can accumulate and transmit changes throughout life, it has been accepted that the carcinogenesis process requires the progressive accumulation of multiple DNA modifications + or EpCAM- breast cancer cells, sorted by flow cytometry, led to the detection of mixed EpCAM+/EpCAM- cells in the blood stream after a couple of days. This simple experiment perfectly illustrates the extreme plasticity of cancer cells et al. studied the impact of EWSR1/FLi1 expression on the functional behavior of Ewing sarcoma cells Low contribute to the maintenance of tumor growth based on ESWR1/FL1 re-expression. Their manuscript illustrates a new model of phenotypic plasticity and gives evidence of the functional impact of this dynamic phenotypic fluctuation associated with a dominant oncogene.Similarly to embryonic cells, cancer cells are not blocked in a defined state and adapt permanently their phenotype under the microenvironment and therapeutic pressure. Indeed, phenotypic and functional plasticity is a common mechanism observed during embryonic development However, the therapeutic pressure plays a significant role in the selective amplification of tumor heterogeneity and contributes to emergence of specific dominant clones driving the tumor heterogeneity et al. identified four subsets of CAF in breast cancer with specific distinct functional properties. In triple negative breast cancers, one of them, called CAF-S1, promotes an immune tolerant environment and stimulates T lymphocytes toward an immunosuppressive phenotype (CD25high FOXP3high). The second, called CAF-S4, increases the T cells' regulatory property to inhibit T effector proliferation. Consequently, the local accumulation of CAF-S1 then contributes to tumor heterogeneity and to local immunosuppression observed in triple negative breast cancers. Such immunoregulation is tightly controlled by the production of local immunocytokinic signals leading to a balance between inflammatory and immunosuppressive effectors et al. revealed that CTCs are competent to modulate tumor associated macrophages in order to increase invasiveness of cancer cells, angiogenesis and immunosuppression As described above, from a clonal disease, the successive mutations in tumor cells play a part in temporal heterogeneity and the establishment of a very complex polyclonal oncogenic disease. In addition to the heterogeneous populations of neoplastic cells, tumor bulk is composed of non-neoplastic resident cells, the extracellular matrix Tumor heterogeneity has challenged the potential benefits of precision medicine. Current methods used to analyze tumor masses and further therapeutic design are based on a global overview of the characteristics of cancer tissues, corresponding to an average picture of all the tumor clones and their micro-environment without considering their diversity et al. detected a high concordant mutation list in CTCs and tissues (e.g. KRAS and BRAF markers), predicting the outcome of anti-EGFR therapy in colorectal cancer patients et al. showed that CTCs were representative of the entire spectrum of mutations present in the primary tumor and distal metastases for patients with breast cancer. Their findings suggested the utility of CTCs for identifying targetable mutations and for being used as a biomarker to reveal cell populations sensitive to current or previous therapies In the last decade, numerous clinical studies revealed the link between CTC numbers and metastatic prognosis et al., who observed variability in the mutational status of the PIK3CA gene in breast cancer patients. The PIK3CA mutation profile has prognostic significance and is potentially predictive for the response to agents targeting the PI3K pathway 8 Similarly, Pailler et al. observed considerable heterogeneity in ROS1-gene abnormalities in CTCs from non-small cell lung cancer (NSCLC), which could explain the mechanism by which tumor cells can escape sensitivity to ROS1-inhibitor therapy et al. then mapped the phenotypic evolution of melanoma CTCs and detected the presence of drug-resistant clones harboring different molecular signatures of potential clinical value Despite these promising results, the existence of heterogeneity in the CTC compartment has been demonstrated, as shown by Pestrin et al. validated a protocol to assess the clonal evolution of metastatic breast cancer, based on single CTC analysis by next generation sequencing (NGS), suitable for the development of new therapeutic strategies in precision medicine et al. analyzed single-cell RNA-sequencing (RNA-Seq) profiles in prostate cancer and concluded that there was CTC heterogeneity in signaling pathways that could contribute to treatment failure et al. investigated ALK-copy number gains (CNG) in individual CTCs by filter-adapted fluorescent in situ hybridization (FA-FISH) and reported a significant association between the dynamic evolution of the numbers of ALK-CNG and progression-free survival (PFS) in NSCLC patients treated with crizotinib, an ALK/ROS1 inhibitor et al. found ESR1 mutations in single CTCs from metastatic breast cancer patients associated with endocrine therapy resistance et al. presented an extensive study of the heterogeneity associated with the components that shape the melanoma micro-environment, assessed by single-cell RNA-seq. The authors discovered different micro- environments associated with distinct malignant cell profiles that could be used as prognostic markers Single CTC analysis could effectively reveal the high heterogeneity, stochastic changes, and driver mutations in cancer cell populations in order to detect drug resistance, and develop new personalized therapeutic strategies as well as their use as prediction markers. De Luca et al. demonstrated that cluster CTCs are able to reorganize into single-file chain-like geometries in a rapid and reversible manner with reduced hydrodynamic resistance. Consequently, the progression of cluster CTCs through capillaries is slowed down and cancer cell clusters can traverse easily thin constrictions for extravasation and migration into distant organs et al. demonstrated that the association between neutrophils and CTCs drove cell cycle progression within blood and increased the metastatic potential of CTCs in breast cancer patients In addition to single CTCs detectable into the bloodstream, CTCs can be observed in clusters composed by cancer cells and/or in association with non-malignant cells. Recent findings suggest that CTC clusters may have a greater contribution to the metastatic process for mechanical and immune features. Indeed, Au et al. compared the dialog between immune cells and CTCs isolated from non-metastatic and metastatic cell lines inoculated in syngeneic immune-competent mice et al. studied a series of non-small cell lung cancer patients However, heterotypic CTC clusters have never been associated with circulating lymphocytes. What could be the relationship between T lymphocytes and CTCs? A close relationship between immune cells and cancer cells has been described through the immune checkpoints 6-108 normal blood cells. Consequently, before single CTC analysis can take place, the first step is to enrich and isolate CTCs. Multiple technologies have been described to do this in individual CTCs, based on the different properties that distinguish them from surrounding normal hematopoietic cells, including biological properties  and physical properties  reviewed previously CTCs are rare cell events in blood with a frequency of around one tumor cell for 10et al. used a qPCR assay to analyze the variability of HER2 and PIK3CA in breast cancer single CTCs. Their findings demonstrated that assessing the heterogeneity for these two markers may uncover tumor evolution mechanisms useful for personalized therapy decisions et al. assessed single-nucleotide PIK3CA mutations and HER2 copy number alterations in single cells in formalin-fixed paraffin-embedded breast tumor samples using the STAR-FISH  methodology. This analysis proved to be useful for predicting clinical outcomes in breast cancer patients subjected to neo-adjuvant chemotherapy followed by adjuvant therapy with trastuzumab Studying genetic variability in single cells has stimulated the development of several high throughput sensitive methods for detecting large patterns of mutations including target-specific amplification using PCR, as a means of querying specific loci of interest  et al. identified 4 new driver mutations in renal cell carcinoma stem cells using WES that constitute important prognostic factors and therapeutic targets et al. combined multi-region WES and single-cell WGS to examine the intra-tumor heterogeneity of rectal tumors. Their results suggest a specific architecture for each tumor related to different diagnoses, prognoses and drug responses In the last few years, there has been a significant increase in the number of studies that use next generation sequence approaches for unraveling single cell heterogeneity. The study performed by Liet al. described a whole-genome bisulfite sequencing (WGBS) assay that makes it possible to analyze heterogeneous DNA methylation patterns in single cells (scWGBS) and compared it with the other two methods: single-cell reduced representation bisulfite sequencing (scRRBS) and single-cell post-bisulfite adaptor tagging (scPBAT) et al. used this methodology to investigate the cell-to-cell variability of different types of regulatory elements and they confirmed its suitability for revealing aspects of epigenetic heterogeneity not captured by transcriptional analysis alone et al. successfully modified the DamID method et al. analyzed the epigenetic status of the genes associated with epithelial mesenchymal transition (EMT) in individual breast cancer CTCs, and explored potential intra- and inter-patient heterogeneity using the agarose-embedded bisulfite sequencing (AEBS) protocol. They found heterogeneous methylation patterns in CTCs with clear infrequent hypermethylation at key promoters of the inhibitor genes of the EMT, suggesting that both epithelial and mesenchymal CTCs can contribute equally to the metastatic process Robust technologies have been developed for mapping epigenetic marks in single cells. Bisulfite conversion followed by sequencing (BS-seq) is considered the gold-standard method for single base resolution and absolute quantification of DNA methylation levels et al. performed a comparative analysis of the most prominent scRNA-seq methods and identified Drop-seq as the best method for analyzing the transcriptome of large numbers of cells with low sequencing depth, SCRB-seq and MARS-seq are preferable for the transcriptome of fewer cells, and Smart-seq2 would be the appropriate method of choice when annotating the transcriptome of very small quantities of cells Single-cell RNA sequencing (scRNAs) is the method selected if the aim of the study is to explore transcriptome heterogeneity et al. reported the heterogeneity of single glioblastoma CTCs and the existence of high variability in signaling molecules relevant to the targeted therapy, a wide spectrum of stemness and differentiation states, variable proliferative capacity and expression of quiescence markers, all of which were related to the success or failure of therapeutic strategies et al. used scRNA to characterize heterogeneity in tumor cells and TME components (mainly immune cells) in breast cancer. The authors identified various signatures in both compartments related to tumor development and the response to cancer therapy et al. proposed the use of standard cell lines in future quality controls et al.et al.Numerous studies show extensive use of scRNAs for unraveling CTC heterogeneity. Patel et al. validated the clinical utility of proteomics in single cells by using scWB, and analyzed variability in metastatic breast cancer cells. They observed high heterogeneity in the expression of 8 key proteins related to breast cancer progression Recent progress in microfluidic technologies and mass spectrometric approaches have led to new single-cell proteomics studies that could be performed with greater sensitivity and specificity. The micro- engraving technique, single-cell barcode chips (SCBCs) and single-cell Western blotting (scWB) are the microfluidic platforms providing the most advanced capabilities Repeatable, minimally-invasive and cost-effective approaches for real time assessment of relevant biomarkers and monitoring cancer therapies in the bloodstream have been developed to overcome the intrinsic limitations of primary tumor and metastasis biopsies. This field of investigation has been termed \u201cliquid biopsy\u201d and includes circulating tumor cells (CTCs), exosomes, circulating cell-free DNA (cfDNA), miRNAs and proteins. CTC characteristics can be considered to be a snapshot of overall tumor bulk (primary tumor and metastases). Compared to other liquid biopsies, CTCs are a little bit more laborious to obtain but can be analyzed at the DNA, RNA, and protein level, as well as with regard to their functional cellular characteristics as a means of providing information that relates to the whole cell et al. conducted a study on this subject and concluded that around 20-40 single cells are required to detect the main subclones with 95% power et al. demonstrated the existence of specific CTC territories, marking the spatial heterogeneity of CTCs. These authors compared the EMT status of CTCs isolated from various vascular territories and observed surprisingly high heterogeneity depending on their location Pooling the cells might provide different results and could mask clinically relevant rare mutations  et al. analyzed the link between the detection of breast cancer CTCs with a mesenchymal phenotype and EMT status of primary tumors + CTCs et al. studied the EMT process and CTC release in pre-clinical models of prostate cancer EMT biomarkers  are differentially expressed in CTCs et al. in which the authors used a single-cell triple omics sequencing technique called scTrio-seq which links the complex contribution of genomic and epigenomic heterogeneities to transcriptomic heterogeneity within a population of cells in vivo monitoring and analysis of single CTCs, as has been shown in different studies Nowadays, most of the studies published focus on revealing cell-to-cell differences at the DNA and RNA level. For overall understanding of single-cell heterogeneity, future studies should focus on the combination of different multi-omic assays on the same cell, such as the study performed by Hou"}
+{"text": "Gastrointestinal bleeding from renal cell carcinoma metastasis is an uncommon manifestation of tumor recurrence and is usually difficult to control. Palliative trans-catheter embolization to control the bleeding has been used and described in the literature.The present report describes a 62- years-old male with local recurrence of RCC who presented with upper GI bleeding as the primary manifestation 10\u2009years after right-sided partial nephrectomy. A pseudoaneurysm of renal artery with erosion into the duodenal lumen was responsible for the massive bleeding and was controlled with coil embolization.This case report highlights the importance of high index suspicion in post-nephrectomy patients for RCC, presenting with new symptoms. Aggressive gastrointestinal workup and adequate awareness of available minimally-invasive endovascular options for controlling GIB in these patients, are of paramount importance. Renal cell carcinoma (RCC) is the third most common malignancy of the urinary tract  and partial nephrectomy 10\u2009years ago. Esophagogastroduodenoscopy revealed an irregular, ulcerative mass lesion in the second segment of the duodenum. Contrast enhanced (CT) scan of the abdomen and pelvic showed a heterogeneous soft tissue mass in the nephrectomy bed extending to the second and third segments of the duodenum. There was also a pseudoaneurysm from right renal artery that was located near the soft tissue mass (arrowheads in Fig.\u00a0Angiographic examination of the renal artery revealed a lobulated pseudoaneurysm with intermittent episodes of hemorrhage into the duodenum. The lesion was successfully excluded using coils Fig.\u00a0 and GIB The patients remained stable after the surgery and was scheduled for systemic chemotherapy. Unfortunately, he decided to leave the hospital against medical advice after two weeks and we could not contact him since then. GI bleeding did not recur during his hospital stay.Gastrointestinal metastases are rare causes of GIB (Bhatia et al., Management of patients with solitary metastatic RCC to the duodenum depends upon the extent and location of duodenal lesion and general conditions of the patient and should be individualized for each patient (Thyavihally et al., This case report highlights the importance of high index suspicion in post-nephrectomy patients for RCC, presenting with new symptoms. Aggressive gastrointestinal workup and adequate awareness of available minimally-invasive endovascular options for controlling GIB in these patients, are of paramount importance."}
+{"text": "Cell death is a tightly regulated process which can be exploited in cancer treatment to drive the killing of the tumour. Several conventional cancer therapies including chemotherapeutic agents target pathways involved in cell death, yet they often fail due to the lack of selectivity they have for tumour cells over healthy cells. Over the past decade, research has demonstrated the existence of numerous proteins which have an intrinsic tumour-specific toxicity, several of which originate from viruses. These tumour-selective viral proteins, although from distinct backgrounds, have several similar and interesting properties. Though the mechanism(s) of action of these proteins are not fully understood, it is possible that they can manipulate several cell death modes in cancer exemplifying the intricate interplay between these pathways. This review will discuss our current knowledge on the topic and outstanding questions, as well as deliberate the potential for viral proteins to progress into the clinic as successful cancer therapeutics. Cancer is a major public health problem, of which incidence and mortality is rapidly growing worldwide. An estimated 9.6 million deaths were attributed to cancer in 2018 making it the leading cause of death globally .Anti-cancer proteins found encoded within viruses are from a variety of origins including the chicken anaemia virus, rodent parvoviruses and human adenoviruses . They arGyrovirus genus  cholesterol/dioleoylphosphatidyl-ethanolamine (tgDCC-E1A) for gene delivery have encouraging results, as liposome mediated E1A gene transfer significantly inhibited growth of ovarian cancers in treated mice [More innovative ways of gene delivery have also been used. For instance, human serum albumin (HSA) which is known to accumulate in tumours, was fused to the apoptin gene to form the resulting plasmid HSA-PEI-pcDNA-Apoptin. This plasmid was shown to be efficiently taken up into the breast cancer cell line MCF7 and also supress tumour growth in nude mice models in vivo . Recentlted mice . This idted mice .Viral gene delivery has advantages over non-viral systems as they are much more efficient at gene transduction in most cell-types. These systems also come with problems however, such as immunogenicity with serious side effects, possibility of insertional mutagenesis and a limit in the size of DNA delivery . Viral-mIt is not surprising that both E1A and E4orf4 have been delivered within the viruses they originated from. Replication deficient HAdV vectors containing the E1A gene are efficient for the delivery of the protein product and subsequent toxicity within ovarian clear cell carcinoma cells . ReplicaSeveral features of naturally occurring adenoviruses can be adjusted to complement tumour-specific replication and toxicity. A good example of this is the development of the HAdV ONYX-015 which contains wild type E1A and E4, but contains an 827bp deletion in the E1B gene. This modified virus produced encouraging results in the early phases of clinical trials and has since progressed to a clinical phase III study combined with standard cisplatin chemotherapy for the treatment of head and neck squamous cell carcinoma (HNSCC) . AnotherLastly, some studies have tried to deliver the purified viral protein directly to cells by fusing the protein to protein transduction domains (PTDs) or cell penetrating peptides (CPPs). This includes the HIV derived TAT peptide which has shown to allow efficient and rapid uptake of cells in vitro and in vivo. This method of delivery has been used for delivery of apoptin as a secretable TAT fusion protein, as well as E1A ,185. ApoViral proteins which can induce cancer specific cell death are a promising and innovative therapeutic option for the treatment of numerous cancer types. The surprising number of similarities between viral proteins with this ability from different viral sources have been evaluated within this review, and their potential mechanisms of action have been summarised. So far, a number of pre-clinical and clinical trials have been carried out but there are still several important questions related to their clinical application that need to be explored see . These aBox 1Which protein domains are required for selective anti-cancer toxicity or do several of these need to co-operate to achieve this effect?Is the intrinsically disordered nature of these proteins essential for their function?Is the multimeric characteristic vital for their function? Does this multimerization occur in the nucleus of transformed cells?Do the frequently observed PTMs of viral proteins drive cancer-selective toxicity? Are additional, currently unknown PTMs involved?Do all the proteins discussed exploit the same mechanism of action? Are these mechanisms cell-type specific?Which is the most effective and safest way of delivering cancer-selective toxic proteins to tumours?If only single protein domains are absolutely required for cancer toxicity, would it be possibly to develop artificial mini-proteins or peptides which mimic the cancer selectivity of the viral proteins?Can cancer-selective viral proteins be used in combination with already FDA approved therapies?Outstanding questions:"}
+{"text": "Neurologic Music Therapy (NMT) is a novel impairment-focused behavioral intervention system whose techniques are based on the clinical neuroscience of music perception, cognition, and production. Auditory Stimulation (RAS) is one of the NMT techniques, which aims to develop and maintain a physiological rhythmic motor activity through rhythmic auditory cues. In a series of breakthrough studies beginning in the mid-nineties, we discovered that RAS durably improves gait velocity, stride length, and cadence in Parkinson's disease (PD). No study to date reports the neurophysiological evidence of auditory-motor frequency entrainment after a NMT intervention in the Parkinson's community. We hypothesized that NMT-related motor improvements in PD are due to entrainment-related coupling between auditory and motor activity resulting from an increased functional communication between the auditory and the motor cortices. Spectral analysis in the primary motor and auditory cortices during a cued finger tapping task showed a simultaneous increase in evoked power in the beta-range along with an increased functional connectivity after a course of NMT in a small sample of three older adults with PD. This case study provides preliminary evidence that NMT-based motor rehabilitation may enhance cortical activation in the auditory and motor areas in a synergic manner. With a lack of both control subjects and control conditions, this neuroimaging case-proof of concept series of visible changes suggests potential mechanisms and offers further education on the clinical applications of musical interventions for motor impairments. Neurologic Music Therapy (NMT) is a novel impairment-focused behavioral intervention system whose techniques are based on the clinical neuroscience of music perception, cognition, and production Thaut, . One of Parkinson's disease (PD) is a neurodegenerative illness defined by characteristic motor symptoms including slow and small movements as well as difficulty with movement initiation and disruptions in timing. Several explanations for the underlying pathophysiology include beta and gamma impairments in subcortical structures such as the basal ganglia (BG)  auditory rhythm very rapidly creates stable internal reference intervals to guide the timing of motor responses and that (2) the dominant synchronization strategy is based on frequency entrainment. Entrainment of distant brain regions most likely relies on synchronization at specific frequencies that can be recorded via whole brain neuroimaging modalities such as magnetoencephalography (MEG).No study to date reports the neurophysiological evidence of auditory-motor frequency entrainment after a NMT intervention in the Parkinson's community. We wanted to share a neuroimaging case-proof of concept series of visible changes that suggest potential mechanisms and provide further education on the clinical applications of musical interventions for motor impairments. We hypothesized that NMT-related motor improvements in PD are due to entrainment-related coupling between auditory and motor activity resulting from an increased functional connectivity between the auditory cortex and the motor cortex.Three right-handed PD participants were recruited from the University of Colorado Hospital Movement Disorders clinic and signed informed consents to participate in the study approved by the Colorado Multiple Institution Review Board. Inclusion criteria included a diagnosis of probable PD according to the UK Brain Bank Criteria  in a magnetically shielded room . Participants were asked to tap with their right index finger with an acoustic burst stimuli  delivered in their right ear every second. A quick practice session was performed prior to the MEG recording session. A total of 6 sequences of 30 s separated by a 5-s rest period were presented. Data was acquired continuously at 678 Hz with an acquisition bandwidth of 0.1\u2013200 Hz. Scalp shape and location was determined with a 3-D digitizer to allow for comparison across subjects in a common coordinate system and for co-localization with an averaged MRI brain atlas. Data was divided into 800 ms epochs. Preprocessing included 3\u201370 Hz band pass filtering, noise reduction, and rejection of epochs with significant artifact. Independent component analysis was used to remove eye blink and other common artifacts  of p < 0.05.Source analysis was performed in Matlab  using the SPM12 toolbox. Following co-registration of the MEG fiducials with each participant's MRI, leadfields were computed using a single shell volume conductor model. Source localization was then performed using a cortically constrained group minimum norm inversion with multiple sparse priors (Litvak et al., Regional time-courses were created via source-space projection (Tesche et al., Five weeks of NMT had beneficial effects on fine motor function in our cohort of three patients with PD . PD-specSpectral analysis in the primary motor and auditory cortices during a cued finger tapping task showed a possible coinciding increase in evoked power in the beta-range suggesting an activity coupling in those two areas most likely due to their simultaneous activation . While tStronger functional connectivity between the auditory and motor cortices was observed after NMT . It is hThis case study provides very preliminary evidence that NMT-based motor rehabilitation may enhance cortical activation in the auditory and motor areas in a synergic manner. Our connectivity findings and the existing literature both suggest that auditory-motor connections may be improved and strengthened by training, even in the PD population. With a lack of both control subjects and control conditions, future controlled trials are warranted to further explore the effects of NMT therapy in those vulnerable patients, especially looking at symptom-specific groups given the heterogeneity of the motor symptoms found in patients with PD.IB and MT: conceived and designed the experiments; IB: performed the experiments; IB and WD: analyzed the data; IB wrote the paper; IB, WD, MT, and BK: reviewed and revised the manuscript and approved the final manuscript as submitted.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Recent reports show an increase in the incidence of Autism Spectrum Disorders (ASD) to 1 in every 59 children up to 8 years old in 11 states in North America. Induced pluripotent stem cell (iPSC) technology offers a groundbreaking platform for the study of polygenic neurodevelopmental disorders in live cells. Robust inflammation states and immune system dysfunctions are associated with ASD and several cell types participate on triggering and sustaining these processes. In this review, we will examine the contribution of neuroinflammation to the development of autistic features and discuss potential therapeutic approaches. We will review the available tools, emphasizing stem cell modeling as a technology to investigate the various molecular pathways and different cell types involved in the process of neuroinflammation in ASD. Autism Spectrum Disorder (ASD) is a lifelong neurodevelopmental disorder characterized by the impairment of social abilities and cognitive functions that can manifest cortical disorganization or neuroinflammation states . As a code novo mutations on genes that segregate with ASD  and 16p11 deletion, are likely involved in brain volume changes and neural connectivity, and its particular function can be studied in animal models and genetically engineered human cells , and 3-maternal immune activation (MIA) during pregnancy   . A commoMET gene  known to regulate cell immune functions amongst other roles  participate in microglial function and neuronal migration and are potentially implicated in altered cortical development in ASD . Marchetto et al.  as the primary genetic cause of RTT . The researchers also pointed out that omega-3 polyunsaturated fatty acids (PUFAs) partially counterbalanced the cytokine changes and the aberrant redox homeostasis and ameliorated the inflammatory status  can be explained in part by impaired regulation of the inflammatory system. In rodent models MeCP2 regulates gene expression in microglia and macrophage . Leonciny status .FMR1) gene due to CGG trinucleotide repeat expansion in the 5\u2032 untranslated region of FMR1. This aberrant expression leads to hypermethylation and gene silencing, leading to the decrease or absence of FMRP   , 63.FMR1 also causes aberrant differentiation in human iPSC-derived neural progenitor cells, particularly a marked induction of the astrocyte marker glial fibrillary acidic protein (GFAP)  . In pararebellum , indicatrebellum , no iPSCpression .Mouse modeling is a crucial tool for autism spectrum studies with the generation of genetically modified strains focusing on understanding the basic features of abnormal neurodevelopment in ASD.+ T cells. The offspring from MIA models displayed general alteration of their immune profile and function, and interestingly, bone marrow transplantation of MIA-derived mice into irradiated control mice did not recapitulate the MIA phenotypes illustrating the importance of the peripheral system context in the immune system activation  displayed increased microglial IL-1\u03b2 resulting in an enhanced tauopathy, immature synapses throughout the cortex and connectivity imbalance with ASD-like behaviors . The next step would be developing a high-throughput screening (HTS) system capable of identifying disease biomarkers and potentially detecting compounds that rescue a phenotype. Since ASD is a complex developmental disorder, studying iPSC-derived fetal-like cells is ideal for establishing a therapeutic approach as early as during gestation time (Figure in vitro platform.Increasing evidence supports the idea of immune system activation in ASD. iPSCs are crucial for a better understanding of complex polygenic diseases with heritable and sporadic forms, such as ASD in order to develop novel biomarkers and identify targets for future therapeutics . Derivine Figure . Recent e Figure , speciale Figure \u201389. It w,,,,iPSC technology is also a remarkable scientific tool to test compounds that could be used in the clinic for ASD individuals. The grouth factor IGF1 was first tested in RTT mouse models  and thenIn summary, iPSC technology is an invaluable tool for asking questions about human-specific neuroinflammation mechanisms, such as the ones observed in syndromic and non-syndromic forms of ASD. Importantly, iPSCs can generate a platform for the discovery of new anti-inflammatory compounds that are tailored to the ASD-specific genetic background and neuropathological phenotypes and offer potential therapeutic options for both onset and progression of the disorder.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The physiological function of the neurovascular unit is critically dependent upon the complex structure and functions of astrocytes for optimal preservation of cerebral homeostasis. While it has been shown that astrocytes exhibit aberrant changes in both structure and function in transgenic murine models of Alzheimer\u2019s disease (AD), it is not fully understood how this altered phenotype contributes to the pathogenesis of AD or whether this alteration predicts a therapeutic target in AD. The mechanisms underlying the spatiotemporal relationship between astrocytes, neurons and the vasculature in their orchestrated regulation of local cerebral flow in active brain regions has not been fully elucidated in brain physiology and in AD. As there is an incredible urgency to identify therapeutic targets that are well-tolerated and efficacious in protecting the brain against the pathological impact of AD, here we use the current body of literature to evaluate the hypothesis that pathological changes in astrocytes are central to the pathogenesis of AD. We also examine the current tools available to assess astrocytic calcium signaling in the living murine brain as it has an important role in the complex interaction between astrocytes, neurons and the vasculature. Furthermore, we discuss the altered function of astrocytes in their interaction with neurons in the preservation of glutamate homeostasis and additionally address the role of astrocytes at the vascular interface and their contribution to functional hyperemia within the living murine brain in health and in AD. Indeed, position emission tomography (PET) imaging studies using the tracer 11C-deuterium-L-deprenyl, directed towards the monoamine oxidase B enzyme, reported that reactive astrocytes are present in patients at early stages of AD, particularly those patients with Mild Cognitive Impairment (MCI)  transgenic AD mice  consist of a calmodulin moiety fused to a M13 calmodulin binding peptide and two fluorescent proteins (cyan-yellow FRET pair)  or adopt the A2 reactive subtype, which may promote neuronal health (Zamanian et al., reactive subtypes may provide an excellent opportunity to assess the reactive phenotype in astrocytes in AD murine models so that the pharmacological effects of modulating astrocytes may be assessed longitudinally. A previous in vivo two-photon microscopy study demonstrated that the hyperactive calcium signaling phenotype exhibited by astrocytes within the cortex of APP/PS1 mice is amenable to pharmacological modulation (Delekate et al., in vivo two photon microscopy study that examined the effects of chronic antagonism of the purinergic signaling within the intact brain of APP/PS1 mice reported a reduction in the fraction of hyperactive astrocytes associated with preservation of synaptic structure and function (Reichenbach et al., in vivo two-photon imaging-based interrogation of astrocytes in AD which enables the testing of candidate therapies directed towards protecting the integrity of the neurovascular unit against the pathological impact of AD.In 1909, Santiago Ram\u00f3n y Cajal proposed that the physiological role of glia was incompletely understood because physiologists did not have the necessary tools to examine glial function Somjen, . The advPK, EH, SH and BB prepared the manuscript and figures.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Targeted delivery of anticancer drugs is considered to be one of the pillars of cancer treatment as it could allow for a better treatment efficiency and less adverse effects. A promising drug delivery approach is magnetic drug targeting which can be realized if a drug delivery vehicle possesses a strong magnetic moment. Here, we discuss different types of magnetic nanomaterials which can be used as magnetic drug delivery vehicles, approaches to magnetic targeted delivery as well as promising strategies for the enhancement of the imaging-guided delivery and the therapeutic action. The majority of anticancer drugs are delivered intravenously and accumulated in tumors containing the abundance of leaking blood vessels. However, this affects healthy tissue and causes numerous side effects. The more efficient approach is realized when drug nanocarriers are functionalized with target molecules , which interact with specific receptors located in certain tumors, allowing for the attachment of the drug delivery vehicles solely to the tumor . Their high magnetism means the microspheres can be easily manipulated by a magnet within the vascular system and, more specifically, remain in the target organ capillaries. Chen et al. utilized a hollow nanoparticle (NP) with a mesoporous shell which creates a higher surface area and a large cavity where drug can be encapsulated in both the mesopores and the cavities  produce more heat under microwave irradiation which allows easier release of the loaded drug. However, doping of iron oxide causes the decrease of the saturation magnetization which diminishes the microsphere potential for magnetic targeting   (PCL) to encapsulate both FeMicroparticles of dry powder chemotherapeutic containing iron oxide NPs  were used for magnetic delivery into lungs with an applied magnetic field  synthesized utilizing magnetic nanocluster (MNC) core and Arg\u2013Gly\u2013Asp (RGD) decorated macrophage shell  biofilm followed by the antibiotic release and the biofilm disruption, revealing a potential for antibiofilm applications.Drug-loaded microparticles prepared by layer-by-layer (LbL) deposition of polyelectrolytes with embedded magnetic NPs were attached to in situ when they are pushed into a tumor. A magnetic field allows for controllable magnetic guidance as well as release, allowing drug delivery to tumor cells without damaging the healthy tissue. This system combines high drug loading capacity, self-propulsion, in situ mechanical trigger release of the drug-loaded sperm, sperm penetration ability, and improved drug availability.Xu et al. reported the development of an unprecedented sperm-hybrid micromotor for targeted drug delivery  plasmonic response with magnetic targeting, Tsai et al. deposited a double layer of Au/Ag alloy on the surface of truncated octahedral iron oxide NPs  and NPs to develop multifunctional micelles  and anticancer drug magnetic delivery.Assembly of iron oxide NPs on polydopamine (PDA) NPs allowed for an enhanced magnetic response and stimuli-controlled drug release for b-poly(acrylic acid) (PS-b-PAA) block copolymer were self-assembled into multilayer magneto-vesicles (MVs) and utilized for incorporation of drugs in the hollow cavity  in MRI. When injected, DOX-loaded MVs conjugated with RGD peptides were efficiently accumulated in tumor cells due to magnetic targeting.Iron oxide NPs with the grafted poly(styrene)-Innovative magnetic drug delivery vehicles were developed based on magnetite NP clusters  (PLGA), FA, perofluorohexane (PFH), Fe3O4, and DOX  in order to ablate the tumor tissue via an increase in size  and poly(sodium 4-styrenesulfonate) and prepared by LbL deposition were utilized as magnetic delivery vehicles Agaricus bisporus) fragments coated with magnetite NPs showed promising properties for targeted delivery  nanocomposite  to enhance the delivery and the drug action. The other key feature of promising magnetic drug delivery vehicles is long-circulating, stealthy systems which will not be cleared by a phagocyte system , but none resulted in FDA approval or commercialization (Wang et al., We believe that the major unsolved problem in magnetic drug delivery is the absence of mechanisms for delivery into the depth of the body. The recent strategy of magnetic or magnetiziable implants seems to be promising but it requires a surgical intervention and in some cases cannot be implemented. Currently, efforts from physicists and engineers are required to move this field forward to real life applications.PP carried out analysis of the literature and wrote a part on magnetic bioprobe synthesis. WM collected the literature and wrote the rest of the discussion on magnetic bioprobes. AA-G wrote part on approaches to magnetic targeting. LB wrote all other sections and oversaw the project.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Although there is broad consensus around the need to accelerate progress towards universal health coverage (UHC) in Sub-Saharan Africa, the financing strategies for achieving it are still unclear. We sought to leverage the lessons learned in financing HIV programs over the past two decades to inform efforts to advance the universal health coverage agenda in the East African Community.We conducted a literature review of studies reporting financing mechanisms for HIV programs between 2004 and 2014. This review is further underpinned by evidence from a mixed-methods study entailing a survey of 195 health facilities across Uganda supplemented with 18 semi-structured interviews with HIV service managers.i) Bi-lateral and multi-lateral funding vehicles: The establishment of HIV-specific global financing vehicles such as PEPFAR and The Global Fund heralded an era of unprecedented levels of international funding of up to $ 500 billion over the past two decades ii) Eliciting private sector contribution to HIV funding: The private sector\u2019s financial contribution to HIV services was leveraged through innovative engagement and collaborative interventions iii) Private sector-led alternative HIV financing mechanisms: The introduction of \u2018VIP\u2019 HIV clinics, special \u2018HIV insurance\u2019 schemes and the rise of private philanthropic aid were important alternatives to the traditional sources of funding iv) Commodity social marketing: Commodity social marketing campaigns led to an increase in condom use among low-income earners v) The use of vouchers: Issuing of HIV-test vouchers to the poor was an important demand-side financing approach vi) Earmark HIV taxes: Several countries in Africa have introduced \u2018special HIV\u2019 taxes to boost domestic HIV funding.Our data shows that there are six broad HIV financing strategies with potential for application to\u00a0the universal health coverage\u00a0agenda in the East African Community (EAC); The lessons learned from financing HIV programs suggest that a hybrid of funding strategies are advisable in the quest to achieve UHC in EAC partner states. The contribution of the private sector is indispensable and can be enhanced through targeted interventions towards UHC goals. Universal health coverage (UHC) is gaining increasing importance as a global health priority . In 2015Although there is broad consensus around the need for accelerating progress towards attaining UHC, the ways and means of achieving are still unclear , 6. It hThe emerging global trend towards regional integration and countries coalescing around larger blocks such as the European Union (EU) or South African Development Community (SADC), presents unique opportunities for collaboration and harmonization of UHC strategies across multiple countries with similar socio-economic characteristics and history \u201311.The East African Community (EAC) is a block of six countries that comprise Kenya, Uganda, Tanzania, Rwanda, Burundi and South Sudan .The treaOver the past two decades, there has been accumulating evidence documenting innovations in financing HIV programs that could be leveraged upon in efforts to advance the UHC agenda in EAC countries \u201322. In st has been acknowledged that UHC and the global HIV response share similar goals of expanding service coverage, attention to marginalized populations and the poor . Others path finder for global health, a call re-echoed at the 22nd International AIDS Conference in Amsterdam in July 2018 [We drew from three inspirations for this review. We drew upon the notion that the international HIV response is a uly 2018 . Our objrisk pooling, revenue raising, purchasing and benefits) which served as a thematic framework for a qualitative content analysis we conducted of our search results. We situate these health financing mechanisms within the universal health coverage goal of people receiving the health services they need without suffering financial hardship such as by reducing dependence on out-of-pocket expenditure and increasing the size of risk pools [http://speed.musph.ac.ug/symposium/). We merged the findings emerging from all the three sources of our review and categorized them under the six themes presented in the Results section.This review is informed by a literature review conducted as part of a broader four-year doctoral research study examining the financing strategies for promoting the sustainability of HIV programs in Uganda . This resk pools . A thirdThe unprecedented international mobilization of funding for HIV services scale-up in SSA since 2003 presents lessons that can be leveraged upon to advance the UHC agenda in EAC . The estOf the six EAC countries, four  are among the 15 PEPFAR focus-countries . The ideFrom the perspective of governments and donors, the private sector  has been driven to cater to the segment of the population with the \u2018ability to pay\u2019 which leaves the majority poor unreached. As such, there have been mounting calls for devising interventions and policy responses aimed at integrating the private sector in the drive to attain the Universal Health Coverage (UHC) targets enshrined in the new sustainable development goals (SDGs) agenda , 33. TheThe calls for policy responses targeting the private sector stem from the notion of a systemic \u2018market failure\u2019 in meeting demand for health care and the need for remedial or corrective measures aimed at promoting Universal Health Coverage . The priIn Uganda, USAID sought to secure the private sector\u2019s contribution towards the costs of HIV service delivery through a counter-part funding scheme that enabled for-profit clinics to commence provision of HIV services starting in 2009 . To thisCommodity social marketing involves adopting commercial marketing techniques that create demand for quality products such as condoms or family planning commodities whose quality has been assured through sustained advertising and other demand-creation campaigns . CommodiVoucher schemes have been defined as \u2018a type of demand-side consumer-led near-cash social transfer that can be redeemed for goods and services\u2019 . VoucherElsewhere, voucher schemes or programs have been used to support poor expectant mothers to deliver in a private health facilities in Rwanda, Uganda and Zambia . LeveragA study in Uganda, documents private sector-led innovations in devising alternative financing mechanisms for anti-retroviral therapy (ART) programs between 2004 and 2014 . These iIn response to calls for increased national ownership of HIV programs, several governments in Africa have introduced earmark taxes for HIV causes \u201352. In ZLessons learned from HIV financing suggest that a hybrid of funding schemes are advisable in the quest to achieve universal health coverage in the East African community. From a public finance perspective, there are calls for increasing the fiscal space for implementing UHC from national budgets. The private sector is indispensable in efforts to realize UHC and should be co-opted through targeted interventions but also with regard to private sector-led innovations in health financing health services. Leveraging the lessons of HIV financing also suggests that tapping into the growing middle class in East Africa to help contribute to financing of health services in the context of UHC."}
+{"text": "However, the later models were questioned due to the presence of aberrantly shortened telomere in the germline of the parents +/\u2013TERT that were used to create the G1 TERT\u2013/\u2013 mice. The physiological relevance of the functions associated with overexpressed telomerase raised also some concerns due to artifactual situations and localizations and complications to quantify the level of TERT. Another concern with non-canonical functions of TERT was the difficulty to separate a direct TERT-related function from secondary effects. Despite these concerns, more and more evidence accumulates for non-canonical roles of telomerase that are non-obligatory extra-telomeric. Here, we review these non-canonical roles of the TERT subunit of telomerase. Also, we emphasize recent results that link TERT to mitochondria and protection to reactive oxygen species suggesting a protective role of TERT in neurons. Throughout this review, we dissect some controversies regarding the non-canonical functions of telomerase and provide some insights to explain these discrepancies. Finally, we discuss the importance of understanding these alternative functions of telomerase for the development of anticancer strategies.Telomerase plays a critical role in stem cell function and tissue regeneration that depends on its ability to elongate telomeres. For nearly two decades, it turned out that TERT regulates a broad spectrum of functions including signal transduction, gene expression regulation, and protection against oxidative damage that are independent of its telomere elongation activity. These conclusions that were mainly obtained in cell lines overexpressing telomerase were further strengthened by  The complex is associated with accessory proteins such as dyskerin (DKC1), telomerase Cajal body protein 1 (TCAB1), non-histone chromosome protein 2 (NHP2), nucleolar protein 10 (NOP10), and GAR1 RNP (GAR1). Telomerase homeostasis depends highly on the coordinated regulation of telomerase RNP assembly, trafficking, and recruitment to telomeres  suggesting the existence of unassembled components. Therefore, a pool of hTERT-free hTR might assemble with other protein components and could demonstrate alternative functions independent of telomerase in cell survival and apoptosis as mentioned by some reports  expression, were rescued by reactivating the expression of telomerase factor to regulate gene expression. Some examples are discussed below, the two most-studied signaling pathways regulated by hTERT being the Wnt/\u03b2-catenin and the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-\u03baB) pathways.In vivo studies carried out in mice lay out the premises for extratelomeric roles of TERT in tumorigenesis. mTERT expression at high levels in transgenic mice (associated with an increased telomerase activity) in several tissues such as mammary gland was associated with spontaneous development of mammary intraepithelial neoplasia and invasive mammary carcinomas (TERT expression could promote the development of spontaneous cancer in mice with wild-type (WT) telomere length  promoted the proliferation of hair follicle bulge cells. Importantly, the effects related to this artificially induced expression of mTERT did not require the telomerase RNA component . Therefore, the question arises about whether these extratelomeric functions of TERT operate in cancer cells, and above which threshold. It was further shown by the same group that mTERT interacted with BRG1, the central catalytic subunit of numerous chromatin-modifying enzymatic complexes (in vitro in pull-down experiments (ex vivo (in cells depleted or not for BRG1) and in vivo by inducing the expression of mTERT placed under the control of a tetracycline regulated promoter. They measured Wnt signaling in the gastrointestinal tract using mice engineered with a Wnt-reporter , mTERT and mTR deficiencies produced indistinguishable phenotypes. In addition, Wnt was activated similarly in WT or mTERT\u2013/\u2013 cells  in the r region , it apper region . The autTERT knockout mice (without detectable telomere dysfunction), tumor development as well as VEGF expression were reduced in TERT\u2013/\u2013 mice compared to WT suggesting that TERT deficiency affects tumorigenesis and tumor vascular development  is another example of a factor whose expression is regulated by TERT. TERT was first reported to activate the transcription of VEGF in embryonic lung cells and HeLa cells . In suppelopment . Mechaniogenesis .de novo methylation of CpG dinucleotides cooperated with Sp1 to activate DNMT3B promoter activity. Indeed, Sp1 inhibition significantly attenuated TERT-mediated DNMT3B up-regulation, while its over-expression restored DNMT3B expression in TERT-depleted cancer cells (In 2003 was published the first study reporting a novel function of hTERT in the regulation of DNA methyltransferases (DNMTs) . Telomerer cells . One of Physical protection of telomeres by capping may explain in some cases the prevention of telomere damages due to oxidative stress (as reported in Fanconi Anemia) . An addicis-element (hTR (Many other articles reported in different cellular systems that telomerase was protecting against oxidative stress and that this protection was associated with reduced levels of reactive oxygen species (ROS) . However-element . Haendel-element . Relatedent  would contribute to antioxidant hTERT effect by promoting the transcription of antioxidant factors including MnSOD and g-glutamylcysteine . In mitoAll these results indicate intricate links between telomerase, ROS, and mitochondria. However, many of these results were obtained in cellular systems designed to strongly overproduce hTERT. The question remains about the relevance of the anti-oxidative function of hTERT during development or in response to stresses in adult in specific tissues or in cancer cells. Recent results indicate that the protein TERT persists in the adult brain while telomerase activity was shut-down before birth . In mousAlthough much is going to be learned upon these new telomere unrelated roles of telomerase, studies may generate different interpretations because of the multiplicity of the models and the lack of accurate tools to detect the endogenous TERT and measure its activity. This can explain some of the discrepancies in the published results pointing out that alternative approaches have to be taken to quantify the level of TERT, determine its cellular localization, or identify its partners. Overall, there is a need to develop appropriate experimental tools to go further in the elucidation of the TERT functions in normal physiology and the context of tumors.TERT overexpression (either WT or mutant variants) have to be taken with caution since the levels obtained are generally much more important than those observed in tumor cells. Indeed, overexpression can alter hTERT localization (high expression in both nuclei and cytoplasm) and the recruitment to telomeres or give rise to artificial protein interactions. Furthermore, TERT overexpression in telomerase positive cells can affect telomere length. It is now documented that telomere length can control some gene expression near the ends of the chromosome either by telomere position effect (TPE) or by TPE over long distances (TPE-OLD)  . Therefoin vitro was retained  into extended trials performed in vitro and clinical practice. Besides, it is clear that in some cases as telomerase is associated with many extratelomeric functions, total inhibition of its expression could induce severe and unpredictable side effects. It is now clear that the therapeutic exploitation of the biology of the telomeres requires the integration of the multiple roles of telomerase in the physiology of not only cancer cells but also normal cells. Therefore, to develop new strategies of telomerase inhibition for anticancer therapy, a more thorough understanding of all the functions of the telomerase complex  and the interplay between these functions in the physiology of the cell is necessary.As pointed out, an accumulation of evidence indicates that TERT plays important functions far from telomere maintenance. These functions can impact cancer cells by giving them a selective advantage. Presently, most telomerase inhibitors designed to inhibit telomerase activity  are not well tolerated by the patients. Indeed, therapy must be prolonged because it could take a long period before telomeres are shortened enough to induce death of the cancer cell. To be fully efficient, it could be necessary to target different functions of hTERT instead of solely those that inhibit its enzymatic activity or accessibility to telomeres. In this case, therapeutic strategies targeting directly hTERT expression will be highly effective and more prompt as it will target all TERT functions. In this line of view, it has been shown that retinoic acid can inhibit the transcription of hTERT leading to cell death. The induction of the death can be the result of telomere shortening but it has been also demonstrated that the repression of hTERT can sensitize cells to conventional chemotherapy in a telomere independent manner . Indeed Telomerase has been described as having a key role in several signaling pathways that are frequently altered in cancers. The major role of hTERT in cancer has been related to the maintenance of telomere length that is a prerequisite event for the tumor cells to survive and proliferate. However, telomere unrelated functions have emerged to allow increased proliferation, resistance to cell death, inflammation, invasion, and metastasis. Therefore, endowed with these non-telomeric functions, TERT can participate to all the major characteristics of the cancer phenotype described by Both authors contributed equally to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Editorial on the Research TopicControversies in the Local Management of Lung CancerAt the time we agreed to edit this special edition of Frontiers in early 2017, the immunotherapy revolution was already established in the second-line treatment of metastatic non-small cell lung cancer (NSCLC)  and evenLewis et al.), a Radiation Oncologist (Sher), and a Thoracic Surgical group . Although no definitive management strategy was recommended as \u201cthe way\u201d to manage Stage III NSCLC, each article does a great job of reviewing the current literature, while offering its own unique perspective. The article by Van et al. additionally discusses the rarely investigated topic of salvage surgery.Three of this issue\u2019s 10 article deal with the controversial topic of neo-adjuvant treatment prior to surgery in the management of Stage III lung cancer from the prospective of a multi-disciplinary team . Both studies, offer different approaches to the hopefully successful integration of immunotherapy with standard chemo/radiation in the near future. Bergsma et al. discuss the rationale and increasingly strong evidence for administering stereotactic body radiation therapy (SBRT) in patients with oligometastatic NSCLC . The work of these investigators and others have led to the NRG LU002 trial that will be investigating the role of SBRT for patients with three or fewer sites of remaining extracranial disease after chemotherapy. Chun et al. have provided a nice review article on heavy ion therapy in the management of NSCLC. Although the recently published prospective randomized trial of passive scattering proton radiation vs intensity-modulated radiation did not reveal any benefit from proton therapy in terms of local failure, radiation pneumonitis, and lung dosimetry, protons resulted in lower heart doses despite larger having larger gross tumor volumes in that trial arm  in the management of surgically resectable SCLC. Because the incidence of early-stage SCLC is increasing  noted an improved overall survival and progression-free survival using combined immunotherapy (pembolizumab) and chemotherapy as compared to chemotherapy alone. Additionally, consolidative durvalumab (a PD-L1 inhibitor) has shown an impressive progression-free survival benefit in patients with stage III lung cancer after the completion of concurrent chemo/radiation  as compared to platinum-based chemotherapy in the first-line setting. The benefit was shown in a population of patients with PD-L1 of \u22651% which means that the majority of patients presenting with metastatic NSCLC can benefit from immunotherapy alone as their initial treatment. Furthermore, Keynote 189 (We are very grateful to the tremendous efforts of the fellow authors, the reviewers, and staff at Frontiers for making this special edition possible.GV and JV both wrote this article.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Cancer of the colorectum is one of the most commonly diagnosed, and has a high mortality owing to the advanced stage at diagnosis. Chemoprevention is therefore a high priority for people at higher risk than the general population. While there are currently no drugs approved for this purpose, recent advances suggest that cyclic-guanosine monophosphate (cGMP) elevating agents could be effective. This second messenger has the well-established role of stimulating secretion in the small intestine, and its levels are tightly controlled by the activity of guanylyl cyclase C (GC-C) receptors that convert GTP into cGMP upon stimulation by the endogenous peptide hormones guanylin and uroguanylin . Additioin vitro, it was originally thought that GC-C agonists could be an effective treatment for colon cancer patients. This idea was supported by work with the weak PDE5 inhibitor sulindac sulphone (exisulind) that killed colon cancer cells in vitro, and caused regression of colorectal polyps in human patients [ApcMin/+ mouse model where polyp initiation occurs by somatic mutation leading to loss of heterozygosity at the Apc locus, and inflammation is not a central driver in the small intestine. Treatment of ApcMin/+ mice with either sildenafil or the GC-C agonist linaclotide equally suppressed polyp multiplicity by 50% [The clinical utility of cGMP-elevating agents for colon cancer has long been an area of interest. Based on reports that guanylin expression was reduced in colon tumors compared to surrounding tissue, and that GC-C agonists inhibited colon cancer cell growth patients . The idepatients , it was patients . An unexTaken together, these studies demonstrate that increasing intestinal cGMP levels can reduce intestinal tumorigenesis in mice by targeting the early stages of tumor initiation. This latter point is supported by the fact that treatment with either sildenafil or linaclotide only affected the number of polyps per animal and did not affect the size or apoptotic index of polyps that formed in either preclinical model. While the reason for the lack of effect on initiated polyps warrants further investigation, these observations clearly do not support the utility of these drugs as a treatment for colon cancer patients. The prevention-effect of cGMP-elevating drugs is likely due to their ability to reduce the size of the proliferative compartment where tumor initiation occurs in the colon . This efLinaclotide (and plecanatide) are synthetic GC-C agonists that were developed for the treatment of constipation by capitalizing on the pro-secretory role of cGMP. However, these drugs override endogenous autoregulatory processes, and diarrhea is a common side effect that could limit their utility for colon cancer chemoprevention . PDE5 in"}
+{"text": "The increase in imaging throughput, new analytical frameworks and high-performance computational resources open new avenues for data-rich phenotypic profiling of small molecules in drug discovery. Image-based profiling assays assessing single-cell phenotypes have been used to explore mechanisms of action, target efficacy and toxicity of small molecules. Technological advances to generate large data sets together with new machine learning approaches for the analysis of high-dimensional profiling data create opportunities to improve many steps in drug discovery. In this review, we will discuss how recent studies applied machine learning approaches in functional profiling workflows with a focus on chemical genetics. While their utility in image-based screening and profiling is predictably evident, examples of novel insights beyond the status quo based on the applications of machine learning approaches are just beginning to emerge. To enable discoveries, future studies also need to develop methodologies that lower the entry barriers to high-throughput profiling experiments by streamlining image-based profiling assays and providing applications for advanced learning technologies such as easy to deploy deep neural networks. Using complex phenotypes to predict functions of genes has been a powerful approach in genetics and clustering mutations by their organismal phenotypes has yielded important insights into functions of many genes and pathways More recently, automated microscopy-based phenotyping has become a powerful method to infer functions and functional relationships of genes, to investigate cellular or organismal structure, behavior and disease mechanisms In drug discovery, automated imaging was used in a number of different applications in pre-clinical development and has been shown to allow scalable and systematic phenotypic profiling of small molecules, establishing itself as a complementary method to target-based in-vitro screening For image-based phenotyping of perturbations, one can distinguish two approaches to experimental design that fundamentally differ with regards to probes as well as image analysis The first approach includes screening applications  that are focused on pre-defined, specific phenotypes with the aim to identify drugs or drug targets that modulate it A. Such iBox 1SegmentationHigh-throughput small molecule profiling is typically based on the staining of subcellular structures and fluorescence microscopy. A selective staining of abundant subcellular structures such as DNA or actin and the subsequent imaging in distinct channels allows the identification of single cells as objects Feature extractionFollowing segmentation, computer vision is used to extract morphology, intensity and texture features of single cells Profile generationSegmentation-based image analysis results in collections of single cell feature vectors for each condition . Various strategies have been explored to process those single cell feature vectors into profiles for downstream analyses. A common method relies on the aggregation of single cell features by summarizing the mean and standard deviation over all cells of a perturbation and other methods using machine learning approaches to generate profiles are reported ClassificationThe aim of many profiling experiments is a classification of compounds. Based on a set of reference compounds and their profiles, classification strategies are used to infer putative MOA or toxicity relationships of formerly unseen compounds. This process is a bona fide machine learning task. Approaches include hierarchical clustering of compounds into groups that share high profile similarity, training support vector machines on profiles for MOA prediction or correlation network analysis Alt-text: Box 1The second application of high-throughput imaging in drug discovery is the more global profiling of perturbations. This approach profiles cells upon exposure to genetic, pathogenic or chemical perturbations and is complementary to techniques like transcriptional profiling , 20, 21.High-throughput imaging has been successfully used for small molecule profiling in human cancer cells to group small molecules with similar activity and mechanism of action (MOA) Image-based phenotypic profiling has also been recently applied to characterize small molecule function in patient-derived primary cells or 3-D cell culture models. A recent study by Booij et\u00a0al. used image-based profiling to quantify the phenotypic effects of kinase inhibitors in a 3-D cell culture model of Polycystic kidney disease to facilitate novel hypotheses for small molecule treatments . AnotherChemical genetics approaches have been pioneered in model organisms to discover drug MOA as well as gene functions Saccharomyces cerevisiae used an algorithm to define a set of query mutant strains from genetic-interaction data. Several chemical libraries were then screened against the selection of deletion strains with the aim to functionally annotate small molecules across relevant biological processes without screening the full deletion strain library In model organisms like yeast or bacteria, sophisticated experimental and analysis frameworks have been established for chemical-genetic studies which might provide further strategies for profiling in human cells This principle has been adopted to pharmacogenomics studies in human cancer cell lines by integrating drug response and the genetic background of cell lines with the aim to identify cancer-specific vulnerabilities i.e. to profile chemical libraries in a large number of genetic perturbations. As such, image-based chemical genetics offers a great potential to systematically characterize small molecules in human cell-based systems and to probe chemical-genetic interactions in complex and monogenic human diseases Microscopy-based profiling experiments are typically carried out in microtiter plates, which enables a rapid scaling of experiments for a large number of perturbations, Box 2Machine learning strategies can generally be separated in unsupervised and supervised approaches.Unsupervised machine learning approaches interpret and learn an abstract representation of the intrinsic structure of data sets and can be applied without a priori definition of labels (phenotypes) to be classified. A commonly applied unsupervised machine learning strategy is clustering of data points into patterns to ultimately derive biologically meaningful information supervised machine learning strategies are typically applied to classification problems and thus rely on pre-defined classes. Annotated training sets with data points representing those classes are used to train a classifier features). Linear and non-linear supervised machine learning classifiers exist, and the choice of the classifiers depends on the classification problem. In many cases, a comparison of the classifier performance is used to identify the algorithm that is best suited for the problem. The training of classifiers requires representative training data sets of sufficient size and quality. To avoid issues such as overfitting and assess classification accuracy statistics, the resulting classifier needs to be evaluated carefully using test data (not used for training).By contrast, deep learning has been exploited as a supervised machine learning technology for biological classification problems. Deep learning uses artificial neural networks, which consist of multiple layers of interconnected linear or non-linear transformations that are applied to the data with the goal to solve a classification problem. The networks are trained over multiple epochs, each time comparing the predicted and true class labels to optimize network parameters with automated algorithms transfer learning or generic deep neural networks provide possibilities for non-experts to apply deep learning without full knowledge of the mathematical details Recently, The high dimensionality and complexity of image data sets typically make analysis strategies with multiple steps and combinations of machine learning algorithms necessary. Here, deep learning strategies provide great potential to automate analysis at many stages from segmentation, feature extraction to classification to reduce manual tuning of analysis pipelines Alt-text: Box 2High-throughput microscopy generates large collections of phenotypic data. The size, complexity and multiparametric nature of such data sets make automated analysis strategies necessary to identify cellular phenotypes that differ from wild type phenotypes and discover novel relationships between phenotypes and the perturbagens which induce them. Simple statistical inference methods such as mean values are often insufficient to comprehensively describe the complexity of data sets Clustering image-based profiles to identify small molecules with shared MAO based on the \u2018guilt-by-association\u2019 rule relies on unsupervised machine learning strategies i.e. 1 \u2013 similarity) rather than absolute distance measures such as the Euclidian distance For large data sets, hierarchical (unsupervised) clustering algorithms are commonly used to cluster small molecule profiles based on their profile similarity. Often, matrices of all pairwise similarities between small molecule profiles are used to derive a distance measure  by fine-tuning the classifier with training data from unseen data sets. Examples show that better classification performance can be achieved by combining deep- and transfer learning when compared to the setup of a classifiers trained from scratch Recently, a number of studies reported the application of supervised machine learning approaches with deep neural networks to classify small molecules by their MOA using annotated image data sets from the Broad Bioimage Benchmark Collection a priori knowledge of phenotypes, which can contradict the unbiased strategy of image-based profiling. Two recent studies propose to use generic deep neural networks that were pre-trained on millions of \u2018consumer\u2019 images for image-based profiling tasks Nevertheless, labeled training data sets imply the Another recently explored application of supervised learning in image-based profiling, particularly deep neural networks, is a novelty detection framework to identify unexpected phenotypes Image-based profiling studies demonstrated the capability to improve the pre-clinical development of small molecules at almost any step of the pipeline from target identification over mechanism of action prediction to toxicity profiling. Increasing the throughput and extending more complex analysis methods of image based phenotypic screens and profiling approaches will help to increase the methodological portfolio of cellular screens to support the drug development process. Community efforts to create annotated datasets that can be shared across laboratories will be required to test and optimize the potential of strategies such as transfer learning to improve discovery science Furthermore, large-scale chemical-genetics approaches inspired from successful studies in model organisms might harbor great potential to characterize drugs and drug-gene interactions in a systematic manner. Particularly, image-based profiling approaches in pre-selected informer panels of human cell lines might be a scalable and versatile tool to deprioritize compounds harboring adverse effects, asses compound efficacy and to generate hypotheses for drug synergism and repurposing.ERC Advanced Grant (SYNGENE) of the European Commission.This work was in part supported by an None."}
+{"text": "Hematopoietic stem cells (HSC) are the most powerful type of adult stem cell found in the body. Hematopoietic stem cells are multipotent and capable of giving rise to all other types of hematopoietic cells found in the organism. A single HSC is capable of regenerating a functional hematopoietic system when transplanted into a recipient. Hematopoietic stem cells reside in the bone marrow in specific multicellular structures called niches. These niches are indispensable for maintaining and regulating HSC numbers and function. It has become increasingly clearer that HSC and their niches can also be regulated by migrating leukocytes. Here we will discuss the composition of murine bone marrow niches and how HSC and their niches are regulated by different types of leukocytes that traffic between the periphery and the niche. Unless otherwise indicated all the studies discussed below were performed in mouse models. Bone marrow (BM) Hematopoietic stem cells niches are very complex structures in which different cell types with overlapping and unique functions cooperate to regulate HSC maintenance, self-renewal, trafficking, and differentiation. Loss of niche cells or niche-derived signals inevitably leads to loss of HSC. A scheme showing the overall structure of the murine BM niche is shown in in vivo deletion of Cxcl12 or Scf in BM endothelial cells (using Tie2-cre mice) was sufficient to cause loss of HSC  led to HSC exhaustion  in endothelial cells led to increased angiogenesis and HSC numbers (Rbpj (which is required for transcription of Notch regulated genes) led to deficits in BM endothelial cells  also leads to the almost complete disappearance of BM sinusoids , 9. Restneration \u201314.Cxcl12-gfp reporter mice, Nestin-GFPdim cells are isolated using Nestin-gfp reporter mice and LepR+ cells are detected using LepR-cre:Tomato mice  in vitro, and upon transplantation in ossicles can generate an ectopic niche that supports extramedullary hematopoiesis  and were also enriched for CXCL12. These experiments demonstrated that these cells are a novel component of the niche  are critical regulators of HSC and niche function and that leukocyte trafficking also impacts HSC. How migrating leukocytes function in the niche is the focus of the second part of the review.In addition to the cell types described above, other stromal cells  have been proposed to be components of the HSC niche in some studies while other studies have shown no role for these cells in HSC regulation. The evidence for and against the role of each of these cells in the niche was reviewed recently . AdditioAll the cell types described above reside in the BM and most of them are intimately associated with HSC. Imaging of HSC location and interaction with candidate niche cells remains one of the most powerful tools to identify new components of the niche. However, an emerging concept in the field is that HSC and their niches can be regulated (directly or indirectly), long-distance, by different organs.The nervous system is the best characterized organ(s) that regulates HSC distally. The initial discovery showed that sympathetic innervation of the BM is necessary for HSC release from their niches into the circulation . Follow in vivo and ex vivo treatments and to mobilize stem cells from the bone marrow to the circulation where they can be harvested for transplantation  increasing their number and thus leading to increased HSC numbers . In femaantation \u201341.Two recent studies demonstrated that the liver and the intestine also regulate BM HSC. Thrombopoietin has long been known to regulate HSC quiescence but the source of this cytokine remained unknown. Using elegant conditional deletion experiments, the Ding lab suggested that BM sources of thrombopoietin did not regulate HSC . Insteadin vivo potential. Examples of this heterogeneity are the use of Hdc-GFP reporter mice to identify Hdc-GFP+ myeloid biased HSC  showed that most HSC associate with sinusoids with a smaller fraction that localizes close to arterioles  whereas HSC that localized to sinusoids could be ROShigh or ROSlow  caused HSC loss (In the last 5 years it has become increasingly clear that HSC are not a homogeneous population and can be fractionated (based on expression of different markers) into subsets with different ased HSC ; the useased HSC ; differeased HSC ; and difased HSC . The mecnn cells . In contnn cells , 22. Imaterioles . The larethidine . Previouethidine , 48. Ther ROSlow . They alnockouts . In agreHSC loss .low HSC in the sinusoids colocalize with megakaryocytes  they demonstrated that monocyte/macrophage ablation was sufficient to downregulate Cxcl12 production in BM reticular stromal cells. They then used CD169-DTR mice, which depletes macrophages but not monocytes, to demonstrate that macrophages controlled niche function . In vivo pharmaceutical COX2 inhibition led to HSC depletion suggesting that these \u03b1SMA1+ macrophages maintain HSC . Depletion of these macrophages using CD169-DTR mice completely blocked HSC engraftment demonstrating a critical role for macrophages during regeneration  reporter mice, the Wang lab found that around 10% of HSC were Hdc-GFP+. In transplantation experiments these Hdc-GFP+ HSC produced higher numbers of myeloid cells than the Hdc-GFP\u2212 HSC indicating that they were myeloid biased  regulate myeloid biased HSC  in HSC as antioxidant treatment rescued the HSC expansion . It is likely that alterations in leukocyte trafficking direct bone marrow hematopoietic output and contribute to the disease phenotypes. This is an area of great interest for future investigations.The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The GAW20 group formed on the theme of methods for association analyses of repeated measures comprised 4sets of investigators. The provided \u201creal\u201d data set included genotypes obtained from a human whole-genome association study based on longitudinal measurements of triglycerides (TGs) and high-density lipoprotein in addition to methylation levels before and after administration of fenofibrate. The simulated data set contained 200 replications of methylation levels and posttreatment TGs, mimicking the real data set.The different investigators in the group focused on the statistical challenges unique to family-based association analyses of phenotypes measured longitudinally and applied a wide spectrum of statistical methods such as linear mixed models, generalized estimating equations, and quasi-likelihood\u2013based regression models. This article discusses the varying strategies explored by the group\u2019s investigators with the common goal of improving the power to detect association with repeated measures of a phenotype.Although it is difficult to identify a common message emanating from the different contributions because of the diversity in the issues addressed, the unifying theme of the contributions lie in the search for novel analytic strategies to circumvent the limitations of existing methodologies to detect genetic association. Even though genome-wide association studies (GWAS) have successfully identified novel genetic variants that confer risk to various complex disorders, the proportion of trait variance that can be explained by the identified variants remains abysmally low compared to the estimates of heritability of these traits obtained from twin studies. It has been argued that analyzing quantitative precursors of a clinical end-point trait, which carry more information on interindividual phenotypic variability compared to an often binary end-point trait, may be a more powerful strategy to unravel the genetic architecture of the underlying complex disorder . HoweverThe major statistical challenge encountered in the genetic association analyses of repeated phenotype measurements is the modeling of the phenotype values across the different time points. Cross-sectional analyses of phenotype values at different time points may not only provide inconsistent inferences but also can exacerbate the problem of multiple testing inherent in GWAS. On the other hand, a na\u00efve multivariate analysis ignoring the correlation structure of phenotype values across the different time points may result in power loss . It is aThe GAW20 provided an excellent opportunity to explore the various statistical issues pertaining to association analyses of longitudinal phenotypes, whole-genome single-nucleotide polymorphism (SNP) data, and methylation (cytosine-phosphate-guanine [CpG]) data. The real data provided in GAW20 includes pedigrees from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study comprising 1105 participants and including genome-wide information on 597,145 variant sites and methylation levels at 463,995 CpG sites. Repeated measurements are available on 2 phenotypes: triglyceride (TG) levels and high-density lipoprotein (HDL) levels, measured twice each before and after the intervention of fenofibrate, a blood lipid-lowering drug. Information was also available on a few additional variables, such as age, sex, smoking status, and study center. The simulated data provided in GAW20 was created to mimic the real data and assumed 5 \u201cmajor gene\u201d causal SNP effects. Each of these effects on TG response was modeled to be proportional to the degree that the physically closest CpG site is unmethylated. Two hundred simulation replicates of posttreatment TG and methylation levels were generated under this growth-curve-based pharmacoepigenetic response model .There were 4 contributions from our group, of which 3 considered the real data while 1  analyzedA primary challenge in analyzing a phenotype in a longitudinal framework lies in the integration of the phenotype values across different time points in a multivariate phenotype vector or a reduced univariate phenotype. All the contributions used logarithmic transformations on phenotypic values to induce normality. Das et al.  considerEnvironmental confounders as well as clinically correlated endophenotypes are known to adversely affect inferences on genetic association , especiaDas et al.  and KulkThe different contributions explored contrasting statistical approaches to analyze TG levels before and after the administration of fenofibrate. The most popular approach to model the longitudinal data in the family-based framework is to use linear mixed effects models, primarily because such models can both account for relatedness within families and correct for population stratification between families via incorporation of principal components . MoreoveStrickland et al.  considerBecause contrasting statistical methodologies were applied to analyze different subsets of the GAW20 data on repeated measurements of TG and HDL levels, it was not feasible to explore the extent of similarity in the results obtained by the different investigators in the group. The phenotype definitions as well as the objectives with respect to these definitions were also not strictly comparable. Thus, it is not unexpected that the significantly associated SNPs obtained by Das et al.  and KulkA majority of the contributions , 10, 12 Although it is difficult to determine whether novel association findings obtained from real data sets are indeed true positives, the probability of the finding to be a false positive is reduced if contrasting statistical methods provide significant evidence of association in similar genomic regions in the absence of confounding effects. Because the phenotype definitions were not identical in the different contributions, it was difficult to evaluate the consistency of the different analytical strategies in yielding similar association findings. However, all contributions that analyzed the GOLDN data \u201312 obtaiFinally, we wish to highlight that a major issue corresponding to any novel methodology is the computational burden involved in the analysis. Even though the transmission-based test using the quasi-likelihood approach requires partitioning of large pedigrees into nuclear families, it is not computationally expensive. On the other hand, large pedigrees can be directly incorporated in linear mixed effects models that assume the genetic and phenotypic correlation structures between individuals within a pedigree, but, being likelihood-based in nature, such methods are often susceptible to inflated false positives when underlying distributional assumptions on cross-sectional as well as time-dependent correlation structures on phenotype values are violated. It may be more appropriate to use empirical thresholds  rather than asymptotic thresholds to determine the significance of a test statistic value to increase the robustness of the test. However, such a strategy may prohibitively increase the computational complexity of the methods.The common aim of the group was to explore powerful statistical methodologies for identifying genetic variants modulating triglyceride levels in a longitudinal framework. Despite the varied statistical approaches to model repeated phenotype measurements, the crucial paradigm unifying the contributions was that analyzing repeated phenotype measurements may be a more powerful strategy compared to cross-sectional analyses for identifying genetic and epigenetic factors underlying a complex trait."}
+{"text": "The measurement of the complex, multidimensional and dynamic concept of old-age social exclusion has been constrained due to theoretical and methodological challenges as well as a reliance on secondary data sources not designed to collect social exclusion indicators. Limitations in measuring social exclusion in later life hinder the expansion of our empirical and conceptual understanding of social exclusion. In this paper, we seek to address these limitations by developing a composite measure of old-age social exclusion using three methods: 1) normalisation through re-scaling with linear aggregation, 2) a sum-of-scores approach with an applied threshold and, 3) classification and regression trees (CART), a machine learning approach. Using the conceptual framework of old-age exclusion presented by Walsh et al., (2017), these three approaches are applied empirically with data from Wave 1 of The Irish Longitudinal Study on Ageing (TILDA). The measures are assessed in terms of their ability to explain a validated measure of psychological well-being. Results suggest that despite the challenges associated with secondary data and measurement techniques that implicitly measure social exclusion, the newly proposed composite measure computed using CART performed better than the other two measures which are more prevalent in the literature."}
+{"text": "Actinobacteria, a large group of Gram-positive bacteria, secrete a wide range of extracellular enzymes involved in the degradation of organic compounds and biopolymers including the ubiquitous aminopolysaccharides chitin and chitosan. While chitinolytic enzymes are distributed in all kingdoms of life, actinobacteria are recognized as particularly good decomposers of chitinous material and several members of this taxon carry impressive sets of genes dedicated to chitin and chitosan degradation. Degradation of these polymers in actinobacteria is dependent on endo- and exo-acting hydrolases as well as lytic polysaccharide monooxygenases. Actinobacterial chitinases and chitosanases belong to nine major families of glycosyl hydrolases that share no sequence similarity. In this paper, the distribution of chitinolytic actinobacteria within different ecosystems is examined and their chitinolytic machinery is described and compared to those of other chitinolytic organisms.The online version of this article (10.1007/s00253-018-9149-4) contains supplementary material, which is available to authorized users. Streptomyces genus, exhibit a complex life cycle producing substrate mycelium, aerial mycelium and spores. They are widely distributed in both terrestrial and aquatic ecosystems. Although members of this large phylum exist as free-living saprophytes, several of them can live inside tissues or organs as commensal or symbiotic partners of plants  were detected only in the presence of chitin  belong to families GH3 and GH20 while exo-\u03b2-glucosaminidases (GlcNase) represent a subfamily within the GH2 family  is also observed (Henrissat and Davies Str. coelicolor A3(2) whose genome encodes 11 GH18 and two GH19 members , GH2 GlcNases involved in chitosan hydrolysis are present only in a minority of species , was shown to bind to both \u03b1- and \u03b2-chitin  and increased markedly the solubilization of both forms of chitin in synergy tests with several chitinases  detected the presence of a protein able to bind to the promoter segment in a crude extract from cells grown in rich medium without chitin. Single-base mutations within the repeated sequences resulted in deregulated chitinase production (Ni and Westpheling The inducibility of chitinases production by the presence of chitin in actinobacteria was first observed by Reynolds  in Str. reg1 gene in Str. lividans (ortholog of SCO2232 in Str. coelicolor) resulted in production of chitinases in the absence of chitin and relieved chitinases production from glucose repression  forming a two-component regulatory system together with chiS in Str. coelicolor resulted in substantially reduced transcription level of chitinases gene chiC both in the presence and absence of chitin . Disruption of cpb1 resulted in a partial relief of chitinase production from glucose repression in the presence of chitin and had no effect on chitinase induction by chitin. However, specific binding to the direct repeats localized in the promoter region of chitinase genes could not be demonstrated for any of these regulatory proteins.Several genes and proteins were proposed as regulators of chitinase gene expression, based on the effects of disruption of these genes on production of chitinases in various conditions. For instance, deletion of the Str. coelicolor  or genes encoding chitin-binding proteins (SCO6345 and SCO7225) was demonstrated by EMSA. Binding occurred with regions having one or more operator sequences, renamed as dre (DasR-responsive elements). Binding was also observed with dre sequences synthesized as oligonucleotides TGGTCTAGACCA(G/C)T. A genome-wide analysis of DasR binding in vivo by the ChIP-on chip approach revealed that DasR binds to the promoters of a large proportion of genes involved in chitinase production and in the metabolism of the chitin monomer GlcNAc  and was suggested to play a regulatory role  but also the SCO2657 gene encoding a putative repressor belonging to the ROK family 2 dimer showing the strongest competition effect.Palindromic sequences corresponding to above consensus were identified in the genomes of csnR gene is localized at the beginning of a gene cluster composed of six genes (csnREFGHK) encoding an ABC transporter, a glycoside hydrolase from family GH4 and a putative saccharide kinase . Mining the available actinomycete genomes, we have however found one strain escaping from this rule: Streptosporangium roseum. While most genomes include, as average, only three to four genes with CsnR-box, we have identified in the genome of Streptosporangium roseum, using the RSAT tool . Thus, in this organism, chitin and chitosan metabolism could be more deeply integrated than in the other organisms studied so far.In Str. coelicolor are spread over all the three clusters. This illustrates the conclusion from this study that GH18 protein sequences do not cluster according to taxonomy  indicating independent evolutionary origins  and plant GH19 chitinases. While the general structural skeleton is conserved among both GH19 groups  which are the first and only GH46 members from Eukaryotes known so far  has been the subject of characterization"}
+{"text": "Camelus bactrianus. The camel MSY assembly was used as a reference for variant calling using short read data from eight Old World camelid individuals. Based on 596 single nucleotide variants we revealed a Y-phylogenetic network with seven haplotypes. Wild and domestic Bactrian camels were clearly separated into two different haplogroups with an estimated divergence time of 26,999 \u00b1 2,268 years. Unexpectedly, one wild camel clustered into the domestic Bactrian camels\u2019 haplogroup. The observation of a domestic paternal lineage within the wild camel population is concerning in view of the importance to conserve the genetic integrity of these highly endangered species in their natural habitat.Polymorphic markers on the male-specific part of the Y chromosome (MSY) provide useful information for tracking male genealogies. While maternal lineages are well studied in Old World camelids using mitochondrial DNA, the lack of a Y-chromosomal reference sequence hampers the analysis of male-driven demographics. Recently, a shotgun assembly of the horse MSY was generated based on short read next generation sequencing data. The haplotype network resulting from single copy MSY variants using the assembly as a reference revealed sufficient resolution to trace individual male lines in this species. In a similar approach we generated a 3.8 Mbp sized assembly of the MSY of  This unique mode of inheritance highlights the MSY as an ideal marker to study male genealogies alongside and in comparison to maternal phylogenies based on the mitochondrial DNA (mtDNA). Due to the lack of recombination, allelic states of single nucleotide variants (SNVs) on the MSY can be combined into haplotypes and robust MSY haplotype phylogenies can be built using the principle of maximum parsimony  took first place at the east coast of the Arabian Peninsula around 3,000 to 4,000 years ago (ya) (Camelus ferus) and domestic (Camelus bactrianus) two-humped camel mtDNA lineages  . Bactrialineages  predateslineages  have beelineages  and to tlineages , where tlineages  and low lineages  have beede novo assembled the Bactrian camel MSY from short read NGS data. The assembly was used as a reference for mapping and single copy MSY variant calling using short read data from five wild and three domestic Bactrian camels one dromedary as outgroup. With this, we created a first backbone Y phylogeny for Old World camels based on slowly evolving biallelic markers.To trace the paternal lineages and reconstruct male-driven population dynamics in Old World camels, specifically in the highly endangered wild camel, we adopted the approach recently described in horses  and de nTrimmed Illumina short reads from nine wild  and five domestic Bactrian camel  genomes were derived from an ongoing project  to detect signatures of selection related to domestication in Old World camelids. In addition, one male dromedary was included as outgroup. Sample details are provided in de novo assembled with SPAdes  was calculated in R for different scenarios using the whole set of SNVs detected in all individuals but the outgroup  of haplogroups D and W was estimated to 26,999 \u00b1 2,268 years before present ybp; . The MRCde novo assembly of the MSY region of domestic Bactrian camels and classified scY regions following the very conservative approach by Camelus ferus shotgun sequenced genome  seems to be much reduced compared to that of domestic Bactrian camels (\u03c0 = 1.17\u221710-5). This may reflect the decline of the wild camel population in Mongolia over the past decades  mya . This isUntil now, no large-scale study has been performed to identify male genealogies in the last remaining and highly endangered wild two-humped camels in the Mongolian GGSPAA and in the Chinese deserts Lop Noor and Taklamakan. A comprehensive survey including a large number of male individuals will be necessary in the future to establish a more comprehensive view on the diversity, introgression patterns and divergence estimates within and between wild and domestic Bactrian camels. Here, we provide the basis for developing a SNV array for a continuous screening of paternal lineages to investigate male-driven population dynamics in Old World camels. This will contribute to conserve the integrity of the wild two-humped camel gene pool.EDTA blood samples for domestic and wild Bactrian camels were retrieved commensally during routine veterinary controls, micro-chipping or radio-collaring of Mongolian wild camels, respectively. All data sets were collected within the frames of the legal requirements of Austria and Mongolia. Micro-chipping of semi-wild camels from the breeding center of the Wild Camel Protection Foundation (WCPF) in Mongolia was performed with the request and consent of the WCPF. Capture and collaring of wild camels within the Mongolian GGSPAA  was condSF performed bioinformatic analyses and lab work for variant validation. SF and BW developed the methodology and wrote and discussed the manuscript. BC, AY, BF, and CW provided samples and interpreted results. GB provided resources and discussions. PB conceived and managed the project and wrote the manuscript. All authors edited the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms (DMM), helping early-career researchers promote themselves alongside their papers. Danny Legge is first author on \u2018 Danny LeggeHow would you explain the main findings of your paper to non-scientific family and friends?Colorectal cancer (bowel cancer) is the second most common cause of cancer mortality in the UK. It is thought that cancer stem cells are responsible for the initiation of colorectal tumours and fuel the regeneration of tumours following the end of treatment. It is hypothesized that destruction of the cancer stem cells is required to prevent relapse of the cancer. Mutation of normal intestinal stem cells or reversion of specialized cells (de-differentiation) to a more stem-like state is suggested to be the origin of cancer stem cells, with both normal stem cells and cancer stem cells sharing molecular signatures. Many of the genes in these signatures are targets of the Wnt signalling pathway and almost all colorectal cancers undergo deregulated Wnt signalling. The \u03b2-catenin protein is the main effector of this pathway. Our study shows that BCL-3, a protein induced by inflammation, is a novel regulator of Wnt/\u03b2-catenin signalling and highlights the importance of this interaction for cancer stem cell function. Our results indicate that this protein could be targeted to reduce de-differentiation/plasticity of cancer cells and therefore target the cancer stem cell phenotype, providing more effective therapies for colorectal cancer patients in the future.What are the potential implications of these results for your field of research?Plasticity of cancer stem cells is recognized as a significant barrier to effective treatments. The ability of cells to de-differentiate, as promoted by the microenvironment, needs to be overcome to prevent tumour regeneration. Targeting LGR5-positive cancer stem cells alone has been shown to be ineffective, as surrounding tumour cells de-differentiate to re-express LGR5 and refuel tumour growth. Our data show that BCL-3 promotes expression of the intestinal stem cell markers LGR5 and ASCL2 in colorectal cancer cells. By targeting BCL-3, it may be possible to reduce this de-differentiation capacity, in addition to suppressing levels of aberrant Wnt signalling, given that BCL-3 functions downstream of mutated APC and \u03b2-catenin  to modulate Wnt signalling.What are the main advantages and drawbacks of the model system you have used as it relates to the disease you are investigating?ex vivo tools that allow us to study colorectal cancer in more physiologically relevant conditions than 2D cell culture work alone. They provide a stepping stone between cell lines and in vivo mouse models. Future work will involve the use of mouse models to understand the role of BCL-3 in cancer stem cell fate in vivo.Three-dimensional organoid and spheroid culture are valuable \u201cDeveloping models that replicate the tumour microenvironment more closely will be key to unlocking the potential of targeting cancer stem cells in colorectal cancer.\u201dWhat has surprised you the most while conducting your research?The BCL-3-mediated regulation of only a subset of Wnt targets involved in maintaining the intestinal stem cell phenotype is intriguing. Our work has shown that not all Wnt targets are regulated by BCL-3; in fact, many of the canonical proliferation-inducing targets usually associated with Wnt signalling are not regulated by modulating BCL-3 levels. Understanding how this is achieved may provide novel insights into the mechanisms of fine-tuning \u03b2-catenin/TCF-mediated transcription.Describe what you think is the most significant challenge impacting your research at this time and how will this be addressed over the next 10 years?Developing models that replicate the tumour microenvironment more closely will be key to unlocking the potential of targeting cancer stem cells in colorectal cancer. The importance of targeting the plasticity of cancer stem cells has already been highlighted, with many of these factors, such as high levels of Wnt signalling and other growth factors in the microenvironment, shown to enhance LGR5 levels in previously differentiated cells. Co-culture of patient-derived tumour organoids with associated mesenchymal and/or immune cells may provide useful models to study the interactions and signalling between tumours and their microenvironment.What changes do you think could improve the professional lives of early-career scientists?Reducing pressure on postdocs to travel in order to gain experience. It can often be difficult for scientists with young families to continually uproot them when working short-term contracts early in their careers. This also applies for scientists no longer living with their children who still want to have an active part in their upbringing. This could be taken into account when considering job applications from candidates who have worked in few institutions. Some PIs might see this as a lack of ambition, but for early-career scientists it may be the only option to continue a career in science and still maintain a healthy relationship with their families outside of work.What's next for you?in vivo models. In the future, I would like to apply for fellowships with the goal of running my own lab.I will soon be starting a postdoc investigating the link between diabetes and colorectal cancer using metabolomics and Twitter handle@leggey86"}
+{"text": "Frailty and the decline in ability to maintain independent living may be forestalled through discussions with healthcare providers and seniors about managing health at home. In addition, the use of technology in supplementing doctors\u2019 visits to assess frailty progression may be easily adopted by some but not others. We conducted this qualitative study to elucidate the context in which seniors access care at home and current barriers to independent living, from the perspectives of both seniors and practitioners. Pre-approved discussion questions were administered to two audio-recorded focus group sessions of 14 participants. The first group were community-dwelling older adults and informal caregivers, while the second consisted of healthcare practitioners. Group members were sampled to include a range of health backgrounds and levels of technological expertise. Thematic analysis with NVivo Software was used to parse out key discussion topics from the audio transcripts. The caregiver/patient group emphasized the stigma of frailty and age-related isolation, desiring transparency and advocacy from care teams. Practitioners/researchers discussed the importance of a holistic biopsychosocial approach to frailty management and the need for standardized frailty measurement. Patients/caregivers used health-tracking devices at home and were more optimistic about telehealth/video-conferencing than practitioners. Awareness of contextual factors surrounding \u201caging in place\u201d and what aspects of care are valued by patients and practitioners is key to advancing home health and paving the way for new evidence-based services in the home."}
+{"text": "Self-assembly has been recognised as a ubiquitous aspect of modern chemistry. Our understanding and applications of self-assembly are substantially based on what has been learned from biochemical systems. In this review, we describe various aspects of self-assembly commencing with an account of the soft structures that are available by assembly of surfactant amphiphiles, which are important scientific and industrial materials. Variation of molecular design using rules defined by surfactant self-assembly permits synthesis of functional nanostructures in solution and at surfaces while increasing the strength of intermolecular interactions through \u03c0-\u03c0 stacking, metal cation coordination and/or hydrogen bonding leads to formation of highly complex bespoke nanostructured materials exemplified by DNA assemblies. We describe the origins of self-assembly involving aggregation of lipid amphiphiles and how this subject has been expanded to include other highly advanced chemical systems. As has been proposed , self-asIn this review, we will describe the processes leading to self-assembly by referring to several examples of supramolecularly active compounds. Initially, we will describe the foundations of self-assembly from a molecular perspective. This will involve first a description of amphiphilic self-assembly of simple lipids followed by the introduction of selected structures formed from synthetic species especially porphyrins, which are currently of interest for molecular electronic or photonic applications. We will then discuss self-assembly that relies increasingly on chemical interactions rather than simple aggregative amphiphilic interactions. We have deliberately focused on so-called small molecule self-assembly with an emphasis on molecules with a biochemical context and will avoid discussions of block copolymers and crystalline assemblies.It is interesting to note that in Nature itself several spontaneous self-assembly processes operate to produce living systems of various complexities. Naturally-occurring phospholipids aggregate to vesicular forms known as cell membranes, DNA and RNA (and the related molecules) compose a supramolecular information storage system, while chlorosomal chromophores self-assemble in such a way that photonic energy collection and transfer are facilitated. Additionally, many biochemical systems rely on processes that can be considered as being based on supramolecular reactivity . Of course, these self-assembly processes cannot occur without first the syntheses of appropriately structured species. We will emphasize this aspect here since molecular covalent structure is probably the first aspect to consider when designing a self-assembling system. By analogy with protein terminology, the molecular structure might be the primary structure while any self-assembled non-covalent form could be referred to as its secondary structure. In human scientific terms, although crystallization processes had been known for some time, perhaps the initial observation of a self-assembly process of an organic soft matter was made in 1888 by Reinitzer  who discSelf-assembly of amphiphiles is of fundamental importance in diverse fields of application including pharmaceutical, food, and cosmetic formulations. Generally, amphiphilic molecules consist of at least two moieties of differing characteristics, for instance, hydrophilic and hydrophobic. Thus, surfactants are typical amphiphiles and the terms \u201csurfactant\u201d and \u201camphiphile\u201d are often used interchangeably. Surfactants are classified on the basis of the charge of the hydrophilic group  and theyi.e., hydrophobicity). This unfavorable interaction can be minimized by aggregation of amphiphilic molecules into micelles  in which the hydrophilic domains become exposed to water and the hydrophobic parts are shielded. This process is reffered to as micellization [Amphiphilicity is one of the main driving forces for self-assembly of surfactants. The thermodynamic properties of amphiphiles in solution are controlled by the strong tendency of hydrophobic tails to avoid direct contact with water  headgroups), and hydrogen bonding. Of these three, hydrophobic interactions make the largest contribution. Note that the formation of two liquid phases at higher temperatures in At higher concentrations above the cmc, surfactant molecules self-assemble into different mesophases. i.e., the bending curvature energy). The cpp is defined as cpp = v/aslc, where v and lc are the volume and extended length of hydrophobic alkyl chain and as is the area occupied by a surfactant molecule at the micellar interface [Generally, self-assembled phases are explained in terms of simple models of the geometric packing parameter (cpp) and the curvature free energy  or store information . In the former, the critical state of aggregation of light-absorbing pigments is fixed according to peripheral chemical groups (and how they interact with a protein scaffold in some cases) while in the latter information is stored in the primary sequence of DNA components and stabilized in protein complexes with the double helices. In synthetic systems containing functional group(s), it is more difficult to predict what form an assembling system will take even if the basic supramolecular modes of interaction are known. This is why simple amphiphilic assembly is so powerful\u2014a wide range of formations is available simply by varying the balance of hydrophilic and hydrophobic components. In the presence of other functionalities including aromatic systems, coordination complexes or hydrogen bonding donor-acceptor complexes the outcome of assembly may be quite different. For example, amphiphilicity has been successfully combined with aromatic systems in the assembly of capsular materials by Hiraoka and coworkers. They have reported several self-assembled formations of amphiphilic hexaphenylbenzene-type molecules where intermolecular interactions are due to aggregation of hydrophobic regions of the molecules leading ultimately to capsules with an internal cavity [In considering the potential functionality of self-assembled materials the design of the molecular species is critical. In the case of traditional lipid amphiphiles their functionality is combined with their ability to form structures for, for instance, encapsulation or stabilization of emulsions. In that case, design rules follow those predicted by the aforementioned phase diagrams and obtaining a particular structure is now a relatively simple well understood matter. However, in the current context there exists the requirement for the introduction of some optical, electronic or other functionality into the self-assembled structures. This is partly inspired by biochemical systems where self-assembly formations can be used to capture incident light  of stirring. This phenomenon may be of importance in the origin of life\u2019s homochirality and has been studied by several workers [Another significant example of dye self-assembly that has been intensively studied is that of J-aggregate formation . A J-agg workers .Larger oligomeric porphyrin systems have also been developed for their self-assembling and supramolecular properties. Porphyrins are suitable for these purposes due to their synthetic flexibility. Shinkai and coworkers have developed porphyrin systems over many years culminating in the use of a porphyrin oligomeric system for the application in the alignment of polymers  Also, poet al. demonstrated assembly of ultralarge molecular species containing porphyrin dendrimer and appropriately substituted fullerenes on solid surfaces [D\u2019Souza and coworkers have made a large contribution in the field of self-assembly by using several different supramolecular effects including crown ether chemistry  and hydrsurfaces . These isurfaces . Their sOverall, it can be seen that by applying molecular design principles in combination with a consideration of the structure of the naturally-occurring systems, it is possible to contruct potentially useful photon harvesting systems from a variety of light absorbent molecules by using self-assembly techniques.The importance of assembly at a surface lies in the possibilities of arranging and addressing individual molecules when they are positioned/adsorbed at an appropriate substrate. Observation of these structures is most often performed using scanning probe microscopy. These techniques have been extensively used and can provide high resolution images of molecules even reaching atomic resolution. Recently, even single molecules (adsorbed on a scanning probe tip) have been used for imaging purposes. Of course, data obtained from STM/AFM experiments are highly instructive for determining self-assembly mechanisms and there are many excellent examples available of potentially useful structures or simply aesthetically pleasing formations.et al. [et al. [While determinations of single molecular conformations and dynamism were amongst the first to be made , the pheet al.  synthesi [et al.  demonstr [et al.  or by roAvailability of surfaces for self-assembly processes has also enabled better observation of the potential materials\u2019 properties of DNA (deoxyribonucleic acid). DNA is almost unique in that it can be programmed to assemble into a (perhaps infinite) variety of structures. The attainment of this capability has been largely due to the effort of researchers in the biotechnological fields. The huge potential of DNA as a self-assembling nanotechnological tool has been proposed by Seeman who summarized its prospects for use in the nanosciences  SubsequeCis/trans isomerism of azobenzene substituents at the edges of DNA nanostructures could be applied to control the form of assembly of the nanostructures leading to linear or cyclic forms  and inter-base-pair \u03c0-\u03c0 stacking although the more critical aspects of DNA rely on its programmability and a knowledge of the specific structures available by programming, many of which have been learnt from study of natural systems. Also, because DNA is a natural biological substance it might be intuitive to assume that it is not especially stable. However, the oldest samples of DNA recovered to date are around 400 million years old [Despite the complexity of the structures available by DNA nanotechnology , they reears old  suggestietc.). Short oligopeptides can also be important components of aggregative self-assembling systems since they can provide moieties with multiple points for interaction especially through hydrogen bonding or formation of dithiol bonds. For these reasons oligopeptides have been studied for self-assembly purposes. Here we will mention several recent results that indicate the efficacy of these molecules for self assembly.Self-assembled structures of DNA indicate the strong influence of the primary structure of the self-assembling material on its final form. Molecular level variation of primary structure is also possible in proteins or oligopeptides. This can have the additional attractive feature of being determined by DNA coding so that uniquely structured proteins can be synthesized using genetic engineering techniques. Oligopeptides have a primary structure (the peptide sequence) and a secondary structure based on intramolecular interactions which give the protein its form . If we Self-assembly is a fascinating subject in modern chemistry in part due to ongoing work of synthetic chemists who are responsible for producing novel molecular species to apply the bottom-up approach to materials synthesis. Despite this, significant progress is often made using \u201coff-the-peg\u201d components such as various chromophores or readily available biological materials including DNA and proteins. It can be expected that observations on self-assembling systems will continue to stimulate investigations of phenomena occuring when molecules interact. As we have illustrated here, interactions for self-assembly range from simple amphiphilic assembly but can be increasingly effective when specific van der Waals forces are included or if stronger forces such as hydrogen bonding are introduced. Opportunities for chemical coding presented by DNA or proteins provide the ultimate control over the resulting structures.It has been recently recognised that self-assembly may be an energy efficient route to prepare novel materials within the nanotechnology paradigm. This has become possible due to the efforts of supramolecular chemists who have incorporated different functional moieties into their self-assembled or aggregated structures. However, there remain great opportunities for discovery of further functional self-assembly systems because of the wide availability and synthetic flexibility of the organic component materials."}
+{"text": "The well-known hazards of repurposing data make Data Quality (DQ) assessment a vital step towards ensuring valid results regardless of analytical methods. However, there is no systematic process to implement DQ assessments for secondary uses of clinical data. This paper presents DataGauge, a systematic process for designing and implementing DQ assessments to evaluate repurposed data for a specific secondary use. DataGauge is composed of five steps: (1) Define information needs, (2) Develop a formal Data Needs Model (DNM), (3) Use the DNM and DQ theory to develop goal-specific DQ assessment requirements, (4) Extract DNM-specified data, and (5) Evaluate according to DQ requirements. DataGauge\u2019s main contribution is integrating general DQ theory and DQ assessment methods into a systematic process. This process supports the integration and practical implementation of existing Electronic Health Record-specific DQ assessment guidelines. DataGauge also provides an initial theory-based guidance framework that ties the DNM to DQ testing methods for each DQ dimension to aid the design of DQ assessments. This framework can be augmented with existing DQ guidelines to enable systematic assessment. DataGauge sets the stage for future systematic DQ assessment research by defining an assessment process, capable of adapting to a broad range of clinical datasets and secondary uses. Defining DataGauge sets the stage for new research directions such as DQ theory integration, DQ requirements portability research, DQ assessment tool development and DQ assessment tool usability. There is growing interest in the reuse of routinely-collected clinical data for comparative effectiveness research, patient-centered outcomes research and clinical quality improvement . However12452791112Current repurposed clinical DQ assessment methodologies found in the literature fall short in supporting design and implementation in two distinct ways. On one hand, tool-driven methods and focus on directly detecting data flaws such as inaccuracies rather than supporting assessment design to evaluate \u2018fitness for purpose\u2019 10. These1410Model-driven software development and QA, is a well-established branch of software engineering that has enabled the systematic evaluation of software products with a fitness-for-purpose approach 1618192021.18192010Basic QA methods rely on qualitative evaluations  that provide measures of perceived quality [quality control standards [2627model-driven software engineering and QA [Quality assessment (QA) methods are used in many disciplines other than biomedical informatics. Some of these methods address one or more of the aforementioned limitations but have not yet been adapted to assessment of repurposed clinical DQ.  quality . This ty quality  to ensurtandards  and methtandards 262728 thg and QA . This fiModel-driven software development and QA is a well-established branch of software engineering that has reduced the number of errors in complex software  1618192021.18192016321631323316313233DataGauge proposes that the three stages of QA be completed by iteratively executing five concrete steps  entity-relationship diagrams [11404144diagrams 43 for thagrams 1140414445. 11404144 or, equi 11404144 to ensurThe third step is to define an analysis-specific DQ standard composed of DQ requirements that fully describe a fit-for-purpose dataset based on the DNM. The DNM serves as an overview and map of the analytical dataset. In this step, it enables the research team to ensure coverage of every value, variable, observation, table and dataset. We define DQ requirements as explicitly-defined constraints that describe the testable features that a dataset must meet to support answering the research question. This step is specific to the research question and DNM . The DQ standard allows the analytics team to explicitly define and agree on DQ requirements for a particular case. We suggest the use of Object Constraint Language (OCL) paired to the entity-relationship diagrams suggested in step 2 as a possible implementation route [495044main source of ambiguity in DQ assessment methods as well as a major threat to systematicity. Specifications development has been the target of much recent DQ research [1552on route 495051. Soute 49504445. Thiresearch 155253. ADataGauge, provides specific, structured guidance to address the complexity of the DQ requirement definition task by integrating existing DQ work outside the clinical data reuse literature. We use two dimensions to guide the definition of requirements: (1) formal levels of data granularity  to suppo153955For our example, DQ requirements were defined in the form of Boolean expressions and Object Constraint Language (OCL) constraints . We chos4851fourth step: extraction and formatting of the repurposed dataset from its database of origin. The DNM guides data extraction from the original database. The database administrator creates a schema with tables matching the DNM then loads the source clinical data into the tables. This schema should have all database rules such as variable type definitions, primary key rules, table relationship rules and other data validation triggers built in. In other words, the DNM serves as a dataset blueprint for extraction. Using this predefined schema to load the extracted data ensures that values match the agreed upon data model, variable types and database relationships. This step is an initial representational DQ test; if the data are not in the right format or variable types do not match, the database software should produce an error. For our example, the final DNM served as a data specification document to guide data extraction. Database tables were created to match the DNM and the raw data were extracted from the source database into the DNM schema using standard SQL queries.The last two steps implement the specifications developed in steps 2 and 3, beginning with the fifth and last step consists of evaluating DQ based on the previously defined DQ requirements. Appropriate DQ test methods [The  methods  are impl methods . SeveralOverall DQ tests revealed several DQ flaws in our test case Table . We wereDataGauge specifies a procedure that supports the systematic design and implementation of clinical dataset and secondary purpose-specific DQ assessments. DataGauge differs from previous work by combining guideline 15 and DQ41141632Recent work in the field of DQ for EHR data reuse has also aimed at enabling systematic assessments in two ways. On one hand, other DQ assessment processes have been published 63 but thDataGauge defines a series of concrete steps for the design and execution of DQ assessments to support implementation and relies on the definition of explicit DQ requirements (Step 3). However, DQ requirement definition is a complex, cognitively taxing activity. The complexity stems from the need for mixed quantitative-qualitative reasoning as well as information from multiple data sources such as the intended analytical design or purpose 15, data 404414153844Users can enrich the DataGauge process by defining their requirements using existing guidelines that may better serve their specific applications. For example, we could apply the 3 \u00d7 3 DQA guidelines , a recendefining a procedure to assess the quality of data or \u201cfitness for purpose\u201d. This is also the case for many DQ frameworks, guidelines and methods and, in the case of DataGauge, it has multiple repercussions. First, the definition of specific DQ requirements for each possible DQ threat is human resource intensive. However, the threats posed by data repurposing [DataGauge has limitations that stem mostly from the vast number of ways each step may be executed. This is an artifact of the general problem of urposing 8 demand urposing 55 of DQ urposing . NeverthDefining the DataGauge process opens many research avenues that require the involvement of the broad community of researchers making secondary use of clinical data. Beyond additional empirical validation of DataGauge\u2019s effectiveness at guiding clinical data reuse efforts , future 64We also propose pursuing research to build DQ assessment practices into the learning health care system along three research directions: DQ infrastructure development, DQ portability  and DQ uWe have presented DataGauge, a model-driven, iterative, team-based process to carry out purpose-specific DQ assessment for the secondary use of clinical data. It addresses a major barrier in the field: the lack of an explicit procedure for the design and implementation of DQ assessments. DataGauge also allows its users to systematically implement their preferred DQ assessment guideline for the definition of DQ requirements. DataGauge has two core contributions: (1) the integration of a number of disparate DQ assessment methods and techniques into a cohesive implementable process and (2) the explicit definition of a DQ assessment design and implementation methodology. This work also contributes by opening new avenues of research on systematic DQ assessment methods such as the development of a platform for shareable DQ requirements and the integrated implementation of existing DQ assessment guidelines."}
+{"text": "The formation and decomposition of inclusion compounds with a solid-solid phase transition may be very selective to the guest molecular structure. This selectivity may function in essentially different ways than defined by the classical concept of molecular recognition, which implies the preferential binding of complementary molecules. Solid inclusion compounds may take part as an initial or/and final state in several processes of different types summarized in this review, which selectivity is boosted by cooperativity of participating molecular crystals. Some of these processes resemble switching electronic devices and can be called smart giving practically absolute molecular recognition. Molecular recognition of neutral molecules is one of the key problems in chemical technologies and in analytical and biotechnological applications  component has an ability to induce the host crystallization. The mixture should have the concentration of this guest above a certain threshold value for this crystallization to be apparent, A vs. relative vapor pressure P/P0\u201d coordinates  in mol of guest per 1 mol of host, C is a sorption constant, N is a cooperativity parameter, which in ideal case of phase transition should have an infinitely high value, N \u2192 \u221e. The integration of sigmoidal sorption isotherms fitted by this equation gives the inclusion Gibbs energy \u0394Gc of guest transfer from its pure liquid or solid state to the saturated inclusion compound  means the stepwise selectivity of guest inclusion. If two guests have very small difference in molecular structure, but the first guest has sorption constant S at the variation of the guest molecular structure, tert-butylcalix[4]arene including a lot of guests inside its molecular cavity  may give another type of selectivity. This is the selective formation of stable intermediate clathrates, An example of absolute molecular recognition of benzene by a number of guest inclusion steps was observed for tetra(ethoxycarbonyl)methoxy thiacalix[4]arene carbamoylmethoxy) tert-butylthiacalix[4]arene .An ideal case for molecular recognition is the host ability to form two polymorphs: stable and metastable ones, tert-butylcalix[6]arene is less selective breaking the studied guest compounds into two groups: (1) remembered guests inducing formation of metastable polymorphs, and (2) non-remembered guests without such ability (Yakimov et al., tert-butylcalix[6]arene may be used in the analysis of binary mixtures if at least one of their components is from the first group. The efficiency of this analysis was demonstrated using DSC for the binary mixtures with one (Safina et al., For comparison, Guest-induced metastable polymorphs of calixarenes capable of an exothermic solid-phase transition have also a potential in 100% separation of binary mixtures of close homologs (Morohashi et al., The phenomenon of polymorphism is more variable than the examples given in this review. In many cases, metastability of a polymorph is in its lower melting point than that of the stable form. Such polymorphs may have more than one melting point with an intermediate exothermic cold crystallization to the more stable forms (Gataullina et al., Cooperativity of guest inclusion by solid host with phase transition provides specific types of selectivity for neutral guest compounds that cannot be observed in liquid solutions. In some cases, this selectivity gives practically absolute molecular recognition and may be called smart because it uses the host polymorphism with a very selective and easily detectable memory of the guest included and released. Besides, of the same molecular recognition level is the very selective formation of stable intermediate inclusion compounds, which may be detected by mass-sensitive sensor and in thermogravimetric curves. This process resembles a smart switch of the initial host crystals recognizing only one guest or few guest compounds.The specific types of structure-property relationships and molecular recognition caused by phase transition at guest inclusion and release may be expected for any solid host capable of clathrate formation. Still, discovery of the host-guest systems with a genuine selectivity for neutral molecules requires an extensive screening, which success cannot be predicted.VG supervised the project and mainly wrote the paper. AG and MZ co-wrote the paper. All authors discussed the reviewed results and commented on the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Cardiac contractility modulation (CCM) is an investigational device-based therapy to enhance ventricular contractility in systolic heart failure patients who are not candidates for cardiac resynchronization therapy (CRT) owing to the absence of wide QRS complexes or who have failed to respond on CRT. The principal mechanism is based on the stimulation of cardiac muscles by nonexcitatory electrical signals to augment the influx of calcium ions into the cardiomyocytes. The majority of patients receiving CCM therapy have concurrent implantable cardioverter defibrillators, and the manufacturer declares both devices can be used in parallel without any interactions. Nevertheless, proper lead positioning of both devices are crucial, and it is mandatory to check device-device interactions during each and every cardiac electronic implantable device-related procedure to prevent adverse outcomes. Cardiac contractility modulation (CCM) can be attained by an investigational device designed to improve the strength of myocardial contractility by delivering nonexcitatory electrical signals to increase calcium ion influx into the cardiomyocytes during the absolute refractory period of the cardiac cycle. The CCM device, Optimizer, is accepted in the United States as an investigational device to treat systolic heart failure patients with narrow QRS complexes or who are nonresponders of cardiac resynchronization therapy (CRT). A CCM unit includes a pulse generator and three pace-sense leads; a sensing lead in the right atrium and two signal-delivering leads implanted at the right ventricular (RV) septum. The manufacturer declares that CCM devices work in parallel with any kinds of implantable cardioverter defibrillator (ICD) system without affecting the ICD function. We present a case in which CCM leads chatter with the ICD lead in the RV which resulted in inappropriate sensing of the CCM signals by the ICD with subsequent delivery of inappropriate shocks.A 72-year-old male with past medical history of myocardial infarction status postpercutaneous coronary intervention, chronic systolic heart failure secondary to ischemic cardiomyopathy, received a single chamber Biotronik implantable cardioverter defibrillator (ICD) with a Medtronic single-coil defibrillator lead (model 6949-65) in 2005. A year later, the patient also received an investigational device, Optimizer III  (model #CCMX8), assembled with St. Jude Medical active fixation pace-sense leads (Model 1388-T), one lead in the right atrium and two in the upper and lower interventricular septum. Prominent electrical signals were identifiable on the patient's surface EKG when CCM was activated.In August 2014, the old Medtronic lead (Model 6949-65) was found to have a sudden increase in RV impedance to >2000 Ohms with \u201cRED\u201d alert warning of the Biotronik device. The particular Medtronic lead was also a subject of a Class-I recall by the Food and Drug Administration. Subsequently, he underwent laser lead extraction and replacement for a new ICD lead, Medtronic Sprint Quattro (Model 6947) dual coil defibrillation lead. The procedure was uneventful. The function of the new ICD system was assessed, and all the device parameters were found within normal limits. Patient's CCM was eight years old at that time and was found no longer functional due to battery depletion. Hence, the device-device interaction with the concurrent CCM unit was not evaluated.In earlier 2015, the patient presented with receipt of six ICD shocks without prior symptoms. Interrogation of the ICD disclosed intermittent, noncyclical, and nonphysiologic noise signals. The intracardiac electrogram recording was shown . All theLead failure was unlikely as all sensing and pacing parameters including lead impendence of the new Medtronic Sprint Quattro lead were normal. The signals  were nonThe patient underwent fluoroscopic examination  on whichThe CCM device along with two St. Jude Medical right ventricular pace-sense leads was extracted, but the same ICD unit was left in place. During the follow-ups over two years, no further noise signals had been detected by his ICD and the patient had not received any more inappropriate shocks.2), Minnesota Living with Heart Failure Questionnaires (MLWHFQ) in narrow QRS systolic heart failure patients despite its lack in mortality benefits or all-cause hospitalizations [Cardiac contractility modulation (CCM) device is designed to enhance ventricular contractility in a subgroup of systolic heart failure patients who are not candidates for cardiac resynchronization therapy (CRT) owing to the absence of wide QRS complexes or who have failed to respond on CRT. Although CCM therapy falls under the investigational category in the United States, it is approved as one of the device-based therapy for heart failure in Europe. CCM therapy can provide a better quality of life and NYHA functional class by improving peak venous oxygen  including ICDs and generally does not cause any interruption with ICD functions. However, functional testing of both Optimizer CCM and ICD systems is crucial and mandated to conduct during every procedure including the time of CCM implantation, an addition or revision of a lead(s) to ensure there is neither oversensing of CCM signals by the ICD nor any device-device interactions. It is important to allow an optimal spacing between the ICD lead and the CCM signal-delivering leads to prevent chattering each other in the RV.To our best knowledge, the consequences of CCM-ICD leads chattering as an outcome of inappropriate delivery of ICD shocks which even warranted the extraction of the CCM device have never been reported. In our case, CCM and the old ICD units were working in parallel without any interactions until the ICD lead was replaced. The diagnosis was challenging since signals were similar to those of ICD lead dysfunction but the leads parameters were normal. Under fluoroscopic examination, it was found that all the leads were implanted 1-2\u2009cm apart as recommended by the manufacturer. However, there was the excessive redundancy of some of the leads, and it was believed to be the etiology of leads chattering and oversensing by the ICD. Our case gives us a valuable lesson regarding the crucial role of CCM-ICD leads positioning and mandatory testing of device-device interactions during each and every CEID procedure.Optimizer is an investigational device based on the concept of cardiac contractility modulation. It is designed to improve myocardial contractility without increasing cardiac oxygen consumption by facilitating the calcium handling of cardiomyocytes. The device has a potential to fill up the present therapeutic gap in the treatment of systolic heart failure patients who have narrow QRS complexes or failed to CRT. The majority of patients receiving CCM therapy have concurrent ICD and the manufacturer declared both devices can be used in parallel without any interaction in between. Nevertheless, proper leads positioning of both devices are crucial, and it is mandatory to check device-device interactions during each and every CEID procedure to prevent adverse outcomes."}
+{"text": "Recent advances in corneal practice & research have largely been centered around interests concerning the endothelial keratoplasty, corneal biomechanics and collagen cross linking of the corneal stroma. This special issue of OPEN OPHTHALMOLOGY JOURNAL addresses these interests with an elaboration of the outcomes of endothelial keratoplasty procedures of Descemet's Membrane Endothelial Keratoplasty (DMEK) and Pre-Descemet\u2019s Endothelial Keratoplasty (PDEK), a perspective on future potent therapies for Fuch's Endothelial Corneal Dystrophy (FECD), a comprehensive review on corneal biomechanics in LASIK and Small Incision Lenticule Extraction (SMILE) and on practical applications of collagen cross linking along with the outcomes of Lasik Xtra.et al. in 2002 [et al. have described the results of DMEK in their first 100 cases using surgeon prepared DMEK roll prepared by a simplified technique. The excellent results obtained seem to stem from the fact that the surgeon was already an experienced Descemet\u2019s stripping endothelial keratoplasty surgeon, with capitalization on the knowledge gained over the reported results of the experiences of various other clinicians combined with standardization of technique.Since, the introduction of the concept of Descemet\u2019s membrane endothelial keratoplasty by Melles  in 2002 , the rap in 2002 . The req in 2002 -5. Marki in 2002 -12. Repo in 2002 . Graft dPDEK is a novel endothelial keratoplasty technique in which the composite of pre-Descemet's stromal layer (Dua's layer) with DM and endothelium is transplanted subsequently to the removal of the recipient's DM . The scret al. explores the current strategies on the use of cultures corneal endothelial cells either as sheets for transplantation or by direct injection of cultured corneal endothelial cells in the anterior chamber as therapeutic interventions. The success of obtaining regeneration of the corneal endothelium by co-injecting cultured corneal endothelial cells along with ROCK inhibitor into anterior chamber in animal studies has prompted their team to further research in human eyes [For over a long period of time, endothelial transplantation seemed to be the only option for the treatment of Fuch\u2019s endothelial corneal dystrophy. FECD has been categorized into three types (i) as early-onset FECD, (ii) as identified genetic loci, and (iii) disease without known inheritance . Missensman eyes . This reet al. to result in a similar reduction in corneal biomechanics when evaluated by Corvis ST and ORA [et al. found a decrease in Corneal Hysteresis (CH) and Corneal Resistance Factor (CRF) in SMILE and did not find differences in postoperative CH or CRF values between SMILE and femto-LASIK treatments [et al. discuss the review of corneal biomechanical properties following LASIK and SMILE for myopia and myopic astigmatism.With increasing popularity of SMILE procedure as a flapless and minimally invasive form of Laser Vision Correction (LVC) for the treatment of myopia and myopic astigmatism, the debate on its effects on corneal biomechanics in comparison to other LVC procedures is being widely investigated. Studies on the long-term outcomes of SMILE point towards its superior performance which shows excellent stability for higher myopia. SMILE also seems to have an advantage in terms of dry eye occurrence postoperatively over LASIK with better Schirmer's, tear film break up time, corneal sensitivity, and corneal nerve regeneration following SMILE as compared to LASIK . The int and ORA . The dec and ORA . Agca eteatments . Howevereatments -34, the et al. also discuss their outcome of simultaneous accelerated corneal cross linking and laser in situ keratomileusis for the treatment of high myopia.This issue also covers a comprehensive review on current trends in practical applications of corneal collagen cross-linking which is a subject of interest to all in corneal practice in recent times. LASIK Xtra is a recently described technique which combines LASIK and accelerated CXL performed simultaneously in the same sitting. Lasik Xtra is thought to afford early stabilization of the cornea after LASIK, and enhance the predictability of refractive outcomes in highly myopic eyes -36. Lim"}
+{"text": "The socio-economic status (SES) are the fundamental causes of gendered health disparity. However, how the gender gap in self-reported health (SRH) mediate by SES at old age over time is still unresolved. Some argue the SES measures play more and more important role to explain the gender gap in SRH at later age because the feminization of poverty and female\u2019s longer widowhood increased the gap over life course through cumulative disadvantage approach. But others SES-SRH gradients in gender gap keep convergent by age since the effects of SES on health for male has declined and make the gender gap in health disparity vanish over time. Our results show for every age, increasing SES is associated with declining risk of reporting poor health and the effects can explain much more for women than men, especially for the younger old below age 70. The effects of SES and marriage on the magnitude of the gender gap are substantial approximately 40 percent among seventy year olds to the full gender gap among 55-64 year olds in 2006."}
+{"text": "Nowadays, SR deregulation is associated with a wide range of neurological and psychiatric diseases including schizophrenia, amyotrophic lateral sclerosis, and depression. This review aims at compelling the most recent experimental evidences indicating that changes in SR-related modulation of NMDARs also govern opposite functional dysfunctions in physiological and pathological (Alzheimer's disease) aging that finally results in memory disabilities in both cases. It also highlights SR as a relevant alternative target for new pharmacological strategies aimed at preventing functional alterations and cognitive impairments linked to the aging process.The N-methyl-D-Aspartate glutamate receptors (NMDARs) are pivotal for the functional and morphological plasticity that are required in neuronal networks for efficient brain activities and notably for cognitive-related abilities. Because NMDARs are heterogeneous in subunit composition and associated with multiple functional regulatory sites, their efficacy is under the tonic influence of numerous allosteric modulations, whose dysfunction generally represents the first step generating pathological states. Among the enzymatic candidates, serine racemase (SR) has recently gathered an increasing interest considering that it tightly regulates the production of  In fact, based on their large distribution throughout the nervous system and their diversity in subunit composition associated with regional specificity in the brain and even with segregated localization at synapse level  will be presented, with the main conclusion that a strict regulation of SR activity is required for a successful cognitive aging. This review could also offer new opportunities for considering new relevant pharmacological strategies specifically targeting the SR-associated pathway to treat memory deficits linked to age-related brain disorders.NMDARs are part of a large multiprotein complex at glutamatergic synapses, that have received much attention over the last decades, due to their role in many types of neural plasticity on the one hand, and their involvement in neurotoxicity on the other hand. They are hetero-tetramers generally formed by two GluN1 subunits associated with the combination of two other partners including either four distinct GluN2 (GluN2A-D) or a mixture of GluN2 with two different GluN3 (GluN3A and 3B) subunits , this is not the case for the cytoplasmic carboxy-terminal intracellular domain that controls the coupling to different intracellular signaling cascades and the receptor trafficking -dependent enzyme serine racemase (SR)  mice which display a 90% decrease in brain d-serine without significant changes in levels of the other amino acids except d-aspartate  of synaptic transmission, a form of long lasting form of synaptic plasticity now viewed as a major functional requirement for memory formation  show slower decay kinetics in SR\u2212/\u2212 mice  serine was significantly lower than that of aged-matched controls  of subjects with only mild cognitive impairment that will probably evolve into dementia  (Madeira et al., Besides, a significant increase in SR expression and d-serine levels in the extracellular space could be viewed as pro-death signals in AD that promotes, in conjunction with the release of glutamate, the neurotoxicity exhibited by inflammatory processes (Barger et al., Considering the current state of knowledge summarized above, the elevated SR expression and the subsequent increase in d-serine. Such modulation impacting NMDAR activation allows the enzyme to control many brain functions in healthy conditions while being a preferential target for pathophysiological insults (Coyle and Balu, in fine in memory deficits indicating that a strict control of SR expression and activity is required to achieve a successful cognitive aging (Figure Nowadays, a wealth of preclinical and clinical evidences argues for a critical role of SR throughout lifespan in the regulation of functional plasticity through the synaptic availability of the NMDAR co-agonist g Figure . These rg Figure . In precg Figure , that cog Figure , though The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In silico progeny simulations together with genome-based prediction of quantitative traits can be used to guide mating decisions. However, the large number of multi-parental combinations can hinder the use of simulations in practice. Analytical solutions have been proposed recently to predict the distribution of a quantitative trait in the progeny of biparental crosses using information of recombination frequency and linkage disequilibrium between loci. Here, we extend this approach to obtain the progeny distribution of more complex crosses including two to four parents. Considering agronomic traits and parental genome contribution as jointly multivariate normally distributed traits, the usefulness criterion parental contribution (UCPC) enables to (i) evaluate the expected genetic gain for agronomic traits, and at the same time (ii) evaluate parental genome contributions to the selected fraction of progeny. We validate and illustrate UCPC in the context of multiple allele introgression from a donor into one or several elite recipients in maize (Zea mays L.). Recommendations regarding the interest of two-way, three-way, and backcrosses were derived depending on the donor performance. We believe that the computationally efficient UCPC approach can be useful for mate selection and allocation in many plant and animal breeding contexts.Predicting the usefulness of crosses in terms of expected genetic gain and genetic diversity is of interest to secure performance in the progeny and to maintain long-term genetic gain in plant breeding. A wide range of crossing schemes are possible including large biparental crosses, backcrosses, four-way crosses, and synthetic populations.  Allocation of resources is a key factor of success in plant and animal breeding. At each selection cycle, breeders are facing the choice of crosses to generate the genetic variation on which selection will act at the next generation. In case of limited genetic variation for targeted traits, the introduction of favorable alleles from donors to elite material is necessary to ensure long term genetic gain. Several approaches have been proposed to introgress superior quantitative trait locus (QTL) alleles from a donor into a recipient. In case of a single desirable allele, it can be accomplished using molecular assisted introgression  and to hin silico simulations of progeny and genome-wide marker effects  is a meaningful measure of the interest of a cross for breeding, it does not account for the parental genome contributions to the selected fraction of progeny that determine the genetic diversity in the next generation. Parental genome contribution to unselected progeny has been studied for several years and is of specific interest in breeding for donor introduction and to manage long term genetic gain and inbreeding rate  to evaluate the interest of a multi-parental cross implying a donor line and one or several elite recipients based on the expected genetic gain (UC) and the diversity  in the selected progeny. We extend here the rational given by e.g., grain yield) implying a priori knowledge on major QTL to be introgressed. We assumed a donor line (D) has been identified and should be crossed with lines from the elite population  in order to obtain high-performing progeny that combine donor favorable alleles in a performing elite background. This donor line can vary in its performance level and its diversity relative to the elite population.We assumed a generic plant breeding population of fully homozygote inbred lines genotyped for biallelic single nucleotide polymorphism (SNP) markers with known positions. We considered a quantitative agronomic trait  evaluate the genetic gain of the selected progeny for the agronomic trait, and to (ii) evaluate the contribution of each parental line to this selected progeny. An illustration of the concept of UCPC is given in To cover diverse types of crosses, we consider a general multi-parental cross implying four fully homozygous parentsectively . A seconth element coded as 1 or -1 for the genotypes AA or aa at locus p-dimensional vector of zeros.Assuming known genotypes at i.e., partially heterozygous progeny. Absence of selection is assumed while deriving the progeny from generation We first concentrate on doubled haploid (DH) lines derived from the ay cross  in a muli.e., The multi-parental coding enables to consider i.e., different physical positions) or at the same QTL. The linkage disequilibrium parameter in the progeny between parental alleles i.e., doubled haploid lines derived from generation In this section we consider a generic quantitative trait defined by the \u2212e\u22122djl) . When j P1 x We aim at predicting the full multivariate progeny distribution  for the agronomic trait, riterion  in a muly of one , the expel)) are :\u03bcC(sel)=We performed two simulation experiments. The aim of the simulation experiment 1 was the validation of the presented formulas for the moments of the distribution of progeny from four-way crosses. In simulation experiment 2, we investigated different crossing schemes  in terms of genetic gain and donor contribution.e.g., grain yield) implying We considered 57 Iodent inbred lines from the Amaizing Dent panel . For in silico simulations, crossover positions were determined using recombination rates obtained with Haldane\u2019s function (in silico). The correspondence between predictors was assessed by the squared linear correlation and the mean squared difference between predicted (derivation) and empirical (in silico) values.In order to validate the derivations for progeny (co)-variances and UCPC method in case of four-way crosses for DH and RIL progeny for selfing generations k\u2208 , we randfunction . The corWe used UCPC to address the question of the best crossing scheme between a given genetic resource  showed a high correspondence with empirical results from ulations  as well ulations  showed sulations   depended only on the performance of the donor, whatever the mean genetic distance with the elite population (results not shown). A similar comparison between three-way crosses and backcrosses showed that the best backcross yielded similar When the donor outperformed the elite population, the best two-way cross was more likely yielding a higher genetic gain than the best three-way cross or backcross . On the ackcross  did not oss (\u03bcT)  in the bmilar \u03bcT  but loweay cross , especiaay cross .i.e., maximizing the expected genetic gain) was a two-way cross for most iterations (90%). This can be explained by the fact that crossing the two best elite lines generates more genetic gain than crossing them to a third less performant elite line, despite a potential gain in progeny variance. Notice that we considered only one polygenic agronomic trait but three-way crosses can be more advantageous for bringing complementary alleles for several traits. Under the formulated assumptions and with available marker effects (see discussion below), the general formula to predict mean and variance of four-way cross progeny makes it possible to identify the multi-parental cross that maximizes a given multi-trait selection objective (see discussion below) without requiring computationally intensive in silico simulations of progeny. The generalization to several generations of selfing for RIL progeny enables in addition to differentiate crosses releasing differently the variance in time (File S2). The presented formula for four-way crosses can also be applied to crosses of two heterozygous parents by considering its phased genotypes as four separate parents. Doing so, our approach can be adapted for heterozygous plant varieties that are common in perennial species and for crosses with hybrids, as well as for animal breeding where the prediction of Mendelian sampling variance can be very useful for mating decisions  it is unlikely to get completely rid of unfavorable parental alleles. Parental genome contribution was bounded in selected progeny due to the low probability of combining all alleles from a single parent. Note that UCPC also allows to follow the contribution of parents to progeny performance by defining a vector of effects based on parental performance marker effects. For instance, considering Predicted genome-wide donor contribution to progeny after selection was bounded to a minimum in case of the worst donor and a maximum in case of the best donor. In line with the predicted distribution of parental genome contribution before selection obtained in maize by Using UCPC, we addressed the question of polygenic trait introgression from an inbred donor to inbred elite recipients with a focus on common plant breeding crossing schemes: two-way, three-way and backcrosses. We assumed that the objective was to derive in one selection cycle an inbred progeny that combined donor favorable alleles in a performing elite background. Such progeny can be used as parental lines for new crosses in order to quickly introgress new favorable alleles in a breeding program. Such a short term vision of genetic resource integration can be complementary to a longer term pre-breeding approach using exotic material .a posteriori the crossing strategy adopted in the Germplasm Enhancement of Maize project  according to specific pre-breeding strategies.We observed that badly performing donors had little chance to pass their favorable alleles to progeny selected for their agronomic trait performance. This is a consequence of the negative covariance between the performance for the trait and donor contribution in case of an inferior donor . To preve.g., drought tolerance), while agronomic flaws  can be counter-selected using threshold selection. Recently it has been shown by More generally, the multivariate context provides the opportunity to deal with several quantitative traits on which selection is directly or indirectly applied. Further traits for which genome-wide estimated marker effects or QTL effects are available can be considered. For external genetic resource utilization, it enables to introgress secondary traits such as polygenic tolerances to biotic or abiotic stresses , it might be of interest to use parental specific effects estimated by e.g., multivariate QTL mapping  or practical limitations . If the genetic correlation between those traits and the traits considered within UCPC is null, the derived progeny distribution and UC for the four-way crosses will still hold.Our approach is totally generic and can deal with any information on the position and the effect of QTL. However, main assumptions should be discussed at this point. We assumed known true genetic positions of QTL and no interference during crossover formation to derive recombination frequencies . In pracThe derived formula for progeny mean and variance holds for mono- and oligo-genic traits, whereas the usefulness criterion underlying UCPC uses normal distribution properties. When considering traits involving a sufficient number of underlying QTL, as it is the case for most agronomic traits and parental genome contributions, this assumption of normality is likely guaranteed by the central limit theorem. If only a limited number of known major QTL should be introgressed from a donor, an allele pyramiding strategy will be more suitable  effects. For biparental crosses , an IBS approach (File S3) considering only polymorphic markers homogeneously covering the genome can be used as an approximation of the IBD contribution.We presented an IBD definition of parental genome contributions using a multi-allelic approach. The multi-allelic coding yields covariance matrices that are four times larger compared to using a biallelic coding. In practice, to obtain a less computationally intensive solution, the genotyping matrix can be reduced to a bi-allelic coding which yields an identity by state (IBS) parental genome contribution that informs on the sequence similarity between one parent and progeny (see File S3). However, in such a case parental contributions do not sum up to one and it cannot be accounted for multi-allelic  that evaluates the interest of multi-parental crosses based on the expected genetic gain (UC) and the parental contributions (PC) in the next generation. UCPC allows to (i) predict the progeny variance of four-way crosses accounting for linkage disequilibrium and to (ii) follow all parental genome contributions to the selected progeny to evaluate the interest of a cross regarding an objective that is a function of the expected performance and the diversity in the selected progeny. Illustration of the use of UCPC in the context of polygenic trait introgression from a donor to elite recipients enabled to draw some major recommendations. As expected, three-way crosses and backcrosses were more adapted to donors underperforming the elite population (inferior donor) while two-way crosses were more adapted to donors outperforming the elite population. We also suggested that three-way crosses should be preferred over backcrosses for polygenic traits introgression. Furthermore, we highlighted the importance of a compromise between UC and PC in case of an inferior donor."}
+{"text": "Family caregivers of hospice patients play an essential role in the delivery of care but have multiple needs during this often stressful time. Cost-effective interventions supporting caregivers are greatly needed. We conducted a four-year randomized clinical trial of a problem solving therapy intervention called PISCES to support hospice caregivers. We recruited 514 caregivers  who were randomly assigned to either a control group  or a face to face group (where the intervention was delivered in three in-person sessions) or a telehealth group (where the intervention was delivered using technology). While the intervention was effective in reducing caregiver anxiety and improving overall quality of life, the intervention was found more effective in the face-to-face group than the telehealth group. We discuss challenges with the technology use and recommendations for the design of future telehealth systems targeting older adults in the hospice setting."}
+{"text": "A different kind of shake-up will hit the science establishment when the New Year dawns in earthquake-prone Japan, reports Nature in its lead story this week. Science kicks off self-referentially with a lead story about its decision to publish a paper on sequencing the human genome from Craig Venter of Celera Genomics."}
+{"text": "Genes conferring resistance to plant viruses fall in two categories; the dominant genes that mostly code for proteins with a nucleotide binding site and leucine rich repeats (NBS-LRR), and that directly or indirectly, recognize viral avirulence factors (Avr), and the recessive genes. The latter provide a so-called recessive resistance. They represent roughly half of the known resistance genes and are alleles of genes that play an important role in the virus life cycle. Conversely, all cellular genes critical for the viral infection virtually represent recessive resistance genes. Based on the well-documented case of recessive resistance mediated by eukaryotic translation initiation factors of the 4E/4G family, this review is intended to summarize the possible approaches to control viruses via their host interactors. Classically, resistant crops have been developed through introgression of natural variants of the susceptibility factor from compatible relatives or by random mutagenesis and screening. Transgenic methods have also been applied to engineer improved crops by overexpressing the translation factor either in its natural form or after directed mutagenesis. More recently, innovative approaches like silencing or genome editing have proven their great potential in model and crop plants. The advantages and limits of these different strategies are discussed. This example illustrates the need to identify and characterize more host factors involved in virus multiplication and to assess their application potential in the control of viral diseases. R gene mediated resistance and recessively inherited resistance, although other cellular mechanisms like autophagy  into short interfering RNAs (siRNAs). The so-called guide strand then takes the RNA-induced silencing complex (RISC), containing argonaute (AGO) proteins, to complementary RNAs which leads to their degradation or translational inhibition. This defense response is counteracted via different mechanisms by viral proteins known as viral suppressors of RNA silencing , either in a direct interaction or indirectly via modifications caused by the Avr on plant factors, according to the guard or decoy models  in virtually any gene implied in a cellular mechanism needed at any step of the viral infection cycle including translation, replication or movement. Indeed, replication of tobamoviruses is impaired in  mutants  whereas  mutants . The movthaliana  and longmon bean . Howevermon bean . The EXAng motif  and the ecycling .It is anticipated that more plant factors involved in virus amplification will be discovered and their mechanism elucidated in the coming years. This represents a promising resource for genetic resistance against viruses. Taking the eIF4 factors as an example, this review presents some possible approaches to turn our knowledge on virus-host interactions into antiviral strategies. From classical breeding to genome editing, all kinds of methods have been applied to model and crop plants to exploit eIF4-based resistance.eIF4 factors are critical proteins involved in the initial step of the translation of eukaryotic mRNAs. eIF4E factors bind to the cap  while a polyadenosine binding protein PABP binds the 3\u2032 poly(A) tail of the transcript . eIF4G fin vitro translation , tobacco etch virus 4E as the resistance gene to turnip mosaic virus .Capsicum annuum) lettuce (Lactuca sativa), pea (Pisum sativum) or barley (Hordeum vulgare) and have been introgressed in many cultivars  X-ray mediated mutagenesis was applied to generate the va recessive resistance (Apium graveolens) deriving CELI . The amino-acid substitution lies outside of the cap binding pocket but could still regulate the cap binding activity of eIF4E 4E triggered resistance to three viruses in the family Potyviridae and one in the family Tombusviridae (eIF4E1 and eIF4E2 without affecting eIF(iso)4E led to large anti-potyviral resistance (eIF(iso)4E but not eIF4E provided effective resistance to plum pox virus (PPV) the causal agent of Sharka 4E-S and eIF(iso)4E-T  the authors could decrease the accumulation of a resistance breaking strain of PVY. They combined this approach with the screening of an EMS mutant library to further demonstrate the implication of the eIF(iso)4E-T but not the eIF(iso)4E-S isoform in the virulence of this PVY strain escaping the resistance provided by the deletion of eIF4E1-S.RNAi has the advantage of being effective on polyploid hosts as shown by the recent work on the allotetraploid tobacco plant . By sileLess intuitively, overexpression of a host factor involved in the multiplication of a plant virus can also provide genetic resistance to this virus. Either a natural resistant variant or a non-functional mutant of the susceptibility factor is overexpressed in transgenic plants in order to outcompete the interaction between the virus and the endogenous functional factor. This dominant negative approach has been successfully described in several studies and represents a good way to transfer virus resistance in crops that have not developed eIF4-based resistance. Mutations in the overexpressed gene either mimic existing variants, derive from protein-protein interaction data or combine these two options . The twoArabidopsis line knocked out for eIF4E1 with a synthetic eIF4E gene combining 6 amino-acid substitutions existing in natural pea alleles. The broad resistance obtained in these Arabidopsis plants illustrates the great potential of using gene engineering to exploit natural variability  transforms the recessivity of the resistance to a dominantly inherited trait. It is also relatively easily applicable to various cultivars and thus preserves existing crop diversity. In the absence of public acceptance for final marketable crops this technology still represents a valuable and efficient tool to study the relevance of given gene modifications that can then be obtained by other means.Arabidopsis , transcription activator-like effectors nucleases (TALENs), and CRISPR  associated (Cas) endonucleases. These technologies often compared to molecular scissors allowing targeted mutagenesis or short indels are continuously improving and their use to generate antiviral resistance is rapidly increasing . The effbidopsis  and morebidopsis  where muHowever, knock-out alleles of redundant genes present the risk of limited efficiency in virus resistance because of their possible impact on the expression of other isoforms or because viruses can adapt to recruit other factors . TherefoGene editing represents a powerful tool to improve crops and seems to be only limited by the delivery of the entire expression system  and the efficacy in regenerating plants from cell or tissue culture. It has the advantage of being versatile and producing plants that do not contain foreign genes. The engineered plants are similar to mutated cultivars or natural variants that have been used for long time in traditional breeding programs. No doubt that the recent decision by the US Department of Agriculture not to regulate plants that have been modified through genome editing will prompt viral resistance into a new era. On the contrary, the European Court of Justice has recently ruled that edited plants fall within the scope of the GMO directive and do not even benefit from the exemption granted to plants mutated by use of older techniques with a \u201clong safety record.\u201d This view of considering living beings according to the techniques used for their generation is not without practical and ethical problems.eIF4-based resistance to viruses perfectly illustrates the recent progress in engineering loss-of-susceptibility resistance, from the observation of a recessive resistance to the latest rational synthetic gene design. These experiences could help in defining a general approach applicable to other host factors. In a first step, high throughput techniques such as transcriptomics, yeast-two-hybrid or virus-induced gene silencing could identify new host partners of viral factors. The second step would consist in evaluating the biological importance of the interaction for the virus life cycle and evaluate the possibility to manipulate the host gene, that is assess the specificity of the interaction in case of a multigene family and evaluate the possibility to manipulate that gene without affecting important agricultural traits. A crucial development resides in obtaining or identifying alleles disrupting the interaction with the virus factor without greatly affecting the plant. Screening methods like reverse yeast two hybrid  or EcoTIAn evaluation of crop performance, of resistance spectrum and of possible interference with other viruses will then need large-scale field trials. The durability of resistance is an important parameter and mathematical models as well as experimental studies are aimed at assessing and improving it . CombiniCS-K wrote the manuscript and drew the figures.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Antipsychotics (APMs) are commonly used off-label to control behavioral symptoms of dementia in nursing home (NH) residents despite FDA warnings. As part of the Centers for Medicare and Medicaid Services\u2019 (CMS) partnership to reduce the use of APMs in long-stay NH residents with dementia, CMS began publicly reporting an APM quality measure on the NH Compare website in July of 2012. This measure proxies for potentially \u201cinappropriate\u201d use by excluding residents with diagnoses in which APMs may be appropriate. While APM use as declined, some question if the quality measure creates an incentive to change documentation of exclusionary diagnoses to show improvements in the publicly reported APM quality measure. These exclusionary diagnoses include: Huntington\u2019s disease, Tourette syndrome, and schizophrenia. Using Minimum Data Set (MDS) assessments from long-stay NH residents in freestanding NHs (2011-2015), we utilized a difference-in-differences framework to compared the proportion of assessments with exclusionary diagnoses in NHs that were required to report the APM quality measure (treatment) to NHs that were exempt from reporting the measure (control). We also stratified the results by grouping residents under and over 65 year of age. We find no change in exclusionary diagnoses immediately following the implementation of public reporting. However, starting in 2014, the use of exclusionary diagnoses increased in the treatment group, especially among residents aged 65+. While APM use declined for all groups over the study period, our results indicate that the reduction in APM use may not be as large as expected, especially after 2014."}
+{"text": "Evidence from multiple disciplines suggests that early\u2010life conditions and environments affect outcomes across the life course. However, less is known about the effects of policy interventions targeted to adults and communities that may have intergenerational consequences on exposed children. In this study, we undertake novel data linkages to examine the effects of the New Deal work\u2013relief programs on long-term health, disability and mortality outcomes of children born between 1920-1940. We first link the American Manufacturing Cohort (AMC) workforce backward to their childhood census records to capture parental and community exposure to New Deal work-relief programs. We then test the hypothesis that employment in New Deal work-relief programs is associated with lower levels of chronic disease, lower rates of disability and delayed mortality for both the children in benefitting households and children in non-benefit households living in areas that received greater amounts of New Deal funding."}
+{"text": "The socio-cultural and legal position of LGBT citizens varies across nations. However, even in the most liberal countries, an historical legacy of stigma impacts on older LGBT people\u2019s access to care. This paper draws upon the qualitative strand of a two-year UK project exploring the end of life experiences and care needs of older LGBT people. (N = 60 in-depth interviews with LGBT participants aged 60+). Findings highlight that the majority of respondents reported ways in which they manage their personal networks to minimize any vulnerability to discrimination. In planning or needing end-of-life-care, respondents identify new \u2018layers\u2019 of decisions about disclosing or hiding their sexual or gender orientation; informed by past experiences and fears about discrimination or exclusion from service providers. In conclusion, older LGBT people\u2019s histories and a legacy of stigma have ongoing profound influences on the means of support available to them at the end of life."}
+{"text": "NMR assignment typically involves analysis of peaks across multiple NMR spectra. Chemical shifts of peaks are measured before being assigned to atoms using a variety of methods. These approaches quickly become complicated by overlap, ambiguity, and the complexity of correlating assignments among multiple spectra. Here we propose an alternative approach in which a network of linked peak-boxes is generated at the predicted positions of peaks across all spectra. These peak-boxes correlate known relationships and can be matched to the observed spectra. The method is illustrated with RNA, but a variety of molecular types should be readily tractable with this approach.The online version of this article (10.1007/s10858-019-00271-3) contains supplementary material, which is available to authorized users. The power of NMR spectroscopy relative to other molecular spectroscopies lies in the ability to detect spectral signals and interactions associated with specific atoms. Requisite assignment of NMR signals typically follows a paradigm of measuring the chemical shifts of local maxima (peaks) within each spectrum followed by correlating signals within and among different types of NMR spectra and associating those peak positions with specific atoms, either by automated methods or interactive analysis. Although automated assignment methods are desirable and work toward this goal is ongoing, interactive methods remain the standard for much NMR assignment. Although interactive analysis is aided by the display of peak-boxes associated with each measured peak, which can display known assignments or other annotations, the tracking of thousands of scalar- and dipolar-coupled peaks in multiple datasets can be challenging. We describe here an inverted approach that focuses on networks of coupled peaks that are predicted from the molecular structure and type of NMR experiment. Instead of picking peak positions and then attempting to assign them, we generate a linked network of assigned peak-boxes at these predicted positions that can then be interactively aligned with the observed spectra. This approach allows the spectroscopist to make simultaneous use of multiple spectral features that can minimize ambiguity in the assignments compared to the process of assigning individual peaks.Our technique relies on a priori knowledge of the molecular topology and the ability to predict chemical shifts and coupling patterns. Both types of information are available for a range of molecule types  is additionally necessary for chemical shift prediction and NOE cross-peak prediction. Predicting chemical shifts of the target molecule is an essential component of the protocol. For RNA molecules we use our previously described attribute-based shift prediction technique .For an RNA (or other molecule) where the 3D structure is known peak-boxes are generated for all hydrogen pairs whose distance is less than a specified limit (often 5 or 6\u00a0\u00c5). Where the 3D structure is not available, NMRFx Analyst uses the secondary structure specified with dot-bracket notation and a built-in set of rules to generate peak-boxes for helical and tetraloop regions. Intra-residue peak-boxes are also generated and are less dependent on the structural information. While this NOESY protocol is unable to generate inter-residue peak-boxes in larger loops, the combination of peak-boxes in helical and tetraloop regions and intra-residue peak-boxes in all regions gives a substantial number of predicted peaks that can be used as a basis for a search to other regions. The intra-residue assignments can be used to get the correct shift assignments which are then used to assign peaks that haven\u2019t been predicted Below is the link to the electronic supplementary material."}
+{"text": "Alternative splicing is an important mechanism used by the cell to generate greater transcriptomic and proteomic diversity from the genome. In the heart, alternative splicing is increasingly being recognised as an important layer of post-transcriptional gene regulation. Driven by rapidly evolving technologies in next-generation sequencing, alternative splicing has emerged as a crucial process governing complex biological processes during cardiac development and disease. The recent identification of several cardiac splice factors, such as RNA-binding motif protein 20 and 24, not only provided important insight into the mechanisms underlying alternative splicing but also revealed how these splicing factors impact functional properties of the heart. Here, we review our current knowledge of alternative splicing in the heart, with a particular focus on the factors controlling cardiac alternative splicing and their role in cardiomyopathies and subsequent heart failure. The heart exhibits adaptive responses to a wide array of genetic and external factors, such as hypertension, to maintain contractile function. When compensatory responses are not sustainable, cardiac dysfunction occurs, leading to heart failure where the heart is unable to pump enough blood through to meet the body\u2019s needs for nutrients and oxygen. The failing heart undergoes several structural alterations, most notably hypertrophy of cardiomyocytes, dilation of the ventricles, an increase in extracellular matrix proteins, and potentially also cell death. Heart failure is an increasingly prevalent and lethal disease that is often caused by underlying cardiomyopathies.Cardiomyopathies are a heterogenous group of disorders where the structure and function of the heart is affected. They either are confined to the heart or are part of systemic disorders. Cardiomyopathies can broadly be categorised as dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), ischemic cardiomyopathy (ICM), and arrhythmogenic right ventricular cardiomyopathy (ARVCM)   complex found primarily within the splicing speckles of the cell nucleus. The spliceosome is comprised of more than a hundred core proteins , which facilitate spliceosome assembly, whereas splicing silencers recruit proteins of the hnRNP family, which can interfere with recruitment of the spliceosome or SR proteins. SR proteins are characterised by the presence of at least one RNA recognition motif (RRM) and a serine/arginine-rich domain (RS domain). The RNA recognition motif domain is required for RNA-binding, whereas the RS domain functions as a protein interaction domain.However, it has been shown that these splice factors can have a dual role as splicing enhancer or repressor depending on the context    during cardiac hypertrophy may play a role in establishing the foetal splicing programme in the hypertrophied heart. This suggests that mRNA isoform regulation plays critical roles in remodelling the heart under pressure overload. The concept that hypertrophy is characterised with re-expression of a foetal splice variant programme was later confirmed by Ames and colleagues in a rat model of cardiac hypertrophy , splicing component 35\u00a0kDa (SC35), serine/arginine-rich splicing factor 1 (SRSF1), epithelial splicing regulatory protein (ESRP), polypyrimidine tract binding protein (PTB), and CUG-binding protein 2 (CUGBP2). They could experimentally confirm that protein levels of a subset of these predicted splicing factors were significantly altered during cardiac hypertrophy. This suggests that chronic pressure-overloaded hypertrophy is closely associated with distinct alternative splicing due to altered expression of splicing factors  null mice were embryonically lethal due to cardiac defects including atrial and ventricular septal defects. Furthermore, knockout of SRp38 resulted in mis-splicing of triadin, a cardiac protein that functions in regulating calcium release from the sarcoplasmatic reticulum during excitation-contraction coupling  was recently shown to be a major regulator of heart and skeletal muscle splicing  causes mis-splicing of ketohexokinase and triggers the onset of cardiac hypertrophy by enforcing fructolysis  is associated with heart failure in humans and mouse models, and the loss of Rbfox1 exacerbates pressure overload-induced heart failure in mice  were shown to cause an early onset and clinically aggressive form of DCM  N2B adult isoform occurs in the heart to adapt to the postnatal cardiac load demands   and calcium voltage-gated channel subunit alpha 1C (Cacna1c)  Ca2+ content was found in Rbm20-depleted myocytes .AONs are designed to bind to a specific splicing RNA sequence to manipulate splicing. Duchenne\u2019s muscular dystrophy (DMD), caused by mutations in the dystrophin gene, is the first disease in which AONs have been clinically tested. The administration of AONs to DMD patients promoted exon skipping of the mutated exon (to avoid premature truncation of the protein) and modest improvements in exercise capacity  (Scaffidi and Misteli Another strategy may involve re-introducing splicing factors by viral means to restore appropriate alternative splicing as many cardiomyopathies are characterised by a downregulation of splicing factors at the protein level.Although therapeutic strategies are underway, further insights into the molecular mechanisms of cardiac alternative splicing are necessary to eventually enable us to manipulate alternative splicing in the benefit of the patient."}
+{"text": "These data are related to our paper \u201cGAPDH-targeted therapy \u2013 a new approach for secondary damage after traumatic brain injury on rats\u201d , in which we explore the role of exogenous GAPDH in traumatic brain injury-induced neuron death, and the therapeutic application of small molecules that bind to the enzyme. The current article demonstrates the induction of apoptosis by exogenous GAPDH and the effectiveness of the hydrocortisone derivative for suppressing the pathogenic action of the enzyme. Specifications TableValue of the data\u2022The current paper illustrate the ability of exogenous GAPDH to cause apoptosis in SH-SY5Y cells.\u2022Apoptotic processes may be induced by GAPDH in different forms, including aggregates.\u2022The GAPDH binder hydrocortisone 21-hemisuccinate (RX624) has no effect on apoptosis-inducing GAPDH properties.1The data presented in this article demonstrate that different fractions of pre-denatured GAPDH may cause apoptotic processes in neuroblastoma cells. We used the GAPDH binder RX624 to preserve cells from exogenous GAPDH 2The procedure of the preliminary GAPDH denaturation and its separation into fractions as well as SH-SY5Y cell culturing conditions are described in detail in a related article"}
+{"text": "Current technologies for understanding the transcriptional reprogramming in cells include the transcription factor (TF) chromatin immunoprecipitation (ChIP) experiments and the TF knockout experiments. The ChIP experiments show the binding targets of TFs against which the antibody directs while the knockout techniques find the regulatory gene targets of the knocked-out TFs. However, it was shown that these two complementary results contain few common targets. Researchers have used the concept of TF functional redundancy to explain the low overlap between these two techniques. But the detailed molecular mechanisms behind TF functional redundancy remain unknown. Without knowing the possible molecular mechanisms, it is hard for biologists to fully unravel the cause of TF functional redundancy.To mine out the molecular mechanisms, a novel algorithm to extract TF regulatory modules that help explain the observed TF functional redundancy effect was devised and proposed in this research. The method first searched for candidate TF sets from the TF binding data. Then based on these candidate sets the method utilized the modified Steiner Tree construction algorithm to construct the possible TF regulatory modules from protein-protein interaction data and finally filtered out the noise-induced results by using confidence tests. The mined-out regulatory modules were shown to correlate to the concept of functional redundancy and provided testable hypotheses of the molecular mechanisms behind functional redundancy. And the biological significance of the mined-out results was demonstrated in three different biological aspects: ontology enrichment, protein interaction prevalence and expression coherence. About 23.5% of the mined-out TF regulatory modules were literature-verified. Finally, the biological applicability of the proposed method was shown in one detailed example of a verified TF regulatory module for pheromone response and filamentous growth in yeast.In this research, a novel method that mined out the potential TF regulatory modules which elucidate the functional redundancy observed among TFs is proposed. The extracted TF regulatory modules not only correlate the molecular mechanisms to the observed functional redundancy among TFs, but also show biological significance in inferring TF functional binding target genes. The results provide testable hypotheses for biologists to further design subsequent research and experiments. Cells usually respond to environmental and physiological stress by reorganizing their DNA transcription programs, leading to correct spatial and temporal expression of different genes \u20133. To suCurrent genome-wide experimental methods for understanding the behaviors of how TFs control cellular gene expression can be divided into two categories , 9. The While integrating the TF binding data and the TF knockout data can help reveal some novel findings in the transcription regulation mechanisms of TFs, it is somewhat surprising that researchers have found that these two datasets overlap with each other at a very low percentage , 13. ThiResearchers have been trying to find possible cellular reasons for the low overlap percentage of the TF binding data and the TF knockout data. It is shown that TFs that have biological back-up functions shared with some redundant paralogs have lower agreement between the ChIP targets and the expression level changes in knockout experiments . These TTranscription factors are thought to cooperate with one another and regulate target genes coordinately . VariousIn this research, a novel algorithm that helps mine out the potential molecular mechanisms for the functional redundancy observed among TFs and thus elucidate the reasons of the low overlap between ChIP results and the knockout experiments is proposed. The overall method can be divided into three stages: candidate search stage, module mining stage and noise reduction stage. Based on the biological concepts that TFs may cooperate with one another thus contributing to the functional backup and redundancy phenomenon, the proposed three-staged method integrated the cellular protein-protein interaction information and the genome-wide mRNA expression data of the TF-encoding genes to mine out the potential TF regulatory modules from the TF ChIP binding dataset. The mined-out TF regulatory modules were then demonstrated that they are highly correlated to the concept of functional redundancy. Further, these TF regulatory modules provided possible molecular mechanism hypotheses behind the idea of TF functional redundancy. In addition, using these mined-out TF regulatory modules, one could identify the so-called module-inferred functional binding target genes of TFs from the original binding data. Then the biological significance of these module-inferred functional binding target gene sets was tested and the results showed that module-inferred functional binding targets are more biological significant than the original binding data. In summary, the proposed method can extract biologically significant and testable molecular mechanism hypotheses for TF functional redundancy. About 23.5% of the mined-out TF regulatory modules have been experimentally verified in the literature. In the last, a cellular example was described in detail to show some of the proven results of the mined-out pheromone response TF regulatory module.k-means data clustering methods [p-value threshold of 0.05 for confidence tests followed by FDR multiple hypotheses correction.The proposed method to mine out the potential TF regulatory modules that help elucidate the molecular mechanisms behind functional redundancy observed among TFs is summarized in Fig.\u00a0 methods  was appl methods  for extr methods  was applp-value threshold of 0.05 was used to pick the potential TF-gene binding pairs in the TF binding dataset. To get the starting candidate sets, the mRNA expression data collected by Ihmels et al., which consists of 1,011 published expression experiments for different cellular conditions [p-value threshold of 0.05 was adopted in the confidence tests and the method finally extracted 238 final confident TF regulatory modules that may involve in Saccharomyces cerevisiae transcription regulation. The distribution of the number of extracted TF regulatory modules per gene/TF was further checked and compared with the distribution of the number of TF binding sites per gene/TF  than the 61 TFs that were shown to be not involved in any TF modules (mean FRS=0.73) with p-value 0.0003*. From this analysis, it was demonstrated that TFs that involve in the mined-out TF regulatory modules are more functionally redundant than those TFs that do not cooperate in any TF modules. Hence the proposed method extracted TF regulatory modules that help explain the molecular mechanisms behind the concept of functional redundancy observed among transcription factors in yeast.Using the Since the extracted TF regulatory modules are to help biologists elucidate molecular mechanisms behind the functional redundancy observed among TFs, these modules are also supposed to be able to help identify the TF functional binding target genes from the original statistically analyzed TF binding dataset , 26. ThuFor the 203 TFs considered in the ChIP experiments of Harbison et al., 186 TFs underwent TF knockout experiments performed by Hu et al. and thus were used in inferring functional targets. After applying the proposed criteria to the original 54,218 TF-gene binding pairs of these 186 TFs, 16,713 module-inferred functional pairs for 182 out of the 186 TFs were identified  module-inferred functional binding target gene sets were tested to be better enriched in prevalence of protein interaction and only 12 TFs (6.6%) had better protein interaction prevalence enrichment in the original TF binding data  than the functional redundancy scores of the rest 85 TFs that were not categorized into any proposed TF regulatory modules (mean FRS=0.878). As a comparison, our proposed method can successfully correlate the functional redundancy observed among TFs to the molecular mechanisms of TF regulatory modules  between the binding data and the knockout data , via thecis-regulatory modules commonly found in metazo a species.Functional redundancy explains part of the reasons of the low overlap between TF binding datasets and the TF knockout datasets. In this research, the concept of TF regulatory module is utilized to propose a novel module mining method for providing biological interpretation on molecular mechanisms of the functional redundancy observed among TFs. It was also demonstrated that the mined-out TF regulatory modules help retrieve functional binding target genes with better biological significance in the protein prevalence study, the ontology enrichment study and the expression coherence study when applied to the original TF binding dataset. Besides that, the proposed method extracted biological significant TF regulatory modules and provided experimental testable hypotheses in the possible modular behavior of transcription regulation in yeast. It is believed that this finding may suggest future research on the modular behavior of the transcription regulation in yeast and will help biologists to further study and understand functions of the Saccharomyces cerevisiae was downloaded from the work of Harbison et al. [p-value of 0.05 as a statistical threshold was adopted for the data. The promoter definition and binding target genes followed the ones used in the study of Harbison et al.The genome-wide in vivo cellular TF binding target gene dataset of 203 TFs in baking yeast n et al.  and usedIn this research, a new method to identify TF regulatory modules that reveal the molecular mechanisms for the functional redundancy observed among TFs is proposed. The overall algorithm can be divided into three different stages See Fig.\u00a0: candidak-means algorithm [k-means is a well-known data mining algorithm that helps learn the group clustering in datasets. And the k-means clustering method was applied on the binding TFs of a given gene identified by ChIP experiments to find out possible candidate TF sets. Since the mRNA expression data are of high dimension, special design and pre-processing should be adopted to have k-means work in the space formed by the expression dataset. To solve the problem, first the statistical approach PCA  [k-means algorithm in this study. The value of k was enumerated from two to the number of binding TFs of a target gene evidenced by the binding dataset. The above steps were repeated for the corresponding binding TF sets of each gene considered in the binding dataset to get all possible candidate TF sets. After this stage, those co-expressed candidate TF sets that may function in a modular manner in regulating specific genes were found.The first stage in the proposed method is to search and select candidate TF sets that may be involved in the same modules. To mine out possible candidate TF sets that may co-regulate a specific target gene, the lgorithm  was usedlgorithm . In thisnalysis)  was usedTo mine out the possible molecular mechanisms behind the candidate TF sets, next a protein interaction network based on the data obtained from the STRING database  was builFinding the minimal cost Steiner Tree of a given network has been proven to be an NP-complete problem , which mp-value threshold of 0.05 in this noise reduction stage.Since the integration of data from high-throughput technologies or literature mining is prone to be biased by the intrinsic noises inherited from the experiments, data analysis pipelines and data mining processes, the noised-induced random results in the extracted potential TF regulatory modules were filtered out in the final step of the proposed algorithm. To reduce the effect of noises, it was required that a confident TF regulatory module should have a higher average value of literature confidence for the interactions in this module than the average value of literature confidence for all protein-protein interactions in the whole network. This was tested statistically by using the Mann-Whitney U test . MultiplAdditional file 1 The mined-out TF regulatory modules. The TF regulatory modules mined out by the proposed module mining algorithm with their corresponding p-values.Additional file 2 The module inferred functional binding targets. In this file, the module-inferred functional TF binding target genes for the 182 TFs considered in this research are listed.Additional file 3 Ontology enrichment test results. The ontology enrichment tests performed for the module-inferred functional binding targets and the original TF binding dataset in three different ontology categories: biological process, molecular function and cellular component.Additional file 4 Protein interaction prevalence test results. The results of protein interaction prevalence enrichment tests for the module-inferred functional targets and the original TF binding data.Additional file 5 Expression coherence test summary. In this file, the results of the expression coherence tests for the module-inferred functional targets and the original TF binding dataset in 40 different expression conditions are summarized.Additional file 6 Detailed expression coherence test results for the 40 different conditions. In this file, the details of the test results of the expression coherence tests for the module-inferred functional targets and the original TF binding dataset in 40 different expression conditions are archived.Additional file 7 Literature evidence of the mined-out TF regulatory modules."}
+{"text": "Tertiary lymphoid structures (TLS), also known as tertiary or ectopic lymphoid organs, develop in chronically inflamed tissues via the process termed lymphoid neogenesis . This prColbeck et al. provide a comprehensive overview of TLS development, prognostic relevance and a variety of functional effects in cancer in their review article Tertiary Lymphoid Structures in Cancer: Drivers of Antitumor Immunity, immunosuppression, or Bystander Sentinels in Disease? The authors also discuss potential novel therapeutic strategies to manipulate TLS development including targeting the TNFR pathway. In a similar vein, the review from Teillaud and Dieu-Nosjean \u201cTertiary Lymphoid Structures: an Anti-tumor School for Adaptive Immune Cells and an Antibody Factory to Fight Cancer?\u201d describes in detail the latest data on the role of TLS in generating antigen-specific humoral and cellular immunity in various tumors. Here the therapeutic potential of TLS in the context of various immunotherapies is discussed.Solinas et al.Immune Checkpoint Molecules on Tumor-Infiltrating Lymphocytes and Their Association with Tertiary Lymphoid Structures in Human Breast Cancer explores the phenotype of breast cancer infiltrating T cells and reveals a positive correlation between PD-1+ T cells in tumor-associated TLS and patient survival. The results of gene expression profiling in this study show that increased checkpoint molecule expression is correlated with the extent of T cell infiltration and TLS development and could help guide patient selection for immunotherapy.In breast cancer, immune checkpoint inhibition has not met the same clinical success as in melanoma and lung cancer patients . The oriA Unique Cellular and Molecular Microenvironment is Present in Tertiary Lymphoid Organs of Patients With Spontaneous Prostate Cancer Regression.\u201d Their results demonstrate that TLS possess a unique composition in regressing prostate tumors. The authors also provide new insights into possible novel immunotherapeutic strategies for prostate cancer by targeting COX2 and T regulatory cells.In contrast to findings in other solid tumor types, B cell- and TLS-associated molecules have been correlated to tumor progression in prostate cancer . Here weZhu et al. entitled Tumor-Associated Tertiary Lymphoid structures: Gene-Expression Profiling and their Bioengineering deals with the possible technological solutions to aid lymphoid neogenesis in cancer using scaffold materials in combination with chemokine queues or relevant cellular components, such as dendritic cells. The authors also review the potential to use gene expression signatures that identify tumors with extensive lymphoid neogenesis as a patient stratification approach for immunotherapy.The perspective by Alsughayyir et al. discuss the differences in regulatory circuits in secondary lymphoid organs and TLS, especially regarding the germinal center reaction, that might explain the contribution of TLS to autoimmune pathologies in their review article Spoiling for a Fight: B Lymphocytes As initiator and effector Populations within Tertiary Lymphoid Organs in Autoimmunity and Transplantation. The authors also provide a detailed overview of the mechanisms of TLS development in autoimmune conditions and transplantation.While TLS induction, and consequent lymphocyte activation, would appear to be favorable in cancer, the inhibition of lymphoid neogenesis might represent a means to limit autoimmunity and transplant rejection. Use of Toll-like Receptor Agonists to Induce Ectopic Lymphoid Structures in Myasthenia Gravis Mouse Models describes the effects of various inflammatory stimuli on the development of TLS and germinal centers in the murine thymus, a characteristic feature of myasthenia gravis in humans. The authors highlight the complexity of Toll-like receptor signaling in lymphoid neogenesis in different peripheral organs and indicate toward potential differences between humans and mice.The original work form the group of Le Panse in Paris addresses a particularly relevant topic\u2014the development of adequate experimental models for studying TLS function in autoimmunity. The original study In summary, our research topic has brought together a collection of reviews and original articles providing the latest insights and opinions in the field of lymphoid neogenesis. We hope all readers will enjoy learning more about TLS and their potential therapeutic relevance in cancer and immune pathologies.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "A recently reported steep increase in the incidence of invasive pneumococcal disease (IPD) in adults in the North East of England was primarily associated with pneumococcal sero-types found in the 23-valent pneumococcal polysaccharide vaccine (PPSV23). This region also has one of the highest rates of alcohol-related premature mortality and morbidity in the UK. Given that alcohol dependence is long acknowledged as one of the strongest risk factors for IPD mortality, we feel there is an increasingly compelling case to look again at the divergence of UK vaccine guidance from that of the World Health Organisation and the Centre for Disease Control in the USA, in the non-inclusion of alcoholism as an indicator condition that would potentially benefit from receiving PPSV23 vaccine. Such a re-think would represent a responsible evaluation of vaccination guidance in the face of newly emerging epidemiological findings and would have the potential to save lives in a very marginalised and vulnerable section of the population. We propose therefore that alcohol dependency , should be re-considered an indicator condition for receiving pneumococcal vaccine in North East England, where mortality from pneumococcal disease has been rising and which already has an excessive burden of alcohol-related mortality. Alcohol use disorder (AUD) is the most important risk factor in adults of working age <65) for invasive pneumococcal disease (IPD), a serious and often life-threatening infection . Previou for invaIn order to reduce the significant public health burden associated with the more severe clinical manifestations of pneumococcal infection, there are two types of vaccine in current use :\u00ae): recommended for infants from two months of age as part of the routine childhood immunisation schedule and pneumococcal polysaccharide vaccine (PPSV23 or Pneumovax23\u00ae), recommended as a single dose for adults over 65 years and \u2018at-risk groups\u2019 aged two years or over.Pneumococcal conjugate vaccine  makes a persuasive case to increase efforts to ensure that all high-risk groups are targeted with this effective vaccine. Given the additional links between alcohol misuse and the more lethal IPD serotypes ,11, we cAlthough the inconclusive nature of some of the evidence around PPSV23\u2019s protective efficacy in those with alcoholism or AUD means that there are probably insufficient grounds at present for a UK-wide revision of vaccine guidance, some form of experimental trial with matching English region(s) of equivalent alcohol impact as controls (such as the North West), would constitute an informative and highly policy relevant intervention using a quasi-experimental design, the benefits of which have recently been summarised by Wilder-Smith et al. . Such a"}
+{"text": "Argon plasma treatment was used to modify the surface of atelocollagen films using a plasmochemical reactor. To evaluate the effects of the treatment, the untreated and treated samples were characterized by Attenuated Total Reflectance Fourier Transform Infrared Spectroscopy (ATR-FTIR), Scanning Electron Microscopy (SEM) imaging, and X-ray Photoelectron Spectroscopy (XPS) techniques. Cell growth was carried out by culturing human immortalized keratinocyte (HaCaT) cells and proliferation was measured via MTT assay. It was observed that argon plasma treatment significantly enhanced the extent of cell proliferation, which was ascribed to the favourable role of plasma treatment in inducing surface oxygen-containing entities together with increasing surface roughness. This can be considered as a potentially promising approach for tissue regeneration purposes. Its abundance is especially concentrated in connective tissues such as tendons, ligaments, cartilage as well as skin. Moreover, it is connected with important biological functions such as tissue formation and cell attachment . A volume of 10 \u03bcL of 12 mM MTT was taken for cell incubation performed at 37 \u00b0C for 4 hours in the darkness. The media were then decanted and washed with phosphate-buffered saline solution (PBS). The produced formazan salts were dissolved with dimethylsulphoxide , and the absorbance was measured at 570 nm to estimate the formazan concentration . The staThe effects of argon plasma treatment upon atelocollagen surface films and HaCaT cell response have been studied by means of surface probe techniques together with the biological assay. It is assumed that the primary effect of argon plasma treatment is to provide and deposit energy via plasma species such as electrons, ions and UV-radiation to the substrate surface leading to cross-linking, bond breaking and different kind of intramolecular rearrangements, which in contact with air or other reactive species can drastically alter the surface properties. The spectroscopic techniques show a decrease of the nitrogen content along with the attenuation of the N-H and C-H bands, which can be attributed to the etching phenomenon. It is observed that argon plasma treatment significantly enhances the extent of cell proliferation ascribed to the favourable role of plasma treatment in inducing surface oxygen-containing entities and increasing surface roughness. The keratinocyte HaCaT cell proliferation notably increases confirming the strong dependence of cell adhesion and proliferation on the surface properties and biocompatibility."}
+{"text": "Lab-on-a-chip biological platforms have been intensively developed during the last decade since emerging technologies have offered possibilities to manufacture reliable devices with increased spatial resolution and 3D configurations. These biochips permit testing chemical reactions with nanoliter volumes, enhanced sensitivity in analysis and reduced consumption of reagents. Due to the high peak intensity that allows multiphoton absorption, ultrafast lasers can induce local modifications inside transparent materials with high precision at micro- and nanoscale. Subtractive manufacturing based on laser internal modification followed by wet chemical etching can directly fabricate 3D micro-channels in glass materials. On the other hand, additive laser manufacturing by two-photon polymerization of photoresists can grow 3D polymeric micro- and nanostructures with specific properties for biomedical use. Both transparent materials are ideal candidates for biochips that allow exploring phenomena at cellular levels while their processing with a nanoscale resolution represents an excellent opportunity to get more insights on biological aspects. We will review herein the laser fabrication of transparent microfluidic and optofluidic devices for biochip applications and will address challenges associated with their potential. In particular, integrated micro- and optofluidic systems will be presented with emphasis on the functionality for biological applications. It will be shown that ultrafast laser processing is not only an instrument that can tailor appropriate 3D environments to study living microorganisms and to improve cell detection or sorting but also a tool to fabricate appropriate biomimetic structures for complex cellular analyses. New advances open now the avenue to construct miniaturized organs of desired shapes and configurations with the goal to reproduce life processes and bypass in vivo animal or human testing. With a The integration of polymeric structures inside channels offers a concrete functionality of the whole device in addition to stability. Thus, TPP prototyping becomes a strong method for functionalization and integration of polymeric components with glass microfluidics for the development of lab-on-a-chip devices, which opens new avenues to fabricate novel biochips devices.\u00ae, so that cellular adhesion control in a 3D environment was proposed ..Euglena Periodic free standing sinusoidal polymeric ridges that can be used for cell manipulation were formed by TPP in channels fabricated by FLAE  86]. Th. Th86]. The ultrafast laser processing of both glass and polymer which can create 3D biomimetic environments with resolutions and hierarchy for organisms and cells is at its infancy and has great potential for further development. In addition, integration of optical interrogation components such as microlenses, micro-mirrors as well as optical circuits for performing pump-probe experiments with laser light greatly enhances importance in terms of the technological aspect. It is also of great interest to offer biological platforms fabricated by ultrafast lasers to develop new 3D cell-culture models in order to overcome tissue organization issues arising from conventional analyses using 2D culture systems . MicroflUltrafast laser micro- and nano-technologies such as FLAE, TPP and their hybrid approach have opened up new avenues for research on 3D processing for both transparent inorganic and organic materials. By employing ultrashort pulse widths and extremely high peak intensities, one can implement precise control of the nonlinear interaction region to create complex 3D structures in glass or polymers. For functional biochips, the glass sample offers robustness for easy manipulation and portability, transparency for optical interrogation as well as chemical stability and good biocompatibility. The ultrafast laser induced chemical modification followed by selective etching enables creating 3D microfluidic structures with flexible geometries inside glass. The technique can be extended to the fabrication of microoptics such as micromirrors and microlenses inside a glass substrate. By ultrafast laser processing of photoresists, one can significantly improve the processing resolution with a level of ~100 nm which is beneficial for fabrication of functional microcomponents for biological studies. Thus, TPP has already become a well-known technology for fabricating microdevices with complex designs.The laser micromachining and micro- and nanostructuring are now accessible to the biomedical field owing to new strategies achieving flexible design and fabrication of biochips. The new hybrid ultrafast laser microfabrication method employs both the 3D microprocessing of glass and 3D \u201cship-in-a-bottle\u201d polymer integration inside embedded glass channels. Such a hybrid technique proved to combine the specific advantages of individual methods and compensate the drawbacks. The fabricated glass-polymer hybrid microfluidic systems which cover both the scale-down and scale-up aspects can be used as biochips for cell manipulation in 3D environments. The assembled device could be used for monitoring of live cells in dynamic flow conditions. With the aim of controlling and studying cell behavior and their molecular signaling in the most appropriate environment, one could expect that the structural sizes should be further reduced in microfluidic devices while the sensitivity of analytic procedures should be increased. The sizes of structures can be reduced to the level of single cell dimensions at which cells can be influenced and manipulated inside glass microchannel. Furthermore, due to fabrication of biomimetic micro- and nano-environments, it is highly expected that new miniaturized organs will be developed that can provide similar in vivo conditions."}
+{"text": "The old dream of tumor immunologists is the construction of efficient anti-tumor vaccines to fight cancer. Anti-tumor vaccine strategies are necessarily focused, however, on patients who are already affected by the pathology in which the tumor not only has eluded the host initial immune response but often further creates suppressive mechanisms that keep counteracting the action of the immune system.This Research Topic was intended to focus on several aspects of anti-tumor vaccinology and particularly on ways to increase the potency of anti-tumor vaccines by acting both on facilitating tumor antigen selection and presentation to cells of adaptive immunity and on reducing the effect of suppressive mechanisms on these immune responses. We are convinced, however, that to fight cancer single immune-based approaches cannot stand alone and thus vaccine approaches need to be complemented by other immune approaches.Garcia-Garijo et al., who provide an overview of the existing strategies to identify neoantigens and to evaluate their immunogenicity. Indeed, only a small fraction of all tumor somatic non-synonymous mutations (NSM) identified represent bona fide immunogenic neoantigens, and even fewer mediate tumor rejection. Thus, the impact of neoantigens for vaccine purposes may be overestimated  vaccine with an immune adjuvant have demonstrated great promise to elicit potent anti-tumor responses for cancer treatment. Insights on future directions are described by the authors.The use of embryonic and pluripotent stem cells for the identification of additional suitable antigens to induce an optimal anti-tumor response are described by Dreau et al.. Interestingly, the treatment results in infiltration of cells that can mediate ADCC function of phagocytes and reduction of suppressive regulatory cells, stressing the fact that effective anti-tumor treatment can also include a drastic modification of the tumor microenvironment.Targeting tumor-associated antigens with specific antibodies in association with stimulating cytokines in novel formulations can be beneficial particularly in case of neoplastic diseases characterized by the pronounced expression of these antigens as it is the case of the unique tumor-associated form of MUC1 in pancreatic ductal carcinoma (PDA) described by Kohler et al.. They discuss advantages and limitations of this approach and explain how this old/novel strategy can be adapted in Biotech-standard production of therapeutic antibodies. As all nominal antigens, tumor antigens become immunogenic only if appropriately processed and presented by antigen presenting cells (APC). A novel therapeutic strategy of combining personalized vaccines in combination with standard therapy and anti-PD1 checkpoint inhibitors is proposed by Bassani-Sternberg et al. as a Phase1b study in resected pancreatic adenocarcinoma (PDAC) patients. The vaccine platform is based on autologous dendritic cells (DCs) loaded with mutated neoantigens and tumor-specific antigens identified through their original proteo-genomics antigen discovery pipeline. The addition of nivolumab to boost and maintain the vaccine effect underscores once more the belief that multiple immunological approaches should be used for optimal triggering and maintenance of the anti-tumor immune response.Mimicking tumor antigens by approaches of anti-idiotype responses is revisited by Zeng et al. who focus on a new type of DC, designated CD137 ligand-induced DC (CD137L-DCs), that induce strong cytotoxic T cell responses. They show that superior potency of CD137L-DCs in APC activity compared to other types of DCs is due to their intrinsic increased Akt-driven glycolysis, thus suggesting that Akt-driven glycolysis could be a therapeutic target to manipulate the function of CD137L-DCs for better clinical efficacy.Ameliorating and/or selecting the optimal DC subpopulation to present tumor antigens are discussed also by Accolla et al. reviewed their work on tumor cells genetically modified by transfection with the MHC class II transactivator CIITA. These modified tumor cells can not only process and present antigens to na\u00efve Th cells but they can also prime virgin tumor specific T cells. Their experimental approach has been extended to isolate MHC-II-bound relevant tumor peptides to formulate novel multipeptide vaccines (MHC-I + MHC-II- bound) against human hepatocarcinoma, presently in clinical trialIncreasing tumor antigen availability and T cell priming are crucial parameters for the efficient response to anti-cancer vaccines. Schluck et al. who concentrate on artificial APC methods employing biomaterials, highly promising tools to activate T cells and evoke robust in vitro and in vivo immune responses. In this perspective, they presented an overview of molecular cues that could be used to selectively expand T cell subsets that are beneficial for strong anti-tumor immune responses.Alternative procedures of tumor antigen presentation and T cell priming are also discussed by in vivo have been also analyzed by Loeffler et al. who studied the immune response of patients undergoing radio-frequency ablation (RFA) of liver metastasis from colorectal cancers. RFA induced and/or boosted T cell responses specific for individual tumor antigens were frequently detectable, but not sufficient for the rejection of established tumors, indicating once more that combination therapies, such as immune checkpoint inhibitors should be considered.Ways to facilitate triggering of anti-tumor immune response Marchini et al. summarized in their review. They also provide information about OV-mediated immune conversion of the tumor microenvironment. As a case study they focus on the rodent protoparvovirus H-1PV and its dual role as an oncolytic and immunomodulatory agent.Oncolytic virus (OV) therapy is also becoming an interesting strategy not only to treat but also to trigger and/or increase the anti-tumor immune response for vaccination purposes as Abdelaziz et al. stress this point and present intriguing new data on unexpected block of MHC-I-restricted tumor antigen presentation without reduction of cell surface expression of MHC-I molecule by using a Human Cytomegalovirus (HCMV)-based vector including a HPV E6/E7 fusion protein in a murine glioblastoma model. The molecular mechanism of lack of MHC-I presentation is not fully clear but it seems to correlate with defects of proteasome function generated by the HCMV vector. Of course this should be taken in serious considerations when approaches of tumor peptide vaccination using HCMV as host for gene sequences of tumor peptides are used.Construction of therapeutic vaccines against tumors must take into account reduced or loss of MHC-I expression in tumor cells as an important mechanism of immune escape. In conclusion, we are confident that this Research Topic will help to better delineate the past and present problems related to the efficacy of anti-tumor vaccines and, based on this background, develop new ideas and strategies to improve their construction and efficacy for tomorrow.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.CM is employed by ISA Pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "First Person is a series of interviews with the first authors of a selection of papers published in Biology Open, helping early-career researchers promote themselves alongside their papers. Ling Wang is first author on \u2018 Ling WangWhat is your scientific background and the general focus of your lab?Absorbed by the self-renewal and differentiation ability of stem cells, I dived into the research on pluripotent stem cell (PSC) growth regulation and somatic cell reprogramming into induced pluripotent stem cells (iPSCs) in Dr Young Tang's lab at the University of Connecticut. I obtained my PhD degree in animal reproduction this year and am doing a short-term postdoc in the same lab. With my colleagues in the Tang lab, we induce mouse iPSCs to investigate how na\u00efve stage pluripotency (germline chimerism) is established. We also work on improving human iPSC induction in different ways. Our robust human iPSC induction systems [>100-fold increase in efficiency compared with the Yamanaka  cocktail] lead us to reveal the key genes and signaling pathways for the enhanced reprogramming. We are now eager to reprogram the somatic cells of large farm animals into iPSCs, which will allow the study of livestock pluripotency regulation and facilitate the breeding of genetically elite agricultural animals.How would you explain the main findings of your paper to non-scientific family and friends?The stem cells isolated in embryos within a few days after the sperm-egg fertilization can give rise to many mature cell types that make up our body. For an adult, our body cells, such as skin cells, can be induced into these very early embryonic stem cells. The induced cells are called iPSCs. The iPSCs can regenerate any of our tissues or organs with minimum immune suppression because our own cells are used. This technology enables cell-replacement therapies to replace a patient's diseased tissue. But the low induction efficiency of human iPSCs hampers its wide application. We are able to amplify the efficiency by >100-fold with proper combinations of genes and cell culture medium components. This robust system allows for the production of large amounts of patient-specific iPSCs in a short time. We also investigate the genes and signaling pathways core to enhanced reprogramming.What are the potential implications of these results for your field of research?\u201cIn addition to speeding up regenerative medicine therapies, this system may enable the fast generation of multiple isogenic iPSC lines for patients\u2026\u201dThis system is of importance for the generation of large amounts of iPSCs, especially for patients whose cells might be refractory to reprogramming. In addition to speeding up regenerative medicine therapies, this system may enable the fast generation of multiple isogenic iPSC lines for patients, to account for variations among iPSC lines and genetic background differences among individuals, allowing for more accurate studies on monogenic and polygenic diseases. This reprogramming system may also facilitate precision medicine, which aims for the right dose of the right medications based on genomic information, environment and the lifestyles of the patients.What has surprised you the most while conducting your research?Given their roles in pluripotency regulation, it is reasonable that NANOG and LIN28 synergize in the formation of large numbers of initial colonies with TRA-1-60 expression. But less than 20% of these colonies have homogeneous expression of TRA-1-60, the pluripotent surface maker. The majority (>80%) of these colonies exhibit irregular shapes and have sporadic expression of TRA-1-60. What are the identities of these heterogeneously TRA-1-60-expressing colonies? By inhibiting the canonical WNT signalling at late reprogramming stage, most of these colonies turn into a more mature human embryonic stem cell morphology and have homogeneous and more intense TRA-1-60 expression. The inhibition of canonical WNT also suppressed meso- and endodermal gene activation during reprogramming. These observations suggest that most of NANOG- and LIN28-induced initial colonies are concurrently undergoing WNT-mediated differentiation as they develop!We further found that NANOG and LIN28-stimulated canonical WNT signaling has a biphasic role, since iPSC colony number greatly reduces if the WNT is inhibited from the beginning of reprogramming.What, in your opinion, are some of the greatest achievements in your field and how has this influenced your research?Somatic cell nuclear transfer (SCNT) by Sir John Gurdon in frogs, the first cloned animals, demonstrates that somatic cells carry the nuclei with complete genetic materials to develop into a normal animal. The success in Dolly the sheep confirms this principle in mammals. Dr Shinya Yamanaka's research into human iPSCs reveals the four genes sufficient to turn the somatic cells back to embryonic pluripotent state.On the basis of these ground-breaking achievements, and other groups' reported factors to promote reprogramming, we examined different combinations of genes and small chemicals and found two combinations (Yamanaka cocktail+NANOG+LIN28+iDOT1L+IWR1 and Yamanaka cocktail+NANOG+ +LIN41+iDOT1L+IWR1) that could induce hundreds of iPSC colonies in a short time.What changes do you think could improve the professional lives of early-career scientists?Active communication with peer researchers and professors. By attending academic conferences, we can present our findings as well as learn about the latest advancement in the research field. This will help us stay focused on the big picture and ultimate goals, not getting buried in the details. It will also guide us in asking the most interesting questions.What's next for you?I am excited to employ our optimized iPSC derivation system for more mechanistic studies on robust human cell reprogramming. It is also exciting to bring this system to translational research. I look forward to all the possible employment opportunities (hopefully) in related research fields.Who impacted you most in your doctoral training?I benefitted a lot from my doctoral advisory committee: my major advisor, Dr Young Tang, and Dr Xiuchun (Cindy) Tian, Dr Kristen Govoni, Dr Theodore Rasmussen and Dr Sarah Reed. They have always been encouraging and patiently provide advice on my project designs. Furthermore, they guide me towards insights from my research findings and help to push my projects further."}
+{"text": "The monitoring of DNA and RNA biomarkers freely circulating in the blood constitutes the basis of innovative cancer detection methods based on liquid biopsy. Such methods are expected to provide new opportunities for a better understanding of cancer disease at the molecular level, thus contributing to improved patient outcomes. Advanced biosensors can advance possibilities for cancer-related nucleic acid biomarkers detection. In this context, peptide nucleic acids (PNAs) play an important role in the fabrication of highly sensitive biosensors. This review provides an overview of recently described PNA-based biosensors for cancer biomarker detection. One of the most striking features of the described detection approaches is represented by the possibility to detect target nucleic acids at the ultra-low concentration with the capability to identify single-base mutations. Early cancer diagnosis and the frequent monitoring of cancer patients are key to achieving the target of reducing the mortality and improving the efficacy of pharmaceutical treatment ,2. DiffeDifferent systems potentially acting as cancer biomarkers are present in the blood, including circulating tumour cells (CTCs) , membranThe detection of cancer biomarkers circulating in the blood is a challenging task mostly due to the low concentration of biomarkers in early-stage patients. Thereby, the demand for new analytical methods for the sensitive and robust detection of molecular signatures of a tumour in the blood of patients has significantly increased over the last few years .In this context, biosensors offer attractive alternatives to conventional platforms, thanks to presently available advanced possibilities for the sensitive target biosensing . BiosensBiosensors are analytical devices that incorporate a biological sensing element and are based on the conversion of molecular recognition events into a measurable signal generated by a transducer. Recent technological progress in microfluidics  and nanoNucleic acids are essential targets in cancer diagnostics and the platform used to identify them should be sensitive (limit of detection (LOD) down to picomolar\u2013femtomolar concentrations) and selective enough to ensure accurate discrimination among biomolecules dispersed in biological fluids such as blood, urine and saliva . DNA susIn this scenario, significant benefits come from the use of nucleic acid analogues in nucleic acid biosensing . DNA synHere, we report an overview of recent advances in PNA-based biosensors with a specific emphasis on cancer diagnosis. Various sensing strategies are reviewed  accordinN-(2-aminoethyl)glycine motifs linked via peptide bonds 3+ and [Fe(CN)6]3\u2212 was applied to read out the presence of target single-stranded ctDNA. More recently, an evolution of the assay has been proposed [\u22121 concentration in a background of wild-type alleles at concentration 100 pg \u03bcL\u22121. The detection of mutation in ctDNA obtained from the plasma of lung cancer and melanoma patients has been demonstrated using the above-described electrochemical biosensing approach.A remarkable application of electrochemical biosensing to cancer diagnosis has been obtained by developing a voltammetric clamp assay for the screening of KRAS mutations in ctDNA from serum samples of cancer patients  43]. A . A 43]. proposed . In thisThe striking features of PNA help in better detection of SNPs linked to several types of cancer. In particular, recent applications of PNA biosensing have considered SNPs within KRAS or EGFR genes. Itogana et al.  recentlyPNA clamping is also useful to detect EGFR mutated gene in patients with non-small cell lung cancer . In partThe development of a sensitive, rapid, and robust bioanalytical platform for the detection of cancer-related DNA or RNA sequences is required to improve current possibilities for early cancer detection and patient follow-up. In this review, we summarised possibilities offered by PNA when used in combination with biosensing platforms for the sensitive discovery of nucleic acid biomarkers. Our purpose is to demonstrate how PNA probes used in biosensing can push down the selectivity and sensitivity of nucleic acid assays. The direct discrimination between closely related nucleic acid sequences can be achieved using PNA probes also in the presence of large non-target molecules, thus making available applications in cancer diagnostics.In this review, we reported an overview of recent advances in the development of PNA-based biosensors with a particular emphasis on applications dealing with cancer diagnostics. The role of PNAs, when used in this specific domain, is discussed. Different established optical and electrochemical biosensors for the detection of clinically relevant DNAs and RNAs greatly benefit from PNA\u2019s enhanced capability to detect sequences bringing point mutations. Electrochemical biosensors using PNA probes have been recently used to identify microRNA sequences. Results obtained propose such biosensors as promising platforms for the development of POC testing.The combination of PNA probes and biosensors using nanostructured materials has been shown to improve the detection performances significantly. Most the advanced optical and electrochemical approaches here discussed take advantage of the neutral charge of PNA and exploit nanostructured materials to enhance the detected signal. Different biosensing platforms using PNA reaching fM sensitivity are already available and can identify both miRs as well as mutations in ctDNAs. The direct use of some of the described platforms on serum or plasma human sample has also been demonstrated.Future perspectives in the field are linked to the ability to provide the final validation of some of the already described platforms in the clinical setting to demonstrate their performance under the most critical conditions."}
+{"text": "The prevalence of diabetes in the hospital is increasing and approximately 18-20% of hospital beds are occupied by someone with diabetes .Attempts to attain target glucose levels with current insulin therapy (multiple daily subcutaneous insulin injections) titrated according to capillary blood glucose measurements can increase the risk of hypoglycemia and increase workload for healthcare professionals . Older aThe significant advances in diabetes technologies, including subcutaneous insulin pumps and continuous glucose monitoring (CGM) systems, over the past 10 years have led to the development of automated insulin delivery (closed-loop) systems. The closed-loop approach involves communication of real-time glucose data provided by a CGM device, to a control algorithm (hosted on a smartphone or the insulin pump), which then instructs subcutaneous insulin delivery via the insulin pump, automatically modifying the insulin infusion rate every 5-10 minutes based on the sensor glucose levels . One of Hybrid closed-loop systems require the user to manually initiate mealtime insulin boluses, while fully closed-loop systems automatically dose insulin without information about meals with the advantage of reduced user interaction.Hybrid closed-loop systems have been approved by regulatory authorities for people with type 1 diabetes and are increasingly being used. So far, no closed-loop system has been approved for the management of inpatient hyperglycaemia but we believe that such systems are feasible and may provide substantial benefits as described in this editorial.The feasibility of fully automated closed-loop insulin delivery without meal announcement in the inpatient setting has been demonstrated to be safe and effective in achieving near-normal glucose control .A randomised controlled trial involving 136 adults on the general wards with hyperglycaemia compared fully closed-loop insulin delivery with standard insulin therapy for a period of up to 15 days or until discharge [Determining those most likely to benefit from closed-loop insulin delivery is critical to support widespread adoption of this technology, and demonstrating efficacy and safety of closed-loop in the more challenging inpatient sub-populations is important for generalisability.Glucose management in people with diabetes receiving hemodialysis can be demanding due to high day to day variability in glucose levels and insulin requirements. A subgroup analysis of the study by Bally et al  examinedAdministration of nutrition support  in the inpatient setting is associated with hyperglycaemia in up to 50% of patients. Management of feed-induced hyperglycemia with standard insulin therapy can be complex due to unanticipated interruptions to nutrition support and frequent changes to feeding regimens demanding considerable input by healthcare professionals. In a randomised controlled study involving 43 inpatients receiving nutritional support, fully automated closed-loop insulin delivery using faster-acting insulin aspart was associated with superior glucose control compared to standard insulin therapy . The cloThe closed-loop approach is an attractive option to positively change the management of inpatient diabetes particularly in the most challenging inpatient populations; larger studies are required to determine if the observed improved glucose control with closed-loop insulin delivery can translate into improved clinical outcomes for patients, and reduce staff work burden and the healthcare costs associated with inpatient diabetes."}
+{"text": "For years, neurophysiological studies of the cerebral cortical mechanisms of voluntary motor control were limited to single-electrode recordings of the activity of one or a few neurons at a time. This approach was supported by the widely accepted belief that single neurons were the fundamental computational units of the brain (the \u201cneuron doctrine\u201d). Experiments were guided by motor-control models that proposed that the motor system attempted to plan and control specific parameters of a desired action, such as the direction, speed or causal forces of a reaching movement in specific coordinate frameworks, and that assumed that the controlled parameters would be expressed in the task-related activity of single neurons. The advent of chronically implanted multi-electrode arrays about 20 years ago permitted the simultaneous recording of the activity of many neurons. This greatly enhanced the ability to study neural control mechanisms at the population level. It has also shifted the focus of the analysis of neural activity from quantifying single-neuron correlates with different movement parameters to probing the structure of multi-neuron activity patterns to identify the emergent computational properties of cortical neural circuits. In particular, recent advances in \u201cdimension reduction\u201d algorithms have attempted to identify specific covariance patterns in multi-neuron activity which are presumed to reflect the underlying computational processes by which neural circuits convert the intention to perform a particular movement into the required causal descending motor commands. These analyses have led to many new perspectives and insights on how cortical motor circuits covertly plan and prepare to initiate a movement without causing muscle contractions, transition from preparation to overt execution of the desired movement, generate muscle-centered motor output commands, and learn new motor skills. Progress is also being made to import optical-imaging and optogenetic toolboxes from rodents to non-human primates to overcome some technical limitations of multi-electrode recording technology. The focus of this review, however, is on how recent advances in quantitative tools to analyze population-level activity patterns are providing new insights into the cortical mechanisms of motor control and motor learning.For many years, neural recording studies of the cerebral cortical control of voluntary movements in awake, behaving animals were dominated by attempts to correlate the task-related activity of single neurons to the externally measurable properties of the executed movements. The development of simultaneous multi-neuron recording technologies and much more powerful computers over the past two decades has dramatically enhanced our ability to study cortical motor-control mechanisms. This has also led to translational applications such as brain\u2013machine interfaces (BMIs) that allow non-human primates (NHPs)14, the field was dominated by \u201crepresentational\u201d models of brain function, which assumed that the activity of single neurons explicitly expressed specific kinds of information, such as particular properties of a sensory input or motor output. Behavioral and theoretical studies suggested that the conversion of an intention to move into muscle-centered motor commands could be described formally as a sequence of sensorimotor transformations between combinations of sensory and motor-related signals in definable coordinate frameworks, culminating in the generation of a descending motor command21. Computational models of voluntary motor control assumed that the motor system explicitly planned and controlled the specific features of reaching movements over which we appear able to impose volitional control, such as their direction, endpoint, spatial trajectory, velocity and output forces34. Representational models of brain function predicted that those controlled properties of movements would be explicitly encoded in the time-varying discharge patterns of single neurons generated while the motor system performed the neural equivalent of solving sets of equations that defined the inverse sensorimotor transformations between desired movement properties and causal muscle activity34. Neural correlates of the controlled parameters and coordinate transformations therefore would be directly observable in the task-related discharge of single neurons and could be identified by analyzing their activity in different motor tasks. Each neuron\u2019s activity should show a consistent correlation to a particular parameter at all times before and during a movement, and the cortical control of movement could be understood by piecing together the contributions made by each neuron.When single-electrode neurophysiological studies of cortical motor control began in the 1960s34.This conceptual foundation motivated many studies that used a wide variety of tasks to try to identify the motor output parameters and coordinate frameworks expressed by neurons in different cortical motor areas, including the primary motor cortex (M1), dorsal premotor cortex (PMd), ventral premotor cortex (PMv), supplemental motor area (SMA), parietal cortex area 5 (PA5) and adjacent medial intraparietal cortex (MIP). These studies revealed important differences in single-neuron response properties and in the strength and timing of correlations with different motor output parameters both within and across cortical areas that presumably reflected the different roles played by each neural population in motor control38. When applied in their most simplistic literal sense\u2014single neurons that unambiguously encode a specific controlled parameter in a specific definable coordinate framework\u2014representational models do not account satisfactorily for the complexity of neural activity during the planning and execution of movements.These findings were consistent with the representational perspective on the cortical mechanisms of voluntary motor control. Ultimately, however, they have not provided a consensus as to the identity of the controlled parameter(s) or coordinate transformations that are encoded in any cortical motor area. Reasons for this failure include non-stationary correlations between single-neuron activity and motor output parameters at different times before and during movement, overlapping ranges of properties among neurons in different cortical areas, and partial correlations of single-neuron activity with multiple motor output parameters, in part because different movement parameters are coupled through the laws of motion and limb biomechanics42. Here, the term \u201cemergent properties\u201d refers to the computational features of a neural circuit that arise from the interactions among the neurons within the circuit. The input\u2013output transformations that generate a movement emerge as collective properties of the interactions among neurons within the circuits.Multi-electrode recordings of the simultaneous activity of many neurons have provided critical neural data to test hypotheses that regard the cortical motor system as dynamical neural circuits whose emergent properties accomplish the computations underlying the planning and execution of voluntary movementsn recorded neurons comprises ann-dimensional \u201cstate space\u201d in which each neuron\u2019s activity forms one axis (dimension) of that space. The instantaneous activity of the entire recorded population occupies a specific point in that state space at a given moment. The activity generating a given movement traces out a trajectory in thatn-dimensional space as time progresses. Furthermore, the activity of overlapping subsets of neurons contributing to the unfolding neural trajectory is correlated in different ways via shared input signals and via the synaptic interactions among the neurons in the circuit. Trying to understand what the circuit is doing just by quantifying every neuron\u2019s discharge rate at every moment in time is intractable. Instead, a more efficient approach that is now being used is \u201cdimensionality reduction\u201d (DR)48. DR seeks sets of time-varying patterns of response covariation (\u201clatent variables\u201d) which are shared by many neurons in the population as well as the weightings that determine how much each neuron\u2019s activity contributes to each latent variable. This reduces the entiren-dimensional neural activity space into a much more compact and tractable low-dimensional space of latent variables that account for the majority of the total variance of the neural activity and that shape the trajectory of neural population activity through state space. The extracted latent variables capture patterns in the statistical covariance structure of the neural population activity which arise while the cortical neural circuits perform the computations required to generate movements. Rather than trying to identify whether a movement parameter is \u201cencoded\u201d by a single neuron, DR parses the statistical covariance structure of population activity patterns to identify multi-neuron correlates of different computational processes.This perspective suggests that one cannot fully reveal how cortical circuits control movements by determining single-neuron correlates with different movement properties. Instead, one should analyze the activity of neural ensembles to try to parse out the internal computational structure by which the circuit contributes to movement control. One can envisage that the activity of48, and other state-space49 and factor47 models. New methods continue to be developed53. All of these methods try to reduce a cost function associated with the covariance structure of the neural activity46. Critically, however, different methods make different assumptions about the statistical structure of the neural data and seek specific features in that structure while ignoring features that might be better captured by other methods46. Thus, the choice of DR method can impact the interpretation and conclusions drawn from a neural data set. Furthermore, some DR methods, such as PCA, are performed on multi-trial-averaged activity and so can be used to analyze data collected during sequential recording sessions using conventional single electrodes, whereas others are performed on multi-neuron activity recorded during single trials to probe circuit function53. The key innovation of all DR methods is that they extract task-related patterns of multi-neuron co-modulation of activity\u2014the latent variables\u2014that are not observable when each neuron\u2019s activity is processed separately.DR techniques are diverse and include principal component analysis (PCA), independent component analysis, factor analysis (FA), hidden Markov models, Gaussian process factor analysis, linear discriminant analysis and \u201cdemixed\u201d PCA (dPCA)58. This preparatory activity has been extensively studied in instructed-delay tasks in which subjects are first given an instructional cue that provides information about the intended movement, such as the spatial location of a reach target, and later receive a \u201cGO\u201d signal to make the movement. Many neurons in PMd and M1 show changes in activity during the delay period which vary systematically with the information provided by the cue, such as broad directionally tuned activity as a function of the intended direction, amplitude and speed of the reaching movement62. Representational models presume that those preparatory neural events implement the sensorimotor transformations that calculate the desired properties of the movement and that the observed single-neuron activity expresses the planned properties of the intended movement62.DR analyses have yielded a number of novel perspectives on long-standing questions about the cortical control of reaching movements. For instance, classic models of the reaction-time process assume that the onset of a voluntary movement is preceded by essential neural events that prepare the motor system to generate a desired movement before it can emit the motor commands to execute it44. They showed that the preparatory activity of the recorded population occupied a local region within the total possible neural-activity state space, dwelled within that local volume for the duration of the delay period, and then transitioned into movement-execution regions of state space after the GO signal appeared45. The instantaneous location of the population activity within the preparatory state-space volume when the GO signal appeared was significantly correlated with the reaction time in each trial64. The preparatory states prior to different reaching movements occupied different regions of state space and the subsequent movement execution-related activity for each movement followed a different trajectory through state space after exiting the preparatory state45.Initial DR studies suggested a different way to view those neural responses65. Those state-space rotations could be simulated by a simple linear dynamical model, suggesting that neural circuits in caudal PMd possessed dynamical properties during movement execution. This is consistent with theoretical models and behavioral evidence that the motor system displays computational properties of a dynamical system70. A critical feature of a dynamical system is that the change in the system\u2019s state at any given moment is determined by its current instantaneous state. This led to the hypothesis that the cortical motor system generates a desired movement by first establishing the corresponding initial preparatory state. Once released from that preparatory state, circuits in caudal PMd contribute to the generation of the motor command by evolving along a neural trajectory in state space pre-determined by the initial preparatory state and driven by its own internal dynamics71. This suggests a biologically plausible mechanism by which the motor cortical circuits can implement computations that accomplish the equivalent of a coordinate transformation between desired movement properties and causal muscle activity38.Strikingly, a subset of the latent variables extracted from neural activity in the caudal part of PMd during movement execution exhibited strongly rotating trajectories through certain dimensions of state space whose amplitude and phase varied systematically as a function of the initial preparatory state and physical properties of each movement62, or that correlates with muscle activity and other evolving properties of the movement during execution34 are the local expression of those state-space changes occurring at the population level within the neural circuit72. More recent DR studies have yielded further novel perspectives on the role of preparatory activity and the transition from the preparatory to the movement-execution state.These findings suggested that the widely documented single-neuron response correlates with different motor output parameters such as preparatory activity that predicts the direction, speed and length of an impending movement58. A single-electrode study that compared PMd activity in reaction-time and instructed-delay tasks found evidence consistent with this prediction but could not distinguish distinct preparatory and movement-execution discharge components in the temporally compressed reaction-time activity54. A recent study that addressed this issue with DR tools found evidence that provided stronger support for that prediction of the classic model73. The investigators identified latent variables in the preparatory neural activity during an instructed-delay period which were maximally orthogonal to some latent variables extracted from execution-related activity recorded after the GO signal. They then showed that the neural activity recorded during the reaction-time period of two different non-delayed tasks always passed through an activation state resembling the preparatory state of the instructed-delay task before transitioning to the orthogonal movement-execution region of state space.Classic reaction-time models assume that the initial preparatory neural events are obligatory and must be expressed not only during the delay period of instructed-delay tasks but also early in the reaction-time period of non-delayed tasks75. DR analyses provide one possible explanation75. They revealed that the activity state space occupied during instructed-delay tasks could be divided into regions that can generate muscle activity (\u201coutput-potent\u201d) and regions that cannot (\u201coutput-null\u201d). Preparatory activity in PMd during the instructed-delay period is in the output-null region of state space . It then transitions into the output-potent region after the GO signal to generate muscle activity75. This was recently extended by a study that found that the preparatory and execution-related regions of state space in PMd/M1 are almost completely non-overlapping and nearly maximally orthogonal76. This occurred because the overall pattern of discharge correlations between all pairs of neurons in the population during the delay period was very different from that during movement execution, even though many neurons were active during both trial periods. This suggested that the dynamical computational structure and resulting emergent properties of the neural circuits change dramatically and rapidly during the transition from preparatory to movement-execution regions of state space76. This could explain how the same neurons can discharge during both preparatory and execution phases of a trial and yet not produce muscle activity during preparation.A long-standing question is why the preparatory activity in PMd during the instructed-delay period does not generate overt muscle contractions and movements65 extracted several \u201ccondition-variant\u201d latent variables related to the different reaching movements and fixed \u201ccondition-invariant\u201d latent variables that were associated with all movements independent of their details. The two sets of latent variables were orthogonal to each other in the dPCA state space. The condition-invariant latent variables explained much more of the total activity variance than the condition-variant latent variables. Importantly, the condition-invariant latent variables appeared to capture the process by which the population transitioned from a stable output-null preparatory region of state space to a dynamical output-potent region of state space that generated the time-varying motor output commands76. This suggests that the condition-invariant activity reflected an internal computational process within the neural circuit that drove the network\u2019s dynamics towards a state that can initiate movement without contributing to the planning or control of any feature of the ensuing movement. Similarly, a PCA-based DR analysis of M1 neural activity while monkeys reached to and grasped four different objects in one of eight different target locations 77 found that the largest component of task-related neural variance was condition-invariant. In contrast, condition-specific activity accounted for only about a third as much of the task-related neural variance. Finally, some components of M1 activity might serve primarily to maximize the separation of neural trajectories for different movements that otherwise might approach and become \u201ctangled\u201d, resulting in undesired motor outputs78.An obvious next question is how the dynamical computational structure of the neural circuits changes during the transition from a preparatory state to a movement-execution state. A study using a dPCA analysis of the post-GO activity in a delayed reaching task78 is that a major component of the task-related activity in M1 reflects aspects of the overall structure of the task such as transitions between stable postures and movement, and may have important functional roles in those processes without contributing directly to the specification of the properties of the motor output. This discharge component had been essentially ignored in prior single-neuron analyses. In contrast, the neural modulations that correlated with specific parameters of the task and that had preoccupied the field for many years comprised a significantly smaller proportion of total task-related neural variance.The novel insight provided by these DR analyses72. This does not mean, however, that those single-neuron responses are uninterpretable epiphenomena. These studies confirm rather than refute the descriptions of single-neuron responses revealed in previous studies, while providing new ways of interpreting their nature, origin and role. Furthermore, the fundamental questions that motivated previous single-neuron studies are still valid and largely unanswered. How does the motor system transform diverse signals about the current state of the external world and the peripheral motor system and about the subject\u2019s own internal physiological, motivational, and cognitive state into motor commands to generate the appropriate movement in the current context to fulfill a particular goal38? How do these processes allow for the volitional control of different properties of a movement in different contexts, such as speed versus accuracy, straight versus curved reach trajectories79 or similar reach trajectories of the hand through space performed while holding the arm and hand in different postures80? What roles do different neural populations and different cortical areas play in these processes and how can one account for the known differences in task-related activity in different cortical areas in a given motor task34? We need to understand what population-level computational processes within and across cortical regions could produce those widely documented single-neuron response correlates and what that reveals about how each population and cortical area contributes to voluntary motor control.The study of population-level activity using DR techniques continues to advance to provide intriguing new perspectives on the cortical mechanisms of voluntary motor control. They suggest that the emergent computational properties of dynamical neural circuits may provide a mechanism by which the cortical motor system can implement implicitly such algorithmic formalisms as sensorimotor coordinate transformations that describe how sensory and central signals may be converted into motor output commands. They indicate that the activity of each neuron is only a local window on the underlying low-dimensional computational processes by which entire neural circuits generate movements78. Studies must expand into other cortical motor areas and to other behaviors such as grasping actions of the hand. A recent comparative study of sensory versus motor areas81 has shown the utility of this approach.So far, however, most DR studies of cortical motor control have focussed on circuit dynamics in caudal PMd and M1 and how they might contribute to the generation of muscle activity82. This indicates that the evidence for rotational dynamics found in caudal PMd65 is not a trivial or inevitable result of the task or the DR analyses. They also indicate that the two regions make different contributions to the control of reaching. A deeper analysis of the latent-variable structure of the activity in the two regions could help to clarify the nature of those differences. Similar approaches might provide a deeper understanding about the known differences in the directional tuning of M1, PMd and PA5/MIP activity in tasks with different degrees of dissociation of the direction of gaze versus reach30 and how neural correlates of causal forces are far more prominent in M1 than PA5/MIP during reaching movements with external loads or in isometric-force tasks86.For instance, the latent variables extracted from reach-related activity in SMA do not show rotational dynamics88. Their findings showed several parallels with the reach studies in PMd/M165, suggesting some common features in the low-dimensional computational structure of the neural mechanisms underlying both behaviors. For instance, they identified distinct preparatory and execution-related regions of state space. Neural activity followed different trajectories through latent-variable space during both grasp preparation and execution, depending on whether the monkeys performed precision-pinch or power-grip actions, on the spatial orientation of the grasp object, and on whether they used the hand contralateral or ipsilateral to the neural recording site. The findings identified condition-variant and condition-invariant latent variables in the neural activity; the latter accounted for most of the total activity variance and were more prominent during movement execution than preparation. Importantly, they also found differences in the properties of the latent variables in the two areas. For instance, the neural activation state showed more prominent time-dependent changes during preparation in PMv than in AIP, suggesting that PMv is more implicated than AIP in preparation for the increasingly imminent initiation of movement as the delay period progressed. Neural trajectories in AIP were more closely coupled to the spatial orientation of the grasped object independent of the grasping hand but were more strongly coupled in PMv to the laterality of the hand used. These differences suggest different but overlapping roles for PMv and AIP in the reach-to-grasp task that, both interestingly and reassuringly, are consistent with earlier studies of single-neuron properties in the same two areas33. Similarly, activity in M1 during a reach-to-grasp task contained condition-variant latent variables associated with object locations and identities77. The level of neural modulation in latent variables associated with object location versus identity shifted progressively in time, so that object location correlates were strongest near the onset of reach and object identity modulations were progressively stronger later in the trial as the hand approached the objects and adjusted its configuration to grasp them.Two studies used demixed DR to compare the activity of hand grasp-related neurons in PMv and anterior intraparietal cortex (AIP)95. For instance, one study95 documented how dorsolateral prefrontal neural populations can simultaneously express both the predominant color and direction of colored-dot random-motion stimuli in separate latent variables but selectively use only the color or the motion direction of the stimulus to choose the direction of a saccadic eye movement in a given trial while discounting the other stimulus property. Finally, to enhance the power of new experiments, we also need more robust hypothesis-validation tools to assess to what degree DR techniques reveal truly novel emergent features of neural circuit processing or simply reflect prior known properties of single-neuron responses96.These various findings also indicate that it should be very informative to extend DR from separate analyses of activity in each cortical motor area to the pooled activity patterns recorded simultaneously in multiple areas of the same monkeys in the same task and using the same DR methods. This might provide unique new insights into how movement-related information is transformed across the distributed cortical motor system during the planning and execution of voluntary movements. DR should also be used to parse out how higher-order cognitive and decision-making processes interact with motor preparatory and execution circuits to select the appropriate action to perform in a given behavioral contextn-dimensional neural state space99. This neural manifold contains the intrinsic statistical structure (the latent variables) resulting from all the combinations of multi-neuron activity co-modulation patterns within the network which are sufficient to control the movements used in a given task. Recent DR studies that leveraged BMI technology suggest that the neural manifold also determines which motor skills are easy to learn and which are difficult.DR reveals that the covariance patterns of multi-neuron activity during the performance of typical motor tasks such as reaching in 2D and 3D physical space occupy a limited region\u2014a \u201cneural manifold\u201d\u2014of the full theoretically possible11. A \u201cdecoder\u201d algorithm translates the recorded activity into control signals for the effector. The unique experimental advantage offered by the decoder is that the recorded neurons are the sole source of its input signals, and the mapping between their activity and effector motions is completely defined by the decoder algorithm. Studies have used BMI tasks to document how subjects learn to control an effector through the decoder and how they alter neural activity patterns as they try to adapt to experimental alterations of the decoder mapping between neural activity and effector motions104.In typical BMI tasks, subjects control the movements of an effector such as a cursor on a monitor or a robotic arm by volitional modulation of neural activity recorded by multi-electrode arrays in cortical motor areas97 used a BMI paradigm to assess the contribution of the neural manifold to motor learning. At the start of each session, the investigators recorded neural activity in M1 while monkeys controlled cursor motions with a familiar (\u201cintuitive\u201d) decoder and used FA to identify the latent variables within the intrinsic neural manifold associated with the intuitive decoder. The investigators then altered the decoder mapping in very specific ways so that the required compensatory changes in recorded neural activity either remained within the intrinsic manifold or had to explore regions of state space outside of the manifold. Within-manifold re-mappings maintained the contributions of each neuron to the latent variables but altered the mapping between the latent variables and cursor motions. This allowed the monkeys to use the familiar covariance patterns of the intuitive manifold but they had to associate them with different movements. Outside-manifold re-mappings altered the way that single neurons contributed to the latent variables but preserved the mapping between each latent variable and cursor motions. This required the monkeys to learn new multi-neuronal activity covariance patterns for each movement.One study97. These results suggested that the low-dimensional latent-variable structure within the intrinsic manifold imposes important constraints on motor learning. A subsequent study probed more deeply how the covariance structure of the intrinsic neural manifold associated with the intuitive decoder influenced adaptation to within-manifold perturbations105. The optimal solution would be to create a new multi-neuron covariance pattern for each reach direction, essentially a new set of latent variables. Instead, the monkeys tended to retain the latent-variable structure of the intuitive manifold and learned how to reweight and reassign different intrinsic latent variables to new reach directions when the decoder mapping was changed. This also could not be explained by redundancy in muscle activity patterns106. This provided further evidence that the circuit dynamics responsible for the multi-neuron co-modulation patterns in the intrinsic manifold, not the activity of single neurons, are the basic computational mechanism of motor control106. This is consistent with other findings that monkeys initially attempt to adapt to decoder perturbations by searching through the neural activity patterns associated with their natural motor repertoire107.The monkeys showed considerable adaptation to within-manifold re-mappings over a few hundred trials in a single recording session but very limited ability to adapt to outside-manifold re-mappings within the same time frame102. Importantly, this longer-term learning involved changes in both the independent and coordinated variance across neurons108. This provided further evidence that the latent-variable structure of the intrinsic manifold allows for rapid motor learning when that structure is preserved but that it can be altered over longer time frames.These results showed that the monkeys could not acquire outside-manifold solutions during a single training session. However, monkeys can adapt to an arbitrary decoder re-mapping if allowed to practice for several training sessions110. They can permit simultaneous observation of the activity of most or all of the hundreds or even thousands of recordable neurons along a long narrow cylindrical volume of neural tissue around the probe. The resulting 1\u2013 to 2\u2013order of magnitude increase in the size of neural data sets will present new challenges and opportunities for data analyses110.Neural data collected with chronically implanted multi-electrode arrays have greatly enhanced our ability to study cortical function but this technology still has important technical limitations. Among them, they provide a very sparse sampling of a small fraction of all the neurons within the implanted cortical volume, the neurons are usually unidentified, and the number of isolatable neurons usually declines substantially over several months. Advances in electrode technology may resolve some of these limitations. For instance, newly developed Neuropixel probes carry about 1000 closely spaced recording surfaces on a shaft that is 1 cm long and 70 \u00b5m wide++ reporter molecules expressed by neurons113 and optogenetic methods to modulate the activity of targeted neural populations114. These techniques have developed rapidly in rodent and other small-animal models. 2P Ca++ imaging allows the simultaneous observation of the spiking activity of most or all single neurons that express the Ca++ reporter within a microscope\u2019s field of view (FOV). One can reliably image the activity of the same identified neurons within the FOV for many weeks or months. One can locate each neuron within the 3D cortical volume and reconstruct the spatiotemporal pattern of activity within that cortical volume. Double-labelling of neurons with different markers can allow one to identify specific neural subpopulations within the FOV. One can examine cortical function from the macro level of hundreds to thousands of neurons to the micro level of single dendritic spines. Ultimately, one could link all of these observations about neural activity to computational models of cortical local-circuit function. These tools have been used successfully in rodent studies of motor control and motor learning, and DR has been used on those data to extract features of the computational structure of neural activity126.However, a different potential solution to these limitations may be two-photon (2P) optical imaging of neural activity using fluorescent signals generated by Ca131. However, progress has been slow because of the lack of the many transgenic lines, promoters and other tools to manipulate gene expression in specific cell types that are available in rodent models. As a result, the field is still largely in the proof-of-concept stage. Nevertheless, successful imaging of fluorescent signals from populations of identified neurons for weeks and months has been demonstrated in several NHP species, including macaque monkeys139, squirrel monkeys113 and marmosets143.The potential power of optical imaging and optogenetic tools has spurred interest in developing similar toolboxes for NHPs135. They have shown that single layer 2/3 V1 neurons are preferentially activated by relatively complex features of arbitrary visual stimuli such as curvature, junctions and corners136 and that the representation of complex natural visual scenes is extremely sparse in layers 2/3 of V1137. Finally, the activity of 150 to 250 neurons has been imaged in M1 of marmosets while they performed reaching movements or attempted to adapt to external force fields during reaching143. These initial results confirm the potential of 2P optical-imaging methods to study the activity of large populations of identified neurons within an FOV in the cerebral cortex of behaving NHPs over extended periods of time.Optical-imaging studies of primary visual cortex (V1) in NHPs have successfully reconstructed the functional organization within an FOV, including visual-stimulus orientation bands and other known features of V1 hypercolumn structure++ imaging methods with the spatiotemporal resolution needed to observe the spiking activity of many single neurons can image to a depth of only about 1000 \u00b5m, so that all NHP imaging studies to date have been limited to cortical layers 2/3. Advances in Ca++ reporter molecules and imaging optics might eventually extend the depth of imaging146, but the light scattering and absorption properties of the heavily myelinated cortical tissue of NHPs present a major technical challenge. Moreover, many important functional areas are buried deep in the sulci of NHPs with gyrencephalic brains, making them inaccessible to direct optical imaging from the cortical surface. Optically refractive GRIN (gradient-index) lenses or periscope-like mirror probes could be inserted into the sulcal folds, but they are relatively large (>1 mm), can cause tissue damage when inserted, and are too rigid to be appropriate for long-term chronic recordings147. Very thin micro-endoscopes that can be inserted to any depth are under development147.Nevertheless, current 2P optical-imaging methods have a number of important limitations. They provide signals about neural spiking activity but not local field potentials. Most Ca150.Furthermore, the FOV of most optical-imaging studies of multi-neuron spiking activity is relatively small, typically ranging from 500 \u00d7 500 \u00b5m to 850 \u00d7 850 \u00b5m, and much less when imaging single dendrites or spines. An FOV smaller than 1000 \u00d7 1000 \u00b5m will image the activity in only a very small part of the entire M1 motor map for the arm or about one visual hypercolumn in V1 of a macaque monkey. This severely constrains the ability to study functional organization over large expanses of a given cortical region. New advances in microscope optics and scanner engines may substantially increase the FOV to dimensions more appropriate for brains of the size in NHPs151. This may compromise the ability of methods like DR, that analyze the covariance structure of multi-neuron activity patterns, to parse out the internal computational dynamics of local neural circuits, especially at a temporal resolution approaching that afforded by microelectrode recordings of neural spike trains.Finally, microelectrode recordings of well-isolated neurons provide streams of discrete action potentials that can be measured with millisecond precision. In contrast, the fluorescent optical signals are noisy and indirect signs of neural spiking activity, and measurement and estimation errors are introduced at every stage in the data acquisition and processing pipeline from signal generation to signal measurement and subsequent analysis. The optical-imaging system can observe only the fluorescent photons that happen to enter the optical aperture of the photo-multiplier sensor as it raster-scans the FOV. The time course of the fluorescent response to a single spike is slow and prolonged compared with the causal action potential. As a result, the fluorescent signals generated by each spike of a high-frequency multi-spike discharge burst with short inter-spike intervals will sum and deconvolution techniques to reconstruct the causal spike sequence can introduce estimation errors. Fluorescent signals from neurons whose somata overlap visually in the FOV further confound the spike deconvolution process. Motions of the brain during scanning cause shifts of the positions of imaged neurons within the FOV, and techniques to co-register sequentially scanned images can introduce errors in single-neuron alignment across images and in the measurement of each neuron\u2019s fluorescent signals across time. These and other sources of measurement and estimation errors may introduce a significant level of uninformative and even potentially misleading noise in the reconstructed multi-neuron activity patterns"}
+{"text": "This work demonstrates a sequential deposition of lead iodide followed by methylammonium iodide using the industrially compatible slot-die coating method that produces homogeneous pin-hole free films without the use of the highly toxic dimethylformamide. This is achieved through the careful selection and formulation of the solvent system and coating conditions for both the lead iodide layer and the methylammonium iodide coating. The solvent system choice is found to be critical to achieving good coating quality, conversion to the final perovskite and for the film morphology formed. A range of alcohols are assessed as solvent for methylammonium iodide formulations for use in slot-die coating. A dimethylsulfoxide solvent system for the lead iodide layer is shown which is significantly less toxic than the dimethylformamide solvent system commonly used for lead iodide deposition, which could find utility in high throughput manufacture of perovskite solar cells. Solar energy and photovoltaics are becoming an increasingly important part of the electrical power generation mix. Essential to reducing the costs of this energy source is the reduction in the cost of photovoltaic modules, many methods to accomplish this are being pursued such as alternative deposition methods for conventionally used silicon photovoltaic materials ,2 and enThe most commonly used deposition method for perovskite photovoltaics in laboratory research is spin coating. This is generally not seen as a viable technique for large scale manufacture due to limits on the size of coated areas  are shown in y number  of the DThe morphology of the lead iodide layers was studied using scanning electron microscopy (SEM), images of the slot-die coated films, from either DMF or DMSO are given in Having produced lead iodide films via slot-die coating the conversion to perovskite was investigated. The most commonly used method to convert lead iodide to the final perovskite is through the use of dip coating, normally by placing the lead iodide film in a dilute solution of MAI in 2-propanol (IPA), often for extended periods of time from a few minutes to tens of minutes. Slot-die coating of MAI formulations directly on to the lead iodide film has also been reported ,28,39, aTo determine the conversion to perovskite and to test and compare the performance of devices, incorporating the slot-die coated DMF and DMSO-based lead iodide films, dip coating was used initially. The films were placed in a solution of MAI for 30 min, a method previously found to give good conversion to perovskite.X-ray diffraction spectra of the perovskites formed from both films are given in As discussed previously in the context of wetting, SEM images of the perovskite formed are given in Having established that the DMSO-based lead iodide films could form good quality perovskite layers and high performance devices the use of slot-die coating, rather than the conventional dip coating, for the deposition of the MAI ink was investigated. To achieve complete conversion of lead iodide to perovskite the MAI formulation would have to sufficiently wet and infiltrate into the lead iodide film to bring the two components in contact with each other and to react and form perovskite ,63. For As well as converting to a high degree the morphology of the resulting perovskite film is critical to device performance and the carrier solvent for MAI will strongly influence the morphology formed. Alcohol solvents with various structures have been shown to influence the morphology of sequentially grown perovskite crystals, in particular a dissolution\u2013recrystallisation process  dependant on the molecular polarity of the solvent has been suggested to be influential . The staAs well as this, the rheology of the solvent and in particular viscosity will determine how rapidly the formulation infiltrates the porous lead iodide film . For sloIn order to investigate the role the solvent in conversion to perovskite for slot-die coating, formulations of MAI in several different alcohols, with various rheologies and volatilities, were prepared, these are listed in It should be noted that the concentration of MAI in the formulation can also alter the crystallisation process and the morphology of perovskite films formed . To contAll the MAI formulations showed complete wetting on the lead iodide surface with static contact angles less than 5Photovoltaic devices were fabricated using the different slot-die coated MAI films, In an attempt to further improve the device performance a modified lead iodide coating process was developed to produce more labile lead iodide films in order to increase conversion to perovskite when slot-die coated with the MAI in ethanol ink. The substrate was pre-heated to 100 Performance of devices made using these films are given in Device fabrication was performed in a humidity controlled (30% relative humidity) clean-room (class 7) environment. Devices were fabricated on fluorine doped tin oxide (FTO) coated glass substrates with a device stack of spray coated compact titanium dioxide blocking layer, slot-die coated mesoporous titanium dioxide scaffold, slot die coated lead iodide layer converted to perovskite using methylammonium iodide by either dip or slot die coating followed by spin coated spiro-MeOTAD hole transport material and evaporated gold top contacts.FTO glass (TEC8) substrates were etched using tape to define electrode areas, zinc powder and hydrochloric acid to remove FTO and rinsed with deionised water then cut into 15 cm by 5 cm sections. Substrates were further cleaned sequentially with acetone, dilute Hellmanex, deionised water and 2-propanol .The compact titanium dioxide blocking layer formulation was made up by dilution of a solution of titanium diisopropoxide bis(acetylacetonate) (Sigma-Aldrich) in IPA. The layer was spray coated on substrates held at 300 A bench-top slot-die coating unit, with in-line forced hot air oven, positioned in a fume-hood was used for coating. The slot-die coating head had a coating width up to 100 mm, patterned shims were used to define coated areas and corresponding meniscus guides  were useThe mesoporous titanium dioxide layer was deposited using slot-die coating, the formulation was made up by dilution of DSL-18NRT titanium dioxide paste (Dyesol) with 1-butanol . The forThe lead iodide layer was deposited by slot-die coating from a formulation of lead iodide (Sigma Aldrich 99%) 20 wt% in either DMF or DMSO . The slot-die coated films were coated in air at 1.0 m\u00b7minFormation of perovskite was achieved by either dip coating or slot-die coating with solutions of methylammonium iodide (MAI) (Dyesol). For dip coating the lead iodide films were submerged in a tray of MAI 10 mg\u00b7mLThe hole transport material spiro-MeOTAD  and glass cover slip with a piece of Kapton tape to protect the hole transport material and perovskite layer from the adhesive before curing, the adhesive was cured by placing under a solar simulator for 10 min. The devices were stored in the dark in a sealed box with desiccant.Current-voltage testing of devices was performed using a Keithley 2400 source measure unit and an Oriel solar simulator as light source (class AAA Newport Oriel Sol3A) calibrated to AM1.5 one sun equivalent intensity using a reference cell fitted with a KG5 filter (Newport Oriel 91150-KG5). Cells were masked to 0.09 cmViscosity measurements were made using a Malvern Bohlin Gemini 200 Nano HR rheometer, equipped with a temperature controlled stage, across a range of shear rates, all inks were found to be Newtonian at the shear rates used and viscosity is quoted as the value found for a shear rate of 25This work demonstrates that for sequential deposition of the perovskite layer by slot-die coating the choice of solvent and coating conditions is critical. For the lead iodide layer the coating quality and device performance can be improved by changing the solvent system. As such, the use of the non-toxic solvent DMSO is demonstrated and leads to high performance devices, this is important in the development of safe and cost effective scalable manufacturing processes for perovskite solar cells.The choice of solvent system for the coating of the MAI layer has been shown to be critical to achieving conversion of the lead iodide layer to perovskite and achieving high performance. The use of ethanol as the solvent system for slot-die coated layers leads to devices with performance approaching those produced using the conventional dip coating method. Combined with an improved lead iodide coating method using a substrate pre-heated to 100 Further improvements to the quality of the perovskite layer will be necessary to achieve higher performance similar to that of spin coated devices and moving towards a viable manufacturing process. Improving the grain size and reducing grain boundaries of the perovskite would likely help this  and furt"}
+{"text": "Trace elements although present in minute quantities in human blood, they play a vital role in many biochemical enzymatic reactions and have been examined critically as a potential key factor in various human diseases including cancers. This study was aimed to determine the association between serum levels of trace elements and invasive cancer of the cervix.This was an analytical cross-sectional study carried out among women seen at the Lagos University Teaching Hospital (LUTH). Fifty histologically diagnosed patients with squamous cells carcinoma of the cervix, who had not had any treatment and 100 cancer-free volunteers were recruited. A structured interviewer-administered questionnaire was used to collect relevant data following which venous blood sample was obtained from each participant. Serum zinc, copper and selenium concentrations were then measured. The associations of serum trace elements and invasive cervical cancer were tested using the independent sample t-test. All significances were reported at P<0.05.There were significantly low serum levels of zinc and selenium in cervical cancer patients with no significant difference seen in the serum level of copper among cervical cancer patients compared to their cancer-free control counterparts.These alterations in trace elements levels may be important in the pathogenesis of cervical cancers; however, future robust prospective studies are needed to determine if routine provision of these supplements will result in improved cervical cancer treatment outcomes in Nigerian women. Cervical cancer is the second most common cancer among women in the developing countries and the seventh most common cancer in the developed countries . Over 50More recently, studies have shown that this element may also play an important regulatory role in initiation of cell-mediated immunity . Recent N) for the study was calculated using the statistical formula by Schlesselman [This was an analytical cross-sectional study carried out among women seen at the cytology and gynaecology out-patient clinics of the Lagos University Teaching Hospital (LUTH), Lagos, Nigeria. LUTH is an over 1000 bedded teaching hospital located in the Central Lagos metropolis in South-West Nigeria. The hospital provides services to patients from the neighbouring South-Western states. It is the largest in the state and offers mainly clinical services among which include gynaecological oncology services. The gynaecology clinic is an-all female clinic with the cytology clinic being an off-shoot of it. In addition to receiving patients from the gynaecology clinic, the cytology clinic is the meeting point for all women from all other clinics of the hospital referred for routine cytological evaluation. The sample size .Copper: The mean level was higher in the cervical cancer patients but there was no statistically significant difference in the level in serum of patients as compared to its level in normal control group of individuals .Selenium: There was a significantly lower mean selenium levels in the cervical cancer patients compared to the control participants .In this study, we investigated the levels of three serum trace elements in patients with histologically diagnosed cervical cancer compared with cancer-free controls. Our study found a reduction in haemoglobin levels among participants with histologically diagnosed cervical cancer and this has been explained to occur as a result of iron deficiency and tumour bleeding in these patients , 23. TheThe study found significantly lower concentrations of zinc and selenium in cervical cancer patients. Zinc and selenium supplements may therefore result in reduced cervical cancer occurrence among high risk Nigerian women. However, future robust prospective studies are needed to determine if these trace element concentrations will impact clinical outcomes and to establish whether routine provision of these trace elements as supplements will result in improved cervical cancer treatment outcomes in Nigerian women.That cervical cancer is the most common gynaecological cancer and a leading cause of cancer death in women in Nigeria;Trace elements although present in minute quantities in human blood, play a vital role in many biochemical enzymatic reactions and have been examined critically as a potential key factor in various human diseases including cancers;The roles of trace elements in the prevention of cervical cancer and other invasive cancers of humans are now subjects of discussions and intensive research interests.The study found significantly lower concentrations of zinc and selenium in cervical cancer patients to their cancer-free control counterparts;There is, however, a relatively low level of practice of cervical cancer prevention among the respondents;The study, therefore, propose that routine provision of zinc and selenium supplements may result in reduced cervical cancer occurrence among Nigerian women.The authors declare that competing interests."}
+{"text": "Recruitment of dementia caregivers whose family members reside in long-term care facilities (LTCFs) poses unique challenges as it traditionally relies on the assistance of facility administrators. The purpose of this presentation is to examine and evaluate new recruitment strategies to determine their effectiveness in an ongoing Stage I randomized clinical trial testing the effects of a Chronic Grief Management Intervention, Video-streamed (CGMI-V) on caregivers\u2019 mental health  and facility-related outcomes . A total of 144 caregivers will be randomly assigned to the CGMI-V or to the minimal treatment conditions. The initial recruitment plan was to build on already-established relationships with more than 35 LTCFs that helped recruit in a previous study. The usual approach was to offer written materials and onsite presentations about the study to facility staff and to dementia family caregivers of facility residents. Within the first six months, recruitment efforts yielded less than a dozen participants, thus we had to refine our approach. Revised recruitment strategies included the adoption of resources from the National Institute on Aging\u2019s ADORE  and ROAR (Recruiting Older Adults into Research) platforms. This new approach included online study advertising on NIH and Alzheimer\u2019s Association research study repositories and advertising on parent institution\u2019s on-hold messaging system. Adoption of these new strategies is yielding an increase in participant screening and enrollment. Results are pending."}
+{"text": "Heterobasidion parviporum  and Ustilaginoidea virens RNA virus 4 (unclassified) was close to 30%  proteins that show similarity to plant RSS proteins . Infection in an RNA silencing mutant of C. parasitica, dicer-like 2 knockout-\u0394dcl-2 has a similar effect  and CHV1 mutant-\u0394p69 in C. parasitica. MyRV1 induces silencing genes dicer-like 2 (dcl2) and argonaute-like 2 (agl2), and CHV1 mutant (\u0394p69) is also impaired in RSS activity (Chiba and Suzuki, Many fungi use the adaptive immune system of RNA silencing to suppress viruses (Hammond et al., in vitro that accelerates the transmission of mycoviruses among vegetatively incompatible strains of R. necatrix (Ikeda et al., Rosellinia necatrix shows very strong incompatibility with different strains without the formation of anastomosis (Inoue et al., R. necatrix is unknown however, it is inferred that zinc chloride reduces the effects of the hyphal secretion that suppress anastomosis (Inoue et al., Helicobasidium mompa hyphal incompatibility is inhibited with the supplementation of active charcoal in the media (Inoue et al., The roles of chemical compounds that affect the programmed cell death pathways involved in mycelial incompatibility were studied to look at their facilitation of heterologous transmission of mycoviruses. One successful case was the use of a zinc compound The determinants of mycovirus coinfections involve multiple factors. One of the constraints that many mycoviruses have to overcome for infection is non-self-recognition. RNA silencing is another major hurdle that influences the success of infection. The roles of nutrients or chemicals or other components of the environment seems to have potential influence in determining infection, but it is a poorly studied field. The biology of coinfection is complex like any other biological phenomena and many factors remained to be explored. On the other hand, it is an important field particularly in manipulating virulence of pathogenic fungi in which mycoviruses are known to play crucial roles. There are attempts underway to alter the non-self-recognition factors in vegetative incompatible populations for successful transfer of mycovirus related to hypovirulence (Zhang et al., VT wrote the first draft. MR edited and wrote the final draft.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The neuropeptide calcitonin gene-related peptide (CGRP) is a potent regulator of cerebral vascular tone and contributes to neurogenic inflammation. Clinical studies have shown that CGRP levels are elevated during the painful phase of migraine headache, then restored to baseline by antimigraine 5-HT1 drugs. Conversely, CGRP is depleted in perivascular nerve terminals from patients who have suffered vasospasm following subarachnoid hemorrhage. We have investigated the mechanisms controlling CGRP expression in the trigeminal ganglia neurons, which provide virtually all of the CGRP innervation to the cerebral vasculature. We found that nerve depolarization, inflammatory compounds, and nitric oxide can increase CGRP synthesis and secretion. Using both adenoviral vectors and transfection approaches, we have shown that the increased synthesis is due to activation of a cell-specific MAP kinase-responsive enhancer upstream of the CGRP gene. Interestingly, the 5-HT1 migraine drugs are able to block this up-regulation by a mechanism that involves a very prolonged elevation of calcium. We have shown that the duration of the calcium signal is a key determinant for whether a MAP kinase responsive gene will be stimulated or repressed by calcium-activated pathways. This observation supports the importance of a finely tuned balance of calcium in the trigeminal neuron, which is intriguing in light of genetic evidence for calcium channel mutations in a rare form of inherited migraine. These studies suggest that modulation of MAP kinase control of the cell-specific CGRP gene enhancer may be a useful therapeutic strategy for neurovascular disorders."}
+{"text": "The National Collaboratory to Address Elder Mistreatment\u2019s model provides hospital emergency departments with training and tools to help recognize and respond to elder mistreatment. The Geriatric Emergency Department (GERI-ED) initiative, supported by The John A. Hartford Foundation and West Health, encourages hospitals to integrate best practices for older adults into their emergency departments by providing guidelines and options for accreditation (GED-A). Recognizing the importance of coordinating efforts to develop tools that can be shared and implemented widely, the Collaboratory has intentionally and strategically aligned itself with the GERI-ED by inviting members of the GED-A team to join the Collaboratory. In this presentation we will describe how aligning these two initiatives has the potential to achieve greater impact than either initiative alone. We will provide a case example of how the elder mistreatment care model is implemented in GERI-EDs, highlighting factors that facilitate and hinder model implementation in such settings."}
+{"text": "Micromechanical fatigue lifetime predictions, in particular for the high cycle fatigue regime, require an appropriate modelling of mean stress effects in order to account for lifetime reducing positive mean stresses. Focus of this micromechanical study is the comparison of three selected fatigue indicator parameters (FIPs), with respect to their applicability to different total strain ratios. In this work, investigations are performed on the modelling and prediction of the fatigue crack initiation life of the martensitic high-strength steel SAE 4150 for two different total strain ratios. First, multiple martensitic statistical volume elements (SVEs) are generated by multiscale Voronoi tessellations. Micromechanical fatigue simulations are then performed on these SVEs by means of a crystal plasticity model to obtain microstructure dependent fatigue responses. In order to account for the material specific fatigue damage zone, a non-local homogenisation scheme for the FIPs is introduced for lath martensitic microstructures. The numerical results of the different non-local FIPs are compared with experimental fatigue crack initiation results for two different total strain ratios. It is concluded that the multiaxial fatigue criteria proposed by Fatemi-Socie is superior for predicting fatigue crack initiation life to the energy dissipation criteria and the accumulated plastic slip criteria for the investigated total strain ratios. Martensitic high-strength steels are distinguished by a high strength to weight ratio, an excellent weight and cost-effectiveness as well as a more environmental friendly energy balance than aluminium alloys. These attributes are of particular importance in today\u2019s challenges such as the design of sustainable transportation systems . Among tExperimental investigations on low and medium carbon-alloyed martensitic high-strength steels have been focused on several fields of research, in the last decades. Fundamental investigations on the morphology and crystallography enabled a profound understanding of the hierarchical architecture of lath martensite. During the diffusionless, shear-dominated transformation from austenite . The chemical composition of the material which was determined by spark emission spectroscopy is given in The underlying martensitic microstructure was analysed with respect to microstructural morphology, corresponding prior austenite grain morphology and crystallographic properties by means of light optical microscopy  and high-resolution scanning electron microscopy  in combination with automated electron backscatter diffraction .During the quenching process, the austenite phase  . Based oThe fatigue crack initiation behaviour of the considered material was investigated by uniaxial strain-controlled fatigue tests which were performed according to the standards from ASTM E606 . The fatIn total strain-controlled fatigue tests of smooth specimens, the cycles for macroscopic fatigue crack initiation are usually defined by a specific load drop of the maximum load ,34. In tSTM E606 .Fully reversed strain-controlled fatigue experiments at RStephens  are alsoAccording to E is the Young\u2019s modulus; b and c represent the fatigue strength and fatigue ductility exponent, respectively. For the derivation of the mentioned coefficients and exponents of the presented law in Equation  and python (Version: 2.7). This martensitic microstructure generator has been developed in a previous study by the authors  and has According to McDowell and Dunne  and PrzyIn order to account for the microstructural influence on fatigue crack initiation, four SVEs were generated in the present study. These microstructural instantiations which are depicted in Periodic boundary conditions are applied on opposite faces of the SVEs in order to simulate bulk material behaviour based on the work of Smit et al. . In the The different SVEs were simulated at two different total strain ratios, at Relluccio , saturatelluccio  postulatThe micromechanical model used in the present study consists of a local phenomenological crystal plasticity (CP) model incorporated into the finite element solver Abaqus 2016 in form of a user material subroutine (UMAT). In a previous study by the authors, the size independent CP model was adapted and extended by kinematic hardening models for the simulation of the cyclic deformation behaviour of the investigated material. The model is able to capture adequately the Bauschinger effect as well as the mean stress relaxation behaviour of SAE 4150 for different strain ranges and strain ratios. The calibration, implementation and model description is described in detail in ; howeverThe local CP model is implemented in a finite strain framework where the total deformation gradient m. Since the modelling of cyclic material behaviour requires the consideration of kinematic hardening, a back stress variable A, B and M are material specific constants [Plastic deformation in body-centred cubic (BCC) martensite may include in-lath- and out-of-lath-plane slip systems, the {110}<111> and {112}<111>, respectively. According to Michiuchi et al. , the {11ectively . The phee et al. ,47,48 diamondAccording to In addition to the result representation for RAn appropriate representation of the life time reduction factor is the visualisation of The experimental based lifetime reduction factors in The non-local accumulated plastic slip cannot capture the effect of an increased strain ratio. Regardless of the applied total strain amplitude, the lifetime reduction factor oscillates around For the sake of completeness, the FIP dependent absolute average fatigue crack initiation cycles as well as the corresponding experimental values from Based on the previous results from The characteristics of the fatigue crack initiation lifetime scatter can be pointed out by means of Martensitic microstructures exposed to fatigue loading exhibit strong local stress and strain heterogeneities due to inherent microstructural variations. These local inhomogeneities reveal the importance of micromechanical fatigue modelling techniques for fatigue crack initiation prediction in the low cycle fatigue regime as well as in the high cycle fatigue regime.A sphere homogenisation technique was introduced for the martensitic microstructure. Fatigue indicator parameters are averaged within a finite sphere in order to introduce an internal damage length scale. The averaged fatigue indicator parameters are termed as non-local fatigue indicator parameters.For fully reversed loadings RPredictions of the fatigue crack initiation lifetime for RIn the present study, micromechanical fatigue crack initiation (FCI) predictions have been made for the martensitic high-strength steel SAE 4150 at Rus study , an adva"}
+{"text": "Multiple discoveries made since the identification of vesicular glutamate transporters (VGLUTs) two decades ago revealed that many neuronal populations in the brain use glutamate in addition to their \u201cprimary\u201d neurotransmitter. Such a mode of cotransmission has been detected in dopamine (DA), acetylcholine (ACh), serotonin (5-HT), norepinephrine (NE) and surprisingly even in GABA neurons. Interestingly, work performed by multiple groups during the past decade suggests that the use of glutamate as a cotransmitter takes different forms in these different populations of neurons. In the present review, we will provide an overview of glutamate cotransmission in these different classes of neurons, highlighting puzzling differences in: (1) the proportion of such neurons expressing a VGLUT in different brain regions and at different stages of development; (2) the sub-cellular localization of the VGLUT; (3) the localization of the VGLUT in relation to the neurons\u2019 other vesicular transporter; and (4) the functional role of glutamate cotransmission. Stricto sensu, cotransmission implies that two neurotransmitters are released from the same neuron. The complementary term \u201ccorelease\u201d is considered by many to imply simultaneous release of two transmitters from the same vesicles. For corelease to occur, two classic transmitters  must be stored within the same synaptic vesicle (SV) in the readily releasable pool (RRP). In the absence of actual corelease from the same SVs  DA neurons typically contain only very low levels or no vglut2 mRNA and thus do not establish many glutamatergic synapses in the dorsal striatum, as revealed by optogenetic stimulation and patch-clamp electrophysiology  DA neurons contain VGLUT2 and release glutamate in the ventral striatum, adult Cholinergic neurons in the brain are also dichotomous in their expression of VGLUT3. On one hand, most if not all cholinergic interneurons of the striatum express VGLUT3  or choline acetyltransferase  by neurons of the VTA, EPN and SUM nuclei  and by vesicle immuno-purification experiments  or the amygdala. In these areas, such \u201cbilingual\u201d neurons release either glutamate or their cognate transmitter (ACh or 5-HT) depending on their firing pattern. The IPN receives a dense cholinergic innervation from the medial Hb; these terminals massively co-express VGLUT1  co-express VAChT and VGLUT3 and consequently signal with both ACh and glutamate  located on DAergic fibers powerfully stimulates DA release in the striatum (for review see Exley and Cragg, vglut2 from DA neurons provides further evidence for a key role of glutamate corelease in the regulation of psychostimulant-induced behaviors (Birgner et al., vglut2 from DA neurons blunted locomotor response to cocaine and amphetamine (Birgner et al., vglut2 gene during the embryonic period, a recent study used a tamoxifen-inducible strategy to KO vglut2 from DA neurons in adult mice. This work reported unaltered locomotor sensitization to amphetamine and cocaine in the absence of VGLUT2 (Papathanou et al., vglut2 on the response of mice to psychostimulants is that embryonic gene deletion leads to perturbed development of the DA system. More work will be needed to examine this question directly. However, some indirect support for this possibility has been obtained. Although constitutive KO of VGLUT2 is lethal immediately after birth due to absence of breathing (Wall\u00e9n-Mackenzie et al., in vitro, VGLUT3-KO 5-HT neurons showed reduced survival, suggesting a potential role in their basal vulnerability.The conditional ablation of Clearly much remains to be done to better understand the functional implications of glutamate cotransmission. Further, more extensive studies using conditional and inducible genetic deletion of VGLUTs at different developmental stages in select neuronal populations, coupled with functional analyses will likely provide further insights in the coming years.In the present review, we provided an overview of glutamate cotransmission in different classes of neurons. What emerges from this global comparison is the particularly heterogeneous nature of glutamate cotransmission in different brain nuclei. There are wide variations in the proportion of neurons expressing a VGLUT in different brain regions and at different stages of development. The sub-cellular localization of VGLUTs in neurons using multiple classical neurotransmitters is also clearly heterogeneous, with frequent segregation of the VGLUTs in relation to the neurons\u2019 other vesicular transporter. Finally, studies of the functional roles of glutamate cotransmission clearly need to be strengthened by additional studies evaluating these roles at different developmental stages and in disease conditions.L-ET and SEM jointly wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "As evidenced by the growing Age-Friendly University (AFU) global network, institutions of higher education are increasingly seeking ways to enhance the experiences of older adults who use them for reasons such as lifelong learning, career development, and intergenerational engagement. This multi-phase study explored the barriers and facilitators for older adults accessing a public university in a small Oregon town. The first phase of the study involved survey data collection from 46 members of the local senior center adjacent to the university campus. For the second phase, researchers recruited a sample from the survey respondents and used snowball sampling to conduct 12 interviews with senior center members, past and current senior center directors, and key contacts among university staff. The third phase of data collection paired student researchers with older adult research participants (N=14) in participatory action research to capture the unique perspectives of the research participants visiting the university campus using photovoice and a follow-up focus group. Quantitative data were analyzed using SPSS while qualitative data were analyzed using team coding and intensive group discussion to develop categories and themes. Findings revealed various opportunities to increase age-friendliness according to the principles outlined by the AFU initiative, such as developing a lifelong learning center on campus, strengthening the university-senior center partnership, and removing accessibility barriers in order to make the university campus friendlier for people of all ages and abilities. These findings are being used in a proposal to join the AFU network and to shape the university\u2019s AFU vision."}
+{"text": "The evolution of the multi-copy family of ribosomal RNA (rRNA) genes is unique in regard to its genetics and genome evolution. Paradoxically, rRNA genes are highly homogenized within and between individuals, yet they are globally distinct between species. Here, we discuss the implications for models of rRNA gene evolution in light of our recent discoveries that ribosomes bearing rRNA sequence variants can affect gene expression and physiology and that intra-individual rRNA alleles exhibit both context- and tissue-specific expression. The ribosome is an RNA-protein assembly responsible for the translation of the genetic information encoded in messenger RNA (mRNA) into proteins. The ribosomal RNA (rRNA) component of the intact ribosome, which constitutes its universally conserved, functional core Noller , is prinTo meet cellular demands for rapid protein synthesis during cellular growth and proliferation, rDNA operons are highly transcribed by RNA Polymerase I. Pre-rRNA transcripts (47S in higher eukaryotic organisms) are processed into the functional rRNAs  present within the ribosome through a highly complex multi-step process referred to as ribosome biogenesis (Pe\u00f1a et al. Two accepted scientific observations give rise to an apparent paradox in rRNA evolution: on the one hand, rRNA genes are highly similar within and between individuals of a given species (Eickbush and Eickbush Concerted evolution, a genetics model proposed in the wake of these observations, seeks to provide a framework for rRNA evolution that entails a combination of gene conversion and unequal chromosome crossover (Eickbush and Eickbush Mounting evidence hints that the evolution of rRNA sequence variation is more complicated than the rapid spread of mutations across rRNA genes and the simple avoidance of deleterious mutations. In 1980, Arnheim et al. reported an evolutionarily conserved intra-individual 28S rRNA sequence polymorphism in four primate species in which the same nucleotide polymorphism was present in the 28S rRNA gene of only a subset of each individual\u2019s rRNA genes (Arnheim et al. Consistent with the notion of concerted evolution, we recently performed a focused analysis on the functional rRNA genes using relatively short-read length human whole genome sequencing data from diverse populations worldwide to show that mammalian rRNA genes are, in general, highly homologous (Parks et al. Escherichia coli. We discovered that rRNA alleles are differentially expressed in response to nutrient limitation-induced stress and that the rRNA allele most upregulated on a relative basis is distinguished by conserved sequence variants clustered in the small subunit head domain of the assembled ribosome (Kurylo et al. Enterobacteriaceae, including Salmonella enterica, which diverged from E. coli more than 120 million years ago. These findings provide compelling evidence that classes of bacteria encode what may be considered an evolutionarily conserved \u201cstress-response ribosome.\u201d As the theory of concerted evolution has been extended to prokaryotes with multiple copies of rRNA (Liao Based on the rationale that beneficial impacts of sequence variation within the rRNA genes on ribosome function, if present, would likely be an evolutionarily conserved phenomenon, we examined whether rRNA sequence variation contributes to physiological programs in laboratory strains of RNA Liao , these rEnterobacteriaceae appear to modulate ribosome function in a manner that influences gene expression and cell physiology to promote survival. Analogously, extremophilic or extremotolerant microorganisms seem to possess unusually high levels of intragenomic rRNA sequence variation (Sun et al. In light of previous literature and the more recent discoveries described herein, we posit that concerted evolution should be expanded to account for the possibility that positive selective pressures favor the maintenance of a plurality of rRNA alleles in the genome Fig. . This maIn addition to uncovering a novel mechanism of gene expression regulation, our recent findings raise important questions about concerted evolution and rRNA. For instance, how do sequence variants in rDNA operons arise in the first place and how are they maintained? Do sequence variations within the rRNA genes correlate with variations within the non-coding regions of the pre-rRNA transcript? How do the potentially distinct constraints on sequence variation within the genes encoding the functional rRNA genes and the non-coding regions of rDNA operon influence and impact the mechanism and occurrence of rDNA recombination events? How is an optimal plurality of rRNA alleles achieved within an individual and is this plurality maintained over the course of an organism\u2019s lifetime? Do the positions of the rDNA operons within the acrocentric arms of chromosomes alter the efficiency of recombination events in a meaningful way? We must also seek to understand how ribosome biogenesis and translation factors coevolve to maintain functional interactions with rRNAs of distinct sequence. Do variations in rRNA sequence drive the evolution of ribosome biogenesis and translation factors or do variations in ribosome biogenesis and translation factors drive the evolution of rRNA sequence? How does rRNA sequence variation relate to the observation that mammalian organisms typically encode multiple distinct isoforms of the core translation factors (Genuth and Barna To begin to answer these questions and to provide insights into the role of rRNA expression in concerted evolution, future investigations must be aimed at examining whether diverse eukaryotic species exhibit rRNA allele-specific expression levels under distinct physiological conditions. In this context, efforts must also be given to establishing a robust means of determining the complete primary sequence of individual rDNA operons within a single cell or organism. As it is difficult to achieve this goal with short-read length whole genome sequencing data, such efforts will doubtless benefit from the implementation of single-chromosome or single-molecule, long-read length technologies (Pollard et al. As we touch upon herein, rRNA may be subject to distinct evolutionary processes and pressures. Understanding how rRNA alleles are maintained in the genome and regulated in expression will be of extraordinary importance given the centrality of the ribosome to cellular physiology. In light of the evidence showing that rRNA sequence variation has the capacity to regulate gene expression and cell physiology (Kurylo et al."}
+{"text": "Australian Aboriginal children experience high levels of dental caries (tooth decay) and are less likely to access preventive dental health services. High-strength fluoride varnish has been shown to reduce the incidence of dental caries and is commonly used in community-based preventive dental health service programs. In New South Wales, Australia, the application of fluoride varnish is restricted to dental and medical professionals. This is problematic in communities with a high Aboriginal population and limited access to oral health services, contributing to the increased risk of developing dental caries in Aboriginal children. Dental assistants are essential members of the oral health team; however, they do not have a defined scope of practice in Australia. Other countries have created formal scopes of practice for dental assistants to include the application of fluoride varnish. This protocol presents a pathway for qualified Aboriginal dental assistants to undertake additional training to legally apply fluoride varnish in New South Wales. The primary objective of this study will be to evaluate the feasibility and acceptability of utilising Aboriginal dental assistants to apply fluoride varnish to Aboriginal children in a school setting at regular 3-month intervals.Six schools across New South Wales (NSW) that enrol at least 12% Aboriginal children will be invited to participate in the 12-month study. Aboriginal children aged 5\u201312\u2009years enrolled in these schools will be enrolled in the study. Six Aboriginal dental assistants will undertake training to apply fluoride varnish. Fluoride varnish (Duraphat) will be applied at 3-month intervals by the dental assistants to the teeth using a small brush. An evaluation will be undertaken to determine the feasibility and cost-effectiveness of this innovative approach. This study protocol has been approved by the NSW Aboriginal Health and Medical Research Council and the NSW State Education Research Application Process.A qualified Aboriginal dental assistant workforce in NSW  legally approved to apply fluoride varnish may increase the sustainability and scalability of fluoride varnish programs and improve the oral health of Aboriginal children in Australia.ISRCTN26746753.The online version of this article (10.1186/s40814-019-0399-4) contains supplementary material, which is available to authorized users. Dental caries (tooth decay) is a widespread chronic disease among Australian children which is largely preventable , 2. AustVarnishes which contain higher levels of fluoride were developed in the 1960s to prevent dental caries . They arUnder current Australian legislation (with exception to the Northern Territory), only medical and dental professionals can apply fluoride varnish . Due to In the Northern Territory, non-dental professionals including Aboriginal Health Workers, Aboriginal Health Practitioners and school or child health nurses are legally able to apply fluoride varnish, following mandatory training . This inDental assistants are essential members of the oral health team. Whilst they are not regulated by the Dental Board of Australia and as such do not have a defined scope of practice, in NSW, Victoria and South Australia, dental assistants are included in legislative frameworks that impose standards on non-registered health practitioners who are involved in the provision of health services . In AustOther countries have created formal scopes of practice for dental assistants to include the application of fluoride varnish , 17. In A small-scale study in Central Northern NSW, Australia, used oral health therapists to deliver 3-monthly applications of fluoride varnish to Aboriginal school children . The stuTo determine the feasibility of utilising Aboriginal dental assistants to apply fluoride varnish at regular 3-month intervalsTo determine whether this model can provide Aboriginal children with at least three applications of fluoride varnish over the 12-month study periodTo explore the confidence of dental assistants applying fluoride varnishTo explore the acceptability of using dental assistants to deliver fluoride varnish in the school settingTo determine the cost-effectiveness of utilising dental assistants to provide four fluoride varnish applications in the school setting over the 12-month study period compared to oral health therapistsThis study protocol presents a pathway for qualified Aboriginal dental assistants to undertake additional training to legally apply fluoride varnish in NSW. The primary objective of this 12-month, single group study across seven schools will be to test the feasibility and acceptability of Aboriginal dental assistants applying fluoride varnish in a school setting for children at risk of dental caries. Secondary objectives of this study are as follows:Aboriginal Community Controlled Health Services are health care services that are operated by the local Aboriginal community. They deliver holistic, culturally competent health care to the local Aboriginal community and liaise with local organisations such as schools on issues affecting the health and well-being of Aboriginal people . Six AboEach Aboriginal Community Controlled Health Service will nominate one Aboriginal dental assistant to participate in the program, who has already completed a Certificate III in Dental Assisting. Each dental assistant will need to successfully complete additional training to be able to apply the fluoride varnish. The further training will be administered through NSW TAFE (HLTOHC006 Apply Fluoride Varnish). Each dental assistant will also receive training on the fluoride varnish application protocol developed specifically for this study Additional file 2:Fluoride varnish day protocol. (DOCX 14 kb)Additional file 3:Fluoride varnish day summary sheet. (PDF 130 kb)"}
+{"text": "Furthermore, recent data indicate that uPA-uPAR binding induces astrocytic activation and a crosstalk between activated astrocytes and the injured neuron that triggers a sequence of biochemical events that promote the repair of synapses injured by the ischemic insult. The translational relevance of these observations is noteworthy because following its intravenous administrations recombinant uPA (ruPA) reaches the ischemic tissue, thus raising the question of whether treatment with ruPA is an effective therapeutic strategy to promote neurorepair functional recovery among ischemic stroke survivors.Urokinase-type plasminogen activator (uPA) is a serine proteinase that upon binding to its receptor (uPAR) catalyzes the conversion of plasminogen into plasmin on the cell surface. Recent studies indicate that neurons but not astrocytes release uPA during the recovery phase from an ischemic injury, and that binding of uPA to uPAR promotes neurorepair in the ischemic brain by a mechanism that does not require plasmin generation. A combined approach of  The last two decades have witnessed significant advances in the treatment of acute ischemic stroke patients. Indeed, thrombolysis with recombinant tissue-type plasminogen activator (rtPA) , the remin vivo is impaired by the production in the ischemic area of several glial-derived inhibitors such as myelin-associated glycoprotein (MAG), the reticulon protein family member NogoA, oligodendrocyte myelin glycoprotein (OMgp), and chondroitin sulfate proteoglycans [Due to their high metabolic rate and an almost complete dependence on glucose as energy substrate, neurons are highly vulnerable to cerebral ischemia. Indeed, while 20\u201340 minutes of interruption of the blood flow to the heart are needed to kill a cardiac myocyte, only 5 minutes of cerebral ischemia are sufficient to induce the death of vulnerable neurons  that is oglycans . Importaoglycans , they prA substantial body of experimental evidence indicates that neurons situated in a thin band of brain tissue surrounding the necrotic core survive the ischemic injury despite exhibiting signs of axonal degeneration and loss of dendritic spines . Importain vivo, today is clear that uPA and tPA play distinct roles in the ischemic brain with a significant impact on neuronal survival and functional recovery. Below we will discuss what is known to this date on the role of uPA in the ischemic brain.The PA system is an enzymatic cascade of proteases and their inhibitors that was initially thought to be solely involved in the conversion of plasminogen into plasmin by the activity of two serine proteases: tissue-type plasminogen activator (tPA) and uPA . HoweveruPA is assembled by an amino-terminal domain that harbors the binding site to its receptor (uPAR), a kringle domain with a sequence that interacts with plasminogen activator inhibitor-1 (PAI-1), and a catalytic domain located in the carboxyl terminus that has the protease domain. uPA is secreted as a 54 kD single-chain polypeptide that was originally considered as an inactive enzyme precursor (prourokinase). However, it was soon evident that prourokinase can convert plasminogen into plasmin, which then cleaves the single chain polypeptide at Lys158-Ile159, converting it into a two-chain form with protease activity . Most of\u2212/\u2212) does not have an effect on OGD- or cerebral ischemia-induced neuronal death in vivo and in vitro [uPA and uPAR expression in the ischemic brain. The expression of uPA and uPAR in the brain varies significantly across the developmental span. Accordingly, although during the early phases of development all neurons express uPA , in the in vitro  strongly\u2212/\u2212) have incomplete neurological recovery following transient occlusion of the middle cerebral artery (tMCAO). Importantly, intravenous administration of recombinant uPA (ruPA) after tMCAO reverted the phenotype of uPA\u2212/\u2212 but not uPAR\u2212/\u2212 animals, indicating that uPA promotes functional improvement following an ischemic stroke, and that this effect is mediated by its binding to uPAR [A better understanding of the role of uPA and uPAR in the ischemic brain was provided by the observation that compared to wild-type (Wt) littermate controls, animals genetically deficient on either uPA or uPAR  or differences in the number of neuronal extensions. However, further observations with 3D confocal microscopy revealed the presence of smooth dendrites in uPA\u2212/\u2212 mice in contrast with dendrites of Wt animals that harbor a significant number of filopodia and clusters of dendritic spines. Further studies with golgi staining in brain sections of Wt, uPA\u2212/\u2212, and uPAR\u2212/\u2212 animals indicated that genetic deficiency of either uPA or uPAR prevents the recovery of dendritic spines following an ischemic lesion. Additionally, the use of PlauGFDhu/GFDhu mice in which a 4 aa substitution into the growth factor domain of uPA precludes its binding to uPAR while preserving other functions of the protease and its receptor [UPA/uPAR binding promotes dendritic spine recovery. Because changes in fractional anisotropy (Fa) and mean diffusivity (MD) of water measured with diffusion tensor imaging (DTI) provide reliable information on the microneuroanatomy of the brain , we thenreceptor  indicatereceptor . These dreceptor , 37.Ezrin, radixin and moesin (ERM) are a group of evolutionarily-conserved proteins that regulate the reorganization of the actin cytoskeleton in different cell systems . A more in vitro and an ischemic lesion in vivo.uPA induces axonal recovery in the ischemic brain. The observation that in the adult brain uPA is found in few growth cones led us to study whether uPA/uPAR also had an effect on axonal recovery. To answer this question, we performed an immunocytochemical study with anti-uPAR antibodies in axons cultured from cerebral cortical neurons at various time-points after the induction of a mechanical injury. These experiments revealed that uPAR is abundantly expressed in the peripheral region of growth cones re-emerging from the injured site. Subsequent studies showed that treatment with uPA accelerated the formation of new growth cones and the re-emergence of axons from the injured border by a mechanism that did not require plasmin generation but was mediated uPAR- and its co-receptors \u03b21 integrin- and LRP-1-mediated Rac-1 activation . These rin vivo in an animal model of tMCAO [uPA promotes a cross-talk between astrocytes and the injured synapse. A growing body of experimental evidence indicates that astrocytes play a central role in the recovery process from an ischemic injury . In lineof tMCAO . More imof tMCAO .The data discussed above suggest a model in which the release of uPA by neurons that have suffered an ischemic injury promotes synaptic recovery at multiple levels, by reorganizing the actin cytoskeleton in the pre- and postsynaptic terminals and triggering a crosstalk between astrocytes and the injured synapse that leads to its recovery after the induction of a hypoxic injury . Future Studies published to this date indicate that uPA has a neurorestorative effect not only in the cerebral cortex but also in subcortical axons. However, it will be interesting to know if this effect is specific to neurons of the frontoparietal cortex and axons of the internal capsule that have been used in the studies published to this date, or if uPA/uPAR binding also have a neurorestorative effect on other brain structures. Moreover, it needs to be investigated whether the recovery of axons and dendrites induced by uPA results in the formation of new tracts and connections between the area affected by the ischemic injury and the healthy brain. Importantly, if should also be investigated if the synaptic effect of uPA also leads to the formation of aberrant connections and tracts with harmful consequences for brain function. Once these and other questions are answered, preclinical and clinical studies are warranted to determine if treatment with ruPA can be used to improve functional outcome in acute ischemic stroke patients. Indeed, the fact that ruPA can be safely administered to acute ischemic stroke patients  greatly"}
+{"text": "Since these cytokines influence greatly the magnitude of the cascade of inflammatory events, the proportion and the actual amount of each among the cytokine group may be a characteristic of each type of infections. Immune modulation by systematically up-regulate or down-modulate these cytokines would conceivably have major therapeutic potential. We have recently shown that two alleles of Ran cDNAs \u2013 RanT/n and RanC/d \u2013 may possess these characteristics. Thus the applica-tion of Ran to the treatment of septic shock, lethal anthrax shock, or adenovirus-induced toxicities may open up many interesting possibilities in the future.Host innate immune response represents a vital immediate defense against infections by a diverse group of microorganisms that include bacteria, viruses, and fungi. Many types of cell surface receptors in mammalian cells specifically recognize particular groups of microorganisms and transmit response signals to the nuclei via multiple signal transduction pathways. These signaling pathways must merge at some point and are likely to be redundant, as the host innate immune response to many microorganisms is remarkably similar; it is characterized by the production of proinflammatory cytokines such as TNF"}
+{"text": "The sustainability problems to the SS has led to a glowing debate about what the full retirement age should be and if working longer is a plausible option for everyone or just for those who have some control over their retirement decisions . All ethno-racial groups have increased their average retirement age over the last years. However, Hispanics\u2019 retirement age is still lower even if they stated they plan to continue to work at retirement . Most studies about retirement timing have focused on middle-class Whites, and the prediction of planned or actual retirement separately. One of the lesser studied complexities of the retirement conundrum concerns ethno-racial differences and cultural-related predictors of retirement timing . This study seeks to extend the understanding of differences between Hispanics and non-Hispanics regarding the timing of retirement relative to when they thought they would retire by including a broad array of cultural and family related predictors. Multinomial regression models were used. The results indicate significant differences between Hispanics and non-Hispanic Whites. Taking care of grandchildren was a significant predictor among Hispanics but not among non-Hispanic Whites. For Hispanics taking care of grandchildren, for over 20 hrs., was associated with a decreased probability of stating they will never retire. The increase of one dependent was associated with an increased on the probability of retiring earlier than planned. The effect of one additional dependent was larger for non-Hispanics."}
+{"text": "Satisfactory homogenization of cultured cells is a necessary prerequisite to any fractionation schedule. Protocols are given for homogenization in iso-osmotic (A) and hypo-osmotic (B) media that should be broadly applicable to any cell type and to any subsequent fractionation procedure. Alternative procedures are also summarized in the Notes section, but detailed operation of some of the automated devices is beyond the scope of this short Protocol Article."}
+{"text": "Background/Purpose: Young and adult children have experienced caring for people who have been diagnosed with dementia. Caregiving needs affect family members who become the primary caregivers in care transition from hospital to home. This study aims to synthesize primary qualitative research on the experiences of children caregivers of older adults with dementia. Method: This is a systematic review describing young and adult child caregivers\u2019 experiences in caring for patient with dementia in home-based care. Data sources were published literature written in English from CINAHL, Scopus, PubMed, and PsychoINFO (published from January 1976 to October 2018). The thematic synthesis approach was also applied to generate theory generating meta-synthesis research (TGMS). and to describe the process of caring for demented patients by caregivers. Result: Eight primary studies reporting 388 potential studies were included. Four themes emerged: 1) well-being which included encouraging and destructive well-being; 2) role transition which included positive or negative role transformations; 3) caregiver needs which included medical and nursing information or knowledges and health care services/community services; and 4) the challenge of dementia which included symptoms of dementia which were impairing. Conclusion The findings of this meta-synthesis study support evidence of well-being among adult children in caring for people with dementia in transition phases. We present thematic synthesis that could be useful to professionals working with caregivers and patients with dementia. We suggest that research importance should shift towards the development and evaluation of care transitions intervention, especially professionals preparing support after diagnosis."}
+{"text": "The failure of NK1 receptor antagonists to show analgesic activity in clinical trials in spite of abundant preclinical evidence for a role of this neuropeptide in nociception, makes it somewhat dangerous to speculate on the nociceptive role of other neuropeptides, especially with respect to therapeutic utility of receptor antagonists! However, CGRP is the primary afferent peptide with the strongest evidence of a role in pain perception. It is found in a greater proportion of sensory neurones than other peptides and is a constituent of A[delta ] as well as C-fibres. Inflammation of peripheral tissues upregulates production of CGRP in sensory ganglia, coincident with the development of hyperalgesia, and CGRP knockout mice have attenuated hyperalgesic responses. CGRP is released into the dorsal horn of the spinal cord (DHSC) by noxious peripheral stimuli and excites nociceptive DHSC neurones on local application. The peptide antagonist CGRP8-37 blocks the response to exogenous CGRP and can reduce the response of DHSC neurones to noxious peripheral stimuli. CGRP8-37 has also been shown to have behavioural antinociceptive properties when given intrathecally. Conversely, injection of CGRP itself to the PAG or n. accumbens has been reported to have antinociceptive effects that are reversed by CGRP8-37. With the advent of potent non-peptide antagonists such as BIBN4096BS we should soon be able to determine whether systemic blockade of all CGRP receptors produces antinociception without limiting side effects."}
+{"text": "Heart disease is a common manifestation in conditions of iron imbalance. Normal heart function requires coupling of iron supply for oxidative phosphorylation and redox signalling with tight control of intracellular iron to below levels at which excessive ROS are generated. Iron supply to the heart is dependent on systemic iron availability which is controlled by the systemic hepcidin/ferroportin axis. Intracellular iron in cardiomyocytes is controlled in part by the iron regulatory proteins IRP1/2. This mini-review summarises current understanding of how cardiac cells regulate intracellular iron levels, and of the mechanisms linking cardiac dysfunction with iron imbalance. It also highlights a newly-recognised mechanism of intracellular iron homeostasis in cardiomyocytes, based on a cell-autonomous cardiac hepcidin/ferroportin axis. This new understanding raises pertinent questions on the interplay between systemic and local iron control in the context of heart disease, and the effects on heart function of therapies targeting the systemic hepcidin/ferroportin axis.  \u2022Iron is essential for normal heart function but excess iron is detrimental to it.\u2022Cardiomyocyte iron levels are a balance between uptake and release.\u2022Cardiomyocyte ferroportin is essential for iron release, and for normal cardiac function.\u2022Hepcidin produced by cardiomyocytes regulates local iron release.\u2022The cardiac hepcidin/ferroportin axis is essential for heart function. This supply is achieved primarily from the recycling of iron from senescent red blood cells in the reticuloendothelial macrophages 2The average humy weight iron predominantly present in ferritin and within the mitochondrial compartment +2 is taken up into cardiomyocyte through LTCCs; a route of uptake that is not coupled to the sensing of size of LIP, because LTCCs are not regulated by IRPs 2+in the heart is considerably lower than that of the liver 2+, impinges directly on excitation-contraction coupling in cardiomyocytes, which may account for the diastolic dysfunction seen in the early stages of disease The requirement for such tight control of cardiac iron levels may also explain why heart failure is a common denominator in conditions of systemic iron imbalance. Iron overload cardiomyopathy is the leading cause of death in primary iron overload and an important co-morbidity in secondary iron overload Another form of iron imbalance is iron deficiency. It is the most widespread nutritional disorder worldwide, including in industrialised nations, where it commonly co-exists with cardiovascular disease The mechanisms underlying the detrimental effects of iron deficiency in heart failure are only beginning to be explored. In part, iron deficiency anaemia affects the heart by reducing muscle exercise capacity, and limiting oxygen availability for use in oxidative phosphorylation within cardiomyocytes 3Irp1 and Irp2 genes. Such mice have an impaired left ventricular response to dobutamine challenge and an exacerbated injury following myocardial infarction Like other cells in the body, cardiomyocytes acquire iron predominantly by uptake of transferrin through TfR1. The importance of TfR1 for cardiac function is supported by the finding that mice lacking cardiac TfR1 manifest severe heart failure One feature of cardiomyocytes is that they also express relatively high levels of ferroportin and hepcidin, despite having no role in systemic iron control The function of cardiac hepcidin was interrogated using two approaches The cardiac hepcidin/ferroportin axis also protects the heart in the setting of systemic iron deficiency. Indeed, animals with hepcidin-deficient hearts developed a greater hypertrophic response to sustained dietary iron restriction than their littermate controls Comparison between cardiac and ubiquitous mouse models of disrupted hepcidin/ferroportin axis further reveals that cardiomyocyte iron levels are a balance between local homeostasis, achieved through the cardiac hepcidin/ferroportin axis and systemic iron homeostasis, controlled by the systemic hepcidin/ferroportin axis. For instance, despite a marked increase in cardiac ferroportin levels, systemic loss of hepcidin responsiveness did not lead to the same cardiovascular dysfunction seen in mice with a cardiac-specific loss of hepcidin responsiveness 4The finding that the cardiac hepcidin/ferroportin axis is essential for cardiomyocyte iron homeostasis and heart function poses a number of pertinent questions. Rat studies have shown that hepcidin RNA and protein are upregulated in both the ischemic portion of the infarcted heart and in the serum of infarcted animals 24\u2009h after myocardial infarction MI British Heart Foundation Intermediate Fellowship FS/12/63/29895.S.L-L. is funded by a S.L-L. drafted the manuscript and produced the figure."}
+{"text": "In social interactions we are constantly categorizing objects and people. While social categories  are sometimes ambiguous, the categorization process seems to be immediate and effective. Our brains are organized hierarchically to achieve efficient categorization. A dynamic interactive model considers social categorization as an outcome of the dynamic interplay between bottom-up perceptual representation and top-down impact of prior social knowledge paired with a category  by calculating the neural pattern similarity of each atypical trial with the average neural pattern of its opponent category . Stolier and Freeman  increasiHand tracking paradigm reflects dynamic updates of a decision process as the hand's attraction toward each category provides an index regarding the extent of its activation. However, hand attraction may also be spontaneously guided through perceiver's bias toward \u201cin-group\u201d faces (Lazerus et al., Perceivers activate relevant stereotypes associated with a category in a quick-and-automatic fashion. Multiple social categories are processed interdependently if stereotypes related to categories overlap. For instance, the Asian race is commonly linked with femininity, meaning that categorizing a typical Asian-male face as male may be hindered. Stolier and Freeman minimized such stereotype-driven biases by collapsing gender when the neural pattern of race categorization was classified and vice versa. However, the relation between the trajectory deviation and neural pattern in the OFC Shkurko,  should bThe function of the pre-SMA/dACC in social categorization remains a large topic of debate. For instance, the dACC was reported to be activated when participants passively viewed stereotypically incongruent faces (e.g., happy Black male; Hehman et al., This commentary points out some novel avenues toward a true characterization of neural mechanism of social categorization process with combined hand tracking and neuroimaging techniques. Additional work investigating perceiver's individual differences in their preferential bias and experiences toward certain categories are warranted. In addition, the neural coupling between rFG and pre-SMA/dACC and the association between neural responses and hand trajectory deviation in the presence of biases should be further investigated. Such investigations will provide a clearer understanding into the role of rFG and pre-SMA/dACC in social categorization. Moreover, little is known about the causal influence of top-down mechanism on the social categorization process. Further investigations are required to improve the understanding of the role of the OFC in social categorization. In conclusion, while this work provided compelling evidence that social categorization is accomplished through dynamic competition in the rFG with assistance from the pre-SMA/dACC, additional work is required to assess the model generalizability and provide a clearer understanding into neural mechanisms that underlie social categorizations, especially in the presence of biases and perceiver stereotypes.XJ and RS both made substantial intellectual contributions to the manuscript and approved the final version for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "A Story Circle refers to a group of individuals in a comfortable social environment sharing personal experiences through stories to explore problems shared by a community and facilitate artistic representation of experiences of interest. In this pilot study, we examined the feasibility of Story Circles to facilitate qualitative inquiry of the experience of cognitive problems among older adults. A convenience sample of six cognitively intact, community-dwelling older adults  with self-reported cognitive complaints participated in a 90-minute Story Circle as well as a follow-up phone call. Each shared a personal story of experiencing a cognitive complaint and related these experiences to those shared by others in relation to a prompt provided by the group facilitator. Participants reported enjoying the Story Circle experience  and interest in participating in future Story Circles . Common themes included a sense of community established during the group that persisted after its conclusion as well as a normalization of the experience of occasional cognitive problems. Story Circles may be a useful data collection method to enhance understanding of complex phenomena within a social context."}
+{"text": "Hepatitis C virus (HCV) is the second largest contributor to liver disease in the UK, with injecting drug use as the main risk factor among the estimated 200\u2009000 people currently infected. Despite effective prevention interventions, chronic HCV prevalence remains around 40% among people who inject drugs (PWID). New direct-acting antiviral (DAA) HCV therapies combine high cure rates (>90%) and short treatment duration (8 to 12 weeks). Theoretical mathematical modelling evidence suggests HCV treatment scale-up can prevent transmission and substantially reduce HCV prevalence/incidence among PWID. Our primary aim is to generate empirical evidence on the effectiveness of HCV \u2018Treatment as Prevention\u2019 (TasP) in PWID.We plan to establish a natural experiment with Tayside, Scotland, as a single intervention site where HCV care pathways are being expanded , pharmacies and prison) and HCV treatment for PWID is being rapidly scaled-up. Other sites in Scotland and England will act as potential controls. Over 2 years from 2017/2018, at least 500 PWID will be treated in Tayside, which simulation studies project will reduce chronic HCV prevalence among PWID by 62% (from 26% to 10%) and HCV incidence will fall by approximately 2/3 (from 4.2 per 100 person-years (p100py) to 1.4 p100py). Treatment response and re-infection rates will be monitored. We will conduct focus groups and interviews with service providers and patients that accept and decline treatment to identify barriers and facilitators in implementing TasP. We will conduct longitudinal interviews with up to 40 PWID to assess whether successful HCV treatment alters their perspectives on and engagement with drug treatment and recovery. Trained peer researchers will be involved in data collection and dissemination. The primary outcome \u2013 chronic HCV prevalence in PWID \u2013 is measured using information from the Needle Exchange Surveillance Initiative survey in Scotland and the Unlinked Anonymous Monitoring Programme in England, conducted at least four times before and three times during and after the intervention. We will adapt Bayesian synthetic control methods  to generate the cumulative impact of the intervention on chronic HCV prevalence and incidence. We will use a dynamic HCV transmission and economic model to evaluate the cost-effectiveness of the HCV TasP intervention, and to estimate the contribution of the scale-up in HCV treatment to observe changes in HCV prevalence. Through the qualitative data we will systematically explore key mechanisms of TasP real world implementation from provider and patient perspectives to develop a manual for scaling up HCV treatment in other settings. We will compare qualitative accounts of drug treatment and recovery with a \u2018virtual cohort\u2019 of PWID linking information on HCV treatment with Scottish Drug treatment databases to test whether DAA treatment improves drug treatment outcomes.Extending HCV community care pathways is covered by ethics . Ethical approval for extra data collection from patients including health utilities and qualitative interviews has been granted (REC ref: 18/ES/0128) and ISCRCTN registration has been completed (ISRCTN72038467). Our findings will have direct National Health Service and patient relevance; informing prioritisation given to early HCV treatment for PWID. We will present findings to practitioners and policymakers, and support design of an evaluation of HCV TasP in England. Our control sites in the rest of Scotland and England were not randomised so there will be confounding and uncertainty in the intervention effect estimates.Hepatitis C virus treatment and prevention strategy in UK (and Europe) is evolving - motivated both by WHO \u2018elimination targets\u2019 and falling drug prices \u2013 which may contaminate our controls.However, our statistical models suggest that we should have sufficient power to detect an intervention effect and can model changes over time.We will develop dynamic transmission and economic models that can estimate cost-effectiveness including the prevention benefit of this intervention.We are conducting multiple nested qualitative studies and training and using peer researchers.Infection with hepatitis C virus (HCV) is a progressive disease that over 20 to 40 years can lead to liver cancer and premature death. HCV is the second largest contributor to liver disease in the UK and one of the few causes that is curable.http://www.hps.scot.nhs.uk/resourcedocument.aspx?id=5863). HCV transmission models suggest that primary prevention through NSP and OST alone is insufficient to achieve substantial reductions (of the order of 40% or more within 10 years) in HCV prevalence among PWID in the UK.We have reviewed the effectiveness of traditional primary prevention against HCV \u2013 opioid substitution treatment (OST) and needle and syringe programmes (NSPs).Prevention of hepatitis C disease and HCV transmission is now possible because highly effective, tolerable, short-course interferon-free direct-acting antiviral therapies (DAAs) are available for all HCV genotypes with cure rates \u2013 defined as sustained virological response (SVR) - exceeding 90%.Clinical guidelines in Europe and USA changed from recommending prioritising HCV treatment to people with moderate-to-severe liver disease towards removing any restrictions and recommending that people at risk of transmission irrespective of fibrosis stage are offered treatment.In a pilot study (\u2018Eradicate C\u2019) in Tayside we showed that we can increase HCV case-finding and engage and successfully treat PWID in the community.Alongside a natural experiment in Tayside, we will collect information to assess the treatment facilitators and barriers. Historically it has proven very hard to engage PWID in HCV treatment.Finally it has been hypothesised that successful HCV treatment in PWID may positively impact on understandings of self and identity and improve treatment of drug use disorders.Our intention is to create and conduct a mixed methods study, including qualitative studies and economic evaluation, of a natural experiment of HCV TasP among PWID. We also will develop methods for evaluating HCV TasP.intervention comprises the scale-up of HCV treatment in PWID which has started early in Tayside. By combining support from Scottish Government, National Health Board Tayside (NHS Tayside) and industry  we can deliver rapid intensive scale-up of HCV treatments for PWID . We have developed multiple integrated community HCV care pathways, including novel care pathways in pharmacies, a low threshold NSP, drug treatment services and prisons ) coordinate and deliver case-finding and treatment across the pathways in Tayside .2) including the cities of Dundee and Perth and the counties of Angus and Perth & Kinross, situated in the east of Scotland with a population of 416\u2009000. It is a mixture of urban and rural environments with some of the most affluent and most deprived areas in Scotland. It is therefore a representative microcosm of many areas in the UK.The region of Tayside co-localises to NHS Tayside which is the provider of healthcare to a geographical area of 2903 sq mi (7519\u2009kmhttps://www.hps.scot.nhs.uk/resourcedocument.aspx?id=6621).Apart from expansion of community HCV care pathways, no new clinical procedures will be investigated and all PWID with chronic HCV will be offered oral DAA HCV treatment compliant with the Scottish clinical guidelines  among PWID in the community (not just in the patients who undergo HCV treatment). Prevalence will be monitored using the NESI and UAM surveys, as detailed below. During 2017 to 2022, three waves of data collection for NESI (n=7500) and five to six for UAM (n=17\u2009000 in England) will measure this outcome.The In our pre-intervention period from 2010/2011 to 2016 there have been four NESI surveys in Scotland  and six UAM surveys in England , which have involved the collection of DBS linked to questionnaire data. Participants are recruited at sentinel sites by a team of trained interviewers in Scotland (at over 100 NSP sites) and by agency staff in over 60 low-threshold drug agencies across England.The DBS samples collected in NESI and UAM have all been tested for HCV antibody, using the same methods (where sensitivity and specificity of the assay on DBS are close to 100%),All NESI and UAM samples will be tested for HCV antibody and RNA PCR to assess the impact of HCV therapy scale-up \u2013 which is critical as trends in chronic infection and antibody status will diverge as more people are cured. In addition, we will undertake RNA PCR testing of all historical samples that were HCV antibody positive shown in Data on HCV PCR positivity among antibody negative samples identify recent infections and is used to estimate HCV incidence \u2013 which has fluctuated between 5 to 10 infections per 100 person-years across the UK during the last 5\u2009years.We updated estimates of the prevalence of PWID in TaysideWe will adapt the Causal Impact synthetic control Model (CIM) as proposed by Brodersen and colleagues.We have performed simulation studies to test power and evaluate the utility of the CIM assuming information on chronic HCV prevalence among PWID shown in . ProvideThe qualitative study design has two distinct arms focusing on the intervention providers, and the intervention recipients.A purposive sample of 30 intervention providers, comprising nursing leads and key individuals from collaborating organisations will be approached directly by the lead hepatitis nurse. Seven focus groups will be convened according to professional role and locality:HCV healthcare specialists (nurses and physicians).Community pharmacists.Prison staff .\u2018Drug workers\u2019 (from OST and NSP services).Each focus group will consist of a maximum of six individuals and ideally comprise multi-agency mixed groups. Individual interviews by telephone will be offered for those hesitant to join a group (estimate 10 interviews). Topic guides informed by previous work in this areaThe intervention recipient arm of the study will comprise both cross-sectional and longitudinal elements. A cross-sectional approach will be employed to recruit 6 to 10 participants who do not take up the offer of treatment. These individuals will be recruited through the treatment pathways or through our peer-researcher networks. The longitudinal element will follow a cohort of up to 40 individuals recruited following their course of HCV treatment. These individuals will be purposively sampled from the existing services in which HCV TasP has been embedded , and then followed-up at 1\u2009year post-treatment (with 70% expected to be followed-up).https://www.youtube.com/watch?v=9ZZo3fKOXlg.Participants will be recruited by hepatitis nurses or other clinical staff in Tayside and the face-to-face semi-structured interview will be conducted by peer-researchers, trained and guided by experienced qualitative researchers. Dr Magdalena Harris explains the importance of the use of peer researchers within the context of EPIToPe: Nvivo v.10 software will be used to code and manage qualitative data. First level analysis will be deductive, guided by the research questions, and peer researchers will be consulted for input and feedback during the analytical process.Interviews and focus-groups will be audio-recorded using encrypted digital voice recorders, transcribed verbatim and anonymised. (https://www.youtube.com/channel/UCBV8smLmkOQVT9D0OR-md1g/videos) we have used the Behaviour Change WheelWe will use the findings iteratively to update the HCV TasP logic model shown in Health Protection Scotland (HPS) link data on diagnostic HCV tests in the four largest Scottish NHS boards (including Tayside)Infectious disease models can test the extent to which observed changes in disease transmission can be attributed to specific interventions,We will test consistency between the model impact projections and observed changes in HCV chronic prevalence and incidence from Tayside to disentangle the impact of HCV TasP from other interventions (OST/NSP) or epidemiological changes, and predict the impact of the TasP on number of HCV infections averted. If they are not consistent then alternative evidence-based hypotheses will be tested for why the model projects a different impact and the best fitting models will then be used to project the impact of the intervention. This will be assessed compared with two alternative counterfactuals where treatment rates are either at pre-scale-up levels in Tayside or at the average level achieved in other UK sites over the scale-up period. The impact of any changes in OST and NSP coverage will also be assessed to determine the contribution of those changes on observed effects. Impact will be assessed in terms of the relative decrease in prevalence and incidence, as well as the number and per cent of infections averted in the intervention model projections compared with each counterfactual over different time frames. These model projections can also be taken forward to evaluate the possible impact of the intervention over next 5 or 10 years.https://www.nice.org.uk/process/pmg9/resources/guide-to-the-methods-of-technology-appraisal-2013-pdf-2007975843781). Probabilistic sensitivity analyses will be used to estimate the parametric uncertainty in the impact and cost projections. Cost-effectiveness results will be expressed in terms of incremental cost-effectiveness ratios and net monetary benefits estimated using NICE thresholds (\u00a320\u2009000 and \u00a330\u2009000 per QALY). We will plot cost-effectiveness acceptability curves to determine the probability of the intervention being cost-effective compared with different willingness-to-pay thresholds. Analyses of covariance methods will be used to summarise the proportion of the variability in the incremental costs and QALYs explained by uncertainty in different input parameters. Univariate sensitivity analyses will consider the effect of changes in important parameters such as time horizon, treatment cost and discount rate.We will evaluate the cost-effectiveness of the intervention  compared with status quo (expected rate of HCV case-finding and treatment among PWID in the rest of the UK) from a healthcare provider (NHS) perspective, with the cost-effectiveness of the different settings where case-finding occurs also being assessed. The cost-effectiveness model will be based on the same dynamic impact model, adapted to include HCV disease progression stages and tracking of health outcomes among PWID after cessation of injecting.We focus on the incremental or additional resource costs associated with the intervention in Tayside. These costs, in part based on our earlier work for other studies, will include such things as the nurse time spent on intervention related activities  as well as additional HCV testing and treatment costs, any additional OST costs due to HCV testing or treatment, and other staff time at the NSP, drug treatment centres and prisons involved with the intervention. Most of the incremental costs can be defined as variable (driven by extra nurse time and HCV testing/treatment costs). NHS HCV care costs and health utilities will be attached to each disease stage, based primarily on previous syntheses and models, which assume that PWID have a lower quality of life (QoL) than non-PWID of a similar age, gender and liver disease stage.Patient and public involvement (PPI) was led by the Hepatitis C Trust and supported by qualitative research assessing barriers and facilitators to HCV treatment access . The SDF were also actively involved in the development of EPIToPe. The input from PPI groups has influenced the design of care pathways and has ensured that peer research is an essential element of the qualitative strand of EPIToPe.A pilot National Institute for Health Research (NIHR) funded study in England (HEPCAT) responding to NICE Guidance on Hepatitis Case Finding was co-designed with Hepatitis C trust. It showed that Hepatitis C Facilitators and peer-support networks can increase the uptake of HCV case-finding and HCV treatment readiness in addiction services. This pilot study and our studies in Dundee/Tayside will influence how HCV treatment can be scaled up in England and our proposed evaluation HCV treatment as prevention.Peer researchers will be trained to conduct the longitudinal study with PWID treated for HCV and will be involved and contribute to the analysis of the findings. Peer researchers and SDF will be members of the project management group and steering committee.Dissemination events will be held in Dundee to discuss and present the findings from the qualitative studies with patient groups and services. These will be facilitated by SDF to support active contribution from our peer researchers. The study findings will be summarised and promoted through SDF website, social media platforms and through their sector-wide conferences in Scotland. Hepatitis Scotland, who are hosted within SDF, together with patient and public groups in England will take an active role in the wider national and international dissemination of the research, it\u2019s translation into patient meaningful materials and its integration into a national policy context. The research will also be promoted via Hepatitis C Trust and Public Health England.Several limitations arise from the \u2018natural experiment\u2019 design as our intervention and controls were not randomised. In the UK and many other countries there is no longer sufficient equipoise in clinicians and policymakers \u2013 given WHO and national strategies on HCV \u2018elimination\u2019 \u2013 to mount an randomised controlled trial of HCV TasP. As a result, there will be confounding and additional uncertainty in the measurement of the intervention effect. However, we consider that a natural experiment and use of synthetic control methods to be a more robust design than simple before and after studies. Our preliminary simulation work also suggests that we should have sufficient power to detect the large intervention effect that is planned.We know also that HCV treatment and prevention strategy in UK (and Europe) is evolving \u2013 motivated both by WHO \u2018elimination targets\u2019 and falling drug prices \u2013 and our control sites in Scotland and England may increase HCV treatment rates earlier than expected. This will complicate the analyses a little and potentially dilute the intervention effect. We are confident that we can adapt the synthetic control methods to take account of changes over time \u2013 and that because Tayside has started so early in scaling up HCV treatment that we will have time to detect a difference in the outcome.The lack of randomised controls means that we have to generate the counterfactual of \u2018no HCV treatment scale-up\u2019 through our HCV transmission model so that we can subsequently estimate cost-effectiveness of the intervention in Tayside. This is not ideal but has become standard practice in economic models of novel HCV treatment interventions \u2013 and we are involved with the modelling of HCV treatment pathways through homeless centres, prison, Accident and Emergency (A&E), pharmacies, specialist drug clinics and NSPs . NHS England\u2019s HCV strategy (2016 to 2019) prioritised 10\u2009000 patients per year in line with the declared priorities of the network which could (and in many cases did) include people who use drugs at risk of transmission."}
+{"text": "Operational taxonomic units (OTUs) level analyses confound with the observation that dysbiosis in gut microbiota is not just limited to eubacteria species, but also to other domains like archaea and eukaryotes. We found that some of healthy eubacterial population retained together with Oxalobacter formigenes and Lactobacillus plantarum colonization in disease condition (p\u2009<\u20090.001 & FDR\u2009=\u20090.05). Interestingly, trans-domain species diversity has been less shared and dysgenic taxa augmentation was found to be higher. Oxalate metabolizing bacterial species (OMBS) and butyrate-producing eubacteria species were found to be decreased in Oxalobacter non-colonizers; and Prevotella and Ruminococcus species which may contribute to oxalate metabolism and butyrate synthesis as well. Our study underscores fact that microbial dysbiosis is not limited to eubacteria only hence suggest the necessity of the trans-domain surveillance in metabolic diseases for intervention studies.Analyses across all three domains of life are necessary to advance our understanding of taxonomic dysbiosis in human diseases. In the present study, we assessed gut microbiota  of recurrent oxalate kidney stone suffers to explore the extent of trans-domain and functional species dysbiosis inside the gut. Trans-domain taxonomic composition, active oxalate metabolizer and butyrate-producing diversity were explored by utilizing  Upon dissecting non-intestinal metabolic disorders like obesity1, cardiovascular disease2 and chronic kidney disease3, it was understood that dysbiosis in gut eubacteria has partial verdict and indicates towards the direction for interventions in the diagnosis, treatment, and probable prevention. Most of the microbiome components have originated from the eubacteria and are diverse in genes, genomes, and their products in gut ecology4. However, other components remain elusive regarding knowledge of their diversity and role in host health.The human gut microbiome is considered as an effective metabolic organ; several host vital metabolite dependencies have been systematically incorporated and disparagingly executed within gut by it. In fact, causes and consequences of many metabolic disorders have been rationalized using high correlation with specific gut inhabitants. Dysbiosis has been usually attributed to eubacteria as previously reported in literature. Variations in the eubacterial community referred to as dysbiosis; disturbs the host health status and is found Methanobacter (archaea) and Aspergillus species (filamentous fungi) were found to be prevalent in the diabetic state5.Trans-domain gut inhabitants include eubacteria, archaea, eukaryotes and their diversity are the key players in gut ecology. Trans-domain diversity inside the human gut is not yet fully explored in healthy state as well as in impaired health condition. In some reports generated on diabetes; 6, and humans by prognosticative ways7. The panoptic power of high throughput sequencing methods was confined to describe the species level taxonomic features of gut bacteria as it has limitations of short-read length as output. Prognosticative detection of disease associated flora is still elusive mainly due to the lack of the species-level taxonomic assignments. Apparently, defining the role of species of the gut inhabitant, along with qPCR-based species-specific detection of Oxalobacter formigenes have been indispensable in kidney stone endurers8 and only the metagenomic sequencing approach has been found productive10.Using high throughput sequencing methods, the variations in healthy gut flora were observed and disease associated bacteria were traced universally. The persistent colonization of unique gut microflora involved in non-intestinal metabolic disorders has been correlated with host health conditions. Moreover, disease associated flora for kidney stone disease was manifested and re-enlisted specifying signature flora in canines11, gave clues about the dynamics observed in the hyperoxaluria condition due to their activities. Here, we are reporting a comprehensive catalog of functional gene diversity using functional metagenomic library. We used the functional genes such as frc-gene to decipher OMBS diversity and but- and buk-gene for butyrate-producing bacterial species (SCFA producer) diversity. Comprehensive reports on species level diversity in gut inhabitants and kidney stone associated dysbiosis in human subjects were lacking. In the present study, we focused on assessment of species-level differences between the compositions of the intestinal flora in individuals with recurrent kidney stone to that of healthy individuals based on 16S rRNA gene traditional clone libraries for the eubacteria, 18S rRNA gene for microeukaryotes and ITS region for the fungal species diversity analysis.Functional metagenome strategy has proven to support the hypothesis related to the metabolic capacities and its diverse origin in the health status. Functional capacities of the eubacteria from the previous observations12. The colonization of Oxalobacter formigenes, a known oxalotrophic bacterium was directly linked to the disease prevalence8. In addition to the case-control study for recurrent kidney stone disease11, included healthy control study subjects to check whether that certain other healthy gut associated bacterial species may also dwell with the recurrent oxalate stone episodes. The comparatives in healthy subjects (HLT) and kidney stone disease subjects (KSD) , reflecting the 20.08% of HLT group flora  Fig.\u00a0. The qPC13; applying the hypergeometric test function (p\u2009<=\u20090.001), we found that such differential bacterial families are present and have their own role in KSD not by chance mechanism.The metagenomic imputation demonstrated the differential abundance of genes involved in oxalate metabolism in KSD  Fig.\u00a0. We founfrc-, but-, and buk-genes in the subpopulation  from p-hydroxyphenylacetic acid28. Absolute findings of novel bacterial species in human gut are leading towards greater exploration of gut microflora then we have ever speculated29. Some of species like Eubacterium siraeum has been reported for biosynthesis of conjugated linoleic acid30 and Klebsiella pneumoniae have a phospholipase D family protein as a novel virulence factor31.On the other hand, species level dysbiosis was found in disease conditions whereas, certain bacterial species which were involved in other diseases were augmented. Lactic acid fermenting-mucosa associated bacteria, Bacteroides plebeius32. Propionate production within the human gut microbiota was reported including Dialister succinatiphilus33. Eubacterium eligens has known for dietary fibers production by pectin34. Downshift pH 5.5 resulted in Faecalibacterium prausnitzii lowering and underlying atopic dermatitis35. Variety of carbohydrates including the inulin, pectin can be metabolized by Faecalibacterium and have efficient processing ability of D-glucosamine and N-acetyl-d-glucosamine36. Faecalibacterium prausnitzii is known anti-inflammatory commensal flora37 which have the ability to grow at oxic\u2013anoxic interphases38. This fact suggests that either hyperoxaluric condition may be responsible for enrichment of some oxalate utilizing bacterial genera that are not observed in healthy subjects; or due to the disturbed microflora inside the gut may impart the hyperoxaluric condition to the host are still unclear.For reduction in glycans and complex carbohydrates helping bacteria were depleted 39 and in rat models phytate has been shown to have inhibitory role on deposition of calcium oxalate stones40. Previous study has shown dissolution effect of lysine on calcium oxalate by considerably lowering the super-saturation of the urine41. Similarly, there are reports showing reduced levels of tyrosine in stone formers compared to control subjects42. Interestingly, our results showed significant degradation of lysine and metabolism of tyrosine by gut microbiota in KSD subjects suggesting that effective concentration of lysine and tyrosine needed for dissolution of calcium oxalate stones was never attained in these subjects, thus chances of recurrent stone formation are increased in these subjects. We observed that gut microbiota of KSD subjects was dominant with gene families involved in fatty acid synthesis. Fatty acid and bile acid malabsorption is a one of the risk factors for hyperoxaluria in mal-absorptive patients and low fat diet is often advocated to these patients to prevent hyperoxaluria43.Our PICRUSt analysis revealed several important findings of gut microbiome in relation to calcium oxalate stone formation. Inositol, which is also known as phytate seems to have important role in preventing calcium oxalate stone formation. Levels of inositol was found to be significantly reduced in people with calcium oxalate stone formers44. The current studies on the gut resident microbial eukaryotes give clues for either beneficial or commensal. Elucidating such crucial piece of gut community to cause of several diseases might be potential treatment factor cannot be denied.In the human gut diverse prokaryotic populations have been studied well compared with that of the eukaryotic fraction which are still underwayMethanobrevibacter smithii and Methanosphaera stadtmanae have the most dominant archaeal groups inside the human gut46. The two fungal phyla Ascomycota (which includes the genera Candida and Saccharomyces) and Basidiomycota are the prominent fungal diversity48. Our observation is also in agreement with the archaeal and fungal diversity in Indian population. Previous reports have indicated that dysbiosis in the fungal population of the human gut can be associated with intestinal disease and infections. In the present study, there is an evident change in the eukaryotic, archaeal and fungal populations in KSD patients as compared with healthy individuals. The results suggest that the selection pressure on the part of the host and the microbes shapes the structure, composition, and function of not only the bacterial populations but also the trans-domain diversity. However, this is the first report indicating a direct correlation between the kidney stone disease and altered diversity of gut microflora involving archaeal and fungal participants. Despite maintaining of an ecosystem the colonization of Oxalobacter formigenes inside the human gut as healthy gut flora10 describing the withholds host health features and other core microbiome as well9. As their absence corresponds to enhanced level of oxalate in systemic fluid49, replacement therapy granted the recovery from hyperoxaluria condition in humans50. Demonstrating the colonization status of Oxalobacter formigenes, we speculate the major role of this bacterium in settlement of functional eubacteria and trans-domain species as well as in symptomatic phase of hyperoxaluria i.e. oxalate stone disease  hereafter referred to as KSD, and Healthy control (n\u2009=\u200948) hereafter called HLT were involved in the present study. Subpopulations from this cohort had been already explained elsewhere as a case-control studyfrc-, but-,and buk-gene as functional genes and Archaeal 16S rRNA gene, microeukaryotic 18S rRNA gene and fungal ITS region as trans-domain gene amplicons were deposited to SRA-NCBI under accession number SRP067039.Eubacterial clone library sequences were deposited at NCBI GenBank with accession numbers KF229803-KF233412 and KF864681-KF866127. Raw sequences generated through Ion Torrent PGM in the present study including Supplementary TablesSupplementary File S2Supplementary File S7"}
+{"text": "We present a case of a 55-year-old male with a history of urethroscopic calculus removal who later developed urinary tract infection (UTI), complicated by periurethral abscess formation with osteomyelitis of the inferior pubic ramus and a urethrocutaneous fistula after surgical drainage of the abscess. UTI with periurethral abscess and urethrocutaneous fistula (watering-can perineum) is a rare complication of UTI. A periurethral abscess with pubic osteomyelitis has not been previously reported. The abscess can be managed by drainage and the fistula can be treated by urethroplasty after an initial suprapubic cystostomy.Urinary tract infection (UTI) with periurethral abscess and urethrocutaneous fistula is a rare occurrence.Escherichia coli. A perineal ultrasound revealed an abscess in the perineum, which extended to the proximal parts of the corpus spongiosum  was obtained and is held on record."}
+{"text": "Results from clinical studies suggest that drug relapse and craving are often provoked by exposure to drug-associated contexts. Since 2002, this phenomenon has been modeled in laboratory animals using the ABA renewal model. In the classical version of this model, rats with a history of drug self-administration in one context (A) undergo extinction in a different context (B) and reinstate (or relapse to) drug seeking after exposure to the original drug-associated context (A). In a more recent version of the model introduced in 2013, the experimental conditions in context A are identical to those used in the classical model, but drug-reinforced responding in context B is suppressed by probabilistic punishment. The punishment-based ABA renewal model is proposed to resemble abstinence in humans, which is often initiated by the desire to avoid the negative consequences of drug use. The goal of our review is to discuss similarities and differences in mechanisms that play a role in suppression of drug seeking in context B and context-induced relapse to drug seeking in context A in the two models. We first describe psychological mechanisms that mediate extinction and punishment of drug-reinforced responding in context B. We then summarize recent findings on brain mechanisms of context-induced relapse of drug seeking after extinction, or punishment-imposed abstinence. These findings demonstrate both similarities and differences in brain mechanisms underlying relapse in the two variations of the ABA renewal model. We conclude by briefly discussing clinical implications of the preclinical studies. A major obstacle in the treatment of drug addiction is relapse to drug use after periods of abstinence  operant learning Bouton , 2000. OAn important difference between extinction and punishment is that during extinction, the subject must learn a new association in which the operant response now leads to no reward (no outcome). In contrast, during punishment, the subject learns about a new relationship between the original operant response and a second stimulus (footshock), which has opposite motivational valence to the original appetitive stimulus . Therefore, the key differences between extinction and punishment are that punishment involves a continued presence of the appetitive stimulus (reward), and that there is an additional aversive stimulus in punishment (shock). This operational difference causes differences in the underlying psychological mechanisms that are responsible for controlling behavior.In extinction, new learning occurs regarding the fact that the response no longer leads to the drug reward (the outcome), and drug seeking is reduced. Extensive research on Pavlovian conditioning has led to the proposal that the extinction context functions as an occasion setter Holland . In thisThe learning that occurs during punishment can form both operant and Pavlovian associations  activity is critical for context-induced relapse to alcohol seeking, independent of the method used to achieve abstinence. Reversible inactivation of LH with muscimol+baclofen (GABAa and GABAb agonists) decreases context-induced relapse to alcohol seeking after either extinction or punishment  core in context-induced relapse to alcohol seeking after either extinction or punishment. NAc core injections of muscimol+baclofen or the dopamine D1-family receptor antagonist SCH23390 decrease context-induced relapse to alcohol seeking after extinction, and NAc core SCH23390 injections decrease context-induced relapse after punishment  has been shown to decrease context-induced reinstatement of extinguished cocaine seeking  on context-induced relapse after either extinction or punishment in context B , even though the discrete cues are previously extinguished in a different context Conklin . The genFinally, the finding that the role of the amygdala in context-induced relapse depends on the method used to achieve abstinence has implications to both animal models of relapse and human relapse. Regarding animal models, this finding highlights the importance of studying relapse under abstinence conditions that more closely mimic the human condition (Marchant et al."}
+{"text": "Acid-secreting parietal cells from the gastric mucosa are widely studied as a model in studies on ion transport and the endocrine/paracrine ECL cells effectively control parietal cell function. Discontinuous gradients of iodixanol for the purification of ECL cells were subsequently simplified to the use of a density barrier. This technique is now commonly used following initial centrifugal elutriation."}
+{"text": "Previous research into cross-cultural interactions in health care settings shows that care providers experience communicating with elderly ethnic minority patients as problematic. According to the social constructionist framework upon which this presentation draws, people negotiate the characteristics they ascribe to the world around them through talk. It is against this backdrop that the presentation \u2013 which is based on a focus group study with end-of-life care providers (n=60) \u2013 sets out to explore how care providers talk about communication difficulties with elderly ethnic minority patients. The presentation demonstrates how the study of communication difficulties can illustrative the challenges of cross-cultural interaction in end-of-life care settings. Through the attention on how communication difficulties are discussed, this presentation shifts the focus from the elderly ethnic minority patients and the reasons for why they are experienced as problematic when it comes to communication, to the actual process where these problems are negotiated."}
+{"text": "Over the past century, treatment of malignant tumors of the brain has remained a challenge. Refinements in neurosurgical techniques, discovery of powerful chemotherapeutic agents, advances in radiotherapy, applications of biotechnology, and improvements in methods of targeted delivery have led to some extension of length of survival of glioblastoma patients. Refinements in surgery are mentioned because most of the patients with glioblastoma undergo surgery and many of the other innovative therapies are combined with surgery. However, cure of glioblastoma has remained elusive because it requires complete destruction of the tumor. Radical surgical ablation is not possible in the brain and even a small residual tumor leads to rapid recurrence that eventually kills the patient. Blood-brain barrier (BBB) comprising brain endothelial cells lining the cerebral microvasculature, limits delivery of drugs to the brain. Even though opening of the BBB in tumor core occurs locally, BBB limits systemic chemotherapy especially at the tumor periphery, where tumor cells invade normal brain structure comprising intact BBB. Comprehensive approaches are necessary to gain maximally from promising targeted therapies. Common methods used for critical evaluation of targeted therapies for glioblastoma include: (1) novel methods for targeted delivery of chemotherapy; (2) strategies for delivery through BBB and blood-tumor barriers; (3) innovations in radiotherapy for selective destruction of tumor; (4) techniques for local destruction of tumor; (5) tumor growth inhibitors; (6) immunotherapy; and (7) cell/gene therapies. Suggestions for improvements in glioblastoma therapy include: (1) controlled targeted delivery of anticancer therapy to glioblastoma through the BBB using nanoparticles and monoclonal antibodies; (2) direct introduction of genetically modified bacteria that selectively destroy cancer cells but spare the normal brain into the remaining tumor after resection; (3) use of better animal models for preclinical testing; and (4) personalized/precision medicine approaches to therapy in clinical trials and translation into practice of neurosurgery and neurooncology. Advances in these techniques suggest optimism for the future management of glioblastoma. To start with I will review refinements in surgery including combination with other innovations.Glioblastoma is the most lethal primary brain tumor. Since the first surgical resection of a malignant astrocytoma was done in 1884, attempts to cure primary cancer of the brain by resection have been made since the start of modern neurosurgery more than a century ago. Since my first encounter with a case of glioblastoma at the start of my neurosurgical career 60 years ago, I have seen improvements in surgical technique, radiotherapy, and chemotherapy increase the median length of survival of patients only from 6 to 15 months. While standard of care for newly diagnosed glioblastoma include maximal resection, followed by radiation therapy given concomitantly with temozolomide followed by adjuvant TMZ chemotherapy, median time to progression is 6 months and overall median survival 15 months. Almost all tumors recur with more aggressive form of tumors and there is no standard of care for recurrent GBM. During the past two decades, applications of biotechnology and several innovative approaches have been tested both in the laboratory and clinical trials; their impact on survival is negligible because glioblastoma remains incurable. Currently, most of the projects for advancing therapy for glioblastoma listed in Table in vitro do not recapitulate conditions of in vivo tumor microenvironment; even clinical trials conducted in mixed population are not adequate to realize impact of an experimental drug.Although several innovations in treatment of glioblastoma have been introduced during the past three decades, evaluation of their efficacy is mostly limited to observation of progression free survival and overall survival. While CT and MRI measure tumor size, metabolic, and other changes at molecular level in response to treatment can be better indicators of response in the absence of an initial reduction of size. Conventional preclinical studies evaluating experimental drugs in cell lines There have been considerable refinements in surgical techniques. In the pre-brain imaging (CT and MRI) era, preoperative diagnosis with pneumoencephalography  raised suspicion of malignancy, which had to be confirmed by histological examination. Compared to modern refinement, neurosurgery of glioblastomas 60 years ago was crude as compared to meticulous dissection of benign brain tumors because it was considered a palliative procedure to relieve intracranial pressure and prolong life for a few months with resignation to the fact that the patient was going to die.Apart from providing adequate sample for histological analysis and removal of a mass to reduce raised intracranial pressure, excision of a tumor provides a cavity for application of local therapies for destruction of residual tumor mass and prevention of recurrence. Maximal removal that is consistent with neurological preservation is usually carried out and has been shown to prolong survival but does not reduce mortality. Radical extirpation of the tumor is often aimed at but is not possible due to infiltration of the tumor into the surrounding brain.Refinements in brain imaging techniques have contributed considerably in improving planning of surgical procedure. Intraoperative imaging, particularly MRI and use of 5-aminolevulinic acid helps in defining the margins of glioblastoma and for maximizing the extent of resection. According to a systematic review of randomized clinical trials, the impact of image-guided surgery on survival and quality of life are uncertain .Techniques such as cortical mapping, fluorescence-guided surgery, and intraoperative mass spectrometry are routinely used in the operating room for brain tumor resection. Optical coherence tomography, still in experimental stage, may fill the need for a non-invasive approach for real-time distinction between tumor and normal brain. Postoperative imaging provides a useful baseline for size of residual tumor and further evaluation of response to adjunctive therapies.One of the major refinements in neurosurgical techniques was the introduction of operating microscope, which had a remarkable impact on improving cerebrovascular surgery. It provides better visualization of distinction between the tumor and the normal brain to avoid damage to normal structures. Other refinements in tools for removing tumor tissue include ultrasonic aspiration to minimize trauma and laser vaporization to reduce bleeding and destroy cells in tumor bed by thermal effect. The FDA-approved NeuroBlate\u00ae System  is a minimally invasive robotic laser thermotherapy tool for glioblastoma that is being studied in the prospective multicenter clinical trial #NCT02392078 due for completion in 2020. The NeuroBlate System is used with MRI to provide a real-time image of a patient's brain for guiding the surgeon. This device is meant for glioblastomas that are not suitable for routine surgery due to their location. The aim is improvement in quality of life of the patient rather than prolonging survival.Surgery is supplemented with innovations in chemotherapy and radiotherapy that will be described separately. In addition to systemic chemotherapy and postoperative cranial radiotherapy, surgery provides an opportunity to apply some therapies during the procedure. Examples are implantation of chemotherapeutic agents and photodynamic therapy.Gliadel wafers consist of biodegradable polymer containing the chemotherapeutic agent BCNU (bis(bis-chloroethylnitrosourea), which are implanted during surgery at the tumor site diffuse into the surrounding tissue and provide therapeutic dose of BCNU locally. A systematic review of phase III trials has shown an increased overall survival from sequentially combining Gliadel wafers with radiotherapy and systemic temozolomide .Photodynamic therapy (PDT) is based on release of singlet oxygen with toxic effects on the tumor that occurs when a photosensitizer at the tumor site is exposed to laser light of a certain wavelength. PDT for cancer using talaporfin sodium with laser is approved in Japan. Progression-free survival of 1 year and an overall survival of 2 years and 8 months was shown in an open clinical trial of intraoperative PDT in glioblastoma . A prospImprovements in diagnostic technologies have played an important role in understanding the genetics and molecular biology of glioblastoma as a basis for developing therapeutics and evaluating their efficacy. Molecular diagnostics is used for discovery of biomarkers of brain tumors and some biomarkers can serve as diagnostics as well as targets for developing therapies, which explains the overlap between the two .Molecular analyses of genetic alterations in astrocytomas have been carried out to identify pathways leading to glioblastoma. Molecular diagnostics is an important basis for developing personalized therapy of glioblastomas. The most frequent single-gene alterations are mutation of the p53 tumor suppressor gene, amplification of the epidermal growth factor receptor (EGFR), homozygous deletion of the CDKN2a gene, and mutation of the PTEN (phosphatase and tensin homology) gene on chromosome chromosome 10q23. While most frequent chromosomal alterations are loss of chromosomes 10 and 9p and the gain of chromosomes 7 and 19 and were discovered by studies involving high-resolution comparative genomic hybridization (Magnetic resonance spectroscopy (MRS) mediated detection of oncometabolite 2-hydroxyglutarate (2HG) produced in tumors harboring mutation in the isocitrate dehydrogenase1 (IDH1). A prospective imaging study showed positive correlation between 2HG concentrations tumor cellularity, which differ significantly among high- vs. low-grade gliomas . These dCell-free DNA shed by cancer cells is a rich source of tumor-specific biomarkers, but DNA from CNS tumors cannot usually be detected in the blood. However, using patient-specific mutations as biomarkers, detectable levels of CSF tumor DNA were identified in 74% of brain tumors such as glioblastomas that abutted on CSF spaces .Alterations in EGFR, PDGFRA, PTEN, TP53, NF1, CDKN2A/B, and TERT promoter mutations are commonly found in primary glioblastoma, while the prevalence of IDH mutations is high in grades II and III astrocytomas, secondary glioblastoma, oligodendrogliomas, and oligoastrocytomas . SurvivaThere is a considerable interest in next-generation sequencing-based technology as it allows comprehensive mapping of genetic alterations such as single nucleotide polymorphism (SNP), fusions, and copy number variations and the epigenetic landscape of DNA methylation in brain tumors. A customized next-generation sequencing gene panel involving 0 genes commonly altered in brain tumors have been developed for the detection of Sahm et al. . With thThere is a need for a practical method to delineate glioblastomas from adjacent normal brain tissue during surgery. Several intraoperative imaging techniques have been developed for determining the resection margin in brain tumors; these include neuronavigation, MRI, ultrasound, Raman spectroscopy, and optical fluorescence imaging. Combined with discovery of contrast agents, both MRI and optical fluorescence imaging have improved resectability of brain tumors . FluoresThere are several biomarkers of glioblastoma and those relevant to management are listed in Table ALDH1A3, an enzyme plays important role in alcohol metabolism and lipid peroxidation is a specific biomarker for glioma stem-like cells (GSCs), and cells with high expression of ALDH1A3 expression are shown to be highly tumorigenic . In sampMGMT (O6-methylguanine-DNA methyltransferase) gene have been associated with response to alkylating chemotherapy  wafer implantation  as a biomarker of gliomas in preclinical and clinical diagnosis . A cliniAmong various biomarkers, only isocitrate dehydrogenase (IDH) mutations (prognostic), MGMT promoter methylation, and 1p/19q co-deletion (predictive) are being routinely used in clinic for glioma patients in the USA as well as the UK. More biomarkers are being tested in clinical trials, and it will be important in the future to distinguish prognostic biomarkers from predictive biomarkers to enable personalized therapeutic choices with least toxicity and better outcomes for patients with malignant gliomas .EGFRvIII amplification is targeted by EGFR vaccine rindopepimut.KIT amplification or mutation is target is targeted by KIT inhibitor imatinibPDGFRA amplification is targeted by PDGFR inhibitor dasatinibPTEN deletion or mutation is targeted by AKT inhibitor or mTOR inhibitor voxtalisibMDM2 amplification is targeted by a MDM2 inhibitor such as AMG232TP53 wild-type is targeted by a MDM2 inhibitor such as AMG232RB1wild-type is targeted by CDK4/6 inhibitor ribociclibExamples of biomarkers that are also targets for therapy of glioblastoma are:MicroRNAs (miRNAs) are small (about 22 nucleotide long) non-coding RNA that regulate gene expression by preventing mRNA translation by base pairing on complimentary sequences of RNA, have been implicated in various pathological processes in the human body. Using glioblastoma tissues and cell lines several groups of miRNAs have been identified whose expression is significantly altered in glioblastoma. Dysregulation of miRNA regulated genes is considered one of the key mechanisms in pathogenesis of glioblastoma, and several miRNAs involved in tumor initiation and progression have been described . TherefoSpecific to glioblastoma, the plasma levels of miR-21, miR-128, and miR-342-3p are found elevated and can distinguish glioblastoma patients from healthy controls or other types of brain tumors . InteresPronounced reduction of miR-218 in patients with highly hypoxic and necrotic glioblastoma contributes to temozolomide resistance as demonstrated in transplanted glioblastoma in mice, whereas tumor growth is significantly reduced with increase in survival in response to temozolomide in mice with high miR-218 . AccordiMolecular-targeted therapy based on miRNA expression in cancer stem cells can facilitate personalized and effective treatment strategies for glioblastoma in the future .Although temozolomide chemotherapy is the standard treatment for newly diagnosed glioblastoma, which is generally well tolerated with lower toxicity than nitrosoureas. However, combination to temozolomide with other anticancer agents have also been investigated.To avoid systemic toxicity of chemotherapy, various methods have been used to limit application to the tumor such as implants in tumor cavity following surgical excision, targeted delivery to glioblastoma following systemic administration, and selective delivery of higher concentrations to the tumor, e.g., by intraarterial chemotherapy. Delivery of monoclonal antibodies (MAbs) in glioblastoma will be discussed in the following section on immune therapy.Delivery of anticancer agents is limited by their inability to reach therapeutic levels in brain tumors with maximally tolerated dose regimens. Drug targeting by conjugating with protein such as transferrin has been extensively studied, as a targeting molecule transferrin helps the transport of drug to glioblastoma which contains abundant transferrin receptors on the surface. Transferrin-bearing therapeutic agents can be targeted to their site of action on brain tumors .Thermosensitive liposomes can encapsulate drugs to release them at the target site in the tumor in response to hyperthermia without exposing the surrounding normal brain to toxicity. Increase in efficacy of doxorubicin by release from a thermosensitive liposomal nanocarrier as compared to non-thermosensitive liposomes has been demonstrated in a mouse model of human glioblastoma .Angiopep-2 (An2) for BBB transcytosis and anti-CD133 MAb for specific delivery to glioma stem cells have been incorporated in a dual-targeting immunoliposome encapsulating temozolomide (Convection-enhanced delivery (CED) involves direct delivery of a therapeutic agent to the brain by injection or a catheter propelling the agent through interstitial spaces under a pressure gradient rather than passive diffusion. It has been used for both chemotherapy drugs and for delivery of macromolecules of some biological therapies for glioblastoma.A prospective, dose-escalation phase Ib study of the topoisomerase-I inhibitor, topotecan, given by CED in patients with recurrent glioblastoma resulted in significant efficacy as assessed by radiographic changes while using doses that were well tolerated by the normal brain . OverallSeveral chemotherapeutic agents used for glioblastoma such as nitrosoureas, temozolomide can cross the intact BBB, but larger molecules such as MAbs may not do so. BBB permeability may be increased in glioblastoma, but this is not a reliable factor in assessing delivery of a therapeutic for brain tumors. Several strategies for drug delivery across the BBB have been described; some of these involve circumventing the BBB, whereas other are directed at osmotic opening of the BBB . DisruptIntraarterial delivery of chemotherapy to the brain provides a many-fold delivery peak drug concentration in the tumor as compared to the same drug dose given systemically because of damage to the blood-brain barrier and neovasculature in the tumor. However, randomized trials on patients with glioblastoma have not shown a survival advantage with intraarterial BCNU as compared to intravenous administration. The limitations of this technique are significant vascular and neurologic toxicity that can lead to visual loss, stroke, and leukoencephalopathy. Although toxicity of intra-arterial chemotherapy could be reduced by using carboplatin- and methotrexate-based regimens, further clinical studies are needed to determine its utility in the treatment of glioblastoma.An animal experimental study has demonstrated the feasibility of direct delivery to brain and glioma tissue of cationic liposome after intraarterial injection via an intracarotid route during transient cerebral hypoperfusion . This maImmune therapy of cancer is progressing rapidly and has been applied to glioblastoma as well. Two types of immune therapies, monoclonal antibodies and vaccines, will be considered in this section. Immune gene therapy will be discussed under the section on gene therapy.Monoclonal antibodies (MAbs) are used for glioblastoma treatment because of their high specificity and affinity for biological targets to improve immunotherapy and for antiangiogenic action by targeting growth factor receptors such as VEGFR, EGFR, and PDGFR . MAbs ovBevacizumab is a MAb that binds to VEGF and inhibits the growth of tumor blood vessels. It is approved for the treatment of several cancers including glioblastoma for a decade. A systemic review of literature shows that use of bevacizumab prolongs OS either alone or in combination with a cytotoxic agent by about 4 months in recurrent glioblastoma but not in primary glioblastoma .The best-known example of an anti-EGFR MAb is cetuximab, which is approved for the treatment of other cancers but not for recurrent glioblastoma as phase II clinical trials failed to show its efficacy. MAbs with TK inhibitors targeting EGFR, a tyrosine kinase (TK), which is a receptor for therapeutic agents for glioblastoma such as T cells, oncolytic viruses, and nanoparticles is being investigated . AnotherDue to their large size, MAbs do not cross the BBB easily and nanobiotechnology-based strategies are required. These are described under the section on nanobiotechnology-based drug delivery.Immune checkpoint blockage is achieved by use of T cell inhibitory molecules such as anti-programmed cell death 1 (PD-1) antibody, which was first approved for the treatment of malignant melanoma. In contrast to use of cytotoxic T lymphocytes (CTL) against cancers, immune checkpoint blockade terminates immune response in a way that may activate exhausted CTL to destroy cancer . This apRationale for clinical trials of immune checkpoint blockade for newly diagnosed and recurrent glioblastoma is provided by results of preclinical studies . Further1. Numerous trials of vaccines employing various strategies against glioblastoma are being conducted from phase I to phase III. Although some have shown promising results, none has come close to curing it. New biotechnologies have enabled better and more effective vaccines for glioblastoma. Some of the more promising of these will be discussed here.The earlier vaccines for glioblastoma were crude preparation made from patients own tumor tissue and results were disappointing. As of August 2018, 88 clinical trials of vaccines for glioblastoma are listed on the US Government web site for clinical trialsDCVax, a dendritic cell (DC)-based personalized cancer vaccine cancer type with purified tumor-specific antigens or tumor cell extracts derived from tumor at the time of resection. DCVax-Brain is approved in Switzerland for the treatment of glioblastoma. In the US, in a phase I trial of autologous DC vaccine, expression level of tumor-associated antigens on glioblastomas cells or glioblastoma stem cell population correlated with prolonged overall survival and progression-free survival . The ongVaccination with autologous tumor lysate-pulsed DCs in conjunction with toll-like receptor agonists administered as adjuvant therapy was tolerated well both in newly diagnosed and recurrent glioblastoma patients. Interestingly, mesenchymal gene expression profile, which is mostly defined by inflammation-associated gene signature, may identifies a subgroup of glioblastoma patients likely to respond to immune-based therapy .Pre-conditioning with a potent recall antigen has been a viable strategy to enhance anti-tumor immune response. Experimental studies have shown that pre-conditioning the vaccine site with a potent recall antigen such as tetanus/diphtheria toxoid improves the efficacy of tumor-antigen-specific DCs . In a raOne of the ongoing phase II clinical trials, # NCT02808364, is evaluating safety and efficacy of \u201cPersonalized Cellular Vaccine for Recurrent Glioblastoma\u201d (PerCellVac2) in recurrent glioblastoma. This trial specifically uses immunization with autologous tumor cells, antigen pulsed DCsor allogeneic peripheral blood mononuclear cells. Results of this trial will be useful for determining the future course of action for cell-based immunotherapy in glioblastoma.A randomized phase III trial NCT00045968 is evaluating long-term effects of addition of an autologous DCVax\u00ae-L vaccine to standard therapy for newly diagnosed glioblastoma, i.e., after surgery and chemoradiotherapy, patients receive temozolomide plus DCVax-L or temozolomide alone. Because of the cross-over trial design, nearly 90% of the patients have received DCVax-L so far and the vaccine has improved the survival rates of some patients and those with median overall survival of 40.5 months are being analyzed further . The triThe epidermal growth factor receptor variant III (EGFRvIII) is an important vaccine target because its expression is tumor specific and has a promising role in immunotherapy of glioblastoma. Phase II clinical trials in patients with newly diagnosed glioblastoma showed that EGFRvIII-specific vaccine therapy improves progression free and overall survival . In a seHeat-shock proteins (HSPs) has been used to deliver a variety of tumor antigens to antigen presenting cells (APC) for immune stimulation. HSPPC-96 vaccine, based on internalization of HSP-96 by binding of to the CD91 receptor on DCs resulting in cleaved tumor peptides on major histocompatibility complex classes I and II, has been studied in patients with recurrent glioblastoma in a phase II, multicenter, clinical trial . A persoRecombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO) targets the neurotropic poliovirus receptor CD155, which is abundantly expressed on glioblastoma cells, and penetrates these cells to cause lysis and release of tumor antigens as well as molecules recognized by cells of the natural immune response . This rein vivo.A phase II clinical trial confirmed the absence of neurovirulent potential following intratumoral infusion of PVSRIPO in patients with recurrent glioblastoma and observed that survival rate of treated patients was higher at 24 and 36 months than the rate among historical controls . PatientNanobiotechnology-based strategies for drug delivery to cancer are described in detail elsewhere . Some ofMicelles can be used as carriers of anticancer drugs such as temozolomide (TMZ) to enhance delivery to glioblastoma. In an experimental study on a mouse model of implanted glioblastoma, pH-responsive micelles containing distearoyl phosphoethanolamine-PEG-2000-amine, N-palmitoyl homocysteine, and platelet-derived growth factor (PDGF) peptide as well as Dylight 680 fluorophore on the surface for targeting were used for delivery of TMZ . This reNanoparticles are promising tool for targeted delivery of oncology drugs. Nanoparticles made of poly(butyl cyanoacrylate) (PBCA) or PLGA coated with polysorbate 80 or poloxamer 188 have been shown to transport antitumor drug doxorubicin across the BBB . In an oIron oxide nanoparticles are particles with superparamagnetic properties, also known as superparamagnetic iron oxide nanoparticles (SPION) have been useful in MRI to locate brain tumors with precision and to target chemotherapeutic drugs into the tumors. Folic acid (FA) has been used as the targeting agent combined with polyethylene glycol (PEG) serving to improve biocompatibility and cellular uptake of nanoparticles. These nanoparticles has applicability beyond MRI mediated tumor detection because a variety of small molecules to target receptor tyrosine kinases on tumor or chemotherapy drugs, can be attached to these nanoparticles to facilitate delivery and efficacy.A biodegradable and nontoxic biopolymer is a universal delivery nanoplatform for design of nanomedicines for intravenous treatment of for malignant brain tumors. A polymeric conjugate of a MAb targeting the brain-tumor barrier for crossing it and attached to an antisense oligonucleotide that inhibits tumor angiogenesis by specifically blocking the synthesis of a tumor neovascular trimer protein, laminin-411, is released into the target tumor cell cytoplasm via pH-activated trileucine . This isA concept of targeted drug delivery to glioblastoma across the BBB is shown in Figure Biodegradable poly-lactic acid (PLA) nanoparticles conjugated with transferrin, an iron-transporting serum glycoprotein were loaded with BCNU for targeted delivery to transferrin receptor expressing glioma cells . EfficacMinicells are achromosomal cells formed in certain mutants of rod-shaped bacteria, are products of aberrant cell division, and contain RNA and protein, but little or no chromosomal DNA . DesigniThe surface of nanocarriers is functionalized with targeting MAbs as ligands to promote drug delivery to tumors with corresponding receptors. One problem with this approach is that when nanocarrier is exposed to biological fluids such as plasma, its surface is covered with various biomolecules forming a protein corona, which masks the targeting ability of the nanoparticle. A pre-adsorption process has been used to attach targeting MAbs to the surface of the nanocarrier, a capsule containing the anticancer drug, which prevents the formation of biomolecular corona and pre-adsorbed MAbs remain functional . The autRadiotherapy is usually combined with chemotherapy following surgery in different sequential combinations. There is no convincing evidence that addition of radiotherapy to chemotherapy increases survival in glioblastoma. Traditionally radiation therapy following surgery was whole cranium radiation, which exposed the normal brain to radiation with adverse effects such as cognitive impairment. Current practice is to use \u201cfocal\u201d or \u201climited-field\u201d radiation therapy covering 2\u20133 cm around the tumor, interstitial brachytherapy, and fractionated radiotherapy.Fractionated radiotherapy means splitting the total radiation dose into several fractions that are given over several weeks in combination with chemotherapy. The rationale for using a fraction of the total radiation dose enables normal cells surrounding the tumor to recover between treatments. Adverse effects of full dose radiation in a single session are reduced by fractionated therapy over several weeks. In case of glioblastoma, 30 fractions of radiotherapy dose of 60 Gy with adjuvant temozolomide is the current standard of treatment . Fractio125I seeds in the tumor cavity after resection to deliver high dose radiotherapy to the residual tumor with minimal radiation exposure in the surrounding brain tissue as compared to external-beam radiation. Nevertheless, radiation may leak into the surrounding healthy brain and may accumulate in other organs via systemic circulation. Three-dimensional iridium-192 (192Ir) high-dose-rate brachytherapy (Ir Knife) allows intratarget dose escalation with superior conformity, which compares favorably with linear accelerator-based stereotactic radiosurgery with a steeper dose fall off at margin of the tumor -chromic phosphate-polylactide-co-glycolide (32P-CP-PLGA) for controlled release of the isotope, combined with radiotracer 68Ga-3PRGD2, which targets integrin \u03b1v\u03b23 receptors or the tumor as well as neovasculature, has shown promising results of brachytherapy in a rat model of transplanted glioblastoma  is a type of non-invasive stereotactic radiosurgery for delivery of a high dose of radiation to a tumor. GKRS is suitable for recurrent glioblastoma as it spares the poorly demarcated healthy brain tissue surrounding the tumor from radiation-induced necrosis . DrawbacIn boron neutron capture therapy (BNCT), another form of heavy particle radiation, irradiation of the glioblastoma with low-energy neutrons is followed by the boron emits an alpha-particle that deposits high energy over a short distance systemic administration of a nonradioactive boron isotope. Monte Carlo modeling for BNCT of glioblastoma has shown that it increases the efficacy in destruction of tumor, but extension of the CTV margin may not increase the outcome of treatment significantly .Hyperbaric oxygen (HBO) is known to enhance the effect of radiotherapy by counteracting hypoxia within tumors, a fundamental feature of cancer cells that limits efficacy of radiation therapy . HBO is Viral oncolysis is a targeted therapy and oncolytic viruses are genetically modified to specifically lyse tumor cells. They are replication-selective rather than replication-defective viral vectors. Oncolytic viruses differ from viral vectors in that they increase in number in tumor cells and lyse the cells directly, not by transducing specific genes. Studies both in a mouse glioma model as well as on glioma stem-like cells from patients suggest that the efficacy of viral oncolysis HSV type 1 may be enhanced when used in combination with inhibitors of histone deacetylases or other proteins that modulate cellular trafficking of these therapeutic viruses . Most ofOncolytic virus delivery should be completely optimal and safe.Viruses should be monitored for replication or dissemination beyond the tumor.Reaction of immune system of the patient to oncolytic viruses should be closely monitored.Oncolytic virotherapy is administered into the residual tumor after resection of glioblastoma and may not penetrate all tumor cells. Some of the precautions that need to be observed during clinical introduction of oncolytic therapy include the following :OncolytGenetically modified bacteria can be used for selective destruction of glioblastoma. Genetically altered strains of bacteria such as Salmonella have been used as bacterial vectors for preferential delivery of anticancer drugs to solid tumors. Historically, bacteria have been used as oncolytic agents for malignant brain tumors. The most promising approach to glioblastoma was the use of genetically engineered bacteria that selectively destroys tumor cells while sparing the normal brain tissue . GeneticHyperthermia, i.e., raising the tumor tissue temperature to 41\u201346\u00b0C damages tumor cells by changes such as protein misfolding and disruption of signaling pathways leading to apoptosis. Hyperthermia can be induced by microwaves, infrared irradiation, ultrasound, and magnetic nanoparticles. In addition to destroying tumor cells, hyperthermia can also be used for targeted delivery of drugs to glioblastoma by thermosensitive release from drug carriers guided to enter the tumor. Gold nanoparticles can be used both as contrast agent for MRI and for photothermal therapy, e.g., gold nanorods have been used for thermal ablation of glioblastoma .Tumor treating fields (TTF), a non-invasive wearable technology, is based on low-intensity alternating electric fields, which disrupt mitosis and inhibit tumor growth. TTF is approved for glioblastoma by the FDA in US. A systematic review of preclinical studies and clinical trials of TTF for glioblastoma has shown that TTF was as effective as chemotherapy but the combination of both prolonged overall survival and progression-free survival of glioblastoma without systemic adverse effects . Combina1 as of August 2018. Gene therapy may be used in conjunction with surgery or as an alternative to chemotherapy/radiotherapy or in cases of recurrences following excision as well as chemotherapy-resistant tumors. With improvement in diagnostic imaging and methods of delivery, it feasible that small tumors detected very early may be treated noninvasively or by minimally invasive gene therapy procedures.No gene therapy for glioblastoma has been approved in the US or Europe yet, but 77 clinical trials are listed on US Government web siteThe first clinical trial of the herpes simplex virus, thymidine kinase, and ganciclovir gene therapy for glioblastoma was conducted a quarter of century ago . HoweverA classification of gene therapy approaches to glioblastoma is shown in Table It can be easily produced at high titers.It can be directly injected as purified particles into brain tumors without the need for virus producing cells.It does not integrate into the host genome. This avoids the risk of insertional mutagenesis.Gene delivery by an adenovirus is independent of the host cell cycle. This feature allows higher transduction rates than with retroviruses because only a small number of glioma cells are replicating at any given time.Disadvantages of adenoviral vectors are as follows:in vivo cannot be quantified.Actual release Antigenicity of viral proteins; this might limit repeated treatments. This problem has been seen in gene therapy trials for cystic fibrosis, but it is uncertain if this problem would occur in the brain, as it is an immunologically privileged site.Unlike retrovirus vectors, they infect all cells of the brain. This lack of discrimination could result in significant toxicity to the normal surrounding brain. This can be remedied by use of tissue-specific promoters. One example is glial fibrillary acidic protein, a gene that is found in glial cells. Transfer of a vector containing a cytotoxicity gene under the control of a glial fibrillary acidic protein promoter should result in expression only within the cells that normally synthesize glial fibrillary acidic protein.Three types of viral vectors have been found to be efficient for delivery of gene therapeutics in most of the clinical trials:  retrovirGlioblastoma expresses high levels of type 2 somatostatin receptors, which can be targeted for improving transduction efficiency in these tumors. An adenoviral vector was designed based on the introduction of the full-length somatostatin somatotropin release-inhibiting factor sequence into it, and it was shown that low doses of this vector were sufficient for infecting high-grade human glioblastoma cells with marked enhancement of gene expression .Results of an open-label, randomized, phase III trial of locally applied adenovirus-mediated gene therapy with herpes-simplex-virus thymidine kinase (sitimagene ceradenovec) followed by intravenous ganciclovir in patients with newly diagnosed glioblastoma after resection can increase time to death or reintervention, but not overall survival . FurtherGene therapy strategies, developed to disrupt normal function of vascular endothelial growth factor receptors, have been successful in experimental models to suppress tumor angiogenesis and growth . Some ofVB-111 (ofranergene obadenovec), a genetically modified adenovirus, selectively targets endothelial cells in neovasculature of tumors . VB-111 Systemic adenoviral delivery and sustained production of endostatin and soluble vascular endothelial growth factor receptor-2 can slow glial tumor growth in animal models by both reducing cell proliferation and increasing tumor apoptosis .Raising the dose of chemotherapy to improve clinical efficacy is limited by toxicity, particularly myelosuppression, and neurotoxicity. Gene therapy using mutant MGMT (P140K) gene-modified hematopoietic stem cells can reduce the toxic effects of chemotherapy on hematopoietic cells, and autologous P140K-modified hematopoietic stem cells transplantation has been used in glioblastoma patients with poor prognosis prior to administration of multiple cycles of chemotherapy, resulting in increase of survival without adverse effects .Glioblastoma frequently develops resistance to temozolomide, which can be overcome by adding O6-benzylguanine (O6BG), but the combination produces myelosuppression. Results of a prospective clinical trial have shown that gene therapy P140K-modified hematopoietic stem cells to confer O6BG resistance improves chemotherapy tolerance and outcome in these patients .Nanobiotechnology, particularly use of nanoparticles, has improved drug delivery in cancer, and this technology can be applied to gene therapy of glioblastoma . A nanopin vitro was shown to reduce gene expression of EGFR and \u03b2-catenin and significantly inhibit their migratory as well as invasive ability  of epithelial growth factor receptor (EGFR) resulting in an uncontrolled multiplication and expression of gene encoding normal EGFR or truncated form called EGFRvIII. Because of the delivery problems with commonly used pharmacologic inhibitors of EGFR, RNA interference (RNAi) would be an ideal approach to target EGFRvIII to destroy brain cancer cells and spare healthy cells. Similarly, small-interfering RNA (siRNA)-based downregulation of DNA repair protein MGMT in tumor cells can enhance the chemosensitivity of malignant gliomas against temozolomide . The siR ability . This issurvival .Implanted neural stem cells (NSCs) are known to migrate to glioblastomas and distribute inside the tumor in experimental animals, indicating their potential use as delivery vehicles for targeted therapeutics including gene therapy. The mechanism of the attraction of NSCs to the tumor has not been elucidated. Various proposed mechanisms that drive NSC migration include multiple factors such as chemoattractant molecules released by the tumor cells and inflammatory or degenerative changes in tumor microenvironment .Intratumoral injection of interleukin (IL)-12 secreting NSCs in mice bearing intracranial gliomas significantly prolongs survival and leads to long-term antitumor immunity. Tumoricidal potency of IL-12 with the extensive tumor tracking capability of NSCs result was thought to render exceptional therapeutic benefit. Genetically engineered NSCs have been shown to specifically target glioblastoma cells after traveling through brain parenchyma and hinder tumor growth through local activation of cyclophosphamide-activating enzyme cytochrome p450 2B6 . SignifiHuman embryonic stem cell (hESC)-derived engineered mesenchymal stem cells (MSCs) have been shown to inhibit tumor growth and prolong survival after they were injected directly into the glioblastoma xenografts in the brains of mice who received concomitant prodrug ganciclovir . A preclCancer stem cells (CSCs), which are a type of tumor cells with self-renewal ability and high tumorigenicity, which contribute to the high rates of recurrence after treatment as well as development of resistance to treatment in glioblastoma patients. Therapeutic strategies for CSCs include inhibition of CSC-specific pathways and receptors by agents that increase sensitivity of CSCs to chemotherapy and radiotherapy, virotherapy, and gene therapy . A subseAptamers that specifically bind to tumor-initiating cells were identified by adopted Cell-Systematic Evolution of Ligands by Exponential Enrichment (Cell-SELEX) technique . These ain vivo expansion as well as long duration of action, and possibility of gene transfer for counteracting tumor immune evasion (Chimeric antigen receptors (CAR)-T cells combine the antigen binding site of a MAb with the signal activating machinery of a T cell, freeing antigen recognition from MHC restriction and thus breaking one of the barriers to more widespread application of cell therapy. CAR-T technology uses retroviral or lentiviral vectors to engineer CARs which graft an arbitrary specificity onto an immune effector cell such as a T cell. These modified T cells are then transferred to the patient. Targeting with CAR-T cells is like that with MAbs with additional advantages of active passage to tumor sites,  evasion .Regression of glioblastoma has been reported following multiple infusions of CAR-T cells targeting the tumor-associated antigen IL-13 receptor alpha 2 (IL13R\u03b12) in a patient with recurrent multifocal glioblastoma and no toxic effects were observed into the resected tumor cavity followed by infusions into the ventricular system . IntraveChemotherapy for glioblastoma can produce \u201cchemobrain\u201d with severe cognitive dysfunction that can persist after the cessation of treatment. Pathomechanism is chemotherapeutic agent-induced inflammation in the hippocampus, which is involved in learning and memory. This inflammation can destroy neurons and other cell types in the brain. A study in rodent model of chemobrain, cognitive impairments due to chronic cyclophosphamide treatment resolved after intrahippocampal transplantation of human NSCs, which triggered the secretion of neurotrophic growth factors for regeneration and reduction of inflammation . A cliniAn example of combination of gene therapy and chemotherapy is clinical trial # NCT02414165 titled \u201cToca 511 & Toca FC vs. Standard of Care in Patients With Recurrent High Grade Glioma.\u201d This is a randomized, open-label phase II/III trial of combination treatment using retroviral vector Vocimagene amiretrorepvec (Toca 511), a replicating virus that only infects actively dividing tumor cells to deliver the gene for enzyme, cytosine deaminase (CD), and sustained release 5-fluorocytosine (Toca FC), the prodrug of the chemotherapy 5-fluorouracil. Once inside tumor cells, CD converts the prodrug to 5-fluorouracil to, which destroys them as well as immunosuppressive myeloid cells, enhancing the patient's immune system to recognize and attack the cancer cells. As of August 2018, the trial is still ongoing but analysis of a subset of phase I (selected to proceed to phase III) showed that durable response rate of 21.7% in patients with recurrent glioblastoma who were treated with a gene therapy combination were alive 33.9+ to 52.2+ months after treatment .Regulatory T cells (Tregs), tumor associated macrophages (TAMs) and myeloid derived suppressor cells (MDCSs) are immunosuppressive cells in microenvironment of glioblastoma, and they inhibit cytotoxic T cells anticancer functions, thus reducing the efficacy of immunotherapy. Tumor cells in glioblastoma acquire new mutations after treatment and make it resistant to further treatment, which requires combination of gene therapy for glioblastoma with enhancement of the immune system's ability to fight it, e.g., immune checkpoint blockade combined with gene therapy prevents cancer cells from hijacking the host immune system . This stTranslation of preclinical research into clinical application is limited by lack of a suitable animal model of glioblastoma. The most commonly used model in the past has been a subcutaneous xenograft of human glioblastoma cell line in an immunodeficient rodent model. A limiting factor in intracranial xenografts is the short survival. Malignant brain tumors induced by injection of chemicals and viruses are not suitable for glioblastoma studies. The most appropriate rodent model is transgenic as genetic engineering allows selective introduction of mutations relevant to human glioblastomas. Advances in genome-wide sequencing will enable creation of mouse models of glioblastoma to reproduce gene mutation patterns of human glioblastoma that are suitable for preclinical testing of personalized therapies .Spontaneously occurring glioblastoma in the dog resembles glioblastoma of human and immune system of dogs is also somewhat like that of humans. CT-guided stereotactic techniques for drug delivery and tumor biopsy from tumors in the brain have been developed for use in dogs. Thus, dogs with spontaneous brain cancers offer a scientifically and ethically attractive system for preclinical evaluation of novel interventions for glioblastoma . ClinicaPersonalized medicine, also referred to as precision medicine is a type of medical care in which treatment is customized for an individual patient taking into consideration the genetic and environmental factors that influence response to therapy. Advancements in genomic/proteomic technologies have been crucial in development of personalized medicine, but other technologies such as metabolomics and adoptive immunotherapy also have contributed significantly to this effort. Personalized medicine is perfectly integrating technological advancements such as nanomedicine for understanding pathobiology of glioblastoma and management of disease in clinic .in vivo environment for drug screening. This chip was used to test combined treatment with two FDA-approved anticancer drugs\u2014pitavastatin and irinotecan. High-throughput drug screening and massive parallel testing of drug response was possible using only a tiny sample from the tumor biopsy to determine the drug combinations and their dosages likely to be effective for personalized therapy of glioblastoma.Selection of an anticancer therapeutic best suited for an individual's glioblastoma is challenging. Conventional 2D cell cultures used in current drug discovery do not reflect the tumor and its 3D environments. A novel 3D brain cancer chip composed of photo-polymerizable poly(ethylene) glycol diacrylate (PEGDA) hydrogel, uses cultured glioblastoma cells that form 3D cancer tissues are is promising technology for drug screening . PEGDA hde novo or acquired resistance to standard-care therapies as well as for targeted therapies, EGFR, or mTOR inhibitors. Despite its nearly universal activation of mammalian target of rapamycin (mTOR) signaling in glioblastoma, tumors are resistant to mTOR-targeted therapy  derived from a patient's skin cells are ideal for personalized cell therapy of glioblastoma. Genetically engineered iNSCs with tumoricidal gene products retain the capacity to differentiate while induced apoptotic response in co-cultured human glioblastoma cells. These iNSCs also demonstrate unique capability to reach distant tumor sites in the murine models of glioblastoma to deliver anticancer molecule TRAIL (TNF-\u03b1-related apoptosis-inducing ligand) with resulting increase in survival . The useIntroduction of new technologies has improved the outlook for cure of glioblastoma although much remains to be done. Prolongation of survival time does not necessarily translate into eventual prospects of cure. Reduction of size of tumor alone is not enough as recurrences and rapid progression of the tumor eventually kill the patient. Improvements in targeted delivery of therapies is important for efficient and safe destruction of the tumor. MAbs with ligands for receptors on tumor surface have been used for targeted delivery of therapies. Although several receptors have been identified on glioblastoma cells, they may occur in other organs. A future challenge is discovery of receptors that are unique to glioblastoma and a combination of receptors may be needed for selective delivery to the tumor.Nanobiotechnology has provided important diagnostic and therapeutic tools and enables more efficient delivery to the tumor across biological barriers. The aim is complete removal of the tumor as even a miniscule amount of residual tumor can lead to fatal recurrence.Immunotherapy is another promising approach and adjuvants have been found useful to enhance response to vaccines, and this approach has been evaluated inclinical trials of various vaccine therapies using autologous tumor antigens or tumor-associated/specific antigen peptide in patients with glioblastoma. Choice of an appropriate target and vaccination strategy combined with an immune modulator to increase the body's ability to mount an immune response against the tumor could lead to more durable responses in patients with glioblastoma. However, control of immune response is still inexact as overstimulation may have a destructive effect on normal tissues. Several clinical trials are currently being planned to test such immunomodulators. One clinical trial will test the combination of vaccination with immune checkpoint blockade There is a trend for immunotherapy to be integrated into the multimodal treatment including radiotherapy and chemotherapy for patients with glioblastoma as the actions of the individual treatment modalities may fortify each other . Future Because, there are limitations on extensive use and repetition of current treatments: surgery, chemotherapy and radiation, the ideal therapeutic agent should be one that can continue to act until the tumor is eradicated. Among novel biotechnologies, gene therapy is usually a one-time treatment and cannot be repeated for residual and recurrent tumor. Among genetically modified microorganisms, bacteria appear to be more promising than viruses. Genetically modifies bacteria that selectively destroy glioblastoma while sparing normal brain tissue can be more precise than any surgical tool and can be left in until the tumor destruction is complete. The bacteria can then be killed with an antibiotic.Multimodal therapy of glioblastoma will be needed as no single method is adequate. Surgery will remain as an essential part of this multimodal approach unless a non-invasive or minimally invasive tool is developed to replace it.There are interindividual difference in response to the growth of glioblastoma and response to treatment as well as variations in genomics of each tumor. Therefore, personalized approach to management of glioblastoma is important. Genetic and transcriptomic profiling of patient tumors by Next Gen Sequencing helps classify patients in to molecular subgroups for personalized approach of treatment. To this end, re-analysis of same genetic, and transcriptome data can help identify genetic or epigenetic alterations and discovery of new targets, that can be helpful in designing new drugs or nanoformulations that can be more efficient in drug delivery and efficacy .The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Despite decades of research, reliable biomarkers for diagnosis and treatment of mood disorders are yet to be found. Brain imaging studies of mood disorders have evolved from studying regional brain abnormalities to investigating the whole brain connectome. However, clinical application of reported connectome metrics remains elusive. Several reasons underlie the lack of progress in this area. These include the reliance of connectome studies on investigating simple pair-wise connections between brain regions rather than on studying network properties and patterns; investigation of a limited number of fronto-temporal brain regions such as the anterior cingulate cortex and the amygdala implicated in early studies of mood disorders; and lack of analytic tools to develop accurate classifiers using large scale complex data. Furthermore, most studies do not account for confounding factors such as age, gender, and comorbid conditions. In this special topic collection of articles, investigators report results from a variety of studies of the brain connectome in major depressive disorder (MDD) that address some of the limitations of studies done so far.Lu et al. report results of a diffusion tensor MRI study in early-stage MDD. They investigated structural connectome graph theory (GT) metrics abnormalities and found that MDD group had a decrease in the small-worldness property within the global brain network. Furthermore, using network-based statistics (NBS), they report weakness in the cortical -subcortical  network in MDD. The finding that these structural connectome abnormalities are present even in early stage first-episode drug-na\u00efve subjects suggests that they may be trait related biomarkers of vulnerability for development of MDD.Anand et al. report findings from a 3-T fMRI study to investigate resting state functional connectivity of the dorsal raphe nucleus (DRN)(serotonin neurons) and the ventral tegmental nucleus (VTA)(dopamine neurons), with the cortical and subcortical regions. Unlike cortical and subcortical areas, ROIs for brainstem nuclei for the human brain are not available in most imaging analysis software. Using a careful anatomical approach they constructed regions of interest (ROI) for DRN and VTA. The results of the study show a significant decrease in DRN-cingulate cortex connectivity in medication-free young MDD subjects compared to healthy controls and a correlation of DRN amygdala/hippocampus complex connectivity with the severity of depressive symptoms. VTA connectivity with the parietal cortex was related to a reduction in depression severity after 8 weeks of treatment with an antidepressant. Further work is needed to study brainstem nuclei connectivity due to their central role in monoaminergic and cholinergic neurotransmission as well as in neuronal systems involved in arousal.Leaver et al. report that blood flow measured with arterial spin labeling (ASL) and GT properties of low-frequency BOLD fluctuations can predict antidepressant response to ECT at baseline. They report that imaging features selected by a support-vector machine model, to distinguish between Responders vs. Non-responders, consistently involved a left frontoparietal network as well as temporal-occipital and temporal-subgenual cingulate networks. Classification accuracy was not high [sensitivity (54\u201364%) or specificity (55\u201375%)], but connectivities within these networks correlated with change in depression scores after ECT treatment. The results of the study underscore the promise of machine-learning tools for diagnostic classification and treatment prediction.Using a machine-learning approach to predict antidepressant treatment response, Zhi et al. report Independent Component Analysis (ICA) and GT metric differences between MDD subjects and healthy controls (HC). Besides finding differences in connectivity between MDD and healthy HC subjects, they report that MDD subjects spend more time in states with weak global connectivity compared to HCs. Functional connectivity strengths between ICA components within each state correlated with changes in depression scores. This report calls to attention the importance of keeping the dynamic nature of the functional connectome in mind while exploring biomarkers of illness severity and treatment response in mood disorders.It has been increasingly recognized that the brain functional connectome is not static and is continually changing. In a sophisticated analysis of dynamic functional connectivity in a large sample of Chinese Han subjects, Klumpp et al. report that regardless of diagnosis of depression or anxiety disorder, poor self-reported sleep quality correlates with abnormal amygdala connectivity. Poor reported sleep correlated negatively with left amygdala-subgenual connectivity and positively with cerebellar-temporal gyrus resting state functional connectivity. The findings of this study suggest that sleep-related abnormalities seen in psychiatric disorders may be transdiagnostic and it is important to control for them in data analysis.Finally, confounding effects of comorbid conditions such as sleep disturbance frequently seen in mood disorders need to be addressed while studying the connectome. Conrin et al. report that gender differences in the hierarchical modularity of the functional connectome changes with age. Differences between males and females start appearing in the 26\u201330 years age group and become more significant by 31\u201335 year age. This change in difference over time was primarily derived from changing hierarchical modular structure in males while in females the modular structure remained more stable. Anxiety and inattention symptomatology correlated with a Task Positive Network (TPN) in males. The findings of this study suggest that the resting or basal configuration of the functional connectome may need to be re-conceptualized with more granularity and that gender differences need to be studied as a function of age.The importance of age and gender effects on connectome metrics is increasingly recognized. Using a novel approach, The reports contributing to the special topic of the connectome in MDD exemplify the challenges involved in the study of the connectome in mood disorders and other neuropsychiatric illnesses. On the one hand, simple models of the connectome such as pair-wise regional connectivity are not able to provide important information regarding network-level patterns and properties. On the other hand, studying network properties which are dynamic and which can be affected by sleep, age and gender requires highly complex analysis. Data reduction methods such as ICA ad GT can provide tools to conduct such analysis, but the consistency of results from these advanced methods needs to be validated and replicated. Finally, machine-learning and deep learning tools need to be developed to the point that they can provide high levels of classification accuracy so that connectomic metrics can be used in clinical practice.The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Human peripheral blood polymorphonuclear leukocytes (PMNs) or granulocytes from a leukocyte-rich plasma (LRP) are banded at an interface between two layers of iodixanol. If the denser layer of iodixanol is omitted the PMNs may alternatively be pelleted. The procedure can be adapted to blood from other species by small changes to the density of the two iodixanol layers. The method works optimally with EDTA- or citrate-anticoagulated blood."}
+{"text": "Introduction\u2003Single-incision pediatric endosurgery (SIPES) for the treatment of acute appendicitis in children has recently gained popularity due to its advantages including minimization of postoperative scars or less incisional pain. The principal disadvantages of SIPES include the limited degrees of freedom of movement and high health care costs. To overcome these issues, some surgeons have reported to use noncommercial ports for SIPES appendectomy.Case Report\u2003In this report, we present a case of a 10-year-old female patient with acute appendicitis undergoing SIPES appendectomy using own homemade glove port and straight rigid instruments.Conclusion\u2003SIPES appendectomy using the glove port is a low-cost alternative to commercially available port systems. It is easy to set up and use. Single port access (single-incision pediatric endosurgery [SIPES]) for laparoscopic appendectomy is increasingly being used.2insufflation and introduction of the monopolar hook and tied to the wound retractor to prevent dislocation  technique. Online content including video sequences viewable at:SIPES provides additional advantages over traditional 3-port laparoscopy such as improved cosmetic and the ability to perform multiple procedures without the need for additional ports.With the aim to further improve the technique of setting up the glove port, we established the following modifications:The fixation of a 5-mm trocar to the wound retractor prevents dislocation and allows the introduction of sharp instruments through the port as the tip of the port cannot violate the glove.All other instruments (2nd grasper and the camera) can be introduced through the 2-mm incisions in the finger tips, therefore time-consuming connection of special cannulas or trocars as suggested by others is not necessary.The hitch stich, the wound retractor, allows easy removal at the end of the procedure.The bariatric scope in combination with the 90\u00b0 angled light connector (Karl Storz) avoids clashing of instruments and the instruments and the telescope/camera head.SIPES appendectomy using a homemade glove port is a low-cost alternative to commercially available ports and it is easy to set up and use. Moreover, the high flexibility of the glove and the wide range of motion of the instruments make SIPES more comfortable than using most SIPES ports currently available in the market. Therefore, this device is a good option even in highly equipped laparoscopic centers."}
+{"text": "Conformational flexibility of proteins remains as one of the major events in protein-protein/DNA/ligand/small molecule binding to achieve its biological function in the cell. The availability of high-resolution structures of protein complexes is a valuable resource for researchers to understand the mechanisms behind such interactions and it is found that the flexibility of amino acid residues at binding sites is crucial for many important functions in the cell.In this article, our statistical method (PreFRP) developed based on fluctuating amino acid residues and various amino acid indices related to flexibility/rigidity were used to study the importance of fluctuating amino acid residues in thermonucleases from pathogenic bacteria, cell penetrating peptides and intrinsically disordered proteins responsible for many neural disorders.The results from our analysis reveal the importance of fluctuating amino acid residues in folding and binding of proteins. The role of moderate and high fluctuating residues in themonucleases, cell penetrating peptide and disordered regions are discussed in detail.Therefore, our analysis will help in understanding the importance of fluctuating amino acid residues in proteins which undergo a conformation change phenomenon. The collection of proteins within a cell determines its health and function and the proteins in the cell interact with other proteins/DNA/small molecules to perform biological functions. During these interactions, the amino acid residues at the interface/binding site alter conformation in such a way to attain stability Minor and Kim have designed an 11 amino acid sequence (chameleon sequence fragment) that folds as an alpha helix in one position and beta sheet at another position of the IgG binding domain of the protein and they demonstrated that non-local interactions can determine the secondary structure of peptide sequences of substantial length et al\u2212. The role of five fluctuating residues in protein structure, folding and stability has been revealed in our previous studies The definition of high, moderate and weak fluctuating amino acid residues by Ruvinsky https://www.genome.jp/aaindex/) were the focus of this study. The indices related to hydrophobicity which reflect flexibility and rigidity were carefully selected from database. The twenty amino acid residues are written in order  to understand the contribution of fluctuating amino acid residues in proteins. The position-specific matrix of each amino acid residue in the indices is given in Hydrophobicity as a physicochemical property is effectively used to characterize secondary structures of proteins and it is considered as a dominant force for protein folding In our previous work, a web server \u201cPreFRP\u201d was developed to visualize and predict fluctuating amino acid residues in proteins Staphylococcus aureus (S. aureus) has been used as a model system to understand various functions in the cell and hence, the importance of fluctuating amino acid residues in thermonucleases has been studied in this research. A dataset of 127 thermonuclease protein structures was retrieved from Protein Data Bank S. aureus) as a reference thermonuclease which resulted in 127 protein structures with less than 3\u00c5 resolution. Fluctuating residues at different positions like helices in the dataset were computed by using PreFRP web server For almost three decades, Many reports on structure and function of small molecules are available in the literature, but studies on peptides showing transport activity are very limited. In the present work, cell penetrating peptide, especially crotamine structure was investigated by computing composition of fluctuating amino acid residues. The peptide sequence and structure were retrieved from Protein Data Bank (PDB ID: 1H5O). The length of the peptide was 42 amino acid residues made up of one alpha helix, two antiparallel sheets, and three disulfide bridges.The proteins with varying length (86 entries) made up of long disordered regions (greater than 30 amino acid residues) were downloaded from disprot database The amino acid indices rank twenty amino acid residues based on their important physicochemical properties which contribute to protein folding. In the present work, seventy of such indices which define rigidity or flexibility of amino acid residues in the proteins were used. The position-specific scoring matrix of seventy indices is shown in The fluctuating index for the amino acid residues in thermonucleases along the sequence is shown in The amino acid composition of cell penetrating peptides is shown in Analysis of sequence composition of ordered and disordered proteins has shown the difference and defines tertiary structures with fundamental knowledge for understanding molecular assembly and protein folding Despite the explosive growth in the number of high-resolution 3D protein structures, a key challenge for protein scientists is to understand how the sequence of amino acid residue code for a particular fold. Statistical analysis of sequence compositions of native folded protein structures revealed the role of certain amino acid residues in regular (helix or extended) and irregular regions (coil-like states). The conformation change phenomenon is mainly driven by high fluctuating residues occur at irregular regions and these residues play important role in folding and binding. Many computational methods were developed to identify fluctuating residues which mainly rely on the sequence or structural similarity. However, the existing methods cannot achieve high accuracy due to less conservation of fluctuation residues in homologous sequences and hence, a statistical method (PreFRP) to predict the amino acid residues in proteins as high, moderate and weak fluctuating was developed in this study. The PreFRP method focuses on the effective relationship between protein sequence, ability to undergo conformation change and functionality of protein structures.In the present study, the higher composition of high and moderate fluctuating amino acid residues in thermonucleases, cell penetrating peptides and intrinsically disordered protein regions was identified. Moreover, the location of high fluctuating amino acid residues in various classical amino acid indices were analyzed and discussed which are classified based on flexibility and rigidity property. Through the article, the importance of fluctuating amino acid residues in conformation change phenomenon was explored which helps protein scientists to understand the role of fluctuating residues in folding and binding of proteins."}
+{"text": "Hybrid thin films that combine organic conjugated molecules and semiconductors nanocrystals (NCs) have been deeply investigated in the previous years, due to their capability to provide an extremely broad tuning of their electronic and optical properties. In this paper we review the main aspects of the basic physics of the organic\u2013inorganic interaction and the actual state of the art of lasers and light emitting diodes based on hybrid active materials. The need for active materials for photonic, optoelectronic and electronic devices with improved performances strongly stimulates the research on innovative materials with semiconducting properties, able to provide advantages with respect to standard inorganic semiconductors in terms of realization costs, active properties engineering and absolute performances. In this very broad field, particular attention has been devoted in the last two decades to conjugated organic molecules, both oligomers and polymers and to semiconductor nanocrystals (NCs).Conjugated molecules are characterized by a combination of the processability and low costs typical of plastic materials with active properties, like charge mobility, luminescence and optical gain, typical of semiconductors.Moreover, they show a strong dependence of the electronic properties on the molecular chemical structure, that allows us to widely tune their properties by properly engineer the molecular backbone. For example light emission fully tunable in the visible\u2013near infrared (VIS-NIR) range has been demonstrated in many classes of molecules by controlling the electron wavefunction delocalization along the molecule acting on the molecule chemical structure  see Fig left.A proper molecule functionalization can be also introduced to make the molecules soluble in common organic solvents, thus allowing the easy deposition of active layers by spin coating , drop caTo date, several demonstrators of organic optoelectronic and photonic devices have been reported like light emitting diodes , solar cConcerning NCs, after the first demonstration of simple synthesis of spherical CdSe, CdS and CdTe NCs , an enorThe wide engineering possibilities of both conjugated molecules and of inorganic NCs also stimulated the research on hybrid organic\u2013inorganic composite materials, aiming to combine the best of the two worlds in order to overcome the individual limitations of the two families. For example, hybrid materials can exploit the good film forming properties of many organic molecules in order to improve the film forming properties of inorganic NCs, or they can show improved charge transport properties with respect to fully organic active layers, thus exploiting the typically much higher charge mobilities of inorganic materials.In this paper we will review the main aspects related to light matter interaction in hybrid organic\u2013inorganic polymer-NC films. In particular we will describe how optical spectroscopy experiments allow to investigate the organic-NC interaction and how the physical properties of hybrid films have been exploited for the realization of active materials for lasers and light emitting diodes. Finally we will present the possible development perspectives of hybrid active materials.In order to understand the electronic and optical properties that can be obtained by combining a conjugated molecule with a NC it is absolutely mandatory to have a deep understanding of the interactions between the two systems that can take place in a hybrid film. This aspect is fundamental to allow the development of electronic, optoelectronic and photonic hybrid devices but, on the other side, it is also extremely interesting for basic science experiments.The first complete experiment on the photophysics of hybrid organic\u2013inorganic films has been performed by N. Greenham et al.  that reaThe same group also demonstrated  that theThe details of FRET from a conjugated polymer to a NC was later investigated by time resolved photoluminescence spectroscopy by Anni et al.  in thin A further confirm that the polymer NCs interaction is mainly related to FRET was obtained three years later in poly[9.9-bis(2-ethylhexyl)fluorene-2.7-diyl](PF2/6) and core\u2013shell CdSe/ZnS QDs , adding Moreover the same group demonstrated that exciton energy migration within the polymer is fundamental to have an efficient energy transfer toward the NCs, as evidenced by the strong energy transfer efficiency increase from cryogenic temperatures to room temperature .These initial works allowed us to fix several important points on the possible processes that can take place in polymer-NC blends also allowing to determine possible strategies to increase the energy transfer efficiency, in order to develop hybrid active materials with engineered light emission properties, or the charge transfer efficiency, in order to develop active materials for photovoltaic devices. In particular the evidence of interaction dependence on the surface functionalization of the NCs stimulated further systematic investigations, like the study of the ligand dependence of charge and energy transfer in blends of MeH-PPV and CdSe quantum dots with TOPO or oleic acid (OA) ligand . This exThe role of the chemical nature and of the thickness of the NCs shell was also investigated  in blendWe observe that in all the previous experiments, the first effect of the polymer-NC interaction in the hybrid film is the presence of PL quenching of the organic component. However this effect is not by itself enough to understand the kind of interaction taking place as a PL quenching can be caused by exciton transfer toward the NCs, but also by electron transfer, resulting in exciton quenching in the organic. A possible way to separate the two effects is to look at the NC PL intensity, as a NC PL enhancement should be expected only in case of energy transfer. Anyway even an organic PL quenching taking place together with a NC PL enhancement cannot be only due to FRET, as a radiative transfer (thus emission of the organic followed by reabsorption by the NC) also leads to the same effect. For these reasons all the experiments aiming to understand in which way the organic and the inorganic component interacts typically combine PL spectroscopy with other techniques, like photoconductivity, time resolved PL or photoinduced absorption. A possible alternative approach to separate the different NCs excitation processes in active hybrid blends, fully based on PL measurements, has been also demonstrated in hybrid poly-CdSe/ZnS NC (PF8-NC) films . In thisIn order to understand the processes leading to NCs excitation in the blend the attention was focused on the excitation density dependence of the integrated NCs PL intensity. In particular it was observed that the excitation density dependence of the NCs integrated PL intensity in the PMMA-NC blend showed an initial linear increase up to an excitation density of about 150 ease see  right. Tattering . ConcernEven if experiments on blend films allowed us to observe several interesting features related to the organic\u2013inorganic interactions that can be directly exploited for the realization of active layers in photonic and electronic devices, sample\u2019s local non uniformities leading due to non uniform organic\u2013inorganic mixing, caused by polymer and NCs aggregation, cannot in general be excluded in blend films and they can strongly affect the energy and charge transfer efficiency . An impoN,N\u2019-dicarbazole-byphenyl (CBP), and a monolayer of CdSe/ZnS QDs deposited on the film surface -propyl)-2,7-fluorene-alt-1,4-phenylene]dibromide (PDFD) and CdTe NCs capped with thioglycolic acid molecules, exploiting of the water solubility of positively charged PDFD to use it as a counterpart for negatively charged CdTe NCs in the LbL assembly [A layer by layer (LbL) alternated organic\u2013inorganic film was also realized by growing a multilayer made of the water-soluble conjugated polymer poly ,20. The Another possible approach is to realized the so called type-II core/shell NCs , like CdA third way to control and reduce the Auger scattering rate is the realization of core/shell NCs, in which a gradual transition from the core material to the shell one is present. The first demonstration of Auger dependence on the core/shell interface was obtained in CdSe/CdS core/shell QDs in which an intermediate CdSe present . This ex present . ASE at All these approaches allowed us to obtain remarkable improvements of the optical gain properties, recently allowing the demonstration of continuous wave lasing at room temperature in colloidal nanoplatelets ,65.Several optically pumped lasing devices based on NCs have been reported to date, exploiting different active materials, laser resonator geometries and realization procedures . In ordeIn the following we will describe the properties of different optically pumped NC lasers, trying to provide a general overview of the variety of spectral properties obtained to date, and evidencing the results made possible by the development of hybrid organic\u2013inorganic materials.A very diffused cavity type in NCs lasers realized is the whispering gallery modes (WGM) one, in which the active material is in a micrometric resonant cavity with spherical or cylindrical symmetry, like spheres, disks, rings, and toroids, embedded in a medium with lower refractive index see . The ligMore recently several groups obtained laser WGM microcavities by exploiting the coffee-ring effect, thus by simply depositing a drop of the solution containing the NCs, and creating a circular microdisk thanks to the accumulation of the active material on the drop border see  center . The firA strongly reduced threshold was obtained in CdSe/CdS core/shell dot/rod nanorods (NRs)  in cavitcrorings , furthermaterial , with a rial [\u22122 .Despite the very easy fabrication procedure, that makes coffee ring micro-disks good templates for lasing characterization, the lack of reproducibility of the emission spectra from different devices strongly limits the applicative perspectives of these systems. A noteworthy demonstration of the quality of WGM microring lasing that can be obtained from colloidal NCs, in well controlled lithographycally fabricated devices, and of the emission properties engineering possibilities in colloidal NCs has been recently obtained by le Feber et al. . High qu7 \u03bcm see  right, whell see  left. Thhell see  right.An innovative type of WGM lasers was also recently demonstrated exploiting a hybrid polymer-NC active system, made by a composite film of PMMA and CdZnS/ZnS QDs . After tA good example of the design flexibility that can be obtained by combining polymer and NCs is provided by the demonstration of WGM lasing from microrings made by bended CdSe\u2013ZnS core\u2013shell quantum dot (QD) doped polyvinylpyrrolidone (PVP) single nanowires . The nancm\u22122 see  right.Another simple way to obtain multimode lasing, without any fabrication step, is represented by random lasers. In these systems the lasing effects is due to constructive interference of light coherently scattered during the propagation in the active material ,77.The first NCs random laser was obtained in CdSe/ZnS core\u2013shell QDs on glass substrates with scratched grooves, showing lasing around 600 nm with a threshold of 25 mJ cm pumping .The first systematic investigation of the random lasing dependence on the NC type and on the scattering centers type was performed on thin films of three different CdSe/CdS core\u2013shell NCs, protected by extra thick shells . The ranThe possibility to obtain optical gain from both the core and the shell states in CdSe/CdS giant-shell NCs (g-NCs) recently allowed the demonstration of multiband ASE from two different states of the core and from the shell, and dual band random lasing in which the feedback comes from scattering by cracks on the film surface see , with a Concerning polymer-NCs hybrid active materials, random lasing has also been demonstrated in CdSe/ZnS core\u2013shell QDS, dispersed in an inhomogeneous polymeric matrix . The sysDespite their possible realization with simple techniques WGM and random lasers typically generate multimode laser emission with poor directionality. In order to have single mode operation and good laser beam quality more complex and controlled cavity geometries are needed, like distributed feedback (DFB) cavities and vertical cavity surface emitting lasers (VCSELs).m is an integer giving the diffraction order, DFB laser resonators have a planar geometry and exploit constructive interference of the light propagating along the film from a periodic grating perpendicular to the propagation direction, that can be obtained when the propagating light wavelength The first demonstration of DFB lasing from NCs films exploited a CdSe NC/titania film deposited on a DFB grating with a period of 350 nm  showing The processing advantages made possible by composite layers realization was recently exploited to realize a DFB laser with a CdSe/ZnS core\u2013shell quantum dots dispersed in a PMMA matrix . The DFBsers see . The samRed, green and blue DFB lasing were also demonstrated under 400 ps pumping in close packed films of CdSe/ZnCdS core/shell QDs  depositeFurther improvements in terms of threshold lowering under nanosecond pump pulses were recently obtained  in a bilThe last type of resonator that we will investigate is the vertical cavity surface emitting laser (VCSEL). With respect to DFB typically VCSEL are characterized by better beam quality, lower threshold and higher efficiency and, for a proper active layer thickness, can also show single mode operation. However VCSELs cavities are typically more difficult to realize, as a precise control of the active layer thickness is mandatory to properly tune the cavity mode, and good optical quality is necessary to ensure low propagation losses. To the best of our knowledge only three NCs VCSELs have been demonstrated to date.The first quantum dots based VCSELs were reported by using engineered CdSe/ZnCdS core/shell colloidal pyramid shaped NCs with aromatic ligands, which form densely packed films exhibiting optical gain across the visible spectrum with less than one exciton per colloidal quantum dot on average . The lasMore recently the first monolithic VCSEL laser has been demonstrated  by usingThe last example of NCs VCSEL laser has been reported integrating an active dot-in-rod (DiR) CdSe/CdS NCs thin film with two highly reflective polymer dielectric mirrors prepared by spin-coating of alternated layers of polyacrylic acid and poly(N-vinyl carbazol) . The lasThe main data about the performances of the described devices are summarized in The narrow PL spectrum, the wide emission tunability, the high emission efficiency and the several chemical strategies to engineer the colloidal NCs properties strongly stimulated the research on NCs light emitting diodes. The actual dimension of the performed research is very broad, as evidenced by the more that 5000 papers published on Scopus indexed journals on \u201cNCs\u201d and \u201cLED\u201d, that makes it impossible to cover in a single paper. For this reason in this paper we will focus our attention only on the main developments steps of LEDs exploiting organic\u2013inorganic blends as active layers. Many other specific aspects of QDs LEDs are already covered by other excellent reviews about the device structure, working principle and commercial applications perspectives ,26,27,28The combination of organic and NCs for the realization of NC-LEDs was actually introduced already in the first report on QDs electroluminescence . The devThe first device exploiting a polymer-NCs blend was reported one year later . The actThe combination of efficient FRET energy transfer from the polymer to the NC and the good quality of the used core/shell NCs allowed the demonstration of efficient monochromatic emission at 630 nm with luminance efficiency up to 0.32 cd/A  in LEDs The importance of engineering the energy transfer between the polymer and the NCs and the phase segregation between the components has been demonstrated by developing functionalized polymers in order to reduce the NCs segregation, allowing an increase of the EQE of one order of magnitude in nanocomposites with respect to blends .Moving to more recent devices the combination of optimized hole injecting electrode and polymer-NCs hybridization thanks to properly functionalized polymers recently allowed us to obtain a high EQE of 3.37% in LEDs with CdSe/CdS/CdZnS red QDs-polymer blends  see Fig.A particularly interesting consequence of the possibility to realize hybrid layers generating light with the contribution both of the organic and of the NCs is the generation of white light emitting systems.The first white hybrid LED exploited a blend between a blue emitting polymer (PDHFPPV) and CdSe QDs of two different sizes in order to have green and red emission, carefully controlling the blend composition in order to prevent complete energy transfer from the polymer to the QDs .White light generation was also observed in LEDs with simpler binary polymer-NCs blends. In particular a combination of PVK and CdSe/CdS core/shell QDs was used  to obtaialancing .Another experiment on binary organic\u2013inorganic blends was performed combining a blue\u2013green emitting organic material (BADF) with CdSe/ZnS core/shell QDs , evidencMoving to more recent experiments a quaternary active layer made by a commercial blue emitting polymer (ADS329BE) blended with blue CdZnS/ZnS, green CdSe/ZnS core/shell, and red CdSe/CdS/ZnS core/shell/shell QDs  was receThe main performances of the discussed devices are summarized in As evident from the previously described results the wide research on organic molecule and NCs allowed strong improvements of the understanding of the emission properties of hybrid organic\u2013inorganic systems, and of the laser and LEDs based on these materials. However, to date no real devices based on these materials are present on the market, evidencing the need of further advances to get this result.Concerning lasers, the possible next steps could involve the development of optically pumped devices with a low cost pumping source, for example pulsed LEDs, already successfully employed to pump organic lasers  and the Moreover, the actual state of the art of organic\u2013inorganic based lasers only include hybrid combination of inert polymers with active NCs, while active host-guest blends are widely used in the fully organic laser community to reach low threshold lasing. Assuming a similar effect of the dispersion in an active matrix also for NCs based lasers, improvements in terms of threshold lowering could be expected.Concerning LEDs, to date the performances of devices exploiting hybrid active materials are still lower than the ones of inorganic NCs LEDs. This situation evidences that to date the chemical approaches to allow good film uniformity and high charge injection and transport in NCs thin films outperformed the attempts to exploit active organic material to improve these aspects. In this case however a very active and wide research is still ongoing and the possibility to exploit further degrees of freedom related to the engineering possibility of the organic component and of its combination with the inorganic part is expected to allow other performances improvements in the future.Among the possible developments of organic\u2013inorganic materials containing semiconductor NCs the recent breakthrough of demonstration of perovskites NCs synthesis  is expecound 3 V  in only ound 3 V , while pound 3 V  (see Figound 3 V , thus pr"}
+{"text": "Targeted gene delivery relies on the ability to limit the expression of a transgene within a defined cell/tissue population. MicroRNAs represent a class of highly powerful and effective regulators of gene expression that act by binding to a specific sequence present in the corresponding messenger RNA. Involved in almost every aspect of cellular function, many miRNAs have been discovered with expression patterns specific to developmental stage, lineage, cell-type, or disease stage. Exploiting the binding sites of these miRNAs allows for construction of targeted gene delivery platforms with a diverse range of applications. Here, we summarize studies that have utilized miRNA-regulated systems to achieve targeted gene delivery for both research and therapeutic purposes. Additionally, we identify criteria that are important for the effectiveness of a particular miRNA for such applications and we also discuss factors that have to be taken into consideration when designing miRNA-regulated expression cassettes. Cell/tissue specific gene delivery is important not only for gene therapy but also to study a range of biological processes within a defined cell population. Targeted gene delivery can be achieved either by application of the gene delivery vector at a specific site (optimizing route of administration), by modification of the vector, or by modification of a transgene by exploiting gene regulatory elements. Even though vector application at a particular site of interest can achieve some levels of targeting , the suiIn the past decade, post-transcriptional targeting by exploiting endogenous microRNAs (miRNAs) has emerged as a powerful tool for targeted gene delivery. miRNAs are short, untranslated, regulatory RNA molecules that tightly regulate the expression of a gene by binding to its target sequence (TS) present in the corresponding messenger RNA (mRNA) ,15. The miRNAs are short, untranslated RNA molecules that regulate the expression of a gene at the post-transcriptional level by binding to a particular sequence that is present in the corresponding mRNA . It is w., where hepatocellular CSCs expressing reduced levels of miRNA122a could be targeted and killed with miRNA122a-regulated cytosine deaminase suicide gene therapy [The first step in post-transcriptionally targeted gene delivery is choosing an appropriate miRNA that is dictated by the nature of the application . It is i therapy . Recentl therapy . Incorpo. incorporated TSs of miRNAs 128, 221, and 222 which are expressed at high levels in their excitatory counterparts [Applications requiring the tracking of a specific population within a mixture of cell types often require miRNAs that are lineage- or differentiation-stage-specific . For insterparts . By studterparts . In a siterparts .Another important application of miRNA mediated regulation of transgene expression is to control tropism of tumor specific oncolytic viruses (OVs) . Viral pFrom the point of clinical gene therapy, miRNA-regulated vectors are important in the generation of immune tolerance against the therapeutic gene in order to obtain a stable and long-term gene expression . The cleIncreasing the yield of viral vectors harboring cytotoxic genes during its manufacture is another area where miRNA-based transgene regulation has been used. Reid et al. showed that HEK293 cells express high levels of miRNA373 and constructed vectors including the TS of this miRNA at the 3\u2019-UTR of cytotoxic genes mitochondrial NADH\u2013ubiquinone oxidoreductase chain and BCL2-associated X protein to prevent expression in HEK293 cells, thereby significantly increasing the overall yield of adeno-associated virus (AAV) . Gene deThe level at which an endogenous miRNA is expressed by cells/tissues is vital to achieve an efficient inhibition of transgene expression . Real tiFor most of the targeted gene delivery applications, perfectly complementary TSs of miRNA are incorporated at UTR region of a transgene . HoweverNext, the number of binding sites present in the vector plays a vital role in the repression level of a transgene expression. It has been observed that the level of transgene repression increases with the number of TSs available for the miRNA to bind until a certain point, after which none or low effects are observed . For insSimilarly, the space between the TSs has been shown to impact the action of miRNAs . We and The ability to limit the expression of a therapeutic gene at specific sites is a prerequisite for targeted clinical gene therapy; similarly, regulated reporter expression is needed for studying a range of biological processes within defined cell populations. miRNA mediated post-transcriptional regulation of gene expression is an extremely powerful and versatile tool to achieve targeted gene expression. Unlike the delivery of therapeutic miRNAs, which can cause adverse side effects and possible off-target effects affecting normal cellular physiology, the use of miRNA binding sites (TS) to inhibit the expression of a therapeutic gene in defined cell types harnesses post-transcriptionally targeted gene regulatory machinery in a safe and effective manner .After the pioneering studies performed by Brown et al. ,70, TSs miRNAs are master regulators of gene expression, exploiting their robustness and versatility by combining them with other targeting strategies like transcriptional targeting with tissue-specific promoters and transductional targeting with capsid-modified viral vectors or surface-modified non-viral vectors can provide a tightly controlled gene expression system which may limit the off target effects of traditional gene therapy, thereby increasing the safety of gene therapy in clinical applications."}
+{"text": "Arrhythmic sudden cardiac death (SCD) represents a major worldwide public health problem accounting for 15\u201320% of deaths. Risk stratification to identify patients at risk of SCD is crucial in order to implement preventive measures in the general population. Several biomarkers have been tested exploring different pathophysiological mechanisms of cardiac conditions. Conflicting results have been described limiting so far their use in clinical practice. The use of new biomarkers such as microRNAs and sex hormones and the emerging role of genetic on risk prediction of SCD is a current research topic showing promising results.This review outlines the role of plasma biomarkers to predict ventricular arrhythmias and SCD in non coronary artery disease with a special focus on their relationship with the genetic biomarkers. Sudden cardiac death (SCD), defined as an unexpected fatal event occurring within 1\u2009h from the onset of symptoms in an apparently healthy subject, remains one of the most challenging tasks in Cardiology . Severe One half of SCDs occur in patients without any known cardiac disease, and even when a cardiac disorder has been diagnosed before the SCD, more than one third of patients had preserved or mild reduced left ventricular ejection fraction (LVEF) . TherefoBiomarkers are measurable parameters that serve for several aims in diagnosing, monitoring and therapy addressing diseases. The most widely explored biomarker types are blood biomarkers  that can be identified in patients with a reasonable cost and minimum invasiveness .They can serve as early diagnosis of sub-clinical disease (surrogate biomarkers). Several blood biomarkers have been evaluated as potential predictors of SCD with conflicting results, probably due to the variety of myocardial disease involved in SCD and the small sample size of the studies \u201310.We performed a review on the current knowledge of blood biomarkers as predictors of cardiac arrhythmic events in non coronary artery disease patients highlighting future perspectives and the impact of genetic diagnosis in the prevention of SCD.Natriuretic peptides are peptide hormones released by the atria and the ventricles in hemodynamic stressful conditions . The maiA meta-analysis to define predictors of SCD and ventricular arrhythmias in ICD patients found that high baseline BNP or NT-proBNP levels were independently linked to ventricular tachyarrhythmia .One of the most accepted theories to explain the relationship between arrhythmic SCD and elevated levels of BNP and NT-proBNP is the so-called mechanoelectric feedback phenomenon . Acute aHowever, the role of natriuretic peptides in patients without impairment in LVEF is not well defined and its role in cardiac channelopathies is unknown.The inflammation cascade was deeply investigated in the past few decades in the pathogenesis of atherothrombosis process and cardiovascular disease. Therefore, research has been focused on possible biomarkers of inflammation that could be linked to coronary artery disease (CAD) and SCD.C-reactive protein (CRP) is an acute phase reactant protein that rises in response to inflammation. Data from the Physician Health Study showed that high basal levels of CRP were linked with an increased risk of SCD in healthy male physicians in a follow up period of 17\u2009years with an almost 3 fold increased risk for the men at the highest quartile compare to men at the lowest . The meaDietary fatty acids have been deeply investigated in cardiovascular disease .Non-esterified free fatty acids (NEFAs) are considered pro-arrhythmic on the basis of their properties to modulate potassium and calcium channels and to alter cardiac membrane homeostasis . The ParIn contrast, long chain n-3 polyunsaturated fatty acids (eicosapentaenoic acid and docosahexaenoic acid) are well known anti-inflammatory molecules and their serum levels were linked with a lower risk for SCD .. In theExtracellular matrix is involved in ventricular remodeling after acute coronary syndromes or in non-ischemic cardiomyopathies. Imbalance between matrix metalloproteinase (MMPs), and tissue inhibitor of matrix metalloproteinase (TIMPs) leads to ventricular dilatation as a result of degradation of the myocardial fibrillar collagen network which in turn results in myocardial fibrosis , 24. HigOsteopontin (OPN) is an extracellular matrix glycoprotein secreted by macrophages and fibroblasts that plays a determinant role for ECM turnover and fibroblasts\u2019 differentiation. Because of his critical role in myocardial profibrotic remodeling, OPN correlates with poor outcomes in patients with acute and chronic HF and predict ventricular arrhythmia occurrence in HF patients with an ICD , 27 Tab.Despite this possible pathophysiological mechanism that link extracellular matrix and SCD, collagen turnover markers are not myocardial specific. In addition, most of the trials on this issue are dated and with few patients enrolled.In several cardiac conditions, there is a gender difference in terms of phenotype expression of the disease, symptoms and arrhythmic events.Risk of SCD is higher for females in LQT-2 syndrome and for males in LQT-3 syndrome, whilst no substantial gender difference for SCD is known for LQT-1 . Males wIt is conceivable that this gender difference in phenotype expression could be related to specific sex hormone\u2019s effect on ion channels function that may be altered in presence of a mutated protein. No clear data are currently available on how sex hormones may act on ion channels although this is an evolving topic.Recently, high serum levels of testosterone and low levels of estradiol has been linked to major arrhythmic cardiovascular events (MACE) in patients with ARVC/D. D. Adkis et al. showed that total and free serum testosterone levels are significantly increased in ARVD male patients with MACE compared to those without cardiac events. In the same study lower levels of estradiol were present in females with MACE compared to those without events. In this study, despite the small number of patients enrolled (54 patients), testosterone levels remained independently associated with MACE in males even after adjusting for confounding factors. Table\u00a0 The sameSplicing is a co-transcriptional mechanism leading to the mature RNA where introns are removed in order to get the messenger RNA (mRNA) able to be exported in the cytoplasm. By alternative splicing a large mRNA population is generated, including several isoforms, which contribute to the huge protein diversity and expression specificity of human genes. In HF patients, chronic activation of neuroendocrine system, tissue hypoxia and LV dysfunction increase the alternative splicing of the sodium voltage-gated channel \u03b1 subunit type V (SCN5A) generating truncated variants that result in nonfunctional channels .. DuringGenetic diagnosis is now considered compulsory in all Mendelian diseases. The identification of the genetic bases of SCD is relevant for both acquired diseases and inherited arrhythmia syndromes, but the benefit of this information to reduce the burden of SCD varies between these two groups.Population studies have demonstrated an higher risk of SCD in families with a previous history of SCD in a first-degree relatives \u201338.These findings from familial studies have driven the search for common genetic variants able to identify individuals at risk of SCD in acquired conditions, such as coronary artery disease. As a consequence, genetic susceptibility to SCD has been shown to be largely determined by common genetic variants (single nucleotide polymorphism (SNPs) (e.g polymorphisms in the KCNQ1 and SCN5A genes), usually located on genes modulating electrophysiological parameters \u201341. GenoThe evidence of a low statistical power in individual SNPs associated with SCD determined the creation of genetic risk scores based on the combination of genome-wide significant variants. This approach currently represents the best option to predict risk of SCD in acquired conditions such as coronary artery disease .A significant part of SCD cases occurring in young individuals are related to inherited arrhythmia syndromes. Cardiac channelopathies are caused by mutations in genes that regulate the expression of cardiac ion channels, responsible for the normal propagation of the excitatory stimuli in the heart . TogetheTo date, the prognostic value of genetic testing is highest for LQTS, where a gene-specific profile for the risk of SCD is well established , 46.. A Unfortunately, genetic information contributes less to risk stratification in other channelopathies or cardiomyopathies, in which the yield of DNA screening is low and the genotype/phenotype correlations are less defined.The large amount of genetic data may evolve into a promising approach to quantify the risk of SCD, particularly early on in life. Nevertheless, the important potential use of genetic-based risk stratification is counterbalanced by the complexity to interpret the susceptibility of different genotypes, also considering that DNA variants might be influenced by a mutual interaction and also cooperate with the environment. Psychosocial impact of a positive genetic result should also be taken into account.Despite significant progress in the development of invasive and non-invasive techniques to identify subjects at risk for SCD, the goal is not fulfilled. Several biomarkers are currently used or have shown potential application in diagnostics, prognosis and treatment response in cardiac conditions. Classical candidate biomarkers of SCD failed to show solid and convincing results, probably due to the small sample size of the studies and the long time from the measure to the event. Integration of single biomarkers into a multimarker approach is promising and potentially useful for SCD risk prediction Fig.\u00a0. Blood b"}
+{"text": "The large body of research on living arrangements at older ages pays little attention to the growing population of childless men and women. We begin to fill this gap by using data from the Health and Retirement Study (HRS) over a period of 14 years (2000-2014) to describe the number of years between ages 65-90 that childless Americans live in four different living arrangements: alone, with spouse, with others, and in a nursing home. Because the number of childless HRS respondents is not large (n = 835 in 2000), we first estimate sex-specific single decrement life tables by race/ethnicity and by educational attainment. We then use Sullivan\u2019s method to calculate living arrangement-specific life expectancy for each group, thus providing a comprehensive descriptive portrait of sociodemographic differences in living arrangements across older ages for childless Americans. Preliminary results show that differences in living arrangement-specific life expectancy by race/ethnicity and educational attainment primarily reflect group differences in mortality. The proportion of later life spent in different living arrangements is generally similar across racial/ethnic groups and education levels. This stands in contrast to large racial/ethnic and educational differences documented in earlier studies of older Americans with at least one living child. Results also show that the proportion (and years) of later life spent living alone is substantial, especially for women (over 50%). We discuss the potential implications of these findings with reference to both projected trends in the childless population and research on associations between living arrangements and health of childless older Americans."}
+{"text": "This data article provides indicators of Ecosystem Service (ES) supply for coral reefs, sandy beaches and coastal lagoons in different ecological states regarding eutrophication. 14 ES are considered: food through fisheries; material; molecules; coastal protection; nutrient regulation; pathogen regulation; climate regulation; support of recreational and leisure activities; contribution to a pleasant landscape; contribution to culture and territorial identity; emblematic biodiversity; habitat; trophic networks; recruitment. For each ecosystem 3 to 4 eutrophication states are described. Indicators of ES supply are filled on the basis of a literature review supplemented with expert-knowledge. A semi-quantification of the indicator value is finally provided. Tendencies and trade-offs between ES are analyzed in How does eutrophication impact bundles of ecosystem services in multiple coastal habitats using state-and-transition models [1]. Three to four eutrophication states are considered, from non-eutrophic to hyper-eutrophic state. 14 ES are considered: food through fisheries; material; molecules; coastal protection; nutrient regulation; pathogen regulation; climate regulation; support of recreational and leisure activities; contribution to a pleasant landscape; contribution to culture and territorial identity; emblematic biodiversity; habitat; trophic networks; recruitment. The capacity of the ecosystem to provide ES is described for each ES in each eutrophication state using qualitative information collected in the literature completed by expert-knowledge. Data are presented in double entry matrix (ES/eutrophication states) for coral reefs , sandy b2For each ecosystem, eutrophication states are described by dominant species and associated biodiversity. First eutrophication state of coral reefs is characterized by the dominance of hard corals First eutrophication state of sandy beaches is described by groups of species defined as reference species living in a non-eutrophic ecosystem, where no green tides occur First eutrophication state of primary production of coastal lagoon is characterized by a dominance of reference species that are typical of a lagoon environment in oligotrophic conditions We used the classification of the Common International Classification of Ecosystem Services (CICES) and the list of marine ES defined by Liquete et\u00a0al. Each step involved a literature review regarding ecosystem responses to eutrophication that was supplemented with expert-knowledge. The literature review encompassed knowledge obtained and disseminated on a global scale, while expert knowledge focused on data observed on a more local scale, based on their field studies. However, experts had a good understanding of these ecosystems which allowed them to pronounce in a qualitative way where data gaps were identified. All information were compiled within The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."}
+{"text": "To determine how concomitant medial collateral ligament (MCL) and lateral collateral ligament (LCL) injuries affect outcome after anterior cruciate ligament (ACL) reconstruction.Patients aged\u2009>\u200915\u00a0years who were registered in the Swedish National Knee Ligament Registry for primary ACL reconstruction between 2005 and 2016 were eligible for inclusion. Patients with a concomitant MCL or LCL injury were stratified according to collateral ligament treatment , and one isolated ACL reconstruction group was created. The outcomes were ACL revision and the 2-year Knee Injury and Osteoarthritis Outcome Score (KOOS), which were analyzed using univariable and multivariable Cox regression and an analysis of covariance, respectively.p\u2009=\u20090.0097) but not compared with MCL repair or reconstruction. A concomitant LCL injury did not impact the risk of ACL revision. Patients with a concomitant MCL or LCL injury reported inferior 2-year KOOS compared with isolated ACL reconstruction. The largest difference was found in the sports and recreation subscale across all groups, with MCL reconstruction resulting in the maximum difference .A total of 19,457 patients  met the inclusion criteria. An isolated ACL reconstruction implied a lower risk of ACL revision compared with presence of a non-surgically treated MCL injury (HR\u2009=\u20090.61 [95% CI 0.41\u20130.89], Non-surgical treatment of a concomitant MCL injury in the setting of an ACL reconstruction may increase the risk of ACL revision. However, surgical treatment of the MCL injury was associated with a worse two-year patient-reported knee function. A concomitant LCL injury does not impact the risk of ACL revision compared with an isolated ACL reconstruction.Cohort study, Level III. The medial collateral ligament (MCL) and the lateral collateral ligament (LCL) of the knee joint are primary restraints to valgus and varus forces, respectively, and do also counteract tibial rotation , 30. TheSuccessful outcomes after non-surgical treatment of isolated MCL injuries , 26, 29 Clinical studies of combined ACL and LCL injuries have so far been limited in the literature. Nonetheless, the role of the LCL in preventing the anterolateral rotatory instability of the ACL-injured knee has been established  and addrThe purpose of this national registry study was to determine how presence and treatment of concomitant MCL or LCL injuries affect the risk of ACL revision and patient-reported knee function after primary ACL reconstruction compared with isolated ACL reconstruction. It was hypothesized that non-surgical treatment of a concomitant collateral ligament injury at the time of ACL reconstruction would increase the risk of ACL revision and result in inferior patient-reported knee function compared with surgical treatment.Data from the Swedish National Knee Ligament Registry (SNKLR) were collected prospectively between January 1, 2005 through December 31, 2016. The inclusion criteria for the study were primary single-bundle ACL reconstruction with hamstring tendon (HT) or patella tendon (PT) autografts and age\u2009>\u200915\u00a0years. Patients fulfilling any of the following criteria were excluded from analysis; the first entry in the SNKLR was ACL revision, prior contralateral ACL reconstruction, a concomitant fracture/nerve injury/vascular injury or posterior cruciate ligament (PCL) injury, double-bundle ACL reconstruction, a graft type for ACL reconstruction other than PT or HT, an unregistered HT graft diameter, combined MCL and LCL injuries or contralateral MCL or LCL surgery.The SNKLR is a nationwide registry established in January 2005 and it comprises over 90% of the ACL reconstructions performed annually in Sweden . The SNKAll the patients in the study cohort underwent primary ACL reconstruction and were stratified by the presence and treatment of a concomitant MCL or LCL injury. The stratification yielded a total of seven separate study groups for analysis. The isolated ACL group was defined as patients undergoing primary ACL reconstruction without concomitant MCL or LCL injury. Patients with a concomitant MCL or LCL injury were identified in the surgeon-reported part of the SNKLR and three groups for the MCL- and the LCL-injured patients, respectively, were created as follows: non-surgically-treated, suture repair and reconstruction. A suture repair of the MCL or LCL is directly reported in the SNKLR and it was therefore identified accordingly in the database. However, the data entry design in the SNKLR does not enable the reporting of a specific method for the surgical reconstruction of a collateral ligament. The surgical reconstruction of an MCL or LCL injury is reported, as the surgeon enters a combination of (1) the presence of a concomitant MCL or LCL injury and (2) the use of a graft in relation to the MCL or LCL injury. Patients with an MCL or LCL injury who did not fulfill the criteria for either suture repair or reconstruction formed the non-surgically-treated MCL and LCL groups.4 is a modified version of the KOOS, where the ADL subscale is excluded due to a potential ceiling effect since most active and young patients do not experience difficulties in ADL. The KOOS4 is therefore an average score of the remaining four subscales, similarly ranging from 0 to 100 , The most important finding in this study was that the presence of a concomitant MCL injury was associated with an increased risk of undergoing ACL revision compared with an isolated ACL injury. The risk of ACL revision was significantly increased for patients undergoing ACL reconstruction and non-surgical treatment of their concomitant MCL injury, while patients treated with either MCL suture repair or reconstruction did not display an increased risk of ACL revision compared with isolated ACL reconstruction. This study also showed that the 2-year KOOS was significantly lower across all study groups in patients with a concomitant MCL injury compared with the isolated ACL injury group. However, patients undergoing surgical treatment for their MCL injury had a clinically relevant inferior KOOS compared with isolated ACL reconstruction, while the differences in the KOOS between the non-surgically treated MCL group and the isolated ACL group were small. The analyses of patients with a concomitant LCL injury were limited by small study groups, however, no significant difference in terms of the risk of ACL revision was found between patients with a concomitant LCL injury and patients with an isolated ACL injury.The non-surgical treatment of isolated MCL injuries has been reported to produce a successful outcome, including high rates of return to sport , 25, 29.The non-surgical treatment of a concomitant MCL injury has also been reported to increase the risk of residual laxity following ACL reconstruction compared with an isolated ACL reconstruction in the clinical setting . If a seTwo factors are especially important to consider when using ACL revision as the primary endpoint in the SNKLR. First, there is a risk that graft failures and inferior outcomes for patients who choose not to undergo ACL revision will not be distinguished. Second, the SNKLR does not include information on return to sport or activity level, which could per se influence a patient\u2019s risk of sustaining a new ACL injury requiring revision. It has previously been reported that the risk of ACL revision is highest during the first two postoperative years, likely due to the fact that most patients return to knee-strenuous activity at some time during this timeframe , 24. ThiThe analyses of patients with an LCL injury were limited by small study groups, which means that these findings should be interpreted carefully. There was no difference in the risk of ACL revision between an isolated ACL injury and any type of treatment for an LCL injury. However, only four patients in the non-surgically treated LCL group and one patient in the LCL repair group underwent ACL revision during the first five postoperative years, which are small numbers to analyze. Moreover, no clinically important differences were found between the non-surgically treated LCL group and the isolated ACL group in the 2-year KOOS.The unspecified grade of the concomitant collateral ligament injuries in the present study limits the ability to draw conclusions. It must also be stated that the study does not differentiate between the degree of valgus or varus laxity among the investigated patients. Nor is the surgical technique for the ACL reconstruction or the collateral ligament procedures known and the treatment was performed by several surgeons. Moreover, there is no information about the pre- or postoperative rehabilitation or the activity level among included patients. Nonetheless, this is the first study from the SNKLR to investigate the impact of collateral ligament injury on the risk of ACL revision, which permits the investigation of one of the largest population-based cohorts for combined ACL and collateral ligament injuries to date. The findings of this study should be considered as one component in the clinical decision-making regarding management of combined ACL and collateral ligament injuries, indicating that non-surgical treatment of the latter potentially increases the risk of ACL revision.Non-surgical treatment of a concomitant MCL injury in the setting of an ACL reconstruction may increase the risk of ACL revision. Clinicians should thoroughly consider the need for surgical treatment for a concomitant MCL injury to prevent residual laxity, potentially increasing the risk of ACL revision. However, surgical treatment of the MCL injury was associated with worse two-year patient-reported knee function. A concomitant LCL injury does not impact the risk of ACL revision compared with an isolated ACL reconstruction."}
+{"text": "Increase in life expectancy has benefits, but also costs from increased expenses related to morbidity and prevention. These costs may be reduced by adopting a healthier lifestyle. The goal of the study was to quantify the economic value of a variety of activities in which older adults partake: e.g. cultural, intellectual, physical and nutritional activities. Research questions: Are the monetary benefits of improved health different when measured on a subjective willingness-to-pay (WTP) approach or on an objective Cost-of-Illness (COI) approach? Is the monetary benefit of active aging larger than the cost associated in doing that? 300 older adults participating in various activities of the local senior center and a control group not participating filled out a life style survey. A choice modelling (CM) approach estimated a subjective monetary welfare and compared it to an objective measure of benefit associated with the occurrence of different health symptoms associated with more active aging. An association was found between the various activities explored and the objective and subjective perspective of health. Moreover, all older adult activities passed the cost benefit test albite the order was different between objective and subjective estimations. Nutrition related activities were found to be the most beneficial. Cultural activity ranked second objectively and subjectively. Intellectual activity ranked last objectively and physical activity ranked last subjectively. Participants will understand the need to provide optimal policy and efficient resource distribution between the various activities offered to older adults. This will result in better health lowering public health expenditures."}
+{"text": "Sensory modulation disorder (SMD) affects sensory processing across single or multiple sensory systems. The sensory over-responsivity (SOR) subtype of SMD is manifested clinically as a condition in which non-painful stimuli are perceived as abnormally irritating, unpleasant, or even painful. Moreover, SOR interferes with participation in daily routines and activities Dunn, , co-occu In adults, the tightly regulated E/I balance is achieved by homeostatic control of the strength and weight of transmissions in response to external stimuli. An increased E/I ratio can lead to a prolonged neocortical activity which may be associated with abnormal sensory processing such as hypersensitivity to different sensory stimuli . CRPS is a chronic pain syndrome of unknown pathophysiology that develops after limb surgery or injury in 4%\u20137% of patients  and secondary (S2) somatosensory cortices, the insula, and the anterior cingulate cortex  have all been reported including during the inter-ictal state . Many studies have reported on greater sensitivity to various non-painful sensory experimental stimuli  in FM  pain-evoked ERPs  study in migraine that these neurophysiological markers may be linked with enhanced activity of S1 and reduced activity of the orbitofrontal cortex . Our research has indicated that lower connectivity values in the theta band at centro-parietal region are correlated with higher scores in SOR.The assessment of pain modulation is performed by using various stimulation protocols which include a combination of different stimulus modalities and psychophysical tests. The latter selectively engage the pain facilitatory bottom-up or pain inhibitory top-down pathways and are believed to reflect the \u201creal-life\u201d modulation process exerted by patients when exposed to clinical pain. One of the most studied mechanisms of the supraspinally-mediated descending pain inhibitory system is the diffuse noxious inhibitory control (DNIC). DNIC engages the activation of the endogenous analgesia system, where upon arrival of data to the brainstem the ascending pain activates descending pain inhibitory pathways, exerting effects on incoming nociceptive inputs Le Bars, . The paiWe propose a neurophysiological mechanism-based model for the interrelation between pain and SMD, namely the SMDolor Model (All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Minimally invasive laparoscopic surgery has gained popularity and has become the standard method for approaching various surgical procedures.(10) However, its use for the treatment of gastric cancer (GC) has always cast doubts on the possibility of properly performing the complex lymphadenectomy involved in these procedures.(2) As with any incorporation of a new technology in surgery, initial reports of its use involved only retrospective case series of selected patients. This large selection bias has always led to questions about the actual effectiveness of the method and its generalizability.Despite this undeniable limitation of initial studies, preliminary results from other centers, as well as our own experience, showed us that the laparoscopic approach to gastric tumors was feasible.(3) The advantages already described of the laparoscopic method, such as lower postoperative pain, earlier recovery and discharge, were maintained. The surgical time was longer, but the most important fact of these initial studies was the certainty that the postoperative complications were equivalent and the early surgical oncological parameters, such as lymph nodes count and surgical margins did not change. These results encouraged us already in 2016 to question whether it was time for a paradigm shift from laparotomic surgery to minimally invasive laparoscopic surgery.(1) Perhaps, at that time we relied on non-ideal and retrospective evidence giving the impression that it might be wishful thinking. However, the results presented in subsequent years of large prospective randomized trials eventually confirmed our initial impression. Undoubtedly a large number of studies have been published on the subject in recent years. Critical analysis of these studies is important, and details should not be confused so that wrong conclusions are not made. Some points should always be considered when analyzing these studies of the use of minimally invasive surgery in the GC: 1) What type of tumor was evaluated: early or advanced? 2) Was the surgical resection distal or total? 3) Was the study prospective randomized or were the cases selected? 4) Are the analyzed outcomes early related to long-term surgical or cancer complications? 5) Was the study of superiority or non-inferiority? 6) Does the data reproduce the reality of my practice? The major milestone in the use of laparoscopic surgery in the treatment of GC was the publication of the results of the South Korean study KLASS-01.(8) This non-inferiority study compared laparoscopic with laparotomic surgery for the treatment of early distal tumors. The laparoscopic method presented lower occurrence of surgical complications related to surgical wound without inferiority in relation to disease free survival in three years. Subsequently the Japanese study JCOG0912 confirmed the equivalence of early surgical results but late oncologic results have not yet been released.(7) Since then, laparoscopic surgery has been considered the standard for resection of early distal gastric tumors. Still evaluating early but proximal tumors, two studies - KLASS-03 and JCOG1401 - have already shown similar early surgical results and it is expected that long-term oncological results will be publish soon.Laparoscopic surgery in advanced tumors has always raised greater concern regarding the possibility of peritoneal dissemination by manipulation of tumors affecting the serosa as well as the possibility of incomplete lymphadenectomy in cases with high likelihood of lymph node involvement. Preliminary surgical results from three studies - JLSSG0901, KLASS-02 and CLASS-01 - did not show any alteration in the number of early surgical complications. Analysis of early oncological criteria such as surgical margins, number of resected lymph nodes and final pathological staging did not differ between groups either. However, long-term oncological results were eagerly awaited. Fortunately, during the last International Gastric Cancer Congress held in Prague in May 2019, the authors of the South Korean study KLASS-02 and Chinese CLASS-01 presented its long-term cancer results. Both demonstrated non-inferiority of laparoscopic surgery in relation to disease free survival in three years. Shortly thereafter, the CLASS-01 study was fully published in JAMA confirming the preliminary non-inferiority data presented for laparoscopic surgery.(11) Thus, we can also state that laparoscopic surgery can be employed to treat advanced distal gastric tumors. With regard to advanced proximal tumors, South Koreans started in 2018 the KLASS-06 study, but no data are available at this time. The question whether oriental data can be extrapolated to Western patients and surgeons is always pertinent. In this context the Dutch study LOGICA serves as a bridge between the two extremes.(4) At the 2019 International Gastric Cancer Congress - Prague, we also had the opportunity to evaluate the initial surgical data from this multicenter study involving 10 Dutch centers and 210 patients. Preliminary data presented did not show any difference between the techniques, but these results have not yet been published. th anniversary. To celebrate this date, a commemorative day was held in Porto Alegre, Brazil, in August, when we had the opportunity to discuss these new studies. If in 2016 we did not have the best scientific evidence to make the transition to the minimally invasive approach, recent data released today supports our initial impression. Thus, considering that most tumors in our country are still distal, we believe that increasingly minimally invasive surgery will become the standard in the surgical treatment of GC.Unfortunately, the large number of patients and funding required in these studies makes it difficult to perform in our country. Therefore, the follow-up of the results of these large international studies is essential to be updated with the latest evidence. If we do not have prospective randomized data, the critical analysis of our own results with the publication of case series is fundamental for the quality control of the technique and to verify if its generalization is possible in our country.(6) This year the Brazilian Gastric Cancer Association celebrated its 20"}
+{"text": "Neural rhythms or oscillations are ubiquitous in neuroimaging data. These spectral responses have been linked to several cognitive processes; including working memory, attention, perceptual binding and neuronal coordination. In this paper, we show how Bayesian methods can be used to finesse the ill-posed problem of reconstructing\u2014and explaining\u2014oscillatory responses. We offer an overview of recent developments in this field, focusing on (i) the use of MEG data and Empirical Bayes to build hierarchical models for group analyses\u2014and the identification of important sources of inter-subject variability and (ii) the construction of novel dynamic causal models of intralaminar recordings to explain layer-specific activity. We hope to show that electrophysiological measurements contain much more spatial information than is often thought: on the one hand, the dynamic causal modelling of non-invasive  electrophysiology can afford sub-millimetre (hyper-acute) resolution that is limited only by the  complexity of the underlying  forward model. On the other hand, invasive microelectrode recordings  can reveal laminar-specific responses and elucidate hierarchical message passing and information processing within and between cortical regions at a macroscopic scale. In short, the careful and biophysically grounded modelling of sparse data enables one to characterise the neuronal architectures generating oscillations in a remarkable detail. Neural rhythms have been associated with a variety of cognitive functions; including working memory  parametric empirical Bayes (PEB) can be used to quantify group effects in multi-subject studies\u2014by optimizing hierarchical Bayesian models and (ii) how Bayesian model comparison allows us to reconcile formally distinct  models and construct DCMs of laminar probe data.i-th subject responses, The first application provides a fresh perspective on the use of non-invasive electrophysiology: M/EEG are often thought to have excellent temporal but limited spatial resolution, see e.g.,  poses the difficult inversion problem of finding neural source estimates in the context of intersubject variability. This involves (i) partitioning the covariance of observed data into observation error and components that can be explained in terms of neuronal responses, that themselves entail components due to second level (between-subject) level variability; (ii) exploiting differential equation models to provide anatomical and physiological constraints on the explanation for first level (within subject) responses\u2014usually in terms of (synaptic) connectivity estimates. The second level covariance components specify whether the parameters of the dynamical model at the first level are random or fixed effects, while dynamical models provide predictions of the dynamics at source and sensor space, which depend upon cortical anatomy and physiology.In summary, hierarchical or empirical Bayesian modelling of the sort implied by Eq.\u00a0 allows uCrucially, the use of Bayesian model reduction (BMR) allows one to reduce the computational burden of inverting PEB models from multiple subjects and enables an efficient scoring and averaging of large sets of (nested) models (Friston and Penny i) and the generative model X is a design matrix containing between-subject explanatory variables. Below, using Bayesian model reduction, we adjudicate among competing hypotheses about the intrinsic connections that show intersubject variability. Effectively, this involves comparing the evidence for random effects models with and without (combinations of) between subject effects on (combinations) of connectivity parameters.Here, In this hierarchical model, constraints on the posterior density over model parameters are provided by the level above. In variational Bayesian inference, the approximate posterior over the second level parameters is obtained by optimising its sufficient statistics  with respect to a (second level) free energy:The key thing about this free energy is that it can be evaluated (using BMR) without optimising the first level posterior. This means the second level parameters  can be optimised or estimated, for any given model of priors, without reinventing the model at the first level. Technically, the inversion of the hierarchical or empirical Bayesian model only requires the posterior density from the inversion of each subject\u2019s DCM. In short, the use of BMR allows one to make inferences at the group level without having to re-estimate subject-specific parameters; see  Bayesian inference considered below uses posterior means obtained from compartmental (conductance based) models . The first level generative model makes predictions of layer specific responses, where we eschew the difficult problem of inverting detailed  models  by using simulated data obtained with a microscopic  model Neural models describe brain activity at different scales, ranging from single cells to whole brain networks. In this review, we consider both population and compartmental models. In the first application using Bayesian model reduction, we consider a neural field model with a canonical cortical microcircuitry following  convolution operator; whereas conductance based models consider the (non-linear) coupling between conductance and voltage. The second distinction is between the behaviour of a neuronal population or ensemble of neurons\u2014as described with their mean or a point probability mass over state space. This contrasts with mean field approaches that model the ensemble density, where different ensemble densities are coupled through their expectations and covariances; in other words, these models include a nonlinearity that follows from the interaction between first and second order moments. This extra realism allows them to reproduce faster population dynamics; for example, somatosensory evoked potentials  currents within the long apical dendrites of synchronized cortical pyramidal cells, see e.g.  inverse problem of mapping responses to laminar-specific neuronal sources quite hard. This mapping has been addressed using methods like current source density , X, creating the model space depicted in Fig.\u00a0As intimated earlier, inferences and Bayesian model comparison at the group level necessitate the use of hierarchical models. In other words, Having established the importance of the (between subject) explanatory variables, we can now focus on the main question; in particular, which factors mediate intersubject variability in gamma band responses. To address this question, we performed an exhaustive search over combinations of second level parameters, that is, the 30 parameters describing the effects of the three explanatory variables on the ten intrinsic connections of our neural field model. Using BMR, we scored every combination of parameters and identified key connections explaining intersubject variability in gamma responses. Bayesian model averages of these parameters are shown in Fig.\u00a0In short, this example shows how non-invasive (macroscopic) data can be used to make inferences at a microcircuitry level. In this instance, we have taken the opportunity to highlight inferences in the setting of hierarchical or empirical Bayesian models that accommodate intersubject variability. Our conclusion is that intersubject variability in visually induced gamma responses is best explained by differences in the intrinsic (laminar) connectivity to and from inhibitory interneurons.We now turn to our second example that involves laminar responses and a slightly different neural circuitry that follows the architecture used in . The first of the above models is a well-known conductance based (microscopic) model  in the periphery of the animal's vision. This cue was presented at one of six potential locations evenly spread on an annulus 10\u00b0 from the fixation point. After the cue, dots appeared at all of the six locations while the monkey maintained central fixation over a two second memory delay. Then, the central fixation dot turned purple and the peripheral stimuli disappeared. This told the monkey to make a direct saccade to the remembered location of the red cue dot to receive a juice reward. We recorded local field potentials from a 24 channel multi-contact laminar electrode implanted within prefrontal cortex.To help locate the electrode relative to the cortical layers, we also trained the monkey to maintain fixation while a white disk with a radius of 11 visual degrees was repeatedly flashed for 50\u00a0ms intervals. A current source density analysis of the visually evoked potentials during this task permitted the identification of the cortical lamina surrounding the electrode.\u00a0 connections rests primarily on laminar specific connectivity. Laminar probes are therefore an exciting technique that allows us to measure brain responses at an unprecedented resolution. When combined with dynamic causal modelling, these responses could be used to address several important questions that we review in the Conclusions below.We have reviewed two recent advances in hierarchical or empirical Bayesian modelling that enable us to deal with the ill-posed (inverse) problem of source reconstruction and disclose processes that generate neural rhythms\u2014and mediate the propagation of information within and between cortical sources. In the first illustration, we showed that non-invasive recordings contain rich spatial information, despite the low resolution of M/EEG; while in the second, we attempted to reconcile models operating at the microscopic and mesoscopic scale\u2014and show that DCM can correctly assign superficial and deep cortical dynamics to laminar-specific responses. This intralaminar DCM affords the same computational efficiency and advantages as all other models in DCM, but can exploit microscopic (laminar-specific) data that embody effects like antidromic currents and back-propagation.Dynamic causal modelling of electrophysiological responses obtained with laminar probes is in a position to address several neurobiological questions: one of the key reasons to use laminar probes is that they can provide direct evidence that distinct cortical layers are involved in particular oscillations and computations. Previous studies of visual cortex suggest that oscillatory activity in the gamma and alpha bands are segregated by layers. Neurons in deep layers (layers 5 and 6) show spike-field coherence in the alpha band while superficial layer (layers 2 and 3) neurons show spike-field coherence in the gamma band (Buffalo et al. Superficial and deep cortical layers also tend to have distinct cortical targets. For example, superficial-layer neurons form the strongest source of cortico-cortical feedforward projections, while deep-layer neurons contribute predominately to cortico-cortical feedback (Markov et al. Therefore, it appears that the functional role of oscillations is shaped both by cortical layer and inter-areal connection types, as reviewed above. This provides an important motivation for using multi-laminar probes to examine cortical activity during cognitive tasks. An equally important motivation, from our perspective, is to interrogate the canonical microcircuit hypothesis, which predicts that neurons in distinct cortical layers contribute to distinct computations (Bastos et al."}
+{"text": "To the Editor: We read with interest the article by Kajon et al.  of viral hexon genes (HAdV-B7 was identified by BLAST analysis (This cluster of HAdV-B7 causing severe ARD in immunocompetent adults appears to have no clear epidemiologic link. We agree that HAdV might be an underrecognized pathogen in severe community-onset ARD. Testing for viral respiratory pathogens should be considered in all patients and not just the immunocompromised."}
+{"text": "In vivo PET studies confirmed that abnormal spreading of serotonergic terminals within the putamen has a pivotal role in the development of LIDs and GIDs. However, glutamatergic, adenosinergic, opioid systems, and phosphodiesterases 10A may also play a role in the development of these motor complications. An integrative multimodal imaging approach combining PET and MRI imaging techniques is needed to fully understand the mechanisms underlying the development of LIDs and GIDs.The purpose of review is to review the current status of positron emission tomography (PET) molecular imaging of serotonergic system in Parkinson\u2019s patients who experience levodopa-induced (LIDs) and graft-induced dyskinesias (GIDs). PET imaging studies have shown that Parkinson\u2019s disease is characterized by progressive loss of dopaminergic and serotonergic neurons. Parkinson\u2019s patients who experienced LIDs and GIDs have an aberrant spreading of serotonergic terminals, which lead to an increased serotonergic/dopaminergic terminals ratio within the putamen. Serotonergic terminals convert exogenous levodopa into dopamine in a non-physiological manner and release an abnormal amount of dopamine without an auto-regulatory feedback. This results in higher swings in synaptic levels of dopamine, which leads to the development of LIDs and GIDs. The modulation of serotonergic terminals with 5-HT According to Braak\u2019s staging of Parkinson\u2019s, the pathological processes begin early in the serotonergic raphe nuclei, prior to the onset of motor symptoms, and precede the damage of substantia nigra -benzonitrile ([11C]DASB) is a second-generation PET ligand with high selectivity for the serotonin transporter (SERT)  is a molecular imaging technique that allows the quantification of biological targets and pathological processes in vivo in the brain , such as serotonergic, which do not possess the molecular machinery to properly control the release of dopamine  scores in preclinical models of Parkinson\u2019s disease induced by 6-hydroxy (6-OH) dopamine  and the previous one , we suggest that the imbalance caused by a normalization of serotonin terminals in the dopamine-denervated striatum creates increased dopamine release after levodopa administration, resulting in an increased negative input to the globus pallidus neurons controlling thalamic output. Greater LIDs might be the results of increased dopamine release at pre-synaptic dopaminergic receptors located at the synapses of striato-pallidal GABAergic neurons in the globus pallidus. These neurons control the projection neurons to the thalamus and thereby the thalamic output. By over-inhibition of these neurons, the dysregulated basal ganglia output then results in LIDs. This is in line with the preclinical evidence of a profound suppression of globus pallidus output activity in monkeys experiencing LIDs .In three Parkinson\u2019s patients with GIDs who received striatal transplantation with foetal ventral mesencephalic tissue, we evaluated the density of serotonergic terminals, using [Taking these results into account, we suggest that SERT/DAT ratios could be used as biomarker for LIDs and GIDs. Moreover, pharmacological modulation of serotonergic terminals sprouting, such as with brain growth factors, might also improve the severity of LIDs.In vivo PET studies confirmed in humans that an abnormal spreading of serotonergic terminals within the putamen has a pivotal role in the development of LIDs and GIDs. Serotonergic terminals\u2019 release of abnormal amounts of dopamine after levodopa administration is the most widely recognized factor underlying the pathophysiology of dyskinesias but cannot be considered a necessary and sufficient condition for the development of this motor complication. The implementation of novel PET ligands is warranted for unveiling unexplored mechanisms of underlying pathophysiology of Parkinson\u2019s disease. An integrative multimodal imaging approach combining different techniques is needed to untwist the debate around putative players on the pre-synaptic side of the cascade that lead to the development of dyskinesias in Parkinson\u2019s disease."}
+{"text": "Flourishing represents living within an optimal range of human functioning. To foster older adults flourishing, our FlourishCare model of care coordination was developed as part of a HRSA Geriatric Workforce Enhancement Program (GWEP) to transform PC sites by delivering coordinated services in 6 rural KY counties. FlourishCare is unique in its integration of academic teams, community health teams and mental health specialists within age-friendly primary care health systems.FlourishCare recognizes that many of the largest drivers of health care costs fall outside the clinical care environment. One of the major components of Flourish is the involvement of community health navigators (CHNs), community education coordinators (CECs) and community coalitions working with the health teams to respond to the social determinants of health. For each patient that is referred and agrees to participation in the program, the CHN performs Flourish clinical and home assessments and obtains medical records. A repeated measure designed was used to assess the 60 patients who have baseline assessments results along with at least a 6-month assessment and in some cases a 12-month assessment (n= 20). Patients have demonstrated a significant increase in their flourishing across all determinants of health. There was also a significant improvement the total FI from pre to post-test at 6-month. These outcomes illustrate that it is important to operationalize the outcomes for older adults by evaluating the success as the ability of the older adult to flourish when they can maintain current functioning, access to resources have sufficient support systems in place."}
+{"text": "Drug repurposing is at the heart of precision oncology. The move from tissue- or cancer-specific treatments to genomic- or actionable-target treatments necessarily entails the reuse of anti-cancer medications licensed for one type of cancer to treat other cancer types , which are being instituted in many cancer centers.The soft repurposing of existing cytotoxics, endocrine therapies and licensed targeted agents has a number of obvious advantages. These are well-characterized in an oncology setting, with extensive individual and institutional use as cancer treatments, albeit not in the particular cancer types under consideration. However, as shown by the SHIVA trial\u2014a Phase II open-label randomized controlled trial (RCT) of molecularly selected targeted therapies vs. conventional therapy in advanced cancers\u2014the palette of licensed targeted agents is relatively limited compared to the range of driver pathways active in cancer , successfully biopsied 948 (of 1043 consented) patients with non-curable metastatic cancers and generated genomic analysis for 843 (89%)  interventional trial includes a wider range of agents, including non-cancer drugs  complex. Robust c-JUN protein expression was confirmed by immunohistochemistry. These findings led to the hypothesis that blockade of the renin\u2013angiotensin system could be a novel treatment option. A literature screen provided additional data substantiating this hypothesis in the context of colon cancer. The angiotensin II receptor antagonist, irbesartan (known to target AP-1 and listed as such in public databases such as DrugBank), was administered as an anticancer therapy, leading to a dramatic and durable response.In contrast the Personalized Oncogenomics Program of British Columbia (NCT02155621), a large  used a wider panel of agents, including a subset of FDA-approved non-cancer drugs with evidence of blood-brain barrier penetration (Byron et al., Much precision oncology work is performed outside of clinical trials\u2014in some centers it is now a standard option for difficult-to-treat patients. The use of case reports is particularly pertinent in such cases, helping to expand our knowledge base to provide supporting evidence to both clinicians and triallists. For example, Cornelius et al report on a case of a 4-month old child with a refractory choroid plexus carcinoma (Cornelius et al., Whether or not generic combinations of repurposed drugs with standard anticancer agents can be used for patients with the same disease is another interesting question. The low toxicity of drug repurposing allows complex combinations that can target several crucial pathways for a given disease and to decrease the risk of resistance observed when using single agent targeted therapy in patients. The recent case report from Berland et al.  confirm The availability of a pool of potentially useful repurposed drugs will be a key determinant of the success of precision oncology. A number of groups have published extensive reviews of possible repurposing targets for specific cancers or groups of cancers, such as AML (Andresen and Gjertsen, In addition to providing an expanded pool of active agents, thereby expanding the range of \u201cactionable pathways,\u201d the repurposing of non-cancer drugs, particularly generic medications offer precision oncology options to clinicians in low and middle income countries (Hernandez et al., All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In most abiotic stress conditions, including salinity and water deficit, the developmental plasticity of the plant root is regulated by the phytohormone auxin. Changes in auxin concentration are often attributed to changes in shoot-derived long-distance auxin flow. However, recent evidence suggests important contributions by short-distance auxin transport from local storage and local auxin biosynthesis, conjugation, and oxidation during abiotic stress. We discuss here current knowledge on long-distance auxin transport in stress responses, and subsequently debate how short-distance auxin transport and indole-3-acetic acid (IAA) metabolism play a role in influencing eventual auxin accumulation and signaling patterns. Our analysis stresses the importance of considering all these components together and highlights the use of mathematical modeling for predictions of plant physiological responses. Recent findings in active auxin transport over organelle membranes and the influence of apoplastic and cytosolic pH on passive auxin flow into the cell highlight the importance of short-distance auxin transport for local auxin maxima in roots exposed to stress.Based on previously published gene expression data, we have identified stress-induced expression patterns of IAA biosynthesis and conjugation genes in the root that could be relevant for IAA accumulation patterns. These results underscore the importance of incorporating IAA homeostasis into models predicting auxin levels and flow.in planta and in silico experiments when unraveling complex hormonal changes in plants.Recent advances in mathematical models involving auxin-related processes highlight the value of combining  Drought and increasing salinity are abiotic stresses that cause major decreases in crop yield worldwide. Drought causes loss of crops through water deficit, whereas increasing soil salinity induces osmotic and ionic stress in the plants. Both abiotic stresses are a threat to the amount of arable land that is fit for our food production. Although the development of crops tolerant to these conditions has received attention auxin  IAA conjugation during abiotic stress affect root responses is another relatively young field of research. The integration of all these different aspects of auxin homeostasis is complicated because the many factors involved all influence each other and there is extensive crosstalk between auxin and other hormones. One promising solution to this problem is the rapidly emerging field of computational modeling of auxin processes in the plant root.RSA and root growth rates during plant development under optimal conditions have been well studied, and it has long been established that these require the phytohormone uxin see . Recentlhalotropism on the side of the root facing a higher salt concentration in planta salt stress experiments with computational modeling, it was concluded that internalization of PIN2 is not sufficient to explain the alteration of auxin flow during halotropism The main mechanism to maintain the \u2018upside-down fountain\u2019 of auxin flow in the root is PAT. Clarification of the role of long-distance shoot-derived auxin transport in abiotic stress has advanced our understanding of the changes in auxin carrier proteins and other proteins that influence auxin flow in the root . InternaOryza sativum), the expression of 21 was found to change in response to salinity and drought acropetal transport of auxin was observed in an abcb19 null mutant, whereas basipetal transport was unaltered Another large family of auxin carriers influencing auxin flow in the root is the ABCB transporter family zifl1 loss-of-function mutants were observed to have reduced PIN2 protein abundance in epidermal root cells after external application of IAA and had gravitropic bending defects.Other genes, whose loss-of-function mutants were recently observed to exhibit altered auxin flow in the root, are putatively involved in abiotic stress tolerance. Mutants of interactor of synaptotagmin 1 (ROSY1-1) showed a decrease in basipetal auxin transport and exhibited increased salt tolerance, which was ascribed to the interaction between ROSY1-1 and synaptotagmin 1 (SYT1) Box 1Auxin transport is, in addition to active processes, dependent on passive movement of IAA into or between cells and movement through the apoplast. The concentration of auxin influences apoplastic pH, which in turn influences passive auxin transport into cells. In roots, high cellular auxin concentrations inhibit cell elongation, whereas in the shoot, in accordance with the acid growth theory, auxin causes cell elongation in vivo. Nonetheless, a mathematical/computational model linking auxin and pH dynamics has been created In vivo measurements of cellular auxin influx and efflux during apoplast acidification will be necessary to elucidate the role of passive auxin transport across the plasma membrane.The effect of auxin on apoplastic pH has been demonstrated by the addition of exogenous auxin to arabidopsis roots, which induced fast alkalization of the apoplast Alt-text: Box 1Changes in auxin transport between different intracellular compartments also influence the auxin that is available for the formation of local auxin maxima. Auxin located in the acidic vacuole, with a pH of 5.0 to 5.5, will tend to move towards the cytosol which has a pH of \u223c7. During salt stress the cytosolic pH drops pils2/pils5 protoplast cells was also observed pils2 arabidopsis mutant, and even more so a pils2/pils5 double mutant, showed significantly longer roots than the wild type and a higher lateral root density, suggesting PILS involvement in auxin-dependent root growth.Isolated vacuoles from protoplasts lacking the tonoplast-located auxin carrier WAT1  were found to accumulate significantly more radiolabeled auxin than wild-type vacuoles, indicating active transport of auxin from the vacuole to the cytoplasm by WAT1 \u2212). To restrict free cell-to-cell movement of IAA during auxin gradient formation, GLUCAN SYNTHASE-LIKE 8 (GSL8) induces an increase of plasmodesma-localized callose. This reduces the symplasmic permeability to maintain local auxin maxima Other forms of passive auxin transport include movement without the interference of membranes. IAA is a small molecule and is therefore able to move freely through the plasmodesmata (PD) in its ionized form  levels are determined by biosynthesis and conjugation. Both processes have recently shown to be affected by abiotic stress in the root.Although several IAA biosynthesis pathways has been described The IPyA pathway  generateBrassica-specific and has mostly been described for its role in secondary metabolism, producing both indole glucosinolates and camalexin et al. showed that, when plants were fed 13C6-labeled IAOx, 40% of the 13C6 atoms was incorporated into IAA, confirming that IAA can be formed from IAOx et al. showed that a cyp79b2 cyp79b3 double-knockout mutant showed reduced growth and reduced IAA production specifically under higher temperatures The IAOx pathway  is BrassIn planta, the levels of IAA conjugates and catabolites correlated strongly with the levels of free IAA in both root and shoot, and high levels of conjugates and catabolites are present when high levels of free IAA occur Levels of free IAA are tightly regulated by several conjugation and degradation processes  [44]. AlEster conjugation is mainly governed by several UDP-glucose transferases (UGTs). In Table S1 we have summarized the UGTs that are currently known to conjugate IAA, but this list is probably not complete. These enzymes respond differently to salt stress (Enzymes of the GRETCHEN HAGEN 3 (GH3) family form amide conjugates of IAA IAA oxidation is responsible for most IAA turnover and leads to degradation of the compound et al. have shown that DAO1 is expressed in cells underlying newly developing lateral roots, and that the knockout has increased lateral root density In addition to the main auxin, IAA, three other auxins have been described IAA metabolism, the enzymes involved, and their responses to salt stress shows the complexity of interpreting and predicting changes in auxin homeostasis. If we combine this complexity with the observed changes in auxin transport and auxin signaling, predicting the effect of changes in any of these steps can be daunting. More knowledge on the specific regulation of biosynthesis and conjugation enzymes, together with a more comprehensive view of all processes affecting auxin levels and response, will greatly improve our ability to predict the effects of changes in these different components. Incorporation of IAA metabolic pathways into models will also be a great leap forwards for predicting auxin accumulation patterns inside the plant because both processes, in addition to auxin transport, may modulate auxin levels.These examples show the importance of including IAA biosynthesis, conjugation, and degradation in the bigger picture of auxin homeostasis and accumulation because these processes may play major roles in the specific regulation of local auxin-mediated responses. However, the wide range of pathways involved in in vivo auxin reporters Predicting the overall role and impact of auxin biosynthesis and short-distance transport compared to long-distance transport in the plant root during development and stress response is a complex task, despite improvements in the sensitivity of et al. predict the effect of auxin on intra- and extracellular pH and how this in turn affects auxin concentrations et al. show that the experimentally observed \u2018all-or-nothing\u2019 expression pattern of auxin transporter-like protein 3 (LAX3) may be explained by bistability that creates a genetic \u2018switch\u2019 Box 2et al. have shown that both root shape and auxin feedback are important to show experimentally observed changes in auxin flow during halotropism To create a realistic root model for reliable predictions about changes in auxin flow and local auxin concentrations, several model characteristics need improvement. Two things that will help towards perfecting static 2D models of the root are a realistic root shape and known auxin feedback loops. Van den Berg Another characteristic of the models that needs development is movement. While informative in short-term changes, predictions by static models become less realistic over time because they lack the changes in local auxin maxima that are needed for or caused by growth and bending. Interestingly, recently growing and bending root models have been realized. For example, a model describing a growing and bending root in which local changes in auxin concentrations can be predicted by changing the dynamics of PIN polarization under the influence of changing elastic fields due to root bending was made Comparable to growing versus static models, the 2D models that are being used now to make predictions of auxin levels are valuable; however, ideally we would want to use a 3D model. Owing to the high complexity, not many 3D root models have been attempted, and those that are available have yet to incorporate many factors. One such 3D model which aims to simulate lateral root emergence through LAX3 and PIN3 modeling has been published Alt-text: Box 2Although highly instrumental, the current root models have not yet incorporated all relevant parameters and are generally too static to accurately predict the magnitude of the influence of local auxin biosynthesis, conjugation, and short- and long-distance transport on the root stress response over longer time-periods. Interestingly, recent advances in root modeling show promising results to help to overcome these issues . NonetheAn example of the relevance of incorporating auxin conjugation and degradation into auxin computational modeling is a mathematical model describing GH3-mediated auxin conjugation et al. showed in a single-cell model that combinations of changes in auxin carriers are necessary to mimic experimentally observed auxin flows et al. and Moore et al. have shown in a whole-root model the importance of changes in auxin influx carriers in addition to efflux carriers for modulating auxin flow To increase our understanding of long-distance auxin transport, Mitchison To date, a model incorporating the changes in auxin biosynthesis and interplay between the different synthesis pathways has yet to be constructed . This follows logically from the fact that much about auxin biosynthesis remains unknown. However, for a full understanding of changes of auxin in the root during stress the incorporation of realistic changes in auxin synthesis will be necessary.in planta experiments take significant time in the creation of tools to change single parameters, multiple parameters are easily changed in the models and putative regulators of auxin flow can be found. These regulators can then be verified by in planta experiments. Ideally, a growing and bending model incorporating as many factors as possible \u2013 different auxin carriers, hormonal feedback, mechanical feedback, pH changes, and the ability to simulate different stresses \u2013 would be useful to make predictions about growth rate and direction during abiotic stress. Furthermore, what modern models are still missing is the ability to show changes in RSA during stress. To elucidate the mechanisms behind different RSA strategies during different abiotic stresses, a model incorporating lateral root emergence and growth through the prediction of the local auxin concentrations is required. Again, such a complex model would need to take into account multiple factors dealing with local auxin maxima around lateral root primordia. Looking to the future of research on complex biological processes, such as the auxin machinery in the plant root, it becomes clear that the field of mathematical modeling will undoubtedly play a key role.Outstanding QuestionsWhat is the contribution of shoot-derived auxin during stress-induced changes in auxin concentrations in the root?How does local regulation of biosynthesis and conjugation contribute to auxin accumulation during abiotic stress?What is the role of local auxin-regulated pH changes during changes in local auxin concentrations in response to stress?Nonetheless, multiple studies have now shown model predictions supporting experimental data and have provided suggestions for follow-up experiments. Although"}
+{"text": "Melanoma cell dormancy is regulated by intrinsic cues that maintain a slow-cycling state in cells and by extrinsic interactions with stromal and immune components of the microenvironment. A key factor is that a significant lapse of time occurs between initial diagnosis, and metastatic recurrence of dormant cells. During this time, the organism ages and age is a poor prognostic indicator for cancer. We have found that melanoma cells form lung metastases more efficiently in aged mice and remain dormant in young mice. Analysis of the immune-microenvironment of the lung reveals that healthy young and aged mice have little difference in infiltration of immune subpopulations; however aged tumor bearing mice have significantly increased immunosuppressive MDSCs and Tregs and decreased CD4+ and CD8+ t-cells in the lung compared with young mice. Our data indicates that aging induces an immunosuppressive lung microenvironment which allows immune-evasion and an emergence from melanoma dormancy."}
+{"text": "Infections in the post-acute phase of cerebral ischaemia impede optimal recovery by exacerbating morbidity and mortality. Our review aims to reconcile the increased infection susceptibility of patients post-stroke by consolidating our understanding of compartmentalised alterations to systemic immunity. Mounting evidence has catalogued alterations to numerous immune cell populations but an understanding of the mechanisms of long-range communication between the immune system, nervous system and other organs beyond the involvement of autonomic signalling is lacking. By taking our cues from established and emerging concepts of neuro-immune interactions, immune-mediated inter-organ cross-talk, innate immune training and the role of microbiota-derived signals in central nervous system (CNS) function we will explore mechanisms of how cerebral ischaemia could shape systemic immune function. In this context, we will also discuss a key question: how are immune requirements critical for mediating repair of the ischaemic insult balanced by the need for anti-microbial immunity post-stroke, given that they are mediated by mutually exclusive immune networks? Our reformed understanding of the immune landscape post-stroke and novel mechanisms at play could guide targeted therapeutic interventions and initiate a step-change in the clinical management of these infectious complications post-stroke. Ischaemic stroke imposes a significant burden on health-care systems and societies across the globe as a consequence of the morbidity and mortality associated with the condition , 2. In aTo date, there is a wealth of information surrounding the spectrum of immune alterations that ensue following a stroke in both patients as well as models of experimental stroke. The onset of immunological alterations in the central nervous system (CNS) is sequential; neutrophils are recruited hours after stroke by activated microglia and endothelial cells, followed by monocytes a few days following the insult, whilst T and B cells infiltrate the ischaemic tissue in the succeeding weeks \u201332. ThisAs well as directly altering immune networks, stroke-driven systemic cytokine signals have also emerged as key players that have been implicated to have divergent effects on outcome following stroke , 36, 37.+ T cells in Peyer's patches  of mice are primed to secrete increased levels of IL-17 and IFN-\u03b3  cells), termed lymphopenia, in circulation as a central feature of stroke-induced immune suppression in patients \u201345, a hand IFN-\u03b3 . Similarnd IFN-\u03b3 . Additiond IFN-\u03b3  whilst tnd IFN-\u03b3 .As such, even innate immune responses are compromised in stroke patients with impairments in the oxidative burst of neutrophils  as well Thus far, we have discussed compartmentalised alterations to systemic immunity post-stroke. In this section, we shall highlight how recruited immune cells interface with locally resident cells and the milieu of cytokines following ischaemic injury in stroke. The identification of meningeal lymphatics in the dural sinuses of the CNS , 63 as wLocal cytokine cues facilitate neutrophil recruitment to the ischaemic hemisphere as early as 6 h post-stroke in an intercellular adhesion molecule-1-dependent manner , 81. NeuThe role of microglia through their interaction with peripherally-derived leukocytes adds an extra layer of complexity as they are double-edged swords with the capacity to propagate and curtail inflammation, and support neurogenesis , 89. ThrBeing one of the first responders to injury or infection \u201397, it cin situ are influenced by not just the subset but also the route of entry into the CNS  through the excessive release of catecholamines, in both patients , 118 anden masse through the generation of functionally poised ones via alterations in haematopoietic output  , 149\u2013152morganii . Equallymorganii , 157. InThus far, we have summarised the plethora of effects that stroke has on systemic immunity as well as the means it employs to shape immune function, taking our cues from established and emerging immunological evidence. Taken together, the net effect of the immune alterations elicited by stroke appear to facilitate the repair of the ischaemic insult given that both mononuclear phagocytes as well as T cells appear to adopt an alternatively activated state , 31, 61.Viewing the paradigm from the vantage point of an immunologist raises some pertinent questions. Is the cost of repairing the ischaemic damage an impairment of antimicrobial defences? Are the various effects on systemic immunity a means to dampen immune responses to antigens that are now exposed to the immune system through a breached BBB following a stroke? Intriguingly, studies have identified that some contexts of stroke \u2013174 and Data from clinical and pre-clinical paradigms of stroke highlight a diverse range of effects on systemic immunity that can be mediated directly and indirectly by the ischaemic damage. An appreciation of not just the changes themselves but the means employed to elicit them could inform the choice of viable therapies to mitigate infections post-stroke by digressing from traditional choices of antibiotics and beta-blockers. It is therefore imperative we re-examine data from clinical trials of immunotherapy in settings of auto-immunity and cancer to appreciate the remit of immunotherapy. By taking cues from these studies, the clinical trials of immunomodulatory therapies in stroke could provide insight into the fundamental mechanisms at play and more importantly, the suitability of immunotherapies for bolstering neuroprotection and antimicrobial immunity in stroke. This in turn could guide approaches for targeted therapies in the clinical management of neuroprotection and infection to improve outcome following stroke.SK conceived the idea for the manuscript. SK and CL wrote and edited the manuscript together.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Although nearly half of all schwannomas involve the head and neck region, nasal and paranasal sinus presentations are quite rarely seen. Cystic schwannoma, characterized by cyst formation lined by S-100 protein positive membrane-like structures is very uncommonly seen in sphenoid sinus with only a single previously reported case. Here we report a young patient of cystic schwannoma of the paranasal sinuses having epicenter in the sphenoid sinus. The tumor had caused extensive erosion of the skull base and paranasal sinuses and extended intracranially that radiologically mimicked as infected mucocele causing loss of vision. This case denotes the aggressive behavior of such uncommon tumors. Schwannomas are slow growing benign tumors originating from the peripheral nerve sheaths. Approximately 25-50% of schwannomas occur in the head and neck region, but tumors originating from the nasal cavity or paranasal sinuses are rare, with just over 100 cases reported in literature . Here weA 22-year old male was seen in our neurosurgical unit having complaints of dull-aching type of holocranial headache since past 6 months and gradually progressive painless diminution of vision of the left eye since past 2 months. He did not give any history of diplopia, nasal obstruction or epistaxis. Neuro-ophthalmologic examination revealed visual acuity of 6/6 in right eye and only light perception in the left eye along with relative afferent pupillary defect and features of optic atrophy on the left side. Neurological examination was otherwise unremarkable. Contrast-enhanced computed tomography (CECT) brain and paranasal sinuses were obtained which revealed a large infiltrative solid-cystic mixed density lesion epicentred in the base of skull predominantly involving the sphenoid sinus causing its expansion and ballooning. The lesion had caused erosion of the left lateral wall of the sphenoid sinus, left anterior and posterior clinoid process, floor of sella and sphenoid sinus and lateral wall of the left orbit with extension into the left antero-medial temporal lobe and left cavernous sinus . On contSchwannoma is a painless, benign slow growing tumor of the peripheral nerve sheath commonly associated with the cochlear nerve at the cerebellopontine angle. They rarely occur in the sinonasal cavities and in this location, they are typically described as solitary encapsulated lesions confined to the nasoethmoid region . SchwannOur patient's schwannoma, presumed to originate from the posterior ethmoidal nerve at the sphenoid sinus, appears to be unique in its presentation as an erosive fronto-ethmoidal mucocele and loss of vision and a location which is very uncommonly seen. The current case is one noteworthy example of mucocele formation secondary to the underlying schwannoma which may mimic features of the more commonly encountered lesions in this region that may cause diagnostic dilemmas and give intraoperative surprises. It remains to be seen if such unusual tumors can be studied in a more extensive way in their earlier juncture of development when the tumors are still small and if with the new radiological techniques like high-tesla MRI the nerves of their origin can be revealed and these tumors subclassified.The authors declare no competing interest."}
+{"text": "Laboratory mice have been the workhorse of immunology research. Well-characterized, inbred mice raised in controlled environments have fostered an understanding of precise immunological mechanisms. Experimental variation has been minimized, but results rarely translate into successful therapies for humans or other animals , 2. SimpBudischak et al. Dietary quality and infection with Trichuris muris affected immune parameters  in the re-wilded mice, but did not reduce parasite load. This study also found that mice on the low-protein diet spent more time foraging, which could result in increased exposure to pathogens. Future re-wilding studies that incorporate disease models and experimental treatments should produce steady progress toward translational outputs by addressing natural variation from the outset, rather than only in clinical trials.Taking laboratory mice out of the box and re-wilding them in an outdoor enclosure is a simple approach to building on the vast amount of laboratory mouse immunology available. A DNA metabarcoding approach was used to quantify variation in feeding habits in a semi-natural environment, rather than the traditional approach of eliminating variation in the laboratory Apodemus sylvaticus) to show that both \u201cimmune\u201d and \u201cnon-immune\u201d genes can be strong predictors of parasite burden Babayan et al. In this case the balance of protective immunity and tissue homeostasis resulted in relatively stable parasite loads and immune profiles. A significant negative association was found between worm burden and cytokine receptors . By contrast there were no significant positive or negative associations with cytokines, highlighting potential problems of serological assays focused on soluble cytokines that don't account for receptor expression.The emergence of various \u201comics\u201d techniques  has opened new research pathways for non-model organisms. Transcriptomics were used for wild wood mice  have serum IgE concentrations up to 200 times higher than non-allergic humans and laboratory rodents. Similar patterns have been observed in other wild species. A primary function of IgE is to induce degranulation of mast cells and basophils that rapidly amplify inflammatory responses upon initial infection by parasites Hellman et al. The reduced exposure to parasites in industrialized nations and the striking differences in IgE levels across species and environments suggests that immunological investigations of animals in natural settings could shed light on the growing allergy problem in humans. Importantly, Hellman et al. also provide thorough analysis and review of Fc receptors, which are necessary for most antibody-mediated effector functions, but are often overlooked in antibody-focused studies.The prevalence of allergy is increasing in industrialized nations and is associated with dysregulated IgE effector functions. Chiroptera) are the second largest order of mammals and are host to a plethora of pathogens with the potential for cross-species transmission. A thought-provoking Hypothesis and Theory article describing unique aspects of the bat immune system proposed that two key features of the bat immune system might account for their ability to harbor pathogenic viruses Schountz et al. First, the IFN locus of the Australian black flying fox  has fewer type I IFN genes than other mammals examined at that time, but that antiviral IFN-\u03b1 mRNA is constitutively expressed at high levels  and led to a 60% decrease in the wild finch population Vinkler et al. Comparison of pathogenicity of the original (1994) and more recent (2006) strains revealed that the increased virulence observed across this time scale has been driven in part by the host's pro-inflammatory response and incomplete host immunity [Vinkler et al.; (Oryctolagus cuniculus) control that began in the 1950s. An evolved 1990 myxoma virus strain became highly virulent because it induced septic shock like inflammatory response that led to immune collapse . The buffalo were monitored for non-specific markers of inflammation every 2\u20133 months over 2 years. Serum haptoglobin was found to be a reliable surveillance marker of recent infection.Simple and cost-effective disease surveillance tools and immunological reagents adaptable for a range of species are required to address issues of pathogen spillover, host-pathogen evolution, and immunity in natural settings. Gasterosteus aculeatus) and native cestode parasites  Lohman et al. Previous studies have shown that two geographically-isolated populations of sticklebacks are equally susceptible to infection, but that one population can suppress parasite growth substantially more than the other (A cost-effective version of RNAseq (TagSeq) was used to fill the species-specific reagent void in a natural host-parasite system of threespine sticklebacks  highlighted that these aggregates of pigmented phagocytes can be found in vertebrates Pye et al. This is a direct demonstration that wild immunology studies can have direct application to conservation and emerging disease solutions. The true test to evaluate any vaccine approach must occur in the wild, or in real-world contexts.The Tasmanian devil facial tumor disease (DFTD) has provided a rare opportunity to scrutinize the interplay between cancer and the immune system on a large scale in a natural tumor model. A vaccinate-and-release study of Tasmanian devils demonstrated that tumor-specific antibodies can be generated and represents a step forward in the search for a prophylactic vaccines in silico analysis prior to embarking on wet lab studies and reagent development can yield more efficient use of limited resources. A comparative analysis of immune checkpoint molecules in two marsupials (metatheria) and seven placental species (eutherians) Flies et al. revealed that many key motifs and binding domains are conserved across more than 160 million years of evolution. The strong selective pressure to maintain immune checkpoints across species and environments suggests these checkpoints could offer stable therapeutic and vaccine targets for human disease and DFTD.As functional experimental studies require significant resource investment , using In summary, wildlife studies, particularly long-term monitoring studies, have begun addressing long-standing questions in immunology. Taking animals out of the lab and into more natural environments has yielded surprising results that are likely to help fill major knowledge gaps regarding the evolution and development of immunity in a wide range of species. We have only scratched the surface of the potential for wild immunology and look forward to finding more answers in the wild in the coming decades.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "A 72-year-old patient was admitted in the emergency room with an 18-hour history of increasing abdominal pain in the right flank and iliac fossa. Laboratory tests showed anemia with hemoglobin at 97 g/l and renal failure with creatinine level at 21 mg/l.Unenhanced abdominal computed tomography (CT) showed signs of cirrhotic dysmorphism of the liver (not illustrated) and diffuse ascites  are exceedingly rare events related to bleeding of small secondary abdominal arteries or veins.Only rare cases of spontaneous omental haemorrhage have been reported. They are usually preceded by trauma or occur in the context of adhesions, torsion, neoplasms, vasculitis, varices, anticoagulation or ectopic omental pregnancy .The implication of epiploic appendages in acute abdominal emergencies is greatly dominated by appendagitis due to acute torsion or infarction. The vast majority of epiploic appendagitis are self-limiting events with only localized peritoneal inflammatory reaction and with characteristic imaging features.To the best of our knowledge a spontaneous hemoperitoneum related to bleeding of an epiploic appendage has never been reported before. In our case the presence of a very long peduncle may have favoured a possible traction with tearing of a small vessel of the epiploic appendage."}
+{"text": "Laparoscopic-adjustable gastric band (LAGB) complications are increasingly recognised as follow-up time increases. These are most commonly related to the gastric band or port site, but complications of the connecting tubing are also reported. We present a case of LAGB tubing penetration through the transverse colon causing abdominal sepsis in a complex surgical abdomen and review prior published cases of abdominal viscus penetration by LAGB tubing. Like complications involving all LAGB components, these often present with non-specific abdominal signs and symptoms and undergo abdominal CT as an early investigation. This makes knowledge of normal and pathological imaging features of LAGB components important in radiology practice. LAGB complications typically present with non-specific abdominal symptoms and signs meaning a CT scan of the abdomen is often an early investigation.4Surgical management of obesity has proven superior to any non-surgical approach.We present the case of a 67-year-old female with a complicated surgical history. She initially presented to our facility with a strangulated large bowel containing ventral hernia, 10 years after undergoing LAGB procedure elsewhere. At this time, she remained morbidly obese and had been lost to follow-up. She underwent emergency surgical hernia repair with resection of necrotic transverse colon and loop ileostomy formation. One year later she presented with a LAGB port-site infection and had the port removed with the tubing sutured to the abdominal wall. During both admissions, the LAGB tubing was repeatedly seen in a stable position adjacent to the transverse colon on CT , with noElective reversal of the ileostomy was then performed 6 months following this but was complicated by abdominal sepsis in the early post-operative period. Abdominal CT demonstrated transection of the remaining proximal transverse colon by the LAGB tubing . This re3 Previously reported cases of LAGB tubing erosion into visceral structures are described in 18 Migration of different forms of intra-abdominal catheter into bowel wall has also been reported, and port system infections and the presence of a free end of tubing are predisposing factors.10 Thus this case, in combination with previous literature, suggests that in patients in which the LAGB is no longer functioning intra-abdominal tubing should be removed when port-site removal or other abdominal surgery is performed. This is perhaps especially\u00a0important when the tubing is seen on imaging to lie near a viscus which may be vulnerable to erosion over time. Awareness of this can help guide radiology reporting and surgical practice.Intragastric migration/erosion of the band is a well-recognised LAGB complication reported to occur in 3.9% of cases, but penetration of the connecting tubing into an abdominal viscus is rare.10Although the number of new LAGB procedures being performed is reducing steadily there are a large cohort of patients with this device already in place. As LAGB tubing complications are primarily related to mechanical stress they are likely time-dependent and prevalence will continue to increase with ongoing follow-up.19,20 This may be diagnostic as in our case, but as demonstrated in While plain radiographs and upper gastrointestinal series may be used to evaluate LAGB complications, most cases will undergo abdominal CT as part of investigation.Complications related to LAGB tubing are increasingly recognised in clinical practice. When combined with the ever-expanding use of CT for investigation of abdominal complaints, this highlights the importance of the imaging features of all LAGB components for radiologists. Clear visualisation of LAGB tubing penetration through the colon as demonstrated here has rarely been reported.LAGB complications can be related to any of the components including the connecting tubing, and tend to present with non-specific abdominal signs and symptoms and undergo abdominal CTLAGB tubing complications often occur in patients who have had previous revision or removal of the LAGB port\u00a0site due to infectionLAGB tubing has the potential to penetrate through abdominal structures and may cause severe illnessThe large numbers of patients with LAGB devices in place coupled with the increase in tubing-related complications as follow-up time increases makes knowledge of the normal and abnormal imaging features of LAGB tubing important in radiology practice"}
+{"text": "Organisational performance measurement is a recognised business management tool and essential for survival and success. There is a paucity of methodological studies of organisational performance measurement relating to non-acute healthcare charities and this study is the first to suggest a set of evidence-informed organisational performance measures for the sector.This study was designed using a two-staged approach. A systematic review of peer-reviewed journal literature between 2003 and 2016 was conducted according to the twenty-seven (27) point checklist of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) complemented by a thematic analysis of eligible data using a cutting and sorting technique to generate a set of common measures of organisational performance for non-acute health charities.Not one study was found relating to organisational performance of non-acute healthcare charities however four records met eligibility criteria relating to non-acute or primary healthcare services with charitable fundraising capability. Three were case studies of specific organisations that related their approach to organisational performance measurement, while the fourth compared a case study organisation to a public service. Three different organisational performance frameworks and 20 organisational performance measures were used across the four studies.The study concluded that (1) demonstration of organisational performance is relevant to non-acute health charities; (2) organisational performance measurement is feasible in this sector; (3) an evidence-based organisational performance measurement framework for the sector has not yet been developed nor has an existing organisational performance measurement framework been adapted for the sector, although the Balanced Scorecard is likely to be an effective option and (4) five leading measures \u2013 Quality of Service; Finance; Stakeholders (Customers and Clients); People and Culture; and Governance and Business Management; could be used to determine organisational performance in these sectors. Finally, \u2018Mission and Purpose\u2019 could be explored as a potential measure. Further research to understand why there is such limited published organisational performance evidence for the sector could be useful. Case studies of organisational measurement strategies of successful non-acute healthcare charities and research into important factors for organisational performance implementation in the sector may contribute to greater uptake and knowledge dissemination. Internationally, the nonprofit sector continues to grow in importance and visibility . In healWhile non-government organisations, not-for-profits and charities share service workloads with government and for-profit providers  an outcoThe healthcare industry itself has a long tradition of extensive and detailed performance measurement , howeverCharacteristics of non-acute health charity business models may be a challenge to organisational performance measurement. The difficulties associated with the conceptualisation of organisational performance due to the financial and legal status and goals of charities, which are based on social values, were documented back in the 1980s and 1990s .In terms of organisational performance measurement methodology, the World Health Organisation\u2019s 2008 European Ministerial Conference Report  on the uThe decision regarding the choice of organisational measures is reportedly one of the major considerations for framework design as the metrics chosen should relate directly to the \u201corganisation\u2019s planned processes and targeted outcomes\u201d .In accepting the challenges of undertaking organisational performance measurement in the non-profit charity health sector, a clear benefit for investment and risk must also be established for both pursuing sector-specific understanding and also individual organisation implementation. The reality is that for organisational performance measurement to be successful \u201cit is essential to take into account the specificities of the sector\u201d The survival of non-acute health charities may be threatened if they do not accept the new age of corporate and service responsibilities, contemporary business management and stakeholder expectations for accountability and excellence. The identification of evidence-informed organisational performance frameworks and measures for non-acute health charities may in-part help overcome the barriers for measurement implementation in the sector, and in turn encourage demonstration of effective business strategy and client care outcomes. Creating a competitive edge through reporting organisational performance in service, stakeholder engagement, and funding could just be what the doctor ordered for non-acute health charities to sustain their programs  This study sought to answer the question: What are the important organisational performance measures of non-acute health charities? The specific aims were to (1) gauge the extent of quality methodological studies of organisational performance measurement frameworks for non-acute healthcare charities; (2) source studies from the sector which have evaluated the feasibility, validity and effectiveness of frameworks in improving organisational performance and client care outcomes; and (3) determine which measures were most valuable to assess the performance of such organisations.This study was designed using a two-staged approach. Firstly, a systematic review \u2013 widely accepted as a gold standard in evidence synthesis , was conThis first stage was then complemented by a thematic analysis of eligible data using a cutting and sorting technique informed by Ryan and Bernard  The study sought scholarly peer-reviewed literature, published between 2003 and 2016, available in English and full-text online relating to organisational performance measurement of non-government organisations (NGOs) in the not-for-profit (NFP) or charitable sectors that provide non-acute healthcare.Internationally there is a wide perspective of definitions relating to non-government, not-for-profit and charitable sectors depending on the field of topic studied : organisations that are not government or public institutions. When excluding for-profit businesses, such organisations are often referred to as the \u2018third-sector\u2019 and characterised by a vision to contribute to community issues.Not-for-Profit organisations (NFPs): NGOs where all of the revenue earned is utilised to pursue the organisation\u2019s objectives. Profits are not distributed back to owners, shareholders or members.Charitable organisations: NFPs that are legally eligible for donations or specific tax concessions.Non-acute healthcare: the provision of non-hospital health service where the primary clinical purpose is support for a patient with impairment or activity limitation due to a health condition. Often referred to as maintenance care, non-acute patients often require care over an indefinite period following initial assessment or treatment as opposed to complex stabilisation.Table\u00a0Table\u00a0The goal was to assess studies of organisations that met all three organisational characteristics \u2013 NGO, NFP and charitable eligibility, which provided non-acute healthcare services.Inclusion criteria were used in the second (screening) and third (eligibility) stages of the four staged PRISMA-flow process. The inclusion decisions were made by the lead author and critiqued by the second and third authors. Records were sought that were scholarly peer-reviewed literature, published between 2003 and 2016 available online in English and in full-text. Two-hundred and sixty (260) articles published between 2003 and 2016 were identified as relevant. Full-text assessment of these publications (Stage 3) was then undertaken using six eligibility criteria.The authors agreed that there were no articles sourced that related solely to organisational performance of non-acute healthcare charities, however four articles met the inclusion criteria  authors names 2) publication 3) year of publication 4) country of origin 5) key search terms 6) article key words 7) organisational performance measurement framework studied and 8) organisational performance measures utilised for the framework. A quality assessment of the eligible studies was also conducted using the four categories of The Rosalind Franklin Qualitative Research Appraisal Instrument - RF-QRA  \u2013The performance measures for each study were collated using a cutting and sorting technique  Table\u00a0A 2008 Canadian study by Schalm  details A 2007 study by Mueller  introducPublished in 2006, Laamanen et al.  comparedThe BSC is the focus of Radnor and Lovell\u2019s 2003 study , which oThree of the studies were case studies of specific organisations Radnor and Lovell found that the majority of successful organisations within a market-based economy \u201cuse PMSs (sic. performance management systems) of varying degrees of sophistication\u201d Three organisational performance frameworks were utilised within the study\u2019s four records Table . No evidThe importance of tailored sector-type and individual organisational performance measures as success reference points within conceptual frameworks and the difficulty in developing organisational performance measures for non-profits has been recognised. The study did not source any comparative studies that identify the most valuable measures for the non-acute healthcare providers in NGO, NFP and charity sectors. As such, this study contributes to the body of knowledge by being the first to propose a set of evidence-informed organisational performance measures specifically for non-acute health charities.Quality of ServiceFinanceStakeholders (Customers and Clients/Patients)People and CultureGovernance and Business ManagementThere were 20 organisational performance measures identified within the four assessed studies Table , which wThree of the four studies included measures that related to Governance and Business Management. Two of those used Kaplan and Norton\u2019s traditional \u2018Internal Processes\u2019 perspective for BSC , p. 54)..4 revealThe importance of stakeholders including clients or patients, was clearly demonstrated. In terms of health care, the World Health Organisation\u2019s European Ministerial Conference Report maps important accountability relationships across seven stakeholder groups within health systems \u2013 Quality of Service as an organisational measure strengthens attention to an organisation\u2019s core service. Gurd and Gao reiterated that patients are \u201cthe focus of healthcare services\u201d  In terms of financial considerations for organisational performance, the issue appears to be more focused on \u2018where\u2019, not \u2018if\u2019, finance sits in a healthcare BSC. Bisbe et al.  discuss Two of the four studies identified people, learning and growth as important measures. As Kaplan and Norton Further investigation of records that had not met all of the eligibility criteria highlighted that some non-profit health organisations seek an organisational performance measure that assesses performance against \u201cachieving the organisation\u2019s final objective\u201d The authors identified limitations to the study that should be considered when interpreting the results and recommendations. These limitations also reinforce the need for further study. While limited source or empty reviews are defendable, the study\u2019s primary limitation is the small number of data sources due to the fact that no studies were found that related solely to organisational performance of non-acute healthcare charities and that only four records met the inclusion criteria. Extending the systematic review criteria beyond peer-review published literature to include grey literature (sourced outside the peer-reviewed literature), or through less restrictive eligibility criteria, may have identified reports of additional eligible records. However, if the latter had been applied, the lack of literature on performance measurement in non-acute healthcare charities sector would have been lost.The present study identifies the need for quality methodological studies of organisational performance measurement frameworks for non-acute healthcare charities. Identifying the reasons for the lack of published evidence relating to organisational performance measurement in this sector could encourage awareness and greater knowledge sharing within the sector. The present study lists frameworks and measures and a comparative evaluation of these frameworks to understand their appropriateness and inform their selection within the sector would be of value.In terms of effective deployment, further research to understand and validate the five BSC recommended organisational performance measures, with the additional inclusion of \u2018Mission and Purpose\u2019 is recommended, along with identification and analysis of indicators to support each measure. Research to understand the important factors for organisational performance implementation within non-acute healthcare charities is also recommended. Demonstrating impact and validating the degree of value of the full-scaled deployment of a tailored set of measures utilising an evidence-based framework such as the BSC would further inform the value of organisational performance measurement to organisations in the sector.Finally, the opportunity to utilise organisational performance measurement to support whole-of-sector development is worth considering. While acknowledging there will always be some differences due to the different strategic orientations of health care organisations, Gurd et al.  encouragThe nonprofit sector continues to grow globally and so too does concern regarding the effectiveness and accountability of non-government organisations, not-for-profits and charities. Organisational performance measurement is a recognised business management tool and it has been suggested as being essential for success and survival. A relationship between performance measurement and organisational effectiveness in nonprofit organisations has been identified yet uptake in some nonprofit sectors has been slow. In healthcare, non-acute health charities form part of the broader global industry and play a role in non-hospital care however there is a literature gap in organisational performance for this sector.This study found there is a paucity of methodological studies of organisational performance measurement relating to non-acute healthcare charities and concluded that (1) demonstration of organisational performance is relevant to non-acute health charities; (2) organisational performance measurement is feasible in this sector; (3) an evidence-based organisational performance measurement framework or tool specifically for the sector has not yet been developed, nor has an existing organisational performance measurement framework yet to be adapted for the sector, although the Balanced Scorecard is likely to be an effective option and (4) five leading measures \u2013 Quality of Service; Finance; Stakeholders (Customers and Clients); People and Culture and Governance and Business Management; could be used to determine organisational performance in these sectors.Further study to understand and validate the five recommended organisational performance measures complemented by a sixth measure - Mission and Purpose, which was identified in the broader literature, would be valuable. Further exploration to understand why there is such limited published organisational performance evidence for the sector could be useful, as would consideration as to which existing organisational performance measurement frameworks might be most successfully adapted for the sector. Case studies of organisational measurement strategies of successful non-acute healthcare charities and research into important factors for organisational performance implementation in the sector may also contribute to greater uptake and knowledge dissemination."}
+{"text": "Oxidative stress is an underlying factor in health and disease Sies, . The conIn this Frontiers Research topic oxidative stress was revisited by discussing old paradigms and suggesting new therapeutic approaches to decreased oxidative stress and reduce the progression of vascular diseases.Sena et al.) playing a major role in several vascular diseases including neurodegenerative diseases  and diabetic complications . This was elegantly discussed by several authors in this research topic.In the vasculature, several sources promote an increment in oxidative stress. Free radicals  are major sources of oxidative stress Sies, . VasculaCarvalho and Moreira discussed how oxidative stress is in the front line of vascular alterations observed in brain aging and neurodegenerative conditions, particularly Alzheimer disease.Oxidative stress may have a critical role in the neurovascular uncoupling underlying brain aging and dysfunction. Louren\u00e7o et al. demonstrated that non-pathological brain aging involves changes in both neurovascular and neurometabolic function in the hippocampus, in close correlation with compromised cognitive function, suggesting a role for oxidative stress. This data supports an impairment of neurovascular response in connection with cognition decline due to oxidative environment-dependent compromised nitric oxide (NO) signaling from neurons to vessels during aging.In addition, Abdulle et al. These authors suggest the use of oxidative stress related read-outs as clinical biomarkers of disease activity and evaluate potential anti-oxidative strategies in systemic sclerosis .Oxidative stress and the potential role of reactive oxygen species in the initiation and progression of systemic sclerosis vasculopathy was reviewed by Santiago et al. with emphasis in the endothelial cell communication with other retinal cells.The synergistic contributions of redox-inflammatory processes for endothelial dysfunction in diabetic retinopathy were discussed by Siques et al.The role of reactive oxygen species in the development of pulmonary vasculature changes under hypoxic conditions was discussed by Kim et al). Melatonin and its therapeutic potential was discussed by Guo et al. on cerebral autoregulation following subarachnoid hemorrhage.In different chapters, authors suggest and discuss some therapeutic strategies to protect the vasculature against oxidative stress. Therapeutic approaches such as policosanol consumption and melatonin have been investigated and discussed. The physiological policosanol consumption resulted in significant lowering of brachial and central aortic blood pressure in a dose-dependent manner accompanied by an improvement in lipid profile resulting in improved anti-oxidant and anti-glycation activities in healthy Korean subjects with pre-hypertension . In addition, due to the role of macrophages in all stages of the inflammatory response by acquiring distinct functional phenotypes that are directed by the tissue type and environmental cues, Takahashi et al. highlighting the anti-inflammatory effects of AM18W-13a extract to reduce inflammation in murine macrophages.Environmental stress factors are important both in adults and in early life. Exposure to stressful environments produced persistent increases in plasma corticosterone and reductions of brain and cardiac NO production followed by a delayed decrease in the NO-dependent component of endothelium-dependent relaxation\u2014changes that collectively accelerated blood pressure increases only in young borderline hypertensive rats (Rodr\u00edguez-Rodr\u00edguez et al. summarize data on specific redox alterations in key cardiovascular control organs induced by exposure to known stress factors in experimental animals and discuss the emerging role of the mitochondria.Importantly, environmental stress factors during fetal and perinatal life can shape the future health of the individual and increase susceptibility to several adult diseases. Suboptimal intrauterine conditions induce alterations in placental redox balance, associated with poor fetal development and low birth weight. This Frontiers Research Topic in oxidative stress is a view into the rich places of research that have yet to be tapped relative to understanding the role oxidative stress plays both in health and disease.We are grateful to our contributors for sharing their important work.CS drafted the editorial. RS and GP read and modified the editorial.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Nicotinamide (vitamin B3) has photoprotective effects and reduces skin cancer incidence in high risk patients. Nicotinamide also improves cognition in animal models. As part of the ONTRAC  phase III placebo-controlled, randomized trial to assess nicotinamide\u2019s efficacy in skin cancer prevention, we included clinical neurocognitive function and patient-reported quality of life assessments at baseline and after 12 months of intervention in individuals with previous skin cancer in order to assess any effect of oral nicotinamide (500 mg po twice daily) on cognitive function and quality of life. In our sample of 310 participants who completed neurocognitive function testing at baseline and at 12 months, we were not able to detect any significant effect of oral nicotinamide on cognitive function nor on quality of life. Further studies of nicotinamide\u2019s effects on cognition in humans might include individuals with pre-existing mild cognitive impairment, and it may be that higher doses of nicotinamide are required to significantly influence cognitive function compared to doses required to reduce skin cancer. In the skin, nicotinamide is able to replenish cellular energy after ultraviolet radiation exposure [As a precursor of nicotinamide adenine dinucleotide  and quality of life (QoL). The NCF objective was pursued given the evidence for the role of nicotinamide in cognitive and neurological function available at the time ONTRAC was designed. In mice, exposure to nicotinamide has been associated with improved short term memory , reducedOf the 386 patients randomized to ONTRAC, 310 and 290 took part in the NCF and QoL substudies respectively . SubstudThere were no differences between the arms in any neuropsychological test at baseline. All mean scores were within the expected range with the exception of verbal memory and learning in which both groups scored 1SD below the expected mean. There was no difference between the arms in the change score from baseline to 12 months, with the exception of the Digit span assessment which yielded a p-value below 0.05; however, this result remained consistent with the play of chance when taking into account the multiple comparisons performed. There was no difference between the arms in cognitive symptoms or in any of the QoL domains at any time point. In our cohort of largely elderly, community dwelling skin cancer patients assessed over a 12-month intervention period, there was no compelling statistical evidence of an effect of nicotinamide on neurocognitive performance nor on QoL. The narrow width of the confidence intervals helps rule out the plausibility of nicotinamide causing a clinically important reduction in NCF or QoL. The effects of nicotinamide on NCF in individuals at higher risk of progression to dementia, for example those with early cognitive impairment but not frank dementia, is currently unknown. There are, as of yet, no published studies of nicotinamide use in this setting, nor as a preventive agent in individuals without cognitive deficit. Whilst some patients with Alzheimer\u2019s Disease given nicotinamide adenine dinucleotide  did show improvement in mini mental state examination and global deterioration scores , others Details of the design of the ONTRAC trial  have been published previously [The NCF substudy assessed verbal learning and memory, verbal and written word fluency, information processing, attention/working memory, and executive function using the following battery of instruments: Hopkins Verbal Learning Test-Revised (HVLT-R) , ControlThe QoL substudy used a selection of scales from the Patient Reported Outcomes Measurement Information System Computer Adaptive Test (PROMIS-CAT) system  includinRaw neuropsychological scores were converted to demographically-corrected T scores   with an Nicotinamide at a dose of 500 mg twice daily for 12 months did not significantly alter neurocognitive function in our participants. It may be that higher nicotinamide doses than our skin cancer chemoprevention dose, administered over a longer duration, are needed to elicit beneficial effects on NCF."}
+{"text": "Electron cryo-microscopy (cryo-EM) is increasingly being used to determine 3D structures of a broad spectrum of biological specimens from molecules to cells. Anticipating this progress in the early 2000s, an international collaboration of scientists with expertise in both cryo-EM and structure data archiving was established . The major goals of the collaboration have been twofold: to develop the necessary infrastructure for archiving cryo-EM-derived density maps and models, and to promote development of cryo-EM structure validation standards. We describe how cryo-EM data archiving and validation have been developed and jointly coordinated for the Electron Microscopy Data Bank and Protein Data Bank archives over the past two decades, as well as the impact of evolving technology on data standards. Just as for X-ray crystallography and nuclear magnetic resonance, engaging the scientific community via workshops and challenging activities has played a central role in developing recommendations and requirements for the cryo-EM structure data archives. Electron cryo-microscopy (cryo-EM) has very recently become a mainstream area of structural biology and medicine, enabling 3D visualization of a wide variety of biologically important complexes that were previously inaccessible to science. Early cryo-EM 3D density maps typically lacked atomic detail, yielding only the overall molecular shape, but could still sometimes be interpreted at a \u201cpseudo-atomic\u201d level via fitting of previously known coordinates or homology models .1 RecentThe development of cryo-EM is directly reflected by the growth of cryo-EM structure depositions contributed worldwide to public data archives . The arcStructure and Nature Structural Biology encouraging electron microscopists to deposit their density maps.The Protein Data Bank (PDB), established in 1971 as a public archive for atomic coordinates of biological structures derived from X-ray crystallography,In 2006, scientists in the UK (EMDB) and USA [Research Collaboratory for Structural Bioinformatics (RCSB) and the National Center for Macromolecular Imaging (NCMI)] initiated a collaboration funded by National Institutes of Health (NIH) aimed to ensure that data archiving and validation standards for cryo-EM maps and models would be coordinated internationally.EMDep, designed and implemented at EBI, was the first system designed to collect and annotate maps and associated metadata for EMDB.In 2012, the Electron Microscopy Public Image Archive (EMPIAR) was established at EBI.The Worldwide PDB (wwPDB) is the global organization that manages the PDB archive.The foundation of any data repository is its data representation scheme. Based in part on the International Union of Crystallography dictionary for small molecule crystallography Crystallographic Information File (CIF),Following the lead of the crystallographic community, an mmCIF extension dictionary containing data terms for cryo-EM experiments was drafted jointly in the early 2000s based on requirements provided by the cryo-EM community. The dictionary was vetted and expanded by the scientific community via multiple workshops, and subsequently integrated by EMDR into the PDBx/mmCIF dictionary for use in the hybrid joint map+model deposition system.Developing a trusted scientific data repository requires careful attention to the interplay among science, technology, and community interest.2004 Cryo-EM Structure Deposition Workshop [The main goal of the Workshop , attende2005 3DEM Developers Workshop to facilitate its integration with major 3DEM packages and electronic notebook systems. There were two important outcomes: (a) the draft dictionary was unanimously accepted by the participants and (b) a set of proposed conventions for describing EM micrographs and density maps was developed.The EM extension dictionary was next reviewed by software developers at the 2011 Data Management Challenges in 3D Electron Microscopy Workshop2015 Building Bridges between Cellular and Molecular Structural Biology Workshop.Data standards for cryo-EM structures were further addressed at the 2010 EM Validation Task Force (EM VTF) Workshop [At the Workshop , an inteThe EM VTF's 2012 white paper notably called for the scientific community to develop new criteria for the evaluation of maps and for the evaluation of fit of the model to the experimental map density.2011 Data Management Challenges in 3D Electron Microscopy Workshop.Validation standards and raw image data archiving were additional topics of discussion at the 2016 Map and Model Challenges). Following the 2017 Joint Challenges Workshop at Stanford, which had over 90 participants [Journal of Structural Biology published in December 2018.Two EMDR-sponsored challenges subsequently aimed to address the 2010 EM VTF's call for improved metrics to evaluate both maps and fit of models to experimental data  to variations in practitioner practice.The Map Challenge provided a unique forum for critically evaluating the standard method for estimating map resolution by FSC , inset. 2017 Joint Challenges Workshop also sparked lively discussions about the potential for model-based metrics to estimate not only model quality, but also to provide one or more independent measures of map resolvability. Several procedures of this type have been proposed and tested. EMRinger evaluates whether density peaks in the map fall within the possible rotameric configuration for the carbon-\u03b2 atom in a side chain.The Looking at the distribution of reported resolution of maps released into EMDB annually over the past few years , one can2019 Model Metrics Challenge and associated 2019 Model Metrics Workshop were designed with the goal of evaluating metrics for map-model fit of moderately high-resolution maps (3.1\u20131.8\u2009\u00c5). A full write-up will be published elsewhere, and we note two findings here. First, the new metrics that by some means combine both model and map quality  appear to be quite useful for ranking sets of structures. Second, refined Atomic Displacement Parameters (ADPs), which were included in about half of the models submitted by challenge participants, could modestly improve fit of the model to the map, particularly for the highest resolution (1.8\u2009\u00c5) target map. The meaning of refined ADPs/B-factors in the context of a cryo-EM density map is less clear. Best practices  will need to be investigated.The The initial EM validation report format released in 2016 focused on assessment of model geometry for PDB entries.\u2022Can estimation of map resolution be better standardized across the community? This would enable fairer comparisons among maps determined in different laboratories and using different software packages.\u2022Additional metrics (beyond atom inclusion) are available that describe map-model fit, including several novel procedures that effectively yield a joint assessment of map and model quality in a broad resolution range. How should map-model fit be reported as part of a structure determination and in a joint map+model deposition?\u2022What best practice recommendations can be made for refinement of ADPs in cryo-EM models at different resolutions?\u2022How should we evaluate multiple structures determined from a single specimen that may have variable quality and resolution?A planned meeting in January 2020 at EBI organized by wwPDB will bring together cryo-EM and data archiving experts to discuss the current state of data archiving for cryo-EM structures derived from the single-particle reconstruction method, and to solicit recommendations on what data should be included and/or made mandatory in depositions and associated validation reports. The following points might be considered as part of the deliberations:"}
+{"text": "Genome Biology has characterized the evolution of candidate hominoid-specific liver enhancers by using massively parallel reporter assays (MPRAs).A recent study in  Enhancers play a key role in cell-type-specific gene regulation, and their disruption has been associated with human disease , 2. AlthPrevious work has moved beyond studying enhancer evolution at the sequence level by mapping enhancer-associated histone modifications across species. One notable such study mapped the active enhancer-associated modification of histone H3 lysine 27 acetylation (H3K27ac) in liver for 20 mammals, including human and three other primates, using chromatin immunoprecipitation with sequencing (ChIP-seq)  seeks toDrosophila species [MPRAs allow simultaneous quantification of thousands of DNA sequences for their ability to drive gene expression , 6. Thes species . HoweverKlein and colleagues first identified a candidate set of hominoid-specific liver enhancers based on enrichment of H3K27ac in ChIP-seq data from human liver, but lack of the enrichment in rhesus, vervet, and marmoset monkeys, in addition to lack of enrichment with the promoter-associated histone H3 lysine 4 tri-methylation (H3K4me3) mark in human. They then sought to test a subset of these sequences with the STARR-seq assay in experimentally tractable human HepG2 cells, which are liver hepatocellular carcinoma cells. The authors restricted their testing to the subset of candidate hominoid-specific liver enhancers that also overlapped strong enhancer chromatin-state predictions in HepG2 cells by the ChromHMM method . As the Focusing on the subset of tiles in human that had orthologous sequences in ten other primates, Klein et al. sought to identify sequence features that could explain the enhancers being active in human, but less active in other primates. When comparing the human and orthologous marmoset sequence, they found some preferential enrichment for motifs for several liver-associated transcription factors. However, when attempting to predict the difference of activity among orthologous sequences in human and other primates based on a gapped k-mer support vector machine , they diThe inability to predict a reduction of activity in orthologs based on sequence motivated Klein and colleagues to directly functionally test the sequences of other primates. Specifically, the authors designed a new STARR-seq experiment focusing on a set of tiles that were active in human and had orthologs in ten other present-day primates. In addition to testing the human sequences and the ten other present-day primate orthologs, the authors also tested nine ancestral reconstructions all together in HepG2 cells.The experimental data revealed that only a minority of the tested tiles showed a reduction in activity relative to human, the expected pattern based on the liver H3K27ac ChIP-seq data. The limited overall reduction relative to human was also seen with the sequence-based predictions. However, there was limited agreement between which specific tiles were predicted to have reduced activity based on sequence and which actually did so in the experiments. The authors did find, however, that the overall clustering of their experimental data was consistent with the phylogenetic relationship among the species. Renormalization of the experimental data relative to the oldest ancestor tested identified a number of tiles having coherent evolutionary trajectories, which could be explained parsimoniously by relatively few gains or losses of activity.Klein and colleagues then investigated associations between mutations and changes in functional activity in the tested enhancers across primate evolution. They found a significant, albeit modest, correlation between the number of sequence mutations and functional divergence along branches of the phylogeny. They then identified a set of \u2018prioritized variants\u2019 to explain significant associations between sequence and functional divergence. Among the prioritized variants, the investigators found a statistically significant enrichment for the C-to-T and G-to-A pair of mutations. This prompted them to test whether there was also an enrichment for CpG deamination relative to its background frequency, which they confirmed to be the case. The authors thus hypothesized that CpG deamination could play an important role in primate enhancer evolution and noted other prior supporting evidence, including its high frequency of mutation, its efficiency at creating new transcription factor binding sites and its ability to alter enhancer methylation patterns.trans environment depend on an assumption that differences at the cis-level will be much more substantial than at the trans-level, which the authors justified based on prior studies.This work by Klein and colleagues is an exciting demonstration of the power of the MPRA technology for studying enhancer evolution, which has several attractive features in this context. One attractive feature is that DNA material from the tested species is not needed, which allows testing of computationally reconstructed ancestral sequences and facilitates the testing of many present-day species. Another strength is that the assay can simultaneously test hundreds of different enhancer sequences across species, with the sequences tested being the same except for the species-specific individual nucleotide differences. Furthermore, the experiment tests all the sequences together in one common environment and thus avoids many potential experimental confounders. Some inferences derived from data from a common Two surprising results of the authors\u2019 study were the limited agreement of species differences in the liver ChIP-seq data with that of the reporter activity and the limited ability to predict which enhancers would show changes in activity based on sequence. Both results underscore the greater challenge associated with predicting differential activity across species compared with absolute activity within a species. The limited agreement between the liver ChIP-seq data and the functional activity in MPRA experiments might be due to differences between primary liver samples and HepG2 cells. Another possible cause of the lack of agreement could arise from inherent differences between what ChIP-seq and MPRA experiments measure. Furthermore, differences in the chromatin and extended sequence context of the experiments, which is the native genome for ChIP-seq and a plasmid for MPRA, might also limit agreement. The inability to predict the activity changes based on sequence suggests opportunities for improved computational models for predicting activity changes from sequence changes or a different application of existing approaches.Despite the above caveats, the study is an exciting step towards a better understanding of enhancer evolution and the relationship between sequence and functional divergence. This study provides support for the hypothesis of CpG deamination as a possible driving force for enhancer modulation. More generally, this work presents an effective approach for investigating evolutionary mutations in enhancers and their resulting functional changes that should be useful to future studies in other systems or species."}
+{"text": "Access of rural older people to health and wellness services is limited and becoming progressively more limited as trends toward increasing centralization of Government and private services continue. \u201cTop-down\u201d or urban centric models for rural service delivery often miss context essential to effectiveness and sustainability. In this symposium, each presenter in this multidisciplinary group of researchers presents innovative, community-based interventions that address these challenges using different methodologies and in respect to different needs Maiden (Psychology) compares the utilization of mental health services by rural older adults over time with their need for such services. Through the lens of social gerontology Holley examines networks of support that have intersected successfully to generate local solutions to unmet needs of rural-dwelling older adults. Crowther and Ford within a nursing and care context explore community-based models that draw upon the role of culture to integrate care for rural older adults. Katz, from an adult development perspective, reports on an educational game-intervention developed to reduce cognitive decline which is tailored specifically for older adults in rural areas. Wiese presents evidence from a pilot home-based approach that demonstrates a model for increasing rates of AD detection and treatment in a rural retired farm worker community in Florida. Our discussant, an emerging scholar in the field of rural gerontology, will reflect on the major themes that emerge from these multidisciplinary perspectives, especially the role of intersecting networks in community-based innovations and rural aging."}
+{"text": "Modern omics techniques reveal molecular structures and cellular networks of tissues and cells in unprecedented detail. Recent advances in single cell analysis have further revolutionized all disciplines in cellular and molecular biology. These methods have also been employed in current investigations on the structure and function of insulin secreting beta cells under normal and pathological conditions that lead to an impaired glucose tolerance and type 2 diabetes. Proteomic and transcriptomic analyses have pointed to significant alterations in protein expression and function in beta cells exposed to diabetes like conditions . These nutritional overload stressful conditions are often defined as glucolipotoxic due to the progressive damage they cause to the cells. Our recent studies on the rat insulinoma-derived INS-1E beta cell line point to differential effects of such conditions in the phospholipid bilayers in beta cells. This review focuses on confocal microscopy-based detection of these profound alterations in the plasma membrane and membranes of insulin granules and lipid droplets in single beta cells under such nutritional load conditions.  This may lead to modified cellular functions, including insulin granule trafficking [The composition of phospholipids in biological membranes determines their cell barrier and cellular communication functions as well as subcellular organelles structure and functions. These properties are determined by the nature of the various phospholipid species and the availability of free fatty acids (FFA) from cellular metabolism and the diet. Yet, the composition of phospholipids in membranes of different subcellular compartments in any given cell may differ greatly. For instance, MacDonald et al.  found sifficking ,4.The basis for these theories was laid by earlier lipidomic investigations of beta cells, such as by Fex and Lernmark  or CortiIn addition to the inherent composition of phospholipids and their turnover in subcellular organelles in beta cells, it is equally important to emphasize the critical role of increased availability of dietary  FFA and their incorporation into phospholipids. This is of paramount consequence upon exposure of beta cells to high levels of SFA  that ensues alone, or in combination with high glucose levels, an array of (gluco)lipotoxic effects that often contribute to the decline in the mass and function of beta cells in islets of Langerhans ,18,19,20Our recent studies on the effect of high glucose and high palmitic acid levels on the phospholipid lipidome of rat insulinoma-derived INS-1E beta cells revealed profound changes in the abundance and distribution of various fatty acids in phospholipids. These studies reveal organelle-specific channeling of polyunsaturated fatty acids (PUFA), arachidonic acid in particular, to nonenzymatic peroxidation and the generation of 4hydroxyalkenals, which affect the cells in several ways ,13. Furt2), on one hand, and their acylation to the phospholipid backbone by lysophospholipid acyl transferase (LPAT), on the other [The fatty acid composition in membrane phospholipids is constantly remodeled by the influence of free fatty acid availability, enzymatic activity of phospholipases, stressful condition  or metabolic diseases. The remodeling is a dynamic and fast process that changes the equilibrium between fatty acid hydrolysis from phospholipids by phospholipase A2  whether plasma membranes of cells are inherently protected against major remodeling of phospholipids and thus preserve their barrier and communication capabilities with the surrounding environment; (ii) to what extent the remodeling of mitochondria membranes may affect their permeability, membrane potential and oxidative phosphorylation capacity; (iii) how the remodeling of phospholipids in the ER modulates protein sorting and chaperoning or alters their capacity to generate mono-layered lipid droplets within this compartment; (iv) could lysosomal function be influenced upon phospholipid remodeling or (v) to what level neurotransmitter or hormone secretion from vesicles or granules in neurons and endocrine cells, respectively, is disrupted of enhanced due to alterations in their tethering, docking and fusion with the plasma membrane and subsequent internalization. Tedious fractionation, separation and isolation techniques of subcellular organelle fractions were practiced in the past to answer such questions. Often, the amount and cross-contamination of the isolated fractions resulted in erroneous analyses. We showed that what was considered a standard and efficient purification method of the plasma membrane fraction of skeletal muscle cells carried in fact a substantial cross-contamination of intracellular microsomal membrane that could greatly obscure the experimental results .We have employed non-targeted lipidomics analysis to study the impact of high glucose and high palmitic acid levels on the turnover of fatty acids in phospholipids of INS-1E cells. These studies discovered significant changes in the content of SFA, MUFA and PUFA . Figure Concomitant exposure of the cells to increasing levels of palmitic acid and glucose further modified the abundance of fatty acids in phospholipids. As mentioned above, these whole cell lipidomic analyses could not detect changes in fatty acid composition in membranes of subcellular compartments in the cells. This limitation also applies to other whole-cell analyses, such as shotgun lipidomics . This meOther mass spectrometry methods have also been used to study beta cells. Recent temporal analysis of palmitic acid-treated INS-1 beta cells was based on isobaric labeling-based mass spectrometry and bioinformatics . It highOur interests in ascertaining the impact of phospholipid remodeling in the beta cell lipidome under nutritional overload conditions led to two independent confocal imaging strategies of INS-1E beta cells. The first employed spectral analysis of the fluorescent probe Laurdan to provide fluidity maps of single cell membranes . The secIG \u2212 IR)/(IG + IR); IG, emission in the range of 400\u2013460 nm; IR, emission at the range of 470\u2013530 nm. The GP value ranges from \u22121  to 1 . In the first case the advantages of fluorescence temporal imaging-based detection methods were exploited to obtain high resolution imaging of subcellular organelles in beta cells. For this purpose, we expressed in INS-1E cells IAPP-mCherry protein that is targeted to insulin granules   in cells that were incubated with increasing glucose concentrations. This indicates that the release of PUFA from phospholipids in the cell sunder high glucose conditions (reported in ) did notositions . The GP ositions  that nonIn the second case the solvatochromic and lipophilic properties of the fluorescent probe Nile Red were exploited to obtain high-resolution micropolarity maps of individual INS-1E cells . The proIn the magnification  it is shCurrent lipidomic analyses of beta cells show that hyperglycemic- and hyperlipidemic-like conditions induce fast remodeling of phospholipids. These modifications may reflect substantial structural and functional changes in the cells. These methods have not yet progressed to allow for subcellular lipidomic analysis in fixed or lived cells. Confocal imaging that provide high resolution maps of subcellular membrane fluidity and lipid micropolarity maps of live cells may complement the lipidomic analyses by depicting membrane remodeling upon various stressful stimuli. Our recent results in lipidomics and lipid imaging in beta cells highlight this potential. This has also been demonstrated in a study that employed mass-spectrometry based oxidative lipidomics and lipid imaging in traumatic brain injury models . Finally"}
+{"text": "The general aim of this review is to outline comprehensively the promising applications of SSC manipulation that could in the nearest future find practical application in livestock breeding. Here, we will focus on 1) the basics of mammalian SSC biology; 2) the approaches for SSC isolation and purification; 3) the available in vitro systems for the stable expansion of isolated SSCs; 4) a discussion of how the manipulation of SSCs can accelerate livestock transgenesis; 5) a thorough overview of the techniques of SSC transplantation in livestock species , and finally, 6) why SSC transplantation is valuable to extend the techniques of spermatozoa cryopreservation and/or artificial insemination. For situations where no reliable data have yet been obtained for a particular livestock species, we will rely on the data obtained from studies conducted in rodents because the knowledge gained from rodent research is translatable to livestock species to a great extent. On the other hand, we will draw special attention to situations where such translation is not possible.We are entering an exciting epoch in livestock biotechnology during which the fundamental approaches  will be enhanced based on the modern understanding of the biology of spermatogonial stem cells (SSCs) combined with the outstanding recent advances in genomic editing technologies and The online version of this article (10.1186/s40104-019-0355-4) contains supplementary material, which is available to authorized users. Spermatogenesis is a delicately orchestrated process of continuous sperm cell production when billions of haploid spermatozoa are produced daily. The reproductive system of sexually mature males requires the presence of a stem cell pool to maintain an extremely high level of daily sperm production  and a differentiation ability while giving rise to the haploid spermatozoa . SSCs orIn postnatal mammalian testes, SSCs reside within a specialized microenvironmental compartment of the seminiferous epithelium located near the basement membrane. These compartments, populated by SSCs and Sertoli cells, are canonically called niches. Moreover, there are several niche-related cell types and structures in the testicular interstitium  and in the seminiferous peritubular region (peritubular myoid cells [PMCs] and peritubular macrophages), which act via paracrine signaling to mutually regulate the SSC fate by balancing SSC self-renewal and differentiation in the niche .The processes of niche organization, SSC self-renewal and differentiation, and spermatogonial development in mammals is complex and is under the control of the myriad of paracrine molecular factors. Readers interested in these processes should refer to the excellent reviews published elsewhere: \u201319, and in vivo. Therefore, GDNF is the most common molecular growth factor used in SSC culture to maintain self-renewal in vitro. bFGF appears to play a minor supportive role in SSC self-renewal because this factor alone cannot fully support the self-renewal of murine SSCs  to induce double-stranded breaks (DSB) in the DNA at very precise locations to initiate the nonhomologous end-joining (NHEJ) or homologous recombination (HR) repairing processes . On the other hand, the SSCs (together with gonocytes) offer more practical option due to relatively simple procedure of their collection from the testes of neonates, juvenile or adult donors . , embryos can be obtained from the in vitro generated spermatids and oocytes. Such an \u201canimal embryo-stem cell breeding system\u201d completes the whole livestock breeding scheme \u201cin a dish\u201d by integrating in vitro germ cell induction, IVF, genome sequencing, and genomic selection [188]. On the other hand, even the possibility of producing sperm in vitro would have had a great impact on livestock industries in case of success. As Aponte . The molecular nature of these pathways is complex, and a detailed overview of these pathways is outside the scope of the present review. Readers interesting in DNA repair by NHEJ or HR should refer reviews published elsewhere . However, for present review, it is important to introduce the difference between two: NHEJ is the more frequent, although imperfect, error-prone repair pathway that results in insertions and deletions (indels) at the break site . These sAdditional file 4:This could indicate either that a) donor stem cells are able to compete successfully with endogenous stem cells for available niches or b) there are vacant niches in the testes of livestock species that can be occupied by transplanted donor cells (discussed in ). , or the xenotransplantation  is mainly considered in livestock. (DOCX 13 kb)Additional file 7:3) fragments of the testicular tissue isolated from livestock donor animal  or of disassociated testicular cell suspension  under the dorsal skin of immunocompromised recipient mice could also be used to obtain fully functional haploid donor-derived spermatozoa . The capability of ectopically transplanted Sertoli cells to rearrange into seminiferous tubule-like structures to support donor-derived ectopic spermatogenesis is fascinating and is the fundamental of the de novo morphogenesis approach (discussed in [195]). Because of the use of mice models, both the xenografting and the de novo morphogenesis approaches help to overcome the costly and time-consuming process of maintaining large animal models in research. On the other hand, the practical application of both approaches in livestock breeding is notably limited by the needs to use the elaborative and costly techniques of assisted reproduction  to generate the progeny from the obtained donor-derived spermatozoa. Therefore, both approaches are considered as invaluable in vivo bio-assays to comprehend spermatogenesis, however with low practical merit as of today. This is in contrast to SSCs intratesticular transplantation, which has its certain disadvantages if exploited as the experimental in vivo bio-assay but suits better to practical application in livestock breeding. Readers interested in the testicular tissue xenografting or de novo testicular morphogenesis should refer to the excellent reviews published elsewere  or to several original papers, which confirm the exclusive experimental merit of these approaches in livestock research . (DOCX 13 kb)Alternativelly, ectopic transplantation of small Compared to cryopreservation of single cell suspension, the approach of whole testis tissue cryopreservation is more challenging; this is because tissue requires longer exposure to cryoprotectants and this can result in higher cellular toxicity before freezing . However"}
+{"text": "We found that targeted sequencing identified a larger number of mutational hotspots and clinically significant amplifications that would have been missed by WES and SNP arrays in many actionable genes such as PIK3CA, EGFR, AKT3, FGFR1, ERBB2, ERBB3 and ESR1. The striking differences between the number of mutational hotspots and CNAs generated from these platforms highlight a number of factors that should be considered in the interpretation of array and NGS-based genomic data for precision medicine. Targeted panel sequencing was preferable to WES to define the full spectrum of somatic mutations present in a tumor.Whole exome sequencing (WES), targeted gene panel sequencing and single nucleotide polymorphism (SNP) arrays are increasingly used for the identification of actionable alterations that are critical to cancer care. Here, we compared The Cancer Genome Atlas (TCGA) and the Genomics Evidence Neoplasia Information Exchange (GENIE) breast cancer genomic datasets (array and next generation sequencing (NGS) data) in detecting genomic alterations in clinically relevant genes. We performed an  However, the functional significance of these alterations is still unexplored and for most patients with metastatic breast cancer, there is a compelling need for selecting clinically relevant beneficial treatment strategies via the identification of genetic alterations driving tumorigenesis.A comprehensive understanding of potentially actionable genomic aberrations in tumor samples is important in guiding precision medicine for clinical decision-making. With the development of next-generation sequencing (NGS) technologies, it is feasible to characterize the individual genomic landscape and to identify disease causal variation for diagnosis and therapy. The recent advances in cancer genomics using targeted enrichment sequencing have reliably identified clinically relevant genomic alterations present in solid tumors4. Molecular profiling of somatic mutations is increasingly being used to help select new treatment regimens in metastatic disease, although as yet there is no proven survival advantage for this approach. This is a particular concern since the open-label randomized, controlled SHIVA trial found that the use of molecularly targeted agents outside of their indications does not improve progression-free survival when compared to empirical treatment in heavily pre-treated metastatic patients5. Others have noted that genomics has not failed, it is just it its early stages of adoption and that N-of-One designs are necessary to adopt personalized medicine since each tumor has such unique biology6. The United States Food and Drug Administration (FDA) has recently approved the NGS-based FoundationOne CDx test that identifies actionable alterations in cancer-related genes and can guide treatment decisions. Likewise, a variety of commercial and academic laboratories engage in NGS, with discussion of results at molecular tumor boards to discuss if findings indicate a druggable treatment target9. However, several technical issues need to be addressed before implementing NGS results into clinical practice. These include consideration of the downstream molecular analysis of: degraded DNA extracted from formalin-fixed, paraffin-embedded (FFPE) specimens, limited amounts of fresh tissue, the degree of stromal cellularity, and variation in the sequencing depth and capture efficiency. These challenges limit the ability to identify clinically relevant aberrations present in cancer cell subpopulations11. In addition, another challenge arising in the analysis of multiple datasets is to identify consistent and reproducible clinically actionable biomarkers from sequencing technologies across cohorts and laboratory platforms. A comprehensive understanding of the detection of genomic alterations in cancer requires an integrative network framework for the analysis of NGS data.Large-scale efforts such as the Catalogue of Somatic Mutations (COSMIC), The Cancer Genome Atlas (TCGA) and American Association for Cancer Research (AACR) Genomics Evidence Neoplasia Information Exchange (GENIE) project were designed to help investigators better understand the impact of somatic mutations in cancer. However, the vast heterogeneity of lesions observed in mutations and copy number alterations (CNAs) varies for different genes and tumor histologiesThe objective of our study was to investigate which platform (array versus WES and targeted panel sequencing) was most sensitive in identifying clinically significant genomic alterations using the TCGA and GENIE datasets for non-metastatic breast cancer patients.The clinical characteristics including age, race, ethnicity, tumor grade and hormone receptor status were compared between TCGA and GENIE breast cancer invasive lobular carcinomas (ILC) and invasive ductal carcinomas (IDC) patients Table\u00a0. No sign12. Figure\u00a013. In both cohorts, missense mutations were more prevalent than truncating and inframe mutations in both ILC and IDC subtypes   in the GENIE and TCGA datasets. We also compared the percentage of mutational hotspots between the TCGA and GENIE dataset after stratifying GENIE samples by PCR- and hybridization capture-based approach. The results showed inconsistency in mutational profiles with significant differences in the percentage of identified mutations and CNAs analyzed by WES, PCR and hybridization capture in ILC and IDC cohorts observed. Fig.\u00a0. However01) Fig.\u00a0. The fre14, hotspots.org16 and 3Dhotspots.org17) as references for evaluating whether the identified mutations through WES and targeted sequencing includes any common polymorphisms. We observed that all these hotspots identified in TCGA and GENIE are occurring recurrently in COSMIC database and many of those are present in cancer hotspots database, a resource for statistically significant mutations in cancer15. We found many novel hotspots in targeted sequencing data that have been missed through the WES approach  has performed an integrated analysis by combining gene copy number and expression to identify novel biological subgroups22. However, a comprehensive understanding of these alterations as putative predictive biomarkers in clinical practice should ultimately facilitate the interpretation of patient data for potential targeted therapy. Thus, the accurate and unbiased identification of recurring CNAs, which are potentially driver events, by using multiple data sets is important to identify the genomic regions of consistent aberration across multiple individuals. We next examined to what extent these two platforms were consistent in detecting actionable genomic CNAs at the sample and gene level. The Fisher\u2019s exact test was used to evaluate the variability in the frequencies of CNA calls. We observed striking differences in the CNA landscape between these two datasets (Q) to 5% to determine the number of genes with statistically significant different proportion of samples with CNAs between the two datasets. Our comparative analysis for ILC revealed that 34/40 (85%) genes had significant variance in copy number gain, 3/40 (7%) genes in amplification and 34/40 (85%) in hemizygous deletion. Likewise, for IDC, we observed differences in 40/40 (100%) genes for gain, 28/40 (70%) for amplification, 40/40 (100%) genes for hemizygous deletion and 9/40 (22%) genes for homozygous deletion. Since chromosomal aberrations are known to be associated with cancer progression26, we analyzed amplification and deletions separately to assess which fraction of calls would have been missed by SNP-based array and targeted sequencing approach. We compared both of the datasets for the identification of significant regions of chromosomal amplification and deletions using GISTIC algorithm on the segmented data. The most significant regions (q\u2009<\u20090.25) of copy number amplification in actionable genes were found in GENIE dataset as compared to TCGA dataset in ILC 28 with the corresponding cancer type in the GENIE targeted panel data obtained from FFPE tissues. We found that there was inconsistency in the frequency distribution of CNAs in both of the data sets for those actionable genes from our list which are considered promising druggable targets for NSCLC, and colorectal cancer, such as KRAS, BRAF, EGFR, ATM, and PIK3CA. In NSCLC alone, we observed higher frequencies of CNAs in many actionable genes in TCGA than in GENIE, such as FGFR1  and PIK3CA  for amplification and CDKN2A , CDKN2B  for deletions  in the TP53 gene was greater in GENIE than in TCGA . Larger number of hotspots and non-hotspots were also detected in GENIE in the NSCLC dataset for genes such as EGFR , NF1  and PIK3CA  in comparison to TCGA. Likewise, TP53 was highly enriched for mutations in the GENIE colorectal cancer data as compared to TCGA data . We also observed higher number of mutational hotspots in 3 actionable genes in KRAS , EGFR  and TP53  in GENIE than in TCGA in NSCLC cases.30, it identified only smaller insertions and deletions while ignoring large duplications and deletions31. RNA sequencing data was not available from the GENIE dataset and thus it was difficult to determine whether the identified mutational hotspots and gene dosage are related to gene expression. The differences are attributable to the methodology used in both datasets and due to the limited capture design in targeted gene panel and an unequal distribution of targeted sites across the genome that would result in a large number of false positive and false negative calls. These results may be used as a better benchmark for future studies aimed at the identification of actionable alterations from the comparison of large-scale genomic data sets.This study represents an integrated comparison of whole exome, SNP-based array and targeted gene panel sequencing in terms of their ability to detect mutations and CNAs in potentially clinical actionable genes from two-large breast cancer cohort studies. We observed that targeted sequencing is more effective in detecting CNAs than SNP-based array. Although targeted capture sequencing focused on hotspot regions and provided increased quality and reliability at a greater depth in comparison to whole genome sequencing (WGS)et al.32 have shown that higher sequencing coverage is required for CNA analysis. Although GENIE has also used higher sequencing coverage to detect CNAs, however, there are low frequencies in CNAs in breast cancer, NSCLC and CRC FFPE samples in comparison to TCGA fresh-frozen tissues. Studies have also shown that copy number analysis between the fresh-frozen and FFPE samples varied to a certain degree suggesting that discrepancy in the CNAs frequencies can be due to tissue-preservation methods34. Another important factor affecting CNA detection is the amount of input DNA that is more than ten-fold higher for the array-based method than sequencing. Thus, the choice of assay and tissue preservation method is important for accurately detecting mutations and CNAs to guide treatment decisions. The MSK-IMPACT tumor profiling assay may distinguish mismatch repair deficiency (MMR-D) and proficient (MMR-P) tumors on the basis of mutational burden in colorectal cancer35. The implementation of the results from these platforms in a clinical diagnostic environment requires immunohistochemistry (IHC) validation per multiple guidelines38. Due to the large variation in detecting genomic alterations between different platforms, many studies have suggested that using multiple computational methods for the identification of genomic alterations reduces the chances of false positive results40. Recently, Shi et al.41 identifies that 69% of the mutations from tumor-only WES pipeline were false-positive and even for matched-normal DNA only 36\u201378% were found consistently in replicate pairs. Since the TCGA cohort is having with or without matched normal controls and GENIE samples have no matched normal controls suggests that caution should be exercised when interpreting these genomic alterations. Torga and colleagues reported very low congruence in tumor-specific genetic alterations for patient-paired samples between the PlasmaSELECT and Guardant360 tests that could lead to different treatment decisions42. These results showed that genetic sequencing assays are not always concordant even when the exact same samples are processed, likely due to inherent differences in assay platforms.We observed that the percent of tumors with CNAs was quite small in GENIE as compared to TCGA, making it difficult to determine the precise spectrum of actionable alterations. The low frequencies in CNAs in these FFPE samples may also be explained due to low input of DNA and degraded DNA that makes the detection procedure complicated for the identification of the regions of deletion. Schweiger 43) and the driver genes that have been mutated by genomic duplication and deletion. Our results highlight some of the issues associated with technical inconsistencies in using molecular profiling for clinical decision-making. NGS technologies continue to evolve with improvements in accuracy along with the rapid production of huge datasets and new methods for identification of recurrent CNAs in multiple samples. However, it is difficult to assess the relative strengths and limitations of different sequencing methods because of the lack of studies that comprehensively compare these technologies. Despite this, variations in the interpretation of copy number changes between the sequencing platforms may become a problem not only for researchers who need to select the method for a dataset of interest, but also a big challenge for clinicians: which platform (array versus NGS) might best detect the underlying genetic driver of the disease in patients? These differences pose a serious challenge when trying to apply these technologies in clinical trials due to the confounding results, which may further impact on treatment decisions for cancer patients. Although both the TCGA and GENIE genomic datasets have CLIA/CAP certifications, validation steps are needed for both the wet and dry bench workflow of NGS-based assays independently by the clinical laboratory before implementation. Furthermore, the platform selection should be based on cross-validating these technologies with more reliable methods such as fluorescence in situ hybridization (FISH) and real-time PCR. There is also a need for more specific guidelines to interpret the clinical significance of actionable CNAs detected by array and NGS technologies for improved \u201cgenomic-based\u201d therapeutic approaches for cancer patients.From a clinical point of view, our results are of high importance in terms of assessing CNAs from SNP-based array in clinical laboratories, with a particular focus on amplifications in CNAs that would have been missed by this approach. The differences in the CNAs frequency across different platforms would also affect the ability to identify the subtype-specific patterns of alterations  and invasive ductal carcinomas (IDC) patients for 40 genes from our curated list as 9 genes were not available on the targeted gene panel. Genes were defined as clinically relevant or actionable based on therapeutic and/or diagnostic implications in cancer patients45. Our gene panel is not Clinical Laboratory Improvement Amendments (CLIA)/College of American Pathologists (CAP) certified, but the majority of these 49 actionable targets are found in CLIA certified gene panels such as the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) (410 genes), OncoKB database46 (476 cancer-associated genes targeted by FDA-approved drugs or standard therapeutic agents) and Foundation Medicine . The intent of our gene panel was to focus on potentially actionable genes with relevance to breast cancer and to maintain a sufficiently focused list in order to permit a detailed comparison of the TCGA and GENIE results as they pertain to clinically relevant gene targets.For both large-scale genomic datasets, we identified a panel of 49 potentially actionable targets in which biomarkers were linked with FDA-approved or investigational therapeutics in breast cancer studies listed on ov Table\u00a0. We anal48. Only GENIE samples that were screened using hybridization-based capture approach, as opposed to PCR-based approach, were analyzed for CNAs. The sample size of this subset of GENIE samples analyzed for CNAs is given in Supplementary Table\u00a027 and non-small cell lung cancer (NSCLC)28 with the corresponding cancer type in the GENIE targeted panel data1 obtained from FFPE tissues. We obtained the mutational and CNA events using cBioPortal for array data from TCGA NSCLC (n\u2009=\u20091144) and targeted gene panel sequencing data from GENIE (n\u2009=\u20093694). The mutational and CNA events for colorectal cancer were also obtained from cBioPortal for array data from TCGA colorectal (n\u2009=\u2009226) and targeted gene panel sequencing data from GENIE (n\u2009=\u20092574).We assessed the whole-exome DNA sequencing and Affymetrix SNP 6.0 array data for 127 ILC and 490 IDC from TCGA cohort and compared these with the third data release for GENIE targeted sequencing data for 248 ILC and 1724 IDC cases. The mutations and CNAs generated from Affymetrix array and NGS technologies were retrieved from cBioportalFor the identification of putative hotspots in clinically actionable genes, we downloaded the mutational hotspot data for TCGA and GENIE cohorts using cBioportal from the sequenced exomes of breast cancer patients (based on prespecified classifications or groups). The Fisher\u2019s exact test was used to evaluate the variability in the frequencies of mutations for 40 actionable genes between both data sets for ILC and IDC subtypes. The Kruskal-Wallis test was applied to assess which mutation types are more prevalent in both breast cancer subtypes.26. CNA was characterized by measured copy number (expressed as a log2 ratio), and by the extent of change in the genome. The CNA thresholds were determined according to the set of discrete copy number calls provided by GISTIC: deep loss/homozygous deletion (\u22122), shallow loss/hemizygous deletion (\u22121), low-level gain (1), and high-level amplification (2). The copy number data was not available from the patients analyzed by PCR method in GENIE data set. The Fisher\u2019s exact test was used to determine whether the frequencies of CNAs are different in actionable genes between TCGA and GENIE datasets analyzed by the array and NGS-based technologies. The identification of significantly amplified and deleted regions among potentially actionable genes was done using the GISTIC algorithm. The data was aligned to genome build hg19. The algorithm was executed within the Broad Firehose infrastructure. The GISTIC analysis was conducted separately on the ILC and IDC subtypes in TCGA and GENIE breast cancer study.To determine the copy number status of an individual gene in any given patient, we used copy number datasets within the cBioportal generated by Genomic Identification of Significant Targets in Cancer (GISTIC) algorithmsStatistical analysis for comparing the mutations and CNAs was performed using GraphPad Prism version 7. The most prevalent mutations among missense, truncating and inframe mutations were calculated using the Kruskal-Wallis test. The Fisher\u2019s exact test was used to calculate the variability for the frequencies of hotspots and CNAs. The two-stage linear step-up procedure of Benjamini, Kreiger and Yekutieli by setting FDR(Q) to 5% was used to correct p-values for multiple testing.This study was performed in strict accordance with the recommendations of data access guidelines of TCGA and AACR project GENIE datasets. We received administrative permission for downloading the restricted-access data for breast cancer patients from the TCGA Data Access Committee (Project # 10345).Supplementary Dataset 1"}
+{"text": "Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. Surgical resection of HCC remains one of the mainstays of curative therapies and is associated with five-year overall survival rates approaching 60%. Despite improved perioperative outcomes, locoregional recurrence within the first two years following hepatic resection is of significant concern with recurrence rates of up to 50%. The use of anatomical resection surgical approaches, whereby the portal venous blood flow is ligated proximal to the tumor bed, is postulated to reduce recurrence rates due to reduction of micrometastatic disease. The aim of this review is to characterize the definition of an anatomical resection (AR) during partial hepatectomy, discuss the theoretical advantages of AR during hepatic resection for HCC, and to present evidence of the impact of AR on outcome measures in patients with HCC. Based on current data, there is a lack of conclusive evidence to support the universal use of AR in cirrhotic patients with HCC. A randomized clinical trial is warranted to further clarify the debate between AR versus non-anatomical resection (NAR) for HCC. Hepatocellular carcinoma (HCC) is the sixth most common cancer and the second leading cause of cancer-related deaths worldwide ,2. HCC mAdvances in perioperative assessment of underlying liver function and radiologic extent of HCC tumor, surgical and anesthesia techniques, and postoperative care have led to significant decreases in morbidity and mortality following liver resection over the past two decades. Currently, the 30-day mortality following resection for HCC in high-volume centers is expected to be less than 5%, and there is a known association between volume and outcome following HCC diagnosis that is also seen in patients treated with surgical resection . DespiteAlthough the concept of anatomical resection (AR) was first proposed nearly three decades ago, its use during the surgical resection of tumors in HCC patients has not been universally adopted. The aim of this review is to characterize the definition of an anatomical resection during partial hepatectomy, discuss the theoretical advantages of AR during hepatic resection for HCC, and to present evidence on the impact of AR on outcome measures in patients with HCC.Anatomical resection, first described by Makuuchi et al. in 1985 [Anatomical resection involves either segmentectomy or sectionectomy\u2014which includes bisectionectomy, hemihepetectomy, and trisectionectomy\u2014and can be accomplished utilizing one of two surgical techniques: (1) Glissonean pedicle transection or (2) ultrasonically guided transection .Glissonean pedicle transection, first described by Couinaud for a left hepatectomy in 1985, was subsequently modified and expanded upon by Takasaki in 1998  to descrAccording to the Glissonean pedicle classification as described by Takasaki, resection of HCC tumors within any of the three segments is done by first ligating the corresponding segmental branch of the Glissonean pedicle and then dissecting along the intersegmental plane of the appropriate hepatic vein, thus resecting the liver parenchyma while preserving the associated main hepatic vein.Further subsegmental resection for tumors limited anatomically to discrete areas within the liver can be accomplished through the resection of one or more \u201ccone units\u201d within the segment by isolating tertiary branches and resecting selectively through a hilar or parenchymal approach.The main limitation of the utilization of a Glissonean pedicle approach to achieve anatomical resection comes from in its use of subsegmental resections or resection of \u201ccone units\u201d, especially in segments 7 or 8 as defined above. Anatomical studies of cadavers demonstrate that there is wide variability in the intrahepatic origin of tertiary branches within the vast majority of Couinaud segments. This especially holds true in segments 7 and 8, where as many as four tertiary branches can supply one \u201ccone unit\u201d, thereby making selecting isolation difficult. Additionally, the isolation of subsegmental tertiary branches of the hepatic artery and portal vein, especially in the posterosuperior segments of the liver (segments 7 and 8), can lead to unnecessary parenchymal dissection in segments of the liver not in the planned transectional plane.The use of intraoperative ultrasound (IOUS) scanning of the liver in conjunction with infusion of indigo carmine dye into the appropriate portal vein was first advocated by Makuuchi et al. in 1985 as a surgical technique to identify the landmarks allowing a targeted segmental or subsegmental area of resected liver .The main limitations of IOUS-guided injection of dye as a technique for performing anatomical resection are that the procedure requires the surgeon to be facile with advanced IOUS techniques and unless arterial flow is occluded to the liver, reliable dye staining can be difficult to obtain.The use of indocyanine green (ICG) fluorescent dye during hepatobiliary surgery has emerged over the past few decades and is now widely utilized . IGC is In surgical cases where tumor location requires either a right or left hemi- or extended hepatectomy or a sectional resection of the liver, the Glissonean pedicle approach is a relatively easy and safe method for accomplishing an anatomical resection due to the anatomical landmarks and extrahepatic location of the pedicles. However, if the tumor is positionally located where a segmental or subsegmental approach is warranted, the Glissonean pedicle approach is technically demanding, and a more useful approach is the IOUS-guided dye approach. For tumors located in segments 7 and 8, further away from the main portal pedicle, the IOUS-guided dye approach is generally more efficacious, especially in the hands of a surgeon experienced with IOUS.The ability to utilize either approach depending on tumor location seen on appropriate preoperative contrast-enhanced imaging is key to performing an anatomical resection for HCC safely. Both techniques rely on liver parenchymal dissection along the right or middle hepatic veins\u2014areas with high potential for catastrophic bleeding unless proper surgical and anesthetic technique with low central venous pressure is adhered to.The high incidence of HCC recurrence following surgical resection may be explained by the high incidence of both intrahepatic metastasis and the multicentric occurrence of de novo HCC in the background of chronic liver disease ,17. EarlThe pathophysiology explaining early recurrence of HCC within the first two years of hepatic resection seems to be best explained by the hypothesis that HCC, unlike other primary or secondary liver tumor malignancies, has a high predilection for invasion into portal venous branches. This allows tumor cells to be disseminated via portal venous flow into other regions of the liver, forming tumor venous thrombi and subsequent satellite or new HCC lesions . TheoretAlthough utilizing an anatomical approach for HCC tumor resection should theoretically offer an advantage in outcomes compared to a non-anatomical approach aimed at preserving liver parenchyma to avoid postoperative liver failure in cirrhotic patients, the published data comparing the two approaches does not offer a consensus with regards to an advantage of one approach over the other.To our knowledge, only one randomized controlled trial has been published examining the differences in outcomes between anatomical and non-anatomical approaches in HCC resection. In 2017, Feng et al. published a randomized trial corresponding to a single institution where 105 patients with HCC were randomized to either anatomical or non-anatomical hepatic resection with two-year local recurrence rate as the primary endpoint . Local rp = 0.001, respectively), there was no difference between the approaches in either overall recurrence rate or overall survival. As concerns about postoperative complications may be one reason for the lack of universal adoption for anatomical resection, there were no differences in perioperative or postoperative complication rates between the two approaches. The main limitation of this study was that by utilizing the primary endpoint of local recurrence defined by the authors as within the same segment as the initial tumor, recurrences in different segments or extrahepatically would be censored in their results. This explains the lack of significance in recurrence-free survival between the two groups. As the hypothesis for the use of anatomical resection is postulated on the theory that anatomical resection reduces micrometastatic disease or tumor cells found in associated portal venous flow, recurrence limited to only the section of the liver that is removed is too limited as a primary endpoint. In addition, as most patients in this study had hepatitis B-related chronic liver disease and few cirrhotic patients, there are concerns over the applicability of the results to patients with chronic liver disease secondary to other etiologies.Although the use of anatomical resection was associated with a significantly decreased two-year local recurrence rate compared to non-anatomical resection . In addition, the AR cohort had lower rates of local intrahepatic recurrence than the NAR cohort  and 5 years (43.9% vs. 25.3%). There were no significant differences in overall mortality or perioperative complications between the two approaches.In 2011, Zhou et al. published the first large meta-analysis comparing anatomical versus non-anatomical resection for HCC . They anUtilizing many of the same extracted studies, Cucchetti et al.  also perA more recent meta-analysis from 2018 by Moris et al. also compared anatomical resection versus non-anatomical resection for HCC by extracting data from 43 studies and including 12,429 patients  . ConsistThe theoretical advantage of an anatomical resection approach for HCC is in the potential reduction of micrometastatic disease within portal venous flow. Although a technically challenging operation with the potential of increasing rates of perioperative complications due to hepatic failure from the increased hepatic parenchyma volume resected, multiple studies have demonstrated no differences in morbidity or mortality compared to non-anatomical resection. However, the evidence for improved outcome measures outside of non-cirrhotic HCC patients is limited, and until a randomized controlled trial is conducted in cirrhotic only patients, the benefit in terms of overall survival and locoregional rates of recurrence anatomical resection for HCC remains unclear."}
+{"text": "Recently Carsten Denkert and colleagues from the Charit\u00e9 in Berlin published an article about the prognostic and predictive role of tumor-infiltrating lymphocytes (TIL) in neoadjuvantly treated breast cancer . One ofThese findings confirm the results of previous studies in breast cancer. For example markers of tumor infiltrating B-cells/plasma cells have been demonstrated to predict response to neoadjuvant anthracycline-based chemotherapy in breast cancer . From pOne of the pioneering studies on tumor infiltrating lymphocytes has been published by Aaltomaa from Kuopio in Finland  and the"}
+{"text": "Young breast cancer patients who have not yet completed their family planning at the time of diagnosis may still have pregnancy desire at the completion of adequate anticancer treatments and period of follow-up. Indeed, young women advocates have recently highlighted that pregnancy-related concerns have high priority . DespiteTo investigate the prognostic effect of conceiving after diagnosis of HER2-positive early breast cancer and in order to provide evidence on the effect of exposure to the anti-HER2 agents trastuzumab and/or lapatinib on pregnancy outcomes, a recent analysis of all the pregnancy events that occurred as part of the NeoAdjuvant Lapatinib and/or Trastuzumab Treatment Optimization  and the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization  trials has been conducted . FollowiThere are two main messages deriving from this analysis. First, these findings reinforce the current recommendation that having a pregnancy after prior history of breast cancer should not be contraindicated after adequate treatment and follow-up , 9. ThisResults from the ongoing MotHER study (NCT00833963) collecting prospective information on patients exposed to anti-HER2 therapies during pregnancy as well as similar analyses from the large adjuvant trials that led to the approval of pertuzumab and neratinib in the early setting are awaited to provide further evidence in order to improve the counseling of young women with newly diagnosed HER2-positive breast cancer facing pregnancy-related concerns."}
+{"text": "International Journal of Molecular Sciences (IJMS) is dedicated to mechanisms mediated at the molecular and cellular levels to respond to adverse genomic perturbations and DNA replication stress . The relevant proteins and processes play paramount roles in nucleic acid transactions to maintain genomic stability and cellular homeostasis. A total of 18 articles are comprised in the series, encompassing a broad range of highly relevant topics in genome biology. These include replication fork dynamics, DNA repair processes, DNA damage signaling and cell cycle control, cancer biology, epigenetics, cellular senescence, neurodegeneration, and aging. Below are highlighting primers for the articles which constitute this recently published IJMS Special Issue.A Special Issue of Although evidence now strongly supports a role of fork reversal for the protection and timely resumption of DNA synthesis when it stalls under conditions of endogenous or exogenously induced DNA damage, the molecular mechanisms and their regulation are still not fully understood. Building upon their interest in the metabolism of unusual DNA structures that arise during periods of replication stress, Eichman\u2019s lab investigated the bacterial RecG DNA helicase and its mechanistic role in fork reversal . Using aDespite the tremendous advances in characterizing the mechanism of DNA replication in eukaryotic cells, progress made in plants lags compared to yeast or mammalian cells. Kwasniewski et al. set out to study the effects of a chemical mutagen ) or gamma irradiation on DNA replication patterns in chromosome metaphase cells of barley by performing pulse 5-ethynyl-2\u2019-deoxyuridine labeling [Protein mono- and poly-ubiquitylation as a component of the replication stress response has been a topic of tremendous interest in recent years. Yates and Marechal have carefully reviewed this subject, providing a definitive resource for understanding the roles of ubiquitylation modification machinery that operates at stalled forks to allow optimal fork restart and genome maintenance . The revDifficult-to-replicate sequences pose a unique challenge to the DNA polymerases delegated to deal with noncanonical DNA structures and copy the genome. This is the very topic of a review article from Kristin Eckert\u2019s lab . SpecialAlternate DNA structures and DNA damage have far-reaching effects on human physiology, including neurodegenerative diseases. This topic is addressed by Konopka and Atkin in the context of amyotrophic lateral sclerosis (ALS), a debilitating progressive neurodegenerative disorder characterized by hexanucleotide repeat expansions . The cenDNA is considered the quintessential information molecule in genome biology. Therefore, the mechanisms of DNA damage and repair are highly valuable to cellular metabolism. Helena et al. review the DNA repair pathways which exist to protect the genome and preserve cellular homeostasis . The anaDr. Marit Otterlei and colleagues have had a longstanding interest in the in vivo response to DNA damage in human cells. Combining both elegant microscopy and mutation analysis, they report their findings from an investigation of the interaction of the replication processivity clamp PCNA with a translesion synthesis (TLS) DNA polymerase known as REV3L that is implicated in DNA synthesis past ultraviolet light-induced lesions . They diThermococcus eurythermalis endonuclease IV, providing a model for studies of related enzymes and shedding light on the repair of AP sites in hyperthermophilic archaea.Wang et al. characterized the catalytic activity of an archaeal thermophilic endonuclease IV to incise apurinic/apyrimidinic (AP) analogues in single-stranded or double-stranded DNA . Using aHuman exonuclease I (EXO1) is a DNA processing enzyme with important pleiotropic roles in cellular DNA metabolism. Guido Keijzers et al. review the replication and post-replication functions of EXO1 to help the reader appreciate the involvement of EXO1 mutations in various cancers . MismatcWRN are linked to the premature aging disorder Werner syndrome, the hereditary disease has served as a window to understanding the molecular basis for genomic stability, yet its precise functions in nucleic acid transactions are still not well understood. The Asaithamby lab addresses the role(s) of WRN in replication fork processing and the post-translational modifications that fine-tune its pathway activities [Since the discovery over two decades ago that recessive mutations in the RecQ helicase gene tivities . The autSingle-strand breaks are one of the most common DNA lesions in the cell and pose a source of genomic instability by interfering with cellular DNA replication and transcription. A comprehensive review from the Yan lab discusses single-strand break DNA end resection and its step-by-step mechanism . An emphUnderstanding how DNA replication initiation is controlled during the DNA synthesis S-phase in mammalian cells is of considerable interest given the number of proteins involved and the importance of ensuring that genome duplication occurs only once per cell cycle. Sokka et al. focused their analysis on the importance of the ATR-activation domain of the activator DNA topoisomerase-2-binding protein 1 (TopBP1) for the suppression of origin firing within the S-phase . By emplXenopus are discussed. In addition, the consequences of checkpoint adaptation are described. This review provides a nice perspective of the cellular response to DNA damage stress, placing it in the context of cancer cell survival.A review by Claudio Talora and co-workers addresses the topic of checkpoint adaptation, a process whereby cancer cells acquire mutations in the face of DNA damage and replication stress to survive and continue to proliferate . AlthougThe Bergoglio lab provides a very comprehensive assessment of dormant origins and their role in response to replicative stress to preserve the genome . Origin Shu-Yan Li and colleagues investigated the basis for variability in the sensitivity of human lung cancer cells as a function of p53 status to the potential anticancer drug 8-chloro-adenosine (8-Cl-Ado) currently in a phase I clinical trial for treatment of chronic lymphocytic leukemia . They deA review from Sudha Sharma\u2019s lab provides a fresh perspective on oxidative DNA damage in the context of the cellular response and repair mechanisms, as well as the effects of oxidative DNA damage on gene expression . A partiCellular senescence and its role in aging and neurodegenerative disease is the subject of a comprehensive review contributed jointly by the Gorgoulis and Papadopoulos labs . The couStuart Maudsley and colleagues present a review article on the importance of G protein-coupled receptor (GPCR) systems as stress sensors for intracellular damage and as regulators of DNA damage response systems . The varAs Guest Editor for this IJMS Special Issue, I am very pleased to offer the collection of riveting articles centered on the theme of DNA replication stress. The blend of articles builds upon a theme that DNA damage has profound consequences for genomic stability and cellular homeostasis that affect tissue function, disease, cancer, and aging at multiple levels and by unique mechanisms. I thank the authors for their excellent contributions which provide new insight into this fascinating and highly relevant area of genome biology."}
+{"text": "Following publication, the authors conducted additional experiments to determine the genetic background of PKR regulatory domain mutant mice used in this study , and in PLOS ONE article, and so was not reported [PLOS ONE article, the genetic background is different between mutant and control animals .\u2022 The genetic background of the PKR regulatory domain mutant mice was not known to the authors at the time the in vivo experiments were conducted for the reported . FollowiPLOS ONE article [in vitro using bone-marrow derived macrophages and in vivo in a mouse model of tuberculosis infection using a different PKR-deficient mouse line harboring a catalytic domain mutation [PLOS ONE article: the authors did not observe a statistically significant difference in CFU in lung between WT and PKR-deficient mice in the mouse model of Mtb infection, as reported in detail in [PLOS ONE article, they were not based on exact experimental replications, as noted in the following table.\u2022 Following publication of the  article , the autmutation  instead mutation . In thesetail in . While tPLOS ONE and EJI experiments are tabulated above. The macrophage experiments in PLOS ONE article [EJI article [EJI article also compared WT mice on a 129S1/SvImJ background and regulatory domain PKR KO mice on a 129S1/SvImJ background, similar to the mice used in [EJI article it was observed that there was no statistically significant difference in Mtb CFU burden between WT and catalytic domain PKR KO mice, both on the C57BL/6J background. The EJI study casts doubt on the candidacy of PKR as a target for HDT of TB.\u2022 The differences between the  article  used WT  article  used WT"}
+{"text": "Increasingly Burden of Disease (BOD) measures are being used to influence policy decisions because they summarise the complete effects of morbidity and mortality in an equitable manner. An important element of producing non-fatal BOD estimates are severity distributions. The Global Burden of Disease (GBD) study use the same severity distributions across countries due to a lack of available country-specific data. In the Scottish BOD (SBOD) study we developed national severity distributions for cancer types. The main aim of this study was to consider the extent to which the use of worldwide severity distributions in BOD studies are influencing cross-country comparisons, by comparing weighted-average disability weights (DW) based on GBD severity distributions with nationally derived severity distributions in Scotland for cancer types.We obtained individual records from the Scottish Cancer Registry for 21 cancer types and linked these to registered deaths. We estimated prevalent cancer cases for 2016 and assigned each case to sequelae using GBD 2016 study definitions. We compared the impact of using severity distributions based on GBD 2016, a Scotland-wide distribution, and distributions specific to deprivation strata in Scotland, on the weighted-average DW for each cancer type.The relative difference in point estimates of weighted-average DW based on GBD 2016 worldwide severity distributions compared with Scottish national severity distributions resulted in overestimates in the majority of cancers (17 out of 21 cancer types). The largest overestimates were for gallbladder and biliary tract cancer (70.8%), oesophageal cancer (31.6%) and pancreatic cancer (31.2%). Furthermore, the use of weighted-average DW based on Scottish national severity distributions rather than sub-national Scottish severity distributions stratified by deprivation quintile overestimated weighted-average DW in the least deprived areas (16 out of 18 cancer types), and underestimated in the most deprived areas (16 out of 18 cancer types).Our findings illustrate a bias in point estimates of weighted-average DW created using worldwide severity distributions. This bias would have led to the misrepresentation of non-fatal estimates of the burden of individual cancers, and underestimated the scale of socioeconomic inequality in this non-fatal burden. This highlights the importance of not interpreting non-fatal estimates of burden of disease too precisely, especially for sub-national estimates and those comparing populations when relying on data inputs from other countries. It is essential to ensure that any estimates are based upon country-specific data as far as possible. Burden of Disease (BOD) studies include both morbidity and mortality by framing them in terms of health loss suffered as a function of time . EstimatThere is a growing appetite for BOD studies to provide more granular estimates for regions within countries in both the GBD study \u201310 and iThe main aim of this study was to consider the extent to which worldwide severity distributions are influencing cross-country comparisons by comparing weighted-average DW based on GBD severity distributions with nationally derived severity distributions in Scotland across a range of cancer types. A secondary aim was to investigate the impact of sub-national severity distributions compared to nationally derived severity distributions, by comparing weighted-average DW from both scenarios across a range of cancers.There were 21 cancer types included in this study. Details of the cancer types included and excluded in this study are available in the online supplementary appendix . Cancer The GBD 2016 modelling process involved calculating cancer incidence directly from cancer mortality using mortality to incidence ratios (MIR) . These MAs part of the Scottish Burden of Disease (SBOD) 2016 study, national and sub-national severity distributions were derived using individual patient records from the Scottish Cancer Registry, which holds registration records from 1980 onwards of all incident cancers diagnosed within the NHS in Scotland . The disPatients were followed up over time and the date and cause of death were obtained from the National Records of Scotland\u2019s register of deaths . Using dAn area-based deprivation score was available for each patient, defined by the Scottish Index of Multiple Deprivation 2016 , which aSeverity proportions of sequelae were calculated for each cancer type and assessed for differences with GBD 2016 95% UIs. For ease of comparison we opted to summarise the effect of severity distributions in a single point estimate. We used sequelae prevalence in conjunction with DW that were sourced from the GBD 2016 study  . PatientThe total number of prevalent cases, severity distribution across the four common cancer sequelae and weighted-average DW for 21 cancer types for Scotland in 2016 are listed in The five cancer types with the highest weighted-average DW were: mesothelioma (0.273); pancreatic cancer (0.191); multiple myeloma (0.187); oesophageal cancer (0.164); and tracheal, bronchus, and tracheal, bronchus and lung cancer (0.153). Conversely the five cancer types with the lowest weighted-average DW were: testicular cancer (0.061), malignant skin melanoma (0.068); thyroid cancer (0.069); Hodgkin lymphoma (0.078); and cervical cancer (0.079).Comparing Scottish severity proportions to the GBD 2016 95% UI for each cancer type yielded several differences. Of the 17 cancers where Scottish severity proportions could be published, the Scottish severity proportion for the diagnosis and therapy phase was not contained within the GBD 2016 95% UI in 16 cancer types. For 12 cancer types this was due to the Scottish severity proportion being lower, with it being higher for the remaining 4 cancer types. In the controlled phase the Scottish severity proportion was not contained within the GBD 2016 95% UI for 10 cancer types . For the metastatic phase, 15 cancer types had a Scottish severity proportion that lay outside the GBD 2016 95% UI . Finally, for the terminal phase the Scottish severity proportion was not contained within the GBD 2016 95% UI in all 17 cancer types .The relative difference across cancer types between the point estimate of the weighted-average DW based on GBD 2016 worldwide severity distributions compared with Scottish national severity distributions resulted in positive values across 17 out of 21 cancer types . In thesIn terms of absolute difference, the largest overestimates would have been made for gallbladder and biliary tract cancer , pancreatic cancer  and oesophageal cancer . The largest absolute underestimate would have been made for mesothelioma .When the relative difference between the point estimates of the weighted-average DW based on Scottish national severity distributions was assessed against severity distributions based on the most deprived fifth of Scottish areas, there were negative values in 16 out of 18 cancer types . In thesThe cancer types where the largest absolute underestimates would have been made were for oesophageal cancer , lip and oral cavity cancer  and multiple myeloma . The largest absolute overestimate would have been made for brain and nervous system cancer .The relative difference across cancer types between the point estimate of the weighted-average DW based on Scottish national severity distributions compared to severity distributions based on the least deprived fifth of Scottish areas resulted in positive values across 16 out of 18 cancer types . In thesThe largest absolute differences in overestimation were observed for pancreatic cancer , other pharynx cancer  and tracheal, bronchus and lung cancer .The magnitude of the differences in point estimates of weighted-average DW were much larger when comparing GBD 2016 worldwide with nationally derived severity distributions, than when comparing differences between national and sub-national severity distributions.This study is the first to evaluate the impact of using published GBD 2016 worldwide, compared to national and sub-national severity distributions on weighted-average disability weights. Our study illustrated that the majority of point-estimates of Scottish national sequelae severity proportions for cancers lay outside the uncertainty intervals given in the GBD 2016 study. By summarising the effects of severity distributions in a single weighted-average disability weight, we illustrated that GBD 2016 worldwide severity distributions would have led to overestimation in the point estimate of disability weights assigned to individual cancer types in a large majority of cases. The range of overestimation varied in size, with the largest relative overestimates being observed in gallbladder and biliary tract cancer (70.8%), oesophageal cancer (31.6%) and pancreatic cancer (31.2%). Although it was less common, there were some instances whereby using GBD 2016 worldwide severity distributions would have resulted in relative underestimation. This was observed for mesothelioma (-20.9%), brain and nervous system cancer (-7.1%) and uterine cancer (-4.8%).Additionally we have illustrated the smaller additional benefit in considering differences in severity distributions across sub-regions of a country. Our assessment of sub-national severity distributions stratified by area-based deprivation quintiles indicated that the use of Scottish national severity distributions would have led to an underestimate of the point estimate of the weighted-average disability weight in the most deprived areas of Scotland across the majority of cancer types. Conversely, the use of Scottish national severity distributions would have led to overestimates of point estimates of weighted-average disability weights in the least deprived areas of Scotland. Considering both these findings, using national severity distributions would have understated the extent of socioeconomic inequalities in YLD associated with individual cancer types.Existing studies of BOD severity distributions are limited. Those already published have been designed to develop severity distributions and have not evaluated the impact of using different severity distributions , 7. A stA major strength of this study lies within the use of the Scottish Cancer Registry  with patWe have chosen to produce sub-national severity distributions based on deprivation, as our secondary focus was around local area estimates with a focus on socioeconomic inequalities. We also acknowledge the limitation that deprivation is not the solely significant factor and that on a disease by disease basis, other stratifications such as ethnicity or gender may be more appropriate and display important intersectional effects . In addiThis study has important implications for policy and practice. In highlighting potential biases in the over and underestimation of point estimates of disability weights, we have illustrated a proportional bias that will carry through to estimates of YLD. In terms of cancer, the magnitude of bias on Disability-Adjusted Life Years (DALYs) would be minor because the majority of DALYs are generated through Years of Life Lost to premature mortality (YLL). However the bias remains for cancer YLD estimates and these concerns extend to other causes of disease, particularly leading causes of YLD and causes of YLD that exhibit wide inequalities \u201334.Further research is required to understand the impact of severity distributions for conditions that may have larger inequalities in case fatality, or severity, than cancers to explore differences across a larger range of diseases. Caution should be taken over interpreting the applicability of our cancer severity distributions to other countries due to differences in demography, social circumstance and access to healthcare systems across countries. There are large resource requirements in undertaking BOD studies. Both independent BOD researchers and collaborators of the GBD need to know where to focus their efforts in order to obtain the maximum benefit of information. Our results have illustrated the importance of ensuring that any estimates are based upon the best available country-specific data, in the context of cancer types, with an additional benefit of using data at lower levels of granularity. BOD researchers should work in collaboration with disease experts in their country to understand sequelae and disability weight definitions to assess for equivalence within country-specific data sources, such as nationally representative surveys.BOD studies are a means to influence policy and practice and these findings are important in highlighting a systematic bias in the point estimates that are being used to rank causes that is largely being overlooked. To a degree, the lack of sub-national severity distributions would negate each other in national results, but would mask differences between regions that have heterogeneous levels of deprivation and therefore underestimate the true extent of inequalities. Consideration should be given to the research questions and within-country context to establish how sub-national severity distributions would be best designed, for example it may be more appropriate to estimate severity distributions for fixed geographical regions. Care must be taken in interpreting YLD estimates too precisely especially with sub-national estimates and estimates comparing populations.S1 File(XLSX)Click here for additional data file."}
+{"text": "This review assesses the latest evidence linking short-chain fatty acids (SCFA) with host metabolic health and cardiovascular disease (CVD) risk and presents the latest evidence on possible biological mechanisms.SCFA have a range of effects locally in the gut and at both splanchnic and peripheral tissues which together appear to induce improved metabolic regulation and have direct and indirect effects on markers of CVD risk.SCFA produced primarily from the microbial fermentation of dietary fibre appear to be key mediators of the beneficial effects elicited by the gut microbiome. Not only does dietary fibre fermentation regulate microbial activity in the gut, SCFA also directly modulate host health through a range of tissue-specific mechanisms related to gut barrier function, glucose homeostasis, immunomodulation, appetite regulation and obesity. With the increasing burden of obesity worldwide, the role for gut microbiota-generated SCFA in protecting against the effects of energy dense diets offers an intriguing new avenue for regulating metabolic health and CVD risk. Cardiovascular disease (CVD) is the leading cause of death worldwide, accounting for one in three deaths in the USA . AlthougAn emerging area of interest in metabolic health and its link with CVD risk is the gut microbiome. The advent of high-throughput metagenomic techniques has facilitated new insights into the role of the gut microbiome in CVD risk . ImportaA number of recent epidemiological studies have highlighted the inverse association between dietary fibre intake and CVD risk factors \u201318. Non-SCFA have a number of potential roles in modulating metabolic health and CVD risk factors through direct and indirect routes.Possibly the most direct route of modulating CVD risk is SCFA modulation of systolic blood pressure (SBP) and diastolic blood pressure (DBP). A recent controlled trial in humans has demonstrated a potential adjuvant effect of butyrate in the reduction of DPB through a reduction in inflammation , and theAn area where the role of SCFA is gaining much interest is their effects in obesity and metabolic regulation (glucose and lipid homeostasis). Epidemiological and robust animal data demonstrates an inverse relationship between dietary fibre intake and adiposity and weight gain. Recent studies are beginning to provide insight into the role of SCFA. Acetate plays a role in central appetite regulation , and incPerhaps the most intriguing role for SCFA that may have the greatest impact on host metabolic health is their importance in orchestrating the epithelial barrier to maintain gut integrity and prevent the translocation of bacterial pro-inflammatory molecules across the gut wall. Of the SCFA produced in the colon, current evidence points towards a key regulatory role for butyrate. A plethora of animal studies have promoted a key role for butyrate in maintaining epithelial integrity , 53 and Recent evidence from animal studies suggest that soluble dietary fibre reduces TMA and TMAO metabolism by 40.6 and 62.6%, respectively, which was associated with increased SCFA production and reduced serum lipids and cholesterol . In contA number of now de-orphaned G protein coupled receptors have been identified for which SCFA act as natural ligands , 66. FreThe role of SCFA in the regulation of blood pressure has been examined, mainly in animal models. Acetate and propionate appear to regulate blood pressure in a complex interplay involving induction of renin production through Olfr78 and counter-regulation through FFAR3. Evidence from knock out models suggests that propionate induces release of renal renin and a rise in BP through Olfr78 but can also induce a reduction in BP that appears FFAR3 dependent \u2022, 69. InSCFA and butyrate in particular have long been recognised as important substrates for maintaining a healthy gut. Butyrate is the preferred substrate for colonocytes. More recently, a role for SCFA in regulating epithelial integrity through co-ordinated regulation of tight junction proteins which regulate the intracellular molecular highway between the lumen and hepatic portal system has been postulated. Hyperglycaemia and increased gut permeability are associated with translocation of bacteria and/or their cell wall components which trigger an inflammatory cascade that has been associated with obesity and insulin resistance \u2022. In micSCFA have been suggested to protect against diet-induced obesity by reducing appetite and energy intake. However, a number of studies have reported that incorporating SCFA into the diet of rodents has no effect on food intake , 79. SimA recent study by Li et al. reported a reduction in energy intake following intragastric administration of butyrate but not through intravenous administration of butyrate . This diThe available rodent and human studies therefore suggest that oral SCFA supplementation does not modulate appetite responses, whilst delivering SCFA to more distally in the gut may reduce energy intake. The SCFA receptors FFAR2 and FFAR3 are co-expressed in glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) expressing cells , leadingIn summary, studies that have targeted delivery of SCFA to the GI tract have shown reductions in energy intake, which may be related to the anorectic gut hormone release and/or direct neural gut-brain signalling via FFAR2 and FFAR3 receptors. SCFA may also modulate body weight and obesity by increasing energy expenditure. Indeed, a number of studies have reported that both acute and chronic administration of SCFAs promotes energy expenditure in rodents , 82, 83.SCFA have important effects on glucose homeostasis through a range of mechanisms. As previously described, improved gut barrier function reduces inflammation and oxidative stress promoting improved insulin sensitivity (reviewed in ). In dieSCFA protect against diet-induced obesity through a number of mechanisms. SCFA produced in the colon stimulate FFAR 2/3 on enteroendocrine L-cells in the colon leading to release of the anorexigenic gut hormones GLP-1 and PYY , 89. TheUsing a targeted approach to delivering propionate to the large intestine, we have demonstrated that propionate induces appetite regulation, reduced food intake and prevent weight gain in humans that may in part be explained by increased GLP-1 and PYY . In miceThere is quite compelling evidence from animal models that SCFA can play an important role in regulating metabolic health and mitigating CVD risk. However, careful interpretation of the evidence is necessary particularly when using global genetic knockout models because of the tissue-specific nature of expression of receptors for SCFA. Furthermore, cognisance must be made of the physiologically relevant concentrations that various tissues are exposed to. Whilst oral supplementation or gavage with SCFA is practical and attractive for animal studies, this is generally not how SCFA appear in the gut in humans. The site and rate of SCFA production in the gut may be critical to the physiological consequences and therefore modelling human physiology is important to correctly interpreting animal studies. Better still, well-controlled human intervention studies are needed to develop a strong evidence base if the research and clinical community are to be convinced of the beneficial role SCFA play in human health. With emerging effects around the importance of SCFA for the regulation of barrier function and inflammation, it is critical that we understand the relevance of these effects for disease mitigation because there are relatively inexpensive options to intervene at the population level. The role of SCFA in managing adiposity and body weight gain is well documented in animals and the emergent role of SCFA in appetite regulation and obesity in humans also presents an exciting opportunity to intervene at a population level to tackle perhaps the most pressing health issue of our time\u2014obesity."}
+{"text": "Predation causes robust long-term stress-related effects on prey individuals even if they do not get consumed by the predator. Here I review the role of basolateral amygdala (BLA) neurons in the mediation of non-consumptive effects of predation. This brain region is critical for the generation and maintenance of fear response across many phylogenetic groups. The exposure to cues of predator presence activates neurons within the BLA. Hormones secreted during stressful episodes cause long-lasting structural changes in BLA neurons, causing facilitation of endocrine response during subsequent exposure to stressful episodes like later predator exposure. Some studies also suggest that BLA is involved in creating anticipatory defensive behavior in response to the expectation of change in the environment. Predation has been considered by both ecologists and neurobiologists as a fundamental biological process (Clinchy et al., in utero can change the growth trajectory of offspring (Dantzer et al., There are two inter-related processes that mediate non-consumptive predation effects on the prey. First, coping with predators evoke a fight-or-flight response which requires the initiation of stress endocrine axis (Harris and Carr, Amygdala is a collection of structurally heterogeneous brain regions in the medial temporal lobe (Sah et al., 2+ during the odor exposure (Butler et al., Toxoplasma gondii reduces fear to cat urine in rats and in parallel causes dendritic retraction within BLA neurons (Mitra et al., Exposure to predator cues activate neurons within BLA . This haBut the neuronal activation of BLA neurons during exposure does not separate incidental activation from involvement in the mediation of fear response. Predator odors do cause Fos expression and neuronal firing in a wide range of brain regions including the medial amygdala and other components of medial hypothalamic zones (Dielenberg et al., Phaseolus vulgaris leucoagglutinin travels to dorsal portion of medial amygdala in rats (Pitk\u00e4nen et al., Nonetheless, several lesions studies show the possible role of BLA in unconditioned behavioral response to predators. Early resection studies of a medial temporal lobe in monkeys, for example, showed the development of \u201cpsychic blindness\u201d in subjects, as a response, to stimuli which were loaded with aversion in non-manipulated animals Lanska, . Fiber sMoreover, BLA might have a heterogeneous role in defensive behaviors dependent on specific predator odors used in the experiments. For example, chronic exposure to odor from ferret anal glands induces a set of physiological changes that are similar to those of chronic stress with robust BLA involvement (Campeau et al., Exposure to predators induce physiological activation of stress endocrine axis through activation of hypothalamus-pituitary-adrenal axis (H-P-A axis; McEwen, The homeostatic process works very well regarding switching the body between with-predator and san-predator episodes as far as such encounter are few and far between. Yet repeated or prolonged activation of stress endocrine axis takes a toll on neural mechanisms that control stress endocrine response through wear and tear McEwen, . EpinephBLA neurons undergo structural plasticity during stressful episodes (Vyas et al., These long-lasting footprints can change the response of animals to subsequent predator encounter. Several correlative studies point towards this direction. Rats show significant inter-individual variations in terms of long-term behavioral change resulting from acute exposure to a predator (Adamec and Shallow, There is an added possibility that changes within the BLA caused by stress hormones can change future secretion of stress hormones themselves through the effects of BLA on downstream paraventricular hypothalamic nucleus responsible for stress endocrine activation. Some paraventricular hypothalamus cells do receive direct projects from BLA, although these projections are sparse (Herman et al., Exposure to ferret odor in early juvenile period increases social play in female rats but decreases play in males, when measured 3 weeks later (Stockman and McCarthy, BLA, apart from its place in allostatic change, is also involved in matching defensive behaviors to changing environments.Several studies have used cues of environmental adversity to study the relationship between BLA and plasticity in the fear response. Early postnatal life has often been used in these studies because it represents a critical period of brain development and behavioral flexibility. Fear to predators in rat pups emerges around postnatal day 10, a period that is similar to the emergence of stress hormone secretion and amygdala development (Moriceau et al., A similar interaction effect can also be seen when pregnant mice mothers are exposed to predator odors and offsprings are tested. Offsprings of predator odor-exposed mothers show enhanced fear to cat urine. Offsprings from predator odor-exposed mothers also show more robust secretion of adrenal glucocorticoids when they are exposed to a novel predator odor (St-Cyr and McGowan, A reverse corollary can also be found whereby living in a sensorily enriched environment can dampen the defensive responses through proximate mechanisms based in the BLA. Relatively short periods of environmental enrichment in rats causes dendritic retraction in BLA neurons (Ashokan et al., Exposure to predators cause both consumptive and non-consumptive consequences for the prey animals. BLA is likely an important mediator of non-consumptive effects of predation on prey behavior. Exposure to predator often leaves a historical trace in the functioning of the stress endocrine axis. BLA is a crucial node in proximate mechanisms of these effects through its reciprocal interaction with adrenal glucocorticoids. The strength of neuroendocrine interactions between BLA and adrenal hormones can be further modulated by the incipient environment. Exposure to predators can also initiate anticipatory investment in defensive behaviors. There is growing evidence that BLA and glucocorticoids are involved in this process. Further experiments are warranted to dissociate incidental relationship from causal sequences.Stress generated from exposure to predators or predator cues have been used to create animal models of fear-related psychiatric disorders like post-traumatic stress disorder and anxiety disorders (Adamec et al., RM contributed to the organization, literature search and writing of this manuscript.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The objective of the Symposium is to improve the understanding of how existing analytic methods and data can be leveraged to make progress in understanding the causes and mechanisms of health-related disparities in Alzheimer\u2019s disease, related dementias and other prominent age-related diseases. Topics will cover a range of academic and administrative topics including: i) advanced analytic methods and modeling of health disparities with application to racial and geographic disparities in AD/ADRD; ii) the role of repeated anesthetic and surgical exposure in generation of disparities in AD/ADRD risk; iii) the nature of health disparities in cognitive aging as parallel to or distinct from health disparities in patterns of aging in other systems in the body; iv) recent advances in machine learning applied to large claims databases involving medical disparities; and v) geographic-related disparities in life expectancy across the U.S. A focus will be made on demonstrating how studies using established administrative data resources such as Medicare claims databases combined with innovative analytic approaches such as partitioning analyses, time-series based methods of projection and forecasting, and stochastic process models can be used to uncover previously overlooked or understudied aspects in this area of research. Analyses of such increasingly available large health datasets provides an opportunity to obtain nationally representative multiethnic results based on individual-level measures that reflect the real care-related and epidemiological processes ongoing in the U.S. healthcare system and allows the targetting of relatively rare diseases in relatively small population subgroups."}
+{"text": "Stem cell-based cardiac regenerative therapy is expected to be a promising strategy for the treatment of severe heart diseases. Pluripotent stem cells enabled us to reconstruct regenerated myocardium in injured hearts as an engineered tissue aiming for cardiac regeneration. To establish a long-term survival of transplanted three-dimensional (3D) engineered heart tissues in vivo, it is indispensable to induce microcapillaries into the engineered tissues after transplantation. Using temperature-responsive culture surface, we have developed pluripotent stem cell-derived cardiac tissue sheets including multiple cardiac cell lineages. The application of gelatin hydrogel microsphere between the cell sheet stacks enabled us to generate thick stacked cell sheets with functional vascular network in vivo. Another technology to generate 3D engineered cardiac tissues using cardiac cells and biomaterials also validated successful induction of vascular network originated from both host and graft-derived vascular cells. The in vivo .In addition with the biophysical advantages of 3D structure in cell retainment after transplantation as described above, the introduction of microcapillaries is an important factor for long-term survival of the transplanted tissue. It is assumed that the transplanted tissue survives only through the direct diffusion of oxygen and nutrition at the initial stage of the transplantation, and vascular formation perfusing the whole engineered tissue would be indispensable for the long-term survival. It means that the successful cardiac regenerative strategy requires re-vascularization mechanisms to validate long-term myocardial regeneration.Cell sheet formulation is one of the principal methods to generate 3D tissues from single cells . Okano eIt is also reported that the tissue thickening by the simple layering of cell sheets is limited for less than\u2009four layers because of the central necrosis due to the shortage of oxygen and nutrition supply . To overAnother method to induce vascular networks into the cell sheet-based 3D structures is to generate \u201cvascularized cardiac cell sheets\u201d using bioreactors , 15. In Another format of 3D cardia tissue is biomaterials-supported engineered tissues which strongly support the structural stiffness of the artificial tissue structure , 16\u201318. The transplantation of hiPSC-ECTs onto a rat MI model revealed an increase of capillaries around the grafted tissue and a fair vascular network formation throughout the regenerated myocardium at 4\u00a0weeks after transplantation . The injIn 3D cardiac tissue formats introduced above, the microcapillary network formation throughout the tissue contributed to the long-term survival of the tissues. It is possible that the mechanism of vascular network formation in vivo includes two different biological processes: (1) Angiogenesis mediated by paracrine factors from transplanted engineered tissues, and (2) physical contribution of transplanted vascular cells which can be incorporated into newly formed vasculatures inside the regenerated myocardium. The sufficient vascular formation by the collaboration of these processes might be advantageous for long-term 3D graft survival and a successful cardiac regenerative therapy. On the other hand, the required extent of in vitro vascular formulation prior to in vivo transplantation is still controversial. It may depend on the balance of the in vitro conditions such as cellular composition/maturation or culture microenvironment, and in vivo conditions of transplanted site such as oxygen concentration or vascular supply which depends on disease conditions of the recipient heart (Fig.\u00a0In the present review, we introduced various strategies to induce microcapillaries for 3D engineered cardiac tissues aiming to promote the effectiveness of stem cell-based cardiac regenerative therapy. Further investigations for the post-transplantation vascularization are anticipated."}
+{"text": "Modern improvement of complex traits in agricultural species relies on successful associations of heritable molecular variation with observable phenotypes. Historically, this pursuit has primarily been based on easily measurable genetic markers. The recent advent of new technologies allows assaying and quantifying biological intermediates (hereafter endophenotypes) which are now readily measurable at a large scale across diverse individuals. The usefulness of endophenotypes for delineating the regulatory landscape of the genome and genetic dissection of complex trait variation remains underexplored in plants. The work presented here illustrated the utility of a large-scale (299-genotype and seven-tissue) gene expression resource to dissect traits across multiple levels of biological organization. Using single-tissue- and multi-tissue-based transcriptome-wide association studies (TWAS), we revealed that about half of the functional variation acts through altered transcript abundance for maize kernel traits, including 30 grain carotenoid abundance traits, 20 grain tocochromanol abundance traits, and 22 field-measured agronomic traits. Comparing the efficacy of TWAS with genome-wide association studies (GWAS) and an ensemble approach that combines both GWAS and TWAS, we demonstrated that results of TWAS in combination with GWAS increase the power to detect known genes and aid in prioritizing likely causal genes. Using a variance partitioning approach in the largely independent maize Nested Association Mapping (NAM) population, we also showed that the most strongly associated genes identified by combining GWAS and TWAS explain more heritable variance for a majority of traits than the heritability captured by the random genes and the genes identified by GWAS or TWAS alone. This not only improves the ability to link genes to phenotypes, but also highlights the phenotypic consequences of regulatory variation in plants. Discovery of variation that underlies quantitative traits remains central to the genetic improvement of agricultural species. Functional variation can alter coding sequence or act to regulate an intermediate phenotype. Regulating the abundance of phenotypic intermediates, such as mRNA expression or protein level, provides a more spatially and temporally subtle target for selection than coding sequence changes, which are more likely to be pleiotropic and therefore maladaptive . Thus, rIn standard genetic mapping approaches, like association or linkage mapping, associations between genetic markers and terminal phenotypes of interest are tested for significance , has been published recently  were set to P = 1 prior to combining with GWAS p-values. Fisher\u2019s combined tests were performed in the same way when including the multi-tissue TWAS results instead of the kernel-only results.The GWAS p-value (mixed linear model with kinship as a random effect) of each SNP in the top 10% of most associated SNPs was assigned to nearest gene and then combined with the TWAS p-value  principal coordinates + PEERs) for that same gene using Fisher\u2019s combined test as implemented in the sumlog method in the  package  in R. TWUsing the k-Nearest Neighbors (KNN) imputed Nested Association Mapping population HMP3.2.1 genotypes described above, kinship matrices were calculated based on the top ten genes identified by each of the TWAS, GWAS, and combined models described in the Goodman diversity panel  found by each method for each trait. This identification of known genes among the top 1% of hits for each method measures how often known genes appear in the tail of the distribution of detected genes and avoids direct comparisons of p-values between differently powered and structured tests that rely on continuous (TWAS) or discrete (GWAS) independent variables.As shown in crtRB1 has expression which is most strongly correlated  with zeaxanthin abundance in our TWAS model that includes genetic and expression-derived covariates (see methods). crtRB1 is not among the top MLM GWAS-detected genes in our study, but the detection of crtRB1 by kernel TWAS is consistent with previous results  with zeaxanthin abundance, but it is not among the fifty most significantly associated genes in our TWAS results, and would not be prioritized by TWAS alone. However, within the peak covering zep1 in P = 0.0025) and zep1  both affect zeaxanthin abundance. Both Fisher\u2019s combined models using the single-tissue and multi-tissue TWAS results also support the importance of both genes.As is clear in hggt1, which has been previously tied to total tocotrienol content  selection TWAS approach should be used in which can remove uninformative terms from the model rather than including them but giving them a very small coefficient. It is also plausible that for more genetically complex traits which are also affected by expression across tissues, the multi-tissue TWAS results are more likely to be informative.The lack of improvement in re-detecting known tocochromanol traits by the multi-tissue TWAS models alone or as part of the Fisher\u2019s combined tests is notable, but unsurprising for these genetically simple and very tissue specific traits. This lack of improvement indicates that kernel-based expression alone is most predictive of the kernel-based metabolites and accuracy is not improved by the incorporation of all other tissues. Rather than comparing the inclusion of all tissues A further cause of the limited improvement for the kernel TWAS or Fisher\u2019s combined test seen in the variance partitioning results is likely because GWAS identifies genomic regions which, when expanded to a 1 Mb window, could cover the functional variants. Furthermore, while the correct functional gene may not be prioritized by GWAS, if the trait is affected by genetic regulation rather than coding sequence change, the sites near the GWAS hit may in fact be more functional than those near the mechanistically significant gene itself even if they are misattributed to the incorrect proximal gene. Using a large independent diverse panel with very low LD to assess the heritability explained by the SNPs identified by each method may also provide a better estimate as the functional variants are not as easily tagged over long distances.While the utility of expression endophenotypes in dissecting traits has been demonstrated here, it should be noted that associations made between endophenotypes and terminal phenotypes are inherently more susceptible to environmental effects than genotype-based associations. This susceptibility to environmental effects likely allows us to associate only the environmentally independent heritable fraction of expression with phenotype in our study, especially because expression data were collected from separate plants than those for which terminal phenotypes were measured. Given that in endophenotype-based association studies, like TWAS, environmental variation separately impacts and increases error in both the independent and dependent variables, methods like TWAS alone may plausibly be expected to perform more poorly than genetics-based associations. However, this shortcoming is partially compensated for by the more direct link between endophenotype and terminal phenotype and the potential discovery of mechanism. The collection of expression data from the same plants and conditions in which the phenotypes are collected would likely benefit the dissection of genotype by environment interactions by highlighting the impact of variation in expression for a specific gene within an environment, but cannot be examined here as terminal phenotypes and expression values were calculated from separate environments and years."}
+{"text": "The media has become increasingly more agenda-driven and politically biased in recent years. This research explores whether the major news outlets fosters an environment of negative sentiment towards the older adult population over a 4-year-period from 2016-2019. The paper uses a content analysis approach. 199 news articles that include keywords such as \"older adults\", \"seniors\" or \"elderly\" are randomly selected among those published in the first week of March in 2016, 2017, 2018 and 2019 from the online archives. Main attitudes towards the older adults are extracted and categorized. In the 4-year span, regression analysis shows that negative attitudes are apolitical and are found in almost two-thirds (64%) of the 199 news articles in both liberal and conservative news outlets, suggesting that the current media creates a ubiquitously hostile environment for older adults. However, more liberal news outlets tend to produce more articles with positive messages about the older adults (p<0.05), and more conservative news outlets tend to create more content that reinforces negative stereotypes of older adults as being vulnerable and less productive (p<0.01). The high percentage of negative attitudes and the ubiquitous negative attitudes in news organizations, in spite of their political leaning, suggests that the media environment has some influence on the news content. Political biases of the organization are associated to numbers of articles with positive messages and negative stereotyping. Promoting professional development and self-regulating mechanisms in journalism could aid in reducing ageism perpetuated in the media."}
+{"text": "Congenital ocular melanocytosis has been shown to be extremely uncommon in studies of numerous infants and children with retinoblastoma and disorders such as retinopathy of prematurity.A 33-month-old Caucasian boy presented with a solid white predominantly endophytic retinoblastoma filling most of the nasal aspect of the fundus and extensive vitreous seeding. Fundus exam of the contralateral eye showed a broad-based flat melanotic area of the choroid extending from the subfoveal region to the ora serrata temporally. The child was treated by enucleation of the retinoblastoma-containing eye (homozygous non-germline RB1 mutation) and is being monitored annually. The patient has been followed for 4\u00a0years.This rare presentation of advanced unilateral retinoblastoma and contralateral isolated choroidal melanocytosis in a young child emphasizes the importance of detailed fundus mapping of the non-affected eye and has potential implications due to the increased incidence of uveal melanoma later in life. Retinoblastoma is the most common pediatric neoplasm of the eye and it accounts for 2.5% to 4% of all pediatric cancers . The incDue to the rarity of ocular melanocytosis and the documented increased incidence of uveal melanoma in eyes with complete ocular melanocytosis , we thou1 OS. The child was treated by primary enucleation of the retinoblastoma-containing OD. Histopathologic evaluation confirmed the clinical diagnosis of retinoblastoma. The child has been followed for more than 4\u00a0years post-enucleation. Follow-up examinations of the fundus OS have shown no change in the patch of choroidal melanocytosis.A 33-month-old Caucasian boy presented with leukocoria right eye (OD). Fundus examination OD revealed a solid white predominantly endophytic retinal tumor filling most of the nasal aspect of the fundus Fig.\u00a0 & b and Isolated choroidal melanocytosis  is a limited form of congenital ocular melanocytosis . ExaminaComplete ocular melanocytosis is recognized to be an important risk factor for development of uveal melanoma . We suspThis rare presentation of advanced unilateral retinoblastoma and contralateral isolated choroidal melanocytosis in a young child emphasizes the importance of detailed fundus mapping of the non-affected eye and has potential implications due to the increased incidence of uveal melanoma later in life."}
+{"text": "Atrial fibrillation (AF), the most common cardiac arrhythmia, is associated with high morbidity and mortality. It is well known that both the prevalence and incidence of AF increase sharply with age, particularly after 65 years of age. AF and aging share mutual bidirectional relationships. On the one hand, aging and aging-related underlying diseases result in myocardial remodeling that may lead to cardiac electrical abnormalities which enhance the occurrence or persistence of AF . On the Even though it is well known that age is the single most important determinant of AF risk, the underlying mechanisms are not completely understood. Some of the mechanisms involved in the aging-AF association may be related with age-dependent left atrial dilation or senile amyloidosis that alter the structure of the myocardial tissue and constitute typical features of the so-called AF substrate . In addiMyocardial fibrosis is characterized not only by an excessive accumulation of collagen fibers  in the interstitial space but also by an increased insolubility and stiffness of the deposited fibers due to an exaggerated degree of intermolecular covalent linkage, or cross-linking within these fibers. It has been reported that HF patients carrying simultaneously these two histomolecular alterations exhibit more severe cardiac dysfunction and worst clinical evolution than patients in whom the two myocardial alterations are not coincident . TherefoThe presence of mMF can be biochemically assessed by using a combination of circulating biomarkers related to collagen type I metabolism. On the one hand, the ratio of serum carboxy-terminal telopeptide of collagen type I (CITP) to serum matrix metalloproteinase-1 (MMP-1) (CITP:MMP-1 ratio) has been shown to be inversely correlated with left ventricular myocardial collagen type I cross-linking in HF patients, as the higher is the cross-linking among collagen type I fibrils, the lower will be the cleavage of CITP by MMP-1 during the process of degradation of the fiber . On the Further studies are required to ascertain whether the use of biomarkers of mMF, as a non-invasive tool to detect the fibrotic-related structural abnormalities that affect atrial electrical properties, may help to stratify the risk of adverse clinical evolution in elderly patients with AF. In addition, it would be necessary to establish whether specific therapeutic strategies to correct myocardial collagen metabolism in aged AF patients with the mMF biomarker profile may help with their clinical handling."}
+{"text": "Filoviridae) cause outbreaks of viral hemorrhagic fever in sub-Saharan Africa. The Egyptian rousette bat (ERB) is a natural reservoir host for the marburgviruses and evidence suggests that bats are also natural reservoirs for the ebolaviruses. Although the search for the natural reservoirs of the ebolaviruses has largely involved serosurveillance of the bat population, there are no validated serological assays to screen bat sera for ebolavirus-specific IgG antibodies. Here, we generate filovirus-specific antisera by prime-boost immunization of groups of captive ERBs with all seven known culturable filoviruses. After validating a system of filovirus-specific indirect ELISAs utilizing infectious-based virus antigens for detection of virus-specific IgG antibodies from bat sera, we assess the level of serological cross-reactivity between the virus-specific antisera and heterologous filovirus antigens. This data is then used to generate a filovirus antibody fingerprint that can predict which of the filovirus species in the system is most antigenically similar to the species responsible for past infection. Our filovirus IgG indirect ELISA system will be a critical tool for identifying bat species with high ebolavirus seroprevalence rates to target for longitudinal studies aimed at establishing natural reservoir host-ebolavirus relationships.With the exception of Reston and Bombali viruses, the marburgviruses and ebolaviruses (family  The family Filoviridae includes two genera of viruses that are known to cause disease in humans and/or non-human primates; the genus Marburgvirus includes one virus species comprised of two viruses (Marburg virus and Ravn virus) and the genus Ebolavirus includes six virus species comprised of one virus each 2. With the exception of Reston3 and Bombali viruses4, the marburgviruses and ebolaviruses cause outbreaks of viral hemorrhagic fever in sub-Saharan Africa10. Reston virus causes disease in non-human primates only, and its circulation appears to be limited to the Philippines and China1. Far less is known about Bombali virus, as its genomic viral RNA was only recently detected in Angolan free-tailed bats (Mops condylurus) and little free-tailed bats (Chaerephon pumilus) in Sierra Leone4. To date, Bombali virus has not reportedly been isolated.Following spillover from a zoonotic source, the filoviruses can be transmitted person-to-person through direct contact with infectious bodily fluids, resulting in large outbreaks of viral hemorrhagic fever with high case fatality5, many of the index cases of marburgvirus disease reported entering bat-inhabited caves or underground mines prior to becoming ill13. Retrospective investigation of three outbreaks of marburgvirus disease among miners working in Goroumbwa Mine in northeastern Democratic Republic of the Congo (DRC) from 1998\u2013200014, miners working in Kitaka Mine in southwest Uganda in 200715, and two tourists that had separately visited the nearby Python Cave, Uganda in 200817 revealed that all of these locations were inhabited by large populations of the Egyptian rousette bat . A longitudinal ecological investigation later identified this bat species as a natural reservoir host for the marburgviruses and a source of virus emergence in humans18.Since the discovery of Marburg virus in 1967Mops trevori) directly over the working area of the\u00a0index case19. The putative index case of the 2007 Ebola virus disease outbreak in the Kasa\u00ef-Occidental province of the DRC was said to have purchased bats for consumption following a reported annual migration of hammer-headed bats (Hypsignathus monstrosus) and Franquet\u2019s epauletted fruit bats (Epomops franquetti)20. Lastly, the presumed index case of the 2014 Ebola virus disease outbreak that started in Guinea was reported to have played in a tree hollow, where DNA traces of Mops condylurus were later identified21.Unlike the spillover events leading to marburgvirus disease, those for ebolavirus disease have been difficult to associate with a specific environment, such as caves. Furthermore, the evidence linking ebolavirus spillover to a particular species of bat is largely circumstantial. For example, the 1976 and 1979 index cases of Sudan virus disease both worked in a cotton factory in Sudan, where a retrospective investigation eight to nine months after the initial outbreak identified a large roof colony of Trevor\u2019s free-tailed bats 22 and Reston virus RNA has been reportedly detected in four bat species captured in the Philippines 23. Yet, infectious virus was not isolated from any of these species23, indicating that they are either dead-end virus hosts, had cleared virus infection prior to sampling, or that current filovirus isolation techniques lack the sensitivity to recover infectious virus from specimens with low viral loads. Serological reactivity of bat sera with ebolavirus antigens using indirect ELISAs, indirect fluorescent tests, bead-based multiplex assays and/or western blots has been reported in 375 bats representing at least 21 species throughout sub-Saharan Africa and Asia32. However, interpretation of this data has been exceedingly difficult due to multiple reasons that include: (1) the absence of a panel of positive and negative bat sera for initial serological assay validation and continuing quality control, (2) the use of various uncharacterized recombinant filovirus antigens, and (3) the application of different statistical methods for establishing cutoff values for seropositivity. Nonetheless, ebolavirus serosurveillance offers several distinct advantages compared to surveillance for active virus infection including a longer diagnostic window , no knowledge of virus-tissue tropism and no requirement for destructive sampling.The majority of research directed towards the identification of the natural reservoir hosts of the ebolaviruses has consisted of cross-sectional surveillance of the sub-Saharan African and Asian bat population for evidence of active and past ebolavirus infection. The predominance of cross-sectional studies can be attributed to the large number of bat species residing within the geographic range of ebolavirus circulation that require investigation, as well as the challenges associated with obtaining diagnostic specimens from a mammal that is difficult to capture due to its elusive nocturnal nature and ability to fly. Collectively, Ebola virus RNA has been detected in three bat species captured in the Republic of the Congo and Gabon  at euthanasia was allowed to clot and then centrifuged at 1,500\u2009g for 10\u2009min. The sera were transferred into polypropylene CryoElite Wheaton vials , and then temporarily stored under liquid nitrogen vapors in the biosafety level four laboratory (BSL-4) until they were double bagged, passed through a dunk tank containing 5% Micro-Chem Plus  and transported to the gamma-cell irradiator. The doublebagged serum aliquots were sandwiched between layers of dry ice and then exposed to 5\u2009\u00d7\u2009106 rads of gamma-cell irradiation using a cobalt-60 source.The bats used to generate the filovirus-specific antisera in this study originated from an ERB breeding colony37 were used as filovirus-na\u00efve sera. These sera were collected and processed in the same manner as outlined above.Sera obtained from filovirus-na\u00efve bats from the breeding colony and negative control bats from previous experimental studiesAll animal procedures were approved by the Institutional Animal Care and Use Committee (IACUC) and performed in compliance with the Guide for Laboratory Animal Care and Use . The animal research facilities at the CDC have received full accreditation by Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC).Procedures conducted with filoviruses or filovirus-infected bats were performed in accordance with Select Agent Regulations  in a BSL-4 laboratory at the CDC. All bat cages were further contained within bio-flow isolator units with HEPA-filtered inlet and exhaust air supplies .ad libitum.All bats were group-housed according to filovirus inoculum in a climate controlled BSL-4 animal area, with a 12\u2009h\u2009day/12\u2009h night cycle. Bats received a quantity of fresh fruit, supplemented with protein/vitamin powder, equal to their body mass daily and water 40. Briefly, roller bottles of Vero E6 cells were inoculated with virus and the cultures were harvested when \u226590% of cells exhibited evidence of infection by immunofluorescence assay. Filovirus antigen lysates were prepared from the cultures by detergent basic buffer extraction of infected cells. Uninfected control antigen lysate was generated in the absence of virus, but otherwise prepared in the exact same manner.Filovirus antigen lysates Table\u00a0 and uninEach filovirus-specific antiserum (n\u2009=\u2009124) and filovirus-na\u00efve serum (n\u2009=\u200919) was tested for reactivity against each filovirus antigen lysate (n\u2009=\u20097) and uninfected control antigen lysate  by sex, age category, or the interaction between sex and age category .The breeding colony was founded from Ugandan wild-caught, filovirus-na\u00efve adult (\u22651\u2009yr) ERBs18. We assume that the seroprevalence of the ebolaviruses in their respective natural reservoir bat hosts approximates this value. However, the prior probability has relatively little influence on determining the magnitude of the cutoff value for seropositivity. The cutoff value for each filovirus-specific indirect ELISA represents the value where the posterior probabilities for the reactivity of the filovirus-specific antisera with homologous antigen and the reactivity of filovirus-na\u00efve sera with this same antigen are equal.For each filovirus-specific IgG indirect ELISA, quadratic discriminant analysis was used to determine a cutoff value for seropositivity by considering: (1) the reactivity of the filovirus-specific antisera group with homologous antigen, (2) the reactivity of the filovirus-na\u00efve sera group with that same antigen, and (3) the prior probability of the filovirus-specific antisera group . The prior probability of each filovirus-specific antisera group was set at 0.15. This value represents the overall population seroprevalence of marburgvirus in its natural reservoir host, the ERBFor each indirect ELISA at its specified seropositivity cutoff value, the filovirus-specific antiserum and filovirus-na\u00efve serum samples were classified as true positive, false positive, false negative or true negative. The sensitivity of each assay was then calculated by dividing the number of individuals with a positive test result by the number of individuals with a history of past infection , and the specificity of each assay was calculated by dividing the number of individuals without a history of past infection (filovirus-na\u00efve group) by the number of individuals with a negative test result.The level of serological cross-reactivity between each group of filovirus-specific antisera and each heterologous virus antigen was calculated by dividing the number of antisera positive for reactivity with a virus antigen by the total number of antisera tested against that antigen , and was expressed as a percentage.After the nucleotide sequences of the filovirus isolates used to inoculate the bats in this study were retrieved from GenBank, the coding regions were translated into amino acids and aligned using the MUSCLE algorithm . Percent identity values were then calculated from pairwise amino acid comparisons generated from the virus protein alignment. A Pearson\u2019s Product-Moment Correlation was performed to assess the relationship between percent serological cross-reactivity and percent amino acid identity .Quadratic discriminant analysis was used to predict which one of the seven filoviruses in the system was most antigenically similar to the filovirus responsible for past infection by considering the relative reactivity of each filovirus-specific antiserum and filovirus-na\u00efve serum with each filovirus antigen, as well as their covariance . First, prior probabilities were calculated for the eight classes used in the analysis (seven filovirus antigen classes and one negative class). Second, classification was performed by calculating posterior probabilities for the inclusion of an antisera/sera sample in each class and then assigning the sample to the class with the highest probability.35 or whole blood36 samples collected from experimentally inoculated ERBs. Five of these samples were collected four weeks post primary Marburg virus inoculation36, while two of the samples were collected at 23 and 27 weeks post primary inoculation following a \u201cnatural\u201d boost 36.To evaluate the ability of our system comprising seven filovirus-specific indirect ELISAs to predict the filovirus species most antigenically similar to the species responsible for past infection, we tested seven Marburg virus convalescent serumA total of 124 ERBs were used in this study that was performed over a two-year time span. The total number of bats dedicated to this study, as well as the size and composition of each group was dependent on the reproductive capacity of the ERB breeding colony, as well as the characteristics and number of bats needed for other experimental studies. The 124 bats were divided into seven groups, with group sizes ranging from 15\u201320 individuals  generated from bats intentionally infected with each of the seven known culturable filoviruses to develop a classification system (fingerprint) to predict which filovirus elicited the antibody response. Supplementary Table\u00a0To further assess the performance and predictive ability of our filovirus IgG indirect ELISA system, we tested five Marburg virus convalescent sera or whole blood samples collected four weeks post primary Marburg virus experimental inoculation and two whole blood samples collected at 23 and 27 weeks post primary experimental inoculation following a \u201cnatural\u201d boost . As expected, marburgvirus-specific IgG antibody levels were markedly lower in these seven convalescent serum and whole blood samples compared to marburgvirus-specific IgG antibody levels in the serum samples from the prime-boosted bats in this study Fig.\u00a0. However43, varying levels of serological IgG cross-reactivity between the ebolavirus species (20\u2013100%)44 and strong serological IgG cross-reactivity within the species Marburg marburgvirus (95%). The low level of serological IgG cross-reactivity between some of the ebolavirus species underscores the necessity of performing all assays within the system to avoid false negative results. Although significant levels of serological IgG cross-reactivity were observed between the prime-boost filovirus-specific antisera and some of the filovirus antigens, when the overall covariance of the seven-individual indirect ELISAs in the system were considered, we were able to predict the filovirus species responsible for past infection 100% of the time using as little as 25\u2009\u03bcL of sera (each serum was tested against each antigen in duplicate). Further evaluation of the performance and predictive ability of our system using seven Marburg virus convalescent serum or whole blood samples collected after primary experimental infection with Marburg virus  confirmed that the system was able to predict the filovirus species most likely responsible for past infection. As expected, the filovirus IgG indirect ELISA system was not able to correctly predict whether past infection was due to Marburg virus or Ravn virus 100% of the time. This finding supports the current classification of Marburg and Ravn viruses into a single virus species, Marburg marburgvirus2.In this study, we generated filovirus-specific antisera from prime-boosted ERBs and collected filovirus-na\u00efve sera to validate and characterize an indirect ELISA system that utilizes non-recombinant, infectious-based filovirus antigens for the detection of virus-specific IgG antibodies from bats. Initial validation of the system revealed that the individual filovirus-specific IgG indirect ELISAs exhibited high sensitivity (90\u2013100%) and specificity (100%). Similar to previous studies using human sera, we observed limited to no serological IgG cross-reactivity between the filovirus genera (0\u201315%)31. Alternatively, false positive serological results can occur when recombinant virus antigens unknowingly share similar epitopes with other virus antigens for which the study population possesses antibodies against46. False positive results can also arise from failing to account for non-specific serological reactivity resulting from the presence of non-virus contaminants in an antigen preparation. Here, we negated non-specific serological reactivity to Vero E6 cell components by subtracting the reactivity of wells coated with uninfected antigen lysate from the reactivity of corresponding wells coated with filovirus antigen lysate. While the majority of previously published ebolavirus serosurveys of bats used recombinant filovirus antigens generated in bacterial expression systems, not all of the studies implemented procedures to negate non-specific reactivity between residual bacterial epitopes in the antigen preparation and antibacterial antibodies in bat sera29. Like the majority of published ebolavirus serosurveys of bats, we performed serial serum dilutions to assess for linearity and specificity30. Most importantly, we included pooled filovirus-specific bat antisera as a positive control and pooled filovirus-na\u00efve bat sera as a negative control in every run to ensure that our filovirus IgG indirect ELISA system continually performed as expected.The robustness and discriminatory power of our system results from its underlying components and various control points. We employed infectious-based filovirus antigens, rather than recombinant virus protein antigens, as a strategy to increase both the sensitivity  and specificity  of the system. Although recombinant filovirus antigens can be generated in large quantities and do not require a BSL-4 laboratory for production, the use of single recombinant virus proteins for antibody detection can lead to false negative results if an individual\u2019s antibody repertoire is not directed against the particular recombinant virus protein that was employed32. Four out of the 11 previously published ebolavirus serosurveys of bats used Ebola virus antigen only to detect ebolavirus IgG antibodies26 and another four of these serosurveys used Ebola and Reston antigens only to detect ebolavirus IgG antibodies29. Based on the low serological cross-reactivity between Ebola virus antigen and Sudan virus antisera (68.4%) and Reston virus antigen and Sudan virus antisera (57.7%) observed in our study, we predict that the serosurveys using Ebola virus antigen or Ebola and Reston virus antigens only would have missed the opportunity to detect bats previously infected with Sudan virus. Likewise, due to the high level of serological cross reactivity between ebolavirus-specific antisera and heterologous ebolavirus antigen that we observed in our study, it is possible that the serological reactivity of bat sera with Ebola or Reston virus antigens in the previous serosurveys was due to past infection with one of the other known ebolaviruses or an undescribed ebolavirus. Although we successfully used quadratic discriminant analysis to predict which of the filovirus species in the system was most antigenically similar to the species responsible for past infection, only nucleotide sequence data can be used to ascertain infection with a particular filovirus. Furthermore, incrimination of an ebolavirus-natural reservoir host relationship requires consistent detection of both active (RNA and virus isolation from tissues/bodily fluids suggestive of a transmission mechanism) and past infection with a particular ebolavirus through space and time.Using filovirus-specific antisera collected from bats that were prime-boosted at the same time not only allowed us to thoroughly examine the level of serological cross-reactivity between the virus-specific antisera and heterologous filovirus antigen, but also provided the opportunity to use this knowledge to evaluate previously published ebolavirus serosurveys of bats36. Others have reported periodic boosting of rabies virus neutralizing antibody titers in a wild colony of big brown bats (Eptesicus fuscus)47. Second, we used a goat anti-bat IgG conjugated to horseradish peroxidase as the secondary antibody in our system. This antibody was generated using sera from ERBs, as well as sera from nine other bat species comprising four chiropteran families (manufacturer product datasheet). While this antibody has been confirmed to react with sera from these 10 chiropteran species and has been used with success to detect IgG antibodies in sera from >27 bat species comprising seven chiropteran families57, it is possible that its reactivity with IgG antibodies from divergent bat species might diminish. If this is the case, the concentration of secondary antibody may need to be optimized prior to testing a new species of bat or an alternative secondary antibody may need to be used. Third, our filovirus IgG indirect ELISA system includes seven virus antigens that represent all of the reported culturable filoviruses. Given the recent discoveries of filovirus RNA from divergent bat families in geographically distant locations , we expect that there are a number of undiscovered ebolaviruses that continue to circulate in nature. However, we believe that the genetic diversity of ebolavirus antigens (up to 61.6%) included in our system will allow for the detection of past infection with a novel ebolavirus, and prediction of the ebolavirus species that is most antigenically similar to the species responsible for past infection.While our filovirus IgG indirect ELISA system enables the robust detection of virus-specific IgG antibodies from bats and was able to predict the filovirus species most likely responsible for past infection, it does have some limitations. First, this system was validated using virus-specific antisera from prime-boosted bats and sera from filovirus-na\u00efve bats. Although all seven of the Marburg virus convalescent whole blood and serum samples collected from ERBs after primary experimental Marburg virus inoculation or following a \u201cnatural\u201d boost were marburgvirus IgG antibody positive, these samples had markedly lower marburgvirus-specific IgG antibody levels compared to samples collected from the bats in this study that were prime-boosted with one of seven filoviruses. This suggests that the sensitivity of the individual filovirus IgG indirect ELISAs may be lower than what was reported here (90\u2013100%) using filovirus-specific antisera from prime-boosted bats and filovirus na\u00efve bat sera. However, statistical determination of seropositivity cutoff values for the indirect ELISAs were largely driven by the variance surrounding the mean reactivity of the filovirus-na\u00efve sera with each of the virus antigens. It is likely that circulation and long-term maintenance of the ebolaviruses in their natural reservoir hosts leads to multiple virus exposures throughout the lifetime of an individual, resulting in boosting of virus-specific IgG antibody levels. \u201cNatural\u201d boosting of virus-specific IgG antibody levels in ERBs that had been previously infected with Marburg virus was observed during a recent experimental transmission study shortly after documenting virus infection and seroconversion in na\u00efve contact batsWe intend to use our filovirus IgG indirect ELISA system to screen archived and incoming specimens from cross-sectional serosurveys of the bat population of sub-Saharan Africa and Asia for evidence of past filovirus infection. If other specimen types exist for bat species identified as filovirus seropositive, they will be tested for evidence of active infection using virus-specific qRT-PCR, pan-filovirus RT-PCR and/or virus isolation techniques. Bat species positive for evidence of active filovirus infection or species exhibiting a seroprevalence equivalent to or larger than that of marburgvirus in ERBs  will be targeted for longitudinal studies aimed at collecting a wide range of specimens for evidence of active and past ebolavirus infection.While most of the virus-specific antisera generated in this study will be pooled to use as positive controls in our indirect filovirus ELISA system, some will be reserved for investigations aimed at determining the mechanisms by which bats clear and control filovirus infections through virus neutralization and cross-neutralization assays, as well as epitope mapping studies. Any remaining filovirus-specific bat antisera may be used to develop a pan-ebolavirus indirect ELISA that utilizes a mixture of non-recombinant, infectious based antigens from culturable ebolaviruses, as well as validate the performance of indirect ELISAs that use recombinant filovirus proteins to detect filovirus antibodies.Supplementary information"}
+{"text": "Saccharomyces cerevisiae, we have recently shownthat GTP levels can also play a role in determining how genes act to respond to changes in cellular energy supply. This review aims to interpret the importance of GTP as an integrative signal in the context of an increasing body of evidence indicating the spatio-temporal complexity of cellular de novo purine nucleotide biosynthesis.This mini-review considers the idea that guanylate nucleotide energy charge acts as an integrative signal for the regulation of gene expression in eukaryotic cells and discusses possible routes for that signal\u2019s transduction. Gene expression is intimately linked with cell nutrition and diverse signaling systems serve to coordinate the synthesis of proteins required for growth and proliferation with the prevailing cellular nutritional status. Using short pathways for the inducible and futile consumption of ATP or GTP in engineered cells of  Life requires energy, and the proliferation of life even more so. The common energy currency in living cells is ATP, generated from oxidative and substrate-level phosphorylation and consumed to drive the fundamental processes of DNA maintenance, synthesis and replication, the expression of genes to produce RNA and proteins, and the transport and movement of chemicals and macromolecules. Of these, gene expression\u2014chromatin remodeling, transcription initiation, transcription elongation, mRNA splicing, and translation\u2014accounts for the majority of cellular energy demand, with ~\u00a075% frequently offered as an estimate \u2014defined as the relative concentrations of all three phosphorylated adenosine nucleotides [ATP]\u2009+\u20090.5[ADP]/[ATP]\u2009+\u2009[ADP]\u2009+\u2009[AMP]  in S. cerevisiae (Kuehner and Brow In prokaryotic systems GTP levels can be directly sensed via influencing the selection of transcription start sites by RNA polymerase (Kr\u00e1sn\u00fd et al. Drosophila cells, mediating the repression of histone genes and E2F, a key driver of cell proliferation (Kozhevnikova et al. E. coli IMPDH was also shown to exhibit the same sequence-specific DNA-binding activity as the Drosophila enzyme, suggesting that moonlighting as a transcriptional regulator may be a broadly conserved function of this enzyme (Kozhevnikova et al. The unusual dynamic spatial organization of the enzymes required for purine biosynthesis into cellular macrostructures, filamentous cytoophidia (Aughey and Liu Cyanidioschyzon merolae (Imoto et al. Upstream of IMPDH, many of the enzymes required for de novo IMP biosynthesis have been observed to dynamically assemble and disassemble into a multi-enzyme cytoplasmic macrostructure termed the purinosome (Pedley and Benkovic Testing the hypotheses discussed above concerning the mechanisms by which high-energy guanine nucleotide status modulates gene transcription will require multidisciplinary investigations using the latest techniques in molecular biology and fluorescence microscopy. How induction of the ATP- or GTP-consuming pathways affects formation of IMPDH filaments and purinosomes, and how the abundance of activated GTPase switch proteins is influenced are key questions yet to be answered. The synthesis and use of high-energy adenine and guanine nucleotides are intimatelylinked see Fig.\u00a0 and obtaThe success of future work will depend on the ability to cleanly dissect the in vivo effects of GTP/GEC from those of ATP/AEC, using tools to manipulate the levels of these closely related nucleotides independently from one another. Recent in vitro studies analyzing the filamentation state and activity of human IMPDH enzymes indicate differential allosteric responses to adenine and guanine nucleotides such that IMPDH cytoophidia formation facilitates the accumulation of high levels of guanine nucleotides when the cell requires them (Fern\u00e1ndez-Justel et al."}
+{"text": "Evidence from observational comparative effectiveness research (CER) is ranked below that from randomized controlled trials in traditional evidence hierarchies. However, asthma observational CER studies represent an important complementary evidence source answering different research questions and are particularly valuable in guiding clinical decision making in real-life patient and practice settings. Tools are required to assist in quality appraisal of observational CER to enable identification of and confidence in high-quality CER evidence to inform guideline development.The REal Life EVidence AssessmeNt Tool (RELEVANT) was developed through a step-wise approach. We conducted an iterative refinement of the tool based on Task Force member expertise and feedback from pilot testing the tool until reaching adequate inter-rater agreement percentages. Two distinct pilots were conducted\u2014the first involving six members of the Respiratory Effectiveness Group (REG) and European Academy of Allergy and Clinical Immunology (EAACI) joint Task Force for quality appraisal of observational asthma CER; the second involving 22 members of REG and EAACI membership. The final tool consists of 21 quality sub-items distributed across seven methodology domains: Background, Design, Measures, Analysis, Results, Discussion/Interpretation, and Conflict of Interest. Eleven of these sub-items are considered critical and named \u201cprimary sub-items\u201d.Following the second pilot, RELEVANT showed inter-rater agreement \u2265\u200970% for 94% of all primary and 93% for all secondary sub-items tested across three rater groups. For observational CER to be classified as sufficiently high quality for future guideline consideration, all RELEVANT primary sub-items must be fulfilled. The ten secondary sub-items further qualify the relative strengths and weaknesses of the published CER evidence. RELEVANT could also be applicable to general quality appraisal of observational CER across other medical specialties.RELEVANT is the first quality checklist to assist in the appraisal of published observational CER developed through iterative feedback derived from pilot implementation and inter-rater agreement evaluation. Developed for a REG-EAACI Task Force quality appraisal of recent asthma CER, RELEVANT also has wider utility to support appraisal of CER literature in general (including pre-publication). It may also assist in manuscript development and in educating relevant stakeholders about key quality markers in observational CER.The online version of this article (10.1186/s13601-019-0256-9) contains supplementary material, which is available to authorized users. Asthma affects an estimated 334 million people worldwide, 14% of the world\u2019s children and 8.6% of young adults [Current asthma guidelines are developed by experts with the goal of signposting evidence-based approaches that will optimize patient outcomes. Their recommendations are based on a synthesis of the available literature and  rely heavily on classical randomized controlled trials (RCTs). RCTs have relatively high internal validity and the ability to clearly establish a causal relationship between an exposure and an outcome . This hiCalls for better integration of a range of evidence sources to inform more holistic respiratory guidelines \u20137 will oThis paper outlines the methodology and process that lead to the development of the REal Life EVidence AssessmeNt Tool (RELEVANT). The tool was created to assist the Task Force in identifying CER studies of sufficiently high quality to warrant consideration by asthma guideline bodies .RELEVANT was developed across six key phases between June 2014 and September 2015, including a literature review and synthesis of the existing literature followed by iterative processes for creating a novel tool , Academy of Managed Care Pharmacy (AMCP) and the National Pharmaceutical Council (NPC). It involved a review of the current literature on reporting standards for outcomes research published prior to 2014 and proposed a number of study design criteria to assist in the assessment of CER within the context of informing healthcare decision making. These two papers were used to identify the quality domains and critical sub-items of these domains that the REG\u2013EACCI Task Force members should incorporate in RELEVANT.Seeking to integrate the Task Force work within existing quality appraisal activities, a number of publications on quality parameters for non-RCT CER were first identified and reviewed \u201314. The The RELEVANT quality domains and sub-items were identified by mapping the components both unique and common to the Berger  and RochA structured taxonomy was developed such that design categories common to both papers were defined as quality \u201cDomains\u201d and within these were labeled \u201csub-items\u201d .The checklist produced  and Inter-rater variability also described as % rater agreement, was evaluated as the percentage concordance among raters at the individual sub-item, pooled primary sub-item, pooled secondary sub-item and combined primary/secondary sub-item level. For example, for a given sub-item, if four of the five raters deemed this sub-item as a \u201cyes\u201d whereas the remaining one rater deemed this sub-item as a \u201cno,\u201d then the inter-rater variability (% rater agreement) would be 4/5\u2009=\u200980%. A percentage agreement that approaches 50% suggests large disagreement that is no better than chance whereas % agreement that approaches 100% suggests strong and full concordance across raters. Raters were invited to provide written feedback on usability of the checklist and to identify areas of difficulty in criterion interpretation or application. Potential areas of divergent interpretation were also explored through interactive discussion with two members of Group A to understand the rationale for their differences in opinions where they occurred.The Task Force members next met at the American Thoracic Society Conference in May 2015  to review the pilot results and enact necessary revisions. Inter-rater agreement was calculated and qualitative feedback invited from participating raters to identify opportunities to reduce inter-rater variability further. Redundancies in sub-items were identified through rater quality feedback and deleted.Task Force rater feedback also recommended that secondary sub-items remained hidden until fulfillment of all the primary sub-items is confirmed in order to streamline the review process and avoid time being spent qualifying more subtle aspects of papers that may ultimately fail to meet the minimum requirement for guideline consideration.A wider pilot of the refined checklist  standardized instructions as to the use of the tool.As in the earlier pilot, raters were not allowed to review papers they had coauthored. Allocation of papers was otherwise random. As before, calculation of inter-rater variability (percentage agreement) was defined by consistent ratings  at a per-criterion level for each paper. Agreement results were then estimated for each paper at the item-, domain and global  level within each rater group and in sum across all rater groups.The results of the pilot were reviewed by the Task Force members at a face-to-face meeting at the 2015 European Respiratory Society Conference . Further qualitative feedback was invited from pilot raters to identify remaining opportunities to remove redundancies, potential ambiguity and associated inter-rater variability.The Task Force members implemented final rephrasing recommendations from the Phase V pilot and approved the tool for use for the primary Task Force CER literature review .To aid ease of RELEVANT implementation for the wider Task Force literature review , an onliMapping the quality recommendations within the primary reference papers Berger et al.  and RochEvaluation of inter-rater agreement of the initial tool indicated wide variation (50\u2013100%) in concordance across individual sub-items: <\u200960% for 8 of 25 sub-items; 60\u201367% for 10 of 25 sub-items and \u2265\u200980% for 7 of 25 sub-items. Domain-level agreement was similarly varied (50\u2013100%). The qualitative feedback suggested this variation was largely driven by differences in semantic interpretation of some of the sub-items and could be addressed by further removal of any redundancies and careful rephrasing and further, e.g. eliminating subjective words (replacing \u201crelevant\u201d with \u201cjustified\u201d) and splitting \u201cdouble-headed\u201d sub-items into separate, discrete sub-items.The 22 raters involved in the extended pilot came from a wide range of countries >\u200910) and included members of the REG collaborator group, EAACI Asthma Section Members, Global Initiative for Chronic Obstructive Lung Disease, Global Initiative for Asthma, the American Thoracic Society and the European Respiratory Society  exist for rating the quality of the best available evidence . Howeverpublished literature and so complements existing quality checklists, which have traditionally focused on quality markers for protocol and manuscript development and from a largely empirical  perspective. Initial drafts of the tool used wording from the previous quality assessment literature, but the pilot work revealed the potential for misinterpretation unless very precise language was used and each criterion had a singular and specific focus. Refer to the Roche and colleagues companion manuscript for clinical applications and evaluations that use the RELEVANT tool [RELEVANT enables quality appraisal of the ANT tool .RELEVANT was developed to assist clinical experts and guideline developers in appraising observational asthma CER study quality. Used in combination with other tools such as the GRADE, RELEVANT can help facilitate critical appraisal of observational studies as well as pragmatic trials and so contribute to a broader appraisal of the available asthma evidence base. It is a time efficient and user-friendly method of quality assessment and has potential utility as a teaching aid, manuscript development guide or as a tool for use by journal peer reviewers. Indeed, any researcher or clinician with the ability to critically read CER  should find the tool self-explanatory and potentially useful as a publication checklist as well as a framework for literature appraisal.RELEVANT development was an ancillary  step towards completion of the original Task Force\u2019s objective of conducting a quality appraisal of the observational asthma CER literature. As such, a quasi-pragmatic rather than entirely systematic and externally validated approach was taken. All primary and secondary sub-items featured in the tool were felt to be important (within the literature and by Task Force members), but expert opinion was used to differentiate between primary (mandatory) and secondary (complementary) sub-items to ensure RELEVANT was comprehensive but also relatively concise to aid in successful practical implementation. The final categorization was based on frequency of reference within the prior literature and on Task Force member consensus judgment. Prioritization and categorization of the primary/secondary sub-items within the checklist could be revisited and adapted for other purposes, as appropriate.While RELEVANT is intended as a tool to assist in the quality appraisal of observational CER, RELEVANT assessments are influenced by the quality of reporting of the research as much as the by the inherent quality of the study itself. While this may result in an under-estimation of the quality of the published work  the Task Force members felt this was unavoidable. An alternative approach could involve contacting each author group and offering them the opportunity to provide more information where a quality limitation resulted from a lack of available data, but there was insufficient Task Force resources available to permit this approach. This emphasizes the need for accurate and comprehensive reporting and the interest of protocol registration.While development of RELEVANT sought to remove subjective interpretation of the quality sub-items, the rater\u2019s appraisal of the fulfillment of the quality markers is unavoidably open to rater opinion and judgment. In turn, the appropriateness of such judgment is inherently affected by raters\u2019 experience and expertise with respect to observational CER. The majority of raters involved in the pilot work, however, were members of REG\u2014a group that has a particular focus on real-life research methods\u2014and so most participating raters would have had substantial prior knowledge and/or involvement in CER. This may have contributed to the high inter-rater agreement recorded especially during the extended pilot testing.There is a need for moderation in the recommended potential uses of the checklist tool to avoid it being widely adopted for purposes other than those for which it was designed. However, there are also potential opportunities to use the tool in training exercises to educate fellows, journals editors and reviewers as to what constitutes quality in CER. If the tool were introduced within graduate-level training, it may also have the potential to help shape and inform the design of more appropriate observational CER in the future.RELEVANT is a user-friendly quality appraisal tool comprising 21 quality sub-items  across seven core quality domains. It was developed to support quality review of observational asthma CER for the purposes of the joint REG-EAACI Task Force literature review, but is also now used among Task Force members to support their peer review activities for respiratory journals and to guide the development of their own research papers. It is the first of its kind to support quality appraisal of published research and to have been developed through iterative feedback derived from pilot implementation and inter-rater agreement evaluation.RELEVANT can be downloaded in Excel or pdf format from the REG  and EAACAdditional file 1. This file includes the goals of the Task Force, an intermediate item-reduce tool, and extended quality assessment tool pilot participants.Additional file 2. This maps the quality recommendations within the primary reference papers Berger et al and Roche et al that resulted in an initial 43-item checklist."}
+{"text": "Saccharomyces cerevisiae and 10 in Homo sapiens. CoQ has the capacity to accept and donate electrons and in cells is found in three different redox states: (i) oxidized (ubiquinone), semioxidized (semiubiquinone) and reduced (ubiquinol). Although CoQ is usually synthetized within the cell, it is possible to supplement this through diet. This characteristic has made CoQ one of the bestselling dietary supplements. Mutations in genes that encode for the multiprotein CoQ synthesis complex result in severe inherited diseases. Furthermore, mitochondrial diseases resulting from mutations in nuclear or mitochondrial encoded genes are often characterized by a secondary CoQ deficiency. A reduction in CoQ levels has also been observed during aging and in many other non-hereditary diseases  is a ubiquitous component of eukaryotic lipid membranes, where it participates in electron transfer and acts as a powerful antioxidant. CoQ has a benzoquinone ring and a polyisoprenoid tail that contains between 6 and 10 units depending on the species e.g., six in Hernandez-Camacho et al.) have reviewed the latest literature reporting the effects of CoQ supplementation on human health. The authors discuss studies reporting positive effects or lack thereof on aging and age-related pathologies. CoQ supplementation has been reported to alleviate disorders caused by mutations in the endogenous CoQ synthesis machinery . However, positive effects of CoQ supplementation in other disorders have also been reported . For example, modest improvements have been described in cardiovascular disease (the number one cause of death in western society) and neurodegenerative disorder . In addition, treatment with CoQ has been shown to have anti-inflammatory effects and a number of published reports suggest that combining CoQ with statins could prevent the side effects resulting from statin treatment.CoQ has been put forward as an anti-aging supplement as well as a potential treatment for several human diseases. In this special issue, Hernandez-Camacho and collaborators (Pierrel) discusses the possibility of using analogs of a CoQ precursor, 4-hydroxybenzoic acid, as a therapeutic alternative to restore electron flow in the inner mitochondrial membrane. To facilitate this, a better knowledge of the mechanisms responsible for CoQ biosynthesis (CoQ-synthome) and how the complex is regulated is necessary.Although, CoQ supplementation is the standard treatment for patients suffering from CoQ deficiencies, not all patients respond to this intervention. This is due in part to the poor bioavailability of CoQ. Fabien Pierrel  discuss how the redox state of CoQ impacts on whether ROS are produced in the forward or reverse direction by respiratory complex I and how ROS produced through reverse electron transport control important physiological functions including regulation of lifespan.Free radicals have long been thought to be responsible for aging and age-related diseases H:quinone acceptor oxidoreductase1 (NQO1) plays a central role in processes of stress adaptation including oxidative stress . Quinzii and col  explain the effects of CoQ deficiency on sulfide metabolism. One of the essential regulators of sulfide metabolism is sulfide:quinone oxidoreductase (SQOR) that oxidizes hydrogen sulfide transferring electrons to mitochondrial ubiquinone. Consequently, deficits in CoQ biosynthesis interrupt hydrogen sulfide oxidation and the production of glutathione. Furthermore accumulation of hydrogen sulfide can cause inhibition of respiratory complex IV further disrupting electron transport.CoQ is the electron carrier which connects enzymes that introduce electrons into the mitochondrial electrons transport chain to those that remove them. The former includes many enzymes that participate in important metabolic pathways such as iron sulfur cluster synthesis, nucleotide synthesis and sulfide metabolism  use the power of yeast genetics to study the role of COQ9 in the assembly and stability of the CoQ-synthome i.e. the multi-subunit complex that synthetizes CoQ in the mitochondrion. The authors perform a careful study where they interrogate the ability of human COQ9 to rescue mutations in its yeast homolog. They authors demonstrate that COQ9 restores CoQ biosynthesis under specific circumstances by increasing the stability of other components of the CoQ-synthome in coq9 mutants, but also show that certain properties of coq9  are not conserved. The approach used by He and collaborators can be extended to other genes involved in CoQ metabolism and mutated in human disease whose function has not been fully characterized.Finally, we have an original article where He and collaborators (AS and PN were in charge of the review process of the papers published in the Research Topic of Frontiers entitled The Redox State of Coenzyme Q and Cellular Homeostasis that are summarized in this editorial.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Cancer develops when pathways controlling cell survival, cell fate or genome maintenance are disrupted by the somatic alteration of key driver genes. Understanding how pathway disruption is driven by somatic alterations is thus essential for an accurate characterization of cancer biology and identification of therapeutic targets. Unfortunately, current cancer pathway analysis methods fail to fully model the relationship between somatic alterations and pathway activity.To address these limitations, we developed a multi-omics method for identifying biologically important pathways and genes in human cancer. Our approach combines single-sample pathway analysis with multi-stage, lasso-penalized regression to find pathways whose gene expression can be explained largely in terms of gene-level somatic alterations in the tumor. Importantly, this method can analyze case-only data sets, does not require information regarding pathway topology and supports personalized pathway analysis using just somatic alteration data for a limited number of cancer-associated genes. The practical effectiveness of this technique is illustrated through an analysis of data from The Cancer Genome Atlas using gene sets from the Molecular Signatures Database.Novel insights into the pathophysiology of human cancer can be obtained from statistical models that predict expression-based pathway activity in terms of non-silent somatic mutations and copy number variation. These models enable the identification of biologically important pathways and genes and support personalized pathway analysis in cases where gene expression data is unavailable.The online version of this article (10.1186/s12859-018-2476-8) contains supplementary material, which is available to authorized users. High-throughput genomic assays have revolutionized our understanding of cancer. Projects such as The Cancer Genome Atlas (TCGA)  and the To interpret cancer genomic data at the level of biological pathways, researchers have developed a large number of pathway analysis methods, many specifically customized for cancer data . For theAlthough the pathways most commonly impacted by somatic alterations in cancer have been identified  and signIdentify pathways that play an important role in the pathophysiology of human cancers.Identify genes whose somatic alterations are significantly associated with pathway activity.Support personalized pathway analysis using only somatic alteration data for known cancer genes.To address these limitations, we have developed a new multi-omics pathway analysis method for cancer genomic data that aims to: To achieve these aims, our method jointly analyzes gene expression and somatic alteration data from human tumors to build statistical models that predict the subject-level pathway activity in terms of the somatic alterations of known cancer genes. Importantly, this method does not require data from matched controls and can analyze pathways lacking topological information. This design is motivated by our hypothesis that biologically important pathways are those for which expression-level activity of the genes in the pathway relative to other cancers of the same type can be well predicted by the somatic alterations present in the tumor. To realize our method, we leveraged three important advances in cancer genomics and biostatistics, namely the development of large cancer genomics data sets that combine gene expression and somatic alteration data, e.g., TCGA , the crehttp://www.dartmouth.edu/hrfrost/MutPath/. This website also contains detailed information on the regression models fit using this approach. Reflecting the data sources used to evaluate our method, Fig.\u00a0Our approach, illustrated in Fig.\u00a0Our method first determines the activity of each candidate pathway within each tumor relative to other tumors of the same cancer type. This step is performed using the single-sample pathway analysis method gene set variation analysis (GSVA)  which taOur approach next determines how well the expression-based activity of each pathway can be predicted from gene-level somatic alterations. This step is performed via the regression of the single-sample pathway scores computed in Step 1 on gene-level indicators of non-silent somatic mutations and copy number variation (CNV) values. These models are estimated using LASSO-penalized multiple linear regression  with theentclass1pt{minimaUsing the regression models estimated in Step 2, one or more of the primary aims can be addressed:Aim 1. To identify biologically important pathways, the pathways are ranked according to the mean Aim 2. To identify genes whose somatic alteration is associated with pathway activity for a specific cancer type, the estimated coefficients for the mutation and CNV predictors in the unpenalized pathway regression models are inspected. If somatic alteration of a gene is retained as a significant predictor in the model for a specific pathway, the gene is deemed to be a potential driver for that pathway in the analyzed cancer type. A list of inferred driver genes for each cancer type can be generated by summarizing predictor significance across all pathway models while taking into account model predictive performance.Aim 3. The regression models estimated in the second step enable personalized pathway analysis using just somatic alteration data for a limited number of cancer-associated genes. Specifically, given tumor-specific mutational status and CNV values for the genes with non-zero coefficients in the LASSO-penalized models, it is possible to predict the activity of each evaluated pathway in that patient. When predictions are based on the unpenalized regression models, an approximate prediction interval can also be computed.R2 values generated for the pathways in the C2.CP collection for each supported TCGA cancer type  Does model predictive performance identify biologically important pathways?(Aim 2) Can the models be used to identify cancer driver genes?(Aim 3) Is model predictive performance sufficient for personalized pathway analysis?Can the models be used to characterize cancer subtypes?To evaluate our proposed method, we analyzed 20 TCGA cancer types using gene sets from the MSigDB curated canonical (C2.CP) and oncogenic signatures (C6) collections  for the predictor in the unpenalized model) and model To ascertain if the models can identify known cancer driver genes, we ranked the somatic alteration predictors for each cancer type according to predictor significance in the pathway models. Specifically, alterations were ranked according to a weight computed as the average across all pathway models in a specific MSigDB collection of the product of predictor significance , errors in the gene-level estimates of non-silent somatic mutations and copy number variation, sparsity of the somatic alteration data, and the fact that the employed non-silent mutation indicators fail to distinguish between gain-of-function and loss-of-function mutations. An additional limitation associated with the leveraged TCGA data is the fact that somatic alteration data types like methylation, mutations of non-protein coding genes and structure features such as fusions and translations are not included as predictors in the regression models. Although the COSMIC cancer gene census provides a comprehensive list of genes with a known cancer association, the census does not quantify the degree or direction of association, provides only approximate cancer type associations for each gene, and likely misses many genes that have a true link to cancer. Limitations of the gene set collections in MSigDB include the variable quality of annotations, bias in pathway annotations , the fact that the analyzed MSigDB pathways do not represent all potential cancer-related pathways, and overlaps between the members of many pathways. An important implication of our use of curated pathways from MSigDB is that our method is unlikely to identify truly novel pathway-cancer associations. The statistical model used to predict pathway activity only includes copy number alterations and indicators of non-silent somatic alterations as predictors; other genomic features that are known to impact gene expression such as epigenetic changes , translocations, gene fusions and mutation of non-protein coding genes are ignored. Given the unknown marginal and joint distribution of the Possible extensions to this method include support for additional data types, modifications to the statistical model, exploration of cancer subtypes, validation on other cancer genomics data sets and creation of tools to support personalized pathway analysis on new tumor genomic data. To more accurately model the somatic alterations that drive gene expression, the current approach can be expanded to include epigenetic modifications , mutations of non-protein coding genes, and features such as gene fusions and translocations as predictors in the regression model. An important issue that must be address in future efforts to integration additional predictor variables will be the limited available of many of these additional genomic data types. Potential enhancements of the statistical model include the addition of interaction terms, predictor weighting based on prior knowledge regarding the role of specific genes in cancer and modification of predictor weights to account for the overlap between pathways. To support formal statistical analysis of the We have developed a new approach for the pathway-based analysis of multi-omics cancer data. Our approach combines single-sample pathway analysis with multi-stage, lasso-penalized regression to find pathways whose gene expression can be explained largely in terms of the non-silent somatic mutations and copy number variations present in the tumor. This method enables the identification of biologically important pathways and genes and can be used for personalized pathway analysis in cases where gene expression data is unavailable. Importantly, this method can be used on case-only data sets and does not require information regarding pathway topology. An analysis of 20 human cancer types using TCGA genomic data and MSigDB gene sets illustrates the effectiveness of our technique. These analysis results also provide cancer researchers with ranked lists of pathways and genes that likely play a key role in the etiology of these cancer types, information that can be used to generate hypotheses for more detailed experimental exploration of cancer pathways and novel driver genes.Additional file 1Additional results and details on the computational pipeline, analyzed data sets and logic used to generate all tables and figures. (PDF 1772 kb)"}
+{"text": "Educational pipelines are effective in medical education with minority student populations. The University of South Alabama has a successful medical pipeline in the NIH/NIMHD-funded USA Center of Excellence \u2013 but no formal pipeline to support entry into careers in aging. In Gerontology and Geriatrics, the preponderance of pipelines focuses on students in advanced degree programs. The need remains largely unmet to inform young students about careers and research pathways in Gerontology before career and academic plans are established. The USA Gerontology Club initiated a student-led outreach to deliver information about careers in aging and academic programs in Gerontology and Geriatrics to high schools in communities with high health disparities. The program seeks to develop peer relationships with high school students to introduce them to careers in aging and related academic opportunities. The presentation includes barriers identified and development of a multi-phased, multi-disciplinary model leading to a formal pipeline for Gerontology."}
+{"text": "Disability-Adjusted Life Years (DALYs) are an established method for quantifying population health needs and guiding prioritisation decisions. Global Burden of Disease (GBD) estimates aim to ensure comparability between countries and over time by using age-standardised rates (ASR) to account for differences in the age structure of different populations. Different standard populations are used for this purpose but it is not widely appreciated that the choice of standard may affect not only the resulting rates but also the rankings of causes of DALYs. We aimed to evaluate the impact of the choice of standard, using the example of Scotland.DALY estimates were derived from the 2016 Scottish Burden of Disease (SBoD) study for an abridged list of 68 causes of disease/injury, representing a three-year annual average across 2014\u201316. Crude DALY rates were calculated using Scottish national population estimates. DALY ASRs standardised using the GBD World Standard Population (GBD WSP) were compared to those using the 2013 European Standard Population (ESP2013). Differences in ASR and in rank order within the cause list were summarised for all-cause and for each individual cause.The ranking of causes by DALYs were similar using crude rates or ASR (ESP2013). All-cause DALY rates using ASR (GBD WSP) were around 26% lower. Overall 58 out of 68 causes had a lower ASR using GBD WSP compared with ESP2013, with the largest falls occurring for leading causes of mortality observed in older ages. Gains in ASR were much smaller in absolute scale and largely affected causes that operated early in life. These differences were associated with a substantial change to the ranking of causes when GBD WSP was used compared with ESP2013.Disease rankings based on DALY ASRs are strongly influenced by the choice of standard population. While GBD WSP offers international comparability, within-country analyses based on DALY ASRs should reflect local age structures. For European countries, including Scotland, ESP2013 may better guide local priority setting by avoiding large disparities occurring between crude and age-standardised results sets, which could potentially confuse non-technical audiences. A Burden of Disease (BoD) approach can be used to summarise the debilitating effects of morbidity and premature mortality in a population in a consistent and comparable manner. This is achieved by framing the effects of morbidity and mortality as population health loss as a function of time, in a composite measure called Disability-Adjusted Life Years (DALYs) . By framThe Global Burden of Disease (GBD) study  providesIn order to retain international and temporal comparability it is essential that estimates are adjusted to reflect potential differences in population demographic structures between comparator groups. The most common approach to achieve this in BoD studies is to calculate directly standardised rates per 100,000 population. This is accomplished by applying a common reference population age structure to the populations which are being compared. This allows for the creation of artificial rates that provide the hypothetical scenario that would have occurred had the two populations being compared had the same age distribution. In BoD studies the most common approach is to compute age-standardised rates (ASR) using the GBD 2017 World Standard Population (GBD WSP)  as commoThe primary aim of a BoD study is to identify the impact of health problems and causes of death in a consistent and comparable manner between causes, sub-groups, locations and time, which is facilitated by using DALYs . From a The aim of our study was to evaluate the impact that the choice of method used for rate calculations (crude or age-standardised) has on the DALYs ranking and rate of causes of disease/injury. This was carried out by comparing crude and age-standardised rates, and assessing differences between age-standardised rates derived using different standard populations (ESP2013 and GDB WSP). We illustrate this using the example of Scotland.Estimates of the number of DALYs were derived from the Scottish Burden of Disease (SBoD) 2016 study . Two difThe unit of analyses used in this study was all ages and both sexes. DALYs were summed to give the observed number of all-cause DALYs and DALYs for 68 causes of disease/injury. Crude rates were calculated by dividing the number of DALYs by the three-year average annual (2014\u201316) Scottish national mid-year population. Two different methods of directly calculating ASR were calculated for all-cause DALYs and DALYs for 68 causes of disease/injury using the ESP2013 and GBD WSP, with an upper age-group of 90\u2009years and above and the under 5\u2009years age-group being split into under 1\u2009year and 1 to 4\u2009years.The SBoD 2016 study directly standardised rates to the ESP2013 to facilitate comparisons across different sub-national areas, therefore this was assessed as the baseline position when comparing standardisation methods. The main study outcome was to assess the absolute and relative difference of ASR of all-cause DALYs and ASR of DALYs for 68 causes of disease/injury, between rates standardised using GBD WSP compared with ESP2013. Causes of disease/injury were ranked by their respective crude rates of DALYs and rankings of ASR using ESP2013 were compared with those using GBD WSP.Formal permission to access linked patient-level National Health Service (NHS) administrative databases as part of the SBoD study was granted by the Privacy Advisory Committee, NHS National Services Scotland (NSS) [PAC Reference 51/14] [25]. All summary data used in this study are provided  mid-year estimate of the Scottish national population is shown in Fig.\u00a0The number of DALYs over the three-year annual average across 2014\u201316 was 1,305,004  for: tracheal, bronchus and lung cancer (3 places); cerebrovascular disease (5 places); Alzheimer\u2019s and other dementia\u2019s (7 places); and chronic obstructive pulmonary disease (4 places). Other increases in rank within the leading 10 causes occurred for: migraine (4 places); drug use disorders (4 places); and anxiety disorders (4 places). Additionally sensory disorders and other cancers which were ranked outside the leading conditions moved up 4 and 2 places respectively and were ranked within the leading 10 causes when ranked based on ASR (GBD WSP). The largest change in rank (ESP2013 vs. GBD WSP) across the full abridged cause list was for neonatal disorders which increased 23 places.The five causes with the largest reductions in ASR of DALYs (GBD WSP vs. ESP2013) were ischaemic heart disease , Alzheimer\u2019s and other dementia\u2019s (\u2212\u2009539), cerebrovascular disease (\u2212\u2009493), tracheal, bronchus and lung cancer (\u2212\u2009445), and chronic obstructive pulmonary disease (\u2212\u2009396)  were Alzheimer\u2019s disease (\u2212\u200954%), atrial fibrillation and flutter (\u2212\u200949%), Parkinson\u2019s disease (\u2212\u200949%), peripheral artery disease (\u2212\u200947%) and prostate cancer (\u2212\u200947%). The five causes with the largest gains in ASR of DALYs (GBD WSP vs. ESP2013) were sudden infant death syndrome (+\u200983%), neonatal disorders (+\u200982%), congenital birth defects (+\u200935%), maternal disorders (+\u200919%) and transport injuries (+\u20096%).Overall, 58 out of a total of 68 causes of disease/injury had lower DALY ASRs (GBD WSP vs. ESP2013). The largest absolute and relative changes in ASR of DALYs were observed for conditions that were leading causes of mortality and that occurred at older ages. The balance in the scale of change was largely due to reductions in ASR and where increases in ASR were observed, they tended to be much smaller.Our study found that the ranking of causes of disease/injury were similar between ranks based on crude rates of DALYs and ranks based on age-standardised rates of DALYs using ESP2013 as the reference population. On the other hand, there were large scale differences in the absolute and relative scale, and in rank order, between causes of disease/injury when rates were age-standardised using GBD WSP as the reference population compared with the ESP2013 or crude rate methods. The largest absolute reductions between standardisation methods were observed in those causes of disease/injury where onset occurs at older ages such as ischaemic heart disease, Alzheimer\u2019s disease and other dementias, and cerebrovascular disease. Overall, the use of GBD WSP in standardised rate calculations reduced rates. The ranking of conditions also changed due to the differences in age-groups weights between the two different standard populations. Some causes of disease/injury where the burden is experienced early in the life course, saw large relative, but small absolute, increases in rate, such as neonatal disorders, congenital birth defects and sudden infant death syndrome.The major strength of this study is that it assesses the effect of different methods of age-standardisation of rates in an objective way using a comprehensive national assessment of BoD. All other parameters remained constant through the analysis so that the impact of the choice of standard population could be illustrated. A possible limitation of the study is the need to truncate the oldest open-ended age-group to 90\u2009years and above to allow for the same age-groups to be used. As the 90\u2009years and above age-group represent less than 1 % of the Scottish population any effect on these findings would be small.There are currently no published literature appraising the impact of using different standard population structures to directly age-standardise rates of DALYs. Interrogation of GBD estimates for the United Kingdom (UK) via the GBD country profiles highlights the disparities in different ways of ranking causes of disease/injury  Surveillance, Epidemiology and End Results programme, which has standardised rates to the US standard population for some time . The AusThese results demonstrate the importance of the choices researchers make when designing BoD studies as a means for supporting evidence-based decision making. This study serves as an important reminder that the use of different reference populations in rate calculations can significantly impact both rates and rankings, which are both crucially important in BoD studies.Currently BoD work internationally focuses on advocating for better country-specific prevalence data as an input, which would have clear benefits. However, it is important to note that improvements to other inputs, such as severity distributions, also have significant potential to improve these estimates . This stFrom the perspective of international comparisons the use of world standard populations in rate calculations remains a valid approach. As more users become interested in the value of BoD estimates primarily to influence national and local policy decisions, the consistency and comparability of estimates across causes must be retained and key messages must be clear. Those using GBD estimates locally for prioritisation must ensure that they consider consistency and comparability of estimates across causes rather than merely comparability across time and countries. For users of the GBD, this can currently be done by using the GBD country profiles , GBD resIn the interests of comparability across the sub-national regions of Scotland our findings support the use of ESP2013 to calculate DALY ASRs as a means of achieving comparability over sub-national regions. We recommend that high-income and European countries, such as those involved in the European Burden of Disease Network (EBoDN) , 22 use Additional file 1. Dataset containing number and rates of DALYs by cause of disease/injury, Scotland, 2014\u201316.Additional file 2. Summary of GBD 2017 results from GBD country profile for the United Kingdom."}
+{"text": "In the original article  referencThe Procedures section  states: \u201cThe Hawk-Eye system (Hawk-Eye SMART productions) was used for matches in the current study; however, this was not available at any of the matches played in South Africa during the 2015 season.\u201dThis sentence should read: \u201cEither commercial or non-commercial video systems were used for matches in the current study; however, these were not available at any of the matches played in South Africa during the 2015 season.\u201dThe Analyses section  states: \u201cThirdly, the effectiveness of sideline video review for identifying HIEs was evaluated by comparing the number of additional HIEs detected on retrospective post-season review between matches with and without the Hawk-Eye system available.\u201dThis sentence should read: \u201cThirdly, the effectiveness of sideline video review for identifying HIEs was evaluated by comparing the number of additional HIEs detected on retrospective post-season review between matches with and without the sideline video system available.\u201dThe Hawk-Eye system is mentioned on two occasions in the article:"}
+{"text": "Technological advances have made it possible to capture a specific assembly of neurons active during a learning event and manipulate the captured cells, demonstrating some form of relationship between brief retention events and the cell assembly. The reductionists' claim of localizing the engram has been met with considerable skepticism. The potential for off-target effects in \u201ccell capture\u201d techniques, such as optogenetics, reveal serious limitations when given the highly interconnected nature of brain networks beyond a selective assembly of cells in a restricted area of manipulation. Recent studies of subcortical-cortical interactions prompted us to review the historic search for the engram, revealing a parallel between the empirical attempts to localize the engram in cortical then subcortical systems. When brought together conceptually, the very extensive independent work of Karl Lashley and Robert Thompson suggest that each held a piece of the puzzle. Recent research implicates the interaction between subcortical memory systems and association cortex in the transformation of mnemonic information from a short-term process of plasticity to a long-term state of stability. We propose that one function of subcortical-cortical connectivity is to continuously update contextually retrieved long-term memory during reconsolidation of newly acquired information processing, creating a constantly evolving emergent engram.Researchers claim to now \u201ccapture\u201d activated cells allocated during a learning experience to represent an enduring change among an assembly of neurons called an engram , its general idea is prevalent throughout contemporary memory research. Indeed, it is prominent throughout cognitive psychology, e.g., in the writings of Endel Tulving with the emergence of multiple memory systems Tulving,  among otThe recent physiological findings described above are consistent with previous studies of coordinated activity within several interactive systems. For example, associative learning of a spatial discrimination was related to fast oscillations or pronounced ripple activity in the hippocampus (Ramadan et al., The interactions among subcortical memory systems and the coordination of spatial processing within the hippocampus and the thalamocortical output of basal ganglia loops (Alexander et al., In summary, the historical search for the engram identified ascending vertical subcortical-cortical networks supporting consolidation processes in studies using the latest technology (Khodagholy et al., BD conceived of idea talking with RM regarding a previous paper. Worked on a novel conceptualization of the engram with the other authors. KB worked on historical account, and the novel conceptualizations with other authors. RB wrote a critical commentary on a high profile journal article using the term engram and helped BD to conceptualize the new emergent engram framework.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The mammalian dura mater encephali is richly supplied by trigeminal nerve fibers, a considerable proportion of which contains calcitonin gene-related peptide (CGRP). As plasma levels of CGRP are increased in some forms of headaches, the question is in which way CGRP is involved in nociceptive mechanisms within the peripheral and the central trigeminovascular system."}
+{"text": "Nursing home residents with and without cognitive impairment (N=38) answered open-ended questions about their day-to-day social interactions and ongoing relationships with family and friends. One author (SW) completed a conventional content analysis of the transcripts and the other (AW), a phenomenological-hermeneutic analysis. Findings from these analyses were combined and examined further using data from measures of social cognition and staff ratings of social behavior. Participants\u2019 social experiences appeared to be determined not only by long-established habits and preferences and length of nursing home stay but also by their cognitive status and social cognition competencies. A central theme was the importance of managing ongoing relationships and day-to-day interactions so as to reduce one\u2019s own stress as well as the burden on others. This presentation details how findings from distinct analytic strategies were combined to characterize the researchers\u2019 understanding of participants\u2019 lives in their networks of care from their own perspective."}
+{"text": "Throughout evolution, endocrine physiology has utilized the development of competitive positive and negative receptor mediated feedback signaling to produce checks and balances for the appropriate regulation of host growth and reproduction based upon environment inputs. The importance of such checks and balances was acknowledged by the awarding of the Nobel Prize in Physiology and Medicine in 1977 to Roger Guillemin and Andrew V. Schally for their discoveries concerning the agonist peptide releasing hormones as the main link between the brain and the pituitary as the central regulator control of reproductive functions in mammals [Based upon these understandings, LHRH peptide \u201csuper\u201d agonist analogs have been synthesized incorporating modified amino acids to stabilize them from the usual rapid proteolytic degradation of the natural agonist . An unexSuch a paradoxical overcoming of normal endocrine checks and balances by a pituitary super-releasing hormone agonist is not limited to LHRH analogs. For example, Tengjiao Cui and Andrew V. Schally report in this issue of ONCOTARGET that treatment with GHRH super-agonists have anti-cancer efficacy against human cancer xenografts via their ability to inhibit the synthesis and release of Insulin-like Growth Factor 1(IGF-l) by normal liver tissue and in tumors . These a"}
+{"text": "Recent evidence suggests that physical and mental health are influenced by an intricate interaction between genes and environment. Environmental factors have been shown to modulate neuronal gene expression and function by epigenetic mechanisms. Exposure to these factors including nutrients during sensitive periods of life could program brain development and have long-lasting effects on mental health. Studies have shown that early nutritional intervention that includes methyl-donors improves cognitive functions throughout life. Choline is a micronutrient and a methyl donor that is required for normal brain growth and development. It plays a pivotal role in maintaining structural and functional integrity of cellular membranes. It also regulates cholinergic signaling in the brain via the synthesis of acetylcholine. Via its metabolites, it participates in pathways that regulate methylation of genes related to memory and cognitive functions at different stages of development. Choline-related functions have been dysregulated in some neurodegenerative diseases suggesting choline role in influencing mental health across the lifespan. Emerging evidence suggests that environmental factors such as repeated exposure to drugs of abuse, stressors, lifestyle factors such as physical activity and diet have substantial effects on mental health and well-being. These factors interact with genes and modulate their expression and function by epigenetic mechanisms . DysreguThe role of the micronutrient choline and other methyl-donors in normal fetal growth and development has been well studied ,7. RecenCholine is not only an essential micronutrient needed for proper organs\u2019 functions but also a neuroprotectant needed for normal development and growth of fetal brain ,14. BesiIn this review, we will focus on the role of the micronutrient choline as a neuroprotectant and summarize research findings that demonstrated a link between maternal supplementation of dietary choline and improvement of cognitive abilities during early development. We will also summarize findings that suggested the potential use of this micronutrient in combination with other methyl-donors to delay or prevent decline in cognitive functions in the aging brain and in some neurodegenerative diseases such as Alzheimer\u2019s disease. At the end of this review, we will address the adverse effects of inadequate supplementation of methyl-donors on neurodevelopment and cognitive functions.The Food and Nutrition Board of the Institute of the National Academy of Sciences of the United States recommends an adequate intake (AI) of 7.5 mg of choline daily per kg of body weight in humans . The AmeCholine and other methyl-donors have prominent role at the level of the brain. Several studies conducted in humans and animal models demonstrated that depletion or supplementation of choline during sensitive periods of brain development such as prenatal, perinatal or early postnatal life contributes to the etiology of neural tube defects ,42. The Choline is classified as an essential micronutrient by the Food and Nutrition Board (FNB) of the Institute of Medicine of the National Academy of Sciences. It is naturally derived from wide variety of foods such as eggs, beans, fish, nuts, seeds, whole grain, some meats and vegetables from which we obtain our needs . The endThe levels of free choline and its metabolites increase in the brain of humans and rodents after ingestion ,58, suggCholine is the precursor for several membrane phospholipids such as PC, PE and sphingomyelin (SM). These choline-containing phospholipids maintain structural and functional integrity of cellular membranes including neuronal membranes. They also participate in other physiological processes essential for normal brain development and functioning including cellular signaling, neuronal myelination and division ,65,66. CCholinergic neurotransmission has been shown to be dysregulated in many neurodegenerative disorders such as Alzheimer\u2019s disease (AD) and this dysregulation may have contributed to neurocognitive impairments often seen in these patients . PostmorCholine has three methyl groups attached to the nitrogen atom of ethanolamine. It indirectly donates its methyl groups and participate in folate-mediated 1C metabolism for the formation of SAM via its oxidation to betaine by choline oxidase. SAM donates methyl groups to DNMTs that catalyze DNA methylation or HMTs that catalyze histone methylation, two key epigenetic mechanisms that modulate gene expression  Figure . SeveralStudies have shown that dietary components interact with our epigenome and could have long-lasting effects ,71. In tDietary components intake during early life could exert long-lasting effects on mental health  as the bAnimal studies have shown that choline supplementation or depletion during sensitive periods of life such as prenatal, perinatal or adolescence has consequences on neuronal activity and brain function of adult offspring later in life. In the context of cognitive functions, prenatal or perinatal choline supplementation improved animals\u2019 performance in memory-related tasks later on in life ,47,75,76Other studies conducted in rodents assessed the effects of methyl-donors deficiency on learning and memory. Mice fed with a diet deficient in folate, methionine and choline (FMCD mice) for 3 weeks during the adolescent period showed impairment in specific tests such as novel object recognition and fear extinction . At the In the context of histone mark changes or histone methylation changes, iron-deficiency in the fetal-neonatal period induced a change in the methylation of the brain-derived neurotrophic factor (Bdnf) promoter in the rat hippocampus and caused an elevation in the repressive histone marks such as H3K9me3 but a decrease in the activation histone mark H3K4me3 along Bdnf . These cThe effects of choline on the symptoms of genetically-related neurological disorders such as Down Syndrome and Rett Syndrome were also studied. A mouse model of Down Syndrome (Ts65Dn) is characterized by depletion of basal forebrain cholinergic neurons and an impairment in functions related to attention, cognition and memory, symptoms often seen in Alzheimer\u2019s disease. Maternal perinatal choline supplementation in this mouse model improved these functions in the adult offspring . Rett SySeveral human studies demonstrated the beneficial effects of gestational choline or maternal intake of methyl donors on cognitive functions in offspring during childhood. These effects were manifested as improvement in memory, attention and problem solving and lasted till children school age years ,86,87. OThe quality and quantity of nutrients that we are exposed to could shape our long-term well-being and mental health. Gene-nutrient interaction is quite complex and has been shown to be regulated by epigenetic mechanisms ,88. The Several studies reported an overall decrease in DNA methylation in Alzheimer\u2019s disease brains. This change was associated with hypomethylation of the amyloid precursor protein (APP) gene promoter with an increase in the expression of APP and an increase in beta-amyloid plaques deposition in specific areas of the brain . Beta-amCholine-containing compounds such as choline alphoscerate or glycerophosphocholine (GPC) and CDP-choline have been used in limited clinical studies and have shown promising neuroprotective effects and a role against age-related dementia . CholineA recent study demonstrated a transgenerational effect of choline on brain functioning in a mouse model of AD . Folate +/-) or \u201cmild Mthfr deficiency\u201d showed impairment in short-term memory function, increased anxiety and disruption in choline metabolism in the cortex and the hippocampus during the first 10 months of life with a decrease in hippocampal Bdnf gene expression. Mthfr+/+ mice fed with low dietary folate showed a decrease in SAM levels and Ach, alteration in the expression of synaptic markers (such as synpatophysin), Bdnf, epigenetic enzymes  and enzymes of 1C metabolism in the cortex or the hippocampus [Another study demonstrated both genetic and nutritional contribution of the methyl donor folate to changes in cognitive functions and brain biochemistry . Mice wipocampus . These fLimited human studies showed promising results of increasing choline and other methyl-donors intake on improving cognitive functions or some aspects of memory later in life. For example, the use of a combination of several methyl-donors including choline, VitB12, VitB6 and folic acid had promising results in patients with early Alzheimer\u2019s disease (AD). These patients showed improved memory and enhanced cholinergic signaling . The autSimilarly, a nutrient supplement \u201cSOUVENAID\u201d that consists of uridine, omega3-fatty acids (DHA) and choline improved memory scores in patients with early AD and resulted in an increase in synapses and neuronal communication in different brain regions ,106. It Another study aimed at comparing the levels of nutrients such as choline, folate, and homocysteine in the blood and CSF of AD patients and patients with mild cognitive impairments. Alzheimer\u2019s disease (AD) patients had high CSF homocysteine levels but low levels of plasma choline whereas patients with mild cognitive impairments showed low CSF folate and high CSF homocysteine compared to controls . These rDetection of biomarkers of dementia, which is often seen in Alzheimer\u2019s disease patients is now considered an essential tool in preclinical diagnosis or prognosis of this disease . A humanUptake of choline by the brain from circulation decreases significantly with aging , which mAnimal studies showed that excessive or inadequate intake of methyl-donors has adverse effects on neurodevelopment and cognition. For example, prenatal supplementation of high levels of folic acid (10 times the levels of the control group) resulted in structural, behavioral and molecular changes . At embrAnother animal study demonstrated the adverse effects of excess intake of methyl-donors during adolescence . AdolescA human study assessed the effects of folic acid supplementation during pregnancy on neurodevelopment in the first year of infant life . InfantsThese selected studies that we summarized above demonstrate that the dose and duration of methyl-donors\u2019 supplementation at critical stages of neurodevelopment are quite important factors to optimize. The current clinical literature and research about this is limited and not conclusive and there are still challenges to face about the ramifications of nutrients supplementation and in particular methyl-donors supplementation on neurodevelopment and cognitive functions. Methyl donors affects the availability of SAM and modulate epigenetic mechanisms such as DNA methylation or histone methylation and impact neuronal gene expression and activity. The effects of supplementation of these nutrients should be further investigated in animals and in humans to ensure the safety of their intake at different stages of life to prevent undesired outcomes. Optimal and safe dosage of nutrient intake should then be determined at different stages of development and in neurodegenerative diseases. Public adherence to dietary recommendations for nutrients supplementation or intake such as methyl-donor supplementation should then be strongly emphasized and better communicated to patients by physicians and nutritional agencies to prevent or mitigate the adverse effects of inadequate nutrient intake on mental health. Educational programs should then be strongly supported to increase public and health professional awareness about the food sources and the beneficial effects of choline and other methyl donors in health across the lifespan. Choline importance in health and the necessity of increasing awareness about its intake in several populations was discussed at the 2018 Choline Science Summit. We refer the readers to an excellent current review about the outcomes of this Summit discussions for further information .Choline and other methyl-donors have been shown to have a role in normal neurodevelopment and neurocognitive functions. Choline is now considered a neuroprotectant that modulates expression of key genes related to memory, learning and cognitive functions by epigenetic mechanisms. This micronutrient is not only critical for normal growth and functioning of the early brain, but also may have promising effects in boosting brain functions and delaying or mitigating the decline in cognitive functions with aging and in neurodegenerative diseases such as Alzheimer\u2019s disease. Inadequate intake of methyl donors has also been shown to have adverse effects on neurodevelopment and cognition. The effects of choline and other methyl donors on brain functioning and the optimal dose for intake should be further investigated across all age ranges. Understanding the role of nutrients on mental health and how they interact with our genes throughout life are quite important. This may facilitate the adoption of a nutrition-based individualized approach that includes adequate methyl-donors supplementation early in life to achieve improved cognitive functions and better mental health later in life. This approach in combination with therapeutic drugs should also be carefully studied in the elderly as a viable option to mitigate the adverse effects of aging or neurodegenerative diseases on cognitive functions."}
+{"text": "OBJECTIVES/SPECIFIC AIMS: The objective of the present study is to determine if decreased adiponectin and increased leptin levels are associated with the development of MetS and identifiable endothelial dysfunction in a cohort of Hispanic pre-pubertal children. To do so we propose the following aims: (1) To measure expression of adiponectin and leptin levels in a Hispanic pre-pubertal cohort and determine their correlation with features of the MetS. (2) To perform proteomic analysis in a Hispanic pre-pubertal cohort. (3) Evaluate early onset of endothelial dysfunction and its correlation with expression of adiponectin and leptin levels in a Hispanic pre-pubertal cohort. METHODS/STUDY POPULATION: A cross-sectional pilot study will obtain a random representative sampling of children aged 6\u201312 years from all geographical areas of Puerto Rico. Children will be assessed regarding pre-pubertal status through Tanner staging and later divided into pre-MetS Versus MetS groups as well as controls. MetS will include children meeting 3 or more of the current International Diabetes Federation (IDF) criteria. Pre-MetS will include children with at least 1 criterion for MetS. Anthropometric data, blood pressure readings, ultrasound-based noninvasive testing for endothelial dysfunction, and laboratory assays will be performed to the study population and data analyzed for correlation. Total adiponectin and leptin levels will be measured using a commercially available quantitative sandwich enzyme-linked immunoassay test. The study will be submitted to the University of Puerto Rico Medical Sciences Campus\u2019 Institutional Review Board (IRB) for approval. Written consent and assent will be obtained from parents and children respectively to ensure patient anonymity. RESULTS/ANTICIPATED RESULTS: We hypothesize that low levels of adiponectin and high levels of leptin will correlate with features of the MetS as defined by the IDF consensus statement, as well as with clinical features of MetS in undiagnosed Hispanic pre-pubertal youth. We also hypothesize that non-invasive testing of endothelial function will correlate both with clinical features of the MetS and with low levels of adinopectin and high levels of leptin. DISCUSSION/SIGNIFICANCE OF IMPACT: The correlation of findings suggestive of endothelial dysfunction and biomarker expression (mainly adiponectin and leptin levels) in a pre-pubertal cohort has yet to be established and could also provide information regarding early atherogenesis in otherwise unidentified youth at risk. Therefore, by using a proteomic approach, this study aims to measure associations between clinical features of the MetS and expression of proteins associated with an adverse cardiometabolic profile in a Hispanic pre-pubertal population. We will concurrently measure the degree of endothelial dysfunction and evaluate whether a correlation exists between previously mentioned protein expression and early onset of dysfunction."}
+{"text": "There was enough evidence from this analysis to recommend an inquiry into the group\u2019s work, and their published outputs are likely to have been misleading researchers within the field of perioperative medicine for some years  . An additional 2-year follow-up study demonstrated an increase in long-term mortality in cancer patients who received 80% oxygen    systematic review, published in the Lancet in 2018, reported that liberal use of oxygen to maintain saturations above 96% was associated with increased in-hospital and 30-day mortality in acutely unwell patients \u2014unstable free radicals in part generated as by-products of oxidative phosphorylation in the mitochondrial electron transport chain  (Page et al. The dissonance between oxygen guidelines and evidence from both clinical outcomes and mechanistic research is reflected in prescribing practices amongst UK anaesthetists. A recent multi-site evaluation of practice demonstrated that intraoperative oxygen administration by anaesthetists varied widely from 25 to 100%, with no obvious down-titration of oxygen in response to sustained supra-normal blood oxygen levels (Morkane et al. the most common component of general anaesthesia, yet as a community, we appear to have little idea how much oxygen we should be prescribing for our patients and what pathophysiological mechanisms we should be basing this prescription on. This somewhat embarrassing paradox at the heart of anaesthetic practice requires urgent resolution if we are to reduce harm and improve the lives of those we care for during and after surgery.Despite a substantial number of high-quality cohort studies and clinical trials, there remains a paucity of high-quality evidence to demonstrate the physiological effects oxygen has during the perioperative period, particularly at a cellular level. Consequently, anaesthetic guidelines and recommendations for perioperative oxygen therapy currently remain poorly grounded in scientific understanding. We would argue that the revelations of the Myles, Carlisle and Scarr\u2019s manuscript on the Schietroma papers should be used to provide perioperative physicians and anaesthetists with a fresh opportunity to discuss oxygen prescribing practices and promote high-quality research in order to clearly define safe and effective care in this area. Oxygen therapy remains"}
+{"text": "Studies with established turf and golf courses have indicated minimal risk of nitrate pollution of groundwater resulting from turfgrass management, but soil nitrate flux in turfgrass sod production farms and golf courses has received less attention. Information about nitrate-N flux at a particular location can be helpful to the sod producer or the golf course manager when efficiently applying N fertilizers and minimizing risk of nitrate pollution. We used an ion exchange resin capsule system to continuously monitor soil nitrate-N fluxes at 12 sites in southern Rhode Island, including turfgrass sod production farms and a low-maintenance environment. Four capsules were placed in the soil at each site and retrieved at intervals coinciding with management and meteorological events to determine nitrate ion accumulation. We found that the golf course green exhibited significantly higher nitrate-N fluxes than the sod farms and the low-maintenance turf. There was significant interaction between sampling date and study site, indicating that seasonal variation in soil nitrate-N fluxes was affected by turfgrass management. The cultural practice of late fall fertilization to stimulate early spring growth in the following year appeared to present some risk of nitrate loss during the winter from the golf course greens in our region. We conclude that site-specific and time-relevant monitoring is needed to produce and manage turfgrasses in an environmentally sound manner."}
+{"text": "Though extracorporeal membrane oxygenation (ECMO) provides life-saving support, this intervention exposes patients to certain risks. Circulating free hemoglobin (fHb) resulting from mechanically induced hemolysis and insufficient haptoglobin/hemopexin may promote thrombosis within the ECMO circuit. Thrombi in the circuit can result in thromboembolic complications in these patients. Prevention of thrombus formation and propagation in the ECMO circuit may improve clinical outcome. fHb released during hemolysis has been shown to have multiple adverse effects, including thrombosis, but the mechanism by which fHb contributes to thrombosis in an ECMO circuit remains elusive. It is well established that (1) high shear stress generated in the circuit may cause hemolysis, and (2) plasma fibrinogen is adsorbed onto the inner tubing of the ECMO circuit over time. Plasma von Willebrand factor (pVWF) mediates platelet deposition at sites of vascular injury under high shear stress by sensing alterations in the hemodynamic environment. This biophysical property of pVWF that enables hemostasis may also contribute to the pathogenesis of ECMO-induced thrombosis. pVWF contains binding sites for both adsorbed fibrin(ogen) and fHb. High concentrations of fHb increase pVWF-mediated platelet adhesion and thrombus formation on a surface-adsorbed fibrin(ogen) under high shear stress. The molecular mechanism(s) by which fHb drives the conformation of pVWF into a prothrombotic state is currently unknown. Reduction of thrombotic risks during ECMO intervention warrants further investigations into the interaction between pVWF and fHb. Extracorporeal membrane oxygenation (ECMO) provides temporary multi-organ support for patients with congenital or acquired heart and/or lung disease or resuscitative support for patients with cardiopulmonary failure. ECMO functionally substitutes the heart and lungs by circulating blood through a gas exchanger similarly to a heart-lung bypass machine but for a longer duration. Patients supported with ECMO can present with both bleeding and thromboembolic risks despite close monitoring of systemic anticoagulation . BleedinIncreasing evidence suggests elevated levels of free hemoglobin (fHb) in blood of patients on ECMO are a major clinical complication , 4. Highvon Willebrand factor (VWF) is a multimeric glycoprotein that plays a critical function in mediating platelet adhesion and aggregation in hemostasis and thrombosis . The matNormally, plasma (p)VWF does not interact with circulating platelets unless it undergoes conformational changes. In hemostasis, when the integrity of the vessel wall has been compromised, pVWF quickly binds to components exposed in the subendothelial matrix  at high shear stress. This interaction provokes structural changes that expose the contact site for the platelet receptor GPIb\u03b1 in A1 domain of VWF, allowing circulating platelets to rapidly bind to the collagen-bound VWF , 15. On We and others have demonstrated the capacity of fHb to block the cleavage of VWF by ADAMTS-13 , 24. SomOn the other hand, we speculate that fHb causes thrombosis on surfaces with adsorbed fibrinogen (like the inner tubing of an ECMO circuit) by strengthening the interaction between VWF and GPIb\u03b1. The concept is based on our identification and characterization of a novel binding activity of fHb for the A1 domain of VWF and how this interaction seems to be associated with high levels of fHb and thrombosis in patients on ECMO . fHb binThe adsorption of plasma fibrinogen to biomaterials is a quick event that transforms the surface to one that promotes platelet adhesion and thrombus formation under high shear stress as seen in ECMO circuits . It is win vitro heparin had a weak inhibitory effect in reducing thrombosis in the presence of high levels of fHb . The more insights we gain from dissecting the molecular mechanisms by which fHb promotes thrombosis via VWF will lay the foundation for the development of potential therapies to prevent fHb-VWF binding and improve clinical outcome.MC, AY, and CV wrote this article. MC and CV designed and performed experiments.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Schizophrenia is a very complex syndrome that involves widespread brain multi-dysconnectivity. Neural circuits within specific brain regions and their links to corresponding regions are abnormal in the illness. Theoretical models of dysconnectivity and the investigation of connectomics and brain network organization have been examined in schizophrenia since the early nineteenth century. In more recent years, advancements have been achieved with the development of neuroimaging tools that have provided further clues to the structural and functional organization of the brain and global neural networks in the illness. Neural circuitry that extends across prefrontal, temporal and parietal areas of the cortex as well as limbic and other subcortical brain regions is disrupted in schizophrenia. As a result, many patients have a poor response to antipsychotic treatment and treatment failure is common. Treatment resistance that is specific to positive, negative, and cognitive domains of the illness may be related to distinct circuit phenotypes unique to treatment-refractory disease. Currently, there are no customized neural circuit-specific and targeted therapies that address this neural dysconnectivity. Investigation of targeted therapeutics that addresses particular areas of substantial regional dysconnectivity is an intriguing approach to precision medicine in schizophrenia. This review examines current findings of system and circuit-level brain dysconnectivity in treatment-resistant schizophrenia based on neuroimaging studies. Within a connectome context, on-off circuit connectivity synonymous with excitatory and inhibitory neuronal pathways is discussed. Mechanistic cellular, neurochemical and molecular studies are included with specific emphasis given to cell pathology and synaptic communication in glutamatergic and GABAergic systems. In this review we attempt to deconstruct how augmenting treatments may be applied within a circuit context to improve circuit integration and treatment response. Clinical studies that have used a variety of glutamate receptor and GABA interneuron modulators, nitric oxide-based therapies and a variety of other strategies as augmenting treatments with antipsychotic drugs are included. This review supports the idea that the methodical mapping of system-level networks to both on (excitatory) and off (inhibitory) cellular circuits specific to treatment-resistant disease may be a logical and productive approach in directing future research toward the advancement of targeted pharmacotherapeutics in schizophrenia. Hints of altered neural circuitry, for example delays in gross and fine motor skill development, often evolve during childhood and may precede the first subtle signs of psychosis during late adolescence in those who will develop the illness (Treatment-resistant schizophrenia (TRS) remains one of the greatest therapeutic challenges in psychiatry. Schizophrenia is a complex neurodevelopmental syndrome; with disease processes occurring  illness \u20134. Adole illness \u20138. The g illness . Even wi illness , 11.Identifying treatments that will benefit patients with TRS remains a significant challenge. Our understanding of personalized treatment response and resistance to medication is limited by an inability to accurately pinpoint the individual genetic, cellular and neural circuit drivers of psychoses. Investigations of neuronal ensembles and cortical networks at the micro-scale level are not possible using the clinical diagnostic and macro-scale imaging tools that are currently available. Moreover, inconsistent clinical definitions of positive, negative or cognitive symptom-specific differences in TRS lead to ambiguous treatment guideline recommendations and a wide variation in clinical approaches to treat TRS in practice. Different phenotypes of psychoses may respond to different targeted treatments that are cellular or neural circuit-specific, but at present we do not have the ability to identify the appropriate targeted therapies for different TRS phenotypes.The Treatment Response and Resistance in Psychosis (TRRIP) working group recently addressed these challenges . MembersTreatment resistance has been most characterized in schizophrenia by how responsive the positive symptom domain is to antipsychotic medications. It is estimated that 70\u201380% of patients with schizophrenia have a phenotype of psychosis that is responsive to dopamine-blocking treatment . HoweverMany treatment-refractory patients present with a psychosis that is positive symptom domain responsive, but have symptoms that are non-responsive within the negative or cognitive symptom subdomains and associated circuits. It is now recommended that patients with symptom profiles that do not respond to antipsychotic medication and are considered treatment resistant be identified as: TRS-positive symptom domain-, TRS-negative symptom domain-, and TRS-cognitive symptom domain-specific. For those patients with combined treatment resistance in more than one domain , identifying all of those specific symptom domains will provide further clarification .2)-blocking agents at therapeutic doses for at least 6 weeks, clozapine is the recommended drug of choice. An estimated 30\u201360% of these patients will respond to clozapine and have what can be described as a clozapine-responsive psychosis  receptor and GABA interneuron modulators as well as nitric oxide (NO)-based treatments may be applied within a circuit context to improve circuit integration and treatment response in TRS. Updates on neurosurgical and neuromodulation targets under investigation in TRS are also included and provide an overview of beneficial circuit-based targets that may improve treatment resistant symptoms in those patients that remain refractory to pharmacological approaches.In this review, we examine TRS from a circuit-based perspective. We start by highlighting the historical development of connectome science in schizophrenia, identifying those early pioneers in psychiatry who originally recognized the disease as an illness of widespread disconnectivity and their valuable contribution to the evolution of network science today. We then examine neuroimaging studies that support both systemic and circuit-level brain dysconnectivity specific to treatment resistance and attempt to explain underlying circuit biology and brain topology that may be unique to this most severe form of the illness. Within a connectome context, attempts to map on-off circuit connectivity synonymous with excitatory and inhibitory neuronal pathways are discussed. Functional correlates of dysconnectivity in schizophrenia are also considered with a focus on cortical network oscillations, giving particular emphasis to the role of gamma band oscillations (GBOs) and their ability to integrate information across large populations of neurons in the illness. Mechanistic models describing underlying neural circuitry and the complex relationship involved in the synchronized firing between excitatory pyramidal cells and inhibitory gamma-aminobutyric acid (GABA)-ergic interneurons are also reviewed to help visualize and understand the inter-relationship between neuronal ensembles within the brain and the complex mechanisms behind their dysfunctional communication in schizophrenia. Finally, we deconstruct how augmenting pharmacological treatments, such as glutamate This review supports the idea that the mapping of cellular and system-level networks to both on (excitatory) and off (inhibitory) circuit phenotypes specific to treatment-resistant disease may be a productive strategy in expanding future research toward customized neural circuit-specific pharmacotherapeutics and directed neuromodulation treatments in schizophrenia. Targeted therapeutics that can improve particular areas of regional functional dysconnectivity that are found to be substantially affected in TRS is an intriguing approach to precision medicine in schizophrenia.Theoretical models of disconnectivity and the investigation of connectomics and brain network organization have been examined in schizophrenia since the early nineteenth century. Historically, there have been a number of influential figures who have made major contributions to the development of modern day network-based science known as connectomics. One of the very first connectionist pioneers in psychiatry was Wilhelm Griesinger 1817\u20131868), a German neurologist and psychiatrist who initially proposed that mental illnesses are brain disorders with pathological and neuroanatomical origins similar to neurological disorders \u20131868, a .Grundriss der Psychiatrie (Outlines of Psychiatry 1900) which was written based on detailed reviews of his clinical cases, he outlined his hypothesis that there is a deficiency in association fiber connectivity in schizophrenia that contributes to an over-activation of cortical sensory regions that can then lead to the development of psychosis (Meynert's student Carl Wernicke (1848\u20131905) further developed the disconnectivity theory of schizophrenia. Although he was best known for his theories regarding the neural circuits involved in higher cognitive functions and the neuropathology of aphasia, he also studied the neuroanatomical and functional aspects of schizophrenia. In his textbook sychosis .One of the most well-known clinicians in the history of psychiatry and recognized as the founder of modern psychiatry was Emil Kraepelin (1856\u20131926), a German psychiatrist who conceptualized schizophrenia as a disorder with both neurodevelopmental and biological origins. Kraepelin was the first to develop a classification system of psychiatric disorders and divided endogenous psychoses into two distinct forms based on disease course and outcome. He described the psychosis involved in schizophrenia as a dementia praecox, a term that combined the cognitive symptoms (dementia) of the illness with an early development of the disorder (praecox) vs. the episodic nature of manic depressive (affective) psychosis .schizein meaning split and phren meaning soul, spirit or mind) to highlight the fragmented thinking or thought disorder that is common to the functional disconnectivity of the illness. Bleuler replaced the term dementia praecox to clearly distinguish schizophrenia from a degenerative illness with a poor outcome. He recognized that progressive cognitive deterioration (characteristic of dementia) was not common in schizophrenia and the onset of symptoms does not always occur early in life (It was the Swiss psychiatrist Eugen Bleuler 1857\u20131939) who then coined the term schizophrenia  and MRI that are able to detail both anatomical and functional connectivity, the disconnection hypothesis of schizophrenia has been refined further. The modern-day disconnectivity hypothesis of schizophrenia initially emphasized the link between the signs and symptoms of schizophrenia and the dysfunctional integration between different cortical areas of the brain, directly related to the underlying abnormalities in neurons and synaptic functioning . AbnormaThe scientific study of connectomics involves mapping out the detailed connectivity of brain regions to characterize the architectural networks of the human brain. Connectomics is therefore a powerful tool to visualize the structural and functional dysconnections associated with schizophrenia. The human connectome provides a detailed map of brain-wide circuit connectivity and allows inference into how brain function may be affected by disruption of the structural organizational network , 34. At Connectomics heavily utilizes graph theory, a specialized discipline of mathematics concerned with the study of graphs or models that represent relations between objects. Large collections of algorithms are used to calculate topological characteristics of both structural and functional brain imaging connectivity data that can be represented in the form of a graph. The graph consists of nodes that represent single neurons or brain regions that are defined by connection endpoints of two line segments that are then linked by edges that illustrate their direct connection to each other via axonal projections, WM pathways or functional coupling between inter-regional brain areas . The cloNeuroimaging studies show impaired structural and functional connectivity in individuals diagnosed with schizophrenia \u201341. The Consistent with these findings, an additional imaging study found significant decreases in WM FA to not only involve the fronto-temporal regions, but also to be widespread throughout each lobe of the brain, including the cerebellum. Major fiber bundles that connect the cortical lobes including the corpus callosum, cingulum and thalamic radiations exhibited the most severe pathology. More than 50% of the cortico-cortical and cortico-subcortical WM fibers that provide the connections between those hub regions that contribute to the \u201crich club\u201d in the brain were affected  and netwFunctional MRI studies have also suggested abnormalities in the connectivity of brain networks in schizophrenia and relate to the structural disturbances that interconnect them. While reduced functional connectivity is a replicated finding among many studies , 46, 47,Widespread dysfunction throughout the entire neural network that involves both cortical and subcortical regions is pronounced in TRS and may have an underlying circuit biology that is unique to this most severe form of the illness. Anatomical regions and neural circuits that have been examined comparing those individuals with treatment resistant vs. treatment responsive disease have uncovered more severe pathological findings in all cortical tissues that have been measured. A number of imaging studies using a variety of structural and fMRI methods have examined TRS to elucidate the difference between the phenotypic subtypes of responsive and non-responsive illness. For detailed reviews see Mouchlianitis et al.  and NakaThe loss of neuronal elements that underlie the symptoms of both TRS and ultra-resistant schizophrenia (clozapine-resistant psychosis) may be more substantial than what is found in those patient phenotypes who have responded to antipsychotic treatment , 52. VolStudies that have specifically compared patients with treatment responsive schizophrenia vs. TRS have reported greater global volumetric reductions of GM in treatment resistant and ultra-resistant patients. There have been consistent reports of reduced GM volumes predominantly within the dorsolateral prefrontal cortex (DLPFC) \u201356, as wThe reduction in cortical GM and WM volumes and distinct WM tract disturbances in TRS may be a consequence of disrupted macro-scale neural architecture and network dysconnectivity that originate within distinct micro-scale neuronal ensembles. Morphometric studies that have been investigated in schizophrenia suggest that cortical volume loss is not related to the reduction of the number of neurons in the cortex, but to architectural neuronal disorganization, reduction in neuronal size, and diminished neuropil  , 66. The18F-DOPA) as a PET radiotracer found a higher level of striatal dopamine synthesis capacity in patients with schizophrenia who responded to treatment vs. those patients with TRS who had equivalent striatal dopamine levels found in healthy controls (1H-MRS) imaging in TRS to examine glutamate changes that may be specific to antipsychotic treatment-resistance  to measure tissue perfusion found increased cerebral blood flow in the left superior temporal gyrus, right supramarginal gyrus, and temporal polar cortex in patients with treatment-resistant AVH . FunctioNetwork-based statistics can be applied to fMRI data to investigate brain networks and to better delineate the differences in the connectome unique to TRS. Although there have been a number of network-based studies in schizophrenia , 45\u201347, In terms of network-based analysis, global network efficiency was significantly reduced in the TRS group compared to controls with significant increases in local efficiency. Reduced global network efficiency indicates that the reduction of functional connectivity and integration between different brain hubs in TRS as a result of the disease process may create surrogate or back-up connections locally  as a homeostatic mechanism and an attempt to compensate for the reduction in longer-range connectivity and restore integration , 80.One possible functional correlate of the aberrant connectivity observed in TRS is disturbances in cortical network oscillations. Oscillations in network activity include the theta (~4\u20138 Hz), alpha (~8\u201313 Hz), and gamma (~30\u201380 Hz) bands. These oscillations are measurable by electroencephalography (EEG) and magnetoencephalography (MEG) and are thought to be reflective of cortical information processing and integration , 81 ImpoThe GBO has been shown to be disrupted in schizophrenia patients during the performance of a wide variety of tasks, including simpler perceptual tasks and more complex and cognitively demanding tasks \u201396. In pA receptors post-synaptic to a subset of inhibitory interneuron processes produce currents with decay periods fitting for the production of gamma oscillations  model and the Pyramidal Interneuron Network Gamma (PING) model . In the llations . Lastly,llations . These fConsistent with the PING model, there is ample evidence to suggest that both excitatory glutamatergic and inhibitory GABAergic activity are disturbed in schizophrenia , 85. DefInhibitory interneurons are particularly sensitive to NMDA receptor antagonists , 113. InParvalbumin+ cells have been extensively studied in schizophrenia and evidence of their dysfunction extends well beyond their contribution to the GBO , 123. PaDespite an improved understanding of the underlying pathophysiology of schizophrenia, particularly with regard to cellular mechanisms contributing to the GBO, a multitude of questions remain. Of utmost importance to the current review is the validity of these findings, many of which have been garnered from animal models of schizophrenia, to TRS. Current cellular and animal models have significant limitations in modeling the illness and few, if any, attempts have been made to replicate the treatment-resistant presentation of the disorder. Secondly, further investigation is required to understand the complex interplay between excitatory glutamatergic cells and inhibitory interneurons in the dysfunctional circuitry of schizophrenia. Specifically, a better understanding of the cellular properties that give rise to the GBO are necessary to better understand approaches for treatment. And lastly, novel treatments and therapeutics need to be designed to target the pathophysiological functioning of GBO circuitry. These approaches may include pharmacological stimulation of the neural circuitry or might be targeted through novel non-pharmacological approaches, such as rTMS which can directly stimulate the GBO.2-blocking medications.Patients who have a phenotype of psychosis that is responsive to dopamine-blocking medication may have dysregulated striatal hyperdopaminergia related to circuit abnormalities within the fronto-striatal complex of the mesolimbic dopaminergic pathway. Glutamatergic projections from the PFC to the ventral tegmental area (VTA) normally regulate dopamine release in the nucleus accumbens. Within this circuit phenotype, hypofunctioning NMDA glutamate receptors on cortical parvalbumin+ GABAergic interneurons will cause an excessive release of glutamate within the VTA. Hyperglutamatergia then leads to overstimulation (on circuit phenotype) of dopaminergic neurons within the mesolimbic dopamine pathway and excessive release of dopamine within limbic structures, such as the nucleus accumbens, amygdala and hippocampus , 131. HyNegative and cognitive symptom domain circuitry involves cortical brainstem glutamate projections that communicate within the mesocortical dopamine circuit. Glutamatergic projections from the cortex onto hypofunctioning NMDA glutamate receptors located on cortical parvalbumin+ interneurons leads to the excessive release of glutamate in the VTA. The excessive stimulation of pyramidal VTA neurons then leads to the inhibition (off circuit phenotype) of mesocortical dopamine neurons and insufficient dopamine release in the PFC and subsequent negative and cognitive symptoms in schizophrenia , 131.2 receptor occupancy is identical to treatment-responsive patients, the lack of efficacy from D2-blocking medication may indicate that hyperdopaminergia may not be related to the symptoms associated with non-response to medications  and a higher binding affinity to many other non-dopaminergic receptors. Clozapine is able to normalize glutamate neurotransmission by increasing NMDA receptor activity in the cortex by a number of different mechanisms. It has been demonstrated that antagonism of D4 receptors can regulate glutamatergic transmission by upregulating AMPA receptors and providing homeostatic stabilization of the excitation of PFC pyramidal neurons by indirect enhancement of NMDA activity . Usually in those patients who have not responded to clozapine, a variety of other antipsychotic medications, antidepressants, anticonvulsants, benzodiazepines or a variety of glutamate augmenting agents have been attempted. Clinical studies have used a variety of agents that can enhance glutamate NMDA receptors (on connectomic) function in an attempt to improve downstream GABAergic (off connectomic) inhibitory effects. GABA interneuron modulators have also been recently investigated as an attempt to inhibit pyramidal cell firing, as well as NO-based therapies to improve intracellular NMDA receptor signaling and other direct circuit-targeted neurosurgical and neuromodulation strategies for their therapeutic benefit in treatment resistant disease.Many drugs that target and co-activate glutamatergic pathways have been of interest as a non-dopaminergic approach to improve antipsychotic treatment in schizophrenia. Strategies to improve glutamate NMDA receptor hypoactivity on GABAergic interneurons have targeted extracellular binding sites on the receptor. The glycine modulatory site has been investigated as a target to improve NMDA receptor hypofunction in schizophrenia and several agonists or partial agonists of this binding site on the NMDA receptor have been studied in clinical trials .The amino acid glycine is a co-agonist of the NMDA receptor and it is required along with glutamate to activate the NMDA ion channel , 140. ThGlycine was first used as an augmenting treatment in schizophrenia close to 30 years ago in a few small open-label clinical trials used at doses between 5 and 25 g per day , 143\u2013145An alternative approach to increasing endogenous brain glycine concentrations has been to block its reuptake and thus improve glutamatergic tone. The amino acid sarcosine, a GlyT1 inhibitor, has also been demonstrated to improve the negative, cognitive and depressive symptom domains of schizophrenia , 156. UnD-serine, an allosteric modulator at the glycine co-agonist binding site, has also been investigated as an augmenting strategy primarily for improving the deficit symptoms of schizophrenia. D-serine may be more effective than glycine as it has a greater affinity for the glycine/serine binding site and also has an increased ability to cross the blood-brain barrier \u2013164. SerDrugs that can downregulate presynaptic disinhibited glutamate release on secondary downstream glutamate neurons have also been explored in patients with TRS and may also work to modulate circuit connectivity. Lamotrigine, an anticonvulsant drug that suppresses presynaptic glutamate release by the blockade of voltage-sensitive sodium channels has been shown to improve clinical response when used as an adjunct to clozapine treatment in ultra-resistant schizophrenia , 174\u2013178An alternative and novel approach that may improve glutamate NMDA receptor signaling and circuit connectivity in schizophrenia is to target the glutamate-NO-cyclic guanosine monophosphate (cGMP) signaling cascade. Nitric oxide is produced in the brain by a complex interaction with a functional glutamate NMDA receptor and there have been a number of clinical studies suggesting that signaling within the glutamate-NO-cGMP pathway may be disrupted in the illness , 181\u2013187Studies examining the effects of the NO donor drug sodium nitroprusside (SNP) in PCP-treated rats has contributed insight into the role of NO in psychosis , 191. ThThe first investigational clinical trial of NO in schizophrenia was conducted at the University Teaching Hospital in Ribeirao Preto, Sao Paulo, Brazil. In this clinical trial, an intravenous infusion of SNP in patients who were already on antipsychotics produced rapid improvement of symptoms (within 4 h of a single infusion) as compared to those patients who received a placebo infusion , 192. SyIn relation to these findings, Dr. Paul Morrison (King's College London) is currently testing the NO-based compound glyceryl trinitrate (GTN) for its ability to improve the cognitive symptom domain of patients experiencing acute psychosis and who are requiring hospitalization . Glyceryl trinitrate is another nitrovasodilator drug that has been used to treat angina and other cardiac conditions including myocardial infarction and congestive heart failure. The biotransformation of GTN involves both enzymatic and nonenzymatic pathways that are linked to the pharmacokinetic and pharmacodynamics properties of the drug , 196. ThKCNS3 gene which encodes the Kv9.3 potassium channel \u03b1 subunit and is essential for control over its fast-spiking abilities . Parvalbumin+ cells innervate multiple pyramidal cells and contain lower mRNA for parvalbumin and GAD67 in those with schizophrenia  and redubilities . Inhibitbilities  and in ubilities . Dr. ChaSurgical modalities that can precisely target particular regions of focal and well-localized dysconnectivity in the brain are currently being tested as a more circuit-specific approach to precision medicine in schizophrenia. Deep brain stimulation (DBS) has been a well-established targeted therapeutic approach that has been used to improve the treatment-resistant symptoms of Parkinson's disease, obsessive-compulsive disorder and treatment refractory depression \u2013202.Neurosurgical DBS strategies are also now being considered to be used in ultra-resistant schizophrenia to target those relevant brain hubs that may improve the interconnectivity of relevant neuronal circuits. The implantation of electrodes into accessible anatomical nodes can be targeted to normalize or reset abnormal patterns of cortical network GBO activity that disrupt neural circuits. The stimulation settings of the electrodes can be titrated to tune the neurons to specific frequencies and recalibrate neuronal asynchrony. There is current interest in targeting several important network hubs using DBS in ultra-resistant schizophrenia involved in basal ganglia-thalamocortical and DLPFC brain circuits. Hubs identified include the hippocampus, ventral and associated striatum, medial and DLPFC, substantia nigra, nucleus accumbens and the mediodorsal nucleus of the thalamus \u2013205. TheCurrently there are two phase I DBS trials investigating this approach in ultra-resistant schizophrenia that are recruiting patients. The first trial at Hospital Santa Creu i Sant Pau in Barcelona  is targeting electrode placement in either the nucleus accumbens or the subgenual ACC. The participants will be randomized to receive stimulation to either of these neuroanatomical sites with the stimulation remaining on until a full 6 months of stabilization is achieved. Those patients who are responsive will then be crossed-over to stimulation-on or stimulation-off groups for 3 months.The principal investigator, Dr. Iluminada Corripio has recently reported positive findings in the first subject who participated in this clinical trial. The patient had a long history of ultra-resistant schizophrenia-positive symptom domain refractory symptoms including manifestations of persecutory, control and delusions of reference. Her referential delusions had become so pronounced that she was unable to leave her home. The patient had a long treatment history typical of ultra-resistant schizophrenia including many trials with a number of different antipsychotic medications, including the use of clozapine (600 mg/day) with little benefit. The patient underwent bilateral electrode implantation in the nucleus accumbens and left-sided unilateral stimulation. Improvement was achieved in both positive and negative symptoms measured 4 weeks post-implantation and after 11 months of open treatment, the patient experienced over a 60% reduction in positive symptoms as measured by the positive symptoms subscale of the PANSS as well as a 33% reduction in negative symptoms, 50% reduction in the PANSS disorganization factor, 33% reduction in PANSS excited factor and 16.7% increase in the depressed factor. The patient continues to do well and is now able to leave her home and has made significant improvements to her overall functioning. For this patient with ultra-resistant schizophrenia, this DBS treatment option was of substantial benefit to otherwise untreatable refractory symptoms .The second DBS trial in ultra-resistant schizophrenia is out of Johns Hopkins University where the study team led by Dr. William Anderson will be recruiting three ultra-refractory patients and will be targeting the local inhibition of the substantia nigra pars reticulata (SNr), a major outflow nucleus of the basal ganglia with the intention of disinhibition and driving the activity of the mediodorsal nucleus of the thalamus . The structure and hypofunction of the mediodorsal nucleus of the thalamus has been investigated in several imaging and post-mortem studies in schizophrenia . All of The use of external neuromodulation devices, a less invasive circuit-based treatment approach than DBS has also become an alternative treatment option for refractory schizophrenia. Repetitive transcranial magnetic stimulation (rTMS) has been the method most investigated. In rTMS time-varying currents are generated in an induction coil and are held over the scalp and applied to stimulate and improve the functioning and synchrony of the GBO networks and GABA inhibitory mechanisms within the brain circuits beneath it. There have been several randomized studies conducted to show that stimulation targeted over the left TPJ, a critical hub involved in the pathophysiology of AVH, can reduce these symptoms \u2013215.Transcranial direct current stimulation (tDCS) is an alternative non-invasive form of neuromodulation that has been used to target specific circuits of the brain to improve treatment-refractory symptom domains of schizophrenia. It is a smaller, lightweight, portable and less expensive option than TMS and could be easily used at home to reduce the burden of having to receive daily treatments within a clinical setting . In thisBased on observations of the dysconnectivity of fronto-temporal circuits from functional neuroimaging studies of patients experiencing AVH \u201362, clinOpen-label and randomized clinical trials that have examined the effects of tDCS to target negative symptoms of schizophrenia have placed the anode over the left DLPFC and the cathode over the right DLPFC or the right supraorbital region or placed it extra-cephalically , 227\u2013229Treatment resistance in schizophrenia continues to be a therapeutic challenge in psychiatry. Within the spectrum of the disease, neural circuits within specific brain regions and their structural and functional links to corresponding regions seem to be further disrupted in TRS. In this review, we have examined TRS from a circuit-based perspective. We highlighted attempts by leading schizophrenia clinicians and researchers to standardize the definition of treatment resistance in schizophrenia and have identified and incorporated recommended terminology with regards to the clinical sub-specifiers or symptom phenotypes that are common to TRS. We discussed the developments of network-based science from the early pioneers who recognized psychiatric illness and schizophrenia as a disease of neuronal and functional disconnectivity. With the development of neuroimaging methods, modern-day connectionists have built upon these theories and have continued to develop and advance network connectomic science today.Our review of schizophrenia and TRS within a connectome context suggests that the structural and functional alterations may be greater in those patients with persistent treatment-resistant symptoms, indicating that there may be fundamental differences within brain network properties that contribute to the inability to integrate the activity and function of distributed neuronal networks that are specific to TRS. Cortical network oscillations and GBO in particular have been reviewed to understand their role in the integration of neuronal information across large neuronal ensembles in the illness. The complex relationship involved in the synchronized firing between excitatory pyramidal cells and inhibitory GABAergic interneurons were also reviewed, including findings specific to dysfunctional inhibitory networks in schizophrenia and parvalbumin interneuron dysfunction and what role these cells may play in dysfunctional pyramidal cell inhibition in schizophrenia.We conclude the review with an overview of several augmenting pharmacological treatments, such as glutamate NMDA receptor and GABA interneuron modulators as well as NO-based treatments and how they may be viewed within a circuit context. Neurosurgical and neuromodulatory approaches were also discussed to highlight a number of beneficial circuit-based targets that may improve circuit integration and treatment response in TRS and improve treatment refractory symptoms in patients who have demonstrated poor response to alternative treatment approaches. The precise mapping of cellular and system-level networks to both on (excitatory) and off (inhibitory) circuit phenotypes specific to treatment-resistant disease remains challenging. Understanding the complexity of the cellular properties that are involved in dysfunctional brain networks in TRS will be critical toward future research in neural circuit-specific pharmacotherapeutics and directed neuromodulation treatments in schizophrenia. The ongoing interest and innovation that has been dedicated toward the understanding of the neural circuitry of schizophrenia and targeted treatment of TRS will hopefully improve personalized outcomes of those suffering from this debilitating disease.M-AM, JP, and JW conducted the literature review. M-AM and JP wrote the first draft of the review. JW, IW, GB, and SD all contributed to and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Management of localized and advanced prostate cancer benefits from several therapeutic options with a surprising improvement in terms of clinical outcome. The selection of patients more likely to benefit from a specific approach still remains a key issue as well as the early identification of patients with aggressive disease which could benefit from a more aggressive treatment strategy. The lack of reliable bio-marker in castration resistant setting able to monitor response to treatment and early inform about tumor progression is an emerging issue. Accordingly, circulating DNA and circulating tumor cells appears a promising and attractive approach despite to date practical applications of these techniques are few and not validated. The aim of this review of the literature is to explore current knowledge on liquid biopsy in prostate cancer focusing on possible future applications. Prostate Cancer (PCa) represents the most common adult malignancies ranking as one of the major cause of cancer related death in men . ManagemSimilarly, advanced stages of the disease count different therapeutic options. As first approach ADT represents the cornerstone of advanced prostate cancer due to the high sensitivity of tumor cells to hormone deprivation. The addiction of further treatment including anti-androgens abiraterone acetate or docetaxel can improve the outcome of patients with metastatic castration sensitive prostate cancer (mCSPC) \u201315.After a first period of hormone deprivation sensitivity, tumor cells develop several mechanisms which lead to overcome the hormone inhibition leading to metastatic castration resistant prostate cancer (mCRPC). In this setting, several different agents have demonstrated to be effective treatment: new hormonal agents , chemotherapy , radiometabolic drugs (Radium 223), and Sipuleucel-T immunotherapy \u201325.The availability of several active therapeutic options has led to different emerging needs in clinical practice requiring the development of reliable markers able to monitor response to treatment and help clinicians to select patients more likely to benefit from one approach rather than another.Prostate-Specific Antigen (PSA) represents a reliable and useful biomarker adopted for early detection and early diagnosis of disease recurrence progression. However, it does not give information about biological features of the disease and it loses its predictive rule in mCRPC setting .Liquid biopsy is an emerging technique which purposes is the detection of tumor cells/tumor DNA from patients' peripheral blood.There are several issues which make the development of liquid biopsies in prostate cancer an attractive approach: (1) the low invasiveness; (2) the early detection of more aggressive tumors since early phases;(3) the early diagnosis of residual tumors or micro-metastases after surgery. (4) the monitoring of tumor response/progression to systemic treatment in advanced setting of the disease and especially in mCRPC; (5) the prediction of tumor sensitivity/resistance to systemic treatments; (6) the acquisition of an accurate genetic assessment of the disease focusing on key alterations which are related to tumor resistance. In particular, several genomic alterations seem to be attractive target due to their correlation to treatment resistance and/or sensitivity to specific treatments \u201330. SomePhosphate and tensin homolog (PTEN) loss. PTEN loss results in PI3K/AKT activation which has been associated to worst survival due to higher tumor proliferation and resistance to hormonal treatment. The inhibition of the PI3K/AKT/mTOR pathway could be an interesting target in this subgroup of patients which could be associated to an Androgen Receptor (AR) inhibition  mutations and in particular AR splice variant 7 (AR-V7) is known to be related to resistance to hormonal treatments including also new hormonal agents abiraterone and enzalutamide (- lutamide .TMPRSS2-ERG gene fusion leads to ETS-related gene (ERG) and steroidogenic enzyme AKR1C3 co-overexpression which promotes AR signaling and represents a promising target in prostate cancer  as well as the identification of the alterations of non-homologous recombination system genes  appears an attractive approach for two reason. First, tumors with repair genes deficiency are related to more aggressive features and poorer survival. Second, therapeutic implications related to these genomic assessments involve a possible sensitivity to platinum cytotoxic therapy. The development of PARP inhibitors represents another possible target for the management of advanced prostate cancer which has already been evaluated in small trials and is currently under clinical investigation  .In 2008, de Bono et al. identified a correlation between CTCs number and median overall survival. In this study carried out on 231mCRPC two distinct subgroup of patients were identified: one (Unfavorable group) which showed a CTCs number of 5 or more and the other (favorable) with < 5 CTCs per 7.5 mL of blood. Overall survival was significantly better in favorable group (21.7 vs. 11.5 months). Moreover, patients who presented a significant decrease of CTCs number during or after treatment (moving from unfavorable to favorable groups) significantly improved their survival compared to patients who continued to present a CTCs number of 5 or more CTCs. According to the results of de Bono et al, a meta-analysis of 10 studies confirmed the prognostic rule of CTCs in patients with prostate cancer .Furthermore, pre-planned analyses of large phase III trials: SWOG 20421 (docetaxel with or without atrasentain in mCRPC patients), COU-AA-301  and AFFIRM  confirmed the prognostic rule of CTCs as independent factor related to OS \u201353.Unfortunately, none of these studies demonstrated an association between CTCs number and response to treatment and so the role of CTCs in this setting still remains unclear. Moreover, another possible issue which could partially explain the failure of this approach in clinical practice is the low detection rate of CTCs in non metastatic patients which ranges only from 5 to 27% . To avoiA combined analysis of COU-AA-301 and IMMC-38 trials showed that an increase of 30% in CTCs count from baseline was independently associated to worst OS in patients treated with abiraterone and chemotherapy . To sustThe only CTCs enumeration resulted in an independent prognostic factor with an unclear role in terms of early diagnosis of disease recurrence/persistence after surgery as well as a predictive response factor. Another interesting approach consists in a characterization of CTCs resulting in a genetic assessment and in a detection of target altered pathways.AR protein has been extensively investigated in prostate cancer CTCs. Through a FISH based assay AR gene amplification detection in CTCs was possible in 40% of cases, a percentage comparable to the AR amplification described in bone metastases biopsy analyses . FurtherDue to the important role of AR-V7 in mCRPC , severalAbout other pathways detected in CTCs, the PTEN loss assessed by FISH and Epic Sciences test  has been associated to worse clinical outcomes , 64 whilNext Generation Sequencing (NGS) involves a series of different techniques able to perform a whole genome sequencing of tumor cells. The possibility to obtain a complete genomic assessment from CTCs appears a novel and promising approach investigated in different studies.In 2014, Lohr et al evaluated a method able to perform a CTCs isolation, enrichment (throuEp-CAM expressing CTCs), genomic amplification and sequencing in metastatic PC . They deAnother interesting issue is the detection of whole blood RNA, without enriching for CTC. In 2012, Ross et al assessed a whole blood RNA transcript based model as prognostic factor in patients with PC. After the analysis of blood collected from 62 men with mCRPC, they identified a six gene model  able to divide patients in two risk groups with different mOS . In the Concerning the several devices utilized for CTCs detection, enrichment and evaluation, only CellSearch has been approved from FDA. However, despite a large range of potential applications  CTCs detection by CellSearch is not commonly adopted in clinical practice. This mainly due to a low sensitivity of the method as well as a conflicting relationship between CTCs and treatment response evaluation. Several other approaches are under investigation. It is likely that CTCs evaluation will be an important factor able to improve our decisions in clinical practice , 69.The evidence that cell-free DNA could be detected in peripheral blood is a well known issue, and its application in clinical practice has been investigated only in last years. Regarding cancer patients, the unique composition of tumors' ctDNA presenting several genomic mutations  which are not detectable in ctDNA originating from normal cells make tumor ctDNA an ideal markers of the disease. Moreover, the possible correlation between mutations detected on ctDNA and genomic mutations of primary or metastatic tumors make cDNA a unique markers able to provide key information by a no-invasive approach.Regarding PC, ctDNA could be detected in peripheral blood and detection of known driver aberrations can be obtained in more than 97% of cases. Moreover, changings in ctDNA genomic mutations could be detected by repeated analyses of ctDNA with high grade of concordance with genomic assessment of primary tumors or metastases , 71.The quantitative assessment of ctDNA has been related to prognosis of patients with PC in different studies , 73. In As known, mutation in DNA repair genes is acquiring an increasing interest in PC due to the association by these mutation and more aggressive tumor features and to the possible benefit derived from a PARP targeted treatment. Mutations in repair genes are common in prostate cancer. In a DNA assessment of 692 men with metastatic PC a total of 84 germiline DNA repair gene mutations  were found in 82 men . This stPARP inhibition is one of the important strategy currently under investigation in patients with metastatic prostate cancer. In a phase II trial 50 mCRPC patients received the PARP inhibitor Olaparib . 17 33%. In ASCOAnother promising target gene is represented by PTEN loss which has show to be a predictive biomarker of response to treatments targeting PI3K/AKT pathway. Hyper-activation of the PI3K/Akt/mTOR resulting from PTEN loss is related to decreased AR transcription output and stability and vice versa. The addiction of ipatasertib (an Akt inhibitor) to abiraterone acetate increased radiological PFS of patients with mCRPC and PTEN loss previously treated with docetaxel based therapy and progressed during at last one previous hormonal therapy .Extracellular vesicles are membrane-enclosed structures that are released from all cells in the body. These vesicles contain several substances such as proteins, lipids, RNA, and DNA and are considered a very promising tumor-related biomarkers. Recently, it has been demonstrated that large extracellular vesicles isolated from plasma of patients with prostate cancer cells are an important source of chromosomal DNA which reflects faithfully genetic aberration of the cell of origin, including copy number variations of genes frequently altered in metastatic prostate cancer (such as MYC and PTEN) . The stuThe surprising potential of CTCs or tumors' ctDNA detection, characterization and genomic assessment have start a revolution which probably will give important results in next years. Despite to date application of these techniques are few probably that better knowledge of genomic anomalies of PC and their correlation with the clinical course of the disease as well as their potential relationship with specific targeted treatments will increase the attention on this issue.RM and FM: conception and design; VD and LG: drafting the manuscript; MSa and AC: review of the literature; LC, MSc, and AL-B: critical revision of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Advanced care planning (ACP) is encouraged as the completion of ACP increases the likelihood for patients to receive their preferable end-of-life care and for caregivers to be less stressed. Common approaches to increase the engagement of ACP target on intervention or information provision to patients in the very late stage of life. Arguing that caregiving experience may influence how people plan their own end-of-life care, the present study focuses on caregiving roles. Using seven waves of data  from the Health and Retirement Study (HRS), 863 older people who were 65+ and alive in 2012 but passed away prior to 2014 were included in this study to examine the relationships between an individual\u2019s caregiving experience (2002-2012) and his/her completion of ACP (2014). Findings from logistic regression showed that caregiving experience did not influence older adults\u2019 (65+) ACP completion in 2014. When considering different types of caregiving experience  among older cohort (75+), the odds of completing ACP for those with spousal caregiving experience were 2.47 times more likely than those without any caregiving experience. However, no relationship was detected among those with parental caregiving experience. Other factors relating to ACP completion were poorer health, death being expected, death due to cancer, older age and being racial minorities. Practitioners and policymakers could consider encouraging older adults (65+) who provide spousal care to engage in ACP. Future research taking longitudinal approaches to identify reasons behind the existence of the relationship is urged."}
+{"text": "In this interesting review West and Lawrence show important points about a major and poorly studied topic: the female urethral stricture. In the review the authors show the management options and observed that multiple open urethroplasty techniques are described with various grafts and flaps, with good medium-term success. Minimally invasive techniques remain well-employed but have poor long-term success, with increased failure with multiple attempts at treatment and concluded that the use of vaginal flaps and buccal mucosal graft present interesting success rates and urethral dilation should be avoided due to disappointing long-term results.An important topic to be discussed is what is the best option for surgical reconstruction of female urethral strictures with buccal mucosa graft? Ventral or dorsal approach? What is the best choice? Both dorsal and ventral approaches are acceptable options for the surgical reconstruction of female urethral strictures . Dr. Nay"}
+{"text": "The health consequences of multiple family member deaths across the life course has received less attention in the bereavement literature. Moreover, recent research shows that black Americans are more likely than white Americans to lose multiple family members. I analyze longitudinal data from the Health and Retirement Study (1992-2014) to assess how multiple family member losses across the life course are associated with declines in health among older adults. Findings suggest that multiple family losses prior to midlife are associated with a number of indicators of poor health  and steeper declines in health as individuals age. Losses after midlife additionally undermine health declines for older adults. Thus, family member loss functions as a cumulative burden of stress across the life course that erodes health in mid- and later-life. Family loss disproportionately burdens black Americans and serves as a unique source of disadvantage for black families."}
+{"text": "The second case showed a mismatch of signal elevation persistence on diffusion-weighted imaging (DWI) and physiologic 18F-FDG distribution in the liver parenchyma. These cases present different imaging features in MM lesions of the liver using PET/CT and MRI, reflecting the high disease heterogeneity in patients with MM and demonstrating that the use of both PET/CT and MRI may offer complementary information.\u0397epatic involvement in multiple myeloma is not common; nevertheless, it is associated with poorer outcome. Heterogeneous features have been described in few published reports so far. We present the imaging findings of PET/CT in comparison to those of MRI for two multiple myeloma (MM) patients, one with a liver lesion suspicious for myeloma metastasis on PET and one with multiple liver lesions suspicious for myeloma metastases on MR\u0399. The subsequent ultrasound-guided needle biopsies confirmed the extramedullary spread of the disease in both patients. The first case exhibited a match in both functional imaging modalities (PET and MRI) but a mismatch of intense metabolic activity on"}
+{"text": "Cardiovascular disease (CVD) is the leading cause of death in industrialized nations and an emerging health problem in the developing world. Systemic inflammatory processes associated with alterations in lipid metabolism are a major contributing factor that mediates the development of CVDs, especially atherosclerosis. Therefore, the pathways promoting alterations in lipid metabolism and the interplay between varying cellular types, signaling agents, and effector molecules have been well-studied. Mycobacterial species are the causative agents of various infectious diseases in both humans and animals. Modulation of host lipid metabolism by mycobacteria plays a prominent role in its survival strategy within the host as well as in disease pathogenesis. However, there are still several knowledge gaps in the mechanistic understanding of how mycobacteria can alter host lipid metabolism. Considering the in-depth research available in the area of cardiovascular research, this review presents an overview of the parallel areas of research in host lipid-mediated immunological changes that might be extrapolated and explored to understand the underlying basis of mycobacterial pathogenesis. One of the leading causes of morbidity and mortality in westernized countries is cardiovascular disease (CVD), such as atherosclerosis  is a successful human pathogen due to its ability to cause tuberculosis (TB) in almost 10 million individuals annually . This hydrophobic core is surrounded by a hydrophilic membrane consisting of phospholipids, free cholesterol, and apolipoproteins  2-induced PGE2 synthesis, which drives the cells toward necrosis -induced alterations in host lipid metabolism leading to either mycobacterial persistence or protective immunity has been previously addressed -1\u03b1, IL-1\u03b2, and IL-6 by host macrophages  gene and production of 25-hydroxy cholesterol as well as miR342-5p which suppresses the sterol biosynthetic pathway  genes, which eventually increases bacterial replication inside the foamy macrophages in granulomatous lesions  or intestinal smooth muscle cells (in M. paratuberculosis infection) could form foam cells and how that would drive the disease course has not been addressed. In this context the role of platelets in host lipid metabolism during mycobacterial infection was only recently addressed, wherein platelets were found to have the capacity to initiate the differentiation of monocytes into epithelioid-like multinucleated giant foam cells of the suppressive phenotype  are involved in the metabolism of sex steroidal hormones with the resultant metabolites produced being implicated to play a role in the gender differences noticed to the susceptibility to cardiac and renal diseases (Jennings et al., Mtb and other mycobacterial infections has been reported, with the male to female ratio of susceptibility to Mtb infection reported to be 1.9/0.6 worldwide (Yamamoto et al., M. avium, M. marinum, and M. intracellulare infection, while ovariectomized females, or females and castrated males treated with testosterone had increased susceptibility to infection (Yamamoto et al., Sexual dimorphism in the relative susceptibility to in vitro technology employing scaffolds made of biomaterials that could be engineered to simulate tissue degeneration or regeneration has revolutionized biomedical research in CVD medicine (Ou and Hosseinkhani, in vitro granuloma mode utilizing PBMCs to study host-pathogen interactions, drug susceptibility as well as mycobacterial drug tolerance and persistence (Kapoor et al., Mtb survival during infection research in in vitro models of Mtb-infected foam cells is critical. Novel methods to generate and evaluate foam cells in vitro have been utilized in the CVD research field (Xu et al., in vitro technology employed in CVD research to study foam cell signaling in mycobacterial research should prove fruitful.3D Decrease in cholesterol efflux, increase in uptake, and excess esterification of cholesterol compounded by the action of lipid peroxidation products generated by inflammatory processes contribute to foam cell formation in atherosclerosis. Since these are critical events in the pathogenesis of atherosclerosis, they have been extensively studied. On the contrary, although a role for host lipid metabolism in mycobacterial pathogenesis has been established, research in the different components that contribute to the alteration in host lipid metabolism and cholesterol homeostasis is still in the nascent stages. The specific cause for reactivation of mycobacterial disease from a controlled state in an infected host is still a critical question that remains inconclusive. It is speculated that the reversible lipid accumulation in foamy macrophages could be a possible phenomenon that is associated with disease reactivation (Caire-Br\u00e4ndli et al., ST performed the literature review and wrote the first draft of the manuscript. SK critically revised the paper. All authors read and approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "While the abscopal effect has been previously described, the phenomenon has been poorly defined in the case of spinal metastases. This article is unique in that we present the first systematic review of the abscopal effect after radiation therapy to metastatic spinal cancer, especially since the spinal column represents one of the most common metastatic locations. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines in the Enhancing the QUAlity and Transparency Of health Research (EQUATOR) resources, a systematic review identified relevant studies via a computer-aided search of MEDLINE and Embase. Ten publications that met the inclusion and exclusion criteria from the PRISMA flow diagram described a total of 13 patients, 76.9% of whom demonstrated image findings of the abscopal effect. In summary, important trends in the nine patients who experienced the abscopal effect in this review include higher doses of radiation and treatment with immunomodulators, both of which may help guide treatment paradigms for spinal metastases superimposed on diffuse metastatic disease. These trends, however, still warrant further investigations with experimental and clinical studies for a mechanistic understanding of the abscopal effect. In 1953, RH Mole first described the abscopal effect as the regression of a tumor remote from the irradiated tissue . A trialMethodsFollowing the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines in the Enhancing the QUAlity and Transparency Of health Research (EQUATOR) resources, a systematic review identified relevant studies via a computer-aided search of MEDLINE  and Embase  (Figure Following removal of duplicated studies, articles were screened for non-human studies. Abstracts without full texts available were removed if information was insufficient to complete the columns in Table While the abscopal effect may not have been explicitly defined in the articles summarized in Table ResultsTen articles discussed the abscopal effect after radiation therapy to metastatic spinal lesions. These ten publications that met the inclusion and exclusion criteria from the PRISMA flow diagram described a total of 13 patients in Table In 2012, Ishiyama et al and Leung et al represented the only case reports that did not include any systemic therapies, yet the abscopal effect was still reported following radiation therapy to the spine , 16. AllAll articles in Table Three authors failed to observe an abscopal effect in four patients. While Grimaldi et al noted regression of the distant lung lesion after spinal radiation in one patient, a second patient with metastatic melanoma treated with ipilimumab did not experience an abscopal phenomenon , 8. In tDiscusssionAlthough regression of lesions distant to the radiation site has been reported since the 1950s, the phenomenon has been sparingly described over the ensuing half-a-century. Only 46 reported cases of the abscopal effect were published within the 31 articles of a systematic review by Abuodeh et al in 2014\u00a0. Within Cancer biologists have determined that a diverse repertoire of receptors on intratumoral T-lymphocytes increases the attack on neoplastic cells , 21. ButIn 2015, a publication in Nature demonstrated that these immune checkpoint inhibitors in conjunction with radiation bolstered the immune-mediated response for superior control of tumor burden . The intThe review by Ngwa et al also concluded that the abscopal effects were associated with higher Gy per fraction of radiation . In the Lastly, abscopal observations may have a higher propensity for success with radiation to the spinal column over other metastatic areas. Hematopoietic stem cells residing in the bone marrow throughout the spine are particularly amenable to direct ionizing radiation that elicits an innate immune recognition of tumor even in the absence of tumor antigens via the release of \u201cdanger signals\u201d - i.e., cellular stress signals . This beThis article is unique in that we present the first systematic review of the abscopal effect after radiation therapy to metastatic spinal cancer. Important trends in the nine patients who experienced the abscopal effect in this review include higher doses of radiation and treatment with immunomodulators, both of which may help guide treatment paradigms for spinal metastases superimposed on diffuse metastatic disease. These trends, however, still warrant further investigations with experimental and clinical studies for a mechanistic understanding of the absopal effect."}
+{"text": "Ischemia reperfusion-induced tissue injuries and organ failure represent the major causes of postoperative mortality and morbidity. Oxidative stress-mediated cell death plays a vital role in this pathology .\u03b3 or brain-derived neurotrophic factor could reduce such types of cell death and attenuate cardiac dysfunction by reducing oxidative stress.Induction of different types of cell death  triggered by reactive oxygen species (ROS) plays an important role in ischemia reperfusion injury (IRI) in multiple organs . In this\u03baB.Reperfusion-induced oxidative stress is the major contributor in IRI. Thus, therapies that increase antioxidant capacity may protect organs against IRI . ThroughAggravated inflammation, which has been shown to subsequently induce oxidative stress, has been proposed as a major cause of IRI and organ injury . AttemptWe hope that the research articles presented in this special issue contribute to the understanding of current advancements and the mechanisms of oxidative stress-mediated cell death in ischemia reperfusion injury. It is also our hope to stimulate further efforts in the investigation of the pathology of ischemia reperfusion injury and the development of therapy for the disease."}
+{"text": "Wearables consist of numerous technologies that are worn on the body and measure parameters such as step count, distance travelled, heart rate and sleep quantity. Recently, various wearable systems have been designed capable of detecting spinal posture and providing live biofeedback when poor posture is sustained. It is hypothesised that long-term use of these wearables may improve spinal posture.To (1) examine the capabilities of current devices assessing spine posture, (2) to identify studies implementing such devices in the clinical setting and (3) comment on the clinical practicality of integration of such devices into routine care where appropriate.A comprehensive systematic review was conducted in adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Guidelines (PRISMA) across the following databases: PubMed; MEDLINE; EMBASE; Cochrane; and Scopus. Articles related to wearables systems able to measure spinal posture were selected amongst all published studies dated from 1980 onwards. Extracted data was collected as per a predetermined checklist including device types, study objectives, findings and limitations.A total of 37 articles were extensively reviewed and analysed in the final review. The proposed wearables most commonly used Inertial Measurement Units (IMUs) as the underlying technology. Wearables measuring spinal posture have been proposed to be used in the following settings: post-operative rehabilitation; treatment of musculoskeletal disorders; diagnosis of pathological spinal posture; monitoring of progression of Parkinson\u2019s Disease; detection of falls; workplace occupational health and safety; comparison of interventions.This is the first and only study to specifically review wearable devices that monitor spinal posture. Our findings suggest that currently available devices are capable of assessing spinal posture with good accuracy in the clinical setting. However, further validation regarding the long-term use of these technologies and improvements regarding practicality is required for commercialisation. Wearables are defined as electronic technologies or computers that can be worn on the body. Since the beginning of the twenty-first century such devices have reduced in size and costs while improving in observation capabilities related to multiple health-related parameters, triggering a shift towards commercialisation and incorporation into everyday activities . In 2016There is a need for real-time postural monitoring and correction as sustained poor spinal posture is associated with the development and worsening of many musculoskeletal disorders , 5. Poorn\u2009=\u200942 studies) overall validation studies for multiple systems have been favourable, although clinical integration of these systems has not yet materialised on a large scale. In a separate review by McCallugh et al. [Wearables monitoring posture have the potential to prevent the aforementioned consequences through real-time biofeedback encouraging the correction of sustained poor posture. It is hypothesised that with long-term use these systems may instil correct postural habits and yield a decrease in the incidence of posture-related musculoskeletal disorders. In a systematic review by Wang et al.  focused h et al.  in the aConventionally, spinal posture is assessed in a clinical setting during routine patient examinations, physiotherapy sessions or formalised laboratory based evaluation. Such traditional methods have been criticised as costly and impractical with a key inability to measure day-to-day posture and provide timely feedback. The gold standard for analysing spinal posture remains radiographical assessment, however the associated cost and irradiation limits frequent repeated use . Other lThis is the first study to review the use of wearables in spinal posture monitoring with aims to (1) examine the capabilities of current devices, (2) identify studies implementing such devices in a clinical setting and (3) comment on the clinical practicality of integration of such devices into routine clinical care. Our findings aim to synthesise the volume of data published across multiple scientific domains  and streamline a method of customised device design, in order to optimise the clinical use of postural sensors and ultimately use the data they can provide to facilitate clinical decision making such as the need for surgical intervention.The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Guidelines (PRISMA) were adhered to for this systematic review across the following five databases: PubMed; MEDLINE; EMBASE; Cochrane; and Scopus . The finInclusion and exclusion criteria are documented below. Duplicate studies were removed, with journal papers chosen over conference papers in the setting of data duplication. In cases where multiple studies included the same dataset, the most recent update was included. A primary screening was conducted by an independent reviewer (LS) who read the full texts of selected articles based on the inclusion and exclusion criteria; (4) A secondary screening was conducted by an independent reviewer (MM) who read the full texts of selected articles based on the inclusion and exclusion criteria. In the setting of discrepancy in study inclusion the senior author (RM) authorised the final decision.Articles involving wearable technology/iesThe wearable technology/ies are able to monitor posture in the sagittal and/or coronal planesThe wearable technology/ies are able to monitor posture of the spineArticles written in EnglishTime of publication between 1980- April 2018.Inclusion criteria:Wearable technology/ies only capable of identifying activity or discriminating between body position Wearable technology/ies only capable of monitoring posture of body parts other than the spineWearable technology/ies classed as robotic or exoskeletonsSystematic reviewsBooksExclusion criteria:Following the selection of articles, data was collated by two researchers (LS and MM). Data was collected as per a predetermined checklist including: type of wearable technology/ies; sensor location/s; presence of feedback system; aims of the study; and outcomes of the study. All included articles were appraised for bias using the Newcastle-Ottawa Scale of Quality Assessment.From the 1427 non-duplicate articles found using the search strategy, 37 articles were selected for inclusion . Among the included studies, ten studies had explicit aims of technological validation while most remaining studies others were limited as a proposal. Only seven studies employed the use of one sensor or single-platform with multiple sensors attached , with the vast majority requiring multiple sensors worn at a single time. Parameters measures ranged from aspects of balance, spinal positioning, motion analyses and incidence of pre-defined postural positions. Two studies were explicitly focused on the analysis of spinal motion during chair-sitting exclusively . One study had an aim to identify the optimal sensor positioning using a spine-based system as opposed to clinical validation (16). No studies included any meaningful cost analyses. When provided, the accuracy rates of devices were high with error ranges within 5 degrees in the majority of capturing moments (>\u200985% of the time). Overall accuracy reporting is detailed later in the discussion.Tables\u00a0Due to limitations in cohort differences and these recordable device parameters between studies it was not possible to meta-analyse data as a means of evaluating any expected postural based measures.In 1994, Tanaka et al. proposed the first wearable system able to measure spinal posture without an observer. The system comprised of three electro-magnetic inclinometers measuring angle of inclination in the sagittal field. The inclinometers were strapped to the chest, thigh and calf. An analog-to-digital converter was incorporated to transpose measured angles into 4-bit digital signals allowing digital reconstruction of the trunk, thigh and calf inclination angles. The proposed system had an angular resolution of 12 degrees, suitable for categorisation of posture as \u201cpoor\u201d or \u201cgood\u201d. While Tanaka et al. reported \u201cgood linearity observed over the wide range of measured angle\u201d there was no formal assessment of the accuracy of the system [Since the proposal of such devices various prototypes capable of measuring spinal posture have been proposed. A wide range of technologies underpin these systems with the most commonly used being Inertial Measurement Units (IMUs). IMUs are generally comprised one or more accelerometers and one or more gyroscopes, and may also include one or more magnetometers Table\u00a0. Forces Some wearables couple IMUs with other technologies to improve overall accuracy of derived data. Plamondon et al. , proposeOther wearables use only accelerometers without the addition of gyroscopes or magnetometers. Harms et al.  proposedWearables measuring spinal posture have many possible clinical applications in the prevention, monitoring and treatment of chronic disease Table\u00a0. Mass prWearables measuring posture have a great potential for use in physical rehabilitation. Low back pain and other musculoskeletal disorders often require significant long-term rehabilitation to strengthen muscles and counteract postural deviations. Monitoring of posture using wearables may help to assist physical therapists ensure patients are properly executing rehabilitation exercises . Furtherp\u2009<\u20090.05) in the comparison of sensor data to a standardised rotating wheel apparatus [Postural wearables have the potential to become the primary treatment modality for some musculoskeletal disorders. Bazzarelli et al.  proposedpparatus . HoweverOther clinical applications for postural monitoring wearables include: detection of falls within the home; prevention of falls through improved postural control; assessment of Parkinson\u2019s Disease severity , 16, 30.While many of the proposed wearables promise the potential use in a wide variety of clinical applications, the biggest challenge remains in the lack of validation of these technologies. Most of the reviewed articles either solely proposed prototype designs or conducted preliminary verification of devices using very small samples over a short-term of time. In order to validate their use for long-term postural monitoring and improvement, larger and longer duration validation studies are required.Compared to their physical activity monitoring counter parts, wearables measuring posture are significantly lagging behind in terms of commercialisation. While the aforementioned lack of validation studies is a major cause, the need for more than one sensor in determining spinal posture presents a significant challenge regarding practicality. Although some of the wearable systems proposed only used one sensor, Fathi et al.  reported2\u2009>\u20090.973. There were, however, increased errors in measurements over 1 h. It is suspected that this increase in estimation errors occurred due to the relative motion of IMU modules against the body [One method to make multiple-sensor wearables more practical is the incorporation of sensors into smart textiles. Kang et al. , proposethe body . DespiteMillington  reviews As devices continue to improve in accuracy and achieve validation we believe the next step towards integration of such wearables would be to establish a link between data output and diagnostic predictability while optimising costs of integration. The implication a diagnostic algorithm in this regard would facilitate healthcare delivery without the need for regular consultation and the potential to remotely highlight populations requiring urgent intervention. This remains a key focus for our own research institution at this stage.This is the only study to specifically review wearable devices that monitor spinal posture. This review reveals that spinal posture can be measured through the use of various technologies but that there is limited data regarding the validation of the same. More research into the accuracy and long-term outcomes of these devices is required for a greater understanding of their clinical applicability. Furthermore, improvements regarding practicality are required before commercialisation and mass uptake can be considered."}
+{"text": "A 38-year-old man with longilinear shape, smoker (38 packs/year) and no other relevant medical history was referred to our department due to the finding of left pulmonary hyperlucency on a chest x-ray. A computed tomography (CT) was performed and a giant emphysematous bulla with thin-walled partitions inside was shown that replaced almost the entire left upper lobe, The patient underwent an exploratory thoracoscopy. Intraoperatively a giant bulla was seen that initially impressed to replace the entire upper lobe. Despite the large size we decided to attempt thoracoscopic resection preserving the remaining healthy parenchyma. Bullectomy was done using linear endoscopic stapling devices. To our knowledge this is the only case with such a large bulla resected entirely by VATS. Giant bullous emphysema (GBE) was first described by Burke in 1937 . SurgeryA 38-year-old man with longilinear shape, smoker (38 packs/year) with no other relevant medical history was referred to our department due to the finding of left pulmonary hyperlucency on a chest x-ray done  because GBE, sometimes referred to as Vanishing Lung Syndrome (VLS) as a clinical syndrome, was first described by Burke in 1937. It typically presents in young males cigarette smokers as in our patient and also can be associated with other conditions . Development of multiple large lung bullae (termed GBE or VLS) is a rare and progressive disease with chest radiographs showing peripheral  bullae in contrast to the more uniformly distributed bullae of centrilobular emphysema shown in smokers. High resolution computed tomography (HRCT) typically shows extensive paraseptal emphysema coalescing into giant bullae and is the best imaging to determine the extension of the disease. Surgery is indicated to treat complications related to GBE or in asymptomatic patients who have a bulla that occupies more than one-third of the hemithorax compressing healthy adjacent lung tissue and when in the clinical follow-up an increase in the size of the bulla is observed. Different thoracoscopic techniques are reported in literature and almost all are nowadays abandoned . The VATWe presented the only case with a bulla of such size resected completely by videothoracoscopy. To obtain satisfactory results, both postoperative and operative care are essential. As we mentioned, the most frequent complication is persistent air leakage and the lack of pulmonary expansion in the postoperative period. The use of adequate mechanical sutures, some type of pleurodesis and mechanical and respiratory kinesiology are key points in this type of interventions. Despite there is not enough evidence published with similar cases resolved entirely by VATS, we consider that it's a safe and feasible procedure in experienced centers.The authors declare no competing interests."}
+{"text": "Coordination of local and systemic responses to environmental cues is mediated by the intercellular transport of small and large molecular signals. In plants, intercellular channels named plasmodesmata (PD) are formed, consisting of a plasma membrane and an appressed ER (desmotubule) traversing cell walls . These cRecent research implicates phytohormones and certain metabolites in the control of symplastic transport . The rolPhyscomitrella patens  was sufficient to restore PD closure and bud dormancy defects in abi1-1 plants  and a MADs-box transcription factor orthologous to Arabidopsis floral repressor SHORT VEGETATIVE PHASE (SVL). In response to high ABA levels (during short days), PKL expression is repressed in wildtype but not in abi1-1. Downregulation of PKL has been shown to be sufficient to complement the formation of PD sphincters and bud dormancy defects in abi1-1 and restores the expression of SVL. SVL binds promoter regions in the sequence of CALS1 and GA2 oxidase genes leading to reduced levels of Gibberellic Acid  and to PD blockage presumably by callose. Both of these ABA-mediated responses are necessary to maintain bud dormancy during short days  was altered in endo-dormant buds.Despite strong evidence indicating that PD closure during dormancy is dependent on callose, staining or immunohistochemistry have not been systematically performed. The work by Together the data suggest that high ABA levels can have two different effects on PD : inducti"}
+{"text": "This article contains data on experimental endpoints of a randomized controlled animal trial. Fourteen healthy piglets underwent mechanical ventilation including injurious one-lung ventilation (OLV), seven of them experienced four cycles of remote ischemic preconditioning (RIP) on one hind limb immediately before OLV, seven of them did not receive RIP and served as controls, in a randomized manner. The two major endpoints were (1) pulmonary damage assessed with the diffuse alveolar damage (DAD) score and (2) the inflammatory response assessed by cytokine concentrations in serum and in bronchoalveolar lavage fluids (BAL). The cytokine levels in the homogenized lung tissue samples are presented in the original article. Further interpretation and discussion of these data can be found in Bergmann et al. (in press). Specifications tableValue of the data\u2022The data presented in this animal study open the way to further research on ischemic preconditioning in clinical studies. The data provide valuable information on the effects of RIP on the lung, especially concerning DAD scores which are not possible to obtain in clinical settings as the lungs of patients cannot be histologically examined in terms of harvesting standardized parts of the organ.\u2022The development of cytokines in serum and in BAL fluid confirm that an immunological response to RIP takes place which shows a different time pattern in each cytokine, depending on the site of measurement as well (either serum or lungs). This is a field for further research in terms of longer protocols after RIP and of identifying cytokines in other tissues, e.g. muscle.\u2022The data open the field for examining early stages in cytokine development, i.e. assessing the mRNA of cytokines in different tissues.\u2022These data might support RIP to become a tool that is easily applied and cheap to improve patients\u2019 outcome after thoracic surgery and might be considered in the clinical setting.1The data of a randomized animal experiment on the effects of remote ischemic preconditioning (RIP) on alveolar integrity and the pulmonary alveolar pro-inflammatory response after injurious one-lung ventilation (OLV) are shared with this data article.The diffuse alveolar damage score was used to determine the effects of injurious mechanical ventilation in a porcine model of OLV The histological images representing the typical consequences of mechanical ventilation-induced pulmonary injury that form the basis for the DAD score are presented in The presented histopathological changes of lung tissue as a consequence of one-lung ventilation and RIP were accompanied by expression of different pro- and anti-inflammatory mediators. The following figures highlight the time courses of cytokine release into serum samples and bronchoalveolar lavage fluids and lung tissues \u2013 levels, separately displayed for controls (n=7) and piglets previously treated with the RIP procedure , Fig. 9.2Mechanical ventilation, especially one-lung ventilation (OLV) is detrimental for the lung Fourteen 2.5 month-old piglets were prepared using the algorithm described in our main manuscript . Blood s"}
+{"text": "Genomics diagnostic tests are done for a wide spectrum of complex genetics conditions such as autism and cancer. The growth of technology has not only aided in successfully decoding the genetic variants that causes or trigger these disorders. However, interpretation of these variants is not a trivial task even at a level of distinguish pathogenic vs benign variants.We used the clinically significant variants from ClinVar database to evaluate the performance of 14 most popular in-silico predictors using supervised learning methods. We implemented a feature selection and random forest classification algorithm to identify the best combination of predictors to evaluate the pathogenicity of a variant. Finally, we have also utilized this combination of predictors to reclassify the variants of unknown significance in MeCP2 gene that are associated with the Rett syndrome.The results from analysis shows an optimized selection of prediction algorithm and developed a combinatory predictor method. Our combinatory approach of using both best performing independent and ensemble predictors reduces any algorithm biases in variant characterization. The reclassification of variants (such as VUS) in MECP2 gene associated with RETT syndrome suggest that the combinatory in-silico predictor approach had a higher success rate in categorizing their pathogenicity. With advances in genomic sequencing, molecular genomics has quickly become a standard in clinical genetics and diagnostics. Molecular genetic testing involves the identification of variants in clinical actionable regions of a single gene or multiple genes that can cause a genetic disorder. Gene based molecular diagnostics tests have the ability to contribute to a wide range of testing types such as screening for specific conditions such as autism or cancer. As the degree of severity of the disease depends on the genes affected and its associated variants along with their phenotype characteristics, multi-gene screening provides a gateway to analyze a set of genes that are found to be associated with a specific or multiple phenotype all at once . The fieAdvances in molecular genomic technologies such as next-generation sequencing that includes whole exome sequencing (WES) and whole genome sequencing (WGS) have aided in screening multiple genes in an instance to identify several single nucleotide variants (SNVs) that contribute to a disease . Many diThe SNVs identified from methods like WGS or WES are evaluated based on the metadata obtained from variant annotation process that is a part of the bioinformatics workflow using information from various data sources such as Online Mendelian Inheritance in Man  and HumaIn this study we employ supervised learning strategies on variants from ClinVar database  to evaluMost of the computational methods use prediction features and then identify and implement the best performing algorithm on a training data set to classify and curate the pathogenicity of variant . Some prhttps://www.ncbi.nlm.nih.gov/clinvar/  FTP site available at clinvar/ . A custoclinvar/ . This reAnother dataset, called Rett syndrome dataset, consists of variants in MeCP2 gene that are associated with Rett syndrome . The dathttps://sites.google.com/site/jpopgen/dbNSFP)  . This daF-measure and Mathews correlation coefficient (MCC) calculated using the number of true positives (TP), true negatives (TN), false positives (FP) and false negatives (FN)   to colleves (FN) .For the development of the best predictor set, firstly we evaluated the two class of attributes or features (independent and ensemble predictors scores) separately using the ranker attribute evaluation method. This provides with a list of the best performing in-silico algorithms. Secondly, we identified the best combination of in-silico predictors that includes top performing independent and ensemble predictors that can best classify the variant as either benign or pathogenic. The \u201cranker\u201d option nested under the classifier attribute evaluation method is used for ranking features (in-silico scores), it is a fast and precise method that considers only relevant attributes and eliminates both irrelevant and redundant features that ranking our methods based on more on correlation. Thus, the algorithm ranks the features based on their strength of classification. We also use Random forest as a classifier method along with the Ranker evaluator method to rank and evaluate the in-silico predictor based on performance.The predictors\u2019 scores on the golden dataset with 4,354 variants bearing stronger evidence to be categorized as pathogenic and benign were used as an input for the machine learning algorithms. For the first step of our analysis we applied the best performing classification methods for the evaluation of our dataset. After identifying Random forest as the best classifier method, we evaluated the performance of the in-silico predictors separately based on the strength of classification of a variant into benign or pathogenic class. Comparing the statistics obtained from the classification method  we identWe also performed evaluation of dependent predictors and independent/ensemble predictors separately using the 10-fold cross validation strategy by implementing random forest method to check for the best performing classification predictors based on accuracy and other statistics of predictions. The ensemble predictors outperform the independent predictors with an accuracy of ~97% along with higher sensitivity, specificity and MCC values .The results from the feature evaluation of the ranking attribute methods for both the independent and ensemble predictors separately identified the best in-silico predictors that can now be used to classify the variant data better into pathogenic and benign sub-categories.VEST3, LTR, Polyphene2 and PROVEAN are identified as the top four ranked independent in-silico predictors and CADD, Eigen, MetaSVM and REVEL are identified as the top four ranked ensemble in-silico predictors. The classification of SNVs with the top four predictors from both independent and ensemble predictor categories together shows a better and stronger evidence to evaluate variant pathogenicity. The higher rate of observed accuracy, sensitivity and the MCC statistics from the classification of our data with just the selected eight features proves that our combined in-silico predictor set can be highly reliable with comparatively minimal algorithmic biases . Figure The 197 variants associated with Rett syndrome collected from the ClinVar database includes 101 variants which are categorized into likely benign/pathogenic, uncertain significant (VUS) and conflicting interpretations of pathogenicity classes, along with 64 pathogenic and 1 benign variant.We used our best in-silico predictor set to reclassify the above (64 pathogenic and 1 benign) variants either as pathogenic or benign with an average classification accuracy of 89% and 100%, respectively . This asThe advances in computer algorithm had been widely utilized in the evaluation of the pathogenicity of a variant. We evaluated the performance of 14 prominent in-silico computational algorithm methods with 4354 SNVs from purged ClinVar database (golden dataset). We also evaluated the performance of eight independent and six ensemble predictors that led us to identify the best combination of in-silico predictors that can categorize variants into either disease causing or not. Our initial investigation revealed that the ensemble prediction algorithms outperformed the independent algorithm with a higher accuracy of variant categorization.Our individual assessment of the in-silico prediction methods shows that VEST3 is the best performing independent predictor method with high accuracy of classifying variants. However, the main limitation is that this algorithm is based on prioritization of missense variants thus creating a partizanship biases in evaluating the non-missense variants. Similarly, Eigen and CADD are the best performing empirical algorithms based on accuracy of classification which is also highly influenced by the algorithm constrain that decreases the sensitivity and specificity of variant characterization. The pathogenicity of variant can also be associated with the different scoring strategies used by either supervised or unsupervised learning methods. This provides us with a strong platform to investigate a combinatory approach that includes both dependent and empirical predictors to evaluate the pathogenicity of a variant.Although there are many studies that performed comparative investigation to identify the best performing in-silico predictor method,  in theirTo select the best combination of predictors, we first used the attribute ranking method for overall ranking of the predictors, followed by combination predictors using each in-silico predictor sub-group (independent and ensemble). We picked the combination with the least number of predictors with the highest prediction accuracy. Based on the statistics obtained (a few combinations are highlighted in After we demonstrated that the algorithm performs well, it was applied to reclassify the variants associated with RETT syndrome listed as uncertain or conflicting clinical significance. This reclassified set can be used to guide further clinical investigation for mutants linked with Rett syndrome along with studies about the effects of mutation on wild type characteristics of the corresponding protein.In summary, our combinatory approach of using both best performing independent and empirical predictors reduces any algorithm biases in variant characterization. Our robust training dataset composed of ClinVar variants filtered based on strong evidences for pathogenic and benign characteristics can reduce the false positive and true negative results. Also, similar filtering approaches for data preparation can be used in development of new methods for accessing the functional effect of a variant. Though in-silico predictors are just one of data point in evaluation of variant pathogenicity along with other information such as allele frequency, our predictor set will aid in consolidated balanced prediction thus increases the confidence of evaluation. This also could provide sufficient evidence for clinical genomicist and researchers to understand and evaluate the pathogenicity of variants whose clinical relevance is unknown.10.7717/peerj.8106/supp-1Supplemental Information 1Click here for additional data file.10.7717/peerj.8106/supp-2Supplemental Information 2Click here for additional data file.10.7717/peerj.8106/supp-3Supplemental Information 3Click here for additional data file.10.7717/peerj.8106/supp-4Supplemental Information 4Click here for additional data file."}
+{"text": "While cognitive decline and memory loss are the major clinical manifestations of Alzheimer\u2019s disease (AD), they are now recognized as late features of the disease. Recent failures in clinical drug trials highlight the importance of evaluating and treating patients with AD as early as possible and the difficulties in developing effective therapies once the disease progresses. Since the pathological hallmarks of AD including the abnormal aggregation of amyloid-beta (A\u03b2) and tau can occur decades before any significant cognitive decline in the preclinical stage of AD, it is important to identify the earliest clinical manifestations of AD and elucidate their underlying cellular and molecular mechanisms. Importantly, metabolic and non-cognitive manifestations of AD such as weight loss and alterations of peripheral metabolic signals can occur before the onset of cognitive symptoms and worsen with disease progression. Accumulating evidence suggests that the major culprit behind these early metabolic and non-cognitive manifestations of AD is AD pathology causing dysfunction of the hypothalamus, a brain region critical for integrating peripheral signals with essential homeostatic physiological functions. Here, we aim to highlight recent developments that address the role of AD pathology in the development of hypothalamic dysfunction associated with metabolic and non-cognitive manifestations seen in AD. Understanding the mechanisms underlying hypothalamic dysfunction in AD could give key new insights into the development of novel biomarkers and therapeutic targets. Alzheimer\u2019s disease (AD) is the leading cause of dementia in the elderly and remains an incurable and devastating neurodegenerative disease  leptin is affected in AD. Leptin is produced in proportion to adiposity and serves as a critical negative afferent signal to the brain and in particular the hypothalamus to regulate body weight and systemic metabolism  have been found in several epidemiological studies to be risk factors for cognitive decline and AD , which contains neurons that synthesize the neuropeptide orexin (hypocretin). Orexin is critical for the maintenance of sleep-wake architecture by promoting arousal with orexin deficiency resulting in narcolepsy (Tsujino and Sakurai, Drosophila or transgenic mouse model of A\u03b2 pathology increased A\u03b2 burden (Kang et al., Substantial support also exists for sleep dysfunction worsening AD pathology and increasing the risk for developing dementia (Mander et al., Closely related to sleep disorders, circadian rhythm abnormalities including disrupted day-night activity patterns are common in AD patients (Musiek et al., The hypothalamus has long been recognized as a major regulator of both circadian rhythm and aggressive behaviors, suggesting a potential role in sundowning. Dysfunction in the hypothalamic SCN, the central pacemaker, is a likely mediator of circadian rhythm disorders in AD (Van Erum et al., Drosophila models exhibit circadian behavioral abnormalities despite normal central clock function, suggesting that A\u03b2-related circadian abnormalities may also stem from a \u201ccentral clock output failure\u201d in which the SCN fails to entrain brain-resident and peripheral clocks (Chauhan et al., Molecular and genetic studies in animal models further support the hypothalamus and in particular the SCN playing a central role in circadian rhythm disorders associated with AD pathology. A mouse model of A\u03b2 pathology was found to have dampened SCN excitability rhythms, concurrent with circadian-associated behavioral disturbances and reduced daytime A-type potassium currents (Paul et al., We have briefly reviewed select recent findings on the metabolic and non-cognitive manifestations of AD that can occur before the cognitive decline and focused specifically on disorders of body weight, sleep and circadian rhythm. We provide evidence that these metabolic and non-cognitive manifestations of AD are due to hypothalamic dysfunction caused by AD pathology and can be bidirectional and feed-forward in nature Figure . FurtherDespite recent advances, there are significant gaps in our knowledge. The hypothalamus is a complex brain region comprised of numerous distinct molecular cell types with each potentially a part of multiple different pathways. While several studies using a candidate-based approach have identified select individual cell types affected by AD pathology (Ishii et al., While cognitive manifestations have deservedly received the bulk of the attention in AD research, non-cognitive manifestations are often correlated with disease progression, increased morbidity including institutionalization, and increased mortality. These non-cognitive signs and symptoms could be developed as inexpensive and readily accessible markers of AD progression in a clinical setting. Moreover, elucidating the underlying molecular mechanisms for these early clinical manifestations of AD may yield important insights into novel pathways affected in AD, which could lead to the development of important new therapeutic targets.All authors participated in the study design, drafted/revised the manuscript, approved the final version and agreed to be accountable for all the aspects of the work.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The 1996 welfare reform law replaced the existing entitlement to cash welfare with a transitional program of temporary aid that has employment as its primary goal. Among the key provisions of the welfare reform legislation were mandatory time limits on benefits and work requirements for all recipients, including those with substance use disorders.Changes brought about by the welfare reform law have important implications for the organization of substance abuse services and the well-being of disadvantaged children whose parents have substance use disorders. The overall effect of welfare reform could be positive. It gives States wide latitude to design programs to help low-income people attain self-sufficiency and has increased interest in developing innovative programming for hard-to-employ welfare populations, including those with substance use disorders . This inResearch on substance use disorders in the context of welfare reform has primarily focused on four questions:What is the prevalence of substance use and substance use disorders among Temporary Assistance to Needy Families (TANF) recipients?To what extent are substance use disorders and co-occurring problems a barrier to employability?Can screening strategies in welfare settings successfully identify and refer clients to substance abuse treatment?What types of services do these clients need to attain self-sufficiency?This article reviews findings on these questions and offers suggestions for how these findings can inform policy and future research.Prevalence rates for substance use problems among TANF recipients vary widely depending on study methodology and on how problem use is defined. Most recent studies cite survey data that relies exclusively on administrative data or self-reports of substance use , both ofThe exclusive reliance on self-report data is a serious limitation of these findings. Many experts now consider data on the prevalence of substance use drawn from the NHSDA to be unreliable because of underreporting. Findings from a study comparing self-report and biological measures of substance use among welfare recipients suggest that substantial underreporting may occur. Although substance use disorders affect a minority of TANF recipients, findings from many studies have shown that TANF recipients who use substances have high rates of other co-occurring problems . For exaStudies which have followed TANF clients over time consistently have found that having a substance use disorder predicts poorer employment outcomes . For exaMost people are reluctant to disclose having a substance use problem because of the stigma involved . TANF reIn a more recent study a, researLittle research to date has examined interventions designed specifically to address substance use problems in women on welfare. Generally, studies indicate that these women have myriad co-occurring problems in the areas of mental health, domestic violence, and medical care, as well as legal issues. Thus, interventions designed to specifically address substance abuse may not effectively address the significant and chronic problems experienced by women receiving welfare benefits. Interventions that provide gender-specific services and coordination across multiple service domains to address the co-occurring problems these women experience may be most effective.Two recent studies examined the effectiveness of case management (CM) at addressing the multiple problems experienced by substance-abusing women on welfare: CASAWORKS for Families (CWF) b and CASCWF was a demonstration program testing an intensive intervention for TANF women with substance use problems in 10 counties around the country b. CWF ofAlthough this was not a randomized clinical trial, results indicate that integrated care programs may be effective for addressing the multiple needs of substance-abusing women on welfare. However, such programs require careful attention to the coordination of services across agencies as well as other implementation issues.CASASARD was the result of a collaboration between researchers and the New Jersey Department of Human Services (NJDHS) to compare intensive case management (ICM) with usual care (UC) in two counties in New Jersey b. Women Overall, best estimates suggest that 8 to 20 percent of women on TANF have a substance use problem that probably interferes with their functioning . Women wOverall, available research supports policies that have identified TANF recipients with substance use disorders as part of a group of hard-to-employ (HtE) recipients who require more intensive services than the typical brief training programs followed by work assignments that most welfare settings offer. However, substantially more research is needed to provide critical answers to the questions posed at the beginning of this article regarding an evaluation of the broad impact of welfare reform on disadvantaged mothers with substance use problems. Given the funding constraints and particular challenges associated with conducting this type of research, it is critical to find new ways for substance abuse health services researchers to collaborate with State and Federal welfare agencies on this agenda. Overall, Federal and State governments face important questions regarding the handling of HtE welfare recipients: What services are effective in helping HtE recipients move toward self-sufficiency? Can States afford to provide these services? And what are the consequences, both human and economic, when such families are removed from the welfare roles? Further research is urgently needed to inform policy in this area."}
+{"text": "Uncorrected refractive errors (URE), predominantly myopia, remains the leading cause of vision loss worldwide including in South Asia.Vision impairment (VI) is a global public health challenge that affects an estimated 253 million people.According to projections reported by Holden et al it is estimated that URE and mainly myopia was the most common cause of distance vision impairment affecting over 108 million people worldwide in the year 2010.The South Asia region comprises eight countries, including India, Pakistan and Bangladesh, three of the 10 most populated countries in the world. The region hosts 23 per cent of the world population and shares a disproportionately large burden of 30 per cent of the global VI.The Refractive Errors Studies in Children (RESC) reported a higher prevalence of myopia in children from urban India (Delhi) compared to rural India (Mahbubnagar). The prevalence of refractive errors in rural Nepal was the least (1.2 per cent). This two-to three-fold higher prevalence of myopia in urban children is predominantly due to increased near work activities. A recent longitudinal study conducted among children in India revealed that an increase in near-work activities such as reading and writing per week, excessive use of electronic gadgets such as computers, tablets, video games and watching television were significant risk factors for progression of myopia.The prevalence of myopia in older adults is highly variable in the region ranging from close to 20 per cent in central India to 43 per cent in Myanmar. This large variability is due to several factors including the age of the participants and other risk factors such as ethnicity. Some myopia in the older age groups may be due to nuclear cataract  of the lens). A good cataract surgery programme will be able to address myopia caused due to cataract.Addressing the myopia challenge in SA needs a multi-pronged approach based on early detection and appropriate correction. As school children form a captive group, school-based eye health programmes or camps can detect myopia in children and provide appropriate correction. Community-based screening programmes (CSP) are often conducted by non-government organisations in this region. The CSPs are conducted as \u201cmake-shift clinics\u201d set-up in areas where limited eye care services are available. All those visiting these clinics are screened for vision impairment. Those with refractive errors are provided spectacles and those with uncorrectable vision loss are referred to a base hospital where services including cataract surgery are provided. The vision centre (VC) model of primary eye care service delivery has evolved in India and now spread to other countries with relevant local modifications.Myopia is considered to be a correctable form of vision loss. Spectacles remain the mainstay for correction of myopia in the SA region. However, with new technological innovations and more predictable outcomes, refractive surgery is increasing especially in urban areas. Recognising the importance of preventing the progression of myopia, several modes of prevention are being tried. Orthokeratology (ortho-k) reverse geometry contact lenses are one such modality. These contact lenses worn overnight temporarily aim to reshape the corneal surface. Pharmacological interventions to reduce myopia and axial elongation have been evaluated in a few studies.This issue of the South Asia edition will provide a comprehensive review of myopia in the region. Ravilla et al provide an overview on spectacle dispensing at the community level. Acharya et al describe the current trends in surgical options for correction of myopia. Murthy et al describe the models of myopia correction at a population level. Verkicherla et al highlight new promising technologies and artificial intelligence in early detection and management of myopia in the region. These models for correction of myopia and application of innovation and technology to address the myopia challenge are also presented.The authors wish to thank Shashank Yellapragada and Dr Rohit C Khanna for contributing to this article."}
+{"text": "Existing population-based surveys have limited accuracy for estimating the coverage and quality of management of child illness. Linking household survey data with health care provider assessments has been proposed as a means of generating more informative population-level estimates of effective coverage, but methodological issues need to be addressed.A 2016 survey estimated effective coverage of management of child illness in Southern Province, Zambia, using multiple methods for linking temporally and geographically proximate household and health care provider data. Mothers of children <5 years were surveyed about seeking care for child illness. Information on health care providers\u2019 capacity to manage child illness, or structural quality, was assessed using case scenarios and a tool modeled on the WHO Service Availability and Readiness Assessment (SARA). Each sick child was assigned the structural quality score of their stated (exact-match) source of care. Effective coverage was calculated as the average structural quality experienced by all sick children. Children were also ecologically linked to providers using measures of geographic proximity, with and without data on non-facility providers, to assess the effects of these linking methods on effective coverage estimates.Data were collected on 83 providers and 385 children with fever, diarrhea, and/or symptoms of ARI in the preceding 2 weeks. Most children sought care from government facilities or community-based agents (CBAs). Effective coverage of management of child illness estimated through exact-match linking was approximately 15-points lower in each stratum than coverage of seeking skilled care due to providers\u2019 limited structural quality. Estimates generated using most measures of geographic proximity were similar to the exact-match estimate, with the exception of the kernel density estimation method in the urban area. Estimates of coverage in rural areas were greatly reduced across all methods using facility-only data if seeking care from CBAs was treated as unskilled care.Linking household and provider data may generate more informative estimates of effective coverage of management of child illness. Ecological linking with provider data on a sample of all skilled providers may be as effective as exact-match linking in areas with low variation in structural quality within a provider category or minimal provider bypassing. There are numerous proven interventions for preventing and managing child illness in low- and middle-income countries (LMICs). Despite the efficacy of these interventions, low intervention coverage and poor quality of care has limited their impact on child survival. Intervention coverage is defined as the proportion of a population in need of an intervention that receives the intervention . GovernmExisting population-based household survey methods have limited accuracy for estimating the coverage of management of child illness due to issues including maternal recall, reporting bias, and disease identification -4. AdditThere are several methodological issues to consider when linking household and health care provider assessments. Linking analyses use information on care-seeking from household surveys to assign an individual to one or more potential sources of care to assess the service environment most likely encountered by individuals seeking care. A recent systematic review found almost 60 studies published since 1990 have linked information from household surveys and service environment assessments to address questions about access to and use of reproductive, maternal, newborn, and child health (RMNCH) interventions in LMICs [We implemented a study in Southern province, Zambia to assess the feasibility of collecting geographically and temporally concurrent household and health care provider data at a small scale in both an urban and rural setting to perform exact-match linking. We also aimed to quantify the degree of bias introduced by using less rigorous linking methods, including multiple ecological linking methods and utilization of facility-only health care provider assessments.The study was nested in a validation study of maternal reports of care-seeking for childhood illness  and was Mothers report approximately 70 percent of children in Southern Province with fever, diarrhea, or ARI symptoms are taken for care, primarily in the public sector . The ZamThe study included two components; 1) a household survey on care-seeking for child illness, and 2) an assessment of health care providers\u2019 structural quality for managing child illness. Ethical approval for the study was obtained from the Institutional Review Boards of Johns Hopkins Bloomberg School of Public Health and Excellence in Research Ethics and Science (ERES) Converge in Zambia. The Zambian Ministry of Health granted permission and the Choma District Health Office provided support to survey government health facilities in the study area.In each of the urban and rural strata, 700 households were randomly sampled from the health facility catchment areas (HFCAs) of five government health facilities in and around Choma town. Households were randomly sampled from the catchment population of three rural health centers using an existing household listing created in 2014 . Urban hHouseholds were enrolled in the study from January 18 to February 13, 2016, and subsequently revisited approximately four to six weeks later for the household care-seeking survey completed between March 3-20, 2016. Mothers were asked about child illness and care-seeking using a questionnaire based on the 2013-2014 Zambia DHS (ZDHS). These included questions about the presence of diarrhea, fever, or suspected ARI in each of their children <5 years in the preceding two weeks. If a child experienced an illness, mothers were asked if care was sought, the source of care, and treatment received. In addition to the series of DHS care-seeking questions, mothers answered questions to ascertain the name of the specific source of care and sequence of care-seeking events. If the name of the source of care was unknown, data collectors were instructed to probe about provider location and other identifying features.Concurrent to household enrollment, health care providers were identified and invited to participate in the provider assessment. The term health care provider will be used to refer to both individual providers such as CBAs and traditional practitioners, and health care outlets that include multiple staff such as health facilities and pharmacies. Public, private, informal, and traditional sources of care were included in the assessment. Community leaders and health workers initially provided a list of commonly utilized care providers offering medicine or alternative treatment for sick children. The list was further expanded with information from participating mothers about common sources of care for treating illness in their children <5 years collected during enrollment. All providers included in the assessment were grouped into categories of providers used in the ZDHS \u2022 Malnutrition Diagnostic \u2022 ARI Diagnostic (stethoscope or respiratory timer)\u2022 General microscopy (functioning microscope and slides)Basic medicines\u2022 Oral rehydration solution\u2022 Zinc\u2022 Artemisinin combination therapy (ACT)\u2022 Oral antibioticSevere/complicated illness medicines\u2022 IV fluids\u2022 Injectable quinine or artesunate\u2022 Injectable antibioticsHuman Resources\u2022 Training (at least one staff member with IMCI or relevant training)\u2022 Guidelines (IMCI guidelines or relevant guidelines or job aid available)\u2022 Supervision (received supervision visit with case management observation in past 3 months)Available services\u2022 Diagnosis and treat malaria (by pathology)\u2022 Diagnosis and treat diarrhea (by pathology)\u2022 Diagnosis and treat ARI (by pathology)\u2022 Diagnosis and treat malnutrition (by pathology)\u2022 Facilitated referral capacityKnowledge\u2022 Average performance on case scenariosThe primary outcome was input-based effective coverage of management of child illness estimated through exact-match linking and ecological linking methods. Effective coverage of management of child illness was calculated as the average level of structural quality experienced by sick children based on their reported care-seeking behavior and linked source of care. Each child was assigned the structural quality score of either their specific reported source(s) of care (exact-match linking) or the closest provider(s) based on measures of geographic proximity . The linking was performed using provider assessment data on all health care providers, to reflect capacity among all categories of providers, and data on only health facilities, to replicate the provider data available through common provider assessments such as the SPA or SARA. We considered estimates of effective coverage generated through the exact-match linking using data on all health care providers to be the most accurate linked coverage estimate. However, we did not assess the validity of the effective coverage estimates generated through the method against a true measure of how sick children in the study area were managed.The input-based effective coverage estimate reflects an upper limit on the proportion of children that could have been correctly managed. Estimates generated using the ecological linking methods and using data on only facility-based providers were compared against the exact-match all-provider coverage estimates to assess their population-level validity, or how closely they reproduced the exact-match all-provider estimates of effective coverage.For exact-match linking, each sick child was linked to the specific source(s) of care from which care was sought, based on the name of the facility, outlet, or provider reported by the mother during the household survey.Online Supplementary Document(Online Supplementary Document). Linked data sets were exported to Stata 14.2  for analysis.For ecological linking, each sick child was linked to the closest provider(s) based on various measures of geographic proximity. Seven methods for ecological linking were employed, depicted in The seven measures of geographic proximity used in the ecological linking can be grouped into three categories: methods linking children 1) to the single nearest provider by distance, 2) to all providers within a defined geographic unit, and 3) using kernel density estimation.Single nearest provider link:Nearest Absolute Distance: Child was linked to the single closest provider based on absolute distance within the reported source of care provider category. This is the simplest method for assigning a child to a specific provider.Nearest Travel Distance: Child was linked to the single closest provider by road distance within the reported source of care provider category. This method is designed to model the effect of road access and quality on care-seeking.Aggregation of Providers within Geographic Unit Link:Radius - 5 Kilometer: Child was linked to all providers within the source of care provider category within a 5 km radius of the child\u2019s home. This method is designed to approximate a 1-hour walking distance from a household to a provider in any direction.Administrative Unit \u2013 HFCA: Child was linked to all providers with the source of care provider category within the health facility catchment area (HFCA) in which the child resides. This method is designed to mimic the effect of using aggregate data at a small scale (enumeration area / cluster) and corresponds with a government health facility designated catchment area.Administrative Unit \u2013 Total Study Area: Child was linked to all providers with the source of care provider category included in the study. This method is designed to mimic the effect of using aggregate data as a medium scale (sub-district).Kernal Density Estimation (KDE): The KDE method was designed to model the level of draw a provider exerts over households as they decide to seek care, based on distance decay and characteristics of the provider. KDE has been used as a means of modeling health care access  and servKDE \u2013 Single Highest: Child was linked to the closest provider within the single provider category that exerted the greatest draw on the child\u2019s household.KDE \u2013 Weighted Aggregate: Child was linked to the closest provider in all provider categories that exerted any draw on the household. The contributions of the linked providers\u2019 structural quality scores were weighted by the draw for the provider category relative to the other provider categories.For the exact-match linking, each sick child was assigned the structural quality score for the specific source(s) from which care was sought. If care was reportedly sought from more than one source, the child was assigned the average score for all providers from which care was sought. If no care was sought for the illness, the child was assigned a structural quality score of zero. If the mother reported a source of care that could not be identified or included in the provider assessment, the child was assigned the average structural quality score for the source of care provider category within the stratum . Effective coverage was calculated as the average structural quality score (a percentage ranging from 0 to 100) across all sick children, including those who were not taken for care (who received a score of 0).For the ecological linking, each sick child was assigned the structural quality score for the source(s) of care that were closest based on various measures of geographic proximity, as described above. All non-KDE ecological linking methods maintained the reported category of source of care. In other words, a child could not be linked to a provider from a category of source of care other than the category reported by the mother  to which he/she was linked might vary depending on the measure of geographic proximity). Similar to the exact-match linking, children that were not taken for care were assigned a structural quality score of zero. Those that could not be linked to a provider from the reported source of care were assigned the average structural quality score for the category of source of care within the stratum. For example, when applying the 5 km radius linking approach, if a rural mother reported that her child was taken to a government health center for care but there was no government health center within 5 km of the household, the child was assigned the average of all government health centers in the rural area. If a child was linked to multiple providers, the average structural quality score for all linked providers was calculated for the child. Effective coverage was calculated as the average structural quality score (a percentage ranging from 0 to 100) across all sick children, including those who were not taken for care (who received a score of 0).To simulate the type of provider data that would typically be available when using a SPA or SARA for linking, we repeated the analysis using only facility data. Coverage was estimated using the exact-match linking method and each of the seven ecological linking methods with only facility structural quality scores. Health facilities were defined as either a government or private clinic or hospital, in line with those providers included in the SARA and SPA surveys. Presuming first-level government facilities offered the most comparable level of structural quality to government CBAs, children that reported care from a CBA were linked to one or more government health centers using the nearest provider and aggregate ecological linking methods, and assigned the average government health center structural quality score for the exact-match linking. Using the exact-match, nearest provider, and aggregate ecological linking methods, children who recieved treatment from all other sources of care  were treated as unskilled sources of care and assigned a structural quality score of zero, equivalent to seeking no care. All other components of the linking methodology and household data remained the same. Using the KDE methods, data on non-facility providers were excluded while modeling care-seeking behavior. A summary of all linking methods employed in the paper is presented in Descriptive statistics comparing the ecological and facility-only links to the exact-match all provider links were calculated. Sensitivity analyses were also conducted to estimate effective coverage using different assumptions for children that could not be linked to a provider within the reported source of care category including: 1) assigning children that could not be linked to a provider based on geographic proximity a structural quality score of zero, and 2) assigning children that sought care from a CBA a score of zero during the facility-only analysis. These sensitivity analyses were designed to mimic the effect of service environment assessments and linking analyses that define health care access based on a capped maximum distance from a household and that ignore the contribution of CBAs in management of child illness, respectively.A total of 335 rural and 469 urban households with at least one eligible mother of a child <5 years were enrolled in the study. At the time of the household care-seeking survey, 43 households (5.3%) were unavailable to complete the survey because the participating mother(s) had moved outside of the study area or to an unknown residence for the remainder of the study period, and 14 households withdrew consent for the care-seeking survey. This resulted in a loss-to-follow-up of 7.1% of households.Online Supplementary Document(Online Supplementary Document). Among the 1084 children included in the household survey, 35% of urban children and 36% of rural children experienced at least one illness meeting DHS criteria in the 2 weeks preceding the survey (Characteristics of participating children and mothers available at follow-up and included in the household care-seeking survey are shown in Table S1 in Online Supplementary Document(Online Supplementary Document)). Government health facilities had the highest structural quality scores, followed by CBAs, private facilities, and pharmacies (Online Supplementary Document(Online Supplementary Document). Facilities performed the poorest on domains related to training and guidelines and knowledge. CBAs performed poorly on availability of basic medicines and management capacity. Pharmacies excelled on measures of medicine availability but failed on all other measures. Shops and traditional practitioners performed poorly on all domains. Online Supplementary Document(Online Supplementary Document) present structural quality scores using collapsed provider categories to preserve anonymity for providers in small categories, however these values are descriptive and do not reflect the category-specific averages used in the aggregate linking approaches. Structural quality scores varied most by category of provider, and in most cases did not vary greatly within provider categories used in the aggregate linking (Table S3 in Online Supplementary Document(Online Supplementary Document)). While there were a few providers whose scores were notably above or below others within their category, these were provider categories that did not align with common source of care categories.All public and private facilities, pharmacies, and government CBAs offering child curative services, and the most commonly utilized traditional practitioners and informal drug outlets in the study area were included in the provider assessment for a total of 83 providers ). This suggests that bypassing within a category of provider was low and absolute distance was a better measure for approximating the true source of care in this setting. Among those children taken to a more distant provider by absolute distance, there was no evidence of systematically bypassing poorer performing providers for better quality providers within the same provider category (data not shown).Using the nearest absolute distance and nearest travel distance linking methods, all children for whom care was sought were linked to a provider (Online Supplementary Document(Online Supplementary Document)). In this setting, rural children on average travelled 5.4 km, up to a maximum of 16 km, to access a rural government facility (Table S6 in Online Supplementary Document(Online Supplementary Document)). However, all children that sought care in the urban area were linked to at least one provider because of the high density of providers. The total area boundary measure linked all children that sought care to at least one provider while the HFCA boundary measure linked all children with the exception of one child that sought treatment from a pharmacy in a rural catchment area with no pharmacies. The average number of providers to which a child linked by aggregate linking method is shown in Table S7 in Online Supplementary Document(Online Supplementary Document).Using the 5 km radius measure, greater than 35% of rural children that sought care were not linked to a provider because they resided more than 5 km from any provider within the reported category of source of care and were assigned the average structural quality score for the category of source of care (Online Supplementary Document(Online Supplementary Document)). The KDE single link method linked 70% of rural children and 84% of urban children to a skilled care provider. The KDE weighted link method linked 73% of rural children and 100% of urban children to a skilled care provider. The KDE single link method reproduced the care-seeking behavior of almost 40% of rural children but only 1% of urban children (data not shown).Using the KDE methods, all urban children and 80% of rural children were linked to at least one source of care, representing a higher care-seeking rate than observed in the study  of rural children and 62% (95% CI\u2009=\u200955-69) of urban children. Using the exact-match linking method, effective coverage of management of child illness was estimated at 60% (95% CI\u2009=\u200956-65) in the rural area and 49% (95% CI\u2009=\u200944-54) in the urban area (Online Supplementary Document(Online Supplementary Document)). Both KDE linking methods generated similar estimates of effective coverage in the rural area (55%) but overestimated effective coverage in the urban area  by overestimating the proportion of sick children taken for care.The single nearest provider and aggregation of providers by geographic unit linking methods generated similar effective coverage estimates to the exact-match linking method ). Under the 5 km radius linking method, the proportion of rural children that could not be linked to a provider from the reported source category increased to 61%, while the proportion of urban children that could not be linked remained low at 9% (Online Supplementary Document(Online Supplementary Document)).Use of facility-only data further reduced the number of children in the rural area that were linked to their specific reported source of care through the single link ecological methods  by excluding care-seeking events with CBAs and other community-based providers (Table S4 in Online Supplementary Document(Online Supplementary Document)). The difference in the facility-only estimates from the exact-match all-provider estimates ranged from -9 to -22 percentage points in the rural area if CBAs were treated as unskilled providers during the linking analysis.Estimates of effective coverage of management of child illness calculated using facility-only data did not differ significantly from the all-provider estimates using the exact-match, single nearest provider, and aggregation of providers by geographic unit linking methods when CBA care-seeking events were linked to government health centers  of care, and structural quality data was collected on most sources of care in the study area. Effective coverage of management of child illness was approximately 15 percentage points lower than skilled care-seeking in the study area due to providers\u2019 imperfect structural quality. All non-kernel density estimation ecological linking methods produced similar estimates to the exact-match linking when children who could not be linked to a provider based on geographic proximity were assigned an average provider category score. Linking using data only on health facilities, like that available through the SPA or SARA, produced similar estimates when first-level health facilities were used as proxies for CBAs. These findings suggest linking household and health care provider data may be a viable method for generating more informative estimates of management of child illness, and less rigorous methods may be as effective as exact-match linking in certain contexts.We found that most mothers could report their sick child\u2019s specific source of care and structural quality data could be collected on the majority of health care providers in the study area, making the exact-match linking method feasible at this small scale. Almost all care-seeking events took place with a provider included in the provider assessment. The method failed to identify some minor sources of care, primarily informal shops in the urban area. Informal shops had very low potential for appropriate management of child illness, suggesting exclusion of these providers from the provider assessment may be justified. However, in settings with greater diversity in sources of care, ability to identify and assess private and community-based providers may be a limiting factor.A number of analyses have used ecological linking methods to assess access to primary care or the effect of service environment on utilization of curative services including KDE , adminisEcological linking methods did present some limitations. In areas with a low density of providers, ecological linking methods such as the 5 km radius method that cap the maximum link distance between a household and provider may fail to link children to a source of care. Conversely, KDE methods may overestimate care-seeking behavior and subsequently effective coverage in areas with a high density of skilled providers due to an overestimation of the draw exerted by providers. KDE was ineffective in modeling care-seeking behaviors in this context. Collecting household data on the category of provider from which care was sought and maintaining this information during linking analyses was important in generating accurate measures due to variation in structural quality between categories of providers. There was evidence in this population of bypassing lower-level providers, such as CBAs, for government health facilities, further emphasizing the need to collect and maintain information on source of care category.The availability of provider data for all sources of care vs only health facilities can also affect estimates of coverage. CBAs are a skilled source of care for some child illnesses in Zambia . We founSPA and SARA surveys often only collect data on a sample of facilities. Our study was too small to explore the effect of sampling on coverage estimates, however, a study by Skiles and colleagues found ecological linking with a sample of facilities resulted in high misclassification of links to closest providers and inaccurate estimates of service environment when compared to a facility census .The generalizability of these results is limited by its small scale and low diversity in sources of care for child illness. The public sector is an important source of care for child illness in many sub-Saharan African countries , howeverLinking household and provider data may generate more informative estimates of effective coverage of management of child illness. Our results suggest ecological linking with provider quality data on at least a sample of all skilled providers may be as effective as exact-match linking in areas with low variation in structural quality within commonly utilized provider categories or minimal provider bypassing. Assessment of non-facility providers is important in areas where these providers are a significant source of skilled care for sick children. Additionally, ecological linking methods must maintain or effectively reproduce apportionment of source of care by category of provider. This methodology is promising because it utilizes existing data collection mechanisms to generate a more complete picture of the management of child illness. This study was conducted on a small scale in an area with high rates of care-seeking for child illness from the nearest public sector provider. More studies are needed at a larger scale and in areas with a more diverse health care provider landscape to further evaluate the feasibility of the linking methodology. Additional research will support the development of guidelines for conducting linking assessments and potentially integrating this methodology into existing data collection mechanisms."}
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+{"text": "HIV drug resistance (HIVDR) poses a threat to the HIV epidemic control in Zambia especially in sub-populations such as the 15\u201324 years where there is poor virological suppression. Understanding the prevalence and patterns of HIVDR in this population (15\u201324 years) will contribute to defining effective antiretroviral therapy (ART) regimens, improving clinical decision making, and supporting behavioral change interventions needed to achieve HIV epidemic control.A cross-sectional analysis of study enrollment data from the Project YES! Youth Engaging for Success randomized controlled trial was conducted. Participants were 15 to 24 years old, who knew their HIV status, and had been on ART for at least 6 months. All participants completed a survey and underwent viral load (VL) testing. Participants with viral failure  underwent HIVDR testing which included analysis of mutations in the protease and reverse transcriptase genes.A total of 99 out of 273 analyzed participants receiving ART had VL failure, of whom 77 had successful HIVDR amplification and analysis. Out of the 77, 75% (58) had at least one drug resistant mutation, among which 83% (48/58) required a drug change. Among the 58 with HIVDR mutations, the prevalence of at least one HIVDR mutation to nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) were 81%, 65.5% and 1.7%. The mutation M184V which confers resistance to NRTI drugs of lamivudine (3TC) and emtricitabine (FTC) was the most common (81%) among NRTI associated mutations followed by K65R (34.5%) which is associated with both tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide fumarate (TAF) resistance. Thymidine analogue mutations (TAMs) which confer resistance primarily to zidovudine (AZT), stavudine (d4T) and other NRTIs were observed at 32.8%. Common TAMs were K70RTQNE (32.8%), K219QE (22.4%), D67N (17.2%) and T215IT (15.5%). The most common NNRTI associated mutation was the K103N (65.5%) which confers resistance to both efavirenz (EFV) and nevirapine (NVP). There was a relatively high occurrence of other NNRTI mutations V106A (36.2%), as well as Y188C (36.2%) and Y181C (36.2%) which confer resistance to etravirine.There is a high prevalence of HIVDR including TAMs despite majority of these patients (90.48%) being on AZT or d4T sparing first line ART among the youth. Emergence of these mutations including the NNRTI associated mutations (Y181C and Y188C) may compromise future second- and third-line regimens in the absence of routine HIVDR testing. HIVDR monitoring at start of ART or at first-line failure can better inform clinical decision making and ART programing. Zambian adults prior to widespread use of ART in Zambia [Zambian adults failing first line ART had HIVDR in 2009\u20132012 [The introduction of universal access to antiretroviral therapy (ART) for chronic HIV care management has been one of the greatest achievements of the last two decades for sub-Saharan Africa (SSA) where the burden of HIV is highest . In Zambn Zambia . Subsequn Zambia . Another009\u20132012 . AnotherWhile HIVDR is recognized as a serious threat to attaining the 90-90-90 goals , 4, therThis paucity of adolescent data is a gap in our knowledge. Pediatric HIV treatment has led to an increased survival of perinatally infected children and adolescents creating a new generation of heavily treatment experienced adolescents and young adults , 12, 13.The 2019 Zambia Population-based HIV Impact Assessment (ZAMPHIA) report highlights these risks with youth achieving the lowest viral suppression rates, 34% in females and 35.7% in males aged 15\u201324 years compared to 73.0% and 74% in male and female adults 45\u201359 years . PrelimiWe thus analyzed baseline study enrollment data collected through a randomized controlled trial entitled \u201cProject YES! Youth Engaging for Success\u201d in order to determine the prevalence and characteristics of HIV drug resistance among ART- experienced youth, aged 15 to 24 years, attending four HIV care clinics in Ndola, Zambia.The cross-sectional analysis was conducted using study enrollment data from Project YES! a randomized controlled trial that tested a clinic-based peer mentoring program for HIV-positive adolescents and young adults (AYA) in four clinics in Ndola, Zambia. Project YES! study methods are described in detail elsewhere  . In brieThe recommended first-line ART regimens in Zambia at the time of this study comprised of two nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs/NtRTIs) along with a non-nucleoside reverse transcriptase inhibitor (NNRTI). The two NRTIs/NtRTIs were tenofovir disoproxil fumarate (TDF) or zidovudine (ZDV) or abacavir (ABC) plus either lamivudine (3TC) or emtricitabine (FTC) whereas the NNRTI was either efavirenz (EFV) or nevirapine (NVP). The second line regimens comprised of two NRTIs (TDF or ABC or ZDV plus 3TC or FTC) sequentially selected based on which NRTIs/NtRTIs were used in first line and a boosted protease inhibitor (PI), lopinavir-ritonavir (LPV-r) or atazanavir-ritonavir (ATV-r). Third line ART typically consisted of tailor-made regimen based on HIVDR results. The typical drugs that were available in public health facilities offering third line ART at the time of the study included the NNRTI etravarine (rilpivarine and doravarine were not yet available) and the NRTIs lamivudine and emtricitabine (for M184V mutations). PIs included lopinavir and atazanavir for patients who demonstrated sensitivity on HIVDR testing. However, in some cases the PI darunavir boosted by ritonavir was available as a third line option. Finally, raltegravir was the only integrase inhibitor available for use as a third line ART. Dolutagravir had not been introduced to the public health sector until late in the intervention phase of this study and the HIVDR testing did not test for integrase inhibitor gene regions.There had been several ART policy changes that affected ART regimens before the study. These had been implemented as part of Ministry of Health directives to health facilities over time and included drug switches from stavudine to zidovudine, nevirapine to efavirenz and more recently tenofovir to abacavir based regimes for children and adolescents. Occasionally, the drug changes were driven by drug availability, but this was rather rare. Unfortunately, there has been inadequate documentation of reasons for drug changes in most study participants medical charts.http://hivdb.stanford.edu/. HIVDR was defined as the presence of at least one drug resistance\u2013associated mutation (DRM) according to the World Health Organizations (WHO) 2009 Surveillance Drug Resistance Mutation list, using the Stanford Calibrated Population Resistance analysis tool . A cross-sectional analysis of all HIVDR results at study enrollment was done to determine HIVDR prevalence and characteristics among adolescents and young adults with virologic treatment failure.Blood samples for HIV viral load testing were obtained and collected in EDTA anticoagulated bottles. HIV viral load was determined using the Cobas Ampliprep/CobasTaqman 96 machine . Blood samples with a viral load of >1000 copies/mL (virologic treatment failure) were further subjected to an HIV drug resistance test using an Applied Biosystems Genetic Analyzer model 3500XL . HIV-1 RNA was extracted from 140 milliliter of plasma using the Qiagene QiAmp viral RNA mini kit . Genotyping encompassed protease and codons 1\u2013230 of reverse-transcriptase genes. Sequences were assembled and manually edited using Sequencer version 4.5 software . The outcomes of the HIV resistance tests were reported using the Stanford HIV drug resistance database at Ethics approval was obtained from the ERES Converge Research Ethics Committee and the Johns Hopkins University Institutional Review Board (JHU-IRB) for the parent Project YES! study. The Ministry of Health -Zambia, through the National Health Research Authority, approved the conduct of the study in the four sites.From December 2017 through May 2018, a total of 276 youth age 15 and 24 years from four clinics were recruited into the parent Project YES! study. One participant had missing study enrollment viral load results and two participants were removed from the analysis as data cleaning revealed they had been on ART for less than 6 months at start of the study. Among the 273 participants for whom study enrollment HIV-1 RNA viral load results were available, 99 participants (36.4%) had viral load \u22651000 copies/mL, signifying treatment failure. Out of these 99 participants, HIVDR amplification was successful in 77.8% (n = 77). A number of specimens with borderline viral loads failed to amplify. Resistance results were originally entered into a Microsoft\u00ae Excel 2010  database and imported into SAS 9.4  for further data cleaning, recoding and statistical analyses. The data included both continuous and categorical variables. Continuous variables, such as age, were described using means and standard deviations, and medians with value ranges and interquartile ranges (IQR\u2019s). Categorical variables, such as presence of a particular mutation, were described using frequency and percentage distributions.Among the 77 youth with an HIVDR test result, 51.7% were female, 48.3% were aged 3\u201310 years and 52% were aged 11\u201324 years at the start of ART, the mean age at the time of the study was 18.4 years, and 72% self-reported to have been perinatally infected . Based oHIV Drug Resistance associated Mutations (DRM) were identified in 75.3% (58/77) of all successful sequences. Of the 77 youth with HIVDR results, 64 were on first line and 13 were on second line ART . The preAmong the 58 patients with any resistance 48 (83%) had resistance to a drug they were currently taking and needed to switch drugs to an effective ART regimen . Out of Of the 45 who needed to switch to second line, 42 where on tenofovir based regimen, 2 on abacavir and 1 on zidovudine based regimens. Of these (n = 45), 19 had the K65R mutation that confers resistance to tenofovir and abacavir but potentiates the effectiveness of zidovudine as a second line option. Additionally, 13.3% (6 out of the 45) needing first line drug change had the type 2 TAMs combination of T215Y, D67N and K70RTQNE which in combination diminish the effectiveness of zidovudine.Drug mutations were categorized based on the WHO2017 drug mutation list and the Stanford HIV drug resistance database . The mosOverall, the 10 most common mutations were M184V (81%), K103N (65.5%), Y188C (36.2%), Y181C (36.2%), V106A (36.2), K65R (34.5%), K70RTQNE (32.8%), G190ASV (31.0%), K101EHP (31.0%) and E138AGQ (29.3%). The prevalence of mutations Y188C and Y181C was at 36.2% for and these  confer resistance to the NNRTI drug etravirine. Among the NRTI mutations, the most common Thymidine Analogue Mutations (TAM\u2019s) were K70RTQNE (32.8%), K219QE (22.4%), D67N (17.2%), T215IT (15.5%) and M41L (5.2%). The ten most common mutations to the drug class NNRTI included K103N (65.5%), V106A (36.2%), Y188C/L (36.2%), Y181C/V(36.2%), G190ASV(31%), K101EHP(31%), E138AGQ(29.3%), A98G(22.4%), P225H(20.7%), and V108I(17.2%). The N88S was the only major PI mutation (1.7%) and there were three PI-Accessory mutations of L10LF (1.7%), K20T (1.7%) and Q58E (5.2%). Additional information of mutations by ART regimen is contained in Figs Our study provides critical data on resistance among adolescents and young adults with viral failure and attending clinical care in Ndola, Zambia and it has three key findings. The study population had similar characteristics for study participants who had successful HIVDR and those who did not. First, we observed a high level of HIV drug resistance, with three quarters (75.3%) of participants with viral load failure having at least one HIVDR mutation, and more than half (62%) showing drug resistance to at least one of their current ARV drugs. This suggests that almost two-thirds of youth with VL failure need an ART drug change while over a third may be failing due to reasons other than HIVDR, such as incomplete adherence and sub therapeutic dosing. It is also possible that participants with incomplete adherence could have HIVDR but with reversion to wild type. The phenomenon of reversion HIV to wild type in the absence of sufficient drug pressure may complicate the interpretation of HIVDR results for study participants who had virologic failure but no HIVDR. Reversion to HIV wild type has been documented in various settings and has been acknowledged as a challenge to interpretation of HIVDR results , 25.High levels of HIVDR mutations are not unique to AYA or Zambia. Several studies among adults from Zambia, South Africa, Togo and Tanzania, have shown a range of HIVDR from 84\u201398% , 27. TheFurther, our study showed that most participants who had HIVDR to a current regimen were failing first-line ART  and needed a drug change to a second line regimen. This data highlights the potential role of delayed clinical decision making in this population. Interpretation of patient laboratory results solely lies with the attending health care workers. Factors that may contribute to delayed decision making may include inaccessibility of routine viral load test, delays in the turn-around times for viral load results , as well as un-timely interpretation of results that are in patient medical records. There is therefore urgent need to strengthen mechanisms to ensure timely availability of viral load results, improve tracking mechanisms for results, and clinical supervision of health care workers to support timely decision making.Secondly, this study found the prevalence of HIVDR mutations to first line NNRTI and NRTI was common (81% and 65% respectively). Only one patient (1.7%) had major protease inhibitor (PI) resistance mutation. This high prevalence of HIVDR mutations to NNRTI supports the 2020 Zambian HIV guidelines on the use of drugs with high genetic barriers, such as dolutegravir (DTG) for all age groups and protease inhibitors (lopinavir-ritonavir) for specific populations such as children ineligible for DTG  for firsAs our study sampled ART treatment experienced AYA, we do not know the prevalence of primary transmitted resistance. However, studies from Zambia and sub-Saharan region have consistently shown an increasing prevalence of primary NNRTI resistance among adults (18 years or more) and pregnant women , 16, 29.In terms of HIVDR to NRTI, the prevalence of any TAMs was at 32.8% and the most common TAM\u2019s were K70R/T/Q/N/E (32.8%), K219Q/E (22.4%), D67N (17.2%), T215IT (15.5%) and M41L (5.2%). TAM\u2019s confer resistance to zidovudine, stavudine and other NRTI. When compared to earlier studies from Zambia [It is concerning to see the high prevalence of TAMs despite the majority of these patients 90.4%) having been on zidovudine or stavudine sparing first line ART at the time of recruitment into the study. Since these patients were on tenofovir or abacavir, there is possibility that the TAMs observed were due to transmitted resistance or to archived mutations from prior drug switches/exposures. Transmitted resistance and archived mutations have reported as possible causes of HIVDR , 30. The0.4% haviThe third major finding of this study was the high prevalence of the Y188CE (36.2%) and Y181C (36.2%) mutations, indicating resistance to third line therapy etravirine and rilpivirine, to which none of our study participants had ever been exposed to. As a result, even before the restricted availability of etravirine in Zambia, more than one out of three (36%) patients with HIVDR may potentially be resistant to the only salvage NNRTI available in the public health sector in Zambia. The high prevalence of the Y181C and Y188C mutations has been demonstrated in earlier studies from the region including Zambia , 26, 11.This analysis was a cross-sectional analysis among treatment-experienced participants and could not determine primary HIVDR or causal factors leading to HIVDR among AYA living with HIV. Data was also not collected on the PMTCT exposure/prior nevirapine use among participants or their parents. Non the less, we believe that our data makes a significant contribution to the database on prevalence and characteristics of HIVDR among AYA which remains limited in literature.HIVDR represents a serious challenge for Zambia\u2019s national and regional health care systems. Many AYA with viral load failure may be resistant to their current regimens and in need of regimen change. Closer monitoring of drug resistant mutations at the start of HIV treatment or at first line failure can better inform clinical decision making and HIV treatment regimen programing.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file."}
+{"text": "C9orf72 expansions in relation to genetic ancestry and age at onset (AAO) and to use these measures to discriminate the behavioral from the language variant syndrome in a large pan-European cohort of frontotemporal lobar degeneration (FTLD) cases.We sought to characterize We evaluated expansions frequency in the entire cohort . We then focused on the bvFTD and PPA cases and tested for association between expansion status, syndromes, genetic ancestry, and AAO applying statistical tests comprising Fisher exact tests, analysis of variance with Tukey post hoc tests, and logistic and nonlinear mixed-effects model regressions.C9orf72 pathogenic expansions in 4% of all cases . Expansion carriers differently distributed across syndromes: 12/101 FTLD-MND (11.9%), 40/800 bvFTD (5%), and 4/495 PPA (0.8%). While addressing population substructure through principal components analysis (PCA), we defined 2 patients groups with Central/Northern (n = 873) and Southern European (n = 523) ancestry. The proportion of expansion carriers was significantly higher in bvFTD compared to PPA  6.4; confidence interval (CI) 2.31\u201324.99]), as well as in individuals with Central/Northern European compared to Southern European ancestry . Pathogenic expansions and Central/Northern European ancestry independently and inversely correlated with AAO. Our prediction model  predicted a diagnosis of bvFTD with 64% accuracy.We found C9orf72 expansions, AAO, PCA-based Central/Northern European ancestry, and a diagnosis of bvFTD, implying complex genetic risk architectures differently underpinning the behavioral and language variant syndromes.Our results indicate correlation between pathogenic  Several studies had shown high frequencies of pathogenic C9orf72 expansions in Northern vs Southern European patients (North\u2013South axis), especially in historically isolated populations (such as the Finnish14), leading to the hypothesis that a Scandinavian founder might be at the basis of the spread of the C9orf72 expansion.15 Other studies (based on the geographic location of the recruiting sites) challenged the North\u2013South axis concept, reporting a high frequency (\u223c25%) of pathogenic expansions in the Spanish population10 or implying to the existence of more than 1 risk haplotype.16\u201319In FTLD, repeat expansions in C9orf72 repeat expansions exhibit marked phenotypic and pathologic heterogeneity, suggesting presence of additional  modifiers.20 Despite conflicting studies reporting either direct or inverse correlation between repeat length and age at onset (AAO), C9orf72 expansions have been suggested to act as a genetic modifier of AAO.21\u201324Patients with FTLD with abnormal ifgcsite.wordpress.com/) phase III initiative, aiming at (1) characterizing C9orf72 expansions in relation to genetic ancestry and AAO and (2) assessing the usefulness of these measures in discriminating the behavioral from the language variant syndrome.We analyzed 1,396 FTLD cases gathered through the International FTD Genetics Consortium (IFGC) . The samples were recruited by clinicians and research groups who are part of the IFGC network and based in Italy, Spain, Germany, the Netherlands, Belgium, the United Kingdom, Sweden, Norway, Slovenia, or the United States . Patients were diagnosed at each contributing site  in a harmonized fashion according to international consensus criteria such as those of Neary et al.2 (for FTLD), Rascovsky et al.25 (for bvFTD), Gorno-Tempini et al.3 (for PPA [semantic dementia or PNFA]), and Strong et al.4 (for FTLD-MND).FTLD cases were collected between 2016 and 2018  , which led to the exclusion of 44 population outliers, and allowed us to address population substructure within the cohort . We also assessed cryptic relatedness and excluded 14 first- or second-degree related individuals, leaving a cohort of 1,396 cases (group 0)\u2014for which C9orf72 expansion status  was known\u2014for analyses. Frequencies of pathogenic expansions were assessed in group 0 and further analyses were performed in (1) 1,295 cases (group 1: n = 800 bvFTD and n = 495 PPA) with known C9orf72 expansion status; (2) 1,179 cases  with known C9orf72 expansion status and AAO data available; and (3) 734 cases  with AAO and repeat counts  .We first assessed the frequency of pathogenic expansions in the entire cohort (group 0). The information on presence/absence of expansions was used as a binary variable . We then investigated differences in the frequencies of pathogenic expansions across bvFTD and PPA and the Nordic and Mediterranean clusters in group 1 (Fisher exact test) and in group 3 (logistic regression); in the latter, we used rc as a categorical variable  considering the following 4 categories: no expansions (rc = 2/3), short expansions (4 \u2264 rc \u2264 8), intermediate expansions (9 \u2264 rc \u2264 24), and long expansions (rc \u2265 25), the latter representing expansions in the pathogenic range (see references t test and logistic regression) and in group 3 . In the latter case, we used rc as a categorical variable (see above).We then evaluated association between AAO and syndrome, genetic ancestry, and expansions  alone and with genetic ancestry as a covariate in group 2  using (1) presence/absence of pathogenic expansions (as binary variable [see above] for group 2) or (2) rc , ancestry as binary variable, and AAO as continuous variable using logistic regression models . A summary of the analyses workflow can be found in All analyses were performed using R studio .29 were available on the NeuroArray.26 We filtered out 7 markers in order to keep 13 informative SNPs  matching 13 of the 20 used in Mok et al.15 We evaluated the proportion of cases carrying at least 1 risk allele  for each marker assessing expansion vs nonexpansion carriers (with/without ancestry stratification).Twenty  of the original 42 single nucleotide polymorphisms (SNPs) constituting the (Finnish) risk haplotypedoi.org/10.5522/04/12418157.All data generated or analyzed during this study are included in this published article and supplementary files 1 and 2 at p = 2.17 \u00d7 10\u22125; OR 6.4; 95% CI 2.31\u201324.99, p = 4.7 \u00d7 10\u22122; OR 1.6; CI 0.0061 [2.5%]\u20130.94 [97.5%]) and long  rc ranges .We assessed the frequency of pathogenic expansions in the entire cohort and across the different syndromes in the group 0 cases . Four pedoi.org/10.5522/04/12418157) to cluster the group 1 cases based on their genetic makeup. There were 2 major clusters: cluster 1 (Mediterranean) included most of the cases (439/500 [87.8%]) recruited from Southern European sites ; cluster 2 (Nordic) included most of the cases (627/795 [78.8%]) recruited from Central and Northern European sites . Samples recruited from Eastern European (Slovenia) and North American sites distributed across both clusters, although with a higher prevalence within cluster 2 (167/795 [21%]) vs cluster 1 (42/500 [8.4%]).We performed PCA  and long  rc ranges .We observed a significantly higher prevalence of pathogenic expansions in the Nordic (35/795 [4.4%]) vs the Mediterranean (9/500 [1.8%]) cluster (Fisher exact test: doi.org/10.5522/04/12418157)\u2014we analyzed the distribution of pathogenic expansions across syndromes and clusters. Stratified Fisher exact test showed significant differences in the distribution of the pathogenic expansions between bvFTD and PPA in the Nordic (but not the Mediterranean) cluster , and between the Nordic and the Mediterranean clusters for the bvFTD (but not PPA) syndrome , suggesting that ancestry (Nordic) and syndrome (bvFTD) are independently associated with pathogenic expansions  and PPA (326/795 [41%] vs 169/500 [33.8%]), respectively  and the Nordic (61.3) and Mediterranean (64.3) clusters  (doi.org/10.5522/04/12418157). We then assessed the relationship between pathogenic expansions and AAO via logistic regression. First, we identified a significant correlation between a decrease in AAO and presence of pathogenic expansions . When we included genetic ancestry in the model, we observed a significant correlation with a decrease in AAO, with no difference in using either cluster  or PC1  as covariate and an almost 4-fold goodness of fit increase . Of note, when comparing the 2 regression models (with/without genetic ancestry as covariate) through the log-likelihood R2 ratio test, the difference (between the 2 models) appeared not to be due to chance (p < 10\u221212) .We assessed AAO in the group 2 cases . Mean AAt test: p = 2.1 \u00d7 10\u22127; CI 2.32\u20135.09; supplementary table 8A, doi.org/10.5522/04/12418157); (2) syndrome\u2014mean AAO 61.7 and 63.5 in the bvFTD and PPA syndromes, respectively , and (3) expansion length\u2014mean AAO 63.2 for both no and short expansions, 61 for intermediate expansions, and 58 for long expansions  . We then assessed the relationship between expansion length (see above) and AAO via logistic regression. First, we identified a significant correlation between a decrease in AAO and both intermediate and long expansions  . When we included genetic ancestry in the model, we observed a significant correlation with a decrease in AAO, no difference in using either cluster  or PC1  as covariate and an almost 3-fold goodness of fit increase . Of note, when comparing the 2 regression models (with/without genetic ancestry as covariate) through the log-likelihood R2 ratio test, the difference (between the 2 models) appeared not to be due to chance (p < 10\u221212) . These findings were further supported by nonlinear mixed-effects model regression using genetic ancestry as random effect covariate .We further evaluated the relationship between expansion length  and AAO in the group 3 cases . First, 29 available to us\u2014were seen in (1) 40/56 (71.4%) expansion carriers vs 380/1,340 (28.4%) nonexpansion carriers in the entire cohort; (2) 33/47 (70.2%) expansion carriers vs 228/826 (27.6%) nonexpansion carriers in the Nordic cluster; and (3) 7/9 (77.8%) expansion carriers vs 152/514 (29.6%) nonexpansion carriers in the Mediterranean cluster. Comparing the proportion of risk allele carriers (expansion vs nonexpansion carriers) for each single marker, 5/13 markers  were significant in the Nordic cluster, and none in the Mediterranean cluster . Rs2477518 showed variable frequencies for the risk allele (T) across expansion vs nonexpansion carriers (and the 2 clusters), thus making this most probably a negligible marker within this stretch, as hinted previously.17 Rs3849942, previously suggested as a surrogate marker for the risk haplotype,15 was not among the SNPs available to us. We used rs868856, displaying strongest linkage disequilibrium with rs3849942 , as informative proxy: the risk allele segregated differently across expansion vs nonexpansion carriers in the Nordic and Mediterranean cluster (as for rs2453556), possibly suggesting these 2 as the most conserved markers of the original risk haplotype across populations in expansion carriers .All of the risk alleles for the 13 markers\u2014shortest informative stretch of the original risk haplotypedoi.org/10.5522/04/12418157) and \u223c0.62  in predicting bvFTD; there were no differences in the outcome when using either cluster or PC1 as covariates in both (LOOCV and K-fold) models.We then sought to build a model to predict syndrome (bvFTD vs PPA) and assess its accuracy. We analyzed both groups 2 and 3 cases using expansion status (presence/absence of expansion for group 2 and the 4 rc factor levels for group 3 [see Methods]), genetic ancestry (using either cluster or PC1) as binary variables, and AAO as a continuous variable in logistic regression models. We observed an accuracy of \u223c0.64  of the Finnish risk haplotype29 appeared to be conserved across the Nordic expansion carriers, whereas there was a similar tendency for (just) 2 of such markers in the Mediterranean expansion carriers. Several studies had shown high frequencies of long C9orf72 expansions in Northern vs Southern European patients (North\u2013South axis).13\u201315 Other studies (based on the geographic location of the recruiting sites) challenged the North\u2013South axis concept,10 or the founder effect implying the existence of more than 1 risk haplotype.16\u201319 All this taken together, our current data appear to support the North\u2013South axis hypothesis and suggest that rearrangements (and instability)19 at the C9orf72 locus might have occurred, reducing the level of conservation of the original risk haplotype across the European population.To our knowledge, the current work is unique in that, prior to characterizing the expansions, we excluded population-substructure bias using genome-wide genotyping data to cluster the cases on the basis of their genetic makeup. After PCA, we identified 2 distinct clusters including samples with geographic ancestry corresponding to Southern Europe (Mediterranean cluster) and Central/Northern Europe (Nordic cluster). Our analyses not only showed that patients from the Nordic cluster presented significantly higher frequency of pathogenic 30\u201334\u2014suggests that C9orf72 expansions might serve as useful genetic fingerprint to define subpopulations of FTLD  found a significant inverse correlation between C9orf72 expansion length and AAO. In addition, and interestingly, our data also indicate that Central/Northern European genetic ancestry contributes to a decreased AAO (independently from the expansions), possibly implying a more complex genetic signature (or architecture), and subsequently molecular mechanisms, underpinning this feature. Clearly, disease mechanisms that involve C9orf72 expansion length and AAO are complex, thus it is likely that additional factors might further modulate their relationship and effect on the phenotype .Despite some previous conflicting reports of direct (or inverse) correlation between While using expansion length, genetic ancestry, and AAO in a regression model to discriminate behavioral from language variant subtypes, we found that such measures supported a prediction of bvFTD with 64% accuracy.35 genetic variability characterizing and differentiating Nordic vs Mediterranean subjects (such as in the case of our cohort) might influence predisposition to harboring longer repeat expansions. In other repeat expansion diseases\u2014e.g., Huntington disease or other microsatellite diseases, including myotonic dystrophy and spinocerebellar ataxias35\u2014the presence of specific haplogroups in Western European populations occurs with a manifold increase in prevalence of repeats compared to other ethnic groups and populations.36 Second, different genetic risk architectures underpinning different  subpopulations of patients may exist within the FTLD population.Our results have a number of implications. First, provided that significant variation exists in the genetic architecture of the Caucasian population,38 These concepts, reinforced by our study, warrant further characterization of genetic, environmental, and additional clinical measures to fine-tune models able to predict disease outcome to complement diagnostic criteria, and possibly assist in the identification of informative cohorts for tailored clinical trials and the development of effective personalized therapies.In a nutshell, our results imply that a significantly higher proportion of FTLD cases, with Nordic rather than Mediterranean genetic ancestry, is likely to develop bvFTD in presence of intermediate and long (pathogenic) expansions, whereas long (pathogenic) expansions are  negligible in PPA, regardless of ancestry. Clearly, multiple factors including genetic heterogeneity, epigenetic changes, ethnicity, as well as environmental factors and habits that may subsist within and across multicultural cohorts, all together, contribute to disease predisposition, onset, and progression."}
+{"text": "Delays in the identification and treatment of under-fives are among the main contributors to the complication. The aim of this study was to assess the magnitude and to identify factors associated with upper respiratory tract infection among under-five children, in public health institutions of Aksum City, Tigray Region, North Ethiopia, 2016.institutional based cross-sectional study was done. Cases were under-five children who had get service. The study participants were selected using Systematic random sampling technique. Data were entered, using Epi-info version 7 and analyzed using SPSS version 22.0. Clinical data from the chart were used to diagnose upper respiratory tract infection types. The binary logistic regression model was used to test the association between dependent and independent variables and multivariable logistic regression was used to identify the associated factors to upper respiratory tract infections.out of 213 study participants 52.6% identified as having at least one type of upper respiratory tract infection, i.e. sinusitis 22 (10.3%), 37 (17.4%) otitis media, 39 (18.3%) tonsillitis and common cold 83 (39.0%). Multivariable logistic regression analysis shows that rural residence 7.6 [AOR (95%CI) ], civil servant father's children 4.49 [AOR (95%CI) ], non-immunization 6.0 [AOR(95%CI) ], mud house wall 4.58 [AOR (95%CI) ], rental house 5.1 [AOC (95% CI)  ], were found to be statistically associated.socioeconomic, maternal and environmental factors had contributed to the upper respiratory tract infection. Strengthening of the existing disease prevention policy as well as improvement of institutional health service behavior is crucial. World Health Organization (WHO) has classified diseases of the respiratory system in the International Classification of Diseases (ICD). Respiratory diseases are categorized according to whether they affect the upper or lower part of the respiratory system ,2. UpperChildhood upper respiratory tract infections also define as the acute inflammation of nasal or pharyngeal mucosa in the absence of other specifically defined respiratory infection . HousingUnder-five children are risky population to get an upper respiratory tract infection due to lack of immune power. The important risk factor associated with respiratory diseases include malnutrition, low birth weight, climatic variations, overcrowding house, air pollution, poor ventilation and lack of environmental sanitation . The preth interval was calculated for each health facility. Finally since the sampling fraction was '2', every 2th children was included in the study and to select the first child from 480/213 =2 were used.Institutional based cross-sectional study was conducted in Aksum town which is found in the central zone of Tigray located at 1024 km away from Addis Ababa the capital city of Ethiopia as well as 241 km from the capital city of the Tigray region Mekelle since December 2015 up to June 2. The study was carried out among under-five who were attentive to public health institution of the city. The required Sample size was determined using the single population proportion formula. The following assumptions were made during calculating the sample; 95% confidence interval with a 5% margin of error, the expected proportion of upper respiratory tract infection (P) is 30% in Addis Ababa. Monthly estimated total patient flow of health facilities are 480, use correction formula to calculate the final sample size using the following formula, since total population is <10000; nf = 193 By adding 10% Non-Response rate, the total required sample size = 213 The sample size was proportionally distributed to three health institution based on the number of patients. Systematic random sampling technique by dividing the total number of eligible patient (P) by the required sample size(s), the number \u201cK\u201d obtained by dividing P/s=K was used to identify the interval among under-five from the sampling frame. Different KA structured questionnaire was used and all the variables of interest were assessed accordingly. The questionnaire comprises four parts; socio-demographic and socio-economic factors, child factors, checklist from clinical data and environmental factors. Four diploma nurse data collectors and two BSc nurses supervisors were trained for three days. Initially the questionnaire was prepared in English and it translated to the local language Tigrigna and translated back to English by different individuals to ensure understandability, and check for its consistency. The data was collected for about two months. Participants who were not interested to provide information at the time of data collection was consider as non-response. As a whole data was checked for completeness and after coding for each questionnaire and checklist data was entered into Epi-Info version 7 and the data was cleaned for inconsistencies and missing values and important amendment were done. Final data were exported to window based statistical package for social sciences (SPSS) version 22.0 Odds Ratio at 95% Confidence Interval was used to ascertain the association between dependent and independent variables as appropriate. Bivariate regression analysis was run to assess the association between the dependent and independent variable, then variable which have a P-value of <0.3 was entered to multiple logistic regression analysis to see the independent effect of predictor variables over the outcome variables. During the multivariable analysis the cut-off point for level of significance was P-value < 0.05 from the model. The strength of statically association was measured by adjusted odds ratios and 95% confidence intervals. The goodness of fit the final logistic model was tested by using Hosmer and Lemeshow test at a P-value of > 0.05. The multicollinearity was checked using VIF <2.5/tolerance test near to 1. Finally the result was summarized and presented using text, graph, frequency tables and other summary statistics.Ethical approval and consent to participate: ethical clearance were secured from the Mekelle University, College of Health Science Institution Review Board (IRB) with IRB Number 21/03/2016. Since the data is from staff Nurses permission from Tigray Regional health bureau (TRHB) and woreda offices was taken. Furthermore, written consent was taken from TRHB officer and verbal consent was agreed by all participants. However, data was recorded anonymously and confidentiallySocio-demographic characteristics: in this study, a total of 213 participants whose children under-five years aged were interviewed making the response rate 100%. The mean (\u00b1SD) age of mothers was 28.85 (\u00b16.66) years ranges from 15 to 46 years. Sixty-five (30.5%) of mothers was in the age range 25-29 years, 178 (83.6%) were orthodox by religion. The majority of mothers 193 (90.6%), were married. Regarding of residence, 166 (77.9%) were from urban, only 47 (22.1%) were from rural. The largest ethnic group was Tigray, 205 (96.2%), followed by Amara 8(3.8%) ( 8(3.8%) .Child-related variables: study subjects were asked about their caretaker of children; one hundred sixty (75.1%) of them had both parents and only 7(3.3%) of them with other guardians. Regarding of their age group 112(52.6%) of them were 6-35 months and 39(18.3%) were less than 6 months old. Two hundred three (95.5%) were delivered in health facilities out of the 171 (80.3%) were normal weight immediately after delivery  had a history of upper respiratory tract infection, 80 (37.6%) were acquired 1-2 times per year and only 2(0.9%) were above seven times per year. One hundred thirty seven (64.3%) of the children were taken intervention and 78(36.6%) of them were treated by antibiotics. Among the total participants 112 (52.6%) of were presented with at least one type of upper respiratory tract infections. Regarding of upper respiratory tract types rate, sinusitis 22 (10.3%), otitis media 37 (17.4%), tonsillitis 39(18.3%) Environmental related factors: all the study subjects were also asked about the living house, 169(79.3%) were non rental house and only 44(20.7%) rental house. One hundred sixty (81.8%) had windows . The odds of having URTI in rural area is 7.6 compared to urban 7.6 [AOR (95% CI) ]. Civil servant father children\u00b4s was statistically associated with upper respiratory tract infection (P<0.05). The odds of having URTI in Civil servant were 4.49 compared farmer 4.49 [AOR (95%CI) ]. Similarly the odds of having URTI in none fully-immunized child is 6 (p<0.01) compared to those who were fully-immunized 6 [AOR (95%CI) ]. The odds of having URTI in mud wall type 4.58 compared with cement 4.58 [AOR (95%CI) ]. Regarding of houses also showed a statistical significant association with upper respiratory tract infection. The odds of having URTI in rental house 5.1 compared to those non rental 5.1 [AOR (95%CI) ]. Family size is significant associated with the upper respiratory tract infection. The odds having URTIs in large family size is 5.3 times higher than family size with small family size compared small family size 5.3 [AOR (95% CI) ]. On the other hand, ethnicity, household monthly income, Age of children, child\u00b4s sex, Previous URTI, place of visit, history of intervention, type of intervention, malnutrition, living condition, availability of windows and practice opening window were not statistically associated with upper respiratory tract infection  . The dif15 . The In this study 80 (37.6%) were infected 1- 2 times per year compared with study conducted in America which was 6-8 in a year ,22. ThisIn this study house wall type had significantly associated; the odds of having URTI in mud wall house 4.58 compared cement 4.58 (AOR (95%CI) ]. But it is lower than the studies conducted in Iran (2007) and Kenya (2013); which indicated that all clients seen under health institutions had from mud type wall ,25. ThisBased on the findings of the current study, it can be concluded that the majority of respondents, 52.6% identified as having upper respiratory tract infection and most of them were acquired 1-2 times per year. It was found that most of rural residents were acquired upper respiratory tract infection. Civil servant father children's was statistically associated with upper respiratory tract infection. Immunization is one prevention measure of upper respiratory tract infection. Overcrowding were risk factor of upper respiratory tract infection.Unidentified respiratory infections are common cause of illness in under-five;Overcrowding, malnutrition are risk factors of respiratory problems.More than half of the respondent identified as having upper respiratory tract infection and most of them were acquired 1-2 times per year;Civil servant father children's was statistically associated with upper respiratory tract infection;Immunization is one prevention measure of upper respiratory tract infection."}
+{"text": "Anguilla bicolor bicolor). The specimens were obtained from Ci Kangean River, Alur Village, Cipatujah District, Tasikmalaya, West Java, Indonesia. The data were generated using DNA metagenomic approach on an Illumina paired-end platform by utilizing the V3\u2013V4 region of the 16S rRNA gene. A total of 151,636 reads with 91.60% effective tags and 155,388 with 84.86% effective tags were generated from the intestine of wild eel fingerling (WF) and elver (WE), respectively. The total OTUs was 100 in WF and 358 in WE. The phyla Bacteroidetes (50%), Firmicutes (15%), Proteobacteria (13%), Fusobacteria (11%) and Verrucomicrobia (8%) were found in WF, and Proteobacteria (64%), Firmicutes (34%) and Fusobacteria (1%) were found in WE. The predominating families in WF were Porphyromonadaceae (50%), Clostridiaceae (12%), Fusobacteriaceae (10%), Verrucomicrobiaceae (8%), and in WE were Enterobacteriaceae (38%), Clostridiaceae (30%), Aeromonadaceae (17%), Moraxellaceae (7%). The predominating genera in WF were unassigned (48%), Cetobacterium (10%), Clostridium (sensu stricto) (9%), Akkermansia (8%), Odoribacter (4%), Bacteroides (4%), Desulfovibrio (4%), and in WE were Plesiomonas (36%), Clostridium (sensu stricto 1) (31%), Aeromonas (17%), Acinetobacter (7%). The amount of lactic acid bacteria found in the intestine of WF was 0.0028% and WE was 0.1218%. The data provide baseline information on the changes in the community and bacterial composition in line with the stages of growth and development of wild Indonesian shortfin eels.This article describes the data on community structure and diversity of intestinal bacteria of Indonesian shortfin wild eel fingerling and elver ( The data are very useful for predicting and assuming the balance of bacterial population in both specimens. In addition, the data are also important for the identification of the presence of Aeromonas hydrophila, a Gram-negative bacterium, which is a cause of death of fish found in warm aquatic environments [The data presented here are intended to provide information on the diversity of bacteria residing in the intestine of the elver and fingerling stages of wild Indonesian shortfin eel (ronments . The PCRronments . The totThe relative abundance of the phyla in the intestines of WF and WE is presented in The family abundance in both samples is shown in Cetobacterium (10%), and Clostridium (sensu stricto) (9%) were the most abundance genera in WF, while Plesiomonas (36%), Clostridium (sensu stricto 1) (31%), Aeromonas (17%), and Acinetobacter (7%) appeared to be predominating in WE.Relative taxonomic abundance heatmap of the genus level is shown in The top 10 genera/species with the high relative abundance were selected to generate a combined taxonomy tree in each sample . The relSome very small amount of lactic acid bacteria was also detected and is shown in Rarefaction and Rank abundance curves are shown in The Venn diagram based on OTUs generated after being normalized and the common and unique information from different samples were analyzed is shown in 22.1The Indonesian wild eel fingerling and elver were obtained from Ci Kangean River, Alur Village, Cipatujah District, Tasikmalaya, West Java, Indonesia . The procedure for isolation of the intestine followed Huang et\u00a0al. [2.2The preparation of the samples' genomic DNA was done using CTAB/SDS method. The concentration and purity of DNA were analyzed on 1% agarose gels. Based on the concentration, DNA was diluted to 1ng/\u03bcL in sterile water.2.3The V3\u2013V4 regions of 16S rRNA were amplified using Phusion\u00ae High-Fidelity PCR Master Mix (New England Biolabs). The PCR products were mixed with the same volume of 1x loading buffer and electrophoresed on 2% agarose gel. Samples with bright and sharp bands between 400-450 bp were chosen for further experiments.2.4PCR products are mixed in a balanced ratio then purified with Qiagen Gel Extraction Kit . The library was generated with NEBNext\u00ae UltraTM DNA Library Prep Kit for Illumina, quantified via Qubit and Q-PCR, and analysed by Illumina platform.2.52.5.1The barcodes of the samples were cut off from their primer sequences, assigned as pair-end reads and merged using FLASH V1.2.7)  to produ  to prod2.5.2Uparse software v7.0.1001  was used2.5.3QIIME V. 1.7.0 was used to generate the alpha diversity for species to measure the average mean of taxa diversity in both samples. The alpha diversity curve was displayed with R software V. 2.15.3."}
+{"text": "Ornithodoros moubata ticks. The 11 sequences that we obtained harbored no notable differences to each other, and all of them were closely related to the genome sequence of the Mkuzi 1979 strain of genotype I.Here, we report the coding-complete genome sequence of African swine fever (ASF) virus strain Liv13/33, isolated from experimentally infected pigs and  Ornithodoros moubata ticks. The 11 sequences that we obtained harbored no notable differences to each other, and all of them were closely related to the genome sequence of the Mkuzi 1979 strain of genotype I.Here, we report the coding-complete genome sequence of African swine fever (ASF) virus strain Liv13/33, isolated from experimentally infected pigs and  Asfarviridae, Asfivirus) and may involve soft ticks of the Ornithodoros genus as vectors and reservoirs of the virus   (O. moubata sensu stricto ticks on pigs as previously described (4 of the 50% hemadsorbing dose (HAD50) of the ASFV Liv13/33 strain. Two hundred and sixty ASFV-free ticks were engorged on infected pigs on the first day of hyperthermia, when pig viremia ranged from 107.8 to 108.1 HAD50/ml. Five engorged ticks were frozen 3 months postinfection for sequencing analysis, and the others were fed on three new SPF pigs to assess their ability to transmit ASFV to naive pigs. These pigs displayed hyperthermia 2\u2009days after being bitten by infected ticks.The strain Liv13/33 was initially isolated in 1983 from a tick of the  Africa) , 3. This Africa) , 5. The escribed . Three 7Animal experiments performed at the air-filtered biosafety level 3 animal facilities at ANSES-Ploufragan were authorized by the French Ministry for Research (project no. 2017062615498464) and approved by the national ethics committee (authorization no. 11/07/17-3).de novo assembled using the SPAdes version 3.10.0 (option: \u2013careful -t 12 -m 50) and MIRA version 4.0.2 (option: IONTOR_SETTINGS -ASSEMBLY:mrpc\u2009=\u2009100) programs. In parallel, reads were mapped on three reference ASFV genomes of genotype I  using Burrows-Wheeler Aligner software version 0.7.15-r1140 (option: mem -M). For each library, contigs produced by the different methods were scaffolded to generate a single consensus sequence validated by an additional BWA alignment. De novo assemblers and alignment software could not deal with inverted terminal repeats (ITRs) present in the ASFV genomes (http://asfvdb.popgenetics.net/), which proposed the most complete and homogeneous revised annotation (DNA was extracted using the High Pure PCR template preparation kit (Roche Life Science) from 400\u2009\u03bcl of heparin blood samples collected from the six pigs during the viremia peak and from supernatants of crushed ticks prepared by filtration at 0.45\u2009\u03bcm. All samples were sequenced at the ANSES Institute  with Proton Ion Torrent technology . Individual libraries were created for each of the 6 pig samples and each of the 5 infected ticks for a total of 11 libraries. The libraries for sequencing were prepared using the Ion Xpress plus fragment library kit and Ion Xpress barcode adapters 1-96 kit (Thermo Fisher Scientific). Magnetic beads from the Agencourt AMPure XP kit  were used for DNA purification steps. The resulting reads were cleaned with Trimmomatic version 0.36  and were first  genomes . The cod genomes . This seMN913970. Raw data from the 11 isolates for this project can be found in the GenBank SRA under accession no. PRJNA587575.The coding-complete genome sequence of isolate OmLF2 has been deposited in GenBank under the accession no."}
+{"text": "BRCA gene mutation have enhanced sensitivity to platinum-based regimens and PARP inhibitors. However, the knowledge regarding BRCA mutation in Thai patients is limited. This study aimed at identifying the prevalence and characteristics of somatic and germline BRCA 1 and 2 mutations in Thai patients with these cancers. Ovarian, fallopian tube, or primary peritoneal cancer patients with BRCA mutation using next-generation sequencing system. Blood or normal tissue paraffin blocks of positive patients were further tested for germline BRCA mutation. The paraffin blocks of tumors with histology of high grade serous, high grade endometrioid, or clear cell carcinoma obtained between June 2016 and December 2017 were analyzedto evaluate BRCA mutation was identified in 24 patients (17.3%): BRCA1 in 13 cases, BRCA2 in 10 cases, and BRCA1 and 2 in the rest one. Germline mutation study in blood or normal tissue in 23 positive patients revealed BRCA mutation in 14 cases, BRCA1 in 8 cases and BRCA 2 in 6 cases. Overall, the prevalence of somatic and germline mutation was 6.5% (9 out of 138 patients) and 8.7% (14 out of 138 patients), respectively. The most common histology associated with BRCA mutation was high grade serous cancer (27.3%). No significant difference was found between patients with or without BRCA mutation in terms of stage, outcome, platinum status, and survival outcome. Tissue paraffin blocks of 178 patients were collected but only 139 were analyzed. Positive BRCA mutation was demonstrated in less than 10% of Thai ovarian cancer patients. Higher rate of mutation was found in high grade serous cancer. Epithelial ovarian cancer (EOC) is the 6th most common cancer among Thai females with the age standardized rate of 6.0 per 100,000 females . Among prognostic factors affecting survival, stage of the disease is the most important one. For instance, 2-year survival rate ranged from 90% in early and 40-50% in advanced stages . Another important prognostic factor is the response to first-line chemotherapy or platinum-sensitivity status. When the recurrences occur either later than 6 months or sooner after the last therapy, the diseases are regarded as platinum-sensitive or platinum-resistant, respectively. Platinum-based chemotherapy is usually used for platinum-sensitive disease; whereas, other non-platinum chemotherapies can be the option for platinum-resistant diseases . Unfortunately, the patients with platinum-sensitive disease, who have responded to platinum-based chemotherapy re-induction, may have subsequent recurrences. The second-relapse generally have lower responses to treatment with platinum or other chemotherapeutic drugs . Hence, maintenance therapy after primary treatment has emerged in order to extend the progression-free period and survival.  BRCA1/2 gene. In patients with BRCA1/2 mutation, the repair mechanism cannot take place leading to cell death eventually . Evidence-based data from previous studies showed that PARPi could prolong remission in patients especially those with platinum-sensitive recurrent ovarian cancer. This benefit of PARPi maintenance therapy on progression-free survival was evidenced especially in patients with either germline or somatic BRCA1/2 mutation . Hence, knowing the status of BRCA1/2 mutation in ovarian cancer patients is important in order to support a decision a clinician for selecting an appropriate treatment option for the patients. Among drugs that are used as maintenance therapy, poly (adenosine diphosphate [ADP]) ribose polymerase (PARP) inhibitor (PARPi) is a recent efficient agent. PARP is an enzyme that repairs the single-strand break DNA in tumor cells. The mechanism of PARPi action is through inhibiting this enzyme, preventing DNA repair, and leading to further damage to the other DNA strand or double-strand break DNA. The double-strand break DNA can be repaired to normal via homologous recombinant pathway byBRCA1/2 mutation, according to previous reports, ranged from 14 to 29% in Asia . Higher percentages of mutation were found in some types of EOC, such as high grade serous cancer, which was found to have BRCA1/2 mutation as high as 28.5% . The prevalence of germline BRCA1/2 mutation may differ across different countries. The genetic test, including testing of BRCA1/2 mutation, in ovarian cancer patients had not been a standard practice in our country. Hence, the prevalence of BRCA1/2 gene mutation in our population remained unknown. The Thai Gynecologic Cancer Society is aware of the increasing role of PARPi in treatment of ovarian cancer, so this study was conducted among tertiary centers for cancer care in Thailand to determine the BRCA1/2 mutation status in Thai patients with EOC.With the possible ethnic influence, the prevalence of The study was approved by local ethic committees of each participating institution. Inclusion criteria were as follows: Thai patients who had EOC, fallopian tube cancer, and primary peritoneal adenocarcinoma (PPA), operation between June 1, 2016 and December 31, 2017, histopathology of high grade serous, high grade endometrioid, or clear cell adenocarcinoma, available paraffin blocks for tissue processing, and available clinical data. In any cases of mixed cell types, these aforementioned histopathologic components must be at least 10% for the pathological processing and examination. Laboratory data BRCA1 and BRCA2 mutation testing in the remaining cases. which were equally distributed to both laboratories.To confirm tumor histopathology and grade, the representative slides containing tumor from each institution were submitted for central pathologic review. The central pathologic review was done by a gynecologic pathologist (S.K.). The paraffin blocks of tumors were then randomly submitted to one of the two qualified genomic laboratories: 1) Center for Medical Genomics, Faculty of Medicine, Ramathibodi Hospital and 2) Chula GenePRO Center, Faculty of Medicine, King Chulalongkorn Memorial Hospital. Tumor cells percentage was reviewed by the pathologists (S.S). A cross-validation of the whole process from DNA extraction through data interpretation between both laboratories was executed in 10 samples before proceeding with the BRCA1 and BRCA2 mutations were analyzed using GeneReader next-generation sequencing (NGS) system . Quality of data sequencing was examined using unique molecular index (UMI) coverage, including 100X > 90% and 60X >95% of BRCA1 and BRCA2 coding regions. The samples that showed inadequate DNA quality or UMI coverage were discarded to avoid false positive and false negative results. DNA extraction and quality assessment were performed using QIAamp DNA FFPE Tissue kit and GeneRead DNA QuantiMIZE kits according to manufacturer\u2019s recommendation . BRCA1/2 mutation, were counselled for germline testing. For germline testing, 5 milliliters of blood were drawn from patients, who had agreed and signed inform consent, using bidirectional direct sequencing. For other patients, the genetic testing was performed using normal tissue taken from the paraffin blocks. The variant classification was preliminarily evaluated by Ingenuity Variant Analysis (Qiagen) and manually reviewed according to the American College of Medical Genetics and Genomics (ACMG)/ the Association for Molecular Pathology (AMP) guidelines . The final result was made after discussion and mutual agreement between both laboratories in all specimens. The patients, who had tissue BRCA mutation was calculated by dividing the number of patients who had BRCA mutation from tumor tissue to total number of patients who had tumor tissue testing. On the other hand, the prevalence of germline or somatic BRCA mutation was calculated different. This number would be divided by the total number of patients who had tumor tissue testing but excluded those patients with tissue BRCA mutation whose peripheral blood or the paraffin blocks with normal tissue were unavailable. The prevalence of tissue Clinical DataClinical data of the patients extracted from their medical records. These data included age, stage of cancer according to the International Federation of Gynecology and Obstetrics (FIGO 2014), histopathology, dates of treatments, outcomes, status of disease, and living status. The patients who developed progression during the course of chemotherapy or had recurrence within 6 months after the completion of chemotherapy were classified as platinum-refractory and platinum-resistant, respectively. or else were classified as platinum-sensitive. Progression-free survival (PFS) was calculated from the date on surgery or the date of start chemotherapy in patients who underwent neoadjuvant chemotherapy until the date of progression, recurrence, or last evaluation. Overall survival (OS) was obtained from the same date that using for calculated PFS to date of death or last follow-up in patients who were alive at the end of the study. Sample Size CalculationBRCA1/2 mutation in EOC . With respect to alpha error at < 0.05 added with 10% loss of data, 160 patients were needed to be included in the study. A target minimum sample size was calculated according to the previous publication reporting 10% prevalence of Statistical AnalysisStatistical analysis of the data was carried out using IBM SPSS statistics for Windows program . Descriptive data were presented as number and percentages, mean with SD or median with range. Patients with BRAC 1/ 2 mutation or without BRAC 1/ 2 mutation were compared using Chi-square or Fisher\u2019s Exact test as appropriate. Survival data were analyzed with Kaplan Meier and compared between groups with log-rank test. A p-value of < 0.05 was considered as statistical significance.A total of 178 patients from 5 cancer institutions were included in this study. the instiutions were Faculty of Medicine Ramathibodi Hospital, Mahidol University (n=52), Chiang Mai University Hospital, Chiang Mai University (n=44), King Chulalongkorn Memorial Hospital, Chulalongkorn University (n=43), Faculty of Medicine and Vajira Hospital, Navamindradhiraj University (n=31) , and Chulabhorn Hospital, Chulabhorn Royal Academy (n=8). All hospitals were in Bangkok, except for Chiang Mai University Hospital which is in the northern part of Thailand.The mean age of the patients was 56.9 \u00b1 11.4 years. Ovarian cancer was the most common diagnosis among the included patients (86.5%), followed by fallopian tube cancer, (9.6%) and primary peritoneal cancer (3.9%). About 57.4% of the patients were in advanced stage of the disease. High grade serous cancer was the most common histopathology (56.7%). Approximately 11.2% of patients had neoadjuvant chemotherapy prior to surgery; whereas, almost all (96.1%) received adjuvant chemotherapy. The most common first-line chemotherapy was carboplatin plus paclitaxel (68.0%). Complete response after primary treatment was achieved in 118 patients (66.3%) and 55 patients (30.9%) had later developed recurrence. BRCA results, there were only 139 patients whose paraffin-blocks could be further processed for the test. The others were disapproved due to suboptimal quality of DNA and sequencing data, so were excluded from further investigation. Out of 139 patients, the tissue BRCA gene mutation was found in 24 cases (17.3%): BRCA 1 mutation in 13 cases (9.5%), BRCA 2 mutation in 10 (7.2%), and both BRCA 1 and 2 mutation in 1 case (0.7%). The remaining 11 patients (7.9%) were reported to have variants of uncertain significance (VUS). Regarding BRCA gene mutation according to the histology. Only high grade serous cancer and clear cell carcinoma showed positive BRCA gene mutation: high grade serous cancer in 21 from 77 patients (27.3%) and clear cell carcinoma in 3 out of 55 ones (5.5%). Among 24 patients with BRCA positive, all except one could be pursued to have germline BRCA gene mutation testing by using peripheral blood in 18 patients and normal tissue of myometrium from paraffin block in the other 5 patients. The results showed germline positive in 14 patients, 8 BRCA 1 mutation and 6 BRCA2 mutation; 13 of which were high grade serous cancer and only 1 was clear cell carcinoma. Thus, among 138 patients who had the data of both germline and somatic, the percentages of germline BRCA gene mutation was 8.7% (14 out of 138 patients), while the percentage of somatic BRCA gene mutation was 6.5% (9 in 138 cases). There were 4 BRCA 1 mutation, 4 BRCA2 mutation , and 1 BRCA1 and 2 mutation. The patients who had germline mutation was significantly younger than those with only somatic mutation . Thus, at least the prevalence rates of germline and somatic BRCA mutation in our study were 8.7% and 6.5%, respectively. BRCA gene mutation identified by next generation sequencing. Three mutation patterns were identified, including 11 frameshifts, 9 nonsenses, and 2 missenses. Missense mutations were observed only in BRCA2 genes, while frameshift and nonsense were found in both BRCA1 and BRCA2. Five novel mutations were observed in 6 patients; whereas, the others were known mutations reported in the NCBI database of genetic variation (dbSNP).BRCA gene mutation regarding age, type of cancer, stage, outcome after primary treatment, and platinum-sensitivity status  compared to 87.2%  in patients without pathogenic BRCA gene ( P = 0.077). This study could not demonstrate any differences between patients with and without tissue y status . Figure BRCA mutation in high grade EOC, fallopian tube cancer, and primary peritoneal adenocarcinoma in 24 out of 139 patients (17.3%). Out of 24 patients, 14 patients revealed germline BRCA 1/2 mutations. Thus, the prevalence of germline and somatic BRCA mutation in our study was at least 10.1% (14 in 138 cases) and 6.5% (9 in 138 cases), respectively. These rates corresponded to those reported by a Taiwanese\u2019s study. Chao et al., (2016) investigated the occurrence of BRCA 1/2 mutation in 99 formalin-fixed paraffin-embedded tumor samples of tumor and normal tissue obtained from Taiwanese ovarian cancer patients by using next-generation sequencing. They found BRCA 1 in 7 cases and BRCA 2 in 6 cases, reporting 12.1% prevalence. In their study, 4 cases (4%) had somatic mutation. Another study was done in Thailand by Manchana et al., (2019). They investigated the frequency of BRCA mutation in 87 Thai high grade serous cancer and high grade endometrioid ovarian cancer, including the fallopian and peritoneal cancers. They used peripheral blood DNA samplers, DNA extracted from formalin-fixed paraffin embedded blocks (FFPE), or a fresh tumor specimen to analyze BRCA mutation via the next generation sequencing system. The results showed germline BRCA mutation detection in 19 patients (21.8%), of which 14 (16.1%) were BRCA1 mutation and 5 (5.7%) were BRCA2 mutation. All positive patients revealed histology as high grade serous cancer. The difference in detection rates of BRCA mutation between our study and Manchanaet al., (2019)\u2019s study was probably due to usage of differed specimens. Our study used only FFPE that might decrease the detection rate due to the variability of tumor samples and intra-tumoral heterogeneity which probably compromised the representativeness of the sample ; whereas, Manchana et al., (2019) used fresh tumor specimen or blood samples aside from FFPE to analyze BRCA prevalence.The present study found tissue BRCA mutation was high grade serous carcinoma in a range of 5.5-16.7%, followed by endometrioid carcinoma (4.3-13%) ,and clear cell carcinoma (6.3-9.1%)  . However, in the present study, tissue BRCA mutation was found in 27.3% of high grade serous carcinoma and 5.5% of clear cell carcinoma, while none in endometrioid carcinoma. This non-similar outcome might be due to very small number of patients with high grade endometrioid carcinoma in our study. However, BRCA2 mutation was found only in clear cell carcinoma. This finding corresponded to the previous reports suggested that BRCA2 mutation is common in this cell type . However, 2 out of 3 patients with clear cell carcinoma had somatic BRCA2 mutation (87.7%) and only 1 patient (33.3%) had germline BRCA2 mutation.The most frequent histology in patients with germline BRCA mutation among various histologies, recently the American Society of Clinical Oncology (ASCO) suggest assessing either germline or somatic BRCA gene mutation in all non-mucinous ovarian, fallopian tube, and peritoneal cancers of high grade . Improvement of treatment outcome is possible through PARPi . Gori et al., (2019) summarized an initial step of BRCA mutation gene investigation by studying BRCA 1/2 mutation on tumor tissue. The test for identifying spectrum of genomic rearrangements  yielded high sensitivity. In the patients, whose tissues were positive for BRCA 1/2 mutation, genetic counseling and further investigation for germline mutation from their peripheral blood should be deferred as the next step of investigation. If the blood test be positive, these patients will benefit from PARPi therapy and should be under close surveillance for a possible development of second malignancy.Due to different reports on prevalence of BRCA 1/2 coding regions, epigenetic and structural changes could not be detected in this study. Thirty nine DNA samples (21.9%) were unable to obtain BRCA mutation status due to insufficient DNA quality. Various factors affect FFPE DNA quality in molecular genomics test, such as tissue fixation time, storage time, and archive temperature . In this study, we selected FFPE tissues blocks during June 2016 to December 2017 and finished the DNA extraction within 2018 (<3 years) to avoid long-term storage effect. Therefore, fixation time and archive temperature could lead to low DNA quality since the samples were collected from 5 institutions and there might be deviation of FFPE tissue handling and collection.The major problem with using tissue sample for testing pathogenic gene was the quality of FFPE clinical specimens. Although next generation sequencing used in this study can sequence entire BRCA gene mutation, the present study did not find any significant differences in terms of age, disease, stage, primary outcome, platinum-sensitivity status, and survivals after treatment. Kuberlac et al., (2019) reported that their patients with both germline and somatic BRCA mutation had younger age and had significantly higher rate of complete pathologic response during the first and second platinum-sensitive relapse, and longer overall survival for advanced stage treated with neo-adjuvant chemotherapy when compared to 52 patients without BRCA mutation. Although this study also found younger age among BRCA mutation, the positive BRCA gene did not serve as a favorable prognostic factor. The small number of patients in this study may limit any meaningful clinical summary regarding the prognostic role of BRCA mutation. Regarding clinical characteristics between the patients with and without BRCA 1/2 mutation positive was presented in about 17% of high grade epithelial ovarian, fallopian, and peritoneal cancers. The most frequent histology was the serous cancer. In conclusion, tissue"}
+{"text": "Glomerulonephritides (GN) are relatively rare kidney diseases with substantial morbidity and mortality. They are often difficult to treat, sometimes with no cure, and can lead to chronic kidney disease (CKD) and end stage kidney disease (ESKD). Kidney biopsy is the diagnostic procedure of choice with variable indications from center to center. It helps in identifying the exact specific diagnosis, assessing the level of disease activity and severity, and hence aids in proper therapy and helps predicting prognosis. There is a global change of pattern of glomerular disease over the last five decades.Retrospective analysis of all kidney biopsies (545 cases) that were done in patients over 12 year-old over last six years in four major hospitals in Kuwait. The indications for kidney biopsy were categorized into six clinical syndromes: nephrotic syndrome, sub-nephrotic proteinuria, nephrotic syndrome plus acute kidney injury (AKI), sub-nephrotic proteinuria plus AKI, isolated hematuria, and Unexplained renal impairment. We calculated the incidence of each type of kidney disease and indication of biopsy.most common indication of kidney biopsy was sub-nephrotic proteinuria associated with AKI in 179 cases (32.8%). Primary Glomerulonephritis was the main diagnosis that was reported in 356 cases (65.3%). Immunoglobulin A Nephropathy (IgAN) was the commonest lesion in primary glomerulonephritis in 85 (23.9%) cases. Secondary Glomerulonephritis was diagnosed in 134 cases (24.6%), 56 (41.8%) of them were reported as lupus nephritis cases. In young adults (below 18 years of age) there were 31 cases reviews, 35.5% were found to have minimal change disease (MCD).IgAN is the commonest glomerulonephritis in primary nephrotic syndromes in Kuwait over the past six years. Lupus nephritis is the leading secondary glomerulonephritis diagnosis. Glomerulonephritides (GN) are relatively rare kidney diseases with substantial morbidity and mortality. They are often difficult to treat, sometimes with no cure, and can lead to chronic kidney disease (CKD) and end stage kidney disease (ESKD). Incidence of ESKD is rising annually worldwide due to a variety of reasons , 2. GN tAll reports of native kidney biopsies performed in four public hospitals from January 2013 to December 2018 were retrospectively analyzed. Minimal age of patients to be involved in the study was 12 years old (Pediatric age in Kuwait is up to 12 year-old). We recorded the following data for each patient: name, age, sex, indication of kidney biopsy, histopathological diagnosis and laboratory investigations such as serum creatinine, 24-hour urinary protein, urine microscopy, virology; hepatitis B surface antigen (HBsAg), hepatitis C antibody (anti-HCV), Human Immunodeficiency Virus (HIV) and serology; anti-double stranded DNA antibody, antinuclear antibody (ANA), complements levels 3&4 . All kidney biopsy specimens obtained were prepared as per the standard protocol and examined by the same renal pathologists located in one hospital. Analysis included light microscopy (LM) and immunofluorescence (IF). However, electron microscopy (EM) was not systematically performed, as this facility was not widely available during that period. Tissue processing was performed from formalin-fixed and paraffin-embedded (FFPE) tissue. Tissue sections were cut at 4\u03bcm thickness. Staining included a hematoxylin and eosin (HE), a periodic acid-Schiff (PAS), a silver stain (Jones\u2019 Methenamine) and a Masson's trichrome stain. Special stains were used when warranted. Immunoglobulins and complement analyses were done using an immunohistochemical antibody panel to immunoglobulins G, M, A , C3, complement 1 q (C1q), and, if needed, to kappa and lambda light chains. The indications for kidney biopsy were categorized into six clinical syndromes: nephrotic syndrome, sub-nephrotic proteinuria, nephrotic syndrome plus AKI, sub-nephrotic proteinuria plus AKI, isolated hematuria, and Unexplained renal impairment. In CKD patients with unexplained deterioration in kidney function, kidney biopsy was performed if kidney sizes were within normal limits by ultrasound with intact corticomedullary differentiation. Automated biopsy guns were used for all biopsies.Histological categories were classified as follows: 1) glomerular disease. 2) non-glomerular diseases like tubulointerstitial diseases. 3) normal kidneys. 4) insufficient material for analysis. Those patients diagnosed with glomerular diseases were further divided into having primary or secondary glomerular diseases. Extensive glomerulosclerosis, severe tubular loss and/or atrophy, some degree of cystic changes and thickened renal blood vessels were considered as suggestive of ESKD. We calculated the incidence of each type of kidney disease and indication of biopsy. Comparison was made between data from each year from 2013 to 2018. The data generated and analyzed were also compared with studies published from Kuwait and different regions of the world.Simple descriptive statistics such as median and mean were used for variables such as age, clinical and laboratory features. Percentage was used for categorical data.Nephrotic syndrome: proteinuria of more than 3 g per day associated with hypoalbuminemia. Sub-nephrotic proteinuria: proteinuria of less than 2 g per day. Acute kidney injury was defined as an increase in serum creatinine of \u2265 26.5 \u03bcmol/L within 48 hours, or increase in serum creatinine \u2265 1.5 times baseline which is known or presumed to have occurred within the prior 7 days, or urine volume <0.5 ml/kg/h for 6 hours [Total of 545 cases were available for review. There were only 120 patients with history of diabetes (21.9%), and 178 cases were known hypertensive (32.5%). Male patients were predominant at 335 cases (61.2%). Mean age of patients at time of biopsy was 39.8 years. Youngest patient was at 12 years old and the oldest patient was a 90-year-old male patient. There were only three cases with HCV positive antibody with a diagnosis of: diabetic nephropathy, membranous nephropathy and extensive glomerulosclerosis. Also we had three cases that had HBsAg positivity their biopsy results showed: minimal change disease, membranous nephropathy, and diabetic nephropathy. There were no HIV positive patients in the biopsy cohort.The most common indication of kidney biopsy was sub-nephrotic proteinuria associated with AKI in 179 cases (32.8%). Nephrotic syndrome followed with 117 cases (21.5%). Nephrotic syndrome associated with AKI came third with 89 cases (16.3%). Least indication for kidney biopsy was isolated hematuria with only 24 cases (8%). There were 71 (13%) cases that got biopsied due to unexplained renal impairment (Table Primary Glomerulonephritis was the main diagnosis that was reported in 356 cases (65.3%). IgAN was the commonest lesion in primary GN in 85 23.9%) cases. Membranous nephropathy (MN) and focal segmental glomerulosclerosis (FSGS) came second and third in 79 (22.2%) and 78 (21.9%) cases, respectively (Table 3.9% case2 at time of biopsy. Nephrotic syndrome associated with AKI was mainly reported as MN in 24 (27%) cases then FSGS (12.4%) and IgAN (11.2%). In 71 cases that got biopsied due to unexplained renal impairment, majority was AIN in 18 (25.4%) cases. Lupus nephritis was diagnosed in 13 (20%) of 65 cases presenting with sub-nephrotic proteinuria; Followed by FSGS and MN each in 11 cases (17%) then IgAN with 9 cases (13.8%). IgAN dominated isolated hematuria cases in 10 out of 24 cases (41.7%)  cases, followed by FSGS with 37 (20.7%) cases. Only 15 (8.4%) cases in this category were due to lupus nephritis. Top three diagnoses in nephrotic syndrome category were MN (30.8%), followed by minimal change disease (MCD) (29.1%), FSGS (12.8%), and lupus nephritis (11.1%). Peak age at presentation was 66 years for MN patients, 55 years for FSGS, and 55 years for MCD. There were 34% of cases of MN with eGFR below 60 ml/min/mTotal of 120 biopsies were done in diabetic patients for a variety of indications. The commonest indication for kidney biopsy in diabetic patients was sub-nephrotic proteinuria associated with AKI in 45.8% of the cases, followed by unexplained deterioration in kidney function in 27.5% of the cases. The commonest diagnosis was diabetic kidney disease in 27 (22.5%) cases followed by FSGS 23 (19.2%) cases, and later came equally IgAN and extensive glomerular sclerosis in 13 (10.8%) cases each. Lupus nephritis and AIN were present in 7.5% and 5% of cases, respectively Table .Table 6Cases done in young adults (12 to 18 years of age) were 31 in total. The main indications for biopsy were sub-nephrotic proteinuria, nephrotic syndrome, and sub-nephrotic proteinuria associated with AKI. The commonest finding in this population was MCD in 11 (35.5%) cases Table Table 7CThere has been a global change in histological pattern of GN over past 5 decades. There was a point in time were MN was the commonest primary nephrotic syndrome . This waThere were two single centered studies carried out in Kuwait looking at GN prevalence. First one was done between 1995-2001 in one center in Kuwait. They found FSGS to be the most common histological lesion accounting for 18.0% of the total biopsies. Minimal change disease was the second primary GN (13.0%), followed by immunoglobulin A deposition disease (7.9%) and membranous glomerulonephritis (5%) . AnotherThe other single center study from Kuwait, about a decade after the first one, looked at kidney biopsies between 2009-2014 showed membranous GN to be the most common lesion 12.1%), followed by IgAN (11.7%), minimal change disease (9.8%), focal and segmental glomerulosclerosis (9.3%) [.1%, follKuwait has diversity of populations living together where about 70% of the residents are expatriates from close by countries like the Middle East and South East Asia. However, this cohort represents equal number of nationals and expatriates. About half of the total number of IgAN cases, as well as other histological diagnoses in this cohort where in Kuwaiti nationals. The difference in the histological patterns of GN found in this cohort in comparison to the other two mentioned earlier can not be attributed completely to ethnic background , 12.Lupus nephritis remains the commonest secondary GN and this finding is universal throughout the world \u201315. HoweThe prevalence of diabetes in Kuwait is high, ranked as one of the top ten countries worldwide in prevalence of diabetes . There wThis study helps in acknowledging the global change in histological pattern in GN. Kidney biopsy is the gold standard diagnostic test and is a powerful tool that should be widely used in cases where renal diagnosis is uncertain, and renal prognosis is warranted before recommending an expensive, possibly toxic therapy. GN registry would be of utmost importance in the future for both diagnostic and therapeutic implications. By diagnosing and maybe understanding pathophysiology of some GN cases one can design an earlier diagnostic assay or measure that would help carrying out quick therapeutic measures to ameliorate associated morbidity and mortality in such cases.Major strength of our study is the multi-center, large sample size, and the relatively long duration that allow for multiple different presentations in glomerular diseases as we saw in other earlier studies that showed changing leading causes of primary nephrotic syndrome worldwide. Also this study is the largest in the region, which could help in future research on development of further diagnostic and therapeutic advancements. Limitations of the study are: 1) The retrospective nature of the study. 2) Absence of electron microscopy for most of the duration of the study period. If it was available it might have added further data on some diagnoses but would not necessarily have affected the final diagnosis in the majority of cases .Commonest indication for kidney biopsy in Kuwait is sub-nephrotic proteinuria associated with AKI. IgAN is the commonest GN in primary nephrotic syndromes in Kuwait over the past six years. Lupus nephritis remains the leading secondary GN diagnosis. AIN is not an uncommon diagnosis and should be highly suspected in cases of unexplained deterioration of kidney function. In diabetic patients, kidney biopsy in the right settings can detect significant different etiologies other than diabetic kidney disease."}
+{"text": "Editor,Despite significant advances in vitreoretinal instrumentation, techniques and surgical adjuvants, the failure rate of primary retinal detachment (RD) repair secondary to proliferative vitreoretinopathy (PVR) has remained for the most part constant over the last few decades, up to 10% , which may give the impression that VCR only lead to macular pathology, especially in highly myopic and diabetic eyes  and 2018 (Cohort 2) was performed to assess the prevalence of pVCR and its role in surgical failure. All vitrectomies were performed by a single surgeon with indentation and shaving of the vitreous base and the use of triamcinolone to enhance visualization of vitreous at the vitreous base and to attempt to detect pVCR. All patients had a follow\u2010up of at least 6\u00a0months.In 2016 and 2018, respectively, initial PVR (\u2265C) was present and removed in 6/91 (7%) and 4/68 (6%) patients, pVCR were visualized in 26/91 (29%) and 30/68 (44%) patients, pVCR were removed in 16/26 (62%) and 21/30 (70%) patients with pVCR, and 3/26 (12%) and 7/30 (23%) patients with pVCR were high myopes (>6D). Retinal redetachment rates were 4/91 (4%) and 0/68 (0%), respectively.In 2016, 3/26 (12%) patients with pVCR developed a redetachment compared to 1/65 (2%) patients without pVCR. In each of the three cases with pVCR and redetachment, pVCR were not completely removed during the first operation and a causative PVR membrane was identified during the second operation. No PVR had developed in the redetachment case without pVCR .Differences between 2016 and 2018 could be attributed to more extensive and targeted staining (better detection) and more effective and safer removal of pVCR in 2018, using a new technique for pVCR removal, Vitreous Wiping periphery secondary to anomalous PVD with vitreoschisis. Figure"}
+{"text": "Keynote at the 20th European Conference on Eye Movement Research (ECEM) in Alicante, 20.8.2019,(Video stream not punlished on internet)"}
+{"text": "Bacteria are essential constituents of bog ecosystems. Here, we report 44 bacterial genome sequences reconstructed from metagenomes sampled across 12 plant species representing Alpine bog vegetation. This resource will facilitate further exploration of the genetic potential of these bacteria and allow researchers to refine their ecological roles in association with their plant hosts. Bacteria are essential constituents of bog ecosystems. Here, we report 44 bacterial genome sequences reconstructed from metagenomes sampled across 12 plant species representing Alpine bog vegetation. This resource will facilitate further exploration of the genetic potential of these bacteria and allow researchers to refine their ecological roles in association with their plant hosts. Sphagnum mosses that have an ombrotrophic lifestyle and depend on their associated microbiome  in Rotmoos and P\u00fcrgschachen Moor in Austria , respectively. Metagenomic data sets were coassembled using MEGAHIT v1.2.9 with metasensitive parameters , resulti14\u2013, respectProteobacteria (17 MAGs), Acidobacteria (8 MAGs), Actinobacteria (7 MAGs), Verrumicrobia (4 MAGs), and Chlamydiae (2 MAGs) (Saccharibacteria (2 MAGs), Eremiobacteraeota (2 MAGs), and Melainabacteria (2 MAGs). Among the whole collection, 18 MAGS were classified as high quality, 22 as medium quality, and 4 as low quality. The estimated completeness rates of the recovered MAGs were in a range of 4.8% to 97.6%, the genome sizes in a range of 493,724 to 6,564,149\u2009bp, and the GC contents in a range of 36.6% to 73.2%. These metagenome-assembled genomes will provide deeper insights into the genetic reservoir of plant-associated microbial communities of Alpine bogs that play important roles for ecosystem services and must be considered in biodiversity conservation.A total of 44 MAGs with a contamination level lower than 10% were recovered and assigned to the following bacterial phyla: (2 MAGs) . MoreovePRJEB39100 and accession numbers ERR4298333 and ERR4298344. The MAG sequences are accessible in the ENA repository under the accession numbers provided in This shotgun metagenome project has been deposited in the European Nucleotide Archive (ENA) database under the study number"}
+{"text": "Brucella canis seropositivity in a convenience sample of dogs from commercial breeding kennels in Ontario, Canada. Overall, 127/1,080 (11.8%) dogs from 23/63 (37%) kennels were seropositive. The prevalence of positive dogs within kennels with >1 positive dog ranged from 3.9% to 100% (median 33%).We evaluated the prevalence of  Brucella canis is a dog-adapted Brucella species that most commonly causes reproductive disease and diskospondylitis in dogs and can be carried long-term and subclinically. Zoonotic infections are uncommonly reported  and followed up with positive results using 2-mercaptoethanol RSAT (2ME-RSAT). We performed PCR on whole (EDTA treated) blood from a subset of >1 positive dog ranged from 3.9% to 100% (median 33%). Whole blood samples from 20 dogs tested by PCR were all negative. We retested 130 dogs 4\u20136 weeks after the initial test  clinically normal dogs from 23/63 (37%) kennels during March 15\u2212December 18, 2019 . We considered reactive an additional 82 (7.6%) dogs that were positive by RSAT but negative by 2ME-RSAT; 63 (77%) of those were from kennels from which positive dogs were identified. The prevalence of positive dogs within kennels that had ial test .,\u2013B. canis bacteria in this population, with high rates in some kennels and the potential for introduction of infected puppies into households.The seropositive rate contrasts with a 1980 study that reported 0.3% seroprevalence in dogs from southwestern Ontario  whereas no problems were reported in others. Whether this reflects lack of recognition of problems, subclinical infection, or early infection that had not yet resulted in overt reproductive disease is unclear.B. canis as a cause of nonspecific disease  and human brucellosis is a concern; physicians are more likely to perform serologic tests that target smooth Brucella species . Physicians should consider the potential presence of B. canis in patients with disease suggestive of brucellosis, especially those with animal contact, and realize the limitations of serologic testing.Underdiagnosis of Brucella canis should be considered endemic to commercial dog kennels in Ontario, with potential human health risks. B. canis screening of breeding dogs is recommended (Brucella status is reasonable."}
+{"text": "We detected Marburg virus RNA in rectal swab samples from Egyptian rousette bats in South Africa in 2017. This finding signifies that fecal contamination of natural bat habitats is a potential source of infection for humans. Identified genetic sequences are closely related to Ravn virus, implying wider distribution of Marburg virus in Africa. Marburgvirus, family Filoviridae, comprises 1 species, Marburg marburgvirus, which comprises 2 marburgviruses, Marburg virus (MARV) and Ravn virus (RAVV) (Rousettus aegyptiacus) has been implicated as the primary reservoir for marburgviruses (The genus https://www.illumina.com) with MARV-specific bait enrichment, followed by sequencing on an Illumina NextSeq, genomic alignment and phylogenetic analysis (https://www.stata.com).We conducted this work in accordance with approved protocols by animal ethics committees of the National Health Laboratory Service  and the University of Pretoria . During February\u2013November 2017, a total of 1,674 Egyptian rousette bats  were captured, aged, and sampled at Matlapitsi Cave, Limpopo Province, South Africa, as described previously (t) >30 were obtained in other studies  were qRT-PCR positive; the remaining rectal swab samples collected during February\u2013November 2017 were all negative. The number of individual positive rectal swab samples ranged from 1 to 3 per positive pool, totaling 11 positive samples. Only 1 oral swab sample pool, from April 2017, yielded a positive qRT-PCR result, containing a single positive oral swab sample . Of 600 We obtained sufficient marburgvirus-specific sequence data only from 1 of the 12 individual positive swab samples for phylogenetic analysis: a rectal swab sample, collected from a juvenile female (bat 8095) in September 2017, from which we recovered 79.2% (15.1/19.1 kb) of the genome. We merged sequencing reads from replicate sequencing runs and mapped 2,472 reads to the MARV reference genome. Maximum coverage per base obtained was 291 reads; some regions had no coverage. The average coverage per base across the genome was 18.5 reads (when we included 0 coverage regions), and the average coverage when we excluded 0 coverage regions was 40 reads. We obtained near-complete coding sequences for the viral protein (VP) 35  and VP40  genes; coverage ranged from 49.7% (VP24) to 89.3% (glycoprotein) in other open reading frames of the genome.The marburgviruses sequence (strain RSA-2017-bat8095) detected from the rectal swab sample of bat 8095 shared a common ancestor with all other RAVV complete or near-complete genome sequences, including 3 human isolates from Kenya . The RSAOf 423 bats tested, 143 (33.8%) were positive for antibodies against marburgviruses (73 adults and 70 juveniles). Lowest overall seroprevalence occurred in April 2017 (17.78%) and ranged from 8.3% in juveniles (9/108) to 55.6% in adults (15/27) . OverallThe period of the lowest seropositivity in juveniles (April\u2013May) resulting in the highest number of potentially susceptible bats at Matlapitsi Cave was the same as previously identified (Our findings highlight the risk for marburgvirus fecal environmental contamination and for Egyptian rousette bat roosting sites as a possible source of virus spillover. Roosting behavior enabling direct physical contact suggests that fecal\u2013oral transmission of marburgviruses in bats can occur. Biting among animals or biting by hematophagous ectoparasites might result in inoculation of wounds with contaminated feces or exposure to contaminated fomites.Our findings, combined with earlier detection of an Ozolin-like MARV in Egyptian rousette bats roosting at Matlapitsi Cave ("}
+{"text": "Proteus mirabilis genome that are related to fluoroquinolone resistance.This study aimed to highlight the importance of mutations within P mirabilis isolates from patients with symptoms of UTIs attending different hospitals in Khartoum State were examined. First, modified Kurby Bauer method was performed for phenotypical detection of resistant isolates. Then polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) followed by sequencing were applied for detection of mutations in GyrA, GyrB, ParC and ParE genes of isolates.This is a cross sectional study performed in different teaching hospitals in Khartoum State from June 2016 to May 2017. A total of (120) P. mirabilis showed 30% resistance to ciprofloxacin. All samples revealed mutation at (serine 83) of GyrA and (serine 84) of ParC by Hinf1 restriction endonuclease digestion. Sequencing was performed for 12 samples. For each gene, two resistant and one susceptible strains were randomly selected. The mutations associated with ciprofloxacin resistant P. mirabilis were as follows; (1/3) GyrA (Ser 83 to Ile) and (2/3) ParC (Ser 81 to Ile). Also it revealed silent mutations at codons of GyrB 474 leucine (3/3), 585 valine (2/3), 612 histidine (1/3) and 639 asparagine (1/3) and ParE 469 isoleucine (2/3), 531 aspartic (2/3) and 533 glycine (1/3).P. mirabilis could be monitored through detection of mutations within DNA gyrase (encoded by gyrA and gyrB) and topoisomerase IV (encoded by parC and parE).Ciprofloxacin resistance in  Proteus mirabilis is a small gram-negative bacilli and a facultative anaerobe, it ferments maltose, but not lactose. Moreover, Proteus mirabilis is one of the common causes of urinary tract infections (UTIs) among Enterobacteriaceae.1Ciprofloxacin is a recommended drug for the treatment of UTIs.4P mirabilis, to four different groups of antibiotics showed that (22.3%) of the isolates were resistant to three or more classes of antibiotics, including cephalosporins, \u03b2-lactam\u2013\u03b2-lactamase inhibitor, quinolones, aminoglycosides and carbapenems.6The basic mechanisms of quinolone resistance are represented by the changes in the active sites of the target enzymes DNA gyrase and topoisomerase IV. The degree of resistance of different regions (QRDRs) encoded by gyrA and parC gene mutations have been described in several studies.Proteus mirabilis urinary isolates collected from different hospitals in Khartoum State. The isolates were collected during the period from June 2016 to May 2017. This study obtained ethical approval number (MLT 711/2016) from the ethical committee of SUST.The study was carried out using 120 in vitro by the Kirby-Baur disk diffusion method against ciprofloxacin (CIP) (5 \u03bcg/ml).7Urine samples were cultured and P.mirabilis was isolated and identified by the conventional standard methods. All the grown isolates were tested for their ciprofloxacin resistance Proteus mirabilis was isolated from overnight growth on nutrient agar. For each isolate, several colonies of pure culture were suspended in (500 \u03bcL) of sterile deionized water in 1.5 ml eppendorf tube for each isolate, and boiled for (10 minutes). Then tubes were centrifuged at (14000 g) for (10 minutes) using a microcentrifuge and supernatant was stored at (-20\u00b0C) as a template DNA stock.9DNA of GyrA, GyrB, ParC and ParE genes were designed by primer3plus (www.bioinformatics.nl/primer3plus) from Proteus mirabilis HI4320 DNA sequences in the Gen Bank database (NCBI) and were synthesized by Macrogen (South Korea).Degenerate oligonucleotide primers  from conI-Taq)  which is a lyophilized master mix. The PCR assay was carried out in a total volume of (20 \u03bcL) of mixture containing (0.5 \u03bcL) of each of the virulence gene-specific primers , (2 \u03bcL) of template DNA and (17 \u03bcL) of water for injection (WFI). The amplification was done using .DNA amplification was done using Maxime PCR Premix kit  and endonuclease digestion was performed as recommended by the manufacturer to detect GyrA (ser 83) and ParC (ser 81) mutations.The PCR product was digested with GyrA, GyrB, ParC and ParE, Sequencing was performed in both directions with the same set of primers used for the PCR by Sanger dideoxy chain termination method.Three products were selected randomly to detect http://www.ncbi.nlm.nih.gov/blast). The sequences were translated into amino acid codons using Expasy translation tool. The protein sequences were then checked for similarity in BLAST.The data was analyzed using statistical software package (SPSS - version 20). The sequences were checked for similarity with reference genes using NCBI\u2019s BLAST (P. mirabilis.The identification scheme confirmed that (120) of the isolates belonged to the species P. mirabilis reflected relatively decreased sensitivity to ciprofloxacin as only 84 (70%) of the isolates were sensitive while 36 (30%) were resistant, with a statistically significant difference (p=0.000).The results of modified Kirby-Bauer method showed that GyrA, GyrB, ParC and ParE genes were designed from alignments of known DNA sequences in the Gen Bank database (NCBI). PCR amplification targeted GyrA gene product (937 bp) which encoded (312) amino acids, GyrB gene product (822bp) which encoded (274) amino acids, ParC gene product (992bp) which encoded (230) amino acid and ParE gene product (972bp) which encoded (324) amino acids on P. mirabilis as seen on 2% agarose gel (Degenerate oligonucleotide primers from conserved regions of the rose gel .P.mirabilis to detect the mutations at the codon (83 ser) of the GyrA gene and (84 ser) of ParC was done by Hinf1 restriction endonuclease digestion. PCR amplified GyrA gene product (937 bp) of all the isolates , and ParC product (992 bp) of all the isolates  as seen on the agarose gel (GyrA and (serine 84) of ParC.Quick screening of the (120) isolates of rose gel  all sampP. mirabilis, performed by alignment with reference strain P. mirabilis HI4320 in GenBank database NCBI by nucleotide blast revealed:Sequencing of all QRDR gyrA possessed serine to isoleucine substitution (G 248 T) this was observed in one strain (33.3%) (Mutations at (codon 83) of  (33.3%) .ParC. Serine 84 to isoleucine (66.6%) at resistant strains (1C and 3C) substitution (G 251 T), codon 81 histidine (33.3%) in sensitive strain (8C) substitution (C 243 T) and codon 116 proline (33.3%) in resistant strain (3C) substitution (A 348 T) (Mutations at codon 84 and silent mutation at codon 81 and 116 of A 348 T) .GyrB, Codon 474 leucine in all strains (100%) including sensitive strain (8B) substitution (A 1422 G), codon 585 valine (66.6%) in resistant strains (1B and 3B) substitution (T1 755 C), codon 612 histidine (33.3%) in sensitive strain (8B) substitution (C1836T) and codon 639 asparagine (33.3%) in sensitive strain (8B) substitution (T1917C)  .ParE, Codon (469) isolusine (66.6%) in resistant stain (3E) and sensitive strain (8E) substitution (C 1407 T), codon (531) aspartic acid (66.6%) in resistant stain (3E) and sensitive strain (8E) substitution (C1593T) and codon (533) glycine (33.3%) in sensitive strain (8E) substitution (1 599 A)  of 1 599 A) .P. mirabilis strains is still under investigation. Moreover, the genus Proteus is isolated from patients, especially from those with UTIs.3During the last decade, an increase in the incidence of fluoroquinolones resistance was reported among aerobic Gram negative bacilli. However, full recognition of reports regarding the emergence of fluoroquinolone resistant P. mirabilis isolates were resistant to ciprofloxacin, this finding agrees with Rajivgandhi et al. from Indiaet al. from Koreaof P. mirabilis resistance to ciprofloxacin, respectively. Different studies revealed different findings; in Sudan, Amir et al. found no resistance to ciprofloxacin in P. mirabilis.15The results obtained from this study showed that (30%) of GyrA and ParC of DNA gyrase and topoisomerase IV enzymes, as well as the subunits GyrB and ParE, which are also components of the target enzymes.13Generally, the possible reasons behind the resistance to ciprofloxacin in Sudan may be the fact that this antibiotic have been in use for a long period and must have been abused, leading most properly to a change in the genome of the bacteria, making the target site of the antibiotic action inaccessible. Important mechanisms of bacterial resistance to quinolone are the genetic mutations in the subunits P. mirabilis always mutate in GyrB (Ser 464 to Tyr or Phe), as mentioned by Saito et al.P. mirabilis GyrB sequence of clinical isolates but revealed silent mutations in the following codons; (474) leucine, (585) valine, (612) histidine and (639) asparagine. Also ParE gene always mutates in  in P. mirabilis,ParE gene fragments from the clinical isolates revealed silent mutations in codons (469) isoleucine, (531) aspartic and (533) glycine. However, no mutations were detected in the corresponding region of pare neither in quinolone resistant nor in sensitive P. mirabilis isolates of this study. However, it is well known that ParE does not have an essential role in fluoroquinolone resistance among P. mirabilis as suggested previously.13P. mirabilis possessed mutations in GyrA (Ser 83 to Ile). This amino acid change is identical to those previously reported for fluoroquinolone resistanceP. mirabilis mutations in GyrA (Ser 83 to Arg or Ile) was proved. Other studies showed different mutations in GyrA with other bacteria; (Ser 80 to Leu 86) of Capnocytophaga spp.E. coliM. bovis.19In this study, ciprofloxacin resistant P. mirabilis sequencing of ParC showed mutation in (Ser 84 to Ile) in this study. This result is in agreement with many researches who proved that Proteus mirabilis always mutated in GyrA (E87) and ParE (D420) for fluoroquinolone resistance.Edwardsiella tarda, another Gram negative bacillus, was found mutant in (Ser 84 to Ile) of ParC which is associated with fluoroquinolone resistance.5E. coli, resistance to ciprofloxacin may be obtained by more than two mutations in both GyrA and ParC genes.mirabilis.In gram negative bacilli, fluoroquinolone resistance is mostly attributed to the antibiotic targets DNA gyrase and DNA topoisomerase IV structure change as the most significant mechanisms.P. mirabilis, decreased susceptibility to fluoroquinolone is caused by mutations at residues (Ser 80 and Glu 84) of ParC of topoisomerase IV, a target of quinolones.ParC and GyrA mutations are needed for acquisition of quinolones resistanceParC but not GyrA, which suggest that ParC is as important as GyrA in decreasing susceptibility to fluoroquinolones in P. mirabilis.In Acinetobacter baumannii, where silent mutation in QRDR regions were reported to be sufficient for fluoroquinolone resistanceP. mirabilis, sensitive strains in this study were found to possess silent mutation in GyrB, ParC and ParE.In contrast to the case of ParC genes mutations in different bacteria; S. pneumoniae at positions serine (83) of GyrA and serine (79) of ParCA. baumannii at positions gyrA (codons 83 and 87) and parC (codons 80 and 84)N. gonorrhoeae at positions Ser (91) of GyrADirect Hinf1 digestion of PCR product have been used by many researchers to screen GyrA and Hinf1 digestion of PCR amplicons have been used to screen GyrA and ParC mutations in P. mirabilis. Mutations at codon (83) of the GyrA gene and (84) of ParC gene result in the loss of natural Hinf1 site as identified. The results indicated that all resistant isolates mutated at serine (83) of GyrA and serine (84) of ParC. When dealing with sequencing, two out of the three sequenced GyrA appeared as non-mutated at Ser (83) while one sample of the other three sequenced ParC resulted as free from any mutations at ser (84). These findings may be attributed to the fact that serine (83) of GyrA and serine (84) of ParC in Proteus mirabilis consist of (AGC) which is almost different from serine in other bacteria (TCC). Thus the loss of natural Hinf1 site (5\u2019\u2026GANTC\u20263\u2019) will result.In this study, direct In Sudan, many studies have been conducted to analyze antibiotic resistance in Gram-negative and Gram-positive bacteria isolated from different clinical specimens of both humans and animals. A wide range of resistance was detected which represent an alarm to the health authority of the country to take an action in order to control this phenomena.25This research received no special fund, thus sequencing was performed to limited number of the isolates with random selection. Moreover, sample collection was limited only to the central teaching hospitals and the rural and terminal medical centers were not reachable.Hinf1 digestion of PCR amplicons is not suitable to screen serine (83) of GyrA and serine (84) of ParC mutations in P. mirabilis. In addition , Proteus mirabilis ParC gene is as important as GyrA gene to cause ciprofloxacin resistance, with only one or two mutations in both GyrA and ParC genes of Proteus mirabilis being enough to obtain resistance to ciprofloxacin. Moreover, the study drew the attention of the clinicians to consider the percentage of resistance to Quinolones in order to try other options of treatment, that means drug susceptibility testing should be adopted to all patients of similar infections before starting a specific treatment.In conclusion, direct RA: Specimen collection and molecular biology work.ME: Approval of the proposal and general supervision, orientation and arrangement.ME & AY: Data analysis and manuscript writing and revision.ME: Is responsible for the integrity of the entire work. All authors have contributed to this manuscript."}
+{"text": "To evaluate the presence and location of late gadolinium enhancement (LGE), increased T2 signal abnormality, right ventricular involvement and cardiac function by cardiac magnetic resonance (CMR) imaging in patients with suspected cardiac sarcoidosis.46 patients with known extra-cardiac sarcoidosis underwent CMR with T2-weighted, LGE and cine imaging for evaluation of cardiac sarcoidosis. Images were evaluated by 2 expert reviewers in consensus using the 17-segment model of the left ventricle (LV) for presence and location  of LGE, presence of increased T2-signal abnormalities, and regional wall motion abnormalities. In addition, right ventricular (RV) involvement was evaluated.13 of 46 (28%) patients demonstrated evidence of segmental LGE suggestive of cardiac sarcoidosis. In these 13 patients, LGE involvement was noted in 51 of 221 (23%) segments, and was predominantly transmural (35%), followed by midwall (27%), subepicardial (25%) and subendocardial (20%). LGE was most frequently located in the basal segments (36%) compared to mid (23%) and apical (22%) segments, and more commonly involved the septal (37%) followed by the lateral (29%), inferior (23%) and anterior (10%) segments. T2-weighted images were evaluable in 11 of the 13 patients, and 24 of 187 segments (13%) demonstrated evidence of increased T2-signal abnormality and was significantly associated with the LGE segmental involvement (p < 0.005). 4 patients (31%) also demonstrated evidence of RV involvement. There was no significant correlation between presence of LGE or increased T2-signal intensity with regional function.Late gadolinium enhancement and increased T2-signal intensity are common findings in the left ventricle in patients with cardiac sarcoidosis, but not necessarily correlated with overall ventricular size and function. Although not previously reported, similar findings are frequently present in the right ventricle as well."}
+{"text": "We assessed the impact of two sand fly insecticide interventions (insecticide spraying and insecticide-impregnated dog collars) on the peridomestic abundance and distribution of mosquitoes (Culicidae) and biting midges (Ceratopogonidae) in western S\u00e3o Paulo (Brazil) in a long-term (42-month) evaluation. Both of these dipteran groups are vectors of diseases of medical and veterinary relevance to humans and domestic animals in Brazil.The interventions in the 3-arm stratified randomised control trial were: pheromone\u00a0+\u00a0insecticide (PI) ; dog-collars (DC) (dogs fitted with deltamethrin-impregnated collars); and control (C) (unexposed to pyrethroids) were extended by 12\u00a0months. During that time, adult mosquitoes and midges were sampled along 280 households at three household locations .Culex spp.) distributed relatively uniformly across all 3 arms: 41.9% at chicken roosts; 37.7% inside houses; and 20.3% at dog sleeping sites. We collected 11,464 Culicoides (15 species) found mostly at chicken roosting sites (84.7%) compared with dog sleeping sites (12.9%) or houses (2.4%). Mosquitoes and Culicoides were most abundant during the hot and rainy season. Increased daytime temperature was marginally associated with increased mosquito abundance  and Culicoides abundance . There was no significant association with daily average rainfall for either group. Household-level mosquito and midge numbers were both significantly reduced by the PI intervention 56%  and 53% , respectively, compared to the control intervention. The abundance of both dipteran groups at dog sleeping sites was largely unaffected by the PI and DC interventions. The PI intervention significantly reduced abundance of mosquitoes inside houses (41%) and at chicken roosting sites (48%) and reduced midge abundance by 51% in chicken roosting sites.We collected 3145 culicids (9 genera, 87.6% Sprayed insecticide at chicken roosting sites reduced the abundance of mosquitoes and midges at the peridomestic level while dog collars had no effect on numbers for any group. Aedes aegypti is the vector of several viruses, most notably dengue, yellow fever, chikungunya, Zika and the filarial roundworm Wuchereria bancrofti which causes lymphatic filariasis  and clustering on municipality."}
+{"text": "Cotton is an important cash crop for both the Indian economy and rural livelihoods. In the present study, metagenomic analysis is used to characterize microbial diversity in cotton rhizosphere soil from the Alwar district, located in the semiarid northeast region of the state of Rajasthan in India. Cotton is an important cash crop for both the Indian economy and rural livelihoods. In the present study, metagenomic analysis is used to characterize microbial diversity in cotton rhizosphere soil from the Alwar district, located in the semiarid northeast region of the state of Rajasthan in India. Gossypium spp.) is an important cash crop for which India cultivates the greatest acreage in the world. It makes up 65% of the raw material requirements for the Indian textile industry . All of the samples were evenly mixed and sieved through 0.2-mm mesh to prepare a composite sample. Genomic DNA was extracted using the NucleoSpin soil kit . Paired-end (PE) sequencing libraries were prepared using the Illumina TruSeq Nano DNA library preparation kit. The size-selected product was PCR amplified, and the enriched libraries were analyzed on a 4200 TapeStation system (Agilent Technologies). Illumina PE libraries with a mean fragment size of 471\u2009bp were sequenced on a NextSeq 500 system using 2 \u00d7 150-bp chemistry. The PE raw reads were processed using Trimmomatic v0.38 , 229,401 genes were predicted, with an average gene length of 351\u2009bp. Approximately 25% of the reads could not be identified taxonomically. Among the 75% identified reads, Bacteria (70%) dominated the microbial diversity, while Eukaryota (2%) and Archaea (3%) formed very small fractions. The most abundant Bacteria phylum was Proteobacteria (32.95%), represented strongly by Acinetobacter (5.36%). The other phyla, in order of abundance, were Acidobacteria (17.14%), Actinobacteria (14.38%), Bacteroidetes (6.28%), Gemmatimonadetes (6.27%), and Chloroflexi (3.32%). Nitrososphaera (3.39%) was the most abundant Archaea genus found present. Functional classification using the COG database distributed genes into general function (15%), amino acid transport and metabolism (11%), energy production and conversion (7%), carbohydrate transport and metabolism (6%), and transcription (6%), among others. Ontology analysis based on the KEGG database distributed genes into metabolism (38%), environmental information processing (11%), cellular processes (3%), and genetic information processing (6%). The genes and pathways identified are only predictions. For cotton rhizosphere, a similar microbial profile was reported earlier  under the accession number SRR12376372. The BioSample accession number is SAMN15693165.This whole-genome shotgun project has been deposited in GenBank under the accession number"}
+{"text": "Opioid misuse was based on heroin and/or prescription pain reliever use, and associated determinants of health and mental health indicators. Five misuse profiles were identified: (1) single heroin or prescription misuse with high-income; (2) female prescription pain reliever misuse with psychological distress and suicidality; (3) younger polyopioid misuse with the highest proportion of Hispanics and heroin use; (4) older polyopioid misuse with the highest proportion of non-Hispanic blacks and disability; and (5) older non-Hispanic white male exclusive dual heroin and/or prescription misuse . The identified risk profiles can inform public health practice to develop interventions for acute and immediate response by providing etiological evidence and to inform prevention and intervention efforts along the continuum from opioid initiation to use disorder.Opioid misuse can lead to use disorder and other adverse outcomes. Identifying sociodemographic risk profiles and understanding misuse patterns in combination with health indicators can inform prevention science and clinical practice. A latent class analysis of opioid misuse was conducted on noninstitutionalized United States civilians aged 18 and older that reported opioid dependence or abuse in the 2017 National Survey of Drug Use and Health ( The statistics demarcating the opioid epidemic in the United States (US) are staggering and sobering. Opioid misuse has resulted in an estimated 1.7 million years of life lost in 2016 . AlthougFactors such as opioid misuse and mortality contributing to the ongoing crisis are complex and not well understood. Some researchers have attributed the overprescribing of opioids as a leading cause to use disorder and addiction ,6,7,8. CVarious factors such as age, race/ethnicity, county population levels, and social determinants of health are related to opioid misuse and overdose deaths . EvidencTo ameliorate the public health burden and reduce opioid-related deaths, a need exists to identify opioid misuse risk profiles. We used latent class analysis to identify profiles of opioid misuse by heroin use, prescription pain reliever use, or heroin and prescription pain reliever use with co-occurring determinants of health, including mental health and other substance use. This study is among the first to use a person-centered approach, to identify opioid misuse risk profiles. While it is known that opioid misuse includes heroin, prescription pain relievers, or a combination of both, the respective misuse risk profiles are unknown. Our study fills a critical gap in the literature by identifying opioid misuse risk profiles to better inform prevention strategies, provide guidance for clinical screening, and tailoring targeted intervention programs.https://www.datafiles.samhsa.gov/study/national-survey-drug-use-and-health-nsduh-2017-nid17938.The current study used the 2017 National Survey on Drug Use and Health (NSDUH), which provided a representative sample of noninstitutionalized US adults 18 years and older that self-reported opioid dependence or abuse in all 50 states and District of Columbia. The NSDUH uses multistage probability sampling to estimate substance use and mental health at the national to substate level among the US noninstitutionalized population using audio computer-assisted self-interviews . The InsOpioid misuse profiles were identified and named using the following 14 observed variables from the 2017 NSDUH: (1) age group ; (2) sex/gender ; (3) race/ethnicity ; (4) sexual identity ; (5) residence based on core-based statistical areas or CBSAs  of 1 milNicotine dependence in the past month was assessed using Nicotine Dependence Syndrome Scale scores, as well as the Fagerstrom Test of Nicotine Dependence scale. Self-reported alcohol and marijuana dependence or abuse in the last year was also ascertained. Dependence or abuse in the past year were ascertained for the following illicit substances: cocaine, hallucinogens, inhalants, methamphetamines, tranquilizers, stimulants (independent of methamphetamine), and sedatives.All analyses accounted for the 2017 NSDUH complex survey design to best provide a representative sample of noninstitutionalized civilian US adults. All models were weighted and accounted for clustering and stratification. A model comparison approach was used to determine the number of classes. Multiple models were created  to then select the best model based on two criteria: (1) High entropy ; and (2) sample-size-adjusted Bayesian information criterion (ssaBIC) . Models n = 476; weighted n = 2,018,922). Age groups were almost evenly distributed between in the sample. The weighted sample was mostly male (60.6%), non-Hispanic white (77.8%), resided in a CBSA with less than 1 million people (48.4%), heterosexual (90.5%), had a family income of $50,000 or more (39.8%), had some college or an associate\u2019s degree (39.2%), employed (53.3%), past criminality (61.8%), self-reported good health (37.1%), had serious psychological distress (56.2%), reported no suicidality (71.9%), and was not covered by private health insurance (64.4%).The sample selected for analysis from the 2017 NSDUH was restricted to noninstitutionalized US adults 18 years and older who self-reported opioid dependence or abuse (The majority of the weighted sample used only pain relievers (66.0%). The weighted sample also reported 55.6% nicotine dependence in the past month, as well as 24.7% alcohol and 17.6% marijuana dependence or abuse in the past year. Other concurrent illicit substance dependence or abuse in the past year (35.2%) was also reported. See Our opioid misuse profiles were identified using LCA. The best model fit selected was a five-class solution that had a low ssaBIC  and high entropy. The entropy or classification accuracy of the selected model was 0.87, which indicated a reliable separation of profiles or classes see . ProfileClass 1, or single heroin or prescription misuse profile (27.3% of sample), misused prescription pain relievers or heroin . This profile was not defined by a single age group but had the highest conditional probability of being 50 and older (35.1%). The single opioid misuse profile had a high likelihood of being male (63.0%), non-Hispanic white (78.1%), identifying as heterosexual (95.3%), reporting a family income of more than $50,000 (72.2%), had some college or an associate\u2019s degree (46.0%), and employed (92.7%), as well as did not report serious psychological distress (60.4%) or suicidality (78.0%). Class 1 exclusively had private health insurance, and had the highest conditional probability when compared to any other class. This class self-reported a higher likelihood of good (44.8%) and very good/excellent health (47.2%).Class 2, or female prescription pain reliever misuse profile (20.3% of sample), primarily misused prescription pain relievers followed by combined heroin and prescription pain reliever use . This class had a higher likelihood of being 18 to 25 (32.4%) and 26 to 34 years old (31.3%). This dual misuse subgroup was found to have the highest conditional probabilities of being female (77.9%), identifying as a sexual minority (22.1%), some college or an associate\u2019s degree (50.0%), other employment classification (30.1%), not arrested (67.2%), and serious psychological distress (89.6%). Class 2 had a high likelihood of making $20,000 to $49,999 (40.4%), residing in CBSAs with less than 1 million (52.8%), with private health insurance (34.0%), reporting serious psychological distress within the past year (76.7%) and suicidality (53.2%).Class 3, or younger polyopioid misuse profile (37.5% of sample), reported heroin, prescription pain relievers, or a combination of heroin and prescription pain relievers . This class was younger as they had a higher likelihood of being under the age of 50. The profile had a higher conditional probability of being 26\u201334 years of age (42.4%), male (71.0%), non-Hispanic white (76.3%), heterosexual (93.8%), family income less than $20,000 (39.5%), arrested and booked (83.2%), self-reported good health (43.0%), and no private health insurance (95.2%). This profile reported the highest conditional probabilities of being Hispanics (9.6%), a high school graduate (45.6%), unemployed (27.4%), residing in a CBSA with less than 1 million (53.8%), and no suicidality (83.9%). This polyopioid class had the highest conditional probability of heroin use compared to all profiles.Class 4, or older polyopioid misuse profile (10.1% of sample), reported use of heroin, prescription pain relievers, or a combination of heroin and prescription pain relievers . The older polyopioid profile had a high conditional probability of being 50 and older (76.9%), male (79.0%), heterosexual (92.6%), and in serious psychological distress (71.9%). This polyopioid profile had the highest conditional probabilities of being non-Hispanic black (23.6%), reporting a family income less than $20,000 (52.9%), disability (79.7%), arrested and booked (91.8%), self-reported fair/poor health (100%), and no private health insurance (100%).Class 5, or older male dual heroin and/or prescription misuse profile (4.7% of sample), was found to misuse either prescription pain relivers or a combination of heroin and prescription opioids . This class was exclusively 50 years and older, male, non-Hispanic white, heterosexual, resided in a CBSA with more than 1 million individuals, self-reported good health, and had no private health insurance. This class had a high likelihood of having a family income of $50,000 or more (77.3%), being a college graduate (54.7%), disabled (44.0%), been arrested and booked (65.8%), and no serious psychological distress (66.7%). This dual misuse group had the highest conditional probability of combined heroin and prescription pain reliver use. See Our covariate analysis using multinomial logistic regression of other substance dependence or abuse revealed the following. First, that the younger polyopioid misuse profile (Class 3) was over 350% more likely to report nicotine dependence in the last month (odds ratio (OR) = 4.49, 95% confidence interval (CI): 1.94\u201310.4), and was almost 78% less likely to report marijuana dependence or abuse  compared to the female prescription misuse profile (Class 2). The older polyopioid misuse profile (Class 4) was over 270% more likely to report nicotine dependence in the last month  than the female prescription misuse profile (Class 2). See Our study revealed five classes of opioid misuse and their respective risk profiles based on sociodemographic characteristics and type of opioids used: (1) A single heroin or prescription misuse class with high probabilities of high-income, employment, and private health insurance; (2) a female prescription pain reliever misuse class with some combination use and high probabilities of serious psychological distress and suicidality; (3) a younger polyopioid misuse class with the highest likelihood of heroin use and being Hispanic; (4) an older polyopioid misuse class with highest probabilities of being non-Hispanic black and disabled with the second highest conditional probabilities of heroin and combined heroin and prescription pain reliever use; and (5) an older non-Hispanic white male exclusive dual heroin and/or prescription misuse class with high-income and no private health insurance residing in high population density areas.Sociodemographic indicators were useful in identifying each profile, as well as possible disparities and points of comparison between profiles. However, participants of color, were limited in our opioid misuse sample. Nevertheless, non-Hispanic blacks had the highest likelihood of being identified with the older polyopioid misuse group. Hispanics had the largest ethnic representation among the younger polyopioid misuse group. Single heroin or prescription misuse and female prescription pain reliever misuse profiles were predominantly non-Hispanic white. The dual older male heroin and/or prescription use class was the only exclusive non-Hispanic white profile. While it may seem that the US media has portrayed the risk profiles of non-Hispanic male whites like those of the dual heroin and/or prescription users, the opioid epidemic involves many racial/ethnic groups in addition to other demographic characteristics . For insWe considered the dual opioid and/or prescription opioid misuse profile to be the highest at-risk group because of the reported likelihood of a combination of heroin and prescription pain reliever use. The combination opioid misuse suggests that this class may have transitioned to heroin use from prescription pain relievers since there was no likelihood of heroin only use. This class exclusively used prescription opioids that are known to be risk factor to heroin use ,26,27,28A temporal effect may also exist with combination opioid use and initiation. Cicero et al.  reportedThe older polyopioid misuse class had the second highest likelihood of combined heroin and prescription opioid use, as well as the second highest likelihood of heroin-only use, followed by the younger polyopioid misuse profile. The younger polyopioid profile had the highest conditional probability of heroin-only use. While these profiles may be affected by temporality and initiation effects of heroin use, as previously discussed, combination opioid and heroin-only use have been associated with various other factors. Factors include geographic residence , socioeconomic status, socioecological factors , sexual identity , overall health , mental health issues , suicidality, and substance-dependence/abuse ,15,18,19Polyopioid misuse may take routes of ingestion via non-intended forms , inhalation , or injection ,31,32. UConcurrent substance dependence and abuse has been positively associated with opioid misuse ,36, moreThe current opioid crisis is unlike prior substance use crises of the past. It is important to develop interventions for acute and immediate response, but it is equally important to conduct research that provides etiological evidence and findings that can be used to inform prevention and intervention efforts along the continuum from opioid initiation to use disorder. The present work sought to add to the body of literature related to the opioid epidemic by identifying risk profiles of misuse among noninstitutionalized adults, which can further help inform prevention science and public health research. While existing studies on opioid misuse and use disorder exist, we took this into consideration when developing our person-centered methodological approach. We used the existing literature to inform our selection of opioid misuse indicators to identify how each one played a role within opioid misuse profiles as well as to identify potential points of interventions unique and in common between profiles. Specifically, we identified unique profiles that may be overlooked or treated as outliers, but may be in dire need of intervention. We also identified possible interactions of social determinants, health, and other substance dependence or abuse unique in each profile that could inform health policy and be a point of intervention to mitigate the distal effects of opioid overdose and death. Furthermore, each profile identified the probability of opioid type that can help develop as well as boost the efficiency and efficacy of interventions and therapies . As such, our primary goal was to identify profiles by which interventions can be tailored to noninstitutionalized populations especially from those that may be hidden in survey data.The NSDUH is a nationally representative instrument for collecting estimates of drug use and mental health. There are, however, limitations associated with using this dataset. One limitation is the use of self-report data, which is subject to the individual bias, truthfulness, and recollection of the responder. To address this issue, the NSDUH employed the use of audio computer-assisted self-interview (ACASI) software instead of human interviewers. While studies have established the validity of the NSDUH, the ACASI design and other implementation procedures are designed to boost recall. Nevertheless, as is the nature with these survey types, a level of under- and over-reporting exists . For theHealth researchers must first identify and understand opioid misuse risk profiles to prevent use disorders that may lead to adverse outcomes such as overdose and death. Understanding risk is critical to create meaningful prevention strategies and develop targeted interventions, rather than relying on universal blanket interventions that may fail medically underserved or underrepresented groups . Our per"}
+{"text": "E. coli is associated with grave health care consequences. The aim of this study was to determine the microbial quality of raw meat, the antimicrobial susceptibility and Extended Spectrum Beta Lactamase (ESBL) production in E. coli isolates from raw meat.Typically, raw meat can be contaminated with antibiotic resistant pathogens at unhygienic slaughter and sale points. Consumption of meat contaminated with antibiotic resistant 2 in 60.5% (124/205) of raw meat samples. Total Coliform Counts in 70.7% (145/205) of samples were in excess of the acceptable limit of 2.5 log CFU/cm2. E. coli was detected in about half of raw meat samples (48%), ranging from 9.5\u201379.0% among the slaughter sites. Isolates were susceptible to meropenem (100%), ceftriaxone (99%), cefotaxime (98%), chloramphenicol (97%), gentamycin (97%), ciprofloxacin (92%) and amikacin (92%), but resistant to ampicillin (57%), tetracycline (45%), sulfamethoxazole-trimethoprim (21%) and cefuroxime (17%). Multi-drug resistance (MDR) was identified in 22% of the isolates. The blaTEM gene was detected in 4% (4/98) of E. coli isolates in this study.Total Plate Counts exceeded the acceptable limit of 5.0 log CFU/ cmE. coli including ESBL producing E. coli that are resistant to most antibiotics in use. We recommend an enhanced surveillance for antibiotic resistance in food products for the early detection of emerging resistant bacteria species in the food chain.The levels of microbial contamination of raw meat in this study were unacceptable. Meat handlers and consumers are at risk of foodborne infections from  The emergence of antibiotic resistance in bacteria commonly found in food animals has garnered attention globally for its potential contribution to human colonization with antibiotic resistant bacteria. Antibiotics are used in food animals for therapeutic and non-therapeutic purposes. The continuous use of antibiotics in food animal production is cited as a major determinant for carriage of antibiotic resistant bacteria in food animals . A propoEscherichia coli is a common colonizer of the intestinal tract of humans and animals, and is widely known to cause bacteremia in humans , PC, PCblaTEE. coli and their resistance patterns. The Chi-square test was used to assess differences in the proportion of E .coli detected in raw meat between the three slaughter sites. A Kruskal-Wallis test was performed to determine if there were significant differences in microbial counts in raw meat among the slaughter sites. Statistical analyses were performed at 95% confidence level using STATA version 15.0.Descriptive statistics were performed on carriage rates of"}
+{"text": "The prevalence of Skeletal Related Adverse Events (SREs) in EGFR mutated non-small cell lung cancer (NSCLC) patients with bone metastases, treated with modern tyrosine kinase inhibitors (TKIs), has been scarcely investigated.We retrospectively evaluated the data of EGFR mutated NSCLC patients with bone metastases treated with TKIs in 12 Italian centers from 2014 to 2019, with the primary aim to explore type and frequency of SREs.vs 29%, p 0.000). Patient Performance Status and liver metastases where independently associated with the risk of developing SREs. Median TKI exposure and overall survival were 11 and 28 months, respectively. Bone resorption inhibitors were associated with a lower risk of death  although not statistically significant at multivariate analysis.Seventy-seven out of 274 patients enrolled (28%) developed at least one major SRE: 55/274 (20%) bone fractures, 30/274 (11%) spinal cord compression, 5/274 (2%) hypercalcemia. Median time to the onset of SRE was 3.63 months. Nine patients (3%) underwent bone surgery and 150 (55%) radiation therapy on bone. SREs were more frequently observed within the 12 months from TKI start than afterwards (71 Bone metastatic NSCLC patients with EGFR mutated disease, treated with EGFR TKIs, have a relatively long survival expectancy and are at high risk to develop SREs. The early SRE occurrence after the TKI start provides the rationale to administer bone resorption inhibitors. Lung cancer is the leading cause of cancer death worldwide .Despite the introduction of modern efficacious therapies, the prognosis of patients with metastatic disease still remains poor although highly variable, being dependent on genomic abnormalities and programmed death-ligand 1 (PD-L1) expression .Genetic analysis allows the identification of somatic sensitizing mutations in epidermal growth factor receptor (EGFR), typically exon 19 deletion (Ex19del) and L858R. These mutations are found in among 15% of lung adenocarcinoma in European patients .First- or second-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) , administered to patients whose tumors harbor these genotype alterations, led to marked tumor response and improved progression-free survival and quality of life over chemotherapy \u20135. ThankThe prognosis of these patients is destined to further improve with the recent introduction in clinics of the third generation EGFR-TKI osimertinib .NSCLC often metastasizes to bone and the frequency of bone metastasis (BM) is 30\u201340% during the clinical course of the disease .The diagnosis of BM negatively impacts on patient\u2019s quality of life (QoL) and is associated with poor survival . About 8SREs is therefore a composite endpoint, which encompasses both major complications, such as fractures, spinal cord compression, hypercalcemia, and local bone treatments, such as surgery and radiation therapy .Published randomized clinical trials did not report whether the greater benefit obtained by modern TKIs over chemotherapy could translate or not into a fewer proportion of SREs .The therapeutic strategies to manage BM and reduce the incidence of SREs include the administration of bisphosphonates (i.e. zoledronic acid) and Receptor Activator of Nuclear factor Kappa B Ligand (RANKL) inhibitors (denosumab). The results of a randomized prospective placebo controlled clinical trial have demonstrated that zoledronic acid is efficacious in preventing and delaying the SRE onset in lung cancer patients with bone metastases . In the In this paper, we present the results of a retrospective multicenter study aiming to define the prevalence of SREs in EGFR mutated NSCLC patients, treated with first/second generation TKIs.We also investigated the natural history of EGFR mutated NSCLC with BM, the prognostic factors, and the impact of bone resorption inhibitors on patient\u2019s outcome.We conducted a retrospective, observational, multicenter study. Medical records of patients with bone metastases from EGFR-mutated NSCLC, treated with TKIs in 12 referral Italian centers from 2014 to 2019, were analyzed.The primary aim of the study was to estimate the frequency of SREs. Secondary endpoints were to define in this study population overall survival, time to TKIs exposure and time to SRE. We also explored, both in univariate and multivariate analyses, prognostic factors, and factors predictive of SREs.versus metachronous bone metastases) and identified through imaging assessment . Patients with bone invasion by contiguity were excluded.To be included in our study adult patients (\u226518 years) with EGFR-mutated lung adenocarcinoma should have had bone metastatic involvement either at diagnosis or during the disease course  according to ECOG, major comorbidities, current or past smoking history, site and number of visceral metastases. We also recorded pathological data, including EGFR mutations, and blood chemistry data: i.e. alkaline phosphatase (ALP), lactate dehydrogenase (LDH), hemoglobin (HB).For each patient, the type of TKI used was collected, specifying date of start and end of treatment. Dates of disease progression under TKI therapy , last follow-up, or death were also recorded.Regarding bone involvement, the following data were collected: time of onset of BMs, if BMs were synchronous or metachronous with respect to first disease diagnosis; if they were osteolytic, osteoblastic, or mixed; and the number of bone sites involved. Furthermore, data about the occurrence of SREs, i.e. pathological fractures, hypercalcemia, spinal cord compression, bone radiotherapy, and bone surgery, were collected as well as whether a specific bone anti-resorptive treatment (bisphosphonates or denosumab) was introduced or not.The study was firstly approved by the Institutional Review Board of the Coordinating Center in Brescia (SURMOS Study no. NP1848) and subsequently by the ethic committees of each participating institution.SURMOS study was conducted in accordance with the Declaration of Helsinki for clinical studies.The primary endpoint was to define the prevalence of major SREs  in EGFR mutated NSCLC patients with bone metastases, treated with TKIs.Among secondary endpoints, we evaluated: 1) the prevalence of SREs according to standard definition , 2) overall survival, that was defined as the time interval between the date of diagnosis of bone metastases and the date of death or the last known alive date, 3) time between primary diagnosis and occurrence of bone metastases, 4) time to the occurrence of SRE from the diagnosis of bone metastases, i.e. the interval between date of diagnosis of bone metastases to the first occurrence of either bone fracture, spinal cord compression, or hypercalcemia, and 5) time of TKI exposure .Descriptive statistics were used for patients\u2019 demographics, tumor characteristics, and frequency of SREs. Categorized variables were expressed as percentages. Cut-off points were identified for continuous variables based on the median value or upper limit of normal ranges .Survival curves were calculated by the Kaplan-Meier method and differences compared by the log-rank test. The Cox\u2019s proportional hazards regression model was employed to assess the Hazard ratios (HRs) and 95% confidence intervals (95% CIs) both in univariate and multivariate analyses, with the lowest risk group as the reference group. Only parameters significantly associated with OS or time to SRE in the univariate analysis (at p < 0.10) were included in the multivariate analysis model.All p values are two-sided and p values less than 0.05 were considered statistically significant. Due to the explorative nature of this study, a formal calculation of the sample size was not performed. It was considered, however, that a minimum of 200 patients would have been required to have an adequate power for statistical analyses. Statistical Package for Social Science, SPSS, software  was used for statistical analysis.A total of 274 patients with bone metastatic, EGFR-mutated, NSCLC were collected to this study. Patient\u2019s characteristics are summarized in The median age was 50 years, 171 (62%) were female and 103 (38%) were male. The PS, available in 243 (89%) cases, was 0\u20131 in 222 (91%) and higher than 1 in 21 (9%) patients, respectively. One hundred eighty-two patients (66%) had a history of smoking habit (present or past). The mutational status, available in 251 patients (92%), was as follows: exons 18 in 14 (6%), exon 19 in 144 (57%), exon 20 in 8 (3%), and exon 21 in 85 (34%) patients. Four patients presented compound EGFR mutations: 1 exon 18 and 21, 3 exon 18 and 20.Twenty-eight out of 51 available patients (55%) presented T790M mutation.One hundred eighty-four patients received gefitinib (67%), 46 afatinib (17%), 43 erlotinib (16%). One patient (0.4%) received osimertinib. The median time to TKI exposure was 11,1 months .In 203 patients (74%) BMs were synchronous with diagnosis of advanced NSCLC, while 71 patients (26%) developed bone metastasis during follow-up. In 12 patients (4%) bone was the only metastatic site, 13% had bone plus one metastatic site, and 83% had at least two different metastatic sites in addition to bone. Concomitant visceral metastatic sites were lung in 162 (59%), liver in 62 (23%), lymph nodes in 205 (75%), adrenal glands in 41 (15%), and Central Nervous System (CNS) in 105 (38%) patients respectively.The burden of bone involvement was available in 265 patients (97%). It was limited (1\u20132 sites) in 125 (47%), intermediate (3\u20134 sites) in 83 (31%), and extensive (5\u201310 sites) in 57 cases (22%). Osteolytic and mixed bone lesions were documented in 163 (66%) cases, the remaining 84 (34%) patients had osteoblastic metastasis. In the minority of patients in which blood parameters were available, hemoglobin levels were often below the normal range and high levels of both ALP and LDH were frequently observed.A total of 173 adverse SREs were recorded in the 274 patients examined in the present study (63%). Seventy-seven (28%) developed at least one major SRE: 55/274 (20%) presented bone fractures, 5/274 (2%) hypercalcemia, 30/274 (11%) spinal cord compression. Fourteen patients (5%) developed both pathological fractures and spinal cord compression, three patients (1%) presented hypercalcemia and pathological fractures. Nine patients (3%) underwent bone surgery and 150/274 (55%) radiation therapy on bone Figure 1The date of appearance of the first SRE was available in 135 out of the total of 173 SRE (78%). All the 77 major SREs were correctly placed during the treatment course. As shown on Forty-one (30%) patients developed the first event before TKI introduction, among the remaining 94 patients, 22/33 (67%) developed bone fractures within the first 12 months of TKI therapy and 11/33 (33%) afterwards; the corresponding distribution of spinal cord compression was 10/16 (63%) and 6/16 (37%), hypercalcemia: 2/4 (50%) and 2/4 (50%), bone surgery: 1/2 (50%) and 1/2 (50%), radiation therapy: 58/81 (72%) and 23/81 (28%), respectively Figure 3One hundred and twenty-two patients (45%) received bone resorption inhibitors: 79 (29%) bisphosphonates, 46 (17%) denosumab, 3 patients (1%) received both drugs.In the univariate analysis depicted in Median follow-up of enrolled patients was 23 months (range 1\u2013117). At the last follow-up examination, 152 patients (55%) were dead. Median overall survival (OS) from the diagnosis of bone metastases was 28 months (95% CI: 24.1\u201331.8) Figure 4Median OS of patients who developed synchronous bone metastases was 29 months (95% CI: 22.8\u201335.2) as opposed to 24 months (range 15.4\u201332.6) of patients who presented metachronous bone metastases (p = 0.010).Among the 33 potential prognostic factors analyzed in univariate analysis, the female gender , EGFR Mutation of Exon 19  and the presence of synchronous bone metastasis  were significantly associated with a lower risk of death.On the contrary, smoking habit , PS \u2265 2 , ALP \u2265220 U/I , and LDH \u2265300 U/I  were significantly associated with a higher death risk Table 3.At multivariate analysis, smoking habit , PS , and the presence of synchronous bone metastasis  maintained a significant association with the death risk. Due to the low number of patients with available data, LDH and ALP were not included in the multivariate model.The administration of bisphosphonates or denosumab was significantly associated with a lower risk of death at univariate analysis  Figure 5Bone metastases have a negative impact on quality of life and prognosis of lung cancer patients due to bone pain and the elevated risk of SREs . The freIn this multicenter retrospective series, involving bone metastatic patients with EGFR mutated NSCLC, the frequency of SREs, according to the standard definition that also includes bone surgery and radiation therapy was 58%. This proportion is similar to that reported in the above mentioned Italian series of bone metastatic lung cancer patients , 94.3% oin vivo studies demonstrated that EGFR is essential for osteoblast proliferation  and subsequently by the ethic committees of each participating institution.All authors contributed to the study design and data collection for all the Italian institutions involved in the study. Material preparation and analysis were performed by ML and CG. The first draft of the manuscript was written by ML, CG, and AlfB. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Cardiovascular magnetic resonance with late gadolinium enhancement (LGE-CMR) identifies areas of myocardial scarring in patients with hypertrophic cardiomypathy (HCM). The presence of LGE identifies HCM patients at risk for ventricular tachyarrhythmias, which is an independent predictor of sudden death in this disease. In this study, we sought to determine whether regions of abnormal tissue at the confluence of both viable myocardium and fibrosis (\"border zone\") (BZ) are more predictive of ventricular tachyarrhythmias than areas of myocardial scarring alone.Cine CMR and LGE-CMR were performed in 145 HCM patients  from two HCM referral centers using standard techniques (0.2 mmol/kg gadolinium-DTPA). LGE was determined by a blinded, independent reader using grayscale thresholds of both 4 and 6 standard deviations (SD) above the mean of normal, remote myocardium. BZ was determined as the difference between the 4 SD and 6 SD thresholds. All subjects underwent 24-h ambulatory Holter electrocardiogram (ECG) within 7.8 \u00b1 8.3 weeks of the CMRThe amount of myocardial scarring (6 SD) alone was 5.5 \u00b1 7.2% of the LV myocardium, while the amount of BZ was 6.5 \u00b1 4.6% of the LV myocardium. Runs of non-sustained ventricular tachycardias (NSVT) were present in 23 patients (16%), ventricular couplets were present 39 patients (27%), while premature ventricular couplets (PVCs) were present in 119 patients (82%). There was no significant association with the extent of myocardial scarring and the occurrence of NSVTs, couplets, and PVCs . However the extent of BZ was significantly associated with the occurrence of NSVTs, couplets and PVCs .These data demonstrate that in HCM patients, the extent of BZ may be a superior predictor of ventricular tachyarrhythmias than myocardial scarring alone . This study indicates the need for follow-up studies evaluating the independent prognostic value of BZ in risk stratification strategies in HCM patients."}
+{"text": "The Money Follows the Person (MFP) program transitions people to the community after extended institutional stays. This study examines effects of this transition on informal caregivers in this new caregiving career stage. Analyses explore whether and how MFP affects caregivers according to caregiver race/ethnicity, and care recipient age and disability type. Data come from surveys with 686 caregivers of persons in Connecticut\u2019s MFP from November 2014-November 2018. Using Pearlin\u2019s Caregiver Stress Process Model, bivariate and multivariate analyses examine predictors of multiple caregiver well-being indicators. Care recipients: older adults (50%), and younger persons with physical (35%), mental health (8%) or developmental (7%) disabilities. Caregivers: non-Hispanic White (62%), non-Hispanic Black (24%), and Hispanic (14%). Caregivers\u2019 average assistance is 5 days/week, 6 hours/day, with 3 activities of daily living and 5 instrumental activities; 11% are paid for caregiving. Compared to other community-based samples, they report low mean levels of burden (4.7 of 16), anxiety (2.2 of 18) and depressive symptoms (31%), and high positive feelings about caregiving (9.5 of 12). A majority feel less stressed (60%) or no change in stress (20%) compared to before and during the institutional stay. Caregivers across the four care recipient groups don\u2019t differ on most outcomes, although more caregivers of people with developmental disabilities (82% vs. 55-61%) report less stress once the person transitions. Black and Hispanic caregivers report more intensive caregiving, but White caregivers report more burden and subjective stress. Findings illustrate the benefits of programmatic support during a newly defined post-institutionalization caregiving career stage."}
+{"text": "Aspergillus. A multidisciplinary mycology meeting can be a useful addition to the care for patients with (I)FDs and can potentially aid in identifying healthcare and research needs regarding the field of fungal infections. The majority of patients discussed at the multidisciplinary meetings suffered from pulmonary infections, predominantly CPA.Invasive fungal diseases (IFDs) often represent complicated infections in complex patient populations. The Center of Expertise in Mycology Radboudumc/CWZ (EMRC) organizes a biweekly multidisciplinary mycology meeting to discuss patients with severe fungal infections and to provide comprehensive advice regarding diagnosis and treatment. Here, we describe the patient population discussed at these meetings during a one-year period with regards to their past medical history, diagnosis, microbiological and other diagnostic test results and antifungal therapy. The majority of patients discussed were adults (83.1%), 62.5% of whom suffered from pulmonary infections or signs/symptoms, 10.9% from otorhinolaryngeal infections and/or oesophagitis, 9.4% from systemic infections and 9.4% from central nervous system infections. Among children, 53.8% had pulmonary infections or signs/symptoms, 23.1% systemic fungal infections and 23.1% other, miscellaneous fungal infections. 52.5% of adult patients with pulmonary infections/symptoms fulfilled diagnostic criteria for chronic pulmonary aspergillosis (CPA). Culture or polymerase chain reaction (PCR) demonstrated fungal pathogens in 81.8% of patients, most commonly  Fungal infections have a large impact on human health, and invasive fungal diseases (IFDs) are associated with high mortality rates ,2,3. It During these meetings, patient cases are discussed in a structured manner regarding medical history, clinical courses, diagnostic test results, microbiological aspects, host immunological aspects, pharmacological issues, and treatment provided so far. Subsequently, recommendations are formulated regarding further diagnostic work-up, treatment, and/or follow-up. Additionally, further specialized microbiological tests , translational immunological work-up , and pharmacological laboratory testing ) are offered, if necessary. Currently, the EMRC is not involved in antifungal stewardship activities, but offers advice on antifungal treatment on a case-by-case basis. Recommendations for antifungal stewardship have recently been published . PatientHere, we aim to provide an overview of the fungal infections and the clinical, microbiological and treatment issues encountered during the multidisciplinary mycology meetings that took place during the first year of systematic registration of the proceedings and outcomes of these meetings. Furthermore, we aim to provide others with a framework for establishing a multidisciplinary team to address the increasing complexity of fungal infection management.All patients discussed during the biweekly multidisciplinary mycology meeting in the EMRC were registered in a database (Microsoft Excel). Patient history and clinical course , diagnostic test results , microbiological results  results, susceptibility testing), information on host immunological factors and employed antifungal treatment (including TDM results) were provided in advance by the presenting physician. If the patient primarily received treatment at Radboudumc, this information was extracted from the electronic patient record .For this study, data from patients discussed at the multidisciplinary meetings between 01-07-2017 and 30-06-2018 were included. Statistical analysis was performed using Microsoft Excel 2016 for Office 365 and GraphPad Prism 5 for Windows .During the 12 months\u2019 period studied, a total of 27 multidisciplinary mycology meetings were held . In the Patient characteristics are provided in Patients were presented at the multidisciplinary meetings primarily by a pulmonologist (37.7%), an infectious diseases specialist (35.1%) or both (3.9%), or by a paediatrician (14.3%), whereas other patients were presented by medical microbiologists, gynaecologists, otorhinolaryngologists, ophthalmologists, neurologists and clinical pharmacists.Among children A, 7 , with three suffering from Candida infection  and a diagnosis of disseminated mucormycosis, disseminated histoplasmosis and invasive pulmonary and CNS aspergillosis in one patient each. CNS infections in 6 patients (9.4%) mostly concerned cryptococcal meningitis (5 patients). Fungal skin and soft tissue infections were present in 3 (4.7%) patients, Aspergillus endophthalmitis in one (1.6%) and one patient was ultimately not diagnosed with a fungal infection, but with chronic granulomatous disease and disseminated nocardiosis.The majority of adult patients B were diAspergillus IgG test results was discussed during the multidisciplinary meeting.The majority of adult patients with pulmonary infections or signs/symptoms  had a prAspergillus noduli and one (4.8%) had a simple aspergilloma. CPA in 2 patients (9.5%) could not be categorized into a subtype.Diagnostic criteria for CPA according to the European Society of Clinical Microbiology and Infectious Diseases/European Respiratory Society (ESCMID/ERS) guidelines  and diagThe most common underlying diseases and comorbidities among the 21 patients with CPA according to the ESCMID/ERS diagnostic criteria were previous (probable) pulmonary infections in 12 (57.1%), asthma in 8 (38.1%), pulmonary surgery for any reason in 7 (33.3%), COPD in 5 (23.8%), bronchiectasis in 4 (19.0%), lung carcinoma with or without systemic treatment in 3 (14.3%) and pneumothorax with or without pleurodesis in 3 (14.3%). Furthermore, 7 patients (33.3%) used immunosuppressive medication , 2 suffered from sarcoidosis (9.5%), 2 (9.5%) suffered from an autoimmune disease and 2 (9.5%) had a primary immune deficiency other than cystic fibrosis (CF). One patient (4.8%) had suffered from pulmonary TBC, whereas another one had a single sputum sample positive for auramine staining and TBC PCR at the time of diagnosis, which became negative a day later (possibly reflecting contamination). None of the patients had a history of non-tuberculous mycobacterial (NTM) infection.Aspergillus species (in 42 patients: a single species in 37 and two species in 5). Candida species were isolated in 9 patients (a single species in 6 and two species in 3), Cryptococcus neoformans was demonstrated in 6 and Mucorales were demonstrated in 4 patients . Among these, a single fungal pathogen was demonstrated in 50 (79.4%), whereas multiple pathogens were demonstrated in 13 (20.6%). The vast majority of these microorganisms concerned patients .Aspergillus species was as follows: A. fumigatus in 28/42 (66.7%), A. niger in 4 (9.5%), A. flavus in 3 (7.1%), A. nidulans in 2 (4.8%), A. terreus in 2 (4.8%), A. glaucus group in one (2.4%) and Aspergillus NOS in 8 (19.1%). Information on voriconazole susceptibility of A. fumigatus isolates obtained at any time during the disease course was available for 25/28 patients in which this fungal pathogen was demonstrated. Voriconazole-resistant Aspergillus (minimum inhibitory concentration of \u2265 2 mg/L) was present in at least one isolate in 10/25 (40%) of patients tested. Most commonly involved Candida species were C. albicans  and C. krusei , with C. glabrata, C. tropicalis and C. dubliniensis being demonstrated in one patient each (11.1%). Lastly, in 2 (50%) patients suffering from Mucorales infection, Lichtheimia corymbifera was demonstrated and Rhizomucor pussilus was demonstrated in the other 2.Distribution of Antifungal treatment had already been administered to 56 patients (72.7%) at the time of first consultation (including the 12 patients with first consultation before 01-07-2017), and 47 patients (61%) were still on antifungal treatment. Recommendations regarding modification of antifungal treatment were given in 44 patients (57.1%). This advice pertained to switching antifungal treatment regimen , starting antifungal treatment , adding  or removing  antifungal drugs to the treatment regimen, stopping antifungals , and in one patient (2.3%) switching antifungal regimen and adding an antifungal drug at a later time point.Our data represent an overview of the clinical cases presented at the multidisciplinary mycology meetings during a 12 months\u2019 period in our Center of Expertise in Mycology in the Netherlands. During this period, 114 consultations were performed for 77 patients with fungal infections, most of whom were adults with a past medical history. The majority of both adult and paediatric patients discussed suffered from pulmonary infections or signs/symptoms . In the majority of cases, consultation had an  impact on patients\u2019 treatment.Aspergillus serological tests, a key parameter in CPA diagnosis, and the requirement of excluding alternative diagnoses. Furthermore, optimal treatment strategies and commonly accepted treatment endpoints for this disease still warrant further research, even though clinical guidelines have been published [Interestingly, more than half of adult patients with pulmonary infections or signs/symptoms had a presumptive clinical diagnosis of CPA or SAIA, CPA combined with IPA or CPA combined with ABPA. Initial presumptive diagnosis demonstrated relatively good agreement with formal diagnostic criteria (21/26 suspected patients fulfilled the ESCMID/ERS diagnostic criteria). The finding that most confirmed CPA patients suffer from the CCPA or CFPA subtype is in line with previous studies . The higublished ,21.Underlying diseases/comorbidities in our CPA patient population are largely in agreement with those described in a large UK study , but difCandida infections, despite this yeast constituting the fourth most common cause of hospital-acquired bloodstream infections in the USA [The relative paucity of IPA patients discussed might reflect a better acquaintance of physicians with this manifestation of pulmonary aspergillosis and the availability of well-established international and national (Dutch) treatment guidelines ,23,24. F the USA : mostly,Further indications of the complexity or atypical nature of cases discussed are the finding that multiple aspects of care were discussed in 83.1% of cases and that host factor criteria for probable IFD, according to the revised European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium (EORTC/MSGERC) definitions  were preThe finding that 23.1% of all paediatric and 12.5% of all adult patients discussed concerned those with respiratory signs/symptoms or an underlying disease with positive microbiological test results of unknown significance stresses the need for better diagnostic tools that help differentiate fungal disease from colonization.A. fumigatus harboured a voriconazole-resistant isolate at any one time during their disease course is remarkable in light of the 10.5% of culture-positive patients with triazole-resistant isolates described in recent Dutch national surveillance data, attesting to the complexity of the patient population involved [The observation that 40% of patients with demonstrated involved .Inherent to the setup of the multidisciplinary meeting, our study does not represent a comprehensive epidemiological overview of fungal infections in the Netherlands, such as recently published . InsteadBy combining complementary expertise, employing a structured approach and providing comprehensive advice on diagnostic work-up and antifungal treatment, the multidisciplinary mycology meeting can have a significant impact on healthcare for patients with (I)FDs. The method of practice-based registration improves the quality of consultation and provides a platform for training and education. Furthermore, obtaining experience in (I)FDs facilitates development of expert opinion-based approaches to diagnosis and treatment, potentially serving as a rationale for future clinical trials.In conclusion, a multidisciplinary mycology meeting proves to be a useful modality to address complex, rare and/or atypical (I)FDs. By providing an (inter)national consultation service and thus concentrating specialized mycological care, clinical experience can be gained by the members of the multidisciplinary team in fungal diseases normally rarely encountered by a single healthcare professional. Furthermore, it may reveal unmet needs regarding diseases previously thought to be rare or those relatively unknown to clinicians, as is the case with CPA in our cohort, thus providing information on which disease entities require more awareness and which clinical issues and needs should be prioritized in further research efforts in a national or regional context."}
+{"text": "Outbreaks of coronavirus disease 2019 (COVID-19) in nursing homes can severely affect older adults. During March 17\u2013April 16, 2020, seven nursing homes in West Virginia reported 307 COVID-19 cases among both residents and staff members; four of the nursing homes reported outbreaks involving 20\u201340 residents. On April 17, the governor of West Virginia issued Executive Order 27\u201320Beginning April 21, nasopharyngeal or nasal swabs were collected from residents by in-house staff members, local health departments, or the West Virginia National Guard. Specimens were tested at a private laboratory using a statewide contract or at other commercial laboratories arranged by the nursing homes, using real-time reverse transcription\u2013polymerase chain reaction. In nursing homes with active outbreaks, all persons received testing who had previously tested negative or had not been tested. An outbreak was defined as the detection of two or more laboratory-confirmed COVID-19 cases within 14 days among staff members or residents in a nursing home. All residents with positive SARS-CoV-2 test results were isolated in private rooms, and transmission-based precautions were implemented by WVBPH in alignment with CDC guidance.During April 21\u2013May 8, universal testing was conducted in all 123 West Virginia nursing homes. Receiving testing was declined by 1.3%  of residents and 1.7%  of staff members. Among the 8,911 residents and 13,687 staff members who were tested, 42 COVID-19 cases were identified in 28 (23%) nursing homes, none of which had previously experienced an outbreak. The 42 cases occurred in 11 residents (0.1% of residents tested) and 31 staff members (0.2% of tested staff members). The 42 identified cases represented 20 single cases from 20 facilities and 22 outbreak-associated cases, representing new outbreaks (ranging in size from two to six persons) in eight facilities . The preIn six of the eight nursing homes with newly identified COVID-19 outbreaks where cohorting of residents with positive SARS-CoV-2 test results and exclusion of staff members with positive test results were implemented, daily follow-up symptom screening of all residents and staff members for 28 days (the upper bound of two incubation periods) found that further transmission did not occur. Two facilities experienced minimal transmission beyond the initial cases detected during universal testing.Universal testing identified eight outbreaks with 17 staff members and five residents who tested positive for SARS-CoV-2, including six staff members and two residents who were asymptomatic . The tesFor the period May 8\u2013July 26, following completion of universal testing and under the new procedures, 18 COVID-19 outbreaks were identified in West Virginia nursing homes, 12 of which involved five or fewer cases. Although universal testing is resource-intensive, it has proven essential to limiting COVID-19 transmission in nursing homes and has reduced the impact of the pandemic on this vulnerable population in West Virginia."}
+{"text": "Little is known about trends in the prevalence of serious mental illness (SMI) and Alzheimer\u2019s disease and Related Dementias (ADRD) in assisted living (AL). We summarize changes in the prevalence of SMI and ADRD in larger AL settings (25+ beds) from 2008-2017 using Medicare claims data. We compare these changes to nursing home (NH) and community rates of SMI and ADRD. We also examine state variability in SMI and ADRD in AL in 2017. The prevalence of SMI in AL increased 37%, from 7.8% in 2008 to 10.7% in 2017; ADRD prevalence increased 34%, from 27% to 36.4%. Over time, NHs exhibited the greatest increases in SMI (53%), followed by AL (37%) and the community cohorts (27%). Increases in ADRD were highest in AL. Rates of SMI in AL ranged from 3.5% in Wyoming to 28.7% in New York. We discuss implications for future research and policy."}
+{"text": "Objective: Symptomatic in-stent restenosis (sISR) is the major cause of medium- or long-term cerebral infarctions in patients who underwent percutaneous transluminal angioplasty and stenting for severe intracranial atherosclerotic stenosis. This study aims to evaluate the feasibility and safety of paclitaxel-coated balloon (PCB) angioplasty for the treatment of intracranial sISR.Methods: We report 11 cases of PCB angioplasty for intracranial sISR. Lesion locations and number were as follows: intracranial internal carotid artery (n = 4), M1 segment of middle cerebral artery (MCA) (n = 1), V4 segment of vertebral artery (n = 6). The technical success rate, periprocedural complications, and short-term outcome were retrospectively analyzed.Results: All procedures were successfully performed without periprocedural complication. Asymptomatic vessel dissection after PCB inflation occurred in one case. Postprocedural diffusion-weighted imaging (DWI) showed new asymptomatic ipsilateral infarction in one case. All 11 cases did not experience ipsilateral stroke or death within 30 days or ischemic stroke in the territory of the target artery between 31 and 90 days after procedure.Conclusion: This preliminary study indicates that PCB angioplasty is feasible and safe for the treatment of intracranial sISR. Further studies are needed to clarify its efficiency and long-term outcome. Intracranial atherosclerotic stenosis (ICAS) responsible for 33\u201337% of acute ischemic strokes in Asian populations . WASID . PercutaHowever, SAMMPRIS trial still demonstrated that 12.2% of patients with symptomatic severe ICAS developed ipsilateral stroke or death within 1 year despite AMM treatment , suggestHigh in-stent restenosis (ISR) rate is one of the discouraging results of intracranial stenting. In the SAMMPRIS trial, during a median follow-up of 35 months, various degrees of ISR were found in 66.7% of patients with infarction and 80% of patients with transient ischemic attack (TIA) who received adequate vascular imaging examination . The useWe conducted a retrospective review of ICAS patients treated with PTAS in our center  from January 2018 to July 2019. Patients who developed sISR and treated with PCB angioplasty were retrospectively analyzed. Patients treated with PTAS and had any of the following events were identified : (1) iscThe criteria are as follows. Inclusion criteria were as follows: (1) 18\u201380 years old; (2) intracranial sISR; (3) baseline modified Rankin score <3; (4) patient understands the purpose and requirements of this therapy and has provided informed consent. Exclusion criteria were as follows: (1) intracranial or extracranial arterial dissection, moyamoya disease, vasculitis, radiation-induced vasculopathy, fibromuscular dysplasia; (2) a severe neurological deficit that renders the patient incapable of living independently; (3) dementia or psychiatric problem that prevents the reliable follow-up; and (4) comorbid conditions that may limit survival to <5 years.A total of 151 ICAS patients who received successful intracranial stenting in our center  were retrospectively reviewed; 85.4% (129/151) of them had valid angiographic follow-ups, and 15 patients (11.6% in 129) developed sISR. In the 15 patients with sISR, three of them rejected PCB angioplasty; one patient did not meet the criteria because of lung cancer, and 11 patients were finally included. All patients or their authorized family members were fully informed the benefits and risks of endovascular treatment and off-label use of the PCB. Clinical and imaging data of the subjects were retrospectively analyzed. This study was approved by the ethics committee of the First Affiliated Hospital of Zhengzhou University . The privacy of patients was strictly protected.The preprocedural management included physical examination, brain magnetic resonance (MR) imaging, or high-resolution MR imaging of the target artery, Mini Mental State Examination (MMSE) score before and after procedure, and dual antiplatelet therapy with 100 mg of aspirin and 75 mg of clopidogrel daily at least 5 days.ug/mm2 and 16% of which will finally be implanted in the vessel wall. SeQuent Please is relatively rigid, which makes it challenging to use in patients with tortuous intracranial vasculature and requires rapid navigation and location to the target lesion; therefore, we used intracranial support catheter  in most cases to support use of the PCB. Via the guiding catheter or Navien, the ISR lesion was crossed with a 0.014-inch Synchro microguidewire  and predilated with bare balloon . The bare balloon was then exchanged for a similarly sized PCB and centered across the lesion within 90 s. The DCB was then slowly inflated and kept at work pressure for 60 s. The ISR degree of residual stenosis was confirmed by DSA after the PCB withdrawn. The technical success of PCB angioplasty was defined as less 50% residual stenosis and stable antegrade perfusion (2b/3a) with no vessel dissection, perforation, or distal embolization  to treat intracranial sISR. The paclitaxel-loading dosage is 3 lization . If the After the procedure, patients were typically monitored in neuro critical care units for 24 h. Postprocedurally, the systolic blood pressure was kept under 130 mm Hg. All patients who underwent PCB angioplasty were continued on 100 mg aspirin and 75 mg clopidogrel daily for 3 months and 100 mg of aspirin daily thereafter. Postprocedural MR imaging and MR angiography were performed within 2 weeks after treatment. The clinical follow-up was scheduled for 1, 3, 6, and 12 months and yearly thereafter.The following data were collected: demographic characters of all patients such as age, sex, location of the target artery, date of last stent implantation, periprocedural complications of last stenting procedure, MMSE scores before and after the procedure, date and feature of the symptomatic neurological symptoms, Mori classification of ISR , degree The feasibility of PCB angioplasty for the treatment of intracranial ISR was determined by the following: (1) if the PCB can be safely transferred to the target lesion within 90 s despite significant tortuous access; (2) if the PCB can be safely inflated in target vessel for 60 s; 3) if the ISR grade was safely improved after PCB angioplasty. Safety of PCB angioplasty in intracranial ISR was determined by the following: (1) there was no hemorrhagic stroke due to microguidewire/microcatheter perforation or vessel rupture or hyperperfusion injury within 30 days after procedure; (2) there was no ischemic stroke due to distal embolization, perforator occlusion, and vessel dissection; (3) there was no stroke or death within 30 days after PCB angioplasty or ischemic stroke in the territory of the target artery between 31 and 90 days after procedure  of the patients were male. Ages ranged from 40 to 71 years with a mean of 56.0 years. The prevalence of dyslipidemia, hypertension, and diabetes was 72.7% (8/11), 36.4% (4/11), and 36.4% (4/11); 45.5% (5/11) of the sISR located in anterior cerebral circulation. The baseline characteristics are presented in All subjects received AMM after the first PTAS treatment. On the baseline of this study, 36.4% (4/11) of the subjects had low-density lipoprotein (LDL) level >1.8 mg/dL, 36.4% (4/11) had hypertension (with systolic/diastolic blood pressure >140/90 mm Hg), 18.2% (2/11) had poor blood glucose control (with blood glycated hemoglobin level >6.0%), 18.2% (2/11) were current smokers, and 36.4% (4/11) lack moderate or vigorous exercise. In total, 27.3% (3/11) of the subjects achieved the goal of AMM .In a total of 11 PCB angioplasty cases, all PCBs were transferred to the target lesion within 90 s and inflated for at least 60 s. Paclitaxel-coated balloon angioplasty was technically successful in 90.1% (10/11) of patients. Asymptomatic vessel dissection after PCB inflation occurred in one patient (9.1%). No distal embolization or snowplow effect was seen during the navigation, location, inflation, deflation, and withdrawal of the PCB catheter. The preprocedure stenosis was 76.4 \u00b1 8.3%, and postprocedure stenosis was 19.5 \u00b1 9.6% ; 9.1%  in ICAS patients , suggestn = 57) patients developed intracranial ISR and 26.3% (15/57) of which were symptomatic . The DCB failure occurred in one case because of the difficult local anatomical conditions . The patients/participants provided their written informed consent to participate in this study.HX and XF wrote this manuscript. SG approved the final submission. All authors participated the surgery operations in 11 patients.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Background: The world, and Italy on the front lines, has experienced a major medical emergency due to the novel coronavirus outbreak. Cancer patients are one of the potentially most vulnerable cohorts of people, but data about their management are still few.Patients and Methods: In this monocentric retrospective study we included all SARS-CoV-2 oncological patients accepted, between March 27th and April 19th 2020, at the Onco-COVID Unit at San Luigi Gonzaga Hospital, one of the few Italian oncological-COVID wards. Data were obtained from medical records.Results: Eighteen cancer patients with COVID-19 were included. The mean (\u00b1SD) age of patients was 67 \u00b1 14 years, 89% were men. Seven (39%) developed infection in communities and 11 (61%) during hospitalization. Lung cancer was the most frequent type of cancer . Seven patients (39%) were symptomatic for COVID-19 at the time of diagnosis and symptoms began 2 (\u00b12) days before. The most common were shortness of breath and diarrhea. Fever was present in 5 patients (28%). Among the 11 asymptomatic patients, 8 (73%) became symptomatic during the hospitalization (mean time of symptoms onset 4 days \u00b14). Six patients (33%) were on active anti-tumor treatment: 2 (33%) received anti-tumor therapy within 2 weeks before the infection diagnosis and 2 (33%) continued oncological treatment after SARS-CoV-2 positivity. Eight (44%) patients died within a mean of 12 days (\u00b18) from the infection diagnosis.Conclusions: Our series confirms the high mortality among cancer patients with COVID-19. The presence of asymptomatic cases evidences that typical symptoms and fever are not the only parameters to suspect the infection. The Onco-Covid unit suggests the importance of a tailored and holistic approach, even in this difficult situation. Over the past few months, the world has to face a major medical emergency due to the novel coronavirus SARS-CoV-2 outbreak. The high transmissibility rate and the rapid spread of the virus have led the World Health Organization (WHO) to declare the state of pandemic on March 11th 2020. More than 6 millions of cases and 370,000 deaths from COVID-19 (the disease caused by SARS-CoV-2) have been confirmed worldwide and Italy rapidly became one of the most affected countries , and the infection evolution are still unsolved. Since the resolution of the current health crisis looks as a long and not easy process, the collection of real-world data is a valuable strategy. This retrospective study aims to collect epidemiological, clinical, laboratory, and therapeutic data from SARS-CoV-2 positive cancer patients hospitalized at the Onco-Covid unit in San Luigi Gonzaga Hospital, Italy, one of the few oncological wards for cancer patients with SARS-Cov-2 infection, in order to provide a deeper insight into the clinical evolution of infection in cancer patients, particularly in lung cancer patients.The study was approved by the Ethics Committee of the AOU San Luigi Gonzaga, Orbassano (Turin). The requirement for specific informed patient consent was waived due to the emergency status, upon the approval of the Ethics Committee. However, patients provided a general written informed consent for clinical data collection at the time of hospitalization.This retrospective study included all SARS-CoV-2 oncological patients accepted at the Onco-Covid Unit at San Luigi Gonzaga Hospital, Orbassano, between March 27th and April 19th 2020.Clinical data was retrospectively retrieved from the medical records, including demographic and clinical features, laboratory, and radiological findings at presentation and during the hospitalization. In particular, following internal hospital protocol, a chest-X-ray or a chest ultrasound was executed at baseline. In case of severe respiratory illness in patients with a not poor prognosis, a computed tomography (CT) scan was also obtained. The radiological assessment was monitored during the hospitalization. However, all laboratory and radiologic tests were performed at the discretion of the treating physicians, taking into consideration patients' general conditions and prognosis.Patient data were censored at the time of data cutoff, which coincides with the closing date of the ward and occurred on April 19th, 2020.A confirmed case of Covid-19 was defined by a positive result on a reverse-transcriptase\u2013polymerase-chain-reaction (RT-PCR) assay  performed on a nasopharyngeal swab- derived specimen, following the WHO criteria .2 in mmHg) to fractional inspired oxygen (FiO2), defined as P/F, was used as clinical indicator of hypoxemia.The ratio of arterial oxygen partial pressure (PaODisease response (investigator-assessed) was defined according to Response Evaluation Criteria In Solid Tumors (RECIST) v. 1.1 criteria and to clinical evaluation.The terms \u201cbest supportive care\u201d were used to define care given to patients with no more indications to active antitumor treatment, aiming at improve the quality of life by preventing or treating symptoms.Descriptive statistics were used to summarize the data; results were reported as means and standard deviations (SD). Categorical variables were summarized as counts and percentages. Analysis was performed with IBM SPSS software.From March 27th to April 19th 2020, we identified 18 cancer patients with confirmed SARS-CoV-2 positivity at the Onco-Covid Unit.The demographic and clinical characteristics are shown in Chronic medical conditions, beside the oncological disease, were present in 12 (67%) patients. Nine patients (50%) had hypertension, 2 (11%) chronic obstructive pulmonary disease, 2 (11%) diabetes mellitus, and 1 (6%) ischemic cardiomyopathy. Seven patients (39%) were in antihypertensive treatment, 8 (44%) in anticoagulant/antiplatelet therapy for primary or secondary prevention, 2 (11%) in hypoglycemic therapy. Before the diagnosis of infection, 4 patients (22%) received systemic glucocorticoids and none of them was under oxygen therapy.Most patients presented with an Eastern Cooperative Oncological Group (ECOG) Performance Status (PS) of 2  and 1 .As shown in Ten patients (56%) had already received a clinical indication to home-based best supportive care before the infection; six patients (33%) were, on the contrary, on active anti-tumor treatment, a first line therapy in 4 (67%) cases. Two patients (11%), with a new cancer diagnosis were potentially candidates to medical treatment, but were still na\u00efve at the time of infection. The last anti-cancer therapy received by patients on treatment was chemotherapy, immunotherapy or tyrosine kinase inhibitors (TKIs) in 2 (33%), 3 (50%), and 1 (17%) patients, respectively. Two patients (33%) received anti-tumor therapy within 3 weeks before SARS-CoV-2 positivity and other two (33%) within 2 weeks. Two patients (33%) continued oncological treatment (TKIs and chemotherapy) after the infection diagnosis.The clinical, laboratory, and radiologic findings of the patients at SARS-CoV-2 infection diagnosis were summarized in There were two main clusters of patients: 7 (39%) patients who developed infection in their communities and 11 (61%) during the hospitalization  were symptomatic for COVID-19 infection at the time of nasopharyngeal swab. The mean duration of symptoms before the diagnosis was 2 \u00b1 2 days. The most common were shortness of breath and diarrhea both occurring in 2 patients (11%). Among the 11 asymptomatic patients, 8 (72%) became symptomatic during the hospitalization (mean time of symptoms onset: 4 days \u00b14). Documented fever was present in 5 patients (28%).2) overcame the 90% in 15 patients (83%) and was <85% in 3 patients (17%). P/F was <200 in 3 patients (17%), between 200 and 300 in 7 (39%) patients and higher than 300 in 3 (17%).Peripheral oxygen saturation (SpOC-reactive protein increase (\u22655 mg/dl) was detected in 14 (78%) patients. High lactate dehydrogenase levels (\u2265240 U/l) were present in 11 patients (61%), while lymphocytopenia and thrombocytopenia in 5 and 4 (28 and 22%), respectively. A procalcitonin increase (\u22650.5 ng/ml) was detected only in 1 patient (6%).A chest radiograph was obtained in 12 patients (67%). The radiographs showed bilateral infiltrates and parenchymal consolidation in 5 and 2 cases (42 and 17%), respectively. A thoracic ultrasound was executed in 5 patients: no anomalies in one case (20%), B-lines in 3 patients (60%), B-lines plus sub pleural consolidations plus irregular pleural line in another case (20%). In 5 patients (42%) no radiological anomalies were evident. A computed tomography (CT) scan of the chest was obtained in 3 patients (17%), with 2 scans showing newly- appeared bilateral ground glass opacities in one case and parenchymal consolidations in the other one.The trend of the P/F analyzed after 7 and 14 days (\u00b12) after the SARS-CoV-2 positivity is shown in Laboratory findings during the hospitalization are reported in A second chest X-ray was performed after 14 days from the diagnosis of infection in 7 patients (58%), showing a radiological improvement in 2 (17%), deterioration in 3 (25%), and stability in 2 (17%) patients. In one of the latter, affected by lung cancer and treated with a combination of TKI and COVID-19 directed therapy, a CT scan was also performed, showing both the persistence of inflammatory lung infiltrates and a tumor partial response.In absence of robust evidences therapeutic management was based on local guidelines and daily multidisciplinary evaluations involving oncologists together with pulmonologists, intensive care, and infectious disease specialists. Seven (39%) patients were prescribed hydroxychloroquine for up to 10 days and 4 (22%) antiviral therapy with lopinavir/ritonavir or darunavir/ritonavir for 7 consecutive days. Antibiotics and systemic glucocorticoids treatment were administered to 15 (83%) and 14 patients (78%), respectively, and just 4 of them were in on steroid treatment before the diagnosis of infection.The most common complication was the progression of oncological disease  followed by Acute Respiratory Distress Syndrome (ARDS)  and septic shock . Nasal and/or pharyngeal swabs tested for SARS-CoV-2 were collected after 14 days from the first positivity in 10 (56%) patients: 6 (33%) resulted negative (with a second confirmatory test performed at 24 h from the previous negative one) and 4 (22%) persistently positive.As of April 19th, 8 (44%) died with a mean of 12 days  from the diagnosis of COVID-19 infection to death. Five (28%) patients have been discharged from the Onco-Covid Unit but remained in the hospital, 4 (22%) have been transferred to another low intensive care COVID department and 1 (6%) to a mild intensive care unit. Five patients (28%) have been discharged from the hospital, 4 (22%) of them with the indication to best supportive care and 1 (6%) to active antitumor treatment. The mean length of hospitalization at data cut-off was 30 days \u00b114 (0\u201353), while it resulted 16 \u00b1 9 days (0\u201337) when calculated from COVID 19 positivity  affected by lung cancer, who developed laboratory-confirmed COVID-19 infection and have been hospitalized at the Onco-Covid Unit of San Luigi Gonzaga Hospital, one of the few oncological wards dedicated to cancer patients with SARS-Cov-2 infection, between March 27th and April 19th, 2020. In our series, 11 (61%) patients developed infection during their hospitalization at our oncology department. The internal transmission was probably due to a patient's contact with a caregiver subsequently known to have been ill, only few days after the identification of the first case in our Region. When the first evidence of infection occurred, we performed screening test even in asymptomatic hospitalized patients in order to provide a rapid isolation of any positive case. Out of 24 hospitalized patients, 10 resulted positive for SARS-CoV-2 infection. Thus, after the transfer of negative patients to other wards, we created the Onco-Covid Unit. From that moment we admitted only infected cancer patients coming from the Emergency Department, where nasopharyngeal swab was always performed before hospitalization. We also empowered the use of personal protective equipment (PPE) such as hand sanitizer, isolation gown, filtered masks, face shield or goggles, and gloves. In their analysis, Zhang et al. reported that 29% of patients had developed COVID-19 infection during hospitalization  were symptomatic, a lower percentage as compared to what has been previously reported , with a mean duration before the diagnosis of infection of 2 days 0\u20137 days). Only 5 patients (28%) had fever and 3 (17%) patients showed a <85% peripheral oxygen saturation at the time of infection diagnosis. Altogether, these data suggest that such symptoms and fever may not be the only useful parameters to suspect COVID-19 in cancer patients. Lung cancer, as in other analyses, was the most frequent type of cancer 56%) and most patients (78%) were diagnosed with stage IV disease .Regarding antiviral interventions, 39% received off-label hydroxychloroquine and 22% lopinavir/ritonavir (or darunavir/ritonavir) following local guidelines subsequently modified because of hydroxychloroquine suspension by regulatory agencies , 14. We Systemic glucocorticoids were administered to 14 patients (78%), mostly taking into account some promising results of glucocorticoids in improving clinical outcomes in patients with respiratory illness, even if data were still conflicting , 17. MorTo date, recent anticancer treatment appears to increase the risk of severe events in case of Sars-Cov-2 infection, except for the results of the UK Coronavirus Cancer Monitoring Project where recent chemotherapy use in cancer patients before infection was not significantly associated with increased mortality , 7, 19. The most common complications in the whole study population were tumor progression (50%), ARDS 17%) and septic shock 6%). The case fatality rate of 44% in this series (to date) is higher than already reported by other Authors , even if a direct comparison with the general population was not performed . ImportaOur study has many important limitations, especially its retrospective nature. For this reason, some cases had either missing laboratory data or radiological evaluations or both . Second, the sample size is small, limiting its generalizability. Third, as we focused on the entire population of cancer patients, sample is highly heterogeneous regarding tumor type, stage of disease, performance status, treatments. Finally, 5 patients (28%) remained in hospitals at the time of data censoring on April 19th, 2020; as a result, outcomes for those patients were not known.To our knowledge, this is the first report of a pure Onco-Covid reality. Although our study reinforces the fragility of oncological patients during this emergency, cancer is not a homogeneous disease and potential differences in therapeutic options and prognosis are substantial, even in advanced stage. For this reason, oncologists have to be involved in the management of all cancer patients affected by COVID-19 for a shared decision-making process aimed at tailoring decisions on every patient reducing any risks of under- or over-treatment. The Onco-Covid Unit has represented an example, although perfectible, of this tailored and holistic approach, even in a challenging situation like SARS-CoV-2 pandemic.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.This study was approved by the Ethics Committee of the AOU San Luigi Gonzaga, Orbassano (Turin). The requirement for informed patient consent was waived due to the emergency status.MR and PB: study concept and design. MR, VB, and PB: data analysis and interpratation. All authors: data acquisition, manuscript preparation, and review. MR and FP: manuscript editing.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The Editorial Office has been notified of the past co-authorships between the reviewers MS, DG, and VS and several of the authors UM, FT, and SN and ensure that the review process met the standards of a fair and objective review. This transparency statement is being included in acknowledgment of the crucial collaborations ensuring the swift dissemination of research in response to the COVID- 19 pandemic."}
+{"text": "Indications for CT included procedure/prophylaxis , management of immune-related adverse event , cancer-related symptoms  or comorbidities . Neither overall CT, bCT nor cCT predicted for worse OS, PFS nor ORR in univariable and multivariable analyses (p>0.05). CT for cancer-related indications predicted for shorter PFS (p<0.001) and was associated with refractoriness to ICI  compared with cancer-unrelated indications. This is the first study to demonstrate that neither bCT nor cCT influence response and OS following ICI in HCC. Worse outcomes in CT recipients for cancer-related indications appear driven by the poor prognosis associated with symptomatic HCC.The impact of corticosteroid therapy (CT) on efficacy of immune checkpoint inhibitors (ICI) is undefined in hepatocellular carcinoma (HCC). We evaluated whether CT administered at baseline (bCT) or concurrently with ICI (cCT) influences overall (OS), progression-free survival (PFS) and overall response rates (ORR) in 341 patients collected across 3 continents. Of 304 eligible patients, 78 (26%) received  Hepatocellular carcinoma (HCC) is at the focus of intense research efforts for the development of immune checkpoint inhibitors (ICI).5Evolving experience in the use of ICI suggests iatrogenic factors as important contributors in shaping clinical responses to immunotherapy.11Immunosuppressive CT may therefore adversely influence outcome in patients receiving ICIWe established a global dataset of 341 patients with HCC treated with ICI between 2016 and 2019 in nine tertiary referral centers in the USA (n=226), Europe (n=68) and Taiwan (n=47) . Patient10.1136/jitc-2020-000726.supp1Supplementary data>10 mg of prednisone  for >24 hours within 30 days prior to ICI. Concomitant corticosteroid therapy (cCT) was defined as stated previously from the day of commencement of ICI until permanent cessation of immunotherapy.Evaluation of corticosteroid exposure was defined based on timing of administration in line with published literature on the topic.Clinicopathologic variables including overall survival (OS) and progression-free survival (PFS) were derived from electronic medical records. OS was calculated from the date of ICI commencement until last follow-up or patients\u2019 death. Response to ICI was evaluated according to RECIST criteria (version 1.1) and best responses to ICI were recorded for each evaluable patient. Electronic medical records were reviewed to identify prescription of oral or intravenous corticosteroid therapy (CT).2 or Fisher\u2019s exact tests. We represented group-specific OS and PFS using the Kaplan-Meier curve method and formally evaluated the difference in median survival times between pre-specified groups using the log-rank test. We performed univariable and multivariable analyses of survival using Cox regression models to evaluate the impact of CT on patients\u2019 OS and PFS. To avoid collinearity bias, we evaluated features relating to corticosteroid therapy including overall CT exposure, timing and indication for CT therapy in separate multivariable models as outlined before.Patient characteristics are summarized as means or medians as appropriate. We conducted analysis of proportions across groups using Pearson \u03c7All statistical analyses were performed using SPSS V.25.0 and Stata V.16.1 , and GraphPad Prism  with all estimates being reported with corresponding 95% CIs and a two-tailed level of significance of p<0.05.Out of 304 eligible patients in the study, the majority were cirrhotic  due to hepatitis C infection . All patients had measurable disease based on RECIST 1.1 criteria at ICI commencement. Baseline tumor staging according to Barcelona Clinic Liver Cancer (BCLC) algorithm showed most patients to qualify criteria for stage C disease .In total, 273 patients (90%) had received prior therapy for HCC and 179 (59%) were sorafenib experienced. During the observation period, the vast majority of patients  received single-agent anti-PD(L)\u22121 ICI, whereas 25 received combined PD-1/CTLA-4 ICI (8%).Evaluation of radiologic response to treatment based on RECIST 1.1 criteria (investigator assessed) demonstrated an ORR of 20%, with 23 complete (7.5%) and 38 partial responses (12.5%). Ninety-nine patients (33%) achieved disease stabilization, whereas 127 (42%) were ICI refractory, defined as progressive disease at first imaging reassessment. After a median follow-up of 10.3 months (95% CI 10.6 to 13 months), 153 patients had died (51%) and all but 72 (24%) had discontinued ICI therapy, mostly due to disease progression . In total, 113 patients (37%) experienced at least one treatment-related adverse event (AE), 57 of which (18%) were of grade >2 according to Common Terminology Criteria for Adverse Events (version 5.0). Permanent discontinuations due to unacceptable toxicity occurred in 11 patients (4%). Median OS from ICI commencement was 12.3 months (95% CI 9.8 to 15.4 months), median ICI duration was 3.7 months (IQR 6) and median PFS was 6 months (95% CI 4.6 to 8.2 months).CT was prescribed to 78 patients (26%), defined as bCT in 14 (5%) and cCT in 64 (20%). Two patients (1%) received CT prior to and during ICI: one patient who received CT for palliation of cancer-related symptoms was ascribed to the bCT group. A second patient who received CT as a single course 7 days prior to ICI for intravenous iron infusion and three subsequent courses during ICI was ascribed to the cCT group. Timing of corticosteroid exposure was not associated with HCC stage, liver function and performance status . Neither>10 mg of prednisone at any point throughout the study was 12.8 months (95% CI 9 to NR) and not different from the 12.2 months  observed for patients who received 0 to <10 mg. Median PFS  and ORR  were also similar between groups. When compared with bCT-unexposed  or cCT-unexposed patients , neither bCT  nor cCT exposure  was indicative of worse OS  and median daily corticosteroid dose p=0.75, . In indeWe document for the first time that corticosteroid use alongside ICI is safe in patients with HCC, mirroring evidence in other indications.19While limited by small sample size and lack of correlative analyses on peripheral immune cell responses following steroid treatment, the multi-center design of our study ensures adequate representation of the various etiologies of HCC and attempts to control for the diversity in clinical practice including corticosteroid prescribing. Given this study enrolled patients treated with ICI as part of routine clinical practice, our sample included patients with Child-Pugh B cirrhosis, largely excluded from clinical trials of ICI in HCC. While impaired liver function is a key prognostic determinant in HCC,To conclude, there is no sufficient evidence to suggest that CT exposure either prior to or during ICI therapy is associated with OS and PFS in patients with HCC; CT exposure does not associate with key clinicopathologic traits of HCC including stage, liver function, alpha-fetoprotein levels and line of therapy. CT for palliative indications identified patients with poorer response and survival from ICI and traces an interesting parallelism with evolving experience in lung cancer where association with adverse features rather than causality has emerged as a likely explanation of the detrimental role of CT."}
+{"text": "A Cross-sectional study using a community-based sample of LBP positive population was conducted. The range of treatment options sought was also collected. Chi-square tests and independent t-test were used to analyze the data. Of 1531 recruited participants, 871(57%) were identified as LBP positive of whom 60% were females. Mean (SD) of age and pain intensity of LBP patients was 33 (11) years and numeric rating scale4.2 (2.6) respectively. Two-third reported minimal/moderate disability. Mean (SD) scores of depression 11.87 (4.05), anxiety (8.32), stress 13.7 (5.98), physical and mental summary scores of SF-12v2 were 47.9 (7.4) and 42.2 (10.4). A multitude of remedial options was sought for the ailment. LBP causes significant disability and psychological morbidity among affected population. This may adversely affect their HRQoL and subsequently productivity. Acupuncture was a preferred treatment sought by Indian LBP patients.Low back pain (LBP) is a major health concern and is closely associated with psychosocial morbidity and diminished Health-related quality of life (HRQoL). This is minimally investigated in community-based samples of developing nations like India. This study is aimed to specifically investigate the\u00a0exposure-outcome associations between LBP and burden of disability (Modified Oswestry questionnaire (MODQ)), psychological morbidities  Global Burden of Disease Study 2016 (GBD 2016) reported LBP as the leading cause for years lived with disability (YLDs) contributing 57.6 million YLDs2. Though, LBP affects all age groups, disability related to it is predominant in working population and most troublesome in low and middle-income countries where it has risen by more than 50% since 19904.The specific etiology remains uncertain, often labeling it to be non-specific. It is often associated with sedentary life style, obesity, smoking and physically demanding jobs such as heavy weight lifting, physical and mental comorbidities5. The adverse psychological and social impact on patient\u2019s health leads to clinically diagnosed or self-reported psychological morbidities7. This psychological disrupt is manifested as irritability, insomnia, depression, anxiety and somatic complaints9. This all impairs the societal participation, function and financial aspect of the affected individual leading to poor quality of life (QoL)11. Further, the cost of LBP is listed high as compared to other disorders, and the direct medical costs are even higher when associated with psychosocial impact, involving elaborate diagnostic procedures and treatment essentially employing the use of tertiary pain clinics and multi-professional teams13.LBP affects the physical, emotional and social functioning of the affected individual. The imposed biophysical limitations impair physical functioning and adversely affect the general health and reconditioning (weight gain and loss of muscle tone)3 with an aim to determine the burden of disability, psychological morbidities, and QoL in participants diagnosed with LBP as well as the range of treatment options sought for LBP. This study provides a better insight of the burden and presentation of psychological features and their treatment seeking behavior within LBP population recruited from community in the context of a developing nation like India.The present report is the second part of the large cohort study3. This project was registered in Clinical trial registry of India vide registration number CTRI/2014/11/005158 dated on 03/11/2014 .The original study is a large community based cross-sectional study using stratified multi-level systematic random sampling and a structured data collection form (DCF). The participant enrolment happened during January 2015-Dec 2016. It was conducted in Punjab, Haryana and Chandigarh area of northern India14. The study was approved by Institute Ethics Committee (IEC), PGIMER, Chandigarh vide approval number PGI/IEC/2014/2 dated March 11, 2014. The study was conducted in accordance with the guidelines and regulations proposed by the IEC, PGIMER Chandigarh.The present report is the second in line of the original large cohort study. The patients diagnosed with LBP in the initial survey were further interviewed for a detailed evaluation of functional disability, psychological morbidities and QoL using standardized questionnaires. Further, the range of treatment options sought for LBP. The Strengthening of Reporting of Observational Studies in Epidemiology (STROBE) criteria was followed while reporting this study3. The study followed the definition proposed by the International Association for the Study of Pain (IASP) to define LBP and face-to-face interview was used to determine study eligibility. Subjects not willing to participate were excluded from the study. The purpose and procedure of the study was thoroughly explained while obtaining written informed consent (IC) from all the prospective participants.Adult participants of either gender between 18 and 65\u00a0years of age diagnosed with LBP in initial interview, willing to participate in further detailed study were interviewedThe information compromising socio-demographic details and medical co-morbidities were obtained from the initial DCF. A trained investigator having good linguistic competence  comprehensive knowledge of disease and competent in conducting survey and was employed for data collection.15, psychological morbidity using Depression, Anxiety and Stress Scale (DASS-21)16, quality of life (QoL) using Short Form -12 version 2 (SF12V2)17, and the range of treatment options sought for LBP using DCF. MODQ is a validated tool in Indian settings and very specific to the LBP population for assessing functional disability. The research team is well versed in using MODQ in their previous studies too. DASS 21 contains all the aspects of psychological morbidity and is a reliable and valid measure of depression, anxiety, and stress in the clinical and non-clinical adult population and different cultural and ethnic groups in a composite manner. Since this was a community setting, we required a concise questionnaire incorporating all the psychosocial aspects. SF-12v2 is the shortened form of SF36v2, which is employed for the generic assessment of the health-related quality of life. The inclusion of SF12 was deemed to its validity and easy to administer and co-administration with other disease-specific instruments.The outcomes assessed were functional disability using Modified Oswestry Low Back Pain Disability Questionnaire (MODQ)15. The participants responded with the statement, which mostly resembled with their present situation. Each item scored from zero to five, and the higher values indicate a more significant disability. The scores obtained are transformed into percentages, zero indicating no impairment, and 100 is the maximum disability possible.The questionaire consists of ten items about the pain intensity, lifting, ability to walk, ability to care for himself, ability to sit, ability to stand, sexual function, social life, ability to travel, quality of sleep. For every question asked has six different options which describe the different potential plots in the subject\u2019s experience concerning the topic16.The Depression, Anxiety, and Stress Scale-21 Items (DASS-21) consist of three self-report scales intended to measure the emotional states of depression, anxiety, and stress. Each scale of DASS-21 contains seven items. The depression scale assesses hopelessness, dysphoria, self-deprecation, devaluation of life, lack of interest/involvement, anhedonia, and inertia. The anxiety scale assesses skeletal muscle effects, autonomic arousal, situational anxiety, and subjective experience of anxious affect. It assesses difficulty relaxing, nervous arousal, and being easily upset/agitated, irritable/over-reactive, and impatient. The stress scale is sensitive to levels of chronic nonspecific arousal. The Scores for each scale are calculated by summing the scores for the relevant items17. The SF-12v2 is a useful, valid and reliable measure of physical and mental health which covers 8 health domains viz Physical Functioning, General Health, Role Physical, Bodily Pain, Social Functioning, Vitality, Mental Health and Role Emotional and domains. The SF 12v2 scales are scored using Likert\u2019s method with raw scores being summated and linearly transformed into 0\u2013100 scale (100 indicate the best level and 0 the worst). Thus, higher scores represent better health status.The SF-12v2 instrument consisting of twelve questions to evaluate the functional health and well-being from the patient\u2019s perspective was employedRange of treatment options sought for LBP such as allopathy, Ayurveda, homeopathy, complementary and alternative medicine (CAM) were recorded.p value)\u2009<\u20090.05 was considered as statistically significant.Data were recorded in Microsoft Excel and transported to SPSS version 22 for analysis. The prevalence of functional disability and psychological morbidities; depression, anxiety, and stress was presented as a proportion of the sample with a 95% confidence interval (95% CI.). Chi-square and independent t-test were applied to examine categorical and quantitative variables, respectively. Throughout the analysis probability value  participants were identified positive for LBP. Of these potentially eligible 871 participants, 805 (92%) consented to participate for further detailed psychosocial evaluation . The mean (SD) body mass index (BMI) was 22.6 (4.5) which were comparable in LBP positive and negative participants. Nearly, 50% of the participants were eligible for medical reimbursement with significantly higher proportion 474 (54%) in LBP positive subjects (p\u2009<\u20090.05).The mean (SD) age of total cohort (n\u2009=\u20091531) was 32.0 (10) years, with significantly higher age 33 (11) years in LBP positive patients (2 with only one-fourth being over-weight and majority 532 (61%) amongst LBP positive patients having healthy BMI. Females had lower BMI 21.5 (4.2) kg/m2 as compared to males 23.9 (4.4) kg/m2, p\u2009<\u20090.05. The overall mean (SD) pain intensity was reported to be moderate; numeric rating scale 0-to-10 (NRS 0\u201310) score 4.2 (2.6) with females reporting significantly lower pain intensity [4.1 (2.6)] as compared to males 4.5 (2.5), p\u2009<\u20090.05. Majority had a history of the blue-collar job 719 (83%) and nearly half had regularly practiced load lifting activity (Table Among LBP positive participants n\u2009=\u2009871), majority 594 (68%) belongs to younger (18\u201335\u00a0year) age group. The mean (SD) BMI was 22.5 (4.4) kg/m, majoritp\u2009<\u20090.05. The overall mean (SD) MODQ score was 17.54 (7.3), with significantly higher scores in females 18.1 (7.3) as compared to males 16.8 (7.2) (p\u2009<\u20090.05) (Table 478/698 (68%) subjects had reported minimal/moderate functional disability and 220/698 (32%) suffer with severe, crippled or bed bound disability at one-year follow-up. Significantly higher proportion of females 139/395 (35%) had severe disability as compared to males 81/303 (27%), p\u2009<\u20090.05). 226/698 (32%) subjects suffered with moderate depression and 13/698 (2%) with severe depression. A significantly higher proportion of females suffer with mild depression 174/395 (44%) as compared to males 102/303 (34%) (p\u2009<\u20090.05) (Table Majority of the patients reported DASS-21 scores within mild range 276/698(40%), having mean (SD) DASS-21 scores for depression scale 11.87 (4.05) with significant difference among males and females ( 226/698 2% subjecp\u2009<\u20090.05) (Table The mean (SD) anxiety score on DASS-21 was reported to be 8.32 (4.48). 126/698 (18%) patients reported mild, 206/698 (30%) moderate, and 59/698 (9%) reported severe anxiety, respectively. A significantly higher proportion of females suffered with moderate anxiety 136/395 (34%) as compared to males 70/303 (23%) (p\u2009<\u20090.05).The mean (SD) stress score on DASS-21 scale was reported to be 13.7 (5.98). 172/698 (25%) patients reported mild, 131/698 (19%) reported moderate, and 17/698 (2%) reported severe stress (Table The mean (SD) of physical and mental summary scores of SF-12v2 were 47.9 (7.4) and 42.2 (10.4), respectively. Among various domains, the mean (SD) highest and lowest reported scores were in Vitality 52.7 (10.1) and Role emotional 38.8 (17.6) domains, respectively (Table p\u2009<\u20090.05 (Table Patients sought a range of treatment options. The most preferred treatments were acupressure 333 (39%), medical doctor/private hospital/public hospital 140 16%), Ayurveda 116 (14%), and physiotherapy 66 (8%), homeopathy 37 (4%), chiropractic 29 (2%), pharmacy 16 (2%). Significantly higher proportion of males preferred acupressure 150/339 (44%) relative to females 183 (36%) %, Ayurve3. These LBP positive subjects were further interviewed to assess the psychosocial morbidity, disability and quality of life using DASS-21, MODQ and SF-12V2 questionnaires, respectively. The range of treatment options sought for LBP was also documented.The present report describes psychosocial profile of patients suffering from LBP enrolled in a large community based study reporting a high prevalence of 57% in the initially enrolled subject cohort of 153118. As predicted earlier, GBD 2016 reported remarkable rise in the burden LBP especially in Low and Middle income countries with LBP contributing 57.6 million (40.8\u201375.9 million) YLDs, largely because of aging and rapidly expanding global population2. The affected subjects reported to have difficulties in performing their activities of daily living resulting in greater isolation, less motivation and finally leading to functional disability of various grades19.Two-third subjects reported to suffer from mild to moderate functional disability while one\u2013third suffered from severe to crippled disability. Severe disability was highest in working age groups (18\u201335\u00a0years). LBP is found to have a considerable impact on work productivity as affected participants reported on average six days of work absenteeism in previous month due to paint. This is especially concerning in a country like India where informal employment is usually the rule and possibilities for job switching are almost nadir. Further, it needs to be emphasized that occupational musculoskeletal health policies, such as regulatory framework for heavy physical work are often either non-existing or poorly monitored20.Though severe depression was reported in 2% participants, two-third subjects did report some grade of depressive symptoms in the present study. Affected subjects are unable to fulfill their traditional and expected social roles in a society21. The deliberation of psychological factors concerning LBP is highly relevant. The negative psychological attributes such as pain Catastrophizing and pain-related fear avoidance behavior, increased somatic awareness and depression are associated with higher perceptions of pain and disability22. Gatchel et al. proposed an apparent worsening of psychosocial sequelae in patients with chronic relative to acute pain23.The disabilities associated with LBP may be an interplay of psychological factors and altered bodily functions25. These observations ignite the requirement screening of anxiety and depression before treatment as independent symptoms in patients with LBP to design more tailored and effective multidisciplinary treatments. The imposed physical limitations result in psychological distress, anxiety and influence the coping strategies and course of pain. Chronic musculoskeletal pain symptoms have enormous economic and subsistence consequences as these usually lead to a loss of independence and social identity.More than half of the affected subjects reported anxiety in our study. This is supported by an earlier study from Tehran enrolling 112 patients with chronic LBP, 46.4% of patients reported symptoms of anxiety and 48.2% patients had depressive disorder (27). Further, another study from Portugal enrolling 284 subjects with chronic LBP reported 51.4% had both the symptoms of anxiety and depression, 21.5% had symptoms of anxiety alone and 6.7% had depressive symptoms while having their first consultation in multidisciplinary pain clinic. The study had used Hospital Anxiety and Depression Scale to measure the psychological morbidity26. Mindfulness-Based Stress Reduction is extensively adopted and listedto produce definite impacts on psychological well-being and symptoms of many disorders including LBP27.Half of the affected subjects reported some sort of stress in the study cohort. Tsuboi Y et al. reported higher perceived stress to be significantly linked with a higher incidence of memorable LBP in the prior month in 571 eldercare workers28. In a large cohort of 1502 patients endeavoring for multidisciplinary spine care, the individual and societal impact of LBP is very high. Specifically, QoL and workability are poor and health care costs are twice as high corresponded to patients seeking primary LBP care29. However, Pellis\u00e9 et al. reported that LBP possesses a little effect on HRQoL in adolescents30. Ludwig et al. reported that LBP-related activity limitations had little influence on both self-rated overall health31. Choi et al. reported the negative QoL in the Korean population32.Overall LBP had significant adverse impact on QoL of study participants. LBP affects all life realms from moderately basic self-care activities to advance social interactions, leisure activities, work, and ultimately have a profound impact on the QoL34.Management of LBP was dominated by acupressure (39%) followed by Medical doctor/ Private hospital/ Public hospital (16%), Ayurveda (14%), Physiotherapy (8%) and Homeopathy (4%) in present report. The preference for acupressure may be related to the belief and cultural practices in India. Acupressure is believed to be originated from India or China and is based on Indian ancient philosophy. In Indian culture it is usually believed to be non-invasive and without side effects. It is believed to be inexpensive and without side effects. Acupressure has been reported to provide better outcome compared to usual care35. Herbal drugs in Indian society are widely accepted to improve one\u2019s condition with fewer side effects, which may be the reason for increased use of the complementary and alternative medicine both in the developing and developed countries36. However, efforts are required to introduce and validate pharmacoepidemiological evidence concerning the safety and practice of Ayurveda medicines37. Various treatment options are available for CLBP management. However, there is insufficient or conflicting evidence about these modalities38.A large proportion of the participants preferred Ayurveda (14%) in the present study. Ayurveda remain the most ancient practice yet living tradition in India and rising interest of traditional medicine globally38. In LBP, limited evidence is available to guide health care professionals on advanced use of recommended evidence-based practice39. Probably alternative and complementary medicine is usually tried as initial treatment modalities because of perception of low/no side effect as reflected by our results.16% sought medical help by visiting medical practitioner public or private. Pharmacological methods seem inadequate as a sole treatment to CLBPThe strength of the study lies in the efficiency of the data acquisition with regards to exposure. To our best knowledge, our study is the first to determine the psychological morbidity, disability and quality of life in patients with LBP in Indian population. However, the limitations was the limited sample size and no follow up. Further, we understand the predictive limitations of cross-sectional studies, i.e. the evidence of a temporal relationship between LBP and psychosocial morbidity can\u2019t be ascertained in our data. Future efforts should assess psychosocial morbidity and functional disability in larger cohorts in a longitudinal manner to fully understand the relationships between psychosocial morbidity, functional disability, and HRQoL in LBP. The current findings may be generalized qualitative and quantitatively to other developing countries, though caution is recommended given the limited sample size or when generalizing the current findings to participants suffering comorbidity.To our best knowledge, this is the largest study of LBP evaluating psychological morbidity, disability, and Health-Related Quality of Life in an Indian population. LBP results in significant disability, which critically affects the quality of life of the patients. A quarter of patients reported depression. Extensive treatment coping strategies were adopted by the patients with more preference given to acupuncture."}
+{"text": "Compartmental surgery and primary reconstruction with microvascular free flaps represent the gold-standard in the treatment of oral tongue squamous cell carcinoma (OTSCC). However, there are still unclear clinical features that negatively affect the outcomes. This retrospective study included 80 consecutive patients with OTSCC who underwent compartmental surgery and primary reconstruction by free flap. The oncologic outcomes, the reliability of the 8th edition American Joint Committee on Cancer (AJCC) staging system and the prognostic factors were evaluated. Fifty-nine males and 21 females  were treated between November 2010 and March 2018 (one patient had two metachronous primaries). Seventy-one patients  had no clinical history of previous head and neck radiotherapy and were considered as naive. Histology showed radical surgery on 80/81 lesions (98.8%), with excision margins >0.5 cm, while in 1 case (1.2%), a close posterior margin was found. According to the 8th AJCC classification, 37 patients (45.7%) were upstaged shifting from the clinical to the pathological stage, and 39 (48.1%) showed an upstaging while shifting from the 7th to the 8th AJCC staging system (no tumors were downstaged). Nodal involvement was confirmed in 33 patients (40.7%). Perineural and lymphovascular invasion were present in 9 (11.1%) and 11 (13.6%) cases, respectively. Twenty-two patients (27.1%) underwent adjuvant therapy. The 5-years disease-specific, overall, overall relapse-free, locoregional relapse-free and distant metastasis-free survival rates were 73.2, 66.8, 62.6, 67.4, and 86%, respectively. Patients with a lymph node ratio >0.09 experienced significantly worse outcomes. Univariate analysis showed that patients with previous radiotherapy, stage IV disease, nodal involvement, and lymphovascular invasion had significantly worse outcomes. Multivariate analysis focused naive patients and showed that lymphovascular invasion, advanced stage of disease, and node involvement resulted reliable prognostic factors, and patients with the same tumor stage and histological risk factors who did not undergo adjuvant therapy experienced significantly worse outcomes. In our series, surgery played a major role in the treatment of local extension; adjuvant therapy resulted strictly indicated in patients with advanced-stage disease associated with risk factors. The incidence of oral tongue squamous cell carcinoma (OTSCC) is currently estimated at 5.21/100,000 population, and ~3.06/100,000 new cases per year are documented in Italy , environmental factors , diet, and occupation .The prognosis of OTSCC in patients with advanced disease is generally poor; in addition, patients with T1-T2N0 disease experience a greater than expected rate of regional and locoregional relapse if inadequately treated .In recent decades, oncologic outcomes of patients with OTSCC have improved due to the introduction of two main concepts: anatomy-based compartmental tongue surgery (CTS) and the systematic reconstruction of oral defects by microvascular free flaps. The principles of compartmental surgery advocate the removal of compartments  containing the primary tumor, with the excision of the lesion along with the potential muscular, vascular, nervous, and lymphatic pathways that may lead to spread and recurrence . The difHowever, despite the improvement in the understanding and management of OTSCC, there are still unclear clinical features that negatively impact the locoregional control and the incidence of distant metastasis that should be better understood.Therefore, the authors performed a retrospective/prospective study of 80 patients consecutively treated for OTSCC with the aim of evaluating the oncologic outcomes after CTS and contemporary reconstruction with microvascular free flap. A comparison of the prognostic reliability of the two TNM staging systems (AJCC 2010 vs. AJCC 2017) and an evaluation of clinical and histological features were performed. An additional objective was to evaluate the weight of adjuvant therapy based on particular histological and clinical findings.The present study was approved by the Ethics Committee \u201cCommissione del Comitato Etico Indipendente della Azienda Ospedaliero-Universitaria di Cagliari\u201d (NP/2018/895).All consecutive patients who underwent CTS and microvascular reconstructive surgery with curative intent between November 2010 and March 2018 for OTSCC at any stage of disease were included. Patients with previous chemotherapy (CHT) and/or radiotherapy (RT) were also included in the enrollment but the analysis focused patients without previous RT for head and neck malignancies who were considered \u201cnaive.\u201d Patients with a clinical history of previous transoral surgery alone performed elsewhere were considered as naive since, in such cases, the CTS allows a resection including the relapsed lesion and the surrounding scar tissue.Eligible for CTS were patients affected by OTSCC more than 2 cm in greatest dimension or with more than 5 mm of DOI at computer tomography (CT) and/or magnetic resonance imaging (MRI) and extended also to pelvis and mandible. CTS was also performed in cT1 tumors when the epicentrum of the lesion was localized in the posterior and lateral aspect of the tongue or in case of any proximity of the tumor to the paramedian and/or lateral septum. Patients with contraindications for microvascular procedures, such as advanced arteriosclerosis underwent pedicled flap reconstruction and were not included in the present study.Correlations of age and comorbidities were established according to the Age Adjusted Charlson Comorbidity Index (AACCI) \u201314.Preoperative head and neck CT and MRI , and subsequently with the IMAGE 1S , with 0 and 30\u00b0 rigid endoscope  .Preoperative histologic diagnosis was obtained for all patients.All patients were clinically and pathologically staged according to the 7th and subsequently to the 8th edition of the AJCC TNM staging system and classified with clinical (preoperative) TNM and pathological (post-operative) TNM , 16, 17.Authors performed a precise retrospective analysis from a histopathological perspective, nevertheless the CTS was applied to all patients with tongue cancer in a prospective way from 2010. The analysis on the basis of the 2017 AJCC classification was performed by a dedicate pathologist to all surgical specimens of all patients treated since 2010.All patients underwent compartmental radical excision of the primary tumor transorally, median mandibulotomy or with a pull-through approach, with ipsilateral or bilateral, selective or radical/modified radical neck dissection .Surgical procedures were classified according to Ansarin et al. : type I Surgical resections were performed following an anatomic-based strategy: unilateral resections were extended from the lingual septum  to the pelvis or mucosa of the mandible , the stylohyoid muscle (posterior margin), and the mylohyoid muscle, which was considered the floor of the compartment (type III glossectomy). Lesions involving both sides of the tongue were resected from pelvis to pelvis and inferiorly to the hyoid bone (type IV\u2013V glossectomy). Patients with mandibular involvement underwent a wider resection, including the corresponding mandibular bone .All surgical defects of the oral cavity were primarily reconstructed with microvascular free flaps. The radial forearm (RF) and anterolateral thigh (ALT) free flaps were the first choice for intraoral reconstruction. Partial glossectomy was reconstructed with RF or perforator ALT flaps, total glossectomy was reconstructed with an ALT free flap or vertical rectus abdominis myocutaneous (VRAM) free flap, and the composite bony iliac crest deep circumflex iliac artery (DCIA) free flap was the procedure of choice in cases in which glossectomy was associated with segmental mandibulectomy to reconstruct composite intra-oral defects since the cutaneous and muscular component of this flap  provides abundant tissue for the reconstruction.Anastomoses were performed using an operative microscope . Arterial anastomosis was performed with synthetic non-absorbable 8/0 or 9/0 nylon sutures. Venous anastomosis was performed with a coupler device . All patients received a single bolus of heparin sodium  at least 5 min before the transfer of the flap.Temporary tracheostomy was performed in all patients to avoid post-operative respiratory distress.Intraoperative and post-operative fluid balance was routinely evaluated with the goal of maintaining intravascular fluid volume for optimal tissue blood flow and oxygenation .All patients had nasogastric feeding tube inserted, which was kept in place until acceptable swallowing function was restored. After 30 post-operative days, percutaneous endoscopic gastrostomy (PEG) was indicated in cases with inadequate post-operative swallowing function.Post-operative treatment consisted of the antibiotic protocol for the head and neck (ceftriaxone 2 g/day iv and metronidazole 500 mg 3 times/day iv for 7\u201310 days), and low molecular weight heparin  associated with an antiembolism stocking for the prophylaxis of deep venous (DVT) and microvascular. An Ear Nose and Throat specialist-in-training monitored the free flap every hour during the first 48 h and every 4 h up to 5 post-operative days according to the internal protocol to detect early signs of vascular impairment that could require surgical exploration/revision of the anastomosis.Hospitalization time and complications were evaluated. According to the Clavien-Dindo System  and GendPerineural invasion (PNI), lymphovascular invasion (LVI), DOI and ENE were evaluated in all patients. The ratio between the positive and overall number of removed nodes was calculated as the lymph node ratio (LNR), which was considered a prognostic value when higher than 0.09 .Adjuvant RT was planned in cases with pT3\u2013pT4 lesions, close margins, multiple nodal involvement, and neural, lymphatic and/or vascular invasion .All patients were included in our post-operative follow-up, planned according to the American Head & Neck Society (AHNS) guidelines . Diseasep < 0.05.Recurrence time was assessed from the date of surgery to the date of the first recurrence. The 5-years DSS, overall survival (OS), overall relapse-free survival (ORFS), local relapse-free survival (LRFS), and distant metastasis-free survival (DMFS) were calculated using the Kaplan-Meier method. Statistical analysis was performed using GraphPad Prism software . Univariate analysis was performed to determine the statistical significance of the oncologic results observed according to different risk factors/clinical features  in all patients and in naive patients ; multivariate analysis focused only naive patients to remove the possible bias due to the changes in lymphatic and vascular network induced by RT that could make outcomes unpredictable; statistical significance was defined as According to Cramer et al.  we evaluFifty-nine males and 21 females  were definitively enrolled in the present study. Seventy-one patients  had no clinical history of previous hand and neck radiotherapy (naive patients), and, among them, one patient (1.25%) underwent CTS with primary free flap reconstruction for two metachronous primaries, and 2 patients were treated for recurrent OTSCC treated elsewhere with conventional transoral surgery alone. Three patients (3.7%) were treated after failure of CHT-RT, and six procedures (7.4%) were performed in patients with recurrent disease who were previously treated elsewhere with surgery and adjuvant RT.According to the 8th AJCC staging system, 19 patients (23.5%) were staged as cT1, 48 patients (59.3%) as cT2, 1 patient (1.2%) as cT3, and 13 patients (16%) as cT4a. Fifty-two patients (64.2%) were staged as cN0, 11 patients (13.6%) as cN1 and 18 patients (22.2%) as cN2. Eighteen patients (22.2%) had malignancies classified as stage I, 28 patients (34.6%) as stage II, 9 patients (11.1%) as stage III, 25 patients (30.9%) as stage IVA, and 1 patient (1.2%) as stage IVC.Patients underwent 81 surgical procedures: 65 type IIIb glossectomy (80.3%), 7 type IVa glossectomy (8.6%), 5 type IVb glossectomy (6.2%), and 4 type V glossectomy (4.9%). Resection of the mandible was necessary in 7 patients (8.6%): marginal mandibulotomy in 4 cases (4.9%) and segmental mandibulectomy in 3 cases (3.7%). A total of 19 patients (23.5%) underwent CTS through a transmandibular approach with a lower lip splitting incision, and 55 patients (67.9%) were treated by a combined transoral and transcervical approach without mandibular splitting.A total of 57 patients (70.4%) underwent unilateral neck dissection, and 22 (27.1%) underwent bilateral neck dissection. Fifty-seven patients (56.4%) underwent selective neck dissections (SNDs), of which the removal of I-III levels was performed in 19 patients (18.8%), the removal of I-IV levels was performed in 35 patients (34.6%), and the removal of II\u2013V levels was performed in 3 patients (3%). A total of 41 patients (40.6%) underwent type III modified radical neck dissections (MRNDs), 2 patients (2%) underwent type I MRND, and 1 patient (1%) underwent type II MRND. Two patients (2.5%) with a clinical history of previous neck dissection underwent CTS solely followed by microvascular reconstruction with neck dissection limited to the area of the vascular pedicle. The age distribution, procedures, reconstruction and histology are detailed in All patients underwent immediate microsurgical reconstruction. RF free flap was performed in 64 cases (79%), ALT free flap in 9 cases (11.1%), VRAM free flap in 5 cases (6.2%), and DCIA free flap in 3 cases (3.7%). All free flap procedures are reported in n = 7), one of the branches of the thyro-lingual-facial trunk was used in all cases, and it was coupled with the internal jugular vein in 3 cases (3.7%), with the middle thyroid vein in 3 cases (3.7%), and with the external jugular vein in 1 case (1.2%).The recipient artery for the microvascular anastomosis was the facial artery in 55 cases (67.9%), the superior thyroid artery in 24 cases (29.6%) and the lingual artery in 2 cases (2.5%). The recipient vein for the microanastomosis was one of the branches of the thyro-lingual-facial trunk in 77 cases (95.1%), followed by termino-lateral anastomosis to the internal jugular vein in 4 cases (4.9%). Venous drainage was obtained with a single anastomosis in the majority of cases (91.4%), and in all cases, it was performed with the coupler device. When a double anastomosis was performed (In 5 cases (6.2%), admission to the Intensive Care Unit (ICU) with hemodynamic and airway monitoring was considered necessary due to the chronic impairment of one or more organ systems .Twenty-one patients (25.9%) experienced post-operative complications that required surgical revision in 17 cases (21%). The most experienced complication was bleeding , followed by free flap sufferance due to venous congestion, which was managed with the revision of the anastomosis , wound dehiscence  and fistula . No total flap failure was observed in the present series .The mean time to the removal of the temporary tracheostomy was 8 days . The mean duration of nasogastric feeding tube use was 18.1 days , and 2 patients underwent PEG for supplemental nutrition. The mean hospitalization time was 19.3 days .Definitive histology showed that 80 lesions (98.8%) were completely removed with free margin, while a close posterior margin was found in 1 patient (1.2%) treated after the failure of CHT-RT for an advanced OTSCC extending to the base of tongue; the patient underwent close follow-up but experienced recurrent disease after 6 months; then, the patient underwent palliative CT and died of the disease 12 months after surgery.Neck dissection yielded a mean number of lymph nodes of 53.1 (range of 0\u2013139); in 77 cases (95.1%), the neck dissection yielded 18 or more lymph nodes, and in 4 cases (4.9%), <18 lymph nodes (3 of these patients were previously treated with neck dissection and underwent revision surgery for recurrent OTSCC).Thirty-seven patients (45.7%) showed an upstage while shifting from a clinical to a pathological stage; according to the 8th AJCC staging system, 19 patients initially staged as cT1 resulted in 6 pT1 (31.6%), 8 pT2 (42.1%), and 5 pT3 (26.3%); 48 patients initially staged as cT2 resulted in 24 pT2 (50%), 22 pT3 (45.8%) and 2 pT4a (4.2%); 1 patient initially staged as cT3 and 13 patients initially staged as cT4a resulted in 1 pT3 (100%) and 13 pT4a (100%); 52 patients initially staged as cN0 resulted in 48 pN0 (92.3%) and 4 pN1 (7.7%); 11 patients initially staged as cN1 resulted in 9 pN1 (81.8%) and 2 pN2 (18.2%); and 18 patients initially staged as cN2 resulted in 16 pN2 (88.9%) and 2 pN3 (11.1%).Thirty-nine patients (48.1%) showed upstaging while shifting from the 7th to the 8th AJCC staging system, and none of the patients were downstaged see . A totalDefinitive nodal involvement was confirmed in 33 patients (40.7%); in 27 patients (33.3%), it was ipsilateral, while in 6 patients (7.4%), it was bilateral or contralateral. In the majority of cases, lymph node involvement was localized: at the IIa cervical level in 23 patients (28.4%), the III level in 14 cases (17.3%), the Ib level in 11 cases (13.6%), the IV level in 8 cases (9.9%), the Ia level in 3 cases (3.7%), the llb level in 2 cases (2.5%), and the V level in 2 cases (2.5%), as shown in PNI was present in 9 cases (11.1%), LVI was present in 11 cases (13.6%), and concomitant PNI and LVI were present in 15 cases (18.5%). The absence of PNI or LVI was reported in 46 cases (56.8%). Only two lesions showed positive p16.Twenty-two patients (27.1%) underwent adjuvant therapy . Eleven Mean time of follow-up was 3.3 years, median time was 1.8 years with a range of 6 months\u22127 years.During the follow-up, 18 patients (22.3%) experienced recurrence of the disease (mean time of recurrence of 10.1 months): 3 patients (3.7%) showed local recurrence (mean time of recurrence of 12 months), 5 patients (6.2%) showed lymph node recurrence (mean time of recurrence of 12.4 months), 1 patient local and node recurrence (1.2%) after 8 months, 5 patients (6.2%) showed locoregional recurrence associated with distant metastases (mean time of recurrence of 7.8 months), and 4 patients (5%) experienced distant metastases alone (mean time of recurrence of 9.8 months) . Of the The 5-years DSS, OS, ORFS, LRFS and DMFS were 73.2, 66.8, 62.6, 67.4, and 86%, respectively . The surPatients with a LNR > 0.09 experienced significantly worse outcomes than patients with a LNR lower than 0.09 .Univariate analysis showed that patients with previous RT, stage IV disease, nodal involvement, and LVI had significantly worse survival rates .n = 71) showed that LVI, LVI-PNI  experienced relapse of the disease, while of the 9 patients with previous RT for head and neck malignancies, 5 (55.6%) relapsed, p = 0.007 and p = 0.017, respectively). Tirelli et al. (p = 0.01) using the 8th edition of the TNM staging system, concluding that DOI > 10 mm is an independent prognostic factor that significantly impacts DSS (p = 0.001). In our series, 39 lesions (48.1%) were upstaged after restaging with the 8th edition of the TNM staging system, and in accordance to the recent literature, DSS decreases progressively according to the increasing pT category. The DSS rates based on the 7th and 8th editions were as follows: pT1 100 vs. 100%, pT2 78.4 vs. 88.7%, pT3 33.3 vs. 71%, and pT4 33.9 vs. 31.2%  showed an upstage while shifting from a clinical T1-T2 to a T3-T4 pathological stage according to the 8th AJCC staging system and, among them, 5 were initially staged as cT1 and 24 were cT2; in these patients, a different surgical approach could have been associated with incomplete resections that were never observed in the present series. Furthermore, before 2017, the choice of the CTS approach resulted in the removal of the T-N tract potentially affected by satellite lesions or micrometastases in 27 patients (33.3%) who showed upstaging from pT1-pT2 to pT3-pT4 while shifting from the 7th to the 8th AJCC staging system; if we had performed a transoral resection in this class of tumors, we would probably have obtained worse prognoses.Tagliabue et al. showed that on 95 patients classified as pT1-3 only 6 patients had the T-N tract involved while in 138 classified as pT4, 31 patients had a positive T-N tract ; these fIn the study by Tirelli et al.  and in oIn our series, the recent revision of the TNM staging system led to an upstaging of the pN in three patients (3.7% of the whole series). The main changes were due to the status of the pathological ENE, defined as the extension of metastatic carcinoma from the lymph node outside the nodal capsule . The prePNI, LVI and LNR are clear signs of an increased \u201cimbalance\u201d between oncogenes and tumor suppressor genes that promotes the neoplastic spread showing aggressiveness of the tumor also if they are not at the margin of the resection. It is hypothesized a morph-functional sequence when defining the steps of the metastatic cascade that includes the promotion of tumor neo-angiogenesis, synthesis of proteinases that helps cell intra and extravasation, synergism between altered adhesion molecules and proteinases, and loss of local immune-surveillance .p = 0.022). In our series, PNI did not significantly impact locoregional control or survival rates , LVI (p = 0.006), PNI (0.003) and nodal metastases (p = 0.02) had a significant negative impact on OS, and after the multivariate analysis, only LVI was associated with significantly worse OS (p = 0.009). In a cohort of 289 patients with OSCC, Quinlan-Davidson et al. (p = 0.01) and DOI > 1.5 cm (p = 0.003) and suggested that it could be considered an independent negative prognostic factor (p = 0.006). Cassidy et al. (p < 0.01), worse locoregional control (p < 0.01) and a lower OS (p = 0.01); consequently, it should be considered an indication for adjuvant therapy. In our series, univariate analysis showed that LVI is a prognostic factor associated with a significantly worse ORFS (p = 0.0025) and DMFS (p = 0.0006). Compared with the findings of Chen et al. , especially when associated with PNI . Complete removal of the extrinsic muscles from their bony insertions does not increase the functional defect any more than partial removal of the muscle involved . In our In conclusion, our study pointed out that CTS was associated with a high rate of tumor-free margins in all stages of OTSCC. Oncologic results obtained with CTS were better than those obtained with traditional transoral or multiblock resections. Immediate free flap reconstruction was not burdened by major complications. Adequate or normal function was regained in all but two patients. Adjuvant therapy was indicated in patients with advanced disease and negative prognostic factors according to AJCC 2017 and was not burdened by complications probably due to the presence of a well-vascularized transplanted tissue.All datasets generated for this study are included in the article/The studies involving human participants were reviewed and approved by Comitato Etico dell'Azienda Ospedaliero-Universitaria di Cagliari. The patients/participants provided their written informed consent to participate in this study.FC, DQ, and RP designed the study, analyzed the data, and wrote the manuscript. EG, CM, VM, and MT collected and analyzed the data. CG and JZ performed the experiments. NC and AF edited the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The Advisory Committee on Immunization Practices (ACIP) recommends that all women who are or might be pregnant during the influenza season receive influenza vaccine, which can be administered at any time during pregnancy   Figure)Figure). Increases in influenza vaccination coverage were observed during 2019\u201320 for Black women , Hispanic women , and women of other races . Correspondingly, the difference in influenza vaccination coverage between White and Black women decreased from 19 to 8 percentage points from 2018\u201319 to 2019\u201320 . A decreThe proportion of women who reported receipt of a provider offer or referral for influenza vaccination was higher among Hispanic women (76.9%) than among White (69.5%) and Black (69.1%) women but was similar to that among women of other races (73.7%). Among women with an offer or referral, influenza vaccination coverage was lower among Black (66.7%) than among White (75.6%) and Hispanic (79.0%) women and women of other races (80.7%) . Among wReceipt of a provider offer or referral for Tdap was lower among Black (55.7%) than among Hispanic women (66.6%), women of other races (71.3%), and White women (81.0%). Among those with a provider offer or referral for Tdap vaccination, Tdap coverage was lowest for Hispanic women (52.5%), followed by Black women (64.7%), women of other races (73.1%), and White women (77.5%).Findings from this survey indicate that approximately 40% of pregnant women do not receive influenza and Tdap vaccines, leaving themselves and their infants more vulnerable to influenza and pertussis infection, with potential serious complications including hospitalization and death  vaccines can decrease the risk for severe influenza and pertussis among pregnant women and their infants; racial/ethnic coverage disparities exist.During 2019\u201320, 61.2% of pregnant women received influenza vaccination, 56.6% received Tdap during pregnancy, and 40.3% received both vaccines. Influenza vaccination coverage among Black and Hispanic women increased, yet disparities persisted; Tdap vaccination increased among Black women but decreased in Hispanic women compared with 2018\u201319.Additional interventions to encourage consistent provider offers or referrals for influenza and Tdap vaccination and culturally competent conversations with patients are needed to address racial disparities in maternal vaccination."}
+{"text": "The treatment of venous thromboembolic disease the treatment of choice is systemic anticoagulation. However, the interruption of the inferior vena cava with filters has been recommended when anticoagulation fails or there is a contraindication. Due to the rising inferior vena cava filter (IVCF) complications, physicians are encouraged to retrieve them when there is no longer recommended. In daily practice, it may be a difficult close follow-up of these patients. In this study, the primary objective was to evaluate the IVCF retrieval rate of all implanted filters in a Spanish registry. Secondary objectives were to analyze the causes of failed retrieval, procedure-related complications, and outcomes at a 12-month follow-up.Three hundred fifty-six vena cava filters were implanted in 355 patients. The types of filter were: Gunther Tulip  160 (44.9%), Optease (Cordis) 77 (21.6%), Celect  49 , Aegisy (Lifetech Scientific) 33 (9.2%), Option ELITE  16 (4.4%), Denali filter (BD Bard) 11 (3.08%), ALN filter (ALN) 10 (2.8%).Removal was achieved in 274/356 . eighty-two  IVCF were not retrieved due to the following: 41  patients required ongoing filtration, 24 IVCF  patients died before retrieval, and 17  impossibility of retrieval because of a tilted and embedded filter apex. There were no major complications observed.The global retrieval rate of IVCF was achieved in 76.9%, and the adjusted retrieval rate was of 94.15% with no major complications. IVCF tilting was associated with failure of filter removal in less than 5% of cases. This study demonstrates that the retrieval procedure of IVCF is controlled by the clinician and not by the interventional radiologist. Venous thromboembolic disease (VTD) is a serious disease that affects 1\u20132 per 1000 of European citizens  retrieval rate of implanted IVC filters. Secondary objectives were to analyze the causes of failed retrieval, procedure-related complications, and outcomes at a 12-month follow-up.The SERVEI-REFiVeC (Registro Espa\u00f1ol de Filtros en Vena Cava Inferior) Registry is a prospective multicenter study endorsed by the Spanish Society of Vascular and Interventional Radiology (SERVEI) and by the Zaragoza University. This Registry received institutional review board approval in May 2016 (CP-CI number PI16 / 0142), and the study was registered in Clinical Trial Gov (NCT02757001). The registry was open from 01 to 04-16 until 01\u201304-18. The form was designed by the research group (GITMI) of the University of Zaragoza.An electronic patient report form was specifically designed for this registry and hosted on the Spanish Society of Vascular and Interventional Radiology (SERVEI), webpage (Sociedad Espa\u00f1ola Radiolog\u00eda Intervencionista (SERVEI), estudios y registros This was open to all members of SERVEI society, after identification and acceptance by the study principal investigator (PI), and all of the interventional radiologists (IRs) had at least 5\u2009years in experience for the placement and retrieval of IVCF. Over 2\u2009years, all patients with an IVCF implantation were consecutively enrolled by an electronic registry. The following data were gathered: demographics, VTE risk factors, filter placement indications, IVCF type, filter dwell time, number of retrieval attempts and retrieval outcome Table\u00a0. The folWe used chi-square or Fisher\u2019s exact tests to compare categorical data between groups. We used the Shapiro-Wilk test to assess continuous data for a normal distribution.We used two-tailed unpaired t-tests to compare parametric continuous data between two unpaired groups, and we used the Mann-Whitney U test for non-parametric data comparisons. We conducted statistical analyses using STATA version 13.1 . All hypothesis tests were two-sided, with a significance level of 0.05.The registry was designed to enroll at least 200 patients with IVCF and recorded clinical follow-up at least one year after recovery, evaluating possible episodes of recurrent PE, DVT or possible death of the patient.From April 2016, until April 2018, three hundred fifty-six vena cava filters were implanted in 355 patients (1 patient received two filters for having double vena cava). The mean age was 59.7\u2009\u00b1\u200913.7\u2009years (range 89\u201319\u2009years. One hundred and eighty-two (51.1%) patients were men and 174 (48.8%) women, 15 Spanish tertiary hospitals participated in the REFiVeC registry. The average IVCF implantation in each center was 23.6\u2009\u00b1\u200925.9 (range 101\u20131 IVCF). The types of filter used in the registry were: Gunther Tulip  160 (44.9%), Optease (Cordis) 77 (21.6%), Celect  49 , Aegisy (Lifetech Scientific) 33 (9.2%), Option ELITE  16 (4.4%), Denali (BD Bard) 11 (3.08%), ALN filter (ALN) 10 (2.8%).VTD risk factors included immobilization in 197 (55.4%), neoplasm in 55 (15.4%), recent surgery in 46 12.9%), history of VTE in 35 (9.8%) and contraceptive use in 24 (6.7%). Of the patients who required a vena cava filter, 309 had one risk factor for VTD, 43 had two risk factors, and 4 had more than two risk factors. The main indications for IVCF were: presence of VTE with contraindication to anticoagulation in 188 (52.8%), Prevention in high-risk patients with DVT in 120 (33.7%), , and recurrent PE despite anticoagulation in 48 (13.4%) , the right femoral vein in 148 (41.5%), the left femoral vein in 25 (7.02%) and the left internal jugular vein in 2 (0.5%) cases. Cavography was performed in all patients during filter removal, 260 (73.03%) patients underwent abdominal computed tomography before IVCF retrieval. The indication of abdominal CT was to facilitate withdrawal  and was performed on the same day before the IVCF retrieval. The abdominal CT, 185 (71.1%) patients had normal findings regarding the position and tilt of the filter; in 41 (15.7%) patients tilting of the IVCF was appreciated <\u200915\u00b0 with the IVC, in 12 (4.6%) patients IVCF tilt was found >\u200915\u00b0. Penetration of the legs in the IVC\u2009>\u20093\u2009mm was appreciated in 2 (0.76%) patients, inclusion of the superior hook in the wall of the IVC or some other element of the filter was observed in 16 (56.1%) patients, and in 4  patients had evidence of thrombosis of the IVCF. Three hundred and one (84.5%) patients were receiving anticoagulation therapy at the time of filter removal, and 55 (154%) patients were not anticoagulated.A total of 274/356 (76.9%) filters were successfully removed. Figure\u00a0Removal difficulties occur in 26 patients (7.3%) . IVCF thrombosis was observed in four patients (1.2%). After fibrinolysis in two patients and thromboaspiration in 2, the filter could be removed without any complications. Complications were found in 12 patients (3.3%): 6 neck hematomas and 5 groin hematoma, (type I complication)  and repeated attempts at recovery in 9/26 patients, IVCF was recovered with an average of 2.1 attempts (range 1\u20133). Despite several attempts (average 2.5 and 1\u20133 range) in 17/26 patients, IVCF could not be recovered and was left as permanent filters  patients, follow-up time was 11.3\u2009\u00b1\u20093.2\u2009months after IVCF recovery. All patients were treated with oral anticoagulation or low molecular weight between 6 and 8\u2009months. There were 2 cases of recurrence of PE after IVCF retrieval. Both were documented with pulmonary CT angiography, echocardiography, and biological markers. One of them, occurred when the patient was not anticoagulated, and was classified as a low-intermediate risk for PE and was treated with new oral anticoagulant treatment. The other, a young patient, diagnosed with hematologic disease and hereditary thrombophilia (homologous Leiden Factor V) was decided on the new placement of definitive filter and anticoagulation treatment for life.The SERVEI-REFiVeC registry is a study of 356 retrievable ICVFs in 355 patients, which gathers the activity of fifteen major Spanish hospitals. This study has limitations since in Spain, there is no consensus, protocol or guidelines accepted by the different societies regarding VTD regarding placement and retrieval of IVCF. Interventional Radiologists are aware of the recommendations of the FDA and other administration to remove all filters as soon as possible, once they are no longer needed. The total recovery rate of FVCI in this study was 76.9%, it might seem low if we compare it with the data from the CIRSE Registry , and 41 (11.5%) patients with the initial intention to retrieve the filter, but finally for different reasons or because there is no clear protocol in their hospital, the petitionary clinician decided not to remove the filter. The adjusted retrieval rate of Vena Cava Filters in SERVEI-REFiVeC reaches 94.15% (291/356). Only in 17 patients (4.7%) was attempted for retrieval but was not possible for different reasons.Several studies have shown that the retrievability of different types and models of filters is similar and there are no significant differences  (Stein et al. Retrievable IVCF has demonstrated efficacy in patients with unstable PE (Dalen and Stein There are important limitations of this study, even though the study was supported by SERVEI, only 15 hospitals participated, and Spain has a total of 118 hospitals with IR (De Gregorio and Urbano In conclusion, IVCF retrieval was achieved >\u200975% in a cohort with no major procedural complications. IVCF tilting and embedded apex was associated with failure of filter removal in less than 5% of cases. This paper does not demonstrate a good correlation between the difficulty of the IVCF recovery and the dwell time. The global retrieval rate was of 76.9%, however the adjusted retrieval rate was of 94.15% comparable with recent studies. This study demonstrates that the retrieval procedure of IVCF is controlled by the clinician and not by the interventional radiologist."}
+{"text": "Salmonella is a significant ongoing concern over the world. Several reports have investigated the prevalence of Salmonella infections in the farm animals in China; however, there is only limited knowledge about the Salmonella cross-contamination in the slaughterhouses. Moreover, the application of genomic approaches for understanding the cross-contamination in the food-animal slaughterhouses is still in its infancy in China. In the present study, we have isolated 105 Salmonella strains from pig carcasses and environment samples collected from four independent slaughterhouses in Jiangsu, China. All the Salmonella isolates were subjected to whole genome sequencing, bioinformatics analysis for serovar predictions, multi-locus sequence types, antimicrobial resistance genes, and plasmid types by using the in-house Galaxy platform. The antimicrobial resistance of Salmonella isolates was determined using a minimal inhibitory concentration assay with 14 antimicrobials. We found that the predominant serovar and serogroup was S. Derby and O:4(B), with a prevalence of 41.9 and 55%, respectively. All the isolates were multidrug-resistant and the highest resistance was observed against antimicrobials tetracycline (95.4%) and trimethoprim and sulfamethoxazole (90.9%). Additionally, the colistin-resistant determinant mcr-1 gene was detected in five (4.8%) strains. Our study demonstrated the prevalence of antimicrobial resistance in Salmonella strains isolated from pig slaughterhouses in China and suggested that the genomic platform can serve as routine surveillance along with the food-chain investigation.The prevalence of antimicrobial resistance in zoonotic  Salmonella infection has increased rapidly in humans and animals, and it is one of the leading cause of foodborne illness-related hospitalization in both developed and developing countries  of 5,467 pig samples  assay using the broth microdilution method, which was described previously  and plasmid types were detected using assemblies of the samples on the in-house Galaxy platform (https://githubcom/tseemann/mlst2016) and abricate v0.8 , London (18%), Livingstone (10.4%), Typhimurium (9.5%), Rissen (6.6%), I 4, [5]12:i:- (3.8%), Anatum (3.8%), Infantis (2.8%), Goldcoast (2.8%), and Uganda (0.9%). The dominant serovars were Derby, London and Livingstone.In this study, 105 non-duplicated isolates were obtained from pig slaughterhouses located in four cities in Jiangsu, China, between March to July in 2017. Among these 105 strains, 52 isolates were recovered from pig carcasses, and 53 isolates were recovered from the environment. As shown in Salmonella isolates. The result of the MIC assay was shown in The broth microdilution minimum inhibitory concentration (MIC) assay was performed to evaluate the drug resistance of Salmonella. While the resistance against IMP and AZI was low in most of the serovars , ST new 10 (one strain), ST new 11 (one strain) and ST new 13 (one strain). Besides, ST155 and ST543 were the predominated STs in S. London and S. Livingstone, respectively. The serovar London had two new serovars which were named ST new 7 and ST new 8. All S. Rissen strains were belonged to ST469. ST19 was considered to be the dominated genotype in S. Typhimurium and S. I 4, [5]12:i:-. Similarly, the serovar Typhimurium had two new sequence types which were named ST new 5 and ST new 6. The newly found sequence type, in serovars Infantis, Livingstone, Mbandaka and Uganda were named ST new 3, ST new 2, ST new 12 and ST new 4, respectively.With further genomic analysis, we found that all these strains belonged to eleven sequence types. Half (49.5%) of the strains were found to be belonged to ST40 (35%) and ST155 (14%) . Our resSalmonella isolates were analyzed using plasmid finder. As shown in S. Derby and S. London had a large number of different types of plasmids; however, the numbers of plasmids in S. Mbandaka and S. Uganda was low. The IncFIB(K)-1-Kpn3 plasmid accounted for the highest proportion in S. Derby (68%) and S. London (94%). Also, the IncR (36%) and IncX1 (25%) plasmids were common in S. Derby. Moreover, we analyzed the plasmids distribution in strains obtained from different sources. As shown in S. Derby had the highest number of different types of plasmids, irrespective of the source (pig carcass or the environment). The IncFIB(K)-1-Kpn3 plasmid was predominant in 76 and 62% of S. Derby isolated from pig carcass and environment, respectively. The S. Goldcoast strains isolated from pig carcass had no plasmids, whereas plasmid existed in strains isolated from the environment. The S. Uganda and S. Mbandaka strains isolated from the environment had no plasmids.The plasmids replicons harbored in tet(A) gene which confers resistant to tetracyclines was the highest prevalent gene with prevalence reach to (95%). Twenty-six resistant genes of beta-lactam class, in addition to eleven plasmid-mediated quinolones-resistant genes have been detected amongst the isolated strains. The widely spreading of these critical resistant genes in the strains pose a great public health concern. Our results also showed that S. Derby strains and O:4(B) serogroup had the highest prevalence of the antimicrobial resistant genes among the other groups and serovars with prevalence % as follows: fosA7 (97%), tet(A) (95%), oqxA (90%), oqxB (84%), qnrS1 (70%), sul2 (50%), and dfraA12 (50%). With further analysis colistin resistant (mcr-1) gene was identified also in five strains, including two strains of S. Derby, two strains of I 4, [5],12:i:- and one S. Typhimurium strain. Of the antimicrobial resistant genes in strains isolated from different source, we found that the dominant antimicrobial resistance genes in S. Derby isolated from the pig carcasses were as follows: blaSHV-187 (41%), sul2(64%), tet(A) (100%), dfraA12 (52%), oqxA (94%), oqxB (82%), qnrS1 (88%), and fosA7 (100%). The dominant antimicrobial resistance genes in O:4(B) serogroup isolated from the pig carcasses were as follows: blaSHV-187 (43%), sul2 (73%), tet(A) (100%), dfraA12 (65%), oqxA (86%), oqxB (73%), qnrS1 (91%), and fosA7 (78%). Besides, the dominant antimicrobial resistance genes in S. Derby isolated from the environment were as follows: blaSHV-187 (40%), sul2 (40%), tet(A) (92%), dfraA12 (48%), oqxA (88%), and oqxB (85%). The dominant antimicrobial resistance genes in O:4(B) serogroup isolated from the environment were as follows: blaSHV-187 (40%), sul2 (48%), tet(A) (91%), dfraA12 (54%), oqxA (77%), oqxB (74%), qnrS1 (68%), and fosA7 (80%) (Data not shown).The antimicrobial resistant genes of the strains were analyzed to explore the underlying mechanism responsible for the bacterial antimicrobial resistance. As shown in China produces and consumes about 500 million heads per annum of the global pork demand . JiangsuS. Derby was the dominant serovar among the 105 isolates, and most of the S. Derby strains were isolated from the environment. (2) All the isolated strains were multidrug resistance, regardless of the source and serovars. The isolates showed a higher percentage of resistance toward antimicrobials TET (95.4%) and TST (90.9%). (3) The most severe multidrug resistance serovar was Uganda, which was resistant to six types of antimicrobials and the most severe multidrug resistance serogroup was O:3,10 (E1). (4) IncFIB(K)-1-Kpn3 plasmid replicon was found to be the dominant plasmid type in S. Derby was regardless of the source. Nevertheless, only by using whole genomic sequencing approach and combined with the sophisticated bioinformatic pipeline, we are able to address the resistome and plasmidome of particular diversified bacterial population, which provide a new way for conducting the foodborne pathogens and epidemiology in China.The main findings of this study are as follows: (1) Salmonella is one of the four major global causes of diarrheal diseases. Pork products are the main source of Salmonella infection and slaughterhouses provide ample opportunities for Salmonella growth and proliferation with contamination arising from the environment, animal carcasses, utensils etc. The prevalence of Salmonella was quite different in slaughterhouses in different countries. In our study, we observed S. Derby as the dominant serovar. In Belgium and France, the dominant serovar was S. Typhimurium and S. I 4,5,12: i:-, respectively . This number was quite alarming since the MDR rate was reported 44.04 and 73.2% in studies conducted in 2017 and 2018, respectively . We specWe also noticed that the resistance to the most of the antimicrobial resistance rate was higher among the isolates originated from pig carcasses than the environmental originated isolates, which indicated that the main source of the isolates was the pigs and mostly the environment was cross contaminated during the current slaughter procedures.mcr-1 gene in five strains, including two strains of S. Derby, two strains of I 4, [5],12:i:- and one S. Typhimurium strain which was much higher than the previous reports , the mcr-1 gene was found only in 37 strains, out of which 35 strains were S. Typhimurium, and the remaining two strains were S. Enteritidis and S. Wandsworth  gene which confers resistant to tetracyclines was the highest prevalent gene. Besides, beta-lactam, and plasmid mediated- quinolones and colistin resistant (mcr-1) resistant genes have been also detected among the isolated strains. IncFIB(K)-1-Kpn3 was also found to be the most prevalent detected plasmid replicon among the isolates and coexisted with the large number of antimicrobial resistance genes. Therefore, there is an urgent need to avoid antimicrobial abuse and develop new antimicrobials. These findings uncovered the prevalence of Salmonella in slaughterhouses in Jiangsu, China, and also provided essential knowledge to guide rational antimicrobials usage if appropriate.In conclusion, the present study provided a comprehensive study on the prevalence of The original contributions presented in the study are included in the article/No ethical approval was deemed necessary for this study. Oral agreement and permission were obtained from the farmers as well as the slaughterhouse manager before sampling.WC: writing the original draft, refined and reorganized the data and its presentation. QL, WC, and ME: conducting the experiments and aiding with the writing. HP: data analysis. LW, CZ, BZ, XX, DL, XY, XH, and HL: sampling, sample preparation, and methodology. MY and YL: conceptualization, funding acquisition and project administration. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "This single-center, retrospective cohort study sought to estimate the cumulative incidence in HIV-1-infected patients of biopsy-proven high-grade anal intraepithelial neoplasia (HGAIN) recurrence after infrared coagulation (IRC) treatment. The study was based on data from a prospectively compiled database of 665 HIV-1-infected outpatients who attended a hospital Clinical Proctology/HIV Unit between January 2012 and December 2015. Patient records were checked to see which ones had received IRC treatment but later experienced a recurrence of HGAIN. Cytology samples were also checked for the presence of human papilloma virus (HPV). A total of 81 of the 665 patients , of whom 65 were men and 16 women, were diagnosed with HGAIN and again treated with IRC. Of these 81, 20 (25%) experienced recurrent HGAIN, this incidence being true of both men  and women . The median time to recurrence was 6 (2\u201319) months overall, 6 (2\u201319) months in men, and 4 (2\u20136) months in women. HPV infection was detected in all patients except two, with HPV-16 being the most common genotype. This rate of incidence of recurrent HGAIN following IRC treatment is consistent with other reports and highlights the importance of continued post-treatment surveillance, particularly in the first year. Anal cancer (AC) is one of the most common non-AIDS-defining cancers , and itsInterrupting the natural history of AC is a challenge. Infrared coagulation (IRC) has been established as an effective treatment for high-grade squamous intraepithelial lesions (HSIL) . It can In a previous study , our groThe study was a single-center, retrospective cohort study based on data from a prospectively compiled database consisting of the digitized medical records of outpatients who were being attended at the HIV Unit of the Hospital Germans Trias i Pujol in Badalona, Spain. The cohort protocol was approved by the local Institutional Review Board (IRB) and all patients gave their written informed consent.The study population was made up of the 665 HIV-1-infected patients of both genders who had been treated using IRC for biopsy-proven HGAIN between 1 January 2012 and 31 December 2015 and who had yielded positive HIV serology results, were being attended at the hospital\u2019s HIV Unit, and were at least 18 years old. Follow-up of all these patients had ceased by December 2019.An anal canal sample was taken for cytological examination and the Papanicolaou test was performed to check for anal canal cytological changes, as described previously .After topical application of 5% acetic acid in the anal canal for 2 min, HRA was performed using the technique described in [If the result of the histological examination revealed HGAIN , patient consent to undergo IRC ablation was obtained. IRC sessions were usually scheduled between 1 and 2 months after the first HRA. During the IRC process, each lesion was identified, infiltrated with local anesthesia, and then repeatedly coagulated using a Redfield IRC 2100 Infrared Coagulator  in pulses of 1.5 s . All proAfter IRC ablation, patients underwent routine evaluations involving visual inspection, digital rectal examination, and anal canal cytology at 3 to 6-month intervals. Major post-IRC complications were recorded. Patients with abnormal cytology results during the follow-up underwent another examination with HRA. If HRA revealed a new lesion, a biopsy was again performed. Patients with biopsy-proven AIN-2 or AIN-3 were advised to undergo further IRC ablation. Patients with AIN-1 were monitored with anal cytology at 3 to 6-month intervals. Patients with normal cytology results after IRC were monitored using anal cytology at 12-month intervals.In the group of women studied, cervical cytology was assessed  using the Papanicolaou method and results recorded according to the Bethesda Classification System, as follows: normal ; ASCUS ; LSIL ; or HSIL.TM II HPV28 real-time PCR assay . DNA was extracted from cell suspensions using the QiAMP Viral RNA kit .When samples were available from the anal canal or, in the case of women, the cervix, these samples were tested for human papilloma virus (HPV) infection with positive results simultaneously identified for HPV type using the AnyplexBaseline was defined as the moment of the patient\u2019s first anal cytology assessment at which HGAIN was recorded, with recurrent HGAIN defined as biopsy-proven HGAIN subsequent to IRC treatment. The follow-up period was defined as the time between baseline and either biopsy-proven recurrence of HGAIN or last visit available after IRC in case of no recurrence.No formal sample size was calculated. The sample was defined as all HIV-1-infected patients with HGAIN (AIN-2 or AIN-3) as diagnosed by histological examination.The cumulative incidence of biopsy-proven HGAIN recurrence after IRC treatment was estimated, and its 95% confidence interval (95%CI) was calculated. The mean time to recurrence was analyzed using the Kaplan\u2013Meier method. Agreement between the cytological diagnosis (Papanicolaou test) and the histological diagnosis (biopsy) was described. HPV infection and IRC safety was described.p value <0.05 was considered statistically significant. Data were analyzed using SPSS version 20 statistical software .A Of the 665 HIV-1-infected patients who were attended at our Clinical Proctology HIV Section with at least an anal canal cytology performed, 81  patients were diagnosed with HGAIN and were treated with IRC. Of these 81, 65 (80%) were men, of whom 60 (92%) were Men who have Sex with Men (MSM) and 5 (8%) were Men who have Sex with Women (MSW), and 16 (20%) were women. The mean age was 43.1 (SD 11.2) years and the median 44 (range 24\u201377 years). The cumulative incidence of recurring biopsy-proven HGAIN was 25% : 25%  in men and 25%  in women. The median follow-up period for the study population was 55 months (range 33\u201371) and the median time to recurrence was 6 months (range 2\u201319). Broken down by gender, the median was 6 months (range 2\u201319) in men and 4 months (range 2\u20136) in women.At baseline, a total of 101 anal lesions in the 81 patients were visually detected by HRA: 30% (19/64) of the men had >1 lesion whereas all the women had only one lesion. At recurrence, 26 lesions in the 20 patients were detected by HRA; here, 6% (1/16) of the men and 50% (2/4) of the women had >1 lesion.n = 81) with abnormal cytological diagnosis  and visualized lesion by HRA had a histological diagnosis of AIN-2  or AIN-3 .Agreement between the cytological and histological diagnosis was described . All patn = 65) were ASCUS 8% (5/65), LSIL 59% (38/65), and HSIL 34% (22/65), while, for the women (n = 16), they were ASCUS 6% (1/16), LSIL 31% (5/16), and HSIL 63% (10/16). The baseline histology results for the men show that 79% (51/65) had AIN 2 and 22% (14/65) had AIN 3, while 63% of the women (10/16) had AIN 2 and 38% (6/16) had AIN 3.The baseline anal canal cytology test results for the men (n = 16) were ASCUS 6% (1/16), LSIL 31% (5/16) and HSIL 63% (10/16), while, for the women (n = 4), they were LSIL 25% (1/4) and HSIL 75% (3/4). The recurrence histology results for the men show that 63% (10/16) had AIN 2 and 38% (6/16) had AIN 3, while 50% of the women (2/4) had AIN 2 and 50% (2/4) had AIN 3.At recurrence, the anal canal cytology test results for the men  and LSIL in 38% (6/16), the remaining 50% women (8/16) yielding normal (negative) results. The four women who presented a recurrence of HGAIN at an anal canal site had at least one historical cervical dysplasia, as revealed in the baseline cytology test.At baseline, 67 out of 81 patients  had samples from an anal canal site for available HPV infection detection. HPV infection was detected in all patients except two . Single HPV infection (for only one HPV genotype) was detected in five patients , and multiple infections (for >1 HPV genotype) in 60 patients . HPV-16 was the most prevalent HPV genotype found at an anal canal site at baseline; this represented 40% of the men  and 50% of the women . Men presented a greater number of HPV genotypes at anal canal sites  relative to women .Of the 20 patients with recurrent HGAIN, 18  had samples from an anal canal site available for the detection of HPV infection. The analysis detected 28 HPV genotypes, of which 13 were high-risk-HPV genotypes , 9 were low-risk-HPV genotypes  and 6 were uncertain-risk-HPV genotypes . HPV infection involving >1 HPV genotype was detected in all patients. HPV-16 was the most prevalent HPV genotype, being present in 47% of the men (95%CI: 25\u201370%) and 100% of the women (95%CI: 44\u2013100%). The men presented a greater number of HPV genotypes at anal canal sites  relative to the women .No major complications related to IRC were reported. Pain was the main adverse event reported by patients. Likewise, no adverse events related with the obtaining of sampled from the anal canal for cytology and HPV assessment were reported.HGAIN is a prevalent pathology among HIV-1-infected patients, and recurrence of HGAIN in these patients, regardless of treatment, is not uncommon. In the present study of 81 HIV-1-infected patients with a long follow-up (minimum 33 months), we found the same cumulative incidence of biopsy-proven HGAIN recurrence after IRC treatment in both men and women, namely 25%.Though our previous results (published in 2013) on the estimated cumulative recurrence of biopsy-proven HGAIN seem to differ from those reported here, the confidence intervals overlap  ,9,10, thOur study has several limitations. First, the small sample size  means that the results found may be an over- or underrepresentation of the real recurrence rate. Second, our study reports the experience of a single center where a screening program for anal cancer prevention has been active since 2005. However, this program may differ from others , which mIn conclusion, the fact that recurrence of HGAIN in HIV-1-infected patients after IRC ablation is a fairly common occurrence highlights the great importance of continued post-treatment surveillance to prevent new episodes, particularly in the first year."}
+{"text": "Much is known about the mental health of combat Vietnam Veterans, but less is known about Persian Gulf and post-9/11 veterans and how they compare to those from earlier eras. Using data from an online survey of Oregon veterans, we examine how PTSD symptoms differ by combat exposure across these three cohorts. The sample , was largely composed of White (88%), male (69%) Veterans. Most served in the Persian Gulf (41%), followed by Vietnam (36%) and post-9/11 (23%) eras. ANCOVAs showed significant cohort differences in PTSD, after controlling for severity of combat exposure and demographics   = 4.24, p < .05). Post-9/11 veterans had significantly lower PTSD symptom severity than Vietnam-era veterans but were comparable to Persian Gulf. There were no cohort differences for noncombat veterans. Future research should investigate why Vietnam veterans continue to have worse mental health than younger veteran cohorts. Part of a symposium sponsored by the Aging Veterans: Effects of Military Service across the Life Course Interest Group."}
+{"text": "The ceramic samples were characterised by means of scanning electron microscopy, X-ray diffraction, energy-dispersive X-ray spectroscopy and atomic absorption spectrometry to explore the incorporation of Mg atoms into the zirconia lattice. The resulting porosity of the samples was calculated based on the composition and density. The final porosity of the cylinder-shaped ceramic samples ranged between 30 and 37%. The mechanical analysis exhibited that the Young modulus increased and the microstress decreased with increasing magnesia amount, with values ranging from 175 GPa for zirconia to 301 GPa for magnesia. The adhesion, viability, proliferation and osteogenic activity of MC3T3-E1 pre-osteoblastic cells cultured on the zirconia/magnesia ceramics was found to increase, with the magnesia-containing ceramics exhibiting higher values of calcium mineralisation. The results from the mechanical analysis, the ALP activity, the calcium and collagen production demonstrate that the zirconia/magnesia ceramics possess robust osteoinductive capacity, therefore holding great potential for bone tissue engineering.Porous zirconia (ZrO Cells seeded on TCPS surfaces were used as control. All substrates were analysed in triplicates, in three independent experiments (n = 9).For the alkaline phosphatase (ALP) activity measurement, 1 \u00d7 105 pre-osteoblastic cell cultures on different ceramic samples was performed by means of a colorimetric assay based on the selective binding of Sirius Red dye in acid solution to the proline-hydroxyproline-glycine sequence of the helical structure of collagen [n = 9).The quantification of secreted collagen levels collected from the supernatants of 1 \u00d7 10collagen . For the\u00ae viability assay for normalisation. After the cell viability assessment, the samples were rinsed with PBS and fixed with 4% paraformaldehyde for 15 min. After removing paraformaldehyde, cells were rinsed twice with PBS and stained with 500 \u03bcL of 2% solution of alizarin red dye in water. To remove the excess dye, samples were thoroughly washed with deionized water. For quantification, each stained sample was extracted by incubation in 500 \u03bcL 10% cetylpyridinium chloride in 10 mM Na2PO4, pH 7.0, for 1 h at room temperature under shaking. A volume of 200 \u03bcL was transferred into a 96-well plate prior to reading and the absorbance was measured at 550 nm. The OD values from the extraction were normalized to 106 cells from the viability assay. Cells seeded on TCPS surfaces were used as control. All substrates were analysed in triplicates, in three independent experiments (n = 9).Calcium deposits, a late marker of osteogenesis signalling the formation of extracellular matrix, were stained with alizarin red. Before staining, the samples were evaluated by means of the PrestoBlueCell viability, collagen production, alkaline phosphatase activity and calcium biomineralisation data are presented as mean values \u00b1 standard deviation. Statistical analysis was performed by means of GraphPad Prism version 8 software using one-way analysis of variance and Tukey\u2019s multiple comparison to evaluate the significant differences among means of values obtained from all five ceramic compositions as well as of TCPS control at each experimental time point. A p < 0.05 was considered significant, if no other indication is stated.2 (lighter) and MgO (darker) grains in SEM . In agreement to SEM and nominal compositions of the samples, EDX data further confirmed the increasing tendency of MgO with the exponentially varying molar Mg/Zr ratios  and cubic , and minor monoclinic  phases  into the c-ZrO2 lattice, whereas Mg atoms in the t- and m-ZrO2 phases were not detectable by XRD. This matched again the larger Mg-miscibility in c-ZrO2 and low miscibility in t- and m-ZrO2 phases and the finding by EDX. The temperature-induced phase transformation to m-ZrO2 was accompanied by a volume increase of 6% (from 132.2 to 140.5 \u00c53) inducing compressive  stress in c-ZrO2 and atomic defect concentration quantified in XRD by microstrain (\u03b5 = 0.34 %), which was significantly larger than that of t- and m-ZrO2 . Such c-t-m transformation further contributes to the mechanical properties of ZrO2-based ceramics, known as transformation toughening [2 were nanocrystalline (CS \u2248 40\u201350 nm), whereas t-ZrO2 was microcrystalline  is possible as also assumed from the elongated crystals in SEM . The larger Zr/Mg substitution ratio for the mixed ceramics compared to 100% ZrO2 (4 at.%) can be explained by the compositional location (right or left from the miscibility area of c-ZrO2) in the phase diagram. The determined microstrain of c-ZrO2 remained almost constant (\u03b5 = 0.08%) for all samples, which pointed on the pre-stressed condition of this phase compared to MgO (\u03b5 = 0.02%) or m-ZrO2 (\u03b5 = 0.05%).Crystallographic study confirmed that the mixed ceramic samples with 25, 50 and 75% MgO consisted of c-ZrOgO phase  as also s in SEM , but itsd by SEM . The lat2 structure , which agreed well with the microscopic investigation by SEM  indicating an incomplete solubility of MgO [2 phase due its slow solubility [To verify a slight deviation in the composition  from the linear rule determined by XRD , left, Aas found , right. y of MgO  and partlubility .2/MgO ceramics (E) increased while the microstress (\u03c3) decreased with an increasing MgO amount. Interestingly, the addition of more than 25 wt.% MgO contributed to a significant drop in microstress compared to MS-ZrO2 following a functional dependency similar to the Zr/Mg molar ratio determined by EDX (2 (4.3 as from 0.34/0.08) for these compositions (2) to 301 GPa (MgO) reaching saturation at higher MgO concentration.The mechanical analysis presented that the transformation toughening in magnesia stabilised (MS) zirconia can be also affected by varying MgO content in the ZrOceramics . It is od by EDX . This faositions . Simulta2(100) ceramics on days 2 and 14, respectively, with the latter (2(75)MgO(25) ceramic samples (2(50)MgO(50) samples (2(75)MgO(25) and MgO(100) that exhibited a granular structure as illustrated in The morphology of the MC3T3-E1 pre-osteoblastic cells on the different compositions of zirconia/magnesia ceramics after 2 and 14 days in culture was investigated by scanning electron microscopy, and representative images are depicted in e latter B indicat samples C,D on bo samples E,F, on w2(100) at both experimental time periods of 2 and 14 days, while the number of viable cells was similar on the other ceramic substrates, ZrO2(75)MgO(25), ZrO2(50)MgO(50), ZrO2(25)MgO(75) and MgO(100). Statistical analysis indicated that on day 2 the ZrO2(100) ceramics presented a significant difference in cell viability compared to all other materials and TCPS control (p < 0.02 up to 0.0001). Additionally, ZrO2(75)MgO(25), ZrO2(25)MgO(75) and MgO(100) reached significantly higher cell viability compared to the TCPS control (p < 0.02 up to 0.0001). On day 14, ZrO2(100) ceramics displayed a significant difference in cell viability compared to all other materials and TCPS control (p < 0.0001), while ZrO2(25)MgO(75) revealed significantly higher cell viability compared to all other ceramic materials and the TCPS control (p < 0.0001).The pre-osteoblastic cell viability on the five compositions of the ceramic materials after 2 and 14 days in culture is presented in 2(100) and ZrO2(25)MgO(75) showing the highest response, presenting at least two times higher values compared to TCPS. The ALP activity on MgO(100) was found to be the lowest among the ceramics, but higher than on the TCPS control. A similar pattern was measured on day 15 with the ZrO2(100) indicating the highest value, which is 30% higher than on day 7. For all ceramic materials, an increase in the ALP activity was found on day 15, compared to day 7. Statistical analysis revealed that on day 7, all ceramics exhibited significantly different ALP activity values when compared to each other and also to the TCPS control, except of the ZrO2(100) vs. ZrO2(25)MgO(75) (p < 0.0001). Similarly, on day 15, all ceramics displayed significant differences among them (p < 0.0001), except of the ZrO2(50)MgO(50) vs. ZrO2(75)MgO(25).Alkaline phosphatase (ALP) activity of cells cultured on the five ceramic substrates was measured after 7 and 15 days, normalised to the total protein concentration, and the results are presented in 2(75)MgO(25), ZrO2(50)MgO(50) and MgO(100), whereas on day 21 the highest values were found on ZrO2(25)MgO(75) and ZrO2(50)MgO(50), however not significant.The levels of calcium produced by the pre-osteoblastic cells cultured on the zirconia/magnesia ceramics on days 9 and 21 are depicted in p values < 0.0001). Among the five ceramic materials, the differences were not found to be significant.To study the effect of porous zirconia/magnesia ceramics on the production of collagen, we quantified the secreted collagen in culture supernatants on days 7 and 15, as shown in The focus of this study was the preparation, physicochemical and mechanical characterisation of porous ceramic scaffolds with varying compositions of zirconia and magnesia and the investigation of their osteogenic response. This is one of the few studies employing porous magnesia ceramic scaffolds for bone tissue regeneration, as magnesia is mainly used as an additive or surface coating material and thus there is limited number of reports on magnesia scaffolds in the literature.2) with 0, 25, 50, 75, 100 wt.% magnesia (MgO), respectively, and designated as ZrO2(100), ZrO2(75)MgO(25), ZrO2(50)MgO(50), ZrO2(25)MgO(75), MgO(100), respectively. The final porosity of the cylinder-shaped samples in this study ranges between 30 and 37%. These variations are due to the lack of control in the level of shrinkage during fabrication.Disc-shaped ceramic samples were produced by combining 100, 75, 50, 25 and 0 wt.% magnesia stabilised zirconia  to 21 MPa (MgO) can be of interest in dentistry [Our results show that the Young modulus increased and the microstress decreased with the increasing MgO amount. Specifically, the Young modulus continuously increased from 175 GPa for zirconia to 301 GPa for magnesia in agreement with the literature ,27 reachentistry  with difentistry ,30,31.2(100) ceramics at both days 2 and 14, and a similar cell morphology with visible cell protrusions on ZrO2(75)MgO(25) ceramics, as well as on ZrO2(50)MgO(50) samples. In a previous report with zirconia ceramics stabilised either with magnesia (MgSZ) or yttria (YSZ), after 1 day in culture, pre-osteoblastic cells adhered well on both zirconia ceramics with a more spread out morphology on YSZ compared to MgSZ [2(75)MgO(25) and MgO(100) that depicted a granular structure, we observed a high number of adhered cells covering the samples at day 2. Particularly on day 14, we observed densely adhered interconnected cells on the MgO(100) ceramics. These results are in agreement with the morphology of human pre-osteoblastic cells presented in a previous report on Mg-tricalcium phosphate microstructured ceramics [Events occurring on the tissue-material interface control the integration of grafts into bone. It is acknowledged that a strong initial adhesion of osteoblastic cells on biomaterials leads to better bonding between implant and bone ,33. By m to MgSZ . On the 20 ceramic2(100) at both day 2 and 14 in culture, indicating the highest proliferation increase after 14 days. Previous reports have revealed the potential of zirconia to promote cell proliferation over three weeks in culture [Among the five ceramic materials, the highest pre-osteoblastic cell viability was found on ZrO culture . All oth culture . In this culture .2(25)MgO(75) and ZrO2(50)MgO(50), and higher calcium in all magnesia-containing ceramics on day 9, the highest secreted collagen on the MgO(100) ceramics at days 7 and 15, and the highest ALP activity on day 7 on ZrO2(100) and ZrO2(25)MgO(75), however these results were not statistically significant. Our findings demonstrate similar levels of collagen production and higher calcium production on magnesia-containing ceramics compared to another study reporting on pre-osteoblasts cultured on magnesia stabilised zirconia ceramics [All five ceramic compositions tested were found to support the osteogenic differentiation markers including the ALP activity, calcium mineralisation and collagen production, demonstrating higher responses compared to the TCPS control. Specifically, we found the highest values of calcium mineralisation on day 21 on ZrOceramics , and shoceramics . Anotherceramics . The relceramics . In thisThe results from the ALP activity, calcium and collagen production clearly demonstrated that the zirconia/magnesia ceramics possess robust osteoinductive capacity, and thus present great potential for bone tissue engineering applications. In addition, ceramic materials can be used as carriers to deliver cytokines such as bone morphogenetic proteins , specifi2(100), ZrO2(75)MgO(25), ZrO2(50)MgO(50), ZrO2(25)MgO(75), MgO(100) according to their composition, and characterised them by means of microscopy, crystallography, spectroscopy and spectrometry to explore the incorporation of Mg atoms into the zirconia lattice and calculate the porosity of the samples. The final porosity of the cylinder-shaped samples in this study ranged between 30 and 37%. The mechanical analysis exhibited that the Young modulus increased and the microstress decreased with increasing magnesia amount, with values ranging from 175 GPa for zirconia to 301 GPa for magnesia. We observed an increase in adhesion, viability, proliferation and osteogenic activity of MC3T3-E1 pre-osteoblastic cells cultured onto zirconia/magnesia ceramics, with the magnesia-containing ceramics demonstrating higher values of calcium mineralisation. Taken together, the results from the ALP activity, calcium and collagen production clearly show that the zirconia/magnesia ceramics possess robust osteoinductive capacity, therefore holding great potential for bone tissue engineering.In this study, we synthesised by sintering porous zirconia, magnesia and zirconia/magnesia ceramic samples, designated as ZrO"}
+{"text": "Melaleuca alternifolia is commonly known as the medicinal tea tree. The complete chloroplast (cp) genome sequence is 160,104\u2009bp in length, with a quantitative molecule structure comprising two copies of inverted repeats (IRa and IRb) of 26,737\u2009bp separated by a large single copy (LSC) of 88,151bp, a small single copy (SSC) of 18,479\u2009bp. A total of 131 genes were identified including 84 protein-coding genes, 37 tRNA genes, eight rRNA genes and two pseudogene , respectively. Phylogenomic analysis suggests that M. alternifolia is closely related to the rest species of Myrtaceae with strong bootstrap values. Melaleuca alternifolia (Maiden & Betche) Cheel (Myrtaceae), commonly known as medicinal tea tree, is a commercially important tall shrub native to eastern Australia that produces valuable tea oil  with default settings and manually adjusted coding regions in Geneious 11.1.5 (https://www.geneious.com).Fresh leaves were collected from Guangxi Forestry Research Institute  and the voucher specimen (accession No.: 617001) was deposited in the Herbarium of Institute of Botany, Jiangsu Province and Chinese Academy of Sciences (NAS). The total genomic DNA was isolated using modified CTAB method  was 160,104\u2009bp in length. Two copies of inverted repeat  separated the rest of cp genome sequence into a large single copy  and a small single copy . The overall GC content of M. alternifolia cp genome was 36.7%. And the base composition of the cp genome is A (31.3%), T (32.0%), C (18.7%), and G (18.0%). A total of 131 genes were identified, containing 84 protein-coding genes, 37 transfer RNA genes (tRNA), eight ribosomal RNA genes (rRNA) and two pseudogene . Among these genes, 13 protein-coding genes contained one or two introns.The cp genome sequence of M. alternifolia with other Myrtaceae, the whole cp genomes of previously published species of Myrtaceae and one outgroup  were aligned using the MAFFT 7.409 (Katoh and Standley M. alternifolia is closely related to the rest species of Myrtaceae with strong bootstrap values (In order to test the phylogenomic relationship of p values ."}
+{"text": "Background: Gemcitabine and cisplatin combined with conventional radiotherapy in treating patients with cervical cancer, resulted in a favourable conclusion but accompanied with high toxicity. The objective of our research was to assess the tolerability, efficacy and feasibility of dual chemotherapy in addition to image-guided adaptive brachytherapy and highly conformal external beam radiation therapy.Methods & Materials: From June 2011 to November 2013, 81 cervical cancer patients with FIGO stage IB2-IIIB medical records were retrospectively reviewed. All patients received whole pelvic radiotherapy (WPRT) to a total dose of 50.4 Gy/ 1.8 Gy Chemoradiotherapy prescription objectives were: concurrent gemcitabine (125 mg/m2) and cisplatin (30 mg/m2) during the 6 weeks of external beam radiation therapy (EBRT) followed by two cycles of gemcitabine  and cisplatin (25 mg/m2 d1-d3) on the tenth week. External beam radiotherapy was followed by image-guided brachytherapy of 24 Gy/ 4 fractions. Version 4 of the common terminology criteria for adverse events (CTCAE v 4.0) was used in grading the toxicities.Results: Sixty-nine patients obtained complete response (CR), six had a partial response (PR), and five patients had stable disease (SD). The disease control rate (DCR= SD and ORR) and overall response rate  were 92.6% and 85.2% respectively. The 3-year and 5-year estimated overall survival (OS) was 75.4% and 66.3%, and the 3-year and 5-year estimated progression-free survival (PFS) were 78.2% and 65.4%. The median PFS time and OS time were 36.8 months and 45.5 months, respectively. Distance metastasis was evident in the lung (3 patients), pelvic wall (2 patients), liver (3 patients) and bone (2 patients). Six (6) had a local relapse, and two (2) patients had local relapse plus simultaneous systemic metastatic tumour.Conclusions: Unlike past results, gemcitabine and cisplatin appear to be tolerable, efficient and feasible when combined with conformal radiotherapy. As the second most frequently diagnosed cancer and the third major cause of death in female, cervical cancer is estimated to have a prevalence and mortality rate of 527,000 and 265,700 respectively, representing 8% of total cancer death and cases in females The open phase III clinical trial conducted by Duenas et al evaluated the therapeutic advantages of chemoradiotherapy, and the results laid the basis for concomitant chemoradiotherapy (CCRT) to be the preferred therapy for loco-regionally advanced carcinoma of the cervix Gon\u017aales et al reported there was a significant reduction in toxicity when gemcitabine and cisplatin were used in advanced cervical cancer patients. The synergy between gemcitabine and cisplatin has been demonstrated by multiple preclinical and clinical trials Gemcitabine is a deoxycytidine analogue and wide-spectrum antimetabolite with antineoplastic activity. The antineoplastic nature of gemcitabine has resulted in its usage in several forms of advanced cancers. Gemcitabine is a drug with single-agent action in recurrent or metastatic cervical carcinoma but has demonstrated clear radio-sensitizing characteristics in preclinical studies, even in human cervical cell lines.The objective of our research was to evaluate the tolerability, efficacy and feasibility of dual chemotherapy using gemcitabine and cisplatin regime in addition to image-guided adaptive brachytherapy and highly conformal external beam radiation therapy in loco-regionally advanced carcinoma of the cervix.Histologically confirmed carcinoma of the cervix patients with FIGO stage 1B2-IIIB tumours treated with concurrent gemcitabine plus cisplatin and IMRT at the Radiation Oncology Department of Zhengzhou University People's Hospital were involved in our research. The study was approved by the institutional review and ethics board of Zhengzhou University. The pre-treatment histories, medical and follow-up records of 81 treated patients from June 2011 to November 2013 were reviewed retrospectively. The 2009 International Federation of Gynecology and Obstetrics staging system were used., gynaecological and general physical examination, tumour biopsy, digital rectal examination (DRE), complete blood count (CBC), biochemical examinations, cystoscopy and rectoscopy). The eligibility criteria included:Histologically confirmed carcinoma of the cervix patientsPatients without a previous history of being treated for any type of cancerKPS score above 70No evidence of distance metastasisPatients with normal liver functionsAll the patients included in our study underwent our institutional pre-treatment workup protocol  were images obtained by diagnostic 18FDG-PET/CT, CT and MRI. The RTOG guidelines were used in contouring. Based on all accessible medical and imaging information, the gross tumour volume (GTVc) was described as the visible macroscopic tumour. The clinical target volume (CTV) involved the regional lymph nodes and primary tumour sites. The primary clinical target volume encompassed gross tumour volume, parametrium, cervix, uterus and upper one-third of the vagina. In instances, where there was involvement of the vagina, the clinical target volume was extended 20 mm into the tumour's vagina caudal. The planning target volume (PTV) was generated using an isotropic expansion with the internal target volume  taken into account. The planning target volume was expanded 1cm laterally and 1.5 cm in the anterior-dorsal direction. Correction of the planning volume was done when necessary The PTV was prescribed to a total dose of 50.4 Gy. Tumour response assessment using magnetic resonance imaging was done after patients had received 45Gy of the total dose. In situations where the rest of the tumour was bigger than four cm in diameter, the PTV received an additional 9 Gy boost while tumours less than four cm after evaluation also received an additional 5.4 Gy boost. The patient received 1.8 Gy per fraction. The organs at risk (OAR) dose constraints were: 50% of bladder volume must not receive above 50Gy, 35% of the intestines must not receive dose above 35Gy, 60% of rectal volume must not receive dose above 50Gy, and 10% of the femoral heads must not receive above 50Gy.2) is 32Gy. The vagina was adequately packed with gauze to keep the rectum and bladder away from receiving a high dose of radiation. Images set obtained by CT- MRI scan was transferred to the Oncentra planning system. microSelectron (Iridium-192) was used during the treatment.All patients received image-guided adaptive brachytherapy (IGABT) dose of 6 Gy in four-fractions (24 Gy) and the total equivalent dose in 2 Gy fraction  on the 7th week immediately after completing chemoradiotherapy plan which, was followed by 14 days of rest. Patients subsequently received two successive 3 weeks' cycle of adjuvant chemotherapy with 1000 mg / m2 of gemcitabine on days 1 and 8 and 25 mg / m2 of cisplatin on day 1-3.Intravenously infused 30 mg/m3, thrombocytes <100, 000/ mm3, or neurotoxicity below grade 3 per CTCAE v4. Blood transfusion was given to patients with haemoglobin (Hb) level of less than 80 g/l. Non-haematological and haematological side effects due to chemotherapy were recorded based on the Common Terminology Criteria for Adverse Effects Version 4.0 The Response Evaluation Criteria in Solid Tumours (RECIST v1.1) was used in evaluating the response of the tumour to the treatment.Multiple parameters were controlled in accordance with the institutional standards of Zhengzhou university people's hospital and were required to meet the standard safety criteria before the commence of every chemotherapy cycle. Haematology and chemistry results were obtained weekly before starting every cycle of chemotherapy. Chemoradiotherapy was paused when the leucocytes were < 2000/mmStatistical assessment was conducted using SPSS Version 23.0. The median PFS and median OS were evaluated with the Kaplan - Meier curve. All the data recorded was entered into the excel file and evaluated in proportions and percentages whenever necessary.The clinical features of the 81 patients involved in our analysis are presented in Table Figure  & 2. The median OS time and PFS time were 45.5 months and 36.8 months, respectively. Distance metastasis was evident in the lung (3 patients), pelvic wall (2 patients), liver (3 patients) and bone (2 patients). Six (6) had a local relapse, and two (2) patients had local relapse plus simultaneous systemic metastatic tumour.Short-term therapy responses were assessed three months after concurrent chemoradiotherapy and IGABT. Sixty-nine patients obtained complete response (CR), six had a partial response (PR), and five patients had stable disease (SD). The disease control rate (DCR= SD and ORR) and overall response rate  were 92.6% and 85.2% respectively. The 3-year and 5-year estimated OS was 75.4% and 66.3%, and the 3-year and 5-year estimated PFS were 78.2% and 65.4% The toxicities of concurrent chemoradiotherapy were graded by CTCAE v4. No interruption was observed during the treatment. The treatment was completed by all patients and toxicity was well tolerated. Nausea was recorded in 9 (8.6%) patients, 4 patients were grade 1 (4.9%), 3 were grade 2, and 2 patients were grade 3. Eight patients and 5 patients had grade 1 and grade 2 diarrhoea, respectively. Ten (10) patients had anorexia, and 6 patients had vomiting. . Thrombocytopenia was observed in 8 patients, and 10 patients had anaemia. Seven patients had grade 1 neutropenia. Late genitourinary and gastrointestinal toxicity was noticed in 13 (16.0%) patients. Six (7.4%) had grade 1upper gastrointestinal toxicities, 5 patients (6.2%) had grade 1 cystitis, and one patient had grade 2(1.2%) cystitis. Grade 1 dryness of the vagina was evident in 4 (4.9%) patients, two had grade 1 (2.5%) shortening of vagina, and three (3.7%) patients had grade 2 vaginal stenosis. Table Radiotherapy alone has unsatisfying outcomes in the management and treatment of locoregionally advanced carcinoma of the cervix. Several studies have been designed and undertaken over the last decade with the objective of improving treatment result. In a meta-analysis performed by Vale C et al on individual patient information, the combined findings of these crucial studies were assessed In concurrent chemoradiotherapy protocols, non-platinum compounds alone were rarely evaluated and were usually overlooked in the literature. In a few studies, 5-FU (fluorouracil) and cisplatin were tested, but the problem was toxicity, and the dimension of frequent treatment gaps was also highlighted. Four out of the five studies in which cisplatin was accepted to be the standard treatment had 5-FU combined with cisplatin Gemcitabine is part of the group of antimetabolites  that inhibits the synthesis of DNA and ultimately causes programmed cell death. Gemcitabine has demonstrated effectiveness against a multitude of tumours, particularly lung and pancreatic cancer. It was also evaluated in gastrointestinal (GI) cancers, breast, urinary bladder, ovary and cancer of the cervix in vivo and in vitro have shown that gemcitabine is a powerful radiosensitizer that dramatically increases the outcomes when coupled with radiotherapy Studies Burnett et al. reported a total response rate of 41% with a reasonable toxicity effect 2 is the peak tolerability dose for gemcitabine when used weekly during concurrent chemoradiotherapy A phase I and II trial conducted by Zarba et al investigated weekly gemcitabine and cisplatin in thirty-six patients. They discovered that a peak acceptable dose of 150 mg / mCompared to prior studies, our research has several unique methodological and patient characteristics. First, we used highly conformal radiotherapy in treating our patients while conventional external beam radiotherapy was used in previous studies. This is the possible reason for the lower rate of haematological toxicity achieved in our studies. In addition, IMRT has been shown to be superior to three-dimensional (3D) and two-dimensional (2D) methods, both in terms of reducing toxicity incidence and bone-marrow sparing The findings of our study are similar to those reported in the literature. Loco-regional control is superior to past studies that used the gemcitabine plus cisplatin regimen. This can be ascribed to the use of intrauterine adaptive brachytherapy other than chemotherapy inclusion. Local failure was a problem in Gonz\u00e1lez et al study, though there was no statistical difference when the rate of local failure was considered . Nevertheless, tumour control is challenging since systemic metastasis is reported in about 40% of patients Modern radiation therapy technique has resulted in outstanding and excellent local control rates. Regardless of tumour size the 3-year local control rate goes beyond 95% and approaches approximately 100% if the equivalent total dose (EQD2) to the volume of the \"high-risk tumour'' is higher than 87 Gy Small sample size, short-follow up, and the retrospective nature of the study are some of the limitations in our study. Notwithstanding these restrictions, we believe our research offers a distinctive perspective into new therapeutic options for patients with locoregionally advanced carcinoma of the cervix. The data presented can serve as a foundational guide for future randomized controlled trials."}
+{"text": "Purpose: The purpose of this study was to investigate the patterns and factors of reversals in decisions about life \u2013sustaining treatment (LST) among older patients with terminal stage of chronic cardiopulmonary diseases. Methods: In a retrospective correlational descriptive study, data were collected using medical chart review from 124 deceased older patients with terminal stage of cardiopulmonary disease who had made reversals of LST decisions in an academic tertiary hospital in 2015. Multivariate logistic regression analysis was used to identify the factors associated with the reversal to higher intensity of LST treatment. Results: Primary decision makers were offspring (72.6%), spouse (13.7%), acquaintance (8.9%), and patients (4.8%), in order. While 31.5% of the reversed decisions were made toward higher intensity of LST, 21.9% were made toward lower intensity of LST, and 46.6% were made for each treatment without change of overall code status. The use of inotropic was the most frequently reversed LST treatment (47.5%), followed by CPR (30.6%), intubation (27.4%), ventilator therapy (24.2%), and hemodialysis (17.8%). Patients who had lung diseases (vs. heart diseases), were single, divorced or bereaved (vs. married), and had acquaintance as a primary decision maker (vs. patients themselves) were significantly more likely to reverse the LST decisions to higher intensity of LST treatment. Conclusion: This study demonstrate the complex and turmoil situation of the LST decision making process among older patients with terminal stage of cardiopulmonary disease and suggests the importance of support for patients and families in their LST decision making process."}
+{"text": "Females were more likely than were males to receive a late-stage diagnosis. The highest percentage of late-stage diagnoses was among females in rural areas . The highest percentages of late-stage diagnoses occurred among persons aged 45\u201354 years in both rural and metropolitan areas ; in urban areas, the percentage of late-stage diagnoses was highest among persons aged \u226555 years (43.1%). By transmission category, the percentage of late-stage diagnoses was highest in all areas among males whose infection was attributed to heterosexual contact .Among 14,502 Black persons who received a diagnosis of HIV infection during 2018, a total of 897 (6.2%) lived in a rural area, 1,920 (13.2%) lived in an urban area, and 11,685 (80.6%) lived in a metropolitan area. The percentage of Black persons who received a late  diagnosis of HIV infection was highest in rural areas (25.2%), followed by urban and metropolitan areas   (Supplemhttps://stacks.cdc.gov/view/cdc/102576). Males were less likely than were females to be linked to care, regardless of area . Males aged 45\u201354 years in rural and urban areas with infection attributed to heterosexual contact  and males aged 13\u201324 years in metropolitan areas with infection attributed to heterosexual contact (62.3%) accounted for the lowest percentage of being linked to care compared with persons with other modes of transmission in those areas.Overall, the percentage of Black persons with HIV infection diagnosed during 2018 who were linked to care within 1 month of diagnosis was 76.7% in rural areas, 77.0% in urban areas, and 77.2% in metropolitan areas  (Supplemhttps://stacks.cdc.gov/view/cdc/102576). The percentage of males with viral suppression within 6 months of diagnosis was lower than the percentage among females, regardless of area . By age group and area, the lowest percentage of viral suppression within 6 months of diagnosis was among persons aged 45\u201354 years in rural and urban areas  and persons aged 13\u201334 years in metropolitan areas (62.6%). In rural and urban areas, the lowest percentage of viral suppression within 6 months of diagnosis was among males aged 45\u201354 years with infection attributed to male-to-male sexual contact and to heterosexual contact . In metropolitan areas, the lowest percentage of viral suppression within 6 months of diagnosis was among males aged 13\u201324 years with infection attributed to heterosexual contact (51.7%) and males aged 25\u201334 years with infection attributed to injection drug use (IDU) (45.0%).Overall, the percentage of Black persons aged \u226513 years in rural areas with HIV diagnosed during 2018 who had <200 copies of viral RNA per mL  within 6 months of diagnosis was 59.6% in rural areas, 59.7% in urban areas, and 63.8% in metropolitan areas   diagnosed HIV infections among Black persons in rural areas was a late-stage diagnosis, a percentage that was higher than that among Black persons in urban (21.9%) and metropolitan (19.0%) areas. The percentages of patients linked to care within 1 month of diagnosis were similar in all areas, whereas the percentages of persons with viral suppression within 6 months of diagnosis were lower in rural (59.6%) and urban (59.7%) areas than in metropolitan areas (63.8%). In all areas, the percentages of persons who were linked to care within 1 month of diagnosis and who had viral suppression within 6 months of diagnosis were substantially below the Ending the HIV Epidemic initiative targets of 95%  infection, and access to care and treatment services varies by residence area.During 2018, rural Black persons received a higher percentage of late-stage HIV diagnosis (25.2%) than did those in urban (21.9%) and metropolitan areas (19.0%). Linkage to care within 1 month of diagnosis was similar across geographic areas; however, viral suppression within 6 months of diagnosis was highest in metropolitan areas (63.8%).Early diagnosis and prompt treatment of Black persons with HIV infection, especially in rural areas, are necessary to reduce disparities in HIV care outcomes."}
+{"text": "Neuroradiological studies have greatly improved the knowledge and diagnoses of cerebral palsy with its underlying pathology, types and accompanying changes in brain morphology. However, there is no published study on cerebral palsy neuroimaging patterns in Ethiopia.Retrospective chart and neuroimaging reviews were conducted among pediatric patients, who attended Ayder Comprehensive Specialized Hospital between January 2016 and August 2019, fulfilling the study criteria. The magnetic resonance images and computed tomography scans reviewed by a neuroradiologist and/or pediatric neurologist were included. Data was collected using a structured checklist and analyzed using SPSS statistical software version 22. Results were represented using tables, graphs and images.The median age at neuroimaging was 2 years. There were more males (54.5%) than females (45.5%) with a male: female ratio of 1.2:1. Majority of the patients had magnetic resonance (81.8%) as opposed to computed tomography scans (18.2%). Most of the patients (69.7%) had been born at term with spastic quadriplegia (33.3%) found to be the leading type of cerebral palsy. 30.3% of the patients had normal neuroimaging studies whereas 69.7% had neuroimaging abnormalities. Anomalies included pathologies of the white matter (18.2%), basal ganglia (15.2%), cortex and lobes (27.3%), corpus callosum (6.1%), lateral ventricles (12.1%), cysts (18.2%) and cerebellum (3%), respectively. Other findings were seen in 45.5% of the patients.Severe forms of cerebral palsy (spastic quadriplegia) were most common with majorly cortical and subcortical brain involvement. Cerebral palsy (CP) is a term used to describe a wide spectrum of non-progressive motor disabilities resulting from brain damage at prenatal and/or perinatal periods of development. It is one of the commonest forms of severe disability occurring in childhood especially after preterm birth . The dis: primary neurulation (weeks 3\u20134 of gestation), prosencephalic development (months 2\u20133 of gestation), neuronal proliferation (months 3\u20134 of gestation), neuronal migration (months 3\u20135 of gestation), organization (month 5 of gestation to years), postnatal development and myelination  . Permission to access patients\u2019 files and images was granted by the Ethics Review Committee and the medical director, Ayder Comprehensive Specialized Hospital, Ethiopia. Retrospective chart and neuroimaging review were employed in this study. Thus, consent was not obtained since the data was analyzed anonymously.The data for this study was collected between April 2019 and August 2019. Purposive sampling was undertaken to determine the neuroimaging patterns of CP among pediatric patients attending ACSH between January 2016 and August 2019. Included patients were aged less than 18 years with a clinical diagnosis of CP  for Muscle Strength in at least one limb with presumed central origin of weakness). They also needed to have CT or MRI scans in the hospital\u2019s computerized radiology system having been reviewed by a neuroradiologist and/or pediatric neurologist. An adapted structured checklist was used to extract data from registration books and medical records. Patients with presence of one or more of: history of malignancy, primary neuromuscular disorder, evidence of developmental regression except in cases of CNS infection in infancy, a known genetic syndrome and brain images not found in the hospital\u2019s radiology system or not reviewed by a neuroradiologist or neurologist were excluded. From the above criteria, a total of 33 patients were included in the study.MRI studies included sagittal and axial T1-weighted images, 400-800/ 20-35/ 1\u20132 (TR/ TE/ excitations), and axial T2-weighted images, 2000-3000/ 30-120/ 1\u20132. CT scans consisted of unenhanced and contrast enhanced CT scans with a single detector scanner , using 3mm-thick slices. The images were reviewed by two of the authors with knowledge of the preceding clinical diagnosis of CP but without knowledge of the specific clinical manifestations of each case, thus the review was partially blinded. The neuroimaging studies were anatomically evaluated for developmental or acquired abnormalities. These included the corpus callosum, deep and peripheral white matter, cerebral cortex, basal ganglia/thalami, and brainstem anomalies besides malformations such as the presence of parenchymal cysts, hydrocephalus, and ventricular contour defects.Data was analyzed using IBM SPSS statistical software version 22. Variables studied were: age at imaging, gestation at birth, imaging modality and CT scan or MRI findings.As seen in Among the 6 patients (18.2%) with white matter anomalies, white matter hyperintensities were observed in 3 patients. Diffuse hyperintensities were seen in case 16, deep white matter linear hyperintensities on T2/T2 FLAIR images in case 18 and bilateral frontal and occipital lobe T2 FLAIR white matter hyperintensities in case 32. Focal deep matter subcortical infarcts were also noted in case 1, white matter loss with diffuse hypointensities in case 9 and white matter intervening into the grey matter was found in case 10.4 (12.1%) patients were found to have basal ganglia anomalies. Case 5, who had right-sided spastic hemiplegic CP presented with well-defined hypoechoic lesion over the left caudate nucleus & anterior limb of the internal capsule. Case 19 also had bilateral basal ganglia posterior T2 FLAIR hyperintensities. Findings in the thalamus were seen in cases 19, 29 and 30 in whom bilateral thalamic hyperintensities, partial fusion of thalami inferiorly and bilateral posterior hyperintensity were seen, respectively.Of 11 patients with these anomalies (33.3%), 3 patients had volume loss in their images. Loss of brain parenchyma mainly bi-occipital lobes, volume loss of the right temporal lobe and bilateral frontal lobe volume loss compared to the temporal, parietal and occipital formations observed in cases 22, 23 and 30, respectively. Atrophy was also noted in 2 patients with left fronto-parietal and right frontal atrophy in case 13, and cortical and subcortical atrophy in case 20. Other findings identified include: bilateral frontal lobe hypointensity (case 4), cortical hypodensity with patchy enhancement (case 9), and bilateral cortical band of grey matter with intervening white matter and frontal nodules similar to grey matter (case 10). Case 16 also had bilaterally symmetrical subcortical hyperintensities. Widening of sulci and prominence of gyri over the right cerebral hemisphere , incomplete separation of cerebral hemisphere anteriorly and left middle cerebral artery (MCA) region chronic infarction were observed in cases 23, 29 and 33, respectively.2 (6.1%) of the patients studied had abnormalities of the corpus callosum. These included thinned corpus callosum in case 12 and partial hypoplasia in case 29.Lateral ventricular pathology was also appreciated in 4 (12.1%) of the patients. Dilated lateral ventricles were observed in cases 9 and 28. Rudimentary falx and right occipital horn of the right ventricle were seen in case 29, whereas a deep right occipital horn posteriorly and temporal/frontal minimal increment in CSF spaces including cisterns were noted in case 31.6 out of the 33 patients (18.2%) had cysts. 2 of these had non-pathological cysts, which include: arachnoid cyst (case 7) and left choroid fissure cyst (case 19). Pathological cysts were found in 4 of the patients with right temporal proencephalic cyst (case 14) and dorsal interhemispheric cyst (29). Multiple cystic lesions with ring enhancing lesions over the bilateral cerebral hemispheres were seen in case 28 while cystic changes which follow CSF signal intensity sparing only the posterior fossa structures were observed in case 22.Only one patient (3%) had cerebellar findings with marked paracerebellar atrophy as seen in case 26.rd ventricle with mega cisterna magna in case 22, absent septum pellucidum with squaring of the frontal horns in case 24 as well as 4th ventricle ex-vacuo dilation and dilated CSF cisterns in case 26. Moreover, absent septum pellucidum was seen in case 29 as well and parenchymal volume loss with widening of the interhemispheric fissure and sulci in case 32.Other anomalies were observed in 15 (45.5%) of the images including: minimally increased CSF spaces (case 8), dilated 3rd ventricles (cases 9 and 28), polymicrogyria  in case 10, and periventricular hyperintensities (case 12). Right parietal old hemorrhage (case 14), dilated prevascular spaces on T2 FLAIR (case 16), and remarkable diffusion weighted imaging (DWI), restrictions/ apparent diffusion coefficient (ADC) hypointensities in the MCA territory (case 17) were also seen. Bilateral periventricular white matter linear T2/T2 FLAIR hyperintensities with no restriction and no post contrast enhancement were found in case 18. Increased subarachnoid space and adjacent T2 hyperintensity were observed in case 20, dilatation of 354.5% (18/33) of patients were males with a higher use of MRI 81.8% (27/33). Most of the children in the study had been born at term, 69.7% (23/33). Normal brain scans were seen in 30.3%. (10/33) as opposed to 69.7% abnormal brain scans (23/33) .Among the patients studied, normal brain scans were seen equally in patients with hypotonic and hemiplegic/hemiparetic CP, 12.1% (4/33) each. Abnormal scans were observed mostly in patients with spastic quadriplegia, 33.3% (11/33), hemiplegic CP and unspecified forms, 12.1% (4/33), spastic diplegia, 9.1% (3), choreoathetoid CP 6.1% (2/33), and Monoparetic CP, 3% (1), respectively. .Distribution of brain findings among the CP types was varied. Patients with spastic quadriplegia had the most findings in their brain scans with miscellaneous findings and cortex/lobe anomalies being the majority, 24.2% and 15.2%, respectively .In this study, the median age at neuroimaging was 2 years. The minimum age was 3 months and the maximum age was 15 years. This is in line with Sharma and Dhande  while MoWe also found a higher number of males than females  with a mThere were also more patients who had been born at term in our study , with onWe found that spastic forms of CP were more common than dyskinetic forms with the majority being spastic quadriplegia . PatientThe use of MRI was also higher than CT scan for CP patients in our study. This conforms to an American study conducted by Wu et al.  where moAlmost one-third of the images studied were normal in patients having hypotonic, spastic hemiplegic and spastic quadriplegic CP as seen in Pathologies were classified into white matter anomalies, basal ganglia and thalamus, cortex and lobes, lateral ventricles, cysts, corpus callosum and cerebellar anomalies as well as other findings as seen in Our study revealed cortical and subcortical brain injury as the most common anatomical feature seen in the MRI and CT scan images of pediatric CP patients in ACSH, Mekelle. Spastic quadriplegia was the most occurring form of CP. Brain imaging may help in identifying timing of brain insults and possible CP etiologies in low-income countries like Ethiopia. Therefore, enabling universal brain scanning for CP patients may serve in aiding future creation and implementation of possible preventive interventions for this lifelong disorder.S1 Dataset(SAV)Click here for additional data file."}
+{"text": "The aim of this study was to define histo-morphological stroma characteristics by analyzing stromal components, and to evaluate their impact on local and systemic tumor spread and overall survival in pancreatic ductal adenocarcinoma (PDAC).Patients who underwent oncologic resections with curative intent for PDAC were identified from a prospectively maintained database. Histological specimens were re-evaluated for morphological stroma features as stromal fibers, fibroblast morphology, stroma matrix density, microvessel density and distribution of immune cell populations.A total of 108 patients were identified undergoing curative resection for PDAC in the period from 2011\u20132016. 33 (30.6%) patients showed parallel alignment of stroma fibers while 75 (69.4%) had randomly oriented stroma fibers. As compared to parallel alignment, random orientation of stroma fibers was associated with larger tumor size , nodal positive disease , higher margin positive resection rates  and a trend for higher rates of T3/4 tumors . In univariate analysis, patients with parallel alignment of stroma fibers had improved overall survival rates as compared to patients with random orientation of stroma fibers . The combination of random orientation of stroma fibers and low microvessel density was associated with impaired overall survival rates . A high CD4/CD3 ratio  and high stromal density of CD163 positive cells were associated with reduced overall survival . In multivariable analysis, the combination of random orientation of stroma fibers and low microvessel density , high CD4/CD3 ratio  and high density of CD163 positive cells  remained independent prognostic factors.Alignment of stroma fibers and microvessel density are simple histomorphological features serving as surrogate markers of local tumor progression dissemination and surgical resectability and determine prognosis in PDAC patients. High CD4/CD3 ratio and CD163 positive cell counts determine poor prognosis. Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid malignancies . The majExtensive desmoplasia is a characteristic macro- and microscopical PDAC feature ,5. PDAC in vitro and xenograft models [The main part of data evaluating interaction between PDAC cells, fibroblasts and extracellular matrix is derived from t models ,7. Only t models ,16. AddiThe aim of this study was to perform a morphological analysis of PDAC stroma analyzing stromal matrix, vasculature and stromal cell populations. Furthermore, we intended to define simple histopathological stroma assessment criteria and aim to evaluate the impact of stroma features on patient prognosis.Patients undergoing oncologic resections with curative intent for PDAC were identified from the prospectively maintained database of the department of surgery at the University Hospital Schleswig-Holstein, Campus Luebeck, Germany, a tertiary hospital and high-volume center of pancreatic surgery. Ethics approval was obtained from Luebeck university ethics committee #17-118A). Patients in the study were resected in the period from 2011 to 2016. The following patient baseline and surgical parameters were included for the analysis: Gender, age at date of operation and type of resection (Whipple versus pylorus-preserving PD (PPPD) versus left pancreatic resection versus total pancreatectomy (TPE)). Histopathological parameters included in the analysis were tumor size, T stage, N stage, M stage, grading according to Broders -118A. Pa. First, Immunohistochemistry staining of T cell markers CD3, CD4 and macrophage marker CD163 was performed to identify stromal immune cell populations . The numOverall survival time was defined from surgery until death of any cause.For statistical analysis, IBM SPSS Statistics for Windows, Version 25.0 was used. Continuous and categorical variables were expressed as median/range and absolute/relative frequencies, respectively. Statistical testing was performed by Chi-squared test or Student\u2019s t-test. Correlation analysis was performed using two-sided Spearman rank test. Median overall survival estimates were determined with Kaplan Meier method. Multivariable analysis was performed with cox proportional hazard model for variables. The significance level was set to p < 0.05 (two-sided). All confidence intervals (CI) reported are 95% confidence intervals.A total of 108 patients undergoing oncologic resections for PDAC in the period from 2011 to 2016 were identified, median follow-up was 17.5 months. The median age at operation was 67 years, ranging from 40 to 86. A Whipple procedure was performed in 33 (30.6%) patients, 55 (50.6%) had a pylorus-preserving pancreatoduodenectomy (PPPD), 6 (5.6%) underwent a left pancreatectomy and 14 (13.0%) had a total pancreatectomy.Median tumor size was 3.0 cm, ranging from 0.8 to 9.0 cm. The most frequent T stage was T2 (54.6%). Most patients showed nodal positive disease (68.4%). 6 (5.6%) patients had distant metastases. Most frequent grading was G2 (54.6%). 23 patients (21.3%) had positive resection margins. 33 (30.6%) patients had parallel alignment of stroma fibers while 79 (69.4%) patients showed random orientation of stroma fibers. In 41 patients (37.3%) stromal alignment was heterogeneous within one slide. In these cases, the slide was classified according to the dominant stromal alignment pattern. Only 7 (6.5%) of 41 patients with heterogeneous stromal alignment had mainly parallel stromal fibers while 34 (31.5%) patients showed mainly random orientation of stromal fibers. To determine the accuracy of stromal alignment assessment in H&E slides, we repeated the analysis of stromal fiber alignment after staining for collagen I. 31.8% of the patients were assessed as showing parallel alignment and 68.2% were determined with random orientation of stroma fibers. Consequently, accuracy of stromal fiber assessment in H&E stained slides is sufficient, and further staining of collagen I does not yield additional benefits. Stromal density was high in 62 (57.4%) patients and low in 46 (42.6%) patients. 82 (75.9%) patients had a low fibroblast density while 26 (24.1%) had a high fibroblast density. Fibroblast morphology was round in 52 (48.1%) patients, 56 (51.9%) showed spindle-like fibroblast morphology. Accurate differentiation of round fibroblasts and immune cells in H&E slides may be difficult. After staining for immune cell populations , assessment of fibroblasts morphology was repeated. The identified pattern of fibroblast morphology was changed for only 2 of 108 cases. Mean microvessel density was 10 microvessels / stroma localization. 57 (52.8%) patients showed a lower microvessel density than 10 microvessel/stroma localization, while 51 (47.2%) had a higher microvessel density. 27 (26.4%) patients had a high CD4/CD3 ratio while 53 (50.0%) had a high density of CD163 positive cells. 77 (71.8%) patients had a high density of p53 positive cells. Details of baseline parameters, histopathology and stroma morphology are displayed in In patients with pancreatoduodenectomy, 30 patients had parallel alignment and 58 patients showed random orientation of stromal fibers. For patients with distal pancreatectomy (5 versus 1 patients) and total pancreatectomy (12 versus 2 patients) the rate of patients with random orientation of stromal fibers was higher as compared to patients undergoing pancreatoduodenectomy.High microvessel density was identified in 43 of 88 patients with pancreatoduodenectomy (48.8%). In patients with distal pancreatectomy, the rate of patients with high microvessel density was 2 of 6 (33.3%) while 6 of 14 patients (42.8%) with total pancreatectomy had high microvessel density.Patients with random orientation of stroma fibers showed larger median tumor size . There was a statistical trend for higher T stage in patients with random orientation of stroma fibers . Patients with random orientation of stroma fibers were more likely to be diagnosed with local lymph node metastases  and had higher rates of tumor positive resection margins . Patients with random orientation of stroma fibers and low microvessel density had higher rates of local lymph node metastases as compared to patients not showing these morphological features . Details are depicted in Alignment of stroma fibers was not correlated with CD4/CD3 ratio , density of CD163 positive cells  or density of p53 positive cells .Median overall survival (OS) of all patients was 15.4 months. Details of survival analysis are depicted in The current study systematically evaluated PDAC stroma morphology and defined simple histopathological stroma classification methods. Random orientation of stroma fibers alone results in local tumor progression mirrored by tumor size and higher rates of margin positive resections. A combination of random orientation of stroma fibers and low microvessel density is associated with loco-regional tumor infiltration and qualifies as independent negative prognostic factor. Immune cell infiltrates determine prognosis, and high CD4/CD3 ratio and high counts of CD163 positive tumor-associated macrophages determine prognosis.In 1986, Dvorak postulated that tumors are \"wounds that do not heal\" and outlined similarities between carcinogenesis and granulation processes of healing wounds . The autMorphology of ECM has been increasingly studied over the past years. Stromal alignment studies mainly focused on breast and ovarian cancer . In a moPatients with parallel alignment of stroma fibers had smaller tumors with less frequent lymph node metastasis and higher rates of R0 resections in the current study. It may be speculated that the desmoplastic transformation during carcinogenesis may have been less pronounced in these patients, resulting in a less tumor promoting stroma. Alignment of stroma fibers qualified as prognostic parameter with a considerable difference in overall survival for patients with random orientation of stroma fibers (22 months) in contrast to patients with parallel alignment of stroma fibers (42 months). However, this stroma feature could not be identified as an independent prognostic parameter. Besides alignment of stroma fibers, also the histopathological variables tumor size, N status and R status all associated with alignment of stroma fibers were prognostic factors in univariate analysis. So, as the most probable cause, these three variables were ruled out in multivariate analysis.in vitro model [Stroma density was not associated with tumor progression or overall survival. We recently demonstrated that dense stroma limited PDAC tumor cells growth and induced markers of epithelial-to-mesenchymal transition in an ro model . The onlro model . The autin vitro models transformation from round quiescent fibroblasts to activated spindle-like shaped myofibroblasts as well as fibroblast proliferation can be achieved by co-cultivation with PDAC tumor cells [Fibroblast density and morphology were not associated with prognosis in the current study. In or cells ,5. It maor cells ,32,33. THypoxia is an important feature of PDAC, and overall survival decreases by the extent of hypoxic regions in PDAC tumors. In contrast to other solid malignancies, hypoxia is in particular pronounced in PDAC ,34. PDACTumor-infiltrating lymphocytes are part of the PDAC microenvironment, and were shown to impact tumor progression and even patient prognosis ,40. CD3 Tumor-associated macrophages (TAM) form a subset population of the PDAC immune-microenvironment. These cells are characterized by positive CD163 expression and orchestrate tumor evasion from immune surveillance by anti-inflammatory cytokine signaling . In our In summary, we present a simple morphological classification method for PDAC stroma. Alignment of stroma fibers and microvessel density were associated with tumor progression, locoregional tumor invasion and surgical resectability. Both random orientation of stroma fibers and low microvessel density qualified as independent prognostic parameters. In consequence, the combination of excessive desmoplasia and hypoxia seems to be of major relevance for PDAC patient prognosis. High CD4/CD3 stromal ratios and high infiltrates of tumor-associated macrophages were associated with reduced overall survival. Simple systematic assessment of stroma morphology may help to assess patient prognosis."}
+{"text": "Is there a role for platinum-based treatment in molecularly selected patients with advanced prostate cancer?In a case series of 508 patients, platinum-based therapy was associated with antitumor activity, especially among patients with known DNA repair gene aberrations. In patients with DNA repair gene aberrations, nearly half had a decrease in prostate-specific antigen levels of at least 50% and experienced soft tissue responses.In patients with prostate cancer and DNA repair gene aberrations, platinum-based therapy may be considered a treatment option. This case series characterizes the antitumor activity of platinum-based therapies in men with castration-resistant prostate cancer with or without DNA repair gene alterations. DNA repair gene aberrations occur in 20% to 30% of patients with castration-resistant prostate cancer (CRPC), and some of these aberrations have been associated with sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition platinum-based treatments. However, previous trials assessing platinum-based treatments in patients with CRPC have mostly included a biomarker-unselected population; therefore, efficacy in these patients is unknown.To characterize the antitumor activity of platinum-based therapies in men with CRPC with or without DNA repair gene alterations.In this case series, data from 508 patients with CRPC treated with platinum-based therapy were collected from 25 academic centers from 12 countries worldwide. Patients were grouped by status of DNA repair gene aberrations . Data were collected from January 1986 to December 2018. Data analysis was performed in 2019, with data closure in April 2019.Treatment with platinum-based compounds either as monotherapy or combination therapy.The primary end points were as follows: (1) antitumor activity of platinum-based therapy, defined as a decrease in prostate-specific antigen (PSA) level of at least 50% and/or radiological soft tissue response in patients with measurable disease and (2) the association of response with the presence or absence of DNA repair gene aberrations.P\u2009=\u2009.20). In evaluable patients, soft tissue responses were documented in 28 of 58 patients (48.3%) in cohort 1 and 21 of 67 (31.3%) in cohort 2 (P\u2009=\u2009.07). In the subgroup of 44 patients with BRCA2 gene alterations, PSA level decreases of at least 50% were documented in 23 patients (63.9%) and soft tissue responses in 17 of 34 patients (50.0%) with evaluable disease. In cohort 3, PSA level decreases of at least 50% and soft tissue responses were documented in 81 of 284 patients (28.5%) and 38 of 185 patients (20.5%) with evaluable disease, respectively.A total of 508 men with a median (range) age of 61 (27-88) years were included in this analysis. DNA repair gene aberrations were present in 80 patients , absent in 98 , and not tested in 330 . Of 408 patients who received platinum-based combination therapy, 338 patients (82.8%) received docetaxel, paclitaxel, or etoposide, and 70 (17.2%) received platinum-based combination treatment with another partner. A PSA level decrease of at least 50% was seen in 33 patients (47.1%) in cohort 1 and 26 (36.1%) in cohort 2 (In this study, platinum-based treatment was associated with relevant antitumor activity in a biomarker-positive population of patients with advanced prostate cancer with DNA repair gene aberrations. The findings of this study suggest that platinum-based treatment may be considered an option for these patients. In various cancer types, responses are enhanced in the presence of underlying double-strand DNA repair alterations in the tumor, resulting in synthetic lethality.12 Some of these aberrations, which can either be found as germline or somatic alterations in homologous recombination DNA repair genes or DNA damage checkpoints, have been associated with sensitivity to platinum compounds and/or PARP inhibition in preclinical studies and in clinical trials.17Genomic aberrations that impair DNA repair genes occur at a frequency of up to 20% to 30% in advanced prostate cancer.20 which included a total of 14 patients with metastatic prostate cancer with DNA repair gene aberrations treated with platinum-based chemotherapy, reported encouraging antitumor activity. The recently presented prospective phase 3 PROFOUND study evaluating the PARP-inhibitor olaparib in molecularly selected patients with advanced prostate cancer harboring DNA repair gene aberrations has shown a significant benefit in radiographic progression-free survival and overall response rate for olaparib compared with the sequential use of abiraterone or enzalutamide, thereby strengthening the previously reported findings of the TOPARP study.23 Data from these trials suggest higher antitumor activity in patients with BRCA2 alterations.22Three published case series,Through the collaborative efforts of an international consortium, we identified a large series of patients with castration-resistant prostate cancer (CRPC) who were treated with platinum-based chemotherapy. Using these data, we performed a retrospective analysis to characterize the antitumor activity  of platinum-based therapies (monotherapy and/or combination) in men with CRPC with or without DNA repair gene alterations.reporting guideline for case series was followed.24Patients with biochemically or histologically confirmed advanced prostate cancer  treated with a platinum compound (cisplatin or carboplatin) either as monotherapy or as part of combination chemotherapy were eligible for this analysis. Patients with primary pure small cell carcinoma of the prostate or insufficient data for analysis of the primary end point were excluded. Clinical data from 25 cancer centers from 12 countries worldwide were collected by local investigators. Investigators were encouraged to include all patients eligible at their site for the analysis. Approval of the local ethics committee was obtained before data collection, and informed consent was obtained depending on local regulations. Clinical data were collected locally at each center and assembled in an electronic master database at the coordinating center. Quality control was assured by queries in cases of nonplausible data and inconsistencies; however, no review of the source documentation was performed. The the The primary outcome measure was evaluation of antitumor activity (decrease in PSA level and soft tissue response) to platinum-based therapy (monotherapy and/or combination therapies) and association of response with the presence or absence of DNA repair gene aberrations in patients with advanced prostate cancer. Local assays for assessment of DNA repair gene aberrations on tumor tissue or circulating DNA (ctDNA) were used. DNA repair gene alterations were defined as deleterious variations, such as protein truncating variations, splice site variations, deleterious missense variation, and homozygous deletions, in genes involved in the repair of DNA damage.25 with percentage change from baseline (increase or decrease) at 12 weeks and, separately, the maximal change (increase or decrease) at any time using a waterfall plot. Clinically significant PSA changes are defined as decreases of at least 50%. Soft tissue response was defined according to the Response Evaluation Criteria in the Solid Tumors guidelines version 1.1, with response being defined as an at least 30% decrease in the sum of the longest diameter of all target lesions , taking the baseline sum as reference. Tumor assessments were performed by local investigators. Time on platinum-based treatment was defined as time from start of platinum-based treatment to progression  or death; overall survival (OS) was defined as time from start of platinum-based treatment to death or last contact. Patients not experiencing an event were censored at the time of data cutoff  or at last contact.The decrease in PSA level is reported as per Prostate Cancer Working Group Criteria,P\u2009<\u2009.05, and all statistical tests were 2 sided. All analyses were done in R version 3.5.0 .Continuous data were summarized by median, minimum, and maximum values. Categorical data were presented as absolute numbers and percentages. Time to event end points were assessed by the Kaplan-Meier method and are presented as median and interquartile range (IQR). The number of missing data points is given for all analyses. Frequency counts of categorical data in subgroups were statistically compared by Fisher exact tests. Between subgroup comparisons of numerical data were carried out by Kruskal-Wallis tests. Time to event end points were compared between subgroups using the log-rank test. The a priori significance level was To simultaneously assess several factors that could be associated with OS, we performed a multivariable analysis using a Cox proportional hazards model (SAS version 9.4 [SAS Institute]), including clinically relevant and established prognostic factors, ie, age, presence of visceral metastases, presence or absence of DNA repair gene aberrations, treatment line, and type of platinum-based treatment (combination vs monotherapy) as independent variables.A total of 508 men who were diagnosed with prostate cancer between 1986 and 2018 were included in the study . Overall, 216 (42.5%) had de novo metastatic disease at diagnosis and treated with platinum-based chemotherapy between 1999 and 2019. A total of 178 patients (35.0%) had molecular profiling, with DNA repair gene aberrations detected in 80 patients  and no aberrations detected in 98 patients . In 330 patients (65.0%), tumor genomic profiling was not performed (cohort 3) .P\u2009=\u2009.20), higher rates of de novo metastatic disease  (eTable 1 in the P\u2009=\u2009.06), although none of the differences were statistically significant. Nearly 70% of patients (341 [67.1%]) had received at least 1 prior line of systemic therapy before platinum-based chemotherapy was started. Of note, a high percentage of patients with visceral metastases  at the start of platinum-based therapy were included.Patients with known DNA repair gene aberrations, compared with patients without DNA repair gene aberrations, had higher median (range) PSA levels at diagnosis , ATM , and BRCA1 (3 [3.8%]). These were somatic alterations in 57 patients (71.3%). Germline alterations were found in 23 patients (28.8%) and were mainly BRCA2 (17 [73.9%]), BRCA1 (2 [8.7%]), and ATM (3 [13.0%]). Baseline characteristics depending on type of DNA repair gene aberration are summarized in eTable 2 in the DNA repair gene aberrations were detected by various methods: 27 patients (33.8%), fresh biopsy material; 24 (30.0%), archival tissue; 22 (27.5%), ctDNA; and 7 (8.8%), unknown methods. The most common aberrations included alterations in P\u2009<\u2009.001).Platinum-based therapy was given as first-line CRPC treatment in 167 patients (32.8%), second-line treatment in 145 patients (28.5%), and third-line treatment in 68 patients (13.4%) . The perP\u2009=\u2009.20) (P\u2009=\u2009.07) (A PSA level decrease of at least 50% was seen in 33 patients (47.1%) in cohort 1 vs 26 (36.1%) in cohort 2 (P\u2009=\u2009.20) A. A softP\u2009=\u2009.07) .BRCA2, 23 of 44 [63.9%]; BRCA1, 0 of 3; ATM, 4 of 11 [36.4%]; other, 6 of 21 [28.6%]; P\u2009=\u2009.02) (Patient groups with different DNA repair gene aberrations had different proportions of PSA level decreases of at least 50% (P\u2009=\u2009.02) C; howeveP\u2009=\u2009.02) . In the Median (IQR) treatment duration on platinum-based treatment was 3.0 (1.7-4.6) months without relevant differences between cohorts . Seven pP\u2009=\u2009.20) (Median (IQR) OS from start of platinum-based therapy was lower in patients without DNA repair gene aberrations compared with patients with known DNA repair gene aberrations (9.2 [5.5-19.5] months vs 14.1 [5.7-33.7] months), although this did not reach statistical significance (P\u2009=\u2009.20) ; Table 2BRCA2 alterations, 9.3 (6.5 to 11.0) months in patients with ATM alterations, 4.1 (3.8 to 4.4) months in patients with BRCA1 alterations, and 4.9 (3.6 to not reached) in patients with other alterations (P\u2009=\u2009.04) (P\u2009=\u2009.01)  OS from start of platinum-based therapy was 15.2 (9.9-33.7) months in patients with P\u2009=\u2009.04) . In a muA total of 31 patients (38.8%) with known DNA repair gene aberrations and 11 patients (11.2%) without DNA repair gene aberrations were treated with platinum monotherapy. In patients with known DNA repair gene aberrations, 10 (32.3%) had a PSA level decrease of at least 50%. Soft tissue response was seen in 14 patients (45.2%) in cohort 1 with measurable disease. Response to monotherapy was lower in patients without DNA repair gene aberrations, with PSA level decreases of at least 50% and soft tissue response in 3 patients (27.3%)  with known DNA repair gene aberrations and 87 patients (88.8%) without DNA repair gene aberrations were treated with platinum-based combination therapy. In patients with known DNA repair gene aberrations, 23 (46.9%) had a decrease in PSA level of at least 50%. Soft tissue response was seen in 14 patients (28.6%) with measurable disease. Response to combination therapy was again lower in patients without DNA repair gene aberrations, with PSA level decreases of at least 50% in 23 patients (26.4%) and soft tissue response in 18 (20.7%)  had an overall PSA level decrease of at least 50% in 81 of 284 patients (28.5%)  treatment duration on platinum-based treatment was 3.0 (1.7-4.6) months and comparable with cohorts 1 and 2  and soft tissue responses in 17 patients (38.6%) with evaluable disease. This series is unique because it is among the largest to date that evaluates patients with identified DNA repair gene aberrations who received a platinum-based chemotherapy, very few of whom had previously received treatment with a PARP inhibitor because use of these agents outside of clinical trials was very limited.In this multicenter retrospective analysis of 508 patients with CRPC, most of whom had received at least 1 prior line of therapy, we found encouraging antitumor activity for treatment with platinum-based therapies in the cohort of patients with tumors harboring DNA repair gene aberrations. Although we observed numerically higher rates of PSA level decreases and soft tissue responses in patients with DNA repair gene aberrations compared with those without, there was no statistically significant difference and no OS benefit. In the subgroup of 44 patients with 26 Besides the SPARC trial,5 the studies were mostly small, recruited a molecularly unselected patient population, and demonstrated only moderate antitumor activity. However, a subgroup of patients seemed to derive benefit,3 namely patients with aggressive variant adenocarcinoma of the prostate .27 With emerging data of a meaningful prevalence of somatic and germline DNA repair gene aberrations in patients with advanced prostate cancer28 and activity of PARP inhibitors in these patients,12 interest in platinum-based treatment arose again, with the hypothesis of increased activity in this specific subpopulation of patients with prostate cancer, analogous to data from patients with TNBC. Generally, combination treatment should be recommended; however, monotherapy remains an option, and there is expert consensus from the 2019 advanced prostate cancer consensus conference for carboplatin with target area under the curve (AUC) of 5 to 6 every 3 weeks as a preferred regimen.33Historically, platinum compounds as monotherapy or combination therapy have been widely studied in prostate cancer.21 olaparib at 400 mg and 300 mg was associated with soft tissue response of 24.2% and 16.2% of patients, respectively, and a PSA level decrease of at least 50% in 37.0% and 30.2%, respectively. This is in line with the overall response rate of 43.9% with rucaparib in patients with measurable disease in the phase 2 TRITON trial.29 Even more importantly, the PROFOUND trial, evaluating olaparib vs physician\u2019s choice of enzalutamide or abiraterone in patients with CRPC and known DNA repair gene aberrations progressing on prior new hormonal agent, demonstrated a median OS of 18.5 months with olaparib in the total population, and an objective response rate of 33% was reported for patients with BRCA1, BRCA2, or ATM alterations.23 Olaparib and rucaparib were approved by the US Food and Drug Administration in May 2020 for patients with advanced prostate cancer and germline or somatic homologous recombination repair gene mutations (rucaparib only for BRCA1 or BRCA2).Response to platinum-based monotherapy in patients with DNA repair gene aberrations in our cohort was comparable with the recently presented trials of PARP monotherapy. In the phase 2 TOPARP-B trial assessing 2 different dosing levels of olaparib in patients with DNA repair alterations,30 presented the results of a prospective cohort study investigating the association of germline DNA repair gene aberrations with CRPC outcomes. In their cohort, response to taxanes was not different between variation carriers and noncarriers; however, duration of response was shorter in carriers, and treatment sequencing seemed to be of importance.31 Therefore, activity of the taxane component has to be taken into some account when interpreting our efficacy data in patients receiving combination treatment.Response to platinum-based combination treatment in our cohort was more favorable than platinum-based monotherapy, and in most cases, a taxane was chosen as the combination partner, which represents the current standard-of-care chemotherapy in the unselected advanced prostate cancer population. However, it seems that in our data set monotherapy was more often used in patients with known DNA repair gene aberrations, whereas in patients without alterations or unknown molecular status, combination therapy was preferred. Taxanes are widely used in advanced prostate cancer in different treatment settings and the combination of carboplatin and paclitaxel as first-line, second-line, or third-line chemotherapy in patients with CRPC. In 2019, Castro et alBRCA2 alterations was encouraging. These results are in line with the PROFOUND results, in which treatment benefit was more pronounced in patients with BRCA1, BRCA2, and ATM alterations compared with alterations in other gene alterations.22 In the exploratory analysis of gene-by-gene radiographic progression-free survival, benefit in patients with BRCA1 and ATM alterations was less pronounced compared with patients with BRCA2 alterations. In the TRITON phase 2 trial, evaluating rucaparib in patients with DNA repair gene aberrations, radiographic and PSA responses were observed in only 2 of 19 patients (10.5%) with exclusively ATM alterations.32 The antitumor activity of platinum compounds in our small cohort of 12 patients with ATM alterations is noteworthy. Overall, different DNA repair gene aberrations are most likely distinct entities with varying responses to platinum as well as PARP inhibition; therefore, they cannot be collectively addressed. More research with prospective trials in molecular subgroups is needed to better characterize which patients might derive benefit.Our results showed consistently higher response rates of platinum-based treatment in molecularly selected patients, even though these patients often received platinum-based monotherapy, which seems to be less active than combination therapy overall. Subgroups for specific types of DNA repair gene aberrations were too small to draw any definitive conclusions, but the response rate (PSA decrease and objective response rate) in patients with Importantly, the activity of platinum-based treatment was also seen in the unselected cohort 3 . This population is possibly most reflective of the general CRPC population seen in many centers around the world, where testing for DNA repair gene aberrations may not be available in daily clinical practice.37Our analysis has several limitations, including the retrospective design and data collection, including missing data in a subset of patients. Furthermore, even though quality control was assured by the coordinating center by queries in the case of nonplausible or inconsistent data, no formal review process of the source documentation of each individual contributing center was performed. Also, there was no control of patients excluded from the database on the center level. The bias was minimized by including all patients treated with a platinum-based chemotherapy and not only patients with known DNA repair gene alteration. Radiographic responses  were assessed retrospectively by local investigators. Patient selection is also an important limitation because the use of a platinum-based chemotherapy, especially in the first-line CRPC setting, could reflect the availability of treatment options; clinical factors, such as the high rate of de novo metastatic disease; and the presence of visceral metastases and/or molecular features. DNA repair gene aberrations were assessed by local assays and were not standardized; therefore, the number of genes tested differed by center. Many patients received platinum-taxane combination treatment and the contribution of taxane and platinum to the response cannot be measured separately. The high number of first-line platinum-based combination treatments suggests that patients with aggressive features were included; of note, we excluded patients with de novo pure small cell carcinoma from the analysis. Molecular profiling was performed in only 178 patients, of whom 80 had a defect (cohort 1) and 98 patients did not (cohort 2). However, the remaining 330 patients (cohort 3) most likely represent a mixed population, including perhaps some patients with DNA repair gene aberrations, and therefore, the results of this cohort have to be interpreted with caution. Currently, several prospective phase 2 trials (randomized and nonrandomized) evaluating carboplatin alone or in combination with docetaxel in molecularly selected patients with CRPC are recruiting.In this multicenter international case series, platinum-based treatment was associated with promising activity in a biomarker-preselected population of patients with CRPC and DNA repair gene aberrations. These results need prospective validation, which hopefully will be provided from the currently recruiting trials in molecularly selected prostate cancer populations. Based on our analysis, platinum-containing therapy should be considered in patients with DNA repair gene aberrations, especially if access to a PARP inhibitor is not available."}
+{"text": "Additional anatomic features present on teeth are called non-metric dental traits. Carabelli\u2019s cusp and shovelling are such traits which are mostly evaluated for identification of ethnicity. The present study aims to determine the prevalence of Carabelli\u2019s cusp and shovelling among Indo-Nepalese and Tibeto-Nepalese ethnic group.A descriptive cross-sectional study was conducted in a tertiary hospital from March 22 to June 22 2019 after obtaining ethical approval from the institutional review committee. The study was conducted among 274 patients and convenient sampling method was applied. Data were analyzed by the help of Statistical Package for Social Sciences version 21.Among 274 cases, 153 (55.84%) cases were Indo-Nepalese and 121 (44.16%) were Tibeto-Nepalese. Carabelli\u2019s cusp (16/26) was noticed in 87 (56.86%) of Indo-Nepalese and 45 (37.19%) of Tibeto-Nepalese. Shovelling  was present in 47 (30.71%) Indo-Nepalese and 79 (65.28%) of Tibeto-Nepalese. Further, Carabelli\u2019s cusp (16/26) was found in 77 (53.10%) females and 55 (55.12%) males. Shovelling was present in 75 (51.72%) females and 51 (39.53%) males. Bilateralism with respect to Carabelli\u2019s cusp was present in 82 (62.2%) cases. Presence of bilateral shovelling on upper central incisors and lateral central incisors were among 117 (94.35%) and 56 (91.80%) respectively.Carabelli\u2019s cusps are frequently found in Indo-Nepalese ethnic group and shovelling of teeth most commonly present in Tibeto-Nepalese population. Further, bilaterism for shovelling of teeth is more common than bilaterism for cusp of Carabelli. Due to their stability and capacity to withstand adverse environment, these traits have been widely applied as a study purpose in forensic anthropology.The present study aims to determine the prevalence of dental morphological traits in both the ethnic groups of western hilly region of Nepal.The descriptive cross sectional study was carried out in the Department of Dentistry, Lumbini Medical College Teaching Hospital Palpa, Nepal from March 22 to June 22 2019. The study was carried out after obtaining ethical approval from the Institutional Review Committee (IRC-LMC 20A/019). Sample size was calculated by applying formula:2 \u00d7 p \u00d7 q/e2n= Zn= Sample sizeZ=1.645 at Confidence Interval, 90%7p= prevalence in previous similar studies (63%)e= margin of error= 5%where,Calculated sample size was 252 and then the study was conducted in 274 patients  of age 14 years and above attending OPD in dental department at Lumbini Medical College Teaching Hospital, Palpa. Convenient sampling method was applied.Patients with fully erupted permanent first and second molars and all upper permanent incisors were included and the patients having history of cross ethnicity, having restored, carious and missing first and second molars, upper incisors of any side were excluded from the study.An informed consent was taken prior to examination. Ethnicity was determined based on history of inhabitant, community, homeland and language. The palatal surface of mesio-palatal cusp of left and right first upper molars  of the subjects were evaluated for cusp of Carabelli. The shovel trait was evaluated in upper incisors . Teeth were examined using mouth mirror and dental probe.Data were analyzed by the help of Statistical Programme for Social Sciences (SPSS) version 21.Presence of Carabelli\u2019s cusp on either of the upper first molar in 6fg Indo-Nepalese ethnic group was 87 (56.86%) in numbers while in 66 (43.14%) cases Carabelli\u2019s cusp was absent. Among Tibeto-Nepalese ethnic group, Carabelli\u2019s cusp was found on 45 (37.19%) patients and absent in 76 (62.81%) patients. Likewise, the numbers of Indo-Nepalese population in whom shovelling was present on either of upper central and lateral incisors was 47 (30.71%) and in 106 (69.29%) it was absent. Similarly, in Tibeto-Nepalese ethnic group shovelling was present in 79 (65.28%) of cases while in 42 (34.72%) cases shovelling was absent. The cusp of Carabelli\u2019s was more frequently found on Indo-Nepalese population in comparison to the Tibeto-Nepalese population. Likewise, shovelling was significantly high on Tibeto-Nepalese populations .Carabelli\u2019s cusp on either of upper first molar was found in 77 (53.10%) females and 55 (55.12%) males while absent in 68 (46.89%) females and 74 (44.88%) males. Shovelling on either of upper central and lateral incisors was observed in 75 (51.72%) females and 51 (39.53%) males.Based on ethnicity, Carabelli\u2019s cusp was present in 50 (64.93%) Indo-Nepalese females and 27 (35.06%) Tibeto-Nepalese females. Likewise, 37 (67.27%) Indo-Nepalese males have cusp of Carabelli on either of first molar and 18 (32.77%) Tibeto-Nepalese have the same. Shovelling was present in 45 (60%) of Tibeto-Nepalese females and 30 (40%) of Indo-Nepalese females. In case of males, 34 (66.66%) of Tibeto-Nepalese and 17 (33.34%) Indo-Nepalese have shovelling on upper incisors .Bilateral presence of Carabelli\u2019s cusp was observed in 82 (62.12%) cases while in 50 (37.88%) cases there was unilateral presence of Carabelli\u2019s cusp. Likewise, presence of bilateral shovelling on upper central incisor was observed in 117 (94.35%) and in 7 (5.65%) cases there was unilaterism of shovelling. For upper lateral incisor, bilaterism was found on 56 (91.80%) cases and unilaterism was found on 5 (8.2%) cases .9 This study aims to find out prevalence of Carabelli\u2019s cusp and shovelling among the population of above mentioned group residing in western hilly region.Evaluation of non-metric dental traits can be applied for identification of ethnic group as there is specific prevalence of these traits among particular ethnic group. Nepal is one of the countries having inhabitants of multi-ethnic population. Among them most of the population living in western part of hilly region fall in Indo-Nepalese ethnicity and Tibeto-Nepalese ethnicity. Indo-Nepalese ethnic group comprises of population living at more fertile lower hills, river valleys and Terai plains adjoining boundary of India. The Tibeto-Nepalese ethnic group represents the community occupying the higher hills from west to east. There are numerous studies conducted to differentiate the Mongoloid and Caucasian ethnicity based on presence of cusp of Carabelli and shovel shaped incisors, but only few works have been done previously among the Nepalese population.10 Sadatullah S et al. observed Carabelli\u2019s cusp on 41.7% of Saudi Population.11 A study conducted on Nepalese population by Subedi et al. showed presence of Carabelli trait on 68.3%.7In this study, among 274 individuals Carabelli\u2019s cusp on upper first molar was observed in 48.2% and shovelling on upper incisors was found on 46% individuals. Study done by M kirtigha et al. on Indian population reported 40.5% of subjects had cusp of Carabelli on first molar and 68.2% had shovelling on upper central incisors.8 Study done by Kharat DU et al. showed shovelling range of 20-25% in population of Sudan and Egypt.12 A study by Srivastava et al. showed only 8% Tamil population having shovelling.13Based on ethnicity, cusp of Carabelli was found on 56.86% of Indo-Nepalese when compared to the Tibeto-Nepalese where it was present on 37.19%. Similarly, shovelling in upper incisors was found on 65.28% of Tibeto-Nepalese population and in 30.71% of Indo-Nepalese population. So, this study reveals high percentage of Carabelli\u2019s cusp in Indo-Nepalese population and more prevalence of shovelling on Tibeto-Nepalese population. This study is consistent with the study where presence of shovelling was higher in Mongolids.14 Subedi et al. presented similar observation on Nepalese population.7 But this study showed Indo-Nepalese ethnic females have higher prevalence of Carabelli\u2019s cusp and Tibeto-Nepalese females have higher prevalence of shovelling with comparison to their male counterparts.Overall sex wise distribution of cusp of Carabelli and shovelling shows no significant sexual dimorphism. This finding is similar to study conducted by Talabani R et al. in Iraq.7 A Nigerian study showed bilaterism of 70.71% with respect to upper first molar.15 Shethri SA reported it to be 82.2% in Saudi population.16 Our findings shows 94.35% bilaterism of shovelling with respect to upper central incisor and 91.80% with respect to lateral central incisors suggesting shovelling has higher prevalence of shovelling than cusp of Carabelli in Nepalese population.In present study bilateral distribution of Carabelli\u2019s cusp in upper first molar is 62.12%. Subedi et al. reported 73.7% in Nepalese population.In this study only the presence of selected non-metric dental traits namely Carabelli\u2019s cusp and shovelling were observed and again those observations were limited to selected teeth. For Carabelli\u2019s cusp only upper first molars were evaluated and for shovelling only upper incisors were evaluated based on frequency of their presence. So, further studies among various ethnic groups with respect to various non-metric traits are necessary for validation of use of non-metric dental traits in determining the ethnic identification. Results from our studies can be applied to the population around Palpa district region.Carabelli\u2019s cusps are frequently found in Indo-Nepalese ethnic group and shovelling of teeth most commonly present in Tibeto-Nepalese population. Further, bilaterism for shovelling of teeth is more common than bilaterism for cusp of Carabelli.None."}
+{"text": "Background: Transient ischemic attack (TIA) and minor stroke (TIAMS) are risk factors for stroke recurrence. Some TIAMS may be preventable by appropriate primary prevention. We aimed to recruit \u201cpossible-TIAMS\u201d patients in the INternational comparison of Systems of care and patient outcomes In minor Stroke and TIA (INSIST) study.Methods: A prospective inception cohort study performed across 16 Hunter\u2013Manning region, Australia, general practices in the catchment of one secondary-care acute neurovascular clinic. Possible-TIAMS patients were recruited from August 2012 to August 2016. We describe the baseline demographics, risk factors and pre-event medications of participating patients.Results: There were 613 participants , and 604 (99%) were Caucasian. Hypertension was the most common risk factor (69%) followed by hyperlipidemia (52%), diabetes mellitus (17%), atrial fibrillation (AF) (17%), prior TIA (13%) or stroke (10%). Eighty-nine (36%) of the 249 participants taking antiplatelet therapy had no known history of cardiovascular morbidity. Of 102 participants with known AF, 91 (89%) had a CHA2DS2-VASc score \u2265 2 but only 47 (46%) were taking anticoagulation therapy. Among 304 participants taking an antiplatelet or anticoagulant agent, 30 (10%) had stopped taking these in the month prior to the index event.Conclusion: This study provides the first contemporary data on TIAMS or TIAMS-mimics in Australia. Community and health provider education is required to address the under-use of anticoagulation therapy in patients with known AF, possibly inappropriate use of antiplatelet therapy and possibly inappropriate discontinuation of antiplatelet or anticoagulation therapy. Transient ischemic attack and minor stroke (TIAMS) account for ~40% of all cerebral ischemic events , 2 and cIn the INternational comparison of Systems of care and patient outcomes In minor Stroke and Tia (INSIST) study , we recrThe rationale and methods of the INSIST study have been previously reported . PatientIn this study, TIAMS was ascertained using multiple overlapping methods; primarily general practice records but also from hospital emergency departments, after-hours GP services, hospital inpatient admissions and discharges and ANVC attendance at John Hunter Hospital . All patDuring this study, there were 1,363 patients where TIAMS was considered a possible diagnosis whereby 643 consented to participate (response rate 47%), and 613  completed the baseline interview. Among 613 participants, 298 were adjudicated as TIAMS of whom 175 (29%) had TIA and 123 (20%) had minor stroke. Prior to the index event, 550 (90%) participants were functionally independent .Participants were somewhat older , and more frequently had focal neurological symptoms, compared to non-participants . Most paIn terms of vascular risk factors, 326 (53%) had never smoked tobacco, 251 (41%) were ex-smokers and 36 (5.9%) were current smokers . The medHypertension was the most common  risk factor, followed by hyperlipidemia , diabetes mellitus , atrial fibrillation (AF) , previous TIA  and previous stroke  . At the Two hundred and thirty-one participants (38%) had at least one known cardiovascular morbidity  at the time of the event, of whom 158 (68%) were taking an antiplatelet agent, 33 (14%) were taking an anticoagulation agent, including 28 with AF. 89 (36%) of the 249 people taking antiplatelet therapy had no known history of cardiovascular morbidity. Among these 89 patients, 19 (21%) had a history of \u201cfunny turn\u201d , 7 (7.9%) had an AF history and 5 (5.6%) had both history of a funny turn and AF. Of these 12 participants with AF, six had a CHA2DS2-VASc score \u22652.We found that 56 of 613 (9.1%) participants were taking an anticoagulant agent at the time of the event, 45 (7.3%) warfarin and 11 (1.8%) a non-vitamin K antagonist oral anticoagulant (NOAC). In patients with a known diagnosis of AF, 47 (46%) were taking an anticoagulant despite 91 (89%) having a CHA2DS2-VASc score \u2265 2. Among 304 participants taking an antiplatelet or anticoagulant agent, 30 (10%) had stopped taking in the month prior to the index event. Anti-platelet or anti-coagulant medications were stopped in preparation for an invasive procedure in 14 (47%), by the participant on their own volition in 9 (30%), because the participant forgot to take the medication in 4 (13%), and because of bleeding in 1 (3.3%). 227 (37%) participants were taking a statin (11% at recommended maximum dose) and 394 (64%) were taking antihypertensive agents.The diagnosis of TIAMS and its management are complex, This study provides a comprehensive and contemporary description of \u201cpossible-TIAMS\u201d patients who have engaged with medical care.All but nine participants were Caucasian, which is in stark contrast to the situation in Auckland, New Zealand where 78% of TIA patients were of European origin, 11% Maori/Pacific and 10% Asian/Other . In our Our study population was of relatively lower socioeconomic status compared to the distribution in the HNECCPHN population (IRSD decile 6 was the most common (42%) followed by decile 7 (32%) reported from the Australian Census 2016) . The proAbout one third of patients were taking antiplatelet therapy (38%) prior to the index event. This likely reflects the prior history of vascular disease. However, many of the participants were taking antiplatelet agents without an apparent indication. This finding of possible inappropriate prescription of antiplatelet agents is consistent with previous studies , 19. AntThis study provides evidence of a clear need for optimization of antiplatelet and anticoagulation therapy in patients with established vascular disease and AF. In particular, GPs should be encouraged to calculate CHA2DS2-VASc scores and consider the need for anticoagulation in patients presenting with AF. Presentation with possible-TIAMS provides a key opportunity to start anticoagulantion therapy if appropriate based on risk stratification and bleeding risk. The finding that antiplatelet or anticoagulation therapy had been stopped in the month prior to the index event in many patients is also a cause for concern. This highlights a need for GPs to carefully consider the potential risks and benefits when considering cessation of anticoagulation or antiplatelet therapy, and the need to promptly reinstitute therapy as soon as it is safe after temporary discontinuation.The prevalence of statin (37%) and antihypertensive therapy (64%) used in the study population seems modest given prevalence of known hyperlipidaemia (52%) and hypertension (69%), as well as the prevalence of diabetes mellitus (17%) and previous stroke (13%). In an absolute cardiovascular risk (ACVR) analysis of a subgroup participating early in the INSIST study, 72% of participants in which ACVR could be calculated had high or moderate ACVR . ConsideThis study has a number of strengths. It is a comprehensive community-based study of TIAMS patients engaging with health systems at any level that used multiple overlapping case ascertainment methods for possible TIAMS. The study also has a number of limitations. There was a modest response or consent rate of 47%. This rate is typical of declining response rates for cohort studies . We did This study provides the first contemporary data on TIAMS or TIAMS-mimics in Australia. Worryingly, we found under-use of anticoagulation therapy in patients with known AF prior to the index event and possibly inappropriate use of antiplatelet therapy. Community and health provider education is required to address the under-use of anticoagulation therapy in patients and possibly inappropriate discontinuation of antiplatelet or anticoagulation therapy.All datasets generated for this study are included in the article/The studies involving human participants were reviewed and approved by Hunter New England Human Research Ethics Committee (The Reference No. is 12/04/18/4.02). The patients/participants provided their written informed consent to participate in this study.Study design: CL, PM, DL, and DQ. Data collection: DQ, HZ, CG-E, AD, NN, and MS. Data analysis: PM, DQ, and ST. Writing: ST, PM, and CL. Manuscript revision: DL, JV, HD, PB, NS, DC, and VF. All contributed for writing and revision: DL, PB, and PR.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "This case series reports a systematic assessment of deep vein thrombosis among patients in an intensive care unit in France with severe coronavirus disease 2019 (COVID-19). High dimerized plasmin fragment D (D-dimer) levels and procoagulant changes in coagulation pathways were reported among patients with severe COVID-19.3 An elevated rate of venous and arterial thrombotic events associated with COVID-19 infection has also been reported.5 This case series reports a systematic assessment of deep vein thrombosis among patients in an intensive care unit (ICU) in France with severe COVID-19.Severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2) was identified as a new coronavirus causing pneumonia and acute respiratory distress syndrome. It has become a pandemic, spreading particularly quickly across Europe and the US. Most deaths are related to severe acute respiratory distress syndrome, but other organ failures, such as acute kidney failure and acute cardiac injury, seem also related to the disease.STROBE) reporting guideline. Patients with severe COVID-19 pneumonia were admitted to our ICU located in the suburban Paris area from mid-March 2020 to the beginning of April 2020. All patients had acute respiratory distress syndrome according to the Berlin definition and required mechanical ventilation.This case series was approved by the ethical committee of the Centre Cardiologique du Nord, which granted a waiver of consent because the research presented no risk of harm and required no procedures for which consent is normally required outside a research context. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology  and Excel 365 (Microsoft Corp). Statistical significance was set at A total of 34 consecutive patients were included in this study. COVID-19 diagnosis was confirmed with polymerase chain reaction on nasopharyngeal swabs of 26 patients (76%); 8 patients (24%) had a negative result on polymerase chain reaction but had a typical pattern of COVID-19 pneumonia on chest computed tomography scan. Mean (SD) age was 62.2 (8.6) years, and 25 patients (78%) were men. Major comorbidities were diabetes (15 [44%]), hypertension (13 [38%]), and obesity . Overall, 26 patients (76%) required norepinephrine at admission, 16 (47%) required prone positioning, and 4 (12%) required venovenous extracorporeal membrane oxygenation . Only 1 3 our population had high levels of D-dimer , fibrinogen  and C-reactive protein . Prothrombin activity  and platelet count  were normal (Deep vein thrombosis was found in 22 patients (65%) at admission and in 27 patients (79%) when the venous ultrasonograms performed 48 hours after ICU admission were included . Eighteee normal .6 Frequent venous and arterial thrombotic events have been reported, with rates from 27% to 69% of peripheral venous thromboembolism and up to 23% of pulmonary embolism.5 The occurrence of pulmonary embolism might be favored by deep vein thrombosis. The main limitations of this study were its monocentric nature and the relatively small size of our cohort. In view of the high rate  of deep vein thrombosis reported in this study, prognosis might be improved with early detection and a prompt start of anticoagulant therapy. Despite anticoagulant prophylaxis, 15% of our patients developed deep vein thrombosis only 2 days after ICU admission. Systematic anticoagulant therapy for all ICU patients with COVID-19 should be assessed.Mortality of patients with COVID-19 admitted to ICUs has been reported to be high, at 50%."}
+{"text": "Pseudomonas aeruginosa is considered as foremost cause of hospital acquired infections due to its innate and plasmid mediated resistance to multiple antibiotics making it a multi drug resistant (MDR) pathogen. Biofilm formation is a pathogenic mechanism harbored by this pathogen which further elevates its resistance to antibiotics and host defense system. The aim of the present study was to evaluate the biofilm forming potential and distribution of pslA gene in multi drug resistant Pseudomonas aeruginosa isolates obtained from different clinical samples. A total of 200 different clinical samples were collected after obtaining written consent from the patients. The samples were subjected to isolation and identification of P. aeruginosa by standard microbiological procedures. Confirmation of isolates was done by polymerase chain reaction targeting oprL gene. Kirby Bauer method was performed for detection of MDR isolates. Congo red agar (CRA) test and Microtiter plate assay (MPA) for observing the biofilm forming ability and amplification of pslA gene was also performed on MDR isolates. The results showed that from 200 samples 52 (26 %) were P. aeruginosa and among them 20 (38.46 %) were MDR isolates. The CRA showed 23 (44.23 %) while MPA detected 49 (94.23 %) isolates as biofilm producers while all the MDR isolates showed biofilm formation by MPA method. The pslA gene was detected in all biofilm forming isolates while 90 % in MDR P. aeruginosa. It was concluded that biofilm forming P. aeruginosa are more resistant to tested antibiotics and biofilm formation is strongly associated with presence of pslA gene.  Pseudomonas aeruginosa is a threatening and emerging public health problem throughout the world particularly in developing countries. It is still a main cause of mortality and morbidity in humans . Pseudoal., 2017).P. aeruginosa both in acute as well as chronic infection in clinical settings  produced by their own self. These EPS are mostly exopolysaccharides, extracellular deoxyribonucleic acid and proteins . Biofilal., 2007). The baal., 2007). There al., 2011).Pseudomonas aeruginosa from clinical samples.The biofilm production retards the antimicrobial therapy against bacteria because the biofilm develops a barrier which reduces the drug penetration leading to treatment failure as well as hindering the recognition of the microorganisms by immune system . In vieA total (n=200) clinical samples were collected aseptically from different healthcare centers of Punjab, Pakistan consisting of burn wounds, surgical wounds, sputum, urine and blood samples which were shifted to laboratory as soon as possible. The samples were collected during January 2018 to December 2018 by obtaining the written consent from the patients after explaining them the purpose and objectives of the study.This study was approved by Institutional Ethics Review Committee of Government College University Faisalabad, Pakistan under code GCUF/ERC/18/03B, and the samples were collected in accordance with international safety rules and ethical standards.The samples were streaked on the plates containing Pseudomonas cetrimide agar  and incubated at 37 \u00b0C overnight aerobically. Isolates were identified on the basis of their colony morphology, cultural and biochemical characteristics .Pseudomonas aeruginosa were confirmed by Polymerase chain reaction (PCR) using specific primer set targeting oprL gene (oprL-F 5'-ATGGAAATGCTG AAATTCGGC-3') and (oprL-R 5'-CTTCTTCAGCTCGACGCGACG-3') with the product size of 504 bp. First the DNA of all the bacterial isolates was extracted with the help of GeneJET Genomic DNA Purification Kit . The DNA was subjected to PCR using the conditions as described by Douraghi et al.   based oin vitro using Congo red agar and microtiter plate assay. The CRA preparation, inoculation and observation of results were done as described by Freeman et al. . BrieflIn microtiter plate assay, overnight cultures were adjusted and diluted using tryptic soy broth (100 folds). Aliquots (250 \u03bcL) of each isolate suspension were then inoculated into a flat-bottom 96-well plate and incubated for 22-24 hours at 37 \u00b0C. Each well was washed twice with 250 \u03bcL of sterile saline followed by shaking to remove poorly adherent or non-adherent bacteria. The plates were then dried using heat which favors the fixation of biofilm. Each well was then stained with 250 \u03bcL of crystal violet (0.1 %) for 15-20 mins. After washing and drying of plates, the dye bound to the adherent cells in each well was dissolved with 250 \u03bcL of 50 % acetone. The optical density (OD) of the biofilms was measured at 594 nm with ELISA reader  as described by Stepanovic et al. (2000). pslA gene was done with primers:  and  generating an amplicon of 119 bp  was used as positive control for the pslA gene. The PCR reaction mixture was prepared (25 \u03bcL) and following thermal conditions were applied. The preliminary denaturation was performed at 94 \u00b0C for 5 minutes. Then 35 cycles were performed . The final extension was done for 10 minutes at 72 \u00b0C in a thermocycler device .The PCR amplification of ung, 2014). P. aerPseudomonas aeruginosa was identified from (n=52) samples on the basis of biochemical tests and PCR method making the cumulative prevalence of 26 %. The distribution of P. aeruginosa isolates on the basis of type of samples was elaborated in Table 1In the present study, a total of 200 clinical samples were collected from different hospitals of Punjab, Pakistan. The results showed that P. aeruginosa were subjected to antimicrobial susceptibility testing and highest resistance was found against Ceftriaxone (94.23 %), Meropenem (92.30 %), Imipenem (90.38 %) and Aztreonam (84.61 %) while the isolates were found most susceptible to Amikacin (38.46 %) and Ciprofloxacin (28.84 %). Among all the isolates, 20 (38.46 %) were found multi drug resistant (MDR) Pseudomonas aeruginosa as shown in Table 2All the isolates of Pseudomonas aeruginosa followed by strong biofilm producers (36.50 %). All the (n=20) MDR P. aeruginosa isolates showed biofilm formation by MPA as shown in Table 3pslA gene was detected in all biofilm forming isolates while (18/20) 90 % in MDR Pseudomonas aeruginosa isolates with polymerase chain reaction showing a 119 bp band on agarose gel as shown in Figure 1On the basis of Congo red agar test 23 (44.23 %) samples showed biofilm forming potential while when the Microtiter plate assay (MPA) was applied 49 (94.23 %) samples showed variable degree of biofilm production. Highest percentage was found (40.30 %) of moderate biofilm producing Pseudomonas aeruginosa is an opportunistic pathogen having greatest concern for infections in various types of wounds, immunocompromised patients, and intensive-care units' patients (ICUs)  found positive for Pseudomonas aeruginosa with most prominent 38.63 % in burn wound samples. The finding of our research was very close to the previous observations (20.05 %) by Samad et al.  in Peshal. (2017) in Islaal. (2017) having al. (2014), Qureshhowed 52  % found al. (2014) are conal., 2017).P. aeruginosa isolates towards Ceftriaxone (94.23 %), Meropenem (92.30 %), Imipenem (90.38 %) and Aztreonam (84.61 %) which are in accordance with the findings of Qureshi et al. (2018[Pseudomonas aeruginosa isolates 20 (38.46 %) were detected multi drug resistant (MDR). The results are lower than the observations of Maita and Boonbumrung  refers to bacteria which show resistance to minimum two specific representatives of minimum two classes of antibiotics . The real. (2018) and Ijaal. (2018) in Pakial. (2018) from Chal. (2018) from Frung (2014) with 51ung (2014) with 58P. aeruginosa were used and compared. It was observed that Congo red agar (CRA) test detected 23 (44.23 %) while the Microtiter plate assay (MPA) detected 49 (94.23 %) isolates as biofilm producers. The efficacy of MPA is better than CRA was also reported by Lima et al.  in Brazal. (2017) in PakiPseudomonas aeruginosa isolates, 49 (94.23 %) were detected to be positive for pslA gene and from the (n=49) biofilm forming Pseudomonas aeruginosa, all the isolates were found positive for pslA gene. Similarly among the 20 MDR P. aeruginosa, all were found positive for biofilm production by MPA but 18 (90 %) were found positive for pslA gene. Very similar results were previously obtained by Heydari and Eftekhar  al. (2014) showed al. (2014) showed al. (2005), Ma et al. (2005) and Houal. (2005), but in, 49 94.2 % were dP. aeruginosa showed biofilm forming potential and 90 % of them were positive for pslA gene. This presence of MDR strains along with biofilm formation is depicting a lethal combination of bacterial armory that poses a serious threat for public health.In conclusion, all the MDR isolates of This study was partially funded by National Research Program for Universities (NRPU) of higher education Commission (HEC), Pakistan (5680/Punjab/NRPU/ R&D/HEC/2016).The authors declare that they have no conflict of interest."}
+{"text": "To the Editor\u2014Coronavirus disease 2019 (COVID-19) is an illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a recently emerged novel virus that is currently spreading globally.1 Its clinical presentation varies from mild, sometimes unrecognized, respiratory symptoms to overwhelming pneumonia and multiple-organ failure leading to death. The virus is probably mainly transmitted via respiratory droplets and can survive on surfaces for several days. The incubation period varies between 4 and 14 days, and patients can be contagious before the onset of symptoms.2 The duration of infectivity is uncertain, with one study reporting that 90% of mild cases had a negative real-time polymerase chain reaction (PCR) test by day 10.3On March 13, 2020, the first outpatient with COVID-19 was admitted to our hospital, a 1,182-bed acute- and tertiary-care hospital in Belgium consisting of 3 separate campuses. In week 13 (March 16\u201322), we observed that 4 patients who had been hospitalized for other reasons presented with COVID-19 . From this day forward, all healthcare workers were obligated to wear surgical masks as personal protective equipment during patient contact, regardless of their own symptoms. Additionally, we created physically separated wards for patients with or without COVID-19.The number of admissions of outpatients with COVID-19 increased from 5 in week 12 to 22 in week 13, 49 in week 14 and 42 in week 15, illustrating the increasing incidence of COVID-19 during the beginning of the epidemic in Belgium. In these same weeks, the screening positivity rates of symptomatic healthcare workers in our hospital were 8.6% (6 out of 70), 31% (17 out of 54), 39% (16 out of 41) and 28% (16 out of 57), respectively and the numbers of patients diagnosed with probable nosocomial COVID-19 were 0, 4, 4, and 23, respectively. We defined probable nosocomial COVID-19 as a diagnosis made beyond 4 days of hospitalization and the absence of clinical suspicion of COVID-19 upon admission. Of 31 probable nosocomial COVID-19 infections, 22 (71%) were observed at geriatric wards.Our data indicate that nosocomially acquired COVID-19 can be observed at the start of a local epidemic and represents another challenge of the pandemic. Despite diverse and strictly followed preventive measures, we observed increasing numbers of new cases in our hospital during the first weeks of the epidemic, especially in geriatric wards. Further studies are required to identify the optimal preventive approach, which will probably include the regular screening of all asymptomatic healthcare personnel working at wards with high rates of nosocomial transmission."}
+{"text": "Frailty and geriatric characteristics were not correlated with mortality.(1) Background: COVID-19 has become a global pandemic and older patients present higher mortality rates. However, studies on the characteristics of this population set are limited. The objective of this study is to describe clinical characteristics and outcomes of older patients hospitalized with COVID-19. (2) Methods: This retrospective cohort study was conducted from March to May 2020 and took place in three acute geriatric wards in France. Older patients hospitalized for COVID-19 infections were included. We collected clinical, radiological, and laboratory outcomes. (3) Results: Ninety-four patients were hospitalized and included in the final analysis. Mean age was 85.5 years and 55% were female. Sixty-four (68%) patients were confirmed COVID-19 cases and 30 (32%) were probable. A majority of patients were dependent (77%), 45% were malnourished, and the mean number of comorbidities was high in accordance with the CIRS-G score (12.3 \u00b1 25.6). The leading causes of hospitalization were fever (30%), dyspnea (28%), and geriatric syndromes  (18%). Upon follow-up, 32% presented acute respiratory failure and 30% a geriatric complication. Frailty and geriatric characteristics were not correlated with mortality. Acute respiratory failure ( On 31 December 2019, the World Health Organization (WHO) was alerted about a cluster of pneumonia of unknown etiology in the city of Wuhan, China [On 11 March 2020, COVID-19 was declared a global pandemic  and by 1The first descriptions of epidemiologic characteristics of the COVID-19 outbreak were reported in China. In a February 2020 study, Wu et al. described 72,314 cases with most patients ranging from 30 to 79 years of age and an overall case fatality rate of 2.3% correlated to preexisting comorbidities such as cardiovascular disease, diabetes or chronic respiratory diseases. Fatal cases were primarily concentrated among older patients, in particular those aged \u226580 years with a case fatality of 14.8% . EvidencThis study aims to describe clinical characteristics and outcomes in older patients hospitalized with COVID-19 in order to improve patient care. Knowledge of COVID-19 infection in this patient set is a vital component in understanding the clinical evolution of COVID-19 andto determine factors predictive of mortality and acute respiratory failure in a proven at-risk population.This is a retrospective cohort study on older patients diagnosed with COVID-19 and hospitalized in 3 acute geriatric wards from 13 March to 4 May 2020. Patients were followed from hospital admission to hospital discharge or death.The patients enrolled in this study were diagnosed according to the WHO interim guidance . ConfirmMedical data of patients were obtained from electronic medical records using a standardized data collection form. Information included demographic data, medical history, underlying comorbidities, geriatric assessment, laboratory values, a chest CT-scan upon patient\u2019s arrival in the ward, and clinical outcomes.Burden of disease in older patients was assessed with the cumulative illness rating scale-geriatric (CIRS-G) . The num-Functional abilities were assessed using the Katz Activities of Daily Living (ADL) and Lawton\u2019s Instrumental Activities of Daily Living (IADL) scales upon arrival . Depende-Frailty status was screened with the Frail Non-Disabled survey (FIND) developed by C\u00e9sari et al. . Patient-The nutritional status of the patient was assessed using the Mini Nutritional Assessment (Mini MNA) . Body ma-The Norton scale assessed risk for pressure ulcers. A score <14 was considered a high risk .-Social environment assessment included living conditions, marital status, and presence or absence of home health care services.As part of usual care, a geriatric assessment was performed during hospitalization by the physicians in charge of the patient:Routine blood tests were performed, and reference limits were defined by the laboratory of the Toulouse University hospital.Due to the high rate of severe acute respiratory failure in older patients with COVID-19 , advance-Acute respiratory failure was defined as an acute episode of supplemental oxygen and signs of respiratory distress observation scales . Respira-Acute kidney insufficiency was identified according to the kidney disease improving global outcomes definition .-Acute heart failure was defined as a rapid onset of new or worsening signs and symptoms of heart failure .-Dehydration was identified if patients presented clinical features or biochemical changes of dehydration.-Delirium was identified if patients presented a score above 3 using the confusion assessment method .Adverse events were recorded during hospitalization:t-test or the Mann\u2012Whitney U test for continuous variables. Univariable and multivariable Cox proportional hazard models with backward selection were performed to identify potential significant prognostic factors of death and acute respiratory failure to determine the hazards ratio (HR) and 95% confidence interval (CI). Variables were entered in the model if they were significant in univariate analysis with a p-value < 0.20. Tests were two-sided, and the cut-off significance was set at p < 0.05. Data was analyzed using STATA\u00ae version 11 .Descriptive statistics were obtained for all study variables. Continuous data are expressed as mean (SD) or median (interquartile range (IQR)) values. Categorical data is expressed as proportions. Survivors and non-survivors were compared using the Fisher exact test or \u03c72 test for categorical variables and using the The baseline characteristics are described in Of the patients hospitalized, 63 (68%) lived at home and 21 (23%) patients lived alone. Concerning patient comorbidities measured with the CIRS-G , the totThe most prevalent severe comorbidities were psychiatric (including dementia) (37 (40%)), and cardiac diseases (23 (25%)). The mean number of medication of patients was 6.3 \u00b1 3.3, and 16 patients (17%) had more than ten medications.According to the FiND criteria , 12 (13%The population set under study was composed of 64 (68%) confirmed cases and 30 (32%) probable cases. Ten patients (10.6%) had CT-scans supporting evidence of a COVID-19 infection but did not present any respiratory tract symptoms upon arrival. Among them, the leading causes of hospitalizations were fever (5 (50%)), delirium (2 (20%)), fall (1 (10%)) and fatigue (2 (20%)). Onset of symptom to hospital admission was of 3 days (range from1 to 7 days).Vital signs were measured on arrival with a mean of pulse was 81.3 \u00b1 22.1 per minute, respiratory rate was 22.8 \u00b1 6.5 per minute, temperature was 37.3 \u00b1 1.0 \u00b0C, and systolic blood pressure was 133 \u00b1 25.6. Forty-two (45%) patients required oxygen upon arrival and the mean saturation of patients without oxygen at arrival was 94.5% \u00b1 2.4%.BNP with a median of 900 (418\u20132331) and of hypersensitive troponin I with a median of 33 (23\u201348).n = 17), 13 patients presented an acute respiratory failure prior to death and 4 patients died for other reasons . Seven patients (7%) were transferred to an intensive care unit (ICU). During hospitalization, a total of 28 (30%) patients presented a geriatric complication and 81 (87%) patients presented at least one non geriatric complication. The mean ADL change at the end of hospitalization was \u22120.6+/\u22121.6 (n = 71).Among deceased patients ) and venous fluids (54 (58%)). Seven patients (7%) were treated using corticosteroids, 8 (8.6%) had a treatment using hydroxychloroquine, and only one patient (1%) was treated with an antiviral (Remdesivir) as part of a research protocol.Out of all the patients, 17 died (18%), with 3 in ICU. Thirty-seven were discharged (39%) . Thirty-five (37%) of them were sent to a rehabilitation center. Five (6%) patients are still hospitalized and two patients are in the ICU. The median time of onset of symptom to death was 13 days (range from8 to15 days).p = 0.03) and lymphopenia  were significantly associated with death. For detailed information on multivariate Cox regression for prognostic factors and after adjustment for gender, see the Using univariate Cox regression, age above 85 was shown to increase the likelihood of death, lymphopenia (<0.8G/L), and acute respiratory failure. No other socio-demographic, clinical, biological, or medical imaging variables were significant. In the final model, only acute respiratory failure , functional ability with IADL , p = 0.04), CRP level , and platelet count  were significantly associated with acute respiratory failure during hospitalization.Age  hospitalized for a COVID-19 infection. The leading causes of hospitalization were fever (28 (30%)), dyspnea (26 (28%)) and more than 45 (48%) patients presented a geriatric syndrome upon arrival .Patients had a high comorbidity burden according to the CIRS-G (12.3 \u00b1 25.6) while 72 (77%) patients were dependent and 42 (45%) malnourished. Among them, 7 (7%) patients were transferred to an ICU, 37 (39%) patients were discharged, and 35 (37%) patients went to a rehabilitation center. The overall case fatality rate was 18%.Among the patient set, 18% were admitted for signs or symptoms  unrelated to typical COVID-19 presentations. Such a prevalence of atypical symptoms in this study confirms the great variety of presentations of the infection in this age group, confirming studies that have reported COVID-19 diagnosis after admission for syncope and delirium , or fallDiagnosis of older patients in this study was further complicated due to a number of false negative RT-PCR results 32%), comparable to other studies . This in%, comparIn terms of clinical outcomes, a large number of patients developed non geriatric (87%) and geriatric complications 30%) during hospitalization. Prevalence of acute respiratory failure was higher than in other studies (32%) ,30. Fall% during Although older age is an important predictor of mortality in COVID-19 patients in the general population, age itself does not seem to be predictive above a certain threshold . Case moThis study observed that comorbidities, polypathology, and in particular chronic respiratory, cardiovascular or diabetes were not correlated with mortality in this population set as opposed with other studies . The higp = 0.03) and lymphopenia upon hospital admission (p = 0.02) were significantly correlated with mortality. Death in COVID-19 infections is primarily associated to the onset of an acute respiratory failure, and in our study 4 patients died of other causes  [Respiratory failure during hospitalization ( state\u2026) . Moreove state\u2026) .The likelihood of acute respiratory failure was associated with a number of factors that were measured in the multivariate analysis. Higher CRP levels and platelet count in the event of acute respiratory failurewas identified and is aligned with the literature on the role of major inflammation as a cause for poor outcomes in older patients . On the Geriatric assessments may not predict death due to COVID-19, at this point, but could help identify patients who are at high risk of developing long-term complications as well as complications due to ICU and those who will benefit from an ICU . As suchThis study has some limitations. The main limitation is the small sample size limiting data interpretation and missing data concerning survival analysis. Secondly, the patient set was drawn from three acute geriatric wards in Toulouse University Hospital creating a population bias. Third, the follow-up time is relatively short to evaluate potential medium- and long-term consequences.In this case series, a majority of older patients hospitalized with COVID-19 were dependent and comorbid. Frailty and geriatric characteristics were not correlated with mortality in this population set. These results may provide valuable insight for the care of elderly patients affected by COVID-19 and may play an important role when discussing advance care planning."}
+{"text": "There are no previous published reports on primary pediatric tumors of the central nervous system (CNS) in Qatar. We undertook this retrospective cohort study to review the diagnosis of CNS tumors in children in Qatar to analyze the presentation characteristics including symptoms, referral pathways, and time to diagnosis.All children registered with Pediatric Neuro-Oncology service (PNOS) were included in the study. Data from the time of diagnosis (October 2007 to February 2020) were reviewed retrospectively. Presenting symptoms were recorded and pre-diagnosis symptom interval (PSI) was calculated from the onset of the first symptom to the date of diagnostic imaging.n = 7) or were asymptomatic at the time of diagnosis (n = 3). The median age was 45 (range 1\u2013171) months. Common tumor types included low-grade glioma (LGG) (47.1%) and medulloblastoma/primitive neuro-ectodermal tumors (PNET) (23.5%). Nine children had an underlying neurocutaneous syndrome. Thirty-eight patients (74.5%) had at least one previous contact with healthcare (HC) professional, but 27 (52%) were still diagnosed through the emergency department (ED). Presenting symptoms included headache, vomiting (36.2%), oculo-visual symptoms (20.6%), motor weakness (18.9%), seizures, ataxia (17.2% each), irritability, cranial nerve palsies (12% each), and endocrine symptoms (10.3%). Median PSI was 28 days (range 1\u2013845 days) for all CNS tumors. Longest PSI was seen with germ cell tumors (median 146 days), supratentorial location (39 days), and age above 3 years (30 days). Tumor characteristics of biological behavior (high-grade tumor) and location  were significantly associated with shorter PSI, as were presenting symptoms of ataxia, head tilt, and altered consciousness.Of the 61 children registered with PNOS during the study period, 51 were included in the final analysis. Ten children were excluded because they were either diagnosed outside Qatar , can improve diagnostic times in Qatar. Further research is required to better understand the reasons for the delay. Primary CNS tumors are the largest group of solid tumors occurring in children \u20133. They Diagnosing CNS tumors in children is a challenge as they are not associated with any unique diagnostic symptoms. The most common symptoms of brain tumors are headache and vomiting, which are common to many other childhood illnesses . PhysiciQatar is a high-income developing country, with a population of nearly 3 million . Eighty-According to the Qatar National Cancer Registry (QNCR) data, the incidence of brain tumors in Qatar is 15% of all childhood cancers among the 0\u201314-year age group . HistoriThere are no previous studies from Qatar reporting the presenting symptoms or diagnostic times for pediatric CNS tumors. We undertook this retrospective cohort study to review the diagnosis of CNS tumors in children in Qatar to analyze the presentation characteristics including symptoms, referral pathways, and time to diagnosis.n = 29) had been diagnosed prior to the establishment of PNOS, we reviewed their medical records from the time of presentation at HGH. The earliest patient in our database was diagnosed in October 2007. The study period therefore extends between October 2007 and February 2020. Age at the time of diagnosis, gender, nationality , and details of primary healthcare contact were also recorded. Histopathological type (where available), location of the tumor, presence of metastatic disease and presence of a neurocutaneous syndrome were noted. All presenting symptoms recorded in the medical notes and length of time (in days) each symptom had been present at the time of diagnosis was noted and analyzed if there had been symptom progression through this period. The date of diagnosis was defined as the date on which diagnostic neuroimaging was performed. Pre-diagnosis symptom interval (PSI) was defined as the time interval from the onset of the first symptom to the date of diagnosis.This is a retrospective cohort study. A review of electronic medical records (EMR) was carried out after the approval by the Institutional Review Board (IRB Number 1589712). All children up to their 18th birthday in our database who were diagnosed with a CNS tumor until the end of February 2020 were included in this study. As the majority .Patient characteristics are presented as numbers and percentages for each characteristic. Both mean and median are presented for the pre-diagnosis symptom interval (PSI) outcome. Because the data of PSI was highly skewed, bootstrap bias-corrected (BCa) 95% confidence intervals (CI) were computed. Student\u2019s n = 7) or were asymptomatic at the time of diagnosis (n = 3), fifty-one children were included in the study. Eleven of these patients were under active therapy at the time of inclusion in this study. The median age at diagnosis was 45 months (range 1\u2013171) with an equal gender ratio. Eighteen (35.3%) patients belonged to the native Qatari population, while the remaining 33 (64.7%) were non-Qataris. Nine patients (17.6%) had neurocutaneous syndromes (6 had tuberous sclerosis (TS) and 3 had neurofibromatosis type 1 (NF)).Table n = 7) or metastatic (n = 2) disease. The two truly metastatic tumors included one case each of medulloblastoma and GCT, whereas the 7 multifocal tumors included 4 SEGA and 3 optic pathway glioma (OPG).Diagnosis for 37 patients (72.5%) was confirmed with histopathology, whereas the remaining 14 (27.5%) patients were diagnosed on neuroimaging alone  and with optic pathway glioma (OPG), 2 with (DIPG) and 2 with other LGG. The most common tumor type in our cohort was LGG (47%), followed by medulloblastoma/primitive neuro-ectodermal tumor (PNET) (23.5%), intracranial germ cell tumor (GCT) (9.8%), high-grade glioma (HGG) (7.8%), and atypical teratoid rhabdoid tumor (ATRT) (3.9%). Thirty (58.8%) tumors were in supratentorial locations, 17 (33.3%) were infratentorial, and 4 (7.8%) in the spinal cord. Forty-two (82.4%) patients had localized tumors at the time of presentation. The remaining 9 patients had multifocal , in addition to head tilt (1) and back pain (1).The three most common presenting symptoms were headache 37.2%), vomiting (33.3%), and ataxia and oculo-visual symptoms (17.6% each). For children under 3 years of age, the most common presenting symptom was irritability, vomiting, and oculo-visual symptoms (27.2%). Headache (62%), vomiting (37.9%), and ataxia (20.6%) were the predominant presenting symptoms for older children. Figure %, vomitiSymptom progression was seen in 19 37.2%) patients. LGG was the commonest tumor type, followed by medulloblastoma, GCT, and DIPG. Three patients had other tumor types. Median PSI was 36 days for patients who had symptom progression. Medulloblastoma and ATRT were associated with the shortest PSI, whereas GCT and LGG had the longest PSI. At symptom onset, the two most common symptoms were headache (26%) and vomiting (21%). LGG had varied symptoms at onset as well as a diagnosis. Four of the five patients with medulloblastoma had vomiting and 3 had headaches at symptom onset. By the time the diagnosis was established, a fourth patient had developed a headache, two had developed ataxia, and two had developed other symptoms. Figure 7.2% patip = 0.049) and high-grade tumor  were significantly associated with a shorter PSI.Figure n = 2, median 455.5 days) was associated with the longest PSI, followed by endocrine symptoms (median 241 days), seizures (47 days), and oculo-visual symptoms (43 days). Irritability (8.0 days), vomiting (14.0 days), and headache (19 days) had the shortest PSI. Raised ICP in our cohort was not associated with shorter PSI. Ataxia (p = 0.039), head tilt (p = 0.021), and altered consciousness (p = 0.018) were significantly associated with shorter PSI.For presenting symptoms, developmental delay (p = 0.113).PSI according to the referral pathway was shorter for those who were diagnosed through ED (19.0 days vs. 33.5 days for those who were diagnosed through non-elective pathways). This difference was not statistically significant  consequences including severe visual impairment and avoidable lifelong need for hormone replacement. Targeted awareness campaign such as This is the first study of its kind from the state of Qatar and provides a baseline for future research. In analyzing the diagnostic times, we have identified the groups of patients who are at risk of diagnostic delay and long-term morbidity. Although not a primary objective of this study, we have also been able to document the pattern of pediatric CNS tumor presentation in Qatar. Our results can be used in future epidemiological research.Our data were subject to parental recall bias as defining the exact symptom onset varies depending on parental health literacy, symptoms awareness, health-seeking behavior, family support networks, and parental anxiety. In common with all retrospective studies using medical notes, we were limited by the quality of data recorded at the time of presentation. We were unable to document the symptom progression in depth due to the unavailability of pre-hospital healthcare records. Details of primary care or outpatient visits before being referred for neuroimaging were missing, making it difficult in some cases to determine the referral pathways and examine if there was a delay at the physician or healthcare level. Some data on original neuroimaging was unavailable making the ICP data incomplete. These deficiencies will be addressed in a future prospectively designed study with a larger cohort."}
+{"text": "Cities across China implemented stringent social distancing measures in early 2020 to curb coronavirus disease outbreaks. We estimated the speed with which these measures contained transmission in cities. A 1-day delay in implementing social distancing resulted in a containment delay of 2.41 (95% CI 0.97\u20133.86) days. On December 31, 2019, a cluster of atypical pneumonia in Wuhan, China, was reported to the regional office of the World Health Organization (WHO). Its etiology was later identified as the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Coronavirus disease (COVID-19) spread rapidly across China and internationally  drops below 1. We analyzed the speed of COVID-19 containment for 58 cities in mainland China outside of Huebei Province that had >20 confirmed cases by February 14, 2020 (+ SD) time between the first confirmed case and the implementation of the first social distancing measure was 13 (+ 4.7) days. By the time these measures were enacted, the median cumulative reported cases in a city was 40, but the range was 9\u2013248 across the 58 cities. The mean time until successful containment was 21 (+ 7) days after the first reported case and 8 (+ 6.8) days following the initiation of interventions. During the period of containment, the reproduction number (Rt) declined by an average of 54.3% (+ 17.6%)   Figure 2R2\u00a0=\u00a00.27; p<0.001) (Using a combination of linear regression and best-subsets model selection (p<0.001)  Figure 1t may be biased by the limited case report data available before February 14, 2020; we lack information about testing rates and priorities in China before February 14. As public health agencies around the globe struggle to determine when to implement potentially costly social distancing measures, these estimates highlight the potential long-term benefits of early and decisive action.We have estimated the value of proactive social distancing interventions in terms of a reduction in days until successful containment. However, because most cities implemented multiple measures quickly and simultaneously, we are unable to disentangle the efficacies of individual modes of social distancing. We note that our estimates of RAdditional information about effects of proactive social distancing on COVID-19 outbreaks in 58 cities in China."}
+{"text": "The increasing popularity of alpacas and llamas outside of South America is undeniable. The associated limited genetic diversity raises questions about health and other genetically determined traits like coat colour. Therefore, a survey studying the prevalence of congenital disorders and coat colours and patterns in South American camelids was performed in Austria, Germany and Switzerland. Moreover, the motivation for keeping these animals, the herd size and breeds was assessed.Huacaya (87.7%), the most common llama breed was Wooly (15.6%). Breeding (69.4%), wool production (63.3%) and keeping them as pets (53.7%) were the most common motivations to keep these animals, although this varied among countries. The three coat colour groups, solid white (24.8%), brown and black (64.8%) and grey (10.4%), occurred at different frequencies. About 7% of the South American camelids with solid white coat showed blue-pigmented eyes, corresponding to the known blue-eyed white phenotype, of which more than every second animal was apparently deaf. Uniform solid coloured animals occurred predominantly (81.4%), whereas pinto (8.8%), speckled (6.4%) and spotted (3.4%), also known as appaloosa, were comparably less prevalent. In total 161 observations of congenital disorders occurring during a 5-year-period were reported. The most prevalent disorders were in the group of musculoskeletal disorders such as spiral toe growth (16.4%), hyperextension of the fetlock joint (12.3%), angular limb deformities (11.0%) and axial rotation of the limbs (8.2%).A total of 146 questionnaires were returned corresponding to 16 farms from Austria, 69 farms from Germany, and 61 farms from Switzerland. In total, the returned surveys reported data on 2770 animals including\u2009~\u200985% alpacas and\u2009~\u200915% llamas. The most common alpaca breed was This survey revealed first insights into the occurrence of different traits and disorders in the current South American camelid population of Austria, Germany, and Switzerland. The identification of the most common musculoskeletal disorders might encourage the breeders to eliminate affected animals from their breeding program to decrease the incidence although traits such as spiral toe growth might also represent phenocopies. Vicugna pacos) and the llama (Llama glama), have become increasingly popular in the last few decades in regions outside South America such as the USA, Australia and Europe [The two domestic South American camelids (SACs) species, the alpaca  database of inherited disorders contains 11 and 17 entries including coat colour-associated disorders for alpacas and llamas, respectively . For ins alpacas . Taken tHuacaya and Suri (OMIA 001528-30538). The Huacaya type resembles the wool of Merino sheep whereas the Suri type has silkier fibres in \u201ccork screw\u201d shaped locks. It was suggested that the Huacaya phenotype is caused by homozygosity of recessive alleles at two linked loci [Classic, Wooly and Suri, although they are not bred as intensively for their fleece as alpacas, are also distinguished by their fleece quality. Although the coat colour of alpacas and llamas, especially the white ones, is essential for the textile industry, the genetic basis of coat colours is mostly unknown. The KIT gene has been postulated as candidate for the dominantly inherited white phenotype in alpacas [KIT genotype was revealed [KIT missense variant that is most likely lethal in homozygous state [KRT2 and ASIP genes seem to influence colour determination of alpacas [MC1R gene might influence coat lightness [KIT and MITF was significantly lower in white animals than in coloured ones [Beside rare disorders, fleece quality and coat colour are economically important genetic traits in SACs. The most important fleece types and the source of the name of the two most common alpaca breeds are ked loci . The thr alpacas  but desprevealed . Recent OMIA 0015-30538. TOMIA 0015-30538. T alpacas , 30 wherightness . For llared ones .This study presents the results of a survey sent to all members of the SAC breeders\u2019 associations of Austria, Germany and Switzerland and then evaluated in order to estimate the occurrence of coat colour traits and congenital disorders in alpacas and llamas.In Switzerland an online questionnaire in both French and German was created, which was given access by an URL-link , as well as if they had noticed animals that had more than one anomaly at a time. This list contained 28 disorders reported to occur in SACs in the scientific literature as well as further abnormal phenotypes to be included in the survey by Swiss farmers. The survey contained a short, illustrated description of disorders, which were divided into five different anatomical or functional groups . The assignment of disorders to groups is given in Additional file 014\u20132019,Huacaya (87.7%) dominated over the Suri (21.8%), whereas 15.6% of the farms have Wooly llamas, Classic llamas 12,2%, and 6.8% Suri llamas.A total of 146 questionnaires were returned corresponding to 16 farms from Austria, 69 farms from Germany, and 61 farms from Switzerland. In total, the returned surveys reported on 2770 animals including 225 alpacas from Austria, 1506 (90.2%) alpacas and 163 (8.8%) llamas from Germany, and 614 (70.1%) alpacas and 262 (29.9%) llamas from Switzerland. Of the 146 participating farms, 78.8% kept only alpacas, 10.8% only llamas, whereas 10.2% of the farms kept animals of both species. Among the alpacas The three most common motivations were to breed animals (69.4%), followed by wool production (63.3%), and keeping SACs as pets (53.7%). In addition, other three less often mentioned motivations were trekking (29.9%), animal-assisted activities 15.0%), meat production (9.5%), zoo (3.4%) and herd protection (2.0%). These motivations differed between countries  translated into English.Additional file 2: Reported congenital disorders from South American camelid farms in Austria (AT), Germany (DE) and Switzerland (CH) during a 5-year-period (2014\u20132019)."}
+{"text": "The purpose of this study was to identify patterns of changes in social isolation and dementia and the interrelations between these developmental trajectories. The study sample included 7,609 Medicare beneficiaries age 65 and older from the National Health and Aging Trends Study 2011 through 2018 surveys. A group-based dual trajectory modeling approach was used to identify distinct groups of developmental trajectories for social isolation and dementia status over the 8-year period. The dual model provided estimates of conditional and joint probabilities linking the two sets of trajectory groups. Changes in social isolation over an 8-year period followed four trajectories: rarely isolated (62.2%), steady increase (13.5%), steady decrease (7.4%), and persistently isolated (16.9%). Changes in dementia risk also followed four trajectories: persistently low risk (80.4%), increasing with early onset (3.9%), increasing with late onset (4.5%), and persistently high risk (11.2%). Over two-third (68%) of the persistently low dementia group were also in the rarely isolated group. Both increasing dementia groups were composed mainly of individuals from the increasing social isolation group (40-43%) and persistently isolated group (24-29%). The persistently high dementia group had the most overlap with the decreasing social isolation group (47%), followed by the persistently isolated group (28%). For the most part, social isolation and dementia evolve in the same direction for older adults over an 8-year period. However, the pattern of associations between these developmental trajectories is complex and may be reversed among long-term dementia survivors."}
+{"text": "BACKGROUND: Communication is important in the care of older adults receiving skilled home health care (SHHC). In a prior national survey, physicians viewed communication and care coordination with SHHC agencies as dismal. The views of SHHC personnel  on this issue have not been well studied. OBJECTIVE: To determine the effectiveness of communication between SHHC personnel and physicians who order SHHC services. METHODS: A nationally representative mailed survey of personnel from SHHC agencies identified through the 2016 Home Health Compare data set from the Centers of Medicare and Medicaid Services. RESULTS: 263 of 2000 surveys returned (13.2% response rate). Responding agencies were mainly proprietary (75.3%) and urban-based (83.7%). Most agencies were in the South (38.8%); 28.3% Midwest, 22.9% West, 12.1% Northeast. Only 62.2% of SHHC personnel completing start of care visits (n=202) reported being able to contact a physician when needed. The most common strategies used to contact physicians are phone (76.0%) and fax (11.2%). The greatest barriers to communication are having to communicate through a third party (64.9%) and a perception by SHHC personnel that \u201cPhysicians [are] not interested in communicating with SHHC Personnel\u201d (45.1%). Failed communication resulted in delayed orders (70.8%) and sending a patient to the emergency room (37.1%). IMPLICATIONS: SHHC agency personnel experience significant barriers in communicating with physicians. Modes of communication remain rudimentary, and there are serious consequences of failed communication."}
+{"text": "To determine the risk factors, presentation and outcome of meningomyelocele repairWe reviewed 150 cases operated for meningomyelocele (MMC) at Jinnah Postgraduate Medical Centre Karachi between May 2015 and May 2018. Data of infants operated for MMC repair was extracted including socioeconomic status, maternal folate intake during pregnancy, head circumference, location and width of the defect, accompanying bladder and limb anomalies and treatments administered. Patients were followed up for a mean period of six months.A total of 150 children were evaluated, out of which there were 83(55.3%) males and 67(44.7%) females. All belonged to low socio economic group and prenatal maternal folate intake as risk factor was positive in 103(68.7%) cases. Mean head circumference was 37.4 cm . Based on their location, 83(55%) of the defects were lumbosacral, 38(25.4%) were lumbar, 16(10.7%) were thoraco lumbar, 10(6.7%) were thoracic and three (2%) were cervical. Mean size of the meningomyelocele sac was 4.3 cm\u00d75.6 cm  and 21(14%) of the babies had a skin defect requiring flap. According to accompanying anomalies, 98(65.3%) of the babies had hydrocephalus, 13(9%) had club foot, four (2.7%) had diastematomyelia and three (2%) had tethered cord. Eighty seven (58%) patients had neurological deficit pre operatively and eight (5.4%) patients with normal power deteriorated after surgery out of which five (3.3%) developed paraplegia and three (2%) developed paraparesis. CSF leak was the major complication encountered in 16(11%) followed by meningitis in seven (5%), while the overall mortality was four (2.6%).The practice of periconceptional folic acid supplementation is essential to reduce the prevalence of neural tube defects (NTDs) in the developing world. Improved maternal nutrition with access to quality antenatal care is vital to decrease the prevalence and health burden. A potentially preventable cause of perinatal morbidity and mortality, NTDs are one of the most common congenital malformations. The incidence is one in every 800\u20131000 live birthsIn MMC, a part of the spinal cord, together with the surrounding meningeal structures, herniates outward through the defective bony arches and skin as a sac. The protrusion of the meninges and spinal cord through open vertebral arches is often associated with paralysis and varying degrees of mental retardation, bowel and bladder dysfunction as well as orthopedic disabilities.Folic acid deficiency is one of the best documented risk factors for the development of NTD\u2019s.We reviewed 150 cases operated for MMC between May 2015 and May 2018. Data of infants operated for MMC repair was extracted including socioeconomic status, maternal folate intake during pregnancy, head circumference, location and width of the defect, accompanying bladder and limb anomalies and treatments administered. Consecutive patients with MMC aged \u22641year, with and without hydrocephalus were included while children having other systemic anomalies, leaking MMC, severe kyphotic deformity, very small MMC with HCP treated with shunt alone and those who had been operated elsewhere were excluded. A multidisciplinary approach was undertaken that included pediatrician, urologist, orthopedic and plastic surgeons. After repair, infants were referred to respective specialty for further treatment and follow up as well. For very large defects, plastic surgery was taken on board for construction of flaps for proper closure. Data was analyzed using SPSS version 23 and the data were expressed as mean \u00b1 SD (standard deviation) and percentage (%), as appropriate.A total of 150 children were evaluated out of which there were 83(55.3%) males and 67(44.7%) females. All belonged to low socio economic group and prenatal maternal folate intake as risk factor was positive in 103(68.7%) cases. Mean head circumference was 37.4 cm . Based on their location, 83 (55%) of the defects were lumbosacral, 38(25.4%) were lumbar, 16(10.7%) were thoraco lumbar, 10(6.7%) were thoracic and three (2%) were cervical as shown in The second most frequently encountered congenital malformations after cardiac anomalies are NTDs and folic acid deficiency is the most widely recognized risk factor which is more common in the low socioeconomic group.11The mean age of presentation in our patients was 2 months \u00b11SD similar to a recent study by Alamgir6Hydrocephalus and the Chiari II malformation were the most frequently observed anomalies in association with MMC.20The major complication of CSF leak was encountered in 16(11%) followed by meningitis in seven (5%) which is similar to infection rates in a series by Demir at 11%There were no other complications till last follow up. However, spinal cord rethetering can occur after the primary surgical repair of MMC and inadvertent introduction of skin elements at first surgery can lead to the growth of intraspinal epidermoid or dermoid cysts.The practice of routine periconceptional folic acid supplementation is negligible and improved maternal nutrition with access to quality antenatal care is vital to decrease the incidence and health burden of this devastating disease. Early surgery with multidisciplinary approach offers the best chance for improved outcomes and survival.MS: Conceived and designed the study.AA: Did data collection and manuscript writing.RR: Did statistical analysis & editing of manuscript.LR: Did review, final approval of manuscript and is responsible for integrity of research."}
+{"text": "Injury is one of the major global public health problems causing significant number of death and disability. The study aims to study the epidemiological and clinical profile of patients presented in emergency department with injury.This was a descriptive cross-sectional study conducted in a tertiary care hospital from September 2019 to February 2020 after obtaining ethical approval from Institutional review board (reference number 007-076/077). A convenient sampling method was applied. Epidemiological factors, chronological factors, causes of injury, anatomical distribution, pattern of injury were studied. Statistical analysis was done using statistical package for the social sciences version 20. Point estimate at 95% Confidence Interval was calculated along with frequency and proportion for binary data.Out of 197 patients, 72 (36.5%) patients had fall followed by road traffic accident 57 (28.9%). Of total, 80 (40.6%) had injury at home and 80 (40.6%) had cut injury. Head and neck accounted for 66 (33.5%) of total injury followed by upper Extremities 50 (25.4%) and lower extremities 47 (23.9%). Eighty-seven (44.2%) of the patients visited emergency within 30 minutes of sustained injury.The top three leading causes of injuries visiting emergency department were: fall, Road Traffic Accident and physical assaults respectively. The most common mode was fall being cut as most common pattern. Head and neck was the most commonest site of injury. The common place of injury was home. Ethical clearance was obtained from the Nepal Medical College Institutional Review Committee (reference number 007-076/077). Patients presenting to the emergency department with injury were enrolled in the study (n= 197).The sample size was calculated as,n = sample sizep = prevalence of injury, 15%e = margin of error, 5%Z = 1.96 at 95% Confidence Intervalwhere,All cases of injury irrespective of age, sex, mode, type, place anatomical distributioin, pattern and the status of patients, after injury were included in the study. People from whom history could not be obtained and those not willing to participate were exclusion criteria in this study.Written consent was obtained from participants. Epidemiological factors like age, gender, educational status, occupation, marital status, religion, and ethnicity were studied. Chronological factors like arrival time, time elapses in presentation to hospital were also included in the study. Etiology, anatomical distribution, pattern of injury and outcome was also studied. A convenient sampling method was applied.The collected data were analyzed in the Statistical Package of the Social Sciences version 20 by using descriptive statistics. Point estimate at 95% Confidence Interval was calculated along with frequency and proportion for binary data.The mean age of the patients was 26.62\u00b118.69 years with minimum age of 1 years and maximum age of 82 years. Majority of the patients were male 134 (68%) and unmarried 107 (54.3%). Majorities were from Hindu religion 131 (66.5%), followed by Buddhist 62 (31.5%), Christian 2 (1%) and Islam 2 (1%). Out of 197 patients, 65 were students (33%), 37 were service holders (18.7%), 23 were housewife (11.7%), 22 were laborer (11.2%), 14 were business holders (7.1%), 8 were unemployed (4%), 7 were farmer (3.6%), 3 were driver (1.5%) and remaining 18 were unknown (9.18%). 56 were illiterate (28.4%) and majority have completed primary level of education  followed by secondary level of education 36 (18.3%), Plus 2 17 (8.6%), bachelors 11 (5.6%), SEE 9 (4.6%). Regarding alcohol use, only 45 were under influence of alcohol (22.8%). One hundred fifty-nine had external injury (80.7%).The most common cause of injury was fall 72 (36.5%) followed by road traffic accidents 57 (28.9%) .Home was the commonest place of injury 80 (40.6%) followed by road 75 (38.1 %) .Head and neck 66 (33.5%) was the most common anatomical site of injury followed by Upper Extremities 50 (25.4%) .Similarly, Cut was the most common pattern of injury 80 (40.6%) followed by laceration 38 (19.2%) .Most patients visited emergency department within 30 minutes of trauma 87 (44.2%) .One hundred twenty were discharge from emergency department (60.9%) and 30 left against medical advice (15.25%) .6 There was predominance of male gender in our study which was similar to studies done in Nepal.8 Majority were Hindu. Students were more prone to injury in our study which was similar to the study done in Africa.6 Most of them were illiterate in our study. Nonalcoholic were almost thrice as common as alcoholic . In a systematic review article to investigate the epidemiology of road traffic injury (RTI) in Nepal, out of 11 only 3-article mention alcohol consumption as a possible causes of accidents.9 Majorities of the patients had some forms of external injury which was similar to the study done in Nepal.7In our study the mean age was found to be 26.62 years while in the study done in Africa, the mean age of the patients was 30.2 years.10 In a systematic review study of injuries and violence related articles in Nepal, falls was the most common cause of neuro trauma whereas road traffic injuries were the most common form of injuries.11 In a fall injuries survey done in Nepal, falls represented 37.2% of total injuries.12 In our study falls accounted for 36.5%. Home was the commonest place of injury which was similar to the study done by Verma S, et al13 in pediatric populations. Injuries to head and neck (33.5%) were the commonest ones followed by injury to upper extremities (25.4%). In total, injuries to extremities accounted 49.2% (n= 97). Injury to extremities were the commonest ones followed by injuries to head and neck (13.9%) in the study done by Shrestha R, et al.7The most common cause of trauma was fall followed by road traffic accident which was similar to the studies done in Nepal.8 In another study done by Joshi SK, et al. open wounds including incised and lacerated ones constitute the most common form of injury.11In our study, cut was the most common pattern of injury followed by laceration and fracture. Cuts and open wounds accounted for 40.2% of all injuries in the study done by Joshi SK.Most of them came to emergency department within 30 min (44.2%). More than 60% patient visited emergency department within an hour.7 However, 15.2% (n = 30) left the emergency department against medical advices.Majority, almost two third, of the patients presenting to the hospital were discharged after appropriate management in the emergency department which was similar to the study done by Shrestha R, et al.The three top most leading causes of injuries visiting emergency department were: fall, road traffic accident and physical assaults respectively. The most common mode was fall being cut as most common pattern. Head and neck was the most commonest site of injury. The common place of injury was home. Most of them visited emergency department within 30 minutes of trauma. Hospital-based single-center study and limited sample size should be considered as the limitation of this study. Therefore, a multi-center study with a large sample size should be considered as these kind of data provide an insight to the magnitude of different types of injuries in tertiary level hospital, and hence will be helpful in guideline and protocol formulation."}
+{"text": "The authors wish to make the following corrections to this paper . The autChange in Main Body Paragraphs: The authors report that some of the data regarding the minimum inhibitory concentration (MIC) for vancomycin reported in their published paper . Most of the S. aureus isolates (98%) were susceptible to tigecycline  were also resistant to ampicillin and ertapenem (Among the 100 isolates of rtapenem . MRSA isS. aureus (VISA). The data also showed that most of the VRSA/VISA isolates were also resistant to ampicillin , cefoxitin , tobramycin (43/44), tetracycline (42/44), and moxifloxacin (41/44). Only one VRSA/VISA isolate was found resistant to tigecycline (2.2%) (see Table 5).The antibiotic susceptibility pattern of the 44 VRSA/VISA isolates is presented in Table 5. The vancomycin-resistant phenotype was confirmed by determining the minimum inhibitory concentration (MIC) of isolates against vancomycin via the broth micro-dilution method, as described by the European Committee for Antimicrobial Susceptibility Testing (EUCAST) of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and the Clinical Laboratory Standards Institute (CLSI) . The MICs of vancomycin for 44 reported VRSA/VISA showed that 14 isolates had MICs > 16 \u00b5g/mL while the other 30 isolates had MICs in the range of 2\u20134 \u00b5g/mL, revealing that these were vancomycin-intermediate vanA was amplified from nine (30%) isolates .Out of 30 isolates, the vancomycin-resistant gene Additional Note: Like the replacement shown in"}
+{"text": "Human Papilloma Virus (HPV) vaccination of the preadolescent (9-14 years) females is the potential solution to eradicate carcinoma cervix. Nonavalent vaccine provides wider coverage than the quadrivalent vaccine. On long-term follow-up, even after single-dose HPV vaccination, the antibody titer remains good. Herd immunity can also be achieved by HPV vaccination. Hence, mass single-dose nonavalent HPV vaccination for sexually naive preadolescent girls can provide almost 100% protections and a cost-effective approach for the developing countries. Cervical cancer is a preventable disease and whole world is now focusing on prevention of carcinoma cervix. Cervical intraepithelial neoplasia (CIN) is the forerunner of cervical cancer. HPV infection is invariably associated with CIN. In carcinoma cervix, HPV type 16 and 18 are responsible for about 70% cases and HPV type 31, 33 and 45 are responsible for another 13% cases. Hence, HPV vaccination is the key to eradicate carcinoma cervix. There are various HPV vaccines been invented so far including bivalent targeting HPV (type 16 and 18); quadrivalent targeting HPV ; and nonavalent targeting HPV . Human papillomavirus 9-valent vaccine, recombinant; 9vHPV (Gardasil 9) was approved by FDA in 2014. Since the end of 2016, only 9-valent HPV vaccine is available in the United States [In the multi-centric Indian clinical trial NCT00923702) quadrivalent HPV vaccine was given and the participants were ended up in 4 groups \u2013 1) 3 dose group: girls vaccinated on days 1, 60 and 180 or later, 2) 2 dose group: girls vaccinated on days 1 and 180 or later, 3) 2 dose group: girls vaccinated on days 1 and 60 by default and 4) Single dose: by default because administration of vaccine was stopped in April 2010 by Govt of India 3702 quad. Forty yHPV vaccine also provides herd immunity. While comparing data of 2003\u20132006 to 2011-2014 it was found that, in sexually active women of 14-24 years the prevalence of HPV is reduced by 89% in vaccinated women (4vHPV) and 34% in unvaccinated women [Australia, United Kingdom and Denmark have achieved high coverage of their population by including HPV vaccination in their national immunization programme . In IndiConsidering all these facts, it would be prudent to initiate the process of including single dose nonavalent HPV vaccination for preadolescent sexually naive girls in the national immunization schedule."}
+{"text": "This randomized clinical trial examines intermediate-term outcomes of endoscopic vs open vein harvesting for coronary artery bypass grafting as part of the Randomized Endo-Vein Graft Perspective (REGROUP) trial. The trial protocol and statistical analysis plan are available in NCT01850082).The randomized clinical trial was approved by the institutional review board at each participating center. Patients gave written informed consent before participation. This study is reported following the Consolidated Standards of Reporting Trials . Data were analyzed in August 2020.In the Randomized Endo-Vein Graft Perspective (REGROUP) trial, participants undergoing CABG at 16 Department of Veterans Affairs (VA) medical centers from March 2014 through April 2017 were randomized to either EVH or open vein harvest (OVH) in a 1:1 ratio. The primary outcome of the REGROUP trial was defined as the first occurrence of a major adverse cardiac event (MACE) composite comprised of all-cause mortality, nonfatal myocardial infarction (MI), or repeat revascularization, over the active follow-up phase; we previously reported no difference in MACE between the 2 groups, with a median follow-up of 2.7 years.5 The median (interquartile range) intermediate-term follow-up was 4.70 (3.84-5.45) years. During the entire follow-up, the primary outcome of MACE occurred in 126 patients (21.9%) in the EVH group, compared with 135 patients (23.5%) in the OVH group  (P\u2009=\u2009.52); nonfatal MI occurred in 37 patients (6.4%) in the EVH group and 42 patients (7.3%) in the OVH group ; and repeat revascularization occurred in 45 patients (7.8%) in the EVH group and 56 patients (9.8%) in the OVH group . An adjusted multivariable Cox regression model found no significant difference in MACE risk.A total of 1150 participants  were randomized, including 574 patients (49.9%) randomized to OVH and 576 patients (50.1%) randomized to EVH, and followed-up for MACE . Groups P\u2009=\u2009.52) . Death f6This randomized clinical trial found that there was no significant difference in MACE occurrence among patients who underwent EVH compared with those who underwent OVH for CABG over a median follow-up of 4.7 years. The saphenous vein is the most common supplementary conduit for CABG, but concerns have been raised about long-term ischemic events when EVH is used. This uncertainty has translated into variable adoption rates of EVH in North America (>80% of patients) compared with Europe (<50% of patients).5 Limitations of this study include lack of imaging evaluation of graft patency and use of only expert harvesters. These results provide strong reassurance that EVH is safe up to 4.7 years after the procedure; a 10-year follow-up is planned.The intermediate-term results of REGROUP are reassuring and demonstrate no significant difference in cardiovascular events between endoscopic or open approaches; leg-wound complications were reduced with EVH."}
+{"text": "Over the last few years there has been a substantial increase in the use of cross sectional imaging modalities to assess the heart. Cardiac MRI (CMR) is now routinely used in the assessment of a variety of cardiac pathologies. It is not uncommon to identify non-cardiac abnormalities during image review. The frequency of non-cardiac findings has been previously addressed using cardiac CT, with 7 published studies totalling 2,495 patients. The prevalence of non-cardiac findings was 529 (21%) with a range of 5% to 69%. The majority of the abnormalities were pulmonary, most commonly small isolated nodules (<10 mm). The diversity and significance of these incidental findings has to date not been assessed with CMR.The purpose of our study was to assess the prevalence of incidental non-cardiac findings found during routine CMR assessment.The reports of 714 consecutive adult CMR studies, performed for all current clinical indications with the exception of adult congenital heart disease, were reviewed retrospectively. These were performed between February and August 2008 on a Philips Achieva CV 1.5 Tesla MRI scanner . The studies were performed and reported by consultant cardiologists, in accordance with SCMR standardised acquisition protocols.A multislice single shot steady state sequence was used as an initial scout scan. Three orthogonal planes were acquired  with a large field-of-view coverage. Axial black blood images were also obtained (10 to 16 slices) using turbo spin-echo and a double inversion prepulse (TE/TR = 20/1500 ms).The mean patient age was 61.3 +/- 15 years (range 16 to 86 years), and 476 (67%) were male. 218 (24%) of the patients had previously undiagnosed non-cardiac abnormalities. These included, renal cysts (9%), aortic pathology (3%), lung collapse/consolidation (2%), liver cysts (2%), lung mass (1%). There were also 2 cases of mediastinal masses, 1 mediastinal lympahadenopathy, 6 increased signal from the hila, 1 renal mass and one large hiatus hernia.The detection rate of non-cardiac findings on routine CMR scans is relatively high and broadly similar to that of cardiac CT. Unlike CT, CMR detects very few incidental lung findings. The CMR scout scan has a larger field of view than cardiac CT, allowing routine imaging of the abdomen, which explains the high number of intra-abdominal abnormalities.Further work is needed to assess the clinical significance of these findings."}
+{"text": "To determine Blood Eosinophilia frequency in newly diagnosed Chronic Obstructive Pulmonary Disease patients.An observational cross-sectional research on newly diagnosed COPD patients with age \u2265 40 years was performed at Ojha Institute of Chest Diseases, Dow University of Health Sciences Karachi. COPD patients diagnosed in outpatient clinic or admitted in Chest Unit during six-month period from September 2018 to May 2019 were selected. Each patient underwent spirometry, and blood was tested for eosinophilia (\u2265 2% eosinophils in blood), after obtaining informed consent and clinical history.Blood Eosinophilia, out of which 86 (57.3%) and 64 (42.7%) patients were Males and Females respectively with mean age of 63.72 \u00b1 10.24 years. Current Smokers were 48 (32.0%), Ex-Smokers 15 (10.0%), and Biomass Exposure was present in 76 (50.7%) of patients. Spirometric severity of COPD was Mild in 11 (7.3%), Moderate in 68 (45.3%), Severe in 59 (39.3%), and Very Severe in 12 (8.0%) patients. Blood Eosinophilia was present in 59 (39.3%) patients of COPD among which majority 43 (72.9%) were having Moderate 24 (40.7%) and Severe 19 (32.2%) COPD respectively.One hundred and fifty COPD patients were diagnosed and evaluated for Frequency of Blood Eosinophilia in newly diagnosed COPD patients was high, among which most of the COPD patients were moderate to severe. Only newly diagnosed cases of COPD were included as the eosinophil count in blood will not be affected by any treatment taken for COPD and so does its disease course. Different factors affect the response to treatment in COPD patients and knowing these may help in proper and timely management and reducing associated morbidity and mortality, blood eosinophilia is also considered among such factors. COPD patients with blood eosinophilia should be managed with inhaled corticosteroids and this will have better symptoms relief and the disease progression will be slowed also. Different evidence suggested that high eosinophil in blood is directly correlated with increased risk of exacerbations in COPD patients. Management of eosinophilic COPD with inhaled corticosteroid also reduces exacerbations. Recently, no such study has been performed in Pakistan on blood eosinophilia in newly diagnosed COPD patients. Therefore, this study was conducted to document frequency of blood eosinophilia in newly diagnosed COPD patients.th September 2018 to 8th May 2019 were selected by purposive sampling. COPD patients with age ranging from 40 to 80 years, were included whereas patients taking tuberculosis therapy or having Asthma, Asthma COPD overlap (ACO) and Bronchiectasis were excluded from study. The sample size was calculated through open EPI software by using the proportion of Hasegawa K, et al., 17% patients with blood eosinophilia in COPD patients,An observational cross-sectional research on newly diagnosed COPD patients was performed at Ojha Institute of Chest Diseases, Dow University of Health Sciences (DUHS) Karachi. COPD patients admitted in Chest Unit during the period of six months from 81 / FVC < 0.70 pre- and post-bronchodilator). Classification of severity of COPD as per spirometry is given in COPD was confirmed in patients according to GOLD criteria such as clinical history and spirometry showing persistent airflow limitation , Eosinophil count and Eosinophilia (yes/no) were collected and further analyzed with SPSS software version 22. Descriptive statistics for age, FEV1/FVC ratio and eosinophil count, and frequency and percentages of gender, age, occupation, risk factor (smoking status and biomass exposure), severity of COPD and eosinophilia was calculated. Chi-square Test was applied for determining difference in frequency of eosinophilia with risk factors like gender, age, smoking status, biomass exposure and severity of COPD. P value <0.05 was taken as significant.After selection of suspected COPD patients, detailed demographic and clinical history including age, gender, occupation, smoking status and biomass exposure was collected from patients. Spirometry of each patient was performed for confirmation of COPD. Spirometry was performed by trained spirometry technician having at least 03 years\u2019 experience, whereas interpretation was done by the consultant pulmonologist having 03 years\u2019 experience. Blood sample of each patient was collected in aseptic environment and sent to laboratory for CBC (Complete Blood Count) for confirmation of eosinophilia. Laboratory results of each patient including FEVIn this study, initially data of patients was collected and evaluated for confirmation of COPD, followed by confirmation of eosinophilia in newly diagnosed patients of COPD. The descriptive statistics of different continuous variables obtained during collection of demographic data like age with mean of 63.72 \u00b110.24 years, and clinical characteristics like spirometric variables , and blood eosinophils count with mean of 3.9 \u00b12.7% obtained during spirometry and CBC respectively are shown in Mild 11 (7.3%), Moderate 68 (45.3%), Severe 59 (39.3%), and Very Severe 12 (8.0%). Eosinophilic COPD was confirmed in 59 (39.3%) patients, and Non-eosinophilic COPD in 91 (60.7%) patients. In Eosinophilic COPD, spirometric severity was Mild 8 (13.6%), Moderate 24 (40.7%), Severe 19 (32.2%), and Very Severe 8 (13.6%)  . The nonCOPD is complex group of disease characterized with chronic respiratory symptoms and permanent airflow limitation, directly associated with increased morbidity and mortality. Early recognition of clinical phenotypes of COPD with use of validated biomarkers such as blood eosinophilia is very important for development of specific therapeutic strategies and appropriate management of COPD.16Blood eosinophils are used as a prognostic biomarker in COPD patients. Increased blood eosinophils are directly associated with worsening of COPD, increased hospital admission, and mortality. Early identification of raised blood eosinophils in COPD patients is very important not only for appropriate management but also for lowering the risk of severe exacerbations.In current study 150 newly diagnosed COPD patients were evaluated, out of which 86 (57.3%) patients were males and 64 (42.7%) were females with mean age of 63.72 \u00b110.24 years. Similar studies on COPD patients showed comparable results, such as; Couillard S, et al.Current and previous studies show that older age is a major risk factor of COPD patients. Current research reported that most of the patients suffering from COPD are in age group of 61-70 years 49 (32.7%), followed by 71-80 years 37 (24.7%), 51-60 years 35 (23.3%), and 41-50 years 29 (19.3%). Similar results were reported by other researchers such as; Hasegawa K, et al.Two important factors that play vital role in the development of COPD are Smoking and Biomass Exposure. Current study reports the smoking history in 42.0% patients including Current smoking in 48 (32.0%) and Ex-Smoking in 15 (10.0%) patients, whereas Biomass Exposure in 76 (50.7%) patients. Different studies report the different prevalence of Smoking and Biomass Exposure, such as; Couillard S, et al.,According to GOLD standard COPD patients were categorized into; Mild 11 (7.3%), Moderate 68 (45.3%), Severe 59 (39.3%), and Very Severe 12 (8.0%). Similar results were reported by Couillard S, et al.Second important aspect of study was presence of Eosinophilic COPD in COPD patients. Current study reports the Eosinophilic COPD in 59 (39.3%) patients, and Non-Eosinophilic COPD in 91 (60.7%) patients. Similar higher prevalence was reported by Couillard S, et al.,Our study has the limitation of being a single center study so its result cannot be generalized. This creates an opportunity to conduct multicenter studies in different regions of the country to determine an overall impact of this phenomenon.It was concluded that frequency of blood eosinophilia in newly diagnosed COPD patients was high, among which most of the patients were having moderate to severe COPD. Therefore, eosinophilia should be considered while managing COPD patients.GMK: Wrote manuscript, did statistical analysis and he is responsible for integrity of research.FFZ: Designed and conceived the study, did statistical analysis and final approval of manuscript.SBUZ & LG: Collected data, literature search and did initial draft write-up."}
+{"text": "High rates of opioid prescribing and comorbid medical conditions increase risk of overdose among older adults. As the US population ages and the rates of opioid use disorder (OUD) increase in the elderly population, there is a need to characterize trends and correlates of overdose in order to more effectively target policy and practice. Using a ~40% random sample of 2015-2017 Medicare beneficiaries ages 65 and older with Part D pharmacy coverage, this study examined medically treated opioid overdoses among US older adults. The sample included 13-14 million beneficiaries per year. The rate of medically treated opioid overdoses among elderly Medicare beneficiaries increased by 15% from 6 per 10,000 in 2015 to 6.9 per 10,000 in 2017. Those with overdose were disproportionately female (63%), non-Hispanic white (83%), with diagnoses of pain conditions (96%), with diagnoses of major depression (63%), and with high rates of conditions that decrease respiratory reserve such as chronic obstructive pulmonary disease. 13% had co-occurring diagnosed alcohol use disorder, 36% were diagnosed with opioid dependence or abuse, and 12% were diagnosed with hepatitis C. Older individuals with overdose represent a complex mix of risk factors; identifying those most at risk  is key in order to address multiple risks, balancing risk reduction with appropriate pain management."}
+{"text": "In 2011, Bluetongue virus serotype 14 (BTV-14) was detected in Russia during routine surveillance, and was subsequently found in a number of European countries. The strain had high sequence similarity to a BTV-14 vaccine strain. We aimed to determine the risk of this BTV-14 strain causing disease in a UK sheep breed. Four Poll Dorset sheep were infected with a Polish isolate of BTV-14 and infection kinetics were monitored over 28 days. BTV RNA was detected in EDTA blood by 4 days post-infection (dpi) and remained detectable at 28 days post-infection (dpi). Peak viraemia occurred at 6 and 7 dpi with Ct values ranging between 24.6 and 27.3 in all infected animals. BTV antibodies were detected by 10 dpi using a commercial ELISA and neutralising antibodies were detected from 10 dpi. BTV was isolated between 6 and 12 dpi. All infected sheep developed mild clinical signs such as reddening of conjunctiva and mucosal membranes, with one sheep demonstrating more overt clinical signs. Two uninoculated control animals remained clinically healthy and did not have detectable BTV RNA or antibodies. The overall mild clinical symptoms caused by this BTV-14 in this highly susceptible sheep breed were in accordance with the asymptomatic infections observed in the affected countries. Bluetongue virus (BTV) of the genus Orbivirus, family Reoviridae, is transmitted between vertebrate hosts by biting midges (Culicoides spp.) [es spp.)  and causes spp.) ,3 of whies spp.) ,5,6. Blues spp.) ,8,9. Altes spp.) , only ines spp.)  due to tes spp.) ,13,14. Des spp.) , their cIn November 2011, a BTV-14 strain was detected in the Smolensk region of Russia and was subsequently detected in central and eastern Europe ,17,18. S10 TCID50 mL\u22121) and were directly cohoused with two uninoculated sheep that were used as negative contact transmission controls (SH05 and SH06). Animals were randomised and observed for clinical signs by independent experienced animal technicians or a veterinarian throughout the experiment and a daily clinical score was recorded for each animal across the following 11 criteria: (1) redness of eyes, (2) redness of oral and nasal mucosal membranes, (3) facial oedema, (4) salivation, (5) nasal discharge, (6) cough, (7) respiratory symptoms, (8) ulcers , (9) food uptake (scoring of reduction), (10) behaviour changes  and (11) reddening/bleeding of the feet . All signs were scored on a scale from 0.5 (very mild) to 3 (severe) in 0.5 increments. Daily body temperatures were also recorded for all animals. This experiment was carried out in accordance with the UK Animal Scientific Procedure Act (ASPA) 1986 which transposes European Directive 2010/63/EU into UK national law. This experiment was conducted in compliance with a national Project License (number 70/6798) granted by the UK Home Office to KED.Four Poll Dorset sheep (SH01 to SH04) were subcutaneously inoculated with 1 mL of BTV-14  was the only sheep to reach an increased body temperature of >41 \u00b0C and a daily clinical score of \u22655 for several consecutive days . Two infAt the end of the experiment (28 dpi), Ct values in the remaining three infected sheep ranged between 29.8 and 32.9 in EDTA blood and BTV was detected in various internal organs . BTV wasBTV outbreaks present a continuous burden to animal health which requires appropriate control responses to mitigate the associated financial losses. The improper use of modified live vaccines has been the cause of a number of European BTV outbreaks  which ha"}
+{"text": "B. indicus) using BovineHD BeadChip. In total, 4138 ROH were detected. The average number of ROH per animal was maximum in draft breed, Kangayam (63.62 \u00b1 22.71) and minimum in dairy breed, Sahiwal (24.62 \u00b1 11.03). The mean ROH length was maximum in Vechur (6.97 Mb) and minimum in Hariana (4.04 Mb). Kangayam revealed the highest ROH based inbreeding (ROHF>1Mb = 0.113 \u00b1 0.059), whereas Hariana (ROHF>1Mb = 0.042 \u00b1 0.031) and Sahiwal (ROHF>1Mb = 0.043 \u00b1 0.048) showed the lowest. The high standard deviation observed in each breed highlights a considerable variability in autozygosity. Out of the total autozygous segments observed in each breed except Vechur, > 80% were of short length (< 8 Mb) and contributed almost 50% of the genome proportion under ROH. However, in Vechur cattle, long ROH contributed 75% of the genome proportion under ROH. ROH patterns revealed Hariana and Sahiwal breeds as less consanguineous, while recent inbreeding was apparent in Vechur. Maximum autozygosity observed in Kangayam is attributable to both recent and ancient inbreeding. The ROH islands were harbouring higher proportion of QTLs for production traits  but lower for reproductive traits  in dairy breeds compared to draft breed. In draft cattle, genes associated with resistant to diseases/higher immunity  and stress tolerant (CCT4) were identified in ROH islands; while in dairy breeds, for milk production . Significant difference in ROH islands among large and short statured breeds was observed at chromosome 3 and 5 involving genes like PTGFR and HMGA2 responsible for milk production and stature, respectively. PCA analysis on consensus ROH regions revealed distinct clustering of dairy, draft and short stature cattle breeds.Genome-wide runs of homozygosity (ROH) are suitable for understanding population history, calculating genomic inbreeding, deciphering genetic architecture of complex traits and diseases as well as identifying genes linked with agro-economic traits. Autozygosity and ROH islands, genomic regions with elevated ROH frequencies, were characterized in 112 animals of seven Indian native cattle breeds ( Runs of homozygosity (ROH), the indicator of genomic autozygosity, may be defined as two contiguous identical by descent (IBD) stretches of homozygous genotypes/segments/haplotypes of a common ancestor in an individual inherited from both of its parents .This autozygosity may arise in inbred as well as non-inbred populations due to several population phenomena like inbreeding, genetic drift, consanguineous mating, population bottleneck, as well as natural and artificial selection . ScanninSince recombination events interrupt lengthy genomic segments, it is anticipated that longer ROH will appear as a result of recent inbreeding in the pedigree. A negative correlation existed between length of the runs and number of generations back the selection or inbreeding event occurred . ConsequCattle breeds in India have evolved over the centuries under diverse agro-climatic conditions as well as breeding and management practices for the purpose of different specialized functions such as dairy, draft and dual (dairy and draft). Consequently, these cattle harbouring putative signatures for specific functions may serve a great reservoir of genetic pool for identification of genes under selection particularly those in ROH regions. Here, three dairy breeds  of sub-tropical hot arid regions, two dual breeds viz. Hariana of sub-tropical hot arid region, and Ongole of tropical semi-arid region were considered. One draft breed, Kangayam of tropical semi-arid region, and one short statured cattle breed, Vechur of tropical hot humid region were also included. All these breeds except Vechur are international breeds, and are bred in good number in different countries across the continents.The present study aimed at delineating autozygosity by identifying and characterizing genome wide ROH patterns in seven Indian native cattle breeds using high density SNP genotyping array (Illumina BovineHD BeadChip). Further, the gene content in ROH regions of these diverse breeds  was also explored to apprehend selection/adaptive footprints.A total of 132 samples of Sahiwal , Tharparkar , Gir , Ongole , Hariana , Kangayam  and Vechur  breeds of cattle were incorporated. The random blood samples were collected from different farms in the country in compliance with the guidelines and regulations of the Institutional Animal Ethics Committee (IAEC), National Bureau of Animal Genetics Resources (ICAR-NBAGR), Karnal . DNA samROH), the average length of ROH (ALROH) and the total number of ROH per breed (nROH) were estimated. The percentage of chromosomes covered by ROH was also calculated. First, the mean ROH length was calculated by summing all ROH (Mb) on a chromosome and dividing by the number of individuals that had ROH on that chromosome; the mean ROH length was then divided by the length of the chromosome in Mb.ROH was estimated for each individual using PLINK v 1.9 . AlthougAlternative to PLINK, an R package called \u201cdetectRUNS\u201d was additionally used to explore genome wide ROH and the results were compared. It makes use of two methods: 1) sliding-window and 2) consecutive runs. The sliding-window based technique is comparable to PLINK ; whereasROHF and HOMF). Inbreeding coefficient based on ROH (ROHF) for each animal was calculated according to PLINK v 1.9  was usedROH represents total length of all ROH in an individual genome while LAUTO refers to the autosomal genome length covered by SNPs included in the array. For each animal ROHF (ROHF > 1Mb and ROHF > 8 Mb) was calculated according to ROH distribution within the length categories: >1 and >8 Mb. Inbreeding based on the observed versus expected number of homozygous genotypes (HOMF) was calculated using PLINK v1.90 by computing observed and expected autosomal homozygous genotypes counts for each sample as follows:where LROHF and HOMF) were also estimated.Spearman\u2019s correlation coefficients among inbreeding measures (https://www.ncbi.nlm.nih.gov/genome/gdv/) was used to identify genes underlying \u00b1 2 MB region on either side of consensus region of top 20 ROH islands. Cattle QTL database  was explored to find the effect of top 20 ROH islands on the underlying QTLs. Test of two proportions was carried out to find the test of significance between the numbers of QTLs affecting the two contrasting groups (dairy vs. draft) under six different traits using XLSTAT. Top five ROH hot spots from the overall ROH group were explored to find the frequency of ROH islands at analogous positions in each cattle breed. Test of K proportion (XLSTAT) was carried out to find out the significant difference of ROH frequencies among the breeds. Gene ontology and pathway analyses were carried out by PANTHER version 13.1 software tool (http://pantherdb.org). Pathway analysis was also carried out by Reactome pathway (https://reactome.org).Overlapping ROH were analyzed by PLINK software. Samples were analyzed overall, breed wise, and utility wise (dairy vs. draft). The number of consensus samples was identified in each group and ROH island frequencies were calculated by dividing the number of consensus samples with total samples in each group. To identify genomic regions most commonly associated with ROH, the samples were analyzed using Manhattan plots of overlapping ROH% across the autosomes for each group. Top 20 ROH islands having a frequency of at least 20% were identified in each group from Manhattan Plots. NCBI map viewer of the bovine UMD3.1.1 (factoextra\u201d (https://cran.r-project.org) to better evaluate the composition of the breeds and to define genetic groups for further downstream calculations. Top 170 ROH regions (loci) of the total samples were selected with a frequency of at least 12.5% for PCA. Three components were extracted out of 6 using Kaiser Rule criterion  was performed using the R software \u201criterion  to deterOut of 132 animals, 20 were removed due to low genotyping (MIND > 0.1). The overall genotyping rate for the remaining 112 animals was 0.99. The quality control measures led to final data on 112 cattle belonging to Sahiwal (13), Tharparkar (17), Gir (15), Ongole (17), Hariana (18), Kangayam (16), and Vechur (16) breeds. Minor allele frequency across the breeds ranged from 0.23 (Kangayam) to 0.26 (Vechur) and observed heterozygosity on an average was 0.35 in all the studied samples (data not shown).ROH) was maximum in Vechur (6.97\u00a0Mb) and minimum in Hariana (4.04 Mb)  and lowest in Sahiwal (24.62 \u00b1 11.03 with a range of 12\u201349). Although, average length of ROH (AL4.04 Mb) Table 1;The total number and length of genome under ROH for each individual in a breed are presented in ROHF> 1 Mb) coefficient of Kangayam cattle was higher compared to that of Gir, Ongole and Vechur. On the other hand, ROHF> 8Mb of Vechur was higher than that of Kangayam and Gir. However, the inbreeding coefficient of Hariana and Sahiwal was lower as compared to other breeds. The correlations of HOMF with ROHF> 1 Mb and ROHF> 8 Mb ranged from 0.810 to 0.959 (HOMF with ROHF> 1 Mb) and 0.839 to 0.979 (HOMF with ROHF> 8 Mb) across the breeds. (ROHF> 1 Mb) values of different breeds/groups are presented in ROHF calculated using PLINK, consecutiveRUNS and slidingRUNS revealed similar patterns in all the breeds  and HMGA2 (High Mobility Group AT-Hook 2) responsible for the milk production and short stature, respectively. There were also significant differences between Gir and Hariana cattle for enriched ROH islands. The detailed functional annotation of genes identified in top 20 ROH islands of dairy and draft breeds is presented in supplementary file (SVIL (Supervillin), LYZL1 (Lysozyme like1), ZEB1 (Zinc Finger E-Box Binding Homeobox 1), and GPX4 (Glutathione Peroxidase 4); and those in dairy breeds were PTGFR, ZAR1L (Zygote arrest-1 like), IFI44 (interferon-induced protein 44), and HELB (DNA helicase B).The Manhattan plots of overlapping ROH % for each group are presented in -2) and G2/M transition with a fold difference of 3.14 (P< 4.35 x10-2) (Gene ontology (GO) analysis identified several enriched GO terms for the ROH gene list in dairy as well as draft cattle Table 5.CSN3) and COP9 signalosome complex subunit 3 (COPS3) were found with highest fold enrichment (31.41). Similarly, 13 genes of steroid metabolic process had an enrichment of 5.92. Panther GO slim cellular component revealed 11 genes with a fold enrichment of 4.46 for cell junction. The key genes were from Cadherin  and Myosin (MYO1A and MYO1B) families. GO cellular component complete revealed five genes with a fold enrichment of 26.18 for Golgi lumen.In dairy cattle, several genes related to mammary gland development were observed in highly enriched GO terms for biological process, metabolic process and cellular component Table 5.LYZL1  as well as genes like CYB561 (Cytochrome B561) and GSR , involved in oxidoreductase activity and antioxidant property, respectively were observed.Under cellular component (microtubule), 13 genes were involved in cytoskeleton structuring and microtubular functions. 30 genes with catalytic activity acting on RNA (fold enrichment 2.53) and 252 genes with catalytic activity (1.28 fold) were also observed under GO molecular function complete Table 5.The structuring of native cattle breeds based on top 170, 92, and 10 contributing ROH islands is presented in B. indicus). Minimum of 13 (SW) to maximum 18 (HR) animals per breed remained after quality filtration. For diversity analysis, the existing number of samples in each breed greater than 12 was adequate and in consonance with other studies  revealing a greater historical relatedness  and/or sROHF> 1Mb) in all the breeds except Kangayam (ROHF > 1Mb = 0.113). The estimates of inbreeding were in agreement with the abundance and length of ROH in the sampled populations. Estimation of inbreeding coefficients using ROH >8 Mb confirmed to be the most consistent with pedigree-based estimates  in some of the present breeds  was similar but higher for others  compared to the estimates of Nellore cows (ROH> 8 Mb) was lower than the current estimates. The average autosomal FROH> 1Mb for Bos taurus breeds ranged from 6-15% . The production/reproduction characteristics of these breeds were in consonance with the proportion of identified QTL in top 20 ROH in each group for these traits (HMGA2 polymorphism observed in this cattle. HMGA2 polymorphism had earlier been found to be associated with the difference in body stature in mice (pygmy size)  and stress tolerant (CCT4). Whereas, dairy breeds had selection sweeps in key genes governing milk production .The dairy and draft cattle breeds had contrasting phenotypic/production and reproduction characteristics. Kangayam had lower age at first calving (39.99 months) than dairy breeds (mean of 45.09 months for four dairy breeds) indicating its higher reproductive efficiency. Whereas, milk production was lower in Kangayam (540 kg/lactation) compared to the average milk production of 4 dairy breeds (1792.75 Kg/lactation) indicating the superiority of dairy breeds for milk production (e traits Table 3.my size) , humans my size)  and cattmy size) . Recentlmy size) .The analCSN3 and COPS3, cadherin and myosin family genes were found to be enriched under GO Slim cellular component (cell junction) in dairy breeds, indicating their explicit role in mammary gland physiology. Cadherin is a calcium-dependent cell-cell adhesion glycoprotein crucial for alveolar epithelial cells differentiation in lactating mammary gland as well as involution of mammary gland after weaning  where genome coverage is found to be almost equal in short (ROH >1 Mb) and long (ROH >8 Mb) ROH regions. The level of genomic inbreeding (ROHF) revealed that the breeds are mostly random bred and hence preserve sufficient genetic variability. The ROH regions observed in these cattle breeds were able to differentiate dairy and draft breeds as well as small stature cattle revealing selection/adaptive footprints. The selection signatures in and around genes responsible for milk production, immunity, stress tolerance, and small stature were identified in dairy, draft, and miniature cattle.In conclusion, our study highlights characterization of autozygosity in seven diverse Indian cattle breeds , Govt. of India.The authors declare that the research was conducted in the absence of any commercial or economic associations that could be construed as a potential conflict of interest."}
+{"text": "Prevention of Human Immunodeficiency Virus infection is a high priority for the government of Nepal, so the government has been scaling up Anti Retroviral Therapy centers throughout the country. The objective of our study was to find out the prevalence of people living with Human Immunodeficiency Virus infection on Anti Retroviral Therapy service.This descriptive cross-sectional study was done in Lamjung district hospital, from May 2017 till August 2017 after taking ethical clearance from the institutional review committee. The study was done in 96 patients and convenience sampling was done. The data collected was entered in Microsoft Excel and analyzed in Statistical Packages for Social Sciences version 17.0, point estimate at 95% Confidence Interval was calculated along with frequency and proportion for binary data.Out of the total 109 patients enrolled at the hospital, 85 (78%) were on ongoing Anti Retroviral Therapy. The predominant age group among patients using Anti Retroviral Therapy was 25-34 years 27 (31.7%) and the five most common clinical manifestation/opportunistic infections were fever 40 (47.1%), diarrhea 34 (40%), fatigue/generalized weakness 32 (37.6%), loss of appetite 25 (29.4%) and headache 18 (21.2%) among them. Out of total patients, 14 (12.8%) of our patients were under 14 years of age. We found 71 (83.6%) of the patients continued the original first-line regimen and in 14 (16.5%) one or two drugs were substituted in the original regimen.Our study showed a similar prevalence of people living with Human Immunodeficiency Virus infection on Anti Retroviral Therapy service with the other studies done within Nepal. After taking informed consent, patients were interviewed to fill up the pre-structured questionnaire and the records were kept confidential and participation in the research was completely voluntary. The sample size was calculated using the following formula.n= required sample sizeZ= 1.96 at 95% confidence intervalp= prevalence of people living with HIV infection on ART Service (50%)q= prevalence of people living with HIV infection no on ART Service (1-p)e= margin of error (10%)where,The calculated sample size was 96 and convenience sampling was done. The data collected was entered in Microsoft Excel and analyzed in SPSS  version 17.0.Out of the total 109 patients enrolled at the hospital, 85 (78%) were ongoing ART among which the female to male ratio was 1.2:1. Out of total patients, 14 (12.8%) of our patients were under 14 years of age and 24 (22%) of the patient had been deferred from the therapy including 9 (8.2%) deaths .The predominant age group was 25-34 year which included 27 (31.7%) of patients followed by 15-24 year which included 20 (23.5%) of patients .The most common clinical manifestation/opportunistic infections were fever 40 (47.1%), diarrhea 34 (40%), fatigue/generalized weakness 32 (37.6%), loss of appetite 25 (29.4%) and headache 18 (21.2%) among our patients .In the study 71 (83.6%) of patients continued the original first line regimen and in 14 (16.4%) one or two drugs were substituted in the original regimen .The study showed ART adherence of above 95% on the adherence scale in our patient.4 The sixty-ninth World Health Organization (WHO) assembly endorsed a new global health sector strategy on HIV for 2016-2021. The strategy guides priorities action for every country for high priority for the prevention of HIV/AIDS-related infection.5 At Lamjung district hospital, ART service has been started since 2010, a total of 109 patients had been enrolled for the therapy. Our patients belonged from three different districts-Lamjung, Tanahun and Gorkha as the district hospital is easily accessible to the individuals of these districts. Presently, 85 patients were continuing ART medicines from the hospital. A number of patients undertaking ART at other district hospitals-like Damauli, Syangja, Gorkha were in the range of 65 to 100 as per communication with focal persons of these centers. Our study showed an increasing number of female patients compared to the male patient which differs from the national HIV/AIDS cumulative reported data. There are increasing numbers of male population migrating abroad for working including India, leading to increased infection among females. These findings were similar in other Western and Far Western regions; a study of Dhangadi showed increasing number of female patients compared to males.6 The present study at our district hospital revealed that the most common clinical presentations/Opportunistic Infections (OI) were fever (47.1%), diarrhea (40%), fatigue/weakness (37.6%), loss of appetite (29.4%), headache (21.2%) and pneumonia (16.5%). These findings were more suggestive of symptomatic primary HIV infection also known as Acute Retroviral Syndrome. A study from central Nepal showed predominant OIs among PLHA were oral candidiasis (32.0%), streptococcal pneumonia (28.7%), salmonella infection (20.7%), cryptosporidial infection (19.3%), and tuberculosis (10.0%).7 In the eastern region of Nepal, study done by Khanal VK et al. showed common OIs were weight loss (74.4%), fever (59.4%), cough (36.3%) and diarrhea (32.5%).8 Poudel BN et al. at Seti Zonal Hospital revealed fever (71.7%), diarrhea (56.6%), pneumonia (52.8%), weight loss (52.8%) and oral thrush (33.9%) to be the major clinical presentation/Opportunistic infections.9 In studies from India done by Singh S et al. the common clinical features were fever (36.6%), respiratory infections (31.7%), lymphadenopathy (30%), hepatosplenomegaly (21.8%) and diarrhea illness (18%).10 The clinical features of admitted HIV infected patients from Pakistan done by Siddique MH et al. at tertiary level teaching hospital showed that the three most common clinical features were weight loss (59.6%), fever (42.3%) and diarrhea (38.8%).11 These clinical features/OIs were similar to the presentation of our patients suggesting a similar strain of virus circulating in the region. Effective use of ART is the most useful intervention for suppressing HIV replication, preventing OIs and prolong the survival of PLHA.13 Our study showed above 95% treatment adherence scale among the PLHA and the findings were similar from a study done at ART center of the western region.14This cross-sectional study was conducted at the ART center of Lamjung District Hospital, Lamjung Nepal and out of the total 109 patients enrolled at the hospital, 78% were on ongoing ART. The National HIV/AIDS strategy 2002-2006 clearly states five priority areas for the prevention of STI and HIV infection within the country. Effective surveillance and efficient management of prevention of HIV/AIDS remains an important element for control of the infection and decrease the morbidity and mortality from AIDS-related illness.Since this study was done in a small sample size and convenient sampling was done, the findings of this study can\u2019t be generalized. Hence, further study with random sampling and larger sample size is recommended. But the finding may have implications in scaling up ART centers and early initiation of ART at the primary care level for HIV prevention to the eligible patients would be a comprehensive strategy to prevent HIV epidemic progression in developing countries like Nepal.Our study showed a similar prevalence of clinical symptoms and opportunistic infections like fever and diarrhea with the other studies done within Nepal."}
+{"text": "IntroductionFebrile neutropenia (FN) is a dreaded complication of cancer chemotherapy and frequently associated with respiratory infections. Flexible bronchoscopy (FB) serves as a useful diagnostic tool in this regard.ObjectiveTo determine the diagnostic yield, safety\u00a0and clinical implications of bronchoalveolar lavage (BAL) in cancer patients with FN, having lung infiltrates on radiographic chest imaging.MethodsWe reviewed medical records of FN patients who underwent FB\u00a0at Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, from July 2015 till July 2018. The culture yield of BAL, resultant change of management and outcome over the subsequent 30 days were retrospectively analysed. Statistical Package for Social Sciences (SPSS) version 20  was used for data analysis.ResultsNinety FN patients, with mean age 26 \u00b1 18 years and\u00a0predominantly males  were included in the study. Seventy-seven (85.6%) had hematological and 13 (14.4%) solid organ malignancy. The mean absolute neutrophil count was 0.20 +/- 0.36/ \u00b5L. BAL cultures were diagnostic in 40 (44%) patients; the etiology was bacterial, fungal and mixed in 25 (62.5%), 14 (35%) and one (2.5%) patient, respectively. All patients were on empirical antibiotics prior to bronchoscopy: 32 (35.6%) on antibacterial alone and 58 (64.4%) on antibacterial plus antifungal therapy. Change of management occurred in 51 (56.7%) patients after BAL results, including de-escalation from dual antibiotics in 28 (55%) and initiation of new culture sensitive antibiotic in 23 (45%). FB-associated complications developed in three (5.6%) non-intensive care patients (ICU), including transient hypoxia in two and minor hemoptysis in one patient, while five (14.8%) mechanically ventilated patients in ICU experienced worsening of oxygenation parameters within 48 hours. Overall, 24 (26.7%) patients died. Mortality was 3.7% in non-ICU and 69% in ICU setting and significantly higher in patients with fungal pneumonias  and with prolonged neutropenia .ConclusionsBAL is a safe diagnostic tool for FN patients with lung infiltrates, with minimal complications and sufficient diagnostic yield to improve diagnosis and management of such patients. Febrile neutropenia (FN), a dreaded complication of chemotherapy and cancer, is attributed with increased hospitalization costs, morbidity and mortality in cancer patients ,2.\u00a0RespiDespite high diagnostic yield, opinion on\u00a0the implications of bronchoscopy for FN patients remains divided. Certain authorities report high mortality with no significant improvement in outcome  while otWhile working at a facility dedicated to cancer patients, we encounter both adult and pediatric patients who develop FN during the long haul of their treatment course. The purpose of this study was twofold; firstly, to determine the diagnostic culture yield and complication risk of BAL for FN patients in our population setting, and secondly to evaluate its implications on such patients in terms of change of empirical to targeted antibiotic therapy and the resultant outcomes in terms of mortality and discharge. One of the concerns that led to the need for such a study in our setup was the high mortality in FN patients despite timely institution of empirical treatment. With this endeavor, we intend to improve evidence-based practice in our setup and improve the quality of patient care.After formal approval from the Institutional Review Board (IRB) of Shaukat Khanum Memorial Cancer Hospital and Research Center, Lahore, we acquired the data of 523 patients who underwent flexible bronchoscopy from July 2015 until July 2018. Of these, all patients with FN who underwent flexible bronchoscopy for diagnosis of lung infiltrates were shortlisted. The relevant clinical information was collected from the electronic medical records of the patients. Study design was observational .Neutropenia was defined as an absolute neutrophil count (ANC) of less than 500/\u00b5l, or less than 1000/\u00b5l with an expected decline to <500/\u00b5l in the subsequent 48 hours . FebrileBronchoalveolar lavage (BAL) using flexible bronchoscopy had been obtained by injecting aliquots of 60 to 100 ml isotonic normal saline in the identified lung sub segment(s) followed by active suctioning. The specimen underwent Gram/Giemsa staining, bacterial and fungal cultures, Mycobacterium tuberculosis culture and rapid polymerase chain reaction (PCR). Additionally, silver staining for Pneumocystis jirovecii pneumonia (PJP) and AFB staining for Nocardia was performed wherever indicated.\u00a0Positive cultures were diagnostic for bacterial and fungal pneumonias while in selected cases, elevated serum fungal markers {-\u03b2-D Glucan and Aspergillus galactomannan} were regarded as diagnostic .Patient medical records were followed for 30 days post procedure for any change of treatment. Change of treatment was defined as either switching over to a culture sensitive antibiotic or de-escalation of antibiotics to single genre where dual therapy was started empirically. Complications in the immediate 48 hours post procedure were noted.\u00a0All data was analyzed in SPSS  version 20 . Independent t- test was used to compare difference of means and p-value < 0.05 was considered significant.A total of 90 patients with FN underwent bronchoscopy and BAL within the defined period, including 59 (65.6%) male patients, with mean age\u00a026 \u00b1 18 years. Out of total, 36 (40%) patients were admitted to intensive care unit (ICU), while 27/36 (75%) were maintained on mechanical ventilation prior to the procedure. Nineteen (21%) patients had a positive blood culture while sputum\u00a0cultures were positive in just three (3.3%) patients. Among mechanically ventilated patients, tracheal aspirate cultures were positive in 6/27 (22.2%) patients. All patients had been started on empirical antibiotics, out of which 58 (64.4%) were on combination antibacterial and antifungal therapy\u00a0(see Table BAL cultures were positive and diagnostic in 40 (44%) patients and the etiology was bacterial, fungal and mixed in 25 (62.5%), 14 (35%) and one (2.5%) patients, respectively. The culture etiology was thus predominantly bacterial and Pseudomonas was identified as the most common etiology of lung infiltrates in our patients, followed by Aspergillus  such patients, based on radiological impressions and supported by raised 1, 3-\u03b2-D Glucan and Aspergillus galactomannan antigen levels. In the remaining culture negative patients, neutropenic sepsis was the final diagnosis in 11 (22%), neutropenic colitis and acute respiratory distress syndrome in\u00a0six (12%) patients each, drug-induced pulmonary toxicity and pulmonary edema in five (10%) each, diffuse alveolar hemorrhage in three (6%) and pulmonary embolism and hypersensitivity pneumonitis in one (2%) patient each.Subsequent to culture results, 51 (56.7%) patients underwent treatment modification. The change of treatment included de-escalation from dual combination  to single genre in 28 (55%) and initiation of a new culture sensitive antibiotic in 23 (45%) patients overall. Change of treatment affected 34 (85%) with positive and 17 (34%) patients with negative BAL cultures. Eleven patients were determined to have sensitivity to an oral antimicrobial and hence parenteral treatment was discontinued.\u00a0The duration of empirical antimicrobial treatment was determined to be longer in BAL culture negative patients for a median of two days compared to culture positive patients , however the difference of means was statistically non-significant . Following the procedure, 66 (73.3%)\u00a0patients were discharged within 30 days after necessary antibiotic modification, including 27 patients with positive and 39 patients with negative BAL cultures.\u00a0BAL culture driven treatment modification affected 76.5% patients discharged.Only three (5.6%) non-ICU patients reported complications within 48 hours of bronchoscopy. These included dyspnea/hypoxia in two and hemoptysis in one patient(s) respectively, both complications being self-resolving in the subsequent 24-48 hours. All 27 mechanically ventilated patients had baseline fraction of inspired oxygen (FiO2) requirement of \u226450%.\u00a0Post procedure deterioration in oxygenation and ventilation parameters  was seen in at least four (14.8%) and a similar number died within five days of bronchoscopy. Only one non-ICU patient required mechanical ventilation after 72-96 hours of bronchoscopy, having worsening hypoxia and radiographic infiltrates, with dual etiology growth on BAL culture, and succumbed to acute respiratory distress syndrome on 2nd ICU and 6th post procedure day. Overall, 24 patients died, bringing the cumulative mortality to 26.7%. The mortality was 69% in ICU, 3.7% in non-ICU patients  and those with longer duration of neutropenic fever . There also appeared to be a higher mortality with prolonged duration of hospitalization as well as empirical antibiotic therapy. There was no statistically significant mean difference of mortality between gender, cancers of different origin and age group (adult versus pediatric). See Table Significant co-morbidities complicated the clinical course in all of the 24 patients who died. Twenty such (83%) patients had severe neutropenic sepsis .\u00a0The main complications included septic shock in 18 (75%), multi organ dysfunction in eight (33%), disseminated intravascular coagulation in six (25%), acute respiratory distress syndrome (ARDS) in six (25%) and acute renal failure in 11 (46%) patients overall. Additionally, eight (33%) patients had severe anion gap metabolic acidosis while three (13%) developed hypothermia in terminal days. Five (21%) patients succumbed to upper gastrointestinal bleeding, three (13%) to pulmonary edema and heart failure secondary to drug-induced cardiotoxicity, two (8%) patients to intracranial hemorrhage, one (4%) patient to pulmonary embolism.\u00a0Among the two non-ICU patients who died, the cause of death was severe upper gastrointestinal (GI) bleeding in one and hypokalemia-induced cardiac arrhythmia in second patient, both events not associated with bronchoscopy.This retrospective study reports an appreciable diagnostic culture yield of BAL for patients with FN and lung infiltrates (44%), with minimal complication risks. The findings are comparable to previous studies in terms of diagnostic yield and safety -11. The As per our findings, the duration of neutropenic fever adversely affects mortality. Previously\u00a0Seneviratna et al.  and PeikThe clinical implications of bronchoscopy for critically ill patients have been challenging to determine, with high mortality recorded in previous studies. Mortality in ICU and mechanically ventilated patients has been reported to be as high as 71% and 93% respectively by Gruson et al. \u00a0and 77% The predominant etiology of pneumonias was determined to be bacterial in our setting . Precedent studies largely report fungal etiologies , while sThe limitations of this study remain its retrospective nature, due to which findings may have been affected by biases of treating physicians. For the same reason, the observation of increased risk of mortality in certain subsets of patients can be reported as prevalence data more than true association.\u00a0None of our patients underwent transbronchial lung biopsy, which in certain precedent studies improved the diagnostic yield ,24. We aFlexible bronchoscopy has an appreciable diagnostic yield with BAL in FN patients with lung infiltrates. This study concludes that\u00a0BAL also has an acceptable safety profile and poses minimal complication risk to patients in both ICU and non-ICU setting, and is largely beneficial in terms of facilitating judicious use of antibiotics, especially de-escalation of unwarranted empirical antibiotic therapy. This study suggests that while there may be no impact of the duration of empirical antibiotics on culture yield of BAL, longer duration of neutropenic fever as well as hospitalization and empirical treatment prior to bronchoscopy may result in poorer outcomes in such patients. This reiterates the approach for early diagnostic imaging and intervention for FN patients. The predominant etiology of infection was determined to be bacterial in our population setting, whereas fungal pneumonias were determined to be associated with significantly higher mortality. Of note, among critically ill patients, especially those maintained on mechanical ventilation, the risk of bronchoscopy-related complications is much lower than the actual mortality."}
+{"text": "Left ventricular diastolic dysfunction (LVDD) serves as a prognostic indicator of adverse cardiovascular events. Cardiac magnetic resonance (CMR) imaging is the gold standard for evaluating ventricular size and systolic function, but there is limited data on the utility of CMR in the evaluation of diastolic function. To assess the accuracy of CMR in assessing LVDD we compared quantitative CMR to Doppler echocardiography (ECHO).20 patients with cardiomyopathy underwent both CMR and ECHO studies. Through plane phase contrast CMR and Doppler ECHO was performed for assessment of early (E) and late (A) mitral inflow velocities, early mitral deceleration time (DT), and early (e') myocardial tissue velocities of the basal lateral wall. The two imaging methods were correlated for measurement of several parameters of diastolic function including E/A ratio, E DT, and e'. Diastolic function was assessed based on a combination of mitral inflow and myocardial tissue velocities and was classified as normal, abnormal relaxation, pseudo-normal or restrictive.There was a statistically significant correlation for measurement of E/A ratio with both techniques , but not for any of the other parameters evaluated . Patients were classified by ECHO into diastolic functional grades as: 4 (20%) normal, 7 (35%) abnormal relaxation, 4 (20%) pseudo-normal, and 5 (25%) restrictive. Diastolic function grade was identical in 10 (50%) patients, differed by 1 grade in 5 (25%), differed by 2 grades in 3 (15%), and differed by 3 grades in 2 (10%). CMR tended to underestimate the degree of diastolic dysfunction in 70% of patients compared to ECHO, and there were 3 patients (15%) who were classified as normal by CMR, but who demonstrated some evidence of diastolic dysfunction on ECHO.CMR can detect the presence of LVDD with reasonable accuracy, although it tends to underestimate the degree when compared with Doppler ECHO."}
+{"text": "Background: Neonatal sepsis is the third leading cause ofneonatal mortality, behind prematurity and intrapartum-related complications.The main objectives of this study are to assess the proportion of sepsis inpreterm newborns and identify the etiologic agents and their antibioticsensitivity patterns. Methods: A longitudinal observationalstudy was done from July 2016 to May 2018. Whenever clinical diagnosis of sepsiswas made, blood cultures and antibiotic susceptibility tests were done.Result: We did 690 blood cultures, 255 (36.9%) showingbacterial growth. The most commonly isolated bacteria were Klebsiellaspecies 78 (36.6%), Coagulase negativeStaphylococcus 42 (19.7%) and Staphylococcusaureus 39 (18.3%). Gram-positive bacteria showed high resistance topenicillin (98.9%) and ceftriaxone (91.3%) whereas Gram-negative bacteria werehighly resistant to gentamicin (83.2%) and ceftriaxone (83.2%).Conclusion: Resistance to the more commonly usedantibiotics such as ampicillin and gentamycin was very high, necessitatingreconsideration of the empiric use of these antibiotics. It is important to choose an antibioticregimen that covers the most common pathogens.8 Neonatal sepsis is classically defined as the presence of symptoms of sepsisin the neonatal period combined with bacteriological isolation of an infectiousagent from blood or cerebrospinal fluid (CSF).9 Early-onset neonatal sepsis refers to the presence of a confirmed infectionin the blood or CSF of patients younger than 3\u2009days of life, and late-onset neonatalsepsis refers to the onset of such infections between 3 and 28\u2009days.10Blood culture remains the gold standard for diagnosis of neonatal sepsis, despite itslow sensitivity which may be due to small volume of the blood sample, or the use ofempirical antibiotics prior to sampling.12 This variation is oftenattributed to the changing pattern of antibiotic use and changes inlifestyle.14The type of organisms causing sepsis varies from one region to another and changesover time even in the same place.15The continuous evolution of drug resistance of pathogens causing neonatalsepsis is a major problem. Notably, methicillin resistant S. aureus(MRSA) and extended spectrum beta lactamase (ESBL) producing bacteria and multidrugresistant (MDR) Gram-negative organisms represent the principal setbacks to fightinginfections. Most Gram-negative bacteria are now resistant to ampicillin and many arealso becoming resistant to gentamicin.17In developing countries, clinically diagnosed sepsis occurs in 49-170 newborns per1000 live births, whereas culture-proven sepsis occurs in 16 per 1000 live births.Although antimicrobial treatment is the cornerstone of the treatment of neonatalsepsis, due to the lack of local data on bacterial profiles and antimicrobialresistance patterns, there is a lack of clear consensus on the choice ofantimicrobials for many settings in LMICs. Therefore, clinicians in LMICs arelimited to use the data from the other settings, mostly from developed countries, toinform their treatment decisions.The primary objective of this study was to assess the proportion of clinical andbacteriologically confirmed sepsis among preterm newborns admitted to selectedhospitals in Ethiopia.The secondary objectives of this study include:To determine common organisms causing sepsis in preterm newbornsTo determine antimicrobial susceptibility of the identifiedmicroorganisms18A multi-center longitudinal observational study design was used which includedall preterm babies (<37\u2009weeks of gestation) who were either delivered in orwere referred to the study hospitals before 7\u2009days of life from July 2016 to May2018. Preterm newborns admitted at >7\u2009days of life were excluded from thestudy as the original study used Ballard score (which is accurate before 7\u2009daysof life) to accurately estimate the gestational age of the babies for inclusioninto the study. Thus, for this analysis, we included those neonates who wereadmitted to a NICU at <7\u2009days. The preterm babies admitted to the NICUs wereidentified based on the study eligibility criteria by trained nurses. Afterscreening, written informed consent was obtained from parents before enrollingthe babies. The maternal medical history and physical examination includinggestational age estimation was done by trained study physicians. Once a clinicaldiagnosis of sepsis was made , patients oftenunderwent necessary laboratory investigations including complete blood count(CBC), blood culture, and CSF analysis and culture to establish the diagnosis ofsepsis. Other investigations were also done as clinically indicated.The study was conducted in five hospitals in Ethiopia: Tikur Anbessa SpecializedHospital (TASH), St. Paul\u2019s Millennium Medical College (SPMMC) and GhandiMemorial Hospital, located in Addis Ababa, and Jimma University Medical Centre(JUMC) and Gondar University Hospital (GUH), located in the southwestern andnorthwestern parts of the country, respectively.Addis Ababa University and all participating institutions provided ethicalapproval of the study. All parents were provided written informed consent priorto their infants\u2019 participation in the study.TM FX40 machine which was inspected daily for a total of5\u2009days. When an alert was observed, the BACTEC bottle was taken from themachine, and sub-cultured on MacConkey Blood agar , andChocolate Agar (candle jar) media and incubated at 35-37\u00b0C for18-24\u2009hours aerobically. At TASH and GUH, the blood specimens were collected andinoculated on brain heart infusion broth and inspected for five days. At allhospitals, further bacterial identification was performed based on the AmericanSociety for Microbiology (ASM) identification guidelines.At all hospitals, a minimum of 1ml of blood was drawn aseptically from theneonates with suspected sepsis using a butterfly needle. At Jimma and St. PaulHospitals, the blood was added into BD BACTEC Peds Plus blood culture bottle andgently mixed. The blood culture bottle was then incubated in the BDBACTECAntibiotic susceptibility testing was carried out using the Kirby Bauer discdiffusion technique using Muller Hinton agar . Antibiotic discswere selected based on CLSI guidelines. Accordingly, penicillin, cefoxitin,ampicillin, erythromycin, clindamycin, trimethoprim-sulphamethoxazole,oxacillin, amoxicillin clavulanic acid, ceftazidime, gentamicin, ciprofloxacin,and chloramphenicol were used. All the antimicrobials used for the study wereobtained from Oxoid Ltd., Basingstoke, Hampshire, UK. The drug susceptibilityresults were measured using calipers and based on zone of inhibition; theresults were reported as resistant, intermediate and susceptible to the treatingclinicians so that they could modify the treatment accordingly.Multi drug resistance (MDR) was defined as bacterial strains resistant to atleast one agent in three or more antimicrobial classes.Escherichia coli ATCC 25922and S. aureus ATCC 25923 were used for media and antibioticdisk performance checks.Data were checked and reviewed regularly for any incompleteness or outliers andany issues were rectified by the site principal investigators before entry intothe database. Reference strains of Data were collected using Case Report Forms (CRF) that were formulated andreviewed by various physicians in their respective field of expertise. The datawere entered into a computer using the data management system (DMS) developedfor this study. Finally, electronic data were transferred, cleaned, merged toone master data and stored centrally using the Structured Query Languagedatabase that was later analyzed in SPSS version 20. Frequencies and crosstabulations were used to summarize descriptive statistics. Descriptivestatistics were also used to present antimicrobial susceptibility patterns.Among all preterm newborns  enrolled into the study, 2,003 had aclinical diagnosis of sepsis, making the overall proportion of clinical sepsis40.7%. Of those diagnosed with clinical sepsis, 1,807 (90.2%) had early onsetneonatal sepsis (EONS) and 196 (9.7%) had late onset neonatal sepsis (LONS).The majority of those with clinical sepsis were male (53%) and 905 (45%) werefemale. There were more early (<34\u2009weeks) preterm newborns with a diagnosisof clinical sepsis, 1,071 (53.4%) than late preterm newborns (34-36\u2009weeks), 932(46.5%). Most were delivered in health institutions  either in thestudy hospitals or health centers.Klebsiella species (spp.) 78 (33.9%) followed byCoagulase negative Staphylococcus (CoNS) 42 (18.2%),S. aureus 39 (16.9%) and E. coli 12(5.2%).Of the study participants with neonatal sepsis, only one-third, 690 (34%) hadblood cultures done, of which 255 (36.9%) showed bacterial growth . NineteeS.aureus was found to be highly resistant to Oxacillin(85.3%). Bettersensitivity to ciprofloxacin was observed among the Gram-positive bacteria (59%)(Gram-positive bacteria showed high resistance to penicillin (98.9%),amoxicillin-clavulanic acid (79.3%) and ceftriaxone (91.3%). ia (59%).Gram-neia (59%).Klebsiella spp.(92%) and S. aureus (92.3%)were found to be predominantly MDR (Multidrug Resistance (MDR) was observed in 199 isolates (91.3%).ntly MDR .19 Higher rates of positive results were reported in Indonesia (65.3%), Georgia(63%) and Yemen (57%).2022The overall culture positivity rate from patients with symptoms of neonatalsepticemia was 36.9%, which was slightly lower than results previously reported fromGondar (46.6%) and Addis Ababa (44.7%).23 In contrast, much lower ratesof positive results were reported from Iran (5.6%), Kuwait (8.7%), and Saudi Arabia(5%).2426This variation could be due tomethodological differences, time of blood culture collection and prior antibioticadministration, all of which might affect the culture positivity rate.On the other hand, the present study culture positivity rate was higher than observedin studies from Nepal (20.3%) and Gondar (32.1%).Klebsiella spp. accounting for 78 (33.9%) followed byGram-positives like CoNS 42 (18.2%) and S. aureus 39 (16.9%). Therewas a similar report from Addis Ababa where Klebsiella spp. (39.2%)and S. aureus (22.2%) were the most commonly isolated organisms. Areport from Sudan showed that Klebsiella (71.1%), S.aureus (15.8%), E. coli (5.3%), Gram-positive cocci (2.6%) andSerratia marcescens (5.3%) were associated with sepsis in newborns.27 In Nigeria as well, neonatal infections were due to Gram-positive andGram-negative organisms such as S. aureus (24.6%),CoNS (24.6%) and Klebsiella spp. (16.4%).28In our study, the predominant isolates causing sepsis were Gram-negative organismswith Staphylococcusepidermidis (34%), Streptococcus viridians (28%) andCandida species (14%). A report from the United Kingdom showedCoNS and GBS being organisms frequently seen in EONS, whereas CoNSand E. coli were most frequently associated with LONS. A study fromthe USA also showed that Gram-positive bacteria such as GBS weremore predominant etiologies of sepsis.25The results of the current study agree with the reports from most developingcountries but differ from those reports from Kuwait where the most frequentorganisms isolated were Gram-positive organisms like 29 given that the deliveries of our patients occurred in health facilities(95%).As shown in this report and reports from other developing countries, most pathogensisolated in the hospital setting before 72\u2009hours of life are similar to thoseisolated afterward. It is highly likely that unclean delivery practices areassociated with infections with nosocomial agents very early in lifeKlebsiella spp. was the predominant isolate in the present study,representing 33.9% of the total isolates, of which K. pneumoniaewas the predominant bacteria identified. Similar findings reported from Georgia, USAshowed K. pneumoniae accounting for 29% and Yemen 36.7%.22Klebsiella spp. (92%), S. aureus (92.7%) andCoNS (100%) were found to be mostly MDR. This frequency ishigher than that found from a study done in Gondar where the overall MDR prevalencewas 65% and S. aureus (61.2%) and K. pneumoniae(74%) were found to be the principal MDR strains.10 In Addis Ababa, Gram-negative bacteria showed high-level resistance toampicillin, ceftriaxone, cephalothin, chloramphenicol, and gentamicin. Multidrugresistance was observed in 45.7% and 84.2% of Gram-positive and Gram-negativebacteria respectively.19A very high prevalence of bacterial causes of neonatal sepsis and an alarmingly highlevel of antibiotic resistance in the isolates were observed in the current study.The overall MDR prevalence was 91.3% and it has been demonstrated that bacteria likeOne of the major limitations of this study is that only about one-third of infantswith a clinical diagnosis of sepsis had a blood culture done. Reasons for this gapincluded failure to order blood culture by the hospital staff as a routineinvestigation for sepsis and difficulty of obtaining blood encountered in some ofthe newborns. The other limitation is the different methods of culture used at thedifferent study sites which affects the blood culture positivity, as conventionalblood culture suffers from poor sensitivity due to the lack of use of nutritionallyenriching substances, inability to neutralize the inherent antimicrobial componentsin blood and/or in patients receiving antimicrobial treatment.Although advances in neonatal care have improved survival and reduced complicationsin preterm infants, sepsis still contributes significantly to mortality andmorbidity among very-low-birth-weight infants in neonatal intensive care units.Bacterial isolates from neonatal sepsis show variation from place to place, andindicates that there is a need for continuous monitoring of causative organisms andtheir drug susceptibility patterns at a local level.Klebsiella spp, CoNS and S. aureus were thepredominant pathogens associated with sepsis. The overall prevalence of MDR was91.3% which was high for most of the isolates. Ciprofloxacin was the most effectivedrug against both Gram-positive and Gram-negative bacteria. Even though there is ahigh rate of resistance seen in this report for the commonly prescribed antibiotics,further research is needed at the community level for revision of treatmentguidelines.A higher proportion of bacterial isolates was observed in this study."}
+{"text": "Since the Global Polio Eradication Initiative (GPEI) was established in 1988, two of the three wild poliovirus (WPV) serotypes (types 2 and 3) have been eradicated.Since May 2016, after trivalent OPV  was withdrawn from use, only bivalent OPV  and injectable inactivated poliovirus vaccine  have been used in routine immunization programs worldwide. In 2018,In 2018, approximately 1.2 billion bOPV, 32 million IPV, and 16 million monovalent OPV type 1 (mOPV1) doses were administered in 35 countries during 105 supplementary immunization activities (SIAs)WPV and cVDPV transmission is primarily detected by surveillance for acute flaccid paralysis (AFP) among children aged <15 years and confirmed by stool specimen testing in WHO-accredited laboratories within the Global Polio Laboratory Network. AFP surveillance performance indicatorsCountries reporting WPV cases and isolations. No WPV cases have been identified outside of Afghanistan, Nigeria, and Pakistan since 2015; the most recent reported onset of a WPV1 case in Nigeria was in September 2016. In 2018, 33 WPV1 cases were reported worldwide: 21 (64%) in Afghanistan and 12 (36%) in Pakistan  were reported by Afghanistan, representing a 38% increase over the 21 cases reported in 2018. Cases were reported from 20 districts, a 43% increase from the 14 districts reporting cases during 2018. Among 54 WPV1 cases detected during January\u2013March 2020, 12 (22%) cases were detected in 11 districts of 10 provinces in Afghanistan, compared with six cases reported in six districts of three provinces during the same period in 2019. In Afghanistan, WPV1 was detected in 83 (25%) of 336 sewage samples collected from 15 of 20 (75%) sites at regular intervals in 2018 and 56 (22%) of 259 samples from 12 of 21 (57%) sites in 2019 .Pakistan reported 147 (84%) of the 176 WPV1 cases in 2019, an elevenfold increase over the 12 cases reported in 2018; cases were reported in 43 districts, a sixfold increase over the six districts with confirmed cases in 2018. During January\u2013March 2020, 42 (78%) WPV1 cases were detected in four provinces , a sixfold increase over the six cases in three provinces  reported during the corresponding period in 2019. In Pakistan, WPV1 was detected in 139 (20%) of 689 environmental surveillance samples from 37 of 58 (64%) sites in 2018 and 371 (47%) of 786 samples from 56 of 60 (93%) sites in 2019 . WPV1 ofCountries reporting cVDPV cases and isolations. During January 2018\u2013March 2020, cVDPV transmission was confirmed in 26 countries. Five countries  reported four cVDPV type 1 emergences, with isolates from 39 AFP cases and 40 environmental surveillance samples. Twenty-three countries  reported 49 cVDPV2 emergences, with isolates from 547 AFP cases in 21 countries and 354 environmental surveillance samples in 15 countries. Among these, the JIS-1 Nigeria emergence has spread to nine countries  of declines in reported WPV1 cases in Afghanistan and Pakistan, the high proportion of environmental surveillance samples with isolation of WPV1 during that time indicated persistent transmission in the historic polio reservoirs. Both countries face ongoing challenges, including vaccine refusals, polio campaign fatigue, and reaching mobile populations , which has a substantially lower risk of reversion to neurovirulence and seeding new VDPV2 emergences than does Sabin mOPV2  transmission continues in Afghanistan and Pakistan. Circulating vaccine-derived poliovirus (cVDPV) outbreaks occur in areas with low immunization coverage.Although WPV1 incidence declined annually during 2015\u20132017, cases in Afghanistan and Pakistan have increased since 2018. The number and geographic spread of cVDPV type 2 (cVDPV2) outbreaks are increasing. The COVID-19 pandemic has resulted in suspension of immunization activities and disruption of poliovirus surveillance.Substantial efforts to address programmatic challenges are essential to safely restore and scale-up polio field activities in 2020, including use of a stabilized type 2 oral poliovirus vaccine to prevent new cVDPV2 emergences."}
+{"text": "Undetectable HCV RNA 12 weeks after the end of treatment (SVR12) has been the valid efficacy endpoint in the era of direct-acting antivirals (DAAs). Its concordance with SVR4 and SVR24 and long-term durability is unknown in Taiwanese chronic hepatitis C (CHC) patients.A total of 1080 CHC patients who received all-oral DAAs and an achieved end-of-treatment virological response (EOTVR), defined as undetectable HCV RNA at the end of therapy, were consecutively enrolled. HCV RNA was monitored 4, 12, and 24 weeks after EOT. Patients who achieved SVR24, defined as undetectable HCV RNA 24 weeks after EOT, were followed annually for assessing SVR durability.Eleven (1.02%) patients experienced HCV RNA reappearance after EOT. The most frequent timing of RNA reappearance was observed at SVR4 (n = 7), followed by SVR12 (n = 3) and SVR 24 (n = 1). The positive predictive value (PPV) and negative predictive value (NPV) of SVR4 in predicting SVR12 were 99.7% and 100%, respectively, whereas the PPV and NPV of SVR12 in predicting SVR24 were 99.9% and 100%, respectively. Pyrosequencing confirmed delayed relapse rather than reinfection for the patient who had detectable HCV RNA at SVR24. Among 978 patients who achieved SVR24, after a median follow-up period of 17.3\u00b18.2 months, the SVR durability is 100% up to a 4-year follow-up.Achievement of SVR12 provides excellent durability of HCV seroclearance after DAA therapy. On-demand HCV RNA beyond SVR12 should be recommended for patients with unexplainable abnormal liver function or high-risk behaviors. Hepatitis C virus (HCV) infection is one of the leading etiologies of liver-related morbidities and mortalities worldwide . ApproxiThe definition of successful HCV eradication is a sustained virological response (SVR), which is defined as undetectable HCV RNA throughout 24 weeks of the posttreatment follow-up period (SVR24) in the interferon era \u20139. ThankCHC patients who received all-oral DAA regimens in the outpatient departments of Kaohsiung Medical University Hospital and two regional hospitals, Kaohsiung Municipal Ta-Tung Hospital and Kaohsiung Municipal Siaogang Hospital, were consecutively enrolled during the daily practice from February 2015 to October 2018. The treatment regimens and strategies conformed to the regional guidelines and the regulation of the Health and Welfare Department of Taiwan , 15. ThePatients who had virological data at posttreatment week 4 (SVR 4), posttreatment week 12 (SVR 12), and posttreatment week 24 (SVR 24) were evaluated for the concordance of SVR4 with SVR 12 and SVR12 with SVR 24. Among the patients who achieved SVR24, HCV RNA was followed annually to assess SVR durability. The study was approved by the institutional review board of Kaohsiung Medical University Hospital (IRB number: KMUHIRB-F(I)-20170053), which conformed to the guidelines of the International Conference on Harmonization for Good Clinical Practice. All patients provided written informed consent.The primary objective was to address RNA reappearance after EOT. The HCV genotype was assessed before treatment and at the time of RNA reappearance. HCV RNA and genotypes were determined using a real-time PCR assay  . For pat9/L] [1/2. The concordance of the virological responses between different time points  was compared and expressed as positive predictive value (PPV) and negative predictive value (NPV). The procedures were performed using the SPSS 22.0 statistical package .Group means are presented as the means \u00b1 standard deviations. The fibrosis index 4 (FIB-4) was calculated by the following formula: age (years) \u00d7 aspartate aminotransferase (AST) [U/L]/, early treatment termination (n = 2), mortality during treatment (n = 1), and remained viremic at EOT (n = 5), 1080 patients who achieved EOTVR were enrolled for final analysis in the current study . The basAmong the subjects, 11 (1.02%) patients experienced virological reappearance, and the most frequent timing of viral reappearance was week 4 (n = 7), followed by week 12 (n = 3) and week 24 (n = 1) after EOT. Of the 1060 patients with SVR12 data available, 1057 (99.7%) achieved an SVR12, leading to a 99.7% PPV and a 100% NPV of SVR4 for SVR12. Of the 979 patients with SVR24 data available, 978 (99.9%) achieved an SVR24, leading to a 99.9% PPV and a 100% NPV of SVR12 for SVR24.The characteristics and serial viral kinetics of the eleven patients who encountered HCV RNA reappearance after EOT are listed in The mean follow-up period in the post-SVR era was 17.2\u00b17.6 months. The SVR durability among the patients who achieved SVR24 was 100% (509/509), 100% (207/207), 100% (48/48) and 100% (13/13) at year 1, year 2, year 3 and year 4, respectively .The current study constantly supported the application of SVR12 as the primary efficacy endpoint in the era of DAAs for Taiwanese patients. With the broad use of more potent DAAs, including the pangenotypic glecaprevir/pibrentasvir and sofosbuvir/velpatasvir, the concordance of SVR 4 with SVR 12 was 99.7%, and the concordance of SVR 12 with SVR24 was 99.9%. Only one case experienced late virological relapse at SVR24. In addition, the durability beyond SVR24 was 100% in the current cohort.Of the patients who relapsed after the end of therapy, two-thirds relapsed within the first 4 weeks, whereas one-third relapsed between posttreatment weeks 4 and 12, indicating that SVR4 may not be a suitable endpoint for primary efficacy analyses. On the other hand, SVR12 and SVR24 were highly concordant, which was in line with previous studies , 19. TheThe SVR durability in patients who achieved SVR24 was 100% beyond 4 years of follow-up in the current study. The result was also similar to that in a long-term follow-up study . The timThere were some limitations in the current study. Gene sequencing was not performed in patients who had HCV RNA reappearance before SVR12. We could not completely exclude the possibility of reinfection rather than relapse in these patients. However, the HCV genotypes were the same before and after treatment, and there were no known risk factors for reinfection , which favored relapse of these patients. Although the SVR durability was 100% at present, a longer follow-up duration is needed for the potential chance of extremely late relapse or reinfection in the cohort . In concS1 Dataset(XLSX)Click here for additional data file.S2 Dataset(XLSX)Click here for additional data file."}
+{"text": "What is the association of molecular alterations in cerebrospinal fluid with clinical outcomes of patients with a diagnosis of lung adenocarcinoma and central nervous system metastases?EGFR variants coaltered with CDK4, CDK6, MYC, and MET were associated with poor outcomes.In this cohort study of 94 patients, next-generation sequencing of cerebrospinal fluid showed that 5 molecular subtypes were associated with survival; the molecular subtype with abundant genetic alterations was associated with the shortest survival and increased risk of death. Specifically, Based on genetic profiling in cerebrospinal fluid, this population experienced heterogenous survival outcomes, and some specific molecular alterations were associated with prognosis; therefore, as liquid biopsy is performed of central nervous system metastases, cerebrospinal fluid may facilitate risk stratifying central nervous system metastases into appropriate outcomes. Owing to the improvement of systemic therapies for lung cancer, patients live longer, but the incidence of central nervous system (CNS) metastases also increases. Cerebrospinal fluid (CSF) has been proven better than plasma to reveal unique genetic profiling of intracranial metastases. How genetic alterations in CSF are associated with the prognosis of this heterogeneous patient group remains elusive.To examine the association of molecular alterations in CSF with the survival of patients with a diagnosis of lung adenocarcinoma and CNS metastases.This retrospective cohort analysis of 94 patients with advanced lung adenocarcinoma and CNS metastases was conducted from July 1, 2016, to July 31, 2018. Patients\u2019 CSF samples were collected, and next-generation sequencing of CSF circulating tumor DNA was performed.The main outcome was survival after diagnosis with CNS metastases. Genotyping of CSF circulating tumor DNA was studied to examine its association with the clinical outcomes of patients with CNS metastases.EGFR variant. The most common genes seen in CSF were EGFR (79 [84.0%]), TP53 (57 [60.6%]), MET (23 [24.5%]), CDKN2A (22 [23.4%]), MYC (20 [21.3%]), NTRK1 (19 [20.2%]), and CDK6 (15 [16.0%]). Cluster analysis identified 5 molecular subtypes of CNS metastases. Patients in cluster I had the shortest median survival after diagnosis of CNS metastases compared with each of the other clusters  and significantly increased risk of death compared with patients in the other clusters . The genetic profiles of cluster I were characterized by a high detection rate of CDK4 (9 of 9 [100%]), TP53 (8 of 9 [88.9%]), MET (7 of 9 [77.8%]), and CDKN2A (7 of 9 [77.8%]). For those with EGFR variants, coalterations with CDK4 , CDK6 , and MYC  were associated with poor outcomes.Of the 94 patients  with lung adenocarcinoma and CNS metastases evaluated, 79 harbored an Patients with a diagnosis of lung adenocarcinoma and CNS metastases experienced heterogeneous survival outcomes based on genetic profiling in CSF. These data suggest that CSF might facilitate risk stratifying CNS metastases into appropriate outcomes and provide reference for further clinical study. This cohort study examines the association of molecular alterations in cerebrospinal fluid (CSF) with the survival of patients with a diagnosis of lung adenocarcinoma and central nervous system (CNS) metastases. Thus, the present study aims to explore the molecular alterations revealed in CSF samples and their associations with survival of patients with lung adenocarcinoma and CNS metastases.Owing to the improvement of systemic therapies for lung cancer, patients live longer, but the incidence of central nervous system (CNS) metastases also increases. Cerebrospinal fluid (CSF) has been proven better than plasma to reveal unique genetic profiling of intracranial metastases. Recent research has indicated that CSF could be used as a liquid biopsy of CNS metastases because CSF reveals unique genetic profiles of patients with non\u2013small cell lung cancer and CNS metastases.STROBE) reporting guideline.This retrospective cohort study was conducted at Guangdong Lung Cancer Institute, Guangzhou, China, from July 1, 2016, to July 31, 2018, among 94 patients with late-stage lung adenocarcinoma and a diagnosis of CNS metastases . Leptomeningeal metastases were diagnosed based on tumor cells detected in CSF samples or detected by leptomeningeal enhancement in brain magnetic resonance imaging. Brain metastases were diagnosed based on metastatic lesions detected by brain magnetic resonance imaging. All patients provided written informed consent, and the study protocol was approved by the Research Ethics Committee of Guangdong Provincial People\u2019s Hospital. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology  with EGFR (GenBank NG_007726) variants was determined by logistic regression analysis. The coaltered genes and the clinical characteristics of the patients were included in the Cox proportional hazards regression models, and hazard ratios (HRs) and 95% CIs were calculated to determine the survival difference. All P values were 2-sided and were considered statistically significant at P\u2009<\u2009.05. SPSS for Windows, version 22.0 (SPSS Inc) was used for all statistical analysis; Prism, version 8.0 (GraphPad Software) was used for making graphics.Patients were divided into several groups using unsupervised hierarchical cluster analysis using R, version 3.3.1 .EGFR (79 [84.0%]), TP53 (GenBank NG_017013) (57 [60.6%]), MET (GenBank NG_008996) (23 [24.5%]), CDKN2A (GenBank NG_007485) (22 [23.4%]), MYC (GenBank NG_007161) (20 [21.3%]), NTRK1 (GenBank NG_007493) (19 [20.2%]), and CDK6 (GenBank NG_015888) (15 [16.0%])  with lung adenocarcinoma and a diagnosis of CNS metastases, 70 received a diagnosis of LM, and the remaining 24 received a diagnosis of BM. All patients had at least 1 molecular alteration detected in a CSF sample. The demographic and clinical characteristics of the included patients are shown in The median survival of the entire cohort was 19.3 months . Unsupervised hierarchical cluster analysis was used to identify 5 major molecular subtypes associated with CSF samples obtained from patients with CNS metastases  .P\u2009=\u2009.009), cluster III , cluster IV , or cluster V   A.EGFR variants, while most patients in cluster II carried ALK (GenBank NG_009445) fusion (CDK4 (GenBank NG_007484) (9 of 9 [100%]), TP53 (8 of 9 [88.9%]), MET (7 of 9 [77.8%]), CDKN2A (7 of 9 [77.8%]), MYC (7 of 9 [77.8%]), and SMAD4 (GenBank NG_013013) (6 of 9 [66.7%]) , CDK6 , and MYC  were found to be associated with poor outcomes in the further analysis of patients with EGFR variants  fusion B. The ge[66.7%]) B; moreovvariants .TP53 coaltered with EGFR variants. However, cluster III was characterized by high detection of MET (11 of 29 [37.9%]) and RB1 (GenBank NG_009009) (11 of 29 [37.9%]) alterations, while cluster IV showed more NTRK1 (9 of 11 [81.8%]) and MYC (6 of 11 [54.5%]) alterations without MET or cell cycle pathway\u2013related genes detected. Cluster V was characterized by low TP53 detection and moderate variant frequency of CDK4 (11 of 26 [42.3%]) and MYC (6 of 26 [23.1%]) (ALK fusions (8 of 19 [42.1%]) as well as a low proportion of EGFR variants (4 of 19 [21.1%]) and no clinically actionable variants (7 of 19 [36.8%]) (Patients in cluster III (27 of 29 [93.1%]) and cluster IV (11 of 11 [100%]) carried [23.1%]) B. With t[36.8%]) B.EGFR variants. To further explore the association of different coaltered genes with the survival of 79 patients with an activated EGFR variant and LM or BM, genes with a detected frequency of more than 5% in CSF were included for interactive survival analysis. Patients with EGFR variants coaltered with CDK4, CDK6, and MYC alterations had shorter median survival than patients without these alterations    after adjusting for other genetic alterations and patient characteristics  A-C. PatiP\u2009=\u2009.07) D. In fureristics .EGFR variants had the same association with the survival of patients with CNS metastases.To our knowledge, this study of 94 patients with advanced lung adenocarcinoma with CSF samples profiled by next-generation sequencing represents the largest reported series to date, and for the first time, we defined 5 subgroups of CNS metastases characterized by different multiple alterations that were associated with diverse outcomes. We also challenged the view that the coexistence of other variants with TP53 and somatic copy number variations were associated with lung cancer.6 Concordant with previous findings, we first found that patients with CNS metastases characterized by TP53 and somatic copy number variations in CSF had poor survival. Cell cycle pathway alterations were frequently detected and may be one of the mechanisms in BM or LM.7 Our study further verified that cell cycle\u2013regulated genes were also identifiers of CNS metastases in patients with poorer survival. Likewise, MET copy number gain has been associated with resistance to gefitinib in LM,8 but we did not see a statistically significant association between MET alterations and inferior survival in our study. Further investigation is needed in this regard.Extracranially, 10 but they need further verification.We identified that a subgroup (cluster I) of patients with lung adenocarcinoma and CNS metastases experienced significantly poor survival associated with the molecular characterization of their CSF samples. This finding supports the heterogeneous response to targeted therapies that is possibly due to different genetic backgrounds. The optimal strategies for this subgroup of patients with a poor prognosis are challenging, and more radical therapies\u2014such as a tyrosine kinase inhibitor plus chemotherapy, antiangiogenic drugs, or preventive local therapy\u2014may be taken into consideration,Our study has some limitations, including its retrospective design. In addition, treatment options based on each molecular subtype were not prospectively explored, so we could not identify the optimal treatments for patients in different clusters.EGFR variants, coalterations with CDK4, CDK6, and MYC were associated with poor outcomes. Thus, the use of CSF samples may facilitate risk stratifying CNS metastases into appropriate outcomes and provide a reference for further clinical study.Our results suggest that genetic alterations in CSF were associated with the survival of patients with advanced lung adenocarcinoma and CNS metastases. In those patients with"}
+{"text": "Perinatal asphyxia is one of the major causes of perinatal and early neonatal mortality in developing countries. The main objective of this study was to observe the prevalence of perinatal asphyxia in babies born at Kathmandu Medical College Teaching Hospital.This was a descriptive cross-sectional study conducted at Kathmandu Medical College Teaching Hospital over six month period (January to June 2019). All preterm, term and post term babies delivered at Kathmandu Medical College Teaching Hospital were included. Ethical clearance was received from Institutional Review Committee of Kathmandu Medical College (Ref.:2812201808). Convenient sampling method was applied. Data analysis was done in Statistical Package for Social Sciences version 18, point estimate at 95% Confidence Interval was calculated along with frequency and proportion for binary data.A total of 1284 babies delivered over six months period were enrolled in this study and 47 (3.66%) babies were asphyxiated, at 95% Confidence Interval (2.64-4.68%). The mean birth weight of asphyxiated babies was 2759.75\u00b165 grams and gestational age was 37.57\u00b12 weeks. Among asphyxiated babies, 15 (32%) babies were normal, 15 (32%) babies were in Hypoxic Ischemic Encephalopathy stage I, 14 (30%) were in stage II and 3 (6%) were in stage III. Twenty Three (49%) asphyxiated babies had antenatal risk factors and all 47 babies had intrapartum risk factors leading to asphyxia.Prevalence of perinatal asphyxia was lower compared to that of other similar tertiary care hospitals. Perinatal asphyxia remains a major cause of neonatal morbidity and mortality. HIE is a syndrome of disturbed neurological function manifested by difficulty in initiating and maintaining respiration, abnormal muscle tone and reflexes, subnormal level of consciousness and often seizures.The main objective of this study was to observe the prevalence of perinatal asphyxia in babies born at Kathmandu Medical College Teaching Hospital.A descriptive cross-sectional study was carried out on neonates with perinatal asphyxia at 10 bedded Neonatal Intensive Care Unit (NICU) of Pediatrics Department, Kathmandu Medical College Teaching Hospital (KMCTH), Sinamangal, Kathmandu, Nepal over six months period (Jan 2019 to June 2019). Ethical clearance was received from Institutional Review Committee (IRC) of Kathmandu Medical College (Ref.:2812201808) and written consent was taken from the parents and possible complications of perinatal asphyxia were explained. Data were entered in Excel and analysis was done in SPSS 18, point estimate at 95% Confidence Interval was calculated along with frequency and proportion for binary data.6 All preterm, term and post term babies born at KMCTH with perinatal asphyxia due to any antepartum cause (e.g. Pregnancy Induced Hypertension (PIH), pre-eclempsia/eclempsia, Oligohydramnios etc.) or Intrapartum cause  were included in this study. Babies with lethal congenital anomalies , Syndromic babies and out born neonates with perinatal asphyxia were excluded.Perinatal Mortality Rate (PMR) of this tertiary hospital is 10/1000 births and Neonatal mortality rate (NMR) is 4.5/1000 live births.7Umbilical Arterial cord pH <7.2 determined by blood gas analysis within first hour of birthApgar score \u22646 at 5 minuteRequirement of >1 minute of positive pressure ventilationSigns of fetal distress 8 The staging of HIE was assessed by Leven\u2019s classification.5 All neonates were managed according to hospital protocol.Detailed obstetric history, birth history, risk factors in the pregnancy, type of delivery and need of resuscitation procedure required at birth were recorded. During resuscitation in labor room/operation theatre, Neonatal Resuscitation Program (NRP) guideline 2015 recommended by American Academy of Pediatrics (AAP) were followed and detailed neurological examination of asphyxiated newborns were performed.Neonates were diagnosed as perinatal asphyxia when at least three of the following four criteria were fulfilled:sample size estimationn = Sample sizeZ = 1.96 for Confidence Interval of 95%9p = Prevalence of perinatal asphyxia in previous study = 15.9%q = 1-pe = margin of error= 2%where,Total of 1284 neonates were enrolled and convenient sampling method was applied. Statistical analysis was done with SPSS 18 version. Outcome and possible morbid conditions and sequelae due to HIE were observed.2. Mean fetal heart sound (FHS) during admission at hospital was 132.60\u00b118.1/min whereas during the delivery of baby, FHS has dropped to 88.87\u00b1 6.3/min depicted . Among 47 asphyxiated babies, 35 (75%) were term babies with male predominance 33 (70%). The mean birth weight of asphyxiated babies was 2759.57\u00b165gms and mean gestational age was 37.57\u00b12 weeks. Similarly, mean Apgar score at 1 min was 3.28\u00b10.7 and at 5 min was 5.15\u00b10.8. Mean maternal age of asphyxiated babies was 25.5\u00b13.2yrs and mean maternal BMI was 20.04\u00b12.4 kg/mdepicted .Twenty Three (49%) asphyxiated babies had antenatal risk factors and all 47 (100%) babies had intrapartum risk factors leading to asphyxia. Intra uterine growth factor (IUGR) among 11 (24%) was the commonest antenatal risk factor whereas prolonged labor 15 (32%) was the commonest intrapartum risk factor. Ten (21%) asphyxiated babies were cried by tactile stimulation only whereas 24 (51%) asphyxiated babies required Bag and Mask ventilation, 4 (9%) required Bag and mask with Chest compression and 6 (13%) babies were intubated. Only 3 (6%) severely asphyxiated babies required all form of resuscitation measures as per NRP guidelines 2015. Out of 47 asphyxiated babies, 32 (68%) developed HIE. Out of which 15 (32%) were in HIE stage I, 14 (30%) were in HIE stage II and 3 (6%) babies were in HIE stage III. All three babies with HIE stage III were intubated and required all form of resuscitation procedure including drugs at birth. .Out of 32 neonates with HIE, 24 (75%) babies\u2019 1 min Apgar score was 0-3 and 30 (94%) babies\u2019 5 min Apgar score was 4-6. Similarly, 19 (59%) babies with HIE had antenatal risk factors and all 32 (100%) babies with HIE had intrapartum risk factors. Among 32 HIE babies, 19 (59%) required Bag and Mask ventilation, 4 (13%) required Bag and mask with chest compression, 6 (19%) required Intubation and 3 (9%) required all procedures of neonatal resuscitation at birth .Outcome of total 47 asphyxiated babies were observed as follows: 45 (95.7%) babies were discharged and 2 (4.3%) babies with HIE stage III were expired. After following 45 asphyxiated babies till one month of postnatal age, 44 (93.6%) babies were neurologically normal and one baby (2.1%) survived with HIE stage III has developed spastic cerebral palsy .11 In our study, the prevalence of perinatal asphyxia is 3.66%. This finding is quite low as compared to other studies done in Nepal as in Nepal Medical College 15.9% by Shrestha S et al,9 26.9% at Kathmandu University School of Medical Sciences, Dhulikhel by Dangol S et al,12 17.3% at College of Medical Sciences, Bharatpur by Gupta SK et al13 and 19.3% at Lumbini Medical College Teaching Hospital by Panthee K et al.14 The possible factors for such a low prevalence of perinatal asphyxia in KMCTH could be due to better intrapartum fetal monitoring  and immediate interventions like emergency cesarean section and instrumental delivery which have helped in reducing intrauterine asphyxia. Availability of level III neonatal care like bubble CPAP, mechanical ventilator support and surfactant replacement therapy at NICU and floor night duty of second on call Obstetricians and Pediatricians with Post Graduate resident doctors involved in every high risk deliveries might have helped in reducing perinatal asphyxia and immediate better neonatal resuscitation care could have reduced its complications of perinatal asphyxia.Perinatal asphyxia contributes significantly to neonatal morbidity and mortality.7 In our study, 5 min Apgar score 4-6, intrapartum risk factors and need of intubation and chest compression during neonatal resuscitation at birth were the major contributing factors leading to HIE. Whereas in a study done by Joseph S et al. in Kerala found need for Endotracheal intubation, Instrumental delivery and umbilical arterial pH <7 were the leading factors associated with HIE.15In our study, majority of the asphyxiated babies 33 (70%) were appropriate of gestational age (AGA). This is similar to Kempegowda study by Sarnappa SB et al. where 80% were AGA.16 Out of those 34 HIE stage III babies, 4 (11.7%) babies developed neurological sequelae and 9 (26.4%) babies expired highlighting that HIE stage III babies were very difficult to survive and if survived, most of them will have sequelae.In our study, 32 (68%) babies with perinatal asphyxia developed HIE, out of which only three babies (6%) were in HIE stage III. Out of these three babies, two babies (67%) expired and one baby (33%) developed neurological sequelae. Whereas a study done by Aliyu et al in Nigeria found 96% asphyxiated babies developed HIE and 34 (13.8%) were in HIE stage III.Perinatal asphyxia still remains major cause of neonatal mortality and morbidities particularly in developing countries. This study highlighted, even with low prevalence of perinatal asphyxia, intrapartum risk factors eg. thick meconium stain liquor, prolonged labor and requirements of neonatal resuscitation procedure eg. Intubation and Bag and mask with chest compression were the common risk factors associated with HIE. Since, this is a single institutional study with convenient sampling, outcome cannot be generalized."}
+{"text": "The role of methyl prednisolone in longitudinal extensive transverse myelitis in children is not completely discovered in developing country like Pakistan. So this is the first study which aimed to evaluate the efficacy of methyl prednisolone in longitudinal extensive transverse myelitis in children.This is quasi experimental hospital based descriptive prospective study. The data was collected from 34 children admitted in Paediatric Neurology department through Outpatient/emergency department in Children\u2019s Hospital and the Institute of Child Health, Lahore for period of one year from January 2018 to December 2018. The children full filling the inclusion criteria were observed before and after giving injection methyl prednisolone 30mg/kg/dose (maximum dose one Gram irrespective of the body weight) once daily for five days in the form of intravenous infusion.Complete recovery was seen in 41.2% while 58.8% showed partial recovery. The correlation of response to treatment (recovery) with gender, area of spinal cord involvement, muscle power and autonomic dysfunction is found at significance level of five percent according to Chi square test.Early consideration and administration of methyl prednisolone in longitudinally extensive transverse myelitis in children can be beneficial and can help to reduce the morbidity. Acute transverse myelitis (ATM) presents with acute onset paraplegia or quadriplegia with sensory and autonomic involvement.3Most of cases are seen in adults while 20% cases are seen below 18 years of age. Mostly cases are idiopathic. Preceding febrile illnesses and vaccination have been reported.Longitudinally extensive transverse myelitis (LETM) is taken to mean myelitis characterized by inflammatory lesion of spinal cord extending over \u22653contiguous spinal cord segments.A variety of other acquired inflammatory and demyelinating conditions can be associated with LETM.9The role of methyl prednisolone in longitudinal extensive transverse myelitis in children is not completely discovered in developing country like Pakistan. So this is the first study which aims to evaluate the efficacy of methyl prednisolone in longitudinal extensive transverse myelitis. It would give a very useful insight regarding formulation of management protocol of LETM locally as well as internationally.This is quasi experimental hospital based prospective study and conducted in Department of Paediatric Neurology, Children\u2019s Hospital & Institute of Child Health, Lahore for a period of one year from January 2018 to December 2018 after obtaining approval from the Institutional Review Board . Informed written consent was obtained from parents or guardians. The data was collected by nonprobability consecutive sampling technique of 34 children admitted in the department of Paediatric Neurology through Outpatient/emergency department.The children of both gender and age ranging from six months to 18 years presenting with acute onset paraplegia or quadriplegia with definite sensory level with or without autonomic involvement of bladder and cardiorespiratory system along with radiologically confirmed findings consistent with longitudinally extensive transverse myelitis with \u22653 contiguous spinal segments involvement were included. While children having spinal cord involvement secondary to other myelocompressive disorders like Pott\u2019s disease, spinal tumors and spinal trauma were excluded. Patients were observed after being scrutinized by TMCWG criteria.Data was analyzed by using SPSS v22. Mean and standard deviation are calculated for quantitative variables like age. Descriptive analysis was done by frequency tables. Frequency and percentage are calculated for qualitative variables like sensory level, autonomic dysfunction, need for mechanical ventilation, findings in MRI spine and CSF analysis. Chi square test is applied to see correlation of different variables with response of treatment.Thirty four children were enrolled. There were 20 males (58.8%) and 14 females (41.2%). Female to male ratio 1:1.4. The age of the children ranged from one year to 13 years with mean age of admission 6.08 years (\u00b13.53 SD). Youngest patient was one year old. Out of 34 patients, 25(73.5%) patients had involved lower limbs only and 9 (26.47%) patients had both upper and lower limbs involvement. Among these children, only 1(2.9%) patient required ventilator. Before treatment with steroid therapy, autonomic dysfunction was found in the form of urinary bladder involvement in 12 patients (35.3%) while cardio respiratory dysfunction was found in 7 (20.6%) patient. Six (17.6%) children had thoraco-lumbar while 5(14.7%), 19(55.9%) and 4(1.8%) had cervical, cervico-dorsal and whole spine area respectively involved in MRI spine. One patient 1(2.9%) had cervico-medullary involvement. Majority of patients had cervico-dorsal area involved in MRI spine. Sixteen (47%) children had normal CSF while 18 (53%) children had both pleocytosis and raised protein values. Thirty one 31 (91.2%) and 3 (8.8%) children had normal and raised CRP respectively. Twenty 24 (70.6%) children had history of prior vaccination while 10(29.4%) had no prior history of febrile illness or vaccination .The correlation of response to treatment (recovery) with gender, treatment, area of spine involved, autonomic dysfunction (bladder and cardiorespiratory) is found significant at significance level of five percent .th day and had been divided into five grades ranging from 0 (lowest) to five (highest) out of total five. According to results, 0/5 and 1/5 grades of power are observed in 5(14.7%) children. 8(23.5%), 7(20.6%), 6(17.6%) and 3(8.8%) children had 2/5, 3/5, 4/5 and 5/5 grades of power respectively after treatment.After five days of treatment completion, power was assessed on 14Longitudinally extensive Transverse myelitis (LETM) is of course less common but clinically more important as early diagnosis and adequate and optimum treatment may prevent many patient from significant morbidities.15In one study18It is that it is a single center study over a short period. We did not use expanded disability status scale Score for measurement of disability as used by study.Despite its limitations, major strength of our study is that it provides an insight to develop treatment protocols in children warranting as first line therapy for early management of this potentially devastating entity in resource limited developing countries like Pakistan, as most of studies are available on western population.21Early consideration and administration of methyl prednisolone in longitudinally extensive transverse myelitis in children can be beneficial and can help reduce the morbidity.MAA: Conceived the idea and designed framework, Data collection, responsible for accuracy and integrity of work.MAA, IJ, MA & MRY: Did manuscript writing and review.IJ & MRY: Did statistical analysis."}
+{"text": "PMP22) in Chinese patients with CMT disease and evaluate their correlations with the clinical manifestations. Using the multiplex ligation-dependent probe amplification (MLPA) technique and Sanger sequencing of PMP22 in a cohort of 465 Chinese families between 2007 and 2019, we identified 137 pedigrees with PMP22 duplications (29.5%), 26 pedigrees with PMP22 deletions (5.6%), and 10 pedigrees with point mutations (2.2%). By comparing our data with the results from other CMT centers in China, we estimate that the frequency of PMP22 mutation in mainland China is ~23.3% (261/1120). We confirmed de novo mutations in 40% (4/10) of PMP22 point mutations. We have also identified two severely affected patients who are compound heterozygotes for recessive PMP22 mutations (novel mutation c.320-1 G>A and R157W mutation) and a 1.5 Mb deletion in 17p11.2-p12, suggesting that c.320-1 G>A might be another recessive allele contributing to DSS in addition to the T118M and R157W mutations. A de novo mutation of S79P in PMP22 was also identified concomitantly with the R94W mutation in mitofusin2 (MFN2). Our study highlights the phenotypic variability associated with PMP22 mutations in mainland China. The results provide valuable insights into the current strategy of genetic testing for CMT disease. NGS technology has increased the potential for efficient detection of variants of unknown significance (VUS) and concurrent causative genes. Greater cooperation between neurologists and molecular biologists is needed in future investigations.Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous group of inherited neuropathies. The purpose of this study is to identify the clinical and genetic diversity of peripheral myelin protein 22 ( PMP22), accounting for 70% of CMT1 and 50% of all CMT cases , Dejerine-Sottas neuropathies (DSS) and CMT1E  disease is the most common hereditary peripheral neuropathy and is characterized by progressive distal muscle weakness and atrophy, distal sensory loss and diminished deep tendon reflex , 2. The MT cases . The delnd CMT1E , 5. Indend T118M , 7, whicPMP22 present with varying levels of severity of the disease.  approved this study (IRB 00006761). Informed consent was obtained from all subjects enrolled in this study.We enrolled 580 patients from 465 unrelated Chinese families with suspected CMT disease or a related peripheral neuropathy between January 2007 and December 2019. We collected data on the clinical features, family history, CMT neuropathy score (CMTNS) and electrophysiological evaluations. For patients with hearing loss, we performed the audiogram, otoacoustic emission (OAE), and auditory brainstem response (ABR). Patients were suspected of having CMT disease if they had a sensorimotor peripheral neuropathy with a positive family history. Patients without a family history were also enrolled if their medical history, neurological examination and results of nerve conduction studies were typical for an inherited neuropathy. Patients with an acquired neuropathy, including inflammatory, immune-mediated, toxic, and metabolic neuropathies, were excluded . The diaPMP22 gene were PCR-amplified using intronic primers and directly sequenced using Applera BigDye version 3.1 (Applied Biosystems) and the automated sequencers ABI 3730XL and ABI 3100 (Applied Biosystems) (primers and conditions are available upon request). We also excluded the mutations in myelin protein zero (MPZ), gap junction protein beta-1 (GJB1), mitofusin2 (MFN2) and ganglioside-induced differentiation-associated protein 1 (GDAP1) by performing direct Sanger sequencing. After 2012, next-generation sequencing (NGS) covering 160 genes related to CMT disease and related neuropathies was performed for patients with an inherited neuropathy after excluding the presence of a PMP22 duplication and deletion  technique in patients with demyelinating, intermediate CMT disease, part of axonal CMT disease  or a CMAP <0.5 mV at median and ulnar nerve) and HNPP , 1,000 genomes (http://www.1000genomes.org/), EVUS (http://evs.gs.washington.edu/EVS/) and GnomAD (http://gnomad.broadinstitute.org/) databases, exclusion of Chinese controls, co-segregation with the phenotype in the available familial cases and the in silico pathogenicity prediction tools SIFT (http://sift.jcvi.org/www/SIFT_enst_submit.html), PolyPhen (http://genetics.bwh.harvard.edu/pph2/index. shtml) and Mutation Taster (http://www.mutationtaster.org/). The splice site mutations were predicted using the software HSF 3.0 (http://www.umd.be/HSF3/HSF.shtml). Variant classification was based on the ACMG standards (2015)  , and thePMP22 duplications, accounting for 29.5% (137/465) of the CMT cases and 55.7% (137/246) of the demyelinating CMT cases. In the remaining 109 patients with CMT1, the disease-causing mutation was identified in 22 with the following distribution: 6 mutations in SH3TC2, 5 mutations in GJB1, 4 in MPZ, 2 in PRX, 2 point mutations in PMP22, 1 in GDAP1, 1 in HK and 1 in NEFL. Twenty-six index patients with PMP22 deletions showed manifestations compatible with HNPP, and 10 index patients with PMP22 missense mutations and small deletions showed phenotypes ranging from CMT1E (2 index patients) to HNPP (2 index patients) and DSS (6 index patients). Thirty percent of the patients with demyelinating CMT disease had no family history. We confirmed de novo mutations in 40% (4/10) of PMP22 point mutations.The male to female ratio was 1.3, and the median age at onset was 26.7 years (ranging from birth to 60 years). Based on the electrophysiological criteria, 246 families were diagnosed with CMT1, 137 families were diagnosed with CMT2, 52 families were diagnosed with intermediate CMT disease and 30 families were diagnosed with HNPP. We identified 137 index patients with The clinical manifestations of CMT1A are summarized in PMP22 duplications in our data with the frequencies observed in other CMT centers (PMP22 duplications in mainland China is ~23.3% (261/1120). We also observed a significant difference between the southern  and northern parts  of China. The data obtained from the Third Xiangya Hospital and Huashan Hospital, which are located in the southern part of China, indicated a detection rate of PMP22 duplications of only 13.5\u201314%, suggesting that other reasons in addition to ethnic differences should be considered.By comparing the frequency of  centers , we estiPMP22 deletions. These patients shared the typical clinical manifestations, including episodic, recurrent peripheral nerve palsy, which was often preceded by a history of minor trauma at vulnerable sites. The onset age and nerve conduction studies were consistent with the results reported in previous studies. The detection rate was 5.6% in our center and 2.1\u20132.4% in most CMT centers, except for Huashan Hospital in Shanghai, where the detection rate was 11.5%.Twenty-six patients exhibited PMP22 by screening exons 2, 3, 4, and 5 (PMP22 deletions and point mutations (the novel mutation c.320-1 G>A and previously reported R157W mutation), which were inherited from their parents separately. Two pedigrees presented the de novo mutation of S72W, one of pedigrees presented the de novo mutation S79P in PMP22 concomitantly with the R94W mutation in MFN2. We will discuss pedigrees 1490, 1903 and 1700 in greater detail to further analyze the rare genetic mutation . Her 46-year-old mother carried a heterozygous c.469C>T mutation. The electrophysiological tests revealed a normal motor nerve velocity but reduced sensory conduction velocity in the median and ulnar nerves  (The c.469C>T (R157W) mutation and a deletion in the ent III1 . The mut 8.3 \u03bcV) .PMP22 gene were observed in patient III1  in the extensors, and the foot flexion and extension were 0/5 and 3/5 (MRC), respectively. A mild diminished sensation in all modalities in the regions below the elbows and knees was observed. His father was clinically and electrophysiologically normal. The molecular genetic testing did not detect any mutations in PMP22 and MFN2  of all CMT cases and 55.7% (137/246) of all demyelinating CMT (CMT1) cases. By comparing the frequency of PMP22 duplications in our study with the frequencies observed in other CMT centers (PMP22 duplications in mainland China is ~23.3% (261/1120). The frequency of the PMP22 duplications was lower than the frequencies reported in Spain (42%)  , UK (39.in (42%) , the USA.3% 261/10. The frin (42%) , 17; howin (42%)  and Kore3.3% 261/20. The f% , UK (3PMP22 duplications presented with symptoms after the age of 20 years. These patients showed a milder disease course than patients with an early onset. These data are consistent with a Japanese study (50%) (de novo mutations in 3.8% (4/104) of PMP22 duplications and 40% (4/10) of PMP22 point mutations, while a study from Germany that included 1330 patients only reported a rate of 1.3% (2/154) for de novo PMP22 duplications   and a stdy (50%) , but thedy (50%) , 19, sugications . A reasoPMP22, MPZ, and GJB1 genes (PMP22 duplications and 20% of index patients (R157W and W39C) with PMP22 micro mutations had hearing problems. To date, 10 point mutations in the PMP22 genes result in hearing loss associated with the neuropathy, not including the R157W and W39C mutations identified in our study. The mutations were mostly located in transmembrane domains 1-3 of the protein. The exact pathogenesis of deafness in patients with CMT disease has not been completely elucidated. One recent study revealed that the loss of cochlear Schwann cells may result in permanent auditory deficits characteristic of hidden hearing loss . G150V has only been identified in a single German study and was submitted to the Clinvar database, but no clinical manifestations and assertion criteria were provided. Our study provides good supporting evidence for the pathogenic effect of this mutation. Two other mutations in the same codon, i.e., G150A  and a 1.5 Mb deletion in 17p11.2-p12. Their parents were heterozygous for the PMP22 point mutations and clinically normal, and presented a only minor impairment in the NCS study, while two others heterozygous for the deletion had HNPP. To our knowledge, only one study has reported the similar compound heterozygous mutation of a T118M point mutation and PMP22 deletion, suggesting that c.320-1G>A might be another recessive allele contributing to DSS in addition to T118M and R157W (PMP22 mutations (S79P and G150C) in the study by Naef and Suter  and a much milder phenotype , the severe clinical symptoms in patient 1700 may be attributed to the S79P mutation in PMP22. However, we cannot exclude the effect of the MFN2 mutation in combination with PMP22. To the best of our knowledge, this report is the first to describe 2 severe disease-causing mutations in PMP22 and MFN2 in a single patient. Due to the rapid progress in NGS, WES, and WGS sequencing techniques, an increasing number of mutations have been identified in different genes, thereby the determination of an accurate diagnosis is more complicated. Additional studies are needed to determine whether the two severe disease-causing mutations exert separate, modified or combined effects on the protein. Therefore, the clinical phenotype should be considered in combination with the genetic results, emphasizing the importance of a careful examination of the medical history to determine an accurate diagnosis.Patient 1700 carried both the PMP22-related neuropathy in mainland China. The phenotypic variability highlights the importance of considering PMP22 mutations in a broad spectrum of demyelinating neuropathies. The c.320-1G>A mutation might be another recessive allele contributing to severe forms of CMT1 in addition to T118M and R157W. The results provide valuable insights into the current strategy of genetic testing for CMT disease. NGS technology has increased the potential for the efficient detection of variants of unknown significance (VUS) and concurrent causative genes. Greater cooperation between neurologists and molecular biologists is needed in future investigations.We conducted a study to provide the most detailed description of http://www.mono-mybg.com/jzjy-cmt.The datasets generated for this study can be found in the The studies involving human participants were reviewed and approved by The Institutional Ethics Committee of Peking University Third Hospital (PUTH) approved this study (IRB 00006761). Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. Written informed consent was obtained from the individual(s), and minor(s)' legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.DF and XL conceived and designed the study. XD provided valuable clinical materials. YZ performed the genetic testing. XL wrote the paper. DF reviewed and edited the manuscript. All authors read and approved the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Serum prostate-specific antigen (PSA) level is the most valuable biomarker in prostate cancer. This study investigates the predictive value of achieving >30% PSA decline at four weeks of first-line androgen signaling inhibitors (ASIs) using a multi-institutional cohort dataset of 254 mCRPC patients. The achievement of >30% PSA decline at four weeks is an independent predictor for overall survival (OS). Interestingly, in patients who did not achieve >30% PSA decline at four weeks\u2014an achievement of the >30% PSA decline at 12 weeks is eventually observed in 30.9% of those patients. To identify the variables that discriminate the patient survival in 97 patients without achieving >30% PSA decline at four weeks of the first-line treatment, a multivariate analysis is conducted. The duration of androgen deprivation therapy before CRPC < 12 months and Eastern Cooperative Oncology Group Performance Status \u2265 1 are identified as independent predictors for shorter OS for those patients.The identification of early or primary resistance to androgen signaling inhibitors (ASIs) is of great value for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This study evaluates the predictive value of prostate-specific antigen (PSA) response at dour weeks of first-line ASIs treatment for mCRPC patients. A total of 254 patients treated with ASIs  at the first-line treatment are retrospectively analyzed. Patients are stratified according to the achievement of >30% PSA decline at 4 and 12 weeks from the treatment initiation. At four weeks of the treatment, 157 patients (61.8%) achieved >30% PSA decline from the baseline. Thereafter, 177 patients (69.7%) achieved >30% PSA decline at 12 weeks of the treatment. A multivariate analysis exhibits >30% PSA decline at four weeks as an independent predictor for overall survival (OS). We note that 30 of 97 (30.9%) patients who did not achieve >30% PSA decline at four weeks consequently achieved >30% PSA decline at 12 weeks, and had a comparable favorable three years OS rate as the 147 patients achieving >30% PSA decline at both 4 and 12 weeks. To identify the variables that discriminate the patient survival in 97 patients without achieving >30% PSA decline at four weeks, a multivariate analysis is performed. The duration of androgen deprivation therapy before CRPC \u2264 12 months and Eastern Cooperative Oncology Group Performance Status \u2265 1 are identified as independent predictors for shorter OS for those patients. These data offer a concept of early treatment switch after four weeks of first-line ASIs when not observing >30% PSA decline at four weeks\u2014particularly in patients with a modest effect of ADT and poor performance status. Prostate cancer (PC) is the most common cancer in men, and estimated numbers in the United States account for 31,620 deaths and 174,650 new patients in 2019 ,11,12,13Prostate-specific antigen (PSA) is widely used for diagnosis and evaluation of treatment effect for PC. It has been well-documented that PSA kinetics from the treatment initiation would serve as a predictive surrogate for OS ,18. Mostn = 134, 31.8%), enzalutamide (Enz) , and docetaxel . Of the patients treated with ASIs at the first-line treatment (AA and Enz), 31 patients experienced treatment failure within 12 weeks or did not have records of serum PSA level at both 4 and 12 weeks. In total, 254 mCRPC patients treated with ASIs (AA and Enz) at the first-line treatment were enrolled in the present study to evaluate clinical outcomes and PSA kinetics.This retrospective study was conducted using multi-institutional cohorts, including Osaka Medical College  and The Jikei University School of Medicine  with their local satellite hospitals. The design of the study has been approved by the institutional review board of Osaka Medical College  and performed with the consent of the World Medical Association Declaration of Helsinki . As showClinical variables in the present study involve Age at CRPC (years) (\u226470/>70), PSA (ng/ml) at diagnosis, Clinical stage at diagnosis (T2-T3/T4), Gleason sum score at diagnosis (<9/\u22659), duration of ADT before CRPC (months) (\u226512/<12), bone mets at CRPC (\u2212/+), lymph node mets at CRPC (\u2212/+), visceral mets at CRPC (\u2212/+), eastern cooperative oncology group performance status (ECOG-PS) at CRPC (0/\u22651). The data of blood examination includes PSA at the diagnosis of CRPC, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and hemoglobin (Hb). The PSA value was measured by automated Chemiluminescence Immunoassays (CLIA)  in all participating institutes. Other laboratory data were measured by the methods of enzyme-linked immunosorbent assay (ELISA) .CRPC was defined according to the PCWG2 guidelines, i.e., serum testosterone level <50 ng/dL with either PSA progression (an increase of 25% and an absolute increase of 2 ng/mL or more above PSA nadir) or radiographic progression . The clip < 0.05 considered to delineate statistical significance, which was performed using JMP\u00ae 13  and GraphPad Prism software .A Chi-square test was performed to evaluate the distribution of each variable by a contingency table. The student\u2019s t-test was examined to assess the difference between the variables. Kolmogorov-Smirnov normality was conducted to check normal distribution in continuous variables. For variables with non-normal distribution, Wilcoxon or Kruskal-Wallis test was evaluated to examine the difference between the groups. Kaplan-Meier curves were calculated to estimate the survival ratio. The ability for outcome prediction of continuous variables in PSA changes was determined by receiver operating characteristic (ROC) curve analysis, and the optimal cut-off values were defined by the Youden index as the point maximizing the difference between true positive rate and false-positive rate across all possible cut-point values ,27. A loThe background of the cohort and clinical characteristics in the present study are shown in p < 0.0001) and Enz . We investigated the ROC curve to determine the optimal cut-off in PSA changes at four weeks of the treatment for the event of achieving >30% PSA decline (PSA30D) at 12 weeks. As shown in We first assessed the correlation of PSA changes between 4 and 12 weeks from the baseline. As shown in p = 0.009, 12 weeks: p < 0.001: p < 0.001, 12 weeks: p < 0.001: p < 0.001), ECOG-PS , bone metastasis , as well as PSA30D at four weeks   had PSA30D from the baseline. Thereafter, 177 patients (69.7%) achieved PSA30D at 12 weeks of the treatment. We next assessed a predictive impact of PSA30D from the baseline at 4 and 12 weeks of the treatment. In agreement with previous studies ,30,31,32= 0.009) . These dn = 147: 93.6%) were consistently offered PSA30D at 12 weeks. On the other hand, of 97 (38.2%) patients without achieving PSA30D at four weeks, 67 (69.1%) patients did not either achieve PSA30D at 12 weeks of the treatment, whereas 30 (30.9%) patients met the criteria for PSA30D at 12 weeks of the treatment.To further investigate the clinical value of early PSA response for patients treated with ASIs at the first-line treatment, we stratified patients into four groups according to the achievement of PSA30D at 4 and 12 weeks . Of 157 To assess whether these four patient groups stratified by the achievement of PSA30D at 4 and 12 weeks exhibited distinct survival outcomes, we assessed OS in these four groups . Of 157 p = 0.642), which prompted us to assess prognostic factors for OS specifically in patients not achieving PSA30D at four weeks of the treatment. To this end, we further performed multivariate analysis for OS in 97 patients who did not achieve PSA30D at four weeks (p = 0.008) and ECOG-PS \u2265 1  were identified as independent predictors of shorter OS for mCRPC patients not achieving PSA30D at four weeks of the first-line ASIs.Although the early PSA decline (PSA30D) at four weeks using ASIs as the first-line treatment seemed to be a significant predictor for an improved OS, we noted that 30 of 97 (30.9%) patients, who did not achieve PSA30D at four weeks, but consequently achieved PSA30D at 12 weeks, had a comparable three years OS rate as favorable as 147 patients achieving PSA30D at both 4 and 12 weeks of the treatment  switched treatment based only on clinical progression . This imp = 0.642), which implies approximately a third (30 of 97) of patients, who were treated with ASIs as the first-line and did not have an early PSA response (PSA30D) at four weeks, still could benefit from continuing the first-line treatment. A recent report from an international collaborative study analyzing the early PSA response (PSA30D) at four weeks of ASIs included a population of post-docetaxel setting (53.2%) [p = 0.008) and ECOG-PS >1  was identified as independent predictors of the shorter OS when no early PSA decline at four weeks was observed in mCRPC patients treated with ASIs as the first-line treatment. These data indicate a possibility of early treatment switch at four weeks of the first-line ASIs when not observing >30% PSA decline (PSA30D) at four weeks, particularly in patients with a modest effect of ADT and poor performance status.Despite the strong positive-correlation of PSA changes between 4 and 12 weeks of the first-line ASIs , 30 of 9 (53.2%) . In theiThe findings in the present study should be interpreted within several limitations. Firstly, this study was limited by its retrospective design that might have caused selection bias. Secondly, with being devoid of clinical records to define the treatment failure, we could not analyze the treatment outcomes from the second-line treatment, especially in comparing survival outcomes according to sequential therapy ,40. ThirThis study investigated the predictive value of PSA30D at four weeks of the first-line ASIs for mCRPC patients. PSA changes at four weeks from the baseline were positively correlated with those at 12 weeks. The achievement of PSA30D at four weeks was an independent predictor for OS. Of note, in patients without achieving PSA30D at four weeks (97 of 254 patients: 38.2%), an achievement of PSA30D at 12 weeks was eventually observed in 30.9% of those patients (30 of 97 patients). To identify the variables that discriminate the patient survival in 97 patients without achieving PSA30D at four weeks of the first-line treatment, a multivariate analysis was performed. Duration of ADT before CRPC < 12 months and ECOG-PS >1 were identified as independent predictors for shorter OS for those patients. These data collectively offer a concept of early treatment switch at four weeks of the first-line ASIs when not observing PSA30D at four weeks, particularly in patients with a modest effect of ADT and poor performance status. Large-scale and prospective studies are warranted to prove the result from the present study."}
+{"text": "Data regarding demography, clinical features, treatment and laboratory parameters were analyzed. Twenty patients were excluded for assessment of disseminated intravascular coagulation (DIC) and thrombotic microangiopathy (TMA) due to lack of laboratory data. Results: COVID-19 patients (n = 65) were investigated, 19 with uncomplicated, 29 with complicated, and 17 with critical course; nine (13.8%) died. Seven patients showed overt DIC according to the ISTH criteria. The fibrinogen levels dropped significantly in these patients, although not below 100 mg/dl. Hallmarks of TMA, such as thrombocytopenia and microangiopathic haemolytic anaemia, were not detected in any of our COVID-19 patients. ADAMTS13 activity was mildly to moderately reduced in 4/22 patients, all having strongly elevated procalcitonin levels. Conclusion: DIC occurred in 7/65 COVID-19 patients but fibrinogen and platelet consumption were compensated in almost all. ADAMTS13 assays excluded TTP and hallmarks of classic TMA were absent in all investigated patients. We hypothesize that the lacking erythrocyte fragmentation and only mild platelet consumption in severe COVID-19 are due to a microangiopathy predominantly localized to the alveolar microcirculation with a low blood pressure gradient.Background: Coronavirus disease-2019 (COVID-19) triggers systemic infection with involvement of the respiratory tract. There are some patients developing haemostatic abnormalities during their infection with a considerably increased risk of death. Materials and Methods: Patients ( Patient age, male sex and pre-existing comorbidities are the major determinants of clinical severity and outcome of coronavirus disease-2019 (COVID-19) caused by Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) . Some haA massive release of VWF from the endothelial cells, as it occurs in severe inflammatory states and systemic infections, can lead to a mild decrease of VWF-cleaving protease, a disintegrin and metalloprotease with thrombospondin type 1 motif 13 (ADAMTS13) . WhetherWe investigated clinical and laboratory patterns in this observational study to understand more about the underlying coagulopathy during COVID-19. In particular, we focused on clinical and laboratory features of DIC and classic TMAs.n = 85) with confirmed SARS-CoV-2 infection who were seen at the University Medical Center, Mainz, Germany, between 3 March and 15 May 2020 were assessed in this observational study. Patient characteristics and laboratory findings were reviewed retrospectively through the electronic hospital information systems . The retrospective study was approved by German law [Landeskrankenhausgesetz \u00a736 and \u00a737] in accordance with the Declaration of Helsinki and by the local Ethics Committee of \u201cLandes\u00e4rztekammer Rheinland-Pfalz\u201d (reference numbers: 2020-14988_2).Patients  from respiratory samples, employing a PCR kit specific for SARS CoV-2 . All other laboratory assays were performed in the accredited (DIN-ISO 15.189) Institute of Clinical Chemistry and Laboratory Medicine of the University Medical Center, Mainz. Renal injury was assessed based on Acute Kidney Injury Network (AKIN) criteria ,25. Prest-test or Mann\u2013Whitney-U-test for continuous variables and by Chi-squared test or Fisher\u2019s exact test for categorical variables, accordingly. p-values are two tailed, and p values < 0.05 were considered statistically significant.Statistical analyses employed SPSS version 22.0 . Descriptive statistics included frequency, mean, standard deviation, median, interquartile range (IQR), minimum and maximum. Explorative group comparisons were performed by A total of 85 patients with proven SARS-CoV-2 infection were seen between 3 March and 15 May 2020. For the assessment of haemostatic alterations, 20 patients were excluded due to insufficient laboratory data .2) was observed in 23/62 (37%) and a history of venous thromboembolic events before COVID-19 in 4/65 (6%). The clinical course of COVID-19 was uncomplicated in 19 (29%), complicated in 29 (45%) and critical in 17 (26%). The overall mortality rate was 14% (9/65), reaching 35% (6/17) in critical COVID-19. Invasive ventilation of 17 critically ill patients was performed over a period of 21  days. Prophylactic or therapeutic anticoagulation was used in 43/46 (94%) patients with complicated or critical COVID-19 manifestation and in 14/19 (74%) of the uncomplicated cases (Sixty-three/65 (97%) COVID-19 patients were hospitalized and 20/65 (31%) had to be treated in intensive care unit. COVID-19 patients were predominantly male (63%) and had a median age of 69  years. Older adults (age > 65 years) accounted for 37/65 (57%). The most common underlying comorbidities were arterial hypertension, cardiovascular disease and diabetes mellitus. Obesity  throughout the course of COVID-19 . AccordiElevated troponin I (>24 pg/mL) indicative of myocardial injury was observed in 27/61 (44%) of all COVID-19 patients . In patiSignificant increases  in AST and ALT were observed in 17/63 (27%) and 9/64 (14%), respectively. Impaired liver function as indicated by hyperbilirubinemia  and pronounced hypoalbuminemia  occurred in 17/64 (27%) and 31/58 (53%), respectively .Among our COVID-19 patients, acute new-onset thromboembolic (TE) events were observed in 4/65 (6%) . These TAs shown in Elevation of INR and D-dimers along with COVID-19 severity was evident . ConsequFibrinogen levels in COVID-19 patients were elevated in 49/58 (84%) at baseline . Particularly all patients (17/17) with critical COVID-19 presented with elevated baseline fibrinogen levels . During the course of COVID-19 maximum fibrinogen concentrations were above normal in the entire COVID-19 cohort  and remaOvert disseminated intravascular coagulation (DIC), as defined by a DIC Score \u22655 points (26), was present in 7/65 (11%) patients .The dynamics of laboratory values included into the DIC score are shown for the seven patients who developed DIC over the course of hospitalisation . The DICSome authors reported that severe COVID-19 may cause thrombotic microangiopathy (TMA) ,29,30,31Anaemia using a haemoglobin cut-off for males (<13.5 g/dL) and females (<12.0 g/dL) was observed in 52/65 (80%) of our COVID-19 patients . HaemoglPlatelet counts were <150/nL in 22/65 (34%) without clear relation to disease severity . HoweverFinally, ADAMTS13 was mostly in the normal range and only 4/22 tested showed reduced ADAMTS13 activity values (<50%) with a minimum ADAMTS13 activity of 17.8% . These mEscherichia coli and Staph epidermidis isolates from the lower respiratory system and blood stream, respectively.It is remarkable that in the four patients with mild to moderately reduced ADAMTS13 activity (18\u201348%) by far the highest procalcitonin (PCT) values were found. Bacterial coinfections were confirmed in two cases by In sum, there were no diagnostic clues for classic TMA  in any of our patients whereas the consistently high VWF levels were compatible with an endothelial activation and/or damage.We present here our single-centre cohort of all consecutive, retrospectively included patients diagnosed with COVID-19 at the University Medical Center Mainz during the first wave of the pandemic from 3 March to 15 May 2020. Our report focuses on the clinical and laboratory abnormalities related to thrombosis and haemostasis. Multiple scientific publications pointing to the high thrombotic risk in COVID-19 ,12,13,32From 65 of the 85 registered COVID-19 patients sufficient laboratory data were available to delineate the frequency and extent of haemostatic abnormalities . Nine ofRoutine haemostatic laboratory parameters showed strongly elevated fibrinogen and D-dimer levels, the latter being exceedingly high in those with critical disease . ProthroOther investigators have labelled the coagulopathy in COVID-19 as thrombotic microangiopathy (TMA) ,46,47,48Whether the  lacking laboratory hallmarks of TMA in our COVID-19 patients and those described in other cohorts ,50 is exOur study has several limitations. Due to the retrospective approach, relevant parameters were not monitored throughout the course of COVID-19. In particular, we did not assess markers of complement activation, which may play a pathophysiologic role in the prothrombotic alterations of COVID-19  and inhiAnother limitation is a bias regarding the severity of COVID-19. Mostly severely symptomatic patients presented at our University Medical Center and were admitted as inpatients and laboratory data on haemostatic alterations were not available from all patients. Therefore, our observational study is merely hypothesis-generating.In sum, our observational data on the haemostaseologic abnormalities in real world adult COVID-19 patients admitted to a single academic centre add results suggesting that the haemostatic alterations in severe COVID-19 are not fully fitting into the established categories of DIC and classic TMA. Further pathophysiologic research is needed to provide clinically useful targets for intervention to improve patient outcome."}
+{"text": "To evaluate the oscillation of laboratory parameters among indoor patients infected with COVID-19.This cross-sectional analytical study was conducted at Tertiary Care Institute, Rawalpindi from 01 March 2020 to 20 May 2020. Three hundred and ninety-two patients with mild to moderate illness, PCR positive for COVID 19 were included. Prevalence of typical symptoms of coronavirus disease cough, fever, sore throat and shortness of breath was recorded.PCR was repeated after seven days of admission, if declared negative, another executed on consecutive day. Discharge Criteria was two consecutive negative PCR.A total of 392 patients enrolled in the study with age range 9-45 and mean 33.22\u00b17.98 years. A total of 8 (2%) patients were females and 384(98%) males. 296(75.5%) did not have a cough whereas 96(24.5%) presented with the trait. 296 (75.5%) patients did not have associated fever whereas 96(24.5%) manifested with fever. Chest x-ray had a bilateral patch in 96 (24.5%) patients only. Ferritin was raised in 96 (24.5%) patients however were recorded within normal limits in 296(75.5%) patients. Coagulation Profile was deranged in 64(16.3%) patients whereas was within range in 328(83.7%) patients. Serum Bilirubin, Serum Alkaline phosphatases, Serum Albumin, Serum Urea, Serum Potassium were essentially in typical tolls in 392(100%) patients. However Serum Alanine Aminotransferase was raised in 32(8.2%), Serum C reactive Protein was elevated in 48(12.2%). An exaggerated values of serum creatinine and serum sodium were noticed in 24(6.1%) and 16(4.1%) respectively.Routine haematological tests, biochemical tests, serological tests, and radiographic tests are crucial to conclusion, foundation and progression of ailment in COVID-19 contaminated patients. Ongoing pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS CoV 2). The outbreak was first recognized in Wuhan, China, in December 2019 as pneumonia of unknown aetiology spreading speedily globally.4Laboratory investigations can be divided into diagnostic markers, prognostic markers and those assessing current or latent infection including immunological markers. The Centers for Diseases Control on Prevention (CDC) from the United States of America (USA) and Hong Kong has developed real-time reverse transcription\u2013polymerase chain reaction (rRT-PCR) assay that can be used to diagnose the virus in respiratory and serum samples from clinical specimens. It received special emergency authorization from FDA when covid 19 started to flood worldwide Various laboratory markers indicate leukocytosis or leukopenia. There may be severe lymphopenia in the early course of disease. Presence of neutrophilia is associated with unfavourable prognosis.5Haematological and chemical laboratory testing plays an important role in diagnosing and managing COVID 19 disease by providing several useful prognostic markers.7Rapid collection and testing of appropriate specimens from patients meeting the suspect case definition for COVID-19 is a priority for prompt clinical management and practising outbreak control. It should be guided by a laboratory expert and to be performed in appropriately equipped laboratories by staff well conversant in the relevant technical and safety procedures.10The following study discusses laboratory parameters of various haematological factors which may be within normal limits or raised in COVID 19 positive patients. It also assess individuals who have radiological findings consistent with COVID 19 disease. Severity was positively correlated to the rise of acute phase reactants and radiological findings. These haematological markers were also assessed for monitoring the progression of disease. Generally, patients who had fever and cough at the time of admission had raised inflammatory markers as compared to asymptomatic patients. Similar is the case with the patient with comorbid. Our study aims to aid in the assessment of risk to help in early recognition of the severity of disease and thereby preventing morbidity and mortality.Objective was to evaluate the oscillation of laboratory parameters among indoor patients infected with COVID-19.This cross-sectional analytical study was conducted at Tertiary Care Institute, Rawalpindi from 01 Mar 2020 to 20 May 2020 approval was taken from the ethical research committee of the Institute (ERC Number \u2013 242/ERC).The minimum sample size required for this prospective cross-sectional analytical study was 373, calculated by using formula (n = [deff *np(1-p)]/ [(d2/z21-\u03b1/2*(n-1)+p*(1-p)]-open epi calculator), with 95% confidence level and 5% margin of error where the hypothesized frequency of raised C \u2013 reactive protein related to coronavirus disease was considered to be (58.7%+/-5 ) as reported by Fu et al.Sample was taken by the throat and nasopharyngeal swabs. Patient was admitted on the first day of positive PCR In a ward completely dedicated to COVID 19 patients. PCR was repeated after 7 days of admission. If it was negative, another PCR was planned on consecutive day. Two consecutive negative PCR were considered fit for discharge. There was adequate spacing between beds of admitted patients. Cohort study with > 44000 patients conducted at China concluded that COVID -19 ailment can range from mild to critical. Our study sample included patients with mild to moderate disease(mild symptoms upto pneumonia constituting 81% of victims as defined by Centers of Disease Control and Prevention).12Patient with comorbid like hypertension, diabetes mellitus, ischemic heart disease, rheumatoid diseases and asthmatic were separately identified and also included in the study. Patients with fever were advised HCQ 400 mg twice a day for two days followed by 200 mg BD for the next 4 days. Alongside oral azithromycin 500 mg OD was given for 5 days. All patients were advised vitamin C, calcium and zinc supplements.Patients developing severe symptoms of chest tightness, dyspnea and decreasing oxygen saturation of less than 90 per cent were excluded from the study as they were shifted to high dependency unit.Data was entered and analysed by using data management software IBM SPSS (version 23.0). The descriptive statistics of continuous variables were presented as mean and standard deviation, while categorical data frequencies and percentages were used. Categorical grouped data was analyzed by either Chi-square, Fischer-exact test, and Pearson\u2019s co-relation as applicable. A p-value of \u22640.05 was considered to be statistically significant.Total three hundred ninety two patients enrolled in the study with age range 9 - 45 and mean 33.22\u00b17.98 years. A total of 8 (2%) patients were females and 384(98%) males. 296(75.5%) did not have a cough whereas 96(24.5%) presented with fever. Fatigue and myalgias were predominant in 112(28.6%) patients. and were absent in 280(71.4%). Shortness of breath was witnessed in 40(10.2%) patients. Chest tightness was present in 96(24.5%). Comorbid prevalence was hypertension in 40(10.2%), diabetes mellitus in 24(6.1%), and asthma in 8(2.0%) patients. Total Leukocyte Count (TLC) was raised in 96(24.5%) patients. Chest x-ray(CXR) had bilateral patch in 96(24.5%) patients only. Ferritin was raised in 96 (24.5%) patients. Coagulation Profile was deranged and normal in 64(16.3%) and 328(83.7%) patients respectively. Association with predominant clinical manifestations (Fever and Cough) endorsed in . Serum BStudy results has demonstrated that fever was the main presenting feature of Covid illness. No basic co-association gathered with sexual direction. Raised serum ferritin, C \u2013 reactive protein and chest x-ray discoveries call for multidisciplinary executives for disease management. Research examination collaborates with the various reported studies regarding the matter.Fu et al completed a review preliminary in Suzhou China to investigate clinical ramifications of dynamic neutrophil to lymphocyte proportion and D-dimer in COVID-19 conceded patients. Evident variations from the norm of research facility blood assessments were found, particularly for peripheral blood cell evaluation and coagulation profile. Frequent findings were hemocytopenia, lymphopenia, leukopenia, and thrombocytopenia . The pace of anaemia was (8%).The coagulation profile uncovered an undeniable rise of fibrinogen (60%) and D-dimer (12%) regardless of within normal limits prothrombin time (PT) and partial thromboplastin time (APTT). As to trial of the liver and renal function, tests were within stipulated range as in our study patients only serum ALT was deranged in (8.1%). The rise of the C-reactive protein level was seen in (58.7%) of coronavirus patients on the other hand our examination revealed (12.2%).11Zhang et al dissected Clinical attributes of 140 patients contaminated with SARS-CoV-2 in Wuhan, China. Of the 135 patients with a chest CT scan on confirmation, the greater part (99.3%) had unusual outcomes, demonstrating run of the mill pictures that were reciprocal numerous ground-glass opacities or consolidation. The blood test consequence of patients upon the arrival of emergency clinic confirmation demonstrated normal leukocytes in the vast majority of the patients (68.1%), with 12.3% expanded and 19.6% diminished numbers. Lymphopenia was noticed in 75.4% of the patients. Most of these patients 52.9% had eosinopenia. Other research facility discoveries incorporated a higher convergence of C-reactive protein 91.9% and D-dimer 43.2%.13Huang et al contemplated Clinical highlights of patients contaminated with 2019 novel coronavirus in Wuhan, China. The blood checks of patients on affirmation indicated leucopenia 25% patients and lymphopenia 63% patients. Coagulation Profile was deranged (p = 0.012) whereas in (16.3%) patients had deranged coagulation profile p = 0.14). Levels of aspartate aminotransferase were expanded in 37% of 41 patients, including (62%) of 13 ICU patients and 25% of 28 non-ICU patients. Of the 41 patients, (98%) had respective various lobular and subsegmental zones of consolidation on CT Chest.. Levels Chen et al assessed employing distinct examination epidemiological and clinical qualities of 99 instances of 2019 novel coronavirus pneumonia in Wuhan, China. On confirmation, leucocytes were beneath the typical range in (9%) patients or more than normal range in (24%) patients. About 38% patients had neutrophils over the typical range. Lymphocytes (35%) and haemoglobin 51% were beneath the ordinary range in numerous patients Platelets were below the normal range in 12% patients or more than typical range in 4%. About 43% patients had contrasting degrees of liver capacity variation from the norm, with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) over the stipulated range.Seven(7%) patients had varying degrees of renal function incapacitation with raised blood urea nitrogen or serum creatinine. Sixty three percent had serum ferritin above the typical range. 63 out of 73(86%) patients had elevated C-reactive protein.15Xu et al inspected in a review study a Group of Patients Infected With Coronavirus Outside of Wuhan, China. On confirmation, the blood checks of 31% patients indicated leucopenia and 42% demonstrated lymphopenia contradictory to our trial participants where raised values noted in Total Leukocyte count among 24.5% patients. Levels of aspartate aminotransferase expanded in 16% patients. 84% patients demonstrated bilateral association on chest radiographs whereas figure was 24.5% study participants.16Liu et al surveyed biochemical files from COVID-19 tainted patients. The most widely recognized research facility variations from the norm were hypoalbuminemia, lymphopenia, diminished level of lymphocytes and neutrophils, raised C-responsive protein, and lactate dehydrogenase. CRP was exceptionally associated with the intensity of lung injury. But co-relation in our study patients revealed to be insignificant  as elaborated in  .1717Wang et al examined the qualities of 34 children tainted with novel coronavirus Shenzhen. In the 34 cases, the white platelet checks of (82%) were typical. Five cases had expanded consistent with 24.5% infected patients of our examination and one case had diminished white cell checks.Neutropenia and lymphopenia was found in one case, individually. C-reactive protein levels and erythrocyte sedimentation rates were raised in 1 and 5 cases, separately. Raised D-Dimer found in 3 cases. The CT scan of these patients indicated bilateral sketchy or nodular ground-glass opacities.18Chen et al made an investigation of 29 patients contaminated with coronavirus. The blood trial of the patients demonstrated ordinary or diminished white cell tally 23/29, diminished lymphocyte check 20/29, expanded C reactive protein 27/29. Albumin was decreased in 15/29, however, it was essentially within normal limits in 100% patients. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, serum creatinine demonstrated no noteworthy changes.19Chen et al assessed intrauterine vertical transmission capability of COVID-19 disease in nine pregnant patients. Information from research centre tests indicated that five of the nine parturients with COVID-19 pneumonia had lymphopenia.6 patients had raised C- reactive protein (>10 mg/L) relevant to our evaluation with the mean value of (8.50\u00b1.96). Three had elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST).20Our examinations were compelled to a restricted period and may have missed time-changing ailment highlights, given the quick advancement of the epidemic.It stays a provoking errand to contain a flare-up of a novel pathogen proficient for individual to individual transmission in this exceptionally portable world, specifically at the point when treatment and counteraction alternatives are constrained.Routine haematological tests, biochemical tests, serological tests, and radiographic tests are crucial to conclusion, foundation and progression of ailment in COVID-19 contaminated patients.Clinical preliminaries should be painstakingly planned and conceptualized to evaluate the disease process, which could be testing given the already overstretched medical resources. The continuous, exceptional episode of COVID-19 diseases comprehensively has underlined the significance of the research facility finding of human coronavirus contaminations to restrain the spread as well as properly treat those patients who have asymptomatic disease.SA: Conceived, designed and did statistical analysis & editing of manuscript, is responsible for integrity of research.AR, BA & MS: Did data collection and manuscript writing."}
+{"text": "Cancer development has been ascribed with diverse genetic variations which are identified in both mitochondrial and nuclear genomes. Mitochondrial DNA (mtDNA) alterations have been detected in several tumours which include lung, colorectal, renal, pancreatic and breast cancer. Several studies have explored the breast tumour-specific mtDNA alteration mainly in Western population. This study aims to identify mtDNA alterations of 20 breast cancer patients in Malaysia by next generation sequencing analysis. Twenty matched tumours with corresponding normal breast tissues were obtained from female breast cancer patients who underwent mastectomy. Total DNA was extracted from all samples and the entire mtDNA (16.6kb) was amplified using long range PCR amplification. The amplified PCR products were sequenced using mtDNA next-generation sequencing (NGS) on an Illumina Miseq platform. Sequencing involves the entire mtDNA (16.6kb) from all pairs of samples with high-coverage . MtDNA variants were called and annotated using mtDNA-Server, a web server. A total of 18 of 20 patients had at least one somatic mtDNA mutation in their tumour samples. Overall, 65 somatic mutations were identified, with 30 novel mutations. The majority (59%) of the somatic mutations were in the coding region, whereas only 11% of the mutations occurred in the D-loop. Notably, somatic mutations in protein-coding regions were non-synonymous (49%) in which 15.4% of them are potentially deleterious. A total of 753 germline mutations were identified and four of which were novel mutations. Compared to somatic alterations, less than 1% of germline missense mutations are harmful. The findings of this study may enhance the current knowledge of mtDNA alterations in breast cancer. To date, the catalogue of mutations identified in this study is the first evidence of mtDNA alterations in Malaysian female breast cancer patients. Breast cancer is the most common malignancy in women and one of the leading causes of cancer-related deaths in women worldwide, with nearly 2.1 million new cases estimated and responsible for the deaths of 629,679 women in 2018 , 4. AlbeMitochondria are the energy synthesising organelles in the cells. They are responsible for the generation of adenosine triphosphate (ATP) molecules through oxidative phosphorylation (OXPHOS). Each mitochondrion contains genetically compact circular double-stranded mtDNA loops with an average of 100\u201310,000 copies per cell at a high copy number. The mtDNA copy number per cell varies widely in different human tissues and is maintained to meet the energy requirement to sustain normal physiological functions of the cell . mtDNA cIt is increasingly apparent that mitochondria play a pivotal role in modulating oncogenesis by virtue of their key functions in energy production, synthesis of building blocks for tumour anabolism, generation of reactive oxygen species (ROS), regulation of cell death and immunosurveillance , 7. The Various types of mtDNA mutations have been detected in breast cancers , 14. ComIn the current study, the entire mtDNA of adjacent normal-tumour pairs of 20 patients with breast cancer was screened using in-depth coverage provided by next generation sequencing (NGS) to catalogue the mtDNA mutations. Understanding the mtDNA alterations may add to the current knowledge of mitochondrial impairment in breast cancer. The relationship of mutations burden and clinical variables of the patients were also assessed. The outcome of this first preliminary study involving Malaysian breast cancer patients will potentially serve as a reference for future studies involving the entire mtDNA in breast cancer.This study was approved by the Medical Research & Ethics Committee (MREC) of the National Institutes of Health Malaysia [NMRR ID-15-2085-28181 (IIR)] and Ethic Committee for Research Involving Human Subjects of Universiti Putra Malaysia (JKEUPM). Written informed consent was obtained from all participants and the study was conducted according to the ethical guidelines of the Helsinki Declaration. A total of 20 female breast cancer patients were recruited between April 2016 and December 2016 from Hospital Kuala Lumpur, National Cancer Institute and Hospital Putrajaya in Peninsular Malaysia. Breast tissue samples were obtained during surgery whilst the demographic and clinical data were extracted from the medical records. Women who were more than 18 years old, pathologically confirmed with primary breast carcinoma and underwent mastectomy surgery for breast cancer were included. Patients receiving neoadjuvant chemotherapy/radiotherapy, with serious infection or concomitant disease and absence of informed consent were excluded from this study. Tumour tissue and its matched control were obtained during mastectomy surgery. Normal breast tissue samples were located in the different quadrant and at a sufficient distance from the tumour. All samples were immediately immersed in liquid nitrogen and stored until further use. The demographic details of patients and clinical features of the samples are summarised in Total DNA was extracted from 50 mg of malignant and corresponding normal tissue samples using the QIAamp DNA Mini kit  according to the manufacturer\u2019s instructions . An ultr5\u2019 AAA GCA CAT ACC AAG GCC AC 3\u2019); R1 (5\u2019 TTG GCT CTC CTT GCA AAG TT 3\u2019) and MTL-F2 (5\u2019 TAT CCG CCA TCC CAT ACA TT 3\u2019); R2 (5\u2019 AAT GTT GAG CCG TAG ATG CC 3\u2019) as previously described [Taq kit  was used for amplification. The 50 \u03bcL of PCR reaction conditions were: 1 x LA PCR buffer, 0.4 mM dNTP mixture, 0.4 \u03bcM primer pairs, 2.5 U TaKaRa LA Taq, and 2 ng of genomic template DNA. Thermal cycling parameters were: initial denaturation at 95\u00b0C for 3 minutes, then 30 cycles at 95\u00b0C for 30 s, 68\u00b0C for 10 s, 60\u00b0C for 15 s and 68\u00b0C for 11 minutes, followed by a final extension at 72\u00b0C for 10 minutes. Agarose gel electrophoresis was performed to validate the size of amplified PCR products. PCR products were quantified using the Qubit dsDNA HS Assay Kit  with the Quantus Fluorometer .Long-range polymerase chain reaction (LR-PCR) was performed to purify mtDNA from isolated total DNA. LR-PCR was performed in two separate reactions to amplify two large overlapping amplicons (9.1kb and 11.2kb) using two sets of primer pairs MTL-F1  according to the manufacturer\u2019s guidelines . An inpuThe Illumina Miseq paired-end FASTQ files of all 20 tumour and matched normal samples were analysed with mtDNA-Server Version 1.0.6. . Server Variants detected in both tumour and corresponding normal tissue samples of a patient were classified as germline mutations as described in previous studies , 29. VarThe predicted functional effects of variants were determined using precomputed values of the Polyphen2, SIFT, CADD and APOGEE algorithms, collected within the MitImpact 3D database  and MutPThe shift in heteroplasmy levels of heteroplasmic point mutations was analysed using a paired t-test. The distribution of germline mutations  and somatic mutations were assessed by dividing the mitochondrial genome into 18 regions , 12s rRNA, 16s rRNA, ATP8, ATP6, COX I, COX II, COX III, CYB, ND1, ND2, ND3, ND4,ND4L, ND5 and ND6). The proportions of mtDNA genes were calculated by dividing the total number of base pairs per gene by the number of base pairs of the entire mtDNA. The proportions of germline mutations and somatic mutations were calculated by dividing the number of mutations in a certain gene region with a total number of mutations. Testing differences in the distribution of mutations across the mtDNA genome between germline and somatic mutations were assessed using a two-sided Fisher\u2019s exact test with rows indicating germline and somatic categories, and columns indicating regions of mutations. The association between the numbers of mutations in relation to gene size were tested for independency with a Pearson correlation analysis. Statistical test was performed using IBM SPSS version 23. A value of P<0.05 was considered significant, whereas values of P<0.01 and P<0.001 were considered highly significant. Tables were generated using Microsoft Excel 2010. Figures were generated using Microsoft Excel 2010 and Adobe Illustrator CS3.The mtDNA mutation study was conducted at the Integrative Pharmacogenomics Institute (iPROMISE) in Universiti Teknologi MARA Puncak Alam Campus in Malaysia. A flow chart summarizing the methodology is shown in The corresponding normal breast tissue specimens act as controls. The mean age of patients at the time of initial surgery was 57.45 years (range 38\u201378 years) . BrieflyLists of homoplasmic and heteroplasmic variants identified by mtDNA-server for all 20 tumour-normal sample pairs are presented in Table 1 of All patients (100%) carried germline mtDNA mutations. In total, 753 germline mtDNA mutations were identified with an average of 37.7 mutations per patient. Among the germline mutations identified, 632 (83.9%) were homoplasmic single nucleotide variants , 63 8.4 and 58 .Of the homoplasmic mutations, 630 (99.7%) were known variants reported in MITOMAP . HoweverA total of 63 (8.4%) germline heteroplasmies at 46 distinct nucleotide positions were detected in 18 individual breast cancer patients . Seven oIndels were found in all patients (100%) accounting for a total of 58 indels at 7 distinct nucleotide positions . All gerSomatic mutations were detected in 18 of 20 patients (90%). A total of 65 somatic mutations were detected, with a mean of 3.25 mutations per tumour sample. Of the 65 somatic mutations, 30 (46.2%) were novel and 35 (53.8%) were known variants in MITOMAP and dbSNP databases . All somOverall, 245 (32.5%) of germline mutations were within the D-loop region, 399 (53.0%) were within protein-coding region, 88 (11.7%) were within rRNA region, 14 (1.9%) were within tRNA region and 7 (0.9%) were within other non-coding regions. A similar pattern of distribution was observed for somatic mutations whereby 7 (10.8%) of somatic mutations were within the D-loop region, 38 (58.5%) were within protein-coding region, 12 (18.5%) were within rRNA region and 8 (12.3%) were within tRNA region. The proportional distribution of germline and somatic mtDNA mutations across the mtDNA genome are depicted in Given the role of protein-coding genes in the OXPHOS for the generation of cellular energy, the distribution of somatic and germline mutations within the OXPHOS cascade protein complexes was studied. Of the 38 somatic mutations observed in protein-coding regions, 32 (84.2%) were non-synonymous while 6 (15.8%) were synonymous . In contIn finding the possible role of tRNA mutations found in the current study, somatic mutations G4309A, G4282A and G5521A were classified as pathogenic when assessed with MitoTIP . Each ofThe functional impact of mutations in the rRNA genes is currently unknown. However, differences in the occurrence of somatic and germline mutations in rRNA genes in the current study is worthy of future investigation. It was found that among 12 (18.5%) somatic mutations in the rRNA genes, a predominant (13.8%) of mutations occurred in the 16S rRNA gene region. Whereas, among 88 (12.7%) germline mutations identified in the rRNA genes (65.9%) were predominantly found in the 12S rRNA gene region.As reported earlier, the D-loop contains a substantial number of somatic (10.8%) and germline mutations (31.9%) in comparison to other genes despite its small size and non-coding properties. The somatic D-loop mutations in 25% of the population, most commonly occurred in the hypervariable region 1 (HVR-1) (4.6%) and HVR-2 (4.6%). Similarly, germline D-loop mutations in all patients (100%) occurred largely in the HVR-1 (54.7%) and HVR-2 (37.0%). Somatic mutations in the HVR-2 especially C150T, C186T and A214G as well as germline mutations from nucleotide positions 146\u2013374 are likely to affect heavy-strand synthesis as they were located at the origin of heavy-strand replication (OHR) sites.The association between the frequency of somatic and germline mtDNA mutations with patients\u2019 age, ethnicity, tumour grades and stages, nodal stages and hormone receptors in breast cancer were investigated. Significant association was found between frequency of somatic mutations in the rRNA gene region and tumour grades (P = 0.01) and tumour stages (P = 0.022). Breast tumour grade III (73%) appeared to express more rRNA somatic mutation than the grade II tumours (11%), while stage III breast tumours (78%) carried more rRNA somatic mutation than the other tumour stages. In addition, the frequency of somatic mutations in the protein coding genes was significantly different between different nodal stages in breast cancer (P = 0.016) compared to other gene regions. An overall lack of associations with various other clinicopathological variables may be attributed to the limited sample size for the current study. MtDNA mutations occur frequently in cancer and have recently emerged as non-invasive cancer biomarkers for evaluating the risk and prognosis of the disease , 37. VarThe D-loop region is the most studied mtDNA variants as it possesses high mutation rate, associated to later stages of cancer and poor prognosis in breast cancer . SeveralAnalysis of mutations in the coding region showed that genes encoding for OXPHOS components that regulate energy production in cells were mostly affected. Complex I genes carried the highest number of mutations as described in In conclusion, the screening of mtDNA in a small cohort of patients with breast cancer in Malaysia identified germline and somatic mtDNA mutations. Evaluation for pathogenicity and functionality suggest mtDNA alterations affect protein functions. It was noted somatic mtDNA mutations were enriched for nonsynonymous changes compared to germline mutations. The findings from this study will serve as a basis in understanding mitochondrial genome of breast cancer in Malaysian population.S1 Table(XLSX)Click here for additional data file.S2 Table(XLSX)Click here for additional data file.S3 Table(XLSX)Click here for additional data file.S4 Table(XLSX)Click here for additional data file.S5 Table(XLSX)Click here for additional data file.S6 Table(XLSX)Click here for additional data file.S7 Table(XLSX)Click here for additional data file.S1 Fig(PDF)Click here for additional data file.S2 Fig(PDF)Click here for additional data file."}
+{"text": "Purpose: Advanced epithelial ovarian cancer (EOC) eventually develops into a recurrent platinum-resistant disease. The response to standard treatment and prognosis in patients with EOC is generally unsatisfactory. This study aimed to assess the efficacy and safety of apatinib combined with etoposide in patients with recurrent platinum-resistant EOC.Materials and Methods: This is a single-center, retrospective, observational study. We have reviewed a total of 33 patients with recurrent platinum-resistant EOC from July 2017 to July 2018, who were regularly treated with apatinib and etoposide until disease progression or unacceptable toxic effects occurred.Results: At the date of the review finished, 15 of 33 (45.5%) patients remained on the combined treatment of apatinib and etoposide, while the other 18 (54.5%) had discontinued. Although no complete response (CR) occurred, the overall response rate (ORR) and disease control rate (DCR) were 36.4% and 78.8% respectively. The median progression-free survival (PFS) was 5.6 months , and the median overall survival (OS) was 10.3 months . The most common adverse event was mucositis oral (60.6%), which caused the treatment discontinued in 4 (12.1%) patients. Other relatively common adverse events were hand-foot syndrome (42.4%), hypertension (39.4%), nausea or vomiting (30.3%), neutropenia (24.2%), fatigue (24.2%) and thrombocytopenia (21.2%). Grade 1 and 2 adverse events accounted for 63.6% (21/33).Conclusion: The efficacy of apatinib combined with etoposide is encouraging in patients with platinum-resistant EOC. Most adverse events of this combined therapy were mild and tolerable. Severe mucositis oral was not rare, which needs more precautions. Ovarian cancer is the most common cause of gynecological cancer-associated death. Over 295,000 women developed epithelial ovarian cancer (EOC) worldwide in 2018, of whom over 184,000 died Angiogenesis is a significant factor in the oncogenesis, development, and metastasis of malignant tumors Anti-angiogenesis therapy combined with single-agent chemotherapy has been proved to be associated with a better clinical outcome in patients with ovarian cancer Patients with recurrent platinum-resistant EOC were reviewed from July 2017 to July 2018 in Hunan Cancer Hospital. Eligibility criteria included age in the range between 18 and 70; diagnosis histologically or cytologically confirmed as EOC; patients developing progressive EOC after cytoreductive surgery and combined chemotherapy; patients resistant to the first-line chemotherapy; at least one measurable solid tumor (> 10 mm) used for efficacy evaluation; Eastern Cooperative Oncology Group (ECOG) performance status 0-2. Exclusion criteria included a diagnosis of other malignancies; previous exposure to the combination of apatinib and etoposide; Karnofsky score below 60; significant abnormality in routine blood test , hepatic and renal function examinations, or electrocardiogram; pregnant and lactating patients. This study has been approved by the Institutional Ethics Committee of Hunan Cancer Hospital and was performed following the Declaration of Helsinki. All patients provided written informed consent before the therapy procedures.Patients were treated with oral apatinib at an initial dose of 500 mg once daily and oral etoposide at a dose of 50 mg once daily on days 1 to 21 of a 28-day cycle. Dose reductions and interruptions were allowed to handle adverse events. When grade 3 or 4 toxicities occurred, apatinib was reduced to 250 mg once daily. Unless recovery to grade 1 or better non-haematological toxicities and grade 2 or better haematological toxicities, apatinib would not be resumed at its initial dosage. For all grade 3 or 4 toxicities , etoposide was withheld until recovery to grade 1 or below non-haematological and grade 2 or below haematological toxicities. Then etoposide was resumed at the initial dose. If toxicities were still intolerable after the dose reduction and interruption or disease progressed, the treatment was terminated.The efficacy of the combination therapy was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, including CR, partial response (PR), stable disease (SD), and progressive disease (PD). Radiologic assessments were conducted by contrast-enhanced CT (CECT) at the baseline and every eight weeks thereafter until progression. Serum CA-125 level, as an adjuvant therapeutic indicator, was detected at the baseline and every four weeks thereafter Statistical analyses were performed using Statistical Package for Social Sciences (SPSS) software . The Kaplan-Meier method was used to create the survival curve.A total of 33 patients with platinum-resistant EOC who were treated with apatinib and etoposide were enrolled in the study. Table All 33 patients were eligible for response evaluation. Although no CR occurred, PR had been observed in 12 patients (36.4%). The ORR was 36.4%. Their median response duration was 4.9 months (range 2.8~14), and 4 of them (33.3%) had a response duration longer than 6 months. Fourteen patients (42.4%) had experienced SD with the median duration of 4.2 months (range 2.8~12.1), of whom 3 (21.4%) patients had a response duration longer than 6 months. The calculated DCR was 78.8%. Figure The median duration of follow-up at the time of data analysis was 7.5 months (range 3.7~14). Eighteen of 33 (54.5%) patients had discontinued the treatment, while the other 15 (45.5%) patients remained on the procedure. The primary reason for treatment discontinuation was disease progression . Other reasons included adverse events 4, 22.2%) and lost to follow-up . Fifteen (45.5%) patients had tumors progressed during the treatment combined of apatinib and etoposide, with the median PFS of 5.6 months  shown by a phase II trial (n=41) Patients reviewed in this study accepted oral etoposide 50 mg once daily (days 1-21 of a 28-day cycle) as the initial dose, which was a conventional tolerable dosage according to our previous clinical observation. During the whole treatment process, no patient discontinued the treatment because of the adverse events of etoposide. Apatinib is suggested as 500 mg once daily in patients with solid tumors by some clinical trials In conclusion, the combination therapy of apatinib and oral etoposide shows promising efficacy in patients with recurrent platinum-resistant EOC. For most patients, apatinib is a safe oral agent that can be added to current chemotherapies in EOC patients. Only a few patients could not tolerate the toxicity of apatinib, such as severe mucositis oral. Further randomly controlled prospective cohort studies will be performed to provide more evidence for the indication of apatinib in EOC."}
+{"text": "Acute Zika virus (ZIKV) infection has not been confirmed in Kenya. In 2018, we used specimens collected in a 2013 dengue serosurvey study in Mombasa to test for ZIKV IgM. We confirmed specific ZIKV IgM positivity in 5 persons. These results suggest recent ZIKV transmission in the coastal region of Kenya. Flaviviridae, was initially isolated in 1947 from the serum of a pyrexic sentinel rhesus macaque in the canopy of the Zika Forest in Uganda (Zika virus (ZIKV), an arbovirus belonging to the family In 2015, the emergence of ZIKV in the Americas (https://inbios.com). Concurrent with this serosurvey, hospital surveillance of suspected dengue patients was established  against ZIKV strain MR766 (African lineage) and DENV  . A ZIKV MAC ELISA specimen with a positive-to-negative ratio 90 assay confirmed 5  as ZIKV, 7 (21.2%) as DENV, 3 (9.1%) as cross-reactive to both viruses, and 18 (54.5%) as negative for ZIKV and DENV; 1 (2.9%) could not be confirmed due to insufficient sample  years.We identified a total of 745 DENV-negative persons from the dengue serosurvey (n = 704) and hospital surveillance (n = 41); median age was 28 (range 0\u201394) years. None were positive by ZIKV rRT-PCR. Thirty-four (4.6%) were positive by ZIKV MAC ELISA, 7 captured in hospital surveillance; 24 (3.2%) were equivocal and 687 (92.2%) negative. Of the 34 ZIKV MAC ELISA positives, the ZIKV PRNTt sample . Of the 90. Of note, the positive participants (median age 57 years) were older than the sample group tested (median age 29 years). The level of transmission of ZIKV in Kenya is unknown, although Kenya has the competent vector (Aedes aegypti mosquitoes), and parts of Kenya are ecologically similar to the Zika forest . This finding merits further investigation to determine all circulating flaviviruses in Mombasa. ZIKV transmission season in Kenya most likely coincides with other arboviruses that share the same vector. Of interest, titers of neutralizing antibodies against ZIKV were low for 3 of the 5 positive participants (1:20 PRNT90 titer), typically observed in acute infections (<10 days after onset of illness). Two participants had high neutralization titers (>1:320), suggesting recent infection (within the previous 90 days).We found 1 participant positive by ZIKV MAC ELISA but negative by ZIKV and DENV PRNTOur study had some limitations. It was conducted in 2018, so specimens had been archived for 5 years. We also had incomplete demographic and clinical data and could not discount concurrent DENV infections. Finally, we might have underestimated ZIKV positives because of weak neutralization by IgM.In conclusion, ZIKV may have circulated at low levels in Kenya in 2013. More research is needed to evaluate current ZIKV circulation and characterize other co-circulating flaviviruses. Enhanced surveillance systems, including for microcephaly and other birth defects, could capture ZIKV patients and determine the epidemiology of ZIKV African lineage in this country."}
+{"text": "Dear Editor,1. The virus typically spreads from person to person via respiratory droplets produced during coughing, and common symptoms include fever, cough, and shortness of breath2. The COVID-19 outbreak was initially identified in Wuhan, capital of Hubei Province, China, in December 2019, and has since spread rapidly globally. It was declared a pandemic on 11 March 2020 by the World Health Organization (WHO)3. As of 26 March 2020, a total number of 480446 cumulative cases of COVID-19 have been reported in 175 countries and regions, including 22030 confirmed deaths, the majority of which have been reported in Italy (7503), Spain (4089) and China (3169)4. In Spain, as of 25 March 2020, most of those who have died were elderly, about 96% of deaths were in those over 60 years old, and 45% had pre-existing health conditions including cardiovascular disease (31%)5.Coronavirus disease 2019 (COVID-19) is an infectious disease provoked by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)6. Sex-disaggregated data for CVD in Spain show differences in mortality between men (46.3%) and women (53.7%)6. Surprisingly, although men (51%) and women (49%) are getting infected by COVID-19 at similar rates, men have been dying from COVID-19 at a significantly higher rate (4.4%) than women (2.5%), and the sex differences regarding vulnerability in those with COVID-19 and preexisting CVD seem to be again reflected in men (35%) and women (26%)5.With 120859 deaths in 2018, cardiovascular disease (CVD) is the leading cause of death in Spain (28.3%)7, with smoking prevalence in 2017 among men in Spain being approximately 25.6% but only 18.8% in women8.Emerging evidence suggests that these discrepancies could potentially be due to gendered differences such as patterns and prevalence of smoking. In this regard, approximately 10% of cardiovascular disease is globally attributed to smokingCould smoking influence the gender-based impact of the outbreak? And the impact itself?9. According to the recent (18 March 2020) systematic review of Vardavas and Nikitara10, smoking is most likely associated with the negative progression and adverse outcomes of COVID-19.These hypotheses could be coupled with new available evidence from the WHO on COVID-19, warning that a weaker cardiovascular system among COVID-19 patients with a history of tobacco use could make such patients susceptible to severe symptoms, thereby increasing the chance of deathAccordingly, we recommend that public health messages and behavioural interventions coming from the Spanish government that focus on how to spread and flatten the COVID-19 infection curve should also consider available evidence-based high-quality smoking cessation advice."}
+{"text": "Enterobacteriaceae members from four districts of the state. Isolation with selective culture media techniques and taxonomic characterization of Enterobacteriaceae bacteria with 16S rRNA gene showed the prevalence of Escherichia coli (37.50%), Escherichia fergusonii (29.41%), Klebsiella oxytoca (36.93%), Citrobacter freundii (37.92%), Citrobacter amalonaticus (43.82%), Enterobacter sp. (43.82%), Morganella morganii (43.82%), Hafnia alvei (32.42%), Hafnia paralvei (38.74%), and Shigella flexneri (30.47%) in the spring water of Sikkim. Antibiotic susceptibility test (AST) showed resistance of the isolates to common antibiotics like ampicillin, amoxicillin as well as to third generation antibiotics like ceftazidime and carbapenem. None of the isolates showed resistance to chloramphenicol. E. coli isolated from spring water of Sikkim showed presence of different virulence genes such as stx1 (81.81%), elt (86.66%), and eae (66.66%) along with resistance gene for ampicillin (CITM) (80%), quinolones (qnrB) (44.44%), tetracycline (tetO) (66.66%), and streptomycin (aadA1) (66.66%). The data indicates a high incidence rate of multiple antibiotic resistant enteric bacteria in the spring water of Sikkim. Additionally, the presence of enteric bacteria in the water samples indicates widespread fecal contamination of the spring water.Every year millions of people die due to fatal waterborne diseases around the world especially in developing countries like India. Sikkim, a northeastern state of India, greatly depends on natural water sources. About 80% of the population of Sikkim depends on natural spring water for domestic as well as agricultural use. Recent waterborne disease outbreaks in the state raises a concerning question on water quality. In this study, we analyzed water quality especially for the detection of  Water is important for every facet of life . SurfaceAntibiotic resistance is responsible for thousands of death annually and which is projected to increase dramatically as a global health hazard . It is eEnterobacteriaceae family are used as a microbiological indicator of water quality and fecal contamination  and ARGs by E. coli can cause a wide range of intestinal and extra-intestinal infections including diarrhea, urinary tract infection, and meningitis , West (W), South (S), and North (N). Lack of such previous reports makes it an important foundation for structuring and devising the future water treatment protocols and for revising and restructuring the government policies to tackle future health risks.Sikkim (27\u00b0 05\u2032 to 28\u00b0 07\u2032 N latitudes and 87\u00b0 59\u2032 to 88\u00b0 56\u2032 E longitudes), an Eastern Himalayan state of India, lies between Nepal and Bhutan . The staaquifers , 2013. Aaquifers , 2019. Saquifers . The depThe study was conducted in different villages of Sikkim, which is a NorthEastern state of India. The State is located off the slopes of Eastern Himalayas between the latitude of 27\u00b0 05\u2032 and 28\u00b0 07\u2032 North and the longitudes of 87\u00b0 59\u2032 and 88\u00b0 56\u2032 East, covering approximately 115 km from North to South and 65 km from East to West. The landscape of this area varies with an altitude between 300 to 8583 m above sea level that comprises lower, middle and higher hills, alpine zones and snowbound land. Sikkim is a multi-ethnic state comprising of both tribal and non-tribal groups . The HimFor the current study, a total of 40 spring water samples (10 samples \u00d7 4 districts = 40 samples) were collected from four districts. Springs were selected based on the prevelance of waterborne diseases in a particular area with the help of the State Institute of Rural Development (SIRD), Government of Sikkim, India. The SIRD department helped in selecting the particular area of different districts, community, and blocks (village level blocks: VLB or Gram Panchyant Unit: GPU) which reported recent waterborne disease outbreaks. More than 80% of the springs water samples in that particular area were collected for microbiological and antibiotic resistance analysis. Springs were further selected based on the number of population dependent, altitude and perennial nature. Selection of perennial nature was based on the reason that those spring water will be used by the community throughout the year and large number of population will be depended. Higher the number of population dependency there will be higher risk of anthropoegenic contamination. Easy accessibility of springs at lower altitude could also be major contributing factor for water contamination . The comWater samples were collected in 1L sterile, wide-mouth, plastic bottles . Before collection, containers were sterilized by autoclaving and washed with aqueous sodium thiosulfate solution [100 g/l (w/v)]. While collecting the samples, bottles were completely submerged into the water and it was opened inside the water source to avoid air contamination. Containers were filled by holding it diagonally; lower part was submerged up to 30 cm with the mouth facing slightly upwards. A gap of 2 cm was left between the cap and water to provide sufficient airspace for the mixing of water before analysis .One milliliter of water samples were enriched in different enrichment media like Lauryol Tryptose Broth , Gram-Negative Broth , Selenite Cystine broth  and Alkaline Peptone Water  and incubated at 37\u00b0C for overnight .Escherichia coli, Klebsiella, Enterobacter, Hafnia, Morganella, and Citrobacter. Salmonella-Shigella agar was used for the isolation of Salmonella and Shigella species. Thiosulfate Citrate Bile Salt agar was used for the isolation of Vibrio species , amoxicillin , cefoxitin , ceftazidime , streptomycin , netillin , amikacin . Chloramphenicol , tetracycline , imipenem , ciprofloxacin , norfloxacin  and ofloxacin  by disk diffusion method. Selection of these antibiotics were made based on their differences in mode of action in bacterial cell. Ampicillin, cephalosporin, and imipenem target bacterial cell wall, streptomycin; tetracyclin inhibits protein synthesis and Quinolones inhibit bacterial DNA replication. A single colony of pure bacterial isolates was inoculated in 5 ml of sterile NaCl (0.9%) to make equivalent turbidity of McFarland 0.5 standard. After that, the suspension was evenly streaked on the Mueller-Hilton Agar (MHA) with a sterile cotton swab. The disks containing different concentrations of antibiotics were impregnated on the plate using sterile forceps (E. coli MTCC10898 was used as an antibiotic sensitive control culture with each batch of AST.The antibiotic susceptibility test (AST) was performed using different classes of antibiotics  forceps . The staThe isolates which displayed resistance to three or more than three classes of antibiotics were designated as multi-drug resistant (MDR) bacteria. The Multiple Antibiotic Resistance (MAR) Index was calculated by using the formula :g to pellet down the cellular debris. Collected supernatant was used as a template for PCR amplification of 16S rRNA. A total of 25 \u03bcl reaction mixture was prepared with 2 \u03bcl of template DNA (100 ng/\u03bcl), 1 \u03bcl of universal 16S rRNA primers (27F 5\u2032-AGAGTTTGATCMTGGCTCAG-3\u2032 and 1492 R 5\u2032-TACGGYTACCTTGTTACGACTT-3\u2032) (10 Pico mole)  , 12.5 \u03bclE. coli isolates were extracted by the Phenol-Chloroform method as described by 2, 0.4 mM of each dNTP  and 1 \u03bcl of each forward and reverse primer   . The PCR, India) , raw mil, India) , and fec, India)  and it h, India) .Antibiotic resistance genes for tetracycline, streptomycin, quinolones, and ampicillin were detected using PCR . A 25 \u03bclt-test at p < 0.05 between presence of bacterial diversity, antibiotic resistance pattern, ARG and virulence gene of isolates from different spring water of Sikkim. Multivariate analysis like principle component analysis (PCA) was performed to establish correlation between the diversity of antibiotic resistant pathogens in different spring water of Sikkim using R statistics (Package:Factoextra). Correlation between antibiotic resistance and virulence gene was tested using Pearson-correlation test with R statistical package \u201cPerformanceAnalytics.\u201d One way ANOVA was used to see significance of the results and significant results were tested using post hoc Tukey\u2019s honestly significant difference (HSD) for significant pairwaise comparison. After Tukey HSD, p-value was adjusted with Tukey correction factor. ANOVA and post hoc Tukey was analyzed using R statistics (package: rstatix and ggpubr).Results were analyzed using Microsoft Excel (Office 365). The significance of the results were tested using Enterobacteriaceae isolates. The bacterial isolates were identified by colony morphology and cell morphology. All the 400 identified medically important bacteria (90%) were Gram-negative, rod-shaped bacteria, and belonged to Enterobacteriaceae family . Molecular characterization using 16S rRNA sequencing showed dominance of the phylum. The Enterobacteriaceae family members were predominant in all the water samples of Sikkim. Among the 400 clinically important bacteria isolated from different districts, Citrobacter amalonaticus , Enterobacter sp. , and Morganella morganii  were predominant followed by Escherichia fergusonii  and Hafnia alvei . District wise bacterial diversity showed that East Sikkim was mainly dominated by Hafnia alvei  and Escherichia fergusonii  whereas South Sikkim was dominated by Shigella flexneri . The Citrobacter amalonaticus , Enterobacter spp.  and Morganella morganii  were dominant in the West Sikkim whereas North Sikkim was dominated by Citrobacter amalonaticus , Enterobacter spp.  and Morganella morganii  ] . All theCitrobacter freundii isolates were highly resistant to ampicillin (75%). Escherichia fergusonii isolates were resistant to ceftazidime (73.30%). Escherichia coli isolates were resistant against both ampicillin (66.66%) and amoxicillin (66.66%) and Klebsiella oxytoca isolates were resistant against cefoxitin (66.66%). The least resistance was found against ofloxacin (5.55%) by Shigella flexneri , cefoxitin (50%), netillin (40%), amoxicillin (40%). Enterobacter sp. showed resistance to ampicillin (50%), amoxicillin (50%), and cefoxitin (40%). Morganella morganii showed resistance to ampicillin, amoxicillin, cefoxitin, and ceftazidime with each accounting for 60% , amikacin (40%), ampicillin (35%), amoxicillin (35%), and cefoxitin (35%)   . Howeverin (35%) . Shigell20, 50%) .post hoc Tukey showed significant difference among east, west, south, and north districts data (Multiple antibiotic resistance (MAR) indexing is one the easiest method for making distinction in antibiotic resistance pattern among different isolates and for making health risk assessment. It indicates whether the identified isolates are from a region of high or low antibiotic use. The MAR index value greater than 0.2 indicates higher risk of source contamination where antibiotics are most often used . MAR valcts data .p-value < 0.05. A significant positive correlation was observed between East and South Sikkim water samples. Water samples from West and North Sikkim were totally different in terms of distribution of antibiotic resistant isolates.The correlation between spring water of different districts of Sikkim using antibiotic resistant isolates as an exploratory variable was carried out by principal component analysis (PCA). The F1 component  possessed 67.40% variability whereas F2  showed 20.50% variability and together they accounted for 87.90% variability of the data. Correlation between the water samples of different districts of Sikkim was significant with a Escherichia coli isolates from East Sikkim carried the lowest percentage of stx1  gene and highest percentage of elt gene . E. coli isolates from North Sikkim showed single virulence gene viz. elt . Isolates from West Sikkim carried highest percentage of eae  gene followed by elt gene . E. coli isolates from South Sikkim showed the highest percentage of stx1  gene followed by elt  and eae  gene (04) gene .Escherichia coli isolates from East and South Sikkim had the highest percentage of ampicillin (CITM)  resistance gene followed by that of tetracycline (tetO)  and quinolones (qnrB) . E. coli isolates from West Sikkim showed highest percentage of ampicillin  resistance gene followed by that of streptomycin  and quinolones . E. coli isolates from North Sikkim showed highest percentage of ampicillin  and tetracycline  resistance genes followed by that of streptomycin  and quinolones  ( 0.0032) .E. coli, it was found that tetracyclin resistance (tetO) gene showed positive association (0.96) with elt gene  and stx1 gene (0.83) (non-significant). Whereas quinolones (qnrB) resistance gene showed positive correlation (0.98) with eae gene with statistical significance (P < 0.05). Streptomycin resistance gene (aadA1) showed negative correlation with stx1 (\u22120.84) and elt (\u22120.78) gene whereas ampicillin resistance gene (CITM) showed positive correlation (0.78) with elt gene but statistically non significant , ampicillin (66.66%) and amoxicillin (66.66%). However certain degree of resistance of the E. coli isolates was also observed against norfloxacin (6.66%) and ofloxacin (6.66%). E. coli isolates were also found resistant to tetracycline (26.66%) and streptomycin (60%) , cephalothin (22.70%), sulfisoxazole (13.30%), and streptomycin (13.10%) , ampicillin (20%), amoxicillin (20%), tetracycline (20%), and ciprofloxacin (5.30%) , streptomycin (aadA1), quinolones (qnrA) and ampicillin (CITM) resistance genes (E. coli isolated from river Ganga were found to have genes for neomycin (100%), streptomycin (33.30%), and ampicillin (6.60%) resistance  . The res(13.10%) . Anotherffluents . On an in Sikkim . The posn Sikkim . In Indi (5.30%) . Similar samples . Study oce genes . In a sisistance . Differeisolates . The occountries .E. coli but their colonization is asymptomatic while expression of stx, elt, or eae genes defines the pathogenesis in humans (E. coli isolated from spring water of Sikkim showed highest percentage of elt gene (63.73%) followed by stx1 gene (38.78%) and eae gene (32.57%)  in the spring water of Sikkim and indicated animal or human origin fecal contamination of water bodies. A similar study on E. coli isolates from river Ganga and Gomati, India showed the presence of virulence genes such as stx1 (82%), stx2 (82%), eae gene (70.60%), and elt gene (33.30%) (E. coli (STEC) have a very high rate of transmission and infection to humans and animals  in humans. The expression of stx1 and stx2 gene leads to hemorrhagic colitis (HC) and hemolytic uremic syndrome (HUS) (E. coli which bear heat-labile (LT) and heat-stable (ST) enterotoxin along with colonizing factor were described as ETEC strain  bearing E. coli strain in the spring water of Sikkim indicates possible future health risks. Poor sanitation facility and population pressure have increased the probability of the presence of virulent gene harboring pathogenic bacteria in the surface water of developing countries.Humans and animals both are colonized by different strains of n humans . E. coli(32.57%) . The pre(33.30%) , 2008. D animals . Drinkin animals . Several samples , 2018. Eme (HUS) . The strC strain , and 63.h Africa . Gain anogenesis . Thus, tEscherichia fergusonii (7.35%) was reported from the spring water of Sikkim , streptomycin (60%), ampicillin (60%), and cefoxitin (40%) (E. fergusonii isolates were resistant to penicillin G (100%), erythromycin (76.90%), and oxytetracycline (23%)  . A similne (23%) . MDR E. e Orissa .Klebsiella. It is the second leading cause of nosocomial infection after E. coli among Enterobacteriaceae. Klebsiella are opportunistic pathogens that cause several diseases like pneumonia, urinary tract infection (UTI), soft tissue infection, and septicemia , ceftazidime (66.66%), ampicillin (60%), and streptomycin (40%) , imipenem (59%), amikacin (71%), gentamicin (71%), ciprofloxacin (81%), and piperacillin/tazobactam (75%). K. oxytoca isolated from urine samples of UTI infected Turkish children showed resistance to ampicillin (97%), cephalothin (48.40%), cefuroxime (36.40%), amoxicillin (18.20%), and ceftriaxone (7.10%) (Another major pathogenic bacterium identified from the spring water of Sikkim was pticemia . Taxonom oxytoca . Howeverchildren . Recent eumoniae . K. oxytin (40%) . Singh e (7.10%) .Citrobacter spp. are commensal bacteria present in intestinal tracts of humans and several animals  and C. amalonaticus (10.95%) were the two major species isolated from the spring water of Sikkim (C. freundii showed its resistance to ampicillin (75%), amoxicillin (58.33%), cefoxitin (58.33%), tetracycline (25%), and streptomycin (25%). Whereas C. amalonaticus showed resistance to ampicillin (50%), cefoxitin (50%), amoxicillin (40%), and netillin (40%) (C. freundii isolated from the stool samples of children aged 3\u201314 years showed resistance to ampicillin (100%), Co-trimoxazole (100%), cefotaxime (100%), amoxiclav (100%), ciprofloxacin (100%), and imipenem (100%) whereas no resistance was reported against gentamicin and amikacin , ciprofloxacin (71.53%), ceftazidime (69.39%), cefotaxime (67.35%), and meropenem (4.08%)  . Commensamikacin . C. freu (4.08%) .Enterobacter is a genus of Gram-negative, rod-shaped, facultative anaerobe, non-spore forming bacteria belonging to family Enterobacteriaceae. They are associated with bacteremia, septic arthritis, endocarditis, urinary tract infection, respiratory tract infection, intra-abdominal infection, skin and soft tissue infection , amoxicillin (100%), chloramphenicol (100%), sulfonamide (100%), trimethoprim (98%), and streptomycin (92%)  were isolated from the Cauvery river, India, in which about 93.85% isolates showed full resistance to all the 32 antibiotics used in that study (nfection . Enterobf Sikkim  showed rf Sikkim . Enterobin (92%) . Howeverfloxacin . In the nfection . Multi-dat study Morganella is a genus of Gram-negative, rod-shaped, facultative anaerobic bacteria, first isolated from pediatric fecal culture by Morganella morganii acts as opportunistic pathogen which causes sepsis, abscess, bacteremia, and UTI (Morganella morganii (10.95%) from spring water of Sikkim , cefixime (100%), cefotaxime (100%), gentamicin (100%), amikacin (100%), and imipenem (100%) (Morganella morganii isolates from Sikkim did not show any resistance to chloramphenicol. Multidrug resistant Morganella morganii (5.59%) was reported from Nigerian hospital wastes  ( and UTI . Isolatef Sikkim  showed rf Sikkim . Morganepatients . Morganeeropenem . Guo et morganii . From a m (100%) . Howeverl wastes . Cephalo (0.50%) .Hafnia alvei (8.10%) and H. paralvei (9.68%) were identified from the spring water of Sikkim , amikacin (40%), ampicillin (35%), and cefoxitin (35%) and Hafnia paralvie were found resistant to amoxicillin (46.66%), streptomycin (40%), netillin (40%), and cefoxitin (33.33%)  . Hafnia neumonia . In a stneumonia . From direported .Shigella a genus of Gram-negative, rod-shaped, entero-invasive bacteria causes shigellosis which is responsible for significant mortality and morbidity in young children and immunocompromised adults  and North Sikkim (1.82%). Shigella flexneri isolates showed resistance to ceftazidime (60%), cefoxitin (40%), streptomycin (40%), netillin (40%), amikacin (40%), and ofloxacin (5.50%). S. flexneri isolates from North Sikkim showed resistance to only ceftazidime (100%) (Shigella flexneri (71.1%) isolates from Shanxi Province, China. Isolates were resistant to ampicillin (98.50%), ticarcillin (95%), trimethoprim/sulfamethoxazole (85.20%), and chloramphenicol (78.60%) (Shigella flexneri (21%) isolates from Iran were found to show resistance to cotrimoxazole (100%), ampicillin (100%), tetracycline (75%), chloramphenicol (50%), cefixime (50%), and ampicillin (33.30%) , ampicillin (83.30%), cotrimoxazole (83.30%), ciprofloxacin (77.70%), and furazolidone (38.80%) (Shigella flexneri (Shigella flexneri (70.1%) which were resistant to sulfamethoxazole/trimethoprim (62.70%), tetracycline (49.30%), ampicillin (46.30%), and chloramphenicol (44.80%) (d adults . In the e burden . Shigelle burden . Shigellf Sikkim . East Sie (100%) . Similar(78.60%) . In anot(33.30%) . A study(38.80%) . The Oceflexneri . The chi(44.80%) . HoweverEnterobacteriaceae family for assessing the spread of antibiotics resistance. So, there exists a chance that more resistant bacteria from different families might have been missed out, and the estimated antibiotics resistance rate might be an underestimation of the problem. However, lack of any water quality studies especially on antibiotic resistance pattern and distribution of antibiotic resistant pathogen makes it unique and it provides a baseline for future water quality research. This study suggested that spring water of Sikkim have high antibiotic resistance bacteria and ARG. Several risk factors such as direct antibiotic application, antibiotic resistance feed as well as environmental factors may have played vital role in distribution of antibiotic resistance in this ecosystem. More studies are needed to reveal a broad picture of antibiotic resistance in spring water of Sikkim and to set standard protocols or policies for proper treatment and management of spring water. Springs are free flowing ground water which flows in the form of surface water. So, there might be chances of contamination either at source, during free-flowing or during distribution of the water up to the household level. Some of the basic ground level management protocols which can be helpful in maintaining the water quality are:Though a large number of antibiotics were used in the current study to detect the prevalent antibiotics resistance pattern, our study was limited by the use of bacteria belonging to (1)Springs should be protected from unnecessary anthropogenic/human disturbances.(2)Frequent cleaning of the community water tanks and supply system using standard protocols.(3)Prevent mixing of runoff water during rainy season to spring water, which carries large number of waste material including fecal from animal and household discharges.(4)Proper chlorination of water source before supplying to the household.(5)Water samples must be tested for both physicochemical and microbiological quality at frequent intervals . Before supplying to the households, quality indicator/parameters should be checked and compared with standard guidelines of BSI and WHO.(6)Putting fences around the springs to prevent direct access to animals as well as humans.(7)Periodical inspection for the presence of indicator organism  in the spring water before supply .(8)Prevent disposal of any kind of waste material near the spring water sources.(9)At household level, proper boiling or filtration before consumption is recommended.The community needs to be educated about general hygiene, different methods available for household-level water treatment, and the importance of clean water for children and their health to avoid impending health disaster associated with the unsafe water supply.Antibiotic resistance has become a major challenge worldwide, especially in developing countries like India. Easy accessibility of antibiotics, self-prescription, incomplete treatment course of antibiotics combined with poor management of waste disposal, poor water quality and hygiene contribute to rapid distribution and occurrence of antibiotic resistance in pathogenic and environmental bacteria. The present study showed there is a high incidence rate of multiple antibiotic resistant enteric bacteria in the spring water of Sikkim and suggests spring water are not suitable for drinking without prior treatment or filtration. The Sikkimese community may be at greater risk of contracting infection due to extensive use of spring water for drinking, cooking and other household purposes. The high rate of antibiotic resistance occurrence among environmental bacteria could be a result of indiscriminate use of antibiotics in human, animal and agricultural sectors. The presence of MDR enteric Gram-negative bacteria in the spring water of Sikkim warrants an instant commitment to the rational use of antibiotics as much as possible. The study indicates the emerging imminent threat from antibiotic-resistant pathogens in the area and mandates for immediate remedial measures including educating the community about proper sanitation, hand hygiene, and drinking water treatment practices to successfully contain the impact on the community. The extent of the problem of this emergence of antibiotic resistance can be managed by conducting antibiotic surveillance program, sensible use of antibiotics, use of the alternative bio-control agents, creating awareness in public about the rational use of antibiotics, and intensive effort between students, doctors, research scientist, industrial participants and policymakers. This study also warrants further examination of spring water samples from surrounding area of South East Asia that share similar geography and have similar livelihood practices to plan a comprehensive approach for the containment of the emerging health problem in the region.This paper is dedicated to the fond memory of Dr. Hare Krishna Tiwari \u2013 a great friend, colleague, and collaborator. His sudden passing away on 27th September 2020, when this article was in production, deeply stunned and saddened us and so many other colleagues alike in the field. His scholarly pursuit, perseverance, and dedication to the field as well as the mentoring and career counseling of scholars will be passionately remembered. This article will bring back the fond memories of what a pleasure it was to be his friend, colleague, and collaborator. I hope this note bears testimony to the honor placed on his dedication, scholarly contribution, and leadership in the field. Dr. Hare Krishna Tiwari was corresponding author of the paper upto the day of its acceptance. Placing of his name, not as a corresponding author in the final version is purely for technical reasons.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/ HT designed the study, supervised the study, and helped in manuscript preparation. AS performed the experiments, analyzed the data, and prepared the manuscript. SD and SS analyzed the data and prepared the manuscript. VG helped in the sample collection, survey, and lab experiments. SK and IN helped in manuscript preparation. YL helped in the selection of study area and official documentation regarding the study. All the authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "COVID-19 has become a national and an international pre-occupation to all doctors. Dealing with patients with clinical suspicion of COVID-19 is a daily markedly growing professional issue for radiologists. The number of COVID-19 cases we deal with is peaking since last March and so is our experience in recognizing the disease patterns and in assessing its severity. The purpose of this study is to assess the role of CT chest in the diagnosis of COVID-19 based on our experience with 220 Egyptian cases.A cross-sectional multicenter study involving 220 patients; 68 (30.9%) females and 152 (69.1%) males, their age range was 10-92\u2009years (average 49.198\u2009years). Non-contrast MSCT chest was done to patients with clinically suspected COVID-19. Data assessment and analysis for lesions probability, pattern, localization, and severity were done.Bilateral affection was seen in 168/220 cases (76.36%). Multilobar affection was noted in 186/220 cases (84.54%). Lower lobes affection was noted in 179/220 cases (81.36%). Peripheral/subpleural affection was noted in 203/220 cases (92.27%). The common CT patterns  and the uncommon CT patterns  were discussed. Associated extra-pulmonary lesions described. Temporal changes, severity scoring, reporting, and possible pitfalls were all assessed.In our experience, CT plays a basic essential role in diagnosing COVID-19 in the current declared pandemic. COVID-19 is the disease caused by the coronavirus named SARS-CoV-2. It has been declared as a pandemic  in DecemThe Egyptian ministry of health latest declaration on the 31 of May 2020, was 24,985 total COVID-19 cases with 1536 new ones (Www.care.gov.eg). COVID-19 is a national and an international pre-occupation to all doctors. As radiologists, dealing with patients with clinical suspicion of COVID-19 is a daily markedly growing professional issue. The number of cases we deal with is peaking since last March as well as our experience in dealing with recognition of the disease patterns and assessing its severity.The aim of this study was to assess the role of CT chest in the diagnosis of COVID-19 based on our experience with 220 Egyptian cases.This cross-sectional study involved 220 patients: 68 (30.9%) females and 152 (69.1 %) males; their age range was 10-92\u2009years (average 49.198\u2009years). Three children two females and a male aged 10, 12, and 13\u2009years old were included in this study. The study was a multicenter study done from the beginning of March to the end of May 2020. All cases were clinically suspected to suffer from COVID-19 and CT chest was requested as a part of the patients\u2019 set of investigation. Most cases were symptomatizing (195/220 [about 89%]) with symptoms ranging from 1\u2009day to 2\u2009weeks\u2019 time, while 25/220 (about 11%) were non-symptomatizing with history of contact with a COVID-19 patient. Symptoms were fever, cough, and dyspnea. Vomiting was present in two patients and headache in one patient. One hundred ten (50%) patients were known to have systemic or chronic diseases .Assessing the patterns of lesions encountered and their prevalence, having the Fleischner society glossary of terms for thoracic imaging (2008)  as our mAssessing associated extra-pulmonary chest lesions.Assessing temporal changes of CT findings in our patients.Surfing the literature for different available published classifications for describing the CT lesions for COVID-19, assessing severity and for reporting.The points of interest in CT assessment and data analysis were as follows:Data was entered on the computer using the \u201cMicrosoft Office Excel Software\u201d program (2010) for windows.Data was then transferred to the Statistical Package of Social Science Software program, version 23  to be statistically analyzed.Data presented using range, mean, standard deviation, median, and interquartile range for quantitative variables and frequency and percentage for qualitative ones.This cross-sectional multi-center study involved 220 patients; 68 (30.9%) females and 152 (69.1 %) males, their age range was 10-92\u2009years (average 49.198\u2009years). Non-contrast MSCT of the chest of all patients was assessed by two experienced radiologists.Bilateral affection was seen in 168/220 cases (76.36%).:Unilateral affection was seen in 52/220 cases (23.64%) as follows32 cases in right lung (14.54%)20 cases in left lung (9.1%)Multilobar affection was noted in 186/220 cases (84.54%).Single lobe affection was noted in 34/220 cases (15.45%) having the following:Single focus in 15 cases (6.81%) .Multiple foci in 19 cases (8.64%) .Table Table This pattern was encountered in 194/220 cases (88.16%).It was mostly subpleural/peripheral in location (92.27%) with vascular thickening noted within the lesions or in their vicinity.Out of the 34 cases with single lobe affection, 26 showed ground glass opacities (76.5%), 13 of whom had a single ground glass opacity lesion.This pattern was encountered in 140/220 cases (66.7%).It was mostly subpleural/peripheral in location (74.75%); however, lobar (15.45%) and central (10%) distribution was noted.Traction bronchiectasis was seen related to consolidation in 72 cases (32.72%), while air-bronchogram was seen in 86 cases (39.1%).In this pattern, ground-glass opacity shows superimposed thickened interlobular septa and intralobular lines.This pattern was encountered in 82/220 cases (37.27%). It was mostly subpleural/peripheral in location with vascular thickening noted within the lesions.Was seen in all of our patients (100%) either within a lesion or in its vicinity.It is most clearly seen related to ground glass opacities and crazy-paving Figs. , 10, 11.Was seen in 142/220 patients (about 64.54%) either within or in the vicinity of a lesion Figs. , and 11.Was seen in 87/220 patients (about 39.54%) seen as lucent locule(s) within a lesion; consolidation, mass, ground glass opacity, or crazy-paving Figs. .Was seen in 82/220 patients (about 37.27%).Many signs have been described in literature , 14 all Was seen in 63/220 patients (about 29%) seen as a focal fairly rounded area of ground glass opacification surrounded by a near complete ring of consolidation Figs.  and 18.Table Posterior multifocal mostly basal trivial pleural thickening was seen in 145/220 cases (66%).Pleural effusion was seen in 13/220 cases (6%); mild in 9 cases (about 4.1%), moderate in 4 cases (1.81%), bilateral in 8 cases (3.63%), and unilateral in 5 cases (2.27%).Loculated right lateral hydropneumothorax was seen in one case (0.45%).Bilateral pleural plaques with foci of calcification were seen in one case with associated asbestos exposure Fig. .Was seen in 90/220 patients (about 40.9%).Table Was seen in 12/220 patients (about 5.45%).Was seen in 7/220 patients (about 3.18%) Fig. .Table In this study, we had three pediatric cases aged 10, 12, and 13\u2009years old, the distribution and patterns of their lungs lesions did not differ from those of our adult patients.None of our patients had a follow-up study, however, in studying and analyzing the CT findings of all cases the following could be concluded as follows:\u27a2 Ground glass subpleural opacities were the earliest lesions encountered that could be seen as a single focus or multiple lesions. It was the only lesion noted in 63 cases (about 29%).\u27a2 Architectural distortion with any of its described lesions and reversed halo signs were the end stage findings. They were mostly lower lobar (78 cases [35.45%]) and bilateral (76 cases [34.54%]).\u27a2 Surfing the literature temporal changes of CT findings were described and suggested a pattern with consecutive appearance of lesions in COVID-19 patients; however, in our study, we met different patterns together in the same patient and even in the same lobe showing ground glass opacities, consolidation, crazy paving, and/ or architectural distortion in 78/220 patients (35.45%) Figs. , and 21.\u27a2 So actually temporal wise, we had early lesions with only ground glass opacities in 63 cases (about 29%), and late cases with only architectural distortion and reversed halo sign in 38 cases (17.27%), with 119 cases (54.09%) showing signs of early, progressive, peak, and absorptive stages all together.\u27a2 So regarding the temporal changes using our CT findings, we can suggest the following classification:Stage 1: Only ground glass opacities detected. This corresponds to the early initial stage in literature.i.Ground glass opacities together with other lesions.ii.Crazy paving or consolidation alone or associated with other lesions.Stage 2: In this stage, the disease progresses and the following can be encounteredStage 3: Signs of architectural distortion and/or reversed halo sign not associated with other lesions. This corresponds to the absorptive stage in literature.We applied the severity score described in the radiology assistant  but withRadiological Society of North America (RSNA) released consensus statement [In our early experience with COVID-19 cases, only those with typical lesions according to the tatement  were diaOsteophyte induced adjacent pulmonary fibrosis and atelectasis is a lesion that may be mistaken for early subpleural ground glass opacification caused by COVID-19; however, the key to its diagnosis is the presence of exuberant osteophytes and the classic paravertebral position of the lesion Fig. .Fig. 22This cross-sectional multicenter study has been conducted on 220 Egyptian patients, 68 30.9%) females and 152 (69.1 %) males, their age range was 10-92\u2009years (average 49.198\u2009years), from March to the end of May 2020. Non-contrast MSCT chest was done to all patients. Data assessment and analysis for lesions\u2019 pattern, localization, and severity was done. Bilateral affection was seen in 168/220 cases (76.36%). Multilobar affection was noted in 186/220 cases (84.54%). Lower lobes affection was noted in 179/220 cases (81.36%). Peripheral/subpleural affection was noted in 203/220 cases (92.27%).The common  and the uncommon CT patterns  were discussed and associated extra-pulmonary lesions were described. Our results globally agree with the published literature 0.9% fema, 16\u201318.In our study, we had only three pediatric patients; the CT findings were ground glass opacification in two cases and consolidation in one case. The lesions were similar to adult\u2019s lesions in distribution. This complies with the findings described in literature .A common pitfall that should be avoided in the diagnosis is mistaking osteophyte induced adjacent pulmonary fibrosis and atelectasis for subpleural COVID-19 lesions. The lesion is classically seen in the paravertebral region and is related to a vertebral osteophyte [In the current situation where the numbers of cases of COVID-19 are in continuous ascent, we considered any CT pattern that reflects inflammation in a patient with clinical suspicion of COVID-19 as a case of COVID-19. Declaring that an inflammatory CT lesions is not COVID-19 because its pattern does not conform with the typical patterns of the disease is not logical in this time of peaking pandemic .Thus, applying the classification systems , 10, 11 Applying a severity score may be requested by clinicians. From our point of view, all the current severity scoring systems of COVID-19 , 20 have\u27a2 They are all based on visual assessment.\u27a2 They are totally subjective.\u27a2 They are time consuming.\u27a2 They are rather sophisticated.\u27a2 The clinician receiving the report needs to be acquainted with the scoring system you are using which is not very feasible if he is not in the same institute or in case of multicenter cases.However, applying a scoring system may be needed for clinical purposes and in case of follow-up studies. We tried applying the severity score described in the radiology assistant  but withIn assessing the temporal changes of our cases, we had early lesions with only ground-glass opacities in 63cases (about 29%), and late cases with only architectural distortion and/or reversed halo sign in 38 cases (17.27%), with 119 cases (54.09%) showing signs of early, progressive, peak, and absorptive stages all together, thus we suggested a classification were stage 1 only have ground-glass opacities detected. This corresponds to the early initial stage in literature, stage 2 where the disease progresses may show ground-glass opacities with other lesions, crazy paving, or consolidation alone or associated with other lesions, and stage 3 showing signs of architectural distortion and/or reversed halo sign not associated with other lesions. This corresponds to the absorptive stage in literature [In the early days of the COVID-19 crises, the role of CT chest in the management was debated both in China and later worldwide. Some authors have recommended it while other authors have restrained its use , 17. TheCT plays a basic essential role in the diagnosing COVID-19 in the current declared pandemic."}
+{"text": "Subjects and Methods. From 95 symptomatic patients confirmed with COVID-19 by RT-PCR from 1 May to 14 July 2020 in Dallah Hospital, Riyadh, Saudi Arabia, CT angiography was done for 25 patients suspected to have pulmonary embolism and have no contraindication for contrast study. 11 cases of them showed CT evidence of acute pulmonary embolism (PE). Retrospectively, CT angiography was analyzed and detailed findings were recorded. This study was approved by the Institutional Review Board of our hospital, and the patient consent was waived.  To evaluate acute pulmonary embolism in patients with 2019 novel coronavirus (COVID-19) pneumonia using pulmonary CT angiography.  The mean age of the included patients was 49\u2009\u00b1\u200911 years; the youngest was 22 years, and the oldest was 64 years. Common symptoms in the 25 cases that underwent CT angiography were fever that was noted in 21/25 cases (84%), shortness of breath in 18/25 cases (72%), cough in 16/25 cases (64%), and severe myalgia/body fatigue in 13/25 cases (52%). The less common symptoms were sore throat in 11/25 cases (44%) and headache in 10/25 cases (40%). Regarding CT findings, 4/25 cases (16%) had unilateral lung disease and 21/25 cases (84%) had bilateral disease, with slight predilection for the right lower lobe . Pure ground-glass opacity (GGO) was seen in 13/25 cases (52%), and GGO with consolidation was seen in 12/25 cases (48%). Common accompanying CT signs included crazy paving stone sign in 15/25 cases (60%) and air bronchogram in 12/25 cases (48%). From the 25 patients that showed respiratory deterioration and elevated serum D-dimer level, 11 cases confirmed to have acute pulmonary embolism, while 14 cases showed negative result for pulmonary embolism. 6/11 were male and 5/11 were female. Pulmonary embolism was diagnosed at a mean of 21 days from symptom onset. Unilateral acute pulmonary embolism was seen in 3/11 cases, while 8/11 cases showed bilateral distribution. Among 11 cases with acute pulmonary embolism, no emboli at the central level could be seen, but 3 cases showed pulmonary embolism at the lobar level, 3 cases at the segmental level, and 5 cases at lobar, segmental, and subsegmental levels.  In patients with confirmed COVID-19, we should maintain a high suspicion for its thromboembolic complications such as acute pulmonary embolism that was mainly diagnosed at the end of 3rd week from symptom onset. We suggest that whenever a CT evaluation of the parenchymal involvement of COVID-19 pneumonia is performed, a simultaneous evaluation of the pulmonary arteries is also essential in order to identify early signs of associated pulmonary embolism. An outbreak of pneumonia of unknown etiology occurred in Wuhan, China, in December 2019, and 2019 novel coronavirus disease (COVID-19) was responsible [It is thought that viral spreading beyond the respiratory system to other organ systems in the 2nd week of the disease course  leads to increased immune-mediated injury and hypercoagulability . Some auHan et al. reported disturbed coagulation function in patients infected with SARS-CoV-2 as compared to healthy controls, including elevated D-dimer, fibrin/fibrinogen degradation products, and fibrinogen levels . Also, tTo date, most radiologic literature has focused on the distinctive chest CT abnormalities caused by COVID-19, including peripheral basal-predominant areas of ground-glass opacities and/or consolidation, often in a bilateral distribution [However, emerging research has demonstrated that the inflammation and hypoxemia caused by COVID-19 may result in deranged coagulation parameters and increased risk of thromboembolic complications, which are associated with significant morbidity and mortality , 11. TheIn our retrospective study, we focus on the development of acute pulmonary embolism as a related complication in patients with COVID-19 viral pneumonia.This study was approved by the Institutional Review Board of our hospital. The requirement for informed patient consent was waived by the ethics committee.Out of 95 positive cases of COVID-19 in Dallah Hospital, Riyadh, Saudi Arabia, CT angiography was done for 25 patients suspected to have pulmonary embolism and have no contraindication for contrast study. 11 of them who showed CT evidence of acute pulmonary embolism were admitted to the ICU.All CT scans were performed using a CT scanner . Gantry position rotation period was 0.4\u2009s, with an X-ray tube voltage of 140\u2009kV and a current of 230\u2013350\u2009mA. Craniocaudal image acquisition of the entire thorax was carried out with a collimation of 1.25\u2009mm (pitch of six) and a reconstruction increment of 0.8\u2009mm. Mean scan time was 2.30\u2009s. All patients underwent CTPA after administration of 100\u2009ml standard contrast media  with an injection rate of 4.5\u20135\u2009ml/s via a 16-gauge catheter inserted into the antecubital vein. Contrast bolus was followed by a 10\u2009ml saline flush using Enhanced Xtream Injector ), and delay was estimated using a semiautomatic bolus tracking system  with a threshold of 80\u2009HU for all examinations. ROI for bolus tracking was measured in the right atrium.All reformations were performed by a senior CT technologist. From the axial CT data sets, multiplanar volume reconstruction (MPVR) and maximum intensity projection images were reformatted.All images were sent to the workstation  and, retrospectively, CT angiography was analyzed and detailed findings were recorded.We defined PE as a partial or complete intraluminal filling defect surrounded by the contrast medium and occupying the entire arterial vessel section . The cenPresence or absence of emboli in the pulmonary artery or its branches was identified by using the nomenclature outlined by Remy-Jardin and Remy , which iStatistical analyses were performed with SPSS for Windows software package . Data were expressed as mean\u2009\u00b1\u2009standard deviation (SD).Out of 95 cases confirmed to have COVID-19 viral pneumonia, 25 patients showed respiratory deterioration.The mean age of the included patients was 49\u2009\u00b1\u200911 years; the youngest was 22 years, and the oldest was 64 years.Common symptoms in the 25 cases that underwent CT angiography were fever that was noted in 21/25 cases (84%), shortness of breath in 18/25 cases (72%), cough in 16/25 cases (64%), and severe myalgia/body fatigue in 13/25 cases (52%). The less common symptoms were sore throat in 11/25 cases (44%) and headache in 10/25 cases (40%).Regarding CT findings, 4/25 cases (16%) had unilateral lung disease and 21/25 cases (84%) had bilateral disease, with slight predilection for the right lower lobe in 10/25 cases (40%) and the middle lobe in 8/25 cases (32%). Pure ground-glass opacity (GGO) was seen in 13/25 cases (52%), and GGO with consolidation was seen in 12/25 cases (48%). Common accompanying CT signs included crazy paving stone sign in 15/25 cases (60%) and air bronchogram in 12/25 cases (48%).In our study, acute pulmonary embolism was diagnosed at a mean of 21 days from symptom onset (range: from 19 to 24 days).Unilateral acute pulmonary embolism was seen in 3/11 cases, while 8/11 cases showed bilateral distribution of acute pulmonary embolism.Among the included 11 cases with acute pulmonary embolism, no emboli could be detected at the central level , but 3 cases showed acute pulmonary embolism at the lobar level, 3 cases at the segmental level , and 5 cThe respiratory rate in the 11 cases with acute pulmonary embolism was 16/min\u201318/min, and oxygen saturation was 95%\u201393% on room air. Blood sampling of patients showed leucopenia, lymphopenia, and thrombopenia. Laboratory tests showed prolongation of the prothrombin time (range: 14.2\u201316.3) with elevated D-dimer level (1.56\u2009mg/ml\u20138.8\u2009mg/ml).The 11 COVID-19 cases positive for pulmonary embolism were admitted to the ICU and followed by the cardiologist and intensivists. Echocardiography was not done for any of our cases.Several recent studies have explored the link between COVID-19 and hypercoagulability, suggesting that the most common laboratory test result abnormalities include elevated D-dimer levels and mild thrombocytopenia . In our The most typical finding in patients with COVID-19 and coagulopathy is an increased D-dimer concentration, a relatively modest decrease in the platelet count, and a prolongation of the prothrombin time; the combination of thrombocytopenia, prolonged prothrombin time, and increased D-dimer level is suggestive of DIC , which wIn our study, acute pulmonary embolism was seen in 11/95 cases (11.6%), which is less than other studies that showed more frequent pulmonary embolism in patients with COVID-19 and reported almost a quarter of the COVID-19 pneumonia patients ; this maSome authors reported that lung injury and impaired gas exchange lead to increased production of proinflammatory cytokines, and contributing viral infection may result in vascular endothelium direct damage .Another study demonstrated severe endothelial injury associated with intracellular virus and disrupted cell membranes, as well as extensive thrombosis, microangiopathy, alveolar capillary microthrombi, and more new vessel growth, compared with those lungs obtained at autopsy from patients who died from influenza .Our study suggests that COVID-19 patients with severe clinical features such as respiratory deterioration and elevated serum D-dimer level may have associated acute pulmonary embolism and need contrast-enhanced CT angiography study for diagnosis.Our results revealed that pulmonary embolism was noted at lobar, segmental, and subsegmental pulmonary artery levels with a clear central pulmonary artery .Imaging features of acute pulmonary embolism in our study in patients with COVID-19 are nonspecific and similar in appearance to those seen in other pathologic conditions, which were also reported by other authors .Our finding is preliminary in nature in our initial experience with COVID-19 cases. CT angiography was not systematically used for all COVID-19 patients, but only for deteriorating patients with high D-dimer levels, so we cannot assess the incidence of PE in COVID-19 patients. No lower limb venous Doppler ultrasound study was done for our patients to evaluate the presence of deep venous thromboembolism. In addition to a small number of our subjects, further study with more numbers is needed.In patients with confirmed COVID-19, we should maintain a high suspicion for its thromboembolic complications such as acute pulmonary embolism that was mainly diagnosed at the end of 3rd week from symptom onset.Whenever a CT evaluation of the parenchymal involvement of COVID-19 pneumonia is performed, a simultaneous evaluation of the pulmonary arteries is also essential in order to identify early signs of associated pulmonary embolism.In any case, early anticoagulant therapy initiated in the early stages of infection will make the CT pictures much less striking compared to the first case studied in the literature and, therefore, the CT could maintain a role in the follow-up of pumonary embolsim in case of disappearnce of symptoms."}
+{"text": "To investigate the Ki 67 expression and its correlation with clinicopathological features and 3 years as well as 5 years survival rate in oral squamous cell carcinoma (OSCC). Total 217cases of OSCC primarily treated with surgery with or without radiation were included. All patients were followed up for 3 years and 150 were followed up of 5 years for disease free survival. The immunohistochemistry was carried out on neutral buffered formalin fixed paraffin embedded tissue to evaluate the expression of Ki67. The Ki67 labeling index (LI) was significantly higher with respect to adverse clinicopathological parameters such as histopathological grading (p<0.001), clinical TNM staging (p<0.001) and nodal metastasis (p<0.001). The OSCC patients survived for less than 3 and 5 years were showed significantly higher Ki67 LI as compared to diseases free survived more than 3 and 5 years(p<0.001). The three years survival rate of OSCC patient significantly higher with low Ki67 LI (\u226445) 96.2%, followed by moderate Ki67 LI (46 to 60) 60.7% and high Ki67 LI (\u226561) 37.7% (p<0.001). The five years survival rate of OSCC patient statistically significantly higher with low Ki67 LI (\u226445)93.3%, followed by moderate Ki67 LI (46 to 60) 46.8% and Ki67 LI (\u226561) 23.3% (p<0.001). The measurement of cell proliferative activity by using Ki67 antigen expression in individual OSCC might provide unique, predictive information on clinical outcome, prognosis and deciding treatment modalities in OSCC. However, up until this point, no single marker is consistently acknowledged for routine clinical use in OSCC patients.2Globally, oral squamous cell carcinoma (OSCC) incidence is 2.7 in 100000 populations. In south-central Asia, the incidence of OSCC cases was highest that is40.9% of all incident cases of OSCC and often associated poor prognosis due to high morbidity and mortality rate.3 Thus, evaluation of proliferative status is conventionally viewed as helpful tool in deciding the biological aggressiveness of any tumor.Cell proliferation is viewed as a key fundamental biological process in the growth and development as well as upkeep of homeostasis of tissue. The biological behavior of tumor such as local invasion/expansion, local recurrence, metastatic potential as well as disease free survival is predicted by assessment of cell proliferation in histopathology by means of immunohistochemical evaluation.4 Ki67 antigen expression is a reliable and potent biomarker for the accurate, simple and prompt identification of the fraction of cells with proliferative potential in a tumor.5 Higher Ki67 expression is an indicator of tumor cells with higher proliferation and locally invasive potential and thus providing one of the best markers for the evaluation of biological aggressiveness of tumor.6Ki67 is a large non-histone protein present in the nucleus and nucleolar region, which is seen in cells undergoingproliferation.9 Despite several efforts made in the literature, still there is a controversy existed for Ki-67 being utilized as the proliferation capacity of cancer cells as a predictive biomarker for tumor grade, nodal metastasis, clinical TNM stage and survival rate. Xie, et al.10(2016) carried out meta-analysis on prognostic implication of Ki-67 expression in OSCC and recommended further studies on Ki67 expression with five-year survival rate by using standardized immunohistochemistry protocols needed to further strengthen its role as diagnostic and prognostic predictive marker.Ki67 expression has been accounted to provide a diagnostic and poor prognostic biomarker for OSCC patients.12Looking at the mandate of five-year survival analysis, the present study was designed to investigate immunohistochemical expression of Ki67 in OSCC with primary focus on three as well as five years survival rate and to assess its predictive value on clinical outcome. These new objectives were investigated on the samples, which were utilized in our previously published papers.The present study was conducted at the Sharad Pawar Dental College and Hospital, Wardha, Maharashtra, India. Institutional ethics committee of Datta Meghe Institute of Medical Sciences, Deemed to be University, Wardha, India was granted the ethical approval for the present study (Ref no. DMIMS (DU)/IEC/2014-15/953, dated 15/12/2014).The written consent was obtained from the patient, who participated in this study.12 with different objectives. The clinically diagnosed and histologically confirmed 217 cases of OSCC, who fulfilled inclusion and exclusion criteria\u2019s, were included. All retrieved cases were primarily treated with wide local surgical excision with normal margins and cervical neck dissection with or without radiation. Patients with coexisting malignancy, previous history of oropharyngeal or oral or any other head and neck cancer, recurrent or distant disease, any other systemic diseases, and pre-operative chemotherapy, radiotherapy, or surgery were excluded from the study. Dissected cervical lymph nodes obtained from surgically excised specimens were examined histopathologically for confirmation of lymph node metastasis. The clinical TNM staging of all OSCC patients were done by using the American Joint Committee of Cancer13 clinical TNM staging system for oral and oropharyngeal cancer. The clinical TNM staging was further broadly categories for OSCC cases into early clinical TNM stage (I and II) and advanced clinical TNM stage (III and IV). Demographic details along with clinical features, relevant habit history, and operative details were obtained. Disease free survival of 3 years as well as for some cases 5 years was recorded on follow up.The study population was retrieved from year 2010 to 2015, which was previously utilized for our research publications14 (2003) neoplastic cells from invasive tumor front region are more informative in studying cell proliferation markers. The histopathological slides of incisional biopsy as well as from resected specimen of OSCC were examined by three oral pathologists independently and those sections showing invasive tumor front of OSCC were utilized for immunohistochemical evaluation of Ki67 antigen expression. All the hematoxylin and eosin stained histopathology and IHC (Ki67) slides were blinded for microscopic analysis. All the included cases were confirmed for histopathological diagnosis of squamous cell carcinoma and were classified in to well-differentiated SCC (WDSCC), moderately-differentiated SCC (MDSCC) and poorly-differentiated SCC (PDSCC). Similarly, three oral pathologists, who were blinded for histopathological grading status of OSCC cases, were independently performed IHC scoring of Ki67. The obtained IHC score for Ki67 were then computed for all OSCC.As recommended by Dissanayake, et al.15 The brown coloration of nucleus indicates the positivity for Ki67 antigen expression, where as the blue color of nucleus due to counterstained in Mayer\u2019s hematoxylin indicates the Ki67 negative cells.The standard procedure of immunohistochemistry (IHC) was done for Ki67, by utilizing appropriate controls on neutral buffered formalin fixed paraffin embedded tissue. The tissue sections were treated with 01 mol/L sodium citrate buffer (pH 6.0) in microwave oven for 10 minute followed by bench-cooled for 20 min, and again the same cycle was repeated for the antigen retrieval. Endogenous peroxidase activities of the tissue were blocked by incubating the tissue sections with 3% H2O2 in methanol for 30 minutes. The non-specific tissue reactions were prevented by incubating the tissue sections with 10% serum for 10 minutes. For IHC detection of Ki67 antigen, pre-diluted Monoclonal Mouse Anti-Human, Ki67 antibody , was incubated with tissue sections at room temperature in a humidifying chamber for 60 minutes. Known hyperplastic lymph node was used as a positive control for Ki-67. One section from positive control was used as the negative control by omitting the primary antibody and by incubating with serum. The horseradish peroxidase labeled polymer anti-mouse secondary antibody  against the primary antibody was incubated at room temperature in humidifying chamber for 30 minutes. To visualized Ki67 antigen antibody complex (expression), the freshly prepared substrate/chromogen solution of 3, 30 Diaminobenzidine (DAB) in provided buffer was used and counterstained in Mayer\u2019s hematoxylin.9 Thus, based on the KI67 LI, the Ki67 expression were categorized in to low: Ki67 LI\u226445, moderate: Ki67 LI 46 to 60 and high: Ki67 LI \u226561.Neoplastic epithelial cells were viewed as positive for the Ki67 antigen expression, if intranuclear DAB staining (brown color) was observed. Every single stained nuclei were counted positive irrespective of intensity of staining. Invasive tumor front areas as well as areas with highest density of Ki67 labeled neoplastic epithelial cells were located by screening the IHC sections at a 100 X magnification by Leica DM LB2 microscope. In the most heavily Ki67 labeled areas, Ki67 positive neoplastic epithelial cell counts were carried outin 5 randomly selected fields at 400 X magnification. Minimum of 1000Ki67 labeled neoplastic epithelial cells were counted in each section. The number of positively stained nuclei was measured as a percentage of the total number counted neoplastic epithelial cells. Ki67 labeling index (LI) was derived as number positive cells for Ki67 multiplied by 100 and divided by total number observed neoplastic epithelial cells. Based on median and also considering the frequency distribution KI67 LI, cut off values for KI67 LI were generated for three groups to avoid the formation of very small and too many groups.The data were statistically analyzed using SPSS, version 17.0 for Windows. One-way ANOVA and Tukey\u2019s HSD test were utilized to find out the differences of Ki67 LI amongst the various histopathological grades, clinical TNM stage, and sites of OSCC. Independent student t test was applied to find out the differences of KI67 LI between metastatic and non-metastatic, early and advanced clinical TNM stage, survived and not survived less than 3 year, and survived and not survived less than 5 years. KaplanMeier survival curves as well as the longrank test were used to estimate and compare disease free 3 and 5 years survival with low, moderate and high Ki67 LI. The level of statistical significance was at p<0.05.Total 217 OSCC patients were included in this study, who were fulfilled the inclusion and exclusion criteria. OSCC cases were predominantly seen in males 159 (73.27%) with male to female 35 (26.72%) ratio was 4.54:1.The age of OSCC patients were ranges from 20 years to 79 years and the mean age of OSCC patient was 50.25 (\u00b112.14) years. The most common site for OSCC was buccal mucosa 84(38.70%) followed by gingivobuccal sulcus 69 (31.79%), tongue 24 (11.05%), retromolar region 16 (7.37%), labial Mucosa 11 (5.06%), palate 10 (4.60%) and floor of mouth 3 (1.38%). Tobacco lime and betel nut (TLB) 135 (62.21%) was the most common habit noted in OSCC patient followed by tobacco lime (TL) 45 (20.73%) and Betel nut (BN) 33 (15.20%). Nearly 95% cases of OSCC were MDSCC 106 (48.84%) and WDSCC 100 (46.08%). MDSCC were the most common histopathological type of OSCC. PDSCC were found in 11 (5.06%) cases of OSCC. Clinical TNM stage IV was the most commonly observed in 94 (43.31%) OSCC followed by Stage III 55 (25.34%) to stage II 52 (23.96%) and stage I 16 (7.37%). Advanced clinical TNM stage was observed in 149 (68.66%) OSCC and early clinical TNM stage was observed in 68 (31.33%) OSCC. The cervical lymph node metastasis was found in 68 (31.33%) OSCC cases. All 217 cases were followed up for 3 years and 148 (68.20%) cases of OSCC were survived. A five year follow up data of 150 cases were available and 81 (54.00%) OSCC cases found to be survived .Statistically significant variations of mean Ki67 LI were found among all groups of OSCC (p<0.001). Ki67 LI were observed statistically significantly in ascending order from WDSCC 43.72 (\u00b15.28) to MDSCC 59.41 (\u00b19.75) to PDSCC 74.59 (\u00b19.20) (p<0.001)  Table 2Table 2.Statistically significant variations of mean Ki67 LI were found among clinical TNM Stage I, Stage II, Stage III, and Stage IV of OSCC (p<0.001). There was statistical significant difference for Ki67 LI observed between Stage III 51.83 (\u00b110.15) and Stage IV 57.17 (\u00b111.71) (p=0.034); Stage I 46.54 (\u00b19.35) and Stage IV 57.17 (\u00b111.71) (p=0.004); Stage II 48.47 (\u00b112.99) and Stage IV 57.17 (\u00b111.71) (p<0.001). The mean of Ki67 LI were statistically significantly higher in Advanced TNM stage55.20 (\u00b111.42) as compared to Early Stage48.01 (\u00b112.19) of OSCC (p<0.001) .There was no statistical significant variations of mean of Ki67 LI found among various sites of OSCC (P=0.374). However, the Ki67 LI was marginally higher in Palate 56.28 (\u00b113.89) followed by Floor of mouth 55.28 (\u00b115.09), Retromolar 55.89 (\u00b16.64), Gingivo-buccal Sulcus 53.74 (\u00b111.82), Tongue 53.50 (\u00b114.43), Buccal Mucosa 52.04 (\u00b112.34) and Labial Mucosa 45.79 (\u00b19.66) .The mean of Ki67 LI were statistically significantly higher in Metastatic 60.23 (\u00b110.99) as compared to non-metastatic 49.03 (\u00b110.83) cases of OSCC (p<0.001).On 3 years of follow up of for disease free survival, the mean of Ki67 LI were statistically significantly higher in Non-survived 60.82 (\u00b110.64) as compared to survived cases 49.28 (\u00b110.97) of OSCC (p<0.001). Similarly on 5 years of follow up of for disease free survival, the mean of Ki67 LI were statistically significantly higher in Non-survived 60.82 (\u00b110.64) as compared to survived cases 49.25 (\u00b110.20) of OSCC (p<0.001) .The three years survival rate of OSCC patient statistically significantly higher with Ki67 LI \u226445(96.2%), followed by Ki67 LI of 46 to 60 (60.7%) and Ki67 LI of \u226561(37.7%) (p<0.001)  Figure . The fiv16 Treatment modalities and prognosis for OSCC were routinely determined based on clinical features such as tumor size, cervical metastasis to lymph node, distant metastasis and histopathological features mainly histological grade with other characteristics such as mitotic activity, vascular or perineural invasion.17 Recently, numerous studies observed that the clinico pathological factors such as advanced age, lymph node metastasis, advanced TNM stage, advanced histopathological grade, the presence of perineural invasion, vascular invasion, tumour\u2013stroma ratio (TSR) and tumour budding were predicator of poor survival in OSCC patients.22Despite of their claimed usefulness in various studies, characterization of OSCC that are at higher risk for recurrence and relapse is major concern. However, use of cost effective, easy and widely use immunohistochemistry to assess molecular markers leads to an increased understanding of biological behavior of OSSC. With the use of molecular markers predicting biological aggressiveness, locoregional recurrence and survival are useful in identification of patients, who needs more individualized intensive treatment regimes such as chemotherapy and radiotherapy in addition to surgery. An increasing number of studies, have revealed that Ki67 as a reliable cell proliferation biomarker was unregulated in numerous tumors and may be used as an important factor in cancer grading and prognostic evaluation.23 Thus, in this study we evaluated Ki67 expression in invasive front region of OSCC with a lager cohort of 217 cases and K67 expression was also correlated with clinical outcome and three as well as five years disease free survival.OSCC is an aggressive neoplasm with unpredictable biological behavior. This results in unfavorable prognosis leading to functional impairment as well as high mortality rate irrespective of type of treatment modality rendered.In this study, we assess the cut of range value for Ki67 LI as low, moderate and high with respect to three and five years disease free survival of OSCC patients. The three year disease free survival rate of OSCC patient significantly higher with low Ki67 LI (96.2%), followed by moderate KI67 LI (60.7%) and high Ki67 LI (37.7%). The five year disease free survival rate of OSCC patient significantly higher with low Ki67 LI (93.3%), followed by moderate Ki67 LI (46.8%) and high Ki67 LI (23.3%). In this study for the first time we introduce the range value for ki67 LI in OSCC that could be use as prognostic indicator for survival and to decide the treatment regime.26 that K67 expression in OSCC was identified as prognostic factor for survival rate. However, several other studies30 have described no association between higher cell proliferation and survival. Recently, Jing, et al.9 (2019) studied Ki67 expression in large cohort of 298 OSCC and found that Ki67 expression was independent prognostic marker in OSCC patients. Ki67 expression was also found to be prognostic marker in oropharyngeal and OSCC with a lager cohort of 239 cases.26 Therefore, it is summarize that the increase in Ki67 expression associated with a poor prognosis of OSCC. It was also suggested that Ki67 is an indicator for treatment failure in OSCC.26 Thus, it was further strengthen that the high cell proliferation identified by Ki67 antigen expression is a reliable prognostic marker in oral cancer.The mean of Ki-67 LI, was significantly higher in OSCC patients survived for less than 3 years as compared to diseases free survived OSCC patients more than 3 years. Similarly, the mean of Ki-67 LI, was significantly higher in OSCC patients survived for less than 5 years as compared to diseases free survived OSCC patients more than 5 years. It has been noticed in previous studies35 and revealed that as the Ki67 LI increases with poorer the degree of tumor cell differentiation. In contrast, few studies36 failed to show correlation of Ki67 LI and degree of differentiation. Disparity in the methodology, assessment of Ki67 immunoreactivity, and sample size may result in these conflicting results. Higher expression of Ki67 protein was discovered in undifferentiated/poorly differentiated squamous cells carcinoma. Therefore, results of the present study further strengthen the fact that, the Ki67 LI could be considered as useful potential biomarker in grading the OSCC.In this study, a significant increase in Ki-67 LI was observed from WDSCC to MDSCC to PDSCC. This results was in agreement with previous studies36 found insignificant correlation with cell proliferation and cervical lymph node metastasis, which are not in accordance with this study results. In this study large cohort of OSCC was used and results are in accordance with previous studies.38 This finding may implicate that tumors with high cell proliferation index may point out towards aggressive behavior of a tumour and a potential for metastasis.The mean of Ki-67 LI was significantly higher in metastatic as compared to non-metastatic OSCC. Other studies36 showed no significant association between Ki67LI and clinical TNM staging. Interestingly, on broadly categories TNM staging, the mean Ki67 LI was significantly higher in advanced stage OSCC as compared to early stage OSCC. These findings are in agreement with previous studies33 suggesting that the increased Ki67 LI indicates the higher intrinsic growth potential of the tumor resulting in advance TNM staging.In the present study, Ki67 LI was significantly higher in TNM stage IV as compared to stage III. However, non-significant difference of ki67 LI was found amongst stage I, stage II and stage III. The previous studies38 the result of this study have also showed non-significant difference of Ki67 LI amongst site of OSCC.In accordance with previous studiesIn this study the Ki67 LI was significantly higher with respect to adverse clinicopathological parameters such as histopathological grading, clinical TNM staging, cervical lymph node metastasis and 3 as well as 5 years disease free survival of OSCC. Thus, it can be suggested that assessment of cell proliferative activity by quantitative measurement of Ki67 positive neoplastic epithelial cells in individual invasive OSCC, may thus reveal unique, predictive information on clinical outcome, prognosis and deciding treatment modalities. Nevertheless, taking into consideration the extensive heterogeneity of tumors, it is recommended further research with standardized uniform immunohistochemistry protocol for Ki67 expression and large cohort of OSCC with 5 to 10 years follow up data to validate the range of Ki67LI for prognosis and treatment outcome."}
+{"text": "IntroductionAvascular necrosis occurs due to impaired blood supply to the bone. It can be caused by fractures, dislocations, chronic steroid use, chronic alcohol use, coagulopathy, congenital source, and many other factors. It mostly affects the femoral head (hip joint). Its management can be conservative or invasive. Total hip arthroplasty is the treatment of choice for third and fourth stage avascular necrosis that can be cemented or uncemented. The purpose of this study is to access the functional outcomes of cementless total hip arthroplasty in patients with avascular necrosis of the hip.Materials and methodsThis prospective study was conducted at a major metropolitan hospital in Karachi, Pakistan over a period of six months. A total of 30 patients of age <60 years, either gender, and a confirmed diagnosis of avascular necrosis of hip with no other associated hip pathologies were included in this study. Demographic features, comorbidities, level of activity, range of movement before the development of\u00a0avascular necrosis, Charnley's class, and laterality were noted. Cementless press-fit extensively porous-coated acetabular cup with or without cancellous screws and cementless press-fit extensively hydroxyapatite coated femoral stem were used through modified Gibson's posterior approach. The patients were checked for early and late complications, the position of acetabular and femoral components by radiography, and overall performance by Harris Hip Score (HHS) and modified HHS over a period of 12 months. All statistical analyses were performed using Statistical Package for Social Sciences (SPSS) version 19.0 .Resultso inclined in 0 (0%), 35o-50o inclined in 23 (77%), and >50o inclined in 7 (23%) patients, while femoral component was found neutral in 28 (93%), valgus in 2 (7%), and varus in zero (0%) patients on radiography at follow-up. On functional assessment, the HHS was 100% in 27 (90%) patients, 96% in 2 (7%) patients, and 83% in 1 (3%) patient with an average of 99.2%, while 29 (97%) patients had excellent and only 1 (3%) patient had a good outcome on modified HHS.The mean age was 43.9\u00b16.7 years with 21 (70%) patients ranging from 40 to 60 years of age. There were 22 (73%) male\u00a0and 8 (27%) female patients. Nine (30%) patients had diabetes mellitus, eight (27%) had hypertension, two (7%) had other comorbidities, and eleven (37%) had no comorbidities. A total of 11 (37%) patients were highly active, 18 (60%) were moderately active, and 1 (3%) was non-active before developing avascular necrosis. There were 4 (13%) patients in Charnley's class I, 15 (50%) in Charnley's class II, and 11 (37%) in Charnley's class III. Fifteen (50%) patients were operated on the left side, seven (23%) on the right side, and eight (27%) bilaterally. No significant early or late complications were noted. Acetabular component was found to be anteverted in 22 (73%), retroverted in zero (0%), neutral in 8 (27%), <35ConclusionsCementless total hip arthroplasty, performed in patients <60 years of age and avascular necrosis of the hip with no other associated hip pathologies, has excellent functional outcomes\u00a0with no pain, limping, physical deformity, difficulty in walking, difficulty in climbing stairs, difficulty using public transport, difficulty in sitting, or difficulty in wearing shoes and socks. They usually attain normal limb length and range of movement. The hip can be classified as the largest joint in the body. Its components include an acetabulum of the pelvic bone and a ball of the femoral head. The bony surfaces are protected with articular cartilage and smooth tissue that cushions the end of the bones and aids mobility in the joint .Pathologies such as osteoarthritis, rheumatoid arthritis, post-traumatic arthritis, and avascular necrosis can profoundly affect the joint and become a source of pain and disability. Moreover, certain pathologies like avascular necrosis can result in the collapse of the femoral head in addition to secondary osteoarthritis. The phenomenon leading to avascular necrosis comprises impaired blood flow to the bone leading to bone cell death. Avascular necrosis commonly involves hip joint  but may also occur in, shoulder, knee, and ankle joints . EtiologThe management of avascular necrosis of the femoral head ranges from conservative to invasive. Conservative treatments, such as reduced weight bearing, physical therapy, discontinuation of steroid therapy, and anti-inflammatory medications, are recommended in the initial stages. Several pharmacological agents such as bisphosphonates and statins have shown clinical benefits in the early-stage of avascular necrosis ,4. OperaThis prospective study is aimed at evaluating the functional outcomes of cementless total hip arthroplasty in patients with avascular necrosis of the hip.Study designThis prospective study was conducted at the Jinnah Postgraduate Medical Center Karachi, Pakistan from January 1, 2019 to June 30, 2019 over a period of six months. All patients aged <60 years of either gender  with a confirmed diagnosis of avascular necrosis of the hip were included in this study. All patients aged >60 years and those with any other associated hip pathologies were excluded from this study.Data collectionA total of 30 patients met the inclusion/exclusion criteria and were included in this study. All patients were informed about the purpose and aim of the study following which both verbal and written informed consents were taken. The demographic features , comorbidities, level of activity, range of movement before the development of avascular necrosis, Charnley's class, and laterality were noted. All patients were operated by using modified Gibson's posterior approach. The cementless press-fit extensively porous-coated acetabular cup with or without cancellous screws and cementless press-fit extensively hydroxyapatite coated femoral stem were used. There were no significant events intraoperatively. Prophylactic antibodies were used from the day of surgery for up to 5-14 days. Patients were kept partial weight-bearing for four weeks and were mobilized progressively full weight-bearing thereafter. The patients were followed for 12 months for early and late complications, the position of acetabular and femoral components by radiography, and overall performance by Harris Hip Score (HHS) and modified HHS.Data analysisData were\u00a0entered and analyzed using Statistical Package for Social Sciences (SPSS) version 19.0\u00a0.\u00a0Continuous data were presented as mean and standard deviation, whereas categorical data were presented as frequencies and percentages.The mean age of the patients was 43.9\u00a0years with a standard deviation of 6.7 years Table .There were 9 (30%) patients aged 20-40 years and 21 (70%) patients aged 40-60 years  male and 8 (27%) female patients  patients with diabetes mellitus, 8 (27%) patients with hypertension, 2 (7%) patients with other comorbidities, and 11 (37%) patients with no comorbidities  highly active and 18 (60%) moderately active patients, and 1 (3%) non-active patient before developing avascular necrosis Figure .The effect of bilateral disease on total hip arthroplasty was determined by dividing patients into Charnley's classes. There were 4 (13%) patients in class I, 15 (50%) patients in class II, and 11 (37%) patients in class III  patients, on the right side in 7 (23%) patients, and bilaterally in 8 (27%) patients Figure .There were no significant early or late complications observed in this study.\u00a0o inclined in zero (0%), 35o-50o inclined in 23 (77%), and >50o inclined in 7 (23%) patients at follow-up , retroverted in zero (0%), neutral in 8 (27%), <353%, retroThe position of the femoral component on radiography was found neutral in 28 (93%), valgus in 2 (7%), and varus in zero (0%) patients at follow-up\u00a0, while mild pain in 2 (7%) patients was observed. There was no limping, difficulty in walking, difficulty in climbing stairs, or difficulty using public transport in 29 (97%) patients, while mild limping, difficulty in walking, difficulty in climbing stairs, or difficulty using public transport in 1 (3%) patient was observed. There was no difficulty in sitting in 30 (100%) patients. This distribution of functional assessment at follow-up is shown in Figure\u00a03%, whileAll patients could easily wear shoes and socks, had no physical deformity, and attained normal limb length at follow-up. Only one patient needed a supportive device to walk.There was no restriction in the range of movement postoperatively. This distribution of the restricted range of movement preoperatively and postoperatively is shown in Table o-110o of flexion, 15o-20o of abduction, 10o-15o of external rotation, and 10o-15o of adduction (Table \u00a0All 30 (100%) patients had 100The overall performance was accessed at follow-up by using HHS and modified HHS. HHS was 100% in 27 (90%) patients, 96% in 2 (7%) patients, and 83% in 1 (3%) patient. The average HHS came out to be 99.2%.\u00a0According to modified HHS, 29 (97%) patients had excellent and only 1 (3%) patient had a good outcome\u00a0Table .This study illustrates encouraging results in patients of avascular necrosis of hip who received cementless total hip arthroplasty over a minimum follow-up period of 12 months. Approximately 96.66% of patients were reported to perform all functions without any assistance, whereas only 3.33% of patients required assistance for walking. The HHS was documented at 100% in 90% patients, 96% in 6.66% patients, and 83% in only 3.33% of patients with an average HHS of 99.16%.Avascular necrosis is a debilitating condition that often results in the collapse of the femoral head besides secondary osteoarthritis. Total hip arthroplasty is the recommended treatment for advanced stages of avascular necrosis and accounts for 5%-12% procedures conducted due to avascular necrosis .The initially published literature about cemented total hip arthroplasty for avascular necrosis was disappointing. In 1988, Salvati et al. reported prognosis of cemented total hip arthroplasty in their patients with a failure rate of 37% over an average period of eight years. Furthermore, they reported a 100% failure in patients less than 30 years of age. Thus, they concluded that the probability of failure was four times greater in patients less than 30 years of age [Another study published in 2014 compared the failure rate of cemented and uncemented total hip arthroplasty in patients older than 55 years of age. According to this study, patients with age 65 years or more depicted superior success rates with the use of cemented implants in comparison to uncemented implants, whereas the results noted for cemented and uncemented implants in patients with age 55-64 years were similar .Uncemented total hip arthroplasty consists of the porous-coated prosthesis that encourages bone growth onto its surface. It was developed to provide an alternative to poor outcomes of early cemented total hip replacements. The initial results for cementless total hip replacements were poor as the smooth surface of cementless prosthesis prevented strong adherence to the bone causing aseptic loosening a few years\u2019 post-surgery . During Cementless total hip arthroplasty has reassuring results in patients <60 years of age and avascular necrosis of the hip with no other associated hip pathology. It is not associated with any significant early or late complications and has outstanding functional outcomes. Patients usually do not experience any pain, limping, difficulty in walking, difficulty in climbing stairs, difficulty using public transport, or difficulty in sitting. They can easily wear shoes and socks, have no physical deformity, and attain normal limb length. They develop no restriction in the range of movement. Therefore, patient satisfaction is high after cementless total hip arthroplasty for avascular necrosis of the hip. Further studies on a larger scale and with a longer duration of follow-up are needed to prove the validity of the above-stated outcomes."}
+{"text": "Correction to: BMC Public Health (2020) 20:171https://doi.org/10.1186/s12889-020-8302-zIn the original article  the firsGlobally, cervical cancer is the fourth most common cancer in women with more than 85% of the burden in developing countries [1]. The majority of cervical cancer mortality occurs in developing countries, where screening and optimal treatment are not adequately available [2]. Cancer of the cervix constituted 22.2% of all cancers among women in Sub-Saharan Africa in 2012 [3]. In Uganda, cervical cancer is the number one cancer killer disease among women, this is followed by breast cancer [4]. With the incidence standing at 52 /100,000 women of reproductive age, it is one of the highest globally. Regrettably, more than half of these women die every year . The Kampala cancer registry shows that Uganda has an age standardized incidence rate of 47.5 per 100,000 against the global estimate of 15.8 per 100,000 [7]. Many of the Cervical cancer cases present with an advanced stage of the disease [8]."}
+{"text": "Medication-related problems (MRPs) remain one of the largest health risks for older adults, yet there are few studies that identify the complete myriad of problems associated with medication use among community-dwelling older adults with chronic diseases. The aim of this study is to identify the range and quantity of MRPs among community-dwelling older adults and determine the relationship between number of MRPs and emergency room (ER) visits. Primary data were collected from a community medication program for diverse older adults (N=206). A comprehensive medication review was conducted to identify MRPs including adverse drug reaction, inappropriate storage, and non-adherence. We conducted multivariate logistic regression to examine the relationship between the number of MRPs and ER visits controlling for health conditions and demographic information including age, gender and race. The mean age of participants was 74.2 (SD=8.8) and 65% were female. Racial groups include Whites (39%), Blacks (21%), Hispanics (29%) and Asian/Pacific Islanders (11%). On average, participants had 5.3 (SD=2.3) health conditions and 18.8 (SD=5.9) MRPs, among which adherence (36%) and coordination of care (28%) were most commonly identified. About 30% had at least 1 ER visit in the previous 6 months. The number of MRPs was significantly associated with ER visits . Older adults experienced a variety of MRPs and for each problem experienced, the odds of having an ER visit increased by 8%. Interventions are needed to assess the myriad of MRPs among community-dwelling older adults and address those potential risks."}
+{"text": "Allergic fungal rhinosinusitis is a noninvasive form of highly recurrent chronic rhinosinusitis. Despite the advancement in medical and surgical strategies, recurrence in AFRS in general poses another challenging problem with reported incidence that eventually can reach more than 60%. Recognition and understanding the pattern of disease recurrence will lead to greater understanding of the disease response in our population.  A retrospective cohort study was performed in King Abdulaziz Medical City in Riyadh, Saudi Arabia. All patients diagnosed with chronic rhinosinusitis and underwent functional endoscopic sinus surgery from the period of January 2006 to December 2016 were reviewed. n\u2009=\u20093) of them had recurrent bilateral disease.  28 patients were found to have AFRS based on clinical, radiological, and microscopic examination suggestive of allergic fungal rhinosinusitis. Among these patients, 53% of them were female and 46% were male. The age ranged from 13 to 55\u2009years, with a mean age of 31.57\u2009years. 28.57% of the patients presented with recurrent allergic fungal sinusitis. The duration between the surgery and symptoms recurrence was around one year. Male and female patients had similar recurrence rate (50%). At first visit, 95% of the patients with nonrecurrent disease presented with nasal obstruction compared to 87.5% of the patients with recurrent disease. On the other hand, patients with recurrent disease had more nasal discharge (87.5%), postnasal drip (37.5%), facial pressure/pain (50%), headache (50%), nasal polyposis (87.5%), hypertrophy of inferior turbinate (37.5%), and proptosis (12.5%). Nasal obstruction (87.5%) and nasal polyps (87.5%) were the most common presenting symptoms for the disease recurrence. The pattern of disease recurrence in the previously unilateral disease was 18% ipsilateral and 27% bilateral. For the patients who had bilateral disease formerly, 17% ( Allergic fungal rhinosinusitis is a distinct clinical entity. A high recurrence rate is a pathognomonic feature of the disease, despite all the development in medical and surgical trials. This study demonstrated that recurrence rate is lower in our population. However, more studies with a greater number of patients are needed in the future to clearly recognize the pattern of recurrence in patients with AFRS. Allergic fungal rhinosinusitis (AFRS) is a noninvasive form of highly recurrent chronic rhinosinusitis. It can be distinguished clinically, histopathologically, and prognostically from the other forms of chronic fungal rhinosinusitis. There are three recognized forms of invasive fungal sinusitis , in addition to two noninvasive forms  . AllergiDiagnosis criteria of AFRS were established by Bent and Kuhn which contain major and minor criteria. Major criteria include type I hypersensitivity, nasal polyposis, characteristics CT scan findings, presence of eosinophilic mucin, and positive fungal smear. The minor criteria include young individuals, coexistence asthma, unilateral predominance, radiographic bone erosion, fungal culture, Charcot\u2013Leyden crystals, and serum eosinophilia .There were multiple research studies done on AFRS locally and worldwide, and few of them questioned the recurrence rate and pattern specifically in the initially involved and noninvolved sinuses. In addition, despite the advancement in medical and surgical strategies, recurrence in AFRS in general poses another challenging problem with reported incidence that eventually can reach more than 60% .Our aim in this research is to shed light on the rate and pattern of recurrence in the sinuses and whether none involved side will be involved later on during the recurrence phase since it is considered as one of the minor criteria for the diagnosis of AFRS.p value less than 0.05 was considered significant.After obtaining the ethical approval, a retrospective cohort study was performed in King Abdulaziz Medical City in Riyadh, Saudi Arabia. Charts of all patients diagnosed with chronic rhinosinusitis (CRS) and underwent functional endoscopic sinus surgery (FESS) from the period of January 2006 to December 2016 were reviewed. Patients fulfilling the Bent and Kuhn criteria for the diagnosis of allergic fungal sinusitis (AFS) were included . Patient28 patients were found to have AFRS based on clinical, radiological, and microscopic examination suggestive of allergic fungal rhinosinusitis. Among these patients, 53% of them were female and 46% were male. The age ranged from 13 to 55\u2009years, with mean age was 31.57\u2009years. The most common clinical presentation was nasal obstruction (92%), followed by nasal polyps (82%), deviated nasal septum (57%), nasal discharge (50%), and headache (42%). Other clinical presentations include facial pressure/pain (28%), postnasal drip (21%), hypertrophy of inferior turbinate (21%), and proptosis and decreased vision (3%). For the past medical history, 46% of the patients had asthma, 17% had allergic rhinitis, and 7% had aspirin intolerance. 32% of the patients underwent nasal surgical intervention previously. The majority of the patients had FESS (21%), and the remaining had septoplasty (10%). At first visit, 95% of the patients who did not have recurrent disease presented with nasal obstruction compared to 87.5% of the patients with recurrent disease. Nasal discharge was more common in patients with recurrent disease (87.5%) compared to patients with nonrecurrent disease (35%). Patients with recurrent disease had more postnasal drip (37.5%), facial pressure/pain (50%), headache (50%), nasal polyposis (87.5%), hypertrophy of inferior turbinate (37.5%), and proptosis (12.5%). Patients with nonrecurrent disease had more deviated nasal septum (65%) and decreased vision (5%). For the past medical history, patients with recurrent disease had higher incidence of asthma (62.5%) and allergic rhinitis (25%) compared to patients with nonrecurrent disease. On the other hand, aspirin intolerance was only found in patients with nonrecurrent disease (10%). Past nasal surgical intervention was done in 37.5% of the patients with recurrent disease, and 30% of patients with nonrecurrent disease. All of the 28 patients had heterogenous opacifications. Maxillary sinus was the most common sinus involved (96%). Anterior ethmoid was involved in 75% of the cases, compared to posterior ethmoid which was evident in 64% of the cases. Additionally, sphenoid sinus was involved in 75% of the cases, and frontal sinus was involved in 71% of the cases. Moreover, 57% of the patients had deviated nasal septum, and 25% had concha bullosa. For the bony defect, 2 patients had infraorbital defect, and only 1 patient had intracranial defect. Among the 28 patients, 11 patients (39%) underwent unilateral sinus surgery, and 17 patients (60%) underwent bilateral sinus surgery. 21 patients (79%) had mucin intraoperatively. Nasal steroid spray was used postoperatively by 17 patients (57%) while 5 patients (17.86%) used nasal steroid irrigation. In addition, 12 patients (43.86%) used oral steroid as well. n\u2009=\u20098) of the patients presented with recurrent allergic fungal sinusitis. The duration between the surgery and symptoms recurrence was around one year, but it ranged from 2\u2009months to 2\u2009years. Male and female had similar recurrence rate . Most of the patients presented with nasal obstruction  and nasal polyps . In addition, half of the patients  presented with nasal discharge, facial pain/pressure, and headache.28.57% (n\u2009=\u20092) ipsilateral and 27% (n\u2009=\u20093) bilateral. For the patients who had bilateral disease formerly, 17% (n\u2009=\u20093) of them had recurrent bilateral disease. In summary, among the 8 patients with recurrent disease, 2 patients (25%) presented with unilateral disease and 6 patients (75%) presented with bilateral disease. The pattern of disease recurrence in the previously unilateral disease was 18% , nasal polyps 23 (82.14%), and deviated nasal septum 16 (57.14%). This was similar to a study conducted in King Abdulaziz University Hospital, Riyadh, Kingdom of Saudi Arabia, in which the most common signs and symptoms were as follows: nasal obstruction 24 (96%), nasal polyps 22 (88%), and deviated nasal septum 17 (68%) .We assessed the past medical and surgical history in all the patients which showed that bronchial asthma is the most common medical history (46.43%) followed by allergic disorders 17.86%). Past nasal surgeries were found in 32.14% of patients. In contrast, the study which was done in India showed that previous nasal surgeries were seen in 20% of cases followed by bronchial asthma (14.2%) and allergic disorders (11.42%) [6%. Past Radiological characteristics were as follows: the most common sinuses involved were maxillary (96.43%), anterior ethmoid and sphenoid (75%), frontal (71.43%), and posterior ethmoid (64.29%). We could not find a research study investigating the types of sinuses involved, and most of them compared radiological findings in terms of unilateral vs bilateral involvement. In this research, bilateral involvement was found in 17 (60.71%) vs unilateral 11 (39.29%). In Makkah in a study conducted in 2017, they found bilateral involvement in 36 (69.2%) vs unilateral 16 (30.8%) [We found in our research that 13 (46.43%) patients had recurrence symptoms during their follow-up. However, 8 28.57%) patients did CT scan which was positive for heterogenous opacification. In contrast to multiple studies, in the eastern province, they found that 54.5% of patients had recurrence, and in Makkah, it was 55% % patient. In addiA high recurrence rate is a pathognomonic feature of the disease, despite all the development in medical and surgical trials. In addition, more studies with more number of patients are needed in the future to clearly recognize the pattern of recurrence in patients with AFRS."}
+{"text": "Agitated behaviors are problematic in intensive care unit (ICU) patients recovering from traumatic brain injury (TBI) as they create substantial risks and challenges for healthcare providers. To date, there have been no studies evaluating their epidemiology and impact in the ICU. Prior to planning a multicenter study, assessment of recruitment, feasibility, and pilot study procedures is needed. In this pilot study, we aimed to evaluate the feasibility of conducting a large multicenter prospective cohort study.This feasibility study recruited adult patients admitted to the ICU with TBI and an abnormal cerebral CT scan. In all patients, we documented Richmond Agitation Sedation Score (RASS) and agitated behaviors every 8-h nursing shift using a dedicated tool documenting 14 behaviors. Our feasibility objectives were to obtain consent from at least 2 patients per month; completion of screening logs for agitated behaviors by bedside nurses for more than 90% of 8-h shifts; completion of data collection in an average of 6 h or less; and obtain 6-month follow-up for surviving patients. The main clinical outcome was the incidence of agitation and individual agitated behaviors.In total, 47 eligible patients were approached for inclusion and 30 (64% consent rate) were recruited over a 10-month period (3 patients/month). In total, 794 out of 827 (96%) possible 8-h periods of agitated behavior logs were completed by bedside nurses, with a median of 24 observations (IQR 28.0) per patient. During the ICU stay, 17 of 30 patients developed agitation  defined as RASS \u2265 2 during at least one observation period and for a median of 4 days (IQR 5.5). At 6 months post-TBI, among the 24 available patients, an unfavorable score (GOS-E < 5 including death) was reported in 12 patients (50%). In the 14 patients who were alive and available at 6 months, the median QOLIBRI score was 74.5 (IQR 18.5).This study demonstrates the feasibility of conducting a larger cohort study to evaluate the epidemiology and impact of agitated behaviors in critically ill TBI patients. This study also shows that agitated behaviors are frequent and are associated with adverse events.The online version contains supplementary material available at 10.1186/s40814-020-00736-5. What uncertainties existed regarding the feasibility?Recruitment and follow-up ratesCompletion of screening logs for agitated behaviors by bedside nursesTime to complete of data collection2)What are the key feasibility findings?Recruitment and follow-up rates were acceptableA majority of screening logs were completed by bedside nursesThe time to complete data collection was satisfactory3)What are the implications of the feasibility findings for the design of the main study?A broadening of inclusion criteria to include patients with a prior history of TBI, neurological disease or major psychiatric illnesses would improve recruitment ratesApplying a deferred consent model would facilitate recruitmentValidation of the ABS or any other agitation scale in the ICU population is warranted for future studiesBehaviors such as agitation, confusion, and aggressiveness are problematic in hospitalized intensive care unit (ICU) patients recovering from traumatic brain injury (TBI). These behaviors create substantial risks and challenges for healthcare providers and may delay mobilization and liberation from mechanical ventilation , 2. AlthThis was a prospective, single-center pilot cohort study of adult patients admitted to the ICU with a TBI. Consent was obtained from the patient or their surrogate. If consent was initially obtained from a surrogate, patient consent was obtained once he or she was judged competent. The protocol was approved by the local research ethics board.The primary objective was feasibility as assessed with the following goals: 1) to obtain consent from at least 2 patients per month; (2) completion of screening logs for agitated behaviors by bedside nurses for more than 90% of 8-h shifts; (3) completion of data collection in an average of 6 h or less; (4) obtain 6-month follow-up for surviving patients. The secondary outcomes were (1) the incidence of agitation, defined as a Richmond Agitation and Sedation Scale (RASS)  score of to obtaiThe study was conducted in the 36-bed ICU of Sacr\u00e9-Coeur Hospital, a University-affiliated teaching hospital and level 1 trauma center in Montreal, Canada.Patients 18 years and older admitted to the ICU with TBI  and an abnormal cerebral CT scan, screened within 48 h of ICU admission to enable the description of a maximum of agitated behaviors, and had an expected stay of more than 48 h (as confirmed with attending ICU physician) were eligible for inclusion. We excluded patients in whom agitated behaviors could be difficult to evaluate because of muscle function loss  or was potentially already an issue prior to admission . We also excluded patients at high risk of short-term mortality .Between September 2018 and July 2019, we screened all new ICU admissions for study eligibility from Monday to Friday. Eligible patients or their substitute decision maker were approached for informed consent.Baseline data included age, sex, level of education, co-morbidities , medication history prior to hospital admission, smoking status, current drug-abuse, or alcohol abuse (self-reported or family reported). We defined chronic alcohol use as the consumption of more than 2 drinks per day or equivalent of 750 ml 40% alcohol per week; and the use of recreational drugs including marijuana as at least once in the week prior to admission . We collIn all patients, we documented 14 agitated behaviors every 8-h nursing shift using a dedicated observation tool. We documented 11 behaviors from the Agitated Behavior Scale  . Given tPrior to starting the study, training sessions were held for all three nursing shifts. These sessions included a review of the study protocol and training for agitated behavior documentation logs. On a daily basis, research staff ensured comprehension of agitated behavior documentation logs by bedside nurses for each enrolled patient. To ensure accurate capture and comprehension of agitated behaviors, when feasible we filmed patients for up to four 1-h periods on separate days following the weaning of sedatives. Two investigators independently reviewed the videos and recorded the presence or absence of the 7 behaviors which could be easily evaluated with the videos, as well as the severity. We compared the patient behavior assessment of the 2 investigators, and between the investigators and bedside nurses documentation logs in order to assess optimal completion of the observation tool . For thePatients were followed until one of the following events: ICU discharge, 28 days, or death. Six months following study inclusion, we contacted surviving patients (or their families in the instance where patients were unable to self-report) by telephone for functional and health-related quality of life outcomes. We evaluated functional outcome with the Glasgow Outcome Scale Extended (GOS-E) and health-related quality of life with the Quality of Life after Brain Injury (QOLIBRI) instrument , 27. TheA total of 30 patients were expected to be recruited in this pilot study . Simple t tests or Mann\u2013Whitney U test, if data was skewed, were used to compare continuous variables, and chi-square or Fisher\u2019s exact tests to compare categorical variables.Continuous variables were described using measures of central tendency and spread . Frequencies, proportions, and 95% CIs were used to describe categorical variables. Student\u2019s During the 10-month study period, 127 TBI patients were screened and 47 (37%) were eligible  of agitated behavior logs were completed by bedside nurses, with a median of 24 observations (IQR 28.0) per patient. For one patient, no behavior logs were completed as the patient was discharged within 8 h of recruitment. A total of 38 videos in 19 patients (varying from 1 to 4 videos per patient) were filmed and independently reviewed by 2 investigators. The raw agreements between the two investigators and bedside nurses for the seven behaviors examined were 81% and 76%, respectively. The weighted kappa for the behavior severity was fair with 0.271 (95% CI 0.149\u20130.393) and 0.255 (95% CI 0.127\u20130.382) for evaluators 1 and 2, respectively. The weighted kappa was moderate between the two investigators with 0.44 (95% CI 0.32\u20130.56). At 6 months, GOS-E and QOLIBRI were obtained for 24 (80.0%) and 14 patients (46.7%), respectively. Four patients were not reachable after multiple attempts and two refused participation, while nine patients had died and one was in a vegetative state.As presented in Table p = 0.056).During the ICU stay, 17 of 30 patients developed agitation  defined as a RASS \u2265 2 during at least one observation period. In these 17 patients, RASS \u2265 2 was reported for a median of 4 days (IQR 5.5), while RASS < 2 was reported for a median of 5 days (IQR 8.5). In comparison to patients who did not develop agitation, patients with agitation were more often male, had moderate TBI, lower median GCS scores, were active drug or alcohol abusers, and were receiving treatment for a diagnosis of ADHD (Table p = 0.14). Other common behaviors manifested by more than 50% of patients at least once during the ICU stay included inattention (65.5%), pulling on tubes and catheters (62.1%), disorientation (58.6%), self-stimulating behavior (55.2%), and uncooperativeness (51.7%). Violent behavior (31.0% of patients) and anger (20.7% of patients) were also commonly reported and more frequent during night-time shifts. When examining the co-occurrence of behaviors, in the 19 patients presenting with restlessness, bedside nurses reported pulling on tubes and catheters (69.7%), uncooperativeness (45.3%), and impulsiveness (43.0%) during the 8-h observation period. The mean daily sum of the 14 behaviors in all patients was 4.6 (SD 6.6) over the first 10 days of ICU stay and was greatest on days 4 and 6 of ICU stay , mostly in patients who developed agitation . For the management of restlessness, nurses reported interventions in 303 of 385 (78.7%) observation periods. A pharmacological intervention was used in 212 patients (55.1%). Antipsychotics, opiates, dexmedetomidine, propofol, and benzodiazepines were used in 20.8%, 19.0%, 13.2%, 10.8%, and 8.1% of cases, respectively. Physical restraints and environmental modifications such as diming the lights or reducing noise level were used on 66 (21.8%) and 25 (8.3%) occasions.Overall, 20 patients (66.7%) were mechanically ventilated during the ICU stay, for a median duration of 5 days (IQR 6.5). The median ventilator-free days within 28 days after ICU-admission was 24.5 days (IQR 8.5) in the entire study cohort, 23 (IQR 4.5) in the agitated group and 28 (IQR 28) in the non-agitated group. Accidental removal of nasogastric tubes, peripheral venous catheter removal and wound dressings were the most common types of interference associated with agitation, occurring in 4 (13.3%), 3 (10.0%), and 2 (6.7%) patients, respectively. Among other significant clinical events, accidental extubation and fall were described in one patient each, both of whom were agitated. The median length of ICU stay was 8.5 days (IQR 11.5) and the median ICU-free days within 28 days  of ICU admission was 18 days (IQR 18.8). ICU, hospital, and 6-month mortality were 13.3% (4/30), 23.3% (7/30), and 30% (9/30), respectively. Hospital mortality was greatest in patients with moderate (2 of 13 patients) and severe TBI (5 of 9 patients).In total, 2 (11.8%) and 5 (38.5%) patients in the agitated and non-agitated groups died, respectively. Five (29.4%) and 4 (30.8%) patients in the agitated and non-agitated groups were discharged directly home whereas 5 (29.4%) and 3 (23.1%) were transferred to a rehabilitation hospital, respectively. Five patients (29.4%) in the agitated group and one patient (7.7%) in the non-agitated groups were transferred back to their referring hospital. In the 17 patients who developed agitation, the median ICU-free days within 28 days of ICU admission was 17 days (IQR 12.0) compared to 22 days (IQR 25.5) in patients without agitation.At 6 months post-TBI, among the 24 available patients, an unfavorable score (GOS-E < 5 including death) was reported in 12 patients (50%). In the 12 remaining patients, low moderate disability, upper moderate disability, low good recovery, and upper good recovery were reported in 2 (8.3%), 3 (12.5%), 4 (16.7%), and 3 (12.5%) patients, respectively. Of the 15 patients with agitation having GOS-E results, 7 (46.7%) had an unfavorable outcome compared to 5 of 9 patients (55.6%) without agitation. In the 14 patients who were alive and available at 6 months, the median QOLIBRI score was 74.5 (IQR 18.5).In this pilot study, we demonstrated the feasibility of conducting a prospective observational study on agitated behaviors in critically ill TBI patients. In our pilot study, we obtained an adequate three-patient per month recruitment rate as well as screening and data collection times of a mean less than 6 h. In addition, the measure of agitated behaviors by ICU nurses was satisfactory with a high proportion of behavioral observation logs being completed, and an acceptable agreement between investigators and bedside nurses for observed behaviors was attained. The fair agreement may be partially explained by the limits of punctual 1-h videos as bedside nurses may have the better knowledge of patient behaviors that allow to better classify them and evaluate their severity. It may also be that bedside nurses, having a better knowledge of their patients, were in a better position to classify behaviors. Research assistant may also have been more stringent in applying behavior criteria. The usefulness of short videos for future studies may be limited. A larger study would need to provide in-depth training of bedside nurses with frequent reminders and the use of teaching tools such as video descriptions of the behaviors. In general, we found nurses to be enthusiastic about the project, most often because they perceived importance of the research question being studied.We also identified numerous strategies for recruitment and methods modifications to improve our protocol for a definitive study. Despite a satisfactory recruitment rate, we identified opportunities to improve recruitment rates including a broadening of inclusion criteria to recruit patients with a prior history of TBI, neurological disease, or major psychiatric illnesses. The broadening of inclusion criteria would offer better description of the true incidence of agitated behaviors. In addition, as availability of family members for consent within 48 h of admission was a challenge, applying a deferred consent model would facilitate recruitment. A priori informed consent was mandated by our research ethic board because of the use of videos. A future multicenter study would not include videos, and given that video was a common reason for consent declination this should facilitate patient recruitment. A waived-consent model should also be considered to improve the external validity of findings. As for the study methods, nurses did comment that the number of behaviors collected was a time burden and efforts should be made to reduce them. Using a shorter version of the QOLIBRI could also simplify procedures.Clinically, we observed a high incidence of agitation defined as RASS \u2265 2 56.7%). Individual behaviors such as restlessness, inattention, pulling on tubes and catheters, disorientation, self-stimulating behavior, and uncooperativeness were observed in more than 50% patients. The incidence of agitation was similar to previous studies in non-TBI ICU patients that reported an incidence of 31.8 to 59% using the RASS and Ramsay score , 30. How.7%. IndiAlthough not the objective of this study, we did observe factors associated with agitation. As in previous studies of non-TBI patients, a history of drug or alcohol use was associated with agitation , 30. In The strengths of this study include prospective behavior documentation by bedside nurses, who are better suited to observe these events than research personnel; and the use of videos to assess documentation of behaviors with the observation tool. The study also estimated the incidence of agitation and individual behaviors in ICU patients, informing future clinical studies. This study also has limitations, including being conducted in a single center. Hence, feasibility in other research sites may be different. As identified with the videos, the intensity scoring for the behaviors may have been suboptimal and additional training will be required for future studies to ensure optimal comprehension of definitions. Although well validated for the evaluation of sedation and agitation in ICU patients, the RASS has not been extensively studied in neurocritical care patients . We opteIn this pilot study, we demonstrated the feasibility of conducting a larger cohort study to evaluate the epidemiology and impact of agitated behaviors in critically ill TBI patients, as well as identified opportunities for protocol improvement. We found that agitated behaviors are frequent in the ICU following TBI and are associated with adverse events, including accidental device removal. Potential risk factors include male sex, substance abuse, ADHD, and moderate TBI.Additional file 1."}
+{"text": "RBM20 are reported in 2% to 6% of familial cases of dilated cardiomyopathy and may be associated with fatal ventricular arrhythmia and rapid heart failure progression. We sought to determine the risk of adverse events in RBM20 variant carriers and the impact of sex on outcomes.Variants in RBM20 variants were retrospectively recruited from 12 cardiomyopathy units. The primary end point was a composite of malignant ventricular arrhythmia (MVA) and end-stage heart failure (ESHF). MVA and ESHF end points were also analyzed separately and men and women compared. Left ventricular ejection fraction (LVEF) contemporary to MVA was examined. RBM20 variant carriers with left ventricular systolic dysfunction (RBM20LVSD) were compared with variant-elusive patients with idiopathic left ventricular systolic dysfunction.Consecutive probands and relatives carrying RBM20 variant carriers ; 7 of 143 had an MVA event at baseline. Thirty of 136 without baseline MVA (22.0%) reached the primary end point, and 16 of 136 (11.8%) had new MVA with no significant difference between men and women . Twenty of 143 (14.0%) developed ESHF . Four of 10 variant carriers with available LVEF contemporary to MVA had an LVEF >35%. At 5 years, 15 of 67 (22.4%) RBM20LVSD versus 7 of 197 (3.6%) patients with idiopathic left ventricular systolic dysfunction had reached the primary end point (log-rank P<0.001). RBM20 variant carriage conferred a 6.0-fold increase in risk of the primary end point.Longitudinal follow-up data were available for 143 RBM20 variants are associated with a high risk of MVA and ESHF compared with idiopathic left ventricular systolic dysfunction. The risk of MVA in male and female RBM20 variant carriers is similar, but male sex is strongly associated with ESHF. It has an estimated population prevalence of 1 in 250 and, in many patients, is a heritable disease.3 many families with DCM exhibit Mendelian, monogenic inheritance. Over 200 genes have been implicated in DCM pathogenesis, although strong supportive evidence for a causative role is limited to a relatively small number.4Significant progress has been made in unraveling the genetic basis of DCM. While common variation and gene-environment interaction contribute to phenotype development,RBM20 are reported in 2% to 6% of familial cases of DCM.5RBM20 resides on chromosome 10 and encodes for the RNA-binding motif protein 20, a modifier of post-transcriptional splicing of over 40 genes. It is suggested that RBM20 variants cause a particularly malignant form of DCM, characterized by fatal ventricular arrhythmia and rapidly progressive left ventricular systolic dysfunction (LVSD).7 If this is correct, diagnosis of pathogenic RBM20 variants has major implications for disease management and the counseling of families. In this study, we examine the natural history of RBM20 variant carriers. Sex differences are well-documented in DCM, including within gene-specific cohorts.10 We sought to explore these differences in RBM20 variant carriers. To provide context to our findings, we compare and contrast the characteristics and outcomes of RBM20 variant carriers with LVSD with patients with idiopathic LVSD (iLVSD) and no identifiable pathogenic gene variant.Variants in Supplemental Material. Patient-level data will not be made available as consent was not sought for public dissemination and due to concerns that information could be used to identify individuals. The study conforms with the principles of the Declaration of Helsinki,11 and participants provided written informed consent for genetic testing. The authors from each center guarantee the integrity of data from their institution and received approval for anonymized patient data collation and analysis.Methods are available in the RBM20 variants were identified. Five were excluded: 1 with hypertrophic cardiomyopathy, 3 with no clinical data, and 1 neonate with a heart failure\u2013related death. The cohort for baseline analysis comprised 149 individuals (32 probands [Table S1] and 117 relatives) from 43 families, 28 of which were represented by \u22652 individuals . All RBM20 variants were missense variants .One hundred and fifty-four individuals with likely pathogenic or pathogenic RBM20 variant carriers are summarized in Table Tables S3 and S4, including columns representing missingness. Seven (4.7%) individuals had malignant ventricular arrhythmia (MVA) before (3/7) or at baseline assessment (4/7). Median (interquartile range [IQR]) age at first evaluation was 35.5 (20.2\u201347.4) years . LVSD was present in 85 (57.0%) patients at or before baseline assessment. Two probands with normal LVEF had unexplained left ventricular dilatation12 and nonsustained ventricular tachycardia on Holter monitor. Fifty-five (47.0%) relatives had LVSD at baseline.Baseline characteristics of Figure S2).Twenty one variant carriers developed new-onset LVSD during follow-up (both probands without LVSD at baseline and 19/61 [31.1%] previously unaffected relatives) with a median (IQR) time to LVSD development of 71 (23\u2013153) months. Estimated median age of disease penetrance in male relatives was 32.1 (27.6\u201340.1) years and 45.5 (37.9\u201353.7) years for female relatives (RBM20 variant carriers (Table Follow-up data were available for 143 of 149 RBM20 variant carriers died during follow-up (3 heart failure\u2013related and 3 sudden cardiac deaths). One woman died of noncardiovascular causes at the age of 86 years, and 1 man died of causes unknown at the age of 48 years.Eight The 7 individuals with MVA at or before baseline assessment were excluded from analysis of the primary composite and secondary MVA end points but were included in the analysis of the secondary ESHF end point.P=0.07 and P=0.98, respectively; Figure RBM20 variant carriers), did show a difference between men and women . Competing risk from heart transplantation did not significantly alter the comparison between men and women for the secondary MVA end point .Thirty 22.0%) of 136 patients (18 men and 12 women) reached the primary composite end point: 16 had MVA events (7 men and 9 women) and 14 had ESHF events (11 men and 3 women). Only 2 women had adverse events before the age of 40 years (sustained ventricular tachycardia and appropriate implantable cardiac defibrillator [ICD] shock) during follow-up. Differences between men and women for the primary composite and secondary MVA end points were not statistically significant (2.0% of 1Table S5).Ten patients who experienced MVA had an LVEF available within 6 months of the event. Median (IQR) contemporary LVEF was 28.5% (23%\u201338%), and 4 of 10 had a contemporary LVEF >35%. A single patient had a contemporary LVEF >45%  reached the ESHF end point  including LVEF  and left ventricular internal diameter at end diastole . Variables not included in multivariable analyses due to >10% missing data were history of smoking, cardiac medications at baseline, PR interval, QRS duration, left atrial diameter, tricuspid annular plane systolic excursion, number of ventricular ectopics in 24 hours, and the presence of left ventricular late gadolinium enhancement on cardiac magnetic resonance scan. LVEF and LVIDd demonstrated strong associations with all end points. Multivariable modeling was explored with and without LVIDd given the greater emphasis placed on LVEF in clinical practice and international guidelines.Univariable Cox regression identified multiple baseline variables associated with the primary end point (P<0.001), carriage of the p.Arg634Gln variant , and history of heart failure  were independently associated with the primary end point (Table S6B). When LVIDd was included in the model, the independent predictors of the primary end point were LVIDd, history of heart failure, New York Heart Association class III or IV at baseline, and carriage of the p.Arg634Gln variant.Multivariable modeling without LVIDd demonstrated that LVEF . Twenty-seven (11.3%) of the iLVSD cohort and 5 (6.6%) of the RBM20LVSD cohort had MVA at or before baseline (P=0.33). As previously, for analyses of the primary composite and secondary MVA end points but not the ESHF end point, these patients, and those with no follow-up, were removed. Median (IQR) follow-up time for the iLVSD cohort was 40 (25\u201364) months and for the RBM20LVSD cohort was 91 (47\u2013181) months (P<0.001). End points were analyzed at 5 years to mitigate for the difference in follow-up time (Table S11)Seventy-six RBM20LVSD versus 7 of 197 (3.6%) with iLVSD . The secondary MVA end point was reached by 10 of 67 (14.9%) patients with RBM20LVSD versus 6 of 197 (3.0%) with iLVSD (P=0.002), and the secondary ESHF end point reached by 7 of 72 (9.7%) RBM20LVSD versus 1 of 221 (0.5%) iLVSD (log-rank P<0.001). RBM20 variant carriage was associated with the primary end point  and retained this association when propensity scores were included in a multivariable Cox model .At 5 years, the primary end point was reached by 15 of 67 (22.4%) patients with 7 of 197 .6% with RBM20 encodes RNA-binding motif protein 20, a trans-acting splicing factor that is highly expressed in striated muscle. It affects the splicing of over 40 genes including TTN and other genes important for sarcomeric function, as well as genes involved in cardiomyocyte calcium homeostasis. The interplay between RBM20 variants and the spliceosome confers intricacy and complexity to the mechanism of RBM20-induced DCM.RBM20 variants associated with DCM frequently result in adverse events with over 1 in 5 patients reaching the primary composite outcome during a median follow-up of 87 months. Compared with a control group of variant-elusive patients, RBM20 variants conferred a 6.0-fold increase in the risk of ESHF or MVA in individuals with LVSD at 5 years of follow-up. RBM20 variants were shown to be highly penetrant in relatives, an important finding when counseling families.In this large, multicenter, international study, we show that 10 In our study, men and women had a similar burden of MVA; however, men experienced earlier and more frequent ESHF events than women, and only 1 woman had a heart transplant. As a result, a trend was seen toward more men reaching the primary composite end point, but this did not reach statistical significance.Men with DCM generally have more severe phenotypes and a poorer prognosis than women.RBM20 to the cytoplasm and altered nuclear splicing of the pre-mRNAs of several cardiomyopathy-linked genes. Splicing models suggest that the pathogenicity of RBM20 missense variants at the same amino acid position could vary even by polarity of the exchanged amino acid.13 In the future, variant-level phenotyping may be required to refine risk assessment.Carriage of the p.Arg634Gln variant was seen to confer additional risk, particularly for MVA events. This variant is located within the arginine-serine-arginine-serine-proline stretch where missense mutations result in mislocalization of LMNA and FLNC have shown that the conventional approach of only offering ICD implantation to patients with severe LVSD is inadequate; in these patients, ICD implantation should be considered in patients where LVSD is only mild or even low-normal.15 Where data were available, nearly half of RBM20 variant carriers with an MVA event had a contemporary LVEF >35%, but only a single case was seen with a contemporary LVEF >45%. Thus, consideration of ICD implantation in RBM20 variant carriers with an LVEF \u226445% seems reasonable. Importantly, women should be regarded as carrying the same risk of MVA as men.The need for ICD implantation and its timing are common clinical dilemmas in the management of patients with DCM. Cohort studies of variant carriers in genes such as RBM20 variant carriers before phenotype development offers the opportunity for regular risk assessment and timely initiation of medications. Future therapies may mitigate against the development of the malignant RBM20 phenotype.16Our findings emphasize the importance of family screening. Nearly a third of relatives with no features of cardiomyopathy at baseline developed LVSD during follow-up. Screening should be considered at a young age given that 3 male relatives required heart transplantation in their teens. The identification of 17 aimed to mitigate against unstandardized data collection that can be a flaw in retrospective, multicenter studies. Some study variables were limited by missing data. Ambulatory ECG monitor and cardiac magnetic resonance scan data were particularly prone to missingness, and this prevented their inclusion in multivariable modeling. How variables such as ventricular ectopy count and late gadolinium enhancement burden contribute to risk stratification in RBM20 variant carriers should be addressed in future studies. Information on ICD programming was not analyzed, and while all centers are expert in device implantation and offer contemporary programming strategies, patients could have been exposed to different practices that may have influenced the frequency of MVA events. Most RBM20 variant carriers were of white ethnicity, highlighting the importance of further research incorporating patients of other ethnicities.Participating centers were all specialist cardiomyopathy units leading to potential referral bias. The use of RedCapRBM20 variants are highly penetrant for a malignant DCM phenotype and specific RBM20 variants associate with adverse events. Both sexes are at risk of MVA, and male sex is strongly associated with ESHF. Impairment of LVEF is a major predictor of the risk of MVA. Further research with larger cohorts and functional studies is required to achieve variant-level risk stratification.The authors are grateful to the patients and their families whose contributions have made this work possible. This study was supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre.This work has been supported by a British Heart Foundation clinical research training fellowship to Dr Cannie (FS/CRTF/20/24022); a British Heart Foundation clinical research training fellowship to Dr Protonotarios (FS/18/82/34024); grant support from Instituto de Salud Carlos III (CM20/00101) to Dr de Frutos; the National Institutes of Health  and the American Heart Association (17GRNT33670495) to Dr Mestroni; the NIH  to Dr Taylor; DETECTin-HF  grant from the The European Research Area Network on Cardiovascular Diseases (ERA-CVD) framework, National Centre for Research and Development to Dr Bilinska; and funding from the Victor Chang Cardiac Research Institute and New South Wales Health to Dr Fatkin.Dr Sengupta reports speakers fees from Pfizer. Dr Elliott reports consultancies for Pfizer, Sarepta, Bristol Myers Squibb, Biomarin, Leal, and Novo Nordisk. The other authors report no conflict.Supplemental MethodsTables S1\u2013S11Figures S1\u2013S4References 38"}
+{"text": "Streptococcus infections in Portugal (n\u2009=\u200989) were higher than in pre-COVID-19 seasons. Between September 2022 and May 2023, the dominant diagnoses were pneumonia (25/79), mostly with empyema (20/25), and sepsis (22/79). A number of cases required admission to intensive care (27/79) and surgery (35/79), and the case fatality rate was 5.1% (4/79). Genomic sequencing (n\u2009=\u200955) revealed multiple genetic lineages, dominated by the M1UK sublineage (26/55) and more diverse emm12 isolates (12/55).Since autumn 2022, observed numbers of paediatric invasive group A  Streptococcus infections (piGAS) has been notified in the context of an ongoing prospective surveillance of piGAS in Portugal, including a high prevalence of pneumonia with empyema. Here, we report the epidemiological and clinical characteristics of the infections between September 2022 and May 2023, as well as the main molecular characteristics and antimicrobial resistance of the S. pyogenes (Lancefield group A Streptococcus (GAS)) isolates.In line with reports from several other European countries , since lA nationwide prospective surveillance of piGAS in Portugal has been ongoing since January 2014. All paediatric departments are invited to notify piGAS with demographic data, clinical diagnosis and outcome, while clinical microbiology laboratories are requested to submit all GAS recovered from normally sterile sites for antimicrobial susceptibility testing and genomic sequencing. Confirmed and probable piGAS are defined according to recent guidelines [After a considerable decrease recorded during the seasons of 2019/20 to 2021/22 (September to August), piGAS in Portugal started to rise again in May 2022. From December 2022 to February 2023 there was a notable increase, and numbers thereafter remained much higher than the average of pre-pandemic years .Overall, between 1 September 2022 and 31 May 2023, 89 piGAS cases were recorded (85 were confirmed and four were probable), which is 4 times higher than the average for the same period in pre-pandemic seasons , and at least 2.5 times the number of cases in any of the previous complete seasons . The median age of the patients was 3 years (interquartile range (IQR): 2\u20136); 45 were males (50.6%) and 44 were females (49.4%).Clinical information was collected through a questionnaire included in the notification form, and was available for 79 cases . In lineThe median overall length of hospital stay was 10 days (IQR: 5\u201317). Paediatric intensive care unit (PICU) admission  and surgical interventions or drainage  were frequent.S. pyogenes and S. pneumoniae identified by PCR in the pleural fluid, and mild limb paresis in a child with a cerebral abscess. Four patients with pneumonia still had respiratory symptoms at 30 days follow-up.Three patients died within the first 24\u202fh of admission with streptococcal toxic shock syndrome (STSS), and one died at day 15 with complicated meningitis. Sequelae at 30 days were noted in 10/79 cases (12.7%), although the type and severity of sequelae were not directly included in our questionnaire and were not systematically reported. The reported sequelae included foot ischaemia requiring amputation in a child with STSS who had both Of the 85 confirmed cases, 13 were diagnosed by real-time PCR on culture-negative samples . Bacterial isolates were available for 55 of the 72 culture-positive cases.emm types and seven gene multilocus sequence types (STs) were retrieved from de novo assemblies [Supplementary materials). The lineages defined by emm1-ST28/1319 (n\u2009=\u200930) and emm12-ST36/242 (n\u2009=\u200912) together accounted for 76.4% of the isolates (the emm types and STs of each isolate can be found in Supplementary Table S1). Screening for the characteristic 27 M1UK sublineage SNPs (the number of SNPs found in each isolate is available in  Supplementary Table S1) [emm1 isolates as M1UK (emm1 isolates (data available in Supplementary Table S1), both belonging to the M1UK sublineage and not to the recently described speC-positive M1DK sublineage [emm12 isolates, analysed together with a dataset of emm12 genomes selected to represent the global diversity of this emm type [emm12 genomes from Denmark [Illumina sequencing was performed (data available in the European Nucleotide Archive (ENA); accession number PRJEB65018), and semblies  (detaile as M1UK . The genemm1 (12/28 cases (43%) vs 2/20 cases with other emm types (10%), Fisher\u2019s exact test, p\u2009=\u20090.02). There were no other significant associations of emm1 with clinical presentation or outcome, although all three deaths occurred in patients with this emm type.Among 48 cases with molecular and clinical information, PICU admission was more frequent among patients with Supplementary Table S1). Only tetracycline (n\u2009=\u20091) and norfloxacin (n\u2009=\u20092) resistance were identified; the first associated with the presence of the tet(M) gene while the latter with the S79F and A121V mutations in the parC gene.Antimicrobial resistance was tested in all available isolates by disc diffusion according to EUCAST guidelines   ,8-15. InRemarkably, this surge has not occurred simultaneously in all reporting countries. In the Netherlands, piGAS has increased since early 2022 , while iUK sublineage (47.3%). The association between emm1 and PICU admission observed in Portugal and Denmark [emm type, which remains significantly associated with invasive disease [emm12 isolates (21.8%) revealed a much higher genetic diversity when compared with emm1, with no apparent expansion of any sublineage. Given that emm12 was significantly associated with non-invasive infections in Denmark [As observed in other countries ,8-10,13, Denmark  supports disease ,18. The  Denmark , its abuThe absence of macrolide and lincosamide resistance among piGAS in 2022/23 follows the decreasing trend recorded among all-age invasive and pharyngeal infections in Portugal ,20 and iPortugal is experiencing an exceptionally pronounced and long surge of piGAS, with no signs of substantial reduction in spring of 2023, despite a brief, unexplained decrease in April. Therefore, GAS should remain one of the main suspected aetiological agents in children presenting with compatible clinical signs. The presence of pharyngitis or rash may be important clues for suspecting this agent. Together with data from other countries, our genomic analysis indicates that multiple sublineages are important in the post-COVID-19 multinational surge of piGAS."}
+{"text": "Preterm birth, one of the leading causes of admissions to the Neonatal intensive care unit, is a major contributor to neonatal morbidity and mortality in developing countries. This study aimed to find out the prevalence of premature neonates admitted to the Neonatal Intensive Care Unit of a tertiary care centre.This descriptive cross-sectional study was conducted from clinical records of preterm neonates (born before 37 completed weeks of gestation) admitted in the Neonatal Intensive Care Unit from 16 July 2020 to 14 July 2021. Following ethical approval from the Institutional Review Committee (Reference number: 077/78-018), the patient's clinical characteristics and systemic morbidities were recorded. Convenience sampling was done. Point estimate and 95% Confidence Interval were calculated.Among 646 admissions, the prevalence of preterm neonates was found to be 147 (22.75%) . The male: female ratio was 1.53:1. The median gestational age and birth weight were 33 weeks (Range: 24-36 weeks) and 1680 g respectively. A total of 73 (49.65%) delivery was followed by premature rupture of membrane. The morbidity due to respiratory problems was highest at 127 (86.39%), followed by metabolic at 104 (70.74%) and sepsis at 91 (61.90%). The renal system was the least affected 5 (3.40%).The prevalence of preterm neonates in the neonatal intensive care unit was higher than in other studies done in similar settings. The prognosis of these newborn has increased during the last three decades due to improvements in neonatal intensive care facilities, yet rates vary widely across different centres.7Compared to term, preterm newborn have a significantly increased risk of complications and death during the neonatal and post-neonatal period.This study aimed to find out the prevalence of premature neonates admitted in the neonatal intensive care unit of a tertiary care centre.This descriptive cross-sectional study was conducted in the Neonatal Intensive Care Unit (NICU) of Bharatpur Hospital, Chitwan, Nepal for a period of one year from 16 July 2020 to 14 July 2021. Data collection was started after receiving ethical approval from the Institutional Review Committee of Bharatpur Hospital (Reference number: 077/78-018). After informed consent from the parents or immediate caretaker, all newborn admitted to the NICU who were born before 37 completed weeks of gestation were enrolled in the study. Both in and out-born were included. Newborn previously admitted to another institute for more than 72 hours before transfer to our institute, who required referral for surgical problems and whose parents denied consent were excluded. The sample size was calculated by using the following formula:Where,n = minimum required sample sizeZ = 1.96 at 95% Confidence interval (CI)8p = prevalence of preterm neonates in NICU from the previous study, 16.48%q = 1-p,e = margin of error, 3%The calculated sample size 589, However sample size of 646 was included in the study.Patient particulars including weight at admission, gestational age, place and mode of delivery, need of resuscitation at birth etc. and maternal factors including age, gravida and parity, causes of preterm birth, pregnancy-associated complications, use of antenatal steroids etc.were recorded at admission to the NICU. Patients were followed till transfer/discharge or referral from the unit or till death. Systemic morbidities encountered during treatment in the NICU were followed and recorded.9 Clinical diagnoses were made based on the standard guidelines being used in the Unit. Relevant laboratory investigations and imaging techniques were used whenever necessary. Sepsis was diagnosed on clinical grounds along with C-reactive protein (CRP), complete blood count (CBC), positive blood culture, and cerebrospinal fluid (CSF) examination. Respiratory distress syndrome (RDS), meconium aspiration syndrome (MAS) and pneumonia were diagnosed by X-ray and ultrasound of the chest along with relevant laboratory and clinical findings. Congenital heart disease was confirmed by Echocardiography. Hypoglycemia was defined as a blood sugar level <45 mg/dl and hypocalcemia as total serum calcium <7 mg/dl.10 Gestational age and hour-specific bilirubin thresholds (adopted from AAP & NICE guidelines) were used to determine the need for phototherapy for Hyperbilirubinemia.12Gestational age was ascertained from the mother's first day of the last menstrual period (LMP). If the mother was uncertain of the LMP, an early trimester USG scan and maturity assessment using Modified Ballard Score were considered.Data was entered in Microsoft Excel version 2010 and analysed using IBM SPSS Statistics version 20.0. Point estimate and 95% CI were calculated.Among 646 total admissions in the NICU, the prevalence of preterm neonates was found to be 147 (22.75%) . The majority of mothers of the preterm neonates were from Province 388 (59.86%) and a total of 128 (87.07%) had their deliveries in a hospital setting .The mean age of the mothers was 24.50\u00b15.30 years, with a median gestational age of 33 weeks at the time of delivery (Range: 24-36 weeks). More than half of the mothers 80 (54.42%) were multigravida. Only about 70 (48.27%) mothers had \u22654 Antenatal care (ANC) visits. A total of 56 (38.09%) underwent caesarean section (CS), the commonest indication being previous CS 21 (37.50), followed by multiple pregnancies 10 (17.85) .Out of total preterm neonates admitted to NICU, 89 (60.54%) were male and 58 (39.45%) were female.The median age (in hours) and weight at the admission of the preterm neonates was 1 hr (Range: 0-72 hr) and 1680 gm (Range: 625-3125 gm) respectively. The most frequent cause of preterm delivery was premature rupture of membrane (PROM) 73 (49.65%), followed by spontaneous onset of labour 44 (29.93%) .The prevalence of respiratory morbidity was the highest 127 (86.39%), followed by metabolic 104 (70.74%) and infectious morbidity 91 (61.90%). Respiratory Distress Syndrome (RDS) and Apnea of prematurity (AOP) were the most common respiratory morbidities. The mean duration of NICU stay was 8.57\u00b17.55 days. The in-hospital mortality rate was 17 (11.56%) .13 A total of 147 preterm neonates (born before 37 weeks of gestation) fulfilling inclusion criteria were enrolled. The average gestational age of the study population was 33 weeks, which is consistent with the study population described in a similar study from Pakistan (32.4 weeks) and lower than similar other studies from Nepal and India (>34 weeks).15 There was male predominance in this study (60.5%) which is consistent with similar other studies from Nepal (56-74.5%) which might suggest that the male gender in Nepalese society gets more attention on the part of caregivers and is brought to seek health services.14In our study, the prevalence of preterm neonates was found to be 147 (22.75%). It is higher than the prevalence reported by similar studies from Nepal and Pakistan (16.4-20.3%).16The median birth weight of the study population was 1700 gm (range 675-3200 gm) which is lower than the study from BPKIHS, Dharan (181 gm) and Pakistan (1795 gm) but higher than a similar study from Lumbini Medical College, Nepal (1188.9 gm).8 However similar other studies from Nepal and India reported PIH as a more common cause of preterm birth (12.9-26%).16The most common maternal risk factor for preterm delivery was PROM (49.6%) followed by spontaneous onset of labour (30%) and multiple pregnancies (6.8%) which is consistent with the study done at Lumbini.14 However, the incidence of RDS and apnea of prematurity in the present study is greater than the similar studies from Nepal (32% and 7%), and India (38.3% and 9%).15 This might be due to the lower mean gestational age of our study population.In this study, 86.4% of all preterm infants had respiratory morbidities of which RDS, apnea of prematurity, and pneumonia were the commonest comprising 65.3%, 27.9%, and 12.9% respectively. This is consistent with the study conducted at TUTH, Nepal which also reported RDS as the most common morbidity among preterm infants.15At least one form of metabolic complication  was encountered in 70.7% of preterm infants. Among these, hyperbilirubinemia (51%) and hypoglycaemia (28.6%) were the commonest. This finding is consistent with similar studies from Nepal and other developing countries.14 Higher incidence of sepsis may be because of the inclusion of cases with clinical sepsis. Additionally, the unit receives a significant number of outborn neonates with sepsis referred from other centres.Sepsis was the second most common individual morbidity after RDS in this study occurring in almost two third of the cases, out of which only 6.5% had positive blood cultures. Among neonates who had sepsis, the majority (70%) were early onset. The occurrence of sepsis in the present study was higher as compared to similar studies from other centres of Nepal (37-40%) and Pakistan (28.6%).16 This study included cases of fluid refractory shock requiring inotropic support only, which could account for the lower incidence. PDA was the most common congenital heart defect found in the study population which is consistent with the finding in similar other studies.16Among other systemic morbidities, cardiovascular, gastrointestinal and neurological morbidities were encountered in 33%, 27.9% and 24.5% of the cases respectively. Around 20% of the neonates had shock which was lower in comparison to a study done in a similar population at BPKIHS, Dharan (43%).15 The incidence of NEC in this study is similar to the study from Pakistan (15.5%) but is higher than studies done at other centres in Nepal and India (2.2%-4%).15 The higher incidence of NEC may be due to the lower mean gestational age of our study population.Feed intolerance (15.6%) and NEC (14.3%) were the commonest GI morbidities consistent with similar other studies.15 However, the incidence of birth asphyxia in this study is higher compared to other studies (3.5%-9.7%).14 This might be because this unit receives a significant number of referred and complicated cases from birthing centres and hospitals of nearby districts.Birth asphyxia was the most common neurological morbidity in the present study, accounting for about 12% of all cases followed by seizures and IVH each accounting for 8%. A similar study from India also reported birth asphyxia and seizures in 11% of their cases.Our study was based on data from NICU at a single tertiary care facility with a small sample size within a limited time frame. So, it cannot be generalised to the broader prospect. Furthermore, since this is a descriptive study, we were unable to find associations between the variables and neonatal morbidities.The prevalence of preterm neonates in the Neonatal Intensive Care Unit was higher than in other studies done in similar settings."}
+{"text": "Premenstrual syndrome is the premenstrual disorder with wide range of prevalence world-wide leading to higher rates of work absences, higher medical expenses, and lower health-related quality of life. The aim of this study was to find out the prevalence of premenstrual syndrome among medical students of a medical college.A descriptive cross sectional study was conducted in a medical college among medical students using self-reported questionnaires based on American College of Obstetricians and Gynaecologists criteria for premenstrual syndrome, and 12-Item Short Form Health Survey for quality of life, from 1 January 2022 to 31 March 2022 after obtaining ethical approval from the Institutional Review Committee (Reference number: 207807955). Convenience sampling was used among students who met the inclusion criteria. Point estimate and 95% Confidence Interval were calculated.Among 113 patients, premenstrual syndrome according was seen in 83 (73.45%)  out of which, 56 (67.46%) showed mild premenstrual syndrome, and 27 (32.53%) had moderate premenstrual syndrome. The most commonly reported affective symptoms of premenstrual syndrome was irritability 82 (98.79%), while the somatic symptoms was abdominal bloating 63 (75.90%).The prevalence of premenstrual syndrome among medical students was similar to in the other studies done in similar settings. The medical students having a regular menstrual period at least in the last six consecutive months, enrolled full-time in undergraduate studies, unmarried were included in the study. While medical students having irregular menstrual cycle, currently pregnant, history of chronic illness, diabetes, high blood pressure, heart disease, thyroid disorder, history of current depression, anxiety, and any other psychiatric disorders, currently using a hormonal method of contraception were excluded from the study. Convenience sampling method was used. Total female students during the study period were 159 . The sample size was calculated using following formula:Where,n = minimum required sample sizeZ = 1.96 at 95% Confidence Interval (CI)p = prevalence taken as 50% for maximum sample size calculationq = 1-pe = margin of error, 5% nWhere,n'= adjusted sample size for a finnite populationN = Total study population1 PMS was diagnosed if at least one of the 6 affective  and one of these somatic symptoms  reported five days prior to the onset of menses in the three prior menstrual cycles and ceased within four days of onset of menses. The response to each PMS symptoms was scored as 0 for 'not at all' and 3 for 'severe' and the highest indicated score was used for calculation. A total score was calculated by summing the symptom scores and dividing by the mean number of symptoms, converting it to a percentage. Mild, moderate and severe PMS corresponded to 0-33%, 33-66% and >66% respectively. It also includes the checklist to mark whether the symptoms occurred one week before periods or after periods or due to other reasons The questionnaires adopted from Shorter Form (SF-12) health survey6 which has been widely used in many research fields to measure general quality of life was also used. It is a brief, well-validated and reliable generic questionnaire to measure general health status, and outcome information. It contains 12 items that measures physical and mental components of health . Physical component consists four sub groups: physical functioning, role limitation due to physical problems, bodily pain, general health perceptions; and Psychological component consists four sub groups: social function, general mental health, role limitation due to emotional problems and vitality. It also provides psychometrically-based physical component summary (PCS) and mental component summary (MCS) scores. The SF-12 is scored so that a high score indicates better quality of life.Thus the final adjusted sample sie was 113. Selfreported questionnaires was used which include the basic demographic and menstrual information of the participants. It consists of questionnaire incorporating all the PMS symptoms. The diagnosis of PMS was based on criteria listed by American College of Obstetrics and Gynecology (ACOG).Data were analyzed using IBM SPSS Statistics version 25.0. Point estimate and 95% CI were calculated.Among 113 female students, the prevalence of PMS was 83 (73.45%) . Out of which, 56 (67.46%) showed mild PMS .Severe PMS-The mean age of the female participants was 22.7\u00b11.3 years .Dysmenorrhea was present among 70 (84.3%) students. A total of 20 (24.1%) student had self-medication and 4 (4.80%) were absent from the college and 1 (1.20%) seek the doctor consultation .The most commonly reported affective symptoms with PMS were Irritability 82 (98.79%), Angry outburst 73 (87.95%), Anxiety 57 (68.67%) while the most commonly reported somatic symptoms were abdominal bloating 63 (75.90), breast tenderness 58 (69.87), Joint or muscle pain 47 (56.62%) .The mean value of PCS among student with PMS was 47\u00b16.8 .7 which reported prevalence of PMS to be 61.1%. This is also consistent with study done in KSA (2014),4 reported the prevalence of PMS as 78.5%. This study is not in agreement with the study done in India (2014),8 where only 22.3% were reported to have PMS. Also differs from the study done in Japan (2017),9 showed low prevalence of PMS as 25.2%. Another study in Nepal (2019),10 also showed 17.2% moderate to severe PMS with the rest 80.7% having no or mild PMS. The differences in prevalence could be due to the difference in the used questionnaire to assess PMS. Variation could also be due to differences in sample size as well as differences in biological, social, cultural and geographical factors among studies.The prevalence of PMS according to ACOG criteria in our study was 83 (73.45%), among which 56 (67.46%) showed mild PMS, 27 (32.53%) showed moderate PMS and none of them had severe form. This findings is consistent with the previous study done in Nepal (2017),12In our study, the frequency of PMS was found to be higher in students with history of dysmenorrhea 70 (84.3%) which is similar to previous studies.13 and Turkey.12 In a study done in medical students in India, the most frequent affective symptom was irritability (35%) and somatic symptom was breast tenderness (41%).14 The commonest affective symptom was irritability (81.2%) and somatic symptom was headache (77%) in a study conducted in another area of Nepal.7The most commonly reported affective symptoms with PMS were Irritability 82 (98.79%), angry outburst 73 (87.95%) while the most commonly reported somatic symptoms were abdominal bloating 63 (75.90), breast tenderness 58 (69.87) which is similar to previous studies done in india15 Study among medical students done in KSA (2014) showed scores in all subscales of SF-36 in the PMS group was significantly lower than those without PMS except for physical functioning subscale.4 Previous studies done in Turkey (2014),11 (2015),12 India (2019)16 and Brazil (2019)5also found significantly lower quality of life among students with PMS. This study showed that the burden of PMS on health-related quality of life was both on mental and physical health-related quality of life.The mean PCS and MCS score among student with PMS was 47\u00b16.80 and 43.30\u00b19.70 which is lower. Similarly, study done in Pakistan (2008) among medical students showed PCS and MCS scores were significantly lower in the PMS group.Our findings have some limitations because the population of this study included a highly selective sample of medical students from one academic institute, which will limit the generalization of the findings. Also questionnaire filling is likely to pose some bias during recall of symptoms.The prevalence of premenstrual syndrome among medical students was similar to other studies done in similar settings. Quality of life among students with PMS was poor thus strategies should be adopted for timely detection and effective management of PMS to ensure their well-being and efficiency."}
+{"text": "Eisenia fetida; sewage sludge (40%) + sawdust (10%) + biodegradable garden and park waste (50%) + Eisenia fetida; biodegradable garden and park waste (90%) + sawdust (10%) + Eisenia fetida. The final substrate compositions consisted of compost mixtures and deacidified peat(O) , serving as a structural additive, in different mass ratios (mass %). The produced plants underwent biometric and physiological measurements as well as enzymatic analyses of stress markers. Based on the conducted studies, it has been found that the substrate productivity depends not only on the content of nutrient components but also on their structure, which is moderated by the proportion of peat in the substrate. The most effective and promising substrate for cucumber seedling production was variant 2 (I), which consisted of 25% compost from sewage sludge (40%) + sawdust (10%) + biodegradable garden and park waste (50%) and 75% deacidified peat. Despite the richness of the other substrates, inferior parameters of the produced seedlings were observed. The analysis of the enzymatic activity of stress markers showed that these substrates caused stress in the plants produced. The study\u2019s results showed that this stress was caused by the presence of Eisenia fetida, which damaged the developing root system of plants in the limited volume of substrate (production containers). The adverse influence of Eisenia fetida on the plants produced could possibly be eliminated by thermal treatment of the compost, although this could lead to significant changes in composition.Compost has a broad application in terms of the improvement of the soil properties. This research work was conducted to present the molecular implications of using compost obtained from different substrates to improve soil parameters for cucumber seedlings cultivation. In the experiment, the following compost mixtures were used: sewage sludge (80%) + sawdust (20%); sewage sludge (40%) + sawdust (10%) + biodegradable garden and park waste (50%); biodegradable garden and park waste (90%) + sawdust (10%); sewage sludge (80%) + sawdust (20%) +  Cucumis sativus L.) is a widespread horticultural plant worldwide due to its economic and social significance [Seed cucumber  using advanced molecular methods.The aim of this study was to determine the impact of using innovative compost with varying organic matter compositions on selected physiological and biochemical parameters of cucumber seedlings (Cucumis sativus L.) was tested.It was hypothesized that compost derived from the mixed biowastes with the combination of deacidified peat affects the growth of vegetable seedlings. Therefore, the development of the composition of the mixture combination for cucumber cultivation (\u22121). The average content of Total Organic Carbon (TOC) and Total Nitrogen  in the peat was 55% and 2.30%, respectively, with a C:N ratio of 23.9. The average content of available forms of phosphorus (P) and potassium (K) was 46.9 and 33.0 mg 100 g\u22121, while the overall content of magnesium (Mg) and calcium (Ca) was 1.37 and 2.13 g kg\u22121. The properties of the substrates used in the experiment varied depending on the compost variant and its contribution to the resulting substrate. The determined pH values of the produced substrates ranged from 5.90 to 7.87. The lowest values were observed for substrate 4 (III), whereas the highest were noted for substrate 6 (III) . The content of K2O, on the other hand, was highest in substrates 2, 5, and 6, while Mg and Ca content were highest in substrate 6  . Meanwhistrate 6 .The content of microelements was also analyzed in the substrates produced in the experiment . The aveThe deacidified peat used in the experiment exhibited low levels of Pb, Cr, Cu, Ni, Cd, Zn, and Hg. In contrast, the use of composts in some cases significantly influenced the increase in the levels of these elements in the substrates used in the experiment. Among the analyzed variants, the substrate with the addition of compost 6 and peat exhibited the highest content of Pb and Cr. Meanwhile, in the substrate with the addition of compost 4, the highest levels of Zn, Cu, Cd, and Hg were observed compared to the other experiment variants. Additionally, the substrate with the addition of compost 3 recorded the highest average content of Ni compared to the other variants.The produced substrates significantly influenced the growth of cucumber plants during the initial stages of development. Cotyledons, which emerge from the developing embryo to initiate growth and development, mainly rely on stored materials within the seeds . HoweverA similar trend was observed regarding the influence of the employed substrates for producing cucumber seedlings on the surface area as well as the number and mass of leaves . The devEisenia fetida.The alteration of substrate structures made from composts was achieved by employing a structural additive. One of the most commonly used organic materials in horticultural production is peat , which w2 (first leaf) and 2538.1 mm2 (second leaf). Notably, the plants from the control group during the same period (21 days after sowing) produced only 1 leaf, with a mass and surface area 35.9% and 2600% smaller, respectively, than the values of these parameters for the plants in variant 2(I) ) for producing ground cucumber seedlings contained 25% compost (derived from sewage sludge (40%), sawdust (10%), and organic waste (50%)) and 75% deacidified peat. The use of this substrate led to the production of ground cucumber seedlings with the best biometric parameters . Ground ant 2(I) . This suant 2(I) . The incant 2(I) . Furthercomposts ,19,20. Hearchers .Eisenia fetida, which is used in the vermicomposting process.An important physiological parameter of plants that indicates their nitrogen status is the relative chlorophyll content in plant leaves ,24. Subs2 supply, light availability, and the presence of biotic and abiotic stress factors [The relative chlorophyll content in the aboveground biomass of plants serves as an indicator of their photosynthetic capacity ,26. Howe factors ,28. Inst factors ,30,31.Approximately 70% to 90% of the incoming solar radiation is absorbed by the leaf, with around 40% to 60% of this radiation being absorbed by the energy antennae, transferring energy to the PSII reaction centers. Under normal conditions without stress, most of the energy is used in photochemical reactions with only a small fraction being emitted as fluorescence or heat. In the presence of stress, the PSII reaction changes, altering the balance between PSII and PSI and the amount of energy emitted as heat and fluorescence . The subEisenia fetida, prompting the expansion of the study to include the analysis of biochemical stress markers. Kooten and Snel [Analysis of the obtained results indicates that the lowest maximal photochemical efficiency of PSII (Fv/Fm) was recorded for the leaves of ground cucumber seedlings A produceand Snel  suggest Enzyme activity measurements: catalases CAT, guaiacol peroxidase GPOX, and superoxide dismutase SOD can serve as markers of plant stress occurring during photosynthesis, one of the products of which is oxygen . This oxEisenia fetida, particularly in substrate variant 6, which was additionally the least nutrient rich. The impact of this compost is evidenced by the observed increase in CAT activity with the increasing proportion of this compost in the substrate composition  is also an enzyme involved in hydrogen peroxide decomposition . HoweverIn the experiment, seeds of the cucumber hybrid variety \u2018\u015aremski\u2019  were used as the seed material. This variety is a popular early cucumber variety known for its high fruit yield and characteristics that make it suitable for processing.A.Sewage sludge (80%) + Sawdust (20%);B.Sewage sludge (40%) + Sawdust (10%) + Biodegradable garden and park waste (50%);C.Biodegradable garden and park waste (90%) + Sawdust (10%);D.Eisenia fetida;Sewage sludge (80%) + Sawdust (20%) + E.Eisenia fetida;Sewage sludge (40%) + Sawdust10%) + Biodegradable garden and park waste (50%) + F.Eisenia fetida.Biodegradable garden and park waste (90%) + Sawdust (10%) + Compost was prepared using different organic matter in various mass proportions (% by mass):3 plastic containers for 3 months. The moisture of the organic matter under composting was monitored weekly. Temperature measurements confirmed the existence of four characteristic phases of composting process including mesophilic, thermophilic, cooling and maturation phases.The organic mixture was subjected to the controlled composting process in six 1 m1.(I): A (75%) + O(25%); (II): A (50%) + O (50%); (III): A(25%) + O (75%);2.(I): B (75%) + O(25%); (II): B (50%) + O (50%); (III): B(25%) + O (75%);3.(I): C (75%) + O(25%); (II): C (50%) + O (50%); (III): C(25%) + O (75%);4.(I): D (75%) + O(25%); (II): D (50%) + O (50%); (III): D(25%) + O (75%);5.(I): E (75%) + O(25%); (II): E (50%) + O (50%); (III): E(25%) + O (75%);6.(I): F (75%) + O(25%); (II): F (50%) + O (50%); (III): F(25%) + O (75%).Based on previously prepared compost and deacidified peat (O)  in various mass proportions (% by mass), substrates for cucumber seedling production were prepared as follows:Cucumis sativus L. seedling production was maintained at 60% of the maximum water-holding capacity (MWHC). The experiment was performed in 3 technological replicas testing six types of compost variants  in four application levels .A controlled pot experiment was conducted using the prepared substrates for cucumber seedling production. For this purpose, the prepared substrates were placed in production pots with a capacity of 0.5 L. Then, 3 seeds of the cucumber variety \u2018\u015aremski\u2019 were sown at a depth of 1 cm in each pot. The pots were placed in a greenhouse with an air temperature of \u00b120 \u00b0C and a relative humidity of 80%. The moisture level in the substrate used for After 21 days from the sowing date, a series of measurements and biochemical analyses were performed to determine the impact of the applied substrates on the produced cucumber seedlings.total) were determined with the dry combustion method using the Elementar Vario El Cube Analyzer . The content of Ca, Mg, Zn, Cu, Cr, Ni, Pb, Cd, and Hg in substrate samples was determined by the absorption spectrometric method using the Polarized Zeeman Atomic Absorption Spectrophotometer Hitachi Z-2000 models  after soil samples mineralization in HNO3. Then, the 1 g dry soil samples were weighed in PTFE containers. Afterwards, 10 mL HNO3 was added. The microwave system (CEM Mars 5 Microwave Digestion System) was used to prepare samples for Ca, Mg, Zn, Cu, Cr, Ni, Pb, and Cd analysis [The substrate samples were air-dried and then sieved through a 2 mm diameter mesh. After that, the samples were homogenized. In substrate samples, the following analyses were determined: pH value was determined in a 1:10 substrate\u2013water suspension using a 4221 pH meter . Electrical conductivity (EC) was analyzed in a 1:10 substrate\u2013water suspension with a HI 2316 EC-meter from Hanna Instruments . The total organic carbon (TOC) and total nitrogen content . The measurements were conducted on the 21st day after sowing and were replicated 20 times for each substrate variant..The measurement of selected chlorophyll fluorescence parameters  in cotyledons and leaves of cucumber seedlings was conducted according to the methodology described in the paper by Mat\u0142ok et al. . The mea2. The mass of cotyledons and leaves was determined using a laboratory-scale RadWag WTB200 . Individual cotyledons and leaves of cucumber seedlings were separated from the rest of the plant and weighed in 20 replications for each substrate variant. The results were presented in grams.The effect of the applied substrates for cucumber seedling production on the size of developed plants was determined through measurements of selected biometric characteristics of cotyledons and leaves. The area and mass of cotyledons and leaves of produced cucumber seedlings were assessed. Measurements of cotyledon and leaf area were conducted using a Leaf Area Meter\u2014AM350  in 20 replications for each substrate variant. The results were presented in mmThe preparation of samples and isolation of analytes from plant material were carried out according to the methodology described by Balawejder et al. .The level of activity of selected enzymes (superoxide dismutase (SOD), catalase (CAT), and guaiacol peroxidase (GPOX)) in the cotyledons and leaves of cucumber plants grown in different substrates was determined according to the methodology described by Balawejder et al. .One-way analysis of variance (ANOVA) was conducted at a significance level of \u03b1 = 0.05 using STATISTICA 13.1 software . The mean values calculated from the three independent replications were analyzed statistically by comparing the results between the variants of the experiment.In summary, while the research has successfully demonstrated the effectiveness of compost and deacidified peat in seedling production, it also highlights the importance of addressing potential stress factors caused by soil organisms. The findings provide valuable insights into optimizing the substrate composition for seedling cultivation and suggest practical applications for the agricultural industry. Further research may focus on mitigating the stress factors associated with these substrates to achieve even better results in seedling production."}
+{"text": "The late presentation of oral squamous cell carcinoma (OSCC) patients in Sudan, with advanced stages and wide field of cancerization (WFC), has a negative impact on these patients. The present study aimed to investigate the different clinical presentations of mucosal changes in WFC associated with OSCC in Sudanese patients.  This a prospective longitudinal study of 93 OSCC cases. Tumor's associated field of cancerization was identified and related clinical mucosal changes were described.  Out of the 93 patients, 57 (61.3%) were males and 36 (38.7%) were females. Eighty-two percent of the patients presented with stage IV tumors. Ninety-two patients had multiple sites involved in the oral cavity with overlap of sites involved. The Gingivobuccal mucosa (74.2%) was the most frequent site involved. Eighty-three (89.2%) of the lesions were surrounded by mucosal changes, of them 32 (38%) surrounded by a grizzle (mixed dark and white) discoloration and 21 (26%) were surrounded by a white-smoke discoloration followed by 17 (20%) and 13 (16%) surrounded by cotton-white and Caf\u00e9 au lait discolorations, respectively. Forty-four (47.3%) lesions had overlapping presentations and surrounded by erythematous patches.  The present study showed that OSCC patients in Sudan present with advanced lesions, mostly associated with WFC, particularly the Toombak dippers. The different mucosal changes seen in the WFC associated with OSCC in these cases are in accordance with the known five mucosal presentations. Malignancies of the oral cavity are considered worldwide a major health issue. Collectively, they rank as the sixth most common cancer globally . In SudaProspective longitudinal hospital-based study carried out at Khartoum Teaching Dental Hospital (KTDH). The main hospital and center of oral and maxillofacial surgical oncology in Sudan. The samples were selected after thorough clinical examination of the oral cavity and head and neck regions for clinically suspicious ulcerative lesions, which were associated with wide field change of the oral mucosa Figures  and 2. PP value. Descriptive statistics were conducted for variables: age, site, TNM staging, etc.Data were entered in a computer master sheet using SPSS version 26. Statistical analysis was set at 95% confidence level, 0.2, the width of the confidence interval, and the level of significance alpha is 0.05. Chi-square test was used to test the difference between categorical variables, and Fisher's exact test was used as an alternative test in case of sparse data. Multivariate analysis and logistic regression were performed for better prediction precision and to control confounders, and both were interpreted in the form of odd ratio and The present study is a prospective longitudinal hospital-based study. The material were patients of OSCC operated at KTDH in the period: November 2018 to April 2022. The study included 93 patients (186 specimens) with OSCC who were diagnosed and surgically treated at KTDH. The patients were 57 (61.3%) males and 36 (38.7%) females. The mean age of the patients at the initial diagnosis was 57.52\u00b1 years with a standard deviation of 12.506 and a minimum of 25 and maximum of 80 years. Regarding the social habits, 38 (39.9%) of the patients were snuff dippers, 19 (20.4%) were tobacco smokers, and 14 (15.1%) were alcohol drinkers . The meaNinety-two patients had multiple sites involved in the oral cavity with overlapping in the presentations and sites involved. The gingivobuccal mucosa and gingivolabial mucosa were the most frequent sites of OSCC associated with WFC; 69 (74.2%) and 58 (62.3%), respectively. The tongue and the floor of the mouth were involved in 23 (24.7%) and 26 (28%) patients, respectively. The palate was the least site involved where only eight (8.6%) cases were recorded in the series . AccordiRegarding the clinical presentation of OSCC lesions in the present study, all the 93 (100%) cases presented with an ulcer as a complaint; 83 (89.2%) of the lesions were surrounded by mucosal changes; of them, 32 (38%) were associated with a grizzle (mixed dark and white) discoloration , 21 26%, 17 20%.Also, of the overlapping presentations, 44 (47.3%) of the lesions were associated with erythematous patches, which highlighted the clinical presentation of a wide field of changes. Swelling and pain were reported among 18 (19.4%) of the patients, and numbness was reported by 22 (23.7%) of them . The meaThe characteristics of these malignant ulcers were as follows: 80 (86.0%) of the ulcers had everted edges and 13 (14.0%) had rolled edges. Most of the margins, 90 (96.8%), were irregular. The ulcer base characteristically had induration in 92 (98.9%) of the cases. Forty-one (44.15%) of the cases had fixation to the underlying anatomical structures. More than half of the lesions (57.0%) were endophytic and 40 (43.0%) were exophytic . Fifty-fDepending on the TNM staging AJCC the 8 edition, in the present study, of the cases, 71 (76.3%) patients presented with an advanced tumor size T4a, 19 (20.4%) cases presented with a tumor size T3, two cases (2.2%) presented with an advanced tumor size T4b, and one case (1.1%) presented with a tumor size T2. At the initial diagnosis, 68 (73%) patients presented with (N2) nodal involvement, 38 (40.9%) of them had N2a stage, and 22 (23.7%) had N1 early nodal involvement. The advanced N3 nodal disease was found in three (3.2%) of the cases. All the cases (93%\u2013100%) showed no distant metastasis (M0) . Of the P value\u2009=\u20090.02). No significant association between smoking and number of sites involved .Toombak-dippers have multiple sites involved more frequently, while non-Toombak-dippers tend to have single site involved; this difference was found to be significant . Patients who presented with white (cotton-white discoloration) patches were significantly at stage IVA (T4a/N0/N1/N2\u2009+\u2009M0) .Toombak-dippers their lesions were more frequently stage IV (T4a\u2009+\u2009N0/N1/N2\u2009+\u2009M0) cases; the difference between them and the nondippers was found to be significant . Ninety-two percent of the snuff dippers presented in the advanced stage IVa, and also 85% of the patients with white patches presented clinically with advanced and very advanced stages IVA and IVB.Multistep carcinogenesis is one of the most breaking through concepts in pathogenesis of cancer. It highlights the process by which the progression from a normal cell to a cancer cell by accumulation of genetic aberrations occurs . GeneticIn the present study, the commonest clinical presentation of OSCC lesions was an ulcer in 93 (100%) of the cases. The ulcer was usually (89.2%) associated with discoloration of the surrounding mucosa. In 32 (38%) cases, the associated discoloration was grizzle (mixed dark and white), in 21 26%) cases, it was white-smoke discoloration, and in rest 17 (20%) cases, it was a cotton-white discoloration. These presentations highlight the clinical characteristics of the wide mucosal alterations among Toombak-dippers as was described previously by Suleiman % cases, , who repRusso et al.  reportedToombak dipping is the most frequently reported risk habit of OSCC, followed by cigarette smoking. The majority of the patients in the present study had advanced stage IV tumors associated with WFC on the initial presentation. The commonest mucosal change of the WFC was grizzle (mixed dark and white) discoloration, commonly followed by white-smoke and cotton-white discolorations."}
+{"text": "Correction to: Sports Medicine 10.1007/s40279-022-01798-6Following online publication, some numerical errors were identified in paragraph 3 of the section entitled, \u201c3.2 Characteristics of Psychological Research Examining Taper\u201d.This paragraph, which previously read:n\u2009=\u200944), with only three articles examining coaches and one article examining both athletes and coaches. In total, the articles included 1531 athletes, of which 1062 (69%) were male and 496 were female (31%). Three studies , equating to 30 participants, did not report or make explicit the gender of the participants. A total of 34 coaches were included in studies . In one article using both an athlete and coach sample, 15 were female and eight were male [37]. The gender of the individual athlete and coach groups was not reported.Most (92%) articles used an athlete sample (Has now been updated to read:Most (92%) articles used an athlete sample (n\u2009=\u200944), with only three articles examining coaches and one article examining both athletes and coaches. In total, the articles included 1588 participants. Of these participants, 1548 were athletes (97%) and 40 were coaches (3%). Of the athletes, 1026 were male (66%) and 475 were female (31%). Of the coaches, 28 were male (70%) and 6 were female (15%). Across four studies , the gender of 47 athletes and six coaches was not reported or made explicit .These errors also affected the numbers reported in Table 2. Table The original article has been corrected."}
+{"text": "Globally around 40% of histoplasmosis has been reported in HIV population, with other risk factors being transplant recipients, immunosuppressive agents  and extreme of ages. Histoplasmosis in India has mostly been reported from the Gangetic plains .This current study was conducted in a tertiary care hospital of northern India between January 1, 2021 and December 31, 2022 to look at the epidemiology, clinical profile and treatment outcome of Histoplasmosis patients in a non-HIV cohort. This was a single centered, observational study. All patients with proven Histoplasmosis (according to EORTC/MSGERC 2019 criteria) were included.Baseline Characteristics: This study involved 20 patients with a mean age of 52.05 \u00b1 10.87 years with 70% being male. All the patients were from endemic areas of Gangetic belt in India. Majority of the patients (80%) were immunocompetent (Table 1). All cases (100%) were diagnosed on histopathology.The common reported complains were fever (75%), weight loss (70%), loss of appetite (75%), skin lesions (25%) and pain abdomen (15%). Mean duration of various symptoms was 3\u00b11.29 months. Hepato-splenomegaly was seen in 45% of cases followed by adrenal involvement (40%), enlarged lymph nodes (35%), skin and oral mucosa involvement (25%) . Out eight patients had who adrenal involvement, five patients (25%) had isolated involvement based on imaging (CT/PET-CT). Cytopenias was seen in upto 75% cases with around 40% had deranged liver functions (Table 2). The most common syndromic diagnosis was progressive disseminated histoplasmosis (PDH) seen in 13 patients with a median age of 49 (30-76) years.13 patients (65%) received induction with Amphotericin B  followed by switching to oral itraconazole and 7 patients (35%) got up front itraconazole. At a media follow up of 8 months, 40% of patients had completed treatment and one had patient died.In a high tuberculosis endemic county like India, Histoplasmosis pose a diagnostic challenge. Although the median time to diagnosis is longer (delay in diagnosis), the overall outcome is good. Majority of our patients were younger immunocompetent individual.All Authors: No reported disclosures"}
+{"text": "Rates of serious injection related infections (SIRI) in persons who use drugs (PWUD) have increased over the past two decades. Admissions for SIRI are an opportunity for screening and vaccination of preventable infections like hepatitis A virus (HAV), hepatitis B virus (HBV) and tetanus given significant barriers to preventive care in the outpatient setting for this population. The purpose of this study was to evaluate rates of screening and subsequent vaccination for hepatitis A, hepatitis B, and tetanus for PWUD admitted to the hospital for treatment of serous bacterial infection.We conducted a retrospective review of adult patients admitted for a bacterial infection requiring > 2 weeks of antibiotics with both infectious disease (ID) and addiction medicine consults. Data on patient demographics, screening recommendations, and testing and vaccination administration were collected via chart review.280 patients were eligible for inclusion. Of the 198 (70.7%) patients determined at risk for HAV, ID recommended vaccination for 21 (10.6%) and 15 (7.6%) received HAV vaccine during the admission. Of the 174 (62.1%) patients at risk for HBV, ID recommended vaccination for 32 (18.3%) and 25 (14.4%) received HBV vaccine prior to discharge. 88 patients (31.4%) had no documentation of prior tetanus vaccination and ID recommended tetanus vaccination for 3 (1.1%). 5 patients (1.8%) received a tetanus booster during admission. In univariable analysis, the strongest factor associated with HAV  and HBV  vaccination during admission was ID recommendation for vaccine.Screening and vaccination for HAV and HBV remains low in the inpatient setting, as does tetanus vaccination in high-risk patients. A large proportion of our population (70%) were at risk for one or more of these preventable infections. Given the limited access and significant barriers to healthcare in this vulnerable population, efforts should be taken to maximize inpatient screening and vaccination for HAV, HBV, and tetanus.Monica K. Sikka, MD, F2G: Grant/Research Support"}
+{"text": "These sentences previously stated:A correction was made in the \u201cOutpatient addiction counseling services are the most used form of gambling-specific help service (39.5% uptake). Self-help groups are the second most frequently used help service (21.1%).The corrected sentences appear below:\u201cOutpatient addiction counseling services are the most used form of gambling-specific help service (65.2% uptake). Self-help groups are the second most frequently used help service (34.8%).Discussion, third Paragraph. These sentences previously stated:Another correction was made in the \u201cTwenty three individuals, (10.7% of the sample who participated in the second wave of the survey) reported using help services. The most widely used forms of support were specialized addiction centers, which by their nature included psychotherapists and psychiatrists (39.5%), followed by self-help groups (21.1%) and remote counseling services (10.5%). 10.5% of respondents reported having sought support from significant others.\u201dThe corrected sentences appear below:\u201cTwenty-three individuals, (10.7% of the sample who participated in the second wave of the survey) reported using help services. The most widely used forms of support were specialized addiction centers, which by their nature included psychotherapists and psychiatrists (65.2%), followed by self-help groups (34.8%) and remote counseling services (17.4%). 17.4% of respondents reported having sought support from significant others.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "International Classification of Diseases 10th edition (ICD-10) is widely used to describe the burden of disease.To describe how well ICD-10 coding captures sepsis in children admitted to the hospital with blood culture-proven bacterial or fungal infection and systemic inflammatory response syndrome.Secondary analysis of a population-based, multicenter, prospective cohort study on children with blood culture-proven sepsis of nine tertiary pediatric hospitals in Switzerland. We compared the agreement of validated study data on sepsis criteria with ICD-10 coding abstraction obtained at the participating hospitals.p\u2009<\u20090.05). The estimated national incidence of sepsis, inferred from ICD-10 coding abstraction, was 12.5 per 100,000 children (95%-CI 11.7\u201313.5) and 21.0 per 100,000 children (95%-CI 19.8\u201322.2) using validated study data.We analyzed 998 hospital admissions of children with blood culture-proven sepsis. The sensitivity of ICD-10 coding abstraction was 60% (95%-CI 57\u201363) for sepsis; 35% (95%-CI 31\u201339) for sepsis with organ dysfunction, using an explicit abstraction strategy; and 65% (95%-CI 61\u201369) using an implicit abstraction strategy. For septic shock, the sensitivity of ICD-10 coding abstraction was 43% (95%-CI 37\u201350). Agreement of ICD-10 coding abstraction with validated study data varied by the underlying infection type and disease severity (In this population-based study, we found a poor representation of sepsis and sepsis with organ dysfunction by ICD-10 coding abstraction in children with blood culture-proven sepsis when compared against a prospective validated research dataset. Sepsis estimates in children based on ICD-10 coding may thus severely underestimate the true prevalence of the disease.The online version contains supplementary material available at 10.1007/s44253-023-00006-1. As evidenced by the COVID-19 pandemic, effective responses of healthcare systems rely on robust surveillance systems and databases. For sepsis, one of the most common diseases causing morbidity and mortality globally, most countries do not have a surveillance system or national database. Surveillance is often done indirectly using the International Statistical Classification of Diseases and Related Health Problems (ICD) coding . In a reInfections remain one of the leading causes of death in childhood . Sepsis,We aimed to assess the accuracy of ICD coding abstraction for the diagnosis of sepsis in children using data from the Swiss Pediatric Sepsis Study, a prospective, population-based cohort study on blood culture-proven sepsis in children . We hypoThe Swiss Pediatric Sepsis Study, a multicenter prospective cohort study in ten pediatric centers in Switzerland, investigated the epidemiology of sepsis in children from November 2011 to December 2015 . The stuFor this secondary analysis, we only included data on sepsis episodes with full information on organ dysfunction and if ICD-10 discharge codes were available. We followed the Standards for Reporting Diagnostic Accuracy statement .During the study years, ICD-10 with German modification codes was used to encode 1 main and up to 49 secondary diagnoses of every hospital stay in the medical statistic dataset of participating hospitals. All hospitals in Switzerland must submit this data to the Federal Office of Statistics annually . ICD codAll children included in the Swiss Pediatric Sepsis Study experienced sepsis as defined by the 2005 IPSCC, and investigators prospectively assigned organ dysfunctions according to the 2005 IPSCC criteria , 17, 18.For the ICD-10 coding abstraction of bacterial or fungal infection, we used pathogen-specific sepsis codes, pathogen-specific codes not associated with sepsis, and unspecific codes for bacterial infections . For the ICD-10 coding abstraction of sepsis, we used the combination of ICD-10 codes for bacterial and fungal infection and SIRS codes  and/or septic shock (A483). For the ICD-10 coding abstraction of sepsis with organ dysfunction, we compared an \u201cexplicit\u201d coding strategy\u2014using a combination of ICD-10 codes for bacterial or fungal infection with ICD-10 codes specifically designed to capture SIRS and sepsis with organ dysfunction \u2014with an \u201cimplicit\u201d coding strategy, additionally including a selection of ICD-10 codes for specific organ dysfunctions .We have presented descriptive statistics of continuous data as median with interquartile range (IQR) and of categorical data as frequency with percentage. We calculated sensitivity, specificity, accuracy, positive and negative predictive values, and positive and negative likelihood ratios of explicit and implicit ICD-10 coding abstraction for sepsis with organ dysfunction using the validated Swiss Pediatric Sepsis Study data as a reference standard. For binomial proportions and likelihood ratios, we calculated corresponding 95% confidence intervals (CIs) , 20.p values based on likelihood ratio tests.To explore the agreement of ICD-10 coding abstraction with validated study data in different subgroups of the Swiss Pediatric Sepsis Study population, we fitted multivariate binomial regression models. We defined agreement strictly as concordance with the validated study data with one exception: For implicit ICD-10 coding abstraction, we allowed for the absence of organ dysfunction in the validated study data because organ dysfunction might have had other reasons than sepsis. We included the patient risk category, acquisition of the infection in the hospital, presence of an organ dysfunction, ICU admission, pathogens, site of infection, and death as explanatory variables. To correct for the correlation between multiple observations at the same hospital, we used a random effect. We have presented the results of regression analysis as odds ratios (ORs) with 95%-CIs and We calculated the incidence of blood culture-proven bacterial sepsis for the study years 2012\u20132015. To calculate age-specific incidence, we divided the number of annual admissions with sepsis in the study by the end-of-year resident population in Switzerland in the respective age groups . We calcp value less than 0.05 significant. We did all analyses and plots with R version 4.2.2 [We considered a two-sided on 4.2.2 .During the 52-month study period, 1005 episodes of blood culture-proven sepsis in 998 hospital admissions met the eligibility criteria . Based on ICD-10 coding abstraction, the 30-day case fatality ratio in children with sepsis was 8% (95%-CI 6\u201311) (50 of 596), although 25% (17 of 67) deaths in children with sepsis were not captured. The sensitivity of the ICD-10 coding abstraction of bacterial and fungal infections varied by pathogen and was better in children admitted to the ICU  admissions were assigned an ICD-10 code for a bacterial or fungal infection, with a correct representation of the causative pathogen in 832 . A total of 596  admissions, including 379  admissions with research-confirmed organ dysfunction, were assigned an ICD-10 code for sepsis. The sensitivity of ICD-10 coding abstraction for sepsis increased from 53% (95%-CI 47\u201360) in 2012 to 65% (95%-CI 59\u201370) in 2015 (p\u2009=\u20090.2). In hospital admissions assigned explicit ICD-10 codes for sepsis with organ dysfunction, the case fatality ratio was 18% (95%-CI 14\u201324) (40 of 221) although 39% (26 of 66) deaths in children with sepsis with organ dysfunction were not captured. The agreement of explicit ICD-10 coding abstraction with validated study data varied by site of infection, pathogen and risk category and was better in children admitted to ICU and in children who did not survive  admissions with research-confirmed sepsis with organ dysfunction had been assigned explicit ICD-10 codes for sepsis with organ dysfunction with an accuracy of 60% (95%-CI 57\u201363) (Table 9% admissp\u2009=\u20090.5). In hospital admissions assigned implicit ICD-10 codes for sepsis with organ dysfunction, the case fatality ratio was 14% (95%-CI 11\u201317) (58 of 426), although 12% (8 of 66) deaths in children with sepsis with organ dysfunction were not captured. The agreement of implicit ICD-10 coding abstraction of sepsis with organ dysfunction varied by risk category was better in children who did not survive and if sepsis was hospital-acquired  admissions with research-confirmed sepsis with organ dysfunction had been assigned implicit ICD-10 codes for sepsis with organ dysfunction with an accuracy of 74% (95%-CI 72\u201377) (Table ed Table .Children suffered from septic shock in 215 (22%), from respiratory dysfunction in 377 (38%), from hematological dysfunction in 286 (29%), from central nervous system dysfunction in 144 (14%), from hepatic dysfunction in 98 (10%), and from renal dysfunction in 71 (7%) hospital admissions. The sensitivity of explicit ICD-10 codes for septic shock was 43% (95%-CI 37\u201350) while it was 54% (95%-CI 48\u201361) for implicit ICD-10 coding abstraction of cardiovascular dysfunction. The sensitivity of implicit ICD-10 coding abstraction was 27% (95%-CI 22\u201331) for respiratory dysfunction, 53% (95%-CI 47\u201359) for hematological dysfunction, 8% (95%-CI 4\u201313) for central nervous system dysfunction, 13% (95%-CI 8\u201322) for hepatic dysfunction, and 58% (95%-CI 46\u201369) for renal dysfunction. The number of organ dysfunctions present was poorly represented by implicit ICD-10 coding abstraction . The estimated national annual incidence of blood culture-proven bacterial sepsis was 21.0 per 100,000 children (95%-CI 19.8\u201322.2) based on validated study data, compared to 12.5 per 100,000 children (95%-CI 11.7\u201313.5) based on ICD-10 coding abstraction of sepsis. The estimated national incidence of blood culture-proven bacterial sepsis with any organ dysfunction was 12.0 per 100,000 children (95%-CI 11.1\u201312.9) based on validated study data, 4.6 per 100,000 children (95%-CI 4.1\u20135.2) based on explicit, and 8.9 per 100,000 children (95%-CI 8.2\u20139.7) based on implicit ICD-10 coding abstraction of sepsis with organ dysfunction. Overall, the incidence of sepsis was underestimated by ICD-10 coding abstraction across all age groups  and not necessarily as septic \u201326.Even for cardiovascular dysfunction, which represents the only sepsis-associated organ dysfunction that can be coded specifically with the ICD-10 system, the sensitivity of explicit ICD-10 code was only 43%. While other organ dysfunctions associated with sepsis are not explicitly represented by the ICD-10 code, we found wide variations in the sensitivities of implicit ICD-10 coding abstraction for specific organ dysfunctions. This was especially accentuated in neonates, where the lack of agreed criteria and scoring systems for organ dysfunction  clashes There is some evidence that hospital claims for sepsis may be biased towards more severely ill patients . This isICD-11 , endorseSeveral limitations of this study need to be considered. First, the organization of the healthcare system in Switzerland and differences in demography and epidemiology of childhood sepsis may limit the generalizability of our findings to other settings. Second, organ dysfunctions captured by implicit ICD-10 codes for sepsis may reflect organ dysfunction resulting from other causes. Third, all children had blood culture-proven sepsis, preventing the calculation of specificity, accuracy, predictive values, and likelihood ratios of ICD coding abstraction of sepsis without organ dysfunction. Fourth, we could not assess the quality of ICD coding abstraction of sepsis due to viral infections or culture-negative sepsis. Given the over-representation of codes for bacterial infections in ICD-10, it is likely that we overestimated the accuracy of the ICD-10 abstraction of sepsis.We found a poor representation of sepsis with organ dysfunction by ICD-10 coding abstraction in children with bacterial sepsis in Switzerland. Based on our data, it is likely that studies assessing sepsis in children based on ICD-10 code abstraction severely underestimate the true burden of disease and that findings will not be comparable to estimates based on ICD-11. New definitions of sepsis in children should prioritize applicability to all clinical settings, to enable clinicians to correctly recognize and report sepsis, which will in turn improve medical coding.Additional file 1: Supplementary Methods.Table S1. Determinants of agreement of ICD-10 codes with pathogens detected in blood culture in neonates and children with sepsis. Table S2. Determinants of agreement of ICD-10 codes with prospective clinical diagnosis of sepsis in neonates and children. Fig. S1. Study flowchart. Fig. S2. Mosaic plot of the number of organ dysfunctions present according to implicit ICD-10 coding abstraction compared to validated study data 7. STARD Checklist."}
+{"text": "Clostridioides difficile infection (CDI) do not provide specific guidance for total duration of oral vancomycin (VAN) TX in patients requiring prolonged concomitant systemic antibiotics (cABX), as limited evidence exists.IDSA guidelines for the treatment (TX) of Enterococci (VRE) isolation and all-cause mortality at 6 months.This was a retrospective study of adult patients with an initial episode of CDI from 2017 to 2022 at NYU Langone Health. Patients were included if they received CDI TX with oral VAN  and > 72 hours of cABX . Prescribing of VAN TX was described as standard duration  vs prolonged duration . The primary outcome was CDI recurrence within 8 weeks of TX completion. Secondary outcomes included risk factors for recurrence, and VAN-resistant After screening 1,350 patients, 218 were included . The median age was 65 years (IQR 54-72), the median Charlson comorbidity index was 4 (2-6), 52% were immunocompromised, 32% required intensive care unit admission, and 66% received high-risk ABX with no differences between groups for any baseline characteristic. Non-severe, severe, and fulminant CDI occurred in 39%, 36%, and 25%, respectively. Patients who received PD had significantly more carbapenem use , a longer duration of ABX overlap with VAN TX , and more infectious disease consultation . After ABX completion, 147 (67%) patients continued VAN TX for a median of 7 (5-10) days, and 30 (14%) patients continued VAN prophylaxis for a median of 6 (5-14) days. Recurrence occurred in 20 (9%) patients, isolation of VRE in 14 (6%), and mortality in 21 (10%), with no statistical differences between SD and PD arms. Stopping VAN prior to completion of ABX was identified as a risk factor for recurrence on univariate analysis .Our findings suggest that in this high-risk cohort, continuation of VAN after completion of systemic antibiotics may decrease risk of recurrence. Prospective studies are needed to determine optimal VAN TX durations and alternative strategies to reduce CDI recurrence in patients who require cABX.All Authors: No reported disclosures"}
+{"text": "This study describes the changing pattern of non-tuberculous, or atypical, mycobacteria (NTM) lymphadenitis over the past five years in Northeast Ohio and analyzes factors that may be associated with this change. Particular attention will be paid to any demographic or geographic associations that can be linked with this pattern, to assess for any changing epidemiology.A retrospective chart review was completed including patients presenting to our tertiary medical center over the past five years. Patients with clinical presentation of lymphadenitis in the context of laboratory documented nontuberculous mycobacterial infection, or presumed infection, were included in the review.Thirteen patients with NTM lymphadenitis presenting in Northeast Ohio were identified during the five years from 2017 to 2022. Three patients (23.1%) presented between 2017 and 2019, while ten patients (77%) presented between 2020 and 2022. The median age on presentation was 16 months old (range of 12 to 40 months). Six were male (46.2%) and seven were female (53.8%). Nine (69.2%) had positive wound cultures for Mycobacterium avium complex (MAC) and four (30.8%) were managed presumptively. Four (30.8%) were managed with medication alone, four (30.8%) were managed with surgical excision alone, and five (38.5%) were managed with both medication and surgical excision. Seven (53.8%) were treated with rifampin and azithromycin, one was treated with clarithromycin and rifabutin, and one was treated with azithromycin and ethambutol. Eight (61.5%) underwent surgical excision. Five (38%) lived within 4 miles of Lake Erie and 8 (62%) lived within 7.5 miles of Lake Erie.Thirteen cases of NTM lymphadenitis were identified over a five-year period in Northeast Ohio. The incidence increased from the years 2017-2019  to 2020-2022 . Of the patients, 30.8% (n=4) responded to medication alone and 30.8% (n=4) responded to surgical excision alone, with 38.5% (n=5) requiring both medication and surgical excision. Medical therapy included combination therapy with macrolide in all cases. It is unclear if the geographic proximity to Lake Erie is contributing to the cases of NTM lymphadenitis in our area, but this needs to be further elucidated.All Authors: No reported disclosures"}
+{"text": "To review the strategies for controlling COVID-19 transmission among doctors involved in aerosol generating procedures.A cross-sectional study was conducted in Pakistan Institute of Medical Sciences, Islamabad from September to November 2020, using a 21-itemed initially piloted self-administered questionnaire designed on Google forms. It was shared with doctors involved in Aerosol generating medical procedures (AGMPs) by using social media applications. After the data was collected, it was analyzed using SPSS version 21.A total of 136 doctors participated in the study that included 59 female and 77 male participants. Our 67 (49.3%) participants screened their patients for signs and symptoms of COVID-19 before a routine checkup. The most common disinfectant used for reusable medical equipment by 62 (45.6%) respondents was alcohol swab, 57 (41.9%) did not disinfect reusable equipment and 17 (12.5%) used Dettol water spray.Majority of the doctors involved in AGMPS are not following the guidelines provided by international and national bodies. As such adherence to guidelines can help prevent COVID19 transmission in frontline doctors especially those involved in aerosol generating procedures. COVID-19 is a highly contagious viral respiratory disease,9COVID-19 is caused by SARS-CoV-2 that belongs to Corona family.10Health care workers are at a persistent occupational threat of developing COVID-19.1th among the affected countries.Pakistan is ranked 28A cross-sectional study was conducted in PIMS from September to November, 2020. The study participants were the doctors of Pakistan involved in Aerosol generating medical procedures. Ethical approval was taken from the Hospital Ethical Committee, Pakistan Institute of Medical Sciences . Sample size of the study was calculated to be 136 using WHO sample size calculator keeping 95% confidence level and 7% margin of error. After a detailed literature review on international and national guidelines on performing aerosol generating procedures a 21-itemed self-made questionnaire was designed on Google forms as in this era of pandemic it was not advisable to collect the data manually. After successfully designing the questionnaire, a short pilot study was conducted on doctors involved in AGMPs. However, they were not included in the final analysis. After some minor changes the link was shared with Pakistani doctors involved in AGMPs by sending the link on social media applications. Convenience sampling was the sampling strategy. Doctors from different specialties including ENT, anaesthesia, dentistry, intensive care, pulmonology, medicine, surgery, paediatrics, neurosurgery and general duty, related to different types of health care facilities were contacted from different cities of Pakistan including Islamabad/Rawalpindi, Karachi, Faisalabad, Peshawar and Gujrat to take part in the study. Sign-in from email account was made mandatory in order to avoid data doubling from the respondents. Once the response of pre-decided sample size was achieved the option of accepting response was disabled. The data was copied from response sheet of Google docs and transferred to SPSS-21. Using SPSS-21 the data was analyzed and descriptive analysis was performed.A total of 136 doctors participated in the study that included 59 female and 77 male participants. Regarding the type of health care facility, 47 (34.6%) were working in surgical units, 25 (18.4%) in medical units, 15 (11%) in operation theatres, 15 (11%) in procedure rooms, 12 (8.8%) in OPDs and 10 (7.4%) in emergency rooms. The city of practice of 61 (44.9%) respondents was Islamabad/Rawalpindi, 32 (23.5%) were from Faisalabad, 28 (20.6%) from Karachi, nine (6.6%) from Peshawar and six (4.4%) from Gujrat. According to 67 (49.3%) participants, patients at their work place are screened for signs and symptoms of COVID-19 before a routine checkup.If the practicing doctor came to know that patient might be a carrier of COVID-19, 77 (56.6%) participants referred the patient to infection control department, 39 (28.7%) deferred the patient for self-quarantine and 20 (14.7%) examined the patient. If the patient coming to respondents showed milder symptoms suggestive of COVID-19, 110 (80.9%) respondents referred the patient to infection control department, 21 (15.4%) examined the patient and four (2.9%) deferred the patients to self-quarantine for 14 days.Participants involved in aerosol generating procedures that included tracheal intubation, nebulizing treatment, airway management, tracheostomy, bronchoscopy, sputum collection, dental procedure, CPR, chest intubation and Ultrasound guided Chest intubation are shown in The disinfectant used for reusable dedicated medical equipment  by 62 (45.6%) respondents was alcohol swab, 57 (41.9%) did not disinfect reusable equipment and 17 (12.5%) used Dettol water spray.According to our respondents the frequency of frequent hand contact surfaces decontamination was done after every procedure in 31 (22.8%), weekly in 26 (19.1%), twice daily in 23 (16.9%), thrice daily in 21 (15.4%), daily in 21 (15.4%), rarely in 12 (8.8%) and twice a week in two (1.5%) cases. For cleaning such surface\u2019s wet mop was used in settings of 57 (41.9%) respondents, alcohol in 39 (28.7%), Dettol water in 15 (11%), detergent in nine (6.6%) and dry mop in four (2.9%).The frequency of minimal hand contact surfaces decontamination was performed daily in 51 (37.5%), weekly in 46 (33.8%), after every procedure in 15 (11%), twice daily in 11 (8.1%), thrice daily in six (4.4%), twice weekly in five (3.7%) and rarely in two (1.5%) of cases. For cleaning such surfaces diluted phenyl water was used in 63 (46.3%), sodium hypochlorite in 28 (20.6%), alcohol based cleanser in 17 (12.5%), soap water in 15 (11%), detergent in seven (5.1%), hydrogen peroxide in four (2.9%) and diluted sodium hypochlorite in 2 (1.5%) settings.The burden of a recent pandemic on a third world country like Pakistan with incapacitated health system is held up by the health care workers. Due to scarcity of health care facilities, the already existing ones pose a great risk of contagion to HCWs, patients and their attendants due to overcrowding. Poor aeration of health care facility, prolonged exposure and non-compliance of SOPs make the matter worse. According to the American Society of Testing and Materials guidelines as discussed by Romano,UK guidelinesThe hand hygiene has been made essential by World Health Organization at five moments,1As for soap and water, the recommended duration of cleaning is 60 to 90 seconds. Local authorities for making infection control guidelines also make it clear that using hand gloves is not a substitute for hand hygiene. Hand hygiene is a must, where and when needed as recommended by World Health Organization.18According to the guidelines set by NHRSC all the non-clinical reusable medical equipment should be decontaminated using alcohol with concentration of 60-90%. Our study depicts that respondents did not strictly follow these national guidelines as 41.9% of participants did not decontaminate these items.2O2 or 60-70% alcohol or 0.1% sodium hypochlorite eliminates virus as they act against the lipid component of virus and destroys it.10For cleaning the surfaces regular use of 5% HNational Institute of Health (NIH) Pakistan in its guidelines mentions chlorine based solutions as having more antimicrobial effect including both enveloped and non-enveloped viruses as compared to alcohol. More than two fifths i.e., 45.6% of our participants used alcohol to disinfect medical equipment. Some of the advantages of alcohol are that it is non-toxic, effective for surfaces or equipment, rapid bactericidal and low cost. This explains the trend of using alcohol by our respondents.18Procedures with lower risk of contagion include airway placement, suctioning, CPR.7In addition to upper GI procedures, lower GI procedures are also considered as high risk but are not included in AGMPs. As along with the body secretions and aerosols, fomites and faeces  can also transmit the infection,For dentists, as eyes and nose are the most affected facial areas where aerosols produced during procedures are radiatedDisinfection of procedure room or Operating theatres should be done at least thrice daily for minimum 30 minutes with disinfectant containing chlorine content in liquid.18Limitations of our study include small sample size as data was collected from doctors of different specialties from only five cities of Pakistan that reduces the generalizability of the results. Regarding the use of PPEs, their reuse was not questioned at all whether these were reused and if reused, whether regularly decontaminated or not.Majority of the doctors involved in AGMPS are not following the guidelines provided by international and national bodies. As such adherence to guidelines can help prevent COVID19 transmission in frontline doctors especially those involved in aerosol generating procedures.MH: Conceptualization of study, data collection, statistical analysis, manuscript writing, and accountable for the accuracy of study.SHW and MS: Edited, reviewed and finally approved the manuscript.FS: Performed data collection and participated in manuscript writing."}
+{"text": "Despite continued efforts to improve the safety of catheter ablation, pericardial tamponade remains one of its more frequent, potentially life-threatening complications. Management of cardiac tamponade is not standardized and uncertainties regarding acute treatment remain.This survey sought to evaluate the management of cardiac tamponade in German EP centers via a standardized postal questionnaire. All 341 identified German EP centers were invited to return a questionnaire on their standards for the management of cardiac tamponade.A total of 189 German EP centers completed the questionnaire. Several precautions are followed to avoid pericardial tamponade: A minority of centers preclude very old patients (19%) or those with a high body mass index (30%) from ablation. Non-vitamin K antagonist oral anticoagulants are briefly paused in most centers (88%) before procedures, while vitamin K antagonists are continued. Pericardial tamponade is usually treated using reversal of heparin by applying\u00a0protamine (86%) and pericardiocentesis under both, fluoroscopic and echocardiographic guidance (62%). A pigtail catheter is mostly inserted (97%) and autotransfusion of aspirated blood is performed in 47% of centers. The decision for surgical repair depends on different clinical and infrastructural aspects. The timing of reinitiation of anticoagulation widely differs between the centers. Approximately 1/3 of centers prescribe nonsteroidal anti-inflammatory agents, colchicine or steroids after pericardiocentesis.The present survey shows that the management of cardiac tamponade is still inhomogeneous in German ablation centers. However, multiple findings of this survey can be generalized and might guide especially less experienced operators and centers in their treatment and decision strategies. Catheter ablation is a well-established strategy for the treatment of cardiac arrhythmias , 2 that Management of cardiac tamponade is not standardized and uncertainties remain such as epicardial puncture technique, reversal of heparin effects, the use of autotransfusion and its modalities, timing of involvement of cardiac surgery in severe cases and postprocedural management .This survey sought to evaluate the management of cardiac tamponade in German ablation centers via a standardized questionnaire including queries on precautions, periprocedural and postprocedural management of cardiac tamponade (questionnaire in supplement).This physician-based survey was conducted by sending out questionnaires to all 341 identified hospitals in Germany performing electrophysiological procedures as assessed via a white list. The questionnaire including 46 questions is shown in the supplementary material. The postal questionnaires were sent to all identified centers and up to two reminders were sent out, in case a center did not answer within 3\u00a0months. The results were obtained anonymously. The survey results are displayed as categorial values (numbers and proportions).A total of 341 German ablation centers were identified and 189/341 (55%) datasets from responding centers were included into our analysis. An overview of the annual EP-procedure load of the centers is given in Fig.\u00a0With 133/189 (70%), many of the EP centers report on having dedicated EP laboratories. An overview of qualification levels of EP physicians is given in Suppl. Figure\u00a01. Of note, 44% of centers have a dedicated EP nursing team.The technical infrastructure in view of EP mapping and ablation platforms varies substantially between the centers. Radiofrequency current with or without a 3D mapping system is used in 174/189 (92%) and cryoballoon in 151/189 (80%) institutions. In contrast, laser balloon ablation is applied in only 9/189 (5%) of the centers, while 6/189 (3%) institutions report to use other ablation systems.In 132/189 (70%) centers, the body mass index (BMI) does not serve as an exclusion criterion for any kind of EP-procedure. However, 57/189 (30%) EP centers report BMI limits: 13/57 (23%) centers have fixed BMI limits for all kind of EP-procedures (BMI of\u2009\u2265\u200930.0 in 1/13 (8%) centers,\u2009\u2265\u200935.0 in 2/13 (15%) and\u2009>\u200940 in in 10/13 (77%) centers), while 44/57 (77%) centers have BMI limits only for left atrial and/or ventricular procedures. Of these, 1/44 (2%) centers state a BMI\u2009\u2265\u200934.9, 19/44 (43%) a BMI range of 35.0\u201339.9 and 21/44 (48%) centers a BMI\u2009\u2265\u200940 as an exclusion criterion. Another center has no fixed BMI limits, one center has only limits for AF procedures and one center did not further specify.Age as an exclusion criterion for EP-procedures was reported by 35/189(19%)\u00a0centers. Age as well as INR limits of the centers are given in Fig.\u00a0Non-vitamin K antagonist oral anticoagulants (NOACs) are paused in 166/189 (88%) of the centers before the procedure, while 23/189 (12%) centers perform interventions on uninterrupted NOAC treatment. Among centers that withhold OAC, 28/166 (17%) pause OAC the day before, 41/166 (25%) pause the evening before and 85/166 (51%) pause on the day of the procedure. 8/166 (5%) centers apply other strategies and 4/166 (2%) do not further specify. Post-intervention OAC is started immediately following the procedure in 26/189 (14%) centers, after defined time ranges in 102/189 (54%) centers  and the following day in 42/189 (22%). In 19/189 (10%) centers no information on postinterventional anticoagulation was provided.An overview of imaging and monitoring modalities as well as the type of diagnostic catheters used for transseptal puncture by the EP centers is provided in Suppl. Figure\u00a03. A total of 111/189 (59%) centers use fluoroscopy alone to guide transseptal puncture, while 56/189 (30%) use transesophageal echocardiography guidance, 12/189 (6%) intracardiac echocardiography and 6/189 (3%) use both imaging modalities; another 4/189 (2%) centers report on other imaging modalities for transseptal puncture . Diagnostic catheters used for transseptal puncture are listed in Suppl. Figure\u00a03B. While 115/189 (61%) of the centers perform transseptal puncture under pressure control, 74/189 (39%) do not.Details on timing of heparin application and the periinterventional target activated clotting time (ACT) are provided in Suppl. Figure\u00a04. Nineteen out of 189 (10%) centers reported weight-adapted application of heparin before transseptal puncture, and 87/189 (46%) centers thereafter. In 78/189 (41%) centers, only a certain amount of the total body weight-adapted heparin dose is administered prior to and the rest after transseptal puncture. 5/189 (2.6%) centers did not provide any information. The majority  of centers state that the amount of heparin before the transseptal puncture is\u2009\u2264\u20095000 units (I.U.), while 4/78 (5%) give\u2009>\u20095000 I.U. and 3/78 (4%) did not further specify. Regarding target ACT levels, 14/189 (7%) centers reported\u2009\u2264\u2009250\u00a0s, 99/189 (52%) ACT levels\u2009>\u2009250\u2013300\u00a0s and 72/189 (38%)\u2009>\u2009300\u00a0s during left atrial/ventricular procedures. No information was provided by 4/189 (2%) centers. Only 32/189 (17%) centers perform ACT measurement before, all others following transseptal puncture. Suppl. Figure\u00a04 shows the intervals of the ACT measurements.The survey revealed that 61/189 (32%) of the EP centers have on site cardiac surgery, whereas 128/189 (67%) centers have not. All centers without cardiac surgery stated to collaborate with external cardiac surgery institutions.Suppl. Figure\u00a05A shows in how many centers and in which kind of procedures invasive blood pressure measurement is performed. Centers and types of procedures with non-invasive blood pressure measurements and the corresponding intervals are shown in Suppl. Figure\u00a05B. The majority of EP centers  have echocardiography permanently available on site in the EP laboratory.Echocardiography to rule out pericardial effusion following EP-procedures is routinely performed directly on the EP table in 151/189 (80%) centers as an institutional standard. Pericardial effusion is primarily or repeatedly ruled out in the recovery room and/or on the ward in 31/189 (16%) centers, 74/189 (39%) centers exclude a pericardial effusion the following day. A total of 26/189 (14%) centers perform an echocardiography again at the day of discharge and 3/189 (2%) centers only if clinically indicated (multiple answers possible). A total of 8/189 (4%) centers use different schemes. Suppl. Figure\u00a06A illustrates postprocedural monitoring modalities and durations, if provided by the centers.Of note, almost all centers  have a dedicated pericardiocentesis set prepared for emergencies in the cath lab and half of the centers  have regular trainings with the EP team to prepare for emergency intervention in case of cardiac tamponade.Whenever pericardial tamponade occurs, 49/189 (26%) centers immediately contact an institutional resuscitation team. Another 25/189 13%) centers always inform a cardiac surgeon in case of pericardial tamponade, whereas more than two-thirds of centers  do not. 33/189 (17%) centers inform the cardiac surgeon only in specific situations as listed in Suppl. Figure\u00a06A. If not already present, 131/189 (69%) centers place an arterial line for invasive blood pressure measurement in case of pericardial tamponade, 33/189 (17%) do not. In 25/189 (13%) centers, an upgrade to invasive blood pressure management is only performed in certain instances  centers, whereas 16/189 (8%) centers use only echocardiography. 117/189 (62%) centers use both, echocardiography and fluoroscopy and another 3/189 (2%) centers do not use any imaging modality for pericardiocentesis. The fluoroscopic projections used by the centers are shown in Suppl. Figure\u00a07.While 145/189 (77%) centers insert an additional sheath into the pericardium after successful pericardial access is achieved, pigtail catheter insertion is reported by almost all centers  and only 5/189 (3%) do not use a pigtail catheter. The sizes of sheaths and pigtail catheters are provided in Suppl. Figure\u00a08.When cardiac tamponade occurs, protamine is administered on a routine basis in many centers [163/189 (86%)]. A third of the centers [60/163 (37%)] administers protamine immediately when cardiac tamponade is diagnosed, 31/163 (19%) centers after safe access to the pericardium is achieved and 53/163 (33%) once all blood is aspirated from the pericardial space. In 14/163 (9%) centers, individual factors such as persistent bleeding, high ACT levels, or the amount of effusion are applied criteria for administering protamine. Five out of 163 centers (3%) did not give any information. In case of protamine administration, 68/163 (42%) centers antagonize the previously administered heparin in a 1:1 ratio and 54/163 (33%) adapt the dosing according to the last ACT measured. 27/163 (17%) centers apply 5000 I.U. protamine as a standard dosage, 5/163 (3%) 3000 I.U. and 8/163 (5%) centers use other dosages. One center did not further specify.Overall, only 5% of the centers ever applied a specific NOAC antidote for adjunct treatment of cardiac tamponade. Accordingly, 179/189 (95%) centers have not used any antidote so far. 56/189 (30%) centers routinely administer clotting factors . Almost two-thirds of the centers  do not give a NOAC antidote whereas 17/189 (9%) would do so. 50/189 (26%) centers would only use an antidote in certain instances as illustrated in Fig.\u00a0With regard to autotransfusion of aspirated blood, 36/189 (19%) centers responded that they reinfuse blood only before protamine administration, while 34/189 (18%) centers also autotransfuse after protamine administration. However, more than half  of the centers do not perform autotransfusion. 15/189 (10%) centers report other approaches. Three centers (2%) did not answer. When autotransfusion is performed, 31/70 (44%) do not use a blood filter, 17/70 (24%) use a blood filter, 4/70 (6%) reinfuse blood via a Cellsafer and 18/70 (26%) did not further specify.Most of the centers [118/189 (62%)] decide for cardiac surgical treatment if the bleeding does not stop after all conventional treatment options within certain periods of time were applied Fig.\u00a0A. 34/189Once pericardial tamponade is successfully treated, 151/189 (80%) centers monitor their patients on an Intensive Care Unit (ICU), another 26/189 (14%) centers on an Intermediate Care Unit, and 9/189 (5%) might use both the ICU or the Intermediate Care Unit. Only 2/189 (1%) centers monitor patients after cardiac tamponade on regular wards and one single center did not further specify.Figure\u00a0Two-thirds of the centers  stated that they do not routinely apply NSAIDs, colchicine or cortisone after pericardial tamponade. Medication applied by the other centers is provided in Suppl. Figure\u00a09. A total of 87/189 (46%) centers cover their patients with antibiotics in case of pericardial tamponade and remaining pigtail catheter.A total of 19/189 (10%) centers restart OAC after a certain number of hours, 48/189 (25%) after a certain time range after pericardial bleeding has stopped, and 84/189 (44%) after a certain number of hours following removal of the pigtail catheter. 35/189 (19%) centers chose a different strategy and 3/189 (2%) centers did not further specify .A total of 108/189 (57%) centers routinely schedule an outpatient follow-up visit in patients after cardiac tamponade, while 81/189 (43%) do not. 22/108 (20%) reported that they schedule their patients at day 7 after discharge. More than half  of the centers perform FU visits between day 7 and 14 and 13/108 (12%) centers later than 14\u00a0days post discharge. Another 4/108 (4%) centers report individualized approaches and 7/108 (6%) did not provide further information.Tamponade is typically a consequence of an acute defect to the heart or intrapericardial vasculature, caused by chronic trauma  or by acute damage, e.g., suboptimal transseptal puncture. These defects enabling bleeding into the pericardial sac typically close spontaneously, a process that can be delayed by anticoagulants. Robust evidence on the best management of tamponade is lacking, but most German EP centers have institutional standards for management of pericardial tamponade. Due to the lack of evidence, their workflows differ Fig.\u00a0. Most prThe survey also identified several measures to reduce the risk of tamponade. Patient selection, mainly withholding ablation procedures in very old or very obese patients, is uncommon. Many centers have established routines for transseptal puncture, typically relying on fluoroscopic guidance. There is also a tendency to reduce the effect of anticoagulants by pausing of NOACs or by administering reduced doses of heparin prior to transseptal puncture.Even though recommendations for the management of cardiac tamponade exist, major differences in patient handling before, during and after this emergency intervention are generally observed , 6.One of the most important steps to prevent major complications during catheter ablation is patient selection and higher BMI, age and INR levels are considered as risk factors by physicians worldwide. In the present survey it is shown, that many German EP centers consider a BMI of 35 as a limiting factor for left atrial procedures or ablation of VTs with the majority of centers refusing to perform catheter ablation in patients with a BMI\u2009>\u200940. Importantly, although several reports have shown that catheter ablation can be safely performed in the elderly , 9\u201311],\u201311,9\u201311]Pericardial puncture in an emergency setting requires a high rate of flexibility and professionalism of the whole team and operators should rely on the technique and imaging modalities they are most trained on . Most ceThe amount of aspirated blood or autotransfusion did not play a major role for clinical outcome in patients with cardiac tamponade in previous studies  but manyAlthough uninterrupted NOAC therapy is recommended for patients undergoing AF ablation therapy, most centers participating in this survey withhold a least one dose at the day before or the day of ablation. However, this strategy also reflects lack on data of randomized controlled trials comparing truly versus minimally uninterrupted NOAC therapy in AF ablation .Intraprocedural anticoagulation during cardiac tamponade might be crucial for a beneficial outcome. In the evaluated German centers, protamine is often administered on a routine basis in the setting of cardiac tamponade. However, the amount of protamine and the time point, when protamine is given, vary substantially. Furthermore, it has to be taken into consideration that protamine administration bears the risk of clot formation inside the pericardial space which might further complicate the acute situation or may increase the risk for late complications such as diastolic dysfunction. However, especially when not having cardiac surgery backup in house, protamine administration should be considered as early as possible.Specific antidotes to NOACs have rarely been used in the surveyed centers to manage tamponade (in only 9/189 centers). Two-thirds of the centers would not apply specific NOAC antidotes, and one-fourth only in certain instances.Despite robust data that left atrial ablation including transseptal puncture can be safely performed on continued NOAC therapy and without differences to uninterrupted vitamin K antagonist therapy \u201316, the Cardiac surgery is usually considered as the last option to treat cardiac tamponade but is reported to be necessary in up to 12.8% of all cardiac tamponades occurring in the EP setting . While cIn hemodynamically stabilized patients after cardiac tamponade, the subsequent clinical management is of particular importance, as these patients are still at risk of death . Thus, eThe current analysis is based on a survey with its characteristic limitations. The survey was only conducted in Germany with response of roughly 50% of the addressed centers. The questionnaire was sent to all German cardiology centers offering EP-services. Since the questionnaire was anonymized, no information can be provided on which centers answered and which did not.The present survey shows that the management of cardiac tamponade is still inhomogeneous in German ablation centers. However, multiple results and aspects of that survey can be generalized and might guide especially less experienced operators and centers in their treatment and decision strategies when acute pericardial tamponade occurs. It might be of value to implement a position paper focusing on the management of cardiac tamponade."}
+{"text": "The COVID-19 pandemic represents one of the greatest public health crises in this century . Since the beginning of the pandemic there were reports of persistence of symptoms after an average recovery period of 2-5 weeks. Long-COVID syndrome was defined as a continuation or onset of symptoms within 3 months of the initial infection, lasting for at least 2 months with no explanation. There are few studies focused on neurological symptoms of long COVID in ambulatory patients who suffered a mild disease.We conducted a prospective cohort study with a univariate and Kaplan-Meier survival analysis with data obtained between January 2020 to November 2022 from ambulatory adults with mild to moderate COVID-19 diagnosed at our UNAM Faculty of Medicine COVID-19 Diagnostic Center in Mexico City. Patients were systematically called every 15 days during 6 months to evaluate self-perceived neurological symptoms after being diagnosed.We assessed 169 COVID 19 patients, the mean age was 39 (SD 15) years, 42% were men, 97% were Mexican, 90% developed a new neurologic symptom after the COVID-19 acute period. The most common symptoms reported during the follow up were in the first 21 days: fatigue (84%), headache (70%), sleep disorders (69%), sadness (61%), concentration difficulties (60%), emotional liability (57%), anger (56%) and irritability (55%) among others. The highest cumulative incidence  was for headache (187), fatigue (168), sleep disorders (108), concentration difficulties (88), anger (81), dizziness (79), paresthesia (73), speaking and thinking difficulties (67) among others.The survival analysis showed an increased cumulative probability to develop neurological symptoms during the 6 months follow-up, with the highest risk for headache (50%) and fatigue (40%).The probability of presenting neurologic symptoms after suffering a mild COVID 19 disease increased during the 6 months follow up. Additionally, most symptoms were of new onset after the initial recovery from an acute mild COVID-19 episode or persisted from the initial illness and fluctuated over the follow-up, except for seizures that were present as an isolated symptom during acute phase and absent during the follow-up.All Authors: No reported disclosures"}
+{"text": "Numerous studies have shown that adherence to published clinical practice guidelines (CPGs) reduces disease morbidity and mortality. However, few benchmarks exist that demonstrate the rate of adherence to CPGs in patients in long-term-care facilities (LTCFs).To evaluate CPG adherence in patients in LTCFs who received consultation from pharmacists who emphasize disease state management (DSM) compared with patients in other LTCFs who received traditional drug regimen review (DRR).A retrospective chart review was conducted in November 2005 for 107 patients who received DSM services in 2 LTCFs and 304 patients who received DRR services in 4 LTCFs for the service period ending September 30, 2005. Chart review was conducted on all patients included in the current census as of September 1, 2005; residents were excluded from the analysis if they were discharged or deceased between September 1, 2005, and the date of chart review. CPG adherence was evaluated for the following 7 conditions: diabetes, coronary artery disease (CAD), stroke, heart failure (HF), hypertension, hyperlipidemia, and osteoporosis. In addition, the 6 most recent pharmacist recommendations for each patient were classified according to disease state.Adherence to CPGs was significantly better  in patients receiving DSM services for the following performance measures for 4 of the 7 disease states: (1) diabetes: antiplatelet or warfarin use or contraindication for use (hypersensitivity or history of serious bleeding event), 89.7% for DSM services versus 71.0% for DRR services, and glycosylated hemoglobin (HbA1c) \u00b27% (86.2% vs. 62.0%); (2) CAD: antiplatelet use (88.2% vs. 56.1%), and angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) use (82.4% vs. 40.9%); (3) HF: ACEI or ARB use (73.3% vs. 44.9%); and (4) osteoporosis: calcium use (85.0% vs. 56.3%). These observed differences in CPG adherence rates for patients receiving DSM services remained statistically significant after multivariate adjustment for likely confounders. Adherence to CPGs was not different between DSM and DRR facilities for the other 3 disease states . The mean number of pharmacist recommendations per patient per month was greater in DSM facilities (0.76) compared with DRR facilities . Pharmacists who provided DSM consultant services were more likely to make a recommendation to improve DSM (51.6%) than were pharmacists in the comparison facilities who provided traditional DRR services .This self-evaluation of the provision of pharmacist consultant services that focus on disease management in addition to DRR found a higher rate of adherence to clinical practice guidelines for 4 of 7 common chronic disease states in long-term-care patients compared with patients who received only traditional DRR services."}
+{"text": "Severe acute respiratory syndrome coronavirus 2 caused the coronavirus disease 2019 (COVID-19), which rapidly became a pandemic. A great number of pregnant women around the world were affected by the COVID-19 pandemic. The risk of severe COVID-19 infection may increase during pregnancy due to physiological adaptations and immunological changes. However, no significant difference was observed in a study comparing the complications of pregnant and non-pregnant women of the same age group . On the other hand, it seems that some obstetric complications in mothers with COVID-19 are higher than in the normal pregnant population, and based on the results of a systematic review, pre-eclampsia, preterm birth, and stillbirth are higher in pregnancies affected by COVID-19 (3). However, the data on maternal and neonatal complications are still inconclusive due to the small sample size of the studies.Here we report the complications and mortality rate of a total of 343 pregnant women who were infected with COVID-19 and hospitalized in a tertiary academic center affiliated to the Tehran University of Medical Sciences, Tehran, Iran from March 2020 to August 2022. The mean age of patients was 32.11 Participant's median length of stay at the hospital was 6 days (interquartile range: 4-8). The results indicated that 82 (23.91%) had severe COVID-19 requiring admission to the intensive care unit. 14 mothers (4.1%) needed endotracheal intubation, and 3 (0.9%) underwent tracheostomy. The frequency of complications among ICU admitted cases was 8 (9.75%) acute respiratory distress syndrome, 2 (2.44%) pneumothorax, 4 (4.88%) acute kidney injury, 1 (1.22%) deep vein thrombosis, 1 (1.22%) myocarditis, and 10 (12.19%) maternal mortalities. These complications were not seen in non-ICU admitted individuals. There were also 8 (2.33%) cases of pre-eclampsia.Data on the pregnancy outcomes of 79 pregnant women was available. The results indicated that 10 (12.7%) cases had a vaginal delivery and 69 (87.3%) were delivered via cesarean section. 39 (49.37%) women had preterm labor, and the number of preterm labor was significantly higher in ICU-admitted (21 [7.78%]) than in non-ICU admitted (18 [34.61%]) cases  could lead to several maternal and fetal adverse outcomes, such as pre-eclampsia, preterm birth, and intrauterine fetal demise . An increased risk of venous thromboembolism was also reported to be associated with the severity of illness (6). Prophylactic anticoagulant therapy was initiated for all pregnant women in our study; therefore, only one case of venous thromboembolism was reported. Our results showed increased cesarean section rates in this referral center during the COVID-19 pandemic. Recent studies have also shown that a high rate of cesarean delivery is related to the severity of COVID-19 disease (7).There was an exponential increase in the COVID-19 vaccination rate in August 2021 in Iran. The last case of maternal mortality from COVID-19 in our hospital was reported 2 months later, on October 6Although most cases were discharged from the hospital without significant morbidity, COVID-19 may lead to major perinatal and maternal complications. Therefore, women with COVID-19 during pregnancy should be evaluated carefully and followed until delivery to reduce adverse outcomes.None."}
+{"text": "This cohort study evaluates cancer care provided to Ukrainian war refugees in Poland. Within the first 6 weeks, the National Cancer Institute in Krakow (NIO) was approached by 112 patients.4 The center adapted swiftly to the new situation by installing hotlines, hiring interpreters, and transforming registration offices and outpatient units. The aim of this study was to analyze whether the Polish medical system was capable of providing appropriate care to refugees without limiting care for local patients.The Russian invasion disrupted all Ukrainian medical services; hence, effective cancer care became difficult, and the cancer burden was high.STROBE) reporting guideline for cohort studies. All available medical documents, in any available language, were analyzed. Patients agreed to participate in the study upon admission to NIO by providing written consent. Descriptive statistics were used to analyze the data. One-sided \u03c72 tests of independence were completed, and differences at P\u2009<\u2009.05 were regarded as statistically significant.This cohort study was a retrospective analysis of 912 medical records, including 304 Ukrainian refugees who were consulted and/or treated at NIO during the first 6 months after the beginning of the war in Ukraine . The National Cancer Research Institute Ethics Committee approved the study. This report follows the Strengthening the Reporting of Observational Studies in Epidemiology  accounted for 30% of all new patients referred to the Institute and increased the overall number of patients at the NIO by 9.7%. The mean (SD) time from the first visit to the initiation of therapy was 27.7 (7.8) days for the refugees and 26.1 (10.2) days for Polish citizens. Patients with breast cancer constituted the largest group (90 patients [31.5%]), followed by patients with colon cancer (15 patients [5.5%]), lung cancer (14 patients [4.9%]), cervix cancer (14 patients [4.9%]), and melanoma (14 patients [4.9%]) .Of 304 cases, 208 refugees (68.4%) continued therapy initiated in Ukraine. In 231 cases (76%), medical records were available; however, a reliable pathology report was not available in 15 cases (4.9%). In most cases (160 patients [52.5%]) there was a need for translation.A total of 1750 consultations were performed within 6 months. Treatment options for nonsurgical oncology included chemotherapy (76 cases [36.9%]), radiotherapy (57 cases [27.7%]), hormonotherapy (44 cases [21.4%]), and immunotherapy (27 cases [13.1%]) . Some paAuthors are aware of potential limitations of the study, such as selection bias; the analyzed population was composed of people capable of crossing the border and healthy enough to arrive. Nonetheless, the study suggests that even with a substantial number of new cases, effective cancer care could be delivered provided that structural changes were applied. Cancer care of local citizens was not adversely affected, even with a high volume of patients."}
+{"text": "During the second wave of Russia-Ukraine war, around 8 million were internally displaced. Negative mental health impact of the war cannot be underestimate. Among internally displaced persons (IDPs), particularly vulnerable category is people with neurocognitive deficits. Stress associated with displacement may cause a change not only in cognitive functions, but also affect the onset or evaluation of behavioral and psychological symptoms.to study the prevalence of neuropsychiatric disorders in hospitalized patients with dementia, who were internally displaced and to compare with general population frequency.64 IDPs with dementia (moderate and severe neurocognitive deficits) who were examined during March-September 2022. Cases of newly arrived persons were taken into account, after 1 to 30 days had passed since their relocation. The diagnosis was verified based on the ICD-10 criteria (F00-F01). The degree of neurocognitive deficit was determined using the MMSE and MoCA tests. Affective pathology was studied using the HAM-D, HAM-A, PHQ-9, AES scales. Psychotic symptoms and behavioral disorders were studied based on clinical examination and medical records. The study was conducted in Lviv Regional Psychiatric Hospital.among the examined patients, 60  had neuropsychiatric disorders. Among this sample, neuropsychiatric symptoms (an isolated symptom or a combination of two or more symptoms) occurred with the following frequency: apathy 16 (26.7%), anxiety49 (81.7%), depressive symptoms 32 (53.3%), agitation and aggression 41 (68.3%), hallucinatory symptoms 8 (13.3%), delusional disorders 34 (56.7%), wandering and disorientation 18 (30%), refusal of food and medicine 12 (20%)Image:In this study the frequency of occurrence of certain neuropsychiatric syndromes among IDPs with dementia differed from the studied average frequency of occurrence of the same symptomatology among the general population. In particular, anxiety symptoms among IDPs with dementia occurred 42% more often than on average among patients with dementia in the general population (with a frequency of 81% vs 39%), agitation and aggression - 28% more often (68% vs 40%), and delusions - 16% more often (57% vs 31%). At the same time, symptoms such as apathy (by 19%) and refusal to eat (by 14%) were observed less often among IDPs with dementia than among dementia patients from the general populationNone Declared"}
+{"text": "This study was conducted to evaluate the relationship between medication compliance and blood pressure (BP) control among members of 13 managed care organizations with essential hypertension (HTN) who received antihypertensive monotherapy for at least 3 pharmacy claims prior to the blood pressure measurement.This was a retrospective review of medical and pharmacy claims over a 4-year period (1999-2002) from 13 U.S. health plans. Data were collected by trained health professionals from randomly selected patient medical records per Health Plan Employer Data and Information Set (HEDIS) technical specifications. Patients were selected if they (1) had received monotherapy or fixed-dose combination therapy (administered in one tablet or capsule) during the time BP was measured (thus those with no BP drug therapy were excluded); (2) had received 3 or more antihypertensive pharmacy claims for the antihypertensive drug therapy prior to BP measurement; and (3) had one or more antihypertensive pharmacy claims after BP was measured. Control of BP was defined according to guidelines of the Sixth Report of the Joint National Committee (JNC 6) on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure . Medication adherence was measured using the medication possession ratio (MPR), and MPR was used to classify patients into 3 adherence levels: high (80%-100%), medium (50%-79%), and low (less than50%). The relationship between medication adherence and BP control was assessed using a logistic regression model.There were 1,017,181 patients with a diagnosis of HTN in medical claims data from which 10,734 (10.6%) were randomly selected for chart review. There were 1,032 patients (9.6%) in the samples who had a diagnosis of HTN but who were excluded because they had no HTN drug therapy. Of the total 9,894 patients (92.2%) who were excluded from the sample, 3,029 patients (28.2%) met all other inclusion criteria but were receiving more than one HTN drug. Of the 840 patients on HTN monotherapy, the mean age was 59 \u00b1 12.2 years; 422 (50%) were women, 16% had diabetes, and 43% had dyslipidemia. The monotherapy HTN drug was an angiotensin-converting enzyme inhibitor (27% of patients), calcium channel blocker (22%), beta-blocker (20%), or diuretic (11%). Of the 840 patients, 629 (74.8%) were determined to have high medication adherence, 165 (19.6%) had medium adherence, and 46 (5.5%) had low adherence. Approximately 270 (43%) of high adherence patients achieved BP control compared with 56 (34%) and 15 (33%) patients with medium and low adherence, respectively. High-adherence patients were 45% more likely to achieve BP control than those with medium or low compliance after controlling for age, gender, and comorbidities .These results demonstrate that 75% of these health plan members with a diagnosis of essential HTN who were selected for receipt of at least 4 pharmacy claims for HTN monotherapy exhibited high medication adherence. However, only 43% of high-adherence patients attained their target (JNC 6) blood pressure goal compared with 33% to 34% of patients with medium or low adherence to antihypertensive monotherapy."}
+{"text": "Staphylococcus aureus bacteraemia (SAB) is associated with high mortality and morbidity. Certain patient groups are predisposed to developing SAB. Careful monitoring of these patients for persistence of bacteraemia and development of complications is important to improve prognosis. There is international consensus on (i) treating patients with at least 2 weeks of IV antibiotics, (ii) performing echocardiography to evaluate for infective endocarditis and (iii) repeating blood cultures 2\u20134 days after initiating empirical treatment. Adherence to trust antimicrobial guidelines is also imperative to national antimicrobial stewardship.To characterize patients at risk of SAB and make recommendations to reduce the incidence and complications of SAB.S. aureus from April to September 2022 in NWAFT. 57 results from 51 patients aged 0 to 96 years were included. The four audit standards were compliance with (i) trust empirical antimicrobial guidelines, (ii) 2-week duration of IV therapy, (iii) echocardiography evaluation for endocarditis, and (iv) repeat blood cultures 48\u201396 hours after initiating empirical treatment. Patients who were on palliative pathway were excluded from analysis of standards two to four. Prognostic outcomes were examined in terms of hospital readmission, recurrence and mortality.Retrospective review of case notes of patients whose blood culture results were positive for 36 patients (70.6%) were found to harbour known risk factors, with the presence of indwelling prosthetic devices (83.3%) and type 2 diabetes (25.0%) being the most common. The most frequent sources of infection were unknown (27.5%) as well as the skin or soft tissue (17.6%). MRSA bacteraemia accounted for 10.5% of all cases. The compliances with (i) trust empirical antimicrobial guidelines, (ii) 2-week duration of IV therapy, (iii) echocardiography evaluation of endocarditis and (iv) repeat blood cultures 48\u201396 hours after initial blood culture were 52.8%, 75.0%, 57.8% and 66.0%, respectively. Rates of hospital readmission, recurrence and mortality were 39.5%, 11.4% and 35.3%, respectively.The incidence of SAB correlates with the presence of risk factors, and SAB is associated with adverse outcomes. There was partial compliance with the audited outcomes. Introduction of trust SAB guidelines to guide clinical approach and adherence to local antimicrobial prescribing guidelines are imperative to improving patient outcomes."}
+{"text": "Management of inhalation injury is largely supportive and consists primarily of mechanical ventilation, bronchodilators, muscarinic receptor antagonists, and inhaled mucolytics and anticoagulants. The purpose of this study is to examine the early changes in pulmonary mechanics after inhalation injury and see if the use of NT affects lung function.Retrospective study was done on Inhalation injury patients over a 12 years period from 01/2009 to 01/2021. Patients\u2019 data collected from their medical records, included patient demographics and outcomes, percentage Total Body Surface Area (TBSA), Carboxyhemoglobin level upon admission, Respiratory Treatments , Tobramycin treatment, Oxygen requirement, Lung compliance (peak airway pressure & Mean airway Pressure), Mode of Ventilation, total Ventilator Day, and number of Hospital Days. Patients with inhalation injury from 2009-2019 were retrospectively reviewed for treatment of inhalation injury. Univariate analysis and multiple logistic regression were performed using Excel and Stata.Of 90 patients with inhalation injury, median age was 53.5 (IQR:31-65) with 30% (n=28) women and median TBSA of 15%(IQR:2-38%). The median length of stay was 21 days (IQR:6-47). Median ventilator days was  and median ICU days was 12 (IQR:3-28). After adjusting for grade of inhalation injury, patients who did not receive NT were 2.7 times as likely to get pneumonia compared to patients who received NT (p=0.037). Initial median carboxyhemoglobin was 3.9 (IQR: 2-9.1). Overall mortality was 21%, but the incidence of death increased with grade of injuryThe Median Mean Airway Pressures were Day 1: 9.5mmHg, Day 2: 11mmHg, Day 3: 13mmHg, Day 4: 12mmHgThe median peak pressures were Day 1; 20mmHg, Day 2: 21mmHg; Day 3: 22.5mmHg; Day 4: 21mmHgPatients with inhalation injury are susceptible to Acute Respiratory Distress Syndrome, indicated by a decrease in lung compliance and increase in the patient\u2019s oxygenation support. The lung compliance of these patients being to change resulting in an increase in their Peak Airway Pressure and Mean Airway Pressure within the first 72 hours. Moderate hypoxemia is present in these patients with the progress of the smoke inhalation injury. The usage of NT did not have a direct benefit to the pulmonary mechanics for inhalation injury when used as a prophylactic strategy. Additional research and clinical trials are needed to better understand the effect of inhalation injury on pulmonary mechanics.Analysis of pulmonary mechanics in patients with inhalation injury can allow clinicians to better tailor ventilator settings to improve clinical outcomes."}
+{"text": "Cost savings can be achieved with the practice of tablet splitting. Previous research has shown weight nonuniformity within tablet halves. However, limited research to date has found that the potential dose inaccuracy resulting from splitting tablets does not significantly affect clinical outcomes.To determine the drug content and weight in split half-tablets of 6 commonly split medications using drug assay analysis.This study was performed by 2 fourth-year pharmacy students using 30 randomly selected tablets of each of the following 6 medications: warfarin sodium 5 milligrams (mg), simvastatin 80 mg, metoprolol succinate 200 mg, metoprolol tartrate 25 mg, citalopram 40 mg, and lisinopril 40 mg. A randomly selected half of the tablets were split by a single pharmacy student using a tablet cutter, and the remaining tablets were kept whole. Drug content was analyzed for 15 whole tablets and 30 half-tablets for each of the 6 drugs using high performance liquid chromatography, an analytical tool used to identify and quantify substances in solution. Drug content uniformity was assessed by comparing drug content within halftablets with one-half of the drug content mean found for all whole tablets in the sample. Weight uniformity was assessed by comparing half-tablet weights, as determined by a Mettler analytical balance, with one-half of the mean weight for whole tablets in the sample. The percentages by which each whole tablet's or half-tablet's drug content and weight differed from sample mean values were compared with proxy United States Pharmacopeia (USP) specification ranges for drug content (95%-105% for warfarin sodium and 90%-110% for the other 5 drugs). Additionally, these outcomes were compared for nonscored versus scored tablets. The percent relative standard deviation , a commonly used measure of the repeatability and precision of assays used to analyze drug content, was also calculated in order to determine whether the drugs met proxy USP specification for %RSD .A total of 43 of 180 half-tablets (23.9%) differed from sample mean values by a percentage that fell outside of proxy USP specification for drug content; warfarin sodium , simvastatin  metoprolol succinate , metoprolol tartrate , citalopram , and lisinopril . Half-tablets outside of proxy USP specification for weight included warfarin sodium , metoprolol succinate , and lisinopril . The %RSDs for drug content and weight fell outside of the proxy USP specification for %RSD for metoprolol succinate  and lisinopril . Mean percent weight loss after splitting was less than 1% for all drugs except lisinopril, which had an average weight loss of 1.25%. The total numbers of scored (nonscored) tablet halves that fell outside of proxy USP specification were 20 (23) for drug content and 10 (13) for weight. When measuring drug content, the numbers of out-of-range half-tablets for scored (nonscored) drugs were 36 (44) at 95%-105%, 9 (23) at 90%-110%, 0 (10) at 85%-115%, and 0 (1) at 75%-125%. When measuring weight, the numbers of out-of-range halftablets for scored (nonscored) drugs were 28 (38) at 95%-105%, 0 (14) at 90%-110%, 0 (3) at 85%-115%, and 0 (0) at 75%-125%.Dose variation exceeded a proxy USP specification for more than one-third of sampled half-tablets of warfarin sodium, metoprolol succinate, and lisinopril and appeared to be greater for nonscored tablets as compared with scored tablets. Drug content variation in half-tablets."}
+{"text": "IntroductionThrombocytopenia is a commonly observed condition in clinical practice, and its diagnosis is often challenging due to numerous aetiologies and variations in clinical presentation. Early identification of thrombocytopenia and its causes can help prevent life-threatening haemorrhagic manifestations.MethodologyA prospective observational study was conducted at a tertiary care hospital from February 2019 to January 2020. This evaluation aimed to determine the causes and prevalence of thrombocytopenia in a tertiary care setting. Patients aged 15 or older with a platelet count of fewer than 150,000/ \u00b5L were eligible for inclusion in this evaluation. Investigations for aetiology detection were recommended.ResultsDuring the one-year study period, a total of 100 patients, including 58 males and 42 females, with thrombocytopenia were selected for the study. The most common age group affected by thrombocytopenia in this study was between 46 and 55 years old. The most common clinical manifestations observed were generalised weakness (70%), haemorrhagic manifestations (60%), fever (50%), joint pain (37%), splenomegaly (35%), headache (30%), breathlessness (23%), lymphadenopathy (22%), hepatomegaly (24%), and abdominal pain (12%). The most prevalent causes of thrombocytopenia were megaloblastic anaemia (19 cases), dengue fever (15 cases), malaria (11 cases), enteric fever (nine cases), immune thrombocytopenia (ITP) (eight cases), and leukaemia (seven cases). Bleeding was reported as a symptom of thrombocytopenia in 60% of individuals in this study.ConclusionIn the study, thrombocytopenia was more common in people aged 46-55 years, and males were more commonly affected than females. Megaloblastic anaemia and infectious disease were the most common causes of thrombocytopenia. Bleeding manifestations were found in 60% of patients with thrombocytopenia. Thrombocytopenia is defined as a decrease in peripheral blood platelet counts below the lower normal limit of 150,000/\u00b5L . A bone The clinical presentations of thrombocytopenia can range from mild to life-threatening, depending on the cause . SpecifiThrombocytopenia is often diagnosed through a routine complete blood count in asymptomatic patients. In some cases, discolouration, purpura, petechial bleeding, nasal bleeding, and gingival bleeding may be observed. Rarely, a platelet count as low as 5,000/\u00b5L may put the patient at risk for bleeding in the central nervous system, gastrointestinal tract, or genitourinary tract . A plateAims and objectivesThe aim of this study\u00a0was to evaluate the various causes of thrombocytopenia and assess the clinical profile of patients with thrombocytopenia.One hundred patients with thrombocytopenia who were hospitalised at the Indira Gandhi Institute of Medical Sciences (IGIMS) in Patna, Bihar, India, between February 2019 and January 2020 were the subjects of a prospective hospital-based study. All patients who participated in this research underwent a thorough clinical evaluation and investigation. The study received consent from the Institutional Ethics Committee of IGIMS, Patna . Data tracking was performed using Microsoft Excel , while IBM Statistical Package for Social Sciences (SPSS)  was used for analysis.Inclusion criteriaPatients with a platelet count below 150,000/ \u00b5L, aged 15 years or older, and those who provided consent for the study were included in the study.Exclusion criteriaPatients aged below 15 years and those who did not provide consent for the study were excluded.InvestigationsThe following investigations were conducted as per the patient's specific needs: complete blood count, peripheral blood smear, coagulation profile, kidney function test, liver function test, and other special investigations such as chest X-ray (posteroanterior (PA) view), abdominal ultrasound (USG of the whole abdomen), bone marrow examination, Widal test, malarial parasite antigen, dengue serology, and Coombs test were performed on patients only when indicated.Table Figure Figure The major clinical manifestations associated with thrombocytopenia. were generalised weakness (70%), haemorrhagic manifestation (60%), fever (50%), and joint pain (37%). Many thrombocytopenic individuals also had splenomegaly (35%), hepatomegaly 24%), lymphadenopathy (22%), and jaundice (14%)  cases of total thrombocytopenia presented with bleeding manifestations. The most common types of bleeding symptoms observed were skin and mucous sites in 18 30%) cases, gum bleeding in 10 (16.6%) cases, and subconjunctival haemorrhage in nine (15%) cases. Figure 0% cases,In the present study, 100 patients were enrolled. Fifty-eight percent were male, and 42% were female. In a study by Shankarappa RS et al., the male-to-female ratio was 60:40 [According to a study conducted by Vimal et al. in South India, the majority of cases 37.4%) belonged to the age category 41-60 years, followed by 21-40 years (33.4%) .4% belon. The stuDengue 21.67%), malaria (6.7%), enteric fever (5.9%), septicemia (5%), chronic liver disease (16.7%), and chronic renal disease (3.4%) were reported as causes of thrombocytopenia in a study conducted in South India by Vimal et al. %, malari.In the present study, haemorrhagic manifestations (60%) were observed in thrombocytopenic patients. Among them, skin  bleeding manifestations were found in 18 (30%) patients, gum bleeding in 10 (16.66%), subconjunctival haemorrhage in nine (15%), melena in eight (13.33%), and haematemesis in seven 11.66%) patients. Other bleeding manifestations included haemoptysis in three (5%) patients, haematuria in two (3.33%), and epistaxis in two (3.33%) patients. According to PatneSV et al., bleeding manifestations were present in 37.50% of patients, and the most common site of bleeding was the skin and mucous membrane [.66% patiThrombocytopenia, a condition commonly encountered in clinical practice, requires a comprehensive evaluation to determine its underlying secondary causes. In certain cases, thrombocytopenia can pose a life-threatening risk, necessitating a platelet transfusion. Improving our understanding of the etiological factors contributing to thrombocytopenia can lead to better management of the disease, resulting in reduced morbidity and mortality.The study identified megaloblastic anaemia as the most prevalent cause of thrombocytopenia. Early diagnosis of megaloblastic anaemia is crucial for achieving better treatment outcomes. Dengue fever was found to be the second most common cause of thrombocytopenia in the study, followed by malaria and enteric fever. Therefore, the presence of thrombocytopenia raises suspicion of these diseases and emphasises the need for prompt treatment of the patients."}
+{"text": "Does the addition of camrelizumab to neoadjuvant chemotherapy (nab-paclitaxel and platinum) improve the pathologic complete response (pCR) rate among patients with resectable stage IIIA or IIIB non\u2013small cell lung cancer (NSCLC)?In this randomized clinical trial that included 88 Chinese patients with resectable stage IIIA or IIIB (T3N2) NSCLC, the pCR rate was 32.6%  with camrelizumab plus chemotherapy vs 8.9%  with chemotherapy alone.Among patients with resectable stage IIIA or IIIB (T3N2) NSCLC, compared with chemotherapy alone, camrelizumab combined with chemotherapy resulted in an improved pCR rate. The benefit of neoadjuvant camrelizumab plus chemotherapy for resectable stage IIIA or IIIB non\u2013small cell lung cancer (NSCLC) remains unknown.To assess the efficacy and safety of neoadjuvant camrelizumab plus chemotherapy vs chemotherapy alone for patients with resectable stage IIIA or IIIB NSCLC.In this randomized phase 2 clinical trial conducted at 2 hospitals in China, patients aged 18 to 70 years with resectable stage IIIA or IIIB (T3N2) NSCLC were enrolled between April 7, 2020, and January 12, 2022.2, and platinum ) or chemotherapy alone, followed by surgery after 4 to 6 weeks.Patients were randomly assigned to receive 3 cycles of camrelizumab (200 mg) plus chemotherapy  rate. Secondary end points included the major pathologic response (MPR) rate, objective response rate (ORR), event-free survival (EFS), and safety. Disease-free survival  was analyzed post hoc. Efficacy was assessed on a modified intention-to-treat basis.P\u2009=\u2009.008). The MPR rates were 65.1%  with camrelizumab plus chemotherapy and 15.6%  with chemotherapy alone. The radiographic ORRs were 72.1%  with camrelizumab plus chemotherapy and 53.3%  with chemotherapy alone. With a median follow-up of 14.1 months , the median EFS and DFS were not reached in either group. The most common neoadjuvant treatment-related adverse events of grade 3 or higher were decreased white blood cell count (6 of 43 [14.0%] in the camrelizumab plus chemotherapy group vs 2 of 45 [4.4%] in the chemotherapy group) and decreased neutrophil count (3 of 43 [7.0%] in the camrelizumab plus chemotherapy group vs 5 of 45 [11.1%] in the chemotherapy group). No treatment-related deaths were reported.Ninety-four Chinese patients were randomized, and 88  received allocated neoadjuvant treatment . Among these 88 patients, the pCR rate was 32.6%  with camrelizumab plus chemotherapy vs 8.9%  with chemotherapy alone  NSCLC, camrelizumab plus chemotherapy, compared with chemotherapy alone, significantly improved the pCR rate with manageable toxic effects.NCT04338620ClinicalTrials.gov Identifier:  This randomized clinical trial assesses the efficacy and safety of neoadjuvant camrelizumab plus chemotherapy vs chemotherapy alone for patients with resectable stage IIIA or IIIB non\u2013small cell lung cancer (NSCLC). Preoperative neoadjuvant therapy has been shown to downstage the lesion, increase the possibility of complete resection, remove micrometastases, and thereby reduce the risk of recurrence.3 However, neoadjuvant chemotherapy or chemoradiotherapy, which has been the standard of care for the past 2 decades, provide only modest benefits, with a pathologic complete response (pCR) rate of 10% to 18% and a 5-year survival rate of approximately 35%.4 Novel neoadjuvant systemic therapies for resectable stage III NSCLC are urgently needed.Approximately 30% of patients with a new diagnosis of non\u2013small cell lung cancer (NSCLC) initially receive a diagnosis of stage III NSCLC.5 In the randomized phase 3 Checkmate 816 trial, the anti\u2013PD-1 inhibitor nivolumab combined with chemotherapy significantly improved the event-free survival (EFS) and pCR rate vs chemotherapy alone as a neoadjuvant therapy for patients with resectable stage IB to IIIA NSCLC,6 resulting in its approval by the US Food and Drug Administration as a neoadjuvant treatment in this population. However, there are no prospective studies comparing neoadjuvant anti\u2013PD-1 inhibitors plus chemotherapy with chemotherapy alone specifically for Chinese patients with resectable NSCLC, especially for those with stage III disease.Immune checkpoint inhibitors, such as anti\u2013programmed cell death (ligand) 1 (PD-[L]1) inhibitors, have revolutionized the management of unresectable stage III NSCLC, and their applications are moving forward to the perioperative stage. Compared with adjuvant therapy, immune checkpoint inhibitors as neoadjuvant therapy may be more advantageous because they can preoperatively facilitate the priming and expansion of tumor-specific T cells and trigger a robust adaptive antitumor response.8 However, data are lacking to support this combination as a neoadjuvant therapeutic strategy for resectable NSCLC. In this context, we performed a randomized, open-label, multicenter, phase 2 clinical trial to assess the efficacy and safety of neoadjuvant camrelizumab plus chemotherapy (nab-paclitaxel and platinum) compared with chemotherapy for patients with resectable stage IIIA or IIIB NSCLC.Camrelizumab is a humanized, selective immunoglobulin G4-\u03ba monoclonal antibody against PD-1. In the phase 3 CameL and CameL-Sq studies, camrelizumab combined with chemotherapy showed an improvement in survival vs chemotherapy as first-line treatment for patients with advanced NSCLC.9 and Good Clinical Practices and was approved by the ethics committee of both sites. Written informed consent was obtained from each participant before study initiation. This trial followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.This randomized, open-label, multicenter, phase 2 clinical trial was performed at 2 sites in China: the Second Affiliated Hospital of Air Force Medical University and Shaanxi Provincial Cancer Hospital. Eligible patients were enrolled between April 7, 2020, and January 12, 2022. This study was conducted in accordance with the Declaration of Helsinki10); had an Eastern Cooperative Oncology Group performance status of 0 or 1; had at least 1 measurable target lesion according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.111; had received no previous anticancer therapy; and had adequate organ function. Key exclusion criteria included the presence of central nervous system metastases, the presence of immunodeficiency disease, previous therapies with immunosuppressants within 14 days prior to the initiation of study treatment, uncontrolled hypertension, and a history of or having pulmonary fibrosis or interstitial lung disease. Full eligibility criteria are available in the trial protocol  and platinum  every 3 weeks for 3 cycles. The choice of platinum was determined by the investigator. Surgery was planned 4 to 6 weeks after the completion of neoadjuvant treatment. Dose modifications and assessments are provided in the eAppendix in Camrelizumab (200 mg) was administered intravenously on day 1 of each 3-week cycle for 3 cycles before surgical resection. Neoadjuvant chemotherapy consisted of nab-paclitaxel  rate , objective response rate , EFS , and safety. Disease-free survival  was analyzed post hoc.Sample size was based on the primary end point pCR rate in the primary analysis. The pCR rate was assumed to be 50% in the camrelizumab plus chemotherapy group and 18% in the chemotherapy alone group, which could be translated to an odds ratio (OR) of 4.55. Under these assumptions, 80 patients would provide at least 80% power to detect the difference between 2 groups with a 2-sided \u03b1 level of .05, based on the Fisher exact test. Accounting for a potential 15% dropout after randomization, we planned to enroll 94 patients.P\u2009<\u2009.05 was regarded as statistically significant. All other P values, if presented, were considered to be nominal and interpreted descriptively. All statistical analyses were performed using SAS software, version 9.4 (SAS Institute Inc).Efficacy was assessed in the full analysis set, which included all randomized patients who received at least 1 dose of the study treatment (modified intention-to-treat [ITT] population). Safety was also analyzed in the full analysis set. Categorical variables are presented as numbers and frequencies, and continuous variables are presented as median (IQR) values. Response end points were calculated with the exact 95% CIs by the Clopper-Pearson method. The 95% CI of the OR was calculated by using exact confidence limits. Time-to-event end points were estimated with the Kaplan-Meier method, along with their 95% CIs calculated by the Brookmeyer-Crowley method for median survival time and log-log transformation for survival rate, respectively. Hazard ratios (HRs) were estimated using Cox proportional hazards regression models. The comparisons between the groups were done using the Fisher exact test for binary response end points. Post hoc subgroup analyses of pCR and MPR were done based on patient characteristics at baseline  and the 95% CI of difference of response rate was calculated by Miettinen-Nurminen method. For the primary end point, a 2-sided A total of 94 eligible patients from 2 centers in China were enrolled and randomly assigned to either the camrelizumab plus chemotherapy group (47 patients) or the chemotherapy alone group (47 patients). Four patients in the camrelizumab plus chemotherapy group and 2 patients in the chemotherapy alone group did not receive planned neoadjuvant treatment and were excluded from the modified ITT population ; 88 ChinAmong the patients who received neoadjuvant treatment, 40 of 43 patients (93.0%) in the camrelizumab plus chemotherapy group and 42 of 45 patients (93.3%) in the chemotherapy alone group underwent surgery . The radiographic ORR was 72.1%  with camrelizumab plus chemotherapy as compared with 53.3%  with chemotherapy alone , with a radiographic CR achieved in 11 of 43 patients (25.6%) in the camrelizumab plus chemotherapy group vs 4 of 45 patients (8.9%) in the chemotherapy alone group and a PR in 20 of 43 patients (46.5%) in the camrelizumab plus chemotherapy group vs 20 of 45 patients (44.4%) in the chemotherapy alone group. In addition, the depth of radiographic response in the target lesions was greater with camrelizumab plus chemotherapy  vs 8.9%  with chemotherapy alone , the median follow-up duration was 14.1 months (IQR 9.2-20.9 months). A total of 19 patients experienced disease recurrence or death , and median EFS and DFS were not reached in either group . The HR Neoadjuvant treatment-related adverse events (TRAEs) were recorded among 41 of 43 patients (95.3%) in the camrelizumab plus chemotherapy group and 40 of 45 patients (88.9%) in the chemotherapy group . Grade 3Among patients with surgical resection, surgery-related AEs were reported for 16 of 40 patients (40.0%) in the camrelizumab plus chemotherapy group and for 14 of 42 patients (33.3%) in the chemotherapy group, most of which were grade 1 or 2 . The mosTo our knowledge, this is the first randomized clinical trial comparing camrelizumab plus chemotherapy with chemotherapy alone in the neoadjuvant treatment setting for resectable stage IIIA or IIIB NSCLC. The addition of camrelizumab to neoadjuvant chemotherapy (nab-paclitaxel plus platinum) resulted in a statistically significant improvement in the pCR rate for patients with resectable stage IIIA or IIIB (T3N2) NSCLC, although the actual pCR rate observed was lower than the statistical assumption in both groups. In addition, the safety profiles of neoadjuvant camrelizumab plus chemotherapy were manageable, with no new safety signals identified.12 The CheckMate 816 study of nivolumab plus chemotherapy vs chemotherapy alone for patients with resectable NSCLC also showed favorable outcomes with neoadjuvant nivolumab plus chemotherapy, including the pCR rate (24.0% vs 2.2%), MPR rate (36.9% vs 8.9%), ORR (53.6% vs 37.4%), and EFS rate at 1 year (76.1% vs 63.4%) and 2 years (76.1% vs 63.4%).6 In our current study, outcomes in either the camrelizumab plus chemotherapy or chemotherapy alone group appeared to be superior to those in the CheckMate 816 study. The differences might be attributed to discrepancies in the chemotherapy regimen, the proportion of squamous cell carcinoma, disease stage of patients enrolled, and race and ethnicity . Although platinum-based doublet chemotherapy was used in both our study and the CheckMate 816 study, another chemotherapeutic agent  was chosen by the investigator in the CheckMate 816 study. Previous reports have shown an effect of perioperative chemotherapy choice on the outcomes of patients with resected NSCLC.14 In contrast, we used nab-paclitaxel as a combination with platinum to avoid the need for corticosteroids and reduce heterogeneity. In addition, patients with stage IB to IIIA resectable NSCLC were included in the CheckMate 816 study (in which approximately 35% of patients had stage IB or II disease), while we enrolled those with stage IIIA or IIIB disease, a patient population with a dismal prognosis. There is evidence that patients with resectable stage III NSCLC derive superior benefit from perioperative systemic therapy as compared with those with stage I or II disease.16Data from the phase 2 NADIM II trial showed that nivolumab combined with paclitaxel and carboplatin, compared with paclitaxel plus carboplatin, resulted in a significant improvement in the pCR rate (36.2% vs 6.8%), MPR rate (52% vs 14%), and ORR (74% vs 48%).12 However, we acknowledge that our findings were insensitive owing to the small sample size and the fact that more than 50% of patients had an unknown PD-L1 TPS because of inadequate baseline tumor tissues.Subgroup analyses showed generally consistent pathologic response benefits with camrelizumab plus chemotherapy vs chemotherapy alone, despite the small number of patients in several subgroups leading to the lower bounds of the 95% CIs crossing 0. Similar results in terms of pCR and MPR rates were observed in patients with a PD-L1 tumor proportion score (TPS) of 1% or higher and in those with a PD-L1 TPS of less than 1%. This was different from that of the NADIM II and CheckMate 816 trials, where the pCR benefit was greater with increasing PD-L1 expression levels.17 No novel safety signal was observed. More patients in the camrelizumab plus chemotherapy group developed TRAEs of any grade than those in the chemotherapy alone group, likely due to the high incidence of camrelizumab-related RCCEP , the occurrence of which was reported to be closely associated with the benefits of camrelizumab treatment.18 This difference was also observed between the 2 groups in terms of TRAEs of grade 3 or above, which might be attributed to cumulative toxic effects by camrelizumab combined with chemotherapy. All these grade 3 or above TRAEs were generally manageable and resolved after symptomatic treatment or treatment interruption, without causing a delay in surgery. The incidence of grade 3 or above TRAEs in both groups in this study was comparable with the phase 2 NADIM II trial,12 but was lower than other studies of neoadjuvant chemoimmunotherapy.20 This difference may be related to different chemotherapy regimens and different administration patterns of nab-paclitaxel . In addition, surgery-related AEs with camrelizumab plus chemotherapy had similar incidences as those with nivolumab plus chemotherapy,6 and did not hinder the feasibility of surgery.The safety profile was consistent with that of camrelizumab plus chemotherapy or nab-paclitaxel-platinum.There are several limitations to this study. First, insufficient follow-up prevented our study from indicating whether the addition of camrelizumab to neoadjuvant chemotherapy significantly improved EFS or DFS. Follow-up will continue to assess these survival end points, which are essential for identifying the clinical value of this combination. Second, due to the insufficient biopsy tissue specimen at baseline, 52.5% of patients had an unknown PD-L1 TPS status, resulting in the fact that our findings might not accurately reflect the outcomes of patients based on PD-L1 expression. In addition, inadequate specimens also hindered the in-depth analysis of biomarkers such as tumor variant burden and tumor infiltrating lymphocytes, which precludes us from determining a patient population likely to benefit from neoadjuvant camrelizumab plus chemotherapy.In this randomized clinical trial, the addition of camrelizumab to neoadjuvant nab-paclitaxel and platinum resulted in an improved pCR with a tolerable safety profile in Chinese patients with resectable stage IIIA or IIIB (T3N2) NSCLC, suggesting that this combination might be a novel neoadjuvant treatment option for this patient population."}
+{"text": "The World Health Organization recently described sudden sensorineural hearing loss (SSNHL) as a possible adverse effect of COVID-19 vaccines. Recent discordant pharmacoepidemiologic studies invite robust clinical investigations of SSNHL after COVID-19 messenger RNA (mRNA) vaccines. This postmarketing surveillance study, overseen by French public health authorities, is the first to clinically document postvaccination SSNHL and examine the role of potential risk factors.This nationwide study aimed to assess the relationship between SSNHL and exposure to mRNA COVID-19 vaccines and estimate the reporting rate (Rr) of SSNHL after mRNA vaccination per 1 million doses (primary outcome).We performed a retrospective review of all suspected cases of SSNHL after mRNA COVID-19 vaccination spontaneously reported in France between January 2021 and February 2022 based on a comprehensive medical evaluation, including the evaluation of patient medical history, side and range of hearing loss, and hearing recovery outcomes after a minimum period of 3 months. The quantification of hearing loss and assessment of hearing recovery outcomes were performed according to a grading system modified from the Siegel criteria. A cutoff of 21 days was used for the delay onset of SSNHL. The primary outcome was estimated using the total number of doses of each vaccine administered during the study period in France as the denominator.P=.03); complete recovery in 24% (7/29) of cases; median delay onset before day 21=8 days ; and no effects of sex. Autoimmune, cardiovascular, or audiovestibular risk factors were present in approximately 29.8% (51/171) of the cases. SSNHL was more often unilateral than bilateral for both mRNA vaccines . There were 13.5% (23/142) of cases of profound hearing loss, among which 74% (17/23) did not recover a serviceable ear. A positive rechallenge was documented for 8 cases.From 400 extracted cases for tozinameran and elasomeran, 345 (86.3%) spontaneous reports were selected. After reviewing complementary data, 49.6% (171/345) of documented cases of SSNHL were identified. Of these, 83% (142/171) of SSNHL cases occurred after tozinameran vaccination: Rr=1.45/1,000,000 injections; no difference for the rank of injections; complete recovery in 22.5% (32/142) of cases; median delay onset before day 21=4 days ; and no effects of sex. A total of 16.9% (29/171) of SSNHL cases occurred after elasomeran vaccination: Rr=1.67/1,000,000 injections; rank effect in favor of the first injection (SSNHL after COVID-19 mRNA vaccines are very rare adverse events that do not call into question the benefits of mRNA vaccines but deserve to be known given the potentially disabling impact of sudden deafness. Therefore, it is essential to properly characterize postinjection SSNHL, especially in the case of a positive rechallenge, to provide appropriate individualized recommendations. Agence Nationale de S\u00e9curit\u00e9 du M\u00e9dicament et des produits de sant\u00e9 [ANSM]) is responsible for assessing the safety of vaccines through the continuous surveillance of all ADRs to quickly detect potential safety issues and take appropriate risk reduction measures. For the COVID-19 vaccination campaign, an enhanced surveillance system has been put in place ).Patient characteristics were expressed as count (percentage) for categorical variables and median (IQR) for quantitative variables according to the administered vaccine and for the whole cohort because of the few elasomeran cases. The Rr was expressed as cases per 1 million vaccine injections. The number of reported SSNHL cases and the number of vaccine injections were estimated by month during the study period. Finally, we performed a binomial test comparing a sample proportion with a hypothetical proportion to analyze the potential association of the Rr of SSNHL with sex, vaccination rank, and unilaterality or bilaterality of hearing loss . The authorization was granted specifically for the French pharmacovigilance spontaneous reporting database placed under the responsibility of the ANSM.This nationwide postmarketing surveillance study was conducted with the authorization of the During the study period, 400 cases of SSNHL after COVID-19 vaccine administration  were registered in the FPVDB. After case review, a total of 42.8% (171/400) of cases fulfilled the criteria of SSNHL . HearingA total of 323 cases of SSNHL after tozinameran vaccine administration were selected, of which 142 (43.9%) cases met the criteria for inclusion; 29 (8.9%) cases were consistent with otologic manifestations other than SSNHL, and 152 (47.1%) cases were not sufficiently documented to draw conclusions .For these 142 cases, the delay onset was \u226421 days for 108 (76.1%) cases, with a median delay onset of 4 (range 2-9) days. Of these 142 cases, 84 (59.2%) were those of female patients. The median age was 51 (range 13-83) years, and 69% (98/142) of patients were aged 30 to 64 years. A total of 35.2% (50/142) of patients had a medical history, which was otoneurological in 11.9% (17/142) of cases. The vaccination rank was known for 88% (125/142) of cases, with the first injection involved in 42.3% (60/142) of cases. Steroids were administered orally in 47.2% (67/142) of cases. SSNHL was unilateral in 87.3% (124/142) of cases. The hearing loss grade ranged between 1 and 3 in 75.4% (107/142) of cases. Tinnitus was associated with SSNHL in 52.8% (75/142) of cases and vertigo in 28.9% (41/142) of cases. Complete recovery was observed in 22.5% (32/142) of cases, whereas no improvement was observed in 53.5% (76/142) of cases and nonserviceable ear in 8.5% (12/142) of cases  and 4.P<.001). No effect of sex or vaccination rank was observed. Case follow-up identified 3.5% (5/142) of cases of positive rechallenge  cases met the inclusion criteria; 5 (8%) cases were consistent with otologic manifestations other than SSNHL, and 22 (37%) cases were not sufficiently documented to draw conclusions .Among these 29 cases, the delay onset was \u226421 days for 26 (90%) cases, with a median delay onset of 8 (range 1-21) days, and 15 (52%) were those of female patients. The median age was 47 (range 33-81) years, and 72% (21/29) of patients were aged 30 to 64 years. A total of 31% (9/29) of patients had a medical history, which was otoneurological in 14% (4/29) of cases. The vaccination rank was known for 27 cases, with the first injection involved in 45% (13/29) of cases. Steroids were administered orally in 55% (16/29) of cases. SSNHL was unilateral in 76% (22/29) of cases. The hearing loss grade ranged from 1 to 3 in 66% (19/29) of cases. Tinnitus was associated with SSNHL in 34% (10/29) of cases and vertigo in 41% (12/29) of cases. Complete recovery was observed in 24% (7/29) of cases, whereas no improvement was observed in 38% (11/29) of cases and nonserviceable ear in 18% (5/29) of cases  and 4.P<.003). A rank effect was found in favor of the first dose (P<.03). No effects of sex or side of hearing loss were observed. Case follow-up identified 3 cases of positive rechallenge , and the median age was approximately 50 years for both vaccines, which is consistent with the usual age of onset of idiopathic SSNHL ,10. ThusFurthermore, we should underline our findings related to the delay onset of SSNHL according to the vaccination rank. A rank effect was found only for elasomeran: the occurrence of SSNHL was higher after the first injection than after the second injection and the booster. In agreement with Safety Platform for Emergency Vaccines and Brighton Collaboration guidelines on postvaccinal SSNHL, as well as with previous data on audiological or cardiac adverse events with mRNA COVID-19 vaccines, we found that the median delay onset fell within the first 2 weeks after injection ,54,57,58Moreover, data supported a possible relationship between exposure to mRNA COVID-19 vaccines and the occurrence of SSNHL. Positive rechallenge cases were documented for 5 tozinameran and 3 elasomeran vaccinations, meaning that repeated exposure to a COVID-19 mRNA-based vaccine led to SSNHL for a minority of patients who had previously experienced the same adverse event. In a pharmacovigilance study, this result alone was sufficient to suggest a high probability of a causal relationship .Since the beginning of the COVID-19 outbreak, the association between SARS-CoV-2 infection and the occurrence of SSNHL has been supported exclusively by cross-sectional studies conducted on limited case series . Almost Our study has some limitations. An important step in assessing vaccine-related adverse events is to compare their rates in vaccinated and unvaccinated populations, as was done for myocarditis . BecauseOther authors have retrospectively compared the incidence of SSNHL cases in the population exposed to mRNA COVID-19 vaccines with that in the general population using a population-based cohort and International Classification of Diseases, Ninth Revision, codes without any data on patients\u2019 medical history or risk factors ,39. In oThis study identified very rare but severe cases of medically confirmed SSNHL after the administration of mRNA COVID-19 vaccines without calling into question the demonstrated benefit of vaccinating a large population in the context of rapid SARS-CoV-2 circulation. On the basis of our findings, particularly those related to the cases of positive rechallenge and grade-5 hearing loss, patients should undergo a comprehensive evaluation of any otologic manifestation occurring after COVID-19 vaccination. Early diagnosis of SSNHL is essential for positive outcomes. Each medical evaluation should be performed for 2 reasons: the prompt initiation of appropriate treatment to improve the prognosis of SSNHL and provision of expert counseling to patients regarding subsequent vaccine injections, given the evolution of SARS-CoV-2, its variants, and new adaptive vaccines. These data are new and of critical interest to patients, physicians, and regulatory policies to tailor public health messages and medical care."}
+{"text": "This study was done to compare the clinical features, laboratory findings and surgical outcomes of pediatric patients with choledochal cysts.Retrospective review of the hospital records of all pediatric patients admitted with choledochal cysts from 2011 to 2021 were collected and analyzed. Patients were divided into two groups; infant (less than one year age) and pediatric (1 to 16 years) for statistical comparison of two groups.The study included 34 children, 9 (26.5%) were infant (<1 year) and 25 (73.5%) were more than one year old. Mean age at diagnosis was 15 months with age ranging from 14 days to 16 years. Females were 19 (55.9%) and males were 15 (44.1%). Type-I choledochal cyst was the most common (73.5%), presentation followed by Type-IVA (26.5%) in our patients. Patients from infant group presented with jaundice in 7 (77.7%), and clay-colored stool in 3 (33.3%) as the most common clinical features, while abdominal pain (88%), vomiting (72%), fever (32%) and pancreatitis (32%) were the frequent presentations among older age group. Post-surgical complications of excision of choledochal cyst were observed in 4 (11.7%) patients.Choledochal cysts have variable presentations depending upon age of the patients. Complete surgical excision of choledochal cyst is the treatment modality of choice and timely surgical management can prevent complications. Choledochal cyst (CC) is a rare congenital dilatation of the bile duct that transports bile from the liver to the gall bladder and small intestine.3Choledochal cysts can result in progressive biliary tract obstruction and biliary cirrhosis.6The exact etiology of CC is largely unknown. However, anomalous pancreatic duct union is reported in up to 70% of cases where the common bile duct (CBD) and pancreatic duct junction occurs outside the duodenum, causing reflux of pancreatic fluid into the biliary tree.8Studies related to this topic are lacking in our local setup. The aim of the study was to find common presentation and outcome of choledochal cyst in both infantile and older pediatric age group that helps the physician in early diagnosis of disease and prevents late severe complications.This study was started after getting approval from ethical review board of Shifa International Hospital (IRB # 109-21). Retrospectively, records of all the choledochal cysts pediatric patients admitted in Shifa International Hospital and Shifa Falahee Community Health Center from 2011 to 2021 were collected.Data was collected on predesigned Performa. Demographic data including name, gender, age at diagnosis and clinical features; fever, nausea, vomiting, abdominal pain, abdominal mass, abdominal distension, jaundice, clay colored stool, dark colored urine, Classic triad and pancreatitis were noted down. In addition, laboratory investigation findings including total and direct bilirubin, alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate transaminase (AST), and prothrombin time (PT), international normalized ratio (INR) serum lipase and amylase. Imaging modalities including ultrasound and CT/MRI abdomen, MRCP (magnetic resonance cholangiopancreatography) were also listed. Patients were divided into two groups; infant (less than one year age) and older pediatric (1 to 16 year age) and all data were compared between these two groups. Patients undergoing surgical procedures were noted.Statistical analysis was done using Chi-Square test. A p-value of <0.05 was considered significant. Statistical analysis was performed using SPSS 23 for windows.The study included 34 children, 9 (26.5%) were diagnosed in infancy and 25 (73.5%) were more than one year old. Mean age at diagnosis was 15 months with minimum age of 14 days of life and maximum age of 16 years. In the infantile group, four patients were neonates with three of them had biliary atresia along with Type-I CC. Regarding gender distribution, females were 19 (55.9%) and males were 15 (44.1%). Consanguinity was reported in three families (8.8%).Type-I Choledochal cyst was the most commonly (73.5%) reported cyst in our patient population, followed by Type-IVA noted in nine patients (26.5%). Details of patients along with clinical features are shown in Diagnostic imaging modalities used were ultrasound abdomen in 19 (56%) patients, CT abdomen in 13 (38.2%), MRI was done in two (5.9%) patients confirming the diagnosis of CC and identifying the types. All patients underwent surgical correction and post-surgical complications were noted in only four patients, including abdominal pain in two and cholangitis and pancreatitis in one patient each.The study highlights that infant and older age pediatric patients have different specific symptoms of choledochal cyst. Females were commonly affected in our study population. A study from Karachi showed a similar female (78%) preponderance.Infantile group including neonate specifically presented with obstructive jaundice and acholic stools whereas in older pediatric age group, only five patients had jaundice and acholic stools (p 0.001). Similar results were concluded by other studies in children.Classic triad of abdominal pain, right upper quadrant abdominal mass and vomiting was found in one patient (2.9%) only. Literature supports the fact that it is a rare presentation in children. Similarly, Fumino et al.In our observation, most of the patients had elevated serum bilirubin level and derange PT/INR especially in infantile group in comparison ALT, AST whereas pediatric age group patients mostly deranged labs were ALT, AST, and serum amylase and lipase levels. Pancreatitis is a serious complication of CC was seen in 9 (26.5%) patients, mainly in older age group.13Choledochal cyst Type-I is the most common type in both age groups followed by Type-IVA. This is in accordance with findings reported from other parts of the world.Cystic excision and Roux-en-Y hepaticojejunostomy were two major surgical procedures done in our patients.20Choledochal cyst (CC) is a rare congenital defect of the bile ducts.It can lead to progressive biliary tract obstruction and biliary cirrhosis.There are five basic types of choledochal cysts based on Todani classification, with Type-I and Type-IVA are frequent.The study identifies common presentations and surgical outcomes of choledochal cyst in children that can helps the primary care physicians in early diagnosis.The study highlights that infant and older pediatric age group patients with choledochal cyst have different specific symptoms of presentation.Early diagnosis allows for timely surgical correction and prevent long term complications.It includes retrospective nature of the study; limited number of patients and lack of long term follow up findings.The study aids in different and specific clinical features of choledochal cysts in children. Information gathered through the study is expected to facilitate the physicians in early clinical suspicion of choledochal cyst and prevention of its late complications.MAF: Data collection, Manuscript writing and analysis. He is also responsible for the integrity and accuracy of the manuscript.SAK: Manuscript writing and review analysis.MIM: Review analysis."}
+{"text": "During the advent of the COVID-19 pandemic, multiple cases were reported of the association between SARS-CoV-2 and invasive pulmonary aspergillosis. The diagnosis of Covid associated pulmonary aspergillosis (CAPA) remains difficult, especially in critically unwell patients. We describe those treated with VV ECMO and diagnosed with CAPA in the national centre for ECMO in Ireland during the COVID-19 pandemic, as well as their treatment course and outcomes.We retrospectively collected data on all patients who received ECMO during the COVID-19 pandemic in Ireland\u2019s national ECMO centre between May 2020 and January 2022. Data was collected from electronic health care records and cross referenced with positive microbiological samples. The 2020 ECMM/ ISCHAM consensus criteria was used to classify CAPA diagnoses.37 patients with diagnosed SARS-CoV-2 infection were treated using ECMO. The average age was 46 years (SD 9.3). 15 (41%) of those were female. The mean number of days spent in an intensive care unit (ICU) was 50 (IQR 45-67). 14 (38%) had diagnosed Hypertension, 10 (27%) had Diabetes Mellitus and 1 (2.7%) had known Chronic Kidney Disease requiring dialysis. CAPA was diagnosed in 7 (19%) cases. Using the criteria, no cases were proven as histology samples were not obtained. 1 (14%) case fitted the criteria for possible diagnosis while 6 (86%) cases fitted criteria for probable diagnosis based on biochemical, microbiological and radiological findings. Of these, all received steroids prior to diagnosis, while 3 (43%) also received tociluzumab. 6 (86%) patients received dual antifungal agents and 1 (14%) patient received voriconazole alone. In terms of outcome, 15 (41%) were discharged to another intensive care unit, 1 (3%) discharged to another acute hospital and 2 (5%) to a rehabilitation unit. 16 (43%) patients died while 3 (8%) were discharged home. Of the 7 patients diagnosed with CAPA, 5 (71%) patients died in ICU while 2 (29%) were transferred to other units with final outcome unknown.Although 2020 guidelines available from ECMM/ISCHAM are used to define strict diagnostic criteria of CAPA, our study demonstrates the need for further research into how other factors may contribute to this diagnosis, including pre-determined risk factors or the use of ECMO.All Authors: No reported disclosures"}
+{"text": "High rates of HIV and sexually transmitted infections (STIs) among people with mpox have been reported. Guatemala has the highest number of mpox cases reported in Central America. Data on this topic in the region is lacking. We report the prevalence of STIs and HIV in people evaluated for mpox at Hospital Roosevelt in Guatemala City.We conducted a cross-sectional analysis of confirmed mpox cases with outpatient care at our institution between July 2022 and January 2023. Sociodemographic and clinical data was retrospectively collected. This analysis includes new diagnoses of HIV, syphilis, chlamydia, gonorrhea, mycoplasma genitalium infection and herpes virus simplex (HSV) infection. Diagnoses were confirmed by serology or nucleic acid amplification tests. Rates of HIV/STIs were assessed and association with sociodemographic, behavioral and clinical characteristics was analyzed through non-parametric statistical tests.Sixty participants with mpox were included. All cis-gender male, 34 (56.6%) younger than 30 years old, 52 (86.6%) were residents of Guatemala City, 57 (95%) men who have sex with men (MSM), 51 (85%) had above secondary education, 36 (60%) with known HIV-positive status. Recent participation in group sex was reported in 9 (15%) participants and inconsistent or no condom use in 49 (81.6%). Among participants with known HIV-positive status 34 (94.4%) had CD4 count > 200/\u00b5L and 32 (88.9%) had a HIV viral load < 200 copies/ml. Two previously undiagnosed HIV infections were detected. Overall, 27 new STIs were found in 20 (33.3%) participants (5 had more than one STI). Comparisons between participants with concurrent STIs and those without are shown in Table 1. Nine cases of syphilis were detected. Eighteen STIs involved mucous membranes . Rates by site are shown in Table 2.At least one STI was detected in a third of the mpox cases with syphilis being the most frequent. Almost half of STIs cases involved the anorectal site. People with previously known HIV-positive status had a significantly higher rate of STIs. HIV/STI care is key to an appropriate mpox management.All Authors: No reported disclosures"}
+{"text": "To evaluate current routine trabeculectomy technique preferences among Australian and New Zealand Glaucoma Society surgeons regularly performing trabeculectomy surgery.Survey of experienced surgeons who perform trabeculectomy.Forty-nine surgeons  participated in the survey. Trabeculectomy was performed as day surgery  under local anesthesia . The surgical techniques most commonly used were a corneal traction suture , fornix-based conjunctival flap  and half-thickness scleral flap . Mitomycin C antifibrotic agent was used in routine cases by 45/46 (97.8%) surgeons. Surgeons applied the antifibrotic agent under the Tenon layer with a pledget  with a concentration of 0.02%  for 2  or 3\u2009min . The Kelly  and the Khaw Descemet  punches were used to perform the sclerostomy. Most surgeons performed a peripheral iridectomy in all phakic patients , but less commonly in pseudophakic patients . Techniques for closure of the limbal conjunctival edge were quite varied with a combination of suturing including purse string , wing  and horizontal mattress sutures . Surgeons reviewed their routine patients four times in the first month  and continued the postoperative topical steroids for 3\u20134 months .Although a wide range of techniques for trabeculectomy exists among surgeons, there are consistent procedures currently in use to optimize patient outcomes. This report will assist surgeons in choosing which surgical techniques fit their best practice. Trabeculectomy is designed to divert aqueous from the anterior chamber via a sclerostomy under a scleral flap to an external bleb. Filtration surgery is an option in patients who are using maximally tolerated medications and/or have had laser treatment and require further lowering of their intraocular pressures. It may also be considered as initial management for those presenting with advanced disease . The tecA survey of glaucoma surgeons attending an online meeting of the Australian and New Zealand Glaucoma Society (ANZGS) (as listed at the end of the paper) was conducted in February 2021. Participation was voluntary and no compensation was offered or provided for responding. The 39-question online survey, divided into five polls, was formulated and modified by the authors after trialing it on four trabeculectomy surgeons.Participants were asked to recall their technique for a routine primary trabeculectomy performed in an adult. Questions on each step of the trabeculectomy were presented and respondents independently answered via an online polling software . At the live presentation, after respondents answered each question, the results were displayed and discussed. During the presentation, participants were also able to type in questions and comments in a \u201cchat box\u201d. This commentary was also recorded as part of the survey.Data were collected and analyzed anonymously. Respondents reported their technique of choice for each surgical step. These data were collated for all respondents. The total number of responses and percentages are presented. Data from the returned questionnaires were tabulated and analyzed using Microsoft Excel .Forty-nine surgeons  participated in the study. Most surgeons were aged 30\u201349 years old  with the rest, 50\u201359 years old  and >60 years old . The majority did glaucoma fellowships in the UK  with the rest in the US  or elsewhere . The number of years in specialist practice was five or more for 32/49 (65.3%) of the surgeons, with the average number of trabeculectomies performed per year greater than 10 by 36 (73.5%) surgeons and greater than 20 by 21 (42.9%) surgeons. All participants answered the majority of the questions; however, there was a loss of two participants from Polls 2, 4 and 5 and a loss of three participants from Poll 3.The majority of patients prior to trabeculectomy did not have any pre-treatment; however, in 22/47 (46.8%), pre-treatment included topical steroid 16/47 (34.0%) and/or topical pilocarpine therapy 8/47 (17.0%) . Only three surgeons routinely used an Ong glaucoma lid speculum . The majority utilized a superior conjunctival flap that was fornix-based 43/47 (91.5%). There were various techniques to fashion the scleral flap including use of a diamond knife and crescent blade 14/47 (29.8%), 11-blade and crescent blade 18/47 (38.3%), crescent blade only 7/47 (14.9%) and 11-blade only 2/47 (4.3%). The scleral flaps ranged in size, with the most common size being 3\u2009\u00d7\u20094\u2009mm 21/47 (44.7%) and half-thickness of the sclera (400\u2009\u00b5m) 38/47 (80.9%). The flap was either rectangular 32/46 (69.6%), trapezoidal 9/46 1(9.6%) or square 4/46 (8.7%). The majority of surgeons used mitomycin C (MMC) 45/46 (97.8%), applied as a pledget under the Tenon layer 36/46 (78.3%) at a concentration of 0.02%\u201437/46 (80.4%). There were a number of surgeons who utilized injection of the MMC under the Tenon capsule 8/46 (17.4%). The most common exposure times for MMC were 3\u2009min 30/46 (65.2%) or 2\u2009min 11/46 (23.9%). Most 29/46 (63.0%) surgeons did not place MMC under the scleral flap. The scleral flap sutures were pre-placed before the sclerostomy in 29/46 (63.0%), with 25/46 (54.4%) using three stitches and 13/46 (28.3%) using two stitches.The most common instrument for making the sclerostomy was a Kelly punch 26/46 (56.5%); however, the Khaw Descemet punch 19/46 (41.3%) was also popular. There were no surgeons who handcut the sclerostomy. The peripheral iridectomy was performed by surgeons in phakic patients very commonly 46/47 (97.9%), however, less commonly in pseudophakic patients at 34/47 (72.3%) in all cases and 11/47 (23.4%) in most cases. The size of the peripheral iridectomy was usually around 1\u20132\u2009mm\u201431/47 (66.0%) or smaller at less than 1\u2009mm\u201414/47 (29.8%). A common technique was to test the flow after scleral flap closure 45/47 (95.7%). The most common type of sutures to close the conjunctiva were 10/0 nylon 36/47 (76.6%) with other stitches used including either monofilament or braided 9/0 polyglactin 910 6/47 (12.8%) or a combination 5/47 (10.6%). The suturing technique for the conjunctival flap was quite variable with surgeons using purse-string sutures 21/47 (44.7%), wing sutures 20/47 (42.6%) and/or horizontal mattress 33/47 (70.2%). The majority of surgeons performed a Seidel test at the end of conjunctival closure 31/47 (66.0%). In terms of intraoperative medications, a subconjunctival antibiotic was used in 37/47 (78.7%), subconjunctival steroid in 45/47 (95.7%) and topical atropine in 19/47 (40.4%).Most surgeons do not posture the patient on day one post-op 43/47 (91.5%). Patients were reviewed either three or four times in the first month 43/47 (91.5%). Topical steroids were mostly used in the first three to six months 40/47 (85.1%). Postoperative subconjunctival 5-fluorouracil anti-scarring injections were routinely performed in 17/47 (36.2%). There was no use of adjunctive devices such as the ExPRESS  or Ologen implant .Although the practice patterns for trabeculectomy have been studied by a number of surveys \u20138, thesePre-treatment with topical steroids was a routine part of trabeculectomy for a third of surgeons 16/47 (34.0%). It was used particularly in eyes with ocular surface inflammation and a history of previous uveitis. Most trabeculectomies were performed under monitored local anesthesia 44/47 (93.6%) as a day procedure 39/47 (83.0%), indicating the trend away from general anesthesia in routine adult patients that has occurred progressively over the past 20 years . TrabecuA corneal traction suture is an effective way of infraducting the eye to provide good exposure of the superior bulbar conjunctiva. Placing a superior rectus suture, although previously one of the most techniques , often rThe Moorfields Safer Surgery System for Trabeculectomy was formulated by Professor Sir Peng Khaw . This haThe scleral flap has evolved over many years with various techniques . The flaThere are several areas where there is significant variability. The use of an anterior chamber maintainer was quite popular amongst the more recently trained of the group. The infusion of fluid maintains the anterior chamber after the sclerostomy so the eye pressure can be adjusted by titrating the flow through the scleral flap . The sizPostoperative guttae atropine 1% 19/47 (40.4%) was in common use and can relax the ciliary muscle with pain relief, may reduce postoperative bleeding, can reduce anterior chamber shallowing as well as reducing the risk of aqueous misdirection, stabilizes the blood aqueous barrier and prevents central posterior synechiae. Disadvantages of its use include a dilated pupil, which may blur vision and increase lens-corneal touch in shallow anterior chambers .There are several limitations of this survey. A multiple-choice format may introduce bias by limiting possible responses to the options offered. However, the choices were carefully designed to include the most common techniques for each step and the chat box discussion further elucidated other options. Furthermore, answers given by some respondents may not accurately reflect their actual clinical practice because of errors in recall. Given that the results were anonymously collected, this would be unlikely. The study included most of the higher volume trabeculectomy surgeons in Australia and New Zealand, although it was not possible to obtain the opinions of every experienced trabeculectomy surgeon in the region. Ideally, trabeculectomy outcomes of all the surgeons involved could be compared to the various techniques in order to determine the most efficacious techniques. There was no attempt to compare the technique to trabeculectomy outcomes; however, the techniques used have been well documented with efficacy established .The significant variations in practice preferences of trabeculectomy techniques among Australian and New Zealand glaucoma surgeons reflect a lack of good evidence to guide practice or maybe it reflects what works clinically, given the variable outcomes that one sees in our glaucoma surgery patients. Although the optimal clinical practice is poorly defined, the results of this survey provide a means for ophthalmologists to critically examine their own clinical preferences through comparison with those of their colleagues and adopt different techniques, given the variable nature of each eye\u2019s response to glaucoma surgery. This survey also provides a baseline against which clinical trends can be identified and assessed in future. It may stimulate consideration of a registry-base and potential randomized controlled trials that could lead to refinement of surgical techniques to improve success rates, ultimately reducing the complications of this highly effective surgical procedure.A wide range of techniques for trabeculectomy exists amongst surgeons.There are consistent procedures currently in use to optimize patient outcomes.Areas of the surgical technique where surgeons had overwhelming consistency included use of a corneal traction suture, fornix-based conjunctival flap, application of mitomycin C, peripheral iridectomy in phakic patients, intraoperative injection of subconjunctival steroid and review three to four times in the first month postoperatively."}
+{"text": "Primary gastric lymphoma is uncommonly reported in India. We retrospectively analyzed their data in a northern Indian teaching hospital.Helicobacter pylori serology were done, with 2 of 3 tests positive being considered diagnostic. We aimed to study (i) the frequency of primary gastric lymphoma among gastric neoplasm patients, (ii) its clinical profile, (iii) the diagnostic procedures needed, and (iv) the frequency of H. pylori infection among them.During a 12-year period (2000-2012), endoscopic and surgical biopsies were assessed for gastric neoplasm. Gastric biopsies from normal-looking areas, rapid urease test, and H. pylori infection was confirmed in 7 (23.3%), 12 (40%), and 21/29 (72.4%) patients by rapid urease test and histopathology and positive anti-H. pylori IgG serology, respectively. By 2 tests, H. pylori was detected in 12 (40%) patients. Though in 60% primary gastric lymphoma was diagnosed on endoscopic biopsy, in 40%, surgical resection was required. The endoscopic and surgical diagnosis groups were comparable in age (53.4 years vs. 52.7 years), sex , H. pylori infection (38.9% vs. 16.7%), presentation with dyspepsia (38.9% vs. 16.7%), organic symptoms (61.1% vs. 83.3%), and the need for repeated endoscopic biopsies before diagnosis (12.% vs. 33.3%).Thirty out of 324 (9.2%) patients  with gastric neoplasm had primary gastric lymphoma. Presentations included dyspepsia , gastric outlet obstruction , upper gastrointestinal bleeding , dysphagia , malignant ascites , and others . H. pylori infection (40%).Primary gastric lymphoma is not uncommon (9.2%) in India, often missed on endoscopic biopsy and is associated with  These data reveal a high frequency of primary gastric lymphoma (PGL) in the study population (9.2%).Helicobacter pylori infection (40%) and PGL.The study also confirms an association between Repeated negative endoscopic biopsies may delay the diagnosis of PGL; the development of newer diagnostic tools for early detection of PGL is important.1 However, there is limited data on frequency, clinical spectrum, and outcome of PGL from India. Most of the earlier reports on PGL from India were either case reports or small series.3 A single study published till date from 2 centers, one from northern, and the other from eastern India showed that 5% of gastric neoplasm in India are constituted by PGL,4 a frequency somewhat similar to that in some of the western and developed eastern countries. Moreover, in this study, endoscopic biopsies missed the diagnosis of PGL, and surgically resected specimens often revealed the diagnosis. This finding raises the possibility that PGL might be missed in India unless it is looked for. Moreover, the available data, though scanty, might challenge the myth that PGL is uncommon in India.Gastric neoplasms (GN), which include adenocarcinoma and primary gastric lymphoma (PGL), are not uncommon causes of cancer-related mortality worldwide.6As defined by Dawson, PGL involves predominantly the stomach and the lymph nodes corresponding to its lymphatic drainage. Involvement of the other lymph node groups or any extranodal organs  in an early stage of the disease practically excludes the diagnosis.Helicobacter pylori causing chronic inflammation of the gastric mucosa is an important factor in the pathogenesis of gastric diseases including gastric adenocarcinoma and PGL.8 However, the data on this issue from India, where H. pylori is endemic, are somewhat scanty. A few studies have shown that high H. pylori IgG titers are also associated with an increased risk of gastric cancer possibly due to increased expression of a cytotoxin-associated gene (CagA)10; while the presence of a marked degree of gastric atrophy and intestinal metaplasia (IM) is associated with gastric adenocarcinoma. Primary gastric lymphoma occurs in patients with a lesser degree of gastric atrophy and IM.11 Accordingly, we undertook a study with the aim to know (i) the frequency of PGL among patients with gastric neoplasm, (ii) their demographic and clinical profile, (iii) the diagnostic procedures needed, and (iv) frequency of H. pylori as compared with a group of historical controls with non-ulcer dyspepsia .The present study included 30 patients with PGL out of 324 with gastric neoplasms whose data were prospectively maintained on a questionnaire including demographic, clinical, endoscopic, histological, and serological parameters as part of the project initially funded by the Indian Council of Medical Research during a 12-year period (2000-2012) in the department of Gastroenterology at Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, a tertiary referral center in northern India. As these data were collected as a part of a prospective study initially, the protocol was approved by the Institutional Ethics Committee.Multiple (6) biopsies were obtained from the tumor margin in 10% neutral buffered formalin during esophagogastroduodenoscopy (EGD) using a video endoscope . To ascertain the type of malignancy, endoscopic biopsy and surgically resected specimens were assessed after hematoxylin and eosin (H & E) staining.H. pylori, IM, and gastritis (grading done by updated Sydney system) after H & E and Giemsa staining.12 These were assessed by expert pathologists, who were blinded to the endoscopic findings. Rapid urease test (RUT) for H. pylori infection was done on one biopsy each from antrum and body. Color change of an in-house solution from yellow to pink over a 2-hour period was used to perform RUT, the same has already been validated in a previous study.13 Three microliters of fasting serum sample was taken for serological examination in a plain vial using an enzyme-linked immunosorbent assay for anti-H. pylori IgG antibody using a commercial kit . Antibody concentration was deemed positive at a cut-off value of \u226530 enzyme immune unit. Positive results in any 2 of these 3 tests were considered to be diagnostic of H. pylori infection.5 Frequency of H. pylori infection among patients with PGL was compared with the data of 101 patients with NUD, currently called functional dyspepsia published earlier as controls.4Biopsies from normal-looking areas were also taken to evaluate for 2) test with Yates correction wherever applicable.Continuous variables were presented as mean \u00b1 standard deviation or median and range or interquartile range. Categorical variables were analyzed by the Chi-squared .A Of 324 patients, 30 (9.2%) had PGL. The median age of patients with PGL was 56 years (range 25-72 years) at diagnosis and 22 patients (73.3%) were male. History of cancer among family members was present in 6 (20%) subjects. Of the 6 patients with a family history of cancers, 1 reported gastric, 2 esophageal 1 colon cancer, and 2 lung cancers among first- and second-degree relatives.14 More than half of the patients complained of epigastric pain (66.7%), abdominal fullness (55.2%), and indigestion (51.7%).Of 30 patients with PGL, 9 (30%) presented with dyspepsia with or without weight loss, 7 (23.3%) with gastric outlet obstruction (1 each with dyspepsia and gastric outlet obstruction had gastric amyloidosis in addition to the PGL), 5 (16.7%) with upper gastrointestinal bleeding, 4 (13.3%) with dysphagia, 3 (10%) with malignant ascites; in 2 (6.7%), the diagnosis of PGL was established on histopathological examination of resected gastrectomy specimens performed with a suspicion of gastric cancer. One patient with PGL with gastric amyloidosis and the other presenting with acute pancreatitis have been reported previously.Most patients (67.9%) reported unintentional weight loss (8.3 \u00b1 3.5 kg weight reduction in 4.3 \u00b1 2.6 months). Alarm symptoms such as anorexia (79.3%) and reduced appetite (65.5%) were often reported; 85.7% had anemia (hemoglobin 9.0 \u00b1 1.6 g/dL).Of 28 patients having records of EGD, the lesion was in the antrum of the stomach in 2 (7.1%), body in 9 (32.1%), gastroesophageal (GE) junction in 1 (3.6%), duodenum in 1 (3.6%), and diffuse in 15 (53.6%). The major endoscopic findings were ulceroproliferative growth in 10 (35.7%), ulceration in 7 (25%), nodular growth in 7 (25%), gastric polyp in 1 (3.6%), gastric outlet obstruction in 1 (3.6%), and unclassified in 2 (7.1%) .Among 28 patients with PGL, 7 (25%) showed the presence of IM. Histopathological examination revealed gastritis in 17/27 (63%), among whom 14 (82.4%) had antral and 3 (17.6%) had body gastritis. Of these 17 patients, 11 (64.7%) showed mild, 5 (29.4%) moderate, and only 1 (5.9%) showed severe gastritis. Lymphoid follicle was also present among 17/28 (60.7%) patients on histology .The diagnosis of PGL was confirmed in 15 (50%) patients on endoscopy and in 3 (10%) on cytology obtained by fine-needle aspiration. The diagnosis of PGL was made on histological examination of surgically resected stomach in 12 (40%) patients in all of whom repeated endoscopic biopsies failed to confirm the diagnosis of PGL. Bone marrow core biopsies also showed lymphomatous infiltrate in 2/16 (12.5%) patients only.Computed tomography data were available in 16 patients with PGL. Using the TNM  staging system, 3 patients (18%) presented at stage I, 4 (25%) at stage II with local or distant nodal involvement, and 4 (25%) at stage III with or without invasion of adjacent structures, distant abdominal nodal extension, without distant metastasis. There were also 5 patients (31.3%) who were at stage IV with advanced disease.Of the 12 patients for whom immunohistochemistry (IHC) data were available, CD20 and leukocyte common antigen were frequently positive among patients with PGL in 9 (75%) and 8 (66.7%), respectively. However, other lymphoma markers like CD3, cyclin D1, cytokeratin, epithelial membrane antigen (EMA), vimentin, B-cell lymphoma 2 (BCL2), CD117, CD34, desmin, and smooth muscle actin (SMA) were positive only in 1 case each. IHC also showed amyloid deposits with kappa light chain positivity in two (16.7%) cases.H. pylori infection was confirmed in 7 (23.3%) and 12 (40%) patients by RUT and histopathology, respectively; 21/29 (72.4%) patients had positive anti-H. pylori IgG serology. Using any 2 of the 3 test positive criteria, H. pylori was detected in 12 (40%) patients with PGL. Among historical controls with NUD, H. pylori infection was detected by RUT in 46/101 (46%), histology in 55/101 (55%), and anti-H. pylori IgG serology in 85/101 (84%). The H. pylori detection rate was comparable among the PGL patients and historical controls with NUD (P = .6).H. pylori infection was also as common among PGL patients as historical controls with NUD.The present retrospective study suggests that PGL is not uncommon in India. About 40% of the patients with PGL may not be diagnosed even with repeated endoscopic biopsies and require histological examination of surgically resected specimens. H. pylori infection is known to have long-term consequences. Chronic H. pylori infection has been shown to predispose to gastric atrophy and gastric cancer development. Histological evaluation of gastric biopsies in patients with H. pylori infection shows that it significantly predisposes to the development of atrophic gastritis and intestinal metaplasia and subsequently leads to gastric carcinogenesis.15 Though gastric adenocarcinoma is the commoner form of GN, PGL is a form of GN with a better prognosis. Hence, its detection has an important clinical consequence.4 In our study, almost one-third of the patients presented with non-specific symptoms (dyspepsia with or without weight loss); these results were in line with other studies which have reported epigastric pain as the most common presentation.17 A family history of cancer was also present in a significant proportion of these patients.Compared with a previous study reporting the prevalence of PGL, we found an even higher frequency of PGL, potentially challenging the myth that PGL is uncommon in India.H. pylori infection, presentation with dyspepsia with or without weight loss, presentation with organic symptoms, and the need for repeated endoscopic biopsies before conclusive diagnosis was established. To the best of our knowledge, no previous study has compared the endoscopically and surgically diagnosed patients with PGL. Both the groups being compared have major implications as it is not possible to predict based on clinical or imaging characteristics which patients may be diagnosed by endoscopic biopsies or would require surgical resection before the diagnosis can be made  were positive. In the earlier studies, only histopathology was considered diagnostic of the infection. However, the frequency of H. pylori infection in our study was similar to existing literature.17 Our data show that careful elicitation of clinical history, including alarm symptoms and family history, is important to diagnose PGL. Unintentional weight loss was a predominant symptom at presentation in our study, in contrast with the data from the west, where weight loss is less commonly seen as a presenting symptom.19 Multiple studies have shown that endoscopic sensitivity declines substantially for the detection of lymphoma compared to other malignant lesions; our study reiterated that methodically taken biopsies are important for pre-operative diagnosis, and some cases may still require surgery and IHC to establish a confirmatory diagnosis.20 Immunohistochemistry is required to establish a definitive diagnosis; it has been recommended that all biopsy specimens be subjected to IHC.22 Although newer diagnostic modalities like texture analysis of positron emission tomography (PET) are coming up, biopsy and IHC remain the gold standard for PGL diagnosis.23 Repeated negative endoscopic biopsies may also delay the time to diagnosis and may eventually lead to dismal outcomes.24We diagnosed The inclusion of historical controls, lack of immunohistochemistry data for all the patients, and its retrospective design are some of the limitations of this study.H. pylori infection is as common among PGL patients as historical controls with dyspepsia earlier called non-ulcer dyspepsia.Primary gastric lymphoma is not an uncommon gastric malignant tumor in India, which contradicts the earlier belief. About half of the patients with PGL may not be diagnosed even with repeated endoscopic biopsies and require histological examination of surgically resected specimens."}
+{"text": "Identification of clinical characteristics and risk factors for mortality in COVID-19 is important for early detection and precise case management. The study aimed to describe the sociodemographic, clinical, and laboratory characteristics of in-hospital COVID-19 deaths in Almadinah Almonawarah city, Saudi Arabia, and to identify risk factors for early mortality among them.This is an analytical cross-sectional study. The main outcomes were demographic and clinical characteristics of COVID 19 patients who died from March till December 2020, during the hospital stay. We collected 193 records of COVID-19 patients, from two major hospitals in Al Madinah region, Saudi Arabia. Descriptive and inferential analysis were performed to identify and relate the factors of early death.Out of the total deaths, 110 died during the first 14 days of admission (Early death group) and 83 died after 14 days of admission (Late death group). Early death group had a significantly higher percentages of old age patients (p=0.027) and males (72.7%). Comorbidities were found in 166 (86%) of cases. Multimorbidity were significantly higher in early deaths than in late deaths 74.5% (p=<0.001). Women had significantly higher mean values of CHA2SD2 comorbidity scores . Moreover, predictors of high comorbidity scores were older age (p=0.005), higher respiratory rate (p=0.035), and raised alanine transaminase (p=0.047).Old age, comorbid illness, and severe respiratory involvement were prevalent among COVID-19 deaths. Comorbidity scores were significantly higher in women. Comorbidity was found to be significantly more associated with early deaths. Coronavirus disease 2019 is a viral respiratory illness caused by SARS-CoV-2 virus.9Poor outcomes in COVID-19 were linked to severe respiratory involvement, cardiac, and renal involvement.14This study aimed to describe the demographic, clinical, and laboratory characteristics of in-hospital COVID-19 deaths in Almadinah Almonawarah city, Saudi Arabia, and to identify risk factors associated with early mortality among them. The study findings would be useful in preparing the health systems to prioritize and locate the resources according to their imminent need, towards holistic care.This is a records-based analytical cross-sectional study involving mortality cases from two large hospitals , selected purposely in Al-Madinah Almonawarah city, Saudi Arabia. We included all COVID-19 PCR positive cases who died in hospital from March to December 2020.Data of 193 deceased patients were extracted from medical records using a standard data collection form designed by the authors. We calculated CHADS2 index The study was approved by the Institutional Review Board (IRB) General Directorate of Health Affairs in Madinah (Ref: #H-03-M-084). All data were anonymous and informed consent was not needed and waived as data were retrieved retrospectively.A total of 193 COVID-19 deaths were reported during hospitalization in the study period (March-December 2020). The median interval from hospitalization to death was 12 days with a range of 0-80 days. Out of them, 110 died during the first 14 days of admission (Early death group) and 83 died after 14 days of admission (Late death group). Nealy half of COVID-19 deaths were of old age [\u226565 years] 98 (50.7%) with a significantly higher prevalence of old age patients in the early death group (p=0.027). Male gender was predominant in overall 134 (69.4%), in early death group 80 (72.7%), and in late death group 54 (65%) . HoweverComorbidities were prevalent in the reported cases, 166 (86%). Diabetes and hypertension were the most common comorbidities; Multimorbidity was significantly higher in the early death group than in the late death group (82 (74.5%) Vs. 35(42.1%); p=<0.001). Whereas, chronic kidney disease was significantly higher in the early death group (p=0.04) . The malNo significant difference in mean CHADS2 or CHA2DS2-VASc comorbidity indices between early and late death groups. However, the early death group had a higher percentage of low and intermediate risk . Women hMoreover, predictors of high multimorbidity scores were older age , higher respiratory rate , raised alanine transaminase (ALT) . Besides, 60 (31%) had evidence of ARDS.Dyspnea, fever, and cough were the most common symptoms. Dyspnea was significantly more prevalent in the early death group 89 (80.9%) versus 55 (66.2%) in the late death group (p=0.021); respiratory failure was reported in 60.6% of deaths; while gastrointestinal symptoms were significantly more prevalent in the late death group 21(25.3%) compared to the early death group 14 (12.7%)  among COVID-19 deaths with a significantly higher prevalence of old age in the early death group (p=0.027). Previous studies reported age more than 65 to be a strong predictor of mortality.26We found a high percentage of comorbidities (86%) and multimorbidity were significantly higher in early deaths than in late deaths (74.5%) Vs. (42.1%). The early death group had a significantly higher percentage of cases with CHA2DS2-VASc scores low and intermediate risks while the late death group has a higher percentage of no risk category. Previous studies28Among comorbidities, chronic kidney disease (CKD) contributed to 9.5% of cases in this study with a significantly higher percentage in early deaths as previously reported CKD was a major predictor of mortality28In this study respiratory involvement was more prevalent in the early death group while gastrointestinal involvement was more prevalent in the late-death group , II. SevThe results of the current study and previous reports indicate that the total CHA2DS2-VASc score rather than individual comorbidity is a predictor of morbidity and mortality. So, CHA2DS2-VASc could be used as a prognostic factor for risk assessment at hospital admission to detect those at high risk and initiate rapid management and close follow-up.46 and liver injuryAbnormal laboratory parameters were present in most cases in our study. We found a high mean creatinine level and elevated creatinine at baseline in 102 (57.6%) of cases, these findings support previous reports describing acute kidney injury in COVID-19 cases.The findings of this study suggest that older age, comorbidities, and respiratory involvement are common findings in the early death group. Older age and neutrophil lymphocyte ratio are potential predictors for early mortality. This can be utilized for triage and prioritization in hospital or ICU admission. Comorbidity scores are useful risk assessment tools for COVID-19 patientsThis study has some limitations, deaths out of hospital were not included and survival analysis could not be performed due to lack of control group.Old age, and comorbid illnesses are more common among early COVID-19 deaths. Comorbidities and neutrophils/lymphocytes ratio were strongly associated with early mortality.It is recommended that clinicians and healthcare workers need to identify COVID-19 patients at risk of severe disease and death for timely and proper intervention. Risk assessment scores can be introduced for the triage of COVID-19 cases as prognostic indicator of morbidity and mortality. Public health authorities should exert more efforts to increase awareness of the elderly and those with comorbidities to seek medical advice early and to follow infection prevention measures to avoid catching COVID-19 disease. Future studies are required to investigate predictors of morbidity and mortality including in and out of hospital deaths."}
+{"text": "We investigated an outbreak of SARS-CoV-2 variant BA.2.86 in an East of England care home. We identified 45 infections , among 38 residents and 66 staff. Twenty-nine of 43 PCR swabs were sequenced, all of which were variant BA.2.86. The attack rate among residents was 87%, 19 were symptomatic, and one was hospitalised. Twenty-four days after the outbreak started, no cases were still unwell. Among the 33 resident cases, 29 had been vaccinated 4 months earlier. By 5 September 2023, outside of this outbreak, 33 cases of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant BA.2.86 had been reported globally from nine countries . This neA case was defined as a care home resident or staff member with SARS-CoV-2 infection detected by lateral flow device (LFD) or reverse transcription PCR (RT-PCR) between 20 and 28 August 2023. Symptomatic cases reported a variety of cough-cold symptoms, chestiness, lethargy, fatigue, drowsiness or loss of taste or smell.An epidemic curve of the outbreak is shown in Given the rapid spread and concerns from the general practitioner (GP) that symptoms were qualitatively worse than observed in previous outbreaks, the care home management team requested UKHSA support. In total, 17 people were LFD-positive (seven residents and 10 staff). Mass swabbing for PCR was done on 26 August for all residents (n\u2009=\u200938) and for all symptomatic or LFD-positive staff members .Overall, 33 of 38 residents tested positive by LFD or PCR (AR\u00a0=\u00a087%), of whom 19 were symptomatic , Table 1All 11 symptomatic staff were tested and one asymptomatic. Overall, 12 of the total staff of 66 tested positive by LFD and/or PCR (AR\u00a0=\u00a018%) and no tested staff were negative. Ten symptomatic staff had recovered within 14 days of symptom onset.The incident management team were satisfied by the care home\u2019s implementation of infection prevention and control measures according to current UKHSA guidance . Staff cSelf-reported vaccination statuses were verified by linkage to the national immunisation monitoring system for all residents and for 10 of 12 staff cases, enabling calculation of the time since their last dose . Thirty-The infection AR among residents vaccinated 4 months before the outbreak was 29 of 34 : 69\u201395) compared with four of four  in those with no evidence of vaccination at this time . This dihttp://dx.doi.org/10.55876/gis8.230908dx) and 27 of the 29 sequences generated for the confirmed BA.2.86 infections in this cluster [All positive PCR tests were sent for whole genome sequencing using the Artic protocol (primer pool version 5.3.2) at UKHSA Colindale Virus Reference Department . In tota cluster .nsp2, 2527G>A; and a non-synonymous change in nsp3, P153L. The clade is most closely related to sequences from Sweden and France (marked A in nsp2: Y441C) with these sequences compared with other BA.2.86 sequences. Additional details on genetic mutations within this clade are made available in the Supplement.The sequences from this cluster formed a unique clade (labelled as Care home outbreak in Supplement.Twelve of 15 LFDs were of the same brand of test kit (Orient Gene), for which previously a sensitivity of 72% (95% CI: 67\u201376%) was observed during a period of predominant Omicron infections . Given cAt the time of the outbreak investigation, data suggested established community transmission of BA.2.86 due to the detection of multiple sporadic cases in different regions of the UK . This isCases were initially detected in the care home described here by LFD tests: symptomatic residents were tested according to current guidance, and while staff testing is no longer required, 10 staff self-tested of their own accord . The majThe AR in this setting was substantially higher than that seen in nine UK care homes that experienced outbreaks in December 2021 to January 2022; the early period in which the Omicron variant circulated in the UK (23%) , althougThe hospitalisation rate among residents was lower than that reported in care home outbreaks during early circulation of the Omicron variant in December 2021 to January 2022 (11%)  and DeltThe high vaccination rate in the care home and lack of substantial vaccine effect against infection in this outbreak 4 months after a booster dose suggests notable immune evasion. This is not unexpected as we have seen rapid waning of VE against infection and mild disease with other vaccines and previous Omicron subvariants . While tStatistical assessment indicated that the LFD predominantly used in this outbreak had non-inferior sensitivity to detect BA.2.86 compared with previous SARS-CoV-2 Omicron strains . HoweverThis outbreak has provided useful epidemiological insight into the characteristics of the SARS-CoV-2 BA.2.86 variant. While the findings may not be generalisable to other settings, we see evidence of limited VE against infection 4 months after vaccination, high transmissibility of the variant but no suggestion of increased severity."}
+{"text": "Cancer patients with pneumonia (PNA) have 2 to 21 times higher mortality rate compared to the general population. The Pneumonia Severity Index (PSI) and CURB-65 scale have been used to predict mortality for patients with community acquired pneumonia (CAP). While these scales are well studied in the general population, there is a paucity of research on the utility of PSI and CURB-65 for predicting outcomes from CAP in patients with cancer. In this study, we assessed the relationship between PSI and CURB-65 score and 30-day mortality of CAP in cancer patients at Memorial Sloan Kettering Cancer Center (MSKCC).A prospective study at MSKCC was conducted between 01/2023 and 06/2023 on patients who presented with clinical symptoms consistent with PNA and had a urine streptococcus antigen test sent for evaluation. PNA was defined as pulmonary infiltrates on chest X-ray or CT < 48 hours of index event and \u2265 1 clinical symptoms . Descriptive statistics were performed to report participant outcomes based on PSI and CURB-65 score and to identify the factors associated with CAP in this population. PSI and CURB-65 scores were derived as described in the literature, based on patient comorbidities (including neoplasia), clinical signs and laboratory values. Higher score is associated with worsening 30-day mortality.For 86 participants with who presented with symptoms of PNA and had a urine antigen test sent, 43 (50%) were diagnosed with CAP . The median age was 70 (range: 29-88), 21 (49%) were male, and 16 (37%) had hematologic malignancies (Table 1). Etiologies of CAP were identified in 8 patients . Of the 28 patients with 30-day outcome data available, 5 (18%) died within 30 days of CAP diagnosis. All 5 deceased participants were categorized as PSI Class IV or V (moderate to high risk); however, these participants only scored 0-2 (low to moderate risk) on the CURB-65 scale (Table 2).We observed a 30-day overall mortality (n=28) of 18%. For cancer patients who present with CAP, PSI class provides a better means to assess mortality risk than CURB-65 score. Further study is needed to validate our findings.Yeon Joo Lee, MD, MPH, AiCuris: institutional research support for clinical trials|Karius: institutional research support for clinical trials|Merck: Grant/Research Support|Scynexis: institutional research support for clinical trials Susan K. Seo, MD, Merck: Grant/Research Support"}
+{"text": "Antimicrobial resistance remains one of the greatest threats to public health. A major contributing factor is overuse of antibiotics, with most prescribing occurring in the outpatient setting. CDS in the outpatient setting can improve antibiotic use by optimizing durations of therapy. The primary objective of this study was to assess the impact of CDS on prescribing of amoxicillin (AMX) and amoxicillin-clavulanate (AMC) for treatment of acute otitis media (AOM). The secondary objective was to assess prescribers\u2019 perception of the CDS.The Nemours Children\u2019s Health Antimicrobial Stewardship Program (ASP) developed antibiotic order panels (OPs) available for ambulatory care providers. The OPs provided guidance for drug formulation, dose, and duration. Providers were notified of implementation through email. Prescribed durations for AMC and AMX for AOM were compared for 3 months pre- and post-implementation. A 14-question survey was emailed to primary care providers to assess perceptions of the OPs and the impact on prescribing practices.The OP utilization rate for AMC from February to April 2022 was 27.7%. In patients \u22652 years, OP utilization resulted in a decreased average duration of therapy compared to no OP utilization, 7.6 vs 9.8 days, respectively. The OP utilization rate for AMX for AOM from April to June 2022 was 15% (342/2356). In patients \u22652 years old, 5-day and 7-day prescriptions increased from 1.7% (8/472) and 9.5% (45/472) to 11.4% (193/1688) and 12.3% (207/1688), respectively. There was a 40% response rate to the survey; 75% reported awareness of the OPs and 72.7% reported routine use. The OPs were most helpful in selection of correct dose (83.3%), duration of therapy (81.3%), and indication (77.1%). Most providers reported improved efficiency (77.1%) and agreed that the OPs led to shorter durations of therapy (81%).Development of antibiotic specific OPs with defaulted durations can be an effective strategy to improve outpatient prescribing of antibiotics. Providers are open to CDS to improve prescribing practices. Education and evidence-based support for the recommended changes in prescribing could further maximize providers\u2019 engagement and implementation of these changes.All Authors: No reported disclosures"}
+{"text": "Subarachnoid neurocysticercosis (SANCC) is the most severe and difficult-to-treat form of neurocysticercosis (NCC).We describe the clinical, radiologic, and serologic characteristics of the largest series of patients with SANCC in a non-endemic area by reviewing the medical records of patients seen at Jacobi Medical Center in New York.From 313 cases of NCC, 103 patients (32.9%) had subarachnoid involvement. Most individuals were male (65.1%) and born in Mexico (37.9%); the mean age was 41.4 years. Thirty-seven patients had only subarachnoid involvement, 50 patients had both parenchymal and SANCC, 5 patients had both intraventricular and SANCC, and 11 patients had all three spaces involved. Seventy-one patients (68.9%) presented with headaches. Of these, 35 patients had intracranial hypertension, and 27 required shunt placement. Thirty patients (29.1%) presented with seizures, most of whom had concomitant parenchymal disease. Fourteen patients (13.6%) presented as an ischemic event, 12 patients (11.7%) had symptoms due to spinal disease, and 8 patients (7.8%) had aseptic meningitis. Screening for spinal disease was performed on 61 patients. Of these, 14 patients (23.0%) had asymptomatic spinal involvement. Delay in diagnosis was found in 48 patients (49.0%) with a median of 12 months; chronic headache was the most common missed symptom (48.2%). Calcified SANCC was found in 37 patients (35.9%). Of these, 18 patients (18.4%) did not receive previous antiparasitic. Based on both CT scans and MRIs, 14 of these patients were categorized as completely calcified, and 23 patients were partially calcified with a cystic component seen on MR T2 images. The cysticercosis antigen in serum and CSF were negative in all cases of completely calcified and only in one partially calcified SANCC.This is the largest series of SANCC reported from a single center in the US and highlights the clinical spectrum. Our data also shows an important under-recognition of this severe form by the clinician and reports that calcified SANCC is common and can occur before and after treatment.All Authors: No reported disclosures"}
+{"text": "Staphylococcus aureus bacteremia is a common condition with high risk for mortality. Recent COVID-19 infection may influence the incidence and outcome of S. aureus bacteremia.Staphylococcus aureus bacteremia from June 2021-June 2022 in a rural community health care system in the Southeastern United States. Primary outcome was mortality\u2014variables included methicillin resistance, persistent bacteremia, ID consult, history of injection drug use, cardiac imaging, and COVID-19 infection within the previous 90 days.We performed a retrospective chart review of individuals with Staphylococcus aureus bacteremia. 79 were MRSA, 99 were MSSA. 57 individuals were deceased within 6 months of the positive blood culture . 31 individuals had known injection drug use complicating their illness, endocarditis was confirmed in 18 (58%) of these individuals compared to 33 (19%) of the entire population. 116 individuals (67%) had an ID consult. This study occurred during the delta and omicron COVID-19 surges in the region \u2013 18 episodes of S. aureus bacteremia occurred within 90 days of a positive COVID-19 test, and 10 (56%) of those individuals were deceased within 6 months of the positive blood culture.172 individuals experienced 188 episodes of S. aureus bacteremia carries a high risk for mortality. Endocarditis was confirmed more frequently in individuals with known injection drug use. Six month mortality in S. aureus bacteremia was higher when bacteremia occurred in the 90 days post COVID-19 infection.All Authors: No reported disclosures"}
+{"text": "The somatoform disorders are a group of psychiatric disorders that present with unexplained physical symptoms.This study aimed at assessing the prevalence and risk factors of somatoform disorders (SD) and their types among patients attending a major psychiatric clinic in Duhok Governorate/Kurdistan Region of Iraq. Our secondary aim was to assess the common presenting symptoms of conversion disorder (CD).637 subjects were randomly selected from the outpatient psychiatric clinic at Azadi Teaching Hospital in Duhok Governorate/Kurdistan Region of Iraq. Structured Clinical Interview for DSM-IV Axis I Disorders-Patient Edition (Version 2.0) was applied to diagnose patients with SDs.p <0.05), and female gender comprised most of the SD in our sample In our sample the prevalence of SD was 24%. CD comprised the vast majority of SD at 75.8%, followed by somatization disorder at 7.8% and undifferentiated SD at 5.2%. SD was most common (60.1%) in adolescents and young adults (ages 15-25 y.o.);  (67.3%), more than fifty percent were married (52.3%), majority were housewives (39.2%) and more than half of the cases were from urban areas (52.3%), but no significant association were found between SD and educational level, marital status, occupation, and residence . Regarding the symptomatic presentation of CD, vast majority of the cases presented with pseudo-seizures which comprised (81%), followed by motor symptoms which comprised (17.2%), and sensory symptoms which constituted (1.7%) only.SD was highly prevalent among patients attending a major outpatient psychiatric clinic in Duhok Governorate/Kurdistan Region of Iraq, and CD was the most common presenting form of SD. Younger age (adolescents and young adults) and female gender comprised the majority of cases. Interestingly, the most common presenting symptom of CD in our sample was pseudo-seizures.None Declared"}
+{"text": "We piloted a pharmacist-led multidisciplinary penicillin allergy de-labelling (PADL) daily ward round to determine the opportunity for PADL in a UK hospital.A daily ward round, delivered by either an antibiotic pharmacist or a junior doctor, identified adult medical and surgical patients between 7 November 2022 and 31 January 2023 with a penicillin allergy (penA) record that was preventing first-line penicillin use. An allergy history was taken before risk stratifying likelihood of future harm from penicillin re-exposure and an allergy testing method was determined [de-label on history (DOH) or after direct drug provocation testing (DDPT)]. Following successful de-label, in agreement with the responsible clinician, the antibiotic was switched to a penicillin antibiotic.Of 7214 inpatients during the study period, 1133 (15.7%) had a penA record. Of 285 allergy histories taken, 105 (36.8%) met high-risk criteria, 45 (15.8%) met low-risk criteria eligible for DOH, 73 (25.6%) met low-risk criteria eligible for DDPT and we were unable to obtain a history from 62 (21.8%) patients. Of 45 low-risk patients eligible for DOH, 40 (88.9%) were de-labelled of which 24 (53.3%) were switched to a penicillin antibiotic. Of 73 patients with a low-risk allergy history eligible for DOC, 16 (21.9%) received DDPT, of which nine were switched to a penicillin antibiotic to complete their antibiotic course. Two DOH patients experienced harm (thrush within the first 5 days and delayed skin reaction after day 5), none of the DPTs had a reaction by day 5. The switches resulted in 170 DDDs of penicillin use (predominantly amoxicillin) and reduced alternative antibiotic use by 174 DDDs (predominantly meropenem and levofloxacin).Penicillin allergy de-labelling patient pathway delivered by pharmacists and junior doctors was safe and effective and well accepted by patients and the wider clinical teams. Further work is required to optimize and streamline these patient pathways to maximize patient and health system benefit."}
+{"text": "Background: Antimicrobial stewardship programs (ASPs) often rely on International Classification of Diseases, Tenth Revision (ICD-10) codes to assess antibiotic appropriateness for provider feedback. Concordance between encounter ICD-10 codes and documented indication for antibiotics based on manual chart review varies greatly (74%\u201395%) in the inpatient setting. Data on concordance between documented indication and ICD-10 code in the outpatient setting are scarce. Methods: We conducted a retrospective cohort study of 650 randomly selected outpatient encounters with antibiotic prescriptions from walk-in and retail clinics between July 15 and September 15, 2021, at Vanderbilt University Medical Center. We performed chart review to compare documented antibiotic indication to the 3 most frequent encounter-associated ICD-10 codes. Also, 12 encounters were excluded due to insufficient available written documentation. The 95% CI for proportion of encounters with concordant antibiotic indications was calculated using Stata version 15.1 software. Results: Of the 638 antibiotic prescriptions with written documentation available for chart review, 204 (32%) were for amoxicillin, 102 (16%) were for amoxicillin-clavulanate, 61 (10%) were for cefdinir, and 56 (9%) were for azithromycin. Overall, 540  of 638 encounters had concordant antibiotic indication based on documentation in the note and associated ICD-10 for the encounter. Of the 540 encounters with concordant ICD-10 and documented indications, 348 (64%), 130 (24%), and 35 (6%) were listed as the first, second, and third ICD-10 codes, respectively. An additional 27 (5%) had a concordant ICD-10 code listed beyond the third position. In total, 125 (19.6%) of 638 encounters did not have the intended antibiotic indication as documented in the note in the 3 most frequent encounter-associated ICD-10 codes (whether a lower position or incongruent ICD-10 code with documentation). Of those 125 encounters, 42 (34%) had a documented diagnosis of strep pharyngitis, 16 (13%) had a documented diagnosis of skin or soft-tissue infection, 11 (9%) had a documented diagnosis of urinary tract infection, and 11 (9%) had a documented diagnosis of acute otitis media. Conclusions: Our data suggest that outpatient antimicrobial prescriptions correlate relatively well with encounter ICD-10 codes. However, most ASP prescribing goals aim to reduce inappropriate prescribing to 10% or fewer of prescriptions based on indication. Therefore, providers may not trust individual prescribing feedback that is based on data that is only correct 85% of the time. For ASPs to accurately assess prescribing and provide trusted, meaningful recommendations and specific feedback to individual prescribers, more reliable and valid data are needed. We intend to evaluate whether requiring outpatient antibiotic indications on prescriptions increases data reliability and validity.Disclosures: None"}
+{"text": "Early antenatal care is critical for the mother and newborn\u2019s health. Antenatal care is often delayed in Sub-Saharan Africa. The study aims to examine the trends and determinants of late antenatal care initiation in the Democratic Republic of Congo, Kenya, and Tanzania from 2007\u20132016. The study employed Demographic Health Surveys data of reproductive-age women seeking antenatal care in the Democratic Republic of Congo (2007-2013/14), Kenya (2008\u20132014), and Tanzania (2010-2015/16). Bivariate and multivariate analysis was conducted per survey, taking sampling weights into account. The determinants of late antenatal care initiation were measured using multivariate logistic regression models and the trends were assessed using prediction scores. Late antenatal care initiation declined in Tanzania (60.9%-49.8%) and Kenya (67.8%-60.5%) but increased in the Democratic Republic of Congo (56.8%-61.0%) between surveys. In the Democratic Republic of Congo, higher birth order was associated with antenatal care initiation delays from 2007\u20132014, whilst rural residency , lower maternal education  and lower-income households  were linked to antenatal care initiation delays in 2014. In Kenya, lower maternal education and lower-income households were associated with antenatal care initiation delays from 2008\u20132014, whilst rural residency  and increased birth order  were linked to antenatal care initiation delays in 2014. In Tanzania, higher birth order and larger households were linked to antenatal care initiation delays from 2010\u20132016, whilst antenatal care initiation delays were associated with lower maternal education  in 2010 and lower-income households  in 2016. Except for the Democratic Republic of Congo, the sub-region is making progress in reducing antenatal care delays. Women from various geographic, educational, parity, and economic groups exhibited varying levels of delayed antenatal care uptake. Increasing women\u2019s access to information platforms and strengthening initiatives that enhance female education, household incomes, and localise services may enhance early antenatal care utilisation. Maternal mortality reduction remains a top priority in the new Sustainable Development Goals (SDG) 3.1 . Sub-SahAntenatal care (ANC) is one of the key strategies for reducing maternal mortality, both directly by detecting and treating pregnancy-related complications and indirectly by identifying women at high risk of birth issues , 4. To lEarly ANC registration aids health providers in providing timely information and medicines based on the health of the expecting mother , 8. DuriAlthough the World Health Organization (WHO) recommends that the first ANC visit should occur within the first 16 weeks of pregnancy , researcRecent studies in the DRC, Kenya, and Tanzania have also found poor early ANC uptake, although the trends in late ANC uptake have not been thoroughly investigated . It is cThe study employs a cross-sectional design with secondary data from publicly available Demographic Health Survey (DHS) surveys in three East African countries, namely the DRC, Kenya, and Tanzania , 9.The study population consisted of DRC, Kenyan, and Tanzanian women aged 15 to 49 years, who had a live birth in the five years preceding each DHS survey between 2007 and 2016. Women who attended at least one ANC visit were included, and only information pertaining to the most recent pregnancy was used.The DHS Program conducts a nationally representative standardized cross-sectional survey involving women aged 15\u201349 years . The DHSThe outcome variable is late ANC initiation categorised as late if the timing of ANC was >4months and early if otherwise . The indThe data were managed, cleaned, coded, and analysed using STATA version 17  than urban women (56.7%), and a similar pattern was observed between rural women (61.4%) and urban women (49.8%) in the second survey. In the first survey, older women aged 25\u201349 years started ANC later (62.3%) than younger women aged 15\u201324 years (59.9%). In the second survey, a similar pattern was observed between older women (57.6%) and younger women (56.4%), but the differences between the two age groups were not statistically significant in either survey. In the first survey, women with primary or no education delayed their first ANC visit (63.5%) more than women with secondary or tertiary education (55.2%). In the second survey, the same pattern was observed among women with primary or no education (60.7%) and women with secondary or tertiary education (50.6%)In the first survey, women with birth order of three or more started ANC later (70.3%) than those with birth order of two (65.2%) or one (57.7%). In the second survey, women with birth order of three or more also initiated ANC later (67.1%) than those birth order of two (61.9%) or one (53.7%). Women in households with 5 or more members started ANC later (63.0%) than women in households with 4 or fewer members (57.6%) in the first survey. In the second survey, women in households with 5 or more members (60.1%) and women in households with 4 or fewer members (51.3%) showed a similar pattern. In the first survey, women in poor-income households delayed their first ANC visit (64.2%%) more than women in rich-income (57.1%) households. In the second survey, women in poor-income households also waited longer to start ANC (63.8%) than women in middle-income (59.9%) or rich-income (49.7%) households.In 2007, older women aged 25\u201349 years commenced ANC later (58.7%) than younger women aged 15\u201324 years (53.7%). In 2014, older women (61.2%) and younger women (58.9%) followed a similar pattern. However, the differences between older and younger age groups were only statistically significant in 2007. In 2007, women with primary or no education started ANC later (59.1%) than women with secondary or tertiary education (53.8%). A similar pattern was observed among women with primary or no education (65.3%) and women with secondary or tertiary education (54.2%) in 2014.In 2007, women with birth order of three or more began ANC later (65.5%) than those with birth order of two (59.8%) or one (52.6%). In 2014, women with birth order of three or more also commenced ANC later (68.3%) than those with birth order of two (62.5%) or one (56.9%). In 2007, higher proportions of women in households with five or more members delayed their first ANC visit (57.6%) than women in households with four or fewer members (54.9%). In 2014, a similar pattern was observed for women in households with five or more members (61.3%) and women in households with four or fewer members (57.9%). In 2007, lower proportions of women in low-income families started ANC later (57.3%) than women in rich-income families (53.8%). In 2014, women in low-income families delayed ANC initiation (66.0%) more than women in middle-income (63.7%) or rich-income families (53.5%)In Kenya, a total of 3,512 and 13,766 reproductive-age women with a live birth in the five years preceding each survey were included in this study in 2008 (baseline survey) and 2014 (comparative survey) respectively. Women in rural areas started ANC later (69.2%) than women in urban areas (62.6%) in 2008. In 2014, a similar pattern was observed among rural women (63.8%) and urban women (51.4%). In 2008, younger women aged 15\u201324 years commenced ANC later (69.2%) than older women aged 25\u201349 years (67.0%). Younger women also started ANC later (59.1%) than older women (58.8%) in 2014. However, for both surveys, the differences in younger and older age groups were not statistically significant.In 2008, women with primary or no education started ANC later (70.5%) than women with secondary or tertiary education (60.7%). In 2014, women with primary or no education also started ANC later (64.1%) than women with secondary or tertiary education (50.1%). In 2008, mothers with birth order of three or more initiated ANC later (72.4%) than those with birth order of two (71.4%) or one (66.8%). In 2014, mothers with birth order of three or more (67.0%) also started ANC later than those with birth order of two (63.5%) or one (56.6%).In 2008, women in families with five or more members delayed beginning ANC (69.7%) more than women in households with four or fewer members (64.5%). In 2014, a similar tendency was observed among women in families with five or more members (62.9%) and women in families with four or fewer members (53.2%). In 2008, women in poor-income households started ANC later (72.6%) than women in middle-income (70.8%) or rich-income (62.1%) households. In 2014, women in poor-income households also began ANC later (66.2%) than women in middle-income (61.9%) or rich-income households (51.1%).In Tanzania, a total of 5,058 and 6,873 reproductive-age women were included in this study in 2010 (baseline survey) and 2016 (comparative survey) respectively. In 2010, rural women delayed their first ANC visit (62.7%) more than urban women (56.0%). In 2016, rural women also started ANC later (53.0%) than urban women (41.7%). In 2010, older women aged 25\u201349 years began ANC later  than younger women aged 15\u201324 years (58.8%). In 2016, older women aged 25\u201349 years also started ANC later (50.2%) than younger women aged 15\u201324 years (48.2%). In both surveys, however, differences between older and younger age groups were not statistically significant.In 2010, women with primary or no education delayed ANC initiation (62.3%) more than those with secondary or tertiary education (47.7%). In 2016, a similar pattern was observed among women with primary or no education (51.8%) and women with secondary or tertiary education (40.3%). In 2010, mothers with birth order of three or more attended their first ANC visit later (76.8%) than those with birth order of two (66.7%) or one (56.1%). Similarly, in 2016, mothers with birth order of three or more began ANC later (63.8%) than those with birth order of two (58.3%) or one (44.2%).In 2010, women in families with five or more members began ANC later (64.1%) than women in families with four or fewer members . In 2016, women in families with five or more members also commenced ANC later (53.9%) than women in households with four or fewer members (38.2%). In 2010, women in poor-income households delayed their first ANC visit (64.6%) more than women in middle-income (63.2%) or rich-income households (56.2%). In 2016, women in poor-income households also started their first ANC visit (56.8%) more than women in middle-income (50.4%) or rich-income (41.6%) households.The results showed that the odds of late ANC initiation were significantly higher among women with primary or no education in the first survey  and second survey . It was also observed that mothers with birth order of two  and those with birth order of three or more  had significantly greater odds of starting ANC late in the first survey. A similar observation was made in the second survey, mothers with birth order of two  and those with birth order of three or more  had significantly higher odds of waiting longer to start ANC.The results also showed that the odds of delayed ANC initiation were significantly higher among women living in households with five or more members in the first survey (AOR:1.21:95%CI:1.08\u20131.34) and second survey . The study also established that women from poor-income  and middle-income  households had significantly greater odds of initiating ANC late in the first survey. These findings were also observed in the second survey, the odds of delaying ANC initiation were significantly higher among women from poor-income  and middle-income  households. The findings also revealed that women residing in rural areas had significantly greater odds of late ANC initiation  in the second survey.According to the study, women residing in rural areas had significantly increased odds of initiating ANC late  in 2014. It was also established that women with primary or no education had significantly higher odds of late ANC initiation (AOR:1.29:95%CI:1.13\u20131.47) in 2014. The findings also revealed that women living in poor-income households had significantly increased odds of late ANC initiation  in 2014.In Kenya, the mother\u2019s education and household wealth were associated with late ANC initiation in 2008 and 2014, and the place of residence, birth order, and household size were linked to late ANC initiation in 2014. The results showed that women with primary or no education had significantly higher odds of late ANC initiation  in 2008 and  in 2014. The findings also showed that women in poor-income  and middle-income  households had significantly higher odds of late ANC initiation in 2008. These findings were also similar in 2014, the odds of late ANC initiation were significantly higher among women in poor-income  and middle-income  households.The findings also revealed that rural women had significantly higher odds of late ANC initiation  in 2014. The study also found that women with birth order of two had significantly higher odds of delayed ANC initiation (AOR:1.12:95%CI:1.01\u20131.24) in 2014. Women living in households with 5 or more members also had significantly increased odds of late ANC initiation  in 2014.In Tanzania, late initiation of ANC was associated with birth order and household size in 2010 and 2016, and delays in ANC initiation were associated with the mother\u2019s education in 2010 and household wealth in 2016. The results showed the odds of initiating ANC late significantly increased among mothers with birth order of two  and those with birth order of three or more . Similarly, in 2016, the odds of starting ANC late significantly increased among mothers with birth order of two  and those with birth order of three or more (AOR:1.76:95% CI:1.35\u20132.30).The study also found that the odds of initiating ANC late significantly increased among women residing in households with five or more members  in 2010 and  in 2016. The findings also revealed that women with primary or no education had significantly increased odds of starting ANC late  in 2010. The study also showed that women from low-income households had significantly greater odds of late ANC initiation  in 2016.The present study attempts to examine the trends and determinants of late ANC initiation using multiple rounds of DHS surveys from 2007 to 2016 in the DRC, Kenya, and Tanzania. The results of this study indicated that there was a general downward trend of late ANC initiation in Kenya between 2008 and 2014 and Tanzania between 2010 and 2016, however, there was an upward trend in the DRC between 2007 and 2014. The findings indicate uneven progress in the reduction of delays in late initiation of ANC over time within East Africa. Differences in the economic, and social environments, as well as the implementation of diverse maternal health policies, could explain this variation.In the DRC and Kenya, rural women were more likely to delay ANC. Previous research has shown similar results , 15. WomConsistent with previous studies, the study found that women with lower household incomes were more likely to delay ANC initiation in the DRC, Kenya, and Tanzania , 20. HigOur findings also revealed that women with poor educational attainment in the DRC, Kenya, and Tanzania were more likely to commence ANC late. This is corroborated by research conducted in Zambia and Ethiopia, which found that women with poor levels of education were more likely to delay ANC enrollment , 24. UneThe study also revealed that the odds of late ANC initiation increased among mothers with more previous births in the DRC, Kenya, and Tanzania. This was also reported by studies in Cameroon  and UganIn Kenya and Tanzania, women with a household size of at least five members were more likely to initiate ANC late, according to the study. The findings are similar to a previous study in Ethiopia . PotentiThe strength of this study is that the study used nationally representative data therefore the findings are generalisable and applicable to countrywide policies and interventions. The study also assessed trends and determinants of late ANC initiation across various countries in the East African sub-region. Thus, highlighting the context-specific characteristics in various countries that must be considered when establishing policies and interventions to improve early access to ANC. However, the study has several limitations, including recall bias due to the self-reported nature of the data and data collected for the five preceding years. Our research also depended on the completeness of data on variables of interest in all rounds of the DHS surveys; as a result, the study did not evaluate other variables such as employment status due to insufficient data. Due to the cross-sectional nature of the study, it was also not possible to establish temporal causalityCountries within East Africa experienced a reduction in late initiation of ANC over time except for the DRC. Rural women, women with low levels of education and socioeconomic status, women with high parity, and women living in large households continue to face challenges in utilising ANC services early. Public health officers should work on increasing awareness about the benefits of early initiation of ANC to all pregnant women. Governments should implement and improve policies that eliminate barriers to accessing maternal healthcare, especially among women of low economic status. These policies should entail making services accessible to women who cannot afford them, increasing access to healthcare for pregnant women who may have to travel long distances, and improving the provision of services at health facilities. Furthermore, government policies aimed at increasing female education would improve the early uptake of ANC services.S1 Table(DOCX)Click here for additional data file."}
+{"text": "More than 90% of HIV-infected patients present with at least one mucocutaneous manifestation during the course of their disease. Insufficient data are available regarding dermatologic findings among HIV-infected patients in Madagascar.This study aimed at evaluating the spectrum of mucocutaneous manifestations and their relationship with CD4 cell counts in HIV-infected patients in Madagascar.A cross-sectional study on HIV-positive patients attending the Department of Infectious Diseases in the University Hospital of Antananarivo in Madagascar was conducted from January 2013 to March 2020. HIV-positive patients older than 18 years and receiving antiretroviral therapy as well as those awaiting antiretroviral therapy commencement were included.Among 328 patients enrolled in this study, 167 (51%) presented with at least one type of mucocutaneous lesion. Oral candidiasis was the most common presentation, followed by seborrheic dermatitis and Kaposi sarcoma. Decreases in CD4 cell counts were substantially correlated with oral candidiasis, syphilis, and condyloma acuminatum.According to our findings, oral candidiasis, syphilis, and condyloma acuminatum may serve as clinical indicators for predicting the immune status of patients. As HIV infection progressed and immune function declined, an increase in cutaneous manifestations was observed. In Madagascar, the prevalence of HIV infection in the general population increased from 0.02% to 0.25% between 1989 and 2018. High prevalence of HIV was found among key populations in Madagascar, with rates of 14.8% in men who have sex with men, 8.4% in injecting drug users, and 5.6% in sex workers .HIV infection is commonly associated with various mucocutaneous manifestations that can be present in all situations. Mucocutaneous disorders develop in more than 90% of HIV-infected individuals at some point during the course of their illness . The epiThe purpose of this study was to describe the epidemiology and the clinical spectrum of mucocutaneous manifestations in HIV-positive patients attending the Department of Infectious Diseases in the University Hospital of Antananarivo in Madagascar.This study was approved by the Ethics Commission of the University Hospital of Antananarivo in Madagascar (23-CHUJRB/CE). Confidentiality was maintained. Patients provided written informed consent to allow their medical records data to be used in research and their case details to be published.A cross-sectional study was conducted in HIV-positive patients (men and women aged \u226518 years) seeking care at the Department of Infectious Diseases at the University Hospital of Antananarivo in Madagascar from January 2013 to March 2020. Patients receiving ART and those awaiting ART commencement were included.Data on the mode of infection, duration of disease, the nearest level of CD4 cell counts (within the last 2 months) at the time of diagnosis of a specific skin condition, treatment regimen, and any prior dermatological history were considered. Physical examination of patients was conducted by dermatologists. Dermatoses were primarily diagnosed clinically, with additional support from mycological, histological, and hematological testing, as necessary.t test (2-tailed) was used to analyze continuous variables. The level of statistical significance was set at P<.05. Regression analysis was performed to assess the relationship between the number of dermatoses and CD4 cell counts.Statistical analysis was performed with Epi Info software . Categorical data were compared using the chi-square test, and the student Among the 345 HIV-positive patients seen during the study period, 7 were excluded due to incomplete data, and an additional 10 declined participation. As a result, a total of 328 patients were included in the study, of whom 215 (65.5%) of them were male. A total of 168 (51%) patients presented with at least one dermatological disease. Among these 168 patients, 130 (77.3%) were receiving ART. Of the total 328 participants, 123 (37%) patients in the age group of 30-39 years were affected by HIV. The median age was 41 (IQR 27-52) years. Among the 328 participants, the primary mode of HIV transmission was heterosexual in 272 (83%) individuals, whereas the number of men who have sex with men was 30 (9.1%). In terms of occupation, 104 (32%) patients worked in the commerce sector, 37 (11.2%) were housewives, 26 (8%) were students, and 8 (2.4%) were health care professionals. The average duration of HIV infection was 9.8 (SD 6.2) years. Additionally, 160 (48.7%) patients had a low level of education.A total of 231 dermatoses were identified in 168 HIV-infected patients. Among these patients, 117 (69.6%) had one type of dermatoses, while 41 (24.4%), 8 (4.7%), and 2 (1.1%) presented with 2, 3, and 4 types of dermatoses, respectively. Infectious dermatoses affected half of the participants, with 111 (66%) patients presenting with fungal infections, which were the most prevalent, followed by viral infections in 35 (20.8%) patients and bacterial infections in 17 (10%) patients. The most common fungal infection was oral candidiasis, while herpes zoster  and syphNoninfectious dermatoses affected 61 (36.3%) of the 168 patients. Among the noninfectious dermatoses, inflammatory dermatoses was the most prevalent, with seborrheic dermatitis being the main condition observed in 27 (11.6%) patients. Regarding neoplastic diseases, 16 patients presented with Kaposi sarcoma (8 men and 8 women), with 6 patients in the age group of 30-39 years . No case3. LTCD4 was less than 200 cells/mm3 in 139 (83%) of 168 patients who had skin manifestations. The mean CD4 cell count of patients with cutaneous manifestations  was significantly lower than the mean CD4 cell count of those without manifestations .The mean CD4 cell count for all patients was 190 (SD 32) cells/mmOf the 328 PLWH in this study, 259 (79%) were receiving ART. Among them, 251 (77%) were receiving a fixed-dose combination of 2 nucleoside reverse transcriptase inhibitors and nonnucleoside reverse transcriptase inhibitors. However, 47 (18%) of the 259 patients had not initiated treatment. Of the 8 PLWH, 2 (3%) who were treated by 2 nucleoside reverse transcriptase inhibitors associated with protease inhibitors were pregnant.P=.001), syphilis (P=.002), and condyloma acuminatum (P=.03) showed statistically significant associations with the CD4 count (<200 cells/mm3). The association of dermatoses with CD4 cell counts is shown in Among the infectious dermatoses, oral candidiasis , reported by Kim et al [The prevalence of mucocutaneous manifestations in patients with HIV was 51% in our study. The mean CD4 cell count (119 cells/\u00b5l) of patients with cutaneous manifestations was significantly lower than the mean CD4 cell count of those without manifestations. Oral candidiasis was the most prevalent of infectious dermatoses and was associated with a mean CD4 count of 97 cells/mmim et al ,11. HoweThe mean age of our study participants was 36.5 (SD 19.1) years. This finding is consistent with results reported by Josephine et al  for patiP<.05). Our results are consistent with those reported by Lahoti et al [Patients with cutaneous manifestations had a significantly lower mean CD4 cell count (119 cells/\u00b5l) compared to patients without signs of cutaneous manifestations , syphilis (P=.002), and condyloma acuminatum (P=.03) showed statistically significant correlations with CD4 cell counts. Several authors reported the association of oral candidiasis with low CD4 cell counts [Among the infectious dermatoses, oral candidiasis P=.00, syphilil counts ,17. In al counts  have deml counts  were unaA negative correlation was found between CD4 cell counts and the number of dermatoses seen in PLWH. This finding suggests that the number of mucocutaneous diseases related to HIV infection should be considered among the key clinical indicators for the prediction of underlying immune status and disease progression. Asian and Indian studies have reported similar results ,21.3. Our result is consistent with results reported in previous studies [3 and the frequency of oral candidiasis (P<.001). Our results are consistent with those reported by Monsel et al [Oral candidiasis was found to be the most prevalent infectious dermatoses, associated with a mean CD4 count of 97 cells/mm studies ,22, whicel et al  from Senel et al  from Indel et al  from IndAmong 231 dermatological diagnoses, seborrheic dermatitis was found to be the most prevalent of noninfectious dermatoses, presented by 27 (11.73%) patients. Our result is consistent with the findings reported by Claasens et al  in South3. Ranaivo et al [Human herpes virus type 8 (HHV-8) is the causative agent of Kaposi sarcoma. The seroprevalence of HHV8 in Africa ranged from 2% to 100% depending on the regions . Kaposi vo et al  reportedvo et al ,31.3. In African populations, prurigo has been linked to arthropod bites and poor socioeconomic conditions [Another important skin problem observed in our study was prurigo, which was present in 13 (5.65%) cases and associated with a mean CD4 count of 106 cells/mmnditions . Our stu3. ART has been shown to reduce the incidence of herpes zoster in adults with HIV, presumably because of immune restoration [3. Several studies have also reported that the risk of herpes zoster is increased in the 6-month period immediately after initiation of ART [Herpes zoster was seen in 12 (5.21%) patients, with a mean CD4 count of 164 cells/mmtoration . Herpes n of ART ,35.3. This finding is consistent with the results reported by Goh et al [Toxidermia was observed in 7 (3.10%) patients among our study population, with benign drug eruptions accounting for 6 of these toxidermia cases. Our result is close to those reported in South Africa by Claasens . Howeveroh et al  in Singaoh et al  in EritrOur study provides data on the epidemiology and spectrum of mucocutaneous diseases in patients with HIV infection attending the Department of Infectious Diseases at the University Hospital of Antananarivo in Madagascar. Oral candidiasis, seborrheic dermatitis, and Kaposi sarcoma were found to be the most prevalent dermatoses. Among 328 participants included, toxidermia was observed in 7 (3.1%) patients. Oral candidiasis, syphilis, and warts showed potential as useful clinical indicators for predicting the immune status of the patients."}
+{"text": "Since the Global Polio Eradication Initiative (GPEI) was established in 1988, the number of wild poliovirus (WPV) cases has declined by >99.9%, and WPV serotypes 2 and 3 have been declared eradicated  the nonpolio AFP (NPAFP) rate, by which an NPAFP rate of at least two per 100,000 persons aged <15 years is deemed sufficiently sensitive to detect circulating poliovirus, and 2) stool adequacy,African Region. Among 24 priority countries in the World Health Organization (WHO) African Region (AFR), 19 (79.2%) met both national AFP surveillance indicator targets in 2022 compared with 17 (70.8%) in 2021 ( in 2021 . In 2022 in 2021 . In 2022Eastern Mediterranean Region. All seven priority countries in the WHO Eastern Mediterranean Region (EMR) met both national surveillance indicator targets in 2021 and 2022. In 2022, 88.2% of subnational areas met both indicator targets compared with 89.0% in 2021. EMR reported 22 WPV1 and 168 cVDPV2 cases in 2022 compared with five WPV1, three cVDPV1, and 118 cVDPV2 in 2021.South-East Asia Region. In the WHO South-East Asia Region (SEAR) priority country of Burma (Myanmar)Western Pacific Region. Of the two priority countries in the WHO Western Pacific Region (WPR), neither Papua New Guinea nor the Philippines met both national surveillance indicator targets during the assessment period. In Papua New Guinea, the NPAFP rate (1.3 in 2021 and 1.4 in 2022) was below target; stool adequacy increased from 50% in 2021 to 57.8% in 2022 but remained below target. In 2021 and 2022, the Philippines met NPAFP rate targets  but missed stool adequacy targets . Across both countries, the number of subnational areas meeting both indicators declined from 20.5% in 2021 to 10.3% in 2022. No poliovirus was detected in the two WPR priority countries in 2021 or 2022.Environmental surveillance for poliovirus, the systematic collection and testing of sewage samples for poliovirus, supplements the sensitivity of AFP surveillance by detecting poliovirus circulation in the absence of confirmed paralytic polio cases. In 2022, 32 (94.1%) of the priority countries**In AFR, the number of sites increased 11.9%, from 371 in 2021 to 415 in 2022, and the overall proportion of sites meeting the target increased from 27.8% to 40.5%. Eleven (47.8%) countries reported an increase in the proportion of sites meeting the indicator in 2022, and seven (30.4%) countries reported a decrease.The number of sites in EMR increased from 162 in 2021 to 294 in 2022, including 120 added in Pakistan. More than 85% of sites met the indicator in each year.In SEAR and WPR, Burma\u2019s single reporting site met the environmental surveillance indicator. The Philippines had 17 environmental sites in 2021, five (29.4%) of which met the indicator. In 2022, 15 sites reported, and four (26.7%) met the indicator.The Global Polio Laboratory Network (GPLN) consists of 144 WHO-accredited laboratories in the six WHO regions, monitored through a standardized quality assurance program of annual on-site audits and proficiency tests  genotype was the only circulating WPV1 isolated from 36 AFP patients, 27 from the two endemic countries (Afghanistan and Pakistan), and nine from two nonendemic countries . In Pakistan, 21 WPV1 cases were related to the YB3C genetic cluster , two of which were orphan viruses.In priority countries during 2021\u20132022, 38 cVDPV emergence groups (eight cVDPV1 and 30 cVDPV2) were isolated from 1,454 AFP patients and 750 environmental samples. The number of cVDPV1 emergence groups increased from four isolated from 16 AFP patients and 33 environmental samples in 2021 to seven from 173 patients and 99 samples in 2022. The number of cVDPV2 emergence groups decreased from 24 isolated from 617 AFP patients and 449 environmental samples in 2021 to 17 emergence groups isolated from 648 patients and 169 samples in 2022.After the COVID-19 pandemic weakened poliovirus surveillance performance  surveillance, which is supplemented by environmental surveillance of sewage samples.During 2021\u20132022, among 34 priority countries experiencing or at high risk for poliovirus transmission, 26 (76.5%) met national AFP surveillance indicator targets, and the number of environmental surveillance sites increased by 31%. However, substantial national and subnational AFP surveillance gaps persist.Maintaining high-quality surveillance is critical to achieving the goal of global polio eradication. Monitoring surveillance indicators is important to identify gaps and guide surveillance-strengthening activities, particularly in countries at high risk for poliovirus circulation."}
+{"text": "Cirrhosis in young adults is an important health problem worldwide and is a common disease. Patients usually present late in a decompensated state with varied complications. However, national data on the exact burden of the disease is lacking. The aim of this study was to find out the prevalence of liver cirrhosis among young adults admitted to the Department of Gastroenterology in a tertiary care centre.A descriptive cross-sectional study was done among patients admitted to the Department of Gastroenterology in a tertiary care centre between 25 November 2021 to 30 November 2022 after receiving ethical approval from the Institutional Review Committee [Reference number: 227(6-11) E2-078/079]. Convenience sampling was done. Point estimate and 95% Confidence Interval were calculated.Among 989 patients, liver cirrhosis in young adults was seen in 200 (20.22%) . Chronic alcohol use was the primary cause of cirrhosis seen in 164 (82%) cases. The most typical presenting symptom was abdominal distension seen in 187 (93.50%) patients. The most frequent complication was ascites seen in 184 (92%) patients. The most frequent endoscopic finding was gastro-oesophagal varices seen in 180 (90%) patients. There were 145 (72.50%) men and 55 (27.50%) women.The prevalence of liver cirrhosis in young adults was found to be lower than the other studies done in similar settings. However, even in the absence of any clear clinical symptoms, substantial liver damage may be present.2Liver cirrhosis refers to a disorder that alters the overall typical architecture of the liver. Globally, the majority of instances are ascribed to non-alcoholic fatty liver disease, viral hepatitis, or excessive alcohol usage.3 Early interventions and preventions are required to stabilize disease progression and to avoid or delay clinical decompensation and the need for liver transplantation.4Various causes of cirrhosis in adults have been studied but the aetiology of cirrhosis in young adults less than or equal to 40 years has not been well studied, and the incidence of cryptogenic cirrhosis remains unknown.The aim of this study was to find out the prevalence of liver cirrhosis among young adults admitted to the Department of Gastroenterology in a tertiary care centre.A descriptive cross-sectional study was done among young adults admitted to the Department of Gastroenterology in Tribhuvan University Teaching Hospital between 25 November 2021 to 30 November 2022 after receiving ethical approval from the Institutional Review Committee of same institute [Reference number: 227(6-11)E2-078/079]. All patients admitted to the Gastroenterology ward of the hospital aged >18 and \u226440 years were included in the study. Patients who do not give informed consent were excluded from the study. Informed consent was signed and confidentiality of the information was ensured. Convenience sampling was done. The sample size was calculated by using following formula:Where,n = minimum required sample sizeZ = 1.96 at a 95% Confidence Interval (CI)p = prevalence taken as 50% for maximum sample size calculationq = 1-pe = margin of error, 7%The calculated minimum required sample size 601. However, 989 patients were included in the study.5Each patient was subjected to a detailed clinical history regarding the duration of illness and symptoms. Predetermined proforma was used as the tool for data collection. All patients were subjected to detailed clinical and laboratory data including demographics, and history of alcohol consumption, medications, substance abuse, and other systemic diseases. Various biochemical studies like alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine transaminase (ALT), serum total globulin/ gamma globulins, serology like antinuclear antibody (ANA), anti-smooth muscle antibody (ASMA), antimitochondrial Aantibody (AMA), immunoglobulin A (IgA), tissue transglutaminase (tTG), liver-kidney microsomal (LKM-1), viral hepatitis markers, HLA-DR3 or DR4) and abdominal ultrasound was done for liver and spleen size, parenchymal echogenicity, portal vein diameter, and ascites. Serum ceruloplasmin, urinary copper levels and slit lamp examination for the Kayser-Fleischer ring were done when indicated.Each patient had undergone upper gastrointestinal (UGI) endoscopy and diagnostic findings were documented. Child-Turcotte-Pugh (CTP) score and Model for End Stage Liver Disease (MELD) scores were calculated for all the patients. Information was gathered using a standardized proforma.Data collected were entered and analyzed using IBM SPSS Statistics version 20.0. Point estimate and 95% CI were calculated.Among 989 patients, liver cirrhosis among young adults was seen in 200 (20.22%) . In a total of 200 cases, liver cirrhosis was seen in 145 (72.50%) men and 55 (27.5%) women. The participants ranged in age from 18 to 40 years, with mean age of 28.92\u00b15.73 years. A total of 68 (34%) Brahmins made up the majority of the study group, followed by 42 (21%) Khas, 25 (12.50%) Newar, 20 (10%) Madheshi, and 6 (3%) Tharus.There were 73 (36.50%) farmers made up the research group, which also included 56 (28%) retired people, 37 (18.50%) people who worked for the government, and 34 (17%) housewives. In this study 113 (56.50%) patients were from rural areas, while 87 (43.50%) patients were from metropolitan areas. A total of 80 (40%) patients were from a moderate socioeconomic class, 70 (35%) from a lower one and just 50 (25%) from a higher one.Chronic alcohol use was the primary cause of cirrhosis in 164 (82%) patients. Other causes were non-alcoholic steatohepatitis (NASH) and chronic viral hepatitis seen in 20 (10%) cases and 12 (6%) cases respectively. The remaining cases, 4 (2%) were labelled as cryptogenic .Abdominal distension was the most frequent manifestation, occurring in 187 (93.50%) cases, followed by anorexia 140 (70%), fatigue 120 (60%), and vomiting 104 (52%). Ascites was clinically evident in 184 (92%) individuals. There were 108 (54%) individuals who had upper gastrointestinal bleeding. The other typical signs were icterus, followed by pallor, pedal edema, and hair loss over the body .There were 108 (54%) individuals who had UGI bleeding. The most frequent endoscopic finding was gastro-oesophagal varices, which were discovered in 180 (90%)patients, followed by portal gastropathy in 150 (75%) patients, peptic ulcers in 15 (7.50%) patients, gastro-duodenitis in 4 (2%) patients, Mallory Weiss tears in 20 (10%) patients and GI malignancies in 2 (1%) patients.The participants were divided into groups based on their CTP classifications. Most cases belong to CTP C 120 (60%) patients .The most common complications was ascites seen in 184 (92%) of the patients. Hepatic encephalopathy (HE) was seen in 36 (18%) cirrhotic patients, followed by spontaneous bacterial peritonitis (SBP) in 26 (13%) patients, and hepatorenal syndrome (HRS) in 22 (11%) patients.6 but lower to the similar studies done in Nepal.8The prevalence of liver cirrhosis among young adults was 20.22% which was high when compared to a similar study done in other tertiary care centres of Nepal,10 The most prevalent cause of cirrhosis in Nepal is chronic alcohol use. Therefore, cirrhosis cases are increasingly being detected in young people, as was shown in the current research, which may be related to early alcohol consumption and dependency. The prevalence of alcohol use, misuse, and dependency among the younger population is increasing, which may be the cause of this condition.In the current investigation, alcoholic liver disease was the most prevalent aetiology of cirrhosis and was found in 164 (82%) individuals which was similar to other studies.9 In the current study, the most frequent finding on UGI endoscopy was gastro-oesophageal varices, which were observed in 180 (90%) patients, followed by portal gastropathy in 150 (75%) patients which was similar to other studies.9In this study, 184 (92%) individuals had ascites followed by pallor in 144 (72%) and pedal edema in 120 (60%), icterus was seen in 148 (74%) patients. In this research, 108 (54%) patients had upper gastrointestinal bleeding. These results were similar to other studies.9 With regards to the gender-wise distribution of the patients, our study showed that ALD was more predominant in males which is similar to other studies.10 The increased prevalence of ethanol use among males compared to women is most likely the cause of the male preponderance over female in all investigations. Additionally, there may be disparities in how the two sexes seek medical attention.The mean age of the patients from our study was similar to these studies.9 The CTP score of our study was similar to the studies carried out at other tertiary centre.9 In our investigation, ascites, which was discovered in 184 (92%) patients, was determined to be the most typical complication of cirrhosis at presentation, followed by UGI bleed in 108 (54%) patients. Rebleeding was seen in 33 (16.5%) patients. Hepatic encephalopathy 36 (18%), SBP 26 (13%), and HRS 22 (11%) followed. According to one of the study, the most frequent complications were ascites in 78.6% of patients, variceal bleeding in 43.4%, hepatic encephalopathy in 21.6%, SBP in 4.2%, HRS in 2.7%, HCC in 1.3%, hypersplenism in 0.4%, and sepsis in 12.8% of patients.9 These findings were consistent with those from our study. In some investigations, SBP incidences between 10% and 30% higher than ours have been reported.12 According to a recent study, hospitalized patients had a prevalence of SBP of 24.7% and 34.9%, respectively.14In the present research, a total of 113 (56.5%) patients came from rural regions which was less compare to other studies.The results of the study cannot be generalised as the population under study is limited to patients admitted to one tertiary care centre. Also, because of the descriptive nature of this study, an association between exposure and outcome cannot be made in this study design and risk factors cannot be made out. A larger study conducted at different centres should be conducted to better understand the exact burden of liver cirrhosis in young adults.The prevalence of liver cirrhosis in young adults in our study was found to be lower than in studies done in similar settings. People need to be made aware of the negative consequences of frequent alcohol use. Early diagnosis of viral hepatitis and alcoholic liver illnesses provides survival advantages, and their treatment may lessen the burden of cirrhosis. In instances of cirrhosis that have already progressed, necessary management and therapy, the avoidance of complications, and routine monitoring and follow-ups may all lower morbidity and death."}
+{"text": "We describe an unusual outbreak of respiratory infections caused by human metapneumovirus in children during the sixth wave of COVID-19 in Spain, associated with the Omicron variant. Patients in this outbreak were older than usual and showed more hypoxia and pneumonia, longer length of stay, and greater need for intensive care. Respiratory infections caused by human metapneumovirus (hMPV) are typically epidemic during February\u2013April. hMPV infections cause bronchiolitis and recurrent wheezing episodes and are responsible for hospitalizations mainly in children <2 years of age  and analyzed clinical characteristics. We performed multiple PCR respiratory panels as standard clinical practice in children in whom infection by RSV, influenza, and SARS-CoV-2 had previously been ruled out by rapid test or PCR.We obtained data from a systematic prospective study conducted over 15 years in all hospitalized children with respiratory infections in Severo Ochoa University Hospital (Madrid) using multiple PCR panels performed at the National Center for Microbiology. This study was approved by the hospital ethics committee. We compared clinical data from hospitalized patients in 2021 with our historical series of hMPV infections collected during 2005\u20132020, before the COVID-19 pandemic. We analyzed data from 48 patients with hMPV infection during October\u2013December 2021; of those, 56.3% were male and 54% were >2 years of age, and median age was 22.7 (interquartile range [IQR] 7.1\u201334.9) months. Twenty-nine (60%) of the cases were detected in December and 1 in October. In 19 cases (39%), we detected co-infection with other viruses, mainly adenoviruses and human coronaviruses. A total of 34 (70.8%) case-patients had fever >38\u00b0C; in addition, 41 (85.4%) had hypoxia, and 34 (70.8%) had an infiltrate visible in their chest radiograph; radiography was not performed in 11 cases. The most frequent diagnoses were pneumonia (35%), bronchiolitis (27%), and episodes of wheezing (16%). Antimicrobial drugs were prescribed in 26 cases (54%). Seven patients (14%) required pediatric intensive care unit (PICU) admission; 2 needed mechanical ventilation. The median duration of fever was 3 (IQR 2.7\u20135) days, hypoxia 5 (IQR 3.5\u20137.5) days, and admission, 6 (IQR 4\u20138) days.We compared the data from those recent patients with data from 498 cases of hMPV infection at the hospital during 2005\u20132020. During that period, 9 (1.8%) cases were detected in November\u2013December and 453 (90.9%) during February\u2013May. Patients in the 2021 season were older than those from the previous 15-year period and had significantly higher rates of hypoxia, pneumonia, antimicrobial drug treatment; they also had longer durations of fever, hypoxia, hospital admission, and PICU admission .In November\u2013December 2021, during the sixth wave of COVID-19 in Spain, the country experienced an extemporaneous hMPV outbreak at the time when RSV epidemic was usually observed. This outbreak of hMPV infections affected children older than were usually affected in previous years; we also observed a more severe clinical course and higher rates of hypoxia, pneumonia, and admission to PICU than historically. We considered that there may have been competition between respiratory viruses that could justify the delay in the RSV outbreak ("}
+{"text": "Objective: To evaluate dermatoscopic features of cutaneous leishmaniasis and to compare its diagnostic accuracy against slit skin smear and skin histopathology.Methods:\u00a0This cross-sectional study was conducted at the Department of Dermatology, Pakistan Navy Station (PNS) Shifa Hospital, Karachi, Pakistan, from August 2021 to August 2022. A total of 200 lesions from 70 patients of cutaneous leishmaniasis diagnosed with slit skin smear for Leishmania-Donovan (LD) bodies and skin biopsy were included via non-probability consecutive sampling technique. Dermatoscopic evaluation was performed via a handheld dermatoscope  on 10x magnification. All dermatoscopic images were analyzed by two different observers who had command of dermatoscopy. Data analysis was done using Statistical Package for the Social Sciences SPSS version 27 .Results: Common dermatoscopic findings were erythema 200 (100%), hyperkeratosis 140 (70%), crusting 50 (25%), ulceration 42 (21%), milia-like structure 58 (29%), tear drop-like structure 46 (23%), yellow tears 70 (35%), and white starburst pattern 68 (34%). Less common findings were yellow hue 28 (14%), orange areas 26 (13%) and scar seven (3.5%). Vascular structures frequently observed were linear vessels 109 (54.5%), dotted vessels 80 (40%), and hairpin vessels 61 (30.5%); less common findings were comma-shaped vessels 52 (26%), arborizing vessels 20 (10%), crown vessels nine (4.5%). Comparison of dermatoscopic features was done with slit skin smear for LD bodies  and histopathology .Conclusions: Dermatoscopy is a non-invasive technique that is helpful in diagnosing cutaneous leishmaniasis, saving time in making rapid diagnosis and saving the need to undergo extensive invasive investigation. Yield of dermatoscopy was comparable to slit smear for LD bodies and histopathology and was found to be effective in making rapid diagnosis with significant accuracy . Leishmaniasis is an infectious disease caused by flagellate protozoa of the genus Leishmania that are transmitted by vector sandflies of the genera Phlebotomus (old world) and Lutzomyia (new world) . More thOur study aimed to compare dermatoscopic findings of CL with slit smear for Leishmania-Donovan (LD) bodies and skin biopsy as the dermatoscope is non-invasive, consumes less time, gives immediate results and in experienced hands the yield is excellent. It can also be of great value, where skin biopsy can be difficult to perform due to lack of facility or chances of scarring after the procedure. This study is unique as no such study has been conducted before that compares the yield of dermatoscopic features of CL with slit skin smear and skin biopsy.This cross-sectional analytical study was conducted at the Dermatology Department at Pakistan Navy Station (PNS) Shifa Hospital, Karachi, Pakistan, over a period of one year from August 2021 to August 2022, after approval from the institutional ethical committee (ERC/2021l/DERMA/44). The sample size was calculated using the OPENEPI calculator using a prevalence of 90.6%, margin of error=5%, confidence level=95% was calculated 131 lesions. A total of 200 lesions from 70 patients of cutaneous Leishmaniasis, diagnosed with slit skin smear for LD bodies and skin biopsy were included via non-probability consecutive sampling technique. Written informed consent was taken from each patient after explaining the study.Inclusion criteriaPatients aged 18 to 50 years who had leishmania lesions  for more than six months,\u00a0irrespective of gender, and who did not receive topical, intralesional or systemic anti-leishmania treatment in the past two months were included in the study.Exclusion criteriaPatients who had lesions  for more than six months and received any topical, intralesional or systemic anti-leishmania treatment in the past two months or more were excluded from this study.All the included lesions were individually examined and assessed. Dermatoscopy was done using a DELTA 20T  with a \u00d710 magnification and all photographs were taken by iPhone 13 pro. All relevant information was taken. At least three dermatoscopic images were taken from each lesion. All images were analyzed by two individual observers to avoid any kind of bias. For better quality images, each lesion was wiped using 70% isopropyl alcohol and it was also used when using dermatoscope between different patients to avoid contamination. Gentle pressure was applied using the dermatoscope to protect vascular structures and prevent vascular collapse.Dermatoscopic characteristics of the lesions, like erythema, crusting, hyperkeratosis, ulceration, teardrop\u2011like structures, milia\u2011like cyst, yellow tears, yellow hue white\u2011starburst pattern, scar, and orange areas were evaluated. Vascular structures in the lesions were evaluated based on morphology including dotted vessels, linear vessels, hairpin\u2011like vessels, arborizing vessels, comma-shaped vessels and crown vessels.Statistical evaluation were performed using the Statistical Package for the Social Sciences (SPSS) version 27 . Frequencies and percentages were utilized for categorical data and Mean + SD was used for descriptive statistics. A one-way ANOVA was used to compare the statistical difference among dermatoscopy of CL, slit skin smear and skin biopsy. P<0.05 was considered statistically significant.Clinical and demographic characteristics of the 70 patients are elaborated inTable 1. The most prevalent dermatoscopic findings were erythema 200 (100%), hyperkeratosis 140 (70%), crusting 50 (25%), ulceration 42 (21%), milia-like structure 58 (29%), tear drop-like structure 46 (23%), yellow tears 70 (35%), and white starburst pattern 68 (34%). Less common findings were yellow hue 28 (14%), orange areas 26 (13%) and scar 7 (3.5%). Vascular structures frequently observed were linear vessels 10 (54.5%), dotted vessels 80 (40%), and hairpin vessels 61 (30.5%), and less common findings were comma-shaped vessels 52 (26%), arborizing vessels 20 (10%), and crown vessels 1 (0.5%).Dermatoscopic features when assessed according to region of body involved includes tear drop structures 77 (38.5%) and dotted 28 (14%), comma-shaped vessels 24 (12%), and arborizing vessels 15 (7.5%), commonly found on face; milia-like structures 15 (7.5%), white star burst pattern 15 (7.5%), and comma-shaped vessels 30 (15%) were most frequent findings in neck; tear drop structure 54 (27%), white star burst pattern 33 (16.5%)\u00a0and arborizing vessels 33 (16.5%) on upper extremities; milia-like structures and\u00a0tear drop structures 34 (17%) and comma-shaped vessels and crown vessels 28 (14%) on lower extremities.Dermatoscopic lesions when evaluated according to the type of lesion, erythema was found to be present in all lesions, milia-like structures, starburst pattern and linear vessels were more common in papular type. Crusting, milia-like structures and hair pin vessels were common in plaque type; yellow tear, milia-like structures, starburst pattern and linear vessels in nodule and hyperkeratosis, crusting, ulceration with hair pin and linear vessels in nodulo-ulcerative type.Dermatoscopic correlation was done with slit smear for LD bodies with p value (p = 0.003) and histopathology (p = 0.001), which was found to be significant. Comparison of dermatoscopic features with histopathological diagnosis and slit smear for LD bodies is shown in Table There are five studies done previously to evaluate the dermatoscopic patterns of CL -20. Our .Hyperkeratosis was seen in 70% of lesions Figure , which wTwenty-one percent ulceration was appreciated, which is as comparable to Y\u00fccel et al. study as 26% nodulo-ucerative lesions were dermatoscoped in our study . Forty-sFifty-eight 29%) milia-like structures were found in this study, which were present more in plaque, nodular and nodulo-ulcerative lesions but not in papular-type lesions as shown in Figure 9% milia-Other vascular structures were dotted vessels 40%, mostly in plaque (p <0.0001). Hairpin vessels 30.5%, 26% comma-shaped vessels and 10% arborizing vessels were appreciated, least common findings were crown vessels appreciated only in a single lesion which was not appreciated in any previous studies -21. A coLlambrich et al. first dermatoscoped 26 lesions of CL in 25 patients and found teardrop\u2011like structures in 53% . Ayhan eThis study is unique, because along with mentioning dermatoscopic features of CL, it also correlates dermatoscopic features of CL with slit skin smear and histopathology. Our study found significant diagnostic accuracy of dermatoscopy in comparison with slit skin smear and histopathology. The P values and mean values of ANOVA show that dermatoscopic features of CL are essentially equal to slit smear and skin biopsy for the diagnosis of cutaneous leishmaniasis. Comparing the skin biopsy, dermatoscopy and slit smear, the results are statistically significant for all three variables with all p values less than 0.05.This study concluded that dermatoscopy is a non-invasive, rapid tool in diagnosing CL. Comparison of dermatoscopic features to slit skin smear for LD bodies and histopathology was found significant with p value < 0.05. Diagnostic accuracy was found to be comparable to slit skin smear and histopathology, helpful in making rapid diagnoses without undergoing invasive procedures. No characteristic features are attributed to CL, but the constellation of features on dermatoscopy which are helpful to rule out differential diagnosis easily. Multi-center studies on larger populations should be done to evaluate the effectiveness of dermatoscopy in diagnosing cutaneous leishmaniasis more accurately."}
+{"text": "Women around the world began reporting menstrual disorders after receiving COVID vaccines. Numerous studies were launched evaluating a possible causal relationship between vaccines and these disorders. To date, it has not been possible to establish causality between the different vaccine compounds and these disorders. Here we identify the main self-reported menstrual disorders in vaccinated women the Dominican Republic.We elaborated a multiple-choice self-questionnaire shared through a link on social networks. Sociodemographic factors, type of vaccine received, number of doses, and symptoms or disorders related to the menstrual cycle that occurred after its administration were addressed.200 participants completed the questionnaire. The ages were mainly between 18 to 28 years (40.5%), 29 to 38 years (39%), 39 to 49 years (18.5%). 74% defined their menstrual cycle as regular (between 21 and 29 days). Most of the vaccines reported were Coronavac (63%), Astra Zeneca (23%) and Pfizer (7%). 81.5% received two doses of the vaccine, while 13.5% had received 3 doses. Most of the disorders reported occurred after the second dose (60%), the most frequent being dysmenorrhea (33%), menorrhagia (31.5%) delayed menstrual bleeding (31%), and heavy bleeding (30.5%). 59.5% considered these symptoms as moderate and 44.5% reported that they were maintained for 2 to 3 months. 65.5% of women reported that they would get vaccinated against COVID again despite these events.Dysmenorrhea, menorrhagia, delayed menstrual bleeding, and heavy bleeding were the most reported disorders in our cohort. Although causality has not been confirmed, health personnel should be aware of these findings and offer the relevant recommendations to women who are going to be vaccinated.All Authors: No reported disclosures"}
+{"text": "NMDA-Receptor antagonists have rapid antidepressant and antisuicidal properties. However, the antidepressant effect is short lasting raising the question of best maintenance strategy, which is unanswered so far. Invasive vagus nerve stimulation (VNS) as a treatment option for refractory and chronic major depression was shown to reduce the need of maintenance treatment sessions in electroconvulsive therapy (ECT) patients.There are no published data on the combination of VNS and esketamine. To determine the impact of the combination of VNS and esketamine in DTD.In this naturalistic observational study, we investigated the short- and long-term impact of combination of VNS and esketamine in n=8 patients with difficult-to-treat depression (DTD). Follow-up evaluations were scheduled prospectively pre-surgery at baseline and every 3 months after VNS-implantation .The mean age of patients was 50,8 years. 50 % of patients (n=4) were female. All patients suffered from severe DTD . Mean number of hospitalizations per months decreased from 0.17 to 0.11 after VNS implantation. 6 of 8 patients were offered maintenance esketamine treatment. Mean MADRS at 12-months was 19 (38.5 % MADRS reduction). The need of mean esketamine treatment sessions decreased from 2.3 at 6-months visit (V6) to 1.37 at V9 and 0.96 at V12 respectively. Termination of maintenance esketamine was possible in 4 cases after a mean of 11.5 months.Combination of esketamine and VNS is a safe and effective treatment option in severely ill DTD patients to relieve disease severity and reduce hospitalizations. Need of esketamine treatment sessions decreases 6 months after VNS implantation.None Declared"}
+{"text": "COVID-19 pandemic had profound societal impact in United States (US) with decrease in overall life expectancy and associated increase in polysubstance abuse.Crude rates of population-based deaths among adults (18-75 years) from firearm injury and drug overdose were obtained from centers of disease control (CDC) WONDER database from period of 2011- 2021. Crude rates of underlying causes of donor (18-75 years) deaths from 2011- 2021 were obtained from United Network for Organ Sharing (UNOS) database. Trends of cause of death and impact of COVID-19 period on deaths from drug overdose and firearm injury were analyzed using joint point regression analysis. Correlation between population and organ-donor deaths was analyzed using spearman's rank correlation coefficient.Average annual percentage change (AAPC) in deaths among the US population from drug overdose was 9.5 % and from firearm injury was 3.4%, with the highest ever rates from both causes in the US seen in 2021 (figure 1).AAPC in cause of death among donors of organs for transplantation was 10.9% from drug overdose and 2.1% from firearm injury (figure 2).There was a significant progressive increase in deaths from drug overdose (1.48 fold) and firearm injury (1.2 fold) from 2019 to 2021 (P < 0.01).There was a significant correlation between population and organ-donor deaths from drug overdose and firearm injury during the COVID-19 period of 2020-2021 ( P < 0.01).rates per 100,000 populationrates per 100,000 populationCOVID-19 pandemic has further exacerbated the trends in US population of deaths from drug overdose and firearm injury (including suicide and homicide). There was a consequent increase in organ donation for transplantation from donors who died from these two causes. Identifying socio-economic, regional and racial discrepancies associated with this rise can help guide public health policies for the immediate and long-term future. Unique risk factors, including increased infectious risk, associated with use of organs from these donors and subsequent long-term graft outcomes in the recipients will need to be monitored.All Authors: No reported disclosures"}
+{"text": "Clinical practice recommendations from American Diabetes Association (ADA) include specific prevention goals intended to reduce the risk of diabetic complications. The Healthy People 2010 (HP2010) initiative, updated to Healthy People 2020, proposes similar objectives for improvement of clinical measures and outcomes in patients with diabetes. Clinical pharmacists are gaining an increasing role in providing diabetes management services, including collaborative practice in medical groups.To compare the rates of attainment of diabetes prevention goals described by the ADA 2009 guidelines and the HP2010 initiative for patients receiving clinical pharmacist interventions in a collaborative practice diabetes clinic versus patients receiving usual care.The setting is a primary care clinic affiliated with a 140-physician multispecialty medical group in the upper Midwest. Diabetes patients were identified from electronic medical records by ICD-9-CM diagnosis codes 250.00 through 250.99 for dates of service in the 12-month period from January 1, 2007, through December 31, 2007. Study subjects had to be aged 18 years or older and have at least 2 visits to a primary care physician (PCP) or the pharmacist-managed diabetes clinic during 2007. Descriptive statistics and chi-square analysis were utilized.Of 7,068 patients at least 18 years of age with at least 1 diabetes diagnosis code for a medical encounter in 2007, 1,298 (18.4%) had a least 1 visit in the pharmacist-managed diabetes clinic, and 321 patients (4.5%) had 2 or more visits. These 321 patients were compared with 321 patients stratified by gender and randomly selected from 3,022 patients who had at least 2 visits with a PCP and no visits in the pharmacist-managed diabetes clinic in 2007. Nine of the 14 HP2010 objectives (64.3%) were attained in the intervention group compared with 7 of 14 (50.0%) in the usual care group. For patients with hypertension at baseline, 44.6% (120/269) in the intervention group versus 48.0% (123/256) in the usual care group achieved goal blood pressure (P=0.430). The low-density lipoprotein (LDLC) goal (less than 100 milligrams per deciliter) was achieved in 76.0% of patients in the intervention group (244/321) versus 59.2% (190/321) in usual care (P less than 0.001). Fewer patients in the intervention group achieved hemoglobin A1c less than 7%  compared with usual care . The proportions of patients with influenza and pneumococcal vaccinations were higher in the intervention group versus the usual care group for 3 of 4 comparisons by age, but neither group met the target goals.Patients who were seen by the clinical pharmacists met more of the preventive care objectives recommended by the ADA 2009 and HP2010 initiatives; however, more patients in usual care met the A1c goal compared with pharmacist-managed patients. The absence of baseline values for A1c, blood pressure, and LDL-C prevented longitudinal assessment of the effects of this clinical pharmacist intervention."}
+{"text": "Sudden neurological deficits due to an acute focal vascular injury of the centra! nervous system is stroke. It is a major cause of morbidity and mortality. Dyslipidemia is any abnormality in the parameter of the lipid profile which has been associated with stroke. The aim of this study was to find out the prevalence of dyslipidemia among patients with ischemic stroke in the Department of Medicine of a tertiary care centre.A descriptive cross-sectional study was conducted in a tertiary care centre among admitted ischemic stroke patients from 5 August 2022 to 14 March 2023 after obtaining ethical approval from the Institutional Review Committee. Overnight fasting blood samples were collected for lipid profile. Convenience sampling method was used. The point estimate was calculated at a 95% Confidence Interval.Among 79 ischemic stroke patients, 42 (53.16%)  had dyslipidemia where high cholesterol was seen in 21 (50%), high triglyceride in 22 (52.38%), high low-density lipoprotein 14 (33.33%) and low high-density lipoprotein in 20 (47.61%).The prevalence of dyslipidemia among ischemic stroke patients was lower than the similar studies done in similar settings. Ethical approval was obtained from the Institutional Review Committee of the same institute (Reference number: 4082022/02). The study included patients who had developed a sudden neurological deficit affecting a vascular territory, with sustained symptoms lasting more than 24 hours and evidence of a stroke on magnetic resonance imaging or non-contrast computed tomography scan, as confirmed by a neurologist. Patients who were discharged or referred to another hospital, and patients who did not undergo neuroimaging were excluded from this study. Convenience sampling method was used. The sample size was calculated using the following formula:Where,n = minimum required sample sizeZ = 1.96 at 95% Confidence Interval (CI)7p = prevalence taken from the previous study as, 80%q = 1-pe = margin of error, 9%The minimum required sample size was 76. However, the final sample size taken was 79.Overnight fasting blood samples were collected from the patient after 8-10 hours of fasting. Lipid profiles were measured where total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) were calculated and measured.7Dyslipidemia is defined according to the third report of the National Cholesterol Education Program (NCEP) Adult Treatment Panel III. One or more of the following is diagnosed as dyslipidemia.LDL Cholesterol \u2265130 mg/dlTotal Cholesterol \u2265200 mg/dlTriglycerides \u2265150 mg/dlHDL Cholesterol \u226440 mg/dlData were entered in Microsoft Excel 2016 and analysed using IBM SPSS Statistics version 21.0. The point estimate was calculated at a 95% CI.Among 79 patients with ischemic stroke, dyslipidemia was seen in 42 (53.16%) . High cholesterol was seen in 21 (50%) with mean total Cholesterol of 188.48\u00b149.26 mg/dl, high triglyceride in 22 (52.38%) with mean triglyceride of 160.83\u00b169.44 mg/dl, high LDL in 14 (33.33%) with mean LDL of 110.86\u00b139.68 mg/dl, and low HDL in 20 (47.61%) with mean HDL of 43.33\u00b18.68 mg/dl.The mean age of the ischemic stroke patients presenting with dyslipidemia in this tertiary care centre was 60\u00b114.93 years with a maximum of 87 years and a minimum of 20 years out of which 23 (54.76%) belonging to the age group less than 60 years and 19 (45.24%) were above 60 years.Gender wise there was male predominance with males being 23 (54.76%) and females 19 (45.24%). A total of 15 (35.71%) males and 6 (14.29%) females had high total cholesterol, 12 (28.57%) males and 10 (23.81%) females had high triglyceride, 9 (21.43%) males and 5 (11.90%) females had high low-density lipoprotein, and 6 (14.29%) male and 14 (33.33%) female had low high-density lipoprotein .Among 42 patients with dyslipidemia, 23 (54.76%) of the ischemic stroke patients were smokers, 12 (28.57%) of them were male and 11 (26.19%) were female. Whereas 10 (23.81%) were alcoholic, 10 (23.81%) were male and none of the ischemic stroke female with dyslipidemia were alcoholic. In our study 37 (88.10%) patient with 21 (50%) male and 16 (38.10%) female were having first episode of ischemic stroke .In our study 30 (71.43%) of the patient presented with weakness of the body in the form of hemiparesis, upper or lower limb weakness unilateral or bilateral, 29 (69.05%) presented with slurring of speech, 9 (21.43%) with facial deviation, 5 (11.90%) with headache, 3 (7.14%) with loss of consciousness and 3 (7.14%) with a tingling sensation. In this study, multi-morbidity was found in 23 (54.76%) patients having more than one disease. Hypertension (HTN) was the commonest risk factor with a total of 18 (42.86%) patients having been diagnosed with HTN, 13 (30.95%) had type 2 diabetes mellitus (T2DM) followed by 3 (7.14%) with cardiovascular disease (CVD), 3 (7.14%) had chronic obstructive pulmonary disease (COPD) and 1 (2.38%) with chronic kidney disease (CKD) .7The prevalence of dyslipidemia among the ischemic stroke patients in our study was 42 (53.16%) with hypertriglyceridemia the most common finding constituting 22 (52.38%) which was similar to the finding from a study in our country 58.33%.8 Unfortunately, there is limited information available on the prevalence, morbidity, and mortality of stroke in Nepal beyond urban areas, and no official reports have been published on the epidemiology of stroke throughout the country.4 However, changes in the epidemiological profile of stroke have been observed in clinical practice and confirmed by a study done in a similar setting.6 In developing countries such as Nepal, the incidence rate of stroke has increased by 100%, whereas in developed countries, it has decreased by 42% over the last four decades.9 This increase in stroke incidence is largely attributed to atherosclerosis, which is a major contributor to ischemic stroke.10 However, dyslipidemia is a modifiable risk factor for stroke, and therefore, its management can play a significant role in reducing stroke incidence.Dyslipidemia is a well-known risk factor for cardiovascular and cerebrovascular events worldwide. Therefore, preventing and managing dyslipidemia can help to reduce the global burden of stroke.10 These results highlight the importance of identifying and managing dyslipidemia in stroke patients, particularly those with ischemic stroke, to reduce the risk of recurrent events and improve overall outcomes.Our findings of a 53.16% prevalence of dyslipidemia in ischemic stroke patients are consistent with a study conducted in northeast China, which found a prevalence of 62.1% in ischemic stroke patients.11 A study in Japan among 2,351 Japanese inhabitants aged \u226540 years of age showed increased incidences of atherothrombotic and lacunar infarctions significantly with the increasing LDL cholesterol level, but no such associations were observed for cardioembolic infarction. Thus, it depicts a positive relation of increased LDL with small artery stroke as high LDL is usually implicated in atherosclerosis.12 In our study, the mean age of ischemic stroke associated with dyslipidemia was 60\u00b114.93 years with most patients less than 60 years 23 (54.76%). A comparable age was also present in studies done in Nepal and India.13The relative risk of stroke associated with elevated serum cholesterol is high, as well as its population-attributable risk given the increase in incidence in elderly populations.14 Our study shows the prevalence of ischemic stroke is more 23 (54.76%) in men than 19 (45.24%) in females, thus men have a higher prevalence of ischemic stroke than females, similar to the study done in a similar setting.14 The Asia Pacific Cohort Studies Collaboration found a 25% increase in ischemic stroke rates for every 1 mmol/L increase in total cholesterol.15 Similar study found the prevalence of dyslipidemia in the eastern part of our country, in a similar setting, to be 46.05%, with high triglyceride (TG) being the most commonly deranged parameter similar to the finding depicted by our study 22 (52.38%).16 Our study found that the prevalence of ischemic stroke was higher in patients with high TG levels and lower in patients with high levels of LDL.One of the studies showed that men experience more ischemic stroke than females, but females experience more subarachnoid hemorrhage. In terms of stroke onset, women are on average 4 years older than men at the age of ischemic stroke.7 We find 23 (54.76%) of the ischemic stroke patients to have multimorbidity with HTN being the commonest associate, which was quite less compared to the findings of a similar study.17Our study revealed the weakness of the body 30 (71.43%) in the form of hemiparesis of the upper limb or lower limbs to the commonest presenting complaint followed by slurring of speech 29 (69.04%) and facial deviation 9 (21.43%) similar to the finding done in a similar setting, which showed hemiparesis 59.16% as the commonest complaint followed by slurring of speech.Ischemic stroke is multifactorial and requires various integrated approaches. So early screening, monitoring and intervention of the different risk factors as well as awareness will help in combating the burden of the disease as it is one of the leading causes of morbidity and disability in the Asian population. Therefore, a more substantial, in-depth, and multicentered prospective investigation should be conducted to examine the severity of the disease and its relationship with various variables in the context of the Nepalese community.The findings from our study cannot reflect the general population because it was a single-centered study with a small sample size. This was a descriptive cross-sectional study so association with risk factors cannot be established.The prevalence of dyslipidemia in ischemic stroke patients was lower than the similar studies done in similar settings. Modifiable risk factors also play an important role in disease causation so timely action and knowledge regarding the risk factor can reduce the disease burden."}
+{"text": "By its nature, the activity of teleoperators seems to be a propitious environment for the development of psychosocial disorders, sometimes severeTo study the frequency of psychiatric disorders among teleoperators and their impact on medical fitness for workThis is a retrospective descriptive epidemiological study. We examined the files of teleoperators who were referred to the occupational medicine department of Charles Nicolle between 2014 and 2022 for a medical opinion of aptitudeA total of 82 cases were identified, 27 of which had psychological complaints. A clear female predominance was noted (21). The average age was 38.22+-6.536 years. All the patients were telephonists at the call-taking station with an average professional seniority of 9.3+-3.395 years. The symptoms noted were: sad mood (19), irritability (15), anxiety (10), sleep disorders (8), loss of vital impetus (8), neurovegetative signs (6), psychomotor slowing (5), concentration and memory disorders (3). Only one patient had suicidal thoughts. Symptoms had been evolving for an average of 34.32+-34.527 months. Psychiatric follow-up was noted in 16 patients. The diagnoses retained were: anxiety and depressive disorder (19), adjustment disorder (4), panic disorder (2), obsessive-compulsive disorder (1), and a satisfactory state of health (1). In some cases, the evolution was marked by complications: addiction(1), tonic stuttering with phobic disorder(1) and speech disorder(1). The prescribed treatments were: an antidepressant(2), an antidepressant-anxiety combination(8) and psychotropic drugs(2). Concerning the ability to work, 21 patients required an eviction from call taking (definitive (9) or temporary for 3 months (7) or 6 months (5) with re-evaluation of the medical ability to work at the end of this period), 1patient had an eviction from night work and an other had a reduction of the working hours.Teleoperators are exposed to several risks which can affect both their mental and physical health and put their medical fitness for work at risk.None Declared"}
+{"text": "Despite numerous reports of state Medicaid drug utilization review (DUR) programs, little data are available about the prevalence of drug related problems (DRPs) in Medicaid patients. A university-based, pharmacist-run DUR program for high utilizers was created as an alternative to imposition of a statutory limit of 7 medications per month in the Utah Medicaid program in 2002. The DUR program was designed to suggest ways that high-utilizing patients could decrease their total number of medications to 7 or fewer prior to imposition of the 7-medication limit at some time in the future.To describe the experience in 1 Medicaid DUR program and to report the prevalence of DRPs and cost-saving opportunities (CSOs) among a population of Medicaid recipients who were high utilizers of prescription drugs.DRPs were identified by 5 clinical pharmacists employed by the Drug Regimen Review Center (DRRC) in Salt Lake City. The purpose of the center was to provide drug therapy review services for a select number of Utah Medicaid recipients (200-300 per month) who exceeded a 7-medication limit during the calendar years 2003 and 2004.Out of 391,890 eligible Medicaid recipients, 242,411 (62%) received at least 1 medication, and 16,958 (4.3%) exceeded the 7-medication limit during the review period. Of those exceeding the limit, the DRRC reviewed a total of 3,706 (21.9%) patients, representing the highest utilizers by volume of medication. The prevalence of DRPs considered clinically important in the review cohort was 79.7% of patients, including therapeutic duplications in 54.6% of patients, dose form optimization in 29.7%, and inappropriate uncoordinated care in 25.3%. The average pharmacy cost per month for patients with at least 1 DRP was $1,081; by contrast, the average pharmacy cost per month for all other patients receiving at least 1 prescription was $91.Approximately 4% of Medicaid recipients exceeded the 7-medication monthly limit. Among the 22% highest utilizers in this group, 48% of nursing home residents and 87% of ambulatory recipients had at least 1 DRP, or an overall rate of 80% of high-use Medicaid recipients or as much as 3.2% of the Medicaid population."}
+{"text": "Cardiovascular diseases(CVD) remain the leading cause of death in the world and over 80% of all cardiovascular-related deaths occur in low and middle income countries. Ethiopia is in epidemiologic transition from predominantly infectious diseases to non-communicable diseases and the CVD is a major public health challenge.The aim of this study was to assess the magnitude and spectrum of cardiovascular admission and its outcomes among medical patients admitted to both Medical Ward and ICU of St. Paul Teaching Hospital from 1st of Jan 2020 to 1st of Jan 2021.Out of 1,165 annual medical admissions, the prevalence of cardiovascular diseases(CVD) was 30.3%. About 60%(212) of patients had advanced congestive heart failure of diverse causes. Hypertensive heart disease (HHD) was the next predominant diagnosis (41%(146)), and also the leading cause of cardiac diseases followed by rheumatic valvular heart disease(RVHD) (18%(64)) and Ischemic heart disease (IHD) (12.2%(43)), respectively. Yong age, rural residence and female sex were associated with RVHD(p = 0.001). Stroke also accounted for 20%(70) of CVD admission (hemorrhagic stroke-17% Vs Ischemic stroke-83%). Hypertension was the predominate risk factor for CVD and present in 46.7%(168) of patients. The mean hospital stay was 12days and in-hospital mortality rate was 24.3% with septic shock being the commonest immediate cause of death followed by fatal arrhythmia, brain herniation, and massive PTE.Cardiovascular diseases were common in the study area causing significant morbidity and mortality. Therefore, comprehensive approach is imperative to timely screen for cardiovascular risk reduction, disease control and complication prevention. Strategies should also be designed to increase public awareness regarding the cardiovascular risk reduction, drug adherence, and possible complications. The impacts of non-communicable diseases (NCDs) are particularly devastating in poor and vulnerable populations . NCDs cuCardiovascular disease remains the leading NCDs related cause of death in the world. Approximately 80% of all cardiovascular-related deaths occur in low and middle income countries and at a younger age in comparison to high-income countries . Africa A cardiovascular spectrum study in Addis Ababa has revealed the five most common cardiovascular diseases such as valvular heart disease (62%), hypertension (14.7%), cerebrovascular disease (11.5%), congenital heart disease (8.5%), and ischemic heart disease (IHD) (6.8%) . AnotherA recent outpatient study conducted in Northern Ethiopia revealed that Hypertensive heart disease was the predominant etiologic diagnosis of cardiovascular disease followed by rheumatic heart disease . In thisThe study was conducted in the department of internal Medicine at St Paul Hospital Millennium Medical College (SPHMMC), which is one of the biggest tertiary governmental Teaching Hospitals in Addis Ababa, the Capital of Ethiopia and the seat of African Union. The hospital receives follow-up patients, emergency patients and referrals from other Hospitals and health facilities all over the country.An institutional based, retrospective, cross-sectional study was conducted at St Paul Teaching Hospital involving all the cardiovascular admissions in the medical ward and ICU from 1st of January 2020 to 1st of January 2021. Admission and discharge diagnosis was captured from the registry to further retrieve the chart of the patient for detailed review of demographic data, major investigations, co-morbidities, underlying background risk factors and control, admission/discharge diagnosis of cardiovascular diseases, duration of hospital stay and outcomes.The study included all eligible cardiovascular admissions among all the medical patients admitted to the study hospital during the stated period. A total of 353 patients with cardiovascular diagnosis among all the annual medical admissions of 1165 patients were evaluated during the specified study period. The exclusion criteria were patients whose medical records were incomplete or patients who were died before adequate diagnosis was made. A total of 40 patients with CVD diagnosis on the HMIS registry were excluded due to incomplete medical records.Relevant patient information was retrieved from the HMIS registry as well as medical records. Cardiovascular diseases included diseases that affect the heart and blood vessels. The main blocks of WHO International Classification of Diseases(ICD)-10th version for Mortality and Morbidity Statistics (MMS) (Version: 04 / 2019) was utilized to sort out the final diagnoses . The uniCardiovascular diseases comprise various diseases affecting the heart and blood vessels.Hypertensive heart disease (HHD) was diagnosed in patients with hypertension presenting with symptoms and signs of heart failure, with or without left ventricular (LV) hypertrophy and left atrial enlargement on two-dimensional echocardiography or Doppler evidence of LV diastolic dysfunction in the absence of significant valvular heart disease or regional wall motion abnormality [ormality . For thoDilated cardiomyopathy (DCMP) was diagnosed in patients with marked LV dilatation and dysfunction in the absence of significant valvular, structural, or congenital heart disease or arterial hypertension [rtension .Ischaemic heart disease (IHD) included any of the three entities: 1. Angina pectoris which is short lived, relieved with termination of the provoking factor or rest and had no typical ECG features of infarction, 2. Acute myocardial infarction which was defined by the presence of elevated cardiac biomarker together with acute onset chest pain, and/or typical ECG changes, 3. Prior myocardial infarction including patients who present with or without heart failure in whom echocardiography detected regional wall motion abnormality in the absence of a history of acute coronary syndrome [syndrome . PatholoPulmonary heart disease (PHD): Right heart failure, also known as cor pulmonale due to altered structure and/or function of the right ventricle evidenced by 2-dimensional echocardiography.Blood pressure control: Controlled BP when the mean BP\u2009<\u2009140/90 mmHg in hypertensive patients of all ages [all ages . Uncontrall ages .Blood Sugar control: Good glycemic control when the mean Fasting blood sugar \u2264\u2009130 mg/dL and /or HbA1C <7% and Poor glycemic control when mean Fasting blood sugar >130 mg/dL and/or HbA1C>7% [HbA1C>7% .In order to ensure the accuracy, completeness, and comparability of data, four senior medical residents were trained to complete data collection format. Data collection was made by the pretested structured check lists to document all the pertinent profiles of the study subjects.After checking for completeness, data was coded, entered, and analyzed using SPSS version 20 software. Descriptive statistics was used to calculate rates. Chi-square was used to estimate the associations between selected predictor variables. A p-value < 0.05 was taken as statistically significant.Ethical clearance was obtained from institutional review board (IRB) of St. Paul Teaching Hospital. Since it was a retrospective study, written consent was waived by the research and ethics committee. Anonymity of the patient profile was upheld.st of January 2010 up to 1st of January 2021, the total cardiovascular admissions constituted 30.3%(353). Majority of the study subjects were females (60%(213)). Addis Ababa together with Oromia regional state constituted 90% of total cardiovascular admissions to St. Paul Hospital Millennium Medical College during the study period  constituted for 41.4%(146) of the total CVD diagnosis as well as the leading etiologic cause of advanced heart failure. Its prevalence increased with increasing age (p<0.001). HHD was more predominant among urban residents than rural ones ((63%(92) Vs 37%(54), p = 0.001)). Valvular heart diseases  accounted for about 34.5% of all advanced cardiac failure cases and 20.5% (73) of all the cardiovascular admissions as shown in the Chronic rheumatic valvular heart diseases(CRVHD) was more predominant in patients coming from outside of Addis Ababa compared to residents of Addis Ababa(82.8%(53) Vs 17.1%(11)(p = 0.001). Echocardiography proven isolated MS and MS with MR constituted 26%(19) and 27.5%(20) of all valvular heart diseases, respectively. The proportion of degenerative valvular heart diseases increased with advancing ages (p = 0.01) whereas rheumatic heart diseases decreased as age increased (p = 0.01). Ischemic heart disease (IHD) accounted for 12.2%(43) of all CVD admissions. Its prevalence has significantly increased with age and males had higher proportion than females(p = 0.001). IHD was more common in residents of Addis Ababa than those who came from out of Addis Ababa but the difference was not significant (p = 0.2). IHD was significantly associated with hypertension and diabetes . From all IHD patients, 90.24% had hypertension with 13.5% had good hypertension control, 59.5% had poor hypertension control, and 27% were newly diagnosed hypertension. Similarly, 41.5% of IHD patients had diabetes mellitus with 41.5% had good glycemic control, 35.3% had poor glycemic control and 17.6% were newly diagnosed T2DM. About 11%(40) of CVD admissions had pulmonary heart disease(PHD) with over 42% of them were attributed to COPD and the remaining were due to chronic PTE and post-TB fibrosis. PHD was more common in patients who came from Addis Ababa than those coming outside of Addis Ababa but the difference was not significant (p = 0.053). Females constituted over two-third of patients diagnosed with dilated cardiomyopathy and peripartal cardiomyopathy accounted for 26.5%(p = 0.01).Vascular diseases (VasD) were the most common cause of cardiovascular diseases next to CHF and HHD. It accounted for about a quarter of cardiovascular diagnosis and females constituted about two-third of the cases. DVT was the leading vascular cause accounting for 44%(37) followed by PTE of about 30%(25). Peripheral arterial disease (PAD) and cerebral venous thrombosis(CVT) accounted for 15.5%(13) and 9.5%(8) of vascular disease admissions, respectively. Pregnancy and related conditions such as caesarian section and puerperium (30.6%(26)); major surgery and prolonged immobilization for medical illnesses(28.2%(24)); and active cancers(11.7%(10)) were the major risk factors of venous thrombo-embolism(VTE). Hypertension and diabetes were significantly associated with PAD. Hypertension was documented as a risk factor in about 85% of patients with PAD followed by diabetes mellitus and chronic kidney disease, each of which were implicated as a risk factor in 25% of cases of PAD. The cumulative rate of vascular diseases have significantly decreased as the age of the patients increased(p = 0.01) .Cerebrovascular accident (stroke) accounted for about 20%(71) of total annual cardiovascular admission with hemorrhagic stroke constituted about 17% and ischemic stroke for the remaining 83% of the total stroke patients. Of all ischemic stroke, cardioembolic stroke accounted for 32.2%. From all the atherothrombotic ischemic stroke groups, 7.5% had hemorrhagic transformation during the course of hospital stay. Stroke was predominant in residents of Addis Ababa than those who came outside of Addis Ababa although the difference was not statistically significant (p = 0.07) but it increased with increasing age(p = 0.001) . There wOf all the 353 annual cardiovascular admissions, 47.6%(168) patients had history of hypertension. Hypertension was prevalent in patients from Addis Ababa than patients who came outside of Addis Ababa ((63.7%(107) Vs 36.3%(61), p = 0.001)). The minimum duration of hypertension ranged from newly diagnosed hypertension up to the maximum of 30 years. Only 20% of patients had good hypertension control (BP<140/90mmHg) with adherence to the medications and have frequent follow up whereas 46.6% of patients had poor hypertension control (BP\u2265140/90mmHg) who were either not adherent to or discontinued their pharmacologic therapy by themselves. About 35% of hypertensive patients were newly diagnosed during their current admission. The control of hypertension in patients from Addis Ababa was significantly better than patients coming outside of Addis Ababa (p = 0.001). The proportion of diabetes mellitus(DM) among the cardiovascular admissions was 17.6%(62) and significantly prevalent in patients from Addis Ababa than those out of Addis Abbaba ((74.1%(46) Vs 25.8%(16), p = 0.001)). The duration of DM history ranged from newly diagnosed DM up to 25 years. About 40% of DM patients had \u2019\u2019good\u2019\u2019 DM control with mean FBS\u2264130mg/dl and/or A1C<7% whereas 46.8% had \u2019\u2019poor\u2019\u2019 DM control (mean FBS>130mg/dl and/or A1C>7%). The control of diabetes in patients from Addis Ababa was significantly better than those coming outside of Addis Ababa (p = 0.001).Among patients with CVD admissions, the minimum hospital stay was one day and the maximum was 80 days with the average hospital stay was 12days. About 57%(201) of cardiovascular admissions were discharged from the hospital with improvement, 10%(36) were discharged with the same condition, and 4.5% (16) were left against medical advice. The in-hospital mortality rate among the cardiovascular admission was 24.3%(86) with the predominated immediate cause of death being sepsis with septic shock(25.6%) followed by fatal arrhythmia (19.8%), brain herniation (15%), massive PTE (14%), and cardiogenic shock (11.6%) .The epidemic of cardiovascular disease (CVD) is a global phenomenon, and the magnitude of its burden is alarmingly increasing in the developing world including Ethiopia . In the Most of the CVD patients (60%) were admitted with the clinical diagnosis of advanced congestive heart failure (CHF) (NYHA class III and IV). This high rate of CHF in the current study is in agreement with other Ethiopian studies ,28. SurpHypertensive heart disease (HHD) was the second predominant diagnosis constituting for 41% of overall cardiovascular admission and also the leading cause of heart failure followed by rheumatic valvular heart disease(RVHD) which constituted for about 18% of all CVD. In most of the previous studies involving both inpatient and outpatient follow up clinics, VHD was considered to be the leading cause of CVD in general and cardiac diseases in particular ,27\u201329. TCerebrovascular accident (CVA) or stroke accounted for 20% of annual CVD admissions with ischemic stroke being the predominant sub-type(83%), and hemorrhagic stroke constituted the remaining 17%. This finding is consistent with the well-established global data and some of Ethiopian studies where Ischemic stroke is the dominant sub-type ,30\u201332. HHypertension, in the current study, was found to be the dominant risk factor for cardiovascular diseases where about 48% of CVD patients had hypertension. However, this finding is higher than some of the previous reports of hypertension burden among the CVD patients in Ethiopia ,17,25,38Vascular diseases including deep venous thrombosis (DVT), pulmonary thromboembolism (PTE), peripheral arterial disease (PAD), and cerebral venous thrombosis (CVT) were common in the present study area and all together constituted about 24% of all the annual CVD admissions. DVT was the leading cause of vascular admission (44%), followed by PTE(30%), PAD15.5%) and CVT (9.5%), respectively. The current vascular disease burden is much higher than the previous cardiovascular spectrum studies .5% and C,18 whichThe mean duration of hospital stay in the current study was 12days with the minimum hospital stay was one day and the maximum was 80 days. This result is comparable with the average of 12.33days of hospital stay for medical admission  and 11.1Due to the retrospective nature of the study, it has a limitation of including additional cardiovascular risk factors including smoking history, obesity, and physical inactivity. Since it was also a hospital based study with limited sample size, it lacks the accurate representation of the actual burden of cardiovascular diseases in the wider community. Furthermore, incomplete documentation is common in the retrospective studies. To avoid the sampling bias, we have incorporated the entire annual medical admissions in the study.In conclusion, cardiovascular diseases are common in the study area causing significant morbidity and mortality. Most cardiovascular diseases have preceding unaddressed but easily modifiable risk factors, controlling which could have prevented or delayed the progression of the disease. Therefore, concerted effort is required from all stake-holders in terms of risk reduction as well as follow-up optimization to delay or if possible to prevent cardiovascular disease development, disease progression and subsequent complications. Strategies should also be designed to increase public awareness regarding cardiovascular risk reduction, drug adherence, and possible complications."}
+{"text": "There is a lack of available data regarding COVID-19 vaccination rates in people living with HIV (PLWH). We examined a group of PLWH to evaluate the association between specific demographics and COVID-19 vaccine uptake.This is a retrospective observational study which included PLWH who were seen in an HIV clinic at an academic medical center in Memphis, TN. 300 randomly selected PLWH who had been seen at least once in the clinic within an 18-month study period during the COVID-19 pandemic were included. Univariate analysis using Chi Square and T tests followed by multivariable regression including significant results from univariate analysis identified factors associated with COVID-19 vaccine uptake.300 PLWH between January 2021 to June 2022 were included in the study. 248 (82.67%) were Black, 27 (9%) were White, 2 (0.67%) were Asian, and 23 (7.67%) were of multiracial/other races. The average age was 47 years old. 243 (81%) were retained in care, defined as 3 visits within the 18-month period with 2 of them being at least 6 months apart. 239 (81.29%) of the participants had a suppressed HIV viral load, defined as HIV RNA < 200 copies/mL. The mean number of total vaccinations in the previous 3 years was 4.61, and the mean number of influenza vaccinations in the past 3 years was 1.64. 207 (69%) of the participants received at least 1 COVID-19 vaccine, with 187 (62.33%) being fully vaccinated, defined as 2 doses of mRNA or 1 adenovirus vector vaccine. Age, number of attended clinic visits, retention in care, viral suppression, and number of previous vaccinations were associated with receiving at least one COVID-19 vaccine in univariate analysis, while only age (odds ratio (OR) 1.07, p< 0.0001), number of influenza vaccinations in the past 3 years , and total number of vaccinations in the prior 3 years  were significant in multivariable analysis.Age and total number of vaccinations in the past 3 years were positively correlated with having at least one COVID vaccine. Number of influenza vaccinations in the past 3 years was negatively correlated with having at least one COVID vaccine. Further study is needed to identify targeted interventions to improve vaccine uptake in this population.All Authors: No reported disclosures"}
+{"text": "To (1) determine the prevalence of heart failure (HF) and cardiovascular risk factors within a hypertensive managed care population, (2) measure blood pressure goal attainment in patients with concurrent HF and hypertension (HTN), and (3) assess the use of drug therapy for diabetic and nondiabetic patients with concurrent HF and HTN, particularly regarding the use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs).Eligible patients were identified through a review of medical and pharmacy claims data from 10 managed care organizations (MCOs) and 2 specialty medical groups  from June 1998 through July 2001. From approximately 850,000 members in the claims database identified as hypertensive, 7,226 were randomly selected for medical chart review. Of these, 6,935 medical charts had a confirmed diagnosis of HTN but not HF, and 291 (4%) had confirmed HTN and HF. The study population 291 patients with HTN and HF provided information on demographic characteristics, prevalence of cardiovascular risk factors and relevant comorbidities, and systolic and diastolic blood pressure. Current antihypertensive therapy prescription fill rate was evaluated using pharmacy claims.Patients with diagnoses of HTN and HF confirmed in the medical chart (N=291) were included in the present analysis. HF prevalence among hypertensive patients was 4% . Mean age of the study patients was 68.3 years, and 52.9% of the patients were female. Key cardiovascular risk factors included gender  (89.3%), age greater than 60 years (73.5%), hyperlipidemia (47.4%), and diabetes (38.8%). Of the total sample, only 30.1% of the diabetic (34 of 113) and 26.4% of the nondiabetic (47 of 178) patients with HF had their blood pressure controlled to the goal level of less than 130/85 mm Hg recommended by the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, the national guideline in effect at the time. Overall, 64.7% of HF patients for whom we had pharmacy claims were receiving an ACE inhibitor or an ARB.The study results indicate a deficit in the treatment of HTN among HF patients with and without diabetes, including failure to achieve blood pressure goals (less than 130/85 mm Hg at the time of this study period). More aggressive quality improvement programs are necessary to educate providers and patients on the importance of treating blood pressure to nationally accepted goal using antihypertensives proven beneficial for hypertensive patients with HF."}
+{"text": "A cross-sectional study design was used. The hospitals were selected randomly. A total of 100 swab samples were taken from door-handles. Isolation and identification of bacteria were done using standard microbiological procedures. An antibiotic susceptibility test, screening and confirmation of ESBLs were performed using the Clinical Laboratory Standard Institute\u2019s guidelines.The presence of drug-resistant Gram-negative pathogenic bacteria and Extended Spectrum \u03b2-Lactamase Producers (ESBLs) in hospital associated fomites like door handles can serve as vehicles in transmission and may be the key factor in epidemiology of ESBL producing bacterial infection not only in a hospital setting but also in the community. The aim of this study was to determine the prevalence of ESBLs and antibiotic resistance of Gram-Negative pathogenic Bacteria isolated from door-handles in two selected hospitals in Pokhara Metropolitan City, Nepal. The study was conducted in selected hospitals in Pokhara Metropolitan City, Western NepalEscherichia coli 28.85%, followed by Klebsiella spp 21.15%, Pseudomonas aeruginosa 15.38%, Proteus spp 11.54%, Enterobacter spp 9.62%, Acenetobacter spp 7.69%, Citrobacter spp 5.77%. The most effective drug of choice was Amikacin, Nitrofurantoin, Norfloxacin, Ciprofloxacin, Tetracycline and Imipenem for many Gram-negative isolates. The overall prevalence of ESBLs in this study was 27.14%. Out of total 15 Escherichia coli isolated, 11(73.3%), Klebsiella spp 9/11 (81.8%); Pseudomonas spp 7/8 (87.5%), Proteus spp 4/6 (66.6%); Enterobacter spp 3/5 (60%), Acenetobacter spp 3/4 (75%) and Citrobacter spp 1/3 (33.3%) were found to be Extended \u03b2-Lactamase Producers (ESBLs).Out of the 100 swab samples cultured, 96 (96%) showed bacterial growth. A total of one hundred and forty isolates were isolated in this study which were further identified based on cultural, morphological and biochemical characteristics. The study also found that door handles/knobs had higher level of contamination in Outpatient Departments (OPDs), Emergency, Laboratory, General wards and Toilets, in that order as compared to Radiology Room, Staff rooms, Intensive Care Unit and Operation Theatre which were lower. The level of contamination varies depending on the traffic exposure and the environment. The most prevalent Gram-negative bacteria identified was The isolation of\u00a0of pathogenic Gram-negative bacteria and ESBLs\u00a0in hospital environments and subsequent detection of high drug resistance patterns indicates a potentially serious public health challenge that strengthens the need for the effective and routine cleaning of door-handles in hospitals. The microorganisms have been frequently isolated from environmental sources that serve as a relay for the bacteria and play major role in its spread of infections between different hosts . SurfaceInadequate treatment regimens, insufficient patient adherence, unregulated drug distribution and trafficking, as well as antibiotic scarcity and poor quality, can all contribute to antibiotic resistance. Target alteration of the drug, bypassing the drug, the impermeability of the bacteria, biofilm formation, efflux of the drug, mutations and plasmid-mediated transfer of resistance genes are major mechanisms of the antibiotic resistance , 6. GramThus, contamination of fomites like door handles with\u00a0antibiotic resistant bacteria\u00a0can be a major threat to public health . MembersS. aureus, K. pneumoniae, Escherichia coli, Enterobacter spp, Citrobacter spp, Pseudomonas aeruginosa, Proteus spp, Streptococcus spp, Salmonella spp, Shigella spp, Campylobacter spp [Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa,\u00a0and\u00a0Enterobacter\u00a0spp (ESKAPE) are the pathogens, designated as \u201ccritical priority status\u201d [Bacterial pathogens that have been isolated from door handles in previous studies included cter spp , 16. The status\u201d . Out of The presence of resistant bacteria in hospital environments are a critical component of nosocomial infection. Hospital door handles contaminated with pathogenic bacteria and ESBL producing isolates increase the risk for infections and may be the key factor in epidemiology of ESBL-producing bacterial infection not only in a hospital setting but also in community. Door handles were pointed in this study because these are frequently touched surfaces shared by healthcare workers, patients and visitors but most neglected from cleaning or disinfection procedures. To our knowledge, there have been no published data available on the contamination of door handles of the hospitals by Gram negative pathogens and ESBL Producers with their antibiotic susceptibility pattern in Pokhara Metropolitan City, Nepal to date. Thus, this study was aimed to provide the baseline data on prevalence of ESBL producers and diversity and distribution of Gram-negative bacterial contamination along with their antibiotic resistance pattern from doorhandles in selected hospitals from Pokhara, Nepal. The isolation of\u00a0pathogenic Gram-negative bacteria and ESBLs\u00a0in hospital door handles and subsequent detection of high drug resistance patterns indicates a potentially serious public health challenge that strengthens the need for the effective and routine cleaning of door-handles in hospitals. The findings of this study might provide insight into the role of hospital-associated fomites, such as door handles, in the transmission of drug-resistant bacteria and the epidemiology of ESBL-producing bacterial infections.The study was conducted in selected hospitals in Pokhara Metropolitan, City, Western Nepal. The Pokhara valley is located in central\u00a0Nepal between 27\u02da55'-28\u02da23' north latitude and 83\u02da48'-84\u02da11' east longitude. A cross-sectional study was carried out following random sampling technique. The hospitals were selected randomly.A total of 100 swab samples were collected from the door handles/knobs of two selected hospitals of Pokhara Metropolitan City, Nepal. The sterile cotton wool swabs were moistened with 5\u00a0ml of normal saline added to the swabs case and excesses were removed by pressing the swab stick against the inner side of the tube according to Chesebrough, 2000 . Individ0C and transported to the laboratory of Janapriya Multiple Campus (JMC), Pokhara for analysis within two hours.The swab was wiped firmly on the entire surface of the door handles/knobs. It was then introduced into a test tube containing sterile Brain Heart Infusion (BHI) broth, labelled, kept below 4All the samples were processed by standard bacteriological procedures . CollectEscherichia coli (ATCC 25922) and Klebsiella pneumoniae (ATCC 700603) were used as the quality control strains. Bacterial isolates that were resistant to minimum one agent in three or more than three antibiotic groups were categorized as multidrug-resistant (MDR) [Pure cultures of identified organisms were plated onto nutrient agar prior to all susceptibility tests. Antibiotic susceptibility testing was performed by the Kirby\u2013Bauer disc diffusion method. The antibiotic disks were firmly placed on the sterile Mueller\u2013Hinton agar plates  seeded with the tested strains, standardized to 0.5McFarland\u2019s turbidity standard and incubated at 37\u00a0\u00b0C and interpreted according to the Clinical and Laboratory Institute Standard (CLSI) guidelines . The disnt (MDR) .Screening test for ESBL detection was done according to the CLSI guidelines . IsolateEscherichia coli (ATCC 25922) and Klebsiella pneumoniae (ATCC 700603) were used in parallel as a part of quality control.The presumptive ESBL-positive isolates from screening methods were retested for ESBL production by the Double Disc Synergy Test according to the CLSI guidelines . Brieflyp\u2009\u2264\u20090.05 was assumed wherever applicable and 95% confidence intervals along with the exact p-values were presented. Data were presented in appropriate table, figures by using counts and calculating percentages, rate etc. Data were computed and described using counts and percentages. The ANOVA test was employed in comparing the distribution of MDR among ESBL producing Gram negative isolates at 95% confidence limit.Data entry and analysis were performed using GraphPad Prism software for window (version 6). A value of A total of 140 isolates were found on the door handles obtained from 96 culture positive samples out of 100 samples processed. The Gram stain identified that (88/140) 62.86% of the bacteria found on the door handles were Gram positive and (52/140) 37.14% of the isolates were Gram negative , followed by Klebsiella spp 11(21.15%), Pseudomonas aeruginosa 8 (15.38%), Proteus spp 6 (11.54%), Enterobacter spp 5 (9.62%), Acenetobacter spp 4 (7.69%) and Citrobacter spp 3 (5.77%) , Tetracycline (80%), Norfloxacin (80%), Imipenem (66.6%), Piperacillin (46.6%), Cefotaxime (26.6%) and Ceftazidime (26.6%) (Table Most of the Gram-negative bacilli isolated were found to be 100% resistance to Cotrimoxazole\u00a0(COT), Gentamycin (GEN)\u00a0and Amoxicillin\u2009+\u2009Clavulanate\u00a0(AMC). The most effective drug of choice were Amikacin (AK), Nitrofurantoin\u00a0(NIT), Norfloxacin\u00a0(NOR), Ciprofloxacin\u00a0(CIP), Tetracycline\u00a0(TE) (80%) and Imipenem\u00a0(IPM) for many isolates. Various antibiotics were used for antibiotic susceptibility pattern determination using Kirby Bauer disc diffusion method. %) Table .Table 3Klebsiella species showed different than that of E. coli isolates. Klebsiella species showed 100% resistance to Amoxicillin\u2009+\u2009Clavulanate, Cotrimoxazole and Piperacillin\u00a0(PI). The most effective drug of choice was Norfloxacin and Amikacin showing 100% sensitivity followed by Imipenem (90.9%), Tetracycline (81.8%), Nitrofurantoin (63.6%), Ciprofloxacin (63.6%), Cefotaxime\u00a0(CTX) (18.1%) and Ceftazidime (18.1%)  and Nitrofurantoin (12.5%). Similarly, Acenetobacter spp also showed 100% resistance to most antibiotics tested and sensitive to only Norfloxacin (50%), Amikacin (25%) and Nitrofurantoin (25%)  Table .Proteus species showed 100% resistance to Gentamycin, Cotrimoxazole and Piperacillin. The most effective antibiotic was Nitrofurantoin with 100% sensitivity followed by Amikacin (83.3), Imipenem (66.6%), Norfloxacin (66.6%), Ciprofloxacin (66.6%), Tetracycline (33.3%), Cefotaxime (33.3%), Ceftazidime (33.3%) and Amoxicillin\u2009+\u2009Clavulanate (16.6%) , Cefotaxime (40%), Ceftazidime (40%) and Imipenem (40%) (Table %) Table .Citrobacter species showed 100% resistant Cotrimoxazole. The most effective antibiotics were Amikacin, Nitrofurantoin and Norfloxacin (100%) followed by Imipenem (66.6%), Piperacillin (66.6%), Ceftazidime (66.6%), Cefotaxime (33.3%), Ciprofloxacin (33.3%), Gentamycin (33.3%), Amoxicillin\u2009+\u2009Clavulanate (33.3%) and Tetracycline (33.3%) ; out of total 11 Klebsiella spp 9 (81.8%); out of total 8 Pseudomonas spp isolated 7 (87.5%); out of 6 Proteus spp isolated 4 (66.6%); out of total 5 Enterobacter spp 3 (60%), out of total 4 Acenetobacter spp 3 (75%) and out of 3 Citrobacter spp 1 (33.3%) were found to be Extended B-Lactamase Producers (ESBLs) . Total of 52 Gram negative bacilli were observed. Out of total 15 E. coli (25%), 4(25%) Klebsiella spp, 5(31.25%) Pseudomonas spp, 1(6.25%) Proteus spp, 1(6.25%) Enterobacter spp, 2(12.5%) Acenetobacter spp. Statistically there was no significant association between the ESBL producing isolates among MDR phenomena (p\u2009>\u20090.05)  were Multi Drug Resistant (MDR) and 22(57.89%) were Non MDR. Out of total MDR isolate, 4 (10.53%) were The presence of drug resistant bacteria in hospital environments are a critical component of nosocomial infection. Contaminated intermediate objects represent a common transition of transmission between patients, from visitors to patients or from healthcare workers to patients , 22, whiIn this study, the level of contamination was higher in door handles of Outpatient Departments (OPDs), Emergency, Laboratory, General wards and Toilets, in that order as compared to Radiology Room, Staff rooms, Intensive Care Unit (ICU) and Operation Theatre (OT) which were lower. The lower level of contamination in ICU and OT could be attributed to the fact that they are not being used as frequently as other places studied, this is in agreement with the findings of Boone and Gerba (2010)  and NworEscherichia coli, Klebsiella spp, Pseudomonas spp, Acenetobacter spp, Enterobacter spp, Proteus spp and Citrobacter spp were the main Gram-negative bacteria isolated in this research work so far.This study also highlighted the presence of potential pathogenic Gram-negative bacteria in door handles of hospitals. Escherichia coli, Salmonella typhi, Shigella spp., Clostridium perfringes, Giardia lamblia, Norwalk virus and Hepatitis A virus; Pseudomonas aeruginosa, S. aureus, Proteus mirabilis, Citrobacter freundii, Enterobacter spp; Streptococcus spp, Klebsiella spp [E. coli and Klebsiella spp. The presence of these pathogenic bacteria on environmental surfaces such as door handles poses a potential risk to vulnerable, immune-compromised individuals.The fact that bacteria of the Enterobacteriaceae found on different door handles may indicate faecal contamination of the hands as the origin. This might be due to the fact that most people may fail to wash their hands and contaminate with faecal and urinal material due to lack of the concept of hand hygiene to stop the spread of infectious agents, which was corresponded with the work of Zhad et al. (1998) , who repella spp . The isoPseudomonas aeruginosa showed 100% resistance to almost all antibiotics tested except sensitive to Amikacin (25%) and Nitrofurantoin (12.5%). Similarly, Acenetobacter spp also showed 100% resistance to most antibiotics tested but was sensitive to only Norfloxacin (50%), Amikacin (25%) and Nitrofurantoin (25%). This is in agreement with the findings of other studies Beta-lactam antimicrobial agents exhibit the most common treatment for bacterial infections and continue to be the prominent cause of resistance to beta-lactam antibiotics among Gram negative bacteria worldwide. The persistent exposure of bacterial strains to a multitude of beta-lactams has induced dynamic and continuous production and mutation of b-lactamases in these bacteria, expanding their activity even against the newly developed b-lactam antibiotics. These enzymes are known as extended-spectrum beta-lactamases (ESBLs) [Enterobacteriaceae and is a serious threat to the currently available antibiotic Armory [Most of the Gram-negative bacilli isolated were found to be 100% resistance to Amoxicillin\u2009+\u2009Clavulanate, Cotrimoxazole and Gentamycin. The most effective drug of choice were Amikacin, Nitrofurantoin, Norfloxacin, Ciprofloxacin, Tetracycline (80%) and Imipenem for many isolates. However,  (ESBLs) , 29. Trec Armory , 29.Escherichia coli isolated, 11(73.3%); out of total 11 Klebsiella spp 9(81.8%); out of total 8 Pseudomonas spp isolated 7(87.5%); out of 6 Proteus spp isolated 4(66.6%); out of total 5 Enterobacter spp 3(60%), out of total 4 Acenetobacter spp 3(75%) and out of 3 Citrobacter spp 1 (33.3%) were found to be Extended B-Lactamase Producers (ESBLs). Overall prevalence of ESBLs in this study was 27.14% (38/140). Similar prevalence rates of ESBL in urinary isolates in Nepal were reported by the findings of Manandhar et al. (2006) [Out of total 15 . (2006) .E coli and Klebsiella species, the Amikacin, Norfloxacin, Nitrofurantoin, Tetracycline and Imipenem were found to be effective drugs of choice likewise in the study done by Stoesser et al. (2015) [In this study most of the Gram-negative isolates were Multidrug resistance and resistant to Cefotaxime, Ceftazidime, Amoxicillin\u2009+\u2009clavulanate, Gentamycin, and Cotrimoxazole which is in agreement with other study who also found 100% resistant to Cefotaxime and Ceftazidime . For ESB. (2015)  reported. (2015) . IndiscrDoor handles are frequently touched surfaces shared by healthcare workers, patients and visitors but most neglected from cleaning or disinfection procedures. The rising antibiotic resistance to bacteria that might contaminate the door handles of hospitals is a major worry worldwide, but particularly in emerging and underdeveloped nations like Nepal; and there is lack of information regarding antimicrobial resistance patterns of commonly isolated pathogens, particularly in the study area. Hence, this study assessed the base line data on prevalence of ESBLs producers and diversity and distribution of Gram-negative bacterial contamination along with their antibiotic resistance pattern from doorhandles in selected hospitals from Pokhara, Nepal. The isolation of\u00a0pathogenic Gram-negative bacteria and ESBLs\u00a0in hospital door handles and subsequent detection of high drug resistance patterns indicates a potentially serious public health challenge that strengthens the need for the effective and routine cleaning of door-handles in hospitals.Finally, a comprehensive survey and research on antibiotic resistance are required to analyze this disastrous national situation and develop management solutions.Door handles are a well-documented breeding ground for pathogens and present a high risk common contact surface facilitating the transmission of potentially pathogenic microorganisms. Door handles design and material of handle itself contributes to the growth of bacteria and might play key role to control microbial transmission . Novel dIsolation of pathogenic drug resistant Gram-negative bacteria and ESBLs from door handles of the hospitals is worrisome. Presence of such drug resistant bacteria including ESBLs in hospital door handles increase the risk for infection and may be the key factor in epidemiology of ESBL producing bacterial infection not only in a hospital setting but also in community. Therefore, hospital staffs, inpatients, outpatients and visitors should adopt the habit of hand washing practice after using the door handles in hospitals. Indeed, regular surveillance and routine surface disinfection of the hospital door handles should be done to prevent cross contamination."}
+{"text": "Teledermatology enables the remote viewing of diagnostic images and clinical histories, with the ability to diagnose and offer treatment recommendations . An incrThis analysis evaluates available trial participant data from the ClinicalTrials.gov trial registry of the US National Library of Medicine. We included all studies related to the use of teledermatology. Relevant participant data were extracted for analysis from their respective ClinicalTrials.gov registration when available. These variables included trial status, funding source, and trial participant demographic information.Our search yielded 35 clinical trials, of which 25 (71%) were completed and 3 (9%) had available results. Of the 35 clinical trials, 7 (20%) are currently recruiting, 2 (6%) have unknown status, and 1 (3%) was withdrawn, with a total mean start year of 2016.62 (SD 4.21). About 77% (27/35) were funded by non\u2013National Institutes of Health, non\u2013US federal funding . In terms of study type, 8 (23%) studies were observational and 27 (77%) were interventional.Among the completed trials with results -6, 1153 We found 3 completed clinical trials related to teledermatology with results on the registry -6. PooleTeledermatology is postulated to improve health equity by eliminating barriers to care. To this end, a retrospective study found a significant reduction in no-show rates among teledermatology visits compared to clinic visits among females, racial/ethnic minority patients, and Medicare/Medicaid beneficiaries . These fNone of the 3 studies with results report income or Medicaid beneficiary status. A study of direct-to-patient teledermatology in a low-income, older adult population found that among those older than 65 years, nearly 32.7% of encounters involved use of video and/or photo sharing compared to 60.6% among those aged <65 years . The purOur findings indicate that disparities exist in the gender and ethnic composition of trial participants for teledermatology along with a lack of adequate reporting of trial participants by race."}
+{"text": "Our aim of study was to evaluate joint fluid cell count for diagnosis among septic arthritis patients confirmed with positive culture in children.Septic arthritis is one of serious pediatric infections that could result motor comorbidities. Historically, joint fluid cell count of 50,000 and over cells/mmPatients with septic arthritis were included at Tokyo Metropolitan Children's Medical Center from March 2010 to March 2023. Septic arthritis was confirmed with positive joint fluid culture for a pathogenic organism. Patients with negative joint fluid culture and patients without joint fluid cell count were excluded. Electrical charts were retrospectively reviewed for demographic data, timing of arthrocentesis, culture result and joint fluid cell count.3. Patients with 50,000 and over cells/mm3 was 23%. The median time from onset to arthrocentesis was 3 (IQR: 2-5) days. The isolated organisms were methicillin-susceptible Staphylococcus aureus (50%), methicillin-resistant S. aureus (9%) and Streptococcus pyogenes (27%), Streptococcus pneumoniae (5%), Klebsiella pneumoniae (5%) and Salmonella spp (5%). The infected joints were hip (59%), knee (23%), ankle (14%), elbow (5%) and shoulder (5%). One patient had hip and ankle arthritis. Nine patients were complicated with septic osteomyelitis. The Pearson correlation coefficient between days from onset of symptoms to puncture and the number of joint cells was 0.093 (p=0.681). A total of 95 patients with septic arthritis were identified. After excluding patients with negative culture and without joint fluid cell count, 22 patients were included for our study. Median age was 5 (IQR: 2-10) years old. Girl ratio was 45%. The median joint fluid cell count was 19,575  cells/mm3.Majority of patients with septic arthritis confirmed with joint fluid culture did not exceed joint fluid cell 50,000 cells/mmAll Authors: No reported disclosures"}
+{"text": "FGF14 GAA repeat expansions have recently been found to be a common cause of hereditary ataxia . The global epidemiology and regional prevalence of this newly reported disorder remain to be established. In this study, we investigated the frequency of GAA-FGF14 ataxia in a large cohort of Brazilian patients with unsolved adult-onset ataxia.Intronic FGF14 repeat locus. Patients were recruited across 4 different regions of Brazil.We recruited 93 index patients with genetically unsolved adult-onset ataxia despite extensive genetic investigation and genotyped the FGF14 (GAA)\u2265250 expansion. The expansion was also identified in 1 affected relative. Seven patients were of European descent, 1 was of African descent, and 1was of admixed American ancestry. One patient carrying a (GAA)376 expansion developed ataxia at age 28 years, confirming that GAA-FGF14 ataxia can occur before the age of 30 years. One patient displayed episodic symptoms, while none had downbeat nystagmus. Cerebellar atrophy was observed on brain MRI in 7 of 8 patients (87%).Of the 93 index patients, 8 (9%) carried an FGF14 ataxia is a common cause of adult-onset ataxia in the Brazilian population, although larger studies are needed to fully define its epidemiology.Our results suggest that GAA- FGF14) gene have recently been shown to be a common cause of adult-onset ataxia  in European and South Asian populations.2 Patients with GAA-FGF14 ataxia displayed a slowly progressive cerebellar syndrome with frequent episodic symptoms and downbeat nystagmus.2Dominantly inherited GAA repeat expansions in intron 1 of the fibroblast growth factor 14  and screening for SCA1, SCA2, SCA3, SCA6, SCA7, SCA10, RFC1-related ataxia, and Friedreich ataxia. The FGF14 repeat locus was genotyped as previously described.7 Expansions of at least 250 GAA repeat units were considered pathogenic.2Ninety-three index patients were recruited in Curitiba , Rio de Janeiro , Amazonas (Universidade do Estado do Amazonas), and S\u00e3o Paulo  in Brazil. Patients presenting with unsolved neurodegenerative ataxia with onset after the age of 20 years were enrolled. Patients had previously undergone comprehensive investigation to exclude acquired and genetic causes, which included whole-exome sequencing \u2265250 expansion . Ancestry analysis of short-read sequencing data8 showed that 1 patient was of admixed American ancestry and 2 patients were of European ancestry. One patient self-reported being of African descent, while the remaining patients self-reported being of European descent.We identified 8 index patients  who carried an xpansion . The expFGF14 ataxia. The median age at onset was 59 years . We identified 1 patient who had an age at disease onset of 28 years, confirming that GAA-FGF14 ataxia can begin before the age of 30 years. All patients displayed a slowly progressive cerebellar syndrome, although none had dysarthria. A single patient experienced episodic symptoms, which were triggered by alcohol intake and stress, while 56% of patients (5/9) reported diplopia and 44% (4/9) reported vertigo and/or dizziness. Horizontal gaze-evoked nystagmus was observed in 78% of cases (7/9), consistent with previous reports showing that cerebellar oculomotor signs are common in GAA-FGF14 ataxia.9 However, none of the 9 patients exhibited downbeat nystagmus. The patient carrying biallelic GAA repeat expansions had a relatively rapid disease progression . In addition, extrapyramidal features were observed in 2 patients.-FGF14 ataxia.9 All other patients were still ambulating independently at the last follow-up, including 2 patients who had a disease duration exceeding 20 years.Overall, the median disease duration was 12 years . Two patients required unilateral walking aid after 7 and 12 years of disease duration, respectively. One patient became wheelchair bound after long-standing disease (15 years), in keeping with previous reports showing that wheelchair dependence is uncommon in GAAFGF14 expansion and age at onset or disease severity,9 we identified 3 patients who presented marked differences in age at onset and disease progression despite carrying an expansion of similar size . Notably, patient 3 developed disease at age 28 years and had a more gradual disease progression (SDFS score of 1 after 23 years of disease duration) compared with patient 4 who developed disease at age 59 years and had an SDFS score of 3 after 9 years of disease duration.In keeping with some reports showing weak to no significant correlation between size of FGF14 ataxia, an extensive workup did not reveal an alternative diagnosis.One patient had evidence of mild axonal sensory polyneuropathy on electrophysiologic studies. Isolated vermis atrophy was observed in 4 patients  on brain MRI, while diffuse cerebellar atrophy was observed in 3 patients . Mild midbrain and pons atrophy was observed along with diffuse cortical atrophy in 1 patient. This patient had a comparatively more severe phenotype, with dystonia of the upper limbs, vestibular areflexia, and was wheelchair dependent. Although it is unknown whether these findings are pathologically related to GAA-FGF14\u2013negative patients, we identified 4 patients who carried a non-GAA expansion (2 (GAAGGA)n, 1 (GAAGAAA)n, and 1 [(GAA)4(GCA)1]n). Non-GAA expansions in FGF14 are likely not pathogenic, as previously shown in segregation studies.1Of the GAA-FGF14 (GAA)\u2265250 expansions were present in 9% (8/93) of patients with unsolved adult-onset ataxia. We identified the first cases of GAA-FGF14 ataxia in patients of admixed American ancestry and African descent. This observation supports the wide distribution of this novel GAA repeat expansion in populations of diverse ethnic backgrounds.In this large and diverse Brazilian cohort, FGF14 ataxia, with a patient of our cohort presenting before the age of 30 years. This result highlights the need to screen for FGF14 expansions in patients with early-onset ataxia to fully define the age at onset spectrum of GAA-FGF14 ataxia. The expansion size of our patient presenting at age 28 years was smaller compared with that of other patients in this cohort who developed disease later in life, which is in keeping with some previous reports showing weak or lack of correlation between age at onset and expansion size.9 This observation suggests that additional yet unknown factors may modify age at onset in GAA-FGF14 ataxia.Our report expands the phenotypic spectrum of GAA-FGF14 ataxia in some, but not all, patient cohorts.9 In our cohort, only 1 patient had episodic symptoms while none had downbeat nystagmus. These results suggest that episodic features and downbeat nystagmus may not be recurrent in all patients. Nonetheless, the core phenotype of our patients, namely a late-onset slowly progressive cerebellar syndrome with frequent oculomotor signs, is consistent with previous reports.9Episodic symptoms and downbeat nystagmus have previously been shown to be common phenotypic features of GAA-11 This patient displayed a relatively rapid disease progression. Additional longitudinal follow-up is needed to fully chart disease progression and phenotypic spectrum in these patients. Furthermore, extrapyramidal signs were found in 2 patients (22%), raising the possibility that this feature may be part of the phenotypic profile of GAA-FGF14 ataxia.We also identified a patient carrying biallelic GAA repeat expansions, which has been previously reported in a few cases.FGF14 ataxia is a common genetic cause of unsolved adult-onset ataxia in the Brazilian population. Our findings also confirm the wide distribution of this novel GAA repeat expansion in populations of diverse ethnic backgrounds.In conclusion, our study suggests that GAA-"}
+{"text": "Acinetobacter baumannii (CRAB) strains. However, resistance to aminoglycosides has increased remarkably in the last few years. Here, we aimed to determine the mobile genetic elements (MGEs) associated with resistance to aminoglycosides in the global clone 2 (GC2) A. baumannii. Among the 315 A. baumannii isolates, 97 isolates were identified as GC2, and 52 of GC2 isolates (53.6%) were resistant to all the aminoglycosides tested. The AbGRI3s carrying armA were detected in 88 GC2 isolates (90.7%), and of them, 17 isolates (19.3%) carried a new variant of AbGRI3 (AbGRI3ABI221). aphA6 was located in TnaphA6 of 30 isolates out of 55 aphA6-harboring isolates, and 20 isolates were found to harbor TnaphA6 on a RepAci6 plasmid. Tn6020 carrying aphA1b was detected in 51 isolates (52.5%), which was located within AbGRI2 resistance islands. The pRAY* carrying the aadB gene was detected in 43 isolates (44.3%), and no isolate was found to contain a class 1 integron harboring this gene. The GC2 A. baumannii isolates contained at least one MGE carrying the aminoglycoside resistance gene, located mostly either in the chromosome within AbGRIs or on the plasmids. Thus, it is likely that these MGEs play a role in the dissemination of aminoglycoside resistance genes in GC2 isolates from Iran.Aminoglycosides are used to treat infections caused by carbapenem-resistant  Acinetobacter baumannii causes a variety of healthcare-associated infections (HAIs), which are mostly untreatable by currently available antibiotics. Most of these antibiotics are ineffective against A. baumannii as it has a high capacity to acquire antibiotic-resistant genes (ARGs) via mobile genetic elements (MGE), including plasmids, transposons, integrons, and resistance islands  and global clone 2 (GC2)  strains are among the critical priority pathogens on the World Health Organization's (WHO's) priority list of antibiotic-resistant bacteria  often carry aminoglycoside resistance genes, including strA, strB, aphA1b, aacC1, aadA1, armA, and aacA4  , aadA1 (streptomycin and spectinomycin resistance), and aphA1b (kanamycin and neomycin resistance) genes are co-located. Tn6020 (a compound transposon flanked by IS26) that carries the aphA1b gene (conferring resistance to kanamycin and neomycin) has been found in some of the AbGRI2 and AbGRI3 variants  containing a 16S rRNA methyltransferase (armA) gene, which confers resistance to most of therapeutic aminoglycosides , which is frequently found on the RepAci6 plasmid family , in the periods 2012\u20132013 (n = 111) and 2018\u20132019 (n = 204). All isolates were initially identified using conventional microbiological methods  gene by PCR  disk diffusion assay when a CLSI breakpoint for Acinetobacter spp. was not available .Antibiotic susceptibility testing was performed by the disk diffusion method using the following 27 antibiotics (\u03bcg per disk): ampicillin\u2013sulbactam (20), piperacillin\u2013tazobactam (110), ticarcillin\u2013clavulanate (timentin) (85), imipenem (10), meropenem (10), doripenem (10), ceftazidime (30), cefotaxime (30), cefepime (30), ceftriaxone (30), tetracycline (30), minocycline (30), doxycycline (30), streptomycin (25), spectinomycin (25), amikacin (30), kanamycin (30), gentamicin (10), neomycin (30), netilmicin (30), tobramycin (10), nalidixic acid (30), ciprofloxacin (5), levofloxacin (5), sulfamethoxazole (300), trimethoprim\u2013sulfamethoxazole (25), and rifampin (30). The results were analyzed according to the Clinical and Laboratory Standards Institute (CLSI) recommendations for . Wayne,  and caliTaq polymerase and PCR buffer. The identity of PCR amplicons was confirmed by DNA sequencing , which was larger than the predicted size, was sequenced by primer walking strategy -Im  belonged to GC2, and all the GC2 isolates were resistant to carbapenems  (Among the 315 ripenem) . As eachripenem) , they weripenem) . The amiripenem) . While tarmA was the most frequent gene, detected in all but nine (n = 88) of GC2 A. baumannii isolates (group 1 and group 2 in aphA6 (n = 55), aphA1b (n = 51), aadB (n = 43), aacC1 (n = 11), and aadA1 (n = 4) genes were detected in the GC2 isolates. The aacC2, aacA4, and aac(6')-Im genes were not observed in any isolate examined ; strA, strB genes; and CR2 element were present in all isolates containing AbGRI1. However, the isolates carrying AbGRI1 varied according to the presence of backbone transposon ; orf region; tetA(B), tetR(B) (tetracycline resistance); and sul2 gene (sulfonamide resistance) (The Long-read sequencing technology such as PacBio or Oxford Nanopore will be required to determine the structure of AbGRI1 in the isolates containing this island.aphA1b (52.5%), this gene was located in Tn6020, and the Tn6020 in these isolates was carried by either AbGRI2-1  or AbGRI2-12b resistance islands . The structure of the AbGRI2-1 and AbGRI2-12b resistance islands is shown in In all the 51 GC2 isolates containing aacC1 and aadA1 genes were found together only in one isolate containing AbGRI2-1 resistance island  carried AbGRI3-4. In the remaining 17 isolates (19.3%), a new variant of AbGRI3 resistance islands was found, which was called AbGRI3ABI221  previously. The sequence of this amplicon was submitted to the NCBI GenBank database under the accession number QQ341795. The sequence of \u0394atr-ISAba24 segment missing 523 bp of the repAciN gene  in the isolates containing AbGRI3ABI221 (accession number QQ341795) compared with the sequence of \u0394atr-ISAba24 in SGH0908 containing AbGRI3-2i (accession number KX011026) is shown in ABI221 resistance islands is shown in Of the 88 I3ABI221 . The PCRI3ABI221 . It was aphA6 gene (56.7%), the aphA6 gene was flanked by ISAba125 in 30 isolates (54.5%); i.e., the aphA6 gene is located in TnaphA6. The amplicon for PCRs linking the aphA6 to the backbone of RepAci6 plasmids on the right and left was amplified in 20 isolates of those containing TnaphA6 (66.6%), and also, PCRs for repeated sequences 1, 2, and 3 produced the expected amplicons, suggesting the presence of a RepAci6 plasmid (Of the 55 isolates containing the  plasmid .aadB (44.4%), this gene was carried by pRAY*. The class 1 integron was not detected in any isolate containing the aadB gene  and group 2 , respectively. It was revealed that all of the isolates containing the armA were located within the AbGRI3 resistance island. The chromosomally located islands carrying the armA gene, named AbGRI3 in 2017  was only detected in one of the isolates tested, while it was present in 21.6 and 25% of GC2 isolates examined in Australia and Singapore, respectively ; however, all the GC2 isolates examined in Australia  can be found in the article/The Ethics Committee of Tehran University of Medical Sciences approved the study IR.TUMS.SPH.REC.1397.291. All patients have signed the informed consent for giving the required specimens for research. Parents/legal guardians provided written informed consent for their children under the age of 18 years to participate in this study.GN performed the microbiological and molecular experiments and wrote and revised the manuscript. MT and MR were the advisors of the project. RG and SG did the molecular experiments. AS and AA were the clinical advisors of the project. AN was involved in the collection of isolates from the hospital. MD conceptualized, designed, coordinated, supported this study, contributed to the acquisition of fund, the analysis and interpretation of data, and performed the revision of the manuscript. All authors have read and agreed to the published version of the manuscript."}
+{"text": "Nonalcoholic steatohepatitis (NASH) is the more severe, inflammatory type of nonalcoholic fatty liver disease (NAFLD). NASH, a leading indication for liver transplantation, is growing in prevalence. The extent of liver fibrosis, ranging from fibrosis stage (FS) of none (F0) to cirrhosis (F4), is a strong predictor of health outcomes. There is little information on patient demographics and clinical characteristics by fibrosis stage and NASH treatment outside of academic medical centers.We conducted a cross-sectional observational study using Ipsos\u2019 syndicated NASH Therapy Monitor database, consisting of medical chart audits provided by sampled NASH-treating physicians in the United States in 2016 (n\u2009=\u2009174) and 2017 (n\u2009=\u2009164). Data was collected online.Of 2,366 patients reported on by participating physicians and included in the analysis, 68% had FS F0\u2013F2, 21% had bridging fibrosis (F3), and 9% had cirrhosis (F4). Common comorbidities were type 2 diabetes (56%), hyperlipidemia (44%), hypertension (46%), and obesity (42%). Patients with more advanced fibrosis scores (F3-F4) had higher comorbidity rates than patients with F0-F2. Commonly used diagnostic tests included ultrasound (80%), liver biopsy (78%), AST/ALT ratio (43%), NAFLD fibrosis score (25%), transient elastography (23%), NAFLD liver fat score (22%), and Fatty Liver Index (19%). Most commonly prescribed medications were vitamin E (53%), statins (51%), metformin (47%), angiotensin converting enzyme inhibitors (28%), and beta blockers (22%). Medications were commonly prescribed for reasons other than their known effects.Physicians in this study, drawn from a spectrum of practice settings, relied on ultrasound and liver biopsy for diagnosis and vitamin E, statins, and metformin for pharmacological treatment of NASH. These findings imply poor adherence to guidelines in the diagnosis and management of NAFLD and NASH.Nonalcoholic steatohepatitis (NASH) is a liver disease caused by excess fat in the liver which can lead to liver inflammation and scarring (fibrosis), ranging from stage F0 (no scarring) to F4 (advanced scarring). The stage of liver scarring can predict the likelihood of future health problems, including liver failure and liver cancer. However, we do not fully understand how patient characteristics may vary at different stages of liver scarring. We looked at medical information from physicians treating patients diagnosed with NASH to understand how patient characteristics might differ based on the severity of their liver scarring. The majority (68%) of patients were stage F0-F2, with 30% having advanced scarring (F3-F4). In addition to NASH, many patients also had type 2 diabetes, high cholesterol, high blood pressure, and obesity. Patients with more advanced scarring (F3-F4) were more likely to have these diseases than patients with less severe disease (F0-F2). Diagnosis of NASH by participating physicians was based on tests including imaging , liver biopsy, blood tests, and whether patients had other conditions that would put them at risk for NASH. The medications that the doctors prescribed most often to their patients included vitamin E and drugs to treat high cholesterol, high blood pressure, or diabetes. Medications were frequently prescribed for reasons other than their known effects. By understanding how patient characteristics vary by stages of liver scarring and how NASH is currently managed may help guide the evaluation and treatment of NASH when NASH-specific therapies become available. Nonalcoholic fatty liver disease (NAFLD) is a disease characterized by the accumulation of fat in the liver . NAFLD tThe persistent inflammation seen in patients with NASH can lead to liver fibrosis (scarring of the liver) . The sevMost studies evaluating variability in liver fibrosis measurements from different techniques have occurred in the context of well-controlled clinical trials or consortia of academic centers, typically involving physicians with specialized training in hepatology. The majority of healthcare in the United States is provided outside of academic medical centers . There iThis study sought to evaluate the demographic and clinical characteristics of NASH patients by their fibrosis stage, determined by biopsy and by non-invasive means. We also aimed to understand how diagnostic testing and treatment regimens varied by patient fibrosis stage, by physician specialty, and by patient ethnicity in a real-world setting  includiThis study was a non-interventional, cross-sectional database study utilizing the Ipsos syndicated NASH Therapy Monitor database. The Ipsos NASH Therapy Monitor contains data from retrospective medical chart audits completed by eligible physicians in the United States. Data is collected annually from physicians who extract patient demographics, disease status, comorbidities, testing, and treatment data on their most recent 5\u201310 NAFLD/NASH patients . All metData in the database was collected online from 174 physicians in the United States from September to November 2016 and by 164 physicians from September to November 2017. Data was collected from 1,622 patient records in 2016 and 1,521 patient records in 2017, for a total of 3,143 records. Participating physicians included primary care physicians (PCPs), endocrinologists, hepatologists, and gastroenterologists. Physicians were randomly recruited from a large access panel and were required to manage at least 20 patients with NASH per month. The data provided was based on a sample of the de-identified NASH patients that they personally managed. Patients were required to have been assigned a clinical diagnosis of NASH, regardless of diagnostic method. Patient records were included in the database if they had a recorded assessment of fibrosis or recorded assessment at diagnosis. Fibrosis stage was recorded from a biopsy report or estimated by non-invasive testing . Patients were excluded if they had a NAFLD fibrosis score below \u2212\u20091.455 without a NASH diagnosis via a biopsy. See Table\u00a0This study measured current patient demographics including age, sex, race, body mass index (BMI), smoking status, insurance type, and employment status . Clinical characteristics such as symptoms at diagnosis, fibrosis stage, and current comorbidities were also measured. Data was also collected regarding patient experiences with NASH diagnosis and treatment. Measures included the specialty of the diagnosing physician, types of diagnostic tests performed, and types of treatments administered. As part of the chart audit, physicians also recorded reasons for prescribing certain NASH-related treatments.Descriptive categorical statistics are presented as numbers and percentage of patients in each category. Patient fibrosis stage could be determined by biopsy or by combinations of clinical and non-invasive tests. All analysis was conducted in SAS 9.4 .After excluding patients with NAFLD and patients with NASH who had an unknown fibrosis score both at diagnosis and at the current assessment, there were 2,366 patients available for analysis. Patient demographic data, sorted by liver fibrosis stage, are shown in Table\u00a02), were most likely to be on public insurance (41%) and were most likely to have a history of smoking (66% were current or former smokers). Mean BMI (33.1\u00a0kg/m2) was lowest among Asian patients; these patients were also the least likely to have a history of smoking (59% had never smoked before). Between 61% and 69% of patients were currently employed with the rate of employment highest among White patients and lowest among Hispanic patients. Black patients had the highest rates of disability leave (14%) and White patients had the lowest rates of disability leave (7%).Just over half (54%) of patients included in the study were White. The next most common patient ethnicities were Black/African American (22%) and Hispanic (20%). There were relatively few patients of Asian descent (3%) and other ethnicities (<\u20091%). Ethnicity data was not available for ten patients. Mean age was similar across ethnicities . The majority (64%) of White patients were male and 55% of Black patients were male; however, a majority of females were Hispanic (53%). White (73%) and Asian (73%) patients were most likely to have private health insurance. Black patients included in this study had the highest mean BMI , percutaneous liver biopsy (66%), AST/ALT ratio (43%), NAFLD fibrosis score (25%), transient elastography (23%), NAFLD liver fat score (22%), Fatty Liver Index 19%), computerized tomography (CT) (15%), AST/platelet ratio index (15%), magnetic resonance imaging (MRI) (14%), and transjugular liver biopsy (12%). When segmented by patient fibrosis stage at diagnosis, ultrasounds were performed most frequently in F1 patients . Rationale for not performing liver biopsy varied with specialty. Endocrinologists (56%) and gastroenterologists (55%) were more likely than PCPs (50%) and hepatologists (48%) to not perform a biopsy because other tests were deemed sufficient to conclude NASH. However, hepatologists, gastroenterologists, and PCPs were less likely to have biopsied patients with F4 fibrosis  than patients with F0-F3 . Endocrinologists diagnosed too few patients (n\u2009=\u20093) with F4 fibrosis to draw conclusions. Gastroenterologists biopsied a smaller proportion of patients (66%) with F0 fibrosis than did hepatologists (77%).Overall, the most commonly prescribed medications for patients with NASH in this study were vitamin E (53%), statins (51%), metformin (47%), angiotensin converting enzyme (ACE) inhibitors (28%), and beta blockers (22%). Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) (13%), Sodium-glucose co-transporter 2 (SGLT2) inhibitors (11%), pioglitazones (11%), dipeptidyl peptidase 4 (DPP-4) inhibitors (7%), and orlistat (9%) were prescribed in a minority of patients. Vitamin E use was highest in patients with F2 (58%) and F3 (55%) fibrosis. Patients with F0 (44%), F1 (48%), and F4 (40%) fibrosis had lower rates of vitamin E use. Pioglitazone prescription rates increased at higher patient fibrosis stages: from 8% of patients at F0 to 16% of patients at F4. In contrast, there were no obvious trends in prescriptions of GLP-1 RA/SGLT2/DPP4/orlistat when segmented by patient fibrosis stage. Beta blockers were prescribed at higher rates in patients with higher fibrosis stages: F0 (8%), F1 (17%), F2 (21%), F3 (25%), and F4 (45%), consistent with the higher prevalence of systemic hypertension with more advanced fibrosis stage in this study. Statins were prescribed at similar levels (between 40% and 60% of patients) across patient fibrosis stages with no clear trends. Of particular note is that the most common reasons for prescribing statins (from a predefined list) were to assist weight loss (54%) and to improve/reverse steatosis (42%). The top reason physicians said they prescribed orlistat (91%), SGLT2 inhibitors (70%), GLP-1 RAs (67%), pioglitazone (56%), DPP4 inhibitors (55%), metformin (46%), and vitamin E (40%) was to assist with weight loss; the second most common reason to prescribe these medications was to improve/reverse steatosis.NASH is highly prevalent and is an increasingly common cause of cirrhosis, liver failure and liver cancer . Liver fHSD17B13 and PNPLA3 [There are several important aspects of this study and findings. The first is that this study included a large proportion of patients (>\u200970%) who received a liver biopsy. This is greater than reported in other real-world settings . Among pd PNPLA3 , 24, ethd PNPLA3 . InteresAbdominal ultrasounds, which have some qualitative utility in detecting hepatic steatosis and ultrastructural changes of cirrhosis , were thPharmacotherapy of NASH in this study was particularly striking. There are currently no Food and Drug Administration (FDA) approved treatments for NASH and there is limited evidence on what types of treatment are appropriate for patients with varying degrees of NASH severity or liver fibrosis. Because there are no FDA approved treatments specific to NASH, NASH management relies on general lifestyle improvements and treatment of comorbidities . The mosThis study has several limitations. It does not necessarily reflect diagnosis and treatment patterns in the wider US population, who are managed by providers with less experience than those contributing to the Ipsos NASH Therapy Monitor database. The high rate of evaluating and managing patients with NASH as a specific criterion for physician participation in this study may, for example, explain the high frequency of liver biopsy. An additional limitation is the age of the data in this study. This data was collected in 2016 and 2017, before the most recent AASLD and EASL guidance on NASH and prior to the plethora of data on performance characteristics of non-invasive tests in NAFLD and NASH. If a chart audit was conducted with the same population of physicians today, we may see increased usage of non-invasive tests for the diagnosis of NASH.In conclusion, this study shows diagnosis and treatment patterns among a subset of physicians who appear highly engaged with management of NASH. Evaluation and management of NAFLD and NASH in non-academic settings does not, however, discernibly follow established guidelines. There is a need for consensus on the standardization of non-invasive tests for NASH diagnosis. Physicians in this study relied heavily on biopsies for the diagnosis of NASH. In the absence of FDA approved therapies for NASH, much of the pharmacotherapy of NASH is directed at weight loss. Updating and disseminating practice guidelines that are practical and evidence-based may be of high value in attenuating the effects of the NASH epidemic."}
+{"text": "Incidence of invasive fungal infections (IFI) in orthotropic heart transplant (OHT) is reported as 3.4\u201310%. Guidelines from The International Society for Heart and Lung Transplantation recommend considering prophylaxis for invasive molds based on risk factors and local epidemiology. Data defining the risk factors for IFI in OHT patients are lacking. The aim of this study is to describe the epidemiology of IFI in OHT patients and analyze risk factors.A retrospective chart review identified all OHT patients who were transplanted at the Cleveland Clinic from 2010-2020. Patients were divided into two groups for comparison: definite or probable IFI within the first year after transplant, and no IFI. We compared the groups to determine independent risk factors for IFI.Table 1 shows the characteristics of both patient groups. Among 33 patients with IFI, there were 17 (51%) Candida, 9 (27%) Aspergillus, 4 (12%) non-Aspergillus mold, and 3 (9%) Cryptococcus infections. Median time to IFI (IQR) was 44 days (10\u2013238.5). Specifically, for Candida it was 12 days (1-271) and Aspergillus was 90 days (8-335). One-year survival was significantly lower in the IFI group . Using multivariable logistic regression analyses, as reported in Table 2, increased odds of IFI were observed with pre-transplant fungal colonization/infection  and left ventricular assist device (LVAD) infection . Post transplant reoperation , and extracorporeal membrane oxygenation (ECMO)  were also associated with increased odds of IFI.We identified 565 OHT patients in the study period; 33 met criteria for IFI with an incidence of 5.8% . In a large, modern cohort of OHT patients, we observed a significant incidence and increased odds of IFI associated with specific, identifiable risk factors during the pre-transplant and post-transplant periods. These results merit additional study of targeted antifungal prophylaxis with agents offering broad yeast and mold activity in OHT patients with certain risk factors.All Authors: No reported disclosures"}
+{"text": "The inappropriate use of antibiotics is common in Bangladesh, contributing to the significant burden of antimicrobial resistance. The WHO has categorized Access, Watch, and Reserve groups of antibiotics (AWaRe classification) to promote optimal use. We explored antibiotic use among hospitalized patients with acute febrile illness (AFI) at five tertiary-level hospitals in Bangladesh.From September 2021 to February 2023, 1544 patients were randomly selected among all hospitalized patients with measured fever (\u2265100.4\u00b0F) or a history of fever in the past 14 days. Blood and urine culture isolates were analyzed for antibiotic sensitivity using the VITEK-2 system.Of enrolled AFI patients, 835 (54%) reported the use of antibiotics prior to hospitalization, with 79% of reported antibiotics from the Watch group, 16% from the Access group, and none from the Reserve group. Five percent of the antibiotics prescribed were not recommended by WHO for clinical practice. The top five frequently reported antibiotics before hospitalization were cefixime (24%), azithromycin (19%), ceftriaxone (16%), amoxicillin (6%), and cefuroxime (5%). Bacterial infection was diagnosed among 205 patients  through Rapid diagnostic tests, culture and Rt-PCR. In-hospital, 1385 (90%) patients received at least one antibiotic. The most frequently prescribed antibiotics were from the Watch group (84%), followed by the Access group (15%) and none from the Reserve group. The top five antibiotics prescribed in-hospital were ceftriaxone (64%), amoxiclav (7%), ceftazidime (3.4%), clarithromycin (2.8%), and moxifloxacin (2.6%). Antibiotic susceptibility testing (AST) results from blood and urine culture isolates showed high resistance pattern to ceftriaxone (45% and 56%) and ceftazidime (63% and 50%). Of blood culture isolates 80% were sensitive to amoxiclav, while 46% of urine culture isolates were resistant to amoxiclav. At least one bacterial organism was identified in only 13% of enrolled patients.List of antibiotics that were reported to be received by the enrolled AFI patients before HospitalizationBefore hospitalization, 132 patients reported receiving antibiotics from Access group, while 662 patients received antibiotics from WATCH groupList of antibiotics received by the enrolled AFI patients during hospitalizationDuring hospitalization, 211 patients received antibiotics from Access group and 1169 patients received antibiotics from Watch GroupList of 235 bactrial organisms which were identified from clinical samples of 205 AFI patients (some patient had co-infection)In conclusion, antibiotics were used in nine of ten patients. The frequent and inappropriate use of Watch group antibiotics in outpatient settings likely contributes to decreased effectiveness and demonstrates the need for improved antimicrobial stewardship.All Authors: No reported disclosures"}
+{"text": "TP53 is the most frequently mutated gene in human cancer. While no TP53-targeting drugs have been approved in the USA or Europe so far, preclinical and clinical studies are underway to investigate targeting of specific or all TP53 mutations, for example, by restoration of the functionality of mutated TP53 (TP53mut) or protecting wildtype TP53 (TP53wt) from negative regulation. We performed a comprehensive mRNA expression analysis in 24 cancer types of TCGA to extract (i) a consensus expression signature shared across TP53 mutation types and cancer types, (ii) differential gene expression patterns between tumors harboring different TP53 mutation types such as loss of function, gain of function or dominant-negative mutations, and (iii) cancer-type-specific patterns of gene expression and immune infiltration. Analysis of mutational hotspots revealed both similarities across cancer types and cancer type-specific hotspots. Underlying ubiquitous and cancer type-specific mutational processes with the associated mutational signatures contributed to explaining this observation. Virtually no genes were differentially expressed between tumors harboring different TP53 mutation types, while hundreds of genes were over- and underexpressed in TP53mut compared to TP53wt tumors. A consensus list included 178 genes that were overexpressed and 32 genes that were underexpressed in the TP53mut tumors of at least 16 of the investigated 24 cancer types. In an association analysis of immune infiltration with TP53 mutations in 32 cancer subtypes, decreased immune infiltration was observed in six subtypes, increased infiltration in two subtypes, a mixed pattern of decreased and increased immune cell populations in four subtypes, while immune infiltration was not associated with TP53 status in 20 subtypes. The analysis of a large cohort of human tumors complements results from experimental studies and supports the view that TP53 mutations should be further evaluated as predictive markers for immunotherapy and targeted therapies. TP53 is the most frequently mutated gene in malignant tumors [TP53 mutations can be found in most cancer types, their prevalence varies strongly between different entities [TP53 mutations are located in the DNA-binding domain (DBD), whereas TP53 mutations in other regions are found at lower frequency [TP53 mutations accumulate in mutational hotspots, including the most frequently mutated amino acids R175, R248, and R273 [The \u201cguardian of the genome\u201d t tumors , 2. Whilentities . The vasrequency . TP53 muand R273 , 12.TP53 mutations has motivated numerous studies to uncover the effect of mutated p53 proteins using cultured cells, animal models, and molecular profiling of human tumors [TP53 mutations contribute to malignant growth: (i) loss of function (LOF) mutations impairing the tumor suppressor functions of p53, including its action as a transcription factor [TP53 mutations are frequently accompanied by at least partial LOF [The diverse spectrum of n tumors , 13\u201317. n factor , 19,  in factor , (iv) actial LOF .TP53 LOF mutations and failure of the mutated p53 protein to induce its classical transcriptional targets including the cell cycle regulator CDKN1A (p21) [TP53 acting through partial LOF include mutations located in the acidic transactivation domains resulting in a truncated protein that retains the ability to induce apoptosis [Among the four possibilities, the evidence for action of p53 through total or partial LOF is very high. Numerous studies have demonstrated the connection of 1A (p21) \u201326. Exampoptosis  and mutapoptosis .TP53 mutations suggest a positive selection pressure on specific mutations driven by specific functional gains and corresponding growth advantages. TP53mut GOF activity was first reported in the early 1990s by the investigation of in vitro and in vivo models of ectopically expressed TP53mut in TP53 null cells that allowed separation of GOF from DN activity [TP53 missense mutations without evidence of GOF capacity has been observed analyzing in vitro and in vivo models of acute myeloid leukemia (AML) [TP53 GOF mutations over others [Distinct hotspots in the distribution of activity , 29. Sinactivity , 30. DN ia (AML) . Concordr others , 33.TP53 mutations are highly prevalent in many cancer types, TP53-targeting drugs have not yet been approved in the USA or Europe. In this context, TP53 mutational diversity and differently acting TP53 mutation types are a hurdle that could be overcome by targeting specific TP53 alterations. For example, a predominant LOF effect should be addressed by restoration of wildtype p53 protein expression, while a predominant DN or GOF effect should be addressed by inhibition of mutant p53 protein levels [TP53 mutations and the corresponding pathogenic mechanisms are warranted.Although n levels . Earliern levels . As a baTP53 mutations on tumor biology in 8331 tumors of 24 cancer types from TCGA. Building on and expanding previous gene expression studies [TP53 mutation types - either of specific variants or variant classes including LOF, GOF, or DN mutations - on gene expression patterns, (ii) separation of common TP53mut-associated expression changes that are shared between many cancer types and specific expression changes observed only in a single or in a few cancer types, and (iii) changes in the immune tumor microenvironment (TME) associated with TP53 mutations.To contribute to fill this gap, we analyzed the impact of  studies , 36, ourTP53 mutations in the coding sequence or at splice sites  and tumors without such mutations .A total of 8331 tumors and 24 cancer types from TCGA were included in the study. The cohort was divided into tumors harboring non-synonymous TP53 mutations in the study cohort, corresponding to 926 different variants , p.R248 (n\u2009=\u2009201), p.R175 (n\u2009=\u2009165), p.R213 (n\u2009=\u200996), and p.R282 (n\u2009=\u200990) were all located in the DBD. In codon 273 the mutations p.R273C (46%) and p.R273H (37%) were most prevalent, in codon 248 the mutations p.R248Q (54%) and p.R248W (39%), while in codon 175 the mutation p.R175H (89%) was by far most prevalent.We detected 4021 individual nts Fig. . The mosTP53 hotspots that were recurrent with an incidence of at least 1% in at least one of the cancer types  in COAD and 11% (5\u201318%) in READ compared to 3.7% (3.1\u20134.4%) in the pan-cancer cohort. R273C contributed with 21% (16\u201327%) in LGG compared to 3.3% (2.7\u20133.9%) in the pan-cancer cohort. R249S contributed with 10% (5.2\u201317%) in LIHC compared to 0.6% (0.4\u20131%) in the pan-cancer cohort. These cancer-specific differences in the prevalence of TP53 mutations can be explained, at least in part, by the differential activity of mutational signatures in different cancer types. For example, the mutations R249S with a GCC\u2009>\u2009CGC transversion that was highly prevalent in LIHC is a characteristic of the mutational signature SBS24 that has been linked to exposure to liver toxic aflatoxins [The prevalence of 31 mutations (53%) was significantly different between TP53mut tumors of different cancer types  tumors with LOF, 1208 (35%) with GOF, 1470 (43%) tumors with DN, and 1788 (52%) tumors with non-DN mutations , we almost never observed more than one differentially expressed gene and not a single differentially expressed gene in the majority (92%) of the analyses. For the second type of analysis (TP53mut tumors vs. TP53wt tumors), we detected more than ten differentially expressed genes in 48 (48%) of the analyses, 2 to 10 differentially expressed genes in seven (7%) of the analyses, and only one or none differentially expressed gene in the remaining 45 (45%) analyses. When summarizing significances over the 24 analyzed cancer types (column \u201cpan-cancer\u201d), not a single differentially expressed gene except TP53 was detected for the analyses of the first type, while more than 100 differentially expressed genes were detected for each of the analyses of the second type. Similar results were observed when we subsampled to larger (n\u2009=\u200920) or smaller (n\u2009=\u200910) groups of tumors  tumors with mutations in codons 175, 248, and 273, (ii) tumors with mutations in codon 175 and LOF mutations, (iii) tumors with mutations in codon 248 and LOF mutations, (iv) tumors with mutations in codon 237 and LOF mutations, (v) tumors with top hotspot mutations (pool of the 10 most abundant missense mutations) and LOF mutations, (vi) tumors with LOF and GOF mutations, and (vii) tumors with DN and non-DN mutations Fig. . These aIn summary, we detected many differentially expressed genes between TP53mut and TP53wt tumors. However, we did not find gene expression patterns characteristic for the subclasses of LOF, GOF, and DN mutations in any of the cancer types.p\u2009<\u20090.05) between TP53mut and TP53wt tumors in at least two-thirds (n\u2009=\u200916) of the cancer types  genes were overexpressed in TP53mut tumors in the majority of cancer types, while the remaining 32 genes (15%) were underexpressed in the majority of cancer types. We analyzed the lists of over- and underexpressed genes for enrichment in a catalog of 186 KEGG pathways and six TP53-related gene lists provided by Fischer et al. [A consensus list of 210 differentially expressed genes included all genes that were differentially expressed  were targets of the DREAM complex (66% of the genes) and related to the GO category cell cycle progression (57%). Many of the underexpressed genes (cluster U1 and U2) were direct p53 targets (53%) and related to the GO category apoptosis (34%). CDKN1A (p21), SPATA18, EDA2R, PHLDA3, and C6orf138 in cluster U2 showed a strongly diminished gene expression in the TP53mut tumors for most of the cancer types. In line with this observation, CDKN1A, SPATA18, EDA2R, and PHLDA3 are known as direct p53 targets regulated by the binding of p53 to the promoter sequence [A heatmap of FCs of the 210 genes in the 24 cancer types showed a high degree of consistency in the direction of expression changes across the cancer types Fig. . Gene clsequence , 41.Fig.TP53 mutations in cancer types (p\u2009=\u20090.33). In some instances, different patterns of differential expression were observed in tumors of the same organ site. For example, TP53mut LUAD (cluster T1) showed strong overexpression of O1/O2/O3, while TP53mut LUSC (cluster T2) showed only moderate overexpression. TP53mut KIRC (cluster T1) showed moderate overexpression, while TP53mut KICH and KIRP (cluster T3) did not show any overexpression of the gene clusters O1/O2/O3.Cancer types were grouped into a cluster of five cancer types showing strong overexpression of gene clusters O1/O2/O3 in TP53mut tumors , a cluster of ten cancer types showing moderate overexpression , and a cluster of nine cancer types showing very low or no overexpression of these genes . Overexpression of the gene clusters O1/O2/O3 that were enriched for indirect, p21-mediated targets corresponded to underexpression of the gene clusters U1/U2 that were enriched for direct p53 targets. Clusters T1, T2, and T3 were not associated with different prevalence of TP53 status  associated with differential gene expression (above median vs. below median) with the ones associated with TP53 to bind to the regulatory DNA sequences of its direct target genes that is predicted for most of the TP53 mutations.We analyzed differential expression separately in each of the 24 cancer types .The enrichment of genes of the glycolysis pathway in the set of overexpressed genes in six cancer types suggests a stronger Warburg effect in the TP53mut tumors of these cancer types. Among the 168 overexpressed genes in the glycolysis pathway, six genes were direct targets of p53  mediating cell cycle arrest, (ii) FAS (Fas), TNFRSF10B (DR5), BAX (Bax), BBC3 (PUMA), and ZMAT3 (PAG608) mediating apoptosis, (iii) DDB2 (P48) mediating DNA repair and damage prevention, and (iv) MDM2 and CCNG1 (Cyclin G) mediating negative p53 feedback. CHEK1 (checkpoint kinase 1), which phosphorylates and activates p53, was overexpressed. Similar gene expression patterns were observed for TP53mut tumors in most of the cancer types, but in PAAD we observed overexpression rather than underexpression of the apoptosis pathway , and overexpression of CCNE1 (CycE) and CDK2. Downstream of the cyclin-dependent kinases, we observed overexpression of RBL1 (p107) and E2F1 . The absence of activation of RB1, the binding partner of E2F1, as well as the observed overexpression of E2F1, are consistent with action of unbound E2F as transcription factor for downstream targets and transition to the S phase.Many of the overexpressed genes in the consensus list contribute to the regulation of the four phases  of the cell cycle Fig. . In TP532F1 Fig. . Our resBUB1B (BubR1), CCNB1 and CCNB2 (CycB), CCNE1 (CycE), CDC20 (Cdc20), CDC25C (Cdc25C), CDK1, CDK2, CHEK1 (Chk1), E2F1, MAD2 (Mad2L1), MCM2, 4, 7 , PLK1 (Plk1), RBL1 (p107), and TTK (Mps1). This observation is consistent with progression through the cell cycle and higher proliferation of TP53mut tumors compared to TP53wt tumors.We observed overexpression of many genes regulating the S, G2, and M phases of the cell cycle Fig. . Among tTP53-mutated HNSC  between cancer types, we found that TP53wt tumors of HPV- and HPV+\u2009HNSC were among the cancer types with the highest CDKN1A expression  higher in the TP53mut tumors of HPV+\u2009HNSC. An unusual TP53-associated expression pattern of cell cycle genes in TP53mut tumors was also observed in CESC  were too low to reach statistical significance. However, many differentially expressed genes were detected in the analyses comparing TP53mut and TP53wt tumors. Thus, while we can not rule out that there are gene expression changes between different types of TP53 mutations, the analyses show that - if they do exist - they are much weaker than the gene expression changes between TP53mut and TP53wt tumors. Furthermore, as an approach to enhance the statistical power, summary of significances across all cancer types did not also lead to significant results for differential expression between different mutation types.Analyzing specific types of TP53 predominantly acts as a transcription factor that binds to specific DNA response elements and exerts its functions via transcriptional regulation [gulation , 52. Altgulation , 55, so Numerous experimental studies including systematic screens of synthetically generated variant libraries  reported and GOF . Furtherutations \u201350. By cTP53 and RB1, respectively, and inactivate the functions of these tumor suppressor genes [RB1 and TP53 act as negative cell cycle regulators, explaining the anomalous TP53-associated expression patterns observed in cohorts that include HPV-induced tumors. When restricting to HPV- HNSC, the typical TP53-associated expression pattern was observed.In the current study, we observed shared TP53mut-associated gene expression patterns across many cancer types and carved out a consensus list of 210 genes that were differentially expressed in at least 16 of 24 cancer types. The overexpressed genes of the list were strongly enriched for G2/M cell cycle genes, while the underexpressed genes were strongly enriched for direct targets of p53 and apoptosis genes in accordance with the literature , 56. Enror genes , 58. BotTP53 mutations in response to immune checkpoint blockade (ICB) is controversial. In a recent meta-analysis combining six whole exome sequencing (WES) data sets across cancer types, TP53 mutations were a negative predictor of ICB response [TP53/KRAS co-mutated non-small cell lung cancer patients benefited from PD-L1 blockage in comparison to docetaxel, while KRAS-mutant patients without additional TP53 mutation did not [TP53/KRAS co-mutated pancreatic ductal adenocarcinoma [TP53 activity sensitized for blockade of the PD-L1/PD1 axis [TP53 that acts as guardian of the genome would increase TMB and the number of neoantigens, the current study showed that the immune TME was unaltered in TP53mut tumors of the majority of cancer types. Upregulated immune cell populations were detected only in very few cancer types and never included CD8+\u2009T cells. Decreased CD8+\u2009T cell populations were detected in the TP53mut tumors of HNSC, LGG, MSI-L/MSS STAD, and MSI-L/MSS UCEC. Altogether, our study suggests that the immune TME is modified in a TP53 status-dependent manner in specific cancer types. Further studies are warranted to investigate the implications for the guidance of immune therapies.The role of response . By cont did not . A distiarcinoma . In modePD1 axis . While iCDK4 and CDK6 were not included in the consensus list, but overexpressed in the TP53mut tumors of respectively 14 and 10 cancer types (just below the threshold 16 for inclusion in the consensus list). CDK1 and CDK2 were included in the consensus list and corresponding inhibitors and are currently tested in phase I, II and III trials. CCNE1 , as well as ADAM17 and CDC20 , are additional examples of genes on the consensus list currently being considered for therapeutic invention [TP53 mutations should by further investigated as a predictive marker to select patients for cell cycle targeting therapies.Many of the genes of the consensus list (52%) were related to the cell cycle. In line with the observation that the expression levels of these genes were prognostic in several cancer types, the cell cycle machinery represents a target for established drugs and agents under development , 64. Amonvention \u201367. CorrTP53 mutations in specific cancer types represent the main limitation of the current study. As gene expression patterns differ strongly between cancer types, pooling of cancer types would lead to a drastic increase in variance and would be ineffective to overcome this limitation. As further limitation, the study was focused on operable, early-stage tumors (TCGA) and on the molecular layer of gene expression. As several studies support a distinct role of different TP53 mutations in metastatic dissemination [Although we analyzed one of the largest comprehensively molecular characterized cancer cohorts available, small sample sizes in the analysis of specific mination \u201370, analTP53 mutation types on mRNA expression patterns across cancer types. Because we detected virtually no mutation type associated alterations, we pooled TP53 mutation types for comparison to TP53wt tumors. We extracted list of 210 genes that were differentially expressed between TP53mut and TP53wt tumors in two-thirds or more of the 24 cancer types. We also performed differential gene expression analysis for each cancer type followed by gene set enrichment analyses and uncovered impaired biological processes in TP53mut tumors of each entity. Analysis of specific immune cell populations showed an influence of TP53 mutations on the composition of the immune TME for 12 of the 32 investigated cancer subtypes. The analysis of a large cohort of human tumors complements results from experimental studies and supports the view that TP53 mutations should be further evaluated as predictive markers for cell cycle targeting therapies, immunotherapies, and others.This is the first study to comprehensively analyze the effect of specific We included 8331 tumors and 24 cancer types from the TCGA for which mutation calls, mRNA expression data were available, and at least seven TP53mut tumors per entity were available (Suppl. Table TP53-mutated (TP53mut) or TP53-wildtype (TP53wt). Tumors harboring missense, nonsense, splice site, translation site, or non-stop mutations or frameshift or in-frame indels were classified as TP53mut. Tumors without mutations, with synonymous mutations, or with mutations in the gene flanks, introns, UTRs, splice regions, or intergenic regions were classified as TP53wt.In the first step, tumors were classified as TP53 mutations were classified as GOF, LOF, DN, and not DN mutations  and RStudio Desktop (version 2.0.443) .TP53 variants was created with the MutationMapper at the cBioPortal [p-values were corrected for multiple testing using the Benjamini-Hochberg (BH) method. A set of hotspots with different prevalences of TP53 mutations in different cancer types was compiled controlling the false discovery rate (FDR) at 10%. The prevalence of mutational hotspots was reported together with 95%-confidence intervals calculated with the Clopper-Pearson method.A lollipop diagram of the distribution of the detected ioPortal , 75. TheioPortal . The recioPortal  and the log2 scale. The significance of differential gene expression was assessed using the Wilcoxon rank-sum test. Exact p-values were corrected for multiple testing using the BH method. Lists of differentially expressed genes were extracted, controlling the FDR at 10%.Sample-normalized gene expression data  were transformed to the TP53 mutations as well as TP53wt tumors. To ensure comparability, differential gene expression analyses were performed with a fixed sample size , and tumors of each cancer type and mutation type were randomly selected for the corresponding analyses. First, we performed comparisons between different TP53 mutation classes . The TP53 mutation class \u201cHotspots\u201d included the top ten most frequent missense mutations: R175H, R273C/H, R248Q/W, R282W, Y220C, G45S, H179R, and V157F. Second, we compared the different TP53 mutation classes to TP53wt tumors.We sought to compare gene expression patterns between tumors with different types of TP53 mutations, we analyzed the differential gene expression between TP53mut and TP53 tumors irrespective of the mutation type. The p-values of the 24 cancer types were summarized to pan-cancer p-values using Fisher\u2019s method [p\u2009<\u20090.05) in at least 16 cancer types. Fold changes (FCs) of the significantly differentially expressed genes were visualized as heatmap with hierarchical clustering using the Manhattan metric to measure the distance between cancer types and between genes and the average linkage method to measure the distance between clusters. Clusters of cancer types were tested for different TP53 mutation prevalence using the Kruskal-Wallis rank sum test.Because we did not detect characteristic gene expression patterns associated with specific s method . A 210-gAnalysis of progression-free interval (PFI) and overall survival (OS) was performed using the TCGA-Clinical Data Resource (CDR) Outcome , C2 (Curated Gene Sets: Martin Fischer and Kyoto Encyclopedia of Genes and Genomes (KEGG), n\u2009=\u2009192), and C5 (Gene Ontology (GO), n\u2009=\u20092). The significance of the enrichment of functional categories in the catalogs was assessed using the Fisher test and corrected for multiple testing using the BH method at FDR of 10%. The strength of enrichment or depletion of a functional category in the consensus gene list was quantified by the enrichment fold change,k being the number of genes in the gene list annotated for the functional category, K the total number of genes in the gene list, n the total number of genes in the functional category and N the total number of the genes in the functional catalog. Significant over- or underexpression of genes in signaling pathways was visualized using KEGG Tools [The Molecular Signatures Database (MSigDB v7.5.1) was downloaded from the GSEA web page  and impoGG Tools .Supplemental FiguresSupplemental Table S1Supplemental Table S2Supplemental Table S3Supplemental Table S4"}
+{"text": "Candida UTI. An ICU-based HAI surveillance network of tertiary care hospitals across India, coordinated by the All-India Institute of Medical Sciences, New Delhi and the Indian Council of Medical Research, modified the US CDC\u2019s National Healthcare Safety Network (NHSN) case definitions to record UTI. Unlike NHSN, India surveillance includes fungal pathogens, such as Candida spp., as eligible pathogens causing HAI-UTI. We describe the epidemiology, microbiology and antimicrobial resistance (AMR) profile of candiduria cases reported to this network to address the knowledge gap on Candida UTI in India.Urinary tract infections (UTI) are common healthcare associated infections (HAI) in low-and-middle-income countries including India, with limited information on Candida sp. who had spent at least 2 calendar days in a participating ICU were included as candiduria events. All candiduria events reported by participating sites from 1 November 2017 to 31 May 2022 were extracted from overall UTI reported for all pathogens. The distribution of events by age, gender, ICU type, urinary catheterization, pathogen and drug resistance profile were performed. UTI rate and device utilization ratio (DUR) were calculated. Network sites performed antifungal susceptibility testing (AST) on Candida isolates using MIC-based method as per CLSI guidelines.Patients with at least one UTI symptom and a positive urine culture with Candida isolates speciated, Candida tropicalis (37%), Candida albicans (36%), Candida glabrata (6%) and Candida auris (6%) were the top four species isolated. Among 220 C. tropicalis isolates tested with AST, 6.9% were fluconazole resistant and 2% of 140 were caspofungin resistant; 7% of 177 C. albicans isolates were fluconazole resistant and 6.5% of 92 isolates were caspofungin resistant; and 48% of 28 C. glabrata isolates were fluconazole resistant and 44% of 18 isolates were caspofungin resistant.Data was reported by 131 ICUs in 39 hospitals. Overall network UTI events including all pathogens were 3600; UTI rates were 2.6 (adult ICUs) and 1.3 (paediatric ICUs); DUR was 0.8 (adult ICUs) and 0.4 (paediatric ICUs). There were 1111 candiduria events, 95% were classified as catheter-associated UTI (CAUTI), and the median age of patients was 65 years (IQR 32\u201374 years) and 58% were male. Among 739 Candiduria events reported from ICUs to the HAI surveillance network-India are common and the majority are classified as CAUTI. Most of the species isolated are susceptible to fluconazole and caspofungin. Additional work is needed to understand the clinical significance of candiduria events reported to the network."}
+{"text": "Traumatic brain injuries are one of the leading causes of mortality, morbidity, and economic burden in context to Nepal. Non-contrast computed tomography is used for rapid diagnosis and repeat computed tomography helps to detect the progression and complications of cerebral injury. The aim of this study was to find out the prevalence of traumatic brain injury among patients admitted in the neurosurgical unit in a tertiary care centre.This descriptive cross-sectional study was conducted among patients admitted to the neurosurgery unit in the tertiary care centre from 1 August 2019 to 29 August 2020. Ethical approval was taken from Institutional Review Committee (Reference number: CMC-IRC/075/076-156). Convenience sampling method was used. Point estimate and 95% Confidence Interval were calculated.Among 350 patients admitted in the neurosurgical unit, the prevalence of traumatic brain injury was 140 (40%) . Change in management was required among 28 (20%) when computed tomography was done within 12-24 hours. Among them, 27 (19.29%) underwent surgical intervention after a repeat computed tomography scan.The prevalence of traumatic brain injury was found to be higher than similar studies done in similar settings. In the acute setting, non-contrast computed tomography (CT) is the cornerstone for rapid diagnosis as it quickly and accurately identifies intracranial haemorrhage that warrants neurosurgical evacuation. Follow-up assessment using a CT scan is frequently necessary to detect the progression and stability of the lesion and evidence of delayed complications and sequels of cerebral injury, which can determine whether surgical intervention is necessary.The aim of this study was to find out the prevalence of traumatic brain injury among patients admitted in the neurosurgical unit in a tertiary care centre.A descriptive cross-sectional study was done among patients admitted in the neurosurgical unit with TBI, undergoing serial CT scans in the neurosurgical unit in a tertiary care centre. The study was conducted from 1 August 2019 to 29 August 2020 after obtaining ethical approval from the Institutional Review Committee of Chitwan Medical College Teaching Hospital (CMCTH) (Reference number: CMC-IRC/075/076-156). Patients with TBI who were subjected to two or more CT scans and gave written consent were included in this study. Patients who were intervened surgically based upon the findings of the first CT scan of the head, TBI less than 5 years of age, patients who expired or were discharged after the first CT head and patients on antiplatelet/anticoagulation therapy were excluded from the study. Data was collected using a selfstructured proforma. Convenience sampling method was used. The sample size was calculated using the formula:Where,n = minimum required sample sizeZ = 1.96 at 95% confidence interval (CI)p = prevalence taken as 50% for maximum sample size calculationq = 1-pe = margin of error, 10%The minimum sample size calculated was 96. However, the final sample size taken was 350.The first CT scan (CT1) of the head was taken as soon as possible after head trauma-CT1 or admission CT scan. The second CT scan (CT2) was done 12-24 hrs after presentation/admission or any time if the patient showed neurological deterioration during the course of management. The third CT scan (CT3) was done 72 hrs after presentation/admission  or any time if the patient shows neurological deterioration during the course of management. The findings of serial CT2 and CT3 were analyzed on the basis of the radiological progression of the hematoma which was judged by the treating neurosurgeon along with the radiologist and the management was done according to the hospital protocol for management. The proforma was prepared including the patient's details of age, sex, time of injury, mode of injury, the interval between trauma and CT imaging, and the Glasgow coma scale (GCS) at the time of presentation to the emergency room. Informed consent from the patient's family was taken. CT findings as recorded by the attending neurosurgeon included type of brain injury, presence or absence of intracranial hematoma, site and the number of intracranial lesions, mass effect/brain oedema, and presence of hypoxic changes. The outcome was based on changes in the repeat CT scans that had influenced management protocol. The outcomes were recorded asConservative: Observation with clinical monitoringMedical management: Lower the intracranial pressure by osmotic diuretic (mannitol), 3% NaCl or hyperventilation (intubation), or decrease oedema by steroids.Surgical management: Craniotomy and evacuation of intracranial hematoma or large contusion and decompressive craniotomy for mass effect.Data were analysed using IBM Statistics SPSS 16. Point estimate and 95% CI were calculated.Among 350 patients admitted to the neurosurgical unit, the prevalence of traumatic brain injury was found to be 140 (40%) . Among 140 patients, 105 (70%) were male and 35 (25%) cases were female. All 140 (100%) patients underwent serial CT2 while only 69 (49.29%) cases underwent serial CT3. The median age of the patients with traumatic brain injury was 33 years. Most of the TBI were seen in road traffic accidents 89 (63.57%), followed by fall injuries 43 (30.71%), physical assault 6 (4.29%), and 2 (1.43%) included trauma due to animal attack.The majority of the TBI lesions after CT1 were contusions 43 (30.71%), followed by mixed lesions 39 (27.86%) and EDH 24 (17.14%) .The majority 122 (87.14%) of the cases underwent serial scan CT2 routinely. Only 18 (12.86%) cases were taken for CT2 based on neurological deterioration. Of the 69 (49.29%) cases undergoing serial CT3, 68 (48.57%) cases were routinely performed. Only 1 (0.71%) case was taken for CT3 based on neurological deterioration that was managed surgically.Impression was categorized based on increasing, static, or decreasing hematoma size. Among 140 patients, 54 (38.57%) patients had increasing hematoma size on serial CT2 scan with 23 (16.43%) decreasing volume and 63 (45%) with static CT scan findings. A total of 69 (49.29%) patients underwent serial CT3 among which 67 (97.10%) had decreasing hematoma and 1 (1.45%) had increasing hematoma .In the current study, 95 (67.86%) patients underwent CT2 within 12-24 hrs, 39 (27.86%) within 7-12 hrs, 4 (2.86%) cases after 24 hrs and only 2 (1.43%) within 6 hrs. Among these, change in management was required in those whose CT was done within 12-24 hr i.e. among 28 cases (29.47%).Among 140 patients, 112 (80%) were managed conservatively and 28 (20%) were managed medically after an initial CT scan. The cases undergoing surgical intervention after repeat CT scan was 27 (19.28%) .In scans based on routine CT, 18 (12.86%) of routine CT cases underwent surgical management. Among those 17 (94.44%) cases had undergone a change in management based on the finding in serial CT scans after neurological worsening. A total of 9 (50%) cases were taken for emergency craniotomies .Among patients undergoing serial CT3, hematoma size was decreasing among 68 (98.55%) patients. Only 1 (1.45%) had an increase in the size of the hematoma, which underwent a change in management from conservative to surgical management. The serial CT was done at 48 hrs from the initial CT1 due to neurological deterioration that showed increasing hematoma and the patient underwent surgical management .7 Because early identification of worsening brain injury may allow for more rapid and early intervention, patients with documented intracranial injuries often undergo frequent routine serial scans given that significant radiological changes may occur with minimal or no clinical and neurological changes.8 The major goal 'detection before deterioration' and timely intervention is the key to serial CT scans.5 This study provides light on the prevalence of traumatic brain injury, the timing of serial CT scans performed and the identification of hematoma progression.In our study, the prevalence of traumatic brain injury among patients admitted to the neurosurgical unit was found to be 140 (40%) which was higher as compared to a study where the prevalence of head injury was reported to be 31.06%.8The majority of these cases underwent CT scans routinely. Within 6 hrs most of the cases were clinically static and beyond 24 hrs only 1 case had changed in management. Likewise, the majority of the cases with clinical worsening had undergone serial CT scans within a 7-24 hrs period. Of 18 cases with clinical worsening, 9 underwent CT scans within 7-12 hrs and 7 cases within 13-24 hrs. Similar study done in India recommended initial CT scan could be followed by a second CT scan within 24 to 48 hrs for the detection of evolving lesions and change in management. The study reported that 75% of the cases who went for surgical management based on the findings of CT2, had CT1 done less than 6 hrs after the injury which was similar to the findings of our study.9 In their study, 81% of scans were routinely done without evidence of neurological deterioration. Likewise, another study reported similar findings with the progression of hematoma in 33.3% of cases within 48 hrs and the incidence of increasing hematoma was predominant in EDH and contusions, either alone or as mixed lesions.8 Repeat CT scans demonstrated lesions earlier than clinical deterioration in a study and the likelihood of significant growth of hematoma increases on subsequent scans.11 This shows that the progression of hematoma is an inevitable process and timely CT scans can diagnose the expanding hematoma before neurological deterioration.In the current study, 38.57% of cases had progression of hematoma with 16.43% decreasing and 45% remaining static. In CT3 almost all cases had resolving hematoma. One of 69 cases had undergone CT3 due to neurological deterioration (oedema) which was managed surgically. In a similar study, 35% of scans showed the progression of hematoma, 43% of scans showed no changes and 22% of cases showed decreasing hematoma.12 Another study reported that overall, 32% of patients with progression of injury on repeated CT underwent one or more changes in nonsurgical management which are comparable to this current study.13 Likewise, a prospective study showed that changes in management decisions were seen in as many as 47 (23%) of cases based upon findings of repeat CT that doesn't corroborate the current study.8 However, the incidence of surgical intervention was seen among 14% of the patients after CT2 and a further 9.7% of cases undergoing surgical intervention after CT3, within 48 hours of trauma which is similar to our present study.In this study, 51 (36.43%) of initial 112 (80%) of patients were managed conservatively and 20 (14.29%) of cases of initial 28 (20%) patients managed medically underwent a change in management after CT2. Surgical intervention was done in overall 27 (19.29%) of cases after CT2. Change in management to medical intervention was seen overall in 34.3% of cases after CT2. However, only one case had undergone a change in management after serial CT3. In a retrospective study, 17% of patients underwent subsequent neurosurgical intervention which is similar to the findings of our study.12 In their study, 161 (95.83%) patients underwent routine repeat CT while 7 (4.17%) cases had repeat CT due to worsening neurological conditions which was similar to our study where 122 (87.14%) underwent routine repeat CT and 18 (12.86%) had repeat CT due to worsening neurological conditions. Of 28 surgically treated cases, 6 (10%) had neurological worsening while the rest had routine CT scans. This finding is similar to the results of our study as out of 27 surgically managed cases, 9 cases (50%) had clinical worsening based on CT2 findings. However, we couldn't categorize the patients based on GCS and document the improvement accordingly.A retrospective study suggested that a routine repeat CT scan within 24 hrs after blunt head trauma might minimize the potential neurological deterioration in patients with GCS lower than 12.9 Another similar study supported a selective approach for repeating head CTs with emphasis on changes in neurological symptoms and GCS.14 In another study it was suggested that a repeat CT scan may be preferred only in the presence of clinical worsening and when CT1 is done within 2 hr after trauma.15A similar study concluded that all patients with a head injury should undergo CT after neurological deterioration because it leads to intervention in over one-third of the patients.The limitation of our study is that the study was carried out among a small population and in a single centre, thus lacks the generalizability of the outcomes.The prevalence of traumatic brain injuries was found to be higher than similar studies done in similar settings. However, scans indicated after neurological deterioration almost always resulted in interventional changes whether surgical or medical. Timely performed serial CT scans are important in changing management of the patients with traumatic brain injury and serve to decrease the risk for neurological deterioration by detecting radiological progression prior to clinical worsening."}
+{"text": "The article reported an increased prevalence of idiopathic normal pressure hydrocephalus (iNPH) among patients with a behavioural variant frontotemporal dementia (bvFTD) (7.25%) in comparison with those with Alzheimer\u2019s disease (1.1%).1 Therefore, we proposed to evaluate this high prevalence of iNPH in patients with FTD (not only focusing on bvFTD) followed at the Leenaards Memory Center of the Lausanne University Hospital between January 2013 and December 2022.We read with great interest the article by Pouclet-Courtemanche and colleagues2 and primary progressive aphasia (PPA) according to Gorno-Tempini3 criteria. Our inclusion criteria were the presence of FTD without any other degenerative copathology and an available brain MRI. The diagnosis of possible or probable iNPH followed the Relkin criteria.4 For quantifying brain changes due to iNPH, we computed the iNPH Radscale5 for every comorbid iNPH patient. This study was approved by the local IRB [PACSMolis PB_2016-02582(390/15)].We selected FTD patients including bvFTD according to the Rascovsky criteriaWe identified a total of 45 FTD patients (30 patients with bvFTD and 15 with PPA). The mean age was 72.6 years old [standard deviation (SD) 14.8], 15 females and 30 males, and the mean MoCA  score was 19.8/30 at the time of diagnosis. Among the 30 patients with bvFTD, the mean age was 73.4 years old (SD 14.8), 9 females and 21 males with the mean MoCA score of 18.9/30.Among the 45 patients with FTD, 5 patients presented a comorbid iNPH (4 bvFTD and 1 PPA), corresponding to 11.1% of the FTD (13.3% for bvFTD and 6.7% for PPA). The mean Radscale was 5.6 . Interestingly, we previously reported that gait instability could be a supportive argument for bvFTD, following the demonstration of increased gait variability in bvFTD patients in comparison with Alzheimer\u2019s disease patients.8iNPH is frequent among older adults with a prevalence reaching around 6% in adults older than 80.9Among the radiological features of iNPH evaluated with the iNPH Radscale, none of the patients had a narrowed vertex sulci or a sharp callosal-marginal angle that is unusual for \u2018classical\u2019 iNPH patients. In addition, the majority of the iNPH patients have an increased temporal horn that may reflect the temporal lobe atrophy found in patients with FTD. An increased temporal horn in patients with iNPH might raise the question of a degenerative comorbidity, as already suggested in a previous study.1 regarding the increased prevalence of iNPH among patients with FTD. Here, we further demonstrate that this increased prevalence concerns both bvFTD and PPA variants with a 2-fold higher prevalence of iNPH in the bvFTD compared with the PPA variants.In conclusion, our 10-year study reinforces the findings of Pouclet-Courtemanche and colleagues"}
+{"text": "Hypothyroidism occurs as a consequence of chronic autoimmune inflammation of the thyroid gland, which occurs due to the reduced function in the secretion of thyroid hormones. The coronavirus disease infection has shown many complications in all organic systems, during the acute phase of infection and in the post-COVID-19 period. SARS-CoV-2 may induce thyroid dysfunction that is usually reversible, including subclinical and atypical thyroiditis. The aim of this study was to find out the prevalence of subclinical hypothyroidism among patients with COVID-19 infection in a tertiary care centre.A descriptive cross-sectional study was conducted in the Department of Internal Medicine of a tertiary care centre from 1 September 2022 to 28 February 2023 after obtaining ethical approval from the Research and Institutional Review Committee (Reference number: 15-079/080). Convenience sampling method was used. Point estimate and 95% Confidence Interval were calculated.Among 38 patients with COVID-19, subclinical hypothyroidism was seen among 23 (60.53%) .The prevalence of subclinical hypothyroidism among COVID-19 patients was found to be similar to other studies done in similar settings. This condition occurs in 3% to 8% of the general population. It is more common in women than men, and its prevalence increases with age. The most common cause of hypothyroidism including subclinical hypothyroidism is autoimmune in nature.2 There have been several studies that COVID-19 infection results in endocrinopathies.6 The thyroid gland tissue with high angiotensin-converting enzyme 2 expression, has been associated with coronavirus infection.6 There is currently inadequate data regarding COVID-19's impact on the thyroid. Available studies were done during the active phase of COVID-19 or included patients admitted to intensive care units.Coronavirus disease 2019 (COVID-19) affects the respiratory system mainly.The aim of this study was to find out the prevalence of subclinical hypothyroidism among patients with COVID-19 infection in a tertiary care centre.This descriptive cross-sectional study was done in the Department of Internal medicine at Nepal Medical College Teaching Hospital (NMCTH) from 1 September 2022 to 28 February 2023 after obtaining ethical approval from the Research and Institutional Review Committee of the NMCTH (Reference number: 15-079/080). Patients who gave written consent were included in this study. Patients who were treated previously for thyroid dysfunction before COVID-19 were excluded from the study. Convenience sampling method was used. The sample size was calculated using the following formula:Where,n = minimum required sample sizeZ = 1.96 at 95% Confidence Interval (CI)7p = prevalence of thyroid dysfunction among COVID-19 taken from previous study, 6.7%q = 1-pe = margin of error, 10%The total size calculated was 24. However, the final sample size taken was 38.1 Subclinical hyperthyroidism is defined as normal serum-free thyroxine (T4) and triiodothyronine (T3) concentrations in the presence of a subnormal TSH (<0.5 mU/l). The venous blood sample was collected and sent for T3, T4 and TSH. For primary hypothyroidism, the T3 and T4 level lower than the normal range (3.32-7.62 pmol/l) & (8.8-23.6 pmol/l) respectively were taken and primary hyperthyroidism was characterized by the higher level of T3 (>7.62 pmol/l) and T4 (>23.6 pmol/l) and low level of thyroid stimulating hormones (<0.4 mIU/l). For subclinical hypothyroidism, T3 and T4 levels are in the normal ranges (3.32-7.62 pmol/l) & (8.8-23.6 pmol/l) respectively but the TSH levels exceed the normal range of 0.45-5.32 pmol/l.Patients were included in this study, only after they gave written consent for history taking, physical examination, and necessary investigations. Basic data including age, gender, occupation, history of COVID-19 infection, and family history of thyroid dysfunction were taken from all the participants in the study. Body mass index (BMI) was measured from all participants. COVID-19 patients were categorized as per World Health Organisation (WHO) clinical COVID-19 disease severity classification.Data were entered in an Excel sheet and analyzed using IBM Statistics SPSS 20. Point estimate and 95% CI were calculated.Among 38 patients with COVID-19, subclinical hypothyroidism was seen in 23 (60.53%) . The median age of the population with subclinical hypothyroidism is 48 years. TSH of more than 10 was detected in 11 (47.83%) among patients with subclinical hypothyroidism. The majority of the patients with subclinical hypothyroidism 16 (69.57%) were males whereas 7 (30.43%) were female .Among patients with subclinical hypothyroidism, COVID-19 severity was mild among 15 (65%), followed by 7 (30%) with moderate and 1 (5%) had severe disease .A total of 11 (48%) patientswith subclinicalhypothyroidism had BMI more than 25 .8 A recent study concluded that COVID-19 susceptibility and its severity might increase the risk of hypothyroidism including subclinical hypothyroidism.10 This is similar to another study conducted in Bosnia, where they found a significant difference in the number of patients with hypothyroidism and subclinical hypothyroidism in 2020 and 2021 in comparison to 2019.11 About 78.3% of patients had subclinical hypothyroidism 2 months post-COVID-19 infection in those with thyroid dysfunction which the persisted in 33.6% of the subjects of the patients after one month of follow up which was higher compared to our study.12 Several studies have identified cases of COVID-19-related primary hypothyroidism. However, they have cautioned the timing of thyroid function tests following COVID-19 and the use of glucocorticoid in the treatment could have an impact on the results including family history and the presence of autoantibodies.4 In contrast to this prospective study another prospective study did not find any alterations in thyroid hormone levels three months after SARS-CoV-2 infection in the cohort with subclinical hypothyroidism.13 In yet another study has demonstrated a significant prevalence of subclinical hypothyroidism in COVID-19 infected patients with a family history of thyroid disease, and/or a high level of thyroid peroxidase (TPO) antibodies.14The prevalence of subclinical hypothyroidism in our study was 23 (60.53%). A hospital-based study reported a prevalence of 20.42%, which is more than double compared to other populations (1.4-7.8%).5 Another study of hospitalized COVID-19 patients conducted in Hong Kong showed that the majority of those with abnormal thyroid function (13.1% of the group) had low TSH concentrations, but only one of 191 participants (0.5%) had a high TSH concentration and a high TPO antibody titre.6 Abnormal thyroid function was common in patients with COVID-19, particularly hyperthyroidism in another study.15In contrary to our finding, several other studies have found hyperthyroidism in COVID-19 patients. A similar study found that the serum concentrations of TSH and total T3 were considerably lower in patients with COVID-19 than in a control group.16 The reasons for this gender disparity in the prevalence of thyroid disorders are not completely understood. In our study, however, subclinical hypothyroidism was more common among males with COVID-19. Similarly, more men than women had abnormal thyroid function tests (64% vs. 36%) in another study of COVID-19 patients.17The patients with hypothyroidism and subclinical hypothyroidism were more likely to be female.19In our study, among patients with subclinical hypothyroidism 1 (5%) had severe COVID-19 infection and mild infection was seen in 15 (65%) of cases. Regardless of disease severity, recently a growing number of studies have been reported in the literature that patients may have other comorbidities weeks and months after the onset of COVID-19 including thyroid dysfunction.21 Apart from high BMI no other risk factors were found that could be linked with subclinical hypothyroidism in our study. This too could also be a confounding factor as thyroid dysfunction particularly subclinical hypothyroidism has been reported to be associated with obesity.23A BMI of more than 25 was seen in 11 (48%) subclinical hypothyroidism cases. Both thyroid dysfunction and higher BMI have been linked with longer disease morbidly in literature.The limitation of our study is that the study was carried out among a small sample size and in a single centre, thus cannot be generalized to the general population. There were several confounding factors which could not be fully excluded from the descriptive study. Multicentre, longitudinal studies looking into this aspect are needed for further insights into thyroid dysfunction status.The prevalence of subclinical hypothyroidism among COVID-19 patients was found to be similar to other studies done in similar settings. Therefore, this indicates that these patients need to be evaluated thoroughly for thyroid dysfunction and this information should be kept in mind while evaluating these patients"}
+{"text": "Front Psychiatry 2022; 24 13). There is frequent comorbidity between psychotic spectrum disorders and substance use disorders, which hinders both psychopathological stability and the approach to addictive behaviors .Dual disorders constitute a clinical entity with increasing current prevalence , with a diagnosis of a comorbid psychotic spectrum disorder for over 3 years. A descriptive analysis of the prevalence of consumption of each predominant substance was carried out, as well as the sociodemographic and clinical characteristics were collected through a semi-structured interview. Statistical analyzes were performed using SPSS v23.0 (significance p<0.05).The predominant user profile was a man (85.7%), with a mean age of around 29 years, single (83.3%), with family support (52.4%), resident in rural areas (92.8%), with unqualified employment (57.1%) and primary studies (60%). Cannabis was the predominant substance (80.9%), followed by amphetamines (71.4%), with polydrug use of both in 78.6% of cases. A significant association was found between this combined use of substances, the relapse rate and the presence of comorbid personality disorder.The paradigm of substance use in psychotic disorders has evolved towards comorbidity with polydrug use and confluence with personality disorders.None Declared"}
+{"text": "To date, there is little data on decolonization in extracorporeal membrane oxygenation (ECMO) patients and if decolonization efforts improve rates of bacteremia with multi-drug resistant organisms (MDROs). We sought to determine if implementation of universal nasal decolonization with daily chlorhexidine bathing will decrease blood stream infections (BSI) in patients undergoing ECMO.A retrospective cohort study was conducted of all patients with admitted to UAB Hospital and placed on ECMO from 12/22/2017-6/1/2022. Data collected included baseline patient characteristics and clinical data, microbiology data, interventions for source control, dates of line placement, appropriate antibiotic treatment, and outcomes. Categorical variables were analyzed with the Fisher exact test, and continuous variables analyzed with the t test or Wilcoxon rank-sum test when appropriate. Only variables found to be statistically significant will be included in the model. A P value < .05 are considered significant.531 patients placed on ECMO were included in this study and separated into groups: Pre implementation: 401 (76%), post implementation: 130 (24%). (Table 1). 61 (15%) pre patients developed bacteremia with an average of 18.1 ECMO days. 29 (22%) of post patients had a BSI with an average of 25.0 ECMO days. While the average number of BSI per 100 ECMO days increased in the post-implementation group (0.58/100 ECMO days to 1.02/100 ECMO days), the overall incidence rate of MRSA decreased (0.22/100 ECMO days vs 0.09/100 ECMO days). Of note, 89 (17%) patients were found to have COVID-19 at time of ECMO, 12.6% of the pre-implementation group vs 31% of the post-implementation group, (p < 0.001).Incidence Rate: Number of BSI per ECMO DaysThere was no statistical significance between the pre and post groups in the study with the amount of time on ECMO, the time from ECMO cannulation to BSI, the amount of BSIs or the amount of MRSA bacteremia. Implementation of universal decolonization with daily CHG reduced rates of MRSA bacteremia. The lack of research in this field and the timing of this study almost exclusively assessing ECMO patients during the COVID-19 pandemic during the post-implementation period warrants further investigation on if decolonization strategies can reduce BSIs and MDROs bacteremia in ECMO patients.All Authors: No reported disclosures"}
+{"text": "The premises and equipment available in schools are essential for developing programs that promote active lifestyles in schoolchildren. The aim of this study was to determine how satisfied coordinators of Active school programs were with their sports equipment and facilities and identify differences by type of school.In the 2021/22 academic year, 580 schools were accredited as Active schools in the Valencian Community (Spain). A representative sample of 257 Active school coordinators  participated. An ad-hoc questionnaire was designed and administered on-line. It consisted of 47 open and closed response questions concerning the actions carried out to promote physical activity and sport and the school coordinators\u2019 degree of satisfaction. The anonymity of all the participants was guaranteed. Descriptive statistics and chi-square tests were conducted on SPSS Statistics v. 26.0 software.\u03c72(3)=11.480; p<.05), gym and sports hall (\u03c72(3)=10.829; p<.05) and equipment for students with functional diversity (\u03c72(3)=33.368; p<.05). Private schools were better represented in the maximum degree of satisfaction than state schools. The Active school coordinators suggested that improvements in outdoor premises (80.9%) and more and better equipment (74.7%) would contribute to increasing pupils' physical activity at school.Active schools in the Valencian Community were equipped with the following facilities/spaces: sports fields or courts (55.6%), gym (55.5%), outdoor playing fields (41.4%), green spaces (10.9%), a football pitch (8.2%), skating rink (5.2%) and swimming-pool (0.8%). The Active school coordinators were quite satisfied with the school areas and playgrounds (65.3%) and sport equipment (75.1%) but dissatisfied with the gym or sports hall (60.7%), toilets and showers (59.5%), or with the equipment for students with functional diversity (66.1%). Significant differences by type of school emerged for school spaces and playgrounds (The degree of satisfaction of the Active schools coordinators was balanced regarding the school equipment and facilities, but lower in state schools than private schools. The authorities should provide state schools with more sports and open spaces, green areas and appropriate equipment to facilitate designing inclusive, effective and sustainable physical activity and sports promotion programs.Grants AICO/2021/342 and Margarita Salas [MS2021]."}
+{"text": "Platelet counts were updated in the RESULTS section (Page 71), FIGURE 2 (Page 72), and TABLE 1 (Page 72).WBC counts were updated in TABLE 1 (Page 72).The ROC for the platelets + WBC + retinopathy model was updated, from 0.89 to 0.87, in the RESULTS section (Page 72) and FIGURE 3 (Page 73).After publication the authors identified inconsistencies regarding the units in their raw data regarding platelet and white blood cell counts. The paper has therefore been corrected. The results and conclusions are unchanged. A summary of corrections is below:The Supplementary Materials file has also been updated accordingly."}
+{"text": "Lower respiratory tract infections (LRTIs) have been associated to significant morbidity and mortality. Conventional microbiology methods often fail to identify the etiological agent due to lack of sensitivity or viral or fastidious pathogens. Pneumonia molecular diagnostics is able to expand the scope of pathogens detected, therefore, we describe our experience in the incorporation of this method, the difference in etiological identification and clinical decision making.We performed a retrospective cohort study of 75 patients with Filmarray pneumonia panel from November 2020 to September 2022. We described demographics, co-morbid conditions, outcomes and correlation with standard cultures in patients who were admitted with LRTI at the Hospital General de la Plaza de la Salud, a 289-bed tertiary teaching hospital in the Dominican Republic.S. aureus (18%), P. aeruginosa  and K. pneumoniae group (10%) and at least one antimicrobial resistance gene was detected in 50% (28/56), distributed as MecA/C and MREJ (35%), CTX-M (38%), KPC (10%), NDM (10%), VIM (8%), IMP (8%) and OXA-48 like (3%). A positive culture was most likely to occur when the number of copies/mL in the panel was \u2265 10\u02c45 . A viral target was detected in 21 patients (28%) alone or coinfecting with a bacterial agent.Amongst the 75 patients, 56.6% were male and the average age was 51 years old. The most common comorbidities were diabetes mellitus (81.6%), hypertension (40.8%) and nephropathy (10.5%). The panels had a positivity rate of 74.6% (56/75) versus a 35% (14/40) seen in cultures. The most frequent microbial targets detected were Not only did the pneumonia panels allow an earlier detection of the etiological agent, but they also identified more pathogens compared to cultures. This enabled targeted management by reducing the unnecessary use of antimicrobials as well as activating infection control measures when necessary (i.e Influenza). The results seen in this study, along with the expanded scope of pathogens detected, will definitely serve as an update into our current LRTI hospital guidelines.All Authors: No reported disclosures"}
+{"text": "Background: The \u2018GeriDerm\u2019 (geriatric dermatology) clinic, is a new dermatology-based service at Hamad Medical Corporation (HMC), accommodating the needs of our elderly population living in the State of Qatar. Due to the global demographic transition towards an elderly population (\u226565 years of age), incidences of chronic diseases, including dermatologic conditions, rise in parallel. Patients of older age are at higher risk of using multiple medications, seeing multiple care providers, often receiving multiple diverging pieces of information, and feeling lost within the system. Taking into consideration the elderly unique characteristics, the Geriatric Dermatology telemedicine clinic is a novel approach to meeting the many challenges our elderly patients face via providing quick, accurate assessments of cognition, functional status, frailty screening, and assessment for polypharmacy.Methods: Data of 1080 elderly patients with various skin disorders from June 2020 to July 2021 was received from the Dermatology Geriatric clinic, and then reviewed.Results: There were 521(48.2%) new cases and 559(51.8%) follow-up cases who attended the clinic either virtually or face to face consultation. A total of 587(54.4%) female and 493(45.6%) male elderly patients attended the clinic. The mean age was 74.6, with a minimum age of 60 and a maximum age of 106 years. 57.9%(625) of GeriDerm patients were Qatari, followed by Palestinian 75(6.9%), Syrian 51(4.7%), Egyptian 46(4.3%), and Indian 44(4.1%); while other nationalities constituted 239(22.1%). The majority of the cases were Contact Dermatitis 146(13%), Bullous Pemphigoid 107 (10%), and Pruritis 101(9.4%).Conclusion: The \u2018GeriDerm\u2019 service at HMC aimed to achieve the best healthcare standards for the elderly population of Qatar during COVID-19 pandemic, and is now established as a continuous advanced technology-based framework facilitating caring for older patients with skin disease via providing a clear pathway for adequate triaging, identification of severe conditions (red flag) requiring in-person clinic visits, while managing non-life threatening dermatoses via a teledermatology based approach."}
+{"text": "The World Health Organization African Region established a 2020 measles elimination goal. In 2016, regional coverage with 1 dose of measles-containing vaccine (MCV) was 68%, and 40% of countries met surveillance performance indicators.The 2020 elimination goal was not met, and in 2021, coverage with a first MCV dose remained <95% in all but two countries. After a 2019 global measles resurgence, incidence in 2021 exceeded that in 2017. Surveillance quality declined during 2017\u20132021, with 62% of countries achieving surveillance performance indicators in 2017 compared with 22% in 2021.Reaching all children with 2 MCV doses and improving surveillance is critical to achieving the renewed 2030 regional measles elimination goal in at least 80% of African countries.Worldwide, measles remains a major cause of disease and death; the highest incidence is in the World Health Organization African Region (AFR). In 2011, the 46 AFR member states established a goal of regional measles elimination by 2020; this report describes progress during 2017\u20132021. Regional coverage with a first dose of measles-containing vaccine (MCV) decreased from 70% in 2017 to 68% in 2021, and the number of countries with \u226595% coverage decreased from six (13%) to two (4%). The number of countries providing a second MCV dose increased from 27 (57%) to 38 (81%), and second-dose coverage increased from 25% to 41%. Approximately 341 million persons were vaccinated in supplementary immunization activities, and an estimated 4.5 million deaths were averted by vaccination. However, the number of countries meeting measles surveillance performance indicators declined from 26 (62%) to nine (22%). Measles incidence increased from 69.2 per 1 million population in 2017 to 81.9 in 2021. The number of estimated annual measles cases and deaths increased 22% and 8%, respectively. By December 2021, no country in AFR had received verification of measles elimination. To achieve a renewed regional goal of measles elimination in at least 80% of countries by 2030, intensified efforts are needed to recover and surpass levels of surveillance performance and coverage with 2 MCV doses achieved before the COVID-19 pandemic.Measles remains a major cause of disease and death worldwide, with the highest numbers of cases and deaths occurring in the World Health Organization (WHO) African Region (AFR)  delivered through routine immunization services***https://stacks.cdc.gov/view/cdc/132420). Reported administrative coverage was \u226595% in 42 (61%) SIAs. Only two of 29 post-SIA coverage surveys reported \u226595% coverage.During 2017\u20132019, estimated regional MCV1 coverage remained stable at 70% but decreased to 68% in 2021 . Six couDuring 2017\u20132021, 42 (88%) countries reported weekly case-based measles surveillance data to the WHO African Regional Office. The number and percentage of countries that met both surveillance indicators decreased from 26 (62%) in 2017 to 19 (45%) in 2019 and to nine (22%) in 2021 .From 2017 to 2019, the number of reported measles casesThe regional laboratory network processed blood specimens from 46,501 suspected measles cases in 2017, 61,636 in 2019, and 41,291 in 2021. Measles genotypes were obtained from confirmed measles cases in 16 (34%) countries; genotypes B3  and D8 Using the previously described model, the estimated number of measles cases in AFR increased 22% from 3,623,869 in 2017 to 4,430,595 in 2021, peaking at 6,377,451 in 2019. The estimated number of annual measles deaths increased from 61,166 in 2017 to 104,543 in 2019 before decreasing to 66,230 in 2021. During 2017\u20132021, an estimated 4.5 million measles deaths were prevented by measles vaccination.The African Regional Commission for the Verification of Measles Elimination (RVC) was established in 2017. During 2017\u20132021, 10 countries established national verification committees to support documentation of progress toward measles elimination. The African RVC met during 2018\u20132019The WHO AFR has made substantial progress in reducing measles cases and deaths since 2000  lived in AFR countries.Surveillance quality improved in 2017, with 26 countries attaining both indicator targets compared with 19 countries in 2016 (Measles incidence continued to increase during 2017\u20132021, reaching a peak in 2019 amid a global resurgence (The findings in this report are subject to at least three limitations. First, immunization coverage estimates are based primarily on administrative data, which might contain inaccuracies resulting from errors in recording doses administered or in population estimates. Second, cases and incidence might be underestimated because of inaccuracies in population estimates, variation in measles surveillance performance and data quality among countries, and because not all persons with suspected measles seek care and thus are not identified by the health system. Finally, the measles case and mortality estimates might contain inaccuracies resulting from errors in the data inputs and are subject to the inherent uncertainty of modeling estimates.Despite not reaching the 2020 elimination goal, implementation of measles elimination strategies substantially reduced measles morbidity and mortality in AFR, with measles vaccination averting approximately 19.5 million deaths during 2000\u20132021 ("}
+{"text": "Infections are a major cause of mortality among patients receiving ECMO treatment. However, little is known about the prevalence and spectrum of infections affecting ECMO patients in India and the factors that contribute to increased risk of infections and mortality in these cases.This study presents a retrospective analysis of ECMO patients admitted between 2018-2022. The study recorded demographic information, ECMO indication, duration, type of infection, and outcomes. The primary objective of the study was to determine the prevalence of microbiologically-proven nosocomial infections. The study also aimed to identify secondary factors associated with an increase in the number of infections and mortality.Klebsiella pneumoniae (27%), Acinetobacter baumanii (15%) and B. Cepacia (13%) with Staphylococcus and Enterococci accounted for only 10% of infections. Additionally, carbapenem resistance was found in 80% and 100% of Klebsiella and Acinetobacter isolates respectively. Candidemia accounted for 10% of infections, with one patient developing candidemia as early as 4 days after ECMO initiation. Our study revealed a mortality rate of 62% among those who developed infections versus 51% in those who did not develop infections. Patients who developed infections more frequently required CRRT . Longer the duration of ECMO, greater the number of infections were observed  (Table-4).During the study period, 37 patients received ECMO support, with a mean age of 44.97\u00b114.19 years. The most common indication for ECMO was respiratory failure secondary to ARDS. 26 (70.3%) patients were placed on VV-ECMO, while 11 (29.7%) patients received VA-ECMO. 29 patients (83.4%) developed infections, with an incidence of 147.1 infections per 1000 ECMO days. Ventilator-associated pneumonia (48.04%) was the most frequently reported type of infection, followed by bloodstream infection (47.1%). The most commonly isolated organisms were Figure-1Distribution (%) of Nosocomial infectionsFigure-2Distribution (%) of PathogensTable-2Requirement of CRRT among ECMO patientsThere was a high incidence of infections (particularly due to carbapenem resistant organisms) in ECMO patients in our study. Infection risk correlated with duration of ECMO and need for CRRT.Table-3Correlation between CRRT & MortalityTable-4Correlation of number of infections with ECMO DurationAll Authors: No reported disclosures"}
+{"text": "Work on atypical schedules could lead to alertness and sleep disorders, which makes people with psychiatric pathologies more likely to exacerbate their illness.To study the impact of psychoaffective diseases on the fitness for night or/and shiftworkA descriptive cross-sectional study was conducted with patients with psychoaffective disorders working atypical hours who have consulted the Occupational Medicine Department of the Charles Nicolle Hospital for statements of medical fitness. The study period was six years from January 2016 to June 2022.Among 224 employees who had shift/night work , 32.1% (n=76) had psycho-affective disorders. The average age was 43.32\u00b18.64 years. The sex ratio (M/F) was 0.46. The average professional seniority was 17.35\u00b19.17 years. The most represented sectors were: health (56%), the electronics industry (5%), finance (5%) and the plastics industry (5%). The most occupied jobs were: nurses (21%), blue collar workers (20%), senior techniciens (20%) and security guards (8%). Psychiatric pathologies were represented by anxiety disorders (80%), psychoses (8%), schizophrenia (8%) and bipolar disorders (4%). The consultants were on medication in 88% of cases. Antidepressants were prescribed in 75% of cases, followed by anxiolytics (54%), antipsychotics (22%) and thymoregulators (4%). Concerning the medical fitness for work of the patients, a definitive eviction from shift/night work was indicated in 56% of cases.A medical assessment of the fitness to work on atypical schedules for workers with psychiatric disorders is required, in particular, during the employment medical examinationNone Declared"}
+{"text": "To evaluate the financial effects in a state employee health plan of a change in the drug coverage policy to include over-the-counter (OTC) omeprazole in a tier-copayment drug benefit design that favored the OTC drug.The policy change in the Arkansas State Employee Benefit Division (EBD) involved 2 principal parts: OTC omeprazole placed in a new OTC copayment tier ($5) and an increase in pharmacy reimbursement to a $13 dispensing fee for each OTC omeprazole prescription. The prescription claims database was used to examine utilization and cost data for beneficiaries who received prescriptions for a proton pump inhibitor (PPI) during the 2-month period (January and February 2004) preceding the change in policy to cover OTC omeprazole compared with the 2-month period following the policy change (March and April 2004).During the first week of the new policy , OTC omeprazole accounted for 47% of all PPI claims. From the third week through the end of the 2-month study period, OTC omeprazole represented 60% of PPI claims. This shift to OTC omeprazole from prescription PPIs produced EBD average savings of $40.86 (40.5%) per PPI claim in the first 2 months after implementation of coverage of OTC omeprazole compared with the immediate previous 2-month period. The average copayment savings for EBD beneficiaries were $4.20 (16.5%) per PPI claim. The average increase in pharmacy reimbursement was 118% ($6.27 per claim in the postperiod versus $2.88 per claim in the preperiod). Despite a 17.2% increase in utilization as measured by days of PPI therapy per member per month (1.91 PMPM) in the postperiod versus 1.63 in the preperiod, EBD savings were $2.11 (38.9%) PMPM. Based upon PMPM savings of $2.56 in the second month of coverage of OTC omeprazole, annual savings would be about $3,978,240 for average eligible membership of 129,500 in this state employee health plan.This policy change to include coverage of OTC omeprazole in the state employee drug benefit plan produced savings to the state of as much as 50% of the total cost of PPI drugs despite an apparent small increase in utilization of PPIs and an increase in pharmacy reimbursement of more than 100%. Plan beneficiaries realized significant savings on average for PPI drugs and particularly for each OTC omeprazole prescription."}
+{"text": "C. difficile can range from colonization to fulminant colitis. Patients with toxin antigen negative, C. difficile nucleic acid amplification (NAAT)-positive diarrhea are frequently only colonized and do not suffer consequences of C. difficile associated disease (CDAD) but receive treatment for CDAD due to the perceived low risk of oral vancomycin vs. the risk of developing CDAD.Clinical spectrum of C. difficile NAAT and negative toxin antigen results at University of Iowa Health Care between 9/1/2021 and 9/30/2022. Chart review was conducted to obtain patient age, immunocompromised state, involvement of infectious disease (ID) consultant, prior C. difficile test status and treatment course.We performed a retrospective cohort study of hospitalized adult patients with positive C. difficile results, 210 (71%) were toxin antigen negative. Patient characteristics and frequency of common risk factors are shown in Table 1. C. difficile colonization was detected \u22654 days after admission in 111 (53%), with internal medicine and stem cell transplant (SCT)/hematologic malignancies (HM) services having the most patients with colonization . Antibiotic use in the prior 30 days was reported in 154 (73%). Of 134 (64%) patients on systemic antibiotics at time of C. difficile testing, antibiotics were discontinued in 29 (22%). Only 43 patients (20%) did not receive any treatment for C. difficile. Median treatment duration was 10 days with 133 (80%) being treated for 10-14 days (Table 2). ID consult was obtained in 48 (23%) and recommended no treatment initially in 11 (23%), 4 of whom were started on treatment in subsequent days. Oral twice a day vancomycin for prophylaxis was given to 28 (13%) patients, 19 (68%) of whom were immunocompromised (16 SCT/HM and 3 solid organ transplant).Of the 295 NAAT-positive C. difficile colonization have similar risk factors as patients with CDAD. Understanding treatment patterns for C. difficile colonization can guide educational activities. Most colonized patients received C. difficile treatment and/or prophylaxis, likely due to ongoing systemic antibiotic use and immunosuppression. Benefit of treatment and prophylaxis in colonized patients remains an unresolved issue.Patients with Kelly M. Percival, PharmD, Gilead Sciences Inc: Advisor/Consultant"}
+{"text": "The U.S. Department of Defense (DoD) health care benefit (TRICARE) provides 9.2 million active-duty and retired uniformed services personnel and their family members with access to a comprehensive pharmacy benefit with low out-of-pocket costs. DoD's Uniform Formulary is available worldwide at DoD's 3 pharmacy points of service . Community pharmacies, military pharmacies, and mail order accounted for 64%, 23%, and 13%, respectively, of DoD's $6.5 billion total drug expenditures during fiscal year (FY) 2007 .To describe the DoD formulary management process and estimate cost savings associated with implementation of DoD's 3-tier formulary.DoD implemented its 3-tier Uniform Formulary in 2005. This implementation required the development of a transparent formulary management process that (a) assesses medications for formulary status based on an evidence-based clinical evaluation and assessment of relative cost-effectiveness using pharmacoeconomic and budget impact modeling, (b) allows open and equitable price competition among pharmaceutical manufacturers based on formulary status, and (c) provides a public forum for beneficiaries and beneficiary organizations to comment on formulary changes. Through April 16, 2008, Uniform Formulary decisions had been implemented in 32 drug classes representing 53% of FY 2007 total drug expenditures. The 32 classes containing 343 drugs were reviewed at 12 quarterly meetings of the DoD Pharmacy and Therapeutics (P&T) Committee and the Beneficiary Advisory Panel, resulting in the classification of 85 drugs (24.8%) in tier 3, 92 drugs (26.8%) in tier 2, and 166 drugs (48.4%) in tier 1. Implementation of the 3-tier formulary was associated with an estimated $926 million in cost avoidance in FY 2007, primarily due to price reductions at military pharmacies and mail order, tier 3 copayments at community pharmacies and mail order, and change in product mix and pharmacy type (point of service). An additional $60 million in rebates were obtained in FY 2007 through the Voluntary Agreements for TRICARE Retail Pharmacy Refunds (UF VARR) program for prescriptions filled at community pharmacies; the UF VARR program first became available for drug classes reviewed in August 2006. The total of $986 million in cost avoidance and rebates represents an approximate 13% reduction, compared with what DoD otherwise would have paid in FY 2007 .As in most private-sector health plans, the DoD formulary management process (a) includes rigorous decision making that is informed by clinical literature evaluations and pharmacoeconomic analyses, (b) results in drug formulary changes that require considerable effort in communication with providers and beneficiaries, and (c) produces drug cost savings derived from increased price competition among drug manufacturers. Unlike private sector health plans, the DoD uses more disclosure of the results of evaluation of the evidence, solicits provider opinions before P&T committee deliberation, and provides the opportunity for beneficiaries to have input before implementation of formulary changes."}
+{"text": "Life's Simple Seven (LS7) scale to a gender-stratified cohort of ART-Naive PLWH and HIV-uninfected controls in adults.Cardiovascular disease (CVD) represents a major cause of premature mortality in people living with HIV (PLWH). However, morbidity is not equal between males and females. There is a need to better understand how gender influences cardiovascular health (CVH) in PLWH in order to identify targets for intervention. Therefore, we applied the Life's Simple Seven (LS7) definitions (Table 1) and compared the distribution of Ideal LS7 metrics between males and females of both study groups. Each LS7 metric was categorized as ideal (2 points), intermediate (1 point) and poor (0 point) and ordinal regressions were employed to investigate associations between gender and each individual LS7 metric. Regressions were adjusted for HIV status, age, income, education level.A cross-sectional analysis was conducted on a cohort of ART-naive PLWH and HIV-uninfected adults recruited from HIV clinics between June 2016 and August 2019 in Mwanza, Tanzania (HIV&HTN cohort). We applied modified Figure 1, the distribution of Ideal LS7 metrics differed between the males and females in both study groups. Males had a higher prevalence of ideal physical activity  and ideal BMI  but lower prevalence of ideal smoking  and ideal blood pressure . The magnitude of these differences also varied by HIV status such that they were larger in PLWH than HIV-uninfected group for smoking (41.3% vs 26.4%), physical activity (41.6% vs 24.8%) and blood pressure (12.7% vs 9.2%) metrics. By contrast, these differences were less pronounced in PLWH vs HIV-uninfected group for the BMI metric (23.1% vs 29.7%).Our study included 997 participants, with 493 PLWH  and 504 HIV-uninfected . As displayed in Figure 1: Distribution of Ideal Life's Simple 7 metrics, stratified by gender for both PLWH and HIV-uninfected controlsCardiovascular health profiles vary by gender and HIV status, with stark differences between male and female PLWH for most metrics. Gender-specific interventions targeting smoking cessation, blood pressure control in male PLWH and physical activity, weight loss in female PLWH are warranted to mitigate CVD risk.All Authors: No reported disclosures"}
+{"text": "Success of split-thickness skin grafting (STSG) is a cornerstone of modern burn care and sets the stage for success in acute, rehabilitative and reconstructive care. Shupp et al, proposed a graft loss grading system, which the authors then modified to reflect true clinical practice and changes in management. Purpose of the quality improvement (QI) project was to design, implement and assess this grading system.A modified graft loss grading system was developed and implemented. Burn patients requiring STSG were tracked over a five month period, and initial (first takedown) and subsequent  graft loss grades and contributing factors were noted. Assessments were performed an APP and burn surgeon with agreement of an assigned grade. Patient demographic data was recorded.63 patients underwent 66 STSG procedures during the review period . Average age was 33.3 years (range: 1-86). Average % TBSA burn was 10.2% (range 0.2-67%). Obesity was present in 33.3% of patients, cardiac disease  in 21.2%, DM in 21.2% and 24.2% of patients were active smokers. Flame burns represented the etiology in the majority (51.5%) of patients. Overall, 10 patients (16%) on initial assessment and 18 patients (29%) on subsequent assessment had evidence of graft loss. Etiology of graft loss included wound bed viability - the default etiology (10 patients/55%), infection (3 patients/17%) and hematoma/seroma (4 patients/22%). Of the 18 patients, 5 (28%) required re-grafting. Of patients with graft loss, 89% had a comorbidity including DM (28%) and smoking history (28%). Malnutrition was felt to contribute in 3 (17%) of patients.A graft loss grading system is a beneficial quality improvement project to characterize the surgical results of burn patients undergoing STSG. This modified grading system better characterizes graft loss outcomes and subsequent changes in management if applicable. Wound bed viability remains a major factor in graft loss, although the majority of these patients had a contributing comorbidity.Implementation of a graft loss grading system can be a valuable quality improvement tool that can be employed by burn centers to assessment surgical results."}
+{"text": "Medical students encounter multiple psychological changes in the transformation from young insecure students to efficient physicians. They have to balance the personal, social and academic dimentions in a busy schedule. This study aimed to find out the prevalence of depression among medical students of a medical college.A descriptive cross-sectional study was conducted among medical students of a medical college from 2 May 2017 to 16 October 2017 after taking ethical approval from the Departmental Research Unit (Reference number: Psy/73/078/079). Students participated voluntarily in the study from first to fourth year and written informed consent was taken. Depression, Anxiety and Stress Scale-42 scale was filled by the students taking their own time and privacy to assess their depression, anxiety and stress. Convenience sampling was done. Point estimate and 95% Confidence Interval were calculated.Among 302 medical students, 86 (28.47%)  had depression. A total of 31 (36.04%) had mild, 31 (36.04%) had moderate, 12 (13.95%) had severe and 12 (13.95%) had extremely severe depression. Among them 55 (63.95%) were males and 31 (36.04%) were females.The prevalence of depression among medical students was similar to the other studies conducted in similar settings. Studies concerning the subjective well-being of medical students should be continued and strategic plans and programs should be conducted to help the students manage their stress and depressive symptoms right from the time they join the medical school and continued till they finish the course. Koirala Institute of Health Sciences (BPKIHS) from 2 May 2017 to 16 October 2017 after receiving ethical approval from the Departmental Research Unit (DRU), BPKIHS (Reference number: Psy/73/078/079). All MBBS students of BPKIHS from the first to the fourth year who provided informed written were included. The students who did not give informed written consent and those who were absent during the study period were excluded. Data was collected using convenience sampling. The sample size was calculated using the following formula:Where,n = minimum required sample sizeZ = 1.96 at 95% Confidence Interval (CI)4p = prevalence of depression among the medical students, 29.9%q = 1-pe = margin of error, 6%6The minimum required sample size was 224. After adding a 20% non-response rate, the sample size of 280 was calculated. However, 302 students were taken for the study. All MBBS students were informed about the purpose of the study and explained the general instructions. Informed written consent was taken prior to the study. The students were allowed to respond in their own time and privacy. The participation was entirely voluntary. Then they were given the questionnaires containing semi-structured sociodemographic profiles and the Depression, Anxiety and Stress Scale (DASS-42).Data were entered and analysed in IBM SPSS Statistics 11. 5. Point estimate and 95% CI were calculated.Among 302 medical students, depression was seen in 86 (28.47%) . Among them, 31 (36.04%) had mild depression, 31 (36.04%) had moderate depression, 12 (13.95%) had severe depression and the remaining 12 (13.95%) had extremely severe depression .Males were 55 (63.95%) and females were 31 (36.04%) Past history of depression was found in 9 (10.46%) students. A total of 19 (41.30%) and 8 (61.54%) of the medical students whose father's and mother's occupation was doctor were depressed. Similarly, 30 (29.13%) of the depressed students had a family monthly income of less than Rs. 50000. History of substance abuse was in 15 (42.86%) students and a history of mental illness in 9 (69.23%) .2 and Nepal (29.9%),4 but lesser than in India where depression among MBBS students was 51.3%.7 However a study done among undergraduates in Sweden showed the prevalence to be 12.7% which was lower than in our study.8 Also, the categorical prevalence of mild 31 (36.04%), moderate 31 (36.04%) and severe depression 12 (13.95%) among the MBBS students in our study is consistent with the studies conducted elsewhere.10 However, the prevalence of extremely severe depression 12 (13.95%) in our study was higher than in India (1.32%).9 The differences in an academic environment, the availability of entertainment, sports and club activities, the policy regarding mental health and the student's own genetic and socio-demographic variables may be responsible for the variation in the prevalence of depression among the students in different medical colleges.In our study, among undergraduate medical students, 28.47% had depression. The findings were consistent with the studies done in Brazil (32.8%),9 The variation may be due to the gender-based disproportionate enrolment of students in our medical college. Additionally, females reported being involved in more club activities, social gatherings and tours; which might have helped them to cope with stress and maintain sound mental health. However, a different study among Turkish undergraduate students has shown no significant differences between the mean depression scores of male and female students.11In our study, male students 55 (64.00%) had a higher prevalence of depression when compared to female students 31 (36.00%). This finding is in contrast to findings from other similar studies.2 Majority 41 (47.67%) of the students having depressive symptoms had poor socioeconomic conditions. The finding is consistent with other similar studies.12In our study, 19 (22.09%) of the medical students' fathers and 8 (9.30%) of the students' mothers were doctors. The study conducted in Brazil showed students having their parents as doctors had higher rates of depression.13 However; it was lower than the Nigerian medical students (28%).14 The common substances of abuse were alcohol and cigarettes. Likewise, 9 (10.46%) of the students having depressive symptoms reported having a past history of depression whereas, 14 (16.27%) of them reported having a family history of depression. Different studies also support the genetic basis of depression.15'17In our study, 15 (17.46%) of the students had a history of substance abuse. The finding is similar to the research conducted among north Indian medical students (20.43%).Hurryingly filling up questionnaires by students may have resulted in an incomplete grasp of questions leading to a different result from the existing conditions. The diagnosis was only done by self administered DASS-42 and no observation was done by a consultant/psychiatrist leading to inadequate authenticity of the result. All were hostellers and this couldnot reflect the scenario of students living in the home. Only students from single institution were involved and can not be generalised as it does not include all medical students from other colleges of Nepal.The prevalence of depression among MBBS students was similar to the other studies conducted in similar settings. Results indicate a substantial number of students are suffering from depression. Beside from improving medical education to more humanistic and student-centered, policy makers and other concerned stakeholders should plan to identify and help them to cope with the depression begining from the first year of medical school."}
+{"text": "Electrophysiological (EP) testing for the assessment of atrioventricular (AV) conduction behaviour was proposed for risk stratification of patients with left bundle branch block (LBBB) after transcatheter aortic valve replacement (TAVR) . Since sWe retrospectively analyzed consecutive patients undergoing TAVR between August 2014 and June 2021 at the University Hospital of Basel. EP testing was performed pre- and immediately post-valve deployment and in the case of LBBB the following day. A surface 12-lead electrocardiographic (ECG) was available before and the day after the procedure in all patients to allow evaluation according to current guidelines  ms in women and 46[42-53] ms in men (p=0.06). The median HV interval in these was 54[42\u201359] ms in women and 56[51\u201361] ms in men (p=0.038). As such, a HV interval >55 ms or \u226570 ms was present in 31% and 8% of women vs 59% and 15% of men, respectively (p=0.049 and p=0.64). The median increase in HV interval pre- and post-valve deployment in patients with new LBBB was 7[2\u201311] ms in women and 11[3-18] ms in men (p=0.27). Nine patients (7.1%) underwent peri-procedural PM implantation due to third-degree AV block .73 patients (57%) demonstrated LBBB post-valve deployment . The 29 patients  that demonstrated persistent LBBB the day after TAVR were invasively studied a third time. The median HV interval the day following TAVR in patients with LBBB was 45[41\u201349] ms in women and 50[48\u201362] ms in men (p=0.048), respectively and a HV interval >55 ms or \u226570 ms was present the day following TAVR in seven (24%) and three patients (10%). Two women (29%) and five men (71%) had HV intervals >55ms (p=0.75). One woman (33%) and two men (67%) had HV intervals \u226570ms (p=0.99). In these 29 patients with persistent LBBB the day after TAVR, EP testing was indicated according to current ESC guidelines criteria in 25 of 29 patients (86%). None of the four women without indication were found to have abnormal HV intervals.Among the 73 patients with LBBB post-valve deployment, LBBB resolved the day following TAVR in 44 patients (61% women and 39% men, To the best of our knowledge, this is the largest cohort to date to assess sex-specific differences in HV conduction in patients undergoing TAVR in the context of the current pacemaker guidelines . We repoDifferences in electrophysiological characteristics of the AV conduction system between men and women have been described previously, outside of the TAVR population . After TLimitations of our study include the retrospective design, low sample size and measurements of the HV interval the day following TAVR. The current ESC guidelines  recommenIn conclusion, women have shorter HV intervals pre- and post-valve-deployment as well as the day following TAVR compared to men. Further studies evaluating sex-specific cut-offs for the HV interval are warranted."}
+{"text": "Objective: It is challenging and difficult to differentiate primary from metastatic hepatic masses solely on cytology. The present study aimed to correlate cytomorphological spectrum of hepatic masses with immunocytochemical markers to differentiate primary from metastases in liver.Material and Method: The present study comprised of 30 clinico-radiologically suspicious cases of neoplastic hepatic masses. Ultrasound-guided fine needle aspiration smears and cell blocks were prepared as per standard technique; two of the smears were air-dried and Giemsa stained to study cytomorphological features. A panel of markers  were studied both in smears and cell blocks.Results: Cytomorphological features on smears were evaluated and correlated with immunocytochemistry in all cases; the final diagnosis was: Hepatocellular carcinoma (n=7), cholangiocarcinoma (n=2), hepatoblastoma (n=1) and metastatic carcinoma (n=20). HepPar-1, CD10 and CD34 demonstrated 86%, 72%, 86% sensitivity and 100% specificity respectively for hepatocellular carcinoma; CK7&CK19 showed 100% sensitivity for cholangiocarcinoma, MOC 31 showed 90% sensitivity and 100% specificity for metastatic carcinoma.Conclusion: The present study recommends a panel of minimum three markers  which were helpful to differentiate hepatocellular carcinoma from metastatic carcinoma that was a major diagnostic challenge solely on cytomorphology. Correlating cytomorphology with these three markers, 100% of the cases could be diagnosed as primary malignancy and distinguished accurately from metastatic carcinoma. The distinction between primary and metastases in liver on cytomorphology alone has been challenging and a matter of much debate. Though some cytomorphological features help to differentiate hepatocellular carcinoma (HCC) from metastatic carcinoma (MC), the distinction between the two still remains a challenge in case of poorly differentiated tumors. A cytopathologist also faces diagnostic challenges to differentiate benign/reactive hepatocytes from well-differentiated HCC (WDHCC). Hence, a panel of immunocytochemical markers (ICC) is advised for the final diagnosis in challenging cases. Various studies were conducted to assess the role of ICC in hepatic masses, using a single marker or panel of markers when a diagnosis on cytomorphology alone was difficult . Also, sDespite the availability of many markers, no single marker is 100% specific and sensitive for either HCC or MC so far . Hence, This prospective study was conducted in the departments of pathology and gastroenterology surgery after obtaining ethical clearance and written informed consent from the patients. 30 clinico-radiologically suspected cases of neoplastic hepatic mass lesions were aspirated. Patients with abnormal coagulation profile, vascular lesions and infective cysts were excluded. Relevant clinic-radiological and serological findings were recorded. The study was approved by the Institutional Ethics Committee USG/CT-guided FNAC was performed as per standard technique using a 23/24 gauge needle. Multiple areas were aspirated for an adequate and representative sample. Two smears were air-dried and Giemsa stained to study morphological features and the rest was preserved at 0\u00b0C for ICC. The remaining aspirate was processed for the cell block (CB). To prepare CBs, the hemorrhagic aspirate was allowed to clot for 1-3 hrs, fixed in 10% buffered formalin, and processed further as routine Hematoxylin & Eosin (H&E) stained histological sections for cyto-histological correlation. ICC was performed on fresh smears (n=16) and on both smears and CB (n=14). For ICC, the smears were fixed in a mixture of cold acetone and methanol (1:1) for 5 minutes; and for CBs, 3-5\u00b5 thick sections were heated to deparaffinize followed by changes in xylene, graded alcohol and hydration in water. All steps were carried out in a moist and humid chamber throughout the procedure. The primary antibodies (Ab) used were as follows: HepPar-1 , CD10 , MOC31 , CK7  and CK19 , CD34 . The Biogenex Super Sensitive Polymer-HRP Detection System was used in conjunction with rabbit/mouse IgG Primary Abs. DAB (diaminobenzidine) substrate for peroxidase was used as an enzyme label forming a stable brown end product at the site of the antigen (Ag). A fresh citrate buffer was prepared with every set of staining and used for Ag retrieval wherever required. Hematoxylin was used as a counter stain. Positive and negative controls were run with every batch.Two authors independently evaluated every case. Granular cytoplasmic positivity for HepPar-1; canalicular, cytoplasmic and membranous stain for CD10; endothelial cell stain for CD34; membranous/membranous and cytoplasmic stain for MOC31; and cytoplasmic stain pattern for CK7& CK19 were considered significant and positive. Statistical analysis was done using the Chi square test and Fisher\u2019s exact test using SPSS software.Of the 30 patients included in the study, 17 were male (56.6%) and 13 female (43.3%), with a male to female ratio of 1.3:1. The patients ranged in age from <1 to >80 years (mean age-48.03 \u00b11.73 years). The most common radiological finding was a single space-occupying lesion (SOL) in cases of HCC and multiple SOLs in cases of metastases .The cytomorphological features studied encompassed cellularity, pattern of cell arrangement, cytoplasmic and nuclear details and the background. Based on these features and correlating with ICC, the final diagnosis was HCC (n=7), CC (n=2), HB (n=1) and MC (n=20) from various sites .The following cytological features were useful in the diagnosis of HCC: clusters of tumor cells surrounded by capillaries  and clusters with transgressing capillaries , bile pigment in tumor cells, intranuclear inclusions (INI), prominent macronucleoli, and atypical stripped nuclei in the background . Smears The MC group showed atypical cells with attempted acinar/papillary pattern, necrosis, and a mucinous and/inflammatory background. The important feature was the presence of benign hepatocytes as separate clusters ; howeverHepPar-1: HepPar-1 showed distinct granular cytoplasmic positivity in 6/7(86%) HCC cases  cases of HCC showed positivity for CD10  and an average was taken which was further graded as 0-4: 0 (no stain), 1 (< 25% cells stain positive), 2 (25-50% cells stain positive), 3 (50-75% cells stain positive), 4 (>75% cells stain positive). In this study, a positive result was found in 6/7 (86%) cases of HCC; grade-1 in one case (3.37%), grade-2 in 3 cases (10%), grade-3 in 2 cases (6.67%), and no staining in one case (3.37%). None of the CC and MCs showed positive stain. There was no correlation between the grade of tumor and positive ICC.CK7: Total of 4 (16.67%) cases were positive for CK7; 2 were CC that showed strong cytoplasmic reactivity and 2 were MC ovary which also showed strong cytoplasmic immunoreactivity  and 5 (25%) were MC  (itivity) . None ofMOC31: MOC31 was expressed in 18/20 (90%) cases of MC; eight showed cytoplasmic positivity with membranous accentuation (40%), eight showed membranous positivity (40%), and two showed cytoplasmic positivity (10%). CC (n=2), in addition to CK 7 and CK19 positivity, also expressed cytoplasmic positivity for MOC31  to confirm the metastatic origin of certain cancers like SmCC lung and AC with NE differentiation.Distinguishing HCC from CC and MC on FNAC of neoplastic hepatic masses has been a diagnostic challenge and it is paramount to differentiate these lesions as the prognosis and treatment approaches are different for all three conditions. The areas of challenge include differentiation of benign reactive hepatocytes from WD HCC, PDHCC from MCs and, CC from HCC or metastases. This difficulty is compounded by limited and or non-representative aspirate, and a hemorrhagic and or necrotic background. In recent years, various ancillary techniques such as ICC have contributed greatly to distinguish these lesions and to overcome the diagnostic pitfalls . The preHepPar-1 (human hepatocyte Ab) recognizes hepatocyte mitochondrial epitope with granular cytoplasmic staining on ICC. Earlier studies showed high sensitivity of HepPar-1 90%) in detecting HCC ,9,10. Ho0% in detCD10 is a commonly used marker for hematolymphoid neoplasms. The positive stain includes a cytoplasmic, membranous/canalicular pattern. The canalicular pattern has been considered specific for hepatocytic differentiation on tissue sections. Saad et al. used CD10 on FNA smears with satisfactory SN (77%) and SP (100%) . The preCui et al. first reported strong expression of CD 34 in sinusoidal vessels in all cases of advanced HCC with a high sensitivity (100%) in detecting HCC . The preMOC31 has been proven a sensitive and specific marker of AC differentiation and thus is used to distinguish AC from mesothelioma both in tissue sections as well as in body fluids. Proca and Porcell et al. showed high sensitivity and specificity 100%) in detecting MC and distinguishing it from HCC ,7. Luoqu0% in detExpressions of various cytokeratins (CK) has recently gained popularity to distinguish primary sites of liver metastases ,11 becauIn conclusion, based on the present study, it is observed that a panel of three markers  would help to differentiate HCC from metastatic AC in conjunction with cytomorphological correlation. Both FNA smears and CB can be used for ICC with similar intensity; however, FNAC may have limitations because of a non-representative sample and or a hemorrhagic necrotic background.The authors declare no conflict of interest.None"}
+{"text": "Dengue epidemics in Asia was almost exclusively a childhood disease but recently dengue in adults have become increasingly prevalent. Yet intravenous fluid replacement (IVFR), the main supportive therapy for dengue, was developed for pediatric dengue. Evidence-based guidance for fluid replacement, especially for older adults with concomitant chronic diseases that both increases risk of severe dengue and complicate fluid replacement, is lacking. We retrospectively analyzed the use of IVFR in adult dengue patients at admission to a tertiary hospital.Medical records of patients diagnosed with dengue  from January 2020 to December 2022 were analyzed. Recovery phase was defined as fever defervescence for >12 hours with rising platelet count. Appropriateness of IVFR was based on disease severity according to the 2009 WHO dengue classification scheme.Preliminary analysis of the first 30 patients found an almost equal number of males (47%) and females. The median age was 52.5 years (range 15.0-83.0). 20 patients had at least one comorbidity with hyperlipidemia (33%), hypertension (23%) and ischemic heart disease (10%) being the most common. Average time from onset to presentation was 4.3 days (95% CI: 3.8-4.9). 16 (53%) met the WHO classification scheme as requiring IVFR at admission; 4 hypotension, 5 acute kidney injury (AKI), 2 hypotension with AKI, 4 hemoconcentration, 1 AKI with hemoconcentration. Of these 16, one also had altered mental status and another had hemophagocytic lymphohistiocytosis-like presentation. Despite 47% having uncomplicated dengue, all patients had IVFR at admission. Total fluid volume administered during hospitalization varied across the population and fluctuated daily for each patient, with 8 patients receiving IVFR beyond the recovery phase. One developed fluid overload while another had IV cannula-related thrombophlebitis. There was no mortality.Preliminary findings of our on-going study suggest excessive use of IVFR and the lack of standardization possibly contributed to two iatrogenic complications. We call for development of evidence-based protocol on fluid management in older dengue patients.All Authors: No reported disclosures"}
+{"text": "Targeted therapies have revolutionized the treatment for many patients with non-small cell lung cancer (NSCLC). Multiple new oral targeted therapies have been approved in the last decade; however, their overall efficacy may be reduced by poor adherence, treatment interruptions, or dose reductions due to adverse events. Most institutions lack standard monitoring protocols for toxicities from these targeted agents. This review describes important adverse events observed in clinical trials and reported by the U.S. Food and Drug Administration for both currently approved and upcoming promising therapies in the treatment of NSCLC. These agents cause a range of toxicities, including dermatologic, gastroenteric, pulmonary, and cardiac toxicities. This review proposes protocols for routine monitoring of these adverse events, both prior to initiation of therapy and while on treatment. Lung cancer remains the number one cause of cancer-related death worldwide. Non-small cell lung cancer (NSCLC) accounts for most lung cancer diagnoses 84%), and the identification of targetable driver mutations has changed treatment options dramatically over the last decade . More th%, and thThere are currently no established guidelines for monitoring toxicities associated with targeted therapy in NSCLC. A survey among cancer centers showed there were limited protocols for monitoring and managing risks associated with targeted therapy . The impOur recommendations were based predominantly on FDA prescribing information. We also evaluated landmark trials resulting in FDA approval, trials cited as providing evidence for the National Comprehensive Cancer Network (NCCN) recommendations in the treatment of NSCLC, related papers, and case reports via a PubMed search on 22 October 2022 using the relevant drugs and \u201cadverse events\u201d as keywords without restrictions to assess common toxicities. Toxicities that occurred in more than 10% of the patient population or that were of significant clinical concern in the landmark trials were included in our monitoring parameters. We also incorporated periodic monitoring parameters that were stated in the package insert.Originally broadly approved for the treatment of NSCLC in 2004, erlotinib\u2019s indications were later narrowed to first-line, maintenance, or subsequent therapy in patients with EGFR exon 19 deletions or L858R substitutions as a result of the EURTAC and IUNO studies in 2016. The most common toxicities observed in multiple studies included: rash (70\u201385%), diarrhea (48\u201362%), and cough (48%). The most common grade 3\u20134 adverse events included: rash (14%) and dyspnea (8%). Other notable adverse events included: ocular toxicity (12\u201318%), ILD (1.1%), renal impairment (0.4%), hepatic failure (0.4%), and hemorrhage associated with elevated international normalized ratio (INR) in the setting of concomitant warfarin use ,31,32.The results of the RELAY study led to the 2020 FDA approval of ramucirumab in combination with erlotinib for the first-line treatment of metastatic NSCLC for patients with EGFR exon 19 deletions or exon 21 L858R mutations. Similar toxicities to erlotinib monotherapy were observed. Adverse events that were described more frequently with the addition of ramucirumab included: hypertension (42%), proteinuria (35%), epistaxis (16%), peripheral edema (13%), and hepatotoxicity (42\u201343%). Hypertension and diarrhea were the most common grade 3\u20134 adverse events noted with the addition of ramucirumab  ,34.Gefitinib was initially approved in the European market in 2009, where it has seen the majority of its use. It has since been approved by the FDA in 2015 for the first-line treatment of metastatic NSCLC with EGFR 19 deletions or exon 21 L858R mutations. The common adverse events of any grade observed in trials included: rash (44.9\u201366.2%), diarrhea (30.8\u201344.6%), and nausea (10.3\u201316.6%) ,35. OtheAfatinib is a tyrosine kinase inhibitor (TKI) that was first approved in July 2013 as first-line therapy for patients with metastatic NSCLC with EGFR exon 19 deletions or L858R substitutions. In a grouped analysis of the LUX-LUNG 3 and LUX-LUNG 6 trials, dermatologic toxicities, diarrhea, and nail changes were the most common adverse events overall , as well as the most common grade 3\u20134 adverse events  . Other nDacomitinib gained FDA approval for first-line therapy in metastatic NSCLC with EGFR exon 19 deletion or exon 21 L858R substitution in September 2018 based on the results of the ARCHER 1050 trial. The most frequently observed adverse events of any grade were: diarrhea (87%), paronychia (62%), acne (49%), and stomatitis (44%), with acne and diarrhea as the most common grade 3\u20134 toxicities . ILD occurred in 1.3% of patients [Osimertinib was first approved for the use of T790M mutated NSCLC previously treated with first-generation TKIs after clinical trials demonstrated improved progression-free survival (PFS) (10.1 months vs. 4.4 months) and objective response rate (ORR) (71% vs. 31%) compared to platinum therapy plus pemetrexed ,13. The Amivantamab-vmjw is an EGFR/MET bispecific antibody that was the first FDA-approved treatment for EGFR exon 20 insertion mutated NSCLC. This was a result of the phase I CHRYSALIS study in which the most frequent adverse events of any grade included: rash (86%), infusion-related reaction (66%), paronychia (45%), and hypoalbuminemia (27%). The most commonly reported grade 3\u20134 adverse events were: hypokalemia (5%), pulmonary embolism (4%), diarrhea (4%), and neutropenia (4%) .Mobocertinib is an irreversible oral TKI that was granted accelerated approval for use in previously treated metastatic NSCLC with EGFR exon 20 insertion mutations in 2021. Common clinical adverse events of any grade reported in trials included: diarrhea (82\u201393%), nausea (30\u201339%), and rash 33\u201345%). Other notable toxicities include changes in ALT, AST, or electrolytes in more than 20% of patients. Grade 3\u20134 adverse events included: lymphopenia (15%) and elevated amylase or lipase (10%) ,44. Mobo%. Other Adagrasib is an irreversible inhibitor of KRAS that has been granted accelerated approval by the FDA in previously treated KRAS G12C mutated NSCLC. In the KRYSTAL-1 study, adverse events of any grade included diarrhea (70.7%), vomiting (56.9%), serum creatinine increase (34.5%), ALT increase (28.4%), AST increase (26.7%), and hyponatremia (23.3%). Grade 3\u20134 adverse events included anemia (14.7%), dyspnea (10.3%), pneumonia (12.1%), and QTc prolongation (6.0%) .Sotorasib, an inhibitor of the RAS GTPase family, was the first FDA-approved therapy for KRAS G12C mutated NSCLC . In CodeCrizotinib was the first drug in its class approved for the treatment of patients with metastatic NSCLC with ALK gene rearrangements. Initially approved for ALK gene mutations, crizotinib\u2019s FDA indication has expanded to ROS1 and MET exon 14 skipping mutations. The initial approval for crizotinib was based on a PROFILE 1014 study in which the most common adverse events of any grade included: vision disorders (71%), diarrhea (61%), edema (49%), and vomiting (46%). Notable grade 3\u20134 toxicities included: hepatotoxicity (14%), neutropenia (11%), fatigue (3%), and dyspnea (3%) ,47,48.Alectinib is a potent, highly selective second-generation ALK inhibitor that was FDA-approved on 6 November 2017 for the treatment of metastatic NSCLC in patients with an ALK mutation. This approval was given based on the results of the ALEX trial, in which the most common adverse events of any grade included: anemia (20%), peripheral edema (17%), and myalgia (16) . NotableBrigatinib is a selective oral TKI that was FDA-approved on 22 May 2020, based on the results of the ALTA-1L trial, in which the most common side effects of any grade included diarrhea (58%), cough (36%), nausea (33%), and hypertension (32%). Notable grade 3\u20134 toxicities included: elevated CPK (2.8%), lipase (3.7%), amylase (5.5%), ALT (4%), AST (4%), and anemia (3%) ,51. The In 2017, ceritinib was FDA-approved for patients with previously untreated metastatic NSCLC with an ALK rearrangement. This was a change from the original indication of patients whose disease had progressed or who were intolerant to crizotinib. This approval was based on the ASCEND-4 trial in which the most common toxicities included: diarrhea, nausea, abdominal pain, vomiting, and fatigue. Notable grade 3\u20134 toxicities included: ALT elevation (31%), AST elevation (17%), and diarrhea (5%) ,22. SimiEnsartinib is a potent next-generation ALK inhibitor and has demonstrated 10 times greater potency than crizotinib ,54. A phLorlatinib is a third-generation ALK inhibitor with a chemical structure different from other ALK TKIs, designed to cover almost all single resistance mutations emerging after first- or second-generation ALK inhibitors . LorlatiThese drugs are currently approved for the treatment of ROS1 rearrangements ,55. AdveThe combination of dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor) was approved by the FDA in 2017 based on the results of an open-label, phase II trial demonstrating an overall response rate (ORR) of 63%. The most frequently reported adverse events of any grade included: pyrexia (64%), nausea (54%), fatigue (36%), and peripheral edema (36%). Notable grade 3\u20134 adverse reactions included: pyrexia (11%), ALT increase (11%), hypertension (11%), and a decrease in LVEF (8%) .Entrectinib was FDA-approved on 15 August 2019, based on the results of three multicenter trials for patients with solid tumors and NTRK mutations . An addiLarotrectinib is a first-in-class highly selective oral TKI that was FDA-approved on 26 November 2018 for adult and pediatric patients with solid tumors with NTRK gene fusions . A recenThe results of the GEOMETRY mono-1 trial led to the FDA approval of capmatinib, a MET inhibitor, for the treatment of metastatic NSCLCs with a MET exon 14 skipping mutation. The most reported treatment-related adverse events of any grade included: peripheral edema (51%), nausea (45%), vomiting (28%), and a rise in serum creatinine (24%). More than 20% of patients experienced an increase in amylase or lipase of any grade, and 4.5% of patients experienced ILD/pneumonitis. Grade 3\u20134 toxicities included: peripheral edema (9%), fatigue (8%), dyspnea (7%), and increased ALT (8%) ,63.While crizotinib is FDA-approved for the treatment of ALK-positive and ROS1-rearranged NSCLC as described above, there is a growing body of evidence that supports its use in MET exon 14 skipping mutations ,64. AdveTepotinib is a selective MET inhibitor that gained FDA approval for use in advanced or metastatic NSCLC harboring MET exon 14 skipping mutation due to the results of the VISION trial. The most common treatment-related adverse events of all grades included: peripheral edema 65%), nausea (26%), and diarrhea (22%) . Notable%, nauseaPralsetinib was FDA-approved on 4 September 2020 for patients with metastatic NSCLC and RET fusion-positive NSCLC based on the results of the ARROW trial . Common Selpercatinib is an oral TKI with potent and selective activity against RET. It was FDA-approved on 21 September 2022, based on the results of the LIBRETTO-001 trial . Common Based on the results of the DESTINY-Lung01 trial, fam-trastuzumab deruxtecan was FDA-approved on 11 August 2022 for patients with metastatic NSCLC with an ERBB2 (HER 2) mutation . Common The ongoing identification of driver mutations in NSCLC has led to the development of a multitude of targeted therapies which bring new opportunities for treatment but can also cause a considerable degree of morbidity, dose interruptions, and treatment delays. Although the FDA includes recommendations for the monitoring of adverse events in the package insert, the degree to which these are followed is unclear. Through the assessment of clinical trial data, case reports, and other adverse events data provided by the FDA, we have developed much-needed protocols for laboratory assessment and clinical monitoring for the targeted therapies currently used in the treatment of NSCLC.The ASCO/ONS guidelines highlight the importance of adherence and monitoring of patients on targeted therapy. It is essential to counsel a patient about the importance of adherence and signs or symptoms of toxicity upon initiation of therapy. Studies have shown that roughly half of the patients are fully adherent to prescribed oral chemotherapy regimens ,71. One An important aspect of the implementation of these proposed monitoring protocols is the consideration of how to best translate the adverse events described in clinical trials into regular clinical practice. The patients studied in trials are meticulously observed in a manner that may not be feasible or realistic in actual practice. Similarly, patients must meet stringent criteria to allow participation in clinical trials. Investigational trials of new drugs across specialties may exclude 26.3\u201352.9% of the adult population of interest depending on age and other comorbidities; oncology trials specifically may have a median exclusion proportion of 26.4% . The ratAnother challenge stems from uncertainty about how these new therapies will affect an individual patient and the degree to which toxicity should be expected. Although providers may be inclined to encourage patients to make their own choices regarding different treatment options, based on the patient\u2019s tolerance for different side effects, many patients would prefer to eschew this responsibility and receive a clear recommendation from their provider . ProvidiOur hope is that the standardization of toxicity monitoring will help to minimize and address the above challenges and improve patient outcomes. Implementing and standardizing such a protocol requires a multidisciplinary approach involving collaboration between pharmacists, nurses, and physicians. Pharmacists can provide medication education, monitor for potential drug interactions, and make recommendations to physicians regarding dose adjustments or changes to the treatment plan. Nurses can assist in monitoring for potential side effects and providing ongoing support to patients, while physicians are responsible for prescribing appropriate oral drugs and monitoring patient progress throughout treatment. Similarly, local community and academic centers should work together to align monitoring protocols to help standardize patient care. More data are needed to determine the full extent of adverse events observed in patients longitudinally as well as which patients are more susceptible to certain toxicities in the presence of prior comorbidities."}
+{"text": "Nevrorthidae is the group of dragon lacewings, an ingroup of lacewings (Neuroptera). Nevrorthidae has often been considered a relic group. Today, dragon lacewings are known in a few regions with rather large distances between them, with some species occurring in southern Europe, Japan, Australia, and one in China. Fossils in amber from the Baltic region (c. 35\u201340 million years old) and Myanmar (c. 100 million years old) support the idea that this distribution is only a remnant of an originally larger distribution. Larvae of the group are slender and elongated and live mostly in water. Yet, larvae are in fact very rare. So far, only slightly more than 30 larval specimens have been depicted in the literature, including all extant and fossil larvae. Here, we report numerous additional specimens, including extant larvae, but also larvae in Baltic and Myanmar amber. Together with the already known ones, this sums up to over 100 dragon lacewing larvae. We used quantitative methods to study the morphology of these larvae and compared these results over time to identify changes in the diversity. Although there are now more specimens in the data set, it is still unbalanced; for example, newly hatched larvae  are only known from Baltic amber. We expected little change in the morphology of the larvae over geological time, as indicated by earlier studies. However, on the contrary, there are morphologies present in fossil larvae that are now extinct. This result is similar to that for other groups of lacewings which have a relic distribution today, as also in larvae of these groups, there is a lower diversity today than in the past.Nevrorthidae, the group of dragon lacewings, has often been considered a relic group. Today, dragon lacewings show a scattered distribution, with some species occurring in southern Europe, Japan, Australia, and one in China. The idea that this distribution is only a remnant of an originally larger distribution is further supported by fossils of the group preserved in ambers from the Baltic region  and Myanmar . Larvae of the group are slender and elongated and live mostly in water. Yet, larvae are in fact very rare. So far, only slightly more than 30 larval specimens, counting all extant and fossil larvae, have been depicted in the literature. Here, we report numerous additional specimens, including extant larvae, but also fossil ones from Baltic and Kachin amber. Together with the already known ones, this sums up to over 100 specimens. We analysed quantitative aspects of the morphology of these larvae and compared them over time to identify changes in the diversity. Despite the enriched sample size, the data set is still unbalanced, with, for example, newly hatched larvae  only known from the Eocene. We expected little change in larval morphology over geological time, as indicated by earlier studies. However, on the contrary, we recognised morphologies present in fossils that are now extinct. This result is similar to those for other groups of lacewings which have a relic distribution today, as these have also suffered a loss in diversity in larval forms. The group Insecta experiences a general decline in diversity and abundance ,3,4,5,6.The diversity of Insecta basically is that of its ingroup Holometabola, or better of several of the lineages within the latter. For looking at historical losses, the holometabolan group Neuroptera, the group of lacewings, is especially interesting as it is generally understood as having been part of the early diversification of Holometabola, but having declined after the Mesozoic.As recently demonstrated, this loss is in fact challenging to show quantitatively . Yet, apFossils of larvae of lacewings can luckily be well recognised as such ,24,25,26One neuropteran ingroup seemingly rather unaffected, at least in certain aspects, is Nevrorthidae, the group of dragon lacewings. The exact relationships within Neuroptera are still a matter of debate, but dragon lacewings seem to represent an early offshoot, either as sister group to all other lacewings or as part of the second branch within the group Osmyloidea ,40,41,42The morphology of dragon lacewings, including that of the larvae, seemed more or less unchanged since the Cretaceous . This rWe here report many new fossil lacewing larvae and provide a quantitative morphological comparison of this much-expanded data set. Our findings partly contradict common expectations.https://www.mdfrc.org.au/bugguide/, accessed on 2 July 2018) and fossil dragon lacewing larvae [The data set for the comparison presented here is based on literature data and newly studied fossil and extant specimens of dragon lacewing larvae. Literature data are based on an earlier overview  summarisg larvae ,72,73,74www.amberinclusions.eu, accessed on 5 September 2023), and on ebay.com (accessed on 5 September 2023) from three traders: burmite-miner, macro-cretaceous, and rmvveta . Extant specimens, seven in total, are part of the Australian Museum Entomology Collection, Sydney.New directly studied material came from various sources. Fossil specimens are all preserved in amber, with a total of 69 specimens in 23 pieces, of which 55 specimens (in nine pieces) are preserved in Eocene Baltic amber (about 40\u201335 million years old) and 14 specimens (in 14 pieces) are preserved in Cretaceous Kachin amber, Myanmar . All fossil specimens were documented on a Keyence VHX-6000 digital microscope . The built-in software automatically fused a stack of images of shifting focus into a single sharp image. Every image was recorded with several exposure times (HDR function ). Each rIf possible, specimens were photographed from both sides. Illumination was cross-polarised co-axial light or unpolarised low-angle ring light with a black or white background. The images with the best contrast were then optimised with Adobe Photoshop 2023 . All visible structures of the larvae were colour-marked and labelled. Corresponding structures were given the same colours.The extant specimens were documented with a Canon EOS 650  equipped with an MP-E 65 mm super-macro lens. Illumination was provided by a Yongnuo Twin Flash . Polarisers in front of the flash and the lens provided cross-polarised light. Specimens were photographed in their original storage liquid. Each image details were recorded with several frames and fused with CombineZM. Adjacent image details were merged manually in Adobe Photoshop CS2 . Images were further optimised  in Adobe Photoshop CS2.Outlines of prominent structures were drawn digitally in Adobe Illustrator CS2 and Inkscape. These include stylets, head, and trunk (no other appendages). The stylet was artificially rotated straight . Also, the trunk was artificially straightened. Only half of the outline was used.Outlines (shapes) were analysed in the program package Shape ,79. HarmIn total, 10 different combinations of shapes were analysed: (1) the head capsule and stylet, (2) the stylet, (3) the head capsule, (4) the head capsule, stylet, and trunk, (5) the head capsule and trunk, (6) the head capsule, stylet, and prothorax (including the neck), (7) the head capsule and the prothorax, (8) the prothorax, (9) the trunk, and (10) the trunk without the prothorax.Haug et al.  attempte(1)Janzen  depicted(2)Nevrorthus (\u201cNeurorthus\u201d) apatelius , only the anterior body region is accessible, in dorso-lateral view , only the anterior body region is accessible, in dorsal view Kobbert  depicted(4)Nevrorthus fallax. Images include an overview in lateral view Kobbert  re-figur(6)Beutel et al.  re-figur(7)Girafficervix baii; fig. 1c, p. 3) from the Jurassic of China. The first specimen (6640) is the better preserved one Websites are usually not considered a \u201cgood\u201d source for scientific research. Yet, given the scarceness of appearances of larval representatives of Nevrorthidae in the literature, we decided to also include data from three websites hosted by organisations that are likely to guarantee a long-time availability. All specimens are from the extant fauna and were retrieved on 3 June 2021.https://friendsofrietvlei.co.za, accessed on 5 September 2023. The website is hosted by Friends of Rietvlei, a registered non-profit organisation. The second specimen (6643) is also seen in dorsal view , the head is available in ventral view  is seen in dorsal view I on the sal view J on the ral view K on the (9)Specimen 6645 (accession number nsw_epa_HUNT_04Williams_r_161299) is well accessible A; it lik(10)Specimen 6646  is well accessible B; it lik(11)Specimen 6647 (accession number nsw_epa_MANN16_batar_ck_220499) is well accessible C; it lik(12)Specimen 6648  is well accessible D; it lik(13)Specimen 6649  is well accessible A; it lik(14)Specimen 6650  is well accessible B; it lik(15)Specimen 6651 (accession number nsw_epa_BEGA23_Paddys_crk_171199) is well accessible C; it lik(16)Specimen 6652 (PED 0871 spec 1) is preserved together with numerous specimens in a single piece of Baltic amber . The spe(17)Specimen 6653 (PED 0871 spec 2) is accessible from the ventral side and less well from the dorsal side A\u2013D. It i(18)Specimen 6654 (PED 0871 spec 3) is only accessible in dorsal view G,H. Othe(19)Specimen 6655 (PED 0871 spec 4) is only accessible from the lateral left side I,J, othe(20)Specimen 6656 (PED 0871 spec 5) is accessible in left and right lateral view of the body D\u2013F. The (21)Specimen 6657 (PED 0871 spec 6) is accessible in dorsal and ventral view B, upper.(22)Specimen 6658 (PED 0871 spec 7) is accessible in dorsal and ventral view B, lower.(23)Specimen 6659 (PED 0871 spec 8) is only accessible from left lateral side of the body A,B. It i(24)Specimen 6660 (PED 0871 spec 9) is only accessible from ventral view of the body C,D. It i(25)Specimen 6661 (PED 0871 spec 10) is only accessible from the right lateral side of the body E,F. It i(26)Specimen 6662 (PED 0871 spec 11) is only accessible from the left lateral side of the body G. It is (27)Specimen 6663 (PED 0871 spec 12) is only accessible from the lateral right side of the body A,B. It i(28)Specimen 6664 (PED 0871 spec 13) is only accessible from the lateral right side of the body C,D. It i(29)Specimen 6668 (PED 0871 spec 17) is only accessible from the lateral right side of the body E,F. It i(30)Specimen 6669 (PED 0871 spec 18) is only accessible from the lateral right side of the body A. It is (31)Specimen 6670 (PED 0871 spec 19) is only accessible from the lateral left side of the body B,C. It i(32)Specimen 6671 (PED 0871 spec 20) is only accessible from the lateral right side of the body D,E. It i(33)Specimen 6672 (PED 0871 spec 21) is only accessible from the lateral left side of the body F,G. It i(34)Specimen 6673 (PED 0871 spec 22) is only accessible from the lateral right side of the body A,B. It i(35)Specimen 6674 (PED 0871 spec 23) is only accessible from the lateral right side of the body C,D. It i(36)Specimen 6676 (PED 0871 spec 25) is only accessible from the lateral right side of the body E,F. It i(37)Specimen 6677 (PED 0871 spec 26) is only partly accessible from the lateral left side of the body E,F. It i(38)Specimen 6678 (PED 0871 spec 27) is only partly accessible from the lateral left side of the body C,D. It i(39)Specimen 6679 (PED 0871 spec 28) is only accessible from the dorsal side of the body I and sit(40)Specimen 6680 (PED 0871 spec 29) is only accessible from the lateral right side of the body A,B. It i(41)Specimen 6681 (PED 0871 spec 30) is only accessible from the lateral left side of the body G,H. It i(42)Specimen 6682 (PED 0871 spec 31) is only partly accessible from the lateral left side of the body ((43)Specimen 6665 (PED 0871 spec 14) is accessible from the lateral left and right side A,B and s(44)Specimen 6666 (PED 0871 spec 15) is accessible from the lateral left and right side E,F and s(45)Specimen 6667 (PED 0871 spec 16) is only accessible from the dorsal side C and sit(46)Specimen 6675 (PED 0871 spec 24) is only accessible from the lateral left side D and sit(47)Specimen 6683 (PED 1373 spec 1) is only accessible from the lateral right side of the body A,B. The (48)Specimen 6684 (PED 1373 spec 2) is only accessible from the lateral left side of the body E and sit(49)Specimen 6685 (PED 1373 spec 3) is only accessible from the lateral right side of the body F and sit(50)Specimen 6686 (PED 1373 spec 4) is only accessible from the lateral right side of the body D and sit(51)Specimen 6687 (PED 1373 spec 5) is only accessible from the ventral side of the body G,H. It i(52)Specimen 6688 (NHMD 115214 spec 1) is accessible from the dorsal and ventral side of the body A\u2013C. The (53)Specimen 6689 (NHMD 115214 spec 2) is accessible from the dorsal and ventral side of the body F\u2013H. It i(54)Specimen 6690 (NHMD 115214 spec 3) is accessible from the lateral right and ventral side of the body D,E. It i(55)Specimen 6691 (NHMD 115214 spec 4) is only accessible from the ventral side of the body I,J. It i(56)Specimen 6692 (NHMD 115214 spec 5) is only accessible from the ventral side of the body K,L. It i(57)Specimen 6693 (NHMD 115214 spec 6) is only accessible from the ventral side of the body N. It is (58)Specimen 6694 (NHMD 115214 spec 7) is only accessible from the ventral side of the body M and sit(59)Specimen 6695 (CCHH 1124-4b spec 1) is only accessible from the lateral right side of the body A,B. The (60)Specimen 6696 (CCHH 1124-4b spec 2) is only accessible from the lateral left side of the body C,D. It i(61)Specimen 6697 (CCHH 1124-4b spec 3) is only accessible from the dorsal side of the body E,F. It i(62)Specimen 6698 (CCHH 1124-4b spec 4) is only accessible from the dorsal side of the body G and sit(63)Specimen 6699 (CCHH 1124-4b spec 5) is only accessible from the lateral right side of the body H and sit(64)Specimen 6700 (CCHH 1124-4b spec 6) is only accessible from the lateral right side of the body I and sit(65)Specimen 6701 (CCHH 1270-4 spec 1) is only accessible from the lateral left side of the body A\u2013C. The (66)Specimen 6702 (CCHH 1270-4 spec 2) is well accessible from the lateral left and right side A\u2013C and l(67)Specimen 6703 (CCHH 1387-1) is well accessible from the ventral, dorsal, and lateral right side A\u2013D. The (68)Specimen 6704 (SMF Be 2192) is only accessible from the lateral left side of the body G and sit(69)Specimen 6705 (PED 0792) is accessible from the lateral right and left side A\u2013D and s(70)Specimen 6706 (PED 1379) is well accessible from the ventral and dorsal side A\u2013C. The (71)Specimen 6707 (BUB 3703) is only accessible from the dorsal side of the body A\u2013C. The (72)Specimen 6708 (PED 0259) is only accessible from the dorsal side of the body A,B. The (73)Specimen 6709 (PED 0327) is only accessible from the dorsal side of the body C,D. The (74)Specimen 6710 (PED 0632) is accessible from the ventral and dorsal side A\u2013C. The (75)Specimen 6711 (PED 0663) is only accessible from the ventral side of the body D,E and s(76)Specimen 6712 (PED 1338) is only accessible from the dorsal side of the body A\u2013C and s(77)Specimen 6713 (PED 2001) is only accessible from the dorsal side of the body E,F and s(78)Specimen 6714 (PED 2447) is accessible from the dorsal and ventral sides of the body A\u2013D. The (79)Specimen 6715 (PED 2622) is accessible from the dorsal side of the body A,B and l(80)Specimen 6716 (PED 2662) is accessible from the ventral and dorsal sides D,E. The (81)Specimen 6717 (PED 2669) is accessible from the lateral right side of the body H and the(82)Specimen 6718 (PED 2744) is only accessible from the dorsal side of the body A\u2013C. The (83)Specimen 6719 (PED 2786) is well accessible from the dorsal side of the body A,B and l(84)Specimen 6720 (Weiterschan BuB 24) is only accessible from lateral right side of the body A\u2013C. The Head and stylet: The analysis resulted in four effective PCs. Principal component 1 (PC1) explains 68.0% of the overall shape variation  explains 19.1% of the overall shape variation . It is dPrincipal component 3 (PC3) explains 4.1% of the overall shape variation . It is dPrincipal component 4 (PC4) explains 3.2% of the overall shape variation . It is dStylet: The analysis resulted in four effective PCs. Principal component 1 (PC1) explains 73.6% of the overall shape variation  explains 10.4% of the overall shape variation . It is dPrincipal component 3 (PC3) explains 7.1% of the overall shape variation . It is dPrincipal component 4 (PC4) explains 3.5% of the overall shape variation . It is dHead:  The analysis resulted in seven effective PCs. Principal component 1 (PC1) explains 39.7% of the overall shape variation  explains 21.9% of the overall shape variation . It is dPrincipal component 3 (PC3) explains 11.0% of the overall shape variation . It is dPrincipal component 4 (PC4) explains 10% of the overall shape variation . It is dPrincipal component 5 (PC5) explains 6.0% of the overall shape variation . It is dPrincipal component 6 (PC6) explains 2.7% of the overall shape variation . It is dPrincipal component 7 (PC7) explains 2.0% of the overall shape variation . It is dBody with stylet: The analysis resulted in seven effective PCs. Principal component 1 (PC1) explains 57.2% of the overall shape variation  explains 17.0% of the overall shape variation . It is dPrincipal component 3 (PC3) explains 6.5% of the overall shape variation . It is dPrincipal component 4 (PC4) explains 5.8% of the overall shape variation . It is dPrincipal component 5 (PC5) explains 3.4% of the overall shape variation . It is dPrincipal component 6 (PC6) explains 2.4% of the overall shape variation . It is dPrincipal component 7 (PC7) explains 1.9% of the overall shape variation . It is dBody without stylet: The analysis resulted in seven effective PCs. Principal component 1 (PC1) explains 35.6% of the overall shape variation  explains 24.1% of the overall shape variation . It is dPrincipal component 3 (PC3) explains 13.3% of the overall shape variation . It is dPrincipal component 4 (PC4) explains 9.6% of the overall shape variation . It is dPrincipal component 5 (PC5) explains 3.4% of the overall shape variation . It is dPrincipal component 6 (PC6) explains 3.1% of the overall shape variation . It is dPrincipal component 7 (PC7) explains 2.1% of the overall shape variation . It is dHead, prothorax, and stylet: The analysis resulted in six effective PCs. Principal component 1 (PC1) explains 55.4% of the overall shape variation  explains 18.6% of the overall shape variation . It is dPrincipal component 3 (PC3) explains 6.8% of the overall shape variation . It is dPrincipal component 4 (PC4) explains 5.2% of the overall shape variation . It is dPrincipal component 5 (PC5) explains 3.0% of the overall shape variation . It is dPrincipal component 6 (PC6) explains 2.0% of the overall shape variation . It is dHead and prothorax: The analysis resulted in eight effective PCs. Principal component 1 (PC1) explains 35.7% of the overall shape variation  explains 17.2% of the overall shape variation . It is dPrincipal component 3 (PC3) explains 13.1% of the overall shape variation . It is dPrincipal component 4 (PC4) explains 8.6% of the overall shape variation . It is dPrincipal component 5 (PC5) explains 7.0% of the overall shape variation . It is dPrincipal component 6 (PC6) explains 5.0% of the overall shape variation . It is dPrincipal component 7 (PC7) explains 3.0% of the overall shape variation . It is dPrincipal component 8 (PC8) explains 2.2% of the overall shape variation . It is dProthorax: The analysis resulted in seven effective PCs. Principal component 1 (PC1) explains 37.8% of the overall shape variation  explains 22.2% of the overall shape variation . It is dPrincipal component 3 (PC3) explains 16.1% of the overall shape variation . It is dPrincipal component 4 (PC4) explains 5.3% of the overall shape variation . It is dPrincipal component 5 (PC5) explains 4.9% of the overall shape variation . It is dPrincipal component 6 (PC6) explains 3.1% of the overall shape variation . It is dPrincipal component 7 (PC7) explains 2.4% of the overall shape variation . It is dTrunk (with prothorax): The analysis resulted in seven effective PCs. Principal component 1 (PC1) explains 35.1% of the overall shape variation  explains 30.5% of the overall shape variation . It is dPrincipal component 3 (PC3) explains 10.6% of the overall shape variation . It is dPrincipal component 4 (PC4) explains 9.2% of the overall shape variation . It is dPrincipal component 5 (PC5) explains 3.2% of the overall shape variation . It is dPrincipal component 6 (PC6) explains 2.3% of the overall shape variation . It is dPrincipal component 7 (PC7) explains 2.0% of the overall shape variation . It is dTrunk without prothorax: The analysis resulted in seven effective PCs. Principal component 1 (PC1) explains 36.2% of the overall shape variation  explains 31.7% of the overall shape variation . It is dPrincipal component 3 (PC3) explains 12.2% of the overall shape variation . It is dPrincipal component 4 (PC4) explains 4.4% of the overall shape variation . It is dPrincipal component 5 (PC5) explains 3.4% of the overall shape variation . It is dPrincipal component 6 (PC6) explains 2.8% of the overall shape variation . It is dPrincipal component 7 (PC7) explains 1.8% of the overall shape variation . It is dThe detailed files resulting from the shape analyses can be found in File S21.The head of one specimen preserved in NHMD 115214 has been figured before . The pieAnkyloleon [Ankyloleon. Hence, an interpretation of the larvae as dragon lacewings is the most parsimonious one.For all new specimens reported here, the interpretation of them as dragon lacewing larvae is relatively clear. The arrangement of the mouthparts immediately indicates that the specimens are larvae of lacewings: no separate maxillae are apparent as they are functionally coupled to the mandibles and lack palps; of the labium only the palps are apparent; all mouthparts are strongly forward oriented (prognathous). The shape of the stylets is very indicative, as stylets that are proximally straight and distally curving are very uncommon. Besides in Nevrorthidae, this morphology is only known in representatives of the extinct group kyloleon ,89, and As pointed out, it has been assumed that dragon lacewings remained more or less unchanged over geological times. Yet, already, the recently reported larvae from the Jurassic  represenThe quantitative analysis performed here further supports this view. In all analysed structures, the area occupied by modern forms is comparably small. Numerous fossils plotting outside this area indicate that they differ from the modern forms. This difference is least expressed in the shape of the stylets B. TherefThe single Jurassic specimen that could be included in the analysis plots in most cases outside of the area occupied by modern forms . The exEarlier studies have already shown losses in diversity for long-nosed antlions, i.e., the larvae of silky lacewings  and larNevrorthidae, so far, did not show a clear pattern of loss. Expanding the data set here has changed this situation ; also, First, it is important to reiterate that not all extant reports of dragon lacewing larvae suggest an aquatic lifestyle. Riek ( p. 487) More tricky to interpret are the recently reported Jurassic larvae . These aThe comparison to larvae of predaceous diving beetles may indeed provide a good comparison for the Jurassic fossils . The large predaceous diving beetle larvae, better known as water tigers, are top predators consuming everything in their range, including fishes, tadpoles, or even adult amphibians . We can The study of Haug et al.  significYet, already the still incomplete data set shows that the anticipated stasis of dragon lacewing larvae is not supported by quantitative data. Instead, dragon lacewings line up with other lineages of lacewings, having declined over time concerning the morphological diversity of their larval stages."}
+{"text": "There is accumulating evidence that SARS-CoV-2 infection, apart from physical complications, can cause a variety of symptoms related to mental health, either during the acute phase of the infection or following the resolution of acute COVID-19 .To investigate the demographic and clinical characteristics of a sample of hospitalized patients with COVID-19.Data were collected from 1 January 2021 to 31 May 2022. In particular, clinical and demographic characteristics of patients hospitalized with COVID-19 at the \u201cAttikon\u201d University General Hospital and who were referred for assessment to the Consultation Liaison Psychiatry unit were collected and analyzed.During the study period, 107 patients, 66 men (62%) and 41 women (38%) with a mean age of 63 years, with COVID-19 were referred to the Consultation Liaison Psychiatry unit for evaluation. Among them, 58 (54.6%) had a previous psychiatric history, while 49 (45.4%) were assessed for the first time by a mental health professional. The most frequent psychiatric manifestations included anxiety manifestations [38 patients (36%)], delirium [37 patients (35%)] and depressive manifestations [15 patients (14%)].The description of demographic and clinical characteristics of hospitalized COVID-19 patients with concurrent psychiatric manifestations highlights the importance of early clinical detection of psychiatric comorbidity by physicians with a view to ensuring that patients\u2019 needs are supported in an integrated, holistic and patient-centric manner.None Declared"}
+{"text": "Congenital cytomegalovirus (cCMV) is diagnosed by detection of CMV in saliva, urine, blood, or newborn dried blood spot (DBS) collected within the first 21 days of life (DOL).In this single-center retrospective study, all patients with a request for DBS testing between 2013 and 2021 were reviewed. We describe the clinical characteristics of children that were diagnosed with cCMV retrospectively via DBS at Texas Children\u2019s Hospital.DBS were requested from the Texas State Health Department and sent to the Center for Disease Control for testing by DNA CMV PCR.Figure 1Inclusion and exclusion criteria of study populationDBS testing was done in 170 children with suspected cCMV. The median age of request for DBS testing was 3 months (IQR 2-6). The most common reason for testing was symptoms suggestive of cCMV with positive CMV testing outside 21 DOL . The most common symptom was sensorineural hearing loss (SNHL) , followed by developmental delays .42 of 170 children (25%) had a positive DBS obtained within the first 21 DOL confirming the diagnosis of cCMV. 21/42 (51%) would have been classified as asymptomatic at birth, 11 (26%) as asymptomatic with isolated hearing loss, 4 (9%) as mild disease and 6 (14%) as moderate/severe disease.Out of the 25 children with SNHL, 15 (60%) were congenital, 5 (20%) early onset and 5 were late onset (20%).Of the 21 children diagnosed with cCMV via DBS that appeared asymptomatic at birth, only 3 (14%) remained asymptomatic at their last follow up. The most common symptom documented at follow up was learning delays  followed by SNHL . Brain imaging was obtained on 18 (86%) of them, and 10 (55%) had at least one abnormality identified that has been associated with cCMV.40 children had at least one follow up visit at one year of age . 36 had at least one complication related to cCMV, most commonly, SNHL  and learning delays , cerebral palsy .Table 1All children with suspected cCMV that underwent DBS testingTable 2Characteristics of children diagnosed with cCMV via DBS retrospectivelyTable 3Signs and symptoms suggestive of cCMV present at time of DBS request in children diagnosed with cCMV via DBSCongenital CMV remains an underdiagnosed condition. Our study highlights the value of DBS for the diagnosis of cCMV, especially in asymptomatic newborns. Universal newborn screening will identify these infants early and allow for timely interventions, that may mitigate the development of long-term complications.Gail J. Demmler-Harrison, MD, Elsevier: Royalties for authorship/book production/editorship|Merck: Advisor/Consultant|Merck: Grant/Research Support|Microgen: Advisor/Consultant|Microgen: Grant/Research Support|Moderna: Advisor/Consultant|UpToDate Wolters Kluwer Health: Royalties for authorship Topics|WEBMD Medscape: Advisor/Consultant|WEBMD Medscape: Honoraria"}
+{"text": "Streptococcus (GBS) in Botswana, we report the presence/expansion of sequence types 223 and 109, a low rate of erythromycin resistance, and 3 novel sequence types. These data highlight the importance of local epidemiologic studies of GBS, a significant source of neonatal disease.In pregnant people colonized with group B  Streptococcus (GBS) is a major cause of neonatal sepsis and meningitis and a leading cause of death in infants globally ), CC17 (10 of 41 [24.4%]), and CC452 (7 of 41 [17.1%]). A minority of isolates (3 of 41 [7.3%]) had MLST profiles not previously described. These were deposited in the PubMLST database and assigned STs 2126 (strain AR1534), 2140 (strain AR1537), and 2145 (strain AR1563). Complete isolate-level data appear in Of 53 GBS-positive samples from the original study, we were able to recover and generate high-quality genome sequences from 41 (77.4%). Serotype and MLST/CC data are presented in Figure 1rotyping . We noteAmong the serotype III GBS isolates, 10 of 10 (100%) were members of the hypervirulent CC17 group. Most of these (7 of 10 [70%]) were ST17, but 2 were ST109, a GBS type previously described as a cause of invasive disease among children in Mozambique and Angola . ST109 htetM gene tetracycline resistance allele. Four isolates (4 of 41[9.8%]), all of which were serotype V/ST1, contained an ermTR gene that confers resistance to macrolides, lincosamides, and streptogramin B (MLS). No other MLS resistance determinants were identified, and no mutations in the 23S ribosomal subunit or the rpo genes were found. No changes in predicted quinolone resistance determinants were predicted by the analysis pipeline.Nearly all Botswana GBS isolates (39/41 [95.1%]) harbored a ermTR and tetM [Streptococcus adhesin (HvgA). Non-CC17 strains were predicted to express Srr1, with 2 exceptions: strain AR1528 (II/CC19), which was not predicted to express either Srr1 or Srr2, and strain AR1531 (Ib/CC12), predicted to express Srr2.All strains contained \u22651 gene encoding a member of the alpha-like family of proteins . AlpST-1 was detected in the 4 serotype V/ST1 strains that also encoded and tetM . That coand tetM . ConsistAfrica has the highest estimated burden of invasive neonatal GBS cases, but epidemiologic data on circulating strains are still limited , 20. GBSTaken together, these data carry messages of both hope and caution. All of the rectovaginal colonization isolates from this cohort of pregnant people in Botswana have capsular serotypes that are contained in the hexavalent vaccine candidate currently in clinical trials , 29. In"}
+{"text": "The objective of this study is to evaluate the predicted mandibular fracture pattern among a sample of patients visiting a dental hospital in Chennai, India based onpatient demographics. This retrospective analysis involved 46 patients out of which 39 were male and 7 were female who were referred to the Oral Surgery Clinic, Chennai.The medical records and orthopantograms for these 46 patients who received treatment for fractures of the mandible from June 2019- March 2020 were reviewed. Parameterssuch as age, gender, pattern of distribution, type of mandibular fracture, combination of the fracture and treatment done, were evaluated and assessed by one examiner andreviewed by 2 independent investigators. Data shows that the angle region to be the most common area to be affected (31.67%), accompanied by parasymphyseal region (28.33%),condylar region (13.33%), dento-alveolar region ( 10%), body (8.33%), symphyseal region ( 6.67%) and finally the coronoid region ( 1.67%). Data analysis also revealed that84.78% of all patients with fractures of the mandible were male and 34.78% of all patients were in the age group of 21-30 years. Most fractures presented with a singlefracture site (60.87%), and among combinations of fractures, fractures of parasymphyseal region along with angle region (41.67%) were seen more commonly. Pearson's ChiSquare Test was used to determine the association linking the type of mandibular fracture and treatment modality used and p value was < 0.05, which was consideredstatistically significant. Thus, the patterns of mandibular fractures delineate a significant occurrence of angle fractures among mandibular fractures, commonly seenalong with fractures of parasymphyseal region and occurring with a significant male predilection. The mandible is the largest and most powerful facial bone, yet fractures of the mandible are known to constitute a large portion of maxillofacial trauma . Due to its prominence, special mobility, and location, the mandible is an unprotected target for injury. MandibleOur study was conducted during the period between June 2019 and March 2020. 86000 patient records were examined and analyzed in this study. There were 46 patients withradiographically confirmed mandibular fractures, 39 of whom were male and 7 of whom were female.[1] Age group between 8-70 years[2] Both genders[3] Patients with ortho pantomographs as records for radiographically confirming mandibular fractures[1] Patients with facial lacerations without fracture[2] All maxillofacial injuries excluding mandibular fractures[3] Patients with development disorders, pathology, tumors of the mandible.The data extracted for the purpose of the study were as follows:[1] Age[2] Gender[3] Pattern of Distribution of Mandibular Fracture[4] Type of mandibular fracture[5] Combination of mandibular fracture[6] Type of treatment modality doneThe findings were thereafter recorded and the subjects were divided into 7 age groups- Group 1: 0-10 years, Group 2: 11-20 years, Group 3: 21-30 years, Group 4:31-40 years, Group 5: 41-50 years, Group 6: 51-60 years, Group 7: 61-70 years.Patients who visited the Outpatient Department of the Oral Surgery Clinic at Saveetha Dental College in Chennai between June 2019 and March 2020 provided data for thestudy parameters. The work was approved by Saveetha University's Institutional Ethical Committee (SDC/SIHEC/2020/DIASDATA/0619-0320). One examiner completed all of theassessments, and the findings were reviewed and recorded by two independent investigators.IBM SPSS version 23.0 software was used to tabulate and analyze the data. The descriptive statistics of frequency and percentage were used to analyze non-parametricdata. The connection between the type of mandibular fracture and the treatment modality was determined using Pearson's Chi Square Test.This study included a total of 46 fractures of mandible cases with complete medical and radiological records.The patients with the youngest and oldest ages were 8 and 70 years old, respectively. According to the age distribution of study participants, patients aged 21-30years suffered the most mandibular fractures (34.78%) as shown in Figure 1(see PDF).The distribution of study subjects based on gender, over a 10 month period, revealed that 39 patients (84.78%) men and 7 patients (15.22%) women experienced mandibularfractures . Location of Fracture (Site) and anatomy: The distribution of study subjects based on fracture sites showed that out of 46 patients,28 patients (60.87%) had unilateral fractures . Angle fractures were more commonly seen (31.67%), followed by Para-symphysis fractures (28.33%),Condyle fractures (13.33%), Dento-alveolar fractures (10%), Body fractures (8.33%), Symphysis fractures (6.67%) and lastly coronoid fractures (1.67%) .Out of the 46 patients, 12 patients presented with combination fractures, out of which para-symphysis with angle fractures (41.67%) were most commonly seen, followed bycombination of symphysis with condylar fractures (16.67%) Para-symphysis with body fractures, para-symphysis with condylar fractures, para-symphysis with both coronoid andcondylar fractures, symphysis with angle fractures and bilateral para-symphysis with angle fractures all yielded the same result (8.33%) . The relationbetween the type of mandibular fracture and the treatment technique utilized was assessed using Pearson's Chi Square Test, and the p value was less than 0.05, indicatingthat it was statistically significant .78.26% of patients required active treatment, with open reduction and internal fixation (with or without inter-maxillary fixation) being the most common treatmentoptions. In 21.74 percent of cases, conservative therapy was adopted. In 50% of instances, conservative therapy was performed when fractures were localized to a singlecondyle region. Active treatment was necessary in 14 cases with fractures involving more than one site on the mandible (18 instances) (77.77 percent) .Since the mandible is the only facial bone that is mobile, the fracture of the mandible is never overlooked because it causes excruciating pain that worsens withmastication and phonation movements, as well as respiratory movements . It is cData on the pattern of mandibular fractures validate known data, particularly in terms of age and gender. This study found that the age group 21-30 years had thehighest frequency of mandibular trauma (34.78 percent), which is consistent with research by Subhashraj et al. (28%) ,Lin et Multiple fractures are common in mandibular injuries, necessitating surgical intervention. Studies on mandibular injuries are vital to determine the frequency andetiology of these injuries, which represent community trauma patterns, as well as to train health care providers to detect facial trauma and offer the necessary treatment.Thus a significant incidence of angle fractures among mandibular fracture patterns which are seen commonly in combination with fractures of para-symphyseal region,occurring with a significant male predilection is seen."}
+{"text": "Approximately 5\u201310% of all pancreatic adenocarcinomas (PDACs) are caused by highly penetrant pathogenic germline variants (PVs). Specific surveillance programs and eventual targeted oncological therapies can be offered to patients carrying some of the known PVs. We prospectively investigated the prevalence of germline PVs in cancer-predisposing genes in patients referred for genetic evaluation at our institution. In our cohort, 20.1% of the tested subjects harbored at least one PV in the genes of interest. Since the mutational burden in patients affected by PDAC or referred for a suspected related hereditary syndrome is high, the incorporation of genetic testing and the adoption of multiple-gene panels within the multidisciplinary management of this disease would be beneficial and desirable.BRCA2 (37.5%), 6 in CDKN2A (25%), 3 in ATM (12.5%), 2 in BRCA1 (8.3%), 1 in CHEK2 (4.1%), 1 in PALB2 (4.1%), 1 in MITF (4.1%), and 1 in FANCM (4.1%). A double PV (BRCA1 plus BRCA2) was found in 1 subject. We observed a nearly 30% (16/55) mutational rate in the subgroup of subjects tested for the suspected syndromes (PDAC and other synchronous or metachronous tumors or an indicative family history), and the frequency was significantly higher than that in patients with only metastatic PDAC (p = 0.05). In our cohort, 39 variants of unknown significance (VUS) were identified, most of which  in genes belonging to the Lynch syndrome spectrum. Conclusion: A clinically relevant proportion of pancreatic cancer is associated with mutations in known predisposition genes. Guidelines instructing on an adequate selection for accessing genetic testing are eagerly needed. The heterogeneity of mutations identified in this study reinforces the value of using a multiple-gene panel in pancreatic cancer.We investigate the prevalence of germline mutations in cancer predisposition genes in patients with pancreatic ductal adenocarcinoma (PDAC) or suspected related hereditary syndromes. Methods: we enrolled for NGS with an Illumina TrueSight Cancer panel comprising 19 CPGs and 113 consecutive subjects referred to cancer genetic clinics for metastatic PDAC, early onset PDAC, suspected hereditary syndrome, or positive family history. Results: Overall, 23 (20.1%) subjects were carriers of 24 pathogenetic variants (PVs). We found 9 variants in  Pancreatic ductal adenocarcinoma (PDAC) is globally one of the most life-threatening malignant neoplasms, with a 5-year survival of around 5% and a 10-year survival of less than 1%, which have been almost unmodified over the past 30 years . PDAC raPDAC research has shown growth in all areas, spanning early diagnosis, surgical techniques, and oncological therapy. An emerging research field is undoubtedly the investigation of possible genetic factors predisposing to PDAC given the estimates of 10% of patients with PDAC having a pathogenic germline alteration .BRCA1 and BRCA2 predispose to the hereditary breast and ovarian cancer syndrome (HBOC), which carries an absolute risk of PDAC of 5\u201310%  [BRCA syndromes, Lynch syndrome (LS), familial atypical multiple-mole melanoma syndrome (FAMM), hereditary pancreatitis, Peutz\u2013Jeghers syndrome, and Li\u2013Fraumeni syndrome, which are caused by mutations in MLH1, MSH2, MSH6, and PMS2, mismatch repair genes (MMR), PRSS1, STK11, and TP53, respectively, confer an increased lifelong risk of PDAC varying from 5 to 15% [PALB2, ATM, BMPR1A, and SMAD4 with FPC [Familial pancreatic cancer (FPC) is suspected whenever two or more first-degree relatives are affected by PDAC . For theulation) . In addi5 to 15% ,13  in LS, or melanoma in FAMM). On the other hand, the genetic testing of affected patients allows for selecting them for poly (adenosine diphosphate-ribose) polymerase inhibitor (PARPi) and/or platinum-based treatment in the case of herapies ,19,20.BRCA 1/2 only in patients with metastatic neoplasia (for accessing second-line chemotherapy), and in subjects with a relevant family history  [The current NCCN guideline  recommenth PDAC) ,22,23. TMethodologically, the use of multigene panels for genetic testing is becoming widespread, since selecting genes exclusively on the basis of clinical and family history may miss several PVs ,17. The We investigate the prevalence of germline pathogenic variants in cancer-predisposing genes in patients with PDAC or suspected related hereditary syndromes.This is a historical single-center  prospective study of consecutive patients. Individuals who had undergone cancer genetic counseling for pancreatic cancer or suspected related hereditary syndromes from 2018 to 2021 were included. Inclusion criteria for genetic testing were: (1) diagnosis of metastatic PDAC, (2) diagnosis of early onset PDAC (before the age of 50), (3) suspected hereditary syndrome , or (4) healthy subjects with positive family history (at least two first-degree relatives affected or three relative affected by PDAC). All patients agreed to and signed the informed consent for genetic testing and its consultation for research purposes. Data were retrieved from the patients\u2019 charts and diagnostic reports and collected into an anonymized database.Blood samples were screened for germline variants by using the TruSight Cancer panel (Illumina) covering 19 cancer predisposition genes , and theGenomic DNA was fragmented and processed with sequencing adaptors and indices via polymerase chain reaction (PCR). Once the sample libraries had been denatured into single-stranded DNA, they were hybridized into specific biotin-labeled probes for the targeted regions. By adding streptavidin beads able to bind to the biotinylated probes, the pool was further enriched. Afterwards, the streptavidin beads bound to biotinylated DNA fragments were pulled down, eluted from the beads, and hybridized for an enrichment reaction followed by PCR amplification. The targeted library was inserted onto the MiSeq platform for cluster generation and successive sequencing.Quality and coverage data analyses were performed using onboard MiSeq Reporter software , which is the mean sequencing coverage for the regions leveled by the Trusight panel of 366.2\u00d7. Across all samples, the fraction of the targeted regions with \u226530\u00d7 coverage was around 94.6%, and 89.1% of all regions targeted by the Trusight panel had \u2265100\u00d7 coverage.https://gnomad.broadinstitute.org/, accessed on 4 July 2022), 1000 Genomes , and the Exome Sequencing Project . Variants were classified according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology criteria [Thereafter, sequencing data were aligned using Burrows\u2013Wheeler Aligner (BWA) software. Genetic variants were detected using GATK software and were exposed to further analysis both if the calculated genotype quality was \u226599 and if the site was identified as a heterozygous or homozygous variant site. Using ANNOVAR, Variant Interpreter (Illumina), and Sophia DDM (Sophia Genetics), the detected variants were subsequently annotated. Polymorphisms at >1% frequency were deleted using the Genome Aggregation Database (criteria  into patNF1) [In the employed panel, high-penetrance genes involve a lifetime risk of cancer >= 40%, while the risk associated with \u201cmoderate\u201d genes is usually <40%, although this notion does not invariably apply to fully penetrant methylated CpG islands (CpGs)  . We firsOver the study period, a total of 113 individuals comprising 82 females (72.6%) and 31 males (27.4%) underwent genetic testing after counseling at our institution. In our cohort, 101/113 (89.4%) were affected by PDAC. Of these, 31 (27.4%) patients were tested because of metastatic PDAC, 15 (13.3%) for juvenile PDAC, and 55 (48.6%) subjects were tested for suspected hereditary syndrome. Within this category, the suspicion of hereditary syndrome depended on the history of synchronous or metachronous tumors (mostly breast cancer) for 26 (23%) subjects, and on family history for 28 (24.8%); 1 patient was affected by PDAC with microsatellite instability. Lastly, in 12 subjects (10.6%) the indication for genetic testing was motivated only by family history, suggestive of hereditary pancreatic cancer. BRCA2 (37.5%), 6 in CDKN2A (25%), 3 in ATM (12.5%), 2 in BRCA1 (8.3%), 1 in CHEK2 (4.1%), 1 in PALB2 (4.1%), 1 in MITF (4.1%) and 1 in FANCM (4.1%). The subject with double PVs (a patient with PDAC and previous double breast cancer) harbored PVs in both BRCA1 and BRCA2.Overall, 23 (20.3%) subjects were carriers of 24 PVs . We also identified 39 VUS in 35 subjects (31%). Lastly, 55 subjects (48.6%) did not harbor any variant in the evaluated genes (both PVs and VUS). MLH1 5/39 12.8%, MSH2 4/39, 10.3%, MSH6 4/39, 10.3% and PMS2 3/39, 7.7%), followed by ATM , BRCA1/ 2 , PALB2 , APC  and CDKN2A, BMPR1A, BRIP1 and CDK4 .The greatest number of identified VUS concerned genes belonging to the LS spectrum , and a significantly higher frequency of PVs in those with PDAC and a consistent family history .Concerning the indications for genetic testing, carriers of PVs were 3 patients with metastatic PDAC , 2 patients with juvenile PDAC , 16 patients tested because of any suspect of a hereditary syndrome  and 2 cases tested only for family history . Statistical analysis revealed a higher frequency of PVs in patients tested because of a suspected hereditary syndrome compared to those tested for metastatic PDAC  and CDKN2A (6.2%). Pathogenic BRCA1/2 mutations confer an increased risk of developing neoplasms, especially of the breasts and ovaries: in our series, three patients with these PVs showed a typical phenotype, highly consistent with the syndrome (including the patient with double mutation). A congruous genotype\u2013phenotype correlation was also observed for patients carrying a PV in CDKN2A.Our data show that the use of nonrestrictive guidelines allow for identifying a relevant proportion of carriers of a PVs associated with a hereditary syndrome; thus, the application of surveillance programs could reduce the overall burden of associated neoplasms . We repoIn our series, the main genes presenting a VUS were those of MMR , highlighting the relevance of data maintenance for updating the encountered variants.We observed a higher rate of PVs in the tested categories of patients because of suspected hereditary syndromes as compared to patients tested merely because of metastatic PDAC, which is maximized by a positive family history . This result underlines that the proper selection of the patients for genetic testing can improve the performance of the test while containing costs.As screening for PDAC is unfeasible due to its low prevalence in the general population, the surveillance of high-risk groups is suggested as the approach for increasing the probability of an early detection. Such an approach, referred to as \u201cdefine\u2013enrich\u2013find,\u201d (DEF), concerns patients with intraductal papillary mucinous neoplasms , with new onset diabetes , chronic pancreatitis, and those with familial pancreatic cancer or predisposing inherited conditions . In thisCDNK2A mutation carriers was relatively successful [There is a consensus as to the management of patients with inherited predispositions increasing the risk of PDAC, who should undergo yearly surveillance by endoscopic ultrasound (EUS) or magnetic resonance (MR) . The preccessful . In a Duccessful .A recent metanalysis indicates that, in high-risk individuals under surveillance, high-risk abnormalities (at MR or EUS plus fine needle aspiration) were significantly associated with surgical appropriateness  and beneficial in 4 out of 10 cases . In accoBRCA1/2 is foreseen) [BRCA1/2, CDKN2A, PALB1, STK11, and MMR, and, recently, ATM) [Our data show that PDAC predispositions play a leading role within hereditary syndromes. The implementation and clarification of the criteria for accessing the genetic testing in patients with PDAC and their families is warranted. In certain European contexts, such as in Italy, although the guideline remains restrictive  , scientioreseen) . The accoreseen) , includely, ATM) ,41,42.In conclusion, our data support the need for further studies to improve our understanding of the impact of genetics on the development of PDAC, which is a main player among tumors in which hereditary syndromes are implicated. Through this process, a broader identification of subjects affected by a hereditary syndrome might be possible, together with their access to dedicated surveillance programs for cancer prevention and an eventual possible improvement in target therapies.A relevant proportion of PDAC is associated with mutations in known predisposition genes. Guidelines instructing on the adequate selection for accessing genetic testing are eagerly needed. The heterogeneity of mutations identified in this study reflects the value of using a multiple-gene panel in pancreatic cancer."}
+{"text": "Dengue fever is a significant cause of morbidity throughout the world caused by the dengue virus (DENV). Four antigenically different dengue virus serotypes  are known to cause infections in humans . Chances for developing dengue hemorrhagic fever-dengue shock syndrome increases significantly with history of previous infection with one of the four serotypes.A retrospective study of hospitalized dengue patients in span of five years was done. One-hundred forty three (143) patients aged>19 years admitted due to fever, positive for NS1 antigen and with DENV serotype results were included. Clinical data were extracted from medical records including demographics, co-morbidities, clinical presentation, laboratory investigations, length of hospital stay and outcome.p>0.05). The clinical outcome of patients was recovery at 98.60%, with only 1.40% mortality. Comparative analyses indicated that the clinical management and outcomes of the patients did not significantly differ according to dengue virus serotype (p>0.05).Out of the 143 adult dengue patients, the most prevalent serotype was DENV 3 at 64.34% followed by DENV 2 (18.18%), DENV 1 (11.19%), with DENV 4 as the least prevalent serotype (6.29%). In terms of clinical manifestations, the most prevalent symptoms were fever (98.60%), myalgia (78.32%), body malaise (69.23%), headache (59.44%), nausea and vomiting in 42.66%. Majority tested positive for Dengue NS1 (87.94%), with more than half testing positive for Dengue IgG at 54.24%. The adjusted risk for dengue with warning signs for DENV-2 was 5.94, indicating that the risk of dengue with warning signs was 5.94 times higher among those with DENV 2 than those with DENV 1; however, the association was not statistically significant. Results showed that the ARR for serotypes 3 and 4 for all dengue severity categories were not statistically significant (This study provided more information on the dengue serotypes, its effect on severity and outcome of the disease. Infecting dengue serotype play an important role in disease severity among adult dengue patients in the Philippines.All Authors: No reported disclosures"}
+{"text": "Few data are available about anticoagulation management beyond 6 months in patients with cancer associated thrombosis (CAT). Our objective was to describe anticoagulant treatment modalities up to 12 months.The management of the anticoagulant treatment beyond 6 months was described in this initially retrospective non-interventional French multicenter study in patients treated with low-molecular-weight heparins (LMWH) still alive at the end of an initial 6-month treatment period. Clinical outcomes, including venous thromboembolism, recurrence, bleeding and deaths have been published previously.Among the 432 patients (mean age 66.5\u00b112.7 years) included in the study, 332 were followed up to 12 months while 96 patients deceased before study end and 4 patients were lost-to-follow-up. At 6 months, anticoagulant therapy was stopped in 74 patients, 56 were switched to vitamin K antagonists (VKA) , 30 to direct oral anticoagulants (DOAC) . LMWHs were maintained in 256 patients . During the follow-up, LMWHs were definitively discontinued in 86 patients (33.7%), the main reason being a favorable course of the cancer , or the thromboembolic disease , whereas concern about bleeding risk was low .Anticoagulation beyond 6 months and up to 12 months was in accordance with clinical practice guidelines suggesting that treatment should be continued as long cancer is active or in the absence of bleeding risk. Anticoagulant treatment discontinuation beyond 6 months was influenced by the favorable courses of both malignancy and thromboembolic disease, as well as patient\u2019s preference. Managinhttps://clinicaltrials.gov/ct2/show/NCT02898051). We previously published the results of the USCAT study, a retrospective non-interventional study with the objective to briefly describe in the real-world practice the use of the anticoagulant treatment beyond 6 months and up to 12 months following index VTE and to document clinical outcomes i.e. VTE recurrence, bleeding and deaths in CAT patients initially treated for 6 months in both PREDICARE and aXa studies [Less is known about reasons influencing anticoagulant treatment strategy beyond 6 month in real-world practice. Several studies mostly uncontrolled have evaluated extended anticoagulant therapy for patients with CAT suggesting that long-term anticoagulant treatment beyond 6 months may be associated with a lower risk of VTE recurrence and bleeding compared to the initial 6-month treatment period , 11\u201314.  studies . In this2.2.1The design and the main results of the USCAT study have been previously described . Briefly2.2Main study objective was to describe the anticoagulant treatment for the management of CAT patients from the 6th month to the 12th month following the index VTE.2.3The same independent investigator had access to the primary data and reviewed medical records of all included patients and recorded data in a standardized case report form. Relevant data, including patient demographics, cancer status and treatment, and anticoagulant therapy were collected up to 12 months after the index VTE event. Information on changes in cancer status, cancer treatment and anticoagulant therapy, specifically notified reasons influencing changes in strategy  was collected. Continuous data were expressed as mean \u00b1 standard deviation or median and categorical variables were expressed as absolute numbers (percentages).The rate of patients continued on LMWHs, VKAs or DOACs beyond 6 months and their 95% confidence interval (95% CI) were also presented. The duration of treatment before the definitive discontinuation of anticoagulation or the switch to another anticoagulant depending on the reasons for definitive discontinuation or switch were graphically summarized by boxplots. Statistical analyses were performed using SAS version 9.4 software  and graphics were performed using R statistical software, version 3.6.2.3.Between 4 August 2011 and 21 April 2016, 719 patients were included in aXa and PREDICARE studies in 59 French centers, of which 432 participated in the long-term follow-up of USCAT study [3.1Therapeutic strategy at 6 months is available for 422 patients of the 432 included patients. Patient\u2019s characteristics according to the anticoagulant treatment strategy at the end of the initial 6-month treatment is summarized in 3.2The anticoagulant treatment beyond 6 months was mostly continued in pancreas (100% continued vs none discontinued) and upper gastrointestinal cancers (92.3% continued vs 7.7% discontinued). Among the 311 patients with a cancer stage of 3\u20134, treatment beyond 6 months, was continued in 277 patients (89.1%) while the anticoagulant treatment was discontinued in 34 patients (10.9%). Similar observations were made among 211 patients with cancer in progression as 187 patients (88.6%) had the treatment continued beyond 6 months while 24 patients (11.4%) had the treatment discontinued at 6 months. Conversely, among the 66 patients with tumor remission, treatment had been discontinued in 22 patients (33.3%) and continued in 44 patients (66.7%).3.3th to the 12th month, 86 patients (33.7%) treated with LMWH had their treatment definitively discontinued mainly due to the favorable evolution of the cancer disease (n=16) or the favorable course of the thromboembolic disease (n=11) after a median treatment duration beyond 6 months of 81.5 and 46.0 days, respectively. Only 3 definitive LMWH discontinuations were related to patient\u2019s decision  remained on VKAs beyond 6 months for a median treatment duration of 183 days. VKAs were definitively discontinued in 12 patients (21.8%) for reasons unrelated to safety concerns while the treatment was temporarily discontinued in 6 patients (10.9%). A switch of VKAs was reported in 8 patients (14.5%) mainly to LMWHs. DOACs were continued in 30 patients (8.6%) beyond the initial 6-month treatment period for a median treatment duration of 183 days. DOACs were definitively discontinued in 8 patients (27.6%) for other reasons than safety concern. There were no temporary discontinuation or switch to another treatment. Unfractionated heparin (UFH) and fondaparinux were each used beyond 6 months in 3 patients (0.9%).4.The description of the anticoagulant treatment in USCAT represents an additional information on the management of CAT patients up to 12 months after the index event in the real world of clinical practice. As previously published , a total4.1At inclusion in USCAT study, i.e. 6 months after the VTE index event, 348/422 patients (82.5%) had an anticoagulant treatment. Anticogulant treatment was mainly continued in patients with stage 3\u20134 (89.1%) and in patients with cancer progression (88.6%). This is consistent with guidelines which recommend the continuation of the anticoagulant treatment beyond 6 month after the VTE index event when cancer is considered as active , 17. Thi4.2Regarding the 7-to-12-month VTE recurrence raw incidence, previous observational studies have emphasized the usefulness of extended anticoagulant treatment beyond 6 months \u201313 where4.3During the 6-to-12-month follow-up the treatment was definitively discontinued in 86 (33.7%), 12 21.8%) and 8 patients (27.6%) treated with LMWHs, VKAs and DOACs, respectively. The main reason for definitive LWMH discontinuation was based on physician\u2019s judgment, when the overall patient condition was considered at lower risk of VTE recurrence related to a favorable course of the cancer or of the thromboembolic disease . Little .8% and 84.4th month, was based of patient\u2019s preference carefully assessed by the physician  and 13 (31.0%) patients, respect-tively. The decision to switch to an oral anticoagulant, usually made around the 6hysician . Our resFurthermore, a discrete choice experiment on COSIMO study patients preferences revealed that the main reason guiding the patient willingness to switch to oral anticoagulation was that oral route of administration was associated with better convenience .4.5Given the observational retrospective nature of our study, limitations were related to the absence of randomization and several missing data that made difficult the comparison of different treatment strategies. Another potential limitation is that DOAC\u2019s were considered as emerging therapeutic options at the time of PREDICARE and aXa studies initiation when predominantely VKA and LMWH were available for the treatment of CAT.4.6NCT02898051; https://clinicaltrials.gov/ct2/show/NCT02898051) studies were homogeneous, allowing the inclusion of a large sample size in USCAT. Moreover, patients characteristics were documented 6 months after the index VTE i.e., at the time when the treatment strategy for the subsequent 6 months was to be discussed. Reasons influencing therapeutic decisions for the extended anticoagulant treatment with LMWHs beyond 6 months in patients with CAT discussed in our study reflect the real-life physician\u2019s experience in the clinical practice.USCAT is the largest observational study to date on CAT patients treated with LMWH beyond 6 months after the VTE index event (N = 432) while a large proportion of patients have completed 12-month follow-up (n=332). Clinical protocols and event adjudication in PREDICARE  and aXa 5.In this real-world practice analysis, anticoagulant treatment with LMWH was continued beyond 6 months and up to 12 months in most patients with CAT. However different factors have influenced physician\u2019s decisions beyond the initial 6 months of therapy. Beyond 6 months, treatment discontinuations were mainly related to the favorable course of the malignancy or the thromboembolic disease, while switches to oral anticoagulants were guided by patient\u2019s preference.Unlike the risk management approach during the initial 6 months, the risk of bleeding was not a major concern that would justify treatment discontinuation beyond 6 months. Based on our observations it therefore seems fundamental to re-assess the anticoagulation strategy after the initial 6 months of therapy to optimize physician\u2019s decision. Establishing more formal clinical practice guidelines for the long-term anticoagulant treatment in CAT patients beyond 6 months with the identification of therapeutic decision making factors may require further clinical research in the form of prospective controlled trials."}
+{"text": "Correction: Malaria Journal (2020) 19:170https://doi.org/10.1186/s12936-020-03224-6\u201cShifting suitability due to climate change will place additional people at risk despite reductions in endemic and seasonal malaria transmission, resulting in a net gain of a low of 58.7 million and a high of 60.4 million people who experience some level of malaria risk in Western Africa by the 2030s.\u201dFollowing publication of the original article , the aut\u201cDespite the dramatic projected reductions in endemic and seasonal malaria transmission risk in Western Africa , shifting suitability due to climate change will still place additional people at risk. Taking moderate and marginal suitability for malaria transmission into account results in an overall projected net gain of 58.7 million (RCP 4.5) to 60.4 million (RCP 8.5) people who will experience some level of malaria risk in Western Africa by the 2030s.\u201dThe sentence has been replaced with the following:The authors thank you for reading this erratum and apologize for any inconvenience caused."}
+{"text": "Pre-eclampsia is a pregnancy-related hypertensive disorder with maternal and neonatal complications. Many studies are done regarding the prevalence of pre-eclampsia in Nepal but ascertaining the maternal risk factors and fetal outcomes are important. The aim of this study was to find out the prevalence of pre-eclampsia among pregnant women admitted to the Department of Obstetrics and Gynaecology of a tertiary care centre.A descriptive cross-sectional study was conducted among pregnant women admitted to the Department of Obstetrics and Gynaecology of a tertiary care hospital from 13 July 2023 to 29 September 2023 after obtaining ethical approval from the Institutional Review Committee. Convenience sampling method was used. Point estimate was calculated at a 95% Confidence Interval.Among 5065 patient, pre-eclampsia was seen in 44 (0.87%) . A total of 16 (36.36%) cases of pre-eclampsia were in the age group 25-29 years and 30 (68.18%) of them were nulliparous. A total of 38 (86.36%) of the newborns of the pre-eclamptic cases had low birth weight. The APGAR score of newborns at the 1 minute after birth was 26 (59.09%) followed by the newborns who needed re-evaluation 16 (36.36%). The APGAR score recorded at 5 minutes showed maximum newborns with normal APGAR score 40 (90.90%).The prevalence of pre-eclampsia among pregnant women was found to be lower than other studies done in similar settings. The non-digitalised hospital records of maternity cases within a duration of 17 months from April 2022 onwards were obtained from the hospital record section after getting ethical approval from the Institutional Review Committee (Reference number: 07(6-11)E-2 080/081). The maternity cases of Nepali origin with no missing information were included. A convenience sampling method was used. The sample size was calculated with the following formula.Where,n = minimum required sample sizeZ = 1.96 at 95% Confidence Interval (CI)p = prevalence taken as 50% for maximum sample size calculationq = 1-pe = margin of error, 2%The calculated minimum required sample size was 2401. After doubling, sample of 4802 was calculated. However, a total of 5065 maternity cases were included in the study.6 The appearance, pulse, grimace, activity and respiratory parameters were scored at 1 and 5 minutes respectively after birth.The study variables were maternal age and parity as risk factors for pre-eclampsia and the fetal viability, birth weight and APGAR scores were considered as fetal outcomes. The parity among the cases was again classified as nulliparous, primiparous and multiparous. The fetal viability was classified as dead or alive newborns; the birth weight of newborns was classified as low birth weight (<2.5 kg), high birth weight (>4 kg) and in between as normal birth weight. The APGAR score recorded was again classified into 3 categories 7-10 , 4-6  and 0-3 (never good requiring immediate attention).Data were entered in Microsoft Excel 2016 and analysed using IBM-SPSS Statistics version 16.0. Point estimate was calculated at a 95% CI were calculated.Among 5065 pregnant women, the distribution of pre-eclampsia was 44 (0.87%) . The mean age among the cases of pre-eclampsia was 30.70\u00b15.09 years. A total of 16 (36.36%) cases were between 25-29 years, 11 (25%) between 35-39 years and only 2 (4.54%) were between 40-44 years. A total of 30 (68.18%) of the cases were nulliparous and 11 (25%) were primiparous .All of the newborns of the pre-eclamptic cases were alive. The mean birth weight of the newborns was 1.84\u00b10.69 years. A total of 38 (86.36%) of the newborns had low birth weight and 6 (13.63%) had normal birth weight. The APGAR score was studied in the first and 5 minutes after birth. A total of 26 (59.09%) of the newborns had APGAR scores between 7-10, 16 (36.36%) had between 4-6 and 2 (4.54%) had between 0-3 in 1 minute after birth. A total of 40 (90.90%) newborns had APGAR scores in between 7-10 and 4 (9.09%) scored between 4-6 in the 5 minute after birth .3 In our sudy, among 5061 pregnant women, 44 (0.87%) had pre-eclampsia which is similar to the study done in Nepal.7Pre-eclampsia is associated with maternal, perinatal and neonatal morbidity and mortality with increased incidence of the disease in developing countries.5 The finding was similar among the pre-eclamptic cases in Uganda as well.8 This age group is the most common age range for marriage and family planning among women which is supported by the highest rate of pregnancy and its associated complications like preeclampsia in this age.This study has found that the distribution of the cases was maximum in age group 25-29 (36.36%). This finding was similar to another retrospective study conducted in Nepal which has also found the highest prevalence of pre-eclampsia in the normal reproductive age group (83.52%). Also, 69.6% of cases of preeclampsia belonged to the age group 20-34 years in a cross-sectional study conducted in Malaysia.4 A similar study done in Saudi Arabia has found that the highest proportion of pre-eclamptic cases (42.0%) were nulliparous.9 The finding was in contrast among the pre-eclamptic cases of Indonesia which reported the distribution of multiparous women being more in the condition.10This study has also found that 68.18% of pre-eclamptic cases were nulliparous, followed by primiparity (25%) and multiparity (6.81%). The nulliparity is also considered an important risk factor for developing the condition.11 It also reported that the risk of fetal demise is over 50% less in cases of mild preeclampsia when compared with severe pre-eclampsia.11 The prevalence of stillbirth was 2.34% among the cases of pre-eclampsia.9 The frequency seemed to increase in the study conducted in Uganda with 12.6% cases of stillbirth in pre-eclamptic women.8As per the outcomes among newborns considered in our study, all of them were alive 44 (100%), and 86.36% had low birth weight. A total of 26 (59.09%) had good APGAR scores in 1 minute which increased to 90.90% at 5 minutes. Studies have found that severe pre-eclampsia represents a significant risk factor for intrauterine fetal demise, with an estimated stillbirth rate being 21 per 1000.12 It supports the hypothesis of placental hypoperfusion due to shallow invasion of fetal trophoblast in pregnancy leading to fetal growth restriction in pre-eclampsia.13 The finding is similar to our study where the highest distribution of low-birth-weight babies was seen among the pre-eclamptic cases.Studies have found that the mean birth weight of babies delivered by mothers who had early onset preeclampsia was lower than those of non-pre-eclamptic across all gestational ages.14 However, similar studies done among pre-eclamptic cases in Indonesia have found that the neonates with normal APGAR score (>7/10) were highly distributed at both 1-minute (80.7%) and 5-minute intervals (94.6%).10 This finding was consistent with the result of our study which reported a higher normal APGAR score at both 1 and 5 minutes in the cases of pre-eclampsia.Studies have found that pre-eclamptic women have infants with lower APGAR scores than healthy women.The limitations of the study are minimum maternal risk factors and newborn outcomes were considered. Thus, a similar study considering various other maternal risk factors such as obesity, blood pressure, blood sugar level, antenatal care facility or any renal or cardiac diseases and fetal outcomes like the fetal size and proportions; haematological and other systemic effects in a larger sample size can be conducted.The prevalence of pre-eclampsia among pregnant women is lesser than in other similar studies done in similar settings."}
+{"text": "The study objective was to determine the prevalence of LBW and immediate (within 24 hours) birth outcomes of LBW neonates born to pre-eclamptic women at Moi Teaching and Referral Hospital (MTRH), Kenya.a descriptive cross-sectional study was conducted among 364 participants (346 singletons and 9 twins) born to pre-eclamptic women at MTRH. A study tool was used to gather data on birth weight and neonatal outcomes. Data was cleaned, coded and entered into SPSS version 22 for analysis. Descriptive statistics were computed for the prevalence of LBW and immediate neonatal outcomes.the study found an LBW prevalence of 180(49.5%) and prematurity of 81(45%). Of the LBW neonates (n=180), 162(90%) were alive and 18(10%) were stillbirths. Their immediate morbidities were, birth asphyxia 51(28.7%), neonatal jaundice 38(21%), hypothermia 18(7.9%) and neonatal sepsis 1(0.7%). Of the neonates that were born alive; 107(59.2%) were admitted to level II nursery care, 53(29.5%) were rooming in with their mothers and 20(11.3%) died within 24 hours.preeclampsia contributes to LBW, nursery admissions and morbidity/mortality of neonates necessitating the need for neonatal units' preparedness for prompt and appropriate management to avert death. More. (2018) .et al. (2020) [et al.(2019) [Congruent to our study findings, other studies have reported birth asphyxia as the leading cause of neonatal morbidity among neonates born to pre-eclamptic women owing to lung immaturity and insufficient surfactant production ,25,31. I. (2020)  that rep. (2020) ,37. Our l.(2019)  that estLimitations: this study was carried out at a national referral hospital that had a possible bias of admitting high-risk pregnancies referred from other regions in the country hence the findings may not be generalizable. In addition, the study included twins who may not share the same risk factors as the singletons.This study was carried out at a national referral hospital that had a possible bias of admitting high-risk pregnancies referred from other regions in the country hence the findings may not be generalizable. In addition, the study included twins who may not share the same risk factors as the singletons. Preeclampsia contributes to LBW, nursery admissions, and morbidity/mortality of neonates necessitating the need for neonatal units\u2019 preparedness for prompt and appropriate management to avert death.Preeclampsia contributes to stillbirth, low birth weight, prematurity, and morbidity due to uteroplacental insufficiency.The findings of low birth weight (49%), prematurity (45%), and fresh stillbirth (9%) among pre-eclamptic women at MTRH, Kenya."}
+{"text": "Determining the etiology of acute respiratory illness (ARI) in immunocompromised children is challenging. The wide variety of infectious and non-infectious causes makes it difficult to optimize empiric antimicrobial treatments, leading to broad, lengthy antimicrobial courses with potential antimicrobial overuse, increased side effects, and interruptions to chemotherapy treatments. The diagnostic yield and safety of bronchoalveolar lavage (BAL) in these patients has long been debated.We conducted a retrospective chart review of BAL procedures performed on immunocompromised children with ARI at St. Jude Children\u2019s Research Hospital between 2017-2021. Microbiological and molecular study results were reviewed, including next generation sequencing (NGS) studies obtained from BAL, upper respiratory, and blood specimens within 7 days of the BAL. Etiology determined by the clinical team, changes in antimicrobial clinical management, and adverse events following the BAL were collected.82 BAL procedures from 57 patients are presented. The most common underlying diagnosis was hematologic malignancy, and 39 (48%) had undergone hematopoietic cell transplant. BAL identified one or more potential respiratory pathogen in 62.2% of ARIs, including viruses (54%), bacteria (48%), and fungi (37%). Of the 12 patients with BAL NGS, 8 (67%) identified likely respiratory pathogens, 5 (42%) correlated with other testing, and 3 (25%) were unique to NGS. 58 (71%) of BALs led to a change in antimicrobial management, either by discontinuation of broad-spectrum antimicrobials (65%) or narrowed antimicrobial regimen (41%). In 7 (12%) patients with suspected infectious etiology, BAL confirmed alternate etiology and avoided initiation of antimicrobials. 12 (15%) of patients underwent new intubation, and 22 (27%) had increased ventilatory requirements within 24 hours of BAL. No patients required new ICU transfer due to the procedure.BAL is a valuable, well tolerated procedure that can aid in the diagnosis of pulmonary disease in pediatric immunocompromised patients. These preliminary findings highlight the benefits of BAL and its potential impact on decision making and clinical management, including avoiding antimicrobial overuse.All Authors: No reported disclosures"}
+{"text": "This case series investigates whether analysis of clinical history via a language model system improves diagnostic accuracy in patients with complex and delayed diagnoses. The GPT-4 (Generative Pre-trained Transformer 4) program allows analysis of clinical history in daily practice.2 We hypothesized that GPT-4 could improve the diagnostic accuracy of clinicians by supplying the most probable diagnosis or suggesting differential diagnoses in complex cases.Artificial intelligence (AI), especially machine learning, has been increasingly used in diagnosing conditions such as skin or breast cancer and Alzheimer disease. However, AI relies on clinical imaging.5 The full medical histories were entered chronologically on April 16, 2023  into GPT-4 (powered by OpenAI via Platform for Open Exploration) without information about definitive diagnosis. The GPT-4 responses were copied out and further analyzed . The study was approved by the Institutional Review Board of the University of Hong Kong and Hospital Authority Hong Kong West Cluster. Written consent was provided for all patients. This report followed the reporting guideline for case series studies.The medical histories of 6 patients from the Division of Geriatrics in the Department of Medicine at Queen Mary Hospital who were aged 65 years or older and had delay of definitive diagnosis longer than 1 month in 2022 were retrieved after resolution.Six patients 65 years or older (2 women and 4 men) were included in the analysis. The accuracy of the primary diagnoses made by GPT-4, clinicians, and Isabel DDx Companion was 4 of 6 patients (66.7%), 2 of 6 patients (33.3%), and 0 patients, respectively. If including differential diagnoses, the accuracy was 5 of 6 (83.3%) for GPT-4, 3 of 6 (50.0%) for clinicians, and 2 of 6 (33.3%) for Isabel DDx Companion . By studOverall, GPT-4 has potential clinical use in older patients without a definitive clinical diagnosis after 1 month but requires comprehensive entry of demographic and clinical  information. GPT-4 may increase confidence in diagnosis and earlier commencement of appropriate treatment, alert clinicians missing important diagnoses, and offer suggestions similar to specialists to achieve the correct clinical diagnosis, which has potential value in low-income countries with lack of specialist care. Clinicians need to be aware that GPT-4 is limited in multifocal infection, and the suggested management plan should be correlated with clinical context, as suggestions may be redundant. Clinicians should consider a drug review and review the possible diagnosis of malignant disease if suggested.This study has several limitations. First, GPT-4 may not detect 2 focuses of infection or pinpoint the source of recurrent infection. Second, GPT-4 did not suggest the use of gallium scan or 18-fluorodeoxyglucose positron emission tomography to look for infections or malignant neoplasms in all but 1 patient. Third, some investigations may not be appropriate . Overall, our findings suggest that the use of AI in diagnosis is both promising and challenging."}
+{"text": "Down syndrome is a common genetic disorder found in about one in every 800 live births. The diagnosis is normally confirmed through conventional karyotyping, through evidence of extra material from chromosome 21.Our sample comprised 644 patients . Full trisomy of chromosome 21 was the predominant alteration observed in 598 of these patients (92.9%). Chromosomal abnormalities of structural type were observed in 26 patients (4%). These were composed of Robertsonian translocations involving chromosome 21 and chromosomes 14 (n = 12), 21 (n = 10), 15 (n = 1) and 22 (n = 1). In addition, two cases showed a reciprocal translocation, one of them involving chromosomes 21 and 5 and another with a complex translocation involving chromosomes 5, 21 and 22. Among the patients with structural chromosomal abnormalities, karyotyping analysis on the parents was performed in relation to 11 patients. Structurally balanced alterations were detected in five of them (45.5%). Mosaicism was identified in 20 patients (3.1%) and usually involved two cell lines: one normal and one with trisomy 21 (n = 15). However, two patients (10%) presented mosaicism involving three cell lines. Five cases (25%) showed a cell line with double aneuploidy, and four of them involved chromosomes 9, 14, 21 and X, respectively. The fifth patient presented an additional marker chromosome. Six patients (30%) among the 20 had mosaicism for trisomy 21 that was lower than 10%. The mean number of cells analyzed in these cases was 42 .-,In our review of the literature, using the PubMed, SciELO and Lilacs databases, we did not identify any studies that evaluated the cytogenetic profile of patients with Down syndrome in Latin America. The frequencies of the different changes to chromosome 21 observed in our study were consistent with those described in the literature.Thus, our study highlights the importance of performing karyotyping analysis on patients presenting a clinical diagnosis of Down syndrome, especially with a proper cell count, because of the low-grade mosaicism. This is important not only for confirming the diagnosis but also for determining the type of Down syndrome chromosomal alteration. This is essential for enabling appropriate genetic counseling for the family."}
+{"text": "The complication rates were then compared between cINPT dressing and standard-of-care dressings on radiated patients following breast surgery.The data collected consist of a total of 83 radiated breasts that underwent implant based reconstruction. cINPT was used in 41 breasts and standard-of-care dressings were used in 42 breasts.Of the cINPT cohort, 2 patients developed seromas that required bedside aspirations (4.8%) and one patient developed an infection (2.4%) with none of the patients requiring re operations. Of the standard of care dressings cohort, 9 patients developed seromas (21.4%), and 3 patients developed infections (7.1%), of which 3 patients required reoperations (7.1%).Patients with prior radiation who received cINPT had lower risk of developing complications compared to patients with prior radiation who received standard-of-care dressings."}
+{"text": "Foundational approaches to burn fluid resuscitation were largely developed with the adult patient in mind. Experience has shown, however, that physiologic nuances between adults and children necessitate an adjusted approach to resuscitation for pediatric patients. As practice has advanced to account for these differences, our burn center sought to evaluate efficacy of resuscitation for our pediatric patient population. The purpose of this study was to examine pediatric fluid resuscitation including trends and complications, and to establish a baseline for future quality improvement initiatives.<14 years of age treated with resuscitation in a burn center between 2017 and 2021. Descriptive statistics were calculated.This was a retrospective review of pediatric patients >20%, of which 23 met inclusion/exclusion criteria. Average admission weight was 31.8 kg and average TBSA of 39%. Contributing mechanisms of injury were flame (61%), scald (35%) and chemical (4%). Concomitant inhalation injury was diagnosed in 17% of patients. Average hourly fluid resuscitation volume was 6.9 mL/kg/TBSA with a mean resuscitation duration of 25.7 hours. Total volume administered throughout resuscitation exceeded recommendations per the Parkland formula for 83% of the sample. Continuous albumin was administered for 74% of patients and was initiated on average at 10 hours post-injury. Boluses of lactated ringer\u2019s and albumin were administered for 30% and 9% of patients, respectively. Urine output for the pediatric patients averaged 60 mL/hr with a mean low optimal urine output of 15.9mL/hr and high optimal output of 25.5 mL/hr. Adverse events occurring during fluid resuscitation included temperature < 36\u25e6C (35%), vasopressor administration (9%), intra-abdominal pressure >12 (13%) and/or >19 (9%), and peripheral vascular pulses < +1 (61%). Prophylactic escharotomy was performed for 35%. Of note, none of the patients were diagnosed with compartment syndrome nor abdominal compartment syndrome and none required abdominal laparotomy. One patient (4%) was diagnosed with acute respiratory distress syndrome. Continuous renal replacement therapy (CRRT) was not utilized for any pediatric patients during or post-resuscitation, compared to 34% of adults resuscitated at the same center. No patients expired in the initial 48 hours post-burn. The overall survival rate for this population was 91.3%, with 87% discharged direct to home.Over a five-year period, 42 pediatric patients were admitted with a burn total body surface area (TBSA) Resuscitation volumes for pediatric patients in a large burn center have exceeded historically accepted rates for resuscitation. Despite the divergence from traditional practice, associated complications remain low, and outcomes have been favorable.Further research is needed to establish benchmarks for pediatric fluid resuscitation."}
+{"text": "Antimicrobial stewardship principles guide the clinical use of antimicrobials, including vancomycin, but paediatric vancomycin prescribing practices have not been evaluated in South Africa.To document the use, prescribing practices and monitoring of intravenous vancomycin and the spectrum of bacteria isolated on microbiological culture in children treated with intravenous vancomycin during a 12-month period at Red Cross War Memorial Children\u2019s Hospital (RCWMCH).A retrospective audit of intravenous vancomycin use in children admitted to RCWMCH during 2019 was performed.p = 0.001). Vancomycin serum trough concentrations were performed in 65/98 (66%) episodes where vancomycin treatment exceeded 3 days, with only 16/65 (25%) of these samples obtained before the fourth dose. Prolonged antibiotic treatment of 14 days or more was not associated with Gram-positive bacteria on culture .All 158 vancomycin prescription episodes for 143 children were included. Overall usage of intravenous vancomycin was 63 days of therapy per 1000 patient days (interquartile range [IQR]: 38\u201372). The median starting dose was 15 mg/kg per dose (IQR: 14\u201315) and median daily dose was 45 mg/kg per day (IQR: 43\u201360). Vancomycin was prescribed as empiric  and directed  treatment. The median duration of treatment for the directed group (7 days) was longer than the empiric group (4 days) (Dosing errors, prolonged empiric treatment and inappropriate vancomycin monitoring were problems associated with vancomycin prescriptions.The study identified multiple opportunities for improved vancomycin prescribing and monitoring. Further research and implementation of improved prescribing practices could contribute to the preservation of vancomycin as an effective antibiotic. This classification is based on spectrum of activity, frequency of use and resistance potential. Vancomycin is a Watch antibiotic and should be prioritised for stewardship and surveillance for resistance.3 Vancomycin\u2019s mechanism of action against Gram-positive bacteria is by inhibition of bacterial cell wall synthesis. It remains the treatment of choice for infection caused by \u03b2-lactam-resistant Gram-positive bacteria such as Enterococcus faecium, \u03b2-lactam-resistant Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus (MRSA).5Children in low- and middle-income countries (LMICs) are leading consumers of antibiotics globally,6 An audit on the impact of stewardship on vancomycin use in children indicated that non-approved indications for prescription, dosing errors and prolonged duration of treatment were problems.7 Real-time intervention and feedback on prescriptions of vancomycin have reduced overall vancomycin use and improved the safety and quality of care in tertiary hospitals.9A pharmacist-led, multicentre, antimicrobial stewardship (AMS) initiative, across 47 private hospitals in South Africa, showed that 1 in every 15 antibiotic prescriptions required intervention when dosing errors and excessive duration were common.24/MIC ratio) of the organism being targeted. For MRSA with a vancomycin MIC of 1 mg/L, an AUC24/MIC ratio > 400 is recommended.10 The 2011 Clinical Practice Guidelines produced by the Infectious Diseases Society of America (IDSA) recommended targeting vancomycin trough concentrations of 15 mg/L \u2013 20 mg/L, which correlates with an AUC24/MIC ratio > 400, in adults with severe bacterial infections. The effectiveness and safety of targeting trough concentrations of 15 mg/L \u2013 20 mg/L in children were not established at the time and a dose of 15 mg/kg per dose administered intravenously six-hourly was recommended.11 Pharmacokinetic modelling suggests that a trough concentration of 7 mg/L \u2013 10 mg/L may be sufficient to achieve an AUC24/MIC of > 400 in over 90% of children with MRSA infection.12 Although optimal dosing and the role of therapeutic drug monitoring (TDM) in paediatric practice remain uncertain,13 current IDSA guidelines recommend individualised targeting of an AUC24/MIC ratio of 400\u2013600 (assuming a vancomycin MIC of 1 mg/L) to achieve clinical efficacy while improving safety.5 Individualised AUC24/MIC targeting is not readily available in LMICs but has been successfully used as an entry point for stewardship elsewhere.14Achievement of adequate plasma and tissue vancomycin concentrations is essential for an optimal clinical response. The effectiveness of vancomycin to treat invasive infections due to Gram-positive bacteria is associated with the area under the concentration-time curve from 0 h to 24 h divided by the minimum inhibitory concentration  in Cape Town, South Africa.A retrospective descriptive study of intravenous vancomycin use in children admitted to RCWMCH during 2019 was performed. The RCWMCH is a 272-bed referral hospital that serves children aged 13 years and younger from the Western Cape province and occasionally from surrounding provinces. All children treated with intravenous vancomycin during the study period were eligible for inclusion and excluded only if records were missing or the prescription chart could not be located in the hospital folder. Study participants were primarily identified from the RCWMCH pharmacy database. In addition, the intensive care unit (ICU) discharge summary database was searched, as vancomycin used to treat children admitted to the ICU is obtained from ICU medication stock and not issued directly from the pharmacy on an individual patient basis.Demographic details, clinical information and vancomycin prescription data on the enrolled participants were extracted from medical records obtained from the RCWMCH medical records department and entered into a REDCap database . The collected clinical information included diagnosis, comorbidities, surgical interventions, documentation of adverse drug events (ADEs) and clinical outcomes. Laboratory information collected included vancomycin trough concentrations and creatinine at the time of vancomycin administration. Details of each vancomycin prescription episode were obtained from the paper-based antibiotic prescription chart (a separate prescription chart from that used for other medication) that is currently in use at RCWMCH. This chart prompts the prescriber to send appropriate cultures prior to antibiotic prescribing and to indicate the suspected clinical diagnosis, source of infection, and an indication as to whether the antibiotic is for empirical or directed treatment. The route, dose, dosing frequency, duration, and start date and time are also captured (Online Appendix 1). Prescription data were collected directly from this antibiotic chart where available, and multiple prescription episodes were collected within a single admission. The total patient days for all hospital admissions during the study period was calculated by and received directly from the Provincial Health Data Centre.\u00ae2 automated system , biochemical or antigen-detection methods, and disc or gradient diffusion AST methods where appropriate. Results of AST were interpreted using the Clinical & Laboratory Standards Institute (CLSI) guidelines.15The collected microbiological information included culture site, organism(s) cultured, antibiotic susceptibility testing (AST) results, and the MIC to vancomycin. All microbiological cultures were performed at the National Health Laboratory Service (NHLS) microbiology laboratory at Groote Schuur Hospital in Cape Town. Bacterial identification and AST were performed using the VitekP-values of less than 0.05 were used to denote statistical significance.Data were analysed using Microsoft Excel (version 2111) and Stata version 15.0 . Categorical variables were described using absolute values and percentages with the associated 95% confidence intervals (CIs); continuous variables were described using median and interquartile range (IQR) for non-normally distributed data. Comparison of the vancomycin daily dose between treatment groups was done using the Wilcoxon rank sum test. To examine whether participants with a Gram-positive organism on culture had increased odds of being prescribed vancomycin for more than 14 days compared to those with negative cultures, odds ratio (OR) were calculated using the STATA immediate command. 16An infection episode was considered community-acquired (CAI) if vancomycin was started within 48 h of admission to hospital and considered hospital-acquired (HAI) if vancomycin treatment was started more than 48 h after hospital admission or within 30 days of discharge from a previous admission.A vancomycin prescription was considered empiric treatment if commenced before culture and antibiotic susceptibility results were available, and all prescriptions for which cultures remained negative or no cultures were submitted to the laboratory. A vancomycin prescription was considered directed when an organism susceptible to vancomycin was identified by culture and AST, and vancomycin was considered the preferred treatment option.17Vancomycin usage was expressed as days of therapy per 1000 patient days (DOT/1000 PD) defined as the number of days that study participants were treated with intravenous vancomycin (regardless of the dose) per 1000 inpatient days including all patients admitted in the hospital during the study period.18 Trough concentrations of 10 mg/L \u2013 20 mg/L were considered therapeutic based on guidelines followed within the study period.18Vancomycin TDM was considered appropriate if a serum trough concentration was performed before the fourth dose for treatment exceeding 3 days, based on the time to reach steady state.Ethical approval was obtained from the University of Cape Town Human Research Ethics Committee  and the RCWMCH research committee (RCC 241/WC_202008_114). A waiver of consent was granted on the basis that the study only used anonymised archived data. The study was done in accordance with the Declaration of Helsinki.A total of 158 vancomycin prescription episodes for 143 children were included , of whicThe overall usage of intravenous vancomycin during the study period was 63 DOT/1000 PD (IQR: 38\u201372). The monthly usage ranged from 1 DOT/1000 PD to 104 DOT/1000 PD. Vancomycin prescription episodes occurred in the following wards: ICU , transplant , surgical , haematology/oncology  and general paediatric .All vancomycin prescription episodes met the definition of an HAI. Most prescriptions  occurred more than 48 h after admission. For the 31 episodes in which vancomycin treatment was started before 48 h, 19 (61%) were transferred in from other hospitals where they had more than 48 h, and 12 (39%) were discharged within 30 days prior to current admission. Vancomycin was prescribed as empiric treatment in 127/158 (80%) prescription episodes and directed treatment for 31/158 (20%). Suspected clinical diagnoses and indications for vancomycin use are summarised in z = 0.3, p = 0.8). Thirty-four (22%) prescriptions were for a total daily dose of 60 mg/kg per day, and 46/158 (29.1%) of the prescriptions were for a total daily dose of \u2265 60 mg/kg per day.A starting dose of 15 mg/kg per dose was identified in 83/158 (53%) prescription episodes, with the median starting dose also being 15 mg/kg per day (IQR: 14\u201315). The median daily dose was 45 mg/kg per day (IQR: 43\u201360) with no significant difference between the median total daily dose in the definitive 46 mg/kg per day (IQR: 40\u201360) versus empiric treatment 45 mg/kg per day (IQR: 43\u201360) groups (Dosing frequencies included six-hourly dosing in 42/158 (27%) and eight-hourly dosing in 89/158 (56%) prescription episodes. Other frequencies included 12-hourly dosing in 11/158 (7%) of which 10  frequencies were based on prematurity and gestational age, and 1  had renal dysfunction; 3  episodes of 24-hourly dosing in which 1  was based on gestation, and 2  had renal dysfunction. In both episodes  where vancomycin was prescribed 48-hourly, renal dysfunction was present. A single dose was given in 11/158 (7%) episodes with 10  stopped after a single dose and 1  episode where the vancomycin was represcribed eight-hourly.z = 3.2, p = 0.001). In 15/158 (9%) prescription episodes, the duration of vancomycin treatment was 14 days or more. These prescriptions included empiric treatment of suspected meningitis or ventriculitis , skin and soft tissue infections (SSTIs) , postsurgical intra-abdominal infection and typhlitis , ventilator-associated pneumonia (VAP) , febrile neutropaenia , spinal abscess  and suspected toxic shock syndrome . One episode of necrotising enterocolitis (NEC) and coagulase-negative staphylococci (CONS) on blood culture  and two episodes of directed treatment for confirmed MRSA BSI  from wound sepsis after cardiac surgery and hospital-acquired pneumonia (HAP) in an episode of flame burns. In 3 of 15 episodes (20%) where vancomycin was prescribed for 14 days or more, Gram-positive organisms were cultured. Similarly, in episodes where vancomycin was prescribed for less than 14 days, 28/143 (20%) isolated Gram-positive bacteria from culture. Thus, the odds of having a Gram-positive organism on culture when treated with vancomycin for 14 days or more compared to the odds when treated for less than 14 days were similar .The median duration of vancomycin treatment was 5 days (IQR: 3\u20137). There was a significant difference in treatment duration between directed  and empiric  vancomycin treatment groups (Therapeutic drug monitoring was performed in 95/158 (60%) of the vancomycin prescription episodes. Vancomycin treatment exceeded 3 days in 98/158 (62%) prescription episodes, and of these, 65/98 (66%) had vancomycin serum trough concentrations performed. The median time of trough concentration collection was before the fourth dose (IQR: 3\u20135).For samples obtained before the fourth dose, the median vancomycin serum trough concentration was 14 mg/L (IQR: 6\u201318).There were 37/95 (39%) serum trough concentrations < 10 mg/L. Irrespective of the timing of serum trough concentration measurements, prescription adjustments based on trough concentrations below 10 mg/L included an increase in dose , dose frequency  or both . Nine  prescriptions were not adjusted.Trough concentrations greater than 20 mg/L occurred in 21/95 (22%) of all prescription episodes where a trough concentration was performed. The dose , frequency  or both  were adjusted. Vancomycin was stopped in 3  and continued without any adjustments in 2  episodes.S. aureus isolates, 8 (47%) were MRSA. There were 15 Enterococcus spp. isolated, 13 of which (87%) were resistant to ampicillin. Vancomycin MICs were performed on 21/38 (55%) of the Gram-positive isolates including all 8 MRSA isolates. All MICs were \u2264 1 mg/L.Cultures were done before initiating 146/158 (92%) vancomycin prescription episodes. Culture results are detailed in Cultures were negative in 88/146 (60%) episodes and the median vancomycin treatment duration in these episodes was 5 (IQR: 3\u20136) days. Vancomycin was stopped within 3 days for 36/88 (41%), within 5 days for 28/88 (32%) and continued for a median of 7 (IQR: 6\u201310) days for 24/88 (27%) prescription episodes.Positive cultures were obtained in 58/146 (40%) vancomycin prescription episodes and the median vancomycin treatment duration in these episodes was 6 (IQR: 2\u20138) days. Vancomycin was the appropriate antibiotic choice and prescribed as directed treatment in 22/58 (38%) prescription episodes and 9/58 (15%) episodes where CONS were identified and of which the clinical significance was uncertain. For 19/58 (33%) episodes, vancomycin was stopped within 5 days as culture either identified an organism for which vancomycin was not the appropriate antibiotic choice or the organism was not deemed clinically significant.2 and from a tracheal aspirate in febrile neutropaenia1; 3/8 (37%) episodes where methicillin-susceptible S. aureus was identified from sputum in an episode of VAP, from a pus swab from a wound infection following cardiac surgery, and from blood culture in febrile neutropaenia, respectively; 1  episode in which Candida albicans was isolated from blood culture in an episode of VAP; and 1  episode in which Streptococcus agalactiae was isolated from blood culture in an episode of NEC.Vancomycin was continued beyond 5 days in 8/58 (14%) when the organism identified was either not susceptible to vancomycin or vancomycin was not considered the preferred treatment option. These included the following: 3/8 (37%) episodes where Gram-negative bacteria were isolated from blood and pus in suspected NECFour ADEs were documented in the clinical records. One episode was associated with a hypersensitivity reaction; three had acute kidney injury (AKI) attributed to vancomycin with all having preexisting chronic kidney disease . Two participants with documented AKI also received furosemide and amikacin, respectively. Whether co-administration of these drugs contributed to AKI is uncertain. Vancomycin TDM and dose adjustment were performed throughout the course of therapy for participants with ADE. Vancomycin was stopped in two (50%) episodes and continued despite the ADE in two (50%) episodes.To the best of the authors knowledge, this is the first description of vancomycin usage and prescribing practices in South African children. Intravenous vancomycin prescription occurs throughout RCWMCH, with ICU unsurprisingly accounting for most usage (51%) during 2019. Comparable vancomycin usage has not been published from healthcare facilities treating children in South Africa.7Vancomycin was prescribed exclusively for HAI and mostly as empiric treatment (80%) and less often as directed treatment (20%) with cultures routinely obtained prior to prescriptions in most (92%). Clinical indications for using vancomycin at initiation of empiric antibiotic treatment included intra-abdominal infection and NEC (26%), HAP and VAP (24%) and SSTI (19%). For directed treatment, indwelling venous catheter-associated infection (24%), HAP and VAP (19%), and intra-abdominal infection and NEC (23%) were common. Vancomycin prescription for inappropriate or non-approved indications was less frequent than previously described in other settings.19 More than two-thirds of prescriptions were for < 60 mg/kg per day. Dosing frequency was most often eight-hourly (56%) or six-hourly (27%) with dosing less frequently than eight-hourly due to prematurity or renal dysfunction.Dosing of vancomycin was variable with only 53% of prescriptions adhering to a starting dose of 15 mg/kg per day and only 22% adhering to the recommended total daily dose of 60 mg/kg per day.22The significant difference in treatment duration between empiric and directed treatment episodes suggests that vancomycin is stopped sooner once cultures are negative than in cases where cultures and AST confirm an infection where vancomycin is the appropriate treatment. However, among the 15 episodes (9%) where vancomycin treatment continued for 14 days or more, empiric treatment accounted for 80% of prescription episodes. These findings are in keeping with studies from other countries indicating that inappropriate prescribing and prolonged empiric treatment are common, with differences among age groups contributing to dosing complexity.12 and may soon be replaced with model-informed precision dosing where available.23 Infectious Diseases Society of America guidelines5 recommend AUC24/MIC targeting, whereas guidelines aiming for vancomycin serum trough concentrations of 10 mg/L \u2013 20 mg/L are still followed at RCWMCH.19 Serum trough concentration monitoring was only performed in 60% of prescription episodes overall and in 66% of episodes treatment for longer than 3 days. Only 21% of TDM samples were obtained before the fourth dose, lower than the 40% reported in a study from France that evaluated 154 vancomycin prescriptions.24 With the very variable dosing found in the study overall, it is surprising that the median vancomycin serum trough concentration in the 20 episodes with samples obtained before the fourth dose was 14 mg/L (recommended range 10 mg/L \u2013 20 mg/L)19 although the variability was wide (IQR: 6\u201318). It was difficult to interpret the serum trough concentrations that were < 10 mg/L or > 20 mg/L, as well as the appropriateness of dose adjustments done in response to these results. Although AUC24/MIC monitoring is not currently available, its future utilisation as an AMS tool may improve vancomycin dosing and safety, which is particularly important as ADEs are likely underreported at RCWMCH.14The optimal dosing of vancomycin and the role of TDM in paediatric practice remain uncertainS. aureus recorded in previous paediatric studies done in Cape Town.26The microbiological results revealed that approximately two-thirds of positive cultures occurred where an indwelling device was present. This finding suggests that improved compliance with infection prevention and control (IPC) could reduce the need for vancomycin prescription. Although blood culture yielded MRSA in 47% of isolates, it is reassuring that no isolates were non-susceptible to vancomycin. The rate of MRSA in was lower than the 72% and 65% in hospital-acquired BSI due to Like many others in LMIC settings, RCWMCH lacks the capacity to implement prospective audit and real-time feedback to prescribers, and discontinuation or de-escalation to narrower spectrum antibiotics based on culture and AST results where appropriate. Among episodes with negative cultures, vancomycin was discontinued in 41% within 3 days and 73% within 5 days of starting treatment. However, among 58 episodes with positive cultures, 8 (14%) continued vancomycin treatment despite the identification of an organism that was not susceptible to vancomycin or where vancomycin is not the preferred treatment option.This study has several limitations. It was performed at a single centre and paper-based medical record review with missing documents resulted in a high exclusion rate (23%). Uniform local guidance on vancomycin prescribing is limited and variable, and the appropriateness of vancomycin treatment based on the documented clinical syndrome could not be assessed. Clinical indications were only collected when vancomycin was initiated, as information on indications for continued prescribing was not available. Furthermore, outcome data were not available and the impact of vancomycin prescription errors on outcomes could not be accurately assessed. As a result of the diversity in prescribing practices among different institutions, results may not be applicable elsewhere.Monitoring antimicrobial consumption and instituting effective AMS interventions remain a challenge in areas where electronic prescribing is not yet feasible. This study emphasises the need to develop and implement uniform guidelines for the prescription and monitoring of vancomycin along with appropriate de-escalation practices as urgent AMS interventions. Similar guidance is important for all other antimicrobials prescribed at RCWMCH. Ongoing education of prescribers and compliance with IPC practices are essential. Future research should focus on defining methods to improve prescribing practices and evaluate future AMS interventions.Dosing errors, prolonged empiric treatment and inappropriate vancomycin monitoring were problems associated with vancomycin prescriptions in the study. Antimicrobial stewardship interventions targeting uniform guidance and concurrently improving IPC compliance may contribute to the preservation of vancomycin at RCWMCH."}
+{"text": "Long-term results after non-operative treatment for children with simple appendicitis seem promising, possibly avoiding appendicectomy in 70 per cent of children after a median follow-up of 5 years. The need for delayed appendicectomy more than 2 years after the initial treatment is rare (0\u20135 per cent) and no complications occurred past 1 year, including children who underwent delayed appendicectomy. Dear Editor,Pilot studies have shown that non-operative treatment with antibiotics (NOT) has a high initial success rate in children with simple appendicitisversus Primary\u00a0Appendectomy\u00a0in Children) trial, an ongoing randomized trial comparing NOT with appendicectomy in children with simple appendicitis; its methods, short- and medium-term results were published in 2015Here, the authors re-evaluated 49 children who previously received NOT for acute simple appendicitis in a feasibility study for the APAC . Of the 14 children who did undergo appendicectomy, four (9 (3 to 20) per cent) were classified as non-responders (failure of NOT within 7 days after start of treatment), and 10 (21 (12 to 35) per cent) as having delayed appendicectomy. Histopathological examination after the delayed appendicectomies showed simple appendicitis (7), non-inflamed appendices (2), and chronic inflammation with fibrosis (1). In none of the children who had delayed appendicectomies was complex appendicitis diagnosed. No complications occurred past 1 year, including children who underwent delayed appendicectomy.In total, 47 of 49 children could be contacted for follow-up at a median of 5.4 (range 3.9\u20137.1) years after initial treatment. Appendicectomy had not been performed in 33 of 47 children (70 (95 per cent c.i. 56 to 81) per cent)  efficacy of NOT compared with surgery, including other relevant outcomes, such as quality of life, disability days, and costs. From the results of the present study it can be concluded that the long-term results after NOT for children with simple appendicitis seem promising, possibly avoiding appendicectomy in 70 per cent of children after a median follow-up of 5 years.Disclosure. The authors declare no conflict of interest."}
+{"text": "Tenualosa ilisha, were analyzed using 16S rRNA gene sequencing. Our findings revealed a significant microbial disparity between sample categories and the habitat of hilsa fish, which will serve as a valuable foundation for further comprehensive studies on the hilsa microbiome.The gut and flesh microbiome of the national fish of Bangladesh,  Tenualosa ilisha) is the national fish of Bangladesh. It contributes ~12% of the total fish production and 1.15% GDP of the country  and flesh (n = 3) was performed within 48 h after the collection. Fish scales from the body of all individual fishes were removed by sterile forceps under aseptic conditions, and fleshes (100 mg) and lower stomach contents (100 mg) from each fish were collected. Genomic DNA was extracted from each specimen after grinding (flesh) and homogenization (gut content) using DNeasy Blood and Tissue Kit  following the manufacturer\u2019s instructions. A NanoDrop 2000c spectrophotometer was used to check the purity and concentration of DNA. The amplicon libraries were prepared using Nextera XT Index Kit (Illumina Inc.) as per the 16S amplicon sequencing library preparation protocol, and V3\u2013V4 regions were amplified through a 40-cycle PCR using 341F and 806R primers (Eighteen adult hilsa fishes were collected and frozen from September to October 2020 from five different sites in Bangladesh . Samplin primers . Paired- fleshes 0 mg and  primers  removed  primers . Sequenc primers . DefaultVagococcus (67.02%), Morganella (13.25%), Enterobacter (5.74%), Plesiomonas (3.51%), Shigella (1.75%), Clostridium (1.60%), Klebsiella (1.02%), and Serratia (1.0%) were the top abundant bacterial genera detected in hilsa fish, with distinct variations in their relative abundances according to the sample categories . The genomic data of the flesh and gut bacteriome of hilsa fish revealed in this study has laid the foundation for shedding light on the microbiome of this economically important trans-boundary fish.The 16S rRNA amplicon sequencing of 18 samples generated 3,696,608 raw reads , of which 390,289 quality reads (10.56%) mapped to 325 OTUs of bacteria. The rest of the reads (90%) were unassigned to any OTUs and might come from host DNA. Among these, 67 and 258 OTUs were identified in flesh and gut samples, respectively, through the SILVA database v.138 . These O"}
+{"text": "The intentional use of drugs before or during sexual intercourse (chemsex) is a phenomenon of special importance in the MSM (men who have sex with men) population due to its impact on mental, physical and sexual health.The objective of this study was to describe the sociodemographic and medical characteristics, psychoactive substances use of a sample of users with sexualized drug use (chemsex) attended by the non-govenrmental organization Apoyo Positivo in the program \u201cSex, Drugs and You\u201d.A cross-sectional descriptive analysis of a sample of users attended by the non-govenrmental organization Apoyo Positivo in the program \u201cSex, Drugs and You\u201d was performed.230 participants were included. Most common drugs used during sexual intercourse were: mephedrone, cocaine, poppers, GHB and methamphetamine. The frequencies of substances consumed during sex were: mephedrone (95%), methamphetamine (80%), GHB (92.2%), ketamine (52%), poppers  (95%), cocaine (89 .7%), speed (amphetamine sulfate) (49.6%) and drugs for erectile dysfunction (86%). 61.3% reported having practiced slamsex intravenous substance use at some time in their life, being a habitual practice at the time of collecting information for 50.7%. The most frequent genitally transmitted infections were: syphilis, chlamydia and gonorrhea. Users reported having been diagnosed with the following genitally transmitted infections: hepatitis B virus (7.4%), hepatitis A virus (18.6%), syphilis (69.6%), human papillomavirus (16 %), herpes (9.4%), chlamydia (43%), gonorrhea (60.5%) and candidiasis (9.7%).Slamsex and STIs are usually reported in our sample. Interventions for chemsex users must include a colaborative model which includes professionals from different areas, including internists and emergency physicians, psychiatrists, psychologists, nurses, social workers and sexologists.None Declared"}
+{"text": "The association between chronic hepatitis B (CHB) and hepatocellular carcinoma (HCC) is well established, however it can be challenging to identify those who require surveillance. The European Association for the Study of the Liver (EASL) guidelines recommend 6-monthly liver ultrasound (US) as the optimal surveillance method and using the PAGE-B score for HCC risk stratification. This score offers good predictability for HCC whilst on nucleoside analogue therapy, and it also appears reliable in untreated patients. It has also been validated for individuals with HIV/HBV coinfection. We aimed to assess the compliance of an Irish tertiary hospital with the EASL guidelines for HCC surveillance.We carried out a retrospective review of electronic medical records of patients with CHB attending the infectious diseases outpatient clinic in Beaumont Hospital, Dublin, Ireland.70 patients were included, of which 20 were co-infected with HIV. Of the 50 patients with CHB monoinfection, 4% (n=2) had cirrhosis and 20% (n=10) were on treatment. 98% (n=49) were undergoing surveillance with 90% undergoing 12-monthly US. We analysed each patient's PAGE-B score from their most recent clinic data and 6 (12%) were stratified as high risk, 24 (48%) as medium risk and 20 (40%) as low risk. Of those coinfected with HIV, 15% (n=3) patients had cirrhosis and all patients were on anti-viral therapy. 7 patients (35%) were undergoing HCC surveillance. PAGE-B scores stratified 5 patients (25%) as high risk, 10 (50%) as medium risk and 5 (25%) as low risk. [Table 1 and 2]The majority of patients with CHB monoinfection are receiving HCC surveillance with annual US. Using the PAGE-B score we identified 40% that are low risk and for which regular surveillance may be deferred. Those who were stratified as medium or high risk would benefit from more frequent 6-monthly US. This audit highlights the benefit of risk stratification in the allocation of resources. There was a lack of surveillance in our coinfected population despite 15 patients (75%) being stratified as medium or high risk. This may be due to clinicians focusing on HIV-associated issues during clinic visits and highlights the importance of addressing both infections when reviewing these patients.All Authors: No reported disclosures"}
+{"text": "To better understand the characteristics of bZIPs in chestnut and their function in starch accumulation, a series of analyses were performed including phylogenetic, synteny, co-expression and yeast one-hybrid analyses. Totally, we identified 59 bZIP genes that were unevenly distributed in the chestnut genome and named them CmbZIP01 to CmbZIP59. These CmbZIPs were clustered into 13 clades with clade-specific motifs and structures. A synteny analysis revealed that segmental duplication was the major driving force of expansion of the CmbZIP gene family. A total of 41 CmbZIP genes had syntenic relationships with four other species. The results from the co-expression analyses indicated that seven CmbZIPs in three key modules may be important in regulating starch accumulation in chestnut seeds. Yeast one-hybrid assays showed that transcription factors CmbZIP13 and CmbZIP35 might participate in starch accumulation in the chestnut seed by binding to the promoters of CmISA2 and CmSBE1_2, respectively. Our study provided basic information on CmbZIP genes, which can be utilized in future functional analysis and breeding studiesThe transcription factors of basic leucine zipper (bZIP) family genes play significant roles in stress response as well as growth and development in plants. However, little is known about the  Throughout the lifecycle of a plant, starch plays roles in development and response to the environment . Short-tTFs play an indispensable role in plant growth, development, and resistance to biotic and abiotic stresses . As one CabZIP1 gene in Arabidopsis slowed plant growth and reduced the number of petals (rT-GA2.1 gene (a member of the bZIP family) mediated by dsRNA can improve the resistance of rice to bacterial pathogens, such as Xanthomonas oryzae pv. oryzae, indicating that rTGA2.1 plays a negative role in response to bacterial pathogens (granule-bound starch synthase (GBSS) and starch branching enzyme 1 (SBE1) genes by binding to their promoters, and are capable of regulating starch synthesis (TubZIP28 (from Triticum urartu) and TabZIP28 (from Triticum aestivum) also participate in the regulation of starch synthesis by interacting with starch synthesis-related genes   (Pyrus breschneideri) (Nicotiana tabacum) (Punica granatum) (Triticum aestivum) (bZIP genes in Chinese chestnut (Castanea mollissima), despite Chinese chestnut being an economically important dry fruit tree species that is favorited for its sweet, fragrant, and waxy characteristics. The waxiness is a critical parameter for chestnut quality and is determined by the starch content in the kernel  , 114 in mestica) , 92 in pneideri) , 77 in ttabacum) , 65 in pranatum) , and 227estivum) . Howevere kernel . Over thublished . These abZIP genes from Chinese chestnut using the whole genome of N11-1, a seedling Chinese chestnut cultivar line (CmbZIP family members. Whole genome duplication (WGD) analysis revealed that segmental duplication might be the main factor that led to the expansion of the CmbZIP family. Transcriptomic data from different development stages of chestnut seeds showed that CmbZIP genes had different expression patterns, and some of them may be related to starch accumulation. These results from this study provide a theoretical reference for CmbZIP genes and insight useful for future studies on Chinese chestnut.In this study, we aimed to identify var line . We perf22.1bZIP gene family members from the whole genome of the seedling Chinese chestnut cultivar N11-1, which version provided relatively complete annotative information at the chromosome level  to 100  aa residues long Table S2bZIP genes in chestnut, we compared the DNA sequences and examined the organization of exons and introns in open reading frames of CmbZIP genes. In total, the number of introns in the CmbZIPs ranged from 0 to 13. Fifteen CmbZIPs contained three introns, accounting for the largest proportion of identified bZIP genes (25.4%). CmbZIP15 (with eight introns) and CmbZIP53 (with 13 introns), respectively, accounted for the smallest proportion of identified bZIP genes (1.6%)  Table S12.4CmbZIP genes were distributed unevenly on 11 of the 12 chromosomes (Chr) of chestnut as well as five contigs (Ctg) (CmbZIP genes. There was only one bZIP gene on the following chromosomes: Chr07 (CmbZIP28), Chr10 (CmbZIP43), Ctg1 (CmbZIP54), Ctg2 (CmbZIP55), Ctg3 (CmbZIP56), and Ctg4 (CmbZIP57); there were two bZIP genes on Ctg5 (CmbZIP58 and CmbZIP59). Eleven CmbZIP genes (18.64%) were located on Chr01, which contained the greatest number of bZIP genes, with 1 and 10 CmbZIPs, respectively, located on the proximate and distal ends of this chromosome. Five CmbZIPs were relatively evenly dispersed throughout Chr06. Three to eight bZIP genes were located on the remaining eight chromosomes.Fifty-nine gs (Ctg) Table S1CmbZIP genes, and no tandem duplications were observed, indicating that segmental duplication events were the major cause of expansion of the CmbZIP family . To predict the selection pressure driving the divergence of CmbZIPs, we also calculated the nonsynonymous substitution rate (Ka) and the Ka/Ks ratio. Seven pairs of duplicated CmbZIPs might have undergone purifying selection from 27.74\u2013116.09 Mya. The selection pressure on CmbZIP20/22 was the strongest (Ka/Ks=0.06). Conversely, CmbZIP09/45 and CmbZIP19/25 might have recently undergone positive selection from 9.50\u201311.65 Mya.We detected 10 pairs of segmental duplications in P family Table\u00a01.2.5bZIP genes family among different species, we constructed four comparative syntenic maps of chestnut associated with Arabidopsis, rice, wheat, and apple  than between chestnut and the two monocots , which might indicate that most of these orthologous pairs occurred after the divergence of dicotyledons and monocotyledons.To gain deeper insight into the evolutionary relationships of the nd apple Table S42.6CmbZIP genes related to starch synthesis, we used published transcriptome data of all genes from the N11-1 version of the reference genome to determine the fragments per kilobase transcript per million mapped reads (FPKM)  had very low levels of expression (FPKM < 0.5) in every sample. The 15 members of subclade IV had relatively high expression levels, with an average FPKM ranging from 29.1 to 130.3 (To confirm the expression patterns of s (FPKM) Table S5CmbZIPs and four physiological characteristics: total starch content, amylopectin content, amylose content, and starch synthase activity  with starch accumulation  or activity of starch synthase during chestnut seed development  in the MEbrown module. Six starch accumulation related genes were found to be co-expressing with one CmbZIP (CmbZIP35) in the MEgreen module. Two starch accumulation related genes were found to be co-expressing with one CmbZIP (CmbZIP13) in the MEred module  Table S5CmPUL1 , CmBA4_1 (-289 bp), CmISA2 (-771 bp), and CmSSS3 (-648 bp and -595 bp). Based on these findings, we can infer that CmbZIPs may regulate the expression of starch accumulation related genes through ACGT cis-elements, and then participate in the accumulation of starch in chestnut seeds.bZIP transcription factors can recognize ACGT sequences in gene promoter regions, particularly A-box (TACGTA), C-box (GACGTC), and G-box (CACGTG) sequences . InteresCmPUL1 Table S72.8bZIP genes in MEgreen and MEred by our interest, CmbZIP35 and CmbZIP13, to identify their potential functions of binding to promoters of starch accumulation related genes. In yeast one-hybrid (Y1H) assays, the Y1H Gold yeast strains containing pCmSBE1_2-AbAi\u00d7pGADT7-CmbZIP35 were able to grow on the screening synthetic dropout medium lacking uracil and leucine (SD-UL) containing 100 ng/mL Aureobasidin A (AbA)   . These gAtbZIP41 (GBF1) and AtbZIP55 (GBF3) might play roles during seed maturation  accumulation in chestnut seeds (CmISA2 (encoding an isoamylase-type starch de-branching enzyme) and CmSBE1_2 (encoding a starch branching enzyme)  (http://pfam.xfam.org/)  and Batch CD-Search web tool (https://www.ncbi.nlm.nih.gov/cdd/)  . A hiddeam.org/) . To idensoftware  was usedov/cdd/) .4.2CmbZIP genes were submitted to ExPASy (https://www.expasy.org) to determine gene length, amino acid length, relative molecular weight, isoelectric point, hydrophilicity, stability, and other physicochemical properties analysis. The protein sequences of 59 CmbZIP genes, 23 AtbZIP genes  was used to annotate and visualize the phylogenic trees  file, and visualized using the online software Gene Structure Display Server (http://gsds.cbi.pku.edu.cn/)  . Conservedu.cn/)  with mot4.4CmbZIP genes were mapped to Chinese chestnut chromosomes based on physical location information from the GFF file using Mapchart 2.32 software   . We usedomestica .4.5CmbZIPs were determined using Tophat2 software  published in a previous study were estimated using GraphPad Prism version 6.02 for Windows (https://www.graphpad.com/). The co-expression modules were identified using WGCNA with the R package (The published RNA-seq data were obtained from the sequence read archive (SRA) in NCBI (accession number PRJNA540079) . All seesoftware . The FPK package . The co- package .4.6We retrieved sequences 1,500 bp upstream of the transcription start site of starch accumulation related genes. These sequences were submitted to PlantCARE to identify cis-elements, which might affect gene expression and function .4.7CmbZIP35 and CmbZIP13 were cloned by reverse transcription PCR using RNA from developing seeds of C. mollissima cultivar \u2018Yanbao.\u2019 We confirmed these sequences using DNAMAN 6.0 software. Subsequently, we fused the two sequences into the pGADT7 vector to construct the pGADT7-CmbZIP35 and pGADT7-CmbZIP13 recombinant plasmids, respectively. The CmSBE1_2 and CmISA2 promoter fragments were cloned by PCR using DNA from \u2018Yanbao\u2019 seeds. The fragments were confirmed and inserted into the pAbAi vector to construct the pCmSBE1_2-AbAi and pCmISA2-AbAi recombinant plasmids. All primer sequences are listed in The open reading frames of To determine the optimal AbA concentration, the Y1H Gold yeast strain containing the recombinant pAbAi plasmids were grown on SD-UL screening medium supplemented with different AbA concentrations . Then, Y5CmbZIP genes were identified in Chinese chestnut. These CmbZIPs were clustered into 13 clades with clade-specific motifs and structures. Segmental duplication was determined as the major driving force of the expansion of the CmbZIP gene family. CmbZIP04, CmbZIP13, CmbZIP14, CmbZIP33, CmbZIP35, CmbZIP38, and CmbZIP56 were confirmed to be highly correlated with starch accumulation in chestnut seeds. We demonstrated that CmbZIP13 and CmbZIP35 may regulate starch accumulation in the chestnut seed by binding to the promoters of CmISA2 and CmSBE1_2, respectively. These results indicated that CmbZIP genes contained information related to starch accumulation in chestnut seeds, which can be used in future functional analysis and breeding studies.A total of 59 The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/XW and HZ designed the experiments. MW and YL collected data of Chinese chestnut genome and RNA-seq. NJ and JL drew all figures of this study. PZ and JL carried out the yeast one-hybrid experiments. PZ and XW performed the bioinformatic analysis and wrote the paper. DW and JZ directed and revised the manuscript. All authors contributed to the article and approved the submitted version."}
+{"text": "Prelabour rupture of membranes is a common obstetrics problem associated with maternal and perinatal morbidity and mortality. The exact cause is not known although various factors are found to be related to this condition. Hence, the objective of this study was to find out the prevalence of prelabour rupture of membranes among pregnant women in a tertiary care centre.This was a descriptive cross-sectional study conducted from 1 November 2021 to 30 November 2022. Ethical approval was taken from the Institutional Review Committee (Reference number: 2078/79/49). A structured proforma was filled out after taking a detailed history from each pregnant woman. Convenience sampling method was used. Point estimate and 99% Confidence Interval were calculated.Among 700 pregnant women, the prevalence of prelabour rupture of membranes was 56 (8%) . Among them, 40 (71.43%) occurred in the term, while preterm (before 37 weeks) occurred in 16 (28.57%) of all pregnancies. Previous miscarriage occurred in 15 (26.78%) followed by gestational diabetes mellitus 8 (14.28%).The prevalence of prelabour rupture of membranes was found to be lower than other studies done in similar settings. PROM complicates approximately 8% of pregnancies in the term,1 while PPROM (before 37 weeks) occurs in approximately 3% of all pregnancies and accounts for one-third of preterm births.2 PROM is a common obstetrics problem associated with maternal and perinatal morbidity and mortality.3Prelabour rupture of membrane (PROM) is the spontaneous rupture of the membrane before the onset of labour.5The exact cause of PROM is not known and the causes could be multifactorial. There are various factors that are related to PROM including prior preterm birth, cigarette smoking, polyhydramnios, urinary and sexually transmitted infection, prior PROM, work during pregnancy, low body mass index, bleeding, and low socioeconomic status.The aim of this study was to find out the prevalence of prelabour rupture of membranes among pregnant women in a tertiary care centre.This was a hospital-based descriptive cross-sectional study conducted from 1 November 2021 to 30 November 2022 after obtaining ethical approval from the Institutional Review Committee (Reference number: 2078/79/49) from the Department of Obstetrics and Gynecology at KIST Medical College and Teaching Hospital, Gwarko, Lalitpur, Nepal. Patients were informed regarding the study and informed written consent was taken prior to the study. All the admitted pregnant women from the gestational age of 28 weeks and above were recruited. Pregnant women with onset of labour within <1 hour of rupture of membrane or with artificial rupture of membranes were excluded. Convenience sampling method was used. The sample size was calculated by using the following formula:Where,n = minimum required sample sizeZ = 2.57 at 99% Confidence Interval (CI)p = prevalence taken as 50% for maximum sample size calculationq = 1-pe = margin of error, 5%The minimum calculated sample size was 661. However, the final sample size taken was 700.The diagnosis of PROM was based on a maternal history of the passage of a gush of fluid per vagina before the onset of labour plus visualization of pooling of amniotic fluid in the posterior vaginal fornix or/and direct visualization of fluid leakage from the cervical canal per speculum examination. Ultrasonographic demonstration of oligohydramnios was taken as evidence of PROM where the history or clinical examination is inconclusive. Thorough history regarding sociodemographic and obstetrics variables was obtained from the patients, and risk factors such as previous miscarriage, previous preterm delivery, previous PROM, cervical surgery/ cerclage, previous cesarean section, abnormal vaginal discharge /genital infection in pregnancy, urinary tract infection, abdominal trauma, coitus in the third trimester, cigarette smoking during pregnancy, bleeding during pregnancy, polyhydramnios, chronic hypertension/ pregnancy-induced hypertension (PIH), diabetes/ gestational diabetes mellitus (GDM), thyroid disorder and anaemia during index pregnancy were documented in structured proforma.Data were entered in Microsoft Excel and analyzed using IBM Statistics SPSS 18.0. Point estimate and 99% CI were calculated.Among 700 pregnant women, the prevalence of prelabour rupture of membranes was 56 (8%) .Out of 56 patients, 25 (44.64%) were in the age group 25-29 years. Twenty-one (37.50%) women were involved in physical efforts and standing work. Fifty-one (91.07%) belong to middle-class families .There were equal number of primi and multi gravida 28 (50%) with nulli parity in 30 (53.57%) cases and most of them were booked cases 48 (85.71%) with \u2265 4 ANC visits 52 (92.85%). Twin pregnancy was seen in 2 (3.57%) cases and 4 (7.14%) had malpresentation in the index pregnancy .Among 56 women, 15 (26.78%) had a previous miscarriage, followed by diabetes in 8 (14.28%) women .6 This is also similar to a study done in Bangladesh with the prevalence of PROM of 8.2%.7 Term PROM was higher 39 (69.2%) than preterm PROM 17 (30.8%). Similarly, a study done in India reported prevalence as 9.8%.8 This study is also in agreement with the systematic review and meta-analysis,9 that showed the pooled prevalence of PROM was 9.2% among pregnant women in Ethiopia. In contrast, a multi-centric study in China,10 showed a high prevalence of PROM to be 18.72%. Also, a study done in Indonesia,11 found that the prevalence of PROM was 22.6%. The differences in prevalence could be due to the difference in the population studied.The prevalence of prelabour rupture of membranes was 56 (8%) among 700 pregnant women. Out of which 40 (71.42%) occurred in the term, while PPROM occurred in 16 (28.57%) of all pregnancies. This finding is similar to the previous study done in Nepal, which reported the prevalence of PROM to be 8.9%.6 In the study conducted in Iran, the maternal risk factors included diabetes 12.7%, hypertension 9.5%, smoking 8.9%, history of premature rupture of membrane 8.9%, urinary tract infection 7.2%, thyroid disorders 5%, history of preterm delivery 4.4%, and cerclage 3.8%.12 However, none of the women in our study had cigarette smoking and cervical cerclage/history of cervical surgery.Our study revealed the most commonly reported causes were previous miscarriage 15 (26.78%), diabetes/gestational diabetes mellitus 8 (14.28%), history of previous cesarean section 7 (12.50%), sexual intercourse in third trimester 6 (10.71%), previous preterm delivery, previous PROM, urinary tract infection, bleeding during pregnancy 4 (7.14%), abnormal vaginal discharge/genital infection in pregnancy, chronic hypertension/PIH, thyroid disorder 2 (3.57%), anaemia, and polyhydramnios during index pregnancy 1 (1.78%). This finding was similar to a previous study done in Nepal, where the frequently associated maternal risk factors were a history of prior abortion 19.5%, urinary tract infection 8.5%, and antecedent coitus 8.5%.7 In consistency, our study also revealed twin pregnancy 2 (6.7%) and malpresentation 4 (7.14%) in the index pregnancy.In the study conducted in Bangladesh, the study of factors revealed aetiology was unknown in 46 (6.8%), low socioeconomic condition 60.6%, anaemia 45%, lower genital tract infection 35.6%, UTI 31%, previous history of PROM 27.9%, malpresentation 15%, multiple pregnancies 6.7%, polyhydramnios 6%, history of recent coitus 12%, DM and GDM 10.5% were commonly associated with PROM.8 Similarly, the maximum cases belonged to the age group 25-29 years 25 (44.64%). A study conducted in Nigeria showed the previous history of PROM, history of preterm delivery, low socioeconomic status, and genitourinary infection were highly predictive of PROM.13 In contrast, the majority of PROM cases were of middle socioeconomic status 51 (91.07%) in this study.A study of factors of PROM in India showed the cause of most PROM cases was unclear but associated with the history of PROM. Most cases of PROM occurred in housewives aged 20 to 30 years old.14 However, the majority of cases had regular ANC with \u22654 ANC visits 52 (92.85%) in this study. In addition, another study in Southern Ethiopia (2022)15 showed hypertension during the index pregnancy (38.7%), history of abortion (37.3%), history of PROM (48%), and history of cesarean section (33.3%) were related to premature rupture of membrane.In a hospital-based study in Southern Ethiopia, previous history of abortion, lack of ANC, previous history of PROM, caesarean delivery, use of a maternal waiting room (MWR), and mid-upper arm circumference (MAUC) <23 cm were identified as determinants of PROM.There are a few limitations in this study. Since this is a descriptive study, the analytical parameters could not be evaluated. Also, the study is based on a single centre hence, the findings of this study cannot be generalized to the general populations across the nation.The prevalence of prelabour rupture of membranes was found to be lower than other studies done in similar settings. Timely identification of the causative factors can help clinicians in identifying at-risk women for intensified obstetric and neonatal care and also in formulating prevention programs."}
+{"text": "School-based interventions are considered the best approach to increase young people\u2019s physical activity levels, although their effectiveness and sustainability remain unclear. This work aims to determine if a school-based physical activity and sports programs (PASP) policy is being evaluated by schools.A representative sample of 257 Active schools in the Valencian Community (Spain) participated in the study. The coordinator of each school answered an ad-hoc on-line questionnaire, consisting of 47 open and closed questions aimed to identify the Active school coordinators\u2019 profiles and the actions implemented to foster PASP and their assessment. Descriptive statistics and chi-square tests were conducted on SPSS Statistics v. 26.0 software.\u03c72(1)=9.385; p<.05) and evaluating the PASP \u03c72(1)=14.154; p<.05) depended on whether the school coordinators had received specific training related to promoting physical activity, sports and health.Fifty-one percent of the Active schools had a commission in charge of designing, implementing, and evaluating the PASP . However, in many cases this commission never actually met (49%) and the rest met with the following frequency: once a school year (14.4%), once a term (4.3%), once a month (1.6%) and weekly (30.7%). Nearly 80% of the schools carried out some form of PASP evaluation: by diagnosis (19.5%), monitoring (43.2%), effectiveness (44.7%) or final meetings in the educational cycle (20.6%). Both having a commission Only half of the Active schools had PASP evaluation commissions and most of these met very infrequently. Although most of the Active schools did evaluate their interventions, less than half focused on their effectiveness. Teacher training was a determining factor in both creating these commissions and developing PASP assessment processes. These results show the importance of improving pre- and in-service teacher training, especially for Physical Education teachers in relation to health education and PASP promotion in school settings.This study was funded by Grant AICO/2021/342 of the CIUCSD (Spain), Postdoc grant Margarita Salas funded by the University of Castilla-La Mancha [MS2021] and predoctoral contract UV-INV-PREDOC20-1339837 funded by University of Valencia."}
+{"text": "To what extent are clinicians adhering to the 2017 Clinical Practice Guideline and using a clinical decision support tool to calculate blood pressure percentiles for pediatric hypertension diagnosis, management, and follow-up?In this cross-sectional study of 23\u2009334 children and adolescents (aged 3-17 years) with elevated blood pressure, less than half had a corresponding diagnosis in their medical record or attended the recommended follow-up visit. Using the clinical decision support tool was associated with higher rates of diagnosis, but the tool was underused.These findings suggest that pediatric hypertension and elevated blood pressure remain underdiagnosed and undertreated among children and adolescents, which may have negative health consequences in adulthood. This cross-sectional study examines the rates of adherence to the 2017 Clinical Practice Guideline for the diagnosis, management, and follow-up of hypertension and use of a clinical decision support tool to calculate blood pressure percentiles in children and adolescents. The 2017 Clinical Practice Guideline (CPG) for the diagnosis and management of pediatric hypertension (PHTN) categorizes a greater proportion of children with elevated blood pressure and PHTN, yet several barriers to CPG adherence have been noted.To assess adherence to the 2017 CPG for the diagnosis and management of PHTN and use of a clinical decision support (CDS) tool to calculate blood pressure percentiles.This cross-sectional study used electronic health record\u2013extracted data from January 1, 2018, to December 31, 2019, among patients visiting 1 of 74 federally qualified health centers in AllianceChicago, a national Health Center Controlled Network. Children and adolescents  who attended at least 1 visit and had at least 1 blood pressure reading at or above the 90th percentile or diagnosis of elevated blood pressure or PHTN were eligible for data to be included in the analysis. Data were analyzed from September 1, 2020, to February 21, 2023.Blood pressure at or above the 90th or 95th percentile.International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10], code I10) or elevated blood pressure (ICD-10 code R03.0) and CDS tool use; blood pressure management ; and follow-up visit attendance. Descriptive statistics described the sample and rates of guideline adherence. Logistic regression analyses identified patient- and clinic-level associations with guideline adherence.Diagnosis of PHTN . Guideline-adherent diagnosis was observed in 8810 children (37.8%) with blood pressure at or above the 90th percentile and 146 of 2542 (5.7%) with blood pressure at or above the 95th percentile at 3 or more visits. The CDS tool was used to calculate blood pressure percentiles in 10 524 cases (45.1%) and was associated with significantly greater odds of PHTN diagnosis . Among 15 422 children with blood pressure at or above the 95th percentile, antihypertensive medication was prescribed to 831 (5.4%), lifestyle counseling was provided to 14\u2009841 (96.2%), and blood pressure\u2013related referrals were given to 848 (5.5%). Guideline-adherent follow-up was observed in 8651 of 19\u2009049 children (45.4%) with blood pressure at or above the 90th percentile and 2598 of 15\u2009164 (17.1%) with blood pressure at or above the 95th percentile. Differences in guideline adherence by patient- and clinic-level factors were observed.In this study, fewer than 50% of children with elevated blood pressure had a guideline-adherent diagnosis code or attended guideline-adherent follow-up. Using a CDS tool was associated with guideline-adherent diagnosis, but the tool was underused. Further work is needed to understand how to best support implementation of tools promoting PHTN diagnosis, management, and follow-up. Another EHR study10 found that although blood pressure was nearly always measured at well-child visits, less than half of children with elevated blood pressure received appropriate, guideline-adherent management. Accurate diagnosis is critical for appropriate treatment planning to reduce the risk of future health consequences, as elevated blood pressure in children is associated with impairments in cardiac  and vascular  structures,14 as well as neurocognitive and psychological effects.15 Consequently, children with PHTN are at greater risk of developing hypertension, metabolic syndrome, and left ventricular hypertrophy in adulthood.17Research shows that children with elevated blood pressure and PHTN frequently go undiagnosed.19 In medicine broadly, heuristic decision-making and implicit bias among clinicians can affect treatment recommendations, particularly among patients who are members of historical minority groups.21 Clinical decision support (CDS) tools in the EHR have been shown to save time and decrease clinician decision-making burden, leading to improved recognition of PHTN.23Numerous barriers to PHTN diagnosis and management have been identified, including high patient volumes and short visit times in primary care; low confidence in blood pressure readings due to poor measurement technique or inadequate equipment; and lack of patient follow-up.To date, most studies examining PHTN guideline adherence, as well as use of CDS tools, have been conducted using the Fourth Report. Our primary aim was to examine the rates of adherence to the 2017 CPG for PHTN diagnosis, management , and follow-up. Our secondary aim was to assess associations with guideline adherence, including patient and clinic characteristics and the use of a CDS tool in the EHR designed to facilitate guideline adherence and patient and clinic characteristics.STROBE) reporting guideline for observational studies. All procedures were approved by Northwestern University\u2019s Institutional Review Board, which waived the need for informed consent owing to the use of retrospective data.This report follows the Strengthening the Reporting of Observational Studies in Epidemiology  or PHTN . Patients were excluded if they were pregnant or diagnosed with heart disease.This study included 23\u2009334 children and adolescents  who attended at least 1 health care visit in the AllianceChicago network during the study period and had at least 1 systolic or diastolic blood pressure reading at or above the 90th percentile (aged <13 years) or systolic blood pressure of at least 120 mm Hg and diastolic blood pressure of at least 80 mm Hg (aged \u226513 years) during the study period, and/or had an Participants in the AllianceChicago network use a centrally hosted, common EHR system (AthenaPractice). All visit information, patient characteristics, vital signs, and orders are recorded in the EHR.The following patient characteristics were extracted as coded in the EHR: sex (boys or girls), age , race , ethnicity , and weight status per body mass index (BMI) percentile . Clinic characteristics included the setting .The CDS tool, available starting January 1, 2018, was designed to automate calculation of blood pressure percentiles, classify blood pressure values, identify abnormal values, provide guidance on obtaining manual blood pressure values, and calculate mean values per the 2017 CPG ; orThe child had at least 1 systolic or diastolic blood pressure value at or above the 90th percentile if younger than 13 years, systolic blood pressure at least 120 mm Hg or diastolic blood pressure at least 80 mm Hg if 13 years or older (hereafter referred to as blood pressure \u226590th percentile), and an elevated blood pressure diagnosis (ICD-10 code I10).The child had at least 3 systolic or diastolic blood pressure values at or above the 95th percentile if younger than 13 years, systolic blood pressure at least 130 mm Hg or diastolic blood pressure at least 80 mm Hg if 13 years or older (hereafter referred to as blood pressure \u226595th percentile), and a PHTN diagnosis . We extracted data concerning receipt of a hypertension-relevant referral .The management options for elevated blood pressure included (1) antihypertensive medications, (2) lifestyle counseling, and (3) referrals to specialists. We extracted data concerning antihypertensive medication prescription  (a complete list is provided in the eMethods in 25).The 2017 CPG recommends that patients with blood pressure at or above the 90th or 95th percentile attend a follow-up visit within 6 months or within 2 weeks, respectively. Thus, patients with blood pressure at or above the 90th and 95th percentiles were included if they attended a first visit between January 1, 2018, and June 30, 2019, and were coded as attending guideline-adherent follow-up if they had a second visit within 6 months of the first. Patients with blood pressure at or above the 95th percentile were included if they attended a first visit between January 1, 2018, and November 30, 2019, and were coded as attending guideline-adherent follow-up if they had a second visit within 1 month of the first  elevated blood pressure diagnosis among children with at least 1 blood pressure measurement at or above the 90th percentile and (2) PHTN diagnosis among children with at least 3 blood pressure measurements at or above the 95th percentile. Outcomes for guideline-adherent management included (1) antihypertensive medications, (2) lifestyle counseling, and (3) referrals for children with blood pressure measures at or above the 90th percentile as well as children with blood pressure measures at or above the 95th percentile. Outcomes for guideline-adherent follow-up included 6-month follow-up attendance among children with blood pressure measures at or above the 90th percentile and 1-month follow-up attendance among children with blood pressure measures at or above the 95th percentile. For the secondary aim, multivariable logistic regressions were used to identify associations with guideline-adherent diagnosis, management, and follow-up. Covariates included in all models were patient sex (boys or girls), age (in years), race , ethnicity , BMI status , clinic setting , and CDS tool use . All analyses were conducted using Stata, version 17 (StataCorp LLC).The sample, consisting of 23\u2009334 children with blood pressure at or above the 90th percentile on at least 1 visit, included 12 811 boys (54.9%) and 10 523 girls (45.1%) with a median age of 8  years, and of diverse racial  and ethnic (11 978 [51.3%] Hispanic or Latino and 10 687 [45.8%] non-Hispanic or non-Latino) backgrounds . Of thosICD-10 diagnostic code (R03.0). Compared with children without the diagnosis code, those with the diagnosis code were more likely to be older (4534 of 5839 children [77.7%] aged \u226512 years vs 1893 of 8139 children [23.3%] aged \u22646 years); Black (2479 of 6084 [40.7%]) vs White (5314 of 13 663 [38.9%]) race and White vs Hispanic or Latino (442 of 1417 [31.2%]), other (53 of 284 [18.7%]), or unknown (243 of 855 [28.4%]) race; Hispanic or Latino (5054 of 11 978 [42.2%]) or unknown (239 of 669 [35.7%]) vs non-Hispanic or non-Latino (3517 of 10 687 [32.9%]) ethnicity; classified with obesity (4337 of 9321 [46.5%]) vs normal (2948 of 9727 [30.3%]) BMI; and have attended a clinic in an urban (7208 of 16 863 [42.7%]) vs suburban (1177 of 3794 [31.0%]) or rural (425 of 2677 [15.9%]) setting. There was no significant difference in diagnosis by sex.Guideline-adherent diagnosis results are presented in ICD-10 code (I10). Children who met criteria had greater odds of having a PHTN diagnosis code if they were older (119 of 1041 [11.4%] aged \u226512 years vs 7 of 493 [1.4%] aged \u22646 years); multiracial (4 of 37 [10.8%]) vs White (79 of 1563 [5.1%]) race; and have attended a clinic in rural (22 of 346 [6.4%]) vs urban (95 of 1714 [5.5%]) setting. There were no significant differences in diagnosis by sex, ethnicity, or BMI status.Of 11\u2009675 children who attended at least 3 visits during the study period, 2542 (21.8%) had blood pressure measurements at or above the 95th percentile at 3 visits or more and thus met criteria for PHTN. Of those children, only 146 (5.7%) had a corresponding ICD-10 code R03.0: 4733 of 8436 [56.1%] vs 4077 of 14 892 [27.4%]) and blood pressure at or above the 95th percentile at 3 visits or more (ICD-10 code I10: 118 of 1089 [10.8%] vs 28 of 1451 [1.9%]) .The CDS tool was used to calculate systolic blood pressure percentile for 10\u2009524 children (45.1%). Associations with CDS tool use are presented in the eResults and eTable 1 in Guideline-adherent management results were similar between blood pressure at or above the 90th and 95th percentiles; thus, results for blood pressure at or above the 95th percentile are presented in Antihypertensive medication was prescribed to 831 children (5.4%). Children prescribed antihypertensive medication were more likely to be older (307 of 4151 [7.4%] aged \u226512 years vs 92 of 5271 [1.7%] aged \u22646 years); boys (572 of 8563 [6.7%]) vs girls (259 of 6859 [3.8%]); White (495 of 9039 [5.5%]) vs Asian (10 of 489 [2.0%]), Black (246 of 3970 [6.2%]), Hispanic or Latino (18 of 924 [1.9%]), and other (5 of 197 [2.5%]) race; non-Hispanic or non-Latino (570 of 7176 [7.9%] vs Hispanic or Latino (236 of 7836 [3.0%]) ethnicity; and have attended a clinic in a rural (221 of 1871 [11.8%]) rather than an urban (490 of 10 915 [4.5%]) setting. There was no significant difference in prescriptions by BMI status.Lifestyle counseling rates were high (14\u2009841 [96.2%]). Children who received lifestyle counseling were more likely to be younger (5195 of 5271 [98.6%] aged \u22646 years vs 4019 of 4151 [96.8%] aged \u226512 years); girls (6680 of 6859 [97.4%]) vs boys (8161 of 8563 [95.3%]); Asian (484 of 489 [99.0%]) or Black (3776 of 3970 [95.1%]) vs White (8718 of 9039 [96.4%]) race; Hispanic or Latino (6816 of 7176 [95.0%]) vs non-Hispanic or non-Latino (7638 of 7836 [97.5%]) ethnicity; and classified with overweight (2346 of 2427 [96.7%]) or obesity (6467 of 6669 [97.0%]) vs normal (5731 of 6010 [95.4%]) BMI. There was no significant difference in counseling by clinic setting.Referrals for specialty services related to elevated blood pressure were provided to 848 children (5.5%). Children who received a referral were more likely to be younger (418 of 5271 [7.9%] aged \u22646 years vs 185 of 4151 [4.5%] aged \u226512 years); White (550 of 9039 [6.1%]) vs Asian (18 of 489 [3.7%]), other (2 of 197 [1.0%]), or unknown (23 of 587 [3.9%]) race; Hispanic or Latino (535 of 7836 [6.8%]) vs non-Hispanic or non-Latino (229 of 7176 [3.2%]) ethnicity; classified with normal (535 of 7836 [6.8%]) vs overweight (134 of 2427 [5.5%]) or obesity (168 of 6660 [2.5%]) BMI; and have attended a clinic in an urban (732 of 10 915 [6.7%]) vs suburban (114 of 2636 [4.3%]) or rural (2 of 1871 [0.1%]) setting. There was no significant difference in referrals by sex.Guideline-adherent follow-up results are presented in Of 15\u2009164 children with blood pressure at or above the 95th percentile who were eligible for the follow-up visit analyses, 2598 (17.1%) attended a follow-up visit within 1 month. Children who attended a guideline-adherent follow-up visit were more likely to be older (1101 of 4118 [26.7%] aged \u226512 years vs 544 of 5128 [10.6%] aged \u22646 years); boys (1529 of 8428 [18.1%]) vs girls (1069 of 6736 [15.9%]); and White (1639 of 8900 [18.4%]) vs Black (611 of 3896 [15.7%]) or Hispanic or Latino (125 of 911 [13.7%]) race. There were no significant differences by ethnicity, BMI status, or clinic setting.7 To our knowledge, this is the first analysis to examine the rates of guideline-adherent PHTN diagnosis and management documented in the EHR using the 2017 CPG. Compared with a prior study in this population using the Fourth Report,12 guideline-adherent diagnosis rates for PHTN using the 2017 CPG were considerably lower (5.7% vs 42%) while the rates of children diagnosed with prehypertension or elevated blood pressure without a diagnosis of hypertension were higher (37.8% vs 17%). Consistent with prior studies, children who were boys, older (aged \u226513 years), and classified with overweight or obesity were more likely to be diagnosed with PHTN or elevated blood pressure.27 Additionally, children seen in urban-based clinics were more likely to have a guideline-adherent diagnosis code for elevated blood pressure, but not PHTN.With the publication of the 2017 CPG for the diagnosis and management of PHTN, the rate of children who meet diagnostic criteria for PHTN has increased.4 Accordingly, 96.2% of patients in this sample received some form of lifestyle counseling, suggesting that recording a guideline-adherent diagnosis had a minimal effect on delivery of guideline-adherent counseling. Children classified with overweight and obesity had 33% and 56% greater odds, respectively, of receiving lifestyle counseling. Among children meeting criteria for elevated blood pressure or PHTN, 5.4% were prescribed antihypertensive medication and 5.5% received a referral for potential blood pressure\u2013related specialty care. Interestingly, antihypertensive medications were more likely to be prescribed to children attending a clinic in a suburban or rural setting, while referrals were more likely to be given to those in in an urban setting. A recent survey of pediatric clinicians in the AllianceChicago network28 found that 71% of clinicians agreed that selecting and prescribing antihypertensive medications was a barrier to PHTN management, and 74% preferred to refer children with PHTN to a specialist for treatment. These findings highlight the need to ensure that pediatric clinicians, particularly those in rural settings where specialty services may not be as readily available, have adequate comfort and familiarity with antihypertensive medications to manage PHTN per the 2017 CPG. Furthermore, reducing barriers to accessing specialty care  is critical for blood pressure management in children.Behavioral change is the first-line intervention recommended for treating elevated blood pressure among children.4 children with blood pressure at or above the 90th and 95th percentiles should attend a follow-up visit within and 6 months and 2 weeks, respectively, for a follow-up blood pressure reading. In the present sample, 54.1% of children with blood pressure at or above the 90th percentile attended a 6-month follow-up visit but only 17.1% of children with blood pressure at or above the 95th percentile attended a follow-up visit within 1 month, similar to a prior study (21%).25 Lack of patient follow-up inherently limits the ability of clinicians to confirm 3 occurrences of blood pressure at or above the 95th percentile and confidently diagnose and treat PHTN. Specific strategies targeting patient attendance, using home or ambulatory blood pressure monitoring,29 and reducing barriers to accessing specialty care might improve follow-up and increase rates of guideline-adherent PHTN diagnosis and subsequent management.Per the 2017 CPG,21 Using EHR-based tools, such as the CDS tool, can be used to mitigate the harmful effects of implicit racial and sex bias and increase equitable identification and management of PHTN.30We observed several differences in guideline adherence by patient-level characteristics. For example, while guideline-adherent elevated blood pressure diagnosis was highest among Black children, rates of antihypertensive medication prescription, referral, and follow-up were higher among White children. Similarly, a higher proportion of boys than girls was prescribed antihypertensive medication and attended follow-up visits. These substantial racial and sex differences in PHTN management may be suggestive of implicit bias.11 Clinical decision support tools are often implemented to support clinicians and improve clinical care, such as increasing adherence to clinical guidelines. Unfortunately, the PHTN CDS tool implemented in AllianceChicago clinics was used on fewer than half the patients with elevated blood pressure readings (\u226590th percentile), and uptake was significantly lower in rural compared with urban clinics. These findings are consistent with prior studies in PHTN and more broadly, indicating that these tools are effective but have low adoption rates.31 Thus, comprehensive implementation strategies are needed to increase uptake of effective CDS tools to promote guideline-adherent PHTN diagnosis and management. For example, a stakeholder advisory panel consisting of AllianceChicago pediatricians and academic partners identified 18 discrete implementation strategies needed to improve CPG adherence, including education and training, workflow changes, and leadership support.19The findings from this study underscore the evidence-to-practice gap in guideline implementation.ICD-10 codes. Finally, the true prevalence of PHTN is unknown, as the diagnosis requires 3 instances of elevated blood pressure at or above the 95th percentile, and the rates of follow-up visit attendance were low.This study has some limitations. First, the focus on high-risk children with at least 1 blood pressure reading at or above the 90th percentile limits the generalizability of these findings. Second, data extracted from the EHR limits the information we have, including whether the management options  were specific to elevated blood pressure ; the method of blood pressure measurement  is unknown; follow-up blood pressure measures may have been normal but not entered in the EHR; or diagnoses entered as text in notes may not be included as 32 However, in this cross-sectional study, elevated blood pressure and PHTN were underdiagnosed and undertreated among children seen in safety-net clinics, and a CDS tool to facilitate diagnosis was underused. Comprehensive implementation strategies are needed to address this evidence-to-practice gap, including strategies to support the implementation of health information technology tools.Adhering to the 2017 CPG is critical for reducing PHTN-related morbidity and mortality among children, adolescents, and adults."}
+{"text": "This cross-sectional study evaluates the consistency of US medical license renewal applications with the Federation of State Medical Boards recommendations for questions regarding physician mental health. Secondary objectives include assessing the consistency between initial and renewal applications and examining the progress made in following FSMB guidelines for initial licensing applications since 2020. To our knowledge, this is the first study assessing the FSMB recommendation consistency on renewal applications.STROBE) reporting guideline. The Mayo Clinic institutional review board waived informed consent because data were publicly available.This cross-sectional study follows the Strengthening the Reporting of Observational Studies in Epidemiology  between February and April 2023.Between March and December 2022, initial and renewal applications from 55 US state and territory allopathic medical licensing boards were collected and scored by 2 authors (R.D. and B.P.) using previously described methods.Initial and renewal medical license applications were obtained from all 50 states, Washington DC, and 4 US territories. For renewal applications, only 3 states or territories (5%) met all 4 recommendations, 28 (51%) met 3 recommendations, 12 (22%) met 2 recommendations, 9 (16%) met 1 recommendation, and 3 (5%) met no recommendations .In 2022, fewer renewal applications met the only if impaired criteria compared with initial applications (40 of 55 [73%] vs 47 of 55 [85%]), but renewal applications more often met criteria for safe haven nonreporting (33 of 55 [60%] vs 23 of 55 [42%]), and only current (49 of 55 [89%] vs 46 of 55 [84%]) compared with initial applications .Compared with 2020 initial applications, more 2022 initial applications met the criteria for only if impaired (47 of 55 [85%] vs 39 of 54 [72%]) and only current (46 of 55 [84%] vs 41 of 54 [76%]) recommendations. However, the 2022 initial applications met safe haven nonreporting (23 of 55 [42%] vs 25 of 54 [46%]) and supportive language criteria less frequently (7 of 55 [13%] vs 8 of 54 [15%]) .The findings of this cross-sectional study suggest that the consistency of renewal applications with FSMB guidelines is notably low, particularly for safe haven nonreporting and supportive language. Notably, the renewal application of only 3 states or territories met all recommendations, suggesting that substantial work is needed to fully support our health care workforce in an era marked by rising physician burnout and mental health issues.There was also marked heterogeneity between initial and renewal applications within the same state. Notably, renewal applications fared far better in safe haven nonreporting. Addressing these within-state discrepancies offers a straightforward and meaningful opportunity to support physician mental health care.Progress since 2020 has been mixed. Initial applications demonstrated an improvement in meeting the only if impaired and only current recommendations, which may suggest an emphasis on ADA compliance. It is concerning that consistency with safe haven nonreporting and supportive language has not improved because reducing stigma is critical to removing barriers to care access. A paradigm shift is needed, where boards see supporting physician mental health as crucial to safeguarding public health.This study had limitations. One limitation was potential changes to applications within the review period. Future research should investigate the association of safe haven nonreporting and supportive language with physicians mental health and their awareness of treatment options."}
+{"text": "Severe COVID-19 patients experience elevated levels of serologic indicators of inflammation which can alter blood cell lineages and cause lymphopenia. The objective of this study was to find out the prevalence of severe COVID-19 among admitted COVID-19 patients in a tertiary care centre.A descriptive cross-sectional study was conducted in a tertiary care centre from 22 June 2021 to 30 September 2021 after obtaining ethical approval from the Institutional Review Committee (Reference number: IRC-PA-146/2077-78). Confirmed COVID-19 patients by reverse transcriptase polymerase chain reaction and admitted in the COVID block during the study period were included and those who were discharged on request or referred or unavailable blood tests were excluded. A convenience sampling method was used. Point estimate and 95% Confidence Interval were calculated.Among 72 admitted COVID-19 patients, 63 (87.5%)  patients had severe disease. The mean neutrophil to lymphocyte ratio and mean lymphocyte to C-reactive protein ratio were 11.60\u00b18.15 and 25.55\u00b120.96 respectively.The prevalence of severe COVID-19 was higher than in other studies done in similar settings. We suggest clinical parameter-based early categorisation of COVID-19 cases to utilize limited resources during the pandemic. These cytokines stimulate several downstream pathways, increasing the production of acute-phase reactants like CRP, and increasing the mobilization of neutrophils. This, along with stress-induced neutrophilia, likely explains the relative lymphopenia.The objective of this study was to find out the prevalence of severe COVID-19 among admitted COVID-19 patients in a tertiary care centre.This was a descriptive cross-sectional study conducted in the Birat Medical College Teaching Hospital, Morang, Nepal during the second wave of COVID-19 from 22 June 2021 to 30 September 2021. Ethical approval was obtained from the Institutional Review Committee of the same hospital (Reference number: IRC-PA-146/2077-78). Those cases who were confirmed COVID-19 positive by reverse transcriptase polymerase chain reaction and who were admitted in the COVID block of the same hospital during the study period were included. Those cases who were discharged on request or referred or whose blood test was not available were excluded. A convenience sampling method was used. The sample size was calculated using the following formula:Where,n = minimum required sample sizeZ = 1.96 at 95% Confidence Interval (CI)5p = prevalence taken as 20% severe COVID-19 in a similar studyq = 1-pe = margin of error, 10%The minimum sample size calculated was 62. However, a total of 72 patients were included in the study.1At admission, patient demography was recorded and categorized into severe and non-severe COVID-19 based on clinical parameters .Baseline laboratory parameters were sent including complete blood count and CRP. Venous blood samples were collected through venipuncture from COVID-19 patients into tubes coated with gel for serum separation. The blood sample was centrifuged at 4000 rpm for 5 minutes within 1 hour. Serum CRP levels  were determined by semiautomated Mispa-i2 specific protein analyzer Nephelometer. Whole blood samples were collected into ethylenediaminetetraacetic acid (EDTA) containing tubes. Total white blood cell (WBC) count, Lymphocyte and Neutrophil count were measured using Beckman Coulter DxH Hematology Analyzer. The NLR was calculated by dividing the absolute neutrophil count by the absolute lymphocyte count. The LCR was calculated by dividing absolute lymphocyte count by CRP (mg/dl).The information was recorded on predesigned proforma and analysed using IBM SPSS Statistics 27.0. Point estimate and 95% CI were calculated.Among 72 admitted COVID-19 patients, 63 (87.5%)  patients had severe disease. A total of 32 (50.80%) were male and 31 (49.20%) were females. The mean age of the severe COVID-19 patients was 54.98\u00b117.80 years. The mean NLR and LCR in severe patients were 11.60\u00b18.16 and 25.34\u00b121.04 respectively .6 severe COVID-19 while in another study done in China, it was 35%.7 In contrast, One study done in Iran showed severe cases in 20% only.5 Whereas in another study done in the initial phase of the COVID-19 outbreak in China, the severe disease was seen in 15.74% of cases only (173/1099).8 Similarly, In another study done in China, the prevalence of severe disease was 5.62% only (5/89).9 These differences in the prevalence of severe COVID-19 can be explained by the following facts. Our study was conducted during the second wave of COVID-19 when the pandemic had the worst course affecting more people severely. This can also be explained by the fact that during the second wave, most of the patients with mild symptoms remained in home isolation and treatment while only severe cases came to the hospital. These facts could be the reasons for the higher number of severe cases in the study.On the basis of clinical features, 63 (87.5%) patients were categorized into severe COVID-19 in this study. A similar study done in Turkey showed (60.65%)5 Similar results were also noted in the study done in Turkey where 59% of males and 41% of females were involved with a mean age of 58.55 years.6In this study, males and females were equally (51% vs 49%) affected indicating no gender is spared from containing COVID-19 and the mean age was 54.98 years. Our results are comparable with the results of a similar study done in Iran. Here males were 57% and females were 43% (n= 70) and the mean age was 42.7 years.10 Other studies also concluded that the higher the NLR, severe the COVID-19 and mortality.12The mean NLR found in our study for severe COVID-19 patients was 11.60 (6.51 in non-severe). This is comparable to a similar study done in India where NLR was more markedly raised in a severe group (10.8 vs 7.36).6 This is similar to the result of a meta-analysis done in Mexico demonstrating that the LCR was decreased in severe cases.13 These lower LCR levels in severe patients could be the result of fewer lymphocytes leading to immune dysfunction and higher CRP levels reflecting the severe systemic inflammatory response of the patients.When looking at the status of LCR in the severe group, it was markedly decreased (25.55 vs 62.23) indicating rising CRP and lymphopenia with the severity of COVID-19. A similar result was also demonstrated in a study done in Turkey, decreasing LCR with the disease severity.Considering the sampling method used in this study, the chances of selection bias are there. This study is further limited by including the admitted patients only and being a single-centre study so this result may not represent the true prevalence of the condition in other settings. We recommend further multicentric studies with large sample sizes.The prevalence of severe COVID-19 in our setting was higher than in other studies done in similar settings. We suggest clinical parameter-based early categorisation of COVID-19 cases to utilise limited resources in the pandemic."}
+{"text": "Laboratory testing for viral infections is not routinely performed in adult patients admitted to the ICU. However, reports indicate that viruses may contribute to significant morbidity and mortality and that viral-bacterial co-infection is associated with poor outcome in this particular patient population. The aim of the study was to document the incidence of respiratory virus infections in critically ill adult patients admitted to the ICU for acute respiratory failure.\u00ae) samples were taken within 24 hours after admission and analyzed by PCR assays for the presence of respiratory syncytial virus (RSV), influenza virus, metapneumovirus (MPV), parainfluenza virus, adenovirus, rhinovirus and coronavirus. Data are presented as median (IQR).The prospective, observational study took place during two consecutive winter seasons in a mixed 16-bed ICU at the Medical Center Leeuwarden, the Netherlands. Adult patients admitted to the ICU, suspected of respiratory failure due to community-acquired pneumonia, were included. After informed consent brushed nasopharyngeal swab (CopanP3<0.05).Thirty-four patients were enrolled. Median age was 66 (54 to 71) years; 65% of the patients were male; median APACHE IV score on admission was 76 (61 to 96). Median ICU stay was 8 (5 to 17) days, with an overall hospital mortality of 12%. Thirteen patients (38%) tested positive for a respiratory virus. The most frequently found virus was influenza (37%), followed by RSV (15%), rhinovirus (15%), MPV (15%), corona virus (9%) and parainfluenza virus (9%). Two of the patients (6%) had a bacterial-viral co-infection (blood culture and PCR positive for Streptococcus pneumonia and rhinovirus in one patient and for Haemophilus influenza and influenza virus in the second patient). Length of stay in the ICU was significantly longer in PCR-negative patients, in comparison with PCR-positive patients (11 (6 to 20) vs. 7 (2 to 8) days, respectively, Respiratory viruses, and particularly influenza virus, are frequently found in adult patients with respiratory failure admitted to the ICU."}
+{"text": "Potential emergence of enterococcal daptomycin nonsusceptibility among patients with no prior exposure to daptomycin poses clinical and public health challenges. We found that development of infections with daptomycin-nonsusceptible enterococci in these patients could be associated with sporadic emergence and clonal spread. The development of daptomycin resistance by enterococci poses treatment and infection control challenges. Emergence of daptomycin-nonsusceptible enterococci (DNSE) during treatment with daptomycin has been reported  patients were male and mean age was 58.9 years (range 26\u201375 years). Seven (77.8%) patients were immunosuppressed, of whom 5 had solid malignant tumors and 3 had diabetes. All patients in our case series had complicated concurrent medical conditions, and all but one had undergone surgery in the 3 months before isolation of DNSE . For 4 pUse of antimicrobial drugs associated with presence of vancomycin-resistant enterococci, such as recent use of vancomycin, third-generation cephalosporins, or agents with activity against anaerobic bacteria  who had Enterococcus faecium, 2 (22%) were E. faecalis, and 1 (11%) was E. gallinarum. Five isolates were available for further study   and 1 year (case 4) after the isolation of the original DNSE in the third patient (not included in this case series).Further support for a possible community reservoir of DNSE was provided by the identification of clonally related DNSE isolates. Of 9 DNSE isolates, 6 (66.7%) were , and 8) . The dapOf the 9 patients, 8 showed evidence of clinical infection, including 3 bloodstream (33.3%), 3 intraabdominal (33.3%: 2 bile and 1 abscess), 1 urinary tract (22.2%), and 1 soft tissue (11.1%) infections. The remaining patient (patient 4) had asymptomatic bacteriuria with normal urinalysis. A potential nidus of infection, including a central venous catheter or inadequately drained abscess, was identified in 5 patients (55.6%) .E. faecium isolate were vancomycin resistant   might or might not be relayed to the clinician in the instance of vancomycin-susceptible isolates.Susceptibilities of the DNSE isolates to antimicrobial drugs with activity against the enterococci are summarized in 2 \u03bcg/mL) , and allFour (44.4%) patients died while receiving therapy for DNSE . Each pa,Two existing studies of de novo development of daptomycin nonsusceptibility describe 1 case each (Enterococcus spp. isolated from beef products were DNSE (\u2013The mechanism for daptomycin nonsusceptibility in enterococci is poorly understood (The limitations of our study include the retrospective observational study design, the small number of cases identified, and lack of a comparison group. Case\u2013control studies could better define risk factors associated with emergence of DNSE. Clinicians should be aware of the possibility of serious infections associated with DNSE even when there is no history of prior daptomycin therapy."}
+{"text": "To the Editor: In response to the emergence of pandemic (H1N1) 2009 virus  2009 infection were identified on April 28, 2009, of which 1 occurred in an elementary school student  had a working telephone number, of which 170 (39%) completed the survey. Thirty-nine (23%) households, representing 181 persons, reported 58 illnesses that met the acute respiratory illness definition, of which 37 (64%) also met the influenza-like illness definition. Median age was 10 years (range <1\u201348 years). Of 57 household members for whom age and student status were recorded, 42 (74%) were students at school A. Thirty-four (60%) reported onset of symptoms before or on the day of school dismissal .>2 illnesses, students became ill before nonstudent household members. In the remaining 7 households, onset dates did not suggest student-to-nonstudent transmission.Household attack rates ranged from 10% to 100% (median 25%). Five (13%) households reporting illness had no ill students who attended school A. In 4 of 11 households reporting Even though the school was closed almost immediately after the first pandemic (H1N1) 2009 case was confirmed in a student, onset of \u224860% of reported illnesses occurred before or on the day of school dismissal, suggesting that unrecognized transmission was already occurring in the school or community. These results are supported by data on confirmed cases of pandemic (H1N1) 2009 in Chicago, which suggest that community transmission was high during the survey period  2009, school closures were concluded to have substantially decreased transmission . PollThis investigation was limited by the relatively low response rate; however, demographics for the sample in our study were similar to those of the school as a whole ("}
+{"text": "Klebsiella pneumoniae is necessary in order to adapt therapeutic recommendations.A study of the dynamics of antibiotic resistance of Klebsiella pneumoniae isolated in urinary and respiratory tract infections.The objectives of this paper pursue the comparative analysis of resistance to antibiotics of strains of Klebsiella pneumoniae isolated from sputum (96 strains) and urine culture (163 strains) from patients hospitalized in the \u201cVictor Babe\u015f\u201d Clinical Hospital of Infectious Diseases and Pneumology, Craiova. The antibiogram was performed by classical diffusimetric method.Retrospective study conducted between 01 January 2013 \u2013 31 August 2013 on the resistance of Klebsiella pneumoniae strains isolated from urine culture compared to those isolated in respiratory infections in case of: a) beta-lactams , b) quinolones (ciprofloxacin 61.8% versus 83.4%), c) co-trimoxazole (45.4% versus 82.8%). The sensitivity profile showed no major differences for: colistin (82.7% versus 81.6%), carbapenems (95.2% versus 97.8%) and aminoglycosides (72.3% versus 75.8%).The resistance to antibiotics was higher in Klebsiella pneumoniae to carbapenems remained high, recommending the use of these antibiotics for infections with resistant germs. The empirical use of antibiotics for urinary tract infections and invasive urological maneuvers may explain the increased resistance profile of germs isolated from urine culture.The sensitivity of"}
+{"text": "In the United States and Europe, prostate cancer is the most common male malignancy and the second leading cause of cancer death after lung cancer. However, in spite of under-estimation and reporting of cancer burden in Pathology-based cancer registries in the developing countries; prostate cancer is now ranked among the emerging male malignancy.To demonstrate that prostate cancer is common among Nigerian males.This is a 5-year retrospective histopathological analysis of prostate cancer diagnosed between January 2005- December 2009 in the Department of Pathology, University of Abuja Teaching Hospital, Gwagwalada, Abuja. The tumours were classified based on WHO classification of Prostatic tumours. Histological grading was done using Gleason grading system.Sixty-six (66) cases of prostate cancer were reviewed. The age range was between 40-89 years with a mean of 64.5 years. There were two bimodal age peaks at the seventh and eighth decades respectively. The surgical procedures were Trucut biopsies 64 (96.9%) and prostatectomy 2 (3.1%). The Gleason scores range from 2 to 10. Three (4.5%) patients were seen before the age of 50 years. There were 9 (13.6%) cases of well differentiated, 37 (56.0%) cases of moderately differentiated and 20 (30.4%) cases of poorly differentiated adenocarcinoma. No other histological types were seen.In this study, there were bimodal age peaks of prostate cancer at the sixth and seventh decades, while moderately differentiated adenocarcinoma is the most common presentation.Publication of this article was funded in part by the University of Florida Open-Access Publishing Fund."}
+{"text": "Escherichia coli (STEC) infections during 2005\u20132010. Despite increased assay use, only half of processed stool specimens underwent Shiga toxin testing during 2010, suggesting substantial underdetection of non-O157 STEC infections.We surveyed laboratories in Washington State, USA, and found that increased use of Shiga toxin assays correlated with increased reported incidence of non-O157 Shiga toxin\u2013producing  Escherichia coli (STEC) are differentiated by the O antigen on their outer membrane and are broadly classified as O157 or non-O157 STEC \u2013producing E. coli strains, serogroup O157 isolates do not ferment sorbitol and are readily identified by culture, appearing colorless on sorbitol MacConkey agar , 781 (83%) cases were O157 STEC and 164 (17%) cases were non-O157 STEC infections. The incidence of non-O157 STEC infections increased dramatically during the 6-year period, from 0.13/100,000 population and 6% of all reported STEC infections in 2005 to 1.13/100,000 population and 41% of all reported STEC infections in 2010  with illness onset during 2005\u20132010 were reviewed to determine incidence trends. Confirmed STEC is defined as the isolation of  in 2010 . Four se>300 specimens were asked to specify the quantity. For the 25 laboratories that reported <300 specimens, a midpoint of the range was assigned. All data were analyzed by using SAS for Windows, version 9.2 .Using data from the Washington State DOH Office of Laboratory Quality Assurance, we identified 74 clinical microbiology laboratories in the state. To assess statewide STEC laboratory testing practices, we developed an online survey and distributed it to microbiology laboratory supervisors at these 74 laboratories during January 2011. Seventeen laboratories reported that all stool specimens are forwarded to a reference laboratory for testing. These 17 laboratories were excluded from the survey sample; however, all indicated reference laboratories were within the state and among the remaining sample (n = 57). Follow-up was completed by email and telephone until a 100% response rate was achieved. The survey requested data on annual number of stool specimens processed for bacterial culture, current protocol for processing stool specimens submitted for routine enteric pathogen testing, and motivations and barriers toward the implementation of Stx testing. If Stx testing was reported, we requested implementation date. Laboratory supervisors were asked to indicate a range for the number of stool specimens processed for bacterial culture at their laboratory during 2010. The 32 laboratories (56%) that reported Fifty-seven laboratories in Washington State collectively processed an estimated 71,000 stool specimens for bacterial culture in 2010; the number of specimens ranged from 61 to 6,017 specimens per laboratory (median 570). The 10 (18%) largest laboratories processed 51% of the total annual specimens, while the 25 (44%) smallest laboratories processed only 5% of the total annual specimens.The following results quantify reported routine enteric pathogen testing protocols for all stool specimen submissions. Of 57 laboratories, 56 (98%) performed routine STEC testing on all submitted stool specimens, either by culture, by detecting the presence of Stx with nonculture assays, or both. Fifteen (26%) reported simultaneous culture for O157 STEC and Stx testing, 37 (65%) cultured for O157 STEC exclusively, and 4 (7%) tested for Stx exclusively , panel AOf the 19 laboratories that tested for Stx, 11 (58%) implemented testing in 2009 or 2010 . When asDuring 2005 through 2010, the number of laboratories in Washington State that tested for Stx increased from 2 (4%) in 2005 to 19 (33%) in 2010, and the incidence of reported non-O157 STEC infections increased from 8 cases  in 2005 to 76 cases  in 2010. The most dramatic increase in reported non-O157 STEC infections occurred between 2008 and 2010, during which time incidence increased nearly 3-fold, from 26 cases  in 2008 to 76 cases  in 2010. This increase in reported incidence occurred at the same time during which most laboratories that test for Stx  implemented testing . This suDespite the increased use of Stx testing, 37 (65%) of the laboratories in Washington State that processed nearly half (47%) of the stool cultures in the state during 2010 cultured for O157 STEC exclusively and, therefore, could not detect non-O157 STEC. Had all specimens been tested for both O157 and non-O157 STEC, we estimate that the incidence of non-O157 STEC would have been 2.12/100,000 population  in 2010, rather than the reported 1.13/100,000 .Enhanced detection and reporting of STEC infections will likely increase workloads for local communicable disease investigators and public health laboratories during a time when funding for public health is limited. At the local level, every reported STEC infection requires an epidemiologic investigation, while additional detection of Stx at clinical laboratories will increase submission volume at public health laboratories.\u2013National studies have found that non-O157 STEC infections are clinically indistinguishable from O157 STEC infections, with comparable hemolytic uremic syndrome attack rates ("}
+{"text": "AKI is a common occurrence in sick hospitalized patients, in particular those admitted to intensive care. Published data suggest that 4 to 5% of all critically ill patients develop severe AKI and require initiation of renal replacement therapy (RRT) ,2. Such During 2009, 56 patients were identified to have received RRT with AKI who were admitted to the ICU at the Royal Wolverhampton Hospitals NHS Trust. Computerised and paper-based case records were examined for these patients to collect the data. AKIN classification was used to classify the severity of AKI.P = 0.003) or if they received mechanical ventilation (P = 0.48) or inotropes (0.04). Of the 27 patients who survived until discharge from hospital, 18 (66.7%) had normal renal function, eight (29.6%) had AKIN stage I and only one patient required maintenance haemodialysis.Median age at admission was 66 years (27 to 85) with 29 males and 27 females. Thirty-one (55.4%) patients had sepsis and 20 (35.7%) patients had ATN as the main cause of AKI. Thirty-two patients (57%) had three organ failures at the time of commencement of RRT. Forty-six patients (82.1%) received haemofiltration only. Thirty-two (57%) patients died, with more than 80% of these occurring in the ITU. There was no significant difference in survival when compared with duration of haemofiltration, length of stay, number of organs failed and number of comorbidities. However, significantly more patients that died had AKI due to sepsis (Individuals who develop dialysis-dependent AKI in the ICU setting in general terms either die or recover. Sepsis is the most common association with death. The need for mechanical ventilation and inotropic therapy are both associated with increased incidence of death."}
+{"text": "Background. Thyroid disorders may affect all of the organ systems of the body and they are also highly associated with a wide variety of skin disorders. The aim of this study was to investigate the prevalence of thyroid function abnormalities and thyroid autoimmunity in patients with pemphigus vulgaris (PV) and to determine the association between thyroid disorders and clinical involvement and systemic corticosteroid treatment in patients with PV. Methods. The study consisted of eighty patients with PV and eighty healthy individuals. Thyroid functions  and thyroid autoimmunity (anti-thyroid peroxidase (anti-TPO), and anti-thyroglobulin (anti-Tg) antibodies) were investigated in both groups. Primary thyroid disease (PTD) was diagnosed with one or more of the following diagnostic criteria: (i) positive antithyroid antibodies, (ii) primary thyroid function abnormalities. Results. Significant changes in the serum thyroid profile were found in 16% (13/80) of the PV group and 5% (4/80) of the control group. Positive titers of antithyroid antibodies (anti-TPO and anti-Tg) were observed in 7 patients (9%) with PV and one in the control group . Hashimoto thyroiditis was diagnosed in 9% of PV patients and it was found to be more prevalent in the mucosal form of PV. PTD was found in 13 of (%16) PV patients which was significantly high compared to controls. PTD was not found to be associated with systemic corticosteroid use. Free T3 levels were significantly lower in PV group compared to the control group and free T4 levels were significantly higher in PV group compared to the controls. Conclusions. PV may exist together with autoimmune thyroid diseases especially Hashimoto thyroiditis and primer thyroid diseases. Laboratory work-up for thyroid function tests and thyroid autoantibodies should be performed to determine underlying thyroid diseases in patients with PV. Pemphigus is an autoimmune bullous disorder which is characterized by the formation of IgG-type autoantibodies against desmosomal adhesion molecules . There i3), free thyroxine (fT4), thyroid stimulating hormone (TSH), anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-Tg) antibodies were measured by electrochemiluminescence assay . The diagnosis of primary thyroid disease was confirmed by the presence of anti-thyroid antibodies and/or abnormalities in thyroid function tests. A total of 80 consecutive PV patients and 80 age, and sex-matched healthy control subjects were enrolled in the study. Exclusion criteria were presence and history of thyroid disease both in the patient and in patient's family, systemic diseases such as diabetes and malignancy, and usage of drugs that interfere with thyroid functions for the last 6 months. Forty-seven of PV patients were under systemic corticosteroid therapy while 33 were new patients without therapy. Serum thyroid profiles of patients and controls were evaluated with analyzing thyroid function tests and thyroid autoantibodies. Serum-free triiodothyronine  and PASS 2008 statistical software programme, student's P < 0.05). Ten (12.5%) of PV patients and 4 (5%) of the controls were found to have abnormalities in thyroid function tests and the difference between groups was statistically significant (P < 0.05). In PV group, levels of fT3 were significantly lower and fT4 levels were significantly higher when compared to control group (P < 0.05). There was no significant difference with respect to TSH levels between patients and controls (P > 0.05). Seven (9%) of PV patients and 1 (1.2%) of controls were found to have anti-thyroid antibodies (anti-TPO and/or anti-Tg) and the difference between groups were statistically significant (P < 0.05). Anti-TPO antibodies were found in 6 (%8) and anti-Tg antibodies were found in 2  of PV patients. In the control group 1 (1.2%) patient had both anti-TPO and anti-Tg antibodies. The frequency of anti-TPO antibodies were significantly higher in PV group than the control group (P < 0.05), while the frequency of anti-Tg antibodies showed no significant difference between groups (P > 0.05) , the average age was 52.5 in PV group and 51.5 in control group. The duration of the disease was 52.4 with a range between 1 month and 168 months. Forty-seven  of PV patients were receiving 5\u2013125\u2009mg/day prednisolon, while 33  were new patients without therapy. Thirty-nine (48%) of the patients had mucosal, 15 (19%) had cutaneous, and 26 (33%) had both mucosal and cutaneous involvement. Thirteen (16%) of PV patients and 4 (5%) of control group had alterations in serum thyroid profiles (thyroid function tests and anti-thyroid antibodies); this finding was statistically significant ( > 0.05) . P < 0.05) and PV group had a higher frequency of PTD. In addition, the frequency of Hashimoto thyroiditis was higher in PV group than the control group (P < 0.05).Primary thyroid disease (PTD) was found in 13 (16%) of the patients: subclinical Hashimoto thyroiditis in 7 (9%), subclinic hyperthyroidism in 2 , subclinic hypothyroidism in 3 , and euthyroid syndrome in 1 (1%). Six of the patients with Hashimoto thyroiditis had anti-TPO, one had anti-Tg, and one had both anti-TPO and anti-Tg while 4 had alterations in thyroid function tests . Four 5. There wP > 0.05). Of the PV patients with PTD, 5 (38.5%) had mucosal, 3 (23%) had cutaneous, and 5  had both cutaneous and mucosal involvement; mucosal involvement was found more prevalent in PV patients with PTD but there was no significant difference when compared with PV patients (P > 0.05). Hashimoto thyroiditis was found in 4 (%30.8) patients with mucosal involvement, in 1 (7.7%) patient with cutaneous involvement, and in 2 (15.4%) patients with both cutaneous and mucosal involvement. PV patients with Hashimoto thyroiditis had a higher frequency of mucosal involvement but this finding was statistically insignificant (P > 0.05). Of the patients with Hashimoto thyroiditis 2 were receiving systemic corticosteroids and 5 were without treatment; we found no significant association between Hashimoto thyroiditis and systemic steroid usage (P > 0.05).Of the 13 PV patients with PTD 6 (46%) were receiving 5\u201340\u2009mg/day prednisolone while 7 (54%) were without treatment. We found no association between steroid usage and presence of PTD in PV patients  in PV patients (9% of PV patients and 1% of the controls). But we found subclinical Hashimoto thyroiditis in all of the PV patients with positive anti-thyroid antibodies. Former studies reported only presence of anti-thyroid antibodies but they found no abnormalities in thyroid function tests , 6. We fOur study differed from the other two studies because we found PTD in all of the patients who were found to have serum thyroid profile alteration and PV patients were found to have higher prevalence of PTD when compared to placebo , 6. In aBoth of the former studies reported that study patients were under low- or moderate-dose systemic corticosteroid treatment and suggested that corticosteroids could suppress thyroid autoimmunity and might be the reason of the lower amounts of anti-thyroid antibodies than expected , 6. Syst3 and HLA D4 both in PV and Graves' disease emphasizes the role of genetic predisposition in these two diseases [Firooz et al. reported that the frequency of thyroid diseases had a threefold increase in the first-degree relatives of PV patients and suggested that genetic susceptibility is responsible for the occurrence of more than one autoimmune disease in an individual . Bartalediseases .As a conclusion, even though the exact causes remain unidentified, the results of our study showed that PV could accompany thyroid autoimmunity and primary thyroid diseases especially Hashimoto thyroiditis. We recommend laboratory testing for thyroid autoantibodies and thyroid function tests in patients with PV even if they do not have a clinical indication of thyroid disease."}
+{"text": "The development of targeted therapies for KRAS, EGFR and HER2 may increase the range of response in patients with colorectal cancer. Mutation at codons 12 and 13 of the KRAS gene has been shown to be predictive of cetuximab response in colorectal cancer. However, due to the combined effects of multiple oncogenes involved in disease progression of patients with colorectal cancer, it seems to be important to identify the molecular factors that characterize therapy-resistance phenotype of tumors.Forty six paraffin-embedded colorectal cancer specimens were analyzed for KRAS mutation and HER2 overexpression/amplification. A high\u2013resolution melting (HRM) assay and single-nucleotide polymorphisms (SNPs) were used to detect somatic mutation in exon 2 notably condons 12 and 13 of the KRAS gene. HER2 overexpression was detected using monoclonal antibody and confirmed by fluorescence in situ hybridization (FISH) analysis.KRAS mutations for codons 12 and 13 were identified in 16/46 (34.7%) of patients by SNP. The alterations in KRAS gene were observed in similar percentage of both codons. Colorectal cancer showed mainly heterozygous 35G>A and 38G>A KRAS gene mutations.HRM analysis showed presence of KRAS exon 2 mutation in 13/46 (28.2%) colorectal cancers. Despite positive SPN results in three cases , HRM technique did not reveal KRAS gene alteration. The concordance rate between the two methodologies was high at 87.5%. KRAS mutation was more frequently observed in poorly differentiated tumors and adenocarcinomas than in other histological types.HER2 overexpression was found in 37/46 (80.3%) of all colorectal cancers and in 62.1%, 61.5% of KRAS mutation-positive cases detected by SNP and HRM techniques respectively. HER2 overexpression was accompanied by amplification of HER2 gene. The subgroup of colorectal cancers with KRAS mutation and HER2 overexpression/amplification was poorly differentiated.In summary, the presence of HER2 overexpression/amplification in KRAS mutation\u2013positive colorectal cancers suggests a possible role for the use of specific tyrosine kinase inhibitors in the treatment of disease."}
+{"text": "There is limited data on the natural history of autoimmune hepatitis (AIH) and on the long-term follow-up of AIH patients who have been referred for regular medical attention.We evaluated the clinical presentation and natural history of AIH in a large cohort of type I AIH patients from Iran.Between 1997 and 2008, 102 patients were enrolled in the study. Patients were diagnosed using the International Autoimmune Hepatitis Group criteria and were followed up for an average of 60 months. Clinical and biochemical data were gathered from all the patients at both the beginning and the end of the follow-up period. Liver biopsy was performed in all patients before treatment, and the biopsies were performed in 28 patients after treatment.Biochemical remission was achieved by 80 (79.4%) patients. Of these, 53 (66.5%) showed near-normal liver histology or liver function test results and sonogram. The remaining 27 (33.5%) patients also achieved clinical and biochemical remission, but developed compensated cirrhosis. After a period of remission, 24 patients (32.5%) relapsed. Among the 22 (21.6%) patients who showed ultimate treatment failure, 6 underwent orthotopic liver transplantation and 3 died of liver failure while awaiting a transplant. Sixteen (72.7%) of the 22 patients who did not respond to therapy were non-compliant with medications and had irregular follow-up. The overall 10-year survival rate in the cohort was 96%.Long-term survival in AIH patients is very good. Prompt diagnosis and appropriate first-line and salvage therapy that includes close follow-up will make liver transplantation a rare necessity in the treatment of this disease. Autoimmune hepatitis (AIH) is a progressive disease of unknown cause that is characterized by chronic hepatitis, abnormal liver enzyme levels, high serum gamma globulin levels, and circulating autoantibodies 2]. It i. It i2].We evaluated the clinical presentation and the natural history of AIH in a large cohort of type I AIH patients from Iran.All AIH patients who were referred to the outpatient Clinic of the Digestive Disease Research Center (DDRC) of Tehran University of Medical Sciences from 1997 to 2008 were enrolled in this study. Baseline evaluation included a complete history and physical examination, complete blood count (CBC), and a comprehensive biochemical and serological profile, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), serum gamma-glutamyl transferase (GGT), serum \u03b3-globulin (GGB), serum albumin, total protein, total and direct bilirubin, erythrocyte sedimentation rate (ESR), prothrombin time, serum creatinine and blood urea nitrogen. Patients were also evaluated for chronic viral hepatitis, Wilson\u2019s disease, \u03b1-1 antitrypsin deficiency, and hemochromatosis by using HBsAg, HBcAb, HBsAb, HCV Ab, serum ceruloplasmin, protein electrophoresis, serum iron, and total iron-binding capacity. Diagnosis of AIH was made according to the criteria for the diagnosis of AIH devised in 1993  and its Percutaneous liver biopsy was performed for all patients at baseline and for 28 patients who consented to a second biopsy at the end of treatment. Specimens were fixed in 10% formalin; embedded in paraffin; and stained with hematoxylin and eosin, Masson\u2019s trichrome, and reticulin. All specimens were evaluated by a single pathologist. Liver biopsies were considered adequate if there were at least 6 portal tracts per high-power field. Specimens were scored using the modified Hepatitis Activity Index, in which necroinflammation is graded from 0 to 18 and fibrosis from 0 to 6 . CirrhosContinuous variables were expressed as mean and standard deviation (SD) values Dichotomous variables were compared using chi-square tests. P value < 0.05 were considered significant. Paired t tests were used to compare variables before and after treatment. Correlations between quantitative variables and the stage of fibrosis at presentation were assessed using Spearman correlation coefficients. Logistic regression analysis was then used to assess the independent association of various variables with the absence of fibrosis in both the first biopsy, performed at presentation, and in the biopsy performed after treatment. Statistical analysis was performed using SPSS, version 16.0 . The study protocol was approved by the Ethics Committee of the Digestive Disease Research Center (DDRC), and informed consent was obtained from all patients prior to enrollment in the study.Among the 102 patients enrolled in this study, 35 and 67 fulfilled IAIHG pre-therapy criteria for definite and probable AIH, respectively. One patient had both AIH and hepatitis C. Twenty-seven patients (26.4%) had overlap syndrome, of whom 19 (18.6%) had AIH/PBC and 8 (7.8%) had AIH/PSC. Seventy-five patients (73.5%) were women. Women comprised 76.0%, 84.2%, and 25.0% of AIH, AIH/PBC, and AIH/PSC patients, respectively . The mean age was 29.1 \u00b1 15.3 years at the time of disease onset and 29.6 \u00b1 15.1 years at the time of diagnosis . Thirty-three patients (32.3%) were older than 40 years and 5 (4.9%) were younger than 10 years. The age distribution showed 2 peaks: one among 11\u201320 year-old patients and the other among 41\u201345 year-old patients. There was no difference in the mean age of patients with the 3 diagnostic categories of AIH. Forty-two patients (41.3%) had histologic cirrhosis (stage 5 or 6) at presentation. Acute presentation was observed in 43 patients (42.2%) and was defined as the presence of recent onset (< 30 days) symptoms (jaundice and/or drowsiness), in conjunction with ALT levels higher than 10 times the upper normal limit and elevated prothrombin time (> 15 s). AIH patients and patients with overlap syndrome did not differ in their response to treatment or progression to cirrhosis. The most common symptoms in descending order were as follows: jaundice (73%), fatigue (66%), abdominal pain (23%), pruritis (20%), arthralgia (16%), fever (14%), and weight loss (3%). At the time of physical examination, splenomegaly and ascites were detected in 58.4% and 16.9% of the patients, respectively. Sixteen women (21.3%) reported menstrual abnormalities. One patient was seropositive for anti-HCV antibodies with very low titers of HCV RNA (HCV-RNA = 250 copy / l). Ninety patients (88.2%) were seropositive for ANA and/or SMA and 1 patient showed anti-LKM-1 antibodies (type II AIH). ANA was the most frequent autoantibody detected (50.0%). Thirty-eight patients (39.5%) had other autoimmune conditions in addition to AIH. The most frequent condition was thyroiditis (16%), followed by diabetes (10%), ulcerative colitis (9%), and rheumatoid arthritis (3%). Baseline demographic, biochemical, and histological data are presented in . In the Mean duration of follow-up was 60.0 \u00b1 38.4 months . Follow-up was regular in 71 patients (69.6%) and irregular in 31 (30.4%). Overall, 80 patients achieved remission (79.4%) and 22 (21.6%) either responded partially or did not respond to treatment. Among the 80 patients who achieved remission, 27 (33.7%) developed stable and well-compensated cirrhosis while in biochemical remission. Of the 22 subjects with treatment failure, 6 underwent orthotopic liver transplantation and 3 died of liver failure while on the transplant list . The remSeveral characteristics of our patients were quite similar to those of AIH patients in other case series reports. These characteristics include the bimodal age distribution of patients at presentation; clinical, biochemical, and histopathological findings at presentation; presence of concurrent autoimmune diseases; and response to corticosteroids . Twenty-"}
+{"text": "Systemic Sclerosis (SSc) has a potentially disabling effect on the foot. The UK PRCA/ARMA standards of care indicate that all people with SSc should receive at least basic information about their foot health, and those with foot problems should have access to self-management advice and care where needed. The aim of this audit was to compare the concordance of foot health services offered in Leeds (UK) for people who have SSc, with nationally agreed standards of care.This audit comprised 91 patients with SSc who were attending either the connective tissue disease outpatient clinic (n=70) or the specialist rheumatology foot health clinic at Chapel Allerton Hospital (n=21). All the patients completed a disease-specific audit tool developed by the UK PRCA.Of the 91 patients, 78 were female and 10 were male (3 unknown) with a mean age of 58 years (range 20-83). In our sample only 35(39%) out of 91 patients reported having received information about their foot health. Fifty-five (60%) of 91 reported having had foot problems in the past, with 54 (59%) reporting current foot problems. Forty-nine (54%) out of 91 reported having had access to foot care previously and 38 (42%) were receiving foot health care currently. Of the 55 patients that had foot problems, a slightly higher proportion 32 (58%) had received foot health information. Forty-five(82%) of the 55 patients with foot problems, reported previous access to foot health care provided through a variety of services: 29 (53%) in a hospital based specialist rheumatology foot health clinic; 5 (9%) in community care podiatry department; 4 (7%) in private podiatry practice; 4 (7%) in general practice; 3 (6%) others. The 21 patients attending the foot health clinic received the following interventions: 21(100%) received toe nail care; 7(33%) finger nail care; 20 (95%) corn and callus reduction; 11(52%) insole provision. The profile of specialist care was: 16 (76%) receiving ulcer care; 3 (14%) nail surgery; with 1 (5%) referred for orthopaedic opinion; and 2 (10%) for specialist vascular assessment.This audit demonstrates that patients with SSc have a relatively high prevalence of foot problems, however this study also shows that access to foot health services is limited. The PRCA/ARMA standards of care recommend that all people with SSc should receive at least basic information about their foot health but this is not reflected in this study."}
+{"text": "Objectives: To investigate the work-related musculoskeletal symptoms among building construction workers.Methods: Total 389 apparently healthy, male volunteers were selected with mean age 34.56\u00b18.33 years and a mean working duration in building construction as 5.76\u00b12.68 years. Musculoskeletal complaints were recorded through a detailed clinical interview and comprehensive questionnaire.Results: Substantial number of building construction workers developed musculoskeletal symptoms including neck pain 29 (7.5%), shoulder pain 41(10.5%), upper back pain 24(6.2%), lower back pain 64 (16.5%), legs pain 93 (23.9%), feet pain 52 (13.4%), head heaviness 44 (11.3%) and whole body fatigue 78 (20.1%). These complaints were significantly associated with long-term duration-response in building construction industry. Furthermore, cigarette smokers had little higher percentage of musculoskeletal complaints compared to non-smoker companions.Conclusions: Building construction occupation is a prolific source of musculoskeletal ailments and complaints were significantly increased with long-term working duration in building construction industry. This industry has a pivotal role in the construction of the infrastructure. The building construction workers are involved in different trades like mason, cement mixer, plumber, electrician, carpenter, and crane operator etc.2The worldwide community, especially the people in developing countries is facing increasing risks of various systemic ailments due to working exposure in different occupational and industrial sectors.3 and accidents.2Building construction workers face a wide range of health hazards in their work sites and are victims of occupational health hazards. These may include exposure to dust, fumes, holding weighty materials and heavy physical work in awkward working postures in the construction industry which can cause various musculoskeletal disorders. Moreover, exposure to tough environmental conditions affects the worker's health and causes various physiological, physical and psychosocial strain and workers become victims of occupation related musculoskeletal disorders4 The worldwide industrial labor community especially the people in developing countries is facing increasing risks of various ailments1 including musculoskeletal disorders.5 The health risks posed by industry are influenced by type, nature of job and duration of working in various industrial sectors.6,7 The musculoskeletal disorders are most common occupational related health problems and are an important cause of functional impairments and disability among building construction workers.8Furthermore, these workers have fatal injuries on-the-job and high numbers of non-fatal occupational injuries, illnesses and workplace mortality.This study aimed to investigate the musculoskeletal symptoms among workers working in building construction industry and also provide information to workers about the working hazards in building construction industries.The present descriptive study was conducted in the Department of Physiology, College of Medicine, King Saud University, Riyadh, Saudi Arabia during the period Oct 2012-March 2013. 540 building construction workers were interviewed; a comprehensive clinical history was taken. The trades of the subjects were as follows: cement mixer 104 (26.7%); concrete workers 42 (10.8%); steel fixer 38 (9.8%); crane operator 15 (3.9%); electrician 48 (12.3%); plumber 37 (9.5%); masons 18 (4.6%); supervisor 50 (12.9%); and general supporters 37 (9.5%). Among them, 300 (77.13%) were non-smokers and 89 (22.13%) were smokers (mean average smoking per day was 4.48\u00b11.49). Building construction workers were further divided into three groups based on the duration of exposure less than 3 ; 3-6  and greater than 6 years . These workers worked for at least 8-10 hours a day for six days per week.All the subjects voluntarily participated in the study and signed the consent form. The Institutional Ethical Committee approved the study.Subjects with known history of gross anemia, diabetes mellitus, pulmonary tuberculosis, malignancy, rheumatoid arthritis, joint deformities were excluded from the study.A well-structured English language questionnaire was developed and was also translated into Arabic, Urdu and Hindi languages. The questionnaire consisted the anthropometric variables, cigarette smoking, occupation conditions, working exposure, any known history of present and past illness, exposure conditions during the working hours, and questions about musculoskeletal problems. The co-authors informed the participants about the objectives of the study. Subjects were questioned about complaints of the musculoskeletal system. The complaints score reflected the presence or absence of the symptoms. 540 questionnaires were distributed among them 389 (72.03%) participants completed and 151 (27.96%) either did not fully completed the questionnaire or were excluded from the study as per exclusion criteria. Finally, we included 389 apparently healthy, volunteer males with mean age 34.56\u00b18.33 years  years who had a working duration in building construction as 5.76\u00b12.68 years .Statistical analysis: The data were entered into the computer; Statistical Package for the Social Sciences (SPSS) software version 19.0 was used. Musculoskeletal findings were recorded in number and percentage (%). Odd Ratio was computed for musculoskeletal complaints with 95% confidence interval. Chi square test and Chi square linear trend were used to compare the musculoskeletal symptoms among subjects. Spearman correlation coefficient was calculated to find out the relation between the age, duration of working in construction industry with musculoskeletal complaints. The level of significance was achieved at p-value less than 0.05.\u00a0Three hundred eighty nine(389) apparently healthy subjects with mean age 34.56\u00b18.33 \u00b1\u00b12.68 years \u00b11-12 years) participated in the study.A large proportion of the subjects had complaints of neck pain 29 (7.5%), shoulder pain 41(10.5%), upper back pain 24(6.2%), lower back pain 64 (16.5 %), legs pain 93 (23.9%), feet pain 52 (13.4%), head heaviness 44 (11.3%), and whole body fatigue 78 (20.1%) , Fig.1.The musculoskeletal complaints were associated with duration of work in building construction industry: neck pain ; shoulder pain ; upper back pain ; lower back pain ; leg pain ; feet pain ; head heaviness ; and whole body fatigue . Moreover, the results also show a significant correlation between age and few musculoskeletal complaints including upper back pain ; lower back pain  however, there was no correlation between the age and other musculoskeletal problems.work duration in building construction industry.Work related occupational exposure to building construction industry and its effects on human health is a leading health problem. We found that high number of the building construction workers developed musculoskeletal problems including neck pain 7.5%, shoulder pain 10.5%, upper back pain 6.2%, lower back pain 16.5%, leg pain 23.9%, feet pain 13.4%, head heaviness 11.3%, and whole body fatigue 20.1%. These complaints were associated with long term et al.9 reported that increased frequency in repetitive work can cause discomfort and pain in the neck, shoulders, and upper extremities. It seems to attribute pain reporting to mechanical tissue overload related to repetitive movements, force requirements, and awkward postures. It is also possible that repetitive work could lead to stress symptoms and musculoskeletal pain.10Kilbom et al.8 reported that subjects working in building construction industry had complaints of the back, knee and shoulder / upper arm pain and most of the workers reported that their complaints are work-related. Complaints of the back and elbow were the most often reported among the workers during work, whereas lower arm/wrist and upper leg complaints were the most often reported among the supervisors.Boschman et al.11 conducted a study in building construction workers and demonstrated that the musculoskeletal symptoms were common in neck 24.7%, shoulders 18.9%; upper back 28.7%; elbows 8.0%; low back 45.0%; wrist / hands 29.6%; hip / thighs 4.7%; knee 10.9% and ankles / feet 10.7 %. The authors demonstrated that bending or twisting the neck, back in awkward positions, static positions and materials handling were reported as the most causative job factors. Congruently, Battevi and Vitelli12 reported a significant increase in work-related musculoskeletal disorders. They found that, a group of construction workers exhibited high prevalence of upper limb disorders. Bye13 conducted a study on the employees in construction industry in order to determine the prevalence of musculoskeletal strain. The author found that, 40.3% of the employees had pain at the time of questioning and the percentage of the complaints increases gradually with age. In the present study, we found that building construction workers had higher upper back pain and lower back pain with increasing age . Multiple logistic regression analysis indicated that prolonged work duration was significantly associated with musculoskeletal disorders. Similarly in the present study, we found a duration-response relationship with longer exposures leading to increased musculoskeletal complaints.Hanklang et al.15 found that building construction workers are at high-risk for musculoskeletal disorders among the working population. Neck and shoulder disorders affect 26.3% of male construction workers. Ashish et al.16 reported that building construction workers spend ample time in lifting, holding, carrying, pulling or pushing loads of material. They reported lifting and holding heavy weights as a source of musculoskeletal disorders involving neck among construction workers. Similarly, based on the preset study results we believe that, work-related musculoskeletal symptoms in building construction workers occur when mechanical workload is higher than physical capacity of human body and this can cause repeated trauma in the musculoskeletal system.Guo 17 also found that building construction workers had higher risk of musculoskeletal complaints. Yu-Sheng et al.18 conducted a study among building construction workers and their result showed that 76.2% of the workers reported musculoskeletal complaints. Shoulder symptoms were reported as the most prevalent work-related symptoms (47.6%), neck pain was the second (43.8%), and low back pain was the third (38.1%). Similarly in the present study we found that the musculoskeletal symptoms were common in neck, shoulders, upper back, low back, legs and feet. The findings of the present study are in agreement with the study of Yu-Sheng et al.18 however, in the present study, the percentages of symptoms were less compared to Yu-Sheng et al.18 The mechanism associated with musculoskeletal symptoms in building construction workers is mainly due to repetitively lifting and carrying heavy objects and also working in tough environment. The sustained activities can be linked to repetitive work, loading of tendons, rupture of the muscle fibers along with muscle disorders.19 Moreover, manual handling of building construction materials in different awkward postures increases the risk of musculoskeletal disorders.20GallagherThe present study adds evidence to the existing literature that a large proportion of labor force working in building construction had higher complaints of neck pain, shoulder pain, upper back pain, lower back pain, legs pain, feet pain, head heaviness and whole body fatigue. Moreover, construction workers working for more than 6 years had higher musculoskeletal symptoms. Cigarette smokers had little higher percentage of musculoskeletal complaints compared to non-smoker companions. The results indicate that building construction job is a prolific source of musculoskeletal ailments and complaints significantly increased with long-term work duration in building construction industry. It is advisable that health risk should be reduced by the mutual collaboration between health officials, building construction workers and their management to adopt appropriate protective measures and to avoid lifting heavy materials manually. Therefore, long term working in building construction industries should be avoided and workers must be given official days off at least two times in a week and two months in a year. The educational programs can be introduced to increase in the workers' knowledge about their health status and work ability. Moreover, based on the present study results workers must be advised to quit the cigarette smoking.Study strengths and limitations: This is a large sample sized study, the data were collected from six building construction sites, three different ethnicity based population was selected and translation of questionnaire was according to the native language of the workers. A limitation to this is that the findings do not exclude the possible impact of psychosocial job stressors on the musculoskeletal symptoms and due to variety of trades in the construction industry the work specific symptoms were not analyzed."}
+{"text": "Arthritis of the temporomandibular joint (TMJ) is a well recognized entity in patients with juvenile idiopathic arthritis (JIA). Recently, magnetic resonance imaging (MRI) evaluations have proven to have much greater sensitivity to detect arthritis compared to ultrasound and place the prevalence of TMJ arthritis in this population between 63% and 75%. There are a number of other rheumatologic diseases which can also present with TMJ inflammation  but the prevalence of TMJ arthritis in these populations is less known. The goal of the current study is to report on TMJ arthritis in non-JIA patients with various chronic childhood arthritides.Between September 2007 to December 2010, 75 patients with various non-JIA arthritis associated rheumatic diseases  were identified via electronic medical records and studied. Diagnoses were based on the expert opinion of one of the 3 pediatric rheumatologist authors. TMJ arthritis was defined as the presence of fluid, synovial enhancement, or evidence of bony changes as examined by contrast enhanced TMJ MRI. Electronic medical records, including clinical progress notes, lab results, and TMJ imaging reports of the seventy-five patients were thoroughly examined and results documented.Eighteen total non-JIA patients (25%) received MRIs of the TMJ during the study period, and 89% of those had documented arthritis elsewhere. Of the 18 MRI evaluations, 7 (39%) showed evidence of TMJ arthritis. Ten of 34 Sj\u00f6gren disease patients were screened for TMJ arthritis by MRI (29%); 4/10 had positive MRI evidence of TMJ arthritis (including condylar flattening). Five of 19 sarcoidosis patients were screened by MRI (26%); 3/5 had positive MRI evidence of TMJ arthritis. Three of 22 MCTD pts were screened by MRI (13.6%); 0/3 had positive MRI evidence of TMJ arthritis. Subjective symptoms were present in 6/18 (33%), and 13/18 (72%) had clinical signs of TMJ dysfunction. Common subjective symptoms noted were pain, clicking, and locking of the jaw. Common clinical findings included jaw deviation during opening and reduced maximal interincisor distance. Only 2/7 (29%) of patients found to have TMJ arthritis had subjective symptoms. The remaining 5/7 (71%) had a positive clinical finding (jaw deviation). None of the patients had both subjective symptoms and positive clinical findings. Concurrent peripheral arthritis was present in 6/7 (86%).TMJ arthritis is present in a subset of patients with non-JIA childhood arthritis. Moreover, the TMJ arthritis in these children can be similarly destructive. Thus, a maxillofacial screening exam should be considered at each visit of a patient with non-JIA childhood arthritis, and subjective symptoms or clinical findings should prompt physicians to consider a TMJ MRI for further evaluation. We are currently evaluating the potential benefit of intra-articular triamcinolone hexactenoide injections of the TMJ in this cohort of non-JIA chronic arthritis patients.Randy Q. Cron: None; Emily Fain: None; George Atkinson: None; Peter Weiser: None; Timothy Beukelman: None."}
+{"text": "Trastuzumab has recently shown efficacy in the treatment of HER2-positive advanced gastric adenocarcinoma. Although antibody-based therapies target the metastatic disease, HER2 status is usually evaluated in the primary tumour because metastatic sites are rarely biopsied. The aim of this study was to compare HER2 status in primary and paired metastatic sites of gastric adenocarcinoma.in situ hybridisation (FISH) and immunohistochemistry (IHC) in 72 secondary lesions of gastric adenocarcinoma and in the corresponding primary tumours.The HER2 status was assessed by fluorescence Concordance of FISH results, evaluable in 68 primary and matched metastatic sites, was 98.5%. Concordance of IHC results, available in 39 of the 72 paired cases, was 94.9%. Only one case showed discordance between primary tumour and metastasis, being negative by both IHC and FISH in the primary and showing HER2 overexpression and amplification in the corresponding pancreatic lymph node metastasis.The high concordance observed between HER2 results obtained by both IHC and FISH on primary tumours and corresponding metastases suggests that in gastric cancer HER2 status is maintained in most cases unchanged during the metastatic process. Tissue specimens of the paired primary tumours (18 endoscopic biopsies and 54 gastric resections) were available for all patients. The HER2 FISH.Cytological smears from metastatic lesions were obtained by multidirectional ultrasound-guided FNAB using a 22-gauge for deep lesion and 22\u201323 gauge for superficial lesions. The aspirated material was smeared on glass slides and air dried. Cellular suspensions obtained from pleural and ascitic fluids were cytocentrifuged and air dried. At least two slides were stained with May\u2013Gr\u00fcnwald\u2013Giemsa for routine cytology. The remaining slides were kept unstained at \u221220\u00b0C until assay. After cytological diagnosis of malignancy, one representative slide was submitted to \u03bcm thick sections that were submitted to both FISH and IHC. For each case, two tissue sections cut at different levels of the histological block were processed to control for tissue heterogeneity.Formalin-fixed, paraffin-embedded tissue blocks, selected on the basis of quality and representativeness of the sample, were cut into 3-HER2 amplification was assessed on both histological and cytological samples using a Spectrum Green fluorophore-labeled \u03b1-satellite DNA probe for chromosome 17 (Chr17) and a Spectrum Orange fluorophore-labeled DNA probe for the HER2 gene locus . Slides were hybridised using a Hybrite denaturation/hybridisation system for FISH (Vysis). Details of the method were previously described  were placed on slides coated with poly-L-lysine. After deparaffinisation and blocking of endogenous peroxidase, HER2 immunostaining was performed using rabbit anti-human c-erbB-2 oncoprotein as primary antibody  at 1/100 dilution. Binding of the primary antibody was revealed by means of the Dako Quick-Staining, Labelled Streptavidin\u2013Biotin System (Dako), followed by the addition of diaminobenzidine as a chromogen.Sections of archival formalin-fixed, paraffin-embedded tissue  and their corresponding metastatic lesions . The main characteristics of the patients are summarised in n=19), pleura (n=4), peritoneum (n=19), skin (n=4), regional lymph nodes (n=2), distant lymph node (n=14) and 10 to other sites. Of the 33 metastatic lesions sampled by cytology, 79% (26/33) were metachronous compared with 26% (10/39) of those sampled by surgery. In all, 4 of the 72 primary tumour specimens were not suitable for HER2 status assessment because of the poor fixation of tissue, whereas all specimens from metastatic sites were adequate for evaluation.The HER2 amplification was observed in 3 of the 33 (9%) cytological and 8 of the 39 (21%) histological specimens. In total, HER2 amplification was present in 11 of the 72 (15%) metastases. Two of the three HER2-amplified cytological samples  showed a HER2 cluster pattern in the whole-tumour cell population, whereas the third sample, a sovraclavear lymph node metastasis, had an average gene copy number of 12 and a HER2/CEP17 FISH ratio of 4.0 in 90% of tumour cells. All three amplified metastatic lesions sampled by cytology were synchronous. A cluster pattern of amplification was present in the eight HER2-positive metastases sampled by core tissue biopsy (seven liver and one pancreatic lesions); seven of these were synchronous and one metachronous.Among the metastatic lesions, HER2-negative metastases, 28 (46%) were disomic and 33 (54%) polysomic. No difference was observed in the distribution of HER2 gene copy number, between FNAB samples  and core biopsy or surgical resection samples  (independent samples t-test=NS).Of the 61 HER2 amplification was observed in 10 of the 68 (15%) primary tumours  of the 58 unamplified primary tumours were disomic, and 24 (41%) polysomic. A r2 of 0.937 and of 0.962 was found for FISH count by two independent observers in primary and metastatic lesions, respectively.The  tumours . Among tHER2 amplification in the primary showed an increase in both HER2 gene copy number (4.5 vs 12.0) and the percentage of amplified cells (33 vs 90%) in the matched metastasis. A single case showed primary vs metastasis discordance, being unamplified in the primary tumour  of the cases resulted positive by IHC, 6 of them showing a immunopositive (3+) reaction in >80% of tumour cells and 1 in 50% of tumour cells. The total concordance between IHC and FISH was 95.6%. FISH and IHC results in the 68 comparable primary tumours are shown in As to the 39 metastasis specimens assessed by IHC, 22 cases were negative by both IHC and FISH, 7 were positive by both techniques and 10 cases were ICH equivocal, 9 of which resulted FISH negative . Table 5HER2 status between primary tumour and metastasis has been scarcely addressed in the scientific literature. Only one study  and HER2/CEP17 FISH ratio (4.0 vs 2.4). The case was also HER2 negative by IHC on the primary; unfortunately, HER2 expression was not evaluable on the metastasis that was sampled by cytology.The HER2 amplification if gene copy number is <4 and equivocal when the number is 4.0 to 6.0 following the American Society of Clinical Oncology/College of American Pathologist guideline recommendations  was present at least in 50% of tumour cells in all the cases scored as positive by IHC.CEP17 copy number (Another question, still matter of debate in breast cancer, concerns the clinical significance of Chr17 polysomy on survival and response to trastuzumab therapy . CompareThe results of the phase III ToGA trial ("}
+{"text": "At least 20 million people are infected with HTLV-I virus in the world, and 3 to 5 % develop the classical neurological or hematological manifestations of myelopathy (HAM/TSP) or T-cell leukemia (ATLL). HTLV-I-infected patients with overactive bladder syndrome may represent 37%. We studied 102 HTLV-1 positive individuals without HAM/TSP divided into two groups according to the presence or absence of overactive bladder (OB) syndrome. Individuals with OB were more commonly female , but the mean age in the two groups was similar . The prevalence of neurological complaints was higher in OB group, especially hand or foot numbness and arm or leg weakness. There was no difference between the groups in neurological strength and reflexes. Weakness remained strongly associated with OB in multivariate logistic regression analysis adjusting for sex and age (adjusted odds ratio and 95% CI 3.59(1.45-8.88) in arms and 6.68(2.63-16.93) in legs). In summary, we have characterized a subgroup of HTLV-1 infected patients based on urinary complaints who have more frequent neurological symptoms compared to those without OB. Longitudinal studies are needed to determine if HTLV-1 associated OB is a precursor of HAM/TSP."}
+{"text": "This study on the prevalence of nosocomial infection in long ignored Niger took place in three (3) national hospitals (HNN HNL and MIG) and two (2) regional reference centres (Maradi and Diffa). These institutions were selected on the basis of use of services and technical platforms.To evaluate the prevalence of nosocomial infections in hospitals in Niger.A point prevalence survey making an assessment on \"any given day\" in each of the participating services, whose main characteristics were: Five hospitals totaling 1506 beds were concerned; 1040 hospitalized patients of whom 524 were male and 516 female bed occupancy 69.05%, 68 samples with microbial susceptibility testing were performed.a prevalence of 7.3% of infected patients (76 patients) and 7.78% of nosocomial infections identified a ratio of infections / infected of 1.05, 93.42% of nosocomial infections are acquired in institutions; specialties most affected are general surgery (26%), gynecology and obstetrics (20%), general medicine (9.2%) and gastrointestinal surgery and pediatrics (7.9%).68 samples coming from the gynecology obstetrics services, general surgery, general medicine and Pediatrics, 51 samples out of 69 have at least one nosocomial strain (positive), 86% of the pus, urine and 71.42% 100% positive catheters; 70 pathogens consisting of 10 identified species, the four most commonlz isolated were: Staphylococcus aureus (41.41%), Pseudomonas (15.71%), Klebsiella (11.42%) and Eschericha coli (10%) species are most involved.This study has allowed us to make an inventory of the quality of care in hospitals and to expose the problem of nosocomial infections long ignored Care in Niger.None declared"}
+{"text": "Human rabies fatal cases were related to animal rabies but it is reported that often lacks of animal rabies data, human case is underreported and rabies immune globulin and vaccine are not available so that these contributed to raise the big issues for rabies control and prevention measures in the developing countries. Recently in central coast region of Viet Nam human rabies fatal cases trend to increase from 1.5 to 2 folds in 2006 and 2007. This study described the clinical manifestations and epidemiological characteristics, post-exposure prophylaxis; and explored the risk factors associate with rabies fatality among twelve patients in central coast region in 2008.A case series descriptive study was used to reviewed medical records, conducted field investigation and interviewed household members of fatal case; And a case-control study was applied to explore the risk factors of rabies fatality.Among 12 fatal cases, average age of fatal case was 20.9 years old and male is higher than female 2 times. Most of victims were pupil (66.7%). Average of incubation period is 97.4 days (20 - 332 days). 100% patient manifested typical symptom of furious rabies with aerophobia, hydrophobia, apprehension of light, excitability. Average time from furious spasm to death is 5.2 days (1 - 30 days). The majority of fatal cases received neither anti-sera (11/12 case) nor vaccination (10/12 cases). Domestic dog bite account for 100% of fatal case and the majority of them were unvaccinated (91.7%) and unleash (83.3%). 60% of local people did not know clean and flush wound with water and soap. Case-control study result showed that risk factors associated with rabies fatality are \"Did not know vaccination for dogs is necessary\"(OR= 33 (CI: 5.1 - 246.4) p<0.001); \"Did not aware of signs and symptoms of animal rabies\" , p<0.05); and \"use suspected rabies animal for food\" .Rabies fatality must\\can be prevented if we address to (1) enhance the active surveillance for animal rabies and vaccination domestic dog; (2) educate the school pupil, dog owner and local people on community prevention; (3) enhance the post-exposure prophylaxis, and anti-sera and vaccine should be available with a reasonable price at the district clinic\\hospital."}
+{"text": "Natural rubber latex (NRL) allergy has become an important occupational health problem in recent years. However, the prevalence of sensitization to NRL among allergic asthmatic patients is unknown. This study was undertaken evaluate the levels specific IgE in sera of 70 adult asthmatic patients  with mild (32 patients) and moderate (38 patients) asthma, whose diagnosis was confirmed by case history, skin test results and RAST 20% of the asthmatics (14 patients) had latex-specific IgE in sera detected by Pharmacia UniCAP. Among the 14 latex sensitized asthmatics 6 patients had mild asthma and 8 had moderate asthma, 10 being male and 4 female. No latex-specific IgE was found in sera of 10 healthy donors. Among the 14 latex-sensitized asthmatics, 12 (86%) had sensitization to house dust; 13 (93%) sensitization to trees; 11 (79%) sensitization to grasses; 11 (79%) sensitization to weeds; 4 (29%) sensitization to cat/dog. There are no correlation between sensitivity to latex determined by latex specific IgE in sera and occupation of these asthma patients. 12 patients among the latex-sensitized asthmatics (86%0 had banana-specific IgE. 50 (72%) of the asthma patients had high levels of total IgE and all latex-sensitized asthmatics had high levels of total IgE. Using a one point RAST inhibition assay employing 10mg/ml of Greer latex extract 50% RAST inhibition was obtained, confirming specificity of the anti-latex IgE in these asthmatics. This study demonstrated a relatively high prevalence (20%) of in vitro reactivity to NRL allergens among patients with asthma. The source of sensitization to latex in these patients remains to be determined."}
+{"text": "Objectives: Orofacial infections are common reasons for dental consultations worldwide. However, there is scarcity of data on clinico-epidemiological profiles reported from primary care dental practices. To address this issue, a study was done to characterize the clinical pattern, age groups affected and sex predilection of orofacial infections in the primary care dental practice. Study design: Clinical data was evaluated from random electronic files of patients for whom antimicrobials were prescribed at two Dental Practices in UK between January 2009 and December 2010. Results: 200 case records were studied. 104 (52%) cases were females. Mean age was 37.2 (+/-15.1) years. 107 (53.5%) cases belonged to age group 21-40 years. Posterior teeth were involved in 112 (56%) cases. Types of disease were as follows: dentoalveolar abscess 63(31.5%), pulpitis 27(13.5%), apical periodontitis 21(10.5%), pericoronitis 21(10.5%), dry socket 13(6.5%), periodontitis 9(4.5%) infected root stump 5(2.5%), facial swelling 5(2.5%) and infections unspecified 36(18%) cases. Conclusions: Orofacial infections affect both sexes equally. 21-40 years is the commonest age-group affected. Dentoalveolar abscess is the commonest infection followed by unspecified infections and pulpitis. Key words:Orofacial infections, primary care dental practice, dentoalveolar abscess and pulpitis. Oral and maxillofacial infections are common health problems and frequent causes of dental consultation worldwide. More than 500 bacterial species are known to constitute normal oral microbiota . MicroorOrofacial infections may be odontogenic or non odontogenic in nature and the vast proportion of odontogenic infections are caused by the endogenous bacterial microbiota in the oral cavity  while noOrofacial infections may lead on to significant complications unless they are managed timely and appropriately. Morbidity and mortality related to these infections depend on the site of involvement and the degree of spread to other tissues. A majority of these infections are confined to the dentoalveolar and/ or facial tissues at the time of presentation, but may spread to local, regional or distal sites if treatment is delayed .In order to manage these infections scientifically, correct identification of the aetiology and pathology of the disease is important. Appropriate choice and duration of antimicrobial prescription for these infections rely upon the age, systemic infection and other co-morbidities of the patient. Analysis of etiopathogenesis and presentations of orofacial infections, in a general dental practice would help to understand the clinical spectrum of these important illnesses and to tailor the right treatment strategy for patients in future. With this purpose, a retrospective study was conducted to determine the types of disease, age groups affected, sites involved and gender predilection among patients treated for orofacial infections in two primary care dental practices.A retrospective study of patients who were treated with antimicrobials in two dental practices in West Midlands, UK between January 2009 and December 2010 was done. From the clinical database of patients treated during this period, every third patient who was prescribed an antimicrobial was identified from prescription records. The clinical data of these patients were retrieved from computer records. Demographic and clinical parameters like age, gender, smoking status, alcohol consumption, relevant medical history, teeth affected, clinical diagnosis and type of treatment provided were identified and recorded.Cases with incomplete records where it was difficult to determine basic data like clinical diagnosis and type of antimicrobial prescribed were excluded from the study. The data retrieved were entered into an excel sheet for the purpose of analysis. The study protocol was formally approved by the institutional review board.Statistical analysis was performed using computer software SPSS for Windows, version 11.5 . Categorical variables were compared with chi square test. Continuous variables were compared by unpaired \u2018t\u2019 test and are presented as mean (+/- SD). Level of statistical significance was set at P <0.05.226 case records were retrieved from computer database where antimicrobials were prescribed. After excluding the data of incomplete case records , 200 cases were identified for final analysis. 104 (52%) were females and 96 (48%) were males. 56 (28%) were smokers, while 90 (45%) were non-smokers. No record of smoking status was available for 54 (27%) cases. 84 (42%) of the patients had history of alcohol consumption, while 60 (30%) had been non-alcoholics. 56 (28%) cases had no data on alcohol consumption.Mean age of the study cohort was 37.2 (+/- 15.1) years. 65 cases (32.5%) belonged to the age group 21 \u2013 30 years. The distribution of cases according to the age groups is shown in Teeth and site affected: Posterior teeth were most commonly infected accounting for a total of 112 (56%) cases, while anterior teeth and deciduous teeth constituted 10 (5%) and 5 (2.5%) cases respectively. Symptomatic involvement of multiple teeth was recorded in 28 (14%) cases. Lower right first molar tooth was the commonest offending tooth (8% of cases) followed by lower left third molar (7%) and second molar (6%). However, appropriate details were unavailable to identify the tooth and the site involved in 45 (22.5%) cases.A large proportion of the infections where found to be in the lower posterior teeth, both right and left sides, with equal predilection 36 (18%) cases each, followed by upper posterior teeth with a predilection for left side (11.5%), upper right posteriors (8.5%), upper left anteriors (3%), deciduous teeth (2.5%), upper right anterior (1.5%) and the least was for lower right anterior teeth (0.5%).Types of disease: Most common infection identified was dental abscess (31.5%), followed by pulpitis (13.5%), apical periodontitis (10.5%), pericoronitis (10.5%), dry socket (6.5%), periodontitis (4.5%), infected root stump (2.5%) and facial swelling (2.5%). However, in 36 (18%) cases the type of disease was not grouped under any of the above category (conditions such as acute necrotising ulcerative gingivitis (ANUG), gingival abscess, referred pain in the teeth secondary to maxillary sinusitis, anticipated infections in traumatic dental extractions or infective endocarditis prophylaxis). A gender specific distribution of the types of disease is shown in the An age specific distribution of disease types is shown in Periodontitis was found to be much more common among patients aged between 31 and 40 years.Treatment modalities given to cases: 104 (52%) cases were given only antimicrobial treatment for their illnesses. Of the remaining cases, 17 (8.5%) were treated with dental extraction, 16 (8%) with wisdom tooth management, 14 (7%) with root canal treatment and 9 (4.5%) with alvogyl for dry socket, in addition to antimicrobial prescription. 21 (11.5%) cases received combination treatment with more than one of the above therapeutic measures along with antimicrobial prescription. 9 (4.5%) cases were referred for specialist opinion and management. In 8 (4%) cases the exact treatment modality, other than antimicrobial prescription, was not recorded in the database.This study provides an overall picture of the types of oral and maxillofacial disease where antimicrobials were used in two primary dental practices. The gender and age predilection, and the common sites involved are also revealed.There was no significant gender difference for clinic visit rate due to orofacial infections in this study cohort. This finding is similar to the earlier observation reported by YM Dailey et al . However45% of cases in the study cohort were non-smokers. Smoking can adversely affect the oral bacterial flora and may predispose orofacial and periodontal disease . BecauseAging is associated with reduction in adaptive immunity and the elderly are more susceptible to oral and dental infections . HoweverDentoalveolar abscess is reported to account for 25% of emergency dental visits for odontogenic infections . In this39.2% of antimicrobial prescriptions were for pulpitis in the series reported by YM Dailey et al . Only 13Significantly higher proportion of males  had apical periodontitis in the present study although a female preponderance of apical periodontitis was reported in the study by Akinbami et al . The proPosterior teeth were most commonly involved with infection in this study. This observation is similar to those by other investiga-tors ,13-15. PA majority of cases in the present study received only antimicrobial prescription as the sole treatment modality. This observation is similar to that reported by YM Dailey et al . Dental In conclusion, dentoalveolar abscess was the commonest infection for which antimicrobials were prescribed. Antimicrobial prescription rates for management of pulpitis by dental professionals are less these days. People in their third and fourth decades of life are the commonest age groups affected by orofacial infections and there is no sex predilection for the disease."}
+{"text": "Surgical ventricular restoration by means of the Dor procedure is a surgical option in patients with coronary artery disease, post- infarction left ventricular aneurysm or ischemic dilated cardiomyopathy with or without mitral regurgitation. The aim of this study was to evaluate our 8 year clinical experience of this procedure.From April 2005 to April 2013, surgical ventricular restoration was performed in 48 patients , mean age 57 (41-74) years. All patients presented with angina and/or heart failure and/or ventricular tachycardia. Postinfarction left ventricular aneurysm was present in all 48 patients and ischemic dilated cardiomyopathy with a large akinetic left ventricle in 8. The preoperative left ventricular ejection fraction was 32+/-9 (19-43) %. Multi-vessel disease was present in 18 patients. Ventricular tachycardia was diagnosed in 10 patients (spontaneous VT in 2). Mitral regurgitation more than grade I was found in 18 patients. The mean EuroSCORE was 7.3+/-2.6 (4-17).All patients underwent the Dor procedure, which included a non-guided endocardectomy to exclude the aneurysm and treat ventricular tachycardia. Coronary artery bypass grafting was performed in all 48 patients and a mitral valve repair was performed in 18. Intra-aortic balloon pumping was used preoperatively in 7 patients and postoperatively in 6 cases and all 48 patients needed inotropic support for more than 24 h. Hospital mortality was 8/48 (16.6%).The Dor ventricular restoration is a good surgical option for treatment of postinfarction left ventricular aneurysm and mitral repair should be done if the regurgitation is more than mild. Eight years results are good compared to the patients EuroSCORE."}
+{"text": "To retrospectively access the outcome and toxicity of a total skin electron beam therapy (TSEBT) in patients with cutaneous lymphoma (CL) or leukemia.Treatment results of 25 patients  with cutaneous manifestations of advanced and therapy-refractory CL  stage IIB-IV or leukemia  treated between 1993 and 2010 were reviewed. All patients were symptomatic. The median total dose was 29Gy, applied in 29 fractions of median 1 Gy each.The median follow-up was 10 months. Palliation was achieved in 23 patients (92%). A clinical complete response was documented in 13 (52%) and a partial response in 10 patients (40%). The median time to skin progression was 5 months (range 1\u201318 months) and the actuarial one-year progression-free survival 35%. The median overall survival (OS) after the initiation of TSEBT was 10 months (range 1\u201346 months) and the actuarial one-year OS 45%. TSEBT related acute adverse events (grade 1 or 2) were observed in all patients during the treatment period. An acute grade 3 epitheliolysis developed in eight patients (32%). Long-term adverse events as a hyperpigmentation of the skin (grade 1 or 2) were documented in 19 patients (76%), and a hypohidrosis in seven patients (28%).For palliation of symptomatic cutaneous manifestations of advanced cutaneous lymphoma or leukemia, total skin electron beam therapy is an efficient and well tolerated considerable treatment option. Cutaneous lymphomas (CL) account for approximately 19% of extra-nodal non-Hodgkin\u2019s lymphoma. The predominate form of cutaneous lymphoma in the United States were T-cell lymphoma (CTCL) between 2001 and 2005, which count for approximately 71% of cases, corresponding to an incidence rate (IR) of 7.7/1.000.000 person-years . The oriBetween 1993 and 2010, 25 patients with advanced, pretreated and therapy-refractory CL stage IIB to IV or cutaneous manifestations of leukemia were treated in palliative intention with TSEBT at the Department of Radiation Oncology of the University Hospital Heidelberg. Even though the underlying diseases were partially different, the clinical situations of these patients as well as clinical challenge in palliation were comparable and therefore analyzed together. All patients were refractory to extensive pre-treatment with topical and systemic approaches as chemotherapy, interferon, and/or PUVA-photochemotherapy. All patients were symptomatic with hemorrhages, pruritus, pain and/or ulcerating skin manifestations. The median time interval between initial diagnosis of the underlying disease and initiation of TSEBT was 2 years (range 0.5-8 years). Further characteristics were listed in Table Radiotherapy was performed as total skin electron beam therapy and the patient standing in an upright position on a rotating base being irradiated by two electron fields with initial energies of 6 MeV that are reduced to 3.8 MeV by a Lucite moderator. Details on treatment setup were published by Funk et al. . It was The data was analysed regarding overall survival (OS) and skin-progression-free survival (PFS). Statistical analyses were carried out with SPSS statistical package  using log-rank test (Mantel-Cox) and Kaplan-Meier\u2019s estimation. Significance was defined as p-value <0.05. All time estimates began with the initiation of radiation treatment. Documented long-term side effects were classified according to the RTOG/EORTC Late Radiation Morbidity Scoring Scheme . Approval of the ethics committee Heidelberg was obtained.The median follow-up time was 10 months range 1\u201346 months). Treatment response regarding palliation with symptom relief, especially of pruritus and regression of cutaneous lesions, was achieved in 23 patients (92%). A clinical complete response was documented in 13 (52%) and a partial response in 10 patients (40%). The median time to skin progression was 5 months (range 1\u201318 months) and the actuarial six-months and one-year skin-progression-free survival were 55% and 35%, respectively . Two patients died due to tumor progression and organ failure during the radiation treatment. One of these 2 patients suffered from a pneumonia finally causing fatal renal failure, the other patient developed fatal renal failure due to a blast crisis during TSEBT. Furthermore, following long-term adverse events were documented during follow-up visits: grade 1 or 2 hyperpigmentation of the skin developed in 19 patients (76%), and seven patients (28%) reported a hypohidrosis.We report the treatment results in 25 patients treated with total skin electron beam therapy between 1993 and 2010 for cutaneous manifestations of advanced, extensively pretreated and therapy-refractory cutaneous lymphoma and leukemia. The overall treatment response with 92% symptom relief, especially of the pruritus and regression of cutaneous lesions, and 52% clinical complete remissions as well as 40% partial remissions demonstrate the efficacy in the setting of advanced and otherwise therapy-refractory disease. In the daily routine, treatment side effects as fatigue and skin reactions seem manageable.A recent development to reduce the significant treatment-related side effects is to identify a lower possible treatment dose while keeping the effective treatment response. In this setting, Harrison et al. identified 102 patients treated for MF with low-dose (5-\u2009<\u200930Gy) TSEBT between 1958 and 1995. Patients had stage classifications T2-T4. The overall response rates were dose dependent with 90% in patients receiving 5 to <10 Gy (n\u2009=\u200919), 98% in 10 to <20Gy and 97% in 20 to <30Gy and efficacy measures as OS and PFS were comparable . In compAn actual publication by Lindahl et al. reviewed 35 patients with CTCL treated with TSEBT in Denmark between 2001 and 2008. Almost all patients had previous treatments and 40% of patients had T2 disease. The median follow-up time was 7.6 months and 25 patients were treated with high-dose (30 Gy) TSEBT and 10 patients in a low-dose (4 Gy) protocol. The group of patients with low-dose TSEBT had inadequate treatment response (CR in 10%) compared to higher-doses . Overall, 28% showed progressive disease, 22.2% in T2 and 35.7% in T3 stage. Median time to progression was 9 months. Side effects related to TSEBT were documented in 88% of patients, including erythema and ulceration in 80%. The most common long-term side effect was alopecia (44%), dry skin (36%), hyperpigmentation (28%), ocular irritation (24%) and temporary loss of finger nails 16%). Furthermore, 2 patients developed basal cell carcinoma and one patient a squamous cell carcinoma. However, in 1 of these 3 patients, PUVA was administered previously, while one other of these 3 patients previously received topical nitrogen mustard. The authors concluded that CTCLs are highly radiosensitive and TSEBT offers significant palliation, but relapse is common and it remains unclear whether prior treatment to TSEBT prolongs the effects of TSEBT %. Furthe. In compIn 2009 Neelis and co-workers published results on 18 patients with CBCL treated with palliative low-dose involved-field (IF) radiotherapy (4 Gy in 2 fractions) and 31 patients with MF treated with 4 Gy, later with 8 Gy in 2 fractions. In total 126 lymphoma sites were treated. All patients were previously treated with different approaches, 15 patients have already had TSEBT. In the group of patients with CBCL, the rate of complete remission (CR) was 75% (33/44 lesions). In patients suffering from CTCL and MF, the remission rate after application of 2 x 2 Gy was disappointing (70% failed to achieve a CR), so the treatment dose was increased to 2 x 4 Gy and a CR rate of 92% (60/65 lesions) was achieved. According to the authors, high-grade side effects were not seen. In conclusion, the authors recommended low-dose IF radiotherapy as standard treatment in patients with cutaneous lymphoma, with the option of re-irradiation at progression . From ouLiterature on cutaneous manifestations of leukemia, e. g. leukemia cutis is very rare. Pepek and colleagues reported on 2 pediatric patients treated with TSEBT and recommended the consideration of TSEBT for palliation . FurtherFor palliation of symptomatic cutaneous manifestations of advanced, PUVA- and chemotherapy-refractory cutaneous lymphoma or leukemia, total skin electron beam therapy is an efficient and well tolerated considerable treatment option.The authors declare that they have no competing interests.HH: analysis and interpretation of data, writing manuscript. FZ: critically revision for important intellectual content, interpretation of data. NR: acquisition and analysis of data. MU: acquisition and analysis of data. FH: critically revision for important intellectual content, interpretation of data. JD: critically revision for important intellectual content, interpretation of data. KH: critically revision for important intellectual content, interpretation of data. MB: substantial contributions to conception and design; critically revision for important intellectual content; final approval for publication. All authors have read and approved the final manuscript."}
+{"text": "For decades, acetabular fractures were treated conservatively. Judet et al. in 1960s established the operative treatment of these fractures by continuous improvement of pre-operative evaluation and classification of fractures. Several studies demonstrated that accurate fracture reduction decreases the incidence of post-traumatic arthritis and improves functional outcome.We report 67 consecutive patients who underwent surgical treatment for acetabular fracture; 44 patients were available for follow-up. In 35 (79.5%) cases, congruent reductions were achieved. The final mean Harris hip score was 81.8 (53-95). Functional outcomes according to Harris score were excellent and good in 31 patients (70.5%).The results of internal fixation of displaced acetabular fractures in our series were satisfactory. Fractures of acetabulum and pelvis constitute only 2% of all fractures , 2 but tBetween March 1996 and September 2010, 67 consecutive patients underwent surgical treatment for acetabular fractures at the Mashhad University Trauma Center. Surgical criteria were acetabular fractures with 2 mm or more displacement in the dome area of the acetabulum, roof arc angle measurement of less than 45 degrees, presence of intra-articular fragments, posterior joint instability, irreducible fracture/dislocations and the need to reconstruct the socket for total hip replacement.Unfortunately 4 cases died due to poor general health and associated injuries and 19 cases were lost to follow-up. Therefore there were 44 patients with complete data. Among these cases there were 34 male and 10 female patients; their age at the time of surgery was between 17 and 78 (mean 43.1 years old), in 19 cases the left acetabulum and in 25 cases the right acetabulum was fractured. The mechanism of injury was road-traffic accidents in 38 patients, fall from a height in 4 and in 2 cases the fractures were due to other causes.There were 9 associated injuries, including 2 cases of head injury,2 abdominal injuries, 2 incomplete sciatic nerve injuries , one ipsilateral subtrochanteric fracture, one ipsilateral femoral shaft fracture and one contralateral femoral shaft fracture.After clinical evaluation and initial resuscitation, all patients had preoperative X-rays taken and a CT scan was also performed for patients admitted after 2001. All fractures were classified according to the criteria of Judet et al.; 16 were simple and 28 complex fractures .Surgery was performed via the \"Kocher-Langenbeck\" , \"ilioinguinal\" and \"extended iliofemoral\" approaches . In 7 caThirty-six (81%) of patients were operated within 2 weeks of injury. Five cases were referred late to trauma center and 3 patients had associated injuries, thus 8 patients were operated after the ideal 2- week post-injury period. A Kocher-Langenbeck approach was used in 20 (45.4%) cases, an anterior ilioinguinal approach in 16 patients (36.4%), and an extended iliofemoral approach in 8 patients (18.2%).There was no residual instability or nonunion at the final follow-up. In 35 (79.5%) cases, congruent reductions were achieved. The remaining 9 patients had incongruent reduction of their fractures: In 5 patients both column fractures were operated 2 weeks following the injury, there were 3 central fracture dislocations with severe comminution  and 1 anIn the current series, radiographic congruency correlated well with functional scoring . Mean Harris score of \"incongruent reduction group\" was 67.3 compared to 85.5 in the \"congruent reduction group.\" It seems that, age affected functional results. Mean Harris score in patients under 40 was 85.3 compared to 79.7 in patients over 40 years old .There were five (11.4%) early complications, including 2 (4.6%) deep vein thromboses treated by cardiologists and 3 (6.8%) wound infections treated by surgical debridement. There were 2 (4.6%) heterotopic ossifications (HO) following a Kocher-Langenbeck approach both of which were treated non-operatively and 2 (4.6%) patients developed symptomatic post-traumatic arthritis managed by total hip arthroplasty . ReductiAcetabular fractures are commonly classified by the \"Letournel\" and \"Judet\" system . This cl"}
+{"text": "Non-invasive positive-pressure ventilation (NIPPV) is the first-line treatment for hypercapnic acute respiratory failure (ARF) secondary to COPD exacerbation in selected patients. Limited data exist supporting the use of fiberoptic bronchoscopy (FOB) during this clinical setting. The aim of this study is to assess the role of FOB during NIPPV in patients with decompensated COPD acute exacerbation.This study is a randomized prospective case-control pilot study carried out on 50 patients admitted to critical care units at Alexandria University Hospital, Egypt suffering from hypercapnic ARF secondary to COPD exacerbation with Kelly Matthay Score from 2 to 4. All patients received NIPPV. Patients were divided randomly into two equal groups: group I  were subjected to additional intervention, early FOB during the first 6 to 12 hours from admission; while group II  received the conventional treatment and NIPPV only. Outcome parameters measured were changes in ABG data, duration of NIPPV, rate of its success, ICU stay and mortality as well as the safety of FOB and possible complications.P = 0.037). Total duration of NIPPV was 28.52 hours in group I versus 56.25 hours in group II (P = 0.001). Length of ICU stay was 4.84 days in group I versus 8.68 days in group II (P = 0.001). Only one patient died in group I versus three patients in group II (P = 0.609).No significant difference was detected between the two groups regarding the baseline characteristics. No serious complications happened from FOB, oxygen desaturation occurred in 4/25 patients (16%), tachycardia in 2/25 patients (8%). In group I, 23 patients (92%) were successfully weaned from NIPPV versus 16 patients (64%) in group II (The early application of FOB during NIPPV in patients with ARF due to COPD exacerbation was shown to be safe. Significant improvement in the outcome of patients who underwent FOB was noticed in terms of improved ABG data, shorter duration of NIPPV, higher percentage of success and shorter ICU stay while no significant difference was detected in mortality."}
+{"text": "In patients with monogenic autoinflammatory diseases, the majority of detected mutations were found just in a single gene, either in homozygous, heterozygous or compound heterozygous state. However, in some patients mutations in several different genes have been detected. Clinical significance of this finding has yet to be established.To describe clinical characteristics of patients with rare combinations of genetic mutations.http://www.printo.it).Seventy-seven centres from 33 countries have been contributing to an international secured web-based registry for autoinflammatory diseases (EUROFEVER), hosted by the PRINTO website , the combination of mutations in two different genes, and in one patient in three genes was found with following distribution of clinical diagnoses: Cryopyrin-Associated Periodic Syndromes (CAPS)=9, Tumor necrosis factor (TNF)-Receptor Associated Periodic Syndrome (TRAPS)=7, Familial Mediterranean Fever (FMF)=5, mild Mevalonate Kinase Deficiency )=2, undefined=9. Out of these patients 18 (56%) carried one high penetrance mutation each. The prevalence of high penetrance mutations among clinically defined groups was most prominent within the CAPS phenotype (8/9) followed by FMF (3/5), MKD (1/2) and TRAPS (3/7). In patients with low penetrance mutations in one of the 4 relevant genes the second mutation was found in one of the remaining 3 genes with the following characteristics: low penetrance (5/14), polymorphisms (3/14), unknown (4/14). In remaining 2 patients the combination of unknown penetrance mutation in one gene and polymorphism in the other was found (both with undefined phenotype).As the availability of molecular genetic analysis for patients with recurrent fever syndromes increases, the amount of detected mutations in more than one gene will grow. The data currently available suggest that the high prevalence mutations overrule the clinical picture of the disease in majority of patients, though clinical significance of second mutations will have to be evaluated in larger patient series.None declared."}
+{"text": "Egg allergy is highly prevalent in children with eczema, however there is little known about the establishment of sensitization and clinical reactivity in infants under 6 months of age.49 infants between the ages of 4-5 months were randomised to receive pasteurized raw egg powder as the intervention for a randomised controlled trial. All infants had moderate to severe eczema with SCORAD score >15, and had no known prior exposure to egg. Data was collected on any allergic reactions to the egg powder, along with background information on the infants and their families including allergic history, health, diet and environment. The infants consumed \u00bc to 1 teaspoon of pasteurized raw egg powder daily for 3 to 4 months unless an allergic reaction to this study powder was confirmed.Positive allergic reactions occurred in 16/49 (32.6%) infants who received the pasteurized raw egg powder. Skin reactions were the most common symptom with skin rashes  in 15/16 (93.7%) infants, as well as urticaria and/or angioedema in 11/16 (68.7%) each. Of less frequency were gastrointestinal (GI) symptoms : 5/16 (31.2%), and respiratory symptoms: 2/16 (12.5%). Severe reactions were observed in 2/16 infants (18.75%) with one infant with FPIES and one case of anaphylaxis. Reactions occurred within 60 minutes in 12/16 (75%) infants, with seven reactions (43.7%) presenting immediately within 5 minutes. Later onset between 1-3 hours occurred in 4/16 infants (25%), with two cases experiencing severe GI symptoms. Delayed reactions after three hours of ingestion were not observed in this group. There were no differences in background characteristics of the infants who reacted compared to those who did not react to the egg powder, including family allergic history, infant medical history, feeding practices, or exposure to other children.Infants with eczema under 6 months of age are at high risk of allergic reactions with their \u2018first\u2019 introduction of egg, including severe symptoms of FPIES and anaphylaxis. This highlights the need to understand the much earlier events leading to food sensitisation."}
+{"text": "Both subclavian and axillary artery aneurysms should be promptly treated after diagnosis due to complications. The primary treatment modality is mainly surgery.Eight patients that were operated on between February 1998 and December 2007 due to true aneurysms of the subclavian and axillary arteries were examined retrospectively in terms of clinical and perioperative parameters. Median age of the patients was 58 (38-73). Six of them were male (75%). Six patients had axillary and 2 patients had subclavian artery aneurysms. : Postoperative intubation time, duration of intensive care unit stay, amount of blood products used, complications as surgical wound infections and bleeding were recorded. After the discharge, patients were examined with Doppler ultrasound at the 1st month and 1st year control visits.Duration of the operation was 2 hours (1-3). Median intubation period was 3.5 hours (2-5). Median duration of intensive care unit stay was 1.5 days (1-2). Median duration of hospital stay was 3 days (2-4). Median unit of blood products used perioperatively was 1 unit (0-3). As early postoperative complication, one patient developed perianastomotic pseudoaneurysm 40 days after the initial operation due to subclavian artery aneurysm. This patient underwent subclavian-axillary bypass using saphenous vein in the second operation again. Another patient that underwent emergency operation due to bleeding had weakness of the affected upper extremity due to preoperative brachial plexus injury. But in order to disappear completely, he needed physical therapy for some period. No early postoperative mortality was seen. Only one patient died 5 years after the operation due to some unrelated causes. Median follow-up period was 106 months (64-170). Secondary patency rate was 100% during follow-up.True aneurysms of the subclavian and axillary arteries are rarely seen. After the diagnosis, the successful surgical repair is possible."}
+{"text": "Systemic sclerosis (SSc) associated interstitial lung disease (ILD) is the leading cause of morbidity and mortality in SSc patients.To detect and determine the prevalence of ILD in patients with SSc in Sulaimani Governorate.A sample of thirty patients with SSc (whom fulfilled the American Rheumatism Association preliminary criteria for the diagnosis of SSc), were collected from Sulaimani internal Medicine teaching hospital from July 2009 to July 2010.2) and high-resolution computed tomography (HRCT) scan.All patients were evaluated in a cross sectional study for the evidence of ILD, almost all patients were submitted to chest radiographs (CXR), pulmonary function tests (PFT) and oxygen saturation by pulse oximetry (Spo45.57) years, with female predominance 27(90%) compare to 3(10%) male.Patients ages ranged from 23-68 years with mean (Majority of patients had limited type of systemic sclerosis 21(70%), and 15(50%) cases had restirictive ventilatory defect. Out of the thirty patients in the study 16(53.3%) patients had evidence of ILD on HRCT.1. ILD is common among patients with SSc (dcSSc type).2. PFT & HRCT are sensitive tools for diagnosis ILD among patients with SSc."}
+{"text": "To establish the percentage of postdromal symptoms in patients suffering from migraine headache according to sex, individual incidences and postdromal stage duration.Migraine postdromes (MP) represent a set of various symptoms which persist for a certain period following a migraine headache attack. Many of those symptoms appear in the prodromal stage or during the headache phase. Most often, patients speak of losing appetite, experiencing nausea, muscular tension, diffuse headache, fatigue, hangover, change of mood or a congitive disturbance. The phase can last as long as 48 hours. Its pathophysiology is unknown, but it probably represents a phase of gradual recovery from an extreme neurological disturbance occurring during migraine. There have been very few studies in this field so far. Methodology: Research has been conducted on a sample of patients suffering from migraine with aura (MA) and those suffering from migraine without aura (M). The MP data have been obtained on the basis of interviews with 500 patients (F:M=400:100), aged between 18 and 40. 12% of the patients have experienced MA, whereas 88% of the patients have suffered from M. The number of patients for each subject of research has been also displayed in the form of percentages.280 (70%) females and 55 (55%) male patients suffer from one or several postdromal symptoms. 480 (88%) patients of either sex experience postdromes lasting up to 24 hours, whereas 60 (12%) of patients experience postdromes lasting over 24 hours. The fatigue symptom is present in 360 (72%), diffuse headache in 165 (33%), a cognitive disturbance in 60 (12%), the loss of appetite in 35 (7%), hunger in 1 (0.2%), depression in 20 (4%), euphoria in 10 (2%), hangover in 55 (11%) and general weakness in 30 (6%).A large number of patients of either sex suffering from M or MA have postdromal symptoms lasting as much as 48 hours, which additionally aggravates their quality of life. It is therefore necessary to consider potential therapeutic protocols aimed at treating these complaints.Key concepts of migraine postdrome:a qualitative study to develop a post-migraine questionnaire."}
+{"text": "The Chinese human adenovirus 7 (HAdV7) 0901HZ/ShX/CHN/2009 was isolated from the hydrothorax fluid of an infant with fatal pneumonia in Shaanxi, China, in 2009. Comparison of the entire genome with the genomes of the other 10 strains of HAdV7 from GenBank revealed homologies of 89.9 to 99.9%, with geographic polymorphism among HAdV-7 field strains circulating in mainland China. Human adenoviruses (HAdVs) can cause a broad range of clinical manifestations in humans, with billions of people infected worldwide . These aAn outbreak of infant severe pneumonia was reported in Shaanxi, China, in 2009 , and twohttp://bio.cse.psu.edu/pipmaker) (Pipmaker (ipmaker)  was usedThe strain HAdV7-0901HZ has a genome of 35,239\u00a0bp in length and a GC content of 51.08%. A total of 48 coding sequences were identified in this genome sequence, including seven predicted genes.JX625134, JN860677, and GQ478341). An exception was HAdV7-GZ07, which has a large fragment deletion at position 28334 to 31162 of the E3 region (accession number HQ659699) and homology of 89.9%. For the vaccine and Gomen strains  the nucleotide sequence similarities were 97.7% and 99.4%, respectivelyThe genome sequence alignment of HAdV7-0901HZ with other HAdV7 strains revealed high homologies of 99.7 to 99.9% (accession numbers Adenovirus infections in the immunocompetent host are usually limited by the immune system. But HAdV7, a member of the B1 subspecies, has been identified in epidemics to be highly virulent and is associated with clinical manifestations of considerable severity, including residual lung damage and fatal outcomes \u201310. ThisComparative genomic analysis of 11 strains of human adenovirus type 7 isolated from this study and the references from GenBank showed that HAdV-7 circulating in mainland China has multiple transmission chains, suggesting the need for surveillance in high-risk populations.JF800905.The nucleotide sequence of the complete genome of HAdV7 strain 0901HZ/ShX/CHN/2009 has been submitted to GenBank under accession number"}
+{"text": "Vascular endothelial growth factor (VEGF) has been shown to be an endothelial cell-specific mitogen and an angiogenic inducer in a variety of in vitro and in vivo models. Furthermore, it has been demonstrated to increase retinal vessel permeability by increasing the phosphorylation of tight junction proteins. Recent work has found elevated levels of VEGF in ocular fluids of patients with proliferative diabetic retinopathy (PDR). Thus, it makes sense to consider anti-VEGF treatments in the management of PDR. The purpose of the current research is to determine if intravitreal bevacizumab as anti-VEGF is helpful in the management of complications of PDR. Dietary habits and an increase in sedentarism are the main culprits of a worldwide epidemic in diabetes mellitus (DM). In the year 2010, more than 285 million people suffered from DM. The World Health Organization has estimated that by the year 2030 there will be 370 million persons affected with DM in the world, and every one of them will be at risk of developing diabetic retinopathy (DR) . Of the total of 43 eyes, 31 (72.1%) eyes had been previously treated with scatter photocoagulation at least six months before intravitreal bevacizumab, no eyes had prior focal/ grid laser photocoagulation, and no eyes had a previous intravitreal triamcinolone injection. Twenty-four (55.8%) eyes were treated with an intravitreal injection of 1.25 mg and 19 (44.2%) eyes were treated with 2.5 mg of bevacizumab. At the end of the two year follow-up , the mean baseline BCVA of logMAR = 0.94 \u00b1 0.38 ETDRS (20/176) improved to a mean BCVA of logMAR = 0.67 \u00b1 0.39 ETDRS (20/94) (p < 0.0005). Final BCVA analysis by sub-groups demonstrated that 35 (81.4%) eyes remained stable, five (11.6%) eyes improved two or more ETDRS lines of BCVA, and three (7%) eyes decreased two or more ETDRS lines of BCVA. These visual improvements were accompanied by a statistically significant decrease in OCT CMT -24.  Of the 43 eyes, 17 (39.5%) eyes showed total regression of retinal neovascularization. Fifteen (34.9%) eyes demonstrated partial regression of retinal neovascularization, and 11 (25.6) eyes showed no regression of retinal neovascularization. When divided by type of retinal neovascularization, of the total of 43 eyes, 15 (34.9%) eyes showed total regression of NVE, 10 (23.3%) eyes demonstrated partial regression of NVE, and 12 (27.9%) eyes showed no regression of NVE. Thirteen (30.2%) eyes showed total regression of NVD, 14 (32.5%) eyes demonstrated partial regression of NVD, and 16 (37.2%) eyes showed no regression of NVD . InteresGiven the off-label cost effective nature of intravitreal bevacizumab, its clinical effectiveness and safety have not been as thoroughly studied as other approved similar drugs. Our results may add evidence that IVB should be used as an adjuvant to PRP in patients with PDR, and that PRP and/or vitrectomy is necessary to control PDR in the long-run in a larger number of patients."}
+{"text": "Not much is known about the fate of victims of cardiac arrest (CA) in Denmark. We performed the present study to describe the events surrounding CA at a regional hospital in Denmark.Retrospective analysis of all consecutive CA at Sydvestjysk Sygehus (SVS) in 2007 and 2012, i.e. two years after implementation of new international resuscitation guidelines. The events were identified using a registry in the Department of Anesthesiology. Using a unique personal identification number, we retrieved the patient records and extracted the relevant data.We identified 246 cardiac arrests; 154 out-of-hospital and 90 in-hospital (and 2 unknown). 66% were male and the median age was 69 years (range 11-99 years). 38% occurred during daytime, 33% during evenings and 29% at night.Over all, the primary cause was unknown in 85/246 (29%). There was a decrease in CA caused by acute coronary syndrome (ACS) from 29/117 (25%) in 2007 to 19/129 (15%) in 2012, and an increase caused by respiratory insufficiency from 18/117 (15%) in 2007 to 31/129 (24%) in 2012.In 2007 83/117 (71%) presented with asystolia/PEA compared to 65/129 (50%) in 2012. The proportion of ventricular tachycardia/fibrillation remained unchanged.27/117 (23%) achieved return of spontaneous circulation (ROSC) in 2007 and 60/129 (47%) in 2012. 18/60 (30%) were discharged or transferred for further treatment in 2012, in comparison to 14/27 (52%) in 2007.Most CA at SVS occurred out-of hospital. The majority were men and the median age was 69 years. They were evenly distributed around the clock. The primary cause was mainly unknown but an increasing number was caused by respiratory insufficiency and a decreasing number by ACS. Asystolia as the presenting rhythm was decreasing. More patients gained ROSC, but the proportion that were discharged or transferred to a university hospital decreased."}
+{"text": "The number of episodes of vascular catheter related bacteraemia (CRB) observed in non-Intensive Care Unit (ICU) patients may be similar or even higher than those observed in ICUs. While we have a lot of information regarding the impact of CRB among ICU patients, there is still lack of information concerning non-ICU patients.To determine predictors of mortality among non-ICU patients with CRB.From Jan 2003 to Dec 2012, a prospective continuous surveillance of CRB including all adult patients admitted to non-ICU wards for more than 48h, was carried out in a tertiary centre. Monitoring of CRB was performed by daily meeting of Infection Control Team and microbiology department. Patients were visited and those cases that fulfilled criteria for CRB were selected. Patients were followed up until discharge. Mortality was defined as in-hospital death from any cause occurring in the 30 days after the onset of CRB. A logistic regression model was performed to identify risk factors for mortality.S.aureus was identified in 235 episodes (40%), coagulase negative in 174 (29%), enterococci in 23 (4%), P.aeruginosa in 33 (6%) and Candida spp in 7 episodes (1%). Independent risk factors associated to mortality in multivariate analysis were: age older than 65y , hospitalization in medical wards  and S.aureus , while type of catheter and place of insertion were not associated.From 2003 to 2012, 590 episodes of CRB were detected in 578 non-ICU patients; 285 in medical wards and 305 in surgical wards. Mean age was 64y (SD 14y) and 37% were females. Mortality was 16.1%. Among all episodes of CRB, 332 (56%) were caused by central venous catheter  and 258 (44%) by peripheral venous catheter. Gram positive cocii caused 72% of episodes, gram negative bacilli 28% and fungi 1%. Among them, S.aureus aetiology had a greater risk of mortality.Among non-critically-ill patients with CRB, those older than 65y, hospitalized in medical wards and with None declared"}
+{"text": "Head trauma is one of the most common childhood injuries, accounting for > 600,000 emergency visits annually. It is estimated that 16% of children with nontrivial head injuries may have skull fractures. There are a number of studies supporting the use of point-of-care ultrasound (PoCUS) in fracture diagnosis. However, there is limited data on the role of PoCUS for skull fracture diagnosis.Our objective was to determine the test performance characteristics for PoCUS performed by pediatric emergency medicine (PEM) physicians compared to CT diagnosis of skull fractures.Patients and Methods: We conducted a prospective convenience cohort study of patients up to 21 years of age who presented to two urban, level II trauma pediatric emergency departments with head injuries and suspected skull fractures requiring CT scan evaluation. After a 1-hour focused US training session, PEM attendings and fellows performed US examinations to evaluate for skull fractures. CT scan interpretations by attending radiologists were the reference standard to determine test performance characteristics of skull US. PoCUS scans were reviewed for errors by an experienced sonologist.PoCUS was performed on 72 subjects with suspected skull fractures by 17 PEM physicians. The mean age was 6.5 years (SD 6.2 years) and 67% of patients were male. History and physical exam findings included scalp hematoma in 63%, vomiting in 31%, loss of consciousness in 13%, Glasgow coma scale < 15 in 11%, and palpable fracture in 7%. The prevalence of fracture was 11.1% (n=8). PoCUS for skull fracture had a sensitivity of 88% (95% CI 53-98%), specificity of 97% (95% CI 89-99%), positive likelihood ratio of 28.0 (95% CI 7.0-112.3), and negative likelihood ratio of 0.13 (0.02-0.81). The only false negative scan was due to a skull fracture not directly under the scalp hematoma, but rather adjacent to it. US scans took a median of 65 seconds (IQR 35-139 seconds) to perform.PEM physicians with focused US training were able to diagnose skull fractures in children with high specificity."}
+{"text": "Staphylococcus aureus (MRSA) in pig farms.The aims of this study were to determine the prevalence, determinants and dynamics of human carriage of livestock associated methicillin-resistant In this prospective cohort study in 50 pig farms in The Netherlands, human nasal samples were collected on 5 time points in 8 months. At start of the study, throat samples and environmental samples were taken. Persistent carriers were defined as persons with 100% of nasal samples positive for MRSA, non-carriers had no MRSA and intermittent carriers had at least one positive sample. Data collection is still ongoing .In total, 281 persons participated in the study. At start of the study, 21% of household members (31/147) and 68% of farmers/employees (90/132) were MRSA positive in nose or throat. Fifty-four persons were persistent MRSA carriers (54/281=19%): 5 household members (5/149=4%) and 49 farmers/employees (49/132=37%). Furthermore, 79 intermittent carriers and 148 non-carriers were found. Sixty-seven percent (33/49) of the residences and 80% (40/50) of the stables harboured MRSA. Working in the stables on a daily base and presence of MRSA in throat samples were significantly associated with persistent carriage .Persistent MRSA nasal carriage is common in persons working at pig farms. A possible explanation is the frequent exposure to high amounts of MRSA in the stables. Working in the stables still is an important factor in persistent carriage, as is throat carriage.None declared."}
+{"text": "In this study we reviewed our experience in a meticulously selected group of patients undergoing redo off-pump CABG from descending aorta to circumflex artery and branches retrospectively.Between January 2001 and May 2013 thirty patients underwent redo off-pump CABG from descending aorta to circumflex artery and branches via left thoracotomy at our hospital. Of the thirty patients, 26 were male (86.6%) and 4 were female (13.4%) with a mean age of 60.5 years. All patients had patent LIMA-LAD anastomosis. Left thoracotomy was performed through the fifth intercostal space. Saphenous vein (6) or radial artery (24) was prepared as grafts at the same time with thoracotomy from the contralateral extremity without any positional problem.Main reasons for operation in this group of patients was new lesion formation in 24 (80%) and graft occlusion in 12 (23.3%), both in 6 (20%). Average operation time was 140.17 minutes, respiratory assist time was 4.9 hours, ICU period was 21.53 hours, hospital stay was 4.6 days. Thirty-six bypasses were performed. Follow up period was 47.8 months. Six patients were lost in follow-up whereas four patients were dead. Twenty were alive and well without any cardiac problems.Redo off-pump CABG via thoracotomy provides a safe and effective surgical approach to the patients who require revascularization of circumflex artery and branches. Therefore if the target area of revascularization is circumflex artery, left thoracotomy avoids such risks of resternotomy. Avoiding risks of resternotomy and CPB could possibly reduce the morbidity and hospital cost."}
+{"text": "In a pilot accuracy study, stool Xpert testing from 115 children with suspected pulmonary tuberculosis (PTB) detected 8/17 (47%) cultureconfirmed tuberculosis cases, including 4/5 (80%) HIV-infected and 4/12 (33%) HIV-uninfected children. Sputum Xpert detected 11/17 (65%) cases. Stool holds promise for PTB diagnosis in HIV-infected children. In a pilot accuracy study, stool Xpert testing from 115 children with suspected pulmonary tuberculosis (PTB) detected 8/17 (47%) culture-confirmed tuberculosis cases, including 4/5 (80%) HIV-infected and 4/12 (33%) HIV-uninfected children. Sputum Xpert detected 11/17 (65%) cases. Stool holds promise for PTB diagnosis in HIV-infected children. The diagnosis of pulmonary tuberculosis (PTB) remains challenging in young children because they seldom expectorate spontaneously, making it difficult to obtain a representative specimen from the lower respiratory tract, and because PTB is typically paucibacillary. As a result, microbiological confirmation is less frequently achieved than in adult cases . CultureMycobacterium tuberculosis may be detected in the stool of children with PTB [The accuracy of Xpert testing of induced sputum (IS) , nasophawith PTB . We therThis was a prospective study in which samples were obtained from an ongoing cohort based at a primary care clinic  and a tertiary pediatric hospital . Children (age <15 years) presenting with suspected PTB were enrolled consecutively (from 11 July 2011 to 26 March 2012). Criteria for enrollment were a cough lasting longer than 2 weeks and at least 1 of the following: (1) household tuberculosis contact in the prior 3 months, (2) weight loss or failure to gain weight in the previous 3 months, (3) a positive tuberculin skin test, or (4) a chest radiograph suggestive of PTB. Children were evaluated at 3 months to assess recovery or response to treatment. We included all children from whom both stool and sputum samples had been collected and where >1.5 g of stool was available (only 0.15 g was used for testing).Children were excluded if they had received treatment for tuberculosis lasting longer than 72 hours, they did not live in Cape Town, they were unable to attend follow-up visits, informed consent was not given, or an IS sample was not obtained. Written informed consent was obtained from a parent or legal guardian. The Research Ethics Committee of the Faculty of Health Sciences, University of Cape Town, approved the study.M. tuberculosis; \u201cnot tuberculosis,\u201d children culture-negative for M. tuberculosis who were not started on tuberculosis treatment and clinically improved at the 3 month follow-up visit; and \u201cpossible tuberculosis,\u201d all other children.Routine history and physical examination were performed at enrollment. All children received baseline chest radiography and human immunodeficiency virus (HIV) testing (HIV rapid test followed by confirmatory polymerase chain reaction for children age <18 months). Patient stool (a single convenience specimen) and IS (2 specimens) were collected at baseline as previously described . IS specSputum ProcessingSamples were decontaminated with N-acetyl-L-cysteine and 1% sodium hydroxide  and then concentrated by centrifugation. Pellet was resuspended in 1.5 mL phosphate buffered saline (PBS). BACTEC MGIT (Becton Dickinson) culture was performed using a 0.5-mL aliquot of the resuspended sample and Xpert using 0.7 mL of the resuspended sample, to which 1.4 mL of Xpert reagent was added and processed per the manufacturer's instructions.Stool ProcessingNext, 0.15 g of thawed stool (confirmed by weighing) was retrieved using pediatric FLOQSwabs . Swabs were then placed in 2.4 mL PBS and vortexed briefly before being removed. The sample was left undisturbed for 20 minutes at room temperature to allow large particles to settle before 2 aliquots of 1-mL supernatant were removed. One aliquot was tested immediately with Xpert and the other was stored at 4\u00b0C for later duplicate testing (within 1 week). Prior to Xpert testing, the sample was centrifuged at 3200 g for 15 minutes. The supernatant was discarded and pellet was resuspended in 1 mL PBS. Xpert testing was then performed per the manufacturer's instructions using a 2:1 ratio of Xpert reagent to sample.The reference standard was a positive liquid culture from at least 1 IS sample. Statistical analysis was performed with Stata version 11.0 . Diagnostic test characteristics were determined with 95% confidence intervals (CIs). A 2-sample test of proportion was used to compare the sensitivity of Xpert in HIV-infected and -uninfected children.Testing was performed on 115 children, median age 31 months (interquartile range 19\u201357 months) of whom 17 (14.8%) were HIV infected and 67 (58.3%) were hospitalized. Of the 115 children, 17 (14.8%) were classified as having definite PTB, 48 (41.7%) as possibly having tuberculosis, and 50 (43.5%) as not having tuberculosis. There were no cases of rifampicin resistance detected.P = .102). Children with definite tuberculosis who had a positive stool Xpert test had a similar incidence of alveolar consolidation  and nodal compression  on chest radiography as children with a negative Xpert test.Duplicate Xpert testing of a single stool sample detected 8/17 (47.1%) children with definite tuberculosis ; however, this analysis is limited by the small sample size (Table Xpert testing of IS detected 11/17 (64.7%) definite tuberculosis cases, while 3 children in the possible tuberculosis group were positive by IS (but not stool) Xpert testing . No children in the not tuberculosis group were positive by IS Xpert testing. The sensitivity of Xpert on stool versus IS was not significantly different (P = .08 for comparison of HIV-infected and -uninfected children). There were no significant differences in chest radiography between HIV-infected and -uninfected children with culture-confirmed tuberculosis. All HIV-infected children had alveolar consolidation and nodal compression. Of the HIV-uninfected children, 72% had alveolar consolidation and 91% had nodal compression . No children with culture confirmed tuberculosis had military infiltrates on chest radiography.Xpert testing on stool samples was positive in 4/5 (80%) HIV-infected children with definite tuberculosis versus 4/12 (33.3%) HIV-uninfected children with definite tuberculosis (P = .09). All 4 smear-positive cases were detected by both stool and sputum Xpert testing.Smear microscopy of IS detected 4/17 cases (23.5%) of definite tuberculosis. Among children with definite tuberculosis, 3/5 (60%) HIV-infected children were smear positive compared with 1/12 (8%) HIV-uninfected children  [Our study used small volumes of stool for testing, as use of larger volumes led to failed Xpert assays (data not shown), possibly due to clogging of filters in the Xpert cartridge. Optimized protocols, which are currently being developed for Xpert testing of stool samples, will permit testing of significantly larger volumes of stool and are likely to enhance sensitivity. Further studies of larger numbers of children utilizing these optimized specimen-processing protocols are required.Xpert testing has enabled rapid diagnosis of PTB and detection of rifampicin resistance in children, which promotes timely initiation of appropriate therapy. Because Xpert is designed for use close to the point of care, use of stool as a sample for Xpert testing may be especially appropriate, given the ease with which stool is obtained in primary care settings. The finding that suggests relatively high sensitivity in HIV-infected children is important, as this group of children is at high risk for rapid progression of disease and mortality. Thus Xpert testing on stool may identify a group of children in whom rapid initiation of tuberculosis therapy may be life saving."}
+{"text": "Results of randomized clinical trials depend on the credibility of the methods reporting to support study findings.n (integer %) for all 24 papers are reported for each criterion.We studied 24 trials from those in the Cochrane Database of Systematic Reviews with 'lupus' in the title and were printable. Each paper was scored by one reviewer using methodological criteria for design, allocation , blindinFour (17%) papers had a sample size justification; 22 (92%) contained two groups and two (8%) contained three groups. Five (21%) stratified patients; yet two (8%) used stratification in the analysis.Six (25%) stated random numbers generated and three (12%) blocked the balance associated with the allocation ratio; yet zero (0%) used blocking in the analysis. Six (25%) used a randomization list concealed from the person deciding patient eligibility, zero (0%) provided an audit trail for randomization, one (4%) stated randomization integrity. Seven (29%) mentioned the randomization constructed with a computer program or random number table.Four (17%) stated the person deciding on the patient eligibility was blinded to block structure and eight (33%) claimed the study was double blinded, even though it was not clear who the two were; indeed one was really triple blinded! For three (12%) patient blinded, six (25%) therapy, four (17%) therapist, one (4%) other caregivers; two (8%) the outcome assessor; zero (0%) data analyst, zero (0%) manuscript writer.P values for group comparisons, four (17%) provided confidence intervals and zero (0%) provided numbers needed to treat. One (4%) specified subgroups in advance [One (4%) checked statistical assumptions, 23 96%) provided baseline data, not all for every patient randomized. Twenty-one (88%) provided % provideSeventeen 71%) had missing data, yet one (4%) mentioned using last observation carried forward, zero (0%) used multiple imputation and zero (0%) mentioned impact on study conclusions . Two (8%1% had miLupus trials did not report many of the methodological criteria that give papers credibility and validity to the study being reported. Reporting should be improved in future reports of studies of patients with lupus and related health problems. Possibly using the CONSORT checksheets would help make lupus papers more credible ,8."}
+{"text": "The prevalence of Food Allergy (FA) is increasing and the correct diagnosis is mandatory among patients with adverse reactions to foods. The oral food challenge tests (OFCT) remain the better tests for FA diagnosis and its usage is essential to avoid misdiagnosis. As severe reactions may occur, staff must be prepared to manage life- threatening situations. The aim of this study was to describe the anaphylactic reactions associated to OFCT in pediatric patients.During the last ten years, 205 OFCT were done in 155 patients for FA diagnosis or to confirm the development of tolerance. Among all tests: 46 were open challenge (median age: 23 mo) and 159 blind challenges (median age: 52 mo) being 3 of them simple blind and 156 double blind placebo controlled challenge test (DBPCCT) Milk was the most frequent food evaluated (n=194), followed by egg(n=9) and wheat (n=2). Anaphylaxis criteria were based on Sampson et al, 2006. All the patients\u2019 guardians signed an informed consent form.From 205 OFCT performed, 17 (8.3%) of them resulted in anaphylaxis, being 13 during DBPCCT. Median age of anaphylactic patients was 6.12 years (range1.28-14.30y). Among these patients, 12 referred previous anaphylaxis. During the OFTC with milk, clinical initial symptoms were runny and itchy nose, cough, itchy throat and redness of face. During anaphylaxis episodes, the cutaneous symptoms were the most frequent (100%) followed by respiratory (70.5%) and gastrointestinal (52.9%) ones. The clinical manifestations started with variable milk volumes (median 5 ml-from 1 to101ml) and anaphylaxis was diagnosed with median volume of 16 ml (1-101 ml). Epinephrine IM was administered in 10 patients at outer thigh in recommended doses and the others recovery with antihistamines or bronchodilators. Biphasic reaction was not observed in any patients. All of them showed complete recovery, without necessity of intensive care.In this study, mild respiratory symptoms were observed immediately before the anaphylaxis episode although not reported in the clinical history. The prompt recognizing and approach to anaphylaxis avoided more severe complications, being the OFCT safe and still considered an important tool in FA diagnosis.None declared."}
+{"text": "Hereditary recurrent fever syndromes (HRFS) can have a profound impact on health related quality of life (HRQoL) but there have been relative few prospective studies.To assess HRQoL in patients aged over 17 years with confirmed CAPS, TRAPS and MKD and to assess the effect of treatment with biologic therapies.Patients completed the 36-item Short Form Health Survey (SF-36). Data were collected on untreated patients and those on long term treatment with biologics. SF-36 measures the impact of disease on overall quality of life. Results are expressed as physical-component summary score (PCS) and a mental-component summary score (MCS). Scores range from 0 at worst to 100 at best, with values greater than 50 indicating a better HRQoL than that of a normal adult in the United States.In CAPS pre treatment HRQoL scores were available on 18 patients, 11 female, median age 43.6 years (IQ 27.9-47.1). The most affected domains were bodily pain, mean score 44, general health 32.5 and vitality 40.3. After treatment with anti IL-1 agents HRQoL was available on 31 patients, 13 female, median age 40.1 years (IQ 27.7:47.8). There was an improvement of more than 20 across all domains except role emotional which improved by 11 and scored above the US average on all domains. There was no significance difference in HRQoL in the 26 patients on long term canakinumab and the 8 on anakinra (one patient provided data on both agents). Data were available on 7 cases of TRAPS who have never received biologics ) and 13 prior to biologics ). HRQoL in patients managed with episodic steroids was near normal across all domains, mean PCS 49.7, MCS 52.6. In patients whose disease was severe enough to require biologics pretreatment scores were significantly lower, mean PCS 38.7 and MCS 43.0. In 19 TRAPS patients on biologics , 3 with AA amyloidosis) HRQoL was significantly better across all domains, mean PCS 49.1 and MCS 51 than prebiologics but no different to those adequately managed with steroids. Of 6 patients with MKD ) all had severe disease . Quality of life on no treatment in 2 cases and ineffective biologics in the others was poor, particularly general health (mean 22.8) and social function (mean 22.5), mean PCS 36.1, MCS 28.0. With effective treatment HRQoL  improved significantly across all domains in 4 assessed patients, mean PCS 48.5, MCS 46.8.HRQoL improves with effective long term treatment. Mean scores were worst in untreated MKD. Self reported improvement was most marked in CAPS c who reported sustained high scores on anti IL-1 agents. There was also improvement in patients with TRAPS and MKD and in treated patients with both diseases HRQoL was almost the US norm. HRQoL data aids holistic assessment of disease activity; the improvements reported here mirror changes in clinical disease activity and inflammatory markers on treatment and help justify the cost and potential long-term risks of biologic therapies.None Declared."}
+{"text": "The aim of this study is to evaluate the efficacy and safety of methotrexate (MTX) alone and combined therapy of Etanercept (ETN) and methotrexate (MTX), in patients with rheumatoid arthritis (RA).Patients with RA were treated in combination with ETN (with doses of 25 mg subcutaneously twice weekly), with oral MTX (doses up to 20 mg weekly), and alone MTX (doses up to 20 mg weekly) in period of two years, in Rheumatology Department of Internal Clinic in Prishtina. Clinical response was assessed using American College of Rheumatology (ACR) criteria and the Disease Activity Score (DAS28) in 60 patients with RA. Radiographic changes were measured in the beginning and at the end of the study with Sharp Score.Of total number of 60 patients  with mean age of 57.63, 10 or 16.6% of patients were treated with combined therapy (ETN plus MTX) and 50 or 83.3% of patients with monotherapy (MTX). The group of combined therapy (ETN+MTX) after the treatment resulted with improvement of acute phase reactants as erythrocyte sedimentation rate (ESR) for the first hour (41.1 vs. 10.3 mm/hour) and C-reactive protein (CRP) (40.8 vs. 6 mg/liter) comparing to the group treated with MTX alone there were no significant changes . Before treatment the severity of the disease was high, where in group with combined therapy (ETN plus MTX) DAS28 was 5.32, and in the group with monotherapy of MTX DAS28 was 5.90. After 2 years of treatment we had significant changes in the results of DAS28, where in group treated with ETN plus MTX DAS28 was 2.12 \u00b1 0.15, while in the group of patients treated with MTX DAS28 were 3.75 \u00b1 0.39 . The group with combined therapy showed less radiographic progression comparing to the group of monotherapy (p < 0.05).According to our results we can conclude that ETN in combination with MTX reduced disease activity, slowed radiographic progression and improved clinical manifestations more effectively than MTX alone within period of 2 years. During the treatment, no serious adverse events were noticed with combination treatment of ETN and MTX."}
+{"text": "Human papillomavirus (HPV) vaccine prevents cervical pre-cancers and cancers caused by HPV types 16 and 18. This study provides information on the HPV types detected in cervical cancers of Alaska Native (AN) women.Cases of invasive cervical cancer diagnosed in AN women aged 18 and above between 1980 and 2007 were identified from the Alaska Native Tumor Registry. A representative formalin-fixed, paraffin-embedded archived pathology block was retrieved and serially sectioned to allow histologic confirmation of lesion (first and last sections) and PCR testing of intervening sections. Extracted DNA was tested for HPV using Linear Array HPV Genotyping Test (Roche Diagnostics) with additional INNO-LiPA HPV Genotyping Assay (Innogenetics) testing on negative or inadequate specimens. All specimens were tested for a minimum 37 HPV types.Of 62 cervical cancer specimens evaluated, 57 (91.9%) contained one or more HPV types. Thirty-eight (61.2%) cancers contained HPV types 16 or 18, and 18 (29%) contained an oncogenic type other than type 16 or 18.Overall, almost two-thirds (61.2%) of the archived cervical cancers had detectible HPV types 16 or 18, a finding similar to studies of US women. As expected, a proportion of cancers would not be prevented by the current vaccines. HPV vaccination and cervical cancer screening are important prevention strategies for AN women. Cervical cancer rates were  average .Infection with HPV causes virtually all cervical squamous cell carcinomas and cervical adenocarcinomas \u20135. StudiOur study assessed HPV genotypes found in invasive cervical cancer specimens from AN women diagnosed from 1980 to 2007. The purpose was to characterize the preventable burden of HPV-associated cervical cancers in AN women to assess the potential impact of HPV vaccination on cervical cancer in this population.Invasive cervical cancer diagnosed from 1980 to 2007 in AN women living in Alaska aged 18 years and older were identified through the Alaska Native Tumor Registry . One repFrom 1980 to 2007, a total of 139 AN women were diagnosed with invasive cervical cancer while a resident of Alaska. Among these, a total of 136 were \u226518 years of age and 90 were diagnosed at the ANMC in Anchorage, Alaska. Archived tissues were located for 71 (79%) of ANMC cases >18 years and 62 (69%) contained representative cervical tumor.The median age of the 62 women with an archived specimen available was 41 years, the same as the median age for all AN women diagnosed with invasive cervical cancer during the period 1980\u20132007 . Among wAll 62 tissue specimens available for HPV typing yielded adequate results: 57 (91.9%) had HPV detected; 56 (90.3%) specimens were positive for one or more HPV types considered oncogenic . HPV 16 The histologic types identified from 62 specimens were: squamous cell carcinoma (84%), adenocarcinoma (11%), and carcinoma, not otherwise specified (5%). Among the squamous cell carcinomas, HPV 16 was detected in 48% and HPV 18 in 12%. Among the adenocarcinomas, HPV 16 was detected in 29% and HPV 18 in 29%.This study of cervical cancers in AN women found that 61% of tumors had evidence of HPV 16 or HPV 18. This is similar to findings from other studies on US women, in which approximately 70% of tumors were attributed to HPV 16 or 18 , 7. An HOur study found some differences in HPV types in cervical cancer compared to the only prior study in AN women. In the prior study of cervical cancer specimens from AN women diagnosed from 1980 to 1989, 53 formalin-fixed and paraffin-embedded cervical cancer biopsies were assayed by PCR for 6 HPV genotypes  .Studies in which HPV genotypes are detected in invasive cervical cancer provide important information to understand the impact HPV vaccines might have on reducing cervical cancer in defined populations. To date, most studies of different regions/ethnicities find similar proportions of cancers caused by HPV 16 or 18. Our study on AN women found a lower prevalence due to HPV 16 or 18, but given smaller numbers this is consistent with other studies. Evaluations of cancers due to HPV 16 and 18 in specific populations as well as vaccine impact monitoring on cancer reduction is warranted. One-third of all cervical cancers are caused by HPV types not prevented by vaccine, and provide support for continued Pap screening.Overall, almost two-thirds (61.2%) of the archived cervical cancers had detectible HPV types 16 or 18, a finding similar to studies of US women. As expected, a proportion of cancers would not be prevented by the current vaccines. HPV vaccination and cervical cancer screening are important prevention strategies for AN women."}
+{"text": "Hepatitis C genotype 4 (HCV-4) is considered to be rare outside northern Africa and southern Europe.To describe the epidemiological characteristics of patients infected with HCV-4 in Poland.The study group included 290 patients with HCV-related chronic liver disease and intravenous drug users with HCV infection recruited in years 2002-2006 in Podlaskie region, north-eastern Poland. In all cases, HCV infection was confirmed by HCV-RNA detection by qualitative nested RT-PCR. HCV genotype was determined by 5'UTR sequencing and comparison with known genotype-specific sequences.HCV 4 was found in 45 (15.5%) of 290 HCV-infected and HCV RNA-positive individuals. 60% of HCV 4 infections occurred in intravenous drug users; 51% of HCV 4-infected patients were also HIV-positive. Among 119 patients whose source of infection was other than drug use, there were 16 (10.5%) HCV 4 cases. Seven (46%) of 13 HCV 4-positive and HIV-negative patients who received combined antiviral treatment had sustained viral response.HCV 4 exists in eastern Poland, and the infection is frequently related to intravenous drug use and accompanied by HIV infection. HCV 4 also causes a proportion of non-drug-related HCV infections. Hepatitis C is a major cause of end-stage liver disease in many parts of the world. Six genotypes 1-6 of hepatitis C virus (HCV) have so far been described . It is cThe objective of this study was to further elaborate on epidemiological features of HCV genotype 4 infections in Poland, to determine factors associated with HCV 4 infection not related to drug use and to describe antiviral treatment response in patients infected with HCV 4.The study took place in Podlaskie voiewodship . Subjects included anti-HCV-positive individuals seen at the Department of Infectious Diseases and Hepatology of the Medical University of Bialystok and HCV-infected clients of the drug treatment center near Bialystok  in years 2002-2006. All subjects were interviewed using a structured questionnaire. The risky exposures considered in our study were intravenous drug use, transfusions of blood or blood products before 1993 (routine blood screening was introduced in Poland in 1992), incarceration and tattoos. The diagnosis of hepatitis C was based on the presence of anti-HCV antibodies  and was confirmed by HCV-RNA testing  as previously described [9]. HCV Informed consent was obtained from each participant and the study protocol was approved by the Ethical Committee at the Medical University of Bialystok. A p-value < 0.05 was considered statistically significant.Among 290 patients with HCV infection who had HCV genotype determined, there were 45 (15.5%) patients infected with genotype 4, 146 (50.3%) with genotype 1 and 99 (34.1%) with HCV 3. The majority of patients with genotype 4 had similar characteristics to those infected with other genotypes and were males (69%) aged between 31 and 50 years of age (66.7%) poorly educated (basic education or lower secondary 55.6%) . The meaWe found that 15.5% of HCV individuals in north-eastern Poland harbored genotype 4. Overall 60% of HCV 4 infections in the present study were associated with intravenous drug use and further 13% were related to transfusions. The association with drug use which was shown in our previous report  is in ac"}
+{"text": "Treponema pallidum ssp. pallidum (TPA), the causative agent of syphilis, is a highly clonal bacterium showing minimal genetic variability in the genome sequence of individual strains. Nevertheless, genetically characterized syphilis strains can be clearly divided into two groups, Nichols-like strains and SS14-like strains. TPA Nichols and SS14 strains were completely sequenced in 1998 and 2008, respectively. Since publication of their complete genome sequences, a number of sequencing errors in each genome have been reported. Therefore, we have resequenced TPA Nichols and SS14 strains using next-generation sequencing techniques.tprD gene, where both tprD and tprD2 alleles were found. The resequenced genomes of both TPA Nichols and SS14 strains clustered more closely with related strains (i.e. strains belonging to same syphilis treponeme subcluster). At the same time, groups of Nichols-like and SS14-like strains were found to be more distantly related.The genomes of TPA strains Nichols and SS14 were resequenced using the 454 and Illumina sequencing methods that have a combined average coverage higher than 90x. In the TPA strain Nichols genome, 134 errors were identified (25 substitutions and 109 indels), and 102 of them affected protein sequences. In the TPA SS14 genome, a total of 191 errors were identified (85 substitutions and 106 indels) and 136 of them affected protein sequences. A set of new intrastrain heterogenic regions in the TPA SS14 genome were identified including the We identified errors in 11.5% of all annotated genes and, after correction, we found a significant impact on the predicted proteomes of both Nichols and SS14 strains. Corrections of these errors resulted in protein elongations, truncations, fusions and indels in more than 11% of all annotated proteins. Moreover, it became more evident that syphilis is caused by treponemes belonging to two separate genetic subclusters. Treponema pallidum ssp. pallidum (TPA) causes syphilis, a globally occurring venereal disease. Since TPA cannot be continuously cultivated under in vitro conditions, genomic data serves as a valuable source for identification of treponemal virulence factors, targets for molecular typing and candidates for potential vaccine development Whole genome sequences of TPA strains Nichols and SS14 were published in 1998 Since the publication of the whole genome sequences of the Nichols and SS14 strains, these genome sequences have been shown to contain a significant number of sequencing errors The chromosomal DNA used for genome sequencing in our study was the same stock used to sequence TPA SS14 strain originally Both genomes were sequenced using the Illumina  and 454 pyrosequencing  techniques. A total of 3 \u00b5g of amplified DNA was used for sequencing.Sequencing reads were assembled using the CLC Bio Workbench . For the Nichols strain, 500 pyrosequencing contigs  and 345 Illumina contigs  matching TPA Nichols reference genome sequence (AE000520.1) were obtained. Similarly, 199 pyrosequencing contigs  and 201 Illumina contigs  were assembled for the SS14 strain. Estimated sequencing coverage was 44 (454 pyrosequencing) and 55 (Illumina) for the TPA Nichols genome and 37 (454 pyrosequencing) and 68 (Illumina) for the TPA SS14 genome.tprC (TP_0117), tprD (TP_0131), tprI (TP_0620), tprJ (TP_0621), and tprK (TP_0897) regions, small insert libraries were prepared, as previously described tprC), TPI-12 (tprD), TPI-13B (TP_0136), TPI-17A (rRNA operon 1), TPI-21B (rRNA operon 2), TPI-25A (tprE), TPI-25B-A (tprF), TPI-25B-B (tprG), TPI-26 (tp92), TPI-32B (arp), TPI-34 (TP_0470), TPI-38 (mcp), TPI-42A (TP_0548), TPI-48 , and TPI-66A (flaB).Sequentially related and repetitive regions of the treponemal genome were amplified separately using a GeneAmp XL PCR kit . For the Drafts of the whole genome sequences were obtained by assembly of the pyrosequencing, Illumina and Sanger contigs with Nichols (AE000520.1) and SS14 GenBank sequences (CP000805.1) using the SeqMan program . Any remaining discrepancies were Sanger sequenced following amplification with specific primers designed by Primer3 Both resequenced genomes were compared with reference Nichols (AE000520.1) and SS14 (CP000805.1) sequences and other treponemal genomes using Lasergene software package  and Geneious. Identification of intrastrain heterogeneity in the SS14 and Nichols genomes was performed using BWA Resequenced whole genome sequences of TPA strains Nichols and SS14 were deposited in the GenBank database under accession numbers CP004010.2 and CP004011.1, respectively.The genome sizes of resequenced (RS) TPA Nichols (Nichols-RS) and TPA SS14 (SS14-RS) strains were 1,139,633 bp and 1,139,569 bp, respectively. For TPA Nichols-RS and TPA SS14-RS genomes, 1,039 and 1,035 ORFs were predicted, respectively. At least one detectable sequencing error was found within 119 genes .tpr genes and other known variable genomic loci Sequencing errors were distributed evenly around the entire chromosome of the Nichols and SS14 genomes with slightly increased accumulation in the In the original TPA Nichols sequence (AE000520.1), a total of 134 errors were identified including 25 substitutions and 109 indels. One hundred and seven errors (79.9%) were found in the coding regions (23 substitutions and 84 indels) and 27 (20.1%) errors were located in the intergenic regions (IGRs) . In the In the TPA SS14-GenBank sequence (CP000805.1), a total of 191 errors were identified including 85 substitutions and 106 indels. One hundred and fifty nine (83.2%) errors were found in the coding regions (81 substitutions and 78 indels) while 32 (16.8%) errors were located in IGRs . In the tprK gene revealed multiple sequence variants of tprK, not only in the SS14 strain, but also in the Nichols strain. Therefore, unlike the original Nichols sequence, variable nucleotides in V1, V4, V5, V6 and V7 tprK regions were denoted by the letter N to indicate detected variability in these positions in the Nichols-RS genome. Alignments of sequence variants identified in at least two independent clones are shown in Sequencing of the small insert libraries prepared from DNA encoding the tp92) locus contains a sequence pattern typical for Treponema pallidum ssp. endemicum (TEN) strains (gene coordinates 1593\u20131649) The corrected versions of the TPA SS14 and Nichols genomes differ in a number of ways. The point mutation in the 23S rRNA gene (A2058G), originally identified by Stamm and Bergen tprJ) locus (gene coordinates 1794 and 1979) where only one version identical to the predominant sequence in the original SS14 sequence was found. In addition to these 42 verified sites in the SS14 genome, further intrastrain variable sites were found in the TPASS_20341 (murC), TPASS_20620 (tprI), TPASS_20621 (tprJ) and TPASS_20967 loci. All newly identified variable sites are presented in tprD) locus, where both tprD and tprD2 alleles tprC and tprD alleles remain identical as previously reported tprD and tprD2 alleles differ from the tprC sequence  in the SS14-RS genome.Almost all previously described sites (n\u200a=\u200a44) showing intrastrain heterogeneity in the SS14 genome In the Nichols genome, we confirmed the previously identified 1204-bp long insertion found in a subpopulation of the Nichols (Houston) strain tprD and tprK were excluded from analyses (tprD and tprK gene sequences). Correction of sequencing errors resulted in a striking increase of genome relatedness within both the Nichols-like and SS14-like subclusters (The whole genome sequences of Nichols and SS14 were compared to previously published genome sequences of TPA strains Mexico A CP003064.1) analyses  and 3. I064.1 anaclusters , at the clusters .\u22124. Based on this estimation, one can expect over 100 sequencing errors scattered throughout the genome. Strain SS14 was completely sequenced in 2008, ten years after the Nichols genome. Since sequencing of the TPA SS14 genome was performed using the CGS approach tpr genes and other known variable genomic loci In the 1998, the TPA Nichols strain was one of the first completed bacterial genomes with an average coverage of Sanger reads of 6.7x tpr genes and other known variable genomic loci A total of 134 errors in TPA strain Nichols and 191 errors in TPA strain SS14 reference genomes were found , which is close to a previous estimation Compared to substitutions, the detected predominance of indel errors resulted in more profound changes in the predicted treponemal proteome. Resequencing of TPA Nichols and SS14 strains revealed considerable changes in annotations of 65 and 63 proteins, respectively, including elongations, truncations and fusions.tprK gene. A similar degree of tprK variability was also observed in the Nichols strain UNC tprK variable regions in the Nichols (Seattle strain) were reported to remain conserved tprK variability found in the Nichols genome was considerably lower compared to the variability detected in the tprK of the SS14 strain.Unlike in the original Nichols genome, we found variability in V1, V4, V5, V6 and V7 variable regions of tp92), TP_0868 (flaB) and TP_0127. In strain SS14 the presence of the A2058G point mutation, in 23S rRNA gene, is responsible for its resistance to macrolides Treponema pallidum ssp. endemicum (TEN) strain et al., which encodes MutS1 homologue Important differences between TPA SS14 and Nichols genomes exist in several loci including 23S rRNA, TP_0326  and so the smaller sample size may have been the reason for identifying only one allele of tprD gene.In addition to the above mentioned differences, dozens of genomic sites showing intrastrain heterogeneity were identified in the SS14 genome. The occurrence of multiple alleles in a population of a bacterial pathogen suggests the presence of contingency genes and an antigenic variation Interestingly, intrastrain heterogeneity identified in the Nichols genome was significantly lower compared to the SS14 strain. Although the reason for this is unknown, one possible explanation involves the number of years that elapsed between the isolation of the strains from patients. However, other reasons including inherent differences in genome structure and regulation cannot be excluded.It is known that treponemes detected in clinical material either genetically belong to Nichols-like or SS14-like strains Correction of 134 and 191 errors in the Nichols and SS14 genome, respectively, resulted in an increased separation of both syphilis treponeme subclusters . As it tSeveral bacterial genomes recently resequenced by next generation sequencing methods Table S1List of errors identified in the intergenic regions (IGRs) in the original TPA Nichols and TPA SS14 genomes.(DOCX)Click here for additional data file.Table S2List of substitution errors identified in the original TPA Nichols and TPA SS14 genomes.(DOCX)Click here for additional data file.Table S3Gene fusions identified in the resequenced versions of the TPA Nichols and SS14 genomes as a result of in-del corrections.(DOCX)Click here for additional data file.Table S4List of indel errors identified in the original TPA Nichols and SS14 genomes.(DOCX)Click here for additional data file.Table S5List of all errors identified in the coding regions of the original TPA Nichols sequence (AE000520.1).(XLSX)Click here for additional data file.Table S6List of all errors identified in the intergenic regions of the original TPA SS14 sequence (CP000805.1).(XLSX)Click here for additional data file."}
+{"text": "Biomarkers have been proposed as potential prognostic indicators following a traumatic brain injury (TBI). Among those, glial fibrillary acidic protein (GFAP) has been one of the most studied. The objective of this study was to assess the prognostic value of GFAP levels in patients with moderate to severe TBI.2 tests were used to measure statistical heterogeneity.We systematically searched Medline, Embase, Cochrane Central, Scopus, BIOSIS, TRIP, conference abstracts, bibliography of selected studies and narrative reviews. Cohort studies including \u22654 patients with moderate or severe TBI and reporting GFAP levels (sampled within the first 24 hours of care) from any biological tissue or fluid, and mortality or Glasgow Outcome Scale (GOS), were eligible. Two independent reviewers screened all citations, selected eligible studies and extracted data using a standardized data extraction form. Pooled results from random effect models are presented using geometric mean ratios (GMRs). In = 404). Four studies presented data on mortality (3 or 6 months) and four studies used the GOS (6 or 12 months) as an outcome measure. We found significant associations between serum GFAP levels and mortality in pooled analysis of three studies (GMR 14.73 (95% CI 5.93 to 34.12); I2 = 79%), and between GFAP and GOS \u22643 in three studies (GMR 8.80 (95% CI 3.94 to 19.66); I2 = 77%). Two studies could not be used in pooled analyses: one presented means of GFAP levels from multiple samplings over time (GMR 1.98 (95% CI 1.06 to 3.70)) while the other presented the highest peak levels of GFAP during the acute phase of care (GMR 3.20 (95% CI 1.82 to 5.65)).We retrieved 4,709 citations and eight studies were deemed potentially eligible. Among those, one was found to be a duplicate publication. Seven studies were thus included (Serum GFAP levels following TBI were significantly higher in patients showing an unfavourable prognosis (death or GOS \u22643). The small number of studies included precluded further exploration of statistical heterogeneity. More investigations of the association between serum GFAP levels and prognosis following TBI are needed before recommending for routine use for neuroprognostication."}
+{"text": "Timing of renal replacement therapy (RRT) in critically ill severe sepsis and septic shock patients with acute kidney injury is highly subjective and may influence outcome. The aim of this study is to evaluate the relationship between timing of RRT and 28-day mortality in patients with severe sepsis and septic shock.All patients diagnosed with severe sepsis and septic shock and treated at the medical ICU in a university-affiliated, tertiary-referral center, from January 2005 to December 2006 were reviewed. Timing of RRT was stratified into early and late by RIFLE  criteria and blood urea nitrogen (BUN) at the time RRT was started. The primary outcome was 28-day death from any cause.P = 0.81). The timing of RRT by serum BUN also showed no significant difference in 28-day mortality before start of RRT by BUN \u226575 mg/dl versus BUN <75 mg/dl .Of the 326 patients diagnosed with severe sepsis and septic shock and admitted to the medical ICU during the study period, 78 patients received RRT. The mean age of the patients was 61.5 \u00b1 14.7 years and 54 patients were male (69.2%). The timing of RRT was categorized into early  and late (Failure) by RIFLE criteria and also categorized into early (BUN <75 mg/dl) and late (BUN \u226575 mg/dl). Comparing the relationship between RIFLE criteria (Risk and Injury vs. Failure) and 28-day mortality showed no significant difference (70.8% vs. 73.3%, Timing of RRT, stratified into early and late by RIFLE and BUN, showed no significant difference in 28-day mortality in patients with severe sepsis and septic shock."}
+{"text": "Intracranial hypertension (ICH) complicates roughly 25% of acute liver failure (ALF) patients with grade III/IV encephalopathy. Intracranial pressure (ICP) monitoring is controversial due to complications in 5 to 20% and absence of documented mortality benefit.n = 487) were not monitored.Using prospectively collected data from the US Acute Liver Study Group registry, we reviewed 630 ALF patients with severe encephalopathy (grade III/IV) and INR >1.5 enrolled between 1 March 2004 through 31 August 2011. ICP monitoring was used in 143 patients (23%); 487 control patients with grade III/IV hepatic coma (P = 0.13 between groups). Of ICP monitored (ICPM) patients, 85% (n = 121) received devices within 24 hours of admission to study. ICPM patients were significantly younger  than controls, more likely to be on renal replacement therapy  but less likely to be on vasopressors . ICPM patients were given more ICH directed therapies . For ICPM patients, the median INR on the day of monitor insertion was 2.2 (1.6 to 2.9) and platelet count 116 (84 to 171); 74% were given FFP  and 19%  received platelets. ICP monitoring was also strongly associated with listing  and receipt of liver transplant . Twenty-one-day mortality was similar between ICPM patients (33%) and controls  when all or only nontransplanted patients  were considered. Of 66 ICPM patients with detailed information, 18 (29%) had evidence of ICH (ICP >25 mmHg) at the time of ICPM insertion (maximum ICP on day 1 ~18 (12 to 26) mmHg). Of 49 patients with a known ICPM device, 14 patients received epidural catheters, six subdural, 11 intraparenchymal, seven intraventricular and 11 lumbar monitors. In only one of 49 ICPM patients was intracranial hemorrhage reported, and this patient survived.The most common etiology of ALF was acetaminophen (51%, In ALF patients, ICP monitor placement is strongly associated with liver transplantation but not with overall or transplant free mortality. In the absence of ICP monitoring, ALF patients may be less aggressively treated for intracranial hypertension. The value of ICP monitoring in ALF remains to be determined but ICPM placement clearly affects the frequency of interventions for elevated ICP."}
+{"text": "To the Editor: Cardioviruses currently consist of at least 3 viruses: Theiler murine encephalomyocarditis virus, encephalomyocarditis virus, and Saffold virus (SAFV) . Nucleotide sequences of SAFV strains described were deposited in GenBank under accession nos. HQ668170\u2013HQ668173.SAFVs detected were further analyzed by amplification of the viral protein (VP) 1 gene (Four (2.7%) of 150 specimens were positive for SAFV . Two of these specimens (CMH023/2007 and CMH038/2007) were obtained in February 2007, one (CMH045/2007) in March 2007, and 1 (CMH143/2007) in November 2007. Co-infections with other viruses were detected in all 4 samples. Two specimens (CMH023/2007and CMH045/2007), were co-infected with noroviruses GII/16 and GII/4 genotypes, respectively. One SAFV-positive sample (CMH038/2007) was co-infected with a group A rotavirus G1P[8] genotype, and another (CMH143/2007) was co-infected with human parechovirus.,,All SAFV-positive specimens were further amplified for the VP1 gene to determine their phylogenetic lineages and genetic relationships with other SAFV reference strains. When we used 3 sets of primers used in other studies  of 4 SAFV strains showed that strains CMH023/2007 and CMH143/2007 were highly conserved (nt sequence identities >97%). These 2 SAFV strains were most closely related to the prototype strain of SAFV1 (EF165067) isolated in the United States (nt sequence identity range 87.6%\u201388.9%) and SAFV strains from China  . In addiThe 4 strains of SAFV were isolated from children with acute gastroenteritis who were co-infected with other viral pathogens . Therefore, we could not determine whether SAFVs identified in this study were associated with acute gastroenteritis. The detection rate for SAFV in children with acute gastroenteritis (2.7%) in our study was consistent with that in a study in Beijing, People\u2019s Republic of China (3.2%)  were circulating in Chiang Mai, Thailand. Further extensive epidemiologic surveillance of SAFV in other areas may provide a better understanding of the distribution, heterogeneity, and association of SAFV with enteric diseases in humans."}
+{"text": "The global prevalence of type 2 diabetes has shown a trend of rapid growth over the past few decades. According to the National Health and Nutrition Examination Survey, U.S. (NHANES 2005-2006) more than 40 per cent of U.S. adults have diabetes or pre-diabetesIn the context of the general rise of diabetics worldwide, a more rapid growth is seen in the Asian regions. IDF estimates for 2010 point out that six Asian countries are among top 10 countries worldwide in prevalence of diabetes viz., United Arab Emirates (18.7%), Saudi Arabia (16.8%), Bahrain 15.4%) Kuwait (14.6%), Oman (13.4%) and Malaysia (11.6%). The top five Asian countries are: India (50.8 million), China (43.2 million), Pakistan (7.1 million), Japan (7.1 million) and Indonesia (7 million). Bangladesh is expected to replace Japan in 2030 and rank at the 8th4. The results of China National Diabetes and Metabolic Disorders Study (June 2007 to May 2008) showed that among adults over 20 yr of age, the total prevalence rates of pre-diabetes and diabetes [including impaired glucose tolerance (IGT) and impaired fasting glucose (IFG)] were 9.7 and 15.5 per cent and the number of diabetics was estimated to be 92.4 million adults at the age of 20 yr or older and 148.2 million adults would have pre-diabetes.4% Kuwai(i) Increased with age; (ii) Males had higher prevalence than females, among adults aged 20-60 yr; (iii) the prevalence was significantly higher among urban residents than among rural residents (11.4 vs. 8.2%), and the gap in underdeveloped areas was larger. But there was no significant difference in prevalence of pre-diabetes between urban and rural residents (14.9 vs. 16.0%), and the prevalence had been as high as 15.9 and 16.6 per cent between developed and underdeveloped rural areas; (iv) There were independent positive correlations between overweight, obesity, central obesity as well as low levels of education and the incidence of diabetes and pre-diabetesetc. The sharp increase in number of people with obesity and pre-diabetes is due to an imbalance between economic development and education. For example, in urban Indian residents the prevalence of diabetes increased from 13.9 to 18.6 per cent within 6 yr, which is higher than that in the town (16.4%) and peri-urban villages (9.2%)National survey in China showed that the prevalence of diabetes had the following characteristics: 11.4 vs. .2%, and et alAgeing population is another problem which people face in the Asian region. Large population and high prevalence of diabetes lead to a rapid increase in the number of aged patients in Asia. For example, Singapore has the fastest growing elderly population in the world. Prevalence of diabetes among people aged 60-69 yr was as high as 32.4 per centBMI levels in the Asian population are generally lower than those in Western countries, but the Asian population are still at a higher risk of diabetes14The fast rise of economy and large population in Asia lead to a huge increase in diabetics. Facing the challenges, the whole nation need to take immediate action to intervene diabetes among people at high risk effectively, prevent the growth of incidence of diabetes, take multi-factor control of long-term complications in diabetic patients and reduce the damage to health caused by the chronic complications of diabetes."}
+{"text": "Preventing needle stick injuries (NSIs) is a challenge faced in virtually every work environment. There are very few studies in India documenting frequencies and consequences of needle stick injuries (NSIs). We report a 30 months ongoing surveillance of NSIs happened in Apollo Hospitals, Chennai .Hospital infection control team document type of NSI, human immunodeficiency virus(HIV), Hepatitis B surface antigen  status of the source, anti HBs antibody titers of HCW, baseline and 6 months tests for HIV if the source was positive for HIV, and provided post-exposure prophylaxis to persons who had NSI.Of the 118 needle stick injuries reported during the surveillance period 47 (40%) were nurses, 25 (21%) were lab technicians, 24 (20%) were doctors, 20 (17%) were housekeeping staff and 2(2%) were other staffs. Hollow bore needle constituted 80.1% (95) of the injuries, solid needles constituted 16.5% (19) of the injuries and other sharps constituted 3.4% (4) of the injuries. On source analysis 17, 9, and 8 were positive for HBsAg, HIV and HCV, respectively. Improper disposal of the needles (27%) & recapping of the needle (25.8%) were the predominant activities responsible for NSIs. 9 HCWs who sustained injury with HIV positive source were given immediate antiretroviral therapy for 4 weeks. Subsequent six-month follow-up showed zero seroconversion.NSIs were common among nurses & lab technicians and commonly take place in ICU. Half of the NSIs were happened after the usage of the needle before its disposal. Zero sero conversion for HIV was seen in NSIs with HIV positive source. Safer disposing methods are needed to reduce the incidence of NSIs.None declared."}
+{"text": "To counter the virus, different vaccines were developed. In Belgium, the Pandemrix vaccine of GSK was used. Part of the Belgian population was vaccinated, especially those belonging to risk groups . In general, vaccine immunogenicity is less effective in immunodepressed patients than in immunocompetent patients.Swine-origin pandemic human influenza A(H1N1)2009 rapidly spread around the world since its initial reporting on the 25In this study the immunogenicity of the Pandemrix vaccine was investigated by measuring neutralizing antibodies against A(H1N1)2009 in sera collected from immunocompetent and immunodepressed patients such as hemodialysed and renal transplanted patients. In total 32 healthy volunteers (control group), 106 hemodialysed patients and 112 renal transplanted patients were recruited. Neutralizing antibodies were measured in sera collected before (day 0) and 1 month after a single shot vaccination (day 30) using a seroneutralisation (SN) assay followed by an immunoenzyme colorimetric reaction to detect influenza A(H1N1)2009 antigen in infected cells. Geometric mean (GM) titers were determined at subject level by individual GM of quadruplicates at each time point. Individual and group level titer ratios (day 30/day 0) with 95% confidence intervals were determined as well.The GM titer ratio for the healthy control group was 38 (23-62). For the dialysed patients, the GM titer ratio was 11 (8-17) and for the group of renal transplanted patients, the GM titer ratio was 5 (3-6). Differences in GM titer ratio between the healthy control group and each group of immunodepressed patients were significant . Thirty out of 32 healthy participants (93%) had at least four-fold increases in SN titers between day 0 and day 30 (seroconversion). Among dialysed participants, 64 out of 106 (60%) had at least four-fold increases in SN titers between day 0 and day 30, and among renal transplanted patients, 49 out of 112 participants (44%) seroconverted between day 0 and day 30. Differences in seroconversion rates between the healthy control group and each group of immunodepressed patients were significant .These results suggest that only 60% of dialysed individuals developed sufficient neutralizing antibody titers after immunization with this vaccine. As for renal transplanted patients, only 44% of the patients developed sufficient neutralizing antibody titers after vaccination. Alternative vaccines, dosing, adjuvants or schedule strategies are needed to achieve effective immunization of these vulnerable populations."}
+{"text": "Hepatitis co-infection with HIV is associated with increased morbidity and mortality.th generation Dialab Elisa kits for patients and control sera.This cross sectional study was carried out among HIV positive patients and HIV negative blood donors, HIV infected patients were recruited from the antiretroviral therapy clinics of the Lagos State University Teaching Hospital, in Nigeria. The diagnosis of HIV infection among patients and predonation screening of control blood donors was carried out using Determine1/2 screening rapid kits. . Reactive patients\u2019 sera were confirmed with Enzyme Linked Immunosorbant Assay (Elisa) based immuuocomb1&11 comb firm kits . Hepatitis B surface antigen (HBsAg) and antibodies to hepatitis C virus (anti-HCV) were assayed using 4Dual presence of HBsAg and anti-HCV was observed in 4(3.9%) of HIV infected patients, while 29(28.4%) and 15(14.7%) were repeatedly reactive for HBsAg and anti-HCV respectively. HIV negative blood donor controls have HBsAg and anti-HCV prevalence of (22) 6.0% and (3) 0.8% respectively. The prevalence of hepatitis co infection is higher among the male study patients 16(50%) than the female32 (45.7%).p > 0.001.Data analysis was done with statistical Package for social sciences  and Chi square tests.This study reveals a higher risk and prevalence of HBV and HCV co infections among HIV infected patients compared to HIV negative blood donors p < 0.001. Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections cause chronic hepatitis, cirrhosis and hepatocellular carcinoma, all of which are of serious public health concern . There iRecently, co infection between hepatitis C virus and HIV have been associated with rapid decline in the CD4 count, rapid progression of HIV infection and with increased morbidity and mortality . HepatitThe significant advancing in HIV management and survival have led to the recognition of chronic hepatitis as the pre eminent co morbid illness which now accounts for the majority of non AIDS related deaths in this population. To define the magnitude of this burden, we have examined the prevalence and risk of co infection with HBVand HCV among Nigerians with HIV infection. The result of this study would provide the baseline for future larger studies.After obtaining ethical approval from the Lagos State University Teaching Hospital (LASUTH) health research ethics committee, a cross-sectional study was conducted in March - August 2006. The study population was adult Nigerian HIV infected patients attending the antiretroviral therapy clinics. Informed consent was obtained from study subjects before specific structured questionnaires were administered to capture demographic data and risk factors which predispose to acquisition of both HBV and HCV co infections.About 5millilitres of blood was collected from each patient and control subjects by venepuncture. The sera from the blood samples were separated and stored at \u221220\u00b0C until tested. Samples were brought to room temperature prior to testing and analyzed according to manufacturer's recommendations at the Blood Screening Centre of LASUTH.Each serum was analyzed for the presence of HBsAg and anti-HCV using commercially available 4th generation Enzyme Limited Immuno Assay (ELISA) kits  with 99.87% specificity and100%sensitivity. The diagnosis of HIV was made in patients using WHO approved Determine1/2 very rapid kits with100% sensitivity and 99.6% specificity. Positive serostatus was confirmed with ELISA based Immunocomb I &II comb firm kits  The data were analyzed using a statistical package for social sciences . Chi-square test was used to assess the significance of differences among groups. A value of less than or equal to 0.001 was considered significant in all statistical comparisons.One hundred and two HIV infected patients comprising 32 (31.4%) males and 70 (68.6%) females with M: F ratio of 1:2.2 was enrolled for this study. Our study examined the prevalence of HBsAg and anti-HCV among HIV infected patients and healthy HIV negative blood donors. We observed HBsAg and anti-HCV positivity of 29 28.4%) and 1514.7%) respectively among HIV infected patients. Among healthy HIV negative blood donor controls, we observed HBsAg and anti-HCV prevalence of 22(6.0%) and 3(0.8%) respectively. The high prevalence of HBsAg 29(28.4%) and anti-HCV 15 (14.7%) among HIV infected patients in this study is comparable with reports by Forbi et al in North Central Nigeria [% and 15 than females 1724.3%) in this study p = 0.001. The difference is not statistically significant. This finding is compatible with previous reports from Jos, North Central Nigeria  and Indi.3% in thWe recommend that HIV positive patients should be routinely screened for HBV&HCV markers before initiation of highly active antiretroviral therapy as this practice would guide correct choice of drug combination. This would in turn reduce morbidity and mortality from antiretroviral drug associated hepatotoxicity among these patients."}
+{"text": "Occult hepatitis B virus infection (OBI) is defined as the presence of hepatitis B virus (HBV) DNA in the liver and/or in the serum of patients with negative results of hepatitis B s antigen (HBsAg) test with or without serological markers of previous viral exposure. The impact of OBI in patients with chronic hepatitis C (CHC) is still unclear.The Aim of this study was to assess OBI prevalence and its potential implications on treatment outcome in a cohort of patients with CHC underwent standard antiviral therapy.Baseline serum samples from 137 HBsAg-negative CHC patients treated with pegylated-interferon and ribavirin (73 Responders/74 Non Responders),were retrospectively analyzed for HBV status.Seventy-three patients (53.3%) showed markers of previous exposure to HBV. HBV DNA was detected in 2 of 137 serum samples (1.5%), both carrying HBV antibodies. Liver biopsies and post-therapy sera were available for 35 patients (12 Responders/23 Non Responders). HBV DNA sequences were found in 13 of 35 specimens (37.1%), all of patients with HBV DNA negativity in basal and post-therapy serum samples. Among OBI-positive patients, 5 (38.5%) carried serological markers of HBV infection. Regarding therapy outcome, in the OBI-positive group there were 5 of 13 (38.5%) sustained virological responders (SVR) compared to 7 of 22 (31.8%) in the OBI-negative one.Despite the high prevalence rate of liver HBV DNA in patients with CHC, SVR was not affected by occult HBV infection. Occult hepatitis B virus infection (OBI) is defined as the presence of hepatitis B virus (HBV) DNA in the liver of patients with negative results of hepatitis B s antigen (HBsAg) test with or without serological markers of previous viral exposure -3. In thSince it is unclear the impact of OBI in patients with CHC, the aim of this study was to evaluate OBI prevalence and its possible implications on antiviral therapy outcome in a cohort of patients treated for CHC.One hundred thirty seven CHC patients with negative results of HBsAg test, treated with pegylated interferon (peg-IFN) and ribavirin, were included in the study. The study was performed according to the 1975 Declaration of Helsinki. Written informed consent was obtained from all patients prior to recruitment. The main demographic characteristics are reported in Among the 137 HCV patients with negative results of HBsAg test, HBV antibodies were detected in 73 (53.3%) , while sIn the present study serum HBV DNA was detected in two of 137 (1.5%) CHC patients with negative results of HBsAg test. A higher prevalence rate was found in liver, where HBV sequences were detected in 13 of 35 (37.1%) specimens. Among the 13 OBI-positive patients, only five (38.5%) carried serological markers of HBV infection. The prevalence rate of OBI in patients with CHC patients reported in the literature varies greatly, ranging from 0% to 52% , 13. Thi"}
+{"text": "Universal recommendation of the evaluation of the temporomandibular joint (TMJ) involvements in juvenile idiopathic arthritis (JIA) is still not available.To assess the valuability of TMJ symtoms or findings as an indicator of mandibular involvement.62 (42 girls) out of 305 children with JIA aged 3-17 years and followed-up at the Paediatric Rheumatology OPD in Oulu University Hospital were involved in this cross-sectional study. Group 1 had new TMJ symptoms or findings and group 2 chronic TMJ symptoms or findings. Subjects were examined by a paediatric rheumatologist and by a dentist.The control group consisted of 68 healthy children (28 girls). We examined OPGs both from patients  and controls  and measured mandibular ramus lenght on OPG (the distance between point Condylion and point Gonion). We calculated the percential difference of the lenght of the contralateral ramus. Condylar changes were graded in five point scale .Ramus lenght in age-matched scale was shorter in both JIA groups compared with controls. The mean persential asymmetry of the ramus was higher in both JIA groups. The corresponding asymmetry was ( 2.8% (range 0.1-9.9) in group 1, 4.3%, (0.1-12.7) in group 2,; and 1.2% (0- 5.8) in controls (p<0.025). The patients with early onset JIA had more severe TMJ changes and shorter length of the ramus than those with late onset JIA.In parallel with earlier studies, TMJ symptoms or findings were unsensitive indicators of mandibular involvements. Sensitive TMJ examinations should be accessible in all patients suffering from JIA including patients without TMJ symptoms."}
+{"text": "The largest described outbreak of chikungunya virus has been occurring on the islands of the southwest Indian Ocean since March 2005. We describe the manifestations of chikungunya virus infection in travelers returning from these islands, with focus on skin manifestations. Alphavirus, family Togaviridae)  mosquitoes . Children <5 years of age were not included because no pediatricians practiced in our hospital. Chikungunya virus was suspected if fever, joint pain, or skin eruption was present. Diagnosis of chikungunya infection was confirmed by an immunocapture ELISA derived from a yellow fever test by using a goat anti-human immunoglobulin (Ig) M antibody , an inactivated cell-culture\u2013grown chikungunya virus and a mouse anti-chikungunya hyperimmune ascitic fluid , and a horseradish peroxidase\u2013labeled antimouse IgG conjugate (Sigma) ; median age was 47 years (25\u201372 years). Seventeen patients had returned from Reunion (77%), 3 from Comoro (14%), and 2 from Mauritius (9%). Twelve (55%) patients were tourists, 8 (36%) were islanders settled in France but returning from visiting their relatives, and 2 (21%) were French residents in these islands. The median duration of stay (residents excluded) was 21 days (2\u201390 days). Symptoms appeared in 19 (86%) patients while they were abroad and within 3 days of return in 3 patients (14%). The median lag time between onset of symptoms and consultation was 13.5 days (range 2 days\u20139 months).Fever and joint pain were noted in all patients. The median duration of fever was 4 days (range 2\u20137 days), and joint pain was mainly distal and symmetric, involving wrist , ankles , phalanx , knees , and elbows and shoulders . The other extradermatologic signs were asthenia in 17 patients (77%), headache in 13 (59%), muscle pain in 12 (55%), swelling in 10 (45%), peripheral lymphadenopathy in 9 (41%), bleeding from the nose or gums in 4 (18%), nausea or vomiting in 3 (14%), and eyesight trouble in 1 (4%). In the 6 patients seen during the first week of symptoms (acutely ill patients), lymphopenia was present in 67%, thrombocytopenia in 50%, and increase of alanine aminotransferase/aspartate aminotransferase in 67%.Skin manifestations occurred in 17 patients (77%). Because skin eruption occurs during the first week of the disease, however, only 6 (27%) patients with these signs were seen at the time of consultation. All 6 had a generalized exanthema consisting of noncoalescent macular or papular lesions . The eleThe main complaint after the first week was persistent arthralgia. The treatment was exclusively symptomatic: pain killers and nonsteroidal antiinflammatory medications.The dramatic ongoing epidemic of chikungunya infection in the southwestern part of the Indian Ocean, particularly Reunion Island, provided the opportunity to describe the skin manifestations of this infection among travelers. The main characteristic of the skin eruption was a generalized macular erythematous exanthema, often with islands of normal skin and a sensation of pruritus. The infection was also characterized by a short incubation period (1\u201312 days). Most patients had fever, arthralgia, exanthema, asthenia, myalgia, and headache.,Among travelers returning from the tropics, febrile exanthema associated with arthralgia is not specific to chikungunya and may be observed with several other viral and bacterial infections and adverse cutaneous reactions (Alphavirus genus consists of 30 species of arthropodborne viruses (,,The"}
+{"text": "To describe the epidemiology and clinical course of patients hospitalized with pandemic (H1N1) 2009 in Kenya, we reviewed medical records of 49 such patients hospitalized during July\u2013November 2009. The median age (7 years) was lower than that in industrialized countries. More patients had HIV than the general Kenyan population. Since pandemic (H1N1) 2009 influenza virus emerged in April 2009, virus-associated hospitalizations and deaths have been reported in many countries  2009 virus by real-time reverse transcription PCR at either the Kenya Medical Research Institute (KEMRI)/National Influenza Center laboratory, or the KEMRI/Centers for Disease Control and Prevention, Kenya laboratory. Testing was performed according to World Health Organization methods (Following detection of pandemic (H1N1) 2009 virus in 2 patients in California, USA, in April 2009, the Kenyan Ministry of Health intensified surveillance at 26 existing influenza sentinel surveillance sites where surveillance was being conducted for influenza-like illness and severe acute respiratory illness. An additional 29 hospitals and clinics in the country were trained to conduct surveillance for these conditions. A hospitalized case-patient with pandemic (H1N1) 2009 was defined as a patient hospitalized for >30 in adults >18 years old  2009 using a standardized case report form that included demographic, clinical, laboratory, and epidemiologic information. For hospitalization duration calculation, the day of admission was hospital day 0. For patients for whom height and weight measurements were available, the body-mass index  was calculated. Obesity was defined as a BMI From June 29, 2009, when pandemic (H1N1) 2009 infection was confirmed in Kenya, through November 29, 2009, 690 patients with laboratory-confirmed pandemic (H1N1) 2009 were identified. Of these patients, 88 (13%) were hospitalized in 12 surveillance hospitals. Most hospitalizations (61 [69%]) occurred during October and November . The medWe could not obtain clinical records for 39 (44%) case-patients. We describe clinical data for 49 (66%) case-patients. No significant differences were found in median age  or sex  between patients with clinical data and patients without clinical data.The 49 case-patients were from 4 public and 3 private hospitals in 4 of Kenya\u2019s 8 provinces. Half (51%) of case-patients were admitted to Siaya District Hospital in Nyanza Province. Thirteen (26%) patients had an underlying medical condition . Of 20 pThe median duration between onset of symptoms and hospitalization was 3 days (range: 0\u201314 days). The most common symptoms at admission were self-reported fever (43 patients [88%]), cough (45 patients [92%]), and vomiting (20 patients [41%]). Eighteen (37%) patients reported diarrhea. Of 22 patients with malaria blood smear results, 5 (23%) had positive results (median patient age 5 months). Of 42 patients with data on antiviral treatment, 10 (24%) had received oseltamivir either before or during hospitalization.Pseudomonas aeruginosa) developed. The patient died after 45 days while receiving mechanical ventilation in the intensive care unit. The next person who died was a 4-year-old boy without underlying illness (HIV status unknown) who had been admitted with a cough, vomiting, and fever. He had malaria confirmed by blood smear and died 4 days after admission. Neither patient received oseltamivir.The median duration of hospitalization was 4 days (range 1\u201351 days). All 4 HIV-infected patients survived without known complications. Two (4%) patients died. The first was a 55-year-old HIV-negative man without underlying illness who had been admitted with acute respiratory illness. He was transferred to the intensive care unit after secondary bacterial infection  2009 infections in hospitalized patients in a sub-Saharan African country outside South Africa. The large proportion of pandemic (H1N1) 2009 hospitalizations among young adults in Kenya is consistent with findings from New Zealand, the United States, and Australia  2009 influenza in Kenya had an underlying medical condition, a lower proportion than in the United States (73%), Ireland (50%), and Chile (37%)  2009 patients with available HIV data were positive for the virus. Although this percentage is higher than the national HIV prevalence (7%)  2009 patients who were obese (20%) is higher than the estimates of the prevalence (5%\u201310%) of obesity in adults in Kenya  2009 was not available quickly enough to inform patient management. In addition, clinicians may not have been aware of the availability of and indications for oseltamivir. The Kenya Ministry of Health has recommended and made available oseltamivir for empirical treatment of hospitalized patients with suspected pandemic (H1N1) 2009  2009 in Kenya. In addition, reported cases were limited to hospitals where influenza surveillance was conducted and hospitals where clinicians were aware that pandemic (H1N1) 2009 testing was available. Most Kenyan hospitals have not been conducting systematic surveillance for pandemic (H1N1) 2009; thus, hospitalized patients with pandemic (H1N1) 2009 were likely missed..Existing and enhanced sentinel hospital surveillance for influenza in Kenya made it possible to describe severe outcomes of pandemic (H1N1) 2009 in this country. Yet, the number of severe outcomes was likely much higher than reported here. Continued surveillance is essential in clarifying the full clinical spectrum and evolution of the pandemic in Kenya, including the role of coexisting conditions such as HIV infection and malaria. In addition, increasing clinician awareness of pandemic (H1N1) 2009 treatment guidelines could improve patient management"}
+{"text": "The relative value of off-pump coronary bypass (OPCAB) surgery as compared to conventional coronary artery bypass operation is still debated. We started a prospective study in 2000 with the aim of using exclusively OPCAB for surgical myocardial revascularization in a single center. The present report analyzes the 13-years results of this approach in a large consecutive patient population.Of the 6111 coronary bypass operation performed in our center between January 2000 and December 2012, 5472 were carried out off-pump. Since 2004 OPCAB surgery was performed in more than 99% of cases, conventional CABG was reserved for patients in cardiogenic shock. The OPCAB approach consisted of the use of a single pericardial sling, pressure stabilizing device, aortocoronary shunt and elastic snares. Prophylactic intra-aortic balloon pump counter-pulsation was used in 495 (9%) of cases.The OPCAB hospital mortality was 1.5% (85/5472). Perioperative myocardial infarction occurred in 60 (1.1%), stroke in 85 (1.2%), major adverse cardiac event in 132 (2.4%) cases. 121 patients needed reoperation for bleeding (2.2%). The mean length of hospital stay was 9.9 (SD 8.5) days.The shift towards beating-heart surgery provides acceptable results, but does not eliminate perioperative mortality and morbidity."}
+{"text": "Tuberculosis (TB) is said to be one of the commonest opportunistic infection in patients with HIV/AIDS.To study the clinical and laboratory profile of patients with HIV/TB coinfection.Fifty adult TB patients having confirmed HIV seropositivity were included in randomized manner. A detailed history and thorough physical examination was done. Laboratory and radiological investigations were carried out as appropriately warranted.Most of the patients were farm workers (30%) followed by manual laborers (22%) and transport drivers (16%). Heterosexual route was found in 86% of patients. Cough was present in 94% while fever and weight loss in 86% and 78% of patients, respectively. Out of 50 patients, 40% had only pulmonary TB (PTB), 46% had pulmonary and extra-pulmonary TB (EPTB), 10% had only EPTB and 4% had multisystemic EPTB. Mediastinal lymphadenopathy was present in 34% while pleural effusion and extra-thoracic lymph nodes was present in 20% and 18% of patients, respectively. Positive smear for acid-fast bacilli (AFB) was found in 25.58% while positive Mantoux test was found in 32.14% of patients.HIV/TB coinfection is more common in sexually active age group and commonest mode of HIV infection is heterosexual transfer. Sputum smear AFB and Mantoux test positivity is low in TB patients having HIV. Disseminated TB is common in HIV. Mediastinal lymphadenopathy is common site among extra-pulmonary tuberculosis. Tuberculosis remains the most common opportunistic infection (OI) and is the commonest cause of death in HIV infected patients. ClinicalIn 2008, there were estimated 9.4 million new cases of TB globally; of which 1.4 million (15%) were HIV positive. An estimated 1.8 million people died of TB globally, of which about 0.5 million were patients with TB/HIV coinfection.In 2008, 1.98 million TB cases were estimated to have occurred in India with 276 000 (24/100 000 population) TB mortality. India, the third highest HIV burdened country, had an estimated 2.31 million (0.36% of adult population in the country) people living with HIV/AIDS (PLHAs) in 2007. It has been estimated that in 2007, about 4.85% of the incident of TB cases in India were HIV-positive.[In persons dually infected with HIV and tuberculosis, the lifetime risk of developing tuberculosis is 50%\u201370% as compared to a 10% risk in HIV negative individuals. Due to tvice versa.Thus, because of the very frequent association of tuberculosis and HIV, it has become necessary to look for tuberculosis in HIV infected individuals and In this paper, we describe the clinical and laboratory findings from a case series of patients with TB/HIV coinfection, in order to obtain a better picture of the clinical profile of these patients.In the present study 50 adult TB patients having confirmed HIV sero-positivity either attending OPD or hospitalized in Guru Gobindsing Hospital and Shree M. P. Shah Medical College, Jamnagar, Gujarat; were selected in randomized manner. A detailed clinical history and complete general physical and systemic examination findings were recorded. All patients were subjected to chest radiograph and sputum smear AFB examination of three samples. Mantoux test using 5 TU of purified protein derivative (PPD) was done and transverse diameter of induration was noted in mm in 28 patients.All the study patients were initially screened by HIV Tridot  and if found positive on screening were confirmed by Immunocomb Bispot  and GENEDIA HIV ELISA . All kits detect antibodies.Apart from clinical manifestations and history of contact with TB patient, the diagnosis of TB was based on (i) sputum smear AFB examination, (ii) chest radiograph, (iii) Mantoux test, (iv) fluid analysis and studies, and (v) response to antituberculosis treatment (ATT). Tissue biopsy/Fine needle aspiration cytology (FNAC) was carried out by obtaining relevant samples in cases of extra-pulmonary TB (EPTB). Antituberculosis treatment on clinical ground was given in suspected TB cases.Other suggestive investigations were also carried out as and when required to establish the diagnosis of TB.Age distribution of the patients is shown in Cough was the most common symptom present in 47 (94%) patients followed by fever, weight loss, and loss of appetite present in 43 (86%), 39 (78%), and 31 (62%) patients, respectively, while dyspnoea, chest pain, and hemoptysis were seen in 28 (56%), 10 (20%), and seven (14%) patients, respectively. The mean duration of the most common presenting symptom (cough) was 12 weeks while fever and weight loss had mean duration of about 14 and 12 weeks, respectively, at the time of presentation. Mean duration of anorexia was 15 weeks and for dyspnoea it was about 8 weeks. The average (mean) duration of symptoms at the time of presentation was 12.2 weeks, which is in overall suggestive of late presentation and contributing to the delay in the diagnosis of TB. The duration of illness in the present study ranged from 2 weeks to 2 years.In the present study, only pulmonary TB (PTB) was seen in 20 (40%) patients, while only EPTB was seen in five (10%) patients . Overall pulmonary involvement of TB was seen in 43 (86%) cases; extra-pulmonary involvement was seen in 30 (60%) cases while disseminated TB accounted for 25 (50%) cases. Out of 43 TB patients having pulmonary involvement sputum smear AFB was positive only in 11 (25.58%). Out of 11 sputum positive patients, six cases (54.55%) had 1+ positivity; two (18.18%) had 2+ positivity; two (18.18%) had 3+ positivity while scanty bacilli were seen in one (9.09%). Among 32 sputum negative cases, 20 patients had disseminated disease suggestive of late phase of immune-suppression, accounting for higher sputum AFB negativity. Mantoux test was done in 28 patients and its results are shown in Pulmonary tuberculosis was the commonest form of TB observed in 43 (86%) patients. Among EPTB mediastinal lymphadenopathy was seen in 17 (34%) patients followed by pleural effusion seen in 10 (20%) patients. Other commoner forms of EPTB were extra-thoracic adenopathy and abdominal  TB seen in nine (18%), and six (12%) patients, respectively. Other forms included pericardial effusion (6%), CNS TB (6%). Disseminated TB was seen in 25 (50%) patients.After the detection and recognition of HIV in 1983, the declining curve of TB infection started to show a sudden rise during the 1990s. Coinfection with TB and HIV has already been reported as one of the most significant global public health concerns. Tuberculet al.[et al.[Most of our study group patients (76%) belonged to the age group of 21\u201340 years, which is the sexually active age and is also the most productive in one\u2019s life. Of all the detected patients, 82% were males and the rest were females. The striking male predominance noted in the present study has also been reported by other authors. The occuet al. reportedl.[et al. found mal.[et al. have fouSexual route  was found to be the major risk factor (86%) while only one patient was an intravenous drug abuser and one patient was homosexual in our study. Three patients (6%) had blood-transfusion-related transmission. Heterosexual promiscuity and casual sex was found to be a major risk factor in the studies by some Indian observers11 while et al.[The average duration of symptoms was 12.2 weeks, indicating that there was a delay in diagnosing tuberculosis and starting treatment. Whether the delay was at the patient or provider level needs further investigation. The duration of illness in our patients ranged from 2 weeks to 2 years. Swaminathan et al. found thTuberculin test positivity (>10 mm) to 5 TU PPD was observed in 32.14% patients in our study. Other authors have reported a wide variation in tuberculin test positivity.11 Positiet al.[et al.[The most common symptom was cough in 47 (94%) patients, while fever was present in 43 86%) and weight loss in 39 (78%) patients. In the series reported by Mohanty et al. fever wa6% and weet al.[et al.[Eleven 25.58%) of our patients had sputum smear for AFB positive. This is very different from the situation in HIV uninfected tuberculosis patients and indicates that smear microscopy is not a sensitive diagnostic tool in the presence of HIV infection. Mohanty et al. has repo% of our l.[et al.Extra-pulmonary tuberculosis is more common in HIV/TB patients, especially with advanced immunesuppression than in non-HIV/TB patients. Extra-pu4Twenty-three patients (53.49%) out of 43 PTB patients had an associated extra-pulmonary focus, and two patients with extra-pulmonary TB had multisystem involvement which is pointing to the disseminated nature of the disease in HIV positive.We conclude that HIV/TB coinfection is more common in sexually active age group and heterosexual transfer is the commonest mode of HIV infection. Sputum smear AFB and Mantoux test positivity is low in TB patients having HIV. Disseminated TB is common in HIV and mediastinal lymphadenopathy is common site among extra-pulmonary tuberculosis."}
+{"text": "Value is defined by improving quality while reducing cost. This study's objective was to evaluate if 8-week mindfulness meditation or exercise programs can result in reduced costs related to Acute Respiratory Infections (ARIs).One hundred forty-nine adults \u2265 50 years were recruited from community and randomized into one of three groups: 1) wait-list observation (control), 2) meditation and 3) moderate intensity exercise. Cost associated with ARI incidence and severity was assessed by tracking self-reported medication use, and number of missed-work days and medical clinic visits, with costs per subject calculated based on average cost for generic medications, a missed-work day ($126.20) and a clinic visit ($78.70). Monte Carlo bootstrap sampling was used based on the incidence of ARI and computed to 95% confidence intervals (CI) from the sampling distributions.The mean total cost per subject for the control group was $214 (95% CI: $105-$358), for exercise $136 (95% CI: $64-$232) and for meditation $65 (95% CI: $34-$104). The majority of the cost savings was through a reduction in missed days of work. The exercise group had the highest medication costs per subject at $16.60 compared to $5.90 for meditation (p=.004) and $7.20 (p=.046) for control. Compared to control, meditation and exercise were associated with a 70% (p=.010) and 36% (p=.334) lower cost respectively.Meditation and exercise reduce the burden of ARI and associated costs. Meditation, more then exercise, brings value to health care spending by enhancing quality of health while reducing cost for ARI. Further research is needed to show how integrative medicine therapies can add value to medical spending for other health care needs."}
+{"text": "Gastric carcinoma development is a multi-stage process that involves more than one gene. Aberrant changes in DNA methylation are considered as the third mechanism that leads to anti-oncogene inactivation, which plays an essential role in tumor development. In this study, we assessed the relationship among the aberrant methylation of the promoter CpG islands of tissue inhibitor of metalloproteinase 3 (TIMP3) gene, its protein expression, and the clinicopathological features of gastric adenocarcinoma.The methylation status of the promoter CpG islands and the protein expression of TIMP3 gene in tumors and adjacent normal mucosal tissues of 78 patients with gastric adenocarcinoma were detected by methylation-specific PCR (MSP) and immunohistochemistry.P\u2009<\u20090.05), but no difference existed among the subgroups of tumors (P\u2009>\u20090.05). Immunohistochemistry analysis confirmed TIMP3 down-regulation in tumor tissues. The rate of TIMP3 gene expression was 100% in non-neoplastic tissues but apparently decreased to various extents at different stages, i.e., decreased to 30% (6/20) at the early stage, to 3.4% (2/58) at the progressive stage, and to 0% (0/78) in metastatic lymph nodes. Among the 70 tumor tissues with negative TIMP3 expression, 64 (91.4%) were hypermethylated and 6 were unmethylated (8.6%), indicating a significant association between hypermethylation and reduced or negative TIMP3 expression (P\u2009<\u20090.01).The CpG island methylation of TIMP3 was detected in tumor tissues, cancer-adjacent tissues, and lymph nodes with metastasis. In increasing order, the hypermethylation frequency of these tissues were 35.9% (28 of 78 non-neoplastic tissues), 85% (17 of 20 early-stage cases), 89.7% (52 of 58 progressive-stage cases), and 100% (78 of 78 metastatic lymph node). A marked difference was found between tumors and non-neoplastic tissues (The hypermethylation of the promoter region in CpG islands is the main mechanism of TIMP3 gene expression and may provide evidence for the molecular diagnosis and stage evaluation of gastric cancer.http://www.diagnosticpathology.diagnomx.eu/vs/1756134016954958The virtual slides for this article can be found here:  Gastric cancer (or gastric carcinoma) is one of the most common malignancies in the world. Disease development in gastric cancer is a multi-stage process that involves more than one gene. Disease factors ultimately act on different genes at different stages, causing a change in gene structure and expression levels that lead to the development of gastric carcinogenesis. Loss of function of an anti-oncogene may occur through various channels. In addition to deletions and mutations, aberrant changes in DNA methylation are considered as the third mechanism leading to anti-oncogene inactivation ,2, whichIn this work, we detected the methylation of the TIMP3 gene promoter CpG island and protein expression in normal gastric mucosa tissues, gastric cancer tissues, and metastatic lymph nodes of 78 patients with gastric cancer using methylation-specific PCR (MSP) and immunohistochemistry. We explored the correlation of gene promoter methylation with its corresponding protein expression and then analyzed the relationship of TIMP3 gene CpG island abnormal methylation with the development, as well as clinical and pathological features, of gastric adenocarcinoma.n\u2009=\u200954; female: n\u2009=\u200924) with a mean age of 56.2\u2009\u00b1\u20097.5\u00a0years. Among the samples obtained, 20 were of early gastric cancer, 58 were of advanced gastric cancer, 44 were of differentiation, and 14 were undifferentiated. Tumor staging was based on the International Union Against Cancer TNM staging standards, Typing of Gastric Cancer Growth Way and Statute of Staging, and gastric cancer typing in Japan [All 78 cases of gastric normal tissue, gastric carcinoma, and metastatic lymph nodes were verified by pathological diagnosis. The tumor samples were obtained between March 1998 to May 2005 at the First Affiliated Hospital and Liaoning Provincial Tumor Hospital from postoperative patients with gastric cancer  for early gastric cancer, 89.7% (52/58) for advanced gastric cancer, 98.7% (77/78) for metastatic lymph nodes, and only 35.9% (28/78) for the normal gastric tissue. A significant increase in TIMP3 gene promoter methylation was observed in all gastric cancer groups . Among the gastric carcinoma cases, 9 in 20 patients were positive for early gastric cancer; 11 cases were negative (55%), 21 cases were positive, and 37 were negative (63.8%) in 58 cases of advanced gastric cancer; and 12 cases were positive and 66 cases were negative (84.6%) in 78 patients with metastatic gastric lymph nodes. The reduced TIMP3 expression that was observed in the gastric cancer groups was found to be statistically significant (00%. AmonP\u2009<\u20090.01). The TIMP3 methylation rate in metastatic lymph nodes in the \u22657 tissue group was significantly higher than the <7 tissue group . The subserosal and serosal tissue group was significantly higher than the submucosal and myometrium tissue group . Increased TIMP3 gene methylation rate was generally observed in diffuse-like growth, lymph node metastases (\u22657), and subserosal and serosal tumors, implying that no relationship existed between TIMP3 gene methylation and tumor size, macroscopic type, and histological type. The positive rate of the 58 cases of advanced gastric cancer tissues was 36.2% (21). TIMP3 protein expression in massive and nested growing tissues was significantly higher than that of diffuse-like growth tissues . TIMP3 protein expression in the metastatic lymph node \u22657 tissues was significantly higher than the <7 tissue   than that of the normal gastric tissue group, which implied that TIMP3 gene promoter CpG island methylation reduced TIMP3 gene expression and was thus the main tumor suppressor-inactivation mechanism in gastric cancer. Gagnon et al. [To explore the relationship between TIMP3 and gastric cancer, as well as its mechanism in gastric inactivation, we detected TIMP3 gene 5\u2032 CpG island hypermethylation in normal gastric mucosa, gastric carcinoma, and metastatic lymph nodes. We found that in >85% of all gastric cancer tissues, the TIMP3 gene 5\u2032 CpG island exhibited aberrant methylation that was significantly higher , confirming that the loss of TIMP3 protein expression was closely related to TIMP3 gene promoter CpG island methylation. Feng HF et al. [In the present study, all 78 cases of normal gastric tissue were positive for TIMP3 protein expression. Among these 78 cases, only 28 (35.9%) were positive for methylation. Among the 20 patients with early gastric cancer, 9 were positive for TIMP3 protein expression and 17 (85%) were positive for methylation. Among the 58 cases of advanced gastric cancer, 21 were positive for TIMP3 protein expression and 52 (89.7%) were positive for methylation. Among the 78 cases of metastatic lymph nodes, 12 were positive for TIMP3 protein expression and 77 cases (98.7%) were positive for methylation. Increased methylation rate was significant among the early cancer, advanced cancer, and metastatic lymph node samples compared with normal tissue samples  may be observed. TIMP3 protein expression of the sample was negative, so these samples were defined as methylation positive.In China, the 5-year survival rate of gastric carcinoma patients is only about 40% after resection. The poor prognosis is associated with extensive local invasion and/or regional lymph node metastasis . Local rKerbel  reportedTIMP3 has a high frequency of genetic variation in many types of human malignant tumors, including mutations, deletions, methylation, chromosomal translocation, and so on . These mThe authors hereby declare that they have no competing interests with one another.ZG and JZ carried out the pathological and PCR examinations, DD and ZG analyzed the data, and ZG drafted the manuscript. All authors read and approved the final manuscript."}
+{"text": "Headache is a common cause of medical consultation, both in primary care and in specialist neurology outpatient clinics. This study analyzed the incidence and characteristics of headache patients during an 18-month period in a tertiary care headache outpatient clinic.Patients visiting a tertiary care headache outpatient clinic at the University Hospital Innsbruck, Austria, were registered consecutively. Diagnosis of primary and secondary headache disorders was in accordance with the revised version of the International Headache Classification (ICHD-II) and data including age, sex, Headache Impact Test (HIT-6), headache frequency, trigger factors and caffeine intake were collected prospectively over an 18-month period.From December 2010 until April 2012 626 patients comprising 897 visits were registered in our headache database. The female to male ratio was 3:1. The median age accounted for 40.7 years (IQR: 28.3 \u00a8C 50.4). Diagnoses of primary headache disorders were grouped as follows: migraine 61% , episodic (12%) and chronic tension-type headache (8%), trigeminal autonomic cephalalgias (4%), other primary headaches (1%), secondary headaches (13%),cranial neuralgias and facial pain (2%) and currently unclassified (15%). The majority of patients with secondary headache disorders were diagnosed with headache attributed to a substance or its withdrawal (10%) The median number of headache days per month was 8 (IQR 4-20). 33% of all patients reported >15 headache days during the previous month.This registry reflects the characteristics of patients seen in an outpatient headache clinic. In accordance with other data from tertiary hospitals migraine was the most common diagnosis in our outpatient clinic followed by tension-type headache. Almost 33% suffered from frequent (\u00a1\u00dd15 days per month) headache reflecting a substantial and growing patient population with medico-economical burden to the headache community."}
+{"text": "Pseudomonas aeruginosa remains a major problem in burn patients. The main objective of this study was to determine the antibiotic resistance pattern and frequency of class 1 integrons among P. aeruginosa strains isolated from patients with burn wound infections in a new Burn Centre in Guilan, Iran.Antibiotic resistance of P. aeruginosa species were identified by standard bacteriological methods. The drug susceptibility test, using 11 antimicrobial agents, was performed for all the isolates via agar disk diffusion method. PCR was carried out for the detection of integrons.The bacterial isolates were collected from 182 patients with burn wound infections and P. aeruginosa in their isolates. Resistance rates to various antibiotics were as follows: cloxacillin (91.8%), cotrimoxazole (86%), cephazolin (83.7%), carbenicillin (74.4%), piperacillin (69.9%), ceftazidime (68.8%), ciprofloxacin (66.3%), tobramycin (58.2%), amikacin (48.8%) and gentamicin (37.2%), while the most effective antibiotic was imipenem with a resistance rate of 23.3%. Thirty nine (45.3%) isolates were detected as multi-drug resistant. The PCR results showed that 37 (43%) P. aeruginosa isolates and 27 (69.2%) multi-drug resistant strains harbored class 1 integrons. A significant correlation was obtained between the presence of integrons and resistance against imipenem, ceftazidime, piperacillin and ciprofloxacin (P <0.001).Out of a total of 182 hospitalized patients in the burn center assessed, 86 (47%) found to have Optimization of using antimicrobial agents and control of infection is recommended to prevent the increasing population of drug resistant organisms in the new burn centre setting in this study. Furthermore, the high frequency of class 1 integrons among multi-drug resistant strains might be responsible for dissemination of antibiotic resistance gene. Pseudomonas aeruginosa, as one of the most common microorganisms worldwide, is a leading cause of nosocomial infections, especially among burn patients  tests. The drug susceptibility test was carried out for all the isolates on Mueller-Hinton plates and zones of inhibition were measured by Kirby-Bauer agar disk diffusion method in accordance with the recommendations of clinical and laboratory standards institute (CLSI). The antimicrobial agents used in this test were as follows: amikacin (30 ug), ceftazidime (30 ug), cephazolin (30 ug), cloxacillin (5 ug), carbenicillin (30 ug), gentamicin (10 ug), imipenem (10 ug), piperacillin (100 ug), ciprofloxacin (5 ug), tobramycin (10 ug), and cotrimoxazole (25 ug) . Pseudomonas aeruginosa ATCC 27853 was used as the control organism. The results were interpreted as susceptible, intermediately susceptible or resistant by measuring the diameter of inhibition zone, according to the criteria designated by CLSI  and the primary isolation was performed on blood agar, McConkey agar and eosin methylene blue agar media. amikacin 0 ug, cef by CLSI , 11. The by CLSI . AmplifiP. aeruginosa in their isolates. P. aeruginosa isolates indicating that the isolates have acquired high level resistance against cloxacillin (91.8%), cotrimoxazole (86%), cefazolin (83.7%), carbenicillin (74.4%), piperacillin (69.7%) ceftazidime (68.6%), and ciprofloxacin (63.3%). A low level resistance was recognized for imipenem (23.3%) and gentamicin (37.2%), while an intermediate level resistance was found against the amikacin (48.8%) and tobramycin (58.2%) (P. aeruginosa isolates harboured class 1 of integrons. Among the multi-drug resistance (MDR) strains, 27 (69.2%) showed class 1 integrons and a significant correlation was found between the presence of integrons and resistance aganist imipenem ceftazidime, piperacillin, and ciprofloxacin (P < 0.001).Out of 182 hospitalized patients in the burn center assessed, 86 47%) found to have  (58.2%) . A totalfazolin 8.7%, carb7% found  (58.2%) . The PCRP. aeruginosa still remains an important opportunistic cause of nosocomial infection and has developed resistance to various antimicrobial agents in burn centers , amikacin (73%), and gentamicin (80%), was reported by BojaryNasrabadi and Hajia  eb et al , it was P. aeruginosa in biomedical publications  had class 1 integrons, as detected by PCR.Different definitions have been employed to characterize multi drug resistant (MDR) isolates of ications . In the ications . Accordi(et al.,, 39 (42.(et al., imipenemfections , 21. A cpatients . In the P. aeruginosa strains isolated from burn injuries and that the majority of studies are conducted regarding the isolation from different clinical samples. In a study carried out by Yousefi et al (P. aeruginosa isolates carried class 1 integrons. In other studies carried out on different clinical specimens in Amazon area of Brazil and Zhenjiang area of China, 41.5% and 38.0% of P. aeruginosa isolates were found to be positive for class 1 integrons, respectively (Literature review reveals that very little has been published on the frequency of class 1 integrons among fi et al  on samplectively , 32.P. aeruginosa (In the present study, a clear difference was observed in the frequency of class 1 integrons between multi-drug resistance and non MDR strains. Several studies have reported higher prevalence rate of class 1 integrons among the MDR strains of ruginosa , 33, 34.Furthermore, a significant correlation was observed between the presence of integrons in the MDR isolates and the antibiotic resistance to imipenems, ceftazidime, piperacillin and ciprofloxacin. These data are in agreement with the findings of Gu et al  in chinaP. aeruginosa strains were lower, in the present study, compared to other studies conducted in the two referral burn hospitals in Tehran. Optimization of antimicrobial use and control of infection is recommended to prevent the increase in the population of drug resistant organisms in the referral burn hospital in Guilan. Moreover, a significant correlation between the presence of integrons and antibiotic resistance among the MDR isolates suggested that integrons might be responsible for the distribution of antibiotic resistance genes among multi-drug-resistant strains.In conclusion, although the frequency and antibiotic resistance rates of"}
+{"text": "The facial phenotype of psychogenic movement disorders has not been fully characterized. Seven tertiary-referral movement disorders centers using a standardized data collection on a computerized database performed a retrospective chart review of psychogenic movement disorders involving the face. Patients with organic forms of facial dystonia or any medical or neurological disorder known to affect facial muscles were excluded. Sixty-one patients fulfilled the inclusion criteria for psychogenic facial movement disorders . Phasic or tonic muscular spasms resembling dystonia were documented in all patients most commonly involving the lips (60.7%), followed by eyelids (50.8%), perinasal region (16.4%), and forehead (9.8%). The most common pattern consisted of tonic, sustained, lateral, and/or downward protrusion of one side of the lower lip with ipsilateral jaw deviation (84.3%). Ipsi- or contralateral blepharospasm and excessive platysma contraction occurred in isolation or combined with fixed lip dystonia (60.7%). Spasms were reported as painful in 24.6% of cases. Symptom onset was abrupt in most cases (80.3%), with at least 1 precipitating psychological stress or trauma identified in 57.4%. Associated body regions involved included upper limbs (29.5%), neck (16.4%), lower limbs (16.4%), and trunk (4.9%). There were fluctuations in severity and spontaneous exacerbations and remissions (60%). Prevalent comorbidities included depression (38.0%) and tension headache (26.4%). Fixed jaw and/or lip deviation is a characteristic pattern of psychogenic facial movement disorders, occurring in isolation or in combination with other psychogenic movement disorders or other psychogenic features. \u00a9 2012 Movement Disorder Society Many systemic and neurological conditions may involve the facial musculature. From tetanus to blepharospasm, the majority of them are characterized by muscular spasms.Movement Disorders journalPMDs involving the face have been largely described as blepharospasm, reported in 3%Seven tertiary movement disorders centers performed a retrospective chart review of PMD involving the face using computerized databases and, when available, videotape examinations of patients evaluated between January 1993 and January 2010. Only patients actively followed up and treated by experts in movement disorders were included. Diagnosis of PMD was made according to the criteria of Fahn and WilliamsThe seven centers retrieved a total of 87 patients with PFMDs, representing the 16.3% \u00b1 15.8% of all the PMDs cases seen during the examined period (range: 5.0% [Rome] to 50.0% [Boston]). Twenty-six cases were excluded because of missing data  or uncertain clinical features, thus resulting in a total of 61 patients with PFMDs , predominantly downward . Sixty pParoxysmal (65%) or fixed (26%) eyelid involvement occurred mostly unilateral with alternating sides (65%). The right side was affected twice as often as the left (11 vs 5). Three cases reported gestes antagonistes . The frontalis muscle was often activated contralateral to the abnormal orbicularis oculi , C; no pThe course was stable (53%) or variable (33%), with diurnal fluctuations in one-fifth. Spontaneous remissions were reported in 13 subjects (21%), with recurrence in 2 after 2 weeks and 10 years. Patients with or without remission did not differ with respect to number of visits, follow-up duration, gender distribution, age, occurrence of primary or secondary gain, resolution of pending medico-legal issues and disclosure of the diagnosis of psychogenicity to the patient. At the latest follow-up visit, spasms were present mostly in the lips (84%) and eyelids (51%). Isolated lip involvement was the most frequent pattern (43%), followed by lips and eyelids (23%) and eyelids alone (13%). Platysma was involved in 61% of patients. Extra-facial contractions involved upper limb (30%), neck (16%), leg (16%), and trunk (5%). When present, limb involvement was ipsilateral to the facial involvement. Dystonia was the most frequent phenotype of extra-facial sites (58%), followed by tremor (14%) and other jerks (10%). All but 6 subjects received a variety of medical and nonpharmacological treatments , and with a variety of features suggesting a psychogenic cause .2,6,7,9,Involvement of the lower lip with downward deviation at the angle of the mouth combined with ipsilateral platysma co-contraction, previously termed \u201csmirk,\u201d1,3\u20135,22The unilateral involvement of facial muscles is common to PFMDs and hemifacial spasm (HFS). However, unlike the synchronous myoclonic jerks or tonic contractions,An uncommon involvement of the orbicularis oculi was demonstrated by 2 patients who could not open their eyes, a condition resembling \u201ceyelid opening apraxia.\u201dFixed dystonia of the oromandibular region has been reported to result from peripheral injury35Albeit commonly reported in PMDs literature,37Our study has several limitations. The major shortcoming is represented by its multicenter retrospective design, which is open to several errors . However, since the facial phenotype of PMDs has not been fully characterized, its study could only arise from retrospective review rather than a prospective design. The reliance on 7 centers employing the same standardized data collection was intended to increase the reliability of ascertainment of this rare phenotype and increase the generalizability of the reported observations. Moreover, the diagnosis of PMDs has been challenging because of historic transitions through the pitfalls of underrecognition, misdiagnosis, overdiagnosis, and diagnosis by exclusion.19In summary, PFMD should be considered when a patient exhibits any combination of the following features: (1) fixed or paroxysmal unilateral facial contractions, specially with lower lip with or without ipsilateral jaw involvement, of maximal severity at onset; (2) inconsistent features such as changes in side and pattern during or between examination; (3) associated somatizations or nonphysiologic sensory or motor findings; (4) reduction or abolition of facial spasm with distraction; (5) response to suggestion or psychotherapy; (6) rapid onset and/or spontaneous remissions; and (7) normal neurological examination. Supportive features are young age, female gender, and associated medical conditions such as depression, headaches, facial pain, fibromyalgia, or irritable bowel syndrome. A prompt diagnosis based on phenomenology will avoid the extensive diagnostic workup characteristic of a diagnosis-of-exclusion approach, prevent unnecessary costly investigations, and permit the institution of appropriate physical, psychological, and medical therapy.9Video 1. This patient had sudden-onset right-arm weakness and fixed tonic muscular contraction affecting the right lower lip. Lip contraction attenuated when opening the mouth and protruding her tongue, and disappeared when laughing or trying to whistle, which functioned as a distracting maneuver. A \u201cla belle indifference\u201d approach is noted. The expression at rest with improvement or disappearance with activity  is opposite to the typical action-induced expression of focal dystonias.Video 2. Segment 1. Patient seen 5 months after sudden onset of fixed jaw deviation. Segment 2. Evaluation one month later, after sudden onset of contralateral blepharospasm. Distractibility with tongue movements and variability to passive manipulation of jaw opening and closing are demonstrated. Segment 3. Evaluation 1 year later demonstrates resolution of the blepharospasm but persistence of the fixed jaw dystonia."}
+{"text": "Purpose. Ischemic central retinal vein occlusion (CRVO) eyes are at high risk of developing neovascular glaucoma (NVG). Our purpose is to investigate the effect of anti-VEGF therapy for macular edema after CRVO on the development of neovascular glaucoma (NVG) in ischemic CRVO eyes. Methods. This is a retrospective case series of 44 eyes from 44 patients with CRVO treated with anti-VEGF therapy for macular edema. The primary outcome was the development of NVG. Results. Of the 44 eyes, 14 eyes had ischemic CRVO, and 30 eyes had nonischemic CRVO. Nonischemic eyes received a mean of 8.4 anti-VEGF doses, over mean follow-up of 24 months. One nonischemic eye (3.3%) developed NVD but not NVG. The 14 ischemic eyes received a mean of 5.6 anti-VEGF doses, with mean follow-up of 23 months. Of these 14 ischemic eyes, two eyes (14%) developed iris neovascularization and 3 eyes (21%) developed posterior neovascularization. Three of these 5 eyes with neovascularization progressed to NVG, at 19.7 months after symptom onset, on average. Conclusion. Anti-VEGF therapy for macular edema may delay, but does not prevent, the development of ocular NV in ischemic CRVO. Significant risk of NVG still exists for ischemic CRVO eyes. Central retinal vein occlusion (CRVO) is a common sight-threatening retinal vascular disorder, with a cumulative 10-year incidence of 1.6% , 3. IschOcular NV results from retinal ischemia, with vascular endothelial growth factor (VEGF) playing a key role in the development of pathological angiogenesis , 7. It hAfter receiving approval by the Institutional Research Board at our institution, we reviewed eyes treated with an anti-VEGF agent (ranibizumab or bevacizumab) for macular edema secondary to CRVO. Patients were evaluated and treated by one of the four retina specialists at our large urban institution from August 2007 to March 2012. Cases were screened and identified through review of CPT codes for anti-VEGF agent and ICD-9 codes for \u201ccentral retinal vein occlusion,\u201d \u201cvenous tributary occlusion,\u201d and \u201cretinal vascular occlusion not otherwise specified.\u201d A control group was not utilized in this retrospective study as the natural history of CRVO has been well elucidated by prior studies and the CVOS , 5.Patients with macular edema due to CRVO with symptom onset no greater than 90 days prior to presentation were included, of both ischemic and nonischemic CRVO types. Patients with medication-controlled open angle glaucoma and dry age-related macular degeneration were included. Exclusion criteria were the presence of NVG or any ocular NV on initial presentation, previous PRP, or a history of proliferative diabetic retinopathy. Patients with follow-up duration of less than 8 months were excluded. The data was compiled from 44 eyes of 44 patients with CRVO that fulfilled the inclusion criteria.Patients were diagnosed as ischemic versus nonischemic CRVO by the treating retina specialist or, if this distinction was not documented in the patient's record, by the investigators based on well-established criteria: the presence of relative afferent papillary defect (RAPD), visual acuity (20/200 or worse), and the extent of nonperfusion on fluorescein angiography, as previously reported . Macular t-test, and nonparametric Spearman's rank correlation were used. Statistical significance was set at P < 0.05. Statistical comparison of our results was performed against a historical control studying the probability of ocular NV and NVG after ischemic CRVO [For statistical analysis, the Snellen visual acuity measurements were converted to logarithm of the minimum angle of resolution (logMAR) units before analysis . Cirrus mic CRVO ; howeverThis study included 44 eyes of 44 patients diagnosed with CRVO. Fourteen eyes of 14 patients had ischemic CRVO, and 30 eyes of 30 patients had nonischemic CRVO, with no bilateral cases . AveragePatients with ischemic CRVO presented on average 14 days after symptom onset, compared with 24 days in the nonischemic group. Total mean follow-up duration was 23 months (range 8\u201341 months) for ischemic eyes and 24 months (range 8\u201364 months) for nonischemic eyes. Ischemic eyes received an average of 5.6 \u00b1 5.1 doses (range 2\u201319 doses) of intravitreal anti-VEGF over a mean period of 12.1 months (range 4\u201331.6 months). Nonischemic eyes received an average of 8.4 \u00b1 5.7 doses (range 1\u201323 doses) of anti-VEGF over a mean period of 18.0 months (range 2.6\u201347.5 months) .P = 0.021). Over the course of treatment, vision improved in 70% of nonischemic patients and 50% of ischemic patients (P = 0.197). Ocular neovascularization developed in 1 of 30 (3.3%) nonischemic eyes and 5 of 14 (35.7%) ischemic eyes (P = 0.002). Mean VA in the ischemic group was 20/400 on initial visit and 20/800 on final visit. Mean VA in the nonischemic group was 20/80 on initial visit and 20/50 on final visit. Mean initial central foveal thickness (CFT) on OCT in the ischemic group was 602 micrometers, with mean final CFT of 386 micrometers. The nonischemic eyes had a mean initial CFT of 488 micrometers, with mean final CFT of 293 micrometers.Nine of 14 eyes (64%) in the ischemic group had initial VA worse than 20/200, compared with 8 of 30 eyes (27%) in the nonischemic group (Five of the 14 (36%) ischemic eyes developed ocular NV, at 16 months after symptom onset, on average. Specifically 2 eyes (14%) developed NVI at 13.2 and 10.5 months after symptom onset, 1 eye (7%) developed NVD at 17.8 months, and 2 eyes developed vitreous hemorrhage (VH) at 8.4 and 30 months, respectively . Four ofP = 0.16). Only 1 (3%) of 30 nonischemic eyes developed ocular NV, specifically NVD. This eye received PRP and did not progress to NVG.The 5 ischemic eyes that developed ocular NV received a mean of 3.6 \u00b1 1.1 injections , whereas the 9 ischemic eyes that did not develop ocular NV received a mean of 6.8 \u00b1 6.2 injections   , which eThe Clinical Trial of Subjects with Macular Edema Secondary to Central Retinal Vein Occlusion (CRUISE)  found thThe one-year results from the Vascular Endothelial Growth Factor Trap-Eye for Macular Edema Secondary to Central Retinal Vein Occlusion (COPERNICUS) study  showed tAnother 2012 prospective randomized study  of 60 CRIn our evaluation of the effect of anti-VEGF therapy on ischemic CRVO eyes, we compare our patients to Hayreh's natural history study  because Most of the eyes in our study received a sporadic combination of macular edema treatment between 2007 and 2012, including anti-VEGF, steroid injection, and focal laser, as determined by the treating retina specialist. Hayreh's natural history study  showed tHayreh and Zimmerman  also fouThree 21%) of the 14 ischemic CRVO eyes in our study developed NVG at a mean of 19.7 months, much later than that described in the natural history study by the CVOS [1% of theP = 0.041). This is appropriate since the anti-VEGF was originally administered to treat macular edema, not in order to prevent the development of ocular NV and NVG.In our study, we compared the 5 ischemic eyes with ocular NV to the 9 ischemic eyes without ocular NV to determine if there were any identifiable factors leading the 5 eyes to develop NV. We found that there was no difference in the anti-VEGF frequency or the time period from symptom onset to anti-VEGF treatment initiation between these groups. The 9 eyes that did not develop ocular NV received on average 6.8 \u00b1 6.2 total doses of anti-VEGF and the 5 eyes that developed ocular NV received 3.6 \u00b1 1.1 total doses of anti-VEGF; the wide variation in the number of doses and the small group sizes precluded statistical analysis, yet there may be a trend toward fewer anti-VEGF doses administered to the 5 NV eyes. Probably the most ischemic eyes had less vision improvement with anti-VEGF doses for macular edema, and this led the treating retina specialist to abandon anti-VEGF for other treatment modalities or observation. The 30 nonischemic eyes in our study received significantly more anti-VEGF doses over a 24-month period than the 14 ischemic eyes (mean of 8.4 doses versus 5.6 doses, resp., The small sample size of 14 ischemic eyes is one of many limitations to this study. The four retina specialists who evaluated and managed the patients determined visit frequency and therapeutic intervention at their own discretion, resulting in varying treatment regimens. Gonioscopy was not routinely used to detect NV of the angle. It is possible that patients with angle NV but without iris NV were not identified in this study. However, previous studies showed that angle NV without iris NV  occurs aThe CRUISE and COPERNICUS trials demonstrate the effectiveness of anti-VEGF for macular edema resulting from CRVO, and the results from these studies imply that ocular NV and NVG are reduced from the administration of anti-VEGF, which is both logical and promising. Our study also suggests that anti-VEGF therapy can reduce ocular NV and NVG. However, as discussed above and as seen in the results of our study, anti-VEGF does not prevent ocular NV and may simply delay the development of ocular NV and NVG. Thus, significant risk of neovascularization remains, perhaps more so if anti-VEGF is delivered sporadically within the first one year of ischemic CRVO onset rather than on a monthly basis in the initial 6 months. Careful long-term monitoring for ocular NV is essential for these patients even while they are receiving anti-VEGF therapy. However, the advent of anti-VEGF agents for macular edema associated with both nonischemic and ischemic CRVO may have ended the era of \u201c90-day glaucoma\u201d secondary to ischemic CRVO."}
+{"text": "Several comorbidities have been independently associated with both predisposition to community-acquired pneumonia and a worse outcome. The goal of this study was to evaluate the impact of comorbidities on the outcome of patients with severe community-acquired pneumonia (SCAP).A prospective, multicentre, observational cohort study of all patients with SCAP consecutively admitted to 14 Portuguese ICUs during a 12-month period. Several comorbidities were evaluated: congestive heart failure, cancer, chronic renal failure, chronic respiratory failure, chronic hepatic disease, alcoholism, diabetes mellitus, neurologic disease, immunosuppression, HIV infection. To evaluate the impact of comorbidities associated with hospital mortality in univariate analysis, a logistic regression analysis adjusted to other variables  was performed.P < 0.001), chronic renal failure , immunosuppression  and neurologic disease , increased the chances of dying in the hospital. Median CCI was also significantly higher in nonsurvivors ). The only independent risk factor for hospital mortality was the presence of at least one comorbidity .A total of 536 (14%) of the 3,766 enrolled patients had SCAP. They were mostly male (66%) with median age 59 (29 to 82) years, median SAPS II 44 (21 to 80) and total SOFA score 8 (3 to 16). Thirty-seven per cent of the cases were microbiologically documented  virus - 18%) and 45% had septic shock. Antibiotic combination was used in 76% of the patients and 61% received a macrolide. Median hospital length of stay was 19 (3 to 70) days and hospital mortality was 35%. Comorbidities were present in 70% of the patients. The most frequent were: diabetes mellitus (21%), chronic respiratory failure (18%) and alcoholism (15%). Median Charlson's comorbidity index (CCI) was 4 (0 to 13). In univariate analysis, the presence of at least one comorbidity (odds ratio (OR) 2.29; 95% CI 1.49 to 3.52), namely cancer (OR 3.80; 95% CI 2.14 to 6.74; In SCAP, the presence of at least one comorbidity doubles the chances of dying in the hospital and is an independent risk factor for hospital mortality."}
+{"text": "Background. We established a dedicated cardiac oncology clinic in 2008 for the rapid diagnosis and treatment of cardiotoxicity related to cancer therapy. In this retrospective observational study, we report on clinical outcomes in women with early-stage breast cancer (EBC) referred to this clinic. Methods. Patients with EBC treated with chemotherapy/trastuzumab and referred between October 2008 and December 2010. Data included patient demographics, staging, cancer treatment/completion, dose delays, left ventricular ejection fraction (LVEF) and cardiac treatment. Results. Forty eight patients: median age 55.5 years, stage I/II disease (77%) and HER-2 positive (98%). The majority of women (n = 32) were referred for decreases in LVEF (from baseline). Overall, 37 (77%) patients experienced at least one drop in LVEF while on treatment, of which 22 patients (59%) experienced a \u226510 percentage point drop. The majority of patients  experienced declines in LVEF while on trastuzumab. Interventions included trastuzumab delays  and cardiac medication (12/48: 25%). A total of 81% of patients completed \u226590% of trastuzumab therapy and 15% of patients discontinued therapy due to cardiotoxicity. Conclusion. The majority of patients referred to our clinic completed therapy. Further studies are needed to determine the impact of this multidisciplinary approach on treatment completion and cardiac outcomes. Breast cancer is the most common malignancy for women in North America . The usen = 32) of patients [In four large randomized control trials  \u20137 of earpatients . In thispatients  for trasIn March of 2007, a panel of experts from across Canada convened in Toronto to develop a Canadian consensus guideline to assist clinicians in the identification and treatment of women experiencing cardiac dysfunction while on trastuzumab . The pann = 127; 68%) of whom were breast cancer patients (early and advanced stages). In 2008, we established a multidisciplinary cardiac oncology clinic to facilitate the rapid diagnosis and treatment of cardiac complications secondary to cancer therapy. The multidisciplinary team consisted of one medical oncologist, three cardiologists, one pharmacist, and one nurse. While the initial focus of this clinic pertained to women with early stage breast cancer exposed to chemotherapy +/\u2212 trastuzumab, the widespread adoption of targeted therapies in oncology has subsequently led to the referral of a much broader patient population. Between October 1, 2008 and December 31, 2010, 188 patients were referred to this clinic, the majority  were done prior to commencing chemotherapy and every 3 months for patients on trastuzumab therapy as per institution policy. Additional cardiac investigations were performed at the discretion of the treating physician.r: 0\u20137) cardiovascular risk factor, 27% having a BMI \u226530 and 23% having a smoking history.  Between October 2008 and December 2010, 48 women with early stage breast cancer receiving potentially cardiotoxic cancer therapy (anthracyclines/trastuzumab) were referred to the cardiac oncology clinic. Baseline patient characteristics and demographics are shown in r: 3\u201318) and the median number of anthracycline cycles was 4 (r: 1\u20136). Reasons for referral to the cardiac oncology clinic included decline in LVEF , pretreatment assessment (3), cardiomyopathy (3), valve disease (2), congestive heart failure (1), tachycardia (1), hypokinesis (1), dyspnea (1), palpations (1), LV dysfunction (1), LV enlargement (1), and abnormal echocardiogram (1).All patients received systemic therapy as outlined in n = 45; 94%) with median LVEF measurements of 63% (r: 50\u201380%). Overall, 37 (77%) patients experienced at least one drop in LVEF, of which 22 (59%) patients experienced a \u226510 percentage point drop from baseline. The majority of these patients  experienced a decline in LVEF during trastuzumab, while 5 (13%) patients experienced a decline in LVEF following completion of all systemic therapy. Cardiac imaging was performed as outlined in n = 39/48; 81%) successfully completed \u226590% (16\u201318 cycles) of their recommended trastuzumab therapy. One third of patients  experienced delays in trastuzumab therapy due to declines in LVEF , of which 12/16 (75%) patients successfully completed their targeted therapy (5 with cardiac medication). Overall, 12 (25%) patients received cardiac medication: 10 ACE inhibitor, 6 beta blocker, and 2 other cardiac drugs. Median cardiac oncology clinic visits were 3 (r: 1\u20138).Treatment outcomes are outlined in n = 18; 37%) had at least one LVEF measurement of less than 50%  as outlined in n = 15/18, 83%), of which 10/15 (67%) had recovery of their LVEF to >50% (5 with cardiac medication). Eight of 18 (44%) patients successfully completed \u226590% (16\u201318 cycles) of trastuzumab. Cardiac intervention for these patients included dose delays  and cardiac medication . Approximately, one third of patients (r: 19\u201345%) discontinued trastuzumab permanently due to cardiotoxicity. These patients had normal baseline cardiac function  and all 7 patients had previous exposure to anthracyclines . These patients had a median of one (r: 0\u20132) cardiac risk factor. Three (43%) of 7 patients were administered cardiac medication and 3 (43%) patients had an LVEF recovery to above 50% (one with cardiac medication). As of December 2010, one patient had a fatal myocardial infarction 16 months after stopping trastuzumab (5 cycles) due to cardiotoxicity.A total of 7 (15%) patients with a median LVEF of 31%   in the an = 7) discontinued therapy permanently due to cardiotoxicity. Approximately, 35% of patients experienced short delays in trastuzumab therapy due to cardiotoxicity; however, with appropriate medical management and surveillance, 77% completed treatment. In this retrospective observational study, we report on the clinical outcomes of early stage breast cancer patients treated with chemotherapy and trastuzumab who were referred to a dedicated cardiac oncology clinic. While the majority of patients were referred to the clinic for a decline in LVEF during trastuzumab treatment, many of these women had previous exposure to anthracyclines, thus increasing their risk of experiencing cardiotoxicity. Completion rates for chemotherapy were high for early stage breast cancer patients seen in the cardiac oncology clinic (94%). Although several patients experienced substantial declines in LVEF (\u226520 percentage points), 81% completed 16 or more cycles of trastuzumab and only 15%  is higher than reported with the HERA trial (4.3%) , but simIn 2010, we established the Canadian Cardiac Oncology Network with the mission of optimizing cardiac care for cancer patients receiving potentially cardiotoxic therapies. Through this multidisciplinary approach, we hope to gain a better understanding of cardiac complications of cancer treatments and develop early detection and intervention strategies to optimize cardiac health in these patients."}
+{"text": "The Barts and the London Heart Attack Centre Extension (HACX) programme was introduced to provide a direct pathway for high-risk non-ST elevation myocardial infarction (NSTEMI) patients from the A&E of a district general hospital to a tertiary intervention centre. As a result, patients have earlier access to angiography and subsequent treatment, including percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG) or nonsurgical interventions. There is no research on the effectiveness of this novel HACX programme.Over 3 months, 33 patients transferred via the HACX pathway and 37 patients transferred via the conventional interhospital transfer pathway (IHT) were followed up. All patients with acute coronary syndrome symptoms, relevant ECG changes  were discussed with the cardiology team at the interventional centre prior to immediate transfer. We assessed patient suitability for angiography, post-angiography procedures, and 3-month mortality outcomes. Data were obtained from the hospital's PAS computer system.The average time for patients to have an angiography via the IHT pathway was 5.5 days. Of the 33 patients (mean age 61 \u00b1 15.2 SD) transferred via HACX, 30 patients (91%) were appropriately identified for an angiogram. Seventeen patients (52%) required PCI, five patients (15%) required CABG, four patients (12%) required nonsurgical intervention, and four patients (12%) required no treatment. Controls included 37 patients (mean age 71 \u00b1 12.6 SD) of whom 17 patients (46%) required PCI, six patients (16%) required CABG, eight patients (22%) required nonsurgical intervention and six patients (16%) required no treatment. At 3-month follow-up, 32 patients (97%) in the HACX cohort and 36 patients (97%) in the IHT cohort were alive.HACX is an effective pathway that accurately identifies and rapidly transfers appropriate NSTEMI patients requiring early coronary revascularisation. However, there was no additional mortality benefit at 3-month follow-up compared to the conventional IHT pathway. Further studies with larger patient cohorts and longer follow-up periods are required to substantiate the benefits of the HACX programme in order to consider whether this service could be implemented nationwide, or whether this is a service that does not need to exist at all."}
+{"text": "Raltegravir(RAL) is a the first compound of a novel class: integrase inhibitors. Aim of our study was to evaluate efficacy and safety of RAL based regimen.We proceeded to retrospective analysis from patients(pts) referring to our service. We searched our databases for epidemiological, clinical, immunological and virological issues. Moreover we recorded HCV and HBV status. We focused our attention on the reason of ARV switching , duration of ARV before RAL introduction, immunological gain, virological suppression and tolerability of the prescribed regimen. We followed side effects in order to define safety of prescribed regimen.We enrolled 70 pts. , according to CDC 1993 they were classified as A(12); B(32);C(26). Median age was 49 years, 42 pts were HCV-positive and only 4 presented an active HBV coinfection. Risk factors for HIV infection resulted: injective drug abuse(33) homosexual(20) and heterosexual(17)exposition. They were switched to RAL therapy for drug resistance(39)(DRR); regimen simplification(7) or drug toxicity (24). Most of patients presented multiple drug failures to ARV therapy . Median follow up was with RAL is 9 months and median extent of ARV before RAL was 9 years. Among DRR. 29 were coming from a PI failure whereas 9 from NNRTI based regimen and one from 3TC monotherapy. The most represented drug associated in new ARV regimen was DRV/rtv (42) followed by etravirine(12) and maraviroc (10).We collected data of immune and virological response after 3 and 6 months, so at 6 months 59 pts.  presented undetectable(<20) viral load and a medium CD4 gain of 89 cc/ml(90 cc/ml in DRR). No relevant side effects were observed.Pts. treated with RAL based therapy presented a good outcome, most of them achieve (after 6 months) virological suppression and immunological recovery. In our case list, darunavir/rtv and RAL obtained the best results with no relevant side effects. So more studies are needed to confirm that RAL based ARV could be very efficacious and safe even in long term follow up period."}
+{"text": "Sleep disturbances are common in critically ill patients on the ICU, with possibly serious consequences . More atWe conducted a multicentre, exploratory survey sent to nurse managers of all adult ICUs in the Netherlands. We used a self-developed questionnaire to describe which factors are important for sleep of ICU patients. Surveys were distributed via mail with subsequent written reminders. Relevant factors in relation with sleep of ICU patients were included in the questionnaire.The survey response rate was 60% (68/114). Characteristics of the sleeping patient on the ICU most often included: lying quiet with closed eyes (89.7%), decreased pulse rate (88.2%) and slower respiration (83.8%). Nonpharmacological interventions to improve sleep of the ICU patients most often comprised: keeping patients awake during the day (94.2%), lights out in the ICU (92.6%), use of a clock (91.2%), reducing noise of the ICU staff (89.7%) and reducing nursing interventions (86.8%). The type of sleep medication was mostly determined only by physicians (57.4%). The assessment of the effects of the sleep medication was mostly determined by nurses and physicians together (58.8%). Most frequent medications used were midazolam (92.6%), propofol (85.3%) and temazepam (75.1%). Nursing autonomy regarding sleep and sedation practices of patients  was judged as poor . How much nursing observations influences sleeping practices in the ICU was judged as good . How the average patient was sleeping on the ICU was judged as moderate . Furthermore, 69.1% of the ICUs mentioned a disturbed sleep-wake cycle, judged predominantly due to too much noise (61.8%), delirium (55.9%), and nursing interventions (48.5%). Most ICUs (83.8%) did not have a sleeping protocol, but 67.6% of these ICUs preferred to implement such a protocol.The average ICU patients are sleeping moderately well, mostly due to a disturbed sleep-wake cycle, delirium and nursing interventions. ICU nurses experience only a moderate feeling of autonomy and influence on sleeping practices. Most ICUs did not have a sleeping protocol, but more than one-half of these ICUs preferred to implement one."}
+{"text": "Food allergy (FA) has increased dramatically in recent years and it is now recognized as worldwide problem and accounts for a bread spectrum of disease. Although food induced respiratory symptoms are less frequent, their presence, usually are associated with other symptoms. In this report we evaluated respiratory and other clinical outcomes during food challenge in children.136 children with the positive food challenge that were on follow up in Cukurova University, Pediatric Allergy and Immunology Division were enrolled to the study. Clinical history, physical examination, skin prick test and food specific IgE levels and clinical outcomes during food challenge were evaluated in all children.. Open food challenge was performed in children younger than 2 years or in older children who refused the food because of different tastes.There were 56 girls (41.1%) and 80 boy (48.9%) with the mean age of 38.9\u00b123.9 months. Cow's milk was the most common allergen in all ages (57.3%) and followed by egg white (30.8%), wheat (17.64%) and peanut (5.1%). Skin reactions  were the major symptoms occurred during food challenge and identified in 96 cases (56.5%). As the second most common symptoms, upper and/or lower respiratory tract symptoms were observed in 62 patients (53.4%) and 12 patients (9.2%) showed gastro intestinal symptoms . Of the positive allergen provocation, 78(57.35%) were immediate type reaction and 20(14.7%) late-onset reaction. 38 patients (27.95%) had combined reactions. 22 patients with respiratory symptoms developed inhalant allergen hypersensitivity (35.48%).In this study we found food induced respiratory symptoms more frequently compared to the previous studies. These patients should be followed up for the development inhalant allergen hypersensitivity."}
+{"text": "There is paucity of data regarding disease patterns and outcome in children with juvenile dermatomyositis from the Indian subcontinent.Retrospective assessment of disease characteristics, complications/ associations, treatment modalities used and outcome in an inceptional cohort of 20 children with juvenile dermatomyositis at a tertiary care centre in western India.Chart review of 20 patients with juvenile dermatomyositis receiving treatment at a tertiary hospital in Mumbai from 1997 to 2010.20 patients  were diagnosed as having definite or probable juvenile dermatomyositis based on the Bohan and Peter criteria.. The mean age at diagnosis was 7.02 years(range 3 to 15.25 years) and the mean duration of disease prior to diagnosis was 7.5 months (range 3 weeks-2 years).The most frequent symptoms at presentation were typical skin rash(100%), proximal muscle weakness(20/20-100%), fatigue(16/20-80%), fever(13/20-65%) and arthralgia(11/20-55%).Dysphagia was seen in 5/20(25%), cutaneous ulcers in 4/20(20%), calcinosis in 3/20(15%), lipodystrophy in 2/20 (10%) and pyogenic infections in 2/20 (10%). Hirsutism was seen in 3/20(15%) and vitiligo in 1/20(5%). One of the patients had associated insulin dependent diabetes mellitus and chronic hepatitis. None of the patients in the cohort presented with or developed cardiomyopathy. All patients presented with at least one of the four serum muscle enzyme levels elevated. Interestingly, a normal range of creatine kinase (CK.) was seen in 11/20 (55%) of the patients. Electromyography was done in 4 patients and muscle biopsy done to confirm the diagnosis in one patient. Magnetic resonance imaging of the thigh muscles was used to as an aid to diagnosis in 10/20 patients and was abnormal in allPulse steroids were used to induce remission in 10 patients and as a rescue for relapses in one patient. IVIG was used as rescue therapy in 2 children with good results. All patients received oral steroids and methotrexate as the standard maintanence treatment. Hydroxychloroquine was added in patients with dominant cutaneous manifestations. 4 children with inadequate response, ulcerative disease or hepatotoxicity received Azathioprine (4/4), cyclosporine (1/4), cyclophosphamide(1/4) as additional therapy. One child with extensive calcinosis is being treated with monthly IVIG, diltiazem and colchicine. The total follow-up period was 62.24 patient-years (range- 0.58 to 12.17 years). A monocyclic course was seen in 15/20(75%), relapsing course in 3/20 (15%) and a chronic progressive course in 2/20(10%).No mortality has been reported till date.There was a considerable delay at the primary care level for the diagnosis of juvenile dermatomyositis. A normal CPK, probably linked to this delay, often led the primary care pediatricians away from the diagnosis. Calcinosis, decreasingly reported in Western series is still seen here and may probably be linked to this delay.MRI has proven to be a useful tool in the diagnosis and has largely eliminated the need for a muscle biopsy.Notwithstanding the delay in diagnosis, absent mortality, absence of cardio-pulmonary complications and a monocyclic course in 75% of our patients are at variance from several series from the West, which report severe disease."}
+{"text": "Limited evidence exists regarding the efficacy of inhaled antibiotics in ventilator-associated tracheobronchitis (VAT) ,2. The a5 colony-forming units (CFU)/ml. Susceptibility to colistin was determined using the Vitek technique . Selected patients received inhaled colistin at a dose of 1 million units every 8 hours for 7 days via a vibrating-mesh nebulizer . Assessed clinical outcomes were cure, defined as resolution of signs and symptoms at day 5, and development of ventilator-associated pneumonia (VAP) at day 10 after initiation of treatment. Microbiological outcomes were defined as eradication and decline termed as isolation of \u2264102 CFU/ml and were assessed by ETA quantitative cultures received at days 3 and 5 after initiation of treatment.Patients were eligible for the study if they had clinical symptoms suggestive of VAT , an absence of an evolving infiltrate on chest X-ray, and microbiological confirmation of VAT with quantitative cultures of endotracheal aspirates (ETAs) with a diagnostic threshold for VAT \u226510Pseudomonas aeruginosa (8/12 patients), Acinetobacter baumannii (5/12 patients), and Klebsiella pneumoniae (1/12 patients). Cure was achieved in nine out of 12 patients. In the three patients with clinical failure, intravenous colistin was administered. Two of them were subsequently cured and one patient developed VAP. Microbiological eradication was achieved in five out of 12 patients while decline was achieved in three out of 12 patients.Our study included 12 patients (eight men and four women) with mean age 58.7 years. The mean values of APACHE II and SOFA scores were 15.5 and 6.8, respectively. Two patients had polymicrobial Gram-negative VAT. Isolated pathogens from ETAs were: According to our limited data, monotherapy with nebulized colistin might be effective in the treatment of patients with VAT. Further investigation is warranted to evaluate whether nebulized antibiotics could effectively treat VAT and reduce the need for systemic antibiotics."}
+{"text": "P = 0.76). Comparing primary and recurrent disease, there was no difference in nodal distribution or frequency for levels I, II, III, and V. Level-IV was more common in the recurrent cases (P = 0.05). Based on the pathologic distribution of nodes, dissection should routinely include levels II\u2013IV and extend to level-V in primary and recurrent cases. Our data does not suggest routine dissection of level-I.The incidence of thyroid cancer is rising in the United States with papillary thyroid cancer (PTC) being the most common type. We performed a retrospective study of 49 patients with PTC who underwent 57 lateral neck dissections (NDs). The extent of NDs varied, but 29 of 57 (51%) consisted of levels II\u2013V. Twelve of 57 (21%) NDs consisted of levels I\u2013V. Twelve of 57 (21%) NDs consisted of levels II\u2013IV. One of 57 (1.8%) necks involved only levels I\u2013IV. One of 57(1.8%) necks involved only levels I\u2013V. One of 57(1.8%) necks involved only levels III\u2013V. Two (3.5%) double-level (III\u2013IV) neck surgeries were also performed. Metastatic PTC adenopathy was confirmed pathologically in 2%-level-I, 45%-level-II, 57%-level-III, 60%-level-IV, and 22%-level-V necks. Level-V was positive in 21% of primary and 24% of recurrent groups ( The incidence of thyroid cancer is rapidly rising in the United States at a rate of 4% per year for the past twenty years . In 2010Papillary thyroid cancer (PTC) is the most common type of thyroid cancer. However, despite its indolent course, it accounts for more than 50% of deaths from thyroid cancer , 4. In 1Previous studies have reported on the patterns of cervical lymph node metastases and have made recommendations regarding the neck treatment \u201311. The The impact of neck dissection on overall survival is unclear , 10, 13.There are many unanswered questions when it comes to the management of lateral neck metastases in PTC. While radical neck dissection is rarely performed for this disease, what extent of neck dissection is appropriate? Which neck levels should be included in these neck dissections? What are the patterns of lateral lymph node metastases in primary versus recurrent cases of PTC? The objective of this retrospective study is to present our data in order to better understand the patterns of lateral lymph node metastases in patients with primary and recurrent PTC and to evaluate outcomes in these patients.We reviewed the medical records of a series of patients who underwent lateral neck dissection (LND) for PTC at Georgetown University Hospital (GUH), Washington, DC, Department of Otolaryngology-Head and Neck Surgery between 1995 and 2009. Institutional review board approval was obtained for this study. All of the patients had pathologic diagnosis of PTC. Data regarding demographics, prior history of thyroid cancer, prior treatments , extent of lymphadenectomy, and total number of nodes removed were collected. Patients who had not received any prior thyroid treatment (surgery with or without radioactive iodine) were categorized as the primary group, and patients who had received prior treatment (thyroidectomy with or without radioactive iodine) for PTC were categorized as the recurrent group. The pathology reports were analyzed to determine the incidence of metastatic disease at each level of the neck. We also gathered information on postsurgical and postradioactive iodine serum thyroglobulin levels, neck control, followup, and current disease status. Neck control was defined as the absence of clinical, pathologic, and imaging evidence of recurrence. Where data allowed, outcomes were also assessed relative to thyroglobulin levels before and after neck dissection.Patients underwent LND either during the initial thyroidectomy or at a later date when recurrent disease in the lateral neck was noted. In all cases, lateral lymphadenopathy was detected based on preoperative radiographic or clinical examination. In the case of recurrent disease, none of the patients underwent LND for serum thyroglobulin (Tg) elevation only. All of the patients had confirmed pathologic involvement at neck dissection. Neck levels were considered positive for disease if they had at least one pathologically metastatic node. P value of <0.05 was considered significant.Analyses were performed comparing the proportion of neck levels documented to contain positive disease. Chi-square and Fisher's exact tests were performed in order to compare nodal positivity in the different neck levels between the primary and recurrent groups. A Forty-nine patients were identified: 27 (55%) women and 22 (45%) men. The mean age in this study was 41 (14\u201369) years. Four (8%) had a family history of differentiated thyroid cancer. Twenty-five patients were treated for primary disease, and 28 patients were treated for recurrent disease. Twenty-three of the 28 (82%) patients in the recurrent group were previously treated for PTC at outside institutions prior to presenting to GUH. The other five patients were treated for both primary and recurrent disease at GUH. All of the patients in the recurrent group had undergone surgical treatment, and 26 (93%) had also received radioactive iodine treatment . The cumA total of 57 neck dissections were performed on 49 patients. Four (8.2%) patients underwent simultaneous bilateral neck dissections. The extent of neck dissections varied, but 29 of 57 (51%) consisted of levels II\u2013V. Twelve of 57 (21%) neck dissections consisted of levels I\u2013V. Twelve of 57 (21%) neck dissections consisted of levels II\u2013IV. One of 57 (1.8%) necks involved only levels I\u2013IV. One of 57 (1.8%) necks involved only levels I\u2013V. One of 57 (1.8%) necks involved only levels III\u2013V. Two (3.5%) double-level (III-IV) neck surgeries were also performed. One of these was performed on the contralateral neck in a GUH patient undergoing bilateral neck dissections. One of these was performed on a patient who was previously treated at an OSH with total thyroidectomy only. Overall, neck dissections included the following levels: 14 of 57 (25%) included level I, 55 of 57 (96%) included level II, 57 of 57 (100%) included level III, 57 of 57 (100%) included level IV, and 43 of 57 (75%) included level V. P = 0.05). Level V involvement was equivalent in the recurrent (24%) and in the primary (21%) cases (P = 0.76).An average of 31 (4 to 94) lymph nodes were removed with each neck dissection specimen. An average of 7 lymph nodes were positive with each neck specimen with a range of 1 to 94 nodes. Among all of the patients treated, metastatic PTC adenopathy was confirmed pathologically in 2% of level I, 45% of level II, 57% of level III, 60% of level IV, and 22% of level V neck levels. When comparing primary and recurrent cases , levels Central neck dissections (CNDs) were performed in 21 of 25 patients in the primary group. An average of 8 (0 to 29) lymph nodes were removed with each neck specimen. An average of 5 (0 to 25) lymph nodes were positive with each neck specimen. Among all of the necks treated in this group, metastatic PTC adenopathy to the medial compartment was confirmed pathologically in 19 of 21 (90%) necks. Two of 21 (9.5%) patients in this group had pathologically positive lateral neck nodes, but did not have positive level VI nodes. One of these patients had positive lateral neck nodes in levels II and III, and one patient had positive lateral neck nodes in levels II\u2013V.CNDs were performed in 5 of 28 patients in the recurrent group. All of these were performed in patients who had their primary treatment at an outside institution prior to presenting to GUH. CNDs were not performed as a part of their primary treatment. An average of 5 (0 to 18) lymph nodes were removed with each neck specimen. An average of 2 (0 to 8) lymph nodes were positive with each neck specimen. Metastatic PTC adenopathy to the medial compartment was confirmed pathologically in 3 of 5 (60%) necks.Twenty-four of 25 (96%) patients in the primary group received radioactive iodine (I-131). The cumulative dose of I-131 following neck dissection ranged from 102\u2009mCi to 650\u2009mCi. Twelve of 28 (43%) patients in the recurrent group received I-131 following neck dissection. The cumulative dose of I-131 following neck dissection in this group ranged from 150\u2009mCi to 507\u2009mCi.Follow-up information was available on 43 of 49 (88%) patients. At a median of 34 (1\u2013111) months, the follow-up status was as follows: 38 of 43 patients (88%) alive without evidence of clinical disease, 4 of 43 patients (9%) alive with clinical disease, and 1 patient (2%) deceased from metastatic thyroid cancer. Of the 4 patients who are alive with disease at last followup, 1 will be treated with external beam radiation therapy for a solitary neck recurrence, one has recurrence in the neck and mediastinum, and 2 patients have distant metastases. Follow-up information was available in 51 of 57 (89%) necks. Pathologic control of disease in the operated neck was seen in 48 of 51 (94%) necks at a median followup of 34 (1\u2013111) months. Three (6%) patients had ipsilateral neck recurrences. Of these, 1 patient recurred in a previously unoperated level I. One patient recurred in a previously operated level III, and another patient recurred in a previously operated level IV. Overall, there were only 2 (3.9%) recurrences within previously operated neck levels.Following neck dissection and radioactive iodine adminstration serum thyroglobulin levels with thyroid stimulating hormone (TSH) suppression and stimulation were analyzed. In the TSH suppression data, 4 of 49 (8.2%) patients had positive thyroglobulin antibodies and were eliminated. TSH-suppressed thyroglobulin information was available in 42 of 45 (93%) patients. Thyroglobulin level was <1.0\u2009ng/mL in 27 of 42 (64%) patients at a median followup of 14 (1\u201376) months. In the rhTSH stimulation data, 4 of 49 (8.2%) patients had positive thyroglobulin antibodies and were eliminated. TSH-stimulated thyroglobulin information was available in 32 of 45 (71%) patients. Stimulated thyroglobulin level was <1.0\u2009ng/mL in 15 of 32 (47%) patients at a median followup of 15 months (1.5\u2013120). We also analyzed the number of cases with undetectable thyroglobulin levels. Undetectable thyroglobulin level was designated as the lowest range reported by the laboratory (either <0.5\u2009ng/mL or <0.2\u2009ng/mL depending upon the laboratory). In the primary group, undetectable thyroglobulin levels were present in 9/16 (56%) under TSH suppression and in 6/14 (43%) patients with rhTSH stimulation. In the recurrent group, undetectable thyroglobulin levels were present in 15/26 (58%) of patients under TSH suppression and 5/18 (27%) with rhTSH stimulation.In the present series, LND was performed to address suspicious lymphadenopathy that was evident on clinical examination, imaging, or intraoperatively. We found no differences in nodal distribution between primary and recurrent cases. Clinical control in the operated neck is excellent in both primary and recurrent cases. The majority of primary patients and a substantial minority of patients with recurrence in the neck demonstrated undetectable stimulated Tg levels in followup. Sivanandan and Soo  describeWhen comparing primary and recurrent groups, there were no significant differences in the rate of positive disease in levels II-III. Level IV was more common in recurrent cases, which was significant. Despite this, due to the high rates of nodal positivity , we woulOverall, level I involvement (2%) was rare; this is comparable to other studies , 14. LevIt is important to determine whether level V lymphadenectomy is necessary in PTC because this portion of the procedure can be associated with postoperative morbidity related to the spinal accessory nerve (SAN). Among the necks treated, metastatic adenopathy was confirmed pathologically in 22% of level V. This is similar to the 21% and 29% incidences described by others, but is lower than the 40% incidence reported by Kupferman et al. , SivananFarrag et al.  divide lWe agree with the ATA recommendations to perform CND in patients with PTC who have clinically involved central neck lymphadenopathy. In patients with clinically uninvolved central neck lymphadenopathy, we also agree with the ATA guidelines to perform elective CND for advanced primary tumors (T3 or T4) . TherefoPathologic neck control in our study was excellent (94%). Only two patients developed recurrences in a previously operated neck level resulting in a 96% neck control within previously operated neck levels. TSH-stimulated undetectable Tg levels were identified in 43% and 27% of our primary and recurrent patients after median followup of 16 (2\u201388) and 14 (1\u201398) months, respectively. In a study of recurrent lateral neck disease by Al-Saif et al. [We recognize that our study is limited by insufficient follow up data on some of our patients. However, we believe that our study gives important insight into the management of lateral lymph node metastases in patients with primary and recurrent PTC. Neck dissection in these cases should include levels II\u2013IV. Level I dissection is not necessary in primary or recurrent cases unless exam or imaging indicates involvement. Our data suggests performing dissection of level V in both primary and recurrent cases. The extent of level V dissection required remains an area for further study."}
+{"text": "Recently, biventricular (ABVC) and left dominant arrhythmogenic cardiomyopathy (LDAC) had been included in the spectrum of arrhythmogenic cardiomyopathy (AC).The aim of the study was to describe using cardiac magnetic resonance, the patterns of ventricular involvement as well as of late gadolinium enhancement (LGE).Medical records and databases from 3 hospitals were reviewed (2006-2010) in order to obtain data of patients with AC. Diagnosis of classic ARVC and BVAC was based on Task Force criteria (TFC). LDAC was diagnosed if LGE was present along with a positive family history. Now all our LDAC patients had genetic diagnosis and meet current TFC.26 consecutive patients were included . Diagnoses were: LDAC in 8 patients (30%),All of them had desmoplakin disease and 3 combined desmoplakin and desmocolin disease. BVAC in 9 (35%) and ARVC in 9 (35%). Right ventricular involvement was present in 19 patients (73%). Among them, 13 patients (50%) had ventricular volumes above the upper limit of normality and 6 (23%) had mild involvement with wall motion abnormalities and microaneurysms. Also, 11 patients (42%) showed LGE in the right ventricle and 25 patients (96%) in the left ventricle. LGE was more frequent in the inferior and inferolateral walls  while the septum was seldom affected . Usually, LGE was subepicardial , but transmural  and intramyocardial  LGE were also observed. Left ventricle systolic dysfunction (LVEF<55%) was observed in 15 patients, ,2 patients (7%) with LVEF< 40% and left ventricular dilatation (LVEDVi>98ml/m2) in 3 patients, (11%)1.LV involvement is a frequent finding in AC 2. The most frequent abnormality is LGE in the left ventricle and the least, left ventricular dilatation 3.LGE was more frequently subepicardial and located in the inferior and inferolateral walls."}
+{"text": "The prevalence of asthma in children has increased in the last decades. One of the risk factors is sensitization to aeroallergens and food allergens, which contribute to severity of asthma and the problematic asthma that are not responding well to therapy. Children with food allergy noticed to have increased bronchial hyperreactivity (BHR) independent of respiratory symptoms.Asthma is an uncommon manifestation of food allergy which is usually seen with other food-induced symptoms. Vapors or steam emitted from cooking food may induce asthmatic reactions.Food-induced asthmatic symptoms should be suspected in patients with refractory asthma, history of atopic dermatitis, gastroesophageal reflux, food allergy or feeding problems as an infant, or history of positive skin tests or reactions to food.This studyincluded asthmatic children (n=659) attended pediatric asthma and allergy clinic at Khorfakkan hospital (1st Oct 2009 \u2013 1st Mar 2011). Skin prick test (SPT) was done for 103 children with evidence of frequent exacerbation of asthma symptoms or refractory asthma. No antihistamine was given for at least 2 weeks before SPT.The SPT includes a series of inhaler  and food (fresh fruits or vegetables) allergens.Out of 103 children, 63 (61.2%) are tested positive to at least one allergen. Forty-three (68.3%) are males. The highest rate of the positive tests are at the age group 5-12 years , followed by age group 2-5 years . This trend is the same between both sexes. Nineteen children are positive to 3 allergens (30.2%), 15 to 2 allergens (23.8%) and 11 to 1 allergen (17.5%). The commonest indoor aeroallergens are house dust mites  dog (11.5%), and cockroaches (10.9%). The commonest food allergens found are horse chestnut (20%), sesame (14%) and cow's milk (12%). Collectively, the indoor aeroallergens are twice positive as food allergens.Aeroallergens and food allergy are important causes of asthma exacerbations in children. This should always be considered in refractory asthma or asthma with frequent exacerbations.None declared."}
+{"text": "Shrimp is a common food allergen and may cause serious reactions.A review of the clinical files of patients who were referred due to suspected shrimp allergy.A retrospective analysis of the clinical charts of 30 patients who were referred to our department between January 2009 and June 2010 due to suspected shrimp allergy. The study included skin prick tests (SPT) to common inhalant allergens and shrimp; skin prick-prick testes (SPPT) with shrimp, total and specific IgE (sIgE) and open food challenge tests (OFC).The average age was 34.9\u00b110.3 years (24-63), 24 (80%) were female. The most common clinical symptoms were cutaneous in 57% and only 2 (7%) had a history of anaphylaxis and 1 presented unspecific symptoms. Twenty-four patients underwent SPT with shrimp and 8 (33%) of them were positive including the 2 with anaphylaxis. Twenty-three patients underwent SPPT and 6 (26%) were positive including the 2 with anaphylaxis. Only these 2 patients had both positive SPT and SPPT. Fifteeen (73%) (out of 22 patients with IgE) had elevated total IgE. Specific IgE was increased in 14 (48%) with values ranging between 0.37 and 91.7KU/L. The 6 patients with positive SPPT also had elevated sIgE. Of the 26 (87%) who performed SPT, 22 (85%) were house dust mite (HDM) positive, including the 7 (87.5%) patients with positive shrimp SPT. Nineteen patients underwent OFC: 14 (74%) were negative, 3 (16%) were positive and 2 (10%) unconclusive. The 3 patients with positive OFC had negative SPPT. The 2 patients with a history of serious anaphylaxis did not undergo OFC. The cumulative doses varied between 31.1and 128.9g. The doses of the positive OFC were between 52.0 and 64.8 g. With respect to comorbid conditions, 10 (33%) had asthma and/or rhinitis; 70% were allergic to HDM and 30% were allergic to both HDM and pollens. Two of the 3 patients with positive OFC as well as the 2 with serious anaphylaxis had a history of allergic asthma and/or rhinitis.The OFC were fundamental for the clarification of the suspected shrimp allergy; only 3 were positive. This reinforces that food challenges are necessary for a correct diagnosis. All the patients with a positive OFC had negative shrimp SPPT and only one had a positive shrimp SPT. The value of total and sIgE did not appear to have any relation to the outcome of the OFC.None declared."}
+{"text": "Obese patients are at risk of developing atelectasis and acute respiratory distress syndrome (ARDS) . The pro2) in PP with ARDS (PaO2/FiO2 ratio \u2264200 mmHg) were matched to nonobese (BMI <30 kg/m2) ARDS patients in a case-control clinical study. The primary endpoints were safety and complications of PP; the second endpoints were the effect on oxygenation (PaO2/FiO2 ratio at the end of PP), length of mechanical ventilation and ICU stay, nosocomial infections and mortality.Morbidly obese patients (body mass index (BMI) \u226535 kg/mP = 0.28). We collected 51 complications, of which 25 in obese patients and 26 in nonobese patients. The number of patients with at least one complication was similar across groups . The PaO2/FiO2 ratio . Length of mechanical ventilation, ICU stay and nosocomial infections did not differ significantly, but mortality at 90 days was significantly lower in obese patients .Between January 2005 and December 2009, 149 patients were admitted for ARDS. Thirty-three obese patients were matched with 33 nonobese patients. Median PP duration was 9 (6 to 11) hours in obese patients and 8 (7 to 12) hours in nonobese patients (PP seems safe in obese patients and may improve oxygenation more than in nonobese patients. Obese patients could be a subgroup of ARDS patients who may benefit most from PP."}
+{"text": "Eastern province of Saudi Arabia is an industrial zone with large immigrant population and high level of tuberculosis case notification among immigrants. The impact of immigration and current trends of tuberculosis transmission among immigrants and autochthonous population in the region had not been investigated so far using molecular tools.Mycobacterium tuberculosis isolates were collected from the central tuberculosis reference laboratory, representing an estimated 79.2% of the culture-positive tuberculosis cases over the study period in the province. These isolates were genotyped by using 24 locus-based MIRU-VNTR typing and spoligotyping followed by first line drug susceptibility testing. The molecular clustering profiles and phylogenetic diversity of isolates were determined and compared to the geographical origins of the patients.During 2009- 2011, a total of 524 p value-0.043, 16-45, p value 0.030), Saudi nationality  and South East Asian origin  were identified as significant predisposing factors for molecular strain clustering.Genotyping showed an overall predominance of Delhi/CAS (29.4%), EAI (23.8%) and Ghana (13.3%) lineages, with slightly higher proportions of Delhi/CAS among autochthonous population (33.3 %) and EAI (30.9%) among immigrants. Rate of any drug resistance was 20.2% with 2.5% of multi-drug resistance. Strain cluster analysis indicated 42 clusters comprising 210 isolates, resulting in a calculated recent transmission index of 32.1%. Overall shared cluster ratio was 78.6% while 75.8% were shared between autochthonous population and immigrant population with a predominance of immigrants from South east Asia (40.7%). In contrast, cross national transmission within the immigrant population was limited (24.2%). Younger age (15-30- The high proportion of molecular clusters shared among the autochthonous and immigrant populations suggests a high permeability of tuberculosis transmission between both populations in the province. These results prompt for the need to strengthen the current tuberculosis control strategies and surveillance programs. Mycobacterium tuberculosis and clinical manifestations of the disease . First line drug susceptibility testing was conducted by using the BACTEC MGIT SIRE kit . The spoligotyping was carried out by using the commercially available membranes   according to the manufacturer\u2019s instructions. All the isolates were subjected to identification as , India] . Standar, India] . The MIRRTIn\u22121=(nc\u2212c)/n. Where nc is the total number of clustered cases, c is the number of clusters and n is the total number of cases in the study. Cross-national transmission was defined as the occurrence of a cluster comprising patients of at least two different nationalities. Isolates displaying double alleles in two or more VNTR loci suggestive of mixed genotypes, which could reflect either mixed infection or contamination, were excluded from analysis. For the analysis of the correlation of drug resistance vs lineage, we chose to regroup sub-lineages defined based on MIRU-VNTR and spoligo data into (larger) lineages as defined by Large Sequence Polymorphism (LSP) based classification of Gagneux et al [p value <0.05 was considered as statistically significant. The drug susceptibility results were classified as sensitive (no resistance), mono (resistance to a single drug), poly  and multi drug resistant tuberculosis (MDRTB) (resistance to both rifampicin and isoniazid). The spoligotyping results were converted into octal codes. Mycobacterial genetic lineages were identified using MIRU-VNTR and spoligotyping data and the online tools available on MIRU-VNTR Plus and SITVIT web sites (www.miru-vntrplus.org & http://www.pasteur-guadeloupe.fr:8081/SITVIT_ONLINE/index.jsp) according to the previously described strategy, combining best-match and phylogenetic tree-based analysis ,21. Moleux et al  in orderMycobacterium bovis by the line probe assay and further identified as BCG vaccine strains by the MIRU typing. During the study period a total of 532 non-repetitive culture isolates were enrolled. This strain collection represented an estimated 79.2 % of the culture-positive tuberculosis cases over the study period in the province, thus virtually reaching the 80% threshold classically considered for defining a population-based study. Among the 532 isolates, 8 isolates were removed from the analysis as they were identified as Of the total enrolled cases, 40.1% were autochthonous and 59.9% were immigrant patients. The immigrant population consisted of individuals from 21 different countries, of which the most represented ones were India (12.9%), Pakistan (10.6%), Indonesia (10.1%), Philippines (7.2%) and Bangladesh (5.3%). The sub grouping of the 59.9 % immigrant cases according to the geographical origin was as follows: SAS (35.3%), SEA (18.3%), WA (3.2%) and AFR (3.1%) . Most patients were belonged to age groups of 15-30 (46.6%) and 31-45 (32.4%) years. However, patients aged <15 years and >60 years were mainly confined to the autochthonous population . A domination of male patients (70.3%) was observed with a male/female (M/F) ratio of 2.4. Interestingly, two study groups, SEA and AFR appeared as exceptions by showing larger proportion of female cases (M/F ratios-0.71 and 0.66 respectively), supposedly mirroring an overrepresentation of women among these specific immigrant groups. Of the total, 389 cases (74.2%) were pulmonary TB, while 135 (25.8%) were extra pulmonary TB cases. Pulmonary TB dominated among the immigrant study groups with more than 72%  of the reported cases whereas extra pulmonary cases were relatively more frequent (32.8%) among Saudi population . Genotyping identified a total of 13 lineages, dominated overall by Delhi/CAS (29.4%), EAI (23.8%), Ghana (13.3%) and Haarlem (8.6%) lineages . The isoThe overall frequency of drug resistance among the isolates was 20.2%, comprising 14.1%, 3.6% and 2.5% of mono, poly-drug resistance and MDRTB, respectively. The rate of drug resistance was slightly and not significantly higher among immigrants (21.9%) than Saudis (17.6%). Although drug resistance was seen among all the lineages, the isolates of the Euro-American super-lineage (50%) were more often resistant than those of the East African Indian (23.6%) and Indo-Oceanic (17.9%) lineages. Of the 13 MDRTB cases, 6 (46.1%) of them belonged to Euro-American lineages followed by 4 (30.8%) East Asian lineages and 3 (23.1%) Indo-Oceanic lineages .Molecular cluster analysis based on MIRU-VNTR allele types and spoligotypes identified 356 distinct genotypes including 42 in clusters comprising from 2 to 24 isolates each and a total of 210 isolates, while 312 types were unique. On the other hand spoligotyping alone obtained 63 types, of which 25 were found in clusters with a size of 2-54 isolates and 38 were orphans. The calculated recent transmission index (clustering rate) in the study was 32.1%. Nine lineages were found among the clustered isolates with high cluster rates, majorly LAM (53.8%), Ghana (48.6%), S (47.1%) and EAI (43.2%) . Figure A detailed cluster analysis over the different study groups was conducted. Analysis of strain clusters against the geographical origins of the patient showed that seventeen nationalities were represented among the total clustered isolates. Thirty-three clusters were shared between any of the study groups while 9 clusters were exclusively composed of patients belonging to a specific country. Such geographically homogenous clusters were prominently seen among the study group SAS (60%) followed by SA (20%) . The three clusters exclusively corresponding to autochthonous patients, comprised EAI, Haarlem and TUR lineages respectively, while the nine clusters solely composed of SAS patients included strains of the Delhi/CAS and EAI lineages. In addition, the largest cluster (21 cases) in the study which was exclusively composed of Philippines nationals consistently corresponded to an EAI2-Manilla genotype (SIT 19) .Interestingly, overall rate of clusters shared between the study groups was 78.6%. On the other hand 75.8% (25 of 33 shared clusters) were shared between autochthonous and immigrant population. The majority of the mixed clusters were found between SA and SEA (40.8%) patients, followed by SA and SAS (25.9%) patients . These mp value 0.004) and South East Asian origin  were significantly associated to be in a strain cluster  and 31-45  showed a significant association with strain clustering. Saudi nationality  in the study, resulting male/female (M/F) ratio of 2.4 was similar to another recent report . This maM. tuberculosis strain lineages between the migrant and the autochthonous populations [A recurrent theme in Western countries receiving migrants is usually distinct distribution of ulations ,26-29 anulations ,30-35 wiulations . In contp value 0.004) and SEA  geographic origins showed significant association with strain molecular clustering. The dominance of the study group SEA is coherent with the considerable population of workers from Indonesia and Philippines in the household who are in constant contact with the Saudi families. Supportively, among the 46 patient isolates in the 11 clusters of SA+SEA, 30 were from Saudi nationals and the remaining 16 were from SEA. Available information showed that 9 of these 16 immigrants were working either as house drivers or housemaids for some of the SA patients in same clusters. Although further occupational data of the enrolled subjects were not available for analysis, these data tend to indicate that transmission of TB in the households is a major factor favoring permeability of TB transmission between autochthonous populations and immigrant populations in the province. Along the same lines, a substantial proportion of the molecular clusters were shared among the immigrant and autochthonous populations. While the strain clustering was higher among the immigrants (45.2%) compared to the autochthonous population (32.4 %), 25 of the 42 clusters identified in total included both migrant and autochthonous patients. The current findings most likely reflect the higher daily social admixing between both patient groups compared to Western countries, and its impact on the tuberculosis epidemiology in Saudi Arabia. Consistently with this proposal, the study group SEA (40.8%) showed the highest number of shared clusters with the autochthonous population followed by SAS (25.9%). As a reflection, Saudi  added to the geographic distribution of TUR strains  is suggestive of local transmission among autochthonous patients of a clone of local origin. However, the low number of TUR isolates identified overall makes this conclusion uncertain. The other six clusters comprised immigrants of same country of origin (eg. a cluster of EAI included two patients from Sri Lanka and another cluster of Delhi/CAS comprised two Pakistani patients) . This fiAlong the same lines, the largest proportion (9 of 13) of clusters homogenously composed of patients from a same geographic region (i.e. different but neighboring countries) was interestingly seen in the study group SAS. This finding plausibly reflects the high number of non-skilled immigrant workers from countries like Pakistan, India, Nepal, Sri Lanka and Bangladesh who live in labor camps under crowded conditions and preferably sharing places with persons of same country of origin. Poor nutrition, lack of fresh air, stress and hardships may also favor reactivation of remote infection followed by transmission under such conditions. Added to that drug resistance might promote subsequent clinical manifestations also ,40. UnfoAnalysis of predisposing risk factors other than geographical origin (see above) for molecular strain clustering showed statistically significant association of age groups 15-30  and 31-45 . The prominent role of younger age group as a possible risk factor in the study is in line with the large number of reported TB cases among young aged individuals in the country . In addiThis study has certain limitations. Classical epidemiological contact investigation was not conducted in order to confirm TB transmission assumed from molecular clustering. Although population-based, the study may underestimate the recent transmission due to the short period of observation. Furthermore no screening experiments for extremely drug resistant isolates were carried out. M. tuberculosis isolates for investigation of clusters suggested by genotyping will reveal the real picture of transmission dynamics and the role of immigrants in the whole country. Nevertheless, we conclude that the socio-economical characteristics of the migrant group in our study population have a distinctive and detectable impact onto the molecular epidemiology and transmission of tuberculosis in the Eastern province of Saudi Arabia. The molecular evidence for cross-national transmission particularly between autochthonous and immigrant population gained from the present population-based study confirms and extends the observation obtained in our previous study, performed on a largely incomplete and only drug-resistant strain collection at a national level . This evFigure S1M. tuberculosis isolates based on MIRUVNTR alleles and spoligo signatures.Molecular clusters of  The UPGMA tree was built and clusters were identified based on isolates sharing identical MIRU-VNTR types and spoligotypes.(TIF)Click here for additional data file.Dataset S1MIRU-VNTR profiles of 524 enrolled cases. The table shows the MIRU- VNTR alleles data and identified lineages of the enrolled study isolates. (PDF)Click here for additional data file."}
+{"text": "Familial Mediterranean Fever (FMF) is the most common autoinflammatory disease characterized by recurrent self-limited attacks of fever accompanying with peritonitis, pleuritis or arthritis. The testing of MEFV gene expanded the frame of various clinical manifestations of FMF.The aim of this study is to determine systemic uncommon non-classical manifestations of FMF and reveal the possible association with autoimmune diseases.We examined 50 patients  with FMF. The mean age of patients was 34.7\u00b112.2. FMF was determined clinically and approved by testing of MEFV gene. To reveal systemic manifestations of FMF investigation of all organ-systems was carried out.Classical symptoms of FMF: abdominalgy, thoracalgy, arthralgy with recurrent fever and pleuritis, splenomegaly, hepatomegaly were seen in almost all patients. Monoarthritis was met in 36 (72%) and polyarthritis in 8(16%) patients. 40(80%) patients developed spondyloarthrtitis, in 11 cases (22%) unilateral sacroiliitis and in 29(58%) bilateral sacroiliitis was observed. All patients with sacroiliitis fulfilled the classification criteria of the European Spondyloarthropathy Study Group for the diagnosis of seronegative spondyloarthropathy. 10(25%) patients of 40 that having sacroiliitis developed significant limitation of lumbar motion, which was assessed by Schober\u2019s test (1-2 cm), had bilateral sacroiliits grade III-IV and fulfilled the modified New York criteria for ankylosing spondylitis. HLA B-27 was examined in 15 patients with symptoms of spondyloarthropathy. In 7 patients it was negative and in 8-positive. In19 (38%) from 50 patients coxarthrosis was revealed and 2 patients underwent total endoprothesis of hips. Skin involvement also was observed during the observation: 4(8%) of them developed erythema similar \u201cbutterfly\u201d rash, livedo reticularis and photosensitivity with high titer of circulating immune complexes, ANA and anti-dsDNA antibodies like systemic lupus erythematosus, 1 patient had hemorrhagic rash on legs with developing of hemorrhagic vasculitis. In 1 patient trophic ulcers, miscarriage were developed with high titer of anticardiolopin autoantibodies as in classic antiphospholipid syndrome. Scleroderma-like syndrome was developed in 1 patient with Raynaud\u2019s phenomenon and skin induration of wrists and face and pneumofibrosis. Also panniculitis (1 patient), aphthae (2 patients), angiorethinopathy(2 patients), mononeyropathy and polyneyropathy ( 2 patients respectively), pneumonitis (4 patients), xerophthalmia (1 patient) like Sjogren\u2019s syndrome were observed. The prevalent mutation of MEFV gene was M694V- in 38patients (79.1%), from which 8(16.7%) were homozygote and 14(29%) were heterozygote (M694V/N).FMF may have systemic manifestations of autoimmune diseases. It may be due to vascular involvement especially in accompaning amyloidosis cases. The peculiarity of ankylosing spondylitis-like syndrome in FMF is its independent existence from carrying HLA B-27 antigen.None declared."}
+{"text": "Drug Utilization Evaluation (DUE) studies facilitate assessing the appropriateness and rational use of medications.The goal of the present study was to evaluate Amphotericin B usage in neutropenic patients. A prospective DUE study was performed in Hematology-Oncology and Stem Cell Transplantation wards at Taleghani hospital for one-year. National comprehensive cancer network, clinical practice guidelines in oncology, American Hospital Formulary Service and other relevant medical practice and up-to dated articles were used to evaluate whether Amphotericin B is properly used according to the guidelines. All data collected by a pharmacist in daily review using information of physician and nursing records as well as laboratory findings. During the one-year study, 35 patients receiving amphotericin B were evaluated. 29 patients (82.9%) received amphotericin B due to neutropenia and fever and 6 patients had confirmed fungal infections. All of the injectable solutions of amphotericin B were appropriately prepared for intravenous infusion. In addition, for all patients, ordering (indication) of the study drug was in accordance with the guidelines. Twenty-five (71.4%) patients received an appropriate dose according to the guidelines. Duration of treatment was properly selected in 21 (60%) patients. Twenty-two (62.8%) patients developed hypokalemia as the most frequent adverse drug event. Although, preparation and indication of amphotericin B was in compliance with the current guidelines, dosage and duration of treatment were considered to be incoherent with the designed protocol used in this study. We conclude more attention should be paid to dosage and duration of treatment with amphotericin B in order to optimize its administration.  Candida and Aspergillus species. Antifungal medications are useful in eradicating fungal infections in subjects with hematologic malignancies precipitated as a consequence of prolonged immunosuppressive therapy especially in those with neutropenia  studies are still used to identify variability in drug use as well as to support interventions that will improve patient outcomes .Due to the frequency of renal toxicity and other side effects associated with amphotericin B , we condPatients and methodsThis prospective drug utilization study was carried out at Taleghani hospital affiliated to Shahid Beheshti Medical University, Tehran, Iran between 2008 and 2009 on 35 patients who were hospitalized in bone marrow transplantation (BMT), and oncology -hematology wards. A questionnaire was prepared based on American hospital formulary service (AHFS) and other reliable articles. This questionnaire included patients\u2019 demographic data such as age, sex, drug history, medical background, and laboratory tests before treatment\u2019s initiation. Blood urea nitrogen (BUN), creatinine, potassium level, magnesium level, and complete blood count (CBC) were the documented laboratory tests. The type of infection, patients\u2019 vital signs during infusion, any adverse drug reactions in the treatment course, and culture results were recorded in the prepared questionnaire. Also a predefined protocol based on national comprehensive cancer network (NCCN) criteria was utilized to assess the appropriateness of the neutropenic cancer patients\u2019 management  and 15 females (42.86%) with mean \u00b1 SD age of 41.88 \u00b1 12.58 years (range 19 to 65 years) were evaluated. Three (8.57%) patients were from the BMT ward. Six patients had proven fungal infections including 2 (5.71%) mucormycosis, 3 (8.57%) aspergillosis and 1(2.86%) candidasis. Distribution of patients based on their underlying disease was shown in Frequency of co-morbid conditions in included patients was shown in Test dose was administered in all of the patients while monitoring vital signs was performed only in 3 (8.75%) transplanted patients. With regard to the dosing, 25 (71.43%) patients received appropriate doses complying with the guidelines whereas dosing in 10 (28.57%) cases was inappropriate, of them 5 (14.28%) cases received higher doses and 5 (14.28%) patients were administered doses lower than the recommonded dose. The period of amphotericin administration was in accordance with the guidelines. Amphotericin B was administered at doses ranging from 0.5 mg/kg/day to 1.5 mg/kg/day with the median of 1.02 mg/kg/day. Total administered dose of this agent had a median (range) of 50 mg (20-40 mg). Treatment duration with amphotericin B was varied from 1 to 67 days with mean \u00b1 SD (19.4 \u00b1 14.4 days). Duration of amphotericin B treatment according to NCCN guidelines was appropriately scheduled for 21 (60%) patients. From 14 individuals with improper duration of treatment, 7 patients received amphotericin B longer than periods justified by guidelines.From 35 patients, 5 (14.28%) patients expired due to underlying blood disorder and 1(2.86%) patient died from aspergillosis. Deteriorating renal function (increase in serum creatinine and BUN) was observed in 9 (25.71%) patients. Five (55.55%) of them received amikacin and vancomaycin simultaneously with amphotericin. Vancomycin and amikacin were administered concomitantly in 29 (60.42%) and 6 (12.5%) patients, respectively. Documentation of culture results during therapy was performed in all transplanted patients but not in other neutropenic individuals. Fever resolved in 23 (65.7%) patients receiving amphotericin B as an empirical therapy. In patients whose fever was not resolved, 6 (17.14%) patients had received the drug for a shorter time-period due to the occurrence of adverse effects in 3 (8.57%) patients and early discharge before fever resolution in 3 other patients. Electrolytes imbalances and infusion related reactions were the most common adverse effects seen with amphotericin. The frequency of all detected adverse events was shown in et al.  and occurred when other nephrotoxic drugs administered concomitantly . As moniAlthough empiric antifungal therapy for management of neutropenic fever in patients unresponsive to antibiotics should be considered because of their susceptibility to invasive fungal infections, however decisions made on continuation of antifungal treatment should be judged based on the documented results of obtained cultures , 22. NevIn conclusion, our findings revealed that usage of amphotericin B in the Hematology-Oncology and Stem Cell Transplantation wards of the study hospital was not fully appropriate and according to the guidelines. As the management of febrile neutropenia in cancer patients is a crucial issue, health care providers\u2019 awareness of antifungal drugs administration in particular amphotericin B monitoring and dosing schedules seems to be essential. Attendance of a clinical pharmacist along with education of nursing staff and monitoring of parameters according to current guidelines and updated protocols can minimize adverse effects and improve treatment outcomes."}
+{"text": "Allergic Disorders are on the rise worldwide and especially in Indian urban set up. Bangalore is an urban city with rising population density and pollution. We evaluated the common symptoms of various allergic disorders in three selected outpatient clinics through a questionnaire survey, in children and adults who presented with symptoms to suggest allergy especially rhinitis and asthma.Internal consistency of the questionnaire was checked. Eighty three patients with symptoms to suggest allergy participated in the survey. We evaluated the common symptoms, duration, family history, perceived triggers and treatment sought through the questionnaire survey. A proportion of them (12%) had skin prick tests  to correlate between perceived and the actual triggers.Forty six patients (55.4%) were males and 44.6% (n=37) females. Common Symptoms in children \u2264 12 yrs , included runny nose (49%), sneezing, nasal obstruction (46.8%) and cough (72.3%). In adults, sneezing and cough predominated equally (63.8%) along with runny nose (50%). Allergic Rhinitis with Asthma was equally seen in adults (22%) and children (19%). 45.8% of our study patients had family history of allergic disorders. Symptoms lasted > 3 to 4 days in a week in the majority (65 %). Commonest perceived triggers included dust (77%), strong odours (24.1%), food items both in children and adults. Discrepancy in perceived and identified triggers by skin prick testing was evident in 2 (out of 10) subjects. 13% of the group was on alternative medicine  at the time of the study and 10 patients (12%) were using only reliever inhalers in spite of ongoing symptoms to suggest asthma.Coexistence of Allergic Rhinitis and Asthma was equally common in adults and children. Dust exposure was the commonest trigger and the differences in perceived and identified triggers should be tested in larger patient groups. As depicted in other studies, suboptimal control of allergic disorders was prevalent in our study patients as well."}
+{"text": "The aims of this study were to describe the epidemiological profile, circumstances of occurrence and post-exposure practices.We conducted a retrospective study on records of people who were victims of accidental exposure to blood (AES) treated in the Department of Infectious Diseases, in the University Hospital Teaching of Point G, Bamako-Mali over 8 years.We collected 40 AES with a male predominance (sex- ratio = 2). The median age was 32 years [19-54 years]. Our study population was composed of students (42.5%), physicians (22.5%), nurses (15%) and surface technicians (sanitizers) (7.5%). The AES had occurred mainly in hospitals (57.5%) and 20% in home care. The surgery department was more concerned (45%). The main circumstances of occurrence were the needle stick (42.5%); puncture by scalpel (22.5%); recapping (10%) and the projection on the mucosa (10%). The majority had done the washing with water / soap (92.5%) of which 25% immediately. Eight people were reported after 48 hours. HIV status of the source patient was known in 47.5% of which 25% were positive. A lady had a positive HIV serology after accidental blood exposure (seroconversion) At the time of AES, serology for hepatitis B and C were not known in the majority of patients and victims sources. Thirty have benefited from ARV prophylaxis.Difficulties encountered in the declaration and management of AES require training of health personnel of University Hospital Teaching of Point G.None declared"}
+{"text": "Infectious mononucleosis has polymorphous clinical aspects. In children, primary Epstein-Barr virus (EBV) infection is often mild or asymptomatic. In adults, the enlargement of lymph nodes, fever and angina may be associated with diverse complications.We studied the clinical and paraclinical features of 176 patients with infectious mononucleosis admitted in our hospital in the last 2 years (2011-2012). We emphasized the clinical aspects of the cases.The incidence of infectious mononucleosis was highest in the age group 15 to 24. The age of the patient has a profound influence on the clinical expression of EBV infection. The incidence of EBV infection is higher in urban environment, where the interhuman contact is closer, and also the addressability to health-care services is better and the laboratory diagnosis is more easily available to the population. The clinical forms of the disease have been grouped according to the severity of illness into the following: light forms \u2013 44 cases (25%), medium forms \u2013 122 cases (69%), and severe forms \u2013 10 cases (6%). A number of 64 cases, considered severe forms, presented mononucleosic hepatitis (36%), 112 cases (64%) were anicteric. 75 cases (42.6%) presented disorders of protein synthesis, factors of coagulation and albumin, hypoglycemia, and dyslipidemia.The most frequent complications during the acute EBV infection were: hepatic (64 cases \u2013 36%); hematologic (19 cases \u2013 11%) - anemia, thrombocytopenia; neurologic (5 cases \u2013 3%) - meningitis, neuritis; pulmonary (2 cases \u2013 1%) - interstitial pulmonary infiltrate, and chronic fatigue syndrome (7 cases \u2013 4%). The therapy consisted in drugs for sustaining the liver functions, corticotherapy accompanied by antibiotic-therapy in the 10 severe cases of central nervous system involvement (15%) and in 15 other cases with hematologic or other complications (20%). Altogether, the combination was utilized in 25 cases (47%), while the rest of 151 cases (65%) didn\u2019t receive corticotherapy.The evolution and prognosis of acute EBV infection is closely connected with the peculiar clinical forms and complications of the disease."}
+{"text": "Increased prevalence of vitamin D deficiency (VDD) in sepsis and its association with sepsis severity has been documented in adults -3. HowevA prospective observational study conducted between January and December 2012. During the study period all consecutive PICU admissions between the ages of 1 and 12 years were screened for sepsis at the time of admission to the ICU. Out of 613 PICU admissions, 124 patients satisfying the criteria for sepsis [P = 0.04). Median 25(OH)D level among patients was 19.7 ng/ml (interquartile range (IQR): 12.5, 31.2) and median 25(OH)D level among controls was 30.4 ng/ml . Prevalence of VDD was high among patients 51% , 42 to 59) compared with the VDD of 17%  in healthy controls (P < 0.001) (Table P = 0.58). Factors such as septic shock, multiorgan dysfunction syndrome (MODS), duration of mechanical ventilation, blood culture positivity, hypocalcemia and length of PICU stay were not modified by the presence of VDD (Table Patients with sepsis had low 25(OH)D levels compared with healthy controls (We found a high prevalence of VDD among children with sepsis when compared with healthy children but VDD was not associated with the severity of sepsis or its outcome."}
+{"text": "This study describes 5.5 years of retrospective data examining hospital and 6-month outcome of patients following decompressive craniectomy (DC). The effectiveness of DC remains uncertain with conflicting results in patients with TBI and stroke ,2.Data were drawn (1 January 2006 to 30 June 2011) from three hospital databases following approval by the institutional board.There were 2,148 neurosurgical admissions with 71 undergoing DC. Forty-eight of 71 (67.6%) survived to hospital discharge and 21/33 in both TBI and stroke groups survived to 6 months. See Table Survival following DC in this institution compares favourably with published data. Reduced survival in 2011 may be a case-mix effect related to increased tertiary referrals. We will now prospectively collect these data including quality-of-life measures."}
+{"text": "Backgroun and Objective: Resistance to multiple antimicrobials is the major cause of debility and death due to infectious diseases around the world. Our objective was to determine the frequency and antimicrobial susceptibility pattern of aerobic microbial isolates in a clinical laboratory.Methodology: All culture specimens of tissue, pus, urine, bone, blood, fluid, stool, sputum, and high vaginal swab received in the Microbiology Department of Clinical & Research Laboratory, Baqai Institute of Diabetology and Endocrinology from May 2010 to January 2011 were included in the present study. Bacterial isolates were identified and their antimicrobial susceptibility pattern was determined.Results: Out of 312 cultured specimens, 272 (87.17%) were found infected with 437 microbial organisms (412 bacteria and 25 Candida isolates). A total of 90 (20.59%) multi-drug resistant (MDR) isolates were found. MDR Escherichia coli was isolated in 40 (34.19%) out of 117 culture specimens which showed the growth of Escherichia coli, Pseudomonas aeruginosa in 17 (22.08%), Methicillin-resistant Staphylococcus aureus in 13 (11.50%), Klebsiella pneumoniae in 7 (22.58%), Proteus species in 6 (31.58%), Acinetobacter species in 3 (33.33%), Enterobacter species in 2 (28.57%), Coliform (Escherichia coli) in 1 (16.67%) and Enterococcus species were isolated in 1 (50%) culture specimen.Conclusions: High prevalence of multi-drug resistant bacteria was found in the present study. Emergence of antimicrobial resistance has become a major challenge in infectious disease medicine. Antimicrobial resistance may be due to misuse of antimicrobials by physicians and self medication in Pakistan. Further large scale studies are needed to validate our findings. The use of antimicrobial agents for prevention or treatment of infections in humans, animals and plants, in any dose and over any time period, cause a \u201cselective pressure\u201d on microbial populations.2 The emergence of resistance to antimicrobial in previously susceptible bacterial pathogens is a major challenge to infectious disease medicine.3Infectious diseases remain a major cause of debility and death around the world and are responsible for worsening of living conditions of millions of people.4 Antimicrobial resistance results in increased morbidity, mortality, and cost of health care. The rate of resistance varies in different studies.5 There was a high rate of nosocomial multi-drug resistant (MDR) organisms isolated from different specimen.6Antimicrobial resistance is a major public health concern in human medicine both in the community and in medical institutions.7 During the last decade, an increase in the rates of antimicrobial resistance has been recognized worldwide and an increased frequency of MDR isolates in the clinical setting has been demonstrated.8Bacterial infections continue to be an important cause of morbidity and mortality in developing countries.9Pseudomonas aeruginosa found in urinary tract infections showed 19% multi-drug resistant strains in a German study.10 In a study in China, an opportunistic pathogen, Acinetobacter baumannii showed 30% drug resistance rate.11 Out of 165 samples received at Lahore Medical and Dental College in Lahore-Pakistan, 89 were found infected.12 While in a study on blood cultures, out of 1824 blood cultures, 508 (27.9%) yielded microorganism growth.13 In another study, the frequency of MDR Pseudomonas aeruginosa among all the Pseudomonas aeruginosa strains isolated was found to be 22.7%.14 Indiscriminate use of broad spectrum antimicrobial in hospital and community contributes to the emergence of infection with multi resistant organisms.15 There is an increase in the prevalence of MRSA among S. aureus isolates.16Pseudomonas aeruginosa found an important cause of nosocomial and a multi drug resistant infections amongclinical isolates in local laboratory.17A study conducted in Ethiopia showed that 54.2% of eye swab cultures were positive for different bacterial pathogens.Clinical laboratories play a pivotal role in providing accurate information and guidance in the treatment of microbial infections. In view of the above findings a study was conducted to determine the frequency and antimicrobial susceptibility patterns of microbial isolates in a clinical laboratory.A descriptive study was conducted at the Microbiology Department of Clinical & Research Laboratory, Baqai Institute of Diabetology and Endocrinology (BIDE), a 24 hours laboratory service from May 2010 to January 2011. Laboratory records and data were used to study the pattern of multi-drug resistant microbial isolates.Inoculation of samples: Blood specimens received in blood culture bottles containing appropriate amount of blood in Tryptic Soy Broth were incubated for 24 hours or overnight at 35\u00b0C. After 24 hours these samples were sub cultured on blood agar, chocolate agar and MacConkey agar plates and incubated at 35\u00b0C overnight. Pus samples in syringe and swab were directly cultured on blood agar, chocolate agar, Sabouraud Dextrose agar and Mac-Conkey agar plates and incubated at 35\u00b0C overnight. Tissue and bone specimens received from foot clinic and Operation Theater in sterilized normal saline were crushed and then cultured on blood agar, chocolate agar and MacConkey agar plates and incubated at 35\u00b0C overnight. Identification of growth was based on colony morphology, gram staining and appropriate biochemical tests.13 Susceptibility to different antimicrobial, based on the type of growth was checked on Mueller Hinton agar by standard Kirby Bauer method.13Antimicrobial susceptibility test by disc diffusion method: The antimicrobial discs used for susceptibility testing were penicillin (10 \u03bcg), ampicillin (10 \u03bcg), amoxicillin (10 \u03bcg), clavulanic acid (30 \u03bcg), piperacillin/tazobactam (110 \u03bcg), oxacillin (1 \u03bcg), cephradine (30 \u03bcg), cefotaxime (30 \u03bcg), cefpirome (30 \u03bcg), cefuroxime (30 \u03bcg), vancomycin (30 \u03bcg), teicoplanin (30 \u03bcg), aztereonam (30 \u03bcg), imipenem (10 \u03bcg), meropenem (10 \u03bcg), amikacin (30 \u03bcg), gentamicin (10 \u03bcg), tobramycin (10 \u03bcg), erythromycin (15 \u03bcg), clarithromycin (15 \u03bcg), clindamycin (2 \u03bcg), nalidixic acid (30 \u03bcg), norfloxacin (10 \u03bcg), ofloxacin (5 \u03bcg), ciprofloxacin (5 \u03bcg), chloramphenicol (30 \u03bcg), sulphamethoxazole (25 \u03bcg), fosfomycin (50 \u03bcg), fusidic acid (10 \u03bcg) by OXOID shown in Multi-drug resistance: Multi-drug resistance was defined as organisms resistant to three or more drugs of the following class; Beta lactams , carbapenems , aminoglycosides  and fluoroquinolones (ciprofloxacin).18Statistical Analysis: Data analysis was done on Statistical Package for Social Sciences (SPSS), version 13.0. Data presented in the form of frequency and percentage.A total of 312 specimens of diabetic foot tissue, pus, urine, bone, blood, fluid, stool, sputum, and high vaginal swab were received in the laboratory. On culture of these specimens, 40 showed no growth, while 272 (87.17%) specimens were found to have microbial pathogens. A\u00a0total of 437 microbial organisms (412 bacteria and 25 Candida species) were isolated in 272 specimens.Escherichia coli was the most frequent species, which isolated from tissue specimens (46:46.46%) specimens, followed by Staphylococcus aureus in (42:42.42%), and Pseudomonas aeruginosa was found in (37:37.37%). Among 98 pus specimens, 90 (91.83%) showed growth on culture and 152 organisms were isolated. Staphylococcus aureus was cultured from 48 (48.98%) and Escherichia coli from 36 (36.73%) samples. In 55 urine specimens, Escherichia coli was the most frequent isolated species (21:38.18%). Pattern of microbial isolates in culture specimens are shown in Staphylococcus aureus was isolated in 16 (47.06%) specimens. Details are given in  All 34 bone culture specimens showed growth of microbial organisms, Escherichia coli was isolated in 117 specimens, out of which 40 (34.19%) were found to be multi-drug resistant. Similarly, 17 (22.08%) isolated Pseudomonas aeruginosa in 77 culture specimens were multi-drug resistant. Out of 113 isolated Staphylococcus aureus in culture specimens, 13 (11.50%) were found to be multi-drug resistant as shown in A total of 90 (20.59%) multi-drug resistant organisms were found among 437 microbial isolates. 19The present study shows local laboratory based data regarding the pattern of antibiotic susceptibility and MDR strains isolated from different clinical specimens. We found 87.17% of the cultured specimens infected with microbial pathogens, having a high prevalence of MDR strains (20.59%). There has been a major shift in the etiology of bacterial infections in the last decade. The more resistant pathogens have replaced the easily eradicable pathogens, thus leaving few options for choosing the right antimicrobial for treatment.20 In another study on fecal isolates, the frequency of MDR bacteria was markedly high (31.7%)21, while in a study on diabetic foot ulcer patients, 45% were found to be MDR.22 Similarly in another study, 77.3% of bacterial isolates in ocular infections were MDR to the commonly prescribed antimicrobial.9 However, in a local study 78% of gram negative bacteria were found to be MDR.23In a study conducted in urinary tract infection (UTI) patients, 90% of the gram negative isolates were found to be MDR.Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, Candida and Proteus species. Similar findings were observed in another study.18 The most frequent isolate in our study was Escherichia coli, which was isolated in 26.77% of the culture specimens, while in other studies it was isolated in 47.4%9, 41.7%24 and 32.39%25 of the cultures. In a study on combat-injured personnel during Operations Iraqi Freedom and Enduring Freedom 57% of the Escherichia coli were MDR26, while in our study 34.19% were found to be MDR. Our study findings are supported by other studies.24,25The most common isolates observed in our study were Staphylococcus aureus (MRSA) has become an enormous problem for health care providers, it is hard to treat and is sometimes called \u201csuper bug\u201d. The prevalence of Staphylococcus aureus isolation was 25.86% in our study while in another study it was 15.49%.27 In our study 11.50% of the total MRSA isolates were found while in other studies the frequency of MRSA were 23.9%28 and 22.9%.29Methicillin resistant Pseudomonas aeruginosa while in another local study it was found to be 22.7%14, similar to the findings of our study. In a study conducted in acute and chronic UTI patients, 19% multi-drug resistant Pseudomonas aeruginosa were isolated10 while in another study in intensive car (ICU) and non-intensive care unit (ICU) patients there were 3% MDR Pseudomonas aeruginosa in 2004 and 2% in 2005 and MDR Pseudomonas aeruginosa was more commonly found in non-intensive care unit (ICU) patients.30In this study we found 22.08% MDR strains of Klebsiella pneumoniae in our study was 22.58%, while in other study it was found to be 11.0%.21 Amongst the gram negative bacteria the most common organism was Klebsiella Species 24.1%.13Frequency of MDR Acinetobacter baumannii31, while 33.33% MDR Acinetobacter species were found in our study.In a New York Hospital study the majority, 70% of the isolates were multi-drug resistant in High prevalence of multi-drug resistant bacteria was found in the present study. Emergence of antimicrobial resistance has become a major challenge in infectious disease medicine. Self and improper medication is a very serious and common issue is Pakistan which play an important role in antimicrobial resistance. Along with self medication misuse of antimicrobials by physicians also makes the situation verse. Further large scale studies are needed to validate our findings."}
+{"text": "The present study aims to report the results and the prognostic and technical factors for hearing preservation during removal of vestibular schwannoma by a retrosigmoid approach.This was a retrospective study conducting on the 286 vestibular showannomas removal surgeries using retrosigmoid approach during October 2007 to 2011.Preoperative and postoperative clinical, audiometric, and imaging data were collected and analyzed. The mean follow-up period was 3 years. Intraoperative neuromonitoring interventions were done for all patients and the complete excision of tumor was established by post-operative magnetic resonance imaging (MRI).Functional hearing (less than 50 dB PTA and greater than50% speech discrimination) was preserved in 7 of 16 patients (43.7%) with grade II tumors, whereas only 11 of 72 patients (15.3%) with grade III tumors retained their functional hearing. Fifteen out of 16 patients (93.7%) with grade II tumors achieved a House-Brackmann (HB) grade I-III, while 63 of 72 patients (87%) with grade III tumors retained HB I-III facial function. Our result in grade IV tumors was excellence in facial nerve preservation (76%) but hearing preservation in the large tumors was only about 1%. Findings of the present study showed that hearing preservation depends on the tumor size and using monitoring and other modern instruments and technical skills preservation rate of it could be higher than before. Overall facial nerve preservation was excellent with greater than 90% achieving HB 1 to 3 function at final follow-up.Hearing preservation, Facial nerve, Retrosigmoid approach"}
+{"text": "Studies in adults suggest that early initiation of anti-retroviral therapy (ART), during treatment of those presenting with opportunistic infections, results in better outcomes than deferred treatment. However, data on the effects of early treatment of children are sparse. Kilifi district hospital (KDH) serves a population of over 250,000. It provides HIV services and ART. All children admitted to the paediatric wards at KDH are routinely tested for HIV.To ascertain the outcomes of early initiation of ART in children in a rural African setting around the time of an acute admission.We retrospectively reviewed inpatient and clinic records of all HIV antibody positive children admitted to the paediatric wards at KDH between May 2007- December 2008. The demographic surveillance system was used to ascertain outcomes.Over the 19-month period, there were 9,377 admissions to the paediatric wards. Of these 407 (5.6%) children had a positive HIV antibody test. 47 children met criteria for starting ART according to Kenyan national guidelines. 22 (47%) of these children started ART in the acute phase, and a further 13 (28%) started subsequently in clinic, but 12 (25%) were lost to follow-up before ART initiation. The median age was 2.9 years (IQR 1-3.9 years). The median CD4 percentage was 11% (IQR 7.6%-15.5%). There was a high rate of default from follow-up even after initiation of ART (40%). Most of the children who remained in care were still alive 19 (90.5%) and had attained nutritional recovery (87%) with a minority having adverse events (13%) 6 months after initiation of ART. Comparing acute versus deferred initiation groups, those started early were younger and had lower baseline CD4 percentages. There was no difference between the 2 groups in terms of incidence of adverse events or survival to 6 months after starting treatment.Our data suggests that commencing ART in children around the time of an acute admission even in children who are severely malnourished may be safe and result in nutritional recovery with good survival. However, due to the high number of defaulters, we were unable to draw definitive conclusions comparing early and deferred initiation. We recommend that defaulter tracing should be an integral part of all ART programmes, and randomised studies to compare timing of initiation in larger cohorts."}
+{"text": "The goal of the study was to classify protocol data recorded during magnetic resonance tomography (MRT) and computer tomography (CT) examinations of the brain in patients with neurological complications of eclampsia; to define the MRT/CT examination data structure; and to perform frequency analysis of main MRT/CT characteristics and estimate their frequency distributions defined by studied pathology. The data included in the study were reported in medical journals and met definite criteria for inclusion.We collected cases of neurological complications of eclampsia reported in English-language medical journals from 1980 to 2008. The study methods include structural and frequency analysis of brain MRT/CT image protocols.The analyzed sample included 77 cases of neurological complications of eclampsia. We extracted the following positions from the plain texts of MRT/CT descriptions: brain injury areas ; injury depth ; brain structures undergoing injury (classification was too complicated); injury nature . Abnormalities in occipital (84.6%) and parietal (70.7%) lobes were the most frequent, injuries in temporal lobes were quite rare (26.9%), but damage in frontal lobes was the most uncommon (24.4%). Combined injury in occipital and parietal lobes was recorded in more than two-thirds of cases (72.4%). Combined injury in occipital-frontal lobes (29.3%) and occipital-temporal (27.6%) lobes were observed in almost one-third of patients. Synchronous injury in the temporal and frontal lobes was the least common (6.9%). Simultaneous damage of three and more lobes was observed quite rarely (14.6%). Most abnormalities were bilateral with frequency not less than 78.0%. Unsymmetrical injury observed in some patients was located in the right lobe in most cases. All analyzed cases include only 7.1% of single left injury and all of them were located in the occipital lobe. Vasogenic edema occurred in 83.5% of cases, while ischemic damage was observed in 10.4%. The incidence of hemorrhage was 6.1%.The analysis reveals a general picture of the most distinctive features of brain damage following neurological complications of eclampsia."}
+{"text": "Infections, trauma, malignances and poorly controlled diabetes are common causes of chronic lower limb ulcerations in developing countries. Infected wound with multi-drug resistant bacteria usually are associated with increased morbidity and mortality. We report the distribution of bacteria pathogens colonizing the chronic lower limb ulcers and their drug susceptibility pattern from Bugando Medical Centre (BMC) a tertiary hospital in Tanzania.Staphylococcus aureus, 8(44.4%) were found to be methicillin resistant Staphylococcus aureus (MRSA).Three hundred non-repetitive wound swabs were aseptically collected from 300 patients with chronic lower limb ulcers using sterile swabs and processed following standard operative procedures. Isolates were identified using in house biochemical testing and in case of ambiguous confirmation was done using API 20NE and API 20E. Susceptibility was determined using disc diffusion test following clinical laboratory standard Institute guidelines (CLSI). Of 300 swabs from patients with chronic lower limbs ulcers, 201 (67.7%) had positive aerobic culture within 48\u00a0hours of incubation. Of 201 isolates, 180(89.6%) were gram-negative bacteria. Out of 180 gram negative bacteria, resistance was detected for ampicillin , amoxicillin/clavulanate , trimethoprim-sulphamethoxazole , ceftriaxone , ceftazidime , gentamicin , ciprofloxacin  and meropenem 28. A total of 41 (35%) of enterobacteriaceae were found to be extended spectrum beta-lactamases (ESBL) producers while of 18 There is high prevalence of ESBL and MRSA isolates in surgical wards at BMC. We recommend infection control and antibiotic stewardship programs in these wards to minimize spread of multi-resistant organisms. Staphylococcus aureus (MRSA)[Klebsiella pneumonia and 25 -45% of Escherichia coli isolated from HCAIs are reported to be ESBL producers[S. aureus has been reported to be the commonest cause of surgical site infections of which 18.8% are reported to be MRSA[In developing countries infections, trauma, malignances and poorly controlled diabetes are the most common causes of chronic lower limb ulcerations,2. An ins (MRSA)-8. In Taroducers-11. Also be MRSA.Clinical experience and outcome of patients regarding chronic lower limb ulcers in this centre has been described in previous publication. This arThe predominance of multi-drug resistant gram negative bacteria colonizing and infecting lower limbs necessitates the scaling up of infection control practices and the introduction of antibiotic stewardship in surgical wards in developing countries.A cross sectional study involving all patients with chronic lower limbs ulcers was conducted between November 2011 and February 2012 in surgical wards of Bugando Medical Centre (BMC), a 1000 bed capacity tertiary hospital in the northwestern part of Tanzania as previously described[A total of 300 non-repetitive wound swabs were collected from 300 patients with chronic lower limb ulcers using sterile swabs. All swabs were processed as previously described. BrieflySusceptibility testing was performed by Kirby-Bauer technique. The 0.5 McFarland of test organism was uniformly seeded over the Mueller-Hinton agar surface and incubated at 35\u00b0C for 24\u00a0hours. Interpretation was made as per CLSI. AntibioThe study was approved by Bugando Medical Centre/Catholic University of Health and Allied Sciences ethics committee and the informed consent were obtained from all patients.Staphylococcus aureus 18, Enterococcus spp 3). Bacteria species isolated were; Pseudomonas spp. 54 (26.9%), Proteus spp. 45 (22.4%), Klebsiella pneumoniae 33 (16.4%), E. coli 26 (12.9%), Staphylococcus aureus 18 (9%), Acinetobacter spp. 9 (4.5%), Serratia spp. 7 (3.5%), Enterobacter spp. 6 (3%) and Enterococcus spp 3 (1.5%).A total of 300 patients with CLLUs were included in the study. Traumatic ulcers were the most frequent type of ulcer accounting for 181 (60.3%) of patients followed by infective ulcers 43 (14.3%), metabolic ulcers 35 (11.7%), neoplastic/malignant ulcers 20 (6.7%), vascular ulcers 11 (3.7%), neuropathic ulcers 8 (2.7%) and ulcerating skin lesions e.g. pyogenic granulomatous 2 (0.7%). Out of 300, 201 (67%) had positive aerobic culture within 48\u00a0hours of incubation. Of 201 positive cultures 180(89.6%) were identified as gram negative bacteria and 21(15.9%) as gram positive bacteria , amoxicillin/clavulanate (60%), gentamicin (8.3%), trimethoprim-sulphamethoxazole (60%), clindamycin (20.7%), erythromycin (13.8%) and 8 (44.4%) were found to be MRSA.Of 180 gram negative bacteria, resistance was detected for ampicillin , amoxicillin/clavulanate , trimethoprim-sulphamethoxazole , ceftriaxone , ceftazidime , gentamicin , ciprofloxacin  and meropenem 28  Table\u00a0Pseudomonas aeruginosa was the most frequent gram negative bacteria isolated while Staphylococcus aureus was the commonest gram positive bacteria. Most of these isolates were multiply\u2013resistant to commonly used antibiotics. This is due to the fact that most of these patients were hospitalized for more than 72\u00a0hrs signifying health care associated infections[The microbiological profile of chronic ulcers of the lower limbs is very important in the provision of appropriate management of ulcers as well as institution-specific antibiotic policy in the surgical wards. As repofections.Klebsiella spp and E. coli colonizing CLLU were lower than those involved in surgical site infections. Also this study confirmed the previous observation[S. aureus were found to be MRSA respectively[Staphylococcus aureus were found to be MRSA.Compared to previous data in the surgical wards the ESBLervation,11 that ervation,21 carryervation, majoritectively,17 whileDespite the importance of these data some limitations were failure to perform; anaerobic culture, molecular characterization and PCR confirmation of ESBL and MRSA phenotype.High prevalence of ESBL and MRSA isolates were observed in surgical wards at BMC. We highly recommend Infection control and antibiotic stewardship programs in these wards to minimize spread of multi-resistant organisms. Coordinated surveillance of multi drug resistant isolates in Tanzania and other developing countries is highly needed so that this worldwide public health problem is controlled.The authors declare that they have no competing interests.MFM, NM, SEM participated in the design of the work, data analysis and interpretation of the results; FM, PC collected specimens; MFM, MM and SEM prepared the first draft of the manuscript; all authors read and approved the final manuscript."}
+{"text": "At our hospital, ventilator-associated pneumonia (VAP) is diagnosed by microbiological and cytological analysis of bronchoalveolar lavage fluid (BALF). Opening hours of the in-house microbiological laboratory are between 8:00 am and 5:00 pm. During off-hours a laboratory technician is on call for urgent samples including BALF. The total laboratory work-up of the BALF takes 2 hours. The aim of the present study was to detect patterns in the submission time of BALF samples.4 cfu/ml and/or presence of \u22652% infected cells.During a 60-month period (January 2006 to December 2010), the day and hour of submission of all consecutive BALF samples obtained from patients suspected of VAP were recorded. VAP was microbiologically confirmed if quantitative cultures were \u226510A total of 376 BALF samples were included. On weekdays, on average a total of 59.8 \u00b1 11.4 were submitted, compared to 34 and 43 samples on Saturdays and Sundays. For more than one-half  of the samples, the on-duty laboratory technician was required: 86 (23%) samples arrived within 1 hour before closing time, and an additional 117 (31%) were submitted thereafter. VAP was diagnosed in 149 (39.6%) samples, of which 79 (53%) after closing hours. BALF samples were obtained more frequently on Thursdays and Fridays (51 and 47 samples respectively) compared to Mondays and Tuesdays (64 and 76 samples). Interestingly, VAP was confirmed proportionally more frequently on Mondays and Tuesdays (26/51 (51%) and 23/47 (49%)) compared to Thursdays and Fridays (20/64 (31%) and 26/76 (34%)).The high number of BALFs processed after laboratory opening hours is of concern because of the suboptimal working conditions . Technicians' time spent on these samples puts a strain on the laboratory in terms of costs and absence of the technicians because of legal recuperation. A higher number of confirmed episodes of VAP early in the week compared to just before the beginning of the weekend, combined with a larger number of BALF samples obtained on Thursdays and Fridays, may suggest that clinicians want to exclude VAP before the weekend resulting in a lower threshold for requesting a BALF."}
+{"text": "To the Editor: To overcome various limitations of phenotyping and 16S rDNA sequence analysis of Cronobacter bacteria, we have established a comprehensive multilocus sequence typing (MLST) scheme as an open access database resource (www.pubMLST.org/cronobacter)  and has been used to study the diversity of the Cronobacter genus and new Cronobacter species (Cronobacter spp. in neonates during the previous 30 years in 6 countries were caused by a single sequence type (ST): C. sakazakii ST4. We were therefore interested in applying the MLST method to the Cronobacter strains associated with the highly publicized cases in the United States during December 2011  sent us the analysis . Ten speC. sakazakii; 1 was C. malonaticus. This predominance of C. sakazakii isolates matches reports of cases and outbreak studies (C. sakazakii isolates were in 6 of 55 STs defined for C. sakazakii (Most (14/15) specimens were atpD (1/390nt), gltB (2/507nt), and gyrB (2/402nt). Specimen 1578 (ST111), isolated from the PIF reconstitution water associated with the case reported in Illinois, is distinguishable from ST4 in 4/7 loci: fusA (5/438nt), glnS (1/363), infB (4/441), and ppsA (19/495). The 2 Illinois strains, 1577 and 1578 (ST110 and ST111), differed from each other at all loci, in total, 35/3,036 nt difference.Specimen 1577 (ST110), isolated from CSF, is a triple-loci variant of ST4, distinguished by 5/3036 nt: XbaI sites (the endonuclease most commonly used with PFGE of Enterobacteriaceae) within the 7 MLST loci. C. sakazakii ST4 strains were also found in feces (specimen 1567), opened PIF (specimen 1571), and tracheal samples (specimen 1576)  in the fusA loci position 378 (A:T).Such sequence-based relationship analysis of isolates is not possible by using pulsed-field gel electrophoresis (PFGE). PFGE and MLST analyze the bacterial DNA content differently, and there are no en 1576) . In addiC. sakazakii strains were received by CDC in 2011. C. sakazakii ST8 was isolated from an opened powdered infant formula tin (specimen 1573) and 2 associated fecal samples from an infant who had diarrhea (specimens 1574 and 1575). One blood isolate (specimen 1569) was C. malonaticus ST112, found in an infant <1 month of age with meningitis who did not survive the infection. This finding is highly noteworthy because it has been proposed that C. malonaticus predominates in adult infections (Several non-ST4 Cronobacter species and are instead predominantly in the C. sakazakii ST4 clonal complex. Such infections in neonates are of high concern because of the risk for associated severe brain damage. As previously stated, whether this association is caused by greater neonatal exposure as a result of environmental factors or particular virulence capabilities remains uncertain (This MLST analysis of 15 strains received by the CDC in 2011 reinforces the conclusion that CSF isolates are not evenly spread across the 7"}
+{"text": "Treatment volumes were achieved with 5-8 noncoplanar beams shaped using a micromultileaf collimator (MLC). Treatment was delivered in 30 daily fractions over 6 weeks to a total dose of 50 Gy using 6 MV photons. Outcome was assessed prospectively.Fifty-two patients with large skull base meningiomas aged 34-74 years (median age 56 years) were treated with FSRT between June 2004 and August 2009. All patients received FSRT for residual or progressive meningiomas more than 4 centimeters in greatest dimension. The median GTV was 35.4 cmAt a median follow-up of 42 months (range 9-72 months) the 3-year and 5-year progression-free survival (PFS) rates were 96% and 93%, respectively, and survival was 100%. Three patients required further debulking surgery for progressive disease. Hypopituitarism was the most commonly reported late complication, with a new hormone pituitary deficit occurring in 10 (19%) of patients. Clinically significant late neurological toxicity was observed in 3 (5.5%) patients consisting of worsening of pre-existing cranial deficits.FSRT as a high-precision technique of localized RT is suitable for the treatment of large skull base meningiomas. The local control is comparable to that reported following conventional external beam RT. Longer follow-up is required to assess long term efficacy and toxicity, particularly in terms of potential reduction of treatment-related late toxicity. The optimal management of large benign meningiomas of the skull base is challenging. Surgery remains the standard treatment and following apparently complete removal the reported control rates are in the region of 95% at 5 years and 90% at 10 years . HoweverLocal control following partial resection of benign meningiomas and at the time of recurrence can be improved with conventional fractionated external beam radiotherapy (RT), with a reported 10-year progression-free survival in the region of 75-90% -17. MoreAlthough in many centers SRS is the preferred treatment option for patients with small to moderate recurrent or enlarging skull base meningiomas, fractionated RT is often performed for larger tumors close to critical structures because of the radiobiological advantage of dose fractionation in reducing the risk of post-radiation long-term complications. In this study, we report the experience with FSRT at our center for patients with large residual or progressive skull base meningiomas.Between June 2004 and August 2009, fifty-two patients with benign skull base meningiomas more than 4 centimeters in greatest dimension were treated with FSRT. Characteristics of patients are shown in Table 3 (range 24.1-94.9 cm3). The PTV was 47.6 cm3 (range 33.5-142.7 cm3). Treatment volumes were achieved with 5-8 noncoplanar beams shaped using a micromultileaf collimator (MLC). Plans were prescribed at the isocentre according to ICRU 50 criteria with PTV covered by the 95% isodose in 3-D. To assess the accuracy of relocation, the isocentre position was verified with a second CT scan performed just prior to the start of treatment. The tolerance of relocation had to be < 1.5 mm in any direction. Daily portal images acquired at 0 and 90\u00b0 through the isocenter were obtained for each patient during the treatment. All patients were treated on a 6-MV LINAC with a 120 leaf MLC (Varian Clinac 600 DBX) and received a dose of 50 Gy in 30 fractions over 6 weeks.The FSRT technical details and procedure using the BrainLab stereotactic mask fixation system have been previously reported . The groA clinical assessment of neurological status and tolerance to treatment was performed every six months. An MRI scan was performed every 6 months for the first 2 years and thereafter every 12 months. Tumor control was defined by the absence of radiological tumor progression. Pituitary function was assessed by complete basal hormonal assessment and dynamic testing, as appropriate, in an endocrine clinic. Vision was assessed by serial ophthalmologic examinations. Tumor control and overall survival were measured from the start of FSRT. Univariate analysis and multivariate Cox proportional hazards regression model were used to test the effect of prognostic factors on tumor control.3 and 29 meningiomas smaller than or equal to 40 cm3 (P = 0.16) Univariate analysis showed no significant tumor control between 23 meningiomas larger than 40 cm. Similarly, tumor location, sex, and age were not correlated with tumor control.Fifty-two patients with large benign skull base meningioma were treated with FSRT. At the time of analysis in December 2010, three patients had tumor progression 18, 30 and 42 months after FSRT and required surgery. After a median follow-up of 42 months (range from 12 months to 72 months), the actuarial tumor control was 96% at 3 years and 93% at 5 years, and respective survival 100%  and 5th (n = 2) nerve palsy during or shortly after treatment, with full recovery after a short course of corticosteroids.Neurological deficits were present in 43 82%) patients. After FSRT 11 (20%) patients had a clinical improvement of neurological deficits  patients, lasting for 4-8 weeks after FSRT. Transient headache occurred in 6 patients. One patient had an increase in seizure frequency. A development of new or worsening of pre-existing hypopituitarism occurred in 10 (19%) patients after a median follow-up of 36 months, requiring hormone replacement therapy with gonadal steroids and growth hormone in 7 patients, GH replacement in 2 patients, and thyroxine and hydrocortisone in 4 patients. The pituitary fossa contained residual tumor in 27 patients, and was included in the PTV. New clinically apparent neurocognitive dysfunction (Grade II RTOG memory impairment) was reported in one patient. No radiation necrosis, cerebrovascular accidents and second tumors were reported.The reported tumor control rate is similar to that shown recently by others following conventional RT [, however longer follow-ups needed to confirm the excellent results obtained in our series. Of note, in our study we have considered only patients presenting with large benign meningiomas more than 4 centimeters in greatest dimension, with a median volume of 35.4 cm3. Milker-Zabel et al. [3 treated with FSRT at University of Heidelberg. At a median follow-up of 5.7 years, 5-year and 10-year tumor control rates were 90.5% and 89%, and respective survival were 95% and 90%. Hamm et al [3 or close to optical structures treated with FSRT with a median dose of 56 Gy with daily fractions of 1.8-2 Gy. At a median follow-up of 36 months the overall survival and the progression-free survival rates for 5 years were 92.9%, and 96.9%, respectively. Grade II-III late neurological toxicity occurred in 5.5% of patients. A similar tumor control has been reported in patients with skull base meningiomas treated with conventional RT, however with an increased risk of recurrence for larger tumors [Although a clear limitation of the study is represented by the relatively short follow-up, neverthless our results and data from literature suggest that FSRT is an appropriate treatment option for patients with large recurrent or enlarging skull base meningiomas with a 5-year control similar or even better than conventional RT.Fifty-two patients with large skull base meningiomas were treated with FSRT between June 2004 and August 2009 at University of Rome \"La Sapienza\". At a median follow-up of 42 months tumor control rates were 96% and 93% at 3 and 5 years, with respective survival of 100%. The rate of complications was acceptable, consisting mainly in worsening vision in 2 patients and pituitary hormone deficits in 10 patients. ional RT -17,26-33ional RT -45(Tablel et al.  reportedr tumors ,28,29. Cr tumors ,28. AlthThe external beam radiation dose for meningioma that represents the best balance of tumor control and a low complication rate has not been defined. Most of published series show no significant difference on tumor control with the use of doses ranging between 50 and 60 Gy, however a dose < 50 Gy has been associated with higher recurrence rates ,27,33. T3 in volume at a dose of 15 Gy, Bledsoe et al [SRS represents an effective and safe alternative treatment option for patients with skull base meningiomas. At doses of 12-16 Gy the reported actuarial 5-year and 10-year tumor local control rates are in the range of 90-95% and 80-85%, as shown in some recent large series -58; howeoe et al  reportedoe et al  using a Hypopituitarism was the most commonly reported late complication. A new pituitary hormone deficit requiring hormone replacement occurred in 19% of patients. Late neurological toxicity was observed in 7% of patients and consisted of worsening of pre-existing cranial deficits in 3 patients and mild neurocognitive dysfunction in one patient. A neurological improvement was observed in 19% of patients; vision remained stable in 46 patients and improved in 7 patients with visual impairment. Since the late effects of radiotherapy in terms of normal tissue damage expressed as radiation optic neuropathy occur usually within 1-5 years of treatment, the low incidence of radiation-induced optic neuropathy and others cranial nerve deficits at a median follow-up of 42 months provide some reassurance about the safety of the present dose and technique for large skull base meningiomas. The present and some other recent series on FSRT -45 and cwith a control of tumor growth at 5 years comparable to that seen following conventional fractionated radiotherapy. For patients with large skull base meningiomas a combination of conservative surgery and postoperative irradiation should always be considered when an attempt to complete resection carries unacceptable risks of neurological deficits. The use of 2-3 mm margin from GTV to generate PTV with FSRT permits a more localized irradiation compared with conventional radiotherapy. Minimizing the radiation dose to normal brain FSRT may reduce the risk of developing late radiation-induced toxicity; however, the potential benefit in reducing long term treatment complications while maintaining a high efficacy will require longer follow-up of a large cohort of patients.We conclude that FSRT is a high precise and safe treatment for the majority of large skull base meningiomas, The authors declare that they have no competing interests.GM conceived of the study, participated in its design and coordination, and drafted the manuscript. LV and VE participated in study design, analysis and interpretation of data, and helped to draft the manuscript. EC and MFO performed the statistical analysis and participated in acquisition and analysis of data. PC, GC and RME critically reviewed/revised the article. All authors read and approved the final manuscript."}
+{"text": "Noninvasive ventilation is a safe and effective method to treat acute respiratory failure, minimizing the respiratory workload and oxygenation. Few studies compare the efficacy of different types of noninvasive ventilation interfaces and their adaptation.To identify the most frequently noninvasive ventilation interfaces used and eventual problems related to their adaptation in critically ill patients.We conducted an observational study, with patients older than 18 years old admitted to the intensive care and step-down units of the Albert Einstein Jewish Hospital that used noninvasive ventilation. We collected data such as reason to use noninvasive ventilation, interface used, scheme of noninvasive ventilation used , adaptation, and reasons for nonadaptation.We evaluated 245 patients with a median age of 82 years (range of 20 to 107 years). Acute respiratory failure was the most frequent cause of noninvasive ventilation used (71.3%), followed by pulmonary expansion (10.24%), after mechanical ventilation weaning (6.14%) and sleep obstructive apnea (8.6%). The most frequently used interface was total face masks (74.7%), followed by facial masks in 24.5% of the patients, and 0.8% used performax masks. The use of noninvasive ventilation for periods (82.4%) was the most common scheme of use, with 10.6% using it continuously and 6.9% during the nocturnal period only. Interface adaptation occurred in 76% of the patients; the 24% that did not adapt had their interface changed to improve adaptation afterwards. The total face mask had 75.5% of interface adaptation, the facial mask had 80% and no adaptation occurred in patients that used the performax mask. The face format was the most frequent cause of nonadaptation in 30.5% of the patients, followed by patient's related discomfort (28.8%), air leaking (27.7%), claustrophobia (18.6%), noncollaborative patient (10.1%), patient agitation (6.7%), facial trauma or lesion (1.7%), type of mask fixation (1.7%), and 1.7% patients with other causes.Acute respiratory failure was the most frequent reason for noninvasive ventilation use, with the total face mask being the most frequent interface used. The most common causes of interface nonadaptation were face format, patient-related discomfort and air leaking, showing improvement of adaptation after changing the interface used."}
+{"text": "Streptococcus pneumoniae 3 years after implementation of the program in the Netherlands. We compared pneumococcal serotypes in 329 prebooster 11-month-old children, 330 fully vaccinated 24-month-old children, and 324 parents with age-matched pre-PCV7 (unvaccinated) controls  and 296 of their parents. PCV7 serotype prevalences before and after PCV7 implementation, respectively, were 38% and 8% among 11-month-old children, 36% and 4% among 24-month-old children, and 8% and 1% among parents. Non-PCV7 serotype prevalences were 29% and 39% among 11-month-old children, 30% and 45% among 24-month-old children, and 8% and 15% among parents, respectively; serotypes 11A and 19A were most frequently isolated. PCV7 serotypes were largely replaced by non-PCV7 serotypes. Disappearance of PCV7 serotypes in parents suggests strong transmission reduction through vaccination.To evaluate the effectiveness of the 7-valent pneumococcal conjugate vaccine (PCV7) program, we conducted a cross-sectional observational study on nasopharyngeal carriage of  Streptococcus pneumoniae (pneumococcus) is a major cause of respiratory and invasive disease worldwide, particularly in children <5 years of age and elderly persons   for children has led to a dramatic decline in PCV7-serotype invasive pneumococcal disease (IPD), not only in vaccinated children , vaccination with PCV7 was introduced for all infants born after March 31, 2006, in a 3+1 schedule of vaccinations at 2, 3, 4, and 11 months with no catch-up campaign. To evaluate how this PCV7 vaccination program affected prevalence of pneumococcal serotypes after 3 years, we conducted a cross-sectional observational study of nasopharyngeal carriage of pneumococci, and we compared data from vaccinated children and their parents with data from age-matched pre-PCV7 (unvaccinated) controls.In 2009, after PCV7 vaccination had been conducted for 3 years, we examined nasopharyngeal swabs for pneumococcal carriage from 2 age cohorts: 1) healthy 11-month-old children who had received 3 primary vaccinations according to the Dutch NIP but had not yet received the booster dose at 11 months of age or had had the booster dose within the week before sampling, 2) healthy 24-month-old children vaccinated according to the Dutch NIP. We also examined swabs from 1 parent each for the 24-month-old children. Exclusion criteria for children were known or suspected immunodeficiency, craniofacial or chromosomal abnormalities, coagulation disorders, use of anticoagulant medication, and having older siblings in the household who had received a pneumococcal conjugate vaccine. Parents were excluded if they had a bleeding disorder or used anticoagulant medication. The study (NL24116.000.08) was approved by an acknowledged national ethics committee in the Netherlands. The study was conducted in accordance with the European Statements for Good Clinical Practice.Data from the vaccinated children cohorts were compared with data from pre-PCV7 control children and their parents derived from a longitudinal, randomized, controlled trial (NCT00189020) that had started in the Netherlands well before national PCV7 implementation for infants. In that trial, children had been included at the age of 6 weeks from July 2005 through February 2006 and were followed-up until 24 months of age. Nasopharyngeal swabs were obtained from children at 12 and 24 months of age and from 1 parent of each of the 24-month-old children; results have been described . All serotype 6A isolates were submitted to the National Reference Laboratory of Bacterial Meningitis  for further discrimination between 6A and the newly discovered serotype 6C by PCR with primers 5106 and 1301 and primers 6C-fwd and 6C-rev (<0.06 \u03bcg/mL), penicillin intermediately resistant (MIC 0.12\u20131.0 \u03bcg/mL), or penicillin resistant (MIC >2.0 \u03bcg/mL)  and 24 months (n = 321) and the parents of the 24-month-old children (n = 296) in which children were enrolled as described previously  and their corresponding 95% confidence intervals (CIs).Data on carriage of Three years after PCV7 implementation in the NIP for all newborns, parents of 11,005 children were invited to participate. A total of 1,045 (9.5%) parents were interested in participating, among which 892 families were assessed for eligibility; 153 families were not assessed because the enrollment target had already been achieved. Of the 892 families, 233 were excluded. The most frequent reason for exclusion was household presence of older siblings who had received a pneumococcal conjugate vaccine (78%). In total, 329 children 11 months of age and 330 children 24 months of age and 1 parent for each of the 24-month-old children (n = 324) were enrolled from February 9 through July 9, 2009.The mean age of vaccinees was slightly lower  than that of the pre-PCV7 controls. At 11 months, the proportion of siblings <5 years of age and the exposure to smoking indoors was lower for vaccinees (both p<0.001). At 24 months, the proportion of male participants and the proportion of children who had received antimicrobial drugs within 1 month before the swab was taken was higher among vaccinees (both p = 0.03). Also, the months of sampling differed between both studies p<0.001; .Prevalence of any of the PCV7 serotypes was 38% among the pre-PCV7 controls compared with 8% among prebooster children at 11 months  and 36% among the pre-PCV7 controls compared with 4% among children 24 months of age  . PrevaleS. pneumoniae among the pre-PCV7 controls was 67% compared with 47% among prebooster children at 11 months of age  and 66% compared with 49% at 24 months of age , respectively  and 30% and 45% among children 24 months of age  in the pre-PCV7 and post-PCV7 cohorts, respectively . In prebectively .Susceptibility testing of all serotype 19A isolates showed that no isolates were penicillin resistant. Among the pre-PCV7 controls and among vaccinated children, respectively, 0 and 3 (6%) isolates were intermediately resistant to penicillin, and 0 and 2 isolates (4%) were nonsusceptible to azythromycin and to erythromycin.Prevalence of any of the PCV7 serotypes was 8% among parents of 24-month-old children in the pre-PCV7 controls and 1% among parents of vaccinated children 3 years after PCV7 implementation . Corresponding figures for non-PCV7 serotypes were 8% and 15% , respectively. A stable pneumococcal prevalence rate of 17% and 16% was observed among parents , respectively . Before Unadjusted associations are shown as ORs in children and parents . MultivaS. pneumoniae was reduced 80%\u201390% among vaccinated children at 11 and 24 months of age. Among parents of vaccinated children, carriage of PCV7 serotypes had almost disappeared. This impressive reduction of PCV7-serotype carriage in infants is larger than that observed in clinical trials, which showed 50%\u201360% reduction in PCV7 rates after conjugate vaccination, and should be attributed to herd effects  (Increased rates of carriage of nonvaccine serotypes were also observed in this study. In vaccinated infants and their parents; serotypes 19A and 11A were the most frequently carried serotypes in the Netherlands. In the United States, multidrug resistant serotype 19A has become a frequent cause of IPD as well as of otitis media in children (Observed changes in prevalence of serotype carriage may not be entirely random but may be directly related to the serotype capsule size, which in turn is related to the polysaccharide composition and metabolic costs of the capsule for the bacterium (In contrast to several other carriage studies (For evaluation of our study results, some potential limitations should be taken into account. First, because our data are observational, we showed associations and no causalities between the introduction of PCV7 and changes in pneumococcal colonization. Although several potential confounders were measured and appeared to differ between the comparison groups, multivariate analysis showed that our results were quite robust. Second, the postvaccination data came from a cross-sectional cohort study including 2 separate age groups, whereas the pre-PCV7 control data were derived from a longitudinal study in which data were collected from the same children at age 12 and 24 months. However, we previously found that potential within-person dependency was not substantially affecting these carriage data, probably because of the large interval between carriage sample collections (Since 2009, pneumococcal vaccines with broader coverage have been licensed and will be introduced into vaccination programs worldwide. The effects of these broader coverage vaccines on potential shifts in pneumococcal serotypes in the nasopharynx are still largely unknown. To predict the long-term health and economic effects, close monitoring is warranted.S. pneumoniae in children and their parents. This finding indicates a major role of infants in transmission of pneumococci in the population.In conclusion, 3 years of vaccination with PCV7 has led to impressive shifts in serotype-specific carriage of"}
+{"text": "The aims of this study were to determine when patients develop feed intolerance, the prevalence of feed intolerance in subgroups, and other factors that influence feed intolerance. Nasogastric delivery of nutrition commonly fails in critically ill patients. However, studies to date have been underpowered to formally define the determinants of feed intolerance.A prospective observational study. Data were collected for 14 days (or until ICU discharge/or death) after commencement of gastric feeding in consecutive, ventilated patients. Gastric aspirates were performed 6 hourly. Feed intolerance was defined as \u22651 gastric aspirate(s) \u2265250 ml. Data are presented as median (range). The association between feed intolerance and LOS was calculated using the Mann-Whitney U test. The ANCOVA test was used to test for a difference between groups in LOS adjusting for covariates.P = 0.02). Prokinetics were administered to 29%; duration 1 (1 to 7) day. Feed intolerance was not associated with ICU or hospital mortality , but was associated with longer ICU and hospital LOS  days vs. tolerant 7 (1 to 51) days, P \u22640.001: hospital; intolerant 32 (10 to 120) days vs. tolerant 26 (3 to 177) days, P = 0.02). There was no difference in APACHE II score between intolerant and tolerant groups (intolerant = 23 (7 to 46), tolerant = 21 (5 to 35), P = NS).In 214 patients  years, APACHE II 21 (5 to 46), ICU LOS 9 (1 to 94) days, hospital LOS 29 (3 to 177) days), feed intolerance occurred in 78 (37%). The first occurrence of feed intolerance was within 5 days of commencing feeding (97%). Patients with trauma (60%), traumatic brain injury (57%) and sepsis (42%) had higher incidence of intolerance than the total population. The neurological group had significantly lower incidence of intolerance (17%; The majority of feed intolerance occurred early in the patient's illness. While mortality was unaffected, ICU and hospital LOS were longer in feed-intolerant patients that were not explained by severity of illness on admission. Further research is needed to determine whether increasing calorie delivery improves clinical outcomes in feed-intolerant patients."}
+{"text": "Cervical cancer is the second most common cancer in women worldwide. Infection with certain human papillomavirus (HPV) genotypes is the most important risk factor associated with cervical cancer. This study analysed the distribution of type-specific HPV infection among women with normal and abnormal cytology, to assess the potential benefit of prophylaxis with anti-HPV vaccines.Cervical samples of 2,461 women  from the centre of Spain were tested for HPV DNA. These included 1,656 samples with normal cytology (NC), 336 with atypical squamous cells of undetermined significance (ASCUS), 387 low-grade squamous intraepithelial lesions (LSILs), and 82 high-grade squamous intraepithelial lesions (HSILs). HPV detection and genotyping were performed by PCR using 5'-biotinylated MY09/11 consensus primers, and reverse dot blot hybridisation.HPV infection was detected in 1,062 women (43.2%). Out of these, 334 (31%) samples had normal cytology and 728 (69%) showed some cytological abnormality: 284 (27%) ASCUS, 365 (34%) LSILs, and 79 (8%) HSILs. The most common genotype found was HPV 16 (28%) with the following distribution: 21% in NC samples, 31% in ASCUS, 26% in LSILs, and 51% in HSILs. HPV 53 was the second most frequent (16%): 16% in NC, 16% in ASCUS, 19% in LSILs, and 5% in HSILs. The third genotype was HPV 31 (12%): 10% in NC, 11% in ASCUS, 14% in LSILs, and 11% in HSILs. Co-infections were found in 366 samples (34%). In 25%, 36%, 45% and 20% of samples with NC, ASCUS, LSIL and HSIL, respectively, more than one genotype was found.HPV 16 was the most frequent genotype in our area, followed by HPV 53 and 31, with a low prevalence of HPV 18 even in HSILs. The frequency of genotypes 16, 52 and 58 increased significantly from ASCUS to HSILs. Although a vaccine against HPV 16 and 18 could theoretically prevent approximately 50% of HSILs, genotypes not covered by the vaccine are frequent in our population. Knowledge of the epidemiological distribution is necessary to predict the effect of vaccines on incidence of infection and evaluate cross-protection from current vaccines against infection with other types. The association of human papillomavirus (HPV) infection with cervical cancer and its precursor lesions is well established ,2. More Based on the etiological role in the progression to cervical cancer, 15 HPV genotypes have demonstrated strong oncogenic potential and are classified as high-risk HPVs . In a suhttp://www.asccp.org/ConsensusGuidelines/2001BethesdaSystem/tabid/5969/Default.aspx. Residual liquid material from ThinPrep samples was used for HPV detection. One millilitre of each collected PreservCyt sample was aliquoted with an individual sterile pipette for molecular study. DNA was extracted with QIacube DNA Investigator Kit  in accordance with the manufacturer's instructions.A total of 2,461 cytological specimens from May 2006 to June 2010 were included in this study. Patients were selected if both molecular analysis and cytology were available and if no previous HPV study had been performed. Cytological samples corresponded to patients attending the specialised gynaecology outpatient clinics of the Hospital Universitario Puerta de Hierro, Madrid, Spain. These patients were selected on the basis of a previous abnormal Pap smear. A second sample was obtained, for which, exfoliated cervical cells were obtained using a cytobrush and collected in PreservCyt Solution . The slides were prepared with a TP2000 (Cytyc) instrument as recommended by the manufacturer. ThinPrep cytological slides were screened and the adequacy and the degree of abnormality were assessed using the criteria set out in The Bethesda System 2001 guidelines HPV DNA detection and genotyping were performed by PCR using the L1 consensus HPV PGMY09/PGMY11 primer set , and flo2 test was used to evaluate statistical significance between genotype, cytological lesion and age. The median age of 33 years was chosen to dichotomise age in the analysis of multiple genotypes infection. The study protocol was approved by our institutional review board and informed consent was obtained in each case.HPV genotype distribution analysis was performed using SPSS version 15.0. The \u03c7There were 2,461 samples from women aged 15-75 years analysed for HPV infection from May 2006 to June 2010: 1,399 (56.8%) were negative for HPV and 1,062 (43.2%) were positive. The cytological diagnosis was: 1,656 (67.3%) with normal cytology (NC); 336 (13.7%) with atypical squamous cell of undetermined significance (ASCUS); 387 (15.7%) low-grade squamous intraepithelial lesions (LSILs); and 82 (3.3%) high-grade squamous intraepithelial lesions (HSILs). The percentage of cases positive for HPV infection in the different diagnostic categories was: 20% in NC, 84% in ASCUS, 94% in LSILs, and 96% in HSILs  from women with negative cytology and 728 (69%) with some cytological abnormality. The cytological diagnosis of abnormal cases was as follows: 284 cases (27%) with ASCUS, 365 (34%) with LSILs, and 79 (8%) with HSILs.Mean age of the patients was 34 \u00b1 10.5 years (range 15-75). Median age of NC patients was 34.5 years, 34.2 years for ASCUS, 32.3 years for LSILs, and 39.6 years for HSILs. The distribution of the cytological diagnoses with regard to age is shown in Table The most common HPV types in the complete series were as follows: 16 (28%), 53 (16%), 31 (12%), 52 (10%), 6 (9%), 18 (8%), 58 (8%), and 66 (8%). The prevalence of other HPV types was: 33 (5%), 39 (5%), 56 (5%), 81 (5%), 42 (4%), 45 (4%), 11 (3%), and 51 (3%). The most common HPV types in cytologically normal women were: 16 (21%), 53 (16%), 6 (10%), 31 (10%) and 52 (8%). HPV18 was found in 6% of NC cases. In abnormal samples, the distribution was as follows (Table Single infection (one HPV type) was observed in 696 (65.5%) samples, and 366 34.5%) patients were infected with multiple HPV types. Double infections (two different genotypes) accounted for 60% of the multiple infections, three genotypes were detected in 26% of these 366 samples, and four or more types in 14%. In women under 33 years old, infections due to more than one HPV type were found in 39.6% of cases, whereas in those older than this, the prevalence was 26.7% (p < 0.01). HPV 16 was the most common genotype detected in co-infections, and was present in 38% of cases, followed by HPV 53 (27%) and HPV 31 (20%). Co-infections were found in 25% of NC, 36% of ASCUS, 45% of LSIL, and 20% of HSIL cases , whereas HPV 18 was found more rarely (8%).Our specimens came from a group of women who attended a cervical pathology unit because of a previous abnormal Pap test result. We selected the HPV-positive cases to investigate the genotype distribution in our area. Several studies have been published concerning genotype distribution in several Spanish regions -18, but Consistent with previously published data, genotype HPV 16 was the most common type in our series, and was detected in 28% of samples. With the exception of Eastern Africa, China, Japan and Taiwan -23, HPV Nearly a third of HPV-positive samples in our series were detected in patients with normal cytology. This prevalence is higher than that of other Spanish studies. This might be due to the fact that the women in our study had an abnormal Pap test and attended a specialised gynaecology unit for cervical pathology.In NC samples, HPV 16 was the most common genotype (21%), followed by HPV 53 (16%). The HPV distribution found in NC cases is similar to that reported by Conesa et al.  from a cIn HSILs, the most frequent type was HPV 16 (51%), followed by 52 (14%) and 31 (11%). In our series, HPV 53 was not detected in HSILs, suggesting that it is not a high-risk type. An interesting finding of our study was that HPV 52 was the second most common genotype in HSIL cases, whereas its prevalence in NC and LSILs was lower.Recently, multiple HPV infections have been analysed because, with the development of anti-HPV vaccines not covering all genotypes, the distribution of infection with types not covered by vaccines could be affected. The elimination of one HPV type could affect the natural history of the remaining genotypes. Therefore, obtaining a solid knowledge of genotype HPV distribution is becoming imperative. Multiple types of HPV have been described in up to 50% of NC and LSIL cases in the population in Northwest Spain , in accoIn the present study, multiple infections were detected in 34% of samples, and were more frequent in younger women (< 33 years). This observation is consistent with the results of Mejlhede et al. , and supIn conclusion, this study demonstrates an important prevalence of high- and low-risk HPV genotypes even in patients with no evidence of cytological anomalies, as reported by Krambeck et al. . We alsoThe authors declare that they have no competing interests.PM designed the experiments, performed analysis and interpretation of data, and drafted the manuscript; LK and DG performed genotyping methods; AMLG performed pathological diagnosis; MJMA performed data analysis; and CB performed pathological diagnosis and supervised the study. VA performed statistical treatment of data.All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2334/11/316/prepub"}
+{"text": "Elderly and especially nursing home residents are at increased risk of infectious diseases due the high prevalence of underlying chronic illnesses, age-related immunesenesence and the close(d) environment typical for this population. The impact of the occurence of infectious diseases on mortality is subject of this study.In the Sentinel Surveillance Network on Infectious diseases in nursing homes (SNIV), elderly care physicians and/or nurse practitioners report weekly numbers of 1) mortality and 2) infectious diseases on the basis of clinical definition. On these weekly time series (mid 2008- beginning of 2011) we used Poisson regression models (which included linear and periodic components) to characterize the association of total death counts with trends in influenza-like illness (ILI), gastro-enteritis (GE), and probable pneumonia.In total 35 nursing homes with a total of 4516 residents participated during part of the 128 week study period. The incidence of mortality and infectious illnesses displayed seasonal peaks in winter. In total 2324 residents died.\u00a0Per 1000 residents, each reported case of pneumonia was associated with 3.4 (95%CI:1.7-5.2) deaths occurring in the same week and 2.2 (95%CI:0.5-3.9) occurring 2 weeks later. Each reported GE case was associated with 1.1 (95%CI:0.4-1.7) deaths one week later. Together with these infections, the linear and periodic terms were no longer significant and were thus excluded from the final model. Of all deaths, our model attributed 745 (32%) to pneumonia and 172 (7%) to GE.Probable pneumonia and gastro-enteritis were significantly associated with overall mortality, while influenza-like illness was not.None declared."}
+{"text": "Anaphylaxis is a potentially life threatening allergic reaction. Failure to identify the inciting allergen places patients at risk of future life-threatening allergen exposure. Anaphylaxis guidelines recommend that all patients who experience anaphylaxis from an allergen encountered in a non-medical setting carry self injectable epinephrine and follow up with an allergist. Very little data is available on outcomes of allergy follow up after an emergency department (ED) visit for anaphylaxis. The aim of our study was to determine the outcomes of allergy follow up after an ED visit for food anaphylaxis.A retrospective cohort study was conducted in an ED setting with approximately 80,000 visits per year. Patients presenting to the ED for anaphylaxis and allergic reactions were screened from April 2008 to June 2010 and all patients who fulfilled NIAID/FAAN criteria for anaphylaxis and provided consent were included. A standardized data abstraction form was used to collect data.Two hundred and twenty patients constituted the study sample and were included in the study. The median age was 33.5 years (IQR 18.8-49.6) years. One hundred and twenty-eight (58.2%) were females. Suspected allergens in the ED were food in 79 (35.9%), medication in 47 (21.4%), insect venom in 27 (12.3%), others in 24 (10.9%) and unknown in 43 (19.5%) patients. A total of 81 patients (36.8 %) followed up with an allergist. Among patients with food anaphylaxis, 40 (50.6%) followed up with an allergist of which 34 (85%) had allergy testing. Among the 34 patients, skin testing was performed on 16 (47.1%), specific IgE antibody tests in 22 (64.7%) and both tests in 5 (14.7%) patients. After testing, 25 (73.5%) had an allergen identified.Allergen identification and avoidance after food anaphylaxis is important in order to avoid future reactions. Our results show that most patients who followed up with an allergist underwent allergy testing and had an allergen identified. These results support current anaphylaxis guidelines."}
+{"text": "Despite use of arterial closure devices (APCDs) and thrombin injection , surgery is needed at times to repair femoral pseudoaneurysms (FPA) in patients undergoing endovascular interventions. We analysed the indications and results of surgical repair in a tertiary referral center performing more than 6.000 angiographies and/or interventions annually.The aim of this retrospective observational study was to identify local and clinical factors related to the need of surgical repair.In this retrospective study, 122 (0.06%) FPAs treated among 21060 patients over a period of five years were assessed. Patient characteristics and therapeutic procedures were analyzed through hospital records.There were 15.163 (72%) coronary and 5.897 (27%) peripheral interventions, respectively. In 89 (73%) patients, FPA was successfully treated by ultrasound guided compression (USGC) alone.Thirty-three (28%) patients underwent open surgical repair. Indication for operative treatment was hemodynamic instability in 9 (7%) patients, rapidly expanding haematoma unsuitable for USGC or after unsuccessful USGC in 23 (19%). One (0.8%) patient had an arterio-venous fistula. Intraoperative findings suggest that atypical endovascular access  and multiple puncture sites and/or laceration of the vessel wall were related to the need for surgery in 22 (67%) cases. Most patients had active antithrombotic therapy. Gender or the nature of procedure (diagnostic vs. intervention) did not increase risk for open repair. One (0.8%) patient died. No amputations were performed. Mean hospital stay of patients undergoing open surgical repair was 11 (range 4-36) days.Technical puncture problems were identified in 2/3 of patients requiring open surgery. Along with major complications, such as arterial dissection, occlusion or arterial spasm, FPAs are a rare but serious complication after diagnostic or interventional angiography -3. AfterThe aim of this retrospective observational study was to identify local and clinical factors related to the need for surgical repair.21060 patients underwent diagnostic or interventional angiography via femoral arterial access at the Swiss Cardiovascular Center, University Hospital in Berne during a period of five years. USGC was performed by an experienced physician (trained angiologist) for up to 40 minutes using the Acuson 128XP  ultrasound scanning equipment with a 5-MHZ B-mode real time linear array transducer. In 31 (34%) patients further compression after successful ultrasound guided compression was applied using a Femostop device . Statistical analysis was performed using SPSS version? SPSS Inc., Chicago, Ill. software. Chi-square test was used to estimate the role of gender, nature of intervention .There were 15.163 (72%) coronary and 5.897 (28%) peripheral interventions. Of them, 122 (0.06%) were treated for subsequent FPA, either by USGC in 89 (73%) patients or by open surgery in 33 (27%). Mean age was 71 years (range 41-91). Patient characteristics are shown in Patient gender or the nature of the procedure  were not statistically significant. Preoperatively, 20 patients (61%) had been anticoagulated (heparin or coumadin). Five (15%) had both clopidogrel and acetosalicylic acid. One patient (0.8%) had undergone thrombolytic therapy for a cerebrovascular insult. One patient (0.8%) had no antithrombotic therapy. In six (18%) cases, there was no reliable information on current antithrombotic therapy.Of the operations, 30 (91%) were performed under general anesthesia, 3 (9%) under spinal or epidural analgesia. Seven (21%) pseudoaneurysms were managed with a staged procedure using vacuum-assisted closure . Five (15%) patients developed a wound infection requiring further surgical therapy before secondary closure. Intraoperative findings suggested a technical puncture problem in 22 (67%) patients . A laterA pulsatile hematoma, pseudoaneurysm, may be the result of any vascular intervention. It may lead to serious consequences, such as major amputation or even death . FPA occSeveral antithrombotic regimes have been described as risk factor FPA, such as heparin, thienopyridines or glycoprotein receptor inhibitors -7. AlthoPreventing pseudoaneurysm formation is a strategy. Our study shows that manual compression alone is effective in 99% of patients undergoing arterial access for diagnostic purposes or endovascular interventions. Minimizing the risk of FPA requires careful puncture technique. Aggressive antithrombotic therapy increases the risk of FPA. The main limitation of our study is the relatively small number of patients and its retrospective nature. The use of glycoprotein IIb/IIIa inhibitors was not always recorded. In conclusion, FPA requiring surgery is a rare but serious complication after diagnostic or interventional angiography. Two thirds of FPAs requiring surgery may be the result of poor puncture technique and inadvertent lesions of the arterial wall. Endovascular access should be planned and executed carefully. In experienced hands, open repair is straightforward."}
+{"text": "The objective of our study was to describe the disease pattern, outcomes and organ support required in treating H1N1-associated pneumonia in a single-centre, district hospital ICU.All of the patients with confirmed H1N1 infection admitted to our ICU during the months of December 2010 and January 2011 were studied. The outcome measures were incidence, severity and support for organ dysfunction, length of stay in ICU and mortality.During the study period 27 patients were admitted. The mean age was 46.6 years (SD 13.6) with 20 (74%) patients being female, of whom two were pregnant. The mean APACHE scores were similar between survivors and nonsurvivors, 14.1 and 13.7 respectively. Twenty patients (74%) required invasive mechanical ventilation with median duration of 9 days (range 2 to 54 days). Advanced techniques like prone position ventilation and high-frequency oscillatory ventilation were required in 20% and 10% of these patients respectively. Two patients were referred for ECMO. Ventilator-associated pneumonia (VAP) ensued in 25% of invasively ventilated patients resulting in an increase in ventilator days (median) from 9 to 19 and ICU stay (median) from 15 to 23 days. Four (15%) required advanced cardiovascular support, 14 (52%) developed acute kidney injury (AKI) of which nine (33%) patients required renal replacement therapy. The ICU mortality was 11.1% and hospital mortality was 14.8%. The cohort who developed AKI had 21% mortality. The median ICU stay (range) was 15 days (2 to 68 days).H1N1 pneumonia was associated with significant morbidity and mortality requiring advanced multiorgan support in the majority of patients. Although the incidence of organ dysfunction in our cohort mirrored that found in the Swift study ["}
+{"text": "MLH1 promoter hypermethylation and MLH1-93G>A promoter polymorphism. However, MSI was not related with MMR protein expression and only 5% of tumors were MSI-High. Furthermore, the incidence of tumors carrying germline mutations in MMR genes was low and only one glioblastoma was associated with Lynch syndrome. Interestingly, survival analysis identified that tumors lacking MSH6 expression presented longer overall survival in high-grade astrocytoma patients treated only with radiotherapy while MSH6 expression did not modify the prognosis of those patients treated with both radiotherapy and chemotherapy. Our findings suggest that MMR system alterations are a frequent event in malignant astrocytomas and might help to define a subgroup of patients with different outcome.Malignant astrocytomas are the most aggressive primary brain tumors with a poor prognosis despite optimal treatment. Dysfunction of mismatch repair (MMR) system accelerates the accumulation of mutations throughout the genome causing uncontrolled cell growth. The aim of this study was to characterize the MMR system defects that could be involved in malignant astrocytoma pathogenesis. We analyzed protein expression and promoter methylation of MLH1, MSH2 and MSH6 as well as microsatellite instability (MSI) and MMR gene mutations in a set of 96 low- and high-grade astrocytomas. Forty-one astrocytomas failed to express at least one MMR protein. Loss of MSH2 expression was more frequent in low-grade astrocytomas. Loss of MLH1 expression was associated with  Malignant gliomas account for 70% of all primary brain tumors with an incidence rate adjusted to the European Standard Population of 5.27 per 100 000 persons per year . PatientMSH2 or MLH1, and less frequently MSH6 or PMS2  for continuous variables. Associations between molecular and clinicopathological features as well as Hardy-Weinberg equilibrium were analyzed using the \u03c7P=0.012), whereas MLH1 and MSH6 expression were not associated with tumor histopathology  presented loss of expression of at least one MMR protein. Loss of MLH1 expression was observed in 17 cases (18%), MSH2 in 21 cases (22%) and MSH6 in 31 cases (32%). In addition, 10 tumors failed to express two MMR proteins simultaneously . Nine tumors did not express the three MMR proteins. Furthermore, MSH2 negative staining was significantly more frequent in low-grade astrocytomas (45%) than in high-grade astrocytomas (16%) (athology .MLH1 was present in 11 cases (12%), MSH2 in 11 cases (12%) and MSH6 in 8 cases (9%). No differences in MMR methylation levels were identified between different tumor grades. Methylation status of MLH1 promoter was significantly associated with loss of MLH1 expression (P=0.021). Specifically, 46% of tumors with MLH1 promoter hypermethylation showed lack of MLH1 expression (MSH2 and MSH6 promoter methylation and their protein expression (MMR promoter methylation was studied in 92 patients. Promoter hypermethylation of pression . We did pression .MLH1-93G>A polymorphism was determined in 96 astrocytoma patients and 200 control subjects. The distribution of genotypes in control samples did not significantly differ from that expected from Hardy-Weinberg equilibrium. MLH1-93GG genotype was found in 57 (60%), GA genotype in 31 (32%) and AA genotype in 8 (8%) patients. We did not find significant differences in distribution of MLH1-93G>A genotypes between low-grade astrocytomas, anaplastic astrocytomas and control subjects. However, carriers of the MLH1-93AA genotype were more represented in the group of glioblastoma patients (P=0.017) (MLH1 promoter hypermethylation (P<0.001) and in tumors that showed lack of MLH1 expression (P=0.030) (P=0.017) . FurtherP=0.030) .MSI analysis was performed in 88 cases and revealed that the most frequent unstable markers in our series were BAT25 (15% of cases) and BAT40 (13% of cases). On the contrary, BAT26 was unstable in 1% of cases.MLH1-93AA genotype were associated with MSI status (Forty-seven patients (53%) were classified as MSS, 37 patients (42%) as MSI-L and 4 patients (5%) as MSI-H, with no differences between tumor grades. The four MSI-H tumors were glioblastomas. Three of these cases showed expression of all MMR proteins and one case presented loss of MSH6 expression. Neither MMR protein expression nor MMR promoter methylation nor I status .MLH1, MSH2 or MSH6 genes , c.1983delA (p.Lys661AsnfsX24) and c.1064GA (p.Arg355Lys), and two novel mutations in MSH6 gene c.4004AC (p.Glu1335Ala) and c. *(24_28) delGTTGA . Univariate survival analysis revealed that loss of MSH6 expression was significantly associated with a better median OS in high-grade astrocytomas (13.8 months vs. 10.1 months) . Age of In order to validate the prognostic value of MSH6 expression on high-grade astrocytomas survival, we evaluated MSH6 protein expression in an independent cohort of 71 high-grade astrocytomas. Fifteen (21%) of these tumors showed loss of MSH6 expression . HoweverP=0.015) (P=0.558)  ; meanwhiP=0.558) . SurvivaMalignant astrocytomas are one of the most devastating cancers with a dismal prognosis. Virtually all high-grade astrocytomas progress and locally relapse regardless of improved diagnosis and multi-modality treatment approach ,3. ThereWe have identified a large number of astrocytomas with defective MMR system expression. Forty-three percent of tumors included in our series failed to express at least one MMR protein at diagnosis, suggesting that this abnormality could be an intrinsic property of a subgroup of tumors. We also showed that MLH1 and MSH6 expression profiles were similar in both low- and high-grade astrocytomas whereas the lack of MSH2 expression was significantly more frequent in low-grade astrocytomas. In this sense, it has been previously reported an increased expression of MSH2 in high-grade astrocytomas compared with low-grade astrocytomas. Therefore, up-regulation of MSH2 levels may be related to an increased cell proliferation rate in astrocytomas ,30. AlthMLH1 methylation of the proximal promoter region and the absence of MLH1 expression in astrocytomas. Thus, we further confirm that MLH1 proximal promoter methylation is important in inhibiting MLH1 transcription as it has been previously reported in colorectal cancer (CRC) [Loss of protein expression could be due to aberrant DNA methylation of cytosine residues in CpG promoter islands that leads to transcriptional silencing of the associated genes . We haveer (CRC) . MoreoveMLH1-93G>A polymorphism, located in a promoter region required for maximal transcriptional activity [-93AA genotype was associated with MLH1 promoter methylation and deficient MLH1 expression never reported before in astrocytomas. The -93AA genotype was also associated with a higher risk of developing glioblastomas. This variant has been previously associated with loss of functional MMR system in colorectal and endometrial cancers [Analysis of the genotypic distribution of activity , showed  cancers ,18,35 an cancers ,36,37. NMSI analysis revealed a low incidence of MSI-H tumors in our series (5%) similar to that previously reported -41. All MSH2 gene [MSH2 mutation in a MSI-L glioblastoma that also carried two additional variants of unknown significance in MSH2 and MLH1 genes. One MLH1, one MSH2 and two MSH6 mutations of unknown significance that could be causing the lack of expression of the associated proteins were also detected. The absence of MMR gene mutations in most of the sporadic MSI-H astrocytomas was in accordance with data reported from sporadic CRC with high level of MSI that do not harbor mutations in the repair genes [Search for mutations in MMR genes showed only two pathogenic mutations. A germline pathogenic mutation in SH2 gene  was founir genes ,16.Loss of MSH6 expression was more common than the absence of MLH1 or MSH2 expression in our series, suggesting an important role of this protein in the pathogenesis of astrocytomas. It has been recently reported that MSH6 alterations arise in gliomas as a consequence of temozolomide treatment ,46. NeveFurthermore, survival analysis showed that loss of MSH6 expression was significantly associated with longer overall survival in high-grade astrocytoma patients in our series. Controversially, we did not find this association when we analyzed MSH6 expression in an independent validation cohort of high-grade astrocytoma patients. However, the treatment approach was different between the two cohorts of patients due to the different recruitment period of patients in each series. For decades, postoperative radiotherapy has been the standard treatment for newly diagnosed high-grade astrocytomas . HoweverSeveral studies have suggested that loss of MSH6 activity confers resistance to temozolomide treatment in glioma and may therefore contribute to progressive tumor growth and tumor recurrence ,46. HoweIn summary, our results demonstrate that MMR system alterations are a frequent event in malignant astrocytomas. We suggest that analysis of MMR genes allows to define a subset of astrocytomas with different outcome and could help to search for new therapeutic strategies.Table S1Detailed clinical characteristics of the study and validation cohort of astrocytoma patients.(XLS)Click here for additional data file.Table S2MLH1, MSH2 and MSH6 expression and methylation status according to MSI levels.(DOC)Click here for additional data file.Figure S1Representative examples of negative  and positive  MSH6 staining in four glioblastoma tumors (WHO grade IV).MSH6 expression was analyzed in formalin fixed, paraffin embedded tumor sections from all patients in the study cohort and the validation cohort. MSH6 staining on these sections was performed using MSH6 clone BC/44  antibody and counterstained with hematoxylin and eosin. MSH6 staining was considered positive when there was obvious nuclear staining in more than 50% of tumor cells .(TIF)Click here for additional data file."}
+{"text": "It is associated with high morbidity and mortality. Valve replacement is the most common open heart surgery procedure in our cardiac center. The use of mechanical valves remains burdened with serious complications such as thrombosis. Valve thrombosis is still associated with high mortalityThe aim of the present study was to investigate mechanical valve obstruction among Yemeni patients.Between January 2003 and April 2007, 2794 patients underwent prosthetic valve replacement in our center, Al-Thawra Hospital. Of those patients, 129 (4.6%) underwent reoperation for te obstructive mechanical valve. Patients with clinical suspicion of prosthetic valve obstruction (PVO) were admitted emergently to the CCU and the diagnosis was confirmed with echocardiography. All patients had heart failure; 95% of them were in NYHA class IV. All were transferred directly from the CCU to the operating room. The mean age was 34.8 \u00b1 13.4 years. Two patients received preoperative thrombolytic therapy that was not successful. Obstruction involved the mitral valve prosthesis in 47 (36.4%); the aortic prosthesis in 16 (12.4%) patients; both valves in 21 (16.3%) patients; mitral valve replacement with tricuspid valve repair in 22(17%); double valve replacement with tricuspid valve repair in 1 (0.8%); redo mitral valve replacement with aortic valve cleaning in 7 (5.4%) cases; aortic valve cleaning in 5 (3.9%) patients; mitral valve cleaning in 5 (3.9%); and 5 (3.9%) patients had redo mitral with aortic replacement.The operations were performed urgently. The etiology of the obstruction was thrombus in 111 (86%), pannus formation in 4 (3%), pannus and thrombus in 6 (4.8%), vegetation in 7 (5.4%) patients, and interposition of suturing materials in 1 (0.8%) patient. The in- hospital mortality was 23/129 (17.8%).The incidence of prosthetic valve obstruction remains high in Yemen. The vast majority of the patients who are referred to our hospital come from remote provinces in the country where regular INR measurement is not readily available. For those who are living in areas without good medical care, certain measures are necessary to avoid this disastrous complication: (1) good patient education, (2) free INR testing and free anticoagulant drugs such as warfarin; and (3) use of tissue rather than mechanical valves. Rheumatic heart disease is the main cardiovascular disease in Yemen affecting children and young adults. The incidence of rheumatic fever and rheumatic heart disease is 1/1000 in the developing countries with high morbidity and mortality.Intracardiac mechanical prosthetic valve replacement was first introduced in the 1960s, and many modifications in design and structural properties have improved the hemodynamic performance and durability of mechanical valves since then. However, prosthetic valve obstruction (PVO) continues to be a potential serious complication with a high risk of mortality. PVO is frequently related to thrombus formation due to inadequate anticoagulation; however, it can also be related to pannus formation due to overgrowth of fibrous tissue.Between January 2003 and December 2007, 4783 operations were performed at the Cardiac Centre of Al-Thawra Hospital. A total of 2794 (58.4%) of these patients were operated upon for prosthetic valve replacement. This number includes valve replacements with or without coronary artery bypass or other cardiac procedures. One hundred twenty-nine of those patients presented with PVO. All patients were admitted as an emergency to the CCU with clinical suspicion of PVO. The diagnosis was confirmed by transthoracic echocardiography in all patients. Transesophageal echocardiography was performed in 24 patients (31%), and cineangiography in 10 patients (7.8%).The obstruction of the prosthetic valve with pulmonary edema and NYHA class IV was present in 123 cases (95.3%), and 7 patients (4.7%) were in NYHA class III. Thrombolytic therapy was tried in two patients, which was not successful. Inadequate anticoagulation level as measured with International Normalized Ratio (INR) was found in most patients. An INR less than 2 was detected in 87 (67.4%) of the patients. The mean INR level in these patients was 1.43 \u00b1 0.24.All patients were transferred to the operating room and urgent redo operations were performed. The right femoral artery was cannulated in 12 (9.3%) patients. The right femoral artery and vein were cannulated in 7 patients (5.4%), and the ascending aorta was cannulated in 122 (94.6%) patients. Venous cannulation was performed bicavally, or by cannulating the superior vena cava together with the right femoral vein. A vent cannula was inserted into the right upper pulmonary vein for left ventricular venting in all patients. Antegrade hypothermic, blood, or crystalloid cardioplegia was administered for myocardial protection; 28-30\u00b0C systemic hypothermia was maintained. In some cases, where the mitral valve was exposed following the right atriotomy, the transseptal approach was preferred due to severe adhesions. The aortic cross-clamping time ranged from 29 to 190 min and the mean time was 85.5 \u00b1 36.4 min, and total perfusion time (TPT) was 135.3 \u00b1 68.73 min.129 patients with PVO were studied retrospectively over 5 years (2003\u20132007). The incidence of PVO during this time is shown in Figures The causes and incidence of prosthetic valve obstruction are shown in Prosthetic aortic valve obstruction was documented in 50 patients; 44 (88%) of them were bileaflet prostheses, 30 of which were St. Jude Medical, 3 CarboMedics, 10 Mira-Edwards, and 1 Sorin-Bicarbon; 4 (8%) were tilting-disc valves, and 2 (4%) were caged-ball valves.There were 108 mitral prosthesis obstructions involving bileaflet valves in 102 (94.4%) of 108 patients , and tilting-disc valves in 6 (5.6%) patients.Of the 129 patients with proven prosthetic valve obstruction, 47 (36.4%) patients underwent mitral valve surgery, 16 patients (12.4%) had aortic valve surgery, and 21 (16.3%) had both aortic and mitral valve operations. Twenty-two (17%) patients had mitral valve replacement with tricuspid valve repair, 1 (0.8%) had double valve replacement (DVR) with tricuspid valve repair, 7 (5.4%) had redo mitral valve replacement with aortic valve cleaning, 5 (3.9%) had aortic valve cleaning, 5 (3.9%) had mitral valve cleaning, and 5 (3.9%) had redo double valve replacement .Intensive Care Unit (ICU) stay was between 4 and 22 days. Eighty-two patients were transferred from ICU to the ward without complications. Forty-seven patients had complications during hospitalization; two patients had bleeding; CVA developed in four patients, and two of them expired. Five patients developed renal failure which required dialysis, three improved, and two expired with multiorgan failure. Nine patients had prolonged intubations due to severe chronic obstructive pulmonary disease (COPD), three of them required tracheostomy; five patients expired due to multiorgan failure and sepsis. Two patients developed hepatic impairment and were managed successfully. 18 patients developed cardiogenic shock, 15 of them expired. Two cases were complicated and one case expired due to other causes. The total in-hospital mortality rate was 17.2% (23 patients).Rheumatic heart disease is the main cardiovascular disease in Yemen and it is associated with a high morbidity and mortality. Valvular replacement with a mechanical valve is the main therapy for advanced valvular heart disease. Mechanical valves need lifelong anticoagulation therapy. The increased incidence of valve dysfunction observed in this series can be explained by the increased number of valve replacement operations performed at our cardiac center year by year as shown in . The maiThrombus formation is due to the interaction of cellular and plasmic components of blood with injured endocardium, structural and metabolic changes due to variable blood flow, and the surface of the mechanical valve that has thrombogenic properties.4 ThromboOur protocol for anticoagulation therapy is to keep the therapeutic level of INR between 2 and 3.5 in patients undergoing mitral or aortic mechanical valve replacement, and between 2.5 and 4 in those undergoing double mechanical valve replacements. Patients receive information regarding the importance of anticoagulation for their prosthetic valves and for their lives. Warfarin dose is adjusted before discharge to reach the desired INR level. Patients are asked to come back to the cardiac center 2 weeks after discharge. However, the vast majority of the patients are referred to our hospital from other provinces of the country, where a regular INR measurement is usually not available. Therefore, it is impossible to say exactly whether anticoagulation is kept within therapeutic range in all patients in the follow-up period after 2 months. Most of the patients who live in towns and villages where there are no facilities to check the INR are probably not following the required level. Others may be not taking anticoagulation either because of poverty, or because they do not follow the medical instructions; still, others may not be monitoring their INR and consequently, inadequate anticoagulation levels were detected in 67.4% (87 of 129) of patients in this study.Thrombus formation on the valves is a condition stimulated by thrombocyte activation and factors such as the adequacy of anticoagulation, cardiac rythym, and blood flow characteristics6Pannus formation, which is an overgrowth of the fibrous tissue, is an inflammatory foreign body reaction that may invade the valve orifice Histological investigations showed that collagen and elastic tissues contain endothelial cells, chronic inflammatory cells, and myofibroblasts in pannus tissue. Pannus tet al.,[9In a study by Devies et al., the mostet al., Lower pret al.,910All patients underwent emergency surgery. All factors transiently or permanently stimulating the coagulation factors and thrombocyte aggregation increase the risk of local thrombus formation. The level of coagulability is determined by the instant effects of procoagulant and anticoagulant factors. Inadequate anticoagulation, loss of atrial contraction, oral contraceptives, systemic drugs, such as estrogen, systemic diseases, such as malignant tumors, a defect on the surface of a mechanical prosthetic valve, and chronic endothelial injury due to variable blood flow can all cause local hypercoagulability.12 ThrombThe mortality rate in PVO is greater in cases with thrombus than with pannus. This is related to rapid hemodynamic deterioration associated with valve thrombosis. Acute thNonsurgical management such as thrombolytic therapy can also be administered to patients with prosthetic valve obstruction due to thrombus formation. In this Prosthetic valve dysfunction is an emergency condition with hemodynamic deterioration and high mortality in valvular reoperations. The high incidence of valve thrombosis among Yemeni patients necessitates urgent steps to find solutions to avoid this disastrous complication. For those who are living in areas without good medical care, there are a number of measures that could be taken: (1) good patient education pre- and postoperation; (2) provision of free anticoagulation drugs such as warfarin; (3) closer attention to INR level monitoring could be achieved with the distribution of free INR kits; and (4) use of tissue valves rather than mechanical valves. All these may be good solutions to address this problem."}
+{"text": "Bacterial resistance to antibiotics is a public health problem. Mastering their distribution is thus a priority. Thus, at the Principal Hospital of Dakar (HPD), a system for collecting and analyzing data of resistance has been established within the Committee against nosocomial infections.We present here the results compiled over a year to help guide prevention activities.Prospective study from January 1 to December 31, 2012 at the HPD. Every day, multiresistant bacteria isolated in the laboratory are subject to a collection of clinical and biological data using a questionnaire. Enterobacteriaceae producing extended-spectrum beta-lactamase (ESBL) and derepressed cephalosporinases of Pseudomonas aeruginosa, multiresistant Acinetobacter and Methicillin Resistant Staphylococcus aureus isolates were analyzed. The data are then analyzed by Epi info.323 BMR were collected during the study period. The average age was 32 years  and the sex ratio was 1.70. ESBL-producing Enterobacteriaceae (80%) followed by Acinetobacter multiresistant respectively (11%), ticarcillin-resistant Pseudomonas aeruginosa (4%) and methicillin-resistant Staphylococcus aureus (4%) were the most common isolates. ESBLs were as follows: 55% Klebsiella, E. coli 32% 11% Enterobacter, and others 2%. Blood cultures were the most common samples (40%), followed respectively by urinary tract infections (37%) and abscesses (16%). The pediatrics department was most affected (45%), followed respectively by the Internal Medicine and Resuscitation (each 23%) and Surgery (9%). A catheter was present in 91% of patients with sepsis and 66% of ESBL infections ESBL-producing Enterobacteriaceae were considered nosocomial.This study shows the important place occupied by multi-resistant bacteria Principal Hospital. ESBL-producing Enterobacteriaceae represent the most common resistant organisms, mainly in the form of nosocomial infections.None declared"}
+{"text": "To the Editor: The prevalence of hepatitis C virus (HCV) infection is high (8% of the population) in Pakistan (>1 genotype (mixed genotype infection) of this virus  for all regions in Pakistan by using molecular-based genotype-specific methods  of HCV RNA in a mixed genotype population  samples and 3,944 (17.8%) were not typeable. A total of 1,007 (5.5%) patients had HCV mixed genotype infections.The distribution of mixed genotype infections in 1,007 patients is shown in Patterns of HCV mixed genotype infections in Pakistan are similar to those reported from India and Iran  in Pakistan had significantly fewer HCV mixed genotype infections than men  (p<0.01). This finding might be the result of women having fewer risk factors for contracting mixed genotype infections. Possible risk factors for infection with mixed genotype infections analyzed were blood transfusions and use of blood products (51.3%); multiple use of needles or syringes (18.4%); sharing razors during shaving or circumcision, piercing instruments, nail clippers, and toothbrushes (13.7%); and major or minor dental surgery (9.5%). Mode of transmission was not clear for 7.1% of the patients.In conclusion, the prevalence of HCV mixed genotype infections in Pakistan is higher than previously reported and higher among men (p<0.01). Comprehensive and detailed investigations are warranted to evaluate the clinical role of chronic HCV mixed genotype infections, provide essential information that can be used to determine type and duration of therapy needed, and predict disease outcome."}
+{"text": "Central line associated bloodstream infection (CLABSI) is the most common healthcare-associated infection in high-risk children and is associated with significant mortality, increased length of hospital stay and increased healthcare costs. There are limited data on the epidemiology of CLABSIs in hospitalized children in Greece.The study aim was to prospectively assess the epidemiology of CLABSIs in 3 children`s hospitals in Greece.We conducted active surveillance for CLABSIs in 2 pediatric intensive care units (PICU), 5 neonatal intensive care units (NICU), 2 oncology units and the Bone Marrow Transplant Unit (BMTU) from September 2012 to February 2013. Surveillance was conducted using the Centers for Disease Control and Prevention definitions.Enterobacter (20%), followed by Klebsiella (16%), E.coli and Candida (14%) and Pseudomonas (11%). Multi-drug resistant organisms predominated with 2/3 (66%) of enterococci exhibiting resistance to vancomycin and 15/24 (62%) of the Gram negatives were resistant to third generation cephalosporins (likely ESBLs). Carbapenem resistance was seen in 1/24 (4%) of Gram negative isolates.There were 34 CLABSIs (25 patients) within the study period resulting in an overall rate of 4.4/1.000 catheter-days. The highest rate was observed in PICUs (14.4) followed by NICUs (2.4), BMTU (1.9) and oncology units (1.8). The most common isolate was Almost all patients had received antibiotics in the previous month (92%). 52% of the children who experienced a CLABSI were oncology patients. 56% of children with CLABSI had received parenteral nutrition and 76% blood transfusion within 7 days from the infection.We found high CLABSI rates in the PICU compared to rates reported in the United States and European Union. Rates in the other units were comparable to rates reported in the USA and EU. The majority of pathogens were MDROs and this is consistent with the high rate of MDROs, especially in adults, reported from Greece. Infection control and antimicrobial stewardship efforts should be developed and focused on units with high CLABSI and MDRO rates.None declared"}
+{"text": "Multidrug resistant strains of A. baumannii are an emerging problem in hospitals. We describe the management of a CRAB outbreak including 12 cases in a surgical department comprising a 40-bed ICU and a 16-bed isolation-ward (IW) for patients with multidrug resistant organisms (MDRO). The IW was originally designed for MRSA patients only.Descriptive epidemiological study of the time period before and after implementation of control measures.Between 23/1/2011 and 10/2/2011 five CRAB cases were detected in the IW. The following control measures were implemented: contact isolation and cohorting of cases, frequent disinfection of equipment and frequently touched surfaces, closure of the common bathroom and education of staff concerning contact and standard precautions. CRAB screening of all inpatients hospitalised on the ward since 15/1/2011 was performed. The screening sites were: 1) tracheal secretion or upper airway, 2) anus, perineum or groin, 3) wound. The screening revealed 3 new cases and the ward was closed for new admissions. Between 16/2/2011 and 22/2/2011 two new CRAB cases were detected on the surgical ICU and CRAB screening of all ICU patients was done revealing 2 more cases.Using repPCR, all isolates were found to be genetically identical. Further active surveillance cultures revealed no new casesuntil 15/3/2011.Consistent and immediate implementation of the infection control measures resulted in the containment of the outbreak.None declared."}
+{"text": "The present study evaluated indications\u2019 validity of cervicoscopic and microcolposcopic examination in LSIL patients with unsatisfactory or negative colposcopy.In the cervico-vaginal pathology unit of the \u201cSan Giovanni Calibita Fatebenefratelli\u201d University of Rome \u201cTor Vergata\u201d, 119 patients with a positive cervical cytology (LSIL), were submitted to the exam for the following two indications: 1) unsatisfactory colposcopy 37 (31.1%); 2) negative colposcopy 82 (68.9%).Cervicoscopy allowed the SCJ visualization in 115 (9.6%) patients. In 4 patients 3.4%, the SCJ visualization was not possible due to cervical stenosis. Cervicoscopy without staining, revealed endocervical squamous columnar junction in 33 (28.7%) patients. The blue dye in panoramic view detected endocervical SCJ in 41 (35.7%), out of 115 patients (>5 mm in 34 (29.6%) patients and >10 mm in 7 (6.1%)).Cervicoscopic examination revealed 7.8% of CIN2-3 in LSIL patients with inadequate or negative colposcopy. In patients with negative colposcopy the percentage of undiagnosed lesions inside the cervical canal was very low. The blue dye added sensitivity to the exam. The better knowledge of the evolution of the cervical disease, concerning timing and modalities of progression, allows to follow up a high number of low grade lesions without treatment , 2. The In the cervico-vaginal pathology unit of the \u201cSan Giovanni Calibita Fatebenefratelli\u201d part of the Division of Perinatal Medicine, University of Rome \u201cTor Vergata\u201d, we performed, from January 2009 until June 2011, 290 microcolposcopy examinations.Inadequate colposcopy 37 (31.1%);Negative colposcopy 82 (68.9%).Among these we retrospectively selected, for the purpose of the study, 119 patients with a positive cervical citology (LSIL), who underwent the microcolposcopy for the following two indications:All the patients signed a written informed consent before the exam.The examinations were conducted by a single operator (E.V.), using a 2.9 Bettocchi hysteroscope (Storz) with a 4 mm single-flow diagnostics sheath for the infusion of saline solution, which allows the continuous distension and cleaning of the cervix. The staining of squamous and metaplastic cells was obtained with Waterman blue (a non-toxic dye introduced and tested for the absence of toxicity and / or adverse reactions by Hamou)  which waThe first step (cervicoscopy) Fig.  consisteThe second step consisted of the staining with the Waterman blue dye and of the examination of the SCJ in panoramic view in order to highlight areas of staining in the cervical canal indicative for the presence of metaplastic or squamous cells at this level Fig. .The third step consisted of the contact examination for the evaluation of cellular aspects (microcolposcopy).The evaluation of cellular abnormalities was graded according to the classification proposed by Hamou , which cResults were divided considering the 3 steps of the examination. The cervicoscopy allowed the SCJ visualization in 115 (96.6%) patients.In 4 patients (3.4%) the SCJ visualization was not possible because of EUO stenosis caused by previous cold knife conization.The SCJ without staining resulted endocervical in 33 (28.7%) patients, and the blue dye detected the SCJ endocervical in 41 (35.7%), >5 mm in 34 29.6%) and >10 mm in 7 (6.1%)  patients from the unsatisfactory colposcopy group, and in 23/82 (28.0%) patients with negative colposcopy .G2 cellular abnormalities were detected in 11 (33.3%) of the patients with inadequate colposcopy, and in 14 (17.1%) with negative colposcopy , the presence of intraepithelial neoplasia ; others were metaplastic inflammatory or atrophic changes.The evaluation of cervical canal has been performed with many different methods and for different indications. Many authors propose endocervical curettage -18, thatFinally, our results show that cervicoscopy identified in LSIL patients with inadequate colposcopy a percentage of 7.8% patients with high grade lesions, otherwise considered negative, and conversely avoided a blind endocervical curettage in the great majority of these patients. The blue dye added sensitivity to the exam and it can be employed in panoramic view without a specific cytologic experience. Microcolposcopy with contact examination resulted to be useful for the prevision of results, grading the lesion with a higher sensitivity, but it requires a specific training.In conclusion, we propose the introduction of cervicoscopy in LSIL patients with inadequate colposcopy in the work up for the prevention of cervical cancer.Further research on endocervical targeted biopsies performed also in negative patients should better establish the negative predictive value of the exam, in order to perform targeted biopsies only in G2 patients, and completely avoiding the endocervical curettage."}
+{"text": "Disorder of Sex Development (DSD) is a congenital condition in which development of chromosomal, gonadal or anatomical sex is atypical. They are complex condition related to social stigma, cultural and beliefs in Indonesian population. In Indonesia, there is only a few study regarding characteristic of DSD patients. The aims of our study was to evaluate the characteristic of patients with DSD in Cipto Mangunkusumo Hospital, Jakarta, Indonesia.We retrospectively reviewed the medical records of patients followed up over the period from 2010 to 2012 in Endocrinology Pediatric Clinic, Cipto Mangunkusumo Hospital, Jakarta, Indonesia. We found 74 patients with DSD. In this paper we excluded 29 patients confirmed as Congenital Adrenal Hyperplasia and 3 patients with Turner syndrome.Of 42 patients, 23 (54.8%) patients had 46,XY DSD; 11 (26.2%) patients had sex chromosome DSD; 3 (7.1%) patients had 46,XY DSD, and 5 patients have not done chromosomal analysis. The age when first diagnosed was ranging from newborn to 14 years old. Most cases referred by pediatrician (33.3%) and urologist (23.8%) with frequent complaint were ambiguous genitalia (52.4%) and severe hypospadia (14.3%). The most frequent of phenotype was hypospadia (66.7%). Twenty five (59.5%) of patients have been raised as boy prior to diagnosis. Twelve patients were raised as girls have 46, XY karyotype and 2 patients raised as boys have 46, XX karyotype. Definite diagnosis of 23 patients with 46, XY DSD was found only in 4 (17.4%) patients. The problem regarding lack of definitife diagnosis was related with the high cost of laboratory examination and socioeconomic problem in Indonesia.Our study suggest that the most common cause of DSD in our clinic was 46, XY DSD. Karyotype and clinical phenotype may help in establishing the diagnosis."}
+{"text": "Primary vasculitis of the central nervous system is a newly recognized, devastating inflammatory disease restricted to the brain and spinal cord. Previously healthy children and adults develop life-threatening neurological deficits including stroke and seizures. Within CNS vasculitis distinct disease entities have been identified in different age groups. The aim was to describe the presenting features of children and adults with CNS vasculitis, to compare distinct entities and their treatment regimens between adult and children and to analyze disease progression and/or relapse.Two cohorts of consecutive patients with primary CNS vasculitis based on Calabrese criteria diagnosed over a 21 year period and followed at tertiary vasculitis centers were identified: 1) adult patients  and 2) pediatric patients . Patient demographic characteristics, presenting clinical features, neuroimaging characteristics, brain pathology results, clinical course including progression and relapse and treatment regimens were recorded. Characteristics of cohorts were analyzed using descriptive statistics. Univariate analysis compared distinct disease phenotypes and treatment regimens. Kaplan Meier survival analysis was performed to determine survival after CNS vasculitis diagnosis.A total of 227 patients were included in the study; 101 adult patients and 126 pediatric patients. In children the median age was 8 years (1-17 years) and in adults 47 years (17-84 years). Pediatric patients showed a male predominance (F: M = 1:1.5) in contrast with the adult cohort (F:M = 1.3: 1). Diagnosis was established on angiography only in 88 pediatric and 52 adult patients, and on brain biopsy with negative angiography in 29 pediatric and 8 adult patients. Vessels involved were: in children 35 small vessel and 91 large vessel, in adults 22 small vessel, 6 large vessel and 48 small and large vessels. Brain biopsy: performed in 49% of adult patients with a male predominance (F: M = 1:1.2) compared to 25% in children with a female predominance ( F:M = 1.9:1). Histology showed only lymphocytic inflammation in children and predominantly a granulomatous pattern in adults . Treatment strategies: in children prednisone in 59 (47%) and cyclophosphamide in 34 (27%), in adults prednisone in 97 (96%) and cyclophosphamide in 46 patients (46%). Relapse or progression of the disease was seen in adults in 26% and in children in 15%.Distinct differences are present in the spectrum of primary CNS vasculitis in adults and children. Biopsy only or angiography only confirmed disease shows different gender predominance in adults compared to children. Adults are treated more frequently with steroids and cyclophosphamide, however relapse rates are lower in children.Marinka Twilt: None; Carlo Salvarani: None; Tania Cellucci: None; Gene G. Hunder: None; Susanne M. Benseler: None."}
+{"text": "Seasonal influenza (SI) infection represents a threat for the elderly. We investigated a nosocomial outbreak of SI in the 300-bed geriatric facility of the Geneva University Hospitals.. All positive viral specimens were processed and sequenced in order to track the transmission dynamics.Based on surveillance of clinical influenza cases, a nosocomial outbreak was suspected at the geriatric hospital. Between 15 Jan and 30 Apr 2012, all suspected cases were screened for respiratory viruses through nasopharyngeal real-time reverse transcription-polymerase chain reaction (RT-PCR) and infection control procedures (droplet precautions with single room isolation whenever possible) were implemented. The first proven case was detected on Feb 3 and the last on Apr 2, 2012. Cases were defined as nosocomial when symptoms occurred after 72 h following hospital admission. Patients and healthcare workers (HCWs) vaccination status were also investigatedOf 155 suspected cases, 73 (47%) had RT-PCR-proven SI; 62/73 (85%) were nosocomial. 26/155 (17%) were positive for other respiratory viruses, and 60 (36%) proved negative. Among all the confirmed cases, four main clusters of nosocomial transmission were identified by viral sequencing. 43/73 (60%) patients were given oseltamivir treatment and only 4 (9%) were inappropriately treated (>72 h from disease onset). Of 23/73 (32%) patients who experienced clinical complications, 4 required enhanced care and 7 died. Over 90% of clinical complications were observed in wards admitting patients with more severe underlying diseases. Vaccine coverage among HCWs was low .Influenza remains a severe infection among hospitalized elderly patients. Very low HCW vaccination rates and gaps in recommended infection control procedures are likely to have contributed to the nosocomial spread of SI, together with the observed mismatch between the vaccine and late circulating H3N2 strain, and the potential weakness of the immune response to vaccination in the elderly. Improved strategies for the prevention and control of SI should be implemented for hospitalized geriatric patients.None declared"}
+{"text": "To understand the relationship between HAART and preterm delivery (PTD).Analysis of prospectively collected data from all patients attending HIV antenatal services at a single UK centre 1995\u20142010. Fisher's exact test two tailed for categorical variables. T-test for continuous variables.Data are presented on all 324 deliveries up to 26/07/2010. 78% of the women were Black African, 10.3% Caucasian. Risk for HIV infection was heterosexual intercourse in 94%, injecting drug use in 1.2%. Median gestational age at first ante-natal clinic appointment was 13 weeks. 7 women took no therapy prior to delivery and 7 took dual NRTI treatment. Data on the remainder are summarised in Table 11. Of these 10 had a preterm delivery (30.3%).Delivery before 37 weeks (PTD) occurred in 14.4% pregnancies of which 62%  before 34 weeks. Difference not significant comparing PTD in patients starting new continuous HAART (17.2%) with pre-conception HAART (12.6%). PTD occurred in 17/142 (12.%) women treated with nevirapine-based HAART compared with 24/102 (23.5%) treated with protease inhibitor (PI)-based HAART (p 0.02). Of the 64 patients treated with a short-course of HAART (START) during pregnancy to prevent mother-to-child HIV transmission 33 were eligible, if willing to delivery by pre-labour caesarean section (PLCS) to receive zidovudine monotherapy (ZDVm) according to the 2008 BHIVA guidelinesThe role of HAART and PI-based HAART in PTD has been controversial. Even in this single-centre study, where all women were managed by one team in accordance with national guidelines, confounders abound. CD4 counts and viral loads differed significantly between patients starting HAART in pregnancy and those taking ZDVm or already on HAART at conception. We therefore compared PTD rates in women who were eligible for, and chose between, START  and ZDVm with PLCS. The rates of PTD were significantly higher (p 0.005)with START (30.3%) than with ZDVm (6.6%) in these ZDVm eligible mothers. These data suggest that PI-based HAART initiated during pregnancy is associated with a significantly increased rate of PTD and that this is influenced by maternal immune status. Further investigation to determine whether other regimens may have less impact on PTD are urgently required particularly with the increasing use of HAART in prevention of mother-to-child transmission."}
+{"text": "Onchocerca volvulus infection and assess the perception of the disease among the inhabitants of this community.This study was carried out in Opi-Agu a tropical semi-urban autonomous community comprising of three villages in Enugu State, Nigeria, between the months of April and June 2010. It was designed to determine the prevalence of A total number of 305 individuals comprising of 148 males and 157 females were examined for various manifestations of onchocerciasis symptoms using rapid epidemiological assessment (REA) method.O. volvulus infection was not observed. Questionnaire responses from 410 individuals revealed that 34.8% respondent from Idi village and 28.1% from Ibeku village believed that O. volvulus infection occurs through poor personal hygiene. Bite of blackfly ranked least (10.6%) among the respondent's knowledge of the causes of onchocerciasis in Opi-Agu community.Out of this number, 119 (39.02%) individuals were infected. Prevalence of infection among age groups and villages varied. Age group 41 yr and above had the highest (31.00%) prevalence, while among the villages, Ogbozalla village ranked higher (45.71%) than the other villages. Overall the prevalence of infection among the sexes revealed that males were more infected (43.24%) than the females (35.03%). Lichenified onchodermatitis (LOD) was the most prevalent (35.29%) onchocerciasis symptom among others identified in the area, while leopard skin (LS) had the lowest (20.17%) occurrence and blindness (0.00%) which is the most devastating effect of Opi-Agu community members had poor knowledge of onchocerciasis, the vector and of its etiologic organism. There is need for integration of community health education with mass chemotherapy. Onchocerca volvulus. The parasite is transmitted to humans who are the only known vertebrate host through the bite of a female blackfly of the genus Simulium, and in Nigeria it is transmitted by S. damnosum complex  determining the various manifestations of onchocercal skin diseases (OSD) and palpable nodules and (iii) assessing the perception of this disease by community members.This study aimed at: (i) assessing the prevalence of Opi-Agu is a tropical semi-urban autonomous community comprising of three large villages located within latitude 7\u00b0 25\u2019 to 7\u00b0 30\u2019 E and longitude 6\u00b0 43\u2019 to 6\u00b0 48\u2019 N  14). Th. Th14). Sampling: Random sampling using lottery method was employed for the selection of 305 subjects  used for the study  among the various age groups were also assessed using percentages.A total of 305 individuals comprising of 148 males and 157 females were examined for onchocerciasis symptoms. One hundred and nineteen (39.02%) persons were infected. Among the villages studied, Idi village had the lowest prevalence (26.88%) while Ogbozalla village and Ibeku village had (45.71%) and (42.99%) prevalences, respectively . A progrO. volvulus infection while the females had 55(35.03%) prevalence (The highest (31.09%) prevalence was observed within age group 41 and above while the least (8.40%) prevalence occurred within age group 9 \u2013 16 years. Age group 25 \u2013 32 years and 33 \u2013 40 years had a prevalence of (22.69%), respectively . Overallevalence . The mosevalence .This was followed by age group 25 \u2013 32 years (37.04%). Palpable nodules were observed in all age groups with the highest (33.33%) prevalence recorded in age groups 25 \u2013 32 years . OnchoceMajority of the inhabitants of Opi-Agu community (26.6%) believed that poor personal hygiene which ranked highest among other causes was the cause of onchocerciasis. This was followed by witchcraft (23.9%) and tsetse fly (22.7%), while bite of blackfly ranked least (14.9%) .S. damnosum) among females. The males while cultivating usually expose their body and are more prone to infection due to bite of blackfly. Okoye and Onwuliri  onchocercal sign. Among age group 9-16 years, leopard skin and lichenified onchodermatitis were entirely absent and palpable nodules ranked least (20%) while maculopapular rashes had the highest (80.00%) prevalence. The finding of this study was is in line with the findings of Okulicz et al.  was established in Nigeria in December 1995 by WHO at the World Bank Headquarters in Washington DC, USA. APOCs strategy for the control of onchocerciasis was Community Directed Treatment with ivermectin (CDTI) aimed at effective and sustainable, community-directed treatment with ivermectin throughout the endemic areas within the geographic scope of the programme, and, if possible, eradication of the vector in selected and isolated foci, by using environmentally safe methods .There is therefore an urgent need for CDTI intervention programme in Opi-Agu autonomous community, Enugu State, Nigeria as a means of controlling the spread of onchocerciasis in the communities and its immediate environs."}
+{"text": "The reduction in intra-ocular pressure (IOP), Visual acuity changes and complications were noted.The mean presenting and preoperative IOP was 35.6+/-12.5mmHg and 25.5+/-6.6mmHg respectively. The mean post-operative IOP was 10.0+/- 5.2mmHg on the second post-operative day and 16.5+/7.3mmHg at 3 months. Post-operative complications included ocular hypotony in 4 (25 percent), shallowing of anterior chamber in 3 (18.8 percent), hyphema and cystic bleb in 2 (12.5 percent) each. None had bleb failure. 5 FU appears to reduce the relative risk of failure of trabeculectomy in those undergoing surgery for the first time .The use of 5-FU during trabeculectomy is associated with significant benefit in terms of intraocular pressure lowering beyond 3 months postoperatively. The results of surgery in Nigerian patients compare well with other reported series. Intra-ocular pressure (IOP) is one of the only risk factor for glaucoma that can be manipulated to alter the cause of the disease. While great success has been achieved with medical treatment; surgery still remains the mainstay of treatment for glaucoma especially among black African patients due to the unavailability and high cost of topical therapy.Trabeculectomy is performed as a treatment for glaucoma to lower the intra-ocular pressure. However, the procedure tend to fail over time because of fibroblastic proliferation and subconjunctival fibrosis that occur during normal healing.1In order to reduce failure rates adjunctive use of antifibrotic agents with glaucoma surgery significantly reduces the risk of bleb failure, although their use has been associated with a number of complications.This study reports the effect of intra-operative 5-FU application during primary trabeculectomy on IOP in this African population.This was a prospective study of all patients with glaucoma who had trabeculectomy with intra-operative use of 5-FU at the Obafemi Awolowo University Teaching Hospital, Ile-Ife, Nigeria between January 2002 and December 2004.Approval for the study was obtained from the Research and Ethics committee of the Obafemi Awolowo University Teaching Hospital Complex, Osun State, Nigeria. All participants gave informed consent.All patients were examined pre-operatively for IOP (Applanation), visual acuity (Snellen's), gonioscopy, and visual field (Humphreys). Patients were initially placed on medical therapy for established glaucoma and immediately advised to have surgery as soon as possible. Post-operatively, patients were evaluated on day 2, the first week and in the first month for anterior chamber formation, IOP measurement and Visual acuity.Thereafter they were followed up every three months for I year and they are still currently being followed by measuring IOP, visual acuity, visual field every 6 months till date. Additional anti-glaucoma medications were administered in those with poor control of IOP. Success was determined by post operative IOP 20 mmHg or less without anti-glaucoma medication at the time of examination.The technique of trabeculectomy used in all patients was Watson'sTrabeculectomy, using an intra-operative sponge soaked in 5 percent 5-FU was performed on 49 eyes of 34 patients. There were 20 males and 14 females with a M: F ratio of 1.4:1. The age range was 8 to 78years; mean age was 39.6 +/- 14.5 years (SD).Most of the eyes 44 (89.8 percent) had chronic open angle glaucoma while 5 (10.2 percent) had chronic narrow angle glaucoma. Most of the eyes 44 (89.8 percent) had 5-FU-augmented trabeculectomy at the first surgery while 5 (10.2 percent) eyes had 5-FU application during a repeat surgery.The presenting intra-ocular pressure ranged from 18 to 56 mmHg, with a mean of 35.6+/- 12.5mmHg (SD). The mean post-operative IOP was 10.0+/- 5.2mmHg on the second post-operative day and 16.5+/7.3mmHg at 3 months. The mean post-operative IOP was 17.4+/- 8.5mmHg and 18.5+/- 6.8mmHg at 6 months and 12 months respectively. Intraocular pressure significantly dropped from mean =25.5+/-6.6mmHg before surgery to mean=18.5+/- 6.8mmHg (p <0.0001)12 months after surgery.nd post-operative day, 45 (91.8 percent) eyes had a post-operative IOP of 20mmHg or less while 4 (8.9 percent) eyes had IOP of over 21mmHg. At 3 months post-operative visit IOP ranged from 6 to 20 in 41 (83.7 percent) eyes. Postoperative IOP was less than 20mmHg in 40 (81.6 percent) eyes and 41 (83.7 percent) eyes at 6 months and 12 months respectively. Post-operative complications included ocular hypotony (25.0 percent), shallowing of anterior chamber (18.8 percent), Hyphema (12.5 percent), cystic bleb (12.5 percent) . 5-FU apThe effectiveness of glaucoma surgery is closely related to the degree of scarring. Bleb failure often occurs over time because of fibroblastic proliferation and subconjunctival fibrosis which occurs during normal process of wound healing. Adjunctive use of anti-fibrotic agents such as 5-FU or Mitomycin C at the sight of surgery significantly reduces the risk of bleb failure.910Topical application of 5-FU was preferred in this study because of it's advantages over post-operative injection of the same. The former is associated with less frequent patients' visits, no risk of ocular perforation nor corneal epithelia abnormalities and decreased discomfort to the patients.1112The use of 50mg/ml concentration of 5-FU for sponge dabbing the sclera surface was due to the tested efficacy of this dosage in post-operative application in the blacks.1213In our study mean intra-ocular pressure was significantly reduced at 12 months. The success rates recorded were 83.7 percent and 81.6 percent at 3 months and 6 months respectively. These findings are in agreement with the report of other workers. Bayeroju and Ubah recorded a success rate of 85,7 percent at six months16In our study, the longest follow up period of 2 years was recorded for only a few of the patients. Follow-up visit in our eye clinic is very poor. Most of the patients stop coming to hospital once they have a slight relieve in their symptoms.Visual acuity improved post-operatively in 5 eyes , worsened in 5 eyes (2 due to advancing cataract) and remained the same in the rest. Visual acuity fell by 2-3 lines in those who had advancing cataracts.Early postoperative complications which were mainly transient  occurred in 11 eyes (22.5 percent) and this was associated with postoperative loss of 2 or more lines of Snellen acuity . Other complications include progressing cataract formation and ptosis. No significant permanent sight threatening complications was detected but it is likely the sample size was not large enough or of sufficient duration to address the long term risk of bleb infection and endophthalmitis, which has been reported in observational studies. Late complications recorded in other studies were endophthalmitis and late bleb breakdown.The use of 5-FU during trabeculectomy is associated with significant benefit in terms of intraocular pressure lowering beyond 3 months postoperatively. The results of surgery in Nigerian patients compare well with other reported series."}
+{"text": "Necrotizing fasciitis (NF) is one of the most severe diseases among surgical infections. There is always severe sepsis, multiple organ dysfunction, septic shock with NF and high mortality rates from 50% to 80 to 100%. Progressive severe sepsis with a lack of local inflammatory symptoms is being characterized as a modern clinical view of NF.A 5-year retrospective analysis of 12,907 admitted patients to the Department of Surgical Infections and Sepsis from 2007 until 2011 years was performed. All patients were admitted by the emergency service. The duration of admitting to the hospital from disease onset was 1 to 7 days, with a mean of 2 to 3 days.Enterococcus faecalis (18.5%), Staphylococcus aureus (15.5%), Streptococcus (14%) and anaerobic cultures (6.6%). All admitted patients had been treated immediately with high doses of intravenous antibiotics and extensive surgical treatment of the infection lesions; following intensive treatment in the ICU was made. Serious attention to immunotherapy was made. Severe reduction of the lymphocytes and hemoglobin seemed clinically significant in prediction of inflammation severity.There were 86 patients with NF in 2007 to 2011. All patients had severe sepsis or septic shock with multiple organ dysfunction proved by laboratory tests and were treated in the ICU. The most frequent accompanying immunodeficient disorders are diabetes, oncology, alcohol and drug addiction, and extensive contusion of soft tissues. There were six patients in 2007 with NF (2 discharged/4 died), 13 patients in 2008 (7/6), 18 patients in 2009 (6/12), 16 patients in 2010 (12/4), and 33 patients in 2011 (15/18) correspondingly. Obtained results show a stable increase of patients with NF. The amount of patients with NF by 2011 was extended 5.5 times compared with 2006. The mortality rates fluctuated between 55 and 66%, less mortality rate was seen in 2010 (25%). On average the mortality rate was 51.5%; this corresponds to the modern literature reviews. The most common organisms isolated were: Accompanying immunodeficient disorders influence rising NF. Early diagnostics and active treatment make better treatment results and decrease mortality rates. Progressive decrease of lymphocytes and hemoglobin is extremely adverse to predict. Using immunotherapy makes clinical results much better. Regular microbiological monitoring of wound infection should make adequate antibiotic therapy."}
+{"text": "The low incidence of colon injury due to blunt abdominal trauma and the lack of a definitive diagnostic method for the same can lead to delays in diagnosis and treatment, subsequently resulting in high morbidity and mortality.A 66-year-old woman with sigmoid colon injury was admitted to our emergency department after sustaining blunt abdominal trauma. Her physical examination findings and laboratory results led to a decision to perform a laparotomy; exploration revealed a sigmoid colon injury that was treated by sigmoid loop colostomy.Surgical abdominal exploration revealed gross fecal contamination and a perforation site. Intra-abdominal irrigation and a sigmoid loop colostomy were performed. Our patient was discharged on post-operative day six without any problems. Closure of the sigmoid loop colostomy was performed three months after the initial surgery. The low incidence of colon injury due to blunt abdominal trauma and the lack of a definitive diagnostic method for the same can lead to delays in diagnosis and treatment, subsequently resulting in high morbidity and mortality.We present the case of a woman who presented with blunt abdominal trauma following a fall who was admitted to our emergency department; sigmoid loop colostomy was performed due to sigmoid colon injury. We compare the outcome in our patient with those reported in the literature.3 cells/\u03bcL), hemoglobin (9.9g/dL) and hematocrit (29.3%) levels. An upright plain abdominal X-ray revealed multiple air-fluid levels. Our patient also had hypertension, and she was taking an angiotensin II receptor antagonist once daily. Surgical abdominal exploration revealed gross fecal contamination and a perforation site  presented due to intra-vehicular accident, five patients (18.5%) presented due to extra-vehicular accident, one patient (3.7%) presented due to assault, and one patient (3.7%) presented due to boating accident [et al. on 82 patients, 57 patients (69.5%) presented due to an out-of-vehicle traffic accident, 18 patients (21.9%) presented due to an occupational accident, six patients (7.3%) presented due to an assault, and one patient (1.2%) presented due to an explosion [et al. on 64 patients revealed that 32 patients (50%) presented due to motor vehicle accident, 13 patients (20.3%) presented due to fall from height, 12 patients (18.7%) presented due to car crashing, and seven patients (10.9%) presented due to assault [et al. reported bull butting in one patient [et al. reported intra-vehicular accident in one patient [Colon injuries generally occur after penetrating abdominal trauma, whereas they are rarely encountered after blunt abdominal trauma. In a retrospective study, the incidence of colon injuries due to blunt abdominal trauma has been reported to be 1.1% . Other catients 7% presentients 18.% presentpatients 9.5% preset al. reported sigmoid colon injury in 12 patients (44.4%), right colon and caecum injury in eight patients (29.6%), transverse colon injury in five patients (18.5%), and rectum injury in two patients (7.4%) [et al., transverse colon injury was seen in 32 patients (39%), right colon injury was seen in 21 patients (25.6%), descending colon injury was seen in 16 patients (19.5%), sigmoid colon injury was seen in 13 patients (15.8%), and rectum injury was seen in five patients (6%) [et al.[et al. reported transverse colon injury [et al. reported sigmoid colon injury [Several mechanisms have been described for colon injuries occurring after blunt abdominal trauma. Crushing of the colonic segment between two objects (between the seat belt and vertebra or pelvis posteriorly) is the most widely accepted mechanism . This repatients 4.4%, rigients 18.%, and reients 29.%, transvpatients .4% [et aet al.[et al. detected isolated colon injury in 20 patients and reported that accompanying injuries were in turn localized to the small intestine, spleen, liver, and kidney [et al., in which colon injuries were most commonly accompanied by small intestine, spleen, liver, and pancreas injuries [et al. detected transverse colon injury [et al. detected sigmoid colon injury [Isolated colon injury following blunt abdominal trauma is a rarely encountered condition. Colon injury is usually accompanied by other intra-abdominal organ injuries, with the small intestine, spleen, liver and pancreas being the leading areas. Isolated colon injury was detected in two patients, whereas colon injury was accompanied by liver injury in 16, spleen injury in 13, and small intestine injury in 12 patients, in the study conducted by Carrillo et al.. Zheng ed kidney . Isolaten injury , whereasn injury . We founIn a patient thought to have a colon injury caused by blunt abdominal trauma, the time between emergency department admission and surgery is of particular importance. A shorter duration minimizes the morbidity and mortality that would be encountered in the post-operative period. The rate of complications associated with colon injury is significantly higher if the duration is longer than 24 h after the injury .At present, there is no single method to accurately diagnose colon injuries caused by blunt abdominal trauma. There are some studies suggesting the efficacy of repetitive physical examination and observation in diagnosing colon injury caused by blunt abdominal trauma in the first six hours, during which the signs of peritoneal irritation appear . Tendernet al. performed resection plus ostomy in 12 patients (44.4%), resection plus anastomosis in 11 patients (40.7%), and primary repair in four patients (14.8%) [et al. performed primary repair in 67 patients (81.7%), and ostomy in 15 patients (18.2%) [et al. performed primary repair in 40 patients (62.5), resection plus anastomosis in 13 patients (20.3%), and ostomy in 11 patients (17.1%) [et al.[et al.[Treatment options include primary closure (colorrhaphy), resection with anastomosis, and colostomy. Primary closure (colorrhaphy) is performed for injuries involving less than 50% of the colonic wall, whereas resection with anastomosis is performed when the tissue loss is more than 50% or when there is extensive mesenteric injury impairing the blood supply . Colostopatients 4.4%, resients 40.%, and prients 14.% [et al.et al.[et al. reported morbidity in 17 (20.7%) and mortality in five (6.1%) patients [et al. reported morbidity in 17 (26.5%) patients, whereas mortality was observed in seven (10.9%) patients [Morbidity and mortality rates following blunt abdominal traumas are increased in colon injuries depending on the difficulties in diagnosis and treatment. Morbidity was observed in 12 44.4%) and mortality was observed in 10 (37%) patients in the study conducted by Carrillo 4.4% and patients . Again,  in five .1% patieIn summary, colon injury due to blunt abdominal trauma is a rare clinical condition, and treatment delays due to difficulties in diagnosis increase the morbidity and mortality rates.Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.GE, MC and FE operated on our patient. GE, MS and TT analyzed and interpreted the data from our patient regarding the blunt abdominal trauma and colonic injury. GE was a major contributor in writing the manuscript. All authors read and approved the final manuscript."}
+{"text": "The aim of this study was to identify and describe brain CT findings in patients with poisoning or drug overdose and altered mental status. In this study, 403 patients with some degree of loss of consciousness who referred due to poisoning or drug overdose were evaluated by brain CT. The most common cause of intoxication was suicide. Intoxication status was determined by the physician and was mainly based on a history of intoxication, positive toxicologic screen result, or physical evidence suggesting intoxication. Among 403 unconscious patients, 229 patients who were ingested or inhaled Benzodiazepine, Carbamazepine, Carbon Monoxide, Ethanol, Methanol, Opium, Tricyclic antidepressants, and Tramadol included in the study. Others had used multiple drugs and/or toxins, or their intoxication was unknown. Mean age of patients was 37.6 \u00b1 17.7 years (14-95). Among them, 181 (79%) were male. Among all patients, 92 had consumed opium (40.2%), 47 had consumed Benzodiazepines (20.5%) and other patients had been overdosed by other drugs or exposed to other poisonous agents. Totally 38 (16.5%) patients had abnormal CT findings. These included 10 cases of infarction, four cases of hemorrhage, two cases of herniation, 13 cases of edema, and 10 cases of basal ganglia changes (including 9 cases of hypodensity and one case of hypodensity with hemorrhage). A good knowledge of the CT findings in unconscious patients due to poisoning or drug overdose seems to be necessary for radiologists and clinicians. This study is unique in that it reported most of the radiological findings in these patients. Poisoning is the third cause of injury related deaths in the United States .The incidence of intoxication is about 1470 per 100/000 in the united stated, with 2.4 million exposures per year  findings in a large group of patients with poisoning or drug overdose associated with altered mental status.We performed this cross sectional study on 403 consecutive unconscious patients with suspected poisoning or drug over dose who who presented to the Loghman-Hakim Poison Hospital (LHPH) in Tehran, Iran were evaluated. The LHPH serves as a tertiary referral center for a population excess of 12 million in the capital of the country and normally sees 28,000 emergency ward presentations due to poisoning and about 12,500 of them are hospitalized each year. It seems that this complex to be the biggest clinical toxicology department in the world from December 2005 to December 2006.This study was approved by our university affiliated hospital\u2019s ethics committee on clinical investigations.We included patients with presentations that appeared to be related to over dose or poisoning according to standard poison control center criteria .These standard criteria were the patient's relative report of ingestion, a witnessed of drug ingestion, finding of empty drug boxes, or a suicide note combined with presentations related to a drug over-dose or poisoning, and toxicology testing when available.All patients showed some degree of unconsciousness and underwent brain CT-scan during the first 24 hours of admission, on a Shimadzu (7800-JAPAN) system.All CT-scans had been performed with the same scanner using the sequential techniques .The window widths ranged from 100 to 120 haunsfield unit (HU) and levels ranged from 35 to 49. In the presence of head trauma history, bone window was performed with window widths of 2000 and level 400, then radiologic features were determined.Brain swelling was classified as three categories: Mild, when the cortical sulci, Sylvian fissure, third ventricle and perimesencephalic cistern were compressed, but visible, in CT. Moderate, when one or two of these structures were not visible. Severe, when three or four of above structures were not visible.Statistical analyses were done by SPSS ver 11.5.Among 403 unconscious patients, 229 who were ingested, or inhaled Benzodiazepine, Carbamazepine, Carbon Monoxide, Ethanol, Methanol, opium, Tricyclic antidepressants, and Tramadol included in the study. Others had used multiple drugs and/or toxins, or their intoxication was unknown.Mean age of patients were 37.6 \u00b1 17.7 years old (14-95). Among them, 181 (79%) were male and 48 (21%) were female. Among all patients, 92 had consumed opium (40.2%), 47 had consumed benzodiazepines (20.5%) and other patients had been overdosed by other drugs or exposed to other poisonous agents  had abnormal CT scan findings. Of these, four patients had skull fracture (three cases showed hemorrhage that could be referred to trauma). Remained 34 patients (14.8%) had abnormal CT scan findings unrelated to trauma. These included 10 cases of infarction, four cases of hemorrhage, two cases of herniation, 13 cases of edema, and 10 cases of basal ganglia changes (including nine cases of hypodensity and two cases of hypodensity with hemorrhage).Totally 47 patients were seen in this group; of them 36 were male (76.6%) and 11 were female (23.4%). Mean age was 34.6 \u00b1 18.4 years old (16-90). 44 cases had suicide (93.6%) and the others had misusing the drug. 12 cases presented with coma (25.5%) and the others had some degrees of loss of consciousness. Totally 5 cases had brain abnormal CT-scans (10.6%). The findings of patients included; one case of infarction (2.1%), two cases of edema (4.2%) , one case of edema with basal ganglia changes (2.1%), and one case of herniation with edema (2.1%).Totally 15 patients were seen in this group. Among them, 10 patients were male (66.7%) and 5 were female (33.3%). Mean age was 28.7 \u00b1 12.2 years old (14-50). 11 cases were hospitalized because of suicide (93.6%) and the others because of misusing the drug. 5 cases presented with coma (33.3%) and the others had some degrees of loss of consciousness. One case had brain abnormal CT-scans (8.5%). This patient had mild edema in the CT scanning.Totally 21 patients were seen in this group; of them 12 were male (57.1%) and 9 were female (42.9%). Mean age was 37.9 \u00b1 15 years old (22-70). One case were hospitalized because of suicide (4.8%), 2 because of misusing (9.5%) and the others for uncurious use . 11 cases presented with coma (52.45%) and the others had some degrees of loss of consciousness. Totally five cases had brain abnormal CT scans (23.8%). The findings of patients were included: three cases of edema (14.3%) [One mild and two moderate], and two cases of basal ganglia changes (9.5%) (Both of them had hypodensity).Totally 10 patients were seen in this group and all of them were male. Mean age was 32.2 \u00b1 12.5 years old (17-50). 9 cases were hospitalized because of misusing (90%). Two cases presented with coma (20%) and the others had some degrees of loss of consciousness. Two cases had abnormal brain CT scans (20%) due to skull fracture that one of them was accompanied with intracranial hemorrhage.Totally 12 patients were seen in this group and all of them were male. Mean age was 43.9 \u00b1 20.3 years old (16-75). 8 cases were hospitalized because of misusing the drug (66.7%). 6 cases presented with coma (50%) and the others had some degrees of loss of consciousness. Totally eight cases (67%) had brain abnormal CT-scans. The findings of patients included: one case of skull fracture that was accompanied with intracranial hemorrhage, one case of intracranial hemorrhage without fracture, and six cases of basal ganglia changes (50%) [5 of them presented with hypodensity and the other one with both hypodensity and hemorrhage].Totally 92 patients were seen in this group. Among them 79 were male (85.9%) and 13 were female (14.1%). Mean age was 44.0 \u00b1 18.6 years old (15-95). 11 cases were hospitalized because of suicide (12%) and 74 (80.4%) because of misusing the drug. 27 cases presented with coma (29.2%) and the others had some degrees of loss of consciousness. Totally 14 cases had brain abnormal CT scans (15.2%). The findings of patients included: seven cases of infarction (7.6%), two cases of hemorrhage (2.2%), three cases of edema (3.3%) [2 mild and one severe], one case of basal ganglia changes (1.1%) (hypodensity), and one case of infarction and hemorrhage(1.1%).Totally 16 patients were seen in this group; of them 10 were male (62.5%) and 6 were female (37.5%). Mean age was 29.3 \u00b1 11.3 years old (18-62). 15 cases were hospitalized because of suicide (93.8%) and 1 (6.2%) because of misusing the drug. 6 cases presented with coma (37.5%) and the others had some degrees of loss of consciousness. Totally 3 cases had brain abnormal CT scans (18.8%). The findings of patients included: one case of infarction (6.3%), one case of edema caused uncal herniation (6.3%), and one case of edema (6.3%).Totally 16 patients were seen in this group; of them 12 were male (75%) and 4 were female (25%). Mean age was 24.8 \u00b1 6.8 years old (16-42). All cases were hospitalized because of suicide. All cases presented with some degrees of loss of consciousness. One case had brain abnormal CT scans (6.3%). The findings of this patient were hemorrhage with hernia and midline shift that was accomplished by skull fracture (thus this hemorrhage could be due to head trauma with skull fracture).Altered mental status is common in patients with poisoning or drug over dose.Typical presentations of drug overdose include decrease in consciousness, agitation, seizures, or movement disorder.Mental disturbances may occur due to pharmacologic effects of the drug  or may be resulted by trauma or a drug-induced vascular accident  or combination of these .The aim of brain CT-scan is rapid diagnosis causes of altered mental condition, such as traumatic intracranial hemorrhage or hematoma.Focal cerebral ischemia of the basal ganglia is one delayed CT-scan finding reported after cyanide, methanol, and carbon monoxide poisoning -15.Another delayed complication of poisons which occur 1 or two days after poisoning is brain edema , 17.One probable risk for obtaining CT-scan in a poisoned patient is transporting the patient from emergency ward for CT-scan. Thus poisoning alone dose not seem to be an indication to obtain brain CT-scan.We all know that MRI is more sensitive than CT for the detection of tissue edema, and also MRI shows poor sensitivity to calcification and it is usually difficult to detect delayed calcified granules. Indeed, MRI gives a better resolution for cortical lesions than CT and also gives better anatomical detail in the case of hemorrhage.Herein we discussed about brain CT-scan findings in our unconscious patients.Methanol is a clear, colorless, highly toxic with a weak odor, slightly sweeter than ethanol.Methanol has a toxic effect on the central nervous system.Bilateral basal ganglia and putaminal necrosis, hypothalamic and cerebellar focal lesions, subcortical white matter demyelination, and edema with hemorrhage in the temporal lobe and bilateral occipital lobes have been reported in patients with methanol poisoning , 6.Putaminal lesions and peripheral white matter findings can also occur in Wilson's disease,  Leigh's Hemorrhage occurs in 13.5% of patients with methanol poisoning that may be due to the direct effects of formate in CNS .We found bilateral symmetrical hypodense lesions in the basal ganglia in 50% of cases with methanol poisoning.One was associated with basal ganglia hemorrhage and Para sagittal ICH, also two patients was associated with white matter hypodensity.et al. patient  are among the most common prescribed medications in the world.et al. reported a case of TCA intoxication that her CT-scan showed progressive cerebellar atrophy .Carbon monoxide (co) intoxication is an emergency condition, which can result in neurological defects or death.Co intoxication may cause different structural defect in the brain.The most common seen changes are bilateral ischemic lesions and necrosis in the grey matter, especially in the globus pallidus , 24.et al. reported necrotic lesions in the purkinje cells of cerebral cortex, in the dentate nucleus, and in the cortex after co intoxication (Narcissi xication .et al (In our study two cases with basal ganglions hypodensity similar to that reported by Yuksel et al .Opium is the most common substance that has been abused in our country.Brain infarction, edema, hemorrhage, and hypodensity changes in basal ganglia were seen in our patients with opium intoxication.Hypoxic brain injury, transverse myelitis, brain atrophy, and toxic leukoencephalopathy were reported as the neuroimaging features of Heroin intoxication , 27.But there is no any report about the effects of opium intoxication.In conclusion, a good knowledge of the CT-scan findings in unconscious patients due to poisoning or drug overdose seems to be necessary for radiologists and clinicians. This study may be useful in that it reported most of the radiological findings in these patients."}
+{"text": "Background and Aim. Distal cholangiocarcinoma associated with choledocholithiasis has not been reported, and the causal relationship remains to be established. We evaluated diagnosis of distal cholangiocarcinoma diagnosed after the removal of choledocholithiasis. Patients and Methods. We assigned 9 cases of cholangiocarcinoma with choledocholithiasis to Group A. As a control group, 37 patients with cholangiocarcinoma without choledocholithiasis were assigned to Group B. Results. Abdominal pain at admission is the only significant difference between Group A and Group B (P = 0.001). All patients in Group A had gall bladder stones, compared with 7 patients (19%) in Group B (P < 0.01). Of the 9 patients in Group A, endoscopic retrade cholangiopancreatography (ERCP) detected normality in 2 patients (22%) and abnormalities in 7 patients (78%). Of the 32 patients in Group B, ERCP detected normality in 4 patients (13%) and abnormalities in 28 patients (88%) (P = 0.597). Intraductal ultrasonography (IDUS) detected a tumor in 8 patients in Group A, while in Group B, IDUS detected normality in 1 patient (3%) and tumors in 29 patients (97%) (P = 1.000). Conclusions. IDUS after stone removal may potentially help in the detection of unexpected tumors. Therefore, we believe that IDUS after stone removal will lead to improve outcome and prognosis. The frequency of cholangiocarcinoma is increasing globally, and it currently accounts for 3% of all gastrointestinal cancers . The 5-yCholangiocarcinoma is anatomically classified as intrahepatic or extrahepatic. Extrahepatic cholangiocarcinoma is classified as either perihilar or distal tumors according to the distance from the cystic ducts. This was a retrospective study of 46 patients with distal cholangiocarcinoma who underwent surgical treatment between April 2007 and December 2011. We assigned 9 cases of cholangiocarcinoma with choledocholithiasis to Group A; these cases accounted for 2.9% of all patients treated endoscopically for choledocholithiasis at our institution. As a control group, 37 patients with cholangiocarcinoma who did not undergo choledocholithiasis resection during the same period were assigned to Group B. Clinical features, endoscopic retrograde cholangiopancreatography (ERCP) findings, and histological diagnoses were analyzed retrospectively. Final pathological reports were reviewed to confirm the diagnosis of distal cholangiocarcinoma. The diameter of the distal bile duct and the morphology of the bile duct narrowing were also analyzed using the ERCP images.All patients with choledocholithiasis diagnosed by radiological visualization (ultrasonography (US), computed tomography (CT), magnetic resonance cholangiopancreatography) underwent endoscopic removal of bile duct stones. After stone removal, cholangiography was performed to confirm the complete removal of choledocholithiasis. Occasionally, owing to some limitations in the detection of small stones and sludge, they were not detected by cholangiography. Therefore, we performed intraductal US (IDUS) for all cases because of residual stones.Patients with distal tumors generally underwent pancreaticoduodenectomy with or without preservation of the pylorus. All patients underwent dissection of the regional lymph nodes, except for the para-aortic lymph nodes.Preoperative demographic and clinical data and pathologic diagnosis data were collected prospectively.\u03c72 test was used to compare qualitative parameters, and the Student t-test was used for quantitative parameters. P values of <0.05 were considered significant.Continuous data were expressed as mean \u00b1 standard deviation (SD). The P = 0.001) was in terms of abdominal pain at admission, and other clinical presentations were similar between both groups. All patients in Group A had gall bladder stones, compared with 7 patients (19%) in Group B (P < 0.01) (Three hundred and eleven patients who were diagnosed with choledocholithiasis between April 2007 and December 2011 underwent ERCP at our institution. Nine of them (2.9%) were diagnosed with distal cholangiocarcinoma by ERCP or IDUS after stone removal despite the tumors not being detected by radiological visualization. There were no statistical differences between the patient groups regarding age or gender. The only significant difference between Group A and Group B ( < 0.01) . The cliP = 0.083). Of the 9 patients in Group A, CT detected no tumor in 6 patients (67%) and a dilatation of the bile duct in 3 patients (33%). In 35 patients in Group B, CT detected no tumor in 6 patients (17%), a dilatation of the bile duct in 9 patients (26%), and a tumor in 20 patients (57%) (P = 0.003). Of the 9 patients in Group A, ERCP detected normality in 2 patients (22%) and abnormalities in 7 patients (78%). Of the 32 patients in Group B, ERCP detected normality in 4 patients (13%) and abnormalities in 28 patients (88%) (P = 0.597). IDUS detected a tumor in 8 patients in Group A, while in Group B, IDUS detected normality in 1 patient (3%) and tumors in 29 patients (97%) (P = 1.000).The diagnostic imaging test results are shown in P = 0.043). The morphology of bile duct narrowing was classified as normal or mild irregularity, unilateral narrowing, or bilateral narrowing. The bile duct morphologies in the Group A patients were normal or mild irregularity in 3 patients (33%), unilateral narrowing in 5 patients (56%), and bilateral narrowing in 1 patient (11%). Of the Group B patients, 5 (14%) presented with normal or mild irregularity, 12 (32%) with unilateral narrowing, and 20 (54%) with bilateral narrowing (A significant difference was observed in the diameter of the common bile duct between the 2 groups (arrowing .P = 0.022). In Group A, lymph node classification was absent in 8 patients (89%) and present in 1 patient (11%). In Group B, the lymph node classification was absent in 24 patients (65%) and present in 13 patients (35%) (P = 0.234)  Group A patients  was well-differentiated adenocarcinoma. In Group B patients, the histological types of the distal cholangiocarcinoma were papillary adenocarcinomas in 3 patients (8%), well-differentiated adenocarcinoma in 20 patients (54%), moderately differentiated adenocarcinoma in 11 patients (30%), and poorly differentiated adenocarcinoma in 3 patients (8%). In Group A, the depth of invasion reached the mucosa in 5 patients (56%), the fibromuscular layer in 2 patients (22%), the subserous layer in 1 patient (11%), and the serosa in 1 patient (11%). In Group B, the depth of invasion reached the mucosa in 7 patients (19%), the fibromuscular layer in 5 patients (14%), the subserous layer in 9 patients (24%), the serosa in 7 patients (19%), and the serosal infiltration in 9 patients (24%). In 7 patients (78%) in Group A, the cholangiocarcinoma invaded the mucosa and the fibromuscular layer at an early stage. The cholangiocarcinoma invaded the subserous layer: invaded the serosa in 22% of the patients (2/9) and infiltrated the serosa in 68% of the patients (25/37) (= 0.234) .P = 0.126). Furthermore, survival time was not influenced by the existence of choledocholithiasis.All patients in Group A were alive. In Group B, the median survival time was 46 months. Survival time was not significantly different between the 2 groups (P < 0.01). Nishimura et al. [Because most patients with cholangiocarcinoma tend to invade the surrounding vessels and nerves, they are unresectable at the time of diagnosis, and consequently patient survival is poor. Early detection and diagnosis are essential for improving long-term survival because the 5-year survival rates of patients with distal cholangiocarcinoma have been reported to be 23%  describea et al. \u20138. Chrona et al. . We consP < 0.05), and multivariate analysis identified additional IDUS as an independent risk factor for the recurrence of bile duct stones.The recurrence rate of choledocholithiasis after stone removal has been reported to be 24% \u201312. TherThree hundred and eleven consecutive patients who underwent ERCP for choledocholithiasis between April 2005 and December 2011 were included in the study. All patients underwent IDUS after stone removal. Fortunately, IDUS detected biliary strictures in 2.9% of cases (9/311) that were pathologically diagnosed as cholangiocarcinoma. In each case, IDUS initially detected a cholangiocarcinoma in the absence of a mass on CT or magnetic resonance imaging. Because the early distal cholangiocarcinomas in 39% of cases 7/18) in our institution were associated with choledocholithiasis, we suggest that choledocholithiasis shows an etiologic association with cholangiocarcinoma. IDUS is very useful for evaluating not only residual stones but also biliary strictures , 18. Bec in our iK-ras, p53, MUC1, and COX2 occurred after chronic inflammation [In another study, histological grading indicated that the cholangiocarcinoma in a group of hepatolithiasis patients exhibited a significantly higher percentage of well-differentiated tumors . Becauseammation , 23.In conclusion, IDUS after stone removal may potentially help in the detection of unexpected tumors. Therefore, we believe that IDUS after stone removal will lead to improve outcome and prognosis. We also hope that this study will assist in the understanding of both distal cholangiocarcinoma associated with choledocholithiasis and the molecular mechanisms underlying choledocholithiasis-related distal cholangiocarcinoma, for which only limited data are available. However, further studies with a higher number of cases are required to support the findings presented here."}
+{"text": "Metastatic adenocarcinoma from an unknown primary site is a common clinical problem. Determining the cytokeratin (CK) 7/CK20 pattern of tumors is one of the most helpful procedures for this purpose since the CK7-/CK20+ pattern is typical of colorectal adenocarcinomas. CDX2, a critical nuclear transcription factor for intestinal development, is expressed in intestinal epithelium and adenocarcinomas. In the present study, we compared the sensitivity and specificity of CDX2 expression and the CK7-/CK20+ phenotype in differentiating colorectal adenocarcinomas from pancreatic and gastric adenocarcinomas.CK7/CK20 staining pattern and CDX2 expression were evaluated in 118 cases of colorectal, 59 cases of gastric, and 32 cases of pancreatic adenocarcinomas. The sensitivity, specificity, and positive and negative predictive values of the CK7-/CK20+ phenotype and of CDX2 expression were analyzed.The CK7-/CK20+ immunophenotype was expressed by 75 of 118 (64%) colorectal and 3 of 59 (5%) gastric tumors and was not observed in any pancreatic adenocarcinomas. The CK7+/CK20+ immunophenotype was expressed in 24/118 (20%) of colon, 28/59 (48%) of gastric and 7/32 (22%) of pancreatic adenocarcinomas. The CK7+/CK20- expression pattern was observed in only 2% (2 of 118) of colorectal carcinomas. CDX2 was expressed in 114 of 118 (97%) colorectal, 36 of 59 (61%) gastric, and 5 of 32(16%) pancreatic adenocarcinomas. There was no significant association between CDX2 expression and tumor differentiation in colorectal carcinomas. In gastric carcinomas, CDX2 expression was more common in intestinal type tumors than in diffuse type carcinomas. The CK7-/CK20+ phenotype showed a specificity of 96.7% in predicting colorectal adenocarcinomas, which was superior to that of CDX2 expression. CDX2 expression at both cut-off levels (> 5% and > 50%) had a higher sensitivity (96.6% and 78%) than the CK phenotype.Both the CK7-/CK20+ phenotype and expression of the antibody CDX2 are highly specific and sensitive markers of colorectal origin. CDX2 expression should be a useful adjunct for the diagnosis of intestinal adenocarcinomas, particularly when better established markers such as CK7 and CK20 yield equivocal results. The CK7-/CK20+ phenotype is superior in its specificity and positive predictive value and might be preferred.The virtual slide(s) for this article can be found here:http://www.diagnosticpathology.diagnomx.eu/vs/4851011866354821 Metastatic adenocarcinoma from an unknown primary site is a common clinical problem that leads to extensive and costly clinical and radiological examinations, sometimes with discouraging results ,2. It isCytokeratins (CKs) represent the epithelial class of intermediate-sized filaments of the cytoskeleton. There are 20 subtypes of cytokeratin (CK) intermediate filaments. These have different molecular weights and demonstrate differential expression in various cell types and tumors . Among tCDX2 is a caudal-type homeobox gene, encoding a transcription factor that plays an important role in proliferation and differentiation of intestinal epithelial cells . The proIn the present study, we examined the expression profiles of CK7, CK20, and CDX2 immunohistochemical markers in primary colorectal, gastric and pancreatic adenocarcinomas in consideration of the potential applicability of these markers in the clinical context of metastatic adenocarcinomas. We also evaluated the sensitivity, specificity, positive predictive value, and negative predictive value of CDX2 expression and CK7-/CK20+ immunophenotype to differentiate colorectal adenocarcinomas from pancreatic and gastric adenocarcinomas.One hundred eighteen colorectal, 59 gastric and 32 pancreatic adenocarcinoma resection specimens were retrieved from the archival files of the Department of Pathology, Fatih University Medical School, between January 2006 and December 2009. Pathological findings, including histological type, histological differentiation, depth of invasion, and lymph node status, were gathered from hematoxylin and eosin stained sections. All cases were reviewed to confirm the diagnosis. The grade and histological type of colorectal and pancreatic adenocarcinomas were determined according to criteria of the World Health Organization (WHO) Classification of Tumors . Well anFour \u03bcm-thick sections were cut from blocks of paraffin embedded tissue, deparaffinized, and rehydrated as usual. To reduce non-specific background staining due to endogenous peroxidase, slides were incubated in Hydrogen Peroxide Block for 15 min. Before immunostaining, antigen retrieval was performed by incubating the slides for 15 min with pepsin  at a concentration of 1mg/ml for CK20. Slideswere microwaved in 10 mM of citric acid at pH6.0 for 20 min for CK7 and CDX2. The slides were incubated for 60 min with primary antibodies to CK7 , CK20  and CDX2  at room temperature. The Standard avidin-biotin-peroxidase complex (ABC) technique was performed using the LabVision Secondary Detection Kit . AEC was used as chromogen. All slides were counter stained with Mayer's hematoxylin.For CDX2, only nuclear staining was considered positive. Cytoplasmic positivity was infrequently encountered, and was considered an artifact. Positive immunostaining for CK7 and CK20 was identified in the cytoplasm, cell membrane, or both. The percentage of positive cells was scored in a semiquantitative method according to the following scheme: 0 (less than 5% of tumor cells); 1+ ; 2+ (26-50% of tumor cells); 3+ (51-75% of tumor cells); and 4+ (greater than 75% of tumor cells). Furthermore, staining in less than 50% of the tumor cells was considered focal, and staining in more than 50% of the tumor cells was considered diffuse positivity. In general, cases showing 3+ and 4+ staining also had strong intense staining, so intensity was not used in determination of the final reactivity score. Normal colonic mucosal tissue was used as a CK20 and CDX2-positive control, and normal pancreatic tissue was used as a CK7-positive control. For negative control samples, the primary antibody was omitted for each run.2and Fisher exact tests were used to compare the differences in percentages of positive results between groups. SPSS 13.0 for Windows was used for all statistical analyses. The sensitivity, specificity, and positive and negative predictive values of the CK7-/CK20+ phenotype and of CDX2 expression were counted.\u03c7Tables 2 = 79.992; p < 0.001). The CK7+/CK20+ immunophenotype was expressed in 24/118 (20%) of colon, 28/59 (48%) of gastric and 7/32 (22%) of pancreatic adenocarcinomas, which was not helpful in the differential diagnosis. However, among the CK20 positive cases, CK20 reactivity was diffuse (more than 50% of cells were positive) in the majority of colorectal carcinomas in 64% (63/99) of the cases and mainly focal ( < 50% of cells were positive) in gastric and pancreatic adenocarcinomas in 71% (22/31) and 100% (7/7) of cases respectively   . In our study, 17(14%) colorectal, 9 (15%) gastric, and only 1 (3%) pancreatic adenocarcinomas showed a CK7-/CK20- immunophenotype.CK7 expression was detected in 22% 26/118) of colorectal, in 80% (47/59) of gastric, and in 97% (31/32) of pancreatic adenocarcinomas. CK20 reactivity was found in 84% (99/118) of colorectal, in 53% (31/59) of gastric, and in 22% (7/32) of pancreatic adenocarcinomas. The CK7-/CK20+ immunophenotype was expressed by 75 of 118 (64%) colorectal and 3 of 59 (5%) gastric tumors and was not observed in any pancreatic adenocarcinomas  and in low grade carcinomas than in high grade carcinomas .CK7 and CK20 expression were compared with the clinicopathological characteristics of the tumors Table . No asso2 = 93.576; p < 0.001). In positive cases, the immunoreactivity was predominantly nuclear with occasional faint cytoplasmic staining. The majority of cases  demonstrated strong and diffuse immunostaining in more than 50% of cells in colorectal tumors. Among the CDX2 positive gastric carcinomas (36/59), reactivity was focal in 22 cases . Among the 32 cases of pancreatic adenocarcinoma, only 5 cases were focally positive for CDX2   colorectal, 36 of 59 (61%) gastric, and 5 of 32 (16%) pancreatic adenocarcinomas . There was no significant association between CDX2 expression and tumor differentiation in colorectal carcinomas (98% of low grade tumors and 91% of high grade tumors were positive for CDX2) . No association was observed among CDX2 expression and anatomical location of carcinomas, tumor stage (pT), or nodal status.CDX2 expression was also compared with the clinicopathological characteristics of the tumors Table . In gast2 = 5.979; p = 0.051). Among the CK7-/CK20- colorectal tumors CDX2 was positive in 16 of 17 (94%) cases.The CK7-/CK20+/CDX2+ phenotype was highest, accounting for 63% (74/118) of colorectal adenocarcinomas. In gastric and pancreatic adenocarcinomas, CK7+/CK20+/CDX2+  and CK7+/CK20-/CDX2-  were the most common patterns respectively. In CK7+/CK20+ tumors, CDX2 expression was observed in 22 of 24 (92%) colorectal, 21 of 28 (75%) gastric, and 2 of 7 (29%) pancreatic carcinomas. This reactivity was diffuse in majority of colorectal carcinomas in 68% (15/22) of the cases and mainly focal in gastric and pancreatic adenocarcinomas in 57% (12/21) and 100% (2/2) of cases respectively  transcription factors generally yield an ''all or none'' signal, with most of the positive cases containing positive signal in > 90% of the tumor cell population; (2) given the nuclear localization of the signal, it is much less likely to be confused with biotin or other sources of false positive cytoplasmic signals; and (3) lack of association between the levels of expression of nuclear transcription factors and the state of differentiation of the tumor . For exaExpression of CDX2 in tumors other than colorectal carcinoma has been previously reported -35,40,41Based on the studies mentioned above CDX2 expression alone does not reliably distinguish between colorectal adenocarcinomas and adenocarcinomas arising elsewhere in the GI tract, particularly pancreatobiliary and gastric adenocarcinomas, although the sensitivityof CDX2 for colorectal cancer is significantly higher than for these latter tumors. Qualitatively, focal and weak CDX2 expression in a given tumor favors extra-intestinal origin whereas uniform intense expression favors intestinal origin. In comparison with the CK7-/CK20+ immunoprofile Tot  found thBoth the CK7-/CK20+ phenotype and expression of the antibody CDX2 are highly specific and sensitive markers of colorectal origin. CDX2 expression should be a useful adjunct for the diagnosis of intestinal adenocarcinomas, especially those with CK7+/CK20+ or CK7-/CK20- profiles. The CK7-/CK20+ immunophenotype is more specific in differentiating colorectal adenocarcinomas from pancreatic and gastric adenocarcinomas than CDX2 expression. The CK7-/CK20+ phenotype is superior in its specificity and positive predictive value and might be preferred.The authors declare that they have no competing interests.RB carried out the data collection, the pathological and immunohistochemical evaluation and interpretation, drafting and wrote the final manuscript; SY and HH participated in pathological and immunohistochemical evaluation and interpretation. All authors read and approved the final manuscript."}
+{"text": "Systolic ankle pressures are measured as part of an ankle-brachial index (ABI) to screen for the presence of peripheral arterial disease (PAD). Despite widespread use of the ABI, there is currently no research evidence investigating the amount of pre-measurement rest required for the systolic ankle pressure to stabilise.One hundred and forty participants meeting current guidelines for screening for PAD volunteered for this study. Following 5 minutes of rest in the supine horizontal position, ankle systolic pressures of the left or right lower extremity were taken using hand-held Doppler. Measurements were repeated at 10 and 15 minutes. Testing was repeated 7-10 days later.A significant drop in ankle pressure of 5.02 mmHg occurred between 5 and 10 minutes (p<0.05) however no significant change occurred between 10 and 15 minutes . Presence of diabetes was associated with a smaller drop between 5 and 15 minutes (mean change 1.85 mmHg) and predicted 14% of the variance in change in ankle pressure . Test-retest reliability after 5 minutes was excellent (intraclass correlation co-efficient (ICC): 0.84) however increased for measurements taken at 10 and 15 minutes (ICC: 0.89 and 0.89 respectively).Results suggest ankle systolic pressures stabilise after 10 minutes of rest. Longer periods of pre-measurement rest did not improve reliability of the measurement significantly. Presence of diabetes affects ankle pressure changes in response to rest, however further investigation is required to identify the cause."}
+{"text": "Progressive idiopathic scoliosis can influence negatively the development and function of 2-3% of adolescents, with health consequences and economic costs, placing the disease in the centre of interest of medicine of the growing age. The aim of this study was to evaluate the effectiveness of Ch\u00eaneau brace in the management of idiopathic scoliosis.A prospective observational study according to SOSORT and SRS recommendations comprised 79 patients (58 girls and 21 boys) with progressiveidiopathic scoliosis, treated with Ch\u00eaneau brace and physiotherapy, with initial Cobb angle between 20 and 45 degrees, no previous brace treatment, Risser 4 or more at the final evaluation and minimum one year follow-up after weaning the brace. Achieving 50\u00b0 of Cobb angle was considered surgical recommendation.At follow-up 20 patients (25.3%) improved, 18 patients (22.8%) were stable, 31 patients (39.2%) progressed below 50 degrees and 10 patients (12.7%) progressed beyond 50 degrees (2 of these 10 patients progressed beyond 60 degrees). Progression concerned the younger and less skeletally mature patients.Conservative treatment with Ch\u00eaneau orthosis and physiotherapy was effective in halting scoliosis progression in 48.1% of patients. The results of this study suggest that bracing is effective in reducing the incidence of surgery in comparison with natural history."}
+{"text": "The value of IL-6 blockade has been established in rheumatoid arthritis (RA) and systemic onset juvenile idiopathic arthritis (SOJIA), but its wider utility in patients with AA amyloidosis and autoinflammatory diseases has been little studied.To assess clinical and serological responses to tocilizumab therapy in adult patients with AA amyloidosis and various autoinflammatory disorders.16 patients at the UK National Amyloidosis Centre with AA amyloidosis and various autoinflammatory disorders that were refractory to various treatments underwent therapeutic trials of tocilizumab. Disease activity and treatment response were monitored by symptoms, serial SAA and CRP measurements and a comprehensive range of standard blood and urine analyses. Amyloid load was evaluated and monitored by SAP scintigraphy.13 (81%) patients had AA amyloidosis , and 3 had severe, longstanding refractory autoinflammatory disorders (1 HIDS and 2 unclassified autoinflammatory disorders). 10 (63%) patients were male. Median age at presentation to our clinic was 48 years . All patients had received at least one previous unsuccessful treatment with anti-cytokine or other disease modifying anti-rheumatic therapies prior to receiving tocilizumab.Median SAA concentration prior to tocilizumab treatment, calculated as the median of all SAA measurements for each individual in the 12 months preceding initiation of therapy, ranged from 10 \u2013 414mg/L; serum SAA concentration following introduction of tocilizumab was a median of 3mg/L for the entire cohort (IQR 3 \u2013 6), i.e. indicating complete normalisation of SAA (Mann Whitney test p<0.0001). All patients reported improvement in symptoms. During median follow-up of 21 months (IQR 11\u201343), SAA values remained normal/near normal in 14 patients; median SAA concentration was 11mg/L and 18mg/L in the two remaining patients, representing substantial improvement from pre-treatment medians of 58mg/L and 198mg/L respectively. 8 patients, all of whom responded completely to tocilizumab, have had follow-up SAP scans, demonstrating regression of amyloid in 6 (75%) and stable deposits in 2 cases.Treatment with tocilizumab has been successful in producing sustained suppression of refractory inflammatory disease, both serologically and symptomatically, in 14 of 16 (88%) of patients treated under our care, with accompanying regression of amyloid deposits in 6 (75%) of these.None declared"}
+{"text": "Treatment of patients with JIA with DMARDs is started immediately after diagnosis, resulting in more effective suppression of disease activity. TNF blockers are recommended in cases of active JIA after the unsuccessful use of DMARDs. The exact role of these agents in the treatment of early-stage JIA is unknown.To evaluate the efficacy of infliximab in patients (n=100) with early and long-standing JIA.100 (60 with early and 40 with long-standing JIA) patients who didn\u2019t respond to DMARDs received infliximab 6-7 mg/kg q8wks. Evaluation of efficacy included 30%, 50% and 70% improvement by the ACR-pedi criteria and remission.At 54 week 100% and 87.5% patients with early and long-standing JIA respectively achieved at least 50% response. After 2 years ACR-Pedi 70/90 response to infliximab was recorded in all patients with early JIA and 100%/88.9% of patients with long-standing JIA respectively. At weeks 54 following infliximab treatment, 89% and 60% of patients with early and long-standing JIA achieved remission. At the end of the second year, remission was reported in 97% of children with early JIA and 72% of patients in the second group. 34% of the patients discontinued due to an adverse event, mainly lack of efficacy (23 patients) and hypersensitivity reactions (11 patients).This 2-years study suggest using IFX as initial treatment for patients with recent onset JIA is more effective than reserving it for patients with long-standing JIA. No difference between groups in adverse events and secondary inefficacy were observed."}
+{"text": "It is well-known that the morphological variability of mucoepidermoid carcinoma (MEC) of the salivary glands may lead to interpretative difficulties on fine-needle aspiration (FNA) diagnosis. In this study we identify morphologic features that may be useful in the FNA diagnosis of MEC. The cohort included 23 cases of MEC; cytology and histology slides were reviewed and assessed for % cystic component, extracellular mucin, mucous and intermediate cells, oncocytes, cells with foamy/clear cytoplasm, keratinized cells and lymphocytes. On FNA 12/23 (52%) cases were diagnosed as consistent with or suggestive of MEC; 6/23 (26%) as salivary gland neoplasm and 5/23 (22%) as no tumor seen. The cystic component was \u226550% in 18/23 (78%) and <50% in 5 cases. The features prevalent in FNA and histology were: mucous cells (96% and 91%), extracellular mucin (91% both), intermediate cells (100 and 83%), lymphocytes (96 and 78%) and cells with foamy/clear cytoplasm (74% both). Oncocytes were seen in 43 and 22% and keratinized cells in 48 and 13% cases. Cases with oncocytes and lymphocytes were interpreted as favor Warthin's tumor on FNA. Presence of mucous cells, cells with foamy/clear cytoplasm, intermediate cells and lymphocytes in a mucinous background are diagnostic indicators of MEC; presence of oncocytes should not refrain from diagnosing MEC in FNA specimens.  Fine needle aspiration (FNA) of salivary gland lesions is a valuable tool to pre-operatively diagnose/assess lesional tissue, determine the need for surgical intervention and assist in planning the appropriate surgical approach prior to resection. This technique is safe and effective with some studies demonstrating overall sensitivity, specificity and accuracy of 92%, 100%, and 98%, respectively ; howeverMucoepidermoid carcinoma (MEC) is the most common malignant neoplasm of the salivary gland origin and accounts for 5% to 10% of all salivary gland neoplasms . The majThe difficulty in the cytologic diagnosis of MEC is related, in part, to the histologic grade of this tumor , 12. HigIn this retrospective study, 23 cases of MEC with preoperative FNA, were evaluated. The patient's ranged in age from 18 to 79 years and received surgical care at the Hospital of the University of Pennsylvania between 1995 and 2008. Cytology and histology slides and clinicopathologic features were reviewed in each case. The cases were assessed for the following features: % cystic component, nuclear atypia, necrosis, extracellular mucin, mucus cells, intermediate cells, oncocytes, and cells with foamy/clear cytoplasm, keratinized cells and lymphocytes. A histologic grade of low, intermediate or high was assessed in each case. The morphologic features noted by cytologic examination were compared to the original cytologic diagnosis in an effort to assess which features were the most consistent/reproducible in providing an accurate cytologic diagnosis and which histomorphologic features were associated with under-diagnosis of MEC by cytologic examination.In this study, 22/23 (96%) of, MECs arose in the parotid gland (average size 1.9\u2009cm) and one (4%) from a minor salivary gland in the tongue. On FNA, 7/23 (30%) cases were diagnosed as consistent with, 5/23 (22%) as suggestive of MEC; 6/23 (26%) as salivary gland neoplasm and 5/23 (22%) as no tumor seen. In the six cases diagnosed as salivary gland neoplasm on FNA, two were diagnosed as favor acinic cell carcinoma (2/6), two were diagnosed as favor Warthin tumor (2/6), one was diagnosed as neoplasm with squamous differentiation (1/6) and another was diagnosed as favor benign mixed tumor versus mucoepidermoid carcinoma or adenoid cystic carcinoma (1/6). On histologic examination, the tumor grade was low in 13/23 (56%), intermediate 9/23 (39%) and high in 1/23 (4%) cases; neural invasion was seen in 4/23 (17%) and lymph node metastasis in 1/23 (4%) cases. The cystic component was \u226550% in 18/23 (78%) cases (see Tables An intraoperative frozen section was performed in 9/23 (39%) cases. The frozen section diagnoses were: MEC 4 cases, low-grade carcinoma 1, adenocarcinoma 1, consistent with Warthin tumor 1, cystic neoplasm 1, and no tumor seen 1 case. The average time interval between FNA and surgery was 5 weeks in 12 cases diagnosed as consistent with or suggestive of MEC. The average time interval was 4 weeks in 6 cases diagnosed as salivary gland neoplasm and 22 weeks in cases where FNA failed to identify tumor  cells, intermediate cells, and mucocytes (often seen lining the microcysts). The combination of these cellular elements in varying proportions can lead to complex histologic patterns causing diagnostic challenges , 12. TheSimilar to histology, the diagnosis of low-grade MEC by FNA can be challenging due to spatial heterogeneity and multiple histologic components. Therefore, adequate sampling of various components within the tumor is essential to arrive at correct diagnosis , 12.In our study, the morphologic features most prevalent in both the cytologic and histologic specimens of MEC were mucus cells (pseudo-goblet cells) and presence of extracellular mucin (both >90%). In addition, intermediate cells (100% in histology and 83% in cytology) and lymphocytes (96% in histology and 78% in cytology) were also commonly noted. The presence of oncocytic cells (43% in histology and 22% in cytology) and squamous/epidermoid cells (48% in histology and 13% in cytology) were less commonly seen. Oncocytic cells were seen 10/23 (43%) cases in histology and 5/23 22%) of cytology cases. One case with oncocytic cells was interpreted on FNA as \u201csalivary gland neoplasm favor Warthin tumor\u201d, 2 as MEC, 1 as acinic cell carcinoma and 1 as suggestive of MEC. On re-review, all contained varying amounts of extracellular mucin, mucous cells and intermediate cells; pseudo-goblet cells/clear cells were seen in 3 cases. The case originally classified as Warthin tumors also contained an excess of lymphocytes. Oncocytic cells have been reported to occur in MEC; in addition, a rare variant of MEC known as oncocytic MEC has been described \u201322. Thes% of cytoWe believe that the most helpful features in differentiating MEC containing oncocytic cells from other salivary gland lesions in FNA specimens is the presence of extracellular mucin, mucous cells and pseudo-goblet/clear cells. Since a major difficulty in utilizing FNA to diagnose MEC is related to sampling, , 12 we bTo add to these challenges, it has been shown that metaplastic/reparative changes can occur in benign salivary gland neoplasms due to physical trauma induced by FNA . These cSeveral studies have discussed the utility of intraoperative consultation in the surgical management of salivary gland lesions. Studies from our institution have shown that the diagnostic accuracy of FNA and frozen section are comparable for the interpretation of salivary gland neoplasms, and the accuracy of both is increased when used in conjunction . In the We believe that the cytologic diagnosis of low-grade MEC remains challenging due to overlapping cytomorphologic features seen in other salivary gland lesions. Among the many cytologic features described, presence of extracellular mucin, mucous cells, and intermediate cells should raise the suspicion of MEC. In addition, oncocytic cells can occur in varying proportions in some cases of MEC and in the presence of above-mentioned features should not dissuade one from making or suggesting a diagnosis of this tumor in FNA specimens."}
+{"text": "We assessed the epidemiology of sepsis syndromes in patients admitted to ICUs of the Piedmont region in northern Italy and investigated the impact of sepsis on ICU mortality in these patients.In this prospective, multicenter, observational study, all 3,902 patients  admitted to one of 24 medical or surgical ICUs between 3 April and 29 September 2006 were included.n = 780) and median ICU length of stay was 3 (1 to 9) days. ICU mortality was higher  and the median ICU LOS longer (15 (7 to 26) vs. 2 (1 to 7), P < 0.001) in patients with sepsis than in those without sepsis. The mortality rate increased with the severity of sepsis . ICU-acquired sepsis was associated with higher ICU mortality rates than sepsis occurring within 48 hours of ICU admission . In multivariate logistic regression analysis, the occurrence of severe sepsis ; P = 0.026) and septic shock ; P < 0.001) were independently associated with an increased risk of ICU death.Four hundred and forty-six of the patients had sepsis, including 160 patients with severe sepsis (4.1%) and 145 patients (3.7%) with septic shock. ICU mortality was 20% (In this large multicenter cohort, severe sepsis and septic shock were independently associated with an increased risk of death. Our data underscore the regional variability in the epidemiology and outcome of sepsis syndromes and may be useful for resource allocation."}
+{"text": "To evaluate the demographic and clinical features of childhood pars planitis, and to determine the therapeutic and visual outcomes of the disease.Medical records of pediatric patients (less than 16 years of age at diagnosis) with pars planitis and at least 6 months of follow-up who were referred to Labbafinejad Medical Center, Tehran, Iran over a 22 year period were reviewed.Overall, 117 eyes of 61 patients including 51 (83.6%) male subjects were included. Mean age at the time of diagnosis was 7.8\u00b13.2  years. Mean best corrected visual acuity (BCVA) was 0.88\u00b10.76 logMAR at presentation which improved to 0.39\u00b10.51 logMAR at final visit (P<0.001). Endotheliitis was present in 23 (19.6%) eyes and was significantly more prevalent in subjects younger than 9 years (P=0.025). Cataract formation (41.9%) and cystoid macular edema (19.7%) were the most prevalent complications. Univariate regression analysis showed that better baseline visual acuity , age older than 5 years at disease onset , absence of endotheliitis  and female gender  were significantly associated with final BCVA of 20/40 or better.Childhood pars planitis was much more common among male subjects. Endotheliitis may be a sign of inflammation spillover and is more prevalent in younger patients. Visual prognosis is favorable in most patients with appropriate treatment. Pars planitis is a subset of intermediate uveitis characterized by aggregation of inflammatory cells and debris over the pars plana (snow banks) or in the vitreous cavity  in the absence of infections or other known inflammatory conditions.7Considering the chronic, insidious nature of pars planitis and the fact that the anterior segment is often quiet in this condition, permanent visual loss may occur in children. There is lack of information on visual outcomes and complications of childhood pars planitis in Iran; we therefore reviewed medical records of patients with childhood pars planitis at our center spanning a time period exceeding 20 years.Hospital records of all patients with childhood pars planitis who were referred to Labbafinejad Medical Center, a tertiary referral eye care center in Tehran-Iran from September 1983 to August 2005 were reviewed. Patients younger than 16 years with a classical presentation of pars planitis characterized by vitritis and presence of snow balls or snow banks, at least in one eye, were included. Patients with associated systemic or ocular disease, or abnormal laboratory tests compatible with a systemic condition known to be associated with intermediate uveitis were excluded. Only subjects with at least 6 months of follow-up were included for the purpose of the study.Data included sex, age at onset of the disease, unilateral or bilateral involvement, initial ocular symptoms and signs, best-corrected visual acuity (BCVA) at presentation and at final examination based on Snellen chart or fixation pattern in preverbal/non-cooperative children, ocular complications and intraocular pressure (IOP). Ophthalmologic examination findings in detail included band keratopathy, endotheliitis, anterior chamber (AC) reaction, anterior vitreous reaction, anterior or posterior synechiae and cataracts on slit lamp biomicroscopy; and snow balls, snow banks, cyclitic membranes, peripheral retinal vasculitis, peripheral retinal neovascularization, papillitis or optic disc atrophy, and cystoid macular edema (CME) on fundus examination. CME was detected clinically or by fluorescein angiography. We also reviewed the results of laboratory tests and recorded treatment data including topical steroids, subtenon injections of corticosteroids, systemic steroids, immunosuppressive agents, laser photocoagulation and cryotherapy, as well as surgical procedures.Statistical analysis was performed using SPSS software . Wilcoxon signed rank test was used to evaluate the difference between initial and final BCVA. Regression analysis (univariate and multiple) was used to determine the effect of factors such as sex, age and BCVA at presentation on final BCVA.One hundred and seventeen eyes of 61 patients including 51 (83.6%) male and 10 (16.4%) female subjects were studied. Mean age at diagnosis was 7.8\u00b13.2  years and mean follow-up duration was 44.6\u00b137.8  months. The condition was bilateral in 56 patients (91.8%). BCVA was based on fixation pattern in 7 eyes and 6 eyes had missing data. Mean BCVA was 0.88\u00b10.76  logMAR at initial examination which was significantly improved to 0.39\u00b10.5  logMAR at final follow-up; none of the BCVA data was based on fixation patterns at final examination. BCVA was 20/40 or better in 68 (58.1%) eyes and less than 20/200 in 13 (11.1%) eyes at final follow-up .The most common symptoms at presentation were blurred vision in 46 patients (75%), followed by red eye and eye deviation each in 6 subjects (10%). Floaters were the initial symptom in only 3 cases (5%). The most common ocular signs at presentation were snow banks in 82 (70.1%), snow balls in 67 (57.3%), vitritis in 63 (53.8%), periphlebitis in 44 (37.5%), anterior chamber reaction in 31 (26.5%), and endotheliitis in 23 (19.7%) eyes. The latter was significantly correlated with the age less than 9 years (P=0.025).The most frequent complications were cataracts in 49 (41.9%), CME in 23 (19.7%), band keratopathy in 20 (17.1%), amblyopia in 20 (17.1%), epiretinal membranes (ERMs) in 9 (7.7%), ocular hypertension in 7 (6%), glaucoma in 7 (6%), vitreous hemorrhage in 6 (5.1%), retinal detachment in 5 (4.2%), and cyclitic membranes and optic atrophy each in 4 (3.4%) eyes. Posterior subcapsular cataracts were the most common form of lens opacities. CME and ERM were diagnosed clinically.The therapeutic regimen included: topical corticosteroids in 40 eyes (34.2%), subtenon injection of triamcinolone in 86 eyes (73.5%) with a total of 253 injections (average of 3 injections per eye), oral prednisolone in 18 patients (29.5%), and oral cyclosporine (one capsule daily for 2 months) in one subject (0.9%). Peripheral retinal photocoagulation and cryotherapy were performed in 10 (8.5%) and 9 (7.7%) eyes respectively for treatment of peripheral retinal neovascularization. Cataract extraction was performed in 17 eyes including 11 eyes with severe lens opacity, of which 6 eyes underwent intraocular lens (IOL) implantation. Mean BCVA was not significantly different between IOL implanted (0.2 logMAR) and non-IOL implanted eyes (1.05 logMAR) (P=0.147). Six other eyes underwent lensectomy without IOL implantation as part of pars plana vitrectomy to facilitate vitreous base trimming. Pars plana vitrectomy was performed on 22 eyes due to complications of pars planitis. Indications for pars plana vitrectomy included severe vitreous organization (13 eyes), vitreous hemorrhage (4 eyes), rhegmatogenous retinal detachment , ERM (2 eyes), tractional retinal detachment (1 eye), and previously failed scleral buckling (2 eyes). The retina was totally attached at final examination in all eyes; however 2 eyes required multiple vitreoretinal procedures.During follow-up, IOP was higher than 21 mmHg in 14 eyes of 9 patients. IOP was controlled in 7 eyes of 5 patients by discontinuation of steroids; 4 eyes of 2 patients required antiglaucoma medications and 3 eyes of 2 patients underwent trabeculectomy.Univariate logistic regression revealed that better BCVA at presentation , age older than 5 years at disease onset , female gender  and absence of endotheliitis at initial examination  were significantly correlated with final BCVA of 20/40 or better. However, multiple logistic regression disclosed that only BCVA at presentation  and female gender  were significantly correlated with final BCVA of 20/40 or better .Pars planitis is considered a type of intermediate uveitis of unknown etiology associated with snow ball or snow bank formation. It is not associated with any systemic disease and is usually bilateral with asymmetric severity. Male to female ratio was 5 to 1 in our series, however the disease has been reported to be more frequent in female subjects in some other reports.Blurred vision was the most common symptom in our study which is consistent with other reports.The most frequent signs in our study were snow banks (70.1%), snow balls (57.3%) and vitritis (53.8%). In a series by Raja et al15Cataract formation and CME have been reported as major complications of pars planitis.In the current study, cataract surgery was performed in 11 eyes because of severe lens opacity and in 6 eyes as part of pars plana deep vitrectomy procedures. Six eyes in the first group underwent IOL implantation whereas in the second group, all 6 eyes were left aphakic. Tessler et alFourteen eyes 12%) in our series developed ocular hypertension during follow-up, of which 7 (6%) responded favorably to steroid discontinuation. The remaining 7 eyes (6%) developed glaucoma; in 4 eyes, the glaucoma was controlled with medications, but 3 other eyes underwent trabeculectomy. In the series reported by Romero et al% in our Vitreous hemorrhage occurred in 5 eyes (4.2%) which resolved spontaneously in one eye; the other four eyes underwent pars plana deep vitrectomy due to nonclearing vitreous hemorrhage. Mean BCVA in these eyes was 0.19 logMAR. Visual outcomes of pars plana vitrectomy for vitreous hemorrhage, as reported by Potter et al,18In the current study, retinal detachment (RD) occurred in 5 eyes of 5 patients (4.2%) including tractional RD in one eye and RRD in 4 eyes. Romero and coworkersTreatment of pars planitis needs a stepwise and individualized approach. In our series, 22 eyes with mild vitreous involvement, good visual acuity >20/40) and no vision threatening complications, received no treatment. In eyes with moderate to severe vitritis, periocular steroid injections (mostly subtenon) were the mainstay of therapy. Oral corticosteroids were given in subjects with poor response to periocular injections or in cases with severe bilateral disease. Topical corticosteroids were added if there was associated anterior chamber reaction. Systemic immunosuppressive agents were required only in one patient to control the inflammation. Cryotherapy and laser photocoagulation were the last options, as suggested by Whitcup./40 and nIn our series, mean BCVA at presentation was 0.88 logMAR which was improved to 0.39 logMAR at final examination (P<0.001). BCVA of 20/40 or better was present in 37% of eyes at presentation and in 68% of eyes at final follow-up; 40% of eyes at presentation and 13% at final follow-up had BCVA less than 20/200. Romero et alThe major limitation of our study is its retrospective nature; some data such as BCVA at presentation in 6 eyes and final BCVA in 6 other cases were missing. Moreover, the study was performed at a tertiary referral center and therefore mild cases were probably not included. Therefore these results may not be generalizable to all pediatric patients with pars planitis. The major conclusion of this study is that, childhood pars planitis is a treatable disease with good visual prognosis as long as early diagnosis, appropriate treatment and regular follow-up are provided."}
+{"text": "Although the number of U.S. hospitals offering an acute pain service (APS) is increasing, the typical structure remains unknown. This survey was undertaken to describe the structure and function of the APS in U.S. hospitals only. We contacted 200 non-teaching and 101 teaching U.S. hospitals. The person in charge of postoperative pain management completed and returned the survey. Seventy-four percent of responding hospitals had an organized APS. An APS was significantly more formally organized in academic/teaching hospitals when compared to non-teaching hospitals. Pain assessments included \u201cpain at rest\u201d (97%), \u201cpain on activity\u201d (63%), and reassessment after pain therapy intervention (88.8%). Responding hospitals utilized postoperative pain protocols significantly more commonly in teaching hospitals when compared to non-teaching and VA hospitals. Intravenous patient controlled analgesia (IV-PCA) was managed most commonly by surgeons (75%), while epidural analgesia and peripheral nerve block infusions were exclusively managed by anesthesiologists. For improved analgesia, 62% allowed RNs to adjust the IV-PCA settings within set parameters, 43% allowed RN adjustment of epidural infusion rates, and 21% allowed RN adjustment of peripheral nerve catheter local anesthetic infusion rates. Despite of improved understanding of pain mechanisms and development of new analgesics techniques , under-tThis survey was designed to examine the structure and function of the APS in three different types of hospitals ) ranging in size from less than 200 beds to over 1000 beds across the US. In addition, we set out to determine the sources of funding for APS as well as evaluate delegated nursing responsibilities and management of commonly used postoperative analgesic techniques , epidural analgesia, and peripheral nerve catheter infusions).http://www.officialusa.com/stateguides/health/hospitals/index.html\u2014a website listing of hospitals in the US. To be considered for this survey, the hospital web page must have included a \u201ccontact us\u201d hyperlink. The research assistant then contacted the hospital and attempted to reach the physician in charge of the acute pain service. If there was no official APS physician, the research assistant requested the name and contact information of a health care provider in charge of postoperative pain control at the hospital. The cover letter and online survey  was used to compare groups  on the reported variables. P values of\u2009\u2009.05 or less defined significance.The Fisher's exact probability test resulting in a two-tailed (two-sided) A total of 108 questionnaires were returned out of 301 requests for participation, yielding an overall response rate of 35.9%. Of these responses, 55 hospitals were university-based medical centers, 40 were nonteaching (private) hospitals and 13 were VA hospitals. The geographic distribution across the US yielded 30 responses from the South, 18 responses from the West, 26 from the Midwest, 22 responses from the Northeast, and 12 unspecified. The size of the hospitals varied: 21 hospitals with fewer than 200 beds (19.4%), 49 with 200\u2013500 beds (45.4%), 34 with 501\u20131000 beds (31.5%), and 4 with more than 1000 beds (3.7%). Eighty one hospitals had an organized APS (75%), and 27 did not (25%) . The likP < .01), and VA Hospitals .Responding university/academic hospitals reported a higher rate of an organized APS (96%) when compared to private hospitals . In 25% of the reporting hospitals, funding for the APS came from the general budget, while no institution reported that the APS was funded by the surgery department. The personnel comprising the typical APS included anesthesiologists (95%), advanced practice nurses , registered nurses , pharmacists (11.3%), physician assistants (8.8%), physical medicine and rehabilitation (PMR) physicians (6.3%), surgeons (5%), neurologists (3.8%), and others  . SeventyP < .05) when compared to 85% (34) of the private hospitals, and 54% (7) of VA hospitals. Pain at rest was routinely measured in 105 hospitals (97.2%) . Pain wiP < .05 when both academic and VA are compared to private hospitals)). Written postoperative pain protocols included requirements for vital sign monitoring, pain assessment and reassessment, and routine IV-PCA and epidural analgesia orders. Of these pain protocols, 52 hospitals (88.1%) included instructions on when and who to call for uncontrolled pain, 49 hospitals (83%) included pharmacological pain interventions, 37 hospitals (62.7%) included emergency \u201ccall orders\u201d, and 34 hospitals (57.6%) included nonpharmacological pain interventions such as activities to improve sleep, reduce anxiety, or improve mood as well as repositioning, deep breathing, guided imagery, heat/cold application, massage therapy, physical or music therapy, and biofeedback. Fifty-five percent  of the responding institutions had formal written postoperative pain protocols . HospitaThe postoperative pain protocols were normally developed in all institutions by using a multidisciplinary team approach. Primarily involved were anesthesiologists (44%), registered nurses (37.3%), the entire APS team (37.3%), multidisciplinary pain committees (35.6%), pharmacists (32.2%), advanced practice nurses (30.5%), surgeons (20.3%) and physician assistants (3.4%) . IV-PCA followup was conducted on a daily basis by surgeons (75%), anesthesiologists (37.1%), registered nurses (36.1%), the APS team (23.1%), physician assistants (16.7%), and advanced practice nurses (10.2%). One hospital did not reply. Epidural followup was conducted on a daily basis primarily by anesthesiologists (76%), the APS team (36.1%), advanced practice nurses (19.4%), registered nurses (16.7%), surgeons (4.6%) and physician assistants (4.6%). Five hospitals did not reply. Peripheral nerve block infusion followup was conducted on a daily basis by anesthesiologists (64.8%), the APS team (35.2%), advanced practice nurses (14.8%), registered nurses (8.3%), surgeons (7.4%) and physician assistants (0.9%). Nine hospitals did not reply . Under routine postoperative orders (written protocols), the RN could administer IV-PCA boluses for uncontrolled pain in 72.2% of the hospitals surveyed. The RN could adjust IV-PCA pump settings within certain parameters in 57.4% of the hospitals. In hospitals without IV-PCA clinician bolus orders, the surgeon or APS would bolus the IV-PCA or make rate adjustments while on rounds or when called by the staff RN. Under routine postoperative orders, the RN could administer epidural boluses for uncontrolled pain in 25% of the hospitals surveyed. The RN could adjust epidural pump settings within certain parameters in 39.8% of the hospitals. In the remaining institutions where epidural analgesia was used, the APS or anesthesiologists would bolus the epidural or make infusion adjustments. Under postoperative orders, the RN could administer peripheral nerve block infusion boluses in 12% of the hospitals surveyed. The RN could adjust PNB infusion pump settings within certain parameters in 19.4% of the hospitals. In the remaining institutions where PNB were used, the APS or anesthesiologist would bolus with a local anesthetic or make PNB infusion rate adjustments . P < .05, when compared to academic). Others measured improvement by higher patient satisfaction ratings (67.6%), improved functional ability (36.1%), fewer side effects from treatment (26.8%), and shorter hospital lengths of stay (25%). Eight percent of the hospitals measured improvement in terms of fewer emergency room visits for unrelieved postoperative pain. One hospital rated improvement in terms of fewer phone calls to administrators. Four hospitals did not answer this question (Ninety percent (97 of 108) of the responding hospitals measured improvement in pain management by improved scores on a numeric rating scale. Ninety eight percent of the university/academic hospitals measured improvement in pain management by improved pain scores as well as 82% of private hospitals (not significant when compared to academic) and 77% of VA hospitals , surgeons or surgery residents (41.7%), APS team (25.9%), advanced practice RN's including certified RN anesthetists (10.2%), RN's (8.3%), and physician assistants (3.7%) . Since the initial reports \u201311, therIt is important to realize that this study has some limitations including a relatively low response rate from all classes of hospitals. It is possible that many hospitals did not respond because they do not have an APS. The responders may have been more likely those who felt that they had optimal APS, likely explaining why the results showed a higher. Another limitation may be related to the way questions were framed. Therefore, the information gathered may be skewed. Nevertheless, despite these limitations, this study provides valuable insight that should provide guidance towards improved functioning of an APS and improved pain management in hospitalized surgical patients.This survey confirms the previous reports of significant variations in the structure and function , 4. AlthAs indicated in this survey, a majority of patients receiving IV-PCA, which is the most commonly used analgesic technique in hospitalized patients, are followed by surgeons without the involvement of the APS. However, as suggested by this survey, surgeons appear to play a limited role in APS. In absence of surgical involvement, it is possible that involvement of nurses with special training in current concepts of postoperative pain management and implementation of pain protocols  may be a practical approach to reducing inadequate pain relief and improving patient satisfaction. Delegation of predefined pain control options to nurses on the surgical ward enables them to initiate pain therapy in a timely manner and adjust the regimen to meet individual patient needs. However, this survey found that nurses were less often directed to adjust IV-PCA settings and even fewer protocols direct nurses about adjustments in epidural analgesia and peripheral nerve blockade therapy. One of the functions of an APS should be to educate the nurses interested in participating in the pain management program. A specialized-nurse-based anesthesiologist supervised APS may be cost beneficial , althougAnother important information from this survey was related to the lack of written protocols in 45% of the hospitals. One of the major functions of APS is to develop clinically useful protocols based on published evidence, even if there is no direct involvement in patient care . This should ensure a more consistent standard of care as well as provide instructions on diagnosis (through appropriate monitoring) and treatment of adverse events. In addition, the protocols would provide instructions on when and who to call for unrelieved pain and instructions for management of special group of patients . http://www.postoppain.org/).It has become increasingly clear that use of evidence-based approach to patient care improves outcome and reduces adverse events . HoweverAnother important finding of this study is inconsistency in pain assessment with activity and reassessment after a pain intervention. Reassessment gives the clinician the tools needed to individualize treatment based on efficacy, side effects, and improvement in pain intensity and patient function. Only 63% of responders evaluated pain scores on activity in spite of good evidence that pain control with activity  is an important factor in postoperative rehabilitation and should be evaluated regularly. This also indicates that most of the hospitals used only pain scores to evaluate improvement in pain management, and only a few hospitals used improved functional ability or side effects from analgesic therapy. However, it is increasingly clear that pain intensity scores alone should not be used to manage postoperative pain. Recent studies have reported increased use of opioids and opioids-related side effects since the introduction of \u201cpain as a fifth vital sign\u201d campaign by the Joint Commission \u201322. TherIn summary, the structure and function of APS in the US hospitals vary significantly, with university/academic institutions being more likely to offer these services than private or VA hospitals. There appears to be lack of consensus regarding the use of pain management of protocols as well as optimal outcome measures for assessing postoperative pain therapy. Further research is required to evaluate the impact of evidence-based procedure-specific pain management protocols and assessment of pain on activity as well as increased role of nurses on overall pain management and postoperative outcome. Finally, the cost benefit of hospital-based APS also needs to be critically evaluated."}
+{"text": "Surveillance of healthcare associated infections (HAIs) is an important step in detecting the pattern of infection prevalent in any hospital.The following study aimed at analyzing the HAIs rates in a Maternity & Children\u2019s Hospital (MCH) in relation to body sites.The study included 12 monthly HAIs of the Maternity & Children\u2019s Hospital, Najran, Saudi Arabia during the year 1430 H (2009G). The total number of beds was 200 and the total number of admission was 15237 patients.E.coli , followed by Coagulase negative Staphylococci ,Klebsiella pneumoniae , Pseudomonas aeruginosa  and Staphylococcus aureus . Other organisms as Enterobacter cloacae, Enterococcus spp .and Candida spp. were recovered at a rate of 2-3%. Influenza virus (H1N1) was detected in one patient. The most common sites of infection in relation to these organisms were urinary tracts , followed by blood , surgical sites .The overall annual infection rate ranged from 0.5-1.3% and the incident ratio of HAI\u2019s ranged from 1.3-3.7/1000 patients days. The total number of patients with HAIs was 117. In this study the most common site affected with HAIs was urinary tract (10-71.4%), followed by blood (30.3-60%), surgical site (10-25%) and respiratory tract (10-25%), The most predominant microorganisms isolated from patients were The current study stressed on the importance of surveillance in detecting the most common organism(s) causing HAIs in certain MCH. It also helps in setting up a plan for the prevention and control of these infections.M. Abdelnasser Other Professor of Microbiology & Infection Control"}
+{"text": "Headaches are more frequent in Chronic Fatigue Syndrome (CFS) than healthy control (HC) subjects. The 2004 International Headache Society (IHS) criteria were used to define CFS headache phenotypes.Subjects in Cohort 1  completed questionnaires about many diverse symptoms by giving nominal (yes/no) answers. Cohort 2  had more focused evaluations. They scored symptom severities on 0 to 4 anchored ordinal scales, and had structured headache evaluations. All subjects had history and physical examinations; assessments for exclusion criteria; questionnaires about CFS related symptoms , Multidimensional Fatigue Inventory (MFI) and Medical Outcome Survey Short Form 36 (MOS SF-36).Demographics, trends for the number of diffuse \"functional\" symptoms present, and severity of CFS case designation criteria symptoms were equivalent between CFS subjects in Cohorts 1 and 2. HC had significantly fewer symptoms, lower MFI and higher SF-36 domain scores than CFS in both cohorts. Migraine headaches were found in 84%, and tension-type headaches in 81% of Cohort 2 CFS. This compared to 5% and 45%, respectively, in HC. The CFS group had migraine without aura , with aura , tension headaches only (12%), or no headaches (4%). Co-morbid tension and migraine headaches were found in 67% of CFS. CFS+MA had higher severity scores than CFS+MO for the sum of scores for poor memory, dizziness, balance, and numbness  and perceived heart rhythm disturbances, palpitations and noncardiac chest pain . CFS+MO subjects had lower pressure-induced pain thresholds  and a higher prevalence of fibromyalgia  compared to HC . Sumatriptan was beneficial for 13 out of 14 newly diagnosed CFS migraine subjects.CFS subjects had higher prevalences of MO and MA than HC, suggesting that mechanisms of migraine pathogenesis such as central sensitization may contribute to CFS pathophysiology.Georgetown University IRB # 2006-481NCT00810329ClinicalTrials.gov  Headaches are common complaints in Chronic Fatigue Syndrome (CFS) and fibromyalgia (FM) ,2. HowevThe CFS case designation requires a 6 month history of persistent, unexplained fatigue that causes significant impairment of activity, plus 4 of 8 associated criteria . These cHeadaches and other CFS related symptoms overlap with fibromyalgia (FM) criteria. The 1990 American College of Rheumatology (ACR) research definition of FM required 3 months of unexplained, widespread pain plus tenderness to manual thumb pressure at \u2265 11 of 18 traditional tender points [The most prevalent headaches in the general population are tension - type (45%), migraine (12%), sinus 3%), and medication overuse headaches (1 - 2%) %, and me,11. TensMigraine is diagnosed by having at least 5 episodes lasting 4 to 72 hr with at least 2 of the following criteria: (i) unilateral location; (ii) pulsatile quality; (iii) moderate to severe pain intensity; and (iv) aggravation by physical activities or active avoidance of movement. Either nausea \u00b1 emesis, or photophobia and phonophobia must occur. Migraines are subdivided into migraine with aura  and migraine without aura (MO) ,13. The Since 67% of migraine subjects meet CFS criteria , we propTwo cohorts of CFS  and healHistory and physical examinations assessed the CFS case designation criteria. \"CFS\" was designated by findings of significant, unexplained fatigue lasting at least 6 months plus the presence of at least 4 of 8 ancillary criteria: (i) problems with concentration or memory; (ii) sleep disturbances; (iii) exertional exhaustion that typically developed 24 hr after excessive physical or mental effort; (iv) muscle pain; (v) joint pain; (vi) headaches; (vii) sore throat; and (viii) sore lymph node regions in the cervical, axillary or inguinal areas . These CCohort 1 was assessed by a series of questionnaires, history and physical examinations. Different combinations of questionnaires were used during their recruitment period. Preliminary results from Cohort 1 suggested an increased prevalence of migraine in CFS compared to HC.Next, Cohort 2 was recruited. Subjects completed an optimized set of questionnaires and had formalized clinical interviews to diagnose migraine with (MA) and without (MO) aura, and tension - type (T) headaches based on IHS criteria (as outlined in the Introduction) . CFS subThe Multidimensional Fatigue Inventory was used to verify the presence of significant physical, mental, and other fatigue measures . Quality2) between these queries and the Fatigue Score. This sum was defined as the \"Neuro-construct\" (score range of 0 to 16). A \"Cardio-construct\" was developed as the sum of scores for rapid heart rate, irregular heart rate, palpitations, and chest pain (range 0 to 16). The explained variance was 30%.The frequencies of several symptoms from individual systems were found to be highly correlated with each other in preliminary studies. Therefore, questionnaires were modified to also score the severities of each symptom. The same 0 to 4 point, anchored, ordinal scale was used, and data collected for some Cohort 1 and all Cohort 2 subjects. The severity scores for the selected symptoms were again found to correlate with each other and the Fatigue Severity Score. The sum of severity scores for numbness in the arms and legs, problems with memory, dizziness and balance was calculated and accounted for 32% of the explained variance (R2 rubber tip (dolorimeter) at a rate of 1 kg/sec on the same 18 anatomical sites. The average was the systemic pain threshold (kg). The pressure required to cause pain was also measured over the frontal, ethmoid and maxillary paranasal sinus regions. The average was the sinus pain threshold [FM was assessed using the 1990 American College of Rheumatology (ACR) research definition. Diagnosis of FM required 3 months of unexplained, widespread pain affecting all 4 quadrants of the body and the axial skeleton, plus tenderness to manual thumb pressure (~4 kg) at \u2265 11 of 18 traditional tender points [hreshold .Means and 95% confidence intervals were calculated for each variable in the HC and CFS groups ,22. CohoThe Cohort 2 HC and CFS and headache subtype data were compared by analysis of variance (ANOVA). If significant, variables were compared by 2-tailed unpaired Student's t-tests with Bonferroni corrections. Fisher's Exact tests were used as appropriate.There were no significant differences in age or gender distribution between HC and CFS subjects in either Cohort 1 or Cohort 2 after Bonferroni corrections of p values . Five felt they had severe flu-like illnesses that never improved. Three gave histories of prolonged, high dose exposures to volatile organic compounds, and two stated symptoms began soon after extensive series of immunizations. Three had perimenstrual migraines that predated their CFS.The HC groups within both cohorts had significantly better quality of life (higher scores) for all domains of the SF-36 compared to CFS subjects Table . Role EmHeadache types were first assessed by self - report questionnaires. HC reported migraines in 12% (Cohort 1) and 16% (Cohort 2), and tension headaches in 22% and 28%, respectively. Migraines were reported to be more prevalent in the Cohort 2 CFS group (69%) compared to Cohort 1 (39%). The point prevalence rates for tension - type headaches were not significantly different between Cohort 1 (62%) and 2 (76%) CFS groups. The combination of migraine plus tension headaches was claimed to be present in 3% of HC and 61% of CFS in Cohort 1. This combination was present in 11% of HC and 60% of CFS in Cohort 2.Cohort 2 subjects were interviewed using IHS criteria to determine their headache type. Point prevalences in HC (n = 21) were 16% migraine, 28% tension and 11% with both. In contrast to questionnaires, interviews of these HC subjects identified migraine in 5%, and tension headaches in 45%. Interviews of 67 CFS subjects identified migraine in 84%, tension headaches in 81%, and both types in 67%. MO was found in 60% (40/67), and MA in 24% (16/67). Two CFS subjects had migraines that were intermittently associated with auras. Tension headaches were present in 78% (31/40) of MO and 88% (14/16) of MA. The CFS+T group (n = 11) included 3 with no headaches.CFS subjects attributed the high prevalences of headaches to their impression that head pain was a usual and often daily manifestation of the severe fatigue and general pain syndrome they experienced. They were often unaware of MO headaches and the potential to use beneficial migraine treatments. Nonsteroidal anti-inflammatory drugs were used by all subjects, raising the possibility of medication overuse headaches as a complicating factor in CFS.Migraine frequency and treatment information were obtained from 51 of the 67 CFS subjects. Headaches occurred on a yearly to monthly basis in 27 subjects (53%). Twenty of these had been previously diagnosed, and 7 were treated with a triptan drug. Half of this subset (10/20) had no specific headache evaluation or treatment plan. Three subjects were symptomatic with migraine during their interviews, and received new diagnoses at that time. All 3 responded to sumatriptan.Headaches were present for 1 to 7 days per week in 47% of the 51 CFS migraine subjects. Only 14 of these 24 had been previously diagnosed, and only 3 were prescribed triptan drugs. Of the 11 with active headaches during the interviews that led to new migraine diagnoses, 10 had beneficial responses to sumatriptan within 12 hours. In total, 13 out of 14 newly diagnosed migraine subjects responded to sumatriptan. This indicates that diagnosis of migraine and its treatment with triptans was of significant benefit in CFS subjects. Migraines were under diagnosed and under treated in CFS subjects.-7 by 2-tailed unpaired Student's t-tests with Bonferroni corrections following significant ANOVA) .The severity scores for each of the 9 CFS criteria (range 0 to 4 for each item) were compiled to examine differences based on headache subtypes. Fatigue Severity Scores were significantly lower in HC than each of the CFS headache subgroups and the composite group of all CFS subjects (p < 10-8), CFS+MO (p = 0.002) and CFS+T . \"Cardio-construct\" scores were significantly higher for CFS+MA (5.9 out of 16) than CFS+MO  and CFS+T (p = 0.049). These results were consistent with the elevated scores of Cohort 1 CFS subjects (Table McGill Pain Scores were significantly higher in the CFS than HC groups of Cohorts 1 and 2 Table . Both thSignificantly more CFS+MO 55.3%) and CFS+MA 46.2%) subjects complained of widespread pain in all four quadrants and their axial skeleton compared to HC  (Table 5.3% and 6.2% subjThe average pressure causing pain at the 18 tender points was measured by dolorimetry. The CFS+MO subgroup had a significantly lower pain threshold (2.36 kg) compared to HC    and loweThe current study was not designed to correlate triggers of migraine or the presence of an aura with precipitating factors of severe episodes of CFS complaints. Migraine triggers include fasting, premenstrual period hormonal status, lack of sleep, nasal irritants and odors . SimilarThe association of migraine with CFS and FM introduces a new perspective for \"functional\" somatization disorders. We agree with Wessely et al.  who statCFS subjects have a high prevalence of migraine headaches that may be overlooked and undertreated. The proportion with an aura was similar to other migraine groups. CFS+MA was associated with higher severity scores for neural problems such as numbness and dizziness, and alterations of heart beat. The lower pressure - induced pain thresholds and hyperalgesia found in the CFS+MO subgroup was suggestive of nociceptive hyperresponsiveness and central sensitization. Appropriate diagnosis and treatment with triptans may be beneficial for CFS subjects and their complex headaches.IHS: International Headache Society; CFS: Chronic Fatigue Syndrome; FM: Fibromyalgia; ACR: American College of Rheumatology; MA: Migraine with aura; MO: Migraine without aura; WPI: Widespread Pain Index; WSP: Widespread Pain; MRI: Magnetic Resonance Imaging; CSD: Cortical Spreading Depression; CSMI: Multisystem Complaints Questionnaire; MFI: Multidimensional Fatigue Inventory; SF-36: Medical Outcomes Survey Short Form 36.The authors declare that they have no competing interests.MKR and JNB made the original clinical observations, and performed the study with the assistance of the other authors. All authors have read and approved the final manuscript.This project was conducted through the Georgetown-Howard Universities Center for Clinical and Translational Science and supported by the National Institutes of Health National Center for Research Resources through Grant 1UL1RR031975; U.S. Public Health Service Award R01 ES015382 from the National Institute of Environmental and Health Science; and the Congressionally Directed Medical Research Program (CDMRP) Award W81XWH-07-1-0618.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2377/11/30/prepub"}
+{"text": "Takayasu\u2019s arteritis (TA) is a chronic inflammatory disease that affects the aorta and its branches. Although it is the third most common vasculitis in childhood, reports with large number of patients are lacking.To evaluate the clinical features and outcome of TA in children and adolescents from Brazil.We retrospectively evaluated 55 patients with Takayasu\u2019s arteritis from 8 Pediatric Rheumatology centers in Brazil. All patients fulfilled the specific classification criteria for TA that have most recently been developed for the pediatric age group. Clinical, data were collected at two time points (at disease onset and at the last available visit).The majority of patients were girls (84%), with mean age at disease onset of 9.3 years, mean age at diagnosis of 10.6 years and a mean follow-up period of 5.6 years. The most common initial clinical manifestations included headache (56.3%), malaise (56.3%), weight loss (45.4%), dyspnea (41.8%) and limb pain (41.8%). The most common cardiovascular finding was hypertension (85.4%). The most frequent laboratory abnormality was an increased erythrocyte sedimentation rate (70.9%). The Mantoux test was positive in 38% of patients. The most common alteration was narrowing or stenosis. The most involved vessels were abdominal aorta (71.8%) followed by left (56.2%) and right renal artery (53.1%). At the last visit the most common clinical manifestations were: headache (22%), inferior limb claudication (14%) and arthralgias (12%); Cardiovascular finding included the absence or decrease of the inferior limb pulses (52%). The treatment included imunossupressors other than corticosteroids in 83.6% and anti-TNF antagonists in 7.2% of patients. Seventeen (30.9%) patients underwent surgical intervention and 5 (9%) died of complication from treatment or from disease related complications.In this large survey of children and adolescents with Takayasu\u2019s arteritis from Brazil a delay in the diagnosis and a high rate of Mantoux test positivity were observed. A death rate similar to the described in literature was found."}
+{"text": "Frizzled homolog 3 receptor was up-regulated in several gastrointestinal cancers such as esophageal and gastric cancers. Moreover, frizzled homolog 3 has recently reported to be expressed in colorectal adenoma specimens. In the present study, we investigated the clinical significance of frizzled homolog 3 protein in colorectal cancer patients. Using immunocytochemical staining, frizzled homolog 3 expression was examined in 186 colorectal cancer specimens, 79 colorectal adenoma specimens, 133 colorectal polyp specimens, 127 colorectal cancer specimens with lymph node and/or distant metastasis, 310 specimens of various non-colorectal cancer metastatic carcinomas and 40 specimens with simultaneous occurrence of colorectal cancer, colorectal adenoma and colorectal polyp. Statistical analysis was used to correlate frizzled homolog 3 protein expression to the clinicohistopathological factors, recurrence/metastasis and survival after follow-up for 42 months in colorectal cancer patients. Frizzled homolog 3 protein was expressed in 100% colorectal cancer specimens, 89% colorectal adenoma specimens, 75% colorectal polyp specimens and 69% normal colorectal epithelial tissues. Moreover, frizzled homolog 3 immunocytochemical scores were highly correlated with colorectal cancer progression. Furthermore, frizzled homolog 3 was expressed in a comparatively lower percentage of metastatic hepatocellular carcinoma and metastatic renal clear cell carcinoma with focal and very weak staining than other metastatic tumor types. On the other hand, the frizzled homolog 3 immunocytochemical scores of colorectal adenomas with synchronous colorectal carcinomas were significantly higher than those of pure colorectal adenomas. Statistical analysis showed that frizzled homolog 3 immunocytochemical scores were associated with Dukes stage and lymph node status. Finally, stratified groups of colorectal cancer patients had significant differences in their recurrence/metastasis and survival. In conclusion, the present large-scale study has clearly showed that frizzled homolog 3 protein can generate clinically important information for colorectal cancer patients.  Colorectal cancer (CRC) is the third most frequently diagnosed cancer worldwide, accounting for more than 1 million cases and 600,000 deaths every year -4. Despi2+ pathway and Wnt/c-Jun N-terminal kinase (planar cell polarity) pathway and Wnts bind to a complex comprised of FZD, receptor tyrosine kinase-like orphan receptor 2/receptor related to tyrosine kinase for activation of downstream signaling [2+ pathway, Wnt activates intracellular Ca2+ signaling, as well as Ca2+ - dependent protein kinases, such as protein kinase C and calmodulin dependent protein kinase II [Wnt factors comprise a large family of secreted glycoproteins that participate in embryonic development by regulating tissue patterning, organogenesis, specification of the body plan and promote tissue homeostasis in the adult . At the ignaling -14. In Winase II -14. In tinase II -14. RhoAinase II -14. In sFZD3 was mapped to chromosome 8p21 [FZD3 mRNA is expressed in various normal tissues  [FZD3 mRNA was expressed in a small cohort of sporadic adenoma and familial adenomatous polyposis adenoma tissues [Human ome 8p21 ,15. FZD3 cortex)  whereas  cortex) -19. A re tissues . The sigThe study was conducted according to the principles expressed in the Declaration of Helsinki. Written informed consent was obtained from all patients or the next of kin for use of those samples in research. Since patient consent was not possible for archival tissues as some patients were deceased at the time of study, the ethics committee specifically waived the need for consent from those patients. The study was approved by the Clinical Research Ethics Committee of the Queen Elizabeth Hospital, Hong Kong Special Administrative Region (HKSAR).Seven cohorts of formalin fixed, paraffin-embedded (FFPE) specimens were recruited: 1) CRC with Dukes classification system stage A (43), stage B (48), stage C (63), stage D (32), total: 186, 2) CAD with mild dysplasia (25), moderate dysplasia (28), severe dysplasia (26), total: 79, 3) colorectal polyp which is specifically defined as non-adenomatous or non-neoplastic polyps which consist of juvenile (35), hyperplastic (40), Peutz-Jeghers (28) and inflammatory polyps (30), total: 133, 4) one FFPE block with lymph node metastasis from each Dukes C specimen, total: 63, 5) one FFPE block each with lymph node and distant metastasis from each Dukes D specimen, total: 64, 6) three hundred and ten non-CRC metastatic carcinomas which the primary tumor was respectively hepatocellular carcinoma (HCC) (23), renal clear cell carcinoma (RCCC) (25), squamous cell carcinoma (SCC1) (30), lung adenocarcinoma (LAC) (25), lung non-small cell carcinoma (LNSCC) (27), papillary thyroid carcinoma (PTC) (24), breast carcinoma (BC) (28), ovary clear cell carcinoma (OCCC) (30), cervical non-small cell carcinoma (CNSCC) (20), fallopian tube serous adenocarcinoma (FTSAC) (22), transitional cell carcinoma (TCC) (23), small cell carcinoma (SCC2) (15) and carcinoma with neuroendocrine differentiation (CND) (18), 7) specimens from forty CRC patients  with simultaneous occurrence of CRC, adenoma and polyp (120), were retrieved from the archives (2005-2008) of the Anatomical Pathology and Cytology Laboratory, Department of Pathology, Queen Elizabeth Hospital, HKSAR, for FZD3 immunocytochemical (ICC) staining. Most cases of the colorectal adenocarcinomas in the first cohort were moderately differentiated (78%), whereas the rest were either well differentiated (5%) or poorly differentiated (17%). The sex distribution of adenocarcinoma patients was 58% male and 42% female. The age ranged from 42 to 89 years old. Of the 79 adenoma specimens examined in cohort 2, 59% was tubular, 35% was tubulovillous, and 6% was villous adenomas. The percentages of mild, moderate, and severe dysplasia in adenomas were 32, 35 and 33, respectively. The sex distribution of adenoma patients was 53% male and 47% female. The age ranged from 28 to 85 years old. The polyps evaluated in cohort 3 were juvenile (26%), hyperplastic (30%), Peutz-Jeghers (21%), and inflammatory polyps (23%). Of the 133 polyps, the sex distribution was 51% male, 49% female and the age ranged from 23 to 76 years old. The clinical information of the patients with simultaneous occurrence of CRC, adenomas and polyps in the seventh cohort were moderately differentiated (75%), well differentiated (7%) or poorly differentiated (18%). The sex distribution of adenocarcinoma patients was 60% male and 40% female. The age ranged from 45 to 87 years old.Monoclonal mouse anti-human FZD3 antibody  was used.Serial tissue sections (4 \u03bcm thick) were cut and antigen retrieval was performed using Bond Epitope Retrieval Solution 2 on the Bond-max automated immunostainer  at 100\u00b0C for 25 minutes. Staining was performed according to a standard protocol in the immunostainer. Polymer detection system was selected to avoid the problem of nonspecific endogenous biotin staining. Esophageal carcinoma was used as a positive control  which waP value < 0.05 was considered to be statistically significant in all analyses. All P values are two-tailed. The difference in ICC scores of FZD3 protein among CRC, CAD and adjacent normal colorectal epithelial cells was studied using non-parametric Kruskal-Wallis test. In addition, non-parametric Spearman rank correlation test was used to examine whether FZD3 ICC scores were correlated with CRC progression and Dukes classification stages. Mann Whitney U test was used to examine whether the ICC scores of CAD with synchronous colorectal carcinomas had significant difference from those of pure CAD. For correlation to clinical parameters, multivariate regression was used to analyze whether FZD3 ICC scores were correlated with the clinico-histopathological factors of the patients and chi-square test was used to examine the association between FZD3 ICC scores and recurrent or metastatic CRC. The overall survival was defined as that from the date of the operation to the date of death due to cancer. The Kaplan-Meier method was used to determine the probability of survival and log-rank test was used to compare the survival between the groups and Cox proportional hazards model was applied to determine the independent prognostic factors of survival. . A As mentioned in the ICC staining and evaluation section, a thickened membranous staining which resembled cytoplasmic staining was detected. Among the 955 slides that we have examined, inter-individual variation was found only in 16 slides (1.7%) and consensus was reached after discussion using a multi-headed microscope. P < 0.0001, Kruskal-Wallis test) and the range and median of the ICC scores in various specimen types were shown in P < 0.0001, Spearman rank correlation test). Moreover, the ICC scores of FZD3 protein in CRC specimens was significantly correlated with Dukes stage . Furthermore, our findings showed that FZD3 protein was expressed in 100% metastatic CRC cells in lymph nodes or/and distant organs from Dukes 3 and 4 specimens, respectively (ICC staining showed that FZD3 protein was expressed in 100% 186/186) of CRC specimens, 89% (70/79) of CAD specimens, 75% (100/133) of colorectal polyp specimens and 69% (129/186) of normal colorectal epithelial tissues adjacent to CRC tissues. A representative photomicrograph of each specimen type in the first cohort was shown in ectively . In lineectively . In caseectively  and 6. /186 of CP < 0.0001, Spearman rank correlation test). Of interest, the ICC scores of CAD with synchronous colorectal carcinomas were significantly higher than those of pure CAD  of CRC, 93% (37/40) of CAD, 70% (28/40) of colorectal polyp. Moreover, FZD3 ICC scores were highly correlated with the stages of progression of CRC (P < 0.001) and lymph node status (P < 0.05) but not for age (P = 0.547), sex (P = 0.813), tumor stage (P = 0.284) and degree of differentiation (P = 0.462). Multivariate regression analysis was applied to examine whether FZD3 ICC scores were correlated with the clinicohistopathological factors of the 186 Dukes A to D CRC patients. Significant associations were found with Dukes stage . The median number of FZD3 ICC scores from the 154 Dukes A to C CRC patients was 321.5. Using this median number as the cut-off point, 27 patients with FZD3 ICC score > 321.5 and 8 patients with FZD3 ICC score \u2264 321.5 had recurrent or metastatic CRC after follow-up for 42 months and the association between FZD3 ICC scores and recurrent or metastatic CRC was highly significant . Finally, the independent prognostic factors of overall survival identified by the Cox proportional hazards regression model were found to be FZD3 ICC score (P = 0.016) and lymph node status (P = 0.037). Overall survival curves were plotted for CRC patients with FZD3 ICC scores > 327 and those with FZD3 ICC scores \u2264 327 where 327 is the median number of FZD3 ICC scores from the 1FZD3 is a receptor for the Wnt-signaling pathway and FZD3 protein is required for the development of major fiber tracts in the rostral central nervous system , neural  Another interesting finding from this study is that the median ICC score of the CAD associated with synchronous colorectal carcinomas is much higher than that of the group consisting of pure CAD, suggesting that a high FZD3 protein expression in CAD may signify a higher malignancy potential. P < 0.05) in survival between moderately high and moderately low expression groups provides a solid evidence that FZD3 protein has important prognostic power. Taken all those findings together, FZD3 ICC staining can potentially be a valuable tool for the prognosis of CRC. In order to validate those findings, a large multi-centre trial with a long-term follow-up on examining its prognostic significance is now being prepared. Human Wnt5A, Wnt5B and Wnt11 are representative non-canonical Wnts transducing Wnt/planar cell polarity signals through FZD3 receptors [in vitro and required a Wnt ligand signal [ The ultimate goal of this study is to explore the clinical significance of FZD3 protein in patients with CRC. As currently there is scanty pathologically used prognostic marker for CRC and therefore it is invaluable to investigate the prognostic potential of FZD3 protein which is demonstrated in this study by the significant correlation of FZD3 ICC scores to Dukes stage, lymph node status, recurrence or metastasis. Moreover, a long-term follow-up of those CRC patients showed that patient with a high FZD3 ICC score may have a less chance of survival. Actually, the specimens with FZD3 ICC scores > 327 were mainly of stages III and IV patients whereas those with FZD3 ICC scores \u2264 327 were mostly of stages I and II patients. This may be one explanation why stages III and IV patients have a greater risk of recurrence, metastasis and shorter survival than stages I and II patients. A more detailed analysis of the data by classifying it into 4 groups based on their level of expression can provide us more information on the prognostic significance of FZD3 protein in CRC patients. The significant difference in survival between high and low expression groups is expected whereas the marginal significant difference (eceptors ,29-31. Aeceptors . Moreoved signal . Therefo In summary, FZD3 protein expression as shown by ICC staining is closely correlated with colorectal carcinogenesis and progression, and can potentially serve as a new prognostic marker. Moreover, FZD3 ICC staining may be helpful to exclude HCC and RCCC in metastatic sites."}
+{"text": "The use of designated emergency teams for cardiac arrest and trauma patients are widely implemented. The use of designated teams in Danish emergency departments has not been investigated.Our aim was to investigate the use and staffing of designated emergency teams in Danish emergency departments.A cross sectional, questionnaire study was sent to the department chairs of all 20 Danish emergency departments. The four level one trauma centres were excluded.Nineteen of twenty (95%) departments responded. Three departments were excluded due to incomplete data.All departments (n=16) received unselected critically ill patients, patients in cardiac arrest and trauma patients. In 16 (100%) departments there were a designated team that responded to cardiac arrest and trauma patients. Only 5 (31%) departments had access to a designated medical emergency team in the emergency department.The cardiac arrest teams consisted of median 6,2 (range 5-10) different personnel groups. Of these, 3 (range 1-6) were physicians with only 0,9 (range 0-2) being senior consultants. The other summoned personnel groups included emergency department nurses, nurse anaesthetists, bioanalysts and porters.The trauma teams consisted of median 9,3 (range 7-11) different personnel groups. Of these, 4,3 (range 2-6) were physicians where 2,6 (range 2-4) were senior consultants. The other summoned personnel groups included emergency department nurses, nurse anaesthetists, radiographers, bioanalysts, and porters.In 4 (25%) departments there were not access to a medical emergency team, and in 5 (31%) an ad hoc team was created by the emergency department personnel. In 2 (14%) departments a team was created by the attending emergency physician. The staffing of the medical emergency teams relied on patient specific diagnosis, symptoms and triage scores.Designated teams for patients in cardiac arrest and trauma patients are widely available in Danish emergency departments. More senior staff is included in trauma teams compared to cardiac arrest teams. In addition few emergency departments in Denmark have designated teams for the reception of unselected critically ill patients. This indicates that emergency care of critically ill patients could be improved."}
+{"text": "To the Editor: West Nile virus (WNV) is a mosquito-borne flavivirus. Sporadic infections with this virus have been found in Africa, Europe, Asia, and the United States. In humans, most infections with WNV cause subclinical or a mild influenza-like illness; encephalitis occurs in some  is the most populated state in northeastern India; it contains \u224850% of the 38.8 million inhabitants of northeastern India. Japanese encephalitis virus (JEV) has caused sporadic epidemics in Assam since 1976. Studies conducted during 2000\u20132002 in Assam showed that 187 (53.7%) of 348 persons with acute encephalitis syndrome were infected with JEV  was started in Assam during May 2006. During its first phase, children 1\u201315 years of age in Dibrugarh and Sivasagar Districts were vaccinated. Mosquito surveillance in the study area and in an earlier study  were children <15 years of age.During the study period, 103 serum samples and 88 cerebrospinal fluid samples were obtained from 167 patients with acute encephalitis syndrome admitted to the Assam Medical College and Hospital in Dibrugarh, which administers to the health needs of Among the 103 serum samples, 80 were positive for immunoglobulin (Ig) M against JEV  and 12 (11.6%) were positive for IgM against WNV . These samples were from persons in 4 districts in Assam  and negative for IgM against JEV . Follow-<80) and JEV (titer <40).Virus-neutralizing antibody titers against JEV and WNV were estimated in pig kidney epithelial cells by using JEV (isolate 733913) and WNV (isolate 68856) and a cytopathic-effect assay in 96-well tissue culture plates (<6 months follow-up were impaired memory (6 patients), irritable behavior (5 patients), impaired hearing (3 patients), incoherent speech and disorientation (1 patient), breathing difficulty (1 patient), impaired speech (1 patient), and quadriparesis (1 patient).All 12 WNV-infected patients had high fever and headache. Convulsions (6 patients), altered sensorium (7 patients), vomiting (5 patients), and neck rigidity (2 patients) were also observed. Signs and symptoms at the time of hospitalization and at follow-up for 6 months  were similar for persons infected with JEV and those infected with WNV. Neurologic sequelae observed at We identified WNV in regions of Assam to which JEV is endemic. The finding indicates that WNV might be the cause of a substantial number of acute encephalitis syndrome cases in this region. Fever and headache were the most common signs and symptoms, as reported ("}
+{"text": "The relatively high frequency of primary brain tumors (PBT) observed in childhood and adolescence in Kuwait has necessitated this epidemiological study. It is based on the records of the Department of Pathology, Al-Sabah Hospital, which examined all brain tumor biopsies done in this age group in Kuwait between 1995 and 2011. During this period, 75 boys (49%) boys and 77 (51%) girls had histologically confirmed PBT. They comprised 122 children (0\u201314 years) and 30 adolescents (15\u201319 years). The boys/girls ratio was 1.03 in childhood and 0.76 in adolescence. The age-adjusted incidence rate was 11.2/ million person-years. Early childhood (0\u20134 years) had the peak frequency of tumors (33%), highest adjusted age-specific incidence rate (3.8/million person-years) of all tumors and the least boys/girls rates ratio (0.38) for astrocytic tumors. Low grade and high grade tumors peaked in 5\u20139 and 0\u20134 years respectively. Risk factors (hereditary syndromes or previous radio-therapy) were identified in three patients. Three (2%) tumors were congenital. High grade tumors comprised 47% of childhood and 23% of adolescence PBT. The most common tumors in childhood were astrocytoma (37%), embryonal tumors (31%), ependymoma (8%), and in adolescence astrocytoma (27%), pituitary adenoma (23%) and glioblastoma (13%). Embryonal tumors formed 44% of PBT in early childhood. Gliomas constituted 54% and 43% of all PBT, but 25% and 57% of high grade tumors in childhood and adolescence respectively. Most common tumor locations were cerebellum (47%), ventricles (19%) and cerebral lobes (17%) in childhood and pituitary (30%), cerebellum (27%) and 13% each for cerebral lobes and ventricles in adolescence. Approximately 57% of childhood and 23% of adolescence PBT were infratentorial.In conclusion, despite the high relative frequency of PBT before the age of 20 years in Kuwait, its incidence rate is apparently low. Compared with Western countries, Kuwait has a lower incidence of malignant gliomas, but a higher frequency of cerebellar and intraventricular tumors. Embryonal tumors are remarkably common in early childhood. Primary brain tumors (PBT) are a varied group of benign and malignant tumors which arise from the brain parenchyma and its surrounding structures. Although an overwhelming majority of these tumors occur in adults, the pediatric and adolescent PBT deserve special attention for several reasons. Firstly, some specific histological types which are common in childhood are rare in adults. More importantly there are indications that pediatric and adult glial tumors have significant differences in their molecular biology and behavior. These have serious implications for future research, treatment and prognostic factors  of PBT in childhood and adolescence  and adolescents (15\u201319 years). Children were further stratified into 5-year age groups- 0\u20134, 5\u20139 and 10\u201314 years. All new cases of primary brain tumors with histological diagnosis in patients within these age groups were identified from the 1995\u20132011 records of the Department of Pathology, Al-Sabah Hospital Kuwait. Patient\u2019s characteristics, tumor type and anatomical location were analyzed. For comparative analysis, the number of all PBT and high grade tumors diagnosed in adults (ages \u226520 years) during the same period were also extracted.Histological classification of tumors was based on the \u201cThe World Health Organization (WHO) Classification of Tumors of the Central Nervous System 2007)\u201d  were collectively referred to as Lobes.Ventricular tumors encompass tumors that are completely or largely (\u2265 two-thirds) within the ventricular system (ICDO site code C71.5).Pituitary tumor is a collective name for pituitary adenoma and craniopharyngioma (ICDO-site code C75.1\u201375.2).Gliomas refers to tumors of presumed glial origin These include astrocytic tumors, ependymoma, oligodendroglioma, mixed glioma and malignant glioma (NOS) and fall under the ICD-O-3 histology codes 9380\u20139384, 9391\u20139460, and 9480.Embryonal tumor is the collective name for medulloblastoma, supratentorial primitive neuroectodermal tumor (sPNET) and atypical teratoid-rhabdoid tumor (AT/RT).Congenital tumor refers to any tumor that manifests within 60 days of life as defined by Arnstein et al. .Between 1995 and 2011, 152 new patients, made up of 75 (49%) boys and 77 (51%) girls, had histologically confirmed PBT in Kuwait. Their ages varied from 24 days to 19 years. Three patients (2%) were less than 2 months old at the time of diagnosis. There were 122 children \u221262 boys (50.8%) and 60 girls (49.2%) and 30 adolescents \u221213 boys (43.33%) and 17 girls (56.67%). The general age distribution was as follows: 0\u20134 years: 50 (32.89%), 5\u20139 years: 46 (30.26%), 10\u201314 years: 26 (17.11%) and 15\u201319 years: 30 (19.74%). The age and sex distribution of PBT in childhood and adolescence is depicted in Figure The age-adjusted incidence rate for PBT below the age of 20 years was 11.2/million person-years. The distribution of the adjusted age-specific rates is shown in Figure Among 841 adult patients (aged \u226520 years) with PBT, 236 (28%) had high grade tumors. In childhood and adolescence 64 (42%) patients had high grade tumors. Further analysis showed that high grade tumors comprised 47% of childhood and 23% of adolescence tumor. The difference was statistically significant . High grade tumors displayed a peak frequency (42%) in the 0\u20134 years age group and a highly significant inverse relationship with age . They occurred in 37 boys (58%) and 27 girls (42%). On the other hand, low grade tumors had a peak frequency (30%) in the age range of 5\u20139 years and an insignificant inverse relationship with age . They were seen in 38 boys (43%) and 50 girls (57%).The group of tumors known as gliomas constituted 54.1% and 43.3% of all childhood and adolescent tumors respectively. In addition, they formed 25% of childhood and 57% of adolescence high grade tumors.They comprised astrocytic tumors (67), ependymoma (11) and oligodendroglioma (1).Astrocytic tumors formed 44.08% of all PBT and were diagnosed in 29 boys and 38 girls. Patients\u2019 ages ranged from 1\u201319 years with an average of 9 years. Most (82.09%) occurred in childhood. The peak frequency (34%) was in the 5\u20139 years age range. The crude incidence rate was 4.9/million person-years for boys and 5.8/million person-years for girls. The crude age-specific incidence rates peaked between 5 and 9 years for boys and between 10 and 14 years for girls. In general, girls had higher rates in all age groups except 5\u20139 years  and 3 cases of subependymal giant cell astrocytoma. Pilocytic astrocytoma made up about 29% of PBT and was diagnosed in 19 boys and 25 girls. About 64% of patients with pilocytic astrocytoma were less than 10 years old, while 75% of the tumor was infra-tentorial. One patient with pilocytic astrocytoma had neurofibromatosis. Another patient with subependymal giant cell astrocytoma had tuberous sclerosis.Sixteen patients- 8 boys and 8 girls- had high grade astrocytic tumors. These comprised 13 glioblastoma (GBM) and 1 each of anaplastic astrocytoma, malignant pilocytic astrocytoma and high grade astrocytic tumor, not otherwise specified. The small size of the biopsy did not permit further classification of the last case. GBM was the second most common high grade tumor. It accounted for 20% of all high grade tumors but 8.55% of all PBT. All were supratentorial. Its age distribution was bimodal with peaks in 5\u20139 years (38%) and 15\u201319 years (31%). One patient (8%) was less than 5 years old.Ependymoma contributed 7.23% to all PBT and occurred in 5 boys and 6 girls aged between 1.5 to 19 years. The median age was 5 years. About 91% of the patients were less than 10 years old. The tumor was infra-tentorial in 8 patients and supra-tentorial in 3. There were 9 WHO Grade II and 2 Grade III tumors.Embryonal tumor was the second most common PBT (26.32%), the leading high grade tumor (63%) and the most common tumor (44%) in the age group of 0\u20134 years. It comprised medulloblastoma (33 cases), supratentorial primitive neuroectodermal tumor (5 cases) and atypical teratoid-rhabdoid tumor (2 cases). Embryonal tumor was diagnosed in 23 boys and 17 girls, aged between 24 days and 19 years. The average age was 5.7 years. About 83% of the patients were younger than 10 years while 55% were less than 5 years old.It had a crude incidence rate of 3/million person-years. Boys had higher age-specific rates than girls in childhood. The rates ratio varied from 1.14 to 1.41  had pituitary tumor. It constituted 30% of adolescence, but only 5.74% of childhood, PBT. There were 9 cases of craniopharyngioma and 7 pituitary adenomas.Craniopharyngioma affected 5 boys and 4 girls aged 4\u201315 years with a median age of 9 years. Seven occurred in childhood and 2 in adolescence.Pituitary adenoma was seen in 6 girls and 1 boy, aged between 16 and 19 years. The median age was 19 years. It formed 78% of all sellar and supra-sellar tumors in adolescence. Six tumors were functional and comprised lactotroph (3), somatotroph (2) and corticotroph (1).Three boys and 2 girls, aged between 2 months and 2 years had choroid plexus tumors. Three were less than 6 months old.These included meningioma (4), neurocytoma (3), germ cell tumor (2) and 1 each of pineoblastoma, chordoma, and lipoma. One patient with meningioma had received radiotherapy for an unspecified cerebellar tumor 15 years earlier.The distribution of the various tumors in childhood and in adolescence is shown in Figure The distribution of childhood and adolescence tumors as a group according to anatomical location is shown in Figure There were 78 infratentorial and 74 supratentorial tumors.Infratentorial tumors formed 57% of childhood tumors and 27% of tumors in adolescence. They were evenly distributed among both sexes. Their frequency peaked (41%) before the age of 5 years and rapidly declined. The inverse relationship with age was statistically significant . About 76% of patients with infra-tentorial tumors were less than 10 years old, while 10% were adolescents. Approximately, 47% of these tumors were high grade.Supratentorial tumors constituted 73% of tumors in adolescence and 43% of childhood tumors. Thirty-six boys and 38 girls had supratentorial tumors. The age distribution was bimodal with peaks in the 5\u20139 years age group (26%) and 15\u201319 years (30%). A dichotomy was observed in the age distribution of low and high grade tumors. The low grade tumors peaked at 5\u20139 (23%) and 15\u201319 years (36%). Conversely, the high grade tumors had a unimodal distribution with peak (33%) before the age of 5 years.Despite an inherent selection bias, the results of this study suggest that the epidemiology of primary brain tumors (PBT) in Kuwait, before the age of 20 years, is characterized by low incidence rate and differences in gender preference, distribution of specific histology, topographic dominance and proportion of high grade tumors between childhood and adolescence tumors.The low incidence rate observed in this study appears paradoxical because of the previously reported relatively high frequency of PBT in this age group. Notwithstanding this oddity, the finding is consistent with reports from other economically developing countries. Stiller and Nectoux have suggested that underdiagnosis may be a major contributory factor to this observation  ratio of 1.03, is seen in childhood PBT in Kuwait. This is most likely a reflection of the gender distribution in the population at risk (B/G ratio: 1.05). The B/G ratio of PBT in childhood as reported in English Literature varies from 1.08 to 2.52, with Pakistan recording the highest ratio . On the contrary, USA has a higher incidence of brain stem tumors (11%) than Kuwait (1%)  appears remarkable in the epidemiology of PBT in Kuwait for several reasons. Firstly, it has the highest age-specific incidence rate and frequency of tumors. Secondly, astrocytic tumors have their lowest boys/girls rates ratio in this age group. It is noteworthy that their rate in girls in this age group is about two and a half times that of boys. Thirdly, the distribution of tumors contrasts sharply with observations in Western countries. Embryonal tumors and gliomas represent about 44% and 38% respectively of all tumors in this age group as opposed to 18% and 52% in USA.Similarly, the leading tumors in this age group in Germany are astrocytoma and ependymoma (Rickert et al. Although one patient with Kenny Caffey syndrome had medulloblastoma, the significance of this hereditary syndrome in the etiology of brain tumors has not been established. Nonetheless, 2% of the patients in this series had generally accepted risk factors for PBT. Since hereditary factors were identified in only 1.3% of the cases, they may be considered insignificant etiological factors for childhood PBT in Kuwait.Finally, about 2% of tumors in this study are congenital. This further confirms the rarity of congenital brain tumors, whose frequency has been reported to vary from 0.5% to 4% among pediatric brain tumors (Manoranjan & Provias The results of this study do not explain the relatively high proportion of primary brain tumors before the age of 20 years in Kuwait. However, they have highlighted the prominent features of childhood and adolescence PBT in Kuwait. Compared with Western countries, Kuwait has a lower incidence of malignant gliomas, but a higher frequency of cerebellar and intraventricular tumors.The similarity between the pattern of childhood tumors in Kuwait and Iran on one hand and dissimilarity with Syria on the other hand suggests intraregional differences in the Middle-East. Adolescence PBT has distinct epidemiological features different from both childhood and adult PBT."}
+{"text": "To examine the patient characteristics, diagnostic criteria, treatment, complications and outcomes of Kawasaki disease (KD) in a cohort of patients of two pediatric hospitals of Emilia Romagna from 2000 to 2010.Retrospective study: 26 patients diagnosed with complete or incomplete KD. Clinical and outpatient statuses were collected.Male-to-female ratio was 1 to 1. Median age at onset: 35,8 months (2-101 months); children < 6 months: 23%. Complete KD: 73%. Age was not significant different between complete and incomplete KD.Season of Onset of disease : winter in 35%, spring 31%, summer 11%, autumn 23%. Diagnostic signs: iperemic conjunctivitis and mucositis in 92% of pts, cutaneous rash in 88%, linfoadenopathy in 54%, alterations of extremities in 50%, desquamation of extremities in 58%; adjunctive signs: perineal dermatitis in 30% and diarrhea in 42%.7 pts (5 boys) developed coronary involvement (group1): markers of inflammation and age at onset were not significantly different between group 1 and group 2 . 28% of pts in group 1 was responder to therapy versus 47% in group 2. Coronary involvement regressed in all but 2 pts (both received late treatment).Male gender and late start of treatment were shown to be independent risk factors for developing coronary involvement, while younger age and incomplete form were not.Late intravenous immunoglobulins seems to be risk factor for persistence of coronary aneurysm, but the small number of patients limits us to have definite conclusions ."}
+{"text": "It is well documented that the incidence of biliary tract pathologies increases with age, and as life expectancy is rising, it is expected that the prevalence of advanced age patients with bile duct pathologies will correspondingly increase leading to an increase in the demand for endoscopic retrograde cholangiopancreatography (ERCP) interventions.Our aims are to assess the outcomes, safety and complications associated with ERCP performed in an elderly population.Patients aged 80 years or over referred for ERCP from January 2008 to December 2012, were identified and retrospectively reviewed.Eighty-three patients  underwent 94 procedures (1-3 procedures/patient). The main indications were cholangitis (53.7%), choledocholithiasis (19.4 %) and blocked stents (14.6 percent). Malignancies represented 12.3% of indications. The overall success rate was 92.5%. Minor events occurred in 19 patients (22.9%) percent . Major events occurred in 4 patients (4.8%): delayed post sphincterotomy bleeding (five days post-procedure) in 1 patient, cholangitis in 2, and one mild pancreatitis. Four deaths occurred within one month of ERCP, due to advanced malignancies.Our study showed that ERCP is safe in the elderly population. Minor complications are usually transient and related to sedation, and mortality is usually related to severity of illness and underlying malignancies."}
+{"text": "Food allergy (FA) is a frequent finding after paediatric liver transplantation (LT). The pathogenesis remains incompletely understood. We here report the clinical characteristics of post transplant food allergy (PTFA) in children currently followed after LT in our centre.The study group consists of 49 LT patients transplanted at a median age of 22 months (3 weeks-16 years). Data were collected retrospectively from medical records and via a doctor\u2019s questionnaire taken from the parents. The diagnosis of FA was based on convincing clinical symptoms followed by a clear response to elimination and provocation. Supervised open food challenge was performed when clinical history and symptomatology were not unequivocal and/or in case of IgE mediated acute symptoms. Skin prick testing (SPT) was performed with fresh products according to standard guidelines.13 (26%) LT patients developed PTFA. None of the patients had symptoms prior to transplantation. 7/13 (54%) have multiple FA. Symptoms with acute onset  are present in 6/13 (46%) compared to chronic symptoms with delayed/subacute onset in 7/13 (54%). In the latter, SPT and/or specific IgE were positive in 5/7 for clinically relevant antigens. 10/13 (77%) presented with gastro-intestinal symptoms , other symptoms were angioedema (4), urticaria (1), anaphylaxis (1) and severe atopic dermatitis (1). 3 patients suffer from treatment resistant cheilitis with oral mucosal lesions. One patient was diagnosed with eosinophilic oesophagitis . In at least 9/13 (69%) patients FA presented in the aftermath of a proven episode of gastroenteritis. The median follow-up since diagnosis of FA is 72 (33-188) months. In terms of prognosis, only 1 in 13 children has outgrown the FA, being able to reintroduce the food allergen in the diet.PTFA is an important clinical problem in children after LT. Patients present multiple, persistent FA mainly with gastrointestinal symptoms. Chronic oral lesions resistant to dietary intervention are seen in 25% of patients. IgE seems implicated in the immunopathology of PTFA in the majority of patients.None declared."}
+{"text": "To determine if computed tomographic pulmonary angiography (CTPA) was overemployed in the evaluation of hospitalized patients with suspected acute pulmonary embolism (PE).Data were gathered retrospectively on hospitalized patients (n=185) who had CTPA for suspected PE between June and August 2009 at our institution.CTPA was done in 185 hospitalized patients to diagnose acute PE based on clinical suspicion. Of these, 30 (16.2%) patients were tested positive for acute PE on CTPA. The Well's pretest probability for PE was low, moderate, and high in 77 (41.6%), 83 (44.9%), and 25 (13.5%) patients, respectively. Out of the 30 PE-positive patients, pretest probability was low in 2 (6.6%), moderate in 20 (66.7%), and high in 8 (26.6%) (p=0.003). Modified Well's criteria applied to all patients in our study revealed 113 (61%) with low and 72 (39%) with high clinical pretest probability. When modified Well's criteria was applied to 30 PE-positive patients, 10 (33.3%) and 20 (66.6%) were found to have low and high pretest probability, respectively (p=0.006). D-dimer assay was done in 30 (16.2%) of the inpatients with suspected PE and all of them were found to have elevated levels. A lower extremity duplex ultrasound confirmed deep venous thrombosis in 17 (9.1%) of the patients with suspected PE, at least 1 week prior to having CTPA.Understanding the recommended guidelines, evidence-based literature, and current concepts in evaluation of patients with suspected acute PE will reduce unnecessary CTPA examinations. Computed tomographic pulmonary angiography (CTPA) has emerged as a prominent imaging technique to investigate patients for suspected pulmonary embolism . In 1980, 3 million CT scans were done in the United States, which increased to 70 million in 2007 . Burge eA retrospective study was done examining a 3-month period (June\u2013August) in 2009 at a 475-bedded hospital, with the institutional review board approval. Electronic medical records of all hospitalized patients who underwent a CTPA for suspected PE during this period were reviewed. Data on demographics, clinical presentation, components of Well's criteria , along wCTPA was done in 185 hospitalized patients to diagnose acute PE based on clinical suspicion. Of these, 30 (16.2%) patients were tested positive for acute PE on CTPA. The Well's pretest probability for PE was low, moderate, and high in 77 (41.6%), 83 (44.9%), and 25 (13.5%) patients, respectively. Out of the 30 PE-positive patients, pretest probability was low in 2 (6.6%), moderate in 20 (66.7%), and high in 8 (26.6%). Modified Well's criteria applied to all patients in our study revealed 113 (61%) with low and 72 (39%) with high clinical pretest probability. When modified Well's criteria were applied to PE-positive patients, 10 (33.3%) and 20 (66.6%) were found to have low and high pretest probability, respectively.A chi-square test of general association was conducted to determine if there is a significant relationship between the frequency of PE status and Well's scoring categories for the entire sample (N=185). Results revealed a statistically significant association (p=0.003). A statistical analysis done on modified Well's pretest probability alone for acute PE revealed a sensitivity, specificity, positive predictive value and negative predictive value of 66.6, 66.4, 27.7 and 91.1%, respectively in our study population. D-dimer assay was done in 30 (16.2%) inpatients with suspected PE and all of them were found to have elevated levels. A lower extremity USG confirmed deep venous thrombosis (DVT) in 17 (9.1%) patients with suspected PE, at least 1 week prior to having CTPA. ventilation perfusion (VQ) scan was done in 36 hospitalized patients compared to 185 CTPA studies during this time period at our institution.CTPA positivity quoted in literature ranges from 13 to 33% in suspected PE patients , 7. In oThe incidence of contrast-induced nephropathy after having CTPA in patients for suspected PE is up to 12% , 9. BrenUsage of VQ scans in suspected PE with normal chest radiograph results in considerably lower radiation exposure with comparable negative predictive value to CTPA . The totIn patients with acute PE, lower extremity duplex USG is positive in 50% of patients with clinical signs and symptoms of DVT , 17. In D-dimer assay is a very sensitive but non-specific screening test for VTE as it is elevated in many conditions . A studyWe acknowledge the limitations of a retrospective study where data might not be completely obtainable but care was taken to gather all of the information at the time of study. To evaluate current practice at our institution, the study was designed to be in retrospective nature, in order to eliminate the Hawthorne effect. We used Well's and modified Well's scoring system in our study but not the revised Geneva scoring system, which only uses objective measures. This may have reduced the interobserver variability in assessing the pretest probability but evidence is lacking to prove that one scoring system is better than the other in hospitalized patients.We recommend the importance of adherence to clinical guidelines to avoid unnecessary CTPA and potential complications associated with radiation and contrast administration."}
+{"text": "Timely reperfusion of the occluded coronary artery is crucial in reducing the amount of myocardial damage in patients with ST elevation myocardial infarct (STEMI). This study aims to examine the common presenting symptoms of patients with STEMI, their modes of arrival at the emergency department (ED) and its impact on door-to-balloon (D2B) time and in-hospital morbidity and mortality.In this retrospective study, the medical records of 619 patients with an admitting diagnosis of STEMI from Tan Tock Seng Hospital, Emergency Department between 1 January 2009 and 31 December 2009 were reviewed. We extracted data from the electronic records of the emergency case notes and inpatient discharge summaries.P < 0.001). There was no difference in D2B time between patients who arrived in the day (06:00 to 17:59 hours) or at night (18:00 to 05:59 hours). Chest pain, shortness of breath and diaphoresis were the three commonest presenting symptoms in patients with STEMI regardless of their mode of arrival. Previous myocardial infarction, PCI or CABG did not influence the mode of transport. Patients who arrived by EMS had a higher incidence of cardiogenic shock  and were significantly older  than patients who arrived by self-transport. Patients who arrived by EMS had a higher in-hospital mortality rate  and a longer mean length of stay compared to those who arrived by self-transport .Among 619 patients, 363 (58.6%) arrived by emergency medical services (EMS) and 256 (41.4%) by self-transport. Three hundred and thirty (53.3%) patients underwent emergency angiography, of which 313 (94.9%) were treated with percutaneous coronary intervention (PCI), eight (2.4%) with coronary artery bypass grafting (CABG) and nine (2.7%) were conservatively managed. The D2B time was significantly shorter in patients who arrived by EMS (60 vs. 82 minutes; In our study population, patients with STEMI who used EMS tend to be older and arrived in cardiogenic shock. They therefore had a higher incidence of in-hospital mortality and morbidity although their D2B time was shorter compared to those who arrived by self-transport."}
+{"text": "Study of peculiarities of rheumatic fever (RF) in adult patients.We have studied prospectively for 5 years 200 patients (56 men and 144 women) with acute rheumatic fever (ARF in 27) and recurrent ARF (in 173) at the age of 15-40 years . Clinical and laboratory  and CRP) and instrumental  studies conducted. The diagnosis of ARF was verified according to the WHO diagnostic criteria in the modification of Jones' criteria, AHA (1999) and WHF (2008).Results: We found that predisposing factors for the development of ARF was the presence of tonzillopharingitis (47.5%), while carriers of group A streptococcus (GAS) was 38.0% among patients examined. Clinical symptoms of carditis with echocardiographic signs of valvulitis occurred in 196 (98.0%) patients. In 54 (27.5%) of them installed valvulitis mitral valve. Valvulitis aortic valve was detected in 24 (12.2%) patients. In 118 (60.2%) patients observed at the same time valvulitis mitral and aortic valves, while in 22 (39.2%) patients are men and 92 (63.8%) patients are women. In 18 (66.6%) patients with ARF was observed mitral valve prolapse (MVP), in 6 (22.2%) were in men, 12 (44.4%) in women. In 9 (4.5%) patients with ARF proceeded pancarditis . Signs of coronaritis with typical anginal pain with ECG signs of ischemia, arrhythmias, heart block were observed in 12 (6.0%) patients with RF. Verification of diagnosis was carried out using the angiography of coronary arteries. The symptoms of coronaritis in this patients disappeared after anti-inflammatory therapy. Polyarthritis with ARF was observed in 40.7% of patients, 25 (14.4%) of patients with recurrent ARF articular syndrome manifested primarily arthralgia. In addition, 6.5% in patients with RF were observed asymptomatic sacroiliitis stage I-II , 7 of patients are men and 5 of them are women.The reducing of clinical manifestations of ARF in adult led to gypo-diagnostics of disease, a consequence of which was the formation of rheumatic heart disease."}
+{"text": "Aberrant coronary arteries represent a diverse group of congenital disorders, many of which may have no clinical significance. Post mortem studies show a high risk of exercise related sudden cardiac death in those with an anomalous coronary artery originating from the opposite sinus of Valsalva (ACAOS) that takes an inter-arterial (anterior) course. However, there is little documentation in life of the long term natural history of anomalous coronary arteries.Databases from two cardiovascular magnetic resonance (CMR) centres  were reviewed. Patients with anomalous coronary arteries undergoing CMR over a 15 year period (1995 to 2009) were identified. Anomalous coronary arteries were classified according to their anatomy and course. Both the electronic and paper records of all patients were reviewed for major adverse cardiovascular events (MACE) defined as cardiovascular mortality, myocardial infarction, revascularisation (PCI or CABG). Cause of death was verified by the Office for National Statistics. Revascularisation or myocardial infarctions were only counted if they occurred in the distribution of the anomalous artery.173 consecutive patients with coronary artery anomalies were retrospectively identified with a median age 54 years (range 1-85). The median follow-up time was 4.3 years (IQR 2.5 - 7.8) with a maximum of 15.6 years. Of the 173 patients, 117 had ACAOS of which 111 were alive, 5 deceased and 1 lost to follow-up. 65 patients (56%) had an inter-arterial course and 52 (44%) a posterior course. The distribution of coronary anomalies is detailed in Table In those patients with ACAOS there were 59 MACE events . 48 MACE events occurred in ACAOS with an anterior course and 11 with a posterior course (p<0.0001) the statistical difference driven by surgical revascularisation and myocardial infarction  S.P. and J.P.G received an educational research grant from Philips Healthcare."}
+{"text": "Present outcome prediction tools for patients with acute-on-chronic liver failure during critical illness are only of moderate accuracy. Regression methods on latent variables  may offer significant advantages over logistic regression techniques as multiple cross-correlations are acceptable in this form of modelling.Between 1 January 2000 and 31 December 2010 all patients admitted to the Liver Intensive Therapy Unit (LITU) at King's College Hospital had daily prospective collection of demographic, biochemistry and bedside physiology. Logistic regression modelling (LRM) and partial least-squares discriminant analysis (PLSDA), Model for End-stage Liver Disease (MELD) and APACHE II scores were compared using receiver operating characteristic (ROC) curve analysis.P < 0.001 for all comparisons) in a model incorporating 30 variables. Cross-validation and permutation analysis confirmed the internal validity of this method.A total of 986 patients (median age 52 (range 16 to 90) years; 603 (62%) male) with cirrhosis and emergency LITU admission were identified. The median APACHE II score was 21 (5 to 50) and the median MELD score 23 (3 to 50). Overall LITU survival was 63% and survival to hospital discharge 51%. Predictive accuracy at day 3 was improved in all models over admission values. The AUROC for LITU survival for MELD and APACHE scores on day 3 was 0.78  and 0.83  respectively. A LRM utilising nine variables had an AUROC of 0.85 . Two-component PLSDA identified 30 variables with independent prognostic significance. Performance in outcome prediction was improved over logistic regression at day 3 - sensitivity 86%, specificity 81%, AUROC 0.91 (0.89 to 0.93, This application of latent variable regression modelling techniques to intensive care datasets demonstrates high accuracy of prediction. Liver-specific outcome schema based on logistic regression may not fully describe the complex cross-correlating interactions that PLS techniques are designed to incorporate. Further validation in other centres and disease groups is warranted."}
+{"text": "We conducted a prospective surveillance study to determine the incidence and epidemiology of CLABSI in the intensive care unit (ICU) at a tertiary teaching medical centre using CDC definition of a bloodstream infection that develops in a patient who had a central line at the time of, or within 48 hours before, the onset of the infection.A cross section observational study was conducted in a 24-bed GICU over 10-months period from April 2008 until January 2009 among patients with central venous catheters (CVCs) inserted in the ICU or operation theatre.A total of 20 CLABSI cases were identified among 155 CVCs in 100 patients with 3106 catheter days. The overall rate of CLABSI was 6.4 per 1000 catheter-days and device-utilization (DU) ratio of 0.81. The mean length of ICU stay for CLABSI and non- CLABSI cases was 37.2 days and 17.4 days respectively, while the median length of ICU stay for CLABSI cases was 16.0 days and for non- CLABSI cases was 10.0 days. This contributed to 6 extra days of ICU stay in CLABSI cases. CVCs inserted via the femoral vein were associated with higher infection rate of 22.2% followed by those of internal jugular vein (15.4%) and subclavian vein (5.1%). Gram-negative bacteria accounted for 50% of the CLABSI cases whereas gram-positive cocci and fungi caused 35% and 15% of these infections respectively.th percentile of the NHSN benchmark. Comparing our findings to the INNIC 2003-2008 studies with 7.4 CLABSI per 1000 catheter-days, our CLABSI rate was lower. However, our DU ratio was higher. Hence, interventions aimed at improving outcomes related to CVCs should seriously be considered.Both of the CLABSI rate of 6.4 per 1000 catheter-days and DU ratio of 0.81 were above the 90None declared."}
+{"text": "Venous hyperoxia may reflect altered tissue oxygen extraction. We aim to assess the relationship between central venous hyperoxia  in circulatory shock. Blood lactate, arterial and central venous blood gases were collected on admission to the study and after 6, 12, 18 and 24 hours of shock. Venous hyperoxia was defined as a ScvO2 difference was lower (4.7 vs. 5.8 mmHg), and the mean base deficit was greater (11 vs. 8 mEq/l) for patients with venous hyperoxia at any time. Mean APACHE II score was higher (28 vs. 24) for patients with venous hyperoxia. The ICU mortality was higher (4/5 (80%) vs. 17/35 (46%)) among patients who already had venous hyperoxia at time 0. The proportion of death remained the same in the next day among patients that persisted or developed venous hyperoxia in the following 18 hours.Preliminary data from 40 patients (205 measurements) are presented. Mean blood lactate levels were higher (3.2 vs. 2.3 mmol/l), the mean venoarterial COThese preliminary data suggest that the presence of central venous hyperoxia is associated with persistent changes in perfusion. The presence of venous hyperoxia at both the onset of shock and in the following hours is associated with a worse clinical outcome."}
+{"text": "Splenic injuries constitute a continuing diagnostic and therapeutic challenge to the trauma or general surgeons practicing in developing countries where sophisticated imaging facilities are either not available or exorbitantly expensive. The purpose of this review was to describe our own experience in the management of the splenic injuries outlining the aetiological spectrum, injury characteristics and treatment outcome of splenic injuries in our local environment and to identify predictors of outcome among these patients.A prospective descriptive study of splenic injury patients was carried out at Bugando Medical Centre in Northwestern Tanzania between March 2009 and February 2011. Statistical data analysis was done using SPSS software version 17.0.P < 0.001), whereas age of the patient, associated injuries, trauma scores (KTS II), grade of splenic injuries, admission systolic blood pressure \u2264 90 mmHg, estimated blood loss > 2000 mls, HIV infection with CD4 \u2264 200 cells/\u03bcl and presence of postoperative complications were significantly associated with mortality (P < 0.001).A total of 118 patients were studied. The male to female ratio was 6.4:1. Their ages ranged from 8 to 74 years with a median age of 22 years. The modal age group was 21-30 years. The majority of patients (89.8%) had blunt trauma and road traffic accidents (63.6%) were the most frequent cause of injuries. Most patients sustained grade III (39.0%) and IV (38.1%) splenic injuries. Majority of patients (86.4%) were treated operatively with splenectomy (97.1%) being the most frequently performed procedure. Postoperative complications were recorded in 30.5% of cases. The overall length of hospital stay (LOS) ranged from 1 day to 120 days with a median of 18 days. Mortality rate was 19.5%. Patients who had severe trauma  and those with associated injuries stayed longer in the hospital (Trauma resulting from road traffic accidents (RTAs) remains the most common cause of splenic injuries in our setting. Most of the splenic injuries were Grade III & IV and splenectomy was performed in majority of the cases. Non-operative management can be adopted in patients with blunt isolated and low grade splenic injuries but operative management is still indispensable in this part of Tanzania. Urgent preventive measures targeting at reducing the occurrence of RTAs is necessary to reduce the incidence of splenic injuries in our centre. The spleen is the most frequently injured organ in blunt abdominal trauma, and a missed splenic injury is the most common cause of preventable death in trauma patients . DespiteGlobally, splenic injuries accounts for 25% of all solid abdominal organ injuries and the mortality rate associated with splenic trauma is reported to be between 7-18% . In deveThe causes and pattern of splenic injuries have been reported in trauma literature to vary from one part of the world to another . Road trIn the past century, the management of splenic injury has continued to evolve from a focus almost entirely on splenectomy to one of selective non-operative management -13. The There is paucity of information regarding the management of splenic injuries in our environment as there is no local study which has been done in our setting particularly the study area. This study was undertaken to describe our own experiences in the management of splenic injuries, outlining the etiological spectrum, treatment outcome and prognostic factors for mortality in our local setting. The study results will provide basis for planning of prevention strategies and establishment of treatment protocols.This was a descriptive prospective study of patients with splenic injuries of all age groups and gender presenting to the Accident and Emergency (A&E) of Bugando Medical Centre (BMC) between March 2009 and February 2011. BMC it is located in Mwanza city along the shore of Lake Victoria in the northwestern part of Tanzania. It is a tertiary care and teaching hospital for the Catholic University of Health and Allied Sciences-Bugando (CUHAS-Bugando) and other paramedics and has a bed capacity of 1000. BMC is one of the four largest referral hospitals in the country and serves as a referral centre for tertiary specialist care for a catchment population of approximately 13 million people from Mwanza, Mara, Kagera, Shinyanga, Tabora and Kigoma.The subjects of this study included all patients that presented to BMC with splenic injuries during the period studied and those who consented for the study. Patients who died before initial assessment and those without next of kin to consent were excluded from the study. Patients who refused to test for HIV infection were also excluded from the study. Splenic injury was diagnosed by combining clinical assessment, imaging investigations  and confirmed at surgery. Recruitment of patient to participate in the study was done at the A&E department after primary and secondary surveys done by the admitting surgical team. Patients were screened for inclusion criteria and those who met the inclusion criteria were requested to consent before being enrolled into the study. All recruited patients were first resuscitated in the A&E department according to the Advanced Trauma Life Support (ATLS) principles and were then taken into the surgical wards or the intensive care unit (ICU) from where necessary investigations were completed and further treatment was instituted. Variables studied included demographic profile , concomitant medical illness, mechanism and cause of injury, associated injuries, prehospital care, injury-arrival time, admission haemodynamic parameters (e.g. systolic blood pressure and pulse rate), trauma scores, Glasgow coma score, grades of splenic injury, estimated blood loss, blood transfusion requirement, treatment offered, complications of treatment. Outcome variables were length of hospital stay and mortality. The severity of injury was determined using the Kampala trauma score II (KTS II) . Severe Criteria for non-operative management included hemodynamic stability (defined as systolic blood pressure > 90 mmHg and pulse rate < 100 beats/min), absence of other intraabdominal injuries detected on abdominal ultrasound or CT scan requiring laparotomy, and limited need for splenic-related transfusion (\u2264 2 units). Non-operative treatment was continued in patients with higher transfusion requirements only if it could be established that these additional transfusions were necessitated by associated injuries. Candidates for nonoperative management were placed on bed rest and monitored for hemodynamic stability and transfusion requirements. Patients had hourly assessment for pulse rate, blood pressure, urinary output, abdominal girth and tenderness, sensorium, temperature and respiratory rate. Daily haematocrit, blood chemistry, radiological monitor and bed rest were the routine for a period of 1 to 7 days. Patients who demonstrated any degree of hemodynamic instability or required further transfusion because of the splenic injury were immediately taken to the operating room. During surgery, the decision to perform splenectomy or to attempt splenic repair was based primarily on the grade of splenic injury, severity of associated injuries and the intraoperative stability of the patient. All patients were followed up till discharged or death. After discharge patients were followed up at the surgical outpatient clinic for up to 6 months. This information was collected using a pre-tested questionnaire.P-values were computed for categorical variables using Chi-square (\u03c72) test and Fisher's exact test depending on the size of the data set. Independent student t-test was used for continuous variables. Multivariate logistic regression analysis was used to determine predictor variables that are associated with outcome. A p-value of less than 0.05 was considered to constitute a statistically significant difference.Statistical data analysis was done using SPSS software version 17.0 . Data was summarized in form of proportions and frequent tables for categorical variables. Continuous variables were summarized using means, median, mode and standard deviation. Ethical approval to conduct the study was obtained from the CUHAS-Bugando/BMC joint institutional ethic review committee before the commencement of the study. Informed consent was sought from each patient before being enrolled into the study.During the period under study, a total of 118 patients with splenic injuries were studied. One hundred and two (86.4%) patients were males and sixteen (13.6%) were females with a male to female ratio of 6.4:1. Their ages ranged from 8 to 74 years with a median age of 22 years. The modal age group was 21-30 years. Ninety-four (79.7%) were below 40 years of age, while 24 (20.3%) were aged 40 years and aboveP = 0.002) and alcoholism , P = 0.016). Their CD4 count ranged from 78 to 696 cells/\u03bcl with the mean of 361 \u00b1 162 cells/\u03bcl. Four (36.4%) patients in the group of HIV positive patients had CD4 count \u2264 200 cells/\u03bcL and the remaining seven (63.6%) HIV positive patients had CD4 count > 200 cells//\u03bcL.The majority of patients, 79 (66.9%) had primary or no formal education. Petty businessmen, 56 (47.5%) and students, 32 (27.1%) were commonly injured followed by peasants, pre-school children and public servants in 14(11.9%), 10(8.5%) and 6(5.1%) patients respectively. Eight (6.8%) patients reported to have concomitant illness. These included diabetes mellitus in 3 (37.5%) patients, congenital heart failure in 2 (25.0%), hypertension, renal disease and chronic chest infections in 1 (12.5%) patient each respectively. A total of 11 (9.3%) patients were HIV positive. Of these, 7 (63.6%) patients had risk factors for HIV infection such as multiple sexual partners , The vast majority of patients, 106 (89.8%) sustained blunt injuries and the remaining 12 (10.2%) patients had penetrating injuries. The blunt to penetrating injuries ratio was 8.8:1. Road traffic accidents (RTAs) were the most common cause of injury accounting for 75 (63.6%) patients. Forty-eight (64.0%) of RTAs were related to motorcycle injuries affecting motorcyclists 22 (45.8%), passengers 16 (33.3%) and pedestrian 10 (20.8%). Other causes were fall from height, assault and sport injuries in 18 (15.3%), 12 (10.2%) and 1(0.8%) patients respectively. Penetrating injuries such as stabbing and gunshot were recorded in 12 (10.2%) patients. There were no cases of iatrogenic splenic injuries.Most of injuries, 98 (83.1%) occurred during the day. The vast majority of patients 86 (72.9%) reported to the A & E department within 24 h after injury. The median injury-arrival time was 18 h (range: 1-268 h). None of the patients received any pre-hospital care and majority of them, 94 (79.7%) were brought in by relatives, friends or Good Samaritan, 22 (18.6%) by police and only 2 (1.7%) patients were brought in by ambulance. The median waiting time  was 3 h (range 1-6 h). The majority of patients, 86 (72.9%) were attended to within 1-2 h of arrival to the A & E departmentIsolated splenic injuries occurred in seventy (59.3%) patients while forty-eight (40.7%) patients had multiple injuries. Associated injuries were reported in 48 (40.7%) patients the commonest being chest injuries in 75.0% of patients. The pattern of associated injuries was as shown in Table According to Kampala Trauma Score II (KTS II), mild (KTS II = 9-10), moderate (KTS II = 7-8) and severe (KTS II \u2264 6) injuries were recorded in 10 (8.5%), 84(71.2%) and 24 (20.3%) patients respectively. The Glasgow coma scale in patients with head injuries indicated that most of them, 20 (62.5%) had moderate to severe injuries. The majority of patients, 92 (78.0%) had systolic blood pressure (SBP) > 90 mmHg on admission and the remaining 26 (22.0%) patients had SBP of 90 mmHg and below.9 (range 3.6- 34.2 \u00d7 109) respectively. The haemoglobin level was less than 10 g/dl in 62 (52.5%) patients. The total estimated blood loss in patients with splenic injuries is shown in Table The median haemoglobin level and white blood cell count on admission were 11.2 g/dl (range 4.2-14.6 g/dl) and 12. 8 \u00d7 10P = 0.002).Splenic injuries were graded as follows. Four (3.4%) patients presented with Grade I, fifteen (12.7%) grade II, forty-six (39.0%) grade III, forty-five (38.1%) grade IV and five (4.2%) patients had grade V. The grade was not established in three (2.5%) patients. We observed that total number of cases in grade III and above was significantly higher than with lower grades of injuries  were admitted in general surgical wards and the remaining 21 (17.8%) patients were admitted in the intensive care unit (ICU) where 12 (57.1%) of them were subjected to ventilatory support for a median duration of 7 days (range 2-14 days).Of the 118 patients, 102 (86.4%) were treated operatively and the remaining 16 (13.6%) patients had non operative treatment. Of those that had operative treatment, 99 (97.1%) patients underwent splenectomy and only three (2.9%) patients had splenorrhaphy. No patient had partial splenectomy. All the patients with grade IV and V injuries had splenectomy. Of the 16 patients with non-surgically managed splenic injury, 13 (81.2%) were successfully treated without further surgical intervention. No patient in the non-operative group underwent angio-embolisation for their splenic injuries. Non-surgical management failed in 3 (18.8%) of these 16 patients 1-7 days  after the initial assessment. These three patients underwent splenectomy with good results. In the group of patients who had splenorrhaphy, one patient who had grade III underwent splenectomy on postoperative day 3 due to failure of splenorrhaphy.P = 0.023). Blood transfusion was given in 60 (58.8%) patients who were treated operatively and in only 3 (18.8%) patients who had non-operative treatment. Comparing the operative and non-operative groups, the average blood transfusion volume given were 3.0 units and 1.0 unit of packed red blood cells respectively. According to multivariate logistic regression analysis, this difference was statistically significant (P = 0.003). They also required a higher amount of red blood cell transfusion as compared to the non-operative group (P = 0.001). Operative management was more likely in patients with lower haemoglobin (P = 0.011) or with more severe splenic injury (P = 0.006). Grades I and II spleen injury was significantly associated with non-operative treatment, while grade III-V was associated with splenectomy (P = 0.002).We noted significant increase in the rate of splenectomy during night hours (Postoperative complications were recorded in thirty-six (30.5%) patients the commonest being surgical site infections in 38.9% of patients Table .P < 0.001). Comparing the non-operative and operative groups, the median length of hospital stay (17.0 versus 18.4 days) was similar (P = 0.005).The overall length of hospital stay (LOS) ranged from 1 day to 120 days with a median of 18 days. The LOS for non-survivors ranged from 1 day to 15 days (median 5 days). The length of ICU stay ranged from 1 to 32 days (median 7 days). According to multivariate logistic regression analysis, patients who had severe trauma  and those with associated injuries stayed longer in the hospital and this was significant  patients were alive and the remaining twenty-three (19.5%) patients died. Table % patientOf the survivors, seventy-two (80.0%) patients were discharged well, fifteen (15.8%) patients were discharged against medical advice (DAMA) and the remaining four (4.2%) patients were discharged with permanent disabilities related to concomitant injuries. Out of 95 survivors, 44 (46.3%) patients were available for follow up at 3 month after discharge and the remaining 51 (53.7%) patients were lost to follow up.In the present study, splenic injuries were found to be most common in the third decade of life and tended to affect more males than females. Similar demographic observation was also reported by other authors ,13,15,16Most patients in this study sustained blunt splenic injuries, which is comparable with other studies ,13,15 buDespite the fact that injury-arrival time did not significantly affect the outcome of our patients in term of length of hospital stay and mortality, the author of the present study still believe that prolonged injury-arrival time contributes significantly to high morbidity and mortality among patients. Early presentation to hospitals and definitive treatment of these injuries has been reported to reduce mortality and morbidity associated with the disease ,11,13.In the present study, none of our patients had received any pre-hospital care at the site of injury and majority of them were brought in by relatives, friends, Good Samaritan or by police who are not trained to care for trauma patients. Only 2 patients were brought in by ambulance. Similar observations have been noted in other studies in developing countries ,15,17. TThe pattern of associated injuries in this study is in agreement with findings from other studies done elsewhere ,22. The et al [In the present study, more than 75% of patients had grade III and above splenic injuries which is agreement with other studies in developing countries ,11,13,15et al  found thThe prevalence of HIV infection in the present study was 9.3% that is higher than that in the general population in Tanzania (6.5%) . HoweverIn recent years the policy of spleen's conservation at operation has been established due to its important role in cellular and humoral immunity and the danger of overwhelming sepsis in asplenic patients -14.The recognition that patients without a spleen have an increased risk of death from overwhelming infection, led surgeons to consider methods of splenic preservation and with the introduction of the CT scan, non-operative management became popular and then predominant . Today, Lack of dedicated trauma centres for caring of trauma patients is a major problem in our community and the intensive care unit (ICU) at our hospital is unable to cope up with a large number of trauma patients as a result majority of patients are still admitted and managed in general surgical wards which are not well equipped in managing trauma patients. In the present study, ICU admission was influenced by injury grade, amount of haemoperitoneum, transfusion requirements, presence of coagulopathy, associated injuries or presence of co-morbidity.The presence of complications has an impact on the final outcome of patients presenting with splenic injuries as supported by the present study. Splenic injuries are commonly associated with other injuries and these may complicate the management and affect the outcome . The patThe length of hospital stay has been reported to be an important measure of morbidity among trauma patients. Prolonged hospitalization is associated with an unacceptable burden on resources for health and undermines the productive capacity of the population through time lost during hospitalization and disability . The oveThe overall mortality rate in this study was higher than that reported elsewhere ,22. FactPost-splenectomy vaccination against encapsulated organisms is highly recommended for all splenectomised patients for trauma before their discharge from hospital, with re-vaccination every 5-10 years and additional antibiotic prophylaxis to compensate for the documented occasional vaccination failure ,31. HoweSelf discharge by patient against medical advice is a recognized problem in our setting and this is rampant, especially amongst trauma patients . SimilarTrauma resulting from road traffic accidents (RTAs) remains the most common cause of splenic injuries in our setting. Most of the splenic injuries were Grade III & IV and splenectomy was performed in majority of the cases (97.1%). Non-operative management can be adopted in patients with blunt isolated and low grade splenic injuries but operative management is still indispensable in this part of Tanzania. The accurate identification of a patient at high risk for poor outcome is necessary for decision making. Urgent preventive measures targeting at reducing the occurrence of RTAs is necessary to reduce the incidence of splenic injuries in our centre. A well-designed randomized clinical trial comparing the short and long term outcome of non-operative versus operative treatment in these patients is highly recommended.The authors declare that they have no competing interests.PLC conceived the study and participated in the literature search, writing of the manuscript, editing and submission of the article. JBM, GG, ABC, RMD and MDM participated in Study design, data analysis, manuscript writing & editing and JMG was involved in study design, data analysis, coordination and supervision of manuscript writing & editing. All the authors read and approved the final manuscript"}
+{"text": "We conducted a prospective survey to determine satisfaction amongst relatives of patients on our ICU. Patient-reported outcome measures have become widely used and accepted in the pursuit of improved quality of care . HoweverWe utilised a 35-point questionnaire-based survey of relatives of patients in our ICU over 10 weeks. Questionnaires were distributed to family members when the decision to discharge from the ICU was made. We limited this to two family members per patient who were in the ICU for more than 48 hours.We received 29 completed questionnaires. Relatives of 24 of the respondents had survived to ICU discharge. Responses were linearly transformed to give percentage scores. Higher values represented a greater degree of satisfaction. Overall care in the ICU, 88.8%. Courtesy, respect and compassion to the patient (93.8%), to relatives (92.2%); assessment and treatment of pain (94.4%), breathlessness (92.9%), agitation (88.9%); emotional support (89.4%); care from nurses (92.0%), doctors (95.5%); frequency of communication nurses (92.9%), doctors (89.7%). Overall decision-making, 91.3%. Willingness of staff to answer questions (90.5%); honesty (90.5%), completeness (91.4%), consistency of information (90.5%); inclusion in decision-making, 78.7%; support during decision-making, 78.7%; time to think about information given, 96.2%.Family satisfaction with our ICU is high, with satisfaction high in both care and decision-making domains. Appropriate inclusion with and support during the decision-making process were areas with lower satisfaction scores. The structuring of options for answering these questions may have been a confounding factor in this finding. However, this may represent genuine lower levels of satisfaction and steps should be taken to improve this. In response to these findings we have invited families to join their relatives' part of the consultant ward round to improve inclusion and support in decision-making. We are currently repeating the survey with these changes in place and will present our findings in the future."}
+{"text": "The lack of surveillance data on nosocomial infections is one of the deficiencies of health systems in Africa. Hospital Principal of Dakar intends to be an exception in this regard.Our objective was to investigate the epidemiological, clinical and bacteriological characteristics of these infections in order to reach a better orientation of prevention activities.Based on a standardized protocol recommended by the national program (PRONALIN) a group of internal, trained investigators of the hospital is deployed in the different services on one specific day from 2006 to 2010. This happens concomitantly in all hospitals in the country. All patients occupying a hospital bed the day of the survey were concerned and any infection occurring after 48 hours of hospitalization was considered nosocomial. The data are validated by a pool of biologists and subsequently analyzed by Epi-Info version 2003.Enterobacter (21.4%), Klebsiella (20%) and Pseudomonas aeruginosa (18.6%). ESBL-producing enterobacteria were implicated in 34% of cases and those producing derepressed cephalosporinase in 12.8%.One thousand and three hundred ninety seven (1397) patients were included. The overall prevalence was 4.24% . The average age was 37 years  and the sex-ratio was 1.15. The most affected services were respectively pediatrics (29.4%), surgery (25%), medicine (22%) and intensive care units (20.6%). Bacteremias were the most common infections (33.3%) followed by urinary tract infections (24.3%), surgical site infections (15.2%) and lung infections (15.1%). The other sites accounted for 15.1% of cases. The microorganisms most commonly responsible for nosocomial infections were: This study shows the important place occupied by multi-resistant bacteria and illustrates the efforts that are still required in some services, despite a general trend towards lower rates of nosocomial infections in recent years.None declared"}
+{"text": "Lobular carcinoma is frequently atypical on conventional imaging. MRI has increasingly been used to evaluate lobular carcinoma in recent years. Our experience has been that lobular MRI findings are also relatively difficult to interpret. In this study we aim to define lobular MRI characteristics to aid preoperative staging accuracy.This retrospective study included all lobular breast cancers which were subjected to preoperative MRI in our Trust from May 2010 to May 2011. Radiologists blinded to the original MRI reports used a questionnaire based on BIRADS to describe the findings. Final surgical histology was used as the gold standard for comparison. Descriptive statistics were performed on data obtained.Full imaging and final surgical histology was available for 24 ladies with lobular carcinoma. In 83% (20/24) of cases the MRI tumour morphology was of a mass (19/20 irregular mass). Mass enhancement varied: heterogeneous 50% (10/20), homogeneous 40% (8/20). MRI 3D reconstruction gave the largest measurement most frequently (11/24), but the third post-contrast sequence most frequently (8/24) provided the most accurate tumour measurement. Enhancement curves were type 2 in 15/24 cases. In 21/24 cases the question of MRI multifocality correlated with final surgical histology. A total of 12.5% (3/24) patients had contralateral lesions identified by MRI.The most common lobular cancer morphology on MRI is an irregular mass with heterogeneous, type 2 enhancement. When compared with surgical histology, the third post-contrast  sequence gave the most accurate tumour measurement most frequently, with 3D reconstruction providing an overestimate in some cases."}
+{"text": "KRAS status, 7 of the 13 (53.8%) patients who had wild-type KRAS achieved a high disease control rate (PR + SD). The median progression-free survival (PFS) and overall survival (OS) in the wild-type KRAS patients was 96 and 245 days, respectively. Pmab may be an alternative treatment strategy for Japanese patients with mCRC who have experienced failure with standard Cmab-based therapeutic regimens.Panitumumab (Pmab) is generally considered to be ineffective after the failure of cetuximab (Cmab) therapy in metastatic colorectal cancer (mCRC) patients. However, a few studies have demonstrated that Pmab is an effective treatment for disease progression following Cmab-based regimens in the USA. In the present study, we evaluated the safety and efficacy of Pmab therapy following the failure of Cmab therapy in Japanese patients with mCRC. We performed a retrospective review of the treatment of 16 mCRC patients who tolerated Pmab with clinical benefits after the failure of Cmab therapy between August 2010 and September 2011 at Shiga University of Medical Science. Fourteen of the 16 patients were administered standard Pmab monotherapy (6 mg/kg) intravenously every 2 weeks and the remaining two patients received Pmab with mFOLFOX6 intravenously every 2 weeks. All patients received Pmab chemotherapy until the occurrence of disease progression. Partial radiographic responses (PR) were observed in 2 of the 16 patients and stable disease (SD) was observed in 5 patients. Nine patients had evidence of progressive disease (PD). According to the  KRAS colorectal cancer (Cetuximab (Cmab) is an anti-epidermal growth factor receptor (EGFR) antibody that has been shown to effectively combine with cytotoxic chemotherapy as first-, second- or third-line treatment against wild-type l cancer \u20133. Howevl cancer . Pmab isl cancer ,6. HowevKRAS status was retrospectively assessed in patients with readily available tumor tissues. Chemotherapeutic response was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST)  . The incThis study protocol was in accordance with the ethical guidelines established by the Declaration of Helsinki. Written informed consent was obtained from all patients.Progression-free survival (PFS) and overall survival (OS) were calculated as the interval between the first day of Pmab treatment and the date of proven recurrence or death from any cause, respectively. PFS and OS were estimated using the Kaplan-Meier method.KRAS and three (19%) had mutant-type KRAS. The median number of previous therapies was three . Seven of the 16 patients (44%) received four or more previous therapies. All patients received prior irinotecan therapy. Fifteen patients (94%) received prior oxaliplatin and 14 patients (88%) received prior bevacizumab therapy. All patients had been previously treated with Cmab and only two of the 16 patients (13%) discontinued Cmab therapy due to the development of HSRs. Other reasons for stopping Cmab therapy included disease progression  and the inconvenience of a bi-weekly schedule . Fourteen of the 16 patients (88%) received standard Pmab monotherapy (6 mg/kg) intravenously every 2 weeks, while the remaining two (13%) received Pmab with mFOLFOX6 intravenously every 2 weeks. All patients in this study were administered standard medications  prior to Pmab administration in order to prevent HSRs.The baseline characteristics of the patient population are summarized in KRAS status, all 3 patients with mutant-type KRAS had evidence of PD and 7 of the 13 patients with wild-type KRAS (53.8%) achieved a high disease control rate (PR + SD). The median PFS and OS in patients with wild-type KRAS was 96 . Partial radiographic responses (PR) were noted in 2 of the 16 patients (12.5%) and stable disease (SD) in 5 patients (31.3%). Nine patients (56.3%) had evidence of progressive disease (PD). In terms of S was 96  and 245 S was 96 , respectOne patient did not exhibit a change in CEA level, regardless of tumor status. Four patients achieved a >50% reduction , 2 patients had a 25% reduction (459.5 to 296.5 U/l and 34.7 to 22.7 U/l) and 1 patient had a minor reduction (442.8 to 380 U/l) in CEA levels and 8 patients had increased CEA levels. Therefore, approximately half of the patients achieved a reduction in CEA levels.A 73-year-old male had been diagnosed with sigmoid colon cancer (T3N1M0 Stage IIIa) 7 years previously, for which he underwent a sigmoidectomy with regional lymph node excision. Two years after sigmoidectomy, the patient underwent partial hepatectomy for solitary liver metastasis. The patient was once again diagnosed with multiple liver metastases several months after the partial hepatectomy, for which hepatic arterial infusion chemotherapy (HAI) was administered. However, due to disease progression despite the HAI, mFOLFOX6, FOLFIRI and Cmab chemotherapy was administered. Thereafter, the patient was also diagnosed with lung and intra-abdominal lymph node metastases and received Pmab therapy, following which disease stability was achieved for \u223c10 months and CEA levels decreased from 4934 to 793 U/l .All patients tolerated Pmab well, with no cases of HSR. Grade 3/4 toxicities included hypomagnesemia in 1 patient and hypocalcemia in another. Other AEs observed included grade 1\u20132 skin rash in 3 patients, grade 2 hypomagnesemia in 2 patients, grade 1\u20132 fatigue in 3 patients and grade 1\u20132 appetite loss in 3 patients. However, none of the patients required discontinuation of Pmab therapy as a result of these AEs.For \u223c40 years, fluoropyrimidine 5-fluorouracil was the only drug available for the treatment of mCRC. However, over the past 10 years, the therapeutic armamentarium for mCRC has expanded significantly with the development and approval of three cytotoxic agents, irinotecan, oxaliplatin and the oral fluoropyrimidine capecitabine . During et al on their clinical experience at the Memorial Sloan-Kettering Cancer Center (Cmab and Pmab bind with a high affinity to EGFRs and prevent the binding of natural growth factor ligands to these receptors . This inr Center . Notablyet al(et al(At present, it is not entirely clear why patients who had disease progression on Cmab were able to derive clinical benefits from Pmab. Recently, Montagut et al revealed al(et al performe al(et al,16. MatuIn conclusion, Pmab therapy may represent an alternative treatment strategy for patients, Japanese or otherwise, with refractory mCRC who have experienced failure with standard therapies, including Cmab-based regimens. Our relatively small clinical experience suggests that Cmab and Pmab may exert their antitumor activity via different mechanisms, however, further study is required to investigate this hypothesis."}
+{"text": "We carried out a cross-sectional analytical survey using data from patients who had done Fluorescein Angiography at the Yaounde Central Hospital Diabetic Retinopathy Prevention and Management Project between October 2007 and January 2010 to identify the risk factors, incidence and severity of different types of diabetic retinopathy. Data from 239 males (57.0%) and 180 females (43.0%) with diabetic retinopathy were included. Their mean age was 58.2 years. A majority of them were living with type II diabetes (96.2%). The mean duration of diabetes was 8.2 years. About sixty percent had both diabetes and hypertension. The average level of glycated haemoglobin was 9.72% (range 6-17.7%). Amongst the 419 patients with diabetic retinopathy, 292(69.7%) had non-proliferative diabetic retinopathy. One hundred and twelve (26.7%) of those with proliferative diabetic retinopathy had a formal indication for laser photocoagulation. Fifteen patients (3.6%) presented with complicated forms of proliferative diabetic retinopathy. Diabetic maculopathy was present in 30 patients (7.2%). Diabetic retinopathy is a frequent complication of diabetes in our setting which stems from inadequate emphasis on preventive measures. The technical requirements for managing some of the existing complications are still unavailable. Fluorescein Angiography is an important diagnostic tool which should be popularized. Diabetic retinopathy (DR) is one of many complications of diabetes. It is the fifth cause of blindness worldwide and the first cause of blindness before the age of 50 in developed countries , 2. It iIn order to report the risk factors, incidence and severity of different types of DR we conducted a cross-sectional analytical study in patients who had done Fluorescein Angiography (FA)at the Yaounde Central Hospital (YCH) Diabetic Retinopathy Prevention and Management Project (DRPMP). We obtained ethical clearance from the YCH Ethics Board and consulted patient records from October 2007 to January2010. We included all patients who were diagnosed with DR using FA.DR was classified using the French Association for the Study of Diabetes and Metabolic Diseases (ALFEDIAM) classification [Data were collected from 419 eligible patient files belonging to 239 males (57.0%) and 180 females (43.0%) who had DR.The incidence of DR was39.9%.Their average age was 58.2 years (range 29-87). The average age for patients with type I and type II diabetes was 51.6 and 59.0 years respectively. Most had type II diabetes (96.2%). The mean duration of diabetes before the diagnosis of DR was 8.2 years.Two hundred and fifty-two(60.1%) had both diabetes and high blood pressure (HBP). The average level of glycated haemoglobin was 9.7%(range 6-17.7%). Thirty patients (7.15%) had diabetic maculopathy; 27(6.43%) with maculao edema and 3(0.7%) had ischemic maculopathy.Amongst the patients with proliferative DR, 26.7%(112) had a formal indication for laser photo coagulation. Fifteen patients (3.6%) presented with complicated forms of proliferative DR.However,non-proliferative DR was more frequent (68.7%) .The mean duration of diabetes before diagnosis of DR is comparable with other reports . GlycaemPoor knowledge about the complications of diabetes, poor compliance with treatment and the absence of comprehensive health insurance may explain these high figures. Many of these patients suffered from complicated forms of retinal disease that require currently unavailable endocular surgery. Additional efforts in primary prevention through lifestyle modifications and risk factor prevention are needed. Secondary prevention by better glycaemic control and early screening for DR should be implemented.DR is frequent in our setting. Even though it occurs earlier in patients with type I diabetes, it is more frequent in patients with type II diabetes. A yearly eye exam in diabetics is highly recommended as such preventive measures are cost-effective , 10. FA"}
+{"text": "Pancreatic cancer remains one of the deadliest malignancies in the western emisphere despite improved surgical technique, chemotherapy and radiation therapy .Due to the late diagnosis of pancreatic cancer, surgery is the gold standard method to increase the patients\u2019 overall survival; pancreaticoduodenectomy (or Whipple procedure), with lymph nodes dissection, is the standardized radical surgical procedure for pancreatic and periampullary tumors; it comprehends the removal of pancreas head, distal common bile duct, duodenum and the distal portion of the stomach (if the pylorus preserving technique is not used) and consequently the reconstruction with gastro-jejunal, bilio-jejunal anasthomosis, and Wirsung-gastric or Wirsung-jejunal anasthomosis .Pancreaticoduodenectomy is a complex high risk procedure that has infrequently performed until the 1980s, due to high mortality and morbidity rates; in the last 2 decades, surgical techniques improved and postoperative adverse events became more infrequent; Cameron et al reported, on a series of 1000 consecutive pancreaticoduodenctomies, a mortality and morbidity rates of 1% and 4% respectively .The aim of our study is to consider pancreatic surgery in a population of elderly patients, in order to evaluate mortality, morbidity and outcome.From 01/01/1994 to 01/01/2013, 54 patients, 33 males (61.11%) and 21 females (38.89%) aged more than 70 years old , underwent radical pancreaticoduodenectoy for periampullar cancer.Tumor localization was: pancreatic head in 32 cases (%), Vater ampulla in 11 (20.37%), distal common bile duct in 6 (11.11%), duodenum in 4 (7.41%).In one case (1.85%), pancreaticoduodenectomy was performed because of pancreatic head infiltration by right colon cancer.All patients underwent pancreaticoduodenectomy with Whipple-Child technique; macroscopic complete tumor ablation was always achieved.Standard lymphadenectomy was performed in 43 cases (79.63%), extended lymphadenectomy in 7 (12.96%).Mucosa-to-mucosa Wirsung-jejunal anastomosis was chosen in 34 cases (62.96%); 19 patients (35.19%) were reconstructed with Wirsung-gastric anastomosis; in 1 case no pancreatic duct reconstruction was performed.Perioperative mortality rate was 3.70%; one patient died for postoperative acute pancreatitis and one for respiratory failure.Morbidity was 14.81%; 2 patients (3.70%) developed postoperative peritoneal bleeding; we have also observed 3 cases of gastrointestinal bleeding (5.56%), portal thrombosis in 2 patients (3.70%) and one pancreatic fistula (1.85%).All postoperative complications have been managed conservatively except peritoneal bleedings, in which re \u2013 operation has been necessary.No differences in terms of morbidity have been demonstrated between the two methods of reconstruction ; Wirsung-jejunal anasthomosis seems to prevent pancreatic atrophy in long surviving patients.Overall 3 years and 5 years survival was respectively 22% and 15%.3 and 5 years survival rates were 24% and 16% in patients without lymph node involvement, 2% in patients with lymph node metastatization.Causes of death have been liver metastasis (25.97%), local recurrence (11.11%), cardiovascular event (3.70%).The considerable increase of the aged population in western civilization within the next years will result in a rising incidence of pancreatic cancer. Until the year 2020 an increment of 20% of patients beyond 65 years old can be anticipated; until now only a few retrospective data analyses evaluating the perioperative and long term outcome in geriatric patients exist .Our experience shows that radical surgery for periampullar malignancies is a good option in elderly patients; despite comorbidities we observed good results in terms of survival, mortality and morbidity, similar to what observed in younger patients."}
+{"text": "Though headache prevalence drops markedly in the elderly, this causes a significant burden on the quality of life of this population. However, few studies have investigated primary headaches at this age range.We aim to analyze characteristics of patients older than 65 attended due to migraine in an outpatient headache clinic in a tertiary hospital.We prospectively considered patients attended from January 2008 to May 2012. Migraine with and without aura was diagnosed accordingly to International Classification of Headache Disorders, II edition (ICHD-II) criteria. For medication overuse headache (MOH) and chronic migraine (CM) we considered ICHD-II revised criteria. We gathered in each patient age, gender, time from onset, complementary tests required, and symptomatic or prophylactic therapies previously used.262 patients  out of 1868 (14%) attended in our headache clinic during inclusion period were older than 65 years, and 71  of them (27.1%) were diagnosed of migraine. Most elderly patients  reported that migraine complaints appeared for the first time before 50 years. 26 cases (36.6%) suffered episodic migraine, 18 (25.4%) CM, and 27 (38%) CM with MOH. Only 3 patients (4.2%) were diagnosed of migraine with aura, one of them appearing after 50 years. All patients had received at least one symptomatic treatment, but only 31 (43.6%) had previously used a preventative.Migraine represents a burdensome group of elderly patients in our headache clinic. In most of them, onset of migraine was reported before the age of 50. Migraine with aura is infrequent in our series. Chronic migraine is a common diagnosis in our population and medication overuse seems to play an important role. Despite the long time from onset, preventatives were not widely used in our elderly patients before referral."}
+{"text": "Objective: To determine the frequency of common causes of short stature in children presenting to the Children\u2019s Hospital & the Institute of Child Health, Multan.Methodology: This cross sectional study was done in Pediatric Endocrinology department, the Children\u2019s Hospital & the Institute of Child Health, Multan, from March to September, 2011. One hundred and sixty nine children with short stature presenting to the outpatient department meeting inclusion criteria were recruited after taking an informed consent. The detailed history, physical examination including anthropometric measurements and relevant investigations were recorded. Causes of short stature (outcome variable) were recorded on a predesigned proforma for final analysis.Results: The common causes of short stature identified were; familial short stature (FSS) 36 cases (21.3%), hypothyroidism 29(17.2%), growth hormone deficiency (GHD) 18(10.7%), insulin dependent diabetes mellitus (IDDM) 16(9.5%) and constitutional delayed growth and maturation (CDGM) 11(6.5%) cases. This was followed by primary malnutrition 8(4.7%), celiac disease 6(3.6%),Turner syndrome 5(3%) cases and unknown syndromes 4(2.4%) followed by other rare causes.Conclusion: Common causes of short stature identified in this study were endocrine diseases followed by normal variant short stature (NVSS), while nonendocrine causes were the least. Altered growth potential may result from disturbance of any of these factors. Short stature, a common problem in child population of developing countries,4-6 Celiac disease is a prominent example of treatable causes of growth failure especially in young children.6 Malnutrition and iatrogenic causes like glucocorticoids, chemotherapy and radiotherapy are other important causes.7 Common endocrine disorders leading to short stature include; hypothyroidism, cushing\u2019s syndrome and growth hormone deficiency.4,8 Turner\u2019s syndrome and skeletal dysplasias, like achondroplasia, are other notable causes. Growth failure is also seen with symmetric intrauterine growth retardation (IUGR) leading to small for gestational age (SGA) babies.1,2,9 Idiopathic short stature is, quite understandably, a diagnosis of exclusion.10 Chronic childhood diseases, if sufficiently severe, can lead to growth failure and short stature, important examples include; renal, pulmonary and cardiac diseases, malignancy, cystic fibrosis and celiac disease.11 Constitutional delay of growth and maturation (CDGM) having subtle defects in growth hormone-insulin like growth factor (GH-IGF) axis, obligates higher rates of overall energy expenditure compared with age and size matched controls, this increased metabolism may result in impaired tempo of growth.12 Puberty is delayed and there is a delayed and reduced pubertal growth spurt, but the final adult height is usually not affected and remains in the lower parental target height zone.13 Those boys whose height predictions fall below160 centimeters, are candidates for treatment with recombinant growth hormone (rGH) according to FDA-approved guidelines is under investigation.14 The final adult height in humans is controlled by multiple genes. In familial short stature, the final adult height is short but within the target range of height for the family.15 Severe malnutrition (3rd degree) is one of the common causes of short stature in third world countries. The nutritional status of children under five years of age is extremely poor in Pakistan, about 40% children under five years old are short statured and will often have lifelong consequences, with diminished skeletal growth.16 Specific nutritional deficiencies can have an effect on child growth. Vitamin D deficiency is an important cause of short stature in third world. The typical infant is exclusively breastfed and has poor exposure to the sun. The treatment regimen improves rickets but does not necessarily correct growth failure, starting treatment in early infancy leads to greater final adult height.17 Endocrine causes are classically associated with being overweight for height. In appropriately treated children with growth hormone deficiency or congenital hypothyroidism, puberty and final adult height are within the normal range in treated cases.rd percentile for age and sex were recruited. Patients with contractures and kyphoscoliosis in whom height could not be measured were excluded. It was a nonprobability consecutive sampling and sample size was calculated with reference to a prospective study done by Moayeri H et al at Iran,18 taking p=0.076 (known proportion for hypothyroidism which was 7.6%),d=0.04 (required absolute precision which was considered 4%) and confidence level of 95% using a software \u201cS size for estimation of population propotion, developed by KC Lun and PeterChaim from National University of Singapore\u201d. Study was conducted at the Paediatric Endocrinology Department, the Children\u2019s Hospital and the Institute of Child Health, Multan; a tertiary care pediatric center, from March to September 2011. Children from both genders, 2-15 years of age having height below two standard deviation (-2SD) or less than 3 Protocol of the study was approved by the institutional ethical committee. After explaining all the details of the study, informed consent was taken from the parents/guardians. All the related terminologies were clearly defined.Short Stature: Height below 2SD or 3rd percentile for age and sex.NVSS : They include, Constitutional delayed growth and maturation (CDGM) and Familial short stature (FSS).Constitutional Delayed Growth and Maturation: Bone age equal to height age, both less than chronological age.Familial Short Stature: Bone age equal to chronological age and both more than height age. Growth Hormone Deficiency (GHD): Levels less than 10ng/ml on insulin stress test.Primary Malnutrition (3rd Degree): Weight less than 60% of the expected weight for age and sex according to NCHS  standard and nutritional history of decreased caloric intake.Celiac disease: Duodenal mucosal changes consistent with Celiac Disease on small intestinal biopsy and raised tissue transglutaminase antibodies i.e. IgA above 7U/ml and IgG above 17U/ml.Hypothyroidism: Free T4 less than 0.93ng/dL and TSH more than 6.4 uIU/ml.Genetic Syndromes: Like  and Chronic Diseases like  were diagnosed from clinical profile and relevant investigations.19 using following formula: [father\u2019s height (cm) + (mother\u2019s height (cm) + 13)] divided by 2 for boys and [(father\u2019s height(cm) \u2013 13) + mother\u2019s height (cm)] divided by 2 for girls. Most children attain an adult height within 10 cm of their target height which provides a quick and rationally precise index of a child\u2019s genetic growth potential. Lower segment was calculated by subtracing sitting height from standing height, upper to lower segment ratio (US/LS) was calculated from these measurements. Weight of the patients was measured using electronic balance and recorded in decimal of kilogram. Puberty was assessed in 11-15 year age group by rating the breast development in girls, genital developments in boys, pubic and axillary hair development in both sexes, according to Tanner\u2032s classification.20,21 Parents were asked for any available previous record. The demographic profile, detailed history including; history of low birth weight (less than 2.5kg), psychosocial aspects and physical examination findings were recorded. This included anthropometric measurements of the patients and their parents. Contemporary height was measured without shoes or head gear on an accurate measuring device (Harpenden Stadiometer). The target height was calculated based on the Tanner\u2019s method Laboratory investigations included , serum free T4 and TSH levels). The patients who had raised levels of Anti-tTGs were confirmed with endoscopic duodenal biopsy. Radiograph of left hand and wrist were done in all patients for rickets and bone age estimation using published standards of Greulich and Pyle\u2019s Atlas of Skeletal Development.rd degree). Karyotyping was done in all female patients to rule out Turner Syndrome. GH was assessed (provocating with insulin tolerance test)in those patients who had strong clinical suspicion of growth hormone(GH) deficiency having baseline investigations within normal limits. Blood samples were drawn at 0, 30, 60, 90 and 120 minutes. The final cause of short stature was decided in consultation with the Paediatric endocrinologist. Short statured patients with chronic diseases were diagnosed on the basis of history, physical examination and relevant investigations. Patients who had weight less than 60% of the expected for age and sex according to NCHS  standard with history of deficient caloric intake, evidence of other micronutrient deficiencies and absence of any chronic disease, were labeled as cases of Primary malnutrition (3 Data was entered in SPSS version (10.0). Descriptive statistics were applied. Mean and standard deviation for age were computed. Frequency of various causes of short stature  was calculated. Confounding variables like age and gender were controlled by stratification. A total of 169 cases  were identified as having short stature; male to female ratio was 1.17:1. All children fell below 3rd centile for their height on 2000 CDC growth charts. Among the study population, height of the patients ranged from 75.2-98cm in 2-5 years, 85-126cm in >5-11 and 112-151cm in >11-15 years of age groups. There were 40 (23.7%) children having age between 2-5 years, 82 (48.5%) children were >5-11years of age, while the rest of 47 (27.8%) cases were >11 to 15 years of age . Family  Children with short stature in 11-15 years age group (n=47) had pubertal development stage I & II in 33(70.21%) followed by 10(21.28%) children with stage III and 4(8.51%) children with stage IV. None of the children had stage V. Most common single etiological factor for short stature was familial / genetic short stature evident in 36(21.3%) children followed by hypothyroidism in 29(17.2%) children. There were 18(10.7%) children with growth hormone deficiency, 11(6.6%) with CDGM, 8(4.7%) with primary malnutrition, 6(3.6%) with celiac disease as a cause of short stature. Diagnosis could not be made in 12 (7%) children as the parents were not willing for investigations . Genetic Growth is an important objective parameter of health of a child. Short stature although not a disease per se, may be a manifestation of several diseases. The etiology of short stature ranges from normal variants like CDGM and FSS to pathological conditions like endocrine and systemic disorders. Timely assessment is very important, because medical intervention if needed will only be effective before epiphyseal fusion.rd degree) 8(4.7%) and celiac disease 6(3.6%) cases. This was followed by other rare causes.Among 169 cases in this study, most common age group was >5 to 11 years 82(48.5%) cases. The observed male to female ratio was 1.17:1. Frequently observed causes of short stature included; FSS 36(21.3%) cases, hypothyroidism 29(17.2%), GHD 18(10.7%), IDDM 16(9.5%), CDGM 11(6.6%), primary malnutrition , followed by NVSS(37.4%) and endocrinological causes were the least (15.9%). Shu et al24 in their study showed that upto 65% cases of short stature were NVSS. The dominance of NVSS was in accordance with other international studies.25 In this study if we categorize the causes in three main etiological groups; the most frequent as a group were endocrinological causes followed by NVSS and then nonendocrinological causes. Similar observation was made by Colacoetal18 Zarger et al,25 and Awan TM et al.26 These values for GHD were relatively higher, probably all these studies were conducted at endocrine referral centers, therefore, problems of endocrine disturbances, especially growth hormone were relatively more. In Utah growth study,27 nonendocrinological causes predominate, endocrine contribution was less than 4% in children with short stature. In the same study, protein energy malnutrition and malabsorption syndrome were responsible for 10% of short stature cases and similarly 12.7% in Indian Bhadada study,3 but in this study 8 children (4.7%) with primary malnutrition and 6 children (3.6%) with celiac disease presented as the causes of short stature. In our study GHD was seen in 18(10.7%) cases whereas it was found to be 23.4%, 22.8% and 13.9% in studies done by Moayeri et al, The shortcomings of this study include failure to calculate and plot growth velocity which requires a regular follow-up at six months to twelve months interval, which was not possible in this cross sectional study. Secondly, it was a hospital based study where patients of specific diseases are referred. Twelve cases remained undiagnosed, because parents were not willing for investigations. The difference in frequency of various causes of short stature reported from different centers can be due to many factors like genetic, socioeconomic, nutritional and other related factors. It is very important to know exactly the frequency of various causes of short stature from a given population in order to differentiate normal variants of growth from individual cases of short stature who need early diagnosis and treatment. Statistics addressing frequencies of various causes of growth failure in Pakistan are not plentiful. This study may help to set a base line data in this region, so early detection of treatable causes would be helpful in a better long-term prognosis. The endocrinological causes of short stature as a group were the most common followed by normal variants short stature and nonendocrinological causes were the least in descending order of frequency. The male to female ratio was almost equal. Larger scale, community based studies may give results which are better representative of a particular population."}
+{"text": "Thoracic injuries are a major cases of mortality during the \u201cgolden hour\u201d of trauma. Less than 10% of all blunt thoracic injuries require a emergency thoracotomy and many potentially life threathening condition can be relieved by principle procedure, such as chest tube insertion. To describe general features correlated to incidence, diagnosis, etiology, sex, age, severity and treatment of the thoracic injury patients and the way to manage it.The retrospective study of the 3115 thoracic injury patients treated during the period of January 1987- June 2012 (26 year) at the Emergency Department of Surgery Dr. Soetomo Hospital Surabaya provides comprehensive data concerning thoracic injury which collected and analyzed.In the past 26 years, the total number of trauma victims treated at the Emergency Department of Surgery as 432639 patients, among whom 3473 patients were thoracic injury. They were 2949 male and 524 female. The oldest patient was 90 years old as a victim of traffic accident and the youngest was 2 month old as a victim of house accident. The numbers of blunt and penetrating trauma patients were 2973 and 500 respectively. The etiology of thoracic trauma consists of 2536 patients (73.02%) due to traffic accident; 625 patients (17.99%) due to criminality; 214 patients (6.17%) due to occupation accident; and 98 patients (2.82%) due to house accident. The majority patients were treated non-operatively (\u00b1 53.51%), drainage intra-thoracic (\u00b1 41.51%) and explorative thoracotomy (\u00b1 4.98%). There were 80 hospital deaths (2.3%), all with severe multi-trauma.The majority of the thoracic injury patient received at the department of surgery Dr.Soetomo Hospital Surabaya were treated non-operatively (\u00b1 53.51%). The overall mortality rate of thoracic injury was 2.3%"}
+{"text": "Objective: Extended-spectrum \u03b2-lactamase producing K. pneumoniae is a serious threat to the patients. This manuscript shows the comparison of phenotypic characterization methods used for ESBL K. pneumoniae and frequency distribution of these isolates in various clinical samples.Methodology: Eleven different types of pathological samples collected on various time intervals were analyzed. K. pneumoniae were identified with API 20E system (bioMerieux) and initial screening of ESBL K. pneumoniae was performed using the ceftazidime antimicrobial disc. Double-disc synergy test (DDST) and CLSI confirmatory test were compared for the phenotypic detection of ESBL K. pneumoniae.Results: A total number of 214 ESBL producing K. pneumoniae were isolated from various clinical samples. Frequency distribution of ESBL producing K. pneumoniae was found to be highest among blood 117 (54.7%) and urine 46 (21.5%) samples. Data regarding the use of various interventions among these patients showed most common presence of intravenous line 209 (97.7%) and urinary catheters 46 (21.5%). Comparison of DDST and CLSI confirmatory test showed that the DDST detected 145 (67.8%) isolates while 213 (99.5%) ESBL K. pneumoniae were characterized by CLSI confirmatory test.Conclusion: The use of CLSI confirmatory test is very efficient in the early detection of ESBL K. pneumoniae especially when the facilities for molecular characterization are not available. An increase in prevalence of ESBLs has been documented in recent years but it varies in different geographical areas of the world.3Extended-spectrum \u03b2-lactamases (ESBLs) are the enzymes, mostly encoded by plasmids in result of mutation due to which bacteria show resistance to various \u03b2-lactam antibiotics including cephalosporins and monbactams.Klebsiella pneumoniae is the most important and most common infectious pathogen in the hospitals environment and is mainly responsible for pneumonia, urinary tract infections, neonatal septicemia and wound infections among children.4 Apart from the other members of Enterobacteriaceae family, ESBLs are highly prevalent in K. pneumoniae.5 Global data show that the rate of ESBL producing bacteria was highest among K. pneumoniae isolated from fourty four percent in America followed by twenty two percent Asia pacific, thirty three percent in Europe and seven percent in North America.6 Many nosocomial outbreaks caused by ESBL K. pneumoniae have been reported among paediatric patients. ESBL K. pneumoniae are associated with high mortality rate among children.7. The most commonly used methods include double disc synergy test, combined disc method and E-test. Several automated systems have also been developed for detection and some laboratories use molecular methods for detection of ESBL phenomenon.8 There are limited number of antibiotic options available to treat the infections caused by ESBL producing strains.9 Present study was conducted with the objective, to evaluate the frequency of ESBL producing K. pneumoniae and comparison of detection methods among various clinical samples collected from a tertiary care children hospital. The early detection of ESBL producing K. pneumoniae strains can help to reduce high morbidity and mortality in paediatric patients.Many tests have been recommended for the detection of ESBL production in vitro. Only the K. pneumoniae strains were included and processed further for ESBL detection. The culture media and antibiotic discs were purchased from Oxoid.The study was conducted at the Microbiology Department of The Children\u2019s Hospital and Institute of Child Health Lahore, Pakistan, from May 2010 to February 2012. Eleven pathological samples including blood, cerebro-spinal fluid (CSF), urine, sputum, peritoneal dialysis catheters, tracheal secretions and pus were collected from paediatric patients were analysed during the study period. The patient\u2019s history regarding the use of various interventions like intravenous line, urinary catheters, endotracheal tube, lumber puncture, peritoneal dialysis catheters, exchange transfusion, nasogastric tube, surgery, central venous pressure line and tracheostomy was also noted. The Brain Heart Infusion Broth (BHI) was used to inoculate the blood samples and after a period of incubation they were sub-cultured on solid media. All of the clinical samples were cultured on different solid media of Blood, Chocolate and MacConkey agar plates (90mm) while the urine samples were cultured only on Cystine Lysine Electrolyte Deficient Medium (CLED). An overnight incubation of these culture plates was done at 37\u00b11\u00baC in an incubator. The bacterial strains were identified using API 20E system (bioMerieux)K. pneumoniae strains were screened as ESBL screening-positive on the basis of resistance to ceftazidime. The screen positive K. pneumoniae strains were further processed for double disc synergy test (DDST) and Clinical Laboratory Standard Institute (CLSI) confirmatory test. In DDST, a disc of amoxicillin-clavulanic acid (AMC) was placed in the center of Mueller-Hinton agar plate (90mm) at 20mm distance to ceftazidime (CAZ 30\u03bcg) and cefotaxime (CTX 30\u03bcg). ESBL production was detected by the appearance of key hole effect due to the enhanced activity of ceftazidime and cefotaxime with clavulanic acid.The K. pneumoniae strains were analysed by CLSI confirmatory test. The CLSI confirmatory test was performed with of ceftazidime (CAZ 30\u03bcg) and cefotaxime (CTX 30\u03bcg) alone and using a combined disc of ceftazidime-clavulanic acid and cefotaxime-clavulanic acid (CAZ/CLA and CTX/CLA 30/10 \u03bcg). The CLSI confirmatory test was considered positive when the inhibition zone produced by the combined effect of ceftazidime or cefotaxime and clavulanic acid increased \u22655 mm than ceftazidime or cefotaxime without the clavulanic acid.10Both DDST positive and negative K. pneumoniae were isolated during the study period. Out of 710 positive culture 214 (30.1%) were ESBL screening-positive K. pneumoniae and 496 (69.9%) were screening-negative positive K. pneumoniae. A total number of 710 K. pneumoniae isolates with ceftazidime showed positivity in all of the isolates. Comparison between DDST and CLSI confirmatory test showed that 145 (67.8%) isolates were identified by DDST and 213 (99.5%) by using CLSI confirmatory test (K. pneumoniae was found to be highest in the blood samples 117 (54.7%) followed by urine 46 (21.5%), endotracheal tube 13 (6.1%), cerebro-spinal fluid 13 (6.1%) and peritoneal dialysis catheters 10 (4.7%). The rest of the samples showed the lesser occurrence of ESBL producing K. pneumoniae  followed by urinary catheters 46 (21.5%), endotracheal tube 18 (8.4%), lumber puncture 18 (8.4%) and peritoneal dialysis catheters 16 (7.5%). The less common interventions were exchange transfusion, nasogastric tube, surgery, central venous pressure line and tracheostomy  confirmatory test (p<0.0001) than DDST (67.8%). CLSI even detected ESBLs in those 69 isolates which were missed by DDST. Dalela worked on ESBLs at Jhalawar Medical College in India, used DDST and CLSI for detection of ESBLs in gram-negative bacteria. Out of his 135 screening positive ESBL isolates, DDST detected ESBLs in 122 (90%) isolates while CLSI detected ESBLs in all isolates (100%).K. pneumoniae. Out of 92 screen positive isolates, DDST detected ESBL production in 32 (34.8%) isolates while CLSI detected ESBLs in 72 (78.3%) isolates.K. pneumoniae isolated from neonatal intensive care unit patients.K. pneumoniae than the other phenotypic methods.Comparison of DDST and CLSI showed that most of the ESBL positive K. pneumoniae varied among different pathological samples, a high percentage of 54.7% was isolated from blood followed by urine (21.5%), cerebro-spinal fluid (6.1%) and pus (1.4%). Frequency of ESBL producing K. pneumoniae in different clinical samples was also reported in a study conducted at 1000 bed teaching hospital, Spain. A very high percentage of K. pneumoniae was found in blood (40%) and catheters (36%) followed by respiratory fluid (26%), urine (23%) and pus (18%).17 Similarly a research work conducted at Agha Khan University, Karachi reported high percentage of ESBL positive K. pneumoniae in blood (60%), urine (24%) and wound (6%).18 Ahmad et al also reported more of the ESBL producing K. pneumoniae strains from blood (44.9%) while less frequency was observed in urine (16.2%), tracheal secretions (10.9%), wound (5.9%) and endo-tracheal tip (5.9%).3 The results of these studies are in agreement with our findings indicating the detection of most of the ESBLs in patients with bacteremia.Frequency distribution of ESBL producing K. pneumoniae infections had some interventions like intravenous lines (97.7%) and urinary catheters (21.5%). A study reported the association of invasive procedures like urinary catheters 6 (26.1%), surgeries (26.1%) and mechanical ventilation 3 (13.0%) among the ESBL positive cases of K. pneumoniae.19 In another study the most common interventions found in 79 cases of ESBL K. pneumoniae infections were central venous catheters 72 (91.1%), urinary catheters 70 (88.6%), surgeries 66 (83.5%), nasogastric tube 56 (70.9%) and tracheostomy 37 (46.8%).20 The ESBL K. pneumoniae infections can vary in patients depending upon the various interventions and how they were used. The intravenous lines and catheters can be a good source infection if not used aseptically.In our study we found that most of the patients with ESBL K. pneumoniae is a serious concern for the hospitals. It is associated with high morbidity among paediatric patients which results in high cost of treatment. An appropriate antimicrobial therapy can only be started timely with the early detection of ESBLs. The CLSI confirmatory test can be used reliably especially when the facilities for molecular charaterization are not available. The detection of ESBL producing strains will also help to establish and implement a strict infection control policy to stop the spread of ESBL K. pneumoniae.ESBL producing Hasan Ejaz: The idea of topic, experimental work and wrote the manuscript.Ikram-ul-Haq: Supervision of experimental work and writing of the manuscript.Saqib Mahmood: Co-supervision in experimental work and interpretation of results.Aizza Zafar: Provided the facilities and technical support for research.Muhammad Mohsin Javed: Helped in manuscript drafting and data analysis."}
+{"text": "To explore the therapeutic efficacy and safety of malignant liver tumor treatment by radiofrequency ablation (RA) combined with low frequency ultrasound radiation with microbubbles (LFURM).Retrospective analysis of 25 patients with malignant hepatic tumors treated by RA/LFURM in the Department of Hepatobiliary Surgery of Kunming General Hospital affiliated to Chengdu Military District, PLA from January 2010 to June 2011. Ultrasound guided RA was performed, which was followed one week later by LFURM. Basal contrast ultrasound, liver function tests, and serum alpha fetoprotein (AFP) were obtained, and repeated 3 and 6 months after treatment. T-test and chi-square were used to compare parametric and non-parametric variables respectively.p<0.05). No tumor recurrence was seen during the 6 month follow-up. Quality of life scores (QOL) were good in 21 patients (84%), improved in 2 patients (8%), unchanged in 1 patient (4%) and got worst in 1 patient (4%). Karnofsky scores (KPS) improved in 19 patients (76%), remained unchanged in 5 patients (2%) and got worst in 1 patient (4%). Both QOL and KPS changes were statistically significant (P<0.05).In 17 cases, gross tumor volume was significantly reduced 6 months after treatment while mean tumor showed a reduction of 50% compared to pre-treatment values. In 7 cases gross tumor volumes reduction was partial, but surrounding tumor tissue showed blood flow signals. One patient had no reduction in gross tumor volume. Levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), alpha fetoprotein (AFP) decreased significantly 6 months after treatment (all RA/LFURM treatment of liver tumors is efficient and safe, and can reduce the gross tumor volumes and protect liver function. Over fifty percent of liver cancer victims live in China. Surgical resection is the most frequent form of treatment for malignant liver tumors. However, in most cases, tumors are detected in late stages when liver function is already very poor. Radical resection can be performed in only 30% of cases which makes recurrence rates very high Of the 25 patients with malignant liver tumors 9 were females and 16 were males. Ages ranged from 23 to 78 years . Liver function (Child-Pugh classification) was class A in 15 patients, class B in 7 patients and class C in 3 patients . Tumor stage was I in 9 patients and II\u2013IV in 16 patients (American Cancer Society). Primary hepatic cancer (PHC) was present in 15 cases and recurrent liver tumor in 10 cases. Hepatocellular carcinoma (HCC) was found in 22 cases and in 3 cases the type was cholangiocellular carcinoma (CC). AFP was positive in 21 cases. Percutaneous contrast ultrasound was performed in all patients before surgery. All tumors were more than 3.0 cm in diameter and in 3 cases the tumors were larger than 5 cm in diameter. More than one tumor were present in 23 cases. There was no extrahepatic spread of the tumor in any of the patients. Data were gathered from a retrospective review of medical charts with approval from the Institutional Review Board.Inclusion criteria: (1)Age between 18\u201380 years old; (2)Tumor lesion could be clearly determined by percutaneous contrast ultrasound; (3)Tumor size between 3\u20138 cm in diameter; (4)The maximum number of tumors was 3; (5)Histopathological diagnosis (HCC or CC) was established by ultrasound guided liver biopsy: (6)No history of previous malignant disease;(7)Patients did not receive any other treatment in the last 3 months.Exclusion criteria: (1)Patients with liver malignant tumor outside the inclusion criteria; (2)The liver function was Child's class C and did not improved by medical treatment; (3)Infiltrative tumor which invaded and produced thrombosis of large vessels;(4)Lymphatic or distant metastasis.2) . Micro vesicle agent was: 10 mL of 5% sodium bicarbonate, 25 mL of 20% vitamin C, and 7.5 mL hydroxyethyl starch. The ultrasonograph instrument (iU22) was purchased from Philips, Inc. . Acoustic contrast agent was SonoVue (2.4 mL).The RA instrument (RFA-1000) was purchased from Beijing Bolaide, Inc. . Low-power Sonostat was purchased from Jiangsu Hanmei Technology, Inc.  were performed.Contrast ultrasound, AFP and liver function tests were done before and 3, and 6 months after treatment. Quality of life (QOL) scores were applied before and 6 months after treatment. P<0.05 are considered significant.Statistical analysis was performed using the Statistical Program for Social Sciences  version 19. Parametric variables were compared with paired T-test while non-parametric viariables were compared using the Chi-square test. Values of The gross tumor volumes ranged from 2.5 cm\u00d72.0 cm to 5.5 cm\u00d74.5 cm, as measured by contrast ultrasound 3 months after treatment in 16 patients. On average, the tumor volume decreased by approximately 30%. There was a significant decrease in tumor resonance. No increase in blood flow was found after treatment, but there was still blood supply to the tissues surrounding the tumor, which was shown by contrast ultrasound examination . Albumin (Alb) levels increased 3 and 6 months after treatment but the differences were not significant . AFP decreased significantly after 3 and 6 months  (P>0.05) in a patient with CC who experienced cancer recurrence and increased significantly  in a patient with HCC who developed intrahepatic metastasis.In some patients ALT increased after treatment but the general liver function improved. There was a significant reduction of AST and TBIL 3 months after treatment  . At one 20%) and aggravated in 1 patient (4%). Difference between the pre-treatment and the post-treatment QOL and KPS were significant . During the second six months of follow-up, there were no significant differences in the QOL scores and the KPS scores between at 6 months and at 1 year after treatment. However, during 1-year follow-up, one of twenty-two patients with HCC developed intrahepatic metastasis , two of three patients with CC experienced cancer recurrence and intrahepatic metastasis , and there was a significant difference in the recurrence and metastasis rate at 1 year after treatment between the HCC and CC groups .During the six months follow-up, none of the patients had tumor recurrence. QOL scores before treatment were good in 15 patients (60%), improved in 5 patients (20%), unchanged in 3 patients (12%) and worst in 2 patients . QOL scores post-treatment were good in 21 patients (84%), improved in 2 patients (8%), and unchanged in 1 patient (4%) and worst in 1 patient (4%). KPS for functional status for pre-treatment were improved in 16 patients (64%), stable in 7 patients (28%) and aggravated in 2 patients (8%). KPS post-treatment were improved in 19 patients (76%), stable in 5 patients (RA with a radiofrequency wave (460 KHZ) increases tissue and cell temperature (80\u223c100\u00b0C), resulting in the irreversible coagulation necrosis of the tumors and the liver parenchyma surrounding tumor LFURM on the other hand produces ultrasonic cavitation affecting tumor micro-circulation. The microbubbles produce cavitation nuclei, which leads to extremely high shear stress force on the air bubble and deforms it until it fractures, with the resulting breakdown of cells and the bio macromolecules close to tumors, via the biological effect of ultrasonication. Moreover, the energy released during the cavitation process generates localized hyperthermia, hyperpiesia, shock wave, high speed micro- aspirating gas stream and free radicals Solid tumors generally contain abundant, poorly differentiated vessels, which are liable to destruction and develop embolism when subjected to ultrasonic cavitation. Low-frequency and low-power ultrasound radiation, when used in combination with intravenously injected microbubbles, can result in cavitation as efficiently as high power ultrasound radiation does. Hence, it may be a safe, minimally invasive treatment for tumors Some research results have shown that the cavitation erosion induced by the low output power destroyed only the new vessels from tumor tissues, but had no impairment on normal tissues. However, the process of ischemia and necrosis of tumor tissues induced by cavitation with ultrasonic radiation microbubbles was slow. The large blood vessels supplying the tumor were not completely destroyed Treatment by RA destroyed tumor cells. Treatment by LFURM attacks tumor micro-circulation complementing the effects of RA. So, the combined use by RA and LFURM could reach to the purpose of conformal treatment, reducing destruction of normal hepatic tissue, protecting liver function as much as possible, and increasing treatment efficacy.The present study found a decrease in the gross volume of tumor with the combination of RA and LFURM. The transient increase of ALT in some patients suggests an effect of the treatment on normal hepatic tissue.However, the liver function recovered after treatment with usual liver protecting measures, suggesting that the impairment in liver function after treatment is reversible. The present study shows a significant difference in the recurrence and metastasis rate at 1 year after treatment between the HCC and CC groups, and such difference may correlate with the pathologic characteristics and biological behavior of CC. Patients with CC usually have no cirrhosis and do not develop choloplania, and their levels of AFP are normal. In addition, the early stage of CC development is insidious, which reduces the likelihood of early interventions. Consequently, the overall prognosis of CC is poor. Slakey et al"}
+{"text": "TKI constitute a new group of drugs evaluated in TC patients. The efficacy of some of them in prolongation of progression free survival has been recently documented. However, possible side effects may affect the quality of life as well as limit their clinical use. Only drugs which were known to inhibit VEGFR were considered. In the study adverse effects were evaluated in patients treated in our centre within the prospective clinical trials phase II and III. The aim of the study was to analyze the frequency and severity of side effects related to TKI in TC patients. Thus, we retrospectively re-evaluated side effects on the basis of Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. The comparison of the drugs was not aimed.37 therapies with TKI due to advanced TC were assessed. 19 subjects were given vandetanib, 15 - lenvatinib, 3 - axitinib. Median treatment duration was 26.7 months (range: 4.0 - 62.2). The drug was discontinued due to TC progression in 9 subjects, adverse events in 5 and for other reasons in 4. Adverse events leading to treatment withdrawal were: weight loss (1), lymphopenia (1), QTC prolongation (1), tracheo-esophageal fistula (1) and purulent meningitis (1).The results are given in table Tolerability and safety of the treatment with tyrosine kinase inhibitors in advanced TC patients was acceptable (most adverse reactions G1-G2). Only in 13.5% cases treatment discontinuation was required."}
+{"text": "Muckle-Wells syndrome (MWS) is a rare inherited autoinflammatory disease. Patients may present with fever, rash, arthralgia, or conjunctivitis. Effective treatment of MWS has become available with the advance of IL-1 inhibition preventing disease sequalae of sensorineural deafness and amyloidosis. Therefore, early diagnosis of MWS is crucial to prevent -organ damage. The aim of this study was to identify key factors contributing to a delay in diagnosis of MWS.In two rheumatology centers a cohort of consecutive children and adults with genetically confirmed MWS were interviewed using a previously developed standardized questionnaire. The tool captures a total of 55 variables including patient related demographic factors, referral process related variables and presenting MWS symptoms at time of MWS diagnosis.A total of 32 patients, 18 females/14 males were included. These were 10 children and 22 adults with active MWS and confirmed mutations of the NLRP3 gene. The median age was 36 years (range 3-75). The median distance from home to the rheumatology center was 20km (range 7-577). The mean time elapsed between first consultation and final diagnosis was 21.9 years (range 0 \u2013 63 years). The major symptoms reported by the patients were musculoskeletal (75%), skin disease (63%), eye disease (47%), relapsing fevers (41%) and hearing loss (34%). Diagnoses preceding the correct recognition of MWS included rheumatic disease (41%), conjunctivitis (41%), hearing loss (31%) and urticaria (28%). No definite diagnosis was made in 25%. Medical subspecialties most frequently consulted first were pediatricians (38%) and general practitioners (31%). In 84% the physician to establish the diagnosis of MWS was a rheumatologist.In patients with MWS, diagnosis is dramatically delayed most likely due to low level of knowledge regarding the disease. As severe disease sequelae like sensorineural deafness and amyloidosis may be prevented by early diagnosis and effective IL-1 inhibition the education of medical professionals in the area of autoinflammatory diseases needs to be intensified. Designated reference centers may contribute in accelerating the process of diagnosis and therapy.Jasmin B. Kuemmerle-Deschner: None; Samuel D. Samba: None; Isabelle Kon\u00e9-Paut: None; Isabelle Marie: None; Katharina Gramlich: None; Sandra Hansmann: None; Theodoros Xenitidis: None; Susanne M. Benseler: None."}
+{"text": "Stenotrophomonas maltophilia is a gram negative bacillus that has emerged as an opportunistic pathogen associated with high morbidity and mortality rates.The aim of this study is to describe the characteristics of bactaeremia due to this strain, their outcome, the antibiotic sensitivity patterns of isolates.In our study, 93% of 33 episodes were nosocomial. There were 22 deaths (71%) 15\u00b112 days after the bactaeremia. 17/31 of patients were exposed to broad-spectrum antibiotic specifically imipinem (IMP) before their positive culture. Among cases, 23 (74%) patient had mechanical ventilation and 29 (93\u00b75%) had central venous catheterization. Antibiotic susceptibility testing revealed that isolates were most sensitive to Ciprofloxacin (CIP) (84%), Trimethoprim-sulfamethoxazole (SXT) (71%) and to Colistin (CS) (58%). Twenty three percent (23%) episodes were polymicrobial. A probable portal of entry was identified in 27\u00b73% of bacteraemic episodes and 57% were catheter-related. Fifty eight percent (58%) of the episodes were treated with monotherapy specifically CIP (35%). Our results were similar to those described by others in the last 20 years. These studies have been mostly retrospective.S. maltophilia infection relies on the cornerstones of modern infection control, such as higher emphasis on control of antimicrobial consumption and consideration of environmental reservoirs.Prevention of None declared"}
+{"text": "A rare, but life-threatening complication in pancreatitis is a spontaneous bleeding from intestinal vessels with or without previous formation of (pseudo-) aneurysms. And yet, the optimal diagnostic and therapeutic strategies remain unclear.We performed a retrospective analysis of all patients with pancreatitis and intraabdominal bleeding at a German tertiary referral center between January 2002 and December 2012.Bleeding occurred in <1%  of patients with pancreatitis. Most involved vessels were arteria lienalis, arteria gastroduodenalis, and arteria pancreaticoduodenalis. All bleedings could be stopped by transcatheter arterial coil embolization. Recurrent bleeding after coil embolization occurred in 2/14 (14%) patients.In cases of intraabdominal hemorrhage in patients with pancreatitis, transcatheter arterial coil embolization should be considered as the first interventional procedure. Acute pancreatitis (AP) is a common disease with an incidence of 19.2 to 42.8/100,000 person-years and a mortality of nearly 5% . HoweverOne of the complications in pancreatitis is spontaneous bleeding from intestinal vessels with or without previous formation of (pseudo-) aneurysms. These life-threatening bleedings are rare complications occurring in about 1-5% of patients with AP or chronic pancreatitis (CP) \u201313. PathSome small case series and review articles describe different diagnostic approaches including contrast enhanced computed tomography (CE-CT) and digital subtraction angiography (DSA) for detection of spontaneous bleeding ,24. DiffIn this retrospective analysis, we report a centre-specific experience of transcatheter arterial coil embolization for intraabdominal hemorrhage in patients with acute or chronic pancreatitis.The study was approved by the local ethics committee . Written consent was specifically waived by the approving institutional review board. We analyzed the administrative diagnosis database for patients with pancreatitis -10 code K85 and K86) between January 2002 and December 2012. A database including all patients undergoing intraabdominal TAE was matched to the patients with pancreatitis.All statistical analyses were performed using IBM SPSS Statistics 20 . If appropriate, descriptive data are presented as mean \u00b1 standard deviation or median, range, and interquartile range (IQR). The Mann\u2013Whitney U test was used to compare continuous data of patients with and without intraabdominal bleeding. All statistical tests were 2-sided and performed in an explorative manner on a 5% significance level.We identified 7,382 cases in 3,421 patients and registered 1,302 patients with AP and 2,119 patients with CP treated at our hospital during the study period. Due to reasons of privacy data protection, personal data are available for only 4,529 (61%) patients. There was no statistically significant difference of age in patients with intraabdominal hemorrhage compared to patients without intraabdominal hemorrhage  vs. 58 years ). Fourteen patients with intraabdominal hemorrhage due to acute (n=11), chronic (n=1), or an acute attack of chronic (n=2) pancreatitis were identified. Regarding patients with AP, 10/11 (91%) experienced their first attack of AP, and 8/11 (73%) developed a necrotizing pancreatitis. Patients\u2019 characteristics and etiology of AP are shown in Nine out of 14 patients (64%) required intensive care unit (ICU) treatment. Mechanical ventilation was necessary in 6/14 (43%) patients, 5/14 (36%) developed a circulatory failure requiring catecholamine therapy, and acute renal injury according to the Acute Kidney Injury Network occurred in 6/14 (36%), 4 of them underwent dialysis .In patients with AP, the median duration from onset of pain to arrosion bleeding was 42 days . The time between onset of pain and bleeding complication in the two patients with an acute attack of CP was 5 and 14 days, respectively. Duration from initial diagnosis of CP and intraabdominal bleeding in the patient without an acute attack was about 60 months.In 13/14 (93%) cases, the source of bleeding was an arterial blood vessel. Only one case showed diffuse venous splenic bleeding. Localizations of bleedings are shown in In 8/14 (57%) cases, a true or false bleeding aneurysm was detected by CE-CT or arteriography.In 13/13 (100%) cases, the bleeding could be located by CE-CT. In one case, no CE-CT was performed before DSA. In contrast, an active bleeding could be seen in only 8/14 (57%) during DSA.All but one  bleedings could be stopped by transarterial coil embolization. In the remaining case, neither the bleeding diagnosed using CE-CT nor an aneurysm could be seen during DSA and therefore no coiling was performed. According to the localization of the bleedings, the most coiled artery was arteria lienalis (7x) followed by arteria gastroduodenalis (3x), arteria pancreaticoduodenalis (3x), arteria gastrica sinistra (1x), arteria hepatica sinistra (1x), and arteria hepatica communis (1x). The median number of coils used per patient was 5 .Only one out of 14 patients (7%) had surgery before intraabdominal hemorrhage. However, in 8/14 (57%) patients, an intraabdominal catheter was placed in order to drain infected necroses. In 6/8 (75%) of theses patients, a percutaneous access was used and in 5/8 (63%) a transgastric drainage was placed. The median number of percutaneous (range 1-6) and transgastric drainages (range 1-5) was 2 in both groups.Five out of 14 patients died before discharge from the hospital. Accordingly, hospital mortality was 36%. Among the 9 patients treated at an ICU, 3 (33%) died before transfer to normal ward. The median time between bleeding and death in all patients was 15 days . Only one patient died as a consequence of intraabdominal bleeding.Recurrent bleeding after coil embolization occurred in 2/14 (14%) patients. Time between coiling and recurrent bleeding was 0 and 9 days.Arrosion bleeding of intraabdominal vessels is a severe complication in acute and chronic pancreatitis. Based on our data the choice of successful treatment in such cases is immediate transcatheter arterial coil embolization (TAE).Symptoms of intraabdominal hemorrhage in patients suffering from pancreatitis are abdominal pain, bleeding from drainages, hemorrhagic shock and decrease of hemoglobin . In caseIn case of intraabdominal bleeding diagnosed by CE-CT or angiography, an interventional angiography and stenting ,31, coilOur data and others identified arteries arising form the celiac trunk as most frequent sources of bleeding  14]. Gi. Gi14]. Patients with severe AP have in any event a high mortality of up to 48% . MortaliIn more than half of the patients (57%) intraabdominal catheter was placed to drain infected necrosis prior to bleeding. Indeed, in addition to pseudocysts, necroses and abscesses, intraabdominal drainages have been associated with increased risk for intraabdominal hemorrhage . MechaniIn cases of intraabdominal hemorrhage in patients with pancreatitis, TAE should be considered as the first interventional procedure. Based on the widely spread availability and minimal invasiveness of DSA as well as the improved technical capabilities of interventional radiology, we therefore consider TAE as a central component in the proposed algorithm ."}
+{"text": "Pseudomonas aeruginosa has a high resistance to external environmental conditions, with a remarkable ability to adapt and numerous virulence factors, being involved in the etiology of nosocomial infections and severe infections in immunodeficient patients. The strains isolated in hospitals need supervision due to the risk of transmission and antibiotic resistance.Pseudomonas strains isolated from pathological products collected from hospitalized patients in non-ICU departments of the hospital.We pursued the epidemiological context to elaborate therapeutic recommendations on first-line antibioterapy adapted to the evolution of antibiotic resistance of P aeruginosa hospitalized in the \u201cVictor Babe\u015f\u201d Hospital Craiova in the period 01 January 2006 \u2013 31 December 2012. We evaluated the studied cases based on the following parameters: the risk of infection with antibiotic-resistant germs (Carmeli score), infection localization and antibiotic resistance profile of the isolated strains of P aeruginosa, achieved by the classical diffusimetric system.The retrospective study included 192 patients diagnosed with infections caused by The annual evolution of cases showed an upward trend since 2009, the age groups most affected were infants (8.3% of cases), small children (11.1%) and the elderly over 65 years (26.5%). According to the Carmeli score, patients were divided into 3 categories: 4 patients (2.1%) with community infections, 112 patients (58.4%) with community apparent infections and 76 patients (39.5%) with probable nosocomial infections. The location of infection was: respiratory (49.6%), ear (16.1%), urinary (12.8%), digestive (10.1%), overinfected wounds (2.7%), sepsis (1.6%), other sites  1%.P aeruginosa to be carbapenem-resistant showed respiratory and urinary localization and wound infections. Colistin was the safest alternative treatment for P aeruginosa strains resistant to meropenem, becoming the most effective antibiotic in the absence of its use for a long time.Antibiotic sensitivity was: colistin 99.1%, quinolone 88.7%, cefoperazone-sulbactam 88%, aminoglycosides 87.7%, meropenem 84.4%, aztreonam 83.9%, piperacillin-tazobactam 82.14% ticarcillin-clavulanate 77.3%, ceftazidime 73.8%, cefpirome 72.7%, ceftriaxone 71.6%, cefepime 60.9%, amoxicillin-clavulanate 16.1%. The comparative analysis of antibiotic sensitivity according to the Carmeli score indicates caution in the use of cephalosporins and quinolones for patients with Carmeli score 3, since these patients probably have infections with antibiotic resistant strains. The risk for strains of P aeruginosa was determined by antibiotic selection pressure, the chemosensitivity data are useful in developing therapeutic recommendations tailored to the local situation.The antibiotic resistance of"}
+{"text": "Rio de Janeiro's Fire Squad is responsible for EMS in the city. During 2010 we implemented 10 ambulances with EKG transmission capability in our city. Our intention was to access the prevalence of acute myocardial infarction in the prehospital setting.We used the Aerotel HeartView EKG system to acquire patient examination and a blackberry phone to transmit and receive the PDF EKG trace. The PDF comes with the cardiologist's interpretation from a remote hospital, the HCOR S\u00e3o Paulo.We realized 503 EKG examinations in total. Of these, 248 (49%) had as the chief complaint chest pain, 101 (20%) shortness of breath, 47 (9%) syncope, 36 (7%) palpitation; other complaints were 15%. We detected 32 examinations (6.36%) with ST elevation MI and 44 examinations (8.75%) with ST depression. Atrial fibrillation was detected in 43 examinations (8.5%). See Figures This experience gave us an idea of the prevalence for acute ST elevation MI in the prehospital setting, so that we can better develop our prehospital thrombolysis protocol and focus our training for cardiology care."}
+{"text": "The HPV prevalence and genotype distribution are important for the estimation of the impact of HPV-based cervical cancer screening and HPV vaccination on the incidence of diseases etiologically linked to HPVs. The HPV genotype distribution varies across different geographical regions. Therefore, we investigated the type-specific HPV prevalence in Czech women and men with anogenital diseases.We analyzed 157 squamous cell carcinoma samples, 695 precancerous lesion samples and 64 cervical, vulvar and anal condylomata acuminate samples. HPV detection and typing were performed by PCR with GP5+/6+ primers, reverse line blot assay and sequencing.The presence of HPV types related to the vaccinal ones  were detected in 16% of carcinoma samples and 18% of precancerous lesion samples. HPV 16 and/or 18 were present in 76% of cervical cancer samples, 33% of CIN1, 43% CIN2 and 71% of CIN3 samples. HPV types 6 and/or 11 were detected in 84% samples of condylomata acuminate samples.Thirty different HPV genotypes were detected in our study, HPV 16 being the most prevalent type both in precancerous lesions (45%) and squamous cell carcinomas (59%). In benign lesions, HPV 6 (72%) was the most common type. Altogether, 61% of carcinoma samples and 43% of precancerous lesion samples contained HPV 16 and/or 18. The prevalence of vaccinal and related HPV types in patients with HPV-associated diseases in the Czech Republic is very high. We may assume that the implementation of routine vaccination against HPV would greatly reduce the burden of HPV-associated diseases in the Czech Republic. Human papillomaviruses (HPVs) have been established as etiological agents of invasive cervical cancer (CC) In spite of the high burden of cervical cancer in Central and Eastern Europe Squamous cell cervical carcinoma (SCC) samples as well as precancerous lesion samples from different anatomical locations were selected from the biobank of the National Reference Laboratory for Papillomaviruses in Prague. These samples were collected between 1993 and 2005, stored at \u221220\u00b0C and analyzed in previous studies.Cervical scrape and biopsy specimens were obtained from women visiting hospital gynecology departments and selected centers of gynecologic-oncology prevention in the Czech Republic nd Faculty of Medicine, Charles University, Prague for squamous cell vulvar carcinoma (VC), vulvar intraepithelial neoplasia (VIN) and vulvar condylomata acuminata (VCA) were also included in the study. The patient\u015b characteristics and histological data were published before Samples from patients surgically treated in the Department of Obstetrics and Gynecology of the 2Twenty-two samples from patients with squamous cell carcinoma of the anus (AC)  and 10 samples of anal condylomata acuminata (ACA) samples , were analyzed. Details on the population, sample preparation and pathological classification were published before Overall, 157 cancer samples from multiple locations, 695 pre-malignant neoplasia samples, and 64 condylomata acuminata samples were included in this study.No informed consent was needed from the patient by the course of law in the Czech Republicbefore 2000. All patients enrolled after the year 2000 signed an informed consent form and the study was approved by the institutional ethics committee PCR and reverse line blot hybridization (RLB) were used for the detection and genotyping of the HPV DNA in samples Detected HPV types were classified into low-risk (LR) , high-risk (HR)  and probably high-risk (pHR)  types of the genus Alpha that contains the mucosal types of HPV To confirm the presence and integrity of the human DNA, beta-globin PCR analysis by PC03/04 primer set The laboratory is accredited according to \u010cSN EN ISO 15 189 and participates regularly in external control of quality programs organized by INSTAND (Germany) and Mendel Center for Biomedical Sciences (Cyprus). Furthermore, the laboratory participated twice in WHO HPV LabNet Proficiency Study of HPV DNA Typing organized by the WHO HPV Global Reference Laboratory http://www.ncbi.nlm.nih.gov/BLAST/).To determine the type of HPV in the specimens positive by RLB only on the agarose gel but not by RLB hybridization, the remaining aliquots of PCR amplicons were used for nucleotide sequencing. The 150 bp products were cut out of the 2% NuSieve GTG agarose gel , purified using the MinElute\u2122Gel Extraction Kit  and directly sequenced using the BigDye\u00ae Terminator v1.1 Cycle Sequencing Kit . The sequence analysis was performed on the ABI PRISM 310 genetic analyzer (Applied Biosystems) and the sequences were analyzed by Chromas software and evaluated by BLAST software  test. For contingency tables, the standard chi-square test and the Fisher exact test were used. The prevalence ratios in SCC in comparison to CIN2, 3 and CIN1 with 95% confidence intervals (CI) were determined using GraphPad InStat (version 3.00) . All tests were two sided and the significance level was p\u200a=\u200a0.05. For assessing the possible impact of HPV vaccines on the prevention of HPV-associated cancer, we estimated the number of cervical cancer cases attributed to 8 HPV types most prevalent in the Czech Republic. We used the numbers of incident cases of cervical, vulvar and anal cancers in the Czech Republic published in 2010 Altogether, 157 carcinoma samples were available for HPV DNA testing. Patients with SCC were significantly younger (P<0.001) than those with other types of carcinomas see . One hunOverall, we detected 9 HR  2 pHR  and 1 LR (HPV 42) HPV types in different types of carcinomas, of which 11 different HPV genotypes were found in SCC samples while the spectrum of HR HPV types in other types of carcinomas was much narrower. Only HR HPV types 16, 33 and 45 were found as a single infection. HPV 16 was the most prevalent type in cervical 73% (63/86), vulvar 25% (12/49) and anal 82% (18/22) carcinomas, followed by HPV 33, 45, 18, and 31 in descending order.HPV vaccinal types (HPV 16 and/or 18) were detected as a single infection in 50% (79/157) of tumors and as a coinfection with other HR HPV types in additional 10% (16/157) of samples. Altogether, 61% (95/157) of analyzed malignant tumors contained one or both vaccinal types. The presence HPV types either closely or distantly related to the vaccinal ones, i.e. HPV 31 and 45 and HPV 33, 52, and 58, respectively, was detected in additional 5% (8/157) and 11% (11/157) of carcinoma specimens, respectively. Sixty-five (76%) of 86 cervical cancer samples contained HPV 16 and/or 18 as a single or multiple infection. The presence of HPV types either closely or distantly related to the vaccinal ones, i.e. HPV 31 and 45 and HPV 33, 52, and 58, was detected in additional 8% (7/86) and 8% (7/86) of SCC samples, respectively.A total of 695 precancerous lesion samples were available for our analyses: 338 from CIN1 cases, 111 from CIN2 and 200 from CIN3 cases and 46 from VIN cases. Median age of women with cervical lesions was substantially and statistically significantly lower (P<0.0001) compared to that of patients with VIN (see study design). Overall, the prevalence of HPV DNA was 76% (528/695). HPV infection was detected in 62% (209/338) of CIN1 samples, 77% (85/111) of CIN2 and 94% (188/200) of CIN3 samples and 100% (46/46) of VIN samples . Among tIn comparison to carcinomas, precancerous lesions contained a larger variety of HPV types. As shown in More than a half of samples contained a single HPV type (56%). Multiple infection was found most commonly in cervical precancerous lesion samples: in 20% (66/338) of CIN1, 21% (23/111) of CIN2 and 22% (44/200) of CIN3 samples. Most multiple infections were coinfections with two or three HPV types. Coinfection with four HPV genotypes was only found in six cervical lesion samples.The vaccinal types HPV 16 and/or 18 were present in 34% (239/695) of precancerous lesion samples as a single infection, in 1% (8/695) as a multiple infection (combined HPV16/18 infection), and in 13% (87/695) in combination with other HPV types. The presence of the types either closely or distantly related types to the vaccinal ones: HPV 31 and 45 and HPV 33, 52, and 58, respectively, was detected in 9% (59/695) and 11% (79/695) of samples, respectively.Altogether, 33% (110/338), 43% (48/111) and 71% (141/200) of CIN1, CIN2 and CIN3 samples, respectively, were positive for HPV 16 and/or 18. Closely related types HPV 31 and 45 were present in 9% (31/338),11% (12/111) and 7% (14/200) of samples, respectively, and distantly related types HPV 33, 52, and 58 in 9% (30/338), 14% (16/) and 13% (25/100) of samples, respectively. LR HPV types were detected in 9% of precancerous lesion samples. HPV 6 and/or 11 were present as either a single or multiple infection in 3% of all precancerous lesion samples, more precisely in 5% (18/338) of CIN1 samples, 1% (1/111) of CIN2 and 1% (1/200) of CIN 3 samples and 9% (4/46) of VIN samples.HR HPV types as a single infection were only detected in 4% (2/54) of VCA samples and as a multiple infection together with LR types in additional 15% (8/54) of VCA samples, while ACA samples did not contain any HR HPV type, with a single sample being positive for two LR types. In VCA samples, 11 different HPV types were detected: 4 were HR , 2 pHR  and 5 LR  HPV types .Altogether, vaccinal HPV types 6 and/or 11 were present in 84% (54/64) of condyloma acuminatum samples from different anatomical locations, in 87% (47/54) of VCA samples, and 70% (7/10) of ACA samples.The overall prevalence of HPV was higher in SCC (95%) in comparison to CIN1 (62%) , CIN2 (77%)  but not in CIN3 (94%)  cases. Similar results were obtained for any HR HPV type detected and for seven HR HPV types most prevalent in SCC samples . For eacIn the Czech Republic 1300 cervical, vulvar and anal incident cancer cases occur, more precisely 990 cervical cancer cases, 189 vulvar cancer cases, and 121 anal cancer cases In this study we provide the largest summary data on the type-specific HPV type specific prevalence in the population of Czech women and men with diseases of the anogenital tract associated with HPV infection. Importantly, the prevalence rates of the vaccinal HPV types as well as those of HPV types which have shown a partial cross protection in clinical trials In this study we analyzed 157 squamous cell carcinoma samples, 695 precancerous lesion samples and 64 condylomata acuminata samples from different anatomical locations. A very sensitive method was used, which is based on the amplification of a short DNA fragment of HPV L1 ORF and allows detection of multiple HPV infections The data on HPV prevalence in precancerous cervical lesions and invasive cervical cancer cases in the Czech Republic were evaluated previously on another set of specimens The published data on the type-specific HPV prevalence in patients with HPV-associated diseases in the Central and East European countries are scarce and most studies have analyzed only very small numbers of specimens. While more studies from Central and East Europe on HPV prevalence in CC were published and included in the meta-analyses The type-specific HPV prevalence in CIN2+ samples found in our study, is the same as the data reported for Europe (88%), with the exception of HPV 16 and/or 18 (61 vs. 52%) In comparison to the summary data for Europe as published by Clifford et al. The present study has shown a significantly higher prevalence of any HPV type, as well as of HR HPV type among SCC cases in comparison to CIN1 (p<0.0001 for both)and CIN2 cases  . The preA meta-analysis of HPV prevalence studies in precancerous lesions and vulvar and anal carcinomas The overall prevalence of HPV as well as HPV type distribution in VC is in our study comparable to other studies. Nowadays it is widely accepted that about 40% of VC cases can be etiologically linked to HPV.Importantly, focused on the prevalence of both vaccinal and cross-reactive HPV types, this study revealed that altogether 43% of precancerous lesions of the cervix and vulva  are caused by HPV 16 and/or 18 and additional 20% by HPV types related to the vaccinal ones . Therefore, a substantial number of precancerous lesions can be considered preventable by prophylactic vaccination in the Czech Republic. The vaccinal LR HPV types HPV 6 and/or 11 were detected in 5% of CIN1, as few as 1% of CIN2 and 0.5% CIN3 and 9% of VIN cases.The overall prevalence of HPV 16 and/or 18 among the analyzed cancer cases was 61% and that of the closely or distantly related types was 12%. The lowest prevalence of HPV 16/18 was observed in VC cases. Based on our data, the development of vulvar cancer can be prevented in about half of cases, thus reducing the need for mutilating surgery that dramatically reduces quality of life for patients.The rate of SCC cases attributable to HPV 16/18 infection in the Czech population is 76%. Even higher is the involvement of HPV 16/18 in AC cases (82%). In view of cross-protective effect of the available vaccines, we can expect the potential benefit from vaccination against HPV in preventing SCC to be as high as 92% for the Czech population.Finally, specimens with the histologically confirmed presence of condylomata acuminata were analyzed. Even though only a limited number of samples were available, the information is very important for the planning of the preventive strategies. We have shown that 89% of these lesions are infected by LR HPV types, with vaccinal types HPV 6/11 being present in 84% of them. These data should be taken into account when considering population-based prophylactic vaccination against HPV.In conclusion, our study reports on the type-specific prevalence of HPV in benign, premalignant and malignant lesions of the anogenital tract in women and man. The prevalence and spectrum of HPV types detected in the Czech Republic are comparable to the data reported for European countries. The observed differences can be mostly attributed to the variation in the methods used for HPV detection. The proportion of patients infected with vaccinal and closely or distantly related HPV types is much higher than originally proposed. Approximately 952 of 1300 incident cancer cases  and 921 of 990 CC cases can be attributed to these HPV types in the Czech Republic. Furthermore, it has been shown that the implementation of routine vaccination not only resulted in decrease in incidence of atypical cervical cytology and precancerous cervical lesions but also in the reduced need for colposcopy and invasive treatment procedures"}
+{"text": "Radiological involvement of the cervical spine has already been assessed in juvenile idiopathic arthritis (JIA) but most studies have been performed in symptomatic JIA and without differentiating subsets of JIA.To describe structural inflammatory cervical spine involvement in pJIA regardless of cervical symptoms and compare observed lesions to those seen in RA using a cross-sectional observational study.All consecutive pJIA followed in a transition program have been included in this study. Demographic and rheumatism characteristics were collected. Laboratory tests and standard radiographies of the cervical spine , hands and feet were performed. A RA control group (<55years), matched for sex and disease duration, was recruited.58 pJIA  and 59 RA (52/7) were included. Respectively, mean age was 23.6\u00b110 years and 43.2\u00b19.6 years and mean disease duration 13.14\u00b111.14 and 12.17\u00b17.1 years. 60% and 80%  were RF positive. Radiographies showed inflammatory lesions in 38/58 pJIA (66%) and 40/59 (68%) RA patients and respectively 3/56 and 2/59 patients underwent cervical surgery.In pJIA with radiological lesions, the most frequent lesions were anterior atlantoaxial subluxation (35%), erosions of the odontoid process (34%) and atlanto-axial impaction (20%). Apophyseal joint ankylosis (AJA) was rare (10%) but involvement of the posterior cervical spine  was more frequent (42%).Presence of radiographic cervical lesions was correlated in univariate analysis with a more severe disease phenotype: more erosive disease (hand and feet), higher number of biotherapies per patient , and higher frequency of surgery  but not with RF status. Multivariate analysis confirmed only the association with the higher number of biotherapies per patients (p=0.04).50% of pJIA with radiographic abnormalities had no clinical symptoms. In pJIA sub-group with cervical symptoms (n=24), patients needed more DMARDs and biotherapies per patient.Finally, comparison between pJIA and RA for radiographic findings showed only differences for two structural features: hypotrophy of vertebrae (24% vs 7%) and AJA (10% vs 0%).Structural cervical spine involvement is a frequent manifestation in pJIA followed at adulthood and is correlated with a more severe disease. Radiologic assessment of cervical spine should be done systematically at onset and regularly during the course of the disease regardless of clinical symptoms. Cervical symptoms may be considered as a warning signal revealing presence of AJA."}
+{"text": "Patients readmitted to ICU have a higher mortality and longer ICU and hospital stay. Furthermore, the readmission rate is used as a quality indicator of critical care unit performance, because this index may reflect the adequacy of treatment. The objective was to evaluate the readmission rate of a tertiary public hospital during a 6-month period.We performed a retrospective analysis of all adult patients readmitted to a 20-bed mixed-case ICU between 1 September 2012 and 28 February 2013. The cases (readmission) were collected from clinical electronic information system.During this period 402 patients were admitted to the ICU. The mortality in the ICU was 24.6% and overall hospital mortality rate was 31.6%. The average SAPS 3 during readmission on the ICU was 52 with a predicted mortality of 34%. The readmission rate was 5.2%, ICU mortality was 23.8% and hospital mortality was 28.6%. The most frequent cause of readmission was nosocomial pneumonia (29%), neurologic causes (19%), sepsis (14%), administrative (14%), postoperative support (10%), metabolic disorders (10%) and cardiology events (5%). The patients were most commonly readmitted form the ward (33%), emergency department (14%), step-down unit (14%), operating theater (5%) and others (33%). The most common supportive therapies after readmission were mechanical ventilation in 38.1%, vasopressors in 28.6%, and renal support in 9.5%.The most common reason for ICU readmission in our unit was nosocomial pneumonia. The mortality of the readmitted patients was not superior to the predicted mortality for the overall cohort of patients."}
+{"text": "TRAPS is an autosomal dominant disease due to mutations in the TNFRSF1A gene.To analyze the clinical features of TRAPS and genotype/phenotype correlations of TRAPS patients enrolled in the Eurofever/Eurotraps registry.The Eurofever Project  is aimed to build a common web-based registry for all Autoinflammatory diseases in collaboration with the Eurotraps Project . A web-based registry collecting demographic and clinical information on Autoinflammatory diseases is available in the member area of the PRINTO web-site.158 TRAPS pts were enrolled from November 2009 to June 2012. analyzed. The majority of pts were adults . The median age at disease onset and at disease diagnosis were 4.1 (range 0.2-63 years) and 25.9 (0-77) years, respectively. The median delay of diagnosis was 10.3 years, with a rate of delay 10 times higher in adult patients. Patients were enrolled by 18 centers in 11 countries, with 18 different countries of origin. 145 (91%) were European Caucasians, 4 Arabs, 3 black Africans, 2 Asiatics, 2 Ashkenazi Jewish, 2 had a mixed origin. 58 pts (36.7%) carried high-penetrant mutations (T50M or involving cysteine residues), 30 pts (19%) other missense mutations previously associated to TRAPS phenotype. Low-penetrant or hypomorphic variants, such as R92Q and P46L, were found in 53 and 5 pts, respectively. 12 pts carried mutations with uncertain association with TRAPS phenotype. High penetrant mutations were observed in 50/123 (40%) pts with pediatric onset and in 8/35 pts (22.9%) with an adult onset (p < 0.001). The prevalence of patients carrying low-penetrant or hypomorphyc mutations were two time higher in the adult onset (48%) compared with pediatric onset (25.2%) (p < 0.001).Mean duration of fever episodes was 10.6 days with mean number of 6.6 episodes/year. In one third of the cohort a mean duration of fever episodes was shorter than 1 week. The most frequent symptoms accompanying attacks were fever, limb pain , abdominal pain and a variety of skin rashes. The prevalence of a number of clinical manifestations significantly differ among the age of onset. Pediatric patients displayed an increased prevalence of enlarged cervical lymph nodes abdominal pain and periorbital edema in respect to patients with an adult onset. Adult onset was characterized by an higher prevalence of respiratory symptoms , serositis and polyarthritis. The most common long term complication was amyloidosis, that was observed in 16 (10%) adult patients. The mean age at onset of amyloidosis was 43 years (range 20-77). Patients who developed AA amyloidosis had significantly longer disease duration than those who have not .TRAPS has a wide geographical distribution and can be observed in different ethnicities. Short episodes (less than 1 week) are observed in 30% of patients. The presentation of the disease in adulthood significantly differs from that observed in pediatric age.None declared."}
+{"text": "Severe community-acquired pneumonia (SCAP) is an important cause of hospital mortality. The goal of this study was to identify variables associated with increased risk of in-hospital mortality at ICU admission.A prospective, multicentre, observational cohort study of all patients with SCAP consecutively admitted to 15 Portuguese ICUs during a 12-month period. Demographic characteristics, co-morbidities, general severity scores , microbiological data and initial empirical antibiotherapy were recorded. Logistic regression analysis was performed to identify predictors of in-hospital mortality.A total of 505 (14%) of the 3,572 enrolled patients had SCAP, mostly male (66%) with a median age 58 (29 to 82). Median general severity scores were: SAPS II 44 (21 to 80), SAPS3 65 (41 to 98) and total SOFA 8 (3 to 17). Comorbidities were present in 74% of the patients and the most frequent were: diabetes mellitus (22%), chronic respiratory failure (18%) and alcoholism (15%). Median Charlson's comorbidity index was 4 (0 to 13). At ICU admission, 44% of SCAP patients had septic shock. Thirty-seven per cent of the cases were microbiologically documented  virus - 20%; Enterobacteriaceae - 18%) and 12% had secondary bacteremia. Antibiotics were administered in the first 3 hours after hospital admission in 71% of the patients and 76% of them received combination therapy. Antibiotherapy was appropriate in 80% with a median duration of 8 days. Median ICU and hospital lengths of stay were 10 and 19 days respectively. Median ICU and hospital mortalities were 25% and 34% respectively. Variables independently associated with hospital mortality were: SAPS II score , severe sepsis , septic shock , inappropriate antibiotherapy  and the use of a macrolide .Disease severity evaluated by SAPS II and sepsis staging score and inappropriate initial antibiotherapy were independent risk factors for in-hospital mortality. The use of a macrolide was independently associated with a reduced risk of death."}
+{"text": "Objectives: Intravenous thrombolytic therapy has established acceptable results in treating ischemic stroke. However, there is little information on treatment outcome especially in different subtypes. The aim of current study was to evaluate early and intermediate prognosis in intravenous thrombolytic therapy for acute ischemic stroke subtypes.Methodology: Forty eligible patients  with definite ischemic stroke who were admitted to emergency department of Imam Reza University Hospital, in the first 180 minutes after occurrence received recombinant tissue plasminogen activator. All investigation findings were recorded and stroke subtypes were determined according to the Causative Classification of Stroke System. Stroke severity forms including modified Rankin Scale (mRS) and National Institutes of Health Stroke Scale (NIHSS) scores were recorded for all patients in first, seven and 90 days after stroke and disease outcome was evaluated.Results: The etiology of stroke was large artery atherosclerosis in 20%, cardio-aortic embolism in 45%, small artery occlusion in 17.5% and undetermined causes in 17.5%. NIHSS and mRS scores were significantly improved during time (P < 0.001 in both cases). Three months mortality rate was 25%. Among the etiologies, patients with small artery occlusion and then cardio-aortic embolism had lower NIHSS score at arrival (P = 0.04). Caplan-meier analysis showed that age, sex and symptom to needle time could predict disease outcome.Conclusion: Intravenous thrombolytic therapy is accompanied by good early and intermediate outcome in most patients with ischemic stroke. Small artery occlusion subtype had less disease severity and higher improvement. Results show that use of rtPA has increased for ischemic stroke treatment due to reduction in patient morbidity and hospitalization time and no need to give long-term treatment, also saving millions of dollars.10 Recombinant tissue plasminogen activator (rtPA) in the treatment of cerebral ischemic stroke has been confirmed by American Food and Drug Administration (FDA) in 1996.11-13 The aim of this study was to evaluate the prognosis of intravenous thrombolytic therapy in ischemic stroke subtypes to investigate the early (7 days) and intermediate (3 months) effect of desired drug. Studies that evaluate the prognosis of etiologic subtypes in patients receiving intravenous thrombolytic therapy are limited and these studies mainly have reported complications following drug consumption. This study was performed by a stroke team and rtPA was administrated in the treatment of acute ischemic stroke as a prospective descriptive-analytical study. The study population consisted of 40 patients who were hospitalized at Imam Reza Hospital Emergency during September 2011 to March 2012 with symptoms of suspected stroke and in 180 minutes of the onset of their clinical symptoms. This study was database of a large trial that is being conducted and named as Tabriz Thrombolytic Therapy for Acute Ischemic Stroke (T3-AIS).14 (that indications and contraindications of rtPA administration has determined) was evaluated and forms were completed. With definite diagnosis of ischemic stroke and in the absence of rtPA administration contraindications, patients were admitted to the neurology ICU, written consent was obtained from patient\u2019s relatives. Inclusion criteria was patients under the Cincinnati Pre-hospital Stroke Scale with at least one of three symbols including unilateral facial weakness, unilateral upper extremity weakness (Arm drift) and abnormal speech, and less than 180 minutes from the onset of their symptoms. Of all patients in the triage room laboratory sampling and brain CT scan were performed. With detailed history taking and physical examination contraindication of rtPA administration from the form shared guideline of American Heart Association and American Stroke Association (year 2010) Clinical Assessment Forms of stroke using National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) were completed for all patients and in the next step was attempted to administer rtPA. Patients after this emergency phase were undergoing routine investigations according to case and to determine the etiology of the disease.15 specific subtype of stroke was determined. The CCS is a questionnaire-style classification scheme for ischemic stroke. The automated algorithm reports the stroke subtype and a description of the classification rationale. It arranges the patient into 5 subgroups  and each subtype of stroke subdivided to evident, probable and possible. The undetermined group is divided into cryptogenic embolism, other cryptogenic, incomplete evaluation, and unclassified categories and NIHSS and mRS were determined for each patient on day 1, 7 and 90. All findings of medical history, physical examination, brain imaging, vascular imaging, cardiac investigations and other items were recorded. In accordance with the Causative Classification of Stroke (CCS)This study was designed as ongoing administration of thrombolytic therapy and in this regard, legal and ethical standards were considered.Statistical Analysis: Obtained data are expressed as mean \u00b1 standard deviation, frequency, percentage and SEM (if necessary). Data were analyzed by SPSS\u2122 17 software. Quantitative variables were compared by using Student T-test and one way ANOVA and multiple regressions and qualitative variables have been compared by using Chi-Square Test and Fisher\u2019s Exact Test. Quintile and Cox regression analysis was used to determine the disease prognosis predicting factors. In all investigated cases, the results have been known statistically significant in case of P \u2264 0.05. In this study 40 patients with ischemic stroke underwent rtPA treatment with mean age of 63.18\u00b113.49 (38 \u2013 88 years) with a median of 67.50 year. The patients were 23 (57.5%) male and 17 (42.5%) female. Average systolic blood pressure was 149.18\u00b131.05 mmHg and mean diastolic blood pressure was 88.08\u00b114.16 mmHg. As regards past medical or social history, 24 patients (60%) had HTN, 10 (25%) had Diabetes Mellitus, 9 (22.5%) were smokers, 5 (12.5%) had hyperlipidemia. AF was detected in 9 (22.5%), and 11 (27.5%) suffered from IHD. Embolus history was noted in 9 (22.5%) out of which 7 cases (17.5%) were ischemic strokes or TIA and in 2 cases (5%) was associated with systemic emboli. Mean NIHSS score on admission equaled 13.38\u00b14.46 with a median of 13. The highest and the lowest scores were 3 and 27 respectively. NIHSS score in 17 patients (42.5%) was more than 15 or in other words had severe stroke on admission. On admission mRS score average was 4\u00b11.25 with a median of 4. The highest and the lowest scores were 1 and 5 respectively. Using the CCS to determine etiologic subtype of stroke 8 (20%) large vessel atherosclerosis, 18 (45%) cardio-aortic embolus, 7 (17.5%) small vessel occlusion and 7 (17.5%) no known cause were involved. With the CSS subdivision, patients were placed in 9 subgroups as follows:7 (17.5%) documented large vessel atherosclerosis, 2 (5%) probable large vessel atherosclerosis, 9 (22.5%) documented cardio-aortic emboli, 2 (5%) probable cardio-aortic emboli, 7 (17.5%) possible cardio-aortic, 7 (17.5%) documented small vessel occlusion, 2 (5%) with obviously unknown factor, 3 (7.5%) with probable unknown cause, and 1 (2.5%) with possible cause. However in one instance, CSS software grouped one of the patients to probable large vessel atherosclerosis, probable cardio-aortic emboli, and unclassified unknown etiology and in another instance one case was classified both as evident cardio-aortic emboli and possibly unknown etiology; we considered them to be probable and evident respectively.  Death at the end of three months had occurred in one case (12.5%) with large vessel atherosclerosis, in 6 (33.3%) of cases with cardio-aortic emboli, in 2 cases (28.6%) with small vessel occlusion and one (14.6%) of those having no specified etiology. It was not feasible to compare data statistically because of uneven distribution.1,2 and to reduce it, administration of rtPA in patients with stroke had come into attention. The minimum benefit of increasing the use of rtPA in the treatment of patients with ischemic stroke include rapid evacuation of hospital beds, reduction of need in and equipment reducing the burden of nursing care.11 However, lack of infrastructural facilities, expensive drugs, side effects of drug prescription and low golden time from onset of symptoms until the drug administration has limited the using of this medication.11-13 Stroke leads to very high medical costs to healthcare systems1 In two other studies done by Coan et al increasing rtPA administration has been reiterated.16,17 However few studies have investigated the prognosis of patients after intravenous thrombolytic therapy according to the etiologolic subtypes.11-13,18-20 Imam Reza Teaching Hospital, a tertiary health center is annually visited by over 1000 ischemic stroke patients. Physicians and nurses are experienced in treatment, having capability for neuro imaging, consultation and brain surgery in a round the clock mode. In addition it has facilities of intensive care units, physiotherapy and nutrition consultations which has provided the infrastructure required for routine and systematic administration of rtPA by triage of ischemic stroke patients and setting up special team. Current study has investigated short and long-term prognosis of intravenous thrombolytic therapy within 3 hours in ischemic stroke subgroups of 40 patients admitted with stroke. Yip et al has concluded that even with slight increase in rtPA administration rate in Canada significant savings in Health Care System expenditures were obtained.12 We too encountered 17.5% ICH rate, four of which were symptomatic and resulted in death. In a study by Walters et al on 120 patients, 16 episodes of acute cerebral hemorrhage occurred, 5 of which were symptomatic.21 Studies have cited different figures for cerebral hemorrhage prevalence varying from 3-13%.12,13,21 This can be attributed to general health of patients studied in each group and presence or absence of diseases and underlying etiology in each etiology. Complications associated with drug especially intracerebral hemorrhage (ICH) has deterred physicians from using it.22 This study has demonstrated significant recovery in mRS and NIHSS scores following treatment. 3-month mortality was 25% and severe morbidity occurred in 10% of patients. About 65% of patients had no or least morbidity according to mRS criteria. Figueroa- Reyes et al studied outcome of ischemic stroke following rtPA in 19 patients out of which 63% suffered no or least morbidity, 26% medium and 5% severe morbidity. One case died one day after thrombolysis.21 Discrepancy in mortality observed in various studies can be due to difference in sample sizes. Generally it can be noted that in all studies most of patients take benefit out of rtPA treatment and recover with sufficient restoration of functions. Key outcomes such as disability, death and recurrence following ischemic stroke differ between subgroups.23,24 In our survey etiologies were large vessel atherosclerosis in 20%, cardio-aortic emboli in 45%, and small vessel occlusion in 17.5%. Of all etiologies, small vessel occlusion followed by cardio-aortic emboli had lowest NIHSS scores. Patients suffering from small vessel occlusion visited the hospital earlier than others. In Walters et al survey over 3 month follow up period, 31% of patients enjoyed favorable results (MRS 0-1), 22% gained average results (MRS 2-3) and 21% had poor results (MRS 4-5) with 21% mortality.25,26 Severity of neurologic deficit in the beginning of the disease has been postulated as the most important factor in prognosis. Accordingly one study showed NIHSS over 17 and age over 70 to be the best one-year prognostic factors of poor outcome.27 However in our study despite high NIHSS scores and advanced ages in patients with poor prognosis, no significant difference was observed in this respect. We saw that age, sex and time between symptoms onset and drug administration were capable of forecasting disease outcome. Similarly Dharmasaroja et al have stated that age over 70, severe stroke (NIHSS \u2265 15) and Intracranial Hemorrhage (ICH) are conversely related to early recovery.28 This study also showed that recovery within three months in patients with small vessel occlusion was higher than others. After three months death occurred in 12.5% of patients with large vessel atherosclerosis, 33.3% of patients with cardio-aortic emboli, 28.6% with small vessel occlusion and 14.3% of episodes had no known etiology. Other studies have shown small vessel involvement and lacunar infarct to have better recovery and less recurrence. Intravenous thrombolytic therapy is accompanied by favorable short and long-term results in patients with ischemic stroke. Symptoms are less severe and recovery is higher in patients with small vessel occlusion. Age, sex and time between symptoms onset and drug administration were capable of forecasting disease outcome. Considering findings of this study intravenous thrombolytic therapy can be recommended especially in milder episodes and small vessel occlusion subgroups. However due to recent administration of rtPA in our center and small sample size of our study it was not feasible to evaluate statistical difference between all subgroups. Conducting a study with larger sample size can yield better and more precise results."}
+{"text": "After more than 30 years, Ipilimumab was the first agent which showed a survival benefit for the treatment of metastatic melanoma. However, only about the 20% of patients have a long-term survival benefit. The combination of ipilimumab with other therapies might improve its efficacy.A new phenomenon also known as abscopal effect refers to a regression of metastatic lesions distant from the primary site of radiotherapy (RT). This systemic response is observed in patients who received ipilimumab.Here we reported the outcomes from patients treated in the ipilimumab Italian expanded access program (EAP) who received RT after ipilimumab progression.Patients with advanced melanoma who had received RT after ipilimumab progression were eligible for analysis. Radiotherapy was available upon physician request for patients who failed ipilimumab therapy and for whom no other therapeutic options were available.21 out of 95 patients treated with ipilimumab in the Italian EAP were eligible for the analysis. The median age was of 58 years (range 21-77); The progression free survival (PFS) from ipilimumab treatment was 4 months (range 3-6), while the time from the end of treatment with ipilimumab and RT was of 5 months (range 4-8).RT was performed on brain in 13 (62%) patients: 8 were treated with whole-brain RT and 5 patients with stereotactic RT. Other RT treatment included bone, metastatic distant lymph nodes, sub-cutaneous metastasis, spinal cord metastatis. The median doses of radiation was of 30 Gy (range 30-50). A local response to RT was detected in 13 patients (62%) while 8 patients (38%) did not show any local regression. The abscopal response has been detected in 11/21 (52%) patients: in details, we observed 9 abscopal partial response , 2 abscopal stable disease , and 10 progression . The median of occurrence of the abscopal response was of 1 month (range 1-4). The median overall survival (OS) for all the 21 patients was of 13 months (range 6-26). The median OS for patients with and without abscopal responses was respectively of 22.4 months  and 8,3 months . 11  out of 13 patients with local response showed an abscopal effect.The RT after ipilimumab treatment may be an option for further potentiate its effect. Local response to RT might be predictive for the abscopal response and outcome. Further studies are warranted in this field to better understand and define the role of RT in combination or sequencing with ipilimumab treatment."}
+{"text": "To determine the knowledge, attitudes, and practice related to influenza vaccinations of health care workers (HCWs).Between May 2008 and December 2009, a self-administered questionnaire was distributed to HCWs participating in one of the 5 two-day training courses for emerging infectious diseases in several regional health jurisdictions of Thailand.p<0.001). The overall influenza vaccination rate was 89%. The awareness of both the health benefit of this vaccine (57.2%) and their heightened risk of acquiring influenza (41.1%) were the two most common reasons for vaccine acceptance. The most common reason for vaccine refusal was the belief that, without underlying disease or co-morbidity, the vaccine was unnecessary (43.2%). Further, the fear of potentially serious adverse effects of the vaccine was also reported as a common reason for not being vaccinated (31.8%). The vaccinated group was significantly more likely to encourage their family members to receive this vaccine (74.6% ) as compared to the non-vaccinated group ( 45.6%) (p <0.001).Of 1466 participants, the response rate of questionnaire was 53.8%. The respondents were physicians (14.8%), nurses (60.2%), and other groups of healthcare professionals (25%). The vaccination rate among nurses (92.8%) was statistically significantly higher than among physicians (86.2%) and other groups (81.1%) (We identified a relatively high coverage of influenza vaccination among HCWs in Thailand. The complacency about their potential risk of influenza complication and the fear of vaccine adverse effect were the major barriers to influenza vaccination. Thus, the provision of proper education program on influenza vaccination is essential for the successful immmunization campaign for HCWs.T. Chotpitayasunondh Employee of Government."}
+{"text": "Brain trauma (BT) is the most common cause of death among children worldwide. In traumatic patient, the skull is the most common involved part. The importance of computed tomography (CT) scan in diagnosis of BT is well established. CT scan is actually a common option for evaluation of patients with cranial trauma. Considering the importance of CT scan in the diagnosis of brain lesions, the present study was aimed to survey the results of brain CT scan in traumatic patient attending the Ayatollah Taleghani Hospital  during 2011. In this descriptive and cross-sectional study brain CT scan results of 365 patients with head trauma attending the CT scan department of Taleghani Hospital (Kermanshah) during 2011 was evaluated. For data collection, pre-prepared tables containing demographic data, cerebral results, lesion and location of fractures were used. Finally the data were analyzed using descriptive statistics. The results show that of 907 patients, 557 were male and 350 female. In this study we performed CT scans on 365 traumatic patients, 326(89.31%) cases of 365 patients had normal brain CT scan and 39(10.69%) cases had positive finding including:3 cases (7.69%) of brain contusion, 5 cases (12.82%) of epidural hematoma, 4 cases (10.26%) of subdural hematoma, 3 cases(7.69%) of subarachnoid hemorrhage, 2 cases (5.13%) of intracranial hemorrhage, 2 cases (5.13%) of intraventricel hemorrhage, and finally 20 cases (51.28%) of skull fracture.Because of the high percentages of normal CT scan with no clinical indication in this study, it is necessary for clinical physicians to pay enough attention and rethink about performing a brain CT scan in a patient, particularly when they are not sure about the necessity of a performing CT scan. Furthermore, there is a need for further studies managing the current trend among physicians in which brain CT scan is going to be a routine application.Brain CT scan, Pediatric, Trauma, Computed tomography"}
+{"text": "Prescribing daily routine chest radiographs (CXRs) in ICU patients is a matter for debate. We aimed at describing current strategies of CXR prescriptions and their diagnostic and therapeutic impacts in a large panel of French ICUs.We performed a postal survey recording ICU habits of CXR prescription and a snapshot single-day  observational study analyzing all of the prescribed CXRs.n = 104 ICUs) CXR prescription was made on a daily routine basis for every patient and only in mechanically ventilated patients in 7% and 37% of the 104 ICUs, respectively. Depending on the ICUs, ICU admission (55% of the ICUs), endotracheal intubation (87%), tracheostomy (87%), superior vena cava device (96%), nasogastric tube (48%), chest tube insertion (98%) and chest tube removal (60%) were systematically followed by a CXR. A written procedure for CXR prescription was available in 12% ICUs.(P < 0.001) and this radiographic finding was unexpected in 20 and 15%, respectively (P = 0.22). On-demand CXR was more frequently associated with treatment modification (which would not have occurred without the CXR) than daily routine CXR : placement/modification/or removal of an invasive device , prescription of another paraclinical investigation , initiation/continuation/or discontinuation of medications . CXR findings were expected and had no impact on management in 56 and 77% (P < 0.001) of the on-demand and daily routine CXR, respectively.On RadioDay, 854 CXRs were performed (8.2 \u00b1 4.6 per center) in 804 patients: 36.5% were prescribed on a daily routine basis. The most frequent indications for on-demand CXR were: follow-up of pleuropulmonary pathology (32%), control after invasive device placement (20%), search for an etiology of respiratory or circulatory failure (13%) and ICU admission (11%). On-demand CXRs were mostly (62%) performed during the morning round. On-demand CXR showed more frequently a tissue abnormality than daily routine CXR (69 vs. 48%, There is an obvious lack of consensus for CXR prescription in French ICUs. The clinical impact of on-demand CXR is higher than that associated with a daily routine prescription."}
+{"text": "The treatment of aortic aneurysms in elderly patients, especially those aged around 80, has undergone a significant change with the introduction of aortic stent (EVAR). Although some studies are in progress regarding the improvement of long-term results with regard to \"open\" surgery, there is no doubt that the exclusion of the aneurysm with a stent is more acceptable in terms of the immediate patient management, morbidity and mortality. In our institution we have had a significant increase in the treatment of patients with aortic aneurysm treated with EVAR. We present data for the last two years 2009 and 2010.In our Centre, from January 2009 to November 2010, 168 aneurysms of the thoracic and abdominal aorta were treated, of which 135 were elective and 33 emergency. Of these 39 % were patients over 75 years of age. In 2009 we operated 52 patients of whom 7 (13:45%) for thoracic aortic aneurysm and 45 (86.55%) for aneurysms of the abdominal aorta. 6 thoracic aneurysms (86%) were operated on electively and 1 (14%) urgently, all with a stent implant. 40 aneurysms of the abdominal aorta (89%) were operated on electively (of these 25 (62.5%) with EVAR and 15 (37.5%) with \"open\" surgery) and 5 (11% ) in emergency . In 2010, 116 patients were treated, of which 20 (17.3%) had an aneurysm of the thoracic aorta and 96 (83.4) an aneurysm of the abdominal aorta. 14 aneurysms of the thoracic aorta (70%) were operated on electively and 6 in emergency (30%), all with EVAR. 80 aneurysms of the abdominal aorta (83.3%) were operated on electively (of these 70 (87.5%) with EVAR and 10 (12.5%) treated with \"open\" surgery) and 16 (16.6%) in urgency (two of these (12.5%) with EVAR and 14 (87.5%) treated with \"open\" surgery).The mortality rate in elective patients was 0.7% , while in emergency mortality was 18% . In one patient who underwent aortic stent there was an acute renal failure with permanent dialysis. Cardiological problems were resolved before discharge.The treatment of aneurysms of the thoracic and abdominal aorta has improved in terms of mortality and morbidity after the introduction of EVAR. In our experience, which tends to expand the use of aortic endoprosthesis, there are no substantial differences in outcome between EVAR and \"open\" surgery. Elderly patients maintain better treatment with an aortic stent graft."}
+{"text": "Critically ill cirrhotic patients awaiting liver transplantation (LT) often receive prioritization for organ allocation. Outcomes in these patients are multifactorial, and identification of patients most likely to benefit is essential. Despite the need for evidence-based allocation criteria based on patient factors and physiology scores, few data currently exist on outcomes. Scoring systems such as MELD and SOFA  are in use, but have not been evaluated in predicting outcome with LT.In a five-center Canadian study , all cirrhotics admitted to the ICU requiring organ support ) prior to undergoing LT between January 2000 and December 2009 were examined. MELD and SOFA scores were evaluated at ICU admission and the day of LT along with other donor factors.n = 166, 84%) versus dead  at 90 days, there were no statistically significant differences in MELD score on admission or day of LT (P > 0.6 for both). There were also no statistically significant differences between SOFA score on admission or day of LT (P > 0.17 for both). Patients alive at 90 days were significantly younger . Patients over 60 had significantly higher 90-day mortality  and a trend towards increased 1-year mortality . There were no significant differences in donor characteristics  comparing patients alive at 90 days to nonsurvivors.A total of 198 cirrhotics  were reviewed. The most common etiologies were hepatitis C (31%) and alcohol (15%). LT occurred a median time of 29 (5 to 101) days from listing and 5 (3 to 10) days from ICU admission. In total, 88% of patients required vasopressors, 56% received RRT prior and 87% were ventilated prior to LT. The median MELD score was 34 (26 to 39) on ICU admission and 34 (27 to 40) on the day of LT respectively. SOFA scores were 12 (10 to 15) and 13 (10 to 17) on ICU admission and on the day of LT respectively. Comparing patients who were alive  undergoing liver transplantation have significantly worse post-LT outcomes. MELD and SOFA scores do not appear to predict outcome post LT in this cohort."}
+{"text": "We report a retrospective analysis of the demographic and clinical profiles of patients in order to assess the results of operative repair for total anomalous pulmonary venous connection (TAPVC) and the long term follow up.In the period between January 1998 and April 2013, 84 patients (48 boys) underwent repair for total anomalous pulmonary venous connection. Their ages ranged from 2 weeks to 1.6 years (mean 4 months). The patients\u2019 weight ranged from 3 to 8 kg (mean 5 kg). About 71% of patients (n=60) were less than the 50th percentile of predicted weight for age and sex. The anomalous connection was supracardiac in 69 (82%), cardiac in 9 (11%), infracardiac in 3(3.6%) and mixed in 3(3.6%) patient. Eighteen (21%) patients had obstructed drainage and 27 patients (32%) had moderate or severe pulmonary arterial hypertension. Fifteen patients (18%) had to be operated upon on an emergency basis. For supracardiac and infracardiac connections, transcardiac approach was used for anastomosis. In cardiac type, coronary sinus was unroofed and the resultant defect along with atrial septal defect was closed with a single patch.All the patients were operated upon using moderately hypothermic cardiopulmonary bypass except 4 patients (circulatory arrest was used). There were 4 (4.7%) in-hospital deaths. Three patients died of pulmonary arterial hypertensive crisis and one developed severe chest infection (died 3 weeks post-operatively with no pulmonary venous obstruction). Follow-up ranged from 6 to 181 months (mean 73 months). There were no late deaths, but 5 patients developed venous obstruction and required balloon dilatation.Mortality continues to be relatively high in infants with total anomalous pulmonary venous connection. Severe pulmonary arterial hypertension appears to be the most important predictor of operative mortality. Severe malnutrition, delayed diagnosis and late referrals possibly contribute to the high mortality."}
+{"text": "In resource-limited settings, such as Kenya, access to CD4 testing is limited. Therefore, evaluation of less expensive laboratory diagnostics is urgently needed to diagnose immuno-suppression in children.To evaluate utility of total lymphocyte count (TLC) as surrogate marker for CD4 count in HIV-infected children.This was a hospital based retrospective study conducted in three HIV clinics in Kisumu and Nairobi in Kenya. TLC, CD4 count and CD4 percent data were abstracted from hospital records of 487 antiretroviral-na\u00efve HIV-infected children aged 1 month - 12 years.3), age 12-35 months (CD4 count < 750 cells/mm3), age 36-59 months . WHO recommended TLC threshold values for severe immuno-suppression of 4000, 3000, 2500 and 2000 cells/mm3 for age categories <12, 12-35, 36-59 and >59 months had low sensitivity of 25%, 23%, 33% and 62% respectively in predicting severe immuno-suppression using CD4 count as gold standard. Raising TLC thresholds to 7000, 6000, 4500 and 3000 cells/mm3 for each of the stated age categories increased sensitivity to 71%, 64%, 56% and 86%, with positive predictive values of 85%, 61%, 37%, 68% respectively but reduced specificity to 73%, 62%, 54% and 68% with negative predictive values of 54%, 65%, 71% and 87% respectively.TLC and CD4 count were positively correlated  with highest correlation seen in children with severe immuno-suppression  and children >59 months of age . Children were considered to have severe immuno-suppression if they met the following WHO set CD4 count thresholds: age below 12 months (CD4 counts < 1500 cells/mmTLC is positively correlated with absolute CD4 count in children but current WHO age-specific thresholds had low sensitivity to identify severely immunosuppressed Kenyan children. Sensitivity and therefore utility of TLC to identify immuno-suppressed children may be improved by raising the TLC cut off levels across the various age categories. The cost of performing a CD4 count in Kenya is estimated at US$12 which is at least 4 times higher than that of a total lymphocyte count. In 2006 the World Health Organization (WHO) recommended the use of total lymphocyte count (TLC) as a guide for initiating ART in children with WHO clinical stage 2 who are aged 8 years and below in settings where CD4 counts are not available [There are an estimated 200,000 HIV-1 infected children in Kenya the majority of whom acquired the infection perinatally -6. Recenvailable . In adulvailable -18.3 for predicting CD4 counts below 200 cells/mm3 in adult studies has been however found to vary widely from 38% to 75% while the positive predictive value has ranged between 64% to 88%[3 or CD4 percent <20% to be associated with high mortality [The sensitivity of the recommended TLC levels of <1200 cells/mm4% to 88%-19. A seortality .As part of the Kenya's efforts to meet the recently published PEPAR II goals, an estimated 100,000 children need to be newly initiated on HAART before 2013 . In ordeThis was a retrospective hospital based cross-sectional survey, carried out at three hospitals in Kenya; Kenyatta National Referral Hospital (KNH) in Nairobi, Mbagathi District Hospital (MDH) in Nairobi, and New Nyanza Provincial General Hospital (NNPGH) in Kisumu, western Kenya. All HIV infected children aged between one month and twelve years on follow-up in the comprehensive HIV care clinics (CCC) at the three hospitals who had medical records on CD4 count and total lymphocyte at enrollment into care prior to initiation of ART were eligible for inclusion in the study.The medical records of children receiving care between January 2004 and July 2006 were reviewed. \"Evidence of HIV status was sought, specifically, by documentation of a positive HIV antibody test for children above 18 months, or positive HIV PCR test result for children below 18 months. For eligible children, data on age, sex, WHO clinical stage, absolute CD4 count and TLC data prior to ART initiation was abstracted from medical records. Any child missing any of these data was excluded. Children were consecutively enrolled from each site until the desired sample size was achieved. We excluded children under the age of one month due to uncertainty of HIV diagnosis in this group.Approval to conduct the study was sought from the Ethical Review Committee of KNH which is the teaching hospital of the University of Nairobi, as well as from the administration of the Mbagathi and New Nyanza Hospitals. Confidentiality was maintained for all abstracted patient records which were identified only by number stored in a secure computer.3, 12-35 months CD4 < versus \u2265 750 cells/mm3, 36-59 months CD4 < versus \u2265 350 cells/mm3 and >59 months CD4 < versus \u2265 200 cells/mm3. Similarly severe immune-suppression by CD4 percentage was defined as CD4% <25%, <20%, <15% and <15% for ages <12 months, 12-35, 36-59, and >59 months respectively [Data was analyzed using STATA version 9.2. Correlation between all pairs of TLC, CD4 cell count, and TLC and CD4%  were determined using Spearman's correlation coefficient. Children were then categorized into four age groups <12, 12-35, 36-59 and >59 months. We also categorized children by presence or absence of severe immuno-suppression based on WHO 2006 age specific immunologic categorizations as follows: age <12 months CD4 < versus \u2265 1500 cells/mmectively .3, 3000 cells/mm3, 2500 and 2000 cells/mm3 respectively [TLC was categorized using WHO age-specific TLC thresholds defining presence or absence of immuno-suppression stratified by the same age categories as follows: < versus \u2265 4000 cells/mmectively . The senWe identified 487 ART naive HIV infected children who had complete records, including 125 children from NNPGH, 186 from MDH and 176 from KNH. Two hundred and twenty three (46%) were female and the median age was 36 months , median CD4 percentage 11.6% (IQR 5.7-19), and median TLC (TLC) was 4500 cells/mm3 (IQR 2700-6655). The median CD4 count decreased with rising age, and was 1060, 777, 565 and 226 cells/mm3 in children of age <12, 12-35, 36-59 and >59 months respectively. The corresponding median CD4% for children in the four age categories in ascending order was 17.5%, 12.3%, 11.9%, and 7.4%. The median TLC was 6895, 6000, 4513 and 2577 cells/mm3 among children of the four age groups (Table Prior to starting ART 95 20%) children had WHO clinical stage 1 or 2 disease, while 392 (80%) had stage 3 or 4 disease (Table 0% childrCorrelation between absolute CD4 counts and the TLC for the whole study population was 0.66 (Spearman correlation coefficient). In the individual sites correlation was as follows: KNH (0.76), MDH (0.55), and NNPGH (0.54). Correlation between CD4 counts and TLC was then explored among different age groups, and stratified by presence or absence of severe immuno-suppression. Correlation among children <12 months was 0.54, for 12-35 months it was 0.44, for 36-59 months, 0.38, and for >59 months correlation was 0.68. The strongest correlation was seen in the oldest group of children (>59 months). Correlation between CD4 count and TLC among children who were severely immunosuppressed was 0.72 which was higher than their counterparts without severe immuno-suppression correlation 0.63. Overall correlation between TLC and CD4% was weak (r = 0.06).To test the utility of TLC as a surrogate marker for CD4 count, sensitivity, specificity, PPV and NPV of TLC was determined using WHO 2006 recommended cut off values for absolute CD4 count as the gold standard. Table 3 to 7000 cells/mm3 improved the sensitivity from 25% to 71%, but decreased specificity from 100% to 73% , meaning that new threshold would identify 7 of 10 immuno-suppressed children needing ART compared to 2 of 10 identified by the previous threshold of 4000 cells/mm3. Given that HIV is uniformly fatal in the absence of interventions, improved sensitivities for the raised TLC threshold favors the use of TLC as a screening tool for severe immuno-suppression in settings where CD4 monitoring is not easily accessible.In order to improve the utility of TLC we explored raising the cut-off values to levels higher than those recommended by the WHO 2006 guidelines. We used the point of maximal sensitivity with least compromise in specificity as the new optimal TLC cutoff point. We thus selected increased TLC thresholds that would give optimized combination of good sensitivity, with acceptable specificity and PPV. This resulted in improved mean sensitivity of the TLC from 36% to 71% for detection of severe immuno-suppression in our population, while retaining acceptable specificity (mean 68%) and PPV (mean 63%). Examining the effect of raising TLC threshold more closely, in the age category <12 months, the proposed raised TLC threshold of 7000 cells/mmOn the other hand, further increasing TLC thresholds beyond the optimized levels we selected based on our cohort data would grossly decrease specificity and PPV for relatively little incremental gain in sensitivity. This would result in unacceptably high numbers of children who are actually not severely immune-depleted being misclassified and started on ART earlier than they require, exposing them unnecessarily to the problems associated with ART including adverse drug effects, development of antiretroviral drug resistance well as increasing the cost of running programs purchase of expensive medications.3 to best predict CD4 < 200 cells/mm3  which was superior to a cut-off value of 1200 [3  [Considering that the clinical staging of disease is also employed together with the immunological criteria in order to initiate HAART, in this study we recommend raising the TLC cut-offs from the current WHO recommended TLC cut-off values. Raising TLC cut off values to improve sensitivity and enable TLC to be used as a better screening tool has been previously proposed by adult studies in Uganda and Kenya ,18. A Ug of 1200 . In KenyNPV 80%) . The higNPV 80%) .Mahajan et al explored the utility of changes in TLC as a surrogate for changes in CD4 counts following HAART initiation among HIV-infected adults in India . The maiThe poor correlation between TLC and CD4% in children in our study is of concern given that CD4% is widely used in children to predict disease progression and is included in WHO guidelines for initiating HAART. MoreoveAn important group of HIV-infected children are those co-infected with tuberculosis as well as other conditions associated with leukocyte changes independent of HIV. Although no pediatric literature was found on this subject, among adults, Martin et al found strong correlation (R = 0.7) between TLC and CD4 count both at baseline and after 1 month of TB treatment in HIV-TB co-infected South African adults . In thisnd line ART in the CDM with potential higher resistance. Thus whereas findings of the DART trial highlight the importance of CD4 testing in patients it remains crucial to similarly evaluate the role of TLC as surrogate for CD4 in HAART-treated children.In a broad context of expanding HIV treatment in settings with limited laboratory recourses, the DART trial, a randomized non-inferiority trial comparing clinically driven monitoring (CDM) verses laboratory and clinical monitoring (LCM) found clinically 5 year survival rates of 87% verses 90% in CDM and LCM arms respectively . While 1We conclude that in these Kenyan children TLC was positively correlated with absolute CD4 count, but current WHO age-specific TLC thresholds had low sensitivity to identify those who were severely immuno-suppressed. Raising the TLC cut-off for all age groups considerably improved the sensitivity of TLC, retaining acceptable specificity and PPV, suggesting that at higher thresholds TLC has good utility as a tool to identify severely immune-depleted children requiring ART in settings where CD4 testing is not readily available. Limitations of our study include the modest sample size and fact that we only obtained single measurements of TLC and CD4. Our findings suggest that rather than shelve the use of TLC due to concerns of diagnostic utility, further research is needed to define optimum cut off values and should preferably be longitudinal with a much larger sample size. Considering the significantly higher cost of performing a CD4 count relative to TLC, and the limited availability of FACSCOUNT machines in Kenya, efforts that will lead to adoption of TLC will remove a major barrier to HAART initiation for HIV infected children, avert numerous deaths and help the country meet the targets of PEPfAR II.The authors declare that they have no competing interests.NG participated in the design, data collection, and drafting of the manuscript. EMO conceived the study, and participated in its design and drafting of the manuscript. MN performed the statistical analysis. DW participated in statistical analysis and manuscript review. DMN participated in the drafting of the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2334/11/259/prepub"}
+{"text": "Nosocomial Infection(NI) affect hundreds of millions of patients worldwide every year that lead to more serious illness, prolong hospital stays, and induce long-term disability. In 2007, a national surveillance system was established in Iran for NI based on National Nosocomial Infection Surveillance (NNIS) system definition.This is the latest report of nosocomial infection surveillance during 2012 in Iran.In this cross sectional study four main group of NI including urinary tract(UTI), pulmonary(PNEU), surgical site(SSI) and blood stream(BSI) and other infections was investigated in 400 hospitals in 2012. Data was gathered through surveillance system that reported to center for communicable disease and analyzed in Iranian Nosocomial Infection Surveillance(INIS) software.Ecoli(16%), Acinetobacter (14%), Pseudomonas auroginosa(12%), Klebsiella(11%), Staphylococcus aureus(8%), Entrobacter(7%) and Candida(6%) were most prevalent causative agents in NI cases.During the study, a total of 47380 cases have been registered. The NI rate was 0.89%. The incidence of UTI was 26.5%, PNEU 24.4%, SSI 15.5%, and BSI 15.5% respectively. The mortality rate was 13.7%. The highest incidence rate was reported in burn ward (11.8%), followed by transplantation(9.1%), ICU(7.8%), NICU(3.5%) and PICU(2.6%). 14.5% of infections were under15 years old. The most invasive measures that have been taken for cases were as follows : venous catheter (23%) , urinary catheter (18%) , suction (22%), tracheal tube(22%), ventilator(22%) and surgery(22%). 71.3% of diagnosis were laboratory based. The results show that it is feasible to collect data from a large number of hospitals that assist for interventions and resource allocation, but because of data under- reporting, it is necessary to encourage and change attitude of authorities and health worker by increasing commitment and holding more justification and educational sessions.None declared"}
+{"text": "Ministry of Health in Peru launched an HIV treatment program with the initial support of the Global Fund in 2004. A few months later, our institution, an NGO working in HIV prevention, entered the treatment program in order to contribute to the national efforts to improve access to HIV care. There are no other available reports on long-term results of HAART in our country.Retrospective medical records review of 149 consecutive patients that initiated HIV treatment through the national program at our outpatient Clinic between February and July 2005. Main clinical and laboratory outcomes were recorded and reported.After an observation period of five years, 127 (85.2%) persons continue their care at our Clinic. Mean baseline age was 34.6 yrs. The group included 34 women (22.8%). Eight patients died (5.3%), 7 (4.7%) patients were referred to other centers at their request, and 7 (4.7%) were lost to follow up. Eighty-five patients (57.0%) were treatment naive at the moment of joining our treatment program. One hundred sixteen patients show current virological success (HIV VL<400 c/ml), with an ITT success rate of 77.8%, and an \"on treatment\" success rate of 89.7%. Ninety-five persons have shown sustained virological success over the 5 years (89 on NNRTI-based regimens). Mean baseline CD4 cell count at the moment of treatment initiation was 86/\u00b5L. Mean CD4 cell count at five years follow up is 254/\u00b5L. Forty-five patients have required change of a drug due to an adverse event . Causes of mortality were opportunistic infections related to IRIS or previously active  and 2 cases of NHL. All deaths occurred within then initial year of treatment. Significant morbidities such as cancer or TB after the first year of treatment occurred in 8 patients (5.3%). No cardiovascular event has been observed in this cohort so far.Outcomes observed at 5 years of HAART are comparable to the ones observed in other treatment programs developed in limited resource settings. The model of care supported by our NGO is highly successful with no additional support from public funding other than medications and monitoring laboratories."}
+{"text": "Background. Transpancreatic precut sphincterotomy (TPS) is an option for difficult common bile duct (CBD) access, and the reports are few, with immediate success rate varying from 60 to 96%. The description of relation between the size of TPS and the immediate success rate of CBD cannulation was not found in the literature. The Aim of the Study. To evaluate the relation of large TPS to immediate success rate of CBD cannulation. Methods. A retrospective analysis was performed in prospectively collected data of 20 patients. TPS was performed with traction papillotome in the main pancreatic duct (MPD) directing towards 11 o'clock. Needle knife (NK) was used to enlarge TPS in five patients, and the other 15 cases had large TPS from the beginning of sphincterotomy. Prophylactic pancreatic stent was inserted in 18 cases, with diclofenac given in 12 cases. Results. The immediate success rate of CBD cannulation was 90% and with an eventual success rate of 100%. The failure in one immediate CBD cannulation with large TPS was due to atypical location of CBD orifice, and the other failed immediate CBD cannulation was due to inadequate size of TPS. Complications included 3 cases of post-TPS bleeding and 3 cases of mild pancreatitis. Conclusion. TPS is an effective procedure in patients with difficult biliary access and can have high immediate success rate with large TPS. The initial success rate of selective CBD cannulation was reported to be 70% after a standard cannulation using guide wire and papillotome with the criteria of 5 attempts of cannulation . Using dBetween January 2012 and October 2013, a retrospective analysis of prospectively collected data of 20 cases of TPS with inaccessible bile duct was conducted. There were 13 male and 7 female patients with a mean age of 54 \u00b1 16 (25\u201382) years. The procedure was performed by a single operator who has experience on ERCP and endoscopic sphincterotomy (EST) for more than 1000 cases. A total of 112 cases of endoscopic retrograde cholangiopancreatography (ERCP) were performed during that period when TPS was started as a precut technique. The inclusion criteria were (1) failed selective deep CBD cannulation after 20 minutes and (2) successful access in the MPD. The exclusion criteria were (1) post-Billroth II gastrectomy cases and (2) failed access to the MPD. After access to the MPD, TPS was performed with the traction sphincterotome directing towards 11 o'clock, and CBD orifice is usually located left to the pancreatic duct after TPS Figures  to get bThe instruments and current setting used were (1) duodenoscope , (2) sphincterotome (Olympus KD-431Q-0720), (3) Boston Scientific Microvasive Jag wire, (4) Wilson Cook Zimmon pancreatic stent 5Fr-4\u2009cm, (5) Wilson Cook Huibregtse HPC-3 needle knife, (6) electrosurgical generator (Olympus PSD 60), and (7) current setting (Endocut setting output of 120Watts and effect 2).The definitions were as follows: (1) inaccessible bile duct was defined as failure after 20 minutes of CBD cannulation , 8, (2) The results were shown in One massive delayed bleeding required surgery with uneventful recovery after failed endoscopic hemostasis and transarterial embolization. This severe bleeding case had undergone large TPS incision. One mild immediate bleeding was treated with endoscopic local epinephrine injection and clipping. The other mild repeated bleeding was managed endoscopically as well. Three cases of mild pancreatitis recovered within 2 days, though they had received prophylactic pancreatic stenting, and 2 cases had diclofenac given rectally. There was no perforation complication.Techniques for difficult deep CBD cannulation include guide wire technique, DGW technique, and precut access. The success rate of CBD cannulation is not high in DGW technique ranging from 47 to 73% but the pancreatitis rate can be as high as 38% , 2. Our TPS was first described by Goff et al. , and verThe immediate success rate of TPS varies from 60 to 96% , 5. No sThe incidence of post-TPS bleeding varies from 3.7 to 5% , our posThe incidence of pancreatitis without prophylactic stenting after TPS ranged from 5.5 to 21% , 7, 13 aThe advantages of large TPS are (1) definite complete unroofing of the papilla that makes CBD cannulation easier enabling a higher immediate success rate of biliary access and (2) probably low incidence of perforation which has been reported in two studies , 18. TheTPS is an effective procedure in patients with difficult biliary access and can have high immediate success rate with large sized TPS."}
+{"text": "Despite the advances in treatment, tuberculosis (TB) remains a global health threat and is the leading co-infection among Brazilian HIV-infected patients. Mortality of TB in the presence of sepsis and shock septic is still high, with respiratory failure being the leading cause of ICU admission. Clinical factors enhancing mortality among HIV-TB patients are yet to be explored.We retrospectively accessed data of HIV/AIDS critically ill patients from January 2007 until May 2012, at a referral infectious diseases hospital. All patients admitted to the ICU with laboratory-confirmed tuberculosis were included in the analysis. Demographic and clinical data were categorized for survivors and nonsurvivors and the results were displayed as frequency (%), median values and interquartile range.P = 0.25), and SAPS II score was 44.5 (37 to 56) versus 47 (39 to 54) (P = 0.58). The most common TB presentation was disseminated disease (56%) followed by pulmonary (44%), with no difference according to survival. The interval of days between ICU admission and TB treatment was not different between groups. Rifampicin (94%), pyrazynamide (94%), isoniazide (92%) and ethambutol (76%) were administered in the majority of patients, while fluoroquinolones and aminoglycosides were administered in 64% and 54% respectively. Nonsurvivors presented with more elapsed time since HIV diagnosis (1 (1 to 7) vs. 26 (5 to 72), P = 0.10); lower nadir CD4 cell count (72.5 (27.5 to 133.5) vs. 24 (14.5 to 63), P = 0.03); and HAART initiated within 30 days after admission ). The main reason for ICU admission was respiratory failure (70%). Nonsurvivors needed mechanical ventilation  and vasopressors  more frequently. Neurological dysfunction was more common in nonsurvivors ). After multivariate analysis, neurological dysfunction was associated with hospital mortality, while HAART in the first 30 days of hospitalization was a protective associated factor.Fifty patients were included. Hospital mortality was 48%. Age was 31.5 years (26.5 to 43) in the survivors group versus 33.5 years (30 to 45) in nonsurvivors (Disseminated TB was the most common presentation in HIV/AIDS critically ill patients. Nonsurvivors were more prone to multiple organ dysfunction syndrome, and neurological dysfunction was associated with hospital mortality. The administration of HAART within 30 days of hospitalization was associated with survival."}
+{"text": "Asthma is a serious public health problem throughout the world. The prevalence of asthma has increased in last two to three decades possibly due to change in indoor and outdoor environment. Allergens are one of the many factors which trigger an attack of asthma. Skin prick test is useful in identifying the offending allergen in bronchial asthma.The study was conducted at allergy center, Kempegowda Institute of Medical Sciences (KIMS) Hospital & Research center, Bangalore from January 2011 \u2013 December 2011. Skin Prick Test was done in 139 patients suffering from bronchial asthma diagnosed based on GINA guidelines. Skin Prick Test was performed using 49 allergens extracts after taking informed consent from the patients. Allergen extracts included 19 pollens, 10 fungi, 5 dusts, 2 dust mites (Dermatophagoides farinae and Dermatophagoides pteronyssinus), 10 insects and 3 epithelia.Out of 139 patients who underwent skin prick test, 40% (56) were males and 60% (83) were females. Majority i e 60% were in the age group of 21 -40 years. 43% (60) had family history of asthma/atopy. 80 % (111) had allergic rhinitis, 24% (34) had chronic urticaria and 24% (33) had allergic conjunctivitis. Out of 139 patients 100 (71.94%) were sensitive for one or more allergens. The common offending allergens found in the study were dust mites (DF and DP) - 49.28%, dusts - 7.2%, pollens - 6.77%, insects - 6.62%, fungi - 4.53%, epithelia - 1.92%.Comparison of asthmatics between those with positive skin prick test and negative skin prick test was done. Those with positive skin prick test had age of onset < 20 years and family history of asthma compared to negative skin prick test patients and found statistically significant (p<0.05).The most common allergens in bronchial asthma were dust mites followed by dusts and pollens. Identifying possible allergens in asthma patients help in allergen avoidance and immunotherapy in these patients."}
+{"text": "Patients (pts) were selected from the Dat'AIDS French prospective cohort if they were prescribed an ABC/3TC containing regimen for the first time between 01/01/2004 and 31/12/2007 and were still actively followed on 31/05/2008 as to ensure sufficient follow-up. All causes of treatment discontinuation were recorded, as well as immuno-virological data and cardiovascular events (CE) during follow-up.Among the 1704 pts included in the study  407 (24%) were antiretroviral (ARV) na\u00efve, 696 (41%) were virologically controlled on ARV treatment (switch), and 601 (35%) were on treatment with detectable VL (failure) at time of ABC/3TC initiation. Previous treatment with 3TC was noted in 92% of the pretreated pts. With a median duration of follow-up of 496 days, the population represents 2636 pts-year.Overall 565pts (33%) discontinued ABC/3TC combination during follow-up . Reasons for discontinuation were poor tolerance in 41% of the cases, including suspected hypersensitivity (HSR) in 4% of the overall population, treatment failure in 20%, and other causes in 39%. This distribution was not different if pts received either a NNRTI (20% of the pts) or a boosted protease inhibitor (46%) in their regimen. Median time to discontinuation was 4.3 years overall and less than one month in case of suspected HSR. Discontinuation for bad tolerance was observed in 38%, 54%, and 35% of the na\u00efve, switch and failure populations respectively, whereas treatment failure was responsible for discontinuation in 15%, 10%, and 29% of the same populations. Major CE were reported in 21 cases (0.08% py). Death was recorded in 27 cases, 9 deaths being AIDS related, 6 related to liver diseases, 6 to cancer, 2 to vascular accidents , 1 accidental, and 3 unknown. At M24, probability of still receiving ABC/3TC was 62%, 77%, and 60% respectively for the defined groups, and VL on treatment was below detection for 86%, 90%, and 71% of them, respectively.In this population of pts who received ABC/3TC containing regimens before HLA screening was routinely available, treatment was maintained with virological success for more than 2 years. Poor tolerance was the main reason for early discontinuation, and was not different if the pts received either NNRTI or boosted PI in their regimen. CE were rare."}
+{"text": "We sought to derive and validate a parsimonious predictive rule incorporating clinical and stress CMR data to characterize major adverse cardiac events (MACE) in patients with suspected ischemia.Training, n=356) and a testing set . Forty-six (6.5%) patients experienced MACE: 24 (7%) in the SETTraining and 22 (6%) in the SETTesting. A parsimonious prediction rule was built by stepwise regression in the SETTraining, considering all clinical, ECG, and CMR parameters using P<0.05 for both entry and stay. History of PCI, wall motion abnormality at rest, non-sinus rhythm, and CMR myocardial ischemia score (ISCH-SCORE) formed the prediction rule (Table-Testing divided into 3 progressive categories based on their ascending predicted probabilities of MACE (low: 1.5 to 10% and high:>10%). The utility of the model was first determined by comparing the predicted and observed numbers of MACE in each risk category in the SETTesting  were excluded due to images of insufficient quality. The remaining 711 patients  were followed for cardiac events (MACE) that occurred within the first 3 years after CMR . We randomized patients in this clinical cohort 1:1 into a training set  and mean AUC of the prediction rule was 82.4% (95%CI: 70%-93%) reinforcing its validity and utility (table-We derived and validated a prediction rule for MACE using clinical and ISCH-SCORE for patients with suspected myocardial ischemia. ISCH-SCORE provided strong and major prognostic utility in this prediction rule."}
+{"text": "Infections caused by human rhinoviruses (HRVs) are important triggers of wheezing in young children. Wheezy illness has increasingly been recognised as an important cause of morbidity in African children, but there is little information on the contribution of HRV to this. The aim of this study was to determine the role of HRV as a cause of acute wheezing in South African children.Two hundred and twenty children presenting consecutively at a tertiary children's hospital with a wheezing illness from May 2004 to November 2005 were prospectively enrolled. A nasal swab was taken and reverse transcription PCR used to screen the samples for HRV. The presence of human metapneumovirus, human bocavirus and human coronavirus-NL63 was assessed in all samples using PCR-based assays. A general shell vial culture using a pool of monoclonal antibodies was used to detect other common respiratory viruses on 26% of samples. Phylogenetic analysis to determine circulating HRV species was performed on a portion of HRV-positive samples. Categorical characteristics were analysed using Fisher's Exact test.HRV was detected in 128 (58.2%) of children, most (72%) of whom were under 2 years of age. Presenting symptoms between the HRV-positive and negative groups were similar. Most illness was managed with ambulatory therapy, but 45 (35%) were hospitalized for treatment and 3 (2%) were admitted to intensive care. There were no in-hospital deaths. All 3 species of HRV were detected with HRV-C being the most common (52%) followed by HRV-A (37%) and HRV-B (11%). Infection with other respiratory viruses occurred in 20/128 (16%) of HRV-positive children and in 26/92 (28%) of HRV-negative samples.HRV may be the commonest viral infection in young South African children with acute wheezing. Infection is associated with mild or moderate clinical disease. Wheezing is a frequent manifestation of lower respiratory tract infection (LRTI) in infants and young children. Viral infections are the commonest cause of acute wheezing. Several respiratory viruses, including respiratory syncytial virus (RSV), influenza viruses, parainfluenza viruses, enteroviruses, human coronaviruses, human metapneumovirus and human bocavirus have been associated with wheezy illness -5.With the improvement of molecular techniques the frequency of HRV detection in clinical samples has increased dramatically -8 providEnterovirus [Since the first isolation of HRV in 1953  approximerovirus ,16,19-23erovirus .The importance of HRV as a cause of acute wheezing illness in infants and young children has not been studied in African children. The aim of this study was to investigate the prevalence of HRV in African children with acute wheezing.A prospective study of children aged 2 months to 5 years presenting with acute wheezing to Red Cross War Memorial Children's Hospital (RCCH) from May 2004 to November 2005 (2 winter seasons) was undertaken. RCCH is a public paediatric tertiary hospital in Cape Town, South Africa that provides care to children mostly from poor socio-economic backgrounds. Children were eligible if they had a history of cough or difficulty breathing within the prior 5 days and expiratory wheezing on auscultation or hyperinflation of the chest. Exclusion criteria were known underlying cardiac or chronic pulmonary disease (other than asthma), presence of stridor or daily treatment with oral corticosteroids for more than 2 days prior. Eligible children were sequentially enrolled from Monday to Friday during working hours. Clinical and sociodemographic information were recorded. Written, informed consent was obtained from a parent or guardian. The study was approved by the Human Research Ethics Committee of the Faculty of Health Sciences, University of Cape Town, South Africa.A nasal swab was obtained using a dry sterile cotton swab inserted sequentially into each nostril to a depth of 2-3 cm and slowly withdrawn in a rotating motion as recommended by the WHO guidelines on the collection of human specimens . The tip2, 200 \u03bcmol/L each dNTP  and 0.2 \u03bcmol/L P1-1 and P3-1 primers [RNA was extracted from 200 \u03bcl of the respiratory sample using the Talent Seek Viral RNA kit  according to the manufacturer's instructions. The purified RNA sample was converted into cDNA using random primers  and the iScript cDNA synthesis kit . Samples were screened for HRV using PCR primers targeting the 5' untranslated region (5'UTR) which had previously been shown to amplify all known serotypes and HRV-C species . In the  primers . Amplifi primers . Cycling primers . All worth sample (n = 58) by an indirect immunofluorescence assay . Further specific virus identification on pool-positive samples was not undertaken. All samples were screened for human metapneumovirus (hMPV), human coronavirus-NL63 (HCoV-NL63) and human bocavirus (HBoV) by RT-PCR and PCR as previously described [A general shell vial culture using a pool of monoclonal antibodies detecting respiratory syncytial virus (RSV), influenza A and B viruses, adenovirus and parainfluenza viruses 1, 2 and 3 was performed on every 4escribed .HM623207-HM623277.The HRV 5'UTR and VP4/VP2 PCR products were purified with a QIAquick PCR purification kit  and sequenced on an ABI 310 sequencer with a fluorescent dye terminator kit . The nucleotide sequences were aligned with known HRV sequences from GenBank, including HRV Ca and Cc reference strains , using CContinuous variables were expressed as median and inter quartile ranges and compared using Kruskal-Wallis Test. Categorical characteristics were analysed using Fisher's Exact test. A p-value of < 0.05 was considered statistically significant.th-75th percentile) age 12.2 (6.2-27.5) months, were enrolled and had a nasal swab taken. More than half, 114 (51.8%), were under 12 months, while 163 (74.1%) were less than 24 months of age, Table Two hundred and twenty children, median  and another in February-April 2005 (autumn) Figure .Co-infection with hMPV, HBoV and HCoV-NL63 was found in 8 (6.3%), 6 (4.7%) and 1 (0.8%) of the 128 HRV-positive samples respectively. Of the 92 HRV-negative samples 5 (5.4%) were hMPV positive, 10 (10.9%) HBoV positive and 3 (3.3%) HCoV positive. Of the 58 samples screened for the common respiratory viruses by general shell vial culture 14 (24.1%) were positive; 4 (6.9%) HRV-positive and 10 (17.2%) HRV-negative.Sequencing of the 5' UTR was performed on 71/128 (55.5%) positive samples using convenience sampling ensuring each month of the study period was included, but without prior knowledge of patient data. Figure Presenting symptoms or signs in HRV-infected and uninfected children were similar, except for fever which was less common in HRV-infected group of children and vomiting which was more common Table . Most chHRV was the commonest viral infection in young African children presenting to a tertiary children's hospital in South Africa with acute wheezing. HRV has previously been reported in older children with wheezing or asthma exacerbations ,29. HoweHRV has also been associated with recurrent wheezing and with the development of asthma in older children -35. HRV-Consistent with other studies, HRV was identified throughout the year with peaks of activity in the spring of 2004 and 2005 and autumn of 2005 ,10,35. IPhylogenetic analysis of the 5'UTR of HRV-positive samples showed the circulation of all 3 species in Cape Town, South Africa. In this study, and as reported by Huang et al. , HRV-C wThe study has some limitations. A control group of asymptomatic or clinically well children from the same time period were not included. However, previous studies have reported that HRV is more frequently found in sick children than in asymptomatic children ,11. HRV HRV may be the commonest virus in young African children with acute wheezing. Infection is associated with mild or moderate clinical disease. Longitudinal studies with frequent samplings and HRV type identification are needed to investigate the role of HRV in wheezing illness in African children and their long term outcome.The authors declare that they have no competing interests.HS conceived the study, carried out experimental studies, analyzed the sequence data and drafted manuscript. LW performed data management and statistical analyses. HZ conceived the study, obtained funding, supervised the clinical study and participated in manuscript preparation. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2334/11/65/prepub"}
+{"text": "To survey genitourinary (GU) organ injury following general trauma, we performed an epidemiologic study of urogenital injuries in trauma patients referred to our hospital .We aimed to assess the epidemiology of urogenital system injuries in southeastern Iran.From April 2009 to November 2011, all patients with GU injuries referred to our hospital were studied. The data including age, sex, type of injury, mechanism of trauma, and prognosis of patients was collected and analyzed.From a total of 3450 patients, 66 (1.91%) had injuries of the urogenital system; 49(74.24%) were male and 17(25.75%) female. The patients\u2019 mean age was 23 \u00b1 12 years (range 2 to 75 years). Of these 66 patients, 61 (94.24%) had blunt trauma, and 5 (7.57%) had penetrating trauma. Motor vehicle accidents were the most common cause of trauma (63.63%). The most common injured organs were kidneys in 41 (62.12%) and the bladder in 9 (13.6%); 47 patients (71.21%) had associated intra-abdominal injuries, and 42 (63.63%) had other accompanying injuries; 23(34.84%) patients required surgical intervention. Three patients (4.54%) died due to the severity of injuries (Injury Severity Score > 12).In our assessment, blunt trauma including road traffic accidents were the main cause of urogenital injuries. Most patients with urogenital trauma had multiple injuries, and required a multidisciplinary approach for management. Disabilities caused by trauma has become one of the most serious public health problems in developed countries as well as countries with low total annual income .There isThe etiology of trauma differs in different populations; we sought to see how the epidemiology of genitourinary trauma varies. Thus, the aim of this study was to report the prevalence and nature of genitourinary injuries to compare with other studies.This study was performed from April 2009 to November 2011 (a 20 month period) at our referral center for trauma patients in Sistan and Baloochestan province (a major province in southeastern Iran). Data collection was done in the emergency department. A total of 3450 trauma patients were seen. Those with urogenital injury were documented. The collected data included demographic characteristics, trauma mechanism, type of injury, severity of injury and associated injuries. The ISS was used to provide an overall score for patients with multiple injuries. Each injury was assigned an Abbreviated Injury Scale (AIS) score allocated to one of the 6 body regions   had injuries of the urogenital system; forty-nine (74.24%) patients were men and 17 (25.75%) women. The patients\u2019 mean age was 23 \u00b1 12 years (range 2 to 75 years). The associated injuries were head and neck injuries in 20 (30.3%), thoracic injuries in 12 (18.18%), abdominal-pelvic injuries in 47 (71.21%), and injury of extremities in 36 (54.54%). Of 66 patients, 61 (94.24%) had blunt trauma and 5 (7.57%) had penetrating trauma. Trauma mechanisms are showed in Twenty-three (34.84%) patients required surgical management of the urogenital system ; 19 patiTrauma is a main cause of mortality in the ages between 1 and 44 years in the United States and some believe that it is the main cause of mortality for this age group worldwide. The rate of injuries leading to disability is 2.5 times the mortality caused by trauma . Wessell"}
+{"text": "More than 50% of JIA patients on Methotrexate (MTX) suffer from MTX-related gastrointestinal adverse effects \u2013 MTX intolerance (1). Nevertheless, the best approach to treat MTX intolerance is unknown.To compare the effect of behavioural therapy or a switch to parenteral MTX with oral MTX on MTX intolerance.45 JIA patients with MTX intolerance were randomised to receive oral MTX with anti-emetics (standard of care), parenteral MTX or oral MTX with behavioural therapy. Primary outcome was the occurrence of MTX intolerance, defined as \u22655 points on a validated MISS questionnaire, after a 3-month intervention period. Secondary outcome measures were: MTX intolerance after 6 and 12 months and the number of patients that discontinued MTX or switched to another treatment arm due to intolerance.After 3 months MTX intolerance resolved in 6 (54.5%) patients on standard of care, 4 (57.1%) patients on parenteral MTX and 4 (36.4%) patients on behavioural therapy. Nine patients (30.0%) discontinued MTX or switched to another treatment arm due to MTX intolerance. Of remaining patients at 6 months, MTX intolerance resolved in 2 (50%), 4 (80%) and 4 (57.1%) patients, and at 12 months in 2 (66.7%), 4 (80%) and 3 (50%) patients in three treatment groups respectively. All treatment arms showed a marked decrease in MTX intolerance score on the MISS questionnaire from on average 15 points to 6 points after 3 months.Behavioural therapy and parenteral MTX were not more effective than the standard of care in treating MTX intolerance. Instead, all treatments strongly diminished MTX intolerance, probably due to changes in cognitions and self-efficacy. Physicians should not discontinue MTX or switch to biologicals in case of MTX intolerance, but rather strengthen the patient\u2019s self-efficacy to cope with MTX intolerance. We propose several strategies to this end."}
+{"text": "To investigate the pattern of left ventricular hypertrophy (LVH) in Anderson Fabry Disease (AFD) using CMR.AFD is an X linked disorder of lysosomal storage that can have various cardiac manifestations, most commonly resulting in LVH. Echocardiographic data on LVH distribution emphasised concentric hypertrophy in males and later onset in females with less hypertrophy. However this modality is often limited in visualisation of the left ventricular apex.27 patients  with genetically proven AFD were assessed by CMR for hypertrophy, its distribution and LGE.8 (30%) of patients had no LVH Fig . Of thosEchocardiography did not detect 4 (15%) of the patients  subsequently found to have hypertrophy on CMR, 1 (3%) of whom had an apical pattern.LGE was seen in 12 (44%) of patients. Of these 12 patients, 6 (50%) had basal infero-lateral LGE only, with 3 (25%) having basal infero-lateral and other varying LGE distribution. A further 3 (25%) of patients had LGE only distributed away from the basal infero-lateral wall.Of the 4 patients with apical hypertrophy, 2 (50%) had basal infero-lateral wall LGE, with 1 (25%) having apical LGE and the other no LGE.This study shows that AFD can manifest in an LV apical hypertrophy phenotype with most demonstrating apical cavity obliteration. It may be that this has not previously been recognised due to limitations of echocardiography in visualisation of the LV apex. Apical as well as basal infero-lateral LGE is also a manifestation of AFD."}
+{"text": "Initiatives involved in implementing a health-care strategy that commits University Hospitals to provide general Infection Control (IC) guidance to the healthcare sector in the municipalities.The objective was to establish 3 networks with participants from 29 municipalities, representing both the elderly and the children, IC teams from the 3 hospitals, and senior managers in hospitals and municipalities.Identify and contact by telephone, email or visits relevant personnel from municipalities, hospitals and relevant institutions, arrange meetings and write proposals for protocols, agendas etc. Assist the municipalities in development of IC organizations, establish a link and dialogue between the municipalities and the IC teams and arrange short educational courses to health care personal.In order to prevent healthcare acquired infections, the network meetings and the educational courses should support IC and prevention of intersectional spread of infections and multidrug-resistant organisms, patient safety, occupational health and safety.After a year- 3 networks were established and municipalities are represented by 2 network participants- 4 annual network meetings were arranged and will be customary- 3 educational courses arranged for annually, 100 participants a year.- Evaluation 93/100 (93%) were generally satisfied with the contents. The courses were massively oversubscribed.A questionnaire completed by senior management in the municipalities with 21/29 responses:- Has the initiative supported competency development? Yes: 18/21(86%), don\u2019t know: 3/21(14%).- Has new knowledge been disseminated in the organizations? Yes: 19/21(91%), No: 1/21(5%), don\u2019t know: 1/21(5%).- Is dissemination of knowledge formalized in the organization? Yes: 12/21(57%), No: 6/21(29%), Don\u2019t know: 3/21(14%)The networks support the development of IC skills in the municipalities. Local networks are trying to disseminate new knowledge, but formalizing it, is a major challenge. There is a need for training of frontline staff. It is of great importance that need for IC counseling in the future is determined.None declared."}
+{"text": "Treatment with Interleukin-1 (Il-1) receptor antagonist (anakinra) has been reported to be effective in some patients with systemic-onset juvenile idiopathic arthritis (SoJIA).To examine the safety and the efficacy of anakinra treatment in a regional cohort of SoJIA patients.We retrospectively reviewed the medical records of patients with SoJIA treated with anakinra (1-3 mg/kg/day) in our unit between December 2004 and july 2010. Anakinra\u2019s effects were studied on several parameters including fever, rash, erythrocyte sedimentation rate, C-reactive protein levels, arthritis joints count, assessment of disease activity (by physician and parent/patient) and pain (by parent/patient). Resulting data were analysed to characterize therapies, clinical course and adverse events.A total of 22 patients were included. Their mean age at the onset of treatment was 8,6  years; disease duration was 2,4  years. They had been follow up for 11-56 months. Fever and rash were resolved in 18 patients (82%) within the first 3 months. Active arthritis persisted at 3 months in 22% of patients, at 6 months in 14%, and at 12 months in 22%. Sixteen patients (70%), including 6 patients receiving anakinra as first-line therapy, attained a complete response. One patient stopped anakinra due to severe skin reaction and two patients due to infections: one severe pneumonia and one positive intradermoreaction. We observed 10 episodes of macrophage activation syndrome in 9 patients (40%), 8 episodes were present at the SoJIA diagnosis and 2 while receiving anakinra.In our experience, first-line therapy with anakinra in SoJIA patients was associated with an improved resolution of symptoms. These results justify further studies of Il-1 inhibition as first-line therapy in SoJIA patients."}
+{"text": "The objectives were to describe a cohort of children presenting with medium/large vessel childhood primary angiitis of the central nervous system (PACNS); to report their short-term neurological outcome; and to evaluate efficacy and safety of implemented management.The study included 68 patients, aged less than 16 years. They had their symptoms within 14 days of admission. They received induction therapy with pulses of intravenous steroids and/or intravenous immunoglobulin followed by maintenance therapy with azathioprine and low-dose aspirin. They were also treated with anticoagulants for 4 weeks along with the induction therapy. They were assessed for; their clinical presentation, disease severity (progressive or nonprogressive), hospital course, adverse effects of the used treatment and outcome. Reports of their neuroimaging studies were also collected.Studied patients were 42 (62.76%) boys and 26 (38.23%) girls. Their mean age was 8.5 \u00b1 3.5 years. The commonest presenting symptoms were motor deficit (70%), headache (64%) and fever (20%), while the commonest presenting neurological signs were hemiparesis (60%), seizure 55% , and decreased level of consciousness (30%). Neuroradiological studies of the brain revealed: ischemic strokes in 50 children (73.5%), hemorrhagic strokes in 10 (14.7%) and ischemic-hemorrhagic lesions in eight (11.8%). Conventional angiography (CA) and/or magnetic resonance angiography (MRA) at the time of admission revealed that 51 (75%) patients had nonprogressive and 17 (25%) had evidence of progressive arteriopathy. Out of the studied patients, 56 (81.5%) survived and 12 (18.5%) died. Male sex, deep coma and intracerebral bleeding causing severe raised intracranial pressure were poor prognostic signs. Survivors were discharged on oral aspirin and 15 of them commenced also on azathioprine. On follow-up it was found that out of the 56 survivors, 11 were normal (19.65%), 14 (25%) had minor disabilities, another 11 (19.65%) had moderate disabilities and 20 (35.7%) had severe disabilities.The spectrum of cPACNS includes progressive and non-progressive forms. Characteristic features on presentation may predict later progression and outcome; identify a distinct high-risk cPACNS cohort; and guide the selection of patients for immunosuppressive therapy. Further studies are required to substantiate our findings."}
+{"text": "To determine whether cardiovascular magnetic resonance (CMR) for left ventricular ejection fraction (LVEF) assessment changes implantable cardioverter defibrillator (ICD) eligibility when compared with echocardiography.A markedly reduced LVEF is considered an indication for ICD placement for the primary prevention of sudden cardiac death. However, despite strict LVEF criteria, most guidelines do not specify the technique by which LVEF should be measured.The study population consisted of patients referred for LVEF measurement by CMR, for consideration of ICD implantation, who also underwent echocardiography within 30 days of the CMR. LVEF was assessed on echocardiography using Simpson\u2019s biplane method. LVEF was determined from CMR based on manual planimetry of SSFP cine images of contiguous left ventricular short axis slices. CMR and echocardiography derived LVEFs were reported by two independent blinded observers.Forty-nine (49) eligible patients were identified  who underwent CMR between March 20, 2007 and Aug 12, 2010. The median number of days between CMR and echo was 3 (IQR 1 to 10 days). The mean LVEF by CMR and echo was 31 +/- 15 %, and 34 +/- 15%, respectively, (p =0.009), with a correlation coefficient (r) between the two of 0.86. Using Bland Altman analysis, the mean difference (CMR - echo) was - 3.1 % with limits of agreement of - 18 to 12 %. CMR resulted in reclassification regarding ICD eligibility in 10 (20 %) patients using an LVEF threshold of 35 %, and 8 (16 %) using an LVEF threshold of 30 %. Tables In this cohort of patients being considered for ICD implantation, echocardiography systematically over-estimated LVEF. Using strict LVEF criteria, CMR changed the eligibility for ICD in a substantial proportion of patients, with, in most cases, CMR determining that the patient was ICD eligible when they were not based on echocardiography."}
+{"text": "There is an emerging body of evidence suggesting that early packed red blood cell transfusion accompanied by fresh frozen plasma, while limiting crystalloids, confers a survival benefit in major trauma . PrehospAll Greater Sydney Area HEMS (GSA-HEMS) prehospital missions involving a blood transfusion over a 66-month period were identified and reviewed. The prospectively completed GSA-HEMS electronic database was utilised to identify patients and extract data.We identified 158 missions involving a prehospital blood transfusion, of which 147 patient datasets were complete. The majority of patients had a blunt mechanism of injury (93.9%) and were male (69.3%) with a median (IQR) age of 34.5 22 to 52) years (Table 2 to 52 yDespite the controversies over the role of fluids in the prehospital environment, the carriage and use of blood is both feasible and safe in a physician-led helicopter emergency medical service."}
+{"text": "The objective was to describe characteristics of HIV-positive patients admitted to the ICU.HIV-positive patients admitted between February 2000 and February 2011, and demographic data, APACHE II score, cause of admission, days of internment, need for mechanical ventilation (MV), previous antiretroviral therapy of high efficacy before admission (HAART), viral load and CD4 count.Pneumocystis jivoreci and bacterial pneumonias in 35%, the most frequent bacteria isolated were Streptococcus, Staphylococcus aureus and Haemophilus influenzae. There were two cases of respiratory Kaposi sarcoma and 26 cases of Mycobacterium tuberculosis. Other causes were decrease in mental state in 157 patients (22%), with the most frequent causes reported being toxoplasmosis, cryptococcus neoformans and brain lymphoma, immediately post surgery in 79 patients (11%), COPD reagudization and asthma (9%), digestive bleeding in 36 patients (5%) and renal insufficiency in 50 patients (7%). From the 715 HIV-positive patients admitted, 479 required MV (67%). Regarding nationality, 276 (38.6%) patients were Argentinean, and the other nationalities were Bolivian, Paraguayan, Peruvian and Korean. The average length of stay was 10.5 days and the mortality was 43%. The viral load average was inferior to 104 RNA/ml in just 44 known patients and the CD4 count was determined in 75 patients, from which the average was 400/mm3. The proportion of patients receiving HAART was just 26%.A total of 3,568 patients were admitted; 715 patients (20.03%) were HIV-positive, 413 patients (57.76%) were masculine and 302 patients (42.23%) feminine, and average age was 33 for men and 35 for women. The APACHE II average score was 13 versus 15.28 for the general population. The most frequent cause of admission was respiratory failure in 329 patients (46%), 57% due to HIV-positive patients have a high frequency of admission to the ICU, and they have a lower risk score in comparison with non-HIV patients. The two main causes of admission where respiratory disease and infectious CNS disease. Significant results were the prevalence of patients from limited countries, high mortality and prolonged stay in the ICU, and poor adherence to antiretroviral therapy."}
+{"text": "The Quantiferon-CMV assay is a test for Cell Mediated Immune (CMI) responses to peptide antigens that simulate CMV proteins. Individuals infected with CMV usually have CD8+ lymphocytes in their blood that recognize these antigens. This recognition process involves the generation and secretion of the cytokine and interferon (IFN). The detection and subsequent quantification of IFN forms the basis of this test.To evaluate the accuracy of Quantiferon-CMV assay in diagnosis of CMV infection in HIV positive patients and compare it with older ELISA method.3, asymptomatic or with suggestive clinical manifestations: neurological , ocular, gastrointestinal, pancreatic or hepatic symptoms. The patients with other associated opportunistic infections were excluded from the study.This is a prospective study on a group of 48 HIV infected patients that are in a constant supervision of the Regional HIV Centre Constanta, Romania. The patients were tested by Quantiferon-CMV assay and by CMV ELISA. In the study were included adults patients with known HIV infection and CD4 < 200 cells/mm3 with clinical manifestations showed both positive reactions (14 patients). The patients who were treated with gancyclovir for CMV retinitis showed positive ELISA IgG, but negative Quantiferon-CMV assay. The sensitivity of Quantiferon-CMV assay was 92.7%.Sixteen women and 32 men were included in the study, with a mean age of 32.8 years (range between 20-62 years), of whom three were antiretroviral naive patients and 45 were multiple experienced. Of these, seven patients were asymptomatic, 41 had different clinical manifestations: pancreatitis (12), esophagitis (3), gastritis (2) colitis (6), liver involvement (9), cholecystitis (7), central and peripheral nervous system involvement (8) retinitis (4). IgM ELISA was negative in all cases, IgG ELISA was positive in 45 patients (95.5%) and Quantiferon-CMV assay was reactive in 38 cases (79.1%). All patients with CD4 < 50 cells/mm3) and CMV reactivation detected by Quantiferon. This test is easy accessible and an efficient method of monitoring therapy with gancyclovir.Quantiferon-CMV assay has increased sensitivity in the detection of CMV reactivation induced by severe immunodepression (92.7%). There is a strong correlation (p < 0.01) between severe immunodepression (CD4 < 50 cells/mm"}
+{"text": "The aim of this study was to assess the adequacy of nutrition provision to mechanically ventilated patients in the acute phase after cervical cord injury. High spinal cord injury is associated with reduced gastric emptying due to excessive sympathetic activity from the isolated thoracolumbar cord , which iA retrospective cohort study. Success of enteral feeding and associated factors were reviewed for 28 days (or until ICU discharge) in all patients mechanically ventilated for at least 48 hours with cervical cord injury in a mixed, level 3 ICU, over a 2-year period. Adequacy of nutrition was defined as net calories delivered (including propofol) as a percentage of goal calories prescribed. Energy requirements were determined using the Schofield equation or a weight-based method . Data are presented as median and range.r = 0.564; P = 0.029) between feed volume and hospital LOS. Feeding did not influence any other clinical outcomes including ICU LOS and mortality. Eleven (65%) patients received prokinetics for 7 days (2 to 20). No patients received TPN or post-pyloric feeding.Seventeen patients were recruited , BMI 27 (23 to 35), APACHE II 14 (8 to 26), ASIA score A - 13, B - 4, ICU length of stay (LOS) 40 days (14 to 78), hospital LOS 82 days (34 to 219), of which two died. Six patients were discharged prior to day 28. Goal calories were 2,140/day . Patients commenced enteral feeding 44 hours (1 to 107) after ICU admission and received a mean 73% (SD = 19%) of nutritional goals over the 28-day study period. Energy delivery by day 4 reached 88% of goals. There was a significant relationship (Despite a high proportion of patients requiring prokinetics, most received adequate nasogastric nutrition during their stay in the ICU. Anecdotal evidence of weight loss and wasting after cervical spinal cord injury suggests that there are complex nutritional requirements in this group of patients and will form the basis for further studies."}
+{"text": "Sir,Streptococcus pyogenes), pharyngitis in children assumes special significance due to the development of rheumatic fever (RF)/rheumatic heart disease (RHD). Streptococcal infections with an estimated death rate of over 500,000 individuals/year place GAS among major human pathogens, exceeded by HIV, Mycobacterium tuberculosis, Plasmodium falciparum and S. pneumoniae, and probably comparable to rotavirus, measles, Haemophilus influenzae type b, and hepatitis B1emm gene (encoding M protein) sequencing based on 5\u2019 regionemm sequence types and 800 emm subtypes have been described, new types/subtypes are still emerging from different regionsGroup A streptococcus  from urban, rural and peri-urban slums were included in the study. A total of 17,071 samples were collected from north India during the study period. Throat swabs (n=14008) from peri-tonsillar and posterior wall of pharynx of pharyngitis patients or asymptomatic carriers, RF/RHD patients (n=11) and skin swabs (n=3063) from skin infected patients were taken. Betahaemolytic streptococcal colonies were isolated using standard protocolWe compiled the epidemiological surveillance data of GAS emm typed by protocol as published earlieremm types, 16 isolates were identical to sequence types and 18 (4.4%) were M non typeable (MNT). The emm types were further designated as emm subtypes based on their variation from parent strain. A total of 70 types were obtained representing 53 known emm types with 33 subtypes, 12 sequence-types and five novel MNT strains (emm 81 (15.7%) was the highly represented type common to both throat and skin infections. The seven most prevalent types- emm 81 (15.7%), 11 (7.9%), 112 (7.6%), 77 (7.4%), 44 (4.4%), 49 (3.7%) and 15 (3.4%) constituted 50 per cent of the isolates. Certain sequence types, like ST854, TP-c2135, AAB51153 and AAD 28609 recovered from Thailand and India, suggest a possible geographical bias in their isolation. MNT sequences - NS 292 and sp11014/VT-15, a rare type emm 1-2 and one new provisional sequence type  were also identified. Most prevalent types found in GAS isolates from throat cultures were emm 81 (16.25%), 11 (10.8%), 77 (10%), 49 (4.6%), 75 (4.2%), 15 (3.3%), 71 (3.3%) and 68 (3.3%) as compared to emm types 81 (16%), 112 (15.4%), 44 (10.3%), 85 (5%), 15 and 1-2 (4.5%) from GAS skin cultures. These emm types constitute 56 per cent each of the throat and skin GAS cultures, respectively. Importantly, except for emm 81 and 15, other predominant types from throat infection were different from those in skin infections. Though several emm types were common to throat and skin sites, yet different types were seen in GAS cultures isolated from these sites, e.g., emm 1, 70, 80, 85, 104 and 5 sequence types were exclusively present in GAS skin cultures, emm 33 and 43 in GAS from RF/RHD patients and 33 different emm types were present only in throat GAS cultures. emm 1-2 was seen in both throat and skin GAS cultures. emm types 33, 43, 49, 74, 80, 93, 112 and NT were present in 11 RF/RHD cases. Hence, specific emm types can be associated with pharyngeal, skin and RF/RHD isolates.GAS isolates  were reconfirmed and  strains .. emm 81emm types was seen from both the regions. Of the 34 GAS isolates from south, 22 different types (64.7% diversity) were observed, the most common being emm 49; and out of 227 GAS isolates 59 emm types were seen with the most prevalent types being emm 112 (12.3%), 82, 11, 105, 108 and 1101112emm types- 1-2, 11, 25, 49, 68, 69, 74, 75 and 90 with the most common being emm 49 and 75 (unpublished data). 59 GAS collected from pharyngitis patients visiting Chandigarh hospital and from villages of district Panchkula, Haryana during March 2000-2001 showed 33 different types with emm 74 to be most prevalentemm 71 to be most prevalent followed by emm 81emm typed showed 23 different types with emm type 49 to be most prevalent in children from the slums, rural and urban areas of Chandigarhemm 81 and 112 to be most common (unpublished data). Recent findings of GAS collected from rural areas of Punjab from 2002- 2007 depict emm 57 to be most prevalent (unpublished data). The pattern of emm type distribution varied from one region to another in north India with the passage of time. Earlier studies from north India showed high diversity of emm types encountered in a single year, but no specific emm type could be associated with the isolation site and those studies stressed upon the selection of emm types for vaccine development and/or need to tailor multivalent vaccine for regional use7emm specific vaccine is not going to work in this region.On comparison with the epidemiological data from south, heterogeneity in GAS emm 11 was common amongst the six serotypes often seen in USA . We further looked for the types considered in the 26 valent multiple-epitope formulation vaccine and found though 50 per cent of those emm types  were seen in north Indian collection of emm types during the last 12 years; yet their frequency was quite less (around 15.4%) as compared to 80-85 per cent coverage of these types seen in western worldemm 81 is not a new emm typeSurprisingly, only emm type diversity from developing nations support the presence of predominant types. In the Indian literature, only about 30 per cent of clinical GAS isolates were serologically M typed, therefore emm sequencing was initiatedemm type was seen in South91112emm type distribution exists7emm 81 is seen prevalent throughout these years and also from both the north and south regions. Kaplan et alemm type are yet to be determined. Hence, it becomes important to monitor continuously the emerging emm types.Reports examining the emm types are not always adequate strain markers, because these can be shared by unrelated clonal types also. These observations would be of great significance and imply the efficacy of currently available vaccines may not be successful in India.The strain variations have been noted within particular M types, and virulence has been linked with a particular isolate rather than being broadly related to a given serotypePilot studies to check the protective efficacy of multivalent vaccine as well as considering a peptide sequence containing a conserved epitope from C-repeat region of M protein, were not encouraging7emm types encountered from north India, their association with isolation site and their divergence from western world are noteworthy. Regional and temporal variations in the prevalent emm types, emergence of new types and presence of M non-typeable strains in our country highlight better understanding of the present scenario and reveal an urgent need not only to reconsider the vaccine development but an alternative preventive approach to combat streptococcal diseases and their sequelae worldwide.In conclusion, our findings like heterogeneous"}
+{"text": "Systemic juvenile idiopathic arthritis (sJIA) accounts for 10-20% of all patients with JIA. The clinical features include fever, evanescent rash, arthralgia and arthritis, myalgia, lymphadenopathy, hepatomegaly, splenomegaly and serositis. Interleukin 1 (IL-1) has been shown to be a major mediator of the inflammatory cascade that underlies sJIA (1). Treatment with anakinra, IL-1 receptor antagonist has been reported to be effective in a subset of patients with sJIA (2).To assess anakinra as a therapy for sJIA in a single-center series.We reviewed twenty-one consecutive patients with sJIA treated with anakinra for at least 6 months in our institution. The diagnosis of sJIA was established according to the International League of Associations for Rheumatology (ILAR) criteria. We analyzed the effect of Anakinra on fever, rash, number of actives joints, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), white blood cell count, platelet count and ferritin levels. Clinically inactive disease was defined according to Wallace criteria. Clinical and laboratory data were obtained using a standard data collection form end resulting data were analyzed using Fisher exact test.. Five of 7 pts (71.4%) treated with anakinra alone and 6 of 14 pts (42.9%) treated with anakinra and glucocorticoids met criteria for inactive disease at 6 months (p= 0.361). Among the 21 patients, 10 (47.6%) received anakinra in the first 6 months of disease. There were no statistically significant differences for demographic, clinical and laboratory features among patients who started anakinra in the first 6 months of disease and those that started it after 6 months from onset of disease. At 6 months after initiation of anakinra treatment 8 of 10 patients (80%) who started anakinra during the first 6 months of disease and 4 out of 11 (36.4%) who started anakinra after 6 months of disease reached clinical inactive disease (p=0.08).At the beginning of treatment mean age (range) was 8.57 (2.15-16.63) years; 19 of 21 patients had fever and median number of active joints was 3 (1-15). After 6 months of treatment 11 patients (52.3%) met the criteria for inactive disease. Among 21 patients 7 (33%) received anakinra in monotherapy and 14 (66.6%) received anakinra with glucocorticoids. There were no statistically significant differences between the two groups for demographic, clinical and laboratory featuresIn agreement with several observations, anakinra is effective in a significant proportion of patients with sJIA. Our observation, albeit on a small number, show that association with glucocorticoids does not significantly affect outcome at 6 months and suggest, on the other hand, that earlier treatment may be associated with a better outcome.None declared"}
+{"text": "The anti- IL-6 Receptor monoclonal antibody Tocilizumab (TCZ) has demonstrated its efficacy in Japanese children with systemic onset juvenile idiopathic arthritis (SJIA).To evaluate the efficacy and safety of TCZ in European patients with active SJIA outside a clinical trial (off-label use).Retrospective review of the files of the patients treated by TCZ in two French, one Swiss and one Italian center. Response to treatment was defined as control of the fever and systemic features for at least 7 days, Improvement of the pediatric ACR score and normalization of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were also considered.18 patients aged 4-15 years were included. The median disease duration at treatment onset was 4.7 years (0.4-8.8). The median dose of prednisone at TCZ onset was 0.63mg/kg/d. Four patients were also on MTX. Fourteen patients had previously failed to respond one or several biologics, including anti-TNF alpha in 10 cases, anakinra in 14 and canakinumab, in 4. All patients but 4 had active systemic and polyarticular features at TCZ onset. The doses of TCZ ranged between 6 and 12 mg/kg every other week at treatment onset. The mean follow-up on TCZ was 18.2 months (range0.5-48). 90% improvement of the pediatric ACR score was achieved by 9 patients after 3 months. The dose of steroids was tapered in most cases (11/14) within 3 months, and five patients could discontinue steroid treatment after 12 months. TCZ treatment was withdrawn in 5 children for adverse events: anaphylactic reaction in 3 cases, skin vasculitis in 2 other cases.In this study TCZ treatment was effective in most patients with SJIA who previously failed one or several biologics. Adverse events require particular attention since almost one third of patients had to discontinue treatment."}
+{"text": "The efficacy of universal screening and brief intervention (SBI) for drug use among primary care (PC) patients is unknown.In this randomized trial (the Assessing Screening Plus brief Intervention\u2019s Resulting Efficacy to stop drug use (ASPIRE) study) we tested the efficacy of a brief negotiated interview (BNI), and an adaptation of motivational interviewing (AMI), compared to no BI. Primary care patient participants had Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) drug specific scores of \u22654. Primary outcome at 6 months was number of days use of the drug of most concern (DOMC) in the past 30 days.Of 528 subjects, DOMC was: marijuana 63%, opioid 17% (prescription opioid 11%), and cocaine 19%. ASSIST score was \u226527 (consistent with dependence) for 18%, mean days DOMC use (of 30 days) was 14.4. At 6 months, 98% completed follow-up and mean days DOMC use was 14.0. Mean adjusted days use of the DOMC at 6 months  was 11.5 (no BI) vs. 11.2 (BNI) (incidence rate ratio (IRR) 0.97, 95% CI 0.77-1.22) and 12.1 (AMI)  (p=0.81 for both comparisons vs. no BI). There were also no significant effects in analyses stratified by DOMC or ASSIST score.In this trial, BNI and AMI did not have efficacy for decreasing drug use. If other trials yield consistent results, widespread implementation of drug screening and BI should be reconsidered, and research should focus on alternative ways to address drug use and consequences in primary care settings. Funding was provided by the US National Institutes of Health ."}
+{"text": "Urinary biomarkers for bladder cancer detection are constrained by inadequate sensitivity or specificity. Here we evaluate the diagnostic accuracy of Mcm5, a novel cell cycle biomarker of aberrant growth, alone and in combination with NMP22.1677 consecutive patients under investigation for urinary tract malignancy were recruited to a prospective blinded observational study. All patients underwent ultrasound, intravenous urography, cystoscopy, urine culture and cytologic analysis. An immunofluorometric assay was used to measure Mcm5 levels in urine cell sediments. NMP22 urinary levels were determined with the FDA-approved NMP22\u00ae Test Kit.Genito-urinary tract cancers were identified in 210/1564 (13%) patients with an Mcm5 result and in 195/1396 (14%) patients with an NMP22 result. At the assay cut-point where sensitivity and specificity were equal, the Mcm5 test detected primary and recurrent bladder cancers with 69% sensitivity  and 93% negative predictive value (95% CI\u200a=\u200a92\u201395%). The area under the receiver operating characteristic curve for Mcm5 was 0.75 (95% CI\u200a=\u200a0.71\u20130.79) and 0.72 (95% CI\u200a=\u200a0.67\u20130.77) for NMP22. Importantly, Mcm5 combined with NMP22 identified 95%  of potentially life threatening diagnoses (i.e. grade 3 or carcinoma in situ or stage \u2265pT1) with high specificity .The Mcm5 immunoassay is a non-invasive test for identifying patients with urothelial cancers with similar accuracy to the FDA-approved NMP22 ELISA Test Kit. The combination of Mcm5 plus NMP22 improves the detection of UCC and identifies 95% of clinically significant disease. Trials of a commercially developed Mcm5 assay suitable for an end-user laboratory alongside NMP22 are required to assess their potential clinical utility in improving diagnostic and surveillance care pathways. Urothelial cell carcinoma (UCC) of the urinary bladder is the 4th most common cancer in the US, with an estimated 73510 new cases and 14880 deaths from bladder cancer in 2012 Urinary biomarkers for the detection of bladder cancer hold great promise and while numerous markers have regulatory approval none have been accepted as a standard diagnostic procedure The constrained accuracy of available biomarkers, along with their expense, has therefore limited introduction of urinary biomarkers into routine clinical practice. Hence there remains an urgent need to identify new biomarkers that might improve diagnostic accuracy, either when used in isolation or in combination with existing biomarker tests The DNA replication initiation machinery represents a final and critical step in growth control downstream of complex redundant oncogenic signalling pathways and is therefore a potentially attractive diagnostic and therapeutic target The aim of this study was to evaluate Mcm5 as a biomarker for detection of bladder cancer alone, in comparison and in combination with NMP22. The prospective blinded observational trial utilized an immunofluorometric assay to measure Mcm5 and the FDA-approved NMP22 Test Kit.Single voided urine specimens were obtained from 1677 patients attending a one stop diagnostic clinic for investigation of haematuria. The diagnosis was established following assessment by cystoscopy, upper urinary tract imaging, urine cytology and culture. Histological confirmation of bladder cancer at subsequent trans-urethral resection was the reference standard and all patients were followed for a period of six months from the time of initial investigations. Patients with a history of recent genito-urinary instrumentation or surgery within the previous two weeks were excluded. Patients with a history of concomitant malignancy or other malignancy within five years prior to study were also excluded. With these exceptions all consecutive patients attending for investigation during the study period were approached for recruitment into the trial.Urine samples were split equally for: (i) urinalysis and microbiological culture, (ii) cytological analysis, (iii) Mcm5 measurement and (iv) NMP22 measurement. Patients underwent upper urinary tract imaging including ultrasound and intravenous urography. Male patients were examined by digital rectal examination for the presence of clinically detectable prostatic disease. Prostate-specific antigen (PSA) testing was not mandated and PSA levels were checked in a proportion of cases in whom cancer was suspected or who requested the test. If PSA levels were elevated patients were offered trans-rectal ultrasound guided core biopsies of the prostate. Typically all haematuria tests were completed within 24 hours and within two weeks for all patients. Clinical data were entered into a database prospectively prior to Mcm5 and NMP22 analysis. The reference standard for detection of bladder cancer was pathological confirmation following trans-urethral resection.Urine samples were analyzed in a blinded fashion for Mcm5 detection, NMP22 testing, and cytologic analyses. On completion of the study, we decoded the patient data and compared immunofluorometric Mcm5 signals and NMP22 results with clinical diagnoses based on cystoscopy, biopsy histology, imaging and urine cytology. Staging and grading of malignant tumours was performed by a specialist uro-pathologist using the TNM (tumour-node-metastasis) classification system Ethical approval was obtained from the Joint UCL/UCLH Committees on the Ethics of Human Research (04/Q0502/1), Addenbrooke\u2019s Hospital Ethics Committee (00/236) and the Newcastle and North Tyneside Research Ethics Committee (2002/161). Written informed consent was received from all participants.Urine samples (50 mL) were centrifuged at 1500 g for 5 min. Cytospin preparations were prepared on poly-L-lysine coated slides using Shandon cytospin tubes and a cytocentrifuge according to the manufacturer\u2019s instructions . Samples were fixed in industrial methylated spirits and stained using the Papanicolaou technique for smears NMP22 was measured by enzyme-linked immunosorbent assay (ELISA) using the FDA-approved NMP22 Test Kit produced by Matritech . The assay run on a Dade Behring BEP 2000 automated ELISA processor . All reagents, calibrators and controls were prepared as recommended by the manufacturer. All standards, quality controls and samples were analyzed in duplicate. Results were calculated using the data processing software supplied with the BEP 2000. The lower limit of detection of the assay was found to be 2 U/mL. Samples with concentrations greater than the top standard were repeated after dilution in assay buffer. The between-batch coefficient of variation was 13.3% at a concentration of 11.3 U/mL, 8.8% at 34 U/mL and 9.5% at 65 U/mL. A result for the NMP22 test was available in 1396 patients, including 195 patients (14%) with a urothelial tumour.Mcm5 was measured by two-site time-resolved fluorescence immunoassay on the AutoDELFIA analyzer (Perkin Elmer). All standards, quality controls and urine samples were prepared and processed as described Sensitivity and specificity characteristics of Mcm5 and NMP22 for the detection of UCC of the bladder are presented as receiver operating characteristic (ROC) curves. The area under the nonparametric ROC curve was used to assess the overall diagnostic performance of each test. Three cut-points were used to demonstrate test performance under different circumstances for Mcm5 as follows: (i) the lower detection limit of the assay where sensitivity of the test was maximal (1000 cells/well) (ii) sensitivity equal to specificity (2150 cells/well) and (iii) 95% specificity (8500 cells/well). Negative predictive value (NPV) and positive predictive value (PPV) were also estimated. An exact 95% confidence interval (CI) for each proportion, including sensitivity, specificity and predictive values for Mcm5 and NMP22, was derived assuming a binomial distribution. The manufacturer\u2019s recommended cut-point for NMP22, 10 U/ml was utilized for all analyses unless otherwise specified.False positive rates (FPR) for the Mcm5 and NMP22 tests in patients with benign diagnosis were compared with clear normal patients using a Chi-squared test. The Mcm5 and NMP22 values were summarized using medians and interquartile ranges (IQR) and compared with the clear normal patients using the Mann-Whitney U-test. For each biomarker, the ROC analysis was repeated for males and females separately and the areas under the ROC curves were compared using a Chi-squared test with one degree of freedom. ROC analysis was also undertaken to examine the sensitivity of the main results to the exclusion of those with benign disease. The values of the urinary biomarkers for patients with different tumour grades and stages and normal patients were compared using Mann-Whitney U-tests between neighbouring categories, and using the Jonckheere-Terpstra test for trend across grades and stages. The Chi-squared test for linear by linear association was used to assess the evidence for a trend in the false positive rates by increasing tumour grade and stage. The sensitivity determined for urinary cytology was compared with that of the immunofluorometric Mcm5 test using McNemar\u2019s test for paired proportions. The accuracy of a biomarker was defined as the value of sensitivity and specificity where the cut-point provided these to be equal. The accuracy of the two biomarker tests was compared using McNemar\u2019s test. McNemar\u2019s test was also used to compare the sensitivity of cytology with that of each biomarker at cut-points providing the same specificity as observed for cytology. Spearman correlation was used to assess the degree to which the biomarkers were distinctive in UCC case and in normal control groups. All statistical tests were two-tailed, and a 5% level was used to indicate statistical significance.A multi-ROC analysis The demographic characteristics, mode of presentation, final diagnosis, and tumour grade and stage for the 1677 patients included in this study are summarized in Following clinical investigation, urinary tract tumours were identified in 222/1677 patients (13%). Nearly all tumours were UCCs, but, investigation also identified one case of adenocarcinoma and two cases of squamous cell carcinoma of the bladder. The UCCs were predominantly bladder tumours, with only seven patients with upper tract tumours. The upper tract UCCs are included alongside the bladder tumours for the analysis reported below. The diagnoses in the remaining patients included other malignancies, benign lesions or cysts of the kidney, benign inflammatory and congenital conditions, urolithiasis, benign prostatic hyperplasia and nephrological diseases. The diagnoses are listed in The Mcm5 test discriminated, with high specificity and sensitivity, between patients with and without bladder cancer, as demonstrated by the large area under the ROC curve (AUC) (0.75 [95% CI\u200a=\u200a0.71\u20130.79]) , statistThe sensitivity, specificity, and positive and negative predictive values (PPV and NPV) for Mcm5 are shown in The NMP22 test discriminated with high specificity and sensitivity as demonstrated by the large AUC  and basIn order to assess the performance of the test in patients with different stages and grades of disease the True Positive Rate (TPR) was calculated for Mcm5 (at the different cut-points), NMP22 and cytology for muscle invasive vs non-muscle invasive  and acroWhere the specificity of NMP22 (cut-point 12.1) was the same as that of positive cytology , the sensitivity of NMP22 was significantly higher (P<0.001) . Where the specificity of Mcm5 (5150-cell cut-point) was the same as that of cytology  the sensitivity of Mcm5 was significantly higher (P<0.001) .False positives were found in 400/1301 (31%) of clear normal and benign diagnosis patients with the Mcm5 test at the 2150-cell cut-point. There was a significantly higher rate of false positive results in female patients, 38% (200/520) compared to males 26% (200/781) (P<0.001). Urinary Mcm5 levels were also significantly higher in normal/benign females compared to males . Furthermore, compared to normal patients, those with, urinary calculi had a significantly higher false positive rate  and higher urinary levels of Mcm5 protein , and for NMP22 a cut-point of 4.6 U/mL provided equal sensitivity and specificity of 67% (123/183 and 742/1100). Although there was modestly greater performance of Mcm5 compared with NMP22 in terms of accuracy , this difference was not statistically significant (McNemar\u2019s test: P\u200a=\u200a0.067).The Spearman correlation coefficients between Mcm5 and NMP22 were moderately high (rho\u200a=\u200a0.54) for UCC cases and negligible (rho\u200a=\u200a0.08) for the normal group, indicating potential for the biomarkers to provide distinct roles within a combination. On the basis of multi-ROC analysis, the immunofluorometric Mcm5 test, in combination with NMP22 at the recommended 10 U/mL cut-point, offers a statistically significant increase in performance (P<0.001) compared with NMP22 alone at the recommended cut-point . As a demonstration, if either NMP22 exceeds 10 U/mL or Mcm5 exceeds the 4200-cell cut-point, this combination provides sensitivity (131/183) and specificity (789/1100) both equal to 72%, which indicates the improvement over use of NMP22 alone where sensitivity (123/183) and specificity (742/1100) both equal 67% . In combination with NMP22 at 10 U/mL the MCM5 test removes false negatives from the NMP22 test, offering an improvement from the 54% sensitivity of NMP22 alone to 75% sensitivity with 65% specificity (2800-cell cut-point), or to 80% sensitivity with 58% specificity (1900-cell cut-point), or to maximal sensitivity of 85% with 45% specificity (1000-cell cut-point).In the combination analysis, with NMP22 (10 U/mL cut-point) and Mcm5 , 100% (31/31) of muscle invasive cancers (i.e. stage \u2265 T2), 93% (40/43) of pT1 tumours and 53% (54/102) of pTa tumours were detected. The total number of patients with carcinoma in situ was low and 86% (6/7) were detected. Grade 1 disease was identified in 46% (10/22), grade 2 disease in 64% (68/106) and grade 3 disease in 96% (53/55) of cases (including 6/7 cases of carcinoma in situ). Importantly, Mcm5 combined with NMP22 identified 95%  of potentially life threatening diagnoses (i.e. grade 3 or CIS or stage \u2265pT1) with high specificity .In an earlier proof-of-concept study we showed that elevated Mcm5 levels in urine cell sediments are highly predictive of bladder cancer Despite numerous studies over the last decade, the reported accuracy of the NMP22 test is highly variable. Many of the earlier studies recruited small to moderate numbers of subjects and reported high sensitivities and specificities, above 80% Our study represents the largest prospective observational trial ever undertaken using the NMP22 urinary biomarker. Notably, the performance at the 10 U/mL cut-point, with a sensitivity of 53% and specificity of 84%, is somewhat below that reported in the pooled analysis, but almost identical to the diagnostic performance reported in the Matritech supported large patient cohort trials using the NMP22 point-of-care proteomic assay Candida species) or mixing of menstrual endometrial contaminants in samples, both sources of extraneous MCM expressing cells. Patients with urinary calculi had the highest incidence of false positive Mcm5 results (44%). As previously reported, higher false positive rates are expected in patients with urinary calculi due to the associated mucosal injury, which exposes the underlying MCM expressing transit amplifying compartment of the transitional epithelium to the urinary tract The analysis of false positive Mcm5 results in this study also revealed an unexpected difference between the male and female groups. The overall false positive rate in females was 38% compared to 26% in males. Rather than being related to benign pathology, the difference was most marked in the clear normal group. These findings require further investigation. Possible causes could be fungal contamination by vaginal flora  Mcm5 and (B) NMP22 tests for detection of bladder cancer in male and female patients.(TIF)Click here for additional data file.Table S1Patient diagnoses.(PDF)Click here for additional data file.Table S2True positive rate of Mcm5 and NMP22 tests and cytology, across stage, for bladder carcinoma detection.(PDF)Click here for additional data file.Table S3True positive rate of Mcm5 and NMP22 tests and cytology, across grade, for bladder carcinoma detection.(PDF)Click here for additional data file.Table S4Comparison of Mcm5 and NMP22 test performance in male and female patients.(PDF)Click here for additional data file.Table S5True and false negative rates of the Mcm5 and NMP22 tests, by tumour grade and stage.(PDF)Click here for additional data file."}
+{"text": "This study was conducted to evaluate the biosafety precautions that applied by diagnostic laboratories in Khartoum state, 2009.A total number of 190 laboratories were surveyed about their compliance with standard biosafety precautions. These laboratories included 51 (27%) laboratories from government, 75 (39%) from private sectors and 64 (34%) laboratories belong to organization providing health care services.The study found that 32 (16.8%) of laboratories appointed biosafety officers. Only, ten (5.2%) participated in training about response to fire emergency, and 28 (14.7%) reported the laboratory accident occurred during work. 45 (23.7%) laboratories had a written standard operation procedures (SOPs), and 35 (18.4%) had written procedures for the lean-up of spills. Moreover, biosafety cabinet was found in 11 (5.8%) laboratories, autoclave in 28 (14.7%) and incinerator in only two (1.1%) laboratories. Sharp disposable containers were found in 84 (44.2%). Fire alarm system was found in 2 (1.1%) laboratories, fire extinguisher in 39 (20.5%) laboratories, and fire emergency exit found in 14 (7.4%) laboratories. Furthermore, 19 (10%) laboratories had a hepatitis B virus vaccination programme, 5 (6.2%) applied BCG vaccine, and 2 (1.1%0) vaccinated the staff against influenza.The study concluded that the standards biosafety precautions adopted by the diagnostic laboratories in Khartoum state was very low. Further, the laboratory personnel awareness towards biosafety principles implementation was very low too. Biosafety is described as a safe method for managing infectious agents in laboratory environment where they are handled and maintained. Implementation of biosafety precautions decreases the exposure to the risk factors inside the laboratory. There are four main biosafety levels for laboratories designated as; level-1 basic, level-2 containment, level-3 and maximum containment is level-4 . In 1949So, biosafety precautions in diagnostic laboratories become a crucial issue that should be followed. These precautions included the practices, safe equipment and facility, protection of laboratory staff and public environment from exposure to infectious substances. We conducted this study to evaluate biosafety precautions which adopted by diagnostic laboratories in Khartoum state.The general objective of this objective of this study was to evaluate the biosafety precautions adopted in diagnostic laboratories in Khartoum State. The specific objectives of this study were: 1) to investigate laboratory biosafety standards practices and techniques in diagnostic laboratories; 2) to determine the awareness of laboratory staff towards potential hazards.Study design: Cross-sectional study.Study setting: The study was conducted in Khartoum state diagnostic laboratories.Study period: December 2008-December 2009.Study subject: Diagnostic laboratories in Khartoum state represented as study subject which included laboratories belonged to government, private institutions and organization providing health services.Sample size: Sample was calculated according to the sample size equation N = Z2pq/d2, n = number of study population participated in the study, Z = constant, p= previous data, q = 1-p, d = level of confidenceSampling technique: Stratified simple random sampling technique was used in selecting laboratories.Data collection: A designed questionnaire and checklist were used to collect data from laboratories. Many variables were involved in these two data collection tools. Variables were characterized in to; variables for safety precaution measures at workplace, variables for personal protection equipment, and variables for services provided inside laboratory. In addition to that, variables of essential biosafety equipment, risk determination, fire prevention and vaccination programme were also included in data collection tools.Data entered and analyzed by statistical package SPSS When data collection phase was finished, visits were made to laboratory participation in this study. The aim of these visits was to check the accuracy of collected data. Any wrong information in the questionnaire of the checklist was corrected. Information collected from labs revised by supervision visits. The main objective of these visits was to check the accuracy of data gathered during the collection mission. Any wrong data corrected before entered into the data analysis programme.A total number of 190 laboratories (labs) were surveyed about their compliance with standard biosafety precautions. These laboratories included 51 (27%) labs from government, 75 (39%) from private sectors and 64 (34%) labs belong to organization providing health care services. The study found that 32 (16.8%) of labs appointed biosafety officers, while 75 (39.5%) working in these laboratories indicated that they attended biosafety training previously. Government laboratories were more likely to train their staff when compared to other private and health organization laboratories, still this different was not significant (P= 0.145).Only 20 (10.5%) labs inspected gas cylinders regularly 10 (5.2%) had previous training in response to fire emergency and 28 (14.7%) reported the occurrence of laboratory accident in the work. Furthermore, 45 (23.7%) labs had a written standard operation procedures (SOPs), and 35 (18.4%) had written procedures for the lean-up of spills . Of the Drinking water was available in 172 (90.5%) labs and toilet for both male and female were provided in 99 (52.1%).Government laboratories were more like to train their staff. Reporting of laboratory accident was very low, only 28 (14.7%) laboratories did that (p= 0.000). Also, entering to the laboratories was investigated and government labs were found more restricted than other laboratories. Moreover 147 (78.4%) lab staff indicated that working temperature was comfortable, and 131 (68.9%) of them said that ceiling and floors were easy to clean .Only 24 (12.6%) laboratories had separated room for sampling and 57 (30%) had special room for patients. Essential biosafety equipment was also investigated and only 14 (7.35%) labs used self needle device in the work. In addition, biosafety cabinet was found in 11 (5.8%) labs, autoclave in 28 (14.7%), and incinerator in only 2 (1.1%) labs. Sharp disposable containers were found in 84 (44.2%) labs, but the difference between government, private and organization laboratories was not significant (P=0.149). Also, only 5 (2.6%) laboratories had waste container chemical materials and 4 (2.1) had radioactive waste containers.Fire alarm system was found in 2 (1.1%) laboratories, fire extinguisher in 39 (20.5%) labs, and fire emergency exit found in 14 (7.4%) labs. Of the laboratories, 47(24.7%) indicated that they kept gas cylinder away from heat sources .Furthermore, 19(10%) laboratories had hepatitis B virus vaccination programme, 5 (6.2%) applied BCG vaccine, and 2 (1.1%) vaccinated the staff against influenza.This study was investigating the compliance of diagnostics laboratory to standard biosafety precautions. The study found that laboratory staff did not wear lab-coat and gloves in all laboratory procedures as the percentage was very low. Also, personnel working in these diagnostics laboratories did not receive the required training in biosafety. In addition, reporting system for laboratory accidents and clean-up of spills was not completely carried out. The percentage of these parameters was low when compared to a similar study in Turkey .The low percentage of benches cleaning, hand wash found in this study may increase the risk of infected with pathogenic agents inside these laboratories. Further laboratory work area precautions were also investigated and only 13(6.8%) laboratories were using international biohazard symbols and signs, while 71 (37.4 %) of them had an entry restrictions to their site. No doubt, application of these precautions will enable laboratory personnel to reduce the risk of acquiring infection or export the infection to the surrounded environment .In study conducted in laboratories across Canada to determine rates of compliance with recommended safety precautions against exposure to blood borne pathogens. The study found that laboratory personnel are highly exposure to body fluids and poor rate compliance with personal protective behaviors, this finding is similar to our study results . EssentiThis study indicated that the standards biosafety precautions adopted by the diagnostics laboratories in Khartoum state was very low. In addition to that, awareness of laboratory personnel towards biosafety principles implementation was very low too."}
+{"text": "Background. The utility of repeat EUS in patients with suspicion for pancreatic cancer after non-diagnostic EUS-FNA study is not well established. Aim. Determine the accuracy of repeat EUS-FNA in patients with suspected pancreatic cancer and prior non-diagnostic EUS-FNA. Methods. Retrospective cohort study. Results. From 2002 to 2008 in our institution 28 patients underwent repeat EUS-FNA for suspected pancreatic cancer. Initial EUS showed a pancreatic mass in 24 (85.71%), no mass in 3 (10.71%) and possible mass in 1 (3.58%). FNA was performed and was negative for malignancy in all patients. Repeat EUS showed pancreatic mass in 27 patients (96.42%) and no mass in 1 (3.58%). FNA was performed in all patients and cytology was positive for malignancy in 6 (21.43%). Out of the 28 patients, 17 (60.71%) were eventually confirmed to have cancer. Overall repeat EUS-FNA correctly determined the true final status in 17 out of 28 patients providing sensitivity for the diagnosis of cancer of 35% (95% CI 14%\u201362%), specificity 100% (95% CI 72%\u2013100%), and overall accuracy of 61%, (95% CI 28%\u201372%). Conclusion. Repeat EUS-FNA provides reasonable accuracy and may be worthwhile in patients with suspected pancreatic cancer who had had prior negative EUS-FNA. Pancreatic cancer caused 35,240 deaths in 2009 making it the 4th leading cause of cancer-related death in the United States . The disEndoscopic ultrasound (EUS) with fine needle aspiration (FNA) has been shown to be both safe and accurate in providing definitive diagnosis in patients with pancreatic cancer . Since EThis is a retrospective review of prospectively collected data in a searchable electronic database. All patients who underwent more than one EUS-FNA in our institution for evaluation of suspected pancreatic cancer with initial non-diagnostic EUS-FNA were included in this analysis. Patients were excluded if tissue diagnosis was secured at the first EUS. The definition of a non-diagnostic EUS-FNA included cases in which FNA was attempted in patients with suspected pancreatic cancer, but the cytology results were negative for malignancy for one of the following reasons: adequate sample material was obtained, but cytology was negative for malignancy, less than the predetermined minimum of four FNA passes were made for any reason, and successful four FNA passes were carried out, but inadequate sample material was obtained.All patients provided informed consent. EUS was done using the curvilinear echoendoscope  as previously described . PatientThe study was approved by the institutional review board (IRB) at the University of Florida, and all patients signed informed consent.Continuous variables were reported as means and standard deviation, while categorical variables were reported as proportions. Statistical analysis was performed by using SAS version 9.1 . The sensitivity, specificity, positive predictive value, and negative predictive value of EUS 1 and EUS 2 were calculated. 95% confidence intervals of those statistics were also calculated for comparison .From January 2002 to November 2008, total of 3895 patients underwent EUS in our institution. Of these, 30 (0.77%) had repeat EUS-FNA for the evaluation of possible pancreatic cancer. Two patients were excluded since tissue diagnosis of malignancy was established with the first EUS-FNA, but a repeat study was requested to obtain additional tissue for special staining. The remaining 28 patients , mean age 62 years (range 34\u201382), were included in the analysis, and the results are reported.The most common presenting symptoms were abdominal pain (78.57%), weight loss (64.29%), and nausea/vomiting (39.29%) . The indInitial EUS evaluation showed pancreatic mass in 24 (85.71%), no mass in 3 (10.71%) patients, and possible mass in 1 (3.58%). FNA was done in all 28 (100%) patients. Initial exam was limited, and less than four FNA passes were made in 5 patients (17.86%) due to difficulty in positioning the echoendoscope or sedating in 3 patients (10.74%), presence of ascites and vascular collaterals in 1 (3.58%), and food obstructing view in 1 (3.58%). The mean number of FNA passes on initial EUS was 4.82 . Cytologic evaluation of the FNA specimen was \u201catypical\u201d in 1 (3.58%), \u201csuspicious\u201d in 4 (14.28%), and \u201cbenign/reactive\u201d in 23 (82.14%). No complications were related to the first EUS.Repeat EUS was performed in all patients after mean of 33 days (range 2\u2013140 days) from the initial EUS exam. At the second EUS-FNA, a pancreatic mass was seen in 27 patients (96.42%) and no mass in 1 (3.58%). The patient in whom no mass was seen had a distal bile duct stricture and biliary stent. FNA was obtained from the area immediately surrounding the stent. Cytology was positive for malignancy on repeat EUS-FNA in 6 (21.43%) patients. The second EUS established the tissue diagnosis of malignancy in 1 (3.58%) patient with prior atypical/suspicious findings at the first EUS and in 5 (17.85%) of the patients with benign/reactive initial cytology. Based on the location of the lesion, malignancy was diagnosed at the second EUS-FNA in 3 (50%) of the lesions in the head/uncinate process and in 3 (50%) of the lesions in the neck, body, and tail. The mean number of FNA passes on the repeat EUS examination was 4.82 (range 2\u20138). Overall repeat EUS-FNA established definitive tissue diagnosis of malignancy in 6 out of 28 patients (21.43%). There were not complications related to the second EUS.n = 17).Out of the 28 patients in this cohort, 17 (60.71%) were eventually confirmed to have cancer. Tissue sampling confirmed malignancy in 11/17 (64.71%), and clinical criterion  established malignancy in 6/17 (35.29%). Of the 11 patients in whom the diagnosis of malignancy was established by tissue pathology, adenocarcinoma was present in 8/11(72.73%), and there was one case of neuroendocrine tumor (9.09%) lymphoma (9.09%) and spindle cell neoplasm (9.09%). Repeat EUS-FNA was able to provide tissue confirmation in 6 (35.29%) of the patients eventually found to have pancreatic malignancy  of the patients were considered to have no malignancy. One (9.09%) was diagnosed with autoimmune pancreatitis, 4 (36.36%) had chronic pancreatitis-associated inflammatory head masses which eventually resolved on followup imaging, 2 (18.18%) had chronic calcific pancreatitis, and in 4 (36.36%) patients no definitive diagnosis was established. Of these 4 patients without established definitive diagnosis but classified as having benign disease, two had a pancreatic mass by both CT and EUS; however, both died from unrelated causes, respectively, two and a half and three years after presentation. The third patient had a suspected pancreatic mass on CT scan, but definitive mass was not seen on EUS. EUS-FNA was repeated total of three times, and all cytology specimens were benign. The patient is still alive and stable over 2.5 years. Lastly, the 4th patient was lost to followup and was considered as having benign disease in this intention to treat analysis. Repeat EUS-FNA correctly determined the true final status in 17 out of 28 patients providing a sensitivity for the diagnosis of cancer of 35% (95% CI 14%\u201362%), specificity of 100% (95% CI 72%\u2013100%), and overall accuracy for determination of the true final status of the patients of 61% (95% CI 28%\u201372%).The main finding of our study is that, in patients with suspected pancreatic cancer and negative EUS-FNA, repeat EUS-FNA had a moderate clinical yield. Repeat EUS-FNA was accurate in predicting the final malignant/benign status in 61% of the patients and provided positive tissue diagnosis in 35% of the patients eventually found to have pancreatic malignancy. At present, there is no universally accepted strategy on how to manage patients presenting with clinical history and imaging findings suggestive of pancreatic malignancy but who have negative cytology on EUS-FNA. The currently available options consist of clinical observation with serial imaging, CT-guided biopsy, surgical exploration with \u201cblind\u201d pancreatic resection, chemoradiation therapy without definitive tissue diagnosis, and repeat EUS-FNA. Clinical observation is rarely a feasible option due to the high anxiety associated with the potential diagnosis of pancreatic cancer, and CT-guided biopsy has fallen out of favor mostly due to the increased risk of intraperitoneal spread of the cancer via the needle track and worse outcome even in patients that are not surgical candidates . SurgicaOur study is not without limitations. All cases were done in a tertiary referral center by highly experienced endosonographers raising concerns about the applicability of our findings in various practice settings. Furthermore, our patient population is relatively small, and therefore the study did not have enough power to evaluate for any predictors for success/failure for the repeat EUS-FNA. In addition, in our study, we aimed to obtain minimum of 4 FNA passes per patient. Unfortunately, there is no uniform consensus on the optimal number of needle passes needed to obtain correct diagnosis. Earlier findings demonstrated that an average of 3.44 passes provided adequate cytological sampling, but more recent higher quality prospective study revealed that 7 passes are needed to achieve FNA sensitivity of 83% , 12. FinIn conclusion, in patients with suspicion for pancreatic cancer and negative EUS-FNA, a repeat EUS-FNA can provide tissue diagnosis in approximately one-third of patients eventually found to have malignancy. Although repeat EUS-FNA provides a relatively low sensitivity and accuracy, it still appears an attractive option given its minimally invasive nature, excellent safety record, suboptimal alternatives for tissue sampling, and the ramifications of a lack of definitive tissue diagnosis."}
+{"text": "Primary exertional headache is included in \"Other Primary Headaches\" (Group 4) in the International Classification of Headache Disorders, 2nd edition (ICHD-II) with primary cough headache, primary sexual headache, and idiopathic stabbing headache. The prevalence of primary exertional headache showed about 1-30.4%.We investigated about prevalence and characteristics of primary exertional headache in Korean marine corps.704 patients were treated due to headache. 79 patients of them suffered from exertional headache. We assessed characteristics of patients, comorbidity of migraine, nature of headache, Visual Analog Scale(VAS), neurologic symptoms, exercise which prompted the headache, and effect of medication. Effect of medication also evaluated with VAS.10.38% of headache group was diagnosed as primary exertional headache. Average age was 20.6 year old and only 1 of 73 patients was female because of homogeneity of military corps. Most quality of headache is pulsating nature (93%) and most location of the headache is bilateral(84%). 3 patients had history or comorbidity of migraine(4%). 16 patients had accompanied symptoms, such as nausea(13 patients), photophobia(1 patient), dizzy sense(2 patients). In analyses of provoked factor, anaerobic exercise is most prompted cause of the headache (67%). 15 patients were provoked due to swimming, and other patients suffered from headache after running, or other aerobic exercise. Average of VAS score was 8.48. After treatment, the score was decreased to 3.40.Prevalence of primary exertional headache in Korean marine corps is similar to previous population-based studies. Low rate of comorbidity of migraine and neurologic symptoms was differed from these studies. Anaerobic exercise and swimming are revealed frequent inducing factors of primary exertional headache. Because of significant lowering VAS scale, ergotamine might be useful drug to treat the headache."}
+{"text": "Positive fluid balance has been associated with an increased risk for mortality in critically ill patients with acute kidney injury with or without renal replacement therapy (RRT). Data on fluid accumulation prior to RRT initiation and mortality are limited. We aimed to study the association between fluid accumulation at RRT initiation and 90-day mortality.We conducted a prospective, multicenter, observational cohort study in 17 Finnish intensive care units (ICUs) during a five-month period. We collected data on patient characteristics, RRT timing, and parameters at RRT initiation. We studied the association of parameters at RRT initiation, including fluid overload (defined as cumulative fluid accumulation > 10% of baseline weight) with 90-day mortality.P < 0.001. In logistic regression, fluid overload was associated with an increased risk for 90-day mortality (odds ratio 2.6) after adjusting for disease severity, time of RRT initiation, initial RRT modality, and sepsis. Of the 168 survivors with data on RRT use at 90 days, 34  were still dependent on RRT.We included 296 RRT-treated critically ill patients. Of 283 patients with complete data on fluid balance, 76 (26.9%) patients had fluid overload. The median (interquartile range) time from ICU admission to RRT initiation was 14 (3.3 to 41.5) hours. The 90-day mortality rate of the whole cohort was 116 of 296 . The crude 90-day mortality of patients with or without fluid overload was 45 of 76 (59.2%) vs. 65 of 207 (31.4%), Patients with fluid overload at RRT initiation had twice as high crude 90-day mortality compared to those without. Fluid overload was associated with increased risk for 90-day mortality even after adjustments. Four to eight percent of intensive care unit (ICU) patients receive renal replacement therapy (RRT) for acute kidney injury (AKI) -4. The oNo studies presenting cumulative fluid balance from ICU admission to RRT initiation exist. Therefore, we aimed to evaluate the association of factors at RRT initiation and especially cumulative fluid accumulation with 90-day mortality in critically ill adults.We performed a prospective, observational cohort study, the FINNAKI study, from 1 September 2011 to 1 February 2012, in 17 Finnish ICUs. The referral areas of these ICUs cover 85% of the Finnish adult population. The Ethics Committee of the Department of Surgery, Hospital District of Helsinki and Uusimaa approved the study protocol and the use of deferred consent with a signed, informed consent from the patient or a proxy obtained as soon as possible. The Finnish National Institute of Health approved the collection of data from medical records of deceased patients if an informed consent could not be obtained.We included all adult patients with either emergency ICU admission or elective post-operative ICU admission with an expected ICU stay of more than 24 hours. We excluded patients 1) with end-stage renal disease (ESRD) on chronic dialysis 2) who had already participated in the FINNAKI study and had received RRT during that previous ICU admission 3) not permanently living in Finland or having insufficient language skills for giving an informed consent, and 4) on intermediate care   and SimpWe calculated the total cumulative fluid balance from ICU admission to RRT initiation (including the day of RRT initiation) and defined the percentage of fluid accumulation by dividing the cumulative balance in liters by patient's baseline weight and multiplying by 100%. We then used the cutoff value of 10% of fluid accumulation as a definition of fluid overload ,23. We ath to 75th percentiles). We used Fisher's exact test to compare proportions and Mann-Whitney U-test to compare continuous data and calculated 95% confidence intervals (CI) for the main outcome. We studied factors associated with 90-day mortality with backwards logistic regression. We used stepwise elimination approach and a significance level of < 0.05 for entry and > 0.10 for removal. We entered the following variables: age, SAPS II score without age points, non-renal SOFA score on the day of RRT initiation, time from ICU admission to RRT initiation (days), initial RRT modality (continuous or intermittent), lactate (mmol/L), base excess (mmol/L), and plasma creatinine (umol/L) at RRT initiation, cumulative urine output on the day of RRT initiation, colloid use prior to RRT initiation (including data from ICU stay and 48 hours prior to ICU admission), presence of severe sepsis (yes/no) during the ICU admission, and fluid accumulation (%) at RRT initiation. We studied fluid overload (fluid accumulation > 10%) as a categorical variable in a separate model with all other covariates being the same as in the first model. We studied the potential interactions in separate models between degree of fluid accumulation (%) and 1) SAPS II score without age points, 2) day of RRT initiation, and 3) presence of severe sepsis 4) creatinine prior to RRT initiation and 5) urine output on the day of RRT initiation. We tested the goodness-of-fit with the Hosmer-Lemeshow test and calculated the area under the receiver operating characteristic curve (AUC) and correct classification rate. We examined the 90-day survival with Kaplan-Meier curves, and compared survival at 90 days between patients with and without fluid overload at RRT initiation with the log-rank test. We considered a two-sided P value lower than 0.05 as significant and made no corrections for multiple comparisons. In logistic regression, we set the significance level at 0.01. We performed the statistical analysis using the SPSS Statistics version 19.0 .We report data as count and percentages or medians with interquartile range , while patients without fluid overload had renal disease as APACHE III admission diagnosis  more frequently. Other baseline characteristics and parameters at RRT initiation stratified according to fluid overload status are presented in Table Of 283 patients with complete data on fluid balance, 76 (26.9%) patients had fluid overload Figure . Patientn = 230) was 3 (2 to 6) and number of intermittent RRT (n = 163) sessions 2 (1 to 4).The median (IQR) number of reported indications for RRT was 3 (2 to 4). The most common indications were oliguria in 223 (78%), high creatinine in 196 (70%), acidosis in 181 (65%), and fluid accumulation in 116 (43%) patients. RRT was initiated on the first ICU treatment day in 124 (41.9%), on day two in 86 (29.1%), on day three in 37 (12.5%), and on day four or after in 49 (16.6%) patients. When patients were classified according to the day of RRT initiation, the degree of fluid accumulation increased until the day three  died in hospital and 116  before day 90. The SAPS II -based standardized mortality ratio (95% CI) was 0.64 (0.52 to 0.78). The hospital mortality of patients with or without fluid overload was 43 of 76 (56.6%) and 49 of 207 (23.7%), P = 0.375), an AUC of 0.816 (95% CI 0.767 to 0.866), and correct classification rate of 74.4%. The results of the final model are presented in Table In logistic regression for 90-day mortality, no interactions between fluid accumulation percentage and 1) SAPS II score without age points, 2) time from ICU admission to RRT initiation, 3) presence of severe sepsis 4) creatinine prior to RRT initiation, or 5) urine output on the day of RRT initiation were present. The final model with fluid overload studied as categorical variable had Hosmer-Lemeshow chi-square 8.6  at RRT initiation had higher crude mortality compared to those without and had an increased risk for 90-day mortality after adjusting for disease severity, time of RRT initiation, RRT modality, and presence of severe sepsis.\u2022 At 90 days, 19% of survivors were still dependent on RRT.AKI: acute kidney injury; APACHE: Acute Physiology and Chronic Health Evaluation; AUC: area under the receiver operating characteristic curve; CI: confidence interval; CRRT: continuous renal replacement therapy; ICU: intensive care unit; IQR: interquartile range; OR: odds ratio; RRT: renal replacement therapy; SAPS: Simplified Acute Physiology Score; SOFA: Sequential Organ Failure Assessment.The authors declare that they have no competing interests.STV carried out the data analysis and drafted the manuscript. AMK, KMK and SN participated in designing the study. OI, SH, JL, LM, MR, VL and IP critically revised the manuscript. VP designed the study and helped to draft the manuscript. All authors participated in the data collection and read and approved the final manuscript.Figure S1: Median daily balance (mL) after renal replacement therapy initiation.Click here for fileFigure S2: Median fluid removal (mL) with renal replacement therapy.Click here for fileFigure S3: Percentage of fluid accumulation prior to RRT initiation according to RRT initiation day.Click here for file"}
+{"text": "Chronic viral hepatitis, not an uncommon situation in clinical practice, raises problems when it comes to the evolution and management of the HIV co-infection. The objective of this paper was to evaluate the prevalence, etiology and evolution of chronic viral hepatitis infections among HIV infected patients (HIP).We performed an observational, retrospective study (1994-2010) on 826 HIP in the evidence of the Craiova HIV/AIDS Regional Centre; we analyzed the clinical and biological data regarding the viral hepatitis chronic infections among HIP.Of the 826 HIP evaluated during the study period, chronic HBV infection was found in 198 HIP (23.97%), chronic HCV infection in 6 HIP (0.73%). Chronic HBV-HDV coinfection was detected in 6 HIP  and chronic HBV-HCV coinfection in 2 HIP (0.24%). The evolution of chronic HBV infection during the study period was as follows: HBs seroconversion in 8 HIP (4.04%), chronic hepatitis-167 HIP (84.34%), cirrhosis-17 HIP (8.59%), undefined (lost to follow-up)-6 HIP (3.03%). Complete data necessary for the evaluation of HBV infection phase were available for 27 HIP; according to these data, the distribution of the evaluated subjects was as follows: HBe antigen negative chronic hepatitis B was detected in 8 HIP (29.63%), HBe antigen positive chronic hepatitis B in 6 HIP (22.22%) and immune control phase in 13 HIP (48.15%). 54 deaths (27.27%) were recorded among chronic HBV infected subjects; 18 deaths (9.10%) were liver related. The evolution of chronic HCV infection during the study period was as follows: chronic hepatitis in 3 HIP (50%) and cirrhosis in 3 HIP (50%). 1 death (16.67%) was recorded among chronic HCV infected subjects; this death was liver related.Chronic viral hepatitis infections are common among HIP, and chronic HBV infection occupies an important place. The evolution of chronic viral hepatitis infections raises problems through its increased morbidity and mortality."}
+{"text": "Background. To describe the standard autofluorescence (FAF), the near infrared autofluorescence (NIA) and optical coherence tomography (OCT) patterns in central serous chorioretinopathy, correlating them with fluorescein angiography. Methods. Cross-sectional observational study, in which patients with at least seven months of CSC underwent ophthalmologic examination, fundus photography, FAF, NIA, fluorescein angiography (FA), and spectral-domain OCT. Results. Seventeen eyes of thirteen patients were included. The presentation features were a mottled hyperFAF in the detached area and areas with pigment mottling. NIA images showed areas of hyperNIA similar to FAF and localized areas of hypoNIA, which correlated with the points of leakage in the FA. OCT showed pigment epithelium detachment at the location of these hypoNIA spots. Discussion. FAF showed increased presence of fluorophores in the area of retinal detachment, which is believed to appear secondary to lipofuscin accumulation in the RPE or the presence of debris in the subretinal fluid. NIA has been related to the choroidal melanin content and there were areas of both increased and decreased NIA, which could be explained by damage ahead the retina, basically RPE and choroid. These findings, along with the PEDs found in the areas of hypoNIA, support the notion of a primary choroidal disease in CSC. Central serous chorioretinopathy (CSC) is an idiopathic syndrome of young to middle-aged adults, characterized by serous detachment of the neurosensory retina with focal and multifocal areas of leakage at the level of the retinal pigment epithelium (RPE), predominantly affecting the macular area . PatientThe understanding of the physiopathology of CSC remains limited due to the lack of significant histopathologic studies. Investigational and diagnostic tools such as fluorescein and indocyanine green angiography have provided some insight into the mechanism of this disease . OpticalThe purpose of this study was to describe NIA and SD-OCT findings in CSC, correlating them with fluorescein angiography (FA). To our knowledge, this is the first study that investigates the correlation between the clinical findings and different imaging modalities, specially with NIA.This is a retrospective, cross-sectional study were patients with CSC were included from September 2008 to May 2009 at the Federal University of Sao Paulo. This study was conducted in accordance with the Declaration of Helsinki and was approved by the ethics committee of the Federal University of Sao Paulo. All patients had experienced symptoms for at least 7 months and none of them had previous treatment.Each patient underwent ophthalmologic examination, color fundus photography, FAF and NIA imaging, fluorescein angiography (FA), and HRA Spectralis spectral-domain OCT (SD-OCT) . The OCT protocol used was volume in the SD-OCT. The volume size was individualized for each patient. FAF, NIA, and FA imaging were performed with the Heidelberg Retina Angiograph 2 system . FAF and NIA images were recorded at 488\u2009nm, using a barrier filter for detection of emitted light above 500\u2009nm, and 787\u2009nm, respectively. At least 5 single AF images of 512 \u00d7 512 pixels were acquired with each method. Several images were aligned and a mean image was calculated after detection and correction of eye movements using image analysis software.Abnormal AF was defined as either increased or decreased fundus AF in comparison with background fundus AF , and claWe included 17 eyes of 13 patients, eight males, and five females, presenting CSC with a mean time of complaint of 12.7 months, ranging from 7 months to 2 years, with age ranging from 26 to 53 years (mean age of 39.3 years). Two individuals had history of using steroids, but had stopped the use for at least 6 months. Fifteen patients had a relapsing desease and two were in the first episode.Fluorescein angiography showed in 8 (47%) eyes focal leakage, in 1 (5.9%) multifocal leakage, in 4 (23.5%) multiple window defect with diffuse leakage, and in 4 (23.5%) no leakage. Ten eyes exhibited serous retinal detachment. Of those, 1 presented with multifocal leakage, 7 with focal leakage, and 2 with RPE changes and multiple windows defects. The detached area revealed hyperFAF in 7 (70%), mixedFAF in 2 (20%), and hypoFAF in 1 (10%). HypoNIA could be seen in 5 (50%), mixedNIA in 2 (20%), and hyperNIA in 3 (30%). The areas of window defects seen at FA in 8 eyes showed hyperFAF in 6 (75%), mixedFAF and hypoFAF in 1 eye each (12.5%). Concerning NIA of the window defects areas, we could find 5 eyes indicating hypoNIA (62.5%) and 3 mixedNIA (37.5%). The overall FAF images revealed hyperFAF in 12 (70.6%) eyes, hypoFAF in 3 (17.6%) eyes, and mixed FAF in 2 (11.8%) eyes. The overall NIA images presented hyperNIA in 4 (23.5%) eyes, hypoNIA in 10 (58.8%), and mixed NIA in 3 (17.6%) eyes. Twelve of thirteen eyes with leakage showed a hypoNIA exactly at the leaking spot. A hypoFAF was found in 3 eyes in the leakage site. The location of autofluorescence alterations were perimacular, following the leakage and the RPE damage sites .\u03bcm, ranging from 220 to 533\u2009\u03bcm. Pigment epithelium detachment (PED) in foveal and/or extrafoveal spots was identified in 11 of the 13 patients, in a total of 22 PEDs in 15 of 17 eyes. Twelve (54.5%) were foveals and ten extra foveals (45.4%). We could observe in 5 eyes a substantial RPE irregularity, characterized by RPE undulations, 2 of them without PED. The Spectralis OCT images revealed 10 (58.8%) foveal neurosensory retinal detachment. The mean foveal retinal thickness was 332.6\u2009A hyperNIA spot in the NIA images could be seen in 8 36.4%) of the PEDs and in 14 (63.6%) corresponding to hypoNIA sites. In 7  of the 14 PEDs that corresponded to hypoNIA images, we could identify a hyperNIA \u201cring.\u201d In 14 (63.6%) of the PEDs, we found that the PED corresponded exactly with the leakage spot detected in FA, and 7 (31.8%) PEDs corresponded to window defect areas in FA, while 1 (4.5%) PED did not correlate with FA alterations. The 14 PEDs that correlated with the point of leakage showed a hyperNIA point in 5 (35.7%) PEDs, hypoNIA with hyperNIA \u201cring\u201d in 4 28.6%), and hypoNIA without ring in 5 (35.7%) of the leakage PEDs . Almost 60% of PEDs corresponded to leaking sites that corresponded to hypoNIA areas, and twelve of thirteen eyes that showed leakage had a hypoNIA spot exactly at the leaking spot. Although FA is still an important exam for the management of CSC, these findings may be useful in guiding the treatment, since OCT and NIA may provide the location of leakage points by means of a noninvasive, dye-free examination, providing safety and precision for the patient and the doctor, matching with the treatment safety pursuit, as we can expect from the subthreshold diode micropulse photocoagulation . This is"}
+{"text": "Animal studies suggest a life-saving benefit for intra-arrest cooling. Transnasal evaporative cooling has sufficient heat transfer capacity for effective intra-arrest cooling and improves survival in swine. A 200-patient study showed transnasal cooling to be a safe and feasible method of intra-arrest cooling. The study also showed a solid trend to improved neurologically intact survival rates in those patients receiving intra-arrest transnasal cooling.To determine effects on neurologically intact survival at 90 days from the addition of intra-arrest transnasal cooling compared with hospital-based cooling alone, patients in witnessed cardiac arrest of any rhythm and with CPR \u226415 minutes after a 112 call were randomized to intra-arrest transnasal cooling versus standard ACLS care in two European EMS systems. Transnasal cooling (RhinoChill (RC); BeneChill Inc., San Diego, CA, USA) was initiated using a mixture of volatile coolant plus oxygen for rapid evaporative heat transfer. In treatment patients, cooling was initiated pre-ROSC, during ongoing CPR. Patients in both groups were cooled upon hospital arrival.Forty-one patients have been included thus far. The median time from the 112 call for EMS to start CPR was 7 minutes and the time to initiate cooling was 17 minutes. ROSC was achieved in 8/19 (42%) of the RC group versus 8/22 (36%) of the control group. Site 1 initiated cooling at 11 minutes, and the ROSC rate at this site was 3/6 (50%) for RC and 1/9 (11%) for controls. EMS CPR was initiated at 5 minutes in RC versus 7 minutes in controls. Site 2 initiated cooling at 20 minutes, and the ROSC rate for this site was 5/13 (39%) for RC compared with 7/13 (54%) in the controls. EMS was initiated at 7 minutes in RC versus 9 minutes in controls.Initiating transnasal cooling extremely early during arrest may be superior to later intra-arrest initiation in relation to ROSC rates. The impact of this ultra-early cooling on outcome remains to be determined."}
+{"text": "To the Editor: Certain arthropod-borne epornitic flaviviruses, namely, West Nile virus (WNV) and Usutu virus (USUV), have spread recently in parts of Europe (Alectoris rufa) and 13 common pheasants (Phasianus colchicus) were collected on 12 hunting properties from C\u00e1diz  , BAGV (p<0.0001), and USUV (p<0.0001) . The sigNeutralizing antibodies to >1 flavivirus were detected in 15 of the 45 VNT-positive partridges and in 6 of the 12 VNT-positive pheasants . SpecifiAnalysis of VNT results in juvenile partridges showed specific neutralizing antibodies to WNV (13%) or BAGV (9%); 4% of these samples were positive for flavivirus but inconclusive for any of the flaviviruses tested . OverallEvidence of infection by at least WNV and BAGV in 2 consecutive seasons strongly supports the premise that these viruses overwintered in the area. Capability of WNV to overwinter in southern Europe was shown in Italy during 2008\u20132009 (Study area in Spain (province of C\u00e1diz) showing the position of hunting properties analyzed."}
+{"text": "Aims. Our objective was to examine Apo J protein expression in a total of 27 early liveborn neonatal deaths (less than 7 days of age) selected from the Scottish Perinatal Study (gestation of 25\u201342 weeks) comparing a group with histological pontosubicular necrosis (PSN) (n = 12) to a control group lacking PSN (n = 15). Methods. Using immunohistochemistry we evaluated postmortem pons and hippocampus from patients with PSN versus controls. Results. In the group with PSN, 11/12 (92%) cases showed positive Apo J neurones in the hippocampus/pons compared with 6/15 (40%) cases without PSN \u2014independent of gestation, presence or absence of clinical asphyxia, duration of labour, or postnatal age. Clinical asphyxia was present in 10/15 (67%) without PSN compared with 11/12 (92%) with PSN. Neuronal Apo J positivity was present in 15/21 (71%) of clinically asphyxiated cases compared with 2/6 (33%) of the cases with no evidence of clinical asphyxia . Conclusions. Apo J neuronal protein expression is significantly increased in cases with PSN compared to cases without PSN\u2014independent of gestation, presence of clinical asphyxia, duration of labour, or postnatal age.  Apolipoprotein J (Apo J),  was first identified from chromaffin granules of the bovine adrenal medulla and in the ram rete testis , 2. LikeAt a molecular level, Han et al. have shown in an experimental animal model of HI that Apo J accumulates in dying neurones and that Apo J-null mice suffered 50% less brain injury compared with wild-type mice subjected to HI (hypoxic/ischaemic) insults .Pontosubicular necrosis (PSN) describes the association on histology between hypoxic death of neurones in the ventral pons and the subiculum in human neonates. Experimental studies have shown that the mode of death in these neurons is apoptosis . We examn = 12) or absence (n = 15) of pontine and/or hippocampal neuronal eosinophilia or karyorrhexis following review of routinely stained sections (haematoxylin and eosin). An anti-Apo J (clusterin) antibody  was used at a dilution of 1\u2009:\u20091000 after pretreatment with 0.01\u2009M citrate buffer in the microwave for 3 \u00d7 5 minutes and visualised with diaminobenzidine. A wider survey of Apo J in other areas in the brain was undertaken in 2 of the positive cases and negative cases. Positive controls included biopsies from a Burkitt's lymphoma and Alzheimer's disease conditions in which clusterin expression has been previously described [U, and prism statistical software.27 cases were selected from the Scottish Perinatal Neuropathology Study, which included Scottish early liveborn neonatal deaths (less than 7 days of age) with the exclusion of infants with known chromosomal, cardiac or central nervous system (CNS) abnormalities, and CNS infections . Detailsescribed , 17. ApoP = 0.584) (see Tables P = 0.599); median postnatal age in the PSN group was 12.72 hours (0\u201351.13) compared with 7.98 hours (0.25\u2013131.67) in controls, (P = 0.495); with no significant differences between groups. Clinical signs of asphyxia were present in 11/12 (91.7%) cases with PSN compared with 10/15 (66.7%) controls without PSN, with no significant difference between groups (P = 0.182).The median gestational age in the cases with PSN was 39 weeks (range 25\u201342 weeks) compared to 34 weeks (24\u201342) in controls without PSN, with no significant difference between groups \u2014independent of gestation, presence or absence of clinical asphyxia, duration of labour or postnatal age (see P = 0.054). 4/12 (33%) cases in the PSN group showed glial expression compared to 7/15 (46%) in the comparison group (P = 0.696). This positivity was localised to the astrocytic cell cytoplasm .In the PSN cases 11/12 (92%) showed Apo J immunopositivity in neurons the base of the pons or hippocampus or both regions compared with 6/15 (40%) with Apo J neuronal positivity in the comparison group \u2014independent of gestation, presence or absence of clinical asphyxia, duration of labour, or postnatal age.Our main finding is significant neuronal Apo J expression in 92% (11/12) of perinatal deaths with pontosubicular necrosis compared with 40% (6/15) of the cases without PSN  . Previous studies have shown that neurones within the trigeminal motor, facial, trigeminal somatosensory, and mesencephalic nuclei in particular contain high levels of Apo J mRNA [We also found Apo J positivity in the brainstem nuclei within the tegmentum of the pons 9/12 (75%) in the pontosubicular necrosis group and 5/15 (33%) in the control group (o J mRNA .P = 0.696). Apo J mRNA has previously been demonstrated in astrocytes and neurones but not microglia [Our study has shown Apo J glial positivity in the group with pontosubicular necrosis 4/12 (33%) and in the group without pontosubicular necrosis 7/15 (46%) with no significant difference between the groups (icroglia . Moreoveicroglia , 20, raiWe found ependymal staining of Apo J in all cases and choroid plexus positivity when present  acting aHan et al. have suggested that in animal models Apo J contributes to caspase-3 independent brain injury or necrosis and have suggested that it may be a therapeutic target for modulating necrotic cell death following acute brain injury . InteresOur results raise the possibility that Apo J is similarly upregulated by hypoxia/ischaemia in the developing human brain, in keeping with animal models and previous studies , 14, 15."}
+{"text": "We assessed neurologic sequelae associated with an enterovirus 71 (EV71) outbreak in South Korea during 2009. Four of 94 patients had high signal intensities at brainstem or cerebellum on magnetic resonance imaging. Two patients died of cardiopulmonary collapse; 2 had severe neurologic sequelae. Severity and case-fatality rates may differ by EV71 genotype or subgenotype. Several major outbreaks of enterovirus 71 (EV71) have been reported since 1974  managed by pediatric physicians . During EV genome detection was attempted by real-time reverse transcription\u2013PCR (RT-PCR) by using TaqMan technology . Briefly, viral RNAs were extracted by using the magnetic bead\u2013based viral nucleic acid purification protocol described by Boom et al.  of all patients and in 321 (66%) of patients with suspected HFMD and herpangina. Samples from 331 (72%) of the 461 EV-seropositive patients were available for genotyping . In addi3 (interquartile range 48\u2013318 cells/mm3), mean (SD) protein level was 43 (18) mg/dL, and mean (SD) glucose level was 69 (13) mg/dL. Of the 32 (34%) patients who underwent magnetic resonance imaging of the brain, 24 (75%) had normal results, 4 (13%) had meningeal enhancement on T1-enhanced imaging, and 4 (13%) had high signal intensity at the brainstem or cerebellum on T2-weighted or fluid-attenuated inversion recovery imaging. All brain parenchymal lesions were located in the brainstem or cerebellum, and the 4 patients with brain lesions subsequently experienced ataxia.Fifty-nine (63%) patients were boys. Mean (SD) patient age was 46 (29) months (range 1 month\u201312 years); 12 (13%) patients were <1 year of age. Initial diagnoses were viral meningitis (60 patients), encephalitis (20), acute cerebellar ataxia (12), acute transverse myelitis (1), and Guillain-Barr\u00e9 syndrome (1). Rash and fever were the most common initial symptoms . Approximately 50% of patients had headache, vomiting, and neck stiffness. Cerebrospinal fluid (CSF) profile was available for 77 patients. Median leukocyte count was 111 cells/mmEV71 was found in 72 (92%) of 78 lower gastrointestinal tract samples, 37 (60%) of 62 upper respiratory tract samples, and 2 (5%) of 37 CSF samples. On the basis of sequence analysis, C4a, with high similarity to strains from China in 2008, was a dominant serotype of EV71 (76%); and C1 was found in 2 patients and C5 in 1 patient.The results of this and previous studies are summarized in The severity of, and case-fatality rate for, EV71 infection in our population were relatively low compared with those of previous reports in which the case-fatality rate ranged from 10% to 26% (We detected EV71 rarely in the CSF of our patients. Possible explanations include the transient presence of the virus in CSF, a lower viral load in CSF, and use of an EV PCR assay that had not been optimized to detect EV71. In our population, the CSF profile of EV71 infection appeared to be broadly similar to that of other cases of viral encephalitis or meningitis. Thus, analyzing the CSF of patients with suspected EV71 infection may provide minimal information.Several studies have shown that EV71 infection rate was most common during the warmer season (We report 94 cases of PCR-confirmed EV71 infection with CNS involvement, including 2 deaths, and provide additional clinical and virologic information about EV71. We confirmed that EV71 commonly involved the brainstem and cerebellum, and therefore ataxia is not uncommon in EV71 infection with CNS involvement. In addition, our study supports the hypothesis that the severity of and case-fatality rates for EV71 infection may differ by genotype or subgenotype of EV71."}
+{"text": "Analysis of polyarteritis nodosa (PAN) characteristics such as laboratory parameters, affected organs, treatment modalities and disease outcome.Our study includes all children aged 1-18 with PAN diagnosed according to EULAR/PRES/PRINTO criteria at Department of Paediatrics, University Hospital Centre Zagreb, Croatia, during the period of 1991-2010.PAN was diagnosed in 12 patients (6 girls and 6 boys). The share of PAN amongst all vasculitides was 4%. The mean age at disease onset was (\u00b1SD) 11.33\u00b13,08 years. Systemic PAN was diagnosed in 7 children (58%), microscopic polyangiitis in 3 (25%), cutaneus PAN in 2 (17%) and classic PAN in 0 (0%). The most consistent symptoms were skin involvement (90%) and arthritis/arthralgia (60%). The CNS was affected in 40% of patients. ESR and CRP were elevated in all patients. Antineutrophil cytoplasmic antibodies were elevated in 3 patients (25%). Antistreptolysin O was elevated in 4 patients (25%). The relation between the severity of skin involvement and involvement of other organs was not found. Therapy mode for all patients was corticosteroids. Immunosuppressive drugs and Rituximab (anti-CD20) were used as additional therapy for patients with severe symptoms. Two patients with microscopic polyangiitis died due to chronic renal and pulmonary failure during the follow-up.In comparison to available studies, we found a difference in distribution of childhood polyarteritis nodosa as well as some clinical characteristics , while other researched features, laboratory and treatment, were similar."}
+{"text": "Beta-thalassemia major (TM) remains to be one of the major health problems particularly in developing countries. Tunisia is a part of the Mediterranean countries mostly affected by this disease which is highly concentrated in small towns in families with low-income earners. The main objectives of this study are to provide a description of the demographic, clinical features and transfusion-related complications in patients with TM living in Tunisia. A standardized questionnaire was sent to clinicians throughout 33 different medical institutions caring for thalassemic patients. 391 transfusion dependant thalassemic patients with a median age of 10.7 years (range 3 months- 31 years) were included in the study. The majority originated from the north west of the country. A moderate iron overload between 1501 and 2500 ng/ml was found in 61patients, while 81 patients (26.9%) had a ferritin level more than 2500 ng/ml and greater than 5000ng/ml in 21 patients (6.9%). 51 patients died from complications related to their disease. Heart failure was the main cause of death. The incidence of cardiac, endocrine, and infectious complications will be reviewed. Preventive measures such as health education, carrier screening and premarital screening remain the best ways for lowering the incidence of these diseases, which might be reflected in financial saving, social s and health benefits. TM is one of the most common hereditary diseases in Tunisia. Although its true incidence is unknown, it is estimated that 4.48 % of Tunisian population harbour thalassemic trait.Lifelong red blood cells transfusion remains the main treatment for severe homozygous beta thalassemia even if hematopoietic stem cell transplantation is more and more utilized being the only definitive curative therapy for homozygous thalassemia.The study was performed as a retrospective and descriptive observation. A standardized questionnaire was sent to clinicians throughout 33 different medical institutions in Tunisia caring for thalassemic patients. The questionnaire was used to collect demographic and clinical data ; markers of iron overload ; transfusion therapy and transfusions complications related to haemochromatosis , chelating therapy .t-test was used to determine differences between continuous variables. The statistical analysis was carried out using software (SPSS version 11.5). A p value <0.05 was considered statistically significant.Statistical analysis: Fisher\u2019s exact test was used to assess intergroup significance between categorical variables, and Student\u2019s Three hundred and ninety one transfusion dependant thalassemic patients  were included in the study. Origin was determined in 382 cases. The majority of the patients come from the west of the country; central west 117cases (30%) and North West 107cases (27.3%). It is important to note that the large migration flows from the western towns of Tunisia to the capital that contributed to the higher appearance of TM in Tunis. However, among the studied patients 22% were from small towns and cared in Tunis, only 5% of them live in the capital. Consanguinity was found in 244 among 324 studied patients (75.3%).Most of the patients 325/391(83.1%) were transfused at intervals of 3\u20134 weeks; 51 patients (13%) were transfused at an interval of 5\u20138 weeks and 15 patients (3.8%)poorly controlled and were transfused only in an emergency situation.). 126 patients (32.2%) received filtrated blood cells while only 14 patients (3.5%) received non phenotypically red blood cells. Transfusion-transmitted infections with hepatitis B and C viruses were diagnosed respectively in 2.3 % and 6.1% of patients. No infection with human immunodeficiency virus was found. A serum antibody screening was realized systematically before each transfusion for 209patients (53.4%) and unevenly for 107 patients (27.3%). Alloantibodies were detected in 26 patients (8.2%) and belonged mainly to rhesus system (76.9%). Direct antiglobulin test was performed in 300 patients. Of the total 300 patients 105 (35%) developed auto antibodies.rd year and 33.3% of patients had started chelation at the age of 3 or later. Deferoxamine was the most commonly used iron chelator (224/391=57.3%) administered initially by intramuscular injection in 191 cases (85.2%) and 99 patients (51.8%) continued to use this route. Subcutaneous bolus injections were used for 61 patients and with infusion pumps for 64 other patients. At the time of the first survey deferasirox was administered to 16.7% and deferiprone was administered only to 12.4% of patients. Serum ferritin levels were evaluated in 301 patients. The majority of the patients revealed high ferritin levels.Chelation therapy was administered to 341 patients (87.2%). Only the third of the patients received chelation therapy before they had completed their 3Fifty- nine patients (19.6%) had serum ferritin levels between 1001 \u2013 1500 ng/ml. A moderate iron overload between 1501 and 2500ng/ml was found in 61patients, while 81 patients (26.9%) had serum ferritin values above 2500 ng/ml and levels higher than 5000 ng/ml were determined in 21 patients (6.9%). The evaluation of serum ferritin levels revealed considerable differences depending on chelating therapy .During two years of the study, a gradual decrease in mean ferritin levels was observed in patients treated with deferasirox versus deferoxamine either administered by pump or independently by injections . Moreover, patients treated with Deferasirox presented with lower mean ferritin levels than those receiving deferiprone (p< 0.001). Analyses of the three treatment groups deferoxamine, deferasirox and deferiprone administered alone showed strong differences between serum ferritin concentrations and treatment groups (p=0.006). Cardiac disorders occurred in 63 among 318 studied patients (19.8%). Mean age of onset was 16.9 years (3\u201330). The youngest patient was died from heart failure related to severe anemia.. Heart failure defined as dyspnea and/or peripheral edema with sinus tachycardia on electrocardiography without signs or symptoms of current or recent infection, thyroid disorders, autoimmune diseases or exposure to cardiotoxic agents was found in 34 among 63 studied patients (53.9%)Pulmonary hypertension was found in 12.5% of the patients while arrhythmias were found only in five among the 63 studied patients. Mean serum ferritin level was significantly higher in patients with cardiopathy compared to those without cardiopathy .Delayed puberty was the most common endocrine complication in this study. It was observed in 46/90 (51.1%) of the patients. Among the 90 patients, 48 were males and 42 were females. Delayed puberty is more common in boys [26/48 boys (54.1%)] than in girls [20/42 (47.6%)]. Growth retardation was seen in 64/239 (26.7%) of patients with mean age 12.9 years (3\u201322years). Thyroid function studies were available for 262 patients. Evidence of reduced organ activity was present in 18 cases (6.8%). Thirteen of 309 patients (4.2%) had diabetes mellitus, all diagnosed after the age of 9 years. The mean age at the time of diagnosis was 15.1 years. Mean serum ferritin level was found to be a contributing factor to endocrine disorders .Splenectomy was performed in 201/372 (54.0 %) of the patients [181 (90%) total splenectomy and 20 (9.9%) subtotal splenectomy]. Mean age of patients at splenectomy was 7 years. Routine vaccination against Streptococcus pneumonia, H. influenzae type b, and Neisseria meningitides had been received by 98.3%, 72 % and 85.2% of patients, respectively. Prophylactic antibiotics with benzylpenicillinbenzatine had been prescribed for 53.5 % of the patients however only 35.8% were treated with oral penicillin.Cholelithiasis was observed in 7.9% of the patients (n = 31). Mean age at detection by ultrasonography was 13 years (range 3\u201322). Twenty four (77.4%) of the 31 patients with cholelithiasis had undergone cholecystectomy (6.1% of the whole population). Mortality occurred in 51/391 (13%) studied patients. The mean age of death was 10.48 years (2\u201321). Heart failure was the major leading cause of death: 20/51 (39%), followed by severe infections: 13/51(25.4%). Five patients (9.8%) died of severe anemia. A significant difference was observed in the rate of mortality related to cardiopathy, type of chelation therapy and serum ferritin levels . 33 deatTunisia is a part of the Mediterranean countries mostly affected by thalassemia, one of the most common genetic diseases in the world. The prevalence of TM is especially high in countries where there are close family marriages.Blood transfusion and iron chelation remain the cornerstone of treatment for patients with TM14DFO was considered for a long time as the gold standard in iron chelation therapy. It has significantly improved life expectancy and the quality of life of patients with iron overload.Heart disease may manifest as pulmonary hypertension, arrhythmias, systolic/diastolic dysfunction, pericardial effusion, myocarditis or pericarditis. 19.8% of our studied patients, suffered from heart disease, compared with a prevalence of 15.1% reported among 566 Sicilian thalassemic patients.19Iron-overload associated endocrinopathy is a frequently reported complication in chronically transfused TM patients with 60% of the patients with a dysfunction of at least one gland.Splenectomy is also beneficial in treating thalassemia major. It reduces patients\u2019 transfusion requirement and iron overload and increases the main level of haemoglobin.TM must be taken as a public health problem in Tunisia. Series of important conclusions can be drawn. First of all, a centralization of care institutions seems to be necessary. Intensified collaboration between smaller regional hospitals taking care of only a few patients and central medical institutions treating a greater number of patients is desirable. The use of individually adjusted intensification of chelation therapy in connection with suitable strategies for treating siderotic complications must be extended. Finally steps need to be taken to develop preventive measures like premarital screening, genetic counseling and prenatal diagnosis because of the cost of treatment depending on the quality of care."}
+{"text": "Sepsis is responsible for a high rate of hospitalization and mortality. Traditional methods for bacterial isolation and identification, such as blood culture, have limitations in sensitivity and specificity and their results usually are not available before 48 to 72 hours. The PCR allows a rapid diagnosis of infectious agents. Broad-range PCR allows an earlier and more sensitive bacterial identification in just one reaction, even after the initiation of antibiotics. Therefore, this study evaluates the use of broad-range PCR in the etiologic diagnosis of septic patients, and compares it with traditional methods of culture.Thirty-five patients with sepsis, admitted to the Emergency Unit of Clinical Hospital of Ribeirao Preto Medical School, were included in the study. Clinical, laboratory, and culture data were collected at hospital admission. On the first day of admission, DNA extraction was performed from serum, plasma and buffy-coat samples from all patients. Broad-range 16S rDNA PCR was then performed using two different pairs of primers (Bak11W/Bak2 and Taf/Tar).Eighteen (51%) patients were female; mean age was 58 \u00b1 18 years; 15 (43%) had severe sepsis and 20 (57%) septic shock, and mortality was 54%. Mean C-reactive protein (CRP) was 14.39 \u00b1 9.52 and 28 (80%) patients have levels of CRP greater than 5.0 ng/l. The primary site of infection was detected in all patients, 20 (57%) patients had respiratory tract infection, nine (26%) urogenital tract infection, three (8.5%) cutaneous infection, and three (8.5%) other sites. Blood culture was positive in 14 (40%) samples. Broad-range PCR was positive in 19 (51%) samples. Only 10 (29%) samples were positive for both techniques. In 11 (31%) patients, neither blood culture nor PCR were positive.Broad-range PCR was effective for diagnosis of bacterial infection in septic patients, and could be an option to be used in patients with severe sepsis and septic shock. Moreover, it is faster than blood culture and can detect bacteria even after the initiation of intravenous antibiotics. The combination of both techniques could increase the likelihood of etiologic diagnostic in septic patients."}
+{"text": "We conducted a bibliometric evaluation to get insight into research activities and tendencies.The search criteria in PubMed were: (1) \u201chuman T-lymphotropic virus 1\u201d as medical subject headings (MeSH) major topic; and (2) publication date from January 2001-December 2010. We retrieved publication year, author names, journal, country of first author, language, free availability, and MeSH terms.The search retrieved 1189 publications by 3969 authors. Twenty-eight authors published >=15 articles. The number of publications did not increase: 600 in 2001-2005 and 589 in 2006-2010. The journals with the highest number of publications are: Journal of virology (126), Retrovirology (58), Blood (47), The Journal of biological chemistry (45) and Virology (41). In 349 publications (30%), the first author was from the USA; Japan contributed 329 publications (28%); Brazil 115 (10%); France 91 (8%); and the UK 54 (5%). The proportion of publications with a first author from Latin America or the Caribbean increased over time ; the proportion with a North American first author decreased . Ninety-six percent (1137) of the publications are in English. The full text of 582 publications (49%) is freely available. The most frequent MeSH terms relate to virology. Clinical/epidemiological MeSH terms are more frequent in publications from Latin America and the Caribbean than elsewhere.The constantly modest number of publications characterizes HTLV-1 as a neglected health problem. The MeSH terms suggest that clinical/epidemiological aspects are investigated much less frequently than virological aspects."}
+{"text": "This study aimed to describe the use of colistin to treat nosocomial infections caused by multidrug-resistant Gram-negative bacteria and to identify risk factors associated with acute kidney injury and mortality in a single center.This prospective longitudinal study evaluates critically ill patients with nosocomial infections caused by multidrug-resistant Gram-negative bacteria. All adult patients requiring treatment with intravenous colistin (colistimethate sodium) from January to December 2008 were considered eligible for the study. Data include demographics, diagnosis, duration of treatment with colistin and 30-day mortality. Data were analyzed using MedCalc 12 .P = 0.032) and vasopressors . Age  and vasopressor use  were independent risk factors for death in the logistic-regression model.Colistin was used to treat an infection in 109 (13.81%) of the 789 patients admitted to the ICU. Colistin treatment started an average of 10 (6 to 14.25) days after admission to the ICU. The 30-day mortality observed in these patients was 71.56%. Twenty-four (22.02%) patients developed acute kidney injury, and 11 of these patients required dialysis. The variables independently associated with the presence of acute kidney injury were concomitant use of vancomycin (OR 3.10; 95% CI 1.10 to 8.69; The concomitant use of vancomycin was associated with increased risk of acute kidney injury. Shock and vasopressors were associated with increased risk for acute kidney injury and death."}
+{"text": "Patients with a partial response (PR) received another course of the same regimen. Patients with a suitable donor and aged <50 years received allogeneic stem cell transplantation . Twenty-three patients (51%) and 3 patients (7%) achieved complete remission (CR) and PR, respectively, following one or two courses of Mito-FLAG, and the overall response (OR) rate was 58%. Nine patients (20%) received allo-SCT and 4 patients (9%) succumbed early. Hematological toxicity and infections were the most prominent toxicities of this regimen. Other toxicities included nausea, vomiting, bleeding, hyperbilirubinemia, renal toxicity and arrhythmia. The probability of overall survival (OS) at 4 years was 19%  and the probability of 4-year disease-free survival (DFS) was 29% for all 23 patients in CR . Our data suggest that Mito-FLAG is a highly effective and well-tolerated salvage regimen for relapsed AML.Patients with relapsed acute myeloid leukemia (AML) have unfavorable prognosis and require innovative therapeutic approaches. In this study we used fludarabine combined with a middle dose of cytosine arabinoside (Ara-C), mitoxantrone and granulocyte-colony stimulating factor (G-CSF) as a salvage therapy for patients with relapsed AML in China. Forty-five patients with relapsed AML were treated with the Mito-FLAG regimen consisting of mitoxantrone (7 mg/m Despite the achievement of an initial complete remission (CR) in the majority of patients with acute myeloid leukemia (AML), the therapeutic results at present remain unsatisfactory. With one or two courses of standard first-line induction chemotherapy, 60\u201380% of patients with newly diagnosed AML achieve CR; however, 50\u201370% of them eventually relapse. The disease-free survival (DFS) rate and the overall survival (OS) rate remain low \u20132. CurreCytosine arabinoside (Ara-C) remains one of the most effective drugs in AML therapy . FludaraBetween December 2003 and March 2008, 45 patients  with relapsed AML were treated with the Mito-FLAG regimen after obtaining informed consent. These patients had received standard first-line induction chemotherapy following initial diagnosis. Hematologic relapse was defined by recurrence of >5% blasts in the bone marrow (BM). Diagnosis and classification of AML were performed according to the French-American-British (FAB) Corporation criteria . The cli2, days 1, 3 and 5), fludarabine , Ara-C  and G-CSF [5 \u03bcg/kg/day subcutaneously from day 0 until the white blood count (WBC) was >20\u00d7109/l].The Mito-FLAG regimen consisted of five days of treatment with mitoxantrone  was established as either 5\u201325% BM blasts, a \u226550% decrease in BM blasts or <5% BM blasts but with Auer rod presence. No remission (NR) was established for patients who did not fulfill the above criteria. BM aspirate was performed following chemotherapy as soon as the patient achieved peripheral blood morphology values required for CR; however, this was not performed later than 50 days from the start of treatment. Early mortality (EM) was defined as mortality from any cause during the first 30 days from the beginning of the Mito-FLAG therapy.The response criteria were established according to revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia . CR was Patients in PR received another course of the same regimen. Patients in CR received allogeneic stem cell transplantation  subsequently if aged <50 years with a suitable donor, whereas those without a donor received maintenance therapy. Antibiotic treatment and supportive care were administered according to local guidelines. Patients with treatment failures received another salvage chemotherapy regimen or palliation therapy subsequently. Hematological and extra-hematological toxicity were assessed according to the World Health Organization (WHO) criteria .DFS was calculated from the first day of remission until the evidence of progression. OS was calculated from the start of Mito-FLAG regimen until mortality.Statistical analysis was performed using the Chi-square test and Kaplan-Meier survival curves were produced. We considered a two-tailed P-value <0.05 to be an indication of statistical significance.Out of the 45 patients, 21 (47%) achieved CR following the first course of Mito-FLAG and 5 (11%) achieved PR. All the patients with PR received second Mito-FLAG regimen and 2 patients achieved CR following the second course. Finally, CR and PR was achieved in 23 (51%) and 3 (7%) patients, respectively, so the overall response rate was 58%. Fifteen patients (33%) were refractory and 4 (9%) succumbed early due to cerebral hemorrhage (n=3) or pulmonary infection (n=1). Patients with abnormal karyotype  had a CR rate of 43.8% and patients with early relapse (n=25) and late relapse (n=20) had a CR rate of 40.0 and 65.0%, respectively. However, analysis of corresponding subgroups stratified according to karyotype and early/late relapse did not show significant differences .9/l) and platelet count (>20\u00d7109/l) was 19 days  and 24 days , respectively. Patients received a median of 5 units  of suspended red cells and 5 units  of apheresis platelets. The incidence of serious infections was high. All but 6 patients experienced fever (temperature >38\u00b0C) during the neutropenic phase. Twenty-one patients (47%) had confirmed grade III\u2013IV infections (according to the WHO criteria), which included pneumonia (29%), sepsis (11%), enteritis (7%), perianal abscess (4%) and stomatitis (2%). The median duration of antibiotic therapy was 25 days . The other WHO grade III\u2013IV toxicities included nausea and vomiting (22%), bleeding (18%), hyperbilirubinemia (4%), renal toxicity (4%) and arrhythmia (2%). The median time of hospitalization was 46 days .Four patients (9%) succumbed early; three from cerebral hemorrhage (n=3) and one from pulmonary infection. As expected, severe myelosuppression was observed in all patients. Hematological toxicity and infections were the most prominent toxicities of the Mito-FLAG treatment. The median number of days to recovery of neutrophil count , the probability of OS at 4 years was 19%  received allo-SCT. Among them, 2 patients received allo-SCT with a matched related donor and 7 patients with a matched unrelated donor. Two patients succumbed due to relapse. Seven patients remained in CR. The median OS time for the patients who underwent allo-SCT was 56 months. The probability of OS at 4 years was 62%  for treating patients of refractory or relapsed AML have been reported. The CR rates were 42 and 52%, respectively, which were similar to FLAG ,21. MitoIn our study, the overall response rate was 58%, similar to that of IDA-FLAG. However, the price of idarubicin is more expensive than that of mitoxantrone in China. In addition, idarubicin has been used in the majority of patients with relapsed AML previously and reuse of idarubicin may result in serious cardiac toxicity and other toxicities. Therefore, Mito-FLAG was selected for relapsed AML in our study. Four patients (9%) succumbed early. Although hematological toxicity and infections were the most prominent toxicities of the Mito-FLAG treatment, the patients recovered quickly. The probability of OS at 4 years was 19% and the probability of 4-year DFS was 29% for all 23 patients in CR. Nine out of 23 patients in CR received allo-SCT and 7 of them remained in CR at the end of follow-up. These results indicate that the Mito-FLAG regimen is a highly effective and well-tolerated salvage regimen in relapsed AML. The toxicity is acceptable, enabling the majority of patients to receive further treatment including allo-SCT."}
+{"text": "The good use of antibiotics stays the best means to protect available ones. Our work aims to estimate the practices of prescription of antibiotics according to the national recommendations in a reference department.A descriptive and analytical prospective audit was conducted from April 2nd till July 2nd, 2012 from all cases of hospitalized patients having benefited from an antibiotic treatment with curative aim.The study concerned 170 patients with a total of 267 prescriptions of antibiotics. The average age was 41 years [15-86 years] and the sex ratio 1.5. The majority of the prescriptions were issued by -doctors in specialization (61.8 %) and- students in the last year of medicine (37.6 %). The main listed infections were: pneumonia (28.3 %), meningitis (21.80 %), opportunist infections during HIV infection (14.70 %) and tetanus (13.52 %). From the point of view of the prescription, 57.70 % of the patients had received a monotherapy: essentially \u00df-lactames (55.43 %), imidazoles (16.5 %) and macrolides (13.9 %). The most commonly used antibiotic combinations were: Amoxicillin-acid clavulanique-spiramycin (37.66 %), ceftriaxone-metronidazole (11.7 %), ceftriaxone-metronidazole-gentamicin (10.4 %). The rate of conformity of the antibiotic prescription with the national recommendations was 74.7 % in particular for the posology (92.50 %), the frequency of administration (95.88 %), the duration of treatment (55.43 %). Only 15.9 % of antibiotic treatments were re-evaluated at the end of 48 hours with a modification of the antibiotic regimen in 60 patients (35.5 %), in particular a broadening of spectrum (83.33 %). The average length of stay was of 14\u00b111 days and mortality was 69.18 %.The rational use of antibiotics is essential to protect available drugs. It would be necessary to train the physicians and to advertise the user guide of antibiotics to improve the quality of the prescription.None declared"}
+{"text": "Hematological manifestations are frequently seen in systemic lupus erythematosus (SLE). Anaemia, leucopenia and thrombocytopenia may result from bone marrow failure or excessive peripheral cell destruction, both of which may be immune mediated. Anaemia is a common manifestation in patients with systemic lupus erythematosus. The most common forms of anaemia, in these patients, are autoimmune hemolytic anemia (AHA), iron-deficiency anaemia (IDA), anaemia of chronic disease (ACD), drug-induced myelotoxicity, anaemia of chronic renal failure and rarely types such as pure red cell aplasia, B12 deficiency anemia and myelofibrosis.To evaluate the types of anaemia in systemic lupus erythematosus and their association with activity of the disease and their impact in quality of life.We examined 86 SLE patients by ACR, 1997 criteria, from them 59 were with hematological abnormalities. Disease duration was calculated from the time at least four and more ACR criteria were fulfilled. Anti-ds DNA antibodies, erythropoietin and ferritin levels were measured at baseline. Disease activity was assessed with the Systemic Lupus Activity Measure (SLAM).The cohort consisted of 59 women with mean age 31.3 \u00b1 1.9 (range 13-68) years and mean disease duration 8 years - 94.56 (range one month to 96 months). Hematological modifications were manifested in 65 (75.6%). Anaemia was more common maniferstation. After the investigations we determined the following forms of anemia: the anemia of chronic disease (ACD) n = 34 (57.6%), iron deficiency anemia (IDA) n = 20 (33.9%), autoimmune hemolytic anemia (AHA) n = 3 (5.1%) and other forms  causes n = 2 (3.4%). Leucopenia was present at 18 (30.5%) patients, limphopenia at 19 (32.2%) patients and thrombocitopenia at 13 (22.0%) patients. Assessment of disease activity by SLAM showed that low disease activity was determined in 12 (20.3%) patients, moderate activity was found in 36 (61.0%) and high activity - in only 11 (18.6%) patients. This demonstrated that in examined patients was predominant moderate activity 61.0% cases and ACD 57.6%.Anaemia is a common manifestation in SLE and it is closely associated with moderate disease activity.These associations are observed after one year of evolution of systemic lupus erythematosus. Different levels of anaemia may be used to monitor the disease activity."}
+{"text": "The aim of this retrospective analysis was to review treatment decisions and outcomes in HIV positive patients with acute hepatitis C in a routine clinical setting. Outbreaks of acute HCV infection have been described in several cities recently. The epidemic affects mainly MSM who are coinfected with HIV and is supposedly linked to certain sexual risk practices. Here, we compared our findings with current knowledge and recommendations.HIV-positive patients with the diagnosis of acute HCV infection were included in the retrospective analysis. The patients came from outpatient infectious disease centers in northern German cities. We looked at markers of HIV and HCV infection and compared patients who received treatment and those who did not. Treated patients were followed up to 72 weeks.3 (range 55-1331 cells/mm3). Two hundred and forty-six patients (77%) received anti-HCV treatment, and 175 (55%) had completed therapy by the time of the analysis. Median treatment duration was 33 weeks (IQR 24.1-49.9). 93 of the 175 treated patients (53%) reached a sustained virological response (SVR). Treatment duration was significantly higher in the SVR group . Seventy-three patients (23%) did not receive anti-HCV treatment. In 19 of the untreated patients (26%) the hepatitis C virus was cleared spontaneously.Three hundred nineteen HIV-positive patients with acute hepatitis C between 2001 and 2008 and were included in the analysis. All patients were male, 315 (99%) patients were of Caucasian origin, 296 (93%) declared homosexual contacts as a risk factor for HCV infection, intravenous drug use was declared in 3 (1%) cases. Median age at HCV diagnosis was 40 years (range 20-69 years). Median HCV viral load was 1.2 x 106 IU/mL. The HCV genotype distribution was as follows: 222 patients (70%) had genotype 1, 7 (2%) genotype 2, 26 (8%) genotype 3, 59 (18%) genotype 4. The median time of HIV infection was 5.5 years (range 0 to 22.4 years). Median HIV viral load was 110 copies/mL (range 25 to 10x106 copies/mL). The median CD 4 count was 461 cells/mmOur findings indicate that acute hepatitis C in HIV infected patients affects mainly MSM who acquire HCV sexually. Patients had a short duration of HIV infection and a stable immunological situation. In this real-life setting from urban regions in northern Germany, treatment rates appear to be high and effective."}
+{"text": "Almost 20% of adverse airway events reported to the Royal College of Anaesthetists 4th National Audit Project (NAP4) occurred in the ICU . NAP4 coA survey was sent to an intensivist at each of the 23 adult ICUs in Scotland.There was a 100% response rate. Nineteen (83%) units used capnography for all tracheal intubations on the unit, two (9%) in over three-quarters, one (4%) in under one-half and one (4%) unit reported never using it. For tracheal intubations prior to unit admission, the corresponding usage was three (13%) always, seven (30%) in over three-quarters, seven (34%) in over one-half and six (26%) in less than one-half of all intubations. Continuous capnography monitoring was in use on 54% of the intubated patients and 63% of the ventilator-dependent patients. Twelve (52%) units reported using capnography in all the intubated and ventilated patients. Of the units not using continuous capnography routinely, two (18%) had no equipment for continuous monitoring.UK Intensive Care Society (ICS) guidelines make strong recommendations for the use of capnography in all critically ill patients during intubation . We show"}
+{"text": "The study was performed to investigate the expression of chemokine receptors (CR) on circulating tumor cells (CTC), which may be of importance for organ-specific metastases and cancer treatment since CR are potential drug-targets.Blood samples from patients with metastatic carcinoma (MC) or melanoma (MM) were enriched for CTC and expression of CR  was evaluated by flow cytometry.CTC were detected in 49 of 68 patients (72%)  with a median number of 3 CTC (range: 1-94)/10 mL of blood. CXCR4 was expressed on CTC in 82% (40/49) of patients  and CCR6 in 29 patients . In MM patients, CCR7 was expressed on CTC in 6 (29%) samples and CCR9 in 12 (57%). A positive correlation between surface expression of CR and organ-specific metastatic pattern was not observed.CR were expressed on CTC of patients with solid tumors. Along with our findings, the observation that CR could be involved in CTC proliferation and migration of tumor cells appoints CTC as potential CR-antagonist therapeutic target. The presence of circulating tumor cells (CTC) was first described in 1869 by Thomas Ashworth. Cells similar to the ones of the tumor were observed in the blood of a man with metastatic cancer  and 39 by metastatic carcinoma [MC]. Twenty mL blood anticoagulated with heparin was collected after informed consent from each patient. Blood was collected before treatment start irrespective of the line of treatment. Samples were drawn after discarding the first 2 mL of blood to avoid potential skin cell contamination from venipuncture and processed within 1 hour after sampling.3 and 0.1 mM EDTA in deionized water) was used to lyse erythrocytes. Cells were subsequently washed with a buffer consisting of phosphate-buffered saline (PBS) containing 0.5% bovin serum albumin (BSA), and 2 mM ethylenediaminetetraacetic acid (EDTA). Cells were counted and resuspended in the buffer at a concentration of 1 \u00d7 108 cells/mL and then enriched for tumor cells by CD45 depletion of the leukocyte fraction using a magnetic bead separation technique  as previously described [Red blood cell lysis buffer . Cells were centrifuged at 200 \u00d7 g for 5 minutes; supernatant decanted ensuring that approximately 200 \u03bcL of SAP buffer remained in the tube. Cells were subsequently stained with antibodies specific for cytokeratin (CK) 7 and 8  and incubated for 20 minutes in the dark at 4\u00b0C.In case of carcinomas cells were stained on the surface with a cocktail containing EpCAM , CXCR4 ; CCR6  and CD45 . For intracellular staining cells were fixed with 1% formaldehyde and thereafter permeabilized. Briefly, pellet was resuspended in 2 mL of a sterile solution containing 0.1% saponin, 0.05% NaNIn case of melanoma, cells were stained on the surface with melanoma-associated chondroitin sulphate proteoglycan , CXCR4 (BD Biosciences); CCR6 (eBiosciences); CCR7  and CCR9 .Cells were acquired on a FACSCanto II system (BD Biosciences) and the whole volume was evaluated. Potential epithelial cells were defined as EpCAM and CK double-positive and CD45 negative. Potential melanoma cells were defined as melanoma-associated chondroitin sulphate proteoglycan-positive and CD45 negative. Data were analysed with the use of FlowJo 7.2.5 software .Chi-squared or Fisher's exact test tests were used where appropriate to evaluate any differences between the parameters examined. Two-sided p < 0.05 was considered to be statistically significant. The analysis was performed using SPSS Inc. Software (version 18.0).CTC were detected in the blood of 49 patients (72%): 28 out of 39 (72%) MC patients and 21 out of 29 (72%) MM patients showed at least 1 CTC/10 mL blood. Characteristics of the patients included in the analysis on CR expression (positive for presence of CTC) are listed in Table The median number of CTC was 3 (range: 1-94)/10 mL. The median number of CTC was 2 (range: 1-21)/10 mL blood in the MC cohort and 4 (range: 1-94)/10 mL blood in the MM group.Results were summarized in Table CCR7 was expressed on CTC in 6 MM patients (6/21 = 29%) and the median number of CCR7-positive CTC was 1 (range: 1-5). CCR9 was expressed on CTC in 12 MM patients (57%) and the median number of CCR7-positive CTC was 2 (range: 1-5).Seventeen (61%) patients with MC presented CTC double positive for CXCR4 and CCR6; 7 (25%) patients showed CTC positive for CXCR4 or CCR6 and 4 (14%) had CTC negative for both the CXCR4 and CCR6. The median number of CTC without expression of CXCR4 and CCR6 was 1 (range: 1-18). Fourteen (66%) patients affected by MM presented CTC positive for at least two of the CR analysed; 3 (14%) patients showed CTC positive for only one CR and 4 (19%) resulted to have CTC negative for expression of all the CR evaluated. The median number of CTC negative for all the CR analysed was 6 (range 3-86).We then asked if expression of the CR on CTC correlated with presence of liver metastasis or lung metastasis. Results are presented in Table In the present study, we investigated a series of blood samples drawn from consecutive metastatic patients with different solid tumors, in order to evaluate the expression of the CR CXCR4, CCR6, CCR7 and CCR9 on CTC. CTC expressed CR in the majority of cases, with CXCR4 being the most frequently expressed CR and CCR6 often co-expressed.The studies published so far about this topic are not directly comparable with our study due to profound differences in strategies employed for identification of CTC. These reports, although more homogeneous in terms of patients, did not enrich the blood specimens for CTC and they used a more extensive definition for CTC identification. Pituch-Noworolska et al. evaluated the immunophenotype of CK+PBMCs and of disseminated tumor cells (DTC) from bone marrow in patients with gastric cancer. CCR6 and CXCR4 expression was determined on CK+cells sorted out from blood (8 samples) or bone marrow (69 samples). CCR6 was expressed in a half of the CK+samples whereas the expression of CXCR4 was much lower . We alsoDespite previous observations of an association between expression of specific CR in primary tumors and metastatic organ preference, we did not find any correlation between CR expression on CTC and specific metastatic pattern. In our study we evaluated the presence of CR on the surface of CTC (i.e. ready-to-home cells) without analysing their intracellular expression. Intracellular expression of CR (in particular nuclear expression of CXCR4) assessed at primary tissue level has been associated to the metastatic destination of tumor cells and to patient outcome in several different cancer entities -20,28-30Presence of CR on CTC makes CTC a potential therapeutic target for CR antagonists. The recent approval of a CCR5 receptor antagonist in HIV paves in fact the way for further effective antagonists to other CR. Various strategies have been employed in preclinical models to target CXCR4 including inhibitory antibodies, small molecule antagonists, RNAi and small inhibitory peptides. CXCR4-directed antibodies suppressed lymph node metastasis in experimental breast cancer  and suppCR are expressed on CTC of patients with metastatic solid tumors. Even though in this study we did not find a positive correlation between CR expression on CTC and metastatic pattern, these receptors could be involved in CTC proliferation and migration of cancer cells, which appoints CTC as potential CR-antagonist therapeutic targets.CTC: Circulating tumor cells; CR: Chemokine receptors; MC: Metastatic carcinoma; MM: Metastatic melanoma.The authors declare that they have no competing interests.AF participated in the design of the study and drafted the manuscript. ZL, AN and JJ carried out the experiments. VK participated in sample collection. UK participated in the design of the study and sample collection and drafted the manuscript. All authors read and approved the final manuscript."}
+{"text": "Recent landmark studies like the MR-IMPACT and CE-MARC have demonstrated the advantage of stress CMR over other imaging modalities in ischaemia detection of coronary artery disease. However to date there are no studies demonstrating how stress CMR influences patient management in clinical practice.A retrospective cohort of 2139 patients who had undergone both adenosine stress CMR (2008-2011) and a coronary angiographic procedure (2006 to 2011) was identified. 142 patients with a diagnosis of cardiomyopathy and 98 patients with previous CABG were excluded. 1899 patients comprised the study group with the latest date of followup being 31.8.2012. Data was extracted from each patient's hospital health record and analysed using STATA version 8.0. This study was undertaken as part of clinical service evaluation.Indications for stress CMR were: symptomatic chest pain (74%), assessment of functional significance of residual coronary disease (12%), assessment of LV function (12%) and nonspecified reasons (2%). Inducible perfusion defects were identified in 1546 (81%) patients among whom 534 (35%) had had prior angiographic assessment. 224 patients underwent percutaneous intervention (PCI) post CMR with the majority performed in those with perfusion defects . In these 206 patients, the perfusion defect matched the territory of the stented coronary vessel in 89% (187) patients. The median time to PCI was 77 days (IQR 37-134) in the matched defect group and 157 days (IQR 79-488) in the unmatched defect group, p<0.003. On follow up (1.6\u00b10.85years), 72% (n=149) denied any symptoms, 18% (n=38) had ongoing symptoms and 9% (n=19) had had a repeat revascularisation procedure. 2% (n=5) patients died during follow up.We have demonstrated that stress CMR can both guide percutaneous intervention and influence patient management. To our knowledge, this is the first study demonstrating not only the diagnostic utility of stress CMR but also its integration into contemporary clinical practice. Further research is needed to determine how it can further improve patient outcomes.None"}
+{"text": "Infective dermatitis associated with HTLV-1 (IDH) is a recurrent and severe childhood infected form of eczema, that usually begins at 18 months in vertically-infected children. IDH may progress to adult T-cell leukemia/lymphoma (ATL). Abnormal T cells (ably), including flower cells, were found in the peripheral blood smears of 30% (9/31) of IDH patients in Bahia, Brazil. Monoclonal integration of provirus assessed by inverted long PCR (ILPCR) was detected in 3 of these patients . The aim of this study was to identify the integration sites of the HTLV-1 provirus in host human genome in the IDH patients with monoclonal integrationhttp://www.ncbi.nih.gov/blast.cgi.The sequences of the PCR products of these 3 patients obtained by ILPCR were mapped on to the human genome using the Basic Local Alignment Search Tool In the two patients with flower cells, integration sites were detected, respectively, in chromosome 1 (1p34.2) and chromosome 3 (3p11.1). In chromosome 1, the provirus was located within PPM1H gene coding region and in chromosome 3, within alpha satellite DNA sequences. The patient with integration in chromosome 1 also presents HAM/TSP. In the IDH patient without flower cells, integration site was identified at chromosome 12 (12q14) and was located near the transcriptional start site of GUCA2B gene.In IDH patients with monoclonal integration, the provirus integration sites can be associated with transcriptionally active regions of the human host genome."}
+{"text": "To evaluate the palliative role of radiotherapy (RT) and define the effectiveness of chemotherapy combined with palliative RT (CCRT) in patients with a symptomatic pelvic mass of metastatic colorectal cancer.\u03b1/\u03b2 for the tumor was assumed to be 10 Gy for the biologically equivalent dose (BED), the median RT dose was 46.8 Gy10 (14.4-78). Twenty one patients (26%) were treated with CCRT. Symptom palliation was assessed one month after the completion of RT.From August 1995 to December 2007, 80 patients with a symptomatic pelvic mass of metastatic colorectal cancer were treated with palliative RT at Samsung Medical Center. Initial presenting symptoms were pain (68 cases), bleeding (18 cases), and obstruction (nine cases). The pelvic mass originated from rectal cancer in 58 patients (73%) and from colon cancer in 22 patients (27%). Initially 72 patients (90%) were treated with surgery, including 64 complete local excisions; 77% in colon cancer and 81% in rectal cancer. The total RT dose ranged 8-60 Gy (median: 36 Gy) with 1.8-8 Gy per fraction. When the 10 (p < 0.05), and CCRT was a marginally significant factor (p = 0.0644). On multivariate analysis, BED and CCRT were significant prognostic factors for symptom control duration (p < 0.05).Symptom palliation was achieved in 80% of the cases. During the median follow-up period of five months (1-44 months), 45% of the cases experienced reappearance of symptoms; the median symptom control duration was five months. Median survival after RT was six months. On univariate analysis, the only significant prognostic factor for symptom control duration was BED \u226540 Gy10 is recommended when possible. Considering the low morbidity and improved symptom palliation, CCRT might be considered in patients with good performance status.RT was an effective palliation method in patients with a symptomatic pelvic mass of metastatic colorectal cancer. For improvement of symptom control rate and duration, a BED \u2265 40 Gy Local recurrence of colorectal cancer after surgery occurred in 10-40% of patients -7. PelviThe role of primary tumor resection for non-curable stage IV colorectal cancer remains undefined. Kleespies et al. reported that palliative resection was associated with a particularly unfavorable outcome in rectal cancer patients presenting with locally advanced lesion expected macroscopic residual tumor or an extensive comorbidity . PatientRT has been considered an effective palliative treatment for patients with symptomatic pelvic tumors of colorectal cancer. Previous studies have used RT as palliative treatment to relieve pelvic symptoms in heterogeneous patients ,11-23. TIn this study, we evaluated the palliative role of RT and defined the effectiveness of chemotherapy combined with palliative RT in patients with a symptomatic pelvic mass of metastatic colorectal cancer.From August 1995 to December 2007, we retrospectively reviewed 80 patients with a symptomatic pelvic mass of metastatic colorectal cancer who were treated with palliative RT at Samsung Medical Center. All patients had disease outside the pelvis and consulted a radiation oncologist for symptomatic palliation.Fifty-eight patients (73%) were initially diagnosed with rectal cancer and 22 patients (27%) with colon cancer. Seventy-two patients (90%) were treated with surgery, including 64 complete local excisions (52 curative surgeries). Eight patients (10%) received chemotherapy alone. Twenty-two patients (27%) received adjuvant RT after curative surgery or salvage RT after local recurrence. The RT dose ranged from 40Gy to 74Gy with 1.8-2.0 Gy per fraction.Patient age at the time of palliative RT for symptomatic pelvic mass ranged from 27 to 85 years (median 57 years). There were 43 males (54%) and 37 females (46%). Eastern Cooperative Oncology Group (ECOG) performance scores were 0 in one patient (1%), 1 in 28 (35%), 2 in 36 (45%), 3 in 13 (16%), and 4 in two (3%) patients. Forty patients (50%) had single organ metastasis regardless of the number of metastatic nodules, and 40 patients (50%) had two or more organ metastases. The common metastatic sites were liver , lung , paraaortic lymph node , and peritoneal seeding .Eighty patients had 95 cases of clinical symptoms. The most common clinical symptom was pain , followed by rectal bleeding in 18 cases (19%), and obstructive symptoms in nine cases (9%). Six patients had two concurrent symptoms, pain and bleeding (five patients) or pain and obstruction (one patient). Seven patients experienced pain recurrence after palliative RT and received palliative re-RT. In these patients, evaluation of the response to palliative re-RT was available, and all cases were independently included in the analysis of symptom response to palliative RT.\u03b1/\u03b2 was assumed to be 10 Gy, the median total BED was 46.8 Gy10 (14.4-78.0 Gy10).RT was administered using 6-15 MV photon beams from linear accelerators. The radiation field included the recurrent mass of the pelvic cavity with 2-3 cm margins. Different RT doses were used according to the patient's performance status and extra-pelvic tumor burden. The median RT dose was 36 Gy (8-60 Gy). All patients received RT once daily, and the dose per fraction ranged from 1.8 Gy to 8.0 Gy (median 2.5 Gy). The total RT doses were converted into the biologically equivalent dose (BED) for comparison. When Twenty-one patients (26%) received CCRT with the following regimens: capecitabine in eight patients, fluorouracil in six patients, oral tegafur-uracil in five patients, and combination regimen in two patients. Thirty-one cases received further chemotherapy after completion of palliative RT. Patient and treatment characteristics are shown in Table Symptom palliation was assessed one month after the completion of palliative RT. For patients with pain as the presenting symptom, effective palliation was defined as decreased or resolved pain or decreased analgesia. For patients with bleeding, effective palliation was defined as improved hemoglobin, stable hemoglobin, resolved hematochesia, or normalized hemoglobin. For patients with obstruction, effective palliation was defined as improved or resolved constipation, decreased laxative use, or no need for intervention such as a stent or colostomy.The follow-up period was defined as the time from the start of palliative RT until progression of symptom or death. Toxicity was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.Survival rates were estimated with the Kaplan-Meier method, and comparisons between the groups were determined using the log-rank test . MultivaThe median follow-up time was five months . The overall survival rate at one year was 22.1%, and the median survival was six months. Overall symptomatic palliation was achieved in 76 of 95 cases (80%). Forty-three cases (45%) experienced recurrence of symptoms, and the median symptom control duration was five months .In 80 patients, 68 cases had the symptom of pain; 54 cases (79%) achieved palliation of pain and 35 cases (51%) experienced reappearance of pain. Eighteen cases had the symptom of bleeding; 15 cases (83%) achieved palliation of bleeding and five cases (28%) experienced reappearance of bleeding. Nine cases had the symptom of obstruction; seven cases (78%) achieved palliation of obstruction, and three cases (33%) experienced reappearance of obstruction.10, 23 of 34 cases (68%) had recurrence and for BED \u2265 40 Gy10, and 20 of 61 cases (33%) had recurrence.Figure 10, hazard ratio; 0.503, p = 0.0406) and CCRT  were favorable factors.On univariate analysis, the only significant prognostic factor for symptom control rate was BED (p = 0.0089), and CCRT was a marginally significant factor (p = 0.0644) Table . In patiAll patients tolerated the palliative treatment. Thirty-eight patients experienced nausea, diarrhea, cystitis, or perineal skin reaction of grade 1 or 2 during treatment. There was no significant difference of treatment related toxicity between RT alone and CCRT . There was no severe toxicity above grade 3 or treatment-related deaths.External RT has been considered an effective palliative treatment in patients with an unresectable pelvic mass of colorectal cancer. Studies reported in the 1960s-1980s showed that relief of pain and/or bleeding was achieved in approximately 75% of patients with doses as low as 20 Gy in ten fractions over two weeks or various doses of 40-60Gy in 1.8-2.5 Gy per fraction -20. Medi10 showed a higher risk of pelvic symptomatic progression when \u03b1/\u03b2 was assumed to be 10 Gy(p = 0.009). In our study, the overall symptom control rate and the one-year symptom control rate were 69% and 40.5% respectively for BED \u2265 40 Gy10 and 32% and 28.5% for BED < 40 Gy10. Since BED was a significant prognostic factor for symptom control rate, it might be better to treat with a higher RT dose to increase the palliation rate and symptom control duration.Some data suggest a correlation between RT dose and the effect of palliation. Wong CS et al.  reportedIn the pelvic cavity, the tolerance dose of normal tissue is a limiting factor when determining the RT dose. The small bowel, which is regarded as one of the most sensitive organs to RT, has a tolerance dose of TD 5/5 with a dose of 50 Gy for 1/3 small bowel irradiation and TD 50/5 with a dose of 60 Gy . The risThere are a few studies on CCRT for palliative intent in patients with distant metastasis. Wong CS et al.  reviewed10 and CCRT to symptomatic pelvic recurrence, prospective randomized trial might be needed.Our study has some limitations. First, this study was retrospectively analysis. It had heterogeneous patient's group and radiation dose. The results may be affected by the selection biases. Second, this study was performed in a small sample size. To conclude the effectiveness of the higher BED\u2265 40 Gy10 is recommended when possible. Considering the low morbidity with CCRT and improved symptom palliation, CCRT might be considered in patients with good performance status.In patients with a pelvic mass combined with distant metastasis, symptom palliation was achieved in 80% of the cases, and the median symptom control duration was five months. For improvement of symptom control rate and duration, a higher BED \u2265 40 GyThe authors declare that they have no competing interests.WP made contribution to conception and design of the study, and revised the manuscript. SHB contributed to acquisition of data, analysis and interpretation of data, and drafted the manuscript. DHC and HN helped in literature research and revision of the manuscript. YSP, JOP, WYL, SHY and HCK participated in design of study. WKK and HKC gave some intellectual recommendation. All authors have read and approved the final manuscript."}
+{"text": "Severe sepsis is the second leading cause for admission to critical care and in spite of advanced care remains associated with a high mortality. When implemented the sepsis resuscitation bundle has been associated with a 20% reduction in mortality and is therefore recommended as standard care for all patients with severe sepsis .All new admissions to seven west of Scotland ICUs were screened during a 12-week period for evidence of severe sepsis or septic shock. Those meeting the criteria were then assessed for sepsis bundle compliance. The Institute for Healthcare Improvement sepsis resuscitation bundle was taken as standard of care. This has a 6-hour time frame and includes measurement of serum lactate, blood cultures taken prior to antibiotics, antibiotics administered within 3 hours, fluids of 20 ml/kg if hypotensive or hyperlatataemia and use of early goal-directed therapy in the event of persistent hypotension/hyperlatataemia in spite of fluid resuscitation.P < 0.01), and where indicated, vasopressor use , CVP measurement , and ScvO2 measurement . ICU mortality was 12/64 patients (18.8%) with severe sepsis and 18/38 patients (47.4%) for those with septic shock. Full bundle compliance and mortality was not different for those reaching ICU early compared with those who were admitted after 6 hours.Of the 652 patients screened, 115 met the definition of severe sepsis or septic shock (17.6%). We collected full data from 108 patients, of which 69 patients (63.8%) had severe sepsis and 39 patients (36.1%) had septic shock. Full bundle compliance was 5.6%. Early ICU admission (within 6 hours) was associated with improved compliance with measured lactate (87.3% vs. 60.4%, At present the sepsis resuscitation bundle is not uniformly implemented. Although compliance with early goal-directed therapy and lactate measurement is better in those reaching ICU early, there is still a large proportion of patients not receiving aspects of the bundle in spite of being in a critical care environment."}
+{"text": "The aim of the study was to establish if the number of organs failing at admission to the ICU and the response to support had a bearing on outcome in patients with severe acute pancreatitis (SAP).Only SAP patients requiring organ support were included in the analysis. Gallstones (55%) and alcohol were the commonest aetiologies. The proportion of patients with one, two or three system failures at baseline, 24, 48, and 72 hours were calculated and related to outcome.A total of 123 patients  with a mean age of 58 years met the study criteria. The numbers of patients presenting with one, two and three organ failures were 29, 70 and 24 respectively, of which the mortality was six (21%), 29 (41%) and 14 (48%). Subsequent figures were 24, 57 and 39 with mortalities of four (17%), 19 (33%), and 24 (62%) at 24 hours; 21, 53 and 43 with mortalities of two (10%), 18 (34%), and 26 (60%) at 48 hours; and 17, 49 and 45 with mortalities of zero (0%), 16 (33%), and 28 (62%) at 72 hours.These data allow prognostication of patients with SAP requiring organ support. At 72 hours, the prognosis of patients with single organ failure is excellent and that of patients with three-organ failure remains poor."}
+{"text": "Candida tropicalis is an important cause of candidemia in immunocompromised patients. Biofilm formation helps the organism to establish infection. Agglutinin like sequence (ALS) genes encodes glycoproteins which are important adhesins. This study was done to detect the presence of ALS genes by PCR in C.tropicalis strains isolated from HIV and non-HIV patients in comparison with biofilm formation.C.tropicalis isolates  were included in this study. Biofilms were formed on 96 well plates as described earlier and ALS genes were detected by PCR using specific primers.Yeast isolates: A total of 48 C.tropicalis isolates, 16 out of 20 (80%) HIV isolates and 17 out of 28 (61%) non-HIV isolates were biofilm producers; 4 out of 20 HIV isolates (20%) and 11 out of 28 (39%) non HIV isolates were biofilm non-producers. Out of 48 isolates, 12/48 (25%) isolates were positive for ALS 1; 24/48 (50%) isolates were positive for ALS 2; 23/48 (48%) isolates were positive for ALS 3. Thirty four out of 48 (71%) isolates were positive for one or more ALS genes. Twenty two of the 34 (65%) were biofilm producers. Of the 14 strains which were negative for all ALS genes, 11 (79%) were biofilm producers.Among the 48 C.tropicalis than ALS 1. The biofilm forming ability of the strains was independent of the presence of the ALS genes and the source of the isolates.ALS 2 and ALS 3 genes were more common in"}
+{"text": "Recent estimates suggest that IgE- mediated food allergy affects 6 %-8 % children and 3%-4 % adults . The present study was conducted to investigate the association of sensitization to food and inhalant allergens in patients of asthma and rhinitis.Diagnosed patients of Asthma and rhinitis were evaluated for sensitization to food and inhalant allergens. Patients (12-62 years) were screened using standard questionnaire. The skin prick-tested (SPT) was done with common foods and aeroallergens in history positive patients of food allergy.Of 1860 patients screened, 1097 (58.9 %) gave history of food allergy. Of the history positive patients 470 were skin prick tested . 29.3 % (138/470) exhibited positive reactions to one or more food(s). Rice elicited SPT positive reaction in maximum ( 6.2 %) cases followed by blackgram (5.9 %), lentil (5.5 %), citrus fruits (5.3 %), pea (3.8 %), maize (3.8%) and banana (3.6 %). Among food sensitised cases 35.5% ( 49/138 ) of patients also showed positive skin reaction to one or more pollen extracts. A majority of the food sensitized patients (52.1 %) were skin test positive to insect allergens while only 14.7 % showed positivity with fungal extracts. Positive skin reaction with food co-existed with positive SPT to insects extracts. Sensitisation to food allergen  was significantly associated with asthma(P=0.0065) whereas inhalant allergens  were strongly related to rhinitis (P<0.01). However sensitisation with pollens was less common in patients of asthma with rhinitis. Sensitisation to food allergens was significantly associated with asthma alone ( P=0.0001). But food sensitivity is significantly less common in cases of asthma associated with rhinitis (P<0.028). Correlations between sensitisation to aeroallergens and ten common foods were analyzed.The results suggest that concommittant sensitisations to food with pollen and insect may enhance the risk of asthma and rhinitis or contribute towards exacerbation of symptoms. The synergistic action of these factors may influence the development and progression of atopic manifestation."}
+{"text": "SKP1, CULLIN, FBX and RBX1 proteins. The Arabidopsis SKP-LIKE (ASK) proteins are also members of a family and some of them interact with FBX proteins directly. To clarify how FBX and ASK proteins combine, we carried out a large-scale interaction analysis between FBX and ASK proteins using yeast two-hybrid assay (Y2H) in Arabidopsis thaliana. FBX proteins randomly chosen from those proteins that interacted with more than one ASK protein were further analyzed for their subcellular localization and in vivo interaction with ASK proteins. Furthermore, the expression profiles of FBX and ASK genes were compared. This work reveals that FBX proteins had a preference for interacting with ASK proteins depending on the domains they contain such as the FBX-associated (FBA) domain, the Kelch domain and leucine rich repeat (LRR). In addition, it was found that a single FBX protein could form multiple SCF complexes by interacting with several ASK proteins in many cases. Furthermore, it was suggested that the variation of SCF complexes were especially abundant in tissues related to male gametophyte and seed development. More than half of the FBX proteins studied did not interact with any of the ASK proteins, implying the necessity for certain regulations for their interaction in vivo and/or distinct roles from subunits of the SCF complex.F-Box (FBX) proteins are encoded by a multigene family present in major lineages of eukaryotes. A number of FBX proteins are shown to be subunits of SCF complex, a type of E3 ligases composed of  Protein regulation is known to be an important system to allow adaptation to various abiotic and biotic stresses such as heat, drought and pathogens as well as for carrying out normal functions for survival. Ubiquitin (Ub)-mediated regulation is one of the key mechanisms for degradation and protein signaling in eukaryotes. In plants, various proteins are regulated by the Ub-mediated system in response to different environmental stresses and developmental signals such as the cell cycle and flowering FBX genes have been isolated from yeast , fruit fly (27 genes in Drosophila melanogaster), and human (69 genes) FBX genes have been identified particularly in plants such as Arabidopsis (897 genes), rice (971 genes) and popular (425 genes) Ub is a small protein composed of 76 amino acids and is highly conserved in eukaryotes. The Ub molecule is attached to its target protein through the sequential actions of three enzymes, Ub-activating enzyme (E1), Ub-conjugating enzyme (E2) and Ub ligase (E3). E3 ligase has an especially diverse gene family in plants, comprising more than 1,400 genes as predicted in Arabidopsis Skp1 homologs, ASKs, in its genome. Of these, ASK1 has been well characterized and its interaction with several kinds of FBX proteins such as TIR1 and COI1 has been reported ask1 mutation caused male sterility and ASK1 is essential for early nuclear reorganization in male meiocytes ask1-1 mutant compared to wild type, implying multiple physiological roles of ASK1-mediated protein regulation ask1 ask2 double mutant showed a developmental retardation during embryogenesis and lethality at the seedling stage Arabidopsis has 21 ASK genes (ASK1-19) had different patterns for expression in almost all the tissues examined two-hybrid assays (Y2H) FBXs and ASKs in several tissues using microarray data from a gene expression search engine. Moreover, subcellular localization and in vivo interaction with ASK proteins were also examined on randomly chosen FBX proteins. These results enable us to predict the physiological functions of SCF complexes including FBX and ASK proteins in tissues and/or cell compartments. This study provides helpful information for further work into Ub-mediated protein regulation through SCF complexes in plants.Previously, we and another group reported that the 19 FBXs including previously cloned genes Recent progress in full-length cDNA, ESTs, and genome information has much facilitated analysis in plants. To generate an interaction map between FBX and ASK proteins of Arabidopsis, we cloned 341 cDNAs of Arabidopsis Y2H was performed between 341 FBX and 19 ASK  proteins . Of thesSince the distinct domains of FBX proteins are supposed to interact with various proteins, the types of FBX proteins as classified by the domains present may affect their selective interaction with ASK proteins. As shown in In vitro interaction between FBX and ASK proteins was shown by Y2H. To examine that these results reflected the in vivo interactions, we performed bimolecular fluorescent complementation (BiFC) analysis using a transient assay system in Nicotiana tabacum , and the other is expressed with much higher specificity in some tissues . Moreover, the former can be classified into 2 types; one is expressed in all tissues (ASKs 1\u20132 and 20), and the other is expressed in active tissues where cell division is occurring, including mitosis and meiosis in particular . The latter expression pattern can be further classified into 3 types; one is expressed preferentially in male tissues such as pollen and sperm cells , the second is expressed preferentially in tissues related to seed development such as siliques and endosperm (ASKs 7\u201310 and 16\u201317), and the third is expressed in both male tissues and tissues related to seed development . Considering the expression of ASKs on tissue side, more than three ASK genes were expressed in every tissue, and in particular large numbers of ASK genes were expressed in male tissues and tissues related to seed development such as siliques, endosperm and testa  interacted with ASKs 2, 3 and/or 4 . Of the 9 FBX genes, seven , four , two (At3g62230 and At4g27050), three  or one (At4g27050) FBX gene(s) showed a correlation in their expression to ASKs 3 and/or 4 in pollen, endosperm and testa, inflorescence, callus and cultured cell, and root, respectively. Since At2g20380, At4g10400, At4g27050 and At5g53840 were observed to interact with only ASK3 by Y2H , whose translation products interacted with ASKs 13, 14 and/or 18  had a correlation in their expression to ASK13 in pollen. Since At2g22030, At4g02310 and At4g29370 were observed to interact only with ASK13 , whose translation products interacted with ASKs 13, 14, 16 and/or 18 , the expression profile implies that these FBX proteins and ASK14 co-act in the tissues. Two FBX genes, At1g30790 and At3g03360, which interacted with ASK14 and ASK16 , whose translation products interacted with ASKs 14 and/or 18  were classified as a cluster with ASK1 except ASK14 in a phylogenic tree in in vivo such as phosphorylation or they may require additional proteins present in order to interact, although it is not excluded that the expression level of protein is not high enough to be detected by Y2H. Indeed, BiFC analysis showed FBX proteins interacted with more ASK proteins than did Y2H. These differences may support the necessity of modifications or other factors in vivo for some kinds of combination of FBX and ASK proteins to occur in plants. Alternatively, these FBX proteins may act differently to SCF complexes, although they have been categorized as FBX proteins.A large population of FBX proteins did not interact with any ASK protein, although they may interact with other ASK proteins which were not used in this study. It is known in many of other species that phosphorylation is necessary for interaction between FBX and ASK proteins GUS expression assays in previous reports ASK gene had significant differences in the tissues where they were expressed and many of the ASK genes were particularly expressed in tissues related to male gametophyte and seed development. There are dramatic changes of intracellular environment in these tissues coupled to meiosis and mitosis, resulting in a rapid turnover of proteins. For these events to occur, many of the proteins may be regulated by Ub-mediated proteolysis through SCF complexes. Indeed, the amount of ubiquitinated proteins dramatically decreased during pollen maturation in maize FBX genes in all tissues compared to the preferential expression of ASK genes in tissues related to male gametophyte and seed development, although there was a distinct expression pattern for each gene  and ASKs  were constructed previously Total RNAs were prepared using the NucleoSpin RNA plant kit (Macherey-Nagel) from Arabidopsis flowers, roots, siliques, stems, leaves and seedlings grown in either continuous white light or darkness for 1 week and then treated with RQ DNase I , following the manufacturer's instructions, to prevent contamination with genomic DNA. First strand cDNAs were synthesized from the total RNA as described previously FBX ORF fragment in pDONR207 was transferred to a pGBK-RC-Gateway vector ASK ORF fragment in pDONR207 was transferred to a pGAD-RC-Gateway vector FBXs  and ASKs  were constructed previously Each B-galactoside to confirm the interaction.Transformation and mating of yeasts were performed as described previously FBXs  and 19 ASKs  were amplified by PCR from plasmids inserted into pDONR207 as templates. Information on the primers used in this experiment is given in FBX and ASK genes were inserted into a pSCYCE vector carrying the C-terminal half (174\u2013328aa) of SCFP3A driven by the CaMV 35S promoter and a pSCYNE vector carrying the N-terminal half (1\u2013173aa) of SCFP3A driven by the CaMV 35S promoter, respectively Agrobacterium tumefaciens strain GV3101, and equal volumes of the FBX and ASK Agrobacterium solutions were combined and infiltrated into 3-week-old leaves of Nicotiana tabacum as described previously The ORFs of four https://www.genevestigator.com/gv/) was used to compare the gene expression of ASKs and FBXs in various tissues.GENEVESTIGATOR  for 4 h at 25\u00b0C under dark conditions. The leaf pieces were filtrated through 50 um nylon mesh and centrifuged at 800 rpm for 5 min. Pellets were gently resuspended in ice-cold solution A , and then incubated on ice for 30 min. The sample was then centrifuged at 800 rpm for 5 min, and the pellet was resuspended in 5 ml of MMg solution  producing a protoplast suspension.Protoplasts were prepared from rosette leaves of 4-day-old Arabidopsis. Twenty leaves were cut into pieces 1 to 2 mm in length. These leaf pieces were treated in enzyme solution  solution 2) at room temperature for 30 min. The sample was gently mixed with 10 ml of solution A and centrifuged at 800 rpm for 5 min. The pellet was resuspended in 4 ml of Murashige and Skoog (MS) solution . After incubation at 25\u00b0C for 10 h in darkness, GFP fluorescence was observed by a confocal microscope (Zeiss Laser Scanning Microscope LSM700).Each ORF fragment of the FBXs in pDONR207 was transferred by LR reaction (Gateway) to pBE2113-GW Figure S1Comparison of expression patterns of ASK genes in various tissues by GENEVESTIGATOR. ATH1: 22k array was used as the platform. Microarray was performed in tissues of callus (1), cell culture/primary cell (2), sperm cell (3), protoplast (4), guard cell protoplast (5), mesophyll cell protoplast (6), root protoplast (7), root cap protoplast (8), columella protoplast (9), lateral root cap protoplast (10), root epidermis and lateral root cap protoplast (11), root cortex protoplast (12), root endodermis and quiescent center protoplast (13), root stele protoplast (14), root phloem protoplast (15), root xylem protoplast (16), root cortex, endodermis and quiescent center protoplast (17), root epidermis protoplast (18), root epidermal atrichoblast protoplast (19), root culture (20), seedling (21), cotyledon (22), hypocotyl (23), radicle (24), imbibed seed (25), shoot apical meristem (26), inflorescence (27), flower (28), pistil (29), carpel (39), ovary (31), ovule (32), stigma (33), petal (34), sepal (35), stamen (36), anther (37), pollen (38), abscission zone (39), pedical (40), silique (41), replum (42), seed (43), embryo (44), endosperm (45), micropylar endosperm (46), peripheral endosperm (47), chalazal endosperm (48), testa (49), general seed coat (50), chalazal seed coat (51), suspensor (52), stem (53), developing meristemoid zone (54), node (55), shoot apex (56), cauline leaf (57), rosette (58), juvenile leaf (59), adult leaf (60), petiole (61), senescent leaf (62), hypocotyl (63), xylem (64), cork (65), leaf primordial (66), stem (67), axillary bud (68), axillary shoot (69), shoot apex (70), roots (71), primary root (72), root tip (73), meristematic zone (74), elongation zone (75), root hair zone (76), stele (77), pericycle (78) or lateral root (79). Percentage expression potential is shown from 0 (white) to 100 (dark brown) % according to the six-grade system.(XLSX)Click here for additional data file.Figure S2Comparison of expression patterns of FBX genes in various tissues by GENEVESTIGATOR. ATH1: 22k array was used as the platform. Microarray was performed in tissues of callus (1), cell culture/primary cell (2), sperm cell (3), protoplast (4), guard cell protoplast (5), mesophyll cell protoplast (6), root protoplast (7), root cap protoplast (8), columella protoplast (9), lateral root cap protoplast (10), root epidermis and lateral root cap protoplast (11), root cortex protoplast (12), root endodermis and quiescent center protoplast (13), root stele protoplast (14), root phloem protoplast (15), root xylem protoplast (16), root cortex, endodermis and quiescent center protoplast (17), root epidermis protoplast (18), root epidermal atrichoblast protoplast (19), root culture (20), seedling (21), cotyledon (22), hypocotyl (23), radicle (24), imbibed seed (25), shoot apical meristem (26), inflorescence (27), flower (28), pistil (29), carpel (39), ovary (31), ovule (32), stigma (33), petal (34), sepal (35), stamen (36), anther (37), pollen (38), abscission zone (39), pedical (40), silique (41), replum (42), seed (43), embryo (44), endosperm (45), micropylar endosperm (46), peripheral endosperm (47), chalazal endosperm (48), testa (49), general seed coat (50), chalazal seed coat (51), suspensor (52), stem (53), developing meristemoid zone (54), node (55), shoot apex (56), cauline leaf (57), rosette (58), juvenile leaf (59), adult leaf (60), petiole (61), senescent leaf (62), hypocotyl (63), xylem (64), cork (65), leaf primordial (66), stem (67), axillary bud (68), axillary shoot (69), shoot apex (70), roots (71), primary root (72), root tip (73), meristematic zone (74), elongation zone (75), root hair zone (76), stele (77), pericycle (78) or lateral root (79). Percentage expression potential is shown from 0 (white) to 100 (dark brown) % according to the six-grade system.(XLSX)Click here for additional data file.Figure S3Comparison of expression patterns of FBX genes in various tissues by GENEVESTIGATOR. AGRO1: AGRONOMICS whole genome tiling array was used as the platform. Microarray was performed in tissues of seedling (1), inflorescence (2), raceme (3), flower (4), shoot (5), rosette (6), leaf (7), juvenile leaf (8) or adult leaf (9). Percentage expression potential is shown from 0 (white) to 100 (dark brown) % according to the six-grade system.(XLSX)Click here for additional data file.Table S1Information of cloned FBXs and summaries of Y2H, BiFC experiments, microarray comparison and subcellular localization.(XLSX)Click here for additional data file.Table S2Comparison between in vitro and in vivo interaction of ASKs and 3 FBXs chosen from .(XLSX)Click here for additional data file.Table S3Primers used in this study.(XLSX)Click here for additional data file."}
+{"text": "Chemo-radiotherapy offers an alternative to primary surgery and adjuvant therapy for the management of locally advanced stage IV squamous cell carcinomas of the tonsil.A retrospective analysis was performed of the outcomes of 41 patients with locoregionally advanced squamous cell carcinoma of the tonsil treated non-surgically at the Yorkshire Cancer Centre between January 2004 and December 2005. Due to long radiotherapy waiting times, patients received induction chemotherapy with cisplatin and 5-fluorouracil followed by either cisplatin concurrent chemoradiotherapy or radiotherapy alone.Median age was 55 years (range 34-76 years) and 28 (68%) patients were male. 35/41 patients (85%) received 2 or more cycles of induction chemotherapy. Following induction chemotherapy, 32/41 patients (78%) had a clinical response. Concomitant chemotherapy was given to 30/41 (73%). All patients received the planned radiotherapy dose with no delays. There were no treatment related deaths. Six (15%) patients had gastrostomy tubes placed before treatment, and 22 (54%) required nasogastric tube placement during or after treatment for nutritional support. 17 patients required unplanned admissions during treatment for supportive care. At 4 months post treatment assessment 35 out of 41 (85%) patients achieved complete clinical and radiographic response. Median follow-up is 38 months (8-61 months). Local and regional control rate in complete responders at 3 years was 91%. Distant metastases have been found in 4 (9.8%) patients. Three year progression-free survival rate in all patients is 75%. The 3-year cause specific survival and overall survival are 75% and 66% respectively.Cisplatin-based induction and concurrent chemoradiotherapy provides excellent tumour control with acceptable toxicity for patients with locally advanced tonsillar cancer. Head and neck squamous cell carcinomas (HNSCC) are the sixth most common cancers , with arThe role of chemotherapy has gradually emerged, and is now taking a more prominent place in treatment algorithms for locally advanced HNSCC. The use of concurrent chemotherapy has improved locoregional control, with optimal results being achieved with cisplatin -10. InduIt has become evident that HNSCC represents a highly heterogenous group of tumours. In order to improve the therapeutic ratio of treatment it is critical to understand the varied aetiology, biology and response to treatment of tumours arising from different anatomical subsites. It is therefore essential to report the outcome of treatment for individual subsites, as opposed to simply grouping them together. In this way, it may be possible to identify tumour sites which would benefit from treatment intensification, or alternatively tumour sites with a favourable outcome for which a treatment de-escalation could be considered to limit toxicity ,3.The oropharynx is a common head and neck cancer subsite accounting for just over 1000 cases each year in UK . TonsillLong radiotherapy waiting times have been a major issue in UK . In our Here we present the outcomes for patients with locally advanced stage IV SCC of the tonsil managed with induction chemotherapy followed by radical (chemo-)radiotherapy. These data, in patients treated in routine clinical practice, demonstrate the feasibility of adding induction chemotherapy without compromising subsequent (chemo-)radiotherapy, and obtaining high rates of tumour control without the need for surgery.From 1st January 2004 to 31st December 2005 patients with a diagnosis of locally advanced stage IV tonsil squamous cell carcinoma without distant metastases who were treated at the Yorkshire Cancer Centre were identified from the radiotherapy database. Patients who received radical surgery and post-operative radiotherapy were excluded from analysis. Data was obtained by a retrospective review of the clinical notes, radiotherapy and chemotherapy records, and the oncology patient database. All patients were treated under the auspices of the specialist Head and Neck multidisciplinary team, following a written protocol. Within this protocol, all patients were investigated and staged with nasoendoscopy, biopsy, computed tomographic (CT) scanning and/or magnetic resonance imaging (MRI) of head and neck region, CT of thorax. Physical examination, dental, dietary, speech and language assessment, full blood count, electrolytes, liver and kidney function tests were routinely performed before initiation of treatment. The disease was staged according to the 2002 classification of the American Joint Committee on Cancer Staging. All patients were treated with induction chemotherapy followed by concurrent chemoradiotherapy or radiotherapy. Outcomes in terms of toxicity, site of relapse, disease free survival (DFS), and overall survival were determined by a retrospective notes review, analysis of radiotherapy treatment records, and oncology databases. Toxicity was routinely documented prospectively using the NCIC-version 3.0 grading system for chemotherapy toxicity, and the RTOG system for radiotherapy toxicity. Waiting time for radiotherapy was defined as the number of days from the clinic at which a decision was made to treat with radiotherapy to the first day of radiotherapy.2 day 1 and 5-fluorouracil (5 FU) 800 mg/m2 days 2-5, three weekly. Patients underwent clinical, haematological and biochemical assessment prior to each cycle; toxicity was prospectively recorded. Further cycles were only given after satisfactory toxicity assessment by medical staff. The number of cycles administered depended upon the wait until commencement of radiotherapy, tumour response and toxicity.Standard induction chemotherapy consisted of 1-4 cycles of cisplatin 80 mg/mAll patients were treated with 3-dimensional conformal radiotherapy. Patients were simulated supine using an individualized neck support and Perspex shell for immobilization. CT images for treatment planning were obtained at 2-5 3 mm intervals from the skull vertex to below the carina. The CT data were loaded into the Helax-TMS VG-1B treatment planning system. The target volume included primary site and bilateral level Ib, II, III, IV, V lymph nodes and retropharyngeal lymph nodes. Treatment was planned with a two phase technique of two parallel opposed photon fields, with a matched anterior neck field. The posterior border of the lateral 6MV photon fields was brought anterior to spinal cord to avoid cord toxicity , and matched electron fields were applied to the posterior neck. Due to prevalent waiting times, radiotherapy was booked prior to commencement of chemotherapy and schedules based upon clinicians' judgement/preferences and not upon chemotherapy responses. Two general schedules were routinely used at the time: i) a conventionally fractionated regimens of 65-70 Gy in 30-35 fractions over six and a half to seven weeks with 50 Gy in 25 fractions over five weeks to the matched anterior neck, and ii) an accelerated hypofractionated regimen of 55 Gy in 20 fractions over four weeks with 40 Gy in 15 fractions over three weeks to the matched anterior neck. During radiotherapy, patients were reviewed twice weekly, by a multidisciplinary team involving clinician, nurse, dietician and speech and language therapy team.Cisplatin 80 mg/m2 days 1 and on the final day of radiotherapy was used for accelerated hypofractionated radiotherapy regimen. Cisplatin 100 mg/m2 days 1, 22 and 43 was used for the conventionally fractionated regimen. Cisplatin was delivered with 2 litres pre-hydration and 2 litres post-hydration with normal saline during an overnight inpatient stay. Carboplatin (area under curve 4) was substituted for cisplatin if creatinine clearance was < 55 ml/min calculated by the Cockroft and Gault formula and confirmed if time permitting by isotopic GFR assessment. Full blood count, urea, serum creatinine were checked prior to each course of chemotherapy.After completion of therapy, each patient was followed up clinically after 4-6 weeks to assess acute toxicity. Tumour response was assessed 4 months after the completion of the treatment. Evaluation of tumour response was routinely evaluated where indicated by a detailed clinical examination of the head and neck, nasoendoscopy and CT or MRI imaging of the primary site and the neck. An examination under anaesthetic and biopsies were performed in the event of clinical, nasoendoscopic or radiological abnormalities. Patients with less than a complete response were evaluated for surgery. Patients who were considered suitable for surgery by the multi-disciplinary team underwent salvage surgery of primary site and/or neck dissection. Subsequently, patients were followed up with physical examination, and flexible endoscopy every 6-8 weeks in the first year after treatment, every 3 months for an additional 2 years, and every 6 monthly until discharge at 5 years.The following endpoints were used for assessment: induction chemotherapy response, overall treatment response, progression-free survival (PFS), locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), overall survival (OS) and cause specific survival (CSS). PFS, LRFS, DMFS, OS and CSS were analyzed using Kaplan-Meier product limit curves. Time was measured from the date of diagnosis. Patients who relapsed but for whom salvage therapy was successful were still considered to have experienced failure at the time of event occurrence. In the overall survival estimates, deaths due to all causes are included in the calculations. Significance of differences between survival curves was calculated by the log rank test. A p value of 0.05 or less was declared statistically significant. Univariable analysis was performed stratified by tumour stage (T stage), nodal stage (N stage) and treatment .45 patients were identified who were treated with radiotherapy for locally advanced stage IV tonsillar squamous cell carcinoma. Four (9%) of these 45 patients were treated with primary surgery and received post-operative radiotherapy and were excluded from analysis. Median age of the remaining 41 patients was 55 years (range 34-76 years) and 28 (68%) patients were male. All 41 patients had pathologically confirmed squamous cell carcinoma; 1 (2%) was grade 1, 12 (29%) were grade 2, and 28 (68%) were grade 3. Patient characteristics are shown in Table The median time between first clinic consultation to the start of radiotherapy was 77 days (range 50-122 days). All patients received cisplatin/5 FU induction chemotherapy during this delay. 6 (14%) patients received one chemotherapy cycle, 23 (56%) received two cycles, 10 (24%) received three cycles and 2 (6%) patients received four cycles. Fourteen (34%) of patients required an alteration or dose reduction of chemotherapy treatment. Following induction chemotherapy clinical response assessment indicated 32/41 patients (78%) had either a complete or partial response. The responses to induction chemotherapy are summarized in Table Chemotherapy was administered concomitantly with radiotherapy to 30 of 41 patients (73%). The decision whether to administer concomitant chemotherapy was made by the treating Clinical Oncologist, based upon tumour and patient factors. These included age, performance status, response and toxicity with induction chemotherapy. The 11 patients who did not receive concomitant chemotherapy had a median age of 58 (range 48-76); 8 of 11 had T3/4 disease (T4 n = 6) and 10 of 11 had N2/3 disease (N3 = 1). The 30 patients treated with concomitant chemotherapy had a median age of 54 (range 43-74); 17 of 30 had T3/4 disease (T4 n = 13) and 29/30 had N2/3 disease (N3 = 9). 4 of the 9 patients receiving hypofractionated radiotherapy with 55 Gy in 20 fractions over 4 weeks received concomitant chemotherapy. 26 of 32 patients receiving conventionally fractionated radiotherapy received concomitant chemotherapy.Of the 30 patients treated with concomitant chemotherapy, 19 received only one of the planned cycles of concurrent chemotherapy, while 11 of the 30 patients completed two cycles of concurrent chemotherapy and no patient received three. All of the 4 patients treated with 55 Gy in 20 fractions over 4 weeks received only one cycle of concomitant chemotherapy. Of the 26 patients receiving concomitant chemotherapy with conventionally fractionated radiotherapy, 15 (58%) received one cycle of chemotherapy and 11 received 2 cycles (42%). Radiation therapy was completed in all patients without any delays greater than 3 days. There were no treatment related deaths.At 4 months post treatment assessment 35 (85%) patients achieved complete clinical and radiographic response . 27 (66%) patients remain alive, with a median follow-up of 43 months (range 36-61 months). Four patients (11%) have died during follow up following a complete response to treatment without any evidence of subsequent disease recurrence. One of these patients died following a carotid blow out without evidence of disease recurrence on post-mortem; the other three deaths were due to myocardial infaction, Alzheimer's disease and a second primary tumour .Local and regional control rate in complete responders at 3 years was 91% and median time to local and/or regional recurrence was 20 months (range 13-23 months). Of the 35 patients with complete remission at four month post-treatment assessment, one experienced an isolated local failure, one an isolated regional failure, one local and regional failure, one locoregional failure with distant metastases. Among the three patients with isolated local and/or regional recurrence, one has undergone salvage surgical resection after 13 months disease free interval. Distant metastases were detected in 4 (10%) patients with a median 13 months of follow up (range 7-27 months). Three of these four patients did not experience locoregional failure. Three year distant metastases free survival rate was 89%. Lung was the distant metastases site in all patients. Three years progression-free survival rate in all patients is 75%. The 2 and 3-year overall survival rate is 76% and 66% respectively, and the 2 and 3-year cause specific survival rates are 80% and 75% respectively. Overall survival outcomes are lower than cause specific outcomes due to the 4 deaths during follow up without evidence of active disease. Figure Univariable analysis revealed that the 3-year progression-free survival and cause specific survival were significantly better for patients with T1 and T2 disease compared to T3 and T4 disease, respectively (p = 0.004 and p = 0.004). However, nodal stage and treatment type did not show a significant association with progression-free survival, distant metastasis-free and cause specific survival. The association of T stage, nodal stage and treatment type with PFS, DMFS, and CSS are given in Tables Grade 3 neutropenia occurred in 4 patients, 2 experienced grade 3 mucositis.Among the 30 patients who had concomitant chemoradiotherapy, there was one case each of grade 3 vomiting and of febrile neutropenia requiring admission. In 6 of 30 patients, carboplatin was substituted for cisplatin owing to renal impairment. At the end of radiotherapy, in the whole cohort of 41 patients RTOG grade 3 skin reaction was documented in 31, and RTOG grade 3 mucosal toxicity in 29 patients. In the 9 patients receiving 55 Gy in 20 fractions over 4 weeks, 6 experienced RTOG grade 3 skin toxicity and 7 experienced RTOG grade 3 mucositis. In the remaining 32 patients receiving conventionally fractionated radiotherapy, 25 experienced RTOG grade 3 skin toxicity and 22 had RTOG grade 3 mucositis.Six (15%) patients had gastrostomy tubes placed prophylatically before treatment. 22 (54%) of patients required nasogastric tube (NG-tube) placement during (n = 17), or after (n = 5) treatment for nutritional support. More than 10% weight loss during therapy was seen in 10 (24%) patients. Seventeen patients required admission for supportive care or nutrition during the radiotherapy and 14 of these were treated with concomitant chemoradiotherapy. 4 out of 9 (44%) patients receiving 55 Gy in 20 fractions over 4 weeks and 19 out of 32 (59%) patients receiving conventionally fractionated radiotherapy required admission.Among 27 surviving patients, as a long-term treatment-related complication 2 patients have been recorded as having grade 3 dysphagia. At present no patient is gastrostomy tube dependent. Trismus has been documented in 4 patients. Four patients developed soft tissue or osteoradionecrosis. One of them received 3 courses of induction chemotherapy followed by concomitant chemoradiotherapy died due to soft tissue, carotid artery necrosis 7 months after the therapy.Concurrent chemo-radiotherapy has been widely adopted as the standard of care for locally advanced HNSCC ,7. CisplInduction chemotherapy followed by sequential radiotherapy is an alternative approach to concurrent treatment which has been shown to have a survival benefit in locally advanced HNSCC -23. AlthOne major concern with the addition of induction chemotherapy is that it may compromise the ability to deliver radiotherapy. In the EORTC/TAX323 study examining induction chemotherapy, it is notable that only 120 of 179 patient receiving cisplatin and 5-FU, and 129 of 173 patients receiving TPF, ever received radiotherapy . The faiThe role of systemic treatment in addition to radiotherapy in locally advanced HNSCC continues to develop. Concurrent chemo-radiotherapy remains a standard of care, while induction chemotherapy has clear evidence of efficacy. However, it remains uncertain whether combining induction with concurrent chemotherapy takes advantage of the benefits of both treatments. Studies are currently underway to investigate the potential superiority of induction chemotherapy followed by concurrent chemoradiotherapy compared with concurrent chemoradiotherapy alone.Radiotherapy waiting times have been a major issue in the UK ,18, partWith implementation of various measures our radiotherapy waiting times have now fallen to 4 weeks in line with the national radiotherapy waiting times target. Nevertheless, in addition to providing data on the use of induction chemotherapy to compensate for protracted waiting times for radiotherapy, this series provides important data on the tolerability and efficacy of induction chemotherapy followed by radiotherapy \u00b1 concurrent chemotherapy outside the setting of clinical trials. Subjects within clinical trials are almost inevitably a fitter selected subset of patients. A major issue with the chemo-radiotherapy trials is whether the results, based upon selected fit patients, can be successfully applied to patients encountered in routine clinical practice. The results of institutional series of patients treated outside clinical trials are invaluable in exploring these issues.The series of 41 patients reported here, treated in 2004-5, demonstrates that induction chemotherapy can be successfully combined with concurrent chemoradiotherapy, without excessive toxicity. Radiotherapy commenced promptly at a median of 21 days (range 10-42) following the adminstration of the final cycle of radiotherapy. Therefore, induction chemotherapy did not preclude the prompt delivery of radiotherapy. Notably, by contrast with the EORTC/TAX323 trial , all patConcomitant chemotherapy was given to nearly three-quarters of the patients in our series. The predominant reason for not giving concomitant chemotherapy to the remaining patients was limited performance status due to progressive symptoms in non-responders to induction chemotherapy; therefore it can be concluded that induction chemotherapy did not compromise patient fitness to commence definitive concurrent chemoradiation. Two-thirds of patients were able to receive only one cycle of concomitant chemotherapy due to toxicity. Compliance is a common problem noted with standard concurrent cisplatin regimens, with nearly one third of patients not receiving all concurrent chemotherapy cycles . SeveralThe overall toxicity of induction chemotherapy followed by (chemo)-radiotherapy appears acceptable. There were no on-treatment deaths; the patient who died 7 months after treatment with a carotid blow out without evidence of disease was the only death which may have been treatment-related. As would be expected, the majority of patients required enteral feeding during or shortly after completing treatment. However, on follow-up only 2 of 27 surviving patients had grade 3 dysphagia and none was gastrostomy-dependant. These data compare favourably with other chemoradiotherapy series; for example in a pooled analysis of three RTOG trials long term feeding tube dependence was 13% .The tumour outcome of the patients presented here is excellent, with 85% of patients achieving a complete tumour response 4 months after completion of therapy. The timing of post-treatment response assessment varies between centres. The 4 month timepoint used here is intended to allow adequate time for post-radiotherapy response to be complete. In line with this concept, a recent study has shown that an 8 week response assessment is too early, with more complete responses being seen at 8 months than 8 weeks post-treatment . For ourThe 3 year PFS for patients receiving induction chemotherapy followed by radiotherapy alone was 82% compared with 72% for those treated with induction chemotherapy followed by concomitant chemoradiotherapy Table . This diTable HPV-16 is recognised as a major aetiological factor in the development of oropharyngeal carcinomas , althougThe role of routine neck dissection after chemoradiotherapy continues to be debated. Some reports ,41 have The choice of treatment modality for the management of locally advanced tonsillar cancer remains controversial and varies between centres, some preferring primary surgery and others non-surgical treatment . The gooIn summary, the non-surgical treatment of tonsillar squamous cell carcinomas offers very high rates of locoregional control and overall survival. Induction cisplatin-based chemotherapy can be combined with radical (chemo-) radiotherapy, without a detrimental effect upon radiotherapy delivery, and acceptable toxicity. Further issues remain to be addressed, including the necessity of both induction and concurrent treatment for tonsillar tumours with an overall favourable outcome; reduced treatment intensity may be possible to reduce toxicity without compromising tumour control. The future of improving the outcomes of head and neck therapy, in terms of both tumour control and toxicity, may lie in our ability to individualise treatment. This will involve the identification of predictive and prognostic markers, including HPV status, and understanding the biological behaviour and outcome of individual tumour subsites.The authors declare that they have no competing interests.RJDP: Data analysis, interpretation, manuscript preparation and approval; KK: Data analysis, interpretation, manuscript preparation and approval; DCO: Data analysis, interpretation, manuscript approval; DW: Data collection, analysis, manuscript approval; KED: Original Concept, Manuscript approval; CC: Original Concept, Manuscript approval; MS: Original concept, data interpretation, manuscript approval.All authors read and approved the final manuscript."}
+{"text": "Ventilator-associated pneumonia (VAP) is the most frequent ICU-acquired infection among patients receiving mechanical ventilation with relative risk of 9 to 27% and with mortality of 25 to 50% ,2. One oAfter ethics committee approval mechanically ventilated (>48 hours) adults were recruited in a prospective randomized controlled, double-blind clinical trial and randomised into PPI or H2RA groups. Patients with admission diagnosis of pneumonia or other acute inflammatory pulmonary disease, severe sepsis/septic shock, and/or regular PPI/H2RA users were excluded. The diagnostic criteria for VAP were: leukocytosis, increased PCT level, fever, purulent tracheal secretion, positive microbiological result of tracheal sample, and new/ increased infiltrate on chest X-ray. Data are presented as median . For statistical analysis Mann-Whitney U test and chi-square tests were used.n = 9) or protocol violation (n = 6). The remaining 79 patients were analysed . There was no significant difference (P >0.05) between the groups regarding demographics: age 67 (56 to 77) versus 72 (58 to 79) years; male/female: 23/15 versus 25/16; length of mechanical ventilation: 5 (3 to 9) versus 5 (2 to 8) days; APACHE II score: 28 (22 to 32) versus 26 (21 to 36) . There was no significant difference in the number of cases with VAP in the PPI versus H2RA groups: 9 (24%) versus 10 (24%). None of the patients developed GI bleeding during their stay on the ICU.Out of 94 patients recruited 14 were excluded due to early weaning/death (The results of this pilot study suggest that there may be no difference in the incidence of VAP and GI bleeding if stress ulcer prophylaxis is performed by H2RA or PPI. As the latter is more expensive, its use as first choice in critical care should be questioned.However, the completion of the study on the planned 198 patients is required to come to the final conclusions."}
+{"text": "Primary vasculitis of the central nervous system is a newly recognized, devastating inflammatory disease restricted to the brain and spinal cord. Previously healthy children and adults develop life-threatening neurological deficits including stroke and seizures. Within CNS vasculitis distinct disease entities have been identified in different age groups. The aim was to describe the presenting features of children and adults with CNS vasculitis, to compare distinct entities and their treatment regimens between adult and children and to analyze disease progression and/or relapse.Two cohorts of consecutive patients with primary CNS vasculitis based on Calabrese criteria diagnosed over a 21 year period and followed at tertiary vasculitis centers were identified: 1) adult patients  and 2) pediatric patients . Patient demographic characteristics, presenting clinical features, neuroimaging characteristics, brain pathology results, clinical course including progression and relapse and treatment regimens were recorded. Characteristics of cohorts were analyzed using descriptive statistics. Univariate analysis compared distinct disease phenotypes and treatment regimens. Kaplan Meier survival analysis was performed to determine survival after CNS vasculitis diagnosis.A total of 227 patients were included in the study; 101 adult patients and 126 pediatric patients. In children the median age was 8 years (1-17 years) and in adults 47 years (17-84 years). Pediatric patients showed a male predominance (F: M = 1:1.5) in contrast with the adult cohort (F:M = 1.3: 1). Diagnosis was established on angiography only in 88 pediatric and 52 adult patients, and on brain biopsy with negative angiography in 29 pediatric and 8 adult patients. Vessels involved were: in children 35 small vessel and 91 large vessel, in adults 22 small vessel, 6 large vessel and 48 small and large vessels. Brain biopsy: performed in 49% of adult patients with a male predominance (F: M = 1:1.2) compared to 25% in children with a female predominance (F:M = 1.9:1). Histology showed only lymphocytic inflammation in children and predominantly a granulomatous pattern in adults . Treatment strategies: in children prednisone in 59 (47%) and cyclophosphamide in 34 (27%), in adults prednisone in 97 (96%) and cyclophosphamide in 46 patients (46%). Relapse or progression of the disease was seen in adults in 26% and in children in 15%.Distinct differences are present in the spectrum of primary CNS vasculitis in adults and children. Biopsy only or angiography only confirmed disease shows different gender predominance in adults compared to children. Adults are treated more frequently with steroids and cyclophosphamide, however relapse rates are lower in children."}
+{"text": "TARGIT-A is a recent prospective randomised multicentre controlled trial comparing intraoperative radiotherapy (IORT) and external beam whole breast irradiation (EB). The aim of this study was to compare localised and generalised findings at follow-up mammography and the need for interventions such as ultrasound and biopsy between women in the two treatment arms from a single recruiting centre.We have compared the 61 women who received IORT alone with the 63 women who received EB alone. All mammograms were reviewed by radiologists blinded to the treatment received. The focal soft tissue appearance was classified. The presence of generalised skin thickening and increased density was recorded. The performance of ultrasound and/or biopsy was recorded.P = 0.04 and 20 of 63 (37%) vs. 5 of 61 (8%), P = 0.001, respectively). Ultrasound at follow-up was more frequent in the IORT group compared with the EB group (15 of 61 (25%) vs. 7 of 63 (11%), P = 0.049).The number of follow-up mammograms and length of follow-up was similar in both groups (2.46 IORT vs. 2.09 EB and 3.27 years IORT vs. 3.0 years EB). There was no difference in the mammographic appearance of the postoperative site between the two groups. However, generalised skin thickening and increase in density were more common in the EB group compared with the IORT group (20 of 63 (37%) vs. 10 of 61 (16%), Generalised reactions on mammography are more common following EB compared IORT. However, follow-up ultrasounds were more frequent in the IORT group."}
+{"text": "The objective of this study is to investigate the prevalence, risk factors, and impact on outcome of electrographic seizures (ESz), nonconvulsive status epilepticus (NCSE), and periodic epileptiform discharges (PEDs) in surgical ICU (SICU) patients.This was a retrospective study of 156 consecutive SICU patients (mean age 65 years old (IQR 54 to 74); 40% women) who underwent continuous electroencephalography (cEEG) monitoring for altered mental status. Poor outcome was defined as death or severe disability (Glasgow Outcome Score 4 or 5).n = 25) had ESz, 5% (n = 8) NCSE, and 29% (n = 45) had PEDs. All eight patients with NCSE were septic. Comatose patients and those with previous liver disease were more likely to have ESz or PEDs compared with noncomatose and those with normal liver function . After controlling for age, coma, and organ dysfunction, the presence of ESz was independently associated with death at hospital discharge ; P = 0.04).The majority of patients were admitted following abdominal surgery (36%) and post liver transplant (24%). Sepsis developed in 102 (65%) patients, almost all patients were mechanically ventilated (94%) and approximately one-half were comatose at the time of EEG monitoring (55%). Sixteen percent (In patients admitted to the SICU, ESz and PEDs are frequent and associated with poor outcome."}
+{"text": "Guillain-Barre syndrome (GBS) is an immune-mediated polyneuropathy that occurs mostly after prior infection. The diagnosis of this syndrome is dependent heavily on the history and examination, although cerebrospinal \ufb02uid analysis and electrodiagnostic testing usually confirm the diagnosis. This is a retrospective study which was performed to investigate the atypical features of GBS.Thirty three patients  with GBS were retrospectively studied and prospectively evaluated at the Child Neurology institute of Mofid Children Hospital of Shahid Beheshti University of Medical Sciences between May 2011 and September 2012.The mean age was 5.4 years .Twenty one patients (87.9%) had previous history of infections. Eight patients (24.2%) admitted with atypical symptoms like upper limb weakness (3%), ptosis (3%), neck stiffness (3%), inability to stand  (9.1%), headache (3%) and dysphagia (3%).According to disease process, weakness was ascending in 26 (78.8%), descending in 5 (15.2%) and static in 2 (6.1%) patients. Cranial nerve involvement was found in 8(24.3%) children, most commonly as facial palsy in 3 (9.1%).In this study, 24.3% of our patients presented with atypical symptoms of GBS as upper limb weakness, ptosis, neck stiffness, inability to stand , headache and dysphagia. An acute inflammatory demyelinating polyneuropathy (AIDP) which has autoimmune basis affecting the peripheral nervous system is called Guillain \u2013Barr\u00e9 syndrome (GBS). Nowadays Guillain\u2013Barr\u00e9 syndrome is the most common cause of acute neuromuscular paralysis in the world. A French physician first described a variant of this syndrome in 1859, so it is sometimes called Landry\u2019s paralysis. After the French physicians, this syndrome was detailed by Guillain, Barr\u00e9 and Strohl, in 1916. The disease has become well-known internationally under the name of Guillain Barr\u00e9 Syndrome .The highest incidence of GBS is in two ends of the human life in early and late adulthood. The disease affects young adults greater than the elderly with a slightly higher male preponderance with a ratio of 1.25-1.5:1 . In IranThe disease is assumed to be autoimmune and operated by a preceding infection, most of the time respiratory or gastrointestinal infections. Generally infections by microorganisms such as Campylobacter jejuni, CMV, Mycoplasma pneumonia, or in\ufb02uenza virus exist several weeks prior to approximately two thirds of GBS cases .Epitopes on the surface of peripheral nerves  resemble some infectious agents\u2019 surface epitopes so the immune system attacks peripheral nerves erroneously . GBS usuMiller Fisher syndrome, acute inflammatory demyelinating polyradiculoneuropathy (AIDP), acute motor axonal neuropathy (AMAN) and acute motor and sensory axonal neuropathy (AMSAN) are considered as four principal subtypes of this syndrome. Oculomotor dysfunction, ataxia and areflexia are triad symptoms of the Miller Fisher syndrome . SymptomPatients with the confirmed diagnosis of GBS will be treated with plasmapheresis or intravenous immunoglobulin (IVIG). Some patients should be under respiratory support when needed. Ventilator support is the requirement of approximately twenty five percent of GBS cases, particularly patients with more rapid motor weakness progression. The efficacy of plasmapheresis and IVIg in the treatment of GBS has been equal. Intravenous immunoglobulin (IVIG) is the treatment of choice of these patients because it is easier to use. Current recommendations corroborate the opinion that the steroid regimen has no more advantage when added to therapy, although this issue is controversial. Longitudinal gradual improvement will be the consequence of treatment in most patients in weeks to months. Affected patients with more aggressive onset tend to have more poorly recovery. Ten to twenty percent of these cases are complicated with a disabling motor deficit overall -13.In this study, we evaluated patients with GBS series between 2011-2012, with the purpose of defining its atypical epidemiological, clinical, laboratorial findings and follow-up profile.This series of patients with Guillain-Barr\u00e9 syndrome were retrospectively studied and prospectively evaluated at the Child Neurology Institute of Mofid Children Hospital of Shahid Beheshti University of Medical Sciences between May 2011 and September 2012. The Child Neurology Institute of Mofid Children Hospital is a third level pediatric hospital that receives patients from throughout the country. The patients fulfilled the clinical criteria for Guillain-Barr\u00e9 syndrome . Based oAll patients were reviewed clinically by a child neurologist. The electrophysiology was performed at the neurophysiology section of Mofid hospital. Data was prospectively collected from all GBS cases and subsequently, cases were analyzed separately. The diagnosis was based on clinical features, lumbar puncture and electrophysiological findings as laid down in the well-established criteria. Onset of weakness, duration of weakness, associated or preceding events and progression of the disease were recorded. A detailed neurological examination was recorded in all patients. The nerve conduction velocity (NCV) studies were done within 24 hours of hospitalization. At least one motor and one sensory nerve were tested in upper and lower limbs. F-wave latencies were recorded if there was only mild slowing of nerve conduction velocity. Electromyography (EMG) was not performed in any patient. All confirmed GBS cases were followed up for 3 months after onset. During a period of 16 months, 33 children including 21 (63.6%) males and 12 (36.4%) females with the confirmed diagnosis of GBS were enrolled in this study. The mean age was 5.4 years . Twenty one patients (87.9%) had a previous history of infection. The most common preceding events of the GBS occurred in winter and were respiratory infections , followed by gastrointestinal infections , dental infection , chicken pox  and heart surgery . In four other patients (12.1%) no triggering factor was found. The interval between these events and the onset of disabilities ranged from 3 to 15 days . The most common presenting symptoms were lameness that was seen in 10 (30.3%), gait imbalance in six (18.2%), lower limb weakness in five (15.2%), steppage gait in two (6.1%) and myalgia in two (6.1%) of the cases. Eight patients (24.2 %) were admitted with atypical symptoms like upper limb weakness (3%), ptosis (3%), neck stiffness (3%), inability to stand  (9.1%), headache (3%) and dysphagia (3%). Lower limb deep tendon reflexes (DTR) were reduced or could not be detected in 27 (81.8%) where upper limb deep tendon reflexes (DTR) were reduced or could not be detected in 11 (33.3%) cases. According to the disease process, weakness was ascending in 26 (78.8%), descending in five (15.2%) and static in two (6.1%) patients. Cranial nerve involvement was found in eight (24.3%) children, most commonly as facial palsy in three (9.1%), followed by bulbar weakness  in two (6.1%), abducence palsy in two (6.1%) and trigeminal palsy  in one (3%) patient. Five patients (15.2%) had sphincter dysfunction of which all were urinary incontinency. Nine patients (27.3%) complained of muscle pain and other sensory symptoms. A lumbar puncture was performed in all cases within two weeks of the onset of the illness. The CSF protein concentration was raised (>45 mg/dl) in 23 (69.6%) patients and the mean concentration was 59.8 mg/dl . CSF pleocytosis was not found.Nerve conduction velocity findings were as acute demyeliniting in 21 (63.6%), axonal in six (18.2 %) and absent F wave in six (18.2%) patients. Based on clinical and electrophysiological investigations, 29 (87.8%) of the cases were classified as AIDP, two (6.1%) of the cases were classified as CIDP and two (6.1%) as Miller Fisher syndrome (MFS). In three patients that were diagnosed as acute GBS, the cauda equine displayed hyperintense thickening in spinal MRI. Nine (27.2%) patients were admitted in PICU and ventilation support was needed for four (12.2%) of them. Twenty six patients received IVIG and four of them received intravenous methylprednisolone too. Four of the patients were treated with plasmapheresis after IVIG - corticosteroid failure and three cases were cured without any medication. The length of hospital stay ranged from 5 to 36 days (mean 7.5 days).After treatment, 19 patients (57.6%) developed significant improvement of functional disability one month later, five of them (15.1%) ameliorated after 3 months and nine (27.3%) patients have not reached complete recovery till now. Among untreated children, two have waddling gait, five have inability to stand, one has steppage gait and two have limb lameness.We have reported eight children who include 24.3% of the total patients who have presented with atypical symptoms of GBS as upper limb weakness (3%), ptosis (3%), neck stiffness (3%), inability to stand  (9.1%), headache (3%) and dysphagia (3%). Jin Park et al. reported an 11-year-old girl with an atypical GBS presentation of generalized weakness, internal ophthalmoplegia  and postural dizziness; The current study is consistent with the symptoms of a 10-year-old girl who was admitted with ptosis and weakness in our study .A 1.5-year-old boy was referred to our hospital with neck stiffness and myalgia. Central nervous system infections were ruled out by CSF analysis and electrophysiologic investigation found acute demyelinating neuropathy as GBS. This is similar to the report of atypical GBS by Etem Pi\u015fkin et al. who diagnosed a 3-year-old girl who suffered from prominent neck stiffness and positive Kernig\u2019s and Brudzinski\u2019s signs. Muscle weakness increased significantly on the second day of hospitalization and the patient lost her ability to walk by the third day .In our series of 33 children with the diagnosis of GBS, 87.8% had clinical and electrophysiological findings suggesting AIDP; 6.1% of the cases were classified as CIDP and 6.1% as Miller Fisher syndrome which is concordant with previous studies. In North America and Europe, Miller-Fisher syndrome has been found to account for approximately 5% of the GBS cases .The male to female ratio was 1.75:1, while previous reports presented a ratio of 1.25-1.5:1 . Most auTwenty one patients (87.9%) had previous history of infections with a mean interval between these events and disability onset of 9.5 days. Two most common preceding events of the GBS were respiratory (42.4%) and gastrointestinal infections (33.3%). Generally, more than two-thirds of GBS cases have a past medical history of acute illness, most commonly infection of the respiratory tract or gastrointestinal system which have been eliminated since the neuropathic symptoms initiated. In several large studies, the time duration between the precedent infection and the symptoms of GBS differs from 1 to 3 weeks which is sometimes longer. In many large studies, the average of 11 days has been reported. Precedent respiratory and gastrointestinal infectious symptoms encompassed 17% to 38% of the patients with GBS in a study conducted by Winer et al. . This study showed that the highest proportion of the syndrome was observed in the winter; however. The syndrome assumed to be sporadic with no significant disparity between seasons or months. This finding is in agreement with a study performed by Barzegar et al. which showed a relationship between the high frequency of upper respiratory tract infections within the cold season and the high incidence of GBS syndrome in winter . A studyThe pattern of cranial nerve involvement in a study conducted by van der Linden et al. on the clinical and epidemiological aspects of Guillain-Barr\u00e9 syndrome in children was bilateral facial nerve paralysis in 55.7% .The mean recovery period in children reported in the literature was about 50 days, which is rather a short time. Total time for recovery of GBS is shorter in younger patients compared with adults. Nine patients (27.3%) persisted with sequels after a period of 16 months follow-up, which is in agreement with thatfound in the literature ,28. Howe"}
+{"text": "The safety and the efficacy of allergen specific Immunotherapy by subcutaneous route in perennial conjunctivitis caused by house dust mite were evaluated in 89 patients for 24 months.Group of 89 patients diagnosed by ophthalmologist included in study. Patients of allergic conjunctivitis included in this study underwent Skin allergy test and specific IgE tests for dust mite allergens. Out of 89 patients 43 received Allergen specific Immunotherapy (SIT) subcutaneous injections with standardized Dermatophgoides farinae (D.f.) and Dermatophagoides pteronyssinus (D.pt.) allergen extract. While 46 patients are only treated by conventional treatment by using local steroids and antihistaminic drops. The vaccine was supplied by a commercial company as per the prescription for each patient. The subjects generally received three concentrations of antigens ending with the most concentrated solution. Later on, maintenance immunotherapy was continued with the 1:50 concentration for 24 months. Results were evaluated on 2, 6, 12, 18 and 24 months by using Total Symptom Score (TSS), Local Medication use, Clinical examination grading, Quality of Life evaluation (QOL).Of the 89 patients included, only 81 completed the study (43 in the Immunotherapy group and 46 in the Non Immunotherapy group). Three out of 43 (6.9%) patients dropped out because of insufficient efficacy in the Immunotherapy group compared to five out of 46 (10.8%) in the non immunotherapy group. Sum of all four primary end point criterias are scored against five group of efficacy evalution. No improvement 8 (9.8% ), marginal improvement 16 (19.7%), improvement 23 (28.3%) and significant improvement 35 (43.2%). In group of 35 improved patients 26 (74.2%) were received immunotherapy while 9 (25.7%) patients did not.Two years treatment with subcutaneous house dust mite immunotherapy significantly reduced symptoms and medication use in allergic conjunctivitis patients. This was associated with a greater subjective improvement and quality of life in patients of perennial conjunctivitis caused by house dust mites."}
+{"text": "MEFV) mutations on the chromosome 16. It is the most frequent periodic febrile syndrome among autoinflammatory syndromes. Eighty % of patients with FMF have MEFV mutations, while around 20% do not have mutations.Familial Mediterranean fever (FMF) is an inherited autosomal recessive disorder, ethnically restricted and commonly found among individuals of Mediterranean descent, caused by MEditerranean FeVer gene ; 41 patients  negative for MEFV mutations were selected and studied. Similarly with MEFV positive patients, in our case-series, most MEFV-negative ones came from Southern and Central Italy. The mean age of FMF onset was 21.8 years, differently from what observed in MEFV-positive population, in which the mean age was 15. The frequency of attacks went from less than 1 attack/month (in 26%) to 1-2 attacks/month (in 54%) and more than 2 attacks/months (in 19.5%). The mean duration of each attack was 83.9 \u00b1 8.91 hours. The typical clinical signs of FMF attacks were: fever , articular pain (76%), abdominal pain (63.4%), oral aphthosis (44%), and chest pain (37%). Thirty-one out of 41 patients had joint involvement in terms of arthritis (21.5%), arthralgias (25%), arthromyalgias (32%), and myalgias (21.5%). Attacks were controlled with a mean dose of colchicine of 1.5 mg/day in all patients (vs a mean dose of 1.3 mg/die in the MEFV-positive population). No statistically significant difference was detected in terms of frequency and duration of attacks, as well as in symptoms distribution and colchicine dosage between MEFV-negative and positive populations.Genetic testing by MEFV-positive patients. These results support the hypothesis of involvement of other low-penetrance genetic systems in the FMF clinical expression.Analysis of our MEFV-negative series of Italian patients revealed a higher prevalence of late-onset FMF, whereas the percentage distribution of symptoms was similar to None declared"}
+{"text": "Patient engagement in health information seeking is associated with beneficial social, emotional, and health outcomes. We analyzed data from the 2008 Health Information National Trends Survey to characterize, and compare patterns of health information seeking and trust in sources of health information among persons who use complimentary and alternative (CAM) approaches to health and medicine and those who do not.SUDAAN was used to calculate population estimates. Weighted frequencies along with crosstabulation and chi-square analyses were conducted.A significantly higher percentage of CAM users (83.2%) reported health information seeking, compared with non-users (65.4%). Differences in health information sources by CAM use were also observed. A higher percentage of CAM users (17.4%) reported use of print resources  and the internet (63.5%), compared to non-users . CAM users (11.6%) reported use of healthcare providers less frequently than non-users (15.0%). Reliance on friends and family for health information was similar among CAM users (3.9%) and non-users (4.2%). An interesting pattern of differences in trust in health information sources by CAM use was also observed. CAM users generally reported less trust in specified sources of information . Additionally, a lower percentage of CAM users (60.4%) reported trust in healthcare professionals than non-users (71.2%). The only source of health information wherein greater trust was reported by CAM users (21.8%) compared with non-users (19.3%) was the internet.Results of our analyses point to distinct patterns of engagement in health information seeking among CAM users and non-users. CAM users appear to be more active information seekers with relatively greater reliance on traditional information sources than non-users. Our results suggest that CAM users may be a ready audience for patient-centered interventions and cost-effective strategies to engage patients more fully and to improve population health."}
+{"text": "Bronchoscopy (BC) is a frequently used diagnostic and therapeutic tool in our ICU. We planned to review the patients and conditions in which the procedure was performed. The objective was to determine indications, diagnostic and therapeutic yield.A retrospective, single-center observational study was carried out. All BC performed in a 20-bed polyvalent ICU of a tertiary university hospital over a period of 30 months (from January 2010 to June 2012) were included. The main variables collected were demographic data and clinical data including comorbidities, endobronchial techniques and results.Pseudomonas aeruginosa and Acinetobacter baumanii. Bronchoalveolar lavage was performed in 62 cases (13%) obtaining microbiological growth in 61% of them, mainly cytomegalovirus and Stenotrophomona maltophilia. Citology was performed in 60 cases (13%); 7% showed the presence of microorganism and 13% revealed precancerous/cancerous tissue changes.A total of 470 BC were carried out in 240 patients admitted to the ICU . All of the procedures were performed in mechanically ventilated patients. The mean patient age was 61 \u00b1 14 years, with an APACHE II score at admission of 20 \u00b1 7. The main cause for ICU admission was respiratory failure (27%). The most common comorbidities were smoking, chronic obstructive pulmonary disease, cardiovascular risk factors and atrial fibrillation. The main indications for performing the BC were percutaneous tracheostomy endoscopically guided (28%), resolution of atelectasis (27%), aspiration of secretions (24%) and hemoptysis (10%). Bronchial brushing was performed in 435 cases (93%) obtaining microbiological growth in 64% of them, mainly BC can be performed at the bedside, avoiding transfers outside the ICU that may cause clinical worsening. Most frequent indications were bronchoscopy-guided percutaneous tracheostomy, resolution of atelectasis, aspiration of secretions and hemoptysis. Microbiological results obtained revealed the presence of aggressive pathogens. BC in ICU provides valuable diagnostic information and has therapeutic utility."}
+{"text": "A lower case-fatality rate may have been caused by a less virulent virus clade. >15 years, and receiving the first dose of oseltamivir >2 days after illness onset. All but 2 case-patients reported exposure to domestic poultry probably infected with avian influenza virus (H5N1). No cases of human-to-human transmission were found. Greatest risks for infection and death were reported among women >15 years of age, who accounted for 38% of infections and 83% of deaths. The lower case-fatality rate in Egypt could be caused by a less virulent virus clade. However, the lower mortality rate seems to be caused by the large number of infected children who were identified early, received prompt treatment, and had less severe clinical disease.During March 2006\u2013March 2009, a total of 6,355 suspected cases of avian influenza (H5N1) were reported to the Ministry of Health in Egypt. Sixty-three (1%) patients had confirmed infections; 24 (38%) died. Risk factors for death included female sex, age  Within the first month, avian influenza (H5N1) was detected in 12 other governorates. Despite control measures that included culling, disinfection, vaccination, and controlled poultry movement, epizootic transmission of avian influenza virus (H5N1) continues.During February 2006\u2013March 2009, avian influenza virus (H5N1) was detected on 907 commercial poultry farms and in 606 backyard flocks. In 2006, poultry farms accounted for 84% of 1,052 outbreaks. In 2007, backyard flocks accounted for 89% of 274 outbreaks. As of March 2009, nineteen of 29 governorates reported infected poultry. The poultry industry in Egypt produces \u22482 million birds per day. Social and economic consequences have been dramatic (losses of \u22482\u20133 billion US$). Backyard flocks are common; 4\u20135 million families (\u224825 million persons) raise poultry at home. During February 2006\u2013March 2009, a total of 3,941 asymptomatic persons exposed to avian influenza (H5N1) from a person with a confirmed case or from infected poultry were tested by using a real-time PCR; none were positive.In March 2006, the first human case of avian influenza (H5N1) in Egypt was reported from Qalubiya Governorate . We repo>38\u00b0C and 1 of the following signs or symptoms ) and specific exposure to ill, dying, or dead poultry. All suspected case-patients are referred to specified fever or chest hospitals for testing and medical care. At these hospitals, oropharyngeal swab specimens and serum samples are obtained. Persons with suspected cases receive an initial dose of oseltamivir and are placed in respiratory isolation areas.The study protocol (NAMRU3.2004.0023) was reviewed and approved by the Naval Medical Research Unit No. 3 Institutional Review Board in compliance with all applicable federal regulations governing protection of human subjects. Suspected cases of avian influenza (H5N1) in humans are reported from all districts in Egypt. A suspected case-patient is a person with influenza-like illness  Central Public Health Laboratory for real-time PCR testing for influenza A virus matrix and H5 genes by using primer\u2013probe sets (Most case-patients with confirmed avian influenza (H5N1) are transferred to Cairo, Egypt, for care at 2 tertiary hospitals. Data are obtained by healthcare providers who initially evaluate suspected cases and by MOH staff when cases are confirmed. Epidemiologic and clinical data are obtained for each patient with a confirmed case by using a standardized case investigation form. For this study, a medical record review was performed at tertiary care hospitals. Clinical and exposure data were not available for all 63 patients.>15 years of age, delayed hospitalization as >2 days between illness onset and hospitalization, and delayed oseltamivir as >2 days between illness onset and the first oseltamivir dose.The number of patients for whom data were available is noted. Children are defined as persons <15 years of age, adults as persons 2 or Fisher exact tests were used. Multivariate analysis to identify risk factors for death was performed by using a backward, stepwise logistic regression model starting with all variables  significant by univariate analyses. The Wald statistic and log-likelihood ratio were used to exclude variables. Multivariate analyses were performed by using SPSS version 18 .Univariate analyses were performed by using Epi Info version 3.4.1 . Unless otherwise noted, \u03c7>15 years of age, 5 (8%) were men >15 years of age, 16 (25%) were girls <15 years of age, and 18 (29%) were boys <15 years of age  were reported, and samples were tested by the Central Public Health Laboratory. Of these, 63 (1%) cases were confirmed and 24 were fatal  . Among 6s of age . Two infs of age . Confirms of age . During s of age .Three family clusters were identified. The first cluster, reported in March 2006, was composed of 2 siblings (21 months and 6 years of age) in Kafr El Sheikh Governorate. The second cluster, reported in December 2006, was composed of 3 family members  in Gharbia Governorate. The third cluster, reported in March 2007, was composed of 2 siblings (4 and 6 years of age) in Qena Governorate. In the first 2 clusters, all shared a common exposure to likely infected poultry and became ill at the same time. In the third cluster, although illness onsets were separated by 4 days, an investigation showed that each child had 2 separate exposures to infected birds. Human-to-human infections were not identified. Household contacts were not given oseltamivir but were followed up closely for 10 days. Secondary infections were not found.>15 years of age, 20 (71%) had delayed hospitalization compared with 10 (29%) of 34 patients <15 years of age (p = 0.002). Fever (97%) and cough (72%) were the most common clinical signs. Sore throat was reported by 45% of case-patients and shortness of breath by 25% . Female patients and adults were ill longer before hospitalization than were male patients and children. Of 40 female patients, 23 (57.5%) had delayed hospitalization (>2 days after illness onset) compared with 7 (32%) of 22 males. Of 28 patients h by 25% . Adults h by 25% .>1 secondary complication developed in 25 (42%). Sixteen case-patients had multiple complications (Forty-six (73%) of 63 case-patients were transferred to Cairo for definitive care. Of 17 case-patients not transferred to Cairo, 5 (29%) died <2 days after being admitted to a governorate hospital. Of 59 case-patients for whom data on complications were available, ications . The mos>1 complication compared with only 5 (15%) of 33 children (p<0.001).Of 19 case-patients with acute respiratory distress syndrome, 18 died. The only survivor was an 18-year-old woman who received intubation for 12 days and oseltamivir 2 days after illness onset. A complication was more likely to develop in adults; 20 (77%) of 26 had Chest radiographs were reviewed for 58 patients. Twenty-five (43%) radiographs showed lobar infiltrates, of which 20 (80%) were bilateral. Of 33 radiographs for children, 27 (82%) showed no abnormalities. Abnormal laboratory test results included those for leukopenia , thrombocytopenia , and elevated levels of aspartate aminotransferase  and alanine aminotransferase .Medication records were available for 60 patients who received antimicrobial drugs. Of 60 patients, 31 (52%) received oxygen, including 22 (37%) who received mechanical ventilation. Twenty (74%) of 27 adults received mechanical ventilation compared with only 2 (6%) of 33 children (p<0.001). Of 60 patients, 16 (27%) had received corticosteroids. Mortality rates did not differ between intubated patients who received corticosteroids and those who did not.>1 dose of oseltamivir. Of 58 patients for whom complete data for oseltamivir was available, 25 (43%) received their first dose <48 hours after illness onset; all but 1 survived. Median duration of treatment was 8 days (range 1\u201337 days). The first dose of oseltamivir was more likely to be delayed for adults. Twenty (80%) of 25 adults had a delay before receiving oseltamivir compared with 13 (39%) of 33 children (p = 0.005).All 62 case-patients who became ill in Egypt received Virus isolates were obtained from 34 (54%) of 63 case-patients. Sequencing of hemagglutinin and neuraminidase genes showed all viruses belonged to clade 2.2 and were closely related to isolates from birds in Europe and the Middle East (<48 hours after illness onset (p<0.001). Of 33 patients whose first oseltamivir dose was delayed, 19 (58%) died compared with only 1 (4%) of 25 patients who received oseltamivir <48 hours after illness onset (p<0.001).Of 63 case-patients with confirmed influenza, 24 (38%) died. Median time between onset of illness and death was 9 days (range 4\u201340 days). Ten (56%) of 18 ill patients died in 2006 compared with 9 (36%) of 25 ill patients in 2007 and 4 (50%) of 8 ill patients in 2008 . Mortali>15 years and delayed hospitalization were independently associated with higher mortality rates. Of 28 adults for whom hospitalization data were available, 12 (43%) were hospitalized in the first 48 hours of illness compared with 27 (79%) of 34 children (p = 0.007). Stratified analysis showed delayed hospitalization was a greater risk factor for death among adults than among children. Eighteen (86%) of 20 adults hospitalized >48 hours after illness onset died compared with 4 (50%) of 8 adults hospitalized <48 hours after illness onset (p = 0.04). None of 24 children hospitalized <48 hours after illness onset died compared with 2 (20%) of 10 children hospitalized >48 hours after illness onset. Nineteen (83%) of 23 female patients hospitalized >48 hours after illness onset died compared with 2 (12%) of 17 hospitalized <48 hours after illness onset (p<0.001).Although adults were more likely than children to have a delay in hospitalization, age <48 hours of illness onset died compared with 1 (8%) of 13 children whose first dose was delayed.Eighteen (90%) of 20 adults whose first oseltamivir dose was delayed died compared with 1 (20%) of 5 adults whose first oseltamivir dose was not delayed (p = 0.005). None of 20 children who received oseltamivir >15 years and having received a first dose of oseltamivir >2 days after illness onset were likely independent risk factors contributing to death.Age, sex, delayed hospitalization, and delayed use of oseltamivir were included in multivariate analysis by using a logistic model to identify risk factors for death. Sex and delayed hospitalization did not contribute to the final model. Because of relatively few cases, high degree of covariance in age, and delayed use of oseltamivir, there was insufficient power to further develop this model. Despite this limitation, analysis showed that age Handling live domestic poultry likely infected with avian influenza virus (H5N1) was the primary source of exposure. Investigations showed that human-to-human transmission was unlikely; even clusters of case-patients had exposure to infected poultry. Of 63 case-patients, 4 (6%) were involved in poultry production or distribution (3 poultry farm workers and 1 seller), 2 (3%) had unknown poultry exposure, and 57 had direct contact with backyard poultry .Exposure data were available for 41 of 57 case-patients with exposure to backyard flocks. Of these case-patients, 33 (80%) reported having had ill birds in their egg-laying flocks and 12 (29%) had recently bought poultry. Of these 12 case-patients, 7 (58%) reported that purchased birds became ill after being brought home. Of 27 case-patients for whom information was documented, 13 (48%) slaughtered or defeathered birds . No caseIn February 2006, avian influenza (H5N1) emerged among domestic poultry in the Nile Delta of Egypt. Within 4\u20135 weeks, it had affected commercial farms and backyard flocks throughout Egypt and resulted in zoonotic transmission to 10 persons in many governorates. Currently, Egypt has reported the third largest number of cases of avian influenza (H5N1) after Indonesia and Vietnam  in Egypt (38%) is lower than that in other countries. As of March 2009, mortality rates were 82% in Indonesia, 50% in Vietnam, 66% in the People\u2019s Republic of China, and 68% in Thailand. Explanations for this observation include lower mortality rates for certain demographic groups, clinician awareness resulting in improved medical care, or less pathogenic virus. The most striking finding is the low mortality rate for children. Although children represent 54% of reported infections, they account for only 8% of deaths. This high survival rate is unlikely to be caused by young age alone. Children were hospitalized earlier in the clinical course of their illness, were more likely to receive oseltamivir within the first 2 days, and appeared to be less ill than adults, as noted by the high proportion of chest radiographs with no abnormal findings and the low proportion of children with respiratory failure. Differences in sensitivity of surveillance methods among countries must also be considered.One must also consider whether the 2.2 virus clade is less virulent. This suggestion is not supported by a report of the 2005\u20132006 outbreak of clade 2.2 virus (H5N1) in Turkey, where of 8 patients 5\u201315 years of age, 4 (50%) died  or in contact with confirmed human case-patients were followed up clinically and tested by using real-time PCR. Although prophylaxis was not given, influenza-like illnesses were not observed and all persons showed negative results. Although serologic testing is needed to exclude infection with avian influenza virus (H5N1), it was unlikely that a large proportion of these persons with high-level exposures to infected birds or humans became infected and supports the decision of the MOH to discontinue testing asymptomatic persons. This finding is consistent with those of studies in Thailand . No illnesses were attributed to exposure to wild birds. Although 3 family clusters were identified, all 7 persons in these clusters had independent exposures. Many families in Egypt raise backyard flocks for eggs and purchase live poultry for meat. Among case-patients, the likely route of infection appears to be direct handling, slaughtering, or defeathering infected birds recently purchased for meat and mingling of recently purchased birds with egg-laying flocks. Recently purchased birds were frequently slaughtered before illness was noted, and purchase was often followed by illness and death among egg-producing flocks.Contact between backyard flocks and wild infected birds could not be estimated, but exposure to feral poultry in canals and waterways near affected households was common. Because persons in Egypt rely on live poultry purchased at markets for dietary protein, the price of poultry influences poultry-buying practices of families. Women in several affected families noted exceptionally low prices for healthy looking birds. These prices indicated that they might be buying infected birds. This finding was true when prices of beef increased in response to decreased availability or increased demand. Despite this knowledge, most persons believed they would be able to slaughter and prepare birds before they became ill or died. This belief was true in most cases but recently purchased birds frequently infected egg-laying flocks, which died within days of exposure.Despite knowledge of overall exposure patterns and identification of groups at risk for exposure, little detailed information on activities that result in infection is available. Although slaughtering and defeathering infected birds appear to be high-risk practices, there have likely been thousands of infected birds sold and slaughtered in homes in Egypt over the past 3 years. Despite this suggestion, we have reports of only 63 cases. Although exposure to avian influenza virus (H5N1) infection is necessary for infection, exposure is not sufficient to explain the epidemiology of cases of avian influenza (H5N1) in Egypt. Whether there is another unknown risk factor or variation in the way women slaughter poultry in Egypt is unclear.,<35% in Indonesia, Vietnam, and China. In Egypt, small children follow their mothers during routine chores, such as feeding and slaughtering poultry. At other times, children will play with poultry, which roam freely around the home. There is a general belief that parents in Egypt will quickly seek medical care for their ill children. This belief is strongly suggested by the fact that children with fever and exposure to dead or ill poultry were consistently evaluated and hospitalized sooner than adults. In addition, many children had mild illness. Mild clinical illness may be caused by early hospitalization, early doses of oseltamivir, or a low virus inoculum.Demographics of influenza cases in Egypt are different from those in other highly affected countries and are useful for determining exposures and activities that result in infection. Women appear to be at greater risk than men of becoming infected, and, once ill, at greater risk of death. In Egypt, the male:female ratio among patients is 1:1.7 and differs markedly from the 1:1 ratio seen globally (This report describes 63 human cases of avian influenza (H5N1) in Egypt during March 2006\u2013March 2009. During April\u2013July 2009, a total of 20 additional cases were identified (83 cases by the end of July 2009) for which data were not available. Analysis of limited information reported to the World Health Organization showed a median age of 4 years (compared with 10 years for the 63 cases), a case-fatality rate of 15% (compared with 38%), and faster hospitalization after illness onset. Ongoing transmission in the summer of 2009 is indicative of persistent disease in poultry, and limited analysis reflects the high proportion of influenza in children. Thus, avian influenza virus (H5N1) remains endemic throughout Egypt. However, human infections are rare and disproportionately affect women and their children, who are responsible for caring for and slaughtering birds within the home. To reduce their risk, specific slaughtering practices and other transmission risk factors should be identified and appropriate interventions implemented. In addition, emphasis on controlling domestic poultry populations and increased use of bird cages, hand washing, and other protective measures specific for women and children should continue."}
+{"text": "Intermediate uveitis (IU) is generally believed to be autoimmune in nature requiring systemic corticosteroid and immunomodulatory therapy. This belief stems from the published reports from the developed countries; and the scenario maybe different in the developing countries that maybe endemic for certain infections. There are no large series available on the etiologic causes of intermediate uveitis from the developing countries. The present series aims to describe the etiology, treatment, and course of IU in North Indian population.In a retrospective analysis, records of 205 patients seen with a referral diagnosis of IU were retrieved and analyzed. After determining the etiology, 122 patients who had a definitive diagnosis of IU and a minimum follow-up of 1\u00a0year were analyzed further. All patients underwent investigations to rule out any possible etiology and received stepwise therapy comprising of depot or systemic corticosteroids, immunosuppressive/immunomodulatory therapy and pars plana vitrectomy. Specific therapy was administered wherever etiology could be determined. The primary outcome measure was recurrence of inflammation after a minimum of 6\u00a0months of initiating treatment.P\u2009=\u20090.011); cystoid macular edema (P\u2009=\u20090.015), and in eyes that received local therapy (P\u2009=\u20090.001). Out of 57 patients who were diagnosed as intraocular tuberculosis, 42 patients (73.6%) received specific antitubercular treatment. Only 5 of 42 patients (11.9%) who received ATT had recurrence of inflammation compared to 7 out of 15 patients (46.7%) who did not receive ATT (P\u2009=\u20090.005).There were 55 men and 67 women, and the disease was bilateral in 82 patients. Tuberculosis was the most common underlying etiology seen in 57 (46.7%), followed by sarcoidosis in 22 (18%), pars planitis in 35 (28.7%), and IU of idiopathic type in 8 (6.5%). Seventy three (59.8%) of 122 patients received systemic steroids, 55 (45.1%) were treated with periocular steroid, and 19 (15.6%) received immunomodulatory therapy. Specific antimicrobial therapy in the form of antitubercular treatment (ATT) was given in 42 patients. The recurrences were seen in 35 patients (28.7%) over a median follow-up of 18\u00a0months. Recurrences were seen more commonly in eyes with snow banking (Tuberculosis is an important etiologic cause of IU in developing countries like India where the disease is endemic. It is important to investigate these patients as specific therapy with ATT helped in reducing the recurrences significantly. Intermediate uveitis (IU) was defined by International Uveitis Study Group (IUSG) as idiopathic inflammatory syndrome, mainly involving the anterior vitreous, peripheral retina, and ciliary body with minimal or no anterior segment inflammation . The terWe analyzed 15-year data (January 1995 through June 2009) from medical records of uveitis clinic of Post Graduate Institute of Medical Education and Research, Chandigarh, India. The medical record of all patients with diagnosis of IU as per the SUN working group criteria was analyzed in detail. Only patients with a minimum of 1-year follow-up were included. All the patients who did not complete a minimum 1\u00a0year of follow-up or where the disease showed significant granulomatous anterior segment inflammation during follow-up were excluded from further analysis. Patients of Fuchs uveitis and Behcet's disease who were initially misdiagnosed as IU were also excluded from further analysis.Treponema pallidum hemagglutination test. Other targeted laboratory tests like serum angiotensin-converting enzyme level, Borrelia serology, chest computed tomography, magnetic resonance imaging (MRI) scan of the brain, and human leukocyte antigen typing were done whenever required. The following algorithm was followed: firstly, all the patients of Fuchs uveitis where vitritis was significant and mislead to the diagnosis of IU were excluded. Secondly, the patients with typical pars planitis as well as those with IU with/without snow banks and posterior synechia were investigated for infectious etiologies like tuberculosis (TB), sarcoidosis, Lyme and systemic associations like MS were ruled out. In patients with preponderant vitritis, etiologies like toxocariasis, lymphoma, candida, and Whipple's disease were ruled out. In patients with prepondrant vasculitis, MRI was done to rule out multiple sclerosis and intracranial lymphomas.All the enrolled patients had their records of history and ocular and systemic examination available at presentation as well as during follow-up visits. All patients had a detailed history recorded in the uveitis clinic file and underwent a complete ophthalmic examination including best corrected visual acuity, intraocular pressure, slit lamp biomicroscopy, and posterior segment examination with both slit lamp biomicroscopy and indirect ophthalmoscopy to examine pars plana area. Ancillary tests including fundus fluorescein angiography, optical coherence tomography, or ultrasound biomicroscopy, and specific laboratory tests were done as and when indicated. Systemic evaluation was done by a senior consultant internist who has special interest in systemic inflammatory diseases. Patients underwent baseline investigations including complete blood counts, erythrocyte sedimentation rate, tuberculin skin test, chest radiography, and Patients were diagnosed as intermediate uveitis of presumed tubercular etiology if the following criteria were fulfilled: (1) a documented positive tuberculin skin test (10\u00a0mm of induration or more) at 48\u201372\u00a0h; (2) evidence of vitritis, snowballs, or snow banking; and (3) all known causes of infectious uveitis except TB and known noninfectious uveitic syndromes ruled out. Pars planitis was defined as subset of intermediate uveitis associated with snow bank or snowballs formation in the absence of an associated infection or systemic disease. When typical features of pars planitis are not present and the etiology could not be determined, then the term \u201cintermediate uveitis of idiopathic type\u201d was used.The patients received treatment if (1) the visual acuity was worse than 20/40, (2) presence of cystoid macular edema, (3) vitreous haze of 2+ or more, and (4) retinal neovascularization. A stepwise graded approach to treatment included periocular steroid injection, systemic corticosteroids, immunosuppressive/immunomodular therapy, and pars plana vitrectomy. In cases with unilateral or asymmetric involvement, the periocular steroid injections were given first, and systemic treatment was initiated only in cases with insufficient effect and/or intolerance to this treatment modality. Systemic steroids (1\u20131.5\u00a0mg/kg body weight) were started in cases with severe bilateral disease and/or in cases with decrease visual acuity due to vitreous opacities. Immunosuppressive agents were started as a steroid-sparing drug or when steroid failed to control the inflammation. IU patients with presumed TB in addition also received antitubercular therapy (ATT). Pars plana vitrectomy was done if the vitritis was very severe at the time of presentation to our center despite receiving initial therapy outside and the laboratory investigations were equivocal and to manage the complications like retinal detachment and vitreous hemorrhage.The primary outcome measure was the recurrence of inflammation occurring after a minimum of 6\u00a0months of receiving treatment. Visual improvement was defined as halving of the visual angle and visual deterioration as doubling of the visual angle. Visual acuity was said to be stabilized if the final visual acuity remained within two lines of the presenting acuity.\u03b1\u2009=\u20090.05.The statistical analysis was carried out using Statistical Package for Social Sciences . All quantitative variables were estimated using measures of central location  and measures of dispersion (standard deviation). Normality of data was checked by measures of Kolmogorov\u2013Smirnov tests of normality. For normally distributed data, means for more than two groups were compared using Kruskal\u2013Wallis test. Qualitative or categorical variables were described as frequencies and proportions. Proportions were compared using chi-square test. All statistical tests were two sided and performed at a significance level of Our study included 205 patients with a diagnosis of IU seen between years 1996 and 2009. Of these 205 patients, 122 fulfilled the inclusion criteria with at least 1\u00a0year of follow-up and were analyzed further. There were 55 men (45.1%) and 67 women (54.9%) with male-to-female sex ratio of 1:1.2. The mean age at diagnosis was 36.1\u2009\u00b1\u200913.3\u00a0years (range 5\u201368\u00a0years). The disease was bilateral in 82 patients (67.2%). Presenting complaints were decreased vision in 100 patients (81.9%), redness in 52 patients (42.6%), pain in 42 patients (34.4%), and floaters in 40 patients (32.7%). The most common sign at presentation was vitritis seen in all 204 eyes (100%) and snowballs in 177 eyes (86.8%). Snow banking was present in 40 eyes (19.6%). Associated anterior segment inflammation was seen in 128 eyes (62.7%).Of these 122 patients, 57 (46.7%) had underlying etiology of presumed TB and 22 patients (18%) had sarcoidosis. Thirty-five patients (28.7%) were diagnosed as pars planitis while 8 patients (6.5%) were diagnosed as IU of idiopathic type (Table\u00a0Seventy three (59.8%) of 122 patients received systemic steroids, 55 patients (45.1%) were treated with periocular steroid. Nineteen patients (15.6%) received immunomodulatory therapy. Twelve patients (9.8%) with good visual acuity and minimal inflammation received only topical steroids. Specific antimicrobial therapy in the form of ATT was given in 42 patients.The most common complications seen over the follow-up were the development of cystoid macular edema (CME) in 92 eyes (45.1%), cataract in 70 eyes 34.3%), glaucoma/ocular hypertension in 23 eyes (11.2%), and epiretinal membrane (ERM) in 29 eyes (14.2%). Other complications noted were optic disc pallor in nine eyes (4.4%), peripheral neovascularization in eight eyes (3.9%), retinoschisis in four eyes (1.9%), retinal detachment in two eyes (0.9%) and vitreous hemorrhage in one eye (0.5%) . Recurrences were significantly higher in patients having cystoid macular edema with 30 of 92 eyes (32.6%) with CME having recurrence compared to 20 of 112 eyes without CME (17.9%) (P\u2009=\u20090.015). Patients receiving local therapy had higher recurrences compared to those receiving systemic therapy with 32 of 86 eyes (37.2%) receiving local therapy in the form of posterior sub -tenon triamcinolone had recurrence as compared to 18 of 118 eyes (15.2%) who did not received local therapy (P\u2009=\u20090.001). Out of 57 patients who were diagnosed as intraocular tuberculosis, 42 patients (73.6%) received specific antitubercular treatment. Eleven patients (19.2%) received only oral steroids without ATT and 4 patients received only topical steroids. Five of 42 patients (11.9%) who received ATT had recurrence of inflammation as compared to 7 out of 15 patients (46.7%) who did not receive ATT. The effect of antitubercular therapy in reducing the number of recurrences of IU in patients receiving ATT was found to be statistically significant (P\u2009=\u20090.005)  over follow-up ranging between 1 and 10\u00a0years  , CME (P\u2009=\u20090.0001) and ERM (P\u2009=\u20090.01). There was no difference in the final visual outcome between different subgroups.The mean visual acuity at presentation was 20/50 (range 20/20\u2014counting fingers at 2\u00a0ft) and final visual acuity was 20/30 (range 20/20\u201320/400). After treatment, visual acuity improved in 107 eyes (52.4%), deteriorated in 16 eyes (7.8%), and stabilized in 81 eyes (39.7%). A final visual acuity of 20/40 or more could be achieved in 85 patients (69.6%). Factors associated with poor visual outcome were cataract , (4) sputum positive for acid-fast bacilli on smear, culture, or both, and (5) histopathological evidence of tuberculosis from cervical or parahilar lymph nodes; and (c) response to ATT. Since the presence of vitritis alone did not qualify the clinical criteria for presumed IOTB, many of these patients were not diagnosed as TB. In the current study, the inclusion criteria were less stringent and modified to include the evidence of vitritis, snowballs, or snow banking as clinical features with a documented positive tuberculin skin test (10\u00a0mm of induration or more).In the present series including patients from India, a country endemic for tuberculosis, nearly 46.7% cases with IU had TB as an etiology. This is a significant finding as none of the previous series from other parts of the world have reported TB as an important underlying cause of IU \u20136. On thIt is important to emphasize this issue because many ophthalmologists may not routinely investigate these patients for TB which can lead to prolonged disease course with multiple recurrences for want of receiving specific antituberculosis therapy. The administration of ATT led to significant reduction in the number of recurrences during follow-up in the present series, thus highlighting the benefit of adding timely ATT in these patients. There were no clinical indicators predictive of possible tubercular etiology at presentation but during follow-up, the eyes with presumed tubercular IU had more tendency to develop retinal neovascularization. Thus, it is important to keep these eyes under close monitoring for the development of areas of capillary nonperfusion and retinal neovascularization.The visual prognosis was good in present series as about 70% patients could achieve a final visual acuity of 20/40 or better. Presence of cystoid macular edema, cataract, and epiretinal membranes were associated with poor visual outcome. Since all these factors indicate an irreversible cause of visual loss, many of these are likely to improve further after the surgical management, thus improving the prognosis even further.In summary, the results of present series indicate that in Indian population, IU is more likely to be due to TB than multiple sclerosis or any other etiology. Timely management of these patients leads to improvement/stabilization of vision in 93% of the eye with 70% achieving a final visual acuity of 20/40 or better."}
+{"text": "Gastric cancer with synchronous liver metastasis remains a clinical treatment challenge. There has been a longstanding debate on the question whether surgical resection could be beneficial to long-term survival. This study is to investigate the effectiveness and prognostic factors of combined curative resection of the stomach and liver lesions in gastric cancer patients with synchronous liver metastases.A total of 30 patients who underwent simultaneous curative gastric and liver resection from March 2003 to April 2008 were analyzed retrospectively. Univariate and multivariate analyses were performed to select independent factors for survival.p\u2009=\u20090.028) and an absence of peritoneal dissemination (p\u2009=\u20090.007) were significantly independent prognostic factors for these gastric cancer patients with synchronous liver metastases. Major adverse events were protracted stomach paralysis in 2 patients and pulmonary infection in another 2 patients, all of whom recovered after conservative treatment.The overall 1-, 2-, 3- and 5-year survival rates of 30 patients were 43.3%, 30.0%, 16.7% and 16.7%, respectively, with a median survival of 11.0 months and 5 patients still living by the time of last follow-up. Single liver metastasis (This descriptive study without control group found that patients with solitary liver metastasis and absence of peritoneal dissemination could have better survival benefit from simultaneous curative resection of the gastric cancer and liver metastases. Liver is one of the most frequent sites of cancer metastasis from gastrointestinal origin, and the major cause of disease death from stomach cancer. The 5-yThe study complied with the declaration of Helsinki and was approved by Biomedical Research Ethics Committee of Zhongshan Hospital of Fudan University (NO.2009-160). All subjects gave written informed consent.From March 2003 to April 2008, a total of 2942 patients with gastric cancer were treated at our institution. From the archived medical records, a complete database was established on 30 gastric cancer patients with synchronous liver metastasis, who had simultaneous complete resection of both gastric cancer and liver metastasis. The database covered all clinico-pathological characteristics. Lymph node grouping was based on Japanese classification on cancer typing[Of these 30 patients were 27 males and 3 females, with age ranging from 33 to 72 years old (median 60 yr). The primary stomach cancer was located at the antrum in 11 cases, at the gastric body in 9 cases and at the cardia-fundus region in 10 cases. On local invasion status, 4 cases had tumor invasion beneath the serosa, and the remaining 26 cases all had tumor invasion beyond the serosa. On lymph nodes status, 7 cases did not have lymph nodes metastasis while the remaining 23 cases were lymph nodes positive. In terms of liver metastasis, 22 patients had one intrahepatic metastasis lesion and 8 patients had 2\u20133 liver metastases. There were 27 patients with metastasis limited to one lobe of the liver (H1), and 3 cases with metastasis on both lobes of the liver (H2). Simultaneous peritoneal metastasis was found in 5 patients. Of surgical approaches, 11 patients had curative distal gastrectomy, 10 patients had curative proximal gastrectomy and 9 cases had total gastrectomy. For liver resection, 7 patients had lobectomy and 23 patients had partial hepatectomy. These patients did not receive any preoperative chemotherapy, but all patients had postoperative adjuvant chemotherapy by experienced oncologists.All patients were regularly followed-up by telephone, with the last follow-up on April 14, 2012. The survival was calculated from the date of surgery to the date of death or last follow-up. There were 25 cases died, all due to cancer recurrence.p\u2009<\u20090.05 was considered as statistically significant.All the data were analyzed with SPSS 16.0 software. The survival was analyzed by Kaplan-Meier and log rank test. Cox regression model analysis was performed for univariate and multivariate analysis, so as to discover independent prognostic factors. Two-sided There were 14 (46.7%) cases with blood transfusion , 24 (80.0%) cases with albumin transfusion , and 12 (40.0%) cases with parenteral nutrition support. Two (6.7%) patients had gastric paralysis after operation and subsequently recovered after nasogastric tube depression for 19 and 22 days, respectively. Two (6.7%) patients had pulmonary infection, one with A. baumanii and treated with antibiotics for 49 days, and the other one infected with Klebsiella pneumoniae and treated for 10 days with anti-infection agents, and both were recovered well. There were no perioperative deaths.All 30 patients had complete follow-up data. By the time of last follow-up, 25 (83.3%) patients died and 5 16.7%) patients were living, with median survival of 11.0 months (95% CI 7.8 to 14.2 months). The 1-, 2-, 3- and 5-year survival rates were 43.3%, 30.0%, 16.7% and 16.7%, respectively  careful preoperative evaluation should be performed to consider if curative resection is possible, and laparoscopy could be considered if necessary; (2) for patients with synchronous single liver metastasis, curative resection should be the treatment of choice; (3) patients with peritoneal metastasis had poor survival; (4) preoperative tumor marker levels should not be the criteria to judge whether surgery should be performed; and (5) the pathological staging of the primary tumor does on have significant impact on postoperative survival.The authors declare that they have no competing interests.KTS, XYQ, YHS and JQ designed research; YNW, JQL, XDG and XFW conducted research; YYH provided pathological databases; YNW and XFW analyzed data or performed statistical analysis; YNW and KTS wrote paper; KTS had primary responsibility for final content; All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2482/12/20/prepub"}
+{"text": "Fifty to 80% of pregnant women suffer from low back pain (LBP), a condition commonly treated by doctors of chiropractic (DC). Holzer Clinic, an Appalachian integrative health facility with 140 multispecialty physicians, utilizes both conventional prenatal and chiropractic care for their pregnant patients. This study assessed the feasibility to conduct a prospective case series of LBP patients receiving concurrent conventional prenatal and chiropractic care overseen by an off-site project manager (PM).Women age 21 and over receiving conventional prenatal care at Holzer Clinic who were referred to chiropractic care for LBP complaints were invited to participate in this IRB-approved study. The PM conducted a phone screen interview to determine eligibility. Completed baseline and 4 week questionnaires were mailed to the PM. Assessments included the Bournemouth Disability Questionnaire (BDQ), Numerical Rating Scale (NRS) for LBP, global improvement (GI) and adverse events (AE).Thirty-nine women consented to participate in the study; 17 met all eligibility criteria. Exclusions were for age, LBP before pregnancy and no DC visit. Of the 13 participants who completed both questionnaires, all were white with a mean age of 28.4 (SD 1.1) and a median gestational age of 11.0 weeks (range 2-30). After 4 weeks of care the mean GI was 72%; mean improvement in BDQ was 5.8 (16%); and mean improvement in pain 2.3 (SD 2.18). AEs were mild (e.g. muscle soreness of less than 48 hours).Although patient outcomes were favorable in this small study, recruitment and follow-up data collection were challenging. It is important to investigate the effectiveness of integrative care for LBP during pregnancy; however, it will require the commitment of adequate resources and collaborations."}
+{"text": "Transfusion associated Hepatitis B virus (TAHBV) continues to be a major problem despite mandatory screening for Hepatitis B surface Antigen (HBsAg). Presence of HBsAg is the common method for detecting hepatitis B infection. Unfortunately, this marker is not detected during the window period of the infection. Nigeria being a developing country cannot afford DNA testing of all collected units of blood which serve as the only possibility of achieving zero risk of transfusion associated HBV. Five different serological makers of hepatitis B virus (HBV) infection were therefore assessed to evaluate the reliability of using HBsAg marker alone in diagnosis of HBV infection among blood donors and to detect the serological evidence of the infection at the window period. This will preclude the possibility of transmitting hepatitis B through transfusion of Hepatitis B surface antigen (HBsAg) negative blood in Nigeria.Between July and August 2009, 92 blood donors were enrolled for the study. The prevalence of 5 different markers of Hepatitis B virus infection was detected using Enzyme Linked Immunosorbent Assay (ELISA). Demographic factors were assessed during the study.HBsAg and its antibody (anti-HBs) was detected in 18 (19.6%) and 14(15.2%) of the 92 blood donors respectively. Anti-HBc IgM was found in 12(13.0%) of the 92 blood donors while Hepatitis B envelope antigen (HBeAg) and its antibody (anti-HBe) were detected in 4(8.9%) and 12(26.7%) respectively from 45 donors sampled. HBeAg is a marker of high infectivity and appears after HBsAg. At least one serological marker was detected in 30(32.6%) of the blood donors. Five (5.4%) of the 92 donors had anti-HBc IgM as the only serological evidence of hepatitis B virus infection.The result of this study shows that five donors have anti-HBcIgM as the only serological evidence of HBV infection. Inclusion of anti-HBcIgM in routine screening of blood donors in Nigeria should be encouraged. This is the first study to assess anti-HBcIgM in the country. HBV infglobally . Of the globally . Approxiglobally ,6The aetiological agent (Hepatitis B virus) is a member of the family Hepadnaviridae and the genus Orthohepadnavirus . It is aFollowing infection by the hepatitis B virus (HBV), the first serological marker to appear in the blood is the HBV DNA, followed by HBsAg, the DNA polymerase and HBeAg. Thereafter, the antibodies to the hepatitis B antigens  can be detected. Screening of donated blood by enzyme-linked immunosorbent assay (ELISA) for HBsAg is the common method for detecting hepatitis B infection . ScreeniFindings indicate that testing done for HBsAg alone is not sufficient to eliminate HBV infection from blood supply -13. A maThis study was therefore designed to evaluate the reliability of using HBsAg marker alone, in diagnosis of HBV infection among blood donors and to detect the presence of a marker which would be indicative of hepatitis B infection during the window period.Of the 92 blood samples tested, HBsAg was detected in 18 (19.6%), anti-HBs in 14(15.2%) and anti-HBcIgM in 12(13.0%). HBeAg and anti-HBe were detected in 4(8.9%) and 12(26.7%) respectively from 45 donors sampled. Table Of the 69 male blood donors enrolled for this study, 15 (21.7%) 13(18.8%) and12 17.4%) were positive for HBsAg, HBsAb and Anti-HBcIgM respectively while 4(8.9%) and 12 (26.7%) were positive for HBeAg and HBeAb respectively among the 45 donors tested. Among the 23 females enrolled in the study no positivity was recorded for HBcAb, HBeAg and its Ab, however, 3(13%) and 1(4.3%) were positive for HBsAg and Ab respectively.  blood donors in Ile-Ife, Osun State were enrolled for the study between July and August 2009. Five millilitres of blood was collected from each donor by venepuncture into a labelled sterile container free of anticoagulants or preservative. Each blood specimen was separated by low centrifugation at 500 g for 5 minutes and the serum transferred into labelled cryovial. Thereafter, the sera were kept frozen at -20C until analysed.Five different markers of HBV infection  were detected by commercial Enzyme-linked immunosorbent assay (ELISA) kit . The kit, reagent and sera were brought to room temperature before starting the assay. The wells of each of the microplate were identified for controls and samples. For each of the assays, there were two negative controls and one positive control. One hundred microlitres each of negative control, positive control and sample were pipetted into the appropriate wells except for HBsAg where 50 \u03bcl was used as stated by the manufacturer. The plates were incubated at 37\u00b0C for 60 minutes, washed with wash buffer 5 times with soaking time of about 30 seconds in between each washing. A second incubation at same temperature and time was carried out after the addition of enzyme conjugate and the plates were washed as previously described. A final incubation at room temperature for 10 to 15 minutes depending on manufacturer's instruction for the specific serological marker was done after the addition of substrate (a chromogen). This made the positive samples turn to blue while the negatives were colourless. Addition of 100 \u03bcl of the stop solution (sulphuric acid) turned the positive samples from blue to yellow. The results were read using a 450 nm filter microplate reader.The prevalence of serological markers was compared in terms of gender by use of chi-square tests.Anti-HBcIgM: Hepatitis B Core IgM Antibody; HBsAg: Hepatitis B surface Antigen; TAHBV: Transfusion Associated Hepatitis B Virus; HBV: Hepatitis B Virus; ELISA: Enzyme Linked Immunosorbent Assay; Anti-HBs or HBsAb: Hepatitis B surface Antibody; HBeAg: Hepatitis B envelope Antigen; Anti-HBe or HBeAb: Hepatitis B envelope antibody.The authors declare that they have no competing interests.MOJ conceived the study. MOJ and OAA were in charge of recruitment of patients and collection of samples. MOJ, OAA and ED undertook laboratory analysis; MOJ analyzed the data and prepared the manuscript; OAA and MOA provided ideas and comments during manuscript preparation. All authors have read through and approved the final manuscript."}
+{"text": "Clinical trials have validated transcranial cerebral oximetry, a non-invasive tool that uses near-infrared spectroscopy to measure cerebral oxygen saturation, as a way to detect cerebral ischemia [We hypothesize that there is a high incidence of cerebral desaturation events  absolute cerebral oximeter monitor remained on patients for the first 6 hours in the ICU. All patients were managed according to the usual ICU standard of care. All care providers were blinded to CDEs during the 6-hour study period. During this time, a portable computer was attached to the cerebral oximeter, bedside physiologic monitor and mechanical ventilator, which recorded all data at 1-minute intervals and allowed data to be stored on a computer database.Complete data were collected on 40 high-risk patients (mean age of patients = 71 (36 to 86), mean duration of intubation (hours) = 22.8 (6 to 240), mean duration of ICU stay (days) = 3.3 (1 to 20)). A majority of the patients underwent coronary bypass grafting only or valve only procedures. A high incidence, 13/40 (32.5%), of CDEs was observed in our study cohort, with some episodes exceeding 2 hours. A higher incidence of postoperative nausea/vomiting (PONV) was observed in patients with CDEs (3/13 vs. 0/27).This observational trial is the first to demonstrate a high incidence of CDEs in the immediate postoperative period (32.5%) among cardiac surgical patients. Our ongoing observational study will attempt to demonstrate correlations between physiologic parameters and these postoperative CDEs."}
+{"text": "In the MACRO study, patients with metastatic colorectal cancer (mCRC) were randomised to first-line treatment with 6 cycles of capecitabine and oxaliplatin (XELOX) plus bevacizumab followed by either single-agent bevacizumab or XELOX plus bevacizumab until disease progression. An additional retrospective analysis was performed to define the prognostic value of tumour KRAS status on progression-free survival (PFS), overall survival (OS) and response rates.KRAS data (tumour KRAS status and type of mutation) were collected by questionnaire from participating centres that performed KRAS analyses. These data were then cross-referenced with efficacy data for relevant patients in the MACRO study database. KRAS status was analysed in 394 of the 480 patients (82.1%) in the MACRO study. Wild-type (WT) KRAS tumours were found in 219 patients (56%) and mutant (MT) KRAS in 175 patients (44%). Median PFS was 10.9 months for patients with WT KRAS and 9.4 months for patients with MT KRAS tumours . The difference in OS was also significant: 26.7 months versus 18.0 months for WT versus MT KRAS, respectively . Univariate and multivariate analyses showed that KRAS was an independent variable for both PFS and OS. Responses were observed in 126 patients (57.5%) with WT KRAS tumours and 76 patients (43.4%) with MT KRAS tumours .This analysis of the MACRO study suggests a prognostic role for tumour KRAS status in patients with mCRC treated with XELOX plus bevacizumab. For both PFS and OS, KRAS status was an independent factor in univariate and multivariate analyses. At present, standard first-line treatment for patients with metastatic colorectal cancer (mCRC) includes combination chemotherapy in conjunction with either an anti-epidermal growth factor receptor (EGFR) agent such as cetuximab The prognostic value of tumour KRAS status has been extensively evaluated in patients with advanced and localised CRC, although results have been conflicting. Some studies have demonstrated a prognostic effect Recent studies of chemotherapy regimens, with or without cetuximab, in the first-line treatment of patients with mCRC have sparked new interest in this issue The interaction of EGFR and vascular endothelial growth factor (VEGF) is well known We undertook an analysis of data from the MACRO study to evaluate the prognostic value of tumour KRAS status in patients receiving combination therapy with capecitabine plus oxaliplatin (XELOX) and bevacizumab. Correlations between KRAS status and response rate, progression-free survival (PFS) and overall survival (OS) were analysed.The Institutional Review Board and Ethic Committee of Hospital Clinico San Carlos, Madrid as Reference Ethics Committee, as well as the Spanish Medicine Agency, approved the study protocol . Study procedures were carried out in accordance with the Declaration of Helsinki and its subsequent amendments and Good Clinical Practice guidelines. Written informed consent was obtained from all patients before enrolment.The design of the MACRO study has been reported previously 2 orally bid d1\u201314) and oxaliplatin (130 mg/m2 iv d1) every 3 weeks followed by XELOX plus bevacizumab or bevacizumab alone until progression.The primary endpoint of the MACRO study was PFS; secondary endpoints included OS, objective response rate (ORR), toxicity and several translational research assessments. Between July 2006 and September 2008, 480 patients were entered into the study; 239 were randomized to maintenance XELOX plus bevacizumab after induction XELOX plus bevacizumab and 241 were randomized to single-agent bevacizumab after induction XELOX plus bevacizumab. Induction XELOX consisted of 6 cycles of bevacizumab (7.5 mg/kg intravenously [iv] d1), capecitabine , the type of mutation found  and the methodology used . These findings were correlated with patient's existing data, including response rate, PFS, OS, rescue surgery and second-line therapy.The primary objective of this ancillary analysis of the MACRO study was to evaluate the utility of tumour KRAS status as a prognostic factor in patients with mCRC who were treated with chemotherapy and bevacizumab. The MACRO study demonstrated that single-agent bevacizumab was not statistically significantly inferior to XELOX plus bevacizumab as maintenance therapy The intent-to-treat (ITT) population of the MACRO study comprised 480 patients, 394 (82.1%) of whom had information on KRAS status and were included in this biomarker sub-study .Patient characteristics according to KRAS status are shown in Questionnaires were completed by 171 (43.4%) of Spanish reference centres and 185 (47.0%) of other centres participating in the study. The most common technique for KRAS determination was DxS (76.4% of cases), followed by sequencing (13.3%), StripAssay (10.0%) and pyrosequencing (0.3%). In total, 219 of the 394 patients (55.6%) had WT KRAS tumours, while 175 patients (44.4%) had some type of mutation. The most frequent mutations were G12D (33.3%), G12V (26.9%), G13D (21.8%), G12C (8.3%), G12S (1.9%), G12A (3.9%) and G12R (2.6%). This information was not available in 19 (10.9%) cases.The confirmed ORR was 57.5% in patients with WT KRAS tumours compared with 43.4% in patients with MT KRAS tumours . Median PFS was significantly longer in patients with WT versus MT KRAS tumours, 10.9 months versus 9.4 months  . A statiWhen patients were analysed for PFS according to treatment received, a similar pattern was observed in the KRAS MT and WT groups. In the XELOX plus bevacizumab maintenance group, median PFS was 12.6 months versus 10.0 months in patients with WT and MT KRAS tumours, respectively . In the single-agent bevacizumab group, median PFS was 10.8 versus 8.7 months in patients with WT and MT KRAS tumours, respectively .A total of 47 patients (11.9%) underwent salvage surgery of metastases, 28 of whom had WT KRAS tumours and 19 had MT KRAS tumours (p\u200a=\u200a0.5574). Resection was complete (R0) in 20 patients (71.4%) with WT KRAS and 12 (63.2%) with MT KRAS tumours (p\u200a=\u200a0.0769). Median PFS in patients who underwent salvage surgery of metastases was 16.2 months versus 12.7 months in WT and MT KRAS patients, respectively . Median OS was not reached in the KRAS WT group and was 23.3 months in the MT KRAS group.The influence of second and further lines of treatment, in particular the administration of an anti-EGFR agent after the discontinuation of the treatment of the study, was examined. Over all subsequent lines of therapy, 54 (24.7%) of the 219 patients with WT KRAS tumours had no subsequent therapy, 109 patients (49.8%) received anti-EGFR therapy, and 56 patients (25.6%) received no anti-EGFR therapy. Among the 175 patients with MT KRAS tumours, 37 (21.1%) received no further treatment, 23 (13.1%). received anti-EGFR therapy, 55 (31.4%) received chemotherapy alone and 60 (34.3%) received chemotherapy with bevacizumab.Subsequent therapy just after the study discontinuation is described in more detail in Median OS was 28.0 months in patients with WT KRAS tumours who received post-study anti-EGFR therapy versus 20.2 months in those with MT KRAS tumours . OS was longer in patients with WT KRAS tumours who did not receive anti-EGFR therapy than in patients with MT KRAS tumours . There was no difference in OS between patients with WT KRAS tumours who did not receive anti-EGFR therapy and those who did  .Reasons for withdrawal from the study were similar in patients with WT and MT KRAS. The most common reasons for withdrawal were: disease progression , toxicity, adverse events or intercurrent disease , surgery  and death . There were no statistically significant differences between the two groups in this respect (p\u200a=\u200a0.1815).Results of the univariate and multivariate analyses for PFS are shown in Predictors of OS in the univariate analysis were: number of organs involved , LDH level , alkaline phosphatase level  and KRAS status . Significant factors in the multivariate analysis were the number of organs involved ; LDH  and KRAS status  .The present analysis of the MACRO study indicates that tumour KRAS status is a prognostic factor in patients with mCRC receiving bevacizumab in combination with capecitabine plus oxaliplatin. Patients with WT KRAS tumours had a significantly greater clinical benefit than those with MT KRAS tumours in terms of ORR (57.5% versus 43.4%), PFS (10.9 versus 9.4 months) and OS (26.7 versus 18.0 months). The same trend was observed when both treatment arms were combined and when analysed separately. Univariate and multivariate analyses showed the independent role of KRAS status for both PFS and OS. This indicates that in the MACRO study, KRAS was a prognostic factor in patients with mCRC receiving bevacizumab in combination with chemotherapy.The prognostic value of KRAS was initially suggested by the RASCAL I study, which included 2721 patients Several studies have evaluated the role of KRAS status in patients with mCRC receiving first-line treatment with bevacizumab  [30]\u2013[35Our study did not aim to determine whether KRAS status was predictive in patients receiving bevacizumab, as all patients were treated with bevacizumab. Results from the studies by Hurwitz et al. Our study has several limitations. Firstly, the KRAS mutation analysis was retrospective, which is common in randomized studies examining the role of biomarkers It is possible that the difference observed in OS may be a result of patients with WT KRAS tumours receiving anti-EGFR therapy after the treatment of the study. In our study, 49.8% of patients with WT KRAS tumours received an anti-EGFR agent after bevacizumab treatment. The difference was apparent in the survival curves for patients with WT KRAS tumours who received anti-EGFR, those with WT KRAS tumours who did not receive an anti-EGFR agent and patients with MT KRAS tumours. Patients with WT KRAS tumours who received an anti-EGFR therapy had significantly longer OS than patients with MT KRAS tumours , yet there was no significant difference in patients with WT KRAS tumours who were treated with an anti-EGFR versus those who were not . Later lines of therapy might influence OS, but response rates and PFS, which are not influenced by second- and third-line therapy, were also better in patients with WT KRAS tumours and may be a more appropriate marker for the success of treatment than OS.In conclusion, this analysis of the MACRO study highlights the prognostic role of tumour KRAS mutation status in patients receiving chemotherapy in combination with bevacizumab, which is consistent with some literature reports but not others. The reasons for the discrepancy between studies are not yet apparent, and sufficiently powered, prospective studies will be required to answer this question. The importance of KRAS mutation type, as suggested by the RASCAL studies  and the correlation of KRAS status with microsatellite instability suggested by the PETACC-3 study"}
+{"text": "The incidence of fistulas found during the surgery for chronic otitis media with cholesteatoma has been reported in a wide range in different geographical areas. This study aims to find the prevalence of labyrinthine fistula in the south of Iran.A prospective cross sectional study of 787 (504 ears belong to 462 patients) consecutive tympanoplasty with or without mastoidectomy for chronic otitis media was performed. Data on preoperative clinical and preoperative and postoperative hearing status and intraoperative findings were analyzed.A labyrinthine fistula was found at surgery in 24 (4.7%) ears of the total 504 ears belonging to 462 patients undergoing surgery for chronic otitis media. Location of the fistula was the lateral semicircular canal in 23, posterior semicircular canal in 1 and promontory in 1 subject. There was a statistically significant difference in preoperative and postoperative AC threshold in 500-3000 Hz frequency and ABG 500-3000 Hz, but there was no statistically significant difference in the other variables.Regarding postoperative hearing outcome in the labyrinthine fistula surgery, it seems that there is no universal method of reporting of hearing results. Past hearing evaluation methods in the literature have been often poorly comparable, based on different methodology. Labyrinthine fistulae are caused by abnormal communications between the inner ear and surrounding structures.Bone resoThis is a cross sectional study of 787 (504 ears belong to 462 patients) consecutive tympanoplasty with or without mastoidectomy for chronic otitis media. The operations were performed at Dastghaib Hospital affiliated to Shiraz University of Medical Sciences as a large otologic referral center in the south of Iran between 2003 and 2008. The preoperative clinical data included the patient's gender and age, presence of vertigo, preoperative (one week before surgery) and postoperative (3 months after surgery) hearing status, symptoms and physical findings were recorded in a question- naire. Chi Square and paired t test were performed for finding out the association between variables.There were a total of 787 ear surgeries on 462 patients. Two hundred and forty (52%) females and 222 (48%) males patients were enrolled. Forty six (9.95%) patients were in pediatric (7-15 years) and 416 (90.04%) were in adult age groups. There was no statistically significant difference on incidence of labyrinthine fistula between pediatric and adult groups. A labyrinthine fistula was found at surgery in 24 (4.7%) ears belonging to 462 patients undergoing surgery for chronic otitis media. From 504 ears, there were two cases of blue line lateral semicircular canal (0.4%). Fistula test was positive in 12 out of 24 patients (50%). Frequency of the clinical signs and symptoms of the 24 patients with labyrinthine fistula was subjective hearing loss (24 patients), otorrhea (19 patients), otalgia (16 patients), tinnitus (15 patients) and vertigo (10 patients), respectively. Of the 24 cases with labyrinthine fistulas, cholesteatoma was found in the mastoid or middle ear in 21 ears (87.5%), and both cholesteatoma and granulation tissue in 3 ears (12.5%).Location of the fistula was the lateral semicircular canal in 23, posterior semicircular canal in 1, and promontory in 1.Two ears had more than one fistula, both of them had fistulas in the lateral semicircular canal and posterior semicircular canal.There were 6 cases of labyrinthin fistula with a size of less than 2 mm, and 19 cases with a size of 2-4 mm. Also none of these fistulas were > 4 mm.There were 5(20.83%) deaf ears preoperatively. These preoperative deaf ears were omitted form hearing evaluation, so hearing evaluation in 19 cases with labyrinthine fistula was done. There were 11 (57.9%) ears with conductive and 8 (42.1%) ears with mixed hearing losses. Anakusis did not occur postoperatively, and a hearing improvement of more than 10 dB in SRT occurred in 4 (20.0%) ears.The fistulae were sealed with a cortical bone chip and bone wax , temporalis fascia and bone wax , cortical bone chip and temporalis fascia  and cortical bone chip, temporalis fascia and bone wax .There was a statistically significant difference in preoperative and postoperative AC threshold in 500- 3000 Hz frequency and ABG 500-3000 Hz (P<0.05), but there was no statistically significant difference in other variables . There wThe incidence of labyrinthine fistula was 4.67% in our study and it is within the range of the incidence of labyrinthine fistula in the literatures. Overall, the incidence of labyrinthine fistulas secondary to chronic otitis media in the modern literature varies from 3 to 13 percent.[6][7]8]8]9]HakuHaku9]HakLocation of the fistula was the lateral semicircular canal 95.83%) and in Grewal et al.'s study was the lateral semicircular canal 96%). Most stu% and in %. Most sIn our service, we normally conducted canal wall-down mastoidectomy in cases of cholesteatoma with labyrinth involvement owing to the socioeconomic characteristics of the population, having a high prevalence of cholesteatoma of large extension at the first diagnosis.Our method of surgery is similar to that of Manolidis,4 Greenberg and Manolidis Grewal eOther studies, however, reported a high incidence of facial nerve dehiscence in fistula cases, 27-55%).[5%.[5] ThThe average preoperative deafness was 8.5%, the average surgically  related deafness 10%, and the total deafness rate due to the fistula was 18.5% in a few studies.[8] In a"}
+{"text": "Enthesitis related arthritis (ERA) is the subtype of juvenile idiopathic arthritis (JIA) as defined by the International League of Associations for Rheumatology (ILAR) classification (2004). Asymmetrical lower limb arthritis and enthesitis are said to be prominent early features with axial inflammation a late feature. In our cohort of patients with ERA we observed this was often not the case- with axial inflammation occurring early and the emergence of 2 distinct clinical phenotypes.To identify patients with ERA who developed axial disease and compare their clinical characteristics to those with peripheral disease.A retrospective case review was undertaken of patients with ERA attending our adolescent rheumatology clinic. Clinical characteristics of patients with confirmed axial disease were compared to those without axial disease.68 patients  with ERA were identified. 36 had axial disease (aERA) confirmed on MRI scan, 32 did not have axial disease (pERA). Male predominance was similar in both groups (86.1% vs 84.4%). Median time to inflammatory spinal symptoms was 2y 8m. In the aERA group, median age of onset was higher (11y 4m vs 9y 8m) as was B27 positivity (82.8% vs 48.5%). Patients had more hip arthritis (69.4% vs 53.1%) as well as sacroiliac and lumbar spine symptoms. In pERA, patients were more likely to have ankle arthritis (78.1% vs 27.8%) and enthesitis (65.6% vs 47.2%). Extra-articular manifestations occurred only in the aERA group . A higher proportion of the aERA group required anti-TNF treatment (47.2% vs 25%).Patients with aERA develop disease at an older age, have a higher rate of B27 positivity, have more hip arthritis and develop extra-articular complications more commonly. Patients with pERA have more ankle arthritis and enthesitis and are less likely to require anti-TNF therapy.Large observational studies are needed to further characterise these 2 clinical phenotypes of ERA."}
+{"text": "This study aims to inform clinicians and researchers about the characteristics of patients admitted to the Eating Disorders Inpatient Unit, NorthWestern Mental Health, Royal Melbourne Hospital across a 4 year period. It is anticipated that this information can provide insights into the potential base rates for particular inpatient diagnosis, chronicity of illness, duration of admissions and planned versus unplanned discharges. Data was collected retrospectively via a hospital file audit of admissions to the unit between the years 2009 and 2012. Across the 4 year period there were a total of 193 admissions to the unit and just over a third of patients (35%) were placed on an involuntary treatment order. On admission, the average eating disorder duration was 5.4 years and eating disorder diagnosis comprised; anorexia nervosa-restricting type (65.8%), anoirexia nervosa\u2013binge purge type (6.8%), bulimia Nervosa (3.2%), eating disoirdfer noit otherwise specified (18.9%) and no eating disorder diagnosis (4.7%). The average duration of admission was 36 days and the majority of discharges were planned (88.4%) compared to unplanned (11.6%). Given the chronicity of illness, these findings emphasise the importance of intensive follow-up given the relatively short inpatient stay which may include outreach services, frequent individual/group outpatient appointments and utilising day patient programs as a step down following discharge."}
+{"text": "Mycobacterium tuberculosis from Tamil Nadu, India.We report the annotated genome sequences of four clinical isolates of  Mycobacterium tuberculosis in India has been reported using various genotyping methods  using the CLC bio Genomics Workbench.The paired-end sequencing was performed on an Illumina HiSeq platform. High-quality reads were mapped to the genome of reference strain The NIRT202 genome was generated by aligning 1.34 million paired reads to the reference genome with mapping coverage between 15 and 53\u00d7. The annotation of the genome revealed 3,304 genes or coding sequences (CDS) and 156 synonymous and 204 nonsynonymous single-nucleotide polymorphisms (SNPs) .Mapping of 6.07 million paired reads to the reference genome resulted in the genomic assembly of strain NIRT203. The mapping coverage ranged from 15 to 130\u00d7. Annotation of the reference assembled genome revealed 3,795 genes or CDS and the presence of 615 synonymous and 829 nonsynonymous SNPs .Mapping of 3.13 million paired reads to the reference genome resulted in a reference assembly of strain NIRT204. The mapping coverage ranged between 15 and 74\u00d7. Annotation of the reference assembly revealed 3,556 genes or CDS and the presence of 330 synonymous and 296 nonsynonymous SNPs .The reference assembly for NIRT206 was generated by mapping 1.34 million paired reads with coverage ranging from 16 to 36\u00d7. Annotation of the reference assembly revealed 3,414 CDS or genes and the presence of 615 synonymous and 829 nonsynonymous SNPs .CP004886 (for NITR202), CP005082 (for NITR203), CP005386 (for NITR204), and CP005387 (for NITR206).The annotated whole-genome sequences have been deposited in GenBank with the accession no."}
+{"text": "Acute kidney injury (AKI) has significant impact both on the morbidity and mortality in patients on the ICU. The current definition and classification of AKI  uses chaThis single-centre prospective observational study is currently recruiting 200 consecutive adult patients with no AKI on presentation to the ICU. Serial samples of plasma and urine are collected on all patients included in the study at 0 hours and then every 24 hours in the ICU stay up to 72 hours and assayed for NGAL using a turbidimetric assay on the standardised automated analyser.Results on the first 27 patients are currently available. The predictive performance of pNGAL at admission for AKI (24 hours prior to creatinine-based (RIFLE) diagnosis) was good (AUC-ROC 0.8 (95% CI 0.88 to 1.03)). The predictive performance of uNGAL at admission for the occurrence of AKI (24 hours prior to creatinine-based (RIFLE) diagnosis) (AUC-ROC 0.77 (95% CI 0.47 to 1.07)) was fair. See Table Early results on pNGAL suggest that it could be an independent predictor of AKI in an unselected population of critically ill adults. Further results are awaited."}
+{"text": "The safety and tolerability of sequential radioembolization-sorafenib therapy is unknown. An open-label, single arm, investigator-initiated Phase II study (NCT0071279) was conducted at four Asia-Pacific centers to evaluate the safety and efficacy of sequential radioembolization-sorafenib in patients with hepatocellular carcinoma (HCC) not amenable to curative therapies.90Y) resin microspheres given as a single procedure. The primary endpoints were safety and tolerability and best overall response rate (ORR) using RECIST v1.0.Secondary endpoints included: disease control rate  and overall survival (OS).Sorafenib (400 mg twice-daily) was initiated 14 days post-radioembolization with yttrium-90 . Twenty eight patients experienced \u22651 toxicity; 15 (52%) grade \u22653. Best ORR was 25%, including 2 (7%) CR and 5 (18%) PR, and 15 (54%) SD. Disease control was 100% and 65% in BCLC stage B and C, respectively. Two patients (7%) had sufficient response to enable radical therapy. Median survivals for BCLC stage B and C were 20.3 and 8.6 months, respectively.Twenty-nine patients with Barcelona Clinic Liver Cancer (BCLC) stage B (38%) or C (62%) HCC received a median of 3.0 GBq  This study shows the potential efficacy and manageable toxicity of sequential radioembolization-sorafenib.NCT00712790.ClinicalTrials.gov  Approximately 650,000 persons die each year from hepatocellular carcinoma (HCC), of whom at least two-thirds live in the Asia-Pacific region 90Y) radiolabelled microspheres  significantly regresses locoregional HCC, but does not address systemic disease Radioembolization with yttrium-90  with radioembolization performed (as a single procedure) at one center (Singapore). The study was registered with the clinical trial registry of the Health Science Authority of Singapore (HSA) in June 2008, and ClinicalTrials.gov (Identifier: NCT00712790) in July 2008.The previously reported Phase I found a greater incidence of grade 3 or 4 adverse events (mainly hand-foot syndrome) when sorafenib was given 11 days after radioembolization (4 events in 6 patients) than after 14 days (no events in 3 patients) when assessments were carried out for at least 30 days after commencement of sorafenib Both studies were conducted in accordance with ISO-14155-1 (2003), the World Medical Association Declaration of Helsinki and all applicable local regulations. Study protocol was approved by each institute's Human Research Ethics Committee namely, the Centralised Institutional Review Board (CIRB), SingHealth, Singapore; the Medical Research & Ethics Committee, Ministry of Health Malaysia; Institutional Review Board, Yangon GI & Liver Centre, Yangon; and Institutional Review Board of Seoul National University Bundang Hospital. Patients were informed of the nature of the study and provided written informed consent.The protocol for this trial and supporting TREND checklist are available as supporting information see .Patients with inoperable HCC including those with extrahepatic disease (except CNS metastases) and/or major vascular involvement (i.e. both Barcelona Clinic for Liver Cancer [BCLC] stages B and C) were eligible for inclusion. A confirmatory diagnosis of HCC was based on histology, or by meeting radiological criteria for HCC by dynamic contrast-enhanced computed tomography [CT] or magnetic resonance imaging [MRI]), with supporting evidence based on positive serology for hepatitis B or C virus, or serum alpha-fetoprotein above normal range (\u2265400 \u00b5g/L) 90Y microspheres are delivered via a temporary transfemoral catheter advanced under fluoroscopic guidance into the hepatic artery branches that supply the hepatic lesions. Pre-treatment planning and treatment is undertaken in the angiography suite by an interventional radiologist. Details of the procedure and post-procedure supportive care associated with 90Y-resin microspheres  administration have been previously described 99mTc-MAA). Planar imaging of 99mTc-MAA was used for treatment planning and calculating the tumor-to-normal (T\u2236N) ratio, with Single Photon Emission Computed Tomography (SPECT) imaging employed in cases where further information was needed for the accurate assessment of the extent of multifocal disease. Radioembolization activity (in gigabecquerels [GBq]) was calculated using the Partition Model 99mTc-MAA during the simulation were assumed to be identical to 90Y-resin microspheres, and the activity was calculated in discrete \u201careas-of-interest\u201d for the tumor, normal parenchyma and lung compartments, limiting the maximum permitted exposure for the non-tumoral liver compartment to 70 Gy 90Y-resin microspheres were selectively infused into the affected lobe(s) or segment(s), or whole liver via a micro-catheter placed in the hepatic artery Radioembolization is a form of brachytherapy during which Sorafenib (400 mg twice-daily) was initiated 14 days post-radioembolization and then given continuously until tumor progression or the emergence of drug-related adverse events. Guidelines for dose adjustments and dose interruptions to sorafenib were as per the standardized schedule reported in the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) study Assessments were made at baseline, 2 weeks post-radioembolization and thereafter at 4-weekly intervals. Baseline imaging assessment was conducted just prior to the start of study therapy and every 3 months or at the investigator's discretion until disease progression. If a complete or partial response was detected on CT, then a confirmatory CT scan was performed between 28 and 35 days later. All responding patients were regularly assessed for eligibility of radical therapy. Patients who progressed were assessed at 12-weekly intervals until death or 18 months after the end of the study. Adverse events and their severity and relationship to the study treatment were recorded from the date of consent to 28 days after the last dose of sorafenib. Toxicity was assessed using the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.The primary endpoints were both safety/tolerability and best overall response rate (ORR), using RECIST version 1.0. Secondary endpoints were: disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and health-related quality of life (HRQoL) using the EuroQol 5-Dimensions (EQ-5D) Index.Adverse events were reported from the date of radioembolization, when sorafenib therapy started, then at monthly intervals thereafter. If an adverse event increased in severity over the next defined interval, it was recorded as a new event in the next interval. PFS and OS were measured from study entry. HRQoL was evaluated at study entry, every month during the treatment period and at 6-month intervals thereafter The sample size for Phase II was computed using the A'Hern single-stage design (2001) A graphical plot was used to explore the pattern of HRQoL over time. To reduce the influence of extreme values in the graphical plot, locally weighted regression was used for smoothing EQ-5D index 131I-lipiodol).Between June 2008 and May 2009, 49 patients were assessed for eligibility and 29 patients were enrolled , received radioembolization and were included in the intention-to-treat analysis for safety . The treatment approach reflected the tumor burden and distribution of tumors within the liver. Patients received a median activity of 3.0 GBq , by whole-liver (69%) and right-lobe (31%) infusion. Median target liver and tumor volumes were 1843 mL (IQR: 1186) and 484 mL (IQR: 994), respectively. Mean lung shunting was 8.1%. A median of 600 mg  sorafenib was administered daily over a median of 4.1 months   . The medTreatment-related toxicities and mean \u00b195% CI changes from baseline liver function tests are presented in Twenty-seven patients (93%) experienced toxicities following sorafenib administration during month 1 , month 2 , month 3 , through month 4 and beyond . These toxicities resulted in sorafenib dose reduction in 11 (39%) and discontinuation in 1 (4%) of patients . Two patTwo patients experienced serious liver-related adverse events which may have been related to treatment. Both cases of serious liver-related adverse events were secondary to disease progression and resolved with active management over 2.5 weeks and 3 months, respectively. A third patient with abdominal extension and symptoms of confusion and jaundice due to hyperbilirubinemia and infection (which may have been treatment-related) was hospitalized, received antibiotic treatment and sorafenib treatment was temporarily interrupted; symptoms were recorded over 4 days. The duration of severe (grade 3+) changes in bilirubin in 2 patients (7%) was recorded over a median of 25 days. One patient had severe upper gastrointestinal hemorrhage at 6.3 months and 7.6 months after the initiation of sorafenib therapy which lasted 8 days and 3 days, respectively. The duration of mild (grade 1\u20132) radiation skin injury in one patient was 11 days.90Y. The pulmonary radiation exposure was 25 Gy. This patient had an unresolved grade 2 sorafenib-related hand-foot syndrome at 1 month post-treatment, before presenting with respiratory symptoms at 2.5 months, whereupon sorafenib was discontinued. The patient died two weeks later. A further patient with a lung dose of 15 Gy was reported to have mild (grade 1) pneumonitis 4.7 months post-radioembolization.One patient with progressive disease died 3 months post-treatment due to respiratory distress attributed to therapy. The patient had a 17% lung-shunt fraction and was administered 3.0 GBq Best overall response  was observed in 7 of 28 patients , which met the pre-determined criteria of 7 responses for potential efficacy. There were 2 (7%) complete responses, 5 (18%) partial responses, 15 (54%) stable disease and 5 (18%) progressive disease. The disease control rate was 79%  overall, and 100% (11 of 11 cases) and 65% (11 of 17 cases) in BCLC stage B and C, respectively. Ten (59%) of the 17 patients with BCLC stage C had extrahepatic spread; disease control beyond the liver was not evident as assessed by RECIST 1.0.Two patients (7%) with BCLC stage B had a sufficient tumor response to enable radical therapy; both patients received RFA and were censored at the time of the procedures.Median time to progression for BCLC stage B was 15.2 months and 9.0 months for BCLC stage C . Median Median overall survivals for BCLC stage B and C patients were 20.3 and 8.6 months, respectively.This study represents the first prospective Phase II evaluation of sequential radioembolization-sorafenib therapy in patients from Asia-Pacific region. The majority of patients included in this trial had advanced HCC and a high tumor burden in the liver (median tumor volume in the liver 448 mL), and were not ideal candidates for TACE. The combination of radioembolization-sorafenib appears to be manageable and consistent with previously published experience with each treatment The incentive for therapeutic intervention to palliate symptoms or extend survival of HCC must be balanced against the degree of hepatic functional reserve and the ability of the patient to tolerate the procedure et al 2012, the dose for uninvolved, normal parenchyma should never be >70 Gy and should preferably remain <50 Gy with some institutions, especially in Asia, having set even lower thresholds of 40\u201343 Gy et al 2013 has shown that the frequency and severity of this complication can be significantly reduced through modifications to the activity calculations , combined with lowering the threshold for radioembolization from a total bilirubin of 3 to 2 mg/dL and the routine use of ursodeoxycholic acid and low-dose steroid over the two months post-radioembolization Liver dysfunction with sorafenib is a rare event There was one case of thrombocytopenia which was a modest (grade 1) event at 3.5 months post-treatment followed by patient death due to progressive disease 2 months later. Thrombocytopenia has been commonly observed in HCC patients following sorafenib administration 90Y-microspheres Pneumonitis is an uncommon event (\u22651/1000 to <1/100) associated to sorafenib treatment et al. 2013 The nature and frequency of serious adverse events observed in the current study are not unexpected for this population of HCC patients with advanced disease against a background of cirrhosis, two-thirds of whom presented with macrovascular invasion, extra-hepatic disease and/or liver dysfunction NCT001126645). In addition, radioembolization is being compared to sorafenib in two Phase III trials in Asia-Pacific and European patients with HCC .The limitations of this study are its small size and single-arm design. There was a significant overlap between the patient population in this study and other published studies with sorafenib in predominantly advanced HCC, thus allowing for meaningful comparisons. The response rate of 25.0% (including 7% with CR) and corresponding disease control rate of 79% (by RECIST 1.0 criteria) with radioembolization-sorafenib combination is consistent with experience with radioembolization alone  for patients with intermediate- and advanced-stage HCC as well as for pre-transplant HCC (NCT00846131).In summary, the results of the current study provide provisional evidence of the potential efficacy and manageable toxicity of sorafenib and radioembolization in a population with predominantly advanced disease. Further investigation of radioembolization and sorafenib in randomized multicenter trials are now ongoing Click here for additional data file.Checklist S1TREND checklist.(PDF)Click here for additional data file."}
+{"text": "The aim was to analyze the prognosis of AIDS patients with organ dysfunctions at ICU admission.P 0.2), and we explored the 7-day, 28-day and 60-day survival of patients with and without independent risk factors.A prospective cohort study, including all patients with HIV/ AIDS diagnosis, who were admitted to a specialized ICU from November 2009 until May 2012. Patients with less than 24 hours of ICU stay were excluded. Demographics and nutritional status were collected. The organ dysfunctions were classified according to the SOFA score, and categorized as absent (0 SOFA point), mild (1 to 2 points) and severe (3 to 4 points). We expressed numeric variables as median and interquartile interval (25% to 75%). We performed a multivariate analysis of possible variables associated with hospital mortality  copies/ml; 57% had at least one opportunistic infection; 55% had used antiretroviral therapy previous to ICU admission. Mechanical ventilation was used by 46% of patients and hospital mortality was 42%. Total SOFA score was 5 (2 to 9) points. Cardiovascular dysfunction was the most common on the first days of stay (51%), followed by respiratory (42%), neurological (40%), renal (35%), hematological (27%) and hepatic (17%). Cardiovascular and renal dysfunctions presented with higher rate of severe dysfunction . Rates of neurological (P = 0.002), renal (P = 0.009) and hematological (P = 0.003) dysfunctions were higher in nonsurvivors. Age, CD4 cell count, malnutrition, and opportunistic infections were included in the multivariate analysis. Neurological dysfunction was the independent risk factor for hospital mortality (odds 3.2 (1.4 to 7.2)). The presence of neurological dysfunction was dichotomized: associated or not with primary neurological diagnosis; survival was lower in the patients with neurological dysfunction and without primary neurological diagnosis . Sixty-day survival was similar in primary and secondary neurological dysfunction, but it remained lower than in patients without neurological impairment.We included 139 patients with HIV/AIDS admitted to the ICU. Median age was 40 (31 to 48) years and 71% were male. Severe malnutrition was common (34%). The CD4 cell count was 84 (25 to 274) cells/mmNeurological dysfunction was independently associated with hospital survival, mainly in those AIDS critically patients without primary neuropathy."}
+{"text": "JIA is a disease that shows wide variations between differing populations. Due to recent international consensus on classification criteria, JIA has been widely described in many countries and population groups. There has been almost no data that describes JIA in an African, specifically Sub-Saharan African setting.To describe disease characteristics and functional disability in two tertiary centres in the Western Cape, South Africa87 children were recruited during random clinic visits to rheumatology clinics at Tygerberg and Groote Schuur Hospital between April 2010 and April 2011. Children were diagnosed using International League of Associations for Rheumatology (ILAR) 2001 classification criteria. Consent was obtained, medical records examined, Childhood Health Assessment Questionnaires (CHAQ), visual analogue scales (VAS) for pain and general wellbeing were completed and all children were examined by a researcher in conjunction with a paediatric rheumatologist. HIV status as well as tuberculosis disease and treatment were investigated.A total of 87 children were enrolled. 9 children were excluded  leaving a total of 78 patients. There was an equal female to male ratio-39 males and 39 females. There were 6 Systemic JIA (7.69%), 17 Oligoarthritis , 11 Polyarthritis rheumatoid factor (RF) positive (14.10%), 21 Polyarthritis RF negative (26.9%), 1 psoriatic arthritis (1.28%), 18 enthesitis related arthritis (23%) and 4 Oligoextended JIA (5.12%). The mean CHAQ for the group was 0.5, the mean VAS for pain was 1.8cm and mean VAS for general wellbeing was 2.5cm. Kruskal-Wallis equality-of-populations rank test showed significant differences (p<0.05) between CRP, ESR, number of active joints and limited joints between subtypes.JIA has a unique epidemiology in the Western Cape of South Africa, with equal male:female predominance and increased rates of Polyarticular RF positive and Enthesitis related Arthritis. Factors such as TB and HIV complicate the issue of JIA in a Sub-Saharan African setting."}
+{"text": "Background. Benign prostatic hyperplasia is the most common cause of lower urinary tract obstruction in the elderly male. Aim. To evaluate the effectiveness, safety, and outcome of open prostatectomy in a Nigerian teaching hospital. Material and Methods. Two hundred and fifty-three men with lower urinary tract obstruction clinically due to benign prostatic hyperplasia (BPH) underwent open prostatectomy over a ten-year period (January 2001\u2013December 2010). Data on patients including age, clinical, laboratory, and histology were reviewed and analyzed to determine treatment outcome. Results. A total of 253 patients were studied. Their mean age was 69.11 \u00b1 10.9 years (range 50\u201398). The most common symptoms at presentation included frequency 229 (90.5%) and poor stream 225 (88.9%). The most common complications at presentation were stones in 41 (16.2%) and bleeding in 37 (14.6%). The most common comorbid conditions were hypertension and diabetes found in 72 (28.5%) and 23 (9.1%), respectively. Transvesical prostatectomy was done for most of the patients, 126 (49.8%). Clot retention and wound infection were the commonest postoperative complications accounting for 19 (7.5%) each. Transient incontinence occurred in 17 (6.7%) patients. There was 1 (0.4%) mortality. Conclusion. Open prostatectomy still has a prime place in the operative treatment of BPH with acceptable postoperative morbidity and very low mortality in the developing world with no facilities for TURP. Open prostatectomy has been the operative treatment for benign prostatic enlargement for several decades until the advent of transurethral resection of the prostate TURP (the gold standard)  and otheAll patients who underwent open prostatectomy for BPH at the UMTH between January 2001 and December 2010 were retrospectively reviewed. Details of their biodata, clinical presentation, diagnostic investigations, operative treatment , histoloThis is a ten-year (January 2001\u2013December 2010) retrospective review of open prostatectomy in 253 patients that had benign prostatic hyperplasia (BPH).The main symptoms at presentation as seen in A total of 38 (15%) patients were anaemic at presentation . The urine culture was positive for bacteria in 135 (53.4%). This warranted antibiotic therapy in these patients. Clinically significant electrolyte derangement  was seen in 18 (7.1%). The premorbid conditions in the patients included hypertension in 72 (28.5%), diabetes 23 (9.1%), arthritis 17 (6.7%), and Parkinson's disease in 11 (4.3%) of the patients; lumbar spondylosis was seen in 9 (3.6%). Dementia 4 (1.6%) and 4 (1.6%) patients had various allergies while epilepsy was seen in 4 (1.6%) and HIV 5 (1.9%). Three (1.2%) were blind and 2 (0.8%) were deaf. Most of the patients had open prostatectomy under spinal anaesthesia 208 (82.2%), whereas general anaesthesia was used in 45 (17.8%) patients. Transvesical prostatectomy was done for most of the patients and accounted for 126 (49.8%), followed by retropubic in 104 (41.1%). Low transvesical was another method in 23 (9.1%).Intraoperative findings were particularly for the prostate itself and the gross appearance of the bladder as depicted in The postoperative complications  includedThe mean weight of the prostate was 103.6 \u00b1 67.0 (range 36\u2013426\u2009g). The histology of removed prostates showed benign features (BPH) in 239 (94.5%) and malignant foci in background benign hyperplasia  in 14 (5.5%) of patients. Until 20\u201325 years ago, open surgery was the most common approach to the prostate in benign prostatic hyperplasia. From the late 1970s, however, the development of endoscopes led to a gradual reduction in the number of open surgical operations for the prostate, and open prostatectomy continued to decrease rapidly in favor of the minimally invasive endoscopic techniques. Therefore, open surgery for BPH is declining though still performed. Skills in traditional open surgery are still the main approach and are in fact mandatory in most developing countries who cannot afford widespread use of minimally invasive techniques of prostatectomy. Open surgery is still important to all surgeons because indications for it still exist. Two hundred and fifty-three patients, who had open prostatectomy for BPH, were reviewed indicating their clinical presentation, associated comorbid medical conditions, and management outcome. The mean age of 69.11 years is not different from other studies . The cliDiverticuli, bladder stones, and hernias are common complications associated with lower urinary tract obstruction. These were dealt with during prostatectomy, the same primary surgery. Obstructive lower urinary tract symptoms complicated by impaired renal function evidenced by elevated creatinine are known to improve or return to normal after variable periods of continuous urethral catheter drainage. This was our experience in most of our patients who improved within 7 to 14 days. Comorbid medical conditions are common among this group of elderly males. This leads to an increased incidence of complications during or after prostatectomy; therefore, a prudent care is required to make them safe for surgery . In thisOpen prostatectomy is still safe though with longer hospital stay than minimally invasive techniques .In this series, the mean weight of removed prostates was 103.6 \u00b1 67.0 with a range of 36\u2013426\u2009g; this is far more than the weight recommended by EAU Guidelines for open prostatectomy which is between 80 and 100\u2009g . This is Clot retention and wound infection were the major postoperative complications in this series comparable to similar studies , 18. TraOpen prostatectomy with its attendant lower mortality and morbidity is still necessary in the operative management of benign prostatic hyperplasia. Open procedures for BPH are still necessary for huge, bleeding, and complicated prostates despite the advent of modern minimally invasive techniques. For safe surgery and avoidance of postoperative complications, comorbid medical conditions associated with advancing age must be addressed."}
+{"text": "To evaluate the positive predictive value of MRI scoring for malignant mass-like (ML) and nonmass-like (NML) lesions based on the BI-RADS descriptors. To identify MRI characteristics of nonmass lesions which predict malignancy for invasive and non-invasive cancers.Retrospective analysis of 486 MRI-guided vacuum biopsies performed at Northwick Park Hospital between April 2006 and November 2011. Each lesion was categorised according to BI-RADS lexicon (ML vs. NML lesions) and time-enhancement curves, and given an overall score of MRI 1 to 5 according to overall level of suspicion for malignant disease where MRI 4 and 5 are considered suspicious or diagnostic for malignancy. Biopsy and surgical histology results obtained.A total of 291 ML and 152 NML lesions, of which there were 150 cancers diagnosed. Positive predictive value of MRI characteristic for malignant mass lesions is 70%. Positive predictive value of MRI characteristic for nonmass lesions is 57%. Segmental enhancement is the most common MRI morphology found in 45% DCIS. No specific features predict for invasive disease in NML lesions. Time-enhancement curves were mainly type 2 (44.6%) and type 3 (52.7%) in malignant ML lesions and unhelpful in predicting malignancy in NML lesions (72% type 2 and 59% type 3 were benign).No specific BI-RADS feature predicts for invasive disease in NML lesions. Segmental enhancement is the most common MRI appearance for DCIS. Time-enhancement curves are unhelpful in predicting malignancy in NML lesions."}
+{"text": "A substantial part of the clientele in an emergency department setting are elderly patients who often consume several prescription medications daily hereby increasing the risk of potential drug-drug interactions. We examined the extent of poly-pharmacy at the time of admission among a group of elderly patients.All patients in the age range 65-79 years admitted consecutively to Holbaek Emergency Department during one week were included. Information on medication at the time of admission was obtained from medical charts.A total of 73 patients, 48% women and 52% men were included, the average age being 72 years. The most frequent reasons for admission were lung diseases (21%), neurological disease (25%), cardiac diseases (15%) and infections (12%). The patients used on average 6.6 prescription medications daily, ranging from 0 to18 different drugs. 10 patients received 1 drug or less. The most frequently used drugs in this group were anti-hypertensive medication (56% of the patients), blood-cholesterol lowering drugs (55% of the patients), drugs to prevent thrombosis (56% of the patients), pain medication (37% of the patients) and diuretics (36% of the patients).A total of 41 patients were prescribed anti-hypertensive medications. 20 patients were prescribed more than one drug to control blood pressure and 5 of these patients were treated with more than two different drugs to control blood pressure. 18 patients in anti-hypertensive treatment were also treated with diuretics. The most frequently prescribed anti-hypertensive drugs were calcium antagonists (n=15), beta-receptor blockers (n=15)and ACE-inhibitors (n=14).A total of 40 patients were prescribed drugs to lower blood cholesterol and 75% (n=30) of these were treated with simvastatin. 41 patients were prescribed drugs to prevent thrombosis, among these acetylsalicylic acid (n=25), clopidogrel (n= 11) and warfarin (n= 10) were the most frequently used drugs.27 patients were treated with pain medication at the time of admission and 15 of these patients received opioids.Cardiovascular drugs are the most predominantly prescribed drugs for elderly patients. Poly-pharmacy is in particular seen among antihypertensive medications. Caution in prescribing new drugs due to potential drug-drug interactions poses a challenge for the attending physician."}
+{"text": "Shwachman-Diamond Syndrome (SDS) is rare inherited disorder. The typical diagnostic triad  is not always present at diagnosis.To review mutations and initial presentation in a Belgian cohort of patients with genetically proven Shwachman-Diamond Syndrome (SDS).A retrospective study in 11 patients with SBDS mutations.rd patient suffers from chronic liver failure due to liver fibrosis. 10/11 experienced recurrent infections . Two patients had an episode of symptomatic (convulsions) hypoglycemia without satisfying explanation despite extensive metabolic analysis.In 10 patients an SBDS mutation was identified in both alleles, patient 11 was heterozygous. The mean age at diagnosis was 2.9 years. All patients had exocrine pancreatic insufficiency. Radiological evidence of skeletal dysplasia was present in 9/10 studied. Neutropenia was present in 8/11 patients. Failure to thrive was demonstrated for all but P8. 2/3 patients experiencing cholestatic hepatitis required admission to ICU. Both had blood CMV PCR(+). The 33/11 patients received a diagnosis of Jeune syndrome (one patient died of respiratory insufficiency) and 1/11 of hypobetalipoproteinemia prior to diagnosis of SDS. A metabolic disorder was first suspected in P11 because of hypertrophic cardiomyopathy. Two couples of siblings in our cohort showed an entirely different course.SDS triad was present at diagnosis in only 6/9. A high index of suspicion is crucial. The peculiar misdiagnoses as Jeune syndrome is striking as are the episodes of symptomatic hypoglycemia and the suspected increased susceptibility to severe CMV disease."}
+{"text": "DGCR8 , which encodes a component of the microprocessor complex essential for microRNA biogenesis, and MIR185, which encodes microRNA 185. Mouse models of 22q11.2DS have demonstrated alterations in brain microRNA biogenesis, and that DGCR8 haploinsufficiency may contribute to these alterations, e.g., via down-regulation of a specific microRNA subset. miR-185 was the top-scoring down-regulated microRNA in both the prefrontal cortex and the hippocampus, brain areas which are the key foci of schizophrenia research. This reduction in miR-185 expression contributed to dendritic and spine development deficits in hippocampal neurons. In addition, miR-185 has two validated targets , both of which have been associated with altered expression levels in schizophrenia. These combined data support the involvement of miR-185 and its down-stream pathways in schizophrenia. This review summarizes evidence implicating microRNA-mediated dysregulation in schizophrenia in both 22q11.2DS-related and idiopathic cases.The 22q11.2 deletion is the strongest known genetic risk factor for schizophrenia. Research has implicated microRNA-mediated dysregulation in 22q11.2 deletion syndrome (22q11.2DS) schizophrenia-risk. Primary candidate genes are  The 22q11.2 deletion syndrome (22q11.2DS), also known as the velocardiofacial/DiGeorge syndrome, is a phenotypically heterogenous disease which is caused by a hemizygous microdeletion on the long arm of chromosome 22 in the region q11.2. The overall prevalence is 1 in 2,000\u20134,000 live births . The disIn particular, 22q11.2DS patients have an estimated 20\u201325% risk for schizophrenia or related psychotic disorders such as schizoaffective disorder . The delThe size of the 22q11.2 deletion varies. The majority of 22q11.2 deletions (around 90%) are 3 Mb in size and span approximately 60 known genes, while the remaining 10% are 1.5 Mb in size and encompass around 35 genes . Both thTBX1), which encodes a T-box transcription factor, that resulted in the characteristic abnormal facies and cardiac defects of 22q11.2DS in patients without a 22q11.2 deletion A+/- mouse model has generated breakthroughs in our understanding of the underlying biological mechanisms of 22q11.2DS schizophrenia-risk. This engineered mouse strain carries a heterozygous chromosomal deletion which spans a segment syntenic to the human 22q11.2 locus. Df(16)A+/- mice show deficits in the synaptic connectivity of hippocampal neurons, including a lower density of dendritic spines and glutamatergic synapses (Df(16)A+/- mice display hyperactive behavior and deficits in spatial working memory-dependent learning (DGCR8), which encodes a component of the microprocessor complex essential for microRNA biogenesis , respectively , typically in their 3\u2032 untranslated regions . In most p250GAP . miR-134ectively . Furthery  that these mechanisms may also be involved in the development of idiopathic schizophrenia.Dgcr8+/- mice confirmed that heterozygous Dgcr8 deficiency was responsible for the reduced biogenesis of microRNAs observed in Df(16)A+/- mice A+/- mice, and showed that this reduction contributed to deficits in dendritic complexity and spine development in hippocampal neurons. In addition, Dgcr8 deficiency resulted in an approximately 20% reduction in miR-185 expression in the hippocampus (miR-185 expression in Df(16)A+/- mice \u2013 a reduction which is much more pronounced than would be expected by the 50% decrease in gene dosage \u2013 may be due to the combined effect of the hemizygosity of the MIR185 gene and the impaired maturation of the pri-miR-185 transcript secondary to reduced Dgcr8 levels plasmic reticulum Ca(2+) ATPase (SERCA2) which maintains Ca2+ levels in the endoplasmatic reticulum. The depletion of MIR185 contributes to SERCA2 upregulation and has been proposed as a mechanism leading to abnormal hippocampal synaptic plasticity in 22q11.2DS mouse models. The microRNA regulation of SERCA2 translation may also be implicated in the elevation of SERCA2 protein observed in the post-mortem brains of idiopathic schizophrenia patients . Four other loci with genome-wide significance in this study contained predicted targets of MIR137 . All four genes have recently been validated as miR-137 targets (The involvement of microRNA-dependent dysregulation in schizophrenia is supported by the results of the large GWAS of schizophrenia performed by the  targets .miR-137 (ZNF804A is listed as a validated target (The miRanda database lists 5,487 genes as targets of miR-137 . Interesd target . This ged target . Other pd target  which pld target .miR-137 risk allele may result in a reduced miR-137 expression (miR-137 risk genotype (Research in post-mortem brain samples suggests that the functional effect of the pression . Furthergenotype .Strong evidence suggests that microRNA dysregulation is implicated in the development of schizophrenia in 22q11.2DS patients. This is consistent with the growing recognition of microRNAs as important regulators of gene expression. As microRNAs integrate different intracellular signals and regulate various signaling pathways , the dysDGCR8 or MIR185 as a risk factor for schizophrenia. This may simply reflect a lack of common functional variants at these loci. This hypothesis is supported by a recent study of genetic regulation of microRNA expression (cis effects on miR-185 expression. A small number of SNPs have been reported to have significant cis effects on DGCR8 expression in human monocytes (DGCR8 expression (As summarized above, emerging evidence from expression and genetic analyses suggests that the same microRNA-regulated pathways may also play a role in idiopathic schizophrenia. However, despite a number of systematic investigations of genes in the 22q11.2DS region and the ever increasing number of GWAS data sets , no genepression . Gamazononocytes , and fibonocytes . Howeverpression .A challenge for future research will be to identify and validate the target genes that are affected by microRNA dysregulation and their respective pathways in a more comprehensive manner . Such reIdiopathic schizophrenia is a multifactorial disorder for which both genetic and environmental factors exert an impact on disease susceptibility . HoweverFurther research into the precise role of microRNAs in schizophrenia is important clinically, since modification of microRNA dysregulation would represent a novel therapeutic approach to this devastating and chronic disease. MicroRNAs are excellent candidates for therapy since they regulate multiple targets in various signaling pathways, thereby minimizing the risk of resistance development or compensatory mechanisms . This viThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Milk oral immunotherapy (MOIT) may be an alternative to avoidance in treatment of patients with IgE-mediated cow milk allergy (IMCMA). We aim to determine the effect of MIOT through a systematic review.Randomized controlled trials on MOIT were identified from 13 databases, conference proceedings, theses and unpublished trials, as part of a review with the Cochrane Collaboration. A total 1945 records were identified and screened. Children and adults with IMCMA were included. Studies were selected and methodological quality assessed independently by two reviewers.% CI 3.2, 11.44). In addition, 26 (30%) in the MOIT group could ingest a partial serving of milk (10-184 mL) while none could in the control group . None of the studies assessed the patients following a period off immunotherapy. Adverse reactions were common (79 of 88 had at least one symptom), although most were local and mild. For every 7 patients receiving MOIT, 1 required intramuscular epinephrine. One patient required it on 2 occasions.138 records were reviewed and 13 were included, representing 4 trials. A total of 170 patients were studied . Two studies used blinding and 2 used an avoidance diet control. Fifty-two (59%) patients of the MOIT group were able to tolerate a full serving of milk (about 200 mL) compared to 7 (9%) of the control group (RR 6.05, 95MOIT can lead to desensitization in the majority of individuals with IMCMA although the development of long-term tolerance has not been established."}
+{"text": "Prevention of secondary brain injury is the cornerstone in the management of patients with severe traumatic brain injury (TBI) and raised intracranial pressure (ICP). Although a variety of monitoring methods are available, due to lack of strong evidence their use varies considerably . The objThe ICUs managing adult patients with severe TBI were identified from the RAIN  study sites, and the Society of British Neurosurgeons. Thirty-one centers were identified, and a telephonic survey was conducted by the investigators. Data were collected using a single-page questionnaire containing 18 questions.All 31 (100%) units used ICP monitoring and parenchymal ICP bolt was the most widely used method (77%). Thirty (96.7%) units used a cerebral perfusion pressure protocol to guide therapy. Twenty-eight (90.3%) units used continuous capnography. Twelve (38.7%) units used transcranial Doppler. Eight (25.8%) units used partial pressure of oxygen in brain tissue. Four (12.9%) units used microdialysis. Only one unit used jugular bulb oximetry. None of the units used near-infrared spectrometry or optic nerve sheath diameter. Eight units (25.8%) used a cerebral function monitor and seven (22.5%) units used the bispectral index for guiding depth of sedation.This survey shows that there is no clear consensus on what types of monitoring should be used to guide management of patients with TBI. A CPP protocol, based on measurement of ICP, is the most widely used method, although a recent randomized control trial did not show any benefit in outcome . Other i"}
+{"text": "Surgical site infection (SSI) continues to be a major source of morbidity and mortality in developing countries despite recent advances in aseptic techniques. There is no baseline information regarding SSI in our setting therefore it was necessary to conduct this study to establish the prevalence, pattern and predictors of surgical site infection at Bugando Medical Centre Mwanza (BMC), Tanzania.This was a cross-sectional prospective study involving all patients who underwent major surgery in surgical wards between July 2009 and March 2010. After informed written consent for the study and HIV testing, all patients who met inclusion criteria were consecutively enrolled into the study. Pre-operative, intra-operative and post operative data were collected using standardized data collection form. Wound specimens were collected and processed as per standard operative procedures; and susceptibility testing was done using disc diffusion technique. Data were analyzed using SPSS software version 15 and STATA.Staphylococcus aureus was the predominant organism 16/56 (28.6%); of which 3/16 (18.8%) were MRSA. This was followed by Escherichia coli 14/56 (25%) and Klebsiella pneumoniae 10/56 (17.9%). Among the Escherichia coli and Klebsiella pneumoniae isolates 9(64.3%) and 8(80%) were ESBL producers respectively. A total of 37/250 (14.8%) patients were HIV positive with a mean CD4 count of 296 cells/ml. Using multivariate logistic regression analysis, presence of pre-morbid illness (OR = 6.1), use of drain (OR = 15.3), use of iodine alone in skin preparation (OR = 17.6), duration of operation \u2265 3 hours (OR = 3.2) and cigarette smoking (OR = 9.6) significantly predicted surgical site infection (SSI)Surgical site infection (SSI) was detected in 65 (26.0%) patients, of whom 56 (86.2%) and 9 (13.8%) had superficial and deep SSI respectively. Among 65 patients with clinical SSI, 56(86.2%) had positive aerobic culture. SSI is common among patients admitted in surgical wards at BMC and pre-morbid illness, use of drain, iodine alone in skin preparation, prolonged duration of the operation and cigarette smoking were found to predict SSI. Prevention strategies focusing on factors associated with SSI is necessary in order to reduce the rate of SSI in our setting. Surgical site infections (SSIs) have been reported to be one of the most common causes of nosocomial infections; is accounting 20% to 25% of all nosocomial infections worldwide . SSIs haIn Tanzania, surgical site infections are still one of the leading causes of morbidity and mortality among patients undergoing major surgery. Previous studies conducted in a district and a tertiary hospital in Tanzania reported the surgical site infections rate of 24% and 19.4% respectively ,12. SurgDespite improvements in operating room practices, instrument sterilization methods, better surgical technique and the best efforts of infection prevention strategies, surgical site infections remain a major cause of hospital-acquired infections and rates are increasing globally even in hospitals with most modern facilities and standard protocols of preoperative preparation and antibiotic prophylaxis. Moreover, in developing countries where resources are limited, even basic life-saving operations, such as appendectomies and cesarean sections, are associated with high infection rates and mortality ,10.This study was conducted to establish the prevalence, patterns and predictors of surgical site infection in our local setting. Here we document multiple factors predicting SSI in a large tertiary hospital in Mwanza, Northwestern, Tanzania.This was an analytical cross-sectional prospective study among patients undergoing major surgery at BMC over a period of 9 months from July 2009 to March 2010. The study was conducted in the surgical wards of Bugando Medical Centre. Bugando Medical Centre (BMC) is a tertiary hospital with bed capacity of 900 and serves about 13 million people.Sample size was obtained using Kish and Lisle method, using an incidence of 19.4% from a previous study and the infection rate among wound classes and the use of drain were also considered , the samPredictor variables such as patient characteristics, preoperative data, intra-operative data and postoperative data were obtained using a standardized data collection form. All patients who underwent major surgery with visible incisions were eligible to participate in the study and requested to consent for study and HIV-testing before being enrolled into the study. HIV test was done using national algorithm of rapid test .http://www.cdc.gov/nhsn/PDFs/pscManual/9pscSSIcurrent.pdf.The patients were assessed preoperatively, intraoperatively and postoperatively. Details that were recorded included; type of surgery, wound class, type and duration of operation, antimicrobial prophylaxis, use of drain, preoperative hospital stay and total hospital stay. Each patient was followed up from the time of admission until time of the discharge and 30 days postoperatively. Surgical wound was inspected at the time of the first dressing and weekly thereafter for 30 days. Superficial surgical site infection was diagnosed if any one of the following criteria was fulfilled: purulent drainage from the superficial incision, organisms isolated from an aseptically obtained culture of fluid or tissue from the superficial incision, at least one of the following signs or symptoms of infection: pain or tenderness, localized swelling, redness, or heat, and superficial incision is deliberately opened by surgeon, and is culture-positive or not cultured. Deep surgical site infection was diagnosed if any one of the following criteria was fulfilled; purulent drainage from the deep incision but not from the organ/space component of the surgical site, a deep incision spontaneously dehisces or is deliberately opened by a surgeon and is culture-positive or not cultured and the patient has at least one of the following signs or symptoms: fever (> 38\u00b0C), or localized pain or tenderness. A culture-negative finding does not meet this criterion, an abscess or other evidence of infection involving the deep incision is found on direct examination, during reoperation, or by histopathological or radiological examination, diagnosis of a deep incisional SSI by a surgeon or attending physician. Pus or pus swabs were obtained from surgical incision and transported to the laboratory within an hour of collection. In the laboratory, the specimens were registered in the log books and processed as per standard operative procedures. Bacterial identification was done using an in house biochemical panel ,15. AntiData were entered into a computer using SPSS software version 15 and analyzed using STATA software 10 according to the objectives of the study. Chi- square test was used to determine for the significance associations between the predictor and outcome variables to all categorical variables and odds ratios were calculated to test for the strength of association between predictor variables. In each variable reference variable was labeled as 1 in case of premorbidity each variable was compared to all others. Significance was defined as a p-value of less than 0.05. In addition to univariate analysis multivariate logistic regression analysis was performed.Failure to perform anaerobic culture might have contributed to the low prevalence of SSI due to inability to establish presence of organisms that require such environment (anaerobic bacteria). The absence of antibiotic policy in the surgical wards might have influenced the results of this study. Other surgical departments such orthopedic and gynecological departments were not included.A total number of 941 patients underwent major surgery at Bugando Medical Centre during the study period. Two-hundred sixty five patients fulfilled the inclusion criteria of these, 15 patients were excluded from the analysis due to loss of follow up Surgical site infection (SSI) was detected in 65 patients, giving an overall infection rate of 26.0% .Fifty-seven 22.8%) patients had pre-morbid illness namely diabetes Mellitus 18 (7.2%), hypertension 37 (14.8%) and HIV 37 (14.8%). The SSI rates for patients with pre-morbidity and those without were 70.2% and 38.4% respectively   patients had history of cigarette smoking. Of these 28 patients (84.8%) developed SSI. There was a statistically significant association between cigarette smoking and SSI  as seen in Table % patient Table Forty-one patients (16.4%) received preoperative antimicrobial prophylaxis. Majority of the patients 27(65%) received ceftriaxone and metronidazole; ampicloxacillin and gentamicin 3 (7.3%); ceftriaxone alone 3 (7.3%); ceftriaxone and gentamicin 3 (7.3%); cloxacillin 3 (7.3%) and ampicloxacillin and metronidazole 2 (4.9%). Antibiotics prophylaxis was administered in the following procedures; laparatomy (19), appendectomy (10), amputation (4), thoracotomy (2), mayo repairs (1), splenectomy (1), excisional biopsy (1), spinal bifida repair (1) and bronchotomy (1). The timing of preoperative antimicrobial prophylaxis ranged from 1 hour to 5 hours with the mean of 1.68 hours and standard deviation of 0.96 hour. The rate of SSI among patients who received pre-operative antimicrobial prophylaxis and those who did not receive were 14.63% and 28.23% respectively  Table The SSI rates for ASA classification I, II and III were 15.2%, 62.8% and 88.9% respectively  , ceftriaxone -metronidazole (23%), ceftriaxone (9.7%), ampicloxacillin -gentamicin (8.5%), ampicloxacillin -metronidazole (8%), gentamicin (7.2%), ceftriaxone-ampicloxacillin (6.1%), ciprofloxacin (4.8%), chloramphenicol (4.8%) ampicloxacillin-metronidazole-gentamicin (3.2%).Among the 250 patients, 193 (77.2%) had clean surgeries, 46 (18.4%) had clean-contaminated surgeries and 11 (4.4%) had contaminated surgeries. There were no cases of dirty surgery. The rate of SSI was 21.24%, 43.48% and 36.36% in clean, clean -contaminated and contaminated wounds respectively , Escherichia coli 14 (25.0%) and Klebsiella pneumoniae 10 (17.9%), while the least isolated bacteria was Acinetobacter spp 1(1.8%). Nine (65%) and 8 (80%) of Escherichia coli and Klebsiella pneumoniae were found to be Extended Spectrum Beta -Lactamases (ESBL) producer respectively i.e resistant to first, second, third and fourth generation cephalosporins. Most of these ESBL producing isolates were isolated from the patients with laparotomy and open prostatectomy. MRSA was detected in 3(19%) of Staphylococcus aureus; of 3 MRSA isolates 2 were isolated from patients who had appendicectomy and one from corrective osteotomy. The resistance rates to ciprofloxacin were 86%, 80% and 54% for Escherichia coli, Klebsiella pneumoniae and Staphylococcus aureus respectively.Out of 65 patients diagnosed to have SSI and specimens collected for microbiological investigation, 56 (86.2%) specimens from different patients had positive bacterial growth within 48 hours of incubation. Only five out of 56 cultured specimens (8.9%) had mixed growth. Common bacteria isolated after various procedures table  were: StIn this study, most of our patients were in the age group 31-40 and showed a female preponderance. Similar demographic observation was reported by another study in India . The rat. Also higher rate of SSI was observed among HIV patients with CD count below 200 cells/\u03bcl .The prevalence of HIV in this study was found to be higher than in general population this has been observed previously . In the Prolonged pre-operative duration of hospitalization with exposure to hospital environment has been reported to increase the rate of surgical infection . In thisIn this study in the univariate analysis it was observed that, the rate of SSI was significantly associated with ASA classification; similar observations have been made by other studies -25. In tThe number of people in theatre during operation has been considered as an independent predictor of SSI . In the In agreement with other studies , the preSurgical wound classification has long been established as an important predictor of the postoperative surgical site infections ,30,31. IStaphylococcus aureus was the commonest isolate for the postoperative wound infections. This is consistent with reports from other studies [Staphylococcus aureus from the exogenous environment or the patient's skin flora is the usual pathogen, whereas, in other categories of surgical procedures, including clean-contaminated, contaminated and dirty, the polymicrobial flora closely resembling the normal endogenous microflora of the affected site is the most frequently isolated pathogens [Staphylococcus aureus was the most common isolate in patients who underwent excisional biopsy, thoracotomy, mastectomy and appendicectomy. studies ,32. It hEscherichia coli and Klebsiella pneumoniae were the most common gram-negative bacteria and were predominantly isolated from in laparotomy and open prostatectomy; similar findings have been reported in other studies [ studies ,33. The  studies ,35. ThesStaphylococcus aureus followed by Escherichia coli and Klebsiella pneumoniae are common bacteria causing SSIs at BMC. Pre-morbidity, use of drain, use of iodine alone in skin preparation, duration of operation of more or equal 3 hours and cigarette smoking were significantly found to predict SSI at BMC on multivariate analysis. A better surveillance system for SSI with feedback of appropriate data to surgeons is highly recommended to reduce the SSI rate in developing countries.Surgical site infections are a major problem in the surgical wards at Bugando Medical Centre and its incidence is higher than that reported in developed countries. Multi-resistant The authors declare that they have no competing interests.BM participated in collecting specimens, collecting clinical data and follow up of the patients, SEM participated in the design and execution of the work, performed, microbiological procedures, data analysis, interpretation of data and preparation of the manuscript, PLC participated in collecting clinical data and manuscript writing, CI interpretation of the data and manuscript writing and WM designed the study. All authors have read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2482/11/21/prepub"}
+{"text": "A/H1N1 infection is a major seasonal cause of illness requiring critical care admission. A high proportion of these patients develop acute kidney injury (AKI) [We studied all A/H1N1-positive admissions to a district general hospital (DGH) ICU during the months of December 2010 and January 2011. The study aimed to describe the incidence of AKI using the creatinine score from the RIFLE criteria and its associations with mortality, incidence and duration of intermittent positive pressure ventilation (IPPV), length of stay in the ICU and provision of renal replacement therapy (RRT).P = 0.0329). Excluding fatalities, the duration of IPPV was longer in patients with AKI  than in patients without AKI . This difference was statistically significant (P < 0.05). Excluding fatalities, the length of stay was longer in patients with AKI  than in patients without AKI . This difference was statistically significant (P < 0.02).Twenty-seven patients were admitted to the ICU who tested positive for A/H1N1. Fourteen (52%) met the RIFLE criteria for AKI. Of these, three (11%) met the RIFLE criterion for Risk (>150% change in creatinine), three (11%) met the criterion for Injury (>200% change in creatinine), and eight (30%) met the criterion for Failure (>300% change in creatinine). Nine patients  received RRT. ICU mortality was three out of 14 (21%) patients with AKI and one out of 13 (8%) patients without AKI. This difference was not statistically significant. Thirteen out of 20 (65%) ventilated patients developed AKI, compared with one out of seven (14%) nonventilated patients. This difference was statistically significant  compared to that of a larger study ["}
+{"text": "Klebsiella pneumoniae is the most common. These pathogens manifest resistance to most of antimicrobials tested and are associated with high mortality rates. The aim of this study is to describe epidemiologic data about nosocomial infections due to carbapenem-resistant Enterobacteriacea and identify risk factors for death.Antimicrobial resistance has emerged and increased in the last 25 years, complicating the treatment of nosocomial infections, especially for extended-spectrum beta-lactamase Enterobacteriacea (ESBL). Furthermore, disseminated use of invasive procedures, particularly in ICU patients favors the emergence of multiresistant pathogens. More recently, Enterobacteriacea has developed a new mechanism of antimicrobial resistance and became resistant to carbapenems. Among Enterobacteriacea resistant to carbapenem, Longitudinal study evaluating patients with infections caused by carbapenem-resistant Enterobacteriaceae, isolated from blood, urine, tracheal secretions, skin and soft tissues, treated accordingly to the Brazilian Society of Infectious Diseases guidelines, from March 2011 to December 2012. Acute Physiology and Chronic Health Evaluation (APACHE II) was calculated to evaluate severity of disease and Sequential Organ Dysfunction Assessment (SOFA) to measure organ dysfunction. Comorbidities were classified according to Charlson comorbidities index list. Patients were followed until hospital discharge.K. pneumoniae was the most common enterobacteria (86.8%), followed by Enterobacter spp. (8%). The mechanism of resistance was identified as Klebsiella pneumonia carbapenemase (KPC) present in 77.2% of K. pneumoniae infections. Shock was present in 81/148 (46.6%) patients and dialysis was used in 62/148 (35.6%). Hospital mortality was 62.6% and associated mortality was 33.3%. Multivariate analysis identified dialysis and pneumonia as independent risk factors for death.During the study period, 174 nosocomial infections caused by carbapenem-resistant Enterobacteriaceae were identified in 148 patients. All infections were microbiologically documented and 136 (78.2%) occurred in patients who were admitted to the ICU. Sepsis (17.8%), polytrauma (14.4%), cardiovascular disease (13.8%) and respiratory disease (11.5%) were the most common diagnosis. Most of the patients (78%) had one or more comorbidities according to Charlson criteria, and 57/148 (43.2%) patients had three or more comorbidities. Median APACHE II was 20.7 (7 to 38) and median SOFA at ICU admission was 7 (0 to 14). Median length of hospital stay was 43 (6 to 230 days). Many patients infected with carbapenem-resistant Enterobacteriae were identified, and most of them were caused by carbapenemase producing bacteria. These infections were associated with high mortality rate. Shock, dialysis, pneumonia, SOFA discharged >6 and APACHE >20 were identified as independent risk factors for mortality."}
+{"text": "HPV16 variants correlate with geographic origin and ethnicity. The association between infection with a specific variant and the cervical disease risk remains unclear. We studied the prevalence, persistence and association with cervical intraepithelial neoplasia (CIN) of different HPV16 variants, using cervical swabs and whole tissue sections (WTS) of biopsies from 548 women in the placebo group of a HPV16/18 vaccine trial. In HPV16-positive samples, HPV16 variants were identified by a reverse hybridization assay (RHA). Laser-capture micro-dissection (LCM) was performed for localized detection of HPV. HPV16 variants were determined in 47 women. Frequency of mixed HPV16 variant infections was lower (8.5%) than for multiple HPV genotypes (39.1%). Among 35 women having consecutive HPV16 variant-positive swabs, 32 (91.4%) had the same variant while in three (8.6%) women a change in variant(s) was observed. HPV16-positive WTS were obtained from 12 women having consecutive HPV16 variant-positive swabs. The same variant was present in WTS of 10 women, while two were negative. WTS of five women were histologically normal. A single HPV16 variant was detected in four women having CIN1-3, while additional HPV genotypes were found in three other women having CIN2 and CIN3. In the WTS of one woman with mixed genotypes, the HPV16 variant was assigned to a CIN2 lesion by LCM. HPV16 variant infections can be effectively studied in cervical swabs and tissue specimens by the HPV16 variant RHA. Multiple HPV16 variants in one woman are rare. The HPV16 genotype consistently detected in follow-up samples usually involves a persistent infection with the same variant. Human papillomavirus (HPV) is a DNA virus that infects cutaneous and mucosal epithelium and induces epithelial proliferation. More than 40 HPV genotypes have been detected in the anogenital region, and clinically most important are the oncogenic (high-risk) HPV genotypes  which are involved in the development of high grade cervical intraepithelial neoplasias (CIN) and cervical cancer , and perDiagnosis of HPV infections is based on detection of its genomic DNA in cervical cell samples or cervical biopsy specimens by molecular methods, such as liquid hybridization  ,11 or thHPV comprises at least 189 distinct genotypes . By defiHPV16 has been studied more extensively than other genotypes, and most information about viral variants is available from the E6, L1 and LCR regions of the viral genome . The avaHPV16 subtypes and variants have been found to correlate with geographic origin and ethnicity of the infected patients. Sequence variation in the E6 region permitted discrimination between several subtypes, which have been designated as European prototype (E-P), African (with Af1 and Af2 as variants), Asian (As), North American (NA) and Asian American (AA) ,20,22. TSeveral studies have investigated the clinical and epidemiological relevance of HPV subtypes and variants. The association between infection with a specific subtype or variant of HPV (mainly HPV16) and the risk of cervical disease remains unclear. Some studies have reported a higher risk for specific variants, whereas other studies did not find any significant association -37. In sThe aim of the present study was to identify the different variants of HPV16 in a large group of women participating in a HPV16/18 vaccine efficacy study who were assigned to the placebo group. The prevalence, persistence and association with cervical intraepithelial neoplasia (CIN) by different HPV16 variants were investigated in follow-up cervical swab and tissue material from the placebo group.Cervarix\u00ae, GlaxoSmithKline Vaccines, Rixensart, Belgium) [HPV16-positive cervical swab and tissue specimens were selected for HPV16 variant analysis. These materials were available from the placebo group of women participating in a previous randomized efficacy trial of an HPV16/18 AS04-adjuvanted virus-like particle vaccine (Belgium) . Only maBelgium) ,39. BrieBelgium) ,39.Women who had entered the vaccine trial were aged 15\u201325 years and were cytologically negative, seronegative for HPV16 and 18 antibodies by ELISA, and HPV-DNA-negative by PCR for 14 oncogenic HPV types  no more than 90 days before study entry. Health-care providers obtained cervical swab specimens for cytology and HPV DNA testing at screening and months 6, 12, and 18. At months 0 and 6, and subsequently every 3 months, women self-obtained cervicovaginal samples with two sequential swabs for HPV DNA testing, for up to 27 months . CervicaAt the start of the current study for HPV16 variants, a subset of 5,144 cervical swab samples from 548 women assigned to the placebo group  had beenhttp://clinicaltrials.gov under study numbers NCT00689741 and NCT00120848. The protocol, consent forms and amendments were approved by the central review board, as well as 32 institutional review boards at study sites in Canada, USA and Brazil, as already described by Harper et al ,39. WomeDNA was isolated from 200 \u03bcl of cervical swabs in PreservCyt suspension by the MagNA Pure LC instrument , using the MagNA Pure LC Total Nucleic Acid isolation kit (Roche Diagnostics) according to the manufacturer\u2019s instructions. DNA was eluted in 100 \u03bcl of elution buffer and 10 \u00b5l was used for each PCR reaction. Cervical tissue materials were processed according to a standardized sandwich method . BrieflyThe stained slides were used for histopathological assessment by an expert pathologist. The three intermediate sections were digested overnight by 100 \u00b5l of proteinase K lysis buffer at 56\u00b0C. Proteinase K was heat-inactivated for 20 minutes at 95 \u00b0C. Ten \u00b5l of extracted DNA was used for each PCR reaction. If necessary, extracted DNA was diluted ten times prior to PCR to circumvent inhibition of amplification.Cervical tissue from one woman was processed by LCM technology for localized HPV analysis. The H&E- and p16-stained whole tissue sections (WTS) were scanned using digital microscopy . Separate, small regions of (borderline) CIN1 and CIN2 lesions as well as normal cervical epithelium were assigned by a pathologist, generally in the first WTS stained by H&E (Section 1). At least one region was selected per lesion grade, obtaining at least 5% of the complete lesion area. The selected areas were excised using the Zeiss P.A.L.M. microbeam ultraviolet (UV) laser microdissection and catapulting system and transferred to an AdhesiveCap500 opaque tube (Zeiss) . LCM was10 PCR primer set to amplify a broad spectrum of HPV genotypes, as described earlier [10 amplimers were used to identify the HPV genotype by reverse hybridization to the LiPA25 genotyping strip . This line probe assay contains probes for 25 different HPV genotypes, i.e. HPV 6, 11, 16, 18, 31, 33, 34, 35, 39, 40, 42, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 66, 68/73, 70 and 74. Cervical swab and (micro-)dissected tissue samples were tested by the SPF earlier ,42. Brie2 concentration was increased from 2 mM to 2.5 mM, as well as the amount of each primer from 15 to 20 pmol. Furthermore, the annealing temperature was raised from 52 to 55 \u00b0C. The amplimers were cleaned-up by ExoSAP-IT reagent and analysed by reverse hybridization on the HPV16 variant strip according to the manufacturer\u2019s instructions.Identification of the HPV variant in HPV16-positive swabs was performed using the E6-based HPV16 variant reverse hybridization assay , as described previously . The HPV The baseline prevalence and distribution of HPV16 variants and presence of mixed variant infections was determined in the first HPV16-positive event of each woman, regardless if the sample was self-obtained or collected by the health-care provider. Three definitions for persistence of HPV16 variant infection detected at consecutive time-points were applied. The HPV16 variant infection was considered persistent if the same variant was detected in cervical samples over a minimum of 10 months (12-month definition), 5 months (6-month definition) or 2.5 months (3-month definition).Only materials from women in the placebo group were selected to rule out influence of the vaccine on the natural history of HPV16 variant infections. At the start of the current study, 5,144 cervical samples from women in the placebo group (n=548)  had been10 PCR/DEIA, and were genotyped by LiPA25. The most prevalent genotypes among HPV-positive swabs were HPV52 (15.4%), 16 (13.5%), 51 (11.5%), 53 (9.5%) and 66 (7.8%). Among the LiPA25-positive samples, 60.9% contained a single genotype, and the remaining 39.1% contained 2 to 7 HPV genotypes.In this subset of 5,144 swabs from the total study population, 1,595 (31.0%) samples were found HPV-positive by SPFSubsequently, we selected 61 women from the placebo group who had at least one HPV16-positive cervical swab during the study period. A total of 207 HPV16-positive swab specimens were available for variant analysis. Among the 207 HPV16-positive swabs from 61 women, 136 (65.7%) were positive and 71 (34.3%) were negative by the HPV16 variant RHA. In total, 47 women tested positive for a HPV16 variant in one or more swabs. In fourteen women, the variant could not be identified in any of their HPV16-positive swabs. All these women had been HPV16-positive by LiPA25 at only a single time point during follow-up. This suggests that these women experience transient HPV16 infections with low viral loads, below the detection limit of the HPV16 variant RHA.The distribution of HPV16 variants found at baseline among 47 women is shown in Among the women with a single HPV16 variant (91.5%), European variants were the most prevalent (76.6%). African (8.5%) and North American/Asian-American variants (6.4%) were less common in this population.Among 35 out of the 47 women that were positive for a HPV16 variant (74.5%), the variant was identified at multiple time points during follow-up. In this group, the dynamics of the HPV16 variant infection was investigated over time. The women in this group had an average total of 10.4 swabs (range 4-13) per individual, obtained during an average follow-up period of 23.1 months (range 9-27) at 3-6 month intervals.In 32 of the 35 women (91.4%), no HPV16 variant changes were observed throughout the follow-up period. Among these 32 women, variant \u2018persistence\u2019 was observed for at least 12 months in 10 women (31.3%), for 6 months in 14 women (43.8%) and for 3 months in 7 women (21.9%). In one woman (3.1%), the interval between two HPV16 Eu 350T-positive swabs was over 12 months, but without any HPV16-positive swabs in between. Thirty women (93.8%) were infected with a single HPV16 variant and two women (6.2%) had multiple variants. In 3 women, a change in HPV16 variants was observed during follow-up. In 2 of 35 women (5.7%), a mixture of HPV16 variants was observed in the first positive sample, and the composition of this mixture changed over time. A mixed infection with two European variants (Eu 350T and Eu 350G) progressed towards a single infection (Eu 350T). In the second woman, a mixed infection of Eu 350T and Af2 resolved to a single infection (Af2). In addition, 1 of 35 women (2.9%) was initially positive for Eu 350G and cleared this infection. After a HPV16-negative period of six months she was positive for a different European variant, Eu 131G. 10 LiPA25 and were on average obtained 22 months after the baseline swab (range 8-39 months). For eight women, tissue specimens were collected between two HPV16 variant-positive swabs. From the remaining four women the tissue sample was taken after the last available HPV16 variant-positive swab. From 12 women in the placebo group who had a HPV16 variant identified in a cervical swab, cervical tissue specimens were also collected. All specimens tested positive for HPV16 by SPFIn 10 of 12 women (83.3%), the HPV16 variant was identified in the processed whole tissue section (WTS), i.e. Eu 131G (n=4), Eu 350T (n=4), and Eu 350G (n=2), while two women (16.7%) remained negative by the HPV16 variant RHA. In all cases, the variant identified in the WTS matched the variant found in the swabs taken before, and -if available- after the biopsy was obtained.The HPV16-positive WTS of the 12 women had been histopathologically examined for the worst lesion according to the CIN  classification system. Five individuals had normal cervical tissue and the specific HPV16 variant, i.e., Eu 131G, could be determined in three of them. Seven women were diagnosed with lesions graded as either CIN1 (n=1), CIN2 (n=4) and CIN3 (n=2). For 4 of the 7 women with a CIN lesion, the WTS was single positive for HPV16, i.e., Eu 350T (n=3) and Eu 350G. No other HPV genotypes were detected by the LiPA25 algorithm. This strongly suggests that HPV16 most likely caused the lesion in these women. The other three women had at least one other HPV type in addition to HPV16  in the WTS . An example of persistence of the same HPV16 infection is shown in The tissue sections of one of these three women were available for localized HPV analysis by LCM technology, in an attempt to assign a specific HPV type to the lesion. Cervical tissue (CIN3) of this woman had been embedded in four blocks. Each block was processed by the sandwich method and macro-dissected into a total of 11 areas for HPV analysis. HPV16 (Eu 131G), 18, and 39 were detected in these areas, often as multiple infections. Three macro-dissected tissue sections could be examined by LCM. In total, 11 regions were assigned by a pathologist, excised by LCM, and analysed for HPV by the LiPA25 algorithm  in HPV16-positive women, who were assigned to the placebo group of an HPV16/18 vaccine trial. The previously evaluated HPV16 variant RHA  proved tRemarkably, the frequency of HPV16 positive swabs containing multiple HPV16 variants was very low, and this is in contrast to the frequency of samples containing multiple genotypes. The reason for this is unknown, but one could speculate that infection with a certain genotype is protective against super- or co-infection with another variant of that same genotype. Also, other studies investigating HPV variants reported surprisingly few mixed variant infections -46. ThisEuropean HPV16 variants were highly prevalent in cervical swabs of our study population (76.6%), while African (8.5%) and North American/Asian-American variants (6.4%) were less common. In women with biopsy-confirmed CIN, only European variants were observed. The sample size of women with CIN is too small to investigate associations between specific variants and risk for CIN. The high prevalence of European HPV16 variants could be explained by the large proportion of women of European descent in this population, as suggested by the recruitment site  and ethnicity of recruited women . Our findings are consistent with previous work by Zuna et al, who found high prevalence of European HPV16 variants (86%) among HPV16-positive women in the USA . In most women, consecutive HPV16-positive swabs consistently contained the same variant. Variant changes were rarely observed in successive HPV16-positive swabs. In two women, a \u2018persistent\u2019 mixed HPV16 variant infection resolved to a single variant infection. Perhaps the immune response was able to clear one particular variant infection, but not the other. Another woman cleared a HPV16 variant but was infected with a different variant after six months. The primary infection did not induce a protective effect against the secondary infection, or perhaps the immune system was suppressed.Data from our study show that most HPV16-positive swabs contain the same HPV16 variant over time, which provides further evidence for a persistent infection. From a group of women with multiple HPV16-positive swabs, also HPV16-positive cervical biopsy specimens were available. In 83.3% of these women, the same HPV16 variant was identified in swab samples as well as tissue specimens, which often contained CIN. The HPV16 variant was not identified in tissue samples of the other women (16.7%). This could indicate a slightly lower sensitivity of the HPV16 variant RHA compared to LiPA25 in FFPE tissue specimens. Although the number of samples analysed was small, these findings suggest that a HPV16 genotype consistently detected in follow-up cervical swabs and tissue samples usually involves a persistent infection with the same variant. A persistent infection with the same oncogenic HPV type, most notably HPV16, increases the risk for the development of (pre)cancerous lesions in the cervical epithelium, whereas re-infection with HPV16 after previous clearing probably is not associated with an increased risk.Cervical tissues were further investigated if the persistent HPV16 variant infection was causative for development of CIN lesions. HPV16 was often found as the single genotype in whole-tissue sections of specimens with a diagnosed CIN lesion. This indicates that HPV16 was driving the lesion. In tissue of one woman, LCM technology was a suitable technique to assign causality of a CIN lesion to HPV16, when also other genotypes were present in the complete tissue sample. This study had limitations. Only a subset of clinical materials available from the previously described vaccine study group  was analIn summary, the HPV16 variant-specific reverse hybridisation assay can be used to investigate prevalence of single and multiple HPV16 variants, to survey the dynamic behaviour of mixed variant infections in consecutive cervical swabs, to monitor persistence of a particular variant, and its association with cervical precancerous lesions. The HPV16 genotype consistently detected in follow-up cervical swabs and tissue samples usually involves a persistent infection with the same variant."}
+{"text": "Key challenges to the study of anaphylaxis are a lack of widely accepted standard working definitions, inadequate reporting of events, failure to agree on a severity threshold for classification as an anaphylactic reaction.To estimate the prevalence of food-allergy anaphylaxis based on the database of the Piemonte Region  Reference Center for Severe Allergic Reactions.The registry monitors a population of 4,400,000 inhabitants and collects data mandatory for prescribing self-injectable epinephrine reimbursed by Regional Health System.Anaphylaxis cases were diagnosed according to NIAID/FAAN criteria, and assigned to one of three levels of decreasing probability using a clinical checklist based on recommendations of the Brighton Collaboration.Among the 1315 reported cases of anaphylaxis, 541 could be classified as food anaphylaxis, with level 1 (38%), level 2 (59%), and level 3 (3%) of probability. 212 patients were children , and 329 were adults . The main implicated food allergens were nuts (31%), egg (16%), milk (15%), fish (8%) and sesame (7%) in children and nuts (26%), vegetables (14%), crustaceans (12%), fresh fruit (10%), fish (7%), legumes (6%), seeds (6%) and flours (5%) in adults.Food-dependent exercise-induced anaphylaxis was reported in 28 patients. Skin and respiratory symptoms were reported respectively in 95% and 81% patients, with no differences between children and adults, while gastrointestinal symptoms were more frequent in children  and cardiovascular involvement was more frequent in adults .Food is an important cause of anaphylaxis, particularly in children  with predominance in boys; this gender preference reverses in adulthood. Egg and milk were specific causes of anaphylaxis in children, while plant-derived foods and crustaceans were more specific in adults. Nuts and fish were triggering allergens in all ages.Checklists and glossary of terms are crucial to harmonize the report of anaphylaxis cases to a surveillance system or epidemiological study."}
+{"text": "To report the long-term outcome of a cohort of Saudi children with systemic lupus erythematosus (SLE)Medical records of all children with SLE treated between 1990 and 2010 at King Faisal Specialist Hospital and Research Center, Riyadh were retrospectively reviewed. The long-term outcome measured by Systemic Lupus International Collaborating Clinics American College of Rheumatology Damage Index (SDI) and death related to SLE. The collected data included: gender, age at disease onset, follow up duration and clinical features at diagnosis and last follow up visit as well as treatment.One hundred and forty two patients (108 girls and 34 boys) were included. The mean age at onset of SLE was 84.5 months (18- 144 months) while the mean age at diagnosis was 111.6 months (24- 156 months) and the mean duration of follow up was 62 months (8- 235 months). All patients treated with corticosteroid and immunosuppressive drugs; 93 (69.3%) patients received cyclophosphamide and 18 patients treated with rituximab. Overall, 66 (46.5%) patients had damage with a mean SDI score of 2.6 within a mean of 62 month of follow up duration. Damage accrual was mostly in the growth (26.8%), renal (16.9%) and neuropsychiatric (14%) domains. 11 patients had progressive renal disease and required dialysis, 4 of them underwent renal transplant. There were 11 deaths related to SLE; 8 of them due to sepsis. Logistic regression analysis showed renal disease required dialysis and renal transplant associated significantly with male gender independently of age of disease onset. In contrast death related to SLE influenced by early onset disease.Our cohort indicates that the long-term outcome was satisfactory. Male gender and early onset disease probably influence the long-term outcome of SLE in children. Infection remains an important cause of death in children with SLE."}
+{"text": "Antibiotic resistance is a major worldwide problem in the ICU . The sitWe conducted a prospective observational study. All data were analysed using descriptive statistics. All Gram-negative culture isolates over a period of 13 months (October 2011 to October 2012) were included in this study. Isolation and identification were performed using the bact alert system and VITEK2, respectively. Sensitivities were determined by Kirby Bauer disc diffusion and broth dilution using VITEK2-AST cards and interpreted according to Clinical and Laboratory Standards Institute criteria. For the purpose of this study, we used MDR to denote isolates resistant to representatives three or more classes of antimicrobial agents, XDR as those resistant to all but one or two classes and PDR as those resistant to all classes of antimicrobial agents available [n) Gram-negative isolates, 195 (78%) were extended-spectrum \u00df-lactamase (ESBL) producers and the remaining 55 (22%) were non-ESBL producers. Among the ESBL producers, PDR, XDR and MDR isolates were 14 (5.6%), 113 (45.2%) and 68 (27.2%), respectively  followed by Acinetobacter aeruginosa (22.5%) and Escherichia coli (20.5%)  followed by Klebsiella pneumoniae (21.8%) and Pseudomonas aeruginosa (14.5%) . Among these 250 (ESBL producers were the most frequently isolated Gram-negative bacterial isolates in this tertiary-care hospital in north India.Among ESBL producers, XDR organisms were most frequent, followed by MDR and PDR organisms. Few of the XDR isolates were NDM producers, which have propensity to spread to other bacteria. In view of significant prevalence of multidrug resistance amongst Gram-negative organisms in the ICU, regular surveillance of antibiotic susceptibility patterns plays a crucial role for setting orders to guide the clinician in choosing empirical or directed therapy of infected patients."}
+{"text": "The aim of this retrospective study was to analyze our experience with operative approach of traumatic rapture of diaphragm (TRD).38 patients with TRD (34 men and 4 women ranging from 13 to 70 years) were treated in 1993-2013. 29 patients (76%) had a left TRD and 9 patients (24%) - right TRD. Multiple-associated injures were observed in 31 patients (82%), and isolated TRD - in 7 patients (18%). Causes of trauma included vehicle crash for 33 patients and fall from height for 5.TRD was diagnosed preoperatively in 32 patients (84%) by contrast X-Ray of gastrointestinal tract, abdominal ultrasound, and CT scan of the chest and abdomen. In 6 (16%) patients TRD was diagnosed during surgery. We did not use pleural centesis to avoid injury of abdominal organs. 27 patients (71%) underwent surgery upon 1 month of trauma episode, and 13 (34%) \u2013 after 1 month to 13 years. Right lateral thoracotomy on the 6th interspace was performed in 9 (24%) patients with right TRD. In case of large raptures the diaphragm was repaired by simple interrupted suture to chest wall on 1-2 interspaces above anatomical juncture-line which allowed repairing the diaphragm out of high tension. 11 patients (29%) with old left TRD underwent left lateral thoracotomy on the 6th interspace. In both left and right TRDs the large diaphragmatic defects were repaired by polypropylene mesh. 18 (47%) patients with acute left TRD were treated by left lateral thoracotomy accompanied by upper-medial laparotomy (11 cases) and laparoscopy (7 cases) for better examination of abdomen and restoring lesions. We observed 3 deaths (8 %) \u2013 2 from severe craniocerebral trauma and 1 from pulmonary thromboemboli.Our experience showed superiority of repairing of diaphragm on 1-2 interspaces above anatomical juncture-line in right TRD to avoid hypertension of sutures and accompanying thoracotomy with laparoscopy in left TRD as a rational surgical approach."}
+{"text": "Introduction. Patients with chronic liver disease (CLD) are more likely to have severe morbidity and fatality rate due to superimposed acute or chronic hepatitis B (HBV) infection. The literature has shown that hepatitis B vaccines are safe and effective in patients with CLD, but the data in cirrhosis liver is lacking. We assessed the safety and immunogenicity of HBV vaccine in patients with cirrhosis liver. Methods. CTP classes A and B CLD patients negative for hepatitis B surface antigen and antibody to hepatitis B core antigen were included. All patients received three doses of hepatitis B vaccine 20\u2009mcg intramuscularly at 0, 30, and 60 days. Anti-HBs antibody was measured after 120 days. Results. 52 patients with mean age 47.48 \u00b1 9.37 years were studied. Response rates in CTP classes A and B were 88% and 33.3%. We observed that the alcoholic chronic liver disease had less antibody response (44%) than other causes of chronic liver disease such as cryptogenic 69% and HCV 75%. Conclusions. Patients with cirrhosis liver will have low antibody hepatitis B titers compared to general population. As the age and liver disease progress, the response rate for hepatitis B vaccination will still remain to be weaker. ChronicThis prospective open label study was conducted in the department of medical gastroenterology. Institutional ethics committee approved the study protocol. Informed consent was obtained from study participants. Patients with CLD of CTP class A and B were enrolled in the study. Both male and female patients between 18 and 60 years who were serologically negative for hepatitis B surface antigen, antibody to hepatitis B core antigen and have no history of hepatitis B vaccination were included. Patients with CTP class-C, having malignancy, acute liver disease, HIV, receiving immunosuppressive medications and life expectancy less than 120 days were excluded. All patients received three doses of HBV vaccine  20\u2009mcg intramuscularly over the deltoid region during all the three visits at 0, 30, and 60 days. A 5\u2009mL of blood was collected in a plain vacutainer tube, the serum was separated, and the analysis for anti-Hbc total and titer for anti-Hbs was done on the same day of the collection of samples. Blood analysis for anti-Hbc total and titer for anti-HBs was done with chemiluminescence analyzer-Access 2 Immunoassay analyzer, and Beckman coulter. Anti-HBs antibody was measured after 120 days, and according to antibody titers patients were classified into good responders, poor responders, and nonresponders. Good responders were defined as those having the anti-HBs titer were > or =100\u2009mUI/mL, poor responders having anti-HBs titer between 10 and 99\u2009mUI/mL, and nonresponders having anti-HBs titer <10\u2009mUI/mL. The secondary outcome was to assess the safety of HBV vaccination in CLD. Patients reported adverse events; infusion site reactions and routine laboratory parameters were considered safety markers of the study.P value < 0.05 was considered statistically significant. Data was entered into excel spreadsheet 2007 and analyzed by using the GraphPad Prism Software version 4. All the continuous data will be expressed as mean \u00b1 SD. Categorical data was expressed as numbers and percentages. Chi-square test was used to detect differences between groups. A two-tailed 52 patients received 3 doses of HBV vaccine; the mean age of patients was 47.48 \u00b1 9.37\u2009years. There were 37 males and 15 females. 30 patients were less than 50 years of age and 22 were more than 50 years. 25 patients were in CTP class A and the rest 27 were in CTP class B. The reasons for CLD were alcohol 27/52 (52%), cryptogenic 13/52 (25%), hepatitis C 8/52 (15%), and others 4/52 (8%). . In thisP = 0.03). Among the patients who were less than 50 years of age, 21/30 (70%) of them were good responders, 6/30 (20%) were poor responders, and 3/30 (10%) were nonresponders. In patients more than 50 years, 9/22 (40%) were good responders, 5/22 (23%) were poor responders, and 8/22 (36%) were nonresponders. On comparing the responders rate between the age groups, patients in age group less than 50 years had significant responder rates (70%) than patients with age more than 50 years. (40%) . We observed that 20/37 (54%) of the males and 11/15 (74%) of the females were good responders, 8/37 (22%) males and 2/15 (13%) females were poor responderss and nonresponders were 9/37 (24%) in males and 2/15 (13%) in females (P = 0.36). When we were individually analyzing the vaccine response across different etiologies, we found that in 27 of the patients with alcohol induced CLD, 12/27 (44%) had good response, 7/27 (26%) had poor response, and 8/27 (30%) were non responders and in 8 patients with HCV related CLD 6/8 (76%) were good responders, 1/8 (12%) poor responders, and 1/8 (12%) were nonresponders. Overall response rates in 52 patients were as follows: 31/52 (60%) had good response, 10/52 (19%) had poor response, and 11/52 (21%) were nonresponders. (P < 0.0001). None of our patients had suffered significant systemic or local adverse reactions. All patients complained of pain and redness during vaccine administration. No other adverse events were observed.We also compared response rates with the child scores; out of 25 patients who were child A score, 22/25 (88%) were good responders, 1/25 (40%) were poor responders, and 2/25 (8%) were nonresponders and in child B class only 9/27 (33%) had good antibody response and 9/27 (33%) had poor response, 9/27 (33%) were nonresponders  had poor antibody response (44%) as compared to other aetiologies of chronic liver disease such as cryptogenic (69%) and HCV (75%) related liver disease. Severity of the chronic liver disease predicts the response rate; the good responders were in CTP class A (88%) as compared to CTP class B (33.3%). It was observed that apart from severity of liver disease, the age of the patients also had contributed to antibody response; patients less than 50 years had a higher rate of response with hepatitis B vaccination than patients above 50 years.  Vaccination with HBV vaccine is extremely safe in general population and in patients with chronic liver disease. The immunogenicity rates of vaccination in general population are >90% whereas in CLD it varied from 18% to 100%. In the present study, the response to standard HBV vaccination with a dose of 20\u2009 Studies conducted by Lee et al., Wiedmann et al. and Keeffe and Krause \u201322 in CL These observations suggest that if we are vaccinating at an earlier age (<50 years) and also at an early stage of chronic liver disease (child A), the immunogenicity of hepatitis B vaccination is superior as compared to patients with age more than 50 years and with child B cirrhosis liver. These observations suggest that if the patient is having advanced cirrhosis liver or in the age group of more than 50 years, it is always better to try different regimens like 40\u2009ug or 80\u2009ug of hepatitis vaccination or other routes of vaccine administrations like multiple intradermal dose. And the literature search had shown that the safety profile of these higher doses was comparable with that of normal dose. There were only few studies having data on multiple intradermal dose of hepatitis B vaccination in chronic liver disease, but it has not been yet approved in vaccination schedule.\u03bcg), and thus comparisons between high and low doses cannot be anticipated.  We had evaluated only using standard dose of hepatitis B vaccine  in patients with cirrhosis liver of CTP classes A and B only and had excluded CTP class C patients. However we have not compared the efficacy of Shanvac HBV vaccine with other available vaccines in the market. Our study populations were diversified and the subjects included in the different etiologic groups were small. We should have attempted with higher dose and/or weekly intradermal doses as per the evidence from the literature of patients with chronic kidney disease. Additionally long-term persistence of antibody titers, the frequency of estimating the postvaccination anti-Hbs titer, and the need for booster dose of hepatitis B vaccine were not evaluated due to technical and financial constraints. Another limitation of our study is that all the patients received the same quantity of HBV vaccine (20\u2009 Patients with cirrhosis liver when compared to general population will have low postimmunization antibody titres against hepatitis B. As the age and the stage of liver disease progress, the immunogenicity of standard dose of hepatitis B vaccination against hepatitis B infection will still remain weak. Hence all the cirrhotics with non-HBV etiologies should be initiated on hepatitis B vaccination protocol at the time of diagnosis to achieve better protection against HBV. If the patient had not achieved seroconversion with standard universal dose of hepatitis B vaccine, reimmunization with a higher dose of hepatitis B vaccine schedule or with multiple intradermal route of vaccination may be considered. Further studies are needed to assess the antibody titres by considering type of vaccine, the dose to be administered, the route of administration, the frequency of antibody testing, and the requirement for booster dose."}
+{"text": "Since 2003, Southern Vietnam has become the most serious affected area by various emerging diseases such as: A/H5N1, SARS, Rubella, etc. Therefore, the establishment of emerging disease surveillance is essential and necessary to provide scientific information for good understand on the emerging diseases and for effective outbreak response.A specific surveillance system for Severe Acute Respiratory Infection (SARI) was established in 02 sentinel hospitals in Ben Tre province from August 2008 to June 2010. Patient\u2019s signature on written ICF had been required before the enrollment. All of the enrolled SARI cases were investigated and their throat swabs were collected for testing. Multiplex RT-PCR was applied to determine 17 viral agents. In addition, blood culture has been performed since August 2009 in order to detect bacterial agents on these SARI cases.Out of 1,842 SARI cases enrolled into the surveillance system, 969 (52.61%) cases had positive testing results, including: 913 (49.75%) cases had positive testing results with viral agents and 56 (9.89%) of 566 blood culture specimens had positive testing results with bacterial agents. Moreover, the proportion of co-infection between virus and bacteria was 0.98%. There were 14 viral agents had been detected including: Inf A/H1N1pdm (1.41%), Inf A (2.61%), Inf B (0.98%), Inf C (0.11%), hRV (18.1%), RSV (14.13%), Boca (3.32%), Adeno (1.68%), Entero (0.65%), Corona HKUI (0.11%), hMPV (2.28%), Parainfluenza type 1 (1.58%), Parainfluenza type 3 (2.23%) and Parainfluenza type 4 (0.33%) viruses. A remarkable attention is that hRV and RSV which were identified as the cause of some sudden deaths in infants in China, Philippines and respiratory outbreak in Cambodia in 2008 were 02 predominant agents.The major concern is that Inf A virus in the South predominates in summer season and this is very different from other regions in Vietnam and even other parts of the world. In addition, viral agents were shifted by seasons: Boca virus (January to April), Inf A (May to July) and RSV (August to November). The results of the surveillance show that the viral pathogens of SARI are variety and most of them have never been detected in the South of Vietnam. In addition, all types of Influenza virus are detected on SARI cases and the viral pathogens vary by the seasons."}
+{"text": "Kawasaki disease (KD) is considered the leading cause of acquired heart disease in childhood in developed countries. Despite diagnose this disease is difficult in the case of infants, it is required a high clinical suspicion to ensure an early treatment. The aim of this study is compare clinical presentation and rate of coronary artery abnormalities (CAA) according to children age.Retrospective analysis of patients diagnosed with KD from January 2006 to April 2011. Epidemiological, clinical and laboratory characteristics, also when the treatment was initiated and the how was the outcome for younger and older than 12 months.35 patients were diagnosed with KD, 13 younger than 1 year (37.1%). 54.3% of them met the classical criteria, while 45.7% were considered incomplete presentation: fever +3 criteria (31.4%) and fever +2 criteria (14.3%), it was more common in children under 12 months (53.8%). Clinical manifestations more frecuent associated with fever were: rash (97.2%), oropharyngeal involvement (94.3%) and conjunctival injection (74%). Laboratory abnormalities are shown in the table. Every case was treated with immunoglobulin, 29 in the first 7 days of fever (82.8%) and 6 later on (17%); fever resolved within 24 hours in 65.7% patients and 48 hours in 20%. Only 4 children required a second dose (3 younger than 12 months). 84.6% of patients younger than 12 months developed CAA, 2 of them with aneurysms. Rate of CAA in over 12 months patients was 18.2% and nobody developed aneurysms. According to the onset time of treatment, 41.4% of patients treated in the first week developed CAA and 50% of patients treated later. Rate of gallbladder hydrops was higher in under 12 months patients (15.4%). Serious outcomes were developed in a 4 months patient with coronary aneurysms up to 6 mm, cardiorespiratory arrest caused by ventricular dysfunction and distal ischemia of limbs which required the removal of several phalanges.Higher rate of coronary involvement in KD infants younger than 12 months, which is more common in those treated after 7 days from onset of fever. Acute-phase reactants such as CRP or PCT could be viewed as coronary artery abnormalities predictors on larger studies. Therefore, cardiac ultrasound should be considered in infants with unexplained prolonged fever and elevated acute phase reactants, even though not meeting all criteria."}
+{"text": "To evaluate the visual outcome of patients who underwent pars plana vitrectomy (PPV) for posteriorly dislocated lens fragments after phacoemulsification.A retrospective chart review was conducted of all patients who had PPV for posteriorly dislocated lens fragments after phacoemulsification between January 2000 and September 2004 in the Vitreoretinal Service at King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia. Demographics, preexisting eye diseases, details of the previous cataract surgery, findings at presentation, details of the vitreoretinal procedures, final visual acuity, and complications observed during the follow-up were evaluated.Of the 60 patients identified, 37 patients (37 eyes) had a full set of data and were included in the study. In 21 eyes (56.8%), PPV was performed within 1 week of cataract extraction; in 15 eyes (40.5%), PPV was performed more than 1 week postcataract extraction. An initial visual acuity of 20/200 or worse was found in 34 eyes (91.9%). The final visual acuity was 20/40 or better in 10 eyes (27%), and 20/200 or worse in 13 eyes (35.1%). Retinal detachments were found in 3 eyes (8.1%): 1 before and 2 after vitrectomy.There was no statistically significant difference in outcome between those having vitrectomy the first week after cataract surgery and those having it later; however, there was a trend of better visual outcome in early vitrectomy patients (within 1 week). Phacoemulsification has become the preferred surgical method for cataract extraction. One of its complications is posterior capsule rupture, which usually occurs during the surgeon's learning phase. It can, however, occur with experienced surgeons. It may result in the dislocation of lens fragments into the vitreous cavity, which can lead to intraocular inflammation, cystoid macular edema (CME), uveitis, increased intraocular pressure (IOP), corneal edema, and decreased visual acuity. Pars plana vitrectomy (PPV) has been used to retrieve posteriorly dislocated lens fragments and restore vision.11341115After approval was obtained from the human ethics committee, the medical records of all patients who had undergone PPV for posteriorly dislocated lens fragments after phacoemulsification between January 2000 and September 2004 at King Khaled Eye Specialist Hospital were retrospectively reviewed. The parameters of the study included demographics, preexisting eye diseases, details of the previous cataract surgery (including date), performance of anterior vitrectomy, and intraocular lens (IOL) implantation. In addition, visual acuity using Snellen charts, IOP, anterior and posterior segment findings at presentation , the approximate size of nuclear fragments in the vitreous, vitritis, vitreous hemorrhage, retinal detachment, CME, and choroidal effusion were evaluated. Other variables studied were the details of the procedure (including date), the interval between cataract extraction and vitreoretinal surgery, use of phacofragmentation (fragmatome) and/or heavy liquids, operative complications such as retinal tear or retinal detachment, final visual acuity, and complications recorded during the follow-up.Visual acuity was measured with Snellen charts. A poor visual outcome was defined as a visual acuity worse than 20/40. An IOP value was considered high when it was 30 mm Hg in cases with no history of glaucoma, with or without maximal medical therapy. Anterior uveitis was recorded when an anterior chamber reaction of +2 was present. The interval between cataract surgery and PPV was divided into 2 groups: within 1 week and more than 1 week. A minimum of 3 months of follow-up data after vitrectomy was necessary for inclusion in the study. Patients with less than 3 months of follow-up data were excluded.Statistical analysis was performed using the chi-square test.Of the 60 patients (60 eyes) identified, 37 patients (37 eyes) met the inclusion criteria and were included in the study. There were 23 men (62.2%) and 14 women (37.8%), with a mean age of 60.2 years . The mean follow-up was 12.1 months . Of the 37 patients, 34 patients (91.9%) had an initial visual acuity of 20/200 or worse, 21 patients (56.8%) had uveitis, 16 patients (43.2%) had corneal edema, 15 patients (40.5%) had vitritis, and 1 patient had macula-off rhegmatogenous retinal detachment. The clinical features are summarized in Clinically significant macular edema (5.4%), Ischemic maculopathy (2.7%), and glaucoma (5.4%) were the preexisting eye diseases detected .Anterior vitrectomy was performed in 30 eyes (81.1%) at the time of cataract surgery. In addition, 33 patients (89.2%) had posterior chamber IOL (PCIOL) placement, 6 patients (16.2%) were left aphakic, and 2 patients (5.4%) had anterior chamber IOL (ACIOL) placement. At the time of PPV, 1 patient had secondary IOL (PCIOL), and 1 patient underwent IOL removal because of IOL subluxation. After the second retinal reattachment surgery, 1 patient underwent IOL removal because of IOL subluxation. The time interval between the date of cataract surgery and the date of PPV ranged from 0 to 122 days. Within 1 week of cataract extraction, 23 eyes (62.2%) underwent surgery, and 16 eyes (43.2%) had a vitrectomy more than 1 week after cataract surgery. In 1 eye (2.7%), a vitrectomy was performed immediately after identification of dislocated lens fragments during the same surgical session.All 37 patients underwent a standard three-port PPV to remove the retained lens fragments. The pars plana phacofragmentation approach was used to remove nuclear fragments in 33 patients (89.2%); the vitreous cutter was used in 8 patients (21.6%). Perfluorocarbon liquids (PFCLs) were used to float the lens fragments anteriorly for removal in 25 patients (67.6%). High IOP (30 mm Hg or more) readings were measured in 10 patients (27%): It normalized without medication after vitrectomy in 7 patients (70%), whereas the remaining 3 patients continued to require antiglaucoma medications; however, none had filtering surgery. The time interval between cataract surgery and vitrectomy among these 3 patients was within 1 week in 1 patient and more than 1 week in 2 patients.New rhegmatogenous retinal detachment macula on occurred in 2 patients between 2 and 4 months after vitrectomy. In 1 patient , retinal reattachment and a best corrected visual acuity (BCVA) of 20/100 were achieved. The other patient  achieved a BCVA of 20/50 but developed recurrent retinal detachment 1 year later. When this patient subsequently underwent scleral buckle removal, cryotherapy air-fluid exchange, endolaser photocoagulation, and removal of the subluxated IOL, his BCVA was 20/200.The visual acuity generally improved after vitrectomy . Before P = 0.3385).The timing of vitrectomy compared with the visual acuity outcome is shown in P = 0.190, Fisher's exact test); however, there was a trend of better visual outcome in early vitrectomy patients (within 1 week).The final visual acuity was 20/40 or better in 27% (10/37) of patients and 20/200 or worse in 35.1% (13/37). There was no statistically significant difference in outcome between patients having PPV within the first week after cataract surgery and those having it later  when the performance of this procedure was delayed.101413Al-Khaier and coauthors114Whereas early vitrectomy is desirable, converting a complicated cataract surgery into a PPV during the same session may not be ideal. Lengthening an already prolonged case can be difficult for the patient. Achieving adequate anesthesia can also become a problem, particularly in the modern era of topical anesthesia.In the current series, delaying vitrectomy for more than 1 week was associated with a higher percentage of patients with poor visual outcome, whereas a higher percentage of patients who underwent vitrectomy within 1 week achieved a visual acuity of 20/40 or better. However, this difference was not considered statistically significant.Margherio et al. observed significant differences in final visual acuities based on lens status. Those with PCIOL had better vision than those with ACIOL, who had better vision than aphakic patients. The authors attributed the findings to the degree of complications encountered at the time of cataract surgery, for which lens status would be a marker.114Borne et al. observed a trend toward higher rates of retinal detachment among patients in whom phacofragmentation was used.114In a large series, Moore et al. reported retinal detachment in 19 (5.5%) of 343 patients after PPV for retained lens fragments.We recommend the following techniques for removing posteriorly dislocated lens fragments. The remaining vitreous attachments to anterior chamber structures, the IOL, and the iris must be removed. Initially, the vitrector can be used to remove small pieces of cortex and softer pieces of nucleus following the removal of all vitreous surrounding the lens fragments. The vitrectomy should be extended peripherally using scleral depression to remove all fragments that may have become embedded in the vitreous base. This step is essential in order to avoid vitreous traction during phacofragmentation. The phacofragmentation probe is used to aspirate the lens material from the retinal surface and elevate it into the mid-vitreous, where it is emulsified. Fragmentation should be kept to a minimum so as to avoid retinal trauma. Although the posterior dislocation of lens material is a serious complication of phacoemulsification, appropriate intraoperative and postoperative management of this complication can result in good visual outcome. The main limitation of this study is the relatively small sample size. In conclusion, there was no statistically significant difference in outcome between patients undergoing vitrectomy within the first week after cataract surgery and those undergoing it later."}
+{"text": "Cause-specific mortality data are important to monitor trends in mortality over time. Medical records provide reliable documentation of the causes of deaths occurring in hospitals. This study describes all causes of mortality reported at hospitals in the Federal Capital Territory (FCT) of Nigeria.Deaths reported in 15 secondary and tertiary FCT hospitals occurring from January 1, 2005 and December 31, 2008 were identified by a retrospective review of hospital records conducted by the Nigeria Field Epidemiology and Laboratory Program (NFELTP). Data extracted from the records included sociodemographics, geographic area of residence and underlying cause-of-death information.A total of 4,623 deaths occurred in the hospitals. Overall, the top five causes of death reported were: HIV 951 (21%), road traffic accidents 422 (9%), malaria 264 (6%), septicemia 206 (5%), and hypertension 194 (4%). The median age at death was 30 years (range: 0-100); 888 (20%) of deaths were among those less than one year of age. Among children < 1 year, low birth weight and infections were responsible for the highest proportion 131 (15%) of reported mortality.Many of the leading causes of mortality identified in this study are preventable. Infant mortality is a large public health problem in FCT hospitals. Although these findings are not representative of all FCT deaths, they may be used to quantify mortality in that occurs in FCT hospitals. These data combined with other mortality surveillance data can provide evidence to inform policy on public health strategies and interventions for the FCT. Cause-specific mortality data are important to monitor trends in mortality over time. Nigeria is one of several World Health Organization Regional Office for Africa (WHO-Afro) countries with no recent data available on adult mortality ). AlthouFCT is home to Abuja, the nation's capital; it is divided into six area councils with a 2008 estimated population of 1,404,201 people and covers an area of 2,824.3 sq. miles. In September 2009, a retrospective review of hospital-based mortality data in the FCT was conducted by the Nigeria Field Epidemiology and Laboratory Program (NFELTP) to identify sociodemographic characteristics and leading underlying causes of mortality among patients admitted to FCT hospitals. This report describes the results of that study, which found almost 40% of deaths among children aged less than 1 year were related to adverse pregnancy outcomes including prematurity, low birth weight, and jaundice. Malaria was the leading cause of death reported among children and adolescents aged 1-14 and HIV was the leading cause of death among adults aged 15-64 years. Data from this study combined with community-based mortality data can be used to identify risk factors and set priorities for public health interventions.NFELTP reviewed medical records of patients seen at all secondary, tertiary, and major private hospitals in the FCT between January 1, 2005 and December 31, 2008. A total of 15 hospitals were included: 2 tertiary government hospitals, 11 secondary government hospitals, and 2 high capacity private hospitals selected purposively, based on annual number of patients treated. Of the selected hospitals, one did not have data available for 2005 and one only had available data for 2008. Data extracted from the records included date of birth, gender, occupation, date of death, geographic area of residence, date of hospital admission, and underlying cause of death (COD) as listed in the medical record was categorized using the International Classification of Disease, Tenth Revision. Age at time of death was calculated by subtracting date of death from date of birth. Length of stay (LOS) was calculated by subtracting date of death from date of hospital admission. For this report, COD frequency and percentage was classified by leading cause group and major cause subcategories, age at time of death was grouped by year, and occupation reported as occupational group or employment status.During January 1, 2005-December 31, 2008, a total of 4,623 deaths were reported . The aveCause of death was missing for 2% of 888 children aged <1, 2% of 403 aged 1-4 years and 3% of 176 children aged 5-14. Among those aged <1 with a cause listed in the medical record, prematurity and low birth weight (15%) were reported most frequently, followed by sepsis (11%) and jaundice (10%). Malaria was the leading COD reported among children in the 1-4 (80 (20%) of 396) and 5-14 (41 (24%) of 171) year age groups. Pneumonia (11%) and sepsis (9%) were the second and third leading causes of death among children aged 1-4 while road traffic accidents (RTA) (13%) and HIV (9%) ranked as the second and third most common causes of death among 5-14 year olds.Among adults aged =15 cause of death was not listed in the medical record for 4% (123) of deaths. HIV was the single leading cause of death reported collectively among adults aged =15 and the number one COD among adults in age groups 15-24 years (48 (21%) of 234), 25-34 years (307 (38%) of 819), 35-44 years (293 (41%) of 709), 45-54 years (151 (29%) of 522), and 55-64 years (40 (14%) of 295). However, HIV was not a leading COD among adults aged =65 years, accounting for only 1% (46 of 270) of deaths in this age group. Death due to injuries sustained in RTAs was the second overall leading COD among adults aged =15 years. RTAs also ranked as the second leading COD among young adults, aged 15-24 years and 25-34 years, and among middle aged adults 35-44 years . Hypertension, the third overall COD among adults aged =15 years was the second leading COD among those aged 45-54 years (11%) and 55-64 years (13%). Among adults aged =65 hypertension was the number one COD (17%).Males and females shared many of the same 10 leading causes of death . The burMortality occurred more frequently among women than in men for only two age groups, ages 15-24 and ages 25-34 (139 (59%) of 234 and 455 (56%) of 819 respectively). Although HIV was a leading cause of death for both females and males aged 15-24 and 25-34 years, death due to HIV occurred four times as often among females aged 15-24 years 39 (81%) and twice as often among those aged 25-34 years 202 (66%) when compared to males in the same age groups, 9 (19%) and 103 (34%) respectively. Maternal causes related specifically to pregnancy and childbirth, the second leading cause of death among females was associated with 10% of deaths for females in both age groups 15-24 years (14 of 139) and 25-34 years (44 of 455).This report is the first to present descriptive data on patient characteristics related to cause-specific mortality in FCT hospitals. Many of the leading causes of death identified in this report are preventable. A substantial proportion of mortality among the <1 year age group was attributable to low birth weight newborns and infections. These findings are similar to findings of other hospital-based mortality studies conducted in Nigeria (4-5) and reflect multi-faceted maternal health problems such as lack of access to prenatal care, poor nutrition, malaria, or HIV/AIDS. High mortality due to malaria in children aged 1-14 years continues to be a problem in Nigeria evidenced by this and other studies (6). Although mortality from RTAs was the second leading COD among children 5-14 (13%) and adults aged =15 (9%), this frequency may be an underestimate of actual RTA mortality burden due to classification of death as \u201cbrought in dead\u201d and injuries listed without an underlying cause. Similar to previous studies conducted in Nigeria (7-9), this report found HIV as a major COD among adults admitted to hospitals. However, these results may be underestimates due to lack of documentation of serologic test results. AMAC, being the administrative center of Nigeria, consists of mainly civil servants and their families. This likely explains the high proportion of deaths among the civil service occupational group.The findings of this report are subject to at least three limitations. First, sociodemographic factors such as financial status, educational attainment, transportation access, and ethnic/cultural beliefs influence hospital utilization and thereby limit the findings of this review to a subset of the FCT's population. Second, varying methods used to assign COD  could have led to over or under estimation of cause-specific mortality. Finally, poor hospital record keeping practices resulted in missing or incomplete data in the medical charts key variables such as unknown age for 6% (193) and \u201cbrought in dead\u201d or COD not listed for 7% (344) of the deceased patients.The absence of cause-specific mortality among individuals that utilize FCT hospitals was a weakness of the existing mortality reporting system. This retrospective review was useful because it was an inexpensive project quickly conducted by the NFELTP residents that resulted in immediate action to strengthen mortality surveillance in the FCT. As an ongoing service to the HHHS, NFELTP residents are developing a prospective hospital-based mortality surveillance system. The findings of this report highlight the importance of improving the health of mothers and children, safety on roads, and HIV prevention in the FCT. Reliable cause-specific mortality data from sources outside health facilities are scare in Nigeria. The current literature is limited to studies conducted in rural areas in pediatric and maternal populations (10-12). Data from this study, integrated with comprehensive community-based mortality data, may be utilized to describe patterns of mortality in the FCT and set priority focal areas for public health interventions."}
+{"text": "Pain location is an important point in the diagnosis of headaches. Our aim was to analyse the diagnostic distribution of the first 100 patients consulting in our specialised headache clinic due to strictly unilateral headache.Headache diagnoses for all patients sent to our headache clinic in the last year and referring to strictly unilateral headaches were analysed according the current ICH-II classification. We receive patients aged 14 or older.The 100 collected patients with strictly unilateral headaches accounted for the 18.9% of the 528 patients seen in our clinic in the study period. Strictly unilateral headaches were more frequent in males (58%). Age ranged from 19 to 81 years. Diagnostic distribution was as follows: cluster headache (38 cases)> a variety of secondary headaches (14 cases)> migraine (11 cases)> cervicogenic headache (9 cases)> hemicrania continua (8 cases)> nummular headache (6 cases)> psychogenic headache (5 cases)> paroxysmal hemicrania (4 cases)> SUNCT syndrome (3 cases)> stabbing headache (1 case)> and probable hypnic headache (1 case).Mean, median and mode of age at onset felt between 47 and 58 years for several diagnoses , between 25 and 35 years for cluster headache, below 25 for migraine and, in general, were older than 55 for secondary headaches.Strictly unilateral headaches account for almost 20% of headaches attending a headache clinic. Trigemino-autonomic headaches in general (52%) and cluster headache in particular (38%) are the most frequent diagnosis, but, if we include cervicogenic headaches, secondary headaches are diagnosed in one out of five cases. Age can be of important help in their presumptive diagnosis. Supported by the PI11/00889 FISSS grant (ISCIII)."}
+{"text": "Toxoplasma gondii.Toxoplasmosis is a parasitic zoonosis, caused by protozoan Toxoplasma gondii antibodies, and by the EIA (enzyme immunoassay) method the IgA Toxoplasma antibodies in HIV infected persons in Bihor County, during the year 2012.Using the CLIA (chemiluminescence immunoassay) method we determined the IgM and IgG Toxoplasma gondii, while 8 (26.66%) patients with antiretroviral treatment were found with the same antibodies. Two cases from the last category (6.66%) were diagnosed with acute forms of the disease, in which we found IgM to IgG toxoplasma seroconversion.The study included 30 patients, with HIV infection, 26 (86.7%) of them with antiretroviral treatment, while 4 (13.3%) of them without treatment. Two patients (6.66%) without antiretroviral treatment were found with protective antibody for Toxoplasma gondii antibodies in HIV infected patients was 33.3%.The seroprevalence of Toxoplasma gondii antibodies in researches with similar purpose. This high percentage proves that Toxoplasma gondii is an additional risk factor for immunosuppressed patients.The obtained value (33.3%) in our study is approximately similar to results reported on seroprevalence of"}
+{"text": "In Australia, the DHHS guidelines for treatment of adults and adolescents have been adopted with an Australian Commentary.An audit was conducted to determine adherence to these guidelines.Case records were examined of 500 sequential adults initiating ART in primary care and hospital sites (125 per site) in Sydney and Melbourne from 2004 to 2008 inclusive. Data on ART initiation and regimen prescribed, as well as adherence to all specific guidelines on patient management and monitoring, were recorded.Of 500 subjects initiating ART (by 54 physicians with mean 14 years HIV experience), 95% were male . ART initiation was mean 3.1 years after diagnosis, via clinical trial in 20.4% and as hospital in-patient in 7.7%. For \"When to start\", adherence to Dec 1 2009 guidelines was 91%, 82% for Nov 3 2008 guidelines, and 88% for guidelines current at ART initiation. Preferred or alternative regimens were prescribed  in 79%, 90%, and 89%, according to 2009, 2008 and guidelines current at ART initiation, respectively. Preferred regimen was prescribed according to guidelines in 50%, 55% and 65%, respectively. Contraindicated ART was prescribed in 4%. Strong recommendations (level A) in 2008 guidelines were adhered to variably: for hepatitis serology (74%), oral/dental check (63%), fasting lipids (52%), fasting glucose (47%), CMV serology (50%), resistance testing (48%), vaccination history 39%, Chlamydia screening (38%), gonorrhea screening (36%), chest X ray (35%), pap smear (32%), urinalysis (26%), and TB testing (9%). Sydney patients were more likely than Melbourne patients to have co-morbidity history assessed , and to commence ART via a clinical trial , but less likely to have treatment adherence ability assessed  with no significant difference in STI testing. Hospital sites were more likely than GP sites to perform investigations - resistance testing , but less likely to discuss lifestyle health promotion .HIV treatment guidelines in primary care and hospital sites in Australia have been largely adhered to for when to start and what to start with, but less closely followed for co-morbidity related parameters."}
+{"text": "To define the impact of multiple injuries without the presence of sepsis in IL-17 responses.Escherichia coli O55:B5; of 5 \u03bcg/ml phytohemmaglutin (PHA); of 5 \u00d7 105 cfu/ml of heat-killed Candida albicans (HKCA), of Pseudomonas aeruginosa (HKPA) or of Staphylococcus aureus (HKSA). IL-17 was measured in supernatants by an enzyme immnunoassay.A total of 32 patients and 17 healthy volunteers were enrolled. All patients were bearing: multiple injuries necessitating ICU admission with an injury severity score more than 16; and systemic inflammatory response syndrome. Patients with infections upon ICU admission were excluded from the study. Heparinized venous blood was sampled within the first 24 hours after ICU admission. Peripheral blood mononuclear cells (PBMCs) were isolated after gradient centrifugation of whole blood over Ficoll. They were incubated for 5 days in RPMI 1640 supplemented with 2 mM glutamine and 10% FBS in the presence of 10 ng/ml lipopolysaccharide (LPS) of P values refer to comparisons between controls and patients.Mean APACHE II score of patients was 14. Release of IL-17 by PBMCs of patients was significantly lower compared to controls, as shown in Figure The presented findings show that early upon advent of multiple injuries IL-17 responses are blunted. This may corroborate with the susceptibility of patients for superinfections."}
+{"text": "Dear Editor,Foot infections are one of the important causes for hospitalization of patients with diabetes and the leading cause of morbidity in diabetic patients.2]2]Diabetic foot lesions may present as ulceration, gangrene, charcot joint, or fracture and are associated with amputation if not treated promptly. The propStaphylococcus aureus, coagulase-negative Staphylococci (CONS), Escherichia coli were the bacterial species most commonly isolated from the patients with diabetic foot lesions .Out of 69 patients with positive cultures, 34 (49%) were only infected with one organism, while others 43 (51%) had mixed infections. The prevalence of aerobeic and anaerobic bacteria were 104 (96.5%) and 5 (4.5 %), respectively. The aerobic and anaerobic organisms both were isolated in diabetic foot ulcers of 4 (6%) patients. S. aureus was the most frequent pathogen (19.4%) that was similar to a previous study in Iran (34.4%).9] Ot[9] Ot8][ Ot[9] OtIn conclusion, our study showed that gram positive bacterial species are the most frequently isolated bacteria from diabetic foot patients that had multidrug resistance phenotype. Imipenem and vancomycin could be the most effective antimicrobial agents against these bacteria. Further understanding of the causative organisms in diabetic foot infections and their antimicrobial susceptibility pattern are essential for the organization of antimicrobial therapy and management of complications of diabetic foot infections such as foot amputation."}
+{"text": "Objective: To assess the demographic and clinico-pathological trends, as well as the management options of adult patients with primary malignant renal tumors over 6 years.Methods: From July 2003 \u2013 July 2009, 55 adult patients with primary malignant renal tumors were treated in two teaching hospitals . Their data were reviewed retrospectively.Results: Of the 55 patients, 44 had renal cell carcinoma (RCC), eight patients had Transitional cell carcinoma (TCC) of the renal pelvis, two had Sarcoma and one Patient had primary renal lymphoma. Among patients with RCC: the mean age was 56 years, male to female ratio was 3:1. The most common presenting symptom was hematuria. Most of the patients were treated with radical nephrectomy, the clear cell subtype was predominant and most of the patients were diagnosed at stage T2. Regarding patients with TCC: mean age was 57 years, all were treated with radical nephro-ureterectomy and removal of bladder cuff, however (50%) of them developed TCC of urinary bladder within 12 months of radical nephro-ureterectomy. Conclusion: In our series of patients with RCC: there is a trend toward younger age at Diagnosis. We still encountered locally advanced and metastatic disease with a lower rate of incidentally Diagnosed tumors.With regard to patients with renal pelvis TCC: there are trends toward younger age affection, localized disease and early development of bladder TCC which indicate the importance of strict surveillance protocol. Primary malignant renal tumors include a wide range of tumors, among them renal cell carcinoma (RCC) and transitional cell carcinoma (TCC) of the renal pelvis are the most common. Others include Sarcomas, lymphomas and leukemia.1 Worldwide, based on probably incomplete figures, about 270000 new cases are diagnosed per year, and about 116 000 patients die per year.2 It constitutes approximately 85% of all primary malignant renal tumors, Approximately 54,000 new diagnoses of RCC are made each year in the United States, and 13,000 patients die of disease.3 Nearly 20,000 new cases are detected in the European Union annually.4Renal cell carcinoma (RCC) overall accounts for 2% of all adult malignancies.5 The incidence rates are 10\u201320% higher In African Americans in both men and women.6 Annual mortality-to-incidence ratio with RCC is significantly higher compared to other urological malignancies making it the most lethal urological malignancy.7RCC is primarily a disease of the elderly with typical presentation in the Sixth and Seventh decades of life. There is a male predominance with a ratio of 3:2.8As for geographical variation, the rates are low in Asian countries and high in the USA and Canada. The incidence has increased more than 30% over the past two decades.6It is generally postulated that the increased incidence rates reflect earlier diagnosis at an earlier stage, largely due to more liberal use of radiological imaging techniques. However, advanced disease has also been diagnosed more frequently and the mortality rate has increased as well.From July 2003 to July 2009, Data were collected retrospectively from the records of adult patients with primary malignant renal tumors presented to Jordan University Hospital and Al-Jumhory Teaching Hospital these data include: age, sex, anatomical side, presenting symptoms, diagnosis, metastasis if any, therapeutic options, histopathological subtype and tumor stage.The numbers of patients who had full data and fulfill these criteria were 55 patients. The study was approved by the authorities of department of surgery in Mosul College of medicine.over 6 years, 41 (74.5%) were males and 14 (25.5%) females, of those patients 44 had RCC (80%), 8 patients had TCC of the renal pelvis (14.5%), 2 had sarcomas (3.6%) and one had renal lymphoma (1.8%) A total of 55 adults with primary malignant renal tumors presented to us Regarding those with RCC: some of the patients characteristics are shown in Ultrasound was the initial diagnostic tool in all patients followed by abdominal computed tomography (CT) Scan and chest X-ray. While MRI, chest CT.scan and bone isotopes scan were done upon clinical suspicion. Selective angiography only done in few patients.Metastasis at presentation was noticed in 14/44 (31.8%) of our patients, the most common metastatic site was the lung in 8 /14 (57.1%), Bone in 5/14(35.7%), liver in 4/14 (28.6%), brain in 2/14 (14.2%), adrenals in 2/14 (14.2%) and skin in 1/14 (7.1%).Considering the management of those patients: 36/44 (81.8%) underwent Radical Nephrectomy, among them 6/36 (16.7%) had metastasis (cytoreductive nephrectomy), only one patient had renal vein involvement and one patient had simultaneous solitary lung metastasis resection. An adrenal gland excision was concomitantly performed in 41.7% of the cases when there is extensive renal tumor, upper pole tumor or radiological suspension of adrenal metastasis.While the other 8/44 (18.2%) were treated non-surgically: 4 of them were treated with targeted therapy (sunitinib), 2 with Interferon-\u03b1, one patient treated with Thalidomide and one patient was interminal stage and only palliative treatment given.Regarding histopathology: conventional clear cell carcinoma was the most common type, The most frequent tumor stage according to the TNM classification system was T2 . PositivAs regards patients with TCC of renal pelvis: 7/8 were males and one female, mean Age was 57 years (49-62); all had renal pelvic TCC, the main presenting symptom was hematuria in all patients , intravenous urography (IVU)and CT. scan done for all patients, all of them had localized disease and treated with radical Nephro- ureterectomy and bladder cuff removal. Tumor stage was T2 in 5 patients andT1 in 3 patients, tumor grade was well differentiated in 3 patients, moderately differentiated in 4 and poorly differentiated in one patient.Cystoscopy done for all patients at the same time of the radical Nephro-ureterectomy and showed no bladder growth but within one year 4/8 (50%) of them developed bladder TCC, all were treated with transurethral resection of bladder tumor (TURBT) and 2 of them require further treatment with intravesical immunotherapy.Two male patients had sarcomas (fibrosarcoma and lieomyosarcoma), treated with radical nephrectomy and proved to have localized disease, one Female Patient presented with left renal mass proved to be renal lymphoma following radical nephrectomy and was referred to oncologist.nd most common urological tumor in Iraq preceded by bladder cancer only, while in Jordan it is the 3rd. one preceded by prostate and bladder cancers respectively.9Renal cancer in general represent 1.6% and 2% of all cancers in Iraq and Jordan respectively ,in both Syria and Lebanon renal cancers represent 1.8% for each, renal cancer is the 2th or 7th Decade of life,7 however, in our patients the mean age was 56 Years and we have 3/44 Patients (6.8%) younger than 40 years old , all of them were females without family history of renal tumors. in a study by Taccoen et al. showed that 7.5% of their RCC series were less than 40 years old,10RCC usually occur during the 64Another study from Jordan showed that the male to female ratio was 3.4:1 and the mean patient age was 54 years.11 This is close to our mean age which was 56 years.In our series, the male: female ratio was 3:1  with a Lower female incidence than the known ratio of 3:2.12 flank pain may be seen in up to 40% of patients and is caused by either bleeding within the tumor or invasion of contiguous tissues.13The main presenting Symptom was hematuria in 38.6% and loin pain in 27.2%. However in other studies they reported hematuria in 40-60% of patients,14 on the other hand, 26% of cases werer diagnosed incidentally in previous Jordanian study11 and 14% only diagnosed incidentally in a study by Al-Marhoon,15 2 of our patients (4.5%) presented with metastatic Symptoms .Constitutional symptoms  in 13.6% while 16% only diagnosed incidentally in our patients, however more than 50% of RCCs are now detected incidentally at earlier stages,16 Among those who present with metastatic disease, 75% have lung metastases, 36% have soft tissue metastases, 20% have bone metastases, 18% have liver metastases, and 8% each have skin and CNS metastases.17 However, in our series: most common metastatic site was the lung in 8 /14 (57.1%), Bone in 5/14(35.7%), liver in 4/14 (28.6%), brain in 2/14 (14.2%), adrenals in 2/14 (14.2%) and skin in 1/14 (7.1%). Lymph node enlargement reported in 6/36 (16.7%).In our series 31.8% had metastatic disease, however up to 40% of patients in other series still present with extra renal growth or metastases.11 Although nephron sparing surgery nowadays represent the state of the art in renal cancer management, but none of our patients was offered a partial nephrectomy due to lack of adequate experience with such operations and technical limitations.Most of our patients (81.8%) underwent Radical Nephrectomy, among them (16.7%) underwent cytoreductive nephrectomy. In another study radical nephrectomy was performed in 91.6% of the patients.4and it accounted for only 55.5% in a Jordanian study,11 while it represent 79.5% in our series.Clear cell carcinoma usually constitutes 70-80% in other series14 However, we still encountered advanced cases which signify either delayed presentation, improper initial assessment causing delayed diagnosis or the limited availability of the modern imaging modalities.Majority of renal tumors are discovered incidentally at earlier stage.Patients with TCC of renal pelvis: Upper urinary tract urothelial tumors involving the renal pelvis or ureter are relatively uncommon, accounting for about 5% to 7% of all renal tumors,3 We had a higher incidence of 8/55 (14.5%), usually men generally are about twice as likely to develop upper tract tumors as are women,7however in our series we have one female only.3 All of them presented with gross hematuria, Had no metastasis and all were treated by Radical nephro-ureterectomy with bladder cuff removal, however, 4/8 (50%) of patients developed TCC of the bladder within 12 months of the radical Surgery, knowing that all patients had normal cystoscopy done at the time of radical surgery. Those patients were 3 males and one female; all had multifocal TCC in the renal pelvis at the time of radical nephro-ureterectomy, the histopathological examination of the resected bladder tumors showed superficial bladder TCC (Ta \u2013T1) with grade 1-2 differentiation.Mean age was 57 years (49-62 years) which is much younger than the reported age range of 75-79 years.18-21 Most of the bladder recurrences occur within 5 years of the development of the upper tract cancer and 82% of them occur during the first two year.22Patients with upper tract tumors are at risk for development of bladder recurrence, with an estimated incidence that varies in multiple reports from 15% to 50%.23 In our series Two (3.6%) male patients (59 and 61 years old) presented with renal mass, underwent radical nephrectomy and the histopathology report proved the presence of fibrosarcoma and lieomyosarcoma respectively and the latter offered further treatment with chemotherapy. One (1.8%) female patient had renal lymphoma following radical nephrectomy for Incidental Renal mass.Primary renal sarcomas, in general, are rare tumors and account for up to 3% of all renal malignancies.In this study there was a trend toward younger age at Diagnosis, especially in females, yet, we have less overall female Incidence. Hematuria and loin pain were the commonest presenting symptoms, we still encountered locally advanced and metastatic disease with a lower rate of incidentally diagnosed tumors which signifies the importance of early consultation and proper assessment of patients with suggestive Symptoms. There are trends toward younger age affection, localized disease and early development of bladder TCC within less than one year following radical surgery in 50% of the patients which indicate the importance of strict surveillance protocol."}
+{"text": "Multiple food allergy is increasing.To find out the frequency of multiple primary food allergy (MPFA) in our patient population; the causal foods and their number per patient; age at diagnosis of food allergy; symptoms; frequency of environmental allergy occurring in those patients.MPFA was defined as primary allergy simultaneously occurring to at least 3 unrelated foods. Allergy to a specific food was considered proven based on at least one of the following: a clear cut clinical history; elimination and reintroduction; a specific IgE level or skin prick test size \u2265 the 95% positive predictive value ; a positive provocation test. Primary allergy to the given food was documented by the involvement of class 1 allergens and/or the timing of food allergy development. Files of all patients visiting our tertiary Pediatric Allergy Center between September 2008 and August 2009 were studied retrospectively.Out of 715 patients 65 subjects (40 boys/25 girls) were found to have MPFA (9%). Age at enrollment ranged from 6 to 192 months (median 5.8 months); age at first diagnosis ranged from 1 to 192 months . The causal allergens were egg (60/65), cow\u2019s milk (57/65), potato (22/65), peanut (21/65), tree nuts (18/65), fish (15/65), soy (14/65), wheat (10/65), banana (6/65) and kiwi (5/65). In 32/65 subjects more than 3 different foods were involved. The symptoms were: atopic dermatitis, gatrointestinal manifestations, urticaria, angioedema, respiratory manifestations, anaphylaxis and failure to thrive in 92%, 61%, 45 %, 41%, 35 % 28% and 21% respectively. Thirty out of 32 subjects having reached the age of 6 years (93 %) also suffered from respiratory allergy.Up to 10% of children visiting a tertiary allergy center might present with MPFA, needing specialized dietary advice."}
+{"text": "Acute myeloid leukaemia (AML) is a heterogeneous group of haematological malignancy. In spite of recurrent chromosomal abnormalities present in a significant proportion of AML patients, more than 50% of the patients have a normal karyotype (NK-AML) and lack reliable molecular markers. NPM1 has been recently characterized as the most frequently mutated gene in AML Patients. The objective of the present study was to profile the karyotype and to assess the types of NPM1 gene mutations in AML patients in south India.in situ hybridization was performed with standard methods. Mutation screening of NPM1 mutation hotspot exon12 performed in DNA by PCR-SSCP and suspected samples were sequenced.A total of 200 de novo AML patients were investigated in this study. Cytogenetic G- banding analysis, Fluorescence Among 200 de novo AML patients 119 showed normal karyotype. Fourty out of two hundred patients showed mutations in NPM1 exon12. Most of the NPM1 mutation were detected in NK-AML (37/40) (92.5%).Three of them showed abnormal karyotype. The highest incidence of mutation was detected in AML-M1 with 47.5% followed by M5, M4, M2 and M3 .Predominant type of mutation was a type A mutation (c.860-863dupTCTG) (75%). Other type of mutations includes tetranucleotide insertion of TGCA (10%), CTGC (10%), GTCA (2.5%) and GTAG (2.5%). All the mutated cases were heterozygous in nature retaining wild type allele and have a distinct sequence in the protein c-terminal.Presence of 31% mutation in the NK-AML in the present study indicates that it is the most prevalent mutation in NK-AML patients in south India. NPM1 mutations are associated with good prognosis in AML. So predominance of NPM1 mutation in the AML especially in NK-AML patients suggests that it could be used as a reliable molecular marker for those patients."}
+{"text": "Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are the most common cause of non-allergic drug-induced systemic hypersensitivity reactions. We have aimed to use the Oral Challenge Test (OCT) to determine alternative and safe drugs to be used by patients with hypersensitivity to NSAIDs, and evaluate its most prevalent reactions.Prospective study including 116 patients with positive history of hypersensitivity to NSAIDs, evaluated at the Allergy Clinic of the Clinical Hospital of Ribeirao Preto Medical School, between October 2010 and July 2014. Patients were evaluated using the European Network for Drug Allergy questionnaire, and underwent single blind, placebo controlled OCT, in a hospital-controlled environment. Patients were required to be clinically stable, and to withdraw antihistamines or corticosteroids seven days prior to the OCT. Patients were given 10%, 20%, 30% and 40% of the therapeutic NSAID dosage, selecting an NSAID different from the one implicated in the allergic reaction. Fifteen minutes after each dosage, patients were evaluated with Peak Flow and blood pressure measurements, heart and respiratory rates and general examination.Among the 116 patients enrolled the study, 85(73%) were females. Eighty-five patients(73%) had history of allergic respiratory disease. Clinical manifestations were: Angioedema (58%), Urticaria(42%), Anaphylaxis(24%), and respiratory symptoms such as nasal pruritus, sneezing, rhinorrhea, dyspnea, and cough (22%). The NSAIDs most implicated by history were: Dipirone(70%), Diclofenac(52%), Acetaminophen(29%), Ibuprofen(21%), Cetoprofen(20%) and Nimesulide(19%). Reactions to two or more drugs were reported by 86 patients(74%). One-hundred and fifty-three OCT were performed, with 28(18%) positive results. The most implicated drugs were Celecoxib (7 tests), Benzydamine(5), Nimesulide(3), Ibuprofen(3), ASA(2), Acetaminophen(2), Etoricoxib(2), Dipirone(1), Diclofenac(1), Meloxicam(1), and Viminol(1). Reactions included Angioedema, Urticaria and respiratory symptoms. One patient presented with anaphylaxis during OCT using Celecoxib.It is well established that COX-2 inhibitors are safe and low-reactive drugs, recommended as an alternative to patients with hypersensitivity to NSAIDs, however in this study we have observed reactions involving Celecoxib. OCT showed to be an effective method to find an alternative and safe choice to the patients with NSAIDs hypersensitivity."}
+{"text": "The aim of this study was investigated if seasonal systemic allergic rhinitis (SAR) induced by pollens and local allergic rhinitis (LAR) induced by perennial allergens may coexist in the same patient.D. pteronyssinus (DP), and Alternaria alternata (AA) were performed.Twenty-nine patients with seasonal SAR (positive SPT to grass and/or olive pollen) with well-defined symptoms during pollen season in addition to nasal symptoms throughout the year were included. Clinical questionnaires, skin tests, serum specific IgE, nasal levels of tryptase and eosinophil cationic protein, and nasal allergen provocation test (NAPT) with grass, olive, The coexistence of dual SAR-LAR was confirmed in 23 patients by NAPT (82.1%) with positive response to AA in 9 patients (22%), to DP in 19 (46.3%), and to both AA and DP in 13 (31.7%). No discordance between SPT and NAPT results was obtained. The SPT and NAPT with seasonal pollens were positive to grass in 11 patients (26.8%), to olive in 20 (48.8%), and to both grass and olive in 11 (26.8%). No significant differences between seasonal and perennial allergens threshold concentrations were observed. The 56.5% of patients reported a seasonal onset of nasal symptom followed by perennial symptoms in the next years. The 30.4% a perennial onset of symptoms with a clear spring worsening, and the 13% could not remember the onset of the disease.These results demonstrate the coexistence of seasonal SAR and perennial LAR in patients who developing symptoms throughout the year and have negative SPT to perennial allergens should be explored."}
+{"text": "Women who inherit a mutated copy of the BRCA-1 or BRCA-2 genes have a higher lifetime risk of developing breast cancer. There have been no large epidemiological studies looking at BRCA-positive patients in the UK.Across the All Wales Genetics Service, individuals with confirmed BRCA mutation, since formal testing began (1995) to 1 January 2015, were included--identified from a prospectively gathered database. Genetics case notes were obtained and retrospective analysis carried out.A total of 419 females with mean age 47 (19\u221281) were included in the study. Of these, 206 were identified using diagnostic testing with the remaining 213 undergoing predictive testing. Of the predictive group who subsequently had cancer, 18 (78 %) developed breast cancer. Seven (39 %) had wide local excision (WLE), six (33 %) had single mastectomy while the remaining five (28 %) had bilateral mastectomies as their primary operation. Five of the predictive group (22 %) had ovarian cancer. Of these, four (80 %) went on to have prophylactic breast surgery too. Of the 13 patients who underwent WLE or single mastectomy, four (31 %) went on to have completion risk reduction mastectomies (RRM). From the remaining 190 individuals in the predictive group with no cancer diagnosis, 102 (54 %) have had no risk reduction surgery, 32 (17 %) RRM only, 31 (16 %) BSO only and 25 (13 %) underwent both procedures.There is variation in the surgical management of BRCA positive patients in Wales. This has implications for service allocation and demands for screening for these high-risk patients."}
+{"text": "Hepatitis B virus (HBV) infection is common in individuals infected with human immunodeficiency virus, and coinfection is associated with higher rates of HBV replication and more rapid liver disease progression than HBV monoinfection. This study evaluates the prevalence and virological profiles of hepatitis B infection in a cohort of long term survivors, with multiple antiretroviral treatments.3 IU/mL.164 HIV-infected subjects (median age: 24 years) on combined antiretroviral therapy (cART) (median duration: 13 years), were evaluated for serologic markers of HBV infection . Markers of HBV infectivity (HBeAg and HBV DNA) were evaluated in all HBsAg carriers; HBV genotype and lamivudine resistance mutations were analyzed in the cases with HBV DNA >1065.9% of the patients (108/164) had markers of past or present HBV infection (antiHBc positives), out of which 51.8% (56/108) were chronic HBV carriers and 30.5% had resolved HBV infection. All subjects were equally exposed to HBV infection, irrespective of their current immune status. Out of 21 patients with isolated anti-HBc antibodies, only 4 had detectable HBV DNA, presumably having occult hepatitis B. HBV chronic carriage rate was not influenced by the immune status. Overall, only 17.8% of the chronic carriers had active HBV replication; severely immune-depressed patients tend to maintain active viral replication more frequently than those with moderate or absent immunosuppression. The majority of the coinfected individuals (68.3%) showed no sign of liver fibrosis (APRI score <0.5), only 3% had severe fibrosis (APRI score >1.5); HBV DNA was directly correlated with APRI score. HBV genotype A was present in all but one of the tested patients. 98.8% of the coinfected subjects have been treated with a cART regimen that includes a drug dually active against HIV and HBV (in 98% of the cases lamivudine (3TC), for a mean time of 6.9 years and in 29.7% of the cases the current dually active drug was tenofovir). 3TC-resistance mutations were present in only 4 coinfected subjects.We found a strikingly low percentage of long term HIV/HBV coinfected patients from our group with active liver disease. A high prevalence of asymptomatic HBV chronic carriage was associated with a good immune status, suggesting that dually active antiretrovirals have an important role in delaying progression of liver disease in HIV/HBV coinfected patients."}
+{"text": "Systemic juvenile idiopathic arthritis (SJIA) is the most common subtype of JIA in Thailand, which represents approximately 33 percents of all JIA patients. The disease course of SJIA and outcome of treatment were varied, depending on multi-factors. In the previous studies, persistent systemic features, younger age at onset, and arthritis of hip are predictors of poor functional outcome in SJIA. Since the development of biologic agents in this era improves the quality of life and outcome in SJIA patients, the disease course and predictors of outcome in SJIA have changed in the past 10 years.To evaluate disease status, functional outcome, structural damage, and prognostic factors of SJIA outcome.Patients who were diagnosed with SJIA according to International League of Associations for Rheumatology (ILAR) criteria in Ramathibodi hospital between April 1997 and April 2013 were enrolled in this study and data records were reviewed. Disease status was evaluated by using European League Against Rheumatism (EULAR). Functional outcome was assessed by American College of Rheumatology core set criteria, including Child Health Assessment Questionnaire (CHAQ), physician global assessment, parent/patient global assessment, number of active joints, number of limited joints, and erythrocyte sedimentation rate (ESR), while radiographs were interpreted by radiologist using Dale radiographic classification system for structural damage evaluation. Prognostic factors of moderate to severe disability (defined using a CHAQ score \u22650.75) and moderate to severe radiographic damage  were analyzed by multivariable logistic regression models.3 was the only significant predictor for structural damage (p 0.028).Fifty-two patients (24 boys and 28 girls) were enrolled. The mean age of onset was 5.4 years old (6 months - 14.1 years). The mean follow up period was 43.1 months (6.3-169.6 months). The most common presentations were fever (100%), arthritis (100%) and salmon rash (75%). The patterns of arthritis were 55.8% polyarthritis and 44.2% oligoarthritis. The most commonly involved joints were the wrist (69.2%) and knee (67.3%). Treatment included systemic steroid (88.5%), disease-modifying antirheumatic drugs (86.5%), and biologic agents (42.3%). Among patients taking biologic agents, five received etanercept, one received infliximab, and fifteen received tocilizumab. Nine patients achieved complete remission, one patient with clinical inactive, thirty-three patients had stable disease, and six patients still had active disease. Six patients (12%) developed macrophage activation syndrome (MAS) during the disease course. Two patients died from MAS and severe infection, one patient died from severe infection. Seven patients (13.5%) had moderate to severe disability. The predictor of a CHAQ score \u22650.75 was initial presentation of polyarthritis (p 0.012). Eleven patients (32.4%) had moderate to severe radiographic damage and neutrophil counts at presentation \u2265 12000 cells/mmPolyarthritis at initial presentation may predict the development of a poor functional outcome. The prognostic factor of radiographic damage was neutrophilia. Infection is the major cause of death in SJIA.None declared."}
+{"text": "Sodium levels were generally higher on day 15 than at baseline  in the group of responders  compared to patients who progressed (PD) . In contrast, potassium was lower on day 14  in the responder group  than in those with progressive disease . The early onset of hypertension is associated with improved clinical outcome in HCC patients treated with sorafenib. Our data are suggestive of an activation of the renin-angiotensin system in patients with advanced disease who developed HTN during sorafenib treatment.Hypertension (HTN) is frequently associated with the use of angiogenesis inhibitors targeting the vascular endothelial growth factor pathway and appears to be a generalized effect of this class of agent. We investigated the phenomenon in 61 patients with advanced hepatocellular carcinoma (HCC) receiving sorafenib. Blood pressure and plasma electrolytes were measured on days 1 and 15 of the treatment. Patients with sorafenib-induced HTN had a better outcome than those without HTN (disease control rate: 63.4% vs. 17.2% (p=0.001); progression-free survival 6.0 months (95% CI 3.2-10.1)  Hepatocellular carcinoma (HCC), the most common primary liver cancer, is increasing in incidence. It currently represents the fifth most common malignancy worldwide and the third leading cause of cancer-related death . The intHypertension (HTN) is frequently associated with the use of angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF) pathway and appears to be a generalized effect of this class of agent -14. PhysThe inhibition of VEGFR-2 by sorafenib leads to a decrease in phosphoinositide 3-kinase (PI3K), Akt, endothelium-derived nitric oxide synthase (eNOS) expression and the production of the potent vasodilator nitric oxide -22.Based on these observations, we performed a retrospective analysis to evaluate whether the development of HTN and changes in serum electrolytes in patients with metastatic HCC receiving sorafenib are associated with the antitumor efficacy of the drug.From 1 July 2011 to 25 March 2015, 61 consecutive patients with Child-Pugh A HCC receiving sorafenib were available for our analysis. Fifty-one (84.3%) were males and 10 (15.7%) females, with a median age at diagnosis of 72 years (range 28-87). Median follow-up was 34 months (range 1-45). Seven patients had BCLC-B and 54 had BCLC-C. Twenty (32%) patients had previously undergone transarterial chemo-embolisation (TACE). The most common liver disease etiologies were hepatitis C (50.8%), alcoholic liver disease (10.2%), fatty liver disease (15%) and hepatitis B (15.2%) (Table Patients who developed HTN after 15 days of treatment had a median PFS of 6 months 95% CI 3.2-10.1) compared to 2.5 months (95% CI 1.9-2.6) for those who did not  Figure . HTN pat-10.1 comFigure DBP did not change significantly from baseline to day 15 of the first cycle of sorafenib in any group, regardless of objective response. Median PFS was 2.1 months (95% CI 0.9-2.6) in patients with grade 1 HTN, 5.2 months (95% CI 1.2-10.8) in those with grade 2 HTN, and 8.5 months 95% CI 3.2-15.3) (p<0.0001) in the grade 3 HTN group , HTN remained an independent prognostic factor for both PFS  and OS .Comparing electrolyte values at baseline and on day 15 Table , we obseIn this retrospective study, a correlation emerged between the development of HTN during treatment with sorafenib and survival of advanced HCC patients. Patients with HTN also had a better DCR than those without HTN. Furthermore, we noticed that the higher the BP, especially systolic, the better the response to treatment with sorafenib. Figure Although a correlation between HTN and response to sorafenib in HCC patients has already been reported in some studies , 29, it Our data revealed a correlation between the change in electrolyte values and sorafenib-related HTN. It can be hypothesized that sorafenib blocks the VEGF receptor, inducing vasoconstriction in the kidneys, activating the renin-angiotensin-aldosterone system and increasing the production of renin. Renin converts angiotensin I into angiotensin II, leading to water retention, hypernatremia and hypokalemia  Figure . Our datOne strength of our study lies in the detailed information it provides on patient characteristics and follow up. However, the study also has some limitations. Despite being a retrospective evaluation, cases were selected consecutively to minimize bias. Secondly, as there was no control arm (patients not receiving sorafenib), a clear distinction between the prognostic and predictive role of HTN in terms of survival could not be made. Although multivariable analysis indicated that HTN was an independent variable, it cannot be ruled out that results were biased by the relatively small sample number.In conclusion, sorafenib-related HTN is potentially predictive factor associated with significantly longer OS and PFS in patients with advanced HCC.st July 2013 and 25th March 2015 at our institute (IRST IRCCS) in Meldola, Italy. Seventy-eight patients with advanced or intermediate stage HCC that was refractory or no longer amenable to locoregional therapies (according to American Association for the Study of Liver Diseases guidelines) were eligible for our analysis. All patients received a standard sorafenib regimen (400 mg bid continuously), dose reductions being made if deemed clinically necessary. Follow-up consisted of CT/MRI scanning every 8 weeks or as clinically indicated. Tumor response was evaluated by modified Response Evaluation Criteria in Solid Tumors (mRECIST) [This retrospective cohort study included all the patients treated for HCC between 1mRECIST) . Treatmeth June 2010.Patients were monitored as follows: days 1, 15, 28 and 60 of cycle 1, and every 2 months thereafter. Disease progression was assessed using mRECIST. Electrolytes were measured on days 1 and 15 of treatment. HCC patients without cirrhosis were excluded from the study. BP was measured on days 1 and 15 of treatment. Patients who had uncontrolled blood pressure at baseline (systolic BP >140 mm Hg and diastolic BP >90 mm Hg) were excluded from the study. HTN was defined as either a maximum or mean systolic BP (SBP) of at least 140 mm Hg or diastolic BP (DBP) of at least 90 mm Hg. HTN grade was defined according to the Common Terminology Criteria for Adverse Events (CTCAE) of the National Cancer Institute, version 4.03 of 14This study was approved by the local Ethics Committee and informed consent was obtained from all patients.The primary objective of this study was to compare progression-free survival (PFS) between patients who developed HTN and those who showed no signs of HTN during the first 15 days of treatment with sorafenib. Our second objective was to evaluate changes in blood electrolytes (sodium and potassium) in patients with HTN compared to those without HTN during the same period. We also planned to compare overall survival (OS) and disease control rate (DCR) between the 2 groups.Appropriate descriptive statistics were used for demographic and tumor characteristics. Mean, median, standard deviation and minimum and maximum values were reported for continuous variables, while count and proportion were reported for non-continuous variables. PFS was defined as the time from the start of sorafenib therapy until disease progression or death from any cause or last follow-up visit. OS was defined as the time-interval between the start of sorafenib therapy and death from any cause or last follow-up visit. PFS, OS and their two-sided 95% confidence intervals (95% CI) were estimated by the Kaplan-Meier method and curves were compared by the log-rank test (at a significance level of 5%). DCR was defined as the proportion of patients to achieve complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD) according to mRECIST.Estimated hazard ratios (HRs) and their two-sided 95% CI were calculated using the Cox proportional-hazard model. After univariate analysis, a multivariable Cox regression model  was used to adjust for these potential confounding factors. We investigated the potential association between HTN/blood electrolyte levels and disease progression, in particular using nonparametric tests to examine the relationship between changes in raw data and disease status of the 2 sequential blood tests.All p values were based on two-sided testing and statistical analyses were performed using SAS statistical software version 9.3 ."}
+{"text": "Mevalonate kinase deficiency (MKD) is a rare autoinflammatory syndrome, characterized by febrile episodes and generalized inflammation.This study aims to describe the genetic and phenotypic characteristics of MKD in a large international patient cohort.Patients were enrolled in the Eurofever registry (EAHC Project No. 2007332), a registry that retrospectively collects information on patients suffering from periodic fever. An expert on MKD validated all patients on clinical and genetic criteria.MVK mutations were included in this study. The median age of onset was 0.5 years. The median follow up period was 11.5 years. The majority of the patients were Caucasian (90%). Ninety-six patients harboured at least one V377I mutation, fourteen of them had a homozygous V377I mutation. The second most frequent mutation was I268T occurring in 29 patients.One hundred and fourteen patients  with two Ninety-nine of 114 patients had recurrent inflammatory episodes, while six patients suffered from a chronic course and nine patients had a chronic course with exacerbations. The median disease duration was five days. The median frequency was 12 per year. Triggers inducing febrile episodes were mentioned in 108 patients, the most important ones were vaccination (n=39), infection (n=18) and stress (n=26).One hundred and twelve patients suffered from gastrointestinal complaints, most of them suffering from vomiting (69%), diarrhoea (84%) and abdominal pain (88%). Ninety-nine patients also experienced mucocutaneous symptoms, mainly pharyngitis (28%), stomatitis (60%) and maculopapular rash (39%). Seventy-one percent of all patients had arthralgia and 57 percent had myalgia. Arthritis was less common and occurred in 28%. Neurological complaints occurred in 46 patients, most of them suffering from headache (38%). Cerebellar syndrome (3%), mental retardation (4%) and seizures (5%) were noted in some patients. Many patients had constitutional symptoms, such as malaise (65%), weight loss (66%), fatigue (63%) and mood disorders (24%). AA-amyloidosis was noted in six patients. One patient suffered from macrophage activation syndrome, a life-threatening complication characterized by high fever, pancytopenia and liver damage.Abnormal IgD levels were observed in 55 of 76 tested patients, while 37 of 40 tested patients showed elevated urinary mevalonic acid excretions. Inflammatory parameters, such as erythrocyte sedimentation rates (98%), C-reactive protein (94%) and white blood count (66%), were abnormal in many patients.This study describes the clinical and genetic characteristics of 114 MKD patients, which is the largest cohort so far."}
+{"text": "Omalizumab is a monoclonal anti-IgE antibody approved for the treatment of severe allergic asthma in patients (pts) older than 6 years in Europe. Its efficacy in other IgE-mediated diseases has been the target of several recent studies.Evaluate the safety and efficacy of omalizumab use in allergic pts aged 6 to 18 years, followed in our Immunoallergology Department.We retrospectively analyzed the clinical files of all pediatric pts treated with omalizumab from December 2009 to July 2013. The evaluated parameters included: adverse reactions to omalizumab, clinical evolution, Asthma Control Test (ACT) and Severity Scoring of Atopic Dermatitis (SCORAD) score evolution and medication decrease. Statistical significance was defined by a p value in the appropriate nonparametric test lower than 0.05.Ten pts  were proposed for treatment with omalizumab due to severe uncontrolled allergic disease: all pts had severe allergic asthma, in 3 cases uncontrolled without oral corticosteroids (OCS). Furthermore, 5 children had severe eczema (SCORAD>40), 1 had severe allergic conjunctivitis (AC), 1 was allergic to cow\u2019s milk and experienced multiple anaphylactic events in the course of milk specific oral tolerance induction (SOTI).This pediatric cohort has been treated with omalizumab for an average of 12 [1-42] months. No adverse reactions were attributable to its administration. Average pretreatment ACT scores were 17 [15-19] and improved significantly (p<0.01) after 16 weeks of treatment to 23 [20-24]. In eczema pts, SCORAD also improved significantly (p<0.01) after 16 weeks from 62 [34-90] to 24 [13-35]. All children discontinued OCS: After 2 months in the asthmatics and 3 months in the child with AC. One child with eczema discontinued cyclosporine and one child reduced his daily dose of azathioprine after 1 month. Due to controlled disease, 2 pts were able to initiate specific immunotherapy. A successful cow\u2019s milk SOTI  was possible after 3 administrations of omalizumab.In this pediatric cohort, omalizumab was safe and effective not only in the control of asthma but also of other uncontrolled allergic diseases. Furthermore, it allowed for disease-altering immunotherapies to be initiated. Additional studies are warranted for the use of omalizumab in non-asthmatic allergic children, however its role seems promising."}
+{"text": "Invasive fungal infections still have high morbidity and mortality rates, especially in immunocompromised patients, given the lack of specific symptomatology and of fast and early diagnosis methods.We present a retrospective study performed between January 2011 \u2013 June 2014 in the National Institute of Infectious Diseases \"Prof. Dr. Matei Bal\u015f\", including patients with invasive fungal infections and complete clinical and biological data.Cryptococcus neoformans in 8 cases (40%) and Candida spp in 12 cases (60%), out of which 75% consisted of non-albicans species. The invasive fungi were isolated from blood cultures in 9 cases (52.4%), cerebrospinal fluid in 8 cases (38.1%), tips of central venous catheters in one case and from other pathological products in one case. The average period from admission to identification was 9.6 days. The antifungal susceptibility test indicated that 16 out of the 20 cases (80%) were sensitive to fluconazole and only 20% were dose-dependent sensitivity types. The patients were treated mainly using monotherapy \u2013 1 antifungal in 10 cases (55%). Fluconazole was the most used agent, in 14 cases (77.8%) followed by voriconazole in 7 cases and posaconazole in 4 cases. The average treatment duration was 37.7 days, the shortest being one day, and the longest 120 days. 6 out of 18 patients (33.3%) deceased: one patient presenting severe bacterial infection treated with prolonged antibiotherapy and 5 presenting C. neoformans meningitis associated with HIV infection.18 patients met the inclusion criteria for the studied period, representing 40% of the patients with potentially invasive fungal infections. The majority of patients were male, and the average age was 44 years. Only 2 of the patients apparently were not immunocompromised, the other 16 presenting HIV infection or fungal infections risk factors. The fungal species identified were Although proper treatment was administered, the mortality in invasive fungal infections remains high, given the fact that they generally appear in already marred or severely immunosuppressed patients."}
+{"text": "The ACR recommendations for the treatment of Juvenile Idiopathic Arthritis (ACR-JIA) were published in 2011 with the aim of providing an evidence-based therapeutic pathway for effective JIA treatment.Our aim was to determine the feasibility of applying ACR-JIA to a real-life paediatric JIA cohort and to evaluate the treatment pathway of those children.We conducted a retrospective analysis of a single-centre paediatric JIA cohort. This included a review of the patient case notes, radiology and drug monitoring data of all children with JIA diagnosed with multi-joint (5 or more joint) disease in the 2 years since ACR-JIA were published.In total, 35 patients fulfilled ILAR criteria for the diagnosis of JIA since 2011: systemic arthritis (n=5), polyarthritis (n=25) and extended Oligoarthritis (n=5). Duration to Methotrexate and Etanercept treatments was calculated, and the frequency of drug monitoring noted.25 females and 10 males  were included in the evaluation. Median age at disease onset for poly/extended oligoarthritis was 10 years (1.5-16), with a median of 12 joints (12-38) active at presentation, and for the systemic group median age at onset was 6 years (2-7), with a median number of 6 active joints (2-10). 3 polyarthritis patients were rheumatoid factor positive (0 extended oligoarthritis and 0 systemics). 22/30 patients with polyarthritis/extended oligoarthritis followed the ACR recommendations for treatment according to their disease severity, commencing methotrexate therapy within a median of 6 weeks (3-37) of diagnosis and etanercept (where relevant) within a median of 7 months (3-24) of diagnosis. 7 patients did not follow ACR-JIA guidelines due to experiencing excessive durations (for disease severity) between diagnosis and commencing methotrexate or etanercept treatment. One patient did not have sufficient regular drug monitoring tests. All patients with systemic arthritis followed the ACR-JIA recommendations for treatment and drug monitoring.Overall, 27/35 patients followed the ACR-JIA recommendations. This evaluation highlights the difficulty of achieving rapid commencement of new JIA therapies and the challenging of regular drug monitoring.None declared."}
+{"text": "There are different classification systems for allergic rhinitis (AR) severity, whose are used to guide treatment. Clinical observation suggests that ARIA method, made by doctors, and visual analogic scale of symptoms (VASS), made by patients, do not obtain the same results in many occasions. The aim of this study was to compare the results of these methods applied at the same time in a cohort of adolescents and adults with AR under specialized outpatient care.Retrospective study of clinical records of patients with AR in treatment between March-2011 and August-2012 at an university hospital in Rio de Janeiro/Brazil, where both classifications have been used routinely since 2010. Four hundred clinical sheets were reviewed, we excluded patients under 12 years old, without at least one cutaneos test positive to aeroallergens and those with incorrect clinical data. Kappa coefficient (Stata 11) was used to measure agreement between them using 2 (mild and moderate/severe), 3  and 6 categories , according to original and modified ARIA classifications.We included clinical records of 124 patients: 88 were women (71%), the median age was 39 years (perc25-75=17-55) and 77 (62%) had associated asthma. Using ARIA modificated method , they were classified as mild=55 (44.3%), moderate=56 (45.1%) and severe=13 (10.4%). Using VASS, patients classified themselves as mild=35 (28.2%), moderate=68 (54.8%) and severe=21 (16.9%). Kappa analysis in the entire sample showed low agreement at 2, 3 or 6 comparison levels between the classifications . The classifications were different in 51 (41.1%) patients when we compared 3 level of severity with lower agreements at 3 or 6 levels of comparison in females, in patients older than 18 years and in those with associated asthma. Better concordance was achieved in patients younger than 18 years , in patients without asthma (moderate) and in males (moderate).Our findings suggest that many patients have a different perception of severity of their disease using VASS when compared with results from ARIA classification, with a low to moderate concordance between the two methods. Presence of asthma, age and gender seems to influence these results. Large studies comparing the outcomes using both methods to guide treatment may help us to define the better one to make therapeutic decisions in clinical practice."}
+{"text": "With the widespread use of combination antiretroviral therapy (cART), life expectancy of HIV-infected patients has significantly prolonged. An increasing number of HIV-infected patients are aging and concurrent use of medications are not uncommon for management of metabolic complications and cardiovascular diseases related to aging and prolonged exposure to cART.We reviewed medical records of all HIV-infected patients aged 40 years or older who had been followed at a university hospital for HIV care in Taiwan between January and December 2013. A standardized case record form was used to collect information on demographics and clinical characteristics, comorbidity, cART, and concurrent medications.10 copies/ml); and to have diabetes mellitus (18.4% vs 4.6%), hypertension (31.0% vs 10.8%), hyperlipidemia (29.4% vs 11.6%), coronary artery disease (6.8% vs 0.5%), and an estimated glomerular filtration rate <60 ml/min/1.73 m2 (11.5% vs 2.7%); and were significantly less likely to have syphilis. Other than HIV infection, patients aged 50 years or older were more likely to have been receiving two or more concurrent medications than those aged 40 to 49 years (22.9% vs 6.4%).During the study period, 610 patients aged 40 to 49 years  and 310 aged 50 years or older  sought HIV care at this hospital. Compared with patients aged 40 to 49 years, those aged 50 years or older were significantly more likely to be female (15.9% vs 3.8%); to have received cART (97.7% vs 94.8%) and a lower plasma HIV RNA load (1.6 vs 1.7 logOur findings show a significant proportion of the HIV-infected patients aged 50 years or older have multiple comorbidities that may increase the risk for cardiovascular and renal complications. Issues of poly-pharmacy among the HIV-infected patients who are aging should be addressed to ensure adherence and minimize drug-drug interactions. The widespread use of combination antiretroviral therapy (cART) has markedly improved the survival of HIV-1-infected patients Prolonged exposure to antiretroviral therapy along with aging may increase risk of developing metabolic complications and cardiovascular diseases among HIV-infected patients. Several studies have provided evidence that comorbidities such as diabetes mellitus The prevalence of HIV-1 infection continues to increase with improvement of accessibility to HIV testing and care in Taiwan After the first case of HIV-1 infection and AIDS was reported in Taiwan in 1984, the number of patients diagnosed as having HIV infection through sexual contacts continued to increase steadily over the next two decades HIV-infected patients in Taiwan are provided with free medical care at designated hospitals around Taiwan by the government of Taiwan, including cART that was introduced in April 1997, and monitoring of CD4 lymphocyte count and plasma HIV RNA load. As of December 2012, it was estimated that 60% of HIV-infected patients sought HIV-related care and initiated cART after the diagnosis of HIV infection was made.This was a cross-sectional study that enrolled HIV-infected patients who were aged 40 years or older and sought HIV care at the HIV clinics of the National Taiwan University Hospital from 1 January, 2013 to 31 December, 2013. Two age groups were identified: patients aged 40\u201349 years and those aged \u226750 years. We collected information on their baseline demographics, clinical characteristics, and medications including antiretroviral therapy, antihypertensives, lipid-lowering agents, and insulin and oral hypoglycemics. Data on comorbid conditions, including hypertension, diabetes mellitus, chronic viral hepatitis, cardiovascular disease, hyperlipidemia, fracture, malignancy, and osteoporosis and information on smoking status and alcohol use were also collected by interview, which were confirmed by review of medical records. The study was approved by the Research Ethics Committee of the National Taiwan University Hospital (registration number: 200904020R) and participants gave written informed consent.Systolic and diastolic blood pressure was measured after the subjects were seated and rested for at least five minutes. Height was determined without shoes by the same machine. Weight was measured by a digital scale, and patients were fully dressed but without shoes or heavy clothing. Body mass index (BMI) was calculated as weight in kilograms divided by the square of the height in meters. Because diabetes mellitus is considered coronary artery disease-equivalent, we examined the status of diabetes mellitus control by retrospectively collecting laboratory data of fasting glucose, glycosylated hemoglobin (HbA1C) among those who received a diagnosis of diabetes mellitus from 1 January, 2012 to 31 December, 2013.Total cholesterol, triglyceride, glucose, HbA1C, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein-cholesterol (LDL-C) levels were determined after at least an 8-hour fast. The data of most recent plasma HIV RNA load, CD4 lymphocyte count, blood urea nitrogen, serum creatinine, estimated glomerular filtration rate (eGFR) that was calculated with the use of the abbreviated Modification of Diet in Renal Disease (MDRD) equation Comorbid conditions were defined by the ICD-9 diagnostic codes or in those who took antihypertensives, hypoglycemics, or lipid-lowering agents. Chronic hepatitis B virus (HBV) infection was defined as presence of HBV surface antigen for 6 months or longer. Hepatitis C virus (HCV) infection was defined as presence of HCV antibody. Osteopenia and osteoporosis were defined on the basis of World Health Organization (WHO) criteria CART was defined as the use of at least 3 agents from at least 2 classes of antiretroviral agents according to the national treatment guidelines for adults with HIV infection. The most commonly prescribed antiretroviral combinations in antiretroviral-naive patients were 2 nucleoside reverse-transcriptase inhibitors (NRTIs) plus 1 non-NRTI (nNRTI), 2 NRTIs plus ritonavir-boosted protease inhibitor (PI), unboosted atazanavir or raltegravir, while triple NRTIs or combination of 3 classes were only infrequently prescribed. Ritonavir was available only in capsule form.2 tests for continuous variables were compared using Student's t test. Baseline and comorbid conditions were compared with two groups. A P-value of <0.05 was considered statistically significant. All P value was two-tailed. Analyses were performed using SAS software (Version 9.3).Categorical variables were analyzed by using X2.During the 12-month study period, 920 patients who were aged 40 years or greater were enrolled, among whom 310 (33.7%) and 610 (66.3%) were aged \u226750 years (elderly group) and 40\u201349 years (younger group), respectively . Clinica10 copies/ml) and BMI (22.9 vs 23.4 Kg/m2) (The two groups of patients differed significantly in many characteristics examined . Compare4 Kg/m2) . Compare4 Kg/m2) , such asOf the 920 patients, 76 (8.3%) were taking oral hypoglycemic agents or receiving insulin replacement for control of diabetes mellitus, 102 (11.1%) lipid-lowering agents, 142 (15.4%) antihypertensives, and 159 (17.3%) hypnotics drugs . More thCompared with those in the younger group, HIV-infected patients in the elderly group were more likely to take medications for management of comorbidities: oral hypoglycemic agents or insulin replacement (16.5% vs 4.1%), lipid-lowering agents (19.4% vs 6.9%), and antihypertensives (26.5% vs 9.8%) . Other t2), higher systolic blood pressure (134 vs 127 mmHg), higher triglyceride level (260 vs 195 mg/dl), lower eGFR (82.7 vs 96.7 mL/min), and lower plasma HIV RNA load (1.5 vs 1.7 log10 copies/ml).The comparisons of clinical characteristics of 85 patients (9.2%) with diabetes mellitus and 835 patients (90.8%) without diabetes mellitus are shown in Because diabetes mellitus is related to long-term metabolic, cardiovascular and renal complications, we examined the status of control by assessing the fasting glucose and HbA1C data of the patients with diabetes mellitus. All of the available results of blood sampling in fasting state (n\u200a=\u200a270) of 85 patients with diabetes mellitus over the 12-month follow-up were stratified into 4 groups : group 1In this cross-sectional study, we found that HIV-1-infected Taiwanese patients who were aged 50 years or older had significantly more comorbidities than those who were aged 40\u201349 years. Polypharmacy was not uncommon in that more than 20% of the elderly patients were taking 2 or more concurrent medications in addition to cART for HIV infection.The prevalence of the elderly group with 2 or more comorbidities is higher than younger group in our study (30.6 vs. 8.6%), which is similar to what have been observed in HIV-infected elderly patients with access to cART in many Western countries With the increasing prevalence of comorbidities, it is not surprising that, other than antiretroviral therapy, use of concomitant medications for management of comorbid diseases were common in our patients. It is therefore important to note some of the negative consequences as a result of polypharmacy. The patients taking multiple drugs for many chronic medical conditions are at potentially increased risk of drug-drug interactions and adverse drug events The prevalence and incidence of diabetes mellitus are increasing worldwide, especially in the elder patients regardless of the status of HIV infection Using Taiwan National Health Insurance data, Jiang et al have found that the prevalence of DM among women and men aged 40 to 59 years increased from 4.63% to 5.47% and from 4.97% to 7.56%, respectively, between 2000 and 2009 In our study, we found that diabetes mellitus was associated with older age and higher BMI, which are consistent with other studies 2 in our elderly patients was 11.5%, which is higher than those in other studies among the HIV-infected population from Brazil (3.9%) Renal function in terms of eGFR usually decreases with age. The prevalence of eGFR<60 mL/min/1.73 mWhile most of patients in this study were receiving cART with good control of HIV infection, the finding of a high prevalence of syphilis is of particular concerns, especially in the patients aged 40 to 49 years There are several limitations of our study. First, it is a cross-sectional survey of patients who sought HIV care at a university hospital. The information examined is mainly from laboratory data that were accumulated during the clinical care. Many other comorbidities were not systematically examined, such as osteoporosis and malignancy. Second, the exposure duration to cART was not taken into consideration in comparisons made between the two age groups. Third, we did not have an HIV-uninfected population for comparison in terms of the frequency of comorbidity. Therefore, it is not known whether the frequency of any comorbidity examined in this study is higher in HIV-infected patients than in HIV-uninfected patients in Taiwan, although several studies have suggested that cART and HIV infection may accelerate aging and increase risk of metabolic, cardiovascular and renal complications In conclusion, our findings show that a significant proportion of the HIV-infected elderly patients In Taiwan have multiple comorbidities that may increase risk for cardiovascular and renal complications. Issues of poly-pharmacy among the elderly with HIV infection should be addressed to ensure adherence and minimize drug-drug interactions. Comprehensive approach to the management of metabolic, cardiovascular and renal comorbidities cannot be overemphasized in the long-term successful management of HIV-infected elderly population.Figure S1The scattered plot of glycosylated hemoglobin (HbA1C) and fasting glucose data collected from the 85 patients with diabetes mellitus during the 12-month study period. PI, protease inhibitor-containing regimens.(TIF)Click here for additional data file.Table S1Comparisons of demographic and clinical characteristics of the patients with and those without diabetes mellitus.(DOCX)Click here for additional data file."}
+{"text": "To the Editor: Porcine coronavirus (PorCoV) HKU15 is a single-stranded, positive-sense, enveloped RNA virus belonging to the genus Deltacoronavirus (family Coronaviridae). PorCoV HKU15 was first identified in 2012 in a surveillance study from China (http://www.oie.int/wahis_2/public/wahid.php/Reviewreport/Review?page_refer=MapFullEventReport&reportid=15133).We recently reported the detection of PorCoV strain HKU15-OH1987 in feces samples from sows and intestine samples from piglets in Ohio, United States; the infected animals were from swine farms where outbreaks of diarrheal disease had occurred in late January and early February 2014 . Furthermore, all of the isolates share high nucleotide similarity (98.9%\u201399.2%) with the 2 PorCoV HKU15 strains in GenBank, HKU15-155 and HKU15-44. To determine the genetic diversity of PorCoV HKU15 strains from the 9 states, we conducted whole-genome sequencing for 1 strain from each state by using 16 pairs of previously described, overlapping primers , data collected on the geographic location and numbers of PorCoV HKU15 cases is also required to be reported weekly. In addition to the 9 states reported in this study, Iowa has also had a recent detection of PorCoV HKU15 . As withDeltacoronavirus spp. , including 9 US strains of porcine coronavirus HKU15.Phylogenetic tree of 4 genera of coronaviruses ("}
+{"text": "To describe the main indications, doses, infusion length and side effects of dexmedetomidine (DEX) administered to children and adolescents admitted to the pediatric ICU (PICU).A retrospective observational study including children (<18 years) admitted to a Brazilian PICU who received DEX between November 2011 and June 2014. Demographic data, indications, initial dose, maximum dose and time of infusion of DEX, side effects and impact on heart rate (HR) and mean arterial pressure (MAP) 6 and 24 hours after the start of infusion.P = 0.798 and 0.379, one-way ANOVA, respectively). In six patients (8%) DEX was suspended for possible side effects.A total of 77 children with a median age of 15 (4 to 84) months, weight of 10 (5.7 to 20) kg and length of ICU stay of 8 (5 to 14) days received DEX, with a mortality rate of 9%. Indications were: weaning from mechanical ventilation (32.5%), neurosurgical postoperative (NCI) and upper airway surgery (VAS) (24.7%), non-invasive ventilation (13%), refractory tachycardia (6.5%) and other indications (23.3%). There was no difference between the initial and maximum doses and infusion length. There was a significant decrease in MAP and HR after 6 hours infusion of DEX in the total group; however, no significant difference occurred between groups when analyzing MAP and HR 24 hours after the start of infusion (Increased DEX indications have been observed in the pediatric population. In this study DEX was demonstrated to be a safe and tolerable drug with few side effects, especially related to the cardiovascular system."}
+{"text": "Hepatitis C virus is one of the major causes of parenterally acquired hepatitis. HCV genotypes exhibit different profiles of pathogenicity, infectivity and response to antiviral therapy. The study was taken up to detect HCV seropositivity and common genotype prevalence in a tertiary care hospital. The other objectives of the study were to detect probable risk factors and HIV/HBV co infections.The duration of study was 2 years. Adult patients clinically suspected of hepatitis, blood donors attending blood bank, pregnant women attending ANC clinic, renal dialysis patients and patients whose blood samples were received for pre-operative evaluation, were the subjects of the study. Serum was subjected to ELISA for anti-HCV antibody detection. Plasma collected from seropositives, genotyped by RealTime PCR. In accordance with prevalence of seropositivity same number of controls were randomly selected and analysis done for association with risk factors using Chi square test.p value 0.004). Rate of HCV-HBV co infection was 6.25% (2/32) and HCV-HIV co infection was 3.12% (1/32). No concomitant HCV, HIV and HBV infection was detected. 12 samples were HCV Genotype 1(60%), 8 were Genotype 3 (40%) and 5 were untypeable.Of the 3581 serum samples screened, 32 were anti-HCV antibody positive (0.89%). Highest number of HCV seropositivity found between 41-50 years (40.62%). Blood transfusion was found to be highly significant risk factor (Blood transfusion is a major risk factor for HCV infection and genotype 1 predominates over genotype 3 in this region."}
+{"text": "Surveillance of antimicrobial consumption is a necessary step to develop and monitor policies to limit antimicrobial overuse/misuse and to decrease the risk of bacterial resistance. In Saudi Arabia, such surveillance data are lacking.To quantify the carbapenems use in intensive care unit (ICU) setting and to detect any variability by ICU type.We conducted a prospective surveillance study in eight different ICUs; five adult and three pediatric/neonatal ICUs at King Abdulaziz Medical City, Riyadh, Saudi Arabia, Riyadh, from October 2012 through December 2013. We estimated the consumption of carbapenems as days of use (which was defined as the aggregate sum of days for which any amount of meropenem or imipenem were administered) per 1000 bed-days or 100 admissions.We recorded carbapenem use for more than 3500 bed-days during 15 months in 8 ICUs having a total 131 bed capacity. The overall carbapenem use was estimated at 133.7 days of use per 1000 bed-days and 150.8 days of use per 100 admissions. The use per bed-days was highest in adult medical surgical ICU (357.0) followed by adult step-down (232.4) and burn (195.4) ICUs but lowest in neonatal ICU (27.7) and adult cardiothoracic ICU (64.9). The use per admissions was highest in adult step-down ICU (467.8) followed by burn (394.9) and adult medical surgical (384.0) ICUs but lowest in adult cardiothoracic (31.2) and pediatric medical-surgical (58.9) ICUs.Approximately, our ICU patients use carbapenems one-eighth of the days spent. There is wide variability in carbapenem use in different ICUs that warrant ICU-specific reporting and pinpoint areas that need more management attention. There is need to identify patient and physician characteristics associated with this high carbapenem consumption.None declared."}
+{"text": "Galactosemia is an autosomal recessive metabolic disorder caused by the deficiency of enzymes involved in galactose metabolism resulting in complications like cataracts, hepatocellular damage and developmental delay. Nonetheless, no report is available on mutations in galactosemia genes from our population. The objective of the present study was to determine blood GALT and GALK activity in infants with cholestasis and congenital cataracts and to establish a spectrum of mutations in GALT and GALK genes.430 infants (2 days-11 months) with cholestasis admitted in Pediatric Gastroenterology over 3.5 years were evaluated for galactosemia. Basic investigations included hemogram, liver function tests, blood culture, urine culture, urine for non-glucose reducing substances and eye evaluation. Screening for GALT deficiency was done using Perkin\u2013Elmer neonatal GALT kit. The levels of galactose-1-phosphate were also measured. Also, 115 patients with congenital cataracts were screened for the galactokinase (GALK) deficiency. Mutation analysis for most common Q188R and N314D mutations in GALT gene was performed by Restriction Fragment Length Polymorphism (RFLP). Single Stranded Conformational Polymorphism (SSCP) analysis and subsequently DNA sequencing were done for identification and characterization of unknown and novel mutations in GALT and GALK genes.55 (12.7%) infants were found to have reduced GALT activity with male: female: 37:18, jaundice in 55 (100%), hepatomegaly in 54 (98%), splenomegaly in 32 (58%), coagulopathy in 23 (42%), encephalopathy in 9 (16%), septicemia in 10 (18%) and cataracts in 12 (22%) were observed. Increased galactose-1 phosphate levels were fraternized with reduced activity of GALT. A total of 16 mutations and 4 polymorphisms were detected. 10 were novel mutations. Reduced blood galactokinase activity was found in 13 (10.2%) patients with congenital cataracts. 4 novel mutations were found in GALK gene.N314D mutation was found to be the most common mutation in our population. 10 and 4 novel mutations were also detected in GALT and GALK genes respectively."}
+{"text": "Various studies1,2,3,4 investigated the effectiveness of 2 % CHG cloths compared with the use of traditional bathing (soap and water) or pre - impregnated cloths with soap solution (no antiseptic) for the reduction of MDROs acquisitions and blood-stream infections in Intensive Care Unit settings.Healthcare Associated Infections (HAI) in Intensive Care Units (ICU) settings are still a challenge; skin decontamination is a recommended intervention to interrupt pathogen transmission through \u201csource control\u201d3. Afterwards, since October 2013, a new procedure was introduced to extend daily bathing with 2 % CHG cloths to all patients in the ICU 3. Patients between periods had similar characteristics.The system used for daily patient hygiene at the General Intensive Care Unit (ICU) of the Rimini hospital until April 2013 consisted of a \u201ctraditional\u201d method (water and soap). Since May 2013, 2 % CHG cloths (Sage Products LLC) were introduced for the daily bathing of colonized/infected patients (targeted decolonization)Results compare two periods in which data were collected and analyzed: Period A - November 2012 / April 2013 - 6 months of daily hygienewith soap and water - Pre - intervention.Period B - October 2013 / July 2014 - 10 months of daily hygiene with 2 % CHG cloths  Intervention. Number of patients Colonized/Infected: decreased by 51.21% . Positive blood cultures decreased by 68.32 %  Return on investment(ROI): estimated decrease of 50% of the total costs, intervention period vs. pre-intervention period.Daily bathing with 2% CHG cloths significantly reduces the number of patients colonized/infected and MDRO acquisitions. The results and the estimated ROI obtained at the General Intensive Care Unit(ICU) of the Rimini hospital, confirm the opportunity of implementing a universal decolonization protocol in ICU settings.None declared."}
+{"text": "Lung abscesses and gangrene are the most severe clinical manifestation and outcome among acute purulent destructive pulmonary disease (APDPD). Mortality ranges from 10 to 35%, and in the presence of diabetes increases up to 30 to 90% ,3. The an = 246). We carried out computed tomography, ECG, echocardiography, laboratory biochemical testing, and bacteriological analysis of pathologic material and blood samples.During the period 2012 to 2013, we examined 408 patients aged 48.5 \u00b1 12.5 years (258 men/150 women) who underwent surgical treatment for APDPD. The patients were divided into two groups: 144 patients with type 2 diabetes, and controls (P = 0.002), and the duration of inpatient treatment was significantly longer . Only 53 (36.8%) of patients with type 2 diabetes and 68 (29.5%) without it had bacteriological positive blood culture. The analysis of the distribution of pathogens in groups is presented in Figure Candida spp. (Figure Patients with type 2 diabetes had much more complications and cases of severe sepsis and septic shock Table . BacteriIn patients with acute purulent destructive pulmonary disease and type 2 diabetes, severe sepsis and septic shock more often prevailed, inpatient mortality rate was 2.27 times higher, compared to patients with normal glucose metabolism."}
+{"text": "Two live rotavirus oral vaccines, RotaTeq (RV5)  and Rotarix RV1)  , are app GlaxoSm of rotavThere were 39 reports of administration by injection (33 for RV1 and six for RV5). This included a cluster of six reports involving RV1 by a nurse who did not receive proper training or read the package insert. Nineteen of the 39 reports (49%) documented an adverse event; irritability (seven cases) and injection site redness (five) were the most commonly reported adverse events. Thirty of 39 reports (77%) did not have an explanation for the error; for those that did, reasons included misinterpreting package insert instructions, confusing the RV1 oral applicator syringe with a syringe for injection, confusing the RV1 vial with a vial used for injectable vaccine, inadequate training, and not reading the package insert.There were 27 reports of eye splashes. In 21 cases, infants coughed, sneezed, or spit vaccine into the eyes of vaccination providers (17), parents (one) or themselves (three). Nonserious adverse events consistent with minor eye irritation were described in 21 of the 27 reports.As a passive surveillance system, VAERS might capture only a small fraction of vaccine administration errors. However, with approximately 55 million doses  distribu"}
+{"text": "To determine diagnostic yield of Closed Pleural Biopsy (CPB) and Cytology in Exudative Pleural Effusion (PE).This prospective comparative study was conducted at Chest Unit-II & Medical Unit-IV of Dow University of Health Sciences, Karachi Pakistan from January 2011 till December 2014.Ninety-four patients with exudative PE were finally included. The mean age (SD) was 44.0 (13.8) years. Overall Specific Diagnosis was reached in 76/94 patients; 46 Tuberculosis PE (TPE) & 30 Malignant PE (MPE). CPB diagnosed all TPE patients alone and 28/30 of MPE. Cytology diagnosed only 10/30 patients of MPE with 8 patients having both CPB & Cytology positive for malignancy whereas in the remaining two cases only Cytology positive. The sensitivity of CPB in detecting TPE and MPE was 93.9% and 82.4% respectively whereas specificity for both was 100%. The diagnostic yield of cytology in detecting MPE is only (33.3%). The diagnostic yield of CPB for TPE and MPE is 100% and 93.3% respectively. The overall specific diagnostic yield of CPB is 78.7%.CPB is better than pleural fluid cytology alone with the later adding little to diagnostic yield when both combined in distinguishing TPE from MPE, the two main differential of exudative PE in a TB-Endemic country. This will help us evaluate two diagnostic modalities and thus will have a positive impact on clinical practice in our area. CPB is an inexpensive and easily learned procedure and its validity will ensure easy, economical and early diagnosis. This will lead to better and early treatment of patients.This prospective study was carried out in Chest Unit-II of Ojha Institute of Chest Diseases and Medical Unit-IV Civil Hospital Karachi, both arePostgraduate Tertiary Care Hospitals affiliated with Dow University of Health Sciences Karachi, Pakistan from January 2011 till December 2014 for a period of four years. Study has approval of Institutional Review Board of Dow University of Health Sciences vide letter # IRB-670/DUHS/Approval/2015/135. Proforma included fields for routine basic investigations, sputum AFB smear x2 and chest radiographic findings. Data was also recorded for Pleural fluid DR, Gram\u2019s stain, Routine Culture and Sensitivity (CS), AFB smear and cytology. Only those found to have exudate type of PE  with minimum of 50 mL of pleural fluid sent for Cytology were included in the study.Mean age with Standard Deviation(SD) of selected patients was calculated and compared among groups based on results of CPB by ANOVA. Pleural fluid cytology findings were also compared by ANOVA. Sensitivity and Specificity and both positive and negative predictive values for CPB were calculated by using a decision matrix.11A total of 94 patients meeting inclusion criteria were selected. The mean age (\u00b1SD) was 44.0 (13.8) years. Overall Specific Diagnosis was reached in 76/94 patients (46 TPE & 30 MPE). CPB diagnosed all TPE patients alone and 28/30 of MPE respectively. Cytology diagnosed only 10/30 patients of MPE with 8 patients having both CPB & Cytology positive for malignancy whereas in the remaining two cases CPB was negative but Cytology positive. As shown in CPB revealed four patterns; Pleural Tuberculosis , Malignancy , Nonspecific Inflammation  and Inconclusive . The mean age (SD) according to the patterns of CPB was 40.9 (13.8) years in TB, 48.1 (13.0) years in Malignancy, 44.0 (13.5) years in Nonspecific Inflammation and 45.9 (14.2) years in Inconclusive. Testing for difference in age according to pattern of CPB using ANOVA within group analysis, we did not find any significant difference .Pleural fluid Cytology had only two groups; Non Malignant  and Malignant . Analysis of mean age (SD) according to groups on cytology was 43.3 (13.4) years in nonmalignant group and 50.0 (16.0) years in malignant group. No significant difference was observed on within group ANOVA analysis .Out of 28 patients confirmed with Malignancy on CPB; only 08 (28.6%) showed malignant cells on Pleural Fluid Cytology whereas in 20 (71.4%) patients with malignancy on CPB, Cytology was negative. Cytology of all the patients diagnosed on CPB as having Pleural Tuberculosis was negative as well. Six patients who had Nonspecific Inflammation on CPB, Cytology also showed no malignant cells whereas 14 patients whose CPB was Inconclusive, two showed malignant cells on Cytology. Details are given in To analyze the cumulative effect of nonmalignant patterns on CPB together along with their malignant component with that of the respective nonmalignant and malignant groups based on pleural fluid cytology; all the nonmalignant patterns  of CPB were merged as one group and analyzed for significance with malignant and nonmalignant findings on pleural fluid cytology using 2x2 table. Significant difference was observed in the malignant and nonmalignant groups of CPB with those of the Pleural Fluid Cytology respectively (p=0.001).The Malignant group based on CPB (n=28) revealed the following histopathological diagnosis:Metastatic Adenocarcinoma (23/28), Mesothelioma (03/28), Squamous Cell Carcinoma (01/28) and B-Cell Lymphoproliferative Disorder (01/28). In two patients in which CPB was negative for malignancy , the Pleural fluid Cytology showed malignant cells. In both of these later cases Metastatic Adenocarcinoma was detected.In total of twenty-five patients with the diagnosis of metastatic adenocarcinoma, the primary origin of malignancy suggested by the Histopathologist was as follows: Lung (11/25), Breast (04/25), Ovarian Carcinoma (02/25), Gastrointestinal (02/25), Renal (01/25), Thyroid (01/25) and in the remaining four cases primary could not be ascertained.The sensitivity of CPB in detecting TPE and MPE was 93.9% and 82.4% respectively whereas specificity for both was 100%. Although some studies on the subject have been published in Pakistani journals; this is the largest study from Pakistan in internationally indexed PubMed Journal with 94 patients; the two others from our country reported on 68 & 63 patients only.15The sensitivity of Closed CPB for detecting TPE and MPE in our study is higher than that reported in various studies (93.9% vs 57%-80% for TPE) and (82.4% vs 40%-73% for MPE) respectively.Our study showed the overall diagnostic yield of CPB was 78.7% which is lower than that reported by Ihsanullah et al.(78.7% vs 95%) and higher than that published by Hussain SF et al. 78.7% vs 46%), both studies are from Pakistan.6%, both 21As shown in 25One explanation for this higher diagnostic yield in our study of CPB over Cytology for detecting MPE is that being a resource-limited country with CPB facility available in a few centers, patients present late with advanced disease implicating more extensive involvement of pleura by malignancy. Besides, the inclusion of patients in our study with clear cut exudative PE, thereby excluding borderline cases which would have decreased the yield, and at least six pleural biopsy tissue specimens, altogether these augment the diagnostic yield.10CPB is better than pleural fluid cytology alone with the latter adding little to diagnostic yield when both combined in distinguishing TPE from MPE, the two main differential of exudative PE in a TB-Endemic country with limited resources."}
+{"text": "Perihematomal edema (PHE) expansion contributes to increased morbidity and mortality after spontaneous intracerebral hemorrhage (ICH). Pathophysiology of PHE is incompletely understood. Recently, the role of cortical spreading depolarizations (CSDs) in secondary brain injury was established in subarachnoid and traumatic brain injury patients. However, the value of CSDs after ICH is not known.2), cerebral blood flow (CBF), cerebral metabolism and intracranial pressure were monitored in the PHE region. Data are presented as median and interquartile range.Patients with ICH fulfilling the inclusion criteria were prospectively enrolled in the observational COSBID study (Co-operative Study on Brain Injury Depolarisations). g.BSamp  connected to PowerLab and LabChart software (Adinstruments) was used for electrocorticography (EcoG). Electrocardiogram patches at the patient's shoulder and bed served as groundings, and a surface reference electrode was glued on the mastoid. The duration of EcoG depressions was defined as the time between depression onset and start of EcoG recovery in the integral of power calculations . Brain tissue oxygen tension (PbtOn = 15) of patients showed expansion of PHE by 25 (10 to 50) ml within 3 to 6 days after bleeding. Neuromonitoring probes were 35 (23 to 58) mm distant from the EcoG strip. CSDs occurred in 73% (n = 11) of patients with PHE expansion. The interval between CSDs was 98 minutes (25 to 308). CSDs were associated with a significant decrease of PbtO2 ; duration 10 (5 to 23) minutes) in 68% (52/77), CBF changes in 95% (19/20) and metabolic derangement in 80% (80/100) of CSDs. PHE expansion was observed in all patients with spreading convulsions (n = 2) and patients with repetitive CSDs occurring as clusters (n = 3).Eighteen patients with ICH (ICH volume: 54 (33 to 69) ml) were analyzed. Hematoma evacuation was performed in 17 patients, one subject underwent craniectomy only. Patients were 60 (55 to 67) years old and 38% female. Monitoring time per patient was 10 (6 to 14) days. A total of 129 CSDs with 16 (10 to 29) minutes of EcoG depression were observed. Eighty-four percent (2 decreases and metabolic derangement. Especially, clusters of CSDs might be associated with detrimental metabolic changes of the perihematomal brain tissue.CSDs are common in ICH patients and associated with perihematomal PbtO"}
+{"text": "Nosocomial infections by the emergence of antibiotic-resistant bacteria are also a real health problem in limited-resource countries. The high frequency of these infections goes along with increased consumption of antibiotics.The aim of this study was to determine drug resistance rate of indicator bacteria isolated from nosocomial infections in inpatients.Hospital bass cross-sectional study was conducted on 299 isolates from inpatients of Cocody University hospital from january to december 2014. Bacteriological culture and examination was done following standard microbiological techniques. Drug resistance test was performed by disk diffusion methods against classes of antimicrobials. The data was analysed for descriptive statistics using EPI Info version 6.2 and Microsoft Excel.Escherichia coli (24.4%) and Klebsiella pneumoniae (19.1%). A total of 92 (51.1%) enterobacteria producing extended spectrum beta-lactamase (ESBL). ESBL have been commonly isolated in pediatric, surgical and intensive care unit, especially in the urine. The rate of resistance to ciprofloxacin were 68.3% for Enterobacteriaceae. About 62 isolates of Staphylococci (20.7%), 45 were Staphylococcus aureus (72.6%) and 17.8% were resistant to methicillin (MRSA). Multidrug resistance rate was 4.4%. MRSA were common in surgery especially in suppurations.Of the total of 299 isolates, strains were respectively from surgical (30.4%), pediatrics (18.7%), medicine (17.7%), neurology (14%), pulmonology (11.4%) and intensive center unit (7%). Enterobacteriaceae were represented by 60.2%, including Pseudomonas aeruginosa were resistance to ceftazidime (CRPA). These strains were isolated in intensive care and pediatrics units.Nearly, 10% of This study revealed that the rate of drug resistance was high for ESBL. These trends need to be monitored regularly. These data should be taken into account in the strategies against nosocomial infections.None declared."}
+{"text": "The management of medication overuse headache (MOH) is often difficult and no specific guidelines are available as regards the most practical and effective approaches. The aim of this study is to compare the cost-effectiveness of two different stratified approaches of drug withdrawal in 100 MOH subjects.In the first approach, called clinically-oriented stratified strategy (COSS), patients were stratified based on the presence /absence of complicated MOH. Patients with complicated MOH received a standard inpatient withdrawal programme whereas patients with simple MOH received an advice to withdraw the offending drug. In the second approach, called patient-preference stratified strategy (PPSS), the patients received information about the effectiveness of the different withdrawal regimens (1) simple advice, 2) outpatient detoxification and 3) inpatient detoxification) and they were treated according to their preferences.The primary outcome measures used for comparing COSS and PPSS were: 1) number of responders ; 2) number of dropouts 3) cost per detoxified patient, 4) number of relapsers at 6 months follow-up.The Number of responders (80% vs 70%) , dropouts (16% vs 18%) and relapsers (12.5 vs 14.5%) did not differ between COSS and PPSS. The cost per detoxified patient was 1211 \u20ac for COSS and 430 \u20ac for PPSS.A patient preference stratified strategy is as effective as a clinically-oriented stratified strategy, but less cost intense.No conflict of interest."}
+{"text": "Kidney diseases are a growing worldwide problem and one of the major public health threats. We analyzed the spectrum of kidney diseases seen over a five-year period in the nephrology in-patient unit of the Yaounde general hospital.This was a retrospective analysis of 225 medical records of patients admitted from January 2005 to December 2009 in the unit with a discharge diagnosis of kidney and urinary tract diseases. The first hospitalization was considered for patients admitted several times for the same disease. Socio-demographic and clinical patient data were recorded.The patients mean age was 44.8\u00b116 years with 135 (60%) males and 211 (93.8%) emergency admissions. All 139 (61.8%) patients with chronic kidney disease (CKD) had chronic renal failure. Acute kidney injury (AKI) (28%), nephrotic syndrome (7.6%), renal colic (1.3%) and acute pyelonephritis (1.3%) were other patterns observed. Chronic glomerulonephritis (25.9%), hypertension (22.3%) and diabetes (20.1%) were the main etiological factors of CKD. All AKI patients were in stage RIFLE-F. AKI was secondary to parenchymal (58.7%), functional (25.4%) and obstructive (15.9%) etiologies. Black water fever (36.4%), sepsis (22.7%), drugs (18.2%), eclampsia (13.6%) and herbal concoctions (9.1%) were the etiologies of acute tubular necrosis while enterocolitis (56.2%), heart failure (31.3%) and digestive hemorrhage (12.5%) were the etiologies of functional AKI.The clinical pattern of renal diseases is dominated by advanced CKD and AKI secondary to preventable causes. This study suggests a need for an array of actions including sensitization, continuous medical education and strengthening of the health system. Kidney diseases are a growing worldwide problem and constitute one of the major public health threats . WhetherThis was a retrospective analysis of medical records of patients admitted from January 2005 to December 2009 in the nephrology-cardiology-psychiatry unit of the Yaound\u00e9 General Hospital (YGH); the main tertiary hospital in the Cameroon capital city. This unit of 25 beds is part of the internal medicine department and constitutes the main national referral nephrology unit. The staff comprised three nephrologists taking care of patients mainly from the center region and neighborhood but also from other parts of the country. This study received administrative authorization from the YGH and was approved by the Ethic Committee of the Faculty of Medicine and Biomedical Sciences (FMSB) of Yaound\u00e9 1 University, Cameroon.During the study period, we used the in-patient register of the unit to identify all patients with a discharge diagnosis of diseases of the kidney and urinary tract. This list was then used to retrieve the individual medical records from the hospital archives department. We considered only the first hospitalization for patients admitted several times for the same disease. For those with several diagnoses, each diagnosis was counted separately. We excluded files with missing data and patients hospitalized for hemodialysis-related complications. Patient information recorded included age, gender, type of admission , kidney and urinary tract disorder, comorbidities, type and etiological factors of AKI, as well as stage and etiological factors of CKD.Acute kidney disease (AKD) referred to any kidney disease of less than three months duration including AKI. AKI was defined as sudden loss of kidney function with recovering within three months. AKI was then classified into functional, parenchymal and obstructive. The RIFLE classification was used to stage AKI severity . CKD ref\u00ae 9 software for Windows . We have reported results as mean (standard deviation) and count (percentages).Statistical analysis were performed using the SPSSDuring the study period, 358 patients were hospitalized for kidney and urinary tract disorder among which 256 (71.5%) fulfilled the study criteria. Only 225 (87.9%) files were available for analysis divided into 139 (61.8%) CKD and 86 (38.2%) AKD. As presented in All CKD patients had chronic renal failure. According to KDOQI classification, 4 (2.9%), 19 (13.7%) and 116 (83.4%) patients were respectively classified in stage 3, 4 and 5. Chronic glomerulonephritis (25.9%), hypertension (22.3%) and diabetes (20.1%) were the main etiological factors of CKD as presented in All AKI patients were in RIFLE-F; with the suspected mechanism of injury being parenchymal, functional and obstructive in 37 (58.7%), 16 (25.4%) and 10 (15.9%) patients respectively. As presented in Among 17 patients with kidney biopsy for nephrotic syndrome, 10 (58.8%) cases were identified as primary including focal and segmental glomerulosclerosis  and minimal change disease  lesions on kidney biopsy. The remaining cases were identified secondary to systemic lupus erythematosus , HIV-associated nephropathy , hepatitis B virus , filariasis  and non-steroidal anti-inflammatory drugs .In a context marked by a scarcity of kidney specialists and units dedicated to renal care, we found that the clinical spectrum of diseases of the kidney and urinary tract observed in an in-patient medical ward were diverse and included CKD, AKI, nephrotic syndrome, renal colic and acute pyelonephritis. They affect mostly young males who frequently are admitted as emergency. This study revealed that kidney diseases dominated by CRF affect young individuals in their economically productive years and who are usually diagnosed late already in end stage as previously reported in similar settings; thus contrasting with the advanced age of patients in developed countries , 9\u201316. TAcute kidney injury was the second most frequent presentation of kidney disease in our setting with unsurprisingly all patients in RIFLE-F. AKI was mainly from renal parenchymal disease dominated by acute tubular necrosis with etiologies similar to previous reports in developing countries , 18. TheThis study revealed that patients admitted in a specialized nephrology unit for kidney and urinary tract diseases in Cameroon are mainly young adults in their economically productive years. The clinical pattern of disease is dominated by advanced CKD and AKI secondary to preventable causes. This study suggests a need for an array of actions including sensitization, continuous medical education and strengthening of the health system to improve the management of patients with kidney disease, and the implementation of a national program to prevent and control risk factors for kidney diseases."}
+{"text": "Little research exists of rates of prescribing errors and prescription modifications, or risk factors for same, in Ireland.A cross-sectional study was performed to examine prescriptions dispensed in a community pharmacy over a period of 5 weeks from November 19 to December 21 2012.In total, 866 prescriptions were examined. The overall prevalence of prescription modifications was 17.9% (155/866), with a mean of 31 modifications per week. Prescription only medicines (POM) comprised 147 (94.8%) of the modifications, 128 (87.1%) of which concerned a prescription error requiring a simple clerical clarification before dispensing could occur, with the remaining 19  potentially having clinical consequences if left unaltered. Half (51%) of all POM modifications occurred through consultation with the patient or their representative. The following factors were associated with increased risk of POM modifications: being a female patient  and being prescribed drugs in the following therapeutic areas: musculo-skeletal  and genito urinary system and sex hormones . Multivariate analysis showed these were significant independent determinants of POM modifications, remaining so after adjustment.The majority of prescribing errors modified involved non-serious clerical errors. However an average of 3.8 POM prescriptions with potential clinical consequences were modified weekly."}
+{"text": "Four cycles of docetaxel/cyclophosphamide (DC) resulted in superior survival than doxorubicin/cyclophosphamide in the treatment of early breast cancer. The original study reported a 5% incidence of febrile neutropenia (FN) recommending prophylactic antibiotics with no granulocyte colony-stimulating factor (G-CSF) support. The worldwide adoption of this protocol yielded several reports on substantially higher rates of FN events. We explored the use of growth factor (GF) support on days 8 and 12 of the cycle with the original DC protocol.Results: In total, 123 patients received the DC regimen. Median age was 60 years, . Thirty-three patients (26.8%) were aged 65 years and older. Most of the women (87%) adhered to the planned G-CSF protocol (days 8 &12). 96% of the patients completed the 4 planned cycles of chemotherapy. Six patients (5%) had dose reductions, 6 (5%) had treatment delays due to non-medical reasons. Thirteen patients (10.6%) experienced at least one event of FN (3 patients had 2 events), all requiring hospitalization. Eight patients (6.5%) required additional support with G-CSF after the first chemotherapy cycle, 7 because of FN and one due to neutropenia and diarrhea.Our study included all consecutive patients with stages I\u2013II breast cancer who were treated with the DC protocol at the Institute of Oncology, Davidoff Center  from April, 2007 to March, 2012. Patient, tumor characteristics, and toxicity were reported. Primary prophylactic G-CSF support on days 8 and 12 of the cycle provides a tolerable option to deliver the DC protocol. Our results are in line with other retrospective protocols using longer schedules of GF support. Adjuvant chemotherapy for patients with early-stage breast cancer has been shown to improve both disease-free survival and overall survival The schedule of G-CSF administration varies among oncologists' practice. Previous studies have suggested that switching from pegfilgrastim to just a few doses of filgrastim might be enough to adequately support adjuvant chemotherapy. Compared with daily filgrastim administration for 7 days (days 8 to 14), fewer doses of 2 (days 8 and 12) and 4  days showed less side effects such as bone pain and incidence of fever The study was approved by the institutional review board of Rabin Medical Center. Consent was not obtained (as was approved by the ethic committee). Patient information was anonymized and de-identified prior to analysis.2 and cyclophosphamide 600 mg/m2 intravenously on day 1 every 21 days for 4 cycles) and received filgrastim  5 \u00b5g/kg subcutaneously on days 8 &12 of each cycle (for at least one cycle) at the Institute of Oncology, Davidoff Center, Rabin Medical Center, Petah Tikva, Israel from April 2007 to March 2012. No prophylactic antibiotic treatment was added.This retrospective analysis included all consecutive patients with stage I\u2013II breast cancer who were treated with the DC protocol . Of the 131 patients who received the DC regimen in our institution within the study timeframe, 123 were included in the current analysis . Median (range) age was 60 (25\u201381) years and 33 patients (26.8%) were >65 years of age Table 1.One hundred eighteen patients (95.9%) completed the 4 planned DC cycles . Five patients (4.1%) discontinued treatment after the first DC cycle due to chest pain, second malignancy, allergy, diarrhea and abdominal pain, or relocation (1 patient each). Of 496 planned cycles, 15 (3.0%) were missed. Six patients (4.9%) required dose reduction for \u22651 cycle (9%\u201325% reduction of the planned dose), and 6 patients (4.9%) had a treatment delay of up to 5 days, none due to medical reasons.The majority of patients  adhered to the planned filgrastim protocol (days 8 &12). Fourteen patients (11.4%) required additional G-CSF support after the first DC cycle, 13 because of FN and 1 due to neutropenia and diarrhea. The median (range) age of the patients requiring additional G-CSF support was 58 (28\u201373) years. In 5 patients (4.1%), the filgrastim dose was decreased after the first DC cycle to only 1 injection per DC cycle due to leukocytosis and severe bone pain Table 2.P\u200a=\u200a0.74). Overall, the median (range) age of the patients requiring hospitalization due to FN was 60 (42\u201373) years. Median age of the older hospitalized group was 72 years compared to 54 years in the younger group. In addition to the 13 FN-related hospitalizations, 14 more hospitalizations were reported due to other reasons including: diarrhea, chest pain, fever, and cellulitis (2 patients each), as well as chronic obstructive pulmonary disease, tonsillitis, bone pain, hearing problem, observation after treatment, and an unknown reason (1 patient each). Of note, 4 additional patients experienced grade 2\u20133 diarrhea but did not require hospitalization. There was no treatment related mortality.Thirteen patients (10.6%) experienced at least one FN event (3 patients had 2 events), all requiring hospitalization. Eight patients (6.5%) experienced the FN event in their first DC cycle. In total, FN events occurred in 16 of 496 cycles (3.2%). The rates of FN events were similar in older (>65 years) and younger (\u226465 years) patients  were assigned to the DC regimen without the G-CSF studied protocol, of whom 5 patients did not get any G-CSF support. This precludes the potential bias that patients prone to develop FN were offered a different G-CSF protocol.In summary, primary prophylactic growth factor support on days 8 & 12 provides a tolerable option to deliver the DC protocol. Our results are in line with other retrospective protocols using longer schedules of growth factor support. Further studies are required to determine the most appropriate G-CSF regimen for the DC protocol."}
+{"text": "Intensive care unit-acquired infections (ICU-AIs) constitute an important world-wide health problem.Our aim was to determine the incidence and attributable mortality due to device associated infection (DAI) in ICU patients in Tunisia.We conducted a prospective observational cohort study over a 6 month period in the medical intensive care unit of Farhat Hached University Hospital (Sousse-Tunisia). Patients admitted to the unit were included in the study if they stayed in the ICU for more than 48 hours.-4) and mechanical ventilation (p=0.04).During the study period 105 patients were surveyed; 16 of them (15.2%) developed 17 episodes of DAI . The most frequently identified infections were central and peripheral venous catheter-associated infection (respectively 21.4% and 10.2%). At ICU discharge, overall mortality was 40%. Independent risk factors for acquiring infection in ICU were the use of central venous catheter (p=0.014) and length stay, those of mortality in ICU were SAPS II of more than 32.5 points (p=0.003), DAI (p=0.002), central venous catheter (p < 10Even if DAI rates in Tunisian ICU were lower than those published in some reports from other North African countries, DAI data, dominated by catheter associated infections show the need for more-effective infection control interventions in our hospital.None declared."}
+{"text": "We determined that the overall antibiotic use rate following successful air enema reduction was 41% (97/234), which decreased from 99% (67/68) in phase I to 18% (30/166) in phase II. In phase I, prophylactic antibiotic usage reached up to 84% (56/67). The quantity of aztreonam for injection accounted for 63% (45/71), and cefamandole nafate for injection accounted for 25% (18/71). In phases II, prophylactic antibiotic usage were reduced to 13% (4/30). The quantity of aztreonam for injection was decreased to 12% (4/33) and cefamandole nafate for injection was 3% (1/33). Antibiotics' options were more diverse. In conclusion, policy intervention was effective in addressing some aspects of antibacterial drug usage among young children with intussusception. However, excessive drug use remains a public health problem. The guidelines for the antibiotic management of intussusception for children must be established in China.China introduced a new policy regarding the management of antibiotic use. We evaluated the reasonableness of antibiotic use among children suffering from intussusception before and after policy. A retrospective study was conducted involving 234 young children with intussusception who were treated between January 1, 2011 and December 30, 2013. Demographics and detailed antibiotics regimens were collected.  Intussusception occurs worldwide; its incidence is approximately 1 to 4 out of every 2000 infants, and with a peak prevalence within their first 3 years of life . In Chinth revision). Informed consent was signed by the parents of each child before the air enema was administered. Surgery was necessary when the air enema either failed or was incomplete [The Institutional Review Board of the Second Hospital of Shandong University approved this retrospective study. Notes were reviewed about children treated for intussusception at the Department of Pediatric Surgery in our hospital between January 1, 2011 and December 30, 2013. Diagnostic information was coded K56.1 , and a P value less than 0.05 was statistically significant.The variables were described as follows: n, median, min, max and proportion. The predominance of each variable between the two phases was compared using \u03c7Of the 234 children in our study, 143 were boys (61%) and 91 were girls (39%). The overall median age was 16 months . 55% (129/234) of the children had mesenteric lymphoid hyperplasia and lymphadenitis according to the imageological diagnosis. 68 and 166 children were included in two phases, respectively.In phase I, the proportion of antibiotics usage was higher; 67 children received antibiotics following reduction, accounting for 99% (67/68), whereas 1% (1/68) did not. 84% of 67 children were prescribed antibiotics following air enema reduction for the purpose of preventing infection (56/67). In phase II, the proportion of antibiotic use decreased to 18% (30/166). 87% of antibiotics were used for treatment (26/30), and only 13% for prevention (4/30).P<0.01). Single or two antibiotics in two phases had no differences (P>0.05). The results are included in The overall antibiotic use rate after successful air enema reduction was 41% (97/234). The proportion and intention of antibiotic use had improved significantly after policy intervention Click here for additional data file."}
+{"text": "RAS gene, increasing the need for reliable RAS mutation testing. We evaluated the completeness and reproducibility of RAS-testing in the Netherlands.In 2013 the European Medicine Agency (EMA) restricted the indication for anti-EGFR targeted therapy to metastatic colorectal cancer (mCRC) with a wild-type KRAS, NRAS and BRAF.From 17 laboratories, tumor DNA of the first 10 CRC cases tested in 2014 in routine clinical practice was re-tested by a reference laboratory using a custom next generation sequencing panel. In total, 171 CRC cases were re-evaluated for hotspot mutations in RAS-testing (65%) and BRAF-testing (71%) by January 2014. The most employed method for all hotspot regions was Sanger sequencing (range 35.7 \u2013 49.2%). The reference laboratory detected all mutations that had been found in the participating laboratories (n = 92), plus 10 additional mutations. This concerned three RAS and seven BRAF mutations that were missed due to incomplete testing of the participating laboratory. Overall, the concordance of tests performed by both the reference and participating laboratory was 100%  for RAS and 100%  for BRAF.Most laboratories had introduced complete RAS and BRAF mutations can be reproducibly assessed using a variety of testing methods.Our study shows that  RAS wild-type [RAS tumors (KRAS and NRAS mutations) who received panitumumab in combination with oxaliplatin-based chemotherapy had a significantly worse outcome in OS and PFS [RAS mCRC. This has increased the need for reliable RAS mutation testing methods to assure the quality of RAS status determination.Anti-Epithelial Growth Factor Receptor (EGFR) targeted therapy, such as panitumumab and cetuximab, is effectively reducing the risk of tumor progression and improving overall survival (OS), progression free survival (PFS) and quality of life in metastatic colorectal cancer (mCRC) patients whose tumor is ild-type , 2. Conv and PFS . This no and PFS  and for  and PFS , to indiRAS genes in samples with >30-50% tumor cells, or alternatively with 15-25% of mutated alleles in the test sample [KRAS exon 2 testing [KRAS exon 2 wild-type tumors (15.9%), as assessed with Sanger sequencing, a KRAS exon 2 mutation was found with next generation sequencing (NGS) [Most molecular testing methods that are used nowadays accurately assess mutational status of t sample , 7. Howet sample . Even wh testing . In a reng (NGS) . This sung (NGS) .RAS-testing, it is of utmost importance to control for reliable performance of routine RAS-testing methods used in clinical practice. In this study, we evaluated the inter-laboratory agreement of RAS-testing amongst 171 mCRC patients of 17 Dutch laboratories.Given the clinical impact of RAS testing (65%). All 17 participating centers performed KRAS exon 2 (codon 12 and 13) and KRAS exon 3 (codon 61) testing. The method most frequently used for KRAS exon 2 was Sanger sequencing of PCR products, either directly ) or to specify the mutation detected with high resolution melting (HRM) analysis or to confirm a real-time PCR result ) [Table In January 2014, 11 of 17 participating Dutch laboratories had introduced full RAS-testing, one laboratory did not test for NRAS exon 2, 3, 4 and KRAS exon 4, three had not introduced NRAS exon 4 (codon 117 and 146), one laboratory did not have KRAS exon 4 codon 117 in their test panel and one laboratory did not test for KRAS exon 3 codon 59 [see Table RAS testing early 2014 and had only tested 3 out of 10 (30%) CRC cases with full RAS-testing.Of the 6 laboratories that had not introduced full RAS-testing direct Sanger sequencing of PCR products was used most often either with or without a prescreen (range 35.7% \u2013 49.2%) [Table RAS testing. In conclusion, full RAS testing had been introduced in the majority of laboratories participating in this study and relied mostly on Sanger sequencing methods.For full %) Table . The useKRAS, 163 for NRAS and 163 for BRAF; see materials and methods). Overall, in 102 samples (61.1% (95% CI 53.5 \u2013 68.2)) a mutation in KRAS, NRAS or BRAF was found at the reference laboratory [Figure The amount and quality of 167 out of 171 received DNA samples was sufficient for successful evaluation by the reference laboratory using NGS of at least one of the target sites , other RAS mutations were found in KRAS exon 3 (n = 3 (3.6%)), KRAS exon 4 (n = 3 (3.6%)) NRAS exon 2 (n = 1 (1.2%)) and NRAS exon 3 (n = 3 (3.6%)). No mutations in NRAS exon 4 were detected. This resulted in a total 79 RAS mutations (47.6% (95% CI 40.1-55.2)) of which only 8 were NRAS mutations. The mean percentage of mutated alleles was 42.1% (SD 15.7%) for KRAS and 46.1% (SD 23.25%) for NRAS [KRAS mutations affected codon 12 (70.5%), especially p.Gly12Asp (23.9%) and p.Gly12Val were common (29.6%) [Figure NRAS mutations were found in codon 61 (62.5%) [Figure KRAS and/or NRAS mutation.A for NRAS . The maj) Figure ; 5 out o) Figure . None ofBRAF mutations occurred in 23 of 163 CRC cases (14.1% (95%CI 9.4-20.1)) [Figure BRAF was 34.5% (SD 14.3%) [KRAS and NRAS mutations in our sample were mutually exclusive with BRAF mutations (OR =2.15 (95%CI 1.80-2.57); Chi-square p<0.01).) Figure  and wereD 14.3%) . Both KRRAS and seven BRAF mutations that had not been detected in the participating laboratories. This concerned mutations in KRAS exon 4 , NRAS exon 2 , NRAS exon 3  and seven mutations in BRAF  that the participating laboratory had not tested for [Table RAS and 100% (144/144) (\u03ba statistic 1.0) for BRAF-testing [Table RAS-mutations were reported back to the respective participating laboratory, and were confirmed with their newly installed Sanger sequencing or NGS approaches for the respective target sites.For 167 samples that could be evaluated by the reference laboratory, all mutations that had been found in the participating laboratories were verified. In addition, the reference lab detected three RAS-mutations is dependent on the percentage of neoplastic cells represented in the test sample; low neoplastic cell percentages may result in missing of RAS-mutations depending on the technique that is used [RAS-mutated (N = 73) and RAS-wild-type (N = 85) samples, the median neoplastic cell percentage was significantly lower in RAS-mutated samples (50.0% (IQR=28) compared to RAS-wild type (60.0% (IQR=20)) samples  [Figure RAS-mutated samples, the mean percentage of mutated alleles correlated with the percentage of neoplastic cells in the test sample (Pearson r = 0.433 (p < 0.01) for KRAS and Pearson r = 0.792 (p = 0.034) for NRAS; Testing sensitivity of  is used . For 1580.0% IQR=8 compareRAS mutations amongst samples with neoplastic cell percentages \u226440% was significantly higher than in samples >40% neoplastic cells (OR 2.45 (95%CI 1.22 \u2013 4.94), chi-square p = 0.011). A similar result was obtained when lowering the cut-off to 30 or 20% neoplastic cells, suggesting that the sensitivity of the RAS mutation analyses were adequate, even in samples with low neoplastic cells. However, care should be taken while reporting wild-type in samples with low neoplastic cells depending on the lower limit of detection of the technique applied to prevent reporting false-negatives.The frequency of RAS-test results of the reference lab oratory and 17 other Dutch laboratories in routine clinical practice, despite differences in testing methods used. Overall, full RAS-testing of KRAS exon 2, 3 and 4 and NRAS exon 2, 3 and 4 has been introduced in the majority of the participating laboratories (65%). Three RAS mutations and seven BRAF mutation were missed due to incomplete testing.Our results show an excellent concordance  of RAS mutations reported in our study matches those previously reported in the literature. Approximately 35-45% of all CRCs contain RAS-mutations in KRAS exon 2 [RAS-mutations occurs in KRAS exons 3 and 4 or NRAS exons 2, 3 and 4 [KRAS, NRAS and BRAF mutations have a strong tendency towards mutual exclusivity [BRAF mutations occurred in 14% of our samples, which seems higher than the reported 9% in the Cancer Genome Atlas [BRAF mutation analysis is incorporated in the test repertoire of most laboratories (71%), some laboratories only test for BRAF on special request by the physician when tumors were previously tested RAS wild-type. BRAF mutation frequency amongst KRAS exon 2 wild-type tumors is reported to be around 8-15% [The frequency of S exon 2 -16, wher 3 and 4 -19. In alusivity . BRAF mume Atlas . While Bnd 8-15% , 18.RAS wild-type and mutant status, the quality of mutation detection for each KRAS and NRAS exon needs to be determined. Reproducibility is one of the measures that signify the quality of diagnostic tests. Poor reproducibility can have several causes: 1) the testing methods used have a difference in sensitivity (ability to identify tumors with the mutation) or, 2) there is variation between different persons/laboratories performing the test (inter-observer variability). In a recently published Italian study, it was found that amongst KRAS exon 2 wild-type tumors, as assessed with Sanger sequencing, a KRAS exon 2 mutation was found with NGS in 28 out of 182 mCRC cases (15.9%). The difference in sensitivity between the testing methods could have partly accounted for the discrepancy found in this study [KRAS external quality assessment program of the European Society of Pathology, less than 5% of all samples were wrongly genotyped for KRAS amongst 100 laboratories in 26 countries [To assure accurate determination of is study . In our ountries .KRAS EQA scheme [RAS mutant samples was significantly higher in samples with neoplastic cell percentages below 40%, which demonstrates that mutations could also be detected in samples with a low neoplastic cell percentage. However, this unexpected observation could be merely coincidental due to small subgroups and difference in tumor sampling in combination with variation in estimating the amount of neoplastic cells, which is known to be high among pathologists [Testing sensitivity is reflected by the limit of detection of the method, but is also limited by the percentage of neoplastic cells represented in the test sample. In fact, low neoplastic cell percentage (~10%) led to 16 of the 29 false-negatives in the 2012 A scheme . For PCRA scheme . Our stuA scheme . In factologists , 23.KRAS exon 2 mutations are the most frequent, there were some laboratories where only KRAS exon 2 mutations or wild-type RAS-status was reported. This could have led to an overestimation of the reproducibility because other RAS-mutations were not present. Secondly, the likelihood of finding false-negatives is higher when only wild-type samples are re-tested. In this series only 54 samples were wild-type for all the tested hotspot mutations and thus could have led to an underestimation of false-negative wild-type samples. The small number of NRAS-mutations found has likely overestimated the reproducibility of this group of mutations. Future studies need to verify whether newly installed methods reproducibly detect NRAS mutations, especially in laboratories that did not report any NRAS mutations in the tested CRC panel.Potential sources of bias in our study could have affected the reported reproducibility. First, centers were asked to send DNA of the first 10 CRC cases tested in 2014. Because RAS-status can be reproducibly assessed between laboratories in routine clinical practice using similar or different testing methods. With constant improvement of testing methodologies and quality controls, this offers good expectations for the future of molecular testing in mCRC. Nevertheless, more in depth analyses with regard to the effect of testing sensitivity and the percentage of tumor cells in the test sample on RAS mutation detection are warranted.In conclusion, our study clearly shows that KRAS, NRAS and BRAF mutations found by the participating laboratories were reported and stored by a third party until study end. Retesting of the samples at the reference laboratory was performed blinded. Approval by a medical ethics committee was not required. All data were reported in de-identified form and are in agreement with the Dutch Data Protection Act.All 22 Dutch institutes that participated in the European Quality Assurance (EQA) scheme of the European society of pathology (ESP) in 2013 were invited to participate in the study. Seventeen laboratories responded and were subsequently requested to send 10 \u03bcl DNA (\u226530 ng) of the first 10 mCRCs tested in routine diagnostics for anti-EGFR targeted therapy from 1st January 2014. In addition, each laboratory was asked to indicate the testing method used, the mutations tested for and the percentage of neoplastic cells in the tissue the DNA was extracted from. Moreover, the KRAS, NRAS, EGFR, PIK3CA, ERBB2, AKT1, BRAF genes and the AMELX/Y gene as a control gene to determine the sex of the patient. Libraries were equimolar pooled and clonal amplification was performed by emulsion PCR using the One Touch 2 system (Life Technologies) and subsequently run on the Ion Torrent Personal Genome Machine (Life Technologies). Torrent Suite Software v.3.4.2. was used to pre-process the raw data. Subsequent mapping and variant calling was performed using SeqNext software v.4.1.2. . The following genes and exons were included in the data analysis: KRAS exon 2, 3 and 4 (NM_004985.3), NRAS exon 2,3 and 4 (NM_002524.3) and BRAF exon 15 (NM_004333.4). The minimum read coverage allowed to call mutant alleles was set at 100 reads. In general, read coverage was more than 500 resulting in a sensitivity of 5% mutant alleles. For a read coverage between 100-500 reads, a limit of 10% mutant alleles was employed. When coverage was low or mutation calling could not be established due to other technical reasons, the run was repeated. When there was still insufficient coverage of the target sites after repeating the run, the samples were excluded from analysis. In total 6 KRAS, 8 NRAS and 8 BRAF target sites had insufficient coverage due to low amount or poor DNA quality. Therefore, we could successfully evaluate a total of 165 KRAS, 163 NRAS and 163 BRAF target sites; for 167 samples at least one of the target sites could be successfully evaluated.A total of 171 DNA samples received from the participating laboratories (one lab contributed 11 samples) were quantified on the Qubit platform (Life technologies). Samples with a DNA concentration below 0.5 ng/\u03bcl were excluded from further analysis. Bar-coded libraries were prepared from 10-100 ng DNA using a custom AmpliSeq panel targeting frequently mutated regions in the Variants were filtered for known SNPs and systematic sequencing artifacts. Next, the somatic mutations found in the DNA-samples by the reference laboratory were compared with the mutations originally found by the participating laboratories to assess the percentage of agreement of the results. The mutations were compared at the genotype level. Each participating pathology center was informed about their individual results and performance.KRAS, NRAS and BRAF. Binominal confidence intervals were calculated using the Jeffrey's interval. The detected mutation(s) in the DNA-samples at the genotype level were compared between the reference laboratory and the participating laboratories and expressed as percentage agreement. Data were evaluated for hotspot mutations in KRAS exon 2, 3 and 4, NRAS exon 2, 3 and 4 and BRAF exon 15. Concordance  was onl"}
+{"text": "Hypersensitivity reactions (HR) to chemotherapy agents are increasingly frequent and lead to the discontinuation of potentially curative drugs. Rapid drug desensitization (RDD) is the only strategy that protects from anaphylaxis, while providing first line treatment options. The safety and efficacy of RDD depends on the outcomes of large series of desensitized patients. We present the outcomes data for platins and taxanes from the Desensitization Unit of the Immunoallergology Department in Lisbon's Santa Maria Hospital.A retrospective review between July 2008 and December 2013 was done. All patients with HR to platins and taxanes who were desensitized were included. The Brigham and Women's Hospital's desensitization protocol with 3 bags  and 12 consecutive steps was used . Frequency and severity of breakthrough reactions during the desensitization procedures were analyzed.135 patients were desensitized to 140 drugs (5 double desensitizations), with a total of 609 desensitizations. The drugs included platins  and taxanes , with a mean of desensitization per patient of 4.6 for platins and 4.1 for taxanes. During desensitization, 77 (12.6%) HR occurred in 49 patients  of which 64 (83%) were induced by platins. All breakthrough HR in the taxanes group occurred during the 1st (9-69%) and 2nd (4-31%) desensitizations. Platin-sensitized patients reacted not only during the 1st (27-42%) and 2nd (18-28%), but also on the 3rd (5-7.8%), 4th (5-7.8%) and other (9-14.4%) desensitizations. Most HR occurred on the last step of the protocol (53-69%). Only one patient did not receive the target dose due to recurrent anaphylaxis.97% of this large cohort of platin and taxane hypersensitive patients were able to receive their target dose through the 3 bag, 12-steps protocol with mild or no HR, confirming the efficacy and safety of protocol. Platin-sensitized patients react in multiple desensitizations, supporting the need for repeated desensitization at each exposure. Interestingly taxane desensitizations induced fewer reactions, which were limited to the first 2 desensitizations. Future studies are needed to assess the safety of shorter protocols after the first 2 desensitizations to taxanes."}
+{"text": "There is a direct relationship between intra-abdominal hypertension (IAH) and acute kidney injury (AKI). The current AKI scales are not always an early marker of renal damage. The use of renal resistive index (RI) measured by eco-Doppler method for early detection of AKI in critically ill patients is postulated. The RI is a parameter obtained from the study of the flow of the arcuate or renal interlobar arteries. The formula is: RI = (systolic peak velocity -diastolic end velocity) / systolic peak velocity. The definite result is an average of 3-5 pulse waves.Our aim is to assess the usefulness of RI by eco- Doppler as an early marker of acute renal failure in patients with risk of IAH.We conducted a prospective observational study between April 2013 and June 2014. The inclusion criteria for our study were patients (age>18 years) admitted in intensive care unit ( ICU) with at least 3 IAH risk factors. Clinical and laboratory variables from all individuals were collected and the IAP  was monitored intermittently with a bladder placement catheter (UnoMeter Abdo-Pressure\u2122). Further on, renal Doppler sonography was performed after inclusion and at least one more posterior determination was done, in order to measure the RI. The exclusion criteria were chronic renal failure history and / or risk factors for altered RI such as dilated urinary tract, renal artery pathology and renal transplant.A total of 25 patients were included: 20 patients were men; average age 52 years (interquartile range 43.5-64), the median IAP was 12 mmHg (10.9-14), the median creatinine level was 0.99 mg/dL (0.59- 2.07). The reasons of ICU admission were: Sepsis 28%, postoperative abdominal surgery 28%, pancreatitis 16%, polytrauma 12%, peritonitis 12% and hemorrhagic shock 4%. Patients who developed AKI showed higher initial RI . We found positive correlation between RI and creatinine levels (p = 0.004).From the 14 patients who presented IAH, AKI was present in 10 cases. From the 11 patients without IAH, AKI was present in 7 cases (no significant differences were found).No correlation could be established between IAH and the RI value or AKI.According to our study, renal resistive index (RI) increase is a predictor of Acute Kidney Injury (AKI).No correlation was found between Intra-Abdominal Hypertension (IAH) and the RI value or between IAH and AKI."}
+{"text": "Juvenile dermatomyositis (JDM) is an uncommon vasculitis in childhood. JDM is the most prevalent idiopathic inflammatory myopathies of childhood. JDM is characterized by proximal muscle weakness and typical skin involvement.To describe demographics, clinical features, laboratory findings and treatment modalities of patients with juvenile dermatomyositis (JDM) at a referral pediatric rheumatology center in Turkey.Retrospective review of forty three patients meeting Bohan and Peter criteria diagnosed as JDM at the Pediatric Rheumatology Department of Istanbul University Cerrahpasa Medical Faculty between the years 2003-2013.Forty three patients were identified; thirty of them (69.3%) were female, thirteen of them (%30.2) male. Mean follow-up period was 48 months (3-168). Mean age for the beginning of the disease was 6.3+/-4.4, mean age for the diagnosis was 6.9+/-4.4. Forty two patients (97.7%) had heliotropic rash and Gottron papules, 39 patients (90.7%) had muscle weakness, 36 patients (87.3%) had erythroderma and 16 patients (37.2%) had calcinosis as the most common clinical features of the disease. Forty one of the patients (95%) had elevated acute phase responses at presentation. Twenty seven of the patients (62.8%) had anti-nuclear antibody (ANA) positivity. Anti-jo 1 and antibodies to extractable nuclear antigen positivity were not found at all. Mean creatine kinase levels at presentation were 2245+/-3404 IU/L, median level was 564 IU/L. Mean time returning to normal levels was 6.6+/-17.8 months, median time was 3 months. Muscle biopsy was performed on 14 patients (32.6%) and all of them showed findings of inflammatory myopathy. Electromyography (EMG) was performed on 25 patients (58.1%) and all of them suggested inflammatory myopathy. All patients had been treated with corticosteroids at different dosages. Methotrexate was used in 41 patients (95.3%), at the mean dosage of 14.5+/-7.1 (7.5-40) miligrams per week and for the mean duration of 45+/-36 months. Cyclosporine was used in 16 patients (37.2%). In 13 of 16 patients with calcinosis (81.3%), alendronate was used. Muscle weakness was present in 39 patients (90.7%) in the beginning, mean duration for the recovery of muscle weakness was 7.9+/-10 months, median duration was 4 months. Only two patients on follow-up period could not achieve self-movement capability. Both were referred to our clinic after a long duration of the disease and had widespread calcinosis. There were no significant relationship between mean duration of the muscle enzymes to return normal values and mean duration of the disappearance of the muscle weakness (p=0.7).Juvenile dermatomyositis is a rare systemic vasculopathy; however, it is an important disease because it may cause severe muscle weakness and paralysis. JDM should be keep in mind by its presentation as muscle weakness and different skin rashes in early childhood. It should be differed from some kind of genetic muscle diseases. Methotrexate and prednisolone should be first choices for the treatment of JDM.None declared."}
+{"text": "Otitis externa (OE) is an inflammation or infection of the external auditory canal (EAC), the auricle, or both this condition has been reported to be found in all age groups. The aims and objectives were, study/determine the prevalence of Otitis externa in the specialist otolaryngology clinic in National Ear Care Center Kaduna, study the pattern of presentation among patients with otitis externa in the specialist otolaryngology clinic in National Ear Care Center Kaduna, and evaluate the choice of drug treatment for otitis externa in the specialist otolaryngology clinic in National Ear Care Center Kaduna.Data of patients diagnosed with otitis externa between January 2009 and March 2013 were extracted from the recorded cases of ear disease seen within the same period. The ages, sex/ gender, complains(symptoms), duration of symptoms, clinical examination findings, diagnosis, mode of drug treatment, number of visits and complication records were extracted from the case notes of the patients and analyzed descriptively using SPSS  version.Pseudomonas spp and klebsiella. Empirical treatment was the commonest treatment modality and about 91% of the patients had complete symptom resolution by second visit. Complication was observed in only one case of necrotizing otitis externa who was retro-viral positive.Out of 13,328 cases of ear diseases seen within the period under review, 133 cases were diagnosed with otitis externa across all age groups. Hospital prevalence stands at 1.0%. There were 81(60.9%) males and 52(39.1%) females in ratio 1.5:1. Children age 0-15 constitute 55(41.3%) while young adults and adults were 78(58.6%). The minimum age at presentation was one year, while maximum age was 64 years. Mean age was 24 years with a standard deviation of \u00b1 1.12 Years. Ear pain as only presenting symptom was the major complain found in this study accounting for 68(51.1%). Acute diffuse otitis externa was the commonest diagnosis accounting for 101(75.9%) and associated clinical findings ranging from tragal tenderness, hyperaemia and oedema of ear canal in 57 (54.9%). Ear swab was not routinely done and only 6(15.8%) of the discharging ears had microscopy done and the organisms were Otitis externa accounted for small fraction of cases seen in our clinic (1%). Acute diffuse otitis externa is the commonest diagnosis made with symptoms ranging from ear pain, ear discharge, hearing loss and itchiness. Most patients were treated empirically with significant success within first two visits. No major complication was recorded within the period under study. Otitis externa (OE) is an inflammation or infection of the external auditory canal (EAC), the auricle, or both . This coData of patients diagnosed with otitis externa between January 2009 and March 2013 were extracted from the recorded cases of ear diseases seen within the same period. Demographic data , presenting symptoms and the duration, clinical examination findings, diagnosis, mode of drug treatment, number of visits and complication records were extracted from the case notes of the patients and analyzed descriptively using SPSS  Version\u2026.Out of 13,328 cases of ear diseases seen within the period under review, 133 cases were diagnosed with otitis externa across all age groups. Hospital prevalence stands at (1.0%). There were 81(60.9%) males and 52(39.1%) females in ratio 1.5:1. Children age 0-15 constitute 55(41.3%) while young adults and adults were 78(58.6%). The minimum age at presentation was one years while maximum age was 64 years. Mean age was 24. years with a standard deviation of \u00b1 1.12 Years. Majority presented within two weeks of onset of symptoms 104(78.2%), while 21.8% presented within 3 weeks and above. Children aged 0-15 years constitute 55(41.3%) while young adults and adults were 78(58.6%) of all cases of otitis externa as shown in In our study otitis externa constitute only 1.0% of all otologic cases seen in our clinic within the period under review. This is different from the findings of Ayotunde et al  in whichth to 6th visits. There were no documented complications in 99.2% of the cases however 1(0.8%) case of retroviral infection with malignant otitis externa had intracranial collection. Necrotizing otitis externa is defined by destruction of the temporal bone, usually in people with diabetes or in people who are immune compromised, and can be life threatening [Acute diffuse otitis was the commonest diagnosis made followed by chronic otitis externa and acute localized otitis externa. David et al in their study in United States found acute otitis externa to be much more common compared to chronic otitis externa . Ear swaeatening . In concOtitis externa accounted for small fraction of cases seen in our clinic (1%). Acute diffuse otitis externa is the commonest diagnosis made with symptoms ranging from ear pain, ear discharge, hearing loss and itchiness. Most patients were treated empirically with significant success within first two visits. No major complication was recorded within the period under study."}
+{"text": "The aim of our study was to determine 1-year prevalence of headache before rupture of saccular intracranial aneurysms (SIA) and 1-year after clipping of SIA.We prospectively studied 199 consecutive patients with SIA .As control served 194 blood donors . Both groups were interviewed about headaches in the year preceding clipping/interview using a validated semi-structured neurologist conducted interview. SIA patients with a past history of recurrent headaches (N=87) were follow-up 1 year after clipping. The remission rates of migraine and tension-type headache (TTH) in these patients was compared to 92 patients from a headache center interviewed twice one year apart. Diagnoses were made according to the ICHD-2.During the year before rupture, 124(62.3%) had one or more types of headache: migraine without aura (MO) -78(39.2%), migraine with aura - 2(1%), probable migraine: 4(2%), TTH: 39(19.6%), cluster headache: 2(1%).Only the prevalence of MO was significantly higher in patients with SIA compare to controls .One year after clipping, the prevalence of MO was significantly more reduced in patients with SIA than in controls .No factors except clipping of the aneurysm could explain the remission of migraine. The prevalence of TTH did not change significantly after clipping of SIA but decreased significantly after treatment in controls.Unruptured SIA is associated with a marked increase in the prevalence of migraine without aura which decreases significantly after clipping.No conflict of interest."}
+{"text": "Background. Endocrine Pancreatic Tumours (PENs) are rare and can be nonfunctioning or functioning. They carry a good prognosis overall though high grade lesions show a relatively shorter survival. The aim of the current study is to describe a single centre analysis of the clinical characteristics and surgical treatment of PENs. Patients and Methods. This is a cohort analysis of 40 patients of PENs who underwent surgery at Sir Ganga Ram Hospital, New Delhi, India, from 1995 to 2013. Patient particulars, clinical features, surgical interventions, postoperative outcome, and followup were done and reviewed. The study group was divided based on grade  and functionality (nonfunctioning versus functioning) for comparison. Results. PENs comprised 6.3% of all pancreatic neoplasms (40 of 634). Twenty-eight patients (70%) had nonfunctioning tumours. Eighteen PENs (45%) were carcinomas (G3), all of which were nonfunctioning. 14 (78%) of these were located in the pancreatic head and uncinate process (P = 0.09). The high grade (G3) lesions were significantly larger in size than the lower grade (G1 + G2) tumours . Pancreatoduodenectomy was performed in 18 (45%), distal pancreatectomy in 10 (25%), and local resection in 8 (20%) and nonresective procedures were performed in 4 patients (10%). Fourteen patients (35%) had postoperative complications. All G3 grade tumours which were resected had positive lymph nodes (100%) and 10 had angioinvasion (71%). Eight neoplasms (20%) were cystic, all being grade G3 carcinomas, while the rest were solid. The overall disease related mortality attributable to PEN was 14.3% (4 of 28) and for malignant PENs was 33.3% (4 of 12) after a mean follow-up period of 49.6 months (range: 2\u2013137 months). Conclusion. Majority of PENs are nonfunctioning. They are more likely malignant if they are nonfunctioning and large in size, show cystic appearance, and are situated in the pancreatic head. Early surgery leads to good long term survival with acceptable postoperative morbidity. Pancreatic endocrine neoplasms (PENs) arise from pluripotent cells of the pancreas , 2 and cPENs can be functioning and present with symptoms attributable to oversecretion of offending hormones or nonfunctioning where no such paraneoplastic symptoms occur , 10. NonDiagnosis of functioning PENs is confirmed by detection of elevated levels of offending hormones in the serum and serum chromogranin A levels , 15. HelThe mainstay of treatment for PENs is surgery , 10. LocThe aim of the current study is to describe a single centre experience with surgical management of PENs including analysis of demographics, presenting characteristics, operative course, surgical morbidity, and followup.We did a cohort analysis from a prospectively maintained database of patients who underwent pancreatic surgery for neoplasms of the pancreas at Sir Ganga Ram Hospital, New Delhi, India, from 1995 to 2013, and using pathological reports and preoperative CT scan as gold standard, we identified 40 patients with PENs.A review of medical files, electronic records, operative notes, and discharge summaries was done to collect information regarding demographics, clinical features, and laboratory results. Patients were categorized into functioning and nonfunctioning PENs based on their clinical behavior, pathology reports, and serum radioimmunoassay for offending hormones. Preoperative CT scans were used to characterize PENs and record neoplasm size and location.Type of surgery performed, operative findings, postoperative hospital stay, and complications were recorded. The complications noted were delayed gastric emptying , postoperative fever (temperature more than 100\u00b0F sustained enough to require medication and search for its cause), wound infection (purulent discharge from the main wound with positive culture report), and intra-abdominal abscess (purulent fluid of any amount inside the abdomen requiring percutaneous drainage or laparotomy). A pancreatic fistula was defined as drainage of fluid with amylase levels at least 3 times the normal serum amylase levels from the third postoperative day. Postoperative mortality was defined as death within the same hospital admission or within 30 days of surgery. Followup was done at 3 and 6 months and then at 6 monthly intervals and evidence of disease recurrence or disease related mortality was recorded.Evaluation of the pathology reports was done to note the tumour size, nodal status, and evidence of distant spread and staging of the disease was done as per the WHO (2010)/TNM/AJCC staging classification for pancreatic exocrine and endocrine tumours . Microsct-test or chi-square test depending on the variables and distribution of data. These tests were 2-sided and a P value less than 0.05 was considered statistically significant.Results were interpreted as mean (SD) and range where applicable. Comparison between groups was made in percentages and numbers or using independent 634 patients underwent surgery for pancreatic neoplasms between 1995 and 2013 at our institute of which we identified 40 patients (6.3%) with pancreatic endocrine neoplasms (PENs). The mean (SD) age of the patients was 48.6 (15.52) years (range: 32\u201379 years). The disease was almost equal in incidence between the sexes with 22 (55%) males.Twenty-eight (70%) tumours were nonfunctioning and twelve (30%) were functioning of which 10 were insulinomas and 2 were gastrinomas. All our tumours were sporadic and there was no association with MEN 1 or any other syndromes.The location of PENs is enumerated in Eight (20%) PENs were tumours of grade G1, fourteen (35%) were of G2, and eighteen (45%) were carcinomas of grade G3 as per the WHO (2010) classification . When thAll eighteen carcinomas were nonfunctioning. Fourteen (78%) carcinomas were located in the pancreatic head and uncinate process and two each were in the tail and neck + body combined.The mean tumour size was 5.0\u2009cms (range: 0.5\u201312.0\u2009cms). Comparison of mean tumour sizes with respect to functionality and grade is enumerated in Abdominal pain was the most common presenting feature of nonfunctioning PENs occurring in 22 of 28 patients (78%). Four (10%) cases were diagnosed incidentally with no symptoms attributable to PENs. The presenting features are enumerated in The mean serum haemoglobin level was 11.6\u2009g/dL (range: 6.6\u201315.9\u2009g/dL) and the mean serum bilirubin level was 0.8\u2009mg/dL (range: 0.4\u22122.0\u2009mg/dL).The types of surgeries performed are presented in Eight (20%) patients had local invasion at the time of surgery of which 4 were unresectable (10%). All of them were carcinomas (grade G3). Two tumours arising from the pancreatic head had infiltration of the transverse colon and the duodenum and were treated with a right colectomy along with pancreatoduodenectomy. Two tumours arising from the tail had locally invaded into the stomach and a total gastrectomy was done along with distal pancreatic resection.All fourteen malignant tumours which were resected had positive lymph nodes (100%) and 10 had microscopic angioinvasion (71%). 8 neoplasms (20%) showed cystic appearance on gross pathology. One patient following pancreatoduodenectomy showed a positive resection margin (R1 resection).The mean duration of postoperative hospital stay was 18 days (range: 6\u201360 days). Postoperative complications occurred in 14 patients (35%) after surgery, all of whom underwent pancreatoduodenectomy. Eight (20%) patients had delayed gastric emptying, four (10%) patients had postoperative wound infection, two of whom had undergone a concomitant right colectomy, two (5%) patients developed postoperative fever, and two (5%) had an intra-abdominal abscess which was drained percutaneously. Six (15%) patients developed pancreatic fistula, all of whom responded to conservative treatment. No complication occurred in patients who underwent distal pancreatectomy or local resection. No perioperative deaths occurred in our study. The overall disease specific mortality attributable to PEN was 14.3% (4 of 28). Disease related mortality for nonfunctioning PEN was 25% (4 of 16) and for malignant PENs was 33.3% (4 of 12) .P = 0.006). Interestingly we also noted that 75% (30 of 40) of PENs were operated at our institute in the second half (2004\u22122013) of the study period. This temporal shift in incidence was seen only in nonfunctioning tumours and we believe that the increased detection is due to improved imaging and better understanding of the disease.The first description of pancreatic endocrine neoplasms was an islet cell adenoma by Nichols more than 100 years back . PENs haP = 0.002) and attribute this to the acute hormonal crisis in functioning PENs. Because functioning tumours can present at smaller sizes, conventional CT imaging may fail to localize them. Somatostatin receptor scintillography and more recently PET scan have shown excellent sensitivity in localizing PENs [111In-octreotide has a sensitivity and specificity of 90% and 80%, respectively [68Ga-labelled somatostatin analogue (DOTA0-Phe1-Tyr3)-octreotide (DOTATOC) is superior to conventional 18F-fluorodeoxyglucose PET as well as 111In-DTPA-octreotide (111In-DTPAOC) SPECT in imaging PENs [Multidetector, triple phase, and thin slice computed tomography detects nonfunctioning PENs with reported sensitivities between 80 and 95% , 26, 27.ing PENs \u201332. For ectively \u201335. PET ing PENs , 36. Ending PENs \u201340. Combing PENs . HoweverP = 0.15). It would be interesting to study the role of microscopic angioinvasion in the prediction of malignancy and survival on a larger cohort in the future.Prediction of malignancy in PENs is a subject of active research and many classification systems and guidelines have been suggested over the years. The old WHO (2004) classification divided PENs into tumours (benign or uncertain behavior) and carcinomas (well differentiated or poorly differentiated) . CarcinoThe role of peripancreatic nodal clearance in PENs also remains an area of controversy. Vagefi et al. suggest enucleation or segmental resections for benign tumours less than 3\u2009cms and state that the role of peripancreatic lymphadenectomy is not clear given the biological nature of these tumours . HoweverP < 0.0001).Kazanjian et al. found that the overall complication rate was 48% after pancreatoduodenectomy, 12.5% after distal pancreatectomy, and none after local resection . We obseP = 0.0006). It would be interesting to study the prognosis of PENs based on cystic changes on a larger population since it appears to be exclusively present in high grade lesions.Cystic PENs have been linked to carcinomas of larger sizes , 47. We Pancreatic endocrine neoplasms are associated with good 5-year survival rates ranging between 77% and 89% in different studies , 25. ThePENs should be kept in the differential diagnosis of all pancreatic space occupying lesions.Nonfunctioning tumours are more common than functioning lesions and they are more commonly diagnosed in the pancreatic head.Pancreatic endocrine carcinomas (grade G3) should be suspected if the lesion is large in size and nonfunctioning, occurs in the pancreatic head, and has cystic changes.High grade (G3) and solid lesions appear to carry a worse prognosis.Early surgery leads to good long term survival with acceptable postoperative morbidity.Published data on Endocrine Pancreatic Tumours is rare and this study provides an insight into the disease.This study provides a comprehensive single institution analysis of data of a rare disease collected over 18 years.This study provides a future paradigm for analysis over larger data and multicenter research.The study is a cohort analysis of a rare disease with a relatively small sample size.30% of patients were lost to followup."}
+{"text": "Acinetobacter infections have increased and gained attention because of the organism's prolonged environmental survival and propensity to develop antimicrobial drug resistance ,2]. We . We 2]. n = 104) to examine outcomes of hospitalized patients in terms of number of organ dysfunctions, ICU length of stay, hospital length of stay and mortality in patients infected with MDR AB infection compared with the patients with MDR non-AB infection.Patient records from the last 3 years from 2011 through 2013 were studied  had greater number of organ dysfunctions, and higher mean lengths of hospital stay (8.4 days vs. 6.1 days) and ICU stay (5.3 days vs. 0.8 days) after the index day than MDR non-AB infection  (Table F critical = 3.934253.MDR AB-infected patients (We demonstrated in patients infected with MDR strains of any organism that patients infected with Acinetobacter have greater number of organ dysfunction, longer lengths of stay in both the hospital and the ICU as well as increased mortality than patients infected with non-Acinetobacter infection when we controlled for severity of illness."}
+{"text": "Nearly six years ago the primary conservative treatment of adolescent idiopathic scoliosis (AIS) in the southern part of Denmark, went from full time bracing and hospitalization to nighttime bracing and an in- and outpatient treatment.To evaluate the effectiveness of nighttime bracing in AIS.Methods: Inclusion criteria were patients diagnosed with AIS and skeletal immature. With an apex of the primary curve from TH7 and below and with a Cobb angel between 20- 45 degrees. The patients were asked to wear the brace at least 7-8 hours pr. night.No other previous treatments were accepted and a follow up at least 6 months out of brace. The brace treatment was continued until two years post menarche or for male at the expected adult height.Cross-measured x-rays were used to compare the primary Cobb angel, the in-brace correction and the outcome Cobb angel. A decreased outcome Cobb angle as well as the overcorrection of the curve measured in brace was recorded as zero.The brace treatment was considered failed if progression > 5 degrees occurred and if surgery were performed.A total of 55 patients, 8 male and 47 female, with a mean age at 14 years (11-16.5) and the mean primary Cobb at 31 degrees (20-41) were included in this study. There were 27 primary thoracic curves, 16 thoracolumbar, 11 lumbar and 1 double curve.The mean time of treatment was 18 month (5-59).The average in-brace correction was 81% (24-100%), with a mean in-brace Cobb of 6,1 degrees (0-26). After ended treatment the mean Cobb angle was 28 degrees (7-50), an average of no progression. The end results were 11 failures (6-15 degrees); equal 20 % and out of these 11 patients, 3 had surgery performed (5%).The results show a good curve control and an acceptable 20 % failure rate, which is equal to other studies. The providence brace is an excellent alternative to standard conservative treatment. Larger studies are needed to establish the relationship between in-brace correction and curve progression during the treatment."}
+{"text": "Advances in tissue characterization with late gadolinium enhancement (LGE) by cardiovascular magnetic resonance (CMR) have highlighted the importance of myocardial fibrosis (MF) in hypertrophic cardiomyopathy (HCM) by confirming that its presence and extent predicts adverse outcomes. Despite of the identification of several genes related to HCM, few studies have investigated the association between genotype and MF. In this study, we sought to investigate the relationship between two most common gene mutations in HCM and the extension of MF by LGE.We retrospectively analyzed 57 patients with HCM and genetically positive for MYBPC3 or MYH7. All patients had CMR examination at 1.5 T MRI system (Philips Achieva). All patients underwent cine-MR with SSFP sequence for left ventricle function evaluation and late gadolinium enhancement for myocardial fibrosis detection. Myocardial fibrosis was measured by a thresholding technique above normal myocardium. Left vnetricle ejection fraction, mass and septum thickness were also calculated. All analyses were performed using CVi42 software . HCM patients underwent clinical genetic testing on lymphocyte-derived DNA. Genes were sequenced through a standard Sanger sequencing protocol. Here we have only analyzed patients in which a causal mutation was identified in either MYBPC3 or MYH7.Fisher exact test, t test and Mann Whitney test when appropriate using Stata 12.vs 37.2). Myocardial dysfunction was rare in this study, with only two patients presenting LV dysfunction (40% and 45%). Other characteristics were similar between groups (Table The MYBPC3 gene mutation was present in 24 patients 42.1%) and the MYH7 in 33 patients (57.8%). The majority of the patients was male in both subgroups, 66.6% and 63.4%, respectively, and the mean age was similar (36.5 % and theps Table . Figure In our group of HCM patients, MYBPC3 and MYH7 gene mutations subgroups had similar phenotype regarding the extent of the myocardial fibrosis measured by late gadolinium enhancement CMR.N/A."}
+{"text": "The use of immunosuppressant drugs and also biological DMARDs in the treatment of juvenile idiopathic arthritis (JIA) may weaken patient's immunity and raise the risk of serious infections, including tuberculosis (TB).To assess the incidence rate of different forms of TB infection in patients receiving biological treatment of JIA.Thirty four children, aged from 3 to 17 years, were observed prospectively receiving biological treatment for JIA. Mean disease duration was 5,29  yrs. Initial screening for TB included PPD test and chest CT.Fourteen of 34 patients  received toziliaumab (TOZ), 6  - abatacept (ABA), 4  - etanercept (ETN), 5  - adalimumab (ADA) and 5  - infliximab (IFL). Mean treatment duration with biologics was 16,3 , from 3 to 46 months. Different types of TB infection were diagnosed in 6  patients while receiving biological DMARDs. Three of them received treatment for systemic JIA, 1 - for polyarticular JIA, 1 - juvenile ankylosing spondylitis and 1- JIA with concomitant uveitis. Different clinical types of TB infection were observed in these 6 patients: one patient receiving TOZ developed infiltrative pulmonary TB with dissemination, two patients (1 on TOZ and 1 on ADA) had primary TB complex and three  were diagnosed with latent TB infection. The common feature TB infection in all patients receiving biologics was the mildness of clinical manifestation of the disease.In addition 3 cases of primary TB complex were observed in patients with systemic JIA before initiation of biological DMARD and required prior specific TB therapy.Children with systemic JIA may be considered to have the higher risk of different types of TB infection. Treatment with biological DMARDs  also may contribute to TB infection. Regular TB screening (at least once per 6 months) is required to the scarcity of clinical manifestation of the infection.None declared."}
+{"text": "Chronic Recurrent Multifocal Osteomyelitis (CRMO) is classified among the rare auto-inflammatory diseases. It has a genetic predisposition and a pathogenesis largely under investigation. Greek publications regarding CRMO in pediatric patients are currently absent.The aim of the study was to describe the disease phenotype, course and outcome of CRMO Northern Greek pediatric patients, and assess the disease activity at diagnosis by the recently proposed Jansson clinical score, which has a cut-off value of 39.Pediatric patients with a diagnosis of CRMO diagnosed and followed-up a tertiary University Hospital during the last decade (2005-2014) were included in this retrospective study.Nine patients  were diagnosed with CRMO. The main presenting symptoms in all patients were inflammatory pain in multiple sites, mainly in the metaphyses and epiphyses of long bones in lower limbs ) and swelling (7/9). 6/9 patients reported hip pain and only 1, clavicular pain. At diagnosis, fever was noted in 5/9 patients, a raised ESR (mean: 52.5mm/h) in 6/9 and CRP >1mg/dl (\u2264 0.5mg/dl) in 5/9. Location of MRI lesions were vertebral (3/9), thoracic rib (1/9), femur (5/9), fibula (5/9) and tibia (3/9). The predominantly affected joints were the hip (5/9) and the ankle (5/9). The calculated clinical score at diagnosis was >39 in 8/9 patients and 36 in 1 pt.In respect to treatment, the applied NSAIDs provided partial pain relief without preventing the disease course in 8/9 patients; notably, indomethacin had no effect in 1/9 pt. Steroids combined with methotrexate were administered in 5/9 patients, but 4/5 required an anti-TNF to achieve remission. In 2/9 patients antibiotics did not alter the progress of the disease.This is the first Greek study that ranks the severity of this rare multi-faceted disease by Jansson clinical score recording a rather severe phenotype, despite the insidious presenting symptoms at onset. As the disease burden was high, half of the patients required biologics for disease taming. Jansson score proved an easy tool that can primary rank the disease severity and identify refractory cases in need for early aggressive treatment."}
+{"text": "Robertsonian translocations (ROBs) have an estimated incidence rate of 1/1000 births, making this type of rearrangement the most common structural chromosomal abnormalities seen in the general population. In this study, we reports 872 cases of ROBs from 205,001 specimens karyotyped postnatally in a single accredited laboratory in China, including 583 balanced ROBs, 264 unbalanced ROBs, 9 mosaic ROBs, and 18 complex ROBs. Ninety-three percent of the balanced ROBs observed were adults with infertility, miscarriage, or offspring(s) with known chromosomal abnormalities. Significant excess of females were found to be carriers of balanced ROBs with an adjusted male/female ratio of 0.77. Ninety-eight percent of the unbalanced ROBs observed were children with variable referral reasons. Almost all of the unbalanced ROBs involved chromosome 21 except a single ROB with  identified in a newborn girl with multiple congenital anomalies. Multiple novel ROB karyotypes were reported in this report. This study represents the largest collections of ROBs in Chinese population. These ROBs are categorized into 4 groups: (1) 583 balanced ROBs Table , (2) 264The 583 cases with balanced ROBs can be further classified into two subgroups based on their ages: 544 (93%) adults with ages ranging from 19 to 64 years-old  and 39 . Of the Of the 39 children  with balanced ROBs, 36 (92.3%) of them are heterologous and only 3 (7.7%) of them are homologous and all of the 3 homologous ROBs are der. Similar to what observed in the adults with balanced ROBs, the distributions of different subtypes of ROBs in these children are nonrandom, with der(13q14q) and der(14q21q) being predominant, constituting 54% and 15% respectively, and all others constituting the remaining \u223c30%.The male/female ratio of the 544 adults with balanced ROBs is 0.72  , showingDifferent from 0.77 of the adjusted male/female ratio in the adults, the adjusted male/female ratio (1.02) was not skewed in the 39 children with balanced ROBs (p>0.5) . Increas259 of the 264 individuals with unbalanced ROBs are children with ages ranging from newborn to 12 years-old . The remOf the 259 children with unbalanced ROBs, the male/female ratio is 1.09 (135/124), when adjusted, 1.17 (1.09/0.93). Although more males are observed in this group, statistically the male/female ratio is not significantly increased (p>0.10).The 9 mosaic ROBs in There are 18 complex ROBs including 2 mosaic ROBs mentioned above (cases 4 and 17), and 16 cases in non-mosaic status. In total, 13 cases were observed in children and 5 cases in adults.The 13 complex ROBs in children include: (1) one ROB of trisomy 18 with concurrent existence of non-contributory der  (case 1), (2) seven ROBs being standard trisomy 21 with concurrent existence of non-contributory der  , (3) one ROB trisomy 21 from contributory der with concurrent existence of a reciprocal translocation between chromosomes 6 and 12 (case 10), (4) one ROB with loss of a chromosome X with concurrent existence of der  (case 11), (5) one ROB with concurrent existence of a balanced der and a der(14) from a translocation between chromosomes 14 and 22 (case 12), (6) one ROB of der with a distal deletion on the der(case 13), and (7) the mosaic ROB containing an unbalanced der in one cell population and a balanced der in the other cell population (case 4).The 5 complex ROBs in adults include one ROB with concurrent existence of der and a reciprocal translocation between chromosomes 3 and 14 (case 14), one ROB with concurrent existence of der and a deletion on one of chromosomes X (case 15), two ROBs of Klinefelter syndrome with concurrent existence of non-contributory der  (cases 16 and 18), and the mosaic one containing two abnormal cell populations, one has three copies of chromosome X and the other has a single copy of chromosome X, and both populations contain a balanced der (case 17).de novo, balanced ROBs resulted in abnormal phenotypes  , all remOf the 263 non-mosaic unbalanced ROB trisomy 21, 5 of them were adult females and all remaining 258 were children. All the 5 adult females were living in the countryside and were referred for chromosome analysis because of infertility. We presume that reasons for these 5 female individuals being referred for chromosome analysis until they were noticed to have infertile problems are more likely because of economic-social situations rather than atypical clinical features of trisomy 21.Excluding the 5 adult females, the adjusted male/female ratio of the 258 children with ROB trisomy 21 is 1.17, showing slight higher male proportion in this group. Our data is similar to the 1.14 of ROB trisomy 21 from the New York State Chromosome Registry on over 10,000 DS reported from 1977 to 1996 , and is Postnatal mosaic ROBs are rare ,30,31. Nde novo der was previously described in two cases, which was similar to the  observed in our study  , 44,X,d,10, the ur study ,38. It iur study .There are several weaknesses present in this study: (1) bias of ascertainments; (2) incomplete clinical information about these individual carrying ROBs; and (3) incomplete follow-up molecular testing, especially for these ROBs with homologous ROBs. Although we think these weaknesses do not affect the result trends observed in this study, the authors cannot rule out the possibility of other ROBs present in the population that were not identified (due to selection bias) and that the clinical impact of the novel ROBs cannot be determined .S1 Fig(TIF)Click here for additional data file.S2 Fig(TIF)Click here for additional data file.S3 Fig(TIF)Click here for additional data file.S4 Fig(TIF)Click here for additional data file.S5 Fig(TIF)Click here for additional data file.S6 Fig(TIF)Click here for additional data file.S7 Fig(TIF)Click here for additional data file.S8 Fig(TIF)Click here for additional data file.S9 Fig(TIF)Click here for additional data file.S10 Fig(TIF)Click here for additional data file.S11 Fig(TIF)Click here for additional data file.S12 Fig(TIF)Click here for additional data file.S13 Fig(TIF)Click here for additional data file.S14 Fig(TIF)Click here for additional data file.S15 Fig(TIF)Click here for additional data file."}
+{"text": "Staphylococcus aureus, MRSA, such as the mec operon carried by staphylococcal cassette chromosome (SCCmec).The spa gene encodes protein A and is used for typing of methicillin-resistant The aim of this study was the molecular typing of MRSA isolated from different forms of infections for epidemiological purposes using spa typing method and SCCmec classification.pa typing was performed as described previously [http://www.spaserver.ridom.de/). Staphylococcal cassette chromosome mec (SCC mec) typing was performed as described previously [A total of 90 MRSA isolates coming from eight hospitals from southern Poland were tested. Isolates originated from: bloodstream and respiratory tract infections (36), surgical site infections (30), chronic wounds 24). S eviously , using t4. S evioThe majority of MRSA strains were of SCCmec type II (42.2%) or SCCmec IV (21.1%). Eleven strains was marked as SCCmec III (12.2%), 8 as SCCmec V (8.9%), 4 as SCCmec I (4.4%) and one as SCCmec VI.The spa type t003 was the most frequently observed (37.8% of strains), then t138 (14.4%), t008 and t037 and t041 (4.4%),mec type II and spa-t003 together were characteristic for 25% of the chronic wounds and 27% in SSI, but 39% in invasive infections.SCC SCCmec III and t138 occurred in 10% of the strains from two hospitals, SCCmecIV and t003 occurred in 6.7% strains from two hospitals.Epidemiological and molecular studies of MRSA isolates allowed to detail insight into the problem of staphylococcal infections. Those methods are less time-consuming than PFGE and give the opportunity for the observation of the current situation and epidemiological trends for resistant strains on the level of ward/hospital or even whole region (supported by a grant DEC-2011/03/B/NZ7/01911).None declared."}
+{"text": "This study evaluated the feasibility, safety, and prognostic outcome in patients with significant unprotected left main coronary artery (ULMCA) disease undergoing stenting.Between January 2010 and December 2012, totally 309 patients, including those with stable angina [13.9% (43/309)], unstable angina [59.2% (183/309)], acute non-ST-segment elevation myocardial infarction (NSTEMI) [24.3% (75/309)], and post-STEMI angina  [2.6% (8/309)] with significant ULMCA disease (>50%) undergoing stenting using transradial arterial approach, were consecutively enrolled. The patients\u2019 mean age was 68.9\u00b110.8 yrs. Incidences of advance congestive heart failure (CHF) (defined as \u2265 NYHA Fc 3) and multi-vessel disease were 16.5% (51/309) and 80.6% (249/309), respectively. Mechanical supports, including IABP for critical patients  and extra-corporeal membrane oxygenator (ECMO) for hemodynamically collapsed patients, were utilized in 17.2% (53/309) and 2.6% (8/409) patients, respectively. Stent implantation was successfully performed in all patients. Thirty-day mortality rate was 4.5% (14/309) [cardiac death: 2.9% (9/309) vs. non-cardiac death: 1.6% (5/309)] without significant difference among four groups . Multivariate analysis identified acute kidney injury (AKI) as the strongest independent predictor of 30-day mortality (p<0.0001), while body mass index (BMI) and white blood cell (WBC) count were independently predictive of 30-day mortality .Catheter-based LM stenting demonstrated high rates of procedural success and excellent 30-day clinical outcomes. AKI, BMI, and WBC count were significantly and independently predictive of 30-day mortality. Previous studies have revealed that medically treated patients with significantly unprotected left main coronary artery (ULMCA) disease  have a 3-year mortality rate up to 50% Over the last 20 years, with the accumulation of operators\u2019 experience, refinement in instruments, and advance in pharmacological development of anti-platelet and anti-ischemic agents, percutaneous coronary intervention (PCI) has been widely accepted as one of the most popular methods for the treatment of atherosclerotic occlusive syndrome, especially for patients with ST-segment elevation myocardial infarction (STEMI) with or without cardiogenic shock This study was approved by the Institutional Review Committee on Human Research of Chang Gung Memorial Hospital (No 102-0789B) and conducted at Kaohsiung Chang Gung Memorial Hospital for retrospective assessment of procedural success rate, safety, efficacy, and 30-day clinical outcomes in patients with significant ULMCA disease with clinical presentations as (1) stable angina pectoris (SAP) (group 1), (2) unstable angina pectoris (UAP) (group 2), (3) acute or recent  non-ST elevation myocardial infarction (NSTEMI) (group 3), and (4) post-ST-segment elevation myocardial infarction (STEMI) angina  (group 4). The participants provide their written informed consent to participate in this study. The ethics committees approve this consent procedure.Our daily clinical practice in Kaohsiung Chang Gung Memorial Hospital is still according to the current guideline for treatment of significant ULMCA disease Between January 2010 and December 2012, totally 342 patients, including those with SAP [13.9% (43/309)], UAP [59.2% (183/309)], NSTEMI [24.3% (75/309)], and post-STEMI angina  [2.6% (8/309)], undergoing PCI/stenting for the significant ULMCA disease were retrospectively enrolled in the current study. Informed consent was obtained from each study subject. The Institutional Review Committee on Human Research at our institution approved the study protocol.For elective or primary PCI, a transradial artery approach using a 6-French arterial sheath is a routine procedure for patients at Kaohsiung Chang Gang Memorial Hospital unless Allen\u2019s test is positive on both sides. Routine trans-radial or trans-brachial arterial approach is also adopted in each patient for LM stenting/PCI using 6-French (F) or 7-F guiding catheter dependent on the LM lesion character and the strategy of stent implantation. Additionally, other vessels with significant obstruction that limited the blood flow were eligible for PCI at the same stage or during hospitalization. The detailed procedure and protocol have been reported in our previous studies Intra-aortic balloon pump (IABP) support was performed via right femoral arterial approach in patients experiencing advanced congestive heart failure (CHF) [defined as New York Heart Association Function classification (Fc)\u2267Fc III], or acute pulmonary edema associated with unstable condition or hemodynamic instability. Moreover, elective IABP support  prior to LM PCI was performed for patients with severe left ventricular dysfunction  without CHF. IABP was promptly removed in patients after LM PCI.Definitions of cardiogenic shock and profound shock were based on our previous report Extra-corporeal membrane oxygenator (ECMO) was inserted at catheterization room for patients whose SBP could not be maintained above 75 mmHg after IABP support and intravenous administration of dopamine >20 g/kg/min.3\u2212LVEDS3)/LVEDD3]\u00d7100.LV function was assessed using transthoracic echocardiography. With the patients in a supine position, left ventricular internal dimensions [i.e. end-systolic diameter (ESD) and end-diastolic diameter (EDD)] were measured according to the American Society of Echocardiography leading-edge method using at least 3 consecutives cardiac cycles. The LV ejection fraction (LVEF) was calculated as: LVEF (%)\u200a=\u200a patients with ECMO support were dead, including 1 in group 2 and 3 in group 3. Of these 4 fatalities, 3 were related to cardiac death and 1 was related to sepsis during hospitalization.Isolated IABP support  was given to 45 patients, including 2 in group 1, 15 in group 2, 24 in group 3, and 4 in group 4 at cardiac catheterization room due to poor LV function, hypotension/cardiogenic shock, advanced CHF, or acute pulmonary edema. The PCI procedure was successful in all 45 patients without procedure-related death. Mortality occurred in 4 patients [17.8% (8/45)] with IABP support, including 3 in group 2, 4 in group 3, and 1 in group 4. Of these 8 patients, cardiac death was implicated in 5 and 3 were related to sepsis during hospitalization.In these IABP support patients, 14 of 45 patients (31.1%) of patients had received prophylactic IABP support for ULMCA stenting. The IABP support was promptly and successfully removed from all of the patients. All of these patients were uneventfully discharged from hospital.The achievement of final TIMI-3 flow and the procedural success rate did not differ among the four groups. Around 80% of all patients had received drug eluting stent implantation. The reasons for those 20% who did not receive drug eluting stent implantation were due to either economic problem or an LM diameter greater than 4.5 mm. The incidence of drug eluting stent use was significantly higher in group 2 than that in groups 1 and 3, but it showed no difference between groups 2 and 4 or among groups 1, 3, and 4. In addition, the incidence of bare metal stent implantation showed a reversed pattern compared to that of drug eluting stent implantation among the four groups. Furthermore, incidence of intra-vascular ultrasound (IVUS) utilization during the procedure showed a pattern identical to that of drug eluting stent use among the four groups. The overall utilization of the IVUS was only 60.5% (207/342) in the current study, mainly due to the economic problem. On the other hand, all of our patients had received high-pressure dilation after stent implantation. The number of PCI vessels and the number of stenting vessels did not differ among the four groups.Multiple stepwise logistic regression analysis demonstrated that acute kidney injury was the strongest independent predictor of 30-day mortality. Additionally, WBC count and BMI were significantly independent predictors of 30-day mortality.This study which investigated the safety and feasibility of coronary stenting in patients with significant ULMCA stenosis yielded several striking clinical implications. First, the results of the present study demonstrated that catheter-based stenting for significant ULMCA disease was safe and feasible with very high procedural and clinical successful rates in real-world clinical practice. Second, in high-risk subgroup of patients and those patients with unstable condition, mechanical-assisted  PCI for significant ULMCA disease offered an additional benefit with high rates of procedural success  and clinical success (95.5%). Third, in the relatively low-risk subgroups , the 30-day clinical outcome in the present study was not inferior to that previously reported for PCI or CABG clinical trials Despite clear recommendation of CABG as the gold standard in the treatment of significant ULMCA disease One important finding in the present study is that more than 300 patients who did not receive CABG due to various reasons (please see the inclusion and exclusion enrollment criteria) were willing to receive PCI for the treatment of their significant ULMCA disease within a period of less than 3 years. This implies that PCI may be an alternative treatment strategy in the treatment of patients with significant ULMCA obstruction in our daily clinical service.Another significant finding is that the outcomes of angiography were excellent  in various clinical settings in the current study. Our findings, therefore, highlight the reliability of PCI as a safe and feasible therapeutic option for patients with significant ULMCA disease unsuitable for CABG.It is noteworthy that in the relatively low-risk subgroups , not only was the procedural success rate (100%) excellent, but the clinical success rate is also very promising . Previous clinical trials have shown that PCI treatment for significant ULMCA disease was associated with a very high successful rate with a very low incidence of 30-day major adverse cardiac event The most important finding in the present study is that the use of prophylactic IABP support  for patients with significant ULMCA disease and poor heart function undergoing stenting provided excellent angiographic results  and good 30-day clinical success . Our findings provide important clinical information and encourage the use of this approach in the setting of significant ULMCA disease in our real word clinical practice.In the current study, the 30-day mortality rate in the non-STEMI  subgroup was around 8% after ULMCA stenting. Interestingly, one previous study has revealed that the 30-day mortality rate was 12% in patients with non-STEMI and significant ULMCA disease after receiving CABG Of particular importance is that mechanical -assisted PCI for the high-risk patients showed 100% procedural success rate and acceptable 30-day clinical outcome [30-day mortality: 17.8% (8/45)]. Further analysis revealed that the 30-day cardiac-related death in this very high-risk patient subgroup was 11.1% (5/45). Therefore, the results of the present study were comparable to those of previous studies The overall 30-day cardiac-related death was 2.9% (9/309) . The accIn concert with the results of the previous studies that identified impaired renal function and acute renal failure as the strong predictors of short-term and long-term clinical outcome in ACS patients undergoing PCI This study has limitations. First, the retrospective nature of this study cannot completely exclude the possibility of the presence of bias. Second, additional information on risk and prognostic stratification of ULMCA disease using PCI as a therapeutic option was not available without routine calculation of the SYNTAX score prior to or after PCI in our daily clinical practice. However, this study did not attempt to exclude any patient in our real world practice and in fact that our results were promising.The study presents high rates of procedural success and excellent 30-day clinical outcomes, without making assertions about safety."}
+{"text": "Sarcoidosis is a multisystem disease affecting different organs with different frequency rates depending on geographical location. Musculoskeletal abnormalities includes osseous lesions , sarcoidal arthropathy, and sarcoidal myopathy. Musculoskeletal involvement is reported in a significant number of patients.This study aimed to determine the prevalence and clinical picture of musculoskeletal sarcoidosis in Iranian cohort of patients with sarcoidosis.We designed a descriptive cross-sectional study including 30 patients with sarcoidosis who had hospitalized in the Rheumatology Department at Ghaem Hospital, Mashhad, Iran. The patients were evaluated for musculoskeletal symptoms using history, physical examination, and paraclinical data.Of the 30 studied patients, 24 were female (80%) and six were male (20%). The mean age at diagnosis was 38 years. Sarcoidal arthropathy (arthritis and periarthritis) was observed in 26 patients (86.6%). Furthermore, the initial presentation was associated with joint symptoms in 19 cases (63.3%); acute arthritis developed in 17 (65%) while bone and muscle involvements each occurred in 2 (6.6%).Sarcoidosis is a common disease in women aged 20 to 40 years. The most common involved joint were consecutively ankles, knees, and wrists, reaching a accumulated frequency of 86.6%; however, bone and muscle involvements were uncommon. Sarcoidosis is an inflammatory disorder characterized by noncaseating granulomas within tissues. Although the etiology of sarcoidosis remains unknown, infectious, occupational agents, and factors associated with the seasons of the year are most likely involved -4. It isArthralgia, along with synovitis and periarthritis, dominates the clinical picture of sarcoidal arthropathy. Acute arthritis presents as symmetric, migratory, or additive polyarthritis that often involves the knees, ankles, wrists, elbows, and the proximal interphalangeal joints and may be associated with Lofgren's syndrome. Ankle and knee involvements are more common and typically symmetric. In patients with the acute syndrome, joint symptoms are often self-limited and are resolved within a few weeks without any permanent joint damage , 10. OccThe aim of the present study was to evaluate the prevalence and clinical picture of musculoskeletal symptoms in Iranian cohort of patients with sarcoidosis who were hospitalized in the rheumatology ward of our referral university center.This descriptive cross-sectional study was conducted on patients with sarcoidosis who were hospitalized in rheumatology ward of Ghaem Hospital, a university and referral center in northeast of Iran that has all specialty fields, over a ten-year period. Overall, from 42 patients with sarcoidosis, 12 patients were excluded due to lack of sufficient data, and 30 patients were included in this study. The definite diagnosis of sarcoidosis was made through histologic findings on biopsy in association with compatible clinical features and laboratory tests. We gathered all patients' data including clinical and paraclinical variables from their prefilled records. Therefore, we recruited patients with noncaseating granulomas in whom other etiologies such as mycobacterial, fungal, and parasitic infections as well as a history of contact with organic substances including organic bread were ruled out , 13. SomOf the total number of 30 patients included in the study, 24 were female (80%) and six were male (20%). The mean age at diagnosis was 38.25 years . Comorbidities amongst patients included hypertriglyceridemia in four patients (13.3%), hypertension in 2 (6.6%), diabetes mellitus in 2 (6.6%), and a history of allergies, heart attack, and obstructive lung disease each in one patient (3.3%). There were no other known rheumatic diseases in any of the patients with sarcoidosis. The most common clinical manifestations in the course of the disease were consecutively musculoskeletal in 26 cases (86.6%), dermatologic in 20 (66.6%), lower respiratory in 17 (56.6%), constitutional symptoms in 15 (50%), ophthalmic in 6 (20%), upper respiratory in 3 (10%), gastrointestinal in 2 (6.6%), involvement of the exocrine glands in 1 (3.3%), and extrathoracic lymph nodes in 1 (3.3%). Of the 30 patients, biopsies were obtained in only five patients (16.6%). In the musculoskeletal system, joint symptoms were observed in 26 patients (86.6%), acute arthritis in 17 (65.4%), periarthritis in 9 (34.6%), bone involvement in 2 (6.6%), and muscle involvement in 2 (6.6%) . The chrLofgren's syndrome was observed in 16 patients (53.3%) including 13 women (81.2%) and three men (18.8%), among which joint symptoms and fever were reported in 15 (93.7%) and 7 (43.7%), respectively. The chronological association between joint symptoms and the development of erythema nodosum and hilar adenopathy in patients with Lofgren's syndrome are shown in The clinical findings in patients with acute arthritis of sarcoidosis included swelling (76%), pain (70%), erythema (52%), tenderness (52%), limited range of motion (41%), pain on passive movement (23%), and warmth (17%). The frequently involved joints were the ankles (94%), knees (35%), wrists (35%), and fingers (23%) with proximal interphalangeal joints involvement in 18%, metacarpophalangeal joints in 12%, and distal interphalangeal joint in 6%. Regarding arthritis, nine out of the 17 patients with acute arthritis had oligoarthritis (53%) and the remaining eight patients (47%) had polyarthritis. All cases of polyarthritis were symmetric. Furthermore, nine patients had additive arthritis whereas there was no case of migratory arthritis. On plain X-ray, except periarticular soft tissue swelling, no other changes such as joint destruction or reduced joint space were detected. Bone lesions were found in only two patients (6.6%) with one patient having multiple lytic and sclerotic lesions in the fingers and toes and another with lytic lesions in both middle fingers, which were accompanied by superficial nodules. As with bone lesions, muscular involvement was observed in two patients (6.6%) presenting as symmetric muscle weakness that were more prominent in proximal than distal parts; moreover, muscle tenderness was present in one patient. Creatine phosphokinase and lactate dehydrogenase levels were elevated in both patients, but no further workup had been done to confirm myositis. Nevertheless, involvement of other organs such as lung, skin, and joints in both patients and bone lesions in one patient were accounted for the histological diagnosis of sarcoidosis. Furthermore, the muscle involvement in both cases was acute with no evidence of chronic muscle disease such as indurations or calcifications.Sarcoidosis is a multisystem disorder with an unknown etiology characterized by specific clinical manifestations and the histopathologic finding of noncaseating granulomas within involved tissues. The disease may present acutely or subacutely within weeks or may have an indolent course of several months. Sarcoidosis presentation is clinically significant because of the involvement of the lungs, and to a lesser extent the eyes, skin, and lymph nodes; however, joint disease, which is present in 35% of patients , 6, is aAs mentioned earlier, regarding the skeletal system, bone lesions occurred in 6.6% of cases in the present study, while the reported prevalence is 1% to 13% , 11, 13.According to the study by Sekine et al. , musclesContrary to findings by other studies, the prevalence of acute arthritis in the present study was significantly higher (65%) due to the possible contribution of race. Since there was a significant prevalence of Lofgren\u2019s syndrome among our patients, the role of genetic factors (e.g. HLA) and the environmental factors should be investigated more thoroughly. Therefore, it is highly recommended to contemplate the diagnosis of sarcoidosis when approaching patients with suggestive symptoms plus joint involvement, especially those of the knees, ankles, and wrists as well as muscle cramps and nodules.We evaluated only hospitalized patients; moreover, our sample size was small and the descriptive study design without any control group had negatively affected the generalization of the present study."}
+{"text": "Emergence of drug resistance has complicated the treatment of Tuberculosis (TB). WHO reports India as one among 27 \u201chigh burden\u201d multidrug resistant (MDR) TB countries. The study was carried out to detect drug resistance of mycobacterial isolates in HIV patients.The clinical specimens collected from HIV seropositive AFB smear negative patients (Group A) with features of TB, AFB smear positive, HIV reactive (Group B) and AFB smear positive, HIV negative (Group C) were processed as per standard protocol. They were inoculated onto Lowenstein Jensen media and the isolates obtained were subjected to drug susceptibility test (DST) by proportion method and Genotype MTBDR plus assay.Mycobacterium tuberculosis complex and 7 (9%) were Mycobacterium avium complex. As per phenotypic method, of 76 isolates, 50 (65.8%) were sensitive to all drugs and 26 (34.2%) resistant to one or more drugs. The MDR and resistance to at least single drug of Group A, B and C were  and  respectively. MTBDR assay showed similar results except one discrepancy i.e., one isolate was resistant to rifampicin that was sensitive in proportion method.In Group A out of 162 patients, 443 clinical samples were collected and 76 mycobacterial strains were obtained from 67 (41%) patients. In this 69 (91%) were The increase of MDRTB in high TB burden settings stresses the need for DST. This helps in providing proper treatment regimens, improve prognosis and prevent the spread of drug resistant TB."}
+{"text": "Daily clinical activities in dental operatory expose dental surgeons to varied forms of ocular events. The purpose of the study was to determine the prevalence and pattern of ocular splashes and foreign bodies among dental surgeons in Nigeria.This questionnaire-based cross-sectional of dental surgeons in Southern Nigeria was conducted between September 2010 and August 2011. The information elicited were demography, experience and type of ocular event, implicated dental procedure and action taken.Of the 185 studied, 148 of them responded. Of these 148 respondents, 56 (37.8%) reported foreign body, 18 (12.2%) splash, 33 (22.3%) both foreign body and splash while 41 (27.7%) reported no ocular event. It therefore means that the overall prevalence of ocular events among the respondents was 107 (72.3%). The prevalence of ocular events was significantly associated with age (p\u2009=\u20090.014), years of practice (p\u2009=\u20090.033) and safety eye goggle use (p\u2009=\u20090.023). The main dental procedures implicated in the ocular events among the respondents were scaling 77 (72.0%), tooth/cavity preparation 17 (15.9%), polishing 11 (10.3%) and forcep tooth extraction 10 (9.3%). The major implicated aetiological agents in the ocular events were calculus 74 (69.2%), saliva 29 (27.1%), mixed blood & saliva 19 (17.8%), tooth particles 15 (14.0%) and blood 9 (8.4%). The predominant action taken by the respondents was to rinse the eye under running water 89 (83.2%).Ocular splash and foreign body events are high among dental surgeons in Nigeria. Age, years of practice and safety eye goggles wear were also found to be associated with ocular events. Eye safety awareness is therefore deemed a necessity for dental surgeon in Southern Nigeria. Work-related ocular injuries, arising from mechanical, chemical, microbiological, and electromagnetic insult are common and constitute a significant morbidity and disability among dentists -4. StudiDental care procedures involve the use of rotary instruments and cutting and use of wires which generate foreign bodies, splatter and aerosols containing water, saliva, microorganisms, blood, tooth particles, lubricating oil, and restorative materials. These materials and fluids, play a significant role in causing injuries to the unprotected eye ,12. AdveOcular injuries in dental practice may have serious and long term effect and sometimes lead to loss of vision in one or both eyes . This wiProtective eyewear during dental procedures and patient-care activities shields the eyes from splatter or debris generated but the compliance with protective eye wear among dental professionals worldwide is poor. Studies among dental surgeons have consistently shown poor adherence to eye safety practices which increases their tendencies to suffer ocular injuries ,9. The pThis cross-sectional study was conducted among 185 dental surgeons of different cadres recruited from six tertiary Oral healthcare centers in Southern Nigeria between September, 2010 and August, 2011. These tertiary hospitals which are actively involved in undergraduate and postgraduate dental workforce training include University College Hospital Ibadan, University of Benin Teaching Hospital Benin City, University of Nigeria Teaching Hospital Enugu, University of Port Harcourt Teaching Hospital Port Harcourt, Lagos University Teaching Hospital Idi Araba and Obafemi Awolowo University Ile-Ife.A pretested self-administered questionnaire designed by the authors was used for data collection.The questionnaire was test and re-tested on ten dental surgeons working in private and secondary health facilities in Benin-City in a four week interval with reliability Cronbach's alpha of 0.85. The information elicited were demography, experience and type of ocular events in the last 12\u00a0months, procedure during which it occurred and action taken. The ocular events that involved fluid were categorized as ocular splash while those that involved solid substances were categorized as ocular foreign body.Ethical approval was obtained from the College of Medical Sciences, University of Benin, Benin-City, Nigeria Research and Ethics Committee. Informed consent was obtained from all the research participants. Data was subjected to frequencies, percentages, cross tabulation using Statistical Package for Social Sciences (SPSS) version 17.0. The test for significance was done using Chi square statistics and P\u2009<\u20090.05 was considered significant.Out of the 185 questionnaires, 148 questionnaires were returned giving an overall response rate of 80.0%. Dentists older than 30\u00a0years constituted 69 (46.6%) of the respondents. The male: female ratio of the respondents was 1.4:1.0. A total of 63 42.6%) of the respondents reported treating more than three patients daily. Of the 148 respondents, 56 (37.8%) reported foreign body, 18 (12.2%) splash, 33 (22.3%) both foreign body and splash while 41 (27.7%) reported no ocular event. It therefore means that the overall prevalence of ocular splashes and foreign body among the respondents was 107 (72.3%). The prevalence of ocular events was significantly associated with age and years of practices. The pattern of safety eye goggle wear among the respondents were never 32 (21.6%), rarely 37 (25.0), occasionally 29 (19.6%), sometimes 39 (26.4%) and always 11 (7.4%). The prevalence of ocular events was significantly associated pattern of safety eye goggle wear  of the respondents reported ocular event experience in this study. This was comparable to 73.0% ocular accidents reported by Zarra and Lambrianidis 2.3% of t. This hiThe implication of blood and body fluids [saliva (27.1%), blood (8.4%) and mixed blood & saliva (17.8%) as aetiological agents in the ocular splashes showcase the possibility of attending dental surgeons contracting infection from infected patient through the ocular mucosa. This is against the backdrop that accidentally contamination of the eye with bodily fluid  in the absence of breach and abrasion carries serious potential to cause bacterial and viral infections . ControlThe most common dental conditions in Nigeria are periodontal disease and dental caries. They are managed by scaling and polishing, cavity preparation for restoration and extraction for the non-restorable and complicated carious cases. This is the obvious explanation of why the main dental procedures implicated in the ocular events were mainly scaling, tooth/cavity preparation, polishing and forcep extraction. However, the majority of actions taken among the respondents with ocular events in this study were restricted to the dental clinic. The predominant action taken was to rinse the eye with water which may have helped to give relief to the affected dental surgeon because calculus and saliva were main aetiological ocular foreign body and splash respectively. Anecdoctally, some of the behaviours were not different from common behaviours of non-professional with foreign body in their eye. Self-medication with eye drop to prevent infection was also reported 3.7% of the respondents. However some actions that took place outside the dental clinic includes eye clinic visit (5.6%) and Human Immunodeficiency virus (HIV) testing (3.7%). This highlighted either a heightened health and ocular concern or the possibility of severe injury that trigger proper ophthalmological care seeking and fear of mucosal HIV transmission. Although, this study finding may be limited by recall bias, the comprehensiveness of the ocular event in relation to foreign body and splash in this study will be an obvious justification for further onsite study.Data from this study revealed a high prevalence of ocular events among dental surgeons in Southern Nigeria. Age, years of practice and safety eye goggles wear were also found to be associated with ocular events. Eye safety awareness is therefore deemed a necessity for dental surgeon in Southern Nigeria."}
+{"text": "Surgical site infections (SSI) after neurosurgery have serious clinical consequences and increase costs. Surveillance of SSI after craniotomy is not carried out enough.To describe the results of a SSI surveillance program among patients after craniotomy.Prospective surveillance in a 700-bed university hospital in Barcelona, Spain. The study included all patients admitted for elective or urgent craniotomy from October 2012 to December 2014. All craniotomies followed up within 30 days of surgery or after 1 year if implant inserted.CDC definitions for SSI were used. Prosthetic implants included plates and screws for cranial osteosynthesis.Propionibacterium spp (26%) Staphylococcus aureus (21%) and gram negative bacilli (33%). Thirteen out of 61 episodes were polymicrobial.Overall, 469 patients were followed; 54% women, median age of 52 years (range: 18-84). Among them, 70% were elective procedures and 30% urgent or delayed. An implant to secure the bone flap to the skull was used in 426 (91%) patients. SSI developed in 61 patients (13%), organ/space 9%, deep incisional 3.5% and superficial 0.5%. Thirty-three patients (54%) required readmission. Mean days from surgery to infection were 40d. Comparison between patients with and without SSI did not show differences in age, sex, type of surgery (elective or urgent), implant insertion, operation duration, and adequacy of antimicrobial prophylaxis. SSI rates vary depending on ASA score and reason for neurosurgery. Common causative bacteria was Coagulase-negative staphylococci (33%) followed by Surveillance of craniotomy has allowed us to determine SSI rates and risk factors for SSI. Our results require the implementation of preventive measures.None declared."}
+{"text": "Investigators from Ruth Children's Hospital, Haifa, and Schneider Medical Center, Petah Tikuah, Israel, evaluated the long-term motor and neurocognitive outcome of 43 children hospitalized during 2002-2012 with acute disseminated encephalomyelitis (ADEM), and identified prognostic risk factors. Investigators from Ruth Children's Hospital, Haifa, and Schneider Medical Center, Petah Tikuah, Israel, evaluated the long-term motor and neurocognitive outcome of 43 children hospitalized during 2002-2012 with acute disseminated encephalomyelitis (ADEM), and identified prognostic risk factors. Patients were treated with IV methylprednisolone 30 mg/kg for 3-5 days, followed by oral corticosteroids. Full neurological examinations and comprehensive neurocognitive and behavioral assessments identified different degrees of neurological sequelae in 26 children (61%) after a mean follow-up of 5.5 +/-3.5 years. Persisting symptoms occurred in 44%. The most common residual impairments included attention-deficit hyperactivity disorder (44%), behavioral problems (32%), and learning disabilities (21%). A full-scale IQ of 70 or less was found as a sequel to ADEM in five (12%) children, compared to 2.2% in the general population. Neurocognitive sequelae were found even in children considered fully recovered at time of discharge. The EEG performed in 16 patients was abnormal in 12 (75%); epilepsy developed in only 3 patients (7%). MRI revealed cortical and subcortical hemispheric lesions in 49% of patients, basal ganglia and thalamus in 31%, brain stem in 26%, spinal cord in 20%, and cerebellum in 15%. Complete resolution on follow-up MRI was found in 65% and partial resolution in 35%. Risk factors for severe neurological sequelae and poor long-term outcome were older age at presentation (p = 0.025) and male gender (p = 024). Neuropsychological testing and long-term follow-up is recommended for all children with ADEM, even in those with no neurological deficits at discharge. [COMMENTARY. The cause of ADHD is highly genetic and involves the dopamine receptor and transporter genes. Environmental factors are also important and a gene-environmental interplay is frequently recognized . Among a"}
+{"text": "Improved survival in patients with haematological malignancy (HM) admitted to the intensive care unit (ICU) has largely been reported in uncontrolled cohorts. Newly diagnosed patients should be admitted, since their prognosis is still to be defined. Nevertheless the admission of the remaining patients remains a matter of substantial controversy.To analyse the survival of HM patients admitted to ICU over a 7-year period (from 2008 to 2014).P-value less than 0.05 were considered significant.We conducted a detailed retrospective study of sequential adult ICU admissions with HM in a single centre, considering numerous variables with regard to their influence on ICU and mortality. Overall survival (OS) was defined as the time from ICU admission to death from any cause, and surviving patients were censored at last follow-up. OS were calculated using the Kaplan-Meier method estimates and the differences assessed by the log-rank test. All Overall, 67 HM patients were included, 62% were male, with a median age of 59 years (IQR: 19-82). The median APACHE II was 22 (IQR: 12-49). The hematologic diagnosis was as follow: 25 lymphomas (37%), 9 Multiple Myelomas (13%), 6 chronic lymphocytic leukaemia (9%) and 28 acute leukaemia or myeloproliferative or myelodisplasic syndromes in acute phase (41%). Disease status at the moment of UCI admission was: 19 (28%) complete response (CR), 24 (36%) newly diagnosis disease and 24 (36%) active disease ; 67% of patients were on active oncologic treatment. Principal ICU diagnosis was sepsis (68%). Median number of organ failure were 2 (IQR: 0-4), and up to 36% of patients presented neutropenia at the moment of UCI admission. Median ICU length of stay was 7 days (IQR: 1-48) and hospital of stay 38 days (IQR: 8-109). ICU mortality was 46% .P = 0.04) Figure P = 0.01) Figure P = 0.009) were the most powerful predictor variables associated with an increased mortality.The rates for ICU, 1-month, 6-month and 12 month mortality were 48%, 55% and 66%, respectively. With a median follow up of 18.5 months (IQR: 8-66), OS was 31%. Figure OS of our HM patients is not worse than that recently reported from specialist units.The decision for or against ICU admission of patients with HM should become dependent of the underlying malignant disease and especially with the status of the disease at the moment of admission. Almost 50% of survivors are still alive one year after ICU admission, suggesting that an important subgroup of HM patients benefit from ICU admission."}
+{"text": "To determine the dietary practices of Saudi cerebral palsy (CP) children.A self-administered questionnaire was used to collect the following information from parents of CP children: demographics, main source of dietary information, frequency of main meals, foods/drinks used for main meals and in-between-meals.Parents of 157 CP children participated. Parents were divided into three, while children were divided into two age groups. The main sources of dietary information included popular media (46.5%) and dentist (36.3%). Most of the children had three meals (71.3%) or two meals (24.8%) daily. Choices for main meals included meats (68.8%), vegetables (65.6%), fruits (28.4%) and puddings (38.9%). The main three drinks choices with main meals included packed juices (59.9%), bottled water (58.8%) and fresh fruit juices (33.1%). The choices for in-between meals snacks included biscuits (61.1%), potato chips (51.6%), fruits (43.9%) and chocolates (41.4%). The choice of drinks with snacks was similar to that used with main meals. In cross-tabulation, older parents used meat (p=.03) and soft drinks (p=.04) more often for their children\u2019s main meals. Older children were given meat (p=.004) and soft drinks (p=.04) more often with main meals. Older children were given potato chips as snacks more often than younger children (p=.02), and there was a trend towards use of chocolates as snacks in older children (p=.08).Parents of CP children need to be educated about dietary practices of their children especially in areas such as the use of packed juices, dairy products, soft drinks and chocolates. Cerebral palsy (CP) is a common form of neuromuscular disability4Cerebral palsy children have a reduced self-cleansing function of the oral cavity due to drooling and abnormal movement of the tongue and facial muscles; their diet is usually rich in pastry food and carbohydrates, and their caregivers have difficulty in practicing an appropriate oral hygiene.6It is well known that a balanced diet also affects children\u2019s dental health. Various factors may play a role in the ability of certain foods to cause dental disease. These include; the potential of the food to: produce acids that lower the salivary pH and provide an environment for bacterial growth and decalcification of enamel, adhere to the teeth, stimulate saliva production, buffer the production of acids and the rate at which a food dissolves.9Although CP population in Saudi Arabia has been shown to exhibit a high prevalence of oral diseases in previous and more recent reportsThis questionnaire type study was conducted in the Disabled Children\u2019s Association Center (DCAC) in Riyadh. The institutional and ethical approvals were obtained from King Saud University, College of Dentistry Research Center and DCAC Research Ethical Committee. A self-administered questionnaire was especially developed to collect the following information from the parents of Saudi CP children.Demographic information such as age and gender of parents and their CP children.Main source of oral health information for their children.Frequency of main meals per day.Foods/drinks used for main meals.Foods/drinks used between-meals.The questionnaire was pre-tested on parents not participating in the study. Some changes were made to make it more comprehensible for parents.After obtaining a written consent from the parents; the questionnaires were handed over to the parents at the time of their CP children routine dental care in the DCAC dental clinic. All the questionnaires had a covering letter explaining the research objectives and ensuring anonymity/confidentiality of the information obtained. Non Saudi parents and parents of children with disabilities other than CP were not included in the study. Parents who could not read or write were assisted in completion of the questionnaire.Collected data were entered into a computer and analyzed using Statistical Package for Social Sciences \u201cSPSS\u201d (Version #16).Descriptive statistics, including the means and standard deviations, as well as frequencies, were calculated. Chi-square and Fisher\u2019s Exact tests were used to determine any significant difference (P\u22640.05) in responses in terms of parental age group, parental gender, CP children\u2019s age group and gender.Parents of 157 Saudi CP children registered in the center completed the questionnaire. Mostly mothers (86.6%) completed the questionnaire; mean parental age was 34.0 years . Mean age of CP children was 6.7 years  . For the purpose of analyses; the parents were divided into three age groups; 20 - 30 years, 31 - 40 years and 41 - 58 years. Similarly, children were divided into two age groups, 2 - 6 years and 7 - 12 years . Of the The main sources of dietary information for the parents of CP children included popular media  (46.50%), dentists (36.30%), child\u2019s health care center (8.30%), child\u2019s school (4.50%) and others (4.50%). Most of the children had either three meals (71.3%) or two meals (24.8%) per day. Choices for main meals included meats (68.8%), vegetables (65.6%), fruits (48.4%) and puddings (38.9%). The main three drinks choices with main meals included packed juices (59.9%), bottled water (58.8%) and fresh fruit juices (33.1%). The choices for in-between meals snacks included biscuits (61.1%), potato chips (51.6%), fruits (43.9%) and chocolates (41.4%). Cheese consumption during snacking was reported by about one-third of the participants only. The choice of drinks with snacks was similar to that used with main meals .p=.03); and used more soft drinks (p=.04) and less fresh fruit juices (P=.05) with main meals. Older children were given meat more often as main meal compared to younger children (p=.004); and were also given soft drinks with main meals more often (p=.04). Older CP children were given potato chips as snacks more often than younger children (p=.02) and less other drinks such as milk with snacks (p=.05). There was an increasing trend towards use of chocolates as snacks in older children (p=.08). All other cross-tabulations were non-significant.Cross-tabulation between parental age groups and various dependent variables showed that older parents as compared to younger parents used meat more often for their CP children\u2019s main meals (Assessing dietary practices is a useful tool in identifying those children at high risk of oral diseases. Feeding difficulties in CP children usually lead to dietary inadequacies,Most of the studies conducted previously regarding CP children dietary intake evaluated the nutritional status, feeding difficulties and feeding methods in relation to growth and general health outcomes,Type and frequency of snacking are important factors in development of oral diseases.Improved nutrition is linked to improved health outcomes and quality of life.The parents of CP children need to be educated about dietary practices of their children especially in areas such as the use of packed juices, dairy products, soft drinks and chocolates."}
+{"text": "In Slovakia, mandatory surveillance of Clostridium difficile infection (CDI) have been established due to electronically national Epidemiological information systems (EPIS) long time ago, but compliance to surveillance are low.The aim of this hospital-based study was to assess real prevalence and outcome of CDI in University Hospital Trnava, Slovakia during years 2010-2014.Clostridium difficile Toxin A/B immunochromatographic rapid assay, R-Biopharm) in University Hospital Trnava  from laboratory information system and medical records.We analysed all patients with laboratory confirmed CDI  accounted for 75,7% (240). The mean age of patients was 72,8 \u00b1 15 years (range 15-96) and 60,3% (191) were women. The most frequently antibiotics used before onset CDI were quinolones  for the treatment of respiration or urinary tract infection. Overall recurrence of CDI was observed within 3 months after the first episode in 6,9% (22) of cases. Total hospital mortality rate was 13,9% (44) and hospital mortality associated with CDI only 1,9% (6).Clostridium difficile and about prevalence in long-term care facility are available in Slovakia.These results show high prevalence HA-CDI in our hospital and emphasizing the importance of implementing better infection control practice in order to prevent further spread. To date no data about specific ribotype of None declared."}
+{"text": "The most common acquired fistula of the urinary tract is Vesicovaginal fistulae (VVF) (1) posing social stigmata for the patient as well as a surgical challenge for the urologist. Here we present our initial experience with Robotic assisted laparoscopic repair of VVF, its safety and efficacy. Seven out of eight fistulas were post hysterectomy; five had undergone abdominal while two had laparoscopic hysterectomy while one was due to prolonged labour. Two had associated ureteric injury. All underwent robotic assisted laparoscopic trans abdominal extravesical approach. Three 8 mm ports for robotic arms, one 12 mm port for camera and another 12 mm for assistant were used in a fan shaped manner. All had preoperative ureteric catheter placed. Bladder was closed in two layers and vagina in one layer. Omental flap placed in all cases except two where it was not possible. Drain and per urethral catheter placed in all cases. Double J stents were placed in two cases requiring ureteric implantation additionally. The mean age of presentation was 39.25 years (26-47 range) with mean BMI being 26.25 kg/m2 (21-32 range). Mean duration between insult and repair was 9.37 months (3-24 months). Only in single case there was history of previous repair attempt. On cystoscopy four had supratrigonal VVF and four were trigonal with mean size of 13.37 mm (7-20 mm). Mean operative time was 117.5 minutes (90-150). There were no intraoperative/postoperative complications or need for open conversion. Mean haemoglobin drop was 1.4 gm/dL (0.3-2 gm). Drain was removed once 24-48 hours output is negligible. One patient had post-operative urinary leak at 2 weeks which ceased with continuation of catheterisation for another 2 weeks. Catheter was removed after voiding cystourethrogram showed no leak at 2-3 weeks postoperatively. Mean duration of drain was 3.75 days (3-5) and per urethral catheterisation (which was removed after voiding cystourethrography) was 15.75 days (9-28). Mean hospital stay was 6.62 days (4-14). Post-operative bladder capacity was 324.28 cc (280-350) on voiding diary. Follow up ranged from 3-9 months. At 3 months of follow-up, these patients continued to void normally and there was no evidence of recurrence of VVF. Robotic repair of VVF is safe and feasible and has additional advantages in the form of precise suturing under 3D vision and certainly a more striking and effective option especially in complex VVF repair associated with ureteric injuries (2). They have demonstrated that robotic repair of VVF is associated with minimal morbidity with excellent 3 month follow up outcomes. As urologists have advanced their robotic expertise, they are now able to tackle the more difficult cases of pelvic reconstruction. VVF can represent a challenge due to both etiology and variability in anatomy. The authors are correct in their commentary that the robotic platform with its 3D vision system and precise instrumentation in the pelvis allow it to be an effective option when considering VVF repair. While urologists can add this to their robotic armamentarium, I would caution that such cases should be only attempted by seasoned robotic surgeons.Trushar Patel, MDAssistant Professor of UrologyDirector of Robotic Urologic Surgery, Florida Hospital TampaMorsani College of MedicineUniversity of South Florida, USAE-mail: trushar.patelmd@gmail.com"}
+{"text": "The purpose of this study was to describe our experience with various nerve and muscle procedures in traumatic adult brachial plexus injuries.Two hundred and nine (n=209) cases of adult brachial plexus injuries were treated in Surabaya from March 2005 to May 2014. Thirty seven cases treated in 2014 were excluded from this study.The number of operative cases of brachial plexus injury increase each year. Fifty nine percent of cases were managed in public hospitals and 41% in private hospitals. Most of the patients were males (86%) and the rest were females (14%). Brachial plexus injury was most prevalent between 21-30 years of age (37%). Motor vehicle accident was the most frequent mode of injury (90%). The right side was the most frequently affected side (77%). The levels of injury were as follows: C5-6 postganglionic (24%), C5-7 postganglionic (19%), C8-T1 postganglionic (3%), C5-T1 (54%). In complete BPI, the combination of C5-7 postganglionic and C8-T1 preganglionic were present in 33% of cases. There were 2 types of surgical intervention: nerve procedure (67%) and muscle procedure (33%). Nerve transfer was the most frequently employed mode of nerve procedures . The most frequently performed muscle procedure was the free functioning muscle transfer (78%)."}
+{"text": "In Morocco as in many African countries, AIDS and its procession of opportunistic infections are a major cause of morbidity and mortality. The purpose of study was to determine the frequency of digestive opportunistic parasitosis in patients infected with HIV.A retroprospective study conducted 20 months in the department of infectious diseases. Were included all patients infected with HIV and opportunistic intestinal parasitosis confirmed in EPS. Data were collected on computer files (Nadis) and analyzed on Epi Info.Among the 70 patients involved, the average age was 37 years with a slight male predominance. The median CD4 was 62cel/mm \u00b3. Digestive opportunistic parasitic were indicative of HIV infection in 54 cases (77%) and in 16 cases (23%) they occurred at the waning of treatment failure. All patients had diarrhea. These opportunistic parasitic agents were isolated only in 56 cases: the cryptosporidiosis (40%), microsporidia (31%), Isospora belli (6%) and Cyclospora (3%). They were associated in 14 cases including Cryptosporidiosis+ Microsporidiosis (18.57%) and Cryptosporidiosis+ Isosporiasis (1.43%) in HARRT the outcome was favorable for 86% of patients (n = 60) and mortality was 14% (n=10).Opportunistic digestive parasites remain common in our context because of late diagnosis of HIV / AIDS. Early detection of HIV will prevent them."}
+{"text": "Although invasive intracranial pressure monitoring (ICPM) has been a mainstay in the management of traumatic brain injury for a number of years, its use in an elective or emergency setting to guide management of patients with hydrocephalus and other CSF disorders is a relatively new concept. This single centre experience examines the safety profile and utility of ICPM in this patient population.We retrospectively reviewed all cases of monitoring over a 10 year period at the National Hospital for Neurology and Neurosurgery, London, UK. 338 cases were identified. Case records were reviewed for diagnosis, indication of ICPM, duration, complications and outcome. All operations utilised Spiegelberg ICP monitors, inserted in a protocolised fashion under sedation.ICPM was undertaken for a number of different conditions including undiagnosed headache (20.4%), IIH (28.7%), NPH (5.3%), high-pressure hydrocephalus  (17.2%) and Chiari malformations/syringomyelia (13.6%). Indications for ICPM included headache (74.0%), visual disturbance (6.2%), gait disturbance (6.2%) and cognitive disturbance (5.0%). Mean monitoring time was 37.3 hrs (range 12-154 hrs). Monitoring was conducted in the presence of a CSF shunt (50.6%), venous stent (3.7%) and previous cranial decompression (6.5%). Dynamic monitoring (eg with different shunt settings or pre/post venous stent insertion) was undertaken in 12.4%. Outcomes from ICPM included insertion of new CSF shunt (21.0%), revision of CSF shunt (13.0%), insertion of venous stent (6.5%), insertion of and lumbar drains for infusion studies (3.6%); importantly, non-operative treatment was pursued in a number of cases including shunt valve adjustment (7.7%) and conservative management (29.9%). Complications included superficial infection , symptomatic intracerebral haematoma  and misplacement ; importantly, there were no cases of deep intracranial infection and the only case of seizures was in the patient with the intracerebral haematoma.This is the largest known series of ICPM for CSF disorders. It shows that ICP monitoring is a safe procedure and may be undertaken as part of routine protocol in the management of complex hydrocephalus patients. The number of cases that were subsequently managed conservatively or with a simple valve adjustment (37.6%) indicates the utility in terms of reducing operative interventions. Further evaluation of positive and negative predictive values based on the results of ICP monitoring and health-economic analyses will push the case for routine ICP monitoring prior to definitive management of all hydrocephalus patients."}
+{"text": "The NLRP3 inflammasome is a key component of the innate immune system serving as an intracellular sensor of microbial components and cell injury. Gain-of-function mutations of the NLRP3 gene, such as single nucleotide polymorphism (SNP) Q705K, lead to autoproteolytic activation of caspase 1, resulting in excessive and uncontrolled production of proinflammatory cytokines. This may represent the mechanism by which an inflammatory loop is triggered leading to a long-term inflammatory phenotype.Our objective was to compare the frequency of SNP Q705K of NLRP3 among patients with juvenile spondyloarthritis (jSpA) and juvenile idiopathic arthritis (JIA).DNA was extracted from blood samples of 37 jSpA patients and patients with oligoarticular or polyarticular JIA, diagnosed according to ILAR criteria. Polymorphism of the NLRP3 (Q705K) was determined using real time and multiplex PCR.Among 37 genotyped patients, 24 patients with jSpA (92.31%) and 9 patients (81.82%) with JIA were carriers of the wild type allele. Only 2 patients in each group were heterozygous for NLRP3 (Q705K) polymorphism (7.69% in jSpA and 18.18% in JIA group). Although the observed frequency among groups was not statistically significant , the frequency of allele polymorphism observed among our study population was higher (10.81%) than previously described in the general population (6.5%).The frequency of SNP Q705K of the NLRP3 gene did not differ among jSpA and JIA patients. There was also no evidence that variant of NLRP3 is a major risk factor for jSpA or JIA, however, lack of susceptibility should be confirmed in a larger group of patients.None declared."}
+{"text": "Ventilator-associated pneumonia (VAP) is the most common infectious complication in critically ill patients. The formation of biofilm on endotracheal tube (ETT) surface plays an important role in pathogenesis of this infection, because it facilitates the growth and survival of microorganisms and difficults the action of antimicrobial therapy.The aim of this study is to evaluate the influence of the persistence of viable microorganisms in the ETT biofilm on clinical and microbiological response to VAP.All patients over 18 years old admitted to the Intensive Care Unit of the Hospital Universitario and Politecnico la Fe , undergoing mechanical ventilation and with VAP diagnosis were included. Clinical and microbiological data were collected at the moment of inclusion and on days 3 and 7 after VAP diagnosis. After ETT removal, ETT was washed and a piece of 0.5 cm length was cut and sonicated and the resulting material was quantitatively cultured (100 uL blood agar plate with counting of colonies with 100 uL in isolation in chocolate blood agar). Clinical response  was evaluated at day 3 and day 7. Median and interquartile range (IR) was calculated for continuous variables, and absolute and relative frequencies for discrete variables. Statistical analysis was done by chi-square test.P. aeruginosa (17.4%), MDR A. baumannii (17.4%) and methicillin-sensitive S. aureus (17.4%). 83% of patients received an appropriate empiric antibiotic treatment. Median SOFA scale at VAP diagnosis was 5 (IR: 3 - 8). EET biofilm (persistence of viable microorganisms after sample sonication) was detected in 61% of the cases. No differences were observed according to the appropriateness of initial empiric treatment  or the use of inhaled antibiotics such as tobramycin or colistin . ETT biofilm was associated with lower percentages of clinical response on days 3  and day 7 .23 patients with VAP diagnosis were included, 60% men, age 55 years (IR: 51 - 67), APACHE II 22 (IR: 15 - 25). The median of days of mechanical ventilation was 17 days (IR: 13 - 20) and until VAP diagnosis was 11 days (IR: 6 - 14). The most common etiological agents were gram-negative bacilli producers of extended-spectrum beta-lactamases (ESBL) (43.6%), multidrug resistant (MDR) Persistence of viable and potentially infectious microorganisms on ETT biofilm is a common phenomenon after VAP and is not influenced by the use of systemic or inhaled antibiotics. Although our sample size does not allow drawing conclusions, the microbiological persistence seems to be associated with a worse VAP clinical response."}
+{"text": "Despite multiple reports demonstrating an improvement in outcomes of critically ill cancer patients admitted to ICUs over the last two decades , there iWe carried out a retrospective analysis of all patients with solid tumours admitted to the Guy's Critical Care Unit (13-bed level 3 ICU) as an emergency between August 2008 and July 2012. Data were collected regarding patient demographics, type of cancer, reason for referral and organ support required during the ICU stay.During the 4-year study period there were 356 unplanned admissions of patients with solid cancer . Three hundred individual patients were admitted and 180-day survival data were available for 293 of these. Mean age at first admission was 65.2 years, 115 (38.3%) were female. The most frequently present malignancies were lung (42.7%), head and neck (17.3%) and renal (6.7%). ICU, hospital and 180-day mortality were 19.1%, 31.0% and 52.2% respectively. Those factors found to be independently associated  with increased risk of 180-day mortality include: metastases ; sepsis on admission ; APACHE II score on admission ; need for inotropes/vasopressors during admission ; and need for renal replacement therapy during admission .In our study, ICU and hospital mortality were lower than the pooled mortalities seen in a recent large systematic review  - despit"}
+{"text": "Critically ill children often manifest acute kidney injury (AKI) as part of their disease process with incidence up to 82% and it is independently associated with poor outcome . Sepsis Children aged less than 12 years who died with septic AKI were screened for percutaneous USG-guided kidney biopsy after obtaining written informed consent from July 2012 to June 2014. Three cores of kidney tissue were taken for histopathological evaluation by light, immunofluorescence and electron microscopic examination. Sepsis and AKI was defined using international pediatric sepsis consensus conference and pRIFLE criteria respectively. Events related to death, laboratory parameters and microbiological details 24 hours preceding death were recorded.n = 15) followed by tubular change alone in 22% (n = 10), glomerular change alone in 5% (n = 2) and blood vessel change in 2.5% (n = 1) of specimens. Twelve specimens were showing a combination of changes . All tubular changes were consistent with acute tubular necrosis (ATN) and changes involved from 5 to 15% of cortex. Thrombotic microangiopathy was diagnosed in 12.5% (n = 5) of specimens. There were no significant difference between ATN versus non-ATN groups with respect to baseline characteristics and events related to mortality.A total of 40 kidney biopsies were done during the study period. Median (IQR) age was 12 (2 to 36) months and PRISM-III was 14 (12 to 18). The most common change was normal histology in 37.5% (The most common change in septic AKI in critically ill children is normal histology followed by ATN. This is consistent with published literature ."}
+{"text": "Single-nucleotide polymorphisms (SNPs) in the region of the Interleukin 28B (IL28B) gene on chromosome 19, coding for the interferon (IFN)-\u03bb3, are involved in hepatitis c virus (HCV), spontaneous clearance. There is little information on the degree of liver fibrosis (LF) in HIV patients, who have had spontaneous clearance of HCV. Our objective in this study is to assess the degree of liver fibrosis in this population, as well as to identify key genetic characteristics associated with spontaneous clearance.Retrospective descriptive study that evaluated from 1 January 2013 to 30 May 2014, the HIV-HCV coinfected patients in which it has been demonstrated spontaneous clearance of HCV infection. The main variables analyzed were (1) genetics: Haplotype determination of genetic polymorphism SNP rs12979860 in the region of IL 28B gene and (2) grade of LF measured in kilopascals (kPa) by transient elastography (TE).We evaluated 205 patients with HIV and HCV coinfection, of whom, 17 patients (8.3%), presented spontaneous clearance. Fourteen patients (82.4%) had HIV CV<20 copies/mL, while the mean CD4 cell count was 396 (SD: 245) cells/mcL. Nine (53%) patients were analyzed for SNP rs12979860 of IL 28B gene. Nine patients (100%) had the CC haplotypes, and no cases of CT and TT haplotypes were detected (p<0.001). LF was measured by TE in 12 (70.6%) patients. The median of LF (Kpa) was 5.95 (IQR 4.78). In four patients (33.3%) were observed significant LF (F3\u2013F4). In the univariate analysis, no significant differences in the median of LF (Kpa) of HIV patients with spontaneous clearance of HCV were observed with respect to the coinfected HIV-HCV patients with SVR to antiviral therapy  or the coinfected HIV-HCV group who did not receive antiviral therapy .Spontaneous clearance of HCV in our series of patients coinfected with HIV infection represents an uncommon clinical phenomenon. The immune status was preserved and most patients had HIV virological suppression. In all patients in which the IL 28B genetic polymorphism was determined, CC haplotypes were found. The degree of LF (Kpa) in this population was low (<9.5 Kpa) and a low proportion of subjects showed significant LF (F3\u2013F4). No differences in the degree of LF were found in this group compared to coinfected patients receiving HCV treatment with SVR and compared to untreated patients coinfected with HIV-HCV."}
+{"text": "Asthma and allergic rhinitis have become a growing public health problem. The airflow obstruction, pathophysiological event that frames the bronchial asthma is usually determined by spirometry. Changes in expiratory flow in asthma are well known but there is controversy with these results in allergic rhinitis. The objective of this project is to compare spirometry values of young adults without respiratory disease with individuals of the same age group who have: allergic rhinitis without bronchial asthma or bronchial asthma without allergic rhinitis.Were studied (randomly selected) 279 students (185 women and 94 men) aged between 18 and 30 years (x = 21.68 \u00b1 2.29) who were in the first three years of the Medical Sciences Faculty National University of Rosario, Argentina, during 2014. Students gave their informed consent to undergo effort spirometry with ATS technique (Multispiro III spirometer), recording the values of forced vital capacity (FVC), forced expiratory volume in one second (FEV1) and forced expiratory flow at 25-75% of the pulmonary volume (FEF25-75). The statistical analysis of the information was conducted using EPI INFO.The current frequency of rhinitis and asthma in the sample was 54.1% and 17.2% respectively. 40.5% of individuals did not show any pathology, 42.3% suffered only current rhinitis and 5.4% only bronchial asthma. Was found significant decrease in FEF25-75 (p=0.01) in subjects suffering from rhinitis alone (3.18\u00b11.35 liters) than individuals without respiratory disease (4.88\u00b11.51 liters). Furthermore, the known decrease in spirometric parameters between subjects with asthma and those who did not have any respiratory disease was observed . No significant differences were found in FVC.This work find the known association between decline in FEV1, index TIFF and FEF25-75 in subjects with bronchial asthma when compared with healthy individuals, but also showed a significantly decreased FEF25-75 only in subjects suffering from allergic rhinitis when compared with healthy individuals. These data are consistent with some studies suggesting that small airway disease, related with a reduction in FEF25-75 may be a marker for early allergic or inflammatory involvement of the small airways in subjects with allergic diseases and no asthma. These data show the need to continue these studies with larger numbers of individuals and adjusting variables involved."}
+{"text": "Due to the close resemblance to a group of histiocytic disorders collectively known as hemophagocytic lymphohistiocytosis (HLH) it is currently classified among the secondary or acquired forms of HLH, and the term To describe clinical, functional and genetic features of MAS in the Italian HLH registry.We reviewed the HLH Italian National Registry to select patients with MAS defined according to the diagnostic criteria established by the Histiocyte Society  with confirmed diagnosis of rheumatologic or autoimmune disease. Clinical data were collected. Functional screening of perforin expression and degranulation was performed using flow-citometry. Genetic study was carried out by direct sequencing of currently known genes that cause familial HLH.features included: fever , splenomegaly , neurologic manifestations , anemia , thrombocytopenia , neutropenia , hypertriglyceridemia , hypofibrinogenemia , hyperferritinemia , hemophagocytosis . Four patients (10.5%) died for disease progression. Functional screening of FHL was performed in 22 cases: perforin expression was normal in 14 and reduced in 8 (36%); degranulation was defective in 3/18 (17%) and normal in the remaining 15/18 cases. At least one test was defective in 10/23 (43%). Mutation analysis included PRF1 (n = 36), UNC13d (n = 22), STX11 (n = 33) and STXBP2 (n = 19) and allowed to identify monoallelic mutations in 11 of the 38 patients (29%), as follows: PRF1 , STX11 , STXBP2 .Among the 813 patients referred to the Registry, 38 (5%) were diagnosed as MAS in the context of a rheumatic disease. Of them 13 were male and 25 female; 30 Caucasian and 8 Indian. Median age was 94  months. The underlying diseases were: sJIA (n = 28), SLE (n = 4), Kawasaki disease (n = 1), Juvenile Dermatomyositis (n = 1), undefined rheumatologic (n = 3) or autoimmune (n = 1) disease. The clinical A significant portion of patients with MAS appear to have functionally defective cytotoxic activity and carry monoallelic variants in genes associated with familial HLH. These data suggest additional similarities in genetic background and cytotoxic activity abnormalities between MAS associated with rheumatic diseases and familial HLH.None declared."}
+{"text": "The advent of biologic medications has considerably increased the potential for treatment benefit in juvenile idiopathic arthritis (JIA), with clinical remission being now achievable in a substantial proportion of patients.To evaluate the outcome of etanercept (ETN) therapy in Italian children with JIA.This is a multicenter, observational study that includes all children with JIA who were given ETN at Italian pediatric rheumatology centers after January 2000. Patients were classified in 2 groups: Group 1: patients who were no longer taking ETN at study start; Group 2: patients who were still receiving ETN at study start. Patients in Group 1 underwent only retrospective assessments, whereas patients in Group 2 underwent both retrospective and cross-sectional assessments. The primary outcome of the study were reasons for ETN discontinuation in patients in Group 1, and achievement of the states of inactive disease (ID), minimal disease activity (MDA) and parent- and child-acceptable symptom state  in patients in Group 2. The above states were assessed through both formal definitions and JADAS cutoffs. The secondary outcome was the evaluation of frequency and characteristics of ETN-related side effects.Twenty-five centers were asked to make a census of all patients followed at the center who met the inclusion criteria for Group 1 or Group 2. A total of 1230 patients were included in the census. Of these patients, 624 were still receiving ETN (Group 2), whereas 606 had discontinued ETN (Group 1). So far, the data of 772 patients (448 in Group 1 and 324 in Group 2) have been collected. Among the 448 patients in Group 1, reasons for ETN discontinuation included disease remission (57.1%), lack of efficacy (25.5%), and side effects (14.9%). The results of assessment of disease state through formal definitions in 305 children of the 324 children in Group 2 who had already undergone the cross-sectional evaluation were the following: ID 42.2%, MDA 63.8%, PASS 80.9%, CASS 76.7%. The percentages of patients who reached the same disease states assessed through JADAS cutoffs were: ID 45.7%, MDA 62.5%, PASS 71.1%, CASS 67.4%. Serious adverse events were seen in 10 of the 772 patients and included inflammatory bowel disease (4 pts), tuberculosis (1 pt), CMV hepatitis (1 pt), varicella complicated by bronchopneumonia (1 pt), bladder carcinoma (1pt), thyroid carcinoma (1 pt); 1 patient died of streptococcal sepsis.A substantial proportion of children currently receiving ETN were in the states of ID or MDA, or were satisfied with treatment outcome. More than half of the patients who had been discontinued from ETN before study start had the medication stopped because of disease remission. Serious adverse events were uncommon.None declared."}
+{"text": "Ipilimumab is an immunotherapy that blocks the function of an immune checkpoint, cytotoxic T-lymphocyte antigen 4 (CTLA-4), and promotes durable anti-tumor responses in a subset of patients. We hypothesized that ipilimumab could be added to androgen deprivation therapy (ADT) as treatment for patients with metastatic prostate cancer in an attempt to limit the amount of ADT (8 months) but provide durable anti-tumor responses. We aimed to correlate immunologic biomarkers with clinical responses, including immune-related adverse events (irAEs).We conducted a single-arm, single-center, observational study from July, 2011 to June, 2013 to determine if finite ADT plus ipilimumab is safe, estimate efficacy and link clinical outcomes to immunologic changes in men with metastatic non-castrate prostate cancer. ADT was administered for only 8 months with concurrent ipilimumab (10 mg/kg) for up to 4 doses at 4-weeks intervals.We screened 30 pts of which 24 were evaluable for efficacy and 27 for safety. The median time to PSA progression was 9.9 (IQR 5.8-13.1) months from treatment initiation, and two of the 24 (8%) patients have PSA responses that are ongoing for 40.7 and 17.9 months, respectively. The trial was closed as pre-specified due to excess toxicity in which 12 of 27 (44%) patients developed grade 3 immune-related adverse events (irAEs), which have been observed with Ipilimumab monotherapy. The most common grade 3 events were transaminitis, colitis/diarrhea, and hypophysitis. Immunological biomarkers were identified that potentially predict for clinical benefit and grade 3 irAEs.This pilot study suggests the combination of ipilimumab plus finite ADT can induce durable responses in a subset of patients with metastatic prostate cancer. irAEs are likely to occur and require careful management. Comprehensive immune monitoring of peripheral blood CD4 and CD8 T cells by flow cytometry and sequencing the CDR3 region of the T cell receptor beta chain revealed potential biomarkers predictive of clinical outcomes. Future studies with lower doses of ipilimumab may need to be tested in combination with ADT."}
+{"text": "Over 10% of total deaths and 50% of cardiac deaths in India are Sudden Cardiac Deaths (SCA) and occur at a young age of 5-8 years. We analysed risk allele plus genotype frequencies and polymorphism associations of 38 SNPs, confirmed in GWAS studies that increasing the risk of SCA in 124 random people in the general population. The data were compared with Caucasians reported in HapMap (n = 113).Following DNA extraction from saliva, genotyping was performed using Illumina golden gate genotyping assay. Allele and genotype frequencies were determined by direct gene count method.Population Genomics indicated Odds Ratio of risk alleles as 1.62 (1.31 -1.92). The carrier rate of risk allele frequency was significantly higher (p = 0.037 to p = 9.18E-37) in Indians compared to Caucasians in 56% of SNPs in H-W equilibrium (15 of 27).6 SNPs showed statistically insignificant comparatively lower risk allele frequency in Indians. Mean increase in higher risk allele frequency SNPs was 2.4 fold (1.1 \u2013 6.7). Frequency in Indians, for the two SNPs with the strongest SCD risk correlate in the gene BAZ2B was 2 times (rs4665058) and 6 times (rs 174230) greater than in Caucasians.Personalized Genomics indicated that even the frequency of risk homozygous genotype, resulting in the SCA threat in affected individuals being the square of the risk allele hazard, was markedly different with 4.7% Caucasians carrying homozygous risk genotype versus 10.6% of Indians (p<.0001). In 18 (out of 38) SNPs studied, the homozygous genotype difference in Indians was more than double). Although interplay of gene-gene interaction in individualized risk prediction is still undefined, 59% (73 of 124) people carried between 10 to 19 risk alleles and 41% (51 of 124) had between 20 to 30 risk alleles , of the total maximum of 76.This is the first report, highlighting extremely high genomic propensity for Sudden Cardiac Arrest in Indians compared to the Caucasians. In India, there is also a high propensity for risk towards homozygous genotype and people carrying several risk alleles for SCA. At the population level, this data reinforces an urgent need to train community in different locations in basic resuscitation skills and at a personal level, it raises an important point to test the vulnerable group for assessing the risk alleles for better individualized preventive action plans could be advocated."}
+{"text": "The level of stress and body self image perception in girls suffering from adolescent idiopathic scoliosis (AIS) is the object of interest of the professionals.Evaluation of the stress level in adolescents with AIS and their self image perception.Observational study. It involved 82 adolescents, ages ranging between 11.0 and 16.0 years, all with IS with Cobb angle between 20-45 degrees. Adolescents were wearing the Ch\u00eaneau orthosis, . The age of examined group was 13.5 \u00b1 1.6 years.The following were used in the evaluation: Bad Sobernheim Stress Questionnaire (Brace and Deformity), Trunk Appearance Perception Scale (TAPS), and Knee \u2013 Feet Perception Scale (KFPS). The BSSQ Brace estimates the stress scoliosis patients have whilst wearing brace, the BSSQ Deformity estimates the stress involved with body deformation. Minimal points number equals 0 (the greatest stress), maximal 24 (the least stress). The TAPS evaluates subjective impression of trunk deformity from 3 viewpoints: looking toward the front, back, and with the patient bending over. Minimal points number equals 1 (the biggest deformity), maximal equals 5 (the least deformity). KFPS estimates subjective impression of knee joints and feet position. Minimal points number equals 1 (the biggest deformity), maximal equals 3 (the least deformity). Additionally results of TAPS and KFPS were compared with clinical examination.Cobb angle was 31.0 \u00b1 8.1 degrees. The BSSQ Brace and Deformity median was 13, the TAPS median of the total score was 4, the KFPS median of the total score was 3. There were significant differences between Cobb angle and TAPS (AIS) and Cobb angle and TAPS clinical examination (p<0.001).Conservative treatment does not severely impact on the level of stress and the self image of adolescents with idiopathic scoliosis."}
+{"text": "Because of increasing prevalence of multi-drug resistant (MDR) pathogens, there are many difficulties in the treatment of hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP). It is known that patients with MDR pathogens have high mortality and morbidity. We need to know the current status of pathogens and antibiotics therapy for a proper choice of initial antibiotics to improve outcome of the patients.This study was aimed at investigating the current pathogens and treatment of HAP/VAP in Korean ICUs. Methods A prospective, multicenter and observational study was conducted in six tertiary referral hospitals in Korea between August 1, 2012 and July 31, 2013. This study included patients who were admitted to adult medical ICUs with diagnosed as pneumonia developing at least 48 hours after admission or initiation of mechanical ventilation. We analyzed the prevalence of their pathogens, and treatment and clinical courses of these patients.During the study period of 12 months, total 134 patients with HAP/VAP were enrolled. Mean age was 65 with 103 (77%) males. Forty-seven (35%) patients had risk factors of MDR pathogens. The duration between admission and diagnosis of pneumonia was 12 days (IQR: 7-22 days). Most of patients (86%) underwent mechanical ventilation. Pathogens were identified in 79 (59%) patients. Among them, MDR bacteria were isolated in 55 (76%) patients. The most common MDR pathogen was carbapenem-resistant Acinetobacter baumannii (60%). However, extended-spectrum penicillin/\u03b2-lactamase inhibitor-based was the most common empirical antibiotics (39%) during initial 48 hours after diagnosis. Glycopeptides were used in 60 patients (47%). As a subsequent therapy between 48 hours and 2 weeks after diagnosis, carbapenem-based regimen was most common (36%). On the other hand, colistin-based therapy was done in 29 (22%) patients. Only 45 (34%) patients showed a clinical resolution within 28 days. They showed a high in-hospital mortality of 51% with 28-day and 60-day of 31% and 49%, respectively.This study demonstrates that carbapenem-resistant A. baumannii is the most common MDR pathogen in Korean medical ICUs. It shows that there is a discrepancy between the common MDR pathogen and the choice of empirical antibiotic therapy."}
+{"text": "The identification of prognostic markers for hepatocellular carcinoma (HCC) is needed for clinical practice. Tripartite motif-containing 35 (TRIM35) is a tumor suppressor of HCC. TRIM35 inhibits phosphorylation of pyruvate kinase isoform M2 (PKM2), which is involved in aerobic glycolysis of cancer cells. We found that expression of PKM2 was significantly increased in HCC tissues. This overexpression of PKM2 was correlated with a high TNM stage and level of vascular invasion. Patients with HCC who were positive for PKM2 expression and negative for TRIM35 expression had shorter overall survival and time to recurrence than patients who were negative for PKM2 and positive for TRIM35. Furthermore, PKM2/TRIM35 combination was an independent and significant risk factor for recurrence and survival. In conclusion, PKM2 (+) and TRIM35 (\u2212) contribute to the aggressiveness and poor prognosis of HCC. PKM2/TRIM35 expression could be a biomarker for the prognosis of HCC and target for cancer therapy. Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide and is the third leading cause of cancer-related deaths. Further, HCC incidence and mortality are especially high in China , 2. To dA review of the evidence has supported the general hypothesis that cancer is primarily a disease of energy metabolism . With reIn a previous study, we identified tripartite motif-containing 35 (TRIM35) as a novel tumor suppressor of hepatic carcinogenesis . TRIM35 PKM2 and TRIM35 mRNA levels were determined in cohort 1 using a quantitative RT-PCR assay because only RNA samples were available. In cohorts 2, 3 and 4, PKM2 and TRIM35 levels were determined using immunohistochemistry tissue microarrays. For the primary group, archived tissue samples for the tissue microarray construction were obtained from patients who received curative resection of HCC between January and December 2007. The median follow-up period was 60.0 months  and the postoperative cumulative survival and recurrence rates (in parentheses) at 1, 3, and 5 years were 84.2% (72.7%), 68% (62.4%), and 66.4% (53.5%), respectively. For the validation group, FFPE tissues of HCC nodules were collected from patients between January and December 2000. The median follow-up period was 29.0 months  and the postoperative cumulative survival and recurrence rates (in parentheses) at 1, 3, and 5 years were 62% (55%), 45% (41%), and 22% (18%), respectively. Patients did not have signs of distant metastasis, nor had they received anticancer therapy before surgery. Cohort 4 included 118 patients with HCC who had first undergone radical resection of HCC, had a relapse a few years later, and then underwent a second resection of HCC.We obtained snap-frozen or formalin-fixed paraffin-embedded (FFPE) HCC tissues and adjacent non-tumor liver tissues from 688 patients with HCC who had undergone curative resection between 2000 and 2013. Most of the HCC patients in the four cohorts were men (85.5%), were carriers of hepatitis B virus (HBV) (82.6%), had liver cirrhosis (72.8%), had an elevated serum alpha-fetoprotein (AFP) level (61.7%), and had a single tumor nodule at the time of resection (83.7%) . ClinicaIn the previous study, we applied gene expression profiling to 49 HCCs and matched adjacent non-tumor liver tissues . Our resAs the HCCs had shown increased PKM2 expression and decreased TRIM35 expression, we performed further analyses to determine the clinicopathological significance of PKM2 and TRIM35 in HCC. The expression level of TRIM35 was negatively correlated with the tumor size, histological grade, and AFP concentration (data not shown). These findings are consistent with our previous observations . ImportaIn addition, we evaluated the clinical relevance of PKM2 and TRIM35 expression to prognosis in the primary cohort. At the time of last follow-up, 135 and 121 of the 236 patients had tumor recurrence and had died, respectively. Kaplan\u2013Meier analysis showed that the median overall survival (OS) time was 40.3 (95% CI: 33.3\u201347.4) months for patients with HCC who were positive for PKM2 and 60.8 (95% CI: 56.9\u201364.6) months for patients with HCC who were negative for PKM2 /TRIM35 (\u2212) expression had the shortest TTR  and OS , whereas patients with the PKM2 (\u2212)/TRIM35 (+) expression pattern had the longest TTR  and OS   primary HCC samples, whereas positive TRIM35 expression was found in 149 of 205 (72.7%) primary HCC samples. PKM2 overexpression was correlated with tumor number, microvascular invasion and higher TNM stage Table . In addiTo test whether the expression levels of PKM2 and TRIM35 were independent of other predictive variables, we applied univariate and multivariate analyses using a Cox multivariate proportional hazard regression model with PKM2/TRIM35 expression and clinicopathologic factors  as covariates. Univariate analysis showed that vascular invasion, TNM stage, the expressions of PKM2 and TRIM35, and the PKM2/TRIM35 combination were the factors that were consistently significant for both OS and TTR in the primary and validation cohorts Table . Serum AIn addition, a multivariate statistical analysis revealed that HCC patients with the signature of TRIM35 (\u2212)/PKM2 (+) expression harbored a 2.25-fold higher risk of cancer recurrence  and a 2.1-fold higher risk of death  in the primary cohort  curve analysis using the IHC data from cohort 4 to determine the efficacy of PKM2 and TRIM35 expression in discriminating early recurrence (less than 3 years) in patients with HCC. As shown in et al demonstrate that there is no evidence for exchange of PKM1 to PKM2 expression during cancer formation .Total RNA was extracted from tissues or cells with TRIzol reagent (Invitrogen) according to the manufacturer's instructions. Reverse-transcription PCRs (RT-PCRs) were carried out with the Prime-Script RT Reagent Kit . Expression levels of the genes were determined by quantitative real-time PCRs and normalized against an endogenous control \u03b2-actin using SYBR Premix Ex Taq (TaKaRa). Data were analyzed using a \u0394\u0394Ct approach and expressed as the target gene/\u03b2-actin ratio [2Cells were harvested by scraping into an SDS sample buffer containing a cocktail of protease inhibitors . Similar amounts of proteins were loaded into the gel, separated by SDS-PAGE gel electrophoresis, and transferred to a nitrocellulose membrane . The membrane was blocked with TBST (0.05% Tween 20 in TBS) containing 5% skim milk and then incubated overnight with the indicated antibodies at 4\u00b0C. The membrane was washed three times in TBST and then incubated with an HRP-conjugated secondary antibody (Pierce) (1:2000) for 2 hours at room temperature. The immunocomplexes were detected using enhanced chemiluminescence (Pierce).The tissue microarray was constructed as described previously . Core sa2) test was used to evaluate the association between the PKM2 expression and clinicopathological parameters. The cumulative recurrence and survival rates were determined using the Kaplan-Meier method (log-rank test). The Cox multivariate proportional hazards regression model was used to determine the independent factors that influence survival and recurrence based on the investigated variables. ROC curve analysis was used to determine the efficacy of PKM2 and TRIM35 expression in discriminating early recurrence (less than 3 years) from HCC patients. A P value < 0.05 was considered significant. All statistical analyses were performed using the IBM SPSS Statistics V19 package .The experiments were repeated at least three times. The significance level of PKM2 mRNA expression in HCC patients was determined by nonparametric Mann-Whitney U tests.. The chi-squared (\u03c7"}
+{"text": "Guillain-Barre Syndrome (GBS) is an acute polyradiculoneuropathy characterized by progressive motor weakness of limbs and areflexia. In this study, our aim was to evaluate the clinical pattern and prognosis of children with Guillain-Barre syndrome.This cross-sectional study was conducted in the Pediatric Neurology Unit of Amirkola Children\u2019s Hospital, Babol, Iran during the period of 5 years from October 2008 to September 2013. We assessed the clinical features, results of electrodiagnostic tests, functional status, treatment and outcome of 17 children diagnosed with GBS.Of 17  children studied, all had motor weakness, 4 children (23.5 %) and cranial nerve palsies. Respiratory paralysis was found in one child requiring assisted ventilation. Antecedent illness preceding GBS was recorded in 7 (41.2%) children. The GBS subtype distribution as per electrodiagnostic studies was as follows: acute inflammatory demyelinating polyradiculoneuropathy (AIDP) in 12 (70.6%) acute motor axonal neuropathy (AMAN) in 3 (17.6%), acute motor sensory axonal neuropathy (AMSAN) in 2 (11.8%). IVIG constituted the treatment given in all of the patients. Complete recovery was observed in 16 children and the remaining one child was dependent to wheelchair.GBS in children is not poor prognostic disorder and our recommendation is administration of IVIG as soon as possible after clinical diagnosis. Except for one child who remained wheelchair bound, there was no mortality or morbidity in long-term observation. Besides, strong limitation of our study was the low number of subjects.  Guillain-Barr\u00e9 syndrome (GBS) is an immune mediated polyradiculoneuropathy with an acute onset and a variable clinical course . It is aBesides, autonomic dysfunction is another main cause of mortality in affected children ,3. NerveIVIG and plasma exchange have made a significant change in the course of the illness .We performed a cross sectional study on the natural history in children with GBS to study their clinical profile using intravenous immunoglobulin (IVIG) in addition to supportive management in long-term assessment (from2008 to 2014).This cross-sectional study was conducted in the Pediatric Neurology Unit of Amirkola Children\u2019s Hospital, Babol Medical University, Babol, Iran during the period of 5 years from October 2008 to September 2013. The subjects of the study were children < 10 yr of age diagnosed with GBS. We assessed the clinical features, results of electro-diagnostic tests, functional status, treatment instituted and outcome.A complete neurological examination was conducted including examination of cranial nerves, motor system and sensory system as well as deep tendon reflexes. Electrodiagnostic study was done in all patients and electrophysiological subtypes of GBS were noted. CSF examination was performed in selected hemodynamically stable children.All children were treated with IVIG in a dose of 2 gm/kg over 2-5 d in addition to conventional supportive and/or intensive respiratory care. Statistical analysis was done using SPSS  and numerical parametric data were presented as percentages.This study has been done with approval of the Ethics Committee of the Babol University of Medical Sciences. All patients\u2019 children were taken informed consent form.We evaluated 17 children with documented GBS admitted in our hospital and followed them four times  after discharge. Eleven (64.7%) were male. Age of our patients on admission time ranged from 2 yr to 9 yr (4.4\u00b1 1.9). The history of antecedent illness was found in 7 subjects (41.2%) in the preceding two weeks. Of these antecedent illnesses, respiratory tract infection was found in 3 cases (42.9%), diarrhea in 2 cases (28.6%) and nonspecific febrile illness in 2 children (28.6%).At admission, all 17 children presented with limb weakness. Cranial nerve palsy was observed in 4 (23.5%) children. Of which, 2 had bulbar palsy and 2 children had facial palsy. Respiratory insufficiency was found in one child requiring assisted ventilation. The GBS subtype distribution as per electrodiagnostic studies was as follows: acute inflammatory demyelinating polyradiculoneuropathy (AIDP) in 12 (70.6%), acute motor axonal neuropathy (AMAN) in 3 (17.6%) and acute motor sensory axonal neuropathy (AMSAN) in 2 (11.8%). NCV (nerve conduction velocity) was performed in all children at first 72 h of admission time except in one child intubated and NCV was done after extubation. CSF analysis was performed in 11 children at 5-7th days of admission and the characteristic feature of albumin-cytological dissociation (<10 mononuclear cells) was observed in only two children. IVIG was administered to all patients (2 gm/kg) in five consecutive days. Physical therapy was ordered for all patients.We followed all patients for long time. In first visit after about three months, 6 (35.3%) patients had normal neurologic examination. In second visit after about six months, 12 (70.6%) patients were normal. in third visit after about 12 months after discharging from the hospital, 16 (94.1%) patients were normal and had complete motor function with normal deep tendon reflexes and only one child was wheelchair bound and finally in last visit after 24 months (about 2 yr), our findings was similar to third visit.GBS is the most common cause of acute flaccid paralysis in infants and children. GBS could be seen in all age groups. We included, 17 cases of <10 yr of age (range 2-9) and 41% of children were below 4 yr. In one study of 61 children younger than 15 yr of age with GBS, found that most of the children who had GBS were below 4 yr, and only one case was seen in the 10-15 yr age group  ( (6). OurFinally, complete recovery after last visit (after 24 months) was 16/17 94.1%) in our study. In Korinthenberg et al study, complete recovery was 92% and in Maneesh Kumar et al. study was 82.4% (4.1% in oIn conclusion, GBS is not poor prognostic disorder in children, especially; we administered IVIG as soon as possible after clinical suspicion. Regardless of the severity of disease on admission time and electrophysiological subgroups, a majority achieved complete motor and sensory recovery. Strong limitation of our study was the low number of cases. Except for one child who remained wheelchair bound, there was no mortality or morbidity in long term observation."}
+{"text": "The aim of this study was to evaluate the clinical profile of patients with chronic urticaria (CU) at first visit in a specialized CU unit.Cross-sectional study of patients seen from January/2012 to June/2014. Patients diagnosed with acute urticaria (n=5) were excluded.Among the 50 CU patients, 70% were female. The mean age at the consultation was 33 years, but the mean age of symptoms onset was 15.3 years. Fifty one percent referred only urticaria, 44% referred urticaria associated with angioedema and 5% presented isolated angioedema. Besides itching, 6 patients complained of burning (12%) and 2 of pain (4%). Frequency of wheals was daily in 33%, weekly in 36% and monthly in 31%. At first visit, Urticaria Activity Score was verified in 24 patients, resulting > 3 in half of them. The most associated atopic disease was rhinitis (45%). Many patients mentioned triggers as medicines (33%), food (23%), stress (17%), viral infection (8%) and physical agents (16%). Only 6% had thyroidopathy. As previous treatment a significant amount of patients received sedating antihistamines (AH) (36%) or oral corticosteroids (24%), with partial improvement in 65% and complete improvement in 29%. Dermographism was positive in 91% of the patients tested (20/22). One of them was diagnosed with cholinergic urticaria and another one with delayed pressure urticaria.The higher prevalence of CU was in middle-aged women. However, strong association with thyroiditis was not found. Sedating AH and corticosteroids are still the most prescribed drugs."}
+{"text": "The purpose of study was to prospectively evaluate the diagnostic performance of dynamic contrast-enhanced MR imaging in the differentiation of malignant lesions from benign ones in patients with BI-RADS 3\u20134 microcalcifications detected by mammography.93 women with 100 microcalcifications had undergone breast MRI from June 2010 to July 2013. Subsequently, 91 received open biopsy and 2 received stereotactic vacuum-assisted biopsy. All results were compared with histological findings. The PPV, NPV and area under curve (AUC) of the mammography and breast MRI were calculated.p<0.05).There were 31 (31.0%) BI-RADS 3 microcalcifications and 69 (69.0%) BI-RADS 4. The PPV and NPV of mammography is 65.2% (45/69) and 90.3% (28/31). The PPV and NPV of breast MRI was 90.2% (46/51) and 95.9% (47/49). Among 31 BI-RADS 3 microcalcifications, the PPV and NPV of breast MRI was 100% (3/3) and 100% (28/28). Among 69 BI-RADS 4 microcalcifications, the PPV and NPV of breast MRI was 89.6% (43/48) and 90.5% (19/21). The AUC of mammography and breast MRI assessment were 0.738  and 0.931  (Dynamic contrast-enhanced MR imaging of breast is able to be applied to predict the risk of malignance before follow-up for BI-RADS 3 microcalcifications and biopsy for BI-RADS 4 microcalcifications. Microcalcifications represent one of the most important mammographic findings of breast carcinomas and are often the only mammographic signs of malignant breast lesion. According to the Breast Imaging Reporting and Data System (BI-RADS) Compared with mammography, dynamic contrast-enhanced Magnetic Resonance Imaging (DCE MRI) is more sensitive to detect breast carcinomas in dense and heterogeneously dense breasts The purpose of our study was to prospectively evaluate the diagnostic performance of DCE MRI in the differentiation of malignant lesions from benign ones in patients with BI-RADS 3\u20134 microcalcifications detected by mammography.This prospective study was approved by the institutional ethics committee of the First Affiliated Hospital of Nanjing Medical University. Written informed consent was given by the patients for their information to be used for our research. Furthermore, our study was also in compliance with the Helsinki Declaration.The patients with BI-RADS 3\u20134 microcalcifications detected by mammography were asked to undergo DCE MR imaging of breast. The time interval of Mammography and DCE MR imaging was no more than 3 months. All mammograms were interpreted independently by two radiologists and agreement was reached after discussion. All MR images were interpreted independently by the same two readers and agreement was reached after discussion. The interobserver agreement was calculated by generalized kappa tests. All patients received open biopsy or stereotactic vacuum-assisted biopsy (SVAB). All lesions were verified by histology. The time period between MRI and histological verification of lesions was no more than one week. The positive predictive value (PPV) and negative predictive value (NPV) of mammography and breast MRI in the area of microcalcification were calculated respectively. Receiver operating characteristic (ROC) curves were calculated for mammography and breast MRI final assessment.A total of 93 women  from one site between June 2010 and July 2013 were asked to participate in the study.The conventional two-view mammograms  were obtained by clinical full-field digital mammography unit, which used molybdenum or rhodium for target and filter . The system's autofilter mode automatically determined peak voltage and milliampere-seconds setting for the study. Microcalcifications were classified according to BI-RADS for mammographic features including calcification morphology and distribution. Images were interpreted independently by two radiologists with more than 5 years of experience in mammography. In cases of discordance, agreement was reached after discussion.3) with fat suppression. For dynamic study we imaged one pre- and five post-contrast sequences. Contrast media  was administered immediately after the end of first (pre-contrast) sequence as a bolus intravenous injection at a dose of 0.1 mmol/kg and at the rate of 3 ml/s, which was followed by a 20 ml saline solution. The total time of the dynamic study was 6 minutes and 26 seconds with a temporal resolution of 1 minute. The necessary part of the examination was post-process by creating subtraction images of each post-contrast sequence and by creating maximum intensity projection (MIP) images.Magnetic resonance imaging was performed with patients in the prone position. The scanner was a 3.0 T system  with an 8 channel bilateral breast coil. The DCE MRI was acquired with a 3D transverse fast low angle shot T1-weighted sequence was performed to 2 patients guided by X-ray mammography . The number of samples taken during the biopsy was 12 and 15. Open biopsy was performed to 91 patients by two experienced surgeons. Specimen radiography was performed routinely on all samples. The histological findings were correlated with the mammographic findings of microcalcification by radiologist and pathologist.All samples were embedded in paraffin and serially cut for histological examination. Histological diagnosis was determined by the pathologist with more than ten years of experience in breast histology. Atypical ductal hyperplasia (ADH) and sclerosing adenosis were considered as benign.All statistical analyses were performed using software SPSS (version 11.5). An assessment of BI-RADS 4 or 5 was considered as a positive finding, while an assessment of 1, 2, or 3 was considered as negative.The degree of interobserver agreement for mammography and breast MRI assessment between two observers was calculated by generalized kappa tests.The PPV and NPV of the mammography and breast MRI in the area of microcalcifications were calculated respectively.Receiver operating characteristic (ROC) curve was calculated for mammography and breast MRI final assessment respectively, and the area under the curve (AUC) was based on Hanley and McNeil method.p value less than 0.05 was considered statistically significant.A All results were shown on the study flowchart .Of 2 SVAB cases, one lesion was diagnosed as ductal hyperplasia and the other was adenosis.Of 91 open surgery cases, there were 50 lesions of benign ones, including 7 lesion of ADH, 5 lesions of sclerosing adenosis and 38 of other benign lesions, while there were 48 lesions of malignant ones, including 15 lesions of DCIS, 9 lesions of invasive ductal carcinoma with DCIS component, 2 lesions of invasive ductal carcinoma combined with mucinous adenocarcinoma and 22 lesions of invasive ductal carcinoma .p<0.05). There were 86 lesions of pure microcalcification, 12 lesions of mass with microcalcification, 1 lesion of spiculation with microcalcification and 1 lesion of architecture distortion with microcalcification  and 69 BI-RADS 4 (69.0%). The interobserver agreement of mammography diagnostic performance was good , 23 lesions of plateau form (Type II) and 23 lesions of washout form (Type III).p<0.05). The PPV and NPV of breast MRI was 90.2% (46/51) and 95.9% (47/49).Among 49 lesions  diagnosed as BI-RADS 2 by DCE MRI, there were 47 lesions of benign and 2 lesion of malignant proven by histological findings. Among 27 lesions  diagnosed as BI-RADS 4, there were 22 lesions of malignant and 5 lesions of benign proven by histological findings. Among 24 lesions  diagnosed as BI-RADS 5, there were 24 lesions of malignant proven by histological findings. , 3 The ip<0.05).The AUC of mammography and breast MRI assessment were 0.738  and 0.931  . The obsAmong 31 lesions of BI-RADS 3 diagnosed by mammography, 3 lesions were upgraded to BI-RADS 4 by DCE MRI, which were proven to be malignant by histology, while the other 28 lesions were degraded to BI-RADS 2 which were proven to be benign. Therefore, PPV of DCE MRI was 100% (3/3) and NPV was 100% (28/28) in 31 BI-RADS 3 microcalcifications.Among 69 lesions of BI-RADS 4 diagnosed by mammography, 22 lesions were upgraded to BI-RADS 5 by DCE MRI, which were verified of malignant ones; 21 lesions degraded to BI-RADS 2 by DCE MRI proven of 19 benign and 2 malignant ones and 26 lesions sustained of BI-RADS 4 verified of 21 malignant ones and 5 benign ones. Therefore, the PPV of DCE MRI was 89.6% (43/48) and NPV was 90.5% (19/21) in 69 BI-RADS 4 microcalcifications .Dynamic contrast-enhanced Magnetic Resonance Imaging provides tissue vascularity information. The assessment of breast MRI together with other imaging modalities mostly mammography, increases the sensitivity and specificity of modality greatly Some studies suggested dynamic contrast-enhanced breast MR imaging is not reliable in the differentiation of benign from malignant microcalcifications The recommended rate of malignancy for BI-RADS category 3 microcalcifications is only 2% or fewer, which is based on follow-up mammograms not proven by histology results. Very little information on the result of SAVB is available for BI-RADS 3. In a study of 100 pure microcalcifications, malignancy was proved to be in 7% of BI-RADS 3 microcalcifications reported by Uematsu et al. Previous studies reported the rate of malignancy ranged from 20 to 34% for BI-RADS 4 lesions  In our study, the PPV of DCE MR imaging for BI-RADS 4 microcalcifications was 89.6% (43/48). The result suggests that DCE MR imaging is able to reduce the number of SVAB or open biopsy for the BI-RADS 4 microcalcifications.As to the contrast-enhanced breast MRI, there is strong evidence that the sensitivity is greater than the specificity of other techniques of breast imaging In our study, five benign microcalcification lesions  were interpreted as positive on MR imaging. Four lesions were mass-like enhancement, including three with plateau type of time-intensity curve and one with persistent type of time-intensity curve. It's probably true that the margin and contrast agent kinetics of mass lesions is helpful for diagnosis. But in clinical practice, it is not always true because some complex adenosis looks like irregular mass and the plateau form of kinetic curve exists not only in malignant lesions but also in benign ones.Baltzer et al In our study, one malignant microcalcification lesion of high-grade DCIS  was interpreted as negative on MR imaging. In this false-negative case, diffuse parenchymal enhancement of both breasts (symmetric enhancement) was noted. This sign is similar to previous studies' Recently, a high-resolution dedicated breast PET [MAMmography with Molecular Imaging (MAMMI)] has been developed to improve primary tumor detection and characterization Several limitations still existed in this study. First, the sample size was small, especially for the cases with BI-RADS 3 microcalcifications. The high rate of malignancy in BI-RADS 3 microcalcifications may be caused by the small sample size. Therefore, future studies with bigger sample size are still needed to confirm our findings. Second, breast MRI was performed without being blinded to mammographic findings. This artificially inflates the diagnostic performance of breast MRI.During the clinical treatment of BI-RADS 3 and 4 microcalcifications, DCE MR imaging of breast is able to be applied to predict the risk of malignance before follow-up for BI-RADS 3 and biopsy for BI-RADS 4. DCE MR imaging of breast is an effective and non-invasive method in diagnosis. In addition, we should be careful to assess suspiciously malignant microcalcification region (BI-RADS 4) with the background of diffused enhancement modality in DCE MRI."}
+{"text": "Early detection of primary tumor site coupled with specific therapy improves prognosis. The low detection rate of the primary tumor site can be attributed to the biological behavior or the small size of the primary tumor to be detected by conventional imaging. The objective of this study was to evaluate the diagnostic accuracy of A retrospective, cross-sectional analysis of 100 PET-CT scans of patients with CUP syndrome between November 2009 and December 2013 was performed. Eighteen patients whose final histopathology results could not be obtained for correlation were excluded from analysis. The hypermetabolic sites were assessed in correlation with histopathology. The diagnostic accuracy, sensitivity, specificity, positive predictive value and negative predictive values were assessed for PET-CT.18F-FDG PET-CT (true positive). The PET-CT scan results were negative for primary site localization in 15% of patients . While 21% had true negative results, 7.3% displayed false positive results. PET-CT scan upstaged the disease in 27% cases. Overall, the diagnostic accuracy was found to be 78%, sensitivity 80%, specificity 74%, positive predictive value 88.7% and negative predictive value 59%.Out of the 82 patients, primary tumor was correctly identified in 57.3% patients by 18F-FDG PET-CT scan in the localization and staging of CUP syndrome.Our data supports the utility of  Cancer of unknown or occult primary (CUP) is defined as the detection of metastatic cancer where the site of primary origin remains obscured even after standardized diagnostic work-up. CUPs account for 3 to 5% of all malignancies, and the median age at presentation is 60 years ,2. CUP iThe median survival in CUP syndrome has been reported as 10-12 months. The prognosis mainly depends on early detection of the primary tumor site coupled with tumor specific therapy. In case of unidentified primary, empiric chemotherapy regimens are offered . Detecti18F-FDG) PET-CT a useful tool in the search of a primary malignant focus. The key role of whole body 18F-FDG PET-CT scan in this field has been shown by previous studies (Metabolic changes are known to precede morphologic changes. Hybrid positron emission tomography-computed tomography (PET-CT) imaging allows whole body survey of metabolic processes together with anatomical correlation, making 18F-fluorodeoxyglucose ). Seventy-four of 100 patients had histopathologically proven metastatic disease with unknown primary site. Twenty-six out of 100 patients were enrolled with a clinical suspicion of malignancy due to history of profound weight loss or progressive weakness with elevated tumor markers or suspicious lesions on cross-sectional radiological imaging where biopsy was not possible.Eighteen patients whose histopathology results could not be obtained for correlation after PET-CT were excluded from final analysis.18F-FDG PET-CT scan according to the standard protocol. Each patient fasted for 6 hours. A dose of 300 MBq (0.21 mCi/kg body weight) of 18F-FDG was injected intravenously to each patient under proper glycemic control. At 60 minutes, whole body PET-CT scan acquisition was performed by a dedicated PET scanner (Phillips Gemini TOF) with 3 min acquisition for each 8-9 bed positions. Contrast enhanced CT scan was acquired over 1 min with a voltage of 70-140 kVp and tube current 80 mA. The CT scan was used for anatomical localization and attenuation correction of PET emission data.All patients underwent The attenuation corrected and uncorrected PET images were evaluated for visual assessment of areas with high metabolic activity. The hypermetabolic foci were anatomically localized on corresponding CT images. Lesion activity was quantified with a Standardized uptake value (SUV). The patient\u2019s history, distribution of pathological lesions and pattern of spread of different tumors was taken into consideration.In the investigation of a primary tumor, detection of the primary malignancy site was considered to be positive (true positive) only when confirmed by histopathology. If findings on PET-CT scan did not turn out to be a primary site by histopathology, these were accepted as \u2018false positive\u2019. Unremarkable PET-CT scans were considered as true negative, while false negative results indicated PET-CT scans where the primary site remained obscured.The data obtained after quantification was statistically analyzed. Quantitative variables (e.g. age) were presented as mean\u00b1SD. Qualitative variables  were expressed as frequency and percentages. The sensitivity, specificity, accuracy, positive predictive value and negative predictive values were calculated by a 2x2 contingency table.Out of the 100 enrolled patients, 74 had histopathologically proven metastatic disease with an unknown primary site. The lymph nodes were the most frequent site of metastasis in 27 patients (36.5%). Liver biopsy was obtained in 15 (20%) patients. The details of metastatic site and histopathologic tumor types are listed in the Twenty-six out of 100 patients were enrolled due to a clinical suspicion of malignancy. Ten (38.5%) out of these 26 patients had hypodense lesions in the liver and 3 (11.5%) had pulmonary nodules on CT, that were all suspicious for metastases but were not biopsied. Likewise one (3.8%) patient had a hypodense lesion in the spleen, 1 (3.8%) had heterogeneous density in the adrenal gland, and 1 (3.8%) had a bulky pancreatic head. Suspicious lesions were detected on magnetic resonance imaging (MRI) scan in the brain in 2 (7.7%) cases, and in the bone in 1 (3.8%) patient. Seven (26.9%) patients had a history of weight loss and progressive weakness along with elevated tumor markers .Out of the 100 patients enrolled with CUP syndrome, 18 patients were excluded from final analysis due to lack of information about their final histopathology results or clinical outcome.Hypermetabolic lesions indicating the primary tumor sites were correctly identified in 47 (57.3%) (true positive). Forty-five of these 47 primary sites were subsequently proven by histopathology. Two scans revealed positive findings in the vocal cords and pyriform sinus, which could not be biopsied; however, these sites were verified as primary sites by MRI scan.In 6 (7.3%) patients, the hypermetabolic lesions that were identified on PET-CT scans did not turn out to be malignant/primary on subsequent biopsy . Four of these FDG-avid lesions turned out to be metastatic lesions on biopsy instead of the primary site. In the remaining 2 cases, biopsy of the sigmoid colon showed a tubular adenoma while the biopsy of the FDG -avid renal lesion turned out to be negative for malignancy.No primary site could be identified in 29 (35%) patients. Within these, 17 (21%) scans were true negatives with unremarkable PET-CT scans without any hypermetabolic site. The remaining 12 (15%) were false negative studies, in which either the known sites of metastasis or additional sites of metastasis showed FDG uptake while primary site could not be identified.max value of the hypermetabolic lesions was reported to be 8.2\u00b14.7 SD.The average SUVFDG PET-CT scan led to a shift in disease stage in 38% of the cases; up-staged 27%, while down-staging 11%. Overall, the diagnostic accuracy was found to be 78%, sensitivity 80%, specificity 74%, positive predictive value 88.7% and negative predictive value 59%.The identified primary tumor sites were; the lung 10/47 (21.3%), head and neck 10/47 (21.3%), colon and rectum 5/47 (10.6%) , stomachOut of the 47 detected primary tumors, 45 were further confirmed by histopathology. Thirteen (27.6%) were adenocarcinoma (Gastric adenocarcinoma 4 (30.8%), colorectal adenocarcinoma 5 (38.5%), pancreatic adenocarcinoma 2 (15.4%), breast adenocarcinoma 2 (15.4%)), 10 (21.3%) non-small cell lung cancer, 5 (10.6%) squamous cell carcinoma (Head and neck SCCa 4 (80%) , and medThe primary sites identified on PET-CT scan and the histologic types on subsequent biopsy are presented in 18F-FDG PET-CT is a functional imaging method based on the increased glucose metabolism of malignant foci. Its key role has already been established in the diagnostic workup of a variety of primary tumors  followed by non-small cell lung cancer (21.3%), and squamous cell carcinoma (10.6%). In addition, we were able to localize ovarian carcinoma, adenoid cystic Ca, nasopharyngeal Ca, follicular thyroid Ca, hepatocellular carcinoma, cholangiocarcinoma, breast invasive ductal carcinoma, alveolar soft part sarcoma, Hodgkin\u2019s disease, Non-Hodgkin\u2019s lymphoma, renal neuroendocrine tumor and gallbladder Ca. These diverse findings are attributed to different biologic and metabolic behaviors of the histological subtypes of CUP . They concluded that SUVmax is a prognostic factor that influences survival in ACUP. Impact of SUVmax on survival was beyond the scope of our current study; however, it is an intriguing area and should be studied across the heterogeneous spectrum of CUP syndrome to identify favorable factors.High SUVlignancy . In our lignancy  in a firFDG PET-CT could not localize primary tumor site in 35% of patients. Despite the high rate of detection of the primary tumor site by FDG PET-CT, certain types of tumors remain obscured. As reported by Alberini JL et al.,  elevatedFalse positive results were detected only in 6 (15%) patients, where the hypermetabolic lesions identified on PET-CT scans did not turn out to be malignant/primary on subsequent biopsy. These false positive findings were observed in the abdomino-pelvic region, where physiologic tracer uptake usually mimics pathologic lesions .In our study, disease stage was modified in 38% of the cases. This is slightly better than the 34.7% stated in a recent review by Pawaskar and Basu . ModificOne limitation to this study was the relatively smaller number of cases, which is attributed to the extremely heterogeneous cohort of patients with CUP syndrome. Basing conclusions on results from a small group is a limitation to proving efficacy of FDG PET-CT scan in the diagnosis of unknown primary tumor site; however, the results suggest that incorporation of FDG PET-CT scan in the early diagnostic phase can improve management.In spite of the heterogeneity of CUP syndrome, the scientific literature and the findings of our study agree to the concept that FDG PET-CT scan is a useful diagnostic tool in detecting an unidentified primary tumor site. Currently, the role of PET-CT scan has been defined in the staging of cancer patients in Oncology . The ind18F-FDG PET-CT imaging in localization of unknown primary tumors across all body regions, as well as in staging CUP syndrome.Our study is in conformity with the published literature on the role of hybrid The study complies with the ethical standards. Approval was taken from the Institutional review board (IRB). As per IRB, no more than the nominal risk is contained since the information of human subjects is documented without any identifiers as well as presenting an entirely anonymous research data set ."}
+{"text": "We describe the experience of our department with positive oral food challenges (OFC) to peanut in children, over a 10-year period.Children who underwent a positive OFC to peanut between November 2001 and November 2012 in the Allergy Department of the University Hospital in Montpellier, France, were analysed with respect to demographics, history of atopic disease, specific IgE values, skin tests results and the severity of both the index reaction and the one elicited by the OFC (according to the Sampson grades of severity)[69 OFC to peanut were positive in 59  patients, aged 3-16 years . 129 OFC turned out negative over the same period of time. All the patients were atopic. The most common allergens were: grass mix (44.1%), cat and dog dander (42.6%), house dust mites (38.2%), molds (29.4%) and cypress pollen (20.5%). 24 (35.2%) patients had allergic rhinitis and 45 (66.2%) had asthma . 29 (42.6% ) patients suffered from atopic eczema. 26 patients (41%) had no history of previous ingestion of peanuts and the avoidance regimen had been recommended either because of positive IgE and/or skin tests (in the context of atopic disease in early life) or because of reactions to cross-reactive tree nuts. 32 OFC were conducted in this population, eliciting 20 grade I reactions (62.5%), 11 (34.4%) grade II reactions and one anaphylactic shock. In the other patient group, with a clinical history of reaction to peanut itself, 29 patients (49.2%) had a history of a grade I reaction and 4 (6.7%) described grade II reactions. The 37 OFC performed in these patients were followed either by grade I or II reactions, namely the reaction was just as severe in 21 (56.7%), more severe in 13 (35.1%) and less severe in 3 patients (8.1%). The lowest eliciting dose, in terms of protein content, was 25 mg.OFC provides data regarding the allergic status and the eliciting dose in patients with a suspicion of peanut allergy. Caution is mandatory, since reactions following OFC may be more severe than the index reaction, despite the slow progression of doses."}
+{"text": "In Belgium, smoke-free legislation was implemented in different phases: in public places and most workplaces in January 2006, in restaurants in January 2007, and in bars serving food in January 2010. We investigated the impact of these smoking bans on the incidence of preterm delivery and mortality of acute myocardial infarction (AMI) in Flanders. The stepwise implementation of smoke-free legislation gave us the opportunity to investigate potential successive changes in health outcomes.We used segmented logistic regression (preterm birth) and segmented Poisson regression , adjusting for (among other things) secular trends and seasonality.Based on 448,520 non-induced singleton live births between 2002 and 2011, we found an immediate change in the risk of preterm birth of -3.13% (95% CI -4.37 to -1.87) on 1 January 2007 (smoking ban in restaurants), and a gradual annual change of -2.65% (95% CI -5.11 to -0.13) since 1 January 2010 (smoking ban in bars serving food). These estimates correspond to a reduction of 6 preterm births per 1000 deliveries. Using data from all fatal AMIs between 2000 and 2009 , we observed an immediate decrease in the risk of AMI in January 2006 (smoking ban at work). The effect was largest for women younger than 60 years. Among elderly men (=60 years), we found an additional gradual effect of the smoking ban in restaurants since 1 January 2007. Our findings correspond to an estimated total of 1,715 fatal AMIs averted from 2006 to 2009.Our studies give further support that smoking bans have public health benefits not only at older age but from early life onwards. A continuation and implementation of smoke-free laws worldwide is warranted."}
+{"text": "Ependymomas are rare tumors of the central nervous system (CNS). They are classified based on tumor histology and grade, but the prognostic value of the WHO grading system remains controversial. Treatment is mainly surgical and by radiation. An improved knowledge of ependymoma biology is important to elucidate the pathogenesis, to improve classification schemes, and to identify novel potential treatment targets. Only 113 ependymoma karyotypes with chromosome aberrations are registered in the Mitelman database. We present the first study of ependymoma genomes combining karyotyping and high resolution comparative genomic hybridization (HR-CGH). Nineteen tumor samples were collected from three pediatric and 15 adult patients treated at Oslo University Hospital between 2005 and 2012. Histological diagnoses included subependymoma and myxopapillary ependymoma (WHO grade I), ependymoma (WHO grade II) and anaplastic ependymoma (WHO grade III). Four tumors were intraspinal and 15 were intracranial. Seventeen samples were successfully karyotyped, HR-CGH analysis was undertaken on 17 samples, and 15 of 19 tumors were analyzed using both methods. Twelve tumors had karyotypic abnormalities, mostly gains or losses of whole chromosomes. Structural rearrangements were found in four tumors, in two of which 2p23 was identified as a breakpoint region. Twelve tumors displayed genomic imbalances by HR-CGH analysis with loss of material at 6q as the most common. 6q loss, which was detected by one or both methods in seven of 12 (58%) abnormal tumors, and 5p gain  were the most common genomic aberrations in this series. Ependymomas are primary neuroepithelial tumors of the central nervous system (CNS) mimicking ependymal cell differentiation. Intraspinal ependymomas are more common in the adult patient population whereas children more often have intracranial tumors . EpendymSurgery is the mainstay of ependymoma treatment and gross total tumor resection (GTR) is an independent prognostic factor affecting both overall (OS) and progression-free (PFS) survival ,6,8\u201310. Only 113 ependymomas  are registered in the Mitelman Database of Chromosome Aberrations in Cancer . ApproxiNo previous studies have investigated the ependymoma genome using a combination of CGH and G-banding techniques. We describe genomic and chromosomal aberrations in a series of histologically heterogeneous ependymomas.The tumor samples used in the present study (19 specimens from 18 patients) were prospectively collected between January 2005 and December 2012. Clinical and pathological details are provided in All tumor samples were processed for cytogenetic analysis using standard methods as described by Mandahl . The chrDNA was extracted from the tumor samples using Maxwell 16  (12 samples), standard phenol/chloroform method (four samples), or MagAttract DNA Mini M48 kit . DNA sample quality and concentrations were measured and assessed using NanoVue Plus .et al . Written, informed consent was obtained from 15 participants. The remaining three patients were included post mortem following permission from the Norwegian Directorate of Health. All tumor samples were collected from an approved biobank.Karyotypes were established from 17 samples, the remaining two samples failed in culture. Tissue was available for DNA extraction and HR-CGH analysis for 17 of 19 samples. Fifteen samples (79%) were analyzed using both methods. The karyotypes and HR-CGH results are presented in Twelve of 17 karyotypes (71%) were abnormal , Fig. 1:HR-CGH analysis was informative in all 17 samples from which DNA was available. Twelve of 17 samples (71%) had genomic imbalances, and all analyzed chromosomes were affected in one or more samples. Gains were noted in nine and losses in 12 samples. No amplifications were found. The average number of aberrations per abnormal sample was 12, and gains (average 5.3) were slightly less common than losses (average 6.9). Five of 12 samples (42%) had simple genomic changes whereas the remaining seven (58%) were genomically complex with an average of 12 affected chromosomes per sample. The most common genomic imbalances in 11 tumor samples  whereas the other two (cases 6 and 7) had near-triploid, complex karyotypes with numerical abnormalities only. HR-CGH was performed on three of four spinal lesions and all three were abnormal. Two tumors displayed complex genomic aberrations and all three had copy number losses at band 22q11.Eight of nine (89%) infratentorial tumors were successfully karyotyped. Four of these were cytogenetically normal and one tumor (case 18) showed Y loss only. Two of the remaining three abnormal tumors (cases 4 and 17) had simple, near-diploid karyotypes with loss of chromosome 6. The last tumor (case 1) had a complex, near-triploid karyotype with several numerical aberrations. DNA material was available for HR-CGH analysis for eight of nine (89%) tumors. Three of these  were abnormal, of which two harbored complex genomic imbalances. Genomic losses at 6p and 6q were found by HR-CGH in all three abnormal infratentorial tumors.All six supratentorial tumors were karyotypically abnormal and in three of five (60%) tumors loss of material from 14q was noted. All four tumors harboring structural rearrangements were supratentorial. HR-CGH results from all six supratentorial samples were abnormal. When excluding the recurrent tumor (case 9-2), three of five (60%) cases displayed simple genomic changes.Sixteen tumors were assessed; five grade I tumors , seven grade II tumors , and four grade III tumors . Case 11 was not included due to its uncertain WHO grade and case 9-2 was not assessed because its corresponding primary tumor (case 9-1) was already included in the grade III group. Case 15 was excluded due to its histology (anaplastic ependymoma with prominent glioblastoma features).Four of five (80%) grade I tumors were informative by G-banding. Three of these (75%) were karyotypically normal, whereas the remaining tumor (case 4) had a simple karyotype with monosomy 6. DNA was available for HR-CGH analysis in three of five tumors and all three were normal.Six of seven grade II lesions were informative by G-banding. One of these (17%) had a normal karyotype. There were no structural chromosomal aberrations found in this group. The most common numerical aberrations were +7, +15 and \u22126 . HR-CGH analyses were performed on all seven grade II ependymomas: one tumor (14%) did not harbor any genomic imbalances, two tumors (29%) displayed simple genomic imbalances, and four (57%) had complex HR-CGH profiles with an average of 17 aberrations per sample.G-banded karyotypes were obtained from all four grade III ependymomas. One karyotype was normal, one tumor had a simple karyotype and two tumors had complex karyotypes. All four tumors were informative by HR-CGH. One of them had a normal profile, one had simple changes, whereas the remaining two tumors (cases 9-1 and 12) had complex profiles.Tumor samples from patients with known disease progression were compared to those with stable disease. Six patients were included  in the progression group, eleven patients  in the \u2018no progression\u2019 group, whereas one patient (case 17) died of postoperative complications and was excluded. There were four grade III, one grade II, and one grade I tumor within the progression group.The progression group was karyotypically heterogeneous. Two patients (33%) had a normal karyotype, two (cases 3 and 4) had karyotypes with simple changes, and the remaining two abnormal tumors were karyotypically complex. Aberrations leading to loss of 6q were found in three of four (75%) abnormal karyotypes. By HR-CGH, one tumor had a normal profile, one had a simple profile, and three tumors had complex changes. The most common imbalance by CGH was loss of material from band 6q22 which was noted in three of four (75%) abnormal samples.The average follow-up for the 11 patients in the \u2018no recurrence\u2019 group was 5.4 years (median 6.1). Karyotypes were successfully obtained from nine of 11 (82%) tumors. Three of these were normal, three were karyotypically simple, while the remaining three samples had complex karyotypes. The most common karyotypic aberrations in this group were +7 and +15 as well as loss of material from the distal end of chromosome 14. These changes occurred in three tumors (50%) each. DNA was available for HR-CGH in all but one of the cases in this group of tumors. Four of them (40%) were normal. Among the six remaining cases there were three samples with simple and three samples with complex profiles. The most common imbalances were gains at 5p and 7p/7q as well as losses from 16p/16q and 22q, which were all found in three (50%) of the six abnormal samples.in vitro and so remained undetected.There was good overall concordance between HR-CGH and G-banding results in the 19 ependymomas we examined . Of the SASH1 [a candidate tumor suppressor gene in breast (TCP1 (involved in tubulin function), ADM1 and CDK11 (involved in cell proliferation) , was associated with disease progression in a mixed patient population. The present series is small and prognostic conclusions cannot be drawn. The potential of 6q loss as a prognostic marker is still in need of prospective evaluation in future studies  ,42,43. Aeration) , five ge)  harbored structural chromosomal rearrangements. Among these, case 11 is of particular interest. This tumor had a dert aThe present study is the first to combine karyotypic and CGH analyses of ependymomas. It provides an overview of the ependymoma genome and is a significant contribution to existing cytogenetic knowledge on these rare tumors. 6q loss and 5p gain were found to be the most common chromosomal aberrations in our heterogeneous patient population. The significance of these findings requires further analysis in larger studies."}
+{"text": "The antiphospholipid antibody syndrome (APS) is a multisystemic autoimmune disease characterized by thromboembolic events, pregnancy morbidity, hematologic, dermatologic, neurologic and other manifestations in the presence of elevated titers of antiphospholipid antibodies (aPL). In recent years, APS has been increasingly recognized in various pediatric autoimmune and nonautoimmune diseases, but the relatively low prevalence and heterogeneity of APS in childhood made it very difficult to study in a systematic way.To evaluate the prevalence of thrombotic and nonthrombotic clinical manifestations in children with positive aPL and determine the long-term outcome of children with APS.A retrospective study with longitudinal follow-up of an unselected group of children who tested positive for at least one aPL subtype  was conducted for assessment of the prevalence of clinical features associated with aPL in children. Testing for aPL was requested by treating physicians given the clinical suspicion of aPL-related clinical manifestations. Data from the European registry extended internationally of pediatric patients with APS (Ped-APS Registry) were used for assessment of the long-term outcome of children with APS. To be eligible for enrollment the patient must meet the preliminary criteria for the classification of pediatric APS and the onset of APS must have occurred prior to the patient's 18th birthday.A total of 159 patients who tested positive for at least one aPL subtype  at the time of or within the first three months after the disease presentation were enrolled. There were 98 (62%) females and 61 (38%) males with mean age at disease presentation 11.4 years (range: 1-18 years). Mean follow-up period was 6.2 years. During this period 25 (16%) patients had thrombotic event , 48 (30%) patients developed hematological manifestations, 25 (16%) patients nonthrombotic neurological manifestations, 19 (12%) patients skin manifestations and 5 (3%) patients cardiac valve disease. Two out of 25 (8%) patients with thrombosis had recurrent thrombotic event. Underlying systemic autoimmune disease was identified in 55 (35%) of patients.The clinical characteristics and outcome was compared with 140 children with APS included in the Ped-APS Registry. Venous thrombosis occurred in 86 (61%), arterial thrombosis in 43 (31%), small vessel thrombosis in 7 (5%) and mixed arterial and venous thrombosis in 4 (3%) patients. Associated non-thrombotic clinical manifestations included hematological manifestations (39%), skin disorders (19%) and non-thrombotic neurological manifestations (16%). Mean follow-up time from the time of APS diagnosis was 6.1 years. Recurrent thrombosis was observed in 19% of pediatric patients with initial venous thrombosis and 21% of patients with initial arterial thrombosis. Sixty-eight (49%) patients included in the Ped-APS Registry had underlying autoimmune disease.Nonthrombotic clinical manifestations were more frequent than thrombotic events (16%) in an unselected group of children with positive aPL. Children with APS have significantly higher thrombosis recurrence rates as compared with adult APS patients.None declared."}
+{"text": "Most international studies on epidemiology of transient loss of consciousness(TLC) were performed many years ago. There are no data about the lifetimeprevalence of TLC in Russia.To identify the lifetime prevalence and presumed mechanisms of TLC in anurban Russian population.1796 individuals  aged 20 to 69years (mean age 45.8 \u00b1 11.9 years) were randomly selected andinterviewed within the framework of multicentre randomised observationaltrial.The overall prevalence of TLC in the studied population was 23.3% (418/1796),with the highest proportion (28%) seen in 40-49 year age group. TLC wassignificantly more common in women than in men (27.5% vs 13.5%). The meanage of patients at the time of the first event was 16  years, with333 (85%) individuals experiencing the first episode of TLC under 30 years.The average time after the first episode of TLC was 27  years. Thefollowing mechanisms of TLC were determined using the questionnaire:neurally-mediated syncope (56.5%), arrhythmogenic onset of syncope (6.0%),nonsyncopal origin of TLC (1.4%), single episode during lifetime (2.1%).Reasons for TLC remained unidentified in 34% cases. 27 persons (6.5%)reported a family history of sudden death, mainly patients with presumablyarrhythmogenic origin (24%).Our findings suggest that the overall prevalence of TLC in individuals aged20-69 years is high. The most common cause of TLC is neurally-mediatedsyncope. These data about the epidemiology can help to developcost-effective management approaches to TLC. In the young, almost all cases of TLC have neurally-mediatedorigin, while in the elderly, cardiac causes and orthostatic hypotensionpredominate. However, the lifetime prevalence of TLC is difficult to obtain due torecollection bias of fainting episodes which occurred many years ago.3 Available evidence as well as limitations of multiple cohort andpopulation-based studies on epidemiology of TLC are summarized in EuropeanGuidelines for the diagnosis and management of syncope and recent reviews.6Even after publication of Framingham study in 2002 we still have to say that dataabout epidemiology and prognosis of transient loss of consciousness (TLC) in thecommunity are lacking.The objectives of this study were to identify the lifetime prevalence and presumedmechanisms of TLC in an urban Russian population.7The data analysed in this paper were collected as part of a multicentrecross-sectional study of the epidemiology of Cardiovascular Disorders in Regions ofthe Russian Federation (ESSE-RF). Participants were from a random population sampleof the residents of the city of Samara (1.1 million residents). Multi-stage randomsampling was used to select people:-four outpatient clinics were randomly selected from a total of 17clinics in Samara City;-within these clinics, 10 residential catchment areas were randomlyselected;-within catchment areas, 50 households per area were randomlyselected.A survey was conducted by specially trained medical staff. Initially, people wereinvited to participate in the study by postcards and/or by phone calls. If we didnot receive any response, than researchers went to the selected homes, explained thegoals of the study, and invited them directly. The results were recorded usingstructured questionnaires and then entered into a database. Initially individualsfrom 25 to 64 years were recruited, while patients from 20 to 24 years of age andfrom 65 to 69 years of age were added later, using the same selection principles. Ofthe 2200 individuals approached, we were successful in recruiting 1796, resulting ina response rate 81.6%.8 The following self-reportedinformation was collected in this module: 1) family history of sudden death (SD)related to cardiac pathology in first-degree relatives (parents and siblings) underthe age of 45 years; 2) one or more episodes of having had a sensation of pulsationor movement in the chest; 3) a history of TLC: age at the time of the first event,as well as 14 questions that allowed to suspect neurally-mediated mechanism of TLC.This questionnaire  in case of normaldistribution, and as medians (Me) and 25 and 75 percentile values if thedistribution was non-normal. Statistical analysis for normally distributed data wasmade using two-sided unpaired This study enrolled 1796 individuals , 418 of whom reported a history of TLC during lifetime,resulting in an overall lifetime prevalence of TLC of 23.3%, with the highestlevel of 28% in those aged 40-49 years . In men,The vast majority of interviewed individuals (79.9%) had no concomitant heartcondition. One-fifth reported arterial hypertension, and 15 patients (3.5%)suffered from coronary artery disease (CAD). On ECG, premature ventricularcomplexes were recorded in 20 subjects (4.8%), atrial fibrillation in 5 subjects(1.2%), and WPW syndrome in 3 (0.7%). Other 23 patients (5.5%) reported recentepisodes of arrhythmias on ECG, but did not know their exact type. Twenty-sevenindividuals (6.5%) reported SD among first degree relatives under age of 45years.The mean age of patients at the time of the first TLC episode was 16 years, with 333 (85.0%) individuals (both men and women) experiencing theirfirst episode of TLC before 30 years of age . Almost Based on the data obtained from the questionnaire, we classified the likelyunderlying mechanisms of first reported episode of TLC in the study population. In all Based on the data collected using the questionnaire, NMS as a tentative mechanismof TLC was identified in 236 (56.5%) individuals. Mean questionnaire scorewithin this group was 2.33 \u00b1 1.77.One or more typical NMS triggers identified through the questionnaire included:syncope occurring in crowded and hot places, 172 (72.9%) individuals; syncopeassociated with prolonged time in standing position, 38 (16.1%) individuals;syncope associated with intravenous injections, medical procedures, 57 (24.2%)individuals; syncope associated with neck movement, 8 (3.4%) individuals;syncope associated with severe pain or emotional stress, 3 (1.3%)individuals.Less than half of the individuals  with presumably NMS had overt andtypical prodromal symptoms, mostly \"blurred vision\" in 101 (95.3%) patients, andfeeling of warmth in 31 (29.2%) patients. Other patients experienced little  or no symptoms at all .In most cases, the recovery was quick, and consciousness restored rapidly.However, in 43 (18.2%) individuals, complete recovery took 30 minutes or more,and 15 (6.4%) individuals experienced drowsiness after TLC.Twenty-five (6%) individuals reported palpitation sensations before TLC. Thirteen(52%) patients described their episodes of palpitation as having sudden onsetand a regular pulse, whereas 9 (36%) patients experienced irregular heartbeatsduring palpitation. Only 16 patients (64%) sought medical help, the followingcardiovascular disorders being diagnosed in 7: CAD (n = 3); arterialhypertension (n = 2); atrioventricular reciprocating tachycardia (n = 1); andatrial fibrillation (n = 1).Using the questionnaire, we failed to identify risk factors potentiallyassociated with life-threatening ventricular arrhythmias. Only 2 (8%)individuals experienced TLC while walking, and none of them complained of lossof consciousness in horizontal position.In 11 (44%) individuals from this group, symptoms of arrhythmia were combinedwith typical NMS triggers. Episodes associated with crowded and hot environmentswere observed in 10 individuals, syncopes associated with prolonged time instanding position in 4 individuals, and syncopes associated with intravenousinjections in 2 individuals. Six of those 11 patients experienced blurred visionand/or had warm sensation at the debut of TLC. Eight patients required more than30 minutes to recover, and 5 individuals reported drowsiness after an episode.Thus, in a proportion of patients in this group, NMS may also have contributedto the development of TLC.In 6 (1.4%) women, loss of consciousness was not associated with any obviouscardiovascular symptom, but they experienced visual or auditory hallucinationsduring prodromal period. None of them had any comorbidity. In 2 women,hallucinations were combined with impaired vision during prodromal period andone \"hot flash\", and collapse was sudden in 3 of them. Recovering phase lastedmore than 30 minutes in 2 women, and 4 of them slept after the episodesuggesting epilepsy as a contributing factor.Nine (2.1%) women reported only one episode of TLC during lifetime. Theseoccurred during pregnancy (n = 5), were associated with specific medicalconditions , or stress related(take-off of an aircraft - 1 patient). They earned 0.38 \u00b1 0.11 points byquestionnaire.Absence of any reported triggers and development of TLC \"for no obvious reason\"was the basis for including such individuals in the group with unidentifiedgenesis of TLC. This group consisted of 142 (34%) individuals, and almost 78% ofthem  had no symptom of any cardiovascular disease.Hypertension had been diagnosed in 31 (21.8%) patients previously, CAD in 8patients, and atrial fibrillation in 2 patients.Sixty-five (45%) patients with TLC of unknown origin did not have any prodromalsymptoms. \"Blurred vision\" during prodromal period was observed in 62 (43%)individuals, feeling of warmth in 17 (12%). Syncope with \"sudden\" fall wasreported by 42 (29%) patients. Rapid and full recovery was seen in the vastmajority of cases; however, in 21 (15%) patients, full recovery took over 30minutes, and some of them (12 patients) slept for a while after TLC.Twenty-seven individuals (6.5%) reported family history of SD. The highestprevalence of SD in close relatives  was recorded in patients withpresumed arrhythmogenic origin of TLC, which was significantly higher comparedto patients with presumably NMS (5.1%) and unidentified reasons (6.3%). Therewas no SD among relatives of persons from the nonsyncopal and single episodegroups.12 To our knowledge, this is the first report oflifetime prevalence of TLC in urban Russian population. The overall lifetimeprevalence of one or more episodes of TLC in our population was 23%, with thehighest prevalence of 28% observed in individuals aged 40-49 years. In women, TLCprevalence was twice as high compared to men .Despite numerous publications, data about the incidence and prevalence of TLC ingeneral population and different clinical settings are lacking, because some of themwere published decades ago.15 These data were confirmed in our study: the mean age at thetime of first TLC in Samara city population was 16  years, with 85% of allTLC developing in patients under 30 years of age. However, contrary to theFramingham study results,1 in ourpopulation the risk of TLC decreased with age. This fact may be partially explainedby the absence of individuals older than 70 years in our study, since the secondpeak of TLC occurrence in the Framingham study was observed at the age of 70 years,for both men and women.The first episode of TLC is known to commonly occur in people aged 10-30 years, withoverall frequency peaking at 13-15 years and after 70 years of age.20 In our study, we also usedspecialized questionnaire, but no further diagnostic procedures, and medicalexamination was conducted according to the protocol of ESSE-RF study.The prevalence of TLC varies with age and its epidemiological characteristics couldbe significantly affected by diagnostic criteria and methods used in a particularstudy. The value of standardized questionnaires for screening has been demonstratedin multiple studies.25The most commonly presumed cause of TLC in our population was NMS, which predominatedin all age and gender groups. Therefore, our results were generally in agreementwith the previously reported TLC scenarios, NMS being the most common cause of TLC,while cardiogenic syncope is usually less frequent, mostly having an arrhythmicorigin. In approximately one-third of cases, the syncope genesis remainsunidentified.5 Tilt-table test, carotid sinusmassage, and implantation of event recorders may be recommended in approximatelyhalf of patients with suspected neurally-mediated TLC without typical symptoms inprodromal period. Importantly, in 15-30% of patients with NMS, the differentialdiagnosis may be complicated due to symptoms overlapping other types ofTLC.28Information about the prevalence of various types of TLC is of utmost importance forclinical practice. Careful medical examination allows confirming theneurally-mediated mechanism in most patients with presumed NMS.In patients with suspected arrhythmic syncope, further diagnostic tests should beperformed to exclude overt heart disease, mainly due to a high prevalence (24%) ofSD among first-degree relatives. This is especially true for patients with syncopeonset during physical exertion and short medical history of TLC. However, forpatients having typical NMS triggers and prodromal symptoms, it is also important toexamine the autonomous nervous system function, because, in some of those episodes,palpitation may be a sign of NMS, which is difficult to differentiate only on thebasis of medical history.Detailed neurological examination, including video-EEG monitoring, is recommended forpatients with suspected epilepsy. At the same time, 3 out of 6 patients withnonsyncopal TLC had a long history of falls, \"hot flash\" as a prodromal symptom,paleness of the skin during loss of consciousness and a short recovery period. Wetherefore recommend that all diagnostic tests recommended for patients with NMSshould be considered in this group.30 Heart diseases and arrhythmias have to be excluded as well,as they often constitute the main risk factors for SD in this category ofpatients.31In patients with unidentified origin of TLC, examination should start with anautonomous nervous system function assessment, due to a potentially high (40%)prevalence of NMS with atypical clinical presentations in this group.5 for the initial evaluation of the vast majority of patientswith syncope.Our study has several limitations. First, despite a lot of methods used inclinical practice, there is no gold standard in syncope evaluation. We collectedself-reported information and data from medical records, accompanied by ECG andblood pressure measurement, which are currently considered enough by EuropeanSociety of Cardiology guidelinesSecond, syncope with different underlying mechanisms might have commonpredisposing factors and prodromal symptoms. Thus, it can be sometimeschallenging to distinguish them. However, NMS is considered the most commoncause of TLC in population. We used a specialized questionnaire with provenaccuracy to diagnose NMS in our study.Third, the results obtained in our study may not be applicable to patients withTLC admitted to tertiary centers, where TLC prevalence and mechanisms will bedifferent.Our findings suggest that the lifetime prevalence of TLC in individuals aged 20-69years is high. The most common cause of TLC is NMS. History of SD in close relativeswas recorded in 24% of patients with presumably arrhythmogenic TLC origin. Theseepidemiological data can help to develop cost-effective management approaches toTLC."}
+{"text": "Attention deficit and hyperactivity disorder (ADHD) and headache are two very common diseases in childhood and both of them have an important impact on quality of life and academic performance . In the Analysis of comorbility between ADHD and headache searching for the presence of ADHD trait in a population of headache patients.Observational study of case series based on collection of clinical-anamnestic data and on the administering of a standardized questionnaire  to evaluate the presence of ADHD traits in all the patients consecutively referred to the Juvenile Headache Centre of Padua (December 2014-May 2015). Inclusion criteria: age 5-18 years; diagnosis of primary headache, using the International Classification of Headache Disorders III, 2013 [Total sample of 180 cases  with mean age at interview of 11.8 years (8-18 years). Headache types: 120 migraine (M) (66.7%), 49 tension-type headache (TTH) (27.2%), 5 headaches with mixed pattern (M + TTH) (2.8%) and 6 other headaches (3.3%). M patients were divided into 107 MO (89.2%), 13 MA (10.8%); TTH were divided into 45 ETTH (91.8%) and 4 CTTH (8.2%). Family history for headache was present in 122/180 patients (71.8%), family history for M in 50/122 (41.0%). Prevalence of ADHD traits was 19.4% in SDQ questionnaires completed by parents and 21.3% in self-assessment SDQ questionnaires from children/adolescents. There was a low level of agreement between parents and children, reflecting heterogeneity symmetrical judgment between the two groups . There were no correlations with the diagnosis of headache or with other clinical features ; statistically significant relationships were found with the worsening of academic performance (p 0.001) and marginally with school absences (p 0.08).This study confirms most literature studies on the possible relationship between headache and ADHD, especially concerning the important impact on quality of life and academic performance \u20133. It coWritten informed consent to publish was obtained from the patient(s)."}
+{"text": "Systemic onset Juvenile Idiopathic Arthritis (SoJIA) is rare pediatric disease, it accounts for 10% of children with Juvenile Idiopathic Arthritis. The onset of disese can be vary nonspecific and may suggest bacterial or viral infection, malignancy or other rheumatic disease. It is highly characterised by its extra-articular systemic illness features and, in some ways, it resembles a fever of unknown origin. Diagnosis is mostly clinical by using ILAR criteria .To assess the frequency of presenting symptoms and laboratory findings in SoJIA patients over 5 years period.This is retrospective study on all SoJIA patients diagnosed in department of pediatric rheumatology from January 2008 until January 2013 using ILAR criteria. The medical records were reviewed. In each case age, gender, presenting symptoms and laboratory data were reviewed.During the study period 12 patients were diagnosed, mean age at diagnosis was 8.9 years (14 month to 15 years). There were an equal distribution of genders. Mean duration of fever at the time of diagnosis was 22.4 days. At the presentation all 12 children had fever longer than 2 weeks (100%), 8 children had salmon rash (66%), 9 had arthritis , 8 had splenomegaly (66%), only 2 hepatomegaly (16%), 10 children had generalised lymphadenopathy (83%), 5 had serositis (40%). Mild anaemia was present in 75% of patients, leucocytosis in 92%, thrombocytosis in 58%. Elevated sedimentation rate and C reactive protein (CRP) were found in 100% patient. Antinuclear antibody (ANA) was positive in 4 patients (30%).Data from our study were consistent with clinical and laboratory findings from other studies and related literature. ANA was positive in 4 children (30%), which is probably false positive result.None declared."}
+{"text": "Few studies have focused on the characteristics of asthma in the elderly (AIE). Our study reflects the characteristics of old adults living in Buenos Aires who have been diagnosed of asthma.An observational descriptive study was performed at five different health care facilities in Buenos Aires. Clinical records during three months of 2014 were searched. Allergists reviewed all clinical histories and elderly was defined as older than 60 years. Clinical and laboratory characteristics were assessed, including severity of asthma (according to GINA), current treatment, evidence of sensitization via skin prick test (SPT), chest radiograph, total serum IgE and relative eosinophil counts.Total 152 patients were included and their average age (SD) were 66.83 years (6.52), 73% women, 78% Caucasian and 22% Hispanic. Late-onset asthma (with asthma onset after 60 years old) was described in 10% of the patients, with mean (SD) age at diagnosis of 69,67  years. Most of the patients had a diagnosis of persistent asthma (74%), while only a 7 % of them had a severe persistent asthma. They all were treated with an inhaled corticosteroid (ICS) + long-acting \u03b2-adrenergic , and the first choice as acute reliever therapy was an inhaled fast-acting \u03b2-adrenergic agonist . The doses of ICS were below 1000 mg/day in 77 % of the patients. Common sensitizing allergens (SPT) included mites (18%), pollens (8%) and fungi (7%). Anaphylactic triggers were predominantly tobacco smoke (40%), even though most of the patients had never smoked before (88%). Exercise (21%) and aeroallergens (20%) also triggered anaphylaxis. The chest radiograph was normal in the majority of the patients (89%). Elevated IgE and eosinophilia were only found in 4% and 30% of the patients, respectively.This is a retrospective study of AIE patients in Argentina. Better understanding of disease characteristics is needed to improve disease management."}
+{"text": "Prompt recognition and immediate therapy is life saving.to review clinical and laboratory data of MAS in 7 children with sJIA.clinical and laboratory data of 7 patients with MAS, treated in our hospital from January 2008 to December 2013, were analyzed retrospectively.seven children  were studied. Two children had incomplete MAS. The underlying disease was not identified in one child. MAS developed during the course of underlying disease (sJIA) in three children. Clinical manifestations at diagnosis included high persistent fever (7), skin rash (6), hepatosplenomegaly (7), lymphadenopathy (6), hemorrhages (5) and central nervous system dysfunction (6). Laboratory data included: high feritin>10 000 (7), cytopenia (7), abnormal liver function tests (7), hypoalbunaemia (7), hypertriglyceridemia (5), coagulopathy (5), decreased erythrocyte sedimentation rate (5). Macrophage hemophagocytosis were found in 4 bone marrow aspiration. Rota virus was isolated in stool in 3 children. MAS was reccurent in two children . Six children responded on immunosupressive therapy and are doing well, one child died.MAS is rare but serious complication of systemic juvenile idiopathic arthritis in children. It is important to keep in mind suddenly clinical and laboratory disturbanses in children with JIA, to recognise and immediate treat MAS in order to decrease mortality.None declared."}
+{"text": "The development of intensive care medicine has led to improved survival of patients with complex illnesses and extensive injuries. Survivors are at risk of acquiring physical and functional deficits that may have negative effects on health-related quality of life (HRQoL). The significance of measuring HRQoL has been underlined by critical care researchers since poor HRQoL is associated with an adverse prognosis.The aim of this work was to examine the development of HRQoL at 2, 6 and 12 months after ICU discharge in a mixed ICU patient population with an ICU-stay > 96 hrs.http://www.icuregswe.org). HRQoL was measured using the Short Form 36 (SF36) questionnaire at 2, 6, and 12 months after discharge from ICU. SF36 domains, age, gender, illness severity on admission (SAPS3 probabilities) and length of ICU-stay were analysed for the entire cohort and for important diagnostic groups. SF36 scores were compared to an age- and gender-adjusted Swedish normal population. Differences in SF36 domains were analysed using non-parametric methods. Medians and interquartile ranges are presented.We analysed admissions during 2008-2014 to 49 ICUs that submitted follow-up data to the Swedish Intensive Care Registry , female gender: 37.2%, SAPS3 prob: 0.36 (0.19-0.55), ICU-stay: 7.0 days (4.9-11.5 days)]. SF36 improved over time in all domains , although some domains remained stable from 6 to 12 months. Patterns of recovery differed between important diagnostic groups . A large proportion of patients (10-25% depending on SF36 domain) had HRQoL scores at 12 months which was below 2 standard deviations of the age- and gender-adjusted Swedish norm. The cardiac arrest group were among those with best, and the COPD group were among those with worst HRQoL at 12 months.HRQoL recovered over 12 months in critically ill patients with a prolonged ICU stay. Recovery varied between diagnostic groups and a large proportion of patients had markedly depressed HRQoL. These findings may have important implications for follow-up and care after critical illness.The Swedish Intensive Care Registry is partly funded by grants from the Executive Committee of Swedish Quality Registries."}
+{"text": "The study aims to evaluate the etiologic spectrum of urinary tract infections (UTI) and antibiotic sensitivity of isolates.At the Infectious Disease Hospital in Constan\u021ba, between January 2014 and June 2014, urine cultures were performed in patients presenting urinary tract infections. Urine was seeded by loops calibrated technique on Columbia agar with 5% sheep blood and Drigalski agar. To identify the germs we used latex agglutination kits for Gram-positive germs and API galleries (BioMerieux) for Gram-negative bacilli. Antibiotics susceptibility testing was performed with the help of Kirby-Bauer disc diffusion method.Escherichia coli, 25 cases (15.6%) Klebsiella spp., 12 cases (7%) Proteus spp., 15 cases (9.3%) Enterococcus spp., 7 cases (4.3%) Staphylococcus spp. and others \u2013 7 cases (4.3%). E. coli was the most common etiological agent of UTI in women (64% of positive cases), men (42.3% of positive cases) and children (47% of positive cases).Out of the total 805 urine samples performed, 160 turned out positive, isolating in 94 cases (58.7%) Most of the isolated germs were highly susceptible to imipenem (94.4%) and fosfomycin (82.28%). Also, a good sensitivity to ceftriaxone (69.2%), quinolones (71.4%) and gentamicin (68.68%) was recorded. In addition, 56.6% of germs were sensitive to nalidixic acid and 56.6% to biseptol. We also noticed low sensitivity of germs to amoxicillin/clavulanic acid \u2013 32.7%.Escherichia coli was found in the highest percentage in urinary isolates, predominantly in women. There is an increased sensitivity of strains involved in urinary tract infections to fosfomycin \u2013 an affordable antibiotic that can be used in the treatment of these cases."}
+{"text": "Recent studies suggest that the incidence of anaphylaxis is increasing, particularly among young children. Food allergens represent the most frequent triggers in children.To determine the key features of anaphylactic reactions and their emergency treatment in children presenting with anaphylaxis to the Paediatric Units or associated Emergency Departments in Ireland.An IPSU monthly multi-study report card is sent to every paediatrician, and anaphylaxis is included in this card from September 2013 to March 2015. Data are gathered using EAACI's Anaphylaxis Registry Form.51 reported anaphylaxis cases to date, with data available for 37. There were 23 (62%) boys and 27 (73%) new patients in this group. Food was the implicated allergen in 29/37 (78%). Peanut and cashew were the most frequent foods involved (24%), followed by egg (17%) and milk (14%). 62% of the cases were exposed to food allergens at home. Skin (92%) and airway symptoms (89%) predominated, with gastro-intestinal (48%) and cardio-vascular symptoms (46%) also frequent. One fatal anaphylaxis occurred, due to peanut. 84% of cases presented to hospital either directly (51%) or referred by a General Practitioner (32%). Adrenaline i.m. was given in 21/37 cases (57%). Adrenaline was self/parent-injected in 4 cases (19%), by a GP in 10 (47%), after arrival in hospital in 6 (28%), and by paramedics in 1 case. In the 10 known patients group, 3/6 (50%) used their prescribed Adrenaline Auto injectors, and 4/10 (40%) had not been prescribed Adrenaline.Food allergens are the main triggers for anaphylaxis in children. The rate of Adrenaline usage clearly needs to improve in Ireland and low usage of prescribed Adrenaline emphasizes the need for educational and other support strategies for patients and physicians."}
+{"text": "Urinary tract infection (UTI) is one of the common complaints with which patients present to the emergency department. There are very few studies from our part of the country for UTI. The most commonly used antibiotics are fluoroquinolones, nitrofurantoin and aminoglycosides. The objective of this study was to evaluate the characteristics of bacteria involved in UTI and the prevalent antibiotic resistance patterns.A retrospective study was performed to investigate the possible association between prescribed antibiotics and resistance of organisms involved in UTI. Patients above the age of 18 who presented to the ED with diagnosis of suspected UTI were included from November 2012 to January 2013. Patients below the age of 18, patients with genitourinary abnormalities including previous genitourinary surgery, patients in septic shock or those with a history of sexual abuse were excluded.E.Coli (77%), Pseudomonas (4%), Klebsiella (5%) and Enterococcus (5%). E.coli was found resistant to common antibiotics like Nitrofurantoin (69%), Norfloxacin (32%), Amoxycillin (52%), Gentamycin (52%) and Cefoperazone sulbactam (35%). Klebsiella had resistance to Norfloxacin (2%), Ciprofloxacin (4%), Gentamycin (4%) and Cotrimoxazole (4%). Pseudomonas was resistant to Ciprofloxacin (4%), Ofloxacin (2%), Cefoperazone sulbactam (4%) and Gentamycin (4%). Resistance to Nirtofurantoin (2%), Ofloxacin (1.4%), Ciprofloxacin (1.4%) and Amoxicillin (4%) was noted in Enterococcus.Out of 207 patients, 34 (16%) had positive urine routine, 16 (7%) culture positive and 52 (25%) were positive for both. Commonly encountered organisms were E.coli. High resistance is noted to commonly prescribed antibiotics probably secondary to antibiotic abuse in the community. Knowledge of resistance patterns will help us use antibiotics judiciously to combat this concerning issue. Antibiotic stewardship is the need for the day.The most common organism noted in UTIs is"}
+{"text": "Systemic juvenile idiopathic arthritis (SJIA) is regarded as an autoinflammatory disease (AID) of unknown etiology related to abnormalities of the innate immune system. A major role in the pathogenesis has been ascribed to proinflammatory cytokines as interleukin (IL)-6 and IL-1.Analysis of treatment results with the IL-6 inhibitor tocilizumabhttp://www.aid-register.de).From 7/2009 to 4/2014 200 patients with SJIA were documented in the AID-registry. 46 of 200 patients  at the age of 1-18 years (median 9) received therapy with tocilizumab . 24 of 46 patients received long term treatment  and were evaluated concerning Wallace criteria [According to Kaplan-Meier analysis 30% reached inactive disease or remission after the first 12 weeks of treatment. A rapid response to tocilizumab seems to be related to long term inactivity of SJIA. Comparison of the three disease courses  revealed significant differences in the outcome; polycyclic courses show the fastest response followed by continuous courses. Worst outcome was evaluated in arthritic courses. Wallace criteria measured after at least 12 months: remission 54%, active disease 25%, inactive disease 21%. 4 (9%) patients were non-responders over the whole time. 60% of the patients showed no measurable CRP within the first 4 weeks and during tocilizumab therapy. Adverse events were reported in 11 (24%) patients: most leukopenia, infections and elevated transaminases, one Hodgkin's lymphoma, one gut perforation.A significant proportion of patients documented with SJIA in der German AID-registry is treated with tocilizumab (23%). We estimated a good response in the first 12 weeks of therapy of 30% and also by Wallace of 76% (inactive disease or remission). The response appears to depend on different disease phenotypes.1The AID-Registry is funded by the BMBF"}
+{"text": "The Netherlands have a low prevalence of Multi drug Resistant organisms (MDRO), in part due to their national guideline concerning MDRO carriers. Apart from being flagged in Electronic Health Records, immediate isolation precautions must be taken if the last MDRO positive culture is less than 1 year ago. No clear guidance is given on duration and termination of electronic alerts and isolation precautions for MDRO positive patients.To determine the proportion of persistent MDRO carriage in patients who were screened in 2014.We performed a retrospective study in our tertiary care university medical centre by reviewing the data of all patients with MDRO alerts who were screened in 2014 to determine if MDRO carriage was still present. Patients with MRSA/VRE/CRE carriage were excluded, since they follow different guidelines.Patients who are carrier of MDRO are cultured twice  at least 24 hours apart. After 2 negative screening results of both sites, the MDRO carriage is considered not to be present anymore.In 2014, 238 patients were cultured for MDRO carriage. Median age was 59 (IQR 29 -70) years, 55% (n=130) was male. Of the initial MDRO positive cultures, the most common material were urine (53%), rectal/perianal/faecal (23%) and sputum cultures (6%). Most common micro-organism was Escherichia coli (n=136) with ESBL as the most prevalent resistance mechanism (35%).The median time between initial positive MDRO culture and control cultures was 499 days (IQR 187-1055)Fifty-six patients tested MDRO positive in the first control cultures. Sixty-seven patients were screened a second time, of which 21 were MDRO positive . 48% (95% CI 37.4-71.6) of the patients with the initial MDRO positive culture < 1 year ago, remained MDRO positive.Of the patients who had been labelled MDRO positive longer than 1 year ago, 26% (95% CI 20.2-34.6%) remained MDRO positive.Twenty-six percent of the patients labelled MDRO positive longer than 1 year ago, remain MDRO positive and can be a source of MDRO transmission within the hospital. Discontinuation of electronic alerts and isolation precautions for MDRO carriage should therefore be based on microbiological screening results.None declared."}
+{"text": "To evaluate the feasibility of using Arabic Hospital Anxiety and Depression Scale (HADS) to assess depression and anxiety among patients attending accident and emergency (A & E) at a University Hospital setting in Riyadh, Saudi Arabia.In this prospective observational study translated questionnaire of HADS was used for patients aged 18 years or above who presented to A & E at King Khalid University Hospital in Riyadh, Saudi Arabia. The study included 257 patients as per an agreed inclusion criteria. The study quantified depression and anxiety and its association with demographic and or illness related variables using SPSS.Out of 257 participants, the dominant age group, ranged between 18-30 years (40.9%) with female participants (55.3%) outweigh the male among all. The overall occurrence of depression was 27.2% : 21.8 % to 32.6%) and anxiety was 23% (17.8% to 28.2%CI). Marital, educational and economic status of participants, were statistically significantly associated (p<0.05) with the levels of anxiety whereas age, marital, education, economic and employment status were associated (p<0.05) with the levels of depression.In the A & E setting at University Hospital in Saudi Arabia, comorbid depression and anxiety is not uncommon as enumerated by using HADS. The identified cases could then be sent for appropriate psychiatric treatment promptly not only to improve quality of individual care but also to reduce the overall health care costs in local context. About 450 million people suffer from mental disorders according to estimates given decade ago in WHO World Health Report 20014In the Arab world the prevalence of psychiatric comorbidities is reportedly high4The HADS is most frequently used assessment tool that was developed by Zigmond10The Arabic version of HADS has been used in different groups of patients both in primary care and hospital settings in Arab countries.The present study, therefore, aimed to screen patients attending the A & E in a tertiary care hospital depression and anxiety as psychiatric comorbidities besides the correlation of it with relevant demographic variables.The present study, a prospective observational survey, was carried out between February to December 2012 at the A & E in King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia. Permitted Arabic version of HADS by the sole proprietor, i.e., GL assessment UK13The printed Arabic translated questionnaire of HADS was provided to each patient who was 18 years of age or more, who could read and understand the questionnaire, whereas significantly medically unstable and known psychiatric patients were excluded in order to avoid discrepancies in interpretation of results. The purpose of the questionnaire was fully described to the patients; consent was duly signed by each participant and they were provided 30 minutes time to fill it. Total number of patients who received the questionnaire were 298 among which 257 responses were included and 41 responses excluded from the study either due to refusal (29 patients) or incomplete filling of the questionnaire (12 patients). The demographic data of the patients were recorded by the A & E physicians on duty including age, gender, marital status, educational status, economical status, presenting complaint and existing medical problems and previous admissions in the hospital or A & E visits. The data was analyzed using SPSS version 16.0 .Out of 257 patients, there were 105 (40.9%) in the age range of 18-30 years and 115 (44.7%) were males. Illiteracy was observed in 84 ((32.7%) patients, 25 (9.7%) had higher education whereas remaining 148 (57.6%) were with primary and secondary literacy. Married patients were 139 (54.1%) and unmarried were 84 (32.7%) whereas 34 (13.2%) were divorced and widowed. Depression was noticed in 27.2% (95% CI: 21.8 % to 32.6%) and anxiety in 23% (17.8% to 28.2%).Of all the study variables marital and economic status had significant statistical association with the level of anxiety (p<0.05). Among them married and divorced/widowed had high association as compared to unmarried subjects, where 28.1% and 26.5% were \u2018cases\u2019 among married and divorced/widowed subjects compared to 13.1% in unmarried subjects. The lower socio economic (40.6%) and middle socio economic status subjects (22.8%) had significantly higher anxiety compared to upper socioeconomic class subjects (13%).Other variables, although, were not statistically significant but anxiety was more common (28.3%) in the age group of 31-60 among those who were never admitted (25.5%), medical related patients (18.8%), and those who had poor prognosis (36.4%). Of all the variables age, marital, educational, employment and economic status were statistically significantly associated with the level of depression (p<0.05). That is high proportion among patients with higher age group(47.20%), married (32.8%), divorced/widowed (41.2%), illiterate (39.2%), housewife (36.6%), unemployed (28.6%), retired(58.8%) and lower socio economic status(53.1%) compared to patients of lower age (17.1%), unmarried (13.1%), secondary (19%) and higher education (16%), employed (17.9%) and upper economic status(16.7%).Other variables, although, were not statistically significant but it is worth mentioning here that depression was found more common among females(27.9%), those who never admitted (30.2%), among medical patients(22.4%) and among those who have poor prognosis (34.5%). Mental disorders will be the second leading cause of global disease burden by 202017The utility of a screening instrument in practice is determined by its case-finding ability. HADS evaluates reliably both depression and anxiety yet remains quick in time and straightforward to complete.The present study evaluating depression and anxiety in hospital population using Arabic translated HADS is probably the first such endeavour in A & E setting in the Arab world. A few studies have been conducted in A & E setting in other parts of the world but on carefully selected pool of patients with lack of a study focusing general pool of A & E patients.11In the present study, the observed occurrence of depression and anxiety was 23% and 27.2%respectively. In comparing with other similar studies, we have to appraise that the present study included all patients attending A & E as per an agreed inclusion criteria in general and did not focus on specific subsets of clinical population unlike other studies which did focus on specific pool of patients either related to their primary or main clinical complain. It did result in them reporting quite variable prevalence rates. Another arguable reason for broad variability between other studies might be due use of different cut off values for case-ness. For instance, in a Turkish study combined prevalence for both depression and anxiety was 30-50% among patient attending A & E with nonspecific chest pain (NSCP).24Other hospital clinic settings having stressful environment comparable to A & E like critical cardiac/coronary care (CCU), prevalence of anxiety was observed up to 24% using HADS cut off score of 10, which is very comparable to findings of the present study.28Its worthy to note that individual demographic variables have appeared influential in several comparable studies for instance, women found more susceptible to depression and somatization than men20Despite statistically significant results there are limitations in terms of over generalization as the present study included those patients who were clinically stable, thus, making the participating sample still fall short of true representation of the whole A & E population. The second limitation of the study is that the suspected cases were not provided structured psychiatric review which would have given sensitivity and specificity in terms of authentic diagnosis of depression and anxiety. However, HADS has been used and recommended without psychiatric evaluation for screening successfully.17The prevalence of depression and anxiety among patients attending A & E in a hospital setting is common and, therefore, it is appropriate to routinely use translated HADS as a screening tool for these patients. It can be a measure evolved in practice in liaison with local psychiatry services to attain not only quality but holistic patient care."}
+{"text": "Gaining informed consent is a key element of safe and transparent patient care. Although cardiac surgery is considered gold standard in many cases of complex cardiac disease, it is associated with significant complications including mortality.To assess patient expectations prior to cardiac surgery, including awareness of complications.Consecutive cases were interviewed over a two week period within a regional cardiothoracic centre in Scotland. Thirty patients were interviewed by the lead author 24 hours prior to procedure to ensure consistency.There were 28 elective and 2 emergency cases. All patients had read the pre-cardiac surgery information booklet and signed the centre's standardised consent form detailing both major and minor complications. 2 patients (7%) gave the wrong name of procedure and 5 (17%) patients were unable to state procedure indication. When invited to list complications, 5 patients (17%) mentioned stroke, however, 22 (73%) were unaware of this potential risk when asked directly. 9 patients (30%) were able to list 3 or more complications. Most frequently recalled were mortality, bleeding and need for repeat operation. 23 (77%) correctly quoted percentage mortality risk. Interestingly, 5 (17%) patients 'did not want to know' and 2 (7%) patients were unable to recall any complications. When considering duration of hospital stay, 3 (10%) patients expected 3-5 days post operatively. 22 (73%) expected a 5-7 day stay whilst 5 (17%) anticipated greater than 7 days. When asked 'How well informed do you feel?', the mean score was 8.5/10.This project offered valuable insight into patient expectations and knowledge of complications prior to cardiac surgery. The results show that the majority of patients were unable to recall more than 3 complications. Of note, some patients stated that they did not want to know nor discuss complications, which may reflect pre-operative mentality rather than disregard for risk. Important reflective points include emphasis on the dynamic nature of the consent process and ensuring patient understanding throughout. Recommendations have included patient information booklets being readily available at the bedside and encouraging patients and families to seek clarification, even after the consent form has been signed at pre-assessment clinic"}
+{"text": "Cryptococcal meningitis (CCM) is one of the leading causes of early mortality among HIV-infected patients. This study was a part of clinical audit  aimed atCryptococcus neoformans) between June 2011 and December 2012 were retrospectively reviewed. Descriptive statistics and Chi-square analysis were generated with Epi Info 7.1.2.0. 95% confidence intervals were reported where appropriate.Clinical records of all patients (age>13 years) admitted to the hospital with a diagnosis of CCM  or a positive culture of 3 was associated with a 1.6 times increased acute mortality risk, the association was not statistically significant . The role of elevated CSF opening pressure at diagnosis was not assessed because only two (1.6%) patients had their baseline opening pressure measured.Of the 127 patients admitted with CCM, only 97 (76.4%) knew their HIV status. Only 44.8% (43/96) of those who knew they were HIV positive were on antiretroviral therapy (ART). Seventeen out of 25 patients (68%) previously treated for CCM had defaulted fluconazole and only 60% (15/25) were on ART. Acute mortality (death within 14 days of CCM diagnosis) was 55.9% (71/127). The median time to death from diagnosis was four days (IQR 2\u20139). The association between CSF WBC count<20cells/mL and increased risk of death within 14 days was statistically significant . Patients with heavy cryptococcal burden (reported as numerous yeasts seen on microscopy) at diagnosis were three times more likely to die within 14 days of diagnosis of CCM . Even though a CD4 count<100cells/mmAcute CCM-related mortality remains high. The number of patients who do not know their HIV status, the number of HIV positive patients not on ART, the high level of non-adherence to fluconazole and the proportion of patients not on ART after at least one previous CCM episode all point to the need of developing comprehensive strategies aimed at encouraging HIV testing and improving patient's retention in HIV care and support."}
+{"text": "Echocardiography is a non-invasive procedure which enables full assesment of cardiac function. The inferior vena cava (IVC) is a compliant blood vessel, easily distended, especially in cases of hypovolemia. Assessment of the physiologic characteristics of the IVC provides a rapid distinction between low and high volume states and offers the clinician a rapid, noninvasive way to guide resuscitation in critically ill patients.To assess the reliability of the distensibility of inferior vena cava (dIVC),measured by ultrasound, as an indicator of fluid responsiveness in ventilated patientsObservational prospective study in a 14-bed Intensive Care Unit . We enrolled 15 patients requiring advanced hemodynamic monitoring . The dIVC was calculate as (maximum diameter - minimum diameter)/minimum diameter and possible responders were defined as dIVC >18%.IVC assessment was done just proximal to the hepatic veins, which lie approximately 0.5 to 3 cm from the right atrium, following the American Society of Echocardiography guidelines. Hemodynamic parameters were collected at baseline and after a fluid challenge. Fluid challenge was made by de maneuver of passive legs raising (PLR) that mimics a fluid challenge of 300 ml. Fluid responsiveness was defined by an increase of > 15% in cardiac output. Demographics characteristics, reason of ICU admission, severity of illness by APACHE and necessity of vasopressor support were also collected.We included 15 patients with an age mean of 64.67 + 14.1, 40% male. Abdominal septic shock was the most frequent reason of ICU admission(40%),respiratory (20%),cardiogenic (13.3%) and others(20%).Median APACHE was 19.27 + 5.86. All patients were on mechanical ventilation with PEEP mean 11.40 + 3.74. All patients were on sensual rhythm and 80% needed vasopressor support. Advance hemodynamic monitoring was made by using PiCCO, Vigileo and Swan-Ganz catheter, 60%, 26.7% and 13.3%, respectively. dIVC was > 18% in 4 patients (26.7%) and 2 patients (50%) responded to fluid challenge. In 11 patients (73.11%) dIVC was < 18% and 10 of them (90.9%) didn\u2019t respond to fluid challenge. Statistical analysis showed no significant differences (p > 0.05).Assessment of the IVC distensibility index in mechanically ventilated patients provides a useful and reliable tool in predicting response to volume in critically ill patients. Although our data do not show a statistical significance probably due to sample size, measuring the VCI should be part of a hemodynamic assessment specific protocol to evaluate the necessity or not of volume, that it is so important in the evolution of critical patients."}
+{"text": "Phoca vitulina) off the coasts of Sweden and Denmark. This virus subsequently spread to harbor seals off the coasts of Germany and the Netherlands. While thousands of seals were reported dead in Sweden, Denmark and Germany, only a limited number of seals were found dead in the Netherlands. To determine the extent of exposure of seals in the Netherlands to influenza A/H10N7 virus, we measured specific antibody titers in serum samples from live-captured seals and seals admitted for rehabilitation in the Netherlands by use of a hemagglutination inhibition assay and an ELISA. In harbor seals in 2015, antibodies against seal influenza A(H10N7) virus were detected in 41% (32 out of 78) pups, 10% (5 out of 52) weaners, and 58% (7 out of 12) subadults or adults. In gray seals  in 2015, specific antibodies were not found in the pups (n = 26), but in 26% (5 out of 19) of the older animals. These findings indicate that, despite apparent low mortality, infection with seal influenza A(H10N7) virus was geographically widespread and also occurred in grey seals.In the spring and summer 2014, an outbreak of seal influenza A(H10N7) virus infection occurred among harbor seals ( Phoca vitulina) caused by influenza A viruses have been reported along the east coast of North America [Mirounga angustirostris) and influenza B viruses were detected in harbor and gray seals  [In the past few decades, various outbreaks of mortality among harbor seals . Phylog America ,2,3,4. F grypus) ,6,7.In spring and summer 2014, increased mortality was reported among harbor seals along the coasts of Sweden and Denmark, associated with infection by an influenza AH10N7) virus . GeneticN7 virus Of interest, while thousands of dead seals were reported along the coast of Germany, only a very limited number of harbor seals (<180) were found dead along the coast of the Netherlands. This raised the question whether the seal influenza A(H10N7) virus had indeed continued to spread among the harbor seals along the Dutch coast or that spread was limited. Main factors that could have limited the spread of the virus include differences in herd immunity and differences in timing of the virus arrival, related to the seasonal behavior of the seals off the coast of the Netherlands . In addition, genetic changes in the virus could have resulted in a lower virulence of the virus for harbor seals, resulting in less severe disease following infection. However, it might also be possible that infection and/or deaths did occur but that the south to east wind direction that occurred in November 2014 in the Netherlands  resultedIn the present study, the spread of seal influenza A(H10N7) virus among seals of the Dutch coastal waters was evaluated by assessing the seroprevalence of antibodies against the seal influenza A(H10N7) virus in serum samples collected from harbor seals and gray seals.Serum samples of seals used in the present study were obtained by the Seal Research and Rehabilitation Centre (SRRC), Pieterburen, the Netherlands and by IMARES\u2014Institute for Marine Resources & Ecosystem Studies, Wageningen University, the Netherlands, and the SRRC and IMARES provided permission to the Department of Viroscience, Erasmus Medical Centre to use the serum samples for the present study. Admission and rehabilitation of wild seals at the SRRC is permitted by the government of the Netherlands (application number FF/75/2012/015) and serum samples provided by the SRRC were collected from blood samples that were collected for routine diagnostics during rehabilitation. Serum samples provided by IMARES were collected from live-captured (and subsequently released) seals in frame of various ecological studies which was permitted by the government of the Netherlands (application number FF/75A/2013/22). Blood sampling was approved by the independent Ethical Committee for Animal Experiments of the Royal Netherlands Academy of Arts and Sciences. Capturing of live seals was performed at the following locations/areas off the coast of the Netherlands: Aardappelbult (Zeeland), Blauwe Balg (Ameland), Dollart (Eems), Hond/Paap (Eems), Pinkegat (Ameland), Renesse (Zeeland), Sparregat (Eems), Steenplaat (Texel) .Blood samples used were collected from live-stranded harbor and gray seals that were admitted to the SRRC for rehabilitation from 2010 to 2015. Blood samples were collected for diagnostic purposes and remaining serum was stored at -20\u00b0Cuntil analysis. In addition, blood samples were collected from live-captured and subsequently released harbor and gray seals in 2010, 2011, 2012, 2014 and 2015 by IMARES. The age of the rehabilitated seals was estimated based on the date of stranding and the body size. Harbor seals were divided into three age categories; harbor seal pups , harbor seal weaners  and harbor seal (sub)adults . Since the estimation of the ages of seals older than one year of age was unclear, subadult and adult seals were not differentiated; these two categories were referred together as \u201c(sub)adults\u201d in the rest of the text. Gray seals were divided into two groups; gray seal pups  and non-pup older gray seals . The ages of live-captured harbor and grey seals were estimated based on the length from nose to tail as indicated for stranded seals. Since the length from nose to tail of each live-captured seal was at least 120 cm, all animals were estimated to be (sub)adults. A summary of the serum samples tested is provided in All collected serum samples were tested using an influenza A virus nucleoprotein (NP) blocking ELISA (IDEXX Influenza A Ab Test) according to the instructions of the manufacturer. This assay detects antibodies against any of the influenza A virus subtypes. A value of sample to negative control ratio of <0.6 was considered positive. In addition, serum samples collected from all (sub)adult harbor seals and non-pup gray seals and the serum samples collected from pups and weaners in 2014 and 2015 were tested for the presence of antibodies against the hemagglutinin (HA) of seal influenza A(H10N7) virus using the hemagglutination inhibition (HI) assay following a standard protocol using 1% turkey erythrocytes and four HA-units of virus . A reverIn serum samples collected from 2010 to 2013, antibodies against the influenza A virus NP were detected in 1  out of 72 serum samples (1%). In 2014, NP-specific antibodies were detected in 2 out of 22 gray seal pups (9%) from which serum was collected in December of that year. In serum samples collected from harbor seals in 2015, NP-specific antibodies were detected in 12 out of 78 stranded pups (15%), 5 out of 52 stranded weaners (10%) and 7 out of 12 live-captured (sub)adult seals (58%). In serum samples collected from gray seals in 2015, NP-specific antibodies were only detected in 1 out of 19 (5%) non-pup live-captured gray seals adult seals were tested for antibodies against seal influenza A(H10N7) virus. From 2010 to 2013, antibodies were detected in 1 out of 29 (sub)adult harbor seals in 2011 (3%), 1 out of 9 (sub)adult harbor seals in 2013 (11%) and 1 out of 16 (6%) non-pup gray seals in 2013. In serum samples collected in 2014, antibodies were detected in 1 out of 14 (7%) non-pup live-captured gray seals in 2014. In 2015, antibodies were detected in 7 out of 12 (58%) (sub)adult live-captured harbor seals and in 5 out of 19 (26%) non-pup live-captured gray seals.Serum samples also were tested of pups and weaners that were admitted for rehabilitation to the SRRC. From 2010 to 2013, no antibodies against influenza A(H10N7) virus were detected in any harbor seal pups (n = 43), harbor seal weaners (n = 80), gray seal pups (n = 10), or non-pup gray seals (n = 16). In 2014, antibodies were detected in 1 out of 22 gray seal pups (5%), but not in any harbor seal pups (n = 19) or harbor seal weaners (n = 34). The seropositive gray seal pup had been admitted to the SRRC in December 2014. In 2015, antibodies against influenza A(H10N7) were detected in 32 out of 78 harbor seal pups (41%) and in 8 out of 52 harbor seal weaners (15%), but not in any gray seal pups (n = 26) or non-pup gray seal (n = 3) Figs .Seal influenza A(H10N7) virus-specific antibody titers detected in (sub)adult seals before the start of the outbreak in 2014 ranged between 1:40 and 1:80 (n = 3), while the geometric mean titers (GMT) of antibodies detected in (sub)adult harbor seals in 2015 against the A/harbor seal/PV14-221_TS/NL strain was 1:573 (s.d. 89) (n = 7) and GMT of antibodies detected in non-pup gray seals was 1:272 (s.d. 75) (n = 5). The single gray seal pup with antibodies against H10N7 that was admitted in 2014 had an antibody titer of 320, while the GMT in harbor seal pups was 1:68 (s.d. 34) (n = 32) and the GMT in harbor seal weaners was 1:180 (s.d. 75) (n = 8) . To studTo study the spread of the seal influenza A(H10N7) virus among harbor and gray seals of the Dutch coastal waters, the seroprevalence of antibodies against seal influenza A(H10N7) viruses in serum samples collected from various age groups of seals off the Netherlands was evaluated using a NP blocking ELISA and the HI assay. Although serum samples from a relatively low number of samples was tested compared to the population of harbor seals, the results of this study indicate that the seal influenza A(H10N7) virus had spread among the harbor seals off the coast of the Netherlands in 2014/2015. This conclusion is supported by the prevalence of 58% HI antibodies against seal influenza A(H10N7) virus in (sub)adult harbor seals captured in 2015, compared to 11% or less in preceding years . Also, HOf interest, one gray seal pup tested negative in the HI assay and positive in the NP ELISA. This might be explained by infection with an influenza A virus of another subtype. Also, 29 harbor seals, in which antibodies were detected using the influenza A/H10-specific HI assay, tested negative in the NP ELISA. This might be explained by differences between the two assays and differences in the protein of the influenza A virus to which the assay was directed. While the influenza A virus NP blocking ELISA detects antibodies against all influenza A virus subtypes, the HI assay is specific for detecting antibodies against influenza A(H10N7) virus.To our knowledge, no seal influenza A(H10N7) virus was detected in gray seals during the recent influenza A(H10N7) outbreak and no increased mortality of gray seals has been reported in northwestern Europe. The detection of antibodies against the seal influenza A(H10N7) virus in 26% of live-captured (sub)adult gray seals indicates that they are susceptible to infection with the seal influenza A(H10N7) virus, but that infection may not result in morbidity or mortality. Antibodies against influenza A viruses in gray seals have been reported previously . The difIn conclusion, in the present study we provide serological evidence that the seal influenza A(H10N7) virus spread among harbor seals off the Dutch coast in 2015, as well as among gray seals. In addition, because the majority of harbor seal pups (59%) and weaners (85%) in 2015 had no detectable antibodies to seal influenza A(H10N7) virus, continued circulation of this virus after the recent outbreak seems unlikely. Continued monitoring and additional studies are necessary to elucidate the spread of the influenza A(H10N7) virus among the various populations of seals of Northwestern Europe.S1 FigCapturing of live seals was performed at the following locations/areas off the coast of the Netherlands: A: Aardappelbult (Zeeland), B: Blauwe Balg (Ameland), D: Dollart (Eems), HP: Hond/Paap (Eems), P: Pinkegat (Ameland), R: Renesse (Zeeland), Sp: Sparregat (Eems), St: Steenplaat (Texel).(TIF)Click here for additional data file."}
+{"text": "Information about lung cancer patients surviving critical illnesses is very scarce. Our aim was to evaluate the outcomes and continuing of anticancer treatments in lung cancer patients surviving ICU admission.Secondary analysis of a prospective multicenter study including patients admitted for >24 hours to 22 ICUs in six countries from Europe and South America during 2011. Readmissions and patients in cancer remission >5 years were excluded. Logistic regression was used to identify predictors for hospital mortality.P = 0.065). Poor PS was the only factor associated with a lower probability of receiving the initial treatment plan . At 6 months, 71% patients were at home, 15% were hospitalized, and 7% were in hospice care; the location was unknown for 6% patients. PS at 6 months was 3 to 4 in 19 (9.5%) survivors.A total of 449 patients  = 55; non-SCLC = 394)) were admitted to ICUs, and out of them 275  were discharged alive from the hospital. Among them, 200 (73%) patients were alive and 72 (26%) had died at 6 months; three (1%) patients were lost to follow-up. Mortality rates were far lower in the patient subset with nonrecurrent/progressive cancer and a good performance status (PS), even those with sepsis, multiple organ dysfunctions, and need for ventilatory support. Cancer recurrence or progression occurred in 53 (26%) hospital survivors. Anticancer treatments were recommended for 108 (39%) hospital survivors and administered to 102. Treatments used were variable combinations of surgical resection (7%), radiation therapy (34%), and chemotherapy (80%). The initial treatment plan required reduction or modification in 35 (34%) patients. Post-hospital mortality was nonsignificantly lower in the patients given the initial treatment plan than in the other patients (17% vs. 32%, Post-hospital mortality in critically ill lung cancer patients is relatively high and many patients require anticancer treatments after discharge. PS before ICU admission is a major determinant of both mortality and ability to receive optimal anticancer treatment in these patients."}
+{"text": "A patient is declared brain dead (BD) when physicians determine permanent loss of brain functions. Unfortunately, criteria for defining BD vary across different countries . We therA multiple-choice questionnaire was developed on an online platform . Direct 2 level while the Netherlands' law states target apnea duration. Number of physicians , number of clinical examinations , and minimum observation time  are variable requisites in different countries. In 50% of nations, additional tests are required. Hypothermia (4%), anoxic injury (7%), inability to complete clinical examination (61%), toxic drug levels (57%), and inconclusive apnea test (54%) are legal indications to perform additional tests. Cerebral blood flow investigation is mandatory in 18% of countries, while it is either optional or used only in selected cases in 82%. Conventional angiography is still the preferred method (50%), followed by transcranial Doppler (43%), angioCT (39%), CT perfusion and angioMR (11%). EEG is always (21%) or optionally (14%) recorded. Russia and Croatia evaluate both EEG and cerebral blood flow (7%).Twenty-eight participants returned the questionnaire (85%). Every country has either specific law (93%) or guidelines issued by the scientific society (89%). Clinical examination, essential to the diagnosis, is the only requirement in 50% of countries. Coma, apnea, absence of corneal and cough reflexes are always necessary. Blood pressure and electrolytes are checked in 64% as mandatory prerequisites. The apnea test is legally defined in 86% of countries. Eighty-two percent of countries require achievement of a target paCOThere are still areas of uncertainty and disparities in brain death diagnosis in European countries. This predisposes to misdiagnosis and confusion both for clinicians and families. Measures to promote uniformity of brain death procedures and clinical practice are therefore desirable."}
+{"text": "The UK has one of the highest deliberate self-poisoning overdoses within Europe . The majAny ICU diagnosis that equals drug overdose/misuseAny ICU diagnosis that equals drug toxicityAny ICU diagnosis that equals self poisoningThis was a retrospective cohort study using data from the Scottish Intensive Care Society database and radiology archive software. Six thousand three hundred and thirty-three patients were available and 332 patients matched the parameters we set. These parameters were:The one hundred most recent patients within this group were then selected.We collected demographic data, details of overdose and CT scan reports for these 100 patients using the hospital clinical information systems.All patients admitted to the Victoria Infirmary ICU with drug overdoses between 13 January 2009 and 4 July 2014 were reviewed. One hundred patients were identified. The mean age was 38 years. Fifty-six patients were male and 44 were female.The median (IQR) length of stay within ICU was 2 (1-3) [range (1-20)] days. Median (IQR) APACHE II score (n=82) was 17 (17-21) [range (4-40)]. Five patients (5%) died while in ICU.Antidepressants were the most commonly abused drug with 32(18%) cases reported. The next major group was alcohol with 29(17%) cases and then benzodiazepine with 22 (13%) cases. The majority of overdoses were mixed substances. 43% of patients had CT scans taken, only 9 (20% of the 43 scanned) of these patients showed signs of head trauma and none of these cases had pathology on their CT scan. 31/34(91%) of the non-trauma cases had negative findings. The remaining 3/34 (9%) had positive CT findings and all of these significantly changed their management. Two of these patients died. Pre intubation GCS was recorded in 63% of patients. The remaining 37% had no GCS information available. The median and mode GCS were both 3.Our initial hypothesis was that CT brain scanning was superfluous in the context of drug overdose and represented a defensive medical practice. The results of this audit have highlighted that very occasionally CT scanning results in discovering pathology that significantly affects subsequent management and disposal. We feel that we should continue with our current practice and that no reduction in CT scanning is indicated.No external funding and no competing interests declared."}
+{"text": "Patients with invasive breast cancer undergo axillary ultrasound \u00b1 ultrasound fine needle aspiration (US-FNA)/core biopsy for preoperative staging depending on the ultrasound appearance. At our institution, abnormal axillary lymph node assessment includes: a cortical thickness >3 mm, focal or eccentric cortical thickening, nodal shape  and replaced appearance with loss of echogenic nodal hilum. Our aims were to evaluate the accuracy of preoperative US + US-FNA/core biopsy for detecting axillary metastatic disease.Excluding those patients who underwent neoadjuvant chemotherapy, we identified 120 patients with invasive breast cancer between January and December 2013, which yielded axillary node metastases on final surgical pathology. We performed a retrospective analysis of the clinical records and used descriptive statistics.Preoperative US correctly identified 60/120 (50%) patients with axillary metastatic disease, 42/60 (70%) had subsequent true positive US biopsies. Of the cases where a biopsy was not performed, 88% (53/60) had one or two positive nodes confirmed after surgery and 12% (7/60) had at least three nodes. Thirty-four of 60 (57%) were from the symptomatic population. Of the total 21 false negative US biopsies from the 18 patients, 81% (17/21) were performed via FNA and 19% (4/21) via core biopsy. Eleven of 18 (61%) were from the symptomatic population. Twenty-nine of 42 (69%) true positive US biopsies were from the symptomatic population.The results highlight the need for a review of our biopsy criteria, which may result in a decrease in our biopsy threshold. An increase in the use of core biopsies may yield greater accuracy in correctly identifying axillary nodal disease."}
+{"text": "Morbidity and mortality rates from AIDs defining cancers have fallen significantly since the introduction of highly active antiretroviral therapy (HAART). Patients are now living longer with HIV and are at a greater risk of other HIV- and non-HIV related malignancies. We report what we believe to be the first UK cancer prevalence study in the modern HAART era.A retrospective review of electronic clinic letters was performed for all patients currently receiving, and those who had died whilst receiving, their HIV care at our centre. Demographics of patients with pre-cancerous changes, an active or previous cancer were recorded.There were 438 active patients  and 18 deceased patients  in April 2014. Thirty-six out of four hundred fifty-six (8%) cancer diagnoses were found overall. Thirty-one out of four hundred thirty-eight (7%) diagnoses in active patients and 5/18 (28%) in deceased patients. More than half of those diagnosed with cancer were aged 50 or over (17/31 [55%]). In active patients 17/31 (55%) were AIDs defining cancers, with the most common type of cancer diagnosis overall being Kaposi's sarcoma (12/31 [39%]). There were 5/31 (16%) cases of non-Hodgkin's lymphoma. The most common non-AIDs defining cancer was basal cell carcinoma of which there were 5/31 (16%) cases, followed by squamous cell carcinoma (3/31 [10%]) and testicular cancer (3/31 [10%]). Other cancers included colorectal (2/31 [6%]) and prostate cancer (1/31 [3%]). In all five deceased patients, cancer was the cause of death. There were four acute presentations with an aggressive glioma, Burkitt's lymphoma, an undiagnosed primary lung malignancy and a late diagnosed cervical cancer. The fifth patient died following the recurrence of a transitional cell cancer of the bladder after an initial diagnosis of seven years earlier. Eighteen out of sixty-nine (26%) of females were found to have at least mild dyskariosis on cervical screening. Anal intraepithelial neoplasia was diagnosed in 4/438 (1%) of patients.Non-AIDS defining malignancies account for almost half of the cancers in our cohort. This number may rise further as patients live longer with HIV. Good communication between oncologists and HIV physicians is paramount to manage the complex interactions of HIV and cancer, increase HIV testing in cancer services and address cancer risk factors in existing HIV patients."}
+{"text": "Previous studies assessing qualitative patterns of stiffness in breast lesions have not matched benign and malignant lesions for quantitative stiffness. The purpose of this study is to compare the qualitative patterns of stiffness of benign and malignant lesions matched for quantitative stiffness.A total of 158 consecutive histologically confirmed benign lesions with a mean stiffness >30 kPa were identified from a prospective database. Forty-nine cancers with the same distribution of stiffness as the benign lesions were identified for comparison. The following features were assessed by two observers; BIRADS score, whether there was stiffness in the lesion, outside the lesion, Tozaki classification, homogeneity of stiffness, the presence of a ring sign, stiffness adjacent to the skin or muscle, and the assessed likelihood of the stiffness being artefactual. Statistical analysis was carried out using the chi-square test.P < 0.0001), Tozaki classification 3 and 4 (43 (88%) vs. 85 (54%), P < 0.001), and presence of a ring sign (40 (82%) vs. 78 (49%), P < 0.001). The following features were more common in benign lesions; stiffness in the lesion (103 (65%) vs. 17 (35%), P = 0.0002), stiffness adjacent to skin (99 (63%) vs. 19 (39%), P = 0.003) and stiffness thought to be probably artefact (74 (47%) vs. 5 (10%), P < 0.0001).Benign and malignant lesions both had a mean stiffness of 73 kPa. The following features show a significant association with malignancy; BIRADS classification 4 or 5 (45 (91%) vs. 99 (63%), Qualitative features show significant differences in frequency when comparing benign and malignant masses. Qualitative features could be used to help classify breast lesions during SWE."}
+{"text": "Cerebral vasospasm (CV) occurs in 18-70% of patients with severe traumatic brain injury (sTBI) and is one of the main reasons for the development of secondary ischemic brain damage and a risk factor for adverse neurodevelopmental outcome.Determine the frequency and timing of cerebral vasospasm (CV) development in patients with severe traumatic brain injury (sTBI) and assess its impact on patient outcomes.The study included 43 patients with isolated and combined sTBI and Glasgow Coma Scale on admission 8 or less . Severe brain contusion was diagnosed in all patients. Emergency surgery was required in 20 patients. All patients received decompressive craniotomy with intracranial hematoma or contusion foci removal. Transcranial duplex investigation was performed every day from 2 till 11 day after admission. We measure blood flow velocity, Lindegaard index, pulsatility index, overshoot ratio. Cerebral vasospasm was diagnosed in case of systolic blood flow velocity (Vs) in the middle cerebral artery 120 cm/sec or more with Lindegaard index 3 or more.CV was detected in 33 (77%) patients. in 16 patients (48%) we diagnosed moderate (Vs 120-200 cm / sec) and in 17 (52%) - severe (Vs > 200 cm / sec) vasospasm. Moderate CV developed at the 4-5 day after injury and was unilateral in 4(25%) and bilateral in 12 (75%) patients. Severe CV developed within the first 3 days after injury and was unilateral in 2(12%) and bilateral in 15 (88%) patients. the duration of the CA exceeded 11 days in all patients. Cerebral vasospasm development was associated with increase in bad outcomes, evaluated by Glasgow Outcome Score . GOS 1-3 was noted in 30% (n = 3) patients without signs of CV, in 31% (n = 5) patients with moderate CV and in 82% (n = 14) patients with severe CV."}
+{"text": "Skin prick testing (SPT) is the standard method for diagnosing allergic sensitization. Correct diagnosis of inhalant allergies, requires knowledge of the most important inhalant allergen sensitizations. Few data are available regarding the prevalence of these sensitizations in Greece.The prospective assessment of the inhalant allergen sensitization rates in a Greek pediatric population.196 patients 3-18 years old (median age 10.3) who referred to our outpatient department with suspected reactions to inhalant allergens were included in the study . Data were collected on the first 20 SPT performed every month for a total period of 12 months (April 2012 to March 2013) and are herein reported for children (<18), only. Evaluation for every skin prick test occurred after 15-20 min exposure, with positive results defined as a wheal \u22653 mm maximum diameter.The seven allergens with the most common sensitization rate were revealed to be olea (52.3%), followed by Grass-mix (42.6%), cat (31.3%), mites , parietaria (24.6%), alternaria (19.5%). These were comparable with a previous evaluation of our population. Sensitization to ragweed and birch (14.9% each) allergens was also present, although these allergens do not exist in southern Greece.13.3% of the subjects were not sensitized to any allergen tested. Single sensitization was revealed in 18.3%, the most prevalent being mites (6.1%), olive (4.6%) and grasses (4.1%). 48% were sensitized to four or more allergens.The application of the Pan-European panel may provide awareness for some inhalant allergen sensitizations that had not been examined in this population before. It also suggests that some sensitizations assessed through SPTs with natural extracts, may be due to cross-reactivity, highlighting the need for component resolved diagnosis."}
+{"text": "Endometrial hyperplasia (EH) is a basis for malignant transformation, atypical hyperplasia (AEH) has the highest cancer threat. Existing methods as cryosurgery, laser-, and electrodestruction, thermoablation may lead to irrevocable destruction of the endometrium. After hormonal treatment EH relapses occur in 15, 9-27, 2%, due to the morphological heterogeneity of endometrial proliferation. The sensitivity to therapy and prognosis is largely determined by receptor status.was to develop treatment algorithm for atypical endometrial hyperplasia in reproductive age women with regard to age, comorbidities and endometrial receptor status.We included 62 women aged 20 to 52 years , treated in Clinical Hospital \"Pheophania\" with a diagnosis of AEH combined with dysfunctional uterine bleeding 52 (82.3%), inflammatory diseases of genitals - 48 (77.4%), endocrine diseases  - 22 (35.5%), which with sensitivity of maintaining reproductive to hormone therapy functions to were considered for personalized treatment. We performed hysteroresectoscopy using \u00abKarl Storz\u00bb equipment, hormone therapy . All patients underwent clinical examination, transvaginal ultrasound scanning including sonoelastography and 3D/4D technology at 1, 3, 6 and 12 months after hysteroresectoscopy; histological study to determine the endometrium receptor applying immunohistochemical method. After 6 months, we performed control hysteroscopy with endometrial biopsy to assess therapy effectiveness. 22 women, who underwent hysteroscopy for infertility before the cycles of in vitro fertilization (IVF) were the control group.Estradiol receptors were found in 65.2% of epithelial cells and in 42.6% of stromal (43.3% and 29.6% respectively in controls); progesterone receptors - in 44.3% of epithelial cells (52.4% in controls). For patients with low expression of progesterone receptor we performed personalized therapy considering age, comorbidities. In increased progestin receptors, we administered GnRH agonists (Diferelin) for 6 months, followed by recovery of menstrual function and purpose of progestins (observations 3 - 4.8%). Treatment was effective in 28 reproductive age women (45.1%); we observed normalisation of menstrual function and ultrasound characteristics of endometrium. In 16 women (25.8%), older than 35 years ablative hysteroresectoscopy was performed to eliminate atypical and basal layers in single block. In 3 women (4.8%) we observed EH relapse (polyposis) during progestins therapy, which required rehysteroresectoscopy, followed by appointment of GnRH agonists (Diferelin) for 6 months and progestins (endometrin). In our opinion, the cause of EH relapse was insufficient electrodestruction due to the specific uterus anatomy. In 14 patients (22.5%) with AEH and comorbidities  hystero/oophorectomies were performed.1. The study of hormone receptor status in patients with EH allows you to clearly define the treatment policy, avoid relapse, optimizing treatment and observation of such patients.2. Personalized pharmacotherapy combined with conserving interventions enabled to treat patients with AEH and significantly reduce surgery and time of treatment.3. Performing hysteroresectoscopy and subsequent hormone therapy is an effective treatment of recurrent AEH.It is recommended to promote programs for introduction of personalized outpatient gynecological care of new level of efficiency and patient safety."}
+{"text": "The frequency of Food Allergy (FA) has been increasing in recent years. The prevalence of cell-mediated FA among this cases is unknown. The major cause for the difficulty of this diagnosis of cell-mediated FA is the absense of a major biomarquer. In this study we select patients with cell-mediated FA based in their Clinical Picture, normal IgE and clinical cure with the treatment with the withdrow of the offending food from the diet.71 patients were selected for the study, with cell-mediated FA. In this group of patients we caracterise their clinical picture.The clinical diagnosis among all the 71 patients studied was: in 62% (44 patients) the clinical diagnosis was Cow\u2019s Milk Enteropathy (CME); in 15.5% (11 patients) the clinical diagnosis was Breast Milk Colitis (BMC); in 8.45% (6 patients) the clinical diagnosis was Abdominal Pain and Abdominal Distention with Motor Impairment (APAD); in only 5.6% (about 4 patients) the clinical diagnosis was Cow\u2019s Milk Enterocolitis( FPIES); in others 5.6% (4 patients) the clical diagnosis was Constipation (C) and finaly in 2.8% (in 2 patients) the clinical diagnosis was Celiac Disease.The highest prevalence among all cases of FA cell ltype mediated was CME, the second clinical picture in frequency was BMC. Less frequent causes of cell mediated FA in Rio de Janeiro was APAD, FPIES, C and CD."}
+{"text": "Pediatric mastocytosis has generally a benign prognosis. However some patients suffer from severe mast cell (MC) mediator-associated symptoms including anaphylaxis.The aim of this study was to identify predictors for MC mediator release symptoms in children with mastocytosis.A total of 25 children  diagnosed with mastocytosis have been studied. Patients were classified according to the type of skin lesions following the WHO classification. Mastocytosis-related symptoms and data on specific triggering factors were systematically recorded for 3 years after diagnosis. Severity was graded according to standard recommendations. Serum baseline total tryptase (sbT) levels  were measured at the time of referral. The extent of cutaneous disease was determined using the technique used to assess burns and is given as percentage of total body surface area (BSA).\u2013378 vs 2\u20139.1ng/dl) and especially among patients with grade 4 symptoms (p<0.07). BSA was significantly higher (p<0.019) in patients with grade 4 symptoms. In line with these findings, the correlation of BSA to sbT levels was significant (p<0.046).The different subtypes of mastocytosis observed included MPCM in 17/25(68%), MC in 4/25(16%), DCM in 1/25(4%), and ISM in 3/25(12%) cases. Skin rubbing and hot bath were the most common triggers for MC-related symptoms. Other clinically relevant triggers were irritability and fever, whereas drugs, food, perioperative and vaccination were rarely involved. The most frequent symptoms were flushing (68%), diarrhea (24%), and anaphylactic reactions (36%). Four children  had grade 4 symptoms. The median sbT for the whole group was 6 ng/dl . A significantly higher (p<0.029) median sbT was found in cases with systemic symptoms vs those without (mean rank 14.97 vs 7.93ng/dl; range, 4Extensive cutaneous disease and higher sbT levels at disease onset can identify children at risk for severe MC mediator release symptoms. Consequently, early antimediator therapy should probably be given to these children."}
+{"text": "The diagnostic performance of cardiovascular magnetic resonance (CMR) utilizing adenosine for detection of myocardial ischemia is well established. However, adenosine requires continuous infusion, which is challenging in the CMR environment, and has frequent side effects. The diagnostic accuracy of stress CMR using regadenoson, a newer vasodilator agent that is administered as a single bolus injection and has fewer side effects, has not been well studied. The aims of this study were: (1) to determine the diagnostic accuracy of regadenoson stress CMR when compared to coronary angiography in patients with suspected coronary artery disease (CAD), and (2) to study outcomes in patients with negative stress CMR perfusion studies to confirm that there are not a significant number of \"abnormal studies\" that are undetected.We studied 126 patients with suspected CAD referred for regadenoson stress CMR . Stress perfusion images were obtained during the first pass of Gadolinium contrast agent one minute after regadenoson (0.4mg IV bolus) injection, and followed by reversal with aminophylline (75-125 mg). Cine imaging was followed by rest perfusion and late gadolinium enhancement imaging 10-15 minutes later. Patients were divided into 2 groups according to probability of CAD. Group 1 included 38 patients, who underwent coronary angiography within 6 months of CMR (Table), and was used to achieve goal 1. Significant CAD was defined by >70% coronary stenosis. Group 2 included 88 patients with normal regadenoson CMR  who were followed-up for 12 months for cardiac death, myocardial infarction (MI), and revascularization. This group was used to achieve goal 2.In group 1, 29/38 (76%) patients had significant CAD, and 35/38 (92%) had visible stress-induced perfusion abnormalities on CMR. The diagnostic accuracy of regadenoson CMR was 89%, sensitivity 93%, specificity 89%, positive predictive value (PPV) 96%, and negative predictive value (NPV) 72%. In group 2, none of the 88 patients had events within the follow-up period.This study provides one of the first assessments of diagnostic performance of regadenoson stress CMR in clinical practice, which was similar to published data for adenosine stress CMR. Importantly, the one-year event rate in patients with normal stress exams was <1/88, i.e. <1.14%. With its known advantages over adenosine, regadenoson is an effective alternative for cardiac MRI vasodilator stress testing in both patients with high and low probability of CAD.N/A."}
+{"text": "Statistical significance between serum 25(OH)D levels and headache in the pediatric population is still controversial. However, a supplementary vitamin D therapy in children with headache allowed us to note an improvement in the clinical symptoms in terms of frequency and severity.To study vitamin D blood levels in primary headaches and to show the relationship with clinical parameters influencing clinical course of the headache.Sixty-seven males (42%) and 92 females (58%), aged between 5 to 18 years, suffering from headache, were divided into three diagnostic categories, according to the ICHD-III classification: migraine with aura (MWA), migraine without aura (MWoA) and tension-type headache (TTH). Serum vitamin D level lower than 20 ng/ml was considered pathological. Immunohistochemical methods of chemiluminescence were used to determine blood 25(OH)D level.Ninety-one patients (57%) received a diagnosis of MWoA, 32 (20%) of MWA and 36 (23%) of TTH. Hypovitaminosis D was found in 56% of the children with MWoA, in 50% of patients with MWA and in 44.4% with TTH. Twelve percent of all the sample showed severe Hypovitaminosis D (<10 ng/ml). There were neither statistically significant differences comparing vitamin D serum levels between males and females in each category of headache (p = 0.36), nor more severe deficiency of vitamin D in overweight children with BMI>90\u00b0C (p = 0.47), and serum concentration was not lower in adolescents and pre-adolescent than children under 10 years. A difference resulted in the limits of statistical significance (p = 0.07) in 25(OH)D serum level in children with MWoA compared to patients with MWA and THH.Our study shows a high incidence of vitamin D deficiency in the pediatric population with headache (56%), particularly in migraineurs without aura. ProbablWritten informed consent to publication was obtained from the patient(s)."}
+{"text": "The operative mortality for total anomalous pulmonary venous connection repair is considered high when coexists with other congenital cardiac lesions. The isolated form however warrants excellent surgical outcomes.We analysed our series to test the validity of the above statement.From July 2007-April 2015, 18 consecutive patients,10 males and 8 females (55/45%), median age 33 months with isolated total anomalous pulmonary venous connection were operated in our department. Of these 8 (44.4%) were of the supracardiac type, 4 (22.2%) cardiac, 5 (27.8%) of the infracardiac type and one mixed case (5.6%). Perinatal respiratory distress was the prominent clinical symptom (61%). Mean cardiopulmonary by-pass time/cross-clamp time was 128/69 minutes. In all cases except the cardiac type repair was performed with direct anastomosis of the connecting vein to the left atrium and atrial septal defects were closed with autologous pericardium.There was one early mortality (5.5%) related to marked pulmonary hypertension and one case of postoperative chylothorax managed conservatively. Median intensive care unit stay was 7 and length of hospital stay 15 days respectively. Mean follow-up was 22 months (range 1-70) with trivial tricuspid regurgitation in 5 patients (33.3%) and moderate in one patient (6.6%). During this period no pulmonary venous stenosis was observed. No reoperation was necessary and no late deaths.Isolated total anomalous pulmonary venous connection is usually diagnosed after birth unlike complex forms where their pathology is conspicuous. The isolated form can be safely operated early with excellent surgical outcomes."}
+{"text": "The clinical course of HIV/AIDS and pattern of opportunistic infections vary from patient to patient and from country to country. in this report we describe the clinical and laboratory profiles of different opportunistic infections (OIs) among 266 immunocompromised patients admitted to a referral hospital in the eastern of Algeria.Between January 2003 and November 2013, 266 HIV infected patients were admitted to our center. Clinical data about patients were collected retrospectively from standardized HIV/AIDS forms filled at admission.Out of 266 patients, 65% were male, the mean age was 37 years and the most frequent route of transmission was heterosexual (86%). 60 % were admitted with obvious clinical signs and symptoms, whereas 40% were asymptomatic, and they were diagnosed through screens or check-up tests. The most frequent clinical symptoms on first admission were oral candidiasis (66.4%), herpes zoster virus infection (18.6%), tuberculosis (16.7%), Pneumocystis jirovecii pneumoniae (12 %), weight loss (10 %), persistent generalized lymphadenopathy (3.5 %), , malignancies (3.2 %), chronic fever (2.5%). We found the low prevalence of AIDS-defining illnesses in central neural system in this study, including progressive multifocal leukoencephalopathy (1.8%), cerebral toxoplasmosis (3 %), cryptococcal meningitis (2.3%).Median viral load was 120000cp/mL. Screening tests were conducted most frequently during blood donations (20%), before surgeries (13 %) and check-ups (6 %).Algeria is among low prevalence countries in the world for HIV/AIDS. Clinical profile of our patients is similar to the developed countries. More than half of the patients diagnosed at late stages of the disease. It highlights the need for early screening and also the need to increase awareness in healthcare providers, in order to improve decisions regarding prophylaxis for prevention and appropriate therapeutic intervention."}
+{"text": "Onychopathies in patients infected with HIV are dominated by onychomycosis. It is one of the early manifestations of HIV infection .the purpose was to study the epidemiology, clinical manifestations and mycological profile of onychomycosis in HIV-infected individuals and to identify the other causes of onychopathies in this population.A total of 88 HIV infected patients, monitoring at Department of Infectious Diseases, were screened for nail involvement over a period of 3 months. Inclusion criteria: Patient who had do not receive any antifungal treatment were included.A total of 88 subjects were examined (45men and 43 women); the average age were 41 years old. Abnormal appearing nails were present in 48 cases. Mycologic evidence of onychomycosis were present in 42 cases. The clinical presentation of onychomycosis was: distal and lateral subungual onychomycosis (47%); white superficial onychomycosis (5%); proximal subungual onychomycosis (21%); total dystrophic onychomycosis (26%). Toenail involvement was seen in 26 patients, fingernail in 11 patients while 5 patients had involvement of both fingernail and toenail. The various aspects noted were: Xanthonychia (19 cases), pachonychia (17 cases), onycholysis (7 cases), leuconychia (6 cases) and melanonychia (4 cases). The culture has allowed the confirmation of onychomycosis in 73.3%. Among the 16 positive dermatophytes cultures, Trichophyton rubrum was isolated in 12 cultures, Trichophyton interdigitale in 3 cultures, and Trichophyton Mentagrophyte in one case. Of the 12 non-dermatophytic cultures, Candida albicans and Candida dubliensis were isolated in 4, Candida parapilosis in 2 while Trichosporon spp., and Penicillium spp. in each one.The prevalence of onychomycosis was 48%. It seems that the incidence of NMD is higher in the HIV patients compared with immunocompetent population."}
+{"text": "Familial Mediterranean Fever (FMF) is an ethnic disease for Armenians. Recurrent attacks of fever with tonsillitis are also clinical symptom of FMF, especially in early childhood. They are also characteristic of the PFAPA syndrome , which can be confused with FMF.To investigate the peculiarities of the coexistence of PFAPA syndrome and FMF in Armenian children.28 children with recurrent episodes of fever and tonsillitis was observed at the National Pediatric Centre for FMF . The diagnosis of FMF was confirmed by Tel-Hashomer criteria and molecular genetic detection of MEFV mutations. PFAPA syndrome was diagnosed based on recognized clinical criteria and excluding other causes of tonsillitis.Coexistence of FMF and PFAPA was in 10 out of 28 patients (36%). They had earlier FMF onset (mean age of 1y. 3 mo.), frequent febrile attacks of abdominal pain and/or pleuritis, pericarditis (7 out of 10 patients), aphthous stomatitis (6 patients), tonsillitis with cervical lymphadenitis (9 children), as well as marked increase of acute inflammatory markers. An average age of PFAPA manifestation was 2 years 2 mo. MEFV gene M694V mutation was found in 8 patients out of 10 with the following distribution of genotypes:: one homozygous genotype (V726A/V726A), 5 compound heterozygotes: (M694V/V726A (2), M694V/F479L (2), M694V/E148Q (1), 4 heterozygotes (M694V/N (3 children), V726A/N (1).Isolated PFAPA syndrome was diagnosed in 18 out of 29 children (mean age of onset - 2 years 4 mo.). They had repeated attacks of fever and tonsillitis, rare - pleuritis or pericarditis (4 children), occasionally - mild abdominal pain and a moderately increased acute phase reactants. 13 out of 18 patients were carriers of one mutation, mostly M694V/N (9 out of 13). The frequency of PFAPA attacks in both groups of patients was similar (1-2 times a month).The coexistence of PFAPA syndrome and FMF was noticed in 36% of investigated children. They were characterized by earlier FMF onset, severe course of disease with frequent febrile attacks and the prevalence of MEFV compound-heterozygous genotype. In contrast, among patients with isolated PFAPA syndrome prevailed heterozygous genotype. M694V mutation was the most frequent.MEFV mutation genetic screening is recommended for Armenian children, especially under the age of 5, with recurrent fever and tonsillitis for early diagnosis of FMF, differential diagnosis with PFAPA syndrome, treatment and prevention of complications."}
+{"text": "Background: Chronic Myeloid Leukemia\u2019s (CML) treatment was optimized since the development of tyrosine kinase inhibitors (TKI) and an increased overall survival during TKI was noticed. During the TKI era, protocols for assessing response and resistance to treatment were developed. Additional chromosomal abnormalities (ACAs) are strongly associated with disease progression but their prognostic impact and influence on treatment response are yet to be defined. The aim of this study was to analyze the impact of ACAs on time to achieve complete cytogenetic response (CCyR), treatment and overall survival.Materials and methods: Since 2005 until 2013, the data from the Hematology and Bone Marrow Transplantation Department of Fundeni Clinical Institute was collected. In this observational retrospective single centre study, 28 CML patients with ACAs at diagnosis and during TKI treatment were included.Results: From ACAs at diagnosis group, the most frequent major route ACAs were trisomy 8, trisomy 19 and second Philadelphia (Ph) chromosome and the most frequent minor route ACAs were monosomies and structural abnormalities (inversions and translocations). From the ACAs during the TKI group, the most frequent major route cytogenetic abnormalities in Ph positive and negative cells were trisomy 8, trisomy 19 and second Ph chromosome and the most frequent minor route cytogenetic abnormalities in Ph positive and negative cells were marker chromosomes and structural abnormalities .Conclusions: In both groups, the time to CCyR was longer and long-term results were inferior in comparison with standard patients but the differences were not significant and in accordance to published data. The 12 months follow-up after the study\u2019s end showed that 26 patients were alive and in long-term CCyR and 2 deaths were reported.Abbreviations: CML = Chronic Myeloid Leukemia, BCR-ABL1 = Break Cluster Region - Abelson gene, TKI = tyrosine kinase inhibitor treatment, ACAs = additional cytogenetic abnormalities, CCyR = complete cytogenetic response, PCyR = partial cytogenetic response, mCyR = minor cytogenetic response, MMR = major molecular response, HSCT = hematopoietic stem cell transplant, HLA = human leukocyte antigens, CP = chronic phase, AP = accelerated phase, BP = blast phase, OS = overall survival, CBA = chromosome banding analysis, +8 = trisomy 8, i(17q) = isochromosome (17q), +Ph = second Philadelphia chromosome, -7 = monosomy 7, -17 = monosomy 17, +17 = trisomy 17, -21 = monosomy 21, +21 = trisomy 21, -Y = loss of Y chromosome, ELN = European LeukemiaNet, IMA600 = Imatinib 600 mg daily, IMA400 = Imatinib 400 mg daily, NILO600 = Nilotinib 600 mg daily, DASA100 = Dasatinib 100mg daily, DASA140 = Dasatinib 140 mg daily BCR-ABL1 oncogene, which leads to uncontrolled proliferation of myeloid elements in all stages of differentiation . The fusion gene is the result of reciprocal translocation  known as Philadelphia (Ph) chromosome, discovered by Nowell and Hungerford in 1960 [3-5]. CML is a multiphase disease, which may be diagnosed in three distinct phases: chronic phase (CP), accelerated phase (AP) and blast phase known as blast crisis (BP). Most patients are diagnosed in CP [6]. Chronic myeloid leukemia (CML) is a stem cell clonal disease characterized by the acquisition of a fusion protein, BCR-ABL1 tyrosine kinase inhibitor (TKI), optimized disease treatment and increased overall survival (OS) from fatal within 3-5 years since diagnosis to a life expectancy of 20 years. During theTKI era, protocols for assessing response and resistance to treatment were developed. Once TKI were established as standard treatment for CML, eight years phase III IRIS trial demonstrated that Imatinib induced a complete cytogenetic response (CCyR) in 87% of the patients with an estimated long-term overall survival (OS) of 85% [7]. The latest results reported that 17% of the patients did not achieve a cytogenetic response (primary resistance) while 15% of the patients lost the obtained response (secondary resistance). Overall, Imatinib did not obtain optimal results in 40% of the patients [7]. During the Imatinib treatment, the monitoring of clonal evolution proved to be very important. The long term monitoring results indicated that most events such as resistance and/ or progression occurred in the first three years, highlighting the importance of regular monitoring in this phase of treatment [7]. One important conclusion of IRIS trial was that the achievement of CCyR within the first 12 months of treatment is associated with long-term optimal response [7]. Currently, the only feature correlated with the treatment failure is the presence of additional chromosomal abnormalities (ACAs) which were observed in 5 to 10% CML patients diagnosed in CP. CML is the first neoplasm in which the knowledge of molecular lesion has enabled the discovery of targeted therapies. Imatinib mesylate, the first generation of The study was conducted in accordance with the applicable regulatory requirements. The protocol was approved by the institutional review board and ethics committee of the participating centre. All the patients gave a written informed consent before participation.The observational retrospective study collected data from the Hematology and Bone Marrow Transplantation Department of Fundeni Clinical Institute, Bucharest. During 2005 until 2013, 199 CML patients were diagnosed and monitored. In this single centre study, 28 (14.07%) CML patients with ACAs at diagnosis (group A) and during TKI (group B) were included. The aim of this study was to analyze the impact of ACAs on time to achieve CCyR, treatment and overall survival.CML was confirmed by fluorescence in situ hybridization (FISH) study for BCR-ABL1 of blood interphase cell nuclei followed by chromosome banding analysis (CBA).Fluorescence in situ hybridization (FISH) study for BCR (22q11.23)/ ABL (9q34) used Dual Color ON BCR/ ABL translocation probe, BCR was marked with green (G) and ABL with red (R). Expected signals patterns: negative 2R 2G  and positive (standard): 1R 1G 2F (presence of BCR/ ABL translocation). The exam analyzed blood interphase nuclei and not metaphases.14]. At least 20 metaphases were analyzed. The karyotype was described according to International System for Human Cytogenetic Nomenclature (ISCN) 2009 [15]. Fresh bone marrow samples were obtained. Samples were prepared by using overnight and cell cycle synchronization cultures and were analyzed by using GTG chromosome banding analysis (CBA) [21].According to the European LeukemiaNet (ELN) recommendations, the cytogenetic response (CyR) was evaluated at month 3 and 6 of the TKI treatment, every 6 months until CCyR, every 12 months since CCyR and at any time on a clinical suspicion of progression .The 2013 ELN recommendations suggest that the presence of ACAs at diagnosis is a warning signal. ACAs during the TKI treatment define TKI failure and are associated with shorter overall survival (OS) on second-line Imatinib [after Interferon alpha (rIFN\u03b1) first line treatment] but not second-line Dasatinib or Nilotinib. ACAs have been reported to have an adverse prognostic value, particularly in the case of major route abnormalities including trisomy 8, trisomy Ph (+der(22)t), isochromosome 17 (i(17)(q10)), trisomy 19 and ider(22)(q10)t. High-risk and major route ACAs can help identify patients eligible for investigational approaches but in daily practice, they do not mandate different initial treatments. Major route ACAs developing during treatment were confirmed to be a signal of acceleration. Cytogenetic abnormalities in Ph negative cells occur in 5% to 10% of the patients and, in the absence of dysplasia, do not seem to adversely affect the outcome. The exception is abnormalities of chromosome 7 (monosomy 7 and del (7q)). Some case reports indicate a risk of myelodysplasia and acute leukemia and justify long-term follow-up bone marrow biopsies [8]. A German working group study identified the presence of ACAs in 79 (6.9%) of 1151 enrolled and Imatinib treated patients. For those patients, the time to achieve CCyR and MMR was longer. Progression free (PFS) and overall survival (OS) were shorter than in patients with standard t  [9]. Two large studies have confirmed the prognostic impact of ACAs detection. An Italian Working Group study which evaluated 378 patients, detected the presence of ACAs in 21 (5.6%) patients for whom the time to achieve CCyR and major molecular response (MMR) were longer. Long-term results in patients with ACAs were inferior but the differences were not significant compared to standard CML patients [10]. ACAs can be divided into major route ACAs represented by trisomy 8 (+8), isochromosome (17q)[i(17q)], trisomy 19 (+19) and a second Philadelphia chromosome (+Ph) and minor route ACA represented by monosomy 7 (-7), monosomy 17 (-17), trisomy 21 (+21), loss of Y chromosome (-Y) and t   . At least one of those abnormalities occurs in 15% of Philadelphia positive cells. Multiple cytogenetic abnormalities  were associated with translocation . The most common chromosomal abnormalities are represented by trisomy 8 (+8) (34%), second Philadelphia chromosome (+ Ph) (30%), isochromosome (17q) (17q) (20%), trisomy 19 (+19) (13%), loss of Y chromosome (-Y) (8%), trisomy 21 (+21) (7%), monosomy 17 (-17) (5%) and monosomy 7 (-7) (5%) [13]. Clonal evolution in CML is a marker of progression and represents chromosomal instability [16]. Shortening of telomere length is frequently associated with disease progression and may be a factor involved in chromosomal instability as telomere length is an important factor in chromosome integrity [16]. The presence of ACAs at diagnosis and during TKI treatment may announce treatment failure and/ or transformation to advanced stage (accelerated or blast) . Major route ACAs discovered at diagnosis may alert to early progression to advanced phase (accelerated or blast) and are important for assessing time to CCyR. Minor route ACAs have not yet proved important for progression [18]. From 11 (5.52%) patients in group A, eight expressed minor route ACAs and three expressed major route ACAs. The most frequent minor route ACAs were monosomies and structural abnormalities (inversions and translocations). The most frequent major route ACAs cells were trisomy 8 (27.27%), trisomy 19 (9.09%) and second Philadelphia chromosome (9.09%). Our results are similar to those published in the literature [19]. This phenomenon is transient and the clinical impact is unclear [20].From 17 (8.54%) patients in group B, 5 patients expressed major route ACAs, 3 patients expressed major route cytogenetic abnormalities in Ph negative cells, 4 patients expressed minor route ACAs and 5 patients expressed minor route cytogenetic abnormalities in Ph negative cells. The most frequent major route cytogenetic abnormalities in Ph positive and negative cells were trisomy 8 (17.64%), trisomy 19 (11.76%) and second Ph chromosome (5.88%). The most frequent minor route cytogenetic abnormalities in Ph positive and negative cells were marker chromosomes and structural abnormalities . The impact of cytogenetic abnormalities in Ph negative cells is still to be determined but they have been described in 2-17% of the patients on Imatinib [In both groups, no minor route abnormalities of chromosome 7 in Ph negative cells were reported.In our study, the median time to BP progression was of 40 months (8-72).At the end of our study, from 28 patients enrolled, 19 patients were in long-term CCyR on TKI treatment, 7 patients received allogeneic hematopoietic stem cell transplant from unrelated donor and 2 deaths were reported. The 12 months follow up after the study\u2019s end showed that 26 patients are alive and in long-term CCyR. The time to CCyR was longer in both groups and long-term results in patients with ACAs were inferior compared to standard patients but the differences were not significant and in accordance to published. The presence of ACAs at diagnosis and during the TKI treatment may announce treatment failure and/ or transformation to advanced stage (accelerated or blast).In our study, the cytogenetic response is heterogeneous. The time to CCyR was longer in both groups and long-term results in patients with ACAs were inferior, but the differences were not significant and in accordance to published data. The follow up after the study\u2019s end showed that 26 patients are alive and in long-term CCyR: 19 patients were in long-term CCyR on TKI treatment, 7 patients received allogeneic hematopoietic stem cell transplant from unrelated donor and 2 deaths were reported.The detection of ACAs during the TKI treatment is a warning sign of disease progression and periodic cytogenetic monitoring is mandatory, allowing real time therapeutic intervention .In this study, we demonstrated the importance of cytogenetic monitoring for the detection of disease progression and early TKI treatment switch or allogeneic stem cell transplantation. AcknowledgmentThis work was supported by the grant PN 41-087/2007 from the Romanian Ministry of Research and Technology. The authors express the gratitude to European LeukemiaNet for their permanent support.DisclosuresNone"}
+{"text": "To study the efficacy of vagus nerve stimulation (VNS) therapy as an adjunctive treatment for intractable epilepsy in patients under 12 years of age, we analyzed 2-year postimplant data of 35 consecutive patients. Of the 35 patients, 18 (51.4%) at 6 months, 18 (51.4%) at 12 months, and 21 (60.1%) at 24 months showed \u226550% reduction in seizure frequency (responders). Although incremental seizure freedom was noted, no patient remained seizure-free throughout the 3 study periods. Partial response (\u226550% seizure reduction in 2 or less study periods) was seen in 8 (22.9%) patients. Twelve patients (34.3%) were nonresponders. Out of 29 patients with primary generalized epilepsy, 20 (68.9%) and, out of 6 patients with focal epilepsy, 3 (50%) had \u226550% seizure control in at least one study period. No major complications or side effects requiring discontinuation of VNS therapy were encountered. We conclude that (1) patients with intractable primary generalized epilepsy respond better to VNS therapy, (2) cumulative effect of neuromodulation with improving responder rate to seizure freedom with continuation of VNS therapy is noted, and (3) VNS therapy is safe and is well tolerated in children receiving implant under 12 years of age. Neuromodulation therapies are nonpharmacotherapeutic options for patients with drug resistant epilepsy who are not candidates for resective epilepsy surgery. In 1997, the US Food and Drug Administration (FDA) approved vagus nerve stimulation (VNS) implant as adjunctive therapy for reducing the frequency of seizures in patients >12 years of age with partial-onset seizures refractory to antiepileptic drugs (AEDs) [Initial studies with randomized controlled trials reporting on the efficacy of VNS involved rather short follow-up duration (3 months to 3.5 months) and \u226550% seizure reduction ranged from 23.4% to 39% of the patients \u201322.Literature search identified 16 studies regarding the efficacy of VNS in children , 23\u201336. Ours is a prospectively collected data analysis retrospective study. All patients with epilepsy being treated at our center maintain daily seizure diary which is entered in the electronic database during follow-up visits. All patients with recalcitrant epilepsy undergo long-term video EEG monitoring and neuroimaging studies including MRI brain examination and are presented at Kaiser multidisciplinary epilepsy surgery case conference to discuss alternate nonpharmacotherapeutic treatment options. A total of 160 patients with drug resistant epilepsy (failed at least 3 AEDs at adequate doses appropriate for the type of epilepsy) who were not candidates for resective surgery received VNS implant from September 1998 to December 2011, 35 of whom were <12 years of age at the time of implant. VNS device from Cyberonics was implanted by our neurosurgeons who had received the required training.To allow wound healing, the VNS implant was not activated until one week postoperatively. Output current was gradually increased in 0.25\u2009mA increments once per week at six weekly visits, then at six subsequent biweekly visits, and then at each of three monthly visits to the clinic. After an informed decision by the parents, type of VNS cycling (standard versus rapid) and parameters were selected by the treating pediatric epileptologist. For standard cycling, the signal on-time was \u226530 seconds and signal off-time ranged from 3 to 5 minutes. For rapid cycling, signal on-time was \u226421 seconds and signal off-time ranged from 0.2 to 1.8 minutes. Rapid cycling was initiated with the parameters of 7 seconds on-time and 0.2 minutes off-time. Output current was adjusted depending on the patient's tolerance to the electrical stimulation and seizure control. Maximum output current used was 3.0\u2009mA for rapid cycling and 3.5\u2009mA for standard cycling. Ongoing AED regimen (dosing regimen and if needed AED) was adjusted as clinically warranted.The efficacy of VNS therapy was analyzed by comparing the mean seizure frequency (prior 8-week period) at baseline (at VNS implant) to that at 6-month, 12-month, and 24-month postimplant study points. We defined the efficacy of VNS therapy as follows: (1) responders: \u226550% reduction of seizures in all three study periods, (2) partial responders: \u226550% reduction of seizures in 2 or less study periods, and (3) nonresponders: <50% response and/or worsening seizure control in all 3 study periods. Efficacy of standard versus rapid cycling therapy parameters was also studied. We analyzed the efficacy of VNS therapy according to the type of epilepsies as well. We also assessed for postoperative adverse events, side effects, and tolerability of both the surgical implantation procedure and the VNS device.Thirty-five patients  with age ranging from 5 years to 12 years  met the selection criteria. Clinical characteristics for the patients at baseline are summarized in Although, among the responders, a complete (100%) seizure control was seen in 4 of 18 patients (22.2%) at 6-month, 5 of 18 patients (27.8%) at 12-month, and 7 of 21 patients (33.3%) at 24-month follow-up period, no single patient remained seizure-free throughout the 3 study periods. A total of 15 (42.9%) patients had \u226550% reduction in seizure frequency in all three periods and a partial response was seen in 8 (22.8%) more patients. Twelve patients (34.3%) showed no clinically significant benefit in all three periods .For the 22 patients who were treated with rapid cycle of VNS, the output current ranged from 0.75\u2009mA to 3\u2009mA and pulse width from 125 microseconds to 250 microseconds, with signal on-time set at 7 seconds to 14 seconds and signal off-time ranging from 0.5 minutes to 1.1 minutes. Seizure frequency reduction of \u226550% was seen in 11 of 22 patients (50%) at 6-month, 11 of 22 patients (50%) at 12-month, and 12 of 22 patients (54.5%) at 24-month follow-up period. The remaining 13 patients were treated with the standard cycle of VNS with output current ranging from 0.75\u2009mA to 3.5\u2009mA and pulse width from 250 microseconds to 500 microseconds, with signal on-time of 30 seconds and signal off-time from 3 minutes to 5 minutes. Seizure frequency reduction of \u226550% was seen in 7 of 13 patients (53.8%) at 6-month, 6 of 13 patients (46.2%) at 12-month, and 9 of 13 patients (69.2%) at 24-month follow-up period.The efficacy of VNS according to the etiologies of epilepsy is shown in Cough and pharyngeal paresthesia commonly occurred during initial application or ramming up of output current. These adverse events were successfully managed by adjusting the parameters. No side effects necessitating discontinuation of VNS therapy were encountered.VNS therapy has been approved as adjunctive treatment for drug resistant focal epilepsy in patients >12 years of age , 23\u201336. Similar to the observations of prior VNS studies, with increasing duration of VNS therapy, a trend towards improving responder rate and seizure freedom was noted in our study as well \u201339. The Optimal parameter settings for VNS therapy are not yet well defined. In current study, both rapid and standard cycle settings of VNS parameters were used. Patients who were treated with rapid cycling showed \u226550% reduction of seizure frequency in all three periods while those treated with standard cycling showed \u226550% reduction of seizure at 6-month and 24-month periods. Both rapid cycling and standard cycling demonstrated the cumulative seizure response to VNS therapy at 24-month period. The comparison of the efficacy between rapid cycling and standard cycling was not conclusive. Our previous study in 39 patients (age ranging from 5 to 72 years) demonstrated a trend towards greater seizure frequency reduction in patients with rapid cycle than standard cycle parameters. It also showed that when compared to adult patients, the response to rapid cycle in pediatric patients was greater . HoweverIn our study, VNS therapy was effective in both focal epilepsy and some types of generalized epilepsy. VNS therapy has been reported to be effective in patients with Lennox-Gastaut syndrome , 29, 30 Our patients tolerated the VNS implantation well. There was no serious wound infection requiring explantation. No major complications or side effects requiring discontinuation of VNS therapy occurred during the 2-year study period.Patients included in this study were offered VNS as an adjunctive treatment modality to ongoing antiepilepsy medication regimen and not after failing most available antiepilepsy medications. Therefore, change in the dosing regimen and, if needed, in the antiepilepsy medications used (which is a limitation of this study) was done per the choice of the treating physician. As many more AED choices (second and third generation AEDs) are available now, with a small study subject size it was not possible to comment on synergism of any specific AED mechanism of action being responsible for the seizure control noted after VNS implant.Many studies have reported lack of improvement in responder rate after failing 2 appropriate AEDs . All theIn conclusion, neuromodulation with VNS therapy can be used successfully as an adjunctive treatment for patients <12 years of age with both focal and generalized drug resistant epilepsies.The cumulative seizure response to VNS therapy necessitates long-term efficacy analysis studies. Due to availability of third generation AEDs it is unethical to design a prospective double blind research study with unchanged AED regimen to further define the findings of this study. Therefore, our retrospective data analysis study has limited but definite scientific contribution."}
+{"text": "Severe reactions and even fatalities occur in patients with food allergy, due to unexpected allergen exposure, but frequency data are scarce. The aim of this study is to investigate the frequency, severity and causes of unexpected allergic reactions to food in adults diagnosed with food allergy.A prospective cohort study is carried out starting January 2012. A total of 180 adult patients with a physician-confirmed diagnosis of food allergy will be included and followed during one year. Outcome measures are frequency, severity and causes of unexpected reactions. Participants complete an online questionnaire after every unexpected reaction and send in the culprit product including the food label. The product is analyzed for suspected allergens.Until now 152 patients (mean age=36 years (range 19-71), 70% female) have been included. The mean number of foods for which the patients are allergic was 5.5 (range 1-17). A total of 118 unexpected reactions were reported during the mean follow-up period of 9.7 months. Ninety-seven patients (64%) had no reactions, twenty-nine (19%) reported one reaction and twenty-six (17%) patients reported more than one reaction (range 2-11). Severity of these reactions was Muller 0: 18%, Muller I: 26%, Muller II: 27%, Muller III: 23% and Muller IV: 6%.Preliminary results show that 44% (n=52) of the unexpected reactions were caused by pre-packaged products, 23% (n=27) by composite meals outdoors, for example at a friends' or relatives home, at school or in a restaurant, 17% (n=20) by fresh products, 8% (n=9) by composite meals at home and 8% (n=10) of the reactions took place abroad.Main causes of unexpected reactions were labelling issues and risk taking behaviour of some patients. Forty-seven products were sent in to be analyzed. In one third of the products analyzed, the suspected allergen was detected.36% of the participants reported at least one unexpected allergic reaction. The mean number of reactions was 1 per person per year; reactions were mostly moderate to severe. Most reactions occurred after consuming pre-packaged foods. Labelling issues were frequently involved."}
+{"text": "Biologics are often used in therapy of DMARDs resistant JIA. The most complicated problem is choosing specific biological agent in particular case. AntiTNF inhibitors are well studied, but the application of Abatacept in real clinical practice hasn't been investigated enough.Retrospective evaluation of the ABA therapy results in process of treating children with JIA.The analysis includes data of 60 patients with JIA who were getting ABA in 2010 - 2013. The average age of patients is 12,5 years (from 6 to 18 years). 21 (35%) patients suffered from active uveitis . 10 (16%) patients were diagnosed as sJIA without current systemic features. Patients received ABA intravenously at a dosage of 10 mg/kg with 2 weeks interval initially (3 infusion) and following every month administration. Efficacy was evaluated in accordance with ACRpedi criteria. Ocular manifestations were evaluated by ophthalmologists.43 (72%) patients continue ABA therapy, in 17 cases ABA was cancelled . 30% patient (18 cases) failed to comply with the infusion schedule due to organization problems.The efficiency of ABA according to the ACRpedi criteria is demonstrated in Table The efficacy of ABA was increased significantly after 12 months of therapy. The regularity of infusions influences the higher effect, thus 70-90% improvement after 12 months were achieved predominantly in patients who had no deviations in infusion regimen (30 vs 4). ABA used as first-line biological agent more often shows 70-90% improvement after 12 months (27 vs 7 antiTNF-failers). Uveitis remission was identified in 53% of cases after 6 months, in 73% of cases - after 12 months, in 69% of cases - after 18 months, in 67% of cases - after 24 four months. 7 patients had adverse events  had uveitis de-novo, 1 patient had body weight gain, 1 patient had verruca vulgaris) but no serious events were observed.Long-term application of ABA is supposed to be highly efficient for treatment of patients with JIA, including patients with uveitis. The increase of positive effect ABA has continued to increase after 24 month period of therapy. The efficiency of ABA depends on the correct infusion regimen and it is higher in biologics-na\u00efve patients. ABA showed a good safety profile in the medium-term period.None declared."}
+{"text": "Fever is a common presentation of HIV/AIDS, malaria and acute respiratory tract infections (ARIs) all of which are major causes of childhood morbidity and mortality in sub-Saharan Africa. Correct management requires accurate diagnosis of the cause of fever. This study was carried out to determine prevalence and pattern of in HIV, malaria and ARI in febrile children under 5 years of age.A cross sectional study of all consenting and consecutive children 6- 59 months and their mothers / care-givers seen at the out patient department of Massey Street Children\u2019s, Hospital presenting with fever. Semi structured questionnaire was used to obtain information from the mothers / care-givers and laboratory investigations were done for febrile children using 5mls of venous blood aseptically collected for blood culture, HIV, PCV and Malaria. Plasmids mediated antimicrobial resistance among bacteria isolates was determined. Data obtained from questionnaire, clinical and laboratory diagnoses were analyzed using EPI-INFO version 3.5.1 software.Among 202 patients studied, 186 (92.1%) and 16 (7.9%) were clinically diagnosed as Malaria and ARIs respectively, but laboratory investigations showed 47 (23.3%) positive for malaria, ARIs 31(15.3%), HIV 10 (5.0%) and anaemia 12(5.9%). The results revealed the prevalence of HIV and ARIs co-infection as 10 (5%); HIV and Malaria 10(5%); Malaria and ARIs 27 (13.4%). The entire Malaria positive cases 47 (100%) were due to Plasmodium falciparum. Haemophilus influenzae isolates 5 (100%) and Streptococcus pneumoniae 23 (82.1%) isolates harboured plasmids which conferred multiple antimicrobial resistant on them.Fever in children may be as a result of Infection with HIV/AIDS, Malaria, ARI, or co-infection of any of the two diseases. Home management of fever was very high among mothers / care-givers. The commonest drugs used for treatment of childhood fever by mothers / care-givers were chloroquine and cotrimoxazole. Streptococcus pneumoniae the major organism isolated was highly resistant to cotrimoxazole."}
+{"text": "The diagnosis of brain death (BD) is important in order to decrease the burden of futile care and procure vital and viable organs for donation. The aim of this study was to find clinical features of patients, diagnostic tools used, attitude to BD and donation rate in a teaching hospital for neurologic diseases in Istanbul.All consecutive BD patients between April 2014-April 2015 were included in this retrospective study. Data were abstracted from medical records. Statistical analyses were performed using SPSS software. The results were expressed as percentages for categorical data and median with interquartile range for continuous variables.Twenty-three patients  had BD diagnosis. Neurologic etiologies were ischemic stroke (52%), intracranial bleeding (39%), hypoxic encephalopathy (4.5%) and transverse sinus thrombosis (4.5%). The Glasgow Coma Scales (GCS) were 9 (5-11) at hospital and 7 (5-9) at ICU admission. The clinical sign encouraging the clinicians to think BD were brain stem areflexia (39%), decreased GCS (34.5%), absence of spontaneous breathing (17.5%) and polyuria (9%). BD was suspected first by ICU physicians in 56.5%. BD diagnosis was delayed for > 12 hours in 11 patients because of being sure about BD (46%), legal observation time (27%), sedation (18%) and hemodynamic instability (9%). Fifteen patients had BD diagnosis with apnea and brainstem testing. The remaining 8 cases had confirmatory diagnostic evaluations of BT angiography (6) and EEG (2) due to inability of performing apnea testing (5), clinical suspicion (2) and uncomfortable feeling in giving the decision (1). Apnea testing was reported before neurologic examination in 26%. No complication was documented during apnea testing. Diabetes insipidus was developed in 78% and desmopressin was given to 39% of polyuric patients. Vasopressors were ordered to 95.5%  and methylprednisolone [60 (36-60) mg/day] to 57%. Levothyroxine [300 (112-400) mcg] was ordered only one time to 39% during the BD diagnosis period. Three (13%) patients were allowed to be donors by the relatives. The therapy was withdrawn in 55% and held on the present support until cardiac arrest in 35% of the nondonors. No information was found for 10% of the nondonors. The time span from BD confirmation to cardiac arrest developed was 120 (60-636) minutes for the nondonors.The main clinical signs encouraging the clinicians to identify brain death are brainstem areflexia and decrease in GCS. Apnea and brain stem testing are the major diagnostic approach. Diabetes insipidus and hypotension are commonly encountered situations in these patients."}
+{"text": "Hand hygiene is the single most effective but least practiced action in breaking the chain of transmission of microbes. Studies have shown a correlation between the compliance of hand hygiene and its impact on the health outcome.A quasi-experimental study was done in three level III ICUs of a tertiary care hospital in Kolkata (January to April 2014). Data were collected on existing hand hygiene compliance rate, ventilator-associated pneumonia (VAP) rate, catheter-related bloodstream infection (CRBSI) rate, catheter-related urinary tract infection (CAUTI) rate, standardized mortality ratio (SMR) and average ICU length of stay in the abovementioned units. Root cause analysis was done and interventions were developed to improve hand hygiene compliance and was implemented (July to October 2014). Comparison was done between preintervention and postintervention periods.In the preintervention period (January to April 2014) the hand hygiene compliance among the caregivers was found to be 40%, VAP rate (8.77), CRBSI rate (3.42), CAUTI rate (5.27), SMR (1.14) and average ICU length of stay was 6 days \u00b1 5.85 SD (median 4.5). Interventions were developed and implemented as follows: education and awareness - road shows; positive reinforcement; secret watch nurse; e-ICU - electronic surveillance; ring the bell once every hour - baseline hand hygiene; visual reminders; availability of alcohol-based hand rub, soap and water and sinks; random hand swabs; and compliance audits. In the postintervention period (July to October 2014) data showed a significant improvement in the hand hygiene compliance (75%). Further analysis showed an association with decrease in the incidence of VAP rate (4.71), CAUTI rate (3.51), CRBSI rate (2.65), SMR (1.05) and average ICU LOS 5.05 days \u00b1 4.03 SD (median 4).Improved hand hygiene compliance can be attributed to decreased incidence of VAP, CRBSI, CAUTI, SMR and average ICU LOS. This does definitely impact the overall clinical outcome. However, continued surveillance of hand hygiene compliance and regular audits is of utmost importance to make the change sustainable."}
+{"text": "To compare the neuro-radiologic findings in Systemic lupus erythematosus (SLE) patients with and without antiphospholipid antibodies (aPL) in different neuro-psychiatric manifestations.This cross-sectional comparative study was carried out at King Khalid University Hospital, a tertiary care teaching hospital, Riyadh, Saudi Arabia from June 2012 to January 2015. Ninety seven SLE patients with neuro-psychiatric manifestations were included in the study and divided into two groups. Group I (50 patients) SLE with aPL and group II (47 patients) SLE without aPL. We compared Demographic features, clinical manifestations and magnetic resonance imaging (MRI) brain findings.Demographic and clinical characteristics of two groups were similar. In Group-I, anticardiolipin antibodies (aCL) were most common (86%). In patients with headache, most of the patients in Group-I had white matter hyperintensities (WMHIs) (50% vs 27%) while most of the patients in Group-II had normal MRI brain (38% vs 73%). Similarly WMHIs were found more in Group-I patients with seizures (60% vs 21%), while ischemia/infarction, atrophy and normal MRI were found in Group-II. MRI brain in patients with neurological deficit and psychiatric disorder were not much different in both the groups.We found no statistically significant differences in frequencies of MRI brain abnormalities in SLE patients with and without aPL antibodies. Each of the three aPL may have a variable effect on the brain. Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease that primarily affects women of childbearing-age. Neurological involvement in SLE is mainly manifested as cerebrovascular accidents, seizures, cognitive impairment, headache and psychosis.5n-107), 24 had a thrombotic event. This difference in prevalence of thrombosis between patients with and without aPL antibody was significant .7anticardiolipin antibodies (aPL) have been associated with the impairment of the normal inhibition of cerebral at herogenesis, leading to an increase in atherosclerotic vascular disease in the brain. aPL mediated complement activation in the brain is also a potential source of nervous system toxicity and dysfunction.MRI is very important tool for the non-invasive assessment of neurological manifestations of SLE. No sufficient data is available to compare MRI brain findings in different neuro-psychiatric manifestations in SLE patients with and without aPL. The objective of our study was to uncover the pattern of abnormalities seen on conventional MRI in a series of SLE patients (with & without aPL antibodies) presenting with neuro-psychiatric manifestations.This cross-sectional comparative study was carried out at King Khalid University Hospital Riyadh, Saudi Arabia from June 2012 to January 2015. The study was approved by the ethical committee of our institution. Ninety seven SLE patients attending rheumatology out-patient clinic or admitted with neuro-psychiatric manifestations, were included in the study. All of them fulfilled the American College of Rheumatology criteria. They were divided into two groups, Group-I, SLE with aPL antibodies (n=50) and Group-II, SLE without aPL antibodies (n=47) patients. Informed consent was obtained for inclusion in the study. Data was collected by filling the questionnaire. History, physical examination and lab work including serological profiling were recorded. aCL antibodies and where necessary lupus anticoagulant (LA) andanti-\u00df2GP1 were obtained. Patients underwent brain MRI on different MR machines including 3.0 Tesla Siemens Vario, 1.5 Tesla GE Discovery 450 and 1.5 Tesla GE Optima 450W. T1-weighted, T2-weighted, fluid-attenuated inversion recovery (FLAIR) and diffusion weighted images were obtained for all the patients. MRI examinations were studied by neuro-radiologist and their clinical data were correlated with the radiological findings by a team comprising of rheumatologist, neurologist and neuro-radiologist. Descriptive statistics  were used to describe the quantitative and categorical study variables. Chi- square statistics and the Fisher\u2019s exact test were used for categorical data. A two-sided p <0.05 was considered statistically significant. SPSS version 18  was used for all analysis.Ninety seven SLE patients were recruited with a mean age of 37.55 \u00b1 11.218 years (range 15-68). Ninety (90/97) patients were female and seven (7/97) were male. Fifty SLE patients in Group-I were positive and forty seven (Group-II) were negative for aPL. There was no significant difference between the two groups regarding demographic features. In group I, aCL antibodies were most common, which were found in 43(86%), followed by lupus anticoagulant in 16(32%) and anti-\u00df2GP1 in 5(10%) of SLE patients. Eleven patients were positive for both aCL and LA, 1 had aCL and anti-\u00df2GP1 and 2 patients had both LA and anti-\u00df2GP1 in their serum.The common neuro-psychiatric manifestations in our study were headache, seizures, neurological deficit and psychiatric disorders . Headache was found in 16(32%) patients of group one followed by seizures in 10(20%), neurological deficit in 14(28%) and psychiatric disorder in 10(20%) patients. In group II, 11(23%) patients had headache, 14(30%) seizures, 12(26%) neurological deficit and 10(21%) had some psychiatric disorder.Differences in the MRI abnormalities in the two groups are presented in In Group-I, out of 16 patients with headache, WMHIs were found in 8(50%) patients followed by normal MRI in 6(37.5%) and only 2(12.5%) patients had ischemia/infarcts. No patient had VST or brain atrophy. Among 10 patients presenting with seizures, 6(60%) had WMHIs, 3(30%) ischemia/infarcts and only one had normal MRI brain. Fourteen patients who presented with neurological deficit had following MRI findings: 4(28.6%) had WMHIs, 6(42.9%) infarction and 3(21.4%) had normal MRI. No MRI abnormalities were found in 6(60%) of 10 patients who had psychiatric disorder. Two patients had WMHIs, one had infarction and one had brain atrophy.Similarly in Group-II, out of 11 patients with headache, WMHIs were found in 3(27.3%) patients while 8(72.7%) had normal MRI. No patient had ischemia/infarction, VST or brain atrophy. Among 14 patients with seizures, 3(21.4%) had WMHIs, 6(42.9%) ischemia/infarcts, 2 brain atrophy and three had normal MRI brain. Twelve patients with neurological deficit had following MRI findings: 4(33.3%) had WMHIs and ischemia/infarction each, 1(8.3%) brain atrophy and 3(25%) had normal MRI. No MRI abnormalities were found in 6(60%) of 10 patients who had psychiatric disorder. Three patients had brain atrophy and one had WMHIs.Demographic features of our study population are consistent with other areas of the world. No differences were noted between the two groups regarding age and sex of patients. Slightly more than half (51.5%) of our SLE patients with neuropsychiatric manifestations were positive for aPL. In a study done in Bahrain, aCL were detected in 23% while anti-\u00df2GP1were detected in 16.6% of SLE patients.Among neuro-psychiatric manifestations; headache, seizures, neurological deficit and psychiatric disorders were the most common symptoms in both the groups. Headache was more common  in Group-I as opposed seizures which were more common  in Group-II. The frequency of neurological deficits (28% vs 26%) and psychiatric disorders (20% vs 21%) were not much different in the two groups. Sanna G et al. and Alfeltra A et al. reported that headache, CVD, seizures and psychiatric disorders were more common in aPL positive group.On MRI brain, WMHIs were observed more in Group-I  while brain atrophy was more frequent in group II . No differences were observed in the categories of ischemia/infarction 24% vs 21%) and venous sinus thrombosis (2% vs 0). Thirty two percent neuro-psychiatric SLE (NPSLE) patients in Group-I and 42% in Group-II had normal MRI brain (p = 0.282). WMHIs were found more in patients with aPL than those without aPL (36% vs 24%), but the difference was not statistically significant .% and venA study by Arinuma Y et al. revealed that 47.2% of SLE patients had abnormal MRI with subcortical WMHIs being the most common finding. However these findings were not significantly associated with aPL.24In patients with headache, most of the patients in Group-I had WMHIs  while most of the patients in Group-II had normal MRI brain . Other findings were not significant in patients with headache. Similarly WMHIs were found more in Group-I patients with seizures , while more patients in Group-II had ischemia/infarction , brain atrophy  and normal  MRI brain. MRI brain abnormalities in patients presenting with neurological deficit were not much different in both the groups. Same is the case for SLE patients having psychiatric disorder as no significant difference was observed on MRI brain. Csepany T et al. reported that infarcts and atrophy were more frequent in aPL group and were more common in patients with neurological deficit.We found no statistically significant differences in frequencies of MRI brain abnormalities in SLE patients with and without aPL antibodies. Each of the three aPL may have a variable effect on the brain. Further studies on large scale may be needed to uncover the pattern of MRI abnormalities in SLE for different aPL antibodies."}
+{"text": "Trauma is the fifth principal cause of death in Singapore, with traumatic brain injury (TBI) being the leading specific subordinate cause .This 8-year retrospective review of patients with severe TBI admitted to the neuroICU (NICU) of the National Neuroscience Institute, Tan Tock Seng Hospital between 2004 and 2011 reports the demographic profiles of severe TBI in the local context, with implications in the management of severe TBI, particularly the utilisation of critical care resources.A total of 780 patients were admitted with TBI during the study period, of which 365 patients (46.8%) sustained severe TBI. The majority (75.3%) of the severe TBI patients were male. There was a bimodal preponderance of severe TBI cases in young adults (age 21 to 40) and older people (age >61). Motor vehicle accidents (48.8%) and falls from <2 m (35.1%) were the main mechanisms of injury. Invasive monitoring was frequently employed in these patients with severe TBI: arterial blood pressure monitoring in 298 patients (81.6%), central venous pressure monitoring in 219 patients (60.0%), and intracranial pressure monitoring in 173 patients (47.4%). The incidence of use of tiered therapy such as sedation, mild hyperventilation, osmotherapy with mannitol, cerebrospinal fluid drainage, barbiturate coma and decompressive craniectomy to control ICP converged with international practices.Young adults and older people involved mainly in motor vehicle accidents and falls respectively were among the high-risk groups for severe TBI. Management of these patients goes beyond the ICU and involves, but is not limited to, social support, emotional motivation and community reintegration of these patients . TBI amo"}
+{"text": "Sub-Saharan Africa suffers from more acute life-threatening indications for blood transfusion compared with high-income countries . The comt test for continuous data.We performed a 1-day retrospective review in June of blood request forms submitted to the cross-match laboratory, followed by a 14-day prospective review in September 2014. Group and save requests were excluded. Each form was audited against the American Association of Blood Banks (AABB) minimum standards for content of a blood request form. Analysis was performed with Fisher's exact test for nominal data and P < 0.0001). The mean number of standards met on the requests from CDH and the rest were 11.25 (SD 0.93) and 8.87 (SD 1.75) respectively (P < 0.0001). Considering all blood requests, the standards met in order from least to most were: signature of requesting doctor (36%), urgency of request (43%), hospital number (59%), indication for transfusion (62%), type of product requested (72%), requesting doctor's name (78%), age or date of birth of patient (84%), gender of patient (89%), quantity of products requested (90%), date form was completed (90%), patient's ward (95%), and patient's full name (100%).A total of 1,163 blood requests were reviewed, 51 from CDH and 1,112 from other wards. Eighteen forms from CDH (35%) and 22 from other wards (2%) met all minimum AABB standards (The audit revealed an important system failure impacting on efficacy and safety of transfusion practice at UTH. Full patient identifiers, as well as vital information such as the indication and urgency, were rarely filled in, which are crucial for the blood bank to prioritise the release of blood products. The audit shows that practice may be significantly improved by a cheap intervention such as a standardised blood request form meeting international standards.UK aid, THET."}
+{"text": "During the last few years in Romania, increased numbers of new HIV infections among ethnobotanicals intravenous drug users (eIVDU) were observed. Although most cases have relatively good immunological status, some patients reclaim antiretroviral (ARV) treatment because of very low CD4 count, severe comorbidities and/or pregnancies despite difficulties related to their adherence.st January 2010 and 31st January 2014.Retrospective analysis of 32 patients, eIVDU, treated with ARV in our hospital between 1From all 32 patients, 27 are males (84.4%). The main reason for starting ARV treatment was represented by severe AIDS-defining illness (71.4%) related to immunodepression with CD4 count below 100 cells/cmm 11 cases (34.3%) and one pregnancy. In our study group the mean CD4 count at baseline was of 110.1 cells/cmm (median CD4 102.5 cells/cmm). 24 patients (75%) received at first triple therapy including NNRTI , the other 8 patients (25%) received from the beginning regimens with protease inhibitors. 7 patients from the first group were then switched to protease inhibitors, mostly after completing tuberculostatic treatment, while 2 patients from the second group were switched to integrase inhibitors because of potential drug-drug interactions involving rifampin. All patients in our study were coinfected with HCV, 9 patients (28.9%) had also HBV, and 15 patients (46.8%) had active tuberculosis. Only 15 patients were truly adherent to ARV (43.7%); we registered 5 cases of abandon and one death. From all 5 patients who discontinued treatment 3 were social cases; from all 28 patients who are currently treated 20 have good family support (71.4%) and 6 (21.4%) receive psychological counseling and methadone substitution therapy. Mean value of CD4 count at 1 month of HAART therapy was of 225.8 cells/cmm, probably related to ARV treatment received correctly during admission in our clinic, but this value decreased to 213.3 cells/cmm at 3 months, probably related to poor compliance at home.Despite the fact that they are recently infected with HIV, increasingly more eIVDU patients are in need of ARV treatment, because mainly of rapid immunodepression and comorbidities associated with AIDS. Family support as well as psychological counseling and substitution therapy with methadone are mandatory for achieving clinical success with HAART, while lack of adherence is the principal cause for immunological and virological failure. Tuberculosis with both pulmonary and extrapulmonary involvement is the principal complication associated with AIDS, involving almost half of the eIVDU in our country."}
+{"text": "Weaning from mechanical ventilation is an important responsibility for ICU nurses .To identify weaning practices among ICU nurses.A cross-sectional, self-administrated survey was developed. Consensus on content validity was achieved through a Delphi procedure among experts. The survey was distributed and collected during the annual congress of the Flemish Society of Critical Care Nurses (Dec. 2014).423 attendants completed the survey (response rate: 66%) of which 342 ICU nurses were included for further analysis. These are employed in general (73%) or university hospitals (27%) and are working in mixed (66%), surgical (18%) or medical (13%) ICUs.Nurses working in university hospitals reported higher availability of weaning protocols . 22% of nurses reported the availability of both weaning and sedation protocol. Protocols are paper-based (23%) or computer-assisted (5%) and in 20% of the cases never used. Nearly 20% of the nurses got some information or training about use of their protocol.Most frequently chosen weaning modes are CPAP (77%), BiLevel/BIPAP (74%) and PSV (59%). Nurses report to autonomously change ventilation modes (68%), pressure support (PS) level (66%) and respiratory rate (49%). Before starting a spontaneous breathing trial (SBT) evaluation of respiratory status (83%), respiratory capacity (73%) and oxygenation (63%) are considered. Spontaneous breathing on T-tube (58%) is the most frequently chosen SBT approach next to CPAP (57%) and PS ventilation with minimal PS (46%). Duration of first SBT between 30 and 120 minutes was found in nearly 50% of responses but it was not associated with the presence or absence of a weaning protocol (p = 0.57). Less than 30 minutes SBT was reported by 45% of nurses. In majority of the cases is SBT repeated 3 times per day (38%) and mostly at the daytime (99% vs. 37%).SBT is considered successful if adequate gas exchange is maintained during the procedure (89%), and prematurely terminated in case of signs of exhaustion (89%), inadequacy of gas exchange (90%) or hemodynamic instability (66%). Prior to extubation almost all nurses (94%) indicate oxygenation as an important parameter.When it comes to weaning, nurses are generally satisfied about the cooperation with MDs. Decision making in weaning is mostly taken by MDs (91%).Less than half of nurses use weaning protocols. Variability in nurses' practical approaches to weaning appears to be considerable. Physicians are mostly involved in decision making on weaning."}
+{"text": "Introduction. Medicine is one of the most stressful fields of education because of its highly demanding professional and academic requirements. Psychological stress, anxiety, depression and sleep disturbances are highly prevalent in medical students.Methods. This cross-sectional study was undertaken at the Combined Military Hospital Lahore Medical College and the Institute of Dentistry in Lahore (CMH LMC), Pakistan. Students enrolled in all yearly courses for the Bachelor of Medicine and Bachelor of Surgery (MBBS) degree were included. The questionnaire consisted of four sections: (1) demographics (2) a table listing 34 potential stressors, (3) the 14-item Perceived Stress Scale (PSS-14), and (4) the Pittsburgh Quality of Sleep Index (PSQI). Logistic regression was run to identify associations between group of stressors, gender, year of study, student\u2019s background, stress and quality of sleep.Results. Total response rate was 93.9% (263/280 respondents returned the questionnaire). The mean (SD) PSS-14 score was 30 (6.97). Logistic regression analysis showed that cases of high-level stress were associated with year of study and academic-related stressors only. Univariate analysis identified 157 cases with high stress levels (59.7%). The mean (SD) PSQI score was 8.1 (3.12). According to PSQI score, 203/263 respondents (77%) were poor sleepers. Logistic regression showed that mean PSS-14 score was a significant predictor of PSQI score .Conclusion. We found a very high prevalence of academic stress and poor sleep quality among medical students. Many medical students reported using sedatives more than once a week. Academic stressors contributed significantly to stress and sleep disorders in medical students. Medicine is one of the most stressful fields of education because of its highly demanding professional and academic requirements. Extensive medical curricula, frequent examinations and fear of failure are sources of constant stress and anxiety for medical students , who maySeveral studies have also reported poor sleep quality in medical students. Most of the medical schools in Punjab, Pakistan offer a 5-year-long Bachelor of Medicine and Bachelor of Surgery (MBBS) degree program divided into 2 preclinical years followed by 3 clinical years. These schools use conventional non-problem-based learning (PBL) teaching methods, which consist of teacher-centered didactic techniques, long lectures, tutorials and practical tasks. Students are frequently assessed with written, oral or practical examinations throughout the year, and each year ends with a final exam held by the University of Health Sciences in Lahore. A passing grade on this exam is necessary to qualify for the next academic year. According to Several studies have reported the prevalence of stress among medical students in Pakistani medical schools. However, the paucity of knowledge on pattern of sleeping difficulties in Pakistani medical students and its association with academic stress warranted this study. This study was designed with two aims: (1) to determine the prevalence of psychological stress and pattern of sleeping difficulties among medical students, and (2) to explore the relationship between academic stressors, psychological stress and poor sleeping habits among medical students.This cross-sectional study was done at Combined Military Hospital Lahore Medical College (CMH LMC) and Institute of Dentistry, Lahore (Pakistan) after approval by the CMH LMC Research Ethics Committee. Students from all yearly courses of the MBBS degree program were included in this study, which took place from August, 2014 to September, 2014. The sample size required for this survey was calculated as 251 participants for a 95% confidence level, a 5% margin of error and a population size of 720 medical students. Students were randomly selected with a stratified sampling technique. First, the students were divided into groups based on their year of study, then random numbers were generated using computer software. A total of 280 self-administered questionnaires were distributed to potential respondents to ensure an adequate percentage response rate. Written informed consent was obtained from all participants. They were informed about the aims of this study and assured anonymity and that only group-level findings would be reported.The questionnaire consisted of four sections: (1) demographics (2) a table listing 34 potential stressors, (3) the 14-item Perceived Stress Scale (PSS-14), and (4) the Pittsburgh Quality of Sleep Index (PSQI). The demographics section recorded data for participants\u2019 age, gender, year of study, residence and background. The table of potential stressors was taken from a similar study in a Pakistani medical school by The PSS-14, developed by The fourth section of the questionnaire consisted of the PSQI, a self-rating questionnaire that assesses sleep quality and disturbances during the preceding month. This instrument comprises 19 individual items and yields an overall score ranging from 0 to 21. Participants who score higher than 5 are considered poor sleepers. It also yields scores on seven other components: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbance, use of sleeping medication and daytime dysfunction .T test was run to analyze association between academic stressors  and PSQI scores.Al data were analyzed in SPSS Inc.,  v.20 software. Frequencies were calculated for demographic variables. Mean PSS-14 scores were calculated and divided into quartiles, then further recoded as a dichotomous variable by combining the upper two quartiles and lower two quartiles . These values were recoded as 1 = high stress levels and 0 = low stress levels, as in an earlier study from Pakistan . The fre\u2009 year 45 (17.1%) and 5th year 45 participants (17.1%).Total response rate was 93.9% (263 of 280 respondents returned the questionnaire). Mean age (SD) of respondents was 21.1 years (1.78). The gender distribution of the respondents was 148 women (56.3%) vs. 115 men (43.7%). Most participants were of Pakistani background  and the remaining 43 respondents (16.3%) were of other nationalities. Most of the participants resided off the medical school campus  and the remaining 102 (38.2%) resided in student residence facilities. The distribution according to year of study was 1st year 58 (22%), 2nd year 67 (25.5%), 3rd year 48 (18.3%), 4th\u20091st-year , 3rd-year  and 4th-year students .Mean (SD) PSS-14 score was 30 (6.97). According to logistic regression analysis, cases of high-level stress were associated with year of study and academic stressors only . UnivariThe frequency and severity are shown for academic stressors in P < 0.05). During the month preceding the survey, 73 (27.8%) respondents got less than 5 h of sleep per day, 233 (88.6%) reported nighttime disturbances, 97 (36.9%) poor sleep latency, 128 (48.7%) daytime dysfunctioning, 94 (35.7%) poor sleep quality and 31 (11.8%) poor sleep efficiency. A few respondents 13 (4.9%) reported using sedatives more than once a week.Mean (SD) PSQI score was 8.1 (3.12). According to these scores, 203/263 respondents (77.02%) were poor sleepers. Logistic regression showed that mean PSS-14 score was a significant predictor of PSQI score . The prevalence of poor quality of sleep among stressed students was 82% (129/157), whereas among non-stressed students, only 69.8% were poor sleepers. Independent sample T test revealed a significant association in mean scores of PSQI scale and academic stressors. Those students who reported academic stressors as often/always had a higher mean score on PSQI scale than their counterparts who reported academic stressors as never/sometimes .The chi-squared test revealed a significant association between stress and poor quality of sleep  and poor sleep quality (77%), which is in consonance with earlier studies conducted in Pakistan. Most of the respondents (55.9%) indicated that they often or always experienced academic stressors, and this subgroup was 2.5 times as likely to suffer from psychological stress and poor sleep quality as their non-stressed counterparts. These results underscore the importance of nurturing a positive learning environment for medical students.An interesting finding in our analysis was that both male and female students were equally likely to experience stress and sleep disturbances. This result is consistent with a report by Cohen and colleagues, who found no significant association between stress levels and gender in a sample of college students . In 2004Another interesting finding in our study was that 77% of the medical students reported poor sleep quality, which was significantly associated with academic stressors. A high percentage of respondents (27.8%) got less than 5 h of sleep per night. This is in consonance with a large-scale study of 2,515 Ethiopian university students, 55.8% of whom reported poor sleep quality. That study also reported a strong association between poor sleep quality, stress, anxiety and depression . Drug miOur results are consistent with previous studies at medical schools in Nepal  and PakiThe cross sectional design of this study limits inferences about causality and temporality between academic stressors, psychological stress and sleeping difficulties. Our sample size consisted of a representative sample of a single medical school. Therefore, these results are not generalizable to whole student population in Pakistani medical colleges. The use of self-administered questionnaires is an important limitation in this study and it may lead to recall bias. Psychological stress and sleeping disturbances were assessed with psychometric instruments which are not completely transposable to the DSM diagnostic criteria for psychiatric illnesses.Our study revealed a high prevalence of academic stress and poor sleep quality among medical students in Lahore. Many medical students reported using sedatives more than once a week. Academic stressors contributed significantly to perceived stress and sleep disorders.10.7717/peerj.840/supp-1Supplementary Information 1Click here for additional data file."}
+{"text": "Pre-hospital patient management with resuscitative procedures is a standard of care in mature EMS systems. Currently, no centralized EMS system exists for the population in Eastern India. This leads to patients presenting to under-resourced facilities highlighting the need for sophisticated ambulance services for inter-facility transfers. This study identifies the need of a centralized process to obtain ambulance services for timely transport of critically ill patients to adequately equipped tertiary care centers, thereby improving patient outcome and achieving the concept of golden hour.A retrospective observational review was done from January 2011 to December 2013 of The Mission Hospital ACLS inter facility transfer ambulance. All triage priority one patients being transferred to the emergency department were included. Demographic analysis was done by multivariate statistical methods.1298 patients were transferred by ambulance during the study period, of which 462 patients (35.59%) belonged to triage category 1 during initial assessment. 449 patients (97.18%) were above 18 years of age, males being 257 (57.23%) and females being 192 (42.76%). Resuscitative efforts were performed on 236 patients (51.08%) including intubation in 58 patients (24.27%) of which 36 patients (62.07%) underwent RSI, with 41 patients (17.15%) being brought on ventilator, 6 patients (0.025%) on pacing and 131 patients (55.51%) received inotropes to manage cardiac instability. 3 patients expired before reaching the hospital.This study highlights the need to for the development of a centralized ambulance coordination service with appropriately trained personnel. This system would reduce the requirement of interfacility transports. This data shows that inter-facility ambulances in Eastern India were successful in transferring critically ill patients, but this situation has evolved due to the lack of a centralized EMS system and placing undue burdens on a few institutions."}
+{"text": "Case-based varicella (chickenpox) surveillance is important for monitoring the impact of the varicella vaccination program. In 2002, the Council of State and Territorial Epidemiologists (CSTE) recommended that all states move toward case-based varicella surveillance by 2005; in 2003, varicella was made nationally notifiable  1). To . To 1). The CDC and CSTE assessment addressed several important aspects of varicella surveillance, including 1) whether varicella is a reportable condition in the state; 2) type and breadth of surveillance conducted ; 3) varicella-specific variables collected ; 4) types of reporting sites; 5) whether varicella surveillance data are sent to CDC via HL7 messaging; 6) whether laboratory testing for varicella is performed in the state; 7) varicella vaccination requirements for school entry; and 8) outbreak control policies. The assessment was pilot-tested in five states and the final version distributed via e-mail in September 2012 to all state epidemiologists.All 51 jurisdictions (50 states and DC) completed the assessment. Forty-four (86.3%) indicated that varicella is reportable in their jurisdiction. Among these 44 jurisdictions, varicella cases are reported by schools , hospitals , and health care providers . A total of 38 jurisdictions (86.4%) conducted case-based surveillance, either statewide or at regional sentinel sites, and 20 (45.4%) conducted surveillance only for varicella outbreaks or cases associated with outbreaks .Among reporting variables, more than 84% of the 38 jurisdictions conducting statewide or sentinel site varicella case-based surveillance reported collecting information on age, sex, and race/ethnicity , vaccination status (94.7%), outbreak association (86.8%), and disease severity (84.2%) . OutcomeVaricella-specific data were transmitted to CDC via HL7 messaging by 19 (43.2%) of the 44 jurisdictions. Of the 22 (50%) jurisdictions that did not send data via HL7 messaging in 2012, 14 (63.6%) had not transitioned to HL7 standards. Seven (31.8%) either had other methods for sending data, were planning to transition to HL7 messaging, or were not collecting case-based data, and one (4.5%) had no plans to transition to HL7. Barriers hindering transition to HL7 messaging included competing priorities and lack of staff and funds. Three jurisdictions reported not knowing whether they were sending HL7 messages to CDC.Of the 51 jurisdictions, 49 (96.1%) reported providing public notification of varicella outbreaks and recommending vaccination as an outbreak control strategy. Other reported control strategies included exclusion from the outbreak setting of 1) patients , 2) persons without evidence of immunity who refuse vaccination , 3) persons not up-to-date on vaccinations who refused vaccination , and 4) immunocompromised persons or pregnant women without evidence of immunity . Overall, 31 (60.8%) of the 51 jurisdictions reported having state guidelines for varicella outbreak control.A total of 41 (80.4%) of the 51 jurisdictions reported having laboratory capability for varicella testing, and 17 (33.3%) routinely provided such testing. In 36 (70.6%) jurisdictions, most testing was conducted as part of outbreak investigation and control. Testing by polymerase chain reaction (PCR) and culture, the most commonly reported types of varicella tests, were available in 26 jurisdictions (51.8%), and the varicella-zoster virus immunoglobulin G test was available in 24 jurisdictions (47.1%).In 2012, 13 (25.5%) of the 51 jurisdictions reported requiring only 1 dose of varicella vaccine for school entry, 20 (39.2%) reported having a 2-dose school entry requirement, and 17 (33.3%) reported having both 1-dose and 2-dose school entry requirements depending on the grade level. One (2%) jurisdiction reported having no varicella vaccination requirement for school entry.Because a large number of varicella cases occurred in the United States at the beginning of the varicella vaccination program  and varicella was not included as a nationally notifiable condition, nationwide reporting of every varicella case was not feasible at that time . In the What is already known on this topic?National varicella surveillance data are important for monitoring trends in varicella epidemiology. In 2002, the Council of State and Territorial Epidemiologists recommended that varicella be added to the list of nationally notifiable conditions by 2003 and that all states move to case-based reporting for varicella by 2005.What is added by this report?As of 2012, varicella has been a reportable condition in 44 of 51 jurisdictions; 38 jurisdictions were conducting statewide or sentinel site case-based surveillance for varicella. However, only 19 jurisdictions had the capability to send varicella-specific data to CDC through Health Level 7 electronic messaging. Among the 51 jurisdictions, 80.4% had the laboratory capacity to test specimens for varicella, and 60.8% of jurisdictions had guidelines for outbreak control. Additionally, all jurisdictions except one had either a 1-dose or 2-dose varicella vaccine school entry requirement.What are the implications for public health practice?Continued work by jurisdictions to collect and improve completeness of reporting of all relevant clinical and epidemiologic data, disease severity and outcomes, and vaccination status, along with full implementation of Health Level 7 systems to allow jurisdictions to send their varicella-specific data to CDC will be useful for continued monitoring of the varicella vaccination program and guiding future varicella vaccination policy.As the varicella vaccination program matures and more cases occur among vaccinated persons, laboratory confirmation is increasingly necessary. Diagnosis of breakthrough disease  is challenging because disease is often mild and might resemble other rash illnesses or insect bites. PCR testing of lesion specimens has been shown to be the most sensitive and specific for diagnosing varicella ,8. With Because varicella disease in vaccinated persons is usually mild, with fewer lesions than in unvaccinated persons, confirming and investigating varicella outbreaks in the 2-dose vaccine era can be challenging and resource intensive . ApproxiCurrently, most jurisdictions conducting case-based surveillance collect varicella-specific information; however, fewer than half are able to send those data via HL7 messaging to CDC. HL7 messaging is the only mechanism available to states for sending the varicella-specific data they collect to CDC.Considerable progress has been made in national varicella surveillance, and national data are now used to monitor trends in varicella incidence. More complete reporting of all relevant clinical and epidemiologic data, disease severity and outcomes, and vaccination status, along with full implementation of HL7 messaging is needed so that CDC can receive the varicella data collected by jurisdictions and use those data to fully monitor the impact of the varicella vaccination program and guide future varicella vaccination policy."}
+{"text": "To describe the characteristics of the patients with tuberculosis (TB) requiring intensive care and to identify the factors associated with in-hospital mortality in an ICU in Portugal.A retrospective cohort study between January 2007 and July 2014 of all patients with TB admitted to the ICU of the Infectious Diseases Department of Centro Hospitalar de S\u00e3o Jo\u00e3o. Comorbid diagnoses, clinical features, radiological and laboratory investigations and outcomes were reviewed. The primary outcome was the in-hospital mortality. A univariate analysis was performed to identify risk factors for death.P < 0.05). There was no association between mortality and HIV status, site of TB disease, concomitant acute disease or development of hospital infections.During the study period, 40 patients with TB were admitted to the ICU; 75% male and median age of 52 years (IQR 37.5 to 62.8). Overall, 22 (55%) patients died in the hospital, of whom 16 (40%) died in the ICU. Comorbid illness was identified in 32 (80%) patients, with HIV infection being the most common, present in 15 (37.5%) patients. The main reason for ICU admission was respiratory failure (70%), followed by sepsis/septic shock (22.5%). Twenty-eight (70%) patients had isolated pulmonary disease, four (10%) had isolated extrapulmonary disease and eight (20%) had association of pulmonary and extrapulmonary disease. Mycobacterial cultures were positive in 31 (77.5%) patients; three patients presented monoresistant strains. Twenty-nine (72.5%) patients required mechanical ventilation and 21 (52.5%) required vasopressor infusion in the ICU; two patients were treated with ECMO. Thirty-four (85%) patients received antituberculosis therapy. The median length of stay was 11.5 (IQR 3.25 to 28.5) days in the ICU and 40.5 (IQR 21.0 to 62.8) days in the hospital. The presence of at least one comorbidity, smoking, age, sepsis/septic shock on admission, high SAPS II and APACHE II score, positive direct examination and PCR in respiratory samples, the need for mechanical ventilation or vasopressor infusion were significantly associated with mortality (In this cohort we found a high mortality rate in the TB patients requiring intensive care. The risk factors for mortality due to severe TB are mainly related to the severity of organ failure, patient characteristics and burden of disease and not to HIV status or site of TB disease."}
+{"text": "TTR) gene. Preimplantation genetic diagnosis (PGD) is currently one of the options available for couples at-risk to avoid disease transmission. The review the PGD cycles for TTR-FAP performed in the last 15 years in Portugal will be presented.Portuguese Familial Amyloidotic Polyneurophaty (FAP) (OMIM #105210) is a rare systemic amyloidosis characterized by a progressive, autonomic and sensory-motor neuropathy. FAP is an autosomal dominant disorder caused by mutations in the transthyretin . Interestingly, if only the cycles of paternal transmission were considered the ratio of normal versus mutated embryos was 1:1,03  whereas if the cycles of maternal transmission were analyzed the ratio of normal versus mutated embryos was 1:1,77 . One hundred and fifty-eight cycles had embryo transfer (mean embryo number = 1.7) leading to 57 biochemical (36%) and 50 clinical pregnancies (32%) . Three pregnancies correspond to frozen embryos transfers. Thirty-seven term pregnancies were singleton , 7 were twins  and one was a triplet pregnancy (two embryos transfer) .Two hundred and thirty-five clinical cycles were performed in 118 couples , with a mean number of 2 cycles per couple and a mean maternal age of 31.4 years old. The mean number of MII injected oocytes per cycle was 8.7. Fertilization and cleavage rates were 74.5% and 98.2%, respectively. Eighty-nine percent of embryos were biopsied (mean number = 5.8) and amplification was obtained in 94% with a ratio of normal PGD for Portuguese type TTR-FAP is a well established procedure allowing the birth of unaffected children with a take-home baby rate similar to the one described in the literature."}
+{"text": "Investigators from Cincinnati Children's Hospital, OH, analysed retrospectively the utility of screening brain/orbital MRIs in 826 children with NF1  seen over a 20-year period between 1990 and 2010. Investigators from Cincinnati Children's Hospital, OH, analysed retrospectively the utility of screening brain/orbital MRIs in 826 children with NF1  seen over a 20-year period between 1990 and 2010. Baseline MRIs of brain and orbits with and without contrast were obtained at 15 months of age or at the time NF1 diagnosis was made. Children identified with OPG were followed with repeat MRI every 3-6 months until OPG was stable. Other patients had annual eye exams and were seen by NF team. Optic pathway gliomas (OPGs) were identified in 18%, with a median age at detection of 3 years. Of 149 with OPGs, 96 (64.4%) were prechiasmatic, 42 (28.2%) chiasmatic, and 11 (7.4%) postchiasmatic; 22 (15%) had radiological or clinical progression requiring therapy. Chiasmatic and postchiasmatic tumors required therapy more frequently than prechiasmatic OPGs (P<0001). Patients with visual deficits at diagnosis (12/22) were more likely to have visual decline despite therapy when compared with patients treated based on radiologic progression (P<.012). Hypopituitarism (6/22) and precocious puberty (5/22) were common comorbidities of patients with chiasmatic and postchiasmatic OPGs and were not a feature of prechiasmatic tumors. Time to therapy after MRI diagnosis ranged from 0.2 and 5 years. Early identification of OPG by screening MRI before the development of vision loss may lead to improved visual outcomes. Children with negative brain and orbital MRI screening at age 15 months or later did not develop symptomatic OPGs. [COMMENTARY. Based on the results of this study the authors advocate the routine MRI screening of brain and orbits of children with NF1 , and is"}
+{"text": "Methotrexate (MTX), the disease modifying antirheumatic drug (DMARD) of first choice in juvenile idiopathic arthritis (JIA), is not effective in 45-50% of patients with polyarticular course JIA. In developed countries, when MTX fails, the next step is to start biologicals. In resource limited settings this step is constrained by prohibitive cost and children failing MTX run the risk of poor disease control or steroid overuse. There is paucity of data on use of other DMARDs or their combinations in such children. MTX and leflunomide (LEF) are known to have differing and complementary actions in modifying the immune response and this combination has been studied in adults. Their combined cost is a fraction of the cost of biologicals.To evaluate the benefits of addition of LEF in children with polyarticular course JIA, non-responsive to standard dose parenteral MTX.In an observational study, 32 children with polyarticular course JIA (JIA defined by modified ILAR criteria) failing standard dose MTX (up to 15 mg/m2/week sc for at least 3 and up to 6 months) received additional LEF (dosage by body weight). Permitted concomitant drugs included pulse steroids for flares and/or low bridging dose of prednisolone, intra-articular steroids and non-steroidal anti-inflammatory drugs. No other DMARDs were or had been used before enrolment. Patients were assessed once every 8-12 weeks. Parameters recorded at each visit included physician global assessment of disease activity, parent/patient assessment of overall well-being, functional ability, number of joints with active arthritis, number of joints with limited range of motion and laboratory parameters, viz., hemogram, ESR and liver enzymes. The primary efficacy outcome was the ACR Pedi 30 criteria. At the end of follow up, Wallace's criteria were used to determine the percentage of children achieving remission25 of the 32 children who followed up for at least 3 months were analysed. The mean follow up duration was 1.61 years (range-0.29 to 3.0 years). At 3 months, 68% of the patients met the ACR Pedi 30 response. 18 of the 21 children (85.7%) showed an ACR Pedi 30 response at 6 months. At 1 year, the percentage of ACR Pedi 30 response was 88.8% with good response rates seen using the ACR Pedi 50 (83.3%), ACR Pedi 70 (61.1%) and ACR Pedi 90 (50%) criteria. Of the 18 children who followed up till the end of the study, 12 (66.6%) met the ACR Pedi 30 criteria and 9(50%) were in clinical remission on medications (off steroids). Adverse effects were observed in 2 children (gastritis and elevated liver enzymes in one each). One child had macrophage activation syndrome temporally related to the introduction of LEF but it is difficult to comment on a causal relationship. Only 2 children among those failing the combination could afford biologicals, thus highlighting the need for such studies. Of the 7 children who were excluded from analysis,3 had developed hepatitis A and 4 had irregular visits.Our findings support the further study of the role of this combination in the management of polyarticular course JIA refractory to standard dose MTX, especially in resource challenged settings. The open observational nature of the study is its limitation.None declared."}
+{"text": "Hand hygiene (HH) is the single most important factor in the prevention of health care-acquired infections. Comprehensive monitoring of hand hygiene compliance is considered integral parts of a successful hospital infection control program. However, measuring adherence to hand hygiene guidelines is resource intensive and complicated by lack of standardized methodology.Our aim was to survey the methodologies used to measure hand hygiene guidelines across different Indian hospitals.The survey was conducted in person among infection control professionals working in different Indian hospitals (one per institution) using questionnaire developed based on WHO hand hygiene guidelines during their participation in international infection control conference held in India during the month of March 2015.Infection control professionals representing 26 Indian hospitals (different types) participated in the survey. In India HH was measured mainly due to quality imitative (11/26 42.30%) or part of accreditation (10/26 -38.46%) requirement. The ICPs monitor HH majority of the time (24/26 92.30%), they focus mainly on monitoring adherence to 5 HH moments (15/26 -57.69%) and monitor during the day time (22/26 -84.61%). Once in a month (12/26-46.15%) and direct observation 22/26 (84.61%) was the preferred mode of monitoring in India.Majority of Indian hospitals monitor compliance to HH guidelines, however comprehensive monitoring of all aspects of HH was missing in many of the hospitals. Clearly, further research to develop efficient, reliable, and comprehensive methods for monitoring hand hygiene compliance is urgently required in India.None declared."}
+{"text": "To determine the risk factors, management modalities, fetomaternal outcome of uterine rupture cases at University teaching hospital in Pakistan.This retrospective descriptive study was conducted at the Department of Gynaecology and Obstetrics Liaquat University of Medical and Health Sciences (LUMHS) for a period of one year from January 1st to December 31st 2012. Main outcome measures were frequency, age, parity, booking status, risk factors, management modalities, fetal and maternal mortality associated with uterine rupture. The data was collected on pre-designed proforma analysed using SPSS Version 16 statistical package.The frequency of ruptured uteri was calculated to be 0.67%, giving a ratio of 1:148 deliveries. Highest incidence was found in age group 25-30 (44.26%) with mean age of 30.36 years. and parity group 2-3 (57.37%) with mean parity 4.08. The risk factors for ruptured uterus include Caesarean section 43(70.49%), injudicious use of oxytocin 33(54.09%), obstructed labour 15 (24.59%) and multiparty 18 (29.50%). Repair of uterus was performed in 47(77.04%) cases. Maternal case fatality was 5(8.19%), while foetal wastage was 51 (83.60%).This study confirms the existence of a serious preventable obstetric problem, with significant maternal mortality and foetal wastage. Integrated efforts include Health education, focused antenatal care, skilled attendance, avoidance of injudicious use of oxytocin, and need of hospital based deliveries in patients with caesarean section which should be intensified to reduce this drastic obstetrical complication. Uterine Ruture is a castrotrophic event with a significant effect on the reproductive function of the women and associated with high rates of fetal and maternal morbidity.1In WHO systemic review of uterine rupture the incidence of rupture in general population was 5.3/10,000 birth. In Neitherland it was 5.9/10,000 deliveries.4Several direct and indirect factors have increased the risk of uterine rupture. These include wide spread poverty, illiteracy, cultural constrants7This obstetric event is closely associated with maternal morbidities such as bladder rupture, vesicovaginal and rectovaginal fistula, foot drop and psychological trauma, anaemia and in long term because of surgical intervention the women may be sterilized which can lead to divorce and loss of economic support, showing that the magnitude of this obstetric complication is enormous.8Uterine Ruture has the unique potential to impact negatively on Millennium Development Goals 4 and 5, that is to reduce perinatal and maternal mortality. This study aimed at establishing the incidence of uterine rupture, predisposing factors and changing trends in our areas, maternal and perinatal outcomes, management modalities at regional referred university hospital. Further review of this problem may be helpful in the development of appropriate preventive strategies, and to reduce such grave obstetrical complication.A one year retrospective analysis of uterine rupture case records was performed at the Department of Gynaecology and Obstetrics Liaquat University hospital LUMHS from January 2012 to December 2012.In this series, complete uterine rupture is defined as a full thickness separation of uterine wall and the overlying serosa. Cases of scar dehiscence constitutes separation of pre-existing scar that does not disrupt the overlying visceral peritoneum.The clinical records of all patients were reviewed with regard to sociodemographic and reproductive parameters including age, parity, booking status, associated risk factors, management modalities, fetal and maternal mortality.The surgical management comprised one of the three methods repair of uterus with tubal ligation, repair of uterus without tubal ligation, or hysterectomy. All patients were followed up until their discharge from hospital.The data was collected on pre-designed proforma and analyzed by using SPSS Version 16 statistical package. Descriptive statistics were used for demographic data and summarized as means with standard deviation or frequency with percentage.The total maternity admissions were 10,004 with 9072 deliveries. The frequency of ruptured uteri was calculated to be 0.67%, giving a ratio of 1: 148 deliveries. Forty three (70.49%) of the patients had scarred uterus and eighteen (29.50%) had unscarred uterus giving a scarred to unscarred uterus ratio of 2.3:1. Out of them 48(78.68%) did not receive any antenatal care, while 13 (21.31%) patients were booked.Mean age was 30.36\u00b1SD4.6 years, with the majority of cases 35(57.37%) aged 25-30 years. The mean parity was 4.08\u00b12.8. Most of women were multipara or grand multipara 35 (57.37%), 18(29.50%) respectively. The gestational age of occurrence ranged from 26-40 weeks with a mean of 37\u00b12.4 weeks. The most important etiologic and predisposing factors were, injudicious use of oxytocin 33(54.09%), obstructed labour 15(24.59%), grand multiparty 18(29.50%), and previous uterine surgery due to caesarean section in 43(70.49%) of patients. The uterine rupture was classified as complete in 32(52.45%) patients and incomplete in 29(47.54%) patients according to the surgical findings. fifty eight (95.08%) patients of the uterine rupture occurred outside the teaching hospital, mainly referred cases from primary 48(78.68%) and secondary health care levels or at local clinics 10(16.39%). Only three (4.91%) patients delivered at our centre.Management was divided according to the type of rupture, parity and condition of the patient. Commonest surgical procedure carried out was uterine repair 47(77.04%), tubal ligation along with repair was done in 16(26.22%) patients. Hysterectomy was performed in 14(22.95%) cases. Two patients (3.27%) needed bladder repair along with hysterectomy.All patients were anaemic, 18(29.50%) patients had severe anaemia (Hb<7g/dl), while 43(70.49%) patients were moderately anaemic (7-10g/dl). All patients needed blood transfusion as part of their intraoperative or postoperative management and mean blood volume transfused was 2.4\u00b10.88 units. Only 8(13.1%) patient required single blood transfusion, while 28(45.90%), 17(27.86%), 8(13.11%) patients required two, three, and four units of blood transfusion respectively.The average postoperative hospital stay was 8.49\u00b12.99 (4-14) days. Majority 51(83.60%) stayed for 8-10 days in hospital, while 8(13.11%) patients stayed for 7 days and 2(3.27%) patients stayed for 14 days.Maternal case fatality was 5(8.19%). Out of them two mothers died due to massive irreversible shock (one going in to DIC), while three patients died due to sepsis. The fetal outcome was poor. The total foetal wastage was 51 (83.60%). There were 34(66.66%) fresh intrauterine death (still birth), and 17(33.33%) old macerated intrauterine death giving overall perinatal mortality was 51 (83.60%). Live birth rate was 10(16.39%) only.Rupture Uterus (RU) is one of most devastating complication and is an index of failure of obstetric care at a point in time in a women reproductive carrier with dire fetomaternal consequences.9Worldwide the reported incidence of this preventable complication has been varied from 2.6 to 0.006% depending upon obstetric services and standards provided in that region.13The incidence of UR in this study was contributed largely by unbooked cases which constituted about 78.68% of patients, as the institution is a referral centre, and received majority of patients in a serious condition which contributes to high mortality. The occurrences of uterine rupture among mostly unbooked patient have also been noted in other studies.6The commonest age of occurrence of uterine rupture in our study was 25-30 years with a mean age 30.3\u00b14.6 years, concordance with the mean age 30.8\u00b1-6.3 years reported Mbamara from Nigeria, while commonest age range of occurrence was 30-34 years.15Like in other studies scarred uterus, prolonged obstructed labour and injudicious use of oxytocics are the major risk factors identified in this study.In this study obstructed labour was the most common factor for rupture of uterus found in 15(24.59%) patients with non scarred uterus 18 (29.50%). Partograph is an important tool to detect deviation from normal labour, and early referral helps in prevention of such castrotrophe. Implementation of proper use of partograph in health setting at all levels is crucial.In current study management of patients was dependant upon type and extent of uterine rupture, degree of haemorrhage, general condition of mother, mothers\u2019 drive for future fertility. Uterine repair with or without tubal ligation performed in (77.04%) patients, may be justifiable because it was easiest and fastest procedure for surgeon. It may also be pointed that fair number of woman\u2019s\u2019 are in early part of reproductive carrier and wants to maintain their reproductive capability as loss of uterus is usually considered as loss of women hood in our society, with grave socio-cultural consequences and results in increased incidence of marriage breakdown with social trauma.Hysterectomy was carried out in 22.95% of cases. Rupture uterus was noted as most common indication for emergency hysterectomy in many studies like Bushra and Shah NIlliteracy, ignorance, poverty, lack of antenatal care, poor access to maternal health services are all contributing factors. Besides this there is tremendious rise in private practitioners with minimal skill in the area as a result mishandling and delayed referral has resulted in increased morbidity and mortality. Restructuring the health system to ensure seamless communication between tertiary centres and the referring facilities is needed.In our study all patients were anaemic and mean blood volume transfused was 2.4\u00b18.8 units, while MehmetIn this study maternal case fatality of 5(8.19%) recorded is similar to coffie (9.8%).This trend if not checked will jeopardize the realization millennium development goal (MGD) 4 and 5, which seek to reduce the maternal and perinatal mortality respectively. Widespread presence of obstetric care centres with adequate health facilities along with law regulating the practice of obstetric by defining who and where and minimum standards required should be regulated. As these measures will reduce if not eliminate the cases of rupture uterus.The present study was conducted with objectives to find out the frequency of uterine rupture, predisposing factors and changing trends in our areas, maternal and perinatal outcomes, management modalities at regional referred university hospital. Further review of this problem may be helpful in the development of appropriate preventive strategies, and to reduce such grave obstetrical complication.This study reveals that there is still a high prevalence of rupture uterus. The observed risk factors for uterine rupture in this study are preventable. Although the etiological profile has changed from obstructed labour to scarred uterus which is now the leading cause of uterine rupture and can be reduced by decreasing the rate of caesarean section by proper selection of patients. Health education, Awareness about sign and symptoms of rupture uterus, high index of suspicion, councelling about need of timely booking and skilled attendance, importance of institutional deliveries especially of those with previous caesarean section, are important factors for reducing maternal morbidity and mortality associated with uterine rupture."}
+{"text": "Systemic lupus erythematosus (SLE) is a disease of autoinmune origin that may involve numerous internal organs of the body. It is associated with high cardiovascular morbility and mortality. The cardiovascular magnetic resonance (CMR) provides us with a global evaluation of patients with active SLE and clinical suspicion of acute myocarditis. OBJETIVES The aim of study was the identification of cardiac alterations in patients with active SLE and clinical suspicion of acute myocarditis.A total of twenty - eight patients were included in the study, with an average age of 30.7 years ( SD 12.7 yrs), 96% female, diagnosed by criteria of American College or Rheumatology (ACR). Cardiovascular magnetic resonance (CMR) was performed on a 1.5 T scanner and include the following sequences: steady- state free precession, STIR T2 weighted (Ts-2W), T1- Weighted spin - echo before and after gadolinium injection and late enhancement.The ejection fraction of left ventricle < 50% was found in 54%, 83.4 % with contractility alterations, 87.5% with valvulitis and affection of the subvalvular apparatus in 50%, pericardial effusion was observed in 62.5% and tissue characterization suggestive of myocarditis for the Lake Louise criteria were found to have global and relative enhancement in 37.7 and 50 % respectively and late gadolinium enhancement (LGE) in 66.7%.In our study group we found that patients with acute myocarditis asoociated with SLE have a high incidence of valvulitis and affection of the subvalvar apparatus."}
+{"text": "Health systems face challenges of improving access to health services due to rising health care costs. Innovative services such as day surgery would improve service delivery. Day surgery is a concept where patients are admitted for surgical procedures and discharged the same day. Though used widely in developed countries due to its advantages, utilization in developing countries has been low. This study sought to establish how utilization of day surgery services was influenced by medical providers, patient awareness and cost among other factors.The study design was cross sectional with self administered questionnaires used to collect data. Data analysis was done by using statistical package for social science (SPSS) and presented as frequencies, percentages and Spearman's correlation to establish relationship among variables.Medical providers included doctors, their employees and medical insurance providers. Most doctors were aware of day surgery services but their frequency of utilization was low. Furthermore, medical insurance providers approved only half of the requests for day surgery. Doctors\u2019 employees were aware of the services and most of them would recommend it to patients. Although, most patients were not aware of day surgery services those who were aware would prefer day surgery to in patient. Moreover, doctors and medical insurance providers considered day surgery to be cheaper than in patient.The study showed that medical providers and patient awareness had influence over day surgery utilization, though, cost alone did not influence day surgery utilization but as a combination with other factors. The health system environment is continuously evolving to meet new health challenges. Escalating health care costs and increase in demand for health services are some of the issues hampering access to health services worldwide. The concept of Day surgery has been implemented in developed countries to reduce the cost of surgery and improve access to health services . Day surIn Kenya, most private hospitals perform day surgery procedures using the same theatres and recovery wards as inpatients instead of designated Day Surgery Units. The first Integrated DSU was set up at the Nairobi hospital in 1998 but has since changed into a short stay facility that accommodates patients for forty eight hours. Upper Hill Medical Centre Day Surgery Unit was the first stand-alone DSU set up in October 2002 and the trend is being emulated. In spite of the minimal literature on existence of DSU's, they are known to provide support to the Kenyan health system . Day surThe study was done at Upper Hill Medical Centre doctor's offices, the Karen Hospital surgical clinics, offices of medical insurance providers and doctors\u2019 clinics in Nairobi, Kenya. The study design was cross-sectional with data being collected at a point in time. The target population included 44 case managers from medical insurances and representatives in companies offering outpatient medical insurance to patients at UHMC and Karen Hospitals; all doctors in Nairobi (2090) from various specialties were targeted to reduce bias; (43) doctors\u2019 employees and (6640) patients from outpatient surgical clinics at Karen Hospital and doctors\u2019 clinics at UpperHill Medical Centre. Cluster sampling was used to determine doctors\u2019 population, stratified sampling to group doctors into various specialties and convenience sampling to identify respondents from the list. Random sampling was used to select patients and doctors\u2019 employees, while, stratified sampling was used for MIPs. All the total of 753 out of 803 sampled responded. Self-administered questionnaires were used to collect the data which took three months. The questionnaires were written in simple language and had standardized questions developed in relation to the objectives. Ethical approval was obtained from Kenya Methodist University's Institutional Research and Ethics Committee (IREC); Ethical committees of Upper Hill Medical Centre and Karen Hospital. Data was analysed as frequencies and percentages. Spearman's correlation was applied to establish relationships among variables and cross tabulation of descriptive data was also done using statistical package for social science (SPSS).Medical providers included doctors, medical insurance providers and doctors\u2019 employees.Doctors were divided into General practitioners (GPs), surgeons and anaesthetists. The study revealed that 195(98.5%) GPs were aware of the services while, 89(92.7%) surgeons and 10(100%) anaesthetists had used the services. Furthermore, 178 (89.9%) GPs were seen to refer patients while only 20 (10.1%) did not. However, most surgeons 51(61.5%) and anaesthetists 5(50%) used day surgery only once a week; 31(32.3%) surgeons and 2(20%) anaesthetist 2-3 times a week; 5(5.2%) surgeons and 2(20%) anaesthetists 4-10 times a week and only 1(1%) surgeon and 1(10%) anaesthetist used the services more than 10 times a week. Patient safety at home, pain control and risk of complications were some of the disadvantages that would discourage utilization; all the doctors were not deterred from using day surgery because of the specific disadvantages. Neither the anaesthetists nor GPs would refuse to use day surgery because of pain though, 3(1.5%) of GPs would be reluctant due to risk of complications. However, when the factors were combined 8(80%) anaesthetists, 93(96.9%) surgeons and 191(96.5%) GPs would be reluctant to use day surgery . FactorsMost providers had existed for more than 10years 25(80.6%) compared to 3(9.7%) who had been there between 3-5years and 1(3.2%) for less than 2years. In spite of the long existence for majority of providers only 15(48.4%) of the requested day surgery procedures were approved mainly due to a combination of factors. Individual factors had minimal influence as type of procedure determined only 1(3.2%) approval and lower costs 2(6.5%), though, company policy influenced the decision to approve most 13(41.9%) requests. However, approvals are also influenced by insurance providers 1(3.2%), patients 2(6.5%) and doctors 16(51.6%), while a combination of insurance providers, patients and doctors would influence 12(38.7%) of MIPs to give approval. Amount of money approved for procedures is mainly determined by complexity of procedure 23 (74.2%) but not by doctors fees 3(9.7%) or combined factors 5(16.1%). MIPs would not be discouraged from approving day surgery because of disadvantages such as pain control 1(3.2%); risk of complications 15(16.1%); patient's general condition 1(3.2%) and capacity of medical centre 1(3.2%) but when the factors are combined it would discourage 23(74.2%) of providers. Moreover, factors discouraging utilization would influence approval of day surgery service with p value of 0.426. Medical insurance providers would rather educate surgeons 13(41.9%), than give incentives (19.4%), dictate terms 2(6.5%) or a combination of the factors 10(32.3%) in order to encourage utilization of day surgery services. Spearman's correlation results reveal that determinants are influenced by motivation factors with a p value of 0.396 and approval of day surgery with a p of 0.359. Consequently, utilization of day surgery services may add value to patients and MIPs. According to 1(3.2%) of respondents it would reduce premiums for patients; improve access of healthcare services 17(54.8%); increase number of insured patients 1(3.2%); increase profits for companies 3(9.7%) while, a combination of the factors would influence 9(29%) of respondents. Opinion of MIPs on day surgery would influence approval significantly with a p- 0.360; while individuals influencing day surgery may be influenced by motivation factors p-0.481 .These were nurses 18(39.1%), Secretaries 19 (41.3%); other support staff 9(19.6%). Most of them 45(97.8%) have heard of day surgery services, while only 1(2.2%) has not heard and their main source of information are the doctors 38(82.6%) while others are friends 5(10.9%), newsletter 3(6.5%). Due to the awareness of day surgery services 43(93.5%) of doctors\u2019 employees would recommend the services to patients, however, some of them would be discouraged to use day surgery due to challenges of taking care of operated site at home 2(4.3%); pain at home 3(6.5%); fear of developing complications 33(71.7%), while the three factors combined would only discourage 8(17.4%) of the doctors\u2019 employees. Most doctors\u2019 employees 33(71.7%) are motivated to use day surgery due to reduced cost, recovery at home and early return to work as a combination of factors. While, spearman's correlation results reveal that duration of service of doctors\u2019 employees would influence their referral habits with a high significance of 99.68%; as well as factors that encourage utilization which is significant with a p- value of 0.350.According to the results, 265(69%) of patients have heard of day surgery and 119(31%) have not, while, 270(70.3%) would opt to use day surgery and 114(29.7%) would opt for inpatient services. Though, 346(90.1%) of patients would recommend day surgery services to others. Most patients 175 (45.6%) would suggest to their doctor about day surgery; while, 6 (1.6%) will suggest to the insurance; 146 (38%) to both the doctor and insurance and only 57 (14.8%) would keep quiet. Although, results from MIPs reveal that only 2(6.5%) of patients would influence MIPs to use day surgery while 16 (51.6%) of doctors would influence the MIPs .According to 88(91.7%) of doctors and 28(90.3%) of MIPs day surgery services are cheaper than in patient while, 2(6.5%) of MIPs and 6(6.3%) of doctors say the costs are similar to inpatient and 1(3.2%) of MIP and 2(2.15) of doctors consider day surgery more expensive than in patient. Medical insurance providers had the authority to decide whether to allocate day surgery services under patients\u2019 inpatient or outpatient cover. This study revealed that most approvals 17(54.8%) were done under outpatient cover rather than inpatient 14(45.2%). Among doctors 79 (82.3%) preferred fee for service against 2(6.5%) MIPs while 28(90.3%) MIPs preferred discounted fee for service which was only supported by 16(16.7%) doctors . PatientThe The role of medical providers from the study indicated that the doctors were aware of day surgery services, which is contrary to previous studies showing that most countries especially in Africa are still struggling with creating awareness among doctors . PopularDoctors were aware of day surgery services though they rarely used the services, while medical insurance providers were not approving most requests for day surgery procedures. Most patients were not aware of day surgery services but those who were aware would consider using day surgery rather than in patient services while, lower cost of day surgery services on its own did not influence doctors and medical insurance providers to use day surgery. Medical providers and patient awareness had an influence on utilization of day surgery services. Cost on its own did not influence utilization of day surgery services but in combination with other factors. The study recommends education to all medical providers on day surgery and need for a policy to guide medical insurance provider on utilization of day surgery services. Educating medical insurance providers on the cost saving aspect of day surgery as opposed to inpatient and improving patient awareness on benefits of day surgery to increase utilization of the services."}
+{"text": "In the intensive care unit (ICU) the need for acute renal replacement therapy (aRRT) is associated with high mortality and risk of end-stage renal disease (ESRD). We investigated long term mortality and progression to ESRD in ICU patients requiring aRRT and factors associated to these.Retrospective analysis of all adult patients admitted to the general ICU, Rigshospitalet, from 1/1-2005 to 31/12-2012, identified through the ICU database, excluding chronic dialysis patients. ESRD was defined as the need of dialysis >90 days or kidney transplant.Of 5766 patients included, 931 (16%) received aRRT, 4762 (83%) did not receive any RRT and 73 (1%) only received aRRT during a later ICU admission. The 90-day mortality was 55% for aRRT patients and 22% for those not requiring aRRT (p < 0.001). The median (IQR) age was 61 (49 - 68) for aRRT 90-day survivors and 65 (55 - 73) for aRRT non-survivors (p < 0.001). The median SAPS II score was 53 (43 - 64) for aRRT 90-day survivors and 61 (49 - 74) for aRRT non-survivors (p < 0.001). Characteristics of aRRT patients developing ESRD and those that did not, are displayed in tables The aRRT patients surviving 90 days were younger and less severely ill at ICU admission as compared to the non-survivors. The survivors developing ESRD had more frequently preexisting chronic kidney disease and higher APACHE II scores as compared to those who did not develop ESRD. aRRT patients had increased risk of ESRD up to 7 years after ICU admission, emphasizing the KDIGO recommendations to follow up AKI patients due to their increased risk for CKD."}
+{"text": "We describe results in unresectable pancreatic tumors treated with USgHIFU hyperthermia ablation plus adjuvant chemotherapy.Forty three cases of non resectable pancreatic tumors were treated from March 2010 to March 2013, and all of them underwent systemic chemotherapy. Clinical responses  were measured by image techniques. They were 29 Stage III cases and 14 Stage IV cases. Complications were also analyzed.Clinical responses (ablation obtained) were 82% in all cases, sustained at 8 weeks of the procedure. We obtained 10 complete responses (25%) at the end of the combined treatment, 9 from stage III patients and 2 from stage IV. Major complications included severe pancreatitis with GI bleeding (1), skin burning grade III that required plastic surgery (2). No deaths were registered. Median Survival was 13 month (6 mo - 2.7 year).HIFU plus SC is a potentially effective and safe modality for the treatment of unresectable pancreatic cancer."}
+{"text": "HEXA gene), Sandhoff disease(SD) (HEXB gene), Gaucher disease (GD) (GBA gene), GM1 gangliosidosis (GG) (GLB1 gene), metachromatic leukodystrophy (MLD) (ARSA gene), and Pompe disease (PD) (GAA gene).Lysosomal Storage Diseases(LSD) are a group of rare recessive inherited metabolic disorders that result from the deficiency of a single enzyme required for the metabolism of lipids, glycoproteins or mucopolysaccharides. There is a lack of data on molecular basis of LSDs in India . The current study involves molecular analysis of patients with Tay Sachs disease(TSD)  followed by sequencing of the respective gene. Enzyme assays performed include total hexosaminidase and hexosaminidase B (TSD and SD), glucocerebrosidase (GD), beta galactosidase (GG), arylsulphatase A (MLD) and alpha glucosidase (PD). The molecular basis of disease in patients with enzyme deficiency was confirmed by bidirectional Sanger sequencing covering all the exons and exon-intron boundaries of the respective genes.During the study period, 131 unrelated families across India were studied. These included 47 families of TSD, 36 families with SD, 15 families with GD, 8 families with GG, 15 families with MLD, and 10 families with PD. Ninety two families (70. 2 %) families showed consanguinity. The age range for patients was between 3 months to 7 years; however, one patient with PD was adult (21 years). The youngest patient had PD. The study identified 218 mutant alleles in 119 patients. Only ten alleles were recurrent. Founder mutation was identified in TSD patients from Gujarat (p.E462V) which will help screening in patients from this state. Also in SD, the mutation hotspot R284X represented 23.3 % of alleles (7/30). No mutations could be identified in 12 patients and the second mutation could not be identified in 10 patients, despite being biochemically confirmed.The study shows allelic heterogeneity in Indian patients with LSDs. A molecular screening strategy for the common mutations could be adopted for TSD and SD patients."}
+{"text": "Algeria has a low HIV prevalence and data on the risk factors and clinical presentation of HIV-infected children are lacking.To describe the epidemiological, clinical characteristics and outcome of HIV-infected children in Setif.A retrospective review was undertaken of the medical records of all patients admitted to the HIV unit of the teaching hospital of Setif which serves a population from a wide geographic catchment area, between January 2002 and November 2013.Of 286HIV-infected patients, 12 were children (4.1%), 8 (66.7%) of whom were male. Ages at diagnosis ranged from 6 months to 12 years (median 5).Of the 10 (83.3%) children who acquired the infection by vertical transmission, median age at diagnosis was 3 years. Only one woman was offered PMTCT interventions with HAART started lately at 38 weeks of pregnancy, oral AZT and replacement feeding to neonate.All neonates were delivered by spontaneous vaginal delivery, 9 of them were breastfed throughout infancy.Children commonly presented with prolonged fever (25%), recurrent cough (n=33.3 %), failure to thrive (n=41.66 %) and recurrent diarrhoea (n=8.3%). One case had tuberculosis associated to herpes zoster, 2 cases of moluscum contagiosum, one case of anal condyloma and one case of visceral leishmaniosis. All cases received highly active antiretroviral. Of those 91.6% were compliant with treatment and had a sustained virologic response below the detectable levels. One child died at age of 6 months.The majority of HIV-infected children presenting to our hospital acquired HIV through vertical transmission. A strong prima facie case for the introduction of mandatory HIV testing of pregnant women must be made because the price paid by HIV-infected newborns for their mothers\u2019 failure to undergo testing and treatment is very high."}
+{"text": "Methotrexate (MTX) is the agent of first choice for the treatment of children with Juvenile Idiopathic Arthritis (JIA). Leflunomide (LFN) has demonstrated to be an effective alternative to MTX. There is a lack of evidence regarding the advantages of combined treatment of MTX plus LFN in JIA.To evaluate the safety and effectiveness of the combined therapy with Methotrexate (MTX) and Leflunomide (LFN) in patients with Juvenile Idiopathic Arthritis (JIA) in clinical practice.We conducted a retrospective descriptive study of patients with JIA visited in a single Unit of Pediatric Rheumatology who had been treated with the combination of MTX plus LFN. All patients were classified according to the International League of Associations for Rheumatology (ILAR) criteria. Included data were: demographics, JIA subtype, reason for starting combined treatment, time on treatment, withdrawals, causes of discontinuation, efficacy and safety (both assessed at baseline and every 6 months during 2 years of treatment). Safety was evaluated analyzing adverse events (AE) based on clinical and physical findings and laboratory values. Ocular effectiveness was assessed grading uveitis according to the Standardization of Uveitis Nomenclature Working Group (SUN) recommendations. Articular effectiveness was assessed by means of: pediatric core set variables with exception of C-HAQ, Protein-C-reactive, JADAS scores 10, 27 and 71, and applying the criteria of minimal disease activity, 30% improvement, inactivity and remission.Nineteen patients  were included: 12 oligoarthritis (63%), 4 polyarthritis (21%), 2 psoriatic arthritis (11%) and 1 undifferentiated arthritis (5%). The mean age at diagnosis was 57 months (4.75 years \u00b1 3.65) and at initiation of combined treatment was 112 months (9.37 years \u00b1 4.12).The mean duration of MTX+LFN treatment was 28.6 months \u00b1 31.6 (range 5-144). An improvement was observed in each variable studied. JADAS scores had improved a 60% at last follow up compared to the baseline. The best rates of improvement were observed at 18 months of treatment: 91.7% improved at least 30%, 83.3% met criteria for minimal disease activity, 83.3% for inactivity and 66.7% for clinical remission. Eight children had uveitis and all of them were in clinical remission according to the SUN criteria at last follow up. Overall, 28 AE were reported. There were no serious AE. The most frequently reported AE was upper respiratory tract infection. One of the two DMARD was stopped in 11 patients (58%) due to AE in 4 children, inefficacy or loss of efficacy in 3 and clinical remission in 4. Gastrointestinal intolerance was the more common cause of discontinuation of one of the two DMARD. Among patients who withdrew the combined treatment 4 switched to anti-TNF therapy and 7 continued monotherapy with MTX or LFN. Eight children are still on MTX plus LFN.In our patients with JIA the combined therapy of MTX plus LFN was well-tolerated and proved to be effective. Most of the patients experienced a substantial improvement either articular or ocular. AE were generally mild. LFN plus MTX could be a safe and effective alternative for patients with JIA who do not respond to MTX or LFN in monotherapy.None declared."}
+{"text": "To determine the frequency of phantom limb sensation (PLS) and phantom limb pain (PLP) in children and young adults suffering landmine-related amputation.All youths with amputation due to landmine explosions participated in this study. The proportions of patients with phantom limb sensation/pain, intensity and frequency of pain were reported. Chi square test was used to examine the relationship between variables. Comparison of PLP and PLS between upper and lower amputation was done by unpaired t-test.There were 38 male and 3 female with the mean age of 15.8\u00b12.4yr. The mean interval between injury and follow-up was 90.7\u00b139.6 months. Twelve (44.4%) upper limb amputees and 11 (26.8%) lower limb amputees had PLS. Nine (33.3%) upper limb amputees and 7 (17.1%) lower limb amputees experienced PLP. Of 27 upper limb amputees, 6 (14.6%) and among 15 lower limb amputees, 6 (14.6%) had both PLS and PLP. One case suffered amputation of upper and lower limbs and was experiencing PLS and PLP in both parts. PLS had a significant difference between the upper and lower amputated groups. Significant relationship was observed between age of casualty and duration of injury with PLP.Phantom limb sensation and pain in young survivors of landmine explosions appear to be common, even years after amputation. Following amputation, individuals usually perceive pain in their missing limb. Phantom limb sensation (PLS) is feeling of a lost body part after traumatic injuries . It is oObservations were made on whole of 41 survivors less than 18 yr old who had suffered amputation caused by landmine explosion in Iran. The study conducted by Janbazan Medical and Engineering Research Center (JMERC) of Iran, evaluated the prevalence of PLP among adolescents and children with amputations. All have been affected by landmines and UXO after armistice of Iran-Iraq war in 1988. The study group reported the intensity of their pain or pain level at presentation, using the verbal descriptor scale (VDS) included \u201cleast possible pain\u201d and \u201cworst possible pain\u201d. Follow-up were assessed at least 36 and maximum 180 months after amputation. Moreover, demographic information obtained from the direct interview included age, sex, age of amputation, duration of injury, living area and type of activity at explosion time. Pain specialist directly examined all subjects. Cases were included if they had any type of amputations in upper and lower limbs or both. If pain was present, the location, severity and persistency would be asked. Statistical analyses were performed using SPSS 22.0 . Data are expressed as means (SD) or numbers and percentage. The proportion of patients with PLS and PLP was reported. Relationship between variables was evaluated using chi-square test. Unpaired t-test (two tailed) was employed for comparison of PLP and PLS between upper and lower amputated subjects. A P value < 0.05 considered statistically significant.\u2003By the time of study, 41 amputees less than 18 yr old, consisted of 38 males (92.7%) and 3 females (7.3%), were identified. Twenty six (63.4%) had only upper limb amputation, 14 (34.2%) had only lower limb amputation and one (2.4%) had both. Three cases had bilateral upper limb amputation and one had bilateral lower limb amputation. Thus, there were 30 upper limb amputations and 16 lower limb amputations (27 subjects had upper limb amputations and 15 had lower limb amputations). Finger level (31.7%) and below the knee (17.1%) were the most common upper and lower limb amputations, respectively. Amputated limbs are listed in Considering our purpose to determine the incidence of phantom limb phenomena among youth amputees who had undergone amputations due to landmine explosions, all of Iranian survivors less than eighteen years included in this study. Similar to many affected countries that more than half of the civilian victims and more than four fifth of child casualties of mine explosions areboys, almost all of participants were male . About tOf the half of subjects who complained of discomforting PLP, only a quarter was incurred upper limb amputation and rest of them had lower limb amputation. Despite current discussion, there have been limited research focused on the subject of PLP and PLS inchildren and adolescents , 25-27. In conclusion, phantom phenomena can be experienced by more than one-third of landmine young survivors. We make suggestions for future studies concerning the control and treat phantom pain in children and adolescents amputees."}
+{"text": "Acute viral (RSV and non-RSV) pneumonia is one of the most common causes of lower respiratory tract infection in infants and children. Although only 2 to 3% of infants with bronchiolitis require hospitalized management based on published literature, in recent years we see more children requiring hospitalization in high-dependency units. Most of these children require intravenous fluid therapy and some form of oxygen supplementation. As there is no standardized evidence-based parenteral fluid therapy protocol specific for acute severe viral pneumonia available, we decided to retrospectively analyze the result of our restrictive fluid therapy protocol.All children less than 5 years age admitted to our PICU from June 2013 to December 2013 with etiological evaluation confirmed acute severe viral (RSV and non-RSV) pneumonia who received a minimum 48 hours of parenteral fluid therapy were enrolled and the data retrieved from the case sheet. The data analyzed were duration of PICU stay, hospital stay, oxygen therapy requirement, duration of oxygen therapy and their relationship to fluid balance on restrictive fluid regimen.P = 0.45) or the duration of ventilation (P = 0.60). Fluid balance in the first 72 hours correlated positively with change in serum sodium levels indicating a fall in sodium levels with more positive fluid balance (Spearman coefficient of 0.452 (P = 0.16)). There was no significant correlation between fluid balance and duration of PICU/hospital stay (P = 0.58/0.75). eGFR calculated using modified Schwartz formula did not correlate with treatment parameters like duration of ICU/hospital stay, mechanical ventilation, and CPAP.A total of 32 children met the criteria for inclusion in the study period, 23 boys (71.9%) and nine girls (28.1%). The median age of children was 9.5 months (IQR 3.3 to 27.3). Of 32 children, 4/32 (12.5%) required invasive mechanical ventilation; 5/32 (15.6%) required NP-CPAP; 12/32 (37.5%) were on HHFNC; and nasal prong oxygen supplementation in 26 (81.3%) children. The median duration of ICU stay was 68.9 hours (IQR 39.2 to 80.2), that of hospital stay was 116.5 (IQR 92 to 179.2). Fluid balance at the end of 72 hours of ICU stay did not significantly differ the need for ventilation  parenteral fluid therapy. eGFR at admission did not influence the fluid balance when they were uniformly initiated on restrictive parenteral fluids. Further studies with calculated sample size may help to confirm the observations."}
+{"text": "Treatment of specific patterns of symptomatic hydrocephalus in the adult patient may be accomplished with endoscopic third ventriculostomy (ETV) as an alternative to insertion of a ventriculoperitoneal (VP) shunt or when VP shunt failure occurs. Treatment of hydrocephalus with a VP shunt, while effective, is associated with a significant shunt failure rate that results in VP shunt revision surgery. This review examines a single center experience with ETV to treat hydrocephalus in symptomatic adult patients.Adult patients (>/=18 years) with a diagnosis of hydrocephalus who were treated with ETV in Calgary between January 1994 and July 2014 were reviewed using a clinic database and registry. All patients were treated by one neurosurgeon.163 adult patients with symptomatic hydrocephalus treated with ETV were identified . Mean age at the time of ETV was 46 years (range 18-83 years). 112 underwent ETV as a primary treatment and 51 patients underwent treatment after presenting with VP shunt failure (secondary ETV). 113/163 patients had a diagnosis of aqueductal stenosis, 22/163 had a diagnosis of tumor. Mean followup was 8.2 years (range 0.3-18.4 years). Symptoms in 149/163 (91.4%) of ETV patients were better or unchanged at last followup. 104/118 (88.1%) of primary ETV patients were shunt free at last followup. 39/45 (86.7%) of secondary ETV patients were shunt free at last followup.Endoscopic (ETV) treatment of hydrocephalus is an effective longterm treatment in a select population adult patients with hydrocephalus. Outcome/results are similar for patients where ETV is used as either a primary or secondary treatment. 87-88% of patients remain shunt free with a mean 8.2 years of followup.1) To understand the role of ETV for primary treatment of hydrocephalus in the adult patient.2) To understand the role of ETV for secondary treatment of hydrocephalus in the adult patient."}
+{"text": "Protective mechanical ventilation has been associated with lower incidence of pulmonary and extrapulmonary complications in major surgery. The aim of the present study is evaluate whether adding an intensive alveolar recruitment protocol improves clinical outcomes and reduces healthcare utilization in patients undergoing cardiac surgery.2/FIO2 <250 at a PEEP of 5 cmH2O) in the immediate postoperative period to either intensive alveolar recruitment or a standard protocol, both using low-tidal volume ventilation (6 ml/kg/ibw). Our hypothesis was that an aggressive alveolar recruitment protocol will be translated to better lung compliance, better gas exchange, fewer pulmonary complications and reduced length of hospital stay when compared with the control group.In this single-center, parallel-group trial, we randomly assigned adult patients presenting signals of deficient gas exchange (PaOP = 0.004). The length of the hospital stay was shorter among patients receiving intensive alveolar recruitment than among those receiving standard care (10.9 (9.9 to 11.9) vs. 12.4 days (11.3 to 13.6); P = 0.045). There was no difference between groups according to extrapulmonary complications and mortality.A total of 320 patients were enrolled in the study, 163 patients in the standard protocol group and 157 in the intensive alveolar recruitment group. Patients of the interventional group presented a higher incidence of pneumonia than patients for the control group (5 (3.3%) vs. 19 (22%), In this trial, an intensive alveolar recruitment protocol associated with a protective mechanical ventilation strategy reduced pulmonary complication and length of hospital stay in patients undergoing cardiac surgery (NCT01502332)."}
+{"text": "Juvenile idiopathic arthritis (JIA) therapy in the youngest patients (pts) is particularly difficult. Etanercept (ETA) and adalimumab (ADA) are approved for use in moderate and severe JIA in pts older than 2 years, but available data about treatment in the youngest children are limited.The aim of study was the evaluation of the effectiveness of TNF inhibitors in pts with JIA who had started therapy before the age of five.13 children aged 2 to 5 years with polyarticular JIA - 2 or extended oligoarticular JIA -11 pts (according to the ILAR criteria) treated with anty-TNF were included in the study (2007-20013). All pts at the start of anti-TNF treatment received two synthetic modified drugs (including methotrexate) and glucocorticoids (GC), in 10 pts intraarticular GC injections were used. The assessment of clinical effectiveness included JIA outcome parameters , JADAS 71 scale and American College of Rheumatology pediatric (PedACR) 30/50/70/90 responses. Disease activity was measured at the baseline and every 6 months.In all (13) pts the first used biological drug was ETA. The treatment of ETA was started in a mean 2,46 year \u00b1 1,2 months of disease. The mean duration of therapy with ETA was 24 \u00b1 11,81 months. At 6 months of ETA treatment 85% of pts achieved PedACR30, high PedACR 50/70/90 responses were achieved in 61% pts. In 8 pts ETA treatment was terminated after at least 18 months remission on the drug (according to the Polish therapeutic program). 4 of them developed a disease exacerbation in mean 3,25 months after the termination of ETA and the treatment was restarted. 2 children (15%) did not respond satisfactorily and they were switched to ADA and at least PedACR 30 response was achieved. In 11 children the treatment of GC was terminated. In all patients the treatment with anti-TNF was well tolerated. No deaths, malignancies or opportunistic infections were reported.In the youngest children with JIA, TNF inhibitor therapy is well tolerated and effective. In case of active disease it is necessary to switch to another biological agent.None declared"}
+{"text": "The rapidly increasing HIV epidemic has fuelled the problem of controlling the spread of tuberculosis. There is a lack of data showing the prevalence of HIVTB co infection from coastal areas of Karnataka. This study was planned to look for the TB and HIV co infection in the Udupi district of Coastal Karnataka and to detect the drug resistance in the study population.Mycobacterium tuberculosis was performed by proportion method.750 smear positive TB cases from Udupi district was studied for HIV co infection. The sputum samples from these cases were processed with modified Petroff\u2019s method and cultured on Lowenstein Jensen media. Drug sensitivity testing for HIV TB co infection was observed in 6.8% (51/750) of the studied population. Male:female ratio is 7.5:1. Maximum cases 29 (56.8%) were in the age group of 36-50 years. Ratio of cases in Udupi: Kundapura: Karkala Taluks was 18:22:11. 42(82.3%) cases belong to category 1 whereas 9 (17.6%) were of category 2. Multi drug resistance was detected in 3 out of 47 (5.8%) culture positive HIV TB co infected cases, in comparison to 3% of HIV negative but TB positive cases. Mortality of HIV TB co infected cases was observed in 5.8%, as compare to 1.1% in HIV negative but TB positive cases.This is the cardinal study highlighting TB-HIV co infection in this coastal area. It shows greater prevalence of MDR in TB-HIV co infected cases thereby stressing the importance of drug sensitivity testing in these patients."}
+{"text": "Studies in different parts of the world indicate that there is high level use of self medication among pregnant women. But there are no scientific evidences on it and factors associated with it in Bahir Dar city administration. The aim of this study was therefore to assess level of self medication and identify factors associated with it among pregnant women attending ANC service at governmental health centers in Bahir Dar city administration.Institution based cross-sectional study was conducted from June 20-July10, 2013. Data were collected using structured questionnaire and analyzed using SPSS version16.0. Back ward logistic regression model was used to assess level of association with self medication practice.A total of 510 pregnant women were included in the study. Of these, 25.1% reported self-medication during the current pregnancy. Self medication during pregnancy was significantly associated with gravida , maternal illness on the date of interview  and location of health facility .A considerable proportion of pregnant women practiced self-medication during their pregnancy with modern medications or traditional herbs. Mothers who were multi garvida, who had maternal illness on the date of interview and who were attending antenatal care were more likely to practice self medication. In developing countries people use herbal medicines routinely in self-care. Some herbal medicines are potent, and their safety is not as evident as people think . GloballThe study was conducted in Bahir Dar city administration, Northwestern part of Ethiopia. Based on the 2007 population and housing census, population of Bahir Dar city administration was projected to be 239,721 for the year 2012 . InstituMulti stage sampling method was used to select the required pregnant mothers. The health centers in Bahir Dar city administration were listed and stratified as rural and urban. From these health centers, two from the rural and three from the urban  were sampled using simple random sampling method. Proportional numbers of pregnant women were assigned to each health center based on the flow of pregnant women per day calculated taking one previous month ANC record. Systematic random sampling method was used to select the pregnant women in each health facility. Information about socio-demographic data, obstetric and medical history and self medication practice of the pregnant women was collected from participants by semi structured questionnaire and by review of antenatal follow up cards using data collection format. Data were entered in to Epi-info version 3.5.2 and analysis was done using SPSS version 16.0. Bivarate analyses were performed by checking Hosmer and Lemeshow test and variables with p < 0.2 were included in multivariable logistic regression. Multivariable logistic regression was used to analyze association between important variables and self medication during pregnancy using back ward logistic regression model. Ethical clearance was obtained from the ethics review committee of the Bahir Dar University. Data collection was conducted after explaining the purpose of the study to the participants and obtaining verbal consent.The majority of the respondents (77.5%) were in the age group of 20 and 34 while 49 (9.6%) of them were 19 and below. The mean (+ SD) age was 26.5 (\u00b16.0). Four hundred sixty eight (91.8%) respondents were married and 40(7.8%) were single. Regarding their educational status, 151(29.6%) were unable to read and write, while 37 (7.3%) of them were able to read and write only. One hundred eight (21.2%) completed primary education, 103(20.2%) had completed secondary school, while 111 (21.8%) had attended higher level education .Sixty five (12.7%) of the pregnant women reported history of chronic disease. Majority of the pregnant women (54.3%) were primigravida and 233(45.7%) were multi-gravida. Three hundred sixty two (71%) of the pregnancies were wanted, 78(15.3%) were mistimed; and 70 (13.7%) were unwanted pregnancies. Forty three (8.4%) of the respondents were hospitalized during their pregnancy. Three hundred ninety nine (78.2%) of the respondents had 1- 2 total ANC visits, and 111 (21.8%) of them had 3 - 4 total ANC visits on the date of interview. Three hundred forty nine (68.5%) of the pregnant women visited the health institutions for routine ANC follow up, 146 (28.6%) of them visited because of illness, 21(4.1%) referred from other health institutions of Bahir Dar city administration, and 2 (0.4%) visited for other reasons .Among, 356 pregnant women who reported history of illness during their pregnancy, 128(36%) reported history of self medication. From this, 88 (68.7%) reported use of modern medication while 27(21.1%) of the pregnant women took traditional preparations. The rest 13(10.2%) took both modern and traditional medication. Not all of the pregnant women with perceived illness took medication to their illness. Accordingly 228 respondents with perceived illness during their pregnancy did not take any medication for their illness. The reasons given for not using medication were fear of damage to the fetus 171(75%), minor illness (24.1%) others 9(3.9%) (waiting next appointment and considering as pregnancy symptom). Among those who took medication for their illness, the basis for self medication were because it is less costly 8(6.25%), assumed that their illness was minor 29(22.6%), long waiting time at the health facilities 15(11.7%), and because they used the drug before 62(48.4%). The source of drug for self medication were pharmacy/drug shop for 47(56.2%), left over drugs for 21(16.4%) friends/relatives for 6 (4.7%), self prescribed herbal preparations for 39 (30.5%) and others (market areas) for 3(2.3%) .Multivariable logistic regression model revealed that only gravida, maternal illness on the date of interview and location of health centers were significantly associated (p < 0.05) with self medication practice during pregnancy. Multi gravida pregnant women were more likely to practice self medication (2.1 times) than those with primigravida . Similarly, pregnant women with maternal illness on the date of interview were more likely to practice self medication (4.8 times) than those who had no maternal illness on the date of interview . Pregnant women who were attending ANC service in the rural health centers were also more likely to practice self medication (4.6 times) than those who were in the urban health centers  .One hundred twenty eight 36%) pregnant women who reported history of illness during their current pregnancy self medicated themselves. Among these 8868.7%) took modern medicines and 27(21.1%) took traditional medicine. Thirteen (10.2%) of the respondents took both modern and traditional herbs for self medication. In this study, 25.1% pregnant women self medicated during their current pregnancy. Among these, 5.3% used herbal preparation for self medication. It is higher than a study done in Addis Ababa where the prevalence of self medication was 12.4% [6% pregna% took moFrom 72 participants who obtained drug(s) from drug stores/pharmacies for self medication practice during pregnancy, 25 (4.9%) of them didn't inform their pregnancy to their provider and 5510.8%) of the providers didn't ask them about their pregnancy. This result is similar with a study done in Addis Ababa . Self me.8% of thA considerable proportion of pregnant women self-medicated themselves with modern medications or traditional herbs. Self medication practices of the pregnant women during pregnancy were significantly higher among women who were multi gravida, who had maternal illness on the date of interview and among women who were receiving ANC in rural health centers.Recommendation: Health education should be given on the risk of self medication during pregnancy to pregnant women. Further community based studies should be conducted to identify factors determining self medication practice among pregnant women since this institution based study cannot be generalized to the community."}
+{"text": "The World Health Organization Regional Office for Africa (WHO AFRO) introduces a step wise incremental accreditation approach to improving quality of laboratory and it is a new initiative in Ethiopia and activities are performed for implementation of accreditation program.Descriptive cross sectional study was conducted in 30 laboratory facilities including 6 laboratory sections to determine their status towards of accreditation using WHO AFRO accreditation checklist and 213 laboratory professionals were interviewed to assess their knowledge on quality system essentials and accreditation in Addis Ababa Ethiopia.Out of 30 laboratory facilities 1 private laboratory scored 156 (62%) points, which is the minimum required point for WHO accreditation and the least score was 32 (12.8%) points from government laboratory. The assessment finding from each section indicate that 2 Clinical chemistry (55.2% & 62.8%), 2 Hematology (55.2% & 62.8%), 2 Serology (55.2% & 62.8%), 2 Microbiology (55.2% & 62.4%), 1 Parasitology (62.8%) & 1 Urinalysis (61.6%) sections scored the minimum required point for WHO accreditation. The average score for government laboratories was 78.2 (31.2%) points, of these 6 laboratories were under accreditation process with 106.2 (42.5%) average score, while the private laboratories had 71.2 (28.5%) average score. Of 213 respondents 197 (92.5%) professionals had a knowledge on quality system essentials whereas 155 (72.8%) respondents on accreditation.Although majority of the laboratory professionals had knowledge on quality system and accreditation, laboratories professionals were not able to practice the quality system properly and most of the laboratories had poor status towards the WHO accreditation process. Thus government as well as stakeholders should integrate accreditation program into planning and health policy. Quality laboratory service is an essential part of a health care delivery for diagnosis and monitoring of disease. But due to lack of awareness on the role of laboratory service in many developing countries, laboratory services have shortage of resource, poor management, ineffective services , 2, low Study Design: a descriptive cross sectional study was conducted using checklist and questionnaire to determine the status of laboratories towards accreditation process and the knowledge of laboratory professionals on quality system essential elements & accreditation in government and private health facilities in Addis Ababa city.Study Area and Period: the study was conducted in Addis Ababa which is the capital city of Ethiopia between December 2013 and February 2014. The city is divided into 10 sub cities and 116 Woreda [6 Woreda . The cit6 Woreda .Source Population and Study Subjects: all health facility laboratories and laboratory professionals in the city of Addis Ababa were source population for the assessment of status of the laboratories towards accreditation process and determination of their knowledge on quality system essential elements & accreditation respectively. The study subjects were health facility laboratories working more than a year and laboratory professionals who had more than a year experience in the selected health facility laboratories.Inclusion and Exclusion Criteria: all laboratory professionals and health facility laboratories having more than a year experience were included in the study. Laboratory professionals and health facility laboratories which were not willing to participate in the study were excludedSampling Procedures: purposive sampling technique was used for determination of the status of laboratory towards accreditation process. All 33 hospitals\u2019 laboratories found in Addis Ababa city were selected for the study of which 14 laboratories were laboratories from government health facilities and the remaining laboratories were from private health facilities, however the study was conducted on 30 health facility laboratories because of exclusion criteria. And a single population proportion formula was used for determination of the sample size for interviewing laboratory professionals on quality system essential elements & accreditation considering the following assumptions: Proportion of 50% was taken due to absence of reliable previous study that shows the laboratory professionals knowledge on quality system and accreditation. Level of significance = 0.05, Marginal of error (d) = 5%, Sample size = n, Z (\u03b1/2) = Z-score at 95% confidence interval = 1.96. The formula for calculating the sample size (n) was as follow: N = Z\u03b1/22P(1-p)/d2; n = 1.962*0.5*0.5/0.052 = 384; then n = 384. According to Health and Health Related Indicators there were 393 laboratory professionals in Addis Ababa [Data Collection Procedures: a WHO-AFRO's accreditation checklist and questionnaire were used for data collection.Checklist: a WHO-AFRO Accreditation checklist was used to assess of the status of participant laboratories towards accreditation. Assessment was conducted in six major laboratory sections/departments and on the whole laboratory facility, the major sections were Clinical chemistry, Hematology, Serology, Parasitology, Urinalysis and Microbiology Laboratories. The checklist's 12 sections provide assessment on the basis of 110 clauses and 250 total possible points. Each item has been assigned a weighted value of 2, 3, or 5 points based on complexity and/or relative importance. Incomplete fulfillment of an item can be scored as \u201cpartial\u201d and awarded a single point, with written explanation. Some clauses in the checklist are \u201ctick lists\u201d and require the satisfactory presence of all sub items listed below the main heading to receive full credit [Questionnaire: the data collection instrument interviewed by data collectors were anonymously closed ended questionnaire. It included different questions, education background, characteristics of laboratory professionals, work experience, and regarding knowledge and attitude of laboratory quality system essential elements and accreditation. Three trained and senior laboratory technologists assessed the laboratory status for accreditation using the WHO AFRO checklist and they interviewed laboratory professionals using questionnaire for data collection. Principal investigator involved in overall controlling activities of data collections and assisted data collectors during the process of data collection and collected filled questionnaires regularly and checked for inconsistencies and omission.Data Management and Statistical Analysis: the collected data were cleaned, coded, fed in to SPSS version 16 statistical software by principal investigator and data clerk. After entry, the data were re-cleaned to correct errors and they were also categorized as necessary. The data entered were checked for consistency, moreover frequencies and cross tabulations were used to check missed values and variables. Descriptive statistics were computed to calculate the percentage of each laboratory score and the responses of the laboratory professionals.Data Quality Assurance: to assure data quality, data collectors were trained for two days and the questionnaire was pre-tested before the actual data collection. Completeness, accuracy and consistency of the collected data were checked on daily bases during data collection by the principal investigator, where those questionnaires found incomplete, inaccurate and inconsistent was returned back for data collectors to be filled again. Data were cleaned, edited and coded before data entry and then recoded after analysis.Ethical Consideration: before any attempt to collect data, approval to conduct the study was obtained from Institutional Review Board (IRB) of School of Medicine, Addis Abba University. Each participant was informed about the purpose of the study, the right to refuse to participate in the study, and anonymity and confidentiality of the information gathered. They were assured that they would not be penalized for not participating and all assessed laboratories were coded for confidentiality purpose.A total of 213 (100%) laboratory professionals were participated of these 135 (63.4%) were males. One hundred thirty (61%) of the respondents were from government health institutions and remaining were from private health institutions. One hundred thirty one (61.5%) were Bachelor Degree holders and 82(38.5%) had diploma. Sixty one (28.7%) respondents had been working as laboratory or section head, and quality officer and more than 179 (74%) had 3 and above years of working experience in laboratory fields. Laboratory professionals were interviewed about laboratory quality system essentials and accreditation, of them 197 (92.5%) respondents replied that they had knowledge on quality system essentials and concerning laboratory accreditation, 155 (72.8%) of the respondents responded that they had knowledge on accreditation. Among those participants who have information on accreditation 151 (97.4%) believed that laboratory accreditation improves the quality of laboratory services in addition 77 (49.7%) believed that their laboratories have a capacity to be accredited by accreditation body .AWHO-AFRO laboratory accreditation assessment checklist was used for assessment of the status of each laboratory. And as part of the checklist, 12 quality system essential elements implementations in each laboratory facility were assessed and discussed separately .Thirty laboratory facilities were assessed to evaluate the document and records practice and this section has 25 points. Accordingly 5 (16.7%) laboratories scored 0 and 23 (76.7%) scored less than 10 with mean score 4.9 and 2(6.7%) laboratory facilities scored 12 (the highest) points.Three (10%) facility scored 0 point, and majority 24 (80.0%) of laboratory scored between 1 and 6 and 2 (6.7%) laboratories scored 8 (the highest score) out of 12 points with mean 2.7 score.Out of 30 assessed laboratory facilities 5 (16.7%) scored more than 10 out of 20 points but 1 (3.3%) laboratory scored 0 point.Out of 30 assessed laboratories facilities on client management and services, 6(20%) laboratories scored 0 point, and majority 20(66.7%) facilities scored less than 5 (50%) out of 10 pointsEquipment part of the checklist had 32 points and out of 30 assessed laboratory facilities 1 (3.3%) laboratory scored the lowest point 2, 1 (3.3%) laboratory facility scored the highest point 22 but majority 15(69.8%) of laboratories scored less than 16 (50%) points.The internal audit section has 5 points and around 97% (29) of the assessed laboratory facilities in internal audit section scored 0, and only 1 laboratory scored 1 (20%) point.Regarding purchasing and inventory, 1 (3.3%) laboratory scored 2 points (the lowest score) and 1 (3.3%) laboratory also scored 25 points (the highest point) and the mean score was 11.2. Of 28, 15(50.0%) laboratory scored between 3 and 10, 12 (39.6%) scored between 11 and 20, and 1 (3.3%) scored 21. Twenty six (86.7%) laboratories scored less than 55% the minimum requirement points.Concerning laboratory information management, out of 30 assessed laboratory facilities, 3 (10.0%) laboratories scored 2 (the lowest score) points and 3 (10%) laboratories scored 12 (the highest score) points out of 14 with mean score 6.6. The remaining 15 (50.0%) laboratories scored between 4 and 5, and 10 (33.3%) scored between 7 and 9. Twenty one (70.0%) laboratories scored less than the minimum requirement for accreditation.Process control and internal & external quality assessment section has 43 points; out 30 assessed laboratory facilities, 1 (3.3%) laboratory scored 2 points (the lowest score), and 1 (3.3%) facility scored 36 points (the highest score). Twenty five (83.3%)laboratories scored below 20 points.Thirty laboratory facilities were also assessed for corrective action activities and the majority 16(53.3%) scored 0 point, and 1 (3.3%) laboratory scored 6 out of 8 points and the remaining 13 (42.9%) laboratory scored between 1 and 4.Out of 30 assessed laboratory facilities for occurrence management, 24(80%) facilities scored 0 point and 4(10%) facilities scored between 1 and 2. The remaining facility scored 10 out of 10.Under facilities and safety section the assessment results showed that out of thirty assessed laboratory facilities 1(3.3%) laboratories scored 3 points (the lowest score) and 1 (3.3%) scored 29 points (the highest score) out of 40 with mean score 14.9. Of 28(93.3%) laboratories, 22 (73.3%) scored below 20 points.Assessment was conducted in six major laboratory sections/departments; such as Clinical chemistry, Hematology, Serology, Parasitology, Urinalysis and Microbiology laboratories including the whole laboratory facility. Results showed that the highest score earned in the laboratory section was 157 (62.8%) and only 1(3.3%) private health facility laboratory scored 157 points in Clinical Chemistry, Hematology, Serology and Parasitology sections which is the minimum required points for accreditation. In addition the microbiology and Urinalysis sections scored 156 (62.8%) and 154 (61.6%) points respectively. Another one private health facility laboratory also scored 138 (55.2%) points in Clinical Chemistry, Hematology, Serology and Microbiology sections which is a minimum required point for accreditation but the remaining 2 laboratory sections scored below the minimum required points (55.2%). In Clinical Chemistry, Hematology, and Serology sections the lowest score was 34 (13.6%) points and the mean scores were 76.9, 76.1, and 75.3 respectively. Regarding Parasitology and Urinalysis laboratories the lowest score were 31(12.4%) with mean score 71.9 and 73.0respectively in addition the lowest score for Microbiology was 32 (12.8%) with mean score 73.8 points. According to the assessment finding, the government laboratory facilities had 81.5(32.6%) the highest average score in Clinical Chemistry section and the lowest average score was from Urinalysis section with 29.8 (74.5%) points. Whereas the private laboratory facilities had 73.3 (29.3%) the highest average score in Clinical Chemistry and Serology sections and the lowest average score was Urinalysis section with 28 (70.0%) points. Six government health facility laboratories were under accreditation process and their highest and lower average scores were108.8 (43.5%) in Clinical Chemistry section and 100.3 (40.1%) in Urinalysis section respectively. However the highest average score for the government laboratory facilities without laboratories under accreditation process was 58.3 (23.3%) in Clinical Chemistry with lowest score 52.3 (20.9%) in Urinalysis section .A total of 30 organizations\u2019 laboratory were assessed to see the status towards accreditation as one facility; according to the finding the highest and the lowest scores were 155 (62.0%) and 32 (12.8%) points respectively and the mean score was 74.1 (29.6%). Out of 30 laboratories, only 1 (3.3%) private laboratory scored 155 (62.0%) which is a minimum required point for WHO-AFRO accreditation program and it is eligible to obtain only for star 1 certification . RegardiAlthough majority of the laboratory professionals had knowledge on laboratory quality system essentials and accreditation and they believed that the laboratories have a capacity to be accredited, almost all laboratories were not establishing quality management system according to expected standards and they were far from accreditation requirements. Even if most of the laboratory professionals believed in the benefit of accreditation for improvement of laboratory quality services, the practicing of quality system essential elements were poor and as result status of most laboratories towards of accreditation were below the minimum requirement by WHO-AFRO Accreditation Process. In this study majority of laboratories scored less than 50% in the quality system essential elements especially the situations were more worst internal audit, corrective action, occurrence management document and records, management review, organization and personnel, and clients management. This finding was found to be comparable with baseline assessment for accreditation conducted in 24 laboratories in Ethiopia that shows majority of the laboratories scored less than 50% , anotherIt is well documented that implementation of laboratory standards are verified through the process of accreditation and accredited medical laboratories demonstrate a well-functioning quality management system, technical competence, and timely and customer-focused services that contribute to patient care . But in In conclusion, most of the laboratories did not have well established laboratory quality management system and practicing of the quality system essential elements was very limited and almost all laboratories did not have an internal audit system for continual improvement of the quality of laboratory services. Although a quality laboratory testing associated with accreditation is expected to improve patient care by aiding the timeliness and accuracy of medical decision making, the status of laboratories toward of accreditation process were poor and only one laboratory was scored the minimum requirement point for WHO-AFRO accreditation process. As the quality of laboratory services is an essential component for the health care system, the successful implementation of the accreditation process will be bringing a measurable quality improvement in laboratory services and consequently on the healthcare system. Therefore, ministry of health, donors, professional associations and stakeholders should start now to make accreditation of medical laboratories a high priority and should undertake coordinated efforts to integrate accreditation programs into their health policy, planning, and health sector development program. As well allocation enough resources for laboratory infrastructure improvement and endorsement of laboratory policy in Ethiopia are crucial."}
+{"text": "Our 700-bed hospital has a 24-7 cathlab service that routinely investigates patients with indications prior to ICU admission following out-of-hospital cardiac arrest (OOHCA). Our aim was to compare survivors and nonsurvivors and evaluate utilisation and prognostic impact of angiography and primary percutaneous coronary intervention (PPCI) in this patient group.A retrospective analysis using Trust electronic databases  of all OOHCA patients admitted to our ICU over 3 consecutive years between 1 November 2011 and 31 October 2014.n = 48) of OOHCA survivors admitted to the ICU had a shockable rhythm compared with 55% (n = 41) of nonsurvivors. Eighty-three percent (n = 45) of survivors admitted to the ICU went to the cardiac cathlab before ICU admission compared with 53% (n = 39) of nonsurvivors. Forty-three percent of survivors had PPCI compared with 26% of nonsurvivors. Eighty-one percent (n = 44) of survivors received therapeutic hypothermia compared with 62% (n = 48) of nonsurvivors.A total of 351 patients presented to our emergency department (ED) following OOHCA in this period, and of these 50% died in the ED, 37% were admitted to the ICU and 13% were admitted elsewhere. Of the 129 patients admitted to the ICU, median age was 66 (range 18 to 93), 71% were male, 68% had a shockable presenting rhythm, median ICU LOS was 3.75 (range 1 to 34 days) and ICU and hospital mortalities were 50% and 60% respectively. Eighty-nine percent (Over 3 consecutive years our annual case mix, ICU and hospital mortalities for OOHCA patients admitted to the ICU have remained stable, while our annual pre-ICU cathlab and PPCI utilisation have risen consistently in both survivors and nonsurvivors. ICU survivors were more likely to have had a shockable rhythm, been to the cathlab, and received PPCI and TH, but all may simply reflect selection bias. Any benefit these conferred to cardiac patients may have been off set by our liberal ICU admission policy to OOHCAs with nonshockable rhythms. Access to 24-7 PPCI in this group may determine survival and we suggest that OOHCA patients should be taken directly to regional heart attack centres."}
+{"text": "The adoption of standardized protocols and specialized multidisciplinary teams foresophagectomy involve changes in routines with the implantation of expensiveclinical practices and deviations from ingrained treatment philosophies. To evaluate the prevalence of standardized protocols and specializedmultidisciplinary teams in S\u00e3o Paulo state, Brazil. Institutions that routinely perform esophagectomies in S\u00e3o Paulo were contactedand questioned about the work team involved in the procedure and the presence ofstandardized routines in the preoperatory care.  Fifteen centers answered the questionnaire: 10 (67%) public institutions and five(33%) private. There were seven (47%) medical schools, six (40%) with a residencyprogram and two (13%) nonacademic institutions. The mean number of esophagectomiesper year was 23. There was a multidisciplinary pre-operative team in nine (60%).There was a multidisciplinary postoperative team in 11 (73%). Early mobilizationprotocol was adopted in 12 (80%) institutions, early feeding in 13 (87%),routinely epidural in seven (47%), analgesia protocol in seven (47%), hydricrestriction in six (40%), early extubation in six (40%), standardizedhospitalization time in four (27%) and standardized intensive care time in two(13%). The prevalence of standardized protocols and specialized teams is very low in SaoPaulo state, Brazil. The presence of specialized surgeons is a reality andstandardized protocols related directly to surgeons have higher frequency thanthose related to other professionals in the multidisciplinary team. Esophageal cancer is a devastating disease. Survival is dismal and inferior to othertumors. Earlam and Cunha-Melo Surgery has been considered an essential part of the treatment of patients withesophageal carcinoma; however, better survival achieved with surgical therapy has paid ahigh price. Esophagectomy is a technically demanding and complex operation with highrates of morbidity and mortality. In 1980, Earlam and Cunha-Melo The outcomes for esophageal resection seem to be influenced by the adoption ofstandardized protocols th neoplasia inmen, corresponding to 2.7% of all malignancies in the state Esophageal cancer in the state of S\u00e3o Paulo, Brazil is the 6Achalasia secondary to Chagas disease is also a health problem. Although the number ofautochthonous cases from S\u00e3o Paulo is small, migration from other areas of the countryfor treatment is very common. Esophagectomy is one of the therapies proposed for dilatedmegaesophagus which represents a significant number of the cases This study aims to evaluate the prevalence of the implementation of standardizedperioperative routines for esophagectomy in the state of S\u00e3o Paulo, Brazil.The study was approved by the Institutional Review Board under number 288.432/2013. Institutions in the State of S\u00e3o Paulo that routinely perform esophagectomy, for benignor malign disease, were contacted and questioned about the team involved in the processand the implementation of standardized perioperative routines.The selection of the contributors was made considering recent publications in the field,participation in meetings, networks and indication of participants. There is no officialregistration of esophagectomies in Brazil. A senior team member were contacted by e-mail or phone, and questioned about: 1) theannual number of esophagectomies performed in the institution; 2) the existence of aspecialized surgical team; 3) the presence of a specialized anesthesiologist; 4) thepresence of a multidisciplinary pre and postoperative team and its members; 5) theexistence of standardized protocols, such as hydric restriction, early extubation,analgesia, routinely epidura, early deambulation, feeding, intensive care time andhospitalization time.Fisher or Mann-Whitney tests were used when appropriate for statistical analysis andp<0.050 was considered signi\ufb01cant. Seventeen institutions were contacted, 15 (88%) answered the questionnaire. Among thosethat answered, 10 (67%) were public institutions and 5 (33%) private. There were 7 (47%)medical schools, 6 (40%) institutions with a residency program and 2 (13%) nonacademicinstitutions. The mean number of esophagectomies per year was 23\u00b118 (range 5-60)   .Thirteen (87%) institutions had specialized surgical team and four (27%) specializedanesthesiologist. There was a multidisciplinary pre-operative team in nine (60%) institutions; countingwith surgeon in nine (100% of those with a multidisciplinary team); oncologist in seven(78%), nutritionist in six (67%), physiotherapist in five (56%) anesthesiologist in two(23%), nurse in three (33%), psychologist in two (33%), endoscopist in two (23%),pulmonologist in one (11%), cardiologist in one (11%) and pathologist in one (11%). There was a multidisciplinary postoperative team in 11 (73%) institutions; counting withsurgeon in 11 (100% of those with a multidisciplinary team), oncologist in nine (82%),physiotherapist in eight (73%), nutritionist in seven (64%), radiotherapist in four(36%), nurse in three (30%), psychologist in three (18%), pathologist in two (18%),anesthesiologist in two (18%), endoscopist in one (9%) and audiologist in ome (9%).Early mobilization protocol was adopted in 12 (80%) institutions; early feeding in 13(87%); routinely epiduralin seven (47%); analgesia protocol in seven (47%); hydricrestriction in six (40%); early extubation in six (40%); standardized hospitalizationtime in four (27%) and standardized intensive care time in two (13%).The outcomes for esophagectomy must not be only measured by mortality and survival It seems to have a clear direct relation between the volume of esophagectomies andoutcomes Even though our report does not evaluate outcomes, the adoption of standardizedprotocols and multidisciplinary care seems to improve outcomes and thus may beconsidered an improvement in care, especially in countries with a high prevalence ofesophageal cancer and achalasia. Findlay et al. There are major difficulties in the introduction of new clinical evidence-basedguidelines into clinical practice Our results show that surgeons are the most specialized staff member and still theleader of the multidisciplinary team. Less than 30% had a specialized anesthesiologist,even with a well-established relationship between intraoperative anesthetic managementand postoperative results There are limitations in this paper. This report studied a small number of institutions.It did not contemplate the entire country due to its heterogeneity. Since the state ofS\u00e3o Paulo has the larger number of esophagectomies per year, it was presumable that itwould have the best results in perioperative care matter. Also, the study did notevaluate outcomes. The prevalence of standardized protocols and specialized teams is very low in S\u00e3o Paulo.The presence of specialized surgeons is a reality and standardized protocols relateddirectly to surgeons have higher frequency than those related to other professionals inthe multidisciplinary team."}
+{"text": "Stablishing when a non-invasive first line approach can be an option in the management of acute respirarory failure due to severe pneumonia represents a major challenge.To analyze the influence of first line non-invasive respiratory support in the outcome of patients admitted with severe pneumonia.We analyzed retrospective data from patients admitted due to severe pneumonia in our polivalent ICU during a 4-year period. Every patient received antibiotic treatment according to current guidelines.We collected data related to the specific initial ventilatory therapy, need for therapy escalation and clinical outcomes.During the period studied, 113 patients were admitted to our ICU due to severe pneumonia  36 (31.8 %) were treated initially with invasive ventilation (MV), 45 (39.2%) with non-invasive ventilation (NIV), 5 (4.4%) with high-flow nasal cannula (HFNC) and 27 (23.9%) with conventional oxygen therapy (COT).NIV was applied to older and more sick (as measured by APACHE II) patients compared to HFNC and COT  ICU stay and mortality was higher in NIV group compared to conventional therapy Higher rate of delayed intubation was observed in NIV patients, not reaching statistical difference between groups (40 % vs 24.2 % p 0.15) In those with delayed intubation, duration of MV was higher [13 days (IQR 6-26) vs 8 (3-11) p 0.006] Those patients requiring escalation to mechanical ventilation presented, as was expected, double mortality (50 % vs 11.5 % p 0.001)Among all patients finally ventilated (63 patients), those with delayed MV had similar age an APACHE II but longer ICU and hospital stay and duration of mechanical ventilation  and a trend to higher mortality .An initial non-invasive oxygen therapy management for severe pneumonia did not impact in outcomes, except for patients finally requiring mechanical ventilation. Non invasive ventilation was probably applied to sicker patients and this fact may explain the worse evolution of this subgroup."}
+{"text": "Despite the recommendation of manufacturers for single-use of syringes and needles for insulin administration, most patients reuse these devices, a practice supported by national guidelines.To estimate the frequency of needles and syringes reuse for insulin administration by patients with type 2 DM. In addition, to review patients' practices related to insulin administration.Cross-sectional study in an emergency department of a public hospital, in Porto Alegre, Brazil. We assessed sociodemographic and clinical variables related to the management of diabetes; physical examination was performed to evaluate the presence of lipodystrophy, injection site infection and hematomas.From October 2014 to January 2015, we included 28 participants. Fifteen (54%) were female, average age was 67 (SD 14) yrs. and average BMI was 30 kg/m2 (SD 8). Household monthly income was less than R$ 1.000 (US$ 317) for 68% of the participants. Median time of insulin therapy was 10 yrs. (range 6 to 20 yrs.); 23 (74%) self-administered insulin injections. Twenty-seven (96%) participants receive needles, syringes and insulin from public health system. Reuse of disposable syringes and needles was reported by 75% of participants. The frequency of re-utilization of needles and syringes ranged from two to 21 times; the median re-use frequency was three (IQR 3 to 7.5). Main reasons for syringe and needle changes was pain (54%), guidance of a health professional (14%) and blunt needle (14%). Twenty-two subjects (79%) reported not having received any guidance from a health professional regarding the reuse of needles and syringes. Only 16 (57%) of the participants disinfect with alcohol the injection site; hand-washing before insulin-administration was reported by 26 (93%) subjects. Although not recommended, twelve (43%) disinfect the needle with alcohol for reuse. Needlesticks injures due to syringes and needles reuse were reported by 13 (46%) participants. Lipohypertrophy was present in two (7%), hematomas in five (18%), and one subject had injection site infection at the time of the evaluation.Reuse rates are high and complications, such as lipohypertrophy and hematomas, are frequent. However, most participants had not received adequate guidance on syringes and needles re-utilization. It is important that healthcare professionals provide adequate guidance for patients with type 2 DM that are likely to reuse syringes and needles."}
+{"text": "Purpose. To determine the functional and anatomic outcomes of rhegmatogenous retinal detachment (RRD) surgery in patients with Down syndrome. Methods. A retrospective chart review was performed of patients with Down syndrome who had undergone surgery for RRD at King Khalid Eye Specialist Hospital between 1995 and 2014. Results. A total of 245 patients with Down syndrome were evaluated during the study period. Eighteen eyes of 15 patients (6.1%) with RRD were identified. Three out of 15 patients (20%) presented with bilateral retinal detachment. All eyes presented with macula off retinal detachment. The retina was successfully reattached in 16/18 (88.8%) eyes after a mean follow-up of 48 months. The final postoperative visual acuity ranged from light perception to 20/125 (median: hand motion) (11/18 eyes). Conclusions. The anatomic success rate of retinal reattachment surgery in patients with Down syndrome is comparable to the general population. Patients with Down syndrome should undergo regular ophthalmic examinations for early diagnosis. Despite late diagnosis and the presence of proliferative vitreoretinopathy (PVR) in some patients, favorable anatomical outcomes can be achieved. Down syndrome (DS) is one of the most prevalent genetic disorders caused by trisomy of all or part of chromosome 21 . It is mSeveral studies have shown that various ocular disorders are commonly seen in DS \u20138. The pThe objective of this study was to report the characteristics and surgical outcomes of RRD associated with Down syndrome.The Internal Review Board/Ethics Committee at King Khaled Eye Specialist Hospital (KKESH) approved this study. A retrospective chart review was performed of all patients with RRD associated with Down syndrome from 1995 to 2014. The charts were reviewed to obtain the following data: age of the patient, laterality, duration of complaint, date of presentation, preoperative best-corrected visual acuity (BCVA), lens status on presentation, attachment or detachment of macula, extent of detachment, number, type, and location of retinal breaks, presence and grade of proliferative vitreoretinopathy (PVR), date of surgery, type of surgery performed, postoperative visits including examination under anesthesia (EUA) or examination under sedation (EUS), postoperative BCVA, postoperative lens status and anatomic outcome of the retina, subsequent surgery, anatomical and visual outcome at the last follow-up, duration of follow-up, and number of EUAs and EUSs.Surgical techniques utilized included a standard 3-port 20/23-gauge pars plana vitrectomy (PPV) starting with a core vitrectomy followed by induction of a posterior vitreous detachment (PVD) along with shaving of the vitreous base. Endolaser photocoagulation was applied around the retinal breaks with or without 360-degree laser photocoagulation under air or perfluorocarbon liquid (PFCL). The intraocular tamponade of nonexpansile concentration of gas  or silicone oil (5000 centistokes or heavy silicone oil) was selected according to the surgeon's discretion. In cases that were combined with a scleral buckle (SB), a 360-degree encircling band  was used, and in 3 cases a segmental silicone tire  was placed under the encircling band. If a scleral buckling was utilized as the sole treatment, the breaks were localized, cryopexy was performed around the breaks, and 360-degree encircling band was used with or without tires.A total of 245 Down syndrome patients were evaluated during the study period. Eighteen eyes of 15 patients (6.1%) with RRD were identified. There were 11 males and 4 females, with a mean age of 11.3 years . The left eye was involved in 10 (55.5%) patients while the right eye was involved in 8 (44.5%) patients. Three out of 15 patients (20%) presented with bilateral retinal detachment. Verified or suspected ocular or head trauma was implicated in 5 (27.7%) of the 18 eyes, no trauma in 4 (22.2%) eyes, and unknown history of trauma in 9 (50%) eyes. At presentation, 2 (11.1%) eyes had a clear lens, 9 (50%) eyes had a cataractous lens, 4 (22.2%) eyes were pseudophakic, and 3 (16.6%) eyes were aphakic. All eyes presented with macula off retinal detachment. The detachment was total in 15 (83.3%) eyes, 3 quadrants of involvement in 2 (11.1%) eyes, and 2 quadrants of involvement in one (5.5%) eye. Two (11.1%) eyes presented with PVR grade B and 6 (33.3%) eyes with grade C . Eight eyes presented with 1 or more horseshoe tears (HST), 3 eyes with giant retinal tear (GRT), 6 eyes with atrophic or operculated holes, and 1 eye with retinal dialysis and in 1 eye, the break was unidentifiable .In the relatively cooperative patients in whom visual acuity could be assessed, preoperative visual acuity ranged from following light to counting fingers (median: following and fixation) (10/18 eyes) and final postoperative best-corrected visual acuity ranged from light perception to 20/125 (median: hand motion) (11/18 eyes). An encircling scleral band alone was performed in 6 (33.3%) eyes. Pars plana vitrectomy alone was performed in one (5.5%) eye. Combined buckle-vitrectomy was performed in 11 (61.1%) eyes. A segmental solid tire under the break was used in addition to the buckle in 5 (27.7%) eyes. Pars plana lensectomy (PPL) was performed in 5 (27.8%) eyes that were kept aphakic except one patient who underwent secondary intraocular lens (IOL) implantation. One eye underwent extracapsular cataract extraction during the primary procedure due to dense cataract. One eye underwent lens aspiration through anterior approach. In two eyes, the cataract was not significant enough to warrant removal. Three (16.6%) patients underwent EUS in the first postoperative visit, 1 (5.5%) patient underwent EUS in the second postoperative visit, and none had EUS in the last visit. No patients needed EUA.Common complications noted after surgery included cataract formation in 1 (5.5%) eye, posterior capsular opacity in 1 (5.5%) eye, high intraocular pressure in 3 (16.6%) eyes, silicone oil emulsification in 1 (5.5%) eye, and endophthalmitis in 1 (5.5%) eye. Persistent or recurrent retinal detachment associated with PVR was noted in 6 (33.3%) eyes. All of the 6 eyes (2 with persistent detachment and 4 with recurrent detachment) underwent repeated surgery and successful reattachment was achieved in 4 of them. Because of the small number of eyes, a meaningful statistical analysis to assess the effect of the extent of detachment, number and type of breaks, and preexisting PVR on final outcome could not be performed.Follow-up ranged from 3.1 to 210.5 months . The retina was successfully reattached after one procedure in 12/18 (66.6%) eyes and after a second procedure in 4/18 (22.2%) eyes. Therefore, the final success rate was 88.8% (16/18 eyes). The results are summarized in We report the results of 18 eyes of Down syndrome patients who had retinal detachment repair. The mean age at presentation in our series is 11.3 years compared to 13 years in the series reported by Ahmad and Pruett  found thIn the literature, the anatomical success rate for retinal detachment repair varies depending on the surgical approach. Pars plana vitrectomy and silicone oil, PPV and gas with or without a combined scleral buckling, demonstrated success rates between 73% and 95% , 16. ForDS is the most common known cause of mental retardation and is characterized by developmental delay and language and cognitive abnormalities. Patients with DS are more likely to present with chronic and complex retinal detachment that is more difficult to repair . AdditioPatients with Down syndrome are usually uncooperative during examination and instillation of medications. In addition, the operated eye is at risk of complications due to rubbing or inadvertent contusion . TherefoThe American Academy of Pediatrics recommended the following for health supervision for Children with Down syndrome: red reflex evaluation at birth, ophthalmologic examination by a pediatric ophthalmologist within 6 months, and annual ophthalmologic examination until 5 years of age, every two years until 13 years of age, and then every 3 years thereafter unless otherwise indicated . We beliLimitations of our study include the small sample size and the retrospective, descriptive nature of our study without a control group. In addition, the incidence of RRD in Down syndrome in our population may be bias as we are a tertiary referral center. Furthermore, several surgeons with a variety of surgical techniques performed our cases.In summary, the anatomic success rate of retinal reattachment surgery in patients with Down syndrome is comparable to the general population. These patients should undergo periodic ophthalmic examination to avoid delayed diagnosis. Despite late diagnosis and the presence of PVR in some patients, favorable anatomical outcomes can be achieved."}
+{"text": "In the United States, an estimated 7% of new diagnoses of human immunodeficiency virus (HIV) infection in 2012 were attributed to injection drug use, and an additional 3% to male-to-male sexual contact and injection drug use  were ineligible. An additional 279 (2%) eligible participants were excluded from analysis.Among 10,002 PWID, 11% (CI = 9%\u201312%) tested positive for HIV. The percentage of PWID with HIV infection was higher among non-Hispanic blacks (16%) (CI = 13%\u201318%) than non-Hispanic whites (5%) (CI = 3%\u20137%). PWID in the South U.S. Census region had higher HIV prevalence (13%) (CI = 11%\u201316%) than those in the Midwest (8%) (CI = 5%\u201311%) and West regions (7%) (CI = 5%\u201310%). The prevalence of HIV infection was lower among PWID who most frequently inject heroin only (7%) (CI = 6%\u20139%) than among PWID who most frequently inject drugs other than heroin or multiple drugs (17%) (CI = 13%\u201321%). Prevalence of HIV infection was 27% (CI = 20%\u201333%) among male PWID who reported male-to-male sex in the previous 12 months. Among HIV-positive PWID, 63% (CI = 55%\u201370%) were aware of their infection.Among the 9,425 PWID included in behavioral analysis, 30% (CI = 28%\u201332%) receptively shared syringes, 70% (CI = 68%\u201372%) had vaginal sex without a condom, 25% (CI = 23%\u201327%) had heterosexual anal sex without a condom, and 49% (CI = 47%\u201351%) had more than one opposite sex partner in the previous 12 months . The perIn addition, 25% (CI = 23%\u201327%) of PWID participated in an HIV behavioral intervention, 39% (CI = 36%\u201341%) participated in drug treatment, and 51% (CI = 49%\u201354%) had an HIV test in the previous 12 months . Ever bePWID with health insurance were more likely to have been tested for HIV in the previous 12 months (55%) (CI = 53%\u201358%) than were PWID without health insurance (44%) (CI = 41%\u201347%) .*** SimiThe change in the percentage of PWID with HIV infection from 2009 (9%) to 2012 (11%) was not statistically significant. Among PWID with HIV-positive test results in 2012, 63% were aware of their infection, which is not significantly different from that found in 2009 (55%) . The perThe 2012 data in this report provide updated estimates of the prevalence of HIV infection and behaviors since the last NHBS survey of PWID in 2009 . The chaThe percentages of PWID who engaged in risk behaviors in 2012 are consistent with 2009 data . These pCompared with the last NHBS survey of PWID in 2009, higher percentages of participants in this 2012 study reported participating in HIV behavioral interventions in the previous 12 months (25% in 2012 compared with 19% in 2009) and having ever been tested for HCV infection  . SimilarThis analysis found that PWID with health insurance were more likely to have been tested for HIV infection in the previous 12 months, to have participated in an HIV behavioral intervention in the previous 12 months, and to have ever been tested for HCV than were PWID without health insurance. These differences suggest that expanding health insurance coverage might allow more PWID to become aware of their HIV and HCV status and to have access to important treatment and prevention interventions.Consistent with previous reports ,8, this The findings in this report are subject to at least four limitations. First, some participants might not have accurately reported their behavior to interviewers, and results might be affected by social desirability bias. Second, because no method of obtaining standard probability samples of PWID exists, the representativeness of the NHBS sample cannot be determined. Although respondent-driven sampling adjusts for some sampling biases , biases To reduce the number of new HIV infections, the National HIV/AIDS StrategyWhat is already known on this topic?Persons who inject drugs (PWID) in the United States are at increased risk for acquiring human immunodeficiency virus (HIV) infection. In 2009, the National HIV Behavioral Surveillance (NHBS) system, which uses respondent-driven sampling to interview and test for HIV infection PWID living in 20 large cities, found an overall HIV prevalence of 9%.What is added by this report?The NHBS in 2012 found an HIV prevalence of 11%  among PWID; of those, 63% had been previously aware of their infection, compared with 55% in 2009, not a statistically significant difference. Among PWID reporting negative or unknown HIV status in 2012, 30% reported sharing syringes, and 70% reported having vaginal sex without a condom in the previous 12 months.What are the implications for public health practice?Many PWID are at risk for acquiring HIV infection because of their drug use practices and sexual behaviors, but more than one third of HIV-positive PWID in urban areas with high HIV prevalence were unaware of their infection. Additionally, three quarters of PWID had not participated in an HIV behavioral intervention in the previous 12 months. To prevent infections, PWID need ready access to sterile injection and drug preparation equipment; treatment for substance use and mental disorders; opioid substitution therapy; counseling, testing, and treatment for HIV infection; education on drug-related and sex-related risks and risk-reduction; and preexposure prophylaxis if they are adults and at substantial risk for acquiring HIV infection."}
+{"text": "Cardiac amyloidosis (CA) is caused by extracellular myocardial deposition of either immunoglobulin light-chain (AL) or transthyretin (ATTR) fibrils. Two forms of ATTR CA cause life-threatening cardiomyopathy: an inherited form arising from misfolding of mutated ATTR  and a sporadic form caused by wild-type ATTR (senile systemic amyloidosis [SSA]). More than half of over 100 reported ATTR mutations are associated with FAC. The most common mutation in the US is Val122Ile found in 3-4% of African Americans (AA). FAC can be difficult to recognize clinically and is likely under diagnosed. The DISCOVERY study aims to determine the prevalence of TTR mutations and FAC diagnosis in a cohort of patients (pts) with clinical features suggestive of CA.This is a prospective, multi-center study in adults with two or more of the following eligibility criteria: heart failure signs and symptoms, intraventricular septal thickness (IVS) of >12 mm, LV diastolic dysfunction, low voltage ECG, or history of carpal tunnel disease (CTD). DNA from blood samples is used for sequencing of the TTR gene coding regions by a central lab. Assessments in pts with TTR mutations include cardiac biomarkers, echocardiogram and optional abdominal fat pat aspiration and 6-minute walk test. Descriptive statistics will be utilized.As of May 2015, 146 pts have been enrolled. At baseline, the mean (Std) age of pts is 64 (13) yrs, 61% are men and 66% are AA. A total of 14 (10%) pts had a Val122Ile mutation and 1 pt had a novel mutation Arg103His. The Gly6Ser polymorphism was found in 8 (5%) pts. The Val122Ile cohort consisted of 40% males with a mean (StD) age of 66 (16). Heart failure signs and symptoms and IVS > 12 mm was reported in 71% and 79% of Val122IIle pts respectively. The majority of pts had NYHA class II (56%) and III (22%) heart failure, 21% had low voltage ECGs and 14% had CTD.These preliminary data suggest that approximately 10% of pts with clinical and/or radiologic findings suggestive of cardiac amyloidosis have a pathogenic TTR mutation which could potentially lead to a diagnosis of FAC. Additional data on clinical features and tissue diagnosis of FAC in these pts will be presented."}
+{"text": "Hereditary ATTR amyloidosis with polyneuropathy, also known as Familial Amyloidotic Polyneuropathy (FAP), is a rare, inherited, progressively debilitating disease with a high unmet medical need. The purpose of this analysis is to assess the impact of this disease on healthcare resource utilization, quality of life, employment status, and activities of daily living (ADLs).A Phase 2 open-label extension study of patisiran in FAP patients was utilized to collect patient-reported outcomes, including EQ-5D, Rasch-built Overall Disability Scale (R-ODS), and a healthcare resource utilization questionnaire.The study included 27 patients, 18 males and 9 females, 29-77 years of age. Baseline data are presented for 14 patients with a Polyneuropathy Disability (PND) Score I and 13 patients with a PND Score II or greater. Characterized by FAP Stage, 24 patients are FAP Stage 1 and 3 patients are FAP Stage 2. Two patients (PND Score II or greater) reported a total of six hospitalizations due to FAP in the past 12 months, each for 3 or more nights in duration. Mean EQ-5D scores were 0.82 (PND Score I) and 0.74 (PND Score II or greater). Patients reported their perceived health status on the EQ-VAS with mean scores of 75 (PND Score I) and 60 (PND Score II or greater). Ten patients (8/10 PND Score II or greater) reported they cannot work because of FAP (mean 61 years of age). Patients also reported inability to perform various ADLs. Most commonly, 77% of patients with PND Score II or greater cannot stand for hours (14% in PND Score I) and 69% cannot run (21% in PND Score I).FAP patients experience considerable burden of illness early in the course of disease and this burden increases with disease progression. The factors described will be influential in the development of a comprehensive FAP cost-consequence analysis. Additional parameters may also be needed to fully capture the totality of disease burden."}
+{"text": "Prompt treatment of malaria following adequate diagnosis helps to reduce morbidity and mortality in children. Lack of resources and adequate manpower in developing countries make malaria microscopy difficult. The Rapid Diagnostic Test kit (RDT) remains unpopular despite its availability and ease of use because of lack of local research on its effectiveness leading to over-prescription of Artemisinin Combination Therapy (ACT).A total of 132 children age range 1-9 years were screened for malaria routinely with rapid diagnostic test kits (RDTs HRP 2) and malaria microscopy at the general outpatient department of OAU Teaching Hospital as well as at a comprehensive health centre at Imesi Ile, South West Nigeria while marking the 2013 World Malaria Day. Needle prick was used to collect blood sample for thick and thin smear. Giemsa stain was used to prepare the slide for microscopic examination.Plasmodium falciparum. In the Microscopy category, 35 (26.5%) children tested positive while 97 (73.5%) tested negative for malaria parasite. Out of the 35 children tested positive, RDT picked 33 as positive and 2 as negative, (sensitivity = 94.3%). While out of the 97 that tested negative for microscopy, RDT picked 94 as negative and 3 as positive (specificity = 96.9%). The positive predictive value and negative predictive values are 91.7% and 97.9% respectively.A total of 132 children were recruited into the study. There were more females (59.1%) than males (40.9%). 35 (26.5%) children tested positive while 97 (73.5%) children tested negative for Rapid Diagnostic Test is an effective diagnostic tool for malaria amongst children in the study population. Primary and secondary health centres in the region should adopt Rapid Diagnostic Test in malaria diagnosis before administration of ACTs to avoid unnecessary treatment."}
+{"text": "Non-invasive ventilation (NIV) is the first line supportive treatment in case of acute hypercapnic respiratory failure (AHRF). NIV efficacy is continuously monitored using clinical parameters . The assessment of NIV efficacy however usually requires repeated blood gas analysis after 30 or 60 minutes of treatment. A reliable non-invasive technique to continuously monitor PaC02 during NIV could simplify this evaluation and allow an earlier adaptation of ventilator settings.pC02) during NIV delivered because of AHRF could be of interest for evaluating PaC02.The aim of this study was to assess whether measuring transcutaneous C02 , connected to the patient 15 minutes before the start of NIV. Blood gas analysis and TcC02 recording were performed before initiating NIV and after 30, 45 and 60 minutes of NIV.The correlation between PaC02 and TpC02 was assessed by linear regression (Spearman) and intraclass correlation coefficient (ICC). The agreement between both techniques was assessed using the Bland and Altmann method for repeated measurements.ICU patients requiring NIV for AHRF (PaC02 >42 mmHg) were included in this prospective observational study. TpC02 values ranged from 42 to 84 mmHg. The correlation coefficient RSAPS 2 between PaC02 and TpC02 values was 0.84. The ICC was 0.906. Bland and Altmann graph is illustrated in figure 20 patients  were included in the study. Age 65 [61-72] years II score 32 [28-46]. At inclusion, PaC02 was 57 [51-68] mmHg, Sa02 94 [92-95] % and respiratory rate 25 [21-29] /min. PaC02 values ranged from 43 to 80 mmHg whereas TpC02 and PaC02 was very good. This suggests that C02 transcutaneous measurement could be of interest to evaluate the course of PaC02 during NIV.In a small group of patients undergoing NIV for acute hypercapnic respiratory failure the agreement between T"}
+{"text": "Colorectal cancer (CRC) is becoming a major public health problem globally . It rankTwo techniques were used: IHC using antibodies for MLH1 and MSH2 gene proteins and MSI tests using a panel of five Microsatellites' markers  that have been validated and recommended for tumor characterization as MS-stable, MSI-H or MSI-L. DNA samples from tumors and normal tissues of 83 patients undergoing curative surgery of sporadic CRC were amplified using Polymerase chain reaction (PCR). PCR products were run on ABI prism 310 sequencer and GeneScan; version 310 software was used for analysis. Paraffinized tissue sections slides from the same patients tissues were used for IHC detection of MLH1 and MSH2 proteins.The prevalence of MSI-H, MSI-L and MS-stable were 44.6 %, 31.3 % and 24.1 % respectively. IHC identified 50 cases (60.2%) with loss of expression of MLH1 and 40 cases (48.2%) with loss of expression of MSH2. Concordance rate between MSI and IHC is 55.4%. Furthermore, 28.9% of no concordance is attributed to other MMR genes not included in our study.MSI and IHC are complementary useful techniques for evaluation of MMR status. Further study with a large cohort is needed to evaluate correlation with clinicopathological characteristics and to be used as prognostics.This work was financially supported by King Abdulaziz City for Science and Technology (KACST) under research no (ARP -30-262)."}
+{"text": "On April 21, 2015, the Fairfield Medical Center (FMC) and Fairfield Department of Health contacted the Ohio Department of Health (ODH) about a patient suspected of having botulism in Fairfield County, Ohio. Botulism is a severe, potentially fatal neuroparalytic illness.A confirmed case of botulism was defined as clinically compatible illness in a person who ate food from the potluck meal and had 1) laboratory-confirmed botulism or 2) two or more signs of botulism or one sign and two or more symptomsAmong 77 persons who consumed potluck food, 25 (33%) met the confirmed case definition, and four (5%) met the probable case definition. The median age of patients was 64 years (range = 9\u201387 years); 17 (59%) were female. Among 26 (90%) patients who reported onset dates, illness began a median of 2 days after the potluck (range = 1\u20136 days).Clostridium botulinum type A.Twenty-seven of the 29 patients initially went to FMC. Twenty-two (76%) patients were transferred from FMC to six hospitals in the Columbus metropolitan area approximately 30 miles away; these transfers required substantial and rapid coordination. Twenty-five (86%) patients received botulinum antitoxin, and 11 (38%) required endotracheal intubation and mechanical ventilation; no other patients died. Within 1 week of the first patient\u2019s arrival at the emergency department, 16 patients (55%) had been discharged. Among 19 cases that were laboratory-confirmed, serum and stool specimens were positive for botulinum neurotoxin type A or Interviews were conducted with 75 of 77 persons who ate any of the 52 potluck foods. Consumption of any potato salad  yielded the highest association with probable or confirmed case status , followed by homemade potato salad . Of 12 food specimens collected from the church dumpster, six were positive for botulinum neurotoxin type A; five contained potato salad and one contained macaroni and cheese that might have been contaminated after being discarded.C. botulinum spores, rather than a pressure canner, which does eliminate spores (The attendee who prepared the potato salad with home-canned potatoes reported using a boiling water canner, which does not kill e spores . In addie spores .This was the largest botulism outbreak in the United States in nearly 40 years . Early r"}
+{"text": "Allergic diseases are common in clinical practice and are considered by the World Health Organization (WHO) as an important health problem .Worldwide, about 500 million people are affected (15%) with a prevalence of 20-30% in developed countries . This study aimed to identify the major aeroallergens and their prevalence in a population of patients living in a polluted oasis situated in the southwest of Tunisia. A total of 67 patients were admitted to the Department of Pneumology and Oto-rhino-laryngology at Gafsa Hospital between August 2007 and September 2008. They were invited to a health examination including skin-prick test, blood sampling and assessment of specific IgE to several common aeroallergens. Of the 67 patients, only 39 were sensitive to allergens (58.20%), 23 of whom were sensitive to more than one type of allergen (58.97%). The most common aeroallergens were tree and grass pollen (32.96%), followed by animal dander (19.78%), mites (17.58%), herbaceous pollen (12.08%), mould (6.59%), latex (6.59%) and cockroaches (4.39%).Although this study was limited to a modest target population of patients, we did observe significant results that highlight the most frequently detected allergens in the region of Gafsa. These results are in agreement with reports from other studies conducted in other areas."}
+{"text": "Investigators at August Pi Sunyer Biomedical Research Institute and University of Barcelona performed a prospective surveillance study in 14 patients with immune-mediating relapsing symptoms of post-herpes simplex encephalitis (HSE). Investigators at August Pi Sunyer Biomedical Research Institute and University of Barcelona performed a prospective surveillance study in 14 patients with immune-mediating relapsing symptoms of post-herpes simplex encephalitis (HSE). The study aimed to compare the clinical and immunologic features of HSE in teenage and adult patients with those of young children. Groups were divided into 6 young children aged 6 to 20 months  and 8 teenager and adult patients aged 13-69 years . All patients underwent repeat serum and CSF HSV PCR and MRI of the brain. CSF was also sent for antibodies to cell surface and synaptic proteins, including NMDA and GABA. Repeat CSF was negative for HSV in all patients with symptoms suggestive of disease recurrence. Symptoms concerning for recurrence differed between groups. Adults and teenagers had longer delays in diagnosis  when compared to children . All Children <20months of age developed choreoathetosis  and decreased level of consciousness  in association with IgG antibodies against NMDA receptor subunits (6/6). In contrast, the teenage and adult patients did not develop choreoathetosis. 3/8 older patients presented with symptoms resembling acute viral relapse; 5/8 developed symptoms while in rehabilitation initially attributed to disease recrudescence. 7/8 patients developed severed neuro-psychiatric and behavioral symptoms. 1/8 developed blepharospasm. 5/8 had CSF antibodies against NMDA receptor and 3/8 against unknown neuronal cell surface proteins. In 5/6 patients the MRI showed new areas of contrast enhancement during relapse that decreased after immunotherapy. 1/8 patients showed spontaneous recovery and other 7/8 were treated with immunotherapy. Therapies included steroids alone, steroids with IVIG, or steroids with IVIG, and plasma exchange. Immunotherapy was beneficial in 100% of patients treated. [COMMENTARY. The current literature supports the hypothesis that HSE triggers auto-antibodies against synaptic proteins, like N-methyl-D-aspartate receptor (NMDAR) and other brain autoimmunity , 3, 4. T"}
+{"text": "HIV-associated obstructive portopathy (HIVOP) is an obstruction of the hepatic microvasculature of unknown origin. The purpose of this study was to describe the clinical and paraclinical presentation of the disease and its impact in terms of morbidity.3, including 7 patients with a history of opportunistic infection) with a biopsy-proven or likely HIVOP have been followed up for an average of 6.1 years.Twenty-nine HIV1-infected patients , occult (14%) or symptomatic (37%) portal hypertension , or fortuitous (8%). Hypoalbuminemia (\u226435\u200ag/L) was present in (31%), thrombocytopenia  in 52% and prothrombin rate <70% in 10%. Esophageal varices were detected in 71%. Thrombophilia was present in 23 patients (80%): in head, protein S deficiency (87%). MRI showed in 82% at least 1 morphological abnormality. The average value of the liver stiffness by Fibroscan was 8.3 kPa. During follow-up, there was no radiological improvement, 15 (52%) patients presented with variceal hemorrhage, 10 patients (34%) ascites, 10 (34%) portal vein thrombosis, 7 (24%) an iron deficiency, and 2 (7%) with a protein-losing enteropathy, including 14 patients (48%) with several events. Four patients (14%) were transplanted, 1 (25%) recurred the HIVOP on the graft, and 1 patient is waiting for a transplant.HIVOP is a severe disease associated with high morbidity related to symptomatic portal hypertension, which occurred in 50% and required liver transplantation in 14%. Noncirrhotic portal hypertension (NCPH) secondary to the progressive obliteration of the portal vasculature is one. The first case, reported in 2001, was thought to be a side-effect of ARVs\u2019 exposure.7 Since then, around 100 cases have been reported worldwide with various denominations, including nodular regenerative hyperplasia, hepatoportal sclerosis, idiopathic portal hypertension, obliterative portopathy, and cryptogenic liver disease.8 NCPH in HIV-infected patients may be secondary to deoxynucleotide exposure,9 thrombophilia,10 or to septic embolism.11 HIV-associated obstructive portopathy (HIVOP) is an obstruction of the hepatic microvasculature of unknown origin, and its incidence in a previous study12 was around 2% of HIV patients with liver biochemical abnormalities. The purpose of this study was to describe the clinical and paraclinical presentation of the disease and its impact in terms of morbidity.Liver diseases are prevalent among HIV-infected patients and are increasingly a cause of mortality and morbidity as effective antiretrovirals (ARVs) allow patients with HIV to live longer.We retrospectively analyzed all (29) HIV patients taken care of at our Liver Department with biopsy-proven (or very likely) HIVOP between March 10, 1993 and May 31, 2015.The inclusion criteria were HIV adult patients with histological result of liver vasculature involvement, either nodular regenerative hyperplasia (NRH) or sinusoidal dilatation.The diagnosis of HIVOP was made if histology showed parenchymal hyperplasic nodules without extensive fibrosis, and atrophic and compressed liver plates between regenerative nodules (NRH); or if a set of clinical, biological, and morphological  arguments were associated with a compatible histological examination of NRH . To rule out other causes of liver disease, all patients with extensive fibrosis or cirrhosis were excluded.All liver-related events, namely complications of portal hypertension like ascites, variceal hemorrhage, portal thrombosis, iron deficiency, exudative enteropathy, and liver transplantation, were recorded.Ultrasound abnormalities were reported such as liver dysmorphia, splenomegaly, bypass channels, or portal thrombosis.Magnetic resonance imaging was sometimes performed and the following abnormalities were collected: signal abnormalities, morphological abnormalities (liver dysmorphia or atrophy), nodules, subcapsular fluid overload, enhancement abnormality, signs of portal hypertension, and portal vein injury .Histological analysis included hematoxylin-eosin, Sirius Red, reticulin argentation stainings, and Perls coloration.Since the study was retrospective without any intervention on patients, an ethical approval was not necessary.Quantitative variables were described by the mean and standard deviation. Categorical variables were described by their percentage. Event-free survival was analyzed using the Kaplan-Meier method.3 (median with CI 97.73%). All patients were infected with HIV type 1. Modes of transmission were male homosexual sexual intercourses for 14 (48%), heterosexual sexual intercourses for 12 (41%), and blood transmission for 3 patients (11%) (blood transfusion in 2 and intravenous drug use in 1). Seven patients (24%) had history of opportunistic infection. Twenty-six (90%) patients had been exposed to didanosine (ddI) several years or months before diagnosis of HIVOP and for an average duration of 4 years.Twenty-nine NRH HIV-patients (19 men and 10 women) with a mean age of 47.8 years were included between March 10, 1993 and May 31, 2015. The average duration of the evolution of HIV disease (based on the first date of HIV positive serology) at the time of diagnosis of HIVOP was 12 years and the nadir of CD4 of 210/mmTwenty patients (69%) had at least 1 liver comorbidity: 19 (65%) had resolved hepatitis B, 1 (3%) had hepatitis C co-infection, 1 (3%) had a resolved hepatitis C infection, 1 (3%) had nonalcoholic steatohepatitis, 2 (8%) had excessive alcohol consumption, and 2 (7%) had positive anti-smooth muscle antibodies but without concern regarding autoimmune hepatitis. Five patients (17%) had cardiac comorbidity  and 5 (17%) had renal comorbidity   and cholestasis, reported in 11 patients (38%). The other presentations were occult portal hypertension , variceal bleeding , isolated cholestasis , isolated cytolysis , ascites , and cytopenia . Finally, the diagnosis was incidental on a liver biopsy in 3 cases (10%), 2 for the evaluation of chronic hepatitis C and the other liver biopsy performed during biliary surgery.At the time of diagnosis, laboratory tests revealed cytolysis associated with cholestasis in 13 patients (45%), isolated cholestasis in 9 patients (31%), and isolated cytolysis in 2 patients (7%). Three patients (10%) showed no liver function abnormalities. Sixteen patients (55%) had hypoalbuminemia (<35\u200ag/L), 15 (52%) had thrombocytopenia , and finally a prothrombin rate <70% was present in 3 (10%) patients.Sixteen patients performed Fibroscan with an average value of 8.3\u200a\u00b1\u200a3.3\u200aKPa.At the time of HIVOP diagnosis, digestive upper endoscopy was performed in 28 patients and showed esophageal varices in 20 of them (69%) as well as gastropathy of portal hypertension in 18 (62%). All patients with varices received a primary or secondary prophylactic treatment consisting on a ligation.The average time between the onset of symptoms and liver biopsy was 1 month. Twenty-two biopsies were transcutaneous (76%), 5 were transjugular (14%), and 2 were surgical (7%). The average length of biopsies was 21\u200amm, and the average number of portal tracts was 11 (Table Nodular architecture was found in 21 biopsies (72%), liver plates were thickened in 15 biopsies (52%), and compressed in 13 biopsies (45%). Sinusoidal dilatation was present in 16 biopsies (55%), and peliosis signs in 2 of them (8%). Regarding fibrosis, it was centrolobular in 6 samples (21%), perisinuso\u00efdal in 8 samples (28%), portal in 11 samples (38%). Macrovacuolar steatosis (<20%) was found in only 7 biopsies (24%).Ultrasound evaluation showed liver dysmorphia associated with splenomegaly in 12 patients (46%), isolated liver dysmorphia in 4 patients (14%), isolated splenomegaly in 4 patients (14%). Eleven patients (38%) had portocaval derivations and 3 (10%) had a portal thrombosis.Twenty-two of the 29 patients (76%) had at least 1 MRI with an average of 2.5 years after the diagnosis of NRH. Eighteen (82%) of these MRIs showed at least 1 morphological abnormality: 7 (32%) had atrophy of the right liver, 5 (23%) had a specific funnel aspect of segment IV, 4 (18%) had dysmorphia, and finally 2 (9%) had liver with bumpy shape.These MRIs showed signal abnormalities in 11 patients (50%): 32% of cases with heterogeneous appearance and 18% of cases with hyperintense bands on T2 sequence. After injection of contrast, there was abnormal enhancement in 7 patients (32%) and subcapsular vascular overload in 2 patients (9%). Nodules were visualized in 27% and micronodules in 23%. Signs of portal hypertension were present in 13 patients (59%). Finally, the portal vein was normal in 11 (50%), its walls were thickened in 8 (36%), and portal thrombosis was present in 5 patients (23%), including 4 (18%) associated with cavernoma.Abnormalities of thrombophilia tests were present in 23 patients (80%): 20 (87%) had a protein S deficiency, 3 (13%) hyperhomocysteinemia, 1 (4%) resistance to activated protein C, 1 (4%) heterozygous mutation of Factor V, 1 (4%) mutation of factor II, 1 (4%) anti-phospholipid and anti-cardiolipin antibodies and one (4%) isolated anti-cardiolipin antibodies.The mean follow-up was 6.1 years. No patient died during the follow-up period.Fifteen (52%) of the patients had a variceal bleeding, 10 patients (34%) developed ascites, 10 patients (34%) had portal vein thrombosis, 7 (24%) had iron deficiency, and 2 (7%) had protein-losing enteropathy. Fourteen patients (48%) had several events, 4 patients (14%) a single event, and 11 patients (38%) remained without clinical event. Seven patients (24%) were treated with anticoagulants (anti-vitamin K), and 1 (4%) was already treated for some other cardiac reason. No complication of anticoagulants was noted. In 1 patient (3%), 2 TIPS were attempted for recurrent gastrointestinal bleeding without success. Four patients (14%) were treated by orthotopic liver transplantation, including 1 patient (25%) who had biopsy-proven recurrence of HIVOP on the allograft two years following transplantation despite pre-emptive anticoagulation. Another patient (4%) is currently listed on national list and is awaiting liver transplantation despite anticoagulation. Survival without event is showing in Figure Twelve (54%) of 22 patients who underwent MRI in the assessment of disease NRH, had at least a second follow-up MRI to evaluate the radiological progression of their disease. Six (50%) had radiological stability of their disease: three (25%) showed an increase of liver dystrophy and/or portal hypertension and three (25%) had portal thrombosis. No radiological improvement was witnessed. However, no recanalization of the portal vein was observed when it was thrombosed, despite anticoagulation treatment.HIVOP has a low prevalence, but may be underdiagnosed since patients are often asymptomatic (62% in our study) at time of diagnosis and liver function test abnormalities may be attributed to liver comorbidities.It is difficult to rely solely on the fine needle biopsy for the diagnosis of NRH: nodular architecture signing the diagnosis of NRH was present in 72% of patients, whereas the others had a biological set of clinical and pathological signs allowing the diagnosis.Disease progression is characterized mainly by the occurrence of variceal bleeding in 52% of patients. Another common event was the occurrence of portal vein thrombosis (34%), which can also aggravate or complicate portal hypertension.13 In a case\u2013control study, cryptogenic hepatitis in HIVpatients, there was a significant association between the occurrence of cryptogenic hepatitis and duration of exposure to didanosine.12 In our cohort, 90% of patients had been indeed exposed to didanosine (an average duration of 4 years) and 45% to zidovudine. However, if some treatments are known to induce vascular disease , no nucleoside inhibitor of reverse transcriptase or protease inhibitor has been clearly associated at this date with occurrence of vascular disease. Age of HIV infection (average of 12 years duration) probably explains that majority of patients received didanosine and it is difficult that this factor was not found frequently in uni- or multivariate analyses. It is interesting that 2 of our patients did not experiment didanosine.In patients living with HIV, NRH could have several possible causes leading to this \u201cendothelitis\u201d morphology. First, opportunistic infections could be involved, as in the case of bacillary angiomatosis. This seems unlikely: only 7 of our 26 patients had a history of opportunistic infection, nadir CD4 cell count was quite high (210\u200acells/\u03bcl) in our patients, and all had controlled HIV disease. Antiretroviral therapy has been implicated: in a recent review, antiretroviral drug-related hepatotoxicity was reported in 2% to 18% of patients and mainly attributed to antiretroviral of first (didanosine as first causative agent) and second generations.We have few arguments for a thrombotic \u201ccruoric\u201d origin of NRH, whether morphological (MRI) or clinical . Benefit of anticoagulants treatment should be discussed in these patients. In our study, 8 patients have been treated with anticoagulants, including 3 after the diagnosis of portal vein thrombosis. None of these patients had bleeding complications, none of the patients repermeabilized its portal thrombosis, and none improved their thrombocytopenia.A patient receiving anticoagulants for a cardiac reason presented variceal bleeding and portal vein thrombosis with cavernoma under treatment. The other 3 patients treated with anticoagulants have not developed thrombosis.We speculate that some portal vein thrombosis can be because of a thickening of the vessel walls (endothelitis) and appears to be irreversible despite anticoagulants. The therapeutic strategy could be to preventively treat the patients with a narrowed caliber of the portal vein on MRI for primary prevention of thrombosis.14 which could promote the development of portal hypertension or NRH. Protein S deficiency may be associated with the NRH.15 Above, an acquired protein S deficiency has been reported in 15% to 20% of patients infected with HIV.17 Eight observations of HIV-infected patients (included in our cohort) having histologically proven NRH18 had all protein S deficiency. A statistical association between protein S deficiency and HIVOP has been shown19 and anti-PS antibodies were found in these patients.10We previously suggested that NRH was linked to a prothrombotic state. Indeed, HIV is associated with an increased risk of thrombosis,In our study, 23 of 29 (80%) patients had at least 1 abnormality in thrombophilia tests. The majority of them (87%) had a protein S deficiency. We have no data for all  on the self-PS antibodies present in these patients. In this thrombophilic background, which could be associated with the immune restoration promoting production of anti-PS antibodies as other self-antibodies, nodular regenerative hyperplasia could be because of the occlusion of small portals veins linked to a prothrombotic state. Then, we discuss the possibility of an \u201cautoimmune\u201d etiology resulting in thrombophilia causing microthrombi. If we confirmed such a hypothesis, the use of immunotherapies  rather than anticoagulants in the treatment of these patients may be relevant.If there was no mortality associated with HIVOP, most of patients had significant morbidity, with symptomatic portal hypertension and/or liver failure. In addition, NRH is burdened with significant morbidity since the rate of liver transplantation was 14% in our series: 4 patients (14%) underwent liver transplantation; they showed association of bleeding complications on portal hypertension and portal thrombosis and malnutrition with refractory ascites. One patient was registered on waiting list for liver transplantation at the end of our study. After liver transplantation, except a case of recurrence on graft, there were no other complications and patient symptoms decreased and their thrombocytopenia stabilized or improved. Among the post-transplant liver biopsies follow-up, one of these transplanted patients treated with anticoagulants presented with pathological signs of recurrence of NRH on the graft 2 years post-transplant; this suggests once again the lack of effectiveness of anticoagulants.The main limitation of our study is the absence of control group of HIV-infected patients without HIVOP, which precludes any calculation of incidence of HIVOP. The second one is the restriction to biopsy-proven cases, which leads to the inclusion of only patients with hepatic abnormalities or symptoms, suggesting an underestimation of the prevalence since asymptomatic patients (evidenced by the post-transplant recurrence) were not included.This report of the largest cohort of patients with HIVOP and with the longest follow-up reveals that HIVOP is often asymptomatic until occurrence of complications, suggesting that it is underdiagnosed. Moreover, we describe occurrence of variceal bleeding (>50% of the patients), portal vein thrombosis (30%), and requirement for liver transplantation (14%) indicating the significant morbidity related to this disease and the need of a systematic screening for HIVOP (with liver biopsy) in HIV-infected patients with liver dysfunction. Finally, we discuss new therapeutic approaches given its immune-mediated thrombotic etiology, including the use of immune therapies rather than anticoagulants."}
+{"text": "First identified in 2005, PARV4 is best characterized in Western cohorts where it is strongly associated with other blood borne viruses and occurs only in individuals with risk factors for parenteral infection . However, studies in Africa have shown evidence of PARV4 in subjects with no clear risk factors for acquisition of blood borne viruses. The clinical significance of PARV4 remains uncertain, but there is growing interest in the role of coinfecting pathogens in shaping outcomes of HIV, and in chronic viral infections as determinants of immunological development in childhood.We studied a cohort of HIV-infected mothers (n=32) and children , and HIV-negative pediatric controls  in Kimberley, South Africa. PARV4 serostatus was determined by ELISA for IgG to the PARV4 VP2 protein. HIV viral load was determined using the Abbott m2000 assay, and CD4 T cell count by flow cytometry.In this cohort, 45/96 individuals (46.9%) were positive for PARV4 IgG, including 19/32 adults (59.4%) and 26/64 children (40.6%). The seroprevalence of PARV4 IgG increased with age, demonstrating acquisition throughout childhood, plateauing by age 6-10 years . There was strong concordance between maternal and child infection, with the mother\u2019s PARV4 status being a clear predictor of IgG in her offspring (p=0.006). HIV-negative individuals were more likely than HIV-positive subjects to be PARV4 IgG positive (p=0.03), although this relationship may be confounded by age. There was no relationship between PARV4 status and HIV viral load or CD4 T cell count in HIV-infected adults or children.The epidemiology of PARV4 in this cohort contrasts strikingly with that in Western countries: the prevalence of PARV4 IgG approached 50%, with evidence for ongoing transmission throughout the early years of life. The observed concordance within families is suggestive of maternal to child transmission. Future studies are planned, to investigate further the relationship between PARV4 status and outcomes of HIV infection."}
+{"text": "Median OS was 8.2 months (95% CI 3.8\u201314.2 months). Median survival in months, based on MSKCC and Heng risk groups, was favorable 89.3 versus 84.5, intermediate 9.5 versus 12.7, and poor 3.9 versus 5.1. None of the IHC markers predicted outcomes of treatment with VEGF or mTOR inhibitors. Only tumor IMP3 expression was associated with inferior OS, although not statistically significant . The study was limited by small sample size.Metastatic renal cell carcinoma with sarcomatoid histology (SmRCC) is associated with poor survival. No data is available from randomized trials on the efficacy of vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) inhibitors in SmRCC. We identified SmRCC patients from a single institutional database. To identify predictive and prognostic biomarkers, immunohistochemistry (IHC) analysis was performed on the tumor samples for downstream targets of VEGF and mTOR pathways. Survival outcomes were stratified by IHC analysis, extent of sarcomatoid component, Memorial Sloan-Kettering Cancer Center (MSKCC), and Heng risk criteria. Twenty-seven patients with SmRCC were included. First line therapy included targeted therapy ( It is estimated that, in 2014, renal cell carcinoma (RCC) accounted for approximately 64,000 new cancer cases and 14,000 deaths in the US [The advances in understanding of the pathogenesis of clear cell variant metastatic RCC (cc mRCC) have revolutionized its treatment with development of drugs targeting angiogenesis and mammalian target of rapamycin (mTOR) pathways. Over the past decade, seven new drugs were approved for clinical use in cc mRCC including tyrosine kinase inhibitors (TKIs) of the vascular endothelial growth factor (VEGF) receptor , all patients with SmRCC were included. Clinical characteristics and treatments received were assessed by chart review. Vital status was obtained from the social security death index. The University of Utah Institutional Review Board (IRB number 67518) approved the study protocol.Except in one patient, primary nephrectomy samples were assessed for diagnosis of SmRCC. In one patient who had not undergone prior nephrectomy, diagnosis was confirmed by core biopsies of the metastatic disease site. Two independent pathologists (Daniel Albertson and Ting Liu) estimated the degree of sarcomatoid component and reported the IHC analysis as outlined below. Sarcomatoid predominant and nonpredominant variants were defined by the sarcomatoid component of \u226520% or <20%, respectively , 22. IHCMedian overall survival was assessed by Kaplan-Meier method with stratified log rank by IHC analysis, extent of sarcomatoid component, MSKCC risk criteria, and Heng risk criteria. Cox proportional hazards models were used to determine hazard ratios (HR) and 95% confidence intervals (CI).n = 24) included targeted therapy (n = 19), immunotherapy (n = 4), and cytotoxic chemotherapy (n = 1). Two additional patients who received first line immunotherapy subsequently received targeted therapy at progression. Patients belonged to the following MSKCC risk groups: 2 (7%) favorable, 18 (67%) intermediate, and 7 (26%) poor risk. Heng risk group stratification was as follows: 1 (4%) favorable, 17 (63%) intermediate, and 9 (33%) poor risk. IHC analysis was performed in 21 tumor samples and in 6 patients tissue was not available. Comprehensive IHC analysis was performed in 17 patients and IMP3 was analyzed in 4 additional patients due to limited tissue availability.The cohort included 27 patients, 18 men (67%) and nine women (33%), with a median age of 63 years (range 39\u201374 years) . Twenty-n = 3).Median overall survival of the cohort was 8.2 months .Median OS based on MSKCC risk criteria  was favocriteria  was as fsurvival . Median http://dx.doi.org/10.1155/2015/181926). Of 21 patients in whom IMP3 analysis was available, the median survival in IMP3 positive patients  was 4.9 months versus 14.2 months in negative patients ; however, the difference was not statistically significant  versus a TKI . The median sarcomatoid percentage in IMP3 negative and positive patients was 10% versus 50%, respectively; P = 0.14. In IMP3 positive patients (n = 14) all patients except one were considered sarcomatoid predominant , whereas sarcomatoid nonpredominant features were observed in 4 of 7 (57%) IMP3 negative patients. This correlation with sarcomatoid predominant and IMP3 positivity was statistically significant; P = 0.03.Of all the markers evaluated by IHC, only IMP3 expression was associated with overall survival  [Given the lack of approved agents, therapies inhibiting VEGF and mTOR pathways are used in the treatment of SmRCC, based on extrapolation of data from randomized trials in cc mRCC. There is a need to identify prognostic and predictive biomarkers to these therapies (VEGF inhibitors versus mTOR inhibitors) in SmRCC. Thus, we conducted IHC analysis of tumor samples for downstream targets VEGF and mammalian target of rapamycin pathways and correlated with treatment and survival outcomes in our patients with SmRCC. In our current analysis, none of the IHC markers predicted response to treatment with either VEGF or mTOR inhibitors. Only IMP3 expression had a trend for association with poor overall survival. IMP3 is an oncofetal protein belonging to the family of insulin-like growth factor II (IGF-II) mRNA-binding protein (IMP) that also includes IMP1 and IMP2 . The bio< 0.001) . HoweverSmRCC is associated with inferior outcomes with currently approved treatments for mRCC. MSKCC and Heng risk stratification hold their prognostic value in these patients with SmRCC. Percentage of sarcomatoid component directly correlated with IMP3 expression. Tumor IMP3 expression is associated with inferior survival. In our cohort the percentage of sarcomatoid component using the traditional cutoff of 20% did not correlate with survival. The main limitation of this study is the small sample size due to the rarity of disease. Lack of uniform reporting of sarcomatoid differentiation is a major concern for identification of this subset of patients. We overcame this issue by reassessment of pathology samples by two independent genitourinary pathologists to confirm the presence and estimate the degree of sarcomatoid differentiation. Another limitation is that laboratory and imaging studies were not performed at predetermined intervals, due to the retrospective nature of study. However all patients received standard of care treatment as per our institutional guidelines. Further validation of these findings is needed in a larger cohort of patients with SmRCC.The immunohistochemistry staining of the tumor tissue was performed for downstream targets of vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways and the scores of all patients (1 to 27) are outlined in the Supplementary Table 1."}
+{"text": "According to recent studies about 1-3% hypersensitivity reactions are accompanied by skin eruptions. Among these toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are rare and the most severe adverse cutaneous drug reactions that predominantly involve the skin and mucous membranes. TEN and SJS affecting approximately 1-4/1,000,000 annually with average reported mortality rate 25-35% (TEN), and 1-5% (SJS). The aim of this work was to study the frequency of severe bullous delayed allergic reactions, like TEN and SJS, their clinical presentations, causative drugs, treatment and the diagnostic approach required.We followed up 33 patients  aged 21-80 years with various severe bullous dermatoses in dermatology department of our hospital.Most of the patients had drug hypersensitivity reactions (n=22) and most of them were female older than 70 years. 3 of them had TEN and 7 suffered from SJS. The causative drugs of TEN and SJS were sulfonamides , NSAIDs  and anticonvulsants . The most common drug was sulfamethoxazole (18%). The most severe reactions were caused by sulfamethoxazole (13%), metamizole (4%) and carbamazepine (9%). Mortality rate was about 4% (n=1).The results of our study indicate that TEN and SJS may occur in about 32% patients with severe bullous dermatoses. Sulfanonamides, NSAIDs and anticonvulsants are the most frequently implicated drugs. Diagnosis relies mainly on clinical symptoms together with the results of a skin biopsy. Due to the high risk of mortality, management of patients with severe bullous dermatoses, especially TEN and SJS, requires rapid identification and interruption of the culprit drug, specialized supportive care and immunomodulatory therapy."}
+{"text": "Osmophobia, or olfactory hypersensitivity, has variable prevalence in children with headache and was proposed as an additional criterion for the diagnosis of migraine in the appendix of the International Classification of Headache Disorders (ICHD)-III beta, showingAll the children admitted for headache to a Pediatric Headache Centre from 01/01/2013 to 31/12/2014 were included in the study. For children admitted in 2014, the diagnosis was carried out according to the ICHD-III beta criteria; for those admitted in 2013 the diagnosis was revised according to the same classification. We investigated the presence of osmophobia and type of offending smells reported by the patients.We included 482 subjects : mean age 10.2 years (range 2.5-17.5). Three hundred and forty-four patients (71.3%) had a diagnosis of migraine without aura, 25 migraine with aura (5.1%); 93 children (19.2%) showed tension-type headache; 17 children (3.5%) had an unspecified form of headache or headache not elsewhere classified; 3 patients (0.62%) presented episodic syndromes that may be associated with migraine. Out of 39 patients (8.1%) reporting osmophobia, almost all had migraine  and only 1 was diagnosed as tension-type headache. Osmophobia was a symptom detected in 10.4% of patients with migraine without aura and in 8% with migraine with aura. The most frequent offending smells were: perfume in 12 cases (30%), 9 food (22.5%), 4 cigarette smoke (10%), 2 food plus perfume (5%), 1 perfume plus cigarette smoke (2.5%), 5 other odours (15%) and 6 undefined (15%).Our study showed a lower prevalence of osmophobia in children with headache than that reported in the literature. However, we confirm that osmophobia is more specific for migraine without aura. As already demonstrated in adults and younger patients, osmophobia should be considered in clinical practice as a peculiar symptom useful in the differential diagnosis between migraine without aura and tension-type headache in childhood.Written informed consent to publication was obtained from the patient(s)."}
+{"text": "Leishmania tropica in 85% and L. major in 15% of patients. After 3 months of megulamine antimonite therapy, patients initial cure rate was 82%.In September 2012, a cutaneous leishmaniasis outbreak began among Syrian refugees in Lebanon. For 948 patients in whom leishmaniasis was not confirmed, we obtained samples for microscopic confirmation and molecular speciation. We identified  The Syrian population has been affected by the protracted conflict and ongoing insecurity in the Middle East. The United Nations High Commissioner for Refugees estimates that >4.1 million refugees have been displaced into temporary settlements in neighboring countries, including 1.5 million into Lebanon   are transmitted by the bite of the female sandfly  began documenting the epidemic during trips to multiple refugee camps in eastern Lebanon ; the epidemic later expanded to camps throughout the country. During the study, 1,275 patients from 213 displaced families were triaged into 3 groups: l) leishmaniasis diagnosed, confirmed, and partially treated; 2) leishmaniasis diagnosed, confirmed, but not treated; and 3) leishmaniasis not diagnosed. The first 2 groups comprised 55 families; the remaining 158 families (948 persons) were triaged for diagnosis confirmation and are included in the subsequent statistical analyses. Data were collected at the refugee camps and included punch biopsy specimens for 1 patient/family. We used punch biopsy for microscopic confirmation and for molecular analysis by PCR using a previously published protocol  patients were <18 years of age. Each family comprised 3\u201313 members (mean\u00a06), and the percentage of family members infected ranged from 8% to 100% (mean\u00a052%). The refugees had fled from areas to which leishmaniasis is endemic and nonendemic. Most of the refugees we encountered had migrated from Aleppo (74 [67.3%] patients), followed by Homos (30 [27.3%] patients) and Damascus (6 [5.4%] patients). Only 1 Lebanese resident with no history of travel during the past 5 years had leishmaniasis. Our sample population was scattered predominately among 4 regions of Lebanon .L. tropica in 85% of patients and L. major in 15%.The refugees in our study had been in Lebanon for 1\u201324 months (mean\u00a05 months) and reported that the first time they saw a cutaneous lesions was 1\u201327 months (mean 5 months) before being examined. Most (77%) patients reported the appearance of the first lesion after being in Lebanon for >2 months, and 53% of patients recalled history of an antecedent insect bite. The head and neck were the most common locations for the cutaneous lesion (43% of patients), followed by the upper extremities (26%) and lower extremities (11%). Patients had 1\u201315 lesions (mean\u00a03). Lesion size ranged from 1 cm to 15 cm (average 2.6 cm). Verrucous lesions, with or without ulceration, were the most common lesion type (56%), followed by plaque/nodular lesions (43%) and papular lesions (2%). Most patients (83%) had dry lesions; 7 persons (4%) had primary wet lesions, and 12 (8%) had both. All patients had active lesions without evidence of healing or scarring. Speciation by PCR yielded >1 of the following: disease compromising the function of vital sensory organs  (27%); lesions >5 cm in diameter (49%); disfiguring facial lesions (37%); special forms, such as sporotrichoid or lymphangietic with satellite lesions (9%); and lesions present for >12 months\u2019 duration (9%) (Fifty-nine percent of patients had ion (9%) . The aboIn May 2013, the World Health Organization (WHO) donated 10,000 doses of megulamine antimonate . As of April 2013, 5,091 ampoules of intralesional or intramuscular medication had been used to initiate or continue treatment of all 1,275 patients triaged. Eighty percent received intralesional therapy, and 20% received intramuscular therapy in accordance with WHO recommendations . Poverty, malnutrition, population displacement, weakened immunity, and poor housing are all risk factors for cutaneous leishmaniasis  and prolonged disease courses necessitating treatment with intramuscular rather than intralesional medication. Local collaboration, early detection, and diagnosis, along with speciation of the parasite, were of paramount importance to ensure the effective delivery of treatment and successful control of the epidemic.Although Lebanon remains hypoendemic for cutaneous leishmaniasis, experience has suggested that rates within Lebanon were previously low and restricted to areas bordering Syria (Syrian refugees in temporary, unsanitary, resource-poor settlements, which are breeding grounds for disease and disease vectors, Beirut, Lebanon, 2012."}
+{"text": "A meta-analysis by deBondt declared ultrasound guided fine needle aspiration cytology (USgFNAC) as the method with the highest diagnostic odds ratio for detecting metastatic nodes in head and neck squamous carcinoma (HNSCC). Sentinel node biopsy (SNB) is another emerging method for evaluating neck nodes in HNSCC with reported high sensitivity and negative predictive value (NPV).The aim of this study was to compare USgFNAC with SNB for the preoperative evaluation of the clinically negative neck in T1 & T2 oral cavity squamous cell carcinoma (OCSCC).This is a prospective observational study in 51 patients with T1-T2 N0 OCSCC. Pre-operative ultrasonography (US) of the neck was performed in all patients. USgFNAC was performed in patients where US was reported as indeterminate or positive. SNB was performed in all patients and was followed by elective neck dissection (END). The sensitivity, specificity, positive predictive value (PPV) and NPV of SNB, USgFNAC and US were calculated considering END and histopathology (HP) as the gold standard.The incidence of occult metastasis on HP was 26.4%. The sensitivity, specificity, PPV and NPV were 71.4%, 100%, 100% and 90.2% for SNB; 50%, 82%, 50% and 82% for US; and 14.3%, 100%, 100% and 76.5% for USgFNAC respectively.The meta-analysis by deBondt with reported highest accuracy for USgFNAC included both clinically positive and negative necks. This study evaluated USgFNAC and SNB in the clinically negative neck in T1-T2 oral cancers and found SNB clearly superior to USgFNAC."}
+{"text": "To assess epidemiological, social and clinical features of patients treated for hereditary angioedema in a referral outpatient clinic at Hospital Santa Casa de Misericordia de Vitoria, ES.An observational, descriptive, cross-sectional study, based on a clinical-epidemiological survey of 51 patients with confirmed diagnosis of hereditary angioedema (HAE) from April 2011 to June 2014. Diagnostic confirmation was through the measurement of C4 and C1 inhibitor (C1-INH) quantitative and functional.Data from 51 patients, 29 (57%) females and 22 (43%) males, from 5 to 88 years old (mean: 32 years) was evaluated. Patients belonged to 7 families, 20 of them from the same family. The mean age of onset was 10 years and of diagnosis 26 years. Fifty (98%) patients were symptomatic, and 28 (55%) had experienced laryngeal edema. Deaths by laryngeal edema had occurred in 6 families. Crisis triggering factors were identified in 44 (86%) patients. Forty-five (88%) patients presented HAE due to quantitative deficit of C1-INH. Maintenance treatment was required for 32 (63%) patients, of whom 26 (81%) used Danazol, 5 (16%) Tranexamic acid, and 1 (3%) both. Thirteen (28%) patients needed icatibant to treat 23 crises.The diagnosis of HAE is still late and deaths due to severe attacks continue to occur. Therefore, it is important that health professionals are able to recognise and diagnose the disease and treat patients appropriately, as well as providing pharmacological services to control the disease."}
+{"text": "To evaluate the potential of FDG PET/CT vs. stand-alone CT in the assessment of histopathologically verified colon cancer in primary staging, re-staging and follow up.70 patients  were included in this retrospective study: 28 (40%) primary staging, 28 (40%) re-staging and 14 (20%) follow-up patients.Fifty-eight (58/70) patients (83%) had a primary tumour stage of \u2265 T3. Patients with a known secondary carcinoma were excluded. Diagnostic contrast-enhanced CT was available in all patients (together with PET or in a separate setting with the same acquisition parameters).The CT and FDG PET reports were examined for all patients. In discordant cases, images of both modalities were re-evaluated by a radiologist and a specialist in nuclear medicine separately.All results were verified with histological findings or imaging and/or clinical follow-up studies for at least six months.In the preoperative setting, additional FDG PET had an influence on the staging in 11 (11/28) patients (39%) comparing to CT alone:Nine (9/28) patients (32%) were downstaged, 6 of them with suspicious organ metastases, 3 patients with suspicious lymph node metastases and 1 patient with both suspicious organ metastases and lymph nodes metastases on CT.Two (2/28) patients (7%) were upstaged by FDG PET/CT, one of them with an unclear lung lesion on CT and a malignant hilar lymph node. The second patient showed peritoneal carcinosis on FDG PET.Comparing with stand-alone CT, only 3 (3/42) patients (7%) from the restaging and follow-up group were downstaged by additional FDG PET, while concordant findings were seen on both imaging modalities for the rest of the patients.This study clearly showed that for primary staging of distant metastases in colon cancer patients FDG PET/CT is more advantageous and overcomes the lower specificity of CT alone.Comparing both modalities in postoperative cases, FDG PET provides additional findings only in few cases."}
+{"text": "After publication of this work , we beca1) In the results, second paragraph, second last sentence, it has to be clarified: High functional improvement (NASS) was associated with high reduction of CSQ catastrophizing (19.4% explained variance), low baseline NASS function (11.4%), NASS pain relief (11.3%), and low baseline NASS pain (5.9%).2) In the results, third paragraph, the results of the 6\u2009month follow-up rely on Table two.3) In the same paragraph later on, the following is more precise: The most important associative factor for high pain relief (NASS) was a low NASS baseline pain level (reflecting high pain) (35.5%), high improvement in NASS function (14.8% explained variance), and a low baseline score on NASS function (13.8%). And later on:High functional improvement (SF-36) was associated with high reduction of HADS depression (20.5% explained variance), low baseline SF-36 function (19.3%) and high baseline depression on the HADS (12.2%), as well as pain relief on the SF-36 (6.6%).4) In Table three Table\u00a0 here, mi5) In the discussion, third paragraph, the following has to be clarified: Our data suggest that patients suffering from severe pain and/or severe disability were more likely to improve and to profit from rehabilitation, because low baseline levels of the pain scores (reflecting much pain) and of the function scores (reflection much disability) were most associated with improvements in these dimensions.These corrections substantially improve comprehensibility and distinctness of the data and the interpretations. However, the corrections do not alter the results and the conclusions of the study.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2474/15/195/prepub"}
+{"text": "Quality of life (QOL) has become an increasingly recognized component of recovery for women with substance use disorders (SUDs) -3. HowevData were collected from 377 women at three county-funded treatment programs. Women were interviewed at 1 week, and at 1, 6, and 12 months post-treatment intake (81% retention). The World Health Organization Quality of Life Measure (abbreviated version) assessed QOL over time. Latent Class Growth Model (LCGM) was performed to identify QOL trajectories of underlying subgroups of the women. The model fit was evaluated by the Bayesian Information Criteria and the sample sizes of the smallest class. Multinomial logistic regression explored demographic, clinical, and personal network factors associated with the QOL trajectories. Lastly, we explored the relationship between the QOL trajectories and substance use over 12 months.The majority of participants were African American (60%), received government assistance (72.5%), and had co-occurring mental and substance use disorders (73.4%); 42 percent used alcohol and/or drugs during the 12 month follow-up period. Mean QOL at intake was 61.2 (SD = 15.62).LCGM indicated three different trajectories in QOL Figure : a) consFindings highlight three distinctive QOL trajectories and their association with substance use treatment outcome. Fifteen percent of the women had consistently low levels of QOL, which decreased over time and increased odds of substance use post-treatment, suggesting this group may need targeted intervention and follow-up."}
+{"text": "Headache is the most frequent presenting symptom of cerebral venous thrombosis (CVT), most commonly associated with other manifestations.We investigated the pattern and location of headache in consecutive sixty patients with confirmed diagnosis of CVT to elucidate clinical characteristics of headache and its profile.Patients with diagnosis of CVT referring to Ghaem hospital neurology department a referral neurology center in north eastern Iran (Mashhad- Iran) were recruited consecutively during one year and followed for 12 months. Diagnosis of CVT was made by magnetic resonance imaging (MRI) combined with MR venography (MRV): both increased signal on MRI T1 and T2 weighted images and the absence of flow was required to confirm diagnosis.Age range was 18\u201383 years (mean: 38.11 years). On presentation, study of location of headache showed 34(56.7%) had diffuse headache, 10(16.7%) frontal, 7(11.7%) hemi cranial, 5(8.3%) temporal and two (3.3%) patients had temporal and occipital headaches. Nine (15%) patients presented with thunder club headache. Only one patient had persistent headache after one year follow up. 51(85%) patients had papilleadema. Duration of headache in 36(60%) patients was between three to seven days.There is no special, consistent, identifiable pattern of headache in CVT patients.No conflict of interest."}
+{"text": "Background. Herpes zoster infection is a painful worldwide disease. Inappropriate and delayed treatment causes prolongation of the disease with debilitating symptoms and postherpetic neuralgia. Method. A cross-sectional study evaluated shingles cases admitted in a teaching hospital with one-year followup in north of Iran from 2007 to 2013. Results. From 132 patients, 60.4% were male. Head and neck involvement occurred in 78 people (59.1%), thoracoabdominal region in 37 cases (28%), and extremities in 16 cases (12.1%), and one case (0.8%) got multisites involvement. 54 cases (40.9%) had predisposing factors including diabetes mellitus in 26 cases (19.7%), malignancy in 15 (11.4%), immunosuppressive medication in 7 (5.03%), HIV infection in 3 (2.3%), radiotherapy in 2 (1.5%), and tuberculosis in one patient (0.8%). The most common symptoms were pain (95.5%), weakness (56%), fever (31.1%), headache (30.3%), ocular complaints (27.3%), itching (24.2%), and dizziness (5.3%). 21 cases (15.9%) had bacterial superinfection on blistering areas and overall 18 cases (13.6%) had opium addiction. 4 cases (3.03%) died during admission because of comorbidities. Postherpetic neuralgia was reported in 56 patients (42.5%) after three months and seven cases (5%) in one-year followup. Conclusion. Shortening interval between skin lesion manifestation and starting medication can accelerate lesion improvement and decrease disease course, extension, and complication. Chickenpox and herpes zoster are caused by varicella zoster virus (VZV), a DNA virus belonging to the herpes virus group. Primary infection with VZV causes chickenpox. after resolving of chickenpox, the VZV remains latent in the nerve cell bodies and less frequently the nonneuronal satellite cells of the dorsal root, cranial nerve, or autonomic ganglia. Herpes zoster, also known as shingles, results from reactivation of the latent infection .There is considerable interest in the disease due to epidemiological variations between geographic location, especially between temperate and tropical regions of the world .VZV remains latent in human nerve tissue and reactivates in approximately 15% to 30% of infected persons during their lifetime, resulting in herpes zoster (shingles). Shingles usually presents as a vesicular rash with pain and itching in a dermatomal distribution [Shingles incidence increases with age, especially after the age of 50 and is more common among immunocompromised persons and among children with a history of intrauterine varicella or varicella occurring within the first year of life; the latter have increased risk of developing shingles at an earlier age .Diagnosis of herpes zoster depends on clinical pictures and laboratory confirmation is not usually indicated. Serologic testing is not helpful. Serology of exposed contacts is not routinely recommended, although it may be requested in certain circumstances  .The most striking feature of shingles is the increase in incidence found with increasing age. Decreasing cell mediate dimmunity (CMI) associated with aging is thought to be responsible for these increased rates. Similarly, the decreased level of CMI among persons with malignancies and HIV infection is thought to be responsible for higher rates of shingles among them. Approximately 4% of individuals will experience a second episode of shingles .Postherpetic neuralgia is the most challenging and debilitating complication of herpes zoster in the immunocompetent host . PersistIn this research we studied clinical characteristics of herpes zoster in patients who are admitted in a teaching referral hospital in north of Iran.This is a prospective-descriptive study about clinical symptoms, signs, and complications of 132 shingles patients who are admitted in a referral teaching hospital in north of Iran with one-year followup. Our sampling method was accessible sampling. Clinical criteria which we considered as shingles were any person with at least one of the following two: abnormal skin sensations with an acute onset of localized maculopapulovesicular unilateral rash, involving at least one dermatome (Zona), or an acute onset of disseminated maculopapulovesicular rash, beyond the involvement of one dermatome.We started this study in January 2007 and recorded herpes zoster patient's data and followed them in two episodes, 3 months and 12 months after discharge from our hospital. This study continued until December 2013. A general physician and a nurse called the patients and recorded the data. Then, the collected data were processed using SPSS software (ver. 13).132 patients were admitted in Razi Hospital (therapeutic center of infectious diseases in north of Iran) in Mazandaran province, during 6 years from 2007 to 2013, with shingles impression.52 cases (39.6%) were female and 80 (60.4%) were male. Mean age was 56.3 \u00b1 20.1.126 cases (95.5%) had past history of chickenpox. The average time from the beginning of symptoms to admission was 5.7 days (SD = 4.240). Head and neck involvement occurred in 78 cases (59.1%), trunk involvement in 37 cases (28%), and extremity involvement in 16 cases (12.1%), and one patient (0.8%) had systemic presentation .The most common symptoms were pain (95.5%), weakness (56%), fever (31.1%), headache (30.3%), ophthalmic complaints (27.3%), itching (24.2%), and dizziness (5.3%) .Although 78 patients (59.1%) had no any comorbid disease, 54 cases (40.9%) had predisposing factors including diabetes mellitus in 26 cases (19.7%), malignancy in 15 cases (11.4%), immunosuppressive medication in 7 cases (5.03%), HIV infection in 3 cases (2.3%), radiotherapy in 2 cases (1.5%), and tuberculosis in one (0.8%) .21 cases (15.9%) had bacterial superinfection blistering areas and overall 18 cases (13.6%) had opium addiction. 4 cases (3.03%) died during admission because of comorbidities. Postherpetic neuralgia was reported in 56 people (42.5%) in three months of followup and seven cases (5%) in one-year followup.Varicella infection is a prerequisite for the development of shingles. In temperate climates in the absence of a varicella vaccination program, the lifetime risk for varicella infection is over 95% [PHN is observed in 9\u201345% of all cases of herpes zoster (HZ) and the incidence has been reported to be as high as 50\u201360% among elderly or immunosuppressed patients , 11. In The dermatomes from T3 to L3 are most commonly involved in HZ  but in tThe incidence rate of herpes zoster ranges from 1.2 to 3.4 per 1,000 person/year among younger healthy individuals, increasing to 3.9\u201311.8 per 1,000 person/year among those older than 65 years, and incidence rates worldwide are similar , 14. ThiAlthough some studies showed that the risk is increased in females , in thisAnother important risk factor is immunodeficiency, such as HIV infection , 21. 2.3In our research all the patients were Caucasian and we cannot compare to other cases. However according to a study in North Carolina, black people were significantly less likely to develop zoster than white subjects .Other potential risk factors include exposure to immunosuppressive drugs and immunotoxins . We alsoThere is no strong evidence for a genetic link or a link to family history. A study performed in 2007 showed that people with close relatives who had had shingles were twice as likely to develop Zona , but ano22.1% of patients in our study had herpes zoster ophthalmicus. This is like other studies. Herpes zoster ophthalmicus involves the ophthalmic branch of the trigeminal nerve and occurs in approximately 10% to 25% of cases [Regarding previous studies in the world varicella vaccination has excellent effect for decreasing Zona and PHN \u201328. UnfoIn this study average time before treatment from the beginning of the symptoms was 5.7 days (std. deviation = 4.240) and this time is too late for improvement after medical therapy and probably for decreasing of complication. If they refer to specialists in first 72 hours and receive antiviral and corticosteroid therapy it helps to decrease duration of the disease, accelerate improvement of the lesions, and decrease symptoms such as pain and may decrease PHN  and otheIt seems that more delay for visiting by physician can result in more complications, especially PHN. For improving this we need more education to community and general practitioners."}
+{"text": "Reliable smear microscopy is an important component of Directly Observed Treatment Scheme (DOTS) strategy for TB control program in countries with limited resources. Despite external quality assessment is established in Ethiopia, there is lower TB detection rate (48%) in Amhara region compared to the World Health Organization (WHO) estimate (70%). This highlights the quality of smear microscopy needs to be evaluated. Therefore, the aim of this study was to assess the quality of sputum smear microscopy performance among health center laboratories in West Amhara region, Ethiopia.A cross sectional study was conducted from July 08, 2013 to July 07, 2014. Data were collected from 201 public health center laboratories using a structured questionnaire. Slides were collected based on Lot Quality Assurance Sampling (LQAS) method and rechecked blindly by trained laboratory technologists. The data were entered into EPI info V.7 and smear quality indicators and AFB results were analyzed by SPSS version 20.Among 201 laboratories enrolled in this study, 47 (23.4%) laboratories had major errors. Forty one (20.4%) laboratories had a total of 67 false negative and 29 (14.4%) laboratories had a total of 68 false positive results. Specimen quality, smear thickness and evenness were found poor in 134 (66.7%), 133 (66.2%) and 126 (62.7%) laboratories, respectively. Unavailability of microscope lens cleaning solution  and dirty smears  were correlated with false negative results whereas no previous EQA participation  was associated with false positive results.The performance of health facilities for sputum smear microscopy was relatively poor in West Amhara region. Hence, strengthening the EQA program and technical support on sputum smear microscopy are recommended to ensure quality tuberculosis diagnostic service. Tuberculosis (TB) still remains a major public health problem that ranks as the second leading cause of death from an infectious disease worldwide. Ethiopia is among the 22 high TB and the 27 high Multidrug Resistant (MDR) TB burden countries. In Ethiopia, according to the 2010/11 national TB survey, the prevalence of smear positive TB among adults was 108 per 100,000 populations ) practiced internal quality control for new AFB reagents and routinely in a weekly manner via known positive and negative control smears. AFB reagents had no clear labeling  at 22 (10.9%) laboratories. More than half, 139 (69.2%), laboratories did not filter 1% carbol fuchsin during staining of AFB smears. Microscope lens cleaning solution, filter paper and lens tissue were not found in 127 (63.2%), 92 (45.8%) and 89 (44.3%) laboratories, respectively.Majority of the laboratories, 167 (83.1%), had low Slide Positivity Rate (SPR) of AFB slides including 19 (9.5%) laboratories with SPR of 0%. Ninety five (47.3%) laboratories had low Annual Negative Slide Volume (ANSV) (< 301 slides per year). Both low SPR and low ANSV were found in 80 (39.8%) laboratories .Of the 39725 slides rechecked blindly, 35110 (88.4%) slides had clean background, 33222 (83.6%) good staining and 31666 (79.7%) normal size. Good specimen quality, normal thickness and good evenness accounted 29138 (73.3%), 28673 (72.2%) and 28377 (71.4%), respectively. However, 183 (88.4%) laboratories did not fulfill the overall six indicators of smearing quality. Specimen quality, smear thickness and evenness were found poor in 134 (66.7%), 133 (66.2%) and 126 (62.7%) laboratories, respectively .Of the 201 laboratories, 68 (33.8%) had at least one microscopy error . At least one major error was found from 47 (23.4%) laboratories. Forty one (20.4%) laboratories had false negative and 29 (14.4%) laboratories had false positive results .Unavailability of microscope lens cleaning solution and dirty smears were correlated with false negative results. Those laboratories with no lens cleaning solution had significantly higher  false negative results (32 [25.2%]) compared to those having cleaning solution (9 [12.2%]). Laboratories having dirty smears had 2.65  times more false negative results (14 [36.8%]) compared to those laboratories with clean AFB smears (27 [16.6%]) .Similarly, no previous participation in EQA program was correlated with false positive results. Those laboratories with no EQA participation in 2013 had 3.43  times more false positives (11 [25.0%]) than previously EQA linked laboratories (18 [11.5%]) .Reliable laboratory service provides results that are consistently accurate. Failure to maintain the quality would result in loss of credibility, waste of precious resources, inaccurate data and poor performance of the program . In thisIn the present study, false positive results were found in 14.4% of laboratories. These results could lead a patient placed on treatment unnecessarily, wasted valuable medication, cause emotional trauma to patients and their families , 4, 6. TLow SPR and/ or ANSV are indicators of poor sputum smear microscopy performance. In this study, 83.1% of the laboratories had SPR of below 5%. Both low SPR and ANSV were found in 39.8% of laboratories. This finding is higher compared to the 2.9% of diagnostic centers with low SPR (< 5%) and low ANSV (< 301 slides) reported in New Delhi .In this study, 41 (20.4%) laboratories had false negative results. These false negative results could cause the spread of TB to family and community, and death . The finThe sensitivity and reliability of sputum smear microscopy often depend on how specimens are collected, smears are made and stained smears are examined . This stThis study was not without limitation since unable to include proficiency testing due to budget constraint.The performance of health centers for smear microscopy reading and smear quality were poor in west Amhara region. Unavailability of microscope lens cleaning solution and poor smear cleanness were factors for false negatives whereas no previous participation in EQA program for false positive results. Hence, strengthening the EQA program and technical support on smear quality indicators are recommended to ensure quality tuberculosis diagnostic service."}
+{"text": "Treatment of early and multiple cutaneous unresectable recurrences is a major therapeutic problem with around 80% of patients relapsing within 5 years . For lesBetween January 2007 and September 2012, 60 patients with relapsed and refractory cutaneous melanoma metastases or in-transit disease underwent 100 courses of ECT with intravenous injection of bleomycin. Response to treatment was evaluated three months after ECT. A long-lasting response was defined as no cutaneous or in-transit relapse after a minimum of six months.Three months after ECT, a complete response was observed in 29 patients (48.4%), a partial response in 23 patients (38.3%) and no change or progressive disease in 8 patients (13.3%). The objective response rate of all treated lesions was 86.6%. Thirteen patients (44.8% of complete responders) experienced a long-lasting response to ECT and were disease-free after a mean duration of follow-up of 27.5 months.The favorable outcome obtained in the present study demonstrates that ECT is a reliable, and effective procedure that provides long-term benefit in terms of curative and palliative treatment for unresectable cutaneous lesions without adversely impacting the quality of life of patients -7."}
+{"text": "Hyperglycemia, a common metabolic disorder in diabetes, can lead to oxidative damage. The use of antioxidants can benefit the control and prevention of diabetesside effects. This study aims to evaluate the effect of nanoceria particles, as an antioxidant, on glucose induced cytotoxicity, reactive oxygen species (ROS), lipid peroxidation(LPO) and glutathione (GSH) content in a human hepatocellular liver carcinoma cell line(HepG2) cell line.In this experimental study, we divided HepG2 cells into thesegroups: i. Cells treated with 5 mM D-glucose (control), ii. Cells treated with 45 mM D-mannitol+5 mM D-glucose (osmotic control), iii. Cells treated with 50 mM D-glucose(high glucose), and iv. Cells treated with 50 mM D-glucose+nanoceria. Cell viability,ROS formation, LPO and GSH were measured and analyzed statistically. High glucose (50 mM) treatment caused significant cell death and increased oxidative stress markers in HepG2 cells. Interestingly, nanoceria at a concentration of 50 mMsignificantly decreased the high glucose-induced cytotoxicity, ROS formation and LPO.This concentration of nanoceria increased the GSH content in HepG2 cells (P<0.05).The antioxidant feature of nanoceria particles makes it an attractive candidate for attenuation of hyperglycemia oxidative damage in different organs. LDiabetes is a metabolic disorder that affects numerous people worldwide. In this disorder, deficiency of insulin action, secretion or both causes impaired metabolism of glucose, which leads to hyperglycemia . HyperglThe liver is the initial organ for metabolism and regulation of glucose. Hyperglycemia has an important role in the onset of liver damage. An important strategy to protect the normal functioning of the liver and control the development of high glucose induced liver damage is inhibition of reactive oxygen species (ROS) generation. According to previous reports, oxidative stress is the biochemical trigger for hepatic dysfunction in diabetic rats . Apoptot3+(reduced) and Ce4+(oxidized) forms at the particle surface. Ceria nanoparticle ability to switch between these oxidation states is comparable to that of biological antioxidants. Nanoceria seems to have both superoxide dismutase mimetic activity (as Ce4+) and catalase mimetic activity (as Ce3+)  . Therefoas Ce3+) . in vitro model have not been investigated. Therefore, in the present study, we evaluated the protective effects of nanoceria against high glucose-induced oxidative stress mediated cell death in HepG2 cells. The beneficial effects of nanoceria in reducing hyperglycemia induce oxidative stress in an All chemicals used were of the highest quality and purchased from Sigma Chemical Co. (USA). Nanoceria particles were purchased from Notrino Co. (Iran). Organic solvents that were of analytical grade, high performance liquid chromatography (HPLC) grade or the best pharmaceutical grade were used. 2at 37\u02daC. Cells were plated for 24 hours prior to the various treatments at the indicated concentrations for the different assays. This experimental study was performed on a HepG2 cell line. HepG2 cells were cultured in MEM that contained 10% fetal bovine serum (FBS) supplemented with 100 U/ml penicillin, 100 \u00b5g/ml streptomycin, and 2 mM L-glutamine in a humidified atmosphere with 5% COHepG2 cells were divided into four groups: i. Cells treated with 5 mM D-glucose (control), ii. Cells treated with 45 mM D-mannitol+5 mM D-glucose (osmotic control), iii. Cells treated with 50 mM Dglucose (high glucose) and iv. Cells treated with 50 mM D-glucose+nanoceria. Cell viability was evaluated by assaying the ability of mitochondria to catalyze the reduction of 3- as the indicator. The fluorescence intensity of Dichlorofluorescein (DCF) was measured using a Shimadzu RF5000U fluorescence spectrophotometer. Excitation and emission wave lengths were 480 and 520 nm, respectively. The results were expressed as fluorescent intensity per 106 cells . Lipid peroxidation (LPO) was estimated using thiobarbituric acid (TBA) as the indicator . For glutathione (GSH) content estimation in HepG2 cells, 5,5\u2032-Dithiobis(2-nitrobenzoic acid) (DTNB) was used as the indicator. Cells were analyzed with the spectrophotometric method . Results are presented as mean \u00b1 SD. All statistical analyses were performed using the SPSS software, version 21. Statistical significance was determined using the one-way ANOVA test, followed by the post-hoc Tukey test. Statistical significance was set at P<0.05. First, we determined the best protective concentration of nanoceria against cytotoxicity induced by high glucose in HepG2 cells. As shown in Figure 1, nanoceria pretreatment (0-200 mM) significantly protected cells from the toxicity induced by high glucose (50 mM). Maximal protective effect was observed at 50 mM of nanoceria. Given this result, 50 mM nanoceria was chosen for subsequent experiments. As shown in Figure 2, treatment of HepG2 cells with a high concentration of glucose (50 mM) resulted in significant loss of cell viability at 24 hours (62%), 48 hours (52%) and 72 hours (43%). The osmotic control (45 mM mannitol+5 mM glucose) did not cause any cytotoxicity in HepG2 cells during the interval of 24-72 hours. Nanoceria at a concentration of 50 mM showed protective effects against hyperglycemic induced cell death in HepG2 cells at 24, 48 and 72 hours. The potential preventive effect of nanoceria against high glucose-induced ROS production in HepG2 cells was assayed following 24, 48 and 72 hours of incubation. Figure 3 shows that the osmotic control group did not significantly affect the intracellular production of ROS but treatment of HepG2 cells with 50 mM glucose resulted in significant increase in ROS production in a time-dependent manner. Nanoceria pretreatment effectively prevented the ROS production induced by high glucose (P<0.05). On the other hand, we observed a significant increase in malondialdehyde (MDA) concentration in HepG2 cells treated with 50 mM glucose after 24, 48 and 72 hours compared to the control group (P<0.05). HepG2 cells treated with 5 mM glucose or 45 mM mannitol+5 mM glucose showed a similar MDA concentration. Interestingly, nanoceria pretreatment significantly (P<0.05) prevented MDA elevation in HepG2 cells treated with 50 mM glucose for 24, 48 and 72 hours compared to the control group . We observed a significantly decreased GSH content (main intracellular antioxidant) in HepG2 cells treated with 50 mM glucose for 24, 48 and 72 hours compared to the control group . HepG2 cin vitro model of glucose toxicity in liver tissue. A low concentration of glucose (5 mM) has no significant effect on cell viability compared with the untreated group (data not shown). However, we observed a significant reduction in cell viability when the HepG2 cells were incubated with a high concentration of glucose (50 mM). Numerous studies have used a high concentration of glucose (50 mM) as an in vitro model for investigation of hyperglycemia induced toxicity which simulated the in vivo condition of diabetic ketoacidosis observed in acute or untreated diabetes  and catalase activity (in the form of Ce3+)  ,37. We pAs indicated in the results, nanoceria at a concentration of 50 mM significantly promoted cell viability in the HepG2 cell line after exposure to a high concentration of glucose (50 mM). This effect was probably from inhibition of glucoseinduced ROS formation. We measured the rate of ROS formation in HepG2 cells that showed a significant increase in the hyperglycemic group compared to the control group. Interestingly, nanoceria prevented glucose induced-ROS formation because of antioxidant properties. Nanoceria significantly inhibited LPO in HepG2 cells which was promoted by hyperglycemia. We assayed cellular GSH as the main cell antioxidant that could scavenge hydrogen peroxide and other ROS . Our datThe protective role of antioxidant against diabetes induced oxidative damage was shown in various studies. Administration of vitamin C in older type 2 diabetic patients inhibited plasma free radical formation and increased cellular GSH content . Also, nIn another study, treatment with red wine significantly prevented the streptozocin-induced oxidative stress in the brains of rats . AdminisWe have shown the protective effects of nanoceria treatment against hyperglycemia-induced toxicity in HepG2 cells which was probably mediated by its antioxidant properties."}
+{"text": "Cardiac magnetic resonance (CMR) allows the detection of acute inflammation, fusion and thickening of pericardial layers and of effusion. We sought to evaluate the diagnostic and prognostic value of CMR in the setting of pericardial disease.CMR was performed in 146 patients  with clinical suspicion of acute pericarditis , pericardial effusion without inflammation , and constrictive pericarditis . Final diagnosis was ascertained by a combined evaluation of different CMR sequences. Patients were followed-up for all-cause and cardiac death.The final diagnosis was AP in 56 patients (38%), PE in 38 (26%), and CP in 42 (29%). Pericardial disease was excluded in 7 patients (5%), with CMR evidence of abundant epicardial fat. The initial diagnosis was changed by CMR in 21% of patients. Initial suspicion was confirmed in 40/46(87%) patients with AP suspicion . PE was confirmed by CMR in 35/47(75%) patients . A CP diagnosis was confirmed in 40/53(75%), while 6 presented signs of AP (resembling a \"transient constrictive pericarditis\"), 5 PE (as \"effusive-constrictive pericarditis\"), and 2 showed no pericardial disease. At Kaplan-Meyer analysis, on a 551-day median follow-up (IQ range 330-1110), patients diagnosed with CP had a worse prognosis than AP or PE patients (P <0.001).CMR has an additive value, as compared to conventional clinical evaluation, both for differential diagnosis of pericardial disease and for risk stratification.N/A."}
+{"text": "Toxic epidermal necrolysis (TEN), the most severe drug reaction, has been reported to be associated with considerable mortality rate. In the past 15 years, the use of intravenous immunoglobulin (IVIG) have improved the prognosis of TEN.We retrospectively studied 32 patients with TEN in a Chinese tertiary medical center between July 1, 2008 and June 30, 2013 to evaluate the clinical manifestations, laboratory tests, treatment of TEN and prognostic factors for the mortality of TEN.Antibiotics (n=12) were the most common offending drugs, followed by non-steroidal anti-inflammatory drugs (n=8), anti-rheumatic drugs (n=2) and Chinese herbs (n=2). Hypertension  and diabetes  were the most common pre-existing conditions. Hepatitis B virus infection, cerebrovascular diseases and cardiovascular diseases pre-existed in 15.6% (n=5), 12.5% (n=4) and 12.5% (n=4) of the 32 patients, respectively. TEN showed higher incidence in the patients with HBV infection. All 32 patients were treated initially with systemic corticosteroids ranging from 50 mg to 150 mg daily. Sixteen patients were treated with combined IVIG . Twenty-nine patients were cured without or with different sequelae. The mortality rate was 9.38% (n=3). The application of IVIG reduced the estimated mortality of TEN to 17%. Delayed use of IVIG, elevated level of urea nitrogen and early onset of the rashes after taking offensive drugs were associated with the mortality of TEN.Systemic corticosteroids in combination with IVIG were effective for TEN in Chinese patients. TEN showed higher incidence in Chinese patients with HBV infection. Delayed use of IVIG, elevated level of urea nitrogen and early onset of the rashes after taking offensive drugs correlated with poor prognosis of TEN."}
+{"text": "Peripheral sensory neuropathy and its risk factors are well-described in adults with type 1 diabetes (T1D). While clinically evident neuropathy is rare in young people with T1D, we and others have shown that subclinical peripheral neuropathy is common [We performed a systematic review of the epidemiology of peripheral sensory neuropathy, and diagnostic accuracy of tools used for its assessment, in young people with T1D. We searched Medline and Embase from Jan 1985 to Mar 2014. Inclusion criteria were studies in young people with diabetes duration > 1 year which tested for sensory neuropathy using nerve conduction velocity (NCV), temperature perception threshold (TPT), vibration perception threshold (VPT) and/or clinical examination.We identified 26 eligible studies, involving 5527 young people with T1D. Only 7/26 (27%) studies were of good methodological quality . Clinical examination yielded a wide variation in the rates of sensory neuropathy, with pooled prevalence of 15% (95% CI 13 to 17). Abnormal VPT was more common, with pooled prevalence 33% (30 to 36), as was TPT, with pooled prevalence 32% (26 to 39). The prevalence of abnormal NCV was similar 36% (33 to 39). Overall, the pooled prevalence of sensory neuropathy, using any test, was 26% (24 to 27). We calculated sensitivity and specificity of the different diagnostic tests that were used in the included studies, in comparison with neuropathies detected by \u2018gold standard\u2019 nerve NCV testing. The sensitivity of VPT ranged from 29-62%, and specificity from 65-100%. Sensitivity of TPT was 19% and specificity was 65% (one study). The sensitivity of clinical examination ranged from 0-100% and specificity from 81-100%.In conclusion, there is marked variation in reported prevalence rates of sensory neuropathy, due to lack of consensus on its definition, classification of abnormal results, and testing methodology. Clinical examination demonstrates the lowest sensitivity for detection of sensory neuropathy in young people with T1D."}
+{"text": "Cardiac magnetic resonance (CMR) has been developed as an important imaging tool for cardiovascular diseases in clinical practice. However, there were few reports about the real world implementation of CMR with regard to its indications and findings.344 patients  with clinical indications for CMR were consecutively recruited in 10 months, at a tertiary referral hospital in China. Indications for CMR, quantifications of structure and function, late gadolinium enhancement (LGE), and diagnoses made by CMR were analyzed.The evaluation of heart failure and cardiomyopathies was the leading cause of referral that occurred in 164 (47.7%) patients, followed by coronary artery disease in 79 (23.0%) patients and ventricular arrhythmia in 65 (18.9%) patients. Quantitative analysis was available in 319 (92.7%) patients where the LV dilatation observed in 208 (65.2%) patients and RV dilatation in 46 (14.4%) patients, respectively. There were 157 (48.5%) patients detected with ventricular LGE, in whom 43 (27.4%) patients displayed typical ischemic pattern and the others had non-ischemic pattern of various presentations. Except the undefined 74 (21.5%) cases, CMR assessment corrected an initial referral diagnosis in 73 (21.2%) patients and confirmed it in 197 (57.3%) patients.All the referrals in this study were appropriate for CMR, mainly indicated for structure and function assessment. CMR helped to identify abnormalities that not detected by other imaging modalities, which would provide incremental diagnostic, therapeutic and prognostic information.This study was supported by a grant from the National Science Funds of China (81271531)."}
+{"text": "Poorly documented self-reported drug allergy (DA) is a frequent problem in daily clinical practice and has a considerable impact on prescription choices. Atopy has been described as a risk factor for drug hypersensitivity (DH). The aim of this study was to better investigate the cases of suspicion of DH reported by patients undergoing subcutaneous allergen-specific immunotherapy (SCIT).in vivo or in vitro specific-IgE  and clinical relevance of these allergens. We excluded cases with unrelated history of DH. For the evaluation of suspected DH, we used the European Network for Drug Allergy(ENDA) questionnaire and the DA work-up followed the ENDA recommendations.In this prospective study conducted since 2013, we firstly evaluated the self-reported cases of DH in patients undergoing SCIT in the Allergy Department of our Hospital. The SCIT has been indicated to atopic patients based on the dust mite Of all 1400 patients undergoing SCIT evaluated on May/2013, 691 replied the first questionnaire, 133(19%) of those self-reported having drug allergies. Forty-five (34%) indicated hypersensitivity to antibiotics(ATB), 46(35%) to non-steroidal anti-inflammatory drugs (NSAIDs), 5(4%) to both ATB and NSAIDs, 31(23%) to other drugs and 6(4%) didn\u2019t remember the medication involved. Of the 133 reports, 65(49%) were evaluated by ENDA questionnaire and 68(51%) refused to go through the drug-allergy evaluation. Of those 65 evaluated cases, forty-two (65%) were women and the mean age was 28 (4 to 70 years). Thirty (46%) cases had history of immediate reaction and the mean time between the reaction and the evaluation was 10 years. Eleven (17%) cases were excluded and the DH investigation has been offered to 54(83%) patients, from whom 38(58%) had possible/probable clinical history of DH. Twenty-five (38%) cases refused or were not interested in undergoing the investigation and 11(17%) are still under investigation. Of 18(28%) who completed the investigation, 11 were with NSAIDs and 7 with antibiotics, all negative.The major result of this study confirmed that DH reactions occurred in less than one quarter of patients with a history suggesting possible DA. Negative results on DA work-up may have occurred due to the loss of sensitization and cofactors not included in the diagnostic procedure. Diagnostics tests in individuals with self-reported DA can exclude these conditions."}
+{"text": "Low-molecular-weight heparin (LMWH) is frequently recommended for the treatment of pregnancy associated venous thromboembolism (PAVTE). Given that prior reports have suggested a wide variation in dosing of LMWH in pregnancy and the use of anti-Xa monitoring in pregnancy, the principal aim of this survey was to assess current practices for the management of PAVTE.An electronic survey was conducted. The target sample was members of the North American Society of Obstetric Medicine and Thrombosis Interest Group of Canada.The final sample consisted of 27/69 hematologists (39.1%), 30/69 internists (43.5%), 8/69 obstetricians (11.6%), and 4/69 from other specialties (5.7%). For the acute treatment of patients pregnant patients with deep vein thrombosis 42/69 (60.8%) preferred LMWH given twice a day 42/69 (60.8%), whereas 25/69 (36.2%) preferred once daily. These results were similar for patients with pulmonary embolism (PE). For long-term treatment more than 70% of the respondents favoured treatment with full doses of LMWH given once a day or twice a day and 16/69 (23.2%) intermediate doses for patients diagnosed with DVT. These results were similar for patients with PE. Fourteen physicians out of 69 (20.3%) did not measure anti-Xa monitoring during acute treatment period and 24/69 (34.8%) never used anti-Xa levels during the long term treatment period. Management during the peri-partum period varied widely according to the time of the diagnosis of PAVTE.In conclusion, our survey shows wide variation in practice regarding LMWH dosing and anti-Xa monitoring in pregnancy associated VTE and calls for trials comparing different long term strategies using LMWH in patients with PAVTE. Low-molecular-weight heparin (LMWH) is frequently recommended for the treatment of pregnancy associated venous thromboembolism (PAVTE) . Normal An electronic self-response survey, using Survey Monkey software was conducted. The target sample was experts and clinicians with experience in the management of VTE associated with pregnancy. An information sheet/electronic statement indicating that participation was voluntary and ensuring confidentiality was provided with each survey. Two groups agreed to collaborate with this project: 1-The Thrombosis Interest Group of Canada (TIGC) and 2-the International society of Obstetrics medicine (ISOM). The protocol was approved by the Ottawa Hospital Ethics and Research board to initiating the survey. The survey was pre-tested among nine thrombosis physicians at the Ottawa hospital, prior to being distributed. The evaluation of the current clinical practice was conducted using a multiple choice option format. Information regarding the type of heparin used for initial treatment and dosing; the type of heparin used for long-term-treatment and dosing; and finally the use of anti-Xa levels to guide therapy during the acute and long term treatment period was collected. Baseline characteristics of the respondents including years of practice, specialty, and knowledge about research methodology, was also captured. Finally, to ensure that the survey was answered by physicians with ample experience in the management of pregnancy associated VTE, a screening question was inserted at the beginning of the survey trying to identify physicians who have treated more than two PAVTE during the last year. This number was reached by consensus among two thrombosis experts (MR and MC).The survey results are reported using descriptive statistics (percentages and 95% CI). Stratified analysis was conducted by years of practice, specialty, and knowledge about research methods accordingly for each question. Data was collected using Microsoft excel, and the analysis was conducted using SAS.The survey was electronically mailed to 305 participants; 246 from the ISOM and 54 from TIGC. One hundred and five of 305 (35%) started answering the survey, of which 5 (4.5%) were disqualified after the initial screening question, and 69/305 (22.6%) completed the entire survey. The final sample consisted of 27/69 hematologists (39.1%), 30/69 internists (43.5%), 8/69 obstetricians (11.6%), and 4/69 from other specialties (5.7%). Eight out of sixty nine had practiced medicine less than 5\u00a0years, 11/69 (15.9%) between 5 to 10\u00a0years, 14/69 (20.3%) between 10 to 15 and 36/69 (52.1%) more than 15\u00a0years.For the acute treatment of pregnant patients with deep vein thrombosis (DVT), 42/69 (60.8%) preferred LMWH given twice a day whereas 25/69 (36.2%) prescribed it once daily. These results were similar for patients with pulmonary embolism (PE), although 6% of the respondents favored UFH for the initial treatment period. More than 70% of the respondents favored treatment with full doses of LMWH given once a day or twice a day for long-term treatment (\u22651\u00a0month after initiation of anticoagulation). An intermediate dose (once a day) was used by a minority physicians for long term treatment [16/69 (23.2%) for patients diagnosed with DVT and 15/69 (21.7%) for patients diagnosed with PE]. Thirty two physicians out of 69 (46.3%) reported using anti-Xa monitoring during the first 30\u00a0days in all patients and 16/69 (23.1%) only in special populations [such as extreme body weight (>150\u00a0kg or\u2009<\u200940\u00a0kg) or kidney disease (creatinine clearance close to 30\u00a0ml/min)] , whereas for those diagnosed within 2 to 4\u00a0weeks before delivery 27/69 (39.1%) physicians favored the use of IV UFH. For those diagnosed within two weeks of delivery an IVC filter in combination with LMWH or IV UFH in more was favored by 37/69 (53.2%) of the respondents.No association was identified between physician specialty  and years of practice  with respect to dosing and the use of anti-Xa monitoring.Our survey suggests that LMWH is the preferred drug for the management of PAVTE but that there is wide variation in dosing strategies and the use of anti-Xa monitoring. A wide variation in strategies used for the initial acute and long term treatment period was found for dosing (once a day vs. twice a day) and for the use of Anti-Xa monitoring corresponding to the different recommendations for anti-Xa monitoring and dosing by available guidelines guidelines ,6 at theOur survey has limitations. Our response rate was low, despite multiple efforts to increase the response rate. Since the initial response rate was low (<15%) following the 2 electronic reminders, two additional measures were taken to increase the response rate: 1-the survey was endorsed by three highly respected experts; and 2-compensation in the form of a voluntary raffle. One factor that could explain our rates is that the number of studies that use e-mail to collect data has been increasing over the last years while the average response rate to the surveys appears to be decreasing ,13. FinaIn conclusion, our survey shows wide variation in practice regarding LMWH dosing and anti-Xa monitoring in pregnancy associated VTE and calls for trials comparing different long term strategies using LMWH in patients with PAVTE.PAVTE: Pregnancy associated venous thromboembolism; DVT: Deep vein thrombosis; PE: Pulmonary embolism; VTE: Venous thromboembolism; IVC: Inferior vena cava filter; LMWH: Low molecular weight heparin; UFH: Unfractioned heparin; OD: Once daily; BID: Twice daily; IV: Intravenous; SC: Subcutaneous.The authors have declared that no competing interests exist.Study concept and design: EG, MC and MR. Analysis and interpretation of data: EG, MC and MR. Drafting of the manuscript: EG, MC and MR. Critical revision of the manuscript for important intellectual content: EG, MC and MR. Statistical analysis: EG, MC and MR. All authors read and approved the final manuscript."}
+{"text": "Whilst much focus has been placed on relating indication for NIV on outcome, little attention has been paid to the duration of NIV and whether or not this might have an impact on outcome.The role of non-invasive ventilation in the intensive care unit (ICU) is generally poorly understood. Published guidelines largely relate to the use of NIV outside the ICUTo review the practice and outcomes of NIV in our institution over a 1-year period and compare those receiving NIV for shorter ( < 48 hours) compared with longer (>48 hours) periods.st January 2014 and 31st December 2014. Patients receiving NIV after a period of mechanical ventilation were excluded from this analysis. Patients were analysed depending on whether they received NIV for a total period of < 48 hours or > 48 hours. For each group, data was collected for % time NIV actually received during their NIV period, number requiring intubation and mechanical ventilation, ICU length of stay and number surviving to ICU discharge.We conducted a retrospective care note analysis of all patients receiving their first NIV period at any time during their ICU admission between 1The notes of 103 patients were reviewed. 49 were female (48%) with a mean age of 69 years (range 19-100 years). Indications for initiation of NIV are highlighted in figure Sixty-nine (67%) patients received NIV for < 48 hours compared with 34 (33%) patients receiving NIV for > 48 hours. Predicted acute hospital mortality (according to ICNARC score) on ICU admission was similar between the 2 groups . When comparing those who received NIV for < 48 hours with those who received NIV for > 48 hours, the median total intermittent duration of NIV was 12 [IQR 5-18] and 136 [IQR 72-227] hours respectively (p < 0.05) and the median % of time actually spent receiving NIV during these periods were 100% [IQR 91-100] and 37% [IQR 18-71] respectively (p < 0.05). The median ICU length of stay was significantly shorter in the < 48 hour duration group (4.9 [IQR 3-11] days v 11.3 [IQR 7-23] days (p < 0.05)) although intubation rates  and % surviving to ICU discharge  were similar and not significantly different (table 8.5-62.5 At our institution, those receiving NIV for < 48 hour time period had a shorter length of ICU stay compared with those receiving NIV for longer periods. Duration of NIV may be an important factor in determining success of NIV and may be worth further exploration in future prospective studies."}
+{"text": "Long-term studies of remission rates in juvenile idiopathic arthritis (JIA) are few and difficult to compare because of different definitions of remission.To assess disease activity in a previously studied cohort of JIA patients after 30 years of disease duration and reveal predictors of persistently active disease.A total of 259 patients with JIA, first referred to our hospital from 1980 to1985, were reexamined clinically after median 15 years of disease duration, and by mailed questionnaires after median 23 years. These patients were invited to attend the present study. All patients were assessed by questionnaires, and those with signs of active disease after 15, 23 and/or 30 years were invited to a clinical reexamination. Inactive disease and remission were defined according to the recently developed preliminary criteria for clinical remission in JIA. Logistic regression analyses were used to assess predictors of active disease.One hundred and seventy-one patients (67%) were included in the study. They were examined after a median of 30 (range 21-40) years of disease duration, median age was 39 (range 28-45) years and 74% were females. After 30 years, 59% of the patients were in clinical remission off medication, 7% were in remission on medication and 34% had persistently active disease compared with 57%, 10%, and 33%, respectively, after 15 years.2 = 65%.Thirty-seven of 57 patients (65%) with active disease at 15 years follow-up had active disease at 30 years follow-up, and 20 patients (35%) went into remission on or off medication. Eighty-four of 97 patients (87%) in remission off medication remained in this category from 15 to 30 years follow-up. Patients in remission on medication at 15 years (n = 17) tended to flare or go into remission off medication. In total 121/171 patients (71%) had an unchanged category of disease activity from 15 to 30 years follow-up. Predictors of persistently active disease at 30 years follow-up were: being diagnosed with a JIA subgroup other than persistent oligoarticular and systemic JIA , being DR1 positive , a short duration of total time in remission , and not being in remission at 15 years follow-up , Nagelkerkes RThe overall remission rates were stable between 15 and 30 years, even though one third of the patients changed category of disease activity. JIA subgroup, genetic factors and time without remission were important predictors of long-term outcome.None declared."}
+{"text": "There is lack of benchmarking data for central line associated bloodstream infection (CLABSI) in Gulf Cooperation Council (GCC) countries. Available data are small isolated reports that do not cover different hospital locations.To estimate location-specific CLABSI rates in GCC region and to compare such rates with published reports of US National Healthcare Safety Network (NHSN) and International Nosocomial Infection Control Consortium (INICC).CLABSI rates and central line utilization between 2008 and 2013 were calculated from aggregated CLABSI surveillance data using NHSN methodology pooled from different ICUs and oncology wards in 6 hospitals in three GCC countries; Saudi Arabia, Oman, and Bahrain. Standardized infection ratio (SIR) of CLABSI in GCC hospitals were compared with published reports of NHSN and INICC.A total 461 CLABSI events were detected during 6 years of surveillance covering 150,492 central line-days and 336,850 patient-days. The overall CLABSI rate was 3.1 per 1000 central line-days (95% CI 2.8-3.3) and overall central line utilization was 0.45. The CLABSI rates showed 40% reduction while central line utilization showed 12% reduction towards the end of surveillance period. CLABSI rates were highest in neonatal ICUs (5.0) and adult oncology wards (4.8) while central line utilization were highest in pediatric (0.86) and adult cardiothoracic ICUs (0.80) and pediatric oncology wards (0.76). After adjusting for differences in ICU types, the risk of CLABSI in GCC hospitals was 146% higher than NHSN hospitals but 33% lower than INICC hospitals. Similar to NHSN hospitals, the majority of CLABSI events (81%) were diagnosed by detecting recognized pathogens in blood cultures.The risk of CLABSI in ICU and oncology patients in GCC countries is probably much higher than the US but the risk in ICU patients is slightly lower than many developing countries. Current findings may be used as a regional benchmark.None declared."}
+{"text": "Biologics are often used in therapy of DMARDs resistant JIA. The important problem is discontinuation of Biologics therapy due to different reasons.Evaluation of 10 years of the experience of Biologics in children, suffering from juvenile idiopathic arthritis (JIA) in single center focused for reasons of withdrawal.The analysis includes data about 435 patients with JIA who have been getting Biologics in 2005 - 2014. The average age of patients is 10,5 years . Disease duration is 7 yrs avg (from 3 to 14 years). Clinical characteristics: soJIA - 70 (17%), JIA with polyarthicular course (poly) - 257 (61%), JIA oligo \u2013 38 (9%), 51 (12%) patients suffered from active uveitis.During the observation Biologics were withdrawn in 123 cases (98 patients). For some patient we changed Biologics several times: in 21 cases - two times (21% of patients), in 2 cases (2%) - thrice. Distribution of reasons for the Biologics discontinuation is presented in Table Infliximab was withdrawn more often due to adverse events (infusion reactions), at the beginning of the treatment or several years later. The other reason is secondary inefficiency after 2-5 years of application. Abatacept was cancelled more often for the reason of inefficiency, adverse events were observed rarely. Etanercept was withdrawn in some cases because of uveitis de novo. Adalimumab was withdrawn basically due to organization problem.Favorable choice of Biologics is changed from 2005 till now. For new initiation we used different biologics in different time. Infliximab was administered in the past (from 2005 to 2012), maximum (14 patients) in 2011. Administration number decrees nowadays . Adalimumab was not commonly administrated before 2011, from 2012 administration count increase from 10-11 per year to 39. Using of Etanercept was increased from 2010 (20-35) and achieved maximum in 2013 (49 patients). Usually we prescribe tocilizumab in systemic JIA and do not change in most cases.Availability of Biologics therapy was increased during last ten years in Russia. That has improved survival of therapy and has given opportunity of using Biologics with good safety profile.None declared"}
+{"text": "Severe acute pancreatitis (SAP) is associated with significant mortality and morbidity. The objective of this study is to examine the profile, outcome and resource utilization for patients with SAP admitted to the ICU in a university teaching hospital over a 5-year period.A retrospective observational study was carried out of all patients admitted to the ICU from 1 January 2008 to 31 December 2012 with SAP. Data were collected from the ICU database (AcuBase), the medical records and the ICU clinical information system. Data collected included patient demographics, etiology of SAP, data for APACHE II, Imrie, Ranson and Acute Kidney Injury Network (AKIN) scores, and requirement for organ support. Outcomes recorded were length of stay, ICU mortality and hospital mortality. Cost of ICU care was calculated based on previously reported methodology.P < 0.05, chi-square test). In total, 834 ICU bed-days were taken up by 38 patients. Based on a median cost for an ICU bed-day of \u20ac2,205 [Thirty-eight eligible patients were identified. Mean age was 51.4 years (range 24 to 86), 68% were male. The commonest etiologies were alcohol (53%) and gallstone pancreatitis (24%). The mean APACHE II score was 18.5 (IQR 14 to 23). Twenty-eight patients (74%) required mechanical ventilation, three of whom required high-frequency oscillation . Twenty-two patients (58%) had evidence of an acute kidney injury on admission (AKIN criteria). Eighteen (47%) required renal replacement therapy and 60% required inotropes. The ICU mortality and the hospital mortality were 26%. There was no significant difference in age, APACHE II, Imrie, or Ranson scores between survivors and nonsurvivors. The median length of stay in the ICU was 11 days (IQR 5.25 to 28.5) and the median hospital stay was 45.4 days (IQR 22.25 to 104.5). Nine patients (24%) required multiple ICU admissions and the mortality was significantly higher in this group (A hospital mortality rate of 26% is similar to that reported recently from a specialist unit in the UK , suggest"}
+{"text": "The purpose of this study is to describe our experience with needle localization technique in diagnosing small breast cancers.This retrospective study included a hundred and twenty patients\u2019 with impalpable breast lesions and they underwent wire localization. All patients had mammography, ultrasound exam and pathohystological results. We use Mammomat Inspiration Siemens digital unit for diagnosing mammography, machine - Lorad Affinity with fenestrated compressive pad for wire localization and ultrasound machine Acuson X300 with linear array probe 10 MhZ. We use two types of wire: Bard hook wire and Kopans breast lesion localization needle, Cook. Comparative radiologic and pathologic data were collected and analyzed.In 120 asymptomatic women, 68 malignancies and 52 benign findings were detected with mammography and ultrasound. The mean age for patients with malignancy was 58.6 years. According BI-RADS classification for mammography the distribution is our group was: BI-RADS 3 was presented in 6 (8.82%) patients, BI-RADS 4 was presented in 56 (82.35%) patients and BI-RADS 5 was present in 6 (8.82%) of the patients. Most wire localizations were performed under mammographic guidance in 58 from 68 patients with malignant lesions (85.29%) and with ultrasound in 10 (14.7%). According the mammographic findings patients with mass on mammograms were 29 (42.65%), mass with calcifications 9 (13.23%), calcifications 20 (29.41%) and architectural distortions or asymmetry 10 (14.71%).Wire localization is a well established technique for the management of impalpable breast lesions. Breast cancer is the most common form of malignancy occurring in women . MammogrWire localization of nonpalpable mammographically detected breast lesion is a well established technique, the importance of wich has grown recent years with the advent of mammographic breast screening programmes and an increasing use of mammography in the investigation of symptomatic breast disease .Mammographic detection of nonpaplable breast cancer permits earlier diagnosis and almost certainly reduces mortality from the disease , 4, 6, 7The key to successful management of these nonpalpable lesions is accurate localization, which is essential for achieving complete surgical excision with optimal cosmetics and minimal morbidity. Imaging guidance is most commonly performed with mammography or sonography and less often with MRI or CT . PatientThe aim of our study is to describe our experience with needle localization technique which we believe to be a safe and accurate method for gaining access to small and highly curable breast cancers.From November 2009 till November 2014, we performed 120 wire localizations in the University Clinic of Radiology in Skopje, Republic of Macedonia. All patients had operative treatment at the University Clinic for thoracovascular surgery. The cytological analysis was done at the department of cytology and histology at the University Clinic of radiotherapy and oncology. Pathohystological analysis was performed in department of cytology and histology at the University Clinic of radiotherapy and oncology and in the Institute of pathology, Medical Faculty, Skopje, R. Macedonia. We retrospective analyzed 68 patients with histology proven breast cancer, mean age 58.66 years. The charts of all patients undergoing wire localization were reviewed for following: age, size of the lesion, quadrant of breast where the lesion appeared, method of localization, degree of suspicion in mammographic findings, presence of microcalcifications, number of lymph nodes involved, and final pathologic diagnosis. The mammograms were assessed using the Breast Imaging Reporting and Data system (BI-RADS) classifications: BI-RADS 0 need additional Imaging Evaluation or prior mammograms; BI-RADS 1 negative. There is nothing to comment on; BI-RADS 2 Benign finding; BI-RADS 3 Probably benign finding ; BI-RADS 4 Suspicious abnormality ; BI-RADS 5 Highly suggestive of malignancy ; BI-RADS 6 Known biopsy-proven malignancy .In our study we include BI-RADS 3, 4 and 5. All patients underwent diagnostic mammography at our institution. The mammographic images were reviewed to confirm the absence or presence of a mass, mass with calcifications, architectural distortion and microcalcifications.The patohistological results were describe according TNM classification of malignant breast tumors.Tumors are often graded based on a scale of one to three indicating how aggressive the cancerous cells are:Low grade (1) - Well-diffentiated;Intermediate grade (2) - Moderately differentiated;High grade (3) - Poorly differentiated.The procedure begins in the Breast Imaging Department. The study was performed using imaging equipment by Mammomat Inspiration Siemens digital unit for diagnosing mammography; machine - Lorad Affinity with fenestrated compressive pad for wire localization and ultrasound machine Acuson X300 with linear array probe 10 MhZ. We use two types of wires: Bard hook wire and Kopans breast lesion localization needle, Cook.Patients were in supine position with examined side by a small pillow and ipsilateral arm raised above head during the ultrasound wire localization. Mammography wire localization was performed in sitting position. The technique involves mammography usually requires the upright mammographic attachment on a normal mammographic unit. Localization was performed under local anesthesia with lidocain. Before the localization a grid or holey plate was used to accurate the position of needle placement in the X and Y planes. The depth was calculated from the lateromedial projection. The position was then checked according to the superimposition of target, hub and shaft of the needle and the required depth was verified on the orthogonal view. Needle is inserted into the breast, directed towards the lesion and taped in place.After surgical removal of the lesion, specimen radiography was performed to ensure that the lesion was adequately excised. The average time required for complete procedure was about 25-30 minutes. Patients discomfort was minimal and no major complications occurred. All patients provided written informed consent before the procedure.Good accuracy of such localizations is required to ensure correct and adequate removal of the lesion and to minimize the degrees of cosmetic disfigurements.Statistical analysis of data obtained during the study was done with statistical program SPSS 13.0 for Windows. Results of the study were presented with descriptive statistics and with distribution of frequency. The valid of the diagnostic test mammography is testing with using pathophysiologic results as a golden standard.The average age of patients with malignant disease was 58.66 \u00b1 7.6 years.Familiar data for breast cancer had 15 patients (22.06%).In this study we analyzed 120 patients who were preoperative wire localized and 68 (56.66%) patients were with breast cancer and in 52 (43.33%) patients were with benign findings.In left breast were 38 (55.88%) and in right breast 30 (44.12%) were malignant lesions. The lesion localization by quadrants was dominant on superior lateral quadrant in 53 (77.94%), superior medial quadrant 4 (5.88%), inferior medial quadrant in 5 (7.35%), inferior lateral quadrant in 5 (7.35%) and retromammillar space in 1 (1.47%).The lesions are visible by ultrasound in 42 patients (61.76%) and 26 (38.23%) lesions were not visible by ultrasound. All lesions were detected by mammography.We analyzed the shape of the masses, the results with the mammography examination showed that the mass was irregular in 28 (41.18%), round in 15 (10.29%) and oval in 10 (14.71%). On ultrasound examination the margins are not circumscribed in 40 (58.82%) and they were indistinct and speculated.The lesions visible by ultrasound were classified in three groups according to the dimensions. In the first group we have 7 (10.29%) patients and the diameter of the lesion was \u2264 5 mm. In the second group we found 24 (35.29%) patients with the diameter of the lesion in range from 6 to 10 mm. In the third group we found 10 (14.71%) patients with the diameter of the lesion in range from 11 to 20 mm.Our study included only patients who had needle localization but didn\u2019t include all patients underwent mammography in our department. Most wire localization was performed under mammographic guidance in 58 from 68 patients with malignant lesions (85.29%) and with ultrasound in 10 (14.7%). According the mammographic features all patients were divided in 4 groups, the results are presented in According BI-RADS classification for mammography the distribution is our group was: BI-RADS 3 was presented in 6 (8.82%) patients, BI-RADS 4 was presented in 56 (82.35%) patients and BI-RADS 5 was present in 6 (8.82%) of the patients.The cytological analysis was performed in 50 patients from 68 in the group at the department of cytology and histology at the University Clinic of radiotherapy and oncology. According to the cytological analysis the patients were distributed in the following groups: I group 37 (54.41%), III group 7 patients (10.29%), IV group 2 (2.24%) and V group 4 (5.88%) of the patients.In this study we didn\u2019t performed core biopsy in any patients.The pathohystological results in our study are presented in According to the grade of the tumor grow the results were G1 stage in 17 (25%) patients, G2 stage in 41 (60.29%) and G3 stage in 10 (14.71%) patients.Preoperative placement of a hook wire into nonpalpable lesions under imaging guidance is commonly perform for patients with suspective findings on mammograms and/or ultrasound for breast cancer. We found that this technique is extremely useful for small lesions and microcalcifications. Although our group of proven cancers is small, it can be representative and comparable with those in literature.In our study the mean age of the patients is 58.66 years old.Sickles reported mean age 57 years old . Basset The data from the previous published studies are in accordance with our study. Our patients are older, which is not a trend in incidence of breast cancer, but it is also a technical factor; that smaller lesions are more easily identified in atrophic breast than in the younger, denser breast tissue.The lesions are visible in 61.76% by ultrasound and 38.23% lesions are not visible by ultrasound.Of 120 cases, 68(56.6%) were malignant and 52(43.33%) were benign. Ductal carcinoma insitu and microinvasivum are in 17.64%.In 308 cases, Shin et al. reported malignancy in 47% and benign lesions 53%. Ductal carcinoma insitu including microinvasivum are in 108(35%) Distribution of types of cancer among our group are: invasive ductal carcinoma in 51 cases (75%), invasive lobular carcinoma 9(13.23%), tubular carcinoma in 6(8.82%) and others 2(2.54%).The study of 72 impalpable cancers were 39(54%) invasive ductal, 23(32%) noninvasive ductal, lobular carcinoma 4 (6%), tubular 1(1%), colloid 5(7%) .Other study of 151 cases reported 83(55%) invasive ductal carcinoma, insitu duct cancer 40(26.4%), microinvasive duct cancer 9(6%), invasive lobular 5(3.3%), lobular neoplasia 13(8.6%) The incidence of malignancy in our study is little higher because our center I the only public center in the country where the procedure is performing. Also we use magnification mammography in diagnosting small breast lesions instead of alternative approach of periodic mammographic follow up.In our study cancer representing with microcalcifications without mass in 29.41%, mass is in 42.65%, mass with calcifications in 13.23% and architecture distorsion and asymmetry in 14.71%.Microcalcifications are estimated to be associated with malignancy in approximately 25% to 35% of cases . CalcifiArchitectural distortion is the third most common mammographic appearance of non palpable cancer, representing 6% of abnormalities detected on screening mammography .Gardenosa and others showed distribution of 543 lesions: mass 224(41%), calcifications 254(47%), mass and calcifications 41(7.55%), architectural distortion 24(4%) .Our results are comparable with these ranges in literature.In our study predominant is ductal cancer in 51(75%) patients.In the reported series involving needle localization technique, the predominant pathologic cancer type in the literature is ductal .In our group microcalcifications associated with malignancy were in 29.41%(20/68).Microcalcifications are estimated to be associated with malignancy in approximately 25% to 35% of cases .In our study dominate intermediate grade 2 tumor grow in 41/68(60.29%), which means moderately differentiated.Gajdos and others reported cancers with intermediate grade in different groups but in all of them dominate G 2 grade . Our resFalse negative FNAC results have been associated with certain features  wich may be commonly observed with impalpable mamographically detect breast lesions then with palpable abnormalities. We rarely recomend biopsy in an inpalpable asymetric density that shows microcalcifications.In our study 97% (66/68) of wire localized lesions, the wire crosses the lesion.In hookwire localization of breast lesions, the cannula is typically advanced through the lesion and the hook-wire deployed so that the thickened portion of wire is located across the lesion .Also in 53/68 (77.94%) patients had localization in superolateral quadrants.Distribution of BI-RADS classification for mammography among our group shows that dominates BI-RADS 4 and it is 82.33%.Theoretically, BI-RADS 4 are indeterminate lesions and malignancy rates can range from 2% to 95% .Our results indicate that hook wire localization of small lesions and microcalcifications permits the surgeon consistent excision of mammographic lesion safely.Careful comunication between radiologist and surgeon appears however to be of great importance. We found it particulary helpful for radiologist to relay verbally to the surgeon.Also Schwartz et al. emphasis close cooperation between surgeon, radiologist, and pathologist insures that the suspicious area(s) are removed in their entirety with the sacrifice of the minimal amount of contiguous normal breast tissue .Wire localization is a procedure that uses a mammogram or ultrasound to locate and identify breast lesion. Using the mammogram as a guide the radiologist locates the area of concern. It is a good tool for marking impalpable and small lesions.Diagnostic mammography is most helpful in deciding a nonpalpable breast lesion should be wire localized. When an abnormality is detected, clinical evaluation and thorough radiologic work up are needed to determine the suspicious for cancer.Wire localization is a well established technique for the diagnosis of impalpable breast lesions."}
+{"text": "Little is known about the reasons for prescribing adrenalin auto-injectors in Slovenian children. Our objective was to evaluate prescription of adrenaline auto-injectors in children in our department in year 2013 and also to evaluate management of anaphylaxis of those children.We retrospectively collected data on interventions of anaphylaxis and allergic-clinic follow-up of 258 children which had adrenaline auto-injectors prescribed in year 2013.Adrenaline auto-injector was prescribed in 258 children (66% boys and 34% girls). In 120 of them adrenaline auto-injector was prescribed de novo. 2% of them were babies, 31% 1 to 5 years old, 52% 6 to 14 years old and 15% 15 to 18 years old. In 66% adrenaline auto-injector was prescribed because of anaphylaxis, in 27% because of urticaria or/and angioedema and in 7% because of other reasons such as food allergy and bronchial asthma or/and recombinant based IgE testing results.In 174 children (67%) adrenaline auto-injector was prescribed because of food allergy, most frequently because of allergy to peanuts (81 children), egg (35 children), tree nuts (19 children) and cow milk (14 children). 77% of peanut allergic children had IgE antibodies to rArah h 2. Among food allergic children 44% had multiple food allergies, 40% asthma and 11% suffered more than one immediate reaction. In 60 children (23%) adrenaline auto-injector was prescribed because of insect sting (49 had anaphylaxis and eleven urticaria or/and angioedema). Allergy to wasp or hornet venom was more frequently confirmed (in 34 children) than allergy to honeybee venom (23 children). 3 children had negative testing results after anaphylaxis due to a sting. In four children parents refused starting specific immunotherapy with Hymenoptera venom after anaphylaxis. In 12 children (5%) the cause of immediate reaction was unknown. Other confirmed reasons for prescribing adrenaline auto-injector were rare .30% of anaphylaxis was treated with adrenaline (auto-injector was used in eight children). 23% of children were not admitted to hospital after anaphylaxis. No child was admitted to intensive care unit.Our data showed that allergy to peanuts was most frequent cause of prescribing adrenaline auto-injector to children during last year. There is need to increase education of management of anaphylaxis in children in Slovenia."}
+{"text": "To estimate the prevalence of oral detectable human papillomavirus (HPV) DNA in HIV-negative men who have sex with men (MSM) attending a sexual health clinic in London and concordance with anogenital HPV infection. Such data are important to improve our understanding of the epidemiology of oral HPV and the potential use of vaccines to prevent oropharyngeal cancers.Paired oral rinse samples and anogenital samples were available from 151 HIV-negative MSM within a larger cross-sectional survey. All samples were tested in parallel for 21 types of HPV DNA using an in-house assay.The median age of participants was 30 (IQR 25\u201335). The prevalence of any oral HPV and of high-risk HPV (HR-HPV) was 13.7%  and 5.9%  compared with 64.9%  and 34.4%  in any anogenital sample, respectively. The prevalence of types prevented by the bivalent (HPV16/18), quadrivalent (HPV6/11/16/18) and nonavalent (HPV6/11/16/18/31/33/45/52/58) vaccines was 1.3% (95% CI 0.2 to 4.7), 2.6% (95% CI 0.7 to 6.6) and 4.6% (95% CI 1.9 to 9.3), respectively. There was no concordance between HPV genotypes detected in oral and anogenital sites.HR-HPV DNA, including HPV 16/18, was detected in oral specimens from HIV-negative MSM attending sexual health clinics, suggesting a potential role for vaccination, but is far less common than anogenital infection. How this relates to the risk and natural history of HPV-related head and neck cancers warrants further study. Lack of concordance with anogenital infection also suggests that oral HPV infection should be considered separately when estimating potential vaccine impact. Human papillomavirus (HPV) infection is associated with cancers at a number of sites in the head and neck, most importantly oropharyngeal cancer, which has been rising in incidence in recent decades.6Estimating the potential benefit of vaccinating MSM requires knowledge of the epidemiology of oral HPV infection. To date, only three studies involving a total of 877 HIV-negative MSM have been conducted to estimate oral high-risk HPV (HR-HPV) prevalence, and results are not consistent 2%, 17%8. LiMost transmission models of HPV infection used to inform vaccine programme design assume that infection occurs through anogenital contact, ignoring the role of oral\u2013anogenital contact. Indeed, estimates of concordance between oral and anogenital HPV infection not only have implications for vaccine assessment but also for understanding the key epidemic characteristics such as route of acquisition, whether anogenital infections are acquired simultaneously or via separate risk acts/partnerships, or whether men transfer infections from one anatomical site to another (auto-inoculation).We describe age-specific oral HPV prevalence and the concordance between detection of type-specific HPV DNA in oral and anogenital specimens from HIV-negative MSM attending a sexual health clinic in central London.Study methods, including sample size calculations, have been reported elsewhere.Participants who enrolled in the final five months of the study were also invited to provide an oral specimen involving a 30\u2005s gargle/rinse with 15\u2005mL of Scope mouthwash according to a published protocol.Here we report HPV prevalence and demographic and behavioural characteristics among participating MSM with both oral and anogenital specimens that were adequate for PCR-based HPV detection, for bivalent (HPV16/18), quadrivalent (HPV6/11/16/18) and nonavalent (HPV6/11/16/18/31/33/45/52/58) vaccine-preventable types together and individually, and for selected other HPV types: 35/39/51/56/59/68/26/53/66/70/73/82. CIs (95%) around prevalence estimates were determined by the Clopper\u2013Pearson (exact) method.There were 522 participants in the full study (n=522) and 177 gave an oral specimen. Participant and specimen numbers are shown in online supplementary figure S1. The study population was slightly younger than MSM attending MMC during the recruitment period (data not shown) and were more likely to be a new patient at the clinic than those who declined to participate; 163/173 (94%) HIV-negative MSM provided oral specimens, 153/173 (88%) were adequate for HPV testing and 151/173 (87%) had at least one matching anogenital specimen . Also, 127/151 (84%) had an anal swab, 135/151 (89%) had an external genital swab and 143 (95%) had a urine specimen.Online supplementary table S1 displays characteristics of substudy participants. The median age of respondents with adequate paired specimens was 30 (IQR 25\u201335), 75% were of white ethnicity and 64% had >30 lifetime sexual partners.Nine MSM had HR-HPV DNA detected in their oral specimens, and three had LR-HPV. Our observed prevalence of oral HR-HPV of 6% was higher than that of the global estimate in healthy men and women  yet the CIs overlap.w1Differences in estimates of oral prevalence between studies could be due to both technical and population differences. Methods of oral specimen collection, processing, storage, DNA extraction and test sensitivity and specificity differ across studies. We followed the oral rinse collection protocol from the Human Papillomavirus Infection in Men (HIM) study that is thought to yield more HPV DNA from the entire oral cavity than oral swabs and used a similar processing method.w2 In a cross-sectional assessment, persistent infections cannot be differentiated from those that are transient, and we did not measure oral cavity symptoms, but our lower oral prevalence as compared to anogenital prevalence may be due to both a lower incidence at oral sites and a lower proportion of persistent infections. While we have grouped HR-HPV types, defined by their oncogenic potential at the cervix, there is only evidence for HPV16 being associated with head-and-neck cancers.w3In the longitudinal Multicenter AIDS Cohort (MAC) study, HPV, particularly HR-HPV, in MSM was more likely to persist at the anus than the oral cavity, while heterosexual men were as likely to have persistent oral HPV as MSM, but less likely to have persistent anal HPV.et al (predominantly MSM)w4 and Parisi et al.w5 However, Edelstein et al found that 15/17 men  had the same type detected at oral and anogenital sites.w6 Lower prevalence in the oral cavity and the lack of concordance with anogenital infection suggest that oral HPV infections are acquired independently of anogenital infections, or that they are less likely to reactivate from latency than anogenital infections, and would also suggest that auto-inoculation does not commonly occur. Differences in sensitivity of the detection methods may also have contributed to some disparity in HPV detection between anatomical sites but is unlikely to account for the magnitude of the difference observed.Our finding of a lack of concordance between oral and anogenital specimens is similar to those in HIV-positive men reported by Videla We have previously demonstrated that our study population is at greater risk of STI acquisition than MSM attending other SHCs in England and MSM who attend SHCs in the general population of Britain.The sample size of this substudy was too small to accurately estimate oral\u2013anogenital concordance  but could estimate oral prevalence within 5% if the true population prevalence was 13%.w7 but whether they are effective against HPV-related head and neck cancers has yet to be shown. The lack of concordance between oral and anogenital specimens suggests that the additional potential benefit of HPV vaccination for preventing oral HPV-related disease should be considered in epidemiological and natural history models, in addition to anogenital HPV infection. Further studies, including meta-analyses, are needed to elucidate the epidemiology and natural history of oral HPV infection.HPV vaccines can prevent oral HPV infections,"}
+{"text": "Failure to accurately estimate energy requirements may result in an impaired recovery. Overfeeding has been associated with increased carbon dioxide production, respiratory failure, hyperglycemia and fat deposits in the liver, while underfeeding can lead to malnutrition, muscle weakness and impaired immunity.This study aimed to determine the metabolic profile of infant and preschool children submitted to mechanical ventilation in the ICU.2) in the first 48 hours of admission. The predicted basal metabolic rate (PBMR) was calculated using the Schofield equation. The metabolic state of each patient was assigned as hypermetabolic (REE/PBMR >110%), hypometabolic (REE/PBMR <90%) or normal (REE/PBMR 90-110%). The ratio of caloric intake to REE was also calculated and ratios of >1.5 and <0.5 were classified as overfeeding and underfeeding respectively.A prospective study was carried out in a pediatric ICU in Rio de Janeiro that included children aged from 1 month to 6 years submitted to mechanical ventilation from June 2013 to May 2015. Indirect calorimetry was used to obtain resting energy expenditure (REE) and oxygen consumption (VO2 was observed in 46.1% of the patients (VO2 \u2264120 ml/minute/m2), a normal value in 40.4% (VO2 >120 to \u2264160 ml/minute/m2) and a high value in only 13.5% of the patients (VO2 > 160 ml/minute/m2). Among the 52 included patients, 18 were fasting at the moment of the examination. The ratio of caloric intake to REE for the remaining 34 patients showed 38.2% overfeeding, 11.8% underfeeding and 50.0% normal feeding.A total of 35 infants and 17 preschool children were included. The male/female ratio was 34/18. In respect of severity of sepsis, 19 patients had septic shock, 24 had sepsis, five had severe sepsis and four had systemic inflammatory response syndrome. We observed a high incidence of hypometabolism (88.5%) and a low incidence of normal metabolism (7.7%) and hypermetabolism (3.8%). A low value of VOPredictive equations do not accurately predict REE in critically ill infants and preschool children, resulting in inadequate feeding. Although hypermetabolism and enhanced energy expenditure are the main clinical features of critical illness in adults, the majority of our patients were found to be hypometabolic which reinforces the need for a different approach between adult and pediatric critically ill patients."}
+{"text": "To analyze the incidence of epilepsy in adult patients with supratentorial glioblastoma, assess the factors influencing the development of epilepsy in these cases, and evaluate patients\u2019 response to antiepileptic drugs (AEDs) in a series of 184 patients.We retrospectively analyzed the 184 adult patients diagnosed with supratentorial glioblastoma. All subjects were treated within our hospital and subsequently died between 2003 and 2013. The incidence of epilepsy was assessed before and after initial resection and reexamined every 2 months thereafter. We evaluated the efficacy of prophylactic AEDs in this patient population based on the gathered incidence data.Of 184 patients, 43 (23.37%) were diagnosed with epilepsy before their initial resection. The total incidence of epilepsy (both pre- and postoperative) was 68.48%. The prevalence of active epilepsy reached over 80% in patients with epilepsy and survival of greater than 13 months postoperatively. Patients with glioblastoma in the frontal and/or temporal lobes had a higher prevalence of epilepsy. In the 43 patients with preoperative epilepsy, total resection of glioblastoma resulted in significantly lower seizure frequency. Patients who received epilepsy prophylaxis with AEDs for at least 6 months had significantly fewer seizures and higher Karnofsky scores than those receiving AEDs for less than one month or not at all.The incidence of epilepsy in adult patients with glioblastoma was high and responded poorly to AEDs in the short term. However, when taken for longer periods, AEDs can reduce the frequency of seizures in patients with glioblastoma. Although research continues to provide progress, the long-term survival of patients with GBM is rarely a reality due to frequent tumor recurrence. [Glioblastoma multiforme (GBM) is the most common primary intracranial tumor, and is characterized by aggressive growth and high patient morbidity.urrence. Epilepsy is common complication of glioma that can significantly decrease patient functioning and quality of life. \u20134 The loRecords of patients treated at our institution between January 2003 and December 2013 were reviewed for eligibility. Patients who meet all of the following criteria were included in the study group, (1) pathological diagnosis of GBM (WHO Grade IV); (2) surgical treatment, chemotherapy, and epilepsy managed entirely within our unit; (3) death between January 2003 and December 2013 in order to assess patients\u2019 entire course; (4) patients aged 18 years or older at the time of pathological diagnosis; (5) presentation of likely GBM 3\u20138 weeks prior to first operation; (6) patients with supratentorial GBM localizations; (7) underwent at least one resection which removed over 50% of tumor volume, followed by adjuvant radiotherapy and thermotherapy.Patients who met the following criteria were excluded from the study: (1) postoperative intracranial hemorrhage, cerebral infarction, or intracranial infection; (2) the appearance/diagnosis of multiple lesions pre- or postoperatively; (3) incomplete or missing medical records and/or incomplete chemotherapy, radiotherapy, and/or AED use; (4) less than 2 months between 2 consecutive operative procedures; (5) and patients who experienced epileptic seizures before diagnosis of GBM. This study was approved by the Institutional Ethics Committee of the First Affiliated Hospital of Chinese People\u2019s Liberation Army General Hospital and adhered to all international ethical standards and practices. All patients provided written informed consent prior to their death.The size of the GBM was determined by the maximum diameter measured on magnetic resonance imaging (MRI). For classification purposes, lesions were divided into categories based on their main anatomical location, including thalamus, bilateral, frontal, temporal, parietal, and occipital.131 intra-tumor radiotherapy  and 3D-conformal radiotherapy (2 Gy \u00d7 25~30 times). Chemotherapies included intravenous nimustine (2~3mg/kg) and oral temozolomide (150-200mg/m2/d for 5 days).Tumor resection and adjunct chemo-radiotherapy were the treatments of choice for included patients. Outcome following tumor resection was graded based on the ratio of preoperative to postoperative volume on MRI. The resultant categories were gross total resection (100%), major resection (\u2265 80%), and partial resection (50\u201379%). Methods of radiotherapy included IVideo electroencephalography (EEG) was performed when patients presented with their first seizure. Epilepsy diagnosis was based on seizure semiology and interictal epileptic spikes on video EEG monitoring. All patients diagnosed with epilepsy were treated with AEDs.Seventy-three patients without preoperative epilepsy received prophylactic AEDs following initial tumor resection. As this is a retrospective study, these patients were administered prophylaxis on a case-by-case basis based on the practice of individual physicians.The AEDs used included valproate (20-25mg/kg), levetiracetam (20-30mg/kg), and oxcarbazepine (15-20mg/kg). Although single drug treatment was the preferred approach, multiple AEDs per patient were used as appropriate when one drug alone did not adequately control seizures.In cases of short term AED administration, the drug was stopped over a 2 week period by decreasing the dose by half each week. In patients who received long term AED administration, a slower tapering was preferred and the drug was decreased by 1/3 each week for three weeks.Patients were seen in clinic every 2 months beginning 1 month after initial resection until death. Patients\u2019 seizures, incidence of epilepsy, and quality of life were evaluated at each follow-up. The incidence of epilepsy at any given time was defined as a cumulative number of patients with epilepsy before this time divided by the entire sample size. The incidence of epilepsy in surviving patients at any given time was defined as the total number of surviving patients with epilepsy divided by the total number of surviving patients. Any incident case of epilepsy between two follow-up appointments was defined as new onset. For the purposes of this study, active epilepsy was defined as at least one seizure between two follow-up appointments. Karnofsky scores were calculated at the 12 month follow-up for patients who survived between 18 and 24 months following initial resection.P < 0.05.Statistical analyses were performed using SPSS . Outcomes were described by percentage and the standard deviation of the mean. Quantitative data were analyzed using an F-test or t-test. Qualitative data were analyzed using Personal Chi-square tests or Kruskal-Wallis tests. The Kruskal-Wallis test and F-test were adopted for analysis of variance between groups. Results were considered significant for values of This cohort included 184 adults with GBM. Of the 184 subjects, 100 were male (54.3%) and 84 were female (45.7%) . The ave131 intra-tumor radiotherapy with a mean number of radiotherapy treatments of 3.14\u00b10.72 (range: 2\u20135). Ninety eight (53.3%) patients underwent 3D-conformal radiotherapy. The chemotherapy drug nimustine was used in 99 cases (53.8%), with temozolomide in the remaining 85 cases (46.2%). Survival time ranged from 4\u201335 months .Each patient underwent between 1 and 3 operative resections (mean: 2.06\u00b10.67), and received their first adjunct thermotherapy or radiotherapy within 2 weeks following surgery. Eighty-six patients (46.7%) received repeat IThe incidence of epilepsy throughout disease progression is depicted in Figs Among the patients with pre-resection epilepsy, the percentage of active epilepsy rose from 40.3% at 3 months post-resection to 80.0% at 13 months post-resection. This trend continued such that 100% of patients with epilepsy had active disease by 29 months post-resection.Of the first seizures experienced, 23 (18.3%) were simple partial seizures, 26 (20.6%) were complex partial seizures, and 77 (61.1%) were partial and secondary generalized seizures.No significant differences in the incidence of epilepsy were found based on gender, age at initial resection, or size of the GBM. However, as expected, significant differences in the incidence of epilepsy were found based on the main location of the lesion. Of the 38 GBM patients with temporal lobe lesions, 18 (47.4%) suffered from epilepsy pre-operatively. In addition, of the 26 GBM patients with parietal lobe lesions, 9 (34.6%) experienced seizures pre-operatively. Thus, temporal or parietal lobe lesions are the greatest risk factors for preoperative epilepsy in GBM patients.High rates of postoperative epilepsy were also observed in these patients, with 15 (39.5%) of the subjects with temporal lobe lesions and 9 (34.6%) of those with parietal lobe lesions experiencing post-operative onset epilepsy. However, the incidence of postoperative epilepsy was highest in the patients with frontal lobe lesions, with 38 of 61 patients (62.3%) developing seizures .131 intra-tumor radiotherapy or between patients receiving nimustine chemotherapy versus those receiving temozolomide. However, patients whose initial operations achieved gross total resections were much more likely to be seizure-free than those who received major or partial resections. Of the 43 patients with preoperative epilepsy, 16 of the 20 (80%) who underwent gross total resections were seizure-free at one month follow-up, compared with 7 of the 23 (30.4%) partial resection patients (P = 0.0032).Ten of 43 (23.3%) patients with preoperative epilepsy presented with one or more seizures in the first month following initial resection . This coP = 0.0067), as well as at follow-ups at 2 through 6 months .Forty-three patients survived for 18~24 months after initial resection and 20 of these patients developed epilepsy before 12 months. No significant difference in survival time and age at first resection was found between the 20 patients with epilepsy and the 23 without. The mean Karnofsky score was 47.25\u00b110.94 in patients with epilepsy at 12 months follow-up, which was significantly lower than 55.65\u00b113.76\u2014the mean score for those without epilepsy  and frontal (82.0%) lobes, corroborating the 2009 findings by Chaichana et al. GBM is characterized by frequent tumor recurrence, and the development of post-resection epilepsy has been previously linked to tumor progression.  It is imThe consensus within the literature suggests that AEDs should be utilized at the first presentation of epilepsy in patients with GBM. , 17\u201319 HThough the data reported herein are limited by the retrospective nature of the study, our results\u2014in contrast to the present literature\u2014suggest that prophylactic AEDs can reduce postoperative epilepsy in the first month after initial resection. This observation remained at postoperative follow-ups at 2 through 6 months. Beyond 7 months, the prophylactic benefit of AEDs was not evident. Furthermore, the percentage of patients with GBM undergoing total resection was low and the rate of recurrence and reoperation was high in the first 6 months following initial resection. Finally, this study lacks the large number of patients that would need to be randomized in order to more clearly show the benefit of prophylaxis.No drugs are without side effects, and consideration should be given to those of AEDs.  However,"}
+{"text": "To determine current practice regarding the use of epicardial pacing wires by cardiothoracic surgeons in the U.K.To determine current practice regarding the use of epicardial pacing wires by cardiothoracic surgeons in the U.K.An internet-based survey was distributed via email to all U.K. cardiac and cardiothoracic surgeons. The questionnaire consisted of 18 questions regarding use and management of epicardial pacing wires.Of 282 questionnaires, 126 responses were received (response rate 44.7%). Around two thirds (68.3%) of respondents routinely used epicardial wires for isolated coronary artery bypass grafts (CABG). Both atrial and ventricular wires were favoured for valve cases: isolated aortic valve(60.3% respondents), isolated mitral valve(63.5%), multiple valves(70%), CABG & valve(63.5%), redo valve(67.5%). The main reasons quoted for not using pacing wires: perception as an unnecessary procedure(22.2%), risk of bleeding(25.4%) and potential for delayed discharge(17.5%). Around half (54%) of surgeons reported practising minimally invasive techniques and 36.8% of these modified pacing wire usage. Two-thirds of surgeons accepted an INR of <2.5 for removal of pacing wires with another 24.6% accepting an INR <3.0 . Seventy percent would not remove pacing wires outside daytime hours although 54% removed them over weekends and holidays. Postoperative day 3 or 4 was the most common day for removal. Forty-five percent of respondent surgeons were comfortable discharging patients the day the wires were removed.Results show considerable variation in practice. Modifications based on peer practice could potentially save bed-days , reduce costs (clarifying indications and reducing routine use) and reduce risk of bleeding (by standardising safe level of anticoagulation)."}
+{"text": "Blood stream infections of abdominal origin are associated with a high mortality rate. No data are available in patients (pts) with postoperative peritonitis (POP).We hypothesized that both patient and microbiological factors determine outcome in critically ill POP pts.Between 1999 and 2014, all consecutive ICU pts admitted for management of POP were prospectively included in a data base. Bacteremic pts (B+) were defined as having at least one positive blood culture in the 24 hours preceding/following surgery for POP. The following data were collected: demographic characteristics, underlying disease, severity scores at the time of reoperation, microbiologic results, outcome and survival. B+ pts were compared to non-bacteremic pts (B-). Results are expressed in mean (SD) or proportions.Overall, 292 pts  year old, 33% with fatal underlying disease) were enrolled, including 58 (20%) B+ pts. Age was similar in both groups while immunosuppression and cancer were more frequent in B+ pts . No difference was observed for the characteristics of initial surgery leading to POP. Delay for reoperation (9 (8) days), location and cause of POP were similar in both groups. At the time of reoperation for POP, SAPS II score was similar in both groups (48 \u00b1 18) while SOFA was increased in B+ pts (9 (4) versus 7 (4); p < 0.05). The organisms cultured from blood cultures (19% multidrug resistant bacteria (MDR), mainly Gram+ strains) were Gram+ (34%), Gram- (47%), anaerobes (14%) and fungi (10%). Among the organisms cultured from the peritoneal space, proportions of E. coli and Enterobacter spp were increased in B+ pts  and , while the proportions of MDR bacteria were similar in both groups. Adequacy of empiric antibiotic therapy was reached in 69% of the cases, similar in both groups, without any difference in the type of agents used, frequency of combination therapy (75 and 80% in B+ and B- groups) or duration of therapy (11 (6) days). The frequency of de-escalation (51% in B+ vs 55% in B- pts) and escalation therapy  was similar in both groups. While death rate was increased in B+ pts , the morbidity criteria did not differ between B+ and B- pts: frequency of reoperations (47% in both groups), duration of mechanical ventilation in survivors (11 (11) days), duration of ICU stay in survivors (18 (12) vs 21 (19) days in B-pts). Positive cultures of enterococci in the peritoneal fluid could be factor of poor prognosis in case of bacteremia .In our ICU population of POP, an increased death rate was reported in bacteremic pts but few elements explain this observation except underlying disease, ongoing cancer and possibly presence of enterococci within peritoneal samples."}
+{"text": "The effects of hyperoxia at a cellular level are well known, with formation of free radical species causing reactive damage. It has previously been shown that hyperoxia is associated with increased mortality in patients resuscitated from cardiac arrest . HoweverWe sought to examine whether mortality varies with arterial oxygenation in the first 24 hours after admission to our intensive care unit (ICU) following out of hospital cardiac arrest (OOHCA).a02) provided as part of severity scoring: hyperoxia was defined as Pa02 > 15, normoxia as Pa02 10-15 and hypoxia as Pa02 < 10 kPa. Hospital mortality was the primary outcome measure and statistical significance was assessed using Fisher's exact test.This was a retrospective, consecutive case series of patients admitted to the ICU at the Victoria Infirmary, Glasgow following OOHCA over a 15 year period between 1999 and 2014. Patients were identified and characterised using the WardWatcher\u2122 database. Three subgroups were generated based on the arterial partial pressure of oxygen  with a median age of 64 years (IQR 52-70 years) admitted following OOHCA. For the 97 patients with complete severity scoring, the median APACHE II score was 31 (IQR 24-35) and mortality prediction 80.3% (IQR 59.4%-87.9%). Survival to hospital discharge was achieved in 29 patients (23.4%), yielding a standardised mortality ratio of 0.95. Median hospital length of stay was 16 days (IQR 8-27 days). Data on arterial oxygenation were available for 103 patients.There was no statistically significant difference in hospital mortality between groups .We demonstrated survival to hospital discharge in almost a quarter of patients admitted to ICU post-OOHCA. Despite international resuscitation guidelines to the contrary , a signi"}
+{"text": "Investigators from hospitals in Brazil tested verbal fluency in 20 adolescent patients, ages ranged from 11 to 16 years (mean 13.8 years), with Sydenham chorea compared with 20 patients with rheumatic fever without chorea and 20 healthy controls, matched for age and gender. Investigators from hospitals in Brazil tested verbal fluency in 20 adolescent patients, ages ranged from 11 to 16 years (mean 13.8 years), with Sydenham chorea compared with 20 patients with rheumatic fever without chorea and 20 healthy controls, matched for age and gender. Performance in verbal fluency and in verbal comprehension tasks differed significantly (P < 0.01) among the three groups. Patients with Sydenham chorea performed significantly worse than healthy control group in phonemic and semantic verbal fluency tasks as well as verbal comprehension (Token Test). The rheumatic fever group also performed worse than healthy controls in phonemic verbal fluency. Severity of motor signs in Sydenham chorea correlated inversely with performance in phonemic verbal fluency. [COMMENTARY. Nineteenth century reports of clinical manifestations of Sydenham or rheumatic chorea refer to speech but not language problems. Cheadle WB of the Great Ormond Street Hospital, London, UK, describes explosive bursts of inarticulate speech, jerky, or Sydenham's speech . The choThe incidence of Sydenham chorea and acute rheumatic fever has declined dramatically in recent years but the disease and neuropsychiatric complications still cause significant morbidity in developing countries. In a follow-up study of 65 Sydenham chorea patients in Turkey, mean age at onset of symptoms was 11.7 +/-2.6 years (range 6-17 years), and 63% were female. History of rheumatic fever was recorded in 30.8% of patients, carditis and EKG valve involvement in 70.5%, normal brain MRI in all of 18 tested, and abnormal slow waves in the EEG of 50% of 18 tested. Recovery following the first attack of chorea occurred in 1 to 6 months in 51.7% of patients, and recurrence in 37.9% [The motor features of rheumatic chorea are often complicated by neuropsychiatric disorders, most commonly obsessive-compulsive behavior, and less frequently ADHD, anxiety, and depression . The pre"}
+{"text": "Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous group of inherited neuropathies that was first described in 1886. CMT1A is the commonest form of CMT and accounts for 70% of demyelinating CMT (CMT1).However, rare cases of superimposed inflammatory neuropathy or radiculopathy, either secondary to degenerative spinal disease or as a complication of enlarged nerve roots, have been reported in CMT1A. There has been one reported case of marked asymmetry with unilateral footdrop without an alternative explanation despite extensive assessment in a 19-year-old male patient.first dorsal interosseous (FDIO) and abductor pollicis brevis (APB) muscles in the upper limbs (UL) and ankle dorsiflexion and plantarflexion in the lower limbs (LL). Asymmetry was defined as a difference of greater than 1 MRC grade in contralateral muscles  and asymmetry of sensation as a difference of 1 point on the CMTES PP and vibration scales. We excluded patients with electrophysiological evidence of superimposed compressive neuropathy and those with examination findings suggesting significant foot, ankle and hip problems or spinal deformities, which are commonly associated orthopaedic complications in inherited neuropathy that can contribute to non-neuropathic motor deficits.We performed a retrospective case series review in a cohort of patients with clinically and genetically confirmed CMT1A followed up at least annually at the inherited neuropathy clinic in the National Hospital for Neurology and Neurosurgery. Routine practice involves annual clinical assessment using the CMT Examination Score (CMTES), which includes Medical Research Council (MRC) scoring of muscle strength and validated scales for quantification of pinprick (PP) and vibration sensation (VS) deficit .We recorded presence of asymmetry in strength in the commonly affected One hundred and eighty patients were included in this review, 40.1% male, mean (SD) age at examination was 41.7 (14.8) years. Asymmetry of strength was seen in 38 patients (21.1%), of whom 24 (13.3%) had asymmetrical UL and 17 (9.4%) asymmetrical LL strength. The distribution of asymmetry in UL was as follows: FDIO  in 13 patients (7.2%) and APB (range: 1\u20133 points) in 14 patients (7.8%). In the LL: ankle dorsiflexion (range: 1\u20132 points) in 17 (9.4%) and ankle plantarflexion (range: 2\u20133 points) in two patients 1.1%; . In threIn terms of sensation, asymmetry was noted in 23 patients (12.8%); PP asymmetry  in nine patients (5%) and VS (range 2\u20134) in 10 5.6%; . AsymmetIn conclusion, we observed motor and sensory asymmetry in a significant minority of patients in this well phenotyped CMT1A cohort. The presence of asymmetry alone in CMT1A does not necessarily suggest that an alternative explanation needs to be sought."}
+{"text": "Dengue is a major tropical infection in Malaysia. It has several presentations and may progress to severe illness. Mortality is high if left unsupported. Warning Signs (WS) ; nausea, vomiting abdominal pain, bleeding and leaking syndrome (LS)  are crucial in dengue assessment. Abdominal pain and tenderness, gastrointestinal bleed, jaundice, hepatomegaly and ascites are predictors of severe illness and require intensive care support as mentioned in the literatures.At present, E-FAST is used widely in emergency unit to aid diagnosis and management in acute emergency and trauma. It has not been used in dengue infection to detect leaking syndrome. The clinical sign of leaking syndrome can be subtle if minimal. Early detection will lead to closer monitoring and anticipation of further change of clinical condition, hence aid in management of dengue.To assess the utility of E-FAST in detecting LS in dengue infection.Cross-sectional study of patients with dengue infection admitted to medical wards in The Department of Medicine Hospital Kuala Lumpur from 18 August 2014 to 30 August 2014. All dengue infection cases received standard treatment. E-FAST was performed by a group of 4 physicians trained by WINFOCUS Malaysia Team. Each scan was performed by a physician, and reviewed by another . All baseline information, clinical and scan findings were recorded.IQR 73). Median days for presentation of illness were 4 days ( IQR 8). 4 (19%) patients presented in defervescence phase and 17 (81%) patients presented in febrile phase. WS were observed in all patients in this study; 3 (14%) patients had 1 WS, 7 (33%) patients had less than 3 WS( < 3 WS) and 11 (52%) had 3 and more WS (\u2265 3WS ) . On discharge, 14 (67%) patients had diagnosis of dengue fever with WS and 7 ( 33%) patients had diagnosis of severe dengue.Total of 21 patients were observed; 13 (62%) males and 8 (8%) females, with median age of 24 years old  patients. 3 out of 9 (33%) patients were clinically detected by clinician versus 6 out of 9 (67%) patients by E-FAST (p < 0.05). 5 patients had pleural effusion; 3 patients detected by clinician and 5 patients detected by E-FAST ( p < 0.05). 9 patients had ascites in which 1 detected by clinician and 9 detected by E-FAST ( p = 0.237). In those with LS , 8 ( 88%) patients had \u2265 3 WS compared to 1 (11%) patients had < 3 WS ( p < 0.05). In LS 7 (78%) patients had diagnosis of severe dengue on discharge and 2 (22%) patients had diagnosis of dengue fever with WS on discharge ( p < 0.05). In those with LS, 3 (33%) patients needed ICU admission and 6 (67%) was managed in general ward (p = 0.149).E-FAST is useful to detect fluid collection for LS in dengue patients with warning signs in Medical ward. Detection of LS is significantly better with E-FAST compare to clinical detection. Larger cohort of study population is needed for further evaluation of E-FAST usage in diagnosis, monitoring and management of dengue infection."}
+{"text": "PFO closure may reduce the frequency and severity of migraine headaches in patients with significant right-to-left shunts.Between January 2008 and March 2013 consecutive patients  with migraine symptoms were given a prior PFO closure with the Cardia PFO occluder for migraine attack prevention. All patients had right-to-left shunts; the shunts were associated with migraine symptoms in 8 patients and all eight had aura symptoms. Septal aneurysm was present in 4 (i.e. 50%) migraine patients. All patients had very frequent migraine attacks, more then 7 times per month. All 8 patients underwent transoesophagael echocardiography after PFO closer with a clinical follow-up after 24 hr, then after 6, and 12 months, and then yearly.An acute migraine attack occurred after PFO closure in 2 (25%) of 8 patients. There was a significant reduction (>50%) in the number and intensity of attacks in 6 (75%) of the 8 patients after the 3-month follow- up period but in 1 (12.5%) similar attacks occurred before closure. After the 12-month follow-up period , migraine had ceased in 5 (62.5%) patients, and 3  had a reduction in the migraine recurrence rate and disabling symptoms. These results were maintained in the follow-up (about 72 months). Only one patient remained migraine attacks, but not more than one attack per month about three month follow up period after PFO closure. There was an overall improvement in 82.5% of the treated patients.Percutaneous PFO closure in migraineurs may provide beneficial mid-term and long-term results, with significant reduction in the intensity and frequency of headache symptoms.No conflict of interest."}
+{"text": "The aim of our study was to estimate the prevalence of headache disorders in three different social settings using the newly published International Classification of headache Disorders(ICHD-3beta).The study population consisted of:1042 students , 1075 workers , 1007 blood donors . All patients were diagnosed according to ICHD-3beta using a semi-structured validated interview conducted by a neurologist or by trained senior medical students.In the whole material, 1-year prevalence of headache was 67%, migraine 15% and tension type headache (TTH) 58%. In females the prevalence of migraine in students(35%) was significantly higher than in workers(16%) and blood donors(19%), p<0.0001.In males the prevalence of migraine in students(15%) was also significantly higher than in workers(4%) and donors(5%), p<0.0001. The prevalence of TTH in females was respectively 77%, 65% and 66%. In males the prevalence of TTH in students (79%) was significantly higher than in workers( 32% )and blood donors(59%), p<0.0001, the prevalence of TTH in donors (59%) was significantly higher than in workers(32%), p<0.0001. Only few (18%) had consulted because of headache. Particularly the very high prevalence of migraine and TTH in students is important and calls for further studies of risk factors and possibilities for preventive measures.We show for the first time convincingly that headache disorders have different prevalence according to social setting. They represent a huge health problem in Russia.No conflict of interest."}
+{"text": "The advent of biologic medications has considerably increased the potential for treatment benefit in juvenile idiopathic arthritis (JIA), with clinical remission being now achievable in a substantial proportion of patients.To evaluate the outcome of etanercept (ETN) therapy in Italian children with JIA.This is a multicenter, observational study that includes all children with JIA who were given ETN at Italian pediatric rheumatology centers after January 2000. Patients were classified in 2 groups: 1) children who were no longer taking ETN at study start; 2) patients who were still receiving ETN at study start. Patients in Group 1 underwent only retrospective assessments, whereas patients in Group 2 underwent both retrospective and cross-sectional assessments. The primary outcome of the study were reasons for ETN discontinuation in patients in Group 1, and achievement of the states of inactive disease (ID), minimal disease activity (MDA) and parent- and child-acceptable symptom state  in patients in Group 2. The above states were assessed through both formal definitions and JADAS cutoffs. The secondary outcome was the evaluation of frequency and characteristics of ETN-related side effects.Twenty-five centers were asked to make a census of all patients followed at the center who met the inclusion criteria for Group 1 or Group 2. A total of 1230 patients were included in the census. Of these patients, 624 were still receiving ETN (Group 2), whereas 606 had discontinued ETN (Group 1). So far, the data of 313 patients (145 in Group 1 and 168 in Group 2) have been collected. Among the 145 patients in Group 1, reasons for ETN discontinuation included disease remission (41.4%), lack of efficacy (31%), and side effects (25.3%). The results of assessment of disease state through formal definitions in 106 children of the 168 children in Group 2 who had already undergone the cross-sectional evaluation were the following: ID 44.3%, MDA 76.4%, PASS 75.2%, CASS 68.9%. The percentages of patients who reached the same disease states assessed through JADAS cutoffs were: ID 41.5%, MDA 50.9%, PASS 61.3%, CASS 56.6%. Serious adverse events were seen in 8 of the 313 patients and included inflammatory bowel disease (3 pts), tuberculosis (1 pt), CMV hepatitis (1 pt), varicella complicated by bronchopneumonia (1 pt), bladder carcinoma (1 pt); 1 patient died of streptococcal sepsis.A substantial proportion of children currently receiving ETN were in the states of ID or MDA, or were satisfied with treatment outcome. The percentage of patients with ID in the cross-sectional cohort was comparable to the percentage of patients who were discontinued from ETN for disease remission in the retrospective cohort. Serious adverse events were uncommon.None declared."}
+{"text": "Tocilizumab was recommended for the treatment of systemic juvenile idiopathic arthritis (sJIA) in children whose disease has responded inadequately to non-steroidal anti-inflammatory drugs, systemic corticosteroids and methotrexate.To study the efficacy and tolerability of Tocilizumab (TCZ) in patients with longstanding refractory to the conventional treatment and TNF-inhibitors sJIA.th, 9th and 12th month.Seven children in the age range 2-12 years (mean 6.3 years) with disease duration 1.2 - 9 years (mean 4.6 years) with active persistent sJIA have been enrolled in one-year prospective study. All 7 patients had oligoarticular joint involvement and received previous treatment with NSAIDS, Methotrexate and corticosteroids. 4/7 had concomitant therapy with Etanercept and 2/7 second DMARD. In all patients TCZ was administered immediately after discontinuation of the biological treatment or the second DMARD in a dose of 8 mg/kg for patients \u2265 30 kg and 12 mg/kg for patients < 30 kg every two weeks. At baseline all patients had active disease. Response to the treatment was measured according to the ACR Pedi criteria at the end of the 1st, 3rd, 6Clinical examination, laboratory investigations, growth parameters' assessment and screening for adverse events have been performed every 2 weeks.st month we found complete resolution of the systemic symptoms and acute phase response in all patients. At the end of the 3rd month, ACR Pedi 30, 50, 70 and 90 responses were achieved by 7 (100%), 5 (71%), 1(14%) and 0 (0%) patients, respectively. By 6th month the observed responses we as follows: ACR Pedi 30 - 7 pts (100%), ACR Pedi 50 - 7 pts (100%), ACR Pedi 70 - 5 pts (71%), ACR 90 - 1 patient (14%). At the end of 9th month ACR Pedi 30, 50, 70 and 90 responses were achieved by 7 (100%), 7 (100%), 6 (86%) and 4 (57%) patients. All patients maintained these parameters by 12th month.At the end of the 1th month. At the end of the observational period the linear growth velocity of all treated patients reached the average normal values per year of their age matched peers.After achieving control of the disease activity, we started to reduce the dose of steroids and/or Methotrexate leading to their discontinuation and monotherapy with TCZ in 4 patients. In all of these patients remission on medication was documented by 12Some patients experienced mild and reversible adverse reactions such as: mild neutropenia or thrombocytopenia, slight increase of liver enzymes and increased cholesterol levels. All side effects resolved with the decrease of the dosage and did not lead to the discontinuation of the treatment.Tocilizumab is an effective and well tolerated drug in children with systemic longstanding persistent JIA, refractory to the conventional treatment and TNF-inhibition. Monotherapy with TCZ is an appropriate option for controlling the disease activity, improving the physical growth and minimizing the overall toxicity of the treatment of this disease.None declared."}
+{"text": "Ongoing studies using genomic microarrays and next-generation sequencing have demonstrated that the genetic contributions to cardiovascular diseases have been significantly ignored in the past. The aim of this study was to identify rare copy number variants in individuals with congenital pulmonary atresia (PA).12 metabolism were identified for the first time. A de novo 1-Mb deletion at 17p13.2 may represent a rare genomic disorder that involves mild intellectual disability and associated facial features.Based on the hypothesis that rare structural variants encompassing key genes play an important role in heart development in PA patients, we performed high-resolution genome-wide microarrays for copy number variations (CNVs) in 82 PA patient-parent trios and 189 controls with an Illumina SNP array platform. CNVs were identified in 17/82 patients (20.7%), and eight of these CNVs (9.8%) are considered potentially pathogenic. Five de novo CNVs occurred at two known congenital heart disease (CHD) loci (16p13.1 and 22q11.2). Two de novo CNVs that may affect folate and vitamin BRare CNVs contribute to the pathogenesis of PA (9.8%), suggesting that the causes of PA are heterogeneous and pleiotropic. Together with previous data from animal models, our results might help identify a link between CHD and folate-mediated one-carbon metabolism (FOCM). With the accumulation of high-resolution SNP array data, these previously undescribed rare CNVs may help reveal critical gene(s) in CHD and may provide novel insights about CHD pathogenesis. Congenital heart diseases (CHDs) are the most common birth defects and cause significant morbidity and mortality in children worldwide. The incidence of CHD has been estimated at approximately seven per 1000 newborns, which has not changed over the past several decades Rare genetic variantions have largely been ignored in the study of complex genetic disorders and other phenotypes DHFR), 10p13dup (CUBN) and 17p13.2del (CAMTA2).More than 1700 genes are thought to play integral roles in mouse cardiac development, and homologs of these genes might be candidate genes involved in CHD in humans This study was approved by the Review Board of the Second Xiangya Hospital of the Central South University. All probands and their relatives who participated in the study gave written informed consent. All participants consented to this study, and blood samples were collected after receiving written informed consent from the patient's parent or guardian on behalf of the children enrolled. After the screening of more than 6950 patients under age 14 with CHD who were admitted to the Department of Pediatric Cardiology at the Second Xiangya Hospital of Central South University, 82 PA patients and their unaffected parents were recruited to this study and began the Cardiac Biospecimen Collection procedure. The patient cohort included 30 males and 52 females from South Central China, with a mean age of 3 years old (range of 10 days to 14 years old). The whole blood samples were collected and stored in the Cardiac Genomic Bank of the Second Xiangya Hospital of the Central South University.Twin studies with congenital malformations are one of the commonly accepted methods for the systematic study of human genetics because twins help elucidate the relationships between genetics, epigenetics, and the environment. Three twin pairs, including two pairs of monozygotic twins and one dizygotic twin pair, were included in this study .Each PA patient and their unaffected parents were assessed using echocardiography, and the diagnosis of PA was further confirmed at the time of surgery. A total of 189 ethnically matched control subjects were also evaluated by echocardiography to exclude CHD.The peripheral blood samples from the PA patients and the parents of those patients with potentially pathogenic CNVs were collected from each individual and followed by chromosome analysis using conventional G-banding techniques at the 550 band level. A lymphocyte culture was performed for all samples according to a standard cytogenetic protocol.Genomic DNA was prepared from peripheral blood using a DNeasy Blood & Tissue Kit  on the QIAcube automated DNA extraction robot .http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE56422. The entries are scheduled to be released on Apr 02, 2014.Genomic DNA samples from the patients and parents were adjusted to a final concentration of 50 ng/\u00b5l. The Human660W-Quad/HumanOmni1-Quad BeadChips  and Illumina BeadScan genotyping system (Beadstation Scanner) were employed to obtain the signal intensities of SNP probes. The Human660W-Quad contains nearly 660,000 SNP markers, and the HumanOmni1-Quad Beadchip contains over 1.1 million loci, including markers derived from the three HapMap studies, the 1000 Genomes Project and recently published studies http://www.idtdna.com/Primerquest/Home/Index). Amplification levels were calculated using the 2\u2212\u0394\u0394CT method.For eight potentially pathogenic CNVs, at least two primer sets were designed within the boundaries of the CNV region  and five PA patients with an intact ventricular septum (PA-IVS), were genotyped using SNP-based microarrays. To explore CNVs that are potentially responsible for PA and avoid overestimating the causality of CNVs, we focused on deletions/duplications  with high confidence. We identified 412 CNVs (256 copy losses and 156 copy gains) with an average of five CNVs (range of 0\u201328) per patient and an average length of 400,250 bp .DHFR), duplication of 10p13 (CUBN) and deletion of 17p13.2 (CAMTA2). The results of these potentially pathogenic CNVs are summarized , and eight of these CNVs (9.8%) are considered potentially pathogenic. The eight pathogenic or potentially pathogenic CNVs were further validated by Real-time quantitative PCR (Primers are listed in mmarized .DHFR (MIM 126060) and other critical genes, such as PDE8B (MIM 603390), AP3B1 (MIM 603401), ARSB (MIM 611542), and DMGDH (MIM 605849). The other CNV was a 10p13 duplication that is 175 kb in size and affected only one gene, CUBN (MIM 602997) (We examined whether PA-associated CNVs encompass gene(s) that related to specific genetic pathways and identified two CNVs that encompass genes associated with folate and vitamin B12 metabolism. A 5q14.1 duplication (chr5:75132315-79958945) spanned approximately 4.8 Mb and encompassed  602997) .The patient cohort also included three pairs of twins: one pair of dizygotic twin sisters who both had PA and two monozygotic pairs who were diagnosed with PA or TOF. Identical 3p26.3-26.1 deletions and 10p15.3-p15.1 duplications were identified in the dizygotic twin sisters with PA , GP1BA (MIM 606672), PFN1 (MIM 176610), and ENO3 (MIM 131370)  were observed. The 1-Mb deletion at 17p13.2 spanned four OMIM morbid genes:  131370) . The sin 131370) . The cli 131370) .We have presented one of the largest genetic studies investigating the role of rare CNVs in the severe heart defect, PA. The data from 82 PA patient-parent trios and 189 controls were analyzed with a well-defined platform (Human660W-Quad/Omni1-Quad SNP-arrays). Copy number variations were identified in 17/82 patients (20.7%), and eight of these CNVs (9.8%) are considered pathogenic or potentially pathogenic. The overall CNV frequency in our study is consistent with that found in previous studies of isolated or syndromic CHD patients based on different microarray platforms using array comparative genome hybridization or SNP arrays DHFR, and another CNV is a 10p13 duplication that affects only one gene, CUBN. Dihydrofolate reductase (DHFR) is a key folate-metabolizing enzyme that catalyzes the reduction of dihydrofolate (DHF) to tetrahydrofolate (THF), as well as folic acid to DHF CUBN, is a receptor expressed in the apical pole of absorptive epithelia 1212, and homocysteine are summarized in Previous research suggests that the risk of CHD may be related to genetic variants in folate pathway-related genes SUMF1, ITPR1, and CRBN. The 5.1-Mb duplication at 10p15.3-p15.1 contained several disease-causing genes, such as KLF6, AKR1C2, and AKR1C4. Fine mapping of these two genomic regions (3p26.3-26.1 and 10p15.3-p15.1) revealed that the twins with PA carry a larger duplication at the terminus of chromosome 10p than their healthy mother  using classic familial linkage analysis Two dizygotic twin sisters of family 1 shared an identical 3p26.3-26.1 deletion and a 10p15.3-p15.1 duplication, while the karyotypes of the twins and their parents were normal at 550 band resolution . The 3p2y mother . RecentlMYH11 has been previously associated with heart disease. Mutations in MYH11 cause thoracic aortic aneurysm/dissection, and recurrent 16p13.1 duplications confer a risk for aortic dissection CAMTA2, designated as calmodulin binding transcription activator 2, is part of a family of activators of the ANF promoter. Camta2 has been shown to interact with Nkx2-5 and promote cardiac hypertrophy in mice CAMTA2 is an appropriate candidate gene for CHD that is caused by a 17p13.2 deletion disorder. The 17p13.2 deletion is rarely reported in the literature, and thus far, only two 17p13 deletions Two other de novo CNVs, one with an 875-kb duplication at 16p13.1 (chr16:15395312-16270740) and the other with a 1-Mb deletion at the 17p13.2 locus (chr17:4041358-5091377), were found in only one individual with PA. Of the 12 genes contained in the 16p13.1 region, DHFR), 10p13dup (CUBN) and 17p13.2del (CAMTA2). Our results suggest that rare CNVs likely contribute significantly to the genetic basis of cardiovascular diseases, such as PA. Our study provides evidence for the association of CHD with FOCM. The discovery of previously undescribed rare CNVs in patients with CHD helps elucidate critical gene(s) for CHD and may provide new insights into understanding the pathogenesis of CHD.In summary, we identified eight rare de novo CNVs (9.8%) in patients with PA including three previously undescribed CNVs: 5q14.1dup  have normal karyotypes.(TIF)Click here for additional data file.Figure S2Illumina SNP-array result of the 6p21.33 deletions in patient 894020 and patient 706346.(TIF)Click here for additional data file.Table S1Primers for Real-time Quantitative PCR Validation.(DOCX)Click here for additional data file."}
+{"text": "Intraabdominal candidiasis (IAC) is a condition associated with a high morbidity and mortality in the Intensive Care Unit (ICU) . Actual Describe the characteristics of IAC in ICU patients and assess possible differences between patients with intraabdominal candidiasis in ICU compared to those in regular wards.Retrospective multicenter, multinational study of IAC over 3 years in 13 hospitals in 5 countries. IAC was defined according to a European consensus definitions. Demographic and clinical data was recorded.481 patients with intraabdominal candidiasis were recorded. 132 patients (27%) were at the ICU at time of diagnosis and 349 (73%) at regular wards . There were no statistical differences in age, sex or comorbidities except for heart disease  and use of dyalisis . APACHE II score was higher in ICU group (mean:18 IQR 25%-75%:14-24) vs wards (mean: 13 IQR 25%-75%:8-18) p= < 0,001.Candida albicans was the most frequent isolated strain in both groups (64% ICU vs 65%ward) follow by C glabrata, C tropicalis, C parapsilosis and C krusei with no statistical differences. Candida colonization, candidemia and septic shock were more present in the ICU population . Echinocandin was initiated in 43,7%, follow by azole in 21% and amphotericin B only 2,7%. Adequate antifungal treatment was more frequent in ICU population , adequate source control was similar in both groups  however 30 day mortality was higher in ICU patients .Time from hospitalization to diagnosis was longer in ICU group (mean: 13 days IQR 25-75%: 6-30 days) compared to regular ward (mean: 11 days IQR 25-75%: 2-20 days), p = 0,006. Secondary peritonitis was the most common source of infection (39% vs 40% respectively) followed by abdominal abscess, biliary tact infection, pancreatitis and tertiary peritonitis without differences between groups. No differences in source of infection or candida species regarding ICU or regular ward were observed. Adequate initial treatment was higher in the ICU population but patients with intrabdominal candidiasis in the ICU remain as a group with high mortality probably in relation to severity of illness."}
+{"text": "Biologic treatments have been introduced for Juvenile Idiopathic Arthritis (JIA) treatment in 2000, and have substantially improved the global prognosis of all disease subtypes. However not all patients respond to one biologic and therapeutic effect of one drug may decrease with time.We aimed to analyse, in current practice, the switch to another biologic, and the drug survival for treatment according to all JIA subtypesPatients included in the juvenile inflammatory rheumatism (JIR) cohort, including ten Swiss, French and Belgian centers for pediatric rheumatology, were analyzed retrospectively.529 JIA patients, sex ratio: 0.5 (175M/354F), aged between 1 to 22 years at the onset of biologic treatment (mean 10.4 sd 4.4) were analysed. Their diseases were as follows: enthesitis-related arthritis (ERA: 19%), oligoarthritis (Oligo: 28%), polyarthritis (Poly: 27%), psoriatic arthritis (Pso: 5%), systemic-onset arthritis (SoJIA: 17%), and undefined (4%). Anti-TNFs were the most frequent biologics used as first line: Etanercept for 66.5% (less frequent for So: 47%), adalimumab for 13.4% and infliximab for 10%. The first biologic remained the only one in most cases (66%). The reasons to stop these treatments were: lack of efficacy for 12% (63), complete remission for 11% (57) and side effect for 7%. The second line biologic the most used was for SoJIA: anakinra (28%) and tocilizumab (24%) whereas adalimumab was the most frequent for other JIA subtypes. Tocilizumab was the top 3rd line for SoJIA (32%), and abatacept for the other subtypes. The mean drug survival in months at the date of inclusion was: 26 for etanercept, 23 for adalimumab, 12 for infliximab, 23 for anakinra, 22 for tocilizumab, 13 for abatacept but half of patients (n=265) were still on treatment at inclusion in the JIR cohort. The mean drug survival was not influenced by JIA subtype. We found a significant difference in patients having received more than two biotherapies, between SoJIA and Poly (25%) compared to other JIA subtypes (5%).Etanercept was the first biologic treatment used whatever the JIA subtype, in this retrospective study that includes patients treated since more than 10 years. Two third of cases were still treated with the first biologic after at the time of inclusion.None declared."}
+{"text": "To report ocular manifestations in Portuguese TTR Met30 FAP patients submitted to liver transplant (LT).Retrospective observational consecutive case series of 78 LT recipients, observed by one ophthalmologist (FN) between January 2007 and July 2015. Demographic data, age at beginning of disease, period of evolution of disease, ophthalmological alterations and ocular surgeries (glaucoma surgery and vitrectomy) were evaluated. Patients were divided in three groups according to date of LT: less than 5 years (group 1); between 5 and 10 years (group 2) and more than 10 years (group 3).Thirty-six patients were male. Twelve, 32 and 34 patients belong to group 1, 2 and 3 respectively. The mean age of patients was 41 years (group 1), 44 years (group 2) and 50 years (group 3). Symptoms and signs of dry eye were present in 33% (group1), 56% (group 2) and 62% (group 3) of patients. Amyloid deposits on pupillary border were observed in 16%, 27% and 41% of eyes according to each group. Scalloped pupil was present in 16%, 25% and 36% of cases, respectively. Amyloid vitreous opacities could be seen in 33%, 40% and 59% of eyes. Vitrectomy and glaucoma surgery was performed in 19 and 24 eyes of group 3, respectively.The prevalence of specific ocular changes increase with time after LT. The need of vitrectomy or glaucoma surgery is common 10 years after LT. Regular ophthalmological evaluation of FAP patients submitted to LT is important to accurately treat sight-threatening manifestations."}
+{"text": "Renal replacement therapy in critical care is associated with increased mortality. It is not known for which patients RRT confers the most benefit, or who will recover function and remain dialysis independent on a long-term basis.All ICU patients receiving CVVHD  for AKI were analysed in a retrospective cohort study of mixed non/surgical patients at a tertiary renal centre over a 2-year period (December 2011 to November 2013). Children <18 years, patients on intermittent haemodialysis or patients requiring plasma exchange were excluded from analysis.n = 306, of which 58% were male. Causes of AKI included sepsis (37%), surgery  and vascular events (9%). Mean values for patients requiring RRT versus all ICU patients: age (65 vs. 62.5 years), APACHE II score (21.2 vs. 14.8), length of stay (13 vs. 8.2 days). Forty-seven per cent of patients received incident dialysis <24 hours of admission, with mean flow rates of 31 ml/kg/hour (2 l) in 39%. Mortality at hospital discharge was 56% for RRT versus 20% in all ICU patients admitted over the same time period.A total of 2,297 patients were admitted to the ICU, of which 14% (319) required CRRT. Thirteen patients were excluded from analysis; The reported incidence of AKI in critical care ranges from 20 to 50%, with the highest rates seen in sepsis . Utilisa"}
+{"text": "To find out the short term outcomes of laparoscopic ventral hernia repair (LVHR) during the last four years.It was a descriptive and prospective case series of 53 consecutive patients out of 107 at Department of General Surgery, Jinnah Post Graduate Medical Center, Unit II, Karachi, from January 2009 to December 2012. These patients were admitted through out patient department with complain of lump, pain and discomfort. Most of the patients were obese. All patients were clinically examined and baseline investigations done. Fifty three (49.5%) patients underwent laparoscopic repair with mesh placement and remaining 54 by open surgical repair.Among 53 patients, mean age was 46 years range (30 - 55). While females were 33(62.2%) and males 20(37.7%). We observed variety of hernias, in which midline and epigastric hernia were predominant. The commonest symptom was lump and dragging sensation. The duration of symptoms ranged between 6 months to one year. About 53 patients (49.5%) had laparoscopic repair with mesh placement. Average hospital stay was two days. Out of 53 patients, 4 (7.5%) had cellulitis at trocar site, seroma in 2(3.7%), 2(3.7%) patient complained of persistent pain postoperatively, port site minor infection was in 2(3.7%) patients, while conversion to open approach was done in 2 (3.7%), postoperative ileus was observed in one (1.8%) patients.This study provides the evidence that, laparoscopic repair with mesh placement in ventral hernia is safe and effective approach compared to open surgical procedure. It has a low complication rate, less hospital stay and low recurrence. Ventral hernia is defined as Primary anterior abdominal wall and Incision hernia not including the groin.3Up till now, many procedures have been described for ventral hernia repair. Primary repair with suture approximation requires laparotomy, with the recurrence rate of 41% to 52% during long-term follow-up.LVHR was first done by Karl LeBlanc in 1992.This study comprises of total 107 patients, out of which 53(49.5%) were scheduled for laparoscopic ventral hernia repair, while other 54 underwent open repair. These patients were admitted through outpatient department, from January 2009 to January 2013 with random sampling. Most of the patients complained of lump, pain and discomfort. Most of the patients complained of lump, pain and discomfort. Majority were obese. All patients were clinically examined and baseline investigations done. Fifty three patients underwent laparoscopic repair with mesh placement and remaining fifty four by open surgical repair. Inclusion criteia for laparoscopic repair was patients who were obese, having hernial defect size of >4 cm, history of multiple abdominal surgeries and American Society of Anesthesiologist (ASA) I, II, while high risk patients  were excluded. Three different types of meshes were used according to availability and affordability. Number of complications were observed on follow up. The data of different variables like age, gender, size of defect, postoperative hospital stay and complications were collected retrospectively and assessed by SPSS version 10. The study was approved by the JPMC Ethics Committee on 27 February 2014.There were total 53 patient who had laparoscopic ventral hernia repair, out of which females were 33(62.2%). Mean age was 46.6 years. There were variety of ventral hernia, in which majority were mid line incisional hernias 18(33.9%) and epigastric 10(18.8%). We have been shifting our open approach towards laparoscopic repair from 2009, and per year cases are shown in Postoperative recovery was uneventful in all. Patients were followed for the complications and we found cellulitis in 4(7.5%) pain at trocar site, 2(3.7%) patients had seroma, 2(3.7%) prolonged pain, conversion to open in 2(3.7%) secondary injury to large bowel, while 2(3.7%) patients developed wound infection and 1(1.8%) prolonged ileus, while there was no hematoma. The hospital stay rages from 3 \u2013 7 days. Incisional hernia is the most common long term complication of abdominal surgery and an important source of morbidity. Treatment involves further major surgeries. Several large studies on laparoscopic ventral hernia repair have been reported. This technique has proven to be a safe and feasible alternative to open mesh repair.11In early 1960s, Before the introduction of polypropylene mesh, incisional hernias were repaired by direct suture techniques,12Types of mesh is now a days debatable issue due to diffeences between the surgeons. The choice of mesh may therefore be difficult in clinical practice. UsherMany studies have reported better surgical outcome with two dual sided ePTFE mesh,Bowel injury during adhesiolysis is a commonest fear in laparoscopic incisional hernia repair procedure.Small sample size and short term follow up as this a relatively newer techniques.Long term follow up will confirm the relevance of this technique."}
+{"text": "Diagnosis of prostatic diseases with Immunohistochemistry still faces challenges because of the peculiar histology of the prostate and difference(s) in reactivity of Monoclonal antibodies (MoAb) to benign and malignant changes.Thirty (30) archived paraffin embedded tissue samples from primary prostate tumors (15 Benign Prostatic Hyperplasia (BPH) and 15 Cancer of the prostate (CaP)) were sectioned at thickness of 5\u00b5m and confirmed as BPH or CaP. Sections from each sample were stained by Immunohistochemistry using the Streptavidin-biotin method and using CK5/6, CK7, CK8,CK20 and Ki67 antibodies (Zymed Antibody products). Appropriate positive and negative controls for each antibody were setup alongside the test slides.BPH samples were reactive to Ck5/6 (93.3%), Ck7 (80%) and Ck8 (100%). Only 13.3% of BPH samples were reactive to Ki67. The reactivity of Ck5/6, 7, 8 in CaP is a contrast with only 3(20%) of samples positive with Ck5/6, 2(13.3%) positive with Ck7 and 14(93.3%) with Ck8. While reactivity of Ck 8 is similar in BPH and CaP, no reaction was recorded in Ck 20 in both BPH and CaP. Ki67 was only reactive in 2(13.3) of BPH samples and 15(100%) of CaP. Only Ck 8 was expressed in both BPH and CaP. There was co-expression of Ck5/6, 7,8 and Ki67 in13.3%; Ck7and Ki67 in 13.3% in both BPH and CaP.The various cytokeratins are individually expressed in both BPH and CaP. Ck5/6 and Ck7 are co-expressed and may be used in the diagnosis of BPH, Ck5/6,7,8 and Ki67 are co-expressed in Prostatic adenocarcinoma and squamous cell carcinoma of the prostate while Ck8 and Ki67 are co-expressed and may be used for diagnosis of Prostatic adenocarcinoma alone. The prostate is the site of two of the most common diseases in elderly men, Benign Prostatic Hyperplasia (BPH) and Prostate cancer (CaP). Both of these conditions are disorders of cell differentiation and cell proliferation . ProstatThe variety of morphologic patterns of different entities of the genitourinary tract can represent a diagnostic dilemma for the pathologist. This is especially true in cases that mimic cancer, in cancer of unknown primary or poorly differentiated tumors in which it is hard to assign histiogenesis needed to plan the correct therapy for the patient . It has The use of Immunohistochemistry in diagnosis is presently widespread because of its sensitivity and specificity. However, diagnosis of prostatic diseases with Immunohistochemistry is still facing challenges because of peculiar histology of the prostate and difference(s) in reactivity to Monoclonal antibodies (MoAb) by benign and malignant changes.The expression of cytokeratins in prostatic epithelium is varied and is well recognized . It has Several biological markers have been reported in literature to be good objective markers of progression of different neoplasms. The Ki67 antigen is a useful proliferation marker . The potThis study therefore examined the individual expression and the then co-expression of some selected cytokeratins and Ki67 in benign and malignant prostatic biopsies with a view to find out differential, combinations of individual or co-expressed proteins that could make diagnosis more specific and precise.Thirty (30) archived paraffin embedded tissue samples from primary prostate tumors comprising 15 benign prostatic hyperplasia (BPH) and 15 cancer of the prostate (CAP) were sectioned at thickness of 5\u00b5m. One section from each sample was stained by the Haematoxylin and eosin method to reconfirm diagnosis of BPH and CaP. Subsequently 2\u00b5m sections from each sample were stained by Immunohistochemistry using the Streptavidin-biotin method using the following antibodies CK5/6, CK7, CK8, CK20 and Ki67 (Zymed Antibody products). Negative and positive controls for each antibody were set up alongside the test slides. The positive controls for Ck5/6, 7 and 8 was the normal ureter tissue which are known to express the antigens, while the control for Ck 20 was malignant colonic tissue which expresses the antigen. The control for Ki 67 was a reactive lymphoid hyperplastic tissue. For the negative controls, test tissue sections were used but the antibodies were replaced at the appropriate stage by Tris buffered saline to confirm that all antibodies are reactive and there was no cross reactivity. All sections were dewaxed and hydrated. They were subsequently heated at 1210C for 10minutes in 10mmol/L Citrate buffer (pH 6.0) and the antibodies applied for 45minutes after passing through peroxidise and protein blocks. The secondary biotin-labeled antibody was incubated for 15min at room temperature. The streptavidin labelled streptavidin-biotin amplification method was carried out for 30minutes followed by 3,3\u2019-Diaminobenzidine (DAB) and haematoxylin counter stain were subsequently applied in sequence. Reactivity was observed as brown coloration. Photomicrographs of reactive sections were taken.The necessary institutional ethical clearance was sought and obtained from Meena Histopathology laboratory.The percentage of cases that expressed each of the monoclonal antibodies (MoAb) in BPH and CaP are presented in The co-expression of cytokeratins and Ki67 in BPH and CaP are represented in The number of monoclonal antibodies in the panel used reactive in BPH and CaP are presented in The co-expression and individual expression of CK5/6, Ck7, Ck8, Ck20 and Ki67 in BPH and CaP was examined. This information intends to make distinction between benign and malignant diseases of the prostate clearer. Our study shows that majority of BPH samples were reactive to Ck5/6 (93.3%), Ck7 (80%) and Ck8 100%)  and is a0%  and iThe reactivity of Ck5/6, 7, 8 in CaP is a contrast with only 3 20%) of samples positive with Ck5/6, 2(13.3%) positive with Ck7, but 14(93.3%) with Ck8. While reactivity of Ck 8 is similar in BPH and CaP, no reaction was recorded in Ck 20 in both BPH and CaP. Ck 20 has been reported % of samp Ki67 wasCo-expression of MoAb in BPH and CaP is represented in Definitive diagnosis of prostatic tumors using individual expression and co-expression of monoclonal antibodies is critical to the selection of options for therapeutic regimens and therefore the information obtained can be used although to a limited extent to make diagnosis more accurate. Consequently, the pathologist needs to be knowledgeable in the use of co-expressed antibodies to make decisions in diagnosis."}
+{"text": "Even with improved prenatal and neonatal care, intraventricular hemorrhage (IVH) occurs in approximately 25-30% of preterm infants, and a subset of these patients develop hydrocephalus. We aim to describe current trends in hospitalization of preterm infants with IVH and post-hemorrhagic hydrocephalus (PHH) using the Nationwide Inpatient Sample (NIS) and Kids Inpatient Database (KID).The KID and NIS databases were combined to generate data for the years 2000 \u2013 2010. All neonatal discharges with ICD9-CM codes for preterm birth with IVH alone or with IVH and hydrocephalus were included.There were 147,823 preterm neonates with IVH, and 9% of this group developed hydrocephalus during the same admission. Twenty-five percent and 28% of patients with Grades 3 and 4 IVH respectively developed hydrocephalus in comparison to 1% and 4% of patients with Grades 1 and 2 IVH. Thirty-eight percent of patients with PHH had permanent ventricular shunts inserted. Mortality rates were 4%, 10%, 18%, and 40% respectively for Grades 1-4 during initial hospitalization. Length of stay has been trending upward for both groups of IVH  and PHH . Average hospital cost per patient (inflation-adjusted) has also increased from $201,578 to $353,554 (IVH) and $260,077 to $495,697 (PHH) over 11 years.The number of admissions of neonates with IVH has increased despite a decrease in the number of preterm births. Rates of hydrocephalus and mortality correlated closely with IVH grade. Incidence of hydrocephalus in preterm infants with IVH remained stable between 8-10%. Over an 11-year period, there was a progressive increase in hospital cost and length of stay for preterm neonates with IVH and PHH with a concurrent increase in the proportion of patients with congenital cardiac anomalies."}
+{"text": "Mevalonate kinase deficiency (MKD) is a rare autosomal recessive disorder causing 1 of 2 phenotypes, hyper-immunoglobulin D syndrome and mevalonic aciduria, presenting with recurrent fever episodes, often starting in infancy, and sometimes evoked by stress or vaccinations. This autoinflammatory disease is caused by mutations encoding the mevalonate kinase (MVK) gene and is classified in the group of periodic fever syndromes. HIDS is characterized by recurrent fever attacks of 3-7 days that begin in infancy and recur every 4-6 weeks. The febrile period is accompanied by lymphadenopathy, arthralgia, abdominal pain, diarrhea, aphthous ulcers, and varying degree of skin involvement. The course and severity of the disease may be quite different. There is no effective or proven therapy for HIDS.We aim to determine the clinical and genetic characteristics together with the underlying MVK genotypes in single center during a period of 2 years.A retrospective review of medical records for patients referred for HIDS over 2 years. We obtain 40 patients  and 25 healthy controls.The median age of first attack was 33 months (range 2-62 months). The median age of diagnosis was 60 months. The most common symptoms of high fever accompanied respectively: lymphadenopathy (n=27), abdominal pain (n=26), arthralgia (n=20), diarrhea (n=15), aphthous stomatitis (n=13), vomiting (n=12) and maculopapuler rash (n=6) were determined. Amyloidosis was found in a patient (0.3%). The mean serum IgD level was 129\u00b192 mg/dl, it was be normal in 43% of patients.We found mutations in 75% of patients (n=30) in exon 3 and 11  in MVK gene. We applied colchicine therapy in 40% of patients while intermittent steroid therapy 20% of patients. Empiric colchicine (40%) and glucocorticosteroids (20%) controlled flares in majority of patients with HIDS. Three patients had also tonsillectomy. We used biologic therapy in 3 patients ( canacinumab (n=2), anakinra (n=1)).In conclusion, HIDS is characterized with early onset an autoinflammatory disease and may to result frequent and uncontrolled attacks.None declared."}
+{"text": "The advent of antiretroviral therapy has transformed HIV infection into a manageable chronic disease, where improving the quality of life of HIV-infected patients has become one of the main focus points for physicians. The aim of our study was to evaluate the prevalence of erectile dysfunction and testosterone deficiency in a cohort of HIV-infected patients monitored in the National Institute for Infectious Diseases \"Prof. Dr. Matei Bal\u015f\" Bucharest, from May 2014 to June 2014.We evaluated a cohort of HIV-infected male patients. They completed a questionnaire to evaluate erectile dysfunction, based on the International Index of Erectile Function \u2013 IIEF . Total testosterone was dosed in a subset of patients reporting erectile dysfunction (mild and moderate or severe) considering normal values >10 nmol/L. Five patients refused the test.42 patients completed the questionnaire; they had ages between 23 and 69 years (mean age 36.8), 38 of them (90.4%) receiving antiretroviral therapy. 15 patients had a degree of erectile dysfunction  and 2 patients had had no sexual activity in the last month: 12 patients had mild erectile dysfunction (score between 19-24), 2 patients had mild to moderate erectile dysfunction (score between 13-18), 1 patient had moderate erectile dysfunction (score between 7-12). Total testosterone was tested for 3 patients, 5 refused the test; all tests revealed normal values (>20 nmol/L).This study showed that erectile dysfunction is highly prevalent, 35.7% of HIV-infected male patients have reported erectile problems."}
+{"text": "Temporary defunctioning ileostomy can reduce the consequences of anastomotic leak following low anterior resection. However, some patients never have their ileostomy reversed and in other cases the time to reversal of ileostomy can be delayed. The aim of this study was to identify the ileostomy closure rate following anterior resection, time to closure of ileostomy, reasons for delay in reversal and whether delay was associated with an increased complication rate.Data were collected retrospectively on consecutive patients undergoing defunctioning ileostomy following anterior resection for rectal cancer, between January 2009 and August 2013. Data were collected on reversal of ileostomy rates, time to reversal, reasons for delayed reversal (defined as > 6 months) and complications following reversal.One hundred seventy patients were studied , of whom 117 (69%) were male. One hundred twenty-seven (75%) patients had their ileostomies reversed. Median time to reversal was 6 months (range 1 - 42). In 63 patients who had delayed reversal, reasons were adjuvant chemotherapy , medical illness , anastomotic leak , and others . Postoperative complications occurred in 33 patients (26%). There was no postoperative mortality. Univariate analysis showed that delayed reversal was associated with an increased rate of complications and longer length of hospital stay following reversal (P < 0.05).One in four defunctioning ileostomies are not closed following anterior resection in our unit. Of those that are closed, approximately 50% have delayed closure beyond 6 months which is associated with increased risk of complications following their ileostomy reversal. Anastomotic leak following anterior resection for rectal cancer may lead to increased rate of emergency re-operation, radiological drainage, and increased length of stay in hospital, as well as increased mortality. Formation of a defunctioning loop ileostomy following resection for rectal cancer has been recommended because it may help to reduce the rates of clinically relevant anastomotic leaks, severity of leaks as well as re-operations related to leakage . BecauseDespite the potential benefits, defunctioning ileostomies carry their own burden of morbidity, with up to two-thirds of patients having stoma related morbidity , as wellUnique patient identification details were obtained from the hospital episode statistics (HES) of our NHS Foundation Trust for all consecutive patients who underwent ileostomy during primary surgery that was coded as anterior resection for rectal cancer (code H33.4) from January 2009 to August 2013. The NHS Trust consists of three geographically separated hospitals within the West Midlands, UK. These patients were selected because defunctioning ileostomy is usually fashioned with the intention to reverse the ileostomy at a future date .Information was obtained regarding each patient\u2019s operation and subsequent clinical progress from electronic medical records as well as case records and clinic letters. Data obtained included patient demographic details (age and sex), stage of disease, type of operation, as well as details regarding reversal of ileostomy, time to reversal, and reasons for delayed reversal (defined as > 6 months). The primary outcome recorded was postoperative complication within 30 days of reversal of ileostomy. The secondary outcome was length of hospital stay.Delay in ileostomy reversal was defined as being more than 6 months from the original defunctioning loop ileostomy procedure. Histological staging of tumors was undertaken by consultant histopathologists by examining the surgical specimens, and was classified according to the Dukes classification of colorectal cancer.Categorical data were compared using Chi-squared statistical analysis. Univariate Cox regression analysis was used to examine the relationship between individual patient factors and delay in reversal of ileostomy, and whether delay was related to adverse outcomes (i.e. the presence of complications).During the study period 170 patients underwent defunctioning ileostomy following anterior resection for sigmoid or rectal cancer. The median age (range) was 69 years (41 - 90 years). Of these patients, 117/170 (68.8%) were male.Tumor staging data were available for all patients. These included Dukes A in 49/170 (28.8%), Dukes B in 57/170 (33.7%), Dukes C in 48/170 (27.9%), and Dukes D in 16/170 (9.6%) .Of the 170 patients who had defunctioning ileostomies, 127 (75%) underwent subsequent reversal of ileostomy. Median time to reversal was 6 months (range: 1 - 42 months). Of these ileostomy reversals, 63/127 (50%) were delayed longer than 6 months. The reasons for delay were due to adjuvant chemotherapy in 22/63 (35%), surgical complications in 13/63 (21%) which included anastomotic leak following the initial operation in 9/63 (14%), adhesive small bowel obstruction in 3/63 (5%), and anastomotic stricture in 1/63 (2%) patient. Medical complications were seen in 14/63 (22%), which included eight patients with acute kidney injury due to high output stoma .When comparing the delayed and non-delayed groups, there were no statistical differences in number of patients or age between the groups. Patients with Dukes A tumor were statistically more likely to be in the non-delayed group, and those with Dukes C and D tumors were more likely to be in the delayed group .The median length of inpatient hospital stay following reversal of ileostomy was 4 days (range: 1 - 62 days). Postoperative complications occurred in 33/127 (26%) patients. There was a statistically significant rate of complications following reversal and a median length of hospital stay following reversal of > 4 days in the delayed group. A further 5/127 (3.9%) patients were re-admitted within 30 days for postoperative complications. There was no postoperative mortality.The following causes were associated with having a permanent stoma: cancer stage IV 23% (10/43), patient refusal 14% (6/43), patient death prior to reversal 11% (5/43) and other causes 21% (9/43) , pelvic recurrence (n = 2), High risk (n = 2), refashioning of ileostomy (n = 1), rectovaginal fistula (n = 1), and medical illness (n = 2)).Comparison between patients in the reversed (R) and non-reversed (NR) group revealed a higher anastomotic leak rate 16% (NR) vs. 7% (R) and stage IV disease 44% (NR) vs. 30% (R) which was found to be significant (P < 0.001).At the end of the follow-up period, there were 116/170 (69%) patients alive without a stoma and 30/170 (17%) alive with a stoma. Twelve of 170 (7%) patients died without a stoma and 12/170 (7%) died with a stoma in the series.Seventy-two (42%) patients received neo-adjuvant treatment. Forty-five had short course radiotherapy (SC) and 27 had long course chemoradiotherapy (LCR). In the stoma reversed group there were 39 SC and 18 LCR and in the non-reversed group six SC and nine LCR. There were 17 SC and eight LCR in early stoma reversal group compared to 22 SC and 10 LCR in delayed group .There were 13 complications in the neo-adjuvant group (four in LCR and nine in SCR) compared to 23 in the non-neo-adjuvant group. There was no correlation to pre-operative neo-adjuvant treatment and complications following ileostomy reversal.The major finding in this study was that reversal of ileostomy in patients having delayed closure is associated with increased risk of complications and increased length of hospital stay. Of those that are closed, approximately 50% have delayed closure > 6 months following their ileostomy formation. Also, one in four defunctioning ileostomies are not closed following anterior resection for rectal cancer in our unit. In 50% of the patients, the delay could be explained by postoperative adjuvant chemotherapy, non-surgical complication and symptomatic anastomotic leakage and small bowel obstruction. Adjuvant postoperative chemotherapy has been proposed as an important reason for delaying stoma reversal , 16. In There was a statistically significant rate of complications following reversal in the delayed group. A recent review published from a Danish group also revealed similar findings to those who had delayed ileostomy closure. They reported a significant association between the delayed ileostomy closure and complications after low anterior resections, 51 (59.3%) versus 27 (37%) (P = 0.005) . One of Rates of stoma closure amongst patients with defunctioning ileostomies following anterior resection have been variably reported, from 68% to 75.1% , 15, andOf all defunctioning ileostomies in this study, 25% were never reversed and subsequently became permanent stomas. The most important reason for a defunctioning ileostomy to become permanent in the present study population was stage IV cancer. Another major reason for not reversing stomas was symptomatic anastomotic leakage following anterior resection. Results from recently published large studies have demonstrated that there is a risk between 18% and 25% for defunctioning ileostomies to become permanent , 20-22. National Bowel Cancer Audit Project (NBOCAAP) 2013 report revealed that nearly one-third of anterior resection patients would be with a stoma at 18 months follow-up. There data support patient counselling for a temporary ileostomy should include a non-closure rate of 40%, a median closure delay of 7 months for those closed, and an approximately 10% chance of death with a non-reversed intestinal stoma at 18 months .The present study of closure of defunctioning ileostomies is based on a homogenous group of patients having a defunctioning loop ileostomy after an anterior resection for rectal cancer. The main conclusion of this study is the increased rate of complications following a delayed loop ileostomy closure. Large randomized controlled trials are necessary to evaluate the correlation between complications and the timing of loop ileostomy closure."}
+{"text": "HIV/HCV coinfection may have important implications for therapeutic and evolving plans. The Knowledge of its epidemiological, clinical features may help to anticipate needs and improve care. The aim of the Study was to determine the epidemic profile of patients co- infected by hepatitis C virus and HIV.A retrospective study was conducted in the infectious department diseases between 2003 and 201 3, were included all patients treated for HIV and HCV with positive serology (ELISA positive). Data were collected on computer files (Nadis) and analyzed on Epi Info.We collected 147 patients with HIV/HCV coinfection . The average age was 40 \u00b1 10 years, males predominated (4H/1F). Intravenous drug use was found in 29.25 % of patients. At the moment of diagnosis of the coinfection, 64 patients (43.5%) were in category C (CDC) . Antiretroviral therapy was prescribed for 131 patients (89%). The viral RNA research by RT-PCR and the genotyping were performed in 39 patients (27 %). The RNA HCV PCR was positive in 28 cases (19 %). The most frequent viral genotypes were 1a and 1b with 14 cases (50%). The IL28B performed in 8 patients had type CC (2 cases), C/T (3 cases), TT (1 case). Liver function tests were normal in 116 cases; liver cytolysis was found in 31 cases. The liver ultrasound was normal (80 cases) or showed lesions of chronic liver disease (30 cases) or ascites (10 cases). Ten patients undergoing treatment with pegylated interferon and ribavirin. Two patients who completed treatment were non-responders. 79 patients (54%) are being used and 27 cases died (18%).The HIV/HCV co-morbidity is a challenge in support of PLHIV. Currently, free access to treatment and explorations of hepatitis C in Morocco as part of a health program (RAMED) is an important step whose impact needs to be evaluated."}
+{"text": "To assess Knowledge, Awareness, practices regarding road safety measures and consequences of Road Traffic Injuries (RTIs) among medical students of Guntur Medical College and Hospital, Guntur.A cross-sectional study was conducted among medical students of Guntur Medical College and Hospital using pretested and semi-structured questionnaire in the month of September 2014. The collected data was entered in MS Excel and analyzed by EPI INFO.Among 206 students interviewed, 166 (80.6%) were females and 40 (19.4%) were males. Among the study subjects, 123(59.7%) drive motorcycles but only 83(40.3%) have a license. Majority 121 (58.7%) had witnessed an accident. 201 (97.6%) out of 206 students knew that wearing helmet is safe, but only 89 (43.2%) wear helmets. Only 30.2% of the study group wears a seatbelt. Most of them, 73 (35.4%), have knowledge of traffic symbols.This study was done on medical students so it cannot be generalized to the public.Observations of the study emphasize that there need to enhance knowledge and awareness among medical students through education training to curb the epidemic of RTIs."}
+{"text": "At least two-thirds of cluster headache (CH) patients that received the ATI Neurostimulation System have achieved profound clinical improvements including acute headache pain relief and/or significant attack frequency reduction. The ATI Neurostimulator is inserted trans-orally using a minimally invasive technique.This analysis aims to characterize the long term safety of the ATI Neurostimulation System in CH sufferers.Patients from the Pathway CH-1 and Pathway R-1 studies were included in the analysis. All adverse events (AEs) including transient swelling and pain, were documented and assessed for relationship to procedure and/or the presence of the neurostimulator.Ninety-eight (98) patients received the ATI Neurostimulator as of May 2014. Fifteen patients (15%) reported no AEs and 83 patients (85%) reported at least one related AE. In total, 341 AEs were reported (average 4.1 AEs/patient). Currently, 216 (63%) of all AEs have resolved; average time to resolution was 69 days (range 0-611). The majority of reported AEs (77.4%) occurred within 30 days of the insertion procedure (peri-op AEs). Of these AEs, 82% of patients experienced sensory disturbances. The large majority (72%) of these events had a mild to moderate impact on the patient's daily activities and were transient, with an average resolution of 110.3 days (range 20-313).The majority of AEs were reported within 30 days of the Neurostimulator insertion procedure and the majority resolved within 3 months. These AEs are not different from standard sequelae reported for other trans-oral procedures and display a similar time course for healing.Conflict of interest."}
+{"text": "In developing countries, acute pneumonia is a very important public health problem.Our goal was to study all the 420 patients with acute pneumonia who were admitted to the Infectious Clinic in Oradea between 01.01.2013-31.12.2013. The diagnosis was performed based on clinical, biological and radiological criteria.Most of the patients came from rural area (60%). 55% of them were female and 45% were male. We had 3 groups of acute pneumonia: lobar pneumonia (39%), interstitial pneumonia (47%) and bronchopneumonia (14%). More than half of the patients had bacterial pneumonia (70%). From these, 68% had unknown etiology. The most affected ranges were the age group 51-55 and 61-65. Most cases of acute pneumonia were diagnosed in autumn. Associated pathology was observed in old patients (47%)The most exposed category of age was represented by adults between 51 and 55 years and 61 and 65 years old."}
+{"text": "Fortis hospital, Noida is the tertiary care referral centre for trauma in Western Uttar Pradesh. The hospital implemented trauma teams in 2011. The purpose of this study is to look at the modal distribution of deaths in cases of major trauma to improve trauma care at our institution and to provide comparative data for other institutions.A retrospective 2-year review from September 2011 to December 2013 was conducted using a database from medical records of the emergency department. Review of patient records included: population demographics, mode of injury, delay in arrival if any, length of stay prior to death, and the cause of death.4226 trauma patients visited emergency department. 2208 (52.24%) patients were discharged, 1537 (36.37%) were admitted to the ICU, and 454 (10.74%) were admitted to the ward. The remainder were Left Against Medical Advice (LAMA) or Dead on Arrival (DOA) due to various reasons, and there were 27(0.63%) deaths in emergency department  due to haemorrhagic and/or neurogenic shock.Of the patients who were admitted in ICU or ward, 48 (1.1%) patients died in the hospital.As per our analysis of those 1.1% patients who died in hospital;\u2022 Majority of patients (71%) were in the age group of 20 to 40years. Male to female ratio was 87:13%.\u2022 41 patients (85.4%) came after more than one hour of injury while only 7 patients (14.5%) came within one hour.\u2022 The most common causes of injuries in those patients were road traffic accidents (77%), compared to gunshot wounds (8.3%), fall from height (12.5%) and blunt injuries (2.1%).\u2022 9 (18.75%) patients died within 24 hours of the hospital stay, 19 (39.5%) died within 72 hours, and 18 (33.3%) died more than 72 hours after admission.\u2022 Most frequent cause of death in our observational study was severe head injury in 22 patients (45.8%), multiple organ failure/sepsis in 10 patients (20.83%), and exsanguination in 6 patients (12.5 %). 10 patients (20.83%) died because of combination of causes.\u2022 Road traffic accidents and their delayed presentations caused a majority of trauma deaths in our observational study of two years. This highlights the need for developing improved emergency care at local healthcare facilities, development of trauma centers, and adoption of transfer protocols for these trauma patients centres to reduce morbidity and mortality."}
+{"text": "In this study, 466 embryos (from zygote to morula stages) were vitrified then thawed embryos have been incubated for in vitro farther development up to blastocyst stage. Also, vitrification and thawing procedures were the same for all experimental groups. Mouse different embryonic cleavage stages were vitrified in ethylene glycol (EG) plus dimethyl sulfoxide (DMSO) and sucrose (VS-1) and EG plus DMSO (VS-2) and thawed by directly placing the vitrified drop into sucrose solution (TS) at 37 \u02daC. High recovery (72\u201397%) of morphologically normal embryos was evident following vitrification and thawing. Development of the vitrified morulae into blastocysts (92%) was higher (p < 0.05). The amount of zygote and 2-cell stages that achieved to blastocyst stage was very low. With progressing the embryo cleavage to morula stage, the embryos that reached to blastocyst were increased to its maximum number. We concluded that the modified vitrification procedure supported better survival of morula stage compared to other cleavage stages in mouse embryos.The effect of modified vitrification was assessed on cellular development capability in mouse embryos cultured  Moreover, ultra-rapid vitrification and thawing also minimize chilling injury, as the cells are exposed to critical temperature zones for comparatively short interval.5 Therefore, good survival and development of oocytes and embryos could be achieved.5,17During cryopreservation, the addition and removal of penetrating cryoprotective agents may create an osmotic imbalance across the cell membrane. This imbalance may cause large volumetric changes in the cells, which may alter morphology, cytoskeletal organization and function.2,12,13 on electron microscope grids,3 in open pulled straws,5 in a cryoloop,6 on solid surface,7 and on cryotop.8 In this study we used the open pull straw for vitrification procedure to determine the best stage in development stages of mouse embryos for vitrification and their cryopreservation cultured in vitro.Various methods of ultra-rapid vitrification of mammalian oocytes and embryos have been used including vitrification in droplets,Animals. Mature female NMRI mice (6 to 10 weeks old) were induced to superovulate with intraperitoneal injections of 7.5 IU PMSG1  and 7.5 IU hCG  given 48 hr apart. Thirteen hr after hCG injection the mice were euthanized by cervical dislocation and ovulated unfertilized oocytes and sperms were collected from females and males. After IVF in the culture medium (HTF solution consisted of 4 mg mL-1 BSA), embryos at various development stages  were vitrified using the VS-1 and VS-2 media.Vitrification of embryos. Embryos were vitrified in cryoprotectants solution (VS) in 0.25 mL open pull straws based on the method described by Kasai et al.2 incubator. All procedures were conducted in room at 25 \u02daC.Thawing. After 2 weeks of storage in liquid nitrogen, embryos were re-warmed for in vitro culture. For re-warming, straws containing the embryos were held at ambient temperature for 10 Sec after removal from the liquid nitrogen. The narrow end was immersed vertically in a well containing TS-1 at 37 \u02daC. After 1 minute embryos were transferred into TS-2 with the same medium for 3 minutes. The embryos were allocated in TS-3 for 3 min (or 3 min .Culture. Vitrified/warmed embryos were cultured in 5% CO2 in air in a humid chamber at 38.5 \u02daC. One to three embryos were vitrified in one straw and cultured after warming in 50 mL droplets (for not more than 6 h) or in 500 mL (for long periods) of the culture medium (HTF solution consisted of 4 mg mL-1 BSA) in culture dishes with covering oil. The embryos were regularly evaluated between 6 and 14 h of culture  software and differences were considered significant at p < 0.05.in vitro farther development up to blastocyst stage. In this experiment vitrification and thawing procedures were the same for all experimental groups. Following thawing the majority of vitrified embryos had morphologically normal shape  were vitrified then thawed embryos have been incubated for al shape . CleavagAs shown in Eighty two out of 89 92%) of vitrified zygotes were recovered, however, only 59/82 (72%) of recovered zygotes were morphologically normal and the rest of them were destroyed   and 2. A% of vitrIn vitrified 2-cell embryos, 110/119 (92%) of them were recovered following thawing, 95/110 (86%) of them were morphologically normal and the rest of recovered embryos were destroyed   and 2. AIn the vitrified 4-cell embryos, 76/79 (96%) were recovered, 68/76 (90%) of this group were morphologically normal and the rest of them were destroyed . Among morphologically normal 4-cell embryos61/68 (89%) were developed to cleavage stage, 48/68 (71%) reached to blastocyst and 20/68 (29%) were arrested.In the vitrified 8-cell embryos, 85/86 (98%) were recovered, 79/85 (93%) of recovered embryos were morphologically normal and the rest of them were lysed . Among morphologically normal 8-cell embryos, 72/79 (91%) were developed to cleavage stage, 63/79 (80%) became blastocyst and 16/79 (20%) were arrested.In vitrified morulae, 93/93 (100%) were recovered, 91/93 (97%) of this group were morphologically normal and the rest of them were destroyed . Among morphologically normal morulae, 87/91 (96%) were developed to farther cleavage stage, 84/91 (92%) reached to blastocyst and 7/91 (8%) were arrested.2,3,9,12,13,19-21Vitrification is a potential alternative to traditional slow-rate freezing for preserving oocytes and embryos in various species. The unique advantage of vitrification is elimination of mechanical injury caused by intra- or extra-cellular ice crystal formation and reduction of chilling injury by shortening duration of exposure of cell to critical temperature point. The concept of ultra-rapid vitrification has been emerged in recent years.2,12,13,19,22An ultra-rapid cooling rate during vitrification can practically be achieved either by minimizing the volume of solution to be vitrified or by making direct contact between vitrification solution and liquid nitrogen otherwise through the combination of the procedures. The major disadvantages of the previous vitrification protocols were the relatively large volume of the vitrified drop and the delay before the drop floating on the surface of liquid nitrogen which probably reduced the actual cooling rate.23,24In our work we eliminated these disadvantages and tried to achieve a higher cooling rate reducing the volume of vitrified drop and immersing in liquid nitrogen immediately onto the surface of the liquid nitrogen (which helped the drop to quickly vitrify and sink in liquid nitrogen). In addition we attempted to reduce cytotoxicity through shortening the total duration of exposure of embryos to cryoprotectants and using an EG-based vitrification solution. It was reported previously that EG had low cytotoxicity for embryos.25-28 and vitrification procedures .29,30Several permeating cryoprotectants have been used for cryopreservation of embryos and resulted in successful production of young. Among the cryoprotectants, DMSO has most frequently been used both in slow freezing18Our method ensured a rapid thawing rate of vitrified embryos by directly placing the vitrified drop into sucrose solution at 37 \u02daC. As expected, we achieved high developmental competence of the vitrified embryos. The aim of the present study was to compare survival rates of mouse embryos cryopreserved at various developmental stages. For the cryopreservation, embryos were vitrified using VS, an EG-based solution. This vitrification solution was foremost developed for mouse embryos as a low-toxicity solution.Mouse embryos at various developmental stages were vitrified by a 2-step method in which embryos were directly suspended in vitrification solution before cooling. When survival was assessed in culture, it was shown that high proportions (92%) of morulae retained the ability to develop to the blastocyst stage . Major mIn conclusion, the morula would be the preferred stage for mouse embryo cryopreservation, because the survival rate of vitrified morulae was 97% as assessed by morphology or by in vitro development up to blastocyst stage."}
+{"text": "Legionnaires' disease, a form of severe pneumonia caused by a Gram negative aerobic intracellular bacteria, was first recognised during an American Legion convention in Philadelphia in July, 1976 [The second largest outbreak of Legionnaires' disease ever registered, encompassing 334 microbiologically documented cases was identified between 7 and 30 of November 2014 in Vila Franca de Xira, Portugal [To report the epidemiology, clinical features, outcome, treatment strategies, complications and lessons learned during the Legionnaires' disease outbreak in an ICU setting.Prospective collection of clinical and epidemiological data of patients admitted with microbiologically documented Legionella pneumonia to the ICU. This data collection was started at the first day of the outbreak, after admission of 5 consecutive patients with the disease.During the outbreak 334 patients with pneumonia were admitted through the emergency room and all either had a positive urinary antigen, culture or serology for Legionella. As much as 29 of the most severe patients were admitted to Hospital Vila Franca de Xira ICU. The main cause of admission was respiratory failure (97%), although more than half also presented renal or even multi-organic failure.Survivors had a median ICU length of stay of 4.48 days (Interquartile range (IQR) 3-5) and a median hospital length of stay of 14.2 days (IQR 11-18.5). Overall there were four deaths in the ICU, a case fatality of 13.7%. Mean duration of hospital stay before death was 2.25 days. Patients were treated with high dose levofloxacin (1.5g/day). Non-responders also received rifampicin after 72 hours [A Legionella pneumonia outbreak was registered in November 2014 in Portugal. Several patients needed intensive care mostly for respiratory failure. A new-onset atrial fibrillation was the most common complication noted."}
+{"text": "The aim of this study was to evaluate whether patients with pollen-induced allergic rhinitis without a physician diagnosed asthma might, nevertheless, have airways obstruction both in and out of the pollen season.Along with the nasal symptomsPatients with allergic rhinitis and grass pollen sensitization were evaluated both during and outside the pollen season. Allergic rhinitis diagnosis and severity grading were made according to ARIA guidelines. Skin prick tests, blood eosinophil counts and total IgE level measurements and pulmonary function tests (during and outside of pollen season) were performed in all subjects.1) and FEV1/FVC ratio, which obtained in and out of pollen season. However, the forced expiratory flow between the 25 and 75% of the vital capacity (FEF25-75) (100 (91-96) vs. 91 (83-104)) and peak expiratory flow (PEF) (92 (83-97) vs. 82 (76-94)) values were significantly lower in pollen season when compared with the values obtained out of pollen season.Thirty patients  with a median age of 11.5 (8.7-13.6) years were included. 12 patients (40%) had mild allergic rhinitis, whereas 18 (60%) had moderate-persistent allergic rhinitis interfering with daily activities. There was no significant difference at spirometric parameters including forced vital capacity (FVC), forced expiratory volume at 1 second (FEVPulmonary functions may be affected in children with pollen-induced allergic rhinitis during pollen season even if they have no history and symptoms of bronchial asthma."}
+{"text": "Food protein induced enterocolitis syndrome (FPIES) is non-IgE mediated disorder triggered by the ingestion of certain food proteins. The diagnosis of FPIES is frequently delayed because of non-specific symptoms and lack of biomarkers.To describe the clinical characteristics and the natural evolution of FPIES provoked by fish in children.We retrospectively studied the medical records of patients evaluated in our practice over a 9-year period.Sixteen children  experienced 47 episodes of FPIES caused by fish. Mean age of onset was 12.3 months (SD 2.2). Among symptoms, vomiting was dominant (100%) while diarrhea was less frequently observed (9%). Only 5/47 cases (11%) were admitted to the emergency unit. None of these children presented with symptoms of hypovolemic shock. Mean time of symptom onset after ingestion was 2.4 h (SD 0.7). The median number of prediagnosis reactions was 3 episodes (range 2-5). Skin prick tests to fish allergen were negative in all cases. Among children, 5 had atopic dermatitis and/or IgE sensitization to egg and 1 had allergic proctocolitis. 7/16 children (44%) had positive atopic family history. Concerning birth data 9/16 (56%) were born after cesarean section and the majority (94%) was full term. 7/16 children (44%) were exclusively breastfeeding for at least 4 months. We also report another 4 children  who presented after one typical episode of FPIES after fish ingestion but parents denied the oral food challenge in order to confirm the diagnosis. Data on the evolution of the syndrome are available at the moment only on 7 children. At a median age of 4 years (range 2.5 - 5.5 y) resolution was observed in none of the cases. At the age of 9, data exist for 2 children; one became tolerant while the other failed to outgrow the symptoms.Our data suggest that the clinical presentation of FPIES due to fish is less severe compared to other foods, especially milk. Moreover it appears that the clinical course of the syndrome is more protracted."}
+{"text": "Hyponatremia is a most common electrolyte abnormality seen in Traumatic Brain Injury (TBI) patients. If it is not treated early it can lead to serious complications, affecting overall neurological outcome.To know the effect of early correction of hyponatremia within 48 hours of onset on neurological outcome in TBI patients.A retrospective analysis of 150 cases admitted to Intensive Care Unit (ICU) diagnosed with different TBI who developed hyponatremia during their ICU stay, from January 2010 till October 2013. Neurological outcome was defined on the basis of initial Glascow Coma Scale (GCS) on admission to hospital and at the time of discharge from ICU. Good neurological outcome was defined if GCS improved significantly than admission; in severe TBI (if GCS 8 \u22653), in moderate TBI if \u22652, in mild TBI if \u22651. Poor outcome group defined, if GCS remained same or even deteriorated than admission. All patients were divided into two groups, whether serum sodium (S.Na) correction was achieved or not within 48 hours of onset of hyponatremia.Statistical association was seen between these two groups and neurological outcome groups. Data was analyzed by SPSS version 21.(90/150) cases were with severe TBI, and 29 & 31% were with moderate and mild TBI respectively depending upon their initial (GCS). Road traffic accident was the most common cause of TBI 46%(70/150), followed by fall from height, 41%. 13 cases due to industrial accidents, 3 sports related, 2 due to assault & 1 due to gunshot injury lead to TBI. In 81 patients (54%) different neurosurgical interventions  were performed depending upon the initial clinical condition. ICP monitoring was done in 47 cases as isolated or in combination with other therapeutic procedures. In 72% of cases correction of hyponatremia was achieved within 48 hours of onset and in 28% it took longer time (>48hours) to correct S.Na. Mean S.Na before treatment was 131.2+2.9, lowest value of 117 mmol/l and mean S.Na post treatment of hyponatremia was 137.6+2.5. Mean duration of onset of hyponatremia was 7.74 days after initial injury and ICU admission. Mean length of stay in ICU was 16.6+9.8, with minimum of 2 and maximum of 55 days .The highest length of stay was seen in severe TBI patients,18.3+8.9 days. Good neurological outcome group remained 83% (125/ 150) and poor outcome group 17%(25/150). In severe TBI (90/150), good neurological outcome was seen in 73 (81%) and poor outcome in 17 patients.There was statistically significant association seen between early serum sodium correction (within 48 hours of onset) and neurological outcome .87% were males & 13% female patients. Mean age was 24.43 years. 60%There is significant association between early correction of hyponatremia and neurological outcome in traumatic brain injury patients."}
+{"text": "In February 2015, organizers of an international conference in Brussels on 27-29 January reported an outbreak of gastroenteritis among its 130 attendees. We investigated the outbreak to estimate its magnitude and implement control measures.On 10/02/2015 we emailed a standard questionnaire to all attendees to gather demographic, clinical and exposure information and laboratory results. We defined cases as attendees with vomiting, nausea, abdominal pain or diarrhea between 27/01-02/02/2015. We interviewed food handlers and tested leftovers of the sandwiches served. Faecal specimens of five cases were tested for enteric pathogens results were reported in the questionnaire. We computed relative risks with 95% confidence intervals (CIs).Salmonella spp. Leftovers of de-frosted salmon used for sandwiches during the first lunch were re-frozen then thawed for the second lunch. No food handlers reported ill. No salmon sandwich was available for testing. None of the other sandwiches tested positive for enteric pathogens.Of 107 attendees who responded, 57 were cases (AR=53%). Disease onset was between 6 hours after consuming lunch on 27 January and noon on 29 January, 54 cases occurred6 hours after the second lunch. 52 cases (91%) reported nausea, 41 (72%) abdominal pain, 38 (66%) vomiting and 27 (47%) diarrhoea. All participants attended both lunches. Participants who consumed salmon sandwiches were three times more likely to become ill (RR= 2.98 95%CI: 1.6-5.5). One stool specimen was positive for Salmon sandwiches were the probable vehicle in this large outbreak, possibly caused by Salmonella. De-freezing and re-freezing salmon leftovers may have contributed to increased pathogen concentration. Food Health authorities need to reinforce compliance with established recommendations and the education of food-handlers on proper handling and storage of leftovers."}
+{"text": "Clinical picture of CAPS syndrome includes periodic fever, skin rash, arthritis / arthralgias, conjuntivitis, and neurisensorial deafness with hereditary pattern and early onset (<1y in 50% of cases). In last decade, atypical manifestations have emerged expanding the clinical spectrum of CAPS.To evaluate the clinical, laboratory and genetic profile of 26 patients of 4 spanish unrelated pedigrees with special attention to the atypical manifestations of the disease.Review of clinical, analytical and genetical data of a cohort of 26 patients from 4 unrelated non-consanguineous Spanish pedigrees.Rash (14/26), arthritis (14/26), and deafness (12/26) were the most common features. Episodic fever accounted in 8/26 patients. 14/26 patients did not present episodic course and disease onset was over 10 years in 17/26 patients. 2/26 patients developed amyloidotic hemorrhagic cystitis and other 2/26 patients explained olfactive disfunction. Amyloidosis was confirmed in 2/26 patients and considered as probable in other 4/26 patients. Acute phase reactants were normal in 7/26 patients. CIAS1 mutations were identified in 23/26 patients . 5/6 patients carriers of an heterozigous Arg488Lys mutation were asymptomatic while it failed to isolate any CIAS1 germinal, somatic or mosaic mutation in 3 members of the same pedigree although their clinical profiles were consistent with Muckle-Wells syndrome (1 case) and CINCA / NOMID (2 cases).Despite the traditional clinical picture of CAPS includes periodic fever, rash, arthritis and deafness with onset usually <1 year, in its absence CAPS cannot be ruled out. The clinical spectre may vary from the chronic afebrile course, to atypical amyloidosis, or olfactive disfunction. The profile of CIAS1 mutations carriers may include asymptomatic individuals or absence of mutations in pedigrees with several members with a highly suggestive clinical profile of severe variants of CAPS syndrome."}
+{"text": "Screening of Yq has become one of the most frequently performed postnatal molecular genetic tests in Egypt. A survey sponsored by WHO estimated the prevalence of infertility among Egyptian couples to be 12% (4.3% for primary infertility and 7.7% for secondary infertility) [We analyzed buccal cells from 98 infertile Egyptian men with average ages 22-45 years (56 with azoospermia plus 42 with severe oligospermia) using multiplex PCR for six common AZFa, AZFb, and AZFc STS markers.Forty-eight (37%) microdeletions with five separate deletions were identified. We found 66.7% of the deletions in the AZFb locus, 20.8% in the AZFa locus, and 12.5% in the AZFc locus. Some common haplotypes (7 of 10) were identified in our sample population. Haplotypes H3 (sY127) and H4 (sY134) were the most common. Separate microdeletions were interestingly localized in infertile Y-chromosome patients.We conclude that a minimum of three tags; STSs-sY86, sY127 and sY134 can be used to screen infertile Egyptian men for Yq microdeletions before assisted reproduction is initiated as a treatment."}
+{"text": "Eosinophilic esophagitis (EoE) is an immune-mediated disease of the esophagus characterized by symptoms related to esophageal disfunction and histollogically by an eosinophil-predominat inflammation. Multiple therapies have been suggested to be helpful in EoE including endoscopic dilation, medical therapy and withdrawal dietary but, the election of what food should be excluded is very difficult.Component-resolved diagnosis and microarray technology have been recently introduced into clinical allergy practice, and may be particularly useful in food-sensitized allergic patients.We studied 67 patients suffering from EoE diagnosed by clinical symptoms and endoscopic biopsy esophageal with > 15 eosinophils/high-powered field. Microarray technique (Thermofisher scientific), including detection of 112 allergens were performed in these 67 patients, in 50 allergic controls with pollen sensitization but without digestive symptoms, and 50 healthy people.Cynodon dactylon or Bermuda grass pollen) 59.5 %, and the following allergens: Lipid transfer proteins (LTPs) from peach (19.40%), hazelnut 17.91% and mugwort 19.40%. Profilins were positive in 9.5% of the patients. Among nuts, allergens from hazelnut and walnut (21.4%) were the most important. Other food allergens as Anisakis, egg or milk, only were positive in 9.5%, 2.3 and 4.7% respectively.Only 7 of the 67 patients that suffered from EoE did not present any allergen sensitization. All control patients presented sensitization to different pollen allergens without any predominant allergen. Nevertheless, among the patients with EoE and with response to any allergen, the predominant were nCyn d 1  from nuts and fruits and antigen 1 from Cynodon dactylon. Our patients are being treated with exclusion of the implicated food and pollen specific immunotherapy with preliminary favourable results."}
+{"text": "Ipilimumab, a fully human monoclonal antibody (IgG1) that promote antitumor immunity by blocking CTLA4, was the first agent which showed a long-term survival benefit, about the 20% of patients, for the treatment of metastatic melanoma. The combination of ipilimumab with other therapies might improve its efficacy.The term \u201cabscopal effect\u201d refers to a regression of metastatic lesions distant from the primary site of radiotherapy (RT). This new phenomenon represent the systemic response observed in patients who received ipilimumab.Here we reported the outcomes from patients treated in the ipilimumab Italian expanded access program (EAP) who received RT after ipilimumab progression.Patients with advanced melanoma after ipilimumab progression were selected for analysis. Patients, who failed ipilimumab therapy and for whom no other therapeutic options were available, were elegible for radiotherapy.21 out of 95 patients treated with ipilimumab in the Italian EAP were eligible for the analysis. The median age was of 58 years (range 21-77); The progression free survival (PFS) from ipilimumab treatment was 4 months (range 3-6), while the time from the end of treatment with ipilimumab and RT was of 5 months (range 4-8).RT was performed on brain in 13 (62%) patients: 8 were treated with whole-brain RT and 5 patients with stereotactic RT. Other RT treatment included bone, metastatic distant lymph nodes, sub-cutaneous metastasis, spinal cord metastatis. The median doses of radiation was of 30 Gy (range 30-50). A local response to RT was detected in 13 patients (62%) while 8 patients (38%) did not show any local regression. The abscopal response has been detected in 11/21 (52%) patients: in details, we observed 9 abscopal partial response , 2 abscopal stable disease , and 10 progression . The median of occurrence of the abscopal response was of 1 month (range 1-4). The median overall survival (OS) for all the 21 patients was of 13 months (range 6-26). The median OS for patients with and without abscopal responses was respectively of 22.4 months  and 8,3 months . 11  out of 13 patients with local response showed an abscopal effect.RT could be a new treatment option after ipilimumab treatment for potentiate its effect. Local response to RT might be predictive for the abscopal response and outcome. Further studies are warranted in this field to better understand and define the role of RT in combination or sequencing with ipilimumab treatment."}
+{"text": "Advances in medicine allow patients with comorbidities to live longer and the need for intensive care increases. It is not unusual for the supply of critical care beds to not meet the demand. In this scenario the critically ill patient is cared for in the emergency department or in regular hospital wards.To describe clinical and epidemiologic characteristics of critically ill patients treated outside the ICU due to an unavailability of beds.Prospective cohort study of critically ill patients treated in the hospital wards of a university hospital during a 1-year period. All consecutive patients denied ICU beds due to a full unit who were treated by hospital ward staff and daily intensivist physician consultation during the period February 2012-February 2013 were included. Patients were followed until admission to the ICU or cancellation of the ICU bed request. Clinical and epidemiologic data were collected. Invasive procedures and therapeutic interventions were noted. Outcome was observed at hospital discharge.Four hundred and fifty-four patients were analyzed. Patients were predominantly male (54.6%) and the median age was 62 (interquartile range (ITQ): 47-73). Median APACHE II score was 22.5 (ITQ: 16-29), median SOFA score was 8 (ITQ: 4-13) and median TISS 28 was 27 (ITQ: 22-30). Reasons for critical care request were respiratory failure (39%), hemodynamic instability (36.3%), neurologic monitoring (14.5%), cardiac monitoring (7.3%) and postoperative care (2.9%). Invasive mechanical ventilation was used in 266 (65.6%) patients, continuous intravenous vasopressors or inotropic drugs for shock treatment were used in 44.9% and intravenous vasodilators in 5.9% of patients. Median time of follow up was 3 (ITQ: 2-6) days, after this time 204 patients were admitted to the ICU and 250 had the ICU bed request cancelled. The motives for waiving critical care were due to clinical improvement in 122 (26.9%) patients, death in 101 (22.3%) patients, decision to withhold treatment due to futility in 25 (5.5%) patients and transfer to another institution in two (0.4%) patients. Hospital mortality was 65%.Caring for critically ill patients outside ICU walls was frequent in the study institution. Patients presented a high severity of disease score, had multiple organ dysfunctions and needed multiple invasive therapeutic interventions. Despite receiving intensive care with specialized consultation, these patients present poor prognosis."}
+{"text": "This gene encodes for the enzyme mevalonate kinase (MVK), which catalyzes a crucial step of the biosynthetic pathway of cholesterol and isoprenoids. The partial deficiency of enzymatic activity causes the Hyper-IgD and periodic fever syndrome (HIDS), whereas it complete deficiency provokes the Mevalonic Aciduria (MA).Mevalonate kinase deficiency (MKD) is a recessively-inherited autoinflammatory condition caused by The aim of this study was to describe the clinical and genetic features of Spanish patients with MKD diagnosed during the past 15 years.MVK analysis was performed by Sanger-based sequencing.The patients\u2019 data as well as the outcome of the administered treatments were collected from charts reviews. MVK mutations. Eighteen different MVK mutations were detected, with the p.[(V377I)] and p.[(I268T)] mutations as the most prevalent, accounting for 54.9% and 26.8% of mutated alleles, respectively. The majority of these mutations (96.4%) were missense mutations. The remainder mutations included premature stop (1.2%), frameshift (1.2%), and splice site mutations (1.2%). In the group of patients with HIDS (n: 38), twelve patients (31.6%) carried homozygous genotypes and twenty-six patients (68.4%) compound heterozygous genotypes. In the group of HIDS patients with homozygous genotypes (n= 12), ten patients (83.3%) carried the p.[(V377I)];[(V377I)] genotype. By contrast, in the group of patients with MA only one patient (33.3%) carried a homozygous genotype (the p.[(I268T)];[(I268T)]).Forty-one patients from different Spanish hospitals were included. Thirty-eight patients (92.7%) suffered from HIDS and three patients (7.3%) from MA. The MKD diagnosis was established in all of them by the detection of biallelic From a clinical point of view, the median age at the disease onset was 6 months (range 0-408), and the median duration of flares was 4.8 days (range 2-17.5). Mandatory vaccinations were identified as triggering factors for acute episodes in eleven patients (26.8%). The most prevalent manifestations during inflammatory episodes were fever (80.5%), lymphadenopathies (70.7%), abdominal pain (63.4%), diarrhea (58.5%), aphthous ulcers (53.7%) and arthralgia (51.2%). AA amyloidosis was only detected in one patient (2.4%), but had a severe course.MVK mutations. Most of patients suffered from the mild MKD phenotype, the HIDS syndrome. Two prevalent MVK mutations, p.[(V377I)] and p.[(I268T)], were found in our cohort, and fever and lymphadenopathies were the most common features in enrolled patients.We herein provide a detailed description of the clinical and genetic features of a Spanish cohort of MKD patients carrying biallelic"}
+{"text": "There is a need for continuous glucose monitoring in critically ill patients. The objective of this trial was to determine the point accuracy and reliability of a device designed for continuous monitoring of interstitial glucose levels in ICU patients .12 ml. Device readings were compared with glucose measurements in arterial blood using blood gas analyzers . We used a linear mixed model to determine which factors affect point accuracy. In addition, we determined the reliability, including duration of device start-up and calibration, skips in data acquisition, and premature disconnections of sensors.Critically ill patients with an anticipated life expectancy >96 hours were eligible for participation, if the platelet count was >30 \u00d7 10We included 50 patients, aged 65 (56 to 72) years with an APACHE II score of 23 (17 to 26). Admission types were medical (62%), elective surgery (22%) and emergency surgery (16%), and 22% had diabetes. For the accuracy analyses we had 929 comparative samples from 100 sensors in 45 patients (11 (7 to 28) samples per patient) during 4,639 hours (46 (27 to 134) hours per patient and 46 (21 to 69) hours per sensor). The Bland-Altman plot showed a bias of -0.6 mg/dl with limit of agreement between -57.2 and 56 mg/dl. Glucose prediction error analysis showed 60% of the glucose values <75 mg/dl within \u00b115 mg/dl and 75.8% of the glucose values \u226575 mg/dl within 20% of the comparative RapidLab results. Clarke error grid analysis showed 75.3% in zones A and 23.5% of the paired measurements in zones B, 0.3% of the paired measurements in zones C and 0.9% of the paired measurements in zones D. Point accuracy did not meet the ISO14971 standard for dosing accuracy, but improved with increasing numbers of calibrations, and was better in patients who did not have diabetes mellitus. Sixty out of 105 sensors were removed prematurely for a variety of reasons. The device start-up time was 49 (43 to 58) minutes. The number of skips in data acquisition was low, resulting in availability of real-time data during 95 (89 to 98)% of the connection time per sensor.The point accuracy of the device was relatively low in critically ill patients. The device reliability was relatively good, although sensors were removed prematurely for a variety of reasons."}
+{"text": "MAS is a severe complication of rheumatic diseases, mostly sJIA. Clinical and laboratory features are similar to those of FHL resulting from mutations in selected genes involved in the cytotoxicity pathway.We investigated the presence of mutations of FHL-related genes and of abnormalities in degranulation and perforin expression, in patients with MAS occurring in the context of sJIA.From the HLH Italian National Registry, we selected patients with MAS defined according to the HLH 2004 criteria and with confirmed diagnosis of sJIA based on ILAR criteria. Mutation analysis was performed by Sanger sequencing of FHL-related genes. Perforin expression and degranulation were analyzed using flow-cytometry.PRF1 (n=7), UNC13D (n=1), STX11 (n=1), STXBP2 (n=4), and Rab27a (n=1). Three patients had mutations in 2 genes. Both degranulation and perforin expression were evaluated in 18 patients. At least one test was defective in 11 patients (61%). The clinical and laboratory features of patients with monoallelic mutation and/or with abnormalities in at least one functional test, were not different from those of the remaining patients. However, re-occurrence of MAS tended to be more frequent in patients carrying mutations (mutated 27% versus non-mutated 10%) and in patients showing abnormalities in at least 1 functional test . One patient died of MAS: she carried the N252S PRF1 variant and showed reduced perforin expression.We identified 31patients  with MAS and sJIA. Eleven patients (35.5%) had 14 monoallelic mutations in Monoallelic mutations in FHL-related genes and partial defect in either perforin expression or degranulation capacity are frequently observed in patients with sJIA who develop MAS. Additional genetic studies are warranted to identify additional genes potentially linked to MAS development.None declared."}
+{"text": "To determine Mortality in Hematological patients admitted at the ICU of University Clinical Hospital of Santiago de Compostela from August 1995 to November 2014.Retrospective observational study of long-term Survival of total Hematological patients admitted to the ICU of University Clinical Hospital of Santiago de Compostela between August 1995 and November 2014. 93 patients were enrolled by variables of Age, Gender, APACHE-II Score, Hematological Disease, Claim Inpatient Admission, Length of Stay, Mechanical Ventilation, Continuous Renal Replacement Techniques (CRRT) and Cause of Death.93 patients studied, 69% male, with Mean Age 57 years and SD 15 years. Mean APACHE-II were 22 with SD 9.5, 68% had an APACHE-II >16. The most frequent Hematological Disease was Lymphoma (44%) followed by Leukemia (33%), Multiple Myeloma (7.5%), Myelodysplastic Syndrome (5%) and Others (10.5%). The most frequent cause for ICU admission was Acute Respiratory Failure (44%). Mean ICU Stay was14 days with SD 15 days. 76% of patients needed Mechanical Ventilation and 29% were into CRRT. Mortality at ICU was 59%, the most frequent Cause of Death was Multiple Organ Dysfunction Syndrome (29%), followed by evolution of Hematological Disease (15%). In a Subgroup Analysis based on Year of Admission, differences in Mortality rates were noticed before and after 2006 (72% vs 48%) with no statistical significance.Mortality at ICU was 59%. Most frequent Cause of Death was Multiple Organ Dysfunction Syndrome (29%) and Hematological Disease (15%). In a Subgroup Analysis based on Year of Admission, differences in Mortality Rates were noticed before and after 2006 (72% vs 48%). Though no statistical significance, we think this notorious difference is based on Hematological treatment improvement and a better Intensive Care support."}
+{"text": "Neuropsychiatric systemic lupus erythematosus (NPSLE) is a diagnostically challenging, severe, and life-threatening condition. Neuroimaging techniques such as magnetic resonance imaging (MRI) are increasingly used to assist the diagnosis and monitoring of the disease course in adults with NPSLE. The role of MRI in the evaluation of children and adolescents with suspected juvenile NPSLE is however unknown.The aim of this study was to describe the abnormalities identified with conventional MRI in children with NPSLE; and any potential associations with clinical and/or serological markers presenting to a tertiary paediatric rheumatology service.Single centre  retrospective case series of patients with juvenile NPSLE seen between April 2003 and October 2010. Contrast enhanced brain MR images of the first episode of active NPSLE were reviewed. All patients fulfilled the American College of Rheumatology (ACR) 1982 revised criteria for the classification of SLE and were classified according to the 1999 ACR case definition for NPSLE syndromes. We excluded patients with a history of alternative neurological conditions. Presenting neuropsychiatric manifestations, immunological findings and treatment are reported. Continuous variables are summarised as median and ranges. Categorical variables are presented as percentages. Fisher's exact test was used to identify the probability of abnormal MRI findings.A total of 27 patients median age 11 (4-15) years, 22 females with suspected juvenile NPSLE were studied. Presenting clinical symptoms included: headaches (85.1%); mood disorder/depression (62.9%); seizures (22.2%); acute psychosis (18.5%); cognitive dysfunction (14.8%); movement disorder (14.8%); acute confusional state (14.8%); aseptic meningitis (7.4%); demyelinating syndrome (3.7%); myelopathy (3.7%); dysautonomia (3.7%); and cranial neuropathy (3.7%). The principal MR findings were: 1) absence of MRI abnormalities despite signs and symptoms of active NPSLE ; 2) focal hyperintensities on T2-weighted imaging in both white and grey matter (33%); 3) diffuse cortical grey matter lesions (3.7%); and 4) diffuse brain atrophy (18.5%). The presence of>2 neuropsychiatric manifestations strongly associated with abnormal MRI findings (p = 0.014). Positive dsDNA antibodies were noted in 74% of patients; positive extra nuclear antibodies in 74%, lupus anticoagulant in 15% and anticardiolipin antibodies in 37%. All children were treated with hydroxychloroquine and high doses of intravenous corticosteroids while other treatments used were: intravenous cyclophosphamide (51.8%); rituximab (40.7%); and plasma exchange (11.1%).In the present study, no conventional MRI abnormalities were observed in the majority of patients with clinically active NPSLE. The presence of >2 neuropsychiatric manifestations was strongly associated with abnormal MRI. Improved MR techniques and the advent of other alternative diagnostic imaging modalities may improve the detection rate of brain involvement in juvenile NPSLE.None declared."}
+{"text": "This study aimed to establish clinical utility of blood cultures taken surrounding ICU admission. Blood culture cost in terms of resources and false results is well established and unnecessary cultures can cause patient harm.All ICU admissions in 2011 were listed retrospectively. Notes were reviewed for those with blood cultures taken during, or within 24 hours prior to or following, ICU admission. Data collected for positive blood cultures included organism, antimicrobial sensitivity, culture timing with respect to ICU admission and antibiotic therapy before and after positive blood culture. Qualitative decisions were made regarding clinical utility of each positive blood culture. Results were deemed useful if management changed - starting, changing or stopping antibiotics or altering antibiotic duration. Confirmatory results or those not altering treatment were not deemed useful. Statistical analysis was performed using the chi-squared test.During 2011 and 2012, there were 450 ICU admissions. In total, 698 blood cultures were taken during, or within 24 hours prior to or following, ICU admission. A total of 135 blood cultures were taken in the 24 hours prior to ICU admission. Of these, 26 grew significant organisms (19.3%). Nine of these cultures were deemed clinically useful (6.7%). A total of 542 blood cultures were taken during ICU admission. Thirty-three of these yielded significant results (6.1%) but only nine (1.7%) were deemed clinically useful. A total of 102 cultures were taken in the first 24 hours of the iCu, of which 17 were positive (16.7%) and six were useful (5.9%). Fifty-three were taken over the next 24 hours, of which two were positive and two were useful (3.8%). Forty-four cultures were taken over the following 24 hours, of which two were positive (4.5%) and one was useful (2.3%). A total of 343 cultures were taken subsequent to this in the ICU, of which 12 were positive (3.5%) and three were deemed useful (0.9%). Of 22 blood cultures taken in the 24 hours post ICU, one was positive but deemed useful (4.5% yield).P = 0.0001). The yield of positive blood cultures and their clinical utility also decrease during ICU stay. This may reflect appropriate empirical antibiotics and lower bacteraemia burden in later illness. Given the low clinical yield and a lack of established sensitive or specific triggers [These results demonstrate overall low clinical utility of blood cultures but specifically that utility of ICU cultures is significantly lower than pre ICU (1.7% vs. 6.7%;"}
+{"text": "We aim to analyze clinical characteristics, subclinical inflammation, and carried MEFV mutation in siblings with FMF.Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent attacks of fever and peritonitis, pleuritis, arthritis or an erysipelas-like skin disorder. The disease may present at any age, more than 80% of patients being symptomatic by the age of 20 yr. Its main long-term complication is amyloid A (AA) amyloidosis, a severe manifestation with poor prognosis. Mutations in the MEFV gene, on chromosome 16We obtain FMF patients who were followed in Erciyes University Faculty of Medicine, department of pediatric rheumatology and their siblings. All children were evaluated with a questionnaire containing 21 questions which symptoms may be signs of FMF. All subjects were invstigated for laboratory disease features, genetic analysis of MEFV mutations.The study included 53 pediatric patients and their 76 sibling total 129 children from 50 different families. In patients, the most frequent mutations were homozygous pM694V (60%), pM694V/pM680I (9.5%), pM694V/pV726A (3.6%) and heterozygous pM694V mutation (3.6%). Therefore, in siblings of the patients had mostly homozygous pM694V (12%), pE148Q/P369S and heterozygous pM694V mutation (35.5%) while 11 (14.5%) sibling had no mutation in MEFV gene. We also completed a questionnaire form included findings of FMF in all subject. We obtained the typical history of FMF ; and transient inflammatory response) in 9 of 76 siblings (12%) from the questionnaire. In addition, the presence of rare but important manifestations such as erysipelas like erythema and leg pain of FMF were determine in patients\u2019 siblings. The exertional leg pain had found in 21 siblings (28%) who carried at least one mutation in the MEFV gene. Also we evaluated acute phase reactants  in all subjects. The siblings with homozygous mutation had elevated levels of SAA and S100A protein than others.Our findings showed that siblings with FMF had different clinical findings each other. In these children should be questioned in terms of FMF findings before screen mutation in MEFV. Fever, serositis symptoms and musculoskeletal symptoms in children, especially presence of homozygous mutation, even if there has no typical attacks, we believe that the colchicine treatment should be considered."}
+{"text": "Her2 FISH amplification showed increasing trend with increasing HER2 IHC ordinals  by both TOGA biopsy (P<0.001) and surgical specimen method (P<0.001). After excluding equivocal cases, the sensitivity (100%), PPV (88.89%) and NPV (100%) of HER2 IHC were unchanged under either surgical specimen method or biopsy method. However, the specificity (96.97%) and accuracy (97.56%) of HER2 IHC was slightly higher under the surgical specimen method than those  under the biopsy method. Of the total 49 cases, the number (n = 14) of HER2 IHC equivocal results under the ToGA biopsy method was 1.75-fold higher than those (n = 8) under the ToGA surgical specimen method (28.57% vs. 16.32%). Therefore, compared to ToGA surgery specimen method, the ToGA biopsy method caused more equivocal IHC cases to be referred to FISH testing and did not increase the detection rates of Her2 FISH amplification.We aimed to compare the assay performance characteristics of HER2 status in mucinous epithelial ovarian cancer (EOC) by ToGA (Trastuzumab for Gastric Cancer) biopsy versus ToGA surgical specimen methods. Forty-nine tissue microarray (TMA) samples of mucinous EOC from Asian women were analyzed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) tests using ToGA trial HER2 scoring methods. The overall concordance between IHC and FISH by the ToGA surgical specimen method is 97.56% and by the ToGA biopsy specimen method is 97.14%. The agreements of HER2 IHC results under both biopsy and surgical specimen methods were nearly perfect (weighted kappa = 0.845). Additionally, the percentage of  The encouraging success of trastuzumab and new anti-HER2 therapies in breast, gastric or gastro-oesophageal junction (GEJ) cancer patients has prompted us to investigate the HER2 status and its possible therapeutic implication in other malignancies, including mucinous EOC ,2. Even Both gastric cancer and mucinous EOC share similar cell morphology, apical mucin secretion, glandular architecture and characteristic HER2 immunostaining patterns, while breast cancer typically does not share these characteristics. It would be more realistic to adopt the Trastuzumab for Gastric Cancer (ToGA) trial scoring method rather than The American Society of Clinical Oncology and the College of American Pathologists (ASCO/CAP) guideline recommendations as a reference guide in assessing the HER2 status in our cohort of mucinous ovarian cancer.Her2 gene copy numbers and HER2 protein expressions in mucinous EOC [Using the TMA and ToGA surgical specimen scoring method, we previously reported the positive correlation between nous EOC . HoweverIn this study, we planned to elucidate and compare the assay performance characteristics of the two ToGA  methods for HER2 reporting in mucinous EOC.All patient-derived study materials were collected and archived under the protocol approved by the institutional review board at Chung-Shan Medical University Hospital (IRB No: CS11008 & CS13239) that met the current guidelines of the Taiwan Government\u2019s Ministry of Health and Welfare (MOHW) and Forum for Ethical Review Committees in Asia and the Western Pacific (FERCAP). All the organizations and operations of this institutional review board are in compliance with ICH-GCP  requirements and the essence of the Declaration of Helsinki. Their characteristics of the TMA derivation were described in our previous report [The first group of 21 cases of Taiwanese mucinous EOC consisted of selected formalin-fixed, paraffin-embedded oophorectomy tissue blocks retrieved from the archives of the Tissue Bank of Clinical Trial Center, Chung-Shan Medical University Hospital.The second group of 28 cases of Asian mucinous EOC was derived from a commercial set of TMA slides . Of all 200 cores in this TMA, there were only 28 cores of mucinous EOC available for this study.All direct patient identifiers had already been permanently deleted so that we were not able to obtain their agreement for use in this study. The reason for lack of consent was that the identity and personal information of an individual who has donated human tissue is no longer identifiable or linked to that individual\u2019s tissue sample.The HER2 immunostains were performed on the fully automated Ventana Benchmark XT autostainer using pathway antiHER2/neu rabbit monoclonal antibody . HER2 IHC score 3+ breast cancer was used as a positive control. Negative controls were obtained by excluding the primary antibody. The slides were mounted with Permount for microscopic examination, and the images were captured by the NIKON ECLIPSE 50i microscope and NIKON DS-Fi1 Digital Camera System for study comparison.Her2 DNA Probe Kit protocol . The dual-color FISH consists of two labeled DNA probes and was performed on sections cut from the same tissue microarrays (TMA) block. The LSI HER2 probe that spans the entire Her2 gene was labeled in Spectrum Orange and the CEP17  probe was labeled in SpectrumGreen then hybridized to the alpha satellite DNA located at the centromere of chromosome-17 (17p11.1\u2013q11.1). Counting two separate fields of at least 20 cells was essential. We calculated the Her2:CEP17 signal ratio by recording the numbers of Her2 gene (red) and chromosome 17 (green) signals from preselected tumor areas. In most cases, tumor cells from matching sites of IHC analysis were scored for the number of red (Her2) and green (CEP17) signals. Signal photos were taken with the NIKON ECLIPSE 80i fluorescent microscope with a PlanFluor oil objective (100x) using a double band-pass filter that permits simultaneous green and red color penetration.The FISH test was performed by the ABBOTT/Vysis PathVysion Her2 FISH testing results in this study.  assessments, our laboratory performance met the proficiency testing (PT) requirements of the Taiwan Division of International Academy of Pathology. Additionally, we participated in the UK NEQS  HER2 test program. We also ran a HER2 control in all cases daily and had one pathologist routinely screen the slides.Her2 FISH amplified patients, specificity was defined as the ratio of HER2 IHC negative cases among Her2 FISH non-amplified patients, positive predictive value (PPV) was defined as the ratio of Her2 FISH amplified cases among HER2 IHC positive patients, negative predictive value (NPV) was defined as the ratio of Her2 FISH non-amplified cases among HER2 IHC negative patients, and accuracy was defined as the ratio of HER2 IHC positive and Her2 FISH amplified cases plus HER2 IHC negative cases and Her2 FISH non-amplified cases among all cases. The overall concordance was defined as the ratio of HER2 IHC positive and Her2 FISH amplified cases plus HER2 IHC negative cases and Her2 FISH non-amplified cases among all non-equivocal IHC cases. Data were analyzed using standard statistical software . All tests were 2-sided and the significance level was 0.05.The consistency between ToGA surgical specimen and ToGA biopsy IHC results were analyzed by categorized variables by weighted Kappa statistics. The strength of agreement beyond chance for different ranges were referred from the report of Landis and Koch . Furthervs. biopsy; linear weighted kappa = 0.845, 95% CI 0.7226\u20130.9676). . Her2 amplification rate of mucinous EOC was 20.41% (n = 10/49). Additionally the percentage of Her2 FISH amplifications increased significantly in a trend through the order of HER2 IHC results  by both ToGA surgical specimen method and ToGA biopsy method, respectively  (Her2 gene non-amplification (n = 6/8) and two cases (25.00%) of Her2 gene amplification (n = 2/8). Under the ToGA biopsy method, fourteen cases were classified as IHC score 2+ , which consisted of twelve cases (85.71%) of Her2 gene non-amplification (n = 12/14) and the same two cases (14.29%) of Her2 gene amplification (n = 2/14). (We demonstrated that the P<0.001) . Under t= 2/14). Her2 FISH by both methods.  in positive concordance, 100% (n = 32/32) in negative concordance and 97.56 (n = 40/41) in overall concordance (kappa = 0.9259); while except for 14 HER2 IHC equivocal cases by the ToGA biopsy method, our data for the relationship between IHC and FISH showed 88.89% (n = 8/9) in positive concordance, 100% (26/26) in negative concordance and 97.14% (34/35) in overall concordance (kappa = 0.9224). Additionally, we identified the one case who showed positive HER2 IHC/ non-amplified methods. Her2 FISH as the reference standard, the HER2 IHC performance characteristics under the ToGA surgical specimen and biopsy methods were evaluated by calculation of sensitivity, specificity, positive predictive values (PPV), negative predictive value (NPV) and accuracy. After excluding equivocal cases, the sensitivity (100%), PPV (88.89%) and NPV (100%) by both ToGA surgical specimen and ToGA biopsy methods are similar. The accuracy under the ToGA surgical specimen method was slightly higher than that under the ToGA biopsy method (97.56% vs. 97.14%) and the specificity was also (96.97% vs. 96.30%) slightly increased  in this study.Previously, we reported that both CEP17 corrected and uncorrected nous EOC . Howevernous EOC . AdditioThe major differences of HER2 IHC between ToGA surgical (large sample) and ToGA biopsy  scoring methods are noted as below:versus a cluster of at least five positive cells in a biopsy specimen. (A tumor is classified as HER2 protein over-expression by IHC positive (score 3+) when there is strong, complete, basolateral or lateral membrane staining in \u226510% of tumor cells in surgical specimen pecimen.  Our dataversus a cluster of at least five positive tumor cells in a biopsy specimen. .  and biopsy method .  and TGA biopsy (n = 1/35) methods (2.44% vs. 2.86%) .  In addit0.9224).  After re. 2.86%)  This is vs. 16.32%).  and Her2 FISH non-amplification.  of HER2 IHC equivocal results under the ToGA biopsy method was 1.75-fold higher than those (n = 8) under the ToGA surgical specimen method (28.57% 16.32%).  Of thoseication.  This indIntratumoral heterogeneities of HER2 status have been previously reported in mucinous EOC ,13. EvenHer2 FISH as a reference standard, we evaluated the performance characteristics of HER2 IHC testing under both the ToGA surgical specimen and ToGA biopsy methods. , but did not increase the detection rates of Her2 FISH amplification  HER2 IHC on the basis of cost effectiveness in assessing the HER2 status in mucinous EOC.In summary, our data demonstrated that: (1) both ToGA biopsy  and ToGA surgical specimen  methods exhibit almost perfect concordance between nonequivocal IHC and FISH  in assessing HER2 status of mucinous EOC , and (2)fication . As a reHer2 FISH amplification. Considering the higher equivocal rate and slightly lower accuracy under the ToGA biopsy method, we prefer to adopt the ToGA surgical specimen method rather than use ToGA biopsy method for the assessment of HER2 status in mucinous EOC.Identifying the exact HER2 status in mucinous EOC is essential for selecting potential candidates for novel anti-HER2 drug therapies. The ToGA surgical specimen method resulted in less equivocal demonstration of HER2 immunoreactivity; while the ToGA biopsy method caused more equivocal IHC cases to be referred to FISH testing than the ToGA surgery specimen method did. Additionally, the ToGA biopsy method using a cluster of greater than five positive cells rather than a percentage cut off did not increase the detection rate of S1 TableHer2 FISH ratios of all 49 cases with primary mucinous EOC.We presented the dataset on HER2 IHC scores under both ToGA surgical specimen and ToGA biopsy methods and (DOCX)Click here for additional data file."}
+{"text": "Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory bone disorder of unknown ethiology. The clinical manifestations of CRMO are highly variable. One to 20 sites can be affected at one time. Since CNO is a systemic disorder that can affect multiple skeletal sites, whole-body imaging techniques (Tc-99 bone scintigraphy or MRI) provide major contribution to the initial diagnostic approach, as well as during follow-up.To evaluate typical patterns of bone involvement on MRI in paediatric patients with CRMO.We retrospectively reviewed 112 MRI performed at the diagnosis and during follow-up from 2010 to 2014 of 40 children with CRMO. Thirty-two patients underwent bone biopsy that confirmed the diagnosis. 28/40 (70%) underwent one or more WBMRI. Coronal STIR images were obtained in all children. Additional sequences were performed in doubtful cases.A total of 360 lesions were detected. Lesions were multifocal in 36/40 patients (90%) and were symmetric in at least one localization in 24/40 patients (60%). In 30/40 patients (75%) lesions were located on the metaphyses of long bones  close to one or both sides of an epiphyseal or apophyseal growth plate and/or on pelvic bones (particularly on the sacro-iliac joints and close to the triradiate cartilage) and/or on clavicle/sternum. The spine was involved in 14/40 (34.1%) patients, in all but 2 in combination to the submentioned locations. No patients had carpal or head bone involvement, 16/40 had tarsal involvement.MRI, and particularly WBMRI, should be considered the diagnostic modality of choice in patients with clinical multifocal pain. Simmetricity, multifocality and particularly specific patterns of lesions appear highly suggestive of CRMO."}
+{"text": "In the last years there is a great concern regarding the effect of HIV and antiretroviral drugs in children born by treated HIV-infected mothers.We started a prospective cohort study regarding HIV and antiretroviral exposure in children followed in the Pediatric HIV Department from the National Institute for Infectious Diseases \"Prof. Dr. Matei Bal\u015f\", Bucharest.st 2006 to December 31st 2012. The patients were followed up for 18 month after birth to establish the HIV status; gestational age, birth defects and mother treatment were noted.We analyzed the data recorded for children perinatally-exposed to HIV followed up in our Department from January 1From 206 children with complete 18 months follow up, 21% (43 cases) were diagnosed with HIV infection and more than 33% had at least one congenital condition.We found birth defects in various organs in studied children: heart (130 cases), musculoskeletal system (47 cases), kidney (20 cases), nervous system (20 cases), digestive tract (10 cases) and metabolic and genetic disorders (2 cases each). 26 from the 163 HIV-exposed children and 6 from the 43 HIV-infected cases were born before 37 weeks of gestation, 4 HIV-exposed and 4 HIV-infected children were small for gestational age. We found low birth weight (<2500 g) in 18 HIV-exposed children and 3 HIV infected children and extremely low birth weight (1000) in one HIV-exposed child.We found congenital malformation in 11 preterm HIV-exposed children and 2 preterm HIV-infected children, but also in 38 HIV-exposed children and 19 HIV-infected babies with normal gestation period.The difference between the rate of congenital malformation and prematurity was not statistically significant (p=0.08) in any of studied groups and HIV diagnosis was not associated with a higher risk of preterm birth (p=0.93). Mother being part of the Romanian cohort was not statistically associated with higher risk of prematurity. We found a significant association between antiretroviral treatment during pregnancy and prematurity (p=0.003). The most used drugs to treat mothers were boosted protease inhibitors (99% cases).In the studied patients we found high risk of prematurity in babies exposed in utero to antiretrovirals, but no association between prematurity and HIV infection in children or mother being part of Romanian cohort."}
+{"text": "Candida antifungal resistance has been repeatedly demonstrated.Systemic Antifungal therapy (SAT) of invasive candidiasis (IC) needs to be started immediately upon clinical suspicion. Controversies exist then about potential harms from antifungal de-escalation (DE).(1) in cases of documented IC, early DE to fluconazole is recommended by US guidelines but discouraged in EU guidelines. in non-documented IC, no data are available to guide SAT DE. These questions are key issues however as the relationship between antifungal use and To investigate whether DE within 5 days of SAT initiation is associated with an increase in 28-day death in SAT-treated non-neutropenic adult ICU patients.Patients were recruited from AmarCAND2, a multicenter prospective observational study conducted in French ICUs . The study included 647 non-neutropenic adult ICU patients who received SAT for a documented or suspected invasive candidiasis and who were alive and in the ICU after 5 days of SAT initiation. The study considered two groups: SAT DE group  and SAT continuation group . The average causal SAT DE effect on 28-day death was performed by using a double robust Inverse Probability of Treatment Weight (IPTW) estimation for observational data.Of 647 included patients, early DE at day 5 after SAT initiation was performed in 142 patients (22%) of whom 48 (34%) SAT was stopped before day 5. The initial SAT was mainly echinocandins (372 patients (58%)) and fluconazole (261 patients (40%)). 276 patients (43%) had a proven invasive candidiasis . Crude mortality before day 28 was 29% in the DE group, 26% in the no DE group. Main variables associated with DE are reported on the Table below. After adjustment on the baseline confounders, early SAT DE was not found to be associated with increased 28-day mortality . Results are not different if analyses are restricted to proven IC , suspected IC , or first line candins therapy . DE increased the number of day alive without SAT (13 days [5-23] vs. 10 days [1-17] p < .01). Figure In non-neutropenic adult critically ill patients with proven or suspected CI, SAT DE within 5 days was not found to be associated with increased day-28 mortality. Alternatively, SAT DE was found to be associated with decreased SAT consumption. These results show for the first time that SAT DE is safe, more particularly in cases of unproven invasive candidiasis.MSD France"}
+{"text": "Ixodidae are an important health problem for domestic and wild animals for direct damages caused by these ticks, but mostly because they are involved in the transmission of many diseases (tick borne diseases - TBDs). Therefore, the surveys on the presence and geographical distribution of ticks in domestic ruminants need to be constantly updated.The aim of the present study was to update the data on the presence and distribution of Ixodidae ticks in cattle and sheep bred in the Basilicata region , an area with a Mediterranean climate favourable to the biology and ecology of ticks. In this region, the breeding of pasturing cattle and sheep is a widespread reality very important from an economical point of view, especially for the natural vocation of animals in using marginal hilly and mountainous pastures.From May to September 2013, sheep and cattle farms  were visited and ticks were collected from 20 animals per farm, preserved in ethanol 70% and then identified at species level using the morphometric keys present in the literature.Rhipicephalus bursa (67.1%), R. sanguineus (34.1%), R. turanicus (25.6%), Dermacentor marginatus (6.1%), Hyalomma detritum (3.7%), Ixodes ricinus (3.7%) and Hyalomma marginatum (1.2%). In the cattle farms, a total of 585 adult ticks were collected and the following species identified: R. bursa (61.3%), H.marginatum (29.0%), R. turanicus (25.8%) sanguineus (25.8%), D. marginatus (9.7%), I. ricinus (9.7%), Ixodes gibbosus (6.5%) and Hyalomma detritum (3.2%).A total of 2,179 ticks were collected. The following species were identified in the sheep farms : The results of the present cross-sectional survey confirm that the environmental and climatic conditions of southern Italy are suitable for different tick species infecting domestic ruminants that are therefore exposed to different TBDs."}
+{"text": "Background: North-eastern region of India continue to suffer from limited resources, added upon by Mongoloid racial similarity and poor cataract surgery rate has contributed to the increase incidence of advanced cataract like phacomorphic glaucoma.Objective: To evaluate the visual prognosis and related complications of phacomorphic glaucoma cases by manual small incision cataract surgeries in North-eastern region of India.Materials and methods: This retrospective case series study includes 65 phacomorphic glaucoma cases diagnosed between June 2009 to December 2011 in Jawaharlal Nehru Institute of Medical Sciences, Manipur. Preoperative routine evaluation includes slit-lamp biomicroscopy, measurement of IOP, gonioscopy of fellow eye, axial length measurement, AC depth and lens thickness by A-scan. Manual small incision cataract surgery with intraocular lens implantation was performed in all the 65 eyes. Complete ophthalmic examination was done at each follow-up visit.Results: The mean preoperative IOP was 35.14 (\u00b16.35) mm Hg and IOP at the 3rd month follow-up was 18.65 (\u00b11.3) mm Hg with a statistically significant lowering of IOP (p < 0.0001) at the last follow-up. Intraoperative complications were minimal. Corneal edema, fibrinous exudates in AC was seen in few cases. Postoperative best corrected visual acuity was 6/6-6/12 in 46 eyes, 6/18-6/36 in 12 eyes, 6/60-3/60 in 4 eyes and less than 3/60 in three eyes. Antiglaucoma medication was discontinued immediately after each surgery.Conclusion: Manual small incision cataract surgery being inexpensive play a key role in management of poor outreach program marker like phacomorphic glaucoma in effectively controlling the IOP and achieving good visual acuity with minimal complications.How to cite this article: Rajkumari V, Kaminibabu KS, Bhabanisana RD, Victor R. Manual Small Incision Cataract Surgery in Phacomorphic Glaucoma: Surgical Technique and Outcome in North-eastern India. J Current Glau Prac 2013; 7(2):43-48. Age 50 years and older constitute the 65% of people visually impaired and 82% of all blind population.6 The statewise prevalence of blindness in the 50+ population was Arunachal Pradesh: 17.56%, Assam: 23.48%, Manipur: 10.66%, Meghalaya: 5.72%, Mizoram: 6.03%, Nagaland: 8.09%, Sikkim: 4.99% and Tripura: 5.96%. Extrapolating the results of the survey to the general population, it was estimated that the 1.38% of the North-eastern population was blind .6 Even though the most common cause in this population is cataract, the number of cataract surgeries in these regions is far from the target.According to a report in 2001-03, the North-eastern Indian states had combined bilateral blindness of 82.49% in 50+ population.7 The recent CSR shown in VISION 2020 12th 5-year plan was disappointing with Assam, Manipur, Arunachal Pradesh, Meghalaya, Sikkim showing CSR < 200/lakh population but Tripura and Mizoram were in a fairly better position with CSR between 200 to 500/lakh population.8 The reason being multifactorial namely limited number of surgeons, skilled manpower and limited facilities restricted to some tertiary level hospitals. Poor CSR can be one of the factors for increased incidence of advanced cataract like phacomorphic glaucoma which imposes extra challenge to the resource available in the region.In 2003 to 04, the cataract surgery rate (CSR) for Assam was 837, Manipur 220, Arunachal Pradesh 599, Meghalaya 510 and Sikkim 443 respectively.11 In India, a study has shown a prevalence of 3.91% phacomorphic glaucoma cases per operated cases for cataract surgery.12 Phacomorphic glaucoma is usually caused by lens swelling in the eye due to intumescent cataract. When the lens swells, angle-closure glaucoma with pupillary block occurs in the acute phase, in the late phase, it can occur without pupillary block as a result of forward movement of the peripheral iris.13Phacomorphic glaucoma is highly prevalent in developing countries as has been documented earlier.1415 The initial lowering of IOP is commonly done with medical treatment with combinations of topical antiglaucoma medications, oral acetazolamide, intravenous mannitol but in 37.5% cases medical treatment has failed to show signs of improvement.10 Equally effective is the laser pretreatment advocated by many surgeons and rarely a procedural syringing.18Management of phacomorphic glaucoma cases includes initial lowering of IOP followed by definitive treatment of removal of lens by cataract surgeries. The potential intraoperative complications like expulsive hemorrhage, weakened zonules tear and unpredictable visual outcome makes management of such cases a challenging procedure.1920Anterior capsule visualization by trypan blue staining  has turned a risky procedure of creating a continuous curvilinear capsulorhexis in manual small incision cataract surgery to a relatively safe and economical procedure though there has been some reported association of postoperative IOP elevation and persistent AC inflammation.This study was carried out to evaluate the visual prognosis and related complications of phacomorphic glaucoma cases by manual small incision cataract surgeries in North-eastern region of India where relatively no data is available. We have attempted to quantify the actual volume of phacomorphic glaucoma cases in our surgeries though shortcoming is inevitable while projecting it to the general population for many reasons one being nonuniformity of study population and other being inherent limitation of retrospective studies like incomplete records and inaccurate documentations despite all possible efforts.111521This retrospective study included all patients with phacomorphic glaucoma from June 2009 till December 2011. A total of 65 eyes were detected to be phacomorphic glaucoma at Jawaharlal Nehru Hospital of Jawaharlal Nehru Institute of Medical Sciences, Imphal, Manipur. Clinical presentation included acute pain on previously painless progressive diminution of vision and redness of eye. Examination revealed circumcorneal congestion, corneal edema, shallow anterior chamber, an intumescent cataractous lens pushing forward the iris and proportionately raising the intraocular pressure (IOP) above 21 mm Hg.15 A gonioscopic examination was often not feasible in the presence of corneal edema and was not use for diagnose but to rule out primary angle closure change in fellow as an exclusion criteria.22 Initial management of IOP > 35 mm Hg was done medically and with 20% mannitol in a case of persistently high IOP > 45 mm Hg to lower IOP < 25 mm Hg. Written informed consent was taken from all the patients prior to the surgery. The surgeries were performed under retrobulbar anesthesia with facial block.The preoperative assessment includes pupillary reaction, slit-lamp biomicroscopy, measurement of IOP (Schiotz tonometry), axial length measurement, anterior chamber depth and lens thickness by A scan , AB scan to examine the vitreous and retina.2324The surgical steps of MSICS have previously been described.Following a superior fornix based conjunctival flap, a frown scleral incision of 6.5 mm partial thickness was made 2 mm away from the limbus and scleral tunnel was extended 1 mm into clear cornea. Paracentesis was made at the 10 o'clock position. The anterior capsule was stained with trypan blue 0.6% for better visualization. The anterior chamber was filled with viscoelastic substance and continuous curvilinear capsulorhexis was made on the anterior lens capsule by capsulorhexis forcep. A sinskey hook was used to hook out one pole of the nucleus out of the bag and the rest of the nucleus was rotated out in the anterior chamber. The nucleus was extracted out of the eye with irrigating vectis. After aspirating the remaining cortex, a 6 mm optic polymethyl methacrylate posterior chamber intraocular lens was implanted in the bag. The viscoelastic was aspirated and the side port hydrated with balance salt solution. The conjunctival flap was apposed and subconjunctival injection of gentamicin and dexamethasone was given.Postoperatively patients were treated with topical antibiotic steroidal drops flurbiprofen. All glaucoma medications were discontinued immediately after the cataract extraction. Complete ophthalmic examination was done at 1st postoperative day and each follow-up visits of 1st week, 1st month, 3rd month and 6th month and included visual acuity test, IOP measurement, slit-lamp examination and funduscopy examination.SPSS version 16.0 was used for data analysis. The p-value of <0.05 was considered as significant.Out of 1,350 operated cases during the period of 2 years and 6 months for cataract cases, 65 were phacomorphic glaucoma cases (4.81% per operated cases for cataract surgeries). The number of female patients was 37 (56.9%) and that of male was 28 (43.1%) with female to male ratio of 1.3:1. The mean age of presentation for male was 66.54 (\u00b18.2) years and that of female was 63.37 (\u00b17.9). The composite detail of total number of patients, age and sex, duration of symptom and preoperative IOP of the study population has been summarized in Of the 65 cases, maximum number of the phacomorphic glaucoma cases presented at the first week. A total of 53 (81.5%) cases in 0 to 10 days, 10 (15.4%) in 11 to 20 days and remaining 2 (3.1%) cases in 21 to 30 days. The preoperative IOP was between 25 and 35 mm Hg in 17 (26.2%) males and 26 (40%) female patients, 36 and 45 mm Hg in 9 (13.8%) male and 11 (16.9%) female patients and 46 and 55 mm Hg in only 2 (3.1%) male patients. Overall the preoperative mean IOP was 35.1 (\u00b16.4) mm Hg.Out of the 65 patients, accurate projection of rays was seen in 56 (86.15%) patients and nine (13.85%) patients had inaccurate projection of light. Of the total, 8 (12.3%) were isolated diabetic patients, 5 (7.7%) were both diabetic and hypertensive and 11 (16.9%) were isolated hypertensive patients. A male patient with HIV seropositive was on ART. The preoperative fellow (nonattacked) eye status was summarized along with the presenting visual acuity (PVA) and associated medical illness in 25The mean axial length was 22.9 mm (SD 0.7) for female and 23.1 mm (SD 1.0) for male and the mean anterior chamber depth was 1.9 (SD 0.2) for phacomorphic eye taken as average of three consecutive reading. Since more than 95% of patients presented for first time, measurement of lens thickness was not consider significant as it can-not rule out the possibility of thicker lens prior to phacomorphic attack.Intraoperative difficulties encountered during surgery are wound insufficiency 3 (4.6%) cases, corneal edema and incomplete cortical clean up 2 (3.1%) cases, capsulorhexis extension to the periphery 5 (7.7%) cases, hard cataract and difficulty in prolapsing the nucleus 3 (4.6%) cases, pupillary constriction 4 (6.2%) cases and iris prolapsed 2 (3.1%) cases. Intraoperative complications were minimal. Premature entry to the anterior chamber in 3 (4.6%) cases and posterior capsular rent in 2 (3.1%) cases were the complications encountered during the surgery. The postoperative complications include striate keratopathy 7 (10.8%) cases, posterior capsular opacification 3 (4.6%), cystoids macular edema 2 (3.1%) and decentralization of lens 1 (1.5%). Intraoperative difficulties and complications along with postoperative complications have been summarized in The final postoperative BCVA was 6/6-6/12 in 46 (70.77%) eyes, 6/18-6/36 in 12 (18.46%) eyes, 6/60-3/60 in 4 (6.15%) eyes and finger counting (1/60)/hand movement or projection of light in 3 (4.62%) eyes. Comparison between the postoperative BCVA, duration of symptom and preoperative IOP has been summarized in 2627Extracapsular cataract extraction was not perform because of the risk associated with the large incision (12-14 mm) and sight threatening complications due to high IOP like expulsive hemorrhage.28Well control studies have clearly shown the advantage of manual small incision cataract surgery over extracapsular cataract extraction in cataract surgery in terms of visual outcome and postoperative recovery which is crucial in such cases.29Phacoemulsification  has advantage over both ECCE and MSICS in reduced conjunctival scaring for subsequent filtering surgeries if at all required.30The greater surgical risk imposed by phacomorphic angle closure especially in the setting of any residual corneal edema, dense and hard nuclei and weaken zonules added upon by its endothelial damaging ability of ultrasound energy because of the close proximity of the phaco tip during nucleus emulsification make the phacoemulsification procedure unfavoring in our setting.2324Manual small incision cataract surgery with trypan blue staining of the anterior lens capsule has a stable anterior chamber because of its shelving scleral wound besides being economical. Venkatesh et al and Ramakrishan R et al have shown the efficacy of MSICS in management of phacomorphic glaucoma cases in terms of visual outcome and safety.123031 Perhaps more important cause could be the increase backlog of poor CSR.78The incidence of phacomorphic glaucoma per operated case for cataract was higher than the previous study by Jain IS et al by 0.9% which could be due to the racial similarity with the mongoloid wereas many studies has reported the relative risk of increase incidence of glaucoma cases due to smaller axial length and anterior chamber depth.1625 Lee et al found that eye with axial length shorter than the population mean were 4.3 times as likely to develop phacomorphic glaucoma compared with eyes with longer than average axial length which they have taken as 23.7 mm for patient of Chinese ethnicity.Lack of biometric data relating axial length distribution among local population has limited our study more so with the possible variation within the same ethnicity and also within a population based on differences in age, gender, refraction error and corneal curvatures. Axial length has been a significant predictor for various forms of glaucoma but such significance is not established for phacomorphic glaucoma which can be seen in narrow angles and open angles both.24For unknown reason, our study have found that female 37 (56.9%) predominate male 28 (43.1%); a similar finding by Ramakrishanan R et al where they have found female to male ratio of 2.41:1 in there study.2 = 0.5). In the third month postoperative follow-up, 83.02% achieving good visual acuity in presentation <10 days of onset, 3.07% of those presented after 10 days could achieve BCVA 6/12 or better. Of the total 7 (10.77%) patients had poor visual recovery of <3/60 with glaucomatous optic changes have been found in one eye, cystoid changes in macula in two eyes, pre-existing diabetic retinopathy in one eye and posterior capsular opacification in three eyes which subsequently under went laser treatment.The final visual acuity was better in those groups which had shorter duration between the onset of symptoms and surgery  mm Hg. In all the cases the IOP was controlled without the need of long-term antiglaucoma medications.Manual small incision cataract surgery is effective in controlling IOP and achieving good visual acuity with minimal complications in the management of phacomorphic glaucoma. MSICS being safe and inexpensive play a key role in checking the poor outreach program marker like phacomorphic glaucoma and allow better quality of life to this section of population which need early diagnosis and interventions."}
+{"text": "The number of adverse drug reactions (ADRs) has been significantly increased since the introduction of regional pharmacovigilance centers (RPVC) in Korea. We compared the reporting and clinical features of ADRs after starting the RPVC in a single tertiary hospital, and investigated the attitude and knowledge of ADR reporting and pharmacovigilance.ADR data were collected from April 2012 to November 2013 in Dong-A university hospital in which started the RPVC since February 2013. We compared the ADR data before and after starting the RPVC. A questionnaire survey was conducted in a total of 436 health care workers.The total number of reported ADRs increased from 420 to 1265. The most common ADR reporters were doctors (59.4%), followed by nurses (29.4%) which was significantly increased from 2012 (8.8%). The most common causative drugs were antibiotics (30.6%), followed by miscellaneous drugs (30.4%), and antituberculosis drugs (10%), and clinical manifestations of ADRs were cutaneous (41.9%), gastrointestinal (24.9%) and neurophsychiatric symptoms (18.5). The distribution of causative drugs and clinical manifestations were differed from those in 2012. Majority of the health care workers reported ADR reporting is necessary (98.9%) and is their obligation (96.3%), while only 38.1% have reported ADR.The number of reported ADRs significantly increased since the introduction of RPVC in a tertiary hospital. The causative drugs and clinical manifestations of ADRs changed. The ADR reporters diversified and they have the knowledge and responsibility to ADR reporting."}
+{"text": "Recently a large clinical trial showed that the use of 13-valent pneumococcal conjugate vaccine (PCV13) among immunocompetent individuals aged 65 years and over was safe and efficacious. The aim of this study was to assess the cost-effectiveness of vaccinating immunocompetent 65 year olds with PCV13 vaccine in England. England is a country with universal childhood pneumococcal conjugate vaccination programme in place  since 2006 and PCV13 since 2010), as well as a 23-valent pneumococcal polysaccharide (PPV23) vaccination programme targeting clinical risk-groups and those \u226565 years.A static cohort cost-effectiveness model was developed to follow a cohort of 65 year olds until death, which will be vaccinated in the autumn of 2016 with PCV13. Sensitivity analysis was performed to test the robustness of the results.The childhood vaccination programme with PCV7 has induced herd protection among older unvaccinated age groups, with a resultant low residual disease burden caused by PCV7 vaccine types. We show similar herd protection effects for the 6 additional serotypes included in PCV13, and project a new low post-introduction equilibrium of vaccine-type disease in 2018/19. Applying these incidence projections for both invasive disease and community-acquired pneumonia (CAP), and using recent measures of vaccine efficacy against these endpoints for \u226565 year olds, we estimate that vaccination of a cohort of immunocompetent 65 year olds with PCV13 would directly prevent 26 cases of IPD, 69 cases of CAP and 15 deaths. The associated cost-effectiveness ratio is \u00a3257,771 per QALY gained (using list price of \u00a349.10 per dose and \u00a37.51 administration costs) and is therefore considered not cost-effective. To obtain a cost-effective programme the price per dose would need to be negative. The results were sensitive to disease incidence, waning vaccine protection and case fatality rate; despite this, the overall conclusion was robust.Vaccinating immunocompetent individuals aged \u226565 years with PCV13 is efficacious. However the absolute incidence of vaccine-type disease will likely become very low due to wider benefits of the childhood PCV13 vaccination programme, such that a specific PCV13 vaccination programme targeting the immunocompetent elderly would not be cost-effective. Streptococcus pneumoniae is the single most common bacterial cause of CAP, with an estimated 5%-40% of cases caused by this pathogen [S. pneumoniae causes invasive disease (IPD) associated with a high mortality depending on age and risk-group [Community acquired pneumonia (CAP) causes a high disease burden among the aging population. The bacterium pathogen \u20133. Furthsk-group .Recently the results of a large clinical trial [clinical trial registration number NCT00744263] in the Netherlands showed that the 13-valent pneumococcal conjugate vaccine (PCV13) currently used in the childhood vaccination programme of many countries has an efficacy of 45.6% (95% CI 21.8%-62.5%) against vaccine-type CAP and 75% (95% CI 41.4%-90.8%) against IPD among those aged 65 years and older  that PCV13 will not be universally recommended for those aged 65 years and over in England. This in contrast to the United States where PCV13 is recommended among adults aged \u2265 65 years . The JCVFuture research should focus on continued monitoring of the circulating vaccine-types. Should the projected declines in IPD and CAP incidence for the 6 additional serotypes in PCV13 are markedly different from the declines in disease due to the 7 serotypes in PCV7, revision of the above conclusions would be warranted.S1 Appendix(DOCX)Click here for additional data file.S2 Appendix(DOCX)Click here for additional data file.S3 Appendix(DOCX)Click here for additional data file."}
+{"text": "Campylobacter spp. (77%) and by nonpasteurized milk purchased from states in which nonpasteurized milk sale was legal (81%). Regulations to prevent distribution of nonpasteurized milk should be enforced.The number of US outbreaks caused by nonpasteurized milk increased from 30 during 2007\u20132009 to 51 during 2010\u20132012. Most outbreaks were caused by  Pasteurization is an effective way to improve milk safety; however, in the United States, illness related to consumption of nonpasteurized milk continues to be a public health problem. The first statewide requirements that dairy products be pasteurized were enacted in Michigan in 1948 . We reviewed outbreaks reported during 2007\u20132012 in which the food vehicle was nonpasteurized milk. Outbreaks attributed to consumption of other dairy products made with nonpasteurized milk, such as cheese, were excluded. We analyzed outbreak frequency, number of illnesses, outcomes , pathogens, and age groups of patients. Data on the legal status of nonpasteurized milk sales in each state were obtained from the National Association of State Departments of Agriculture  outbreaks, followed by Shiga toxin\u2013producing E. coli (13 [17%]), Salmonellaenterica serotype Typhimurium (2 [3%]), and Coxiella burnetii (1[1%])  . Three o (1[1%]) . The num010\u20132012 .Salmonella and 28% of illnesses caused by Shiga toxin\u2013producing E. coli were in children 1\u20134 years of age (Information about the age of patients was available for 78 outbreaks . For 59%s of age .How milk was obtained was reported for 68 (84%) outbreaks. Nonpasteurized milk was obtained from dairy farms (48 [71%] outbreaks), licensed or commercial milk sellers (9 [13%]), cow- or herd-share arrangements (8 [12%]), and other sources (3 [4%]) . Of the Campylobacter spp. nearly doubled. The average number of outbreaks associated with nonpasteurized milk was 4-fold higher during this 6-year period (average 13.5 outbreaks/year) than that reported in a review of outbreaks during 1993\u20132006 (3.3 outbreaks/year) . Public health officials should continue to educate legislators and consumers about the dangers associated with consuming nonpasteurized milk; additional information can be obtained at"}
+{"text": "The Acumulated Surveillance Rate at 20 years based on LT Indication: 70% in Fulminant Hepatic Failure group, 50% in the Alcoholic Cirrhosis group and 35% in Hepatitis C Virus Cirrhosis. In Re-transplantation group, Acumulated Surveillance Rate at five years (2008-2013) is just 23%.809 LT cases, 12 of which were Hepatorenal Transplantations, 3 required a Re-Transplantation. Media of LT: 36 LT/year. Gender: 79.35% were Male and 20.64% Female with a Mean Age of 51 years old. Blood Group Predominancy: A positive (49%) followed by the group 0 positive (39%). The most frequent indication of TL was: Alcohol-related Cirrhosis (43%), followed by Idiopathic (43.01%) and Fulminant Hepatic Failure (6.18%). The most common indication for Re-Transplantation was Hepatic Artery Thrombosis (34%) followed by Primary Allograft Dysfunction (28.57%). Mortality at 20 years: 34.86%, the most frequent cause of Death was: Recurrence of Underlying Disease (28% with a 80% rate in Hepatitis C Virus Cirrhosis) followed by Bacterial/Fungal infections (20%). The Acumulated Surveillance Rate at 20 years is 47% in our series, higher in comparison with the overall data provided by RETH (37% using Kaplan-Meier Curve Alcohol-related Liver Disease, Hepatitis C Virus and Hepatocellular Carcinoma are the most frequent Indications of LT in the current Transplantation Program. Acumulated Sirveillance Rates are similar to the ones found in other Transplantation Programs. The main Cause of Death is Recurrence of the Underlying Disease, followed by Infectious and Cardiovascular Diseases. High Mortality Rates in Re-transplantation Group leads to a more careful selection of cases."}
+{"text": "We sought to evaluate the effect of application of the revised 2010 Task Force Criteria (TFC) on the prevalence of major and minor MRI (Magnetic Resonance Imaging) criteria for Arrythmogenic Right Ventricular Cardiomyopathy (ARVC) versus application of the original 1994 TFC. We also assessed the utility of MRI to identify alternative diagnoses for patients referred for ARVC evaluation.Nine-hundred-sixty-eight consecutive patients, referred to our institution for cardiac magnetic resonance imaging (CMR) with clinical suspicion of ARVC from 1995 to 2010, were evaluated for the presence of major and minor CMR criteria per the 1994 and 2010 ARVC TFC. MRI criteria included right ventricle (RV) dilatation, reduced RV ejection fraction, RV aneurysm, or regional RV wall motion abnormalities. Quantitative and qualitative RV measures of end diastolic volume (RVEDV) and RV ejection fraction (RVEF) were available in 45% and 85% of cases, respectively.Of 968 patients, 220 (22.7%) fulfilled either a major or a minor 1994 TFC, and 25 (2.6%) fulfilled any of the 2010 TFC criterion. Among patients meeting any 1994 criteria, only 25 (11.4%) met at least one 2010 criterion. All patients who fulfilled a 2010 criteria also satisfied at least one 1994 criterion. Per the 2010 TFC, 21 (2.2%) patients met a major criteria and 4 (0.4%) patients fulfilled at least one minor criterion. Eight patients meeting 1994 minor criteria were reclassified as satisfying 2010 major criteria, while 4 patients fulfilling 1994 major criteria were reclassified to only minor or no criteria under the 2010 TFC. Eighty-nine (9.2%) patients had alternative cardiac diagnoses, including 43 (4.4%) with clinically significant potential ARVC mimics. These included cardiac sarcoidosis, RV volume overload conditions , and other cardiomyopathies.Application of the 2010 TFC resulted in reduction of total patients meeting any diagnostic MRI criteria for ARVC from 22.7% to 2.5% versus the 1994 TFC. The inclusion of myocardial fat would not have changed the diagnosis in any patients. CMR identified alternative cardiac diagnoses in 9.2% of patients, and 4.4% of the diagnoses were potential mimics of ARVC.None."}
+{"text": "Carbapenem resistant gram negatives (CRGN) have emerged in intensive care units (ICUs) worldwide.The aim of this study was to identify the incidence of gut colonization by CRGN, risk factors, evaluation of colonized patients for nosocomial infection.Patients (>15 years) admitted to Medical and Anesthesiology ICUs and stayed >48 hours were screened for rectal colonization by CRGN for eighth months. Rectal swab was obtained from each patient weekly and swabbed on selective CHROMagar TMKPC. Any bacterial colony isolated from the selective media was Gram stained and then species identification was performed by API20E/20NE. Patients colonized on admission were excluded. Study population was followed up for CRGN infection during their stay.Acinetobacter baumannii (73-49%), Pseudomonas aeruginosa (32-21%), Klebsiella pneumoniae (26-17%), Enterobacter cloacae (6-4%) and other CRGN (13-9%).The median time for colonization was 11 (3-55) days. In multivariate analysis, the most significant risk factors for colonization were; length of stay in ICUs, respiratory failure, intubation, use of steroids, transfusion, central venous catheterization and use of colistin. Forty seven nosocomial infection episode with CRGN were detected in 36 (38%) colonized patients and the same pathogen was detected in 37 (78%) episodes. In 24 (66.7%) patients, colonization was detected before the onset of nosocomial infection. On the other hand, seven nosocomial infection episode with CRGN was detected in 5 (2%) non-colonized patient (p<0.05).During the study period, 945 patients admitted to ICUs; however 419 patients stayed less than 48 hours and 195 patients were colonized by CRGN on admission. 331 patients enrolled into the study. The median age was 66 (16-98) and 50.5% was female. Rectal colonization was detected in 95 (29%) patients and 150 CRGN bacteria were identified. These microorganisms were; Colonization with CRGN bacteria is an emerging problem in ICUs and is a significant risk factor for the development of nosocomial infections. Rectal screening of high risk ICU patients is needed for infection control and appropriate consideration of empirical treatment in severe ICU patients.None declared."}
+{"text": "Non-Hodgkin\u2032s lymphomas (NHLs) are heterogeneous group of malignant lymphoproliferative disorders.This was a retrospective study aimed to classify NHLs into B cell and T cell types; in addition to demonstrate the histological patterns and correlate it with gender, age and site of the biopsy.The study was conducted in Histopathology Department, National Heath Laboratory, during the period 2007-2010. Formalin fixed paraffin wax embedded tissue blocks which were diagnosed as NHLs by routine Haematoxylin and Eosin (H&E) stain during the period 2000-2008 were used. Haematoxylin and Eosin (H&E) stain were done. Immunohistochemistry stains performed according to Dako cytomation protocol 2007. Lymphoid markers which were used in this study are CD45 (LCA), CD20 (B cell marker), CD3 (T cell marker), CD15 and CD 30. Epithelial marker which was used is CK MNF116. The total number of samples collected was 66; two of them were excluded because of poor processing. Another two specimens were excluded because they are non-reactive with lymphoid markers. The remaining 62 specimens were confirmed to be NHLs and classified into B cell and T cell types.The study showed that B cell NHLs represented 87.1% while T cell NHLs were 12.9%. The Male: Female ratio was 1.6:1. The major affected age group was (47-67) years . The most frequent histological grade was intermediate grade NHLs . The most common site of NHLs in this study is the lymph node  followed by stomach (19.4%).Extranodal locations are the most common sites affected with T cell NHLs. In conclusion; this study confirmed the fundamental role of immunohistochemistry in diagnosis and classification of NHLs. Malignant lymphoma is a primary malignant neoplasm of lymphoid tissue arising from the expansion of malignantly transformed lymphocytes, which may contain one or more genetic abnormalities . It is dThe etiologic factors of NHLs included genetic alterations, weak immune system, certain drugs after an organ transplant, and certain infectious agents such as Helicobacter pylori, HIV, Human T-cell leukemia/lymphoma virus type 1, Hepatitis C virus and Epstein-Barr virus (EBV) , 3. SurvIn Sudan, little work has been done concerning NHLs. In Soba Teaching Hospital during the period 1979-1989 they found that there were 1205 patients with malignancy, 51 patients of them with NHLs . The male-female ratio was 4.1:1, the age of patients ranged between few months to 90 years old, and the age group (40-70) years show higher frequency of NHLs .The incidence of extra nodal NHLs is increasing worldwide. The evaluation of cases of NHLs in Kuwait between 1998 and 2003 according to the site of presentation and their classification in to primary nodal and extra nodal revealed that there were 422 cases of NHLs diagnosed at this period, among which 97 cases (23%) were primary nodal, 132 cases (31%) were early nodal, and 193 (46%) were disseminated primary nodal. In general, there was a male prevalence of primary nodal cases (63%). The most common histological subtype among extra nodal cases was diffuse large cell lymphoma which accounted 71%. The most common anatomic site involved was gastrointestinal tract, which accounted 45% of all cases [T cell non-Hodgkin\u2032s lymphoma represents approximately 10-15% of all lymphomas diagnosed in western countries. Varied geographic frequency of T cell NHLs has been documented ranging from 18.3% of NHLs in Hong Kong to 1.5% of NHLs in Vancouver. This may in part be a reflection of increased exposure to pathologic factors such as Human T cell leukemia virus-1 and Epstein-Barr virus in Asian nations. T cell NHLs commonly present with extra nodal sites .In Pakistan a retrospective study reviewed 557 cases of diffuse large B cell NHLs from 1988 to 2004. The median age was 48.7 + /-15.3 years, M: F ratio was 2:1. The distribution according to the primary site was lymph node 322 cases (58%), extra nodal site 325 cases (42%) including gastrointestinal tract 63%, bones 8%, spine 5%, and unusual sites less than 3% . In GreeIn southeast Turkey retrospective analysis carried out on 490 cases of NHLs, with the purpose of evaluating the clinico-pathologic features of these patients. The patients were assessed with regard to their characteristics including age, gender, and histological distribution, stage, extra nodal involvement, presenting symptoms, and biopsied site. Of the patients 314 (64%) were males and 176 (36%) were females. The overall median age was 43 years (ranged: 14-90 years). The patients were classified according to the Working Formulation (WF) system: 71 (14.4%) were low grade, 342 (69.8%) were intermediate grade, 43 (8.7%) were high grade, 34 (6.7%) had other lymphomas. 320 cases of intermediate grade NHL reveled that 78% were B cell lymphoma, whereas 16% were T cell lymphoma and 6% were unclassified lymphoma. Extra nodal involvement was found in 218 (44.5%) patients. The most common affected sites were small bowel, stomach, and tonsil 72 (33%), 63 (29%), and 19 (8.7%) respectively .Fifty three cases of NHLs were studied in India. Of these, seven cases with primary extra nodal lymphomas. A detailed morphological assessment was done and classified using the international working formulation. The two most common types encountered were diffuse large cells lymphoma and small lymphocytic lymphoma. Immunohistochemistry was done and revealed thirty eight (72%) showed B cell expression and 12 cases (22.5%) showed T cells expression. Three cases did not express either marker. B cell diffuse large cell lymphoma (26%) was found to be predominant B cell NHL. The commonest T cell lymphoma was T cell lymphoblastic lymphoma (67%) .NHLs are common neoplasm in Middle East. The extra nodal forms are apparently far more frequent there than in the west. In addition, a peculiar form of primary intestinal lymphoma, namely proliferative small intestinal disease, has been described in Middle Eastern and Mediterranean countries. Several reports indicate high incidence of NHLs in Turkey, for 4 years 185 patients with NHL were in Cukurova University hospital. This constituted 13% of all malignant neoplasm diagnosed in oncology clinic, the mean age for men was 45.5years and 41 years for women. 54% of these cases were nodal lymphoma and the remaining 46% were extra nodal lymphoma, the stomach was the most common localization (43%) followed by the intestinal involvement (30%) and the abdominal mass (27%) .In Japan Waldyey-er's ring lymphomas is common and comprises about 10-20% of all lymphomas. In contrast, in USA the frequency of involvement of Waldyey-er's ring lymphoma has been reported to be about 7-10%. It should be included in nodal or extra- nodal lymphomas. It will be very difficult to conclude the argument now; however, it is quite clear that W-NHL has unique clinical features different from those other nodal or extra-nodal lymphoma.One hundred and four unselected cases of NHLs in adult Chinese patients in Hong Kong were typed, using monoclonal and conventional antibodies, by immuno-enzymetic labeling methods on cryostat sections or cell smears. The total included 69 cases (66%) of B cell and 26 cases (25%) of T-cell. The diffuse large cell (centroblastic or immunoblastic) types formed the largest proportion 45% of B cell NHLs. Of 26 cases of T cell lymphoma 25 were peripheral type; of these 25, the most frequent subtype (42.3%) is immunoblastic lymphadenopathy-like lesion. The incidence of T cell lymphoma in china is not markedly higher than that of western countries . PrimaryA retrospective study was conducted on extra nodal NHLs diagnosed at the surgical pathology laboratory at Buenos Aires University, in Argentina between1985 and 2004. Overall mean age of the patient was 49.4 and the frequency was greater in males. All cases were B cell phenotype with a higher frequency of high grade lymphomas [A histological study of adult lymphoma was conducted in Lagos aimed to document the histologic types, age and sex distribution. The male and female accounted for 64% and 36% giving M: F ratio1.8:1. The most frequent site was cervical lymph node. The age group (46-55) accounted about 65% of patient of NHLs. Intermediate grade, high grade and low grade variants of NHL accounted for 39%, 34%, and 27% .There is a wide variation in the prevalence of various subtypes of NHLs worldwide. During the period 1998 to 2006 the prevalence of different subtypes of NHLs were determined based on age, sex, site of disease and ethnicity in Kuwait. The ethnicity group comprised Kuwaiti Arab, non Kuwaiti Arab, Asians and others. The prevalence of B and T cell NHL was 81.8% and 14.2%, retrospectively. The most common age group was (41-60) years old. The most common subtypes in Kuwaiti Arabs were diffuse large B cell lymphoma (45.5%), follicular lymphoma (15.5%) and mycosis fungioides (9.3%). In non Kuwaiti Arabs, the most common subtypes were diffuse large B cell lymphoma (48%), B cell small lymphocytic lymphoma (15.8%) and follicular lymphoma (12.7%). Overall non Kuwaiti Arabs exhibited the highest prevalence (59%) and 54% cases had extra nodal presentation .Bone morrow biopsy is an integral part of staging work-up for non-Hodgkin\u2032s lymphomas. Characteristic of bone morrow involvement in NHLs with respect to incidence, histological pattern and morphology of infiltration and its discordance with the history of primary anatomic site revealed that the involvement of bone morrow by lymphoma showed to be 27 cases 55.1%. The incidence of involvement was higher in T cell when compared with B cell NHL .Extra-nodal NHLs preferentially involve the skin. Among them, 65% are T cell NHLs, 25% B cell. Mycosis fungoides is the most common form of low grade malignant peripheral cutaneous T cell lymphomas. Lymphomas originated from follicular center cells are the most common type of cutaneous B cell lymphoma. The prognosis is good, since the average survival time from diagnosis is 12-14 years. Primary malignant lymphoma of skin accounted about 1-3.5% of all NHLs in children. It has been suggested that these lymphomas represent a unique entity occurring in younger age than usually expected in children with NHLs .Primary cardiac lymphoma is defined as NHL mainly located in heart and/or the pericardium. It is rare and affects the elderly men. Common manifestations are pericardial effusion and heart failure. The diagnosis is usually late and prognosis is poor. This study aim to Classify NHLs by using immunohistochemistry into B-cell and T-cell, demonstrate histological patterns of NHLs and to correlate histopathology of NHLs with age, gender and the site of biopsy.Study design: This is a retrospective study aimed to review cases reported as Non\u2013Hodgkin\u2032s lymphomas by routine histopathology stain Haematoxylin &Eosin (H&E). The diagnosis was confirmed and classified them into B-cell and T-cell NHLs by using ImmunohistochemistryStudy area: The study was conducted in department of histopathology in National Heath Laboratory in Khartoum during the period 2007-2010. In this period of time the national health laboratory received specimens from the entire parts of SudanStudy sample: Formalin fixed, paraffin wax embedded tissue blocks from lymph node or extra nodal locations were used.Sample size: All samples reported as Non-Hodgkin\u2032s lymphoma during the period 2000-2008 were included in the study. The total number of sample was 66 samples.From each formalin fixed paraffin wax embedded block three microns sections were cut by rotary microtome and then placed on slide which was labeled by laboratory number of the block; for routine histological stain(Haematoxylin& Eosin) as described by Mayer, 1903, clean, grease-free slides were used while commercial silanized slides provide by(Dako Cytomation 2007), with labeled of marker were used for immunohistochemistry stain. Both type of slides incubated in oven at 60C for 1 hour. Take sections to Distilled water: placed them in Xylene (5mins) 2 changes to remove wax hydrated through absolute ethyl alcohol (5mins) and then 90% ethanol alcohol (5mins) and then 70% ethanol alcohol (5mins) and placed in Distilled Water (D.W).Data analysis: The data obtained from this study analyzed and interpreted by SPSSSixty six paraffin blocks were collected retrospectively from archive of Histopathology Department in National Health Laboratory. These specimens were previously diagnosed as Non-Hodgkin's Lymphomas (NHLs) using routine H&E stain. Two samples were excluded for their inadequate processing which were not suitable for performing immunohistochemistry stain. After use of immunohistochemistry another two samples were excluded because of their positivity for Cytokeratin  and their non-reactivity for lymphoid marker LCA (Leukocyte Common Antigen). The study was performed in 62 specimens. The specimens were reviewed and the diagnosis were confirmed as NHLs then classified into B cell and T cell types using immunohistochemistry. Both sexes were included in this study, males constituted 38 cases (61.3%) while females were 24 cases (38.7%). Male: female ratio is 1.6:1. The ages of the study ranged from 5 years to 87 years. The mean age was 47 years. The age group (47-67) years showed higher incidence of NHLs, comprising 24 cases (38.7%). The age group (26-46) years showed the lowest incidence of NHLs, comprising 8 cases (12.9%). The sites of biopsies were as follow 25 cases (40.3%) lymph nodes followed by 12 cases (19.4%) stomach; while other sites of biopsy were 25 cases (40.3%). The most frequent type of lymph node in this study was the cervical lymph node which represents 9 cases (14.5%) of all site of specimens . The othThe distribution of histological patterns into B cell and T cell NHLs revealed higher incidence of B cell in all histological patterns compared to T cell NHLs.Non-Hodgkin\u2032s lymphomas (NHLs) are heterogeneous group of malignant lymphoproliferative disorders. This study showed that B cell NHLs represent 87.1% while T cell NHLs were 12.9%. This high percentage of B cell NHLs was long-established by Ameen R et al. Their results showed that B cell NHLs were 81.8% and T cell NHLs were 14.2% . These fAndrew M et al found in Hong Kong 1.5% of patient with NHLs were T cell type. This low incidence of T cell NHLs may be due to the reported varied geographic frequency of T cell NHLs in China . The stuThe study concluded the fundamental role of Immunohistochemistry stain in diagnosis and classification of NHLs into B cell and T cell. Also, the B cell NHLs constitutes the predominant immunophenotype. In addition, the age group (47-67) years was the most affected group with NHLs, and the lymph nodes were the most common site of biopsy affected by B cell NHLs. Further, extranodal locations were the most frequent sites of biopsy affected with T cell NHLs."}
+{"text": "Juvenile arthritis (JIA) is chronic potentially disabling disease, which may form certain psychological features in childrenThe purpose is to reveal difference in psychological status of children depending on the clinical type of JIA.clinical interview; L\u00fcscher 8-color test; Spielberger-Khanin test; CMAS (A. Prikhozhan adaptation); family drawing test; non-existent animal test, house tree man test; pathodiagnostic testA tendency for higher level of personal anxiety is found in patients with oJA (33.3%), to a lesser extent in patients with pJA (20.7%) and sJA (17.6%). The patients have low social adaptation  and signs of school stress . Cognitive disorders  and aggression  are more frequent in patients with JA. Communicative disorders are equally usual in patients with sJA (35.3%) and pJA (32%) and found in 22.2% of patients with oJA. Dissatisfaction with appearance is more frequent in patients with sJA (11.8%) and oJA (11.1%) than in patients with pJA (7.5%). Chronic low mood slightly prevails in patients with pJA (13.2%) over sJA  and occurs in 5.5% of patients with oJA. Different neurotic fears are found with virtually the same frequency in patients with pJA (28.3%) and oJA (27.8%) and also in 5.9% of patients with sJA. Domestic stress is equally felt by patients with all JA types . Hospital adaptation is harder for patients with oJA (5.5%) and pJA (3.8%) than for patients with sJA (0%).Children with different types of JIA have been found to have certain differences in psychological status. Chronic low mood is more frequent in patients with pJA than in case of other types of the disease. Cognitive disorders and aggression are more frequent in patients with sJA. Patients with oJA are characterized by more frequent symptoms of personal anxiety, low social adaptation and school stress. Domestic stress indicators can be noted in patients with all types of JIA. Clinical psychological status of patients with JIA needs further study with larger material to reveal stable tendencies and develop psychocorrective programs.None declared."}
+{"text": "The early identification of severe sepsis and septic shock and early implementation of the SSC bundles were associated with reduced mortality . The fain = 274) and nonsurvivors (n = 261).We analyzed 535 consecutive patients with septic shock (sepsis-induced hypotension persisting despite adequate fluid resuscitation) from the EPOSS database , which was developed to monitor and assess treatment efficacy in patient with severe sepsis and septic shock. Patients were admitted to participating ICUs  in the Czech Republic from 1 January 2011 to 5 November 2013. Patients were divided into two groups: survivors  versus 160 (62.0%) P = 0.376, APACHE II score 27 (15 to 40) versus 28 (15 to 40) P = 0.737. Statistically significant differences between survivors versus nonsurvivors were found in the parameter 'Consensus initial antimicrobial therapy with microbial cultures' 178 (79.5%) versus 128 (58.4%) P < 0.001 and in the parameter 'Administration antimicrobials within the first hour' 163 (59.9%) versus 171 (70.7%) P = 0.001. Administration of 30 ml/kg crystalloid for hypotension or lactate 4 mmol/l (3 hours) and application of vasopressors (6 hours) were in both groups without statistically significant differences.Survivors versus nonsurvivors were similar in: age 65.8  versus 66.5  We found that correct choice of antibiotics improves outcome of septic shock patients. The choice of empirical antimicrobial therapy depends on complex factors related to the underlying disease, susceptibility of pathogens, patient's history and clinical syndrome. Adequate initial antimicrobial therapy as an important factor of survival along with suitable initial fluid resuscitation and application of vasopressors should be a priority for healthcare in human septic shock."}
+{"text": "Enthesitis related arthritis (ERA) is a chronic inflammatory disorder primarily affecting the axial skeleton as well as peripheral joints and entheses. DMARD's are succesful in controling peripheral disease; however their effectiveness is diminished when axial inflammation is present. The use of anti tnf\u03b1 medications in adult patients with ankylosing spondylitis is well documented. Nevertheless, data regarding their use in children with the juvenile spondylarthritis(jspa) are missing.To assess the efficacy and safety of adalimumab, a fully humanized anti-tnf\u03b1 monoclonal antibody, as monotherapy in jspa/ERA.16 patients  who met the EULAR criteria for ERA and the ASAS criteria for AS were enrolled. Following NSAID treatment failure, the patients received 24 mg/m2 of adalimumab subcutaneously every 14 days for 12 months. Patients had MRI proven sacroilitis, inflammatory lumbar pain(ILP) and were HLA-B27 positive. Outcome measures were presence of morning stiffness, duration of morning stiffness, CRP measurement, pain assessment  and physician assessment (based on 10 cm VAS). Mean time from diagnosis to initiation of treatment was 4 months (range 3-7 months), while from the onset of symptoms till the beginning treatment mean time was 12 months (range 5-28 months). Patients were reviewed at 3, 6, 9 and 12 months following initiation of treatment and had repeat MRI scans at 3 and 9 months.At the beginning of the study all patients had ILP (mean pain VAS:6.8 cm), morning stiffness with a mean duration of 75 min and positive MRI findings. Mean physician VAS was 4.6 cm and mean CRP was 69 mg/dl(range: 25-102 mg/dl). At three months the mean CRP was 18 mg/dl, physician VAS was 1.9 cm, pain VAS 1.6 cm; morning stiffness improved by 80% and 57% of patients showed improved MRI findings. Reassessment at 6 months showed improvement of morning stiffness (18%) and its duration(9 min) as well as further improvement in mean physician VAS(1.2 cm) and pain VAS(1 cm). At 9 months mild further reduction in the prevalence(13%) and duration of morning stiffness(7 min) and improvement in physician VAS(0.5 cm) and pain VAS(0.7 cm) was recorded. Mean CRP was 9 mg/dl. 19% of patients showed persistent although improved MRI findings. The majority of these children had bilateral sacroilitis in the beginning of the study. At 12 months 8% had morning stiffness, and its mean duration was unchanged(7 min). Mean pain and physician VAS values were similar to those at nine months  Mild-moderate adverse reactions were seen in 37%.This is a novel study in the pediatric population showing that adalimumab monotherapy in early stages of jspa/ERA is effective and safe. Adalimumab leads to early remission as defined by reduction of pain and stiffness. Overall, patient improvement is gradual and sustained. No further improvement was noted beyond 9 months of treatment. MRI findings show slower improvement; however 19% of patients had radiological evidence of inflammation at nine months. More studies are required to prove its long term benefit and safety.None declared."}
+{"text": "HIV testing opportunities in Italy are frequently limited to the hospital setting. Experiences in other countries show that offering HIV testing in other facilities could improve HIV testing uptake.An internet-based survey was conducted between March 10 and April 3, 2014.A total number of 348 questionnaires were collected. Responders were 88% male. Most represented age groups were 25\u201334 (35%) and 35\u201344 (25%). Most of the responders identify themselves as homosexual (81%) or bisexual (9%). Half of responders had an HIV test within 2 years (56%) while 18% never tested for HIV. Among all responders, 61% had more than 2 sexual partners in the past year. Reported condom use in the past year was: always 39%, always but once 11%, sometimes 27%, never 14%. Most known places to have an HIV test is the hospital (95%), STI clinic (58%) and chemical analysis laboratory (54%); most used places are hospital (73%), STI clinic (30%), laboratory (22%) while 5 responders reported having had a self-test at home. Preferred places where to have an HIV test is self-testing at home (53%), hospital (36%), pharmacy (32%) and headquarter of an organization (31%). Most known testing method is draw blood from vein (97%), which is also most used (80%) but the least preferred (31%) while saliva (65%) and finger prick (56%) are the preferred choices. Most responders know that physicians (84%) and nurses (77%) are those who perform HIV tests and most of them had an HIV test with them (60% and 65% respectively). Physicians are the preferred operators (54%) followed by self-testing (46%), nurses (46%) and peer-volunteers (39%). The ideal HIV test should be: reliable (86%), with no medical prescription (75%), free (63%), rapid (55%), with no personal information collected (45%), with the opportunity to speak with a peer-counsellor (36%).Changing HIV testing policies in Italy is urgently needed in order to grant a better access to the service: waiting for the results and bureaucratic obligations represent the major barriers to be removed. Home-testing and community-based testing seem to be among the best ways to offer new opportunities though they may require a change in the legal, social and cultural context to be implemented and home testing will not allow any kind of support for newly diagnosed people."}
+{"text": "In France, influenza vaccination coverage remains poor among healthcare workers (HCWs) despite annual vaccination campaigns in healthcare institutions.To evaluate the influenza vaccination coverage in HCWs in Northern France and to describe information and vaccination campaigns.A descriptive study was performed in healthcare institutions during February 2015. An online questionnaire was sent to the Infection Control Teams (ICT). They were asked to indicate their influenza vaccination coverage and the institutional means used to inform and vaccinate HCWs against influenza.A total of 259 healthcare institutions (35%) answered. The overall influenza vaccination coverage for medical and non-medical staff reported during winter 2014-2015 was 19.7% [14.5-25.1] (n=219). The coverage was 36.3% (n=159) among doctors and midwives and 19.9% (n=169) among nurses and assistant nurses.An information campaign was organized in 96% of healthcare institutions. Different communication mediums were used such as posters (76%), information on the hospital website (31%), individual e-mail (29%) or letter (23%), specific meetings (27%). The majority of healthcare institutions used 1 or 2 mediums (67%) whereas one third used 3 or more.A vaccination campaign was organized in 98% of healthcare institutions. It was mostly led by the Occupational health Team (OHT) (39%) and/or the ICT (48%), but also by others (36%) such as the hospital pharmacy and the administration. The HCWs could be vaccinated directly by their colleagues (57%), the OHT (51%), a designated mobile team of HCWs (16%) and/or the ICT (9%). In 14% of cases, other options were implemented. The majority (62%) of healthcare institutions used one mean of vaccination, whereas 30% used 2 and only 8% used 3 or more. The night staff had access to vaccination means in 66% of healthcare institutions organizing campaigns.The influenza vaccination coverage is consistent with those previously reported in France and other countries. Despite most of the healthcare institutions organizing information and vaccination campaigns, it is far from the 75% recommended by the French health authority. Efforts should be made to enhance the vaccination coverage in order to prevent healthcare-associated influenza.None declared."}
+{"text": "Vigna unguiculata [L.] Walp.) yields are considerably low in Namibia due to lack of improved varieties and biotic and abiotic stresses, notably, recurrent drought. Thus, genetic improvement in cowpea aims to develop cultivars with improved grain yield and tolerance to abiotic and biotic stress factors. The objective of this study was to identify agronomically desirable cowpea genotypes after mutagenesis using gamma irradiation. Seeds of three traditional cowpea varieties widely grown in Namibia including Nakare (IT81D-985), Shindimba (IT89KD-245-1), and Bira (IT87D-453-2) were gamma irradiated with varied doses and desirable mutants were selected from M2 through M6 generations. Substantial genetic variability was detected among cowpea genotypes after mutagenesis across generations including in flowering ability, maturity, flower and seed colors and grain yields. Ten phenotypically and agronomically stable novel mutants were isolated at the M6 each from the genetic background of the above three varieties. The selected promising mutants\u2019 lines are recommended for adaptability and stability tests across representative agro-ecologies for large-scale production or breeding in Namibia or similar environments. The novel cowpea genotypes selected through the study are valuable genetic resources for genetic enhancement and breeding.Cowpea ( Vigna unguiculata L. Walp.) is a leguminous species used as food, forage, and vegetable crop mainly in the tropics  derived through gamma irradiation.In South Africa, cowpea mutants were developed through selections from the Mnditions . Furthernditions . The usenditions . Some vanditions . Wani , Shindimba (IT89KD-245-1), and Bira (IT87D-453-2) through continuous selections from MThree cowpea genotypes widely grown in Namibia, namely, Nakare (IT81D-985), Shindimba (IT89KD-245-1) and Bira (IT87D-453-2) were obtained from Likorerere Farmers Co-operatives at Kavango Region, Namibia. The seeds were irradiated at the International Atomic Energy Agency (IAEA), Agriculture and Biotechnology Laboratory, A-2444 Seibersdorf, Austria using a CO60 source Gammacell Model No. 220. Various doses were used to establish the optimum irradiation level that can achieve optimum mutation frequency with least possible and unintended damage. The three varieties were gamma irradiated as follows: Bira , Nakare  and Shindimba . Preliminary tests showed that the three varieties differed in their optimal requirement of irradiation doses and was used as the bases for using different doses for each genotype . The 0 GTable 1. The M1 and M2 generations were evaluated at Mannheim Research Station during the 2009/2010 and 2010/2011 seasons, respectively. The M3 generations were established at Bagani research station during the 2011/2012 season. The M4 and M5 were established at Omahenene Research Station in 2012/2013 and 2013/2014 season, respectively.A series of selection experiments were conducted at three different sites; namely Mannheim, Bagani, and Omahenene. Mannheim Research Station is located in Oshikoto region along the north central of Namibia and it is situated at an altitude of 1234 m above sea level (masl). Bagani Research Station is located at (1007 masl) north east in the Kavango East region, whereas Omahenene research station is situated in the Omusati Region in North-Western Namibia at altitude of 1109 masl. In general, climatic, biological conditions of the selection sites vary considerably. Physicochemical properties of the sites are provided in 1 seeds was done under normal growing conditions with supplemental irrigation during dry spell. Each row of the M1 generation contained 26 individuals, making a total of 104 plants per irradiation dose. At harvest the M2 seeds were bulked in separate bags according to irradiation doses . During the M2 to M5 generations\u2019 variable number of individual plants ranging from 50 to 100 per irradiation dose were assayed for qualitative and quantitative observations.Plots were arranged in a randomized complete block design using two replications. Plants were established using intra-row spacing of 20 cm and inter-row spacing of 75 cm. Seedlings were thinned to one plant per hill after 2 weeks from planting. Weeds were controlled manually. Planting of the MFigure 1. The irradiated seeds (M1) were planted in the field at Mannheim research station under standard cultural practices. All the pods, from the M1 plants that survived were harvested and bulked according to their respective radiation doses and genotypes. Consequently, the harvested M2 seeds were planted in the field at Mannheim as M2 population during 2010/2011 season in the form of progeny rows for individual plant selection and to develop the M3 seeds. The M3 seed from selected M2 plants were planted at Omahenene and Bagani Research Station during 2011/2012 for evaluation. The M3 plants at both sites were evaluated in the field using morphological and agronomical attributes. Pods from selected M3 plants were harvested. During 2012/2013, the M4 seeds obtained from the selected M3 population were planted at Omahenene Research Station as single-plant progenies and segregants were selected with desired traits. During 2013/2014 the M5 seeds obtained from the selected M4 population were planted at Omahenene Research Station as single-plant progenies and selection were made toward desired trait on single plant basis. Uniform, non-segregating mutant progenies, were bulked at this stage to hasten the breeding cycle. During 2014/2015 the M6 generation was evaluated at Omahenene, Bagani, and Mannheim using suitable lines selected for seed yield and related traits.The selection procedure was undertaken based on methods adapted from 2 to M5 generations. The data collected included: days to 50% germination (DG), percent seed emergence (ES%), number of abnormal individuals or visual phenotype mutants (ABN), total number of surviving plants per plot (TNP), number of main branches (NMB) averaged over 10 randomly selected and tagged plants, days to 50% flowering (DTF), days to 50% pod setting (DPS), days to 50% maturity(DMT), number of pods per plant (NPP) averaged over five pods per selected plant, pod length (PL) expressed in cm and averaged over five pods per plant, pod weight per plant (PW) in gram, number of seeds per pod (NSP) averaged over five pods per plant, 100 seed weight (HSW) in gram and SYP in gram. The qualitative data collected included variation in flower color (FC) and seed color (SC) during the M1 and M2 generations. Additional qualitative data such as, pod shape (PS), pod color (PC), seed coat texture (SCT), and growth habit (GH) were collected from M2 to M5 generations. Data were analyzed and descriptive statistics summarized using the SAS statistical program  ranged between 79 to 89%, respectively (Table 2). Nakare and Shindimba mutants had ES of 0% at irradiation does of 250, 300, and 400 Gy. Phenotypic abnormalities such as albinism, leaf deformity, single stem, seedless pods or short pod sizes were invariably observed at the following doses and genotypes: 450 and 600 Gy (Bira); 150 and 200 Gy (Nakare); and 100, 150, and 200 Gy (Shindimba) . Segregation of FC (white and purple) were observed at the M2 with the following doses and genotypes: 300, 450, and 600 Gy (Bira), 100 and 200 Gy (Nakare), and 100, 150, and 200 Gy (Shindimba) . SC variations were observed during the M2 . White, brown, red, and cream SC were common in Bira mutants across all irradiation doses. In addition to these Nakare and Shindimba had speckled, chocolate, light brown, black, mixed and dark brown SC when subjected to irradiation doses of 100, 150, and 200 Gy . Bira mutants displayed relatively high seed yields varying from 98 to 200 g/plant at 0 and 600 Gy, respectively (Table 2).During the M3 to M5 generations, because of the strength of irradiation treatment and segregation. The following doses allowed successful selections of mutants during the M3 to M5: 300, 450, and 600 Gy (Bira), 100 and 150 Gy (Nakare), and 100 and 200 Gy (Shindimba). Surviving and phenotypically stable individuals were advanced at each selection generation at Omahenene and Bagani Research Stations. Qualitative traits had limited variation during M3 to M5 (Table 3). Bira mutants displayed purple FC irrespective of doses and test generations, while Nakare and Shindimba segregated for white and purple FC . Both Bira and Nakare mutants had straight PS similar to the controls. However, Shindimba segregants had straight and coiled pod types . Variable SCs including white, brown, red, cream, speckled, chocolate, light and dark brown, black and mixed were observed during the M3 to M5. Bira mutants had smooth SCT, while Nakare and Shindimba had mainly rough and smooth seed texture. Bushy, erect and spreading GHs were detected during the M3 to M5 .Variable number of individual plants was available for selection during M3 to M5 (Table 4). The percent seed emrgence (ES%) reduced significantly with increased irradiation dose. Maximum seed germination was achieved 3 days after planting irrespective of irradiation doses (Tables 6). Shindimba mutants relatively flowered early (40 days) at the M3 (Table 4).Quantitative traits of agronomic importance were measured during the M4 a relatively shorter days to flowering (44 days) was recorded at 300 Gy (Table 5). Contrastingly, the number of days to flowering was 37 days at the M5 at using 600 Gy (Table 6). Nakare derived mutants flowered relatively earlier (10 days) at 100 Gy at the M3 (Table 4). At the M5 Nakare mutants recorded a minimum of 61 days to flowering at 0 and 150 Gy (Table 5). At the M3, Shindimba mutants displayed a minimum of 15 and a maximum of 84 days to flowering at 200 and 100 Gy, respectively (Table 4). Nakare mutants recorded the lower days (25) for pod setting (DPS) at the M3when using 100 Gy. Comparatively, the higher number of DPS (98 days) was measured in Shindimba at 200 Gy. At the M4 a minimum DPS of 48 days was recorded for Bira derivatives at 300 Gy. A maximum DPS of 86 days was recorded for Bira mutants at 400 Gy, Nakare at 100 and 150 Gy and Shindimba at 100 and 200 Gy (Table 5). At the M5, Nakare mutants recorded the lower DPS (41 days) at 100 Gy, while Bira genotypes had the higher DPS of 88 days at 300 Gy, Table 6). During the M3, Nakare mutants matured 32 days after planting at 100 Gy. At the same dose rate Shindimba displayed late maturity (98 days) at the M3 (Table 4). During the M4 Bira mutants matured earlier (54 days) at 450 Gy. Delayed maturity (115 days) were recorded for Nakare at 150 Gy and Shindimba at 100 and 200 Gy (Table 5). At the M5 Bira measured early maturity (62 days) with the highest dose of 600 Gy. Interestingly, this genotype matured late (115 days) when subjected to irradiation dose of 300 Gy (Table 6). Nevertheless, Bira recorded lower NPP (1 pod/plant) at 600 Gy and higher (5 pods/plant) when irradiated at 300 Gy (Table 4). At the M4, 1 pod/plant was recorded for Bira at 450 and 600 Gy and Shindimba at 200 Gy (Table 5).At the M3 the longer pod size measured at 23.5 cm was recorded for Nakare at 100 Gy (Table 4). At the M4, Shindimba mutants resulted from 200 Gy measured longer pod size of 31 cm (Table 5). Bira mutants induced with 300 Gy produced longer pod size (30 cm) (Table 6). Relatively heavier pod size (4003 g/plant) was recorded for Bira at 300 Gy (Table 4). At the M4, Bira had pod size measured at 325 g/plant at 300 Gy. Notably this genotype had reduced pod weight (1 g/plant) at the highest irradiation dose (Table 5).At the M3, the highest number of seeds of 18.6/pod was recorded for Bira at 600 Gy and Nakare 150 Gy (Table 4). At the M4 19 seeds/pod was achieved in the mutants of Bira at 600 Gy and Shindimba at 100 Gy. At the M5, mutants of Bira derived from 300 and 450 Gy and Nakare 150 Gy recorded 20 seeds/pod, the highest in this trial (Table 5). Hundred seed weight (HSW) at M3 was relatively heavier measured at 109 g for Nakare mutants derived from 150 Gy (Table 4). At the M4 the higher HSW (115 g) was recorded for Bira at 450 Gy (Table 5). During the M5 Bira displayed higher HSW of 171 g at 450 Gy (Table 6). High seed yield per plant is an economic trait for cowpea growers. At M3, higher seed yield of 3500 g per plant was recorded for Bira mutants derived from the mutagenic treatment of 300 Gy (Table 4). During the M4 generation Bira and Nakare mutants derived from 300 Gy and 100 Gy had a relatively higher seed yields of 287 and 199 g/plant, in that order (Table 5). At the M5 generation Bira mutants yielded 570 g/plant, while Nakare had 298 g/plant when subjected to 450 Gy and 100 Gy, respectively (Table 6).The NSP varied significantly between irradiation doses and genotypes. At the MThe present study revealed the important roles of induced mutations in cowpea breeding. It was evident from this study that increased Gy doses above 150 Gy can be lethal for the cowpea breeding line such as Nakare, while a dose above 200 Gy is lethal for the breeding line Shindimba. Other authors have reported the negative effects of increased mutagenic doses affecting various crops\u2019 establishment and survival for breeding .2 to M5 generations. Chlorophyll mutants observed were plants with yellow and striped leaves, albinos or yellow to pale leaf and stem pigmentations. Virescence mutants showed broad pale green leaf with its margin resembling a spinach leaf . According to The present study showed the presence of clear phenotypic differences among the tested mutant lines when compared to their respective controls. Overall, increased irradiation dose was associated with visual phenotypic mutants. Mutants displayed visual phenotypic differences including chlorophyll, leaf, upright single stem, pod, and seed during the M2 were genetically diverse owing to phenotypic segregation. The genetic diversity assessed in these mutants were tall/dwarf plant heights, early/late maturity, leaf shapes, branching habit, GH, PS, FC, SC and texture, seed weight and yield (Tables 6). Both the qualitative and quantitative parameters measured in the study were useful for selection of cowpea mutants. According to 2 generation. However, mutations of cells of somatic tissues are not transferred to the next generation. 3 generation. Single seeded pods were also reported by In the present study, mutants at the MTable 3). According to previous studies (Tables 6). The mutation treatment had positive effect on the number of days taken to 50% flowering whereby some of the breeding lines flowered 11 days before the control. Bira mutants subjected to irradiation of 300 Gy flowered 80 days after planting (Table 3). In the present study, other main phenotypic changes observed were increased NMB especially in mutants with spreading GH. Mutants with bushy GH had reduced number of branches per plant. These characters are indicated to be associated with some physiological properties of the plant including leaf senescence and indeterminate GH . It is r studies , 2013, t3 to M5 in all the breeding lines. Significant observations made in the present study were increased PL and seed yield measured during the MFigure 6. Therefore, there is a need to breed for insect pest tolerance in cowpea. 2 to M5 generations and identified promising genotypes. The selected mutants\u2019 are recommended for adaptability and stability tests across representative agro-ecologies for large-scale production or breeding in Namibia or similar environments. The novel cowpea genotypes selected through the study are valuable genetic resources for genetic enhancement and breeding.The present study demonstrated that most characters of cowpea which are of interest to plant breeders can be altered through mutations using the gamma irradiation technique. Furthermore, new plant attributes were created in the high yielding and well adapted local cowpea varieties. Various pests were observed on mutant cowpea during this study LH and HS designed the research. The experiments were carried out by LH under the supervision of HS. The manuscript was prepared by LH, HS, and HG.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Computer-based learning (CBL) has been widely used in medical education, and reports regarding its usage and effectiveness have ranged broadly. Most work has been done on the effectiveness of CBL approaches versus traditional methods, and little has been done on the comparative effects of CBL versus CBL methodologies. These findings urged other authors to recommend such studies in hopes of improving knowledge about which CBL methods work best in which settings.In this systematic review, we aimed to characterize recent studies of the development of software platforms and interventions in medical education, search for common points among studies, and assess whether recommendations for CBL research are being taken into consideration.We conducted a systematic review of the literature published from 2003 through 2013. We included studies written in English, specifically in medical education, regarding either the development of instructional software or interventions using instructional software, during training or practice, that reported learner attitudes, satisfaction, knowledge, skills, or software usage. We conducted 2 latent class analyses to group articles according to platform features and intervention characteristics. In addition, we analyzed references and citations for abstracted articles.P=.03), articles measuring online activities (P=.01), and articles citing a review by Cook and colleagues on CBL (P=.04). There was an association between number of citations and studies comparing CBL versus CBL, independent of publication date (P=.02).We analyzed 251 articles. The number of publications rose over time, and they encompassed most medical disciplines, learning settings, and training levels, totaling 25 different platforms specifically for medical education. We uncovered 4 latent classes for educational software, characteristically making use of multimedia , text , Web conferencing , and instructional design principles . We found 3 classes for intervention outcomes: knowledge and attitudes , knowledge, attitudes, and skills (11.8%), and online activity . About a quarter of the articles  did not hold references or citations in common with other articles. The number of common references and citations increased in articles reporting instructional design principles (Studies in this field vary highly, and a high number of software systems are being developed. It seems that past recommendations regarding CBL interventions are being taken into consideration. A move into a more student-centered model, a focus on implementing reusable software platforms for specific learning contexts, and the analysis of online activity to track and predict outcomes are relevant areas for future research in this field. Medical education is a field that reflects the constant revision of medical knowledge, educational technology, and teaching strategies. For over a century, education in general  and mediThe increasing interest in and pervasiveness of CBL and Web-based learning was accompanied by research on how such methods compared with traditional instruction on a wide spectrum of educational end points, leading Friedman in 1994 to reflect on the research we should be doing on CBL . In 2000The apparent lack of accommodation of this recommendation in subsequent studies, which kept growing in variety of setting and design, led Cook in 2005 to establish an agenda for research in medical education, suggesting once again that CBL research should look at relative benefits between different CBL methods . In 2008While the issue around CBL arose nearly 22 years ago, and over 8 years have passed since the Cook et al meta-analysis, comparative research between CBL methods is still a contemporary problem . It is rThus, this work aimed to identify reports of CBL software and CBL interventions, specifically in medical education, and systematically describe features of educational software, instructional design considerations, and the design, setting, and end points of CBL interventions. Finally, we intended to summarize these findings through determining subgroups of similar articles about educational software features and intervention end points, and to understand the extent to which prior work is being taken into consideration by analyzing the reference and citation network of these publications.We included medical education studies written in English regarding the development of educational software, interventions using educational software, or both. We considered interventions during training or clinical practice that reported effects on learner attitudes, knowledge, and skills, as well as records of online activity. We included pretest-posttest studies, randomized and nonrandomized studies, parallel group and crossover studies, and studies in which a software-based intervention was added to other instructional methods .We did not include studies that exclusively surveyed perceptions and attitudes of students or professionals toward CBL in general, nor studies that solely described course structure or reported how CBL strategies were implemented in medical schools.We designed a strategy to search MEDLINE, Scopus, Web of Science, and EBSCO databases. Search terms were \u201cmedical education,\u201d \u201cmedical students,\u201d \u201ce-learning,\u201d \u201cblended learning,\u201d \u201cinformation technology,\u201d \u201cinstructional design,\u201d \u201csoftware,\u201d and \u201cWeb-based platform,\u201d among other terms. The exact queries are available in Working independently and in duplicate, reviewers  screened all article titles and abstracts, and in full text all potentially eligible abstracts, abstracts with disagreement, or abstracts with insufficient information. Independently and in duplicate the reviewers considered the eligibility of studies in full text with adequate chance-adjusted interrater agreement of .92 by intraclass correlation (ICC) using the psych package, version 1.5.1  for the We conducted data extraction and reporting in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines ,16. Revik classes, commonly called latent classes [We manipulated and prepared data for statistical analysis using NumPy  and pand classes . Interpr classes . Startin classes . We crea classes . Summary classes .We obtained references of the included papers from Scopus using digital object identifiers (DOIs). We obtained citations of the included papers from Google Scholar by searching for each of the articles by title and abstracting the papers on the \u201ccited by\u201d link. This procedure was carried out using a script built with the WebDriver library  for the We analyzed the distribution of the total number of references and citations for each paper, and grouped papers based on whether they had \u22651 references or citations in common. We looked for the relationship between the number of citations and interventions comparing traditional instruction versus CBL methods, or CBL versus CBL. In addition, we assessed whether the number of related papers was associated with educational software latent classes or intervention end point latent classes, and with specific references to reviews by Cook and colleagues on CBL ,12,28. WThe search strategy yielded 3776 citations, of which we identified 595 potentially eligible articles based on their abstract. Of these, we excluded 344 articles based on a full-text review. In total, we included and analyzed 251 articles. Overall mean ICC was .98. Specific ICCs are reported for variables that were not always explicitly present and relied on reviewer judgment, or when <.95. The number of publications rose over the years, from 13 of the 251 publications in 2003\u20132004 (5.2%), to 82 in 2012\u20132013 (32.7%). Medical schools in Germany, the United Kingdom, and the United States contributed more than 30 papers each between 2003 and 2013. Medical schools in Australia, Canada, and Spain contributed more than 10 papers each. A total of 146 studies were conducted on clinical specialties (58.2%), 70 studies on basic sciences (27.9%), and 36 studies on surgical specialties (14.3%). Radiology was the clinical specialty with most studies, in 23 articles (9.2%), followed by pediatrics with 13 (5.2%). The basic science subjects with most publications were anatomy with 18 articles (7.2%) and physiology with 9 articles (3.6%). The most studied surgical specialties were urology with 12 studies (4.8%) and general surgery with 10 (4.0%). There was at least one article in most basic sciences and medical specialties, as Of the 251 studies assessed, 113 reported blended learning environments  and 138 reported e-learning environments . A total of 217 studies used websites (86.5%), 16 used videoconference (6.4%), and 16 other studies used email (6.4%); 9 used podcasts (3.6%) and 9 used portfolios (3.6%). Wikis  and CDs  were both reported in 8 studies. Blogs were reported in 6 studies (2.4%). E-books were reported in 4 studies (1.6%) and audience response systems in 3 articles (1.2%).Of the 251 studies, 174 provided content in text format (69.3%), and 138 used images (55.0%). Video was reported in 99 studies (39.4%) and diagrams in 94 studies (37.5%). Audio was used in 85 articles (33.9%), and animations were reported in 28 articles (11.2%).A total of 138 studies reported unspecified features (55.0%). The software provided feedback to the learner in 103 studies (41.0%); 103 articles reported quizzes (41.0%), 66 reported clinical cases (26.3%), 54 described simulations (21.5%), and 45 tracked learner performance (17.9%). Features allowing collaboration between learners and instructors were reported in 38 studies (15.1%). Virtual patients were reported in 18 studies (7.2%) and games were described in 10 studies (4.0%).Of the 251 studies, 47 reported communication and content sharing through discussion forums (18.7%), 27 reported the ability to store documents (10.8%), and 7 used instant messaging communication systems (2.8%). Calendar features were also reported in 7 studies (2.8%).The media principle was apparent in 74 studies , followed by the segmenting principle in 34 studies  and the contiguity principle in 23 studies . The pretraining principle was identified in 16 studies  and the signaling principle in 13 studies . The coherence principle was identified in 10 studies  and the modality principle in 9 studies . Finally, the personalization principle and the voice principle were identified in 5 studies each .multimedia.We considered 4 distinct classes for educational software, according to the model statistics in text.Class 2 was composed of 64 studies (25.5%) using websites, and to a smaller extent email, to deliver instructional content mostly in the form of text. Interactive features were less frequent than in class 1, and instructional design considerations were scarce. We thus labeled class 2 Web conference.Class 3 was composed of 54 studies (21.5%) making use of websites and videoconference platforms to provide video and audio content. Interactivity and instructional design principles were nearly nonexistent. We thus labeled class 3 instructional.Class 4 contained 18 studies (7.2%) mostly using Web-based interactive multimedia apps in which the use of multiple instructional principles was frequent. We thus labeled class 4 The four right-hand columns in intervention end point latent class described below.Of the 251 articles included in this study, we identified 212 conducting interventions on the end points of interest (84.5%). A total of 81 of 212 studies were conducted with medical students from preclinical years (38.2%) and 56 studies involved students during clinical rotations (26.4%). In addition, 32 studies were conducted with specialist medical doctors (15.1%), and 31 studies were conducted with medical residents (14.6%).In total, 55 interventions were carried out with <50 participants (25.9%), 97 studies had a sample size ranging between 50 and 200 participants (45.8%), and 59 studies were conducted with >200 students (27.8%).Of the 212 studies, 54 were conducted over <1 week (25.5%), 90 articles reported interventions lasting between 1 week and 3 months (42.5%), and 50 studies were conducted for >3 months (23.6%).In addition, 84 studies repeatedly tested participants in a pre-post approach (39.6%), and 93 made use of control groups (43.9%). A total of 61 studies were randomized (28.8%) and 37 studies had participants from more than one institution (17.5%); 40 studies compared different CBL approaches (18.9%), while 53 studies compared CBL with traditional methods (25.0%).The mean MERSQI score for the assessed studies was 9.54 (SD 1.84).v ersus no intervention (3.3%). In addition, 5 studies compared the use of 3D models versus 2D images (2.4%). A multitude of other comparisons were performed, such as exploratory versus blocked learning approaches [Of the 212 studies, 28 studied controlled interventions between blended learning approaches and traditional lectures (13.2%), while 11 studies compared e-learning approaches with traditional lectures (5.2%). A total of 8 studies compared spaced repetition versus bolus learning (3.8%), and 7 studies compared e-learning proaches -75, compproaches ,76,77, iproaches , and mulproaches ,79-81. MKnowledge outcomes were assessed in 120 of 212 articles (56.6%). Objective knowledge was assessed using multiple choice quizzes in 98 of 120 studies (81.7%), 9 articles used free-text fields (7.5%), and 8 articles used open-ended questions . In addition, 5 studies used true/false questions (4.2%). Judgments of knowledge were collected using Likert scales in 27 studies (22.5%). Researchers directly assessed knowledge in 9 studies (7.5%). A total of 31 studies were conducted in a laboratory setting (25.8%). Knowledge assessment was part of a final examination in 39 articles (32.5%), and in 9 studies assessment was part of a formative assessment (7.5%). Of the 120 studies, 90 reported that interventions improved knowledge acquisition (75.0%), while 27 studies did not find significant effects (22.5%) and 3 multicenter randomized controlled trials reported that interventions did not positively affect knowledge acquisition (2.5%) ,82,83.Of 212 studies, 172 assessed student attitudes (81.1%); of these, 163 used Likert scales (94.8%) and 34 used free-text fields (19.8%). In 8 articles researchers assessed participants\u2019 attitudes directly (4.7%). A total of 29 studies were conducted in a laboratory setting (16.9%) and 16 studies made use of focus groups (9.3%). In addition, 161 studies found positive attitudes toward interventions (93.6%), 8 found neutral attitudes (4.7%), and 3 reported negative attitudes (1.7%) -86.Of 212 studies, 31 assessed subject skills (14.6%). In 26 of these studies, skills were assessed directly by researchers (84%) and in 16 studies assessment was conducted in a laboratory setting (52%). In addition, 24 studies found positive effects on skills acquisition (77%), 5 reported that the interventions had no effect on assessed skills (16%), and 2 reported that the intervention had negative effects (6%) ,86.Online activity was measured in 76 of 212 studies (35.9%). Of these studies, 46 measured total logins to the system (60%), 39 measured time spent in the system (51%), and 18 measured the number of times students used specific learning tools (24%). Further, 16 studies measured the number of student posts (21%), and 12 measured the number of times students viewed the learning materials (16%). A total of 41 studies found no relationship between activity patterns and learning outcomes (54%), 34 articles reported increased activity to have positive effects on learning outcomes (45%), and 1 study found a negative effect (1%) .knowledge and attitude. Class 2 contained 25 intervention studies (11.8%). In addition to assessing knowledge and attitudes, articles in this class also assessed skills. We labeled class 2 knowledge, attitude, and skill. Class 3 contained 12 studies that assessed online activity, specifically through the number of posts and number of reads (5.7%). Attitudes were always assessed, but knowledge and skill assessment were nearly absent. We labeled class 3 online activity. We considered 3 distinct classes to group the 212 studies taking into consideration intervention end point variables. Class 1 contained 175 articles assessing knowledge and attitudes (82.5%). We labeled class 1 Of 212 studies, 25 correlated different variables with knowledge outcomes (11.8%). Of these, 1 study correlated system interactivity with knowledge scores and concluded that lower levels of interactivity benefitted knowledge acquisition . CorrelaWe obtained references and citations for 227 of the 251 articles included in this review 90.4%). The mean number of references was 26.12 (SD 17.41). In total, the abstracted articles had 4010 references to other articles. The most referenced articles were from Ruiz et al %. The me, GreenhaOf the 227 articles, 169 had at least one reference or citation in common with other abstracted articles (74.4%), and were thus said to be related, as depicted in P=.02). Studies comparing traditional versus CBL methods were cited a mean of 11.92 times (95% CI 9.31\u201314.6). Studies comparing different CBL methods were cited a mean of 16.71 times, which was statistically significant . Articles from the Web conference class had a mean of 5.02 relationships to other studies  and articles in the instructional class had a statistically significant mean of 6.78 studies  in common. Regarding the intervention end point latent classes, articles in the knowledge and attitude class had a mean of 2.63 related studies (95% CI 1.46\u20133.80) and the knowledge, attitude, and skill class had a mean of 2.88 studies in common, reaching statistically significance versus the knowledge and attitude class . Articles from the online activity class had a mean of 6.78 related studies , also reaching a significant value when compared with the knowledge and attitude class.Regarding educational software latent classes, articles in the multimedia class had a mean of 3.95 related studies (95% CI 2.99\u20134.91), while the text class had a mean of 4.98 , which was significantly different. Finally, articles not citing the Cook et al work had a mean related article count of 4.42 (95% CI 3.74\u20135.11), while articles citing Cook et al had a mean count of 6.64 . Of the 251 studies we analyzed, most used interactive websites making use of text and images (46%) and, to a smaller extent, websites delivering text-based materials (25%). A similar number of reports delivered instruction using Web conferencing systems (22%), and a smaller group of studies reported highly interactive websites with multimedia learning content built according to instructional design principles (7%). Of the 212 interventions, most did not use comparison groups and lasted between 1 week and 3 months. CBL versus CBL studies were less numerous than traditional versus CBL studies. Nearly all studies assessed student attitudes, of which a large fraction also assessed knowledge (82%), and a smaller fraction assessed knowledge and skills (12%). A smaller set of studies looked specifically for patterns of online activity, namely the number of reads and posts (6%). Finally, nearly 75% of articles had references and citations in common, while 25% of the analyzed articles did not have any references in common. Articles comparing different CBL methods were cited more often than were studies comparing traditional versus CBL methods, independent of publication date. Articles reporting instructional design principles, articles measuring online activity, and articles citing the Cook et al CBL reviews had significantly more references and citations in common than did other articles.The last systematic review and meta-analysis of this topic encompassed data from 1990 to 2006 and highlighted the problems of intervention variability and lack of evidence for comparative effects of CBL methods ,13,28. RThis study has limitations. We scrutinized databases that frequently index medical education articles. Although we did not query EMBASE, Scopus covers most of the literature indexed in EMBASE and thus Scopus provided a reasonable proxy. However, we did not abstract the gray literature or references from other articles, and thus our article search cannot be considered exhaustive. We narrowed the study participants to medical education only. This can be considered a limitation insofar as these findings cannot be generalized to other health professions. Other reviews have performed similar searches including articles in health professions in general . We perfThis study also has strengths. We performed a broad analysis of the literature and accounted for aspects that, to our knowledge, were not previously assessed, such as specific platforms and their features, and correlations assessed between learning end points and types of comparisons. We systematically summarized data using latent class analysis, which, to our knowledge, was for the first time performed in this setting. We described the article citation network and explored relationships between these and the article latent classes and CBL considerations, which, to our knowledge, were also for the first time performed in the field. Finally, we have made these results available through an interactive visualization that allows researchers to deeply explore articles .Our findings show that, while CBL in medical education varies significantly, most published articles are from medical schools in a small set of countries. Medical education has geographical specificities, which makes contributions from different geographical areas particularly enriching and should incite more schools to conduct research in this field.Over 25 platforms and software projects were built specifically for medical education, despite having significant overlap in goals and features. While a few provided means to interact with learning materials, such as microscopy images , in waysThe diversity of methods encompassed by CBL in terms of delivery medium, context, learner, and purpose, without reports of instructional design considerations, obfuscates the effect of different intervention aspects, for which instructional design\u2014or the lack of it\u2014is partly accountable ,9,13,121Studies generally report positive outcomes on knowledge, attitudes, and skills. Interestingly, studies that found no positive effect in any of the learning outcomes were often randomized controlled trials ,83-86, sEven though 25% of the articles seemed not to be based on common CBL literature, our findings suggest that research is moving toward favoring studies comparing CBL methods rather than comparison with traditional methods. Indeed, we found that, while traditional versus CBL articles were more numerous, articles comparing different CBL methods were cited more often than articles comparing CBL versus traditional settings. We take this as a sign that recommendations put forward by previous authors are being taken into consideration ,9,11. ArThe shift to student-centered models needs to continue. However, only a few reports put students at the center of the education process, focusing usually on aspects related to teaching . Part ofWe have come a long way in CBL in medical education. While the field is highly variable and some studies seemed to be unaware of advances in the field, recommendations on comparing different CBL methods seem to have been taken into consideration. Incorporating instructional design principles in the design of learning materials and developing further educational software in ways that can be shared between researchers are paths for further improvement. A focus on measuring online activity and correlating it with other outcomes may provide insights into ways to keep promoting student-centered approaches tailored to specific learning settings."}
+{"text": "Three interventions were implemented to improve the paediatric eating disorders service at the Austin Hospital. The primary changes consisted of (i) introduction of a multidisciplinary initial assessment clinic, (ii) increased utilisation of Family-Based Treatment (FBT), and (iii) institution of aggressive inpatient feeding. A retrospective audit from 2011, 2012 and 2013 was conducted extracting medical records data. Service referrals doubled (28 in 2011 to 58 in 2013), associated with greater acuity at initial presentation (50% vs 65% at <90% expected body weight). The vast majority of admissions for medical stabilisation occurred within 2 weeks of presentation, reflecting this greater acuity (78% vs 92%). Readmission rates halved (33% to 17%) with a dramatic 75% reduction in patients requiring >3 admissions (33% to 8%). A 59% uptake of FBT by 2013 led to substantial improvements in weight restoration, from 46% to 71% of patients achieving >90% expected body weight within 6 months. Increased utilisation of FBT is expected to further improve outcomes. FBT patients were more likely to achieve complete weight restoration (odds ratio 1.7). This escalating number and severity of service referrals demands additional resources and funding if the complex psychiatric and medical needs of our patients are to be adequately addressed.Service Initiatives: Child and Adolescent Refeeding and FBT stream of the 2014 ANZAED Conference.This abstract was presented in the"}
+{"text": "Millennium Development Goals (MDGs) represent the widest commitment in history to addressing global poverty and health. MDG-4 commits international community to reducing mortality in under 5 by two-thirds between 1990 and 2015. According to Lancet Neonatal Survival Series (LNSS), since 2000, child mortality after the first month (from 29 days to 5 years) fell by a third . In 2010"}
+{"text": "Predicting those who are likely to survive with good neurological outcome following out of hospital cardiac arrest (OHCA) is important for patients, their carers and society - however prognostication following OHCA is difficult. The European Resuscitation Council and the European Society of Intensive Care Medicine (ESICM) have published an advisory statement regarding prognostication in comatose survivors of cardiac arrest. The guiOur objective was to investigate timing of prognostic decisions on neurological recovery after cardiac arrest and which investigations are used to aid decision-making for all patients admitted to our intensive care unit (ICU) following OHCA over a 19 month period.We conducted a retrospective observational study of neuroprognostication practice following OHCA in a large tertiary referral ICU. In addition to a survey of current practice, we assessed mortality in this group and neurological outcomes of survivors.118 patients were identified for inclusion in analysis and of those notes were available for 107 (90.7%). 49.5% of patients survived to hospital discharge. The process of neuroprognostication was documented for 43 patients . Investigations used to aid prognostication included: CT scanning (22 (51.2%)), EEG (3 (7.0%)). Clinical finings included: brainstem death testing (2 (4.7%)), absent pupillary reflexes (22 (51.2%)), status epilepticus (16 (37.2%)). No patient underwent magnetic resonance imaging (MRI), somatosensory evoked potentials (SSEP) or measurement of biomarkers of neurological injury.In our centre, a high proportion of survivors of OHCA survived to hospital discharge with favourable neurology, although the use of investigations to aid neuroprognistication is inconsistent and some recommended modalities are unavailable, even in a tertiary centre. Further large-scale audits are warranted to elucidate current neuroprognostication practice and availability of evidence based investigations."}
+{"text": "Critically ill septic patients have high rates of death, complications and resource use, mainly in emerging countries.To investigate the impact of organizational factors on the outcomes of septic patients in a large sample of Brazilian ICUs.Retrospective cohort study in 6,779 patients with severe sepsis  or septic shock  directly admitted from the emergency department to 69 ICUs ; medical-surgical; n= 57(83%)) during 2013. We retrieved demographic, clinical and outcome data from an electronic ICU quality registry (Epimed Monitor System). We surveyed ICUs using a standardized questionnaire regarding organizational aspects, staffing patterns and process of care. We used multilevel logistic regression analysis to identify factors associated with hospital mortality.38 (55%) ICUs had critical care training programs. Median graduate nurse-bed ratio was 0.23  and board-certified intensivists were present 24/7 in 16 (23%) of ICUs. Routine clinical rounds occurred in 59 (86%) and daily checklists were used in 34 (49%) ICUs. Sepsis protocol was implemented in 83% ICUs. The most frequent sources of infection were pulmonary ) and urinary tract ). Invasive mechanical ventilation was used in 1,373 (20%) patients and dialysis in 289 (4%) patients. SAPS 3 score was 54 (47-62) points. ICU and hospital mortality rates were 19% and 26%. Adjusting for relevant patients' characteristics , case-volume and type of ICU, average graduate nurse/bed ratio during shifts ) and the number of other implemented protocols (OR = 0.932 (0.862-1.008)) were associated with lower mortality. In a second model, the presence of intensivist nurses 24/7 in the ICU (OR = 0.600 (0.390-0.924)) was also associated with better outcomes.Nurse staff patterns and the implementation of clinical protocols were associated with mortality in septic patients and are potential targets to improve care of these patients in emerging countries."}
+{"text": "External drainage (ED) of cerebrospinal fluid (CSF) is often used during management of brain insult. In absence of robust data and consensual guidelines, weaning ED remains challenging. The objective of the study was to assess the proportion of secondary normal pressure hydrocephalus (NPH), being treated with delay after ED weaning and to evaluate the resulting morbidity.All adult patients admitted in intensive care unit for brain insult between 1st january 2010 and 31st december 2013, managed with ED, were included in this retrospective monocentric observationnal study. Rate and delay of shunt surgery after ED weaning were analysed in the light of neurological prognostic assessed by modified Rankin scale (mRS). Literature review. National numeric survey adressed by email in all french neurosurgical center.Among the 144 patients (57.6% of men) studied, 39% of the survivors developped a secondary NPH. Among them, 62, 5% were shunted early (from day 1 to day 7 after ED weaning) and 37.5% were treated with a delay (from 8 to 420 days after ED weaning). Identified risk factors of failure of the weaning test were: severity of initial neurological status (Glasgow score 9.5 vs 11), long delay between insult and ED insertion (226hrs vs 67hrs), low CSF outflow through ED (137mL/24h vs 194 mL/24h), high mRS at the moment of ED weaning (5 vs 4). Mean benefit of shunt insertion was 1 point of mRS in this population. Literature review found no evidence based data or guidelines to wean ED. National survey confirm the heterogeneity of ED weaning management.This study confirms the imprecision of ED weaning in absence of guidelines and robust data, resulting in delayed management of secondary NPH in more than one in three patients. Methods of ED weaning should be more studied and probably up-graded."}
+{"text": "The Hsp70/Hsp90 chaperone cycles depend on the coordinated interplay of several co-chaperones including Hsp40, Hop and peptidyl-prolyl isomerases such as FKBP52. Because of the many proteins involved in these interactions it is often difficult to delineate all possible combinations of subunits in the complexes formed. We employed mass spectrometry to monitor the assembly and to determine the favoured pathways within these chaperone cycles. Combining the subunit composition with chemical cross-linking and proteomics allowed us to define interaction interfaces, protein dynamics and new intermediates. The Hsp70/Hsp90-based cellular machinery stabilises proteins for correct folding or re-folding in response to stress. It requires a cohort of co-chaperones that interact at different stages of the Hsp70/Hsp90 cycles and consequently regulate specificity for the high number of substrates. Client proteins include steroid hormone receptors, transcription factors or kinases -3. A genHsp40 is required to form complexes with Hsp70 and act as a catalyst to bind partially folded substrates or clients , 9. We pHsp90 plays a role at the later stages of the Hsp70/Hsp90 cycle. It interacts with misfolded proteins to prevent their aggregation, however, Hsp90 alone cannot refold these proteins to their native state . Its maiRecent developments have made mass spectrometry (MS) a powerful tool in structural biology. MS allows the determination of subunit stoichiometries, interaction modules and the topology of protein complexes . Signifi2(Hop)1 is the predominant complex although binding of a second Hop was also observed albeit at low intensities. Likewise, incubation with the immunophilin FKBP52 [2(FKBP52)1 and (Hsp90)2(FKBP52)2 complexes [We first explored the heterogeneity of the Hsp90 complexes formed in the presence of the co-chaperones Hop, FKBP52 and Hsp70 . Hop is n FKBP52  led to tomplexes .2(Hop)1 complex was also observed and was more prevelant than its analogue (Hsp90)2(FKBP52)1. A control experiment revealed no interactions between Hop and FKBP52 alone, confirming that Hop and FKBP52 compete for binding sites on Hsp90. Interactions between Hsp90 and Hsp70 were not observed when incubating the proteins alone. However, in the presence of equimolar amounts of Hop a (Hsp90)2(Hsp70)1(Hop)1 complex formed 1(Hop)1(FKBP52)1.We next challenged the Hsp90/Hop complexes with different amounts of FKBP52; one Hop could readily be exchanged by FKBP52. The (Hsp90)d Figure  underlyiD values for the binary interactions and the generation of a model of the Hsp90 cycle. In this model, dimeric Hsp90 can bind one copy of either Hop or FKBP52 and both intermediates can bind another copy of the same or the other co-chaperone. Furthermore, Hsp70 cannot bind Hsp90 without prior binding of Hop to Hsp90. KD values calculated from these reactions give insights into the favoured binding events at the cellular concentrations of chaperone proteins [These experiments allowed the calculation of Kproteins .1(GR)1 complex indicating that interactions with Hsp40 are transient and of a catalytic nature. Indeed, incubating Hsp70 with GR alone did not result in binding of the client, but Hsp40 and GR clearly formed an (Hsp40)2(GR)1 intermediate complex [Client binding to Hsp70 is facilitated by the co-chaperone Hsp40 . We ther complex .2(Hop)1(Hsp70)1, while post-translationally modified Hsp70 integrated as an Hsp70-dimer [We then considered the transfer of the GR client from Hsp70 to Hsp90. For this we first investigated complex formation of Hsp70, Hop and Hsp90 without client protein. We found that unmodified Hsp70 incorporated one Hsp70 molecule into the intermediate complex (Hsp90)70-dimer . IncludiThe presence of an Hsp70 dimer in the client-transfer complex was surprising and contradictory to previous studies . We therE. coli homolog DnaK (PDB IDs 2KHO and 4B9Q) best accommodate the majority of our cross-links implying that the two conformations readily interconvert in solution . Intere2(Hsp70)1(Hop)1(GR)1 or (Hsp90)2(Hsp70)2(Hop)1(GR)1 depending on the status of Hsp70 post-translational modifications. We further employed chemical cross-linking to define the arrangement of the subunits within this complex. We observed a number of inter-protein cross-links verifying that two Hsp70 molecules are present in the final complex. Our cross-links also positioned the TPR-binding motifs of Hop in upward- and downward-facing arrangements as suggested previously [2(p23)2(GR)1, without Hsp70 or Hop present eviously  and locat Figure , confirmE. coli [in vivo. As Hsp90 also plays a role in tumour growth, by stabilising essential proteins, prevention of Hsp70 dimerisation and association with Hsp90 suggests new avenues for therapeutic interventions in cancer.In this research perspective we highlight the power of advanced mass spectrometry to investigate heterogeneous and dynamic protein assemblies. In summary we not only observed the established catalytic role of Hsp40 during substrate binding to Hsp70 but also in the dimerisation of Hsp70. Anti-parallel Hsp70 dimers have been proposed previously in yeast  and E. cE. coli  but thei"}
+{"text": "Ten cross-sectional studies have examined a potential association between migraine and multiple sclerosis (MS); some of them found an association between the two conditions, 2 whileThe aim of the present study was to investigate the prevalence and the clinical features of different types of headaches in subjects affected from MS respect to a control group.One hundred and fifty adults  with a diagnosis of MS and 150 sex and age-matched controls  from the general population were evaluated by means of an ad hoc semi-structured interview according to the International Classification Headache Disorders (ICHD-3-beta) criteria. All subjects filled out validated questionnaires about fatigue, Fatigue Severity Scale (FSS) and Modified Fatigue Impact Scale (MFIS). The \u03c72 and Kruskal-Wallis tests were used when appropriate.The two groups differed significantly for education level and employment. Among the 150 patients with MS, 1 (0.7%) presented a radiologically isolated syndrome (RIS), 17 (11.3%) a clinically isolated syndrome (CIS), 20 (13.3%) a primary progressive form (PPMS), 96 (64%) a relapsing remitting form (RR), and 16 (10.7%) a secondary progressive form (SPMS). Headache was reported by 80 (53.3%) MS cases and 71 controls (47.3%), (p = 0.356); migraine was reported by 47 (31.33%) cases and 51 (34%) controls, tension-type headache was present in 21 (14%) MS affected vs 14 (9.33%) controls (p = 0.245). The simultaneous presence of migraine and tension-type headache was statistically higher (p = 0.002) in MS (28.8%) compared to controls (8.5%). Women with MS presented a low correlation between migraine and menstruation compared to controls while migraine normally improves during pregnancy as much as in controls (p = 0.65). The preliminary analysis of FSS and MFIS scores showed that fatigue resulted overall higher in MS patients with or without headache.Although MS patients showed a high prevalence of headache, particularly migraine, the overall prevalence was not significantly different compared to the general population. Fatigue, a well-known symptom of MS, seems to be primarily correlated to disease and poorly influenced by the presence of headache. Moreover, women with MS and migraine should be reassured regarding the possibility that their headache could improve during pregnancy as in those without MS.Written informed consent to publication was obtained from the patient(s)."}
+{"text": "Intracranial calcifications underlie certain brain diseases which may be de novo or systemic. But calclfications un-connected to pathologies are classified physiological.To evaluate physiological intracranial calcifications in Douala with establishment of earliest age range of detection.Prospective study of brain computed tomograms was done from April to October 2009 using Schumadzu CT Scan machine. Axial, reconstructed and bone window images as well Hounsfield unit measurements were used for final evaluations. Results were analysed with SSPS 3.132 patients with 75 males and 57 females were studied and 163 separate calcifications were identified due to co-existent calcifications. The highest calcification was in choroid plexi, constituiting 56.82% of the studied population. This was followed by pineal gland. Both were commonly co-existent with advancing age. These calcifications were first seen at 10-19years. No type of physiological intracranial calcification was seen below age 10. The least calcification of 0.76% of population was in dentate nucleus.No intra-cranial physiological calcifications started earlier than 9years in Douala, a city in Cameroon, Central Africa. Intracranial physiological calcifications are unaccompanied by any evidence of disease and have no demonstrable pathological cause . This was done using Schumadzu CT scan machine with continuous rotational system. Axial sections were done using slice tissue thickness of 2mm from the base of the skull to the sella turcica, thence 5mm from the sella to the vertex. IV Iopamidol at 1mm/kg was given when indicated. Images were reconstructed to achieve sagital and coronal images. Hounsfield unit (HU) measurement and bone window were employed in some cases of doubt so as to differentiate calcifications from acute haemorrhage. The HU of calcifications is above 100HU while HU of acute haemorrhage is in the range of 60-90HU taking into account the effect of partial volume averaging. The structures evaluated consisted of (a) the pineal gland, (b) the choroid plexus, (c) the habenula, (d) the basal ganglia, (e) the tentorium cerebelli, sagittal sinus and falx cerebri, (f) vessels and (g) lens and other structures which could be calcified. Patients consent was obtained. The ethical board review committee\u2019s approval was obtained. All patients with any pathology linked or associated with intra-cranial calcifications and those with improper data documentation were excluded. Results were analysed using SSPS 3.132 of 174 brain computed tomograms were considered optimal for our study and analysed. There were 75 males (56.82%) and 57 females (43.18%) with age range of 0.4-81years and mean age of 45.5years. Largest population studied was 38 in 40-49 year age range with 24 males and 14 females. This age range also had the highest number of intra-cranial calcifications of 58 (35.58%) of the total number of 163 intracranial calcifications detected in this study. In this 40-49years, 40 (68.96%) calcifications were seen in males and 18 (31.04%) females with male: female ratio 2.22:1. This is followed by 26 calcifications  in the 50-59 age range. 8 calcifications  were seen in 80-89 year age range. No calcification was seen below 10 years of age in both sexes. In older age of 70 years and above, females had more calcifications whereas from 69years and below, males had more calcifications. The highest number of calcifications of 75, constituting 46.01% of total number of detected calcifications and 56.82% of total studied populations was seen in the choroid plexus (atria), with 44 calcifications in males and 31 in females . Highest number of choroid calcification 24 (32%) was in the 40-49 year age range with male predominance followed by 15 in the 50-59years with female predominance.Pineal gland calcifications were 61 (37.42%) of all calcifications and 46.21% of studied population. It was the second highest with 36 cases in males and 25 in females . Peak age is also 40-49years followed by 50-59 years. Least calcifications of 1 case were in the dentate nucleus in a female. The earliest age of calcification of choroid plexus/pineal gland in males was in 10-19 year age range whereas earliest calcifications of choroid plexus/pineal gland in females were 20-29 years. Both show equal predominance of choroid plexus/pineal calcifications with increasing age, females tend to have increasing pineal gland calcifications than males.Anterior falx calcifications (21) is more than posterior falx calcification 3 (anterior to posterior 7:1). Both show male predominance  and . Earliest calcification of anterior falx started at 20-29 year age range. Highest incidence is also at 40-49 years, with 6 cases in males and 3 cases in females . Posterior falx calcifications started at 40-49 years.Intra-cranial calcifications can be physiological or pathological. When physiological, it is asymptomatic and detected incidentally in neuro-imaging  and 37.42%  respectively. This choroidal plexus calcification predominance has been reported by other authors , pp55-60The pattern of choroid plexi calcification in this study was symmetrical and bilateral in 100% of positive cases of intracranial calcifications. Such calcification increased with age with maximum of 80% in 80-89 years. Choroid plexi calcifications are known to occur in all ventricles, most commonly in the glomus within the atrium of lateral ventricles near foramen of Monro. Other sites are tela choroidea of third ventricles, roof of fourth ventricle along foramen of Luschaka , p237. Ird of the population in some literature  contains several calcified concretions called \u201cbrain sand\u201d or acervuli corpora arenacea. . Hypoparathyroidism and pseudohypoparathyroidism are the most common causes of pathological basal ganglia calcification  is usually defined as bilateral calcium accumulation in the brain parenchyma, most often within the basal ganglia. Various terms have been used to describe basal ganglia calcification including calcification(s) of the basal ganglia, basal ganglia calcification(s), Fahr syndrome, intracranial calcification, pallidal calcification, and striopallidodentate calcinosis . Physiologic calcifications can be seen in the cerebellum, with the dentate nucleus being the most common site as noted in this study .All types of intracranial calcifications increased at old age except for lens and other non-defined calcifications (No any type of intracranial calcification was seen below 10 years of age in Douala. The commonest physiological intracranial calcification is choroid plexi, followed by pineal gland. Both calcifications started at 10-19 year age range and both also show male predominance, Choroid plexus calcifications were all bilateral and symmetrical. Choroid plexus and pineal gland calcifications were co-existent with advancing age. The least calcification is in the dentate nucleus of cerebellum."}
+{"text": "Beta-lactams (BL) are one of the most prescribed antibiotics (AB) class. They are frequently implicated in hypersensitivity reactions (HSR), with common skin involvement. However, infectious conditions might also induce cutaneous lesions, especially in children, and they constitute an important differential diagnosis to BL HSR.To characterize suspected BL HSR and analyse the prevalence of allergic reactions in our study population.We retrospectively reviewed the clinical data from all children (<18 years-old) referred to our Allergology Department for suspected BL HSR between 2011 and 2013.Eighty children  with a mean age of 6.7 yrs (SD=4.035) where evaluated for 83 suspected BL HSR. The mean time elapsed between the reaction and the clinical assessment was of 3.1 yrs (SD=3.36). The most frequently implicated drugs were amoxicillin/clavulanate (54.2%) and amoxicillin (32.5%). BL were prescribed for tonsillitis in 32.5%, otitis in 21.7% and upper airways infection in 19.3%. Cutaneous lesions were the most frequently reported (94%) manifestations, with maculopapular exanthema (MPE) being the most common. In 45 reactions (54.2%), the time of onset was unknown; in 4.8% the reaction was immediate and in the remaining cases non immediate (41%). In 23 cases (27.7%) there was no history of previous exposure to the suspected drug; 15 children had previous exposure with a similar reaction. In the group of patients with immediate reactions or unknown time of onset (n=49), determination of specific IgE (sIgE) for penicillin G, V and amoxicillin was performed in 43 (87.8%), and skin prick tests in 42 patients (85.7%), all with negative results. Of all patients, 16 (20%) underwent intradermal testing (IDT) and only one patient had a positive result with PPL 1/1; late reading was done in 3 cases, all negative. Oral provocation test (OPT) with the suspected BL (single or continued at home) was performed in 74 cases (89.2%) with positive result in 6 patients (8.1%), all of them exclusively with late cutaneous involvement.Suspected BL HSR was only confirmed in 8.1%. Although MPE caused by BL treatment in children is rare, there are no clinical distinctive characteristics from MPE related to infections, making allergy diagnosis workup mandatory. The authors raise the question of the need of sIgE determination and skin testing in less severe reactions, instead of performing directly the OPT."}
+{"text": "Mevalonate kinase deficiency (MKD) is a rare autoinflammatory disease, caused by mutations in the isoprenoid pathway that lead to fever episodes. Approximately 300 MKD patients are known.Our objective is to describe the clinical features and therapeutic response in a large group of MKD patients, in order to increase knowledge of this rare disease.The Eurofever registry (EAHC Project No. 2007332) is retrospectively collecting clinical information on anonymized patients affected by autoinflammatory diseases. Cases were independently validated by an MKD expert.MVK mutations and three patients with one MVK mutation in combination with elevated urinary excretion of mevalonic acid were used for analysis. The group consisted of 39 males and 46 females. Median age at onset was 6 months; in 60 patients (70.6%) the disease started within the first year. Median disease duration at enrolment in the registry was 13.1 years. The majority of patients were Caucasian. The most frequent mutation was V377I, occurring in 70 patients, including 12 patients that were homozygous for this mutation. I268T was the second most frequent mutation (n = 23). The majority of patients (75 of 85) had a recurrent disease course. The median duration of a fever episode was 5 days, 80.8% had a duration of 3 to 7 days. Median attack frequency was 12 per year. Triggers for disease activation were known in 38 patients and included vaccination (n = 28), stress (n = 20) and infection (n = 12). Nearly all patients (83 of 85) suffered from gastrointestinal symptoms, mainly diarrhea (n = 66), abdominal pain (n = 65) and vomiting (n = 51). Seventy-one patients had cervical lymphadenopathy. Mucocutaneous symptoms included aphthous stomatitis (n = 47), maculopapular rash (n = 31) and pharyngitis (n = 34). Arthralgia (n = 59) and myalgia (n = 47) were more prominent than arthritis (n = 27). Many patients display malaise (n = 47), fatigue (n = 50) and weight loss (n = 44), sometimes independent of fever attacks. IgD-levels were increased in 42 of 61 tested patients and urinary mevalonic acid excretion was increased in 27 of 28 tested patients. Non-steroidal anti-inflammatory drugs (NSAIDs) were mainly given during attacks and relieved symptoms in 33 of 46 patients, including 5 patients who noted complete suppression of inflammatory symptoms. A complete response on corticosteroids was seen in 13 of 48 patients , another 29 patients reported improvement. Anakinra was completely effective in 5 of 26 patients and partially effective in 17 others. Etanercept was used by 19 patients, one patient reported complete response, 11 patients some improvement; failure was noted in 7 patients. Statins failed or worsened disease in 7 patients, 4 patients reported some improvement.Eighty-two patients harbouring two This study describes the clinical characteristics and response to therapy in a large international cohort of MKD patients.None declared."}
+{"text": "Objectives. We sought to determine the prevalence and aetiology of LVT among patients undergoing echocardiography. Methods. We reviewed case notes and echocardiographic data of patient diagnosed with LVT using noncontrast transthoracic echocardiography. Definition of various conditions was made using standard guidelines. Mean \u00b1 SD were derived for continuous variables and comparison was made using Student's t-test. Results. Total of 1302 transthoracic echocardiograms were performed out of which 949 adult echocardiograms were considered eligible. Mean age of all subjects with abnormal echocardiograms was 44.73 (16.73) years. Abnormalities associated with LVT were observed in 782/949 (82.40%) subjects among whom 84/782 (8.85%) had LVT. The highest prevalence of 39.29% (33/84) was observed in patients with dilated cardiomyopathy, followed by myocardial infarction with a prevalence of 29.76% (25/84). Peripartum cardiomyopathy accounted for 18/84 (21.43%) cases with some having multiple thrombi, whereas hypertensive heart disease was responsible for 6/84 (7.14%) cases. The lowest prevalence of 2.38% (2/84) was observed in those with rheumatic heart disease. Left ventricular EF of <35% was recorded in 55/84 (65.48%). Conclusions. Left ventricular thrombus is common among patients undergoing echo, with dilated cardiomyopathy being the most common underlying aetiology followed by myocardial infarction. Multiple LVTs were documented in peripartum cardiomyopathy. The development of left ventricular thrombus (LVT) is a well-known complication in various cardiac conditions with the highest rate observed in acute anterior myocardial infarction and congestive heart failure (CHF) as a result of severe left ventricular (LV) systolic dysfunction , 2.The prevalence of LVT, especially in settings where early percutaneous coronary intervention (PCI) facilities are available, is seemingly reducing with estimates ranging between 5% and 15% , 3. SolhThe constellation, of endothelial injury, hypercoagulability, and blood stagnation, which are well described previously as Virchow's triad, is responsible for the formation of thrombus , 9. In ATransthoracic echocardiography (TTE) is still the widely employed modality in diagnosis of LVT because of its access, safety, and convenience. It has been demonstrated to have sensitivity of 90\u201395% and specificity of 85\u201390% in a setting of adequate imaging , 12 when E wave deceleration time and abnormal wall motion score index were both associated with LVT formation [Improved LV cavity assessment and thrombi detection using TTE contrast studies were noted to be better than noncontrast TTE, especially for mural (laminar) and small thrombus . This leormation .In this retrospective study, we reviewed demographic data and aetiology of LVT in patients undergoing echocardiography at the University of Maiduguri Teaching Hospital over a three-year period.We reviewed case notes and echocardiographic data of patient diagnosed with LVT using noncontrast transthoracic echocardiography at the University of Maiduguri Teaching Hospital, Maiduguri (UMTH), Nigeria, from January 2011 through December 2013. Data form was designed comprising patients' age, gender, associated comorbidities, and echocardiographic indices. E- and A-filling velocities, their ratio (E/A), and the deceleration time of E-wave velocity were determined from 3 to 5 consecutive cardiac cycles.The echocardiographic procedures were performed with MyLab 50CV (Esaote) and Siemens Acuson X300 with variable 1.7\u20132.2\u2009MHz transducer to ensure adequate imaging analyses. The diagnosis of LVT was reached when a mass was noted adjacent to the myocardium on multiple plane views throughout the cardiac cycle and associated regional wall motion abnormalities . RegionaDilated cardiomyopathy was diagnosed in the presence of globular LV with LVIDD of >56\u2009mm, LV sphericity index ratio of less than 1.5 and EF < 40% . Diagnos t-test. A P value of <0.05 was considered significant. The conduct of this study was approved by the Research and Ethics Committee of the UMTH as part of the Heart Failure Registry.The data was analysed using SPSS v 16.0 Chicago, IL, USA. Mean \u00b1 SD was derived for continuous variables and comparison was made using Student'sA total of 1302 transthoracic echocardiograms were performed from January 2011 through December 2013. Seventy eight (5.99%) studies were excluded due to incomplete imaging, inconclusive data, and poor image quality. Of the remaining 1224 echocardiograms, 162/1224 (13.24%) were reported as normal studies. One hundred and thirteen (10.64%) of the abnormal images were paediatric studies, while 949 (89.36%) were adult studies. All subjects included in this study came from various parts of the northeast geopolitical zone of Nigeria, where UMTH serves as the major referral tertiary hospital.P = 0.71). Male subjects with LVT were significantly older than the females . Abnormalities associated with LVT were observed in 782/949 (82.40%) of subjects. The demographic and echocardiographic profile of subjects with and without LVT is illustrated in The 949 abnormal adult echocardiograms reviewed were made of 463/949 (48.79%) males and 486/949 (51.21%) females. The mean age of all subjects with abnormal echocardiograms was 44.73 (16.73) years compared to 45.43 (13.44) for subjects with LVT. (Eighty four (8.85%) cases of LVT were identified. Forty one (4.32%) was recorded in males while 43/84 (4.53%) cases were recorded in females. Off-axis (free-style) imaging was used in identifying 12/84 (14.29%) cases. The highest prevalence of 39.29% (33/84) was observed in patients with dilated cardiomyopathy, followed by MI with a prevalence of 29.76% (25/84). Eighty seven percent of the cases of MI involved the anterior wall, with the remaining 13% involving the inferior and the inferior-posterior region. Of the patients having LVT following MI, old infarction was documented in 11/25 (44%), whilst 10/25 (40%) presented within the first week of the onset of symptoms. Only 4/25 (16%) of patients with MI presented with LVT within 24 hours of onset of symptoms. Eighty eight percent (22/25) of cases of myocardial infarction were observed in males. Peripartum cardiomyopathy accounted for 18/84 (21.43%) of the LVT, whereas HHD was responsible for 6/84 (7.14%) cases. The lowest prevalence of 2.38% (2/84) was observed in those with RHD. A gender-based distribution of the different aetiologies of LVT is illustrated in Among the 84 subjects with LVT, 11 (13.1%) presented for echocardiography with thromboembolic complications . There wNine (81.8%) of the subjects with thromboembolic complications presented with solitary apical thrombus while 2/11 (18.2%) had multiple LVT of varying sizes. All subjects presenting with thromboembolic complications from PPCM and DCM had an EF < 35%.Treatment modalities were identified in 76/84 (90.5%) including all cases that presented with thromboembolic phenomenon. These patients were treated using anticoagulant doses of low molecular weight heparin (enoxaparin), unfractionated heparin (for patients unable to afford enoxaparin), and warfarin adjusted to achieve therapeutic INR.Four (36.4%) of the patients that presented with thromboembolic complications (a case of stroke and two cases of gangrene and a case of pulmonary embolism) died during hospitalization. One subject with peripheral gangrene had an above the knee amputation, whilst one left the hospital against medical advice and died at home.Data on follow-up echocardiography at one month was identified in only 36/84 (42.9%) with 16/36 (44.4%) cases of complete resolution of LVT. Level of adherence and duration of anticoagulation could not be conclusively ascertained.The mean left ventricular end diastolic dimension in subjects with LVT was 60.45\u2009mm (7.65) with 69/84% (82.14%) having dilated left ventricular end diastolic dimension >56\u2009mm. The mean left ventricular EF was 28.83% (9.64). Left ventricular EF of <35% was recorded in 55/84 (65.48%) while 40/84 (47.6%) had an EF < 30%. Seventy eight (92.86%) of the subjects with LVT had an EF of <50%. Regional wall motion abnormality was recorded in 29/84 (34.52%), while left ventricular dyssynchrony was documented in 16/84 (19.05%). Left ventricular hypertrophy was documented in 12/84 (14.29%). Left ventricular apical aneurysm was observed in 1/84 (1.19%) subject while pseudoaneurysm with apical LVT was identified in 1/84 (1.19%). Echocardiographic profile of the subjects is illustrated in The various locations of LVT are illustrated in We report a prevalence of 8.85% for left ventricular thrombus among patients with abnormal echocardiogram over a three-year period at the University of Maiduguri Teaching Hospital. This to our knowledge is the first report on the prevalence of LVT among patients undergoing echocardiography from the northern part of Nigeria. Seventy six percent of LVT in our series involved the apical segments, in keeping with reports from other studies. The apex is the most common region involved in LVT in patients with MI as well as nonischemic cardiomyopathy.The highest prevalence of 39.3% was recorded among patients with nonischaemic DCM. This is in keeping with previous reports by other workers , 26. DilMyocardial infarction accounted for the second highest prevalence of 29.8%. Left ventricular thrombus is a well-documented complication of myocardial infarction, with prevalence varying from 60% in the prethrombotic era to between 5% and 15% in settings where early PCI is instituted , 28. HowMore cases of myocardial infarction were recorded in male subjects, reflecting the higher prevalence of coronary artery disease among males compared to females. Involvement of the anterolateral wall results in large area of wall motion abnormality, favouring stasis and thrombus formation . A combiPeripartum cardiomyopathy in our series had LVT prevalence of 21.4%. This is similar to what was reported by Sliwa et al. among black patients at Baragwanath Hospital , but higAlthough HHD constituted the most common diagnosis among the cases reviewed, the prevalence of LVT was 7.1%, all occurring in those with impaired LV systolic function. Information on LVT complicating HHD without MI or profound global hypokinesis is scarce. The role of hypertension in enhancing prothrombotic or hypercoagulable state by impacting on all components of the Virchow's triad, termed the thrombotic paradox of hypertension or the Birmingham paradox, was reported by Lip . In the Rheumatic heart disease is an uncommon cause of LVT in our series. The prevalence of 2.3% was observed in two patients having severe chronic rheumatic mitral regurgitation with dilated and poorly contractile ventricles. We speculate that the LVT observed in these patients is a result of the increased LVIDD and low EF rather than the rheumatic aetiology of valve lesion. Intracardiac thrombus in the setting of RHD is commonly observed in left atrium and left atrial appendage of patients with mitral stenosis , better About 13% of all subjects with LVT had thromboembolic complications at the time of presentation for echocardiography, mainly in patients with myocardial infarction and DCM. Stroke was the commonest presenting thromboembolic phenomenon among subjects with myocardial infarction, whilst peripheral gangrene predominated in those with DCM. Embolic complications were reported in about 10% of cases of MI in the prethrombolytic era . The oveDespite the advancements in the area of LVT assessment with the use of contrast agents, TTE is widely accepted as the primary screening tool for LVT in clinical practice, especially when the procedure is tailored to detection of LVT with use of multiple imaging planes including off-axis (free-style) imaging . Off-axiThe catastrophic thromboembolic risks of LVT may be reduced by appropriate treatment of MI using thrombolytics and, where available, PCI. Guidelines on antithrombotic therapy and prevention of thrombosis recommend the use of warfarin in patients with anterior MI and LVT, or high risk for LVT, as well as patients with systolic dysfunction and documented LVT . Given tOur study has a number of limitations. Being a retrospective study, we are unable to assess the outcome of LVT in the subjects. Given the higher accuracy of contrast echo for the detection of LVT, the prevalence reported in our study may be an underestimated, as some cases of laminar and small thrombi might have been missed out. Similarly, echocardiographic studies might not have been focused on detection of LVT in some cases, resulting in reduced yield. Our diagnosis of IHD is not supported by determination of cardiac markers. Assessment of other risk factors associated with intracardiac thrombosis has not been done, making assessment of causality rather inconclusive. However, the aim of our study was to determine the prevalence of LVT among patients undergoing transthoracic echo in our centre."}
+{"text": "Autonomic nervous system (ANS) dysfunction is present in up to one third of patients with tetanus. The prognostic value of ANS dysfunction is known in severe tetanus but its value is not well established in mild to moderate tetanus.Medical records of all patients admitted with tetanus at two academic tertiary care centers in Karachi, Pakistan were reviewed. The demographic, clinical and laboratory data was recorded and analyzed. ANS dysfunction was defined as presence of labile or persistent hypertension or hypotension and sinus tachycardia, tachyarrythmia or bradycardia on EKG. Patients were divided into two groups based on presence of ANS dysfunction (ANS group and non ANS group). Tetanus severity was classified on the basis of Ablett criteria.Ninety six  patients were admitted with the diagnosis over a period of 10 years. ANS group had 31 (32%) patients while non ANS group comprised of 65 (68%) patients. Both groups matched for age, gender, symptom severity, use of tetanus immunoglobulin and antibiotics. Twelve patients in ANS group had mild to moderate tetanus (Ablett I and II) and 19 patients had severe/very severe tetanus (Ablett III and IV). Fifteen (50%) patients in ANS group required ventilation as compared to 28 (45%) in non-ANS group (p = 0.09). Fourteen (47%) patients died in ANS group as compared to 10 (15%) in non ANS group (p= 0.002). Out of those 14 patients died in ANS group, six patients had mild to moderate tetanus and eight patients had severe/ very severe tetanus. Major cause of death was cardiac arrhythmias  in ANS group and respiratory arrest  in non ANS group. Ten (33%) patients had complete recovery in ANS group while in non ANS group 35(48%) patients had complete recovery (p= 0.05).ANS dysfunction was present in one third of our tetanus population. 40% patients with ANS dysfunction had only mild to moderate tetanus. ANS dysfunction, irrespective of the need of mechanical ventilation or severity of tetanus, predicted poor outcome. Tetanus is still a major health problem in developing world. Care of this potentially fatal, though preventable, disease has been revolutionized with advent of mechanical ventilation. However, still a significant minority, at least 10%, would die despite every effort , howeverAll patients admitted to two tertiary care centers in Karachi, Pakistan over a period of 10 years, were identified through ICD-9 coding system of the hospital medical records. The charts were reviewed retrospectively. The demographic, clinical, laboratory data was recorded and analyzed.The autonomic dysfunction was defined as presence of labile or persistent hypertension (>140/90 mmHg) or hypotension (<90/60 mmHg) and persistent sinus tachycardia (heart rate >100 bpm), tachyarrhythmia or bradycardia (heart rate <50 bpm) alternating with tachycardia on EKG. These values were recorded at resting state, not during tetanic spasm. Brief episodes of tachycardia or hypertension are common in ICU and could be related to pain or anxiety. The values in ICU were mostly recorded in sedated and relaxed position. Continuous automated blood pressure and heart rate monitoring was done in all ICU patients. Blood pressure and heart rate were checked every four hour for the ward patients. The data regarding arterial lines is not available. The values recorded during tetanic spasms were not included in the study. The decision to admit these patients was based mostly on availability of ICU beds. Patients with only locked jaw without any autonomic abnormalities on admission were electively admitted to ward.Severity of tetanus was classified based on Ablett criteria. The poor outcome was defined as either death or partial recovery at the time of discharge from the hospital. Partial recovery was defined as neck pain, back pain, walking difficulty and abnormal gait at discharge, in various combinations. Complete recovery was defined as absence of all of the symptoms and normal gait on examination at discharge.t test) methods.The data was analyzed on SPSS version 10.0. Statistical analysis employed descriptive and univariate (chi-square and Ninety six patients were identified. Sixty four (67%) were men and 32 (33%) were women. Their mean age was 44 (11\u201375) years. Identifiable risk factors were present in only 49 (51%) patients, recent trauma being most common which was noted in 27(28%) of the patients. Other risk factors were skin wounds, either infected or uninfected; 10 (11%), needle injury; 8 (9%) and recent surgery; 8 (9%).Most common clinical features were trismus; 89 (93%), neck stiffness; 73 (76%), muscle spasms; (67) 70%, followed by dysphagia; 57 (59%), back stiffness; 42 (44%), dysarthria; 19 (20%), abdominal pain; 10 (11%) and subjective breathing difficulty; 7 (8%).All patients received TIG  and almost all (99%) received benzodiazepine infusion. About one third (34%) of the patients received paralytics and 4 (5%) were also given magnesium sulphate. Majority of patients  were given antibiotics.The EKG abnormalities include sinus tachycardia in 44 (46%) patients, cardiac ischemia in 5 (5%), sinus bradycardia in 2 (2%) and heart block in 1 (1%) patient. Blood pressure abnormalities include persistently elevated blood pressure in 8 (8%) patients, persistent hypotension in 2 (2%) and labile hypertension in 14 (15%).Forty five (47%) patients recovered fully, 27 (28%) had partial recovery and 24 (25%) patients died. Major cause of death was cardiac arrhythmias  followed by respiratory arrest . All of the patients who had respiratory arrest were in general wards and never intubated. Fifty eight (60%) patients admitted to ICU. 43 (44%) required mechanical ventilation. Mean hospital stay was 17 (1\u201363) days. The hospital stay was prolonged in patients who required ventilation (25 vs 9 days)ANS group had 31 (32%) patients while non ANS group comprised of 65 (68%) patients.Severity of tetanus in ANS group was mild to moderate (Ablett I and II); 12 patients and severe/very severe (Ablett III and IV); 19 patients. 15 patients out of these 19 with severe tetanus required mechanical ventilation. Fourteen of 31 (47%) patients died in ANS group as compared to 10/62 (15%) in non ANS group (p= 0.002)  declare that they have no competing interests.MW: conceptualization, data analysis, manuscript preparation. BAK: data entry and analysis, statistical analysis, manuscript preparation. NT: data acquisition, manuscript preparation. RS: data acquisition, data analysis, manuscript preparation. NAS: conceptualization, manuscript preparation. NS: conceptualization, manuscript preparation.The pre-publication history for this paper can be accessed here:"}
+{"text": "Viral hepatitis C (VH C) is a global problem of the public health. Different interventions for achieving the Global Health Sector Strategy on viral hepatitis targets  were considered. Increased diagnosis and treatment rates would be required to achieve these targets in all countries, even with the introduction of high sustained viral response therapies.The latest global HCV disease burden estimates showed that about 71.1 million people worldwide are viremic, corresponding to a prevalence of 1%. The prevalence of HCV is not homogenous: the WHO Eastern-Mediterranean Region is with the highest number of infected subjects (15 millions), followed by the European Region (14 million). In Bulgaria, the incidence of VH C is 0.63-1.30 at 100 000 population (2008-2020) and in Pleven region is 0.38-3.8, respectively.Retrospective study was conducted upon epidemiological, demographic, clinical, laboratory and viral characteristics in fifty cases of VH C confirmed with positive anti-HCV, evaluated by ELISA. Thirty eight of cases were hospitalized in different clinics of the University Hospital \u201cDr Georgi Stranski\u201d-Pleven (2017-2018) and remainders were blood-donors registered in Regional Center of Transfusion Hematology-Pleven. Surgical interventions (26.32%), blood infusions (23.68%) and hemodialysis (15.79%) were at highest risk for VH C. Twenty five hospital patients were with chronic VH C (66%), five with cirrhosis (13%) and eight (21%) with acute hepatitis C. Twenty of the patients (53%) were asymptomatic about hepatitis and were hospitalized because of different comorbidities (p < 0.0005).We propose an algorithm for early diagnosis of VH C based on mandatory screening for anti-HCV in risk groups, especially before invasive procedures. The early detection of HCV infection will reduce the complications and nosocomial infections.\u2022\u2002Different scenarios developed to achieve the WHO Targets in all countries assume an implementation of national policies to prevent new infections and to diagnose current infections through screening.\u2022\u2002The early detection of HCV infection will reduce the complications and nosocomial infections."}
+{"text": "Most ingested foreign bodies pass through the gastrointestinal tract spontaneously. However, some foreign bodies may get impacted in the upper gastrointestinal tract. A variety of endoscopic techniques and instruments are indicated for the removal of such impacted foreign bodies. This study was conducted to find out the prevalence of successful endoscopic removal of foreign bodies.This descriptive cross-sectional study was conducted among patients who presented at the Department of Gastroenterology with complaints of upper gastrointestinal foreign body ingestion from 2/11/2008 to 23/07/2020 after taking ethical approval of the research proposal was taken from Institutional Review Board (Reference no 13). Convenient sampling was done. The data were entered into Microsoft Excel and analyzed in Statistical Package of Social Sciences version 22.A total of 119 cases were identified with foreign bodies ingestion. In hundred patients, foreign bodies 100 (84 %)  were extracted completely. Complete extraction failed in 19 (16%) patients. Six (5%) patients were treated by push technique and 10 (8.4%) patients with failed retrieval, received surgical intervention for foreign body removal.Endoscopic removal technique of foreign bodies in the upper gastrointestinal tract was successful in most of the cases and is associated with few complications. Data was collected from 20/01/2008 to 23/07/2020 retrospectively. The study was conducted at Gastroenterology Unit, Medicine Department, National Academy of Medical Sciences, Bir Hospital. The study included all patients with a history of impacted foreign bodies, confirmed by endoscopy in more than 18 years of age group. We excluded patients with a history of ingested foreign bodies but not detected on endoscopy, patients referred to other centers, incomplete records, or who underwent direct surgical intervention. All medical records including age, sex, type of foreign body, associated signs and symptoms, used endoscopic devices were reviewed. The sample size was calculated as follows,2 \u00d7 p \u00d7 q / e2n\u2003= Z2) \u00d7 (0.956) \u00d7 (1-0.956) / (0.04)2\u2003\u2003= 16p = prevalence of success rate in foreign body extraction as per Emra, et al. 95.6%q = 1-pe = margin of error, 4%Taking the non-response rate 10%, the calculated sample size is 111.However, 119 participants were included in our study. Convenient sampling was done. Written consent was obtained from all the participants.Various instruments (Forceps and Dormia baskets) were used to retrieve the impacted foreign bodies. Repeat endoscopy was done after the foreign body retrieval.The data were entered into Microsoft Excel and analyzed in Statistical Package of Social Sciences version 22.The total number of participants in our study was 119. In 100 (84%)  patients, foreign bodies were extracted completely. Complete extraction failed in 19 (16%) patients. Among patients in whom the foreign body was extracted completely, 58 (79.5%) were male patients and 42 (91.3%) were female patients. Six (5%) patients were treated by push technique and 10 (8.4%) patients with failed retrieval, received surgical intervention for foreign body removal.The percentage of complete removal was only 5 (56%) for <25 years of age but nearly 34 (87%) for 25-49 years and 40 (87%) in 50-74 years. Complete removal was 21 (83.3%) for the 75 years and above age group. About 42 (92%) of females and 58 (79.5%) of male patients had complete removal of foreign body. About 89 (87%) of cases with food as the foreign body had complete removal whereas 11 (68.8%) of non-food items were completely removed. Around 89 (83%) of the items located in the esophagus were removed completely whereas 11 (100%) of the non-esophagus items were removed. The complete removal percentage using forceps and Dormia basket was nearly the same .Seventy-three (61.3%) patients were male and 46 (38.3%) were female. One hundred and three (86.6%) cases of ingested foreign bodies were food whereas nonfood were in 16 (13.4%) patients respectively. Chicken bone and chicken were found in 51 (42.9%) patients and 29 (24.4%) patients respectively. Some patients had ingested fruit seeds, lapsi in 7 (5.9%) patients, and mango seed in 1 (0.8%). Other ingested meat like buff and mutton were observed in 6 (5%) patients and 4 (3.4%) patients respectively. Fishbone was found in 3 (2.5%). Jack fruit, a lump of food, vegetables were visualized in 1 (0.8%). True foreign bodies (nonfood) were found in 16 (13.4%). Five (4.2%) had accidentally ingested dentures. The wire was seen in 4 (3.3%) patients with denture impaction. Coin, hair, part of Percutaneous Endoscopic Gastrostomy (PEG) tube, pin, stone, and two buttons were observed in only 1 (0.8%) .About 46 (39%) of cases were of age 50-74 followed by 25-49 of 39 (32.8%), 75 and above the age 25 (21%). About 9 (8%) of cases were less than 25 years of age. Nearly 103 87% of the cases were related to food items. In about 108 (91%) of the location was esophagus. The most widely used tool was the Dormia basket followed by Shark tooth forceps, Crocodile forceps, and rat tooth forceps. 69 (58%) of cases were treated with a Dormia basket and the remaining using forceps.17. Our study concluded that the most common foreign bodies were food boluses, located in the esophagus (90.8%). Various other studies have suggested the esophagus as the common site of impaction of foreign bodies.20 Mosca S, et al. showed almost all the foreign bodies were found in the esophagus.21In this study, a total number of 11 9 patients had foreign body impaction in the upper gastrointestinal tract. Endoscopic procedures were performed in almost all patients within 24 hours of attending the hospital. Foreign body impaction was more prevalent in male patients (61.3%). These findings were consistent with several studies from eastern and western regions.23 A study from Manipal Teaching Hospital by Koirala K, et al. compared esophageal foreign bodies in pediatric and adult populations the result of which showed that out of total cases of foreign body impaction, 44.4% of patients were children and 55.5% were adults. The coin was the most common foreign body in the pediatric population (82.1%) whereas bones were the commonest ones (91.4%) in adults.24 Two previous studies from Nepal showed chicken bones were a common foreign body.6 Bony foreign bodies comprised the majority of identified foreign bodies.19 In our study, the majority of foreign bodies were pieces of bone (chicken bone 42.9% and fishbone 2.5%) and meat boluses. The other foreign bodies included food boluses, fruit seeds, dentures, wire, coin, button, hair, stones were found in each patient (0.8%). In our study, most patients were in the age group of 50-74 years (38.7%), followed by 25-49 years (32.8%). The most common age group was the fifth decade of life in a previous study from Nepal and India.23In a prospective study done by Shrestha D, et al. from Nepal in patients with a clinical diagnosis of esophageal foreign body from July 2013 to July 2017, out of 1 01 cases of esophageal foreign body, there were 57% cases of chicken bone, followed by 17% mutton bone and 12% meat bolus which was consistent with our study.8Different endoscopic methods and equipments were used depending upon the types of foreign bodies. Food bolus was removed either in bloc or in a piecemeal fashion with help of a retrieval basket or forceps. Endoscopic management was done in 109 patients. Among them, complete extraction of foreign bodies was achieved with the help of Dormia basket in 58 patients (84.1%), followed by various types of forceps or snare. Gentle pressure was applied with the tip of the endoscope to the esophageal food bolus, following air insufflation The most frequently used accessory devices were retrieval baskets , retrieval forceps, or polypectomy snares . Other studies also showed retrieval net, rat tooth forceps as common retrieval systems used. It is suggested from animal studies and clinical practice that the retrieval net is appropriate for the removal of smooth objects .25 We reported a 98.8% success rate of endoscopic removal of foreign bodies and a 1.25% failure rate whereas a study from China success rate was 94.1% and the failure rate was 5.9%. Most of the foreign bodies that fail endoscopic removal were dental prostheses, iron slices, or complex and ultra-long objects.5In our study, one denture without wire could be removed from the esophagus but failed to retrieve in 4 patients (80%). Open thoracotomy was required in one patient to remove such a foreign body. Those foreign bodies are likely to cause laceration and perforation because of impaction in the esophagus. Ill-fitting dentures may easily dislodge in the esophagus during chewing food or drinking. Three (75%) cases were referred to the otolaryngology department. A similar study from the ENT department of the same center showed meat and bone (68.33%) were the commonest foreign body in the esophagus, followed by dentures (15.5%). All dentures were removed under conscious sedation but one required open thoracotomy.29 Similarly Wu WT, et al. also focused on the early intervention within 24 hours for minimizing the complications. A total of 172 patients (52.7%) were found to have ingested foreign bodies; 73.5% were removed smoothly, 10.3% were treated by push technique and 16.0% with failed retrieval received alternative treatments.30In a study done by Yao CC, et al. endoscopic management was a safe and highly effective procedure in extracting foreign body ingestion and food bolus impaction. 93.5% of foreign bodies in the current study cohort were successfully extracted and 5 patients required surgical interventions.19The most common underlying pathology was esophageal stricture . Nearly half of the patients (49.9%) developed complications. As the duration of impaction increased, the success rate by endoscopy decreased.Most upper GI foreign bodies in adults are related to food bolus impaction with bone and meat. Therapeutic endoscopy by an experienced skilled endoscopist with suitable accessories is a reliable, safe, and effective method in managing foreign bodies from the upper gastrointestinal tract."}
+{"text": "The coronavirus epidemic started in Tunisia on March 12, 2020. Nursing students in hospital internship are among the professional categories most exposed to the virus.To identify stressors during a COVID-19 pandemic among senior nursing students at the military health school.Descriptive, retrospective study conducted in March 2021 of the 60 senior nursing students enrolled in the military health school. We developed a self-questionnaire with questions about potential stressors during a COVID-19 pandemic.Our population was 54.3% male and 45.7% female. The mean age was 22.6 years. Most of the senior students (54.3%) worked in units dedicated to the care of patients with COVID-19. The main stressors reported by the students were fear of seeing patients die (84%), contaminating family (81.4%), being assigned to a COVID unit (78%), lack of protective equipment (75%), catching COVID-19 (67%), contaminating colleagues (64%), delay in teaching (61%), lack of competence and making mistakes (53%).The COVID-19 pandemic is a time of major stress for nursing students. Psychological support should be provided.No significant relationships."}
+{"text": "Community-acquired pneumonia (CAP) is an important complication in immunocompromised adults (ICAs). In hospitalized patients, the burden of CAP in ICAs is not well defined. The primary objective of this study was to define incidence, epidemiology, and outcomes of ICAs hospitalized with CAP in the city of Louisville. The secondary objective of this study was to estimate the burden of CAP in ICAs in the US.This was a prospective population-based cohort study of consecutive hospitalized adult Louisville residents with CAP at all adult hospitals in Louisville from 1 June 2014 to 31 May 2016. An ICA was defined as a patient with any of the following medical conditions or treatments: (1) primary immunodeficiency disease; (2) advanced-stage cancer (stage III or IV cancer or hematologic cancer); (3) advanced HIV infection (CD4 T-lymphocyte count < 200 cells/mL or < 14%); (4) solid organ transplantation; (5) hematopoietic stem cell transplantation; (6) receiving cancer chemotherapy; (7) receiving biological immune modulators; (8) receiving corticosteroid therapy with a dose \u2265 20 mg prednisone or equivalent daily for at least 14 days prior to hospitalization; or (9) receiving disease-modifying antirheumatic drugs (DMARDs). The annual population-based CAP incidence among ICAs was calculated. Mortality was evaluated during hospitalization and at 30 days, 6 months, and 1 year after hospitalization.Figure\u00a01 depicts the immunocompromising conditions. Per 100,000 adults in Louisville, each year 75 ICAs are hospitalized with CAP (95% CI: 68-78), corresponding to an estimated 190,106 ICAs hospitalized with CAP in the US. Mortality during hospitalization was 8% in ICAs vs 6% in non-ICAs; at 30 days 23% in ICAs vs 11% in non-ICAs, at 6 months 42% in ICAs vs 20% in non-ICAs, and at 1 year 52% in ICAs vs 27% in non-ICAs.A total of 7449 unique patients were included, with 854 (11%) ICAs identified. This study indicates that nearly one out of nine hospitalized CAP patients are immunocompromised, and 190,000 ICAs may be hospitalized due to CAP each year in the US. We found a twofold increase in mortality at every time point after discharge for ICAs compared to non-ICAs hospitalized due to CAP. Further strategies to prevent CAP and improve outcomes in ICAs hospitalized with CAP are necessary.Forest W. Arnold, DO, MSc, Gilead Sciences, Inc.: Grant/Research Support."}
+{"text": "We are facing a growing popularity of gambling, partly due to the rapid rise of internet related technologies. This growth has been linked to a considerable increase in problem gambling and gambling disorder, which has been an established non-substance addiction. The aim of our study was to assess the prevalence rate of gambling disorder among the Slovenian population.National Survey on the Use of Tobacco, Alcohol and Other Drugs was conducted in 2018 on a nationally representative sample , using mixed-mode data collection (CAWI and CAPI). Responses were obtained from 9,161 respondents, of those 18.4%  reported to have gambled in the last 12 months (i.e. gamblers). Gambling disorder symptoms were assessed using Berlin Inventory of Gambling Behavior - Screening, consisting of 14 items with a yes/no response option, which measure 9 gambling disorder criteria (DSM-V). Participants who reported at least 5 out of 9 gambling disorder criteria were classified as disordered.Data shows that 4.3% of Slovenian gamblers met the criteria for gambling disorder. Significantly higher shares were observed among men  and among younger generations (highest shares among 15-19 year olds (19.4%) and 20-24 year olds (14.5%)). The same goes for money spent for gambling. Namely, males  and younger generations (highest shares among 20-24 year olds (9.2%) and 30-34 year-olds (6.9%)) were more likely to spend more than 100 EUR in a day for gambling.Data obtained in the present study indicates the extent of gambling disorder symptomatology and highlights key demographic groups with risk for gambling disorder. These findings are consistent with previous comparable studies and provide a basis for tailored public health measures in Slovenia with an emphasis on early intervention.\u2022\u20024.3% of Slovenian residents, who engaged in gambling in the last 12 months met the criteria for gambling disorder.\u2022\u2002Males and younger generations were more likely to report gambling disorder symptoms and spent more money on gambling. The data shows the need for tailored public health measures."}
+{"text": "In this crisis situation when everybody has been emphasizing on preventive measures, screening, early recognition and provision of necessary equipment, less emphasis has been laid on the mental health of the sufferers who have been listening news and following social media reporting catastrophe linked with COVID 19.To look for the psychiatric morbidity and associated socio-demographic factors among patients tested positive and isolated for covid-19All patients tested positive for covid-19 and admitted in Covid-19 ward of Malir hospital without any associated complications were included in the study. General Health Questionare-12 (GHQ-12) was administered to look for the presence of psychiatric morbidity. Chi-square test and binary logistic regression analysis were the tests applied to look for the relationship of various socio-demographic factors with presence of psychiatric morbidity among the target population.Out of 61 patients included in the study, 45 (73.7%) showed the presence of psychiatric morbidity while 16 (26.3%) did not show psychiatric morbidity when screened with GHQ-12. 43 (70.4%) were male while 18 (29.6%) were female. Mean age of the patients was 35.21 \u00b12.355 years. Regression analysis revealed that advanced age and female gender have statistically significant relationship  with presence of psychiatric morbidity among patients of covid-19.A considerable number of patients had psychiatric morbidity after being tested positive for covid-19 and isolated in the health facility. Female patients and patients with age more than 40 years were found to be more at risk of developing psychiatric morbidity among the patients admitted in covid-19ward."}
+{"text": "Delirium is characterized as a short-term consciousness and cognition disturbance which tends to fluctuate during the course of the day. It is a common and serious problem, mainly in hospitalized older adults, potentially avoidable and often poorly recognized.We propose an analysis on the theme through a work that evaluates the requests for psychiatric consultation made in a district hospital in Portugal during the course of 12 months.We identified all patients on the requests for psychiatric consultation and obtained a demographic, clinical and consultation requests by medical specialties data and conducted statistical analysis using Excel.We identified 106 consultation requests, in which 41 cases were eventually diagnosed as delirium. Most (83%) were hyperactive delirium, 12% were hypoactive delirium and 5% were mixed delirium. Incidence was higher in males (59%) and in those aged between 66 and 80 years old (56.1%). Most consultation requests were made by Internal Medicine (46.3%), followed by General Surgery (26.8%), Pulmonology (14.6%), Orthopedics (9.8%) and Neurology (2.5%). Finally, we analyzed which symptoms mentioned in the request made physicians consider requesting a psychiatric evaluation. Approximately half of the cases (48.8%) reported psychomotor agitation, followed by temporal/spatial disorientation (41.5%) and aggressive behaviour (17.1%).We highlight a still notorious lack of proper identification of delirium, resulting in symptoms being incorrectly interpreted as a psychiatric disorder. This may cause a delay in the adequate diagnosis and management of the condition, increasing the morbidity and mortality of patients.No significant relationships."}
+{"text": "We aimed to ascertain the real-world diagnostic accuracy of bone scintigraphy in combination with free light chain (FLC) assessment for transthyretin (ATTR) cardiac amyloidosis (CA) using the histopathological diagnosis derived from endomyocardial biopsy (EMB) as a reference standard. We retrospectively analyzed 102 patients (22% women) with suspected CA from seven Austrian amyloidosis referral centers. The inclusion criteria comprised the available results of bone scintigraphy, FLC assessment, and EMB with histopathological analysis. ATTR and AL were diagnosed in 60 and 21 patients , respectively, and concomitant AL and ATTR was identified in one patient. The specificity and positive predictive value (PPV) of Perugini score \u2265 2 for ATTR CA were 95% and 96%. AL was diagnosed in three out of 31 patients (10%) who had evidence of monoclonal proteins and a Perugini score \u2265 2. When excluding all patients with detectable monoclonal proteins (n = 62) from analyses, the PPV of Perugini score \u2265 2 for ATTR CA was 100% and the NPV of Perugini score < 2 for ATTR CA was 79%. Conclusively, ATTR CA can be diagnosed non-invasively in the case of a Perugini score \u2265 2 and an unremarkable FLC assessment. However, tissue biopsy is mandatory in suspected CA in any other constellation of non-invasive diagnostic work-up. Cardiac amyloidosis (CA) is an infiltrative storage disease causing progressive heart failure . It is cAlthough the diagnosis of AL requires organ biopsy with the typing of deposits, it can be ruled out non-invasively using free light chain (FLC) assessment . ATTR CAThis was a multicenter retrospective analysis including patients with suspected CA and diagnostic work-up conducted between 2017 and 2020 in Austria. The inclusion criteria comprised available results of (1) bone scintigraphy, (2) FLC assessment, and (3) EMB with histopathological tissue analysis. Ten contacted referral centers for cardiac amyloidosis throughout Austria performed a systematic retrospective medical record search and seven sites provided data from 109 patients, of whom 102 fulfilled all inclusion criteria. Scintigraphy was performed using a 99 m technetium-labeled tracer and planar acquisition. Cardiac tracer uptake was visually graded using the Perugini score, into grade 0 (no uptake), grade 1 (faint uptake), grade 2 (uptake similar to ribs), and grade 3 (uptake more than ribs) [FLC assessment included the quantification of the serum kappa-to-lambda ratio and immunofixation electrophoresis (IFE) in both serum and urine. The estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease formula. The presence of monoclonal protein was defined by an abnormal FLC ratio  or documented monoclonal band in serum or urine IFE . p-value < 0.05 was considered statistically significant. All statistical analyses were performed using IBM SPSS Statistics Version 27 .Categorical variables are expressed as counts with percentages, continuous variables as means \u00b1 standard deviation or medians with quartiles, as appropriate. Diagnostic accuracy read-outs of Perugini score for EMB-derived amyloid subtyping were expressed as sensitivity, negative predictive value (NPV), specificity, and PPV. A TTR  and another patient had one mutation .The study cohort consisted of 102 patients (22% women) and the number of patients provided per center ranged from 2 to 46. The number of patients per year increased from 15 patients in 2017 to 32 patients in 2020. Median age was 75 (68\u201378) years and median N-terminal B-type natriuretic peptide (NT-proBNP) was 2652 (1580\u20135167) pg/mL. Among 85 patients with Congo-red-positive EMBs (83%), ATTR CA was diagnosed in 60 patients (71%) and AL CA in 21 patients (25%), and one further patient had concomitant AL and ATTR. Other diagnoses included ApoA4 amyloidosis (n = 2) and AA amyloidosis (n = 1), whereas amyloidosis was ruled out in 17 patients (20%). Among patients with ATTR, 2 (3%) had the hereditary form (hATTR) and 59 (97%) had the wild-type form (wtATTR). One patient with hATTR had two variants in p = 0.003), were older (median age 77 (73\u201380) vs. 70 (60\u201376) years, p < 0.001), and were less often women . Among the two patients with hATTR, the patient carrying two mutations had evidence of monoclonal protein due to an abnormal FLC ratio of 1.757 (eGFR of 78 mL/min/1.73 m\u00b2), whereas the other mutation-carrier had unremarkable FLC assessment results. Further baseline characteristics are shown in Scintigraphy revealed a Perugini score of 0/1 in 45 patients (44%) and a Perugini score of 2/3 in 57 patients (56%). Single-photon emission computed tomography (SPECT) was performed in 56% of scintigraphies. FLC assessment was indicative of monoclonal protein in 62 patients (61%) and unremarkable in 40 patients (39%). Among these 62 patients with FLC assessment indicative of monoclonal protein, 11 (18%) had monoclonal bands, 14 (23%) had an abnormal FLC ratio, and 37 (60%) had both a monoclonal band and an abnormal FLC ratio. Of those with monoclonal bands (n = 48), there were 22 (46%) with an isolated monoclonal band in their serum, 2 (4%) with an isolated monoclonal band in their urine, and 24 (50%) with monoclonal bands both in their serum and urine. Patients with a Perugini score \u22652 compared to those with a Perugini score < 2 had evidence of monoclonal bands less often . Thus, the specificity and PPV of Perugini score \u2265 2 for ATTR CA were 95% and 96%. Counts of EMB-derived diagnoses stratified by Perugini score are illustrated in In a retrospective, multicenter study including patients with suspected cardiac amyloidosis, bone scintigraphy with Perugini score \u2265 2 yielded 100% specificity and 100% PPV for cardiac ATTR amyloidosis if AL was ruled out by means of FLC assessment. However, 10% of patients with ATTR and unremarkable FLC assessment results had a Perugini score < 2, and a Perugini score of <2 had an NPV of 79% for ATTR CA. These data reflect clinical practice throughout Austria and as such provide contemporary and novel insights into the diagnostic accuracy of bone scintigraphy when adopted in a real-world setting. The data confirm that ATTR CA can occur with all grades of myocardial tracer uptake during scintigraphy. Particularly at early stages with a less severe extent of amyloid load, ATTR CA can be associated with no or faint myocardial tracer uptake . Of noteConfirming the overall excellent diagnostic accuracy of bone scintigraphy for the diagnosis of ATTR CA, the results of our study are in line with existing literature. For instance, in a recent meta-analysis involving 39 studies with a total of 3636 patients, the pooled sensitivity and specificity values of visual scoring using bone scintigraphy for the diagnosis of ATTR CA were 97% and 96%, respectively . InteresThe differentiation of CA from other cardiomyopathies with a hypertrophic phenotype can be challenging. Clinically relevant phenocopies include hypertrophic cardiomyopathy, hypertensive heart disease, athlete\u2019s heart, and, rarely, arrhythmogenic right ventricular cardiomyopathy ,25. In pThe limitations of our study include its retrospective character, potentially introducing selection bias, which is indicated by the relatively high proportion of patients with evidence of monoclonal protein. This may impair the generalizability of absolute counts reported in our study. The assessment of baseline characteristics such as symptoms, medical history including red flags of CA, and features of echocardiography was beyond the scope of our study, which is another limitation. Scintigraphy tracers varied by site due to different protocols, and scintigraphy was partly based on planar images, because SPECT was not routinely performed at all participating sites during the study period. Nevertheless, the studied population likely covers a vast majority of the patients with suspected CA undergoing both non-invasive diagnostic work-up and EMB in Austria between 2017 and 2020.These real-world data acquired throughout Austria confirm that ATTR CA can be diagnosed using bone scintigraphy in the case of unremarkable FLC assessment results. They also underscore that tissue biopsy and histopathological analysis are required in any patient with suspected amyloidosis and evidence of monoclonal protein, irrespective of the scintigraphic result. Given that a Perugini score < 2 is not suited to rule out ATTR CA, tissue biopsy should be considered in any patient with suspected CA in the case of a Perugini score < 2."}
+{"text": "We diagnosed 66 peripheral nerve injuries in 34 patients who survived severe coronavirus disease 2019 (COVID-19). We combine this new data with published case series re-analyzed here  to provide a comprehensive accounting of lesion sites. The most common are ulnar (25.1%), common fibular (15.8%), sciatic (13.1%), median (9.8%), brachial plexus (8.7%) and radial (8.2%) nerves at sites known to be vulnerable to mechanical loading. Protection of peripheral nerves should be prioritized in the care of COVID-19 patients. To this end, we report proof of concept data of the feasibility for a wearable, wireless pressure sensor to provide real time monitoring in the intensive care unit setting. Severe coronavirus disease 2019 (COVID-19) frequently requires intensive care unit (ICU) admission and prolonged periods of mechanical ventilation. ICU acquired weakness (ICU-AW) is an established neuromuscular complication of severe COVID-19 . ICU-AW Unfortunately, the recovery from PNI is notoriously slow and frequently incomplete in the general population , and theStudy approval was granted by the Northwestern University Institutional Review Board. Patients were identified in retrospective fashion for admissions between April 1, 2020 and March 31, 2021 to 1 of 3 academically affiliated medical centers. This included 2 inpatient rehabilitation hospitals  and 1 tertiary care hospital . For the majority of PNIs (62 out of 66), the diagnosis and localization were supported by electrodiagnostic testing and/or neuromuscular ultrasound , as well as additional published cases from the same site n\u2009=\u200912) , we calc2 , we caWhen our current data is combined with prior case series of PNIs in survivors of COVID-19 Table , there aWe report on a large case series of 34 patients with 66 PNIs associated with survival from severe COVID-19. In majority of these cases there are\u2009\u2265\u20092 PNIs affecting the same person , which highlights the handful of key anatomical locations that require extra attention to protect nerve health in the hospital setting as well as demonstrates the feasibility of a wearable, wireless pressure sensing system that can provide real time feedback in the ICU setting."}
+{"text": "CDH1 (E-cadherin) result in increased lifetime risk of diffuse-type gastric cancer and lobular breast cancer. CDH1 variants are also associated with hereditary cleft lip and palate (CLP), the mechanism of which is not well understood. We sought to determine the prevalence of CLP in families who carry P/LP CDH1 variants. Patients with P/LP CDH1 variants who were enrolled in a prospective clinical trial were reviewed (NCT03030404). The cohort included 299 individuals from 153 families that had 80 unique P/LP variants in CDH1. The rate of CLP was 19% (29/153) in families reporting CLP in at least one family member, and 2.7% (8/299) among individuals with confirmed germline CDH1 P/LP variants. There were 22 unique variants in CDH1 among the 29 families that reported CLP, or a CLP rate of 27.5% per variant (22/80). 10 of the variants were not previously reported to be associated with CLP. We observed that 24% (7/29) of CLP-associated gene variants involved large-scale (\u22651 exon) deletions. Among families with CLP, 69% (20/29) had a member diagnosed with gastric cancer, and 79% (23/29) had a member with breast cancer, which were similar to rates observed in non-CLP families (p >0.3 for both). Our analysis suggests that the prevalence of CLP in families with germline CDH1 P/LP variants was high in this large cohort, and there was no genotype-phenotype pattern. Genetic testing for CDH1 variants should be considered in families with CLP and history of either diffuse-type gastric or lobular breast cancer.Pathogenic and likely pathogenic (P/LP) germline variants in the tumor suppressor gene  Lifetime disease penetrance estimates for gastric cancer and breast cancer in patients bearing a P/LP variant in CDH1 are approximately 25\u201342% and 42\u201355%, respectively  and cleft lip and palate (CLP). CLP, the most common congenital craniofacial abnormality, is a uni- or bilateral non-union of pharyngeal arch 1 structures and occurs in approximately 1 in 700 live births  from 153 different families, the majority of whom identified as White (CDH1 P/LP variants was 2.7% (8/299), 19% (29/153) of families identified at least one relative with CLP . Of the study participants and their relatives identified with CLP (n = 47), 15 were positive for a P/LP variant in CDH1, 1 was an obligate carrier, and 31 were untested but at-risk to carry the familial CDH1 variant. Individuals with CLP were 45% (21/47) female, 19% (4/21) of whom had a personal history of breast cancer. Advanced gastric cancer was identified in 13% (6/47) of individuals with CLP. For families with CLP, 69% (20/29) reported at least one member with advanced gastric cancer, and 79% (23/29) reported breast cancer, which were similar to rates observed in non-CLP families .To evaluate the association between as White . AlthougCDH1 genotype of the cohort . Truncation of E-cadherin was predicted in 55% (16/29) of families reporting CLP based on either nonsense or frameshift variants in CDH1  compared with 21 missense mutations in the CLP-negative families (17%). The missense cryptic splice variant in the CLP-positive subgroup was not located within a cadherin-repeat linker region. Surprisingly, variants located at EC-EC linker regions were found in families without a history of CLP. The most common location for a CDH1 variant in both subgroups was in EC4. The frequency of variants of intracytoplasmic or transmembrane domains were similar in both CLP-positive and CLP-negative groups.Next, we analyzed the e cohort . There wwith CLP . The rat in CDH1 . An addiCDH1 P/LP variants. The rarity of DGLBC syndrome and CDH1 P/LP variants presents challenges for any analysis. A prior study of CDH1 variant data pooled from the literature and public genetic variation databases found that 13% of CDH1 variants were associated with syndromic CLP (only DGLBC and Blepharocheilodontic syndrome) and non-syndromic CLP  pathway . Chi-squared statistical test was used where appropriate.The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Patients were enrolled in National Institutes of Health (NIH) protocol number 17-C-0043 (NCT ID: NCT03030404) from 2017 to 2021. The study was approved by the institutional review board of the National Institutes of Health (reference number 385481) and informed consent was taken from all patients. Patients were enrolled if they had positive genotyping for a P/LP variant in CDH1 pathogenic variants identified a family member with cleft lip/palate. This rate of cleft lip/palate associated with germline CDH1 variants should be incorporated into considerations for genetic testing in patients with a personal or family history of diffuse gastric cancer or lobular breast cancer.Approximately 1 in 5 families with germline"}
+{"text": "The inverted papilloma is a benign neoplasm, prone to malignancy, and bearing a high rate of post-op recurrence. There is much debate in the literature concerning the issue that an endoscopic approach may offer a benefit over an external approach.Demonstrate the efficacy of an endonasal endoscopic approach in the treatment of inverted papilloma.Retrospective.Retrospective analysis of patients with inverted papilloma operated at the University Hospital - FMUSP from 1994 to 2004.Twenty-eight patients' records were studied. Nine patients (32.1%) had tumor recurrence, one being operated via the endoscopic method and eight by external approach.Krouse's staging system for inverted papillomas can facilitate both treatment planning and comparison of surgical outcomes. The use of the endoscopic approach resulted in fewer relapses than when the external one was used in cases with the same tumor staging.The use of the endoscope in this type of surgical treatment is an important success factor in the treatment of inverted papilloma. The inverted papilloma is a benign neoplasia that has its origin in the lateral nasal wall epithelium. Histologically, it is characterized by an epithelial growth towards the stroma1. These are rare tumors, with an incidence of 0.5 to 1.5 cases per 100 thousand inhabitantsThey mainly affect male patients, between the 5th and 6th decades of life and cause nasal obstruction, rhinorrhea and epistaxisThus, with the progress of endonasal endoscopic surgical technique, this treatment option for the nasosinusal inverted papilloma is under discussion, being compared to traditional external approaches. In the present study we compared the postoperative results of both surgical techniques, staging patients according to the classification proposed by KrouseWe studied the charts of all the patients diagnosed with nasosinusal inverted papillomas who were operated upon at the Department of Otorhinolaryngology of the University Hospital of the Medical School of the University of S\u00e3o Paulo (HC/FMUSP) between January, 1994 and April, 2004, after proper approval by the Hospital Ethics Committee. Twenty-eight charts had all the necessary information and minimum follow up of 4 months.All the patients underwent preoperative CT Scan and were divided in four staging groups, based on the Krouse's5 classification for the nasosinusal inverted papilloma , Table 4The study includes information on patient's gender, tumor side, time from symptoms onset until medical consultation, nasal obstruction, rhinorrhea, epistaxis and headache, prior treatment, papilloma-associated squamous cell carcinoma areas, intra and post operative complications, recurrence and postoperative follow up.Patients' treatment was always surgical, aiming at full tumor removal and also of the periosteum of the tumor insertion region. External, endonasal endoscopic, or a combined approach was decided upon based on tumor extension and site. Nonetheless, due to advances in endonasal endoscopic surgical techniques that have happened during the study period (1994-2004), there has been a trend towards external approach in the patients operated early on, and more endoscopic or combined approaches in the more recent cases, even in extensive tumors.Of the 28 studied patients with nasosinusal inverted papillomas, there was male prevalence - 21 cases (75%). Seven patients were females (25%). Tumor involved the right side in 13 patients (46.4%) and the left side in 15 (53.6%), and there was no bilateral involvement. Age varied from 18 to 70 years, with average of 52.9 years. Symptoms onset until consultation at the University Hospital - USP, varied much, between 3 and 240 months, with an average time span of 59.2 months. Regarding main symptoms, 27 patients presented nasal obstruction (96.4%), 20 rhinorrhea (71.4%), 13 epistaxis (46.4%) and 16 headache (57.1%). Six patients (21.4%) had already been operated upon in another service, one of them had undergone two operations and another one had had five surgeries.Based on the Krouse's classification, considering preoperative paranasal sinus CT Scan and the presence of tumor malignancy, we had two patients in T1 (7.1%), seven cases in T2 (25.0%), 18 T3 (64.3%) and one T4 patient (3.6%) with squamous cell carcinoma in the pathology exam. External surgical approach was carried out via transmaxillary sublabial in 12 patients (42.85%). Twelve cases were operated upon only endoscopically (42.85%) and four of them underwent combined surgery - endoscopic and external with sublabial incision (14.3%). The two T1 cases were operated endoscopically (100%). Among the seven T2 patients: three suffered endoscopic surgery (42.85%), three external (42.85%) and one was combined (14.3%). Eighteen T3 cases: seven endoscopic (38.9%), eight external (44.4%) and three combined (16.7%). The only T4 case was operated through an external approach (100%).The rate of surgical complications was low, there was one case of sphenopalatine artery injury (3.6%), without other intra-operative complications. Two patients (7.1%) had synechia in the postop, one in the middle meatus and another between the lower conchae and the nasal septum.There was tumor recurrence in nine patients (32.1%), with diagnostic time between 4 and 45 months, 11 months in average. Average postop follow up was of 32.7 months, varying between 4 and 92 months. Among the nine cases of tumor recurrence, two had already been operated in another facility (22.2%). There was no recurrence in any of the two T1 cases. One among the seven T2 cases presented recurrence (14.3%), and this one was operated via the external approach. Seven patients among 18 T3 had recurrences (38.9%), with one endoscopic case (14.3%) and six external approaches (85.7%). The T4 patient had a recurrence (100%).When we consider the number of recurrence cases divided by the total number of patients operated by surgical approach, separated by staging, we obtained: T2- no recurrence case among the three endoscopic cases and one among the three external approaches (33.3%). The only patient operated by the combined approach had no recurrence during the study period. T3- endoscopic: one recurrence among the seven cases (14.3%), external: six recurrences in eight operated cases (75%) and combined: no recurrence. T4- external: one case (100%). Globally speaking, the endoscopic approach presented recurrences in 12 operated cases (8.33%), the external approach had eight in twelve (66.66%) and the combined approach did not present recurrence (0%).Inverted papilloma is a benign tumor of the lateral nasal wall and the paranasal sinusesAlthough it is a benign lesion, the inverted papilloma is locally aggressive, bears high recurrence rates and is associated to squamous cell carcinomas in 5 to 15% of the casesKrouse's classification for the inverted papilloma is based on preoperative CT Scan and the presence of malignant disease, allowing for surgical planning, but also a standardization to compare postoperative resultsThe present review showed two cases staged as T1 (7.1%), and both of them were approached endoscopically, without recurrence and one T4 case (3.6%) with squamous cell carcinoma associated, operated externally and with postoperative tumor recurrence. Since treatment modality was the same in T1 and T4 cases, we are unable to compare surgical approaches.Among the seven T2 cases, there was one recurrence among the three cases operated externally (33.3%) and there was no recurrence in the three endoscopic cases and in the combined approach patient. However, T3 group is the one with the largest number of patients and the one that allows better comparison among treatment modalities. Eighteen T3 cases were operated, seven via endoscopy, with one recurrence (14.3%); and eight externally with six recurrences (75%); and three cases operated via the combined approach, without recurrences, suggesting that the endoscopic approach may be beneficial in the nasosinusal papilloma surgery exclusively or in combination with the external access, since it allows better visualization of tumor extension and its insertion.Our ten year review with 28 cases of nasosinusal inverted papilloma pointed to a greater trend towards recurrence among the cases with more tumoral extension. The endonasal endoscopic approach used alone or in combination with the external access proved to be efficient and bearing lower tumor recurrence rates when compared to the external approach alone in cases classified as T2 and T3, according to Krouse's classification. Thus, we conclude that the endoscope use, during surgery, is an important tool in order to obtain success in the treatment of nasosinusal inverted papilloma."}
+{"text": "Psoriasis affects approximately 2\u20133% of the population worldwide, although the overall prevalence in Asia is <0.5%. Scalp psoriasis is a common initial presentation of psoriasis, which affects almost 80% of patients with psoriasis.This retrospective descriptive study investigated 1,671 patients with psoriasis with scalp involvement registered with the Malaysian Psoriasis Registry (MPR) from January 2007 to December 2018.A total of 21,859 patients with psoriasis were registered with the MPR during the study period; among them, scalp involvement was seen in 7.6% . Female sex preponderance (61%) was observed in the majority of Malay patients (58.5%), followed by the Chinese (16.9%), Indian (17.1%) and other ethnic patients (7.5%). A positive family history of psoriasis was identified in 22.7% (n=380). Approximately 34.8% (n=581) and 11% (n=172) of the patients had nail changes and psoriatic arthropathy, respectively. The mainstay treatment modality was topical treatment (93.6%), followed by systemic therapy (10%) and phototherapy (0.5%). The comorbidities found among the patients with scalp psoriasis included hypertension (27.9%), obesity (26%), dyslipidaemia (21%), diabetes mellitus (18.4%), ischaemic heart disease (5.4%) and cerebrovascular disease (1.3%). Approximately 23% reported a Dermatology Life Quality Index (DLQI) of >10, which indicated moderate-to-severe impairment.The proportion of patients with psoriasis with scalp involvement in our study (7.6%) is much lower than previous reports. Scalp psoriasis markedly negatively impacts the DLQI. Herein, we describe the demographics, clinical characteristics, treatment given and quality of life among patients with scalp psoriasis in Malaysia using data obtained over a 12-year period from the Malaysian Psoriasis Registry (MPR).Psoriasis is a common, chronic, immunologically mediated inflammatory disease with polygenic predisposition and is associated with triggering environmental factors.6 A DLQI of >10 indicates moderate-to-severe impairment of HRQOL. Descriptive statistics were presented as numbers and percentages for categorical variables. Means with standard deviations were used for normally distributed data and medians with interquartile ranges for non-normally distributed data. Collected data were tabulated using the Statistical Package for Social Sciences for Windows version 22.0 .This retrospective descriptive study investigated 1,671 patients with psoriasis with scalp involvement who were registered with the MPR from January 2007 to December 2018. The demographic data, medical history, clinical findings, treatment modalities and Dermatology Life Quality Index (DLQI) were obtained for descriptive analyses. Published in 1994, the DLQI was the first dermatology-specific quality of life questionnaire. It consists of 10 questions concerning patients\u2019 perception of the impact of skin diseases on different aspects of their health-related quality of life (HRQOL) over the last week. The domains include symptoms and feelings, daily activities, leisure, work and school, personal relationships and treatment. The total score ranges from 0 to 30, with higher scores indicating a greater impact on HRQOL.Table 1)A total of 21,859 patients with psoriasis were registered with the MPR during the study period, of whom 7.6%  showed scalp involvement. Female patients  accounted for the majority of the patients with scalp psoriasis (61%), yielding a male-to-female sex ratio of 1:1.56. In terms of ethnicity, most patients with scalp psoriasis were Malay , followed by Chinese , Indian  and other ethnicities . A positive family history of psoriasis was identified in 22.7% (n=380) of the patients. The mean age at onset was earlier in the women (29.16\u00b116.78 years) than in the men (35.53\u00b117.41 years). . Arthropathy was seen in 11% (n=172) of the patients with scalp psoriasis. Symmetrical polyarthropathy was the predominant form observed (34.4%), followed by oligo/ monoarthropathy (32.8%) and distal hand joint arthropathy (25.2%); spondylitis/ sacroiliitis and arthritis mutilans each accounted for 3.8% of the scalp psoriasis cases associated with arthropathy. Nail changes were seen in 34.8% (n=581) of the patients, of which nail pitting was the most common finding (49.4%)   were using topical treatment. Topical corticosteroids were most commonly used (81.1%), followed by tar preparations (73.3%), keratolytics (46.2%), calcipotriol with betamethasone dipropionate (11.5%) and vitamin D analogues (11.2%). Phototherapy was prescribed for 0.5% (n=10) of the patients, of whom all received narrow band UVB. Systemic therapy was used by 10% (n=164) of the patients with scalp psoriasis in the MPR. Methotrexate was the most commonly prescribed form of systemic treatment (68.3%), followed by sulphasalazine (15.2%), acitretin (11.6%), cyclosporin (2.4%) and systemic corticosteroids (1.8%). Biologics accounted for only 4.3% of the systemic treatments used by the patients with scalp psoriasis.Regarding comorbidities, hypertension was the most common type observed (27.9%), followed by obesity (26%), dyslipidaemia (21%), diabetes mellitus (18.4%), ischaemic heart disease (5.4%) and cerebrovascular accident (1.3%).The DLQI was recorded in 39% (n=651) of the patients with scalp psoriasis in the MPR. Of these patients, approximately 23% reported a DLQI of >10, which indicated moderate-to-severe impairment of HRQOL. A DLQI of 0-1 (no effect on patient\u2019s HRQOL) was obtained in 16.1%; a score of 2-5  in 34.8%; a score of 6-10 (moderate effect on patient\u2019s HRQOL) in 25.8%; a score of 11-20 (very large effect on patient\u2019s HRQOL) in 20.4%; and a score of 21-30 (extremely large effect on patient\u2019s HRQOL) in 2.9%.7 The frequency of scalp involvement in patients with psoriasis has been reported to range from 50% to 80%8; thus, the scalp represents the most commonly involved area of the body. Scalp psoriasis can be observed at the onset of disease or later. Scalp involvement can co-occur with any other type of psoriasis and at different phases of the disease .9 A 2017 nationwide survey of over 12,000 patients with psoriasis in China reported a mean age at onset of scalp disease of 30\u00b114 years in men and 27\u00b115 years in women,10 which is comparable to the mean age at onset of scalp psoriasis in our study . The male-to-female sex ratio among the patients in our study was 1:1.56, showing a slightly higher prevalence among women, which was comparable to the ratio of 1:1.15 obtained by Egeberg et al.7 Our findings of a positive family history of scalp psoriasis among 22.7% of the patients is similar to those from a study conducted in China, which reported a positive family history among 23.1% of 12,0 patients with psoriasis.10Scalp involvement was seen in 7.6%  of all patients with psoriasis registered with the MPR  from 2007 to 2018. This proportion (7.6%) is significantly lower than previous findings.2 Nail pitting was the most common form of nail change observed, which is similar to prior MPR findings.2 The prevalence of psoriatic arthropathy has been reported to range from 6% to 42% in patients with psoriasis.11 The cause of the wide variation may be attributed to the different screening strategies employed.11 The prevalence of psoriatic arthropathy in the patients with scalp psoriasis in the MPR was 11% compared with 13.7% in the MPR between 2007 and 2016.2 The most common pattern of psoriatic arthropathy in our study was symmetrical polyarthropathy (34.4%), followed by oligo/monoarthropathy (32.8%). This differs from MPR findings from 2007 to 2016, which showed oligo/monoarthropathy (37.3%) to be the predominant form, followed by symmetrical polyarthropathy (30.6%).2 In comparison, Kumar et al. showed the symmetrical polyarticular form to be the most common pattern (58%), followed by spondyloarthropathy (49%), asymmetric oligoarthritis (21%), isolated spondyloarthropathy (5%), predominant distal interphalangeal arthritis (3%) and arthritis mutilans (1%).11The proportion of patients with nail changes in our cohort was lower than the 57.1% observed in the MPR from 2007 to 2016.12 Similarly, patients with psoriasis and nail dystrophy had a threefold higher risk of developing psoriatic arthritis than those without nail dystrophy.12The association between psoriatic arthropathy and other features of psoriasis is well known. The risk of developing psoriatic arthropathy is increased by 3.89 times among patients with scalp psoriasis compared with that among those without scalp psoriasis.13 Topical agents (93.6%) were also the mainstay treatment in our cohort study, with topical corticosteroids (81.1%) being the most common topical treatment prescribed. Wang et al. revealed topical corticosteroid therapy as the most common treatment for scalp psoriasis,3 which typically provides good control of the disease. This is followed by topical tar preparations, keratolytics, calcipotriol, vitamin D analogues, emollients and dithranol.4 The factors that may influence the choice of treatment include disease severity, patient preference, prior response and cost.13 Systemic treatments are usually provided to patients with scalp psoriasis with intractable diseases.4Psoriasis can be treated with topical therapy, phototherapy or systemic therapy. Topical therapy is recommended as the first-line treatment for all patients.14 The prevalence of comorbidities, including hypertension, dyslipidaemia, diabetes mellitus and ischaemic heart disease, among patients with scalp psoriasis in the MPR is higher than that among patients with psoriasis in China,9 for whom lower rates of hypertension (16.4%), dyslipidaemia (13.7%), diabetes mellitus (7.8%) and ischaemic heart disease (2.4%) have been reported. The findings of the comorbidities among the patients with scalp psoriasis in our study are similar to those from the MPR from 2007 to 2016, with hypertension (27.9%) representing the most common comorbidity reported, followed by obesity (26%), dyslipidaemia (21%), diabetes mellitus (18.4%), ischaemic heart disease (5.4%) and cerebrovascular accident (1.6%).2The association between psoriasis and several systemic comorbidities is well known. Patients with psoriasis are 2.2 times more likely to have metabolic syndrome than the general population.15 The most frequent and distressing symptoms of scalp psoriasis are itching and scaling.5 Scalp psoriasis is associated with significant impairments in the DLQI and negative impacts on patients\u2019 self-confidence and social acceptance.9 This can be attributed to the visibility of the scalp region, which is considered a difficult-to-treat area, as scalp skin is relatively difficult to access, therefore reducing the efficacy of topical treatment.16 The significant number of patients with missing DLQI data  may limit the interpretation and generalisability of these findings.Approximately 23% of our patients had a DLQI of >10, which indicated moderate-to-severe impairment of HRQOL. This rate is lower than that in the study conducted by Cakmur et al. in Turkey: 58% of the patients with scalp psoriasis reported a DLQI of >10.The limitations of this study include the retrospective study design and the significant number of missing data, which might impact the accuracy of the results reported. Missing data could result from the lack of data collection from patients or inadequate documentation.This study describes the demographic characteristics, clinical features, treatment modalities and DLQI among patients with scalp psoriasis in Malaysia. Demographic studies on scalp psoriasis are limited worldwide. There is a need for more demographic studies on scalp psoriasis to help improve the care and treatment among patients."}
+{"text": "Background: Transmission-based precautions against varicella-zoster virus (VZV) in healthcare settings are determined by the extent of rash  and the immune status of the host. At our facility, immunocompetent patients with localized disease are placed in standard precautions whereas patients with disseminated disease and/or immunocompromised status are placed in airborne and contact isolation. The use of molecular diagnostics has increased recently, and patients can have a PCR positive for VZV in cerebral spinal fluid (CSF) without evidence of pneumonia or disseminated rash. These patients are classified as disseminated disease, but it is unlikely that they are spreading VZV via respiratory aerosols in the absence of other symptoms. Infection prevention guidance is limited in this situation, and these patients may be in unneeded isolation, with the potential for adverse patient effects and overutilizing PPE resources. We have described the clinical characteristics of patients with a PCR positive for VZV in CSF, and we evaluated the risk for transmitting VZV via airborne aerosols. Methods: A retrospective, single-center chart review was performed on all patients admitted with a PCR positive for VZV in CSF between July 2017 and November 2021. Chart review was performed to gather data regarding clinical presentation, patient characteristics, and risk factors. Results: In total, 38 patients were identified who had a PCR positive for VZV in CSF; 22 (57.9%) were male and 16 (42.1%) were female. The median age was 47 years . Also, 15 patients (39.5%) were immunocompromised. Moreover, 26 patients (68.4%) had a rash; 19 (50%) had localized rash; and 7 (18.4%) had disseminated rash involving \u22653 dermatomes. However, 12 patients (31.5%) had neither rash nor pneumonia. Furthermore, 5 patients (13.1%) had PCR positive for VZV in CSF and developed rash within the following 2\u20137 days (2 with disseminated rash). In addition, 6 patients (15.8%) had pneumonia. Of the 6 patients with pneumonia, 4 (10.5%) were immunocompromised and 3 (7.9%) were above 65-year-old. 32 patients (84.2%) were kept in airborne and contact precautions. 1 (2.6%) patient had a documented record of at least 1 dose of Shingrix vaccine. Conclusions: Most patients with a PCR test positive for VZV in the CSF were not immunocompromised and did not have evidence of disseminated rash or pneumonia. The risk of airborne transmission of VZV via small aerosols appears to be low in patients with a PCR test positive for VZV in the CSF without evidence of disseminated rash or pneumonia. Airborne isolation may not be required for many of these patients.Funding: NoneDisclosures: None"}
+{"text": "Immune-related adverse events (irAEs) are unpredictable autoimmune-like toxicities induced by immune checkpoint inhibitors (ICI). irAEs are a consequence of a breakdown in self-tolerance. ICIs can induce autoantibody formation, and the presence of antinuclear autoantibodies (ANAs) has been reported in patients who developed irAEs. Our goal was to compare ANA patterns by indirect immunofluorescence at different timepoints before (baseline) and after the initiation of ICI treatment and to analyze the role of ANA pattern changes as predictors of irAEs. This is a 2-year-follow-up prospective study of 152 consecutive patients with solid tumors treated with anti-PD-(L)1 blockade agents. They were included from September 2018 until March 2020 in the Hospital de la Santa Creu I Sant Pau . We grouped patients into three groups: ANA de novo (patients who showed new ANA patterns at any time after ICI initiation), ANA (ANA positive at baseline without changes in the ANA patterns after initiation of treatment) and non-ANA (ANA negative at baseline and after ICI initiation). We did not find any association between the appearance of ANAs and irAE rates or the number and types of irAEs. However, patients in the ANA de novo group showed higher severe irAE rates (grade \u2265 3) than the other groups. Additionally, in most of the patients with severe irAEs (83.3%), changes in ANA patterns preceded irAE onset. In conclusion, we found ANA induction during ICI therapies in 22 patients and our results suggest that the appearance of ANAs may predict the severity of the irAE. Immune checkpoints, such as PD-1 (Programmed cell death 1 receptor) and CTLA-4 (Cytotoxic T lymphocyte antigen 4), are the main regulatory molecules of the immune system that maintain immune homeostasis and self-tolerance. PD-1 is a T cell surface receptor that recognizes and binds to the endogenous ligands PD-L1 and PD-L2 on antigen-presenting cells (APCs) and on tumor cells. Its recognition by ligands attenuates T lymphocyte effector function, including proliferation and cytokine production. Similarly, CTLA-4 is a co-inhibitory molecule that blocks T-cell activation by direct competition with CD80/CD86 on APCs. Blocking these receptors restores T effector functions and enhances endogenous anti-tumor immunity [Immune checkpoint inhibitors (ICI) improve the survival of patients with solid tumors, such as melanoma and lung cancer ,4,5,6. DEmerging studies indicate that irAEs are a consequence of a breakdown in self-tolerance mediated at least in part by antigen-specific T-cell responses, B cells, autoantibodies and cytokines ,8,10. ThAutoantibodies are involved in the pathogenesis and inflammation of some traditional autoimmune diseases . The preAntinuclear antibodies (ANAs) comprise a spectrum of autoantibodies directed against the nuclear and cytoplasmic components of normal human cells. ANAs are laboratory markers that support the diagnosis of autoimmune-mediated diseases such as systemic lupus erythematosus, systemic sclerosis, Sj\u00f6gren disease and autoimmune myositis ,22. TheyThe presence of ANAs in patients who receive ICI therapies and develop irAEs has been reported. Most published studies have focused on analyzing the predictor role of pre-existing ANAs prior to ICI therapy and their association with the risk of irAEs ,26,27. SNinety-five (70.9%) patients were male and 39 (29.1%) were female. The mean age was 67.7 (\u00b11.01) years. The most frequent tumor type was non-small cell lung cancer (NSCLC) in 91 (67.9%) patients, followed by 20 (14.9%) cases of melanoma, 10 (7.5%) of renal cancer, nine (6.7%) of head and neck cancer, and four (2.9%) of bladder cancer. In regard to the stage, 82 cases of NSCLC (90.1%), 16 of melanoma (80%), 9 of renal cancer (90%) and 100% of head and neck and bladder cancer cases were metastatic (stage IV). Nine cases of NSCLC (10.1%) and 1 of renal cancer (10%) were stage III locally advanced and 4 cases of melanoma (20%) were stage III resected. None of the patients included in the study had a previous history of autoimmune disease.Sixty-four (47.7%) patients received anti-PD-(L)1 blockade agents as a first-line treatment and 57 (42.5%) as a second-line treatment or beyond. Five (3.7%) patients received ICI as an adjuvant therapy and eight (5.9%) patients received it as manteinance therapy after chemoradiation. Anti-PD-(L)1 blockade agents were administered as monotherapy in 104 patients (77.6%), in combination with another immunotherapy agent in 19 (14.2%) patients and with chemotherapy in 11 (8.2%) patients.n = 22); the second group (ANA) included patients with ANA in all serial samples without changes in patterns (n = 37); and the third group (non-ANA) included patients without ANA in all serial samples (n = 75). The baseline characteristics of patients segregated into groups are detailed in Based on ANA presence, patients were divided into three study groups: the first group (ANA de novo) included patients with or without ANA in baseline samples who developed new ANA patterns after ICI initiation (Eighty-one patients (60.4%) developed irAEs: the median number of iRAEs was two (IQR 1\u20132.5). 39 (29.1%) patients developed 1 irAE and 42 (31.3%) patients developed two or more irAEs. The maximum number of irAEs developed per patient was seven. A total of 154 irAEs developed in 81 patients. Mild irAEs (grades \u2264 2) were more frequent than severe irAEs (grades \u2265 3): according to CTCAE, 85 (55.2%) irAEs were grade 1; 47 (30.5%) were grade 2; 15 (9.7%) were grade 3 and 7 (4.5%) were grade 4. No grade 5 irAEs were developed.With regard to the type of irAE, dermatological toxicities including rash and pruritus were the most frequent manifestations and were observed in 56 (41.8%) of patients, followed by endocrine manifestations in 21 (15.7%) patients, hepatitis in 12 (8.9%) patients and colitis in 10 (7.5%) patients.The earliest toxicity was rash; the median time of onset was 28 (IQR 9\u201350.5) days. In contrast, the latest toxicities developed were artralgias and colitis, which appeared after 128 (28.5\u2013196) and 110.5 (61.75\u2013187.3) days. The characteristics of the irAEs are shown in Forty-five (33.6%) patients had ANA at baseline samples, and 59 (44%) patients had ANA after ICI initiation. The comparison of IIF patterns between samples collected at baseline and after ICI initiation revealed that 22 (16.4%) patients (14 patients who were ANA negative and eight patients who were ANA positive in baseline samples) developed ANAs de novo after ICI initiation. Representative IIF images are shown in The individual characteristics of patients from the ANA de novo group are detailed in p = 0.85). Considering only patients who developed irAEs, 28 (34.5%) patients presented with ANA at baseline and 37 (45.6%) had ANA at any time point. There was no difference in irAE prevalence between the groups of patients: ANA de novo, ANA and non-ANA groups . Among the groups, there were no differences in either the number of irAEs developed or the time of appearance and the type of irAE (p = 0.05) (Preexisting ANA at baseline was not associated with irAE development. There were 53 patients without preexisting ANA who developed irAEs and 17 patients with preexisting ANA who did not develop irAEs during the follow-up period ( of irAE . However = 0.05) A.When we compared the presence of irAEs during the 12 months of follow-up among the three groups, we found differences in the time of grade \u22653 irAEs onset B,C. We dp = 0.01). These results were also confirmed in the NSCLC population (the major and most homogeneous population in our cohort)  .To the best of our knowledge, this is the first study that specifically associates ANA pattern development after ICI initiation with the clinical features of irAEs according to three study groups: ANA de novo, ANA and non-ANA. Our results showed the development of ANAs in a subset of patients after ICI initiation. Although these patients did not share common clinical characteristics and we did not find an association between the presence of ANAs and the development of irAEs in patients who received ICI, the ANA de novo group showed higher severe IRAE rates than the other two groups. In most patients with severe irAEs (83.3%), ANA development preceded irAE onset, which suggests that ANA screening could help predict the severity of the irAE.We showed that 16.6% of patients receiving ICI developed ANAs de novo, suggesting, in line with other authors, that checkpoint blockade is related to the T-cell-dependent activation of autoreactive B cells and autoantibody production ,31. It hWe did not find differences in irAE prevalence between patients with and without pre-existing ANAs nor between patients with and without ANAs in serial samples after ICI initiation. These results are consistent with other studies ,26,27,29ANA development was not associated with higher rates of irAEs, the number of irAEs or the type of irAE. However, a trend toward its association with the severity of irAE was found. In addition, the ANA de novo group showed a higher OS and PFS. Considering that the development of irAEs is associated with immune checkpoint blockade response , this isWe showed that ANA appearance preceded irAE manifestations in 83.3% of the patients who suffered grade \u2265 3 irAEs. This finding suggests that the early appearance of ANA could be a useful predictive biomarker of severe irAEs. In concordance with our results, Das et al. showed that patients with early B-cell changes experienced higher rates of grade 3 irAEs . They foWe are aware that our study has some limitations. Although we included a large cohort, few patients developed the same irAE subtype so as to be studied as a subgroup. It is well known that autoantibody positivity can differ depending on the organ affected. Interestingly, after ICI, autoantibody positivity is frequent in irAEs involving endocrine function, skin and muscle, but rare in irAEs affecting other organs or systems . AdditioIn conclusion, our findings suggest that antinuclear autoantibody screening during immune checkpoint-blockade therapies could be useful for monitoring patients to predict severe irAEs. This screening could consequently improve the early detection and management of irAEs and avoid treatment interruption. However, further studies integrating humoral and cellular autoreactivity are needed to elucidate the role of these autoantibodies in the pathogenesis of irAEs.One hundred and fifty-two consecutive patients diagnosed with solid tumors treated with anti-PD-(L)1 blockade agents alone or in combination with chemotherapy or other immunotherapy drugs at Hospital de la Santa Creu I Sant Pau  were prospectively included from September 2018 to March 2020 and monitored by the Department of Medical Oncology and the Department of Immunology. The end of the follow-up was September 2020. Patients with prior autoimmune diseases were excluded from the study. All patients included received at least one dose of ICI. We could not collect the pre-treatment (baseline) samples of 10 patients. After the first dose of ICI, eight patients discontinued ICI treatment due to progression criteria and no additional samples were collected after ICI-initiation. Thus, in line with our goal, we included samples at baseline and after ICI initiation from 134 patients.Written informed consent was obtained from each patient and ethical approval for the study was granted by the Institutional Ethics Committee . Patients\u2019 data were collected from electronic medical records.IrAEs were defined as adverse events with a potential immunologic basis that required close monitoring and/or potential intervention with immunosuppressive or hormone replacement. Patient symptoms, physical examination and laboratory data were assessed every 3\u20134 weeks. Thyroid function was evaluated at baseline and every six weeks thereafter. IrAE severity was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 .Serial serum samples from each patient were collected at baseline and after initiation of ICI treatment for a maximum of six months of follow-up . Additionally, when a patient experienced a grade \u22652 irAE, an extra sample was collected. All samples were frozen and stored at \u221220 \u00b0C until autoantibody determination.The detection of ANA was based on indirect immune-fluorescence (IIF) in agreement with international recommendations . Assays p values lower than 0.05 were considered statistically significant. All analyses were performed using Graph Pad Prism 7 software.To describe our population, numbers and percentages were used for qualitative variables, while means  and medians  were calculated for quantitative variables with normal and non-normal distributions, respectively. The Kolmogorov\u2013Smirnov test was applied to analyze the data distribution. Comparisons between groups were tested with Student\u2019s t or the Mann\u2013Whitney test according to normal distribution. ANOVA and Kruskal\u2013Wallis tests were used to compare more than two groups. Fisher and Chi-square tests were used for the comparison of frequencies. The long-rank Mantel\u2013Cox test was used to analyze differences in overall survival (OS), progression-free survival (PFS) and the moment of irAE onset during the follow-up period. All"}
+{"text": "Effective strategies at educating high risk IBD patients about COVID-19 and the benefits of vaccination is critical.The primary objective of this study was to assess the impact of early adulthood (18-25 years) on COVID-19 vaccination compliance. Secondary objectives were to assess the impact of early adulthood on vaccine hesitancy and reasons for non-compliance.A retrospective chart review was performed on all eligible IBD patients. Inclusion criteria: patients followed at Women\u2019s College Hospital, age 18 years and older, diagnosis of Crohn\u2019s disease (CD), Ulcerative Colitis (UC) or Indeterminant Colitis (IC). Data was collected between January 01 and August 31, 2022. Demographic data, level of immunosuppression and COVID-19 vaccine status were collected. All participants identified as not fully vaccinated (defined as less than 3 COVID-19 vaccines) were enrolled into the second phase of the study in which a modified Oxford COVID-19 Vaccine Hesitancy Scale was administered, and reasons for vaccine hesitancy discussed and addressed using a prepared educational template. Chi-square test evaluated the impact of age on vaccination status. Adjusted logistic regression was also performed. Fisher exact test evaluated the impact of age on willingness to accept vaccination counseling. Generalized linear regression model evaluated the impact of this on vaccine hesitancy.287 patients were included in the study of which 254 (89%) were immunosuppressed, 197 (69%) were female. 144 (50%) had CD, 136 (47%) had UC and 7 (2.4%) had IC. There were significantly more young adults who were under/unvaccinated 22/82 (27%) compared to older adults 22/205 (11%), p=0.0006 . Gender, IBD phenotype, immunosuppression status did not significantly affect vaccination status. The only variable found to significantly affect vaccination status on adjusted logistic regression was age, >25 years associated with OR 3.25 (95% CI 1.63-6.50) for full vaccination. 32/39 study subjects who were un/under-vaccinated agreed to counseling (82% of the early adults and 82% of older adults). Gender, IBD phenotype, immunesuppression status and age had no impact on uptake. Linear regression modeling found no significant impact on vaccine hesitancy by age, gender, IBD phenotype or immunesuppression. The main reasons described by patients for hesitancy included safety concerns and potential side effects (43%), perceived low risk (27%), prior COVID-19 infection (17%), lack of knowledge of current public health guidance (13%).Early adult IBD patients were found to be significantly less compliant with obtaining COVID-19 vaccines. This hesitancy mainly stems from concerns regarding vaccine safety and efficacy and perceived low risk. More targeted education strategies are required to increase awareness and ensure vaccine compliance.NoneNone Declared"}
+{"text": "Around 45% of patients with uveal melanoma (UM) develop liver metastases on average 3 years after diagnosis of the primary tumour. After clinical detection of metastases, median patient survival is approximately one year. Early identification of metastases through liver surveillance is important so that targeted treatment can benefit affected patients, aiming to prolong their survival. The aim of our retrospective study was to investigate and correlate the characteristics of UM patients diagnosed and treated at a UK supraregional referral center, the Liverpool Ocular Oncology Centre (LOOC), and who were included in the Centre\u2019s liver screening programs for screening for liver metastases. \u201cReal-world\u201d data on the frequency of liver screening in patients after diagnosis and treatment of primary UM are lacking. Through the liver screening program, we found that metastases were detected in 37% of the 615 UM patients studied. A new output based on the prognostic indices of the Liverpool Uveal Melanoma Prognosticator Online version 3 (LUMPO3) model was fitted to the dataset of these patients and accurately estimated the time of onset of metastases.Purpose: To determine liver screening frequency and modality in UM patients following primary treatment, and the characteristics of detected metastases. Methods: A 10-year retrospective study of 615 UM patients undergoing liver surveillance in Liverpool. Information was collected from liver scan reports of these patients. Results: Of 615 UM patients analyzed, there were 337 men (55%) and 278 women (45%). Median age at primary treatment was 61 years . At study end, median follow-up was 5.1 years, with 375 patients (61%) alive and 240 deceased (39%). Of the deceased patients, 187 (78%) died due to metastatic UM; 24 (10%) deaths were due to other causes; and 29 (12%) patients died of unknown conditions. In total, 3854 liver scans were performed in the 615 UM patients, with a median of 6.2 scans per patient . Liver MRI was most frequently performed (62.8%). In total, 229 (37%) UM patients developed metastases during the study period: 150 were detected via liver surveillance and 79 were observed post-mortem. Conclusions: Metastatic UM onset is related to the size and genetic profiles of the primary UM, and can be predicted using the model LUMPO3. Regular liver surveillance allowed for timely detection of metastases, and through metastasectomy can lead to prolongation of life in some patients. Liver metastases are the leading cause of death in patients with UM . AlthougBAP1 loss  had a median age of 61 years . The median primary tumor largest basal diameter (LBD) and ultrasound height (UH) were 14.6 mm (range 2.4\u201326 mm) and 6.3 mm (range 0.7\u201320.2 mm), respectively. Patients underwent different types of surgical and non-surgical treatments including enucleations 314 (51%); plaque brachytherapy 131 (21%); proton beam irradiation 118 (19%); local resection 35 (5.7%); endoresection 15 (3%); and endoresection + plaque brachytherapy 2 (0.3%).Of the 615 cases, 57 (9%) UM had extraocular extension (EOE), and 183 (30%) UM had ciliary body involvement (CBI). Histology was not available for all cases, e.g., in some intraocular biopsies where the cells were very sparse, or where treatment was commenced based on clinical features only. Where histomorphological analysis was possible, 334/578 (58%) tumors showed epithelioid cells, 238/363 (66%) had closed loops, and 369/369 (100%) UM showed between 1 and >7 mitotic counts per 40 high-powered fields.Genetic information was also not available for all UM, either due to no consent from the patient for genetic testing, or insufficient cellular material for DNA extraction. The following genetic alterations associated with outcome were detected in the cohort: chromosome 1p loss [135/432 (31%)], chromosome 3 loss [330/550 (60%)], chromosome 6p gain [137/432 (32%)], and chromosome 8q gain [257/433 (59%)].The median follow-up of the 615 patients was 5.1 years (range 0.2\u201332) . Of thesp < 0.001); presence of epithelioid cells (p < 0.001); presence of closed loops (p < 0.001); high mitotic count (>7) (p < 0.001); CBI (p < 0.001); EOE (p < 0.001); and the genetic alterations-chromosome 3 loss (p < 0.001) and chromosome 8q gain (p < 0.001)  .A total of 3854 liver scans were performed on the 615 patients, with a median of 6.2 scans per patient . Liver MRI was the most performed modality, 2419 scans (63%). Overall survival (OS) for patients undergoing MRI alone was 23 years , followed by 14 years  for patients undergoing US only, and 10.2 years  for patients who underwent both MRI and US  Table 2Table 2.In 615 UM patients, 286 (46%) had their first scan at the time of primary tumor treatment, but only 2.4% had metastases detected in that first scan. In total, 229/615 (37%) UM patients developed metastases during the study. Of these, 150 patients (24%) had their metastases diagnosed during the liver surveillance program and a further 79 (13%) were detected on autopsy . In sum,In the 150 patients with metastases detected by liver screening, a total of 1600 scans were performed; whereas in the 386 patients with no metastases detected during this study, a total of 2114 scans were performed .n = 87 (58%); M1b, n = 50 (33%); and M1c, n = 13 (9%). The median time from primary treatment to the detection of UM metastases was 2.6 years . Eighty-one (54%) UM patients undergoing liver screening developed metastases within 2 years of primary tumor treatment; 27 (18%) developed metastases between 2\u20133 years; and 42 (28%) patients developed metastases 3 years after primary tumor treatment (The median diameter of the largest UM metastases (LDML) was 36 mm . Metastases categorized according to the AJCC TMN showed; M1a, reatment A. The mereatment B. The cuThe survival curve showed a median OS of the 150 patients with metastases detected by liver surveillance, of 3.5 years  . Thirty-n = 108 (17%)] were associated to the poorest outcome\u2014OS time was 2.0 years . Overall survival for Group 2 [n = 121 (20%)] and Group 3 [n= 386 (63%)] were 6.8 years  and 26.4 years , respectively.Kaplan\u2013Meier survival curves were examined for patients categorized according to the three groups defined in Methods\u2014Time to Detection and are shown in In total, 17 (11%) of the 150 patients with metastatic disease underwent metastasectomy. They had a median time to detection of metastases of 3.1 years  and a median time to death after UM metastases detection of 1.4 years  . The remIn this extensive retrospective study, we undertook a detailed analysis of radiological reports of 615 UM patients who underwent liver surveillance between 2008\u20132018 in Liverpool, and correlated the liver screening characteristics with features of the primary tumor as well as with outcome. Our analysis showed that: a) there was a 37% incidence of UM metastases in this cohort; b) the onset of metastases is related to various clinical, histological and genetic parameters of the primary tumor; c) MRI was the most frequently used surveillance technology; d) the median period from primary treatment to UM metastases detection was 2.6 years ; e) median period from UM metastases detection to death was 1 year ; f) the output of the new model based on the prognostic indices of the LUMPO3 model can accurately predict the time of onset of metastases in UM patients; and g) liver surveillance enabled earlier detection of metastases and their surgical removal in some UM patients, leading to slightly prolonged survival.The incidence of UM metastases in our study of 37% is similar to previously reported data. For example, Diener-West  when scrOur liver surveillance program demonstrated similar results to other national  and inteFrom our clinical imaging study, where 54% (81/150) of UM patients developed metastases within 2 years, the overall median time to metastases detection after primary treatment was 2.6 years (range 0.1\u201317.8 years), and survival was 1 year  when calculated from the time of detection of liver metastases. We compared the results with previous studies reporting the outcome of metastatic disease of UM, which are summarized in Seventeen UM patients in our study underwent metastasectomy and had an improved OS compared with patients receiving only palliative care. This agrees with other published series that demonstrated a survival benefit for patients after hepatectomy for UM metastatic disease, when compared to inoperable patients ,44,45,46A study published by the Institut Curie  describeWe performed a 10-year retrospective review of liver scan reports of 615 UM patients diagnosed and treated at the LOOC prior to 2018.A total of 2254 UM patients were identified from the Ocular Oncology Biobank (OOB), who had given consent to have their health records reviewed for research purposes. The study was approved by both the Health Research Authority (HRA) (NRES REC REF: 18/NW/0748) and the Confidentiality Advisory Group (18/CAG/0181). Of the 2254 UM patients treated at the LOOC, 1448 (64%) cases were excluded since no radiological reports were found for these patients within the records at the Liverpool University Hospitals NHS Foundation Trust (LUHFT): i.e., these patients had their liver surveillance examinations elsewhere in the UK, and hence these data were not accessible/available for review. For 806 (36%) UM patients, radiological reports were found in the LUHFT records; however, in 191 (23%) cases, the radiological examinations were not relevant for the purposes of this study. Therefore, liver scan reports to 615 UM patients, who underwent liver surveillance between 2008\u20132018, were found and reviewed for this study.Where available, the following data were collected from the medical records: (1) date of first liver scan; (2) number of liver scans performed; (3) number, size and location of the metastases detected; (4) time from primary treatment to detection of first metastases; and (5) time from detection of metastases to death. After collecting information from the liver scan reports, data was returned to the OOB for pseudo-anonymization of the analysis dataset, including any additional available clinical information: i.e., patient demographics (age/gender); anatomical data of the primary UM\u2014e.g., LBD, UH, CBI, EOE; histological data including presence or absence of epithelioid cells (Epi), presence/absence of connective tissue loops (\u2018loops\u2019), and mitotic count per 40 high power fields (Mitoc)-; as well as genetic data from tumor cells, including information on the status of chromosomes 1p, 3, 6p, 6q, 8p and 8q (where available). Follow-up and outcome data were also added, where the date of the last follow-up was defined to 01/05/2020. Data from a small number of UM patients analyzed in this study who underwent metastasectomy have been previously published ; they have been included in this analysis, since we have obtained longer follow-up information.Primary tumors were categorized according to the American Joint Committee on Cancer (AJCC) Tumor Nodal Metastases (TNM) staging (8th edition) (35).The imaging modality used and referred to in the surveillance reports were varied and included MRI, US and computer tomography (CT).To classify the size of the metastases, the \u2018M\u2019 sub-staging according to the AJCC/TMN staging system for metastatic UM was used (35). Patients were classified into 3 groups according to the diameter of their largest detected liver metastases .Patients were divided into three groups according to the median time of detection of metastases: Group 1\u2014patients with UM who developed metastases within 2 years of the primary treatment of UM. Group 2\u2014UM patients who developed metastases 2 years after treatment of the primary UM; Group 3\u2014UM patients in whom metastases were not reported during the period of liver screening.Pseudo-anonymized data were collected, filed, and processed in Excel format . Categorical variables were summarized with counts and median with range and expressed as frequencies and percentages. A new model in which two predictors (outputs of LUMPO3) were considered: (1) prognostic index of death due to other causes; and (2) prognostic index of death due to metastases; was used to estimate the time of onset of metastases . StatistOur study presents an extensive retrospective analysis of liver surveillance, evaluating its frequency and time interval, in UM patients treated in one of England\u2019s supraregional ocular oncology centers. The new model based on prognostic indices output by LUMPO3 can accurately predict the time of onset of metastases in UM patients. With the LUMPO3 predictions provided, different screening strategies in these patients can be implemented. It has disclosed several noteworthy points despite missing data, particularly that liver surveillance can enable early detection of metastases and potentially, in some patients, lead to prolonged survival benefit through metastasectomy. Therefore, it is necessary to identify UM patients with a high-risk of metastases and excise UM metastases in a timely manner, possibly in combination with other liver-directed treatments. Ongoing basic research may enable the development of adjuvant clinical trials for high metastatic risk UM patients to target UM deposits when there is a low metastatic tumor volume. This study also reveals a need for comparative studies across health systems and causal analysis, to establish consensus for liver screening strategies in UM."}
+{"text": "What are the humoral immune response rates and risk factors associated with diminished response after COVID-19 vaccination in recipients of solid organ transplant?In this systematic review and meta-analysis of 29 studies and 11\u2009713 recipients of solid organ transplant, seroconversion rates increased with progressively increased numbers of mRNA COVID-19 vaccine doses. Older age, recent transplantation, deceased donor status, active use of antimetabolites, and recent exposure to antithymocyte globulin or rituximab were risk factors associated with diminished humoral immune response after receiving 2 doses of mRNA vaccines.These findings suggest that more efforts are needed to modulate the risk factors associated with reduced humoral responses among recipients of solid organ transplant. This systematic review and meta-analysis assesses the current evidence on vaccine response and risk factors associated with diminished immune response in recipients of solid organ transplant. Recipients of solid organ transplant (SOT) experience decreased immunogenicity after COVID-19 vaccination.To summarize current evidence on vaccine responses and identify risk factors for diminished humoral immune response in recipients of SOT.A literature search was conducted from existence of database through December 15, 2021, using MEDLINE, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov.Studies reporting humoral immune response of the COVID-19 vaccines in recipients of SOT were reviewed.Two reviewers independently extracted data from each eligible study. Descriptive statistics and a random-effects model were used. This report was prepared following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Data were analyzed from December 2021 to February 2022.The total numbers of positive immune responses and percentage across each vaccine platform were recorded. Pooled odds ratios (pORs) with 95% CIs were used to calculate the pooled effect estimates of risk factors for poor antibody response.I2\u2009=\u20090%), antimetabolite use , recent rituximab exposure , and recent antithymocyte globulin exposure .A total of 83 studies were included for the systematic review, and 29 studies were included in the meta-analysis, representing 11\u2009713 recipients of SOT. The weighted mean (range) of total positive humoral response for antispike antibodies after receipt of mRNA COVID-19 vaccine was 10.4% (0%-37.9%) for 1 dose, 44.9% (0%-79.1%) for 2 doses, and 63.1% (49.1%-69.1%) for 3 doses. In 2 studies, 50% of recipients of SOT with no or minimal antibody response after 3 doses of mRNA COVID-19 vaccine mounted an antibody response after a fourth dose. Among the factors associated with poor antibody response were older age , deceased donor status (pOR, 0.66 ; In this systematic review and meta-analysis, the rates of positive antibody response in solid organ transplant recipients remained low despite multiple doses of mRNA vaccines. These findings suggest that more efforts are needed to modulate the risk factors associated with reduced humoral responses and to study monoclonal antibody prophylaxis among recipients of SOT who are at high risk of diminished humoral response. We conducted this systematic review and meta-analysis to summarize the current evidence on vaccine responses and identify risk factors associated with diminished humoral immune response among recipients of SOT.The US Food and Drug Administration (FDA) has approved the COVID-19 mRNA vaccines BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) and has granted emergency use authorization (EUA) for the adenoviral vector vaccine Ad26.COV2.S (Janssen).PRISMA) reporting guideline. This study was registered in the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42021277109).A systematic search was conducted independently by 2 of us (N.C. and K.M.) in MEDLINE, Embase, Web of Science (Clarivate), Cochrane Library, and ClinicalTrials.gov databases for research available through December 15, 2021. Complete search terms are included in the eMethods in the 23 Conflicts were resolved by mutual consensus between reviewers.Two authors (N.C. and K.M.) independently reviewed all studies and selected studies that reported the immunogenicity of COVID-19 vaccines in recipients of SOT, described as study participants in the methods and results. We included clinical trials and observational studies consisting of prospective cohort, retrospective cohort, and case-control studies. We excluded studies of humoral immunity after COVID-19 infection in study participants. Corresponding authors were contacted for immunogenicity testing or vaccination information if needed. We used Google Translate (Alphabet) to translate non-English studies during title and abstract screening. The Newcastle-Ottawa scale was used for assessing the risk of bias of the studies  with 95% CIs of factors associated with vaccine response were extracted. If ORs were not available, crude numbers were extracted for OR calculation.The checklist for critical appraisal and data extraction for systematic reviews of prediction modeling studies was used.25 Funnel plot and Egger regression were used to assess the publication bias.26 If the P value of Egger regression was P\u2009<\u2009.1, the publication bias was considered significant.27 Factors with concerns of publication bias were further adjusted by the Duval and Tweedie trim-and-fill method.28 We assessed the heterogeneity of effect size estimates of each study using the I2 statistic. The I2 statistic ranged from 0% to 100%, with I2less than 25% indicating low heterogeneity; I2 of 25% to 60%, moderate heterogeneity; and I2 greater than 60%, substantial heterogeneity.29P values were 2-sided, and statistical significance was set at P\u2009=\u2009.05. Data were analyzed from December 2021 to February 2022.Descriptive statistics were used to characterize humoral immune response, the primary outcome, for each COVID-19 vaccine platform and for each number of doses. We then performed a meta-analysis with Comprehensive Meta-Analysis software version 3.3 (Biostat) to identify risk factors associated with poor humoral immune response. To determine the factors associated with humoral immunogenicity, pooled ORs (pORs) with 95% CIs for binary variables and differences in means (with SEs) for continuous variables were calculated using meta-analysis with the random-effects model. If the study provided both adjusted and unadjusted ORs, we used adjusted ORs for calculations. If the primary study provided ORs of the factors associated with vaccine nonresponse, we used log transformation to calculate ORs associated with vaccine response of those specific factors. We performed sensitivity analyses using a leave-1-out method.106 were included in the systematic review, of which 29 studies were included in the meta-analysis  and 4.1% (0%-5.9%) for neutralizing antibodies (2 studies69)  seroconversion rate after 1 dose of mRNA vaccine was 10.4% (0%-37.9%) for antispike antibodies (18 studiesudies69) . The mea105) and 22.6% (0%-47.5%) for neutralizing antibodies (8 studies95) (105) and 15.3% (0%-35%) for neutralizing antibodies (5 studies69). The mRNA-1273 vaccine demonstrated a weighted mean (range) seroconversion rate of 51.4% (29.9%-76.2%) for antispike antibodies (7 studies105) and a mean of 26.9% for neutralizing antibodies (1 study12). The mean (range) antibody testing time after the second dose was 31.9 (8-81) days for all vaccines, 33.8 (8-81) days for the BNT162b2 vaccine, and 25.2 (14-28) days for the mRNA-1273 vaccine. Humoral immune response rates after 2 doses of mRNA vaccines by the different testing modalities are summarized in eTable 4 in the The weighted mean (range) total seroconversion rate after 2 doses of mRNA COVID-19 vaccines was 44.9% (0%-79.1%) for antispike antibodies (53 studiesudies95) . Among s99) and a mean of 60% for neutralizing antibodies (1 study81) .Three doses of mRNA vaccines showed higher total seroconversion rates  with a weighted mean (range) of 63.1% (49.1%-69.1%) for antispike antibodies (8 studiesstudy81) . Two stustudy81) . The mea30 reported high positive antibody response rates after 4 doses of mRNA vaccines, with a mean response rate of 83.3% for antispike antibodies; however, the study also included study participants with positive antibody response after the third dose. A study by Kamar et al98 included only study participants with negative or low positive antibody response after the third dose, and reported a seropositivity rate of 48.7% after 4 doses of the BNT162b2 vaccine for antispike antibodies.A study by Alejo et al9 reported that 16.7% had positive antispike antibodies after 1 dose of Ad26.COV2.S, and Prendecki et al86 reported 43.6% had positive antispike antibodies after 2 doses of AZD1222. Masset et al100 reported that either 2 doses of AZD1222 followed by 1 dose of mRNA vaccine or 1 dose of AZD1222 followed by 2 doses of mRNA vaccine resulted in antispike antibody seroconversion in 75% of participants. Among inactivated COVID-19 vaccine platforms, only CoronaVac (Sinovac Biotech) has been studied in recipients of kidney transplants, and the seroconversion rate for antispike antibodies was 15.2% after 1 does (1 study58) and 40.8%  after 2 doses.89 There were no studies available for other vaccine platforms response in recipients of SOT at the time of our data search. Humoral immune response rates by the COVID-19 vaccine types and doses are summarized in eTable 5 in the For study participants vaccinated with the viral-vectored vaccine platform, Boyarsky et alP\u2009=\u2009.001)103  (26 studies103) (Increased age was associated with lower seroconversion rates. The pooled difference in means (SE) of 10 studies showed study participants with antibody response were 3.94 (1.1) years younger than those without antibody response (.001)103 . Male sedies103) . Body madies103) .P\u2009<\u2009.001; I2\u2009=\u20090%) (10 studies103) (66 showed study participants with positive antibody response had 2.17 (0.71) years longer from transplantation to vaccination compared with those without antibody response (P\u2009=\u2009.002)  . Time fr\u2009=\u2009.002) .103 reported on antimetabolite use at the time of vaccine administration, which was associated with lower seroconversion rates   target of rapamycin (mTOR) inhibitors, which was associated with higher seroconversion rates   use at the time of vaccine administration, which was not associated with antibody response   . A total2\u2009=\u200942%) . Further2\u2009=\u200921%) .103 and antithymocyte globulin (ATG) exposure74 within 12 months of vaccination were associated with lower seroconversion rates  (Both rituximab exposureI2\u2009=\u20090%) . All dat92 Davidov et al,93 Ducloux et al,80 Haskin et al,47 Kantauskaite et al,82 Masset et al,56 Rozen-Zvi et al,66 Sanders et al,103 or Villanego et al.74 The pORs of rituximab exposure and seroconversion lost significance after removing Haskin et al47 from the analysis. The pORs of mTOR inhibitor use and seroconversion lost significance after removing any 1 of the following studies: Benotmane et al,32 Cucchiari et al,10 Grupper et al,45 Kantauskaite et al,82 Korth et al,53 Peled et al,62 Rabinowich et al,63 Rashidi-Alavijeh et al,64 Sanders et al,103 or Villanego et al.74Results of sensitivity analysis are reported in eFigure 2 in the We found evidence of publication bias for age, BMI, lymphocyte count, antimetabolite use, mTOR inhibitor use, and ATG exposure , the US (NCT04969263), and the Netherlands (NCT05030974) to evaluate immunogenicity in solid organ transplant recipients after modulation of immunosuppression.Our study has identified several risk factors associated with the lower seroconversion rate after 2 doses of mRNA COVID-19 vaccines in recipients of SOT. Recipients of SOT who were older, had recent transplants, or received deceased donor organ transplants had lower seroconversion rates. Unfortunately, we cannot determine specific cutoffs of age or time after transplantation associated with poor antibody response based on our study design. Similarly, recipients of SOT who were actively using antimetabolite immunosuppression  or who had recent exposure to rituximab or ATG within 12 months had lower seroconversion rates. We hypothesize that lower seroconversion with these agents could be caused by direct suppression of B-lymphocyte function or suppression of T-lymphocyte-dependent B-lymphocyte activation.81 As of December 20, 2021, the US FDA has issued an EUA for tixagevimab-cilgavimab, a combination of long-acting monoclonal antibodies (mAb), for preexposure prophylaxis in patients who are immunocompromised, including recipients of SOT.116 Although the EUA states that mAb preexposure prophylaxis should not be considered an alternative to vaccination, there is inherent tension between the strategy of active immunization through vaccination and passive immunization with mAbs. Long-acting mAb preexposure prophylaxis is a valuable resource to add protection for recipients of SOT who have received all available and recommended doses of COVID-19 vaccines but who have demonstrated poor humoral immunity or who have the risks factors associated with lower seroconversion rates identified in our study. But for recipients of SOT who have not received all available doses of COVID-19 vaccines, there are now 2 options: to proceed with vaccination according to the recommended schedule or to postpone vaccination and pursue mAbs. The risk factors identified in this study for lower seroconversion rates after 2 vaccine doses may also help to inform transplant professionals who must advise their patients on time-sensitive decisions about active vs passive immunization by weighing the likelihood of benefit from vaccination compared with the likelihood of benefit from mAbs.Despite higher seroconversion rates with progressively higher numbers of vaccine doses in recipients of SOT, the durability of the antibody response to repeated vaccination and the clinical outcomes in infection rates, disease severity, and mortality remain unknown.Additional unanswered questions include the optimal number of doses for a primary vaccination series, particularly in recipients of SOT with risk factors associated with lower seroconversion rates. Additionally, the role of antibody testing to determine strategies for additional doses or mAbs, the appropriate antibody cutoff level or other tests to ascertain immunity, and the most just allocation of scarce vaccine supply toward first doses or additional and booster doses at the global level are questions worthy of investigation and discussion.This study has some limitations. One limitation of COVID-19 vaccine immunogenicity research in recipients of SOT to date is the overrepresentation of the mRNA platform. Many recipients of SOT, particularly those living outside the US, may not have been fully vaccinated against COVID-19 or may not have access to mRNA vaccines owing to vaccine scarcity. Second, several techniques of SARS-CoV-2 antibody testing were used in the studies, and there is no criterion standard at this time. Third, the correlation between humoral immune response and the clinical efficacy of COVID-19 vaccines in recipients of SOT remains unclear. Fourth, most study participants were recipients of kidney transplant, with relatively fewer other organ transplant types. Fifth, the data regarding other vaccine platforms, including the heterologous prime-boost strategy, in recipients of SOT are extremely limited.In this systematic review and meta-analysis of 29 studies and 11\u2009713 recipients of SOT, seroconversion rates among recipients of SOT vaccinated with mRNA vaccines were higher with successive doses but remained lower than those among the general population. The availability of long-acting mAbs for preexposure prophylaxis presented an additional option for solid organ transplant recipients who have been vaccinated but may still be at inordinate risk for COVID-19, and mAbs are an additional consideration for recipients of SOT who have not yet been vaccinated and who may have multiple risk factors associated with a lower immune response to vaccination."}
+{"text": "By measuring binding and neutralizing antibodies against the viral spike protein, the authors found that the levels of both antibodies correlated with the degree of vaccine efficacy. The higher the antibody level, the greater the protection afforded by the messenger RNA (mRNA) vaccine. Antibody levels that predict mRNA vaccine efficacy can therefore be used to guide vaccine regimen modifications and support regulatory approvals for a broader spectrum of the population. \u2014PNKSymptomatic COVID-19 infection can be prevented by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines. A \u201ccorrelate of protection\u201d is a molecular biomarker to measure how much immunity is needed to fight infection and is key for successful global immunization programs. Gilbert  SARS-CoV-2 binding and neutralizing antibodies correlate with the degree of vaccine efficacy and protection for the Moderna mRNA COVID-19 vaccine. In the coronavirus efficacy (COVE) phase 3 clinical trial, vaccine recipients were assessed for neutralizing and binding antibodies as correlates of risk for COVID-19 disease and as correlates of protection. These immune markers were measured at the time of second vaccination and 4 weeks later, with values reported in standardized World Health Organization international units. All markers were inversely associated with COVID-19 risk and directly associated with vaccine efficacy. Vaccine recipients with postvaccination 50% neutralization titers 10, 100, and 1000 had estimated vaccine efficacies of 78% , 91% (87 to 94%), and 96% (94 to 98%), respectively. These results help define immune marker correlates of protection and may guide approval decisions for messenger RNA (mRNA) COVID-19 vaccines and other COVID-19 vaccines. On the basis of their demonstrated efficacy to prevent COVID-19 in phase 3 clinical trials, to date, seven COVID-19 vaccines have been granted an emergency use listing by the World Health Organization (WHO) (The coronavirus efficacy (COVE) phase 3 trial (NCT04470427) of the mRNA-1273 COVID-19 vaccine, which is being conducted in the US in adults aged 18 and over, showed estimated vaccine efficacy against COVID-19 of 94% in the primary analysis (50) nAb titer\u2014correlated with protection against SARS-CoV-2 replication after challenge in vaccinated rhesus macaques (80) nAb titer as correlates of risk of COVID-19 and as correlates of mRNA-1273 vaccine protection against COVID-19 in the COVE trial.Correlates of protection, which are immunological markers that can be used to reliably predict the level of vaccine efficacy against a clinically relevant end point, such as COVID-19 . Thirty-four percent of baseline SARS-CoV-2\u2013negative per-protocol participants were age 65 or over, 40% were deemed to be at risk for severe COVID-19 illness (referred to as \u201cat risk\u201d), 47% were assigned female sex at birth, 32% were Hispanic or Latino, 46% were white and non-Hispanic, and 54% were from communities of color, with 18% Black or African American. Table S2 and figs. S1 and S2 describe the day 29 marker case-cohort set and the day 57 marker case-cohort set, which augment the immunogenicity subcohort with all vaccine breakthrough COVID-19 end point cases and make up the sets of participants included in the analyses of antibody markers measured at day 29 or day 57 as correlates, respectively.Table S1 describes demographics of the randomly sampled immunogenicity subcohort (n = 46) and after day 57 (n = 36), respectively (fig. S3). Average follow-up of vaccine recipients was 116 days after day 29 and 88 days after day 57. All immune correlates analyses were prespecified, as detailed in the supplementary file Statistical Analysis Plan (SAP).Analyses of day 29 and day 57 antibody markers as correlates included vaccine breakthrough COVID-19 end points starting 7 days after day 29  = 0.53 to 0.62; fig. S4]. Together, the spike IgG and RBD IgG markers were tightly correlated  as were the ID50 and ID80 markers . Accordingly, some results focus on spike IgG and ID50. Each bAb marker was correlated with each neutralization marker at each time point (r = 0.73 to 0.80).At day 57, almost 100% of vaccine recipients had positive or detectable antibody response by all four markers  Multiplicity-adjusted P values indicated significant inverse correlations with risk, with estimated hazard ratios for upper versus lower tertiles ranging between 0.20 and 0.31  and estimated hazard ratios per 10-fold increase in marker value ranging between 0.19 and 0.54 (fig. S17). 50 titer above a given threshold, with zero COVID-19 end points at ID50 titer above 1000 IU50/ml , and it decreased to 0.014 (0.0067 to 0.028) at titer of 10, to 0.0056 (0.0039 to 0.0080) at titer of 100, and to 0.0023 (0.0013 to 0.0036) at titer of 1000 (The estimated cumulative incidence of COVID-19 by the end of blinded follow-up (100 days after day 57) for the entire vaccine group was 0.0033 . On the basis of nonparametric threshold regression, this cumulative incidence decreased across vaccinated subgroups with day 57 ID IU50/ml . The shath titer . Based o of 1000 . The gen50 titer levels, which, for a given titer level, is the estimated covariate-adjusted percent reduction in cumulative incidence of COVID-19 by the end of blinded follow-up as a result of vaccination generating the given titer level compared with being unvaccinated , and at day 57 ID50 value of 10, 100, and 1000 IU50/ml, respectively, vaccine efficacy was 78% (54 to 89%), 91% (87 to 94%), and 96% (94 to 98%) . Vaccine efficacy estimates also increased with day 29 ID50 neutralization titers: 79% (\u221262 to 90%), 93% (90 to 95%), 97% (95 to 99%), and 99% (97 to 100%) at the same IU50 per milliliter values (fig. S22). to 98%) . The inc50/ml /ml, vaccine efficacy was 85% (31 to 92%), 90% (77 to 94%), and 94% (91 to 96%), respectively. Another conclusion of these analyses is that subgroups with neutralization titer 10 IU50/ml  or with 50 titer  (fig. S29C). A similar pattern of results occurred for all other nAb markers . By contrast, estimated vaccine efficacy appeared to vary only minimally with each bAb marker when unmeasured confounding was assumed . The sensitivity analysis based on E-values  assuming the existence of an unmeasured confounder associated with both the antibody marker and COVID-19 outcome that would make the estimated vaccine efficacy by marker curve flatter, with the specified amount of unmeasured confounding detailed in the SAP (section 12.1.2). The analysis indicated that vaccine efficacy estimates still increased with day 57 IDGiven the overlap of marker distributions in vaccine breakthrough cases and vaccine recipient noncases  of vaccine efficacy was mediated by day 29 ID50 titer and 48.5% (34.5 to 62.4%) by day 29 ID80 titer (table S9).For bAbs at both time points, and for nAbs at day 57, a challenging issue is understanding vaccine efficacy for vaccine recipients with negative or undetectable antibody levels, given that <2% of vaccine recipients had negative or undetectable antibodies. Consequently, the 95% CIs about vaccine efficacy for these subgroups were wide, and assessment of mediation through these markers was not technically possible because of insufficient overlap of marker values in placebo and vaccine recipients. However, day 29 ID50 titer. Therefore, if nAbs circulating on day 29 could be removed but the other consequences of vaccination remained, overall vaccine efficacy would be expected to be reduced by 68% , from 92 to 56%. However, because >98% of vaccine recipients achieved detectable nAbs by day 57, these day 29 mediation results do not reflect a complete deactivation of the nAb response to the level at both day 29 and day 57 (undetectable) that would have been obtained without vaccination. Yet, under the reasonable assumption that the vaccine\u2019s effect on the risk of COVID-19 operating through the day 57 ID50 marker is nonnegative, 68% is a lower bound for the proportion of vaccine efficacy that is mediated through ID50 at both day 29 and day 57 . In comparison, hemagglutination inhibition titer against the B/Brisbane/60/2008-like (Victoria lineage) strain of influenza virus  mediated an estimated 57% of vaccine efficacy against virologically confirmed influenza B/Victoria illness  or calibrated to WHO international standards, enables comparison with other studies and vaccine platforms. Immune correlates results for the COV002 trial  and 140 (43 to NC) IU50/ml, compared with COVE results at ID50 titer of 4 (<LOD = 2.42 to 22) and 83 (16 to 188) IU50/ml. These results support that nAb titers have a similar quantitative relationship with vaccine efficacy for the two vaccine platforms, which is promising for potential applications of a neutralization biomarker. The materials and methods provide a sensitivity analysis comparing correlate of protection results between COV002 and COVE.Pseudovirus neutralization results can also be compared between the trials using IDWith the caveats of different study end points and hosts, the COVE results are also consistent with results on spike IgG and nAb titers as correlates of protection against SARS-CoV-2 replication in mRNA-1273\u2013vaccinated rhesus macaques. For instance, all macaques with spike IgG > 336 IU/ml at 4 weeks after second dose were protected from >10,000 subgenomic RNA copies per milliliter in bronchoalveolar lavages  against COVID-19 to new subgroups for the same vaccine  or for bridging to a modified dose or schedule for the same vaccine . Less evidence is available to buttress the use of a humoral immune marker to predict long-term protection, to bridge to a new vaccine within the same vaccine platform, or to bridge to new spike variant inserts for the same vaccine. An open question challenging the latter application is whether higher nAb responses to emergent SARS-CoV-2 variants, such as Delta, will be needed to achieve similar levels of vaccine efficacy, although modeling data are beginning to support the ability to make cross-variant predictions  and a lack of experimental assignment of antibody levels, which implies that the study could evaluate statistical correlates of protection or surrogate end points but not mechanistic correlates of protection (20211123-1Click here for additional data file."}
+{"text": "ObjectiveThe purpose of this study is to isolate the organisms which are developing resistance and to recognize the drugs against which resistance has emerged so that antibiotic policy can be formulated for the proper and effective use of antibiotics.Setting and designAn observational study was conducted for a period of six months from July 1, 2021 and December 31, 2021 in LGH.MethodsStatistics regarding the culture and sensitivity of the organisms isolated from different sources were collected from the surgery department. 195 cultural and sensitivity reports were analyzed for identification of genus/species of bacteria and sensitivity of the organism.\u00a0ResultsOut of 195 culture reports, 124 showed significant growth of organisms exhibiting resistance to either single or multiple drugs. Escherichia and acinobactor was the most common organism isolated with a total of 30 each , followed by pseudomonas 21 (17%), Klebsiella was 13 (10%), Proteus was 10 (8%), Methicillin-resistance Staph-aureus was seven (5%), Methicillin-sensitive Staph-aureus was five (4%), Staphylococcus epidermidis was four (3%), Providencia, Streptococci, Enterobacter species and Citrobacter species were one (1%).Maximum resistance was detected with frequently used first-line antimicrobials such as Ceftriaxone, ampicillin and Clavulanic acid.\u00a0Least resistant were Azithromycin, Cefoxitin, Cefaclor among the gram-negative and gram-positive bacteria.ConclusionAntimicrobial resistance (AMR) was more against frequently used antibiotics that are accessible for an extended duration. Variation of resistance and sensitivity pattern with time is identified. Periodic AMR monitoring and rotation of antibiotics are suggested to restrict further emergence of resistance. Antimicrobial resistance (AMR) is a growing public health concern where the microorganism is able to survive exposure to antibiotic treatment . There aThe skin has a major role as a physical barrier against harmful bacteria but higher temperature and humidity in a post-operative wound create a favorable environment for the growth of gram-negative bacilli, Corynebacterium spp. and S. aureus . SSI hasSSI in clean surgeries is not uncommon. Gastrointestinal surgery has a higher rate of SSI than other procedures. Among the types of gastrointestinal procedures, colorectal surgery has the highest risk due to the presence of multiple bacteria in the large gut and rectum . We are In Lahore general hospital we are facing a big challenge regarding dealing with SSI most of which are caused by organisms that are antimicrobial-resistant. Social factors such as deficient hygienic practices, demographic variations and overcapacity have been enumerated for the emergence of AMR. Irrational and inappropriate usages of antibiotics in humans and animals for treatment and other usages (as growth promoters) have been thought as the main causes for the rise of hospital and community-acquired resistant infections by the World Health Organization (WHO).The main cause of Multidrug resistance SSIs is not known in LGH. In view of this fact, this study was conducted to identify the group of organisms that have developed the resistance in surgical unit 1 in LGH, to identify the classes of the drug against which this resistance has emerged. On the basis of these findings, we will be able to formulate the proper and effective use of antibiotics.Study design and durationWe conducted an observational study for a period of six months\u00a0from July 1, 2021 to December 31, 2021 after the approval from ethical committee.Data collectionThe data regarding culture and sensitivity of the organisms isolated from different sources such as blood, wound swab/pus, urine other sources such as sputum or tips of CVPs were collected. One hundred and ninety-five culture sensitivity reports were included from the patients.Inclusion and exclusion criteriaThese patients were admitted to Surgical Unit 1, Lahore General Hospital, Lahore, and remained admitted for period of more than seven days and acquired a surgical site wound infection. These samples were sent to laboratories for identifications of organisms and antimicrobial sensitivity. Organisms resistant to more than one drug were considered MDR. Patients that were not remained admitted to the hospital for seven days were excluded.\u00a0Statistical analysisCollected data were statistically analyzed by IBM SPSS Statistics ver. 24.0 . Descriptive statistics were used for the analysis of results.Total 195 cultures and sensitivities were analyzed in 85 patients. Among them 59 (69.4%) were male and 26 (30.5%) were female. Out of 195 culture reports, 65 showed no growth while 124 showed 12 different bacteria and 6 (4%) showed the presence of Candida species\u00a0, Acinetobacter species was 30 (23%). Pseudomonas was 21 (16%), Klebsiella species 13 (10%), Proteus species 10 (8%), MRSA seven (5%), S. aureus five (4%), Staphylococcus epidermidis four (3%)\u00a0 while resistant in 66 53.22%), Cefipime sensitive in 30 (24.19%) while resistant in 94 (75.80%), Cefoparazone+Salbactum sensitive in 44 (35.48%) while resistant in 80 (64.51%), Amoxicillin+Clavulanic acid sensitive in 13 (35.48%) while resistant in 111 (89.51%), Ceftazidime sensitive in 14 (11.29%) while resistant in 110 (88.70%), Ceftriaxone sensitive in seven (0.80%) while resistant in 117 (94.35)\u00a0, Azithromycin 123 (99.19%), Clarithromycin 122 (98.38%), Piperacillin+Tazobactem 120 (96.77%), Cefuroxin 118 (95.16%) and Cefoxitin 120 (96.77%) , Erythromycin 123 (99.19%), Linezolid 116 99.53%), Nitrofurantoin 124 (100%), Cefotaxime 121 (97.58%), Penicillin 123 (99.19%), Tetracycline 119 (95.96%), Ampicillin+Salbactum 124 (100%), Norfloxacin 124 (100%), Fosfomycin 122 (98.38%), and Ampicillin in 123 (99.19%)\u00a0, Gentamycin 12 (57.14%), Imipenem 11 (52.38%) and Amikacin 11 (52.38%) the most and to Cotrimoxazole one (4.7%), Doxycycline one (4.7%) the least, while resistant to all other antibiotics. Klebsiella was sensitive to Amikacin seven (53.84%) the most and to Cefuroxime one (7.6%), Cefotaxime one (7.6%), Tetracycline one (7.6%), Fosfomycin one (7.6%) the least, while resistant to all other antibiotics\u00a0, Amikacin eight (80%), Cefipime seven (70%) the most and to Doxycycline one (10%) the least, while resistant to all other antibiotics.\u00a0MRSA was sensitive to Doxycycline four (57.14), Clindamycin four (57.14%) the most and Tetracycline one (14.28%) the least, while resistant to all other antibiotics.Staphylococcus aureus was sensitive Clindamycin five (100%) the most, Azithromycin one 20%) the least. Staphylococcus epidermidis was sensitive to almost all the drugs\u00a0(Table 0% the leProvidencia species was sensitive to Cefipime one (100%), Amoxicillin+Clavulanic acid one (100%), Ceftazidime one (100%), Ceftriaxone one (100%), Ciprofloxacin one (100%),\u00a0Cotrimoxazole one (100%),\u00a0Gentamycin one (100%), Imipenem one (100%), Meropenim one (100%), Cefotaxime one (100%) while resistant to all other antibiotics.Streptococci were only sensitive to Cefipime one (100%), while resistant to all other antibiotics.\u00a0Enterobacter was sensitive to Amikacin one (100%), Gentamycin one (100%), Meropenim one (100%) while resistant to all other antibiotics.Citrobacter was sensitive to Amikacin one (100%), Cefipime one (100%), Cefoparazone+Salbactum one (100%), Ciprofloxacin one (100%), Imipenem one (100%), Levofloxacin one (100%), Meropenim one (100%), Piperacillin+Tazobactum one (100%), while resistant to all other antibiotics\u00a0Table .\u00a0The diagnosis of infection in critical patients is important because early appropriate antimicrobial therapy improves outcomes. The accurate and timely provided pathological data by the laboratory supports better outcomes for post-surgical patients, especially in an era of increased AR.In our study, the main prevalence of SSI in patients was gram-negative bacteria, i.e., 84% while gram-positive bacteria were 16%. In studies done in India  and NigeAccording to an Iranian study, Acinetobacter was most sensitive to Amikacin 6% with resistance incidence of 88.9% and Ceftazidime 3.4% and Cephalexin 3.4% with resistance incidence of 97% in each  while stIn our study, Colistin 53.33% Amikacin 30%, Imipenem 26.6% and Doxycyclin 26.6% were most active against Acinetobactor with only 10% sensitivity against Piperacillin and 100% resistance against Ampicillin.Pseudomonas aeruginosa was found in 17% of culture sensitivity reports in our study while recent studies in Iran  showed 2Klebsiella was found in 8% culture sensitivity reports of our study while a study done in Egypt  the prevProteus was found in 8% of culture sensitivity reports of our study while according to a study in Nigeria  the prevProvidencia was found in 1% culture sensitivity reports of our study while data from a research study in Egypt  showed PThis study will not only help in the determination of antibiotic prescription in the surgical unit, but it also helps in the promotion of rational use of antibiotics in the community and all personnel who are authorized to prescribe the antibiotics. This will help the administration in formulating the appropriate antibiotics policy. There are a few limitations of these studies including the sample size which is small as compared to other studies. We were not able to correlate the resistance to prior antibiotic exposure of these patients.Hospital-acquired SSIs are a major risk factor for the negative outcomes in post-surgical patients. Every member of the surgical team has a responsibility to understand the importance of evidence-based practices during preoperative, intraoperative, and postoperative phases.\u00a0It includes devising an antibiotic prophylaxis policy. Strict implementation of operating room regulations is required especially in emergency settings, such as hand hygiene, operating room sterilization, restriction in the number of personnel during procedures and taking proper measures regarding pre-operative patient skin antisepsis.Perioperative minimum use of drains is also recommended to prevent SSI in patients. Cultures and swabs should be taken before starting antibiotics and labeled accurately. Prolong use of antibiotics has a major role in causing the emergence of resistant organisms in post-operative patients. In present-day surgical practice, the implementation of standard guidelines in our hospitals is required to lower the risk of antibiotic resistance crisis."}
+{"text": "Coronavirus Disease 2019 pandemic is raging across the world and has affected pregnant women as well. There is limited information regarding COVID-19 in pregnant women. The study aimed to find the prevalence of COVID-19 among all pregnant women who delivered during the study period in a tertiary care center.th August to 15th November 2020 after obtaining ethical clearance from the Institutional Review Committee of a tertiary care center. All the women who delivered in the hospital during the study period were enrolled and they were subjected to COVID-19 Reverse Transcriptase Polymerase Chain Reaction test. A total of 667 samples were taken using convenience sampling technique. Data were analyzed using the Statistical Package for the Social Sciences version 24 software. Point estimate at 95% Confidence Interval was calculated along with frequency and proportion for binary data.This was a descriptive cross-sectional study conducted in a tertiary care center from 16Among 667 pregnant women, the prevalence of COVID-19 was 47 (7.05%) . Though the majority of women were asymptomatic 40 (85.1%), 5 (10.64%) developed mild disease, 1 (2.12%) each had severe and critical COVID-19 pneumonia.The prevalence of COVID-19 among pregnant women delivering in our center is similar to other studies done in similar settings. In our study, we found that the majority of women had been asymptomatic and were diagnosed on routine testing. Hence, it is important to test all pregnant women before delivery for Coronavirus Disease 2019 irrespective of the presence or absence of symptoms. Many have lost their dear and near ones to this unforgiving pandemic.Coronavirus Disease 2019 (COVID-19); caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first emerged in Wuhan, Hubei Province, China in November 2019 and was declared a global pandemic in March 2020 by World Health Organization (WHO); has brought the world down to its heels.Pregnant women have not been spared either. The effects of this disease in pregnancy are still under study and information regarding the epidemiology and effects of COVID-19 in pregnancy is limited more so in a country like Nepal.The aim of this study was to find the prevalence of COVID-19 among all pregnant women who delivered during the study period in a tertiary care center.th August to 15th November 2020. Ethical clearance was obtained from the Institutional Review Committee of the Institute of Medicine. All women who delivered during the study period and who had had the COVID-19 tests were studied. It was hospital protocol to subject all women admitted for delivery in the center to COVID-19 Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) test and all the women who delivered in the hospital during the study period were enrolled. All patients diagnosed with COVID-19 via a nasopharyngeal swab were analyzed. A convenience sampling technique was used.This was a descriptive cross-sectional study conducted in the Department of Obstetrics and Gynecology of a tertiary care center. The duration of the study was 3 months from 16The sample size was calculated using the following formula:2 \u00d7 (p \u00d7 q) / e2n\u2003= Z2 \u00d7 0.5 \u00d7 (1 - 0.5) / (0.04)2\u2003\u2003= (1.96)\u2003\u2003= 601Where,n= minimum required sample sizeZ= 1.96 at 95% Confidence Interval (CI)p= prevalence of COVID-19 among all pregnant women who delivered during the study period in a tertiary care center taken as 50% for maximum sample size calculationq= 1-pe= margin of error, 4%Adding a non-response rate of 10%, the final sample size was 662. However, a total of 667 samples were taken.Our study participants were the pregnant women with laboratory-confirmed SARS-CoV-2 infection on an RT-PCR assay performed on a nasopharyngeal swab before or during delivery hospitalization. Data were collected from patient files regarding age, parity, occupation, and travel history, history of exposure, symptoms, and treatments received if any were also recorded. Other variables studied were comorbidities associated, mode of delivery, maternal and perinatal outcomes.The criteria for classifying COVID-19 positive patients into severity grades are as follows:4Asymptomatic: Those who reported being in usual health without signs or symptoms of COVID-19.4Mild COVID-19: Symptoms requiring no additional oxygen supplementation or treatment beyond standard labor and delivery care.4Severe COVID-19: Dyspnea, respiratory rate 30 breaths per minute or higher, oxygen saturation 93% or less on room air, or findings consistent with pneumonia on chest X-ray, or a combination of these.4Critical COVID-19- any or all of the following: respiratory failure (need for intubation and invasive ventilation), septic shock, and multiple organ dysfunction or failure.Data were analyzed using the Statistical Package for the Social Sciences version 24 (SPSS) software and results were presented in appropriate tables. Point estimate at 95% Confidence Interval was calculated along with frequency, proportion, mean and standard deviations for binary data.Among 667 women, who delivered in our hospital during the study period, the prevalence of Coronavirus Disease 2019 was 47 (7.05%) . The mean age of the COVID-19 positive women was 29\u00b14.438 years varying from a minimum of 20 years to a maximum of 35 years, and the majority 27 (57.4%) were multigravida. Regarding occupation, most were homemakers 36 (76.60%), followed by five health care workers  .The average duration of hospital stay was 4.89\u00b13.661 days .Of the 47 women; only 5 (10.64%) had symptoms when they were tested, the rest 42 (89.36%) were diagnosed on screening at the time of admission for delivery; while 2 (4.2%) developed symptoms postdelivery. Similarly, 5 (10.6%) had a history of exposure  and only three (6.38%) reported travel history, rest 44 (93.62%) COVID-19 positive pregnant women reported no travel history .Twenty-three (49%) had some associated comorbidity, most commonly hypertension in 8 (34.7%) and diabetes in 5 (21.7%). Others were hypothyroidism 5 (21.7%), Rheumatic Heart Disease 2 (8.7%), obesity 2 (8.7%), obstetric cholestasis 1 (4.3%), Takayasu arteritis 1 (4.3%) and thrombocytopenia 1 (4.3%).Though the majority 40 (85.1%) of the women were asymptomatic, 5 (10.6%) developed the mild disease, 1 (2.12%) had severe disease and 1 (2.12%) developed critical COVID pneumonia. All patients recovered and there was no mortality .The mean gestational age at COVID-19 diagnosis was 37.83\u00b12.24 weeks . The mean age of gestation at delivery was 38.38\u00b12.24 weeks . There were 8 (17%) preterm births and one twin set. The mode of delivery was decided as per obstetric indications and only one patient underwent emergency cesarean Section (CS) at 37 weeks for worsening critical COVID19 pneumonia. Out of 47, only 4 (8.5%) delivered vaginally, rest 43 (91.5%) had CS births. Eleven (23.4%) had elective CS and 32 (68.08%) had emergency surgery .There were 48 babies born to the 47 COVID-19 positive women including one twin set. There were no intrauterine fetal deaths (IUFD), neonatal deaths (NND), or stillbirths. There were 9 (18.7%) babies with low birthweight. Three babies (6.25) had low APGAR scores at one minute while 2 (4.17%) of them had improved APGAR at five minutes; one baby born to the mother with critical COVID-19, still had low APGAR even at five minutes. The baby was diagnosed to have perinatal depression and was admitted to the Neonatal Intensive Care Unit (NICU), intubated and mechanically ventilated but made a good recovery. There were two others needing admission to NICU for Respiratory Distress Syndrome (RDS) and Meconium Aspiration Syndrome (MAS) while three (6.25%) babies were admitted to Neonatal Unit (NNU) for transient tachypnea of the newborn (TTN), RDS, and supportive care for the preterm baby born at 28 weeks .9The effects of COVID-19 during pregnancy are a burning concern as the disease is showing no signs of abating any time soon. Literature on COVID-19 in pregnancy is evolving each day-some have shown poor outcomes, some have reported favorable outcomes while others found no definite difference in COVID-19 course in pregnant as compared to non-pregnant subjects.7 Majority had no travel or exposure history pointing towards community spread of the disease, similar to study in South India by Nambiar, et al. and Shah, et al. from Gujrat.10Most of the women in the present study were asymptomatic (85.1%) and were diagnosed on screening at admission at the time of delivery. Fever was the commonest symptom, with all 7 (14.9%) symptomatic patients having fever. Chen, et al. and Nambiar, et al. reported similar results; most patients were asymptomatic and the commonest symptoms were fever, cough, and fatigue.5 Shah, et al. also reported that only 7 of 125 (5.6%) pregnant women experienced severe COVID-19 infection.10 It is postulated that relative suppression of cell-mediated immunity in pregnancy may be responsible for milder symptoms in COVID-19-positive pregnancies though adequate evidence is not available to conclude the definite effect of this virus in pregnancy.11 However, Khoury, et al. have reported a higher rate of severe disease in 16.2%.12Five women (10.6 %) had mild disease, 1 (2.12%) developed the severe disease, and another 1 (2.12%) developed the critical disease. Guan, et al, in a study from China reported a severe disease rate of 8% in their pregnant population as compared to 15.7% risk of severe disease in the general population.14 Khoury, et al. reported 14.6% preterm births whereas Chen, et al. reported that four of the nine patients had preterm delivery but the preterm delivery was not associated with COVID-19 pneumonia.12 In our study majority delivered at term with only 8 (17%) preterm births and those were unrelated to COVID-19.Some studies showed increased rates of preterm labor.6The high Cesarean Section rate of 91.5% in COVID-19 positive patients in our study is double the institutional rate of 45% during the same period for non-COVID-19 patients. In a study by Nambiar, et al. there was a similarly disproportionate increase in the rate of cesarean sections (52.28%) when compared to an institutional rate of 23% in non-COVID-19 pregnancies.15 The high CS rates could be attributed to a higher proportion of high-risk pregnancies with associated comorbidities in our study and an increased number of repeat Cesarean Sections.The delivery policy for COVID-19 patients in our hospital was as per the Royal College Of Obstetricians and Gynecologists (RCOG), which recommends that the mode of delivery be determined primarily by obstetric indications.6 The babies were not tested for COVID-19 as the protocol was to test babies only if they became symptomatic. Mothers were allowed to room in with the babies and allowed to breastfeed with strict hand wash instructions and wearing a mask every time. This was in accordance with the RCOG, which recommends against the routine separation of COVID-19-affected mothers and their babies, and WHO guidelines, which states that 'the benefits of skin-to-skin contact and breastfeeding substantially outweigh the potential risks of transmission and illness associated with COVID-19 infection'.16 Only the babies of the two sick mothers were put in the care of their family members till their mothers were in ICU.All the newborns did well in our study. None of the babies developed any symptoms of COVID-19, similar to the study by Nambiar, et al.The limitations of the study were the small sample size, short duration, and single center. Neonates were not tested for COVID-19; hence we failed to shed any light on the chances of vertical transmission.The prevalence of COVID-19 among pregnant women giving birth in our study is similar to other studies done in similar settings. In our study, we found that the majority of women had been asymptomatic and were diagnosed on routine testing. Of the symptomatic ones, most had only mild diseases that required no special treatment, however, we must watch out for severe cases since they may deteriorate rapidly. Our study stresses the importance of testing all pregnant women before delivery for COVID-19 irrespective of the presence or absence of symptoms."}
+{"text": "Esketamine nasal spray has been developed for patients with treatment resistant depression.A cohort Temporary Authorization for Use (ATUc) allowed to collect for a 6-month period the first data in real lifeOn 02/08/2019 the French National Agency for Medicines and Health Product Safety granted an early access program for Esketamine nasal spray framed by a specific protocol for patients without therapeutic alternatives. Each treatment request was approved based on inclusion and exclusion criteria. Clinical evolution, treatment management and safety were then spontaneously reported by psychiatrists.From 09/23/2019 to 03/25/2020, 66 patients were treated. The median age was 53 years and 41 (62.1%) were females. At treatment request, 52 patients (79%), presented a severe current depressive episode based on clinical judgment. The median duration of the disease was 12.2 years and the current episode was 2.6 years. Since the beginning of the current depressive episode, all patients (66) were prescribed \u22652 antidepressants (mean 4.2). Esketamine was initiated in a complete hospitalization setting in 27 patients (55.1%) and in day hospitalization in 22 patients (44.9%).Safety profile was consistent with the one described during clinical study. The most frequently adverse events reported (>10%) were dizziness, sedation, sleepiness, anxiety and dissociation. Most of them appeared after treatment administration and were transient.ATUc ended on 12/18/2019 after Marketing Authorization granted by European Medicines Agency. Data reported by French psychiatrists are the first collected in this specific population and provide descriptive information on patient characteristics, burden of disease; Esketamine management and practical use at hospital levelData analysis performed by RCTs and poster conception coordinated by Medergy and funded by Janssen"}
+{"text": "To analyze the karyotype test and myeloid panel with next-generation sequencing findings in patients with myelofibrosis, and to compare transplant characteristics in patients referred for bone marrow transplantation.Hospital Israelita Albert Einstein between 2010 and 2020. Retrospective, single-center study with patients diagnosed with myelofibrosis treated at versus 50%). The median follow-up of transplant patients was 2.4 years and the overall survival at 2 years was 80% (95%CI: 62-100%). A total of 104 patients with myelofibrosis were examined. Patients who had not been submitted to tests in our service were excluded. The final sample comprised 69 patients. Of these 69, 56 were submitted to karyotyping and 22 to myeloid panel with next-generation sequencing. Karyotype was normal in 60% of the patients and altered in 40%. The prevalence of high-risk molecular mutations was higher in patients referred for bone marrow transplantation (100%  The molecular analysis enables estimating the patient\u2019s risk and thus instituting more aggressive treatment such as bone marrow transplant for patients at higher risk, being a relevant tool to guide therapy. Given the significance of molecular analysis for therapeutic decision-making in myelofibrosis, collection and disclosure of data on the prevalence of cytogenetic changes and findings of next-generation sequencing in affected patients is important. The estimated median overall survival of patients with primary MF or MF secondary to PV is 4.5 years, compared to 7.06 years in patients with MF secondary to ET. The primary causes of death include leukemic transformation, cardiovascular events and complications of cytopenia, such as infection or bleeding.Myelofibrosis (MF) is a BCR-ABL-1 negative myeloproliferative neoplasm. This type of neoplasm can be primary . These patients have lower survival rates and higher risk of progression to acute myeloid leukemia (AML).Genetic markers are determinant of outcomes in patients with MF and have been incorporated into formal prognostic systems, such as MIPSS70+ and GIPSS.Other risk factors which contribute to progression to AML include unfavorable karyotypes, circulating blast percentages higher than 3%, platelet counts less than 50,000, TP53, and high-risk somatic mutations such as ASXL1 (frequency of 22%), SRSF2 (9%), EZH2 (5%), IDH1/2 (3%) and U2AF1 Q157 (16%).Myelofibrosis is associated with the presence of 3 cardinal and often mutually exclusive mutations: janus kinase 2 V617F (JAK2V617F), calreticulin (CALR) and myeloproliferative leukemia virus (MPL) oncogene.Unfortunately, BMT is associated with at least 50% of transplant-related deaths or severe morbidity such as graft-versus-host disease (GVHD) in MF patients. In a Mayo Clinic study with MF patients submitted to allogeneic BMT, the 5-year overall survival was 62%. Hence, risks associated with BMT must be weighed according to life expectancy, should the patient not receive BMT. For this type of assessment, molecular genetic risk factors of patients must be determined.Despite the availability of new therapeutic agents to tackle MF, the only treatment with curative potential is allogeneic bone marrow transplantation (BMT).To analyze the karyotype test and myeloid panel with next-generation sequencing findings in patients with myelofibrosis, and to compare transplant characteristics in patients referred for bone marrow transplantation.Hospital Israelita Albert Einstein (HIAE) between 2010 and 2020. Patient data  were collected, as well as transplant data of patients undergoing BMT .Retrospective, single-center study based on medical records of patients diagnosed with MF treated at Patients diagnosed with myelofibrosis treated at HIAE between 2010 and 2020. Primary and secondary MF diagnosis were defined according to 2016 World Health Organization (WHO) diagnostic criteria.Patients with available clinical, laboratory and therapeutic data in medical records.Inability to retrospectively collect patient and clinical outcome data.Overall survival was defined as survival from the date of diagnosis to the date of death from any cause. Patients who were alive at the time of analysis were censored.Overall survival was estimated using the Kaplan-Meier method. Categorical and continuous variables were reported using descriptive statistics. Statistical tests were performed using R software, version 4.0.0.This project was approved by the Ethics Committee of HIAE. Certificate of submission to ethical assessment CAAE: 47080621.1.0000.0071; # 5.208.295.ersus 50%) , deletion of 20 (22%), deletion of 5 (18%), deletion of 9 (13%), trisomy 9 (13%) and monosomy 7 and 17 (9% each). In the 22 patients examined using NGS, the following variants were detected: JAK2 (54%) ASXL1 (50%), TET2 (31%), CALR (22%), SRSF2 (22%), EZH2 (22%), U2AF1 (18%), SF3B1 (13%), MPL (13%), CBL (13%), IDH2 (9%) . The presus 50%) .Sixteen patients underwent BMT. Median follow-up was 2.4 years, with a 2-year overall survival of 80% (95%CI: 62-100%). Of these 16 patients, 11 were women (68%) with median age at diagnosis of 54 years and median age at the time of BMT of 57 years. Median time from diagnosis to BMT was 5.6 years (1 to 19 years). Half of patients were asymptomatic at diagnosis and had been referred for investigation of changes in blood cell count. At diagnosis, 8 patients had splenomegaly (50%), 4 had night sweats (25%) and 2 had lost weight (12.5%). Of the 14 patients amenable to cytogenetic assessment, 11 were normal (78%) and 3 had changes . Ten patients carried the JAK2V617F mutation (83%), 1 carried the CALR mutation and 1 carried the MPL mutation (8%). Other mutations detected were ASXL1 (33%), SRSF2 (16%), TET2 (16%), ETV6, EZH2 and U2AF1. Primary MF accounted for 60% of cases, whereas MF secondary to ET was diagnosed in 40% of patients.Out of 16 transplants performed, 5 were matched-sibling, 5 were matched unrelated 10/10 human leukocyte antigen (HLA) donors, 2 were mismatched unrelated, 1 was cord blood, and were 3 haploidentical . Seven pOf 16 transplants performed, 5 were matched-sibling, 5 unrelated 10x10, 2 unrelated with mismatch, 1 cord blood and 3 haploidentical.The main risk factors for transformation into AML are unfavorable karyotypes, such as monosomies or inv(3)/i(17q), and high-risk somatic mutations, such as ASXL1 (population frequency 22%), SRSF2 (9%), EZH2 (5%), IDH1/2 (3%) and U2AF1 Q157 (16%).Findings of three clinical trials suggest patients carrying the ASXL1 mutation respond less to JAK2 inhibitors, while patients carrying the CALR type 1 mutation show longer-lasting responses.These mutations affect patient survival and response to treatment.One of the major causes of death in patients with MF is leukemic transformation, which occurs in 20% of cases. This may have reflected that, in this study, NGS panels were used to help decide whether patients at higher risk should be referred for BMT.The prevalence of high-risk somatic mutations in patients submitted to NGS in this sample was higher than the prevalence reported in the general population .(1) ThisThe only potentially curative treatment is BMT, which has a high morbidity and mortality.Most drugs available for MF treatment are palliative and aimed to alleviate symptoms, reduce complications and improve quality of life, with no impact on the natural history of disease or survival.In spite of the small number of patients undergoing BMT in this study, results were consistent with findings reported in prior studies using the BuFlu regimen with appropriate busulfan doses. Optimization of conditioning regimens and use of JAK2 inhibitors are thought to improve engraftment rates in BMT for myelofibrosis. However, new strategies are needed to reduce GVHD incidence and post-transplantation relapse rates, to improve clinical outcomes of transplanted patients.Patients undergoing allogeneic transplantation had shorter 1-year survival relative to patients receiving clinical treatment. However, over the course of 6-year follow-up, MF patients treated with BMT who had intermediate-1 or higher-risk DIPSS had better long-term survival, despite higher early mortality rates. Low-risk patients did not benefit from BMT and had poorer survival rates compared to patients undergoing clinical treatment.Gowin et al. compared the survival of 1,928 patients with myelofibrosis submitted to allogeneic BMT (551) or clinical treatment .versus-host disease after allogeneic bone marrow transplantation. However, new strategies are needed to reduce the incidence of graft-versus-host disease and improve clinical outcome of these transplanted patients. Karyotype analysis and graft-versus-host disease can be used to estimate a patient\u2019s risk. These approaches may inform the need of more aggressive treatment in higher risk patients, such as bone marrow transplantation. Molecular analysis is thought to be a relevant tool to guide therapy.Optimization of conditioning regimens and use of JAK2 inhibitors are thought to improve engraftment rates in bone marrow transplantation for myelofibrosis. Ruxolitinib has important immunosuppressive effects, and may help control graft-"}
+{"text": "The year 2020 was marked by the COVID-19 pandemic. Health services were overwhelmed by the demands for care. Paramedics were both the main actors in the fight and the victims of this pandemic.The objective of our work was to assess paramedics\u2019 feelings and beliefs about COVID-19.Descriptive and cross-sectional study including paramedics  from the military hospital of Tunis. Data collection was carried out by a clinical psychologist. we studied paramedics\u2019 feelings and beliefs about COVID-19.A total of 161 paramedics agreed to answer our questionnaire. The average age was 37.73 years. The average number of years worked was 14.95 years. There were 85 women (52.8%) and 76 men (47.2%). The feelings about COVID-19 were anxiety in 127 (78.9%) paramedics and indifference in 34 (21.1%). The factors that could influence the spread of the pandemic were divine influence (25.5%), the organized fight against viruses (70.2%), our genetics (9.9%), mutations of the virus (6.8%), the BCG vaccine (21.7%), the Tunisian climate (5.6%), our food (13%).The beliefs and feelings of paramedics regarding COVID-19 are many and varied. These factors must be taken into consideration because they influence the involvement of paramedics in the fight against the virus and their compliance with health and safety rules."}
+{"text": "This study aimed to 1) establish the success rate of matching offspring in the Northern Ireland Cerebral Palsy Register (NICPR) to mother-infant pairs within the Northern Ireland Maternity System (NIMATS); and explore changes in 2) quality of maternal data (NIMATS) and 3) maternal characteristics over the study period.Data for individuals with cerebral palsy (CP) born between 1990 (commencement of NIMATS) and 2012  were transferred to the Honest Broker Service, who performed data linkage. Offspring were primarily matched between NICPR and NIMATS using the unique Health and Care Number (HCN). Where this was unavailable in NIMATS, matching from offspring to mothers/pregnancies was performed using surname, gender, date of birth +/- postcode. Changes in completeness and quality of data and maternal characteristics were explored per year and visualised using histograms. All pre-processing and analyses were performed using R.From 1263 included CP cases, 377(30%) were matched using HCN. A further 121(9%) were matched by secondary strategies. Substantial improvements in completeness of maternal data were observed over time (body mass index (46.2% to 97.7%); BP (44.8% to 95.3%); age 100% complete throughout). An apparent tendency to round systolic and diastolic blood pressure to the nearest ten was observed. This tendency decreased over time which potentially led to an overestimation of hypertension detected in earlier years. Characteristics of mothers also changed over the study duration, seen in increasing proportions with BMI\u226530 kg/m2 (9.97% to 18.9%). Age of mothers also increased with decreasing proportions aged<25y (33.7% to 19.6%) and increasing proportions aged\u226535y (9.7% to 20.4%). No change over time was observed in maternal blood pressure variables.Matching success was affected by incomplete NIMATS coverage in earlier years and lag time in CP diagnosis being confirmed by NICPR . Over time, completeness and quality of maternal variables in NIMATS has improved meaning future studies using these linkages will be more reliable."}
+{"text": "Background: Short and long-term sequelae after admission to the intensive care unit (ICU) for coronavirus disease 2019 (COVID-19) are to be expected, which makes multidisciplinary care key in the support of physical and cognitive recovery.Objective: To describe, from a multidisciplinary perspective, the sequelae one month after hospital discharge among patients who required ICU admission for severe COVID-19 pneumonia.Design: Prospective cohort study.Environment: Multidisciplinary outpatient clinic.Population: Patients with severe COVID-19 pneumonia, post- ICU admission.Methods: A total of 104 patients completed the study in the multidisciplinary outpatient clinic. The tests performed included spirometry, measurement of respiratory muscle pressure, loss of body cell mass (BCM) and BCM index (BCMI), general joint and muscular mobility, the short physical performance battery , grip strength with hand dynamometer, the six-minute walk test (6-MWT), the functional assessment of chronic illness therapy-fatigue scale (FACIT-F), the European quality of life-5 dimensions (EQ-5D), the Barthel index and the Montreal cognitive assessment test (MoCA). While rehabilitation was not necessary for 23 patients, 38 patients attended group rehabilitation sessions and other 43 patients received home rehabilitation.Endpoints: The main sequelae detected in patients were fatigue (75.96%), dyspnoea (64.42%) and oxygen therapy on discharge (37.5%). The MoCA showed a mean score compatible with mild cognitive decline. The main impairment of joint mobility was limited shoulder (11.54%) and shoulder girdle (2.88%) mobility; whereas for muscle mobility, lower limb limitations (16.35%) were the main dysfunction. Distal neuropathy was present in 23.08% of patients, most frequently located in lower limbs (15.38%). Finally, 50% of patients reported moderate limitation in the EQ-5D, with a mean score of 60.62 points (SD 20.15) in perceived quality of life.Conclusions: Our findings support the need for a multidisciplinary and comprehensive evaluation of patients after ICU admission for COVID-19 because of the wide range of sequelae, which also mean that these patients need a long-term follow-up.Impact on clinical rehabilitation: This study provides data supporting the key role of rehabilitation during the follow-up of severe patients, thus facilitating their reintegration in society and a suitable adaptation to daily living. Coronavirus disease 2019 (COVID-19) is a relatively new disease in the public health context, which was first notified in Wuhan (China) in December 2019. The WHO declared COVID-19 a pandemic on 11 March 2020 because of its alarming levels of propagation and severity On the other hand, the 2010 meeting of the Society of Critical Care Medicine coined the term \"post intensive care syndrome\" (PICS) to describe the physical, cognitive and mental health deficiencies that present after admission to intensive care once the acute phase of disease has passed Before the SARS-CoV2 pandemic, studies had described the sequelae after admission for adult respiratory distress syndrome, reporting a significant proportion of surviving patients with considerable sequelae in their functional capacity and state of health in their first months of recovery The arrival of the COVID-19 pandemic led to an exponential increase in the number of critical patients requiring intensive care. As a consequence, the intensive care units (ICUs) were overwhelmed by patients with severe hypoxia secondary to bilateral pneumonia and many of them had serious and multifactorial disabling sequelae. These sequelae were associated with a prolonged stay in ICU, respiratory distress This new reality has led some hospitals to create tools to facilitate the follow-up of these complex patients. In June 2020, the Hospital Universitario Virgen de la Victoria  established a multidisciplinary circuit consisting of the main specialties involved in the treatment of COVID-19 and its medical consequences. During the first visit, one month after hospital discharge, sequelae were detected at a one-stop clinic where interventions were initiated. In the subsequent follow-up visits, both sequelae and interventions were monitored.The aim of this study was to evaluate the sequelae found at one month after hospital discharge among patients with COVID-19 severe bilateral pneumonia from a multidisciplinary approach with different specialists. In the initial post-ICU visit, ICU specialists and, subsequently, specialists in physical medicine and rehabilitation, endocrinology and nutrition, mental health and pneumology.An observational retrospective study of patients who required admission to the ICU of the Hospital Universitario Virgen de la Victoria  between April 2020 and October 2021 for severe COVID-19 pneumonia.All of the patients admitted to the ICU had indications for aggressive measures, with a need for oxygen > 15 L/min and partial pressure of oxygen in arterial blood (PaO2) < 200 mmHg. Our study included survivor patients, who were given appointments for the post-COVID-19 multidisciplinary care circuit, where they were assessed at a \"one-stop clinic\" by specialists in physical medicine and rehabilitation, endocrinology, pneumology, mental health and intensive care. Because the Hospital Universitario Virgen de la Victoria is a referral centre for other health districts, we excluded both patients who had been referred from other hospitals as a consequence of pressure on the healthcare system within the epidemiological context and foreign patients because of the difficulty of completing their follow-up.Using the medical records of the patients, we compiled the baseline sociodemographic characteristics, comorbidities, treatment required during their stay in the ICU, type of life support, mechanical ventilation, need for prone positioning, muscle relaxation, treatment received and complications after hospital admission. We also collected outcomes from the assessments of different specialists and the need for the inclusion of these patients in the rehabilitation programme, whether in group sessions or at home. The assignation of rehabilitation groups was based on the functional status of patients and the perceived sequelae at the first evaluation.During a one-year follow-up period, we collected data from patients at the first and subsequent 3-, 6-, 9- and 12-month visits. Some patients did not require follow-up because they improved and were discharged from the rehabilitation programme. Not all patients required evaluation by all of the specialists included in the programme.The clinical protocol of the multidisciplinary care included:Medical history with details of quality of life before COVID-19, independence for activities of daily living, need for assistance when walking, fatigue, physical exercise habits, pain and weakness.Data collected during hospitalisation: duration of hospitalisation (days), ICU stay (days), administered respiratory therapy, duration of mechanical ventilation (days), treatment given, duration of muscle relaxant exposure (days) and cycles of prone positioning.Otorhinolaryngological sequelae.Psychological/psychiatric sequelae: those sequelae that were described in the mental health visit using a clinical interview, and a record of the use of benzodiazepines and antidepressants consumed.Respiratory sequelae: the need for oxygen therapy on discharge and at subsequent check-ups, dyspnoea , spirometry  Nutritional sequelae Data collection on sequelae:Physical examination: General joint mobility and general muscular mobility.The short physical performance battery  Grip strength with a hand dynamometer The six-minute walk test (6-MWT) Physical examination and tests:The functional assessment of chronic illness therapy-fatigue scale (FACIT-F) The European quality of life-5 dimensions questionnaire (EQ-5D) The Barthel index The Montreal cognitive assessment test (MoCA) Quality of life questionnaires:The study was approved by the Regional Ethics Committee of the Hospital Universitario Virgen de la Victoria (project Id. POSTUCI21-1654-N-21) in accordance with the Ethical Principles for Medical Research Involving Human Subjects adopted in the Declaration of Helsinki by the World Medical Association  and the Regulation (EU) 2016/679 of the European Parliament and of the Council 27 April 2016 on the protection of natural persons with regard to the processing of personal data and on the free movement of such data . Therefore, alphanumeric codes were used by the specialists and researchers during the evaluation sessions and preparation of database in order to maintain privacy and confidentiality of the participants. All patients who were included in the present study gave informed consent for the use of their anonymised data in the knowledge that this was a descriptive study for baseline characteristics. They also authorised their long-term follow-up. Patients were able to revoke their informed consent and withdraw from the study whenever they wished. Only one patient did not wish to participate in the study and did not sign the informed consent.The baseline sociodemographic and clinical characteristics of the patients are expressed as a mean and standard deviation [mean (SD)] for quantitative variables, and absolute values with percentages [n (%)] for qualitative variables. The sequelae and results derived from tests/questionnaires at the clinic during the follow-up were also expressed using quantitative (continuous or discrete) and qualitative variables. All statistical analyses of the database were performed using the IBM SPSS Statistics version 24 .A total of 360 patients with severe COVID-19 pneumonia were admitted to the ICU of the Hospital Universitario Virgen de la Victoria from April 2020 to October 2021 and the multidisciplinary post-ICU clinic included 104 patients who completed the study. Of the remaining patients, 127 died during the hospital admission, 74 did not meet the inclusion criteria  and 55 were lost to follow-up after discharge.We collected the baseline sociodemographic and clinical characteristics of the 104 patients, which are shown Table The patients were predominantly male (77.9%) and the mean age was 56.7 years (SD 13.8). According to the usual body mass index (BMI) before the hospital admission, the patients were mainly classified into class 1 obesity (30.8%) and overweight (29.8%), followed by class 2 obesity (17.3%), class 3 morbid obesity (15.4%) and normal weight (6.7%). Regarding smoking habits, 44.2% of patients described themselves as former smokers and 3.8% were smokers.The most prevalent comorbidity in these patients was arterial hypertension (48.1%), followed by dyslipidaemia (30.8%) and diabetes mellitus (27.9%). However, there were other previous medical complications that were also considered in the study. Thus, 23 patients (22.2%) had a previous history of respiratory problems: obstructive sleep apnoea (OSA) (10.6%), asthma (8.7%) and chronic obstructive pulmonary disease (COPD) (2.9%); 11 patients (10.6%) had a cardiological history: ischaemic heart disease (4.8%), arrhythmias (2.9%), valvular heart disease (1.9%) and hypertensive cardiomyopathy (1.0%); 8 patients (7.7%) had a history of orthopaedic problems: prior fractures (3.8%), osteoarthritis (1.9%) and myalgia (1.0%); and only 2 patients had a history of kidney disease (1.9%).The mean stay in the ICU was 21.9 days (SD 19.6) and the mean period of hospitalisation was 47.3 days (SD 49.6). Regarding the clinical procedures of these patients, invasive mechanical ventilation was necessary for 53.8% of patients, and 46.2% of patients required high-flow nasal cannula therapy. All of the patients who required mechanical ventilation underwent an initial therapy with high-flow nasal cannula and the mean delay in orotracheal intubation from admission was 1.3 days (SD 2.2). The mean duration of mechanical ventilation was 27.1 days (SD 21.6) and tracheotomy with prolonged orotracheal intubation was necessary for 60.71% of patients who had mechanical ventilation.The mean number of prone positioning cycles was 3.7 (SD 2.1).The pharmacological treatment administered during the ICU stay was primarily tocilizumab (58.7%) and glucocorticoids (98.0%), followed by other drugs employed exclusively during the first wave of COVID-19, such as hydroxychloroquine (21.2%), lopinavir-ritonavir (19.2%) and interferon beta (17.3%). During the admission, 6.7% of patients received muscle relaxants for a mean period of 7.7 days (SD 6.7).A multidisciplinary team assessed the sequelae after hospital discharge from different specialities Table .In nutritional terms, there was a weight loss of 10.8 kg (SD 7.9) and an active BCMI of 9.6 kg (SD 2.5) in men and 9.5 kg (SD 6.5) in women.Important otorhinolaryngological sequelae were observed in these patients (22.11%). Specifically, the patients were mainly diagnosed with aphonia (13.5%), followed by aural or glottic granuloma (2.9%), tracheal stenosis (2.9%), hearing loss (1.9%) and tracheostomy fistula (1.0%).Regarding the psychological/psychiatric abnormalities, we found important sequelae related to mood disorders and emotional responses. Thus, 17 patients (16.3%) were diagnosed with anxiety and/or depression during the follow-up: anxiety (5.8%), depression (2.9%) and mixed anxiety-depressive disorder (11.5%); and 12 patients showed adjustment disorder (11.5%). In contrast, 11 patients showed a condition compatible with a normal experiential reaction (10.6%). Secondary to these mood abnormalities, 26.0 % of patients reported insomnia and an elevated consumption of psychotropic drugs (28.8% benzodiazepines and 26.9% antidepressants).From a respiratory perspective, we assessed mMRC dyspnoea and the need for home oxygen therapy on hospital discharge. There were different degrees of dyspnoea in 64.4% of patients: grade 1 in 31.7%, grade 2 in 24.0% and grade 3 in 8.7% of patients. On hospital discharge, 37.5% of patients required home oxygen therapy and 8.7% were still receiving this therapy at the six-month follow-up visit.Among the patients with impaired joint mobility (36.5%), the main limitation of joint mobility was observed at shoulder (11.5%) and shoulder girdle (2.9%) level. The examination of muscular mobility revealed sequelae in 51.9% of patients, and the main sequelae were lower limb (16.4%), upper limb (5.8%) and general (6.7%) limitations.Twenty-eight patients reported painful conditions (26.9%). Mainly, neuropathic pain (13.5%), meralgia paresthetica (7.7%), multiple enthesopathies (5.8%) and lumbar-sciatic pain (4.8%.). Distal neuropathy was present in 23.1% of patients, more frequently in lower limb (15.4%), and brachial plexopathy was only reported in patients who required mechanical ventilation .Regarding the physical state, 19 patients required aid to walk at the first visit (18.3%) using a walking stick or frame (15.4%) or wheelchair (2.9%). The degree of fatigue/tiredness reported by the patients was predominantly fatigue on moderate effort (48.1%) followed by fatigue on great (18.3%) and mild (9.6%) efforts. The Barthel index for activities of daily living showed a score of 91.50 points (SD 16.31), which indicates a moderate-slight dependency.In terms of cognition, the MoCA test was conducted on 47 patients and the mean score was > 26 points, which is compatible with mild cognitive deterioration. A second analysis of the MoCA test after adjusting for age revealed worse results in patients with \u2265 65 years than in patients under 65 years with a mean score of 16 points (SD 9) and 22 points (SD 9), respectively.The patients who underwent a one-year follow-up at the multidisciplinary post-ICU clinic were divided into three groups according to the rehabilitation procedures. Thus, 23 patients did not require rehabilitation (22.1%), 38 patients required group rehabilitation sessions (36.5%) and 43 patients received home rehabilitation (41.4%) with a set of exercises to follow.As shown in Table The respiratory functional testing was performed with spirometry and measurements of MIP and MEP in order to evaluate the respiratory muscle strength Table . The spiIn addition to spirometry, measurements of MIP and MEP were conducted on the patients considering sex. While men had a mean MIP of 81.6 cm H2O (SD 29.8) and a mean MEP of 95.6 cm H2O (SD 41.6), women had a mean MIP of 68.8 cm H2O (SD 44.0) and a mean MEP of 70.2 cm H2O (SD 22.2). The MIP values were normal for both sexes but the MEP values were lower than the reference values (100 cm H2O for men and 80 cm H2O for women).The EQ-5D showed a perceived quality of life of 60.6 points (SD 20.2) and high percentage of negative responses  in the different dimensions of the questionnaire  regarding fatigue, impaired physical function, anxiety and depression The cognitive dysfunction of patients with mild symptomatic COVID-19 has been also evaluated using the MoCA test and evidence of decline cognitive has been observed without establishing its pathogenesis Regarding the quality of life, Halpin and colleagues found a significant impact on quality of daily life in ICU survivors compared with patients with mild or moderate COVID-19 using the EQ-5D-5L scale Major studies, such as the cohort study of Huang et al. with a sample of 1,733 patients, have reported sequelae after hospital discharge in patients with COVID-19 including sleeping difficulty, mood disorders, fatigue and muscular weakness Concerning dyspnoea, 64.4% of patients had some degree of mMRC dyspnoea and 37.5% required home oxygen therapy on hospital discharge. However, at six-month follow-up only 8.7% of patients needed oxygen. It is worth noting that 66 patients who required examination by a pneumologist showed, during the multidisciplinary follow-up circuit, normal spirometry findings, normal MIP for both sexes but a reduced MEP relative to the reference values Rehabilitation plays a key role in the multidisciplinary follow-up of patients after hospital discharge For evaluation of nutritional status, we considered BCM and BCMI The main point of interest in this observational study is the multidisciplinary nature of the sequelae suffered by patients who were admitted to the ICU for severe COVID-19 pneumonia at our hospital. In this respect, the Hospital Universitario Virgen de la Victoria pioneered the treatment of patients with severe hypoxia using high-flow nasal cannula therapy in the ICU, unlike other centres where these patients remained on general wards. It is worth noting that, even though orotracheal intubation was necessary for 53.8% of the patients, the sensation of dyspnoea and perceived fatigue during follow-up reached 64.2% and 76.0% respectively, and the general sequelae described after multidisciplinary evaluation were considerable with about 78% of patients requiring rehabilitation.The main limitations of this study are the small sample size and the fact that not all the patients were examined and evaluated by all the specialties who were included in the multidisciplinary programme, which could imply bias in the interpretation of the results; for instance, certain tests, such as spirometry, were only conducted in patients who had a bad respiratory prognosis on hospital discharge. It would have been beneficial the inclusion of patients during the post-COVID follow-up without requiring ICU admission in order to report on a broader and more complete range of sequelae after home discharge patients. A long-term follow-up and an increase in the sample size are necessary to better characterise the consequences of COVID-19.We conclude that a post-ICU multidisciplinary approach in patients with severe COVID-19 pneumonia is fundamental because of the wide range of sequelae. The role of early rehabilitation is key to minimise the disabling effect of these sequelae to optimise the extent of independence and maximise the reintegration in society of these patients."}
+{"text": "Parents of hospitalized children with chronic illness (HCCI) during the COVID-19 epidemic may face huge pressure and worry, leading to mental health issues. Parent\u2019s depression and anxiety disorders increase the risk of mental health problems in the child and affect his/her recovery.The aim of this study was to assess the prevalence rate of depressive and anxiety symptoms among a pilot sample of parents of HCCI (in- and out-patients) with diagnosis of epilepsy (9), cystic fibrosis (8) and congenital heart anomalies (6) during COVID-19 pandemic. Pediatric patients were under a regular Children Hospital medical and psychological follow-up program.We conducted a cross-sectional study among 23 Italian parents  of HCCI during the COVID-19 epidemic period. We performed face-to face interviews and assessed depressive and anxiety symptoms with the Patient Health Questionnaire (PHQ-9) and the Generalized Anxiety Disorders (GAD-7) questionnaire during scheduled follow up visits.The anxiety score of parents of HCCI was 4.43 \u00b1 3.17, of which 39.1% of parents were anxious (\u22655 points), while the depression score was 4.04 \u00b1 2.67, of which 30.4% of parents show depressive symptoms (\u22655 points). The prevalence of comorbid depressive and anxiety symptoms was 26.1% among the entire sample.Preliminary data of our pilot study showed a high prevalence of anxious depressive symptoms and comorbidity among parents of HCCI. Timely provision of psychologic interventions are needed during and after COVID-19 pandemic in order to empower parenting and promote children recovery and quality of life.No significant relationships."}
+{"text": "Background: It has been demonstrated that Egfl7 promotes tumor cell escape from immunity by downregulating the activation of tumor blood vessels. Aim: to analyze mRNA expression of EGFL7 within the tumor microenvironment of high-grade ovarian serous carcinoma and its association with a number of intraepithelial CD4+/CD8+ lymphocytes and ICAM-1 expression. Methods: qPCR analysis of EGFL7 mRNA in cancer cells and adjacent stromal endothelium microdissected from formalin-fixed paraffin-embedded tumors of 59 high-grade ovarian serous carcinoma patients, was performed. Infiltration of intraepithelial lymphocytes (CD4+/CD8+) and expression of ICAM-1 were evaluated by immunohistochemistry and compared between tumors with different statuses of EGFL7 expression. Results: EGFL7 was expressed in cancer cells , endothelium , or both cancer cells and adjacent endothelium . ICAM-1 was expressed on cancer cells , stromal endothelium , or both epithelium and endothelium . EGFL7-positivity of cancer cells and endothelium was associated with lower intraepithelial inflow of CD4+  and CD8+ lymphocytes  but impact neither epithelial nor endothelial ICAM-1 expression . The patients\u2019 median follow-up was 23.83 months (range 1.07\u201378.07). Lack of prognostic significance of EGFL7-status and ICAM-1 expression was notified. Conclusion: EGFL7 is activated in the cancer cells as frequently as in the endothelium of human high-grade ovarian serous carcinoma. Activation of EGFL7 in cancer cells and/or endothelial cells could negatively impact diapedesis regardless of localization. Ovarian cancer (OvCa) is the leading cause of death from gynecological malignancy in the developed world. The overall five-year survival rate for patients with advanced OvCa is only 30\u201340% . NotwithInstead of being targeted for immune destruction, OvCa has the ability to escape immune surveillance by creating a highly suppressive environment . Tumor eBlood vessels, which are a part of the tumor microenvironment, constitute a natural physical barrier that regulates the immune response via diapedesis . ActivatEGFL7 is an endothelial cell-derived protein that regulates vascular tube formation. Its expression is downregulated in mature vasculature, upregulated in proliferating endothelium ,14,15 anEGFL7 promotes tumor escape from immunity by downregulating the activation of tumor blood vessels [Using experimental approaches, it has been demonstrated that, when expressed by cancer cells,  vessels . EGFL7 i vessels . This ob vessels .EGFL7 is a plasma membrane-associated sialidase  that could accumulate at distant sites from the producing cells [EGFL7 transcripts observed in several human cancer tumors come from activated cancer epithelium or up-regulated endothelial cells of the surrounding stroma.Since ng cells , it is iLaser Capture Microdissection (LCM) technology enables harvesting the cells of interest directly or can isolate specific cells by cutting away unwanted cells to give histologically pure enriched cell populations .EGFL7 within the cancer epithelial nest and the adjacent stroma (tumor microenvironment) of High Grade Ovarian Serous Carcinomas (HGOSCs) and its impact on the number of immune cell effectors  infiltrating cancer epithelial nests, as well as correlation with ICAM-1 expression of adjacent blood vessels.The aim of this study was to analyze the expression of A cohort of 59 HGOSC patients was treated with primary debulking surgery (PDS) at the Department of Gynecologic Oncology, Oncological Center of Gdynia, Polish Red Cross Hospital Gdynia (Poland) between September 2013 and December 2015. The patients were informed that surgical specimens would be used for conventional pathological diagnosis and that the remaining tissues would be used for research. No personal patient data was required for this study and the protocols carried no risk, so only verbal informed consent was required from the patients. The protocol was approved by the Ethics Committee of Medical University of Gdansk (Permit Number: NKBBN/263/2012). Disease staging was defined according to the International Federation of Gynecology and Obstetrics (FIGO) staging system [We analyzed 59 formalin-fixed paraffin-embedded (FFPE) tissue samples from primary tumors for immunohistochemical (IHC) evaluation of expression of ICAM-1, CD4 and CD8 and for qPCR analysis of Egfl7 mRNA transcripts.The immunohistochemical stainings were performed on whole sections of representative FFPE blocks. The staining was performed according to the following protocol  and heated in a pressure cooker. The slides were incubated for 90 min with the primary antibodies. The reaction was visualized by the Novolink polymer detection system (Novocastra Laboratories). Appropriate positive  and negative controls  were included for each case. The results of immunohistochemistry were evaluated by two independent pathologists who were blinded to the clinical data.ICAM-1 expression in cancer nests was evaluated with the high-Score method. The score was calculated according to the commonly used formula  . EndotheFive areas with the most abundant lymphocyte distribution (hot spots) were selected and micro-photographs were taken. The quantitative analysis was performed with Multiscan 14.2 software. The number of CD4+ and CD8+ cells was counted exclusively within cancer nests. For each case, the mean index of CD4+ and CD8+ cells per single high-power field was counted and then statistically analyzed.Separate populations of cancer and endothelial cells were harvested using LCM performed as follows. The selected, representative paraffin blocks were cut into 4 \u00b5m slices and mounted on slides with PEN-membrane (25 \u00d7 76 mm) . Next, a brief staining protocol was applied, composed of deparaffinization in fresh xylene for 1\u2009min twice followed by 100% ethanol for 1\u2009min, 95% for ethanol 1\u2009min, and 70% ethanol for 1\u2009min. The slides then were transferred into distilled water for 2\u2009min before staining with Hematoxylin for 2\u2009min. Subsequently, slides were rinsed in distilled water until clear before undergoing dehydration in 70% ethanol for 1\u2009min, 95% ethanol for 1\u2009min, 100% ethanol for 1\u2009min, and xylene for 1\u2009min. Areas for microdissection were marked on the original hematoxylin-eosin\u2013stained slide to include two targets, cancer nest and vessels in the surrounding stromal connective tissue. Microdissection was performed within the next 2\u2009h with the PALM MicroBeam ZEISS Microscopy system. Tissue material was separately collected into AdhesiveCap .n = 118, two samples for each patient) using RNeasy FFPE Mini Kit (Qiagen) according to the manufacturer\u2019s protocol. The quantity and quality of the isolated RNA were determined with NanoDrop 1000 UV Spectrophotometer (Thermo Scientific). Reverse transcription for the 118 microdissected samples was performed with iScript Advanced cDNA Synthesis Kit for RT-qPCR protocol (Bio-Rad).Total RNA was extracted from the microdissected FFPE tissues (EGF7 was performed using TaqMan Gene Expression Assay (Applied Biosystems) following the manufacturer\u2019s protocol using the LightCycler 480 II system (Roche). The samples were analyzed in duplicates.qPCR to evaluate the expression of p-values of <0.05 were regarded as significant in each of the analyses. All analyses were performed with the statistical software Statistica 13 (Stat Soft Inc.)The Shapiro\u2013Wilk test and Leven\u2019s tests were used to evaluate normality and equality of variances. Data for continuous variables are expressed as median with maximum and minimum values. As the assumptions of the tests were not met, statistical analyses were carried out using the Mann\u2013Whitney test for quantitative variables. Furthermore, the Chi-square test and Fisher\u2019s exact probability tests for comparison of qualitative variables were used. Overall survival curves were estimated by the Kaplan\u2013Meier method and compared with the use of the two-sided log-rank test. The median age of the patients was 59 years (range 39\u201386), and the median duration of follow-up was 23.83 months (range 1.07\u201378.07). The 5-year disease free survival (DFS) rate was 20.35 %. The clinicopathological HGOSC data are presented in EGFL7 within the tumor microenvironment (epithelium and/or adjacent endothelium) was detected in 13 of 59 (22.03%) HGOSCs. Expression of EGFL7 was detected in cancer epithelium , endothelium , or in both: cancer epithelium and adjacent endothelium . The presence of expression of EGFL7 had no impact on progression free survival (PFS) and overall survival (OS) of the patients (p = 0.175 and p = 0.912 respectively). We noted the increase in the PCR product only in a low proportion of samples; therefore, the initially planned quantitative analysis was not possible and the qualitative scoring (positive/negative) had to be applied. In detail, activation of EGFL7 expression of cancer cells and endothelium are presented in Association of clinicopathological HGOSC population data and EGFL7 was expressed in cancer epithelium, endothelium or in both, it had no impact on OS .No matter We observed that ICAM-1 was expressed by both cancer and endothelial cells C. ICAM-1 expression in cancer cells was noted in 47 cases (79.66%) and in endothelial cells in 46 cases (77.97%); in 40 cases (67.8%) the expression was observed in both compartments. ICAM-1 expression in cancer cells was the score with the high-score method with a median expression level of 20 (range 0 to 200); 43 cases (91.48%) were scored as 1+ (median expression level of 20 range 5\u201390) and four (8.52%%) as 2+ (median expression level of 80 range 60\u2013100).Endothelial ICAM-1 expression was calculated as the proportion of positive vessels  and then scored semi-quantitatively with a 4-tier system using the thresholds of 1%, 30% and 60%. Thus, 13 cases (22.03%) were scored as 0, 25 (42.37%) as 1+, 12 (20.34%) as 2+ and nine (15.25%) as 3+. There is no difference in the expression of ICAM-1 in the different clinicopathological subgroups shown in . Moreovep > 0.05).Based on the median ICAM-1 score in cancer cells (20), we dichotomized the group into a high expressing subgroup  and a low expressing subgroup . Similarly, the median proportion of ICAM-1-positive vessels (18.75%) was used to divide the high expressing subgroup  and low expressing subgroup . The clinicopathological characteristics related to ICAM-1 status of cancer and endothelial cells are depicted in EGFL7 and ICAM-1 expression in either compartment (p > 0.05). EGFL7 expression in cancer cells was observed in 6/47 (12.77%) ICAM-1-positive and in 3/12 (25.00%) ICAM-1-negative tumors; ICAM-1 scores were also similar whether EGFL7 was expressed or not. Analogously, EGFL7 expression in endothelia was observed in 7/46 (15.21%) ICAM-1-positive and in 1/13 (7.69%) ICAM-1-negative cases; the proportions of ICAM-1 expressing vessels were also similar in both groups CD4+ and (IE)CD8+ infiltrates between tumors with different EGFL7-positive cancer cells (n = 9) were less infiltrated with (IE)CD4+ and (IE)CD8+ lymphocytes compared to negative ones (n = 50) .Tumors with EGFL7-positive endothelial cells (n = 8) were less infiltrated with (IE)CD4+ and (IE)CD8+ lymphocytes compared to negative ones (n = 51) .Tumors with EGFL7-positive cancer and endothelial cells (n = 4) were less infiltrated with (IE)CD4+ and (IE)CD8+ lymphocytes compared to the negative ones (n = 55) .Tumors having simultaneously EGFL7 expression has been previously analyzed in one study on human ovarian cancer tissue samples derived from 177 patients [EGFL7 was performed using formalin fixed paraffin-embedded tissue microarrays; 72 of 177 analyzed cases (40.7%) had tumors with serous histology, but information about grading was not specified [EGFL7 expression were noted in 23 of 72 (31.9%) serous cancers. Survival analysis performed for the entire cohort showed that the epithelial ovarian cancer patients having tumors with high EGFL7 expression had a poorer DFS but similar OS to those with low EGFL7 expression [patients . In thatpecified . High lepression . EGFL7 mRNA transcripts in HGOSC using a different methodology, thus, the results of both studies are difficult to compare. Here, we analyzed EGFL7 expression is frequent in epithelial ovarian cancers as we detected EGFL7 mRNA transcripts in 13 of 59 (22.03%) HGOSC cases. Unfortunately, we did not manage to perform quantitative analyses of mRNA in microdissected tissue samples, thus, the impact of intensity of expression of EGFL7 mRNA on OS and PFS was not assessable. However, the EGFL7-status of the tumor microenvironment (cancer epithelium and adjacent endothelium) had no predictive and prognostic value in the analyzed cohort of HGOSC patients. Interestingly, our study supports the suggestion that EGFL7-expression levels were found to correlate with a higher tumor grade in gliomas [EGFL7 expression in human cancer needs to be carefully analyzed as EGFL7 may play a complex role in cancer biology depending on cancer origin [EGFL7 secretion: cancer cells, endothelium or both.  gliomas  and colo gliomas , not inf gliomas , but a b gliomas . These ar origin ,24,25,26EGFL7 is plasma membrane-associated sialidase, which could accumulate in distant tissues from the producing cells [EGFL7 observed in OvCas [EGFL7 on diapedesis using LCM technology, which enables harvesting the epithelial and endothelial cells directly to give histologically enriched cell populations for separate qPCR analyses [Since it had been proven that ng cells , it is iin OvCas  comes franalyses .EGFL7 mRNA at least in endothelial cells as these reflect upregulation of EGFL7 gene in activated cancer vessels due to neoangiogenesis and/or inflammatory process. The presence of EGFL7 mRNA transcripts found in microdissected cancer cells indicates the endogenic activation of the EGFL7 gene in human HGOSCs. To the best of our knowledge, this is the first study documenting the activation of EGFL7 in human HGOSC. Interestingly the frequency of epithelial and endothelial activation of EGFL7 was comparable. Further, ICAM-1 was also found to be expressed both on cancer epithelium and endothelium of adjacent stromal vessels, thus we decided to assess the correlation between EGFL7 and ICAM-1 matched according to the source of origin.We expected to detect EGFL7 negatively regulates the expression of ICAM-1 in endothelial cells [EGFL7-status. Similarly, a lack of difference in ICAM-1 expression was observed for cancer ICAM-1 expressing cells with different Egfl7-statuses.Although it was suggested that al cells  we did nOur understanding of the role of ICAM-1 in ovarian cancer development remains limited. The elevated expression of ICAM-1 in freshly isolated ovarian cancer cells  suggestsEGFL7 on diapedesis we decided to compare intraepithelial immune infiltrates between tumors having EGFL7 activated in cancer nests and/or adjacent vessels and those without EGFL7 activation.To assess the potential impact of EGFL7 mRNA transcripts in the epithelium and/or endothelium of tumor microenvironment was associated with a lower influx of adaptive immune effectors (CD4+ and CD8+ lymphocytes) into cancer nests. This provides direct information that in some parts, immune escape is achieved by limiting the influx of immune effectors into cancer tissue by activation of EGFL7. The role of epithelial and endothelial EGFL7 should be further evaluated in HGOSCs. The presence of EGFL7, the retrospective design and the small size of the cohort involved. Its strength lies in separate analyses of EGFL7 transcripts in epithelium and adjacent endothelium of histologically homogenous group HGOSC tissue samples and consistency of the treatment of patients under uniform standards enabling the assessment of the prognostic significance of all the analyzed biomarkers.The weakness of the current study is the lack of quantitative assessment of EGFL7 activation in cancer cells and its upregulation in the endothelium are frequent in HGOSCs and could negatively impact diapedesis. EGFL7 associated down-regulation of ICAM-1 was not observed. The function and predictive value of EGFL7 mRNA transcripts should be evaluated in larger cohorts.Endogenic"}
+{"text": "Background: The IDSA recommends that when determining empiric treatment for a given patient, clinicians should consider previous organisms and associated antibiotic susceptibility data in the prior 6 months when multidrug-resistant/extended-spectrum \u03b2-lactamase gram-negative rods (MDR /ESBL GNR) is suspected. The presence of MDR GN in cultures on previous hospitalization or in surveillance cultures leads to use of broader-spectrum empiric antibiotic in subsequent admissions. We sought to determine whether the presence of an MDRO in 1 hospital admission dictates the need for broader-spectrum antibiotic use in subsequent hospitalizations when a different site is considered the source of infection. Methods: The study was conducted at a 700-bed tertiary-care level I trauma center. Infection control records were reviewed for patients aged 21\u201399 years admitted between July 1, 2013, through January 31, 2014, who had any ESBL or MDR GNR at any site including surveillance culture. The charts were surveyed until January 31, 2016, for ESBL or MDR gram-negative organisms at any site during subsequent hospitalizations. The CDC definition of MDR/ESBL was applied. Results: Of the 50 people followed, 34 patients (68%) had ESBL/MDR recovered at a single sentinel site, 6 patients (12%) had ESBL/MDR in multiple sites, and in 10 patients (20%) had ESBL/MDR only in surveillance cultures during their primary hospitalization. In 34 patients with a single sentinel site MDRO/ESBL in their primary hospitalization, 16 (47%) were identified in urine, 13 (38%) were identified by bronchoalveolar lavage (lung), 4 (12%) were identified on skin or MS, and 1 (3%) was identified at another site. When lung and urine were the sole sites of recovery of MDRO/ESBL in primary hospitalization, respectively, 3 patients (23%) and 2 patients (12.5%) subsequently developed MDROs in a secondary site on subsequent admissions. Overall, 10 bacteremia episodes occurred in 8 patients among 189 total admissions. MDRO/ESBL Klebsiella spp were identified in the cultures of 5 patients (50%), MDRO Acinetobacter spp were identified in the cultures of 3 patients (30%), and ESBL E. coli was identified in the cultures of 2 patients (20%). The organism causing bacteremia was present at a different sites during the same admission in only 3 (30%) of these cases: 2 were cultured from urine and 1 was cultured from a pulmonary source. Conclusions: The presence of MDRO at 1 site in a previous hospitalization may not be sufficient evidence to justify very broad antibiotics for patients during subsequent admissions, especially when another site is considered the source of infection. More studies are needed on natural history of MDRO in different patient populations with different risk factors.Funding: NoneDisclosures: None"}
+{"text": "A subset of hospitalized patients will require critical care after their gastrointestinal endoscopy (GIE) and predicting which patients are at high risk of requiring critical care remains an important challenge.To identify protective and aggravating clinical risk factors associated with critical care involvement within 7 days of inpatient GIE in adults and to develop a tool that could assist in risk-stratifying patients at high risk of requiring critical care post-endoscopy.This was a single-centre retrospective case-control study of adult patients who underwent inpatient GIE while admitted to ward-level care at Toronto General Hospital from years 2015 to 2019. Cases were defined by inpatients who required critical care response team and/or critical care admission within 7 days of GIE, compared to control patients who did not require critical care throughout admission. Chart review and linked secondary sources were used with defined inclusion and exclusion criteria. Both univariate and multivariate analyses were performed comparing patient baseline, clinical history  and endoscopy characteristics.We identified a total of 275 patients with 302 endoscopies as cases and 2069 patient controls who satisfied inclusion criteria. Critical care involvement was most commonly due to cardiovascular-related complications  followed by respiratory complications . Amongst cases, death occurred in 9 (3%), 25 (9%) and 67 (22%) within 72 hours, 7 days and 30 days respectively post endoscopy. The strongest associations with critical care involvement within 7 days after GIE included a history of discharge from critical care (OR 2.29 CI 1.70-3.04) and/or recent mechanical ventilatory support (OR 2.27 CI 1.30-3.91) in the 30 days prior to endoscopy, having several co-morbidities involving major organ systems  and patients admitted under surgical (OR 3.82 CI 2.54-5.71) or transplant services (OR 4.63 CI 2.94-7.26). The majority of adverse events among cases were not found to be complications directly related to GIE . Patients with a history of pulmonary hypertension (OR 5.68 CI 0.53-60.70) and ASA score III/IV (OR 3.28 CI 1.01-10.73) had the highest odds of probable or definite endoscopy-related adverse events.This study is the largest to date to examine risk factors associated with critical care requirements post GIE in the tertiary care inpatient setting. The risk factors we have identified can be used to create a tool to determine which inpatients may benefit from anesthesia consultation and support during their endoscopic procedure.NoneNone Declared"}
+{"text": "Background: Taking antibiotics outside the guidance of a clinician (nonprescription use) is a potential safety issue and runs counter to antibiotic stewardship efforts. We identified the symptoms and illnesses and situations that may predispose patients to take antibiotics, and we compared these findings between patients attending public primary care clinics and private emergency departments. Methods: A cross-sectional survey was conducted between January 2020 and March 2021 in 6 primary care clinics and 2 emergency departments in the United States. We queried patients about 5 symptoms and illnesses , and 72% were female. Most respondents identified as either Hispanic or Latina/Latino (46.6%) or African American or Black (33%), followed by White (15.8%), and other (4.6%). Most respondents had visited public clinics (72%). The most common insurance status for our respondents included Medicaid or county financial assistance program (56.6%), followed by private insurance or Medicare (36.7%) and self-pay (6.7%). In public primary care clinics, only 23% had private insurance or Medicare compared to 72.9% in private emergency departments. Of those surveyed, 69% agreed that antibiotics would improve the recovery from sinus infections, followed by bronchitis (64%), sore throat (64%), cold/flu (61.4%), and diarrhea (31.5%). The proportions of respondents who believed that antibiotics would improve the recovery from diarrhea  and sore throat  were significantly higher among public versus private outpatient respondents. We did not find significant differences for cold/flu, sinus infection, or bronchitis between these 2 healthcare systems  may also curtail these unsafe practices and reduce antibiotic resistance.Funding: NoneDisclosures: None"}
+{"text": "Antibiotics have completely transformed medical practice by enabling the treatment of infections that were formerly fatal. However, misuse of antibiotics encourages the formation and spread of germs that are resistant to therapy, hastening the emergence of bacterial resistance. This was a retrospective study that aimed to gather information about the variation in bacterial susceptibility of various patient age groups in a public hospital in Qassim, Saudi Arabia from January 2020 to December 2021. The study included reviewing bacterial susceptibility results that were collected from the laboratory department of the hospital. Four thousand seven hundred and sixty-two isolates were collected. The age of 46.41% of the patients was more than 63 years and the age of 28.96% of the patients was less than 48 years. The most prevalent bacteria were Staphylococcus aureus, Escherichia coli, and Klebsiella pneumoniae. The resistance of gram-positive and gram-negative bacteria to different antibiotics in the elderly group was generally higher than the resistance rates in younger patients. For example, in patients less than 48 years old, the resistance of Staphylococcus haemolyticus to clindamycin (53.3%), ampicillin (91.4%), ciprofloxacin (68.2%), erythromycin (86.1%), and penicillin (93.18%) was high. In patients aged more than 63 years, Staphylococcus haemolyticus was highly resistant to sulfamethoxazole (54.8%), clindamycin (63.9%), ampicillin (98.1%), ciprofloxacin (79.1%), erythromycin (93.2%), gentamicin (63.6%), and penicillin (98.7%). Before prescribing the antibiotics, it is important to assess the microbes that patients have and to be aware of the bacterial isolates\u2019 patterns of antibiotic susceptibility among patients of various age groups. Antibiotics have completely transformed medical practice by enabling the development of cancer chemotherapy, organ transplantation, and the treatment of diseases that were formerly fatal . Early uClostridioides difficile infection [The World Health Organization classified antibiotic resistance as one of the top 10 dangers to global health in 2019 . In the To ensure that patients receive the appropriate antibiotic, an antibiogram might be employed. The antibiogram is a quick and convenient tool for determining the diseases and susceptibilities that are common in a particular institution. Antimicrobial stewardship practices are necessary, along with the traditional antibiogram, to guarantee that patients receive the appropriate antibiotic therapy based on a suspected site of infection, hospital location, and patient characteristics ,6. TogetCumulative antibiograms at a hospital can conceal differences in patient demographics, hospital departments, or anatomical areas. The information provided by hospital-wide cumulative antibiograms may not be sufficient to enable informed choices regarding the optimum care for hospitalized patients ,6,7. A sGarcia et al. reported that the mode of action of the antibiotic affected the pattern of antibiotic resistance in relation to patient age. While antibiotics that target ribosomal functions (such as aminoglycosides) or cell wall synthesis  do not exhibit an age-dependent pattern and have a consistent level of resistance across all age classes, antibiotics that target DNA synthesis (such as fluoroquinolones) exhibit a direct correlation with the age of patients, with higher rates of resistance among the older population . Ji et aGlobally, there is a lack of research on the variation in bacterial resistance across patients of different ages. Therefore, the objective of the current study was to examine the differences in bacterial susceptibility of different patient age groups in a public hospital in Qassim.This was a retrospective study that was conducted to gather information about the variation in bacterial susceptibility of various patient age groups in a public hospital in Qassim, Saudi Arabia from January 2020 to December 2021. The study included reviewing bacterial susceptibility results that were collected from the laboratory department of the hospital.The study includes the microbiology culture findings and sensitivity data of the microorganisms responsible for specific infections from patients admitted in 2020 and 2021. The study did not include the patients\u2019 duplicate isolates. The information gathered comprised the total number of bacteria, the most common gram-negative and gram-positive bacteria in various patient age groups, and the rates of susceptibility for both gram-negative and gram-positive bacteria. An Excel sheet was used to collect and evaluate the data. Numbers and percentages were used to represent the results. Subtracting 100 percent from the susceptibility rate yields the resistance rate.In the present study, we used the age group classification of the Lin et al. study. Age was classified into the following age groups: 0\u201314 years old (pediatric group), 15\u201347 years old (youth group), 48\u201363 years old (middle-aged group), and \u226564 years old (elderly group) . HoweverThe data were collected after obtaining approval from the Regional Research Ethics Committee of the Qassim region with an approval number of 1443-862269.Staphylococcus aureus (19.36%), Escherichia coli (13.56%), Klebsiella pneumoniae (10.59%), and Acinetobacter baumannii (8.05%). The number and percentages of bacterial isolates in patients less than 48 years old are shown in Four thousand seven hundred and sixty-two isolates were collected in the hospital during 2020 and 2021. The age of 28.96% of the patients was less than 48 years. The most prevalent bacteria in patients less than 48 years old were Staphylococcus aureus (19.18%), Klebsiella pneumoniae (11.51%), Escherichia coli (11.08%), Acinetobacter baumannii (8.27%), and Staphylococcus epidermidis (6.22%)  .Klebsiella pneumoniae (13.76%), Staphylococcus aureus (11.13%), Escherichia coli (10.63%), Acinetobacter baumannii (9.19%), and Staphylococcus epidermidis (8.01%)  .Pseudomonas aeruginosa was highly resistant only to sulfamethoxazole (Resistance rate = 51.7%). Proteus mirabilis was highly resistant to ampicillin (76.5%) and to aztreonam (60.0%). The resistance of Klebsiella pneumoniae to ampicillin, aztreonam, ceftazidime, cefotaxime, and cefuroxime was more than 50%. The resistance of Escherichia coli to ampicillin (64.7%) was high. The resistance of Acinetobacter baumannii to all of the tested antibiotics . The resistance of Proteus mirabilis to sulfamethoxazole (58.8%), ampicillin (82.61%), aztreonam (64.0%), ciprofloxacin (56.0%), and cefuroxime (51.1%) was high. The resistance of Klebsiella pneumoniae to sulfamethoxazole, ampicillin, aztreonam, ceftazidime, cefotaxime, and cefuroxime was more than 50%. The resistance of Escherichia coli to ampicillin (75.4%) and aztreonam (55.6%) was high. The resistance of Acinetobacter baumannii to all of the tested antibiotics was high. The resistance rates of Enterobacter cloacae to ampicillin (95.2%), aztreonam (55.6%), ceftazidime (51.2%), cefotaxime (56.4%), and cefuroxime (67.6%) were high . The resistance of Proteus mirabilis to all of the tested antibiotics except gentamicin was more than 50%. The resistance of Escherichia coli to ampicillin (76.8%), aztreonam (60.6%), ciprofloxacin (53.5%), and cefuroxime (50.7%) was high. The resistance rates of Acinetobacter baumannii and Klebsiella pneumoniae to all of the tested antibiotics were high. The resistance of Enterobacter cloacae to ampicillin (100.0%), aztreonam (63.6%), ceftazidime (57.7%), cefotaxime (68.6%), and cefuroxime (78.4%) was high  and the elderly group (more than 63 years old) were higher than the resistance rates in younger patients (less than 48 years old).Staphylococcus aureus to ampicillin (77.6%) and penicillin (90.5%) was high. The resistance of Staphylococcus haemolyticus to clindamycin (53.3%), ampicillin (91.4%), ciprofloxacin (68.2%), erythromycin (86.1%), and penicillin (93.18%) was high. The resistance of Staphylococcus hominis to ampicillin (90.0%), erythromycin (71.2%), and penicillin (93.2%) was high. Staphylococcus epidermidis was highly resistant to ampicillin (92.5%), erythromycin (68.6%), and penicillin (90.1%). The resistance rates of Enterococcus species to sulfamethoxazole (78.3%), clindamycin (50.0%), and erythromycin (57.1%) were high  and penicillin (89.3%) was high. Staphylococcus hominis was highly resistant to ampicillin (90.5%), erythromycin (57.5%), and penicillin (92.1%). Staphylococcus epidermidis was highly resistant to ampicillin , ciprofloxacin (59.2%), erythromycin (71.8%), and penicillin (97.0%). Enterococcus species were highly resistant to sulfamethoxazole (85.7%), ciprofloxacin (54.3%), and erythromycin (68.4%)  .Staphylococcus aureus to ampicillin (72.9%) and penicillin (91.3%) was high. Staphylococcus hominis was highly resistant to ampicillin (89.4%), ciprofloxacin (60.5%), erythromycin (78.1%), and penicillin (90.1%). Staphylococcus haemolyticus was highly resistant to sulfamethoxazole (54.8%), clindamycin (63.9%), ampicillin (98.1%), ciprofloxacin (79.1%), erythromycin (93.2%), gentamicin (63.6%), and penicillin (98.7%). The resistance rates of Staphylococcus auricularis to clindamycin (57.1%), ampicillin (93.9%), ciprofloxacin (61.1%), erythromycin (51.1%), and penicillin (96.0%) were high.Regarding gram-positive bacterial susceptibility in patients aged more than 63 years, the resistance of Staphylococcus epidermidis was highly resistant to clindamycin (55.4%), ampicillin (97.1%), ciprofloxacin (71.9%), erythromycin (72.8%), and penicillin (97.5%). The resistance of Enterococcus species to sulfamethoxazole (85.71%), ciprofloxacin (65.3%), erythromycin (78.1%), and gentamicin (56.5%) was high. Staphylococcus capitis was highly resistant to clindamycin (52.0%), ampicillin (89.7%), ciprofloxacin (65.3%), erythromycin (51.0%), and penicillin (95.5%) ( (95.5%) . In geneStaphylococcus epidermidis and Staphylococcus haemolyticus were resistant to several antibiotics, mainly in elderly patients, but fortunately the resistance rates to linezolid and daptomycin were very low. Similarly, previous studies found that despite the rising usage of linezolid and daptomycin, resistance to these drugs has been identified but is still relatively rare [The present study showed that several gram-positive bacteria such as ely rare ,12,13.Acinetobacter baumannii and Klebsiella pneumoniae were resistant to almost all of the tested antibiotics in elderly patients. Similarly, previous studies showed that Acinetobacter baumannii and Klebsiella pneumoniae have high resistance rates to antibiotics [The present study also showed that most of the gram-negative bacteria were resistant to several antibiotics, and that ibiotics ,15. NoneIn general, the resistance of gram-positive and gram-negative bacteria to different antibiotics in the elderly group was higher than the resistance rates in younger patients. According to the National Institute for Public Health and the Environment, antibiotic-resistant bacteria are a problem, especially for weak individuals like the elderly . HossainThe Center for Infectious Disease Research and Policy indicated that because they spend longer than younger people in hospitals and long-term care institutions and have more chronic diseases, elderly individuals are more likely to be exposed to multidrug-resistant organisms and are at a higher risk for infections . The CanThe percentage of male patients in the present study was higher than that of female patients. About 52.81% of the patients aged more than 63 years, 57.29% of the patients aged less than 47 years, and 60.10% of the patients aged between 48 and 63 years were male. Several previous studies found that the susceptibility rates of bacteria to antibiotics in male patients are different than those in female patients ,24,25,26Knowing the sources of samples is also important in the preparation of a stratified antibiogram. For example, the resistance rates of bacteria in a blood sample could differ from the resistance rates of bacteria that were isolated from urine samples. Kuster et al. reported that isolates from different anatomical sites showed variation in antimicrobial susceptibility rates . The maiBacterial co-infection is relatively infrequent in hospitalized COVID-19 patients . NeverthThe resistance of gram-positive and gram-negative bacteria to different antibiotics in the elderly group was generally higher than the resistance rates of younger patients. It is important to assess the microbes that patients have and to be aware of the bacterial isolates\u2019 patterns of antibiotic susceptibility among patients of various age groups before prescribing the antibiotics."}
+{"text": "TP53 mutation detected by Next generation sequencing (NGS) and the presence/absence of deletions of 17p13 detected by FISH. The study which is the largest series to date includes 2332 CLL patients referred for analysis of del(17p) by FISH and TP53 mutations by NGS before treatment. Using a 10% variant allele frequency (VAF) threshold, cases were segregated into high burden mutations (\u226510%) and low burden mutations (<10%). TP53 aberrations (17p [del(17p)] and/or TP53 mutation) were detected in 320/2332 patients (13.7%). Using NGS analysis, 429 TP53 mutations were identified in 303 patients (13%). Of these 238 (79%) and 65 (21%) were cases with high burden and low burden mutations respectively. In our cohort, 2012 cases did not demonstrate a TP53 aberration (86.3%). A total of 159 cases showed TP53 mutations in the absence of del(17p) (49/159 with low burden TP53 mutations) and 144 cases had both TP53 mutation and del(17p) (16/144 with low burden mutations). Only 17/2332 (0.7%) cases demonstrated del(17p) with no TP53 mutation. Validated NGS protocols should be used in clinical decision making to avoid missing low-burden TP53 mutations and can detect the vast majority of TP53 aberrations.Limited data exists to show the correlation of (tumour protein 53)  TP53 mutation (TP53 mut) referred to as TP53 aberrations can be found in 8%\u201310% of previously untreated chronic lymphocytic leukaemia (CLL) patients and in up to 30%\u201340% of relapsed/refractory cases. TP53 aberrations represent the most relevant risk factors for both progression free and overall survival following chemoimmunotherapy  (Deletion of chromosome 17p [del(17p)] and otherapy . The ints in CLL , 7. Histin situ hybridization (FISH). The cut-off for a positive result varies within laboratories with the threshold >20% of cells with del(17p) deemed to be a clinically relevant clone (The assessment of del(17p) is routinely performed by Fluorescence nt clone . Howevernt clone .TP53 mutational analysis, however it may misclassify cases of TP53 mutations as wildtype when variants with allelic frequencies below the detection limit of Sanger sequencing are present. Recent studies using next generation sequencing (NGS) have shown that TP53 mutations can be present at low clonal abundance in tumour cell populations, termed low-burden and have in certain studies the same detrimental effect on disease course (TP53 network of ERIC (European Research Initiative on CLL- www.ericcll.org) suggest a threshold of 10% allelic burden for reporting mutations detected by NGS segregating these into high burden ) and low burden (<10% VAF) mutation  by FISH and TP53 mutation screening was performed by NGS with a panel covering exons 2-11 as previously described . Normally analyses with read depths below 5000 are failed.The study was conducted according to the Declaration of Helsinki. Patients were diagnosed according to iwCLL guidelines . In all escribed  or by anA VAF cut-off of 1% was used to exclude false positive variants within the cohorts. Pathogenicity assessment of all variants was performed according to ERIC guidelines .TP53 aberrations detected in 320/2332 patients (TP53 mutations were identified in 303 patients (13%). More than one TP53 mutation was detected in 76 patients  and low burden mutations (<10%). The high and low burden separation was based on the VAF of the most prevalent TP53 mutation. 271 (63%) were classified as high burden mutations . 158 were classified as low burden mutations  (Altogether 2332 patients entering first line treatment were included in this study with mean 5%) Figure\u00a02TP53 coding mutations between high and low burden cases . However, 17 cases demonstrated del(17p) only (0.7%). Average del(17p) was 40% (range 10-91%) in del(17p) only cases and was significantly higher in del(17p)/TP53 mut cases (55% (range 10-100%: p<0.05). One hundred and fifty-nine patients (159) were TP53 mutated only cases (49/159 with low burden TP53 mutations) and 144 cases with both del(17p) and TP53 mutation  with TP53 aberrations for both del(17p) and TP53 mutation by NGS in cases of treatment na\u00efve CLL. Using NGS analysis, 429 TP53 mutations were identified in 303 patients (13%). Current guidelines from the TP53 network of ERIC suggest a threshold of 10% allelic burden for reporting mutations detected by NGS (TP53 mut/del(17p) wt] in this cohort would have been misclassified as TP53 proficient cases. This is an important observation given the recent publication that clearly demonstrates a shorter survival in cases with VAFs of 5-10%  of all mutations in the total cohort. A similar pattern was evident in both low and high burden subgroups confirming the disease specific TP53 mutation profile in CLL  whereas TP53 aberrations were detected in 13.7% of patients. This is in keeping with recent data from independent groups that utilized various NGS strategies and bioinformatics pipelines (Combining FISH data on del(17p) with ipelines , 13, 18.TP53 mutation in 17/2332 (0.7%) which is in keeping with the literature  in the chemoimmunotherapy setting (In this study we have demonstrated the existence of del17p) in the absence of a 7p in theterature . The avecontrary , 14. Scr setting , 19. In  setting . This suTP53 aberrations are still relevant in the era of novel therapies. Long term survival outcomes remain inferior in cohorts of patients with TP53 aberrations  and TP53 mut occur together or when greater than one TP53 mutation is found. Whilst this is of interest it has yet to be verified in larger cohorts or indeed in separate treatment regimens. In our current study 55% (176/320) were single hit with 45% (144/320) of cases demonstrating a multi hit CLL. In this study \u22652 TP53 mutations were detected in 76 patients with the majority of cases in the TP53 mut/del(17p) wt cohort (46/76) with the remaining 30 cases in the TP53 mut/no del(17p) cohort. This reinforces the need to redefine a VAF threshold to aid in the selection of TP53 mutated patients benefiting from targeted treatments.This has been further addresses in a recent study demonstrating that patients treated with single-agent ibrutinib carrying only a single survival . In thisTP53 mutations in a series of CLL cases. The use of NGS prevents cases being misclassified as normal TP53 due to its enhanced sensitivity. In the investigation of TP53 aberrations, NGS is an important strategy for patient management in this setting.In conclusion, in the largest series to date we have demonstrated the presence of low and high burden The original contributions presented in the study are included in the article/Using the NHS Health Research Authority decision tools this study classes as clinical audit  and therefore formal research ethics is not required.MAC, AS and PT conceived the project. DW, LC, DC, PS, MM and DC performed data analysis. DD, SL, EE, AH, MRC, DO\u2019S, JQ, PM, JS, KM, FF, SI, NC, AS and PT provided clinical input. All authors read and agreed with the manuscript.FF work is funded by the Cancer Research UK ECRIN-M3 accelerator award C42023/A29370.Author SL has received honoraria from Abbvie, Janssen, BMS/Celegene and Sanofi. DG has received honoraria, consultancy and/or research funding from Roche, AstraZeneca, Novartis, Janssen, Elli Lilly, Incyte, Promega and Illumina and is founder of Univ8 Genomics Ltd. Author NC has received honoraria from Novartis, Incyte and Astellas and research support from Novartis. Author AS received honoraria from Astra Zeneca, Janssen, Roche, Adaptive Biotechnology, Exact Sciences and AbbVie, and received nonrestricted educational grants from Astra Zeneca and Janssen and in-kind contributions from Illumina and Oxford Nanopore technologies. Author FF received honoraria from Abbvie, Janssen-cilag, Beigene, Astra-Zeneca and BC platform.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Mental health problems are frequent among children and seems to predict mental disorders in adulthood.The study aimed whether the gender differences affects the Strengths and Difficulties Questionnaire (SDQ) assessments performed by parents and teachers in Republic of Georgia.In 2019 a cross sectional survey in four main cities of Georgia was conducted; Totally 8-10 y old 16654 children from 211 public schools were included. SDQ completed by parents and school teachers was used to determine emotional and behavioral problems among Georgian children.16654 (74%) parents out of 22553 were agreed to participate in the study. 1565 (9.39%) children were rated screen positive in top five percentile by either parent or teacher or both of them. Cut-off scores for 99-95 percentiles (top 1-5%) was defined. Boys were more likely to be rated screen positive than girls, especially by teachers: parents rated screen positive 7.5% of females, teachers - 7.2%, while males 9.4% and 11.5% respectively. Pairwise correlation coefficients (0.53) revealed moderate correlations according to p-values (< 0.05) between scores and all correlations were statistically significant.The study defined the cut-off scores of SDQ for 8-10 y old children and a gender differences in prevalence of mental health problems in Georgia. SDQ could be used in primary healthcare and school settings to identify children with special needs. This work was supported by Shota Rustaveli National Science Foundation of Georgia (SRNSFG), grant - FR-18-304.No significant relationships."}
+{"text": "EGFR-mutant non\u2013small cell lung cancer (NSCLC). The phase II component examined preliminary efficacy in epidermal growth factor receptor exon 20 insertion (EGFRex20ins) NSCLC. Overlapping toxicities, mainly diarrhea, limited the tolerability of the combination. EGFRex20ins circulating tumor DNA (ctDNA) was detected in the majority of patients; failure to clear ctDNA was consistent with lack of tumor response.This study examined the safety and tolerability of erlotinib and the heat shock protein 90 inhibitor onalespib in EGFR-mutant non\u2013small cell lung cancer (NSCLC). This study sought to determine the safety and tolerability of onalespib plus erlotinib in EGFR-mutant NSCLC and to evaluate the preliminary efficacy of the combination in epidermal growth factor receptor exon 20 insertion (EGFRex20ins) NSCLC.Onalespib is a novel heat shock protein 90 inhibitor (HSP90i). Previous preclinical and clinical studies with HSP90i have demonstrated activity in EGFRex20ins. The phase II component targeted a response rate of 25% versus a background rate of 5%. Prospective next-generation sequencing (NGS) of 70 cancer-related genes, including EGFR, via plasma circulating tumor DNA (ctDNA) was performed. Toxicity was graded by Common Terminology Criteria for Adverse Events (CTCAE), version 4, and response was determined by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1.Standard 3+3 dose escalation was followed by a phase II expansion in EGFRex20ins patients, no responses were observed, median progression-free survival was 5.4 months , and the disease control rate (DCR) was 40% . EGFRex20ins was detected in nine of 10 ctDNA samples at baseline; on-treatment ctDNA clearance was not observed. Grade 3 diarrhea was the predominant toxicity in 45% of patients. The recommended phase II dose is DL \u22121 (minus): erlotinib 150 mg orally every morning and onalespib 120 mg/m2 intravenously on days 1, 8, and 15 every 28 days.Eleven patients were treated . Two dose-limiting toxicities (DLTs) occurred in dose level (DL) 0 and zero in DL \u22121 (minus). In 10 EGFRex20ins ctDNA was detected in the majority of patients; failure to clear ctDNA was consistent with lack of tumor response (NCT02535338).Overlapping toxicities of erlotinib and onalespib, mainly diarrhea, limited the tolerability of this combination, and limited clinical activity was observed, so the trial was closed early. Plasma  EGFR E19del) and the EGFR L858R mutation in exon 21 represent the vast majority of EGFR-activating mutations and are exquisitely sensitive to approved EGFR tyrosine kinase inhibitors (TKIs). Erlotinib is a first-generation EGFR TKI and one of several EGFR TKIs currently FDA approved for these canonical EGFR mutations based on improved response rates and progression-free survival (PFS) compared with platinum-based chemotherapy.1EGFR exon 20 insertions (EGFRex20ins) are a collection of driver mutations comprising approximately 4% to 12% of all EGFR mutant lung cancers.3 Although EGFRex20ins usually have the same transforming ability as more common EGFR-activating mutations and are thus considered oncogenic drivers, they are typically unresponsive to first- and second-generation EGFR TKIs due to the modified structures of their kinase domains.4 Osimertinib, although FDA approved for EGFR E19del, L858R, and T790M-positive NSCLC, is not approved for EGFRex20ins, but it has modest preclinical activity and anecdotal reports of response and is being studied in a National Cancer Institute (NCI) cooperative group study (NCT03191149).6 Newer generation EGFR TKIs, such as poziotinib and mobocertinib (TAK-788) or the EGFR/mesenchymal\u2013epithelial transition (MET) bifunctional antibody amivantamab (JNJ-372), have improved clinical activity with higher response rates and are in clinical trials but are not yet approved for routine clinical use.10Epidermal growth factor receptor exon 19 deletion  as a single agent with an overall response rate of 17% and median PFS of 2.9 months ; a high rate of diarrhea and an unusual side effect of ocular visual changes were observed.14Heat shock protein (HSP) complexes act as molecular chaperones that participate in stabilizing and activating client proteins. Cancer cells use HSP90 to protect mutated and overexpressed proteins from ubiquitin-mediated degradation.16 Maintaining prolonged knockdown of HSP90 client proteins has been a challenge in the development of this class of drugs in NSCLC. Oncoprotein knockdown by onalespib is prolonged relative to its plasma half-life in NSCLC cell lines and xenotransplants.17 Preclinical activity of HSP90 inhibition with onalespib has been shown in several oncogene-driven tumors, including EGFR TKI-sensitive and -resistant EGFR-mutant NSCLC, anaplastic lymphoma kinase\u2013rearranged NSCLC, BRAF-mutant melanoma both sensitive and resistant to dual BRAF and MEK inhibition, and KIT mutated gastrointestinal stromal tumors both sensitive and resistant to imatinib.20 Onalespib has single-agent activity in EGFR-mutant NSCLC, is synergistic with erlotinib in EGFR-mutant NSCLC, and delays the emergence of resistance to EGFR TKI treatment in cell lines and xenotransplants.20Onalespib lactate (AT13387) is a non-ansamycin small molecule that potently inhibits HSP90 chaperone activity and promotes degradation of client oncoproteins that mediate resistance to EGFR TKIs.EGFR-mutant NSCLC, the phase II portion of this study sought to explore whether combination strategies with HSP90 inhibition and EGFR TKIs may increase activity specifically in EGFRex20ins NSCLC.In addition to determining the safety and efficacy of erlotinib plus onalespib in a phase I dose escalation trial in EGFR-activating mutation. In dose escalation, patients with EGFR E19del, L858R, L861Q, or G719X must have received prior EGFR TKI therapy for metastatic disease with evidence of disease progression. Patients with EGFRex20ins must have received prior platinum-based chemotherapy with disease progression on or after treatment. Patients must have had an Eastern Cooperative Oncology Group performance status \u2264 2; measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; and adequate hematologic, renal, and liver function. Key exclusion criteria included active central nervous system metastasis ; corrected QT interval by Fredericia (QTcF) > 470 ms; left ventricular ejection fraction \u2264 50% as demonstrated by echocardiogram or multigated acquisition (MUGA) scan; or any major medical condition that would interfere with participation.Eligible patients were required to have NSCLC harboring an NCT02535338). The study was conducted according to the tenets of the Declaration of Helsinki. The study was approved by the Central Institutional Review Board for the NCI in accordance with an assurance filed with and approved by the Department of Health and Human Services at each of the participating investigational centers. All patients provided written informed consent prior to study participation.The study was approved by independent ethics review boards and in accord with an assurance filed with and approved by the Department of Health and Human Services by each site  and a dose de-escalation level of onalespib at 120 mg/m2 (DL \u22121 (minus)) if more than one dose-limiting toxicity (DLT) was observed at the starting dose level  were permitted for drug-related adverse events. Onalespib was administered intravenously (I.V.) on days 1, 8, and 15 on a cycle of every 28 days. The starting dose of onalespib in combination with erlotinib (DL0) was 150 mg/mse level . Treatme>72 hours. Hematologic toxicities qualifying as DLTs included febrile neutropenia; Gr 4 neutropenia for >7 days or thrombocytopenia < 25,000/mm3 (Gr 4) if associated with a bleeding event that did not result in hemodynamic instability but required an elective platelet transfusion; or a life-threatening bleeding event that resulted in urgent intervention and admission to an intensive care unit. Delay in starting the second cycle of \u226514 days due to toxicity related to one or more protocol drugs was also considered a DLT. The first 28-day cycle was considered the DLT period.Adverse events were graded by Common Terminology Criteria for Adverse Events (CTCAE), version 4. DLTs were defined as \u2265Gr 3 non-hematologic toxicity except nausea, vomiting, or diarrhea that could be controlled by appropriate medical intervention or prophylaxis and that resolved to \u2264Gr 1 within 48 hours with medical intervention, except electrolyte toxicities that can be corrected to \u2264Gr 1 within 48 hours. Gr 3 rash attributed to the combination was considered a DLT if it remained Gr 3 despite maximal medical management  for EGFRex20ins were treated at the recommended phase II dose (RP2D) of erlotinib and onalespib determined in the dose-escalation portion of the study  regulations as part of standard of care. Subjects were permitted to enroll if the EGFR mutation was identified based on tissue mutational analysis or circulating tumor DNA (ctDNA) mutational analysis.Plasma was collected for pharmacokinetic analysis of onalespib. Blood samples at C1D8 were drawn into lithium heparin\u2013containing tubes prior to onalespib infusion and at 0.5, 1, 2, 3, 4, 6, 8, and 25 hours after the start of onalespib infusion.22 Briefly, two 10-mL tubes of whole blood were collected in Cell-Free DNA BCT blood collection tubes  prior to treatment, every two cycles (every 8 weeks), and at progression. At the time of this study, Guardant360 included targeted analysis of single-nucleotide variants in 68 to 70 clinically relevant cancer genes, as well as small insertions/deletions, gene fusions, and copy number gains (CNGs) in a subset of genes including EGFR and common resistance mechanisms to EGFR TKIs . The variant allele fraction (VAF) was calculated by dividing the number of tumor-derived DNA molecules at each location by the total number of unique ctDNA molecules at the given nucleotide position. We used 5% VAF-detectable EGFRex20ins ctDNA at baseline to analyze clinical outcomes based on a previous association of 5% ctDNA or above with overall survival in NSCLC.23ctDNA analysis was completed using a commercially available targeted next-generation sequencing (NGS) assay  that is CLIA certified, College of American Pathologists accredited, and New York State Department of Health approved. ctDNA isolation and analytic methods have been described previously.EGFRex20ins and were heavily pretreated; over half of the patients (54%) received three or more prior lines of therapy. Mean systemic area under the curve exposures overlapped for the onalespib dose levels of 120 mg/m2 and 150 mg/m2 due to higher variability at the lower dose .Eleven patients were treated: nine in dose escalation and two in expansion; the patient characteristics are provided in 2 IV D1, D8, D15 on a 28-day cycle), so patients were subsequently enrolled in DL \u22121 (minus), per the 3+3 design. No DLTs occurred at DL \u22121 (minus) . The Gr 3 maculopapular rash at DL0 was asymptomatic but involved more than 30% of body surface area. The Gr 3 hypophosphatemia met DLT criteria, as it was not corrected to grade 1 or better within 48 hours. Common drug-related adverse events (AEs) of any grade were diarrhea (100%), rash (64%), fatigue (55%), increased bilirubin (27%), and nausea/vomiting (55%). The most common drug-related Gr 3 AEs were diarrhea (45%), maculopapular rash (9%), and hypophosphatemia (9%) (Two DLTs (Gr 3 maculopapular rash and Gr 3 hypophos-phatemia) occurred among the three patients treated at dose level 0  .EGFRex20ins and one EGFR E19del), although half of the patients (5/10) with EGFRex20ins treated with erlotinib and onalespib had some degree of tumor shrinkage , with two patients discontinuing for toxicity with a median disease control of 3.5 months  and a disease control rate of 40%. Median PFS was 5.4 months  , and two by investigator decision.No objective responses were noted in the 11 patients treated with erlotinib and onalespib (10 hrinkage . In pati0.9\u20135.7) . Of the EGFRex20ins was detected in ctDNA at baseline in nine of 10 patients and failed to clear  in all nine patients with longitudinally collected samples after initiation of treatment. Among the 10 patients treated, eight unique EGFRex20ins were observed that represent the most frequent EGFRex20ins encountered in clinical practice, including the two most common EGFRex20ins: A797_V769dup and S768_A770dup.3 Comutations were assessed, and of the nine patients with detectable EGFRex20ins ctDNA, seven patients (67%) at baseline also harbored p53 co-mutations (78% at end of therapy). 10.1016/j.cllc.2021.05.001) represents co-alterations at baseline and at the end of treatment. In the absence of objective responses, it is unclear that any changes in co-alterations at the end of treatment represented potential acquired resistance mechanisms versus passive acquired alterations34.EGFRex20ins baseline VAF was associated with time on treatment. With EGFRex20ins low VAF (<5%), mean time on treatment was 4.37 months; with high VAF (\u22655%), the mean time on treatment was 1.28 months (P = .004). The overall impact of treatment on VAFs of the EGFRex20ins was modest . This patient had progression of disease at first response assessment with concomitant failure to clear ctDNA.s modest . Also inEGFR-mutant lung cancer, including in combination with erlotinib, and modest activity as a single agent in EGFRex20ins NSCLC.24 In this study, the addition of onalespib to erlotinib in EGFR-mutant NSCLC among 10 of 11 patients harboring EGFRex20ins yielded no objective responses in the first 11 patients treated, including eight patients dosed at the RP2D . Given the lack of response and the changing landscape of treatment of advanced EGFRex20ins with the development of next-generation EGFR inhibitors such as poziotinib, mobocertinib, and amivantamab, the investigators recommended early trial closure prior to accrual completion following consultation with the trial sponsor (NCI).HSP90 inhibitors have shown modest clinical activity in 2 I.V. on days 1, 8, and 15 IV and erlotinib at 150 mg orally every day on a 28-day cycle determined to be the maximum tolerated dose (MTD) and RP2D.Overlapping toxicities of erlotinib and onalespib, mainly diarrhea and other gastrointestinal side effects, limited the tolerability of this combination. At the first dose level, DLTs in two of three patients (rash and hypophosphatemia) necessitated a dose de-escalation, with onalespib at 120 mg/m10.1016/j.cllc.2021.05.001). The PK profile was similar to what has been reported previously.25 However, doses achieved in combination with erlotinib were limited by overlapping toxicity and were lower than in the phase I trial of single-agent onalespib. In the single-agent study, the MTD of weekly onalespib was 260 mg/m2 on days 1, 8, and 15 of a 28-day cycle and 120 mg/m2 twice weekly on a 28-day cycle.25 Lower doses of onalespib may limit target engagement. Although onalespib has been shown to concentrate in tumors in preclinical in vivo models, with a half-life up to 65 hours which far exceeds the plasma half-life, suppression of mutant EGFR in patients may be more transient.17Pharmacokinetic (PK) studies were evaluated with onalespib in the nine subjects in dose escalation  was able to reliably detect EGFRex20ins in 90% of patients (9/10) at baseline, often following several lines of previous therapy.EGFRex20ins from ctDNA following treatment. Previous studies have shown that the VAFs of targetable alterations tends to decrease following effective therapy. Moreover, clearance of these alterations from ctDNA has been associated with response to therapy and improved outcomes in numerous cancer types, including NSCLC with common EGFR-activating mutations E19del and L858R.27 In this study, the failure to reach undetectable levels of ctDNA in any patient following treatment corresponded to a lack of clinical or radiographic response to erlotinib and onalespib. This prospective trial adds further evidence to support the use of ctDNA to monitor treatment response (or lack thereof) and may aid in the early identification of patients who may derive more or less benefit from specific EGFRex20ins-directed therapeutics in future clinical trials. TP53 co-mutations at baseline were detected in the majority of patient ctDNA samples , comparable to the rate of p53 co-mutation in the largest known series of EGFRex20ins with broad genomic profiling in tissue (56%).3TP53 co-mutations have also been shown to be prognostic for inferior clinical outcomes, including overall survival, in NSCLC harboring the most common EGFR mutations, E19del and L858R, and potentially a negative predictive factor for clinical outcomes to EGFR TKIs in these less common EGFR mutations, as well.28 Future studies should also examine the impact of p53 mutations on clinical outcomes in less common EGFR mutations such as EGFRex20ins NSCLC.Lack of objective radiographic response corresponded with the failure to clear EGFRex20ins VAFs at baseline (defined as <5%) had the longest time on treatment compared with high baseline VAFs , with the majority of these patients being removed from the study for progressive disease , overall response rate was 17%, and median PFS was 2.9 months . Although no responses were observed after adding the EGFR TKI erlotinib to the HSP90 inhibitor onalespib, median PFS was comparable at 5.4 months . Preclinical activity of other HSP90 inhibitors has been shown in combination with next-generation EGFR TKIs, such as osimertinib, that have more activity against EGFR-mutant non\u2013small cell lung cancer (NSCLC).Onalespib is a novel heat shock protein 90 inhibitor (HSP90i). Previous preclinical and clinical studies with HSP90i have demonstrated activity in EGFR-mutant NSCLC and evaluate the preliminary efficacy of the combination in EGFR exon 20 insertion (EGFRex20ins) NSCLC.This study sought to determine the safety and tolerability of onalespib plus erlotinib in 2 intravenously weekly .The recommended phase II dose is erlotinib 150 mg orally every day and onalespib 120 mg/mEGFRex20ins NSCLC, as no responses were observed.Overlapping toxicities of erlotinib and onalespib limited the tolerability of this combination, with grade 3 diarrhea being the predominant toxicity in 45% of patients, and the combination demonstrated limited activity in EGFRex20ins circulating tumor DNA (ctDNA) was detected in the majority of patients; failure to clear ctDNA was consistent with lack of tumor responsePlasma 1"}
+{"text": "Clival tumors present challenging entities regarding their treatment options. Due to their proximity to critical neurovascular structures, the operative goal of gross total tumor resection is rendered more difficult by a high risk of neurological deficits. Retrospective cohort study of patients treated for clival neoplasms through a transnasal endoscopic approach between 2009 and 2020. Assessment of preoperative clinical status, length of operation, number of approaches, pre- and postoperative radiotherapy, and the clinical outcome. Presentation and clinical correlation with our new classification. In total, 59 transnasal endoscopic operations were performed on 42 patients over 12\u00a0years. Most lesions were clival chordomas; 63% of the lesions did not reach the brainstem. Cranial nerve impairment was present in 67% of the patients, and 75% of the patients with cranial nerve palsy improved after surgical treatment. Interrater reliability for our proposed tumor extension classification showed a substantial agreement (Cohen\u2019s \u03ba\u2009=\u20090.766). The transnasal approach was sufficient to achieve a complete tumor resection in 74% of the patients. Clival tumors exhibit heterogeneous characteristics. Depending on clival tumor extension, the transnasal endoscopic approach can present a safe surgical technique for upper and middle clival tumor resection, with a low risk of perioperative complications and a high rate of postoperative improvement. Due to their anatomical location and close proximity to critical neurovascular structures such as caudal cranial nerves and basilar and carotid arteries2, pathologies of the clivus are generally difficult to treat4, and gross total resection (GTR) may require several attempts and approaches7. Despite their challenging nature, current evidence on clival pathologies lacks specific classifications with prognostic value for the extent of resection (EOR) and progression-free survival. Several authors have offered grading depending on anatomical location9, growth pattern10 and histopathological features11.Midline tumors of the clivus located at the posterior cranial fossa may cause cranial nerve impairmentThe aim of this study was to assess the clinical outcomes of patients undergoing transnasal endoscopic resection of clival tumors, and to present a new tumor extent classification to estimate the complication rate and probability of a single-staged approach.We performed a consecutive case study of all patients treated endoscopically for tumors of the clivus, reviewing all patients who received operations via a transnasal endoscopic approach in our neurosurgical department between January 2009 and January 2020. We excluded patients suffering from skull base osteomyelitis or degenerative pathologies such as basilar invagination due to their distinct clinical outcome.Pre- and postoperative data  were retrieved from our records. We reviewed the preoperative goal of the operation ; clinical information included occurrence and side of cranial nerve palsy and duration of symptoms. The clinical status before and after operations and in follow-up was assessed according to the Karnofsky Performance Status Scale (KPSS).If available, preoperative diagnostic imaging included pre- and postoperative computed tomography (CT) and magnetic resonance imaging (MRI) of the craniovertebral junction.CE1: Intraosseous lesionCE2: Destruction of the osseous clival cortical boneCE3: Brainstem reached without compression or infiltrationCE4: Compression/infiltration of the brainstemWe classified tumor extension in 4 distinct subgroups: clival extension (CE) 1\u20134 depending on the preoperative CT and MR imaging. The classification was evaluated by 2 individual reviewers . Due to the retrospective nature of the study, patient consent was not required and was therefore waived by the local ethics committee .Written informed consent was obtained from our patient presented in the case presentation.2 test. Likelihood ratio (LR) was used to assess changes in odds.We performed statistical analyses using SPSS Statistics 26 . Binomial dichotomized data were compared using Fisher\u2019s exact test, and categorical data were compared using the \u03c7t test when appropriate. The association between potential factors and transient and permanent postoperative impairment (using follow-up data or discharge data for those with a missing follow-up) was analyzed using ANOVA for variance testing and linear regression modeling. The following factors were assumed as potentially predictive: symptom duration, length of operation (LOO), EOR, CE1-4 classification, preoperative treatment such as previous radiation therapy, tumor malignancy, and age. Interrater reliability (IRR) was assessed with the Cohen\u2019s \u03ba coefficient.Median or mean values were compared using a student\u2019s p values less than 0.05 were considered statistically significant.In total, 59 transnasal endoscopic operations were performed in 42 patients over 12\u00a0years. All 42 patients had neoplastic lesions. Median age was 53\u00a0years (IQ range 29\u201369\u00a0years), and 25/42 (59.5%) of the patients were females. Median symptom duration was 39\u00a0days (IQ range 14\u2013154\u00a0days).Most cases  presented with clinical symptoms related to the clival lesion, such as cranial nerve palsy , followed by the glossopharyngeal nerve  and oculomotor nerve . In 19/42 patients, lesions were diagnosed due to headache symptoms (45.2%) , followed by tumors including all parts of the clivus , the upper clivus  and the lower clivus . In 7/42 (16.7%) patients, tumors were identified incidentally during regular CT staging for tumor follow-up. In 3 patients (7.1%), the initial endoscopic operation was performed after a previous radiation therapy.Median preoperative KPSS was 90% (range 20\u2013100%). Preoperative MRI, CT scan, and navigation were available for all patients.Slow-growing tumors were diagnosed in 26/42 (61.9%) cases: chordoma 16/42 (38.1%), chondrosarcoma G1 4/42 (9.5%), hamartoma 1/42 (2.4%), Rathke\u2019s cleft cyst 2/42 (4.8%), Langerhans-cell histiocytosis 1/42 (2.4%), hemangioma 1/42 (2.4%), or epidermoid 1/42 (2.4%).In 16/42 (38.1%) patients, the histopathological analysis revealed a malignant tumor: metastasis 8/42 (19%), adenoid cystic carcinoma 2/42 (4.8%), plasmocytoma 1/42 (2.4%), rhabdomyosarcoma 1/42 (2.4%), chondrosarcoma G3 1/42 (2.4%), aggressive dedifferentiated chordoma 1/42 (2.4%), neuroblastoma 1/42 (2.4%), and one neuroendocrine tumor (2.4%).Using the CE classification described above, most patients  had lesions with erosion of the cortical bone without contact with the brainstem (classified as CE2). Intraosseous lesions (CE1) were identified in 6/42 (14%), compression of the brainstem (CE4) in 10/42 (23.3%) and extent to the brainstem without compression (CE3) in 6/42 patients (14%) . All operations were performed with 18-cm endoscopes of 0\u00b0 and 30\u00b0 . The 4-handed technique via both nostrils was used in accordance with the technique described in previous publications from our study groupPreoperative MR and CT imaging as well as intraoperative navigation were used in all cases . Intraoperative leakage of cerebrospinal fluid (CSF) was observed during 19/59 (32.2%) operations, and dural reconstruction was performed in 24/59 (40.7%) operations . Intraoperative CT imaging was conducted in 5/59 (8.5%) cases.In 43/59 72.9%) of operations, the preoperative goal was GTR of the lesion. In 6/59 (10.2%), the initial indication for operation was a diagnostic biopsy. STR or tumor debulking were the goals in 8/59 (13.6%) and 2/59 (3.4%) cases, respectively  operations, STR in 26/59 (44.1%), tumor debulking in 5/59 (8.5%), and only a biopsy in 7/59 (11.9%) cases (Table p\u2009=\u20090.063). Patients undergoing a second surgical tumor resection during the initial hospital stay underwent a second transnasal endoscopic approach  or a different transcranial approach . Two patients underwent a dorsal craniocervical fixation.In 18/42 (43%) patients, 2 or more operations were needed to complete a GTR due to residual tumor on the postoperative MRI  or tumor recurrence during follow-up (3/18 patients 17%). The relative risk for multiple approaches was higher in patients suffering from lesions of the lower clivus (75%) compared to patients suffering from upper or middle clivus pathologies, but the association failed to reach statistical significance , necessity of staged approaches for tumor resection , and occurrence of complications (p\u2009=\u20090.009). Preoperative radiotherapy showed a trend of increased risk for perioperative complications but failed to reach statistical significance .The CE classification significantly correlated with the postoperative KPSS (Adverse events occurred in 22% (13/59) postoperative courses. CSF leakage requiring surgical revision occurred in only 2/59 (3.4%). Adverse events that did not require surgical revision included disorders of sodium balance after 3/59 operations (5.1%), hypocortisolism with transient hydrocortisone substitution in one case (1.7%), a urinary tract infection in 1/59 (1.7%), respiratory complications in 2 cases (3.4%), and meningitis in one case (1.7%). Thirty-day mortality was 0%.The median length of hospital stay was 9\u00a0days . Median postoperative KPSS was 90% (range 20\u2013100%).Data on recommended adjuvant therapy was available for all patients and recommended in 33/42 (79%) of them: 16/42 (38.1%) underwent postoperative photon radiotherapy , and 17/42 (40.5%) patients were recommended proton beam radiotherapy of the clival area . In total, 9/42 (21.4%) patients underwent follow-up imaging without further adjuvant treatment.Follow-up data was available for 34/42 (81%) of patients after a median of 37\u00a0months (IQ 6\u201360\u00a0months). At follow-up, 12/16 (75%) patients with previous preoperative cranial nerve palsy had recovered completely, and 18/34 (52.9%) of the patients remained stable at follow-up . Tumor reoccurrence (3/4) or postoperative worsening of previous neurological status (1/4) accounted for the 4/34 (11.7%) patients who had deteriorated at follow-up.A 60-year-old female patient presented in the outpatient department with paresis of the abducens nerve on the right side. The initial CT and MRI scans revealed an osteodestructive mass of the clivus Fig.\u00a0. A transClival tumors are rare and comprise various types of tumor entities with distinct histopathological and anatomical features. Depending on the type of neoplasm and the extent of the lesion, patients may present with cranial nerve palsies or symptoms of intracranial hypertension.Preoperative planning and patient advising should not only include the possible entities, but also the prospect of multiple operations and possible neurological outcomes after operative treatment. Up to now, anatomical classifications to estimate the extent of clival lesions have been sparse, and none of them focus on the relation of the tumorous lesion to the brainstem or intra/transclival extension . We classified clival tumor extension with high IRR, prognostic value for neurological outcome (KPSS), and the occurrence of multiple approaches  in patients undergoing a transnasal endoscopic approach.14 and acceptable morbidity compared to more open lateral approaches, such as the subtemporal15, far lateral16 or transpetrosal approach17. In our patient cohort, the transnasal endoscopic approach provided excellent resection results with a low complication rate. Further operative treatment from a different transcranial approach was necessary in only 6/42 patients (14%).In our study, we included patients undergoing a transnasal endoscopic approach for clival pathologies. Our aim was to include all patients with transnasal endoscopic operative treatment of clival tumors to describe the outcome of this specific technique, as patients usually undergo transnasal treatment for minimally invasive biopsy or tumor resection. The optimal approach for clival tumor resection remains a matter of debate. The advantages of the transnasal endoscopic approach remain the limited invasiveness, wide exposure of the clivusIn our study, we aimed to provide a simple preoperative grading method to advise patients undergoing an initial transnasal endoscopic approach for suspected clival tumor lesions. Our grading system was not applied to patients undergoing other surgical approaches and did not require the histopathological diagnosis of a chordoma.18. This classification included 4 criteria  and was applied to histologically confirmed chordomas. Compared to our study, other researchers included patients who mostly underwent an open microscopic approach  and required the histopathological confirmation of a diagnosed chordoma.Some classifications have been proposed for grading and scoring specific tumor entities of the skull base, such as the Sekhar Grading System for Cranial Chordomas19. The recovery rate was satisfying, with 75% of the patients recovering from preoperative cranial nerve palsy after operation. The transnasal endoscopic approach proved to be a safe approach with a low complication rate 3.In our cohort population, two-thirds of the patients presented with cranial nerve palsies, congruent with current literature describing mostly deficits due to compression of the abducens nerve in Dorello\u2019s canal Due to the limited number of cases included and the monocentric and retrospective nature of our study, the prognostic power and conclusions may be limited.We included various tumor pathologies, as the classification is intended to be used prior to histopathological diagnosis, but the postoperative outcome significantly depends on the tumor entity and need for postoperative treatment. To estimate the real potential benefits or pitfalls of the proposed classification, it should be verified and applied to a higher number of patients in a possible multicenter study.21. Especially for lesions reaching to the lower clivus and craniovertebral junction, GTR may be limited due to a reduced exposure.While the benefits of the transnasal endoscopic approach have been presented above, it has some anatomical limitations regarding the lower clivus22. We did not investigate the learning curves in our department but feel that the benefits of endoscopic surgical approaches may surpass the open approaches when performed on a regular basis.We found satisfying results applying the endoscopic transnasal approach regarding the EOR, low complication rate, and encouraging clinical outcomes. In our department, the endoscopic approach is mainly performed by 2 senior neurosurgeons with many years of experience with endoscopic skull-base operation, which may explain the low rates of CSF leaks and overall complicationsThe transnasal endoscopic approach remains a safe approach with a wide exposure for upper and middle clival tumors and satisfying extent of tumor resection results. More than half of the patients presenting with preoperative cranial nerve palsies recovered completely after transnasal endoscopic operations, and the overall complication rate remained low."}
+{"text": "Post-Diphtheritic Paralysis (PDP), one of the most severe complications of diphtheria, is caused by exotoxin of Corynebacterium diphtheria. This study was planned since there has been a resurgence of diphtheria in India in recent years due to a number of epidemiological factors. .  Thirty-five children with PDP were studied in a tertiary care hospital in Southern IndiaNeurological complications occurred in 38.5% of 91 patients with faucial diphtheria. Of the patients, 13 (37.1%) were unimmunized, 12 (34.3%) were partially immunized, two (5.7%) were completely immunized, and eight (22.6%) had unknown status. Isolated bulbar palsy and bulbar palsy followed by limb weakness were seen in 20 (57.1%) and 15 (42.9%) of the patients, respectively. The first symptoms of PDP occurred 5-34 days after the onset of local diphtheria infection. Eleven (31.4%) out of the 35 patients had received antitoxin between days 5-7 of illness. Ventilation-dependent respiratory failure occurred in three (8.6%) patients with PDP. Nine (25.7%) patients had evidence of co-existent myocarditis, while myocarditis with renal failure was seen in two (5.7%) patients. Four (11.4%) patients died, three from severe cardiomyopathy and one from aspiration. Demyelinating neuropathy was noted in 64% of the patients. Children with bulbar palsy recovered in 4-7 weeks, while limb symptoms improved in 6-17 weeks. PDP should be considered in any child presenting with bulbar palsy/quadriparesis following previous history of fever/sore throat. Awareness and availability with timely administration of ADS within 48 hours are essential to reduce PDP, as antitoxin seems ineffective if administered after the second day of diphtheritic symptoms.  Post-Diphtheritic Paralysis (PDP), one of the most severe complications of diphtheria, is caused by exotoxin released by toxigenic strains of Corynebacterium diphtheria . NontoxiThis was a retrospective observational study from January 2015 to December 2017. Ninety-one children identified as probable or confirmed diphtheria were evaluated, and among them, 35 children with post-diphtheritic palsy were identified. The patients\u2019 demographic profiles, age, gender, and immunization status with calendar of events in their semiology were recorded. Children were considered completely immunized if they had received all the recommended doses of diphtheria toxoid, including booster, as per the national immunization schedule. All patients with a diagnosis of diphtheria were put on parenteral crystalline penicillin. Eleven out of 35 patients had received antitoxin between days 5-7 of illness. All the patients were managed in the isolation ward. Detailed clinical examination with appropriate investigations, including throat swab for staining and culture for Corynebacterium diptheriae, nerve conduction studies, electrocardiography, and echocardiography, was conducted, and results were tabulated and analyzed. Ethical clearance was obtained from the institutional ethical committee. A total of 91 children were identified as probable or confirmed diphtheria cases, and 35 were diagnosed with post diphtheritic paralysis. Among the 35 PDP cases, 23 (65.7%) were boys. Fifty-seven percent of patients with PDP were aged 6-10 years with a median age of presentation of 8.6 years, and they mostly (91.4%) belonged to rural areas of Karnataka and Andhra Pradesh. The immunization profile showed that of the patients, 13 (37.1%) were unimmunized, 12 (34.3%) were partially immunized, two (5.7%) were completely immunized, and eight (22.6%) had unknown status. The detailed demographic and clinical features of the patients are presented in All the 35 children had compatible clinical manifestations of diphtheria: fever with sore throat and dysphagia in the preceding 5-34 days prior to presentation. Nine (25.7%) patients had neck swelling with pseudomembrane. There were no cases of cutaneous diphtheria. The first PDP symptom was palatal palsy in all the 35 patients with a latency period of 10 (range 5-34) days after the onset of faucial diphtheria. Isolated bulbar palsy and palatal palsy followed by quadriparesis were seen in 20 (57.1%) and 15 (42.9%) patients, respectively. The median duration of progression of weakness was 10 days (range 7-15 days). Weakness was symmetric in 14 patients and asymmetric in one patient. Limb symptoms never preceded bulbar symptoms in any of the cases. Cranial nerves involved were nine and 10 in all the 35 patients, and the seventh nerve was additionally involved in one patient. Cerebellar ataxia was seen in five (14.3%) patients. Nine (25.7%) patients had evidence of co-existent myocarditis, while myocarditis with renal failure was seen in two (5.7%) patients. Three (8.6%) patients (of whom one child had respiratory muscle involvement) required mechanical ventilation for an average of three (range 1-6) days. Twenty-five (71.4%) patients required nasogastric tube nutrition. Eleven (31.4%) had received diphtheritic antitoxin between days 5-7 of illness. Of the 11 patients, eight developed quadriparesis (of whom five had myocarditis and another three developed cerebellar ataxia), and three developed isolated bulbar palsy. Of the remaining 24 patients who had not received diphtheritic antitoxin, 17 developed isolated bulbar palsy, and seven developed quadriparesis (with features of myocarditis in four patients).Corynebacterium diphtheriae was seen in smear with throat swab culture positivity in five (14.3%) patients. Nerve conduction velocity (NCV) was performed in 11 children and revealed demyelinating neuropathy in seven children, axonal neuropathy in two children, and normal status in two children. CSF study was done on two patients, and results were unremarkable. Cardiac enzymes were grossly elevated in five patients, mildly elevated in two patients, and normally elevated in two patients. Four (11.4%) patients with PDP died, three from severe cardiomyopathy and one from aspiration, of whom three were unimmunized and one had unknown immunization status. All the four patients had received ADS between days 5-7 of illness.Initial improvement of bulbar symptoms occurred by day 33 (range 15-50 days) after the onset of neurological symptoms. In the surviving 11 patients with quadriparesis, limb symptoms recovered by day 72 (40-120 days), with a muscle power grading of 3/5(MRC). At the time of discharge, 10 (28.6%) surviving patients with quadriparesis could not walk independently. The average duration of hospital stay was 25 (range 7-45) days.There have been recent reports of sporadic diphtheria outbreaks from various states in India. In 2010, India shared 3123 77.1%) of 4053 diphtheria cases reported to WHO . This ha7.1% of 4PDP is reported to be more common in unimmunized and partially immunized people, with limb involvement being more common and variable latency of disease in the unimmunized . Kanwal The incidence of diphtheritic polyneuropathy is directly proportional to the severity of intoxication . PDP is The latency period reported varies from 10 days to 3 months . The lat The involvement of other cranial nerves  was described with varying frequency in various studies, ranging between 30%-84% of patients , 15 withThere appears to be an inverse relationship between latency and recovery of motor symptoms \u2013 a longer latency corresponds with an earlier regression of limb weakness. In this study, limb weakness progression was seen in 42.9% of the cases while the rest 51.9% patients with bulbar palsy recovered without further progression to limb weakness. The reason behind isolated palatal palsy in children with no systemic involvement is probably lack of toxin dissemination .Antitoxin administration aims to block cellular binding and uptake of diphtheria toxin. Although no formal clinical trials of antitoxin administration have been performed, the incidence of paralysis only seems to be reduced if antitoxin is administered during the first 2 or 3 days of diphtheritic infection . AntitoxSegmental demyelination of peripheral nerves is the characteristic lesion, with additional axonal degeneration in the most severe cases . ElectroAlthough throat cultures provide an accurate means for diagnosis of diphtheria , isolatiCerebrospinal fluid (CSF) studies may be normal or show elevated protein . Logina et al. reported elevated CSF proteins in 12% of their PDP patients . CSF stuWe noted initial improvement of bulbar symptoms by day 33 (range 15-50 days) after the onset of neurological symptoms and improvement in limb weakness to 3/5 by day 72 (40-120 days). At the time of discharge, 10 28.6%) surviving patients with quadriparesis could not walk independently. Mortality was 11.43% in this study, causing cardiogenic shock secondary to post-diphtheritic myocarditis, while Kanwal et al. (.6% surviPDP should be considered in the differential diagnosis of acute flaccid paralysis, especially in children presenting with bulbar palsy/quadriparesis following previous history of fever and sore throat. Timely diagnosis and differentiation from other neuropathies are important for rational management. Awareness of regular immunization, both primary and booster DPT vaccination, is the need of the hour as it is the simplest, most cost-effective practical approach in preventing complications due to this vaccine-preventable disease. VK: Concept and designed the studySV: Collected the data and helped in data analysis. SK: Analyzed data and drafted the manuscriptNB: Literature search, Concept of study and supervised seizure controlAB: Edited and refined draftNone of declare."}
+{"text": "Altered acetyl CoA acetyltransferase 1 (ACAT1) expression has been reported in diverse cancers. However, the expression of ACAT1 and its prognostic value in oral squamous cell carcinoma (OSCC) has remained unexplored.In this study, the expression of ACAT1 was analysed by immunohistochemistry (IHC) in 61 OSCC patients and compared between OSCC and adjacent pre-tumour tissue of 21 patients.The expression of ACAT1 in OSCC tumours is heterogeneous between patients. More specifically, 52.38% of the patients show low expression of ACAT1 in both tumour and adjacent pre-tumour tissues, 9.52% of the patients show high expression of ACAT1 in both tumour and adjacent pre-tumour, 19.05% of the patients have high expression of ACAT1 in tumour tissue and low expression of ACAT1 in adjacent pre-tumour tissue and another 19.05% of the patients have low expression of ACAT1 in tumour tissue and high expression of ACAT1 in adjacent pre-tumour tissue.Comparison of ACAT1 expression, one of the key enzymes in the ketone body metabolic pathway, divided OSCC patients into two groups: 1) similar expression and 2) different expression of ACAT1 in tumour and adjacent pre-tumour tissue. No significant association between ACAT1 levels and overall survival was observed. Oral squamous cell carcinoma (OSCC) is the most common malignancy of oral cancer with high mortality and 5-year survival is less than 50% . There iFormalin-fixed paraffin-embedded fresh human OSCC and adjacent pre-tumour biopsy specimens were selected to evaluate the expression of ACAT1 between OSCC and adjacent pre-tumour tissues. These included 21 OSCC samples with their adjacent pre-tumour tissues that were harvested at surgical removal from hospitals . All the OSCC patients were histopathologically diagnosed. Fresh tissues were immediately fixed in formalin for histological study. Adjacent pre-tumour tissues were harvested far from the margin of tumours. Additionally, 40 OSCC paraffin embedded tissues without adjacent pre-tumour tissues were obtained from the archives of the Oral and Maxillofacial Department, Tehran Medical University. Altogether, an overall of 61 OSCC patients with paraffin blocks were used to evaluate the association of ACAT1 expression with survival probabilities. This research project was approved by the Ethics Committee of Shahid Beheshti University of Medical Sciences (IR.SBMU.MSP.REC.1399.528).The formalin-fixed tissues obtained at surgical removal were dehydrated and embedded in paraffin. Four-micrometer-thick paraffin sections were prepared from OSCC and adjacent pre-tumour tissues, followed by deparaffinization in xylene and rehydration in serial dilutions of ethanol. The tissues were incubated in PBS 3% hydrogen peroxide for 10 min. Next, the antigen retrieval was performed using citrate buffer (pH = 6) at 90 \u00b0C for 15 min. The tissues were then incubated with the ACAT1 primary antibody  for 1 h at RT, followed by three washes with PBS and incubation with primary antibody amplifier master for 20 min, after washing with PBS, slides were incubated with the secondary antibody for 30 min, followed by washing in PBS. The signal was developed with DAB substrate solution, then counterstained with hematoxylin and dehydrated with serial dilutions of alcohol and mounted.The stained slides were observed using a light microscope. For each slide, the intensity staining score was applied as follows: 0 (negative), 1 (weak), 2 (moderate) and 3 (strong)) . The scoThe statistical analysis was performed using Graphpad Prism software version 8. The ACAT1 percentage of positive cells and its total score were compared between OSCC and adjacent pre-tumour tissues using paired sample T test. Survival analysis was performed using the Kaplan\u2013Meier method and log-rank test with Python software and the lifelines package. p-values < 0.05 were considered statistically significant.low/Normallow (11 out of 21 patients (52.38%)), ii/OSCClow/Normalhigh (4 of 21 patients (19.05%)), and iii/OSCChigh/Normallow (4 of 21 patients (19.05%)) and iv/OSCChigh/Normalhigh (2 of 21 patients (9.52%))  and low ACAT1 protein expression in 38 of 61 patients (62.3%). We then evaluated the ACAT1 expression in adjacent pre-tumour tissues and looked for possible differences with OSCC tumour tissue. To this end, we took advantage of 21 samples for which both OSCC tumour and adjacent pre-tumour tissues were available. Variable ACAT1 protein expression was observed in pre-tumour tissues, similar to OSCC tissues. Indeed, out of the 21 patients, high ACAT1 protein expression was found in the pre-tumour tissue of 6 patients (29%) and low ACAT1 protein expression in 15 patients (71%). We then wanted to evaluate whether the percentages of ACAT1 positively stained cells and ACAT1 total score staining were similar or different between tumour and their adjacent pre-tumour matched tissues in our 21 patients. We performed a paired sample T test and found a higher percentage of ACAT1 positive cells in tumour tissues compared to adjacent normal mucosa tissues  whereas no significant difference was observed between the total scores of tumour and adjacent pre-tumour tissues  . Additio(9.52%))  (Table S(9.52%)) .We then investigated the association of ACAT1 expression according to the percentage of positively ACAT1 stained cells, the score of percentage and ACAT1\u2019s total staining score with the survival of OSCC patients. Kaplan\u2013Meier analysis revealed no significant difference in overall survival between stratified groups according to high and low levels of ACAT1 .low/Normallow, OSCClow/Normalhigh, OSCChigh/Normallow and OSCChigh/Normalhigh. In 2016, Fan and colleagues reported an upregulated ACAT1 activity despite comparable gene and protein expression in human leukaemia cells, head and neck cancer and lung cancer cells, compared to their corresponding normal cells [low/Normallow and OSCChigh/Normalhigh).OSCC is the most common subtype of oral cancer. Overall, cancer is a disease with mitochondrial metabolism alterations which seems to benefit from dietary therapeutic approaches. The association of enzymes responsible for catalyzing ketone bodies with the progression of cancers, including prostate and kidney, has been recently reported ,8. AmongSince the expression levels of ACAT1, one of the key enzymes in the ketone body metabolic pathway, are variable between OSCC patients, a high-fat low-carbohydrate diet (ketogenic), which increases the amount of blood ketone bodies, would probably not be able to disrupt the metabolism and therefore would not increase the death of oral squamous cancer cells in all OSCC tumours. These results suggest that ACAT1 staining could help stratify patients into different groups with respect to their potential response to a ketogenic diet, although this statement would still need to be strengthened by analysing other ketolytic enzymes.In conclusion, our measurements of ACAT1 protein expression did not show any clear common trend regarding the relative expression levels of this enzyme between OSCC and adjacent pre-tumour tissues. Further studies would be required to elaborate on the reason behind these variations of ACAT1 expression among OSCC patients. The main limitation of this study was the evaluation of other ketolytic enzymes including 3-hydroxybutyrate dehydrogenase 1(BDH1), 3-hydroxybutyrate dehydrogenase 2 (BDH2) and succinyl CoA: 3-oxoacid CoA transferase 1 (OXCT1) in the tumour and pre-tumour tissues of the OSCC patients. To conclude on the clinical application of this study, OSCC patients with observed low ACAT1 expression in their tumour compared to the pre-tumour tissue may respond better to ketogenic diet therapy, although further investigations of BDH1, BDH2 and OXCT1 related to the ketolysis would be required."}
+{"text": "Chronic Recurrent Multifocal Osteomyelitis (CRMO), also known as chronic nonbacterial osteomyelitis (CNO), is a rare autoinflammatory condition affecting the bones. It occurs primarily in children and teenagers and is characterised by bone pain and swelling in the absence of infection or tumour. The incidence of CRMO remains uncertain, with estimates ranging from 0.4-1 per 100,000 person years.The primary aim of the study was to identify the incidence of CRMO in patients under the age of 16 in the United Kingdom (UK) and Republic of Ireland (ROI). Additional aims include describing the demographics, clinical features, treatment, and healthcare needs of patients with CRMO. A prospective surveillance study was undertaken via the British Paediatric Surveillance Unit. A monthly e-reporting card was sent to all registered paediatric consultants in the UK and ROI. A parallel surveillance study was sent via the British Society for Children\u2019s Orthopaedics to identify patients managed solely by orthopaedics. A standardised questionnaire was sent to the reporting clinicians to collect further information.During initial 13 months of surveillance, 168 cases were reported. 23 questionnaires were not returned (13.7% of reported cases). After de-duplication, and removal of cases outside the reporting time period and age-group, 82 confirmed and 8 probable cases were included in these interim results. The estimated incidence of CRMO is 0.605 cases/100,000 children per year.Median age at time of diagnosis was 10 years (range 3-16). 53 (58.9%) of cases were female. Median delay from symptom onset to diagnosis was 5 months and 16 patients (17.78%) had a delay of greater than 12 months. Most (48.9%) of the cases were diagnosed by paediatric rheumatology specialists. Other cases were diagnosed by orthopaedics (16.7%), general paediatricians (15.6%) or by a multidisciplinary team. 34 cases (37.8%) reported requiring hospital admission related to CRMO.The most common presenting feature was bone pain (96.67%). 34 patients (37.8%) presented with clavicular pain, and thirty-one (34.4%) had unifocal bone pain. Patients also presented with bone swelling (52.2%), joint swelling (20.0%), fever (12.2%) and general malaise (13.3%). A median of 3 radiological investigations were reported for each case, of which 61 (67.7%) cases had whole body MRI performed. Additionally, 33 cases (36.67%) had bone biopsy. At initial reporting, the most common treatment was NSAIDs (90.0%) and bisphosphonates (33.3%).Our results estimate the incidence of CRMO as 0.605 cases per 100,000 person years. The study will continue to capture new CRMO cases for a further 12 months. Reported cases will be followed up for 24 months. This prospective study of all incident cases of CRMO within the UK and ROI will provide insight into the medium-term outcomes and treatment strategies used by clinicians. These results will provide a valuable baseline for further research and improvement in care for patients with CRMO."}
+{"text": "Following first reports of paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS) in April 2020, services have rapidly been developed to manage these patients. In our tertiary paediatric rheumatology service a daily virtual PIMS-TS multidisciplinary (MDT) team meeting was set up in January 2021. This meeting facilitates discussions between the tertiary centre (routinely including paediatric rheumatology and infectious diseases/immunology teams) and general paediatric teams in district general hospitals (DGHs) and within our centre. The aim of this project was to evaluate the service and understand general paediatric opinion in order to consider the future direction of the meeting.We looked at a one month period after meetings were initiated and compared it with a one month period a year later (February 2021 and February 2022) to define patient numbers and outcomes. Alongside this we constructed an online survey aimed at general paediatricians to determine opinion of the current structure of the MDT and how it may be developed in the future. The survey was sent to general paediatricians within our own centre and in the eleven DGHs falling within our region. Results were analysed descriptively.During February 2021, 19 new referrals were discussed within the PIMS-TS MDT; each referral was discussed for a median of 5 days (interquartile range (IQR) 3\u20136 days). Of these, 11/19 (58%) had a final primary diagnosis of PIMS-TS and 5/19 (26%) patients were transferred for tertiary care (of whom 4/5 (80%) had PIMS-TS). In February 2022, 14 new referrals were discussed for a median of 2.5 days (IQR 2\u20135.75 days). Of these, 3/14 (21%) had a final diagnosis of PIMS-TS and 2/14 (14%) were transferred for tertiary care (of whom neither had PIMS-TS).We received responses from 20 general paediatricians covering 9/11 (82%) DGHs within our region plus our own centre. Most clinicians had discussed up to 6 patients in the meeting (9/20 (45%) 1-3 patients; 9/20 (45%) 4-6 patients; 2/20 (10%) >6 patients). All clinicians felt the MDT helped facilitate appropriate diagnostic work-up and treatment decisions. 18/20 (90%) felt that the meeting helped avoid unnecessary tertiary paediatric transfers. Interestingly, 9/20 (45%) felt that a routine PIMS-TS MDT meant they were more likely to discuss a patient with rheumatology (1/20 (5%) less likely). All clinicians felt the meeting improved care for patients and most felt it increased their confidence in looking after patients with PIMS-TS  and was useful for continuing professional development/training experience .Considering the future direction of the meeting, all clinicians felt it should be continued but most  felt it should be aimed at a wider patient group. 11/20 (55%) felt a later time of day would be more convenient (currently 11am). Over half  thought it should be combined with a currently separate meeting for acute COVID-19 patients (7/20 (35%) don\u2019t know; 2/20 (10%) no). A minority  reported difficulty accessing the meeting.As the initial phase of the pandemic draws to a close and numbers of PIMS-TS cases decline this is important data to reflect on how services can go forward into the next phase. While numbers of PIMS-TS cases reduced, the meeting was still well-used and evolved to include patients with other diagnoses. The survey confirms that most general paediatricians believe it improves patient care and would like the meeting to continue but that review of the format may be helpful. Particular considerations are to broaden the scope of the meeting beyond PIMS-TS, revise the timing and consider how to improve ease of access to the meeting for all.Further work will focus on evaluating patient numbers and diagnoses over the full period of the PIMS-TS MDT and adapting the format of the current MDT in response to the feedback received."}
+{"text": "Impulsivity is not a classical psychiatric diagnosis like schizophrenia, depression, bipolar or borderline personality disorder. It is a symptom that could occur in almost all psychiatric disorders and in some neurological or systemic diseases.In this study we examine the influence of bipolar disorder\u2019s (BD) treatment on the impulsivity.We performed a cross sectional study on 30 patients diagnosed with BD and consulting at the Psychiatric department of HediChaker Hospital. Patients were euthymic during the time of the study confirmed by administration Young Mania Rating Scale (YMRS) and Montgomery Depression Rating Scale (MDRS). The socio-demographic data and treatment models were obtained. Impulsivity was evaluated using the Barratt Impulsiveness Scale (BIS-11).The study sample consisted of 30 patients (10 men and 20 women). The mean age of the sample was 45.83 years (SD= 11. 63). Seventeen patients (56.7%) were married. Half of the participants were using an association of mood stabilizer (MS) and an antipsychotic (AP), 36.7% and 13.3% were receiving respectively only mood stabilizer or an antipsychotic. The mean BIS11 score was 75. 60 (SD=5.51) and 76.7% had a high level of impulsivity. No correlation was found between the level of impulsivity (BIS-11 scores) and using MS, AP or MS+AP .Further studies should be realized to identify pharmacological treatment of impulsivity among people with BD."}
+{"text": "This cohort study examines the characteristics of high-risk therapeutic devices approved by the US Food and Drug Administration for use in children and adolescents between 2016 and 2021. Thus, physicians often repurpose or modify devices designed for adults to meet pediatric needs.5 and Humanitarian Device Exemption6 databases to identify all high-risk (class III) therapeutic medical devices with first-time approvals between January 1, 2016, and December 31, 2021. We abstracted regulatory and therapeutic characteristics and classified devices as approved for children (aged <18 years) or adults (aged \u226518 years) . Fifteen pediatric devices (60%) were cardiovascular devices, which included 11 defibrillators (44%).Of the 124 high-risk therapeutic devices approved by the FDA from 2016 to 2021, 2 (2%) were approved for use in children only, 23 (19%) for both children and adults, and 99 (80%) for adults only . Among tPediatric devices were approved based on 43 pivotal studies, of which 15 (35%) enrolled pediatric patients . This toP\u2009<\u2009.001). Among the 14 postapproval studies for pediatric devices, after a median (IQR) follow-up of 2.8 (2.3-4.0) years since device approval, 5 studies (36%) were progressing adequately and 1 (7%) had been completed.Postapproval studies were required for 10 of 25 pediatric devices (40%) compared with 67 of 99 adult devices (68%; Findings of this cohort study of high-risk therapeutic devices approved by the FDA from 2016 to 2021 suggest that, despite programs to increase pediatric medical device development, few devices are evaluated and approved for pediatric populations compared with adults. Furthermore, most pediatric devices are studied only in adult populations or in small numbers of pediatric patients. Postapproval studies could increase safety and effectiveness data for devices with limited premarket pediatric data or support labeling expansion of adult devices to pediatric patients. However, less than half of devices had FDA-mandated postapproval studies that enrolled children, and only 1 such study had been completed.Limitations of the study include potential lack of generalizability to low- and moderate-risk devices. The findings support the critical need for new policies and further collaboration among regulators, academia, and industry to advance pediatric device development and address unmet device requirements in children."}
+{"text": "Inflammatory markers were 2\u201320 times higher in patients with respiratory failure (p < 0.05). The majority of patients on MV (7/9) developed complications, including ARDS (acute respiratory distress syndrome), acute renal injury, and cerebral anoxic encephalopathy. Patients with respiratory failure had a significantly longer length of hospital stay than patients without respiratory failure (p < 0.05). The majority of the admitted adolescents in the ICU received steroid treatment. None of the patients died. An additional review of a 6-month postvaccination approval period indicated that the majority of ICU admissions were unvaccinated, obese, black patients and all patients who developed respiratory failure were unvaccinated. Our study highlights and supports the need for maximizing opportunities to address vaccination and healthcare gaps in adolescents as well as promoting public health measures including correct use of masks, effective vaccination campaigns for this age group, and additional passive preventive interventions for COVID-19 disease in adolescents especially with comorbid conditions, and in minority populations.We report our experience of COVID-19 disease with hypoxemic respiratory failure among patients aged 12\u201321 years admitted to the intensive care unit at two tertiary care institutions in Northeastern and Midwestern United States. Our results showed that during the main study period that spanned the initial surge at both geographic locations, adolescents with SARS-COV-2 infection admitted to the ICU with respiratory failure were more likely to be male, black, and morbidly obese and with two or more comorbidities. The majority (79%) were admitted with COVID-19-related pneumonia and 15 developed respiratory failure; two-thirds of patients with respiratory failure  required mechanical ventilation (MV). More than two-thirds of patients  with respiratory failure were obese with BMI > 30 compared to those without respiratory failure ( Globally, COVID-19 disease caused by SARS-COV-2 continues unabated with over 400,000, 000 confirmed cases including about 6 million deaths, reported to WHO as of March 2, 2022 .Severe COVID-19 disease is caused by unabated viral replication in pneumocytes and alveolar epithelial cells, with resulting exaggerated inflammatory immune response that leads to causing alveolar damage and vascular leakage , 5. ManaHere, we characterize adolescent patients with severe Covid-19 respiratory disease who were admitted to two ICU centers in NE and MW US.The objective of our retrospective descriptive study was to define the epidemiologic characteristics of adolescent patients with COVID-19 respiratory failure admitted to Intensive care units (ICUs) at two tertiary care centers in Northeastern and Midwestern United States (NJ and Iowa) during the initial wave of the COVID-19 pandemic. Board-certified intensivists run both ICUs and both ICUs are in locations where climate, COVID epidemiologic rates, and bed sizes are similar.2/FiO2 ratio < 300 who are unable to maintain their O2 saturation above 92% with a nonrebreathing mask were started on HFNC or were intubated depending on their ability to ventilate as per ICU clinical decision making.Adolescence was defined as the age group 12\u201321 years of age, per WHO definition. All adolescents admitted to the ICUs with positive SARS-COV-2 PCR during the study period at the two tertiary care centers were included. The main period of study occurred during our initial surge . Pfizer-BioNTech COVID-19 vaccine received the U.S. Food and Drug Administration (FDA) Emergency use authorization for adolescents aged 16\u201317 years old on December 11, 2020, and for children aged 12\u201315 years old on May 10, 2021. We conducted additional subgroup analysis on this cohort following approval . Patients with other viral/bacterial coinfections were excluded. Patients with hypoxemic respiratory failure were compared with those without respiratory failure. Respiratory failure was defined based on the use of a high-flow nasal cannula or mechanical ventilation. The use of respiratory support was at the discretion of the ICU provider. Patients with PaOWe reviewed medical records of patients hospitalized with SARS-COV-2 in intensive care units at our tertiary health care systems in Northeastern NJ and Northwestern IA, the United States to describe trends and patterns and respiratory complications. Pre-existing chronic conditions were analyzed by the Agency for Healthcare Research and Quality Chronic Condition Indicator tool  using ICp value of\u2009<\u2009.05 was considered statistically significant.Testing for SARS-CoV-2 on nasopharyngeal swabs was done by use of real-time reverse transcription polymerase chain reaction  during initial hospital admission. This study was approved by our respective institutional review boards as exempt from consent. Comparisons between study groups for categorical variables were performed with chi-square [A total of 47 adolescents were admitted to the intensive care unit during the main study period at both geographic locations (38 in NJ and 9 in Iowa). Demographic and clinical characteristics of all hospitalized patients at both geographic locations are presented in The majority of adolescents (79%) were admitted with COVID-19-related pneumonia and a third of the total admitted 15 (32%) developed respiratory failure. Two patients were admitted with COVID-19 triggered Diabetic ketoacidosis. None of the patients were diagnosed with myocarditis or multisystem inflammatory syndrome in children (MIS-C).p < 0.05). Fever (35%) and respiratory symptoms 61.6%) were the common presenting symptoms followed by GI symptoms (27.6%) in form of nausea and vomiting. A majority (9/11) of pts presenting with shortness of breath developed respiratory failure (p=0.0002).The median age was 13 years (IQR 12\u201318 years) and 57% of patients were female . A significantly greater proportion  of adolescents needing ICU admission were Black non-Hispanic or Latino Hispanic (p < 0.0001).The majority of obese patients (87% (11/13)) admitted to ICU developed respiratory failure and all patients  with 2 or more comorbidities  developed respiratory failure . Chest radiographs showed bilateral infiltrates in 11(23%) patients. Eighty-nine percent (42/47) of all ICU admissions received COVID-19 therapeutics. The majority  of patients in the ICU received steroids for treatment; 8 (17%) patients received hydroxychloroquine; 5 patients received (10.6%) remdesivir; 3 received azithromycin (6.4%); 1 (2.1%) received tocilizumab. One-third of the patients (30%) received empiric antibiotics for \u2264 48 hours, and 6 patients (12.7%) needed inotropic support. Most (89%) of the patients were discharged at \u2264 14 days. All patients that did not require HFNC or mechanical ventilation were discharged at \u2264 14 days compared to only a third of those with respiratory failure .p < 0.01). All patients with respiratory failure presented with respiratory symptoms at admission. A high proportion of patients with respiratory failure  had two or more pre-existing medical conditions/comorbidities, and more than two-thirds of patients  with respiratory failure were obese with BMI > 30 compared to those without respiratory failure (p < 0.0001). Patients with BMI > 40 were 4.3 times more likely to develop respiratory failure than those with normal BMI.A significantly higher proportion of black patients compared to other ethnic groups admitted to the ICU developed respiratory failure (57%) . IL-6 was only obtained in two patients. Median CRP levels were elevated three times (58.15 vs. 20.8), median LDH levels were elevated twice (358 vs. 158.5), median CPK 14 times (387.5 vs. 27.5), and median IL-6 levels were elevated 20 times in patients with respiratory failure than patients without respiratory failure ((162.1 vs. 6.4), (p < 0.05)). Inflammatory markers  were 2\u201320 times higher among patients with respiratory failure compared to patients without respiratory failure (p < 0.0001). All patients with respiratory failure received steroids and 5/15 (33%) patients with respiratory failure received remdesivir compared to none of the patients without respiratory failure (p=0.002). The mean duration of hospitalization was significantly longer for those with respiratory failure (16.9) (\u00b12.8) days versus 10.3\u2009\u00b1\u2009(3.5) days, (p < 0.001). Three patients stayed for more than 4 weeks, compared to none of the patients without respiratory failure (p < 0.0001).All patients with respiratory failure (15/15) received COVID-19 therapeutics compared to 19 (59%) patients without respiratory failure  required invasive mechanical ventilation. All (100%) of those requiring MV had underlying asthma. The mean duration of mechanical ventilation was 11 (\u00b11.6) days. Complications were seen in 7/9 (77%) of the mechanically ventilated patients, including ARDS (acute respiratory distress syndrome), acute renal injury, and one patient who sustained cerebral anoxic encephalopathy. None of the patients died.Analysis of a subgroup of comparison patients admitted from June 1, 2021, to December 21, 2021, showed 22 adolescents admitted to intensive care units at both geographic locations (12 in NJ and 10 in Iowa). Initial data from the subgroup shows the emergence of a new picture as compared with the main period. ICU admissions and respiratory failure occurred mostly in unvaccinated, obese, and minority (mostly black) adolescents.Our study describes the epidemiology of severe SARS-COV-2 infection based on the presence or absence of respiratory failure during the period March 2020 to October 2020 in the adolescent population at two different geographic locations in the Northeastern and Midwestern United States. Additionally, we conducted a subgroup analysis of patients admitted to both centers following vaccination approval and availability for patients \u2265 12 years old .More than 75% of adolescents in our study were admitted with pneumonia, and a large proportion developed respiratory failure. Overall, a greater proportion of black African American patients developed respiratory failure. Morbid obesity posed a significant risk factor for developing respiratory failure. Two or more comorbidities including diabetes mellitus and pre-existing respiratory disease also were significant risk factors for developing respiratory failure. Our study shows a correlation between body habitus, and other comorbid factors that affect respiratory function placing older children and adolescents at high risk for complicated COVID-19 with respiratory failure. Current data, from the 2017\u20132018 National Health and Nutrition Examination Survey (NHANES), shows that 19.3% of U.S. children and adolescents are obese with the adolescent age group accounting for the highest rates at 21.2% . Our stuWhile adolescents may represent a small fraction of SARS-COV-2 hospitalization, significant illnesses needing ICU care can occur. Adolescents in our study were severely affected and a large proportion of those with respiratory failure needed MV.Inflammatory markers like IL-6 and CPK were > 15 times elevated in the respiratory failure group. Patients with respiratory failure had significantly higher values of inflammatory markers portending a poor prognosis and the majority of patients with MV had complications. None of our patients died. Utilization of available COVID-19 therapeutics was greater in the respiratory failure group according to NIH guidelines at the time, and steroids were most commonly used. Additional analysis was done after availability of vaccines and showed that the majority of adolescents that were admitted to the ICU and all of those developing respiratory failure were unvaccinated and obese. Our results thus show that there is a need for encouraging the vaccination of adolescents at all levels. Additionally, other preventive measures including management of obesity as mentioned above, as well as, consideration for passive immunoprophylaxis need to be encouraged as well.The medical community has been radically changed in terms of pandemic possibilities and the potential for new threatening trends. Adults typically bear the weight of most trends. Early prevention intervention in adolescents may be the next great move to curb disease complications.Adolescents during the initial wave were severely affected, and a large proportion had respiratory failure and needed MV. Evaluation of recent trends shows that unvaccinated minority adolescents who are obese remain at risk for respiratory support and would benefit from targeted efforts to promote vaccinations. Additionally, this group should be considered for COVID-19 passive immune therapy and therapeutics to prevent complications. As COVID-19 rages on with its changing epidemiology and variants surge all across the globe, preventive interventions in adolescent health would play a central role in promoting adolescent as well as adult health See ."}
+{"text": "Background: Infection prevention and control (IPC) is key (1) to keeping health workers and patients safe from contracting infections during care, (2) to enabling continuity of essential health services, and (3) to pandemic preparedness and response. Frontline health workers are at 3-fold increased risk for COVID-19 (Lancet 2020) and account for 6% of COVID-19 hospitalizations (CDC 2020). With the support of the US Agency for International Development Bureau of Humanitarian Assistance (USAID/BHA) and collaboration of the Haitian Ministry of Health (MSPP), MSH\u2019s Rapid Support to COVID-19 Response in Haiti project (RSCR Haiti) developed an instrument to assess select public hospitals and identify IPC gaps that informed COVID-19 response and system strengthening measures for increasing patient and provider safety. Methods: The IPC tool contains 13 IPC domains and 80 questions, for a total of 600 points. It was developed based on the World Health Organization IPC Assessment Framework for Health Facilities (2018) and US Centers for Disease Control Facility Readiness Assessment for COVID-19 (2020). In total, 39 health facilities chosen by the MSPP across all 10 departments of Haiti were evaluated in October 2020. Data were analyzed in Microsoft Excel by category, site, and IPC capabilities then classified as inadequate, basic, intermediate or advanced. Results: IPC capabilities scored as inadequate in 18% and basic in 67% of hospitals (Graph 1). No institution was advanced. Among health facilities, IPC programs existed in only 18%; IPC guidelines or procedures were present in 38%; staff were trained regularly in 12%; and healthcare-associated infection surveillance was performed in 19%. Systems for COVID-19 triage existed in 56%; 39% had IPC commodity management systems; 45% provided COVID-19 training; 26% practiced monitoring of staff and patients for COVID-19; 36% had protocols for an influx of COVID-19 cases; and 72% practiced risk communication  is key  to keepiFunding: United States Agency for International Development Bureau of Humanitarian Assistance (USAID/BHA)Disclosures: None"}
+{"text": "Enterobacteriaceae is a growing concern. Identifying and monitoring resistance in isolates from human-related environments are of clinical and epidemiological significance in containing antimicrobial resistance. This study aimed to contribute towards the fight against antibiotic resistance and ameliorate the management/treatment of Enterobacteriaceae-linked diseases in Cameroon.  The emergence of multidrug-resistant food-borne pathogens of animal origin including  Cloacal swabs from healthy broilers were enriched in buffered-peptone-water and cultured on EMB agar. Antibiotic susceptibility was tested on Mueller-Hinton-Agar by disc diffusion. Plasmid-borne genes for extended-spectrum beta lactamase (ESBL) and resistance to Quinolones (PMQR) and Aminoglycosides were detected by standard endpoint polymerase chain reaction (PCR). Enterobacteriaceae genera, the most prevalent were Escherichia coli (81/394\u2009=\u200920.56%), Salmonella spp (74/394\u2009=\u200918.78%), and Klebsiella spp (39/394\u2009=\u20099.90%) respectively. Overall, 84/394 (21.32%) were ESBL producers, 164/394 (41.62%) were resistant to quinolones, 66/394 (16.75%) resistant to aminoglycosides with 44.0% (173/394) expressing MDR phenotype. Poor hygiene practice  and rearing for >45 days,  were associated with increased carriage of MDR. Plasmid-borne resistance genes were detected in 76/84 (90.48%) of ESBL-producing isolates, 151/164 (92.07%) quinolone resistant isolates and 59/66 (89.39%) aminoglycoside resistant isolates with co-occurrence of two or more genes per isolate in 58/84 (69.05%) of ESBLs, 132/164 (80.49%) of quinolone resistant isolates and 28/66 (42.42%) of aminoglycoside resistant isolates.  A total of 394 isolates were identified belonging to 12 Enterobacteriaceae with ESBL and MDR in broiler chicken in the West Region of Cameroon. Most PMQR genes in bacteria were found at levels higher than is seen elsewhere, representing a risk in the wider human community. This study found high carriage and widespread distribution of  Enterobacteriaceae is a heterogeneous Family of Gram negative non-spore forming bacilli which primarily live in guts of humans and other higher animals where they can be pathogens or members of the normal intestinal microflora but are also widely distributed in soil, water, and decaying matter  compared to third generation Cephalosporins [79/394 (20.1%) for ceftriaxone and 65/394 (16.5%) for cefotaxime], and Aminoglycosides [12/394 (3.1%) for amikacin and 58/394 (14.5%) for gentamicin]. Compared to early reports such as that of Robert et al. 2001  may go unchecked but in the face of an opportunistic infection, the treatment becomes difficult due to the developed MDR  can be explained in two ways: first, it may be that the plasmid-borne resistance gene responsible for the resistance phenotype was not tested since the genes tested were not exhaustive; second, it may be that other genetic mechanisms than plasmid mediation such as chromosomal encoded resistance and chromosomal mutations may be responsible [In this study, we detected plasmid-borne resistance genes to all the three drug classes of choice used against blaTEM1 59/84 (70.24%), blaCTX-M 19/84 (22.62%) and blaKPC 30/84 (35.71%) of the TEM, CTX and KPC enzyme families in isolates. These are genes for Class A beta lactamase enzymes which are highly disseminated among important Enterobacteriaceae pathogens. This is an indication of the risk of their further dissemination and the resistance they confer owing to their occurrence in MGEs and also their ability to expand their spectrum of activity as new antibiotics are developed especially by shuffling of chromosomal genes and mutations [We observed a high prevalence of the beta lactamase genes 19/84 22.% and blaqnrA 65/164 (39.63%) and qnrB 34/164 (20.73%). These are clinically important genes to monitor in epidemiological studies because of their enrichment in human-associated environments, mobility, and presence in pathogens [aac(6\u2032)-IB-CR gene 97/164 (59.15%), though a low level mediator of resistance to ciprofloxacin [qnrS gene 86/164 (51.83%) tie with the high resistance to this antibiotic 142/394 (37.1%) recorded in this study. Worth noting is also the prevalence of the efflux pump mediator gene qepA which though being relatively lower, 32/164 (19.51%) is high compared to those recorded in other geographical locations with 0% recorded by Cr\u00e9met et al. in a French hospital [qnrS and qepA as low risk gene due to their low dissemination in clinical and human-related environment [aac(6\u2032)-IB gene coding for an N-acetyltransferase is the most clinically important gene to monitor in epidemiological studies because of its enrichment in human-associated environments, mobility, and presence in pathogens [aac(6\u2032)-IB-CR gene 97/164 (59.15%), responsible for PMQR. However, the aph(3\u2032)-IA and the ant(2\u2032)-IA genes considered non-epidemiologically important because of their previous low enrichment in human-related environment and pathogens [aph(3\u2032)-IA and 14/66 (21.21%) for ant(2\u2032)-IA. This indicates that these genes are gradually being enriched in the community and there is need to curb their further dissemination.In this study we equally noted a high occurrence of the quinolone resistance genes 5/164 39.% and qnrhospital ; and 0.3hospital . Though 5/164 39.% and qnr5/164 39.% and qnrathogens . This ge5/164 39.% and qnrThese ESBL, PMQR and PMAR genes have also been isolated from human pathogens showing a generalised circulation between humans and animals , 56, 69.Molecular methods such as the DNA microarray have been developed to simultaneously detect microbes in pathologic samples . It woulEnterobacteriaceae showing phenotypic resistance with corresponding plasmid-borne resistance genes, a widespread and a fairly uniform distribution among broilers in poultry farms across the study area. Enterobacteriaceae from chicken in this Region showed high resistance to Penicillins and Tetracyclines and low resistance rates to 3rd generation Cephalosporins and Aminoglycosides. Poor hygienic conditions at poultry farms and rearing chicken for long periods were associated with increased carriage of multi drug resistant Enterobacteriaceae. Plasmid-mediated genes for ESBL production, quinolone resistance and aminoglycoside resistance were extensively distributed in both pathogenic and commensal Enterobacteriaceae with high co-occurrence of the genes in the isolates. The high prevalence of MDR especially in clinically important genera like Salmonella, Escherichia and Klebsiella indicates the necessity for continuous monitoring and for stakeholders to put efforts and resources to improve sanitation at poultry farms and combat resistance development and misuse of antibiotics in animal farms.This study showed a high carriage of"}
+{"text": "Efficacy of telemedicine for stroke was first established by the Stroke Team Remote Evaluation Using a Digital Observation Camera (STRokE DOC) trials in California and Arizona. Following these randomized controlled trials, the Stroke Telemedicine for Arizona Rural Residents (STARR) network was the first telestroke network to be established in Arizona. It consisted of a 7 spoke 1 hub telestroke system, and it was designed to serve rural, remote, or neurologically underserved communities.The objective of STARR was to establish a multicenter state-wide telestroke research network to determine the feasibility of prospective collection, recording, and regularly analysis of telestroke patient consultations and care data for the purposes of establishing quality measures, improvement, and benchmarking against other national and international telestroke programs.The STARR trial was open to enrollment for 29 months from 2008 to 2011. Mayo Clinic Hospital, Phoenix, Arizona served as the hub primary stroke center and its vascular neurologists provided emergency telestroke consultations to seven participating rural, remote, or underserved spoke community hospitals in Arizona. Eligibility criteria for activation of a telestroke alert and study enrollment were established. Consecutive patients exhibiting symptoms and signs of acute stroke within a 12\u2009h window were enrolled, assessed, and treated by telemedicine. The state government sponsor, Arizona Department of Health Services' research grant covered the cost of acquisition, maintenance, and service of the selected telemedicine equipment as well as the professional telestroke services provided. The study deployed multiple telemedicine video cart systems, picture archive and communications systems software, and call management solutions. The STARR protocol was reviewed and approved by Mayo Clinic IRB, which served as the central IRB of record for all the participating hospitals, and the trial was registered at ClinicalTrials.gov.The telestroke hotline was activated 537 times, and ultimately 443 subjects met criteria and consented to participate. The STARR successfully established a multicenter state-wide telestroke research network. The STARR developed a feasible and pragmatic approach to the prospective collection, storage, and analysis of telestroke patient consultations and care data for the purposes of establishing quality measures and tracking improvement. STARR benchmarked well against other national and international telestroke programs. STARR helped set the foundation for multiple regional and state telestroke networks and ultimately evolved into a national telestroke network.Multiple small and rurally located community hospitals and health systems can successfully collaborate with a more centrally located larger hospital center through telemedicine technologies to develop a coordinated approach to the assessment, diagnosis, and emergency treatment of patients manifesting symptoms and signs of an acute stroke syndrome. This model may serve well the needs of patients presenting with other time-sensitive medical emergencies.Clinical Trial Registration number: NCT00829361. It was designed to serve rural, remote, or neurologically underserved communities.Efficacy of telemedicine for stroke was first established by the sequentially conducted Stroke Team Remote Evaluation Using a Digital Observation Camera (STRokE DOC) trials in California and Arizona.The original Arizona telestroke network recently celebrated its 10th year anniversary inspiring a look back at the original but unpublished data and a look forward at all the subsequent developments built on the network's foundational learning.The STARR network registry consisted of a 7 spoke 1 hub telestroke system and its objective was to prospectively collect, record, and regularly analyze telestroke patient consultations and care data for the purposes of establishing quality measures, improvement, and benchmarking against other national and international telestroke programs.5STARR, a prospective, single-arm, multicenter trial, was open to enrollment from October 24, 2008 to March 31, 2011 . Mayo Clinic Hospital, Phoenix, Arizona served as the hub primary stroke center and its vascular neurologists provided emergency telestroke consultations to seven participating rural, remote, or underserved spoke community hospitals in Arizona. Refer to Eligibility criteria for activation of a telestroke alert and study enrollment were: adult (age \u226518 years), suspicion of an acute stroke syndrome by emergency medical services (EMS) and emergency department (ED) triage, objective signs of focal neurological deficits on ED arrival, Cincinnati Prehospital Stroke Scale score of \u22651, and time window since onset or since last known to be at baseline state was 12\u2009h. Exclusion criteria were: inability to obtain consent and incarceration.The seven participating spoke hospitals included Copper Queen Community Hospital , Verde Valley Medical Center , Flagstaff Medical Center , Kingman Regional Medical Center , La Paz Hospital , Maricopa Integrated Health System , and Yuma Regional Medical Center . The distances between the hub and the closest and farthest spoke hospital were 21 and 236 miles, respectively (34 and 380 kilometers). The bed capacity of the spoke hospitals ranged between 25 and 449 Refer to .The hub telestroke consultation team included five American Board of Psychiatry and Neurology ABPN-certified vascular neurologists, one American College of Graduate Medical Education (ACGME) vascular neurology fellow, and one Neurovascular Education and Training in Stroke Management and Acute Reperfusion Therapies (NET-SMART) graduate vascular neurology nurse practitioner who were supervised by a vascular neurologist. The telestroke service operated 24/7/365.6Each spoke hospital's regional EMS providers, ED physicians, nurses, hospitalists, intensivists, radiologists/teleradiologists, radiology technologists, pharmacists, laboratory technologists, and information technologists received telemedicine orientation and training, in addition to acute stroke education. The hub personnel helped the spoke personnel to learn how to conduct the National Institutes of Health Stroke Scale (NIHSS) and to adopt a uniform stroke alert system, acute stroke care algorithm, and common paper or electronic acute stroke order sets, which adhered to the applicable American Heart Association/American Stroke Association (AHA/ASA) guidelines at the time of the study.Members of the Mayo Clinic hub telestroke team  nurse, Information Technology (IT), and clinical research coordinator) spent a minimum of 2 days at each spoke hospital campus before go-live and at least one day annually thereafter for ensuring telestroke skill maintenance and for providing acute stroke continuing medical education.Every hub vascular neurologist was licensed in the state of Arizona and underwent credentialing, privileging, and requisite annual telemedicine practice peer reviews specified by each of the participating spoke hospitals. A standard telestroke service line contract agreement was signed by hub and spoke hospital officials. The state government sponsor, ADHS research grant covered the cost of acquisition, maintenance, and service of the selected telemedicine equipment as well as the professional telestroke services provided. During the study interval, spoke hospitals did not pay the hub hospital an annual subscription fee. Professional reimbursement for each telestroke consultation was not sought from government or nongovernment payers during the study period.The STARR algorithm began with community emergency medical services (EMS) and/or spoke hospital ED personnel recognition of a possible acute stroke syndrome meeting STARR eligibility criteria (see above). Pre-hospital notification to the intended recipient hospital was triggered by EMS. The spoke ED activated a toll free telestroke hotline number, which resulted in a direct connection to either the hub on-call vascular neurologist's digital pager and/or cellular phone. No intermediate switchboard operator was positioned between the referring spoke hospital and the on-call vascular neurologist.According to the STARR protocol algorithm, the hub vascular neurologist was obligated to respond by telephone within 10\u2009min and by video telemedicine within 20\u2009min of receipt of telestroke alert activation. In the event of no telephone response in 10\u2009min, the spoke hospital re-activated the telestroke hotline and/or dialed hub hospital switchboard to be connected to the vascular neurologist on-call. These time intervals served as targets and were the subject of on-going quality assurance and quality improvement initiatives.5The STARR telestroke consultation overview, its features, suggested target time intervals, and an illustrative case has been previously published.The STARR trial protocol PR08-005156-09 was reviewed and approved by Mayo Clinic IRB, which served as the central IRB of record for all the participating hospitals. The STARR trial was registered at ClinicalTrials.gov.The equipment and software utilized in the STARR study could be grouped into three main categories: (1) telemedicine video cart systems, (2) picture archive and communications systems (PACS) software, and (3) call management solutions.Telemedicine video cart systems used as communications endpoints at spoke hospitals included BF Technologies Telemedicine Carts  and comprised Windows-based PC's running AccessVideo\u2122 software to deliver secure Health Insurance Portability and Accountability Act (HIPAA) compliant two-way audio/high resolution video over standard Ethernet dedicated Internet services. In addition, GlobalMed Pole Series Mobile Video Carts , which combined a Windows-based PC, integrated iRez i5770 pan/tilt/zoom camera, and EasyShare VC software, were used to provide secure HIPAA compliant two-way audio/video conferencing sessions at several spoke hospitals.\u00ae, and PacsOne (part of the turnkey BF Technologies Telemedicine Cart solution). The OnePacs  system stored and transmitted DICOM data that could be accessed via a web-based study viewer or locally on server-based software installed at each spoke site. ResolutionMD  enabled access to DICOM radiology images from web browsers and mobile devices by implementing proprietary U.S. Food and Drug Administration Class II accredited technology that safeguarded patient data behind the spoke hospital's firewall.PACS software implemented for access to digital imaging and communications in medicine (DICOM) files included OnePacs, ResolutionMDFinally, PacsOne, a DICOM 3.0 compliant PACS application, was implemented in conjunction with all BF Technologies Telemedicine Cart installations. Lastly, RingCentral , a cloud-based communications solution, was used to automatically direct incoming telestroke alert calls from spoke hospitals to the on-call vascular neurologist's digital pager and/or cellular phone based on pre-programmed daily schedules.Summary statistics were calculated for each variable.The telestroke hotline was activated 537 times by participating spoke hospitals during the study period. For 68.2% (302/443) of subjects, the precise date and time of stroke symptom onset was discoverable and documented and for the remainder it was unknown. In 14.2% (63/443) of instances, the subject awoke from sleep with their neurological deficit. The mode of arrival at spoke hospital ED was ground ambulance in 65.7% (291/443), air ambulance in 0.5% (2/443), private automobile in 33.4% (148/443), in-patient in 0.2% (1/443), and not documented in 0.2% (1/443). The first documented blood pressure values were 151\u2009mm Hg median systolic  and 87\u2009mm Hg median diastolic .Five vascular neurologists participated in the study, with a range of individual contributions. In descending order, vascular neurologists contributed 180, 102, 80, 72, and 9 of the 443 subjects' telestroke consultations during the study. For 40 out of 443 (9.0%) an ACGME vascular neurology fellow and in 23 out of 443 (5.2%) an NET SMART trained vascular neurology nurse practitioner contributed to the telestroke assessment under direct vascular neurology supervision.Subject demographics include median age 69.1 years . Of all the subjects, 346/443 (78.5%) were non-Hispanic, 95/443 (21.5%) Hispanic, and 2/443 (0.5%) Not specified.The baseline medical history and vascular risk factors of the participating subjects included coronary artery disease in 126 out of 443 (28.4%), diabetes mellitus in 118 out of 443 (26.6%), myocardial infarction in 81 out of 443 (18.3%), hypertension in 310 out of 443 (70.0%), congestive heart failure in 34 out of 443 (7.7%), stroke in 106 out of 443 (23.9%), peripheral arterial disease in 23 out of 443 (5.2%), hyperlipidemia in 211 out of 443 (47.6%), transient ischemic attack in 58 out of 443 (13.1%), atrial fibrillation in 69 out of 443 (15.6%), obstructive sleep apnea in 22 out of 443 (5.0%), family history of stroke in 88 out of 443 (19.9%), current smoking in 104 out of 443 (23.5%), smoking history in 207 out of 443 (46.8%), current alcohol consumption in 160 out of 443 (36.1%), and alcohol history in 195 out of 443 (44.0%).The medication use of the participating subjects included anticoagulant in 30 out of 443 (6.8%), antiplatelet in 237 out of 443 (53.4%), lipid-lowering medication in 176 out of 443 (39.7%), anti-hypertensive medication in 272 out of 443 (61.4%), and hypoglycemic medication in 94 out of 443 (21.2%).Urine pregnancy and drug toxicology screens were ordered by clinical investigator staff only when they were felt to be indicated. Urine pregnancy tests were ordered in 11 subjects, and all were negative. Urine drug toxicology screens were ordered in 76 out of 443 (17.2%) and of those ordered, 22 out of 76 (28.9%) were positive.Subjects' pre-stroke Modified Rankin Scale score mean and standard deviation (SD) was 0.5 (1.0) with a range of 0 to 4, Modified Rankin Scale score at ED presentation mean and SD was 2.8 (1.5) with a range of 0 to 5, and NIHSS score mean (SD) at presentation was 8.1 (8.4) with a range of 0 to 40.Non-contrast computed tomography (NCCT) head studies were acquired in all subjects and interpreted independently by a local spoke hospital radiologist and hub teleneurologist in 315 out of 443 (71.1%) and exclusively by the local spoke hospital radiologist in 128 out of 443 (28.9%). The overall quality of the scans was determined to be excellent in 347 out of 443 (78.3%), fair but interpretable in 17 out of 443 (3.8%), and quality not assessed in 79 out of 443 (17.8%). The NCCT was judged to be abnormal in 260 out of 443 (59.1%).Radiologic evidence of an acute stroke was reported in 92 out of 443 (20.8%), chronic stroke in 199 out of 443 (44.9%), and signs of edema present in 14.6% , hyperdense artery signs in 17.8%, intracerebral hemorrhage in 8.1% , subarachnoid hemorrhage in 4.2%, acute subdural or epidural hematoma in 1.2%, intracranial neoplasm in 1.9%, cerebral atrophy in 29.2%, aneurysm clip in 0.4%, cyst in 0.4%, shunt in 1.2%, evidence of previous craniotomy in 2.3%, hydrocephalus in 0.8%, vertebral basilar dolichoectasia in 0.8%, parenchymal calcium deposition in 3.8%, and chronic small vessel ischemic changes in 28.8%.Radiologic contraindications to intravenous thrombolysis were identified in 17.4% of NCCTs. Mean (SD) ASPECT score was 9.7 (0.9).In 291 out of 443 subjects (65.7%), the onset of the stroke was witnessed by a family member, friend, companion, or bystander who accompanied the subject to the ED. During the telestroke consultations, the neurologists obtained information regarding the subject's history from the patient directly (323/443 (72.9%)), a family member (303/443 (68.4%)), a companion (32/443 (7.2%)), an ED nurse (282/443 (63.7%)), an ED physician (328/443 (74.0%)), an ED resident (37/443 (8.4%)), and/or other (14/443 (3.2%)).Neurologists received telepresenter bedside assistance with their telemedicine examination of the subject in the ED by the ED nurse (376/443 (84.9%)), ED physician (89/443 (20.1%)), ED resident (27/443 (6.1%)), mid-level practitioner (1/443 (0.2%)), family member or companion (66/443 (14.9%)), and/or other (20/443 (4.5%)).The telestroke consultations began in 437 out of 443 (98.6%) subjects and they were successfully completed in 430 out of 443 (97.1%) subjects. The 7 telestroke consultations that started but could not be completed each failed due to an Internet connectivity issue, which could not be immediately rectified.In 254 out of 443 (57.3%) of the subjects' telestroke consultations, a technical observation arose. Of all the subjects' consultations with technical observations, 44.1% included an audio problem, 48.8% included a video problem, 51.6% included a radiology problem, 20.5% included an Internet connection problem, and 11.8% included a problem not otherwise classified. Of the 254 subjects' consultations with technical observations, 181 out of 254 (71.3%) had no effect on clinical diagnosis and decision making, 69 out of 254 (27.2%) delayed clinical diagnosis and decision making, and only 4 out of 254 (1.6%) prevented a clinical diagnosis and/or decision making from occurring.The technology deployed during the consultations included the telephone in 435 out of 443 (98.2%), BF Technologies (BFT) audio video in 297 out of 443 (67.0%), BFT DICOM in 297 out of 443 (28.0%), Global Med audio video in 103 out of 443 (23.3%), iPhone Calgary Scientific in 98 out of 443 (22.1%), OnePACS teleradiology in 84 out of 443 (19.0%), Computer PACSone in 82 out of 443 (18.5%), iPhone PACSone in 17 out of 443 (3.8%), and other in 4 out of 443 (0.9%). The most frequently preferred sequence of technology deployment during telestroke consultations was first telephone communication, second audio video telemedicine connection, and third teleradiology access.After the telestroke consultations, the ED admitting diagnoses were ischemic stroke with administration of intravenous (IV) alteplase in 100 out of 443 (22.6%), ischemic stroke without IV alteplase administration in 170 out of 443 (38.4%), transient ischemic attack in 30 out of 443 (6.8%), intracerebral hemorrhage in 21 out of 443 (4.7%), subarachnoid hemorrhage in 2 out of 443 (0.5%), non-cerebrovascular related in 59 out of 443 (13.3%), and unknown in 61 out of 443 (13.7%).The CTA head and neck studies were conducted in 99 out of 443 (22.3%). In 36 out of 99 (36.4%), an arterial occlusion was observed; in ICA, 22 out of 99 (22.2%), MCA-M1 11 out of 99 (11.1%), MCA-M2 6 out of 99 (6.1%), ACA 3 out of 99 (3.0%), Basilar 1 out of 99 (1.0%), and PCA 0 out of 99 (0%). The magnetic resonance angiography head and neck studies were conducted in 206 out of 443 (46.5%) and 51 out of 443 (11.5%), respectively. Carotid ultrasound studies were conducted in 235 out of 443 (53.0%), echocardiogram trans-thoracic studies in 197 out of 443 (44.5%), and trans-esophageal in 52 out of 443 (11.7%).Magnetic resonance imaging (MRI) brain studies were conducted in 307 out of 443 (69.3%) and in 108 out of 307 (58.6%) a clinically relevant acute ischemic stroke was identified. The NCCT studies were conducted within 48\u2009h post-stroke in 134 out of 443 (30.2%), and a clinically relevant acute ischemic stroke was identified in 72 out of 134 (53.7%). Mean (SD) ASPECT score was 7.9 (3.0) with range 0\u201310. Hyperdense MCA sign was identified in 27 out of 134 (20.1%) of the NCCT studies.The IV alteplase was administered to 100 out of 443 (22.6%) of the subjects in the study. Post-thrombolysis, any intracerebral hemorrhage was detected in 12 out of 100 (12.0%), symptomatic ICH in 5 out of 100 (5.0%), and asymptomatic ICH in 7 out of 100 (7.0%). ECASS HI-1 was detected in 2 out of 12 (16.7%), HI-2 in 1 out of 12 (8.3%), PH-1 in 3 out of 12 (25.0%), and PH-2 in 5 out of 12 (41.7%). The outcomes post-SICH were 4 out of 12 (33.3%) complete recovery, 5 out of 12 (41.6%) recovery with sequelae, and 3 out of 12 (25.0%) fatal. Major systemic bleeding occurred in 2 out of 100 (2.0%) of subjects receiving IV alteplase, and hemilingual angioedema occurred in 1 out of 100 (1.0%).Follow-up brain imaging studies confirmed the presence of an acute ischemic stroke in 233 out of 443 (52.6%) of subjects overall.Etiologies of the ischemic stroke were classified by TOAST criteria as follows: Large Artery Atherosclerosis 11.8%, Cardioembolic 48.1%, Small Vessel (Lacunar) 17.5%, Stroke of Other Determined Etiology 3.0%, and Stroke of Undetermined Etiology 19.5%.Interventions of any kind occurred in 36 out of 443 (8.1%) of the subjects. The interventions were (arranged from most to least frequent) other 23, craniotomy for ICH evacuation 4, Inferior Vena Cava filter placement 4, carotid angioplasty and stenting 3, decompressive hemicraniectomy 3, cardiac catheterization 3, carotid endarterectomy 2, endovascular thrombectomy 2, and intracranial aneurysm coiling 1 (note some subjects had \u22651 intervention).Subjects' disposition status after ED assessment was 312 out of 443 (70.4%) admitted to Spoke Facility (Originating Site) and 131 out of 443 (29.6%) transferred from Spoke Facility (Originating Site). Of those subjects transferred from Spoke Facility to another facility, 29% were transferred to Mayo Clinic Hospital Stroke Center in Phoenix and 71% were transferred to another regional stroke center. The units to which the subjects were admitted were 103 out of 443 (23.3%) intensive care unit (ICU), 199 out of 443 (44.9%) Medical-Surgical Telemetry Unit, 41 out of 443 (9.3%) Discharged home, 4 out of 443 (0.9%) deceased, and 96 out of 443 (21.7%) Other/Unclassified.The 90-day follow-up was conducted by neurology nurse research coordinators directly with subjects by telephone whenever feasible, by delegated caregivers or family members whenever necessary, and supplemented by paper and electronic medical records from health care providers. A 90-day follow-up was successfully conducted for 310 out of 443 (70.0%) of subjects. The subjects' 90 days Modified Rankin Score and Barthel Index Score are presented in Place of residence, for those subjects with 90 days follow-up, was distributed as follows: House/Apartment (independent) 64.0%, House/Apartment (dependent) 28.6%, Nursing Home/Extended Care Facility 2.8%, Assisted Living Facility 1.1%, Rehabilitation Facility 3.2%, and Other not classified 0.3%. The living status in those subjects with 90-day follow-up data was 91.6% alive, 8.4% deceased.As specified at the beginning of this article, the original Arizona telestroke network celebrated its 10th year anniversary in 2021, inspiring inspection and publication of the original trial data, assessment of how successfully the original objectives were met, recognizing all the subsequent developments built on the network's foundational learning, and taking a glance forward to the future.The STARR trial objective was to assess the feasibility of prospective collection, recording, and regularly analyzing telestroke patient consultations and care data for the purposes of establishing quality measures, improvement, and benchmarking against other national and international telestroke programs.8The success of STARR included the recruitment of multiple disparate and geographically separated rural and remote hospitals to collaborate in a novel state-wide government funded digital health research study, development of telestroke service contracts, utilization of a centralized IRB for telemedicine research, adoption of a hybrid of in-person and virtual research trial teaching, learning, and ongoing communication as well as trial coordination, utilization of an evidence-based pragmatic telestroke clinical algorithm across the network, documentation of standardized data entry fields for telestroke clinical care and research, incorporation of stroke specialty trained fellows and nurse practitioners into telestroke practice and research, deployment and evaluation of a multitude of telemedicine technologies in a single trial, and acquisition of complete data through to the conclusion of subjects' hospitalization for stroke despite operating within different electronic medical records.A weakness in STARR is the 133 out of 443 (30%) of subjects for whom 90-day follow-up data could not be determined. This was anticipated to be a potential issue given that subjects were generally residing in remote and rural communities in the state: Some were non-residents, some were vacationers, some were homeless, and some reported no permanent address.9 Sixty one (FIN) and 100 (STARR) acute ischemic stroke subjects, respectively, had already received IV alteplase in the first 2 years of the programs. Mean age was comparable: 70 (FIN) and 69 (STARR). Fifty-one percent (FIN) and 50% (STARR) female, median and range of subjects' NIHSS were 10 and 3\u201326 (FIN) and 8 and 0\u201340 (STARR).The STARR network was very much comparable to the Finnish telestroke network (FIN) for benchmarking, as each was at the 2 years mark in 2011.Telestroke consultation duration was nearly identical, 25\u2009min (FIN) and 24\u2009min (STARR). Mean onset to treatment time and SD was 130 and 45\u2009min (FIN) and 165 and 45\u2009min (STARR). The proportion of telestroke patients who received IV alteplase was higher (61/106 (57.5%)) in Finland and relatively lower (100/443 (22.6%)) in STARR. However, a higher percentage of patients in FIN versus STARR had acute ischemic stroke versus non-cerebrovascular diagnoses. If one looked at the proportion of STARR patients with ischemic stroke who received IV alteplase, the result was 100 out of 234 (42.7%), which was more similar to FIN experience.Symptomatic intracranial hemorrhage post-thrombolysis was similar between these networks (6.7% (FIN) and 5.0% (STARR)). In hospital or end-of-stay mortality was 9.8% (FIN) and 8.4% (STARR). Forty-nine percent (FIN) and 56% (STARR) of telestroke patients had a favorable outcome.Reasons to withhold IV alteplase were similarly reported across the two trials: mild or quickly resolving symptoms 49% (FIN), 45% (STARR), stroke <3 months 4% (FIN), 3% (STARR), dependent for activities of daily living (mRS >2) 4% (FIN & STARR), NIHSS >25 in 4% (FIN & STARR), intracranial hemorrhage on computed tomography (CT) 4% (FIN), 5% (STARR), INR >1.7 in 2% (FIN), 3% (STARR), history of diabetes and previous stroke 2% (FIN), 8% (STARR), uncontrolled hypertension 4% (FIN), and 7% (STARR).However, the trials differed in their respective reporting of etiologies other than stroke, resulting in withholding of IV alteplase 15% (FIN) and 37% (STARR) and symptom onset >3\u2009h in 9% (FIN) and 26% (STARR), which may reflect trial differences in telestroke alert activation criteria and any pre-consultation screening protocols.11The NCCT head studies were acquired in all subjects and interpreted independently by a local spoke hospital radiologist and hub teleneurologist in 315 out of 443 (71.1%) and exclusively by the local spoke hospital radiologist in 128 out of 443 (28.9%).When STARR is compared against a nationally agreed-on minimum data set of variables designed to evaluate new and existing telestroke networks and services, STARR achieved 14 out of 16 (88%) Suggestions for Measuring Telestroke Processes , 23 out of 28 (82%) Suggestions for Measuring Telestroke Outcomes .12STARR achieved 2 out of 6 (33%) Suggestions for Measuring Patient and Provider Satisfaction , and 11 out of 12 (92%) Suggestions for Monitoring Telestroke Technology Quality .13When STARR is compared against an internationally agreed-on minimum data set of variables designed to evaluate new and existing telestroke networks and services, STARR achieved 12 out of 12 (100%) Details about Telestroke Program/Network, 10 out of 10 (100%) Details about Initiating Hospital, 17 out of 17 (100%) Telestroke Consultation, 5 out of 7 (71%) Patient Characteristics , 5 out of 5 (100%) Presentation to hospital, 10 out of 10 (100%) General clinical care within first 24\u2009h, 10 out of 10 (100%) Thrombolysis treatment, 13 out of 13 (100%) Endovascular treatment, 8 out of 8 (100%) Neurosurgery treatment, 7 out of 7 (100%) Processes of care beyond the first 24\u2009h, 5 out of 5 (100%) Discharge information, and 6 out of 6 (100%) Post-discharge and follow-up.15 Simultaneous use of multiple telemedicine vendor technologies has given way to the selection of a single highest performing vendor.14Based on the preliminary learning from the STARR trial and contributions from other national and international pioneers in telestroke, there have been many advancements and developments in Mayo Clinic telestroke and acute care telemedicine in general. Regionally focused telestroke networks at Mayo Clinic have converged into one enterprise-wide national telestroke network.16 Disparate and variable oversight, management, operations, and administration have yielded to a centralized medical and administrative leadership structure and commonly used evidence-based management guidelines.17 Sporadic and episodic data collection has given way to continuous quality assurance and quality improvement according to national and international criteria.13Small teams of telestroke doctors stretched to their limits have ultimately collaborated in a single large deep pool of telestroke doctors, each suitably trained, licensed, and credentialed in multiple states and health systems.19 Data from original telestroke networks have made health economic analyses possible.20\u201323 Prehospital telemedicine enabled ambulances and mobile stroke units complement the work of hospital-based telestroke networks.24 Since the learnings of 500 telestroke subjects in STARR, more than 32,000 telestroke patients have been assessed and treated at Mayo Clinic, enterprise wide.Telemedicine training programs for students, residents, fellows, and advanced practice providers are routinely available.25\u201335 Other multicenter national and international acute care telemedicine research consortiums have developed and are conducting feasibility and efficacy trials.32 Telestroke has matured beyond its original focus in the ED and now exists across the continuum of care.37 The telemedicine network's existence, maturity, and stability helped greatly during the coronavirus disease 2019 (COVID-19) pandemic and eased the stress endured by our health care system.38\u201340Telestroke has helped spawn acute care telemedicine in various other acute care clinical domains, including hospital neurology, neurosurgery, neurocritical care, sports concussion, emergency psychiatry, emergency medicine, pediatrics, neonatology, obstetrics, and gynecology to name a few.The emergence, success, and early learnings of a state-wide telestroke research network in a health care institution helped inform the development of larger multistate and national telemedicine networks as well as the extension of the acute care telemedicine model into other time-sensitive clinical care domains.All authors meet authorship criteria, have approved this article, and can take responsibility for all or part of the data."}
+{"text": "Treatment of skin and soft tissue infections (SSTIs) are a growing reason for Emergency Department (ED) visits. Inadequate treatment of SSTIs has been reported in up to 25% of patients treated in ED. The purpose of this project was to describe prescribing patterns for SSTIs from the ED.Single center retrospective cohort study of SSTI patients discharged from ED between July 1- December 31, 2020. The primary outcome was to describe the proportion of patients receiving guideline directed therapy (GDT) for SSTIs. Secondary outcomes include describing the proportion of patients readmitted within 30 days, the reason for readmission, and to compare 30-day readmission rates in patients who received GDT versus non-GDT.Of 876 patients screened, 576 were excluded primarily for being admitted to the hospital. Of the 300 included patients, 117 (39%) received GDT and 183 (61%) received non-GDT. Fifty-six of 300 patients were readmitted within 30 days, of which 21 (17.9%) had received GDT and 35(19.1%) had received non-GDT (p=0.8). Readmissions related to persistence or progression of SSTI were not significantly different between GDT and non-GDT, 9 patients and 11 patients respectively (p=0.57). The remaining 36 patients (64.3%) were readmitted for reasons unrelated to SSTI.The majority of prescribed antibiotic therapy for SSTI did not conform to GDT. However, 30-day readmission rates were not significantly different between the groups. Further research on GDT and ED treated SSTI is needed.All Authors: No reported disclosures."}
+{"text": "Non-tuberculous mycobacteria (NTM) cause a wide variety of clinical syndromes, including extra-pulmonary infections. Skin and soft tissue infections (SSTI) and bone infections caused by NTM are often associated with traumatic inoculation and data to guide diagnosis and treatment is limited. We sought to better understand skin and soft tissue infections (SSTI) and bone infections caused by NTM.All NTM clinical isolates recovered at Brooke Army Medical Center from 2012-2022 were initially screened and SSTI and bone isolates were included. Corresponding electronic health records were reviewed for epidemiologic, microbiologic, and clinical data. Infections were defined as recovery of \u2265 1 NTM isolate from skin, soft tissue, or bone cultures with a corresponding clinical syndrome.M. abscessus. In infected patients, 8 (38%) had combined medical/surgical therapy, 8 (38%) had surgery alone, 4 (19%) had medical therapy alone, and 1 (5%) patient received no treatment. No infectious disease consultation was sought for 7 (87.5%) patients who received only surgery nor for the patient who received no treatment. Time from symptom onset to isolate recovery was a median of 64 days (IQR 48-108), with a median of 33 days (IQR 6-60) from isolate recovery to directed medical therapy. At the end of the study period 2 of 21 patients had died.Forty isolates from 27 corresponding patients were analyzed with a median of 1 isolate [IQR 1-1] per patient. Two-thirds  were female with a median age of 51 years . A total of 21 (78%) patients had infecting isolates, most commonly secondary to surgery (28.6%) or trauma (33%). Six of 21 (29%) had bone infections, 5  were secondary to trauma, and 2  had both bone and SSTI isolates recovered. The majority were rapid growers (81%), most frequently Data supporting diagnosis and treatment decisions in SSTI and bone NTM infections is sparse. In this study the majority of NTM isolated were determined to be the cause of true infections. We confirm that surgery and trauma are the most common mechanisms of exposure. The delay between symptom onset and directed therapy demonstrates a need for additional studies delineating specific criteria for diagnosis and treatment.All Authors: No reported disclosures."}
+{"text": "Cerebral palsy is a major cause of neurodisability in children in Pakistan. The study aims to evaluate the risk factors, types and neuroimaging findings in children with cerebral palsy.All children diagnosed with cerebral palsy, between 1-16 years presenting to Shifa community health center were enrolled from January 2020 to July 2021. Informed consent was taken from parents.A total of 89 patients were included, 62 (69.7%) male and 27 (30.3%) females. Mean age was 4.4 \u00b1 2.8 years. Majority of babies were born at term 74 (84%) and 15 were preterm (16%). Most of the patients were born in hospital 55 (62%), 13 (14%) were born at home. Mean birth weight was 2.3 \u00b1 0.3. Consanguinity was present in 56 (62.9%). Birth asphyxia 38 (42.7%) was the most common cause of cerebral palsy. Maternal antenatal risk factors identified were anemia 13 (14.6%), PIH (9%) infections (6%) were significant risk factors (<0.05). Neuroimaging was done in 37 (38.7%) of the patients only.Male gender is more affected in our cohort. Maternal anemia, pregnancy induced hypertension and low birth weight are significant modifiable risk factors. Prevention of these can reduce the incidence of cerebral palsy. Cerebral palsy is a major cause of lifelong neurodisability worldwide.6The etiology of cerebral palsy is multifactorial.10Topographical classification of cerebral palsy is used internationally to identify the motor deficit.The motor disorders may be associated with disturbance of sensation, perception, cognition, behavior, seizures and secondary musculoskeletal problems.The aim of this study was to evaluate different types of cerebral palsy and their causative risk factors by exploring prenatal, natal and post-natal history and to correlate these findings with neuroimaging findings. There is scarcity of data on neuroimaging findings in children with cerebral palsy in Pakistan. This study will also highlight potential benefits of imaging with a focus on improving etiological understanding which may help formulating management plans for preventable causes of cerebral palsy in our country.The study was conducted in Pediatric OPD of Shifa Falahee Community Health center (SFCHC), Islamabad from January 2020 to July 2021. The community center serves mainly the underprivileged families and provides care at a very minimum fee, it also serves a large catchment area and receives referral from neighboring provinces. All children with disorders of movement, posture and tone diagnosed as cerebral palsy between 1-16 years were enrolled. Children with neuropathies, myopathies, metabolic and neurodegenerative diseases were excluded. A detailed history on antenatal, natal, postnatal events was taken on a predesigned form. Previous records were reviewed for NICU admission, need for phototherapy, exchange transfusions. In case where birth records were not available to check for APGAR scores, history of delayed cry was noted. Mode of delivery and place of delivery, gestational age at delivery and birth weight were noted. Complete neurological examination was performed to determine the clinical type of CP. Neuroimaging findings on CT/ MRI if done any time from birth to time of OPD visit were recorded. Informed written consent was taken from parents. Approval was taken from Institutional Review Board .Data was analyzed on SPSS version 23. Mean and standard deviation were calculated for quantitative variables like age, gestational age, height, and weight. For qualitative variables like gender, type of CP and neuroimaging findings, frequency and percentages will be calculated. P value of <0.05 will be taken as significant.A total of 89 patients were included in the study; of these 62 (69.7%) were male and 27 (30.3%) were female. Mean age was 4.4\u00b12.8 years. Spastic variety was the most common type of cerebral palsy as shown in A significant majority 38 (42.6%) had history of delayed cry suggestive of birth asphyxia. At birth 37 (41.6 %) needed neonatal intensive care unit admission. Consanguinity was seen in 56 (62.9%) and 17 (19.1%) also reported family history of cerebral palsy. Most common maternal risk factor was anemia 13 (14.6%) followed by pregnancy induced hypertension (9%) and infections (6%). No risk factors were identified in majority of mothers (57%).Neuroimaging was done in only 37 (41.5%) patients, among these CT scans was done in 23 (25%) and MRI brain was performed in 14 (15.7%). Cerebral palsy is a wide spectrum neurological disorder with lifelong implications both for patient and his family.15We enrolled 89 patients diagnosed with cerebral palsy in our community health center over a period of 13 months.19Maternal anemia, pregnancy induced hypertension (PIH) and infections were significantly associated with risk of CP (<0.05). Anemia has also been reported from India reflecting poor nutritional status.Among the natal risk factors observed in our study, low birth weight (LBW) 15 (16%) was significantly associated with risk of cerebral palsy (<0.05). History of delayed cry was more common with SVD (57%) (p <0.05) conferring the risk of birth asphyxia. Home deliveries by untrained birth attendants (Dais) were reported in 13 (14%) of the babies. Overall, in Pakistan it is estimated that 50% of the births take place at home.24Neurological types of cerebral palsy were spastic, ataxic, dyskinetic and hypotonic. Spastic quadriplegia is the most common reported (53.9%) followed by spastic diplegia (18%). Studies from India report a similar pattern of 61% and 22% respectively.27Neuroimaging was done in 37 (38.7%) of the patients only. CT scan was done more frequently in 23 (25.8%) and MRI in 14 (15.7%). This is due to wider availability and convenience of doing CT scan in children as compared to MRI. However, MRI has better detection rates in identifying brain abnormalities. Predominant abnormality noted on neuroimaging were white matter injury in the form of cortical atrophy, periventricular leukomalacia. Grey matter injury like gliosis and encephalomalacia indicative of post- meningitic sequela, vascular insults, and structural malformations in three patients. Brain abnormalities were detected in 33 (89%) of the scans, these are consistent with population based studies done on neuroimaging finding in CP in European countries. However, the number of patients who had neuroimaging done in our cohort was low reflecting the access to care. Neuroimaging helped in identifying the exact etiology and neuroanatomy of the brain insult. Neuroimaging findings were significantly correlated with etiologies (<0.05). Neuroimaging is recommended in all cases of cerebral palsy for better understanding of the neuroanatomical disease process.Birth asphyxia leading to hypoxic ischemic insult to the developing brain is the most common cause of cerebral palsy in our patients 38 (42.7%). It presented with spastic quadriplegia (29) in majority of patients. Brain infections like meningo-encephalitis were the second leading cause 13 (14.6%). Post-meningitic sequelae presented as spastic quadriplegia in majority (nine) patients, followed by ischemic stroke and intracranial bleed 6 (6.7%). Kernicterus was reported in three patients (3.4%) two had quadriplegia while one had dyskinetic CP. Structural malformation like pachygyria, dysgenesis of corpus callosum, hydrocephalus identified on the basis of neuroimaging reports three patients presenting as quadriplegic, diplegic and monoplegic respectively. No cause could be identified in 19 (21.3%) patients. Given the high rates for consanguinity and family history of CP reported, we need to understand the genetic basis of disease. It is estimated that some 30% of CP might have genetic causation.28Prevalence of cerebral palsy is not known in Pakistan. Male gender is more affected in our cohort of patients. Maternal anemia, pregnancy induced hypertension, LBW are significant risk factor for cerebral palsy in Pakistan.SAK: Conceptualization, data collection, analysis, manuscript writing.ST: Data collection, analysis, drafting.MIM: Data analysis, drafting, final review."}
+{"text": "Lr67 and Lr34 are similar in that they both condition resistance to many diseases, in a non-race-specific manner, and code for cellular transporters. Lr34 plays a critical role in breeding wheat for disease resistance in large part because it interacts with other resistance genes to result in effective and durable resistance. To determine if Lr67 interacts with other resistance genes in a similar manner as Lr34 six different doubled haploid populations were developed which segregated for either Lr67 or Lr34 along with a second resistance gene, either Lr13, Lr16, or Lr32. The presence or absence of each of these genes in the progeny lines was determined by molecular marker analysis. These six populations were tested for leaf rust field resistance in the same environments to compare the effects of Lr34 and Lr67 alone, and in combination with Lr13, Lr16 or Lr32. Lr67 and Lr34 significantly reduced the levels of rust severity, Lr34 showed a significant interaction with Lr13 but Lr67 did not. Both genes interacted with Lr16, and Lr67 had a significant interaction with Lr32. This analysis demonstrates the similar effect of Lr67, as seen with Lr34, on the interaction with other resistance genes to give a better level of resistance than with single resistance genes. While Lr67 is not widely deployed in agriculture, it could play an important role in disease resistance in future wheat cultivars.The wheat multi-pest resistance genes  Puccinia triticina Eriks. pathogen population has evolved virulence for most of the race-specific resistance genes widely deployed in wheat cultivars  with other Thatcher NILs containing different resistance genes. From F2 families ten to 16 plants with the lowest infection type when inoculated with P. triticina race 1 were selected and grown to maturity. Seed from these selected F2 plants was then grown in a rust nursery and the five or six most resistant F3 lines, homozygous for Lr34 were selected and harvested. Two homozygous F4 lines per cross were tested as seedlings in the greenhouse and three to four plants of one F4 line were tested as adults in greenhouse tests. Selected lines with Lr34 and a second leaf rust resistance gene were also field tested over two years. These authors found that Lr34 enhanced resistance, both at the seedling and adult plant stages, in combination with many effective resistance genes, and this also resulted in lower adult plant infection types and leaf rust severity levels in the field. However, combinations involving Lr34 with less effective or ineffective genes had the same level of resistance as Thatcher-Lr34.Lr13, Lr34, and Lr37. For glasshouse studies, they used a single F4 line from crosses between the pairs of Thatcher isolines that contained each of these resistance genes. These same F4 lines and six to eight sister lines from the same crosses were compared in field trials. They found that the two gene lines generally had better resistance as measured by latent period, field resistance, and the microscopic development of fungal structures. Interestingly, they also noted significant variation between sister lines for the Lr34 + Lr13 gene combination in which partial resistance was found in field trials. No variation was found among the sister lines from the gene combinations involving Lr37 since the level of resistance was nearly complete.Lr67 is also race non-specific, is only effective at the adult plant stage, and confers multi-pest resistance to stripe rust  to highly effective (Lr32). Both Lr13 and Lr16 are in many Canadian wheat cultivars, such as Carberry , Lr16 (RL6005), Lr32 (RL6086), Lr34 (RL6058), and Lr13 + Lr34 (RL6114) had annual rust severity averages in inoculated nurseries in Manitoba Canada over the years 2003\u20132021 of 76.6, 65.6, 30.8, 23.2, and 10.3%, respectively, compare with Thatcher at 81.9% .Some of the most common leaf rust resistance genes in Canadian wheat are and Lr34 . In thisCarberry , because to Lr13 . Howevern Canada  but nearseverity . In cont to date ; howeverLr67 and Lr34, the objective of this study was to determine if Lr67 also interacts with other resistance genes. To test this we developed six doubled haploid populations from the crosses with either single gene lines with Lr34 or Lr67 and each of the near-isogenic lines with either Lr13, Lr16, or Lr32. Each progeny line was genotyped with molecular markers to determine if the line had the resistant or susceptible allele of each gene involved in the population, except for Lr13 which was determined by rust testing at the adult plant stage. Progeny from these crosses were field tested over four years to determine the resistance level of lines in each phenotypic class; susceptible, those having the resistant allele for either Lr34 or Lr67 alone, those only having the resistant allele of the second resistance gene , and those with both genes.Given the many similarities between Lr34 (RL6058), Lr67 (RL6077), Lr13 (RL4031), Lr16 (RL6005), and a Katepwa backcross line with Lr32 (BW196R). The progeny populations consisted of 78 lines (Thatcher-Lr13/Thatcher-Lr34), 74 lines (Thatcher-Lr13/Thatcher-Lr67), 58 lines (Thatcher-Lr16/Thatcher-Lr34), 85 lines (Thatcher-Lr16/Thatcher-Lr67), 114 lines (Thatcher-Lr34/BW196R), and 113 lines (Thatcher-Lr67/BW196R). DH populations were generated using the maize pollination described by Doubled haploid (DH) populations were developed from the crosses between Thatcher near-isogenic lines with Lr34, Lr32, Lr16, and Lr32. The Lr34 locus was genotyped using a PCR marker, caIND11, that targets an indel in the Lr34 gene sequence  as described by Lr67 and Lr16, KASP assays were performed as described by To classify the progeny for the presence or absence of the genes targeted in each population, DNA markers were used to classify sequence . Both LrcsSNP856  and kwm7csSNP856  respecti56  using PROC GLIMMIX (beta distribution) with the presence or absence of the genes, and their interaction, in each progeny line of the population as dependent variables and replication within each year as the random variable. Within each population, the groups of lines with all the possible gene combinations were compared pairwise to each other using LSMEANS.Lr13 and Lr34 were significant in the Lr13/Lr34 population, as was the interaction between Lr13 and Lr34 (Lr34 (23.8%), lines with only Lr13 (84.3%), and lines with neither gene (85.7%)  compared to lines with only Lr67 (37.0%) and lines that only had Lr13 were similar (80.5%) with lines that had neither gene (79.0%) (The effects of both and Lr34 . The lin (85.7%) . When thher gene . In the 34  .Lr16 and Lr34 were significant in reducing leaf rust severity in the Lr16/Lr34 population, and the interaction between the genes was also significant (p <\u20090.01). Lines with both genes had the lowest leaf rust severity (24.6%), followed by lines with only Lr34 (34.7%), lines with only Lr16 however had a similar level of leaf rust severity (82.2%) as the lines with neither gene (80.3%) . Again lines with both genes had the lowest level of severity (38.0%), followed by lines with only Lr67 (50.1%) and lines with only Lr16 were similar (82.0%) to lines with neither gene (82.3%) (Both  (80.3%) . Similar (82.3%) .Lr32/Lr34 population, both genes significantly reduced leaf rust severity (p\u2009<\u20090.01); however, their interaction was not significant. Lines with both genes were very resistant (3.1%), followed by lines with only Lr34 (16.9%) or only Lr32 (38.1%), compared to lines with neither gene (82.6%) (Lr32/Lr67 population both genes significantly reduced leaf rust severity (p\u2009<\u20090.01), their interaction was however significant (p\u2009<\u20090.01). Again lines with both genes had the lowest leaf rust severity (2.1%), followed by those with only Lr67 (23.6%), those with only Lr32 (29.7%), and those with neither gene (77.0%) (In the  (82.6%) . However (82.6%) . Similar (77.0%) . Each cl (77.0%) .Lr34 and Lr67 interact in combination with other resistance genes in progeny populations. They were each paired with Lr13, Lr16, or Lr32 in populations segregating for one of those genes and either Lr34 or Lr67. In the populations that segregated for Lr13, the effect of Lr13 was significant in the population with Lr34 but not with the population involving Lr67. There was a significant interaction between Lr13 and Lr34 whereas there was no significant interaction between Lr13 and Lr67. It appears that Lr34 and Lr67 differ in their interaction with Lr13. The lack of interaction with Lr67 may reflect the marginal resistance provided by Lr13 and that fact that most of the virulence phenotypes in Canada are virulent on Lr13. During the years of the field tests the frequency of virulence to Lr13 in the population was close to 100%  . Overall Lr16 had a significant effect on leaf rust in these populations and had significant interactions with both Lr34 and Lr67  , most isand Lr67 . The effis study . Both Lrike Lr13  and bothCarberry .Lr32. Alone Lr32 was very effective in reducing the severity of leaf rust, as were both Lr34 and Lr67. The lines with two gene combinations of Lr32 + Lr34 and Lr32 + Lr67 were even more resistant than any of these genes alone. Virulence has not been detected in Canada to Lr32 and the Thatcher-Lr32 line is moderately resistant in field trials. Both Lr34 and Lr67 had the ability to enhance the resistance of Lr32 when in combination with this resistance gene. However, the interaction was only significant between Lr32 and Lr67  and Lr67 (RL6077) showed similar resistance phenotypes, both lines were initially thought to have Lr34 and were used interchangeably as a source for Lr34 in the 1950s by the CIMMYT wheat breeding program (Both ultivars . Deployeultivars . Interes program .Lr34 are also common in Canadian wheat cultivars (Lr34 (Lr34 appears to be key to its high level of resistance, as progeny lines derived from Pasqua with the four other resistance gene were fairly susceptible (Lr2a, Lr16, Lr23, Lr13, Lr34, and Lr46 (Lr34 and Lr46 with the other resistance genes. These multi-pest resistance genes along with others, such as Sr2, appear to function very well in combinations with other genes to condition effective and durable resistance, often by boosting the effect of other resistance genes (Lr34/Yr18/Sr57 interacted with Lr68 to reduce leaf rust and Sr2/Yr30 to reduce rust severity to leaf, stem, and stripe rust in a segregating population.Gene pyramids involving ultivars . The higrs (Lr34 . Lr34 apceptible . Similarand Lr46 , in whicce genes . RandhawLr67 could play a similar and important role in leaf rust resistance, like Lr34 or Lr46, if it was combined with other resistance genes, such as Lr16 and Lr32, in which it could interact to result in lower levels of leaf rust severity and improved durability of resistance. However, Lr67 failed to show the same significant interaction with Lr13 that Lr34 demonstrated, and the effect of Lr34 alone was stronger than that of Lr67 in each of the pairs of populations. In contrast, the interaction between Lr32 and Lr67 was significant whereas that between Lr32 and Lr34 was not. While Lr67 was deployed in many CIMMYT wheat cultivars from the 1950s (It appears that he 1950s , it is nThe original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author.BM and CH planned the experiments, analyzed the data, and co-wrote the manuscript. CH developed the populations analyzed in this study and conducted the molecular marker analysis of all progeny lines. BM conducted the leaf rust phenotyping of the populations. All authors contributed to the article and approved the submitted version.Funding for this project was from Agriculture and Agri-Food Canada.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Approximately 30% of individuals diagnosed with schizophrenia suffer from treatment-resistant or refractory schizophrenia. The gold standard for treatment is clozapine. However, a significant number of patients discontinue clozapine treatment and this carries a poor prognosis.This study explores patients\u2019 motives for cessation of clozapine therapy and its prevalence.A longitudinal, retrospective and descriptive study on a period of 20 years, at the psychiatry department A of the Razi hospital in Tunisia. Data was collected from the medical files of patients trated by clozapine using a pre-established sheet.The studied sample included 64 patient records. Treatment with clozapine was stopped spontaneously or following a medical decision in 37 patients (57.8%). The total number of clozapine stops in these 37 patients was 70. Indeed, each one of these patients had stopped treatment at least once. Clozapine was discontinued by some patients in the study sample for poor compliance(45.9%), for adverse side effects of treatment (16.2%) and by treating physicians for poor response treatment (8.1%). Clozapine was discontinued by 11 patients for hematological adverse reactions, representing 27.9% of the total number of clozapine discontinuations. Withdrawal of clozapine was indicated in 2 cases of agranulocytosis(18.2%), in 2 cases of moderate neutropenia(18.2%), in 3 cases of eosinophilia (27.2%), in 3 cases of thrombocytopenia (27.2%) and in 1 case of severe anemia (9.2%).Clozapine discontinuation was essentially caused by poor patients\u2019 observation and hematological adverse reactions appearance.Future research should seek to further investigate clozapine cessation factors in order to better benefit from the medical virtues of this molecule.No significant relationships."}
+{"text": "Pathway of psychiatric care is defined as the sequence of contacts with individuals and organizations initiated by the distressed person's efforts and his significant others to seek appropriate health care. This study aimed to find the prevalence of non-psychiatric referral as first encounter among patients attending the psychiatry outpatient department of a tertiary care hospital.th March 2015 to 25th April 2015 in the outpatient department of the department of psychiatry of a tertiary via direct interview using the World Health Organization's encounter form. Ethical approval was taken from undergraduate medical research protocol review board (Reference number 105/071/072). Psychiatric diagnoses were made by respective consultants using the International Classification of Diseases-10 Clinical Descriptions and Diagnostic Guidelines criteria. Data was entered in the Microsoft Excel 2007 and analyzed by Stata version 15. Point estimate at 95% Confidence Interval was calculated along with frequency and percentage for binary data.A descriptive cross-sectional study was carried out from 29Out of 50 patients, 26 (52%)  of new cases in the outpatient department had non-psychiatric referrals. Among them, 13 (26%) referred from faith healers, 7 (14%) from the general hospital and 6 (12%) from medical out patient department.The prevalence of non-psychiatric referral for the patients seen for the first time in the psychiatry outpatient department was similar to findings from studies done in different parts of South East Asia. So, timely identification and treatment of mental illnesses is of vital importance. Treatment from unqualified medical practitioners and faith healers is a common practice, and is attributable to the delay in proper treatment.The aim of this study was to find out the prevalence of non-psychiatric referrals among new patients visiting the psychiatry out-patient department (OPD) of a tertiary care hospital.th March 2015 to 25th April 2015 in OPD in the department of Psychiatry BP Koirala Institute of Health Sciences (BPKIHS), Dharan, Nepal. Ethical approval was taken from undergraduate medical research protocol review board (UM-RPRB) BPKIHS formed under the institutional review committee (IRC) (Ref. No.105/071/072). Patients visiting the psychiatry outpatient department for the first time were included in the study. Patient on follow up visit and those refusing to give the consent were excluded from the study. Convenience sampling was done and the sample size was calculated as,A descriptive cross-sectional study was carried out from 292 \u00d7 p \u00d7 q / e2n\u2003= Z2 \u00d7 (0.87) \u00d7 (1-0.87) / (0.1)2\u2003\u2003= (1.96)\u2003\u2003= 43.44\u2003\u2003= 45Where,n = minimum required sample size,Z = 1.96 at 95% Confidence Interval (CI),4p = past prevalence of non-psychiatric referrals among new cases taken from a previous study, 87%q = 1 - pe = margin of error, 10%Taking a 10% non-response rate, the calculated sample size was 50. Therefore, we took 50 participants in the study. Data was collected in the OPD by face-to-face interview by the researchers with the patients or patient's informant using standardized encounter form by World Health Organization. The participants were informed regarding the study prior to the interview and taken an informed consent. The Psychiatric diagnoses were made by the respective psychiatric residents and confirmed by the respective consultants using ICD-10, Clinical Description and Diagnostic Guidelines (CDDG) criteria. All first point of care apart from the direct psychiatric consultation were taken as non psychiatric referral.Data was be entered in Microsoft excel 2007 and analyzed by STATA 15. Point estimate at 95% Confidence Interval was calculated along with frequency and percentage for binary data.The prevalence of non-psychiatric referrals among firstencounter patients visiting the psychiatry OPD was 26 (52%) (38.2-65.8 at 95% CI). Out of them, native or religious healers accounted for 13 (26%) while 7 (14%) first consulted general hospital and 6 (12%) to other medical practitioners.The most common symptoms first experienced by the subjects were depressive symptoms 4 (8%), panic 4 (8%), mania 4 (8%) and anxiety 2 (4%). Five (10%) were involved in impulsive activities and 2 (4%) had visual and auditory hallucinations. Rest 5 (10%) had other symptoms like premature ejaculation, headache, alcohol dependence syndrome and seizures.Fourteen (28%) of our subjects were diagnosed to have mild, moderate or severe depression. Next to it, 8 (16%) had bipolar disorder. Panic disorder 6 (12%) and mania 6 (12%) were next common followed by schizophrenia 5 (10%). Other remaining 9 (18%) were diagnosed to have early ejaculation, migraine with insomnia, unresponsive episodes of different durations and mood disorder with psychotic symptoms.In about 34 (68%) of the cases, it was found that friends, relatives or neighbors initiated the first contact while in the rest 16 (32%) it was patient himself/herself.We found that 2 (25%) of those patients with anxiety symptoms, 2 (67%) of those with hallucinations, 3 (18%) of patients with mania, 3 (18%) of patients with panic disorder and 4 (40%) of those with depressive symptoms consulted the non psychiatric services.Similarly, 11 (38%) patients of the patients from within 50km of tertiary care centre, 1 (33%) of those from >50km hill and and 10 (5.5%) people from >50km terai first consulted native religious healers.Data regarding the distance from tertiary care centre and their place of first referral showed that 18 (63%) of people from within 50km, 1 (34%) people from >50km hill and 7 (39%) people from >50km terai region had their first referral to non psychiatric services.It was observed that 21 (72%) patients from within 50 km of tertiary care center had their first referral within 6 months of first consultation to any non psychiatric services. Similar was the result for people from >50km terai 13 (72%) while only 2 (66%) of those from >50km hill had their first referral within 6 month of consultation to non psychiatric services.Our study found that 39 (78%) of the patients sought referral from non psychiatric services within 6 months of the development of their first symptoms. 6 (12%) made the initiation within a year while it took more than 5 years for 4 (8%) of them. 1 (2%) sought the contact in the period between 1 year to 5 years.The results showed that majority of people from <50 km from tertiary care centre had their first mental health consultation within 6 months 24 (82%) while 13 (72%) of those from >50 km terai also sought the care within 6 months. Those from more than 50 km hill had significant time lag in consultation with only 2 (66%) seeking care within 6 months.5 The findings of our study show that 52% of our patients had referral from the non psychiatric services.A better understanding of the way in which people understand and seek care for mental disorders is important for planning mental health services, for the organization of training and for the organization of referrals to psychiatrists from other sources of health and social care.15 A large-scale study by the World Health Organization (WHO), one of the largest in this field, investigated referral pathways in 11 countries and demonstrated that the main contact point before attending psychiatric care was a general practitioner , a hospital doctor (Nairobi), and a traditional healer (Ujung Pandang).1 This is in accordance to our study which also showed that major referral pathways to mental health are non psychiatric services. The role of relatives, friends and neighbors was found to be greater in the initiation of contact than the patient himself/herself. This is consistent with the findings of the study done in Italy done by Valeria Del Vechho et al.11Many studies from various countries have described the help-seeking behavior of patients with psychiatric disorders.The study was of short duration and sample mostly representative of urban population was the major limitation of our study. As the study was hospital based, convenience sampling was done because of which the study might not be representative to the community. Recall bias might have contributed to some of the limitations.The findings of our study showed that more than half of the cases of mental illness had sought non psychiatric care as their first consultation. This is similar to the studies conducted by World Health Organization and studies in South East Asia Region. Reducing delays in accessing the services and providing early intervention"}
+{"text": "Contraception plays a key role in preventing unwanted births. It also decreases the pregnancy and childbirth-related morbidities and mortalities, but many women don't use contraception particularly in the postpartum period. The main objective of this study was to find out the prevalence of contraception use among postpartum women in a municipality.A descriptive cross-sectional study was conducted among married women of reproductive age in Dhulikhel municipality of Kavrepalanchok from January to September 2019. Ethical approval was obtained from Institutional Review Committee and permission was taken from Dhulikhel Municipality before the study. The sample size was 332. A convenience sampling method was used. A semi-structured questionnaire pre-tested in Panauti municipality was used. Data entry and analysis were done using Statistical Package for Social Sciences version 20. Point estimate at 95% Confidence Interval was calculated for descriptive analysis.Out of total 332 women, 146 (40%)  used postpartum contraception. Injectable/Depot was used by 61 (42%) women. Total 97 (52%) of the non-users intended to use contraception in the future. The most common reason for contraception use was women not wanting the next child soon 91 (62%) and reason for non-use was feeling contraception as unnecessary 73 (39%).The use of postpartum contraception was poor, and only half of the non-users intended to use contraception in the future. Thus, contraception use should be encouraged during all possible contact times, and counselling should be made universal to improve postpartum contraception services' uptake. Contraception also helps to empower women by giving more choice over fertility and gives opportunities for education and career development.6 Also, very less information on postpartum contraception use is known about Dhulikhel municipality.Despite many programs of Nepal focusing on family planning, 24% of women have unmet need for contraception and 21% of births take place before the recommended twenty four months interval.Thus, this study aims to find out the prevalence of postpartum contraception use among women living in Dhulikhel municipality of Kavrepalanchok.A descriptive cross-sectional study was done at Dhulikhel municipality of Kavrepalanchok district of Nepal. The duration of study was from January 2019 to September 2019. Ethical approval was taken from Institutional Review Committee of Dhulikhel Hospital (Reference number 123/18) and permission to conduct study was taken from Dhulikhel municipality (Reference number 221). After explaining the objective of the study in detail, verbal consent was taken from each respondent. Women below the age of 49 years who had given birth within 6 weeks up to three years prior to the survey were included in the study. However, those women having still birth, neonatal or infant mortality or having any contraindication for contraceptive use were excluded from the study.The sample size was calculated using the given formula.2 \u00d7 p \u00d7 q / e2n\u2003= Z2 \u00d7 (0.27) \u00d7 (1-0.27) / (0.05)2\u2003\u2003= (1.96)\u2003\u2003= 302Where,n = the sample sizeZ = 1.96 at 95% Confidence Interval7p = prevalence of postpartum contraception use, 27%q = 1-pe = margin of error, 5%After taking the non-response rate of 10% the final sample size was 322.Five enumerators from medical and public health background were oriented before data collection. Data was collected using semi-structured questionnaire which was pre-tested at ward number five of Panauti municipality before the survey. Necessary modifications were done in the questionnaire before the actual study.There are 12 wards in Dhulikhel municipality. Out of 12 wards, six wards i.e., ward number 1, 3, 4, 7, 9 and 11 were selected by probability proportion to size method. Household was considered as one unit and number of households in each ward were selected by proportion which gave the sample size of 38, 46, 67, 59, 56 and 66 in the above wards respectively. As many of the households didn't have eligible women and many households were empty during preliminary survey, convenience sampling method was used for the final data collection. One woman from each household was approached and if more than one eligible woman were present in a household, then the one with youngest child was selected. Households were taken until sample size was fulfilled.A descriptive analysis of socio-demographic variables was done using mean, frequency, percentage and standard deviation. Data entry and analysis was done in Statistical Package for Social Sciences (SPSS) version 20.Out of total 332 women, 146 (44%) were using postpartum contraception at present which included all forms of contraception i.e., modern or natural methods.The mean age of women was 26.21 \u00b14.27 years (Mean\u00b1SD). Total 260 (78%) women were Hindu and Janajati 172 (52%) by caste. Total 167 (50%) women had education up to SLC and 173 (52%) were home makers. Most of the women 180 (54%) lived in joint family and 299 (90%) had mass media exposure regarding contraceptive methods. Total 310 (93%) women had delivered in a health facility and 246 (74%) had normal delivery .Total 260 (78%) women have had resumption of menorrhea and the mean duration of amenorrhea was 5.9 \u00b13.77 months (Mean\u00b1SD). Out of 260 women who had resumption of menorrhea, 43 (16.5%) had resumption in less than three months, 93 (36%) in 3 to 6 months while 124 (48%) had resumption in greater than 6 months duration.Around 41 (12%) women gave history of ever having unwanted pregnancy but none of them responded to have aborted the unwanted conception.Total 117 (35%) women reported to have used any contraceptive method in the past and out of them, 49 (42%) reported to have had adverse effect with 20 women (41%) experiencing bleeding problem, 15 (31%) irregular cycle, 8 (16%) weight gain and 5 (12%) others which included weight loss 2 (4%), amenorrhea 2 (4%) and pain abdomen 1 (3%).Out of total 332 women, 158 (48%) said that they know about postpartum contraceptive methods but only 119 (75%) out of them could correctly list at least two names of postpartum contraceptive methods .Among 310 women who had given birth in a health facility, 237 (76%) received counseling regarding postpartum contraception while only 177 (57%) received counseling regarding adverse effects of contraceptive methods following delivery. Total 150 (63%) women reported having being counseled by nurses, 77 (32%) by doctors and 10 (5%) by nursing students. Likewise, only 100 (30%) women out of 332 reported to have received counseling regarding postpartum contraception during immunization of their child.Out of 332 women, total 146 (44%) women reported to be using any form of postpartum contraception and most commonly reported method of contraception was Depot 61 (42%) while use of long acting reversible contraceptive method (LARC) was 50 (34%) .Among contraceptive users, 91 (62%) women said that the reason for using contraception was not wanting another child soon while 4 (3%) said that they were advised by health worker and one (1%) said that she was advised by family member. Total 219 (66%) women said that decision of contraceptive use is jointly made by them along with husband while 63 (19%) reported making decision by themselves and 50 (15%) by husband.Out of 332 women, 186 (56.02%) were non-users and 73 (39%) women among them stated using contraception as being unnecessary while 4 (2%) gave other reasons which were unavailability of intended method and current pregnancy .Out of 186 non-users, 102 (54.83%) women didn't use contraception but also didn't want any child soon due to various reasons thus giving the unmet need of 57 (31%) among study group.Out of 186 postpartum contraception non-users, 97 (52%) intended to use some form of contraception in the future and the contraceptive of choice were Norplant, sterilization and Depot reported by 20 (20%), 13 (13%), and 13 (13%) women respectively while 41 (42%) women said that they don't know what method they intended to use.The use of postpartum contraception in this study was poor and only some women had intention to use contraception in the future. Although counseling about contraception was done, women were not informed about the side effects of contraceptive methods.9 and also studies from Bangladesh10 and Ethiopia13 showing utilization below 50%. But higher uses of postpartum contraception were found in Kenya14 (86%) and Liberia15 (77%) which may be due to more acceptability and accessibility to contraceptive services in those places.The result of this study indicates poor utilization of postpartum contraception which is in line with studies done in Nepal17 Ethiopia,18 Kenya14 which may be due to the easy accessibility, availability, less effect on lactation and ease of administration.The most common method of contraception used by women in this study was found to be injectable method or Depot which is similar to many studies done in Nepal,17 but very high intention to use was found in other parts of the world like Bangladesh10 Ethiopia19 and Ohio.20 The difference in socio-demographic structure, awareness, availability of services might have affected the intention of women to use postpartum contraception in the future.This study found that only around half of the postpartum contraception non-users intended to use any form of contraception in the future. This finding is consistent with findings from studies Nepal8 (42%) but higher proportion of women knew about it in Liberia15 (79%) and Indonesia (77%).21Women who knew about postpartum contraception was below 50% which is similar to study from Kailali20 and Nigeria.22Our study showed that current non-users of contraception intended to use long term method or permanent method compared to those who were already using any method of contraception which is consistent to findings from Ohio8 Ethiopia,13 and Egypt.23Most common reason stated for not using any postpartum contraception in this study were feeling it as unnecessary and amenorrhea which were also seen in study done in Kailali,16 But the Nepal Demographic Health Survey showed 13% counseling in the postpartum period in the country, which might be due to the difference between service provider and coverage between different sectors.6 As the main service provider in our study was tertiary level teaching hospital, the service coverage might have been greater than the national data.Counseling regarding postpartum contraception was received by 3/4th of the women which is similar with other studies from Nepal.This study had certain limitations. Being a crosssectional study, the study could not explore more about the women's experience and reasons for utilization or non-utilization of postpartum contraception. Due to lack of feasibility and cost, the study participants couldn't be randomly selected at household level. As the study was done in different wards of Dhulikhel municipality, it doesn't represent whole of Kavrepalanchok or Nepal.The use of postpartum contraception was poor and knowledge about postpartum contraceptive devices was also not good. Women didn't feel the need of contraception; thus, counseling should be made universal at all contact periods starting from pregnancy."}
+{"text": "In a cohort of persons living with HIV in Hong Kong, surrogate virus neutralization testing for COVID-19 yielded a median level of 89% after the third dose of an inactivated COVID-19 vaccine, compared with 37% after the second dose. These results support using a 3-dose primary series for enhanced immune protection. After the third dose, the median sVNT rose to 89% , paralleling a significantly higher percentage with sVNT positivity  (The median sVNT level was 37% (IQR 24%\u201353%); 64% of participants tested positive (sVNT 6\u201317.33) . In mult6\u201317.33)  Table 2.>30%) was 79% after 27\u201355 days in our study and 71% after 41 days in the Brazil study. Our immunogenicity results on the completion of a 2-dose schedule of CoronaVac in PLHIV were remarkably similar to those reported in Brazil  and the Centers for Disease Control and Prevention (https://www.cdc.gov/hiv/basics/covid-19.html). Recent studies have shown that the effectiveness of current COVID-19 vaccines against new variants, such as Omicron, could be reduced; immunogenicity was lower after 2 doses of inactivated vaccines than of mRNA vaccines (https://www.coronaviruspreventionnetwork.org) may provide evidence for enhancing vaccination strategy for PLHIV amid the emergence of new variants.The anticipated suboptimal clinical outcome for PLHIV after COVID-19 has been shown in population-level studies (Additional information about 3-dose primary series of inactivated COVID-19 vaccine for persons living with HIV, Hong Kong."}
+{"text": "Background: The arterial blood gas (ABG) parameters of patients admitted to intensive care units (ICUs) with acute neuromuscular respiratory failure (NMRF) and non-NMRF have not been defined or compared in the literature. Methods: We retrospectively collected the initial ABG parameters  of patients admitted to ICUs with acute respiratory failure. We compared ABG parameter ranges and the prevalence of abnormalities in NMRF versus non-NMRF and its categories, including primary pulmonary disease (PPD) , pneumonia, and pulmonary edema. Results: We included 287 patients . The difference between NMRF and non-NMRF included the median (interquartile range (IQR)) of pH (7.39 (7.32\u20137.43), 7.33 (7.22\u20137.39), p < 0.001), PaO2 (86.9 (71.4\u2013123), 79.6 (64.6\u201399.1) mmHg, p = 0.02), and HCO3 (24.85 (22.9\u201327.8), 23.4 (19.4\u201326.8) mmol/L, p = 0.006). We found differences in the median of PaCO2 in NMRF (41.5 mmHg) versus PPD (63.3 mmHg), PaO2 in NMRF (86.9 mmHg) versus pneumonia (74.3 mmHg), and HCO3 in NMRF (24.8 mmol/L) versus pulmonary edema (20.9 mmol/L) . NMRF compared to non-NMRF patients had a lower frequency of hypercarbia (24.6% versus 39.9%) and hypoxia (33.8% versus 50.5%) . NMRF compared to PPD patients had lower frequency of combined hypoxia and hypercarbia (13.2% versus 37.8%) but more frequently isolated high bicarbonate (33.8% versus 8.9%) . Conclusions: The ranges of ABG changes in NMRF patients differed from those of non-NMRF patients, with a greater reduction in PaO2 in non-NMRF than in NMRF patients. Combined hypoxemia and hypercarbia were most frequent in PPD patients, whereas isolated high bicarbonate was most frequent in NMRF patients. Acute neuromuscular respiratory failure due to Guillain\u2013Barr\u00e9 syndrome (GBS), myasthenia gravis (MG), or amyotrophic lateral sclerosis (ALS) is a common reason for admission to the intensive care unit (ICU) and ventilation ,2. Sever2) is less than 60 mm of mercury (mmHg), and the partial pressure of arterial carbon dioxide (PaCO2) may be either normal or low. Type 1 respiratory failure occurs mainly due to ventilation perfusion mismatch, such as increased dead space in chronic obstructive pulmonary disease (COPD), causing ventilation without perfusion, or due to a shunt whereby the alveoli are perfused but not ventilated, as in pneumonia and pulmonary edema. In type 2 (hypercapnic) respiratory failure, PaCO2 is greater than 50 mmHg, and PaO2 may be normal or low; this occurs mainly due to hypoventilation [Respiratory failure (RF) occurs when the respiratory system fails to maintain gas exchange and is classified into types 1 and 2 according to blood gas (BG) abnormalities. In type 1 (hypoxemic) respiratory failure, the partial pressure of arterial oxygen  parameter ranges and prevalence of abnormalities in NMRF vs. non-NMRF patients. We aim to describe the ABG parameters for different diseases separately with regard to ABG parameter ranges and prevalence of ABG abnormalities.We conducted a retrospective, cross-sectional study between January 2015 and May 2021 at 4 tertiary centers in Saudi Arabia,  in Jeddah, National Guard Hospital in Riyadh, King Saud University Medical City in Riyadh, and National Guard Hospital in Jeddah). The institutional review boards approved the protocol in each institution. All centers recruited NMRF cases, whereas the non-NMRF cases were recruited from King Abdulaziz University Hospital. We retrospectively collected data for patients who presented with acute respiratory failure (ARF) during the study period. Inclusion criteria included (1) age of 18\u201380 years; (2) patients admitted to ICU; (3) diagnosis of acute respiratory failure (ARF) as the indication for ICU admission (see below for ARF definition); and (4) patients with ARF due to one of the following diagnoses: (A) GBS; (B) MG; (C) amyotrophic lateral sclerosis; (D) pneumonia; (E) known cases of chronic obstructive pulmonary disease (COPD); (F) known cases of bronchial asthma; (G) known case of Bronchiectasis; (H) heart failure; (I) noncardiac pulmonary edema; and (J) other known causes of ARF, such as pulmonary embolism and pulmonary fibrosis. Our exclusion criteria were (1) intubation due to sepsis, (2) blood gas collected after the date of intubation, (3) cardiac arrest suffered at initial presentation, and (4) coexistent diabetic ketoacidosis (DKA).2) in mmHg, partial pressure of oxygen (PaO2) in mmHg, and bicarbonate level (HCO3) in mmol/L.Arterial blood gas (ABG) parameters: we refer to the first ABG taken from the patient before or at the date of admission to the ICU. We excluded ABG values that were taken after the date of ventilation. Parameters include pH, partial pressure of carbon dioxide  parameters: we refer to the first blood gas taken from the patient (including venous blood gas if ABG was not available) before or at the date of admission to ICU. Parameters included pH, PaCOAcute respiratory failure (ARF) refers to cases admitted to ICU due to respiratory distress caused by one of the diseases mentioned in the inclusion criteria (above) with no additional reason for ICU admission. Cases of ARF were identified by chart review, requiring at least two documentations from ICU and/or emergency physicians indicating the presence of ARF or respiratory distress as an indication for ICU admission. We also excluded cases with coexisting indication for ICU admission, such as sepsis ((A)Guillain\u2013Barr\u00e9 syndrome (GBS): Patients presenting with acute-onset generalized weakness and areflexia that reaches the maximum within four weeks; objective evidence of a diagnosis is from an electrodiagnostic test and/or cerebrospinal fluid.(B)Myasthenia gravis (MG): this diagnosis is based on clinical presentation with objective evidence of diagnosis either through positive serology (acetylcholine receptor antibody or anti-muscle-specific kinase antibody) or a positive decrement in response to repetitive nerve stimulation.(C)Amyotrophic lateral sclerosis: indicated by the presence of progressive weakness with upper and lower motor neuron signs and objective evidence of diagnosis in an electrodiagnostic test performed by a neuromuscular specialist.Group 1 was the NMRF group, which included patients with the following:(A)Pneumonia with X-ray or culture confirmation;(B)Known cases of COPD and use of bronchodilators prior to admission;(C)Known cases of asthma and use of bronchodilators prior to admission;(D)Heart failure with objective evidence on X-ray or echocardiogram;(E)Bronchiectasis confirmed by chest CT;(F)Noncardiac pulmonary edema;(G)Others causes of ARF, including pulmonary embolism based on CT angiogram, pulmonary fibrosis, cystic fibrosis, and combined etiologies from the causes mentioned above.Group 2 was the non-NMRF group, which included patients with the following:2, PaO2, HCO3) in patients presenting with ARF due to NMRF and non-NMRF. To define and compare the ranges of arterial blood gas parameters a.PPD . This category represents the ventilation perfusion mismatch mechanism;b.Pneumonia: this category represents the acute shunting mechanism; andc.Pulmonary edema: heart failure and non-cardiac pulmonary edema; this category represents the chronic shunting mechanism.We compared the ranges of ABG parameters between NMRF and the following three categories of non-NMRF:(2)2 > 50 mmHg), hypoxia (<80 mmHg), and high bicarbonate levels (HCO3 > 22 mmol/L) between NMRF and non-NMRF and between NMRF and the three categories of non-NMRF mentioned above.We compared the prevalence of acidosis (pH < 7.35), hypercarbia (PaCO(3)We defined the ranges and prevalence of ABG parameters for each of the diseases included in our criteria separately.(4)2 > 50 mmHg).We compared the proportion of patients with NMRF and non-NMRF who fulfilled the definition of type II respiratory failure (PaCO(5)We compared the proportion of patients with NMRF and non-NMRF who had both hypercarbia and hypoxia.(6)We compared the proportion of patients with NMRF and non-NMRF who presented with isolated high bicarbonate levels (defined as >22 mmol/L).(7)We compared the proportion of patients with NMRF and non-NMRF who had either hypercarbia or hypoxia.(1)We defined and compare the ranges of ABG parameters between NMRF and non-NMRF patients in severe ARF cases (defined as requiring intubation for \u22655 days or death due to ARF within 5 days).(2)We defined and compare the ranges of combined BG (CBG) parameters (which includes venous BG when ABG prior to intubation was not available) between NMRF and non-NMRF.(3)We compared data provided by King Abdulaziz University hospital with those provided by other centers for NMRF cases.2 tests, and Fisher exact tests were used to compare the data between patients with NMRF and non-NMRF, as appropriate. Because this was a retrospective study, we used a convenient sampling approach, including all available cases that satisfied the inclusion and exclusion criteria; therefore, the sample size was not calculated as priori. Statistical analysis was performed using STATA version 13 .The characteristics of patients were analyzed using the median  and frequencies, as appropriate. Mann\u2013Whitney U tests, \u03c72) were higher in the non-NMRF compared to NMRF group . Hypoxia was more prevalent in non-NMRF (50.5%) and pneumonia (58.7%) patients compared to NMRF patients (33.8%) (p < 0.05). High normal or elevated bicarbonate levels were more prevalent in NMRF (76.8%) and PPD (73.9%) patients compared to pulmonary edema cases (44.1%).The prevalence of ABG abnormalities among the various categories of ARF is presented in 2 were observed in bronchiectasis and COPD patients. The lowest levels of PaO2 were observed in pneumonia, COPD, and bronchiectasis patients. The highest levels of HCO3 were observed in bronchiectasis and COPD patients, followed by ALS. The prevalence of ABG abnormalities for each disease is presented in The ranges of ABG parameters for each disease are presented in p = 0.02). The proportion of patients with NMRF and non-NMRF who had combined hypercarbia and hypoxia was greater among PPD (37.8%) than NMRF (13.2%) patients (p < 0.01) (p < 0.01) (p = 0.002) and compared to PPD (80%) patients (p < 0.001).We found that 17 (24.6%) and 87 (39.9%) patients with NMRF and non-NMRF, respectively, fulfilled type II respiratory failure criteria ( < 0.01) , whereas < 0.01) . The pro2 were observed in PPD patients. The lowest levels of PaO2 were observed in pneumonia patients. Pulmonary edema and pneumonia patients had the lowest HCO3 levels. The ranges of CBG parameters are shown in 2 and HCO3 levels than non-NMRF patients; in contrast, there was no difference in PaCO2. A comparison of data between the study centers revealed no differences  compared to NMRF 24.6%) patients. Combined hypoxemia and hypercarbia were most characteristic of PPD, whereas isolated high bicarbonate was characteristic of NMRF. A majority of NMRF patients in our cohort presented with either normal or mild hypoxemia and with normal PaCO% patient mmHg [2 ,2. This  mmHg [2 . The abn mmHg [2 . As NMRF2 levels ranging between 28 and 54 mmHg, which is similar to our data; however, the previous study reported a higher level of PaO2 than our data, with a mean of 101 mmHg [2 was found to be normocarbic, at 37 mmHg (31\u201345 mmHg) [2 levels of 41 mmHg (37\u201346 mmHg), which is consistent with our results, whereas average PaO2 levels were found to be 70 mmHg (61\u201393 mmHg) among intubated GBS cases, which is slightly lower than the PaO2 levels reported in our cohort [When each neuromuscular disease was analyzed separately, we found that MG and GBS shared a common profile, with a low proportion of patients with hypercarbia  and a low proportion with hypoxia . This is in contrast to the ALS group, where the proportions of hypercarbia and hypoxia were higher  than in the GBS and MG groups. A study examining MG exacerbation revealed PaCO101 mmHg . Regardi45 mmHg) . Additior cohort . This lar cohort . In GBS r cohort . Howeverr cohort . The samr cohort .2 of 79.9 vs. 86.9 mmHg, respectively. This finding is consistent with studies that have looked at COPD exacerbation cases and found an elevated mean of PaCO2 of 59 mmHg [2 and PaO2 to be 54 mmHg and 63 mmHg, respectively [2, whereas PaO2 levels vary between 60 and 80 mmHg [Non-NMRF cases span various mechanistic categories. PPD, including COPD, asthma, and bronchiectasis, causes ABG abnormalities through ventilation perfusion mismatch, whereby there is an area in the lung ventilated without gas exchange. Our study showed that the levels and prevalence of hypercarbia are higher in PPD compared to NMRF . Hypoxia occurred more frequently in PPD (51.1%) compared to of NMRF (33.8%), with a median PaO 59 mmHg . Anotherectively . This is 80 mmHg . PneumonOn average, arterial bicarbonate was higher among NMRF cases than non-NMRF cases. When NMRF was compared to different categories of non-NMRF, the difference in bicarbonate was more prominent versus pneumonia and pulmonary edema, whereas PPD had a similar level of bicarbonate. However, an important difference between NMRF and PPD is that patients with NMRF are more likely to present to ICU with isolated high bicarbonate (without hypoxia or hypercarbia) compared to PPD patients. Prior studies that looked at the serum bicarbonate level among patients with ALS have showed that 80% of those with elevated serum bicarbonate died within 5 months, whereas patients with normal serum bicarbonate levels remained alive at 15 months of follow-up . Among MOur data can be used in conjunction with the clinical context but not as a stand-alone test. The clinical implications of our findings\u2014in the appropriate clinical context\u2014include helping physicians to identify the underlying cause of acute respiratory distress in cases presenting for the first time without a prior clinical history. This will guide further clinical testing and consultation with the relevant specialties to confirm clinical suspicion. In addition, our data may alert physicians to a coexisting disorder contributing to acute respiratory distress in patients known to have certain disease, particularly when the pattern of ABG results does not fit the pattern expected of the known disease. Our data may guide planning of future clinical studies that address respiratory distress in neuromuscular and non-neuromuscular diseases when it comes to using ABG in inclusion criteria or for calculations of effect size or sample size. Nonetheless, we emphasize the importance of taking the whole clinical picture into consideration when interpreting ABG results, rather than considering ABG results in isolation, which could limit the usefulness of our data. Finally, defining the magnitude of ABG changes in NMRF and non-NMRF patients in a single study with similar methodology may contribute to a deeper understanding of the identified concepts associated with acute respiratory failure.Our study is subject to several limitations. The retrospective and observational nature of the study could contribute inherited bias. We did not incorporate oxygen saturation or respiratory rate data in our analysis. Another limitation of our study is that non-NMRF cases were included from only one center. However, because we collected the initial ABG upon presentation before therapeutic interventions, we believe that our data represent the disease course rather than a variation in the clinical practice in each center, although the later cannot be totally excluded (In conclusion, our data provide the expected range of ABG changes among patients admitted to ICU, and we found that hypercarbia occurred in a quarter of patients with NMRF. When compared with NMRF, PPD patients presented more frequently with hypercarbia, whereas pneumonia patients presented more often with hypoxia, and pulmonary edema patients have less elevated bicarbonate levels. Combined hypoxemia and hypercarbia are characteristic of PPD, whereas isolated high bicarbonate is characteristic of NMRF."}
+{"text": "This study provides an update of survey-based data providing an overview of interventional electrophysiology over the last decade. Overall infrastructure, procedures, and training opportunities in Germany were assessed.By analyzing mandatory quality reports, German cardiology centres performing electrophysiological studies were identified to repeat a questionnaire from 2010 and 2015.A complete questionnaire was returned by 192 centers performing about 75% of all ablations in Germany in 2020. In the presence of the COVID-19 pandemic, a total of 76.304 procedures including 68.407 ablations were reported representing a 38% increase compared to 2015. The median number of ablations increased from 180 in 2010 to 377 in 2020. AF was the most common arrhythmia ablated (51 vs. 35% in 2010). PVI with radiofrequency point-by-point ablation (64%) and cryo-balloon ablation (34%) were the preferred strategies. Less than 50 (75) PVI were performed by 31% (36%) of all centres. Only 25 and 24% of participating centres fulfilled EHRA and national requirements for training centre accreditation, respectively. There was a high number of EP centres with no fellows (38%). The proportion of female fellows in EP increased from 26% in 2010 to 33% in 2020.Comparing 2020, 2010 and 2015, an increasing number of EP centres and procedures were registered. In 2020, more than every second ablation was for therapy of AF. In the presence of an increasing number of procedures, training opportunities were still limited, and most centres did not fulfill recommended EHRA or national requirements for accreditation. Over the last decades, cardiac electrophysiology has become a pivotal subspecialty of cardiology with growing numbers of catheter ablations every year . In manyTo ensure overall quality, safety, and optimal patient care national and international standards as well as trained specialists in the field of cardiac electrophysiology are encouraged to match this development. In order that aspiring physicians in the field of cardiac electrophysiology receive proper training as heart rhythm specialists, national and international cardiology societies have developed training programs and curricula \u20139.To provide an overview and assess the current national status of physician training and patient care in cardiac electrophysiology including infrastructure, training conditions, and ablation procedures, we initiated this survey in 2010 . This muhttps://www.dimdi.de/dynamic/de/klassifikationen/ops/anwendung/zweck/index.html).Consulting the national legally mandatory quality reports of German hospitals, 340 centres were identified currently performing electrophysiological studies with the following reported OPS (operation and procedure code): 8\u2013835.2 (radiofrequency (RF) ablation), 8\u2013835.3 (irrigated RF ablation), 8\u2013835.4 (ablation with other energy sources), 8\u2013835.9 (MESH ablation), 8\u2013835.a (cryo-ablation), and 8\u2013835.8 (ablation with 3-D mapping). , the number of OPS given is not equal to the number of procedures performed. Centres coding for less than 30 ablation procedures a year were excluded to prevent the accidental inclusion of centres employing external electrophysiologists or coding OPS for externally performed procedures.Upon identification of the centres, we contacted the cardiology or interventional electrophysiology department by e-mail and/or phone to complete the same questionnaire that was utilized in previous surveys from 2010 .Among the included parameters in the questionnaire were: type of hospital; staff numbers and functions in cardiology and electrophysiology, gender aspects, infrastructure, number and types of EP procedures, techniques used, imaging modalities, presence of or distance to cardiac surgery. Furthermore, more detailed information on protection methods of the esophagus during AF ablation was requested. Gathered data were anonymized and consequently analyzed using R-Studio Version 1.4.1106 .Of all the centres, coding more than 30 ablation procedures per year, 192 (56%) answered the survey and were included in this analysis  were available in 110 (57%) centres.The electrophysiological departments were mainly part of a cardiology clinic (90%) with only 19 EP centres (11%) being independent with their own budget. A total of 106 centres (55%) were certified training centres for cardiac electrophysiological procedures by the German cardiac society (DGK). Heads of cardiological departments of 31 centres (16%) counted invasive electrophysiology as their main area of expertise. In 148 centres (77%), at least one catheter laboratory was exclusively used for invasive electrophysiology over 90% of the time. Thirty-five centres (18%) used two laboratories predominantly for EP procedures. 3-D mapping systems , device implantations were exclusively performed in operating rooms. The primary operator implanting these devices was a cardiologist in 147 (77%) centres and a surgeon in 8 (4%). Both cardiologists and surgeons performed these procedures in the remaining 36 (19%) EP centres.101 centres (53%) used the catheter laboratory also for all electrical device implantations, 12 (6%) centres in more than 50% of cases and 45 (23%) centres in less than 50% of cases. In the remaining centres  of departments with 27 centres (14%) having more than one head of department   and 3441 physicians in training  were employed. A total of 403 EP consultants  were employed with 36 (19%) centres having only one and 146 centres (76%) having two or more EP consultants in their team. EP Consultants from 139 centres (72%) also performed coronary interventions  training positions reported. In 46 (24%) centres, only one fellow was trained as a heart rhythm specialist. No less than 2 fellows were employed in 22 (11%) centres and at least 3 or more fellows in 51 (27%) centres. In contrast, 72 (38%) centres had no EP fellows  EP consultants performed catheter ablations with only one EP consultant present in the cardiological team in 7 centres (4%). Of these primary operators, 203 (37%) were less than 40\u00a0years old, 214 (39%) between 40 and 50, and 132 (24%) more than 50\u00a0years old; 53 (10%) worked part-time.For EP fellows, there were a total of 432 ; 59 centres (31%) performed less than 50 PVI and 25 (13%) centres were not ablating AF at all.A median number of 377 catheter ablations per centre were performed in 2020 with two or more physicians present throughout most ablation procedures in 134 (70%) centres  centres in all cases; 78 (41%) in over 50% of the cases.  followed by SVT , atrial flutter , and ventricular tachycardias   using a trans-septal and 61 centres (41%) a retrograde approach to reach the left ventricle. Of note, VT were not ablated in 43 (22%) centres. If necessary, 44 centres (23%) reported to perform epicardial ablations  or substrate modification using, e.g. defragmentation . In 72 centres (43%), imaging before AF ablation was routinely performed (MRI in 11 (7%), CT in 35 (21%), rotational angiography in 17 (10%); 3-D Echo in 9 (12%)). Consecutive atrial arrhythmias after AF ablation were ablated in 147 (77%) of participating centres. Sedation with propofol was the preferred standard approach (95%). Only a small number of centres  performed ablations under general anesthesia.The energy source predominantly used by the 167 centres  ablating AF was point-by-point radiofrequency current with 64% of all PVI vs. 34% cryo-balloon ablations (Table 2 blockers (78%) after ablation [Though rare, an atrio-esophageal fistula remains one of the most feared late complications after PVI because of its often lethal outcome . Therefoablation , reducinablation \u201316.Cardio-surgical back-up was available in-house in 64 (38%) of the centres performing AF ablations. If not available in-house, the distance to the next hospital having a cardio-surgical unit ranged from 1 to 150\u00a0km (mean: 35\u2009\u00b1\u200931\u00a0km). Surgical AF ablations were performed in 44 (26%) centres with 10 (6%) centres performing surgical AF ablations as stand-alone operations.n\u2009=\u200948) of the responding centres fulfilled the requirements provided by the EHRA or DGK ).The requirements to be accredited as an EP training centre according to the European Heart Rhythm Association (EHRA) and the German Cardiac Society (DGK) are illustrated in Table Reporting data from German centres performing electrophysiological studies, this multi-centre observational study is able to describe clear trends in electrophysiology over the recent decade comparing data from 2010 , and 202As training requirements differ not only in Europe but also in the U.S. it is difficult to determine an exact number of necessary ablation procedures needed to be an experienced EP centre . ReferenVery recently, a survey of members of the \u201cYoung DGK\u201d (median age 33\u2009\u00b1\u20093.3\u00a0years) regarding training opportunities for cardiology was published . The majIn the presence of increasing ablation numbers with growing complexity and novel ablation technologies, a high degree of sub-specialization is needed to perform these ablations. It is therefore surprising that (1) only 11% of the centres have an independent EP department (with/without its own budget) and (2) the majority of EP consultants also performs PCI on a routine basis. This proportion even increased in comparison with data from 2015 (63 vs. 72%). One may speculate that these aspects as well as the above-mentioned limited training opportunities require more dedicated independent EP centres in the future.Despite an overall increase of female physicians in most cardiological specialties, only less than 10% choose a career in EP . AddressAs it was seen in 2010 and 2015, PVI remains the most performed catheter ablation procedure even showing an increase in number compared to prior results . Considering that during the COVID-19 pandemic more elective PVI were cancelled than urgent ablations such as VT ablations, the true number of scheduled PVI may have been even higher. Nevertheless, the trend of an un-proportional increase in PVI as compared to all other ablation procedures over the last decade is demonstrated by survey comparisons from 2010, over 2015 to 2020  performed in Germany in 2020 and gives the chance to observe trends over a decade of electrophysiological advances. As the responding centres account for most ablations performed in 2020, smaller clinics might not be well represented in this survey, leading to the possibility of a slight over-estimation of median number of ablations per centre. To prevent the over-estimation of small centres where fewer catheter ablations are performed, we excluded centres coding for less than 30 ablations per year. This again might over-estimate the percentage of possible training centres fulfilling all requirements by the DGK and EHRA. Data about complications and specific outcome would have been of interest . But as this survey was devised to assess structural conditions in electrophysiological patient care and physician training, these data are not available.The present multi-centre observational study demonstrates a distinct rise in the need for electrophysiological treatment with increasing numbers of EP centres and performed ablation procedures as compared to 2010 and 2015. Only about a quarter of the centres fulfilled requirements of the EHRA and DGK for EP training centres, respectively. Training positions for physicians in electrophysiology have not adapted to this rising demand and have remained constant over the years. Women are still only scarcely represented in the field of interventional electrophysiology. PVI with point-by-point radiofrequency current (RF) as the mainly used ablation strategy remains the most performed ablation."}
+{"text": "Staphylococcus aureus carriage, targeted VRE surveillance is performed to identify and isolate colonized patients to reduce transmission. To assess risks and benefits of empiric therapy, we evaluated this surveillance procedure.Vancomycin-Resistant Enterococci (VRE) are major pathogens for severely immunosuppressed patients. Because VRE are common pathogens in our institution, such patients are often empirically treated to cover VRE, exposing them to broad-spectrum antimicrobials. Analogous to nasal screening for Methicillin-resistant vanA PCR, and the other was inoculated on CHROMEID\u00ae VRE (Biomerieux) if the PCR was positive. Subsequent clinical cultures of any site within 14 days of surveillance screening were reviewed for VRE.All patients admitted to two inpatient hospital units from 01/01/2019 to 12/31/2021 had routine perirectal VRE surveillance ordered and results retrospectively reviewed. One swab from each Culturette set was tested by 1133 patients were screened; 46 (4.1%) patients had VRE colonization. Within 2 weeks following VRE screening 20 patients had clinical samples that were positive for an Enterococcus species (14 in the first 7 days and 6 in days 8-14). The most common sites of clinical cultures were urine, 8 (40%), wound, 4 (20%), intra-abdominal, 4 (20%), and blood, 2 (10%). No clinical culture sample contained VRE.The rate of VRE carriage was low in this population, raising the question of the value of broad-spectrum empiric therapy coverage for VRE. No VRE infections were subsequently detected in any patients irrespective of surveillance. The negative predictive value for clinical VRE infection was 100% with negative surveillance screening in this population.All Authors: No reported disclosures."}
+{"text": "The Baby-Friendly Hospital Initiative\u2019s (BFHI) \u2018\u2018Ten Steps for Successful Breastfeeding'\u2019 has been the cornerstone of national and international strategies for decades; however, adherence is suboptimal. Despite successive National Strategies, breastfeeding rates remain low in Cyprus.The overall experience of a consecutive sample of 568 mother-baby dyads (response: 70.8%) across all public (N = 5) and 29 (of 35) private maternity clinics was operationalized as the sum score of full, partial or no implementation of each WHO/UNICEF BFHI self-assessment questionnaire item, with the exclusion of Step 6 (exclusivity). Associations with initiation and continuation of any (BF) and exclusive breastfeeding (EBF) up to the 6th month were explored in logistic regression after adjusting for potential confounders, including breastfeeding self-efficacy.At mean score 5.6 (SD = 2.4), the overall 10 steps experience was low , even among those who breastfed exclusively . EBF and BF initiation and continuation showed a stepwise association with self-reported experience of the 10 steps. Across quartiles of increasing scores, the prevalence of EBF was 7.1%, 15.1%, 17.0% and 35.6%. The quartile of mothers who assessed their experience more favourably were 8-  and 4-times  more likely to initiate BF and EBF, even though only 6.5% continued EBF by the 6th month. Step 7 (rooming-in) and step 9 (no pacifiers) were least practiced but more strongly associated with EBF initiation.While breastfeed intention may determine the actual experience of the 10 steps, implementation across maternity clinics appeared fragmented, despite clear association with successful initiation and continuation of BF, at the same time that the Cyprus National Committee for Breastfeeding is embarking on the first BFHI accreditation of maternity clinics.\u2022\u2002Despite successive National Strategies identifying breastfeeding as Public Health priority, adherence to the WHO/UNICEF\u2019s 10 Steps appears fragmented across Cypriot maternity clinics.\u2022\u2002Despite low overall adherence, mothers reporting experiencing more of the 10 steps were more likely to initiate and continue breastfeeding."}
+{"text": "Limited data are available locally; we aim to describe the clinical spectrum and outcome of mucormycosis in Saudi Arabia.A retrospective multi-center study including all patients with clinical and pathological evidence of mucormycosis in 3 tertiary care centers in Saudi Arabia from January 2009 to December 2019.Rhizopus (50%) and Mucor (15%). Most patients received medical therapy with amphotericin B (79%), and more than half were treated surgically. The 1-year mortality rate reached 48%, with higher mortality observed in disseminated and rhino-orbital-cerebral infections than in other sites.Thirty-three patients were identified during the study period. The mean age was 42 years. People with diabetes accounted for 48% of the patient population. The most common site of infection was cutaneous (27%), followed by isolated sinusitis (21%) and pulmonary and rhino-orbital-cerebral mucormycosis (each 18%). The most common isolated species were Our study addressed the epidemiology of mucormycosis in Saudi Arabia and showed comparable patterns of clinical and mycological aspects to worldwide reports. Further studies are needed to evaluate mucormycosis risk factors and prognosis based on the species, site of infection and therapy type. They were previously classified under the phylum of Zygomycetes, and infection with these agents was referred to as zygomycosis. . HoweverApophysomyces the most commonly identified species  from January 2009 to December 2019. All centers provide care for a large patient population, including solid organ and hematological malignancy patients, hematopoietic stem cell transplant recipients and solid organ transplant recipients.2.2Our study population included all patients with histopathologic or cytopathologic evidence of hyphae morphologically consistent with zygomycetes and associated tissue damage or patients with clinical and/or radiological evidence of infection and recovery of Mucorales by specimen culture obtained by a sterile procedure from a normally sterile site . Patient2.3Continuous data were described using median averages and interquartile ranges, while categorical data were described using frequencies and percentages. Data were collected using Microsoft Excel and entered into Statistical Package for the Social Sciences (SPSS) software for analysis.33.1A total of 33 patients were identified during the study period. The mean age was 42 years. People with diabetes accounted for 48% of the patient population, and 42.42% were diagnosed with hematologic malignancy. Solid organ and bone marrow transplant recipients represented a small proportion of the study population. No patients received deferoxamine therapy, were intravenous drug users, or were diagnosed with HIV. Further details are provided in 3.2The most common site of infection was cutaneous (27.27%), followed by localized sinusitis (21.21%) and pulmonary and rhino-orbital-cerebral mucormycosis, each representing 18.18% of cases . Most pa3.3Rhizopus species accounting for the majority of isolated organisms (50%), followed by Mucor species (15%). , with s (15%). . Rhizopurganisms .Figure 13.4Therapy included the combination of surgical debridement and antifungal therapy in 18 of the 33 cases (54.54%), while 11 patients were treated with antifungal therapy alone (33.3%). Three patients did not receive any therapy; 2 had cutaneous involvement, and 1 was an immunocompetent patient with pulmonary involvement who refused treatment. One patient with cutaneous mucormycosis was treated with surgical therapy alone; medical therapy was not provided as the diagnosis was established post-mortem .Table 3MThe most commonly used antifungal was amphotericin B , with amphotericin B lipid complex used in 15 of those cases and liposomal amphotericin B in the other 11 cases. Other agents used included Posaconazole in 2 patients and itraconazole in 1 patient.Most patients with rhino-orbital-cerebral mucormycosis received surgical therapy (5 of 6 cases). Of patients with isolated sinusitis, 6 of 7 were also treated with surgical debridement; 1 patient with hematological malignancy was not treated surgically due to advanced disease and risk of complications. More than half of patients with cutaneous infection were treated surgically (5 of 9 cases). All patients with gastrointestinal mucormycosis were treated medically . Granulo3.5Death within 1 year of diagnosis occurred in 16 patients (48.48%). Ten of 18 patients who received combined surgical and antifungal therapy died (55.56%), while 5 of 11 patients treated with antifungal therapy alone died (45.45%). Patients with rhino-orbital-cerebral infection had the highest mortality among infection sites, with 4 deaths occurring in the 6 cases. Pulmonary and isolated sinusitis mortality occurred in 3 of 6 and 4 of 7 cases, respectively. Three of 9 patients with cutaneous infection died; 1 had hematologic malignancy, 1 was a liver transplant recipient, and 1 had diabetes and extensive cutaneous involvement treated with surgical debridement only as the diagnosis was established post-mortem. One patient with disseminated infection died, and another with gastrointestinal infection who was too critically ill for surgical therapy and was treated with amphotericin B only .4Our study has illustrated the baseline clinical characteristics, presentation, mycology and outcome of mucormycosis in Saudi Arabia. The observed young, predominantly male patient population is similar to a global review of more than 900 reported cases . DiabeteWorldwide, including in the Middle East, rhino-orbital-cerebral mucormycosis is the most commonly reported site of infection . HoweverRhizopus species, consistent with the global epidemiology  and approved by the institutional review board in each participating center.This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.The authors have no conflict of interest to disclose."}
+{"text": "Nasal airway obstruction is a prevalent chief complaint in the contemporary facial plastic surgery practice. Studies report an asymmetric distribution of plastic surgeons across the United States with a disproportionately high concentration of surgeons practicing in urban areas. The lack of elective specialist care creates unique challenges for these patients who may need to travel and dedicate time to reach a nasal surgery expert. We conducted a retrospective chart review to report our experience from practicing functional nasal surgery in such a non-urban setting in the United States. A total of 103 patients underwent functional nasal surgery (FNS) between May 2015 and August 2021 including septoplasty, inferior turbinate reduction, septorhinoplasty and nasal valve procedures. We present the epidemiological characteristics, surgical techniques used and postoperative complications and illuminate the unique characteristics of practicing FNS in the non-urban setting. Studies report an asymmetric distribution of plastic surgeons across the United States: a disproportionately high concentration of surgeons practice in urban areas . Li et\u00a0aet\u00a0al.  identifiWe conducted a retrospective chart review with the approval of the Ethics Committee of our institution. A total of 103 patients underwent functional nasal surgery (FNS) between May 2015 and August 2021 including septoplasty, inferior turbinate reduction, septorhinoplasty and nasal valve procedures . All patients had failed previous management with at least 6\u00a0weeks of intranasal steroids. All surgical procedures were performed by the lead author.Sixty-four patients self-identified as males (62.1%) and 39 as females (37.9%). Ages ranged from 16 to 78\u00a0years (mean 38.05). Fifty-two patients (50.5%) reported a history of nasal trauma. Seven patients (6.8%) had previous FNS (reported septoplasty and/or inferior turbinate reduction) and 94 (91.2%) reported no previous nasal procedures. Forty-three patients (41.7%) were never smokers, 42 patients (40.8%) were active smokers and 18 patients (17.5%) reported past smoking history. Eighteen patients (17.5%) had a diagnosis of diabetes at the time of surgery .Spreader grafts were used at 46 patients (44.7%), columellar struts at 46 patients (44.7%), alar batten grafts at 41 patients (39.8%), caudal septal grafts at 7 patients (6.8%), other grafts reported at 16 patients (15.5%), autologous auricular graft harvested at 6 patients (5.8%) and inferior turbinate reduction performed at 27 (26.2%). Osteotomies were required in 26 patients (25.2%). Caudal septal grafts were reported when the L-strut required replacement . Other grafts included on-lay grafts, alar rim grafts and lateral crura strut grafts .Six postoperative complications (5.8%) were reported in four patients (3.9%). These included three posterior septal perforations, two cases of severe postoperative bleeding, one infection and one case of minimal persistent bleeding that required medical attention. All septal perforations were asymptomatic. The infection manifested with minimal drainage in the mid-columellar incision and resolved with a course of antibiotics. The minimal postoperative bleeding occurred in a patient who was managed only with inferior turbinate reduction.Limited by the relatively small size, we report our experience from FNS in a non-urban center. About 50.4% of our patients reported history of nasal fracture, making post-traumatic FNS a major part of our practice; 40.7% of our patients were active smokers, and 17.4% reported past smoking history, numbers unparalleled to any rhinoplasty studies. A tertiary center study reported 11% active smokers and 30% previous smokers among patients undergoing nasoseptal surgery [Our results illuminate the unique characteristics of practicing FNS in the non-urban setting. Solid clinical expertise is required to manage these challenging patients.None declared.None."}
+{"text": "This multicenter, open-label randomized clinical trial conducted in China compares the efficacy and safety of adjuvant capecitabine with concurrent chemoradiotherapy vs concurrent chemoradiotherapy alone for treatment of patients with locoregionally advanced nasopharyngeal carcinoma. Is the addition of adjuvant capecitabine safe, and does it improve failure-free survival (FFS) among patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) who receive concurrent chemoradiotherapy?This multicenter, open-label randomized clinical trial of 180 patients with LA-NPC met its primary end point of FFS benefit in favor of the addition of adjuvant capecitabine to concurrent chemoradiotherapy for treatment of patients with LA-NPC. The capecitabine compliance rate was 79%; the incidence of grade 3 or 4 treatment-related adverse events was 61% (55 of 90) in the capecitabine group and 52% (47 of 90) in the group receiving concurrent chemoradiotherapy alone.These findings suggest that treatment with adjuvant capecitabine confers an FFS benefit and is well tolerated in patients with LA-NPC, although future trials should determine optimal dosing and duration of adjuvant capecitabine. Induction or adjuvant chemotherapy with concurrent chemoradiotherapy (CCRT) are first-line treatment options for treatment of locoregionally advanced nasopharyngeal carcinoma (LA-NPC). Adjuvant platinum regimens are, however, poorly tolerated, highlighting the unmet need for an efficacious, tolerable adjuvant regimen.To investigate the efficacy and safety of adjuvant capecitabine with CCRT for the treatment of patients with LA-NPC.3; fluorodeoxyglucose F 18 positron emission tomography/computed tomography maximum standard uptake value of the primary gross tumor volume larger than 10.0; or multiple nodal metastases and any larger than 4.0 cm.This open-label randomized clinical trial recruited patients from March 31, 2014, to July 27, 2018, at 3 institutions in China, with at least 3 years of follow-up. The data collection cutoff date was February 9, 2022. Eligibility included stage III-IVb nasopharyngeal carcinoma and at least 1 of the following: T3-4N2 or T1-4N3; plasma Epstein-Barr virus DNA titer higher than 20\u2009000 copies/mL; primary gross tumor volume larger than 30.0 cm2 twice daily for 14 days every 3 weeks for 8 cycles) or observation following CCRT .Patients were randomly assigned 1:1 to receive either capecitabine . The incidence of grade 3 treatment-related adverse events (TRAEs) was higher in the capecitabine group than in the control group (54 of 90 patients [60.0%] vs 46 of 90 patients [51.1%]). Treatment-related adverse events included xerostomia (17 [18.9%] vs 9 [10.0%] patients), mucositis (21 [23.3%] vs 15 [16.7%] patients), and anorexia (8 [8.9%] vs 4 [4.4%] patients). The incidence of grade 3 delayed treatment-related adverse events was comparable in both groups (9 of 83 [10.8%] vs 7 of 81 [8.6%] patients).There were 180 patients enrolled . Among 90 patients in the capecitabine group, 76 (84.4%) had at least 2 high-risk factors; among 90 patients in the control group, 80 (88.9%) had at least 2 high-risk factors. All patients completed CCRT, except 1 patient in the capecitabine group who received 1 cycle of cisplatin. Of the 90 patients in the capecitabine group, 85 (94.4%) received capecitabine, with 71 (78.9%) completing 8 cycles. With a median (IQR) follow-up of 58.0 (49.5-80.1) months, 18 events were recorded in the capecitabine group vs 31 events in the control group. Failure-free survival was improved with adjuvant capecitabine (3 years, 83.3% vs 72.2%; 5 years, 78.5% vs 65.9%; hazard ratio, 0.53 ; In this randomized clinical trial, adjuvant capecitabine at the full dose following CCRT was well tolerated and improved failure-free survival among patients with LA-NPC and high-risk factors. Further investigations assessing optimal dose and duration are warranted.NCT02143388ClinicalTrials.gov Identifier:  The use of adjuvant fluorouracil and gemcitabine in combination with cisplatin yielded no difference in failure-free survival (FFS) and overall survival (OS), due in part to its inferior tolerability compared with induction chemotherapy, with only 50% to 75% of patients able to receive the full treatment dose.17 Chen et al9 did not demonstrate a survival benefit using adjuvant fluorouracil with cisplatin after follow-up of approximately 5 years16 despite enriching for a high-risk subset of patients with LA-NPC; of note, only 62.9% of participants tolerated 3 cycles of adjuvant fluorouracil with cisplatin. Although superiority of adjuvant fluorouracil with cisplatin was not demonstrated, it cannot be concluded based on that trial that CCRT alone was noninferior to CCRT and adjuvant fluorouracil with cisplatin.The role of adjuvant chemotherapy in LA-NPC, using regimens such as cisplatin with fluorouracil25 In addition, a recent randomized clinical trial of adjuvant capecitabine given at metronomic dosing for 1 year conferred FFS and OS benefits among patients with high-risk LA-NPC.19 Here, we report the efficacy and safety results after a median follow-up of 58.0 months in a randomized clinical trial of adjuvant capecitabine given at the full dose for 6 months.Capecitabine has proven single-agent activity in recurrent metastatic NPC and is efficacious when combined with cisplatin for induction chemotherapy in patients with LA-NPC.26; (5) no prior radiotherapy, chemotherapy, or surgery (except for diagnostic investigations) for the tumor; (6) adequate organ function; and (7) presence of 1 or more of the following unfavorable prognostic factors: T3-4N2 or T1-4N327; plasma EBV DNA titer higher than 20\u2009000 copies/mL28; primary gross tumor volume (GTV) greater than 30.0 cm29; a maximum standard uptake value of primary GTV higher than 10.0 on fluorodeoxyglucose F 18 positron emission tomography/computed tomography (18F-FDG PET/CT)30; or multiple nodal metastases and at least 1 larger than 4.0 cm.31 Exclusion criteria included (1) prior malignant tumors within 5 years of NPC diagnosis; (2) concurrent pregnancy; (3) concurrent immunotherapy or hormone therapy for other diseases; and (4) severe comorbidities. The protocol was reviewed and approved by the Ethics Committee of Sun Yat-sen University Cancer Center (SYSUCC) and by ethics committees and institutional review boards of the other participating hospitals on March 19, 2014. The study was registered on ClinicalTrials.gov May 7, 2014,32 and was performed in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. The first patient was recruited on March 31, 2014, and the second patient was recruited on July 23, 2014. Trial accrual was completed on July 27, 2018. Data analyses were performed based on a data collection cutoff date of February 9, 2022. All patients provided written informed consent. No one received compensation or was offered any incentive for participating in this study. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.The trial was designed by investigators from 4 institutions  or observation (control group) following CCRT. Randomization was performed at the Clinical Trials Center of SYSUCC on the day of study recruitment prior to CCRT. A computer-generated sequence was used to obtain the randomization list without stratification. After obtaining informed consent, the investigators at each institution contacted the study coordinators at the Clinical Trials Center and received treatment assignment information. The statistician (Y.G.) and study coordinators were uninvolved in the treatment of patients and data monitoring.2 every 3 weeks for 2 to 3 cycles depending on the duration of radiotherapy. Patients randomized to the capecitabine group then received 8 cycles of oral capecitabine at a dosage of 1000 mg/m2 twice daily for 14 days every 21 days,21 commencing 4 weeks after CCRT. Chemotherapy dose modifications were based on the nadir blood counts and acute toxic effects of the preceding cycle.All patients underwent CCRT and received intravenous cisplatin at a dosage of 100 mg/m33 Prescribed doses were 68 to 72 Gy, 60 to 68 Gy, 60 to 64 Gy, and 54 to 58 Gy in 30 to 32 fractions to the primary planning target volume, lymph node planning target volume, high-risk planning target volume, and low-risk planning target volume, respectively. Plan review was performed centrally by study investigators .All patients received intensity-modulated radiotherapy (IMRT), based on the principles of ICRU  reports 50 and 62. Details of the IMRT technique and delineation of target volumes, including primary GTV, GTV of all involved lymph nodes, high- and low-risk clinical target volumes, and the corresponding planning target volumes, were as previously described.18F-FDG PET/CT. If 18F-FDG PET/CT was unavailable, CT of the chest and abdomen and skeletal scintigraphy were performed. Plasma EBV DNA assays were performed centrally at SYSUCC for standardization.Patients underwent the following evaluations within 2 weeks before randomization: physical examination and nasopharyngoscopy, Karnofsky performance status evaluation, hematologic and biochemical analyses, EBV DNA titer, magnetic resonance imaging or CT of the head and neck, and 18F-FDG PET/CT was performed. When feasible, fine-needle aspiration or biopsy was performed for patients with suspected recurrence. Salvage treatments for recurrent disease were at the discretion of the physician in charge.Trial participants were reviewed at the following intervals: weekly during IMRT, prior to each cycle of capecitabine, every 3 months for the first 3 years, and every 6 months thereafter. All end points were assessed and validated by the physician in charge. The surveillance protocol included hematologic and biochemical analyses, contrast-enhanced magnetic resonance imaging or CT of the head and neck region, and CT of the thorax and abdomen 3 and 6 months after CCRT and annually thereafter. A plasma EBV DNA assay was performed during the last week of CCRT, and nasopharyngoscopy was performed 1 month after CCRT to evaluate tumor response. When the presence of recurrence was indeterminate, The primary end point was FFS, defined as time from the date of randomization to a documented relapse or any death. Patients unavailable for follow-up or alive without disease relapse were censored at the date of last follow-up. Secondary end points included OS, defined as time from the date of randomization to any death, with patients unavailable for follow-up censored at the date of last follow-up; distant metastasis\u2013free survival (DMFS), defined as time from date of randomization to documented distant metastasis or any death; and locoregional relapse\u2013free survival (LRFS), defined as time from the date of randomization to documented locoregional relapse or any death. Patients with distant metastasis as a first event were censored for LRFS at the date of distant metastasis and vice versa; if distant metastasis and locoregional relapse occurred concurrently, patients were considered as having an event for both DMFS and LRFS. Patients unavailable for follow-up or alive without distant metastasis or locoregional relapse were censored at the date of last follow-up.34Treatment compliance and treatment-related adverse events (TRAEs) during and after treatment were also recorded. For the capecitabine group, TRAEs were assessed at baseline and prior to each chemotherapy cycle until capecitabine completion or at the time of treatment discontinuation. For the control group, TRAEs were assessed at baseline, prior to each concurrent cisplatin cycle and 3 and 6 months after CCRT. Grading of TRAEs was performed using the Common Toxicity Criteria for Adverse Events, version 4.0, and the Radiation Therapy Oncology Group radiation morbidity scoring criteria. Delayed TRAEs were assessed using the latter.37) at a significance level of 5.0%. This HR would correspond to a 15.0% improvement in 3-year FFS with the addition of adjuvant capecitabine to CCRT.38 Considering a 4-year recruitment period and 3 years of follow-up, 164 patients (82 per group) were needed, assuming the distribution of survival times for both groups would follow an exponential distribution. This yielded a total cohort size of 180 patients (90 per group), accounting for a dropout rate of 10.0%.The sample size for this study was calculated using the PS: Power and Sample Size Calculation, version 3.1.2, software. A 2-sided log-rank test with 54 events in both groups provided at least 80.0% power to detect a hazard ratio (HR) of 0.46 when the 3-year FFS rate in the control group was 70.0%  principle. Safety data were summarized for all patients who started the assigned treatment. Survival curves were derived using the Kaplan-Meier method and compared using the log-rank test. Unstratified Cox proportional hazards regression models were used to estimate HR. Corresponding 95% CIs were based on the Wald test. The proportional hazards assumption was tested by including time-dependent covariates in the Cox models within the PROC PHREG module (test for interaction), and by assessing whether the Schoenfeld residuals were independent of time using simple linear regression and a trend test. Graphical methods were used to check the proportional hazards assumption using smoothed plots of scaled Schoenfeld residuals against time. Linear and log time scales were used for the assessment of proportional hazards.At the data collection cutoff date of February 9, 2022, the prespecified number of events (54 events) for the primary end point was not reached. The trial steering committee opted to report the results on the following grounds: there was (1) a lower than expected number of events despite enriching for a high-risk study population, (2) there was a substantial decrease in events beyond the third year of follow-up (9 vs 40 events in the first 3 years), and (3) the study period had reached 8 years with a median follow-up of nearly 5 years and a minimum follow-up of 42.5 months for the last patient enrolled.P < .05 was considered statistically significant. Statistical analyses were performed using SAS, version 9.4 (SAS Institute Inc); STATA, version 16 (StataCorp LLC); and R, version 4.0.2 . Figures were drawn using GraphPad Prism, version 9.0.0 (GraphPad Software).A 2-sided Between March 31, 2014, and July 27, 2018, 206 patients were screened, of whom 180 patients  were enrolled and randomly assigned to the capecitabine group  or the control group  . Pretrea2  received capecitabine, with 71 (78.9%) completing all 8 cycles; 5 patients did not initiate treatment, 8 patients completed 1 to 3 cycles, 4 patients completed 4 to 5 cycles, and 2 patients completed 6 to 7 cycles. The median (IQR) relative dose intensity of capecitabine was 100% (84.7%-100%)  showed complete response and 12 (13.3%) showed partial response; and for 90 patients in the control group, 79 (87.8%) showed complete response and 10 (11.1%) showed partial response . The medP\u2009=\u2009.03)  . The ratP\u2009=\u2009.03) .3, and an EBV DNA titer higher than 20\u2009000 copies/mL. An exploratory analysis for FFS performed for patients with or without a detectable EBV DNA titer after CCRT suggested an inferior FFS for the former, although statistical significance was not reached  were higher in the capecitabine group (54 of 90 patients [60.0%]) than for the control group (46 of 90 patients [51.1%]) , whereasThe incidence of grade 3 or 4 delayed TRAEs was 9 of 83 (10.8%) in the capecitabine group and 7 of 81 (8.6%) in the control group (eTable 7 in P\u2009=\u2009.03). Of 90 patients, 71 (78.9%) completed the full course of capecitabine, to our knowledge the highest compliance rate reported thus far among adjuvant chemotherapy trials.19 Our results support the use of capecitabine as an effective and tolerable adjuvant regimen for treating patients with LA-NPC.This randomized clinical trial addressed the unmet clinical need for a tolerable adjuvant regimen after CCRT by showing the efficacy and safety of single-agent adjuvant capecitabine in 180 patients with LA-NPC. With a median follow-up of 58.0 months, we recorded FFS rates in favor of CCRT with adjuvant capecitabine at 3 years (83.3% vs 72.2%) and 5 years  having received induction chemotherapy. That trial, but not ours, showed improved OS, although the cumulative dose intensities of capecitabine in both trials were comparable. The discordance in results thus suggests a need to further investigate the optimal duration and dosing of adjuvant capecitabine in LA-NPC because there could be antiangiogenic and immune modulation properties with metronomic dosing.43 Patients\u2019 preferences and likelihood of compliance for a 6-month vs a 1-year course of treatment also need to be considered.Nevertheless, we acknowledge the relevance of our trial may be questionable with the recent shift toward induction chemotherapy in LA-NPC.42 This suggestion is further supported by recent trials for patients with NPC that reported FFS and corresponding OS benefits after 3 to 4 years of follow-up.47 An updated meta-analysis will provide insights regarding whether progression-free survival remains a valid surrogate for OS among patients with LA-NPC given the emergence of effective salvage therapies.Although OS was not significantly different in the ITT population, the 3-year OS difference was 5.5% in favor of adjuvant capecitabine. The lack of statistical significance for OS is a consequence of the low number of death events even though we had enriched for high-risk factors in our study population (156 of 180 patients [86.7%] had \u22652 risk factors). The low number of deaths in our study could be due to the efficacious salvage therapies used at the time of recurrence, which included anti\u2013programmed cell death 1 antibody treatment and local metastasis\u2013directed therapies  who received this deintensified treatment.49 To clarify, the predominant use of 2 cycles of cisplatin was due to the IMRT fractionation schema, as treatment was completed within 6 to 6.5 weeks. Several studies have reported that cumulative dosing of 160 to 200 mg/m2 of cisplatin with radiotherapy is adequate to yield a survival advantage over radiotherapy alone among patients with LA-NPC.52This study has several limitations. First, this trial did not meet the expected number of FFS events. The trial steering committee opted to report the study results at this juncture because longer follow-up may not have yielded the required number of events given the acute decrease in event rates beyond the third year of follow-up. Second, the high risk factors included in the eligibility criteria were chosen based on retrospective series.The results of this randomized clinical trial indicated that treatment with adjuvant capecitabine following CCRT was well tolerated and had a high compliance rate. Long-term follow-up of nearly 5 years confirmed an FFS benefit with this treatment regimen. These results suggest that single-agent capecitabine may be considered an adjuvant regimen when treating patients with high-risk LA-NPC."}
+{"text": "Coronavirus disease 2019 (COVID-19) in the recent times have instilled signs of immunosuppression globally which has further precipitated increasing range of opportunistic infections. Mucormycosis is a distressing opportunistic fungal infection with a high incidence and is the third commonest acute invasive infection following candidiasis and aspergillosis. The aim of the present observational study is to delineate the enigmatic histopathological profile between mucormycosis cases seen prior to pandemic (PPM) and pandemic associated mucormycosis (PAM). Tissue archives of 105 histopathologically diagnosed cases of mucormycosis were included and analysed for demographical details and histopathological parameters like fungal load and localization, granuloma formation, necrosis, inflammatory infiltrate and tissue invasion. 0ut of 105 included cases, 11/105 (10.48%) were reported PPM and 94/105 (89.52%) PAM. Among 94 cases of PAM, 51/94 (54%) cases also showed COVID-19 positivity, while 43/94 (46%) did not. Of all the histological variables, increased fungal load and necrosis were observed in PAM relative to PPM cases. The histopathological variables like fungal load, necrosis, granuloma formation and tissue invasion, could help the clinician in assessing the clinical status at the time of tissue diagnosis and improve the treatment accordingly. Key words:COVID-19, fungal load, granuloma, mucormycosis, necrosis. Mucormycosis is an acute and deadly fungal illness caused by Mucorales fungal species with a high aggressive potential for contiguous spread and a poor prognosis . It mighThe health scenario post 2019 has been dominated globally by a novel strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which has multisystemic implications like cardiovascular abnormalities, renal failure, strokes and a high propensity for pulmonary symptoms . With a Mucormycosis tends to occur along with several risk factors including uncontrolled diabetes mellitus (DM), prolonged use of corticosteroids, haematological malignancies, solid organ or hematopoietic stem cell transplantation, human immunodeficiency virus infection, intravenous drug abuse and advanced age which ultimately leads to severe immunosuppression serving as a common ground in COVID-19 patients as well .The clear cut association between the drastic rise of Mucormycosis in COVID-19 patients still remains a gray area although several hypotheses have been suggested in the literature. The most widely accepted one is the adjunct of corticosteroids combined with microangiopathy in diabetes and chances of peripheral microthrombi in COVID-19 patients makes the host immunocompromised (affects the ability of macrophages to prevent the germination of the spores of these fungi) and forms the appropriate milieu for development of Mucormycosis .There have been multiple endeavours in reporting the time-sensitive Mucormycosis in COVID-19 inflicted patients but no study has been yet formulated which documents the difference between the histopathological spectrum of Mucormycosis prior pandemic and pandemic associated. Since the global healthcare system is presently burdened with dealing with the secondary complications associated with COVID-19, a better knowledge about the pathogenesis and the histological characteristics of this deadly invasive fungal infection might help in enhancing the treatment modalities.In this present study we aimed at studying the enigmatic histopathological realm of Mucormycosis in prior pandemic and pandemic associated cases with particular emphasis on fungal load and localization, granuloma formation, necrosis, and tissue invasion in haematoxylin and eosin (H&E) stained tissue sections in the hope that it will shed some light on its progression. An attempt has also been made to hypothesize the possible pathophysiology of Mucormycosis in prior pandemic and pandemic associated patients Fig. .The present observational study with retrospective measure was conducted in the Department of Oral Pathology and Microbiology, PGIDS, Rohtak, Haryana from April to August, 2021 after getting the Institutional Ethical Clearance (PGIDS/BHRC/21/46). 105 histopathologically diagnosed cases of Mucormycosis were collected from archives and split into two groups. Group-I prior pandemic Mucormycosis (PPM) comprised 11 cases of Mucormycosis which reported before COVID-19 pandemic, whereas Group-II pandemic associated Mucormycosis (PAM) consisted of 94 cases that occurred during the pandemic period.Inclusion criteria:1. Cases with suggestive clinical features and microscopic confirmation of characteristic broad, pauci-septate or aseptate, ribbon like hyphae with wide-angle branching diagnostic of Mucormycosis were included in study group.Exclusion criteria:1. Clinically suspicious cases lacking histopathological corroboration or those treated in outside hospitals were excluded from the study.Cases during PP and PAM were subcategorized as:Group 1 - PPM cases with diabetesGroup 2 - PPM cases without diabetesGroup 3 - PAM cases with diabetes, COVID-19 history and other comorbiditiesGroup 4 - PAM cases with diabetes, COVID-19 history and no other comorbiditiesGroup 5 - PAM cases with non-diabetic, COVID-19 history and other comorbiditiesGroup 6 - PAM cases with non-diabetic, COVID-19 history and no other comorbiditiesGroup 7 - PAM cases with diabetic and non COVID-19 historyGroup 8 - PAM cases with non-diabetic and non COVID-19 historyHaematoxylin & Eosin stained tissue sections of all the included cases were scanned at 40x/high power field (HPF) magnification by two independent observers (KR & AN) for histopathological parameters such as fungal load and localization, granulomatous response, necrosis, inflammatory infiltrate, tissue invasion and alteration in maxillary sinus lining.2. The fungal load was quantitated at several HPFs and graded as occasional (1+), mild (2+), moderate (3+) and marked 4+) respectively + respect.3. Similarly, granuloma formation was categorized into absent/occasional (0/1+), mild (2+), moderate (3+) and marked 4+) depending on the quantity of granulomatous foci + dependi.4. The predominant localization of fungal element at several sites including necrotic areas, granulomas, soft tissue without granuloma, soft tissue & bone, soft tissue necrosis & bone, and solitary bone tissue was recorded. Necrosis were sub-divided into, absent/occasional (0/1+), identifiable (2+), noTable (3+), and extensive (4+) .5. Likewise, inflammatory response was categorized into absent, mild (1+), moderate (2+) & marked (3+). Invasive fungal sinusitis was recorded as present, only when hyphal forms were identified within mucosa, blood vessel or bone, otherwise considered as absent .Fig. - Statistical testp-value of less than 0.05 was considered statistically significant in the non-parametric Chi-square test. Association between prior pandemic and pandemic associated Mucormycosis cases with various histological parameters were analysed.All statistical analyses were performed using Microsoft Excel worksheet and SPSS Statistics for Windows Version 25.0 . A two-sided The present study included 105 cases of mucormycosis, out of which, 11/105 (10%) were reported PPM and 94/105 (90%) PAM cases. Among 94 cases of PAM, 51/94 (54%) cases also showed COVID-19 positivity, while 43/94 (46%) did not. Male predominance was evident with male: female ratio being 2.6:1. The patients age ranged from 2 to 82 years with the mean age of 50.33\u00b114.82 years. Mean age of male patient was calculated to be 49.02\u00b113.79 and female patient is 53.75\u00b116.80. Predisposing factors were identified in 85/105 (79%) patients, among which 73/85 (90%) cases recorded with only DM and 10/85 (10%) with concomitant comorbidities alongside DM. The most common site of involvement was noted in the right maxillary sinus region (31/105-30%) followed by the left maxillary sinus involvement (21/105-20%), bilateral maxillary sinus (13/105-13%), palate (11/105-10%), right maxillary sinus and orbit (11/105-10%), left maxillary sinus and orbit (11/105-10%) and left alveolus (7/105-7%).- Fungal loadp value 0.001)  .- Fungal localizationp value of 0.002 , a larger load of granulomatous foci were observed amongst PPM cases.  cases showed absence of granuloma, 0/11 (0%) with mild and 4/11 (36%) with moderate granuloma. In PAM cases, 78/94 (83%) cases were observed with no granuloma formation, 1/92 (1%) with mild and 15/94 (16%) with moderate granulomas. Although there was no statistical significance observed   cases did not show necrosis whereas 2/11 (18%) cases exhibited identifiable grade of necrosis. In PAM cases, 20/94 (21%) cases presented with no necrosis, while 13/94 (14%) indicated noTable necrosis, 24/94 (26%) with identifiable and 37/94 (39%) with extensive necrosis. Chi-square analysis of the above results was found to be statistically significant (e 0.002) .- Inflammatory infiltrateMajority of PPM cases were observed with moderate (7/11- 63%) inflammation which was succeeded by mild (1/11-10%) and absent (3/11-27%). A considerable number of PAM cases displayed mild inflammation (41/94-44%) followed by moderate (28/94-30%) and absence (24/94-25%) of inflammation along with a single case of extensive infiltration by inflammatory cells (1/94-1%) .- Tissue invasionp value 0.662)  with tissue invasion. However, amongst PAM cases, 13/94 (11%) presented with tissue invasion, which was not significant statistically (e 0.662) .- Patternp value 0.003).Pattern 1 distribution as revealed in Fig. ROM is a potentially fatal infection resulting in angioinvasion, mycotic thrombosis and ischemic necrosis of tissues, which could end up in exenteration of the orbit . AlthougIn a recent publication, 187 cases of COVID-19 associated Mucormycosis (CAM) in India were reported, with an incidence rate of 0.27% amongst hospitalized cases. Two folds increase in the case load of Mucormycosis has been reported since the last year and currently a staggering 14,872 cases of CAM have been identified in India  which is comparable to the present study where the mean age was calculated as 50.33\u00b114.82 years and seen affecting more in males (72%) as compared to females (28%)  is the most frequent co-morbidity in Mucormycosis in about 73.5% in India with the incidence of 1.6 cases/1000 patients. However, in western countries diabetes is associated with only 17% cases of Mucormycosis  higher grade of fungal load in COVID-19 positive cases (46%) subsequent to pandemic rather than the prior pandemic era. It is assumed that the extreme immunosuppression brought about by COVID-19 could favour a higher fungal load which in turn could lead to vast necrotic areas in Mucormycosis cases amid the pandemic.The fungal load, explicating the amount of Mucorales in the tissue has an inverse proportionality to the survival rate of the affected individuals was recently reported by Ashina gal load . We haveGranulomas are evolutionarily ancient structures that have been considered as a protective mechanism to destroy or encapsulate foreign materials from further spreading, which elucidate its role in determining the prognosis of Mucorales infections . In the et al. , while only a couple of PPM cases (18%) presented with necrosis. In agreement with Ashina et al. , our obsInflammatory cells play a crucial role in the host defence and we found mild to marked inflammation in PAM cases 70/94 - 75.0%), while it was mild to moderate in majority of Mucormycosis 8/11- 73%) cases which took place during prior pandemic. The data was found to be consistent with the previous study regarding inflammation in Mucormycosis but no consistent association with survival rate and inflammatory infiltration was denoted , whereas pattern 1 with necrotic predominance was seen in PAM (45%), which could correlate with poorer immuno-compromised status of the patient and dire treatment outcome.Considering the aforementioned histopathological parameters and their subsequent patterns, these might deduce biological differentiation amidst PPM and PAM and further substantiate as evidence that PAM cases are more aggressive in comparison with PPM cases. However sharing our institutional experience of histopathological spectrum of Mucormycosis reported ahead of pandemic and during pandemic might open a platform for discussion, which could support the clinician in evaluating patient\u2019s progress and thus enhancing better treatment modalities and necessary follow up of such patients. Additionally we attempted to hypothesize the possible pathophysiology of Mucormycosis in prior pandemic and pandemic associated patients as elaborated in Fig. Our study focused on multiple histopathological facets of Mucormycosis yet the cases does not represent the entire spectrum of this diverse pathology. The follow-up data of the patients were insufficient for proper corroboration.Using the histopathological variables like fungal load, necrosis,granuloma formation and tissue invasion, our study provides useful insights for clinical and histological profile of COVID-19 positive cases affected with Mucormycosis and which could help the clinicians in assessing the clinical status at the time of tissue diagnosis optimizing the treatment protocol. We endorse a large-scale multi-centric prospective study that would help gain useful data on the main factors aggravating pandemic associated Mucormycosis, thereby managing unprecedented surge of Mucormycosis."}
+{"text": "Patients with COVID-19 are at risk of developing secondary complications such as invasive pulmonary aspergillosis and mucormycosis. This is a retrospective study including all cancer children diagnosed with COVID-19-associated pulmonary fungal infection (CAPFI) during the period 2020\u20132021. A total of 200 patients were diagnosed with COVID-19, out of which 21 (10%) patients were diagnosed with CAPFI, 19 patients (90%) with COVID-aspergillosis (CAPA), and 2 (10%) patients with COVID-mucormycosis (CAM). Patients with CAPFI were classified using the \u201c2020 ECMM/ISHAM consensus criteria\u201d; proven in 2 (10%) patients, probable in 12 (57%), and possible in 7 (33%) patients. Although the hematological malignancy patients were already on antifungal prophylaxis, breakthrough fungal infection was reported in 16/21 (75%), 14 (65%) patients had CAPA while on echinocandin prophylaxis, while 2 (10%) patients had CAM while on voriconazole prophylaxis. Overall mortality was reported in 8 patients (38%) while CAPFI-attributable mortality was reported in 4 patients (20%). In conclusion, clinicians caring for pediatric cancer patients with COVID-19 should consider invasive pulmonary fungal infection, even if they are on antifungal prophylaxis, especially with worsening of the clinical chest condition. A better understanding of risk factors for adverse outcomes may improve clinical management in these patients. The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic has markedly affected pediatric cancer patients. Children with malignancies were assumed to be at higher risk for severe coronavirus disease 2019 (COVID-19) due to their immunocompromised state; however, many studies reported that most pediatric cancer patients experience only mild to moderate COVID-19 infection . Among pAspergillus spp., with an incidence ranging from 19.6% to 33.3% [Patients with primary COVID-19 have increased susceptibility to secondary pulmonary infections, and many studies have reported co-infection with to 33.3% . Chest cto 33.3% . COVID-1The true incidence of CAPA is unknown as there is a lack of standardized diagnostic criteria with a mortality rate of about 48.4%, despite the widespread use of antifungals . Data abA retrospective study included all pediatric cancer patients diagnosed with COVID-associated pulmonary fungal infections (CAPFI), either aspergillosis (CAPA) or mucormycosis (CAM) diagnosed and treated in Children Cancer Hospital Egypt (CCHE) during the period from May 2020 to December 2021. The Children\u2019s Cancer Hospital Egypt is a tertiary pediatric oncology center in Cairo, Egypt. It is also the biggest oncology center in Africa and the Middle East, with more than 300 inpatient beds and accepting around 2000 new pediatric oncology cases annually. Data analysis included demographics, cancer diagnosis and treatment, COVID-19 severity, and management. We also analyzed the radiological, mycological, and histopathological data for COVID-associated pulmonary fungal infection. The severity of COVID-19 infection was classified as mild, moderate, severe, and critical . The treA diagnosis of COVID-19-associated pulmonary aspergillosis (CAPA) was defined based on the 2020 European Confederation of Medical Mycology/International Society for Human and Animal Mycology (ECCM/ISHAM) consensus criteria .Proven CAPA is defined by invasive growth of Aspergillus hyphae identified by histopathology/microscopy obtained by biopsy from a pulmonary site or Aspergillus positive culture or positive Aspergillus PCR or a combination obtained from sterile aspiration.Probable CAPA requires either pulmonary nodules or cavitating infiltrate or both detected by chest CT combined with mycological evidence with at least one of the following: microscopic detection of fungal elements in bronchoalveolar lavage (BAL), or culture or serum galactomannan index > 0.5, or BAL galactomannan index \u2265 1.0.Possible CAPA requires either pulmonary nodules or cavitating infiltrate or both detected by chest CT in combination with mycological evidence obtained via non-bronchoscopic lavage.Patients were classified as possible CAPA, probable CAPA, or proven CAPA:For diagnosis of COVID-associated mucormycosis (CAM), COVID-19 should be confirmed by a single RT PCR test, along with clinical, radiological, microbiological or histopathological evidence suggestive of mucormycosis as defined by ECMM/MSG worldwide guidance ,14.Response rate at 12-week treatment for patients using mycology study group and EORTC response criteria .Success  was defined as the disappearance of all signs and symptoms of fungal infection with clinical and/or radiological improvement compatible with the responding disease.Failure was defined as progressive fungal infection while on therapy or death attributed to the fungal infection as a primary or contributing cause .Definitions of response criteria are: The tabulated information was presented using standard descriptive statistics. Median and interquartile range (IQR) were used to describe continuous data. One-year overall survival (OS) was estimated using the Kaplan\u2013Meier method with survival duration calculated in days from the date of diagnostic RT-PCR. IBM-SPSS Statistics Version-20.0 was used in conducting data analyses.We analyzed the electronic medical records of 400 children who presented with signs and symptoms suspicious of COVID-19; thus, PCR testing was done to prove or exclude the infection during 2020\u20132021. In that sample, 200/400 (50%) were COVID-19 positive, among which 21 patients had evidence of COVID-associated pulmonary fungal infection .The median age was 7 years (ranged from 2 to 21 years), and 14/21 (66%) were male. The primary diagnosis was hematological malignancy in 71% , post auto-HSCT 10% (2 patients), and solid tumor in 19% (4 patients). Most patients with hematological malignancies had CAPA during induction phase chemotherapy (52%), while three patients (14%) during consolidation phase chemotherapy, and one patient (5%) during maintenance phase treatment. The two patients of Auto-HSCT had CAPA during the pre-engraftment phase. The reported clinical features for developing fungal infection aside from COVID infection were prolonged severe neutropenia (ANC < 100 or more than ten days) reported in 95% , long-teAccording to severity grading for COVID-19, 14 (66%) patients had moderate COVID-19, while 2 (10%) patients had a severe form, and 5 (24%) patients classified as very severe COVID-19. The median time for COVID clearance among our patients was (20 days) (range = 7\u2013120 days).The only available antiviral in our center was Remdesivir which was given to 19 (90%) patients for 10 days during the viral phase. The immune-modulatory treatments were given for patients with lung involvement and respiratory distress: steroids were given to 21 (100%) patients, while IL-6 inhibitor (tocilizumab) was given for severe cases with respiratory distress not responding to steroid treatment for 4 (20%) patients.Anticoagulant LMWH prophylaxis (1 mg/kg/24 h) if moderate COVID-19 was given to 4 patients and threptic (1 mg/kg/12 h) if severe was given to 7 (52%) patients.The treatment protocol for COVID-19 in our patients includes:A total of 21 (10%) patients were diagnosed with (CAPFI) among 200 children with cancer diagnosed with COVID-19 during the period (2020\u20132021). A total of 19 patients had CAPA and 2 had CAM. According to ECMM/ISHAM Consensus criteria, possible CAPA was diagnosed in 7 patients, probable in 12 patients, while 2 patients had proven CAM.Diagnosis of CAPF in our patients based on clinical, radiological, microbiological, and histopathological findings :Radiological finding: The radiological finding was defined according to the fungal definition: pulmonary nodular lesion more than 1 cm with a halo sign was reported in 11 (52%) patients, wedge-shaped consolidation patch was reported in 4 (20%) patients, and 6 (28%) patients had cavitary lung lesion in CT images.Mycological finding: Detection of galactomannan (GM) > 1 was reported in 13 patients (11 on serum and 2 on the BAL). Direct microscopic detection of fungal pathogens was detected in 3 patients. Tissue culture was also done on those samples and revealed Aspergillus flavus in one patient and Mucorales in the other 2 patients.Histopathological finding: Only two acute myeloid leukemia patients had histopathological biopsies; the pathological finding revealed aseptate fungal spore and hyphae, branching at the right angle, with positive PAS and GMS stain suggesting Mucorales.The median time from COVID-19 infection to the diagnosis of fungal infection in our study group was 11 days .Breakthrough fungal infection was reported in 16/21 (75%) patients receiving antifungal prophylaxis: 14 were on echinocandins (AML patients and ALL patients during induction), 2 patients on voriconazole (breakthrough CAM), and 2 patients on fluconazole (Hodgkin lymphoma patients undergo HSCT).n = 19) were treated with voriconazole as first-line treatment (dose 7 mg/kg/12 h). The two patients with CAM were treated with L-ampho B  as maintenance treatment. All patients were monitored with drug levels to remain antifungal on the therapeutic dose. Success was reported in 13 patients (62%), with a 12-week complete response reported in 7 (33%) patients and partial response in 5 (24%) patients. Failure was reported in 8 (38%) patients  among pediatric cancer patients diagnosed and treated in the Children\u2019s Cancer Hospital, Egypt. The incidence of CAPFI was 10% among patients with COVID-19, 19 patients with CAPA, and 2 with CAM. Success was reported in 62% of patients, while failure was reported in 38%. CAPA was the main attributable cause of death in 20% of patients.Most pediatric oncology patients present with a mild to moderate course of the disease, compared to healthy children . There iAspergillus and non-Aspergillus fungal infections have been reported in patients with severe COVID-19 pneumonia and were associated with poor outcomes [Several studies described the incidence of influenza-associated pulmonary aspergillosis (IAPA), ranging from 7% to 30% ,19,20. Ioutcomes ,22. Abououtcomes . The maioutcomes . In our Many reports described COVID-19-associated pulmonary aspergillosis (CAPA) in critically ill patients, with incidence reported at about 20\u201330% ,26. It iMany definitions were used to classify CAPA based on clinical, radiological, and microbiological evidence combinations. We used ECCM/ISHAM definitions  to classIn our study, pulmonary nodular and cavitary lung lesions were reported at 52% and 28%, respectively. The radiological finding of CAPA is mostly nonspecific, making the diagnosis difficult. Cavitary lesions and nodules are also relatively common but may be a late finding [Diagnostic tests used for diagnosis of CAPA are fungal markers, fungal PCR, cultures, and histopathology with increasing validity of diagnosis with multiple tests positivity ,28. PosiECCM/ISHAM guidelines for treating CAPA recommend voriconazole or isavuconazole for 6\u201312 weeks [Due to severe lung damage caused by SARS-CoV-2, potential coinfection with less common mold infection as mucormycosis and fusarium should be considered . The maiBreakthrough invasive mold infections have been reported among patients with hematological malignancies and HSCT on mold-active prophylaxis . BreakthData about COVID-19 related mortality in cancer patients are controversial. In the Abi Vijenthira study, adult patients with hematologic malignancy and COVID-19 had a 34% risk of death, whereas pediatric patients had a 4% risk of death . In a syThe limitations of the study were: lack of diagnostic tools such as fungal PCR, inability to document fungal infection by BAL being highly infective or by histopathology as critically ill patients and unavailability of antifungal susceptibility testing.In conclusion, COVID-19-associated pulmonary aspergillosis and mucormycosis are still challenging among pediatric cancer patients undergoing chemotherapy. Fungal markers are helpful in diagnosis, and rapid initiation of antifungals is mandatory. The clinician should be aware that COVID-19 is an additional risk factor for pulmonary fungal infection among pediatric cancer patients associated with a high mortality rate."}
+{"text": "Despite the progress of its management, COVID-19 maintains an ominous condition which constitutes a threat, especially for the susceptible population. The cardiac injury occurs in approximately 30% of COVID-19 infections and is associated with a worse prognosis. The clinical presentation of cardiac involvement can be COVID-19-related myocarditis. Our review aims to summarise current evidence about that complication. The research was registered at PROSPERO (CRD42022338397). We performed a systematic analysis using five different databases, including i.a. MEDLINE. Further, the backward snowballing technique was applied to identify additional papers. Inclusion criteria were: full-text articles in English presenting cases of COVID-19-related myocarditis diagnosed by the ESC criteria and patients over 18 years old. The myocarditis had to occur after the COVID-19 infection, not vaccination. Initially, 1588 papers were screened from the database search, and 1037 papers were revealed in the backward snowballing process. Eventually, 59 articles were included. Data about patients\u2019 sex, age, ethnicity, COVID-19 confirmation technique and vaccination status, reported symptoms, physical condition, laboratory and radiological findings, applied treatment and patient outcome were investigated and summarised. COVID-19-related myocarditis is associated with the risk of sudden worsening of patients\u2019 clinical status, thus, knowledge about its clinical presentation is essential for healthcare workers. The pandemic of COVID-19 had an immense impact on nearly every aspect of the modern world. Until August 2022 585 million people have been infected, and 6.4 million died ,4. CardiThe study was conducted following PRISMA guidelines  and was A systematic search was performed using EBSCOhost searching engine. MEDLINE, MEDLINE Ultimate, Health Source\u2014Consumer Edition, Health Source: Nursing/Academic Edition, Academic Search Ultimate and ERIC databases were screened. The research included papers published from 1 December 2019 until 1 June 2022. Two researchers (S.U. and M.B.) independently searched databases using the following keywords: (COVID-19 or coronavirus or 2019-ncov or SARS-CoV-2 or CoV-19 or novel coronavirus OR SARS CoV OR SARS-CoV-19) AND . Initially, 1588 papers were identified. After the automatic exclusion of non-English articles and duplicate removal, 695 papers were assessed and eventually, 17 articles were included in the analysis. Studies which one researcher positively qualified were left to the decision of the third investigator (M.F.). Further, reference lists, papers which cited selected articles and two similar systematic reviews [Inclusion criteria were: full-text peer-reviewed articles in English, case-report formula, age of patient \u226518 years, myocarditis after the COVID infection, laboratory-confirmed COVID infection , diagnosis of myocarditis by ESC criteria . ExclusiSimilarly to the study selection, data were extracted independently by two researchers (GI and MJ) and discrepancies were solved by the third (SU). Data regarding demographics and medical history, COVID presentation, applied diagnostics, treatment methods and outcome were collected . We haveAfter the full-text assessment, 59 studies and 70 patients were included in the analysis. All the counted percentages were calculated from the number of patients who had reported specific parameters.n = 16, 35%), obesity , dyslipidaemia  and asthma .Men constituted 50 out of 69 (73%) cases which reported sex. Age was reported in every case; the mean age was 44 (SD 15.67). Only in 1 reported case patient was vaccinated; however, the vaccination scheme was not fulfilled\u2014the patient received one dose of an unspecified vaccine 9 days before admission. Prior medical history and comorbidity status were reported in 46 cases\u201415 patients (33%) had no previous significant medical history. The most frequent comorbidities were hypertension , cough , chest pain/discomfort , diarrhoea  and weakness/fatigue . Symptoms were reported in 68 patients. Most frequent symptoms were dyspnoea  and 18 patients (42%) were febrile (over 38 C). Heart rate (HR) was reported in 46 cases, and the exact value was shown in 44 cases. The mean HR value was 112 beats per minute (SD 26.5), and tachycardia (over 100) was reported in 33 patients (75%). Blood pressure was described in 44 patients, and the exact value was shown in 40 cases. Mean systolic blood pressure was 105 mmHg (SD 26.17), and diastolic was 66 mmHg (SD 16.83). Hypotension  occurred in 15 patients (34%). Oxygen saturation without oxygen supply was reported in 37 cases; the mean value was 90% (SD 8.06), and 21 (57%) patients were considered to have low saturation (below 95%).The time relationship between COVID and myocarditis, i.e., myocarditis concurrent with the infection or after a specific period, was reported in 69 cases. In 46 patients (67%), myocarditis occurred during the infection. In the remaining 23 patients (33%), myocarditis followed infection. The time between infection and myocarditis was reported in 20 cases (87% of cases of myocarditis after COVID), and the mean time was 52 days (SD 49.13). Method of confirmation of COVID infection was declared in 56 patients. Polymerase chain reaction (PCR) showed the virus presence in 45 cases (80%), COVID was diagnosed based on serology results in 5 patients (9%), biopsy analysis revealed infection in 4 patients (7%), antigen test was performed in 2 cases (4%).The status of inflammatory markers was reported in 62 patients The reported markers included: C-reactive protein (CRP) ); ); procalcitonin ); ferritin ); interleukin-6 ; erythrocyte sedimentation rate  and fibrinogen (reported and elevated in 1 case).Most frequently reported cardiac biomarkers included: troponin ), brain natriuretic peptide (BNP) or N-terminal BNP (NT-proBNP) ) and DDimer ).All the values are from the earliest assessment during patients a hospital stay. We decided not to provide mean or median values of the reported markers due to different normal range values and laboratory assessment methods.n = 22, 38%), sinus tachycardia , T wave abnormalities , low QRS voltage or low QRS progression , ectopic rhythm origin\u2014including atrial fibrillation . Ventricular tachycardia occurred in 4 patients (7%).Electrocardiography results were reported in 58 cases. No pathological changes were reported in 3 patients (5%). Most frequent changes were: ST wave abnormalities (Chest X-ray findings have been reported in 30 cases (43%). The radiograph description of the heart has been mentioned in 3 cases, out of which 3 demonstrated cardiomegaly as a cardiac abnormality. Changes in lungs, however, have been reported in 19 case reports (27%), primarily multifocal opacities suggestive of viral pneumonia.The result of coronary angiography (CA) has been reported in 23 cases (33%). None of them revealed any relevant coronary artery stenosis.Computed Tomography (CT) has been performed in 42 cases (60%). Changes in heart have been stated in 11 patients (26%), out of which pericardial effusion was described in 6 cases and cardiomegaly in 4 patients. The changes in lungs have been observed in 31 cases (74%), mostly bilateral ground-glass opacities and pleural effusion characteristic of viral pneumonia. 1 case report mentioned evidence of pulmonary embolism in CT findings.The findings observed in Magnetic Resonance Imaging (MRI) have been reported in 33 cases (46%). The number of cases fulfilling Lake Louis criteria constituted 22 cases (67%), whilst 11 cases (33%) did not meet Lake Luis criteria. Nonischemic myocardial injury has been observed in 25 cases (76%). Myocardial oedema was confirmed in 17 cases (52%), systolic dysfunction in 11 cases (33%), hypokinesia in 7 cases (21%) and pericardial effusion in 5 of them (15%).The echocardiography results have been mentioned in 66 out of 70 cases (94%). Systolic dysfunction has been described in 55 patients (83%), among which 13 (24%) cases reported on biventricular. The Left ventricular ejection fraction (LVEF) has been measured in 46 cases, and the average LVEF turned out to be 28%. Heart wall hypokinesia or akinesia was reported in 24 cases (36%). The observation of pericardial effusion has been described in 19 cases (29%), heart hypertrophy in 13 cases (20%) and mitral or tricuspidal regurgitations in 6 cases (9%).Myocardial biopsy has been performed in 23 out of 70 cases (33%). The Dallas Criteria for myocarditis have been fulfilled in 21 (91%). The most commonly reported changes were diffuse lymphocytes infiltration which was found in 21 cases (91%), myocyte necrosis, mentioned in 5 cases (21%) and oedema in 4 described cases (17%).The sufficient information for establishing fulfilment of criteria of clinically suspected myocarditis, according to the European Society of Cardiology (ESC) guidelines , has beeThe first criterium, I. ECG/Holter/stress test features was fulfilled in 34 out of 68 cases (50%), the second criterium, II. Myocardiocytolysis markers was fulfilled in 64 out of 68 cases (94%), the third criterium, III. Functional and structural abnormalities on imaging (echo/angiography/CMR) was fulfilled in 58 out of 68 cases (85%) and the fourth one, IV. Tissue characterization by CMR was met in 24 out of 68 cases 35%). The analysis of treatment implemented in the care of described patients revealed the applied pharmacotherapy in 65 out of 70 cases (92%). Antibiotics were used in 43 out 65 cases (66%), among which azithromycin in 14, piperacillin/tazobactam in 10, meropenem in 8, vancomycin in 7, doxycycline in 7, colchicine in 7 and ceftriaxone in 6 cases. Steroids have been used in 42 cases (65%), with methylprednisone being most often prescribed\u2014in 24 cases. Vasopressors were used in 24 out of 65 cases (37%). Anti-viral drugs were applied in 18 out of 65 cases (28%), among which remdesivir in 9 and Lopinavir + Ritonavir in 5 cases. Inotropics were used in 16 out of 65 cases (25%), among which dobutamine was prescribed in 10 cases. Furtherly, anti-hypertensive drugs in 14 cases, hydroxychloroquine in 14 cases, IVIG in 14 cases, diuretics in 11 cases, anticoagulants in 11 cases, antiplatelet therapy in 10 cases, tocilizumab in 5 cases, NSAIDs in 4 cases and PPIs in 4 cases. The information about medical procedures performed in the care of described patients was mentioned in 34 out of 70 cases (49%). Mechanical ventilation has been applied in 14 patients (41%), and breathing support, meaning CPAP, high-flow or just oxygen, in 8 cases (24%). Extracorporeal membrane oxygenation (ECMO) was used in 16 patients (47%), and Continuous Renal Replacement Therapy (CRRT) in 7 patients (21%). Cardiac devices (ex. Impella CP) have been implemented in 10 cases (29%). The performance of pericardiocentesis or pericardiotomy has been mentioned in 6 cases (18%). Resuscitation was performed in 3 out of 34 cases (9%) and heart transplant in 1 out of 34 patients (3%).Adverse events complicating the course of illness have been described in 38 out of 70 cases (54%). The cardiogenic shock occurred in 15 out of 38 cases (40%), acute respiratory distress syndrome (ARDS) in 12 (32%), heart failure in 5 (13%), acute kidney injury (AKI) in 5 (13%), mixed distributive and cardiogenic shock in 4 (11%), septic shock in 3 (8%). Other complications mentioned included: disseminated intravascular coagulation (DIC), lower limb ischemia, lower limb myositis, facial nerve palsy and pulmonary infection.The final outcome has been reported in 63 out of 70 cases (90%). In 53 cases (84%), recovery has been achieved. The number of days till the patient\u2019s discharge was stated in 22 out of 53 cases (42%), with the average number of 16 days and the range from 3 to 52 days. Death was the outcome in 11 out of 63 cases (17%). The number of days from admission to the hospital till death has been given in 7 out of 11 cases (64%), with the average number of 9 days with the range from <1 day to 33 days. Most important features are shown in A summary of the most important findings is shown in Reported patients were predominantly men (73%). Myocarditis occurred in relatively young patients (mean age 44 years). Notably, 33% of patients had no previous medical history. Given that, the phenotype of the myocarditis patient\u2014a mid-aged man with no or a few comorbidities, does not suggest severe illness and can be falsely comforting for a physician. In 33% of cases, myocarditis occurred sometime after the COVID infection. Center for Disease Control and Prevention reports that myocarditis can be diagnosed several months after the infection. In the observed cohort of 36,005,294 patients, 89.6% were diagnosed with myocarditis in the same month as COVID infection, 6.6% 1 month after, and 3.9% \u2265 2 months after . In our Some of the most reported symptoms were dyspnoea, cough, chest pain and reported weakness. These are the typical myocarditis manifestations, and as they overlap the symptomatology of the COVID infection, making an appropriate diagnosis can be challenging . NoteworInflammatory markers, including white blood count, CRP, procalcitonin, ferritin, and interleukin-6, were typically elevated. The precise pathophysiology of COVID-related myocarditis remains unsolved, and a cytokine storm remains one of the hypotheses . SignifiNoteworthy, cytokine storm as a reflection of the hyperactive immune response is not the only proposed hypothesis for explaining myocardial injury by COVID-19. COVID molecules invade i.a. heart cells via the protein receptor angiotensin-converting enzyme 2 (ACE2). ACE2 is also associated with the modulation of the myocardial inflammatory response. The affected heart cells were noted to have a higher expression of the ACE2 receptors ,78. GiveCardiac markers, such as troponin or NT-proBNP, were elevated in most cases. The rise of both biomarkers in COVID infection was associated with a poor prognosis. Notably, the prognosis of the patients with preceding cardiovascular disease remained favorable . The higDescribed electrocardiographic findings present a wide range of changes and are not characteristic of myocarditis. On the other hand, physiological ECG was reported only in 5% of cases, suggesting that the ECG can successfully serve as a screening tool for myocarditis.Although endomyocardial biopsy (EMB) has lost its popularity , it reman = 24), suggestive of myocardial oedema. Even though there are no echocardiographic changes unique to myocarditis, the assessment of echocardiographic parameters is recommended prior to the EMB procedure. It allows excluding pericardial effusion or intracavitary thrombus, as well as it could help to exclude other causes of heart failure and may have a prognostic value [The deterioration of left ventricular systolic function was present in 83% of the described patients. This finding remains consistent with other systematic reviews: Jaisiwal et al.\u201474% , Ho et aic value . Moreoveic value .n = 22) of patients. It is also a prognostic marker for the increased risk of adverse cardiac outcomes in patients with myocarditis [n = 17) of reviewed cases, may affect myocardial function. It can be an expression of diffuse inflammation due to systematic response, vascular leakage induced by endothelial barrier dysfunction or direct myocardial damage caused by SARS-CoV-2 [Cardiac magnetic resonance is considered a noninvasive gold standard for diagnosing myocarditis . Late gacarditis . MyocardRS-CoV-2 ,94.n = 9) which can be a non-specific manifestation of various primary or acquired cardiomiopathies [n = 19). Normal X-Ray findings were described in 12% (n = 4). The 22 patients (31%) who underwent CA were predominantly men (n = 16), and their age ranged from 19 to 69, with a median of 42.5 years. Although CA is not a standard procedure in the diagnostics of myocarditis, the patients presenting acute retrosternal pain and dyspnoea at a relatively young age raise the alarm for myocardial infarct procedures [The most often quoted abnormal finding in X-Ray was cardiomegaly  into the COVID treatment was an attempt to address this pathological pathway. Indeed, the RECOVERY platform trial has proven that steroids play an important role in reducing COVID-19 mortality . DexametTreatment with non-steroidal anti-inflammatory drugs (NSAIDs) in myopericarditis is another unsolved problem. There are studies supporting the hypothesis that it can be potentially harmful and should be avoided in myocarditis , as wellAs ARDS was the most common complication, antibiotics were used, i.a., to prevent bacterial superinfection. The most willingly used antibiotic was azithromycin ,73,104. Surgical procedures like mechanical circulatory support or heart transplant are warranted particularly for patients with cardiogenic shock in the course of fulminant myocarditis, whose clinical state is deteriorating despite optimal medical treatment. Similarly, cardiac devices implementation should be considered in patients with myocarditis-related atrioventricular blocks or after a myocardial infarct. These technics should be considered early, when the highest possible pharmaceutics doses are insufficient to facilitate recovery ,89.The overall incidence of combined in-hospital mortality and heart transplantations associated with myocarditis, presented in 2018 in the study from Multicenter Lombardy Registry, was 3.2% , much loOur study is not free from limitations. The most important one is that the data for our analysis come from the case-report papers, which provide poor quality evidence. Further, most of the reported cases demonstrate very dramatic situations\u2014patients with severe and sophisticated course and complications\u2014which is attractive for the publication reasons but does not reflect the typical clinical situation. Given that, the generalizability of our conclusions is limited, especially in epidemiology. Conversely, presented descriptions give a detailed, patient-level evaluation of each case. Submitted data was frequently incomplete\u2014not every parameter was regularly described. We tried to choose and analyze only the most repetitive factors. Laboratory parameters were unsuitable for statistical analysis, as laboratories use different evaluation techniques and normal range values. Considering it all, quality or bias assessments could not be performed. Our study provides a current, interim summary of the data, while the results of more extensive, well-designed studies are unavailable.This systematic review provides the most recent summary of the reported COVID-related myocarditis. We present the complex summary of COVID-related myocarditis, which can serve as a reliable source of knowledge on that topic. Importantly, in approximately one-third of patients, myocarditis occurs a few weeks after infection, even up to 6 months. The necessity of considering COVID as a cause of myocarditis in relatively young and healthy populations should be strongly highlighted. Susceptible patients should be carefully observed after the COVID infection, even the poorly symptomatic one."}
+{"text": "Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can affect the nervous system and result in neurological symptoms. The most common feature of central nervous system involvement is hypoxia and congestion. This study aimed to evaluate the histopathology of cerebral tissue in deceased patients with coronavirus disease 2019 (COVID-19).In a case series study, we took cerebral samples of 30 deceased patients with COVID-19 through supraorbital bone from January to May 2021. The samples were fixed in a formalin solution, stained with haematoxylin\u2013eosin dyes and studied by two expert pathologists. The Ethics Committee of AJA University of Medical Sciences approved this study with code IR.AJAUMS.REC.1399.030.The mean age of the patients was 73.8 years, and the most common underlying disease was hypertension. Cerebral tissue samples showed hypoxic\u2013ischaemic changes in 28 (93.3%), microhaemorrhage in six (20%), lymphocytic infiltration in five (16.7%) and thrombosis in three samples (10%).Hypoxic\u2013ischaemic change was the most common neuropathology in our patient. Our study showed that many patients with severe COVID-19 may develop central nervous system involvement. HighlightsNeuropathology of 30 deceased patients with coronavirus disease 2019, the most comprehensive autopsy study in Iran.Presence of pathology in more than 93% of the patients.Presence of microhemorrhage in 20% of the patients.Presence of encephalitis in 16.7% of the patients.Unlike the Delta wave of the coronavirus disease 2019 (COVID-19) pandemic, where most patients died due to respiratory distress caused by viral pneumonia, the mortality rate is decreasing in the Omicron wave. In contrast, the morbidity rate seems to increase by recognising new complicationsBased on neuropathological studies, a wide range of cerebral tissue damage may occur during COVID-19, which may contribute to the long neurological complaint. One autopsy study reported focal haemorrhage, axonal injury, accumulation of macrophages and areas of necrosis with loss of white matter compatible with acute encephalomyelitis in a deceased patient with COVID-192 less than 90%, PaO2/FIO2 less than 300 mmHg and more than 50% pulmonary involvement on computed tomography (https://irimc.org/news/id/45952). We obtained written informed consent from the first-degree relatives of deceased patients before the sampling. All of the selected corpuses were transferred to the dissection room of the same hospital for the sampling, 6\u201324 h after death. We used a 16-gauge Jamshidi needle for the sampling. We took the cerebral samples through the right or left supraorbital bone and took a 2\u20134 cm vermiform sample by mild suction. Both the trainee physician and assistant who performed the sampling were equipped with a face mask and goggles, a long-sleeved fluid-resistant gown and nonsterile, nitrile, latex gloves. The dissection room is also equipped with negative-pressure ventilation.This study was a single-centre prospective case series on deceased patients with COVID-19. We registered our study in Iran\u2019s National Committee for Ethics in Biomedical Research, with the ethical code IR.AJAUMS.REC.1399.030. We performed this case series in an academic hospital in Tehran between January and May 2021. Our subjects were deceased patients with PCR-confirmed severe COVID-19 admitted into the ICU during the same period. The severity of the disease was defined as the 9th Edition of diagnosis and treatment of COVID-19 by the Iranian Ministry of Health, consisting of high-risk patients with a respiratory rate of more than 30 per minute, SpOWe took at least two cerebral tissue samples from each corpus. The sample tissues were placed in a container of formalin 10%, embedded with paraffin. We sent the sample tissues to the pathology laboratory of the same hospital. All tissues were stained with hematoxylin and eosin dyes after cutting by the microtome machine. Two expert pathologists studied the tissues separately, using a light microscope. We finally collected all clinical and pathological data and analysed them using the SPSS software, version 26, by Fischer\u2019s exact test. This case series has been reported in line with the Preferred Reporting Of CasE Series in Surgery (PROCESS) Guideline2. This included 17 patients (56.7%) with overweight, six patients (20%) with class 1 obesity and one patient (3.3%) with class 2 obesity, defined by the Centers for Disease Control and Prevention. The common symptoms were shortness of breath in 28 (93.3%), cough in 22 (73.3%), fatigue in 20 (66.7%), fever in 13 (43.3%) and loss of consciousness in 12 (40%). Hypertension and ischaemic heart disease were the most common underlying illnesses in 25 (83.3%) and 21(70%) patients, respectively. Other underlying diseases were diabetes mellitus in 13 (43.3%), chronic renal failure in 10 (33%) and chronic lung disease in two (6.7%) patients. Primary laboratory findings showed leukocytosis  in 10 (33%), leukopenia (WBC<4000) in four (13.3%) and normal WBC in 16 (53.3%) patients. Two patients (6.7%) had a platelet count below 100\u00d7105 at the time of admission. The D-dimer level was below 400 ng/ml in 14 patients (46.7%), between 400 and 800 ng/ml in nine patients (30%) and more than 800 ng/ml in seven patients (23.3%). C-reactive protein was in the normal range in two (6.7%), between 10 and 40 in seven (23.3%), 40\u201380 in 19 (63.3%) and more than 80 mg/l in two (6.7%) patients.We collected 30 cerebral tissue samples from 30 patients. None of the samples failed during the sampling. Our patients included 23 males and seven females. The mean age of patients was 73.8+13.4 years, and the mean time from the onset of symptoms to death was 16.4\u00b19.4 days. Twenty-four patients (80%) had BMI above 25 kg/mP=0.355), C-reactive protein level and encephalitis (P=0.185) by Fischer\u2019s exact test.The histopathological study revealed cerebral pathology in 28 of 30 (93.3%) cerebral tissues. The most frequent neuropathological findings included hypoxic\u2013ischaemic changes in 28 (93.3%) samples. Other findings consisted of microhaemorrhage in six (20%), lymphocytic infiltration compatible with encephalitis in five 16.7%) and thrombosis in three samples (10%) : S. Soleiman-Meigooni.Not commissioned, externally peer-reviewed."}
+{"text": "This study examines the challenges faced by Dementia Friendly Communities (DFC) during COVID-19 pandemic and the strategies used to address these challenges from the perspectives of DFC stakeholders in the U.S. Data were collected in 2020 through an online survey of 183 stakeholders  involved who were in DFC design, implementation, or evaluation. Three challenges rated most critical by participants included limited funding (40.4%), difficulties to provide services due to policies to contain COVID-19 (35.7%), and lack of staffing (29.3%). Three rated most important strategies included seeking funding and government support (31.1%), developing partnerships and relationships with multiple sectors (29.1%), and recruiting persons with dementia and family caregivers as advocates (27.5%). Communities demonstrated resilience during the COVID-19 pandemic to implement DFC- related activities. To sustain DFC, enhancing national awareness, acquiring additional funding, and firm cogency from staff members, local/state government, and local communities are needed."}
+{"text": "Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus which impairs quality of life in children and adolescents. Given the wide variety of symptomatic presentations in pediatrics, the varying time to diagnosis, and differing severity (including stricturing phenotype) initial treatments are not standardized. An important part of this individualization, beyond the health care practitioner counseling involves the patients\u2019 and parents\u2019 preferences which incorporates personal beliefs and attitudes.The study aim was to qualitatively describe parental and patient preferences regarding treatment options in EoE.This was a cross-sectional qualitative research study conducted in the EoE clinic at BC Children\u2019s Hospital, Vancouver. Parents and their children completed semi-structured survey questions regarding treatment preference in EoE. Patients along with their parents who completed their survey questions were included in the study. Incomplete forms were excluded from the study.The survey was attempted by 15 children, 7-11yrs of age, and 42 children, 12-18yrs of age, along with their parents. Completed response by both parent and their children were seen in 47 patients, 40 were adolescents 12-18yrs of age and 7 were 7-11yrs of age. Parent treatment preferences were diet in 17/47(36.2%), medications in 21/47 (44.7%) and 9/47 (19%) were unsure. 75% of parents who preferred dietary management thought it was less risky than medication. Parents who chose medication thought it would be easier (8/21) and more effective (8/21). Most of the parents\u2019 decisions were influenced by the physician  and more so by the gastroenterologist . In 12\u201318-yr olds, 6/40 (15%) had preference for diet, 25/40 (62.5%) preferred medication and 9/40 (22.5%) were unsure. 3/6 adolescents thought that diet was less risky and 4/6 thought it was more effective than medication. Among the teens who preferred medication, 17/25 (68%) felt it to be easier and 9/25 (36%) thought it would work better than diet. Teenagers found their parents to be helpful for deciding (50%) and doctor (50%) with the gastroenterologist again playing a prominent role. In the 7 to 11yr old age group, 4/7 (57.1%) predominantly had preference for dietary treatment.The overall preference in the adolescent age group is for medication supported by patients\u2019 and parents\u2019, with ease of use being a primary driver for adolescents, whereas ease of use and effectiveness were drivers for the parents. Parents were more often interested in dietary therapy than the adolescents. With regards to parents of younger children and younger children themselves, dietary management was the preference as they felt it to be less risky. The numbers, though small, represent one of the few studies done on patient preference in EoE. Future studies should include formal qualitative studies and preferences could ultimately be tied to better counseling and tracking adherence to therapy.NoneNone Declared"}
+{"text": "Invasive pulmonary aspergillosis is known to complicate the coronavirus diseases-2019 (COVID-19), especially those with critical illness. We investigated the baseline anti-Aspergillus antibody serostatus of patients with moderate-critical COVID-19 hospitalized at 3 COVID-19 Treatment Units in Uganda. All 46 tested patients, mean age 30, and 11% with underlying respiratory disease had a negative serum anti-Aspergillus IgM/IgG antibody immunochromatographic test on day 3 (mean) of symptom onset (range 1\u201326), but follow up specimens to assess seroconversion were not available. Demographic characteristics, co-morbidities and clinical outcomes of the patients were retrieved from the Integrated Biorepository of H3Africa Uganda (IBRH3AU) electronic database. IBRH3AU is situated in the Department of Immunology and Molecular Biology, School of Biomedical Sciences, Makerere University College of Health Sciences, Kampala, Uganda. The biorepository has in storage well annotated different sample types from over 500 COVID-19 patients and out of these, 46 serum samples of the eligible patients were randomly selected.Thawed serum samples of the eligible patients were examined using the commercially available anti-Aspergillus IgM/IgG antibody immunochromatographic technology (ICT) lateral flow assay, which has excellent sensitivity (88.9\u201391.6%) and specificity (96.3\u201398%) This study was approved by the Makerere University School of Biomedical Sciences Research and Ethics Committee Approval number; MHREC 1868. Patients records were registered using anonymous alpha-numeric codes and principles outlined in the Declaration of Helsinki were observed.We tested 46 serum samples from 46 unique individuals . The median age of the participants was 34 (range: 14\u201354) years. Forty (87%) patients had co-morbidities, mainly diabetes and cardiovascular diseases. The median duration of illness prior to hospitalization was 3 days (range: 1\u201326 days). Shortness of breath was the most common symptom reported by 42 (91.3%) participants followed by cough (37%), headache (32.6%) and fever (26.1%). Table 1Sixteen (34.8%) patients were hospitalized in the intensive care unit, with 8 (50%) of them requiring invasive mechanical ventilation. Twenty-seven (58.7%) patients received azithromycin, 12 (26.1%) hydroxychloroquine and 16 (34.8%) dexamethasone in addition to supportive care. Table 1Serum anti-Aspergillus IgM/IgG lateral flow assay tests were negative for all the patients.th to 10th dayThere is increasing evidence on the increased frequency and poor outcomes of invasive pulmonary aspergillosis in patients with severe/critical COVID-19The knowledge of the risk factors and burden of CAPA remains limited. There is no known established risk factor for the development of CAPA and patients with CAPA in most cases do not have the classic risk factors for invasive aspergillosisThus, the diagnostic work up for CAPA remains a work in progress. Among ICU patients, CAPA patients had a lower positive culture or polymerase chain reaction (PCR) or galactomannan test on bronchoalveolar lavage fluid compared to influenza patientsTo-date, no randomized clinical trial has evaluated any antifungal regimen for the treatment of CAPA. Current treatment approach is based on the basic principles of antifungal therapy extrapolated from experience and evidence of treating invasive aspergillosis in other population. As such, voriconazole or isavuconazole have been recommended as first-line treatment for possible, probable, and proven CAPAThe reader should consider the following limitation while interpreting the finding of our study. Importantly, the diagnosis of CAPA requires a combination of factors including mycological, host, clinical and histopathological factorsIn summary, among patients hospitalized with severe/critical COVID-19 in Uganda, we failed to find any evidence of current or prior immune response to Aspergillus infection. This finding potentially provides a useful clinical information on the rarity of Aspergillus infection among COVID-19 patients in Uganda. However, further research utilizing better diagnostic modalities is required."}
+{"text": "Although intestinal obstruction is a very common surgical emergency, there is a dearth of evidence regarding its prevalence at our institute. The objective of this study is to find out the prevalence of intestinal obstruction among patients admitted to the Department of Surgery of a tertiary care centre.st January, 2014 to 31st March, 2015. Data were collected retrospectively with ethical approval from Institutional Review Committee (Reference number: 106/071/072). All patients admitted to the surgery ward of the hospital with an age of 18 and above were included in the study. Convenience sampling was used. The data were recorded and analyzed using Microsoft Excel and Statistical Package for Social Sciences version 16.0. Point estimate at 95% Confidence Interval was calculated along with frequency and proportion for binary data.A descriptive cross-sectional study on a total of 6735 admitted patients' in Department of Surgery a tertiary care centre was conducted from 1Out of the 6735 admitted cases, the prevalence of intestinal obstruction among the admitted patients in the surgery department of the tertiary care centre was found to be 100 (1.48%) . The most common presentations were pain in the abdomen 93 (93%), vomiting 74 (74%), and abdominal distension 55 (55%).The prevalence of intestinal obstruction in our study was lower than the similar studies done in similar settings. Data were collected retrospectively with ethical approval from Institutional Review Committee (Reference number: 106/071/072). All patients admitted to the surgery ward of the hospital with an age of 18 and above were included in the study. Patients below 18 years of age, those with an incomplete set of information or misplaced files were excluded from the study. Convenience sampling method was used and the sample size was calculated as below:A descriptive cross-sectional study was conducted in the Department of Surgery, B.P. Koirala Institute of Health Sciences, Dharan, Nepal from 12 \u00d7 p \u00d7 q) / e2n\u2003= (Z2 \u00d7 0.0987 \u00d7 0.9013) / 0.022\u2003\u2003= 2p = prevalence of intestinal obstruction, 9.87%q = 1-pe = margin of error, 2%Since convenience sampling was used in the study, doubling the sample size, we got 4802. However, 6735 cases were taken. Out of the total 6735 patients admitted to the surgery department, the files of 100 patients diagnosed with IO were retrieved in their complete form. Data regarding the demographic profile, clinical presentation, general physical examination, per abdominal examination, digital rectal examination (DRE), systemic examination findings, investigations Ultrasonography (USG), X-ray abdomen, Contrast-Enhanced Computed Tomography (CECT) abdomen] and type of management done  were recorded in a predesigned proforma and analyzed using Microsoft Excel and Statistical Package for Social Sciences version 16.0. Point estimate at a 95% Confidence Interval and descriptive statistics were interpreted as frequencies, percentages.Out of the 6735 admitted cases, the prevalence of IO among the admitted patients in the surgery department of the tertiary care centre was found to be 100 (1.48%) . Among the 100 patients taken into consideration, 65 (65%) were male and 35 (35%) were female with a male to female ratio of 1.85:1. Most of the paients were beweeen 48-58 years of age. Most of the patients were from Sunsari district 22 (22%) followed by Saptari 16 (16%) and Jhapa 16 (16%) .History of previous abdominal surgery was present in 40 (40%) cases, of which the most commonly performed previous surgeries were exploratory laparotomy 35 (35%), gynaecological surgery 22 (22%) and appendectomy 17 (17%). Likewise, 5 (5%) of them had a past history of pulmonary tuberculosis and 3 (3%) had diabetes mellitus. The inquiries into their personal history revealed that 35 (35%) of the respondents smoked tobacco, 36 (36%) consumed alcohol, 22 (22%) were vegetarians and 78 (78%) had a mixed diet. The most common presenting complaint was abdominal pain 93 (93%) followed by nausea/ vomiting 74 (74%), not passing stool or flatus 60 (60%) and abdominal distension 55 (55%) .The most common findings on physical examination were abdominal tenderness 91 (91%), abdominal distension 63 (63%) and an absence of bowel sound 7 (7%). Digital Rectal Examination (DRE) was performed on all the patients with 92 (92%) of them having no abnormal findings, 4 (4%) having a suspected intraluminal mass, 3 (3%) revealing ballooning of the rectal mucosa, and 1 (1%) patient revealing traces of blood in the examiner's finger after DRE. The commonest investigation performed on the cases was abdominal X-ray 100 (100%) followed by USG 89 (89%) and CECT abdomen 3 (3%).Looking at the presentation of IO, 65 (65%) cases had a subacute presentation and the remaining 35 (35%) had an acute presentation. The commonest underlying condition of IO was postoperative adhesion 43 (43%) followed by volvulus 25 (25%) and malignant obstruction 12 (12%) .A nearly equal proportion of the patients received conservative management 49 (49%) and surgical management 51 (51%). The commonest performed operation was adhesiolysis 13 (25.49%), release of band 8 (15.68%), resection of sigmoid colon with double-barrel colostomy 6 (11.76%) and resection of ileum & anastomosis 6 (11.76%) .Among the operated patients, small bowel obstruction was found in 29 (56.86%) and large bowel obstruction in 22 (43.13%) cases. The commonest intraoperative finding was adhesions and bands causing constriction and kinking in the small intestine 18 (35.29%) followed by sigmoid volvulus 8 (15.68%). Among the operated patients, 14 (27.45%) had postoperative complications, namely 5 (9.80%) respiratory tract infections, 3 (5.88%) wounds infections, 3 (5.88%) electrolyte disturbance and 3 (5.88%) having other complications.6 Our study showed a male predominance (65%) in patients presenting with IO with a male to female ratio of 1.85:1 which is also comparable to the studies done in African countries: Nigeria  and Uganda ; but lesser as compared to two independent studies done in South India  and East India .8 The most common age group affected according to our study was 48-58 years, which is consistent with the studies done in East India (41-50 years) and South India (51-60 years).2The prevalence of IO in our study was found to be 1.48% which is lesser than that of a study done in South India (1.90%) and in Ethiopia (4.80%) but very low compared with that of a study done in East India (9.87%).1 However, in a study done in East India, abdominal distension was found to be the commonest presentation of IO (93%) followed by vomiting (91%) and constipation (82%).2The triad of presentation of IO according to our study was pain abdomen (93%), vomiting (74%), and abdominal distension (65%) which are quite similar to the findings of a study done in South India in the same order of presentation.9In our study, 40% of the patients had a previous history of abdominal surgery, with exploratory laparotomy being the commonest one (35%), followed by gynaecological procedures (22%) and appendectomy (17%). An explanation could be due to the extreme manipulation of the bowel during exploratory laparotomy and the relatively common occurrence of gynaecological and appendectomy surgeries. Similar results were also seen in a study done in the United States of America where the incidence of previous surgery was 63%, however, in that study, colorectal surgery (34%) was the commonest one followed by gynaecological surgery (28%) and exploratory laparotomy (20%).10 Postoperative adhesions (43%) were the commonest underlying condition of obstruction found in our study which is comparable to other studies in South India (40%), Pakistan (41%) and the United States of America (54%).12 The second most common underlying condition in our study was volvulus (25%) which is contrasting with those done in South India and East India where the obstructed hernia was found to be the second most common underlying condition of IO.2 This difference could be explained owing to the awareness of the public and also to the fact that hernias are electively repaired because of which, the obstructed hernias are becoming less common. Malignant obstruction secondary to tumours (12%) was the third most common underlying condition in our study followed by other causes such as intussusception, band by Meckel's diverticula, hernia, bezoars etc. which were almost similar to the study done in Turkey where adhesions accounted for 48%, sigmoid volvulus 15.50% and tumours 20%.13Our study reported small bowel obstruction in 56% of the patients studied which is lower when compared to the findings of a study done in Athens (76%).13 Respiratory tract infections (9.80%) were the most common postoperative complication in our study followed by wound infections (5.88%) and electrolyte imbalance (5.88%) with a fairly substantial number of patients (72.55%) having no postoperative complications. This is similar to the findings of the study done in South India where septicemia was found in 10% of cases, respiratory tract infections in 4% and wound infections in 4%.1In our study, 49% of patients were managed conservatively while 51% needed surgical intervention. In a study done in Turkey, 58.70% were treated conservatively.Since, all the case files of IO could not be retrieved as they were incomplete or misplaced in the record section, the actual disease burden of IO could not be estimated in this study.The prevalence of IO among admitted patients in the Department of Surgery at our institute was lower than the similar studies done in similar settings. Pain abdomen, vomiting and abdominal distension comprised the triad of clinical presentation. The common underlying conditions were postoperative adhesions, sigmoid volvulus and tumours. An equal proportion of patients received conservative and operative management with a substantial proportion of operated patients not having any postoperative complications."}
+{"text": "The mortality and morbidity of meconium aspiration syndrome in neonates born with meconium-stained amniotic fluid in developing countries are still high. In Nepal, few studies have estimated the prevalence of meconium-stained amniotic fluid among newborns. The study aimed to find out the prevalence of neonates born through meconium-stained amniotic fluid among deliveries in a tertiary care centre.This descriptive cross-sectional study was conducted among neonates born in a tertiary care centre from November 2021 to March 2022. Neonates born during the study period with meconium-stained amniotic fluid were studied. Ethical approval was obtained from the Institutional Review Committee. Convenience sampling method was used. With permission from the Department of the Neonatal Intensive Care Unit, the data were collected and entered in a Microsoft Excel sheet. Point estimate and 95% Confidence Interval were calculated.Among 576 neonates, the prevalence of neonates born through meconium-stained amniotic fluid was 77 (13.37%) .The prevalence of neonates born through meconium-stained amniotic fluid was found to be similar to other studies done in similar settings. The common causes of respiratory distress are Transient Tachypnea of newborns, Hyaline Membrane Disease and Meconium Aspiration Syndrome.2The prevalence of respiratory distress in a tertiary care centre in Nepal was found to be 6.55% among the total live births and 30.83% among the admitted cases of the Neonatal Intensive Care Unit (NICU) with an estimated mortality of 4.50%.4If the foetal meconium passes into the amniotic fluid then it is called Meconium Stained Amniotic Fluid (MSAF) and usually occurs in approximately 15-20% of term pregnancies and 30-40% of the post-term pregnancies.The study aimed to find out the prevalence of neonates born through meconium-stained amniotic fluid among deliveries in a tertiary care centre.A descriptive cross-sectional study was conducted among neonates born in Kathmandu Medical College Teaching Hospital (KMCTH) from November 2021 to March 2022. Ethical approval was obtained from the Institutional Review Committee of KMCTH. Neonates born during the study period with meconium-stained amniotic fluid were studied. The inclusion criteria were all newborns born in KMCTH within the study period. The exclusion criteria were patients whose parents did not give consent for the study, neonates with birth injuries, neonates with congenital malformations, multiple gestations and preterm babies. Convenience sampling method was used. The sample size was calculated using the given formula:Where,n = minimum required sample size,Z = 1.96 at 95% Confidence Interval (CI),p = prevalence taken as 50% for maximum sample size calculationq = 1-pe = margin of error, 5%The minimum sample size calculated was 385. However, the final sample size taken was 576.Data were entered in Microsoft Excel sheet. Point estimate and 95% CI were calculated.Among 576 neonates, the prevalence of neonates born through meconium-stained amniotic fluid was 77 (13.37%) . Out of 77 meconium-stained liquor, 27 (35.06%) had thin meconium .Thirty-eight (49.35%) women were nulliparous among 77 women who gave birth to neonates who had meconium-stained amniotic fluid. Low-segment Caesarean Section was the mode of delivery in 50 (64.93%) women .Among 77 neonates born through meconium-stained amniotic fluid, 8 (10.39%) developed meconium aspiration syndrome .Premature rupture of membranes was seen in 6 (7.79%) mothers of neonates born through a meconium-stained amniotic fluid .11 Studies conducted in Nepal have revealed the prevalence of MSAF about 6.5%-14.6%,12 among all live deliveries, the prevalence of MAS among MSAF about 6.6% to 8.6%,12 and neonatal mortality from MAS about 5.4% to 11.3%.12 The study conducted in India found the prevalence of MAS among MSAF as 7.7% to 21.5%,6 and mortality among MAS as high as 13.8%.6 The most common complication of MAS is Respiratory distress and other morbidities were convulsions, sepsis, shock, hypoxic-ischemic encephalopathy, hyperbilirubinemia and hypoglycemia.13In our study, the prevalence of meconium-stained amniotic fluid among neonates was found in 77 (13.37%) deliveries. The incidence of MAS was high in Nepal with an overall incidence of about 2.0 per 1000 live births.12 among all live deliveries, the prevalence of MAS among MSAF about 6.6% to 8.6%,12 and neonatal mortality from MAS about 5.4% to 11.3%.12Several studies conducted in Nepal have revealed the prevalence of MSAF about 6.5%-14.6%,12 The cost of care and utilisation of critical care services are frequent targets of concern for the healthcare system in a resource-limited setting.MSAF is an important determinant for both maternal and neonatal morbidity and mortality. The complicated MSAF needs prolonged admission of neonates in the NICU.14 The perinatal morbidity and mortality related to MSAF can be decreased if major risk factors are recognized early and closely monitoring of the labour and careful decisions are made about the timing and mode of delivery.14Meconium-stained amniotic fluid not only poses risk to the newborn but also significantly increases the rate of maternal complications such as meconium-laden amniotic fluid embolism, intrapartum chorioamnionitis, puerperal endometritis, wound infection, increased risk of operative delivery and its complication.7 However, Meconium aspiration syndrome (MAS) is still an important cause of neonatal mortality and morbidity in neonatal intensive care units (NICUs) in developing countries.12With the improvement of obstetric practices and perinatal care, the incidence of MAS and other causes of Respiratory distress is decreasing in developed countries.This study is a single institution-based descriptive cross-sectional study, the results might not be completely generalizable in other settings. So, a study design with a higher level of evidence is recommended for future studies. There may be non-response data as data will be collected from the patient party. There may also be information bias and respondent bias.The prevalence of neonates born through meconium-stained amniotic fluid among deliveries was similar to other studies done in similar settings."}
+{"text": "Coronary artery perforation (CP) is a rare but life-threatening complication of percutaneous coronary intervention (PCI). This study aimed to assess the incidence, management and outcomes of CP over time.A single-centre retrospective cohort study of all PCIs performed between January 2010 and December 2020. Patients with CP were divided into two cohorts (A+B), representing the two halves of the 11-year study.The incidence of CP was 68 of 9701 (0.7%), with an increasing trend over the two 5.5-year periods studied (24 of 4661 (0.5%) vs 44 of 5040 (0.9%); p=0.035). Factors associated with CP included chronic total occlusions (CTOs) (16 of 68 (24%) vs 993 of 9633 (10%); p<0.001), type C lesions (44 of 68 (65%) vs 4280 of 9633 (44%); p<0.001), use of intravascular ultrasound (IVUS) (12 of 68 (18%) vs 541 of 9633 (6%); p<0.001), cutting balloon angioplasty (3 of 68 (4%) vs 98 of 9633 (1%); p<0.001) and hydrophilic wires (24 of 68 (35%) vs 1454 of 9633 (15%); p<0.001). Cohorts A and B were well matched with respect to age , sex  vs 31 of 44 (70%); p=0.179) and renal function (chronic kidney disease: 1 of 24 (4%) vs 4 of 44 (9%); p=0.457). In cohort A, CP was most frequently caused by post-dilatation with non-compliant balloons (10 of 24 (42%); p=0.009); whereas in cohort B, common causes included guidewire exits (23 of 44 (52%)), followed by stent implantation (10 of 44 (23%)). The most common treatment modality in cohorts A and B was balloon inflation, which accounted for 16 of 24 (67%) and 13 of 44 (30%), respectively. The use of covered stents (16%) and coronary coils (18%) during cohort B study period did not impact all-cause mortality, which occurred in 2 of 24 (8%) and 7 of 44 (16%) (p=0.378) in cohorts A and B, respectively.The incidence of CP is increasing as more complex PCI is performed. Factors associated with perforation include CTO or type C lesions and use of IVUS, cutting balloon angioplasty or hydrophilic wires. Coronary artery perforation (CP) is a rare complication of percutaneous coronary intervention (PCI).Earlier reports have established several risk factors predictive of CP, which are typically split into patient, angiographic and procedural factors.This work demonstrates an increasing incidence of CP likely explained by a growing complexity of PCI procedures performed.The perforations were also graded according to the Modified Ellis criteria.These results will inform clinicians on the factors that contribute to an increased risk of CP.Furthermore, awareness of this complication can enable prompt recognition and treatment of such patients, ultimately improving patient outcome.Coronary perforation (CP) is the iatrogenic extravasation of blood or contrast from a coronary vessel, following a percutaneous coronary diagnostic or interventional procedure. It is associated with a 13-fold increase of in-hospital major adverse events and a 5-fold increase in 30-day mortality.1Several risk factors for CP have been identified. Clinical predictors include advancing age, female sex and presence of renal impairment. Angiographic factors include complex vessel anatomy, calcification, the presence of type C lesions (angulated or tortuous vessels) and attempt at percutaneous coronary intervention (PCI) for chronic total occlusion (CTO).4\u20137Modern coronary angioplasty increasingly involves the use of adjunctive PCI techniques to treat complex lesions in an ageing population. Two large UK registry studies have reported a CP incidence of 0.33%\u20130.56%.9This study aimed to compared the incidence, management and outcomes of CP across two halves of the 11-year study period (A+B). Additionally, we compare the changing trends in PCI complexity by looking at surrogate markers, namely intravascular ultrasound (IVUS), hydrophilic wires, rotablation, cutting balloon angioplasty and CTO procedures.This retrospective cohort study identified all PCI procedures performed between 1 January 2010 and 31 December 2020 inclusively, at the Queen Elizabeth Hospital, Birmingham, UK from a prospectively maintained electronic database. All patients who had a PCI procedure complicated with CP within this study period were retrospectively identified. The total CP population was then split into two further cohorts, A and B, for statistical analysis and comparison. The cohorts represented the first and second 5.5-year period within the study period. Cohort A included all perforations identified between 1 January 2010 and 2 July 2015, and cohort B referred to those that occurred between 3 July 2015 and 31 December 2020.Two independent researchers collected data on the following parameters: patient demographics, comorbidities, angiographic characteristics, operator factors, treatment modalities, outcomes . Cardiac tamponade was defined as the accumulation of extravasated fluid in the intrapericardial space.11The two independent researchers analysed the angiographic appearance of the patients in search of results consistent with perforation and to analyse the vessel anatomy. CP was further stratified according to the Modified Ellis criteria, which differentiated CP into five distinct types .12 1312 1310.1136/openhrt-2021-001916.supp1Supplementary data2 test. Sample means were tested via a two-tailed t-test. All p<0.05 were deemed statistically significant.Statistical analysis was conducted using SPSS software V.23.0 . The normality and distribution of continuous data were tested using a Shapiro-Wilk test. For normally distributed data, a mean and SD were calculated. Categorical data were summarised as a percentage and statistically tested using a \u03a7CP occurred in 68 cases out of 9701 PCI procedures, with an overall incidence of 0.7% . Cohort Baseline characteristics are shown in Over the 11-year period studied, amongst patients with CP, there was a significantly higher number of type B2 lesions treated in cohort A (7 of 24 (29%) vs 3 of 44 (7%); p=0.013) and in-stent restenoses treated in cohort B (0 of 24 (0%) vs 9 of 44 (18%); p=0.026) . There wPatients with CP were more likely to have had PCI attempted for CTOs (16 of 68 (24%) vs 993 of 9633 (10%); p<0.001) and type C lesions (44 of 68 (65%) vs 4280 of 9633 (44%); p<0.001) . ProceduIn cohort A, the most common cause of CP was post-dilatation with non-compliant balloon (10 of 24 (42%); p=0.009) . OverallIn cohort B, the majority of type I and II (7 of 44) perforations were managed conservatively through observation (5 of 7 (71%)), while balloon inflation was used in a minority of cases (2 of 7 (29%)). Similarly, type III perforations (19 of 44) were largely treated by covered stent deployment (7 of 19 (37%)) or balloon inflation (6 of 19 (32%)). Emergency cardiac surgery was performed to treat type III perforations in a minority of cases (3 of 19 (16%)). In contrast to cohort A, the use of coronary coils was the main modality in treating type V perforations in this cohort (7 of 18 (39%)).Overall, amonngst CP cases, compared to cohort A, cohort B were more likely to reach the composite outcome of tamponade, death or requirement for cardiothoracic surgery (3 of 24 (13%) vs 14 of 44 (32%); p=0.079). Type III perforations wereassociated with the highest frequency of composite adverse outcomes compared with any other perforation type (10 of 17 (59%)). Of all reported deaths, eight of nine (89%) were due to type III left anterior descending perforations. One death occurred in a type II perforation after cardiogenic shock. Cardiac tamponade was a poor prognostic factor, contributing to 50% and 71% of deaths within cohorts A and B, respectively.This retrospective cohort study investigated the incidence, management and outcomes of an 11-year dataset of CP at a large regional cardiac centre. The study demonstrated that the incidence of CP was rising across the 11-year study period. The study also confirms the poor outcomes following type III perforations and found that the presence of cardiac tamponade was a poor prognostic indicator. Furthermore, a greater proportion of poorer composite outcomes were observed during the latter 5.5-year study period. Surrogate markers of PCI complexity were factors associated with perforation.During the period studied (2010\u20132020 inclusively), the incidence of CP rose from 0% to 1.46% per annum. The overall incidence of CP is slightly higher than those reported in large UK registries from 2008 and 2013, but similar to a Netherlands-based study from 2016.Furthermore, the study identified notable peaks in the incidence of CP in 2013, 2016 and 2020. While the peaks in 2013 and 2016 could be explained by the introduction of new consultants in the department, the peak in 2020 is likely related to the COVID-19 pandemic. Due to the high intensive care bed occupancy, there was an overall decline in the number of interventional procedures performed but an increase in PCI performed in patients who would have otherwise been candidates for cardiac surgery.This study found that patient factors associated with CP include increasing age and smoking history, which are both associated with more significant coronary artery disease. Previous studies have also identified female sex and comorbidities as risk factors for CP.Over the 11-year period studied, there were poorer outcomes observed in the latter 5.5 years (cohort B), despite the introduction to our centre of covered stents and coronary coils in 2016.et al.The study also confirms the gravity of type III perforations as the incidence and overall mortality of this subtype were 0.31% and 27%, respectively, both of which were greater when compared with the results published by Al-Lamee This study is a retrospective data analysis from a single regional cardiac centre, thus the findings are subject to the inherent limitations of a retrospective cohort study. There was no control group or angiographic follow-up; thus, it is difficult to comment on target vessel failure or rates of re-intervention following covered stent deployment. In addition, the study did not analyse the effect of individual operators on the incidence of coronary perforation and patient outcomes. Despite a high volume of procedures performed at this centre, the number of cases within the CP cohort and its subsequent subgroups was low. This reflects the rarity of this complication. A multivariate analysis was performed, but not shown, due to a relatively small sample size yielding statistical insignificance. Thus, the study was unable to identify independent predictors of CP. Data on coronary vessel calcification were unavailable thus the study was unable to determine the full extent of vessel disease on the incidence of CP. Furthermore, an analysis of multiple comorbidities on the risk of CP was not conducted."}
+{"text": "Many COVID-19 patients continue to test positive for COVID-19 beyond the typical quarantine period. Persistent positive testing complicated hospital discharges to nursing home (NH) based rehabilitation facilities when (in May 2020) New York State (NYS) required a negative COVID result prior to NH admissions. To meet the needs of medically stable persistent positive patients, NYS approved 19 NHs as COVID-only facilities (COF). These facilities provided rehabilitation services and allowed hospitals to regain critical space for incoming acute care patients. In the present study we describe the (1) establishment of a 100 bed COF, (2) patients admitted to the COF and care provided, and (3) predictors of successful discharge to the community.Information on the establishment of the COF was obtained from interviews with NH leadership and clinical staff. Patient, treatment, and outcome data were obtained from the NH\u2019s electronic health record. Of 319 COF admissions over four months, 54% were female and the mean age was 80 years (SD=10.56). 51% had cognitive impairment and the mean number of comorbidities was 6.75 (SD=2.47). All patients received physical and occupational therapy while 37% received speech therapy. Medical treatment included: anticoagulants (52%), oxygen (37%), antibiotics (35%), inhaler/nebulizers (31%), and oral steroids (15%). 59% of COF stays resulted in successful community discharges. This outcome was more likely for patients who had fewer comorbidities, less speech therapy, and did not require antibiotics. Implications for COVID care as well as leveraging NH potential during crisis will be discussed."}
+{"text": "Identifying opportunities to safely reduce antibiotic prescribing is necessary for prescribers and antibiotic stewardship teams to minimize unwarranted antibiotic use. We aimed to quantify excess antibiotic use in General Surgery.We retrospectively audited the antibiotic prescribing for patients discharged from the General Surgery specialty in an acute hospital in the south-west of England between 01/08/21 and 31/08/21 using an audit tool developed by Public Health England. The appropriateness of prescribing was determined for each patient at three antibiotic decision time-points: at initiation, the pre-72h antibiotic review, and treatment duration. Two infection specialists and a general surgeon reviewed each patient. Indication and excess days of therapy (DOTs) were calculated at each decision time-point and expressed as a proportion of total DOTs.Eighty-six patients were prescribed 1162 DOTs; 192 (16.5%) excess DOTs were prescribed in 38 patients (44%), with zero excess days identified in the remaining 48 patients (56%). Seventy-five of 192 (39%) excess DOTs occurred at initiation; 55/192 (29%) after the pre-72hour antibiotic review; and 62/192 (32%) due to protracted antibiotic courses. There was concordance between the general surgeon and infection specialist for the majority of apportioned excess DOTs. However, the surgeon apportioned fewer excess DOTs 160/1162 (13.8%). Overall IV antibiotics accounted for 53.4% of total DOTs. Seventy-two of 86 (83.7%) patients received 620 intravenous DOTs; of these, 79 (12.7%) IV DOTS were unnecessary.We have identified excess antibiotic prescribing in General surgery with comparable excess DOTs at all three time-points."}
+{"text": "Caesarean section is one of the most common obstetric operations performed. Primary caesarean section in multiparous women means the first caesarean section done in the multiparity who had previously delivered vaginally. This study aimed to find out the prevalence of primary caesarean section among multiparous pregnant women visiting a tertiary care centre.A descriptive cross-sectional study was conducted among multiparous women in a tertiary care centre from 15 June 2020 to 14 June 2021. Ethical approval was obtained from the Institutional Review Committee (Registration number: F-NMC/420/075/076). Demographic data were collected using predesigned proforma in parous women who had a previous vaginal delivery. A convenience sampling method was used. Point estimate and 95% Confidence Interval were calculated.Among 1158 multiparity, primary caesarean section was found in 155 (13.39%) . Most women 62 (40%) belong to 21-25 years and the majority were second gravida 51 (32.90%). The emergency caesarean section was done in 149 (96.12%). Indications for primary caesarean section were fetal distress 63 (40.63%), non-progress of labour and breech 12 (7.74%). Post-operative complications were uneventful in 110 (70.96%) cases.The prevalence of primary caesarean section in multiparous women was found to be higher than the other studies done in similar settings. Solomon coined the phrase\" dangerous multiparous\" while Feeney preferred the term \"unpredictable multiparous\" because of unforeseen complications that may occur in multi para.This study aimed to find out the prevalence of primary cesarean section among multiparous pregnant women visiting a tertiary care centre.This descriptive cross-sectional study was conducted in the Department of Obstetrics and Gynaecology of National Medical College and Teaching Hospital for a duration of one year from 15 June 2020 to 14 June 2021. The ethical approval was obtained from the Institutional Review Committee of the National Medical College and Teaching Hospital (Registration number: F-NMC/420/075/076). Women who had previous one or more vaginal deliveries, previous instrumental deliveries, previous assisted breech deliveries, stillbirths and intrauterine death were included. Pregnant women with gestational age less than 28 weeks, previous myomectomy, and previous abortion were excluded from the study. A convenience sampling technique was used. The sample size was calculated using the following formula:Where,n= minimum required sample sizeZ= 1.96 at 95% Confidence Interval (CI)p= prevalence of taken as 50% for maximum sample sizeq= 1-pe= margin of error, 3%The calculated sample size was 1068. However, we have taken 1158 multiparity women meeting the selection criteria.Data was collected and noted on a structured proforma. On receiving a case, participants were explained about the study in detail. They were assured of confidentiality and informed written consent was taken. Detailed history including present pregnancy and past obstetric history was taken. All baseline investigations . The decision for caesarean section was based on clinical evaluation of the progress of labour, fetal condition, and also maternal condition. The type of anaesthesia was decided by the anaesthetist. All intraoperative details were noted and complications were managed promptly. All babies were attended by a paediatrician. The postoperative period was monitored and all complications were managed promptly. Both the mother and the baby were followed up after delivery for the entire duration of the hospital stay. A discharge card was given and postoperative visits after 6 weeks were advised.Data were analysed using the IBM SPSS Statistics 20.0 and results were tabulated in Microsoft Excel 2016. Point estimate and 95% CI were calculated.Among 1158 multiparous women, primary caesarean section was found in 155 (13.39%) . Most of them 62 (40%) were in the age group of 21-25 years and 53 (34.19%) were in the age group of 26-30 years. The mean age was 26.79\u00b10.38 years. Most of them are gravida second 51 (32.90%). Only 15 (9.67%) multiparity were booked cases. The maximum number of multiparity undergoing primary caesarean section was after 37 weeks of gestation seen in 122 (78.71%). Emergency caesarean section was performed in 149 (96.12%) in which 3 (1.93%) lead to caesarean hysterectomy for rupture uterus and hand prolapse. Spinal anaesthesia was the commonest anaesthesia used for 147 (94.83%) women .Most common indication for caesarean section in the parous woman was fetal distress 63 (40.64%) followed by breech and non-progress of labour 12 (7.74%) and then oligohydramnios in 11 (7.09%) .Normal findings was seen in 79 (50.96%) followed by meconium stained liquor 24 (15.48%), oedematous bladder 12 (7.74%), placenta praevia and thinned lower segment 8 (5.16%) .In this study, 158 babies were born as there were 3 (1.93%) cases of twins. The majority of the babies 44 (27.84%) weighed in the group of 2.6-3 kg. The Appearance, Pulse, Grimace, Activity, Respiration (APGAR) score of 8-10 at 5 min was 104 (65.82%) which improved from 1 min 14 (8.86%). Maximum of the babies 25 (39.68%) were admitted for observation care and then 18 (28.57%) were meconium aspirated babies .There were 10 (6.33%) stillbirths and 14 (8.86%) neonatal death, the commonest cause of stillbirth was obstructed labour and rupture uterus and secondly neonatal death was meconium aspiration, birth asphyxia, prematurity .6 These cases were studied with respect to the indications for caesarean section, postoperative complications, maternal and perinatal morbidity and mortality. Some studies show the primary caesarean rate among multiparity to be 7.73%, 10.28%, 11.38%, and 12.61%.7\"10 This is due to referral of cases to a tertiary centre for surgery, complicated cases, caesarean delivery on maternal request, and keeping small family norms.This study includes 155 cases of multiparity who underwent primary caesarean section giving a prevalence of 13.38%. A multipara who has earlier delivered vaginally may still require a caesarean section for safe delivery.12 and contrast to the study done at Karachi.13 Maximum number of cases were unbooked (90.32%), and this led to ignorance of antenatal checkup in cases of multigravidas.In this study, most of the patients 40% belong to 2125 years followed by 34.19% in the 26-30 years age group similar to the study done in Andhra Pradesh and Vijayawada14 The operation performed was lower segment caesarean section with emergency caesarean 96.12% and elective 3.87% which is similar to the study done in Karachi.13 The caesarean hysterectomy was done in 1.93% of cases for rupture uterus and hand prolapse. The most common cases of primary caesarean in parous women were fetal distress (40.63%), non-progress of labour and breech (7.74%), and oligohydramnios (7.09%) similar to other studies.15 and contrast to the study done at Karnataka.16 Normal findings were seen in 50.96% of cases followed by meconium (15.48%), edematous bladder (7.74%) placenta praevia and thinned lower segment (5.16%). The indications for fetal distress are 40.63% is more than Madhya Pradesh (25.58%),6 and Kerala (27.07%).7The maximum number of multiparity women undergoing primary caesarean section was 59.35% at 37 to 40 weeks which is similar to the study done at Nagpur, Maharashtra (61.5%).14 In this study, 158 babies were born and there were three cases of twins. The majority of the babies 27.84% weighed in the group of 2.6-3 kg which is similar to other studies.16 There were 6.32% stillbirths and 8.86% neonatal death, the commonest cause of stillbirth was obstructed labour and rupture uterus, and secondly, and neonatal death was meconium aspiration, birth asphyxia, prematurity which is similar to the other studies.17 There were no cases of maternal mortality.Postpartum haemorrhage was seen in 12.25% which was treated with medical management and blood transfusions followed by 9.67% wound sepsis which is similar to other studies.This study was conducted in one tertiary hospital, so these results cannot be generalized to the whole country also the study had convenience sampling, and there could have been selection bias in the selection of cases. Since the study site was a tertiary centre in Province 2 a significant number of complicated cases which needed immediate caeserean section were referred to our centre.The prevalence of caesarean section was found to be higher than in other studies conducted in similar settings. Most of the cases underwent emergency caesarean sections and fetal distress was found to be the most common indication of the caesarean section."}
+{"text": "This presentation advances studies of population health by estimating the association between new bereavement and binge drinking rates among adults aged 50 years and older. In other reports, bereavement is associated with significantly higher rates of binge drinking among older adults. In 2019, the state of Georgia used an optional module in the Behavioral Risk Factor Surveillance Survey (BRFSS) to measure the prevalence of new bereavement. This is the first effort to capture population-level data on bereavement in Georgia. 45% of adults (4 million persons) aged 18 and older were newly bereaved in the 24 months prior to survey. Highest bereavement rates: adults aged 55 to 64 years (51%), unemployed (49%), and Black respondents (60%). Binge drinking rate for bereaved was 31 % (versus 23.6% not bereaved). Combined bereavement and binge drinking increased risk for poor mental health (OR = 2.83) and smoking (OR = 4.54)."}
+{"text": "There is a lack of objective evaluation with validated tools in school children with intellectual disability (ID). Standardized and validated tools, allowing children evaluations and follow-up, exist but are poorly used. Our action-study wishes to develop evaluation practices to better adapt to the specific needs of children with ID.We evaluated the multidimensional profiles  of children with ID attending regular or adapted school system.School children, aged 5 to 13 years old, with mild to moderate ID were enrolled in this French cohort study. The multidimensional evaluation consisted of a school evaluation grid proposed by the French educational system, a scale of school needs (GEVA-sco), an intellectual assessment (WISC IV), a behavior adaptative scale (Vineland II) and a behavior rating scale (the French Nisonger Child Behavior Rating Form (Nisonger CBRF)). The results of this multidimensional assessment were analyzed.Between November 2014 and June 2016, 121 children were enrolled, 3 children were lost to follow-up. Analysis was performed on 118 children. Seventy one (60.2 %) were male. Fifty-two (44.1%) were aged 6 to 9 years. Sixty-eight (57.6%) children were in regular schools and 50 (42.4%) in adapted schools. Children in regular schools had a higher mean IQ score (57.5) than children in adapted schools (43.5). The adaptative behavior profile of children in regular school is less severe than in children in adapted schools.Multidimensional evaluations allow optimizing and personalizing support. Evaluation of adaptative behavior is more informative than cognitive profile which does not differentiate between children skillsNo significant relationships."}
+{"text": "Staphylococcus aureus (MRSA) nasal polymerase chain reaction (PCR) swabs for skin and soft tissue infection (SSTI). We investigated the use of the nasal MRSA PCR swab to reduce the inappropriate empiric use of vancomycin and piperacillin-tazobactam for SSTI at our institution.Large cohort studies from the Veteran\u2019s Administration support the negative predictive value of the methicillin resistant Between July and August 2021, we educated Hospital Internal Medicine (HIM) and Internal Medicine Residents (IMR) on the basics of SSTI management and the utility of a negative nasal MRSA PCR swab. Data on empiric use of vancomycin and piperacillin-tazobactam for SSTIs were collected 3/1/2021 to 7/1/2021 (pre-intervention) and 8/30/2021 to 12/29/2021 (post-intervention). We excluded patients who didn\u2019t have an SSTI, weren\u2019t managed by IMR or HIM, and whose empiric antibiotics were for another indication. To account for antibiotics started in the emergency department (ED), a patient was regarded as having received appropriate empiric antibiotics if they were de-escalated in the first 24 hours of being admitted to IMR or HIM.Example of education material. These fliers were distributed to resident rooms following a series of noon conferencesPre-intervention there were 106 patient encounters. In 56 of these (52.8%), patients were placed on inappropriate empiric antibiotics. Post-intervention, there were 72 patient encounters. In 23of these (31.9%), patients were placed on inappropriate empiric antibiotic for an absolute risk reduction (ARR) of 20.9% with a statistically significant 95% CI (6.522 - 35.249) and a number needed to treat (NNT) of 4.78. Nasal MRSA PCR testing increased from 40.6% to 56.9%. The ARR among the HIM teams was 21.3% and was statistically significant with a 95% CI (4.24 - 38.394). Their proportion of MRSA testing increased from 41.5% to 50%. The IMR teams had an ARR of 14.8%, which was not statistically significant . Their MRSA nasal PCR testing increased from 37.5% to 72%.Education on SSTI treatment coupled with use of the MRSA nares PCR appeared to improve empiric antibiotic choices. Residents stated that the nasal MRSA PCR facilitated empiric antibiotic choice. Positive ARR was seen in whole and sub-group analyses of physician teams. We theorize that the lack of statistical significance in the IMR group was related to a small sample size.All Authors: No reported disclosures."}
+{"text": "Background: Hearing loss (HL) is the most common form of sensory disorder in humans. Molecular diagnosis of HL is important for genetic counseling for the affected individuals and their families.Methods: To identify potential genetic causes, we performed whole-exome sequencing and related biomedical informatics for 351 non-syndromic HL patients and their family members.Results: In the present study, we report the identification of four compound heterozygous variants in the CDH23 gene from four affected families, including four novel variants  and two frequently reported variants .Conclusion: Our findings significantly expanded the mutation spectrum of CDH23-associated autosomal recessive hearing loss. Approximately 466 million people worldwide suffer from hearing problems, which is projected to reach 900 million by 2050 . In deveyndromic . Geneticyndromic . Approxiyndromic .CDH23 gene were first identified in patients with Usher Syndrome (CDH23 have been curated in Human Gene Mutation Database (HGMD). Among them, 40 different recessive mutations of CDH23 are associated with non-syndromic deafness 12 . Most of the CDH23 variants are associated with Usher syndrome type 1 or syndromic deafness (USH1D).Mutations in the Syndrome , which iSyndrome . To dateCDH23 gene from four probands with profound congenital sensorineural deafness.In the past 3\u00a0years, we recruited a cohort of 351 affected individuals with congenital sensorineural deafness using whole-exome sequencing and associated bioinformatics analysis. Here, we reported the identification of four novel variants in the A total of 351 affected individuals with congenital hearing loss and their parents in 323 families were recruited by local hospitals for exome sequencing analysis. Detailed medical histories were collected for all affected individuals and their families. A series of tests were performed for each of the affected individuals, such as high-resolution CT and magnetic resonance imaging (MRI) scans. All the participating individuals signed written informed consent.https://swissmodel.expasy.org/), potential effects of the identified variants on CDH23 protein functions were predicted using SPDBV 4.10 software (https://swiss-pdb-viewer.software.informer.com/4.1/).Blood samples from the affected individuals and their family members were taken for DNA extraction. Exome-enriched genomic libraries were prepared using the Agilent SureSelect Human Expanded All Exon V6 kit and sequenced on an Illumina NovaSeq6000 with an average of 100x coverage. Genomic reads were aligned for SNP calling and further analysis for identification of candidate causal variants which are predicted by multiple programs, such as Varsome, MutationTaster, Polyphen-2 and SIFT. Detected variants with MAF >0.001 based on gnomAD or in-house Chinese Exome Database were eliminated as previously described . SelecteIn family 1, two daughters were affected with hearing loss . The proIn family 2, the proband was a 4\u00a0years old girl . She didIn family 3, the affected boy  passed nIn family 4, the affected boy  was diagHearing threshold tests using pure tone audiometry examinations show severe bilateral sensorineural hearing loss for all the affected probands . The third most frequently mutated gene in this cohort is the MY O 15A gene . Ten additional genes with 1%\u20135% mutation rates included CHD7 (4.22%), SOX10 (2.41%), CDH23 (2.41%), MYO7A (1.81%), MITF (1.81%), EYA1 (1.81%), ESRRB (1.20%), PTPN11 (1.20%), TECTA (1.20%), and PTPRQ (1.20%).During the last 3\u00a0years, 351 individuals with congenital sensorineural deafness from 323 unrelated families were examined by exome sequencing. Among them, potential causal variants were identified in 166 affected individuals (51.4%). Among the 166 affected individuals, nearly one-third of them  were identified with variants within the CDH23 gene (NM_022124.6) from five patients in four families identified by exome sequencing  contains 26 extracellular cadherin (EC) repeats and one non-canonical domain  for multiple sequence alignment analysis using Ugene program (http://ugene.net/). As shown in To examine the evolutionary conservation of the five amino acids that were mutated in the patients, CDH23 protein sequences of 10 different species from Xenopus to human were retrieved from reference sequences at NCBI (in silico tools. Both REVEL (Rare Exome Variant Ensemble Learner) and CADD (Combined Annotation Dependent Depletion) predicted that all the missense variants to be deleterious. More detailed analysis using Varsome online tool (Version 11.3) predicted all the variants  and Usher syndrome type 1D deafness . DFNB12 is characterized by prelingual-onset sensorineural NSHL, without the impairment of visual or vestibular functions (The  cochlea . Recessiunctions . On the unctions .CDH23 have been curated in Human Gene Mutation Database (HGMD). Among them, missense/nonsense variants account for the majority, which are located in the extracellular region  in the hair-cell tip link  and Usher syndrome type 1D (OMIM: 601067) or Usher syndrome type 1F (OMIM: 602083)  .CDH23 mutations were predicted to acquire an acceptable auditory and speech outcome after CI . In fact, patients with after CI . In our CDH23 gene from five affected individuals with autosomal recessive non-syndromic deafness (OMIM: DFNB12). Our findings significantly expanded the mutation spectrum of CDH23-associated autosomal recessive hearing loss.Taken together, we screened 351 affected individuals with hearing loss and their parents using exome sequencing. Here, we reported the identification of four novel variants  in the"}
+{"text": "Lateral neck masses present clinically as neoplastic or non-neoplastic lesions of lymph nodes, salivary glands, and thyroid. Non-neoplastic lesions, if evaluated timely, may not transform into malignancy thus reducing clinical burden. A cytomorphological study using fine needle aspiration is a reliable method for the diagnosis of such masses. The aim of this study was to find out the prevalence of non-neoplastic lesions of lateral neck mass specimens received in the Department of Pathology in a tertiary care center.This descriptive cross-sectional study was carried out in the Department of Pathology among lateral neck mass specimens of a tertiary care center from January 2019 to December 2020 after obtaining ethical approval from the Institutional Review Committee (Reference no: 155/19). A convenience sampling method was used and data analysis was done in Microsoft Excel 2019. Point estimate at 95% Confidence Interval was calculated along with frequency and proportion for binary data.Out of 300 lateral neck mass specimens, non-neoplastic lesions were found in 246 (82%) . The involvement of lymph nodes in 117 (47.6%) was the most common finding followed by thyroid 112 (45.5%). Among non-neoplastic lesions, the cytomorphological features of benign nodular goiter 93 (37.8%) was the most common lesion followed by reactive lymphoid hyperplasia 73 (29.7%).The study showed that the prevalence of non-neoplastic lesions was similar to that of other national and international studies. These can frequently present as enlarged lymph nodes which can be due to metastatic or inflammatory causes, thyroid disorders, or salivary gland tumors. Other causes could be branchial cyst, thyroglossal cyst, epidermal cyst, or soft tissue tumor.2Lateral neck mass is one of the common clinical problems which have a wide pathologic spectrum.The clinical evaluation of these lateral neck masses is difficult because of the diversity of lesions. Hence, earlier evaluation of lateral neck masses with cytomorphological study avoids unnecessary surgeries in non-neoplastic or inflammatory conditions.The objective of this study was to find out the prevalence of non-neoplastic lesions among lateral neck mass specimens received in the Department of Pathology, Dhulikhel Hospital-Kathmandu University Hospital (DH-KUH).A descriptive cross-sectional study was conducted in the Department of Pathology in a tertiary care center from January 2019 to December 2020. Ethical approval was taken from the Institutional Review Committee of DH-KUH (Reference no: 155/19). In this study, all the patients attending the Department of Pathology, DH-KUH in the study period having fine needle aspiration cytology (FNAC) of lateral neck masses were included. Convenience sampling was done and the sample size was calculated as,2 \u00d7 p \u00d7 (1 - p) / e2n\u2003= Z2 \u00d7 (0.5) \u00d7 (1-0.5) / (0.1)2\u2003\u2003= (1.96)\u2003\u2003= 96Where,n = minimum required sample sizeZ = 1.96 at 95% Confidence Interval (CI)p = prevalence, 50%, for maximum sample sizeq = 1-pe = margin of error, 10%Taking a 10% non-response rate, the sample size was 106. After clinical examination, informed consent was obtained from patients. Under aseptic precautions, FNAC was done using a 22-24 gauge needle fitted to a 10ml disposable syringe. After immobilizing the target swelling, multiple passes were given to get sufficient material. Smears were prepared and stained with May Grunwald Giemsa (MGG) and Papanicolaou (PAP) stains. The Ziehl Neelsen (ZN) stain for Acid Fast Bacilli (AFB) was done in those cases, where clinically suspected as tuberculosis (TB), and also in those cases where purulent or cheesy material was aspirated.The cytological features evaluated included cellularity , cell arrangement, nuclear and cytoplasmic characteristics, and background elements. The cases were analyzed by the primary investigator. Inadequate samples were not included in the study.The data were collected using proforma consisting of demographic characteristic and cytomorphological variables. The stained slides were examined under a light microscope by the primary investigator. The data were analyzed using Microsoft Excel 2019. Point estimate at 95% Confidence Interval was calculated along with frequency and proportion for binary data.Out of 300 specimens collected in the study, the prevalence of non-neoplastic lesions was 246 (82%) .The age of the patients ranged from 3 to 79 years including both male and female, the median age of occurrence being 39 years. Majority of the cases 37 (31.6%) among lymph nodes were in the age group 2029 years, 33 (29.5%) of the thyroid gland lesions were in the age group 50-59 years and 4 (23.5%) of the cases of salivary gland lesions were in the age group 10-19 years. Out of all cases, 11 (4.4%) patients were seen in the age group below 10 years .There were 87 (35.3%) male and 159 (64.7%) female patients. The incidence of lymph node lesion was significantly higher in females 62 (53%) than males 55 (47%). Similarly, in thyroid lesions, 89 (79.5%) were females and 23 (20.5%) were males. The incidence of salivary gland lesion was slightly higher in male 9 (53%) .The distribution of cytomorphological spectrum of nonneoplastic lesions of lateral neck masses result showed lymph nodes lesion 117 (47.6%) as the predominant site of FNAC followed by thyroid lesions 112 (45.5%) and salivary gland lesions 17 (6.9%). Among 117 cases of lymph node lesions, reactive lymphoid hyperplasia 73 (29.7%) was the main cause of lymphadenopathy followed by tubercular lymphadenitis 29 (11.8%) and nonspecific/suppurative inflammatory lesions 15 (6.1%). Out of 112 thyroid lesions, benign nodular goiter lesions were 93 (37.8%) and lymphocytic thyroiditis (including Hashimoto's thyroiditis) 19 (7.7%). Among 17 (6.9%) salivary gland lesions, all the lesions were diagnosed as chronic sialadenitis .1 A lateral neck mass may suggest a wide range of entities in a differential diagnosis, including reactive, infectious, developmental, and neoplastic conditions.3Lateral neck mass is one of the challenging diagnostic problems to the clinician. Although surgical biopsy is the gold standard method of tissue diagnosis, FNAC has become one of the first line investigation method to evaluate the lateral neck masses.4 Similarly, Soni, et al. observed the involvement of 66.15% female and 33.89% males which were similar to our study which constituted 35.3% male and 64.7% female.5In the present study, cytomorphological features of 246 cases of non-neoplastic neck masses were analyzed. Maximum numbers of cases were observed in the age group of 20 to 29 years and 50 to 59 years respectively. Our study is similar to the study by Agrawal, et al. which showed female preponderance and similar age group distribution.6 In the various pathological spectrum of lymphadenopathies, reactive hyperplasia constituted the majority of the cases (29.7%). The findings were similar to the study conducted by Agrawal et al. which constituted lymphoid hyperplasia as the predominant cause of lymphadenopathy.4Reactive lymphadenopathy may present as a tender, mobile swelling and should be considered in the context of a recent infection or regional injury. Resolution of the underlying infectious or inflammatory origin results in normalization of the node within weeks.In the present study, tubercular lymphadenitis (11.8%) was the other common lesion among lymph nodes.7 Hence, FNA smears with ZN stain is the first line diagnostic technique.8 With the prompt diagnosis and treatment of tuberculosis morbidity and mortality can be reduced.9Though the diagnosis of tuberculosis can be made by Enzyme Linked Immunosorbent Assay (ELISA) and Polymerase Chain Reaction (PCR) but these methods are very costly and are not available at many centers.10Thyroid lesions are the commonly encountered lesion in the world and FNAC is a safe and cost-effective diagnostic modality in screening thyroid masses. In our study, among thyroid lesions, colloid goiter was the commonest lesion which constituted about 37.8% of cases. Rout, et al. also observed colloid goiter as the common thyroid swelling (42.2%) in his study.11 Hence, earlier diagnosis of such lesions through aspiration cytology prevents surgical intervention.In thyroid aspiration cytology, marked cellular smear is one of the common issues, where increased cellularity with loss of cohesion may be present in hyperplastic /adenomatous goiter, adenoma, or carcinoma. The importance of earlier diagnosis of thyroid lesion by using FNAC is that thyroiditis and colloid goiter can be managed with a conventional method, likewise, lymphomas and undifferentiated carcinomas may be managed with radiotherapy or chemotherapy.13 In this study, all the salivary gland lesions were diagnosed as chronic sialadenitis which accounted for 6.9% which was similar to findings from study by Manjula, et al.14Chronic sialadenitis is one of the pitfalls in salivary gland cytopathology as the associated malignancy might not be aspirated which leads to a false-negative diagnosis. Besides, the presence of reactive cellular atypia might also lead to over diagnosis and patient might undergo unnecessary surgery.The prevalence of non-neoplastic lesion was high among the lateral neck masses with about four in five specimens being non-neoplastic. Benign nodular goiter was the most common cytomorphological findings in the thyroid gland. Reactive lymphoid hyperplasia and chronic sialadenitis were the main lesions among lymph nodes and salivary gland respectively."}
+{"text": "MECP2 duplication syndrome (MDS) in 1999, efforts to characterise this disorder have been limited by a lack of large datasets, with small case series often favouring the reporting of certain conditions over others. This study is the largest to date, featuring 134 males and 20 females, ascertained from the international MECP2 Duplication Database (MDBase). We report a higher frequency of pneumonia, bronchitis, bronchiolitis, gastroesophageal reflux and slow gut motility in males compared to females. We further examine the prevalence of other medical comorbidities such as epilepsy, gastrointestinal problems, feeding difficulties, scoliosis, bone fractures, sleep apnoea, autonomic disturbance and decreased pain sensitivity. A novel feature of urinary retention is reported and requires further investigation. Further research is required to understand the developmental trajectory of this disorder and to examine the context of these medical comorbidities in a quality of life framework.Since the discovery of  MECP2 duplication syndrome  is a rare, X-linked, neurodevelopmental disorder caused by a duplication of the methyl-CpG-binding protein 2 (MECP2) gene, with an estimated birth prevalence of 1/150,000 liveborn males ), followed by InterRett (n = 40 [20%]), the 2020 MECP2 Duplication Syndrome Family Conference (n = 15 [7%]), our study website (n = 13 [6%]) and sharing of our study on MDS-related websites and by word of mouth (n = 18 [9%]). Fully completed questionnaires were provided for 138 (67%) and partially completed for a further 16 (8%). Data were available for 134 males [87%] and 20 females [13%]; n = 76 [49%]), followed by Europe (n = 51 [33%]), Oceania (n = 21 [14%]), Asia (n = 5 [3%]) and South America (n = 1 [1%]). The median age at data completion was 8.76 years for males (range = 0.94\u201351.59 years) and 10.17 years for females (range = 4.88\u201331.36 years).As of the census date (1 November 2021) for this study, questionnaires had been administered to families of 205 individuals with MDS. The main source of ascertainment was Facebook (n = 17) followed by patent ductus arteriosus (n = 3), pulmonary vein stenosis (n = 2), coronary artery anomaly (n = 2), and one each for bicuspid aortic valve, accessory tricuspid valve tissue, patent foramen ovale, ventricular hypertrophy, pulmonary vein anomaly and Brugada syndrome. Pulmonary hypertension was reported in three of 147 (2%) individuals and was the cause of premature death in one male individual at the age of 11 months.Congenital heart disease (CHD) was reported in just under one-fifth of individuals (27/146 [18%]), with some individuals having more than one heart defect .Pneumonia was the most common respiratory infection reported , with beThe prevalence of asthma in this population remained consistent, affecting approximately one-fifth to one-quarter of individuals in all age groups. Croup was less frequent\u2014reported to occur in one-quarter (31/133 [23%]) of individuals less than 5 years of age and less than one-fifth of individuals older than 5 years of age .n = 51) received a short-term course of antibiotic (each lasting less than six weeks), while some (n = 9) received a long-term/preventative course of antibiotics (each lasting more than six weeks) or a combination of both short-term and preventative antibiotics (n = 17). Prior to the past year, 41/139 (29%) individuals had received a prolonged course of prophylactic antibiotics for a respiratory infection, with the main prophylactics being azithromycin, amoxicillin and trimethoprim.More than half (77/135 [57%]) of individuals had received antibiotics for a respiratory infection in the past 12 months: most  had been hospitalised at least once due to a respiratory problem. For those who had ever been hospitalised for a respiratory problem, the median number of estimated hospitalisations increased slightly over successive and specific age epochs for both males and females .Over a half  had aspirated fluid or food into their lungs in the past 12 months. More than a half (78/146 [53%]) were reported to be unable to effectively cough up chest secretions. Special equipment and/or therapies were used by 77/147 [52%] of individuals  to assist with management of respiratory problems. Airway clearance devices and/or techniques including suction machines, cough assist machines, positive expiratory pressure (PEP) masks, vest therapy, chest physiotherapy and postural drainage were utilised by 57/147 . One-fifth  used oxygen therapy or an oxygen concentrator. Similarly, 21/147  individuals required bilevel positive airway pressure (BIPAP), continuous positive airway pressure (CPAP) or automatic positive airway pressure (APAP) machines to aid in breathing.More than four-fifths (119/146 [81%]) of individuals were reported to have some evidence of autonomic disturbance, either previously, currently, or both. Over two-thirds (101/145 [70%]) had cold peripheries , while oSeizures were reported in over 60% (90/148) of individuals , with a Caregivers reported the most common seizure trigger as infection (35/56 [63%]) followed by fever (30/56 [54%]), arousal from sleep (29/56 [52%]), sleep deprivation (22/56 [39%]), emotional upset (15/56 [27%]), feeding (14/56 [25%]), sudden noise (13/56 [23%]) and facial tactile stimuli (3/56 [5%]).The most frequently used anti-seizure medications (ASMs) or medicinal cannabis preparations used included levetiracetam (55/74 [74%]), valproate/valproic acid , clobazam (31/74 [42%]), lamotrigine (25/74 [34%]) and epidiolex/CBD  had treatment-refractory seizures. Approximately one-third (27/87 [31%]) had been diagnosed with status epilepticus, with a median of 2\u20133 (range: 1\u201350) episodes per person. A half (46/86 [53%]) had on occasions needed rescue medications including diazepam, midazolam and lorazepam\u2014and less commonly, clonazepam, propofol, phenytoin and paraldehyde.n = 8), duration (n = 5) and severity (n = 5). For one individual, no changes were observed; and for another, there were no data available. The median time for these improvements to occur was three weeks (range: 1\u201312 weeks). Two individuals who experienced benefits from the ketogenic diet had to cease the diet because of the development of pancreatitis in one and constipation in the other.Eleven individuals had trialled a ketogenic diet to control seizures beginning at a median age of 10 years (range: 1.8\u201316.5 years). Improvements in seizure control were reported for nine including by frequency (n = 2), duration (n = 2) and severity (n = 2). For two individuals, there was no change in seizure control. Where data were available, improvements were observed at 2 weeks, 4 weeks and 6 months for three individuals, respectively, following insertion of VNS. One individual had had a corpus callosotomy without any apparent benefit to seizures.Six individuals had a vagus nerve stimulator (VNS) inserted to control seizures at a median age of 13.9 years (range: 7\u201333 years). Improvement in seizure control was reported for four including by frequency .Almost all (130/142 [92%]) individuals had experienced a gastrointestinal disorder . The mosn = 22) also received nutritional supplements, liquids and/or medications through the button\u2014similarly for those with a gastrojejunostomy button (n = 3) and nasogastric tube (n = 2).Feeding difficulties were reported in two-thirds (96/145 [66%]). A little under two-thirds (89/138 [64%]) took all food and drinks orally. For others, all food and drink were provided either via a gastrostomy button (41/138 [30%]), gastrojejunostomy button (6/138 [4%]) or a nasogastric tube (2/138 [1%]). Of those with a gastrostomy button, some . Reason/s for the insertion of a feeding tube reported by caregivers included feeding difficulties (46/52 [88%]), to reduce respiratory infections (33/52 [63%]), to give medication (32/52 [62%]), to increase health and wellbeing (32/52 [62%]), to gain weight (29/52 [56%]), individual being too tired to eat (16/52 [31%]), abdominal bloating (3/52 [6%]) and to facilitate a ketogenic diet (1/52 [2%]).Twelve individuals underwent a Nissen fundoplication at a median age of 1.75 years (range: 2 months\u201310 years) to treat gastroesophageal reflux disease (GERD)\u2014all reporting positive outcomes.Ear infections were frequently reported, with over half (88/145 [61%]) experiencing an ear infection during their lifetime . One-thip = 0.011).Over one-third (50/140 [36%]) had experienced sinusitis and over half (88/140 [63%]) one or more episodes of pharyngitis/tonsillitis. Of those who experienced pharyngitis/tonsillitis, 40/84 (48%) had had a tonsillectomy and 8/84 (10%) also an adenoidectomy. A higher proportion of females (89%) than males (59%) had experienced pharyngitis/tonsillitis (p = 0.055).Over one-third (55/143 [38%]) of individuals had experienced at least one urinary tract infection , with EsEpisodes of urinary retention were reported by caregivers in 41/142 (29%) individuals , wherebyScoliosis was reported to have affected one-quarter (33/143 [23%]) of individuals , two of n = 18), muscle contractures (n = 17) and septic arthritis (n = 2) were reported.One-third (46/142 [32%]) of individuals had experienced a bone fracture, with most incidents being seizure or accident/fall related. Some individuals (19/143 [13%]) had been diagnosed with osteoporosis or osteopenia. In just under one-third (41/140 [29%]), additional muscle and/or orthopaedic conditions such as hip dysplasia and/or dislocation  were reported to have abnormal pain sensitivity . Primarin = 31), adenoidectomy  and tonsillectomy (n = 2). Benefits from surgery were reported for three-quarters (19/25 [76%]) of individuals, while one caregiver reported no benefit from adenotonsillectomy and five were awaiting results of another sleep study or were unsure. Breathing assistance was provided via use of CPAP (n = 15) and BIPAP (n = 6) machines for sleep breathing disorders. Under one-third (n = 18) also received oxygen therapy.Sleep apnoea was diagnosed in 61/143 43%;  individuThis largest study to date provides in-depth phenotyping of 134 males and 20 females with MDS. We confirm the higher prevalence of pneumonia, bronchiolitis, bronchitis, gastroesophageal reflux and slow gut motility in males than females. We also confirm the presence of seizures, gastrointestinal problems including constipation and feeding difficulties, scoliosis, fractures, sleep apnoea, autonomic disturbance, decreased pain sensitivity and urinary retention in both males and females affected by this disorder . We expan = 5) scored lower than males (n = 43) on a RTT Clinical Severity Scale (CSS) [A previous clinical sample reported a milder phenotype in females with MDS , such thle (CSS) , while ole (CSS) . HoweverCongenital heart disease is a leading cause of birth defects, affecting an estimated 0.8% to 1.2% live births worldwide and is associated with a slight increase in mortality ,11. We fThis study also provides a clearer understanding of the frequency of infections in MDS and differentiating between pneumonia and other respiratory infections. Consistent with previous studies, pneumonia was a major health issue and was the key LRTI in our study population ,14. Our Whilst the general population prevalence of asthma in children is difficult to estimate because of definitional issues  the 2017Reports of autonomic disturbances in previous studies have been scant ,20,21,22Our large sample size and the use of time-to-event analysis account for the age of the individuals at data collection to provide a better estimate of age at seizure onset , with a An interesting finding in our study was the reporting of urinary retention in 41/142 (29%) of individuals, including retention for greater than 24 h in some. Urine retention has been reported as a rare side effect of ASMs such as carbamazepine , levetirThe prevalence of scoliosis in previous studies was higher\u2014for example, in the French cohort, 23/43 males (53%) had scoliosis and/or kyphosis compared to 33/143 (23%) in our study. It should be noted that the median age of the French cohort was 12 years (range: 2\u201348 years), older than that of our cohort, which was 9.16 years (range: 0.94\u201351.59 years), which may explain the difference in prevalence. Interestingly, we noted approximately one-third (32%) of individuals had experienced bone fractures being seizure or accident/fall related. Whilst 19/143 (13%) of individuals were diagnosed with low bone density, it should be noted that the use of valproate for epilepsy in RTT may also increase the risk of bone fractures  and coulDecreased pain sensitivity reported in just over half (55%) of individuals was less frequent compared to previous studies ,38,39,40The key limitation of this study was the selection bias of individuals with MDS in families from primarily English-speaking backgrounds as the questionnaire was not translated to other languages due to lack of funding. As a result, most families were recruited from the USA, the UK or Australia. Furthermore, an unknown proportion of individuals reported in this study have previously been reported in the literature. Health data ascertained in this study have also been parent reported and might be subject to recall error. To limit recall error, we asked caregivers to refer to medical records where available. Other domains that require further characterisation within this dataset include the developmental domains and behavioural patterns of hand stereotypies, bruxism, sleep and autistic behaviours, each associated with RTT and thus will provide a clearer delineation between the behavioural phenotype of these two similar disorders . HoweverIn summary, this study provides a comprehensive evaluation of medical comorbidities in MDS and a valuable baseline for comparison with RTT. We highlight the burden of respiratory infections and gastrointestinal disorders in the male phenotype and demonstrate that phenotypic penetrance in the female phenotype presents a similar disease burden to males. The size of our community sample has provided a more accurate understanding of the likelihood of developing seizures and spinal curvature in MDS and an expanded phenotype that may be important for clinical care. The high rates of medical comorbidities require further work to understand the impact on quality of life as well as management."}
+{"text": "Despite significant improvements in outcomes, traumatic arterial limb injuries remain a significant cause of limb loss and mortality.This study sought to identify predictors of mortality and major amputation in patients undergoing revascularization after femoropopliteal arterial trauma.This was a retrospective review of a trauma registry from an urban trauma center in Brazil. All patients admitted to our hospital with a femoropopliteal arterial injury from November 2012 to December 2017 who underwent vascular reconstruction were included. Univariate analyses and logistic regression analyses were conducted to identify factors independently associated with the primary outcome of amputation and the secondary outcome of mortality.Ninety-six patients were included. Eleven patients (11.5%) had an amputation and 14 (14.6%) died. In the logistic regression model for amputation, patients with ischemia duration greater than 6 hours were approximately 10 times more likely to undergo an amputation compared to those with ischemia duration less than or equal to 6 hours (adjusted odds ratio (AOR) [95% confidence interval (CI)]: 9.6 [1.2-79.9]). The logistic regression model for mortality revealed that patients with ischemia duration greater than 6 hours were approximately 6 times more likely to die compared to those with ischemia duration less than or equal to 6 hours (AOR [95% CI]: 5.6 [1.3 to 24.7).Ischemia duration remains the most important factor independently associated with limb loss and mortality for patients undergoing femoropopliteal arterial revascularization after traumatic injuries. Physiological status on admission and trauma scores are also important. Trauma is one of the main causes of death globally-Brazil is a very large country and has a highly heterogeneous healthcare system. Most Brazilian cities lack organized emergency care and the scarcity of resources is a significant challenge to definitive treatment of complex vascular lesions, requiring patients to be transferred to referral hospitals, resulting in significant treatment delays and potential negative impacts on outcomes. National best-practice guidelines for pre-hospital or intra-hospital management of these injuries are not available and institutions with protocolized care are the exception. A few publications have described the management of vascular trauma and their outcomes in Brazil,5The aim of this study was to identify factors independently associated with major amputation and mortality in patients undergoing revascularization after femoropopliteal arterial trauma. Identification of these factors may suggest areas in which opportunities for quality improvement exist at both institutional and trauma system levels.The study was approved by the Research Ethics Committee .This was a retrospective review of a vascular trauma registry. This electronic institutional registry captures all patients with vascular injuries admitted to our hospital and is maintained by the vascular surgery team. Specific vascular data are entered by the attending surgeon involved with each case immediately after the surgical procedure. At the time of patient discharge, the document is completed with information regarding outcomes occurring during the in-hospital period. For the purposes of the present study, all patients undergoing femoropopliteal arterial vascular reconstruction after sustaining blunt or penetrating trauma from November 2012 to December 2017 were included.Variables abstracted included patient demographics, mechanism of injury, evidence of ischemia on admission, vascular injury type , presence of associated peripheral nerve injury (intraoperative diagnosis), types of treatment , use of perioperative heparinization , presence of soft tissue lesions, and additional surgical procedures performed. The primary outcome was amputation and the secondary outcome was death, both within 30 days.t test as appropriate. Multivariate logistic regression models were then estimated including all factors associated with each of the outcomes from the univariate analyses based on clinical relevance and a p-value cutoff of 0.25. These models were used to identify independent associations between the various risk factors and amputation or death. P values < 0.05 were considered statistically significant.Statistical analysis was performed using R version 3.2.5, MINITAB, and SPSS version 18. Overall descriptive statistics were calculated for the study population. Univariate analyses were performed for both outcomes to identify factors independently associated with amputation and mortality. Categorical variables were analyzed using Pearson\u2019s chi-square test or Fisher\u2019s exact test (when expected frequencies were below 5) and continuous variables were analyzed using the Mann-Whitney test and Student\u2019s This study is reported using the STROCSS guideline criteria.A total of 101 patients met the inclusion criteria during the 5-year study period. Three patients who needed primary amputation at admission and two patients with incomplete medical records data were excluded. Mean age was 27 years (range 8 to 62 years). Mean revised trauma score (RTS) was 7.152 (range 1.163 to 7.841) and mean injury severity score (ISS) was 15 (range 9 to 34). Additional characteristics are summarized in Among the 11 patients undergoing amputation, with a mean age of 27 years, 10 (90.9%) were male; 10 (90.9%) had ischemia lasting more than 6 hours; all had evidence of ischemia on admission; the mechanism was blunt trauma in 6 (54.5%) patients and penetrating trauma in 5 (45.5%); 5 (45.5%) had an associated fracture, 5 (45.5%) had peripheral nerve injury, and 7 (63.6%) had soft tissue injury; 7 (63.6%) underwent associated surgeries; 4 (36.4%) presented with hemodynamic instability; 6 (54.5%) had superficial femoral artery (SFA) injury and 5 (45.5%) had popliteal artery injury; in 7 (63.6%) patients arterial section was the mechanism of vascular injury and 4 (36.4%) had thrombosis; 9 (81.8%) underwent treatment with great saphenous vein (GSV) interposition and 2 (18.2%) had temporary shunts; 2 (18.2%) had local perioperative heparinization, 6 (54.5%) had systemic heparinization, and 3 (27.3%) did not receive heparin; and 7 (63.4%) patients underwent fasciotomy .The logistic regression model for amputation showed that patients with ischemia duration greater than 6 hours were approximately 10 times more likely to undergo an amputation compared to those with ischemia duration less than or equal to 6 hours . With each unit increase in RTS, the likelihood of amputation reduced by 43% (95%CI: 2-96%) .The 14 deaths occurring in this series were secondary to brain injury in two cases, to complications from ischemia-reperfusion syndrome in five cases, to exsanguination in six cases , and to pulmonary embolism in one case.All 14 of the patients who died were male, with a mean age of 25 years. Mean RTS and ISS were 4.559 and 20, respectively. Eleven patients (78.6%) had ischemia duration exceeding 6 hours; 13 (92.9%) had ischemia on admission. The trauma mechanism was blunt in 6 (42.9%) patients and penetrating in 8 (57.1%); 8 (57.1%) patients had associated fracture, 3 (21.4%) had peripheral nerve injury, and 11 (78.6%) had soft tissue disruption; 10 (71.4%) underwent associated surgeries; 10 (71.4%) presented hemodynamic instability on admission; 3 (21.4%) had common femoral artery (CFA) injury, 10 (71.4%) had SFA injury, and 1 (7.2%) had popliteal artery injury; in 9 (64.3%) the mechanism of vascular injury was artery transection and in 5 (35.7%) it was thrombosis; 1 (7.1%) underwent embolectomy, 6 (42.9%) had GSV interposition, and 7 (50.0%) had temporary shunt; 2 (14.3%) had local perioperative heparinization, 5 (35.7%) had systemic heparinization, and 7 (50.0%) did not receive heparin; and 7 (50.0%) patients underwent fasciotomy .The logistic regression model for mortality revealed that patients with ischemia duration greater than 6 hours were approximately 6 times more likely to die compared to those with ischemia duration less than or equal to than 6 hours (AOR [95% CI]: 5.6 [1.3 to 24.7). Additional factors independently associated with mortality were hemodynamic instability and ISS. Hemodynamically unstable patients were approximately 9 times more likely to die (AOR [95% CI]: 9.3 [2.4-36.6]). For each unit increase in the ISS, the likelihood of death increased by 14% (95% CI: 3%-26%) .In the present study describing the experience of a Brazilian trauma center with the treatment of femoropopliteal arterial injuries over a 5-year period, ischemia duration greater than 6 hours and low RTS were found to be independently associated with amputation after revascularization. It was also demonstrated that prolonged ischemia duration, hemodynamic instability on admission, and elevated ISS were independently associated with mortality.These findings are in accordance with a meta-analysis by Perkins et al.,,Our findings that ISS and hemodynamic instability are factors independently associated with mortality after vascular trauma are in agreement with a single-center retrospective cohort study published by Perkins et al.3The findings from this study suggest that aggressive hemorrhage control in the prehospital setting and reduction of ischemia duration are key points to avoid loss of limbs and life. Tourniquets are not widely used in our city and there is no protocol for use of this bleeding-control tool by pre-hospital care teams. Another peculiarity of our emergency care system is that some patients are transported to the trauma center by the police, due to urban violence, and law-enforcement personnel are not equipped with or trained to use tourniquets. This may explain why some patients arrived at the hospital with poor physiological status. One of the authors has previously demonstrated that use of tourniquets is associated with a sixfold reduction in mortality in patients with peripheral vascular injuries.Temporary shunts are a tool that can potentially shorten the duration of ischemia. Glass et al.This study has several limitations including its retrospective design, the relatively small number of participants, and its single-center nature. Also, the ischemia duration being recorded as a dichotomized variable (more or less than six hours) precluded a more detailed analysis of the implications of time-to-revascularization. Associated venous lesions were not evaluated, therefore it was not possible to establish whether their presence or absence had an impact in the outcomes.In summary, our findings suggest that ischemia duration remains the most important factor independently associated with loss of limb and life for patients undergoing femoropopliteal arterial revascularization after traumatic injuries. Physiological status on admission and trauma scores are also important prognostic factors in this setting. Local protocols to guide the best treatment for these patients must be established and the greatest efforts must be made to reduce the duration of ischemia before revascularization."}
+{"text": "The coronavirus epidemic started in Tunisia in March 2020. Health personnel have been in the front line in the fight against this virus since that date. The COVID units of the hospitals and the different hospital services have been reinforced by student nurses .To evaluate the degree of stress perceived during the COVID-19 pandemic by student nurses. To identify coping skills during a COVID-19 pandemic.Descriptive, retrospective study conducted in March 2021 on the 60 senior nursing students enrolled in the military health school. We used the Cungi (1997) stress scale and developed a self-questionnaire on coping skills used by the students.Our population was 54.3% male and 45.7% female. The average age was 22.6 years. The majority of the senior students (54.3%) worked in units dedicated to the care of patients with COVID-19. On the Cungi Stress Rating Scale, students had very low (13%), low (27%), and high (60%) stress levels. The main coping methods used were watching movies and listening to music (81%), playing sports (80%), praying (75%), rigorously applying social distancing measures and wearing protective gear (73%), talking with friends or psychologists (62%), doing yoga or meditation (34%), drinking herbal tea, alcohol, or taking psychotropic drugs (23%).The COVID-19 pandemic is a time of major stress for nursing students. The coping methods used seem insufficient. Psychological support should be provided.No significant relationships."}
+{"text": "Studies have consistently shown a high proportion of antimicrobial usage in hospitalized COVID-19 patients despite low prevalence of bacterial co-infection. Improving antibiotic utilization is one of the main goals of antimicrobial stewardship program (ASP). This study aimed to determine the impact of prospective audit and feedback intervention (PAF) performed by ASP pharmacists on antibiotic utilization in hospitalized COVID-19 patients.A retrospective chart review was conducted at a 90-bed Veteran Affairs hospital. This study included patients who were admitted to the hospital due to laboratory confirmed COVID-19 infection from November 1, 2020 to January 31, 2021. The primary outcome of this study was to evaluate the impact of ASP PAF on avoiding the unnecessary use of antibiotics in hospitalized patients with acute COVID-19. The secondary outcomes included the prevalence of bacterial co-infection in hospitalized COVID-19 patients and the clinical outcomes.A total of 199 patients were included in this study. Sixty-one patients (30.7%) had antibiotics started empirically upon hospital admission. Fifty (82%) out of 61 patients had antibiotics discontinued due to the lack of indication for antibiotics during their hospital admission, with 47 (94%) was done by ASP team versus 3 of them (6%) was done by Internal Medicine. Fifty-eight of these patients were followed by ASP team, with 28 patients (48.3%) met SIRS criteria upon admission and 25 (43.1%) with elevated procalcitonin level. The overall readmission rate was 5.8%, with readmission rate of the intervention group to be 6.4% and the non-intervention group to be 5.6% (p = 0.29). The overall mortality rate was 13.1% in hospitalized COVID-19 patients, with 19% reported in the intervention group and 10.1% in the non-intervention group (p = 0.09). Overall, only 5 patients (2.5%) had laboratory-confirmed bacterial co-infection upon admission. Sixteen patients (8%) were found to have microbiologically confirmed nosocomial infection.The findings suggested that ASP PAF safely and effectively avoided the unnecessary use of antibiotics in hospitalized patients with acute COVID-19 infection. In addition, low prevalence of microbiologically confirmed bacterial co-infection was observed.All Authors: No reported disclosures."}
+{"text": "The relationship between dementia and neuropsychiatric symptoms is well documented. Yet, little is known about the prevalence of neuropsychiatric symptoms among diverse homebound persons living with dementia. Guided by an intersectionality framework we asked: 1) Is there an association between the presence of individual neuropsychiatric symptoms and racial and ethnic groups? 2) If so, do these symptoms differ by dementia stage among groups? We conducted a cross-sectional study of n=190 receiving skilled home healthcare in Utah, New York, and New Jersey and enrolled in the DSM-H trial. We prospectively measured symptom prevalence with the Neuropsychiatric Inventory Questionnaire and dementia stage using the Quick Dementia Rating System. We performed Chi-square tests to determine the association of individual symptom prevalence with race and ethnicity and cross tabs to descriptively stratify individual symptom prevalence by dementia stage among groups. Participants were 11.9% Hispanic, 28% non-Hispanic Black, 56.1% non-Hispanic white (white). The prevalence of delusions was significantly higher in Hispanic and non-Hispanic Black groups than whites (41.7% & 41.8% vs. 22.5%) and elation/euphoria in Hispanic and non-Hispanic Black groups than whites (20.8% &12.7% vs. 5.4%). Delusions were most prevalent in non-Hispanic Black groups with mild dementia (53.8%) and Hispanics with moderate dementia (50.1%), while elation/euphoria was most prevalent for Hispanics with severe dementia (33.3%). Other neuropsychiatric symptoms showed no significant differences. These findings expand our knowledge of differences in neuropsychiatric symptoms among racial and ethnic persons living with dementia, which can inform future studies and targeted interventions that address disparities and improve care."}
+{"text": "In developing countries, the diagnosis of congenital heart diseases (CHD) is growing as the availability of echocardiography is increasing with most diagnoses made after birth. However, the access to pediatric surgery is still low and is mainly done by global surgical campaigns rather than local surgeons. Ethiopia has trained its local surgeons, and this is expected to improve the care of children with CHD. We aimed to evaluate the experience of local pediatric CHD surgery and its outcome in a single-center in Ethiopia.A hospital-based retrospective cohort study was done by including all patients with CHD and acquired heart disease in patients under the age of 18 operated at children's cardiac center in Addis Ababa Ethiopia. We set in-hospital mortality, 30-day mortality, and the prevalence of complications including major complications after cardiac surgery as the primary outcomes.A total of 76 children were operated. The mean age at the time of diagnosis and surgery was 4 (\u00b15) and 7 (\u00b15) years, respectively. Forty-one (54%) were female. Ninety five percent of the 76 operated children were with the diagnoses of congenital heart diseases while the rest (5%) with acquired heart disease. Of those with congenital heart disease, Patent ductus arteriosus (PDA) accounted for (33.3%), Ventricular septal defect (VSD) for 29.5% and Atrial Septal Defect (ASD) for 10% and Tetralogy of Fallot (TOF) for 5%. According to the RACS-1 category, 26 (35.1%) were in category 1, 33 (44.6%) were in category 2, 15 (20.3%) were in category 3 and none of the children were in category 4 and 5. In-hospital mortality was 2.6% whereas there was no patient who died within 30 days after discharge. Operative mortality was 2.6%.Various types of lesions were treated in the hands of the local teams with VSD and PDA ligations as the commonest of all. The 30day mortality was within acceptable range and this outcome shows congenital and acquired heart diseases can be operated on in developing countries with good outcome despite the limited resources. Global efforts to reduce neonatal and infant mortality rates have been underway with special emphasis on low- and middle-income countries . SpecifiCongenital heart diseases (CHD) occurs in 11.89 per 1000 children . Due to In developing countries, the diagnosis of CHD is growing as the availability of echocardiography is increasing with most diagnoses made after birth . But CHDThere were 78 cardiac centers or units which were performing regular open-heart operations in Africa and from these 22 were in Sub Saharan Africa, with only 2 in the Horn of Africa . The ChiEthiopia trained local cardiac surgeons as well as other members of a complete cardiac surgery team, and this is expected to improve the care of children with congenital heart disease. Therefore, we aimed to assess the experience of local pediatric surgery and its outcome in a single-center in Ethiopia with patients included in the study operated by a single operator, a pediatric cardiac surgeon.This hospital-based retrospective cohort study was conducted at the Children's Cardiac Center of Ethiopia based in Addis Ababa on children operated between July 2019 and May 2021. All patients under the age of 18 having either congenital or acquired heart disease were included. Those with age \u226518 years were excluded.Data was collected retrospectively from hard copy patient charts after patients were discharged from the hospital. These charts include data records from the outpatient follow up clinic, cardiology ward, ICU, operating room and the perfusion team. The data were first filled into a google Forms predetermined questionnaire by the pediatric cardiac surgeon.The collected data included age, weight, gender, cardiac procedure type with Risk Adjustment for Congenital Heart Surgery-1 category (RACHS-1), cardiopulmonary bypass (CPB) time and aortic cross clamp (Aox) time, intensive care unit (ICU) stay, postoperative length of stay, duration of mechanical ventilation, 30-days mortality, in-hospital mortality and operative mortality, the later defined as 30-days mortality combined with in hospital mortality.Outcome measures: We set in-hospital mortality, 30-day mortality, and the prevalence of complications including major complications after cardiac surgery as the primary outcomes. In-hospital mortality was defined as death of any cause during hospitalization for surgery until discharge. A 30-day mortality was defined when death occurred outside of the hospital but within 30 days after cardiac surgery performed. Complication was defined as a deviation from the expected outcome of cardiac surgery.Data were described by mean, median or proportion after distribution of data was tested using histograms. To assess the correlates of cardiac surgery complications, univariate analysis was done using fisher's exact test or logistic regression. Variables were included in the final multivariable logistic regression if univariate analysis showed P value < 0.25. Data analysis was performed using STATA version 12.1, StataCorp LP, College Station, Texas, USA. P <0.05 was considered as statistically significant.Ethical considerations: Ethical approval was obtained from the Children's Cardiac Center to publish the data used in this paper.We included 76 children who had surgery, 41 (54%) of which were females. The mean age at the time of diagnosis was 4 (\u00b14) years. The mean age at time of surgery was 7 (\u00b15) years. At the time of surgery, none were newborns, 2 (3.3%) were infants, 16 (26.2%) were toddlers and the rest were above the age of 3. The mean age time elapsed from diagnosis until surgery was 3 (\u00b12) years. The number of children with Cyanotic heart disease was 6 and the rest 70 had acyanotic heart disease .All the patients (except one) underwent their first heart surgery and only 3 (3.9%) of the case had associated syndromes- where 1 (1.3%) case had Down's syndrome and 2 (2.6%) had William's syndrome. There were no laboratory tests done to determine syndromes but rather on general appearance befitting physical descriptions of some syndromes. None had a family history of congenital heart disease. Twenty-nine (47.5%) children had a previous hospital admission documented related to their diagnosed congenital heart disease. Ventricular septal defect (VSD) was identified in 28 (29.5%) cases. Of these, 14 (50%) had peri membranous VSD, 5(18%) has muscular, 5(18%) had peri membranous with an inlet extension 7.7%, 3(10%) subaortic, and the rest had other different types of VSDs. The mean size of the VSD was 11.2 (\u00b1 4.7) mm. Patent ductus arteriosus was identified in 32 (33.3 %) cases. Atrial septal defect (ASD) was seen in 10 (10.4%) children with Secundum ASD as the commonest type. The mean size of ASD was 14.1 (\u00b18.1) mm. Severe pulmonary hypertension as per preoperative TTE was identified in 45 (59%) cases whereas mild and moderate pulmonary hypertension was identified in 18 (23%) .A total of 99 procedures were done, with some children requiring more than one procedure during the same surgery. PDA Ligation, VSD repair, ASD Repair, Complete repair of TOF, DSS resection, AV Repair, MV Repair were done in 30 (30%), 27(27%), 14(14%), 5 (5%) and 4 (4%), 4(4%), 2(2%) children, respectively. According to the RACS-1 category, 26 (35.1) were in category 1, 33 (44.6) were in category 2, 15 (20.3) were in category 3 and none of the children were in category 4 and 5 .Midline sternotomy 53 (70%) was the commonest surgical approach followed by left thoracotomy 23 (30.2%) and only one patient underwent right thoracotomy for plication of postoperative diaphragmatic paralysis after completion of Fontan circulation abroad. Fifty-three (70%) needed CPB. The median CPB and Aox time were 123 and 86 minutes, respectively. Post-operatively, 65 (85.5%) children needed mechanical ventilation only on the day of surgery with the center exercising a rule of early extubation. One patient needed eight days of ventilation due to a complicated ICU course .Thirteen (17%) children had post-operative complications. Arrythmia 5(6.8%) was the most frequent post-operative complication. Pneumonia 3(4.1%), multiorgan failure 3(3.1%) and open sternum 2(2.7%) were other frequent complications .Post-operative inotropic support was required in 40 (52%) children. Of these, 16 (40%) were taking two or more types of inotropes. Adrenaline was given to 18 (45%) children. Noradrenaline, dobutamine and milrinone was taken by 4 (5.2%), 6(7.8%) and 12(26%) respectively. Post-operative medications given to patients included furosemide , spironolactone , enalapril , sildenafil citrate , acetylsalicylic acid , captopril  and atenolol . In a univariate analysis, need for inotrope , days on mechanical ventilator  and length of ICU stay  were significantly associated with the presence of complications after cardiac surgery. However, in final multivariate model, none showed significant association with complications .The median length of intensive care unit and hospital stay were 3 and 6 days respectively. Fifty-nine (97.4%) were alive at discharge. In-hospital mortality was 2.6% and there was no patient who died within 30 days after discharge. One 6 years old girl who developed and treated for Post cardiotomy syndrome 5 weeks after her first surgery died 3 months into her follow up as a result of a home cardiac arrest that was not resuscitated effectively. Operative mortality was 2.6% the mortality summary is reported .To our knowledge this is the first study assessing the outcomes and correlates of complication of pediatric cardiac surgery in Ethiopia. Most patients had acyanotic congenital heart disease. Post-operative complications are associated with patient morbidity, mortality and increase hospital stay . StudiesThe 2.6% mortality rate reported in this study is encouraging and are in line with outcomes in other developing countries that reported mortality rates ranging from 0\u201326.4%13\u201315]. A study from Indonesia reported 26.4% operative mortality rate  which is. A studyWe have shown that the need for post-operative inotrope, number of days on mechanical ventilation and length of ICU stay were associated with presence of complications. Similar findings were identified in the study from Indonesia . The neeIn low resource settings, the diagnosis of congenital heart disease is expected to increase with improving health seeking behavior and cardiovascular investigation. Our center is the only center that can do open-heart surgery on a regular basis for about 110 million population of which more than 40% are under 15. This warrants the establishment of more centers as well as increase the current capacity of our center (currently only works in one-third of its capacity) to treat more patients. With more professionals trained in the field, more hospitals with ability to do open heart surgery and catheterization and better availability of consumables we can see that indeed saving as many children with heart disease is a possibility. This study is intended to show the current realities of pediatric cardiac surgery in Ethiopia. Finally, if more resources are invested to train health professionals and improve the health system as well as purchase of necessary consumables by the government to match the demand the care of congenital heart disease can be enhanced in Ethiopia.In conclusion, most of the operated patients had acyanotic congenital heart disease. In-hospital and operative mortality was low and encouraging. Further expansion of cardiac surgery service in Ethiopia is recommended."}
+{"text": "This case series reports on the frequency and outcomes of breast imaging\u2013identified ipsilateral axillary lymphadenopathy after recent COVID-19 vaccination among women. We tabulated IAL frequency, follow-up imaging results, and outcomes. The Pearson \u03c72 test was used to compare categorical variables, and the t test was used to compare continuous variables. All statistical tests reported were 2-tailed, and P\u2009<\u2009.05 was considered statistically significant. The Stanford University institutional review board approved this Health Insurance Portability and Accountability Act\u2013compliant study with waiver of informed consent. This study followed the reporting guideline for case series.In this single-center study, we searched radiology reports from March 19 to October 30, 2021, to identify women with recent COVID-19 vaccinations (\u22646 weeks) and breast imaging\u2013detected IAL, recording patient risk factors, symptoms, vaccination date, and vaccine manufacturer. Aligning with guidelines at the time,As shown in the The remaining 49 patients with IAL (16%) had recommendations for ultrasonography. A total of 13 symptomatic patients had no risk factors (4%), while 36 patients (12%) had risk factors, including prior breast cancer (23 of 36 [64%]), suspicious ipsilateral imaging results (3 of 36 [8%]), current breast cancer (4 of 36 [11%]), or current regional malignant neoplasm (6 of 36 [17%]) . Two patBased on ultrasonography, 29 of 47 patients(62%) had IAL that completely resolved (22 of 34 patients [65%] with risk factors and 7 of 13 patients [54%] without risk factors) . Based o6With more than 70% of US adults receiving the COVID-19 vaccine, evidence-based guidelines for postvaccination IAL are necessary. Although the reported frequency of IAL varies (3%-44%), our data on the frequency of IAL (10%) are similar to those reported for patients in clinical trials (14%).6Our study provides a timely assessment of the management and outcome of IAL after COVID-19 vaccination. Of 47 patients with IAL undergoing ultrasonography, 62% had complete IAL resolution, including 22 patients with risk factors. Of patients without risk factors, very few (13 of 308 [4%]) had persistent symptoms requiring ultrasonography or biopsy. Of all patients, including those eventually undergoing biopsy (13 of 308 [4%]), none had malignant neoplasms. However, follow-up for patients with risk factors is important to identify the small number of malignant neoplasms reported by other authors.The major limitation of this study is the single-institution design. Further multi-institutional assessments would clarify the patterns and outcomes of postvaccination IAL. Our study shows that IAL after COVID-19 vaccination is frequently a benign reactive finding, supporting expert society guidelines that individualize management approaches tailored to patients\u2019 risk factors, symptoms, and imaging findings."}
+{"text": "After Russia decided to start COVID-19 vaccination of international students who are getting their education on its territory, they received an opportunity to get a single dose of COVID-19 Sputnik Light vaccine. What motives can such international students have for being vaccinated in the situation of uncertainty?Our goal is to define the structure of motivation for COVID-19 vaccination among international students who are getting education at different departments of the university.In October 2021, we surveyed 409 international students getting education at Ulianov Chuvash State University in Cheboksary, who agreed to COVID-19 vaccination.rd year students (32.03%) and 4th year ones (21.52%). 8 students out of the surveyed (1.96%) had been vaccinated outside Russia, 4 \u2013 in Russia (0.98%). 8.56% of the pool had had COVID-19, 57.7% had not, 33.74% could not give a certain answer. Main motives for COVID-19 vaccination were: unwillingness to be ill (57.21%), unwillingness to have any limitations imposed (22.98%), unwillingness, especially of medical students, to have problems in their studies (12.22%), inclination towards following their relatives\u2019 advice (5.13%), desire to follow the surrounding people\u2019s example (1.98%). In personal conversations, the students often expressed their wish for being vaccinated with a 2-component Sputnik V vaccine for a better protection from illness.Those who applied for vaccination were mostly 3The survey of the international students\u2019 motives showed that most of them have positive attitude to COVID-19 vaccination and feel inclined to be vaccinated with a Russian vaccine in order to reduce the risk of getting ill.No significant relationships."}
+{"text": "Juvenile inflammatory myositis are systemic autoimmune diseases of unknown aetiology that are characterized by inflammation of skeleton, muscles, skin, and internal organs. Studies from different regions have reported different incidence and age at onset suggesting that the clinical and demographic features may differ by race and geographic regions. This study aims to describe the characteristics of disease among Libyan children who have been treated in the main rheumatology unit covering most of the population in LibyaTo describe the demographic and clinical features of patients with juvenile dermatomyositisTo determine the outcome of children with juvenile dermatomyositis and factors affecting the outcome.This is a retrospective descriptive study conducted by reviewing patient records diagnosed with juvenile dermatomyositis from 5/2000\u20132/2022.Twenty-one patients were included, female to male ratio was 6:1. Mean age at disease onset was 7.7 \u00b1 2.8 years and their mean follow-up period was 4.36 \u00b1 3.2 years. Most of the patients (14.7%) presented before 1 month of starting symptoms. Most of the patients , were diagnosed as dermatomyositis, 2 (9.5%) as polymyositis, 2 (9.5%) as amyopathic myositis, and 4 (19%) as overlap syndrome. Family History of dermatomyositis was positive in 4 (19%) of patients and family history of other autoimmune diseases was positive in 5 (23.8%) patients.Around half of the patients had monocyclic disease course , 5 patients (23.8%) had polycyclic disease course and other 5 patients (23.8%) had chronic persistent disease course.MRI proximal muscles and EMG were used for diagnosis in 10 patients (48%) and 16 (76.1%) respectively, and muscle biopsy was used in 2 patients to confirm the diagnosis.One overlap patient had severe lung fibrosis on CT scan chest with restrictive lung disease and 4 patients (19%) had restrictive lung disease with normal CT scan chest.Methyleprednisolone pulses were used in 10 patients (50%) with 3 (15%) who required more than one pulse of intravenous prednisolone. Immunoglobulin was used in 12 (60%) of the patients. All patients needed oral prednisolone and methotrexate was used in 15 (75%) of the patients. Other drugs used were Azathioprine in 3 overlap patients, cyclophosphamide and Mycophenolate mofetil in one patient with overlap syndrome. Hydroxychroroquine was used in 6 (30%) of the patients.In the last visit, 12 patients (60%) were in remission, 7 (58%) of them presented before 1 month of disease onset. Fifty-eight percent of the females and 66.7% of the males were in remission. Five patients (25%) had short stature, 3 (15%) had chronic cutaneous changes, 1 (5%) had arrythmia, 2 (10%) had calcinosis, 2 (10%) had osteoporosis, and one patient died.A female predominance was noted with age at presentation comparable to other studies.The most frequent manifestations were skin manifestations and musculoskeletal features were the second most frequent symptoms.Patients has low rate of complications with low rate of calcinosis and mortality and none of them had gastrointestinal manifestations.Males were more likely to be in remission."}
+{"text": "The identification of the psychosis high-risk state in help-seeking patients with depressive symptoms offers the possibility of detection and intervention at the early stages of schizophrenia.Estimating the 5-year follow-up rate of the manifestation of psychosis and levels of functioning in patients with the clinical high-risk state and depressive symptoms.81 inpatients (average age 19.6 years) with depressive symptoms and attenuated psychosis (60 patients with APS and 21 patients with BLIPS). Average duration of inpatient treatment was 56.3 days, antidepressant therapy  and antipsychotic therapy  were conducted. All patients were followed up after discharge at least during 5 years (average follow-up 7.1 years). Levels of functioning were assessed on the PSP scale.The manifestation of psychosis was identified in 21.0% (17 patients) (on average in the third year of follow-up), complete symptomatic and functional remission was established in 11.1% (9 patients) (PSP 100-81), complete symptomatic and incomplete functional remission was established in 27.2% (22 patients) (PSP 80-61). Incomplete symptomatic and incomplete functional remission \u2013 in 24.7% (20 patients) (PSP 60-41) and 13.5% (11 patients) (PSP<40).The combination of antidepressants and antipsychotics therapy in patients with the clinical high-risk state for psychosis reduced the risk of psychosis manifestation but did not significantly affect the level of outcome compared to other studies.No significant relationships."}
+{"text": "IntroductionAmong female genital tract-related malignancies, ovarian tumors are the leading cause of mortality. The present study was conducted to identify the various histopathological spectrums of ovarian neoplasm (ON) according to the World Health Organization (WHO) classification in a single center.Material and methodsThis cross-sectional study was conducted over a period of one year (November 2020 to October 2021) in the Department of Histopathology, Chughtai Institute of Pathology (CIP), Lahore, Pakistan. The study included 390 cases of ovarian neoplasms (ONs). After proper fixation and thorough gross examination, sections were routinely processed and examined. The distribution of the various histomorphological spectrum of ovarian tumors was studied according to the WHO classification.ResultsOut of the 390 cases studied, 320 (82.05%) were benign, 11 (2.82%) borderline, 57 (14.61%) malignant, and two (0.52%) metastatic tumors. Surface epithelial tumors (SETs) (246 (63.08%)) were the most common of all, followed by germ cell tumors (GCTs) (115 (29.48%))\u00a0and sex cord-stromal tumors (SSTs) (27 (6.92%)). The largest percentage (36.15%) of ONs was seen in 21-30 years of age group.ConclusionThe present study shows various histopathological features of ONs. Benign tumors are more common than malignant tumors. Among the\u00a0benign tumors, serous tumors were most common of all. Thus, an accurate histological diagnosis is important to initiate a proper management plan. Ovarian neoplasms (ONs) comprise 3%\u00a0of all cancers ,2, and aOvaries are paired organs in the female reproductive system which can undergo various changes throughout an individual\u2019s life under the effects of different hormones. This could lead to different types of diseases, benign or malignant ,7. Most The present cross-sectional study was conducted over a period of one year (November 2020 to October 2021) at the Chughtai Institute of Pathology (CIP), Lahore, Pakistan, after obtaining\u00a0approval from the institutional review board (letter no. CIP/IRB/1053). A total of 390 cases were included in the study. The specimen was received and fixed in 10%/formalin. After proper fixation of 24-48 hours, representative sections were taken and routinely processed with paraffin embedding. Tissue sections of four to five microns were cut using a microtome and stained with hematoxylin and eosin. The slides were reviewed by two pathologists having a special interest in female genital tract pathology, and the tumors were classified according to the WHO classification of ovarian tumors.Data were analyzed using SPSS, version 22 . The large data were sorted into various datasets based on the distribution of tumors as surface epithelial tumors (SETs), germ cell tumors (GCTs), sex cord-stromal tumors (SSTs), and metastatic tumors. The patients were divided into different age groups, and the frequency of ONs was analyzed.Inclusion criteriaAll ovarian neoplasms and all age groups were included.Exclusion criteriaNon-neoplastic ovarian lesions and poorly fixed and autolyzed specimen were excluded.The present study included a total number of 390 cases of ONs. The age range lies between 10 and 80 years Table . Benign The morphological and cytological characteristics of tumor cells are used to classify ONs . Given tIn the present study, a total of 390 cases of ONs were analyzed, out of which SETs were the most prevalent, comprising 246 cases (63.08%), GCTs 115 (29.48%), SSTs 27 (6.92%), and metastatic tumors two (0.52%). The majority were of benign category, i.e., 320 (82.05%), followed by malignant tumors 57 (14.61%). The borderline category included 11 (2.82%) cases, and two (0.52%) were metastatic tumors.The findings of our study are consistent with two other studies ,13. RegaGCTs rank the second most common ON with a total number of 115 cases 29.48%) , out of 8% , out In the present study, 27 cases (6.92%) of SSTs were included. Fibroma cases were 10 (2.56%) and accounted for a majority of them, followed by adult granulosa cell tumors, seven (1.79%). Our results were nearly identical to those of Bhagyalakshmi et al.  and ThakThe current study demonstrates a wide range of histopathological spectrum of ONs. Overall, benign tumors were more common than malignant tumors; in particular, SETs were the most common neoplasm, followed by GCTs. Serous cystadenoma was the most frequent neoplasm in the benign category, and serous carcinoma was in the malignant category. The majority of the cases were present in the 21-30 years of age group. ONs require an accurate diagnosis to be treated effectively."}
+{"text": "Heat shock proteins are induced in a wide range of abiotic and biotic stresses. They are well known for cellular chaperone activities and play an important role in protecting plants through regulation of homeostasis and survival. A comprehensivecharacterization and comparative analysis of the Hsp70 family members within the closely related plant species helps in better interpretation of these proteins' contribution to cell function and response to specific environmental stresses. Therefore,it is of interest to glean insights from the protein sequence analysis of PgHsc 70 and OsHsp70 genes. Thus, we document data from the sequence and structure analysis of PgHsc 70 and OsHsp 70 gene a. Plant defense mechanisms are induced rapidly and plants adapt at morphological, molecular and physiological levels ,2,3.TheIn the environmental stress conditions, the cell survival and sustenance is dependent upon protein native conformation and preventing protein aggregation. In the event of environment stress conditions, chaperone proteins, assist to fold cellular proteinsinto three-dimensional conformation and avoid abnormal folding and aggregation ,11. HeatBased on the molecular weights, five families of heat shock proteins are identified. The major HSPs families are chaperonin (Hsp60/GroEL), 70-kDa Hsp (Hsp70/DnaK), Hsp90, Hsp100/ClpB, and the small heat shock proteins (sHsp) .Of thesThe yield improvement of crops in the unfavorable abiotic conditions is a challenge. In particular the role played by Poaceae crops in food demand is well known, contributing high amount of calories in the human diet ,28.WheaThe complete nucleotide sequence and the CDS of Pennisetum glaucum heat shock cognate 70 kDa protein (PgHSC70) and Oryza sativa hsp70 gene for heat shock protein 70 (OsHSP70) registered in GenBank and their protein sequences are obtained inFASTA format from National Center for Biotechnology information (NCBI). The gene and protein structural and functional analysis of sequences was done using in-silico tools. The gene structure of PgHSC70 and OsHSP70 were predicted based on the genome and coding sequences using the Gene Structure Display Server. This server analyses exon/intron organization of PgHSC70 and OsHsp70 genes. In the gene structure analysisexons/introns and intronic phase distribution  were identified and marked. Based on position relative to reading frame three intron phases exist: insertion between two codons (phase 0), insertion after first base codon (phase 1) orafter second base codon (phase 2).Using MEME suite sequence motifs were scanned over the nucleotide sequences in PgHSC70 and OsHSP70 genes. Input of cDNA sequences of PgHSC70 and OsHSP70 genes were given to the MEME suite. In a default setting, it can help in predicting up to threemotifs and selected for finding distribution of motifs with three different parameters. Parameters were optimized in MEME suite set to 10 as maximum number and 1 as minimum occurrence of motif site per sequence. All the other parameters were kept indefault value. Predicting the width and the occurrence number of motifs, in order to minimize the E-value, was automatically done with MEME suite.Using Plant CARE database cis-acting regulatory elements (CREs) were scanned in PgHSC70 and OsHsp70 genes. The PgHSC70 and OsHsp70 genes cDNA sequences were uploaded and evaluated for cis-regulatory response elements presence in promoter regions topredict computationally the regulatory elements. For the response elements shown, a matrix value of \u22655 was considered for acceptance on the sense strand. The obtained cis-elements were compared with each other.Plant small RNA-targeted gene prediction was performed on sequences PgHSC70 and OsHsp70 genes using psRNATarget server. The miRNA target sites were analyzed using default parameters.For identification of similarity of PgHSC70 and OsHsp70, the homology search of each protein was performed by BLAST using blastp algorithm respectively. Using multiple sequence alignment (MSA) tool ClustalW2, the protein sequences of all the identifiedhomologues of PgHSC70 and OsHsp70 were aligned. Using the BLOSUM 62 substitution matrix evolutionary alignment was inferred with progressive method. The phylogenetic tree was constructed for the identified PgHSC70 and OsHsp70 proteins using ClastalW2.Physicochemical characterization of the target protein sequences of PgHSC70 and OsHsp70 such as mol. wt, aa composition, isoelectric point (pI), instability index (II), the total negative and positive residues, extinction coefficient (EC), grandaverage of hydropathicity (GRAVY) and aliphatic index (AI) were analyzed using Expasy's ProtParam prediction server.SOPMA tool was used to predict PgHSC70 and OsHsp70 proteins secondary structure for assigning positional possibility of various regions of \u03b1-helix, \u03b2-strands, turns as well as random coils likely to fold. The method makes use of predictingconsensus from multiple alignments of the relative frequencies of each amino acid anchored in the X-ray crystallographic solved protein templates.PgHSC70 and OsHsp70 subcellular localization was predicted using CELLO v.2.5 which is a multiclass support vector machine classi\ufb01cation system. SignalP was used to verify the presence of signal peptide cleavage sites and their locations in both proteins,which works on the basis of a combination of several neural networks, namely artificial neural network (ANN) and Hidden Markov Model (HMM).Using STRING  v 9.1 protein-protein interactions (PPIs) analysis was done. The STRING repository consisted of PPIs concerning stable protein complexes, functional and regulatory interactions. The PPIs ofPgHSC70 and OsHsp70 were searched individually by submitting a protein query sequence in the search box of STRING. Determining the protein\u2013protein interaction network would empower study of signaling pathways.In protein folding and formation a functional and stable confirmation is determined by disulfide bonds among its cysteine residues. To predict cysteine bonds (disulfide bonds) presence and absence and their bonding patterns CYS_REC tool was used.The targets in PgHSC70 and OsHsp70 were predicted for putative acetylation, methylation, phosphorylation, ubiquitination, and N-glycosylation sites. phosphorylation at serine, threonine and tyrosine residues in the PgHSC70 and OsHsp70 proteins werepredicted using NetPhos 3.1 was used. To complete this task it ensembles neural networks and residues having scores 0.5 threshold as phosphorylated. The N-glycosylation sites of the target proteins were predicted with NetNglyc 1.0 server, with threshold valueof >0.5. By default the predictions are done only on the Asn-Xaa-Ser/Thr sequons.The estimation of intrinsic disordered regions (IDRs) of PgHSC70 and OsHsp70 was made by DisEMBL tool.The protein structures of PgHSC70 and OsHsp70 was modeled using the bovine HSC70 (PDB ID: 1YUW) as template sequence exhibiting the highest similarity identified by BLAST against the PDB database. DS was used to design a homology model of bothproteins and the each protein model with less geometric function was selected and energy minimized in CHARMm force field using DS minimization algorithms. For structural validation, the obtained final models are further subjected to PROCHECK forPsi/Phi Ramachandran plots analysis. Protein binding/catalytic sites are identified using DS Analyze Binding Site tool.The homology models of PgHSC70 and OsHSP70 were analyzed for docking with brassinolide. Using DS LibDock docking simulation was performed. The obtained confirmations were then summarized and analyzed for interactions. The interactions showing highestscores and docking energy were considered best for protein-ligand complex structure.Comparative alignment of genomic and cDNA nucleotide sequences of PgHsc70 and OsHSP70 genes is shown in Figure 1(see PDF). The intron phases consisted of phase 0, 1 and 2. Exon count and intronic phase distribution was similar in both the genes. Two exonswere present in both the genes and their distribution was found at phase 0 (exon 1) and phase 2 (exon 2). Phase 1 intronic phase distribution was found in both the genes. The intron length varied with OsHSP70 intron of 1935 bp while PgHSC70 intron is 141 bp.The MEME tool identified 10 significant conserved motifs as shown in Figure 2(see PDF). The length of conserved motifs varied from 21 to 50 amino acids. The consensus sequence motifs identified are given in Table 1(see PDF).In silico analysis of cis-regulatory elements (CREs) in the CDS sequence of PgHSC70 and OsHsp70 genes revealed different elements in the upstream region (Table 2-see PDF). In PgHSC70 a total of 33 CAREs whereas, in OsHSP70, 29 CAREs were identified anda few were uniquely present in each gene. Cis-elements were found responsive to light, meristem-specific activation, abscisic acid, methyl jasmonate, gibberellins, low temperature, seed-specific regulation, root-specific expression, anoxia, and circadianregulation. The CCGTCC motif, ABRE, W box, CCAAT-box, GC motif,, G-Box, MYB recognition site STRE, MYB, TGA-element, plant_AP-2-like, WRE3, and unnamed-1 are the common CREs found in both the genes. All of them were present on sense strand with matrixvalue \u2265 5.The plant small RNA target analysis server (psRNATarget) was used to predict miRNA target sites. The miRNAs comprising target sites in PgHSC70 and OsHSP70 genes were identified with expectation score lower than 4.0 (Table 3 -see PDF)). MSA using ClustalWwas constructed by aligning seven PgHSC70 protein sequences along with twelve OsHsp70 protein sequences. Phylogenetic tree based on MSA is shown in Figure 3(see PDF). Comparative phylogenetic analysis of PgHSC70 and OsHsp70 revealed major groups of HSP70genes with paralogous as well as orthologous genes. Each group contained both PgHSC70 and OsHsp70.The Expasy's ProtParam tool determined the length (649 and 648 aa), mol. wt. (71105.48 and 70997.56 Da), isoelectric point (pI=5.10 and 5.16), the total negative and positive charged residues of PgHSC70 and OsHsp70 proteins . Proteins are found be acidic (pI<7). The amino acid composition analysis revealed that Ala (58) was the most abundant amino acid in both the sequences, while Trp (3) was the least abundant (Table 4-see PDF). PgHsc 70 had the atomiccomposition C2777H4999N861O995S24, while OsHsp70 had the atomic composition C3108H5007N861O987S24.The calculated extinction coefficient (EC) of PgHsc70 and OsHsp70 proteins was found to correlate with the cysteine, tryptophan and tyrosine content at 280 nm as 37735 and 39225  and 37360 and 38850 M\u22121cm\u22121, respectively. The instability index (II) values were 34.52(PgHsc70) and 33.69(OsHsp70) classifying both proteins as stable. Similarly, the aliphatic index (AI) had high value of 81.79 (PgHsc70) and 83.56(OsHsp70), indicating proteins are thermo stable.The estimated half-lives for both proteins were 30 h in mammalian reticulocytes (in vitro), >20 h in yeast (in vivo) and >10 h in Escherichia coli (in vivo). The GRAVY was -0.427 (PgHsc70) and -0.399 (OsHsp70), respectively. Both proteins arehighly water soluble. Table 5(see PDF) shows the predicted physicochemical properties of the PgHSC70 and OsHsp70. In Figures 4 and 5(see PDF), the secondary structure of protein sequences of PgHSC70 and OsHsp70, predicted using SOPMA server are shown.The evaluated percentage \u03b1-helices, \u03b2-turn, extended strand, and random coils with output width 70 is given in Table 6(see PDF). From the computed percentage of each conformation, \u03b1-helix predominated, followed by extended strand randomcoil and random coil in both the proteins. The high percentage of random coils indicates protein flexibility and more interactions. Also, high coiled structural content might be because of flexible glycine and proline amino acids in the proteins.The sub cellular localization of proteins PgHsc70 and OsHsp70 predicted by CELLO was found to be cytosolic in nature. The SignalP analysis revealed that none of the proteins have any of signal peptide. Using CYS_REC tool the cysteine residues in theproteins determined revealed that the protein PgHsc70 contain cysteine residues in the positions 20, 273, 319, 326, 366, 483 and 609. But all are not involved in disul\ufb01de bonding; Cys326 is probably SS-bond with a score of 1.9. On the other hand, OsHsp70revealed that cysteine residues were present in the position 20, 272, 318, 325, 365, 482 and 608 and probably Cys326 is SS-bonded with a score of 1.9. At the molecular level the disulfide bridges presence is a positive factor for stability. Table 7(see PDF)shows the results obtained using CYS_REC tool.NetPhos 3.1 & NetNglyc servers identify post-translational modification sites. NetPhos retrieved the information related to kinases PKC, Unsp, CKI, cdk5, CKII, PKA, RSK, DNAPK, CKI, PKG, EGFR , SRC and cdc2 involved in the phosphorylation of bothproteins and an extra one kinase INSR unique to OsHsp70. In both the proteins high score of 0.691 predicted for site having threonine and the percentage amino acids composition obtained is shown in Figures 6a and 6b(see PDF). Using NetNglyc server, theN-glycosylation sites  of the PgHsc70 protein were predicted with a score of 0.66, 0.57, 0.58 and 0.74 respectively. The N-glycosylation sites of OsHsp70 protein predicted were  with scores of 0.6378, 0.5774, 0.5874 and 0.7403. The plot of predicted N-glycosylation sites is shown in Figures 7a and 7b(see PDF).Using String, the interacting partners predicted in both PgHsc70 and OsHsp70 is shown in the Figure 8(see PDF). From the analysis, the functional partners observed in the string network of PgHsc70 protein were HSFA2, HSF1, HSP101, HSP90.1, Hsp81.4, Hop3,HSP81-3, LOS1, J3 and Hop1. The functional partners observed in the string network of OsHsp70 are OsJ-17347, OS11T0703900-01, OsJ_11911, HSP81-2, OsJ_12871, DJA6, and OS04T0107900-02. These interactions give some insights into understanding the functioningof these proteins in response to heat stress and tolerance. Using DisEMBL the predicted intrinsic disorder regions (IDRs) of PgHSC70 and OsHsp70 is shown in Figure 9(see PDF).Homology modeling was done to predict the 3-D structures of PgHSC70 and OsHsp70 based on the template structure HSC70 (PDB ID: 1YUW) from bovine, at a resolution of 2.6 \u00c5 deposited in PDB. The template protein had identity of 81% (PgHSC70)and 80.18 % (OsHsp70). The initial models of PgHSC70 and OsHsp70 proteins were built using the crystal coordinates information of the template 1YUW. The models generated by DS, were scored with discrete optimized protein energy (DOPE) geometric function,and the model with the lowest DOPE score was taken as final model as shown in Figure 10(see PDF). After the proteins were energy minimized, the final models were validated using PROCHECK. Corresponding to core regions most favorable Psi/Phi valuecombinations are present in the darkest areas in Ramachandran plot. Each of the protein models displayed 90% accuracy. Overall, the homology model of the PgHSC70 have 94.6% of the residues occurring in most favored region, 4.4 % in allowed regions, andonly 1.1 % of the residues in disallowed regions. In comparison, the OsHsp70 homology model have 94.6% residues in favored region, 4.9 % residues in allowed region and 0.5 % residues in outlier region.Molecular docking of PgHSC70 and OsHsp70 with brassinolide was studied in order to identify the critical interactions and their variation. Using LibDock the docking results for brassinolide on PgHSC70, showed high binding affinity with score of 115.231and binding energy of 0.00119\u2009kcal/mol, in comparison target OsHsp70 showed a LibDock score of 146.59 and binding energy of -26.586 kcal/mol. In the PgHSC70-Brassinolide complex, the electrostatic and \u221287.3 and -835.7 kcal/mol of van der Waals energiesrespectively and for OsHsp70-Brassinolide complex -18.332 and 4.139 kcal/mol were found to be higher. Docking analysis revealed both H-bonds and close interactions within the docked site of PgHSC70 and OsHsp70 . The PgHSC70-Brassinolidecomplex formed five hydrogen bonds, 3 with residue THR271, each one with LYS59 and LYS277, and the closest interactions are also found with the amino acid residue GLY236. Whereas the OsHsp70-Brassinolide complex formed two hydrogen bonds with two residuesASP35 and LYS129 and found to interact with the amino acid residue ILE133. The docking studies clearly indicated that the ligand and receptor were bound together closely to stabilize complex structure in OsHsp70 and PgHsc 70 as done in our previous study [We have documented the characterization of Hsp70 gene family members, PgHSC70 and OSHsp70 genes, and their proteins sequences in pearl millet and rice respectively. The results indicated conserved relationships and distinct functions of PgHSC70 andOSHsp70 highlighting the wide participation of these family members in environmental adaptation. Data from docking analysis of the homology models with brassinolide is also reported."}
+{"text": "People presenting first-episode psychosis (FEP) benefit from early intervention programmes, although they are scarce in low- and middle-income countries (LMICs). In Brazil, there are just a few of them unequally distributed across the country.We aimed to describe the workings of the Ribeir\u00e3o Preto Early Intervention for Psychosis Programme (Ribeir\u00e3o Preto-EIP) \u2013 an outpatient service for first-episode psychosis patients residents in the Ribeir\u00e3o Preto catchment area in Southeastern Brazil.A retrospective cohort of all patients attended throughout four years (2015-2018) was analysed. We excluded patients who attended only the first consultation and those with an initial diagnosis other than a psychotic disorder. Data was obtained through retrospective analysis of medical records.Our service had 358 new referrals during the four-year period, and 237 patients were followed on average (median) by 14 months. Most of the patients were male (64.1%), single (84.8%), with a median age of 23.5 years (age ranged from 9 to 86 years). Schizophrenia was the main diagnosis (43.4%), followed by substance-induced (25.7%) and affective psychosis (18.6%). Taking follow-up diagnoses as gold-standard, initial diagnoses of bipolar disorder and schizophrenia spectrum disorders had the highest positive predictive values, 83% and 81% respectively. Most referrals to our programme were made by tertiary care (63.7%), followed by secondary (28.5%) and primary care (7.8%).Here we presented a large sample of FEP patients in a representation as trustworthy to the reality of our programme as possible. Our analysis suggest that Early Intervention Programmes can be successfully implemented in LMICs.No significant relationships."}
+{"text": "Fungi are ubiquitous in the environment, and for patients with risk factors, they can present as pathogens. Unusual fungi often pose a diagnostic challenge and when encountered in practice, albeit infrequently, can delay diagnosis and treatment.Over a period of three years (2018-2020), such cases were followed up till death or discharge and all details were noted down. All patients were diagnosed to have invasive fungal disease according to the EORTC/MSG criteria. Species identification was performed using MALDI-TOF MS and antifungal susceptibility testing (AFST) was done using standard CLSI guidelines.Candida guilliermondii (2), Candida pelliculosa (2), Lodderomyces elongisporus (1) from the blood samples, and Trichosporon asahii (6), Candida guilliermondii (1), Candida kefyr (1), and Geotrichum spp. (1) from the other samples. Certain Candida species showed higher MICs to azoles and echinocandins. Trichosporon and Geotrichum showed higher MICs to azoles.A total of 14 cases of rare yeasts were noted out of a total of 155 infections due to yeasts. Among these 5 presented with fungemia and 9 with invasive fungal infections (IFI). Of the IFI clinical isolates, there were 2 pus samples and 7 sterile fluids. The majority of these 14 patients were male (11) and belonged to extremes of age (8). The risk factors included CKD (2), prior history of tuberculosis (2), CLD (1), congenital heart disease (2), and type 2 diabetes mellitus (1). Pathogens isolated were Candida pelliculosa (fungemia) and Trichosporon asahii .Unfortunately, half of the patients (7) received no antifungals. Of those who did, 4 received mono therapy with azoles or Amphotericin B, while other 3 received combination or sequential therapy with azoles, echinocandins and Amphotericin B. Of the 14 patients, 3 patients expired. The etiological agents in these cases were This study aims to highlight the clinical presentation of uncommon yeasts, presenting both as bloodstream infections (BSI) and as invasive disease. Improved methods of detection will help us improve our diagnostic accuracy of uncommon pathogens. The clinician should liaise closely with the laboratory, and treatment should be instituted according to the AFST data.All Authors: No reported disclosures."}
+{"text": "What are the molecular characteristics and clinical features of synchronous multiple primary colorectal cancer (sMPCC)?This cohort study of 239 patients with sMPCC found that the deficient mismatch repair (dMMR)/microsatellite instability\u2013high (MSI-H) frequencies in sMPCC were significantly higher than those in single primary colorectal cancer. The MMR/MSI status of each lesion might be different in sMPCC and can be classified into 3 subgroups: all dMMR/MSI-H, dMMR/MSI-H and proficient MMR (pMMR)/microsatellite stability (MSS), and all pMMR/MSS.These findings suggest that sMPCC can be classified into subgroups according to the MMR/MSI status of each lesion, which might be applied to guide personalized therapies for better disease management. This cohort study evaluates the molecular characteristics and clinical features of synchronous multiple primary colorectal cancer. Synchronous multiple primary colorectal cancer (sMPCC) is clinically rare, but its incidence has increased over the past decade. However, little is known about the molecular and clinical features of sMPCC, which may differ from those of single primary colorectal cancer (SPCRC).To evaluate the clinical characteristics and pathogenic variations in lesions and the molecular typing of sMPCC.From November 2012 to April 2021, patients with colorectal cancer (CRC) treated at the Sixth Affiliated Hospital of Sun Yat-sen University were enrolled in this cohort study. Follow-up ended on January 31, 2022.The primary outcome was mismatch repair (MMR) status of each lesion in all patients examined using immunohistochemistry (IHC). Microsatellite instability (MSI) and tumor mutation burden (TMB) were also calculated.EGFR and PIK3CA variants were more common, whereas TP53 variants were less prevalent in patients with sMPCC than in those with SPCRC. Moreover, higher tumor mutation burden was associated with higher MSI in patients with sMPCC rather than in those with SPCRC.A total of 13\u2009276 patients with CRC were enrolled, and 239 patients with sMPCC  with available clinical data were evaluated. Seventy-eight patients with sMPCC and 94 with SPCRC also underwent next-generation sequencing (NGS)\u2013based molecular testing. The deficient MMR (dMMR)/MSI-H frequencies in sMPCC were significantly higher than those in SPCRC, which was confirmed by both IHC (50 of 239 patients vs 872 of 13\u2009037 patients) and NGS (17 of 78 patients vs 5 of 94 patients). According to the MMR/MSI status of different lesions in patients with sMPCC, they were further divided into 3 subgroups: all dMMR/MSI-H, dMMR/MSI-H and proficient MMR (pMMR)/microsatellite stability (MSS), and all pMMR/MSS. The In this cohort study of sMPCC, the incidence of dMMR/MSI-H in patients with sMPCC was significantly higher than that in patients with SPCRC. These findings suggest that sMPCC can be classified into 3 subgroups according to the MMR/MSI status of each lesion, which might be applied to guide personalized therapies for better disease management. Although the incidence rate varies slightly in different regions, a meta-analysis4 showed that the overall incidence rate of sMPCC in all CRCs was approximately 1.1% to 8.1%. The relatively low incidence rate has led to a lack of large-scale research on sMPCC. Most studies investigating sMPCC have focused on the clinical characteristics and epidemiology of small samples.5 Only a few studies have provided genome-wide characterization of sMPCC,7 and, to our knowledge, there are no integrated studies on the clinical phenotype and molecular characteristics of sMPCC.Synchronous multiple primary colorectal cancer (sMPCC) is a relatively rare colorectal cancer (CRC) that refers to the simultaneous occurrence of 2 or more independent primary malignant tumors in the colon or rectum of the same patient. According to recent reports,Moreover, with the progress of immunotherapy in microsatellite instability\u2013high (MSI-H) CRC, the mismatch repair (MMR)/MSI status plays an important role in CRC treatment. It remains unclear whether the MMR/MSI status of different sMPCC lesions is consistent.In April 2020, we treated a patient in their 50s with sMPCCs and multiple liver metastases. The patient had 3 tumors located in the ascending colon (T3N2M1), transverse colon (T3N0M1), and upper rectum (T4aN2M1). Genomic sequencing of the rectal lesion revealed that the patient had MSI-H status. Therefore, after fully evaluating the condition and consulting with the patient, we performed a conversion strategy with 6 courses of programmed death (PD)\u20131 blockade (200 mg/dose) combined with mFOLFOX6 for 2 weeks between courses. The patient\u2019s symptoms were alleviated rapidly, and laparoscopic resection of the whole colon and upper rectum was performed as planned without delay. Remarkably, all gastrointestinal lesions and lymph nodes in the patient had a pathological complete response. The patient received 3 additional doses of PD-1 blockade therapy (200 mg/dose) after surgery. During follow-up, routine radiological examinations, including computed tomography, magnetic resonance imaging, and contrast-enhanced ultrasonography, proved that the patient had maintained no evidence of disease status for more than 18 months. On the basis of this case, we focused on evaluating the molecular typing of sMPCC by MMR and MSI status and pathogenic variations of sMPCC. We performed a large-scale, retrospective cohort study of sMPCC to evaluate the clinical characteristics and pathogenic variations in each lesion and performed molecular typing in sMPCC for the first time, to our knowledge.8 and its later amendments or comparable ethical standards. This cohort study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cohort studies, and the protocol was approved by ethics committee of medical research of the Sixth Affiliated Hospital of Sun Yat-sen University. All the patients were fully informed and signed the informed consent form.All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki3 From November 2012 to April 2021, after excluding patients whose clinical data were incomplete or lost to follow-up, patients with CRC, including patients with sMPCC who underwent surgery at the Sixth Affiliated Hospital of Sun Yat-sen University, were included. We conducted a retrospective single-center study of all eligible patients with sMPCC. Each lesion in patients with CRC underwent pathological examination and immunohistochemistry (IHC).According to the Warren and Gates criteria, the detailed criteria of sMPCC are as follows: (1) pathologically confirmed as adenocarcinoma, (2) separated from one another, (3) exclusion of metastases from the primary CRC, and (4) diagnosis together or within 6 months of each other.The treatment and baseline information of each patient were collected using a medical record system. During the study period, follow-up methods included telephone interviews, outpatient examinations, and readmission. Follow-up ended on January 31, 2022, or when death occurred. All patients were initially followed up once every 3 months initially after the operation and then every 6 months from the third year to the fifth year if there was no recurrence. Physical examination and serum carcinoembryonic antigen and carbohydrate antigen 19-9 tests were regularly performed each time, and computed tomography was reexamined semiannually.The entire tumor tissue was subjected to microscopic examination, and formalin-fixed, paraffin-embedded tissue samples were obtained. Sections (4-\u03bcm thick) were stained with hematoxylin and eosin and examined. Immunohistochemical analysis was performed using monoclonal antibodies against MLH1 (MAXIM), MSH2 (LBP), MSH6 (ZSGB-BIO), and PMS2 (ZSGB-BIO), according to established protocols. Slides were incubated overnight with primary antibodies at 4\u2009\u00b0C. Horseradish peroxidase\u2013labeled secondary antibody from a MaxVisionTM HRP-Polymer goat anti\u2013mouse/rabbit IHC kit  was applied, and the slides were incubated for 30\u2009minutes at room temperature, followed by a 5-minute incubation at room temperature with 3,3\u2032-diaminobenzidine. Finally, the sections were counterstained with hematoxylin and mounted using Permount (BIOS). The results were visualized and interpreted by 2 experienced pathologists (Y. Zhao and S. Bai).9 The generated sequences were mapped to the human genome HG19 using the BWA-MEM algorithm (version 0.7.10-r789)10 for both tumor and normal samples. Polymerase chain reaction duplications were marked and removed using Picard command line tools version 1.103 (Broad Institute). Base quality recalibration and local realignment processing were performed using the Genome Analysis Toolkit .11 Somatic single nucleotide variations and small insertions/deletions were identified using MuTect (version 3.1-0-g72492bb)12 and Strelka (version 1.0.14).13 The effects of variants were annotated using the Variant Effect Predictor (version 83)14 and Oncotator (version 1.5.1.0).15 Somatic copy number variants are determined using ADTEx.16 Structural variations were determined using CREST.17 MSI status was evaluated using NGS by calculating the length of 309 microsatellite sites. The tumor mutation burden (TMB) value was determined by the number of somatic single nucleotide variations and insertions/deletions per megabase of the 3\u2009427\u2009939-bp coding region.Targeted next-generation sequencing (NGS) was performed on each lesion of 78 sMPCC with sufficient specimens using Onco PanScan . Briefly, total DNA from tumor tissues was extracted using a QIAamp DNA Tissue Kit (Qiagen). DNA libraries were constructed using a KAPA HTP Library Preparation Kit (Illumina), according to the manufacturer\u2019s protocol. Quality control was performed using FastQC (version 0.11.2) and Trimmomatic (version 0.33).P < .05 was considered statistically significant. According to the data distribution characteristics, continuous variables were presented as mean\u2009(SD) or median (IQR), and categorical data were presented as numbers or percentages. Continuous variables between groups were compared using a t test when they followed a normal distribution; otherwise, a Mann-Whitney U nonparametric test was applied. Categorical variables were compared using the \u03c72 test or Fisher exact test. Survival analysis of the overall survival (OS) and progression-free survival (PFS) rates was performed using the Kaplan-Meier method and assessed using a log-rank test.Statistical analysis was performed using SPSS statistical software version 26.0 (IBM) and R statistical software version 4.0.4 for Windows . Two-tailed According to the IHC results of each lesion, the MMR status of all 239 patients with sMPCC was divided into proficient MMR (pMMR) (189 patients [79.1%]), dMMR (40 patients [16.7%]), and dMMR and pMMR (10 patients [4.2%]) groups. According to the genomic sequencing results of each lesion, the MSI status of 78 patients with sMPCC was divided into MSS (61 patients [78.2%]), MSI-H (10 patients [12.8%]), and MSI-H and MSS (7 patients [9%]) groups. MMR status was highly consistent with MSI status (75 patients [96.2%]) . The results of MSI status detected by NGS were consistent with those of MMR, with incidences of 17 of 78 patients and 5 of 94 patients, respectively .APC (103 of 158 tumors [65%]), KRAS (78 of 158 tumors [46%]), TP53 (49 of 158 tumors [31%]), PIK3CA (39 of 158 tumors [25%]), and EGFR (36 of 158 tumors [23%]), whereas the most frequent variant genes in patients with SPCRC were APC (79 of 111 tumors [71%]), TP53 (71 of 111 tumors [64%]), KRAS (44 of 111 tumors [40%]), FBXW7 (22 of 111 tumors [20%]), and PIK3CA (14 of 111 tumors [13%]). We also found that variant genes were significantly different among the 3 subgroups. The top 5 variant genes in the MSI-H group were APC (15 of 22 tumors [68%]), FAT4 (14 of 22 tumors [64%]), TCF7L2 (13 of 22 tumors [59%]), KMT2B 12 of 22 tumors [55%]), and ARID1A (10 of 22 tumors [45%]); those in the MSI-H and MSS group were APC (8 of 14 tumors [57%]), KMT2B (6 of 14 tumors [43%]), KMT2C (6 of 14 tumors [43%]), ATM (6 of 14 patients [43%]), and PRKDC (6 of 14 tumors [43%]); and those in the MSS group were APC (80 of 122 tumors [66%]), KRAS (60 of 122 tumors [49%]), TP53 (44 of 122 tumors [36%]), PIK3CA (26 of 122 tumors [21%]), and EGFR (25 of 122 tumors [20%]) , we found that the most enriched gene variant type in patients with sMPCC was C>T (G>A)  had pathogenic or likely pathogenic germline variations (PGVs), and 11 (13.75%) had SPCRC. Patients with PGVs were comparable between the sMPCC and SPCRC groups  TMB values were 55.6 (44.7-68.3) mutations per megabase among the 10 patients in the MSI-H group, 39.9 (27.0-87.8) mutations per megabase among the 7 patients in the MSI-H and MSS group, and 4.2 (3.3-5.6) mutations per megabase among the 61 patients in the MSS group. On the basis of the TMB value (cutoff\u2009=\u200910 mutations per megabase), all tumors harboring high TMB (TMB-H) were identified in the MSI-H subgroup (10 of 10 patients [100%]), 6 of 7 patients (85.7%) with TMB-H in the MSI-H and MSS subgroups, and 5 of 61 patients (8.2%) with TMB-H in the MSS subgroup . HoweverP\u2009=\u2009.99). Similarly, patients with dMMR had a median PFS of 95.2 months vs 103.3 months in patients with all pMMR . Although no statistically significant difference in OS and PFS was observed between the 2 groups according to MMR status, the trends of OS and PFS were obviously different. A similar trend was observed for MSI status. In patients whose tumors were all MSI-H/MSI-H and MSS, the OS was 95.7 months vs 58.0 months in patients with all MSS  . Meanwhile, the incidences of the other most frequently variant genes, including PIK3CA, EGFR, ARID1A, NF1, SOX9, FAT4, and TCF7L2, were all higher than those in patients with SPCRC. Moreover, we found that higher TMB was associated with higher MSI in patients with sMPCC than in patients with SPCRC. Furthermore, we found that variant genes differed among the 3 subgroups. The top 5 variant genes were APC, FAT4, TCF7L2, KMT2B, and ARID1A in the MSI-H group; APC, KMT2B, KMT2C, ATM, and PRKDC in the MSI-H group; and APC, KRAS, TP53, PIK3CA, and EGFR in the MSS group. Finally, although we found that patients with pathogenic or likely PGVs were comparable between sMPCC and SPCRC, patients with sMPCC with a family history were more likely to harbor PGVs. In addition, there was no significant difference in pathway enrichment between the different subtypes of sMPCC compared with SPCRC.Genomic analysis revealed that the most enriched gene variant type in patients with sMPCC was C>T (G>A). The incidence of The limitations of our study include but are not limited to the lack of sMPCC cases treated with molecular typing\u2013guided treatment. Larger-scale studies and long-term follow-up are needed to further confirm the molecular typing\u2013guided treatment in patients with sMPCC and to correlate the pathological response resulting from this individual strategy with PFS and OS. Prospective trials are necessary to define the role of molecular typing combined with individual therapy in curing and reducing recurrence in patients with sMPCC.Our results revealed that the incidence of dMMR/MSI-H in patients with sMPCC was significantly higher than that in patients with SPCRC. We propose that the MMR/MSI status of each lesion in patients with sMPCC should be verified before treatment, and that these patients can be divided into 3 subgroups according to their MMR/MSI status. Our findings indicate that patients with sMPCC with different MMR/MSI statuses may be treated with personalized therapies for better disease management."}
+{"text": "Intravenous (IV) vancomycin is a commonly prescribed antimicrobial. However, there is limited literature assessing IV vancomycin appropriateness. The objective of the study was to assess the appropriateness of IV vancomycin prescriptions in a Canadian acute care hospital.Prospective audit and feedback (PAF) was conducted on all new IV vancomycin prescriptions in hospitalized adults (age \u2265 18 years) at the University of Alberta Hospital from January 17 to February 11, 2022. Appropriateness was assessed against institutional prescribing guidelines . Verbal and written feedback were provided to the attending teams.A total of 109 prescriptions were audited. Median age was 57 (IQR 43-72) years and 42% were female. 65 (60%) were admitted to Medicine, 18 (17%) to Surgery, and 26 (24%) to Intensive Care units. MRSA colonization was present in 32 (29%) patients, \u03b2-lactam allergy recorded in 21 (19%), and acute kidney injury (AKI) in 21 (19%). Infectious Diseases consultation (IDC) occurred in 29 (27%). The top indications were skin and soft tissue, pulmonary, and bloodstream infections (Table\u00a01); 70% of prescriptions were empiric in nature.Overall, 43 (39%) prescriptions were assessed to be suboptimal. Antimicrobial Stewardship program (ASP) recommendations were made in 56 prescriptions, totaling 63 unique recommendations. Vancomycin was recommended to be discontinued in 24 (43%) cases or changed to a different agent in 15 (27%). Regimen optimization (duration or frequency change) was recommended in 4 (7%). ASP recommended investigations in 8 cases and IDC in 12. Full or partial acceptance was achieved in 49 cases (88%).IDC was associated with greater appropriateness  as was MRSA colonization , but AKI was not . Adjusting for age, AKI, and MRSA colonization, IDC remained a significant predictor of vancomycin appropriateness .IV vancomycin prescriptions were suboptimal in 39% of cases. IDC was associated with increased appropriateness. This pilot informs the need for antimicrobial stewardship intervention and the importance of IDC at our center.Dima Kabbani, MD, MSc, AVIR Pharma: Grant/Research Support|AVIR Pharma: Honoraria|GSK: Honoraria|Merck: Grant/Research Support."}
+{"text": "Foreign body (FB) in the aerodigestive tract presents more commonly in children and remains a surgical emergency with potential for fatal complications.To describe management and outcomes of aerodigestive FB managed at University of Ilorin Teaching Hospital (UITH) and proffer preventive measures.A 9-year retrospective review of all patients with foreign body in the aerodigestive tract managed between March 2011 and July 2020.Sixty-six patients were studied. Median age was 9years with M:F ratio =1.6:1. FB was ingested in 38(57.6%) patients, aspiration occurred in 28(42.4%). Denture was most common FB 20(30.3%); plastic whistle/valve placed in dolls or football accounted for 4(6.1%). When ingested, FB was impacted in cervical 17(44.7%), upper thoracic 10(26.3%) and middle thoracic 2(5.3%) oesophagus. Oesophagoscopy was used in 30(8.9%) for retrieval. When aspirated, FB was located in the right bronchus 10(35.7%), left bronchus 7(25.0%), hypopharynx and trachea 2(7.1%) each, and cricopharynx 1(3.5%); no FB was found in 3(10.7%) patients. Direct Laryngoscopy was the method of retrieval in 3(10.1%) patients while others had rigid bronchoscopy. Mortality rate was 1.5%.Children are most vulnerable group. Preventive effort should include public health education and close monitoring of children by parents and care givers during play. Foreign body (FB) ingestion and aspiration are common surgical emergencies in otolaryngology and cardiothoracic practice. It is commoner in the extremes of ages but especially among the paediatric age group with a wide spectrum of clinical problems and surgical complications.6FB in the air and food passages are the sixth most common cause of accidental death in the United States with over 3,000 deaths resulting from such aspirations per year.9As toddlers play, they may put FB in their mouths unnoticed by an adult observer. Any attempt to talk, laugh or sing, may result in the FB being swallowed or aspirated inadvertently. In absence of an adult witness, the classical diagnostic history of a FB aspiration may be missed.Retained FB may be initially asymptomatic but later produce a variety of respiratory symptoms.12This study investigates the incidence, management and complications of FB retrieval from the ADT in our setting, with a comparison of our 9 years' experience with what is described in the literature. We suggest preventive measures.Records of patients with clinical or radiological suspicion of FB ingestion or aspiration referred for emergency care at the otolaryngology or cardiothoracic divisions of UITH between March 2011 and July 2020 were retrospectively revised. Patients were managed independently by the units but where patients condition dictated, combined team approach was implemented. Information extracted included age, gender, type of FB, clinical-radiological presentation, endoscopic retrieval method, complications, hospital stay and outcomes. Data was complemented with information from operation notes. Permission was obtained from the Institutional Ethical Review Board with assigned number NHREC/02/05/2010 and approval number ERC PAN/2020/02/0116; and patients' identities kept confidential.Sixty-six patients presented with FB in the ADT over the 9years-5months period. Forty-one (62.1%) patients were males (M:F ratio of 1.6:1). Ages ranged from 8months to 80years (median 9years). The most frequent age group was 0\u20139years accounting for 35(53%) followed by 30\u201339years and 70\u201379years with 7(10.6%) each .Twenty-four (36.4%) were of pre-school (\u22645years) while 37(56.1%) were of paediatric (\u226415years) age groups. Whilst 38(57.6%) patients presented with FB ingestion, 28 (42.4%) had aspiration. Though the type of object was either not stated in 9(13.6%), none seen in 3(4.5%) and not applicable in a patient with suspicious history and retropharyngeal abscess who declined intervention 1(1.5%), denture accounted for the vast majority of FBs being present in 20(30.3%) patients. Metallic bolt/screws/cap, disc-lithium watch battery and plastic whistle/valve placed in dolls or football accounted for 4(6.1%) each; peanut \u2013 3(4.5%); Light Emission Diode (LED) bulb, ear ring, biro base cork, office pin and kola-nut \u2013 2(3.0%) each. Others, accounting for 1(1.5%) each include vegetable fragments, coin, plastic bead, maize, sharpener, metallic washer, sugarcane peel and key. Out of the 53 patients whose objects were identified, 45(84.9%) were of inorganic material while 8(15.1%) were organic .Though both aspiration and ingestion of FBs were more common among children and young adults, no occurrence of aspiration occurred in the older adults nor elderly. Neither aspiration nor ingestion occurred in 20\u201329 age group . The medGender comparison for aspiration and ingestion, with 16 males of 28 cases of aspiration (57.1%) and 25 males in 38 cases of ingestion (65.8%) had P = 1. We had 2(3.3%) morbidities and 1(1.5%) mortality.Most common FB aspirated of 28 cases were plastic whistle/valve in dolls or football with 4(14.3%) cases . PeanutsAmongst 38 cases of FB ingestion, 20(52.6%) were secondary to dentures, 4(10.5%) were disc-watch batteries while others were 1(2.6%) each . The mosRigid oesophagoscopy (RO) was utilized in 30(78.9%) of cases. Two patients refused oesophagoscopic evaluation despite history of FB ingestion and in 1 patient, the FB had descended into the bowel . Five paToddlers and younger children are more likely to place objects in the mouth during play. Thirty-seven (56.1%) of the 66 patients in our review were paediatric patients with a male preponderance similar to earlier studiesEar-rings, biro base-cork, peanuts and LED bulb were the most frequently aspirated FBs. The commonest side of the airway affected was the right.6Denture was the commonest FB in this series, all occurring as ingestion . This maWe observed an increasing incidence of disc-battery ingestion, perhaps due to increase usage in small electronic devices and toys.Disc battery ingestion should be managed with utmost urgency  because We recorded no FB ingestion or aspiration between ages 20\u201329 years. This is the age group for self-awareness and self-care. Dentition is intact hence they hardly wear dentures; even if they do, it is well-fitting. Furthermore, unlike the very young and elderly, laryngeal reflex, laryngoesophageal coordination and oesophageal peristalsis are intact.Endoscopic removal is preceded by imaging to determine the location of FB, evaluate surrounding tissue and exclude complications like migration, viscus perforation or tissue penetration. Preoperative imaging thus facilitates planning and increases chances of successful removal. Radiolucent FB not visible on plain radiograph may be displayed on fluoroscopy, CT-scan or MRI. Ventilation-perfusion scan may be helpful in aspirated FB.12FB in the oesophagus that defies removal by oesophagoscopy would require oesophagotomy.Mortality rate of 3.6% recorded from aspirated FB is high compared with 1% documented in earlier studies.23We conclude that aerodigestive foreign bodies remain a frequent indication for emergency oesophagoscopy and bronchoscopy. Children are most vulnerable and are particularly prone to aspiration. Increased awareness and availability of orthodontist services has increased the use of dentures in adults yet not matched by adequate maintenance of the device has increased its occurrence as an ingested and impacted agent.Therefore, the need for preventive measures cannot be overemphasized given the high risk of mortality associated with FB in the ADT in spite of advances in imaging and endoscopic technology worldwide. A nationwide educational campaign in Israel achieved 35% reduction in incidence of FB aspiration in children over a 3-year period.24 We therefore, recommend education of parents, care givers, school teachers, pupils and the entire community on the danger of FB ingestion or aspiration and appropriate preventive measures.Teaching on preventive measures should be included in health education of mothers at the antenatal clinic and in curriculum for school pupils. Writing materials especially biros with detachable base should be prohibited from use in primary and secondary schools while recommending those with non-removable base. Dentures should be fabricated with radio-opaque component to ease identification and routine follow-up to the orthodontist should be encouraged for early identification and rectification of faulty fitting.Our study is limited by its retrospective design which was responsible for some missing information and also by lack of data on long term follow-up of the patients."}
+{"text": "Pseudomonas aeruginosa is a major concern which is increasing globally resulting in limited therapeutic choices. This study aimed to find out the prevalence of Pseudomonas aeruginosa isolates among clinical samples showing growth of a tertiary care centre.Carbapenems resistance due to metallo-beta-lactamase production in A descriptive cross-sectional study was conducted on various clinical samples which showed growth in the Department of Microbiology of a tertiary care centre between 1 September 2020 to 28 February 2021 after receiving ethical approval from the Institutional Review Committee (Reference number: 03-G/020). Convenience sampling was done. All timely received clinical specimens were inoculated and incubated at 37\u00b0C for 48 hours and identified by standard microbiological techniques. Point estimate and 95% Confidence Interval were calculated.Pseudomonas aeruginosa were isolated. Among them, 6 (8.82%) were found to be metallo-beta-lactamase positive.Among 1049 clinical samples showing growth, 68 (6.48%)  Pseudomonas aeruginosa was similar to the studies done in similar settings. As metallo-beta-lactamase production was detected among isolated species which can be spread very rapidly and may develop a problematic scenario in treatment procedures, regular surveillance along with judicious use of carbapenems should precede.The prevalence of  Pseudomonas aeruginosa can develop antibiotic resistance by various mechanisms, enzyme production is the major mechanism of acquired resistance.1 Antibiotic resistance due to metallo-beta-lactamase (MBL) enzyme production is a global threat to antimicrobial therapy due to its rapid spread, potent carbapenemase activity, and resistance to beta-lactamase inhibitor and ability to hydrolyze all beta-lactam antibiotics except aztreonam.3Pseudomonas aeruginosa was first reported in Japan in 1991, since then there is a substantial increase in reporting worldwide.4 The early and proper detection of MBL-producing Pseudomonas aeruginosa is crucial for properly treating critically ill patients and for the rapid initiation of strict infection control procedures to prevent nosocomial spread and dissemination of resistance.MBL-producing Pseudomonas aeruginosa isolates among clinical samples showing growth in a tertiary care centre.The objective of this study was to find out the prevalence of A descriptive cross-sectional study was conducted on various clinical samples showing growth processed in the Department of Microbiology of Lumbini Medical College and Teaching Hospital between 1 September 2020 to 28 February 2021 after receiving ethical approval from the Institutional Review Committee (Reference number: 03-G/020). All properly collected, timely delivered clinical specimens received in the study period which showed growth on culture were included whereas improperly collected dry swabs and lately delivered clinical samples showing growth which were were excluded. Convenience sampling was done and the sample size was calculated using the formula:Where,n= minimum required sample sizeZ= 1.96 at 95% Confidence Interval (CI)Pseudomonas aeruginosa isolate, 4.15%5p= prevalence of q= 1-pe= margin of error, 2%6 All isolated Pseudomonas aeruginosa were subjected to in vitro antibiotic sensitivity test Kirby-Bauer disc diffusion method as recommended by Clinical Laboratory Standard Institute.7The required minimum sample size calculated was 383. Doubling the sample size, we get 766 but a sample size of 1049 samples was taken for the study. Various clinical samples  were collected from both sexes and all aged patients from various departments. All timely received clinical specimens were inoculated on Mac Conkey agar, Blood agar, and Chocolate agar and were incubated at 37\u00b0C for 48 hours. Identification of the bacteria was done by standard microbiological techniques like by study of morphological characteristics of isolated colonies along with observing pigment production, staining reaction and various biochemical properties.Pseudomonas aeruginosa were screened as possible MBL producers. So all screened positive isolates were tested for MBL production by Imipenem-EDTA combined disk method (CDT) and Double disk synergy test (DDST). In CDT two imipenem disks (10 |jg) were placed 25 mm apart from centre to centre. Then 10 microlitre of 0.5 M Ethylenediamine tetraacetic acid (EDTA) was added. An increase in inhibition zone diameter of \u22657 mm in the imipenem-EDTA disk as compared to the imipenem disk alone was considered as MBL producers.8 In DDST imipenem disc (10 \u03bcg) was placed on Mueller Hinton Agar media inoculated with test organism and 10 mm apart a blank filter paper disc was placed to which 0.5 M 10 microlitre EDTA solution was added. Enhancement of zone of inhibition between Imipenem and EDTA disc was considered MBL positive.9All imipenem-resistant Data were entered and analysed in IBM SPSS Statistics 18.0. Point estimate and 95% Confidence Interval were calculated.Pseudomonas aeruginosa were isolated. A total of 35 (51.47%) were isolated from male patients and 33 (48.52%) from female patients. Maximum Pseudomonas aeruginosa was isolated from the inpatient department 50 (73.52%) whereas 18 (26.47%) from the outpatient department. Total of 15 (22.05%) of Pseudomonas aeruginosa were isolated from the Department of Surgery, 14 (20.58%) from the Department of Obstetrics and Gynaecology, 13 (19.11%) from the Intensive Care Unit (ICU), 6 (8.82%) from the medical ward, 4 (5.88%) from Department of Emergency and 2 (2.94%) from Department of Orthopedics. The isolation of Pseudomonas aeruginosa in different age groups showed that 20 (29.41%), 18 (26.47%), 19 (27.94%) and 11 (16.17%) were from \u226420, 21-40, 41-60 and >60 age groups respectively. The mean age of patients with Pseudomonas aeruginosa infection was 37.13\u00b123.94 years. The sample-wise distribution of Pseudomonas aeruginosa is tabulated below   ed below .Pseudomonas aeruginosa isolated from urine sample, 3 (15%) were MBL producers. A total of 1 (14.28%) and 2 (40%) MBL producers are isolated from the sputum and endotracheal secretions respectively. Polymyxin B 63 (92.64%) followed by imipenem 61 (89.70%) were two most sensitive drug for Pseudomonas aeruginosa (Out of 20 (29.41%) ruginosa .Pseudomonas aeruginosa. Out of which 5 (83.30%) MBL producing Pseudomonas aeruginosa were multidrug resistant  were found to be metallo-beta-lactamase-producing esistant .Pseudomonas aeruginosa is emerging as one of the leading cause of healthcare-associated infections worldwide. In our study, among 1049 samples showing growth of bacteria, Pseudomonas aeruginosa was isolated from 68 (6.48%). This prevalence rate was somewhat higher and lower than other studies 4.15% and 8.59% respectively.10 Among 68 total isolated Pseudomonas aeruginosa 53 (73.5%) were isolated from inpatient department patients and 18 (26.5%) from outpatient department patients. Similar to our study high rates of Pseudomonas aeruginosa were reported from the Inpatient departments in many other studies 83.1%, 73.22% and 80%.11Pseudomonas aeruginosa causes serious infection mainly in immunocompromised hosts such as those with severe burn or wound surgery and also in those indwelling devices.12 In our study the highest number of Pseudomonas aeruginosa were isolated from urine samples followed by pus samples and least from endotracheal tubes. A similar observation was reported in another study.11 Most of the other studies showed the highest isolation from pus specimens.13 The high rate of isolation from the urine samples in our study may be due to its ability to cause urinary tract infections in most people.12Pseudomonas aeruginosa can develop antibiotic resistance by various mechanisms, enzyme production is the major mechanism of acquired resistance.1 Among 10 different antibiotics that were tested to isolated bacteria, polymyxin B followed by imipenem were the two most effective drugs showing 92.6% and 89.7% sensitivity respectively. Ceftazidime was found to be the least effective drug showing 44.1% sensitivity. This result was found to be similar to results published by other studies.15Pseudomonas aeruginosa ranges from 20 to 85%.12 In our study 21 (30.9%) of isolated Pseudomonas aeruginosa were multidrug-resistant that were resistant to more than 3 antibiotics belonging to different classes. Some studies showed higher MDR isolates than our study 69.1%, and 63.3%.16 Out of a total of 68 Pseudomonas aeruginosa isolated in our study 6 (8.8%) were found to be MBL positive. This was similar to the result shown in another study 8.7%.13 However higher rate of MBL-mediated resistance was reported by many different studies 18.2%, 21.8%, 22.4%, 30.9% and 31.4%.19 This variation in the prevalence of MBL in our study may be due to our geographical location, infection control practice and method of detection.20According to various studies MDR Pseudomonas aeruginosa, 6 isolates were MBL positive by both CDT and DDST. But other studies showed a high number of MBL positivity by CDT compared to DDST.17 This may be due to the small sample size resulting in a low number of imipenem resistant isolates so that no more variation between the two test methods was found. Sixty percent of Pseudomonas aeruginosa isolated from endotracheal tube culture were positive for MBL production. There was another study which also reported maximum MBL positivity from endotracheal tip culture.2 Patients with indwelling devices act as the major risk factor for the development of resistance.4 All most all 83.3% of MBL producing Pseudomonas aeruginosa were MDR. All MBL-positive isolates showed almost completely resistant to ceftazidime, gentamicin and imipenem, whereas 16.7% of sensitivity was shown by ciprofloxacin, amikacin, tobramycin and aztreonam. Polymyxin B was sensitive to 83.3% of MBL-positive Pseudomonas aeruginosa so was remained the only effective drug of choice. Other studies also reported polymyxin B as the most effective antibiotic.18In our study out of 7 imipenem-resistant In this study, phenotypic methods were used for the detection of MBL. The molecular method for detection of responsible gene sequence which is considered the gold standard was not done. Similarly, this study was done for a short period with small sample size. These were the limitations of this study.Pseudomonas aeruginosa in our hospital setting was found to be similar to other studies done in similar settings. Similarly, MBL producers among them were lower as compared with other different studies. As MBL-positive isolates exhibit resistance to many antibiotics belonging to different classes along one of the most effective antibiotic imipenem, it results in a very limited choice of antibiotic to treat, we should always monitor its prevalence and should always use carbapenems judiciously.The prevalence of"}
+{"text": "This cross-sectional study examines psychiatric disorders among children after a mass terrorist attack in Nice, France, in 2016. Three years later, more than 4700 consultations have been performed.Between 2015 and 2016, France was affected by mass terror attacks. There were approximately 30\u2009000 people\u2014tourists, locals, and many families\u2014in Nice, France, during the 2016 terrorist attack. In this attack, 86 people died, including 15 children.Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) diagnoses in children. We hypothesize that there is no association between age and PTSD frequency.We report preliminary results of a prospective longitudinal epidemiologic cohort. This study of consecutive outpatients aims to assess the frequency of PTSD and other STROBE) reporting guideline. Parents provided written informed consent, and the children provided verbal agreement.This cross-sectional study was approved by the National Ethics Committee and followed the Strengthening the Reporting of Observational Studies in Epidemiology  and Kiddie Schedule for Affective Disorders and Schizophrenia  were used. DIPA and K-SADS were semistructured interviews that lasted 1 hour and assessed DSM-5 diagnoses.P value of <.05 was considered significant. In a first step, a descriptive analysis was performed, and frequencies were computed for qualitative variables, and mean, SD for quantitative variables. In a second step, a bivariate analysis was used based on a priori hypotheses. Fisher exact tests were used to compare the frequency of psychiatric diagnoses across age brackets.Descriptive statistics were used for continuous variables, and Fisher exact tests were used to compare the frequency of psychiatric diagnoses across age. Statistical analysis was performed from January to June 2022 using R version 4.2.2 . All tests were 2-tailed, and a Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) diagnoses per age group are presented in the This study included 271 outpatients among the 1217 (22%) registered after the attack, with a mean (SD) age of 9.0 (4.1) years  and 139 males (51%). The mean (SD) number of diagnoses per child was 2.4 (1.8). The frequencies of the Anxiety disorders included specific phobia (151 of 270 [56%]), separation anxiety disorder (77 of 270 [29%]), generalized anxiety disorder (56 of 270 [21%]), social anxiety disorder (15 of 270 [6%]), obsessive-compulsive disorder (3 of 270 [1%]). ICD included intermittent explosive disorder (25 of 270 [9%]), oppositional defiant disorder (44 of 270 [16%]), conduct disorder (5 of 268 [2%]), ADD (43/270 [16%]), and ADHD (30 of 270 [11%]). Some participants fulfilled the criteria for several disorders; thus the sum of diagnoses was greater than the total number of patients.The association between DSM-5 diagnoses and age groups are presented in the 4 Studies using Diagnostic and Statistical Manual of Mental Disorders  did not consider developmental specificities and found a lower rate of PTSD.5 Our results are consistent with the literature underlying the link between age and anxiety disorders in this population.6 The strength is the homogeneity of the population. This study had limitations. For example, we were unable to observe anxiety and PTSD frequencies within the cohort prior to July 14, 2016. These results evidence the need to create pediatric referral centers without age limitations and develop public health policies to care for pediatric PTSD after mass terrorist attacks.In this cross-sectional study, the high frequency of PTSD was not associated with age, while most of the other disorders were. Studies using DSM-5 showed a high rate of PTSD in youths after a terrorist attack."}
+{"text": "Women receiving a prenatal diagnosis of fetal anomalies are a high-risk population for psychological distress leading to mood disorders. Even so, to date we have no evidence of studies who investigated the levels of maternal anxiety and depression in pregnant women receiving a prenatal diagnosis of fetal CNS anomalies.The aim of this study was to assess the prevalence of anxiety and depression levels in a pilot sample of pregnant women at the Prenatal Diagnostic Unit of the Bambino Ges\u00f9 Children Hospital.We collected data among 43 women who receipt fetal brain anomaly diagnosis . Prenatal diagnosis including: ventriculomegaly (37.2%), posterior cranial fossa (23.3%), choroid plexus cysts (11.6%), anomalies of CC (7%) and other (20.9%). Pregnancies with assisted reproductive technology were 14%. We use the Patient Health Questionnaire (PHQ-9) and the Generalized Anxiety Disorders (GAD-7) questionnaires to assess anxious-depressive symptoms.showed a rate of mild-to-severe anxious depressive symptoms by 60.5% and 48.8% respectively. In detail: 41.9% mild, 14% moderate and 4.7% of severe anxiety. Meanwhile, 41.9% mild and 7% moderate depression. The prevalence of comorbid depressive and anxiety symptoms was 39.5% among the entire sample.Preliminary data showed a high prevalence of anxious depressive symptoms and comorbidity among pregnant with CNS fetal anomalies. Women receiving a fetal CNS anomaly diagnosis may need additional psychological support or counselling.No significant relationships."}
+{"text": "The war initiated by Russia against Ukraine in February 2022 has resulted in the largest refugee migration in Europe since World War II, estimated by UNHCR (2022) at 6.3 million persons. In the first two months, almost 3.5 million war refugees crossed the Polish border, of which over 95% were Ukrainian citizens."}
+{"text": "Background: During the COVID-19 pandemic, the World Health Organization (WHO) has recommended hand hygiene (HH) stations  at entrances and exits of every public or private commercial building, including healthcare facilities (HCFs). Methods: Enumerators observed the HH materials present at the entrances and exits of 37 public HCFs in the Moroto and Kotido districts and patient and visitor use of those HH materials. When handwashing stations were nonfunctional or out of water, no HH observations were made. Results: Of the 37 HCF entrances and exits assessed, 4 (11%) met the recommended guidance for HH materials: 3 (8%) had water and soap, and 1 (3%) had ABHR and water and soap. In other HCFs, 12 (32%) had no HH station present, 13 (35%) handwashing stations had no water, and 8 (22%) had water but not soap. Of 180 persons observed, 52 (29%) attempted HH and only 10 (6%) used appropriate HH technologies (4 with ABHR and 6 with water and soap). Of 52 people who attempted HH, 42 (81%) used only water without soap. All HH observed occurred when entering facilities; no HH occurred when exiting (0 of 68). Of those 52 who performed HH, 48 (92%) performed HH for the recommended time of >20 seconds. However, only 9 (5%) of 180 adhered to suggested HH technologies and length of time (used water and soap scrubbing for \u226520 seconds or used ABHR). Conclusions: We detected poor HH practice by patrons at entrances and exits of HCFs, which may be due to lack of appropriate HH materials, particularly lack of soap. Optimal strategies for adherence to WHO-recommended HH practices at entrances and exits of public and private commercial buildings, including HCFs, should be explored.Funding: NoneDisclosures: None"}
+{"text": "Low Scottish survival rates after out-of-hospital cardiac arrest (OHCA) resulted the launch of the Scottish out-of-hospital cardiac arrest strategy in 2015. Data-linkage including SAS data and other datasets has enabled monitoring the impact of the strategy and COVID-19 on bystander cardiopulmonary resuscitation (bCPR) and 30 days survival rates.All incident OHCA cases between 2011 and 2020 cases where resuscitation has been attempted were identified in the SAS data. These OHCA cases have been linked with a broad range of other administrative datasets including unscheduled care datamart (UCD), hospitalisations (SMR01) and deaths data. The Community Health Index (CHI), a unique identifier used across all health records in Scotland enabled this data linkage through direct and probabilistic linkage (CHI retrieved and used for further linkage). Descriptive analysis and logistic regression analyses were used to assess the impact of both the implementation of the strategy and the COVID-19 pandemic.Over 27,000 non-traumatic OHCAs with resuscitation attempted by the SAS, between 2011 and 2020 were identified. Successful data-linkage improved over time reaching >85% at the end of data collection. Confounder adjusted logistic regression showed higher adjusted odds of bCPR (OR=2.7) and 30days survival rates (7.3% versus 10.2% or increase from 44.5 per million population to 58.5 per million population) comparing 2014-15 and 2018-19 data. Initial analyses show that during the COVID-19 pandemic (March 2020-February 2021) bCPR percentages remained stable however 30days survival rates dropped to 6.9%.The launch of the Scottish OHCA strategy and subsequent initiatives to improve bCPR rates has led to an increase in bCPR and 30 days survival rates. However, the COVID-19 pandemic has had a negative impact on survival. Analyses are underway to gain insight in detailed explanations for these findings."}
+{"text": "Mycobacterium tuberculosis complex, mainly by M. tuberculosis. Annually, 1 million children develop TB disease and many more present a latent form of infection. The objective of this study is to define the epidemiological trends of the different clinical presentations of TB in pediatric population.Tuberculosis (TB) is a disease caused by A retrospective, cross-sectional study, carried out at a pediatric referral hospital in Mexico between 2012-2021. Pediatric patients diagnosed with TB were included. Descriptive statistics were performed in order to summarize the demographic, clinical and paraclinical characteristics of pediatric patients with TB. A Chi-squared univariate analysis was performed evaluate the association between several variables of interest with mortality.Diagnostic criteria for TB in children according to the Mexican Clinical Practice GuidelinesA total of 100 patients were included in the study. Pulmonary TB was the most common presentation (51%), followed by ganglionic (21%), meningeal (14%), and milliary (7%). A male predominance was observed (54%). Mean age of presentation was 7.8 years \u00b1 1.5, most lived in urban areas (79%) and had a positive COMBE (57%). Half of the patients had BCG vaccination. Fifty-two patients were successfully cured, 36 patients were receiving antituberculous treatment and fatality rate was 12%. Meningeal TB was the most fatal clinical presentation. Fever was the most common sign (65%), followed by cough (56%) and weight loss (37%). The most common sign of meningeal TB were generalized seizures (10/14), fever (10/14), and vomiting (7/14). Brain imaging was performed in all patients with meningeal TB: hydrocephalus (71.4%) and basal arachnoiditis (64.3%) were present. Cerebrospinal fluid analysis was also performed: 11 patients had pleocytosis, 10 had hyperproteinorrhachia, and 10 had hypoglycorrhachia. Clinical TB presentation (p=0.009) and immunodeficiency (p= 0.015) were significantly associated with mortality.Epidemiological Characteristics According to TB Clinical Presentation.Signs and symptoms in children according to their clinical presentation of TB.Clinical, radiological and cerebrospinal fluid characteristics in meningeal TB.Pediatric TB cases in this referral hospital indicated an equivalent proportion of pulmonary and extrapulmonary TB. Most of the patients with milliary and meningeal TB were not vaccinated; however, BCG vaccination was not significantly associated with mortality. Patients with extrapulmonary forms of the disease and with immunodeficiency were associated with mortality.Clinical outcomes of children with TB according to their epidemiological characteristicsAll Authors: No reported disclosures."}
+{"text": "Literature on childhood Functional Neurological Disorders (FNDs) is spare. Clinical presentations are vaguely characterized and often misdiagnosed in younger ages. Their main neurological features enrol: Psychogenic non-epileptic seizures (PNES), Functional movement disorders (FMDs), sensory alterations, cephalgia and feeding problems.The study was aimed to better characterize the childhood population of FND, because of they represent an emerging challenge for clinicians, giving its higher presentation in the younger age and the difficulties of an early and differential diagnosis as well as an effective management.Our study retrospectively examined the characteristics of 82 FNDs children and adolescents  referred as neurological inpatients of an urban academic neuropsychiatric department, from 2014 to 2019. Three main clinical aspects were analysed: type and pattern of symptoms manifestations (DSM-5 criteria); Life Events; family functioning.FND accounted for 2% of 5-years consultations of neurological inpatients (M: F=1:2). The clinical presentation was characterized in 70% by pattern of co-expressed neurological symptoms: FMDs (9.5%); PNES (12%); dizziness/lipothymia (12%); paraesthesia/anaesthesia (16%). Generalized pain was associated in 38% of the reported patterns while cephalgia in 44%. Sleep disorders were reported in 40%. Previous psychiatric diagnoses were uncommon (2 out 82). Antecedent stressors were identified in 97% of patients for personal illness history and in the 93% for chronic illness in the family anamnesis. Family problems were in 25% of cases.Our data contributes to better characterize the childhood population of FND, describing clinical patterns of presentation, highlighting putative antecedent stressors and risk factors"}
+{"text": "The study on its applicability to direct clinical specimens is still limited. We studied the value of 16s rRNA gene sequencing from direct clinical specimens on antimicrobial management.Inpatient adults whose attending physician requested 16s rRNA gene sequencing and corresponding bacterial culture from a direct clinical specimen were prospectively included between January and December 2021. Diagnostic yield and the impact of 16s rRNA gene sequencing on antimicrobial management were investigated.A total of 434 specimens from 374 patients were requested. All patients had a complete follow-up and had a definitive final diagnosis. The sensitivity and specificity of 16s rRNA gene sequencing were 38.3% and 93.9%, respectively. The agreement between 16s rRNA gene sequencing and conventional culture among specimens obtained from bacterial infection cases was 83.8% . Among bacterial infection cases, the proportion of 16s rRNA gene sequencing positive/culture-positive was 32.4% (82 specimens), and the proportion of sequencing positive/culture-negative was 5.9% (15 specimens). The impact on antimicrobial management occurred in 10 (2.3%) specimens, which all resulted in the continuation of antibiotics. An impact on antimicrobial management was highest in the skin and soft tissue infection, followed by bone and joint infection. In contrast, CAP/HAP/VAP was less likely to benefit from this test. Long turnaround time was the limitation of the test in this study, the median (interquartile range) was 11 (9-13) days in the 16s rRNA gene sequencing positive group, and 2 (1-4) days in the 16s rRNA gene sequencing negative group.The overall diagnostic yield of 16s rRNA gene sequencing in bacterial infection cases was fair. 16s rRNA gene sequencing was useful in selected cases, but it cannot replace traditional culture. The negative result did not exclude bacterial infection. Restrictions on test requests may improve test utilization in this setting.All Authors: No reported disclosures."}
+{"text": "During the Covid Outbreak, the deployment of psychiatric phone-based consultations (PbC) became a large necessity.The main objective of our study was to assess, 4 months after the end of the lockdown, the degree of satisfaction of the PbCs compared to that of usual face-to-face consultations (FC) in young adults presenting a first episode of psychosis (FEP) or entering schizophrenia (SCZ).All patients beneficiated from PbCs conducted by hospital care staff during lockdown. A 15-items questionnaire evaluating satisfaction was carried out remotely (score ranging from 1 to 10). Primary outcome was satisfaction with consultation allowing the comparison of a group preferring FC (FC+) against a group in favor or equivalent of PbC (PbC +).30 patients were recruited (mean age 26.93 years old (4.9 SD), Male 56%. Diagnoses were SCZ 60% and FEP 40%. 20/30 participants belonged to (FC+) group. Total scores of satisfaction for the PbC differed between the (PbC+) group (mean 9 (1.69 SD)) and (FC+) group ) p < 0.05. The (FC+) group tends to have PbC more frequently (40%) than the (PbC+) group (10%) and to find the phone interface more stressfull (40%) than the PbC+ group (10%). The (FC+) group tends to less wish (40%) PbC follow up in future than the (PbC+) group (90%).This study shows that the PbCs were favorably evaluated by a third of the patients. The anxiety-inducing experience of the PbC in the (FC+) group could be explained by the severity of their pathology."}
+{"text": "To determine the clinical spectrum and underlying etiologies of children presented with precocious puberty at The Children\u2019s Hospital &The Institute of Child health, Lahore.It is a retrospective review of all the children presented with precocious puberty over one year, from January 2015 to December 2015; at the department of Paediatric Endocrinology & Diabetes, The Children\u2019s Hospital & The Institute of Child Health, Lahore.Total 43 cases of precocious puberty (PP), with 26 females were reported in one year. Central precocious puberty (CPP) constituted 55.8% (24/43) and was found to be more prevalent in female (22/24). In 20/24 cases (83.3%) of central precocious puberty underlying etiology was idiopathic. Peripheral precocious puberty was found in 19/43 cases (44.1%) with male predominance (15/19). Congenital adrenal hyperplasia was the most frequent (12/19) underlying cause of peripheral precocious puberty in our cohort.Precocious puberty could be a manifestation of underlying serious medical condition. It should be thoroughly evaluated with the aim to diagnose the underlying pathology and to treat them promptly. Precocious puberty is defined as precocious manifestation of pubertal development i.e., secondary sexual characters. The consensus about the age to investigate a precocious puberty is before the age of eight years in a girl and 9 years in a boy. The primary concern in precocious puberty is to look for its underlying etiology because precocious puberty could be a clinical manifestation of underlying serious etiology like brain tumour, adrenal or gonadal tumors etc., which needs prompt evaluation and management. However, the secondary concern is rapid bone maturation with early closure of epiphysis leading to short final height.1There are two main underlying mechanisms of precocious puberty. If there is early activation of hypothalamic-pituitary-gonadal (HPG) axis, it is called gonadotropin dependent  precocious puberty. It\u2019s estimated incidence in American girls is 1 in 5000 \u201310,000.4Second mechanism is increased autonomous production of sex steroids, independent from hypothalamic-pituitary axis activation. Source of these sex steroid are gonads, adrenals, exogenous administration, or ectopic production from tumors. This type of precocious puberty is called gonadotropin independent  precocious puberty. Peripheral precocious puberty (PPP) has varied etiology including congenital adrenal hyperplasia, virilizing adrenal tumors, gonadal tumors, hypothyroidism, Macune-Albright syndrome and testotoxicosis.5In Pakistan, precocious puberty is a neglected area and little work has been done so far to look at its etiology in our population. The Children\u2019s Hospital & The Institute of Child Health, Lahore is a tertiary care hospital with huge referral of children with pubertal problem in its endocrine department. The purpose of conducting this study was to assess the clinical profile and causes of precocious puberty in our population. Our own data could be a representative of our population and will be helpful in making our local guidelines.After taking approval by institutional review board , records of all children with precocious puberty presented to the Department of Paediatric Endocrinology & Diabetes, The Children\u2019s Hospital & ICH, from January 2015 to December 2015 were retrospectively reviewed in detail. Boys less than eight years of age and girls less than nine years of age with appearance of any secondary sexual character were included in this study. Children with atypical genitalia were excluded from this study.History including age of presentation, duration of symptoms, presenting complains, pattern of secondary sexual character, history of hypothyroidism, any past neurological event  and developmental delay were noted. Examination including height, weight, vitals, dysmorphism, pigmentation, tanner staging, complete genital examination, abdominal examination, and neurological examination were retrieved. Hormonal profile including baseline pituitary function test (luteinizing hormone (LH) and follicle stimulating hormone (FSH), thyroid function test, insulin like growth factor-1 (IGF1), adrenocorticotropin hormone (ACTH) and cortisol), testosterone, dehydroepiandrosterone sulfate (DHEASO4), estradiol, and 17-OH progesterone (17 OHP) were noted. GnRH stimulation test was done by giving triptorelin acetate 0.1 mg subcutaneous followed by 20 min and 60 min of LH and FSH in cases where needed. Imaging including bone age by Greulich-Pyle method, ultrasound pelvis and abdomen, and MRI brain or abdomen reviewed thoroughly. All the information were recorded on predesigned proforma. Children with isosexual and concordant pattern of precocious puberty showing pubertal response of gonadotropins either on basal or on GnRH stimulation test were classified as central precocious puberty. All cases of CPP underwent brain imaging (CT/MRI) to look for underlying organic brain pathology. Children with discordant pattern of puberty with prepubertal gonadotropin response on GnRH stimulation test were considered as PPP. Each case peripheral precocious puberty was thoroughly investigated to look for the source of sex steroid hormone production. Children with peripheral precocious puberty and raised 17-OH progesterone (>300 nmol/l) were labeled as congenital adrenal hyperplasia. Peripheral precocious puberty with clinical suspicion of hypothyroidism, having raised TSH (> 10 uIU/ml) and low Free T4(<0.89 ng/dl) were diagnosed as chronic primary hypothyroidism. PPP due to adrenal tumors were confirmed by CT/MRI proven adrenal masses in the presence raised adrenal androgens . PPP due to gonadal tumors were confirmed by biochemical evidence of excess of testosterone (> 30 ng/dl) or estradiol (> 31 pmol/l) with CT/MRI proven gonadal masses.Macune- Albright syndrome is defined as precocious puberty due to auto-stimulated ovaries or testis  and FSH level (< 2 IU/l) on GnRH stimulation) in presence of hyper pigmented macule and/or fibrous dysplasia. The genetic evaluation of Macune-Albright and testotoxicosis is not available in Pakistan.Data was analyzed by SPSS Version 20. Age of presentation was presented by calculating mean with range. Rest of data was presented by calculating frequencies and percentages.Total 43 cases of precocious puberty, including 24 cases (55.8%) of CPP and 19 cases (44.2%) of PPP, were presented at the Department of Paediatric Endocrinology & Diabetes, The Children\u2019s Hospital & The Institute of Child Health, Lahore. Overall, precocious puberty was more common in females (26/43) than male (17/43) in our study. Among females CPP constituted 84.6% (22/26) and PPP were 15.4% (04/26 cases). In male, PPP was more common (15/17) than CPP (02/17).Mean age of presentation of precocious puberty was 4.48 + 2.06 years. 19/43 cases (44%) presented between 1 - 5 years of age and 24/43 (56%) between 5-9 years. Six cases (14%) had a family history of precocious puberty. Advanced bone age was found in 40/43 (93%), however, three cases (7%) had delayed bone age due to underlying chronic untreated hypothyroidism. Mean duration of symptoms before presentation was 11.98 \u00b1 9 months.Most frequent clinical presentation in males was pubarche 12/17 (70.6%), followed by increased phallus length 4/17 (23.5%) and tall stature 1/17 (5.9%). In female 11/26 (42.3%) presented with premature breast development, 10/26 (38.5%) with pubarche and 5/26 (19.2%) with menarche.In female central precocious puberty was the most common type of precocious puberty (22/26) with idiopathic being the most common cause (19/22), followed by hydrocephalous (2/19), and hypothalamic hamartoma (1/19). Four cases of peripheral precocious puberty were reported in females with three having untreated hypothyroidism and one having ovarian tumor as an underlying etiology .Among male peripheral precocious puberty was the most common (15/17) type of precocious puberty with congenital adrenal hyperplasia (CAH) being the most common (12/15), followed by virilizing adrenal carcinoma (1/15), wilms tumor (1/15) and testotoxicosis (1/15). There were only two cases of central precocious puberty in male with one having underlying cerebral atrophy  and in other cause was idiopathic .Traditionally, precocious puberty was defined as onset of secondary sexual characters at an age which is 2 to 2.5 standard deviation (SD) below the mean age of onset of puberty for sex.11Precocious puberty is broadly classified into two main types. Central precocious puberty which is an early maturation of hypothalamic-pituitary-gonadal axis and is characterized by normal sequential appearance of isosexual secondary sexual characters.Precocious puberty is reported to be more prevalent in females than males with female to male ratio reported to be 10:1 approximately.In our study the most common cause of CPP was idiopathic (83.33%), the same trend was reported by Irum et al18In our cohort that most common cause of PPP was congenital adrenal hyperplasia (63.16%), followed by hypothyroidism (15.79%), ovarian tumor (5.26%), adrenal tumor (5.26%), wilms tumor (5.2 6%) and testotoxicosis (5.26%). This trend is also observed by Irum et al.Our study is the only study showing the clinical profile of precocious puberty with their underlying etiology in our province \u2013 Punjab. Our data support that CPP seems to be more common in female, however, PPP seems to be more common in male. Most of our CPP patient were having normal brain imaging, so we need to have our local guidelines for indication of brain imaging in CPP. In our cohort most of PPP were sequel of delayed presentation of early detectable conditions like CAH and hypothyroidism. Early diagnosis and prompt treatment of these conditions can change their prognosis.This is a retrospective study and is conducted only over a period of one year. There is a need for prospective study with emphasis of management aspects and long term follow up.Precocious puberty has varied underlying etiologies. In our population central precocious puberty is more common in female with idiopathic being the most common cause. However, in male peripheral precocious puberty is more prevalent with congenital adrenal hyperplasia being the commonest underlying etiology.SA: Conceived the idea, data collection, Literature search, result processing, writing manuscript. Responsible and accountable for integrity of work.JM and QM: Data collection, literature search, result processing.TS: Literature search, writing manuscript."}
+{"text": "The resected map was created by subtracting normalized VOIpost from the normalized VOIpre divided by the number of cases. The resected maps of TCA and EEA were compared by subtracting them. Results: Twenty patients underwent EEA and 135 patients underwent TCA. The tumor resected map demonstrated that the resected area of EEA frequently accumulated on the central skull base, while that of TCA accumulated near the central skull base. The border of both approaches matched the circle that connects neural foramens at the skull base. Conclusions: The resected area of SBMs by EEA and TCA was well visualized by voxel-based-lesion mapping. The circle connecting the neural foramens was the border of EEA and TCA.Background: We aimed to evaluate the resected area of endonasal endoscopic approach (EEA) and transcranial approach (TCA) for skull base meningiomas (SBMs) using voxel-based-lesion mapping and visualized the appropriate tumor location in each approach. Methods: We retrospectively examined 182 patients with SBMs who underwent tumor resection in our hospital between 2014 and 2019. Pre- and post-operative SBMs were manually delineated on MRI to create the voxels-of-interest (VOI Surgical treatment for skull base meningiomas (SBMs) aims to achieve radical resection while preserving neurological functionality. It is challenging to approach medially seated SBMs via transcranial approach (TCA), as the operative fields are deep-seated and surrounded by critical neurovascular structures. The endonasal endoscopic approach (EEA) has also been recently applied for central SBMs . The criVoxel-based-lesion mapping on MRI allows quantitative visualization of the therapeutic effect of brain tumors ; therefoWe retrospectively examined 182 consecutive surgeries for patients with SBMs, who underwent tumor resection in our hospital between January 2014 and December 2019. Among them, we excluded two cases with radiation-induced meningiomas, four with multiple lesions, 18 with World Health Organization (WHO) grade 2 or 3 meningiomas, and three cases who did not undergo enhanced magnetic resonance imaging (MRI). The remaining 155 surgeries were included in our cohort. The institutional ethics committee approved this study. Written informed consent for the publication of images and clinical data was obtained from all patients.SBMs were classified into four subgroups according to the location of the tumor: frontal base (FB), sphenoid-middle fossa (SpM), petroclival (PC), and posterior fossa (PF)  The routEEA and TCA were considered separate surgeries in cases of combined surgeries for large SBMs with broad attachments. Tumors adherent to critical neurovascular structures were retained and scheduled stereotactic radiosurgery (SRS) was performed.All clinical data, including neurological findings, operative records, and radiological images, were obtained from the medical records. All patients were followed up for more than three months after the surgery. Clinical outcomes were evaluated by comparing preoperative Karnofsky performance status (KPS) scores and three months postoperatively. We defined an increase in KPS score as an improvement of clinical outcomes. Neurological deficits were also evaluated three months after the surgery. A recurrence was defined as a tumor enlargement which required additional surgeries or radiation therapy. Cerebrospinal fluid (CSF) leakage was defined as a complication when the surgical repair was needed.We evaluated tumor removal rates based on intraoperative findings, a method in-line with conventional methods of assessment; gross total resection (GTR) was defined as resection without microscopic remnants, subtotal resection (STR) was defined as resection of over 95% of the tumor, and partial resection (PR) was defined as resection of under 95% of the tumor.http://rii.uthscsa.edu/mango/mango.html (accessed on 2 April 2019) [http://vinci.sf.mpg.de/ (accessed on 1 August 2018) [pre\u201d and \u201cVOIpost\u201d, respectively. Step 2: Pre- and post-operative MRI were normalized onto a 1.0 mm isotropic, high-resolution T1-weighted brain atlas, provided by the Montreal Neurological Institute (MNI) 152 using a mutual information algorithm with 12 degrees of freedom transformation with FSL-FLIRT. By using the obtained transformation matrices as normalized VOIpre and normalized VOIpost, VOIpre and VOIpost were then resliced and registered onto MNI152. These procedures were necessary to perform the lesion mapping of VOIs in standard MNI152 space. Overall, we collected normalized VOIpre and normalized VOIpost from 155 surgeries. Step 3: We created a tumor location map from the sum of normalized VOIpre divided by the number of cases and a residual location map from the sum of normalized VOIpost divided by the number of cases. The resected location map was created by subtracting the sum of normalized VOIpost from the sum of normalized VOIpre divided by the number of cases. Step 4: A tumor resected map by both approaches was obtained by subtracting the resected location map of TCA from that of EEA. Areas with positive values indicated a frequently resected area by EEA, and areas with negative values indicated a frequently resected area by TCA. The border of the positive and negative areas suggests the border of surgical indication of both approaches.All imaging data were acquired from gadolinium-enhanced T1-weighted images of either 1.5 or 3.0T MRI. Voxel-based lesion mapping was performed using an image analysis software developed in-house in combination with the Oxford Centre for Functional MRI of the Brain (FMRIB) Linear Image Registration Tool (FLIRT) provided by FMRIB Software Library (FSL) . The in-il 2019) . The worst 2018) . Pre- anA total of 20 EEA surgeries and 135 TCA surgeries were performed. The EEA group consisted of 7 males and 13 females, with a mean age of 57.8 \u00b1 11.8 SD. The TCA group consisted of 36 males and 99 females with a mean age of 57.8 \u00b1 12.2 SD. The location of EEA comprised three surgeries (15.0%) with FB, ten surgeries (50.0%) with SpM, and seven surgeries (35.0%) with PC. The TCA group consisted of 31 surgeries (23.0%) with FB, 36 surgeries (26.7%) with SpM, 46 surgeries (34.1%) with PC, and 22 surgeries (16.3%) with PF. Staged-combined surgery of EEA and TCA was performed in eight surgeries for four patients. The characteristics of patients was shown in We achieved GTR in zero surgeries (0%), STR in 17 surgeries (85.0%), and PR in three surgeries (15.0%) in the EEA group. We achieved GTR in 60 surgeries (44.4%), STR in 63 surgeries (46.7%), and PR in 12 surgeries (8.9%) among the patients in the TCA group.Five patients (25.0%) experienced recurrence from residual tumors after EEA: a patient with cavernous meningioma underwent an adjuvant surgery and two SRSs; another patient with cavernous meningioma underwent an adjuvant surgery and SRS; two patients of petroclival meningioma underwent an adjuvant surgery; and a patient of parasellar meningioma underwent an adjuvant SRS. Twenty-one patients (15.6%) experienced a recurrence of tumor after TCA; a patient with optic canal meningioma underwent an adjuvant SRS; two patients of tuberculum sellae meningioma underwent an adjuvant surgery; seven patients with petroclival meningioma underwent an adjuvant SRS; two patients with petroclival meningioma underwent an adjuvant SRS and an adjuvant surgery; a petroclival meningioma patient underwent an adjuvant SRS and two adjuvant surgeries; another patient of petroclival meningioma underwent two adjuvant SRSs and an adjuvant surgery; a patient of cavernous meningioma underwent an adjuvant SRS; two other patients with cavernous meningioma underwent an adjuvant surgery; a patient of sphenoid ridge meningioma underwent an adjuvant surgery; and two patients with sphenoid ridge meningioma underwent an adjuvant SRS. Twelve patients (8.9%) after TCA and one patient (5.0%) after EEA underwent scheduled SRSs of the remaining tumors.In total, 1 patient (5.0%) improved, and 19 patients (95.0%) displayed no change in KPS score after EEA. A total of 19 patients (14.1%) improved, 104 patients (77.0%) demonstrated no change, and 12 patients (8.9%) demonstrated deterioration in KPS score after TCA.One patient (5.0%) suffered from diplopia after EEA. A total of 3 patients (2.2%) suffered from anosmia, 3 patients (2.2%) had a visual defect, 19 patients (14.1%) suffered from diplopia, 11 patients (8.1%) suffered from facial numbness, 3 patients (2.2%) suffered from facial palsy, 2 patients (1.5%) suffered from hearing loss, 7 patients (5.2%) suffered from dysphagia, 5 patients (3.7%) suffered from motor paralysis, and 1 patient (0.7%) suffered from ataxia after TCA. One patient who underwent TCA suffered from aspiration pneumonia and died during the perioperative period.Postoperative CSF leakage occurred in three surgeries (15.0%) of EEA and two surgeries (1.5%) of TCA. All patients recovered after the surgical repair.The tumor resected map by both approaches for SBMs is shown in We retrospectively studied 155 consecutive surgeries in patients who underwent tumor resection for SBMs. Voxel-based-lesion mapping was used to visualize the resected area of SBMs by EEA and TCA. The circle connecting the neural foramens was considered to be the border of EEA and TCA. The resected area by EEA and TCA covered all parts of the skull base.Our strategy for SBMs has been to radically resect tumors with functional preservation. Several types of TCA for SBMs based on microsurgical anatomies have previously been reported ,18,19,20Previous reports regarding the extent of tumor resection were based on microscopic findings during the surgery ,19,22,23The location, residual, and resected maps in the present study were created from our institutional data and may not be applicable to data from other institutions. Other limitations of the voxel-based-lesion mapping used in this study are as follows: VOIs were manually created, the number of EEAs was small, and enhanced lesions might include structures other than the remaining tumors. Future investigations should be performed with a large number of cases using automatic VOI creation.Voxel-based-lesion mapping was used to visualize the resected area of SBMs by EEA and TCA quantitatively. Central SBMs could be resected well using EEA. The circle connecting the neural foramens was the visible border between both approaches. The resected area by EEA and TCA covered all parts of the skull base. The results of the present study might indicate the appropriate approach for SBMs."}
+{"text": "To expand the genotypes and phenotypes of sodium voltage-gated channel alpha subunit 1 (SCN1A)-related epilepsy.We retrospectively collected the clinical and genetic information of 22 epilepsy patients  carrying 22 variants of SCN1A. SCN1A mutations were identified by next-generation sequencing.Twenty-two variants were identified, among which 12 have not yet been reported. The median age at seizure onset was 6 months. Sixteen patients were diagnosed with Dravet syndrome (DS), two with genetic epilepsy with febrile seizures plus [one evolved into benign epilepsy with centrotemporal spikes (BECTS)], one with focal epilepsy, one with atypical childhood epilepsy with centrotemporal spikes (ABECTS) and two with unclassified epilepsy. Fourteen patients showed a global developmental delay/intellectual disability (GDD/ID). Slow background activities were observed in one patient and epileptiform discharges were observed in 11 patients during the interictal phase.This study enriches the genotypes and phenotypes of SCN1A-related epilepsy. The clinical characteristics of patients with 12 previously unreported variants were described. SCN1A is a member of the voltage-gated sodium channel (VGSC) gene family (OMIM:182389) and has been mapped to 2q24.3. SCN1A is the most clinically relevant gene in a wide spectrum of epilepsy phenotypes ranging from febrile seizures to Dravet syndrome (DS)  in SCN1A  . Baulac in SCN1A . Data frutations . As of 2enotypes . HoweverSCN1A heterozygous variants were enrolled at the Neurology and Pediatric Department of Xuanwu Hospital Capital Medical University between September 2015 and November 2018. In the cohort, 367 patients with epilepsy without acquired factors were assessed by the epilepsy panel. Of these, 22 patients carried SCN1A variants. Clinical registrations, including name, sex, date of birth, perinatal conditions, age at the onset of seizures, clinical manifestations, family history, genetic data, video electroencephalography (EEG), magnetoencephalography (MEG), brain magnetic resonance imaging (MRI), and therapeutic regimens, were established for all patients without acquired factors. Follow-up clinical information was collected online or by telephone call.Patients with epilepsy with SCN1A mutation screening was performed using next-generation sequencing of epilepsy-associated genes or whole-exome sequencing. Variants were validated using Sanger sequencing. The SCN1A isoform was referenced (NM_001202435 and GRCh37/hg19). All the samples were sequenced on an Illumina Nova series platform  by Kangso . We analyzed the data as follows. Synonymous changes and single nucleotide polymorphisms with a minor allele frequency greater than 5% were removed.1 The clinical significance of the identified variants was interpreted according to the guidelines set out by the American College of Medical Genetics. The pathogenicity of the identified variants was predicted using the Mutation Taster server,2 Polymorphism Phenotyping version 2 (Polyphen-2),3 PROVEAN, and Sorting Intolerant From Tolerant (SIFT).4SCN1A variants identified in the patients were compared with those identified in a comparison group of approximately 150,000 individuals from the Genome Aggregation Database and SCN1A mutation database.5This research was approved by the Ethics Committee of Xuanwu Hospital Capital Medical University. Written informed consent was obtained from the parents or guardians of all patients included in this study.SCN1A mutation: febrile seizures in sixteen patients, myoclonic seizure in one patient, simple partial seizure in one patient and secondary generalized tonic-clonic seizure (GTCS) in one patient. Status epilepticus was present in 13 patients. For seizure-precipitating factors, low-grade fever in ten patients, vaccines in two patients and hot baths in twelve patients were identified.The 22 patients  were from 22 unrelated families. Demographic and clinical characteristics are summarized in SCN1A variant with the proband with a history of febrile seizures in childhood. The twin sister of patient 28 with DS carrying the same SCN1A (p.Arg1892Ter) heterozygous mutation died from a sudden unexpected death in epilepsy (SUDEP) at the age of 16. The father of patient 22 suffered febrile seizures plus and became seizure-free at 8 years of age.All 22 patients had normal perinatal period and 11 patients had a family history of febrile seizures or epilepsy. The father and brother of patient 27 shared the same No patient had a developmental delay before seizure onset. Fourteen patients showed global developmental delay/intellectual disability (GDD/ID) during the disease course. These patients showed a delay in at least two of the following domains: motor skills, speech and language, cognitive skills, and social and emotional skills . PatientSCN1A mutations are shown in Electroencephalography was obtained in 17 patients, and abnormalities were detected in 12 patients. Slow background activity was observed except for epileptiform discharges in one patient. All 11 patients had epileptiform discharges during the interictal phase. Generalized spike waves, polyspike-and-waves were captured in one patient. Focal or multifocal epileptic discharges were present in six patients. Both focal and generalized epileptic discharges were observed in four patients. Clinical seizures were captured in four patients. Two patients (9 and 25) exhibited focal to bilateral tonic-clonic seizures. Patient 1 experienced myoclonic seizures. Patient 7 had myoclonic seizures, eyelid myoclonic seizures and automatism seizures at different times. Typical electroencephalogram changes in four cases with Among the 22 patients with brain MRI results, 17 showed a normal MRI. The MRI abnormalities included small left occipital gyrus (patient 21), left hippocampus higher signal in FLAIR (patient 18), post-operative changes of bilateral frontal and parietal lobe and corpus callosotomy (patient 8), slightly small bilateral hippocampus (patient 7) and abnormal signal in posterior horn of bilateral ventricles (patient 4).SCN1A variants included sixteen (72.7%) with DS, two (9.1%) with genetic epilepsy with febrile seizures plus [one evolved into benign epilepsy with centrotemporal spikes (BECTS)], one (4.5%) with focal epilepsy, one (4.5%) with atypical childhood epilepsy with centrotemporal spikes (ABECTS) and two (9.1%) with unclassified epilepsy.The phenotypic spectrum of patients with SCN1A heterozygous mutations. Twenty-two kinds of pathogenic mutations were identified in the SCN1A mutations, including eleven missense, four non-sense, six frameshift and one splicing site mutation. Seventeen were confirmed to be de novo, four were inherited  (SCN1A variants are summarized in All patients underwent genetic sequencing and carried es plus)  and one es plus)  and ten SCN1B  and SCN9A  were also detected in two patients (patients 4 and 16) and one patient (patient 10), respectively, all with DS.Variants of uncertain significance of SCN1A mutations , which might cause more severe protein structural changes. Eight patients (72.7%) were diagnosed with DS, one (9.1%) with generalized epilepsy with febrile seizures plus (GEFS +) converting to BECTS and two (18.2%) with unclassified epilepsy. Three (75%) of four patients with missense mutations in the pore region of the Nav1.1 channel had DS and one (25%) had ABECTS. Five (71.4%) of seven patients with missense mutations in other regions had DS, one (14.3%) had focal epilepsy and one (14.3%) had GEFS +.In our cohort, eleven patients carried The age at which the final follow-up was taken of the 19 patients in our cohort ranged from 3 to 19 years. The mean follow-up period was 43 months. Eight patients were seizure-free for 5 months to 3 years. Patients 1 with DS had self-remission without antiepileptic medication. Seven patients were seizure-free with antiepileptic medication: two patients with DS (patients 12 and 18) and patient 29 with BECTS had valproate and levetiracetam combination therapy; patients 27 with GEFS + had levetiracetam monotherapy; two patients with DS (patients 14 and 25) were on valproate and topiramate or valproate, levetiracetam and clobazam therapy; and one patient with unclassified epilepsy accompanied by right limb dysplasia and right external auditory canal atresia (patient 13) had valproate, levetiracetam and clobazam therapy.Eleven patients still had seizures, and their age at last follow-up ranged from 3 to 19 year 5 mo. Eight of these patients had tried at least three antiepileptic drugs. Two patients (patients 16 and 22) with DS presented increased myoclonic seizures after exposure to oxcarbazepine. Patient 8 with DS underwent epileptic lobectomy , corpus callosum resection, vagus nerve stimulation and acupuncture. She still experienced weekly GTCSs.SCN1A mutations have been expanding. As SCN1A mutations have been identified in epilepsy patients. In this study, 12 unreported mutations from 12 patients were identified, and the clinical features and mutations of the patients were described. BECTS and ABECTS are both parts of the spectrum of idiopathic rolandic epilepsy syndromes (IRES) (N-methyl-D-aspartate 2A (GRIN2A), \u03b3-aminobutyric acid A receptor (GABAA-R), DEP domain-containing 5 (DEPDC5), and RNA binding protein fox-1 homolog 1/3 (RBFOX1/3) (SCN1A (c.2624C > A) variant was diagnosed with ABECTS  variants were reported to have Rolandic epilepsy , respectively, adding strong evidence that the SCN1A variants might be responsible for IRES.The spectra of phenotypes and genotypes of s (IRES) , which aBFOX1/3) . One path ABECTS . Patientepilepsy . IRES isSCN1A-related epilepsy, some investigators have attempted to make a prognosis based on SCN1A mutations. For instance, SCN1A mutations in the pore region of the Nav1.1 channel in DS patients was 54.1% . Recent works showed the role of hyperactivity of GABAergic interneurons in a mechanism of cortical spreading depression (CSD) initiation, which is relevant as a pathological mechanism of SCN1A mutations  variant was detected in sudden unexplained nocturnal death syndrome  can be found below: GenBank, The studies involving human participants were reviewed and approved by the Ethics Committee of Xuanwu Hospital Capital Medical University. Written informed consent to participate in this study was provided by the participants\u2019 legal guardian/next of kin. Written informed consent was obtained from the individual(s), and minor(s)\u2019 legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.RM: writing \u2013 original draft and visualization. YD, LiZ, XQ, LuZ, and SP: resources. LG: writing \u2013 reviewing and editing and validation. CW: data curation and conceptualization. YW: supervision, project administration, and funding acquisition. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "We previously reported an alarming increase in cases of nosocomial Candidemia at our hospital which were associated with acute COVID-19 infection (Abstract 287 IDWeek 2021). We reinstated mitigation strategies including staff education, line insertion check list and antimicrobial stewardship. 1041 patients with acute COVID-19 were admitted to our hospital in 2021 (January to December) and 6 out 12 cases (50%) of Nosocomial Candidemia were seen in patients with acute COVID-19 infection. We re-evaluated the risk factors and mortality of hospitalized COVID-19 patients with Candidemia.We performed a retrospective chart review of the 6 patients with Candidemia and confirmed COVID-19 infection at our 292-bed community teaching hospital in Chicago, Illinois from January through December 2021. We report a descriptive analysis of the demographic characteristics, comorbidities, complications, and outcomes of these patients comparing both years.The average age of our study population was 71 years (older); 67% were male. The average hospital length of stay (LOS) was shorter 28 days. The mean time from admission to the development of Candidemia was slightly longer 18 days. Associated co-morbidities included cardiovascular diseases (CVD) in 83%, diabetes mellitus (DM), in 50%, and obesity in 50%. Treatments for COVID-19 included Steroids (100%), Remdesivir (50%) and Baricitinib (33%). All patients were managed in the intensive care unit (ICU) and 67% had a central in place at the time of Candidemia. Half of the patients (50%) required hemodialysis (HD); all patients were treated with multiple antibiotics. The average LOS in the ICU was 18 days (shorter). Despite antifungal treatment, 80% expired.Incidence of Candidemia in acute COVID-19 infections decreased by 56% in one year after reinstating mitigation strategies in our hospital. However, Candidemia remains a menace in hospitalized patients with acute COVID-19 infection. Associated risk factors remain history of CVD, DM, obesity, prolonged hospital LOS, requirement for multiple CL, HD, treatment with multiple antibiotics, treatment with steroids (100%) and a long stay in the ICU. The mortality of COVID-19 patients with Candidemia remains very high.All Authors: No reported disclosures."}
+{"text": "Following publication of the original article , we haveThey should be as follows:Fig. 7 Demethylation at enhancer region (cg08889930) significantly negatively correlated with NUP37 mRNA expression. A Diagram showing the CpG islands in the promoter region of human NUP37 gene. B Heatmap showing overall methylation patterns in the DNA sequence of human NUP37 gene. C Correlation heatmap visualizing the relationship between NUP37 mRNA expression and the methylation level of CpG island at DNA sequence of NUP37 gene. D\u2013F Scatter plot showing that NUP37 mRNA expression significantly negatively correlated with the methylation level of cg08889930 in HCC patients from 3 independent datasets. G NUP37 mRNA expression in Huh7 cells significantly increased after decitabine treatment ***p < 0.001, based on ANOVA. H NUP37 mRNA expression in Huh7 cells significantly reduced after treatment with CPI-455. ****p < 0.0001, based on ANOVA. I\u2013J Representative immunoblot of HCC cells (Huh7) lysates showing that decitabine increased NUP37 protein expression and CPI-455 decreased NUP37 protein expression. The NUP37, GAPDH and MCM2  bands of Huh7 cell lysates were obtained from same gel.Funding note: This study was funded by the grants from National Key Research and Development Program (No 2019YFC1316000) and the Zhejiang Provincial Program for the Cultivation of High-level Innovative Health Talents. The funders played no roles in the study design, the collection, analysis and interpretation of data, the writing of the report, and the decision to submit the article for publication."}
+{"text": "Anxiety manifestations are one of the most described symptoms during pregnancy. Meanwhile, the effect of the coronavirus disease 2019 (COVID-19) pandemic on the mental health and anxiety distress in particular, of pregnant and postpartum women remains unclear.The purpose of our study was to evaluate anxiety among prgnant women during covid19 and describe its associated factorsIt was a comparative cross-sectional case- control study in a Tunisian gynecologic department. All women were in the third term of pregnancy. Anxiety symptoms were evaluated using Beck Anxiety Inventory (BAI). The data were compared to a control group assessed in a similar study conducted before the pandemic in the same city. Eighty pregnant women was investigated during the covid pandemic and 100 pregnant women investigated before the COVID-19 outbreak in Tunisia was assigned to the control group.Pregnant women during COVID-19 scored less on BAI than controls (15.49\u00b19.223 vs 17.40\u00b17.410). Less patients presented moderate to severe anxiety during pandemic (38.8% (n=31) than controls 51% (n=51)). The difference between groups in means and prevalence values was not significant. The negative results could be related to the low power of the test (P=0.36).Despite the expected psychological distress among vulnerable population , Covid-19 didn\u2019t impact anxiety prevalence or scores among pregnant women in our current study .No significant relationships."}
+{"text": "Tobacco use is the underlying cause of ill health, preventable deaths, and disabilities worldwide. The Tobacco Product Control and Regulation Act 2011 prohibits the sale of tobacco in public places including educational institutions but non-compliance to the law had not been assessed. This study aimed to find out the prevalence of non-compliance to the Tobacco Product Control and Regulation Act among vendors in the vicinities of schools in a metropolitan city.This descriptive cross-sectional study was conducted in a metropolitan city in August 2018. Ethical approval was taken from Institutional Review Committee [Reference number: 23(6-11-E)2/075/076]. A convenience sampling method was used to recruit vendors within 100 meters radius of secondary schools. The data were collected through face-to-face interviews using a semistructured questionnaire. Point estimate and 95% Confidence Interval were calculated.Out of total 217 vendors, non-compliance to the section 3 of section 11 of Tobacco Product Control and Regulation Act was found in 195 (89.86%) . Among the non-compliers, 110 (56.41%) were selling both smoked and smokeless tobacco products, 78 (40%) were selling smoked and 7 (3.59%) were selling smokeless tobacco products.The non-compliance with Tobacco Product Control and Regulation Act's prohibition of tobacco sales within 100 m of schools in Kathmandu Metropolitan was similar with other studies conducted in similar settings. Guided by FCTC, Tobacco Product Control and Regulation Act (TPCRA) came into force in May 2011. Subsection 3 of section 11 of the TPCRA 2011 prohibits the sale of tobacco within 100 meters of public places, including all educational institutions.3Tobacco use is a significant contributor to ill health, preventable death and disability worldwide.4 Monitoring of tobacco use and prevention policies on a regular basis is essential to reverse tobacco epidemic.5The tobacco consumption in general population of Nepal is high (28%) with average age of initiation of 17.8 years.This study aimed to find out the prevalence of noncompliance to the Tobacco Product Control and Regulation Act among vendors in the vicinities of schools in a metropolitan city.A descriptive cross-sectional study was conducted among the vendors having shops within a 100 m radius of secondary schools of the Kathmandu Metropolitan City of Nepal. Data were collected in August 2018. The ethical approval was taken from Institutional Review Committee of Institute of Medicine, Tribhuvan University, Kathmandu, Nepal [Reference number: 23(6-11-E)2/075/076]. Convenience sampling method was used. We selected a total of seventeen schools which included 6 government and eleven private secondary schools. The vendors who provided a consent were included in the study. Those who didnot provide a consent were excluded from the study. The sample size was calculated using the formula,Where,n= minimum required sample sizeZ= 1.96 at 95% Confidence Interval (CI)p= prevalence taken as 50% for maximum sample size calculationq= 1-pe= margin of error, 7%A minimum required sample size of 196 was obtained. However, a total of 217 samples were included into the study.3 Tobacco Products (Control and Regulatory) Regulation 20126 and Nepal Demographic and Health Survey 2016.7 The tool consists of items related to non-compliance, sociodemographic factors, outlet types and inspection by the authority. The non-compliance was assured when the vendor was not following subsection 3 of section 11 of TPCRA and on observation found packed or unpacked tobacco products inside or outside of the shop.The data was collected face-to-face using a semistructured questionnaire with vendors. The items of the tool were guided by TPCRA 2011,The responses were checked on daily basis and cleaned it before entering the data into Epidata version 3.0. Data were analyzed using IBM SPSS Statistics trial version. Point estimate and 95% CI were calculated.Out of total 217 vendors, non-compliance to the section 3 of section 11 of TPCRA was 195 (89.86%) . Among the non-compliers, 110 (56.41%) were selling both smoked and smokeless tobacco products, 78 (40%) were selling smoked and 7 (3.59%) were selling smokeless tobacco products .One hundred seventy eight (91.28%) retails outlets were predominantly fixed type which comprised of grocery shop, bakery, tea stall, paan (betel nut) shop and supermarket compared to mobile shop such as ghumti pasal (moving shop) and thela (handcart) .The mean age of the non-compliers was 36.11\u00b18.78 years. Out of total non-compliers, there were 121 (62.05%) males while remaining 74 (37.95%) were females. Most of the vendors were literate 181 (92.82%). Sixty four (32.82%) vendors were consuming tobacco products. Among tobacco consumers, 35 (54.68%) were consuming smoked product, 10 (15.62%) were consuming smokeless products, and 19 (27.70%) were consuming both products .Among the non-compliers, only 47 (24.10%) of the vendors had heard about the TPCRA 2011, out of which 40 (85.10%) of participants specifically knew that prohibition of tobacco sales within 100 meters of the educational institutions. Thirty four (17.43%) shopkeepers reported inspection by authorities to monitor the compliance with the TPCRA. Among 34 (17.43%) inspected vendors, the inland revenue department in 9 (26.48%) vendors. Similarly, 2 (1.02%) vendors reported being fined for violating the TPCRA .Only 4 (2.05%) outlets had signage board indicating tobacco is not sold there, however they found were selling. Prevalence of tobacco sales by minor and pregnant were 11 (5.64%) and 15 (7.70%) respectively. The prevalence of tobacco sales to minors and pregnant women were 122 (61.3%) and 98 (49.8%) respectively .9 Similarly qualitative study in Nepal found that the tobacco policy and laws focused on control of tobacco on use among youth were not implemented properly.10 A contrasting findings from Mohali district of Punjab state of India showed non-compliance rate of 7.7% only.11 The variability in findings could be due to enforcement and socio-religious factors.The findings of this study talk about the noncompliance status of TPCRA and its associated factor. In this study out of 217, most 195 (89.86%) vendors were non-complying with subsection 3 of section 11. Similar studies conducted in Delhi and Mangalauru cities of India reported high non-compliance 84.22% (n=57) and 95.84% (n=48) with comparable regulations prohibiting tobacco sale by vendors near schools.12 This indicates that the awareness level of signage board is less in Kathmandu.In Mumbai the tobacco selling outlets are mostly permanent (67.6%) almost same as shown by our finding in Kathmandu (91.28%). The display of signage board prohibiting sale of tobacco products in Mumbai is 49%, in Delhi is 38% , in Mangaluru is 10% and in our study it is only 4%.12 Studies showed that easy access to tobacco among students and adolescent is one of reason for increased consumption as well as sale in Asian countries including Nepal.13Self-tobacco consumption was 32.8% in our study while study in Mumbai also reported similar stat of 53.2%. Mumbai people consume more smokeless form to tobacco (77%) compared to Kathmandu citizens who are consuming mostly smoked tobacco products (54.7%).14 Poor enforcement and lack of awareness by law enforcement agents have hindered implementation of tobacco control policies in Kenya and Uganda.16 Enacting the law without robust measures for enforcement has led to widespread non-compliance for tobacco control legislation in the metropolitan city of Mumbai.12 Proactive participation of schools and legal systems has been recommended to enforce and decreases children's tobacco exposure.9Active enforcement is necessary for the policy implementation.16 Also, the economy of Nepal is dependent on tobacco business and economic scholars supports for increased tobacco taxation.17Closing all the factories and industries would stop the production and hence sales of tobacco products. The potential of tobacco taxation to raise revenue cannot be ignored. In China conservative estimates suggest that 10% increase in tobacco taxation there is increase in revenue by 5%.This study has some limitations. Study cannot be generalized as the sampling method was nonrandom. The study also possesses respondent bias. The vendors may be unwilling to report that they are violating the law due to fear of legal sanctions. The study was done only in metropolitan city so it may not reflect TPCRA enforcement near secondary schools of rural areas. The data was only collected in between 10 am to 6 pm on working days.The non-compliance with TPCRA's prohibition of tobacco sales within 100 m of schools in Kathmandu Metropolitan City was similar with other international studies. As such, we recommend stricter government monitoring of tobacco sales around schools with special focus on students and teachers, active enforcement and regular inspection of the law and providing alternative business opportunities and increase sustainable livelihood measures for vendors to reduce the prevalence."}
+{"text": "Several studies have shown that residual mood symptoms affect the psychosocial functioning of patients with bipolar disorder (BD) in euthymia.To evaluate specific areas of functioning in this population and to explore the relationship with residual mood symptoms.This is a descriptive and analytical cross-sectional study including patients with BD (DSM V) in euthymia followed on ambulatory basis to the Mood Disorders Unit of the Psychiatry A Department at Hedi Chaker Hospital in Sfax between January and April 2019. Patients were considered euthymic if they scored below 7 on the Young Mania Assessment Scale (YMRS) and under 8 on the Hamilton Depression scale (HDRS-17). Residual manic and depressive mood symptoms were assessed using YMRS and HDRS-17. The Short Function Evaluation Test (FAST) was used to evaluate the overall and specific functionning domains.The alteration of the domain-specific functioning is defined by the following thresholds: autonomy>1, professional functioning>1, cognitive functioning>2, financial problems>1, interpersonal relations>3 and leisure time>3.We recruited 62 patients with a mean age of 45.65 years (SD = 13.3) and a sex ratio 1.13.The medians of YMRS and HDRS scores were respectively 2[0-5] and 2[0-7]. Global functionning impairment was observed in 85.5% of patients. Marked impairment of professional and cognitive functioning was observed in 98.4% and 77.4%, respectively. Alteration of the relational sphere was significantly more frequent in patients with residual depressive symptoms (p=0.009); impairment of autonomy was significantly more frequent in subjects with manic residual symptoms (p=0.005).Residual symptoms should be considered as specific targets of treatment to improve functioning."}
+{"text": "Candida, Aspergillus and Pneumocystis spp. in blood and marrow transplantation. Rezafungin once-weekly (QWk) was compared to caspofungin once-daily (QD) in two double-blind, randomized, controlled trials in patients with candidaemia and/or IC: STRIVE  and the recently completed ReSTORE . STRIVE demonstrated the efficacy and safety profile of rezafungin. ReSTORE showed rezafungin noninferiority to caspofungin for 30 day all-cause mortality (ACM) and global response at Day 14 with comparable safety. Patient-level meta-analyses of efficacy and safety from both trials are presented.Rezafungin is a next-generation echinocandin in development for treatment of candidaemia and invasive candidiasis (IC) and for prevention of invasive fungal disease caused by Details of STRIVE and ReSTORE were previously described. In this analysis of data from both trials, patients who received rezafungin QWk  were compared with those who received caspofungin QD (70 mg on Day 1 followed by 50 mg) for \u226514 days (up to 4 weeks). Efficacy endpoints included 30 day ACM (primary US FDA), mycological response at Day 5 (secondary), and time to first negative blood culture (TTNBC) (exploratory). Safety was evaluated by adverse events (AEs).Groups were well matched (Table 1). Figure 1 shows 30 day ACM . Mycological response at Day 5 was 73.4% (102/139) and 64.5% (100/155) in rezafungin and caspofungin groups, respectively . In patients with positive blood culture before randomization, median TTNBC was 22.3 h in rezafungin-treated versus 26.3 h in caspofungin-treated patients . The summary of AEs (Table 2) demonstrates similar outcomes for rezafungin and caspofungin groups.In the Phase 2/3 patient-level meta-analysis, rezafungin QWk demonstrated efficacy with a similar 30 day ACM rate and safety comparable to that of caspofungin QD. Data for mycological eradication at Day 5 and TTNBC support results from the primary efficacy endpoint and provide initial evidence for the theory that high, front-loaded drug exposure leads to faster fungal clearance. Further analysis of this integrated dataset may provide additional insights on rezafungin efficacy and safety."}
+{"text": "Prescribing of fall-risk increasing drugs (FRIDs) may be an important driver of falls in older adults. Understanding the types and frequencies of FRIDs prescribed to older adults presenting with falls to an emergency department (ED) may help identify opportunities for deprescribing. We performed a cross sectional analysis of data collected from a pharmacist-led fall-prevention program focused on older adults presenting with a fall to an academic ED in the southeastern United States between August 2020 \u2013 December 2021. ED pharmacists identified older adults (\u226565 years old) presenting with a chief complaint of \u2018fall\u2019 and then performed a medication reconciliations to verify and obtain data on outpatient prescription drug use. FRIDs were identified in accord with the 2019 American Geriatrics Society Beers Criteria and the Centers for Disease Control and Prevention Stopping Elderly Accidents, Deaths, & Injuries (STEADI-Rx) list. The ED pharmacists performed medication reconciliations on 424 unique older adults presenting with a fall. The cohort had a mean age of 81.3 years and were mostly female (63.3%) and white (84.9%). Prescription use of FRIDs were identified in 45.8% (194/424) of older adults presenting with a fall. An estimated 25.5% (108/424) of the subjects were prescribed 2 or more FRIDs. The most common FRIDs identified were antidepressants (25.9%), anticonvulsants (18.6%), opioids (12.7%), benzodiazepines (8.5%), and antipyschotics (3.1%). . Prescription use of FRIDs, including use of 2 or more FRIDs, was common in older adults presenting with a fall to the ED."}
+{"text": "Lodging reduces grain yield in cereal crops. The height, diameter and strength of stem are crucial for lodging resistance, grain yield, and photosynthate transport in barley. Understanding the genetic basis of stem benefits barley breeding. Here, we evaluated 13 stem related traits after 28 days of heading in a barley DH population in two consecutive years. Significant phenotypic correlations between lodging index (LI) and other stem traits were observed. Three mapping methods using the experimental data and the BLUP data, detected 27 stable and major QTLs, and 22 QTL clustered regions. Many QTLs were consistent with previously reported traits for grain filling rate, internodes, panicle and lodging resistance. Further, candidate genes were predicted for stable and major QTLs and were associated with plant development and adverse stress in the transition from vegetative stage to reproductive stage. This study provided potential genetic basis and new information for exploring barley stem morphology, and laid a foundation for map-based cloning and further fine mapping of these QTLs. Lodging largely impairs grain yield and quality, especially for high-yielding cultivars , which iCrop yield is affected by the source, sink and flow. Stems are the most important storage organs during assimilation translocation after anthesis , and plaMany studies have been done on barley lodging . Based oIn recent years, many studies on stem related traits in barley were reported. Such as In the study, we performed QTL mapping of 13 stem related traits after 28 days of heading using a barley DH population, including uppermost node diameter (UND), second node diameter (SND), third node diameter (TND), uppermost internode length (UIL), second internode diameter (SID), third internode diameter (TID), second internode length (SIL), third internode length (TIL), uppermost internode diameter (UID), main stem length of fracture (MSL), stem fresh weight (SW), third internode breaking force (TIBF) and lodging index (LI). The aims were to explore the relationship between stem internode traits and lodging traits, and to predict and screen out candidate genes related to stem development. The study will deepen our understanding of the genetic basis of stem, and provide new insights to boost lodging resistance breeding in barley.A doubled haploid (DH) population with 122 lines derived from six-rowed barley Huaai11 and two-rowed barley Huadamai 6 was employed to identify QTLs . These aThe heading date of each line was recorded, after 28 days of heading, three plants with uniform growth were randomly selected from each replicate and their main stems were cut at the root to measure phenotypic data of stem related traits, and the mean value for each phenotype was used for the analysis. The main stem length , uppermost internode length , second internode length  and third internode length  were measured using a straight edge, the uppermost node diameter , second node diameter , third node diameter , uppermost internode diameter , second internode diameter  and third internode diameter  were measured at the middle of them with a slide caliper. The breaking force of third internode  was measured using a prostrate tester , and the fracture site was arranged in the center of the third internode 2) was computed using: H2 =VG/(VE/N + VG), N was the number of environments . The best linear unbiased predictor (BLUP) of stem traits was forecast using the R package lme4. The broad-sense heritability (Hronments . In thisA high-density genetic linkage map of this double haploid population was constructed by http://plants.ensembl.org/Hordeum_vulgare/Tools/Blast)  \u226510% and positioned in at least two years (including BLUP) as a stable QTL. To determine whether the QTL is novel, we compared the physical locations of loci detected here with those reported. The sequences of flanking markers were searched at the National Center for Biotechnology Information (NCBI). By searching the coding sequences, the predicted candidate genes of the main QTL in the physical interval were obtained from Barley genome assembly Morex_v2.0. The orthologs of other plants genes in the barley reference genome were identified using the Ensembl Plant Database (s/Blast) . We revis/Blast) .We phenotyped 13 stem related traits 28 days after the heading in 2021 and 2022 Table\u00a01.The best linear unbiased predictor (BLUP) of stem lodging traits was used for Pearson correlation analysis Figure\u00a02In total 103 QTLs were mapped on all chromosomes of barley except 1H for stem related traits using the ICIM BIP module in 2021 and 2022, including UND (10 QTLS), SND (5), TND (7), UID (9), SID (13), TID (12), UIL (6), SIL (7), TIL (4), MSL (9), SW (6), TIBF (8) and LI (7) Table\u00a02,In a multi-environment QTL analysis, 93 MET QTLs were identified for UND (9 QTLS), SND (5), TND (8), UID (8), SID (10), TID (10), UIL (6), SIL (8), TIL (3), MSL (10), SW (5), TIBF (6) and LI (5) , SND (6), TND (8), UID (7), SID (7), TID (7), UIL (2), SIL (7), TIL (2), MSL (8), SW (5), TIBF (4) and LI (2)  plays a role in nitrogen sensing or signaling and the efficiency of photosynthetic or water use (RDRP1 gene (HORVU6Hr1G074220) and RDRP2 gene (HORVU6Hr1G074180) regulate organic acid and amino acid metabolites, biogenesis and spikelet development by small RNA (HvGA20ox3 (HORVU3Hr1G089980) that encodes enzyme involved in gibberellin (GA) biosynthesis (14-3-3D gene (HORVU7Hr1G061920) and BRI1 gene (HORVU7Hr1G068990) located in the region plays an important intermediate in GA signal transduction and involves in the signaling of BRs  on chromosome 7H (81.89-83.77 Mb), the gene maintains the transition from vegetative stage to reproductive stage, thereby influencing spikelet morphology and the internode development .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "To evaluate the risk factors for poor outcomes after surgical and endovascular treatment of aneurysmal subarachnoid hemorrhage (aSAH).Patients with \u2265 18-years of age and aSAH were included, while patients who died within 12 h of admission or lost follow-up were excluded. All participants underwent standardized clinical and radiological assessment on admission and were reassessed at discharge and at 6-months follow-up using the Glasgow Outcome Scale (GOS).Death at discharge was associated with female gender, anterior communication artery (ACoA) aneurysm location and presence of atherosclerotic plaque in the surgical group, and with age in the endovascular group. Both groups had clinical condition on follow-up associated with mFisher score on admission and hypertension. GOS on follow-up was also associated with presence of atherosclerotic plaque and multiple aneurysms in surgical group, and with age in endovascular group.Subjects treated surgically are prone to unfavorable outcomes if atherosclerotic plaques and multiple aneurysms are present. In patients with endovascular treatment, age was the main predictor of clinical outcome. Subarachnoid hemorrhage (SAH) is a subset of stroke that occurs in relatively young patients and that have poor prognosis in most cases: about 50% dies in the first month and 40% of those who survive remains functionally dependentFor the last two decades, the treatment of SAH secondary to aneurysm rupture has changed due to the increasingly use of endovascular coiling, especially after the results of the International Subarachnoid Aneurysm Trial (ISAT)et al.et al.Following studies have investigated the subpopulations in which coiling or clipping would be more beneficial. According to Pierot Even though the risk factors for poor outcomes after the surgical treatment of ruptured aneurysms are well known , evidence regarding the risk factors for poor outcomes after endovascular coiling is still lacking. Therefore, considering the importance of comparing the different risk factor to better indicate the treatment, the aim of this study is to assess risk factors for poor outcomes after surgical and endovascular treatment of ruptured intracranial aneurysms.This prospective cohort study was performed in Central Institute of Clinical Hospital from School of Medicine, University of S\u00e3o Paulo (HC-FMUSP), and was approved by the Ethics and Research Committee of HC-FMUSP. All methods were performed in accordance with the relevant guidelines and regulations. Each patient was fully informed about the study and provided informed consent as approved by the local Institutional Review Board.This study enrolled patients from HC-FMUSP Division of Neurological Surgery between January 2018 and November 2019. Patients were eligible for enrollment if they were 18 years of age or older and admitted in the emergence department of the Central Institute of HC-FMUSP with diagnosis of ruptured aneurysm. Patients who died within the first 12 h after admission or lost follow-up after hospital discharge were excluded.Participants\u2019 characteristics assessed included age, gender, hypertension, diabetes mellitus, smoking, alcohol abuse and previous SAH. The clinical condition at admission was assessed through the Hunt\u2013Hess scale (HH). The radiological assessment included the modified Fisher classification (mFisher) on admission, multiple aneurysms, aneurysm\u2019s location and size, and presence of atherosclerotic plaque in intracranial arteries. Time from ictus until intervention, clinical and surgical complication during in-hospital stay were also assessed. The patients were followed for 6 months and evaluated using the Glasgow Outcome Scale (GOS). The follow-up consultations were carried out at the HC-FMUSP Vascular Neurosurgery Clinic or by phone calls.Descriptive statistics were applied to describe the clinical and demographic characteristics of the patients studied. Continuous variables were described as mean (standard deviation) or median (interquartile distance), as appropriate under normal data analysis. Categorical data were described as frequencies . Logistic regression was used to assess predictors of poor outcomes in short-term outcomes . Predictors of long-term outcomes (GOS) were assessed through ordered logistic regression. A two-tailed alpha level of 5% was adopted. The analyses were performed using the Stata software, version 17.0. Data from microsurgical and endovascular group were analyzed separately and the results were subsequently compared and discussed.A total of 112 patients were included. Seventy-six were submitted to microsurgical treatment and thirty-six to endovascular treatment . The oveThe microsurgical group had a mean age (SD) of 55.69 \u00b1 12.43 and included 54 (71%) females, 22 (28.9%) males, 39 (51.3%) patients with hypertension, 18 (23.6%) with diabetes mellitus, 7 (9.2%) with a previous SAH, 9 (11.8%) with alcohol abuse and 30 (39.4%) were smokers  and 2. TThe median (IQR) size  of the aneurysms was 6\u00b15 mm, 19 (25%) patients had atherosclerotic plaque, 12 (15.7%) patients had multiple aneurysms. MFisher was assessed on 75 patients: 20 (26.6%) had mFisher 0\u20132, 26 34.6%) had mFisher 3, 29 (38.6%) had mFisher 4. Regarding the ruptured aneurysm location: n = 27 (35.5%) were in PCoA, n = 24 (31.5%) were in MCA, n = 12 (15.7%) were in anterior communication artery (ACoA), n = 5 (6.5%) were in ICA and n = 8 (10.5%) were in other arteries, which included ACA, PICA, pericallosal, AICA, ophthalmic, vertebral and basilar arteries  and 4..6% had mEighteen (23.6%) patients were dead at discharge. Among the 58 patients followed 6 months later, 4 (6.8%) died after discharge (GOS 1), 2 (3.4%) presented severe disability (GOS 3), 14 (24.1%) had minor neurologic deficits (GOS 4) and 38 (65.5%) returned to their original functional level (GOS 5) . The staThe endovascular group had a mean age (SD) of 58.39 (14.3) and included 25 (69.4%) females, 11 males (30.5%), 19 (52.7%) patients with hypertension, 10 (27.7%) with diabetes mellitus, 5 (13.8%) with a previous SAH, 7 (19.4%) with alcohol abuse and 9 (25%) were smokers  and 2. TThe median (IQR) size  of the aneurysms was 5\u00b15 mm, n = 12 (33.3%) patients had atherosclerotic plaque, n = 6 (16.6%) patients had multiple aneurysms. MFisher was assessed on 34 patients: n = 7 (20.5%) had mFisher 0\u20132, n = 9 (26.4%) mFisher 3, n = 18 (52.9%) mFisher 4. Regarding the ruptured aneurysm location: n = 5 (13.8%) were in PCoA, n = 3 (8.3%) were in MCA, n = 8 (22.2%) were in ACoA, n = 9 (25%) were in ICA and n = 11 (30.5%) were in other arteries, which included ACA, PICA, Pericallosal, AICA, Ophthalmic, vertebral and basilar arteries  and 4.Eleven (30.5%) patients were dead at discharge. Among the remaining 25 patients who were followed 6 months later, 4 (16%) had died during the follow-up period (GOS 1), 5 (20%) presented severe disability (GOS 3), 4 (16%) had minor neurologic deficits (GOS 4) and 12 (48%) had returned to their original functional level (GOS 5) .The statistical analysis revealed that age  hypertension  and mFisher 3  were associated with clinical outcome in follow-up. Age  was also associated with death at discharge.In this study, death at discharge was associated with female gender, ACoA aneurysm location and presence of atherosclerotic plaque in patients surgically treated, while only age was associated with the same outcome in patients who underwent the endovascular procedure. Both groups had clinical condition on 6 months of follow-up associated with mFisher score on admission and hypertension. Additionally, the multivariate analysis demonstrated that the presence of atherosclerotic plaque on imaging and multiple aneurysms could predict clinical long-term outcomes in patients treated surgically, while only age was associated with long-term outcomes in the endovascular group.Studies have shown that higher mFisher grade and hypertension are associated with poor long-term outcomes in patients with aSAH, regardless of the type of treatmentet al.The association between systemic hypertension and intracranial aneurysm formation and ruptured is well established, but the mechanism behind this association is not fully understood. The link between systemic hypertension and IA might be the renin-angiotensin system (RAS). RAS plays an important role in vasorelaxation/vasoconstriction, vascular remodeling, and maintenance of arterial wall integrityet al.Although the neurological status on admission is considered the most important predictor for aSAH outcome, this study found no association between initial HH scores and short- or long-term outcomes for both groupsper se. Additionally, most aneurysms were bigger than 3 mm, limiting the analysis. However, the surgical group had a positive association between death at discharge and ACoA aneurysm location.The aneurysm location and size are also important factors when choosing between the two procedures. Some studies indicate that PCoA and MCA location are risk factors for intraprocedural rupture and poor outcomes when coiledThe presence of atherosclerotic plaque on imaging was associated to poor clinical outcomes 6-months later in the group treated surgically. The pathophysiology behind the unfavorable outcomes of patients treated with aneurysms treated via surgery when compared with those treated via embolization was not yet clarified or even sufficiently investigated. The finding of this study suggest that the surgical treatment may lead to the inadvertent mobilization of intravascular atherosclerotic plaques, leading to microembolization and microinfarcts.Multiple aneurysms were also predictors of poor outcomes in follow-up. Few studies have evaluated the impact of multiple lesions on long-term outcomes, most of them suggest that patients with unruptured multiple lesions do not have increased risk of rupture or poor clinical outcomesThis study presents limitations that should be considered aiming a proper interpretation. First, the results\u2019 analysis is limited by the small sample size, especially in the endovascular group. Second, the loss of follow-up, due to impossibility of following long-distance patients and giving up the participation in the study, limited the long-term analysis. Finally, the inconsistent results regarding the association of aneurysm size and location with clinical outcomes may be explained by the treatment selection bias.Premorbid hypertension and severity of aSAH on imaging are predictors of poor outcomes, regardless of the type o treatment undergone. Subjects treated surgically are more susceptible to unfavorable outcomes if atherosclerotic plaques are present on imaging. This finding suggests that the vessel manipulation during the surgical procedure may cause inadvertent mobilization of atherosclerotic lesions, leading to detachment of microemboli into the cerebral circulation. Studies about pathophysiology of this process, which may explain the better results of endovascular procedures in many cases, are still lacking. Multiple aneurysms in the context of aSAH were associated with poor outcomes when treated surgically. In patients who underwent endovascular treatment, age was the main predictor of clinical outcome."}
+{"text": "Abnormal uterine bleeding is the most common presenting complaint in the perimenopausal age group. Endometrial biopsy obtained by dilatation and curettage is the preferred modality of investigation to determine the causative pathology of abnormal uterine bleeding. The objective of this study was to find out the prevalence of the benign histopathological findings in perimenopausal women presenting with abnormal uterine bleeding.This descriptive cross-sectional study was conducted among patients between 1st June 2020 to 30th September 2021. Ethical approval was taken from the Institutional Review Committee of Kathmandu Medical College (reference number: 305202002). Using the convenience sampling method, 96 cases of endometrial biopsies were studied under light microscopy. Data was analyzed using the Statistical Package for the Social Sciences version23.0. Point estimate at 95% Confidence Interval was calculated along with frequency and proportion for binary data.Among the 96 specimens, the prevalence of benign findings was 93 (96.9%) . Among them, the commonest benign histopathologic spectrum was hormonal imbalance pattern in 40 (41.7%) followed by normal menstrual pattern 35 (36.5%). Five (5.2%) cases showed chronic endometritis. Six (6.2%) cases of endometrial hyperplasia without atypia were identified. Three (3.1%) cases showed endometrial atrophy. Four (4.1%) cases showed endometrial polyp.The prevalence of benign histopathological findings among endometrial biopsies in the study was similar to other studies. So far limited data is available regarding the endometrial patterns seen in perimenopausal women in our population.However, most of the cases of AUB in perimenopausal age are of benign nature without requiring any invasive surgeries. Endometrial biopsy obtained by dilatation and curettage is the preferred modality of investigation to determine the causative pathology of AUB.The objectives of this study were to find out the prevalence of benign histopathological findings in perimenopausal women presenting with AUB.th September 2021. The institutional review committee of Kathmandu Medical College and Teaching Hospital provided the ethical approval (reference number:305202002). Using convenience sampling technique, endometrial biopsy specimen submitted to the Department of Pathology for histopathologic evaluation during the study period were included in the study. The sample size was calculated as,This was a descriptive cross-sectional study conducted among patients 1st June 2020 to 302 \u00d7 p \u00d7 q / e2n\u2003= Z2 \u00d7 (0.5) \u00d7 (1-0.5) / (0.1)2\u2003\u2003= (1.96)\u2003\u2003= 96where,n= required sample size,Z= 1.96 at 95% Confidence Interval (CI),p= prevalence taken as 50% for maximum sample size,q= 1-pe= margin of error, 10%Therefore, the calculated sample size was 96. Hence, 96 endometrial samples were collected. The endometrial samples were fixed in 10%formalin for 12-24 hours and the entire tissue was submitted for routine processing. 5|j thickness sections taken from paraffin blocks were stained with Haematoxylin and Eosin (H&E) and studied under light microscopy by a pathologist. Patients with cervical-vaginal pathology and systemic causes of abnormal uterine bleeding were excluded from the study. Relevant demographic data were obtained from requisition form provided with the specimen.Data were entered and analyzed using the Statistical Package for the Social Sciences version 23. Point estimate at 95% Cl was calculated along with frequency and proportion for binary data.In the present study, out of the 96 cases of endometrial biopsies included, the prevalence of benign histopathological findings was 93 (96.9%) (93-100 at 95% CI). Only three (3.1%) cases showed histopathologic evidence of endometrial malignancy. Majority of patients with AUB had a hormone imbalance pattern on endometrial biopsy 40 (41.7%). Endometrial atrophy was noted in three (3.1%) cases. Six (6.2%) cases showed endometrial hyperplasia without atypia. Five (5.2%) cases showed features of endometritis. In four (4.1%) cases AUB was due to endometrial polyp .Histopathologic changes favoring hormone imbalance included disordered proliferative endometrium 32 (80%), non-secretory endometrium with endometrial and stromal breakdown in 3 (7.5%) and pill effect in 5 (12.5%) cases.Most of the women presenting with AUB fell into the 40-44-year age group, 38 (39.58%), followed by 45-49 year age group, 32 (33.33%) and 50-54 year age group, 26 (27.08%) .Menorrhagia, in 35 (36.4%) cases, was the most common presenting symptom .Despite having AUB, a significant number of cases showed normal cyclical endometrium where 24 (25%) showed proliferative endometrium and 11 (11.5%) showed secretory endometrium.5 A new classification for the causes of abnormal uterine bleeding is based on the acronym PALM-COEIN - Polyps, Adenomyosis, Leiomyoma, Malignancy, Hyperplasia, Coagulopathy, Ovulatory disorders, Endometrial causes, Iatrogenic and Not classified, was developed by the International Federation of Gynaecology and Obstetrics in November 2010.8 When unscheduled bleeding occurs, especially if it is heavy or prolonged, further investigations such as trans-vaginal ultrasound and, hysteroscopy with biopsy if indicated, are needed.9 The accuracy of endometrial biopsy for the detection of endometrial abnormalities has been reported to be as high as 96%.10 Diagnosis and the management strategies of AUB is not complete without evaluation of histopathological characteristics of endometrial biopsy.11 Endometrial biopsy tissue obtained by a simple procedure of D and C (Dilation and curettage) is an effective and safe diagnostic step in evaluation of AUB and for the diagnosis of endometrial pathologies.13The endometrium undergoes a complex regular cycle of periodic proliferation, differentiation, breakdown and regeneration which forms the basis of normal menstrual cycle; any deviation from it would result in abnormal uterine bleeding. Clinically AUB manifests as menorrhagia, polymenorrhea, polymenorrhagia, metrorrhagia, menometrorrhagia, intermenstrual bleeding, etc.14 We also observed that the common age of AUB was noted in the 40-44 years age group (39.58%) followed by 45-49 years age group (33.33%) and 50-54 years age group (27.08%) which is similar to the study done by Valson and Bhatiayani, et al. Probable reason of increased incidence of AUB in this age group (40-50 years) is that the women in this age group are in their climacteric period. As women approach menopause, cycles shorten and become intermittently anovulatory due to the decline in the level of ovarian follicles and estradiol level.16AUB is common in the perimenopausal age group. In a study conducted by Chapagain in a tertiary hospital in Nepal, majority of cases of AUB seen in perimenopausal age group was between 40-44 years (45.5%).14 which was similar to the observation made by Chaudhary, Razzaq, et al. and Shrestha in their studies which were conducted in a population of similar race, socio-economic status and environment as our study.19 Study conducted by Abid, et al. however found polymenorrhea as the commonest presenting complaint.20Menorrhagia (36.4%) was the most common presentation followed by polymenorrhea (26%) in our study. In the study conducted by Chapagain, menorrhagia was the commonest presenting complaint (40.3%) followed by menometrorrhagia (23.4%).22 In our study the commonest histological pattern in perimenopausal women was hormonal imbalance pattern (41.7%) followed by normal cyclical pattern . Among the cases showing hormone imbalance patterns, histomorphologic features showed predominantly disordered proliferative endometrium (32/40 cases), glandular and stromal breakdown (3/40 cases) and pill effect (5/40 cases). Abid, et al. also reported hormonal imbalance pattern was the commonest in perimenopausal age group (54%). This correlates with the fact that perimenopausal age is transition from normal ovulation to anovulation.20Various studies have shown benign histopatholgical changes in patients presenting with AUB.22Thirty-five women with AUB showed normal cyclical endometrium which was the second common pattern in our study. Out of these 36 cases, 24 (25%) showed proliferative endometrium and 11 (11.5%) revealed secretory phase endometrium. This is in contrast to the studies done by Das et al, Razzaq et al, Bhatiyani and Singh, et al. who reported normal cyclical pattern to be the commonest pattern of endometrium. Their studies included endometrial biopsy in a wide age range while our study took into account only cases which fell into the perimenopausal age group (40-54 years).23 We observed endometrial hyperplasia without atypia in six cases (6.2%). Three of these cases were present in the 45-49 year age group and the other three in the 50-54 years age group. Endometrial hyperplasia without atypia is a proliferation of endometrial glands of irregular size and shape without significant cytological atypia. It is most commonly diagnosed in perimenopause with symptoms of abnormal, non-cyclical vaginal bleeding. It is a result of prolonged estrogen exposure unopposed by progesterone or progestational agents acting on the entire endometrial field.24 In the study done by Abid et al, endometrial hyperplasia was present in 5% of cases withAUB and the incidence was most common in the postmenopausal and perimenopausal age group.20Endometrial pathologies such as endometrial hyperplasia, polyps, submucous leiomyoma and endometrial carcinoma should be suspected and evaluation of endometrium is necessary in AUB in perimenopausal women.25 This variation may be due to socioeconomic status, hygienic conditions or exposure to surgical intervention.We observed inflammatory pathology only in 5 cases (5.2%). All these cases showed features of non-specific chronic endometritis. Abid, et al. reported a lower incidence of endometritis (9.1%) in perimenopausal age group than in reproductive age group (18%) which they attributed to the fact that the women in reproductive age group had a greater chance of exposure to casesarian sections, spontaneous and therapeutic abortion and intrauterine contraceptive device etc. hence prone to develop chronic endometritis. Perveen, et al. found chronic endometritis in a larger number of cases (37%).26A small number of cases demonstrated atrophic endometrium (3.1%). All three cases were in the 50-54 age group and no history of menopause was present in them. This pattern is most common in post-menopausal women however, anovulation seen in perimenopasual age group eventually leads to permanent loss of ovarian function manifested as atrophic or inactive endometrium.20Endometrial polyp was present in four cases (4.1%). None of the polyps showed atypical hyperplasia or carcinoma. Azim, et al. demonstrated an increasing frequency of polyp with advancing age.Our study was a descriptive hospital-based study carried in a selected age group of women in a short duration of time, therefore might not be representative of the entire population. However,this study would provide a database with regards to benign histopathological patterns in AUB in perimenopausal age groups.The prevalence of benign histopathological findings among endometrial biopsies in the study was similar to other studies. Hormonal imbalance pattern is the predominant benign histopathologic pattern seen in perimenopausal women presenting with AUB. Histopathologic findings in an endometrial biopsy helps gynaecologists to decide appropriate management strategies."}
+{"text": "Infective endocarditis (IE) remains a disease with high morbidity and mortality. The aim of this study was to determine the clinical characteristics and echocardiographic features of patients with IE.We analyzed patients with either definitive or probable diagnosis of IE who were hospitalized in a teaching hospital in Mashhad, Iran between June 2011 and January 2020. Patients who survived were followed up by echocardiography for at least 6-month after hospital discharge.n = 12, 14.6%), followed by ventricular septal defect  and Tetralogy of Fallot (TOF) . Three (3.6 %) cases had rheumatic heart disease and 12 (14.6 %) were injecting drug users. The most common causative pathogen was Staphylococcus aureus, detected in 7 (19.4%) cases. Follow-up echocardiography revealed right or left ventricular failure in 10 (12.1%) cases. Cardiac complications occurred in 41 (50%) cases and systemic complications in 63 (76.8%). All-cause mortality was 41.5% (n = 34) and 6 (18.1%) patients died due to cardiovascular complications.A total of 82 cases with IE were included of which 62 (75.6%) received definitive diagnosis. The mean age was 39.7 \u00b1 18.7 years and 52 (63.4%) were male. The most common preexisting structural cardiac abnormality that predispose patients to IE were congenital heart diseases (28 %) of which bicuspid aortic valve was more common  were the most common predisposing condition which may necessitate a revision in the IE prophylaxis recommendations. Infective endocarditis (IE) is a life threatening condition that is associated with a great economic burden . DespiteRecently, a shift in the IE predisposing conditions has occurred in high-income countries from chronic rheumatic heart disease to intravenous illicit drug using (IVDU), degenerative valve disease, and intracardiac devices , 6, 8. RSerious cardiac and systemic complications are common in IE. Recent studies reported about 80% of IE patients experience at least one complication , 7. Of sAlthough cross-sectional and cohort studies reported short and long-term survival rates of IE patients, there is limited information available about the long-term echocardiographic outcome of patients who survived from episodes of IE. Available studies on IE in Iran reported an increasing trend of hospitalization due to IE in the country, with 7\u201325% mortality rate , 10\u201312. It was a retrospective cohort study that was conducted in a 1,000 bed teaching hospital affiliated to Mashhad University of Medical Sciences, Iran between May 2011 and January 2020 . We reviPatients underwent echocardiography at the time of hospital admission for diagnosis and if needed, for evaluation of complications during admission, and once at least six months after discharge if survived at the time of follow up.Major systemic embolic events (SEE) were described as occurrence of any major embolic event: peripheral limb ischemia, pulmonary embolization, neurologic accident and coronary ischemia.Pericardial effusion was categorized to mild (<1 cm), moderate (1\u20132 cm) and Severe (>2 cm) by fluid thickness in echocardiography.Indications of cardiac surgery were defined according to 2015 European society of cardiology guideline .According to the 2013 American College of Cardiology and American Heart Association (ACCF/AHA) guidelines, severe heart failure was defined as LVEF <30% associated with NYHA III \u2013IV .p < 0.05.Normality of data was assessed using the Kolmogorov-Smirnov test. Mean and standard deviation (SD) were used for normally distributed variables and median and interquartile range for non-normally distributed variables. Frequency and percentage were used for categorical variables. The Chi-square or Fisher's exact tests were used to compare categorical variables. Kaplan Meier curve and Cox proportional hazard model was done by STATA (version 14). The level of statistical significance was From May 2011 to January 2020, 94 patients were hospitalized with primary diagnosis of IE, of which 12 were excluded. Finally, 82 cases were analyzed with mean age of 39.7 \u00b1 18.7 years, of whom 52 (63.4%) were male . ElderlyThe most common non-cardiac underlying comorbidity was chronic obstructive pulmonary disease (COPD/asthma) in 17 (20.7%) cases, followed by hypertension in 14 (17%), end stage renal disease (ESRD) requiring hemodialysis in 13 (15.8%), and diabetes mellitus in 13 (15.8%). Eight (9.7%) cases were taking immunosuppressive drugs, and 3 (3.6%) had active malignant neoplasms.Sixty-four (89.0%) cases had native valve IE (NVE) and 8 (11.0%) prosthetic valve IE (PVE). Of those with NVE, 3(4.6%) and 6 (9.2%) had rheumatic and degenerative heart disease, respectively.n = 23, 28 %), with bicuspid aortic valves (BAVs)  and ventricular septal defect (VSD) as the predominant lesions . The most common type of VSD in patients was peri membranous and none of them underwent surgical VSD closure. IE was associated with intravenous illicit drug using (IVDU) in 12 (14.6%) episodes and central-venous catheter infection in 8 (9.7%). Endocarditis involved cardiovascular implantable electronic device (CIEDs) in one patient with a history of permanent pace maker.Congenital heart diseases were the most common predisposing condition , and major embolic events  and congestive heart failure  were the most common complications that were identified during physical examination and initial diagnostic workup , 26\u201375]. The most common symptoms were fever in 71 (86.5%), followed by malaise in 71 (86.5%), loss of appetite in 65 (79.2%), shortness of breath in 62 (75.6%), cough and excessive sweating, each in 31 (37.8%), dizziness 25 (30.4%), muscle pain 25 (30.4%), nausea/vomiting 20 (24.3%), chest pain 15 (18.2%), arthralgia 12 (14.6%), headache 11 (13.4%), and syncope 4 (4.9%) . On admic workup .Involvement of the coronary arteries occurred in three patients: the first was a patient who developed left circumflex (LCX) artery embolism with aneurysmal formation in the proximal part detected by coronary angiography. The second case was a 61-year-old diabetic man who presented with fever and arthritis of hip joint. He developed anterior ST-elevation myocardial infarction (STEMI) caused by left coronary artery embolism during hospitalization. On echocardiography, he had a large mobile vegetation on the mitral valve. Last patient was a 50-year-old woman who developed a rare complication of pseudo aneurysm and extensive abscess formation in the anterior wall of the aortic root and right coronary artery during hospitalization.Staphylococcus aureus  of which 3 (42.8%) were methicillin resistant, followed by viridans streptococci, enterococcal species, and pseudomonas species . Acinetobacter was detected in one patient. Forty-six (56.1%) cases were categorized as blood culture negative infective endocarditis (BCNIE) (The causative pathogen was isolated from blood culture in 36 (43.9%) cases. The most common pathogen was  (BCNIE) .All patients underwent trans-thoracic echocardiography (TTE), and in 43 (54.4%) cases trans-esophageal echocardiography (TOE) was also done .In 17 (26.6%) of 64 cases with NVE, the infection involved right-sided valves, in 45 (70.3%) left-sided valves, and in 2 (3.1%) there was bilateral valve involvement. The most common site of vegetation was mitral valve in 24 (29.2%) episodes, followed by tricuspid valve in 17 (20.7%) and aortic valve in 17 (20.7%). Fourteen (17%) cases had vegetation at multiple sites . The median diameter of vegetations on aortic, mitral and tricuspid valves were 10, 11.5, and 14 mm, respectively.via venous port, and 2 (10.5%) were on hemodialysis. One patient was a healthy woman with a history of eyebrow tattooing 2 weeks prior admission.In those patients with right-sided valve vegetation, 11 (57.8%) cases had history of intravenous drug use, 2 (10.5%) had cancer and receiving chemotherapy The most common type of valve involvement was regurgitation in 66 (80.4%) cases and the most common valve complication was perforation in 41 (50%): aortic valve in 17 (20.7%) cases, and mitral and tricuspid valve, each in 12 (14.6%).The median of ejection fraction (EF) and median of pulmonary arterial systolic pressure (PAP) were 47.5%  and 47.5 mm Hg , respectively. Left ventricular enlargement and right ventricular dysfunction were identified in 19 (24.1%) and 36 (45.6%) cases, respectively. Although echocardiographic evidence of severe pericardial effusion and tamponade were not detected in any patients, 31 (39.2%) episodes were complicated with mild or moderate pericardial effusion.The mean length of hospital stay was 35  days. Seven (8.5%) cases transferred to the intensive care unit (ICU) with median length of ICU stay of 6 days .The most common complication during hospital stay was adverse drug reactions related to antibiotic therapy that were occurred in 27 (32.9%) cases, followed by acute renal failure in 19 (23.2%), and congestive heart failure in 14 (17.1%) . Five (6Cardiac surgery was indicated in 59 (72%) cases, of which 34 (57.6%) underwent heart surgery. The most common indication of cardiac surgery was severe heart failure in 46 (78%). Early post cardiac surgery death occurred in 7 (8.5%) episodes during hospital stay.In hospital mortality occurred in 28 (34.1%) cases. Death was attributed to non-cardiac causes in 21 (77.7%) episodes and cardiac complications in 6 (22.3%). Non-cardiac causes of death included septic shock and multi organ failure in 13 (15.8%), neurologic catastrophes in 4 (4.8%), neoplasia in 3 (3.6%), and pulmonary emboli in one case (1.2%).Using telephone follow up, patients who survived to hospital discharge were asked to return to the hospital for a clinical evaluation and follow up echocardiography. The median follow-up was 330 days . Follow up echocardiography was performed using TTE in 36 (3.9%) and TEE in 4 (4.9%) cases.The median left ventricular ejection fraction (LVEF) was 53%  on follow up echocardiography. Ten (12.1%) cases had persistent ventricular failure, including 2 patients with severe RV failure as complication of right-sided IE. One of them underwent redo-tricuspid valve replacement (redo-TVR) due to severe transvalvular regurgitation of repaired infected tricuspid valve. Persistent vegetation was noted in 2 patients after corrective heart surgery. Prosthetic valve malfunction including increased trans-valvular gradient, and pannus or thrombus formation were found in 5 cases.Thirty-Nine (47.5%) cases responded the follow up call, of which 36 (43.9%) underwent follow up echocardiography. Nine (11%) cases lost to follow up and six (7.3%) patients died within 6 months after discharge.One patient experienced recurrence of IE. He was 44-year-old intravenous drug users with methicillin-resistant staphylococcal right-sided IE that readmitted 3 months after the first episode of IE with cardiogenic shock and large obstructive vegetation on the TV leaflets resulting in severe stenosis and regurgitation. He died before surgical intervention could be performed.Post-discharge complications identified in 18 (45%) patients, including heart failure in 6 (16.6%), healthcare-associated infections in 4 (11.1%), and renal failure in 3 (7.5%). Four (10%) cases underwent post-discharge cardiac surgery.n = 40, 88.9% and n = 5, 11.1%, respectively) (p: 0.692). Furthermore, mortality rate was higher in the episodes of BCNIE in comparison to other cases  (p: 0.432).In cases with blood culture negative infective endocarditis (BCNIE), the frequency of congestive heart failure  was higher than those with positive blood culture results (p = 0.037) and septic shock   on multivariate Cox proportional hazard model were heart failure  .Kaplan Meier plot was used to assess the general pattern of survival which showed high intensity of mortality in initial days and then plateau to the end of study . The resP < 0.001) (The short- and long-term prognosis in infective endocarditis (IE) was defined to be poor in this study. One third of IE cases died during hospital stay and 11% of those who survived to hospital discharge subsequently succumbed to death. Echocardiography revealed persistent ventricular failure in 12% of IE cases who were alive at median 11-month follow up. Previous research also indicates that 1-year mortality of IE has not changed over the last 2 decades, ranging from 15 to 30% . High ra< 0.001) .The most common foci for major embolic events were central nervous system (CNS) and pulmonary circulation. Overall, IE was complicated by neurovascular complications in 30% of the episodes in our study. Similarly, rates of 20\u201340% have been reported for neurological complications in IE previously . Once nep = 0.037) and septic shock   . SOFA sc< 0.001) . Further< 0.001) .Congenital heart disease and intravenous illicit drug using (IVDU) were the most common predisposing conditions of IE in our study. Chronic rheumatic heart disease, however, was responsible for <5% of cases of IE. This could be indicative to a shift toward non-rheumatic heart diseases as predisposing conditions of IE in Iran that is similar to the transition that occurred in most of developed nations . ChronicThe most common affected heart valves were mitral and tricuspid valves in 29.2% and 20.7% of cases, respectively. We did not perform a trend analysis in this regard. However, a recent shift toward more frequent involvement of aortic and tricuspid valves in IE patients was reported in a 16-year study of IE patients in Tehran, Iran . High prS. aureus was the most common causative pathogen that was isolated in 19% of cases, followed by viridans streptococci, enterococci and pseudomonas species. A high proportion of blood culture negative IE (BCNIE) in our study can be attributable to several factors, including high rate of prior antibiotic therapy, inappropriate timing of specimen collection, and limited microbiology resources. BCNIE has been associated with difficulty in diagnosis and treatment, and poor outcome  was poor, with more than one third IE cases die during hospital stay and one in ten of those who survived to discharge die within 6 months after discharge. Furthermore, persistent ventricular failure was detectable in 12% of IE cases who were alive at median 11-month follow up. Predictors of in-hospital and 1-year mortality were heart failure and septic shock. High rate of systemic and cardiac complications occurs in IE patients, with major embolic events and congestive heart failure were the most common complications on admission.Congenital heart disease and intravenous illicit drug using (IVDU) were the most common predisposing conditions of IE in our study while chronic rheumatic heart disease was responsible for <5% of cases of IE; the finding that highlights a shifting from rheumatic heart disease as underlying abnormality toward a congenital heart disease, followed by IVDU and prosthetic heart valves. The important role of congenital heart diseases as predisposing conditions of IE may necessitate a revision in the IE prophylaxis recommendations.A high proportion of blood culture negative IE (BCNIE) in our study can be attributed to high rate of prior antibiotic therapy, inappropriate timing of specimen collection and limited microbiology resources, as well as endemicity of some fastidious microorganisms such as Brucella species or Q fever as the causative pathogens of IE in Iran.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The patients/participants provided their written informed consent to participate in this study.HP and FH: study concept and design. FS and SK: analysis and interpretation of the data. FH, FG, AF, HA, and LB: drafting of the manuscript. All authors contributed to the article and approved the submitted version.This research was conducted with funding support from the vice-chancellery for research of Mashhad University of Medical Sciences (Research Project Number 971829).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Coronavirus disease 2019 (COVID-19) associated pulmonary aspergillosis (CAPA) has emerged as a complication in critically ill COVID-19 patients. Corticosteroids are standard of care for COVID-19 patients. Prolonged corticosteroids have been associated with an increased risk of CAPA, but duration of use associated with this risk remains unknown. The objective of this study was to evaluate if the duration of corticosteroid therapy \u2264 10 days vs > 10 days affects the risk of developing CAPA.This single-center, retrospective, cohort study included patients \u2265 18 years old admitted to University Hospital between March 2020 and December 2021, diagnosed with severe COVID-19 pneumonia requiring mechanical ventilation, and who received at least 3 days of corticosteroid treatment. CAPA was defined according to 2020 European Confederation of Medical Mycology and the International Society for Human and Animal Mycology consensus guideline. Baseline characteristics, CAPA, and secondary outcomes were compared using appropriate bivariable analyses. Steroid duration was evaluated as an independent predictor of CAPA in a logistic regression model.Final analysis included 278 patients . Baseline characteristics were similar between groups, with the exception of acute kidney injury and solid organ transplantation. Median duration of steroids was 6 days in the \u2264 10 day group vs 18 days in the > 10 day group. In total, 20/278 (7.2%) patients developed CAPA. Patients treated with > 10 days of corticosteroid therapy had significantly higher incidence of CAPA  and duration was independently associated with CAPA . Secondary outcomes including inpatient mortality , mechanical ventilation free days at 28  and secondary infections (28.4% vs 44.9% p = 0.0220) were all significantly worse for > 10 day corticosteroid cohort.Duration of corticosteroid treatment > 10 days in critically ill patients is associated with an increased risk of CAPA. Though patients may require corticosteroids for non-COVID-19 indications, clinicians should attempt to limit prolonged courses of corticosteroids in COVID-19 patients.All Authors: No reported disclosures."}
+{"text": "The wrong labels were allocated to the different parts of the pie chart in the legend.In the published article, Rossouw L, Lalkhen H, Adamson K, Von Pressentin KB. The contribution of family physicians in coordinating care and improving access at district hospitals: The False Bay experience, South Africa. Afr J Prm Health Care Fam Med. 2021;13(1), a3226. The original incorrect legend for Figure 1:Discharged (1%)Admit (91%)Transferred (8%)The revised and updated legend for Figure 1:Transferred (1%)Discharged (91%)Admit (8%)The publisher apologises for this error. The correction does not change the significance of study\u2019s findings or overall interpretation of its results or the scientific conclusions of the article in any way."}
+{"text": "In 2019, 36,801 new HIV cases were reported in the United States. Emergency Department routine HIV testing is crucial to identify new asymptomatic HIV infections. Early diagnosis followed by prompt antiretroviral therapy decreases morbidity and mortality and reduces HIV transmission. The Emergency Department (ED) at Memorial Hermann Hospital (MHH) - Texas Medical Center (TMC) in Houston, Texas, implemented an ED-routine HIV screening program in June 2017. At times, the testing for HIV yields indeterminant results. Consequences of indeterminate HIV tests include individuals unaware of their HIV infection status transmitting infection and not receiving antiretroviral therapy.th Generation (GEN) ADVIA Centaur TM Ag/Ab COMBO (Siemens)) followed by a confirmatory test (GenniusTM HIV1/HIV2). A second confirmatory test is performed if screening and first confirmatory tests yield conflicting (indeterminant) results (HIV1 RNA PCR or a repeat 4th GEN test).39,288 adults who presented to ED MHH \u2013TMC from June 2017 to March 2022 with a Glasgow score > 9 were tested using an Opt-Out protocol for HIV infection. Testing comprised a screening assay (HIV 4824 (2.0 %) patients tested positive for HIV infection; 94 (0.2%) yielded indeterminate test results. 61 (64.8%) of the patients with indeterminate findings received confirmatory testing; 37 (39.4%) before leaving the hospital . Of the 57 (60.1%) who left the hospital before confirmatory testing, 24 (42.1%) were traced and tested . 33 (35.1%) were lost to follow-up (11 of whom were reported homeless or in unstable housing).The primary cause of failure to follow up testing on patients who tested indeterminant during an ED visit is a loss of contact with the patients after leaving the ED. In turn, failure to link these patients to HIV care relates to a failure to complete confirmatory testing before completion of the hospital visit. Therefore, the quantitative results presented will enable the assessment of the best deployment of resources in capturing those patients currently lost to follow-up.Norma Perez, DO, Theratecnologies, Inc: Advisor/Consultant."}
+{"text": "Genetic defects in the development, maturation, and/or function of the immune cells can lead to Inborn errors of immunity (IEI) which may predispose patients to malignancies. The overall risk for cancer in children with IEI ranges from 4 to 25% and the type of malignancy is highly dependent on the specific mutant gene underlying IEI. We investigated 3056 IEI patients registered in the Iranian national registry between the years 1999 and 2020 in this retrospective cohort study. The frequency of malignancy and its association with the type of IEI in these patients were evaluated. A total of 82 IEI patients with malignancy were enrolled in this study. Among them, predominantly lymphoma was the most common type of malignancy (67.1%), followed by leukemia (11%), and cancers of the head and neck (7.3%). Among identified lymphoma cancers, non-Hodgkin\u2019s lymphomas were the most frequent type (43.9%) followed by different subtypes of Hodgkin\u2019s lymphoma (23.2%). Solid tumors (18.3%) appeared to be very heterogeneous by type and localization. The correlation between the type of malignancy and survival status and the association between the type of malignancy and IEI entities were unremarkable. The awareness of the association between the presence of IEI and cancer highlights the importance of a synergistic effort by oncologists and immunologists in the early diagnosis of malignancy and personalized therapeutic strategies in IEI patients.The online version contains supplementary material available at 10.1186/s13223-022-00747-2. Primary immunodeficiency disorders (PIDs) or inborn errors of immunity (IEI) are a heterogeneous group of inherited disorders, usually associated with specific gene mutations , 2. The The type of malignancy is highly dependent on the IEI subtype and the patient\u2019s age , 12. AccFor documentation, an evaluation sheet was developed to contain all patients\u2019 demographic and laboratory data as well as clinical manifestations. We screened 3056 patients diagnosed with IEI in the Iranian PID registry (IPIDR) between the years 1999 and 2020 , 18. TheWe designed a comprehensive questionnaire that included; demographic information including the patients\u2019 age at the first clinical presentation, the diagnosis and also the last follow-up visit, diagnostic delay; clinical complications such as infections, immune dysregulation, lymphoproliferative disorders and malignancies; laboratory tests data including the initial immunological work-up at the time of referral to our research center including the serum immunoglobulin titers, complete blood counts with differential, lymphocyte subsets and specific diagnostic tests for malignancies.For each patient, cancer complications before and/or after diagnosis were recorded. The diagnosis of malignancy was based on international criteria by using clinical, radiological, laboratory and histological evidence. The evaluation for cancer diagnosis was reviewed for all patients by an oncologist and a subspecialist related to the affected organ. For each record, the date of cancer diagnosis and the topography and morphology codes were obtained . Site-specific general population cancer rates were also obtained by 5-year age\u00a0groups, sex, state, and calendar year.p-value\u2009<\u20090.05 was considered statistically significant. The association between nominal variables was analyzed using the Lambda correlation coefficient.Data were analyzed using the SPSS statistical software package version 25.0 . The Shapiro\u2013Wilk test was used to validate the assumption of normality for a variable, and the nonparametric or parametric tests were carried out according to the normality assumption. A We analyzed data on malignancy types, clinical manifestations, and immunological findings from eighty-two IEI patients with malignancy , clinically diagnosed in 50 patients 61%), followed by syndromic combined immunodeficiency (CID) in 20 patients (24.4%), defects in intrinsic and innate immunity in 5 patients (6.1%), diseases of immune dysregulations in 3 patients (3.7%), non-syndromic CID in 3 patients (3.7%) and, there was one patient with unclassified IEI (1.2%) , followed by agammaglobulinemia in 7 cases (14%), selective antibody deficiency (SAD) in 2 patients (4%), hyper-IgM syndrome (HIGM) in 2 patients (4%) and, IgAD in only one patient (2%). Among CVID patients, the most prevalent malignancy was lymphoma in 27 cases (71.1%), followed by leukemia in 3 cases (7.9%), solid tumor in 5 patients (13.2%) and, benign epithelial neoplasm in only one patient (2.6). For patients diagnosed with agammaglobulinemia and malignancy, lymphoma (57.1%) and leukemia (42.9%) were the principal malignancies reported.The cancer patients with syndromic CID consisted of A-T in 15 patients (75%), hyper-IgE syndrome (HIES) in 4 patients (20%) and, Nijmegen breakage syndrome in only one case (5%). The most prevalent malignancy in A-T patients was lymphoma (66.7%), and then solid tumor in 3 cases (20%). Additionally, in HIES patients, lymphoma was presented in 3 cases (75%).Patients with innate immunodeficiency (5 cases) included chronic mucocutaneous candidiasis (CMCC) in three patients (60%) and, Mendelian susceptibility to mycobacterial diseases (MSMD) in two (40%). The type of malignancy in CMCC patients was solid tumor (2 out of 3 patients), and in two MSMD patients, solid tumor and lymphoma were reported. Two autoimmune lymphoproliferative syndromes (ALPS) patients (2 out of 3 patients) with lymphoma, and one patient (1 out of 3 patients) with regulatory T cell defect were reported in the immune dysregulation cluster. Immunodeficiencies affecting cellular and humoral immunity involved only three cases (3.7%) of leaky and hypomorphic combined immunodeficiency (CID). As the above data suggests, not all these immunodeficiencies presented an equal susceptibility to the development of cancer.p\u2009=\u20090.05 and 0.003, respectively) , whose average age was 20\u00a0years . The resSeveral studies have reported the incidence of malignancies among IEI patients. Among them, Maffeis et al. (2019) reported the incidence of tumors among 690 patients with IEI, diagnosed from 1990 until 2017 in Brescia, in which, 25 out of 690 patients (3.6%) developed 33 tumors. Of the 25 affected patients, 8 patients suffered from common variable immunodeficiency (CVID), 5 from CID, 3 AT, 2 from Hermansky-Pudlak type 2 (HSP2), 2 XLA, 2 from WAS, 2 from HIES, and 1 from SCID . Our datOur data indicated that different types of malignancy could be associated with specific types of IEI. Therefore, education of physicians about the risk of malignancies in IEI, patient monitoring and considering underlying IEI as a probable cause of malignancy in children and adolescents will optimize the diagnostic process, personalized treatment, and ultimately improve management and, eventually survival of patients. The molecular diagnosis of these IEI patients with different types of cancers should be conducted using next generation sequencing in future studies as an important step toward targeted management. Moreover, a prospective study with a larger number of patients would fully elucidate the association between malignancy and type of IEI.Additional file 1: Fig. S1: Frequency of type of malignancy based on the IUIS classification. Table 1: Immunodeficiencies affecting cellular and humoral immunity, Table 2: Combined immunodeficiencies with associated or syndromic features, Table 3: Predominantly antibody deficiencies, Table 4: Diseases of immune dysregulation, Table 6: Defects in intrinsic and innate immunity. Fig. S2: Survival analysis of cohort of 82 IEI patients with malignancies based on the IUIS classification. Table 1: Immunodeficiencies affecting cellular and humoral immunity, Table 2: Combined immunodeficiencies with associated or syndromic features, Table 3: Predominantly antibody deficiencies, Table 4: Diseases of immune dysregulation, Table 6: Defects in intrinsic and innate immunity."}
+{"text": "A total of 72% required additional laser and 60% required PPV. In the older than 50 group, 86% of vitrectomized eyes had VA improvement and 3% had decreased VA. A total of 8% required laser and 8% required reoperations. In the conventional treatment eyes, 30% improved VA and 48% had decreased VA (p < 0.05). Additional procedures required included laser in 70% and PPV in 17%. In both age groups, eyes that underwent PPV had better final visual outcomes than eyes that received conventional treatment for PDR.The purpose of this study was to evaluate the long-term, real-world outcomes of pars plana vitrectomy (PPV) for complications of proliferative diabetic retinopathy. A retrospective review involving 64 patients with proliferative diabetic retinopathy that underwent PPV in their worse-seeing eye were followed for a minimum of 8 years. The fellow eye underwent conventional treatment. Patients were divided into two groups by age: patients younger than 50 years of age and patients older than 50. In the younger than 50 group, 89% of vitrectomized eyes had improved visual acuity (VA) while 3.6% had decreased VA. A total of 14% of vitrectomized eyes required additional laser and 11% required reoperations. In the conventional treatment eyes, 25% had improved VA while 68% had decreased VA ( The prevalence of diabetes continues to increase globally. Worldwide, there are over 460 million patients with diabetes and that number is projected to increase over the next decade . In the One of the major complications and causes of severe vision loss in patients with PDR is TRDs, and repair of TRD is the most common indication for pars plana vitrectomy (PPV) in eyes with PDR . TRDs tep value of <0.05 was used to determine statistical significance. Analysis and descriptive statistics were calculated using Microsoft Excel  software version 16.64.This is a retrospective review of patients with diabetes mellitus who presented with complications of PDR requiring pars plana vitrectomy including VH, TRD, or TRRD in one eye and had conventional treatment in their other eye between 2003\u20132006. Conventional treatment included panretinal photocoagulation for PDR and focal laser to microaneurysms for macular edema initially. Anti-VEGF was not utilized initially as treatment for macular edema as it was not the standard of care at the time. Once anti-VEGF became the standard of care for macular edema, it replaced focal laser, and patients were treated with anti-VEGF if they developed center-involving macular edema. No grid focal treatment was performed. Both eyes were treated as needed during the follow-up period based on the standards of care at the time. Treatments during the follow-up period included added PRP laser for increased proliferation or mild VH, focal laser/anti-VEGF to microaneurysms for circinate exudates and center involving macular edema, phacoemulsification with intraocular lens implantation for visually impairing cataract progression, and PPV for VH, TRD, or TRRD. Patients with PDR in both eyes were included. Exclusion criteria included monocular patients, patients that had indications for PPV in both eyes at presentation, or those who had significant cataract requiring combined cataract extraction/vitrectomy. All patients completed at least 8 years of follow-up. Demographics, best corrected visual acuity (BCVA) outcomes at last follow-up, complications, and number and type of treatments required during the follow-up period were evaluated. Data were analyzed separately for patients younger than or equal to 50 years of age and patients older than 50 years at presentation. In each group, the eye that underwent initial vitrectomy was compared to the other eye of the patient, the conventional treatment eye. The study was conducted according to the tenets of the Declaration of Helsinki. Visual acuity was recorded and converted to the logarithm of the minimal angle of resolution (logMAR) for statistical analysis. A comparison of continuous variables was performed utilizing a student t-test, while categorical data were analyzed using a Chi squared test. A A total of 64 patients met the inclusion criteria and were included in the study.A total of 28 patients younger than 50 years of age were included. Average age was 40 years (range 21\u201349) and mean self-reported duration of diabetes was 18 years (range 10\u201330). Mean hemoglobin A1c was 10.7 (range 8\u201314). Average follow-up was 9.5 years (range 8\u201317). All patients were bilaterally phakic. Nineteen eyes (68%) were lost to follow-up for 6 months or more during the 8-year period. .p < 0.05). At last follow-up, BCVA improved in 25 eyes (89%) and decreased in one eye (3.6%). Two eyes (7%) had final BCVA of hand motion (HM) or less. Procedures required during the follow-up period included additional laser in four eyes (14%)  and re-operation with PPV in three eyes (11%) for RRD in one eye (with C3F8 tamponade) and recurrent VH (no tamponade used) in two eyes. Cataract progression occurred in 11 eyes (40%) with six eyes (21%) undergoing phacoemulsification with intraocular lens (phaco/IOL) implantation for visually impairing cataracts. Two eyes (7%) developed glaucoma, with one eye requiring filtering surgery (3.5%). On average, additional procedures required occurred at 25.4 months (range 1 m\u201311years). (p = 0.90).In the eye initially treated with vitrectomy, indications for surgery included TRD in 15 eyes (54%), TRRD in two eyes (7%), and VH in 11 eyes (39%). A total of 17 eyes (60%) underwent PPV with hyaloid removal and laser photocoagulation and 11 eyes (40%) had PPV with laser photocoagulation and gas tamponade with C3F8. Mean pre-op BCVA was 20/200 (range 20/80\u2013LP) and final BCVA was 20/80 (range 20/30\u2013LP) (1years).  Comparinp < 0.05). At last follow-up, BCVA improved in seven eyes (25%) and decreased in 19 eyes (68%). Ten eyes (35%) had a final BCVA of HM or less. Procedures required during the follow-up period included additional laser in 20 eyes (72%), in 17 for PDR and in three for macular edema, anti-VEGF with bevacizumab for macular edema in two eyes, and PPV in 17 eyes (60%). Indications for surgery during the follow-up period were TRD in 12 eyes (43%), TRRD in four eyes (14%), and VH in one eye (3.6%). Four eyes (14%) developed glaucoma and seven eyes (25%) had cataract progression with three eyes undergoing phaco/IOL (11%). On average, additional procedures required occurred at 28.3 months (range 2 m\u20130 years). There was no difference in timing of additional procedures between the vitrectomized and conventional therapy eyes (p = 0.68). Statistically significant differences (p < 0.05) were present between the initially vitrectomized eyes and the conventional therapy eyes in terms of initial and final BCVA, percent improvement in BCVA and percent worsening in BCVA, and additional procedures required. At final follow-up, no patients were scheduled to receive specific treatments and all patients were scheduled to follow at 6\u201312-month intervals.In the eye treated with conventional therapy, average initial BCVA was 20/80 (range 20/20\u2013HM), while mean final BCVA was 20/400 (range 20/30\u2013NLP)  and average self-reported duration of diabetes was 18 years (range 4\u201330). Average hemoglobin A1c was 9.4 (range 6.4\u201312). Mean follow-up was 9.3 years (range 8\u201314). Three patients were bilaterally pseudophakic and 33 patients were bilaterally phakic. Nineteen eyes (53%) were lost to follow up for 6 months or more during the 8-year period.p < 0.05). At last follow-up, BCVA improved in 31 eyes (86%) and decreased in one eye (3%). Five eyes (14%) had final BCVA of count fingers (CF) or less. Procedures required during the follow-up period included additional laser in three eyes (8.3%), in two eyes for progressive neovascularization and in one eye for macular edema, anti-VEGF with bevacizumab for macular edema in one eye, and re-operation with PPV with laser and no tamponade for rebleeding in three eyes (8.3%). Visually significant cataracts requiring phaco/IOL occurred in 16 eyes (44%), and five eyes (14%) developed glaucoma. On average, additional procedures required occurred at 32.1 months (range 1 m\u20134years) (p = 0.86).In the eye initially treated with vitrectomy, indications for surgery included TRD in 10 eyes (28%), TRRD in two eyes (5%), and VH in 24 eyes (67%). A total of 26 eyes (72%) underwent PPV with hyaloid removal and laser photocoagulation and 10 eyes (28%) had PPV with laser photocoagulation and gas tamponade with C3F8. Mean pre-op BCVA was 4/200 (range 20/200\u2013LP) and final BCVA was 20/80 (range 20/40\u2013HM) (\u20134years) . Comparip = 0.48). Statistically significant differences (p < 0.05) were present between the initially vitrectomized eyes and the conventional therapy eyes in terms of initial and final BCVA, percent improvement in BCVA and percent worsening in BCVA, and additional procedures required. At final follow-up, no patients were scheduled to receive specific treatments and all patients were scheduled to follow at 6\u201312-month intervals.In the eye treated with conventional therapy, average initial BCVA was 20/100 (range 20/25\u201320/400), while final mean BCVA was 20/200 (range 20/30\u2013NLP). At last follow-up, BCVA improved in 11 eyes (30.5%) and decreased in 17 eyes (48%). Thirteen eyes (36%) had BCVA of 5/200 or less. Procedures required during the follow-up period included additional laser in 25 eyes (69%), with 20 eyes requiring laser for PDR and five eyes for macular edema, anti-VEGF with bevacizumab in one eye for macular edema, and PPV in six eyes (17%) for TRD. Six eyes (17%) developed glaucoma and six eyes (17%) had cataract progression, with five eyes (14%) undergoing phaco/IOL for visually significant cataracts. One eye required enucleation for phthisis. On average, additional procedures required occurred at 24.9 months (range 2 m\u20137 years). There was no difference in timing of additional procedures between the vitrectomized and conventional therapy eyes  initial treatment with vitrectomy was associated with greater improvement of visual acuity and less additional procedures at final follow-up compared to eyes treated with conventional therapy, and (2) younger patients treated with conventional therapy had greater rates of needing subsequent PPV compared to older patients.Overall, initial vitrectomy surgery was associated with significant improvement in final visual acuity in both the younger and older age groups compared to conventional therapy. These findings are prescient since the eyes undergoing initial vitrectomy had more advanced disease relative to the other eye, yet they had better final visual acuities. Given the long-term follow-up period of at least 8 years in these patients, initial vitrectomy surgery seemed to have provided a stabilizing and protective effect to the eye against the progression of PDR.In our study, the younger group of patients that were treated with conventional therapy required more PPV interventions compared to the older group during the follow-up period. This is possibly related to the status of the hyaloid, with older patients more likely to have a complete PVD. Although, multiple eyes initially treated with vitrectomy required additional procedures during the follow-up period, there was no difference in final BCVA between those that did not require additional procedures and those that did, indicating that the additional procedures were likely not providing further baseline VA gains compared to initial PPV. Studies have demonstrated that progression of DR is dependent on the status of the vitreous . In a stThe ideal time to perform PPV in eyes with complications of DR remains controversial. The only large study that evaluated the benefits of performing earlier vitrectomy vs. observation was the Diabetic Retinopathy Vitrectomy Study (DRVS) in 1985 . In the One limitation was the number of patients lost to follow-up. Obeid et al., have shown the frequency and detrimental effects of missed appointments in diabetic patients, particularly in eyes treated with anti-VEGF vs. PRP . NeverthThe cost of diabetes care is significant and worldwide many patients are challenged to keep numerous appointments and pay for costly ophthalmological treatments, including anti-VEGF injections. Severe complications of diabetes affect socioeconomically challenged patients disproportionately, resulting in poorly insured and uninsured patients exhibiting more end-stage renal disease and blindness. In the US, 25% of all healthcare expenditures go to the care of diabetes and its complications . In a coOur study shows real-world long-term results of eyes of patients with diabetes treated for complications of DR. During the 8-year follow-up period, many patients missed appointments, failed to come in expeditiously when visual acuity decreased, and presented with advanced disease despite having photocoagulation. Patients that were lost to follow-up for a period of time were included in the analysis and were found to have significantly worse BCVA, underscoring what happens in real-world retina practices and not in patients closely followed within a study protocol. The results of this study demonstrate the stabilizing effect of vitrectomy on PDR disease progression. Strengths of this study include the long-term follow-up data of at least 8 years. Weaknesses include the retrospective nature, patients lost to follow-up for periods over 6 months, and the lack of hyaloid status assessment. It is important to note that patients lost to follow-up for a period of time were included in the analysis, representing a real-world scenario, but this confounds final BCVA between groups and represents a limitation for the study. Future studies should investigate outcomes based on hyaloid status rather than age, since these would provide more information regarding the ideal timing of vitrectomy in eyes with advanced PDR to prevent complications."}
+{"text": "Background: This cross-sectional study investigated the prevalence of, and factors associated with, filled prescription medications (FPMs) among United States (US) service members (SMs).Methods: A stratified random sample of active duty SMs from the Air Force, Army, Marine Corps, and Navy was obtained from military workforce records. Participants  completed a questionnaire on demographics, physical characteristics, and lifestyle factors and approved access to their FPM for the previous 6\u00a0months. FPMs were obtained from the military Pharmacy Data Transaction Service that included all prescription medications dispensed at military medical treatment facilities, abroad, at retail pharmacies in the US, and/or through mail-order programs.Results: About two-thirds (65%) of SMs had \u22651 FPM in the 6\u00a0months surveillance period. Central nervous system (CNS) agents had the highest prevalence (41%), followed by anti-infective agents (20%), eye/ear/nose/throat preparations (20%), gastrointestinal drugs (18%), autonomic drugs (17%), skin and mucous membrane agents (13%), antihistamine drugs (12%), respiratory tract agents (12%) and cardiovascular drugs (9%). Among CNS agents, overall prevalence of dispensed non-steroidal anti-inflammatory drug (NSAIDs) was 30%. The odds of any FPM was independently associated with female gender, older age, higher body mass index, former tobacco use (smoking and smokeless tobacco), lower alcohol consumption, and was highest among Army, lowest among Marine Corps personnel.Conclusion: In this sample of SMs, dispensing of prescription medication was high, especially NSAIDs, but dispensing of cardiovascular drugs was much lower compared to the general US population, likely because of the younger age and higher level of physical activity of SMs. Prescription medications (PMs) are provided to patients for treatment of specific medical conditions and are considered important components of treatment guidelines for many types of medical disorders . SpendinExamining broad patterns of PM use in representative samples can provide useful information on the most common classes of PMs prescribed in clinical practice. An important area of interest in pharmacoepidemiology is the types and distribution of PMs offered to patients . There hThe United States Department of Defense Pharmacy Data Transaction Service (PDTS) records all prescriptions dispensed to United States military SMs . This prThis cross-sectional investigation was a secondary analysis of data from a study designed to investigate the effects of dietary supplements on SM health . The NavDetails of the sampling frame, solicitation of SMs, subject recruitment flow chart, sample size determination, and response bias have been previously reported . BrieflyThe online survey was designed to provide information on participant demographics, physical characteristics, and lifestyle factors. Demographics included questions on gender, date of birth (for age), education level, and military service. Physical characteristics included questions on height and weight. Lifestyle characteristics included questions on the frequency and duration of aerobic and resistance training, and use of cigarettes, smokeless tobacco, and alcohol. For cigarettes and smokeless tobacco use individuals reported if they had never smoked/used, if they smoked/used but quit (and the date they quit) and if they smoked/used \u2264 3 times/week, 4\u20136\u00a0times/week or every day. For alcohol, SMs were asked to report on the typical amount and frequency of consumption of beer, fermented fruit drinks, wine, and liquor; examples of each were provided on the questionnaire.Once participants were identified by completing the informed consent and questionnaire, the list of these SMs was sent to the Armed Forces Health Surveillance Branch of the Defense Health Agency (DHA). From the Defense Medical Surveillance System relational database , the DHAThe AHFS is a system for classifying drugs based on physiological changes induced by the drug (therapeutic action) and mechanisms of action at the molecular level . Drugs are classified by 6-digit numbers containing three levels of information. The first tier is the broadest classification and subsequent tiers are more specific. For example, the first tier number 28 identifies \u201ccentral nervous system agents\u201d; the second tier 28:08 identifies \u201canalgesics and antipyretics\u201d; the third tier 28:08:04 identifies \u201cnonsteroidal anti-inflammatory agents\u201d.2 (kg/m2). Weekly duration of aerobic and resistance training (min/week) was calculated by multiplying reported weekly exercise frequency (sessions/week) by the reported duration of training (min/session). Alcohol consumption was quantified using the National Institute of Health assumption that a \u201cstandard drink\u201d contained 17.74\u00a0ml of alcohol  Version 26, 2019 . Body mass index (BMI) was computed from the questionnaire responses as weight/height alcohol . StandarFPMs were classified by their first tier 2 digit codes in the AHFS Pharmacologic-Therapeutic Drug Classification (PTDC) . Included was a classification for \u201cany FPM\u201d that encompassed all PTDCs. First tier PTDCs with the highest prevalence (\u226510%) were further analyzed through their third tier 6-digit codes . If no prescription was filled in a first tier PTDC it was not included as a category in tables. For prevalence calculations, an individual could be included in >1 PTDC if they had a FPM in other PTDCs, but they were only included once within a specific PTDC regardless of the number of FPMs within the 6-months surveillance period. When calculating the total number of prescriptions, all were counted including multiple refills by SMs.n = 24,942; 93% of sample).FPM prevalence (percent) with 95% confidence intervals (95%CI) was calculated for each first tier PTDC for the entire sample and stratified by gender and age. Prevalence was also calculated for the entire sample third tier PTDCs where the prevalence in the first tier was \u226510%; these values are reported in the text. Prevalence calculation was (number of SMs with \u22651 FPMs in PTDC)/ X 100. Univariable logistic regression examined differences in FPM prevalence (dependent variable) across various strata of the demographic and lifestyle characteristics (independent variables). A reference stratum of each characteristic was defined with an odds ratio (OR) = 1.00 and other strata of that variable were compared to the reference stratum. Where variables were ordinal , chi-square tests for linear trend (Mantel-Haenszel statistics) were also performed. Multivariable logistic regression determined the odds of any FPM (dependent variable) adjusted for all demographic and lifestyle factors (independent variables). Since logistic regression requires complete data on all variables, only participants who completed all demographic and lifestyle items on the questionnaire were included in the multivariable analysis  were successfully contacted  and of these, 26,680 (18.2%) signed the informed consent and completed the questionnaire.From the sample frame of 200,000 SMs, 73%  (29.9%), followed by opiate agonist (10.1%), miscellaneous analgesics and antipyretics (9.6%), and antidepressants (7.6%). The most prevalent anti-infective agents in the third tier categories were cephalosporins (5.1%), aminoglycosides (3.6%), and quinolones (3.1%). The most prevalent eye/ear/nose/throat preparations in the third tier categories were miscellaneous anti-infectives (7.8%), miscellaneous anti-glaucoma agents (7.1%), and miscellaneous anti-inflammatory agents (4.3%). The most prevalent gastrointestinal drugs in the third tier categories were antihistamines (5.2%), protectants (5.0%), and miscellaneous gastrointestinal drugs (4.5%). The most prevalent autonomic drugs in the third tier categories were centrally acting skeletal muscle relaxants (8.0%), \u03b1- and \u03b2-adrenergic agonists (5.2%), and \u03b2-adrenergic agonists (2.5%). The most prevalent skin and mucous membrane agents in the third tier categories were scabicides and pediculicides (4.6%), corticosteroids (3.5%), and anti-bacterials (2.8%). Among antihistamine drugs, the most prevalent third tier categories were second-generation antihistamines (10.1%), ethanolamine derivatives (1.7%), and phenothiazine derivatives (1.0%). Among respiratory tract agents, the most prevalent third tier categories were antitussives (5.5%), mast cell stabilizers (5.4%), and miscellaneous respiratory agents (1.6%).p < 0.01), but not for aerobic exercise (p = 0.07).The present study involving a large sample of SMs  found that 65% of SMs had at least one FPM in a 6-month period. When FPMs were placed into AHFS PTDCs, the most often used drug classes  were CNS agents (41%), anti-infective agents (20%), eye/ear/nose/throat preparations (20%), gastrointestinal drugs (18%), and autonomic drugs (17%). When drugs were further sub-classified by their tier PTDCs those with the highest prevalence included NSAIDs (30%), miscellaneous analgesics and antipyretics (10%), centrally acting skeletal muscle relaxants (8%), miscellaneous anti-infectives (8%), antidepressants (8%), miscellaneous anti-glaucoma agents (7%), \u03b1- and \u03b2-adrenergic agonists (5%), antihistamines (5%), cephalosporins (5%), and protectants (5%). FPMs were independently associated with female gender, older age, higher BMI, former tobacco use (smoking and smokeless tobacco), lower alcohol consumption, and service in the Army or Air Force compared to the Marine Corps. A large majority of ambulatory visits in the military services are accounted for by injuries and diseases of the musculoskeletal system  at leastThe prevalence of any FPM in the present sample (65%) was generally higher than in nationally representative civilian samples. One study  in 1998\u2013There has only been one previous study  of FPMs Comparisons of specific PTDCs in the present study with that of previous studies involving representative samples of the US population are complicated by the use of different categorization systems, methods of data collection, and diverse reporting periods . In addition, military access to healthcare and PMs are totally free of charge (no copays), as mentioned earlier. Kantor et al.  analyzedData from NHANES  and othe2) and obese (BMI \u226530.0\u00a0kg/m2) individuals utilize more health care than their normal weight (BMI 18.5\u201324.9\u00a0kg/m2) counterparts  and obese (\u226530.0\u00a0kg/m2) soldiers were musculoskeletal system and connective tissue disorders, mental health, and endocrine/nutritional/metabolic disorders  and those who had never used. A causal relationship has been established between smoking and many types of medical problems including cardiovascular disease, certain cancers, respiratory diseases, reproductive health problems, and other health maladies . Health The reduction in the prevalence of FPMs with increasing alcohol consumption may be associated with patients voluntarily reducing consumption when taking PMs. Many PMs interact with alcohol by interfering with metabolism of the drugs through mechanisms involving absorption, distribution, metabolism, or excretion, or by enhancing the influence of PMs at the effector site . There aThe lack of association between FPMs and the duration of weekly aerobic exercise and resistance training in the multivariable analyses was surprising because higher levels of physical activity are generally associated with lower health care utilization and health care costs . One natThe current study recruited a large stratified random sample of SMs from all branches of the United States military. The pharmacy database used in this study contained virtually complete information on medications dispensed to SMs thus providing a comprehensive assessment of FPMs provided to SMs. However, filling a prescription does not imply conformity with the prescription regime and data on actual compliance was not available. The FPMs examined here were only those prescribed by medical care providers and obtained through pharmacy channels. Medications that SMs obtained over-the-counter without a prescription  were not included. Nonetheless, prescriptions provided to active duty military personnel are free of charge so SMs are more likely to use the medical/pharmacy route to obtain medications than civilians making comparisons to civilian data challenging. Another limitation was that compared with the requested stratified sample  respondent demographics differed slightly . NonetheIn the current study, 65% of SMs had \u22651 FPM in a 6-month period. The most often filled prescriptions were in drug classes CNS agents (41%), anti-infective agents (20%), and eye/ear/nose/throat preparations (20%). FPMs were independently associated with female gender, older age, higher BMI, former use of tobacco (smoking and smokeless tobacco), lower alcohol consumption, and service in the Army or Air Force compared to the Marine Corps. Comparisons with the previous military study  suggests"}
+{"text": "Objectives: Post-cholecystectomy syndrome (PCS) refers to the continuation or recurrence of biliary colic and any other gastrointestinal symptoms present prior to cholecystectomy. Given that PCS is rare and underestimated in Saudi Arabia, this study aimed to determine the prevalence of PCS among Saudis.Methods: This cross-sectional study included randomly gathered subjects who self-administered the validated European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire from September 6 to October 7, 2022.Results: A total of 518 participants who underwent cholecystectomies were included; most were female (73.6%), 153 (29.5%) were 19 to 25 years old, and the vast majority were Saudi Arabian (91.1%). The average preoperative weight was 71 \u00b1 20.7 kg (range 20 to 258), and the mean current weight was 69 \u00b1 19.4 kg (range 30 to 257). About 137 (26.4%) had a chronic disease, most frequently hypertension (37.2%). In the past week, most participants experienced some trouble doing strenuous activities (42.9%), slight pain (37.6%), fatigue (32.2%), insomnia (37.5%), and weakness (38.2%). There were no significant associations between age, nationality, or residence with the QLQ-C30 score . A significant association was observed between gender and QLQ-C30 score , with females scoring higher than their male counterparts. Females also reported having a higher quality of life than males.Conclusions: The prevalence of PCS was higher than reported elsewhere. Gallstones and other gallbladder problems are commonly treated with cholecystectomy . LaparosGallstone disease continues to be one of the most common digestive disorders in the world. The rate of gallstone formation increases with age. In recent years, ultrasonographic data on the incidence of gallstones have been reported. The reported incidence of gallstones in the United States is about 10%-15%, with millions of new cases diagnosed each year. Although the true incidence of gallstones in Saudi Arabia is unknown.Since its successful implementation in 1987, laparoscopic cholecystectomy (LC) has rapidly become the standard treatment for symptomatic gallstone disease. It is already well-established in Saudi Arabia . GallstoIn general, the diagnosis, clinical symptoms, and management of gallstones are the same for cholesterol and pigment stones but mostly depend on the location of the stone. Patients with gallbladder stones may experience biliary colic, which is described as episodic attacks of severe pain in the right upper quadrant or epigastrium lasting at least 20-30 minutes, with pain radiating to the right back or shoulder, which improves with analgesics .Abdominal ultrasonography and endoscopic retrograde cholangiography are the preferred modalities for diagnosis . CholecyPost-cholecystectomy syndrome (PCS) refers to the continuation or recurrence of upper abdominal pain (primarily the right upper quadrant)\u00a0and several gastrointestinal symptoms comparable to those seen before cholecystectomy. This condition might be the persistence of symptoms produced by gallbladder pathology or\u00a0the appearance of new symptoms that are usually linked to the gallbladder.\u00a0For the first time in 1947, Womack and Crider defined post-cholecystectomy syndrome as \"the presence of symptoms after cholecystectomy\u201d . SymptomPCS affects at least 15% of people, and symptoms might appear for anywhere from days to years . There aAny patient with PCS requires symptomatic treatment and a thorough workup to determine the exact cause of the symptoms; liver functions and abdominal ultrasounds are usually the first tests requested, with further investigations customized accordingly . ComputeStudy designA cross-sectional study was designed to assess the prevalence of PCS among the communities of Saudi Arabia. The minimum sample size required was 385 subjects representative of the Saudi population (32 million) with a confidence level (CL) of 95% and a confidence interval (CI) of 5%. Only completed surveys were included.Data collectionA sample of 518 individuals was collected randomly using a self-administered validated Arabic version of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire on the website and trained medical students through interviewing the general population from September 6 to October 7, 2022. The socio-demographic data were assessed for all participants.\u00a0In addition to the EORTC QLQ-C30 questionnaire to determine the prevalence of post-cholecystectomy syndrome (PCS) in Saudi Arabia.EORTC QLQ-C30The EORTC Core Quality of Life questionnaire (EORTC QLQ-C30) is designed to measure cancer patients' physical, psychological and social functions. The questionnaire is composed of multi-item scales and single items. It has been translated and validated into over 100 languages and is used each year in more than 5,000 studies worldwide.Statistical analysisAll data were recorded in a pre-designed and validated excel sheet. Data were represented in terms of frequencies and valid percentages for categorical variables. Data were analyzed using IBM Corp. Released 2015. IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY: IBM Corp.\u00a0to perform all statistical calculations.Ethical considerationsEthics approval was obtained from the Research and Studies Department at the Directorate of Health Affairs in Taif . Participant identity was kept confidential.A total of 518 participants who underwent cholecystectomy were enrolled in the current study; most were females (73.6%), while 137 (26.4%) were males. Regarding age groups, 19 (3.7%) of the participants were aged less than 18 years, 153 (29.5%) were 19 to 25 years old, 137 (26.4%) were 26 to 35 years old, 115 (22.2%) were 36 to 45 years old, 62 (12%) were 46 to 55 years old, and 32 (6.2%) were aged 55 years old. The vast majority were of Saudi Arabian nationality (91.1%), and 46 (8.9%) were of non-Saudi nationality. More than one-third of the participants (36.9%) were residents of Makkah, 64 (12.4%) were from Riyadh, and 56 (10.8%) were from Madinah. The average preoperative weight of the participants was 71 \u00b1 20.7 kg (range 20 to 258), and 69 \u00b1 19.4 kg (range 30 to 257) was their present average weight. Most of the participants were in the healthy weight range both preoperatively (36.7%) and currently (37.8%). About 137 (26.4%) had a history of chronic diseases (Table The most reported chronic disease among the study participants was hypertension (37.2%), followed by asthma (36.5%), diabetes mellitus (33.6%), anemia (6.6%), and heart diseases 5.1%), while 10.9% had other chronic diseases , the EORTC QLQ-C30 questionnaire was used. Our results revealed that after the surgery, most of the participants had a little trouble doing strenuous activities, like carrying a heavy shopping bag or a suitcase (42.9%) or walking long distances (37.3%), while more than half had no trouble walking short distances outside of the house (56.2%) and about one-third (31.7%) had a little trouble in walking short distances. Most respondents did not need to stay in bed or a chair during the day (39%) or help with eating, dressing, washing, or using the toilet (74.9%). Most participants were slightly restricted in their work or other daily activities (42.5%) and slightly restricted in pursuing their hobbies or other leisure time activities (41.3%).After the surgery, the majority of the respondents did not experience shortness of breath (48.3%), loss of appetite (35.3%), vomiting (46.9%), constipation (43.6%), or diarrhea (53.9%), while about one-third experienced slightly from shortness of breath (34.4%), loss of appetite (34%), vomiting (31.9%), constipation (31.9%), and diarrhea (26.6%). Most of the participants experienced slight pain (37.6%), the need to rest (32.2%), trouble sleeping (37.5%), weakness (38.2%), slight nausea (37.8%), and tiredness (38.8%).38.6% of the participants reported that their pain did not interfere with their daily activities, and 59.7% had no difficulty concentrating on things\u00a0like reading a newspaper or watching television. The majority of the respondents did not experience stress 42.3%), worry (42.1%), annoyance (41.9%), or depression (50.2%), while about a one-third experienced slight stress (35.5%), worry (35.7%), annoyance (33.8%), and depression (27.4%). Also, most of the participants did not have difficulty remembering things (56%), and their physical condition or medical treatment did not interfere with their family life (65.4%), social activities (64.5%), or financial status (67.4%)  stated that they were in good health, 139 (26.8%) had very good health, and 109 (21%) had excellent health, while 31 (6%) of the participants had very poor health and 18 (3.5%) had poor health  stated that they had a good quality of life, 139 (28.8%) had a very good quality of life, and 109 (22.4%) had an excellent quality of life. In comparison, 31 (4.1%) of the participants had a very poor quality of life, and 18 (5.4%) had a poor quality of life . A significant association was observed between gender and QLQ-C30 score ; females had higher scores compared to males  of the participants were between 19 to 25 years old, and the vast majority were Saudi Arabian (91.1%). More than one-third of the participants (36.9%) were residents of Makkah. The average preoperative weight of the participants was 71 kg. More than one-third of participants had healthy weight preoperatively (36.7%) or currently (37.8%). One-quarter (26.4%) of the participants had a history of chronic diseases. The most reported chronic disease among the study participants was hypertension (37.2%), followed by asthma (36.5%), diabetes mellitus (33.6%), and heart disease (5.1%), while 10.9% had other chronic diseases. This was consistent with the findings reported in the study conducted by Chen et al., which reported the association between cholecystectomy and previous gallstone disease and metabolic syndrome, including DM, hypertension, and cardiovascular diseases .Most of the participants had a little trouble doing strenuous activities, like carrying a heavy shopping bag or a suitcase (42.9%) or walking long distances (37.3%), while more than half (56.2%) had no trouble walking short distances outside of the house. More than one-third (39%) of the respondents did not need to stay in bed or a chair during the day. Less than half of the participants (42.5%) were slightly restricted in their work or other daily activities;\u00a0also, they were slightly restricted in pursuing their hobbies or other leisure time activities (41.3%). About one-third experienced shortness of breath (34.4%), loss of appetite (34%), vomiting (31.9%), constipation (31.9%), and diarrhea (26.6%). Most of the participants experienced slight pain (37.6%), need to rest (32.2%), trouble sleeping (37.5%), and weakness (38.2%), the percentage of the previously mentioned symptoms were found to be higher compared to the parallel study which carried out by Talsethet al. in which most of the previously mentioned symptoms were reported in only less than 10% of the participants, and this could be attributed to genetic and environmental factors .More than one-third (38.6%) of the participants had pain, but no interference with their daily activities, and more than half (59.7%) had no difficulty concentrating on things like reading a newspaper or watching television. About one-third experienced slight stress (35.5%), worry (35.7%), annoyance (33.8%), and depression (27.4%). This was consistent with the findings of the congruent study conducted by Jen et al., in which post-cholecystectomy pain could result in depression, subsequently affecting the quality of life .Regarding the overall health status of the participants,\u00a0less than half (42.7%) stated that they had good health, 139 (26.8%) were in very good health, and 109 21%) had excellent health. In comparison, 31 (6%) of the participants had very poor health, and 18 (3.5%) had poor health;\u00a0these percentages were found to be higher compared to the other study conducted by Dalboet al. in which only 50% of participants were having a positive perception about their health [% had excMore than one-third (39.4%) stated that they had a good quality of life, (28.8%) had a very good quality of life, and 22.4%) had an excellent quality of life, while (4.1%) of the participants had a very poor quality of life and (5.4%) had poor quality of life, similar findings were found in the parallel study conducted by Atif et al. which also revealed that most of the participants had improved quality of life following cholecystectomy [.4% had aThere were no significant associations between age, nationality, and residence with the QLQ-C30 score. A significant association was observed between gender and QLQ-C30 score. Females had higher scores than males, which contradicts another study by Michelson et al. in which women were found to have lower quality-of-life scores compared to males .Due to the self-reported questionnaire used in this study, there are some limitations, including some personal bias due to some participants answering the questions randomly. As well, the questionnaire was distributed online, which may result in some sampling bias toward younger participants who regularly use online means.The prevalence of post-cholecystectomy syndrome was found to be high. Participants had good satisfaction with their health. Females reported higher quality-of-life scores than males. These findings should be considered by Saudi healthcare professionals to raise awareness of the symptoms and risks of PCS in the Saudi community."}
+{"text": "To prevent the spread of SARS-CoV-2, containment measures were implemented leading to huge healthcare changes worldwide. This study aimed to describe the impact of COVID-19 pandemic on surgical oncology healthcare in a large Italian sample.A retrospective observational study included 99651 patients admitted to the hospitals of Piedmont  to undergo oncological surgery, provided in ordinary hospitalization. We compared data of 2020 with 2016-2019 mean values. Data were stratified by tumor site, year, month and admission way. Chi-squared tests were used to assess differences in the percentage of admission modes between 2020 and 2016-2019.An overall reduction in oncological surgery (-12.3%) was observed in 2020 (n = 17923) compared to the mean of period 2016-2019 (n = 20432). A relevant decrease began in March (-11%), continued in April (-18%) and peaked in May (-26%). There was a greater reduction in surgery of breast (-19.2%), bladder (-17.5%), colorectal (-16.5%), kidney (-14.2%), prostate (-14%). Little or no difference was observed for liver (-5.2%), body of uterus (-0.54%), ovary (-0.07%), lymphoma (+4.5%). There was a marked reduction of non-emergency admissions (-13.6%), in particular for some tumor sites: colorectal (-19.4%), breast (-19.4%), bladder (-18.7%). The overall volume of surgeries following an emergency access was unchanged (-0.3%). The proportion of hospitalizations with emergency access increased (p < 0.001).Our results highlight the burden of the reduction in cancer surgery in 2020 and the risk of delays in diagnosis and treatment for time-dependent conditions. For cancers that can be diagnosed early thanks to screening, the reduction in surgery is likely to be an indirect consequence of discontinuing screening activities. Therefore, further studies are needed to assess, as soon as data are available, the trend in 2021, and to compare our results with those reported in other European countries.\u2022\u2002The COVID-19 pandemic caused a significant decline in cancer surgeries in 2020 in Piedmont, Italy. It is necessary to compare our results with those reported in other European countries.\u2022\u2002These results show an increase in the proportion of oncological surgical admissions following emergency access in 2020 compared to the average for 2016-2019."}
+{"text": "Due to the ongoing coronavirus disease 2021 pandemic and lockdown, eye care services have been compromised globally. The magnitude of ocular diseases across all populations in Nepal are few and far between and rare during this pandemic. This study was aimed to find out the prevalence of ocular morbidity among patients visiting the department of Ophthalmology of a tertiary care hospital during the pandemic.A descriptive cross-sectional study was conducted among the patients visiting the department of Ophthalmology of a tertiary care hospital from 18 August 2021 to 30 September 2021. Ethical clearance was taken from the Institutional Review Committee (Reference: 078/079023). Convenience sampling was done. Basic demographic data, clinical characteristics, visual status and prevalence of ocular morbidities were noted. Data entry was done using Statistical Package for the Social Sciences version 26. Point estimate at 95% Confidence Interval was calculated along with frequency and percentage for binary data.Out of 650 study subjects examined, 454 (69.8%)  study subjects had at least one ocular morbidity in at least one eye. Refractive error 153 (33.7%) was the commonest ocular morbidity followed by headache 52 (11.5%), dry eyes 50 (11%), non-communicable diseases related ocular morbidity 41 (9%), and age related cataract 37 (8.1%).The prevalence of ocular morbidity in our study was higher than findings from other similar studies done at national and international levels, though the causes of ocular morbidity was similar. Studies depicting the magnitude of ocular diseases across all populations in Nepal are few and far between and rare during COVID-19 era.6The coronavirus disease 2019 (COVID-19) has exposed the health systems of many countries including Western and Lower-middle-income countries like Nepal, the effect of COVID-19 and lockdown has been severe.This study was aimed to find the prevalence of ocular morbidity among patients visiting the Ophthalmology outpatient department (OPD) of Chitwan Medical College (CMC) - Teaching Hospital during the second wave of COVID-19 pandemic and lockdown restrictions.This descriptive cross-sectional study was done in Chitwan Medical College (CMC) - Teaching Hospital among the patients visiting the Department of Ophthalmology. After obtaining ethical clearance from Institutional Review Committee (IRC), (Ref: CMC-1RC/078/079-023) the study was commenced and conducted over a period of one month from 18 August - 30 September 2021 post IRC approval during COVID-19 pandemic with lockdown measures on. All patients visiting the department of Ophthalmology willing to get enrolled in the study were included in the study. The patients who were not willing, who did not provide an informed consent, patients with chronic debilitating systemic conditions, patients encountered in emergency wards were excluded from the study. Convenience sampling technique was used, and the sample size was calculated using the formula,2 \u00d7 p \u00d7 q / e2n\u2003= Z2 \u00d7 0.155 \u00d7 (1-0.155) / (0.04)2\u2003\u2003= (1.96)\u2003\u2003= 306Where,n= required sample size,Z= 1.96 at 95% Confidence Interval (CI)6p= prevalence of ocular morbidity reported by a similar study, 15.5%q = 1-pe = margin of error, 4%The required sample size was 306. As convenience sampling was done, the sample size was doubled to 612. Considering non-respondent rate of 5%, total sample size becomes 643. However, our study included 650 study subjects.7 was used to grade the HR status.In a safe environment with strict COVID-19 precautions protocol set by CMC-Teaching Hospital, the study subjects were examined. When in doubt, and before admission the study subjects were advised to undergo a real-time polymerase chain reaction (RT-PCR) test for COVID-19 infection. After explaining the purpose of the study and confidentiality of data collection, informed consent was obtained from each participant or parent/guardian in the case of a small child. The study participants were evaluated in detail in the following sequence: visual acuity measurement of each eye separately (unaided and with a pinhole), extra-ocular movement assessment, cover test, cover-uncover test, refraction using a Heine Beta 200 retinoscope, anterior segment examination with a slit lamp, and dilated fundus examination using an indirect ophthalmoscope using +90 D Volk lens, Tropicamide eye drops were used for fundus dilatation. Keith Wagener and Barker's classification of Hypertensive Retinopathy (HR)8In addition, a new proposed classification for HR based on fundus findings correlated with optical coherence tomography findings where applicable was also used to detect accurate retinopathy status.9 (ETDRS). Schirmer's test, tear film break-up time (TBUT), clinical activity score for thyroid eye disease patients, fluorescein staining, intraocular pressure (IOP) measurement, syringing were done in subjects where indicated.The stages of diabetic retinopathy were graded using Early Treatment Diabetic Retinopathy StudyThe participants were advised to undergo investigations and or admissions when and where necessary. The patients not willing to provide informed consent were automatically excluded from the study. A refractive error diagnosis was made in the following way, for myopia any refractive error more than -0.5Dioptre (D) and for hypermetropia +1.0D. An interobserver value of Kappa was used for the validity of diagnosis and any value more than 0.8 was considered strong agreement.Statistical Package for the Social Sciences (SPSS) version 26 was used for data entry and analysis. Descriptive statistics were applied, and results were expressed as frequencies whereas continuous variables were expressed as mean\u00b1SD or median. Point estimate at 95% CI was calculated along with frequency and percentage for binary data.Out of 650 study subjects were examined, 454 (69.8%)  study subjects had at least one ocular morbidity in at least one eye. Refractive error 153 (33.7%) was the commonest ocular morbidity followed by headache due to Ophthalmic cause 52 (11.5%), dry eyes 50 (11%) non-communicable diseases related ocular morbidity 41 (9%) and age-related cataract 37 (8.1%) .The mean age of presentation was 45.1 years (1.90\u00b117.3). Gender wise females 290 (63.9%) outnumbered the males. Most of the study participants were from urban areas 394 (86.8%). Seventy-two (15.8%) study subjects had a history of COVID-19 infection or were currently positive whereas, 29 study subjects (6.38%) were not aware about their COVID-19 infection status. Occupation wise housewives 190 (41.9%), farmers 74 (16.3%), and students 43 (9.5%) were the common study subjects. Two-hundred and twenty-one (48.7%) were vaccinated with at least a dose of COVID-19 vaccine .When the clinical characteristics of the study subjects were analysed, 385 (84.8%) of the study subjects had normal visual acuity (best corrected), 368 (81.1 %) study subjects had normal anterior segment, 449 (98.9%) of the study subjects had normal pupillary reaction and 413 (91.0%) of the study subjects presented with normal fundus .Fifteen (3.3%) study subjects and 11 (2.4%) study subjects had hypertensive and diabetic retinopathy .10A total of 650 subjects were enrolled in the study, 1300 eyes were evaluated in detail. The mean age of presentation was 45.1 years (1-90\u00b117.3). Gender wise females outnumbered the males. The demographic findings of the current study  were com6 where the prevalence of ocular morbidity was found to be 15.5%, this could have been attributed by the fact that this study was a hospital based study done during peak COVID-19 pandemic, so only patients needing Ophthalmic care must have visited the hospital during the study period , this finding from the study did not relate with a study done elsewherey period .15 The findings from the current study also suggested that refractive error (33.7%) and dry eyes (11.7%) are still the leading causes of ocular morbidity in both COVID-19 infected and non-infected study subjects. High prevalence of refractive error, dry eyes and to some extent computer vision syndrome (16 The lower number of age-related cataracts (8.1%) in the study subjects might be due to the slow progression of disease and lack of hospital visits due to accessibility issue in lockdown specially for the senile (elderly) population.When looking at the causes of ocular morbidity and prevalent ocular diseases, the study findings hinted towards a gentle rise in non-communicable diseases associated ocular morbidity, and emerging rarer ocular morbidities like pseudotumor cerebri, psuedotumor oculi, orbital cellulitis, intraorbital abscess, and intraorbital tumour . These fsyndrome  in the s16 The evolution of positive clinical findings due to non-communicable diseases like hypertension, diabetes mellitus, thyroid eye disorders, classical and common migraine  study subjects showed the robust vaccination campaign Nepal adopted and their success during the hard times of second wave of COVID-19 pandemic (Majority of the study subjects within this study belonged to urban areas, this finding in the study can be explained by the lockdown measures and COVID-19 restrictions, which meant patients living nearby to the study hospital had access to visit the hospital. However, patients from rural areas could not visit the hospital as mobility was strictly prohibited. Most of the study subjects being females, farmers and students was attributed by the workload they had to bear during the restrictions, strict lockdown and the physical and mental stress they had to go through during COVID-19 pandemic. The youths and students forming larger number of study subjects in the current study was attributed by online studies, webinars and use of various social media and digital platforms during COVID-19 era leading to eye related problems and digital eye strain which related well with the findings from a study done elsewhere.pandemic .The study was done in a tertiary hospital of urban, central Nepal thus the study sample may not be representable to other parts of Nepal. We would like to recommend further, to explore and find out the changing ocular morbidity and prevalence of ocular diseases during COVID-19 era by doing similar studies in other parts of Nepal.The prevalence of ocular morbidities in our study was higher than findings from similar study done at national and international study, though this study was done during COVID-19 pandemic with strict lockdown measures at the hospital. The study could also conclude that refractive error remains the most prevalent ocular morbidity and visual impairment followed by migraine headache, dry eyes and ocular morbidity due to systemic non-communicable diseases. Non-communicable diseases related ocular morbidities have been more prevalent during COVID-19 pandemic. Relatively rarer ocular conditions like pseudotumor oculi, intraorbital abscess, pseudotumor cerebri, cranial nerve palsies, and orbital cellulitis have been diagnosed to be ocular manifestations of COVID-19 infection, and these conditions should be managed judiciously and may need admission. The study could also conclude dry eyes and computer vision syndromes to be more prevalent during these times."}
+{"text": "IntroductionMetaplastic breast cancer (MBC) is a rare malignancy that accounts for < 1% of all breast cancers. The aim of this study is to evaluate the clinicopathologic characteristics of MBC patients treated at a tertiary cancer center.Materials and methodsIn this study, the authors retrospectively analyzed the prospectively maintained data of MBC patients treated at a tertiary cancer care center in North India between January 2019 and July 2022.ResultsA total of 28 MBCs were identified. The median age of presentation was 47 years (range 27-81 years). Seventeen patients (60.7%) presented with clinical T3/T4 disease, and axillary nodal involvement was detected in 11 patients (39.3%) at presentation. Two patients had metastatic disease at presentation. A preoperative diagnosis of MBC on core biopsy was attained in five patients (17.9%), and the most common histologic subtype was sarcomatoid carcinoma. Triple-negative receptor status was observed in 15 patients (53.6%). Six patients (21.4%) underwent upfront breast conservation surgery and another six (21.4%) upfront mastectomy. Thirteen patients (46.4%) underwent mastectomy following neoadjuvant therapy. Definitive axillary nodal metastasis was found in eight patients (32%). Following neoadjuvant chemotherapy, five patients (35.7%) had stable disease, disease progression was evident in five patients (35.7%), partial response in four patients (28.6%), and no patient evinced complete response.\u00a0Adjuvant postoperative radiation therapy was administered in 16 patients (57.1%). At a median follow-up of 13.2 months (range 4-26 months), 16 patients (57.1%) were alive with no evidence of disease, one patient (3.6%) was alive with disease, nine patients (32.1%) died of disease, and two patients (7.2%) died of other causes. One patient suffered from locoregional recurrence and nine patients developed distant metastasis.ConclusionMBC is an infrequent entity among breast carcinomas in India, which is similar to the reports of MBC worldwide. The diagnosis of MBC is difficult and requires the use of immunohistochemistry. Most of the cases in our study presented with a larger tumor size; however, they displayed a relatively lower incidence of nodal involvement as well as hormone receptor negativity. Being a rare and heterogeneous disease, large-scale studies are essential for better understanding and management of these tumors. Constituting < 1% of all invasive\u00a0breast cancers, metaplastic breast cancer (MBC) is a seldom encountered malignancy . The terA retrospective analysis of the prospectively maintained data of MBC patients managed at a tertiary cancer care center in North India from January 2019 to July 2022 was undertaken, following the guidelines of the institutional ethics committee. The authors evaluated the data with respect to patient age, gender, tumor size, lymph node status, clinical stage, histologic grade, receptor status (estrogen receptor (ER), progesterone receptor (PR), and Her2/neu), ductal carcinoma in situ (DCIS) component, type of surgical procedure, chemotherapy  and/or radiotherapy  and outcome. The treatment protocol of MBC at our institute follows the same principles of invasive carcinoma of the breast. Patients with early disease  were offered upfront surgery followed by adjuvant treatment . Patients with locally advanced disease (T3/T4 or N2/N3) or those who needed tumor downstaging for breast conservative surgery were treated with neoadjuvant chemotherapy (NACT) followed by the appropriate surgery and then adjuvant radiotherapy (RT) \u00b1 hormonal treatment . At our center, taxane-based NACT is preferred in patients with MBC. The response following NACT was evaluated by using the response evaluation criteria in solid tumors (RECIST).A total of 28 MBC cases were identified based on histopathology reports, and tumor subtyping was done according to the latest 2019 WHO classification. The incidence was 1.14% of all invasive breast carcinomas presenting at our center during the study period. The clinicopathological characteristics of the 28 cases have been detailed in Table The median age at diagnosis was 47 years (range 27-81 years) with only one male patient in our data set. Clinical examination revealed T3/T4 disease in 17 patients (60.7%) and involvement of axillary lymph nodes in 11 patients (39.3%). Fourteen patients (50%) displayed locally advanced breast cancer , and two patients (7.1%) harbored distant metastasis on presentation. On core needle biopsy, MBC was misdiagnosed as invasive breast carcinoma, no special type (IBC NST) in 14 patients (50%), and phyllodes tumor in four patients (14.3%). In these patients, a histopathologic diagnosis of MBC was made on the resection specimens after the surgery. Preoperative diagnosis of MBC on core needle biopsy was achieved in five patients (17.9%). In our series, the most common pathological subtype of MBC was biphasic sarcomatoid carcinoma (SC), which was conspicuous in 13 patients (46.4%)  was identified in 11 patients (39.3%), Her2/neu positivity was encountered in three patients (10.7%), out of which two patients revealed exclusive Her2/neu positivity (7.1%). An unexpected finding was the lower percentage of triple negativity for hormone receptors, evident in 15 patients (53.6%). Comparing triple negative MBCs (TNMBC) with Non-TNMBCs (NTNMBC) {Table 3}, sarcomatoid carcinomas exhibited a higher percentage of TNMBC (66.7%) versus the other histologic subtypes, progressive disease was identified more in the NTNMBC subgroup (44.5% in NTNMBC vs 20% in TNMBC), while distant metastasis was almost similar in both the subgroups. The TNMBC subgroup revealed a higher percentage of disease-free status (66.7%) juxtaposed with the NTNMBC subgroup (46.2%).Thirteen patients (46.4%) underwent a mastectomy and axillary clearance following NACT. Upfront mastectomy  was performed in six (21.4%) patients while breast conservative surgery (BCS) was possible in six cases (21.4%). Three patients did not undergo surgery, as there was evidence of distant metastasis on positron-enhanced tomography/computed tomography (PET/CT) imaging. Twelve patients (48%) manifested pathological T2 (pT2) disease, six patients (24%) had pathological T3 (pT3) disease, and seven patients (28%) divulged pathological T4 (pT4) disease. None of the patients bore pT0 and pT1 disease. Lymphovascular invasion (LVI) was ascertained in five patients (17.9%), and the DCIS component was apparent in only three patients (10.3%) in our cohort.Axillary sampling was executed in nine patients (36%) while axillary clearance was conducted in 16 patients 64%). Node negative (pN0) emerged in 17 of 25 patients (68%) on final histopathology. Among those with metastatic axillary nodes, six patients (24%)\u00a0had pN1 disease, one each (4%) pN2 and pN3 disease. Corresponding to the histologic subtype, axillary lymph nodal metastasis was observed in 30.8% (4/13) of SC, 50% of SCC (2/4), and 20% each in HGAS (1/5) and MCHMD (1/5) . At the last follow-up, there was one locoregional recurrence and nine patients endured distant metastasis. At a median follow-up of 13.2 months (range 4-26 months), 16 patients (57.1%) were alive with no evidence of disease (NED), one patient (3.6%) was alive with disease (AWD), nine patients (32.1%) died of disease (DOD), and two patients (7.2%) died of other causes (DOOC). The oncological causes of death were\u00a0brain metastasis in some patients and lung metastasis in others.MBC is a heterogeneous group of invasive breast carcinomas characterized by the transformation of part or all of its glandular component into a non-glandular or metaplastic component, such as squamous cells and/or mesenchymal-looking elements, including but not restricted to the spindle, osseous, and chondroid cells . The lata.\u00a0Epithelial-only carcinomas, which include low-grade adenosquamous carcinoma (LGAS), high-grade adenosquamous carcinoma (HGAS), and\u00a0squamous cell carcinoma (SCC).b.\u00a0Sarcomatoid carcinoma, which is divided into\u00a0i. Pure (monophasic), which includes spindle cell carcinoma (SpCC) and metaplastic carcinoma with heterologous mesenchymal differentiation (MCHMD), and\u00a0ii. Biphasic, which includes sarcomatoid carcinoma (SC) with both epithelial and sarcomatoid areasc.\u00a0Mixed metaplastic carcinoma (MMC), which includes\u00a0i. A mixture of different metaplastic elements, and ii. Metaplastic and conventional adenocarcinomatous components .Table The incidence of MBCs in our study 1.14%) was slightly higher than in the standard literature. The median age at diagnosis for patients with MBC reported in the literature ranges from 46-59 years . In our % was sliIt is difficult to establish a histopathological diagnosis of MBC on core biopsy. A study conducted by Park et al. showed that preoperative diagnosis of MBC on core biopsy was possible only in 4.2% of cases . In our Immunohistochemistry (IHC) is an integral part of the diagnosis of MBC. In the situations mentioned in Table Although fine needle aspiration cytology (FNAC) was not encountered in our study, it usually is an initial investigation performed for breast carcinomas, and the cytology features of MBC thus ought not to be overlooked. Clues for the diagnosis of MBC on FNAC are the presence of biphasic tumor cells with atypical spindle cells, atypical squamous cells, osteoclast-like giant cells, and/or matrix with or without a component of atypical ductal cells. However, it should be borne in mind that a cytologic diagnosis of MBC may not be attainable because of selective sampling of various pathological elements . The sigIHC is an important tool not only for the diagnosis of MBC but also for management with regard to hormonal therapy. The vast majority (> 90%) of MBCs lack expression of ER, PR, and Her2/neu ,21-23. HDue to the rarity of this tumor, there are no standard guidelines for optimal management, and treatment is similar to IBC NST. Surgery is the mainstay of treatment, and treating MBC is challenging owing to the poor response to NACT and the absence of novel targeted therapies . The majErjan et al. reported that in 33 of the 81 MBC patients (~ 40%) who received NACT, 14 patients (42.4%) had disease progression, and only two patients (6%) achieved a pathological complete response . In our In summary, although MBC is a rare malignancy, it should be a consideration when encountering patients with a rapidly growing breast lump. Core biopsy often fails to diagnose MBC and a high index of suspicion while confronting an atypical morphology not fitting into conventional IBC or malignant phyllodes tumors can help clinch the diagnosis. IHC is an invaluable tool in this diagnostic pursuit. A notable detection in our study is the sizeable number of hormone receptor-positive MBCs (39.3%). The majority (53.6%)\u00a0are TNBC; however, unlike TNBC, their response to NACT is dismal. Upfront surgery is preferred whenever feasible. NACT may only select patients with better tumor biology; nonetheless, there is an increased risk of progression on NACT. Patients who unveil disease progression on NACT should be re-assessed for distant metastasis before offering surgery. Owing to it being a recherche entity, the smaller sample size can be a limiting factor in extrapolating the findings of our study. Thus, a larger series of patients is required to conduct clinical trials and to discover molecular targets for the identification of subgroups of the disease, so that potential tumor-specific targeted therapies can be developed and prognosis be enhanced."}
+{"text": "Immune thrombocytopenia (ITP) is primarily considered a bleeding disorder; its impact on patients\u2019 health-related quality of life (HRQoL) is under-recognized. We aimed to assess how aligned patient and physician perceptions are regarding ITP-associated symptoms, HRQoL, and disease management in India.Patients and physicians (hematologists/hemato-oncologists) from India who participated in the global ITP World Impact Survey (I-WISh) were included in this subgroup analysis (survey). Physicians were recruited via a local, third party recruiter in India. In addition to completing a survey themselves, physicians were asked to invite consulting patients on a consecutive basis to complete a survey. All surveys were completely independently by the respondents online in English. The respondents took 30\u00a0min to complete the questionnaire. Patients also completed the newly developed ITP Life Quality Index (ILQI) that included 10 questions on the impact of ITP on the following: work or studies, time taken off work or education, ability to concentrate, social life, sex life, energy levels, ability to undertake daily tasks, ability to provide support, hobbies, and capacity to exercise.A total of 65 patients and 21 physicians were included in this study. Average disease duration from diagnosis-to-survey-completion was 5.3\u00a0years. The most severe symptoms reported by patients at diagnosis were menorrhagia (15 of 19 patients [79%]), anxiety surrounding unstable platelet counts (17 of 28 patients [61%]), and fatigue (27 of 46 patients [59%]); these were also the key symptoms they wanted to be resolved. In contrast, physicians perceived petechiae (19 of 21 patients [90%]), bleeding-from-gums (8 of 21 patients [86%]), and purpura (16 of 21 patients [76%]) as the most common symptoms. While the important treatment goals for patients were healthy blood counts (42 of 65 patients [65%]), improved QoL (35 of 65 patients [54%]), and prevention of worsening of ITP (33 of 65 patients [51%]), physicians\u2019 goals were reduction in spontaneous bleeding (17 of 21 physicians [81%]), better QoL (14 of 21 physicians [67%]), and symptom improvement (9 of 21 physicians [43%]). More than half the patients reported that ITP affected their work life/studies, social life, and energy levels, thereby negatively impacting their QoL. Patients were almost entirely dependent on family and friends for support.This survey highlights the substantial discrepancy in patients\u2019 and physicians\u2019 perceptions regarding ITP-associated symptoms and treatment goals in India. Based on the identified gaps, educating physicians on aspects of ITP beyond bleeding, and highlighting patients\u2019 under-recognized symptoms/needs through support-systems should be prioritized in the future.The online version contains supplementary material available at 10.1186/s41687-022-00429-y. Immune thrombocytopenia (ITP) is an acquired autoantibody-mediated bleeding disorder characterized by both accelerated platelet destruction and impaired platelet production, which an estimated incidence in adults between 1.6 and 3.9 per 100,000 person-years based on the platelet count threshold used . ImproveRecently, the ITP World Impact Survey (I-WISh) was conducted to discern how ITP and associated treatments affect patient lives and to evaluate how aligned patient and physician perceptions are regarding symptoms, HRQoL, and disease management , 9, and The I-WISh India-specific analysis is based on data collected as part of I-WISh 1.0, a cross-sectional survey of adult patients (age\u2009\u2265\u200918\u00a0years) with ITP and hematologists or hemato-oncologists who treat patients with ITP. The global I-WISh study was conducted in 13 countries .Patient surveys were sent via mass email to patient support networks and physicians who were requested to disseminate the surveys to patients. A steering committee of disease experts and patient advocates led the design of the survey materials and endorsed them prior to initiation of data collection. Physician surveys were emailed by local fieldwork agencies. Physicians were recruited via a local, third party recruiter in India. Physicians invited patients to complete the survey following a routine consultation for their ITP. In addition to completing a survey themselves, physicians were asked to invite consulting patients on a consecutive basis to complete a survey. All surveys were completely independently by the respondents online in English. As the surveys were online, it was not possible for any respondent to omit to answer any question. However, where deemed appropriate, respondents were allowed to select \u2018Not applicable\u2019 or \u2018Don\u2019t know\u2019 for certain questions. In these cases, the \u2018Don\u2019t know\u2019 or \u2018Not applicable\u2019 responses were removed from the individual analyses, but these patients were otherwise eligible for inclusion in all other analyses. Overall, the respondents took 30\u00a0min to complete the questionnaire. Fully deidentified respondent information was collated and aggregated by local fieldwork partners such that the surveys were unlinked and anonymized. Surveys and details of the survey methods, including how patients and physicians were identified, have been outlined in the supplementary material and published previously , 9.To understand the level of agreement that the respondents had with a statement in the survey, a Likert scale of 1\u20137 was used; for assessment of symptoms, a score\u2009\u2265\u20095 on the Likert scale implied that the symptom in question was considered to be \u201csevere\u201d by the patient. Patients also completed the newly developed ITP Life Quality Index (ILQI) that included 10 questions on the impact of ITP on the following: work or studies, time taken off work or education, ability to concentrate, social life, sex life, energy levels, ability to undertake daily tasks, ability to provide support, hobbies, and capacity to exercise ; additioAll methods were carried out in compliance with EphMRA guidelines and in full accordance with the US HIPAA 1996. Separate protocols were submitted for the patient and physician surveys . Survey materials and protocol were reviewed and approved by the Western Institutional Review Board. Patients and physicians were given an overview of the study and ethical approval details; those who wished to participate had to provide consent via a tick/check box before initiating.It being a descriptive, exploratory study, it did not include sample size calculations. The local recruiter conducted a feasibility assessment prior to launching data collection to confirm the achievable sample size for this study.Patient and physician survey data were analyzed separately using descriptive statistics. Analyses were descriptive, and no formal hypothesis was tested. Missing data were not imputed. Analyses were conducted using STATA statistical software version 15.1 .Overall, 21 physicians and 65 patients completed the survey questionnaire from March 09, 2018 and May 02, 2018. Patients were recruited by either experienced physicians treating ITP (64 of 65 patients [98%]) or patient association groups (1 of 65 patients [2%]). Accurate estimates on the number of individuals who were approached for participation in the survey could not be obtained. All respondents who participated in the survey questionnaire provided their demographic information, along with details of their diagnostic processes (Table The mean (standard deviation [SD]) age of the patients was 33 12.62) years, with 39 of 65 patients (60%) being male. The symptom burden was moderate to high in 24 of 57 patients (42.1%), of whom 17 patients (71%) reported a poor health score . Patients met an average of 5 healthcare professionals  before an accurate diagnosis of ITP, which was confirmed by physicians specialized in the management of ITP in 56 of 65 patients (86%). Overall, 21 of 65 patients (32%) expressed a delay in ITP diagnosis, thereby leading to severe anxiety  in 8 of 21 patients (38%) (Table 2.62 yearAll physicians included in the survey were either hematologists n\u2009=\u200913) or hemato-oncologists (n\u2009=\u20098). More than half of the physicians who participated in the survey (12 of 21 physicians [57%]) practiced in a private setting. Of the average caseload, about 87 of 625 (13.9%) were patients with ITP. ITP was rated as a \u201csomewhat less important\u201d condition by 14 of 21 physicians (67%). Nearly one-fourth (5 of 21 physicians [24%]) of the physicians perceived that 26%-50% of patients were misdiagnosed , fatigue (46 of 65 patients [71%]), petechiae (39 of 65 patients [60%]), hematoma (30 of 65 patients [46%]), and anxiety surrounding unstable platelet counts (28 of 65 patients [43%]). The mean (SD) duration of the disease from diagnosis to survey completion was 5.3 (6.77) years. At survey completion, the most commonly reported symptoms were fatigue (35 of 65 patients [54%]), heavy menstrual bleeding (10 of 26 patients [38%]), anxiety surrounding unstable platelet counts (23 of 65 patients [35%]), petechiae (19 of 65 patients [29%]), and hematoma (11 of 65 patients [17%]) , bleeding from gums (18 of 21 physicians [86%] vs 18 of 21 physicians [86%]), purpura (16 of 21 physicians [76%] vs 18 of 21 physicians [86%]), epistaxis (14 of 21 physicians [67%] vs 13 of 21 physicians [62%]), and heavy menstrual bleed (11 of 21 physicians [52%] vs 12 of 21 physicians [57%])  were work life/studies (19 of 50 patients [38%]), absence of work/education (16 of 48 patients [33%]), and energy levels (19 of 65 patients 29%])  , and the top 4 reported reasons with a severe impact were anxiety surrounding unstable platelet counts (38 of 65 patients [58%]), importance of stable platelet counts (38 of 65 patients [58%]), fluctuation in platelet counts for no apparent reason (34 of 65 patients [52%]), and frustration with ITP symptoms (31 of 64 patients [48%])  reducing their work hours and 9 of 36 patients (25%) seriously considering a reduction in their work hours. Patients reported an average of 11.1\u00a0h of missed work per week due to the impact of ITP Fig.\u00a0. The totOverall, 39 of 65 patients (60%) expressed the need for support  for an average of 33.7\u00a0h/week; homemaking (27 of 39 patients [69%]), transportation (26 of 39 patients [67%]), healthcare (25 of 39 patients [64%]), and management of finances (20 of 39 patients [51%]), were the primary reasons for which support was requested. The key support providers were parents (19 of 39 patients [49%]) and spouses (9 of 39 patients [23%]) (data not shown).Physicians felt that anxiety about platelet counts and frustrations around having a long-term, rare disease had a severe adverse impact on most of the patients (~\u200990%). Daily activities were severely impacted in 4 of 20 patients (21%) and 5 of 20 physicians (25%) felt that ITP had negatively impacted patients\u2019 relationship with their spouses. Overall, interference of ITP in the level of patients\u2019 physical activity was reported as severe by 6 of 20 physicians (30%), and 18 of 20 physicians (90%) felt that ITP greatly impacted patients\u2019 ability to play contact sports or sports with a chance of bleeding injury. A negative impact of ITP on patients\u2019 sex lives (8 of 18 physicians [44%]) and concerns around increased risk of bleeding impacting travel plans (9 of 20 physicians [45%]) was reported by 45% physicians (data not shown).Almost all physicians (20 of 21 physicians [95%]) did not use any QoL tool, but expressed their desire to use a patient self-assessment questionnaire . Most physicians (16 of 21 physicians [76%]) expressed that use of a mobile-based app would help in recording patient QoL, while 10 of 21 physicians (48%) expressed that combining paper- and mobile app-based approach would be the preferred method to use. No major differences were observed in the response assessments of physicians based on their workload (data not shown).ITP diagnosis to treatment required an average of 0.9\u00a0months, with over half of the patients (34 of 65 patients [52%]) undergoing a period of \u201cwait and watch.\u201d The important treatment goals for patients were healthy blood counts (42 of 65 patients [65%]), improvement in QoL (35 of 65 patients [54%]), prevention of episodes on worsening of ITP (33 of 65 patients [51%]), reduction in spontaneous bleeding (18 of 65 patients [28%]), and an overall improvement in symptoms (17 of 65 patients [26%])  patients. At the time of survey completion, the most frequently administered treatments were corticosteroids (38 of 65 patients [58%]), androgens (9 of 65 patients [14%]), anti-CD20 (9 of 65 patients [14%]), thrombopoietin receptor agonists , and other immunosuppressants (7 of 65 patients [11%]); the average duration of these medications was 4.7\u00a0months. When the symptom burden was low, most patients reported undergoing treatment with corticosteroids (27 of 33 patients [82%]), and as the burden increased to moderate and above, corticosteroid use decreased slightly (17 of 24 patients [71%]). The use of androgens (8 of 33 patients [24%] to 11 of 24 patients [46%]), anti-CD20 (9 of 33 patients [27%] to 11 of 24 patients [46%]), and TPO-RAs (3 of 33 patients [9%] to 7 of 24 patients [29%]) increased with increasing symptom burden. Data on treatment satisfaction were based on a low patient number (data not presented here) (data not shown).Approximately 39% of the newly diagnosed patients were given a trial of observation only. Even among patients who had been previously treated for\u2009>\u200912\u00a0months since diagnosis, 30% were put on observation instead of being treated. Splenectomy was considered in 23% of the patients with chronic and recurrent course. Platelet count monitoring was done more routinely in newly diagnosed patients every 15\u00a0days) compared with patients with chronic ITP (every 1.7\u00a0months). The major treatment goals for physicians were reduction in spontaneous bleeding (17 of 21 physicians [81%]), better QoL (14 of 21 physicians [67%]), symptom improvement (9 of 21 physicians [43%]), healthy blood counts (6 of 21 physicians [29%]), and reduction in fatigue symptom (5 of 21 physicians [24%]). Nearly 90% of physicians (18 of 21 physicians [86%]) believed that they discussed and agreed on treatment goals with their patients, and 14 of 21 physicians (67%) aimed to limit the immunosuppressive effect of the treatment , the ability to reduce bleeding risk (80%), and keeping side effects to a minimum (79%). For both newly diagnosed and chronic ITP,\u2009~\u200980% of physicians preferred oral treatment options as the first line of treatment. Corticosteroids (19 of 21 physicians [90%]) and intravenous immunoglobulins  were the preferred treatments in newly diagnosed patients with ITP. TPO-RAs (19 of 21 physicians [90%]) and anti-CD20 (17 of 21 physicians [81%]), followed by androgens (16 of 21 physicians [76%]), were the preferred treatment options in patients with persistent and chronic ITP , followed by androgens (8 of 21 physicians [38%]) and IVIgs/anti-CD20 (7 of 21 physicians [33%] each), were preferred, while during second relapse other immunosuppressants (9 of 21 physicians [43%]) followed by corticosteroids (8 of 21 physicians [38%]) were preferred; by the third relapse, TPO-RAs (11 of 21 physicians [52%]), followed by anti-CD20 therapy (8 of 21 physicians [38%]), were the preferred treatment option (data not shown).Based on physician perspective, patients treated with TPO-RAs had the least incidence of side effects. A total of 13 of 21 physicians (62%) agreed that they were satisfied with the current treatment options available. Lack of efficacy (21 of 21 physicians [100%]), followed by side effects (19 of 21 physicians [90%]), and cost/coverage (17 of 21 physicians [81%]), was the most important reason for a change in therapy (data not shown).When compared with patients, a lower proportion of physicians were completely satisfied with the various aspects of ITP disease\u2013related care and management (data not shown). While responding to questions on access to information on ITP for their patients, 9 of 21 physicians (43%) expressed that patients faced at least some level of difficulty in accessing information. About half of the physicians indicated that they provided disease management\u2013related information in a leaflet format explaining the contents of the leaflet (9 of 21 physicians [43%]). From the patient perspective, 40 of 65 patients (62%) had not received any information from their HCP. For patients who recieved information from their HCP, it was either through a leaflet (10 of 25 patients [40%]) or through HCPs showing the website content during consultation (8 of 25 patients [32%]) or by being directed to the website for accessing information about the disease (7 of 25 patients [28%]). A large proportion of patients did not have any contact with patient support groups (61 of 65 patients [94%]) (data not shown).Among 64 of 65 patients (98%) who visited a specialist doctor, an average of 6.5 visits were recorded in the last 12\u00a0months, and of these patients, 49 (77%) perceived the frequency of visits to be adequate. None of the patients reported consultation with a psychologist (data not shown).To the best of our knowledge, this questionnaire-based survey is the first of its kind among patients with ITP and treating physicians in the Indian subcontinent, and provides an insight into the perceptions of both patients and physicians regarding disease diagnosis, signs and symptoms, impact of patient HRQoL, and the approach toward disease management.A marked difference was observed in the number of patients with ITP seen by physicians in the last 12\u00a0months before survey completion between the Indian and global survey data  . In IndiHeavy menstrual bleeding, fatigue, and anxiety surrounding unstable platelet counts were predominantly reported as severe by patients at both diagnosis and survey completion. Physician perspectives on the frequency and/or severity of the most common symptoms and their impact on QoL were not always similar to those reported by patients. While fatigue was reported as severe by\u2009~\u200960% of patients at diagnosis, about 33% of physicians perceived it as a symptom that severely affects patient QoL. This trend in underestimation of fatigue by physicians was observed in both the Indian and global data . HoweverThe assessment and improvement of HRQoL parameters generally require a multidimensional approach and should be tailored for the patient, while taking into account the healthcare system, cultural, and economic backgrounds of individual countries . In thisPhysician ability to effectively and compassionately communicate the nature of disease and management options is important to build trust in a patient\u2013physician relationship, and shared decision-making is a key element in improving patient\u2013physician communication . AlthougA shared-decision model could also help in ensuring that the treatment goals of patients and physicians are completely aligned. Our survey results showed that achievement of healthy blood counts was the most important goal for patients, while for physicians, it was reduction in spontaneous bleeds. Interestingly, improvement in QoL was one of the most important treatment goals for both patients and physicians, underlining the importance of assessing HRQoL among patients with ITP. This was consistent with the global I-WISh data, wherein improvement in QoL was one of the top 3 goals among 38% of patients and 64% of physicians .Overall, the survey data outcomes and driven conclusions must be interpreted with caution, given the small sample size of the respondents, specifically the patient group. Also, this survey did not capture the number of treatment lines received by patients or the remission status. Recall bias and the use of a non-validated HRQoL questionnaire (ILQI) are some of the other limitations of the study. However, the study results need to be considered in the light of the fact that ITP is a rare disease, and currently, in India, there is limited education/awareness among patients regarding the disease.Based on the overall respondent assessment, the study highlights the need for education/training of physicians and other healthcare workers on all aspects of ITP disease management\u2014especially fatigue, anxiety, and menorrhagia\u2014and general awareness among physicians and patients on disease management, including treatment goals, and the impact of ITP on QoL. Additionally, it also emphasizes some of the neglected aspects of ITP and provides a good starting point for large-scale future studies in this therapy area.Additional file 1. Figure S1: Symptoms that patients want to be resolved.Additional file 2. Figure S2: Physician perspective on fatigue.Additional file 3. Figure S3: Prescribed treatments based on platelet counts."}
+{"text": "Objective measure of lifestyle of the older adults living in the community is void in the literature. To obtain both objective and subjective measurements to ascertain mobile and day and night lifestyle of older adults living in the community, and to build lifestyle model of older adults in the community by sociodemographic character. This study is a cross-sectional research. 200 over-50-year older adults who own smartphone and live in southern Taiwan were interviewed. Wrist accelerometers to detect behavioral circadian rhythm, GPS app in smartphone to survey mobility, and questionnaire to assess psychological and social status. Preliminary finding of six participants (2 men and 4 women) was analyzed. Data show that participants about 60 years old have large discrepancies in comparison with participants in their 50s: lower sleep efficiency (73 vs 83), earlier Most active 10 hour midpoint (11.48vs 14.13 hour), higher interdaily variability (0.84 vs 0.75), wake after sleep onset (100.39vs 47.78 minutes), and higher exercise frequency (4.33 vs 1.66 times per week). In addition, men have more chronic disease, bigger waistline (103.5 vs 77.5 cm), higher BMI (30 vs 22.5), lower middle to vigorous physical activity time (39 vs 79 minutes), and more total sleep time (356 vs 317 minutes). Age and sex seem to be significant factors determining lifestyle of older adults. Other sociodemographic parameters will be further analyzed."}
+{"text": "To correlate compliance to personal protective equipment (PPE) protocols and risk of exposure to SARS-COV-2 infection in endoscopy staff.We included 85 endoscopic procedures performed at Lahore General Hospital from May to July 2020. Standard operating procedures (SOPs) were implemented for patient selection, risk stratification and personal protective equipment (PPE) use for endoscopy staff. Patient and endoscopy staff were followed for Covid-19 infection. PPE scores for staff and Covid-19 positivity on follow-up were correlated using student\u2019s t test.st assistant and 9 (10.5%) developed infection and for 2nd assistant PPE score was <9 in 19(22.3%) endoscopies and 5 (5.9%) tested positive for covid-19. Infectivity of endoscopy staff was 6.2%. Association between PPE score and risk of Covid-19 was not significant. .Following 85 procedures included, 2 (2.3%) patients became Covid-19 positive. PPE score was <9 in 5 (5.8%) procedures for endoscopist and Covid-19 developed in 2 (2.3%) of them, PPE score was <9 during 19 (22.3%) procedures in 1Compliance of SOPs for infection control reduces risk of acquiring Covid-19 infection during endoscopy. Proper use of PPE is effective for safety of endoscopy staff. Severe acute respiratory tract syndrome following exposure to corona virus 2 (SARS COV-2) is responsible for viral pneumonia labeled as COVID-19 infection. It was first discovered in last month of 20193Covid-19 infection spreads either by direct contact with or inhalation of respiratory air droplets. Infected person can spread this disease either by touching infected hands on different surfaces from where healthy individuals are exposed to this virus by touching same surfaces and then touching their nose, mouth or eyes with infected hands or by shedding these viruses in air while sneezing or coughing. 5Due to exponential spread of this highly infectious and lethal viral infection, routine clinical services including diagnostic and therapeutic procedures were immediately curtailed.7In addition to risk of transmission through infected aerosols being generated during procedure, in endoscopy room COVID-19 can also spread via direct person to person contact or while handling contaminated endoscopic equipment, accessories and body fluids.10Despite viral infection still rampant world-over even after more than nine months of being declared as pandemic by WHO, diagnostic and therapeutic endoscopic services have gradually resumed as was inevitable. In order to ensure safety of endoscopic staff during endoscopic procedures, GI societies have developed guidelines regarding patient screening, use of personal protective equipment (PPE) during procedures along with safety standards for handling of equipment and accessories.6However, efficacy of these measures in protecting endoscopy staff from COVID-19 infection still needs to be gauged and will only be known over time. We therefore planned an observational study to correlate compliance to PPE protocols and risk of SARS-COV-2 infection in endoscopy staff.We planned an observational study at Endoscopy suit of Lahore General Hospital from May 2020 till July 2020, peak time of pandemic in Pakistan when only emergency endoscopic services were available at few tertiary care centers. Our center decided to start limited number of urgent procedures after developing Standard Operating Procedures (SOPs) for selection of patient for procedure, number of personals allowed in procedure room, PPE for endoscopist and procedure assistants. These SOPs were based on recommendation of American Society of Gastrointestinal Endoscopy (ASGE).11Every patient enrolled for endoscopy was stratified as High risk, Intermediate risk and low risk for Covid-19 infection based onFever (Temperature > 37.5 C) in last 14 daysExposure to family member or close contact with suspected or confirmed Covid-19 infectionBelongs to or has travelled to area with higher risk for Covid-19 infection in last 14 daysPatients with none of these features were low risk, patients with fever alone or those with no fever but both exposures to suspected or confirmed patient and resident of high risk area were intermediate risk patients while patient with fever and one of other two features were high risk patients.For low-risk patient, endoscopy staff were advised to wear hairnet, goggles, surgical mask, single use gown and one pair of gloves while for intermediate and high-risk patients, PPE used included hairnet, goggles/face shield, N95 or Filtering face piece (FFP) II or III face mask with two pairs of gloves. Endoscopy staff was required to wash their hands with soap and water or alcohol-based rub before and after each contact with patient, contact with infectious material and during donning and doffing of PPE. Endoscopy staff was advised to keep reasonable distance from patient while taking consent, checking vitals and giving procedure related instructions.Temperature of each patient was checked before entering endoscopy room. No relative or caregiver was allowed in suit unless essential for specific assistance. All patients were offered surgical mask while intermediate or high-risk patients also wore gloves before entering endoscopy suit. Surgical mask was removed just before starting procedure once patient was under conscious or deep sedation. It was replaced on face once patient had recovered from sedation and had oxygen saturation >90%.Compliance of these SOPs was ensured by filling of proforma in real time during procedure that included information regarding indication for procedure, details of patient\u2019s risk stratification, duration of procedure and time of patient stay in endoscopy suit and PPE used by each person present in suit. Patients undergoing procedure and endoscopy staff involved in procedure were followed up on phone at day-7 and day 14 after procedure for development of symptoms suggestive of Covid-19. Patients were advised Covid-19 testing after two weeks while endoscopy staff with suspected symptoms were tested for COVID-19 infection and were provided care as per standard protocols.\u00ae (Armonk NY:IBM corp). Quantitative variables were expressed as mean \u00b1 standard deviation (SD) whereas qualitative variables were given as percentage.Data was analyzed using SPSS 22st assistant and 2nd assistant were scored giving two marks each for mask, gloves and goggles/face shield, 2 marks for Tyvek kit while one score for disposable gown, one score each for hairnet and shoe cover. Maximum score possible was 10. Scores were deducted, two each for not wearing mask and gloves, one each for absence of face shield/goggles and gown. PPE score of six or less was considered inadequate score. PPE scores of endoscopy staff, duration of procedure and stay time of patient in suit were correlated with Covid-19 infection in staff during 14 days of follow up using unpaired student\u2019s t test while type of procedure and risk category of patient were analyzed for association with Covid-19 infection using chi square xPersonal protective equipment (PPE) used by endoscopist, 1We included total of 85 procedures carried out at Lahore General Hospital during three months. It included 53 (62.4%) upper GI endoscopies, 13 (15.3%) colonoscopies and 19 (22.4%) Endoscopic Retrograde Cholangiopancreaticography (ERCP). Procedures performed were of acute emergency in 28 (32.9%) patients, urgent in nature in 51(60%) patients and elective only in six (7.1%) cases. Major indications for procedures included upper GI bleeding in 28(32.9%) patients, obstructive jaundice in 17 (20%) patients, dysphagia in 13 (15.3%) patients, bleeding per rectum in six (7.1%) patients and abdominal pain in five (5.9%) patients. Mean age of patients was 44.89 (\u00b115.6%) and it included 52(61.2%) male patients and 33 (38.8%) females.On pre-procedure screening, eight (9.4%) patients had history of fever, six (7.1%) complained of cough and three (3.5%) had travel history to high-risk area as well. Total of 10 (11.8%) procedures were of intermediate risk category while rest were low risk. However, we tested 61 (71.8%) patients for Covid-19, out of which only two were positive who were treated as high-risk patients with level one protective measures.Deep sedation with propofol was used for 81 (95.4%) patients while four (4.8%) underwent procedure with conscious sedation. Endoscopic variceal band ligation was done in 21 (24.7%) patients, six (7.1%) had stricture dilatation, biliary stenting was performed in 17 (20%) patients, biliary stones were removed in two (2.4%) patients and diagnostic biopsy was taken in eight (9.4%) patients. Mean duration of procedures was 24.4 (\u00b117.8) minutes while mean patient stay time in endoscopy suit was 34.64 (\u00b124.6) minutes.st assistant PPE score was 8.95 (\u00b11.9) and 8.59 (\u00b12.7) was mean PPE score for 2nd assistant.Total number of persons in endoscopy room during procedure apart from patient himself were three in 18 (21.2%) procedures, four in 55 (64.7%) and five in 12 (14.1%) procedures. Mean PPE score for endoscopists in 85 procedures was 9.74 (\u00b10.95), for 1st assistant of 27 (31.8%) procedures Covid-19 test was performed and nine (10.5%) were positive. Fortunately, all nine members recovered without need for medical treatment. Testing was needed only for nine (10.5%) 2nd assistant members due to symptoms and five (5.9%) turned out to be positive with eventless recovery from Covid-19 infection.On two weeks follow up, Covid-19 test was carried out in 73 (85.9%) patients and only two were positive. Both patients recovered without hospitalization and none reported symptoms or positive test in family members. Covid-19 testing was done in endoscopists of 19 procedures due to minor symptoms and two (2.3%) were positive, while endoscopists of remaining procedures were asymptomatic. Both positive cases recovered without need for hospital admission. Similarly out of 85 procedures, for 1These 16 Covid-19 infection events were documented in 12 procedures. We compared procedure related variables between procedures resulting in Covid-19 infection in any staff member with procedures where no one got infected as shown in st Assistants mean PPE score for positive persons was 6.22 (\u00b12.53) as compared to 7.94 (\u00b12.4) in those without Covid-19 infection. . Mean PPE score for Covid-19 positive 2nd assistants was 6.2 (\u00b13.84) as compared to full 10 for those free of infection. .Mean PPE score in Covid-19 positive endoscopists was 10 as compared to 9.2(\u00b11.65) in those with no infection . For 1st assistants with Covid-19 infection, two had PPE score of 3, one had 5 score, three had 6 score, one had 7 score and two had full 10 score. PPE score of 6 or less was significantly associated with risk of infection in 1st assistant.  Similarly of 5 infected 2nd Assistants, two had 2 score and three had 5 score and correlation of \u2264 6 score with Covid-19 infection was not significant in 2nd assistant.  However both infected endoscopists had full 10 PPE score. Therefore, despite variable correlation between PPE scores and Covid-19 infection, majority of staff members who developed Covid-19 infection had sub-optimal personal protective equipment during procedure.On individual evaluation of nine 1Despite being rampant in almost every country of the world for more than one year with health services and economy of even developed countries being paralyzed, only effective remedy for Covid-19 infection is prevention. Social distancing, frequent hand washing and isolation of infected individuals are THE effective tools for controlling its spread in community.14We, in this observational study have evaluated compliance of standard operating procedures (SOPs) developed in light of ASGE guidelines for endoscopic procedures. However, despite triage protocols and patient screening, endoscopy staff can still be exposed to Covid-19 infection as significant number of Covid-19 patients are asymptomatic. PPE use is warranted to control this risk. We have also determined the efficacy of PPE in saving endoscopy staff from getting infection.st assistant and 5.9% (5/85) in 2nd assistant where PPE<9 was seen in 22.3% (19/85) procedures for both 1st and 2nd assistants.Covid-19 infection transmission was noted in 12 (14.1%) of total 85 procedures carried out in time of peak infection in region. Despite statistically non-significant association between PPE score and Covid-19 infectivity in endoscopy staff, Covid-19 infection rate was 2.4% (2/85) in endoscopists, for whom PPE score less than 9 was observed in only 5.8% (5/85) procedures and infection rate increases to 10.6% (9/85) in 1Elective endoscopic procedures were cancelled at start of pandemic due to risk of infection and shortage of PPE in line with international consensus statements.A survey from Italy reported only 1 out of 802 patients undergoing endoscopy to be Covid-19 positive on 2 weeks post-procedure follow up. They reported only 4.3% Covid-19 infections among endoscopy staff during these procedures.19In a study of more than 99,000 health care workers in UK and USA, it was estimated that health professionals have more than 10-fold risk of catching COVID-19 infection  as compared to individuals in community. It was further concluded that adequacy of PPE can significantly curtail this risk.21We followed patients and endoscopy staff for symptoms of Covid-19 infection for 2 weeks post-procedure. As disease is also prevalent in community, study population can be exposed to virus outside endoscopy suit as well. Therefore, it is impossible to be certain that those infected, were exposed during endoscopy. We tested almost all patients undergoing procedure for Covid-19 infection 2 weeks after procedure but for endoscopy staff, PCR testing for infection was only performed for symptomatic individuals and it risks under-reporting of disease as a significant percentage of infected cases remain asymptomatic. Testing each staff member after procedure was not possible due to limited supply of testing kits in this pandemic and that too for screening. Our study lacks control group with no PPE during procedures, however it is not practical for a highly infectious and potentially lethal disease like Covid-19.Despite these limitations, risk of Covid-19 infections in endoscopy staff can be avoided by effective implementation of safety protocols and appropriate PPE use by endoscopy staff needs to be assured.Compliance of standard operating procedures for infection control reduces risk of acquiring COVID-19 infection during endoscopy. Proper use of PPE is effective for safety of endoscopy staffAD: Conception and design, data acquisition, approval of the version, agreement to be accountable for all aspect.SS: Conception and design, analysis and interpretation, drafting of article, approval of the version, agreement to be accountable for all aspect.FA: Conception, data analysis, revising manuscript critically, final approval of the version and agreement to be accountable.AS: Designing of study, data acquisition, revising manuscript critically, final approval of the version and agreement to be accountable.SR: Conception of study, data acquisition, revising manuscript critically and agreement to be accountable.GNT: Conception and design of study, revising manuscript critically, final approval of the version and agreement to be accountable."}
+{"text": "Patient symptom management is a fundamental goal of cancer home hospice care. However, informal family caregivers, who are primarily responsible for daily patient care, also experience negative symptoms, especially at the end of the patient\u2019s life. While research has attended to patient symptom progression in home hospice, little research focuses on caregiver symptoms. To address this, we examined the frequency of both patient and caregiver symptoms to determine how these symptoms change in the last two months of the patient\u2019s life. Sixty-three cancer hospice caregivers from 4 US states prospectively reported daily patient and caregiver symptoms via an Interactive Voice Response phone system. We analyzed data from up to the last 60 days of the patient\u2019s life. Most caregivers were female (71.4%), Caucasian (88.9%), spouses of the patient (46%); average age was 59 years old (SD=13). Patients were mostly female (54%), with diverse solid tumor cancer diagnoses, and 72 years old (SD=11) on average. Most commonly reported moderate-to-severe patient symptoms were fatigue (67%), pain (47.5%), and loss in appetite (42.3%). Most common moderate-to-severe caregiver symptoms were fatigue (57.8%), trouble sleeping (45.1%), anxiety (52%), and depression (40.4%). Patient and caregiver symptoms were significantly correlated . Mixed-effects models found that both patient and caregiver symptoms (collapsed by week) worsened as patient death approached (ps <.01). Researchers and clinicians who are aware of the strong relationship between patient and caregiver symptoms are best able to address caregiver symptoms as part of hospice care, particularly as patient death approaches."}
+{"text": "Liaison psychiatry services (LPSs) provide psychiatric care to general medical patients. This paper aims to evaluate LPS provision for children and young people In England.The annual Liaison Psychiatry Surveys of England (LPSEs) included questions on paediatric services from 2015 (LPSE-2). Questions were developed in consultation with NHS England and the Liaison Faculty of the Royal College of Psychiatrists. We analysed data from LPSE-2 and three subsequent surveys.LPSs were systematically identified by contacting all acute hospitals with Type 1 emergency departments listed by NHS England. All identified LPSs were emailed a copy of the questionnaire, with follow-up emails and telephone contact for non-responders. Responses by email, post or telephone were accepted.The number of acute hospitals with access to paediatric LPSs increased from 29 (16%) in 2015 to 46 (27%) in 2019; all of these hospitals had access to adult LPSs. The number of paediatric LPSs with at least 11 full time equivalent (FTE) mental health practitioners (MHPs) has increased from 6% to 24% and from none to 16% with 13 FTE or more MHPs. For both LPSE-4 and LPSE-5, there were only two acute hospitals where both 8 FTE MHPs and 1.5 FTE consultants were present. For LPSE-4, only one site met the Core 24 criteria (for adults - there are no criteria for paediatric LPSs) of 11 FTE MHPs and 1.5 FTE consultants, and for LPSE-5, both these sites exceeded them. Other paediatric services did not meet the adult core 24 criteria for a LPS.Acute hospitals with access to 24/7 paediatric LPSs increased from 12% to 19% between LPSE-4 and LPSE-5. In LPSE-5 68% of paediatric LPS worked to a one-hour response time target to the ED. This is an increase from 42% (14/33) in LPSE-4.There are still far fewer paediatric than adult LPSs, but the provision of paediatric LPSs improved from 2015 to 2019, with more services, more staffing, and faster response times. Services need to continue to improve as few services match the adult core 24 criteria for an LPS."}
+{"text": "In a survey of movement disorders in patients in a State Hospital the finger-nose test was included because of increasing interest in the cerebellum in schizophrenia. It was expected that this would reflect the pathobiology of schizophrenia and be unrelated to the type of medication.Abnormalities of movement and involuntary movements have gone from being considered part of schizophrenia to side-effects of medication to now demonstrably present in those who have never taken anti-psychotic medication. Soft neurological signs (SNS) are increased in schizophrenia, unrelated to medication, considered not to indicate brain localization, yet often include the finger-nose test which localizes to the cerebellum.All available patients in a State Hospital were examined for movement disorders. They were rated on the following scales: Abnormal Involuntary Movement Scale (AIMS) for Tardive Dyskinesia (TD), Simpson-Angus Neurological Rating Scale for Parkinsonism (SANRS), Barnes Akathisia Scale (BAS), a Dystonia scale and the finger-nose test.250 patients were included, 174 were examined or observed for movement disorder: 120 had no missing data, 54 refused part of the exam. Their mean age was 47, 62% male, 53% black, 26% Hispanic, 17% white.Medication: First Generation Antipsychotic (FGA) 35 , Second Generation Antipsychotic (SGA) 159 (734mg), both FGA and SGA 56 (1907mg), no antipsychotic 3; anticholinergic or amantidine: FGA 57%, SGA 16%, both FGA and SGA: 50%.Tardive Dyskinesia: all 23%, FGA 36%, SGA 25%, both 7%Parkinsonism: all 38%, FGA 43%, SGA 33%, both 34%Akathisia: all 3%, FGA 0%, SGA 4%, both 3%Pseudo-akathisia: FGA 11%, SGA 4%, both13%Dystonia: all 10%, FGA 13%, SGA 11%, both 8%Intention Tremor: all 16%, FGA 0%, SGA 21%, both 16%Half of those with Intention Tremor had Parkinsonism, a third had TD and a half were on anti-Parkinson medication.None of these differences were statistically significant at p = 0.05 though intention tremor did show a trend (p = 0.08). The difference between FGA and SGA only became significant when all movement disorders were added together with those on anticholinergics with no movement disorder.When compared with rates in similar State Hospitals in the 1970s tardive dyskinesia was now half the rate and Parkinsonism about the same.Overall rates of movement disorder are not very different between FGA and SGA. The surprise was that intention tremor only occurred with SGAs. Why?"}
+{"text": "Neck pain is a common health problem throughout the world causing significant individual disability and economic burden on health care facility. Many factors are mentioned as a cause or association in relation to neck pain, of which degenerative and posttraumatic cause are the main ones. The aim of this study is to assess cervical spine Magnetic Resonance Imaging (MRI) patterns in patients presented with neck pain.A retrospective analysis of 160 patients who had cervical spine Magnetic Resonance Imaging (MRI) for evaluation of a neck pain was done. The study was conducted between February to August 2018 at Tikur Anbessa Specialized Hospital. The patients' clinical history and magnetic resonance imaging reports were reviewed from their medical records. All patients who have cervical spine Magnetic Resonance Imaging (MRI) for a neck pain were included in the study. Those patients with acute traumatic neck pain were excluded.From a total of 160 patients, 71(44.4%) were males and 89(55.6%) were females. Degenerative cervical spine findings such as intervertebral disc degenerations were seen in 127(79.4%) patients. Non-degenerative imaging findings such as neoplasm and infection were seen in 10(6.3%) patients only. The MRI was normal in 23(14.4%) of them.The most common cause of neck pain from this study is degenerative changes of the cervical spine, which was predominant in the older age groups. Non-degenerative causes such as neoplasm and infection were less common findings. Our study evaluated the common cervical spine MRI abnormalities seen in patients with neck pain.The study was conducted at Department of Radiology, Tikur Anbessa Specialized Hospital (TASH), Addis Ababa, Ethiopia from February to August 2018. The hospital is the largest tertiary level referral and teaching hospital in the country. It is one of the centers of excellence in Ethiopia in undergraduate, post graduate and subspecialty programs in health sciences. The radiology department is one of the many departments in the institution with experienced radiologists. The department is equipped with high-tech radiologic machines including MDCT (Multi Detector Computed Tomography) machines with 64 and 128 slices and high-resolution MR scanner with 1.5 tesla strength.Retrospective descriptive study was conducted by reviewing cervical spine MRI reports of patients with neck pain presented to department of radiology. Cervical spine MR images were acquired using Philips Medical Systems Achieva 16 channels 1.5 T strength MR scanner with standard neck and brain receiving coils. All patients, who had cervical spine MRI evaluation for an indication of neck pain during the period under review, were included in this study. Patients with acute trauma to the neck and those with primary complaint other than neck pain were excluded from the study. The cervical spine MRI images were interpreted by neuroradiologists with more than 10 years of experience and fellows in neuroradiology. MRI reports and clinical data records of patients with neck pain were retrieved from the radiology department patient record chart and recorded on a well-prepared format designed to include patients' sex, age, clinical indication and imaging findings by the principal investigator.Data processing and analysis; The data was cleaned, coded and entered to statistical package for social sciences (SPSS) version 20 for analysis. Frequencies, mean, standard deviation, percentages and cross tabulation were determined and summarized. Association studies between some of the variables were done using chi square test using P-value of <0.05 as statistically significant association.Ethical considerations: Data collection was started after getting permission from the ethical review committee of the department of radiology at Addis Ababa University. Patient confidentiality was maintained by omitting patients' name and hospital identification number from data collecting format and selected representative images.From a total of 160 patients in this study 71(44.4%) were males and 89(55.6%) were female patients. The mean age was 46.3 \u00b1 13.3years with a range of 18\u201385 years. Participants in age range of 41\u201350 years were 31.9%, whereas younger ages (<21 years) were 1.9%. A 2.5% of the participants were >70 years of ages.Degenerative cervical spine findings with resultant neural foramina and/or spinal canal stenoses were seen in 127(79.4%) patients, among these, 68(53.5%) were female and 59(46.5%) were male. Non-degenerative imaging abnormalities such as neoplasm and infection were seen in 10(6.3%) patients. Cervical spine MRI was normal in 23(14.4%) of them.Intervertebral disc (IVD) degenerative changes in the form of desiccation/dehydration, IVD loss of height and disc osteophyte complex in combination or alone were seen in 126(78.8%) patients  and all A disc osteophyte complex with either disc dehydration and/or loss of height was seen in 75(46.9%) patients, with age group > 40 years contributing 85.3%. There was no statistically significant difference among female and male participants regarding IVD degenerative changes (P=0.112).th decade followed by the 3rd decade (27.8%). Only 1(5.6%) patient was seen in age <21 years and no patient seen in age >60 years (A disc osteophyte complex with either disc dehydration and/or loss of height was associated with age group of > 40 years (P< 0.0001). Intervertebral disc herniations excluding disc osteophyte complexes were seen in 18(11.25%) patients, out of which 8(44.4%) were male and 10(55.6%) were female. A 38.9% of them were observed in the 560 years . C5-C6 l60 years .Single level herniations were seen in 11(61.1%) as compared to multiple level herniations which were seen in 7(38.9%) patients. Neural foramina and spinal canal stenoses were seen in 117(73.1%) and 110(68.8%) patients respectively. Imaging findings suggesting spinal cord compression with signal change were seen in 24(15%) patients. Spondylolisthesis was seen in 2(1.3%) patients. Findings suggesting spine tuberculous infection were seen in 3(1.9%) patients. Neoplasms were suspected in 3(1.9%) patients. Other non-degenerative abnormalities categorized under miscellaneous were seen in 4(2.5%) patients. There were three cases of Chiari I malformation (two with syrinx) and one case of congenital block vertebra.The role of cervical spine MRI for evaluation of neck pain has been described in many literatures considering its excellent image contrast in demonstrating IVD, spinal cord, vertebral bone marrow, foraminal stenosis and other many aspects of anatomies such as ligamentous structures , and 12.Intervertebral disc degenerative findings in the form of desiccation/dehydration, loss of height and disc osteophyte complex in combination or alone represent the most common degenerative findings (78.8%) with involvement of more than one-disc level in all cases. Increased prevalence of degenerative findings was seen with age, especially with age above 40 years. This is a similar finding with previous retrospective studies done in Nepal and Nigeria on patients with neck pain that undergo cervical spine MRI evaluation showing degenerative changes such as intervertebral disc desiccation and bulge to have increased prevalence with age ,13.th decade (38.9%) followed by the 3rd decade (27.8%). The C5-C6 level was the most commonly affected level (56.5%) and single level involvement was more common than multiple level involvements. Similar epidemiologic finding was seen in a previous study that included 750 symptomatic patients and showed 159 patients to have disc herniations and C5-C6 level as the most common involved level. Multiple level involvement was seen only in 23 patients (IVD herniation was seen in 18(11.2%) patients with the highest number of patients seen in the 5patients . Disc hepatients .Non-degenerative abnormalities were not common findings. They were seen in 10(6.3%) patients. Two studies on patients with neck pain found non-degenerative pathologies in 12.1% and 35.5% respectively , 17. TheMRI is said to be the modality of choice for imaging spine infections with several imaging findings, such as disc space sparing, multilevel subligamentous spread, and large abscesses, can suggest the diagnosis of tuberculous over pyogenic infection, the two most common spine infections . In thisImaging findings suggesting neoplasm were seen in three (1.9%) patients, two intramedullary neoplasm suggesting glioma and one vertebral metastasis with similar prevalence to previous studies , 15.Out of the 160 patients in this study, 23(14.4%) patients had no remarkable cervical spine MRI findings. The absence of abnormal imaging findings in these patients may be related to different nonstructural factors such as patient background situations including psychosocial, demographic and socioeconomic factors as many previous studies tried to link up and explain neck pain with different perspectives .This study has a number of limitations. This study didn't also follow the treatment given to see patient response, especially those patients with degenerative findings. Control group would have been a good input to compare patterns of degenerative spine changes, especially in relation to advancing age. Detailed clinical backgrounds of patients such as socioeconomic and psychosocial factors were not considered in this study which would have been useful to assess these factors in relation to the pattern of imaging findings among study individuals.In conclusion degenerative cervical spine findings were the most common MRI patterns seen in symptomatic patients in this study showing increasing prevalence with age. Nondegenerative imaging findings such as neoplasm and infection were less common findings."}
+{"text": "To describe clinical and multimodal imaging features in a cohort of choroidal macrovessels.Demographics and multimodal imaging features of 16 eyes of 13 patients with choroidal macrovessels were reviewed. The multimodal imaging included colour fundus photography, fundus autofluorescence (FAF), spectral domain enhanced depth imaging optical coherence tomography (OCT), en face OCT, OCT-angiography (OCT-A), B-scan ultrasonography (US), fluorescein angiography (FFA) and indocyanine green angiography (ICGA).Three patients had bilateral involvement. On colour fundus photography, three patterns were evident . Vessel orientation was horizontal (11 eyes), oblique (4 eyes) or vertical (1 eye). In 2 eyes, the vessel was extra-macular. OCT in all cases showed a hyporeflective choroidal area with posterior shadowing and elevation of the overlying retina. Subretinal fluid was present in 4 eyes. FAF (12 eyes) was normal (7 eyes) or showed a hypofluorescent/hyperfluorescent track (4 eyes) or linear hyperautofluorescence (1 eye). En-face OCT (2 eyes) revealed the course of the macrovessel at the level of choroid and choriocapillaris. On OCT-A (2 eyes) the vessel had a reflectivity similar to surrounding vessels but larger diameter. B-scan US (8 eyes) showed a nodular hypoechogenic lesion. FFA (5 eyes) showed early focal hyperfluorescence (4 eyes) not increasing in later phases, or was normal (1 eye). ICGA (6 eyes) showed early hyperfluorescence of the vessel.Choroidal macrovessels can mimic other entities, leading to underdiagnosis. Appreciating relevant features on different imaging modalities will aid a correct diagnosis. In the previous reported cases, the majority are isolated case reports,The pathogenesis of CM is not understood, and it is unclear whether it is a congenital or an acquired condition, and if it is associated with systemic vascular abnormalities. In the previously reported cases CM was located in the temporal macula, had a horizontal orientation, a diameter ranging between 200 and 300\u2009\u00b5m and a length between 6 and 11\u2009mm. Given its rarity, CM is often not recognised or can be misdiagnosed, potentially masquerading as other conditions, like parasitic infestations,Electronic medical records for all patients attending the Ocular Oncology and Medical Retina Services of Moorfields Eye Hospital between January 2015 and January 2020 were searched for the term \u2018choroidal macrovessel \u2019.Data collected for each patient included sex, age, ethnicity, disease laterality, symptoms, ocular and systemic diseases. All patients underwent a comprehensive ophthalmological examination including best-corrected visual acuity , intraocular pressure, slit lamp biomicroscopy and dilated funduscopy. Multimodal imaging used to study the CM included colour fundus photography , ultrawide field pseudocolour fundus photography , fundus autofluorescence (FAF) , near infrared reflectance  images, fundus fluorescein angiography (FFA) and indocyanine green angiography (ICGA) , spectral domain enhanced depth imaging (EDI) optical coherence tomography (OCT)  and swept source OCT (Topcon Corporation), OCT-Angiography (OCT-A) and OCT en face , ocular ultrasound . Some images were acquired using the \u2018multicolour\u2019 setting of the Heidelberg Spectralis, combining red, green and blue wavelength reflectance imaging.We identified 16 eyes of 13 patients with CM that fulfilled the criteria for this study. Patient demographics, disease laterality, disease location, symptoms, systemic and ocular comorbidities are listed in There were 5 males and 8 females, and the mean patient age was 66 years . The recorded ethnicity was Caucasian in 4 patients (31%), African in 2 (15%), African Caribbean in 1 (8%) and unknown in 7 (46%). The left eye was affected in 8 patients (62%), the right in 2 patients (15%) and both in 3 patients (23%). Symptoms, of decreased central vision and metamorphopsia, were present in only 2 eyes (13%) with a best corrected Snellen visual acuity of 6/60 (1.0 logMAR) and 6/18 (0.48 logMAR), respectively. The remaining 14 eyes of 11 patients were asymptomatic with a mean best corrected Snellen visual acuity of 6/7.5 (0.10 logMAR).Recorded systemic diseases included hypertension in 5 patients (39%), diabetes mellitus in 3 patients (23%), hypothyroidism in 1 patient (8%), peripheral vascular disease in 1 patient (8%), heart disease in 1 patient (8%), hyperlipidaemia in 1 patient (8%), benign prostatic hypertrophy in 1 patient (8%), vertigo in 1 patient (8%) and breast cancer in 1 patient (8%).Ocular comorbidities included glaucoma in 4 eyes (25%) from 3 patients, age-related macular degeneration (AMD) in 3 eyes (19%) from 2 patients, non-proliferative diabetic retinopathy in 2 eyes (13%) from 1 patient, retinal detachment in 1 eye (6%), central retinal vein occlusion in 1 eye (6%), branch retinal vein occlusion in 1 eye (6%). One patient with bilateral CMs had a history of retinal detachment, central and branch retinal vein occlusion in one eye and of neovascular AMD (nAMD) in the other eye. Data on refractive error or axial length were not available.Clinically and on colour fundus photography CM had three distinct patterns . In typeThe CM was macular in 14 eyes (88%) and extramacular in 2 eyes (12%). Macular CM extended temporally in 7 eyes (50%), superotemporally in 4 eyes (29%), superonasally in 1 eye (7%), both nasally and temporally in 1 eye (7%), both superiorly and inferiorly in 1 eye (7%). Among the 2 extramacular CMs, one was located inferotemporally to the optic disc and the other above the supero-temporal vascular arcade. The average length of the CM measured with the calliper function on OCT was 7.3\u2009mm . The orientation of the CM was horizontal in 11 eyes (69%), oblique in 4 eyes (25%) and vertical in 1 eye (6%) . A taper10.1136/bjophthalmol-2020-318095.supp1Supplementary dataEnhanced depth imaging-OCT (EDI-OCT) allowed detailed choroidal imaging. The scans demonstrated the course of the lesion. In all 16 eyes (100%) the CM presented as a round or oval choroidal area with hollow reflectivity and posterior shadowing, occupying the entire thickness of the choroid and causing elevation of the overlying retina and posterior displacement of the sclerochoroidal junction . The vesThe choroidal thickness was adjusted for the age of the subjects and the location of the CM (macular/extramacular) using reference values reported before.Other OCT features included RPE irregularity in 8 eyes (50%), ellipsoid band disruption in 5 eyes (31%) or disturbance in 5 eyes (31%), subretinal fluid (SRF) in 4 eyes (25%). The SRF was macular in 3 eyes (19%) and extramacular in 1 eye (6%). Macular SRF was subfoveal in 2 eyes (13%) and extrafoveal in 1 eye (6%). The average vertical and horizontal diameters of the vessel\u2014measured using the calliper function at the level of the ampulla of the CM when visible (14 eyes)\u2014were 233\u2009\u00b5m and 429\u2009\u00b5m, respectively. OCT findings for our patient cohort are summarised in FAF was performed in 12 eyes (10 patients) and showed no abnormalities in 6 eyes (50%), a hyperautofluorescent/hypoautofluorescent track in 4 eyes (33%)  and lineOCT-A is a non-invasive diagnostic tool offering a rapid three-dimensional visualisation of blood flow in retinal, choriocapillaris and choroidal circulation without injecting any contrastOcular B mode US was performed in 8 eyes (seven patients) and showed in 6 eyes (75%) a nodular lesion with low internal reflectivity and an average thickness of 0.84\u2009mm  , while iFFA performed in 5 eyes (5 patients) showed focal hyperfluorescence due to window defects in the early phase that did not increase in intensity or width in the late phases, with staining in four eyes (80%). No evidence of arterio-venous anastomosis, ischaemia or late leakage was detected. In 1 eye (20%) with extramacular CM the wide field FFA was normal.Features on ICGA in 6 eyes of 6 patients showed hyperfluorescence of the CM and delineation of its serpiginous shape in the early phase, while in the later phases the fluorescence decreased to become similar to the surrounding vessels with focal hypofluorescent spots . Both FF10.1136/bjophthalmol-2020-318095.supp2Supplementary dataCM is a relatively rare anatomical abnormality, which can be confused with parasitic infections or even vascular fundus tumours. To date this series is the most sizeable collection of CM cases reported, with this entity mainly described in case reports in older adults. We observed a patient outside the commonly reported range, aged 27 years, and therefore an early onset or congenital nature of CM cannot be excluded. The youngest affected individual in the literature is a case reported by Turgut and Kobat in a 12-year-old with retinitis pigmentosa.CM is considered an isolated ocular finding, since no confirmed systemic association has been found. The systemic conditions previously reported in the literature include: hypothyroidism in 2 patients,CM has seldom been found with other ocular disorders in the past, occurring with dry AMD in only three patientsPrevious reports found only unilateral CM. In our study, we observed bilateral CMs in 23% of cases. CMs reported previously were all located within the macula, temporal to the fovea with extension towards the equator. Instead, in our cohort we observed CMs at the nasal edge of the fovea and some were extramacular. We also found CMs with an oblique and a vertical orientation. All these observations are novel, and it would be interesting to see if larger studies corroborate these.et alet alet al hypothesised that a CM may hasten AMD from relative ischaemia due to compression of the choriocapillaris or direct mechanical action on the RPE cells.Choudhry and Rao,FAF was normal in 50% of eyes with CM but other patterns were a hyperautofluorescent/hypoautofluorescent track or linear hyperautofluorescence. These findings may represent different stages of the abnormality and its local effects on the overlying RPE. Previous data about FAF are limited and included a variable hyperfluorescence over the lesion.The visualisation of choroidal vascularity on OCT-A is not always straightforward owing to the presence of imaging artefactsICGA is an important tool to understand the vascular nature of the CM and helps to rule out choroidal vasculitis and other alternative diagnoses, such as a choroidal haemangioma. FFA showed non-specific findings, in line with those previously reported,Oedemagena Tarandi and Alaria Americanus, cause a serpiginous cicatricial track at the level of the RPE generally accompanied by exudation.Parasitic infestations are a frequent differential diagnosis of CM as the pigmented chorioretinal atrophic spots may be confused with residual scars from an inflammatory process. Nematode infections, especially Some cases are referred with a possible choroidal neoplasm, particularly circumscribed choroidal haemangioma. However, circumscribed choroidal haemangioma has different features: on OCT it has a dome-shaped configuration and circumscribed dilated choroidal vascular channels, and on ICGA has an early filling with early maximal fluorescence and a late wash-out.Other vascular lesions also need to be ruled out. Vortex veins ampullae are venous in nature while CMs appear to be arterial. CMs differ from retinochoroidal anastomoses that shunt retinal venous drainage into the choroid, since they do not communicate with the retinal circulation. Moreover, none of our cases had a history of previous ocular trauma, inflammation and perifoveal teleangectasis that could have caused abnormal shunts.The limitations of our study include the retrospective nature and the small sample cohort, hence the repeatability of our fundoscopic classification needs to be verified. There is likely to be an ascertainment bias as CMs in the posterior pole, rather than in the periphery, are more likely to be detected. We acknowledge that the measurement of the length or calibre of an irregular curved structure in three dimensions is prone to bias. OCT-A was performed in only 2 eyes, so it is unclear how far our findings would generalise to CM. No data on axial length are available. Longitudinal studies including larger numbers of patients will help overcome these barriers to better understand the epidemiology, pathogenesis, natural history and prognosis of CM. Multimodality imaging could help make more easily the diagnosis of this entity, and therefore, will become better recognised."}
+{"text": "C9orf72 hexanucleotide repeat expansion (HRE) alone or C9orf72 and multigene sequencing panel testing. We compared the incidence of pathogenic (P), likely pathogenic (LP), and uncertain variants in C9orf72 and other ALS-FTD genes, as well as age at testing, in patients of different REA. The diagnostic rate in patients of European REA  was significantly higher than in patients of underrepresented REA  (p < 0.001). Patients of European REA were more likely to have the C9orf72 HRE (21.3%) than patients of underrepresented REA (10.4%) (p < 0.001). The overall distribution of positive test outcomes in all tested genes was significantly different between the two groups, with relatively more P and LP variants in genes other than C9orf72 identified in patients of underrepresented REA. The incidence of uncertain test outcomes was not significantly different between patients of European and underrepresented REA. Patients with positive test outcomes were more likely to be younger than those with negative or uncertain outcomes. Although C9orf72 HRE assay has been advocated as the first, and in some cases, only genetic test offered to patients with ALS-FTD in the clinical setting, this practice may result in the reduced ascertainment of genetic ALS-FTD in patients of diverse REA. Preliminary evidence suggests that commonly used genetic tests may be less likely to identify a genetic etiology for ALS-FTD in patients of underrepresented race, ethnicity, and ancestry (REA), as compared to European REA. Patients of underrepresented REA may therefore be less likely to receive accurate and specific genetic counseling information and less likely to have access to gene-targeted therapies currently in clinical trials. We compiled outcome data from 1911 ALS-FTD patients tested at a commercial laboratory over a seven-year period for  Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by the loss of upper and lower motor neurons. Individuals with ALS experience progressive paralysis that ultimately results in death within an average of three to five years after symptom onset . ALS hasALS affects individuals of all races, ethnicities, and ancestries (REA); however, the incidence rates vary across REA groups in the United States of America. The European or white REA group has the highest incidence, followed by African American or black, then Asian. Non-Hispanic REA has a higher incidence of ALS than Hispanic REA . The incIn addition to the variation in incidence rates of ALS across REA groups, clinical presentations of the disease differ across groups. The average age of onset of ALS symptoms is younger in Black or African American people 50\u201359 years) than that of individuals in other REA groups (60\u201369 years). Hispanics have an average age of onset that is approximately four years lower than the age of onset for non-Hispanic patients. The mean duration from symptom onset to diagnosis is lowest among African Americans (15.6 months) and highest among Asians (20.4 months) , while a years thC9orf72, TARDBP, SQSTM1, VCP, FUS, TBK1, CHCHD10, and UBQLN2 [C9orf72 gene is the most identified genetic cause of both ALS and FTD. This gene was discovered in 2011 and is responsible for approximately 40% of fALS and fFTD cases, and up to 7% of sALS and sFTD cases [A genetic etiology is identified in approximately 70% of familial ALS (fALS) and familial FTD (fFTD) cases, 15% of sporadic ALS (sALS) cases, and 7% of sporadic FTD (sFTD) in North American research cohorts, which consist primarily of patients of European descent ,10,11,12C9orf72 HRE first appeared in Scandinavia approximately 1500 years ago and spread throughout Europe with the conquests of Vikings. The geographical distribution of the C9orf72 HRE and Viking routes are remarkably similar, supporting this theory on the spread of this variant [C9orf72 HRE has remained most prevalent in European patients. In a 2012 study of a global cohort of 4448 individuals with ALS and 1425 with FTD, the frequency of C9orf72 HREs was determined across different ethnic groups; clear variation was found with the highest frequency in patients of European REA [Genetic and historical evidence suggests that the  variant ,15. Todapean REA ,17,18. Dpean REA ,24,25,26C9orf72 HRE assay, and whole-exome sequencing [C9orf72 HRE cannot be detected via sequencing, clinicians must order the HRE assay separately. Some clinics offer testing for the C9orf72 HRE as the first and sometimes only test for patients with ALS-FTD due to its high prevalence in patients of European REA [Current US ALS management guidelines do not address the offer of genetic testing, and there is a lack of consensus among clinicians on what testing should be offered to patients and in what clinical scenarios ,28. Commquencing . Since tpean REA ,29,30. TMissed genetic diagnoses are expected to negatively impact the care of patients of underrepresented REA. The current understanding of gene-disease relationships is based primarily on the study of individuals of European REA, and patients of underrepresented REA are less likely than Europeans to receive a definitive genetic diagnosis for their disease across many medical specialties ,34,35,36C9orf72 HRE analysis exclusively or C9orf72 HRE analysis with reflex to multigene-panel or single-gene analysis  and reads were aligned to a reference sequencing (hg19). All variants were interpreted per the American College of Medical Genetics variant classification guidelines, and only uncertain, likely pathogenic, and pathogenic variants were reported [This study was deemed exempt from review by The Ohio State University Institutional Review Board (IRB) in Columbus, Ohio. A retrospective review of a commercial laboratory testing database was performed to identify a cohort dataset consisting of all patients who underwent ALS-FTD genetic testing at the Prevention Genetics Laboratory from 2013 to 2020. The cohort included representation from both the USA and Canada with samples received from multiple different national ALS-FTD centers and Canadian provinces. This dataset included 1911 individuals of diverse REA between the ages of 8 and 96 years old who underwent analysis A. C9orf7reported . C9orf72 HRE testing exclusively and for those that had C9orf72 HRE testing followed by multigene or single gene sequencing. For cases that underwent C9orf72 HRE testing, Fisher\u2019s exact test was performed to determine the distribution of positive C9orf72 HREs across REA groups. For tests performed on the distribution of multigene panel results, distribution of testing ordered, and cohort diagnostic yields, chi-square testing was performed to identify significant differences across REA groups. One-way ANOVA tests were performed to determine if age at testing differed by genetic test outcome. A two-way ANOVA test was performed to determine if the age at testing differed by the genetic test outcome between those of European and underrepresented REA.The collected data included the clinician-reported patient ancestry, patient year of birth, test ordered, date of test order, and test result including variant(s) identified and interpretation. All tested individuals with REA information provided were sorted into nine REA groups, closely matching ancestral groups in the gnomAD population database , European (Non-Finnish), Other, South Asian, and Mixed Non-European). Genetic test outcomes and ages at testing were then compared between REA groups. Cases were collapsed into European (European (Finnish), European (Non-Finnish)) and Underrepresented REA  for most analyses. Analysis was performed for cases that underwent Among 1911 cases in the tested cohort, 1592 (83.3%) were classified as European Non-Finnish, 73 (3.82%) as African/African American, 12 (0.63%) as Ashkenazi Jewish, 22 (1.15%) as East Asian, 3 (0.16%) as European Finnish, 33 (1.73%) as Latino, 87 (4.55%) as Mixed Non-European, 11 (0.58%) as South Asian, and 78 (4.08%) as other B. After p < 0.001). Among patients of African/African American REA, 5/73 (6.85%) were found to have the C9orf72 HRE and 4/73 (5.48%) had P/LP variants in SOD1. Among patients of Ashkenazi Jewish REA, 5/12 (41.67%) were found to have the C9orf72 HRE. Among patients of East Asian REA, 1/22 (4.55%) had a P/LP variant in TARDBP. Among patients of European Finnish REA, 1/3 (33.33%) were found to have an LP in SOD1. Among patients of European Non-Finnish REA, 339/1592 (21.29%) were found to have the C9orf72 HRE, 19/1592 (1.19%) had P/LP variants in SOD1, 3/1592 (0.19%) had P/LP variants in FUS, 3/1592 (0.19%) in MAPT, and 2/1592 (0.13%) had variants in TBK1; a P/LP variant in TARDBP, VCP, TREM2, VAPB, GRN, PSEN1 was identified in one case each. Among patients of Latino REA, 2/33 (6.06%) had the C9orf72 HRE, and a P/LP variant in SOD1 and MAPT were found in one case each. Among patients of Mixed Non-European REA, 17/87 (19.54%) were found to have the C9orf72 HRE and 1/87 (1.15%) had a P variant in PSEN1. Among patients of Other REA, 3/78 (3.85%) had the C9orf72 HRE and 1/39 (2.56%) had a LP variant in GRN. Among patients of South Asian REA, 1/11 (9.09%) tested positive for the C9orf72 HRE  or likely pathogenic (LP) variant identified in an autosomal dominant gene or two P or LP variants in a recessive gene) was 421/1911 (22.03%). Testing was more likely to establish a genetic diagnosis in patients of European REA  than for patients of underrepresented REA  . The incidence of the p = 0.012, p = 0.64), suggesting that there are differences in the outcomes of panel testing between individual REA groups, such as between African/African Americans and Asians. The overall rate of positive, negative, and uncertain results on sequencing panel testing was determined across all REA groups and between European and underrepresented patients who underwent panel testing (see C9orf72) compared to patients of European REA  and after collapsing European and underrepresented REA (p = 0.459). The highest rate of uncertain results was found in patients identified as \u201cOther\u201d REA (26.3%), while the lowest rate was found in patients identified as Ashkenazi Jewish (0.0%). The rate of uncertain test outcomes was 8.9% and 11.6% for patients of European and underrepresented REA, respectively.The proportion of uncertain results did not significantly differ by REA group for those that underwent sequencing panel testing. This was observed comparing all REA groups individually .The patient age at testing and test outcomes were compared across the cohort and across REA groups. For patients who underwent C9orf72 HRE analysis exclusively versus the addition of multigene panel testing) did not differ between patients with European vs. underrepresented REA (p = 0.87). The type of test ordered  did not appear to be associated with the type of testing ordered  (p = 0.87). This suggests that clinicians are not considering patient REA in their ordering practices. Our results may reflect clinician bias towards offering the C9orf72 HRE as a sole test; had more patients of underrepresented REA had more comprehensive testing, the proportion of positives in genes other than C9orf72 could potentially be even higher. It is unclear from this data why clinicians ordered C9orf72 HRE analysis exclusively in some cases while in others ordered the analysis of additional genes. Although this could reflect clinical factors not included in our dataset, such as family history, it could also reflect variable and inconsistent clinical practice. Genetic testing guidelines for ALS-FTD are needed to improve the diagnosis in underrepresented and all ALS-FTD patients worldwide.Notably, a significantly higher proportion of patients of underrepresented REA tested positive in genes other than C9orf72 HRE analysis as a first test to patients of underrepresented REA is indicated in clinical practice in North America and potentially other geographic areas with a history of European colonization and admixture across REA groups. However, additional genetic testing should be offered for patients of underrepresented REA who test negative for the HRE, given that a higher proportion are expected to have pathogenic variants in other genes, such as SOD1. The offer of C9orf72 HRE assay as a sole genetic test may result in reduced ascertainment of genetic ALS-FTD in patients of underrepresented REA and is not recommended for this group. Our data suggest that the offer of the In this large cohort, the rate of uncertain test outcomes (results with variant(s) of uncertain significance as the only finding) was not significantly different between patients of European and underrepresented REA. Similarly, a study of genetic test outcomes in a midwestern US ALS clinic reported that uncertain test outcomes were not more common in non-Caucasian than Caucasian patients . This fiC9orf72 compared to Europeans, and such genes (including SOD1) have been associated with earlier presentations of ALS symptoms than C9orf72 [These test outcome data reveal that patients with positive test results were more likely to be younger than patients with negative or uncertain results. Additionally, of those that tested positive, patients of underrepresented REA were more likely to be younger than those of European REA. This could reflect increased exposure to environmental or lifestyle risk factors, or genetic factors. We found that patients of underrepresented REA were relatively more likely to have pathogenic variants in genes other than  C9orf72 . This fi C9orf72 . We sugg C9orf72 ,49. We n C9orf72 ,50.Although the aim of this study was to investigate the genetic profile of ALS-FTD in patients of diverse REA, patients of European REA comprised the majority of the studied cohort. Many analyses were limited by small numbers in individual REA groups, necessitating the collapsing of different groups into one underrepresented REA category, potentially obscuring important differences. In order to better investigate the genetic profile of specific REA groups, patients from those groups  should be specifically recruited and studied. Another limitation to this study was that clinician-reported REA was used for this analysis as opposed to genetically determined ancestral assignment. Clinician-reported REA included a variety of geoancestry descriptors that were used as a proxy for the geoancestry categories used in the gnomAD database. The lack of consistent terminology and the intermixing of race, ethnicity, and ancestry terms when reporting REA information has been a barrier to investigating the impact of REA in clinical genetic testing ,51. As aC9orf72 HRE test is indicated for ALS-FTD patients of underrepresented REA in North America; (2) Additional comprehensive genetic testing should be offered for patients of underrepresented REA, either concurrently or as a second step if negative for the HRE; (3) patients with early-onset ALS-FTD should also be considered candidates for comprehensive genetic testing. As genetic testing becomes more widely adapted in patient care, it is crucial to understand the genetic profile of ALS-FTD across all REA groups. This study of a large North American clinical laboratory cohort identified significant differences in the genetic etiologies of ALS-FTD between REA groups and confirmed that genetic testing for ALS-FTD is more likely to establish a diagnosis in patients of European REA, compared to underrepresented REA. Our findings have several implications for clinical genetic testing practice: (1) the offer of the Genetic testing protocols which maximize the identification of genetic ALS-FTD in patients of all REA are critically needed as gene-targeted therapies reach clinical trials. The development, evaluation, and publication of REA-specific or comprehensive pan-ethnic genetic testing guidelines will help all patients benefit from the coming age of personalized genetic medicine in ALS-FTD."}
+{"text": "To evaluate the results of pars plana vitrectomy (PPV) and silicone oil (SO) tamponade with or without encircling scleral band for repair of rhegmatogenous retinal detachment (RRD) in children with buphthalmos.Retrospective comparative nonrandomized interventional case series including consecutive patients who underwent PPV with or without encircling band and SO tamponade for RRD associated with buphthalmos.The study included 19 eyes of 19 children. Mean age was 8 years, range 3\u201316 years. Mean follow-up period was 28 months, range 19\u201363 months. Globe survival has been achieved in 15 out of 19 eyes (79%). Phthisis bulbi was reported in four cases (22%). Eight patients (42%) achieved ambulatory vision. Most eyes initially achieved anatomical success.Despite the poor visual and anatomical results of RRD repair in eyes with buphthalmos, globe survival might be the rationale for surgery in such cases. Globe preservation could avoid the psychological and social consequences of phthisis bulbi in non-operated children. Rhegmatogenous retinal detachment (RRD) is a major cause of loss of vision in adults. RRD occurs often in children. The reported incidence is 3\u201312% of all cases. Rarely, RRD is associated with primary congenital glaucoma . The cliThis is a retrospective comparative interventional non-randomized case series that included children who had PPV for RRD associated with buphthalmos. Data of patients was retrieved from the medical records of all pediatric patients operated for RRD in a tertiary retinal center; Magrabi eye hospital, Tanta, Egypt, during the period from June 2008 to April 2019. Preoperative examination included; best-corrected visual acuity (BCVA) assessment and intraocular pressure (IOP) measurement when those were possible, slit-lamp examination, fundus examination using indirect ophthalmoscopy, and B-scan ultrasound evaluation.A single surgeon (HG) operated on all cases under general anesthesia. An encircling scleral band style 240 (2.5 mm) was combined with PPV except in patients who had functioning filtering bleb, aqueous filtering devices, e.g. Ahmed\u2019s valve, or presence of scleral ectasia. Pars plana lensectomy was performed in all phakic children without intra-ocular lens (IOL) implantation. PPV consisted of core vitrectomy; triamcinolone acetonide (TA)-assisted induction of posterior vitreous detachment (PVD). Perfluorocarbon liquid (PFC) stabilized the posterior retina during shaving the vitreous base. The surgeon then performed air-fluid exchange, endo-laser retinopexy to retinal breaks and in an encircling 360\u00b0 pattern. Finally, SO/air exchange was done. The surgeon routinely used SO 5000 centistokes (cSt) in all patients. Inferior surgical iridectomy (at 6 O\u2019clock) was created in all aphakic eyes. Sclerotomies were closed using 7/0 vicryl sutures.Cooperative children were instructed to maintain prone position 8 h per day for 1 week. Those children had slit-lamp examination in the first postoperative day. If possible, fundus examination, and color fundus photography were done to asses and document retinal reattachment. The follow-up was scheduled at 1, 3, and 6 weeks, and then every 8 weeks. In each visit, we recorded BCVA and IOP when possible and assessed retinal re-attachment. Uncooperative or young children had examination under general anesthesia; where anterior segment was examined using the surgical microscope, IOP was measured using schiotz tonometer and the fundus was examined using the indirect ophthalmoscope.The term globe survival refers to eyes that did not need enucleation until the end of the follow-up period. Main outcome measures were retinal reattachment, improvement of BCVA and globe survival rate.Patients who developed recurrent retinal detachment under SO during follow-up, had revision surgery that consisted of SO removal, TA-assisted removal of any residual vitreous cortex and peeling of epiretinal membranes. The surgeon performed relaxing retinotomy and/or retinectomy for immobile and shortened retinae when needed followed by air/fluid exchange, drainage of sub-retinal fluid, endolaser retinopexy and finally SO 5000 cSt injection and closure of sclerotomies using 7/0 vicryl sutures.Silicone oil was removed in all eyes that had stable retinae for at least 6 months. The technique consisted of 2-port 20-gauge or 23-gauge sclerotomies or both combined). One port was used for infusion, and the other for SO aspiration. The retina was thoroughly examined looking at the retinal periphery and the site of retinal breaks. SO was extracted manually or aspirated followed by multiple partial air/fluid exchange. Sclerotomies were closed using 7/0 vicryl sutures. The parents of all children recruited for the study provided a written informed consent after receiving thorough explanation of all surgical procedures entailed, prognosis for vision, and possible complications.The study recruited 19 eyes of 19 children. Male gender constituted 16 patients (84.2%). Mean age was 8.3 years, (range 3\u201316 years). At the time of recruitment, 18 children (94.7%) already had sub-scleral trabeculectomy (SST) and one child (5.3%) had glaucoma drainage device; Ahmed glaucoma valve done elsewhere. In terms of number and location of retinal breaks, 6 eyes (31.6%) had giant retinal tear (GRT), 3 eyes (15.8%) had multiple retinal tears; whereas 5 eyes (26.3%) had a single retinal break. We are unable to detect retinal breaks in 5 eyes (26.3%). An encircling scleral band was combined with PPV in 8 cases (42%). A scleral band was not applied in the remaining 11 cases. One eye had functioning Ahmed glaucoma valve, 6 eyes had scleral thinning and/or ectasia and 4 eyes had functioning bleb.All cases had successful retinal reattachment after the first surgery. During the follow-up period, 4 patients (21%) had revision of surgery and silicone reinjection due to recurrent RD. By the end of follow-up period 6 eyes (31.6%) had recurrent RD under SO that was either localized or total. SO was removed after stability of retinal status for at least 6 months in 4 out of 19 cases (21%). SO was not removed in the remaining cases due to poor visual potential, hypotony or band shaped keratopathy, which prevented proper retinal evaluation. The rate of globe survival with free ocular movements in all directions of gaze was 78.9%.Different degrees of exotropia developed in 6 eyes (31.6%). Four eyes (21%) developed phthisis bulbi at variable periods during follow-up.In 14 patients, IOP was controlled without anti-glaucoma drugs. IOP elevation developed after surgery in 5 patients, of which 2 patients required cyclophotocoagulation using diode laser and 3 patients had their IOP controlled using anti-glaucoma medications.The cornea remained clear in 13 eyes. In 6 eyes SO migration to the anterior chamber with prolonged contact to the endothelium resulted in band keratopathy that contributed to their final poor visual outcome.Post-operatively, 8 eyes (42%) achieved ambulatory vision, of which 2 eyes had final BCVA of 2/60 and 6 eyes had final BCVA of 1/60. Final BCVA remained stationary (HM or PL) in 6 eyes (31.5%). Vision deteriorated in 5 eyes (26%). Poor visual outcome occurred mainly due to band keratopathy, PVR, and glaucomatous optic atrophy.Congenital glaucoma is a major cause of blindness in children, despite its low incidence (1:10.000 births). The disease is bilateral in approximately 75% of cases. Male patients account for approximately 65% of cases. Many authors corroborate the theory of polygenic pattern of inheritance . In pediRepair of retinal detachment in eyes with buphthalmos carries poor visual and anatomical results, thus globe preservation might be the rationale of surgery in such cases. Surgical repair and globe preservation conservation could avoid the psychological and social consequences of phthisis bulbi in non-operated eyes. Moreover, ambulatory vision might be obtained in some eyes."}
+{"text": "Although they are often considered contaminants, coagulase negative staphylococci (CoNS) can be pathogens especially in immunocompromised patients. National and local guidelines recommend treatment durations of 7 to 14 days, depending on specific clinical scenarios. The objective was to characterize the duration of treatment for CoNS bacteremia and clinical outcomes at our cancer center. \u226518 years old with \u22651 blood culture with growth of CoNS between 1/1/17 and 12/31/19 at our cancer center. Patients with complicated CoNS bacteremia and polymicrobial infections were excluded.We conducted a retrospective chart review of adult patients st negative blood culture was 12 days; 29 (30%) patients were treated for a total duration of >14 days . The catheter was retained in 67 (68%) and exchanged in 4 (4%) of the cases. Three (3%) patients had recurrence of bacteremia within 30 days of treatment completion, and 8 (8%) patients were transferred to the ICU within 7 days of the index blood culture. The 30-day crude mortality rate was 10%. The most commonly used antibiotic for treatment was vancomycin , and 32 (34%) patients on vancomycin had an increase in serum creatinine of \u2265 50% from baseline. Five (5%) patients discontinued vancomycin due to nephrotoxicity, and 4 (4%) patients required hemodialysis.Among 128 patients identified during the study period, 98 met inclusion criteria . Most patients  had a hematologic malignancy as the underlying oncologic diagnosis, and 68 (69%) were hematopoietic stem cell transplant recipients. The median total antibiotic duration was 13 days, and median duration from the date of 1Figure 1. Results OverviewAmong 128 patients identified during the study period, 98 met inclusion criteria. Of those included, 36 had one set of blood cultures that were positive for CoNS and 62 patients had at least two sets of blood cultures that were positive for CoNS.Figure 2. Duration of Antibiotic TreatmentWe evaluated duration of treatment based on total antibiotic duration and duration from date of 1st negative blood culture. The number of patients is noted above each bar.\u226414 days for uncomplicated CoNS bacteremia, nearly 1/3 of patients were treated for > 14 days. Recurrent bacteremia was uncommon despite catheter retention in most patients. Relatively high rates of vancomycin associated nephrotoxicity highlight opportunities for antimicrobial stewardship to limit duration of vancomycin therapy among cancer patients with uncomplicated CoNS bacteremia. Although the majority of patients were treated for All Authors: No reported disclosures"}
+{"text": "To determine the clinical and radiological outcome of proximal femur shaft fractures in school going children treated with locking compression plates (LCP).th June 2018 to 25th September 2020. Children of either gender and age 6 to 12 years old with subtrochanteric and proximal one third femur factures fulfilling the inclusion criteria were enrolled in this study. Open reduction and internal fixation with 4.5 mm narrow locking compression plates (LCP) were done in all. Post operative clinical outcome was evaluated by using Flynn scoring system and graded as excellent, satisfactory and poo results. Radiological assessment of fracture union was done through anteroposterior (AP) and lateral X-ray radiographs.This descriptive study was conducted in Orthopaedic Division Lady Ready Reading Hospital Peshawar from 25A total of 60 children with mean age 9.01\u00b11.61 SD (range 6 to 12 years) were included in our study. Oblique fractures were present in 23(38.3%) children, spiral in 20(33.3%), transverse in 11(18.3%) and comminuted in 6 (10%) children. The radiological union time was 13.3\u00b11.2 weeks (range 9.4 to 18 weeks). Majority  of children had excellent clinical outcome according to Flynn\u2019s scoring system while satisfactory outcome was noted in 7(11.6%) children. No cases of delayed union, mal union, nonunion and implant failure was reported.The results of our study indicated that proximal femoral shaft fractures in school going children treated with locking compression plates had excellent clinical and radiological outcome. We therefore recommend locking compression plate as the implant of choice to fix proximal femoral shaft fractures in school going children. Subtrochanteric femur fractures in children accounts for approximately 4 to 10% of all femur fractures.5These fractures are treated with locking compression plates(LCP) to avoid excessive per operative radiation hazards and to minimize the post operative complications of flexible intramedullary nails.11The objective of our study was to determine the clinical and radiological outcome of proximal femur shaft fractures in school going children treated with locking compression plates. The results of our study will help us in formulating guidelines for treating subtrochanteric and proximal femur shaft fractures in school going children in our set up.th June 2018 to 25th September 2020. The study protocols were approved by the Ethical Review Board of Lady Reading Hospital . Children of either gender and age 6 to 12 years of age with closed subtrochanteric femur fractures (Fielding Type-II and Type-III fractures)This descriptive study was conducted in Orthopaedic Division Lady Ready Reading Hospital Peshawar, from 25Open reduction and internal fixation with locking compression plates (LCP) were performed under general anaesthesia. Preoperative second-generation intravenous cephalosporin (Cefuroxime) was given. The fracture was reduced under vision and lagged . An appropriate length 4.5mm narrow straight titanum locking compression plate (LCP) was utilized to stabilize the fracture with at least six cortices above and six below the fracture. Unicortical locking screws were inserted for fractures near the physis or joint. All the surgeries were done by the same team of expert orthopaedic consultants. Check X-ray was advised next day. Post operatively hip, knee and ankle exercises were started by physiotherapist on first post operative day and patient was discharged. Intravenous antibiotics were continued for three days.nd week for initial three months and then every 3rd month until one year. In each visit clinical outcome was evaluated by using Flynn scoring systemth months after surgery.th week after complete radiological union provided the child has full range of hip and knee motion, painless weight bearing and squatting.Post operatively all the patients were assessed by an orthopaedic consultant other than the operating surgeon in outpatient department every 2The data was analyzed with SPSS version 20. Important quantitative variables like age and union time was presented as mean and standard deviation while qualitative variables like gender, cause of fracture and side of fracture was presented as frequencies and percentages. The data was presented in table and graph where necessary.th week post operatively while full weight bearing at 12th weeks and onwards. Majority 53 (88.4%) of patients had excellent clinical results according to the Flynn scoring system while satisfactory results were noted in 7(11.6%) patients. No poor results were reported. Hip and knee range of motion were normal. All fractures united. No cases of delayed union, mal union, nonunion and implant failure was reported. Superficial skin infection was reported in 4(6.6%) patients which was resolved with daily dressing and antibiotics. Limb length discrepancy (LLD) was noted in 3(5%) children. Shortening of about 1.5 cm was noted in 1(1.6%)and lengthening of about 1.5 cm in 2(3.3%) children. The average hospital stay was 6\u00b12 days (range two to 10 days). Plates were removed in 41(68.3%) patients . The removal was easy in 23(56%) patients and difficult in 18(43.9%). The difficult plate removal patients were cases with post op duration of 32 weeks. No refracture was reported on average follow up of 12th weeks after plate removal.The total number of patients in our study were 60. The mean age was 9.01\u00b11.61SD (range 6 to 12 years). Male were 43(71.6%) and female 17(28.3%). Right femur was fractured in 39(65%) and left in 21(35%). Majority  of fractures were caused by motor vehicle accidents while 17(28.3%) children sustained fractures due to fall from height. Fielding Type-II fracture was noted in 9(15%), Type-II in 22(36.6%) and proximal one third femur in 29(48.3%). The patterns of fractures were oblique in 23(38.3%) spiral in 20(33.3%) transverse in 11(18.3%) and comminuted in 6 (10%). Most  children were received in hospital within 24 hours of sustaining the fracture, 22(36.6%) in 24 to 48 hours and 7(11.6%) in 48 to 72 hours. The average radiological complete union time was 13.3\u00b11.2 weeks (range 9.4 to 18 weeks). Partial weight bearing was allowed at 6Good outcome results have been reported in paediatric subtrochanteric and proximal femur shaft fractures treated with open reduction and internal fixation with locking compression plates (LCP).We had observed superficial skin infection in 4(6.6%) children and limb length discrepancy (LLD) in 3(5%) children. Shortening of about one cm was noted in 1(1.6%) and lengthening of about 1.5 cm in 2(3.3%) children. Studies have shown that although small overgrowth of femur fracture is common in children, limb length discrepancy of more than two cm can affect child\u2019s normal posture and walking and require surgery for correction.In our study we adopted the open method of plating to fix subtrochanteric and proximal one third fractures (Radiographs I-IV). Some studiesTwo possible issues of LCP application needs to be mentioned here. First, the cost of titanum locking compression plate can be an important issue particularly in developing countries like Pakistan where LCP cost is four times that of conventional plates.th weeks after plate removal. Becker T et alWe had not documented any refracture after plate removal on an average follow up of 12First, the design of our study was descriptive rather than comparative. Second, we could not analyze some variables of our study like surgery time, blood loss and body mass index. Third, our follow up after plate removal was short. We recommend further studies to address all such limitation and verify our results.The results of our study indicated that proximal femoral shaft fractures in school going children treated with locking compression plates had excellent clinical and radiological outcome. It had minimum complications. No image intensifier was needed in these fixations. We therefore recommend locking compression plate as the implant of choice to fix proximal femoral shaft fractures in school going children.FASH conceived, designed and did statistical analysis & editing of manuscript.MAA did review and final approval of manuscript, he is also the accountable for the accuracy or integrity of the work.NU did data collection and manuscript writing."}
+{"text": "The corona virus disease 2019 is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 belonging to corona viruses which are enveloped positive stranded RNA viruses. Non-critical coronavirus disease 2019 patients often lack follow up visits which has led to incomplete understanding of disease process. The aim of this study was to find out the prevalence of persistent symptoms in such patients during two months follow-up to a district hospital.This descriptive cross-sectional study was conducted in a district hospital from September 2020 to February 2021 among non-critical corona virus disease 2019 patients admitted to the isolation center of Nepal. Ethical approval was taken from the ethical review board of Nepal Health Research Council (reference number: 1707). Convenience sampling was done. Data was collected using a structured questionnaire. Data analysis was done using Statistical Package for the Social Sciences version 26. Point estimate at 95% Confidence Interval was calculated along with frequency and proportion for binary data.Out of 132 patients, 66 (50%)  patients had persistent symptoms at two-month follow-up. Forty-eight (36.4%) patients showed one symptom, 15 (11%) had two symptoms, and 3 (2%) had two or more symptoms. The most frequent symptom reported was fatigue in 17 (13%), cough in 15 (11%), myalgia in 9 (7%), and headache in 9 (7%).The prevalence of persistent symptoms at two months follow up in our study was lower than findings from other international studies. Several observational studies describe more one third of patients experiencing persistent physical and psychological symptoms as long COVID 19.5 Despite earlier data show shorter recovery time with mild disease, there is wide variability in duration for symptom resolution.6Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) belonging to coronavirus family.7 There is huge gap of knowledge on clinical course of non-critical COVID-19 after being discharged from hospital.8Spectrum of severity in COVID-19 patient varies widely from asymptomatic to critical with majority being only mild symptomatic.Thus, this study was done to find out the prevalence of persistence of COVID-19 symptoms among non-critical patients at two-month follow-up.A descriptive cross-sectional study was conducted at the COVID-19 isolation hospital of Myagdi district, Nepal from September 2020 to February 2021. Ethical approval was taken from the Journal of Nepal Health Research Council (reference number: 1707). Non-critical COVID-19 patients, who do not develop any complications of COVID-19 and who do not need ICU or ventilatory support; fell under inclusion criteria of study. Exclusion criteria of study included patients deceased or admitted to the ICU, patients transferred to tertiary health care center for further management, and those who were unable to make follow up visit or unable to answer a phone within day 60 of symptoms onset. Subjects with medical emergency, vulnerable groups and children were also excluded. Convenience sampling was done and the sample size was calculated using the formula,Where,n = minimum required sample sizeZ = 1.96 at 95% Confidence Interval (CI)p = prevalence taken as 50% for maximum sample sizeq = 1-pe = margin of error, 9%The required sample size was 119. Adding a 10% nonresponse rate, we arrived at a sample size of 131. We included 132 patients in the study. All data were collected after informing participants about study objectives and significance of the study.Data were entered and analyzed using the Statistical Package for the Social Sciences with version 26. Point estimate at 95% CI was calculated along with frequency and proportion for binary data.Of the 132 patients included in the study, the prevalence of persistent COVID-19 symptoms at two months follow up was 66 (50%) (41.5-58.5 at 95% CI). The remaining 66 (50%) were completely free from any COVID-19 related symptom. Fourty-eight (36.4%) had one symptom, 15 (11%) had two symptoms, three (2%) had two or more symptoms .The mean duration of follow up was 60.9\u00b11.035 with minimum of 59 and maximum of 65 days.The most common symptoms in the order of their frequency were fatigue in 17 (13%), cough in 15 (11%), myalgia in 9 (7%), headache 9 (7%), loss of appetite in 9 (7%) . None ofThere were 104 (78.8%) males and 28 (21%) females with a male: female ratio of 3.71:1. The mean age of the participants was 36\u00b114 years. Persistent symptoms at two month follow up was more in age group of 2630 years .This study showed that patients who recovered from non-critical COVID-19 illness, 50 % of them reported at least one symptom particularly fatigue and cough, during two month follow up visit. The fundamental strength of our investigation was well documented follow up of patients with non-critical COVID-19 presentation at two months of disease course.10 A study done in Granada, Spain showed that 62.5% of patients hospitalized for COVID-19 infection report persistence of some symptom after a mean period of 50 days from discharge, dyspnea and asthenia being the most frequent, which resembles findings of this study.11 Report of WHO and China joint mission on COVID-19 stated that median time from illness onset to recovery is about 2 weeks for mild cases and 3 to 6 weeks with severe or critical disease.12Clinical presentation of non-critical COVID-19 patients at the time of hospital admission was found to be similar to previous studies done in UK and Italy.Regular follow up visit and care is essential for COVID-19 patients as some findings may be mild at initial presentation but persists during disease course hampering patient's quality of life. Subjective complaints of COVID-19 patients must be taken in medical care even after discharge from hospital and appropriate assessment must be made. Follow up visit at several intervals must be studied to analyze detail course of disease rather than only after two months. Similarly, follow up visit study must also take in account the psychosocial impact on patient's quality of life. Presence of other co morbid conditions and smoking history was not taken into consideration which has potential major role for symptoms persistence and duration of illness.This was a descriptive cross-sectional study done in a single institution in a limited sample size. The findings may not be generalizable. Convenience sampling was done to enroll patients. Further studies must be done in a larger sample size. Also, we followed-up the patients at two months. We could not find out if the symptoms continue to persist, and if they do, until when.The prevalence of persistent symptoms at two months follow-up in our study was lower than findings from other international studies. With this study we found out that symptoms persisted even in those with mild initial presentation. This implies necessity of regular follow up visit and assessment for optimal patients care."}
+{"text": "T315I mutation (16%). Median follow-up was 15 months for CML and 4.5 months for Ph+ ALL patients. Best response was a major molecular response in 58% of CML and 41% of Ph+ ALL patients. Of 20 patients who started ponatinib due to intolerance to previous TKIs, 9 (64%) CML and 4 (67%) Ph+ ALL achieved a major molecular response. Three-year estimates of overall survival were 85.3% and 85.6%, respectively, in CML and Ph+ ALL patients; estimated progression-free survival was 81.6% and 48.9%. Adverse reactions were reported in 34 patients (68%); rash (26%) and dry skin (10%) were most common. Reported cardiovascular adverse reactions included vascular stenosis (3), arterial hypertension (2), chest pain (1), palpitations (1), and vascular occlusion (1). This Belgian registry confirms results from the PACE clinical trial and supports routine ponatinib use in CML and Ph+ ALL patients who are resistant or intolerant to previous TKIs or with the T315I mutation.Data on clinical use of ponatinib are limited. This prospective registry aimed to evaluate outcomes of ponatinib treatment in routine practice over 3 years (2016\u20132019) in Belgium (NCT03678454). Patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) were treated with ponatinib per current label. Fifty patients (33 CML and 17 Ph+ ALL) were enrolled. Fifty-five percent of CML and 29% of Ph+ ALL patients had received \u22653 prior tyrosine kinase inhibitors (TKIs). Reasons for starting ponatinib were intolerance (40%), relapse or refractoriness (28%) to previous TKIs, progression (16%), or The online version contains supplementary material available at 10.1007/s00277-021-04507-x. Treatment with tyrosine kinase inhibitors (TKIs) has led to a major improvement in the prognosis of patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) . TKIs seT315I mutation, for which no other marketed TKI is effective ), even though patient baseline characteristics might indicate certain risk factors for cardiovascular events. In the PACE trial, 31% of CP-CML and 25% of Ph+ ALL patients reported treatment-emergent AOEs of any grade. This difference could be due to the appropriate patient selection and monitoring, the implementation of the risk minimization activities, and a possible underreporting of AEs in a real-life situation as compared to a clinical trial or shorter follow-up period; this difference was also observed for the frequency of other AEs. The Common Terminology Criteria for Adverse Events grading was not collected for the purpose of this registry, limiting the clinical interpretation (severity) of the described AEs.Several retrospective observational studies reporting clinical use of ponatinib have been published \u201314. HoweT315I mutation. Major molecular responses were observed as best response in most CML patients and a large proportion of Ph+ ALL patients. In Ph+ ALL patients, deep molecular responses seemed to occur more frequently in intolerant versus non-intolerant patients. The registry revealed no new safety signals other than those previously reported [In conclusion, the results obtained in routine clinical practice in Belgium are in line with those of the PACE trial, therefore supporting the use of ponatinib in patients with CML and Ph+ ALL after failure or intolerance to previous lines of TKIs or who have the reported , 8. The ESM 1(DOCX 22 kb)"}
+{"text": "Despite known benefits of hospice, inequities exist. Using data from a multi-site pragmatic trial in a representative groups of hospices, we examined inequities in length of stay (LOS) and general inpatient use (GIU) for 12,153 patients with dementia (primary and secondary diagnosis) using descriptive statistics and association tests. There were significant associations between race/ethnicity and GIU and LOS (p< 0.001). In those with primary diagnosis of dementia, Asian (31%) and Black/AA (24%) individuals had significantly greater utilization of GIU than Hispanic (19%) and white individuals (21%). Greater inequities were found in those with a secondary diagnosis. LOS amongst Asians were shortest with 78% having an LOS \u226614 vs 50-59% in other groups. Differences in long-stay >60 days (7%) vs 14-22% in other groups were found. There were similar differences examining by primary vs. secondary diagnosis. These inequities point to cultural and systems factors that require further study and intervention."}
+{"text": "This study investigated the occurrence of undesirable weight change (UDWC) and reduced sleep quality (RSQ), and major factors associated with these changes during COVID-19 pandemic amongst university older employees (age 50+). Participants (n = 846) were recruited throughout campus and completed an online survey. Summary statistics were used to describe characteristics of the study participants and frequency and level of UDWC and RSQ. Proportional odds models were used to assess major factors associated with UDWC and RSQ. The results showed 416 (43.2%) participants reported UDWC and 474 (49.2%) RSQ. Age was inversely, and obesity positively associated with UDWC and RSQ. With each 5-year increase in age, the OR (95% CI) was 0.87  for reporting UDWC and 0.90  for reporting RSQ. Obese individuals were significantly more likely to report a worse UDWC and RSQ (OR (95% CI) = 1.58  and 1.56  respectively)."}
+{"text": "Patients with inherited retinal dystrophies (IRDs) were recruited from two understudied populations: Mexico and Pakistan as well as a third well-studied population of European Americans to define the genetic architecture of IRD by performing whole-genome sequencing (WGS). Whole-genome analysis was performed on 409 individuals from 108 unrelated pedigrees with IRDs. All patients underwent an ophthalmic evaluation to establish the retinal phenotype. Although the 108 pedigrees in this study had previously been examined for mutations in known IRD genes using a wide range of methodologies including targeted gene(s) or mutation(s) screening, linkage analysis and exome sequencing, the gene mutations responsible for IRD in these 108 pedigrees were not determined. WGS was performed on these pedigrees using Illumina X10 at a minimum of 30X depth. The sequence reads were mapped against hg19 followed by variant calling using GATK. The genome variants were annotated using SnpEff, PolyPhen2, and CADD score; the structural variants (SVs) were called using GenomeSTRiP and LUMPY. We identified potential causative sequence alterations in 61 pedigrees (57%), including 39 novel and 54 reported variants in IRD genes. For 57 of these pedigrees the observed genotype was consistent with the initial clinical diagnosis, the remaining 4 had the clinical diagnosis reclassified based on our findings. In seven pedigrees (12%) we observed atypical causal variants, i.e. unexpected genotype(s), including 4 pedigrees with causal variants in more than one IRD gene within all affected family members, one pedigree with intrafamilial genetic heterogeneity , one pedigree carrying a dominant causative variant present in pseudo-recessive form due to consanguinity and one pedigree with a de-novo variant in the affected family member. Combined atypical and large structural variants contributed to about 20% of cases. Among the novel mutations, 75% were detected in Mexican and 50% found in European American pedigrees and have not been reported in any other population while only 20% were detected in Pakistani pedigrees and were not previously reported. The remaining novel IRD causative variants were listed in gnomAD but were found to be very rare and population specific. Mutations in known IRD associated genes contributed to pathology in 63% Mexican, 60% Pakistani and 45% European American pedigrees analyzed. Overall, contribution of known IRD gene variants to disease pathology in these three populations was similar to that observed in other populations worldwide. This study revealed a spectrum of mutations contributing to IRD in three populations, identified a large proportion of novel potentially causative variants that are specific to the corresponding population or not reported in gnomAD and shed light on the genetic architecture of IRD in these diverse global populations. The study was performed to identify the underlying cause of inherited retinal degeneration (IRD) in 409 individuals from 108 families. Primarily, these families were recruited from three different geographic regions: Mexico, Pakistan and European Americans from the United States. Blood samples were collected from all individuals for genome analysis. This analysis detected causative variants in 61 out of the 108 pedigrees. A total of 93 gene variants were found in the 61 families. Among these, 54 were previously reported as causative variants and the remaining 39 have not been reported in IRD pedigrees. Interestingly, 54% of these novel variants were not listed in gnomAD. In addition to these findings, complex causative genotypes were observed in 20% of pedigrees. Overall, causative variants were detected in 63% Mexican, 60% Pakistani and 45% European American pedigrees. This study revealed the distribution of IRD causative variants in pedigrees with diverse ethnic and geographic backgrounds. Inherited retinal degenerations (IRDs) are a group of diseases, which result in dysfunction or progressive degeneration of retinal cells causing a profound bilateral loss of vision. IRDs are relatively rare. It is currently estimated that IRDs affect 1 in 3000 individuals .Retinal disease genes have been identified previously by linkage analysis, homozygosity mapping, and sequencing the coding regions of several genes associated with genetic and genomic markers. The subsequent development of targeted screening panels for pathogenic variants in known IRD genes greatly improved genetic diagnosis but failed to identify novel variants and novel genes involved in IRD \u20135. Gene The affordable cost structure of whole-genome sequencing in recent years \u201313 has eWhole-genome sequence data were obtained on 404 subjects from 108 unrelated pedigrees with a diagnosis of inherited retinal dystrophy. The study cohort included pedigrees from Mexico (35), Pakistan (15), Ashkenazi Jewish (2), India (2), and USA (European ancestry) (54).The pattern of inheritance was observed to be recessive in 76 pedigrees, dominant in 25, and X-linked in 7. However, after completing the analysis, the pattern of inheritance was corrected in 4 pedigrees based on the causative mutations detected. One pedigree with multiple consanguineous marriages (RF.197.0113) was originally classified as recessive but determined to be dominant with a pseudo-recessive pattern of inheritance. Similarly, two pedigrees RF.VI123.0514 and RF.VI153.0216 were originally classified as dominant and recessive respectively but mutations in X-linked genes were identified as the underlying cause of the phenotype. One pedigree originally classified as dominant (RF.VI116.1215) was re-classified as recessive.Analysis of sequence data identified 202 female and 202 male subjects consistent with our records and validated relationships based on identity by descent (IBD) mapping analysis. The total number of reads obtained on each individual ranged from 765 million to 1,903 million, of which 78% ~ 95% were detected as appropriately mapped reads indicating the high quality of sequence data. Analysis using GATK best practice pipeline identified 30,071,475 single nucleotide variants (SNVs) in total, including 23,409,845 single nucleotide polymorphisms (SNPs) and 6,661,630 INDELs. The number of variants in each sample ranged from 3.77 to 4.84 million SNVs. A total of 18,301,653 known and 11,769,822 novel (based on dbSNP147) SNVs were observed in 404 subjects. Among the total number of identified SNVs, 21,026,019 (70%) were identified as very rare SNVs . The rare and moderate/possibly disease-causing SNVs included 186,501 (0.61%) while only 53,101 (0.18%) of them were predicted to be deleterious/probably damaging.3.77 to 4.84 million SNVs including ~850,000 small INDELs were detected from autosomes in every individual and no outliers or plate biases were observed. Similarly, no outliers were observed in the X and Y chromosome data. The heterozygous and homozygous ratios were normal on autosomes as well as sex chromosomes in each female and male sample. Among the total SNVs observed, 112,335 (0.37%) were annotated as missense variants. These include 79,428 (71%) known and 32,907 (29%) novel variants.We observed a total of 56,299 CNVs including 25,357 deletions, 13,223 duplications, and 17,719 insertions in 404 samples. More than half of the CNVs, 29,142 (52%) were found to be common as they were found in more than 30 samples. The CNV calling software (GenomeStrip) detected CNVs with lengths greater than 1000bp. In our analysis, we identified CNVs ranging from 1000bp to 313,600bp. The CNVs were called with a quality score, and those <1 were classified as likely false positives.ExAC database has constraint Z scores for 18,225 genes. In our analysis, we included 271 retinal disease-associated genes from the RetNet database [AGBL5 and IFT88 [Analysis of WGS variants identified 93 causative variants (88 SNVs and 5 CNVs) in 61 of the pedigrees (57%). 89 of these causative variants include 35 novel and 54 previously reported variants detected in 45 known IRD genes in 59 pedigrees Tables . In two nd IFT88 , 14.In 22 pedigrees , 26 rare, potentially pathogenic novel (not previously reported as causative) variants in 17 different known IRD genes were identified as likely causative mutations. Seven of these pedigrees also have 8 previously reported mutations in known IRD genes. Among the variants detected, 9 were homozygous (in 8 pedigrees), 21 compound heterozygous (in 10 pedigrees), 2 dominant acting heterozygous (in 2 pedigrees), and 2 were X-linked variants (in 2 pedigrees) . Five ofPedigrees with variants of uncertain significance (VUS). Among the novel potentially causative variants observed in RAX2 (p.Arg79Gln in RF.176.0113), PEX6 , DRAM2 (p.Leu246Pro in RF.H.0506) and IFT140 (p.Arg137Gln in RF.AG.0991) are listed in CinVar as VUS.Further analysis of the IRD pedigrees with these five VUS did not detect additional potentially causative variants in known or novel genes that are sufficient to cause disease. Future experimental evaluation of novel potentially pathogenic causative variants and VUS, and detection of these variants in additional unrelated IRD cases will provide evidence for an appropriate classification of their clinical relevance.Thirty-five previously reported mutations in 18 known IRD genes were identified in 25 pedigrees . These pUSH2A variants as the underlying cause of disease in eight different pedigrees. Among these, only one was a novel variant while the remaining 15 were reported previously  A 1.6Mb deletion in EYS segregating with IRD. Analysis of the WGS of two affected (II:1 & II:2) and one unaffected sibling (II:3) from a Mexican pedigree RF.VI96.0210  LCA5 gene deletion in a pedigree. A 110Kb homozygous deletion in LCA5  was identified in a consanguineous Pakistani pedigree RF.277.0113. This homozygous deletion includes 1 to 4 exons of LCA5. PCR amplification and sequencing of the deleted region using primers located in the flanking sequence identified specific boundaries of the deletion and its segregation with LCA in RF.277.0113 (277.0113 .(C) A 22.8Kb deletion in the CERKL gene. In pedigree RF.T.8.11, a previously reported nonsense mutation p.Arg257* in the CERKL gene was identified in the heterozygous state by exome sequence analysis in the proband I:1 who was adopted (53). Whole-genome sequence analysis of this individual identified a large novel heterozygous 22.8 Kb deletion  on chromosome 2 (CERKL gene. The nonsense change is predicted to truncate the protein or result in nonsense-mediated decay (NMD) of the transcript [CERKL may also result in the formation of a truncated protein due to coding region frameshift or the transcript may undergo NMD. Both sequence alterations detected in the CERKL gene in this individual are predicted to lead to the loss of functional protein; null mutations in CERKL have been established as the underlying cause of IRD [mosome 2 . Analysi adopted . Whole-ge of IRD , 56.(D) A large structural change involving two genes. Clinical evaluation of eight affected individuals in a four-generation pedigree (C790) led to the diagnosis of autosomal dominant macular degeneration (MD) with no non-ocular abnormalities co-segregating with the MD phenotype  and one unaffected (IV:5) offspring of an affected female (III:3) were observed to carry a rare heterozygous potentially pathogenic variant c.659T>G, p.Phe220Cys (Allele frequency in gnomAD = 0.00002) in the rhodopsin gene. While samples of the parents of these individuals were not available for genetic analysis, the novel rhodopsin variant c.659T>G, p.Phe220Cys was not detected in either maternal grandparents (II:1 & II:2) suggesting the possible paternal (III:4) inheritance of this variant in the three siblings . Further, this variant was not detected in the rest of the pedigree excluding the possible involvement of c.659T>G, p.Phe220Cys as the variant responsible for IRD pathology in the rest of the extended pedigree. The two affected individuals IV:3 and IV:6 have both the large deletion encompassing (E) Compound heterozygous deletions in CNGB3. Whole-genome sequence analysis of pedigree RF.M.0592 with a single affected individual identified a novel 7Kb heterozygous deletion  and an additional previously known 7bp heterozygous indel (c.819_826delCAGACTCC) in CNGB3 gene that results in p.Arg274Valfs*13 [Valfs*13 . The fraMoreover, our analysis identified deletions and sequence alterations in non-coding regions with either unknown impact or yet to be annotated. As state above, experimental and analysis approaches will need to be developed to validate this class of potential disease-causing mutations.Analysis of the WGS identified atypical causal variants in 7 pedigrees including four pedigrees from Mexico, one from Pakistan, one European American and one of India origin .IMPDH1 gene associated with autosomal dominant RP  and three unaffected members (III:1 and III:2 and IV:2) of a four-generation Mexican pedigree RF.VI104.0514 was analyzed. WGS analysis identified two potentially pathogenic variants in two separate genes in affected individuals from different generations. Two affected siblings II:3 and II:4 were observed to carry a homozygous nonsense variant c.2950C>T; p.Arg984* in ssive RP , 59. Howand II:4 . This vapedigree . Patientdetected . The agen S1F to  while IVOPN1SW  and TOPORS  associated with dominant color blindness (Tritenopia) and dominant retinitis pigmentosa respectively [OPN1SW mutations, the retinal degeneration phenotype in this individual is consistent with the phenotype associated with TOPORS  and a known heterozygous PRPF31  mutation in affected twins and not in their unaffected sibling [PRPF31 than with PRPF8. The paternal grandfather (I:1) is reported to be affected with IRD, while the clinical status of the father (II:3) is unknown.RF.VI111.0514 Mexican pedigree includes affected fraternal twins and an affected grandparent. WGS analysis of the affected twin sisters (III:4 & III:5) and their unaffected sibling (III:2) identified novel heterozygous damaging variant in  sibling . Sanger PRPF3 gene in five affected members in the heterozygous state, in three in the homozygous state and none of the unaffected relatives. Analysis of all members of this pedigree for this variant revealed the segregation of the c.1481C>T PRPF3 with the disease in the pedigree RF.197.0113 in a pseudo-recessive pattern due to the consanguinity  gene on the X chromosome inherited from the mother (III:2). The clinical symptoms reported in the affected individual are more consistent with severe RP phenotype associated with PDE6G mutations; color vision was not tested in this individual.A consanguineous European American pedigree RF.M.1111  with an PRPH2  [ROM1  [th decade and mild central vision loss consistent with the phenotype associated with the p.Arg142Trp mutation in PRPH2 [ROM1 mutation p.Leu114Alafs*9 mutation is unknown.In the RF.K.0216 pedigree  from Indg142Trp) , 64, 70 Alafs*9) , 71 werein PRPH2 . The impIMPDH1 gene associated with autosomal dominant RP was observed in one pedigree (RF.VI13.0707); and a previously known dominant mutation in PRPF3 (c.1481C>T) was detected in RF.197.0113 in a pseudo-recessive pattern due to multiple consanguineous marriages. In addition, potentially pathogenic variants in two independent genes both segregating with the disease and each sufficient to cause pathology were detected in four out of the 7 pedigrees with atypical genotypes. Besides these 7 pedigrees, we previously reported the identification of mutations in two independent genes as the underlying cause of IRD in separate branches of a pedigree by WGS in a European American pedigree [In summary, a novel de-novo causative variant c.940A>G, p.Lys314Glu in the AGBL5 and IFT88 in causing IRD in the two unrelated pedigrees [WGS sequence analysis detected potentially pathogenic candidate causative variants in genes previously not associated with IRD segregating with disease in two pedigrees in this cohort and we have reported these findings earlier , 14. Ouredigrees , 14.The initial clinical diagnosis of pedigrees spanned a broad spectrum including RP in 18, cone dystrophy in 1, macular dystrophy in 1, Leber congenital amaurosis (LCA) in 2, Usher syndrome in 2, with the majority (37) having unclassified retinal degeneration . Re-eval(A) Analysis of pedigrees from Mexico. In the current study, WGS analysis of 35 pedigrees with recessive retinal dystrophy excluding STGD1 detected 18 previously reported and 13 novel (42%) causative mutations in known IRD genes in 22 pedigrees (63%) leaving the remaining 13 pedigrees unresolved  and two additional pedigrees from our previous studies with causative mutations in USH2A [resolved . Nine (73 novel 4% causati(B) Analysis of pedigrees from Pakistan. In this study, we have analyzed 15 consanguineous Pakistani pedigrees with multiple affected members and identified causative mutations in 9 IRD genes in 9 pedigrees (60%) while the causative mutations were not detected in 6 pedigrees (40%) (es 40%) . Among tes (40%) . Four ofes (40%) , 4 and 50% . Amon(C) Analysis of pedigrees from the United States. Fifty-four pedigrees, which comprise 50% of the total analyzed in this study are of European ancestry. Causative mutations were detected in 24 (45%) pedigrees that included 25 known mutations (~59%), 14 novel single nucleotide changes (SNVs) and 3 novel structural changes , while the remaining appear to be unique to the European population (s Tables . Two varpulation .(D) Pedigrees of Indian ancestry. Two pedigrees recruited in the United States are of Indian origin in which three previously reported causative mutations were detected (Tables d Tables  and 4.(E) Pedigrees of Ashkenazi Jewish ancestry. In this study a previously known homozygous p.Lys42Glu mutation in DHDDS was detected in two Ashkenazi Jewish pedigrees recruited in the United States , Pakistani (60%) and European American (45%) pedigrees varied. The number of novel IRD causative mutations detected in each of these cohorts also varied from about 42% and 41% in both Mexican and European American pedigrees to 60% in Pakistani pedigrees. Further, among the novel IRD causative SNVs, 20% of those detected in Pakistani pedigree were not listed in gnomAD database while 50% and 75% of novel SNVs in European American and Mexican pedigrees were not in the gnomAD database .Analysis of the whole-genome sequence of this cohort comprised of 404 individuals from 108 pedigrees with inherited retinal degeneration identified 93 causal variants in 232 individuals in 61 (57%) pedigrees. Among the causative variants detected, 39 (42%) are novel and 54 (58%) are previously reported variants in 44 well established IRD associated genes and two IRD genes we recently reported . AlthougIMPDH1 was detected in one affected individual in our cohort. This is the first report of a de-novo variant in the IMPDH1 gene.The outcomes of the analysis of 108 IRD pedigrees provided insight into the genetic architecture of IRD. Overall novel mutations were identified in genes known to be associated with IRD in 36 pedigrees while previously reported mutations were detected in 25 pedigrees. The majority of the mutations (60%) were missense mutations including stop gain variants, 23% frameshift, while only 5% were structural variants and 12% were potential splice altering variants. All the causative CNVs detected in this study were novel. Analysis of the sequence flanking these deletions revealed microhomologies suggesting potential non-homologous end-joining leading to these deletions . AtypicaIt is interesting to note that only a small proportion of novel causative genes were identified despite a significant proportion of our pedigrees originating from understudied populations. Further, the two novel genes observed to carry causative mutations in our cohort were detected in small pedigrees of European Americans , 14. TheThe families analyzed in this study included families that are primarily from understudied populations from Pakistan and Mexico and a third, well-studied European American population. About a third of the pedigrees included in this study are from Mexico with a unique population in which the genetics of IRD are not well understood. Comprehensive genetic analysis of IRD in this population has been reported primarily in two publications including one of our own , 83\u201385. ASRGL1 [IFT43 [ZNF513 [SLC24A1 [CLCC1 [RPE65 is the most common causative mutation found in this population [The second population included in our analysis is from the Punjab province of Pakistan. Until recently, the genetics of IRD in this population was not well studied. The structure of the Pakistani population is unique with endogamous sub-populations of multi-ethnic origin and high consanguinity in each of these populations \u201390. Our ASRGL1 , IFT43 [1 [IFT43 , ZNF513  [ZNF513 , SLC24A1[SLC24A1 , and CLC1 [CLCC1 ) while tpulation , 91, 107pulation \u2013122. ConInterestingly, the mutation detection rate was lower (45%) in European American pedigrees compared to the rate in Mexican and Pakistani pedigrees . Despite the well-studied nature of this population, 41% of the mutations detected in this study cohort are novel. Furthermore, 50% of these novel causative SNVs are not listed in gnomAD database.USH2A is most frequently associated with IRD followed by EYS, CERKL, CRX, IMPG1 and RPGR in the current study cohorts , South Asian (for the Pakistani), or European (for the European American) populations Tables , 4 and 5mericans \u2013138. Thimericans .This study using WGS and in-depth integrated analysis of the nature and type of mutations in different populations, provided insight into the population-specific genetic architecture of IRD and enabled it\u2019s comparison to other worldwide populations. Such information will be helpful in the design of efficient population-specific tools for molecular diagnosis, genetic counseling, and decision on the selection of therapies. Further analysis of the 47 pedigrees that remained unresolved in this study may lead to the identification of causative variants in novel genes or non-coding variants that can contribute to the phenotype by modifying enhancer-promoter interactions or other yet to be identified functions of non-coding sequences.The study protocol adhered to the tenets of the declaration of Helsinki and was approved by the Institutional Review Boards of the University of California San Diego, USA; University of California San Francisco, USA; University of Michigan, Kellogg Eye Center, USA; Johns Hopkins University School of Medicine, USA; University of Arizona, USA; Retina and Genomics Institute, Yucat\u00e1n, M\u00e9xico; Genetics and Ophthalmology, Genelabor, Goi\u00e2nia, Brazil and University of Punjab, Lahore, Pakistan. Preliminary information on the clinical history of the patients and their family members were collected for the study along with the family history. Blood samples were collected from all available family members after obtaining their written consent to participate in our study.Pedigrees with at least one individual with a diagnosis of non-syndromic inherited retinal degeneration (IRD) were recruited. Patients with a primary diagnosis of Stargardt (STGD1) were excluded from this study. Self-reported ethnicity information was recorded.A total of four hundred and nine individuals from 108 unrelated families were analyzed by performing whole-genome sequencing. Among these, 203 individuals were affected and 206 were unaffected with 206 females and 203 males. 15 families were recruited from Pakistan, 35 from Mexico, 2 from India, 2 were Ashkenazi Jewish, and the remaining 54 families were of European ancestry from the USA.ABCA4 and recessive RP mutation panels , selected retinal disease gene resequencing arrays [The 108 pedigrees in this study had previously been examined for mutations in known IRD genes using a wide range of methodologies available. A set of 31 pedigrees with 1 to 5 affected members were previously analyzed by sequencing whole-exomes of selected members using Nimblegen V1-V3  or Agilent V1-V5 + UTRs probes  to identify disease-causing gene mutations but remained unresolved. Similarly, probands of the remaining 77 pedigrees were initially analyzed using various targeted mutation or gene screening panels that were available in the past two decades [g arrays , targeteDNA isolation was performed using standard techniques from whole blood samples of patients using the Qiagen DNeasy blood kit  as previously described . WGS wasThe called variants were annotated with SnpEff v4.11 , PolyPheExAC Browser (Beta) Exome Aggregation Consortium has a Z-score for each gene to evaluate its intolerance and conservation against three types of mutation; synonymous, missense and loss of function (LoF). The scores were originally developed to find disease-relevant de-novo mutations. In this study, we examined if the scores could be used to prioritize disease causative genes.To identify rare deleterious SNVs, insertion-deletions (INDELs) and other types of structural variants as possible candidate variants, the following filtering criteria were used: allele frequency < 0.005 in 1000Genome project, < 0.05 in our inhouse cohort and < 0.05 in our 409 samples. Further, the allele frequency was validated using the ExAC and gnomAD databases. Highly deleterious variants were assessed and scored as: SnpEff putative impact = \u201cHIGH\u201d or PolyPhen2 Prediction = \u201cpossibly/probably damaging\u201d or CADD Phred Score > = 30. Relatively deleterious variants were scored as: SnpEff putative impact = \u201cHIGH/MODERATE\u201d or Polyphen2 Prediction = \u201cpossibly/probably damaging\u201d or CADD Phred Score > = 20.http://www.hgmd.cf.ac.uk/ac/index.php), ClinVar classification on clinical relevance using the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) guidelines, relevant population specific information and the known/reported physiological function of the corresponding gene [Following initial filtering, selected variants were further analyzed based on segregation, pattern of inheritance, status reported in Human Genome Mutation Database  identified in the IRD families by WGS was performed by dideoxy sequencing as previously described .ZNF80 and GPR15 were quantified using a CFX Connect Real-Time PCR Detection System  as described previously [Copy numbers variation of the exons of candidate genes and two reference genes eviously , 123.A set of 95 unrelated ethnically matched Pakistani control samples were analyzed using dideoxy sequencing to validate novel variants identified in pedigrees from Pakistan, as described previously , 151. A Segregation analysis of identified large insertion and deletions were validated by quantitative polymerase chain reaction (qPCR) analysis as described before .S1 FigIMPDH1 c.940A>G, p.Lys314Glu variant.(A) Fundus image from right eye of IV:2 from RF.VI13.0707 pedigree with the heterozygous  The image demonstrates a waxy pallor of the optic disc, retinal vascular attenuation and mottling and light pigmentation of the retina in keeping with retinitis pigmentosa (RP). In addition, to normal RP features there is marked macular atrophy, with lacquer cracks are observed in the macular region of both eyes with clusters of pigment surrounding the area of atrophy. (B to D) Fundus images of IV:1 and II:3 from pedigree RF.VI104.0514: (F) Fundus images of IV:1 with the CLN3 mutation show macula discoloration and early Bull\u2019s eye pattern and subtle mottling of the retina at age 10.  Fundus images of II:3 show marked chorioretinal atrophy with large clusters of pigment suggestive of end-stage disease due to C2orf71. PRPF8 and PRPF31 genes(E) Composite left eye color fundus image of RF.VI111.0514 case, III:5 with mutations in . Image demonstrates way disc pallor, pigmentation of the fundus and retinal vessel attenuation suggestive of retinitis pigmentosa.(TIF)Click here for additional data file.S1 Table(XLSX)Click here for additional data file."}
+{"text": "Trauma is a major cause of morbidity and mortality worldwide. Prompt use of pre-hospital care is associated with reduced early and late morbidity and mortality from trauma. This study aimed to assess the time to reach the facility and the pattern of pre-hospital care provided for trauma patients.A cross-sectional study design with a structured interview questioner was used for patients presenting to Addis Ababa Burn Emergency and Trauma Hospital Emergency Department from April 1 to May 30, 2020.Out of 238 interviewed patients, the most common means of transportation from the scene to the initial health facility were taxi 77(32.4%) and ambulance 54(22.7%). The time of arrival from the scene to the initial health care facility was within one hour, 133(56.1%) and in 1\u20133 hours 84(35.5%). Some form of care was provided at the scene in 110(46.2%) of cases. The care provided was bleeding arrest 74(31.1 %), removing from wreck 51(21.4%), splinting/immobilizing injured area 38(16%), position for patient comfort 19(8%), and others. Relatives were the most common care provider 49(45%) followed by bystanders 37(33.9%), trained ambulance staff 19(17.4%), and police 2 (1.8%). The main reasons for not providing care were lack of knowledge 79(61.2%), and lack of equipment 25 (19.4%).The study showed relatives and bystanders were the first responders during trauma care. However, ambulance utilization for pre-hospital care was low. There was trauma patients delay to arrive to hospital. Only half of the patients presented to the health facility within Golden hour. Injury is a major cause of early death and disability worldwide. Every year approximately 5 million people die in the world. Deaths from severe injury occur in one of three phases: Immediate (death occurring from overwhelming injury), intermediate or subacute , and delayed  \u20133.The most effective way to prevent mortality and morbidity from trauma is the prevention of occurrence of trauma but providing effective pre-hospital care minimizes morbidity and mortality. Most deaths in the first hours of trauma are airway obstruction, hypoxia, and hemorrhage all of which can be reduced using effective first aid measures,4.Prompt pre-hospital care can also prevent delayed death of trauma patients with proper wound and burn care, immobilization of fractures, and support of oxygen and blood pressure in traumatic brain injury. Pre-hospital care reduces mortality and morbidity from serious illness and injuries. It is estimated that about 45% of mortality and 35% morbidity can be reduced by providing robust out of hospital emergency care.In low and middle-income countries without formal emergency care system around 80% of deaths in severe trauma occurred in pre-hospital setting, 6. In EThis study aimed to assess the time to reach the facility and the pattern of pre-hospital care provided for trauma patients visiting a tertiary care trauma center in Addis Ababa.Study area period: This study was conducted from April 1 to May 31, 2020 at Addis Ababa Burn Emergency and Trauma (AaBET) Hospital. AaBET Hospital is a part of St. Paul's Hospital Millennium Medical College. It is an emergency dedicated center with level 3 trauma care. It provides emergency and critical care services, Orthopedic, Neuro-surgery, General surgery, and Plastics surgery services. The emergency department has 60 beds and the overall hospital bed is 300. Annual emergency room patient visits ranges from 15,000 to 20,000.Design and sampling: A hospital-based cross-sectional study design was used. The source population was all trauma patients seen in Addis Ababa Burn Emergency and Trauma (AaBET) Emergency Department (ED). All adult (age >15 years) trauma patients who came to AaBET Hospital Emergency Department during the 2 months study period were included. Patients sent to ED from regular Out Patient Department (OPD) for admission, death on arrival, and patients who came for follow-up were excludedSample size determination: Sample size calculated by using the single population proportion formula, prevalence of (0.17) was used where 17 % of patients received pre-hospital care  were male with a male to female ratio of 3.6:1. The mean age was 32.25 years with an SD of 13.45years. Most patients were from Oromia 117(49.2%) and Addis Ababa 104(43.7%). Regarding occupation, the majority were day laborers 81(34%) followed by farming 40(16.8%). ((16.8%). .Clinical profile: The most common mechanism of trauma was a road traffic accident 102(42.9%) followed by falling 62(26.1%). Trauma to extremity region 135(56.7%) was the most common site of injury followed by the head 86(36.1%). Upon arrival, patients were triaged to yellow-green 185(77.8%), 39(16.4%) orange, and 16(5.9%) red side. The majority of patients had sustained the injury at work 87(36.6%), public gathering 46(19.3%), pedestrian 44(18.4%), passenger 35(14.7%), and driving 19(8%) (g 19(8%) .Pre-hospital care: One hundred ten patients (46.2%) received some form of pre-hospital care mainly first aid at the scene. Cares provided at the scene were positioning patient 19(8%), bleeding arrest 74(31.1 %), splinting/immobilizing injured area 38 (16%), removing from wreck 51(21.4%) and others like calling police or others for help 7 (2.9%).Relatives were the most common care provider (49(45%)) followed by bystanders 37(33.9%), trained ambulance staff 19(17.4%), and police 2 (1.8%) provided first aid. The main reasons for not providing care were lack of knowledge 79(61.2%), followed by lack of equipment 25 (19.4%), fear of procedure 11(8.5%), fear of medico-legal issue 9(7%) and others like fear of transmitted diseases 5(3.9%).One hundred thirty-three (56.1%) patients presented to the first health facility within one hour. 57 (33.5%) of them transported to first health facility using taxi. Time of arrival and mode of transport is shown in Inter health facility referral: A total of 155(65.1%) were referred from different areas, only 83(53.5%) were referred with communication. The most common source of referral was public hospital 79(46.7%) followed by public health center 74(43.7%) and private facility 16(9.6%). About 142 were transported by ambulance, 20 with taxi, 9 by private car and one patient walking.Determinants of pre-hospital care: Chi-square test was used to assess the association between socio-demographic, mode of transport, mechanism of trauma, and type of trauma with the delivery of pre-hospital care. Only mechanism of injury had statistically significant association with provision of pre-hospital care  (ue=0.04) .This study showed the overall utilization of pre-hospital care for trauma patients was 11046.2%) which showed improvement from a study done in Addis Ababa Tikur Anbesa Specialized Hospital (TASH) seven years back (16.7%), also higher than the study from India 26.5%, southwest Nigeria 8.6%6.2% whic. It is cTime to the health facility is crucial factor for trauma patients. Based on The Golden hour concept one hour is determined to be determinant for patients' better survival. In thisThe majority of scene care provisions in our study were none trained relatives; this is consistent with the reports from developing nations. HoweverThe explanation for this may be because most of the providers are none trained bystanders and relatives, unlike the developed countries where care is by personnel with advanced training and equipped ambulances. It is better to train the community on first aids via community health workers and awareness creation with mass media.Upon analysis for means of transportation to the initial health facility, our study showed taxi was the most common means 32.4%) followed by ambulance (22.7%), walking with support 15.5%), and others. This was in keeping with studies done in Tikur Anbessa, Vietnam, and India where the majority of patients were transported by taxi and private vehicles% followe,13. A st.5%, and Although this study provided a good incite to pre-hospital care of trauma patients, it was conducted during a pandemic which jeopardized the health system shifting the majority of resources for the pandemic subsequently interfere with the pattern of some variables. This study is hospital-based, single centered making, cross- sectional and short study period making it liable for selection bias and limits generalizability.In conclusion, this study showed relatives and bystanders were the first responders during trauma care. However, ambulance utilization for pre-hospital care was low. There were trauma patients delay to arrive to hospital. Only half of the patients presented to the health facility within Golden hour."}
+{"text": "Patients who are admitted to the hospital with Coronavirus Disease 2019 (COVID-19) often have protracted hospitalizations complicated by bacterial or fungal co-infections. This also raises the question whether there is some feature of COVID-19 that predisposes to development of specific co-infections. To begin answering that question, we sought to review the distribution of microorganisms identified in bacterial and respiratory cultures in patients admitted with COVID-19.In a retrospective review of all patients admitted with COVID-19 in the year 2020 at a single academic tertiary medical facility, all positive blood and respiratory cultures were reviewed. Common contaminants were removed. Duplicate growth of the same organism within the same patient was not counted as a separate event.Staphylococcus aureus (3.94% of patients with COVID-19), followed closely by Enterococcus (2.41%), Klebsiella (1.65%), and Escherichia (1.27%). Staphylococcus aureus was also the most frequently isolated organism in respiratory cultures (7.24% of patients with COVID-19), followed by Pseudomonas (3.43%), Klebsiella (1.78%), Serratia (0.89%), and Stenotrophomonas (0.89%).787 patients were admitted with COVID-19 for the specified time frame. There were 131 and 147 unique events of documented bacterial or fungal growth seen in blood cultures and respiratory tract cultures, respectively. The most commonly identified organism in blood cultures was This suggests that the distribution of pathogens implicated in coinfections in this patient population may not be substantially different from what might be expected in patients admitted for reasons outside of COVID-19. Further investigation with a larger patient population would provide more generalizable data, including patients admitted for reasons outside of COVID-19.All Authors: No reported disclosures"}
+{"text": "CDH1 mutation. We studied the efficacy of preoperative platinum-based chemotherapy in nonmetastatic PUC and immune checkpoint inhibitors (ICIs) in advanced PUC.Plasmacytoid urothelial carcinoma (PUC) is a rare, aggressive histologic variant of urothelial cancer characterised by a diffuse growth pattern and Cases of nonmetastatic PUC and advanced PUC treated with ICIs at our institution were identified. Outcomes were compared to those of a published cohort of patients with urothelial carcinoma not otherwise specified.N\u2009=\u200921) had progression-free and overall survival of 4.5 and 10.5 months, respectively, and a 38% response rate. FGFR3 and DNA damage response gene alterations were observed in 3 and 15% of cases, respectively.We identified 81 patients with nonmetastatic PUC. Of the patients with localised disease who underwent neoadjuvant chemotherapy, pathologic complete response and downstaging rates were 12 and 21%, respectively. Pathologic downstaging was not associated with significant improvement in clinical outcomes. Up to 18% of localised disease and 28% of locally advanced cases had unresectable disease at the time of surgery. ICI-treated advanced PUC (PUC is associated with high disease burden and poor chemosensitivity. Increased awareness and recognition of this disease variant will allow for new treatment strategies. The presence of variant histology does not appear to compromise the efficacy of preoperative chemotherapy in patients with UC of squamous or glandular differentiation.9 However, the utility of preoperative chemotherapy for patients with PUC remains poorly defined. Anti-programmed cell death 1 (anti-PD1)/programmed cell death ligand 1 (PDL1) immune checkpoint inhibitors (ICIs) are also used to treat patients with UC13 and have an emerging role in preoperative therapy.15 However, the efficacy of these agents in PUC has not been studied.Preoperative cisplatin-based chemotherapy increases pathologic responses and cancer-specific survivalIn describing our institutional experience in the management of PUC, the primary objectives of this study are to (1) define the clinicopathologic features of PUC at diagnosis, (2) determine the response of PUC to preoperative platinum-based chemotherapy, and (3) further describe the genomic landscape of this under-studied disease entity. We also described the clinical activity of ICIs in a cohort of patients with advanced PUC.1 Tumours were characterised by a diffuse and discohesive growth pattern with minimal stroma reaction. Tumour cells had eccentric or centrally located nuclei. Cytoplasmic vacuoles and signet ring cells were identified in all cases at variable proportions.This work was performed under an institutional review board\u2013approved protocol. Cases of PUC of the bladder diagnosed at our institution were identified, and all cases were reviewed by a genitourinary pathologist (H.A.-A.) to confirm the diagnosis. Cases diagnosed between 2000 and 2017 with clinical follow-up were included for primary clinical analysis  treated with neoadjuvant cisplatin and gemcitabine for whom clinical outcome data have been reported was used as a comparator for this analysis.16Pathologic stages were compared between patients with clinically localised PUC who underwent either neoadjuvant chemotherapy before cystectomy or cystectomy first. Outcomes were also compared between patients with PUC and patients with UC NOS. A cohort of patients with UC NOS .21 Alterations in DNA damage response (DDR) genes were also evaluated. DDR status was classified based on the presence of mutations in 34 genes that are involved in different DDR pathways and are in the MSK-IMPACT sequencing panel. The expanded database was also used to identify patients with advanced PUC who received anti-PD1/PDL1 ICIs.An expanded pathology database of cases of PUC diagnosed between 2000 and 2020 was used to identify cases that were genomically profiled  was calculated from the date of radical cystectomy (or attempted surgery) to the date of radiographic evidence of recurrence or death. Patients whose cystectomies were aborted were excluded from RFS analysis. Overall survival (OS) was calculated from the date of radical cystectomy (or attempted surgery) to the date of death. Survival was estimated by Kaplan\u2013Meier and compared by log-rank test. Cox proportional hazard models were used for univariate and multivariate analyses, and interactions were tested between histology (PUC vs UC NOS) and response (responders vs non-responders). Analyses were conducted with SAS version 9.4 . All tests were two sided, and n\u2009=\u200962, 77%) had clinically localised disease; 19 (23%) patients had locally advanced disease at diagnosis, defined as the presence of fixed tumour at examination under anaesthesia or unequivocal radiographic evidence of locoregional lymphadenopathy. Baseline characteristics of the study population are listed in Table\u00a0We identified 81 patients with nonmetastatic PUC .Of the 62 patients with localised muscle-invasive PUC, 29 (47%) underwent surgery first. Thirty-three (53%) patients received neoadjuvant chemotherapy, all of whom received cisplatin-based chemotherapy. Pathologic staging of these patients is shown in Table\u00a0Of the patients who received neoadjuvant chemotherapy, 10 (30%) patients received triplet chemotherapy regimen , and 6 (18%) patients received more than four cycles of chemotherapy (up to six planned cycles). Cystectomy was aborted in 6 (18%) cases at the time of surgery due to locally advanced, unresectable disease following chemotherapy. All six patients had fixed bladders\u2014three to the pelvic side wall, two to the intestines and/or rectum, and one to both. Three of these patients had positive biopsies that confirmed disseminated disease.Following neoadjuvant chemotherapy, pathologic downstaging to non-muscle-invasive disease (<ypT2 ypN0) was observed in 7 (21%) patients, 4 (12%) of which had pathologic complete response. Of the remaining three patients, two had carcinoma in situ and one had pT1 disease. Triplet chemotherapy, extended number of chemotherapy cycles, or other clinical variables were not associated with response to neoadjuvant chemotherapy , triplet chemotherapy regimen , and >4 cycles of chemotherapy . Although resection was attempted for every patient with locally advanced PUC after chemotherapy, the surgeries of 5 (28%) patients were aborted due to inoperable disease at intraoperative assessment.Among those who received systemic therapy, 10 (56%) had locally advanced disease per examination under anaesthesia, 7 (39%) had radiographic evidence of regional lymphadenopathy, and 1 had both features. Most patients received cisplatin (p\u2009=\u20090.009).Four (22%) patients had pathologic responses, with 2 (11%) pathologic complete responses. Median RFS and OS for patients with locally advanced PUC were 5.7 and 10.6 months, respectively, with 19% of patients alive at 2 years. The OS of patients whose tumours were found unresectable during surgery was significantly shorter than the OS of those who underwent resection  was used as comparator for RFS and OS.16 The percentage of patients with pathologic complete response was lower in patients with PUC as compared to patients with UC NOS, but this difference was not statistically significant . The percentage of patients with pathologic downstaging (<ypT2 pN0) was significantly lower in patients with PUC than in patients with UC NOS .A previously published cohort of patients with muscle-invasive UC NOS of the bladder treated with neoadjuvant cisplatin and gemcitabine .Patients with PUC treated with neoadjuvant cisplatin-based chemotherapy had significantly inferior RFS and OS than patients with UC NOS who received neoadjuvant chemotherapy  had relapses: one at 3.2 months, who died after 3.5 months, and another at 17.6 months, who died after 40.9 months. The third patient remained recurrence-free at 21.9 months follow-up.Of the 29 patients with clinically localised PUC treated with cystectomy first, 11 (38%) patients had documented recurrences\u20145 (45%) osseous, 4 (36%) nodal, 2 (18%) peritoneal, and 1 (9%) pelvic. One patient had two sites of disease at first recurrence. Of the 4 nodal recurrences, 3 (75%) were retroperitoneal lymphadenopathy.Of the patients with clinically localised PUC who received neoadjuvant chemotherapy, 17 patients (52%) had documented recurrences\u2014sites of recurrence included: 4 (24%) nodal , 4 (24%) peritoneal, 4 (24%) local, 3 (18%) osseous, 2 (12%) hepatic, 2 (12%) pulmonary, and 1 (6%) brain.Of those with locally advanced disease treated with chemotherapy, cystectomy was aborted in 5 (28%) cases. The most common patterns of failure were peritoneal , osseous , nodal , hepatic , and pulmonary . Three cases of peritoneal recurrence presented as bowel obstruction.Between September 2014 and May 2020, 21 patients with advanced PUC were treated with ICIs (19 with anti-PD1/PDL1 monotherapy and 2 with anti-PD1 and anti-CTLA4 combination). Baseline characteristics are tabulated in Supplementary Table\u00a0Among the 19 patients with advanced PUC, 6 (32%) experienced radiographic response. Median progression-free survival and OS were 4.5 and 10.5 months, respectively .4 Deleterious CDH1 alterations were noted in 20/33 (61%) cases.Thirty-three tumours in our database of 122 pathologically reviewed and confirmed cases of PUC were sequenced using MSK-IMPACT . For the ICI-treated subset, 16/21 (76%) had MSK-IMPACT performed, with median TMB of 18.4 mutations/Mb . The median TMB for ICI monotherapy responders and non-responders was 15.3 and 14.3 mutations/Mb, respectively (p\u2009=\u20090.8).Median tumour mutation burden (TMB) for the cohort was 14.9 mutations/Mb ; this represents the 75th percentile among all UC (UC NOS and variant histologies) in our MSK-IMPACT database (23 Five (15%) tumours harboured six alterations in DDR genes: ERCC2 (I174M and I444M), ATM , BRCA2 (E23Vfs*17), and RECQL4 (X822_splice). Neither ERCC2 alteration has been functionally validated, but the mutated residues are at or near the helicase domains.Alterations in DDR genes have been shown to be associated with platinum responsiveness.24 we observed higher rates of alterations in TP53  and RB1  compared to UC NOS from The Cancer Genome Atlas data set.25 Only 1 (3%) case in the PUC cohort harboured an alteration in FGFR3  and 1 residual non-muscle invasive disease (5%) were noted, an observation consistent with our findings.30 We also observed a low rate of genomic alterations in DDR genes, including ERCC2 and ATM, which have been reported to be associated with response to platinum-based chemotherapy.32PUC might also be associated with reduced chemosensitivity, as we observed decreased pathologic response and survival than in UC NOS. A post hoc analysis from the AUO-AB05/95 adjuvant trial33 but contrasts with a series of 13 patients with advanced PUC treated with ICI who had poor survival.34 More recently, an interim analysis of a Phase 2 trial of rare genitourinary cancers reported promising activity with ipilimumab and nivolumab, although only one PUC case was enrolled and responded to treatment at the time of reporting.35Treatment with anti-PD1/PDL1 ICI was associated with durable benefit in a third of patients in our series. Our observed response rate was comparable to ICI data from trials of patients with metastatic UC,CDH1 alterations in PUC and further characterised other genes that are frequently altered in PUC. The current series represents the largest cohort of genomically characterised PUC and is independent from our previous analysis, which reported truncating CDH1 mutations in 26/31 (84%) cases.4 Compared with published UC NOS sequencing data, we observed higher rates of alterations in TP53 and RB1 and lower rates of alterations in FGFR3 and DDR genes, which is consistent with other PUC series.36Our genomic analysis confirmed the high rate of truncating 1 To ensure that all cases that were included in our study were PUC, a detailed histopathologic review was performed on each case to confirm the diagnosis.Our study was limited by its size, single institutional, and retrospective nature, with patients treated over a 20-year period. This is unfortunately inevitable due to the rarity of PUC. During this 17-year period, different histomorphological definitions existed; these were updated and consolidated recently.37 In fact, in our small cohort of patients with advanced PUC, durable responses were observed in one-third of patients, supporting further investigations in the treatment of PUC with ICI. Indeed, the aforementioned Phase 2 trial of ipilimumab and nivolumab is still actively enrolling (NCT03333616). In fact, the Alliance A031702 Phase 2 trial of nivolumab, ipilimumab plus cabozantinib is a basket trial for rare genitourinary cancers, and it includes an arm for PUC (NCT03866382). Improved awareness of PUC as an aggressive disease entity is needed to ensure appropriate case selection in order to identify and refine therapeutic strategies for patients with PUC.In summary, in our series of pathologically verified PUC, preoperative chemotherapy response and clinical outcomes were poor relative to UC NOS, indicating that therapeutic strategies other than platinum-based chemotherapy are urgently needed. Genomic analyses have not identified potential therapeutic targets. We found a higher TMB in our cohort; this observation, in addition to PDL1 being expressed in 21\u201336% of cases, suggests a potential susceptibility to anti-PD1/PDL1 checkpoint blockade.Supplemental Legends (for figures and tables) and Supplemental TablesSupplemental Figures 1 and 2"}
+{"text": "We examined the relationship of reported childhood trauma and PTSD symptoms in a sample (N = 105) of individuals aged 19 to 80 receiving treatment for substance use and opioid use disorders in federally qualified health centers. Fifty-two percent of the sample was age 39 or younger, 30% were in their 40s and 18% were aged 50 and older. Thirty-two percent did not graduate high school and 36% had a high school education or equivalent. Seventy percent reported experiencing adverse childhood experiences (ACES). Although harmful alcohol use was low, 83% of the sample reported substantial or severe substance use, with 41% of the total reporting opioid use. ACES predicted current PTSD symptoms. Telehealth treatment considerations include: 1) internet access, 2) health and mental health literacy, and 3) monitoring for dissociation when using mindfulness-based relapse prevention treatment."}
+{"text": "Posttraumatic stress disorder (PTSD) is twice as prevalent in women as in men, and is an established risk factor for chronic disease, but few studies have comprehensively assessed lifetime PTSD in middle-aged and older civilian women. We surveyed 33,328 women aged 54-74 from the Nurses\u2019 Health Study II from August 2018 to January 2020 to understand trauma exposure, PTSD based on the Diagnostic and Statistical Manual of Mental Disorders Version 5, and trauma-related treatment use. The majority (82.2%) of women reported one or more lifetime traumas. 10.5% of those with trauma had lifetime PTSD and 1.5% had past-month PTSD. The most common trauma types were sudden or unexpected death of a loved one (44.9%) and interpersonal or sexual violence (43.5%). Almost 30% experienced occupational (nursing-related) trauma. Interpersonal or sexual violence event types explained the largest proportion of PTSD cases (33.6%) out of seven categories of events assessed. Only 25% of women with trauma ever accessed trauma-related treatment, but this proportion was higher (66.4%) among those with diagnosable PTSD, and among those with current depression (35.9%). Treatment was most common among women who experienced interpersonal/sexual violence and lowest among those with occupational trauma, but treatment satisfaction did not vary by worst trauma type. Psychotherapy was the most common type of treatment. These results demonstrate that trauma is nearly universal in middle-aged to older women, which has important implications for their long-term health and well-being\u2014particularly in the era of COVID-19 which is likely to produce additional trauma in this population."}
+{"text": "During that year we noticed an alarming increase in cases of nosocomial Candidemia: 26 versus an average of 2.8 cases per year over the previous 5 years. 19 of the 26 episodes (73%) of Candidemia occurred in patients who were admitted with acute COVID-19 infection. Recent reports suggest that hospitalized patients with COVID-19 are at increased risk for developing Candidemia, however their clinical characteristics, risk factors and outcomes have not been well described. We evaluated the risk factors and mortality of hospitalized COVID-19 patients with Candidemia. We performed a retrospective chart review of 19 patients with Candidemia and confirmed COVID-19 infection at a 292-bed community teaching hospital in Chicago, Illinois from January through December 2020. We report a descriptive analysis of the demographic characteristics, comorbidities, complications, and outcomes of these patients. The average age of our study population was 65 years; 68% were male. The average hospital length of stay (LOS) was 34 days. The mean time from admission to the development of Candidemia was 16 days. Associated co-morbidities included cardiovascular diseases (CVD) in 79%, diabetes mellitus (DM), in 68%, and obesity in 50%. Underlying kidney disease was present in 10%. Treatments for COVID-19 included convalescent plasma (53%), remdesivir (53%), steroids (52%) and tocilizumab (19%). All patients were managed in the intensive care unit (ICU) and 95% required multiple central line (CL) placements. Most of the patients (58%) required hemodialysis (HD); all patients were treated with multiple antibiotics. The average LOS in the ICU was 25 days. Despite anti-fungal treatment, 68% expired. The 28-day mortality was 50%. The occurrence of Candidemia in our hospitalized patients with acute COVID-19 infection was associated with a history of CVD, DM, obesity, prolonged hospital LOS, requirement for multiple CL, HD, treatment with multiple antibiotics and a long stay in the ICU. The mortality of COVID-19 patients with Candidemia is high. The development of strategies to mitigate the occurrence of nosocomial Candidemia in this population of patients is urgently needed.All Authors: No reported disclosures"}
+{"text": "Mycobacteria tuberculosis (MTB) complex infections in children. Given the rarity of MTB OAI, the epidemiology, disease manifestations, and treatment are poorly characterized. We describe 21 children treated for MTB complex OAI over a 26-year period at a tertiary pediatric center in southern California. Osteoarticular infections (OAI) account for 10-20% of extrapulmonary We conducted a retrospective review of children diagnosed with MTB complex OAI and cared for between 31 Dec 1992 to 31 Dec 2018 at a single tertiary care pediatric hospital with close proximity to the United States-Mexico border. Mycobacterium bovis. Of the eight cases of vertebral OAI (the most common site), one was culture-positive for M. bovis. Open bone biopsy was the most common procedure for procurement of a tissue sample and had the highest culture yield (Table 2). The median duration of antimicrobial therapy was 52 weeks (IQR 52-58). Successful completion of therapy was documented in 15 children (71.4%). Seven children (33.3%) experienced long term sequelae related to their infection.We identified 21 children with MTB complex OAI during the study period (Table 1). Concurrent pulmonary disease (4.8%), meningitis (9.5%), and intra-abdominal involvement (14.3%) were all observed. MTB complex was identified by culture from operative samples in 15/21 children (71.4%); 8/15 (51.3%) cultures were positive for Table 1. Twenty-one children with Mycobacteria tuberculosis complex osteoarticular infections.Table 2. Surgical sample type and percent positivity.M. bovis , representing a higher percentage than in previous reports and potentially reflecting its presence in unpasteurized dairy products in the California-Baja region. Local epidemiological trends in endemic MTB complex species should be considered when evaluating and managing MTB complex OAI. Bone biopsy produced the highest culture yield in this study. Given the rarity of this disease, multicenter collaborative studies are needed to improve our understanding of the presentation and management of pediatric MTB complex OAI.Among the 21 children with MTB complex OAI assessed, 8 of 15 (53.3%) children with a positive tissue culture had Vanessa Raabe, MD, MSc, Pfizer Sanofi (Scientific Research Study Investigator)"}
+{"text": "We examined the relationship of reported childhood trauma and PTSD symptoms in a sample (N = 105) of individuals aged 19 to 80 receiving treatment for substance use and opioid use disorders in federally qualified health centers. Fifty-two percent of the sample was age 39 or younger, 30% were in their 40s and 18% were aged 50 and older. Thirty-two percent did not graduate high school and 36% had a high school education or equivalent. Seventy percent reported experiencing adverse childhood experiences (ACES). Although harmful alcohol use was low, 83% of the sample reported substantial or severe substance use, with 41% of the total reporting opioid use. ACES predicted current PTSD symptoms. Telehealth treatment considerations include: 1) internet access, 2) health and mental health literacy, and 3) monitoring for dissociation when using mindfulness-based relapse prevention treatment."}
+{"text": "Tuberculosis has high burden in developing countries like Nepal. This study aims to determine the prevalence of tuberculosis among patients admitted in the department of medicine of a tertiary hospital.st January 2017 to 31st December 2019 was done. Ethical approval was obtained from Institutional Review Committee (Ref: drs2006181387). Convenience sampling method was used. A descriptive analysis of demographic, clinical and laboratory profile of patients was made using Microsoft Excel version 2016. Point estimate at 95% Confidence Interval was calculated along with frequency and proportion for binary data.A descriptive cross-sectional study of all the patients admitted to the tertiary care hospital from 1Among 6829 patients admitted to the department of medicine, 209 (3.06%) (2.65-3.47 at 95% CI) patients were diagnosed with tuberculosis. Among them, 147 (70.33%) were males and the mean age was 49.77 years. Pulmonary and extra-pulmonary tuberculosis were present in 153 (73.20%) and 56 (26.79%) patients, respectively. Bacteriological confirmation was limited to 107 (70%) of pulmonary tuberculosis and 3 (5%) of extrapulmonary tuberculosis. Fever was the commonest presentation in 166 (79.42%) followed by cough in 164 (78.46%), anorexia in 108 (51.67%), weight loss 104 (49.76%), and others.The study showed that the prevalence of tuberculosis among admitted patients was higher than national prevalence. Ethical approval was obtained from Institutional Review Committee-Patan Academy of Health Sciences (Ref: drs2006181387) before the start of data collection. Convenience sampling was done and the sample size was calculated as,A descriptive cross-sectional study of patients admitted to the Department of Medicine of Patan Hospital from 1Where,n = minimum required sample sizeZ = 1.96 at 95% Confidence Interval (CI)p = prevalence taken as 50% for maximum sample sizeq = 1-pe = margin of error, 2%As convenience sampling technique was used, the sample size was doubled to 4802. Adding 10% for missing data, the sample size of 5282 was reached. But we collected data from 6829 patients.All adult patient (15 years of age and above) admitted in medical ward, geriatric ward, step down, medical intensive care unit and private wards under Medicine Department of Patan hospital with diagnosis of tuberculosis (both pulmonary and extra pulmonary) from 1st January 2017 to 31st December 2019 were included in the study. A total of 209 hospital records of patients with tuberculosis were identified and analyzed.12 Those patients who had never smoked or who had smoked less than 100 cigarettes in their lifetimes were defined as never smokers. Those patients who had smoked at least 100 cigarettes in their lifetimes but had quit smoking at time of interview were former smokers. Others who smoked currently at the time of interview and had smoked more than 100 cigarettes in lifetime were current smoker. The amount of smoking was expressed as pack year which was calculated by multiplying the number of packs of cigarettes smoked per day by the number of years the person had smoked.We used the Centers for Disease Control and Prevention (CDC) definitions for smoking.A known case of HIV as per previous report or patients' self-declaration was considered as positive for HIV. For patients with unknown HIV status, case file and investigation were reviewed and were grouped as positive or negative based on available information. Those patients whose HIV reports were not available were grouped as status unknown.13A diagnosis of patients status for diabetes was established based on patients history, self-declaration, or report as available in case files. Blood investigation criteria for diagnosis of diabetes included fasting plasma glucose of more than 125mg/dl, two-hour postprandial plasma glucose level more than 199 mg/ dl or glycated hemoglobin (HbA1C) more than 6.4%.14Anemia was said to be present when hemoglobin level was below 12 gm/dl in female and 13 gm/dl in male. Anemia was further classified into mild, moderate and severe using the blood hemoglobin level cut-offs of 11 gm/dl and above, 8-10.9 gm/dl and below 8 gm/dl respectively.15 Individual patient files were accessed and reviewed for relevant data by the study investigators. A standard performa was used to retrieve and record the demographic, clinical and laboratory data of the patients. The proforma was anonymized generating a unique patient identifier for each patient.Hospital records of patients admitted with a diagnosis of tuberculosis were identified from the patient record section of the hospital, which archives the patient records following International Statistical Classification of Diseases and Related Health Problems Version 10.Data was collected in standard paper proforma and later entered into a secure computer system using Microsoft Excel Version 2016. A descriptive analysis of all obtained data was done and point estimate at 95% CI was calculated along with frequency and proportion for binary data.Among 6829 patients admitted in department of medicine of Patan Hospital, 209 (3.06%) (2.65-3.47 at 95% CI) were diagnosed with tuberculosis. Out of the 209 patients diagnosed with tuberculosis, 147 (70.33%) were males and 62 (29.67%) were females, and the mean age of participants was 49.77 years. The mean length of hospital stay among these patients was 6.9 days.153 (73.20%) patients had pulmonary tuberculosis, with involvement of at least one extrapulmonary sites in 29 (18.95%) patients and more than one in 6 (3.92%) patients. 56 (26.79%) patients had extrapulmonary tuberculosis with involvement of various organs .Smoking, diabetes, and HIV co-infection was present in 90 (43.06%), 25 (11.96%) and 3 (1.43%) patients, respectively. 64 (71.11%) of the smokers were current smokers. The mean pack years among 87 smokers was 15.21. Mean HbA1c among 23 diabetic patient was 8.65%.Fever was the commonest presentation in 166 (79.42%) followed by cough in 164 (78.46%), anorexia in 108 (51.67%), weight loss 104 (49.76%). Other symptoms were breathlessness in 99 (47.36%), chest pain in 48 (22.96%), haemoptysis in 27 (12.91%) patients .Laboratory investigations showed the abnormal leukocyte counts in 68 (32.53%) patients, raised neutrophil lymphocyte ratio (NLR) in 167 (79.91%) patients, raised erythrocyte sedimentation rate (ESR) in 119 (92.25%) patients and anemia in 177 (84.69%) patients .Among all patients who underwent sputum microscopy, 73 (34.93%) patients had positive sputum smear for AFB. Data on sputum for Xpert MTB/RIF was available for 80 patients (14 positive for sputum AFB and 66 AFB negative patients), out which 48 (60%) were positive. 14 (100%) patients with AFB positive sputum and tested for Xpert MTB/RIF were positive for Xpert MTB/RIF. However, among 66 patients with sputum for AFB negative status, 34 (51.51%) patients were positive for Xpert MTB/RIF .Among 153 patients of pulmonary tuberculosis, 73 (47.71%) patients had sputum positive for AFB, 34 (22.22%) patients were positive by Xpert MTB/ RIF and 14 (9.15%) patients were positive for both AFB and Xpert MTB/RIF tests. In total, 107 (69.93%) patients were bacteriologically confirmed pulmonary tuberculosis whereas 46 (30.07%) were clinically diagnosed pulmonary tuberculosis.Among 56 patients of extra pulmonary tuberculosis, only 3 (5.35%) had tissue sample positive for either AFB or Xpert MTB/RIF and the remaining 53 (94.65%) patients were clinically diagnosed with extra pulmonary tuberculosis.16 Three percent patients among all admissions in the medicine department in the present study were diagnosed with tuberculosis. Although relatively lower prevalence of tuberculosis is observed in hospital settings as a large proportion of patients are managed in outpatient basis,7 hospitalized patients imply more severe infections and/or presence of coinfections and thus requires special consideration for the diagnosis and management.Tuberculosis has high burden in Nepal. National tuberculosis prevalence survey 2018-19 has estimated the prevalence of tuberculosis to be 0.41% among the population.15 The older population commonly infected in the present study can largely be attributed to high risks of multiple co-morbidities and severe tuberculosis infection requiring hospital admission in older patients.11 Pulmonary tuberculosis is the commonest site of tuberculosis infection accounting for more than 80% of all tuberculosis, followed by lymphatic system as the commonest extrapulmonary site.5 Previous studies from Nepal comprising outpatients and inpatients have shown high prevalence of lymph node involvement, contributing to up-to 42% of all extra-pulmonary tuberculosis.16 Higher involvement of pleura 77% and central nervous system 11% in the present study conducted among inpatients could be due to the high severity with involvement of these sites needing hospitalization. This finding supports the previous finding of pleural involvement (55% and 73%) as the commonest extrapulmonary site among hospitalized patients.18Tuberculosis can infect anyone irrespective of their age and sex but is common in young males, the commonest age group being 25-34 years and male to female ratio 1.7:1 reported previously.19 In 2018, only around half of all reported pulmonary tuberculosis globally were bacteriologically confirmed.1 Although, data from high income settings with easy access to sensitive diagnostic tests like Xpert MTB/RIF have reported higher rates of bacterial confirmation,1 timely diagnosis lags behind in the developing countries.19 The conventional AFB microscopy has limited sensitivity in diagnosis9 and Xpert MTB/RIF is not readily available in resource-poor settings.20 Bacteriological confirmation limited to 70% of pulmonary tuberculosis and 5% of extrapulmonary tuberculosis in the present study with on-site facilities for microscopy and Xpert MTB/RIF points to the limited functional capacity of test facilities and underutilization of available tests in clinical diagnosis.Diagnosis of tuberculosis remains a major challenge in the developing countries.5 HIV co-infection increases the risk for tuberculosis infection by 30 folds5 and significantly increases the rate of progression of latent tuberculosis infection to disease.21 National Tuberculosis Program has emphasized for screening of HIV infection in all tuberculosis patients7 but the coverage of HIV testing in tuberculosis patients remain low in Nepal. HIV status was known in only around 40% patients in the present study with HIV prevalence of 1.43% among the population tested. This finding emphasizes on the need for strengthening HIV screening among all patients with tuberculosis.Only 5-10% of people infected with Mycobacterium tuberculosis develops tuberculosis disease but the risk is significantly higher among people with HIV co-infection, smoking and diabetes.23 Smokers are twice as likely to be infected with tuberculosis and die from the disease.5 Similarly, Diabetes Mellitus also increases the risk of tuberculosis infection by two to three folds and has negative effect on treatment outcome.24 The high prevalence of smoking and diabetes in the present study supports the similar findings reported previously.24Smoking has strong adverse effect on immune system of pulmonary tree and increases susceptibility to tuberculosis in a dose response manner.25 The clinical presentation varies widely depending on the site of infection and other patient variables, but are often empirically used to make a diagnosis of tuberculosis in resource-poor settings with limited access to reliable tuberculosis diagnostics. A cautious approach to obtaining detailed clinical data combined with laboratory findings like blood counts28 and ESR5 in the absence of specific tuberculosis diagnostic can improve the diagnostic outcomes and guide monitoring of treatment response. Approaches to looking at relative neutrophil elevation compared to lymphocytes (neutrophil-lymphocyte ratio) is highly predictive of tuberculosis progression28 and should be routinely used in the monitoring of tuberculosis patients.Tuberculosis in most of the patients presents with clinical syndrome of respiratory symptoms like prolonged cough and hemoptysis, and non-specific constitutional symptoms like fever, loss of appetite and unintentional weight loss.Given the retrospective nature of the analysis done on the secondary data of hospital records, there were limitations in the study. The possibility of missing data, especially the negative findings in the patient records could have influenced the results. However, attempts were made to review the complete patient records for pertinent data, and the findings from patients' history and laboratory records over the course of hospital admission were triangulated to retrieve the best available evidence.Tuberculosis is a common cause of infections among hospital admitted patients in Nepal. Although a classic presentation of cough and fever are generally expected in tuberculosis, a large proportion of hospital admitted patients have extra pulmonary involvement which often present with atypical symptoms. Conventional AFB microscopy has limited sensitivity for the diagnosis of tuberculosis and improved access to reliable point-of-care diagnostic tests like Xpert MTB/RIF is urgently required. Findings from detailed history taking and hematological and biochemistry testing should be cautiously interpreted for timely identification and treatment of tuberculosis."}
+{"text": "Rates of sexually transmitted infections (STIs) and uptake of HIV pre-exposure prophylaxis (PrEP) during the 2020 coronavirus pandemic are unknown. We evaluated data from the Veterans Affair Maryland Health Care System (VAMHCS) data to determine rates of STI and PrEP linkage in our Veterans.We extracted patient-level data on demographics, STI testing , International Classification of Diseases (ICD) diagnosis codes and refills of TDF-FTC and TAF-FTC. We compared the ratio of positive STI tests in 2018, 2019 and 2020 using chi-square tests. Individuals eligible for PrEP were defined as patients with a newly positive STI result or an ICD diagnosis of: high risk sexual behavior; an STI mentioned above; or gender identity disorder. We excluded anyone with a positive HIV test or a creatinine >1.8. We identified patients initiated on PrEP through pharmacy refill data to define initiation of care. Finally, we used chi-square tests to compare differences of initiation of PrEP between years and demographics.The STI positivity rate significantly increased (p< 0.01) from 44.2% (2018) and 42.9% (2019) to 61.6% (2020) [Table 1]. The median ages of those who had a positive STI test were 50 (2018), 44 (2019) and 44 (2020). In 2020, 17% of patients eligible for PrEP filled PrEP. Engagement was similar (p=0.33) in 2019 and 2018, where 14% and 11.6% of patients eligible for PrEP received a prescription  [Figure 1]. The median age of those refilling PrEP were: 44 (2018); 43 (2019) and 41 (2020)). In 2020, we observed a statistically significant difference (p< 0.01) in initiation of PrEP in care among Black patients with 11.7% of eligible patients filling PrEP as compared to white patients (26.2%) and other races (23.3%) [Figure 2]. Table 1. Rate of positive tests at VAMHCS from 2018-2020.Figure 1. PrEP Cascade at VAMHCS by year. Non-statistically significant (P=0.33) when comparing engagement in care between different years.Figure 2. Racial distribution of PrEP eligibility and initiation by year at the VAMHCS.While during the coronavirus pandemic in 2020, fewer Veterans sought STI testing at the VAMHCS, the number of positive STI results remained steady, leading to a higher positivity rate. The rate of initiation of PrEP did not differ between 2020, 2019 and 2018. Racial inequities in initiation of PrEP increased in 2020.All Authors: No reported disclosures"}
+{"text": "The management of COVID-19 poses diagnostic challenges with regard to concomitant bacterial pneumonia. This may result in unnecessary antibiotic therapy. This analysis described the experience of an urban academic medical center\u2019s management of non-ICU patients diagnosed with COVID-19 during the initial months of the pandemic and assessed the rate of concomitant bacterial pneumonia in this population.Legionella pneumophilia or Streptococcus pneumoniae antigen test, respiratory pathogen panel, and sputum culture. If patients did not have evidence of bacterial pneumonia, the threshold for appropriate discontinuation of antibiotics was 48 hours.This retrospective analysis evaluated patients 18 years and older admitted to Thomas Jefferson University Hospital (TJUH) between March 1, 2020 and July 31, 2020 who had a positive COVID-19 test, were symptomatic, and received at least one dose of antibiotics. Antibiotic therapy was considered appropriate if there was objective evidence of bacterial pneumonia. Per the TJUH COVID-19 guidelines, objective diagnostic criteria assessed included the following: MRSA nasopharyngeal swab, urine 50 patients were included in the final analysis. Upon admission, 7 (14%) patients had clear chest radiographs, and 9 (25%) of the 36 patients with a procalcitonin drawn had a level \u2265 0.25, indicating a potential bacterial infection. 15 (30%) patients were known to be COVID-19 positive prior to being administered antibiotics. Additionally, 22 (44%) patients had an infectious diseases service consult during their admission. 25 (50%) patients were continued on antibiotics > 48 hours. The mean duration of antibiotic therapy in the entire population was 3.4 days (82 hours). The monthly average duration of antibiotic therapy trended downward as the pandemic progressed. The most common empiric antibiotic regimen was ceftriaxone and azithromycin, received by 28 (56%) patients. Only 2 (4%) patients were diagnosed with bacterial pneumonia.In a sample of 50 COVID patients the overall rate of concomitant bacterial pneumonia was 4%. Given this finding, it is vital to remain judicious with the use of antibiotics and to employ the assistance of antimicrobial stewardship colleagues when managing patients diagnosed with COVID-19.Claudine El-Beyrouty, PharmD, BCPS, Astellas (Advisor or Review Panel member)Shionogi (Advisor or Review Panel member)"}
+{"text": "Paddling pools are a source of entertainment for many children. In cooler climates, parents often attempt to heat up the water temperature by adding freshly boiled water into outdoor pools. Our Regional Burns Centre has seen many of these injuries and we wanted to investigate trends and prevalence.Utilising the local Burn Injury Database, we searched for paddling pool related injuries which occurred between 2015-2020. We retrieved age, burn size and depth, need for surgical intervention and outcome, as well as circumstances surrounding the injury.We identified 26 injuries over six years, of which 11 were in 2020. The age of children ranged between 6 months and 13 years old (median 4 years 8 months). The majority, 22 (84%) of patients, had superficial partial thickness injuries. Only five patients (19%) had burns larger than 2% TBSA and only a single patient required general anaesthetic procedure to clean and dress the wounds. Two patients were admitted (length of stay 2- 5 days). Burns affected a range of locations with the majority being lower limbs (11) and upper limbs (8). Head and neck area was affected in 4 cases followed by flank (3), abdomen (2) and buttocks (2). Injuries occurred between April and August and the majority happened during the Friday \u2013 Sunday period 18 (69%). All burns occurred between 11:00 and 18:30, with average time being 14:40.Paddling pools represent a common potential risk to children. With the recent of COVID-19 pandemic leading to closure of the schools, there has been a significant increase in paddling pool sales, resulting in an increase in these injuries and, without relevant education, they are expected to become more common."}
+{"text": "Neonatal mortality rate is highest in sub-Saharan Africa and Southern Asia region. The present study is undertaken to find out the prevalence of neonatal sepsis, recognize bacterial pathogens, neonatal risk factors, major symptoms, and their antibiotic sensitivity pattern in neonates in tertiary care hospital in southern Nepal.nd January 2017 to 20th February 2018 after approval (Ref: 125/2016-17). The sample size was calculated and convenience sampling was done. Data were collected from hospital records and microbiology laboratory and analysed by Statistical Package for Social Sciences.A descriptive cross-sectional study was carried out in a tertiary care hospital from 2Staphylococcus aureus in 229 (63.08%) was found maximum followed by Klebsiella pneumoniae in 48(13.22%). The major symptom observed was Respiratory distress in 245 (20.41%) while culture positive was seen in poor cry in 94 (53.10%). Mainly effective antibiotics against Gram-positive and gram-negative organisms were Linezolid in 250 (94%) and Imipenem in 46 (90.19%), whereas Penicillin-G in 254 (99.21%) and Ampicillin in 38 (94.74%) found resistance towards organisms respectively.Out of 1200 clinically suspected cases, early-onset neonatal sepsis was seen in 290 (79.89%). A positive culture was seen in 363 (30.25%) in which maximum bacterial growth was found in 254 (69.98%) males. Preterm gestational age was seen in 265 (73%), low birth weight in 284 (78.23%), a vaginal delivery mode in 279 (76.90%), and delivery in hospital in 232 (63.91%). Likewise The high prevalence of neonatal sepsis in our study reflects a huge challenge to reduce the neonatal mortality rate to 12 by 2030 of Sustainable Development Goals. Bacterial isolates exhibited higher resistance towards commonly used antibiotics. NMCTH is a tertiary care hospital in the southern part of Nepal (province two). Total neonates admitted in the pediatric and neonatal wards were 2965. The present study included all the inborn and outborn neonates with symptoms of sepsis (\u226428 days) while excluded those that don't indicate sepsis clinically. All the information regarding age, sex, birth weight, gestational age, mode, and place of delivery, clinical sign, and symptoms were recorded with the help of the pediatric department and hospital records. Among 1200 suspected neonates, blood was collected and processed microbiology laboratory for isolation,identification, and culture sensitivity. The assortment was based on signs and symptoms as described by previous studies.6 Convenience sampling and the sample size was calculated using the formula.This was a descriptive cross-sectionalstudy conducted in the Paediatric ward and NICU from 2n = required sample sizeZ = 1.96 at 95% Confidence Interval (CI)7p = prevalence of neonatal sepsis (48%)e = margin of error (3%).Where,The total sample size was calculated to be 1065. However, 1200 samples were collected for the study.61-2 ml of blood was collected with aseptic precaution before administration of starting any antibiotic therapy and carefully transferred into a culture bottle containing Brain Heart Infusion(BHI) Broth immediately to assure the ratio (1:10).8 The culture bottle did not show growth after 24hr were observed for 7 days before regarded as no growth.6 Antimicrobial susceptibility tests were performed of the bacterial isolates to some normally used antibiotics by the Kirby Bauer disk diffusion method and interpreted according to Clinical Laboratory Standards Institute (CLSI) guidelines.9 All antibiotic discs used were of Hi-Media, Mumbai, India. Staphylococcus aureus ATCC 25923 and Klebsiella pneumoniae ATCC 700603 were used as control organisms for antibiotic sensitivity testing.The culture bottles were incubated at 37\u00b0C for 7 days aerobically and were observed each day for turbidity, hemolysis of red cells, gas bubbles, and clot formation. During incubation, the first, second, and third subcultures were done on solid media. The axenic isolates obtained from subcultured plates were identified subsequently by standard microbiological techniques like colony morphology, Gram-staining reactions, and biochemical reaction.All the data obtained were entered in the Microsoft Excel worksheet and was analyzed using the Statistical Package for the Social Sciences (SPSS) software version (22.0).One thousand two hundred blood cultures of neonates were evaluated during the study period. Out of 1200 clinically suspected cases of neonatal sepsis, 1024 (84.33%) were early-onset and 176 (14.67%) were late- onset in which positive blood culture was found in 290 (28.32%) and 73 (41.47%) cases respectively. Neonates ages ranging from 1 to 28 days with a mean age of 2.69\u00b14.39 days. The mode was equal to 1 day and median equal to 1day. Among 1200 enrolled neonates 843(70.25%) were male and 357(29.75%) were female. The male and female ratio of this study was 2.3:1. The occurrence of neonatal sepsis was 363(30.25%). The highest frequency of bacterial growth was seen in 254 (69.98%)male neonates; EONS in 290(79.89%); low birth weight in 284 (78.23%); preterm gestational age in 265 (73%); spontaneous vaginal delivery in 279 (76.86%); delivery in hospital in 232(63.91%) .The frequent clinical symptoms observed at the time of admission were respiratory distress 245 (20.41%), fever 210 (17.50%), poor cry 177 (14.75%), and the maximum percentage of bacterial growth were seen in poor cry 94 (53.10%) .Among positive cases, the bacterial spectrum of isolates was shown in In the present study,the most effective antimicrobial agents against Gram-positive organism was Linezolid 250(94%)Whereas,Penicillin-G 254(99.21%) and Amikacin 190(81.20%) were found resistance. For Gram-negative organisms, Imipenem 46(90.19%), was highly sensitive while antibiotics such as Ampicillin 38(94.74%) and 3rd generation cephalosporin were found resistance towards the isolates in our study. Antibiograms of gram-positive and gram-negative bacteria are shown in  Table 4Table 4 r7 The NMR of Nepal is 21/1000 live birth, however, the NMR of Province 2 is thirty.1 In this study, the prevalence rate of neonatal sepsis was 30.25% which reflects a high incidence compared to other regions. This finding was approx similar to that of Jain et al. (28.30%), Shrestha et al. (30.85%) from the western and central part of Nepal.11 respectively and Li et al. (28.26%) from Shanghai, China12 but our finding was higher than previously reported by Gyawali et al. (15.1%), Pokhrel et al.(20.7%), Chapagain et al. (14%), Yadav et al. (16.9%), Ansari et al. (12.6%), Shrestha and Subedi et al. (6.1%) from central part Nepal.17 Aku et al. (17.3%) from Ghana, Mehar et al. (22%) from India.18 On the other hand, our finding was lower than the report of Thapa et al. (37.12%), Lakhey et al. (48%), from Nepal.19 Kayange et al. (39%) from Tanzania, Zakariya et al. (41.6%) from India, Ullah et al. (57.1%) Pakistan, Gatabelew et al. (77.9%) Ethiopia.22 Inconsistent in a positive rate of blood culture in different studies might be due to different reasons like the variation in culture methods, study plan, administration of prior antibiotics from the primary center, unsuccessful control of hospital-acquired infection.13 Male neonates (70.25%) enrolled more frequently than females. The same type of neonatal admission was also found in previous studies, Aku et al. (60.7%), Gatabelew et al. (58.2%), Lakhey et al. (56 %), Shrestha and Subedi et al. (63.7%), Ansari et al. (61.4%).16 This is probably due to the prevalent custom of taking more care of male babies for health concerns in our society.7The causative organisms associated with neonatal sepsis vary from place to place and the episode of the causative organism is dissimilar in different hospitals and even in the same hospital at different times.16 but the result was lower in another study.7 Thus male babies were suspected to double of neonatal sepsis than female babies due to X-linked immune regulatory gene factor resulting in the host's vulnerability to infections in males.24 From the clinically suspected cases of EONS and LONS blood culture positive was found higher in LONS (41.47%) than EONS which is in harmony with the study of Kayange et al. (51.4%)20 but different with other studies.10The study has shown a male-female ratio of 2.3:1 similar to the other studies.25 but Kayange et al. reported the opposite.20The majority of culture-positive sepsis was found in our study within Male neonates(69.98%) which is comparativelyhigher thanother various studies ranging from(52.3%-63.5%)25 whereas, in the study of Chapagain et al. (83.3%), Yadav et al. (71.2%), Li et al.(52.79%), Kayange et al.(45.31%) prevalence of LONS was higher.20 Since causative agents in neonatal EONS acquired from mother during birth play role in early infection.16In the present study, the incidence of EONS(79.89%) was higher which is in agreement with previous finding (57.1%-91.39%)25 in contrast to this finding term baby are more prone to sepsis.14 Birth of baby before 37 weeks of gestational age might have a poor capacity to increase neutrophil production in accordance to demand to overcome the problem associated with neonatal bacterial sepsis.26We find out preterm(73%) neonates are more susceptible to sepsis which is consistent with various authors' findings25 dissimilarity was observed in the study of Yadav et al. and Li et al.12 This study found out that the baby who delivered in a hospital setting privileged from sepsis(63.91%) as in the finding of Gatabelow et al.(75.79%) and Kayange etal.(69.80%).20 Here in our study it may be due to the lack of proper environmental monitoring of the hospital and delivery room.Probably due to the unhygienic condition of the vagina during birth and carelessness about the safety precaution of medical personnel who assist the delivery, the baby who delivered by normal vaginal route has a higher rate of sepsis (76.90%) similar to the other findings of different researchers.25 whereas, authors found the opposite.20 Maturation of Immunological barriers starts around 32-34 weeks of gestational age and accelerated after birth. So that the level of mucosal antibody is lower in underweight neonates to combat with bacterial antigens.27Low birth weight neonates(78.23%) were found more prone to sepsis as compared to normal birth weight babies these findings are tandem with the study of different authors.19 In our study maximum percentage of bacterial growth sepsis was seen in poor cry followed by lethargy, respiratory distress, and fever these findings were similar to other studies.19The major clinical manifestations of our study were respiratory distress(20.41%), fever(17.50%), poor cry(14.75%) which is the findings of others study.S. aureus, followed by K pneumoniae, Streptococcus spp, Pseudomonas aeruginosa, E. coli, CONS, Enterobacter spp., and Proteus spp. These bacterial isolates are the predominant causative agent for neonatal sepsis identified by several studies.23The bacterial profile exposed that the higher incidence of 28 Aku et al.(69%) from Ghana, Geyesus et al.(67.5%) from Ethiopia.25 It indicates that the majority of the infections were transmitted from medical personnel, relatives because S. aureus is ubiquitous in nature and the major normal flora of skin and nose, careless about the hygiene who care neonates and manipulation of peripheral intravenous lines set up on neonates may acquire these bacteria.6 However, a study from Pokhrel et al.(77%), Gyawali et al.(55.9%), Kayange et al.(61.1%), Mehar et al.(56.7%),Yadav et al.(54%), Ullah et al.(78.6%), Zakariya et al.(82%) found gram-negative bacilli predominant over gram-positive cocci.21The result indicates that gram-positive bacteria 270/363 (74.39%) has preponderance over the gram-negative bacteria 93/363(25.61%) the similar findings were also obtained by Ansari et al.(63.8%), Khanal et al.(73%) Lakhey et al.(72.3%), from Nepal.25 and unlike in these studies.21 The etiological agent varies due to the environmental condition of the hospital, sanitation of medical personnel, and geographical area.We found S. aureus and K. pneumoniae was the most common isolate in neonatal sepsis accounting for 63.08% and 25.61% among total isolates. This finding was similar to the finding of other studies.S. aureus was found in both onset of sepsis as similar to the other study.25 but in contrast to this, a different organism was found in the different onset of sepsis.12 In our study the most effective antibiotics against major isolate S. aureus, CONS, and Streptococcus spp. were Linezolid and vancomycin similar to the previous study.13 As observed from the current study, For Klebsiella pneumoniae and other Gram-negative bacteria meropenem, imipenem and Levofloxacin be the drug of choice for treatment of neonatal sepsis. Gram-negative isolates showed a high degree of resistance to commonly used antibiotics such as ampicillin, Piperacillin as well as 3rd generation Cephalosporin. This study agreed with studies.28 from Nepal. The liberal use of broad-spectrum antibacterial increases the risk of acquisition of pathogens by interfering with the development of normal flora.29The single predominant Overall, Neonatal sepsis is a life intimidating condition. So, the knowledge of major symptoms, care about associated risk factors, prevalent etiological organism, and current effective antibiotics should be known. Respiratory distress was the major symptom and common risk factors were vaginal delivery in the hospital, birth weight less than 2.5 kg, and a gestational period of fewer than 37 weeks. We found S. aureus was the most common isolate in both onsets of sepsis. We strongly recommend medical personnel working in NICU should be trained and maintain hand hygiene with proper disinfection during the procedure and use of Linezolid and Imipenem against gram-positive and gram-negative bacteria respectively as compared to the broad-spectrum antibiotics which are more rampantly used nowadays. This vital information helps Neonatologist to manage and treat neonates with sepsis. Thus, reduction in mortality will reduce the NMR in the southern part along with overall in Nepal to meet the SDG-3."}
+{"text": "The Coronavirus Disease 2019 (COVID-19) Public Health Emergency (PHE) has had a substantial impact on the provision and utilization of healthcare services. Given the high mortality rate associated with COVID-19 amongst older adults, COVID-19 is likely to have a profound impact on all hospice users due to disruptions in providing services. Our work describes how Medicare beneficiaries have utilized the Medicare Hospice Benefit (MHB) during the PHE and how that compares to utilization of the MHB prior to the PHE. We conducted a retrospective analysis of 100% Part A and Part B Fee-for-Service (FFS) Medicare claims from January 1, 2019 \u2013 December 31, 2020. We identified approximately 42.3 million unique Medicare FFS beneficiaries from January 2019 through December 2020. Of these, 1.6 million (3.8%) had at least one hospice claim and 1.7 million (4.0%) had at least one Medicare Part A or Part B claim with a COVID-19 diagnosis during the same time period. The rate of COVID-19 amongst FFS Medicare patients who utilized hospice was 8.3%. Average per-beneficiary per-month hospice visits fell by 28.2% for aides and 15.4% for nurses from December 2019  through December 2020 . CMS should continue to monitor the prevalence of COVID-19 amongst hospice users and measures of hospice utilization amongst all hospice users in order to better understand how the PHE impacts the provision of the MHB and ensure beneficiaries continue to have access to needed services."}
+{"text": "State Medicaid programs are rebalancing their long-term care spending from nursing home to home and community-based services (HCBS). Emphasis on person-centered and person-directed care warrants investigation into models of HCBS delivery that promote quality of life. We performed a scoping review of the literature to catalogue the breadth of the studies describing HCBS waiver programs targeting adults (18+). We identified 757 articles, and after duplicate removal and reconciliation, we excluded articles on children or adolescents, non-peer reviewed reports, international studies, and articles that did not describe HCBS waiver programs. After abstract and title review, 292 articles met our inclusion criteria. Most included articles (22.3%) were single state descriptive evaluations or evaluations of service use patterns among participants. 17.8% of included articles examined multi-state or national variation in program trends, while 17.1% made national program conclusions without a major focus on interstate comparison. Less common were studies examining integrated care or dual-eligibles (7.5%), PACE (3.4%), medication management (3.1%), quality and satisfaction of both consumer and caretaker perspectives (3.8%) and consumer-only perspectives (5.1%). The remaining articles focused on HIV (4.1%), TBI (1.4%) or ID/DD (14.4%) waiver programs. The 8.9% of articles addressing quality and satisfaction consisted mostly of interviews, either with state Medicaid administrators or with care recipients and/or caregivers. Consumer reported satisfaction and unmet care needs were the primary outcomes examined. Given the heightened focus on long-term care as a result of the ongoing coronavirus pandemic, this review justifies further exploration into the delivery and outcomes of state-directed HCBS waiver programs."}
+{"text": "The purpose of this study was to analyze data from the American Burn Association National Burn Repository (NBR)with particular focus on patient ethnicity and burn etiology. We hypothesize that burn etiology, severity and other characteristics will be significantly different between differing ethnic groups throughout the database. This information can be used to augment burn prevention strategies by targeting at risk ethnic groups.Data on burn patients was derived from the American Burn Association National Burn Registry including all burn entries for a 10 year period (2009 to 2018) from 46 burn centers. The ethnic categories for this study were White, Black, Hispanic, Indigenous and Asian. The study also involved analysis of patient demographics, burn severity, context of injury, and hospital course.White patients were the largest group (64.0%), had the highest proportion of flame injury (53.1%) and shared the highest mortality rate with indigenous patients . Black individuals (22.2%) had higher rates of scald burns (53.2%), the shortest average hospital stay (16.8 days) and along with indigenous patients the highest rates of assault/abuse (2.0% and 1.9% respectively). Hispanic patients (10.0%) had more scald burns (47%), the largest proportion of men (66.5%), the highest incident of work-related injuries (18.0%) and the largest average TBSA at 10.1%. Asian patients (2.7%) had the largest proportion of scald injury (63.1%) and the smallest proportion of male patients (54.5%). Indigenous patients (1.1%) had higher rates of flame burns, suffered full thickness burns at the highest rate (32.8%), had the longest average stays in hospital (21) and the ICU (15) and had the highest rates of blanks for data entry.This study found multiple significant differences in burn populations when compared by ethnicity. We have found that the indigenous population suffered full thickness burns at the highest rate and have had the longest average hospital stay as well average ICU stay. We have also had the unexpected finding of higher rates of unknowns in the indigenous population which may reflect racial bias at an institutional level nationally."}
+{"text": "Candidemia is associated with significant morbidity and mortality. The impact of infectious diseases consultation (IDC) on clinical outcomes in patients with candidemia is not well established. We evaluated the impact of IDC and a management bundle on clinical outcomes in patients with candidemia.Candida species identified at Alberta Precision Laboratories between December 1, 2019 to November 30, 2020 and hospitalized at the University of Alberta Hospital, Edmonton, Canada were included. Patients who died within 48 hours and those who left against medical advice within 24 hours of initial positive blood culture result were excluded. Demographics, management, and outcome data were collected. A complete management bundle was defined as having all the following elements performed: IDC, repeat blood cultures, empiric echinocandin therapy, ophthalmology consult, and echocardiogram.A retrospective chart review of adult (age \u2265 18 years) patients with at least 1 blood culture growing Candida albicans was identified in more than half the cases. The primary source was intra-abdominal in 12 (39%), central-line associated in 8 (26%), and urinary in 6 (19%). IDC occurred in 27 cases (87%), echocardiogram in 22 (71%), ophthalmology consult in 10 (32%), and follow-up blood cultures in 30 (97%). 20 (65%) patients received empiric echinocandin. Of the remainder who received empiric fluconazole, 4 (36%) grew non albicans Candida species.Thirty-one patients were included for study; mean age was 56 \u00b1 17 years and 65% were male. 14 (45%) cases were admitted under critical care, 7 (23%) surgery, and 10 (32%) medicine. 3/17 (18%) required intensive care unit admission following candidemia diagnosis. Higher in-hospital mortality was observed in cases without IDC than those with IDC  and in those that did not have a complete bundle . However, IDC was not associated with the receipt of individual bundle components nor the complete bundle (p=NS).In patients with candidemia, lower in-hospital mortality was observed in patients who received IDC. Larger studies are required to confirm our findings and assess whether the implementation of a candidemia management bundle is beneficial. Dima Kabbani, MD, AVIR Pharma Edesa Biotech (Scientific Research Study Investigator)Merck (Scientific Research Study Investigator)"}
+{"text": "Osteomyelitis of the jaw is a relatively rare entity in the post antibiotic era. The aim of this study is to describe clinical characteristics, microbiology and antibiotics use  for treatment. We review 5 years of experience at Banner University Medical Center-Phoenix (BUMC-P) of proven cases of OM jaw by clinical, pathological, radiological criteria.Retrospective study of cases. From January 2011 to November 2015 ,157 cases of osteomyelitis of the jaw, we excluded cases of radiation therapy or neoplasia to the head and neck region, a history of antiresorptive medication use. A total of 34 patients with diagnosis of osteomyelitis of the jaw were reviewed. All patients met criteria for diagnosis of osteomyelitis and underwent surgical debridement and received antibiotics that included parenteral, orals and combined. We reviewed clinical, microbiology, antibiotic use. A successful outcome was defined as elimination of clinical symptoms, restoration of function and if available radiographic evidence of arrest and resolution of bony necrosis. This retrospective study involved 34 patients. Most common organisms were oropharyngeal flora 22 samples (65%): streptococcus anginosus group. 4 samples grew unusual gram negative bacteria. 10 (29%) samples grew fungal species. Antimicrobial regimen was divided in: intravenous (n=14) (41.2%), oral (n=7) (20.6%) and combination intravenous followed by orals as follows: 13 (38.2 %).The average antibiotic duration was 8.1 + 4.7 weeks. We were able to follow up 30 patients, average follow up was 32.1-44.7 weeks. The overall success rate was (n=24) 80% with uneventful healing and. (n=6) (20%) treatment failure. There was more failure in the oral antibiotics group (n=3). This study is limited by small numbers. Surgery and cultures should guide treatment of osteomyelitis of the jaw. The use of oral antimicrobial therapy was associated to a higher likelihood of treatment failure. Although rarely linked as a cause of osteomyelitis, the authors think that the cultivation of candida spp should prompt appropriate coverage. More study is required to understand the efficacy of oral antimicrobial therapy in treating osteomyelitis of the jaw.All Authors: No reported disclosures"}
+{"text": "To assess the demographics, risk profiles and outcome indicators of one of the few government-supported programs on pre-exposure prophylaxis (PrEP) in the English-speaking Caribbean.st 2018 to November 30th 2019, with a descriptive summary analysis of the data extracted.Chart review of all persons enrolled into the national PrEP Program from its inception on March 1Of the 134 persons enrolled into the program most identified as men who have sex with men (67.9%), followed by men who have sex with men and women (14.9%); there were 20 persons, mostly men (85%), in sero-discordant relationships. PrEP uptake was 96%; however, the continuation rate (continuing for three consecutive months after initiation) was 61.5%. Continuation status for many could not be ascertained due to loss-to-follow-up. PrEP-associated toxicity prevalence was 2.3%, although side-effects occurred in 52% . HIV positivity during the study period was 1.5%.Uptake of Barbados\u2019 national PrEP Program is excellent but fairly low continuation rates and the HIV positivity rate indicate the need for improved pre-ART initiation education and follow-up processes. Service utilisation is mainly by men who have sex with men, and provision expansion to other civil society partners and private practitioners, as well as increased public awareness could increase access by other high-risk groups. Daily oral HIV pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate /emtricitabine (TDF/FTC) has been proven effective and safe in high-risk groups, which prompted the World Health Organization (WHO) to recommend it as an additional HIV prevention choice for these vulnerable groups . Althoug\u00ae kit, confirmatory HIV testing, syphilis (VDRL), hepatitis B/C, HTLV 1 and 2, liver and kidney functions, and urine for PCR chlamydia and gonorrhoea testing was taken. After a negative rapid test, persons were offered PrEP and uplifted tablets right away at LRU but had up to a one-week wait at Equals. They were advised to contact the site/doctor with any queries or reports of severe side effects before their 3-month appointment.Barbados is a small independent nation in the Caribbean where the HIV prevalence rate among the general population aged 15 to 49 years is 1.5%, with a higher prevalence of 11.8% in MSM . Ninety This study aimed to provide an assessment of the national program, specifically the demographic composition and risk profiles of the enrolled, along with core outcome indicators during the first two years of program rollout. This will help to provide empirical evidence to adjust and guide the Barbados national program, and be useful for other countries where comparable population and HIV epidemic dynamics are at play, and policy makers await information from similar settings to inform their PrEP implementation.\u00ae spreadsheet and the analyses were conducted using the analytical software SPSS v.26 . These consisted of simple descriptive analyses, calculation of core indicators  as suggested by the WHO .One hundred and thirty-four (134) persons were enrolled into the program during the study period. The majority were cisgender men (94%), with 6 cisgender women and 2 transgender women. Clients averaged 30 years old, with most identifying as MSM (67.9%), followed by men who have sex with men and women (MSMW) (14.9%); there were 20 persons in sero-discordant relationships: 9 men who have sex with women (45.0%), 8 MSM (40.0%) and 3 women who have sex with men (15.0%). The majority were Barbadian (85%), with most of the other nationalities coming from the Caribbean region, and an almost equal number of persons had enrolled at either site . Most persons had no co-morbidities (60.0%), but among those who did, asthma was the most common (47.1%), followed by hypertension (15.0%).Upon enrolment, 20.8% of persons reported previous STIs, commonly syphilis (67.8%), followed by chlamydia (25.0%) and gonorrhea (25.0%). When tested on enrolment, there were 18 cases of reactive titers indicating infection with syphilis (13.4%), 3 cases of chlamydia (2.2%), 2 of gonorrhea (1.5%) and 1 case of HTLV-1 infection (0.7%), for a total of 24 prevalent infections (17.9%). A notable number of persons reported that they always used condoms during the 6 months prior to enrolment (23.8%). Most had had more than three partners in the preceding 6 months (34.4%), whilst others had two partners (31.3%), one partner (29.8%) or none (4.6%). Six (6) persons did not commence anti-retrovirals (ARVs) for PrEP after enrolment due to likely allergy, deferral of decision or comorbidities that prevented the administration of the medication.During monitoring while on PrEP, only 2 persons reported symptoms of STIs, but screening tests revealed 4 new syphilis infections, 2 new chlamydia infections and 1 case of hepatitis C. There were minor elevations of liver enzymes, none reaching the threshold for discontinuation of PrEP, and only one patient had a creatinine clearance of less than 60 mL/min. Side effects occurred in 52% of patients, with some patients reporting multiple side effects. They were mostly gastrointestinal in nature  (74.0% of persons with side effects), although headaches (14.2% of persons with side effects) and sleep disturbances  (14.2% of persons with side effects) were also commonly reported. There were no serious adverse events, but one person with a history of multiple allergies discontinued the medication after a possible allergic reaction. Amongst persons who had at least one follow-up visit and were asked about change in their condom use since starting PrEP (40/67), most reported no change (60.0%), whilst others used condoms less (25.0%) or more (10.0%). Some pointed out that condoms were only used less with regular partners or because they had a mild latex allergy. Persons missed an average of 3 pills in the previous 30 days, mostly because they forgot.PrEP uptake was based on the WHO definition , as the p < 0.00). Persons who continued enrolment were likely to be slightly older  compared to those who had discontinued or been lost to follow-up , t (101), p = 0.02. Having three or more partners within the 6 months prior to enrolment was associated with continued enrolment (73.2%) when compared to persons who had one (44.8%) or two partners (6.2%) over that same period (p < 0.02). Interestingly, those who reported always using condoms in the 6 months before enrolment were also more likely to have continued enrolment (81.5%) versus those who did not always use condoms (50%) (p < 0.00). Nationality, risk category  or the presence of any side effects were not correlated with continued enrolment in the program as can be seen in Analysis of characteristics associated with continued enrolment (defined as not discontinued or been lost to follow-up) by the end of the study period showed that more persons remained enrolled at Equals (75%) than LRU. Being lost to follow-up \u2013 defined as having missed an appointment by over 2 months with no reason noted in the records \u2013 was significantly associated with enrolment at LRU .This program evaluation presents important lessons for similar design and patient counselling for HIV and STI programs in the region. Whilst the excellent uptake rate (96%), low toxicity prevalence (2.3%), HIV positivity (1.5%) and risk compensation are positive trends, the low continuation rates (61.5%), high loss to follow-up and mostly MSM client base highlight needed improvements in program design, including better pre-initiation counselling, follow-up procedures and possibly task-shifting with expanded capacities or the designation of personnel solely responsible for PrEP provision, as was practiced at Equals, This could accompany the decentralisation of PrEP provision to more private providers and CSOs providing sexual and reproductive health services, enabling the integration of PrEP into other health care services and expansion of clientele to other high-risk populations, especially women. Increased public sensitization on the availability and role of PrEP will be necessary to expand the service and decrease any stigmatization of PrEP as key population-specific, but will need to be balanced with the cost of expansion. Additional and uniform recording procedures will allow further future delineation of factors associated with continuation, adherence and behaviours, and should be accompanied by a qualitative component for more detailed insight into contexts and influences.Authors hold sole responsibility for the views expressed in the manuscript, which may not necessarily reflect the opinion or policy of the RPSP/PAJPH and/or PAHO."}
+{"text": "There is a paucity of knowledge about pulmonary hypertension (PH) in sub-Saharan Africa and an urgent need for itsinvestigation in this context. The impact of HIV infection in PH is also unknown.To determine the aetiology, clinical presentation, severity and current management of PH at a tertiary-level hospital in CapeTown, South Africa (SA).Demographic and clinical data, including from special investigations, were captured retrospectively for all patients referred to theGroote Schuur Hospital Pulmonary Hypertension Clinic between October 2015 and November 2017 (n=58) and entered into an onlineregistry. Descriptive statistics were used to present the baseline data at enrolment.Patients were mainly young and female and almost half (48.3%) had severe symptoms according to World Health Organizationclassification. The main aetiologies were pulmonary arterial hypertension (PAH) and chronic thromboembolic PH. More than a fifth of thepatients were HIV-positive, with nine patients presenting with HIV-associated PAH. The median time from initial presentation to referralto a specialist centre was 227 days (interquartile range: 72 - 625 days). Only a small number of patients were on PH-specific treatment atenrolment and a notable number never underwent right-heart catheterisation.PH diagnosis is often delayed and even at a tertiary institution with a dedicated clinic and access to special investigations, PHis suboptimally investigated and managed. Expansion of this registry to better understand the phenotype of this disease in SA can improveoutcomes for these patients through awareness, early identification and effective management. PH isclassified into five groups by the World Health Organization (WHO)based on aetiology:[2]Pulmonary hypertension (PH) is a debilitating and progressive life-threatening disease. PH is characterised by an increase of \u226525 mmHgin mean pulmonary artery pressure (mPAP) at rest (as measuredduring right-heart catheterisation (RHC)),Group 1: Pulmonary arterial hypertension (PAH)Group 2: Pulmonary hypertension due to left-heart disease (PHLHD)Group 3: Pulmonary hypertension due to lung diseases and/orhypoxia (PH-LD)Group 4: Chronic thromboembolic pulmonary hypertension(CTEPH)Group 5: PH with unclear and/or multifactorial mechanisms.[3]Most other African studies have focused onspecific subgroups of PH, such as PH related to sickle cell anaemia[4]and PH related to schistosomiasis.[5]There is an urgent need to studyPH in the South African (SA) context, especially given the highprevalence of HIV in this setting,[6]which is known to be a risk factorfor the development of PAH.[7]There is a paucity of knowledge on the prevalence, severity, aetiology,presentation and outcome of PH in sub-Saharan Africa. The PanAfrican Pulmonary Hypertension Cohort (PAPUCO) registry has provided some insights, highlighting the different aetiologies of PHin Africa  and exposing the poor accessto investigative strategies for this condition and the lack of researchon affordable treatment.[8]France[9]and Switzerland[10] have been instrumental in characterising patients with this disease,describing its natural history and providing insight into outcomesof patients on PH-specific treatment. This preliminary report servesto highlight some of the findings from the Groote Schuur HospitalPulmonary Hypertension Registry (GSHPHR), with the aim ofbetter understanding the aetiology, clinical presentation, severity andcurrent management of PH in SA.The Pulmonary Hypertension Clinic and Registry at Groote SchuurHospital (GSH), Cape Town, were set up in 2015, in partnershipwith the Jenna Lowe Trust. Jenna Lowe was a young woman affectedby PH and was a vocal and outspoken advocate for the awarenessand treatment of PH in SA. Following her death, the trustees havecontinued to work to raise the profile of and support research inboth PH and solid-organ transplantation. Similar internationalregistries, such as those in the USA,All patients referred to the GSH Pulmonary Hypertension Clinic(PHC) from October 2015 to November 2017 were eligible forinclusion into the registry. Demographic and clinical data, as wellas data from special investigations, were captured retrospectivelyfrom medical records. Clinical data included: PH group; presentingsymptoms; pre-existing medical conditions; current treatment; riskfactors for PH; current WHO functional class; date of onset of initialsymptoms, and whether or not an initial diagnosis other than PH wasconsidered. Relevant findings from the clinical examinations wererecorded. Special investigations captured included results of: chestradiographs and other imaging; electrocardiograms; pulmonaryfunction tests; 6-minute walk tests; echocardiograms; RHCs, andblood investigations.Ethical approval was granted by the University of Cape Town\u2019sHuman Research Ethics Committee (ref. no. R008/2016 and ref.no. 205/2018); necessary approval was also obtained from treatingfacilities. Data were captured via an online registry using REDCap,a web-based data collection tool that is compliant with good clinicalpractice. The registry is password-protected and was accessible onlyto the specified investigators.Descriptive statistics were used to present the baseline data fromenrolment into the registry. Continuous variables were summarisedas medians with their associated interquartile ranges (IQRs) andcategorical variables were presented as frequencies and percentages.Data were captured from 58 patients under the care of the PHC. Themajority were female  and the mean (SD) age at enrolmentwas 44 (16) years. Of the total number of patients, 26 (44.8%) were classified as Group1,five (8.6%) as Group 2, five (8.6%) as Group 3, and 22 (37.9%) asGroup 4 Of the patients in Group 1, eight (30.8%) had idiopathic pulmonaryarterial hypertension (IPAH), six (23.1%) had PAH associated withconnective tissue disease, nine (34.6%) had HIV-associated PAH,one (3.8%) had portopulmonary hypertension, two (7.7%) had PAHrelated to congenital heart disease and one (3.8%) had drug- andtoxin-associated PAH Presenting symptoms were recorded for 57 patients. Almost allof these patients had dyspnoea on exertion as one of their initialpresenting symptoms . Other common presentingsymptoms included chest pain , cough and oedema  The WHO functional class at enrolment wasrecorded for 57 patients. It was noted thatthree patients (5.3%) were described as classI, 26 (45.6%) as class II, 22 (38.6%) as classIII and six (10.5%) as class IV When patients initially presented withsymptoms to a healthcare provider, a diagnosisother than PH was made in 30 cases (51.7%).In eight cases (13.8%) it was unknown whetheranother initial diagnosis was made. The mostcommon of these initial diagnoses were heartfailure , asthma and pneumonia  (http://www.ajtccm.org.za/public/docs/GSHPHR_DATATABLE_ADDENDUM.pdf).The most common coexisting medicalconditions were hypertension ,pulmonary embolus  and HIVinfection . The full list can befound in HIV infectionMore than one-fifth  of thecohort is HIV-positive, all of whom wereon antiretroviral treatment at the time ofenrolment. In seven cases (53.8%) the viralload was noted to be suppressed, whereas itwas either unsuppressed or not documentedin the six remaining cases. The median(IQR) CD4 count was 560 (260 - 709) cells/\u00b5L. The majority of these HIV-positivepatients  had HIV-associatedPAH. The remaining cases included twopatients (15.4%) with CTEPH, one (7.7%)with portopulmonary hypertension and one(7.7%) with PAH associated with congenitalheart disease .Chronic thromboembolic pulmonary hypertensionOf the 22 patients with CTEPH, three (13.6%)had previously received thrombolysis, three (13.6%) had an inferior vena cava filter and five (22.7%) had had apulmonary thromboendarterectomy.Only five patients were on PH-specific treatment at the time ofenrolment into the clinic, with three classified as Group 1 (11.5%)and two as Group 4 (9.1%). Four of the patients were on monotherapy(sildenafil only), whereas one patient (with HIV-PAH) was on dualtherapy (sildenafil and bosentan). None of the patients were documented to have a positive family historyof PH. One patient (2% of 51 captured cases) was documented to havea history of anorexigen use, although this was not the aetiology of PH.Two patients (3.9% of 52 captured cases) had a history of substance abuse.SmokingA positive smoking history was recorded for 20 patients (34.5%), witha median (IQR) of 15 (4 - 30) pack years.History of an echocardiogram prior to being referred to the clinicwas recorded in 49 out of 56 patients (87.5%). Owing to difficultiesin standardising the reporting of pulmonary artery pressure duringechocardiography, comparable reports of the systolic pulmonaryartery pressure were available in only 12 of these records, witha median (IQR) reading of 64.5 (61.0 - 77.5) mmHg. The ejectionfraction was recorded in 27 of the patients, with a median (IQR) of64% (55 - 71%). Annotated comments in the echocardiogram reportspecific to PH were noted at the following frequencies: dilated rightventricle in 31 cases (63.3%); dilated right atrium in 28 cases (57.1%);paradoxical wall motion in 6 cases (12.2%), and D-shaped septum in8 cases (16.3%).Less than half of the cohort  had a RHC performed priorto enrolment or during their initial work-up at the clinic; however, thiswas performed in almost all (88.5%) of the Group 1 patients. Onlythree of the Group 4 patients (13.6%) and one of the Group 2 patients(20%) and none of the Group 3 patients had had a RHC. Of the threeGroup 1 patients who did not undergo RHC, one was deemed toosick for the procedure. The reason for the other two patients notundergoing RHC could not be determined. The median (IQR) mPAP was 57 (45 - 68) mmHg and the median(IQR) pulmonary vascular resistance was 12.5 (8.4 - 16.6) Woodunits. Pulmonary capillary wedge pressure was recorded for 24 of thepatients, with a median (IQR) value of 12.5 (9.5 - 18.5) mmHg. Forthe patients without significant right-to-left shunts in whom cardiacoutput could be reliably determined, the mean (SD) cardiac outputwas recorded as 3.48 (1.13) L.[1]following the administration of nitrates. A second patient (with IPAH) had a fall of \u226510 mmHg, but only reached a mean of 63 mmHg. Vasoreactivitytesting was performed using intravenous nitrates for all but one ofthese patients, who received inhaled nitrates during RHC at a privatefacility. Vasoreactivity testing was performed for 14 of the 27 patients(51.9%): 12 patients were from Group 1 (52.2%), one was from Group4 (33.3%) and one was from Group 2 (100%). Of these, only onepatient (5.9%) with HIV-PAH had a notable fall in mPAP (defined asa decrease of \u226510 mmHg to reach a mean of \u226440 mmHg)Chest X-ray findings were recorded for 37 patients. No abnormalitieswere reported in two (5.4%) of these patients. The most commonabnormal findings were enlarged pulmonary artery tracts , followed by cardiac enlargement . The full listcan be found in The analyses of 33 electrocardiograms were captured. The majority were in sinus rhythm. Sinus tachycardia was seenin six cases (18.2%), whereas atrial fibrillation was recorded in onecase (3%). The most frequently noted abnormal morphology wasright ventricular hypertrophy , followed by right atrialhypertrophy  and nonspecific ST\u2013T wave changes , respectively. The full list can be found in Forced expiratory volume in the first second (FEV1) was recorded in47 patients, with a median (IQR) of 2.28 (1.74 - 2.78) L. Forced vitalcapacity (FVC) was recorded in 46 patients, with a median (IQR) of2.9 (2.42 - 3.36) L. The median FEV1/FVC ratio for these patients was78.9% (IQR: 73 - 84.7%). A transfer factor for carbon monoxide wasrecorded for 37 patients. The median (IQR) result was 17.3 (11.73 -19.67) mL/min/kPa.A 6-minute walk test was performed in 27 patients (46.6%) at enrolment,26 of whom had oxygen saturations recorded before and after the test.The median (IQR) distance attained was 400 (330 - 495) m. The medianoxygen saturation at rest was 94% (IQR: 91 - 96%) and 93% (IQR: 89- 97%) after the test. Two of the patients (7.4%) reached <150 m, four(14.8%) managed 150 - 300 m, 13 (48.2%) managed 300 - 450 m andeight (29.6%) managed to walk >450 m [11]the time from onset of symptoms to diagnosisof PAH was >2 years in 20% of patients, and similar delays in referraland diagnosis were identified in the GSHPHR. This is likely due tothe insidious nature and often nonspecific symptoms of this disease.Inherent problems in the SA public health sector, such as a lack of accessto diagnostic tests, long waiting times for specialist appointments anda high burden of other infectious and non-infectious diseases,[12]mayalso complicate the diagnosis of PH.PH is an underdiagnosed and under-resourced disease and, to ourknowledge, this is the first description of a cohort of SA patients with PH. Like other PH cohorts, our patients were young, predominantlyfemale and almost half had severe symptoms (WHO class III-IV).Very few were on PH-specific treatment at the time of enrolment. Inthe REVEAL registry,[3]are classified as Group 2, the patients inthe GSHPHR are mainly classified as Group 1 or Group 4. The relativefrequency of aetiology of PH reflects referral bias to the PHC at ourhospital, with Group 2 or Group 3 patients likely managed at otheroutpatient clinics.While the majority of PH patients reported on elsewhere (includingin the PAPUCO registry)14]and France[15]have shownthe prevalence of HIV-associated PAH among HIV-positive patientsto be approximately 0.5%. When the burden of HIV in SA isconsidered, the proportion of patients with HIV-related PH in ourcohort is a considerable under-representation. It is unknown whetherthis is because the burden of HIV-associated PAH is dwarfed by otherinfectious and non-infectious lung disease, or whether the impact ofHIV infection as a single aetiological contributor to the developmentof PH has been overestimated. In the PAPUCO registry, HIV wasfound to be a comorbidity more often than it was found to be acausative factor of PH.[3]Previous studies from Switzerland[1]Although almost all the Group 1 (PAH) patientsunderwent RHC, this was not true of patients in the other WHOgroups. In the state sector, it is difficult to motivate for cardiaccatheterisation if no PH-specific treatment is being proposed, and thisis reflected in the small number of patients from groups 2, 3 and 4 whounderwent cardiac catheterisation. An additional methodologicalconcern with RHC was that pulmonary capillary wedge pressure wasnot universally measured, and thus the diagnosis of Group 2 PH wasnot always conclusively excluded.Owing to limited access to investigations, the work-up of patientsin the GSHPHR did not meet standards mandated by internationalguidelines. While the majority of patients had undergoneechocardiography prior to referral, a considerable number neverhad a RHC performed, either prior to referral or during their initialwork-up at the clinic. The European Society of Cardiology/EuropeanRespiratory Society (ESC/ERS) guidelines state specifically thatRHC is required for the diagnosis of PAH and CTEPH and thatechocardiography alone should never be used to initiate specifictreatment of PH.[1]In this cohort, vasoreactivity testing during RHCwas not performed consistently for patients according to guidelinerecommendations, and sometimes it was performed in patients forwhom it was not indicated. In addition, vasoreactivity testing wasperformed almost exclusively with intravenous nitrates, insteadof with the recommended inhaled nitric oxide, epoprostenol or intravenous adenosine,[16] as use of these agents in this setting (andeven sometimes in the private sector) is prohibitively expensive.ESC/ERS guidelines also state that vasoreactivity testing toassess the benefit of high-dose calcium channel blockers should beperformed only for patients with IPAH, hereditary PAH and druginduced PAH.As with many retrospective studies involving review of medicalrecords, the quality of the available information during data capturehas been a notable limitation. This problem could be mitigated infuture by introducing a standard form for prospective data collectionduring both enrolment and follow-up visits, including necessarydemographic and clinical data, as well as listing the standardinvestigations expected and how they should be recorded.As already stated, this was not a cross-sectional study and therelative frequencies of PH aetiologies reflect referral bias to our centre.Currently the registry also consists almost entirely of patients fromhospitals in the state sector. Barriers to care among these patients havealready been outlined. The reported results may not be generalisable toother state hospitals or the private sector. However, we believe that theinherent limitations to optimal PH care experienced at our institution,which has tried to actively encourage referrals, cohort patients in aspecialised PHC, and motivate for pulmonary vasodilators, are likelyalso prevalent elsewhere in the state and private sectors. As the registrycontinues to expand and include both private and state patients, theinformation yielded may become more generalisable.Despite deficiencies, this registry provides initial insights into PHand its management in the state sector in SA, particularly regardingPAH and CTEPH. We found that PH diagnosis is often delayed andeven at a tertiary institution with a dedicated clinic and access tospecial investigations, PH is suboptimally investigated and managedcompared with international guidelines.Ultimately, this registry needs to expand to include good-qualitydata from patients from multiple tertiary-level hospitals in both theprivate and the public sector in SA. Data collected through sucha national registry will help to further the understanding of thephenotype of this disease in SA and through earlier identification,motivation for effective treatment, research and advocacy, hopefullyimprove outcomes for patients with PH.Appendix 1GSHPHR Data Table"}
+{"text": "IntroductionInterstitial lung disease (ILD) is a heterogeneous group of over 200 parenchymal lung diseases with a myriad of etiologies. Interstitial lung disease registries from around the world show varying prevalence and incidence of these diseases. The aim of this study was to determine the epidemiology and characteristics of ILD in Pakistan.MethodsThis web-based registry, which is the first multicenter registry of ILD from Pakistan, recruited patients from 10 centers of five major cities between January 2016 and March 2019.ResultsA total of 744 patients were enrolled in the registry. The five most frequent ILDs were idiopathic pulmonary fibrosis (IPF) 34.4%, hypersensitivity pneumonitis (HP) - 17.7%, idiopathic nonspecific interstitial pneumonitis (iNSIP) - 16.8%, connective tissue disease-associated ILD (CTD-ILD) - 16.3%, and sarcoidosis - 9.1%.ConclusionIdiopathic pulmonary fibrosis is the most prevalent ILD in Pakistan, followed by HP and iNSIP. An ongoing prospective registry with longitudinal follow-up will help us further elaborate on the clinical characteristics, treatment, and survival outcome of patients with ILD. The term interstitial lung disease (ILD) encompasses a group of heterogeneous diseases that affect the lung parenchyma. The etiology of the disease is diverse. Two thirds of all ILD are idiopathic, most common of these is idiopathic pulmonary fibrosis (IPF) and idiopathic non-specific interstitial pneumonitis (iNSIP). Other causes of ILD may be secondary to environmental and occupational exposures as in hypersensitivity pneumonitis (HP) or as a manifestation of connective tissue disease (CTD) . The diaAlthough several worldwide epidemiologic studies on ILD have been carried out, the data from these studies is variable, partially dependent on the diagnostic criteria used -4. AdditSerially published data between 2008 and 2016 on the relative frequencies of ILD limited to few centers from Pakistan suggests that 30 to 40 percent of reported ILD cases were IPF -9. The sThis article was previously presented as an abstract at the CHEST Annual Meeting on October 18-21, 2020.In this prospective national registry under the supervision of the Pakistan Chest Society (PCS), recruitment of participants was done from January 2016 till March 2019. A total of 10 centers from five major cities across Pakistan participated in the registry  was obtained for all participating centers and they were requested to assign a principal investigator (PI) who was responsible for patients\u2019 registration. The PI was required to furnish a written high-resolution computed tomography (HRCT) report from a radiologist trained in reading HRCT relevant to ILD. A written histopathology report was to be provided in cases where a biopsy was performed. The opinion of rheumatologists was also sought in cases of CTD-related ILD. The purpose of this multidisciplinary discussion (MDD) resource group was to maintain uniformity in the diagnostic criteria.http://pcsregistry.ildpak.com/public/login) while the physician retained a hard copy of the questionnaire as a source document.The questionnaire was specifically designed for the registry. After obtaining the written informed consent, patients more than or equal to 18 years of age with relevant history and HRCT images of the chest consistent with ILD were included. Data was gathered on demographics, occupation, history of environmental exposure, comorbids like diabetes, hypertension, chronic obstructive pulmonary disease (COPD), gastroesophageal reflux disease (GERD), history of drugs that can cause ILD like bleomycin, amiodarone, methotrexate, or cyclophosphamide and family history of ILD. Findings of HRCT scans, serology for CTD-ILD, and pulmonary function tests (PFTs), mainly consisting of spirometry and diffusing capacity of the lungs for carbon monoxide (DLCO) in a few cases, were recorded. Active lung parenchymal infections like pulmonary tuberculosis (TB) were ruled out by sputum or bronchoalveolar lavage (BAL) for acid-fast bacillus (AFB) smear, Gene-Xpert, and culture when there was a high clinical suspicion of infection. Patients with a clinical history of previous tuberculosis, lung carcinoma and history of exposure to radiation were excluded from the registry. The electronic copy of questionnaire was uploaded on an online database  version-22 . Descriptive statistics was presented as mean\u00b1standard deviation for numerical data and frequencies percentages for categorical data. Analysis of variance (ANOVA) and Chi-square test of significance were applied to evaluate the association between type of ILD and study variables. P-value <0.05 was considered statistically significant.A total of 744 patients were enrolled in the registry. The final ILD diagnoses were as follows: IPF 256 (34.4%), HP 132 (17.7%), iNSIP 125 (16.8%), CTD-ILD 121 (16.3%), sarcoidosis 68 (9.1%) and 42 (5.7%), and other ILD . Overall, 679 (91.3%) patients lived in urban areas. IPF patients were older (>60 years) and with history of current or past smoking with statistical significance (P<0.001). All ILD, except for IPF, had a statistically higher proportion of females (P<0.001). The most common clinical symptoms were cough in 674 (90.6%) and dyspnea in 519 (69.75%). On physical examination, crepitations were audible in 674 (90.6%) and rhonchi in 83 11.2%) while clubbing was seen in 247 (33.2%). Gastroesophageal reflux disease (GERD) was present in 195 (26.2%) patients and was statistically significant with iNSIP and IPF (P=0.021). Echocardiography was done in 432 (58.1%) patients, of which 206 (47.7%) showed pulmonary arterial hypertension (PAH); 44.7% had mild PAH, 30.1% had moderate PAH and 25.2% had severe PAH  was 58.2 \u00b118.7%. FVC % of predicted was presented as box-and-whiskers plot showing the median, interquartile range and outliers (if any) for ILD patients. The median FVC for IPF was 59 (range: 25-99.99), for iNSIP was 54 (range: 25-99.99), for CTD-ILD was 60.5 (range: 26-99.99), for sarcoidosis it was 67 (range: 26-99.99). The HP patients had the lowest FVC % of predicted median that was 45.5 (range: 25-82) where four cases had \u226585 FVC and considered as outliers Figure .IPF accounted for the highest proportion of reported ILD which is 34.4% in our registry. This finding is consistent with earlier local published data , 9. IPF The second most common ILD in our registry was HP 17.7%) whereas it accounted for the majority in the Indian registry 47.3%) [7.3% [4]..7% whereWe have seen iNSIP (16.8%) and CTD-related ILD (16.3%) as the next two most frequent ILD in our registry. CTD-ILD was also the second common ILD in the Indian registry (13.9%) with rheumatoid arthritis (RA) being the commonest subtype followed by scleroderma which is similar to our findings . FemalesSarcoidosis was found in 9.1% which is much less than in earlier studies from Pakistan which reported 15.3% to 18.5% , 9. ThisThere could be several limitations in our ILD Registry. The current data was collected from major urban cities of Pakistan which does not represent our rural population. The lack of use of a detailed questionnaire pertaining to the history of exposures and the non-availability of serum precipitins to identify inducers might have led to an underdiagnosis of HP. Differentiating fibrotic HP from IPF has generally remained a difficult task as well.Another limitation in our registry was the scarcity of histopathological confirmation attributable to a number of factors. The majority of cases were IPF which do not require lung biopsy while the iNSIP and HP presented with severely restricted lung function.Registry data from Pakistan concludes that IPF was the most common ILD followed by HP, iNSIP, CTD related ILD and sarcoidosis. There has been slight variation in the relative frequencies obtained from various geographic areas of this populous country, but most values have been in line with earlier studies. An expansion of the ILD registry to other cities and rural areas of the country with longitudinal follow-up of currently enrolled patients and more stringent validation of data by MDD in tertiary care and National Coordinating Centers could further expand the network and refine disease information."}
+{"text": "Antiproliferative activity of somatostatin analogs (SSAs) has been demonstrated in digestive neuroendocrine tumors (NETs), but few data have been published in patients with pulmonary NETs. We therefore conducted a retrospective study to provide additional data on the outcome of patients with metastatic lung NETs submitted to front line SSAs.Patients with metastatic lung NET treated with first line SSA-monotherapy (octreotide or lanreotide) in two different reference Institutions were reviewed. Outcome measures were progression-free survival (PFS) overall survival (OS), overall response rate and safety. We also explored prognostic factors associated with PFS.The outcome of consecutive patients (pts) with metastatic lung NETs, who underwent first-line treatment with SSAs, recruited from 2014 on 2019 in two Italian reference Institutions, was retrospectively evaluated.Thirty-one patients entered the study: 14 (45.2%) with typical and 17 (54.8%) atypical carcinoid. Six patients (19.4%) had a carcinoid syndrome. 60.0% of patients had Ki-67 \u2264 10%. Two (6.5%) patients obtained a partial response, 24 (77.4%) disease stabilization while 5 (16.1%) had progressive disease. Median progression free survival (PFS) was 28.6 months, median overall survival (OS) was not attained. Ki-67 \u2264 10%, typical carcinoid histotype and non-functioning disease, were associated with a non-significant PFS prolongation. PFS in patients with atypical carcinoids and in those with Ki-67 >10% was greater than 19 months.The long PFS and OS obtained in this case series suggest that SSAs could be effective as first line approach in the management of patients with progressive, metastatic pulmonary NET. Bronchial carcinoids are a rare group of well-differentiated lung neuroendocrine tumors (NETs) with an incidence in western countries ranging from 0.2 to 2/100 000 persons/year . AccordiIn patients with unresectable locally advanced or metastatic disease the goals of medical management are to control both hormone-related symptoms and tumor growth . Lung NEMore data on the efficacy of SSAs in patients with advanced lung carcinoids, not previously submitted to systemic antineoplastic therapies, are therefore needed.This retrospective study was designed to provide additional data on the efficacy of SSAs as first line therapy in patients with metastatic lung carcinoids.We retrospectively reviewed data of consecutive patients with metastatic lung NET, treated with first line SSA monotherapy, from January 2014 to December 2019, at the Medical Oncology Unit of ASST Spedali Civili di Brescia and at the Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors of the European Institute of Oncology of Milan (IEO). To be included in the study the patients had to meet the following inclusion criteria: histopathological confirmed diagnosis of Lung NET according to 2015 WHO criteria , locallyFollow-up visits during SSA therapy were performed approximately every 3 months and included a physical examination, complete blood count and biochemical profile. The evaluation of tumor response was assessed approximately every 6 months. Computed tomography [CT] scan or Positron emission tomography [PET] with Gallium 68 were the imaging techniques employed. The best overall response was defined according to the RECIST 1.1 criteria. Adverse events were evaluated over the whole duration of SSA administration and classified according to CTCAE v4.0.Treatment with SSAs consisted in an intramuscular injection of octreotide long-acting release (LAR)  or a subcutaneous injection of lanreotide depot (at dose of 60 mg or 120 mg every 4 weeks).The primary study end point was progression free survival (PFS), defined as the time elapsing from SSA initiation to disease progression or death whichever occurred first. Patients with no event and alive were censored at the date of the last follow-up. Secondary endpoints were: overall survival (OS), defined as the time from SSA initiation to death from any cause. Survivors were censored at the date of their last follow-up; best overall response under SSA; toxicity.Patient and tumor characteristics, the type of SSA (duration of treatment) and toxicities were described with conventional descriptive statistical analysis. Due to the explorative nature of this study, no sample size was determined. Any associations between clinical-pathological features and clinical benefit  to the treatment was tested using the exacted Fisher test. The cut-off date for the analysis was June 2020. Receiver operating characteristic (ROC) curve analysis was used to identify the optimal cut-off value of Ki-67 for the prediction of disease progression Figure 1Data of thirty-one consecutive patients, meeting the eligibility criteria, were analyzed. The clinical and pathological and characteristics and type of SSAs administered are summarized in Thirteen (41.9%) patients were male, median age at SSA initiation was 62 years (range 20-82 years). The majority of patients (93.5%) had an ECOG PS 0.Fourteen patients (45.2%) had a typical carcinoid, 17 (54.8%) an atypical carcinoid. Six patients had a carcinoid syndrome. One tumor, classified as atypical carcinoid, had Ki-67\u226520%. This latter tumor was classified as an atypical carcinoid due to the well-differentiated phenotype. Necrosis was described in only one patient (3.2%). Radiological staging at diagnosis was performed with thoracic and abdominal CT in 17 (55%) patients. PET Gallium or Octreoscan were performed in 16 (51.6%) patients. All disease lesions displayed great uptake of the radiotracers.Metastases were synchronous in 18 (58.1%) patients and metachronous in 13 (41.9%). Eighteen (58.1%) patients underwent surgery of the primary tumor which consisted in lobectomy in 3 patients (9.7%), lobectomy plus lymphadenectomy in 11 patients (35.5%) and atypical resection in 4 others. Liver was the most frequent metastatic site (61.3%). The other metastatic sites were bone (38.7%), contralateral lung (19.4%), extra-regional nodes (19.4%) and peritoneum (9.7%).Median time from diagnosis of primary neuroendocrine tumor to SSA therapy start was 13 months (range: 3-82). Twenty-seven (87.1%) patients received octreotide LAR, 26 at the standard dose of 30mg/4 weeks (one of them subsequently switched to a dose of 30mg/3 weeks), and one at standard dose of 20mg/4 weeks. Seven (22.6%) patients received lanreotide depot, six at standard dose of 120mg/28 days and one at 60mg/28 days. Three of them received both Octreotide and Lanreotide, in succession. The\u00a0median treatment duration was 30 months (range: 3-82). Three patients (9.7%) developed mild diarrhea, no other adverse events were noted.After a median follow up of 44 months (range 11-103 months), 20 patients (64.5%) underwent disease progression and 17 (54.8%) stopped the SSA therapy. Second line therapies were capecitabine plus temozolomide (CAPTEM regimen) in 7 patients, everolimus in 4 patients and peptide receptor radio-nuclide therapy (PRRT) in 4 patients. The remaining two patients received best supportive care. At the date of the last follow-up examination, 11 (35.5%) patients were free from progression and still under SSAs.Two patients (6.5%) obtained a partial response (PR), 24 (77.4%) stable disease (SD), whereas five patients (16.1%) had disease progression. After a median follow up of 44 months (range 11-103), the median PFS was 28.6 months : 1.5-41.8 months) Figure 2A not significant more prolonged PFS was observed in patients with Ki-67 \u2264 10%, typical carcinoid, non-functioning disease, no liver metastases as opposed to their respective counterparts Figure 2None of following parameters were associated with PFS: age (<60 vs \u226560 years), gender, smoking exposure, primary tumor surgery, site of metastasis, time interval between diagnosis and treatment start (<1 vs \u22651 year), SSA administered (octreotide vs lanreotide) Table 2.Somatostatin analogs are standard treatment in the management of well-differentiated neuroendocrine tumors of the gastro-entero-pancreatic tract, both functioning and non-functioning. On the basis of the results of the two prospective randomized studies , 30, theIn this retrospective series the 2 SSAs: octreotide and lanreotide, were shown to be active as first line therapy in patients with advanced/metastatic lung NET with a proportion of partial responses and stable diseases not different from that obtained in the GEP NET setting. The good overall survival should be interpreted considering the short follow-up and the few events observed, that limit the generalization of this result. The 28-month PFS is promising, considering that lung carcinoids, in particular atypical ones, generally have a worse prognosis than GEP NET patients . The difAs expected, atypical carcinoid was associated with a lower PFS than typical carcinoid, although not statistically significant. However, the 19 month PFS of patients with atypical carcinoid is a better outcome compared with historical reports . As mentIn our series the PFS was negatively influenced by the functional status  confirming a previous observation . HoweverIn summary, the long PFS obtained in this patient series with progressive, metastatic pulmonary NET, uniformly submitted to first line SSAs suggest that these drugs could be potentially efficacious in this patient setting, confirming previous observations , 22. TheThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by ethics committee of European Institute of Oncology. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.EL, ABe, NF, and FS contributed to conception and design of the study. EL organized the database. PM and AA performed the statistical analysis. AA, EL, and ABe wrote the first draft of the manuscript. All authors contributed to the article and approved the submitted version.This study was in part supported by The Italian Ministry of Health with Ricerca Corrente and 5 \u00d7 1000.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Cryptosporidium spp. is a protozoan having the potential to cause zoonosis in humans and animals. Despite the zoonotic importance of this protozoan parasite, limited data are available about its prevalence in zoo felids in North-Eastern China. Hence, the current study was designed to determine the occurrence and molecular characterization of Cryptosporidium spp. from the fecal samples of captive zoo felids. Fecal samples (N = 244) were collected from different felids from five different zoos of North-Eastern China. 18S rRNA gene was amplified from the genomic DNA using species specific primers in nested polymerase chain reaction (nPCR) and Cryptosporidium parvum and Cryptosporidium spp. was found. The overall prevalence of Cryptosporidium was 9.43% (23/244). The 18S rRNA gene similarity analysis showed that 6 Cryptosporidium isolates were Cryptosporidium parvum and the remaining 17 Cryptosporidium isolates were resembling to a Cryptosporidium spp., which is similar to Cryptosporidium NEV10. Phylogenetic tree was constructed based on 18S rRNA of Cryptosporidium spp. The similarity of Cryptosporidium parvum was with its other isolates in China, India, Iran, Iraq, Turkey, Czech Republic, Spain and USA while Cryptosporidium NEV10 alike had a close relationship with Turkish isolates. In conclusion, Cryptosporidium was prevailing in feline animals of China zoo and zoo officials are directed to consider their control policy as it can be a cause of zoonosis. Cryptosporidium is an important enteric parasite/protozoan in human beings, pets, domesticated and wild animals and is among the top four causes of moderate-to-severe diarrheal disease in young children in developing countries , Black Panther (Panthera pardus) and Manul (Felis manul) are the notable epidemiological studies on wild felids in China , Bengal tiger (Panthera tigris tigris), white tiger (Panthera tigris), Jaguar (Panthera onca), white lion (Panthera leo), African lion (Panthera leo leo), cheetah (Acinonyx jubatus), caracal , African serval  and bobcat (Lynx rufus) from the different zoos of Beijing, Dalian, Longyan and Harbin.The present study was designed to find out the prevalence and molecular identification of Panthera tigris altaica) (146), African lion (Panthera leo) (8), Bengal tiger (Panthera tigris tigris) (8), Caracal  (18), Cheetah (Acinonyx jubatus) (16), Jaguar (Panthera onca ) (11), Lynx (Lynx canadensis) (5), White lion (Panthera leo) (13), White tiger (Panthera tigris tigris) (8) and African serval  (11). Estimated relative abundance of the sampled species was 60%. We observed maximum individual animals at different sites available within zoos for defection and collected freshly deposited fecal samples from the ground of the cages . Fecal samples were mixed with 5% freshly prepared solution of potassium dichromate  in 1:3 mass to volume ratio and stored at 4 \u00b0C.From May 2018 to September 2019, 244 samples (20\u201330 g each) were collected from Beijing zoo (38), Dalian tiger zoo (38), Fujian Meihuashan South China tiger Breeding Research Institute (10), Harbin zoo (56) and Harbin tiger zoo (102) of China . The zoog for 25 min. The layer between the 1:2 solutions and 1:4 solutions was aspirated very gently and put into a new 50 ml centrifuge tube. Distilled water was supplemented up to 45 ml and centrifuged at 3,000\u00d7g rpm for 10 min. Discarded the supernatant and dissolved the sediment (oocysts) with 500 \u00b5L distilled water . The 1:2 solution and 1:4 solution have different specific gravity. In 50 ml centrifuge tubes, 15 ml of the 1:4 solutions were layered over 15 ml of the 1:2 solutions. A 10 ml aliquot of the sieved feces was layered at the top and centrifuged at 1,000\u00d7ed water .Genomic DNA was extracted from oocysts using QIAamp DNA Mini Stool Kit  with slight modification in manufacturer instruction. The modification adjusted were lysis temperature at 80 \u00b0C and elution buffer to 80 ml to increase the DNA concentration. The genomic DNA was stored at \u221220 \u00b0C until further usage.Cryptosporidium spp. Forward primer (F1) 5\u2032-TTCTAGAGCTAATACATGCG-3\u2032 and reverse primer (R1) 5\u2032-CCCTAATCCTTCGAAACAGGA-3\u2032 was used in the first step of PCR to amplify a product of 1,325 bp. A product of 830 bp was amplified in the second PCR step using forward primer (F2) 5\u2032-GGAAGGGTTGTATTTATTAGATAAAG-3\u2032 and reverse primer (R2) 5\u2032-AAGGAGTAAGGAACAACCTCCA-3\u2032  and sent for sequencing to Comate Biosciences Co., Ltd. . Successfully sequenced data was run on NCBI for similarity analysis using BLAST.MegAlign  was used to align the obtained sequences for genotyping. These sequences were submitted to GenBank (accession numbers can be seen in data availability). The phylogenetic tree was constructed using the Maximum-Likelihood method on MEGA version 6.0.Cryptosporidium were shown in percentages by dividing the positive Cryptosporidium sample to the total number of samples. Chi square test of independence at significance level \u03b1 = 0.05 was used to determine the association of Cryptosporidium prevalence with the sampling site. Sampling sites (zoos) and prevalence (positive and negative sample) were handled as nominal variable and Chi square test of independence was applied using IBM SPSS Statistics 20.Descriptive frequencies of Cryptosporidium  in Siberian tiger, 12.5% (1/8) in Bengal tiger, 37.5% (3/8) in white tiger, 15.38% (2/13) in white lion, 40% (2/5) in lynx and 25% (2/8) in African lion while it was not prevalent in caracal (18), cheetah (16), jaguar (11) and Serval (11)  specimens were found positive for poridium . Among tval (11) .Cryptosporidium spp. prevalence. The relationship between these two was significant X2  = 76.15, p = 0.00. The effect size for these finding, Cramer\u2019s V, was very strong, 0.56. As can be seen in A chi-square test of independence was performed to examine the relationship between zoo and Cryptosporidium parvum and the remaining 17 isolates resembled to Cryptosporidium spp. NEV10 (JN245625). For explaining the phylogenetic relationship, a tree was constructed based on 18S rRNA using the maximum likelihood method  that was isolated from a diarrheic calf in Turkey. Six Isolates with accession numbers MN557138, MN557143, MN557146, MN557149, MN557151 and MN557155 were identical to that of Cryptosporidium parvum.Similarity analysis of the 18S rRNA gene showed that 6 out of 23 were d method . CryptosCryptosporidium was prevalent in 9.43% (23/244) in five captive felids of Chinese Zoos. Lynx was having the highest prevalence rate for Cryptosporidium 40% (2/5) and lowest prevalence was observed in Siberian Tiger 8.22% (12/146). While, in term of locations the prevalence ranges from 0% to 39.3% in five different zoos. Harbin zoo was having the highest prevalence rate of Cryptosporidium.In present study, Cryptosporidium in different wild and captive animals. In the case of zoo felids, only manul (Felis manul) was found infected with Cryptosporidium felis in Zhengzhou zoo of China (Lynx rufus) with Cryptosporidium parvum in the USA  and humans . Variousof China  and Bobc the USA . The preCryptosporidium prevalence in the present study is 9.43% (23/244) in five captive felids of Chinese Zoos it coincides with the results reported previously in wild red fox in Spain 8% (7/87) and in animal sources  in China 7% (6/84)  and in free-living wild felids in Brasil  (Cryptosporidium in wild and captive reptiles in USA 3% (15/528) and in captive Asiatic black bears (Ursus thibatenus) in China 2.4% (4/218) (Cryptosporidium in carnivores (10%), primates (66.7%) and artiodactyls (25%) (Cryptosporidium was found in one Indian star tortoise (Geochelone elegans), one Prairie bison (Bison bison bison) and one black wildebeest (Connochaetes gnou)  in southeastern New York State (The % (6/84) . Higher %, 2/13) . Fewer s (4/218) . In Italls (25%) . In Lisbes gnou) . While ilona zoo . In wildrk State .Cryptosporidium  . Same inporidium  while anporidium . In 1996lona zoo .Cryptosporidium parvum and Cryptosporidium spp. NEV10 alike were identified in zoo felids. Cryptosporidium parvum has a zoonotic potential and previously found in preweaned calves and humans in China (Cryptosporidium parvum (accession no. GQ865534) in Bengal tiger has been submitted to NCBI GenBank before the findings of current study. To the best of our knowledge, manul (Felis manul) was infected from Cryptosporidium felis in Zhengzhou zoo which was the only published report of any zoo felid having cryptosporidiosis in China . Previously, Cryptosporidium spp. NEV10 was only found in diarrheic calf in Turkey. Because of the limited knowledge of this species, its significance about the public-health and whether zoo felids from China are the new host of this species is unclear. The prevalence of zoonotic Cryptosporidium parvum and Cryptosporidium spp. NEV10 alike might have link with the contaminated feed and water as zoo felids were fed with chicken and beef. Findings of this study demonstrated that, felid species were the suitable hosts for very common zoonotic Cryptosporidium sp. (C. parvum) and Cryptosporidium spp. NEV10 alike.Another However, during this study all the members of a felid species available at zoo were not accessed, as animal freely roam in the garden of the zoo.Cryptosporidium parvum in the zoo felids of China and those hosts may act as carrier of zoonoses by shedding the oocysts of Cryptosporidium parvum. The identification of an unknown Cryptosporidium spp. which has a close relationship with Cryptosporidium NEV10 from Turkey directs for further investigation as it was detected from diarrheic calf but now it was found from zoo felids. This study directs the attention of animal welfare zoo officials to take control measures such as proper housing and management to provide environment that allow animal to grow, mature, reproduce and minimizes the effect of disease due to parasites.The study under taken showed that first evidence of molecular identification of"}
+{"text": "Lynch syndrome increases lifetime risk of endometrial cancer to 40-60%. Screening with molecular tumor testing for mismatch repair (MMR) proteins have been recommended. This study aims to evaluate the incidence of MMR deficiency and germline mutation in endometrial cancer Thai patients. Immunohistochemistry for MMR proteins, including MLH1, MSH2, MSH6 and PMS2 were tested in 166 surgical specimens. Patients who had MMR deficiencies were offered genetic counseling and a germline testing using gene-panel next generation sequencing. MSH6 (n=2), PMS2 (n=2), and MLH1 mutations (n=1). Incidental germline mutations in other genes were detected in 3 patients . Among 5 Lynch syndrome patients, 2 patients (40%) did not meet the revised Bethesda guidelines. Eight patients who met the revised Bethesda Guidelines but having MMR proficiency had genetic testing, but no germline mutation was detected. Fifty-eight of 166 patients (34.9%) had one or more MMR deficiencies which were: MLH1 and PMS2 in 42 patients (25.3%), MSH2 and MSH6 in 11 patients (6.6%), and MSH6 in 5 patients (3.0%). Of the 40 patients (24.1%) who met the revised Bethesda guidelines, 19 patients (47.5%) had MMR deficiency. In contrast, MMR deficiency was found in 39 of the 126 patients (31.0%) who did not meet the revised Bethesda guidelines. A total of 27 patients with MMR deficiencies agreed to have germline genetic testing. Germline MMR mutations were detected in 5 patients (18.5%) including MMR deficiencies were detected in 34.9% of the endometrial cancer patients. Germline mutations were diagnosed in 3.0% of this cohort (5/166 patients). Lynch syndrome screening with MMR immunohistochemistry should be considered in all patients regardless of personal or family history of Lynch syndrome-related cancers. MLH1, MSH2, MSH6, PMS2, or EPCAM deletions, which may associate with epigenetic silencing of MSH2 . The incidence of MMR gene mutations in the general population is between 1:2000 and 1:660 . Lynch syndrome is classified as a predisposition to multiple types of cancers. The two most common Lynch syndrome-related cancers are colorectal and endometrial cancer. The lifetime risk for developing colorectal cancer increases from 4-5% in the general population to 40-60% in Lynch syndrome patients, and the lifetime risk of endometrial cancer increases from 3% to 40-60%. Other lifetime risks of cancers in Lynch syndrome include ovarian cancer (12%), stomach cancer (13%), small bowel cancer (5%), urinary tract cancer (4%), brain cancer (4%), and biliary tract cancer (2%) . Interestingly, the incidence of Lynch syndrome in endometrial cancer is slightly higher than in colorectal cancer, 1.4-5.9%  and 0.7-3.6%, respectively .Hereditary endometrial cancer occurs in approximately 3-5% of all endometrial cancer patients. Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC) is the most common cause of hereditary endometrial cancer . Lynch syndrome is an autosomal dominant syndrome caused by genetic defects in one or more DNA mismatch repair (MMR) genes. This syndrome is associated with germline MMR gene mutations, including BRCA mutations; therefore, all patients with these cancers should be offered BRCA germline testing . In contrast, Lynch syndrome is less prevalent; therefore, initial screening with clinical criteria, including personal and family history of Lynch syndrome-related cancers or molecular tumor testing is usually performed. The most common clinical criteria is the revised Bethesda Guidelines which are as follows; age at diagnosis below 50 years; synchronous or metachronous ovarian; colon or other Lynch syndrome-related cancers at any age; having a first degree relative with Lynch syndrome-related cancers being diagnosed before age 50 years old; or having two or more relatives with Lynch syndrome-related cancers at any age . Although the Revised Bethesda Guidelines remain the current clinical criteria for identifying individuals at risk for Lynch syndrome, these guidelines miss a large proportion of patients . The Society of Gynecologic Oncology (SGO) and American College of Obstetricians and Gynecologists (ACOG) recommend the process of molecular evaluation of patients at risk for Lynch syndrome as follows: molecular tumor screening with immunohistochemistry for MMR genes expression and/or microsatellite instability followed by germline genetic testing if the screening test is positive .Approximately 15-20% of patients with epithelial ovarian, tubal and peritoneal cancer have MMR immunohistochemistry is sufficient for determining MMR deficiency in endometrial cancer since it has been reported to have a high concordance (94%) with microsatellite instability . Moreover, immunohistochemistry is less expensive and widely available especially in developing countries. Although, MMR deficiency testing is routinely performed in many countries, this screening test is not yet recommended in some countries including Thailand. This study aimed to evaluate the prevalence of MMR deficiency and germline MMR mutation in endometrial cancer Thai patients.This study was conducted on endometrial cancer patients who underwent primary surgery at the King Chulalongkorn Memorial Hospital, Bangkok, Thailand between January 2013 and January 2019. This study was approved by the Institutional Review Board, Faculty of Medicine, Chulalongkorn University. All study participants provided informed written consent prior to study enrollment. Patients with either endometrial cancer or synchronous endometrial and ovarian cancer were included. Patients who had no formalin fixed paraffin embedded block and incomplete medical records were excluded. The surgical specimens were reviewed by two gynecologic pathologists. MMR immunohistochemistry screening was performed on surgical specimens for 4 MMR proteins: MLH1, MSH2, MSH6, and PMS2. Normal MMR expression was defined as nuclear staining within tumor cells. The nuclear staining using nuclei of infiltrating lymphocytes and/or normal stromal cells were used as a positive internal control. Negative expression or loss of expression was defined as the complete absence of nuclear staining within tumor cells but presence of staining in normal endometrial and stromal cells. MMR deficiency was defined as negative or loss of expression of at least one of the four MMR proteins mentioned above and MMR proficiency was defined as intact MMR expression.Demographic data, including age at diagnosis, parity, menopausal status, body mass index (BMI), family or personal history of cancer, pathological data, and previously received treatments, were retrieved from the medical records. Endometrial cancer patients were grouped according to the criteria of the revised Bethesda Guidelines. Patients with loss of MMR expression were offered genetic counseling by a geneticist. Germline testing was performed using DNA extracted from saliva or peripheral blood leukocytes. Full gene sequencing and deletion/duplication analyses were performed using the next-generation sequencing technology with 119 multi-gene panels associated with hereditary cancers  . Variant classification is a systematic process for assessing the evidence gathered during variant review and applying a formal variant classification based on the recommendations from the American College of Medical Genetics (ACMG) . However, all results were re-checked and analyzed by geneticist at our institute. If germline mutation was detected, genetic counseling was provided to both patients and their relatives, if they agreed, and comprehensive cancer surveillance was provided.Statistical analysis was carried out using SPSS version 22.0 . Categorical variables were calculated using a Chi-square or Fisher Exact test. Continuous variables were tested using a Student t-test. Statistical significance was determined as p-value less than 0.05.A total of 166 endometrial cancer patients were included. Demographic data and pathological data are shown in Among 166 patients, 58 (34.9%) had one or more MMR deficiencies: MLH1 and PMS2 in 42 patients (25.3%), MSH2 and MSH6 in 11 patients (6.6%), and MSH6 in 5 patients (3.0%). There were no significant differences in clinicopathological characteristics between patients with and without MMR deficiency. Of the 40 patients who met the revised Bethesda Guidelines, 19 patients (47.5%) had MMR deficiency. In contrast, MMR deficiency was found in 39 of the 126 patients (31.0%) who did not meet the revised Bethesda Guidelines. Using the clinical criteria of diagnosis at age below 50 years and synchronous cancers, MMR deficiency was found in less than half of the patients; 43.8% (14/32 patients) and 45.5% (5/11 patients), respectively. In patients aged over 60 years, MMR deficiency was detected in 19 of 65 patients (29.3%): MLH1/PMS2 (n=15), MSH2/MSH6 (n=3), and MSH6 (n=1). MSH6 [c.2295C>A (p.Cys765*) and c.2239delC (p.Leu747*)], 2 patients with PMS2 [c.811G>A (p.Gly271Ser) and c.2404C>T (p.Arg802*)], and 1 patient with MLH1 mutation [(c.109G>A (p.Glu37Lys)]. MSH6 mutations were found in 1 patient with loss expression of MSH2/MSH6 and 1 patient with loss of expression of MSH6. Among 3 patients with loss of expression of MLH1/PMS2, the PMS2 mutation was found in 2 patients and MLH1 mutation was found in 1 patient (Germline testing was performed in 27 of the 58 MMR deficient patients (46.6%). Twenty-four patients were lost to follow-up or could not be contacted, 4 patients denied testing, and 3 patients died. Of the 27 patients, MMR deficiencies included: MLH1/PMS2 in 16 patients (59.3%), MSH2/MSH6 in 7 patients (25.9%), and MSH6 in 4 patients (14.8%). Five of 27 patients (18.5%) had germline MMR mutations, which included 2 patients with  patient .BRCA1 [c.1265_1266dupAT (p.Ser4231lefs*8)], 1 BARD1 . All these 3 patients were younger than 60 years and had loss expression of MLH1 and PMS2 deficiencies. Only the patient with BRCA1 mutation had a family history of gynecologic cancer with unknown origin. The patient with PTEN mutation had co-incident findings with pathognomonic skin lesions of Cowden syndrome, such as papillomatous papules on the face and mucous membranes and multinodular goiter. All endometrial cancer patients with germline MMR mutations, including 3 other gene mutations, were younger than 60 years. Incidental germline mutations in other genes were detected in 3 patients including; 1 MSH6 mutation were older than 50 years. Moreover, 40% of the patients who had germline MMR mutation did not meet Bethesda Guidelines. . Most patients with MMR proficiency (61.9%) met the criteria of age below 50 years, 3 patients (14.3%) had a family history of cancers, and 5 patients (23.8%) had synchronous cancers. Germline testing was performed in 8 of 21 patients (38.1%) with MMR proficiency but met the revised Bethesda Guidelines. None could detect germline MMR mutation. Based on the finding that germline MMR mutations were found in 18.5% (5/27) of the patients with MMR deficiencies, the predictive prevalence of germline MMR mutation in all endometrial cancer patients in this study was 6.5%. Germline MMR mutation was diagnosed in 6.3% of patients younger than 50 years (2/32 patients) and 4.3% of patients between 50-60 years (3/69 patients). The mean age of the patients with germline MMR mutation was significantly younger than sporadic patients . Both patients with delines.  Seven ofMSH6 mutation, the mean age is over 50 years . In contrast, the mean age in sporadic endometrial cancer patients is 61-63 years . The current study showed the mean age of 50 years in patients with Lynch syndrome versus 57 years in sporadic patients. The incidence of Lynch syndrome in endometrial cancer patients diagnosed before 50 years old (5-13%) is higher than patients between 50 and 60 years (3-5%) . This is in agreement with our study where rates are 6.3% and 4.3%, respectively. The loss of MMR expression in this study was found in 58 of 164 patients (35%), in agreement with previously published studies: 25% to 35% . Germline MMR mutations were detected in 5 of 27 patients (18.5%) including MSH6 (n=2), PMS2 (n=2), and MLH1 mutations (n=1). Among 5 patients with germline MMR mutation, 3 patients (60%) met the revised Bethesda Guidelines; all patients with germline mutation were younger than 60 years. Early onset of cancer is common in all hereditary cancer syndromes. The mean age of endometrial cancer patients with Lynch syndrome is 47-49 years  except those with BRCA1, 1 PTEN, and 1 BARD1). Among these three genes, only PTEN mutation associates with increased risk of endometrial cancer. PTEN mutation is a cause of Cowden syndrome, which is an autosomal dominant cancer syndrome and increases risk of multiple early-onset cancers such as breast, thyroid, endometrial and colon cancer. The lifetime risk of endometrial cancer increases from 3% to 40-60% . The patient with PTEN mutation in this study also met the clinical criteria of Cowden syndrome, such as papillomatous papules on the face and mucous membranes and multinodular goiter. The association of BRCA mutation and increased risk of endometrial cancer is controversial. However, BRCA1 mutation may increase risk for serous subtype of endometrial cancer but not endometrioid subtype .Incidental germline mutations in other genes were detected in 3 patients . As a result, there are not only high false positive rates, but also increased costs of genetic testing. Immunohistochemistry for MMR proteins are a more cost-effective screening approach and highly sensitive to identify Lynch syndrome patients . One large population-based study reported that up to 70% of endometrial cancer patients with Lynch syndrome did not meet these clinical criteria and 60% were diagnosed aged above 50 years . About 40% of patients with germline MMR mutation in the current study did not meet the Bethesda Guidelines, similar to rates reported in a previous study . MSH6 mutation. Low or no microsatellite instability is commonly found in the MSH6 mutation carriers. The MSH6 mutation is important in Lynch syndrome as it has a 5-fold increased risk of endometrial cancer when compared with colorectal cancer . Therefore, the MMR immunohistochemistry was used in the current study as an initial screening tool for germline MMR mutation. The Joint ACOG/SGO recommended Lynch syndrome screening in tumor tissue with microsatellite instability and/or MMR immunohistochemistry. If high microsatellite instability and/or loss of MMR expression are detected, germline MMR testing should be considered . The microsatellite instability and immunohistochemistry analyses have high sensitivity and specificity to screen patients at risk of Lynch syndrome. In addition, both techniques have high concordance (93-100%) . MMR immunohistochemistry can be used alone or in conjunction with microsatellite instability . In general, immunohistochemistry is less expensive, more cost-effective, and widely available . On the other hand, the major limitation of microsatellite instability testing is less accuracy in identifying endometrial cancer patients with the PMS2 expression, very few had germline MLH1 or PMS2 mutations . Therefore, the loss of MLH1/PMS2 expression, including high microsatellite instability, may not be associated with a germline MMR mutation. It usually occurs in sporadic endometrial cancer patients who have MLH1 promoter hypermethylation or somatic MMR mutation . The PCR for MLH1 promoter methylation was not performed in 42 tumor specimens with loss expression of MLH1 due to unavailability in our institute. Therefore, the number of true candidates for further germline testing should be lower. In this study, the loss of MLH1/PMS2 expression was found more frequently in patients over 60 years old than the other MMR proteins. However, no germline MMR mutation was found in this age group. Most of these patients should be diagnosed as sporadic cases and could be explained by the occurrence of MLH1 hypermethylation or somatic MMR mutation. The loss of MLH1/PMS2 expression was the most common MMR deficiency in this study (25.3%). Although 10-20% of endometrial cancer patients had loss of MLH/Lynch syndrome screening in endometrial cancer patients is crucial to identify which patients should be offered genetic counseling and genetic testing in order to prevent further Lynch syndrome-related cancers. Synchronous or metachronous cancers are common in Lynch syndrome patients. Although, colorectal cancer is the most common Lynch syndrome-related cancer, endometrial or ovarian cancer was the first diagnosed cancer in nearly 50% MMR carrier women. The presence of gynecologic cancers was 11 years (median duration) before colorectal cancers . Twenty-year cumulative risks of cancers after endometrial cancer diagnosis has been reported including, 48% risk for colorectal cancer, 11% for kidney and ureter cancer, 9% for bladder cancer, and 11% for breast cancer . Intensive cancer surveillance with risk reducing surgeries should be considered. Additionally, a risk assessment should be offered to all family members to reduce cancer-related risk. Furthermore, MMR dysfunction either MMR deficiency by immunohistochemistry or MSI-high is one prognostic factor and indicates candidates for novel treatments with immune checkpoint inhibitors .Major drawback in this study was endometrial tumor tissues were derived from only one institute. All endometrial cancer patients did not perform germline testing. Genetic testing was done in nearly half of patients with MMR deficiency and almost 40% of MMR proficient patients who met the revised Bethesda Guidelines. A multicenter trial with a larger number of endometrial cancer patients is required to demonstrate the incidence of germline MMR mutation in the Thai population. In conclusion, Lynch syndrome screening with MMR immunohistochemistry should be considered in endometrial cancer patients, regardless of personal or family history of Lynch syndrome-related cancers. Further genetic counseling and testing should be offered to patients at risk for Lynch syndrome and their relatives in order to diagnose and prevent other Lynch syndrome-related cancers.TM designed the research study, collected, analyzed and interpreted the data and wrote the manuscript; CA and ST performed the histological examination and interpreted the immunohistochemistry study; PP provided genetic counseling, interpreted the genetic database. All authors read and approved the final manuscript."}
+{"text": "While self-reported loneliness generally declines after age 65, the likelihood of experiencing chronic illnesses increases. During the Covid-19 pandemic, social isolation measures have changed the social context of many people. We address three research questions: 1) What is the predictive strength of chronic illnesses, relationship quality, and their interaction on loneliness? 2) Has Covid-19 altered experienced loneliness relative to pre-pandemic? 3) Was loneliness during Covid-19 associated with the number of prior chronic illnesses in 2016? To answer these questions, we have analyzed data from participants in the Health and Retirement Study (HRS) included in the early 2020 release who also completed the 2016 wave (N = 1106). On average, in 2016, these participants were age 74.64 (SD = 6.66) and reported 2.57 (SD = 1.39) chronic illnesses. In 2016, unadjusted multiple regression models revealed that chronic illnesses (\u03b2 = .38) and relationship quality (\u03b2 = -.41) were associated with loneliness (R2 = .28). When covariates were added, these values were attenuated but remained statistically significant. In 2020 during the pandemic, 8% of these participants reported they often felt lonely and 26% reported feeling lonelier since the start of the Covid-19 pandemic. People who had more chronic illnesses in 2016 reported feeling lonelier in 2020 as did people whose relationships were poorer quality (p < .05). Further analyses with final data from HRS are needed to confirm these trends. These findings highlight the importance of having longitudinal information to identify individuals at high risk and most likely to benefit from interventions."}
+{"text": "This research examines disparities in rates across the 4 states for 4 behavioral health indicators: substance use disorder (SUD), tobacco use disorder (TUD), opioid use disorder (OUD), and excessive drinking. Results varied across states with RI reporting the highest rates of substance (7.0%) and tobacco use (10.8%) disorders, CT had the highest rate of opioid use disorder (2.2%), and MA and RI reporting the highest rates of excessive drinking (9.3%). Overall, MA had the greatest disparities in rates for all indicators (SUD: 6.6% (5.35-15.99%); TUD: 10.2% (2.67-24.20%); excessive drinking: 9.3% (5.63-19.98%)), indicating behavioral health disparities by community are most pronounced in MA. This study found behavioral health issues are prevalent among New England older adults and should no longer be overlooked. Furthermore, visualizing the community rates makes disparities evident and may guide resources and services to areas of highest need.Behavioral health issues in older adults are prevalent and have negative consequences on quality of life and overall health, yet are often untreated. The present study compares state and local community rates of behavioral health indicators of older adults age 60+ in Massachusetts (MA), New Hampshire (NH), Rhode Island (RI), and Connecticut (CT). For this study rates were calculated from the following data sources: Medicare Current Beneficiary Summary File 2014-2018  and the Behavioral Risk Factor Surveillance System . Small area estimation techniques were used to calculate age-sex adjusted community rates for more than 170 health indicators ("}
+{"text": "The aim of this study was to describe and compare the mental health status of doctors and medical undergraduates in selected institutions during COVID-19 pandemic.A cross-sectional analytical study was conducted among doctors working in major tertiary care hospitals two of which, risk is unpredictable and high, the other where all patients are positive for COVID-19 and among medical undergraduates. The doctors were selected using disproportionate stratified sampling and medical undergraduates using stratified cluster sampling. Data were gathered using a Google form containing socio-demographic details, perception on the pandemic and the General Health Questionnaire-12(GHQ-12).There were 468 participants in the study and among them 243(51.9%) were doctors. Mean age of the doctors\u2019 is 34.54(SD = 7.43) years and more than half (50.06%) were in post graduate training. Majority were worried about their health (65%) and their loved one's health (90.1%). Among doctors 220(90.5%) felt that they have moderate or higher risk of acquiring COVID-19 and 15.6% would not have worked due to the risk. According to GHQ-12, 182(74%) doctors were psychologically distressed  and it was significantly associated with age less than 35 years (p = 0.039) and worry about interruption of their daily routines(p = 0.010).The mean age of 225 medical undergraduates was 25.20 (SD = 1.34) years and 176(78.2%) of the participants were psychologically distressed . Majority (59.11%) believed that they are at high risk of getting COVID-19. Their distress was significantly associated with the worry about the impact of COVID-19 related restrictions on their daily routines (p = 0.000).Binomial logistic regression confirmed that doctors were distressed due to impact on their income whereas both doctors and medical undergraduates were distressed due to impact on daily routines.Nearly three quarter of both doctors and medical undergraduates were psychologically distressed during COVID-19 pandemic. The worry was due to contracting illness, financial issues and the COVID-19 regulations."}
+{"text": "Cardiomyopathies are diseases of heart muscle that may originate from genetic defects, cardiac myocyte injury or infiltration of myocardial tissues. Dilated cardiomyopathy is the most common phenotype and is often a final common pathway of numerous cardiac insults. Mostly it remains unknown in the absence of echocardiography, histopathology and genetic evaluation. Though common it is underdiagnosed with not much of data available in our setup.st of February to 31st July 2018 for the period of six months in Shree Birendra Hospital, a tertiary care military hospital at Chhauni, Kathmandu. Pediatric age group patients and those who refused to give consent were excluded. Data obtained were entered in Microsoft Excel 2010 and analyzed by IBM SPSS 21.This study was analytical cross-sectional study of hospital data on Echocardiographic findings in 65 patients of DCM visiting cardiology unit for Echocardiographic evaluation from 1Among 65 patients enrolled 40 (61%) were male and 25 (39%) female with male to female ratio of 1.6:1. Elderly people (61-75 years) with an average age of 65 were commonly involved and they presented mostly with congestive heart failure, 32 (49%). Echocardiographic evaluation showed 36 (55%) with mildly dilated Left Ventricle (5.6-6.0cm). Majority had reduced Left ventricular systolic function with an average Ejection fraction (EF) of 39.6%. No significant difference between male and female with the average EF% (P=0.990) and there was no significant relation between age and average EF% (P=0.091).Dilated Cardiomyopathy is the commonest cardiomyopathy phenotype mostly presenting with congestive heart failure. It is often underdiagnosed in our part of the world, however echocardiography will easily detect the condition. Various etiologies such as genetic defects, cardiac myocyte injury and infiltration of myocardial tissues leads to CM. Dilated cardiomyopathy (DCM) is the most common type with enlargement of one or both of the ventricles resulting in systolic dysfunction with reduced ejection fraction (EF%).7 DCM approximately accounts for 25% of the Congestive heart failure (CHF) cases and remaining 75% are due to ischemic, hypertensive or non-systolic heart failure.9 Genetic and specific studies in highly specialized centers can identify causes in about 50% cases and remaining are the diagnosis of exclusion, termed idiopathic variants.12The annual mortality rate has a wide range between 10% and 50%.The aim of this study is to determine incidence, and evaluate Echocardiographic findings in patients of DCM.st of February to 31stJuly 2018 for the period of six months in Shree Birendra Hospital (SBH), a tertiary care military hospital at Chhauni, Kathmandu. Diagnosis of DCM was done on the basis of history, clinical features (symptoms & signs) and Echocardiographic evaluation. Data from register book were retrieved after ethical approval from institutional review committee. Standardized questionnaire developed by the researcher was used to obtain clinical and socio-demographic characteristics of the patients after informed consent. Pediatric age group patients and those who refused to participate were excluded.An analytical cross-sectional study was done utilizing hospital data on Echocardiographic findings in 65 patients of DCM visiting cardiology unit for Echocardiographic evaluation from 1Maximum internal diameter of left ventricle (LV) during diastole less than or equal to 5.5cm considered normal. M-mode measurement of LV during systole and diastole used for calculating Ejection fraction (EF) where EF% less than 50% considered reduced. Left ventricular diastolic dysfunction (LVDD) grade one defined by E/A ratio less than one and grade two as E/A ratio more than one  with some structural LV filling defect .Echocardiography was performed by Cardiologists to see cardiac structural and functional abnormalities. Machine used was SIEMENS Model: ACUSON SC2000 having the facility of two dimensional view, M-mode and color flow Doppler imaging. Data obtained were entered in Microsoft Excel 2010 and analyzed by software IBM SPSS 21. Statistical significance between male and female with EF was calculated by means t-test whereas relationship between age and EF by ANOVA . P<0.05 was considered significant.Among 65 patients enrolled 40 (61%) were male and 25 (39%) female with male to female ratio of 1.6:1. Most of the cases have unknown etiology 53 (81%). On Echocardiography, 36 (55%) had mildly dilated Left Ventricle (5.6-6.0cm) . AdditioFunctional Mitral regurgitation in 48 (74%) with Grade I Left ventricular diastolic dysfunction in 56 (86%). Majority had reduced Left ventricular systolic function with Ejection fraction between 21% and 30%, an average of 39.6% .Elderly age group (61-75 years) with an average age of 65, were encountered frequently 34 (52%) and the most common clinical presentation was congestive heart failure 32 (49%) .Besides, mild pericardial effusion found in 2 (3%) and none of our cases had any intra-cavitary thrombus or vegetation.On applying two sample means \u2018t-test\u2019 there was no statistical significant difference between average EF% of both male and female (P = 0.990) .Similarly, by ANOVA  there was no relationship of age and average EF% (P = 0.091) .13 53% were male and 47% female, similar to our study with males outnumbering females. Most of our patients presented with congestive heart failure (49%) supported by Animasahun BA et al.14 where it was 54.5%. Similar result was evident in the study by Towbin JA et al.12DCM was more common in male than female (61% vs 39%) and frequent on the elderly with the mean age of 65 years in our study population. In the study done by Suha MA et al.2 In our study association of RV dilation was 18%.Dilated Left ventricle (LV) is mandatory for the diagnosis of DCM, however Right ventricle (RV) may similarly be affected, Mathew T et al.3 Meese RB et al,15 Ballester M et al,16 Chandraratna PA et al.17 and its presence predicts poor outcome, Donal E et al.18Incidence of functional Mitral Regurgitation (MR) in our study was 48%. Functional MR, which occurs as a consequence of regional or global LV dysfunction despite a structurally normal mitral valve, is a common complication in patients with DCM, Jun K et al,19 Lavine SJ et al,20 Appleton CP et al.21 and Pinamonti B et al.22Some degree of Left ventricular diastolic dysfunction (LVDD) is inevitable in DCM ranging from grade one to four. We had 86% cases with LVDD grade one. Assessment of diastolic function in DCM also correlated by studies Nishimura RA et al,23 Also evidenced byFolland ED et al.24 and Stamm RB et al.25LV systolic dysfunction quantified by measuring Ejection fraction (EF) in percentage and the estimated EF% assumes uniform or global left ventricular function, Shah PM.26 and Gottdiener JS et al.27 The limitations of our study being the data of a single center and lack of etiologic evidence.None of our cases had intra-cavitary thrombus, however it is a common complication in patients with DCM, Asinger RW et al.Patients commonly present with symptoms and signs of congestive heart failure and a simple Echocardiography will easily detect the condition. However, etiologic diagnosis is not possible mostly in a resource limited settings. More research works to be done to understand this common heart failure condition and our aim should be to diagnose preclinical DCM cases and thereby reduce significant mortality and morbidity."}
+{"text": "Objectives: To study the differential diagnosis of HIV-infected patients with suspected central nervous system (CNS) infections and the association of CD4 counts with the final diagnosis.Methods: We analyzed HIV-infected patients from a prospective cohort study on the diagnostic accuracy of clinical and laboratory characteristics in adults with suspected CNS infections in an academic hospital in Amsterdam, the Netherlands, who underwent cerebrospinal fluid (CSF) examination.Results: Thirty-four (9.4%) out of 363 patients with suspected CNS infections were HIV-positive of whom 18 (53%) were diagnosed to have CNS infection, with median CD4 counts of 255 cells/\u03bcl. The spectrum of CNS infections consisted of progressive multifocal leukoencephalopathy in three patients (17%); cryptococcal meningoencephalitis, toxoplasma encephalitis, angiostrongylus eosinophilic meningitis, and HIV encephalitis each in two (11%); and cytomegalovirus encephalitis, neurosyphilis, tuberculous meningoencephalitis, histoplasma encephalitis, and varicella-zoster virus meningitis each in one (6%). Clinical characteristics and blood parameters did not differ between HIV-infected patients with CNS infections and other diagnoses. The best predictor for CNS infections was the CSF leukocyte count . The diagnosis of CNS infection was not associated with the CD4 count . Two patients (11%) with CNS infections died and two (11%) had neurological sequelae.Conclusions: Half of the patients with suspected CNS infections are diagnosed with a CNS infection, and this was not related to CD4 counts. The best predictor for CNS infections was the CSF leukocyte count. Human immunodeficiency virus (HIV) is a neurotrophic, neuroinvasive, and neurovirulent pathogen , which cDiagnosis of CNS infections in HIV-infected patients can be challenging as a variety of conditions should be considered in the differential diagnosis, and it may be caused by a broad spectrum of pathogens with diverse and overlapping clinical manifestations . The cauWe describe a population of HIV-infected patients included in a prospective study on the diagnostic accuracy of clinical and laboratory characteristics in patients with suspected CNS infections. We analyzed the causes of CNS infections, the differential diagnosis, and the association of CD4 counts with the final diagnosis.We studied HIV-positive patients over 16 years included in a cohort of patients with suspected CNS infections in an academic hospital in Amsterdam, the Netherlands, who underwent CSF examination. The methods have been described in detail previously . Data coThe final diagnosis was classified by two researchers based on all available clinical data, including microbiological examination of CSF. The classification was performed sorting each diagnosis into one of the following five categories: (1) CNS infection, (2) nervous system inflammation without infection, (3) non-infectious non-inflammatory neurological disorder, (4) non-neurological infection, and (5) other systemic disorder. Outcome was scored using the Glasgow outcome score (GOS). A favorable outcome was defined as a score of 5, and an unfavorable outcome was defined as a score of 1\u20134.U-test was used for continuous variables, whereas Fisher's exact test and chi-square tests were used for categorical variables, as appropriate. The area under the curve (AUC) was measured using the receiver operating characteristic curve (ROC). A p-value < 0.05 was considered as statistically significant. The study was approved by the medical ethical committee of the Academic Medical Centre, Amsterdam, the Netherlands.Continuous data were described with medians and interquartile range and categorical variables with frequency and percentage. The Mann\u2013Whitney Between February 2012 and May 2015, 363 patients with suspected CNS infections were included of whom 34 were HIV-infected (9.4%). Overall, out of 363 cases with suspected CNS infections, 88 (24%) had CNS infection, 38 (11%) non-infectious non-inflammatory neurological disorders, 121 (33%) non-neurological infections, 108 (30%) non-infectious non-neurological disorders, and 8 (2%) non-infectious neuro-inflammatory disorders. The median age of included HIV-infected patients was 44 years, and 24 of 34 (70%) were male. On admission, 19 (55%) patients were on cART, 1 (3%) stopped treatment shortly before admission, and 10 (29%) were not taking cART despite being diagnosed with HIV infection. In four (11%) patients, HIV infection was newly diagnosed during the workup of neurological manifestations.3) in 20 of 34 (59%) patients (Presenting signs and symptoms included fever in 10 patients (29%), headache in 16 (47%), neck stiffness in 2 (5%), altered mental status  in 5 (14%), and focal neurological deficits in 3 (8%). The median CD4 count was 255 [interquartile range (IQR) 92\u2013480]. Out of 34 patients, 15 (44%) had a CD4 count below 200, 11 between 200 and 500 (32%), and 8 above 500 (24%). CSF examination showed an elevated leukocyte count  vs. 44 (IQR 30\u201364); p-value: 0.04], and the CSF-to-blood glucose ratio was lower . ROC analysis showed an AUC of 0.77 (95% CI 0.61\u20130.94) for the CSF leukocyte count and 0.75 (95% CI 0.57\u20130.93) for CSF protein concentration in diagnosing CNS infections. Other clinical or laboratory features, including the CD4 count, were not associated with the diagnosis of CNS infection .Out of 34 HIV-infected patients, 18 (53%) were categorized as having a CNS infection, 7 (21%) with non-infectious non-inflammatory neurological disorders, 6 (18%) with non-neurological infections, 2 (6%) with non-infectious non-neurological disorders, and 1 (3%) with non-infectious neuro-inflammatory disorders. Of those who were finally diagnosed with CNS infection, 13 (72%) were male and 5 (28%) females with a median age of 43 years. Eight (44%) patients with CNS infections were on cART, and one discontinued treatment 1 month before. Their median CD4 was 205 (IQR 55\u2013455). Out of 18 patients with CNS infection, 4 (22%) had a normal CSF leukocyte count. Only 1 (6%) out of 18 patients with CNS infection and 3 (19%) out of 16 with other diagnoses had completely normal CSF. The CSF leukocyte count was higher in patients with CNS infections .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "This study examines the prevalence and associations between recent violence experience, mental health and physical health impairment among Female Sex Workers (FSWs) in north Karnataka, India.Multi-morbidity, in particular the overlap between physical and mental health problems, is an important global health challenge to address. FSWs experience high levels of gender-based violence, which increases the risk of poor mental health, however there is limited information on the prevalence of physical health impairments and how this interacts with mental health and violence.We conducted secondary analysis of cross-sectional quantitative survey data collected in 2016 as part of a cluster-RCT with FSWs called Samvedana Plus. Bivariate and multivariate analyses were used to examine associations between physical impairment, recent (past 6 months) physical or sexual violence from any perpetrator, and mental health problems measured by PHQ-2 (depression), GAD-2 (anxiety), any common mental health problem (depression or anxiety), self-harm ever and suicidal ideation ever.511 FSWs participated. One fifth had symptoms of depression (21.5%) or anxiety (22.1%), one third (34.1%) reported symptoms of either, 4.5% had ever self-harmed and 5.5% reported suicidal ideation ever. Over half (58.1%) reported recent violence. A quarter (27.6%) reported one or more chronic physical impairments. Mental health problems such as depression were higher among those who reported recent violence (29%) compared to those who reported no recent violence (11%). There was a step-wise increase in the proportion of women with mental health problems as the number of physical impairments increased . In adjusted analyses, mental health problems were significantly more likely among women who reported recent violence (e.g. depression and violence AOR 2.42 (1.24\u20134.72) with rates highest among women reporting recent violence and one or more physical impairments (AOR 5.23 (2.49\u201310.97).Our study suggests multi-morbidity of mental and physical health problems is a concern amongst FSWs and is associated with recent violence experience. Programmes working with FSWs need to be mindful of these intersecting vulnerabilities, inclusive of women with physical health impairments and include treatment for mental health problems as part of core-programming.Samvedana Plus was funded by UKaid through Department for International Development as part of STRIVE  led by London School of Hygiene and Tropical Medicine and the What Works to Prevent Violence Against Women and Girls Global Programme led by South African Medical Research Council"}
+{"text": "What are the clinical outcomes and associated factors among children and adolescents hospitalized with COVID-19 in sub-Saharan Africa?In this cohort study of 469 children and adolescents hospitalized with COVID-19 in 6 sub-Saharan African countries, morbidity and mortality were substantially higher than reported among those in non-African settings and were independently associated with age younger than 1 year and select noncommunicable disease comorbidities.This study\u2019s findings may have implications for clinical practice and health policy regarding pediatric COVID-19 in African countries; given their high risk of adverse outcomes, COVID-19 vaccination and therapeutic interventions are needed for African children and adolescents. Little is known about COVID-19 outcomes among children and adolescents in sub-Saharan Africa, where preexisting comorbidities are prevalent.To assess the clinical outcomes and factors associated with outcomes among children and adolescents hospitalized with COVID-19 in 6 countries in sub-Saharan Africa.This cohort study was a retrospective record review of data from 25 hospitals in the Democratic Republic of the Congo, Ghana, Kenya, Nigeria, South Africa, and Uganda from March 1 to December 31, 2020, and included 469 hospitalized patients aged 0 to 19 years with SARS-CoV-2 infection.Age, sex, preexisting comorbidities, and region of residence.An ordinal primary outcome scale was used comprising 5 categories: (1) hospitalization without oxygen supplementation, (2) hospitalization with oxygen supplementation, (3) ICU admission, (4) invasive mechanical ventilation, and (5) death. The secondary outcome was length of hospital stay.Among 469 hospitalized children and adolescents, the median age was 5.9 years ; 245 patients (52.4%) were male, and 115 (24.5%) had comorbidities. A total of 39 patients (8.3%) were from central Africa, 172 (36.7%) from eastern Africa, 208 (44.3%) from southern Africa, and 50 (10.7%) from western Africa. Eighteen patients had suspected (n\u2009=\u20096) or confirmed (n\u2009=\u200912) multisystem inflammatory syndrome in children. Thirty-nine patients (8.3%) died, including 22 of 69 patients (31.9%) who required intensive care unit admission and 4 of 18 patients (22.2%) with suspected or confirmed multisystem inflammatory syndrome in children. Among 468 patients, 418 (89.3%) were discharged, and 16 (3.4%) remained hospitalized. The likelihood of outcomes with higher vs lower severity among children younger than 1 year expressed as adjusted odds ratio (aOR) was 4.89  times higher than that of adolescents aged 15 to 19 years. The presence of hypertension , chronic lung disease , or a hematological disorder  was associated with severe outcomes. Age younger than 1 year , the presence of 1 comorbidity , and the presence of 2 or more comorbidities  were associated with reduced rates of hospital discharge.In this cohort study of children and adolescents hospitalized with COVID-19 in sub-Saharan Africa, high rates of morbidity and mortality were observed among infants and patients with noncommunicable disease comorbidities, suggesting that COVID-19 vaccination and therapeutic interventions are needed for young populations in this region. This cohort study assesses clinical outcomes and associated factors among children and adolescents hospitalized with COVID-19 in 6 sub-Saharan African countries. Of the more than 315 million cases and 5.5 million deaths reported to be associated with SARS-CoV-2 as of January 13, 2022, more than 29 million cases and 22\u2009000 deaths are estimated among children and adolescents aged 0 to 19 years.10 Data primarily from China, Italy, the UK, the US, and several European countries have revealed that between 1% and 5% of all COVID-19 cases occur in children, with an overall mortality rate of 1% or lower in hospitalized children.9After 2 years of the COVID-19 pandemic, several studies11 Despite increasing knowledge about COVID-19 in children, data from African countries are limited.15 Most reports about COVID-19 among African children have been small single-center studies with scarce data on clinical presentation and outcomes.18 Sub-Saharan Africa has a high prevalence of both communicable  and noncommunicable  diseases that also occur among children.20 Combined with the high prevalence of comorbidities, limited availability of intensive care may have substantial consequences for COVID-19 outcomes in sub-Saharan Africa.21 In the multicenter African COVID-19 Critical Care Outcomes Study,22 almost 50% of adults with COVID-19 died within 30 days of intensive care unit (ICU) admission, with up to 23 excess deaths per 100 patients compared with the global average. Limited critical care resources, organ dysfunction at admission, and select comorbidities accounted for this excess mortality. Both children and adults experience inadequate availability of and access to SARS-CoV-2 testing and high-quality intensive care in constrained sub-Saharan African settings.23 Access to hospital care is limited and varies within and across countries and regions.25 The burden of SARS-CoV-2 infection, including severe disease requiring hospitalization, is underestimated in sub-Saharan Africa28 and is potentially more underestimated among children, who are less likely to be evaluated for infection.15 To address this issue, the present study assessed clinical manifestations, outcomes, and factors associated with outcomes among children and adolescents hospitalized with COVID-19 in 6 countries in sub-Saharan Africa.The African continent has a young population; children younger than 18 years constitute almost 50% of people.STROBE) reporting guideline for cohort studies.29This cohort study was a multicountry retrospective record review that pooled data from hospitalized children and adolescents aged 0 to 19 years with SARS-CoV-2 infection confirmed through reverse transcriptase polymerase chain reaction testing. Study review and approval, including waivers of informed consent and permission to use deidentified information from existing data sets or medical records, were obtained from institutional and/or national research ethics committees and/or regulatory bodies in participating countries , Ghana (2 facilities), Kenya (1 facility), Nigeria (2 facilities), South Africa (10 facilities), and Uganda (3 facilities) between March 1 and December 31, 2020. These countries were selected based on regional representation  to participate in the study. For between-country comparisons of outcomes, western and central African regions were combined to maximize available sample size and statistical power. Data on race and ethnicity were not collected because the racial profile across the 6 countries was more than 90% Black or African descent, and the ethnic diversity across the 6 countries was too broad  for meaningful categorization or analysis. Detailed information about participating health care facilities  is available in eTable 1 and eFigure 1 in 30 demographic and clinical data were extracted from national or institutional COVID-19 data sets and/or hospital records. Data collected included age, sex, preexisting comorbidities, WHO-defined COVID-19 severity stage at admission,31 and diagnosis of multisystem inflammatory syndrome in children (MIS-C) temporally associated with COVID-19.32 To accommodate partial or complete lack of laboratory and imaging data  required for MIS-C diagnosis in our study settings, cases were characterized as suspected MIS-C when at least 2 required multisystem abnormalities that were clinically observable or measurable were documented in the medical records and/or databases from which study data were extracted. This requirement was in addition to fulfilling WHO criteria for the diagnosis of MIS-C that pertained to ruling out \u201cother obvious microbial cause[s] of inflammation\u201d32(p1) plus confirmation of COVID-19 through a positive result on reverse transcriptase polymerase chain reaction testing.Using World Health Organization (WHO) pediatric COVID-19 case report forms,We selected an ordinal scale primary outcome with 5 ordered categories: (1) hospitalization without oxygen supplementation, (2) hospitalization with oxygen supplementation, (3) ICU admission, (4) invasive mechanical ventilation, and (5) death. This 5-scale primary outcome provided a measure of COVID-19 illness severity ranging from 1 (mild disease) to 5 (death). The secondary outcome was length of hospital stay.Baseline demographic and clinical characteristics were summarized using frequencies and proportions; medians and IQRs were applied to categorical and continuous variables. For missing data on preexisting comorbidities, we performed multiple imputation using chained equations to generate 20 data sets. Most comorbidities had missingness less than 10%, with the exception of diabetes (23%), chronic lung disease (26%), cerebral palsy (28%), and cardiac disease (35%).P\u2009<\u2009.15 in bivariable analyses. In our analyses, the proportional odds logistic regression model compared lower severity levels with higher severity levels . The proportional odds assumption was evaluated using \u03c72 and parallel line tests. Using robust SEs, the bivariable and multivariable proportional odds logistic models were fitted to account for potential within-cluster correlation of outcomes owing to shared processes and quality of care. Adjusted odds ratios (aORs) and associated 95% CIs were used to characterize the association between factors and disease severity.Multivariable proportional odds logistic regression analysis was used to identify factors associated with outcome severity among those with SARS-CoV-2 infection by including only factors that were considered clinically relevant and had a significance level of 33 accounting for death. Factors with significance levels of P\u2009<\u2009.15 in bivariate models were included in a multivariable proportional subdistribution hazards model to estimate adjusted subdistribution hazard ratios (asHRs) and associated 95% CIs. Overall survival was estimated using the Kaplan-Meier method, and the log-rank test was applied to compare survival differences by sex, region, WHO COVID-19 severity stage, and number of comorbidities.We examined factors associated with the probability of hospital discharge over time using a competing-risk analysis of the Fine and Gray proportional subdistribution hazards modelP\u2009<\u2009.05 was considered statistically significant. All regression models were applied to the 20 imputed data sets, and estimates were combined according to Rubin rules.35 All analyses were performed using Stata software, version 16.1 (StataCorp LLC).Two-sided Data from 469 children and adolescents from central Africa (39 patients [8.3%]), eastern Africa (172 patients [36.7%]), southern Africa (208 patients [44.3%]), and western Africa (50 patients [10.7%]) were analyzed. The age range for the cohort was 3 months to 19 years, with a median age of 5.9 years . Among 468 patients, 223 (47.6%) were female, and 245 (52.4%) were male . Data on31 but no experimental therapeutic medications  for the treatment of COVID-19 were locally available.The most frequently documented symptoms of SARS-CoV-2 infection were cough (170 of 460 patients [37.0%]), fever (143 of 461 patients [31.0%]), rhinorrhea (116 of 463 patients [25.1%]), and respiratory distress (76 of 328 patients [23.2%]). Eighteen of 297 cases (6.1%) were clinically suspected (6 patients) or confirmed (12 patients) as MIS-C  were discharged from the hospital, 39 patients  died, 16 patients  remained hospitalized , and 1 patient  had missing outcome data. Among 69 patients admitted to the ICU, 22 (31.9%) died. Of the 39 total deaths, information on the presence or absence of clinical features of MIS-C was available for 26 patients (66.7%); among those, 4 patients  had confirmed or suspected MIS-C. Twelve of the 39 deaths (30.8%) occurred among the 78 children who were younger than 1 year.Among those with complete information, 160 of 463 patients (34.6%) were either admitted to the ICU (69 of 461 patients [15.0%]) or required supplemental oxygen (143 of 452 patients [31.6%]). A total of 76 of 379 patients (20.1%) received noninvasive respiratory support via high-flow nasal cannula, and 34 of 436 patients  required invasive mechanical ventilation. Overall, the clinical disease severity outcome among 469 patients was distributed as follows: 305 patients (65.0%) had mild severity, 72 (15.4%) received supplemental oxygen, 18 (3.8%) received mechanical ventilation, and 39 (8.3%) died. The southern region of Africa had the highest proportion of patients requiring ICU admission and/or oxygen supplementation (109 of 208 patients [52.4%]). The sequence of events from hospital admission to clinical outcomes is shown in P\u2009=\u2009.008), the presence of 2 or more comorbidities , WHO COVID-19 severe disease stage , and WHO COVID-19 critical disease stage  were associated with higher risk of death. There were no significant regional differences in the risk of death (P\u2009=\u2009.01) times higher than that among adolescents aged 15 to 19 years. The presence of hypertension , chronic lung disease , or a hematological disorder  were also independently associated with more severe outcomes. The presence of HIV infection  was not associated with more severe outcomes , the presence of 1 comorbidity , and the presence of 2 or more comorbidities  were associated with reduced rates of hospital discharge. The rate of discharge among children and adolescents living in southern Africa was significantly higher compared with those living in eastern Africa . Discharge rates in western Africa  and central Africa  were comparable with those in eastern Africa.The median length of hospital stay was 9 days  among patients who recovered and 8 days  among those who died. Among 10 patients (1 with missing data) who remained hospitalized at the time of data collection, the median length of hospital stay was 18 days . In the adjusted competing-risk analysis of time to discharge, age younger than 1 year  cohort of African children with COVID-19.17 In that study, 11 of 51 hospitalized children (21.6%) required ICU admission; of those, 4 children required mechanical ventilation, but none died.This multicountry cohort study of pediatric COVID-19 in sub-Saharan Africa revealed relatively high morbidity and mortality, with greater likelihood of more severe outcomes among children younger than 1 year and those with hypertension, chronic lung disease, or a hematologic disorder. Furthermore, in a competing-risk analysis of time to discharge, age younger than 1 year, the presence of 1 comorbidity, and the presence of 2 or more comorbidities were independently associated with reduced rates of hospital discharge. Overall, 34.6% of hospitalized children and adolescents were admitted to the ICU or required oxygen supplementation, and 21.2% of those admitted to the ICU required invasive ventilation. The region with the highest proportion of children and adolescents requiring ICU admission and/or oxygen supplementation (52.4%) was southern Africa, where there was better availability of high-quality critical care than in other sub-Saharan African countries.39 study of the Democratic Republic of the Congo, in-hospital mortality among those younger than 20 years was 11.8% (4 of 34 patients), all of which occurred among adolescents; this hazard of death was almost 7 times that of adults aged 20 to 39 years . A South African surveillance study of childhood deaths identified SARS-CoV-2 infection in antemortem and/or postmortem sampling among 11.7% of 171 children who died, and 90% of SARS-CoV-2\u2013associated deaths were among infants.40 This finding was consistent with our finding of higher frequency of severe outcomes, including death, among infants and with the results of a study conducted by Oliveira et al41 in Brazil. In a global systematic review of severe pediatric COVID-19 illness, Kitano et al15 also reported that infants had the highest mortality, and the overall case fatality rate was significantly higher in low- and middle-income countries (0.24%) than in high-income countries (0.01%). In our study, mortality was high after ICU admission (31.9%) and substantially greater than the 0% to 0.5% mortality observed in pediatric studies conducted in high-resource settings15 but closer to the mortality (approximately 50%) reported in the African COVID-19 Critical Care Outcomes Study involving adults.22Overall, 8.3% of inpatients in the present study died. In comparison, among 766 patients with COVID-19 from a previous Nachega et al45 In 1 study,45 among 43\u2009465 US children diagnosed with COVID-19 from March 2020 to January 2021, 28.7% had underlying medical conditions; the most important risk factors associated with hospitalization or severe COVID-19 were type 1 diabetes, obesity, cardiac or circulatory congenital anomalies, hypertension, neuropsychiatric disorders, and complex chronic disease. In our study as well as the Oliveira et al41 study from Brazil, an increase in COVID-19\u2013associated mortality occurred as the number of preexisting comorbidities increased.We also found that hypertension, chronic lung diseases, and hematologic disorders were independently associated with severe clinical outcomes, including death. Preexisting comorbidities have been associated with worse COVID-19 prognosis in children and adults in other studies.48 However, a recent data review by the WHO found that HIV infection in adults was a risk factor associated with severe and critical illness at hospital admission and in-hospital mortality after adjusting for age, sex, and underlying conditions.49In this study, HIV infection was not associated with worse outcome severity, possibly because of low numbers of children living with HIV. This finding necessitates further research. Of note, published data on the association of HIV infection with COVID-19 outcomes among adults has been inconsistent.Our findings have several implications for clinical practice or health policy. The high morbidity and mortality among hospitalized African children and adolescents with comorbidities suggest that targeting these populations for prompt COVID-19 vaccination may be warranted when vaccines become available. Therapeutic interventions should be specifically evaluated among children and adolescents with severe COVID-19 illness and made available as appropriate. In addition, limitations in the quality and scope of pediatric general and critical care services in Africa need to be addressed to improve outcomes among children and adolescents with severe COVID-19 illness and other serious health conditions.15 included hospitalized, nonhospitalized, and asymptomatic patients. Our data are not generalizable to outpatient populations. In addition, because of limited hospital resources in sub-Saharan Africa, there may be higher thresholds for hospitalization compared with those in more resource-rich settings, potentially producing a cohort of inpatients who had more severe illness.This study has several limitations. Our findings of higher COVID-19\u2013associated in-hospital mortality among children and adolescents in sub-Saharan Africa compared with those in non-African settings needs to be interpreted with consideration of important factors. First, we studied only hospitalized children and adolescents, whereas most published studies from China, Europe, and the USSecond, a high prevalence of concurrent endemic infections and noncommunicable diseases, malnutrition, and associated dietary deficiencies may have had implications for COVID-19 outcomes in sub-Saharan Africa. Third, MIS-C did not appear to be a major factor associated with mortality in our study; of 26 evaluable deaths, only 4 (15.4%) had confirmed or suspected MIS-C. However, MIS-C cases were likely underestimated owing to the limited availability of tests .25 The finding of greater use of intensive care, oxygen supplementation, and mechanical ventilation in the southern African region vs other regions as well as the lower risk of in-hospital death in this region likely reflected varied availability of resources across African regions. Furthermore, these results highlight the opportunity for improved outcomes afforded by greater availability of high-quality pediatric intensive care.Fourth, the limited availability of essential equipment and the narrower scope of pediatric intensive care (compared with adult care) in sub-Saharan Africa likely had implications for the high mortality observed in the present study cohort.Fifth, the retrospective study design relied on record extraction of routinely collected and available data; however, fewer than 6% of extracted outcome data were missing, and we used multiple imputation techniques for missing data on comorbidities to minimize biased OR estimates. Sixth, limited availability of laboratory tests and diagnostic procedures may have produced underdiagnosis of COVID-19 and some associated features  and precluded reporting and further analysis of immunological status among children living with HIV infection.Seventh, our lack of a SARS-CoV-2\u2013negative comparator group and the general limited access to diagnostic testing prevents us from drawing conclusions about the relative prevalence and severity of COVID-19 vs other pediatric diseases in sub-Saharan Africa. In addition, statistical modeling of outcomes for each region was limited by small numbers within regions. However, the power of our study comes from pooling data across health facilities and regions as well as adjustment for any potential facility-level differences that may have had consequences for outcomes.In this cohort study of 6 countries in sub-Saharan Africa, morbidity and mortality rates among hospitalized children and adolescents with COVID-19 were substantially higher than those reported in non-African settings and were associated with age younger than 1 year and select noncommunicable disease comorbidities. These findings provide new data that may be used to inform pediatric COVID-19 health policy in Africa. With hundreds of millions of African children and adolescents at risk of adverse outcomes, COVID-19 vaccination and therapeutic interventions are much needed for this population."}
+{"text": "COVID 19 vaccination will protect us from getting COVID-19. Some side effects are common which are signs that our body is building protection. This side effects will go away in a few days. The aim of this study is to find out the side effects seen among health care workers after second dose of covishield vaccination.nd April 2021 till 30th April 2021. Ethical approval was revceived from Institutional Review Commitee. Convienient sampling was done. The second dose of covishield vaccine was administered 12 weeks after its first dose. The vaccine was administered intramuscularly into deltoid muscle. Statistical Package for the Social Sciences were used for analysis.This was a descriptive cross-sectional study conducted at a tertiary care centre from 22Out of 220 cases taken, 178 (80.90%) complained of pain at injection site after second dose of covidshield vaccine followed by 97 (44.09%) complaint of fatigue, 43 (19.54%) complaint of headache, 18 (8.18%) complaint of chills, 11 (5.00%)complaint of fever, 6 (2.72%) complaint of dizziness and 5 (2.27%) complaint of nausea.Pain at injection site, fatigue and headache were common side effects seen after second dose of Covishield vaccination. Regarding the potential risk in case of COVID-19 vaccine development is whether the immune responses elicited by a vaccine could enhance SARS-Cov-2 acquistion or make disease worse when infection occurs after vaccination.The aim of this study is to know the side effect of this second dose of vaccine among healthcare workers.th April 2021 till 10th May 2021. Ethical approval was taken from Institutional Review Committee of Kathmandu Medical College and Teaching Hospital (Reference no: 0904202101). All the health care workers who have given consent were included in this study. Healthcare workers who has not given written consent and who are not vaccinated with second dose of Oxford-Astrazeneca's Covid-19 vaccine were excluded from the study in this study.The descriptive cross-sectional study was conducted at Kathmandu Medical College and Teaching Hospital between 20Sample size was calculated by using formaula,Where,n = sample sizeZ = 1.96 at 95% Confidence Interval3p = prevalence from the previous study, 13.8%q = 1-pe = margin of error, 5%The vaccine was administered after 12 weeks of first dose of covishield vaccine administration. It was administered Intramuscularly (IM) into deltoid muscle. Total 220 cases were included in this study. Health Care workers were enrolled in this study after receiving second dose of Covishield Vaccine by taking written informed consent. Everyone were given opened end question after 2 days to 7 days of vaccination. Statistical Package for the Social Sciences were used for analysis.Out of 220 cases who have taken second dose of covishield vaccine, 135 (61.36%) were male and 85 (38.63%) .Among 220 cases, when we distributed the cases according to age 105 were between age group 25 to 34, 72 were between age 35 to 44 and and 43 were between age group 18 to 24 .When we arrange the cases we found that, pain at injection site 178 (80.90%), fever 11 (5.00%), fatigue 97 (44.09%), headache 43 (19.54%), chills 18 (8.18%), diarrhoea 0 (0%), dizziness 6 (2.72%), and nausea 5 (2.27%) are the side effects complaint after second dose of covishield vaccination .6 When we were looking for the side effects after second dose of covishield vaccine we found out that not all but some people were found to have side effect after second dose of covishield vaccine.Covishield is the local version of Oxford-AstraZeneca COVID-19 vaccine. Serum institute of India, which is the largest vaccine manufacturer by volume, tied up with AstraZeneca to produce 1 billion doses of its COVID-19 vaccine.7In this study, maximum number of health care workers 178 (80.90%) complaint of pain at injection site after second dose of covishield vaccine. Similarly, 97 (44.09%) complaint of fatigue, 43 (19.54%) complaint of headache, 18 (8.18%) complaint of chills, 11 (5.00%) complaint of fever, 6 (2.72%) complaint of dizziness and 5 (2.27%) complaint of nausea. This study was similar to the study reported before which shows pain, tenderness, warmth at the site of injection, fatigue, chills, headache, muscle pain, nausea, joint pain and feverishness as a very common side effect of covishield vaccine of which chills and nausea were reported as common side effect after second dose of vaccination.The limitation of the study is that we could not collect the data from other population who have received second dose of covishield vaccine.Vaccine have numerous positive effects including disease prevention. But there are some side effects felt after second dose of Covishield vaccine which mostly include pain at site of injection, fatigue and headache."}
+{"text": "Immunotherapeutic strategies are increasingly used in the treatment of a number of malignancies including high grade urothelial carcinoma (HGUC) of the bladder. Because of this, detailed and accurate assessment of the tumour immune microenvironment is paramount. In this study, we aimed to correlate the composition of the tumour immune microenvironment with oncologic outcome and the expression of two cancer testis antigens (CTAs), CT10 and PRAME, potential cancer vaccine targets, as well as major histocompatibility complex I (MHC I), a molecule associated with tumour immune escape and resistance to immunotherapy.Triplicate tissue microarrays (TMAs) were constructed using 207 cases of HGUC of the bladder. Oncologic outcome data was gathered for each case. Consecutive sections from the TMA blocks were stained with CD3, CD4, CD8, FOXP3, PD1, PD-L1, CT10, PRAME, and MHC I. 21% and 15% of cases expressed CT10 and PRAME, respectively. 88% of cases showed absent or decreased MHC I expression. CT10-expressing tumours showed a significantly worse disease specific survival . CT10, PRAME, and MHC I expression significantly correlated with other some immune parameters. CT10 and PRAME are expressed in a subset of HGUC and CTA and MHC I expression correlate with a number of important immune parameters. Together, these findings highlight the potential for exploring novel immune therapeutic strategies in HGUC. Additional studies evaluating the clinical relevance of these findings are warranted. High grade urothelial carcinoma (HGUC) of the bladder  is a comet al. who showed that 77% of the studied cases expressed at least one of nine CTAs while 61% of cases expressed two or more CTAs[In addition to therapy targeting programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) which is being used in the treatment of a number of malignancies including HGUC\u201312, cancmore CTAs. Preferemore CTAs; interesmore CTAs.Integral to the proper functioning of the normal immune system is Major Histocompatibility Complex I (MHC I), a cell surface protein complex present on all nucleated cells. MHC I normally functions to present \u201cnon-self\u201d cytosolic peptide antigens to CD-8+ T cells, eventually leading to propagation of the cytotoxic pathway leading to cell death of malignant or virally infected cells. Because of its importance in the establishment of a cytotoxic response, lack of MHC I expression on tumour cells has not surprisingly been proposed as an important mechanism in tumour immune escape and resistance to immunotherapy, 24\u201326.The aim of this work was to expand our understanding of the tumour immune contexture in HGUC of the bladder using an immunohistochemical approach. In light of the ongoing developments in the study of MHC I, CTAs and cancer vaccines, we chose to assess the association of CTAs with immune markers and impact on oncologic outcomes.This project was approved by the Research Ethics Board at Sunnybrook Health Sciences Centre in Toronto, Ontario, Canada (REB 187\u20132016).All cases were identified through a retrospective search of the laboratory information system, Sunquest CoPath (n=235), as previously described. BrieflyThe following demographic and clinicopathologic data was recorded for each case: age at diagnosis, patient sex, smoking status, tumour size, tumour focality, presence/absence of carcinoma in situ, presence/absence of lymphovascular invasion, margin status, presence/absence of lymph node metastases, history/type of neoadjuvant therapy (if applicable), pT stage, AJCC stage, date of last known follow up, date of disease relapse (if applicable), and date of death (if applicable). Evidence of disease relapse was based on operative and/or radiologic findings. Only deaths that occurred within the hospital or under the palliative care service were accessible.Triplicate 1 mm core tissue microarrays (TMAs) were constructed from 207 of the available cases; 28 cases were excluded from the TMAs due to lack of tissue or when a suitable tumour block for punching was not available. Technical details regarding construction of the TMAs have been previously described. 4-microImmunohistochemical expression was assessed in immune cells (ICs) and/or tumour cells (TCs), depending on the marker being evaluated. The identification of TCs and ICs was based on morphologic features alone with assistance of H&E slides. All scoring was done by a single reviewer who is subspecialist genitourinary pathologist (MRD).CD4, CD8, FOXP3, and PD-1 expression was assessed in ICs . For each marker, the absolute number of positive cells was evaluated in one hot spot/core (i.e. 1 representative 40x field/core), with the results averaged across all cores per case. PD-1-positive cases were dichotomized into high and low groups based on the median value of positive cells/40x field. PD-L1 expression  was assessed in ICs (cytoplasmic or membranous staining of any intensity) and TCs . The Ventana Benchmark Ultra automated staining platform was utilized according to the manufacturer\u2019s protocol with the Optiview DAB IHC detection kit. TCs and ICs staining was assessed as present or absent with the estimated percentage of positive TCs and positive ICs recorded for each TMA core. The results were then averaged across the triplicate cores to give one estimate of percentage TCs and percentage ICs for each case. The degree of PD-L1 staining was considered positive when > 25% of TCs or ICs showed expression. MHC I expression  was assessed in TCs; the percentage of TCs with cytoplasmic staining was noted and the cases were categorized as follows: positive (>75% of TCs), decreased expression (25\u201374% of TCs), or negative (< 25% of TCs). CT10  was asseAll statistical analyses were performed using the SPSS software 24.0 . The prognostic significance of PRAME, CT10 and MHC I was assessed using log rank test with Kaplan Meier analysis for disease specific survival (DSS) and progression free survival (PFS). Hazard ratio and 95% confidence interval were calculated using Cox proportional regression model. The Pearson correlation coefficient was computed among the expression of each antibody. P values less than 0.05 were considered to be statistically significant.The mean and median age at diagnosis was 70.3 and 71.0 years of age, respectively (range 33\u201393 years). Males  were more commonly affected compared to females . 59 (29%) of the patients had no smoking history, while 38 (18%) and 82 (40%) patients respectively were current or former smokers, respectively. Information regarding smoking status was not available for 28 (13%) patients.131 (63%) tumours were more than 3 cm in size while 70 (34%) were less than 3 cm in size; 6 (3%) tumours were not measured. 193 (93%) tumours were unifocal while the remaining were multifocal . 91 (44%) cases demonstrated the presence of carcinoma in situ while the remaining 116 (56%) did not. 139 (67%) cases demonstrated the presence of lymphovascular invasion, 4 (2%) cases were indeterminate, and the remaining 64 (31%) did not demonstrate the presence of any lymphovascular invasion. 83 (40%) cases showed lymph node metastases while 115 (56%) did not; the remaining 9 (4%) cases lacked any lymph nodes. Soft tissue margins were positive in 52 (25%) cases. 7 (3%), 30 (15%), 111 (54%), and 59 (28%) cases were staged as pT1-pT4 respectively. 7 (3%), 22 (11%), 95 (46%), and 83 (40%) were staged as AJCC Stages 1\u20134, respectively.CD4, CD8, FOXP3, PD-1, and PD-L1 expression has been previously characterized in this cohort[CTA and MHC I expression shown in A total of 202 cases were evaluable for MHC I expression: 25/202 (12%) cases demonstrated normal/retained expression, 18/202 (9%) cases demonstrated decreased/low expression, and the remaining 159/202 (79%) cases showed absent expression. There were no cases where the individual scores for triplicate cores were discordant.The Pearson correlation coefficients between the assessed immune parameters are shown in A total of 73 patients received some form of neoadjuvant therapy prior to cystectomy , 46 with chemotherapy/radiation; 4 patients received both BCG and chemotherapy/radiation). Of the 31 cases which were positive for PRAME, 15 (48%) were pretreated. Of the PRAME-negative cases, 58 (34%) were pretreated . Of the 42 cases which were positive for CT10, 15 (36%) were pretreated. Of the CT10-negative cases, 58 (36%) were pretreated . 3 of the pretreated cases  were positive for both PRAME and CT10. None of the cases which had been pretreated with both BCG and chemotherapy/radiation expressed were positive for either PRAME or CT10.With regards to oncologic outcome, follow up data was available for 131 cases . Tumour recurrence was identified in 76/131 (58%) cases. 21/76 (28%) patients had metastatic disease. 24/131 (19%) patients were in palliative care at the time of last known follow-up. 4/24 patients in palliative care did not suffer from recurrence. 45/131 (34%) patients had died, 2 of which whose deaths were attributed to causes other than HGUC .et al.\u2019s study which evaluated the expression of nine different CTAs. In addition, we utilised TMAs compared to whole tissue sections and our cohort is composed entirely of muscle invasive tumours whereas tumours ranging from pTa to pT4 were included in the aforementioned study.The tumour immune microenvironment is dynamic and complex and its evaluation has become increasingly important in a number of malignancies including HGUC of the bladder. Clinical trial data has shown checkpoint inhibition to be effective in the treatment of these variably aggressive malignancies\u201310 and bet al. (n= 94) which showed that patients with CT10 positive tumours had improved disease free and overall survival compared to patients with CT10 negative tumours[Previous studies suggest that CTA expression by malignant cells is a poor prognostic factor, particularly in lung cancer\u201336 howeve tumours. As indiImportantly, a number of clinical trials are studying cancer vaccines in human malignancies and several have shown promising results in the treatment of bladder cancer, 41\u201343. Of note, we did not identify any heterogeneity among CTA-expressing tumours in that all cases which were found to be positive for CT10 and/or PRAME expressed the antigen relatively equally throughout all evaluated TMA cores (both high and low expressing tumours). In addition, we did not observe any background expression in normal tissue elements . These findings are important, as they indicate that CTA assessment in small samples (i.e. biopsies) is reliable and a viable tool for evaluating CTA expression.It is well known that antigen presentation by the MHC I-tumour antigen complex is a necessary step in the initiation of anti-tumour CD8+ T cell response. Loss ofIn conclusion, we have identified a number of interesting associations with regards to our characterization of the expanded tumour immune microenvironment in HGUC. Our understanding regarding the dynamics of the tumour immune microenvironment is evolving, and there is still much to be understood regarding the significance of correlations between different immune parameters. Further exploration of different components of the tumour immune microenvironment in a prospective multi-institutional cohort is warranted."}
+{"text": "The FDA has issued emergency use authorization (EUA) for neutralizing monoclonal antibodies (mAb) for the treatment of mild-moderate coronavirus disease 2019 (COVID-19) in patients who are at high risk of disease progression. The EUA allows for COVID-19 mAb infusion to occur up to 10 days from symptom onset and due to logistics, mAb treatment typically occurs later in this 10 day window. Efficacy of early versus late mAb treatment is unknownIn this single center, retrospective case-control study, we performed a risk factor analysis of patients with mild COVID-19 infection treated with mAb on the composite outcome of subsequent evaluation in the Emergency Department (ED) or inpatient admission December 2020 through May 2021. Multivariate analysis of variables found to be significant in univariate analysis was performed using STATA 15 statistical softwareTwo-hundred eighty-eight patients who received mAb treatment were included in analysis. The mean age was 58.6 years and 59.7% were female, 64.9% white, and 27.1% African American. Following mAb infusion, 31 (10.8%) had disease progression resulting in an ED encounter or inpatient admission. Patients who received early (days 1-5 of symptoms) mAb infusion were less likely to have progressive disease than patients with late (days 6-12 of symptoms) infusion; . Zero of 21 patients who received mAb infusion on day 1-3 of symptoms had disease progression. Patients with CHF , cirrhosis , CKD  and hypertension  were more likely to have disease progression. There were no differences in sex, race, BMI, or symptoms between groups. Multivariate analysis revealed cirrhosis  and CKD  increased risk of disease progression while early mAb infusion was protective Infusion of mAb for the treatment of mild to moderate Covid-19 within 5 days of symptom onset reduces rate of disease progression compared to delayed (day 6-12 of symptoms) infusion. This finding was significant when controlling for comorbidities. Efforts should be made to infuse high risk patients with COVID-19 mAb therapy within 5 days of symptom onsetAll Authors: No reported disclosures"}
+{"text": "The COVID-19 pandemic has led to a dramatic rise in the incidence of rhino-orbito-cerebral mucormycosis (ROCM) in India. The purpose of our report is to describe the prevalence of ROCM in the context of SARS-CoV-2 infection during the second Indian COVID-19 wave, as well as its diagnostics proceeding, and to discuss the challenges met in the time frame from the suspected diagnosis to the therapeutic decision in such patients. We conducted a retrospective multicentre case series study at six centres of Sudhalkar and Raghudeep group of hospitals in India. ROCM was confirmed in 38 (2.5%) of the 1546 patients admitted with SARS-CoV-2 infection. The average time to establish a diagnosis was 16 days. In total, 19 (50%) patients suffered from type 2 diabetes and were mostly treated with hypoglycaemic agents (in 90% of cases). The standard of care for SARS-CoV-2 management included systemic steroids therapy, intravenous remdesivir for 5 days, and concomitant prophylactic antibiotic therapy following admission. The median (IQR) blood glucose levels in all patients during the course of hospitalisation was 320 (250.5\u2013375) mg/dl. A total of 16% of patients had an irreparable functional loss, and the mortality was 5%. We may hypothesise that excessive administration of antibiotics that profoundly affects human microbiota, coupled with poorly controlled glycaemia and unprotocolised haphazard steroid administration, contribute to a favourable setting for mucormycosis infections. Rhino-orbital-cerebral mucormycosis (ROCM) is a rare invasive fungal infection of the nasal and maxillary sinuses and the orbit. The causing agent, Mucorales, from the family of mucormycetes fungi, includes more than 300 species and may be responsible for opportunistic infections, especially in immunosuppressed patients . ParticuAcute SARS-CoV-2 infection, as well as the non-specific treatment , exposes COVID-19 patients to the risk of opportunistic infections, including mucormycosis. Several predisposing risk factors for the development of ROCM were identified retrospectively. These include uncontrolled diabetes, immunosuppression, hemochromatosis, ketoacidosis, and damage to the physical barriers of the immune system .The diagnosis of ROCM is based on clinical signs and instrumental confirmation . In the We report here a case series of ROCM, managed by ophthalmologists, in six referring centres of Sudhalkar and Raghudeep group of hospitals in India. The purpose of our report is to describe the prevalence of ROCM in the context of SARS-CoV-2 infection during the second Indian COVID-19 wave, as well as its diagnostics proceeding, and to discuss the challenges met in the period from the suspected diagnosis to the therapeutic decision in such patients.We conducted a retrospective multicentre, case series study at six centres of Sudhalkar and Raghudeep group of hospitals in India. Medical records of all adult patients admitted for COVID-19 Pneumonia from 1 February 2021 until 10 May 2021 were screened to identify those with suspected and confirmed ROCM. The ROCM diagnosis was based on the European Organisation for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium (EORTC/MSG) guidelines [In patients with identified ROCM, the following data were collected: demographics, the signs and symptoms of COVID-19 infection, laboratory findings at admission and during the course of therapy, the treatment administered, the duration of hospitalisation, the duration of steroid therapy, the presenting complaints with particular reference to COVID-19 associated infections/sequelae, the therapy administered for COVID-19 associated complications, and final outcomes.The primary objective was the prevalence of ROCM in the studied population. The secondary objective included the analysis of patient characteristics and infection management.p < 0.05.Results are expressed as frequency and percentage for categorical data, and as a median and interquartile range (IQR) for continuous variables. The chi-squared test was used, wherever appropriate. Statistical significance was set at In the period from 1 February 2021 to 10 May 2021, 1546 patients were admitted with a COVID-19 pneumonia diagnosis. Of these, in 51 (3.2%) patients, the ROCM was suspected, and in 38 (2.5%) was confirmed. The median (IQR) follow-up for these patients was 52.5 (28\u201372) days.p = 0.023). Other comorbidities included hypertension in five patients (13%), hypothyroidism in four patients (10.5%), dyslipidaemia in three patients (8%), impaired renal function in one patient (2.6%), cardiac insufficiency in one patient (2.6%), and rheumatoid arthritis in one patient (2.6%).The median (IQR) age was 54 years (32\u201374.5) and body mass index (BMI) was 24.5 (22.2\u201328.2), and 26 (68%) were males. In total, 15 (39%) patients had no comorbidities before the hospital admission, while 19 (50%) patients suffered from type 2 diabetes (median (IQR) HbA1c levels at admission 7.9 (6.7\u20139.1)). The presence of diabetes was associated with a higher risk to develop ROCM , treatment included oral hypoglycaemic agents in 17 (90%) cases, meaning that only 2 (10%) patients had insulin therapy.In diabetic patients  score  at 13/25The standard of care included systemic steroids therapy, intravenous remdesivir for 5 days, and concomitant prophylactic antibiotic therapy following admission for all patients. As a primary steroid therapy, 14 (37%) patients received high-dose dexamethasone (16 mg daily) for 10 days, 19 (50%) patients received methylprednisolone (125 mg daily) for 7 days, and 5 (13%) patients received oral prednisolone in an average dose of 1 mg/kg/day for 14 days. All patients received tapering doses of oral prednisolone during 3 weeks following discharge. Multiple antimicrobial  and antiparasite (ivermectin) agents were administrated to all patients for the period from 3 to 10 days. Eight (21%) patients received oral voriconazole for 5 days for presumed invasive pulmonary aspergillosis. In addition, six (16%) patients developed antibiotic-induced diarrhoea and were managed successfully with oral metronidazole. Low-molecular-weight heparin was given in 27 (71%) patients for the entire duration of their hospitalisation. All patients received oral supplements (such as zinc and vitamin C).All 38 patients received insulin therapy during hospitalisation. The median (IQR) blood glucose levels in all these patients during hospitalisation was 320 (250.5\u2013375) mg/dl over a median (IQR) time of 11 (7\u201314) days. Only 16 (42%) patients achieved blood glucose levels < 200 mg/dl at any point in time. Ketoacidosis occurred in two (5%) patients in a median time of eight days from corticoid therapy initiation.The median (IQR) time to diagnosis of ROCM from the day of hospital admission was 17.5 (12\u201322) days. A diagnosis of ROCM was established in 10 (26%) patients during hospitalisation, in 8 (21%) within a week of discharge, in 15 (39.5%) within the first two weeks of discharge, and in 5 (13%) within the first month after discharge. None of the patients developed any other form of mucormycosis (such as cutaneous/pulmonary). The median (IQR) hospitalisation time in these 38 patients was 23 (15\u201328) days.Ocular involvement occurred in 21 (55%) patients. The main ophthalmic symptoms were ptosis in 19 patients (90%), ophthalmoplegia in 18 patients (47%), total vision loss in 15 patients (39%), and orbital oedema in 11 patients (29%). None of the patients had bilateral orbital involvement.In total, 33 (86.8%) patients underwent surgical intervention for ROCM. Fungal elements were detected in all 33 patients, using the potassium hydroxide (KOH) wet mount preparation. Histologic findings confirmed the presence of perivascular fungal hyphae, along with the classic signs of tissue infarction and necrosis. The identified fungal hyphae were pauciseptate, with broad and right-angle branching, consistent with the clinical diagnosis. Their structure was confirmed with the periodic acid\u2013Schiff (PAS) staining. Culture and species identification were carried out in 23 patients (69.7%). The most commonly identified species were Rhizopus (60.9%), followed by Mucor (21.7%) and Absidia (17.4%). As all specimens were obtained from sterile sites, the fungal growth in culture media, together with histopathological evidence of vascular necrosis and the presence of fungal hyphae in surgical samples, was conclusive for mucormycosis .Five patients (13.2%) who improved with medical management alone had possible invasive mucormycosis based on the EORTC/MSG consensus definitions for invasive fungal disease: the presence of one host factor (uncontrolled blood glucose levels/immunosuppression), clinical evidence, and radiologic evidence based on CT scan of the head and sinus region.All patients with established ROCM diagnosis were treated with intravenous amphotericin B  with a median (IQR) dose of 0.9 (0.3\u20131.0) mg/kg/day over a median (IQR) duration of 21.5 days (14\u201328). A total of 17 (45%) patients received additional therapy with oral posaconazole, with a loading dose of 600 mg on day 1, followed by a maintenance dose of 300 mg/day over a median (IQR) duration of 60 (42\u201380) days.In total, 27 (71%) patients benefited from at least endoscopic debridement, 6 (16%) received orbital exenteration (eye loss), and 3 (8%) patients required hemi-mandibulectomy . Finallyp = 0.03). However, no association of lethal outcome and diabetes status was found.Patients with pre-existing diabetes were more likely to require aggressive interventions such as exenteration or hemi-mandibulectomy  benefitted from the in-hospital diagnostics of ROCM, whereas most of the patients were returning to the hospital for ophthalmologist consultation after discharge. The majority of patients had already established risk factors for mucormycosis and were exposed to well-known risk factors for ROCM. Finally, 16% of patients had an irreparable functional loss, and the mortality was 5%.The immunosuppression (induced by SARS-CoV-2 infection and by steroid use), and exposure to high blood glucose levels (due to steroids use and preexisting diabetes) are well-depicted risk factors for any invasive fungal infection, including mucormycosis ,15,16,17The particularity of the fulminant mucormycosis is in relatively few general symptoms and predominant localisation in the oro-facial zone. This localisation puts patients at risk of severe functional loss\u2014namely, loss of vision or even death. The context of the COVID-19 pandemic has led to a dramatic increase in the number of patients at risk and, therefore, the raise of ROCM. In our observation, 39% of patients had no comorbidities before hospitalisation. However, we did not consider these patients being free of any comorbidities before the COVID-19, because of the absence of precise medical history prior to the index hospitalisation. Previously published studies already reported a high incidence of ROCM in young patients with few comorbidities admitted for COVID-19 pneumonia, particularly in the western Indian state of Gujarat ,21,22,23In our case series, patients with diabetes were at higher risk for extensive surgical interventions. Aggressive surgical debridement, combined with systemic antifungal therapy, probably accounted for a lower mortality rate during our observation. However, lethal outcomes associated with ROCM recurrence may have occurred later in the course of the disease.One of the features of therapeutic interventions for COVID-19 pneumonia, particularly in India, is the wide administration of antibiotics to prevent secondary bacterial infection, even in immunocompetent patients. A veritable cocktail of antibiotics, ivermectin, and even voriconazole was administered in some patients preventively. The potential association of mucormycosis with the administration of voriconazole has been documented earlier . We may The standards of hospital hygiene in India were already not optimal before the COVID-19 pandemic . During The small number of included participants and the retrospective nature of the study are the major limitations of our analysis. Different causative factors have to be studied; however, the heterogeneity in therapeutic approaches and the lack of medical history documentation prior hospitalisation precluded the use of advanced statistical methods such as propensity score matching. A large cohort analysis may be useful in this case. However, the descriptive nature of our cases may add to the literature allowing in the future a meta-analytic approach.To conclude, 2.5% of adult patients hospitalised with SARS-CoV-2 infection suffered from ROCM, an uncommon but dangerous complication of COVID-19, leading to vision loss in 16% of cases and mortality in 5%. Aside from the effort to control known risk factors, physician awareness should be reinforced to enable earlier diagnostics and access to treatment. Further epidemiological studies are needed to improve the quality of management of such patients."}
+{"text": "The extent of vestibular end organ dysfunction associated with genetic pediatric hearing loss is not well-understood. We studied children with a known genetic cause of hearing loss who underwent routine preoperative vestibular testing prior to cochlear implantation between June 2014 and July 2020. Vestibular testing included videonystagmography, rotary chair, video head impulse testing, and/or vestibular evoked myogenic potentials. Etiology of HL was determined through history, physical examination, imaging, laboratory testing, and/or genetic testing. Forty-four children  met inclusion criteria; 24 had genetic non-syndromic and 20 had genetic syndromic forms of HL. Mean age at the time of testing was 2.8 \u00b1 3.8 years (range 7 months\u221217 years). The most common cause of non-syndromic HL was due to mutations in GJB2 (n = 13) followed by MYO15A (3), MYO6 (2), POU3F4 (2), TMPRSS3 (1), CDH23 (1), TMC1 (1), and ESRRB (1). The most common forms of syndromic HL were Usher syndrome (4) and Waardenburg (4), followed by SCID/reticular dysgenesis (3), CHARGE (2), CAPOS (1), Coffin-Siris (1), Jervell and Lange-Nielsen (1), Noonan (1), peroxisome biogenesis disorder (1), Perrault (1), and Trisomy 21 (1). Overall, 23 patients (52%) had PVL. A larger proportion of children with syndromic forms of HL had PVL  compared with children with genetic non-syndromic HL , though without statistical significant (p = 0.3). The occurrence of PVL varied by affected gene. In conclusion, PVL is a common finding in children with syndromic and non-syndromic genetic HL undergoing vestibular evaluation prior to cochlear implantation. Improved understanding of the molecular physiology of vestibular hair cell dysfunction is important for clinical care as well as research involving vestibular hair cells in model organisms and in vitro models.Hearing loss (HL) is the most common sensory deficit in humans and is frequently accompanied by peripheral vestibular loss (PVL). While often overlooked, PVL is an important sensory dysfunction that may impair development of motor milestones in children and can have a significant negative impact on quality of life. In addition, many animal and  Hearing loss is the most common sensory impairment in humans, affecting nearly 5% of the world population . In chilvia the same nerve , and contain paralogous structures that are responsible for mechanotransduction of stimuli (hair cells). As such, it follows that pathology that causes hearing loss can also frequently cause PVL.Peripheral vestibular loss (PVL) frequently accompanies hearing loss, and vestibular impairment is estimated to affect around 50% of patients with sensorineural hearing loss (SNHL) \u20136. Such GJB2 gene  an identified genetic cause of hearing loss, and (2) completion of vestibular testing prior to cochlear implantation at our institution between June 2014 and July 2020. Patients were identified through our internal REDCap database of patients who have undergone cochlear implantation at our institution , 22. FurGJB2), multi-gene panels including dozens to hundreds of genes sequenced, and exome sequencing. Test interpretation was performed in accordance with consultation from a geneticist, when necessary.Hearing loss etiology was determined through history, physical examination, imaging, laboratory testing, and clinical genetic testing. Genetic testing was not standardized and was performed on a case-by-case basis based on clinical judgement and test availability. Genetic tests performed included single-gene sequencing  if results of at least one vestibular test were abnormal.Toys with flashing lights were used to attract young childrens' attention during testing, when needed, including to control direction of gaze during VNG testing and to maintain appropriate neck turning and tension during cVEMP testing. Continuous electromyography was monitored during cVEMP and oVEMP testing to ensure continued sufficient muscle contraction throughout the test. The acquisition software automatically rejected any VEMP response with inadequate muscle tension.Many patients also underwent routine motor evaluation by a licensed physical therapist prior to cochlear implantation. Patients <5 years of age were assessed using the Peabody Developmental Motor Scales, Second Edition (PDMS-2) Gross Motor Quotient (GMQ) . The GMQPatients \u22655 years of age were assessed using the Bruininks-Oseretsky Test of Motor Proficiency, Second Edition (BOT-2) body coordination composite score. This is derived from the BOT-2 bilateral coordination subtest and balance subtest, which consist of 7 and 9 items, respectively . The tott-test was used to assess differences in motor function outcomes between patient groups. A Mann\u2013Whitney U-test was used to assess differences in age between patient groups.Statistical analyses were conducted using R version 3.6.3 . Differences in characteristics between patient groups were assessed using a chi-square test for categorical variables. An independent-samples We initially identified 149 patients who underwent routine pre-cochlear implant vestibular testing at our institution during the study timeframe. Of these, 44 patients had a known genetic cause of their hearing loss and had not previously undergone cochlear implantation. Demographics and clinical features of the study sample are summarized in GJB2 (n = 13) followed by MYO15A (3), MYO6 (2), POU3F4 (2), TMPRSS3 (1), CDH23 (1), TMC1 (1), and ESRRB (1). The most common forms of syndromic hearing loss were Usher syndrome (4) and Waardenburg (4), followed by SCID/reticular dysgenesis (3), CHARGE (2), CAPOS (1), Coffin-Siris (1), Jervell and Lange-Nielsen (1), Noonan (1), peroxisome biogenesis disorder (1), Perrault (1), and Trisomy 21 (1). A full summary of causative genetic variants identified in the patient sample can be found in the As shown in All patients had at least one imaging study performed. These included magnetic resonance imaging (MRI) of the temporal bones in 39/44 (89%) subjects and fine cut non-contrast computed tomography (CT) of the temporal bones in 39/44 (89%). Both forms of imaging were obtained in 34/44 (77%) subjects. No imaging abnormalities were identified in 37/44 (84%) subjects, a cochlear abnormality was identified in 3/44 (7%), and a cochleo-vestibular abnormality was identified in 4/44 (9%) .All patients underwent cVEMP testing as part of their vestibular evaluation, and 43/44 (98%) also underwent rotary chair testing. Additionally, VHIT was performed in 6/44 (14%) patients and oVEMP testing in 7/44 (16%). Patients who underwent VHIT testing ranged from 5.0 to 17.5 years of age. Patients who underwent oVEMP testing ranged from 2.5 to 17.5 years of age. No patients underwent caloric testing.p = 0.3). There was not a significant difference in age between patients with syndromic hearing loss (median = 11.6 months) compared to those with non-syndromic hearing loss . Patients with syndromic hearing loss were significantly more likely (p = 0.02) to have abnormal cVEMP outcomes  than patients with non-syndromic hearing loss .Results of these specific vestibular tests are summarized in n = 27, 84%) were evaluated using the PDMS-2 while the remainder were evaluated using the BOT-2. Among patients evaluated with the PDMS-2, the mean gross motor quotient (GMQ) percentile rank was 36.6 (SD 21.3). Among the five patients evaluated with the BOT-2, the mean body coordination percentile rank was 39.4 (SD 33.7). Patients with normal vestibular testing findings had a greater Peabody GMQ percentile rank score  compared to patients with evidence of PVL , though this difference did not reach statistical significance   compared to patients with non-syndromic hearing loss . This result also did not reach statistical significance  . The results from this study expand the genotype-phenotype correlations of prior studies with respect to genetic mutation and vestibular dysfunction in the setting of genetic hearing loss. In particular, we show measurable effects on the peripheral vestibular system for mutations in six of eight causes of apparent genetic non-syndromic hearing loss. Further research should focus on expanded testing of the vestibular system in children and adults with hearing loss. This study also demonstrates trends toward delayed motor development in patients with PVL vs. those with normal vestibular function, as well as patients with syndromic forms of hearing loss. Our results further emphasize the importance of early identification and rehabilitation of vestibular deficits in patients with genetic hearing loss. Delayed motor development in patients with syndromic hearing loss may be multifactorial and result from dysfunction in systems other than or including the vestibular system.in vitro studies of human cochlear hair cell function (A gene-specific understanding of the effect of mutations on the cochleovestibular system is necessary to improve pre-operative counseling for children with severe to profound hearing loss and to guide subsequent rehabilitation. Further insight into the effects of specific genetic mutations on PVL will also have important implications for future research on genetic hearing lossMany scientists use vestibular hair cells as a proxy for function , 29. Thifunction .jacob.brodsky@childrens.harvard.edu.This study is a retrospective analysis of confidential clinical genetic analyses that were analyzed in an anonymized fashion for the purposes of this study. The raw data from the anonymized analyses are available from the corresponding author upon request. Requests to access these datasets should be directed to Jacob R. Brodsky, AW, AS, GZ, MK, DP, GL, and JB: study concept, design, manuscript review, revision, and approval. AW, AS, MK, and JB: data collection and analysis and manuscript composition. All authors contributed to the article and approved the submitted version.All financial support for this study was provided by the Department of Otolaryngology and Communication Enhancement at Boston Children's Hospital.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Disorders of glucose metabolism are a serious acromegaly comorbidity and may be differently impacted by medical treatments of acromegaly. In this retrospective longitudinal multicenter study, we investigated the outcome of glucose metabolism and its predictors in patients treated with Pasireotide LAR (PAS-LAR) alone or in combination with Pegvisomant (PAS-LAR\u2009+\u2009Peg-V).Acromegaly patients treated continously with PAS-LAR or PAS-LAR\u2009+\u2009Peg-V for at least 6 months.p\u2009<\u20090.001). Among patients treated with Pas-LAR alone, GH at baseline was higher in those with worsening of glucose metabolism (p\u2009=\u20090.04) as compared to those with stable glucose status. A significantly higher reduction of HbA1c was observed in patients treated with PAS-LAR\u2009+\u2009Peg-V, as compared with those treated with PAS-LAR alone (p\u2009=\u20090.005).Forty patients  were enrolled. At last visit, 27/40 patients (67.5%) reached biochemical control of acromegaly. Overall, glucose metabolism improved in 3 , worsened in 26 (65%) and remained unchanged in 11 patients (27.5%). Glucose metabolism worsened in 25 patients (73.5%) treated with PAS-LAR and in a single patient (16.7%) treated with PAS-LAR\u2009+\u2009Peg-V (Our data confirmed that glucose metabolism in patients treated with PAS-LAR is often worsened, and may be predicted by entity of baseline GH hypersecretion and by the dose of PAS-LAR. Moreover, our data, although limited by small numbers, may suggest that the combination treatment PAS-LAR\u2009+\u2009Peg-V can improve glucose homeostasis in selected patients. Acromegaly is a systemic disease, caused by the hypersecretion of growth hormone (GH) and type I insulin-like growth factor (IGF-I), that occur in almost all cases due to a pituitary tumor secreting GH . The GH Previous studies on glucose metabolism in acromegaly investigated the prevalence of diabetes mellitus, reported between 13 and 31.9% of cases \u201310. AddiA longitudinal, observational, retrospective multicenter study was performed on consecutive acromegaly patient with acromegaly before (baseline) and after (end of study) treatment with PAS- LAR and PAS- LAR plus Peg-V.All patients were enrolled according to the following inclusion and exclusion criteria.Acromegaly patients treated with first gen-SRLs for at least 6 consecutive months and considered partial/complete resistant or intolerant to SRLs , 17 at tpatients on treatment with PAS- LAR and PAS- LAR plus Peg-V, for at least 6 months;patients older than 18 years;Concomitant treatment with drugs known to influence glucose metabolism , with the exception of glucocorticoid replacement therapy for central hypoadrenalism and anti-diabetic therapies for patients with glucose abnormalities at baseline;Demografics and patients\u2019 clinical history were collected from records. Biochemical markers of acromegaly and glucose metabolism were collected both at baseline and at last evaluation visit (end of the study).partial: in case of a reduction of random GH and/or IGF-I\u2009>\u200950% with respect of pre-therapy values in absence of biochemical control of acromegaly disease and/or a reduction of tumor volume > 20%;complete: in case of a not-significant reduction of IGF-I and random GH value and/or of tumor volume.Resistance to conventional SRLs was defined , 17:partAt baseline, active acromegaly was diagnosed in patients with random GH higher than 1.0\u2009ng/mL and IGF-I concentrations above the normal ranges for age . During improved, in case of reduction/withdrawal of anti-diabetic treatments or improvement of serum glucose paramentes;worsened, in case of increased dosage or new prescription of anti-diabetic treatments or worsening of serum glucose paramentes;unchanged, in case of manteinance of the same anti-diabetic treatments or in case of not clinically significant variations of glucose parameters.Data of glucose metabolism status were collected at baseline and at end of the study (last visit). According to medical history, fasting or after oral glucose tolerance test (OGTT) blood glucose and glycated hemoglobin (HbA1c) patients were classified as euglycemic, with IGT (impaired glucose tolerance)/IFG (impaired fasting glucose) or diabetes mellitus (DM) . During Registry databases were approved by institutional review boards of each institution and informed consent was waived for individual patients. All procedures performed in studies involving human participants were in accordance with the ethical standards and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.t tests were used to compare categorical and quantitative un-paired data. A P value\u2009<\u20090.05 was considered statistically significant.All data were expressed as mean and standard deviation. Fisher exact and Student A total of 40 patients, 25 females (62.5%) were analyzed. Mean age at study entry was 35.4 years (SD: 11.7). The first line treatment was pituitary surgery for 36 patients (90%) and medical therapy with first generation SRLs for the remaining 4 patients (10%). All 40 patients who entered the study had undergone previous therapy with first generation SRLs. At baseline, all patients had active acromegaly with partial resistence to first generation SRL in 11 cases (27.5%) and complete resistant in the remaning 29 cases (72.5%). Thirty-four patients were treated with Pasi- LAR alone (85%) and 6 patients with Pasi-LAR plus Peg-V (15%).At baseline, the glucose metabolism was considered normal in 18 patients (45%), 13 (32.5%) were affected by IGT/IFG and 9 patients (22.5%) by DM. Eleven patients (27.5%) were diet-controlled, 3 patients (7.5%) treated with oral hypoglycemic drugs and 6 patients (15%) with insulin. The remaining 20 patients were not treated for glucose abnormalities (50%).The baseline clinical features of the two treatment groups are summarized in Table At the end of the study, 27 patients (67.5%) reached biochemical control of acromegaly. Glucose metabolism improved in 3 (7.5%), worsened in 26 (65%) and remained unchanged in 11 patients (27.5%). In particular, 6 patients were considered euglycemic (15%); 20 patients (50%) had IGT/IFG and 14 patients (35%) DM. Eleven patients (27.5%) were on treatment with low calorie low glycemic index diet, 14 patients (35%) with oral hypoglycemic drugs and 9 patients (22.5%) with insulin. The remaining 6 patients did not follow specific therapeutic indications (15%). The clinical features of the two treatment groups are summarized in Table At baseline, glucose metabolism was considered normal in 17 patients (50%), 12 (35.3%) had IGT/IFG and 5 patients (14.7%) had DM. Nine patients (26.5%) were diet-controlled, 2 patients (5.9%) treated with oral hypoglycemic drugs and 4 patients (11.8%) with insulin. The remaining 19 patients did not require treatments for glucose abnormalities (55.9%) (Table p\u2009=\u20090.04) in patients with worsening of glucose metabolism at the end of the study compared to patients with stable glucose status during the study period. No improvement of glucose metabolism was observed during PAS- LAR treatment . Additionaly, we found that 12 of the 25 patients who experienced worsening of glucose metabolism had IGT/IFG or DM at baseline and the remaing 13 patients had normal glucose metabolism at baseline. Among these 13 patients, 5 patients were treated with oral hypoglicemic drugs and 2 patients with insulin  then in those on treatment with 40\u2009mg/monthly, whereas the worsening in HbA1c was significantly greater with the higher dose in both patients with biochemically controlled and active acromegaly Table .Table 3Hp\u2009<\u20090.001)   and 4 patients by DM (66.4%). At the end of the study, glucose metabolism was unchanged in 2 33.3%), worsened in a single patient (16.7%) and improved in 3 cases (50%). Therefore, combination treatment with PAS- LAR plus Peg-V was associated with a lower frequency of glucose metabolism worsening and with a higher frequency of glucose metabolism improving as compared to PAS- LAR alone . Alternatively, though not confirmed in Muhammad et al. [This improvement of glucose metabolism can also be due to the biochemical efficacy of this combination therapy, that we recently described to be effective in a group of acromegaly patients affected by a disease resistant to multimodal treatments . In factd et al. , it may The significant limitations of this study are its retrospective design and the absence of randomization for the acromegaly treatment. Likewise, the small size of the group of patients treated with PAS- LAR plus Peg-V reduced the power of comparative analysis. However, although the number of patients by us reported on treatment with PAS-LAR in combination with Peg-V is limited, experiences on glucose outcomes with this new form of therapy are scant and controversial , 42, 44.In conclusion, we confirm previous data that glucose metabolism is often worsened during second line medical treatment with PAS-LAR in acromegaly. Our results suggest that this glucose worsening may be due to the use of PAS-LAR according to guidelines (45) in acromegaly patients with severe disease which in turn require high doses of the drug. In fact, both high GH levels per se as well as PAS-LAR may directly and potentially synergistically be detrimental for glucose metabolism. In this light, our data, although limited by small numbers, are among the first to suggest that the combination treatment PAS-LAR plus Peg-V can not only improve biochemical control but also glucose homeostasis in selected patients. If confirmed in larger studies, this combination could be suggested earlier in the treatment of patients with resistant acromegaly and concomitant abnormalities in glucose metabolism."}
+{"text": "To evaluate the role of the Emergency Medicine team (EM) within a London Emergency Department (ED) in assessing and managing patients detained under Section 136 of the Mental Health Act, 1983 (S136).S136 allows detention and transfer of people to ED and psychiatric hospitals for further assessment. EDs are optimised for the investigation and management of the medically unwell, but attending ED may also delay access to psychiatric services if required. Minimal research has been performed to investigate the relative benefits of transferring people under S136 to ED versus psychiatric hospitals.Electronic notes were searched to identify those attending under S136 between 01/04/2017 and 31/03/2018. Scanned medical notes were reviewed and data extracted regarding patient demographics, length of ED stay, reason for S136 use, investigations and interventions undertaken by EM.This identified 95 attendances by 87 patients. The mean age was 35 years (range 15-75) and 59% of attenders were male. The mean duration of stay was 7 hours 34 minutes (range 6 minutes - 25 hours 50 minutes).Reasons for S136 use were abnormal behaviour (32), expressed suicidal ideation (29), overdose (15), self-harm (13), overdose plus self-harm (4), being found wandering (1) and was unclear for 1 presentation.In 39 attendances no investigations beyond history and examination were performed by EM. Only 6 patients had investigations that were not bloods, electrocardiogram or urinalysis. These included X-radiograph trunk (4), computed tomography (CT) head (3), X-radiograph limb (3), CT cervical spine (1), Focused Assessment with Sonography for Trauma (1).No interventions were given by EM in 55 attendances. Twenty-nine different medications were prescribed and 18 patients were prescribed intravenous fluids. Three had wounds dressed, 3 glued, 3 sutured and 1 stapled.There were difficulties categorising the reason for S136 use, as clear documentation was often unavailable, but the vast majority of patients were detained due to abnormal behaviour, expressed suicidal ideation and self-harm.Few attending ED under S136 received investigations or interventions that could not be offered within a psychiatric hospital. There was a wide range in duration of stay within ED, however 65% of attendances were longer than the standard 4 hour target.Future research may assess the relative benefits of ED versus psychiatric hospitals in assessing those detained. This could aid services in meeting both the physical and psychiatric needs of patients whilst making efficient use of available resources."}
+{"text": "Emergence of more antimicrobial-resistant pathogens and repeated occurrence of infectious disease (ID) outbreaks highlight the importance of ID specialists. This study aimed to assess the working status of ID specialists and identify problems faced by ID professionals in Korea.An online-based survey was conducted over 11 days , targeting all active adult (n=281) and pediatric (n=71) ID specialists in Korea . An online-based survey link was forwarded to them via text messages and e-mails by the office of the Korean Society of Infectious Diseases and the Korean Society of Pediatric Infectious Diseases. Questions regarding the practice areas of the specialists were divided into five categories: (1) clinical practices of outpatient care, inpatient care, and consultations; (2) infection control; (3) antibiotic stewardship; (4) research; and (5) education and training. We investigated the weekly time-use patterns for these areas of practice.A total of 144/281 (51.2%) adult ID specialists and 51/71 (71.8%) pediatric ID specialists participated in the survey. Among them, 144 (73.8%) respondents were involved in all practice categories investigated. The most common practice area was outpatient service (93.8%), followed by consultation (91.3%) and inpatient service (87.7%)(Table 1). Specialists worked a median of 57 (interquartile range: 50\u201365) hours weekly: patient care, 29 (14\u201337) hours; research 11 (5\u201319) hours; infection control 4 (2\u201310) hours; antibiotic stewardship, 3 (1\u20135) hours; and education/training, 2 (2\u20136) hours (Table 2).We identified areas of practice and patterns of time use among adult and pediatric ID specialists in Korea. Most experts were in charge of all necessary areas  in medical institutions with limited resources. It is expected that these problems can be solved by appropriately compensating individuals and medical institutions for their invisible activities (including infection control and antibiotic stewardship) and by securing additional human resources.All Authors: No reported disclosures"}
+{"text": "To explore the value of real-time dynamic ultrasound and magnetic resonance imaging (MRI) in the diagnosis of rotator cuff injury.  From January 2020 to June 2021, the clinical data of 55 patients with rotator cuff injury were collected. All patients were examined by real-time dynamic ultrasound and MRI at the same time within two weeks before surgery, which was confirmed by arthroscopy. The value of real-time dynamic ultrasound, MRI, and the real-time dynamic ultrasound combined with MRI in the diagnosis of rotator cuff injury was evaluated.  Among the 55 patients with rotator cuff injury, real-time dynamic ultrasound showed full-thickness rotator cuff tear in 12 patients (21.82%), including type I in 2 patients (3.64%), type II in 6 patients (10.91%), and type III in 4 patients (7.27%), and partial rotator cuff tear in 31 patients (56.36%), including type IV in 16 patients (29.00%), type V in 5 patients (9.09%), and type VI in 10 patients (18.18%). MRI showed full-thickness rotator cuff tear in 12 patients (21.82%), including type I in 2 patients (3.64%), type II in 6 patients (10.91%), and type III in 4 patients (7.27%), and partial rotator cuff tear in 37 patients (67.27%), including type IV in 20 patients (36.36%), type V in 7 patients (12.73%), and type VI in 10 patients (18.18%). The combined examination showed full-thickness rotator cuff tear in 12 patients (21.82%), including type I in 2 patients (3.64%), type II in 6 patients (10.91%), and type III in 4 patients (7.27%), and partial rotator cuff tear in 39 cases (70.91%), including type IV in 21 cases (38.12%), type V in 7 patients (12.73%), and type VI in 12 patients (21.82%). The diagnostic accuracy of real-time dynamic ultrasound in complete tearing, partial tearing and the overall accuracy were 92.31%, 73.81% and 78.18%, respectively. The diagnostic accuracy of complete tear, partial tear and the overall accuracy of MRI were 92.31%, 88.00% and 89.09%, respectively. The diagnostic accuracy of complete tear and partial tear and overall accuracy in the real-time dynamic ultrasound combined with MRI were 92.31%, 95.24%, and 94.55%, respectively. The diagnostic accuracy and overall diagnostic accuracy of the combined examination of partial tears were higher than those of the real-time dynamic ultrasound and MRI examinations alone.  Real-time dynamic ultrasound and MRI have high application value in the diagnosis of rotator cuff injury, and the combined diagnosis is conducive to improving the diagnostic accuracy of patients with partial tear. The shoulder joint is the joint with the largest range of motion in the whole body, which mainly relies on the rotator cuff formed by the muscles around the shoulder joint to maintain the stability and activity of the shoulder joint. The rotator cuff is a sleeve-like structure composed of subscapularis muscle, supraspinatus muscle, infraspinatus, teres minor, and tendon wrapping humeral head, so as to maintain the stability of the shoulder joint. The incidence of rotator cuff injury caused by rotator cuff tendon degeneration increases with age. Rotator cuff tear is one of the most common causes of shoulder pain and activity limitation in patients. Epidemiology shows that rotator cuff tear accounts for 30%\u201370% of the causes of shoulder pain. The diagnosis of rotator cuff tear is complicated, and it is not uncommon to misdiagnose scapulohumeral periarthritis \u20133. Rotat\u2009 Inclusion criteria were as follows: patients all confirmed with rotator cuff injury by arthroscopy; real-time dynamic ultrasound and MRI were performed; aged >18 years; and approved by the ethics committee of our hospital.\u2009 Exclusion criteria were as follows: contraindications to MRI or real-time dynamic ultrasound; other treatments before the examination; clinical data suggest space-occupying lesions in the shoulder; and incomplete imaging data.From January 2020 to June 2021, the clinical data of 55 patients with rotator cuff injury were collected. There were 26 males and 29 females, and they were 21\u201370 years old, with the average age of (52.96\u2009\u00b1\u20098.29) years old, and the course of disease was from three days to 12 years, with the average course of disease of (32.49\u2009\u00b1\u20099.53) months. There were 42 patients with history of trauma, 3 patients with hypertension, and 6 patients with diabetes. Clinical manifestations include different degrees of shoulder pain and limited activity. This study was approved by the Hospital Ethics Committee, and informed consent was obtained from patients and their families.All patients underwent simultaneous real-time dynamic ultrasound and MRI examinations within two weeks before surgery, which were finally confirmed by arthroscopy. Real-time dynamic ultrasound was performed using Philips IU22 color ultrasound instrument with C12-5 broadband linear array probe at the frequency of 5\u201315\u2009MHz, and special software for skeletal muscle was used. When the patient is sitting, the examination sites mainly included supraspinatus tendon, infraspinatus tendon, subscapular tendon, teres minor tendon, and joint capsule. The transverse and longitudinal sections were examined, and the dynamic examination of the patient's shoulder joint was conducted when necessary. A diagnosis was made whether or not the shoulder joint is injured and the degree of injury, and the glenohumeral joint position was adjusted. The rotator cuff on the affected side was observed dynamically, and the shoulders on both sides were scanned by contrast.MRI examination was performed using Philips Achieva 3.0 T TX superconducting MRI device from the Netherlands, using a coil dedicated to the shoulder joint. A cross-sectional scan was performed, the scanning plane was perpendicular to glenoid, and the scanning range was from acromion to humeral neck, with fast spin echo and T2 weighted sequence (TR/TE\u2009=\u20094000\u2009ms/78\u2009ms). An oblique coronal scanning was performed, and the slice was horizontally parallel to the long axis of the supraspinatus muscle, ranging from the lateral end of the clavicle to the shoulder peak. Spin-echo T1-weighted imaging (TR/TE\u2009=\u2009450\u2009ms/13\u2009ms) and short-term inversion recovery sequence (TR/TE\u2009=\u20094000\u2009ms/28\u2009ms) were performed. An oblique sagittal scan was performed with the slice perpendicular to the long axis of the supraspinatus tendon, covering the humeral head and the entire glenoid, spin-echo T1-weighted imaging (TR/TE\u2009=\u2009450\u2009ms/13\u2009ms), and short-term reversal recovery sequence (TR/TE\u2009=\u20094000\u2009ms/28\u2009ms). Scanning parameters were as follows: FOV\u2009=\u200924\u2009cm\u2009\u00d7\u200924\u2009cm, matrix\u2009=\u2009640\u2009\u00d7\u2009640, layer thickness of 3.5\u2009mm, and layer spacing of 1\u2009mm. HPZ400 workstation is adopted for data processing with software.The results of ultrasound and MRI were evaluated by two radiologists with rich clinical experience, respectively. In case of different opinions, the general practitioner made a consultation and finally reached an agreement. Finally, the results were compared with those of the arthroscopy.Diagnostic Criteria of Real-Time Dynamic Ultrasound [trasound . The echMRI Diagnostic Criteria [Criteria . ImagingClassification of Arthroscopic Rotator Cuff Injury [f Injury . Complets). The t test or one-way analysis of variance was performed and the count data were expressed as (n(%)). The \u03c72 test or Fisher's exact probability test was performed, and P < 0.05 indicated that the difference was statistically significant.SPSS22.0 statistical software was used for data analysis. The measurement data were expressed as  of full-thickness rotator cuff tear, including 2 patients (3.64%) of type I, 6 patients (10.91%) of type II, and 5 patients (9.09%) of type III, and 42 patients (76.36%) of partial rotator cuff tear, including 22 patients (40.00%) of type IV, 8 patients (14.54%) of type V, and 12 patients (21.82%) of type VI.In 55 patients with rotator cuff injury, real-time dynamic ultrasound showed full-thickness rotator cuff tear in 12 patients (21.82%), including type I in 2 patients (3.64%), type II in 6 patients (10.91%), and type III in 4 patients (7.27%), and partial rotator cuff tear in 31 patients (56.36%), including type IV in 16 patients (29.00%), type V in 5 patients (9.09%), and type VI in 10 patients (18.18%), as shown in Tables In 55 patients with rotator cuff injury, MRI showed full-thickness rotator cuff tear in 12 patients (21.82%), including type I in 2 patients 3.64%), type II in 6 patients (10.91%), and type III in 4 patients (7.27%), and partial rotator cuff tear in 37 patients (67.27%), including type IV in 20 patients (36.36%), type V in 7 patients (12.73%), and type VI in 10 patients (18.18%), as shown in Tables .64%, typThe combined examination of real-time dynamic ultrasound and MRI showed that there were 12 patients (21.82%) of full-thickness rotator cuff tear, including 2 patients 3.64%) of type I, 6 patients (10.91%) of type II, and 4 patients (7.27%) of type III, and 39 patients (70.91%) of partial rotator cuff tear, including 21 patients (38.12%) of type IV, 7 patients (12.73%) of type V, and 12 patients (21.82%) of type VI, as shown in Tables 4% of typThe diagnostic accuracy of real-time dynamic ultrasound for complete tear was 92.31%, while that for partial tear was 73.81%, with an overall accuracy of 78.18%. The diagnostic accuracy rate of MRI for complete tear was 92.31%, while that for partial tear was 88.00%, and the overall accuracy rate was 89.09%. The diagnostic accuracy of complete tear, partial tear, and overall tear in the combined examination was 92.31%, 95.24%, and 94.55%, respectively. The diagnostic accuracy and overall diagnostic accuracy of the combined examination of partial tears were higher than those of the real-time dynamic ultrasound and MRI examinations alone, as shown in The rotator cuff tear injury mainly involves the supraspinatus muscle, and the injury is mainly located in the ischemic risk area about 1\u2009cm from the supraspinatus muscle stop point. The tears of infraspinatus, subscapularis muscle, and teres minor alone are very rare because the supraspinatus muscle is located at the intersection of forces around the shoulder joint, and thus it is extremely vulnerable. Studies have shown that the main pathogenesis of rotator cuff tear injury is long-term strain and tendon degeneration, combined with impact and compression under shoulder. Acute or repeated trauma and shoulder instability are also important causes of the disease. The main symptoms of rotator cuff injury are pain and limited movement. Clinically, there are many related complaints about shoulder diseases, and clinicians easily misdiagnose due to lack of understanding of rotator cuff injury \u201311. At pIn the 55 patients with rotator cuff injury, real-time dynamic ultrasound showed full-thickness rotator cuff tear in 12 patients (21.82%), including type I in 2 patients (3.64%), type II in 6 patients (10.91%), and type III in 4 patients (7.27%), and partial rotator cuff tear in 31 patients (56.36%), including type IV in 16 patients (29.00%), type V in 5 patients (9.09%), and type VI in 10 patients (18.18%). MRI showed full-thickness rotator cuff tear in 12 patients (21.82%), including type I in 2 patients (3.64%), type II in 6 patients (10.91%), and type III in 4 patients (7.27%), and partial rotator cuff tear in 37 patients (67.27%), including type IV in 20 patients (36.36%), type V in 7 patients (12.73%), and type VI in 10 patients (18.18%). On real-time dynamic ultrasound, partial tear of the supraspinatus tendon was characterized by a decrease or sometimes increase in irregular echo reflections at the tendon edge in the focal area. On MRI, the partial tear was characterized by focal areas in weighted image with discontinuous fibers filled with fluid signals. T2-weighted image of the fat suppression sequence shows lesions more clearly because it better showed that the tendon tear is full of liquid. In addition to the focal tendon defect, there was also wear on the tendon surface or a change in the tendon diameter. A full-thickness tear means that the continuity of the rotator cuff tendon fibers is completely interrupted, which leads to the communication between glenohumeral joint and subacromial space . On MRI,Among the missed diagnosis results of real-time ultrasound examination, there was one patient with partial tear, which was mainly caused by lack of experience and the patient's pain could not guarantee the shoulder joint internal rotation and abduction position. The other 3 patients were torn inside tendon, and no obvious lesions were found by ultrasound. By analyzing all the missed diagnosis results, it can be found that the accuracy of ultrasound diagnosis of complete rotator cuff tear is higher, but it is relatively lower for partial rotator cuff tear. MRI showed that 2 patients with type VI rotator cuff injury were undetected, and the diagnosis of type VI was difficult. When effusion appeared in the joint cavity and the acromion glide sac, the intra-tendon signal would decrease due to the partial volume effect, which was similar to the moderate signal of tendon degeneration, which easily caused missed diagnosis.The results of this study showed that the combined examination showed full-thickness rotator cuff tear in 12 patients (21.82%), including type I in 2 patients (3.64%), type II in 6 patients (10.91%), and type III in 4 patients (7.27%), and partial rotator cuff tear in 39 patients (70.91%), including type IV in 21 patients (38.12%), type V in 7 patients (12.73%), and type VI in 12 patients (21.82%). MRI examination has the advantages of non-invasiveness, non-radioactivity, anatomical repeatability, and excellent tissue contrast. It can perform multi-angle and multi-plane scanning imaging and can provide normal and abnormal imaging images of multiple tissue structures at the same time. Rotator cuff injury is mainly the morphological change of tendon to different degrees. After the rotator cuff is torn, there is liquid infiltration in the split position or fissure, which manifests as the morphological and signal abnormalities of tendon on MRI image. The liquid signal shows low signal on TWI and high signal on TWI. When the inner layer of the supraspinatus tendon is torn, fluid will penetrate, and the torn tendon will have obvious high signal. Therefore, MRI has a high accuracy in the diagnosis of type IV rotator cuff injury , 17. WheThe diagnostic accuracy and the overall diagnostic accuracy of the combined real-time dynamic ultrasound and MRI examination of partial tears are obviously improved as compared with those of the separate dynamic ultrasound and MRI examination. For real-time dynamic ultrasound, intra-tendon tear, tendonitis, tendon degeneration, and granulation tissue proliferation have similar ultrasound image manifestations. Therefore, simple abnormal ultrasound needs to be combined with the accompanying signs around the shoulder joint and even requires the patient to perform multi-axial exercise, while the examiner should perform multi-sectional examination. However, for MRI-induced injury to type V rotator cuff, especially when effusion is present in the glide sac of acromion or the bursa of deltoid muscle, the lesion is more likely to be displayed with the infiltration of effusion. However, a long course of disease, especially accompanied by thickening and ossification of the coracoid-shoulder arch, hyperplasia, and fibrosis of the glide sac at the acromion, may easily result in misdiagnosis . BenedetIn summary, real-time dynamic ultrasound and MRI have high application value in the diagnosis of rotator cuff injury, and the combined diagnosis is conducive to improving the diagnostic accuracy of patients with partial tear."}
+{"text": "This cohort study compares racial, ethnic, and geographic location diversity of participants in a clinic-based vs 2 remote COVID-19 clinical trials. Were racial, ethnic, and geographic location demographics of participants enrolled in 2 remote clinical trials with online recruitment more diverse compared with those of participants in a clinic-based COVID-19 study?This cohort study was a secondary analysis of 1410 participants enrolled in 3 COVID-19 studies conducted in 2020 during the early COVID-19 pandemic and found that remote clinical trials with online recruitment had increased racial, ethnic, and geographic location diversity among study participants.These findings suggest that remotely conducted trials with inclusive social media recruitment may be considered as potential components to address insufficient representation and enrollment of diverse populations in clinical trials while continuing to research this important aspect of clinical trials. Racial and ethnic diversity among study participants is associated with improved generalizability of clinical trial results and may address inequities in evidence that informs public health strategies. Novel strategies are needed for equitable access and recruitment of diverse clinical trial populations.To investigate demographic and geographical location data for participants in 2 remote COVID-19 clinical trials with online recruitment and compare with those of a contemporaneous clinic-based COVID-19 study.This cohort study was conducted using data from 3 completed, prospective randomized clinical trials conducted at the same time: 2 remotely conducted studies (the Early Treatment Study and Hydroxychloroquine COVID-19 Postexposure Prophylaxis [PEP] Study) and 1 clinic-based study of convalescent plasma . Data were collected from March to August 2020 with 1 to 28 days of participant follow-up. All studies had clinical sites in Seattle, Washington; the 2 remote trials also had collaborating sites in New York, New York; Syracuse, New York; Baltimore, Maryland; Boston, Massachusetts; Chicago, Illinois; New Orleans, Louisiana; and Los Angeles, California. Two remote trials with inclusive social media strategies enrolled 929 participants with recent SARS-CoV-2 exposure  and 231 participants with COVID-19 infection (Early Treatment Study); the clinic-based Expanded Access to Convalescent Plasma for the Treatment of Patients With COVID-19 study enrolled 250 participants with recent COVID-19 infection. Data were analyzed from April to August 2021.Remote trials used inclusive social media strategies and clinician referral for recruitment and telehealth, courier deliveries, and self-collected nasal swabs for remotely conducted study visits. For the clinic-based study, participants were recruited via clinician referral and attended in-person visits.Google Analytics data were used to measure online participant engagement and recruitment. Participant demographics and geographical location data from remote trials were pooled and compared with those of the clinic-based study. Statistical comparison of demographic data was limited to participants with COVID infections  to improve accuracy of comparison given that the Hydroxychloroquine COVID-19 PEP Trial enrolled participants with COVID-19 exposures and thus had different enrollment criteria.P\u2009<\u2009.001). Among 230 individuals in the Early Treatment Study vs 236 individuals in the clinic-based trial with ethnicity data, 71 individuals (30.9%) vs 11 individuals (4.7%) identified as Hispanic or Latinx (P<.001). There were 29 individuals in the Early Treatment Study with nonurban residences  vs 6 of 248 individuals in the clinic-based trial with residence data (2.4%) (P\u2009<\u2009.001). In remote trial online recruitment, the highest engagement was with advertisements on social media platforms; among 125\u2009147 unique users with age demographics who clicked on online recruitment advertisements, 84\u2009188 individuals (67.3%) engaged via Facebook.A total of 1410 participants were included. Among 1160 participants in remote trials and 250 participants in the clinic-based trial, the mean (range) age of participants was 39 (18-80) years vs 50 (19-79) years and 676 individuals (58.3%) vs 131 individuals (52.4%) reported female sex. The Early Treatment Study with inclusive social media strategies enrolled 231 participants in 41 US states with increased rates of racial, ethnic, and geographic diversity compared with participants in the clinic-based study. Among 228 participants in the remotely conducted Early Treatment Study with race data vs participants in the clinic-based study, 39 individuals (17.1%) vs 1 individual (0.4%) identified as Alaska Native or American Indian, 11 individuals (4.8%) vs 22 individuals (8.8%) identified as Asian, 26 individuals (11.4%) vs 4 individuals (1.6%) identified as Black, 3 individuals (1.3%) vs 1 individual identified as Native Hawaiian or Pacific Islander, 117 individuals (51.3%) vs 214 individuals (85.6%) identified as White, and 32 individuals (14.0%) vs 8 individuals (3.2%) identified as other race (These findings suggest that remote clinical trials with online advertising may be considered as a strategy to improve diversity among clinical trial participants. This research was conducted with approval from the Western Institutional Review Board with reliance agreements with collaborating institutions, and all participants gave written informed consent. We conducted a cohort study using 2 remotely conducted randomized clinical trials for SARS-CoV-2 prevention and treatment (the Early Treatment Study [NCT04354428]10 and Hydroxychloroquine COVID-19 Postexposure Prophylaxis [PEP] Study [NCT04328961]11) and 1 clinic-based randomized clinical trial .12 For remote studies, between March and August 2020, participants were recruited through national online advertising , clinician referral, and self-referral through the study website. We tracked the COVID-19 positivity rate by zip code and focused recruitment to areas with rapidly increasing incidence rates.13 This dynamic digital media strategy and advertising outreach was tailored weekly. Advertising featured people representative of populations disproportionally impacted by the COVID-19 pandemic. We tracked engagement using Google Analytics web analytics service (Google). The clinic-based trial recruited through clinician referral alone. Inclusion criteria for remote Early Treatment Study and clinic-based Expanded Access to Convalescent Plasma for the Treatment of Patients With COVID-19 study participants included adults with confirmed COVID-19 infection.This cohort study is reported following the Strengthening the Reporting of Observational Studies in Epidemiology , with real-time operational support for technical difficulties, missed doses of study medication, late daily surveys, and shipment forecasting.Remote trials were conducted with a completely remote study design using Health Insurance Portability and Accountability Act of 1996 (HIPAA)\u2013compliant telemedicine, electronic informed consent, and electronic data capture. Consent was offered in English and Spanish, and study staff fluent in Spanish were available. Couriers delivered study kits to participants containing study medication and supplies  as previously described.15 Survey options for the race category included Alaska Native or American Indian, Asian, Black or African American, Native Hawaiian or Pacific Islander, White, and other if racial identity was not captured in available options. Survey options for ethnicity included yes or no to Hispanic or Latinx. Outcomes for White individuals were compared with those of members of other racial and ethnic groups because this study was conducted specifically to address the overrepresentation of people who identify as White in trials. We compiled a map of participant locations using 3-digit ZIP Code Tabulation Areas.We collected demographic, including race and ethnicity data , and geographic data by self-report using electronic surveys. Community classification was assigned according to US Department of Agriculture rural-urban commuting area codes, which we classified as urban, peri-urban, small town, or rural by participant zip code.t test and Fisher exact test with a significance level of P\u2009<\u2009.05 by 2-sided tests. Statistical comparison of demographic data was limited to participants with COVID infections  to improve accuracy of comparison given that the PEP Trial enrolled participants with COVID-19 exposures and thus had different enrollment criteria. All analyses and mapping were done in R statistical software version 4.0 . Data were analyzed from April to August 2021.Descriptive data were analyzed by A total of 1410 participants were included. The remote trials enrolled a total of 1160 participants (231 participants in the Early Treatment Study and 929 participants in the Hydroxychloroquine COVID-19 Postexposure Prophylaxis Study) from 41 states. The mean (range) age of remote trial participants was 39 (18-80) years, and 676 individuals (58.3%) reported female sex as assigned at birth. Of 250 participants enrolled in the clinic-based study, the mean (range) age was 50 (19-79) years and 131 individuals (52.4%) reported female sex as assigned at birth. Participants in remote trials collected and shipped 14\u2009380 of 15\u2009890 expected nasal swabs (90.5%) for the primary outcome. Retention was high for remote trials, with participants completing 17\u2009129 of 18\u2009893 expected surveys (90.7%) over the follow-up period.12 Among 228 participants in the Early Treatment Study with race data vs participants in the clinic-based Expanded Access to Convalescent Plasma for the Treatment of Patients With COVID-19 study, 39 individuals (17.1%) vs 1 individual (0.4%) identified as Alaska Native or American Indian, 11 individuals (4.8%) vs 22 individuals (8.8%) identified as Asian, 26 individuals (11.4%) vs 4 individuals (1.6%) identified as Black, 3 individuals (1.3%) vs 1 individual identified as Native Hawaiian or Pacific Islander, 117 individuals (51.3%) vs 214 individuals (85.6%) identified as White, and 32 individuals (14.0%) vs 8 individuals (3.2%) identified as other race (P\u2009<\u2009.001). Among 230 individuals in the Early Treatment Study vs 236 individuals in the clinic-based trial with ethnicity data, 71 individuals (30.9%) vs 11 individuals (4.7%) identified as Hispanic or Latinx (P\u2009<\u2009.001). There were 29 individuals in the Early Treatment Study with nonurban residences  vs 6 of 248 individuals in the clinic-based trial with residence data (2.4%) (P\u2009<\u2009.001). When restricted to the same catchment area , 40 of 127 individuals in the Early Treatment Study were White and non-Hispanic (31.5%) compared with 202 of 248 individuals in the clinic-based study (81.5%) (P\u2009<\u2009.001).Racial, ethnic, and geographic diversity were observed at increased proportions in the remotely conducted Early Treatment Study .10,11,12A total of 307\u2009632 unique users clicked on online recruitment advertisements for the remote trials, and 125\u2009147 (40.7%) unique users had age demographics associated with their Google Analytics data. Of these, more than half  engaged via Facebook compared with 35\u2009029 individuals (28.0%) via Google, 1753 individuals (1.4%) via Twitter, and 4255 individuals (3.4%) via other, smaller platforms. There were 10\u2009455 online users who clicked through the advertisement and accessed the prescreening survey (7.5%), with the highest rate among users ages 18 to 24 years on Facebook  . CliniciGeographic distribution was centered on trial sites. Participants were enrolled a median  19  miles from each trial site in the remote trials and 11  miles from the clinic-based study site . Enrollm14 without risking the spread of SARS-CoV-2 or other respiratory viruses.In this cohort study, racial, ethnic, and geographic diversity were observed at increased proportions in the remotely conducted Early Treatment Study. These findings suggest that remote COVID-19 trial participation may be an important step toward inclusive evidence for public health advancement. In remote trials, protocols may be conducted with high fidelity and safety monitoring,8 While remote trials in this study enrolled a higher proportion of participants outside of large urban centers than the in-clinic comparison study, additional research regarding geographic inclusion is needed given that the proportion of rural participants was low.Completely remote trial designs with inclusive social media strategies may address some of the structural barriers that disproportionally impact members of racial and ethnic minority groups in the US. Further work is needed to make clinical research more inclusive and address structural racism and the urban-rural divide that impact access to clinical trials.There are several limitations to this analysis. Online analytic data does not capture the racial or ethnic identity of users. Comparison between completely remote trials and our clinic-based study was post hoc, and disease severity and motivations for participation may differ significantly among participants of a treatment trial, prevention trial, and postillness study. To minimize these differences, statistical comparison was limited by confirmed COVID-19 infections to the remotely conducted Early Treatment Study compared with the clinic-based study. While we found that some aspects of diversity were increased among participants in remote vs clinic-based studies, we did not examine other elements of demographic diversity  and did not evaluate whether trial participation was representative of community COVID-19 prevalence. We did not capture indirect benefits associated with a remotely conducted trial. These include the shift to fragmented time commitment, because participants must self-collect specimens and respond to surveys, rather than time needed to travel to and attend appointments, which may be associated with reduced barriers to participation for participants with childcare needs and fixed working hours. We did not collect data on differences among study personnel characteristics, technical skills, or expertise or study operational costs. Future work is needed to investigate whether these findings may extend beyond the context of the COVID-19 pandemic.This study found that demographic and geographic diversity were increased in the remotely conducted Early Treatment Study vs a clinic-based trial. Our findings suggest that remote trial participation and online recruitment may be associated with improved research equity and inclusion of participants from more diverse racial, ethnic, and geographic communities."}
+{"text": "Childhood pneumonia is one of the leading causes of death in low-income countries. The diagnosis of pediatric pneumonia is a critical epidemiological duty for treatment effectiveness and vaccine surveillance. Previous studies have demonstrated an important lack in correlation between CXR findings and the clinical WHO case definition of severe pneumonia. Lung Point of Care Ultrasound (POCUS) has demonstrated in multiple studies to be more sensitive and specific for diagnosing pneumonia in the pediatric population. With no exposure to radiation, extensive availability in limited-resource settings, and easy interpretation, this modality can be a breakpoint in making a more accurate correlation between pneumonia clinical findings and diagnostic imaging. 50 children from 1-59 months meeting the WHO case definition of severe pneumonia were enrolled at the Emergency Department at University Teaching Hospital (UTH) in Lusaka, Zambia. Children underwent lung POCUS and CXR. Correlation between symptoms and all abnormalities  seen in both imaging modalities were analyzed by calculating the proportion of children with abnormalities on CXR and ultrasound. Each participant was assigned a score based on findings. 0 = normal, 1 = consolidation only, 2 = Consolidation and non-consolidation  and 3 = non-consolidation  only.44 (90%) of children had abnormalities on CXR and 46 (94%) on POCUS. Five children (10%) had normal findings on CXR vs 3 (6%) on Lung POCUS. 4 (8%) had consolidation only on CXR vs 0 (0%) on POCUS. 19 (39%) had consolidation and non-consolidation  on CXR vs. 20 (41%) on POCUS. 21 (43%) had non-consolidation  only on CXR vs. 26 (53%) on POCUS.Figure 1. Scores Asigned Based on Imaging Findings for CXR and Lung POCUSFigure 2. Chest X Ray Anterior Posterior (AP) view showing Bilareral Interstitial PatternFigure 3. Lung POCUS (Point of Care Ultrasound) findings of bilateral Consolidation and non-consolidation pattern and bilateral interstitial pattern (only finding on CXR)More children with clinical pneumonia had normal findings on CXR than on POCUS. POCUS was a better imaging technique to show consolidation and non-consolidation patterns than CXR. The higher proportion of children diagnosed with consolidation and non-consolidation patterns on POCUS suggest that CXR might not be the ideal gold standard to diagnose pneumonia in children.All Authors: No reported disclosures"}
+{"text": "Increased antibiotic prescribing rates during the early phases of the COVID-19 pandemic have been widely reported. We previously reported that while both antibiotic days of therapy (DOT) and total days present (DP) declined in the first 5 months of 2020 at Veterans Affairs (VA) acute care facilities nationwide relative to the comparable period in 2019, antibiotic DOT per 1000 DP increased by 11.3%, largely reversing declines in VA antimicrobial utilization from 2015 \u2013 2019. We now evaluate whether these changes in antibiotic use persisted throughout the COVID-19 pandemic.Data on antibacterial use, patient days present, and COVID-19 care for acute inpatient care units in 108 VA level 1 and 2 facilities were extracted through the VA Informatics and Computing Infrastructure; level 3 facilities which provide limited acute inpatient services were excluded. DOT per 1000 DP were calculated and stratified by CDC-defined antibiotic classes.From 1/2020 to 2/2021, care for 34,096 COVID-19 patients accounted for 13% of all acute inpatient days of care in the VA. Following the onset of COVID-19 pandemic, monthly total acute care antibiotic use increased from 533 DOT/1000 DP in 1/2020 to a peak of 583 DOT/1000 DP in 4/2020; during that month COVID-19 patients accounted for 13% of all DP . In subsequent months, total antibiotic use declined such that for the full year the change of antibiotic use from 2019 to 2020 (a decrease of 18 DOT/1000 DP) was similar to the rate of decline from 2015 to 2019 . The decreased DOT/1000 DP from 5/2020 to 2/2021 occurred even as the percentage of all DP due to COVID-19 peaked at 14 - 24% from 11/2020 to 2/2021.Although rates of antibiotic use increased within the VA during the early phases of the COVID-19 pandemic, rates subsequently decreased to below previous baseline levels even as the proportion of COVID-19 DP spiked between 11/2020 and 02/2021. Although the degree to which the initial increase in antibiotic use is attributable to concerns of bacterial superinfection versus changes in case-mix  remains to be assessed, these data support the continued effectiveness of antimicrobial stewardship programs in the VA. Matthew B. Goetz, MD, Nothing to disclose"}
+{"text": "Management of endocrine and hepatic disorders is very important for better management of patient with COVID-19 infections. Hepatic and endocrine dysfunction needs clinical assessment, continued monitoring, and specific treatment. It is important to understand clearly the potential mechanisms causing hepatic and endocrine injuryTo assess the endocrine and hepatic dysfunctions in patient with COVID-19 pneumonia with severe and critically ill status.This retrospective analytical study was performed on 75 patients admitted to intensive care or high dependency units (ICU/HDU) in Obaidullah Hospital, Ministry of Health, United Arab Emirates. All patients were subjected to the following on admission: history taking, general and local examinations, routine laboratory studies , and other laboratory tests: C-reactive protein (CRP), D-dimer, Chest X-ray. Endocrine and hepatic function tests and other laboratory studies are repeated daily to show the progress of endocrine and hepatic functions.P values are 0.001, 0.04, and 0.023 respectively). There was significant difference between serum electrolytes before and after admission . There was significant difference between liver function test before and after admission The age range of the studied group was between 35 years and 107 years with mean age 59.98 \u00b1 12.88. The sex distribution was  and . The associated comorbidities were 4 patients had bronchial asthma (5.3%), 12 patients had chronic kidney disease (16%), 30 patients had diabetes mellitus (40%), 26 patients had hypertension (34.7%), 2 patient had hypothyroidism (2.7%), 12 patient had ischemic heart disease (16%), and 21 patients did not have any comorbidities (28%). There was significant difference between glucose level, thyroid stimulating hormone and free t4 before and after admission (Hepatic, pancreatic, thyroid functions, and electrolytes are affected by COVID-19 infection. These could act as surrogate biomarkers for better management of hepatic, pancreatic, thyroid functions and electrolytes disturbances in patients with COVID-19 infection. Since December 2019, the new coronavirus (2019-nCoV or COVID-19) was detected in Wuhan, China. The COVID-19 has then rapidly spread worldwide , managinDespite the earlier clinical trials, especially those performed in the USA, China, and Italy, have marked the main clinical manifestations including fever, cough, fatigue and breath shortness, the subsequent studies highlighted the extra-pulmonary disease manifestations. These trials marked that after the adult respiratory distress syndrome corona-virus 2 (SARS-CoV-2), a progressive disease and even the infectious virus itself may progress to involve many systems in the body and multi-organ failure. The liver is the main organ for detoxifying and metabolizing of toxic materials and drugs, and the maintenance of hepatic functions is important for engaging all available treatment modes in the management of COVID-19. Hepatic dysfunction needs clinical assessment, continued monitoring, and specific treatment. For a better management of COVID-19, it is important to understand clearly the potential mechanisms causing in hepatic injury .The aim of the study was to assess the endocrine and hepatic dysfunctions in patient with COVID-19 pneumonia with severe and critically ill statusThis is a retrospective analytical study have been done in Ibrahim Bin Hamad Obaidullah Hospital, Ministry of Health, United Arab Emirates. This retrospective study was performed on 75 patients who already have been admitted to intensive care or high dependency units (ICU/HDU) from January 2021 to May 2021. The data were collected retrospectively from the hospital filing system. All patients were subjected to the following on admission: careful history taking, general and local examinations, routine laboratory studies , and other laboratory tests: C-reactive protein (CRP), D-dimer, and chest X-ray. Endocrine and hepatic function tests and other laboratory studies were repeated daily to show the progress of endocrine and hepatic functions. All hepatotoxic medication stopped. The laboratory tests were done using reagents from Siemens Company, Germany. The reagent for electrolytes was Quiklyte. The reagents for liver function tests were DBI, ALTI, ASTI, ALB, and TP. The reagents for kidney function were UREA and CRE2. The device used for CBC was ADVIA 560, Hematology System, Siemens Company, Germany. Clinical inclusion criteria: adult in-patients diagnosed with severe and critically ill COVID-19 infection. Severe disease: patients with respiratory rate > 30 breaths per minute, SpO2 < 94% on room air , ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) < 300 mmHg, or lung infiltrates > 50%. Critical disease: patients with respiratory failure, septic shock, and/or multi-organ failure. Clinical exclusion criteria: other adult/pediatrics patients diagnosed with asymptomatic, mild, and moderate COVID-19 infection.(x), and standard deviation (SD); and analytic statistics: e.g., Student\u2019s t test which is a test of significance used for comparison between two groups having normally distributed quantitative variables and Mann-Whitney test which is a test of significance used for comparison between two groups having quantitative variables which are not normally distributed. P value < 0.05 was considered statistically significant (S).Results were collected, tabulated, and statistically analyzed by IBM personal computer and statistical package SPSS for windows version 21, EpiCalc and Microsoft Excel. Two types of statistics were done: descriptive statistics: e.g., percentage (%), mean P values are 0.001, 0.04, and 0.023, respectively). It also showed that there is significant statistical impairment in serum electrolytes  before and after admission . Regarding liver functions, there is statistical significant impairment in liver function test  before and after admission  , laboratory data   on and after admission  and . The outcome of the studied group was 52 patients deteriorated (69.3%), 23 patients improved (30.6%).This study showed that the associated comorbidities of the group were 4 patients had bronchial asthma (5.3%), 12 patients had chronic kidney disease (CKD) (16%), 30 patients had diabetes mellitus (DM) (40%), 26 patients had hypertension (HTN) (34.7%), 2 patient had hypothyroidism (2.7%), 12 patient had ishemic heart disease (IHD) (16%), and 21 patients did not have any comorbidities (28%). This study showed the progress of patients\u2019 symptoms where the shortness of breath (SOB) deteriorated in 52 patients (69.3%), improved in 23 patients (30.6%).The cough symptom deteriorated in 52 patients (69.3%), improved in 23 patients (30.6%). The progress of patients\u2019 radiology (chest X-ray) where it is deteriorated in 52 patients (69.3%), improved in 23 patients (30.6%).The length of hospitalization was more prolonged in patient with comorbidities than patients without comorbidities (35.65 days versus 22.32 days) (Table This study showed that the age range of the studied group was between 35 years and 107 years with mean age (59.98 \u00b1 12.88). The sex distribution of the studied group was  and .The outcome of the studied group was 52 patients deteriorated (69.3%) and 23 patients improved (30.6%) respectively.This in agreement with the study done by James Lok et al. . It statThe associated comorbidities of the studied groups were 4 patients had bronchial asthma (5.3%), 12 patients had chronic kidney disease (CKD) (16%), 30 patients had diabetes mellitus (DM) (40%), 26 patients had hypertension (HTN) (34.7%), 2 patient had hypothyroidism (2.7%), 12 patient had ischemic heart disease (IHD) (16%), and 21 patients did not have any comorbidities (28%).A large-scale trial of the Centers for Disease Control and Prevention of the United States  demonstrThis study showed the progress of patients\u2019 symptoms where the shortness of breath (SOB) deteriorated in 52 patients (69.3%), improved in 23 patients (30.6%). The cough symptom deteriorated in 52 patients (69.3%), improved in 23 patients (30.6%). The progress of patients\u2019 radiology (chest X-ray) where it is deteriorated in 52 patients (69.3%), improved in 23 patients (30.6%)This result showed the effect of the already present comorbidities and endocrine and hepatic dysfunction on the progress of the patient symptoms and radiology. Most patients deteriorate after admission due to the effect of these factors.The length of hospitalization was more prolonged in patient with comorbidities than patients without comorbidities (35.65 days versus 22.32 days).The study showed that there was statistical significant difference between glucose level, thyroid stimulating hormone (TSH), and free t4 before and after admission.Huang et al.  showed lWang et al.  showed pA study by Li et al  showed tThe study showed that there was significant statistical difference between serum electrolytes  before and after admission.Hugo De Carvalho et al.  stated t+, and Mg2+. Hyperglycemia and electrolyte disturbances in patients with COVID-19 are feasible; so, the measurement and follow-up of these cases can be efficient in the management and prevention of the severe sequelae of the disease.H. Sarvazad et al.  stated tThe study also showed that there was statistical significant difference between liver function test  before and after admissionIn the study of James Lok et al.  between Zeng-hong Wu et al.  reportedP value 0.001), laboratory data   on and after admission  (on Table .The study showed that there is deterioration in vital signs and laboratory data post admission mostly due to the effect of associated comorbidities and endocrine and hepatic dysfunction.This retrospective study found that pancreatic, thyroid functions and electrolytes are affected by COVID-19 infection. These could act as markers for better management of pancreatic, thyroid functions, and electrolytes disturbances in patients with COVID-19 infection.Severity of COVID-19 patients was significantly associated with liver malfunction. COVID-19 patients with severe disease have elevated serum ALT, AST levels, and decrease in serum albumin level. The findings of the study put a basis for good management of the liver clinically for COVID-19 patients."}
+{"text": "This suggests that children's experience of school could be a potentially important modifiable risk factor for low attainment in children with mental health problems. Previous research on the relationship between children's depressive and externalising symptoms, experience of school, and academic attainment is inconclusive. The aims of this study were (i) to test bidirectional associations between children's school experience and depressive and externalising symptoms at age 10-11 and 13-14, (ii) to ascertain whether school experience age 13-14 is associated with academic attainment age 16, and (iii) to test whether school experience mediates the relationship between depressive or externalising symptoms and attainment.Data was used from the Avon Longitudinal Study of Parents and Children . A cross-lagged model was used to investigate bidirectional associations between school experience (enjoyment and connectedness) and depression and externalising at age 10-11 and 13-14. The same framework was used to test if school experience aged 13-14 mediated associations of depressive and externalising symptoms with later attainment.Depressive and externalising symptoms at 10-11 were negatively associated with school connectedness , and school enjoyment at 13-14 . School enjoyment at 13-14 was positively associated with attainment at 16 , and partially mediated associations between depressive and externalising symptoms at 10-11 and attainment at 16 .Results may be subject to residual confounding.School enjoyment is a potentially modifiable risk factor that may affect educational attainment of adolescents with depressive or externalising symptoms. Adolescent depression is associated with poorer social functioning,  friendshVarious aspects of the school experience have been previously defined . \u201cSchoolStudies have consistently showed that school enjoyment is prospectively associated with academic attainment . For exaImportantly, there is emerging evidence that children's academic attainment, school experience and their socioemotional well-being can be improved by school-based interventions. For example, a recent RCT in India reported that a school-based intervention which focused on teaching problem-solving skills and engaging students and teachers in decision-making improved student's perceptions of their school and reduced rates of depressive symptoms . A UK-baIn this current study we focused on two key aspects of school experience: school enjoyment and connectedness. We had three main aims: (i) to test the associations between depressive and externalising symptoms and school enjoyment and connectedness at two time points (ages 10-11 and ages 13-14), (ii) to explore associations between school enjoyment and connectedness at ages 13-14 and academic attainment age 16, and (iii) to test whether school enjoyment or connectedness at ages 13-14 mediates the relationship between depressive or externalising symptoms at age 10-11 and academic attainment at age 16.22.1http://www.bristol.ac.uk/alspac/researchers/our-data/. Ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees. Informed consent for the use of data collected via questionnaires and clinics was obtained from participants following the recommendations of the ALSPAC Ethics and Law Committee at the time.Data was used from the Avon Longitudinal Study of Parents and Children (ALSPAC). Pregnant women resident in Avon, UK with expected dates of delivery 1st April 1991 to 31st December 1992 were invited to take part in the study. The initial number of pregnancies enrolled is 14,541 (for these at least one questionnaire has been returned or a \u201cChildren in Focus\u201d clinic had been attended by 19/07/99). Of these initial pregnancies, there was a total of 14,676 foetuses, resulting in 14,062 live births and 13,988 children who were alive at 1 year of age.  and 14 (T2) ( 14 (T2) . This quExternalising symptoms. Externalising symptoms were measured via maternal report using the Conduct and Hyperactivity subscales of the Strengths and Difficulties Questionnaire at mean ages 11.5 (T1) and 13 (T2) ( 13 (T2) . Both suSchool experience. School experience was assessed via self-report at ages 11 (T1) and 14 (T2). Previous research has posited multiple overlapping constructs related to school experience,  point score at age 16 (T3), obtained via linkage to the National Pupil Database. GCSEs are qualifications taken at age 16, which represented the end of compulsory education in the UK for this cohort. Capped GCSE point scores are continuous scores representing the best 8 grades at GCSE. Each grade has a different value  and these are summed to produce the total score , housing tenure (owner/mortgaged vs other), highest parental education , self-reported material hardship (yes/no), parity, IQ and earlier school enjoyment  were calculated from the paths from age 10-11 depressive/externalising symptoms to age 16 attainment. The direct effect (c\u2019) is the association between age 10-11 depressive/externalising symptoms and age 16 attainment whilst adjusting for age 13-14 depressive/externalising symptoms, enjoyment and connectedness.Potential mediation of the association between depressive/externalising symptoms and academic attainment via school experience was also tested within the structural equation modelling framework. Three indirect effects  a minimally adjusted model  and (ii) a model additionally adjusted for child IQ. As previously argued,  although2.4Missing data were imputed for all variables in the model using multiple chained equations for the sample of subjects with complete data on GCSE attainment at age 16 and at least one measure of depressive or externalising symptoms and one school experience measure at one time point. Imputation was conducted using the MICE package in R . Data we33.1The mean GCSE point score was 344.67 (SD: 78.83). Mean IQ score at age 8 was 103.88 (SD: 16.42), indicating scores slightly above the standardised average of 100. Distributions of school experience variables were skewed towards a positive school experience, and distributions of depressive symptoms and externalising towards lesser symptoms (Table S2).Correlations between school enjoyment and connection were 0.73 : 0.72, 0.74) at ages 10-11 and 0.58  at ages 13-14. Correlations between depressive and externalising symptoms were 0.24  at ages 10-11 and 0.21  at ages 13-14.Descriptive statistics suggest that the analysis sample was of higher average socioeconomic position compared to the full ALSPAC sample (Table S2). For example, mean GCSE point score in the full ALSPAC sample was 318.94 (SD: 93.95) compared to 344.67 (SD: 78.33) in the analysis sample; similarly average maternal age at birth in full ALSPAC sample was 28.64 (SD: 4.86) vs 29.31 (SD: 4.55) in the analysis sample.3.2Fit for the latent models of school experience, depressive and externalising symptoms was good . Loadings were moderate to high on all items (0.43 \u2013 0.95), apart from one item (\u201cSchool is a place where I get excited about the work I do\u201d) with a very low loading of 0.01 (Tables S2 - S4). This item was retained in the model to allow comparison with previous findings from the ALSPAC cohort.3.3The key results are shown in Stability of school enjoyment, depressive and externalising symptoms over time. School enjoyment showed moderate stability between ages 10-11 and 13-14  whilst connectedness showed lower stability . Externalising showed the highest stability between time points  whilst the stability of depressive symptoms was lower .Associations between school experience and externalising symptoms at ages 10-11 and 13-14 . There was weak evidence of a negative association between school enjoyment aged 10-11 and externalising at age 13-14 . We also found weak evidence for a positive association between school connectedness age 10-11 and externalising age 13-14, though confidence intervals crossed the null .There was clearer evidence of negative associations between externalising age 10-11 and school experience at 13-14 . Modelling hyperactivity and conduct problems separately indicated stronger associations with school experience age 13-14 for conduct problems than for hyperactivity/impulsivity at 10-11 (Tables S17 & S18). Associations were similar for males and females, except for that of age 10-11 externalising symptoms with age 13-14 enjoyment which was larger for boys than girls (Tables S12 & S13). Associations did not differ notably when additionally adjusted for IQ.Associations between school experience and depressive symptoms at ages 10-11 and 13-14 . A similar pattern of results was found for depressive symptoms. There was weak evidence of a negative association between school enjoyment age 10-11 and depressive symptoms age 13-14 . We also found evidence for a positive association between connectedness age 10-11 and depressive symptoms age 13-14 .Negative associations were observed between depressive symptoms age 10-11 and school experience age 13-14 . Analyses stratified by sex indicated that associations were larger for girls than boys (Tables S13 & S14). There was only minimal attenuation of associations after additionally adjusting for IQ.Associations between depressive/externalising symptoms age 13-14 and academic attainment age 16 . Externalising symptoms at both ages 10-11 and 13-14 were negatively associated with attainment at age 16 , as were depressive symptoms . These associations were attenuated by approximately 25-50% once adjusting for IQ.Associations between school experience age 13-14 and academic attainment age 16 . After adjusting for potential confounders, school enjoyment at age 13-14 was positively associated with attainment at age 16 ; but connectedness was not . Adjusting for child IQ did not substantially change these estimates. The association between school enjoyment and attainment was notably larger for girls than boys Does school experience mediate the association between depressive/externalising symptoms and attainment?  There was evidence that school enjoyment partially mediated the association between externalising and depressive symptoms ages 10-11 and attainment at age 16 (1 * b1). The proportion of the association between age 10-11 externalising and age 16 attainment mediated via age 13-14 enjoyment was 4.7% ; for depressive symptoms to attainment the proportion mediated via enjoyment was 2.2%, . However, there was minimal evidence of mediation via school connectedness .4The aims of this study were: (i) to test associations between depressive/externalising symptoms and school experience at two time points in secondary school (ages 10-11 and ages 13-14), (ii) to explore whether school experience at ages 13-14 was associated with academic attainment age 16, and (iii) to test whether school experience at ages 13-14 mediated the relationship between depressive/externalising symptoms at age 10-11 and academic attainment at age 16.Results support negative associations between depressive and externalising symptoms at age 10-11 and school connectedness at age 13-14. There was weaker evidence for associations between depressive and externalising symptoms age 10-11 and school enjoyment age 13-14. We found some evidence for associations between school experience age 10-11 and depressive and externalising symptoms age 13-14, though confidence intervals crossed the null. School enjoyment at age 13-14 was positively associated with attainment at age 16, and partially mediated the relationship between earlier depressive and externalising symptoms and attainment. Although the magnitude of associations was modest, our findings suggest that children with symptoms of depression, conduct problems and inattention/hyperactivity may find school less enjoyable after the transition to secondary school, which in turn affect their later academic attainment.4.1The negative associations between externalising symptoms at age 10-11 and connectedness aged 13-14 indicates that an aspect of school experience most affected for children with externalising difficulties is their relationships with teachers and pupils. This complements existing findings that externalising negatively impacts on peer relations,  which maReduced school enjoyment and connectedness for children with attentional and behavioural problems likely results from a complex interplay of individual and societal factors. School culture in the UK rewards quiet, focused and obedient behaviour,  and can 4.2Similarly to externalising, children suffering depressive symptoms at the transition to secondary school were less likely to feel connected to teachers and peers at age 13-14. This fits with previous findings that depression is associated with impaired relationships . The ass4.3Consistent with previous research,  we foundImportantly, there is evidence that school enjoyment and connectedness is modifiable. Whilst there is limited evidence for the effectiveness of individual interventions to improve children's emotional well-being,  trials u5This was a large prospective cohort study with repeated data on depressive and externalising symptoms and school experience along with linked educational data. The study design attempted to ascertain the direction of relationships and we were able control for some known confounders including child IQ. Nevertheless, as an observational study, results will be subject to residual confounding, selection bias and may suffer from reverse causation. Attrition in ALSPAC is high and associated with sex and socioeconomic factors,  and whil6In summary, we found evidence that depressive and externalising symptoms were prospectively associated with school connectedness, with weaker evidence for other pathways. School enjoyment was associated with academic attainment, and may partially mediate associations between depressive and externalising symptoms and later academic attainment, indicating a possible avenue for intervention.http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf); This research was specifically funded by the UK Medical Research Council (MR/M020894/1) and the Health Foundation's Social and Economic Value of Health Programme (Grant ID: 807293). The Medical Research Council (MRC) and the University of Bristol support the MRC Integrative Epidemiology Unit (MC_UU_00011/1). TC received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 733206, LIFE-CYCLE project. AH received funding from the Health Foundation's Social and Economic Value of Health programme, grant number:\u00a0807293. LDH is supported by a Career Development Award from the UK Medical Research Council (MR/M020894/1). This work is part of a project entitled \u2018social and economic consequences of health: causal inference methods and longitudinal, intergenerational data\u2019, which is part of the Health Foundation's Social and Economic Value of Health Programme (Grant ID: 807293). The Health Foundation is an independent charity committed to bringing about better health and health care for people in the UK. JALL was supported by the UK Economic and Social Research Council [grant number ES/P00881X/1]. Dr Wright is funded by a Cancer Research UK Population Research Postdoctoral Fellowship (C60153/A23895). GDS works in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol [MC_UU_00011/1].The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and will serve as guarantors for the contents of this paper. A comprehensive list of grants funding is available on the ALSPAC website (The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."}
+{"text": "Improvements in both musculoskeletal and non-musculoskeletal manifestations are important treatment goals in psoriatic arthritis (PsA).These post hoc analyses determined whether additional benefits related to various PsA domains are observed in patients simultaneously achieving 50% improvement in American College of Rheumatology criteria (ACR50) and 100% improvement in Psoriasis Area Severity Index (PASI100), the primary endpoint of the SPIRIT-H2H study.N\u2009=\u2009566) were categorised into two sets of four response groups irrespective of treatment allocation : patients who simultaneously achieved ACR50 and PASI100 response, achieved ACR50 response only, achieved PASI100 response only, or did not achieve ACR50 or PASI100 response after 24 and 52\u00a0weeks of treatment. Patients achieving simultaneous ACR50 and PASI100 response were compared with the other patient response groups at the corresponding time point for efficacy and health-related quality of life (HRQoL) outcomes.Patients with active PsA and psoriasis in SPIRIT-H2H (Patients simultaneously achieving ACR50 and PASI100 responses at week 24 or 52 showed higher rates of ACR70 response, minimal disease activity, Disease Activity in Psoriatic Arthritis\u2009\u2264\u20094, resolution of enthesitis and dactylitis, and HRQoL improvement at weeks 24 and 52, respectively, than the other corresponding response groups at both time points.High levels of disease control, such as those obtained with simultaneous achievement of ACR50 and PASI100 response, were linked to better outcomes across a wide range of endpoints that are important for patients with PsA. Patients meeting this combined endpoint showed more comprehensive and thus greater control of disease activity.Trial registrationNCT03151551The online version contains supplementary material available at 10.1007/s10067-021-05891-5. Psoriatic arthritis (PsA) is a chronic inflammatory disease that presents with both musculoskeletal and non-musculoskeletal manifestations , 2. MuscThe Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), the European League Against Rheumatism (EULAR), and the American College of Rheumatology (ACR)/National Psoriasis Foundation share common treatment goals for patients with PsA: to improve health-related quality of life (HRQoL); achieve robust improvement of musculoskeletal manifestations; prevent structural damage; and control non-musculoskeletal manifestations, including skin disease \u20134. Kavanp\u2009<\u20090.001) ); resolution of enthesitis (Spondyloarthritis Research Consortium of Canada [SPARCC] Enthesitis Index\u2009=\u20090 or Leeds Enthesitis Index [LEI]\u2009=\u20090) among patients with enthesitis at baseline (SPARCC Enthesitis Index\u2009>\u20090 or LEI\u2009>\u20090); resolution of dactylitis (Leeds Dactylitis Index-Basic [LDI-B]\u2009=\u20090) among patients with dactylitis at baseline (LDI-B\u2009>\u20090); and no impairment of physical function . Additionally, change from baseline was evaluated for SPARCC and LEI among patients with enthesitis at baseline, LDI-B among patients with dactylitis at baseline, HAQ-DI, and 36-Item Short Form Survey (SF-36) physical component score (PCS) and SF-36 mental component score (MCS).Non-musculoskeletal endpoints were the proportions of patients at weeks 24 and 52 who achieved a PASI75, PASI90, and PASI100 response; resolution of fingernail psoriasis (Nail Psoriasis Severity Index [NAPSI] fingernails\u2009=\u20090) among patients with fingernail involvement at baseline (NAPSI\u2009>\u20090); and a Dermatology Life Quality Index score of 0 or 1 .Baseline characteristics of each response group were summarised and compared descriptively  for the week-24 and week-52 groups.Categorical endpoints were examined at week 24 according to response group at week 24. The proportions of patients achieving responses to categorical endpoints were analyzed using logistic regression with non-responder imputation in the ITT population and included treatment, concomitant csDMARD use at baseline, and moderate-to-severe PsO involvement as factors. Differences between CR24 (who simultaneously achieved an ACR50 and PASI100 response at week 24) and each of the other three response groups at week 24  were also evaluated using Fisher\u2019s exact test. Similar analyses were performed at week 52 for CR52 (who simultaneously achieved an ACR50 and PASI100 response at week 52) compared with each of the other three response groups at week 52 .t-tests.Adjusted change from baseline in endpoints of interest in each response group was evaluated using an analysis of covariance model that included treatment, moderate-to-severe PsO at baseline, and baseline value as factors. Missing data were imputed using a modified baseline observation carried forward approach. Differences in least squares mean change were evaluated using Analyses were performed using SAS Enterprise Guide 7.15. Sankey diagrams were created to visualise the trajectory of response at week 52.A total of 566 bDMARD-na\u00efve patients with active PsA and PsO were included in these analyses; 283 patients received ixekizumab and 283 patients received adalimumab. When categorised by response at week 24, 181 patients simultaneously achieved an ACR50 and PASI100 response (CR24), 94 patients achieved an ACR50 but not a PASI100 response (JR24), 121 patients achieved a PASI100 response but not an ACR50 response (SR24), and 170 patients did not achieve an ACR50 or PASI100 response (NR24). When grouped according to response at 52\u00a0weeks, 185 patients simultaneously achieved an ACR50 and PASI100 response (CR52), 97 patients achieved an ACR50 but not a PASI100 response (JR52), 114 patients achieved a PASI100 response but not an ACR50 response (SR52), and 170 patients did not achieve an ACR50 or PASI100 response (NR52).A total of 483 patients (85.3%) completed the 52-week treatment period  higher rates of the musculoskeletal-related outcomes MDA and VLDA at weeks 24 and 52, respectively (Table p\u2009\u2264\u20090.001) than in SR24 and SR52, respectively, and NR24 and NR52, respectively. A similar pattern of relative differences between CR24 and JR24, and SR24 and NR24, and between CR52 and JR52, and SR52 and NR52 was seen for changes from baseline in enthesitis, HAQ-DI, and general HRQoL measured by SF-36 PCS and MCS scores at weeks 24 and 52, respectively  are summarised in the Online Resource and shown in Table Considering non-musculoskeletal outcomes, patients in CR24 or CR52, by definition, achieved all PASI responses at weeks 24 and 52, respectively. The highest rates of complete nail resolution at weeks 24 and 52 were reported for these response groups, respectively ; a statistically significant difference was observed only in comparison with NR24 and NR52, respectively (Table A majority (62.7%) of patients in CR52 had already achieved a simultaneous ACR50 and PASI100 response at week 24 (the primary endpoint); other patients in this group had achieved an ACR50 response only (13.0%) or a PASI100 response only (15.1%) at week 24  are described in the Online Resource Fig.  and S3.To optimise the benefits of treatment and improve the HRQoL of patients with PsA, all symptoms need to be considered . Indeed,The primary endpoint of the SPIRIT-H2H trial was a combination of both validated joint and skin measures . ACR50 iAlthough HAQ-DI and SF-36 HRQoL endpoints improved to a greater extent in patients in JR24 or JR52 than in those in SR24 or SR52, respectively, the improvements were generally highest in CR24 and CR52, respectively, confirming the value of the combined endpoint. These SF-36 findings are possibly explained by improvements in joint function having a large impact on the PCS component of the SF-36, although improvement in the MCS was also greatest in patients with an ACR50 response, with or without a PASI100 response . In contrast and as expected , the higWe found that more than half of patients in SR24 or SR52 and about one-third of patients in NR24 or NR52 also achieved an ACR20 response at weeks 24 and 52, respectively. However, response rates for other musculoskeletal and composite endpoints at these times in these response groups were generally low.EULAR recommends that consideration should be given to each musculoskeletal and non-musculoskeletal manifestation when managing patients with PsA, and that treatment decisions be made accordingly . GRAPPA Patients in CR52, JR52, or SR52 achieved response rates for other endpoints at week 52 that were generally similar to or higher than those achieved at week 24, indicating that the combined endpoint does not lose its association with other PsA endpoints over time. Results also indicate that continued treatment, even when a response is not achieved after 24\u00a0weeks of treatment, can be beneficial for many patients.The current analysis was limited in that it was post hoc. In addition, as only small proportions of patients had dactylitis at baseline, LDI-B response rates should be interpreted with caution. As radiographic progression was not assessed in the SPIRIT-H2H trial, it was not possible to determine potential correlations between simultaneous achievement of ACR50 and PASI100 and inhibition of structural damage.In conclusion, this post hoc analysis of data from the SPIRIT-H2H study showed that the primary endpoint of simultaneous achievement of an ACR50 and PASI100 response at week 24, irrespective of active treatment arm, signalled additional benefits at week 24 across a wide range of efficacy endpoints, including HRQoL, that are important for patients with PsA. Similar findings were seen in week-52 analyses. Patients meeting this primary endpoint are more likely to achieve a disease state of remission, which is the stated aim of PsA treatment according to GRAPPA and EULAR recommendations.Supplementary file1 (PDF 284 KB)Below is the link to the electronic supplementary material."}
+{"text": "The impact of COVID-19 on dementia caregivers is gaining new interest. It is unknown how the pandemic has impacted caregivers\u2019 burden and existential suffering. Analyses were performed on data for dementia caregivers (n=89) enrolled in the Indiana University Telephone Acceptance and Commitment Therapy for Caregivers (TACTICs) pilot trials. Individuals were primary caregivers of a family member with dementia and had clinically significant anxiety measured by a GAD-7 score >10 or between 5-9 with reported interference in life. COVID-19 anxiety was measured using the NIH CoRonavIruS Health Impact Survey (CRISIS) questions. Caregivers were on average 55.2 years of age with 56.2% being child or child-in-law, 71.9% were white and 24.7% were Black. Mean burden scores, measured by the Zarit Burden Index, were higher (44.29) compared to means reported across the literature (26.7) indicating the sample experienced higher than normal levels of burden. Mean existential suffering scores measured by the subscale of Experience of Suffering Scale were lower (9.37) compared to means across the literature (11.5) indicating that overall participants experienced lower levels of existential suffering compared to those in previous studies. A significant relationship was found between COVID-19 anxiety and burden levels , with higher levels of COVID-19 anxiety associated with greater burden. A non-significant relationship was found between COVID-19 anxiety and existential suffering . Results highlight the impact of COVID-19 anxiety as an external stressor on dementia caregiving. and the importance of considering context of external stressors when implementing intervention protocols for caregivers of individuals with dementia."}
+{"text": "To identify the number of patients currently on melatoninTo determine the average duration of use of melatonin in patients under the care of S-CAMHS in ABUHBTo investigate whether behaviour interventions were tried and reinforced from time to timeTo identify any areas of improvementData were collected at St. Cadoc's hospital, in January, 2021. S-CAMHS database was used. Out of total 346 patient currently being managed with pharmacological therapies, 115 (33.2%) are currently on melatonin. 57/115 were randomly selected as a sample for this this project. Patient notes and EPEX software were also used to collect information regarding the sleep management practices.During analysis, it was noticed that within the sample, only 46 patients were actively on melatonin. Melatonin is prescribed for sleep related issues in ASD (8/46), ADHD (15/46), ASD and ADHD (10/46), ADHD and mood disorder (0/46), ASD and mood disorder (6/46), ADHD and behaviour difficulties (2/46), ASD with behaviour difficulties (1/46), mood disorder (4/46).39/46 patients are currently on melatonin for more than a year (85%). These patients also include 10 patients who have been using melatonin for 5 years or more.35 patients (76%) reported improved sleep or some benefit from melatonin.Evidence for implementation of parent-led sleep behavioural interventions:Prior to commencing melatonin- Clear evidence available for 35 patients only (76%). These interventions were however not deemed helpful by most of the service users.While prescribing melatonin- Clear evidence available for 39(85%) patients. Evidence base for melatonin was also discussed during this visit.During last follow-up visit- Evidence available for 31 patients only (67%).Majority of patients under S-CAMHS ABUHB remain on melatonin therapy for longer than one year. Most of these patients have reported benefit from this therapy and preferred to remain on it despite being informed about evidence base for melatonin. Also, there is evidence for implementation of sleep behavioural interventions prior to prescribing melatonin, however their benefit remains unclear.Recommendations:The quality of education on sleep hygiene offered should be assessed and improved if neededFormal group sessions/workshops on sleep hygiene/parent-led sleep behavioural interventions at regular intervals might be useful in reducing the chances of long term polypharmacy or unlicensed drugsUse of outcome measures such as Child Sleep Habits Questionnaire at intervals can be helpful in identifying any improvement from educational/pharmacological interventionsS-CAMHS database (for patients actively on medications) needs a review and update"}
+{"text": "The National Institutes of Health All of Us (AoU) research program is building a diversified database of 1 million+ adult subjects. With this database, we seek to describe the sociodemographic characteristics of those with documented vaccinations.The AoU recruited subjects \u2265 18 years beginning in 2018. Eligible subjects were subsequently divided into five vaccine cohorts based on their vaccine history . The vaccine cohorts were compared to the general AoU cohort. Subjects in the influenza cohort had documented influenza vaccinations from 09/2017-05/2018. Other vaccine cohorts comprised subjects with \u2265 1 lifetime record(s) of vaccination by 12/2018. The Pneu < 65 and \u2265 65 cohorts comprised those who received pneumococcal vaccination before or after (inclusive) 65 years old, respectively. Descriptive statistics for all cohorts were generated using survey and electronic health record (EHR) data.We analyzed 315297 subjects in the AoU dataset R2020Q4R2. The cohort sizes were: influenza (n=15346), HepB (n=6323), HPV (n=2125), and Pneu . For all vaccine cohorts, comparing the 95% confidence intervals (CIs), the proportions of whites and non-Hispanics/Latinos were statistically higher than the general AoU cohort, the largest being from the Pneu \u2265 65 cohort (Table 1). For educational attainment, the Pneu < 65 (36.5%) had the smallest proportion of college or advanced degree graduates while the largest was observed in the Pneu \u2265 65 cohort (59.0%). The proportions of subjects with < &10k in annual household income (AHI) were largest among Pneu < 65 (17.1%) and smallest among Pneu \u2265 65 (3.8%). In contrast, the largest proportion of subjects with \u2265 &100k AHI was among Pneu \u2265 65 (25.3%) and the smallest among Pneu < 65 (15.8%).Table 1. Sociodemographic characteristics of subjects in the All of Us research program based on vaccine receiptRacial and ethnic disparities in vaccinations were apparent. Pneumococcal vaccination at age 65 years and above was more prevalent among white, non-Hispanic/Latino subjects who were also more educated and affluent. Conversely, those receiving pneumococcal vaccination before age 65 years were less educated and had lower AHI. All Authors: No reported disclosures"}
+{"text": "To analyze the incidence of epididymal anomalies (EAs) associated to spermatic obstruction in patients with undescended testis (UT) according to testicular position and age.We studied 87 patients (110 testis) with cryptorchidism and analyzed the presence of EAs correlated with the testicular position, age and patency of the processus vaginalis (PV). To analyze the relations between the testis and epididymis we considered three situations: (a) Normal pattern: the epididymis was attached to the testis at the head and tail and epididymis totally attached to the testis; (b) EAs: when the epididymis was attached to the testis only at the head  and (c) The mean age of the patients was 5.18 years (SD=2.867). Of 110 testes analyzed, 14 were abdominal (12.72%); 83 inguinal (75.45%) and 13 suprascrotal (11.81%). Normal relationships between testis and epididymis were observed in 54 patients (62.1%) with no significant differences in relation to the patient's age (p=0.666). Epididymal tail disjunction was observed in 23 patients (26.44%), with no significant differences in relation to age (p=0.59). EAs associated to spermatic obstruction were observed in 16 patients (18.4%), also with no significant differences in relation to age (p=0.684). We did not observe significant correlation between the testis position and the incidence of EAs (p=0.119). We did not observe significant correlations between patency of the PV (64.7%) and incidence of EAs (p=0.742).Epididymal anomalies associated with spermatic obstruction are present in almost 20% of undescended testes, without significant correlation with age, testicular position and patency of the PV. This information needs to be correlated to the infertility risk of this congenital anomaly. Undescended testis can be associated with several anatomical anomalies. Epididymal anomalies (EAs) and patency of the processus vaginalis (PV) are among the most frequent, with a highly variable incidence reported in the literature: from 36 to 79% -4. UndesSeveral studies have examined the relationship of EAs and patency of the PV -11. On tWe hypothesized that disjunction of epididymal head and total disjunction of epididymis are usual in undescended testes and more frequent in testes situated in high position and with patency of the PV. The aim of this article is to evaluate the incidence of epididymal anomalies associated with spermatic obstruction in patients with undescended testis (UT) according to testicular position, patient age and patency of the PV.This retrospective single-center study was approved and was carried out in accordance with the ethical standards of the hospital's institutional committee on human experimentation - IRB number 30706720.8.0000.5259.From January 2011 to January 2020, we studied 87 patients with cryptorchidism (110 testes). All patients underwent orchidopexy and the testes were divided into three groups according to their position: A) abdominal: testes located above the inner inguinal ring; B) inguinal: testes located between the inner and outer inguinal rings; and C) suprascrotal: testes located below the outer inguinal ring. During surgery, three parameters were analyzed: A) testicular position; B) relationship between testis and epididymis; and C) persistence of processus vaginalis (PV).To analyze the relations between the testis and epididymis, we used a previous classification , 13: TypAll parameters were statistically processed and graphically described. The Wilcoxon-Mann-Whitney test was used for comparison of quantitative data (p <0.05). The Chi-square test was used to analyze the population contingency under study (p<0.05), calculated by Graph Pad.All the 87 patients were aged between 1 and 10 years (mean=5.18/SD=2.867). Of these patients, 29 (33.33%) had cryptorchidism on the right side, 35 (40.22%) on the left side and 23 (26.43%) were bilateral. Of 110 testes, 14 were abdominal (12.72%), 83 inguinal (75.45%) and 13 suprascrotal (11.81%). The correlation between EAs and patient age can be seen in We did not observe epididymal atresia  in our sample. The normal relationships between testis and epididymis (Type I and II) were observed in 54 patients (62.1%), with no significant differences in relation to patient age (p=0.666). We observed normal relationships between testis and epididymis in 12 of the suprascrotal testes (92.3%); 50 of inguinal testes (60.2%) and 7 abdominal testes (50%).The disjunction of epididymal tail (Type III) was observed in 23 patients (25.3%), with no significant differences in relation to patient age (p=0.59). Disjunction of epididymal tail was observed in 5 (35.7%) of abdominal testes and 18 (21.7%) of inguinal testes. This anomaly was not observed in suprascrotal testes.Disjunctions of epididymal head and total disjunction of epididymis  were observed in 16 patients (18.4%), also with no significant differences in relation to patient age (p=0.684). The anomalies associated with spermatic obstruction were observed in 15 (18.1%) of the inguinal testes, 2 (14.3%) of the abdominal testes and only 1 (7.7%) of the suprascrotal testes.We did not observe significant correlation between the testis position and the incidence of epididymal anomalies in our sample (p=0.119). We observed 13 patients (11.31%) with bilateral cryptorchidism. In these 13 patients, 8 of them (61.53%) had epididymal anomalies and in 3 of them (23.07%) the epididymal anomalies were bilateral. In bilateral cases of undescended testis the anomalies associated with spermatic obstruction (Types IV and V) were observed in 6 cases (46.15%) and in 2 of them (15.38%) the patients had total disjunction between the testis and epididymis (Type 5) in both sides .Open PV was found in 74 cases (64.7%) of cryptorchidism. We did not observe significant correlations between patency of the PV and incidence of EAs (p=0.742). The normal relationships (Type I and Type II) occurred in 24 (66.7%) of the cases of PV obliterated and in 45 (60.8%) of the cases of PV patency. Epididymal tail disjunction occurred in 6 cases (16.7%) in obliterated PV and 17 cases (23%) in patency of the PV, and the anomalies associated with infertility (Types IV and V) were observed in 6 cases (16.7%) of obliterated PV and 12 cases (16.2%) of patency of the PV.Epididymal anomalies can occur due to abnormal involution of the mesonephric duct adjacent to the testis . The epiKnowledge of EA associated with cryptorchidism is relevant in clinical practice to prevent accidents during orchidopexy and to counsel patients and predict infertility in the future, such as in cases of epididymis atresia, disjunction of epididymal head and total disjunction between the testis and epididymis , 17.Turek et al.  found hiEAs can be classified as disjunction anomalies, epididymal atresia and elongated epididymis , 13, 18.The epididymis is anatomically connected to the gubernaculum, which in turn is attached to the testis and scrotum. An interesting and controversial theory suggests that the epididymis is one of the organs responsible for testicular migration, through its peristaltic and secretory activity in the second gestational trimester . This thMollaeian et al.  studied Some studies have found an association of patency of the PV with EAs and cryptorchidism, suggesting there is a common stimulus, probably androgenic, participating in the epididymal development, testicular migration and closure of the PV , 23. TheThe main limitations of our study are: a) small sample size; b) uneven age distribution; c) impossibility of histological analysis to observe patency of epididymal ducts ; and d) we do not have long-term follow-up of patients with types 4 and 5 epididymal abnormalities to ascertain if they have developed infertility. A perfect study would be to, prospectively, follow patients diagnosed with undescended testis until they reach adulthood.We found epididymal anomalies associated with spermatic obstruction in almost 20% of undescended testes and their incidence had no correlation with age, testicular position and patency of the PV. This information needs to be correlated to the infertility risk in this congenital anomaly."}
+{"text": "This cohort study reports the outcomes of using positive behavior supports to promote masking in school-aged children with autism spectrum disorders (ASD) and/or attention-deficit/hyperactivity disorder (ADHD) attending a summer day treatment program. However, policy makers and parents are concerned about students\u2019 ability to mask effectively.4 We report the outcome of using positive behavior supports to promote masking in verbal school-aged children with autism spectrum disorders (ASD) and/or attention-deficit/hyperactivity disorder (ADHD) attending a summer day treatment program.The effect of pediatric transmission of SARS-CoV-2 on the spread of COVID-19 remains a concern in creating policies for school reopening.STROBE) reporting guideline. Children attended the 4-week day camp on weekdays for 6 hours/day. Groups of 10 children were supervised by 6 to 7 graduate and undergraduate students. Activities included group discussions, sports, board games, snack and lunch, and recess; all activities were held outdoors. A token economy allowed children to earn points for behaviors, including helping, sharing, following activity rules, and sportsmanship. Activities were divided into 10- to 15-minute intervals,5 and behavioral data were taken continuously. A masking bonus was recorded by a research assistant for each interval during which a child properly wore a face covering over their nose and mouth for most of the interval. Points were redeemed at the end of the day for small prizes. We analyzed data on face covering during the second, third, and fourth weeks of the program Monday through Thursday (Fridays followed a different schedule). Data from the first week were excluded, as the research protocol and tracking were under development. Demographic data and clinical diagnoses were reported by guardians at enrollment as part of intake paperwork. The association between frequency of face covering and a child\u2019s age was assessed using simple linear regression  in Stata SE version 16.1 (StataCorp).In this cohort study, we examined face covering behavior in 104 children aged 5 to 13 years who participated in a summer treatment program at the University of Washington (UW) Autism Center during July 2020. Informed consent was obtained verbally, and all procedures were reviewed and approved by the UW institutional review board. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (P\u2009=\u2009.01) (Our sample included 104 children with a mean (SD) age of 8.9 (1.7) years; 84 (81%) reported a gender of male, 89 (86%) attended public school, and 71 (68%) had an individualized education program. Reported race/ethnicity included 1 child (1%) who reported being American Indian or Alaska Native; 17 (16%), Asian; 4 (4%), Black or African American; 5 (5%), Hispanic or Latino; 71 (68%), White; and 16 (16%), other or multiple categories. Clinical diagnoses were as follows: ASD, 28 (27%); ADHD, 37 (36%); ASD and ADHD, 29 (28%); and none, 11 (10%). During the 3-week period, staff recorded face coverings during 30\u2009539 total intervals  with an mean (SD) of 24.47 (4.85) intervals per day per child. During this period, 89 children (86%) wore a face covering during at least 75% of all observed intervals . This inP\u2009=\u2009.01) .6 but included direct observation and extended to children with greater special education needs. Limitations include a small sample size, a high staff to child ratio, no data on prior masking behavior, and no interrater reliability. As policy makers and school personnel consider plans for in-person activities, face covering can be used as part of a constellation of practices to reduce the transmission of SARS-CoV-2 in pediatric settings.Our carefully tracked interval data indicate that a group of school-aged children, most of whom had ASD and/or ADHD, were capable of face covering across activities. Our findings are consistent with recent reports of face covering in school-aged children"}
+{"text": "Antimicrobial susceptibility testing (AST) is critical in identifying the optimal antimicrobial regimen for individual patients with serious gram-negative infections. Limitations to AST for newly developed antibiotics include the lack of commercially available AST methods, challenges of implementation due to regulations, and delays in obtaining results. The purpose of this study was to evaluate the access to AST for cefiderocol (FDC), imipenem-relebactam (IPR), meropenem-vaborbactam (MEV), and eravacycline (ERV) in hospitals across the U.S.An electronic survey was distributed to the American College of Clinical Pharmacist Infectious Diseases Practice and Research Network in May 2021. Hospital baseline demographics and current practices were collected. rd party reference microbiology labs . AST for FDC was performed by 13 (35%) in-house labs, 4 (50%) core labs, and 1 (20%) reference lab. AST for IPR was performed by 11 (30%) in-house labs, 2 (25%) core labs, and 1 (20%) reference lab. AST for MEV was performed by 25 (68%) in-house labs, 3 (37.5%) core labs, and 1 (20%) reference lab. AST for ERV was performed by 1 (20%) in-house lab, 1 (20%) core lab, and 0 reference labs. 15 (30%) respondents were not able to get AST for any of the novel agents at their respective microbiology labs. Turn-around-times (TATs) for FDC, IPR, MEV, and ERV were \u226572 hours for 33 (66%), 35 (70%), 21 (42%), and 35 (70%) hospitals, respectively. When compared with 3rd party reference labs, in-house labs with the ability to perform AST for these novel agents had significantly shorter TATs (p< 0.05). The average number of requests for AST for these novel agents was 20 times a year with an average of 113 minutes spent per patient on the coordination of AST. Based on 50 responses, specimens were sent to in-house microbiology labs , core microbiology labs , and 3Access to AST for these novel agents varied across hospitals in the U.S. Nearly 1/3 of the respondents were not able to obtain AST for these agents at all. Long TATs exist and a great deal of time is spent per patient for coordinating AST for these novel agents. There is a crucial need for a multidisciplinary, collaborative approach to resolve the challenges in obtaining AST for newly developed antibiotics to provide patient care. All Authors: No reported disclosures"}
+{"text": "This study examines differences in opioid prescribing rates among a nationally representative sample of Medicare beneficiaries across rural and urban areas, as well as among beneficiaries with chronic overlapping pain conditions (COPCs). We assess whether prescribing patterns exceed the Centers for Disease Control and Prevention guidelines for dose and duration, and identify socioeconomic and health risk factors associated with opioid prescribing using logistic regression analyses. Data were from the 2010-2017 Medicare Current Beneficiary Survey files. Rural-Urban Commuting Area codes were used to identify patients\u2019 residential location. The Area Health Resource Files were used to identify market characteristics such as primary care and mental health shortage areas. With the exception of 2010, over years 2011-2017, higher percentages of community-dwelling rural beneficiaries received opioid prescriptions (21.8-25.4%) compared to their urban counterparts (19.1-23.7%). During the same time period, facility-dwelling rural beneficiaries were more likely to receive opioid prescriptions (39.8-47.2%) compared to their urban counterparts (28.8-35.0%). Higher percentages (18.8%) of the community dwelling population in rural had COPCs compared to urban (15.2%), and a higher percentage of rural beneficiaries with COPCs (31.4%) received an opioid prescription than their urban counterparts (22.2%). Previous research points to other factors contributing to a lack of alternatives to opioids for pain management in rural areas, including greater reliance on primary care providers, lack of access to chronic pain specialists and alternative therapies, and travel barriers. Improving the capacity of rural primary care to deal with COPCs and expanding access to specialists via telehealth warrants further attention from policymakers."}
+{"text": "To estimate the prevelance of Generalized anxiety disorder (GAD) in adult patients with diabetes mellitus (T1DM or T2DM) during COVID-19 pandemic.Random sample of 115 Adult Libyan patients (\u226518 years) were drawn from 1200 Medical records of diabetic patients previously diagnosed in a primary care clinic . Patients were recruited and diagnostically interviewed through outpatient visits and through Phone calls. Anxiety was assessed using Generalized Anxiety Disorder 7-item instrument (GAD-7), personal information, Co morbidities and History of COVID-19 infection within period of 3 weeks.The statistical analysis done by SPSS version 23, using ANOVA test. The GAD-7 scores ranged from 0 to 19 for the diabetic patient, 82 patients scores ranged from 0 to 4 with varying degrees of non-signifacant to subsyndromal symptopms of Generalized anxiety disorder, 24 patient with Mild GAD, 7 patients with moderate GAD and 2 patients with severe GAD. GAD is present in 28% of the patients who participated in the study. Additional epidemiological studies are needed to determine the prevalence of anxiety in the broader population of persons with diabetes."}
+{"text": "COVID-19 created a \u201cperfect storm\u201d for financial exploitation directed at older adults. We invited adults aged 60 and older enrolled in gerontology research registries at Virginia Tech, Florida State University, Wayne State University, and University of Pittsburgh to complete an on-line survey about experiences with financial exploitation by strangers. The 997 respondents ranged in age from 60 to 98 ; most identified as White (93.4%), female (64.2%) and living with a spouse/partner (58%). Approximately one-half of respondents (56.87%) reported experiencing a scam attempt about COVID-19 issues. Most contact by scammers was electronic (49%) and frequently occurred two or more times (40%). Most respondents ignored the request . However, 9% sent the requested payment, and 4% gave the scammer their personal information. Confidence in financial matters and having attended financial educational programs protected older adults from being scammed."}
+{"text": "To compare the usage of remote consultations before and after the first wave of the SARS-CoV-2 outbreak and explore mental health workers\u2019 views on the usage of telemedicine.An online questionnaire survey was developed, and disseminated to mental healthcare professionals via e-mail and social media. Quantitative data were analysed using descriptive statistics and qualitative data were analysed using Braun and Clarke's six step procedure for thematic analysis.1There were 40 responses from mental healthcare professionals of varying grades from different sub-specialties, predominantly from the UK. Compared to before the SARS-CoV-2 outbreak, there was an increase in usage of telephone (9(22.5% to (29)72.5%) and video consultations (4(10%) to 17(42.5%)). Respondents reported an increase in virtual MDTs (35(87.5%) during the pandemic, 9(22.5%) pre-pandemic).Based on a 5-point Likert scale, the mean technical quality of telephone consultations was 3.56/5 (Range 2-5), with 75% rating telephone consultations as not being as good as face-to-face consultations. The mean technical quality of video consultations was 3.58/5 (Range 2-5), with 63% rating video consultations as not being as good as face-to-face consultations. 25 (62.5%) respondents felt comfortable using telephone consultations during the pandemic, 20(50%) felt comfortable using video consultations. Recurring themes identified from the qualitative data regarding reasons for the technical quality ratings were: connection issues, poor infrastructure and security concerns.Nine (23%) respondents felt that using video conferencing consultations had a detrimental impact on the mental health of patients while 14(35%) felt that telephone consultations had a detrimental impact on patients\u2019 mental health. Recurring themes for health practitioners\u2019 perceived effect of the use of telemedicine on patients\u2019 mental heath were the loss of personal touch and reduced patient engagement.There was a substantial increase in usage of remote consultations during the first wave of the SARS-CoV-2 pandemic among mental healthcare professionals. The results reported in the present study suggest there are numerous barriers to the use of telemedicine in psychiatry, which require future exploration, ideally through interview or ethnographic studies."}
+{"text": "Adherence with antipsychotic medication is an important factor in the prevention of relapse in psychotic disorders such as schizophrenia. Long acting antipsychotic injections promote improved adherence. In recent years, second generation antipsychotic long-acting injections have become increasingly popular, and little has been written about the use of the older depot medications. Here, we explore the current use of one of the first-generation antipsychotic long acting injections in Birmingham and Solihull Mental Health NHS Foundation Trust.An 18-month retrospective case-note review of all patients who started zuclopenthixol decanoate during the first 6 months of 2018 (n = 45)71% were maleThe mean age was 37 (range 19-65)The most common diagnoses were: schizophrenia (51%), bipolar affective disorder (18%) and schizoaffective disorder (13%). We noted that 2 individuals (4%) had a primary diagnosis of recurrent depressive disorder, 2 (4%) had a primary diagnosis of emotionally unstable personality disorder.60% of those who were prescribed zuclopenthixol decanoate discontinued it within the 18-month follow-up period.The vast majority of discontinuation occurred within the first 6 months, and after this, few individuals stopped treatment.The most common reason for discontinuation was side effects (57%), with other reasons including patient choice (7%), non-compliance (7%), pregnancy (4%), or needle phobia (4%).Key findings included: -Zuclopenthixol decanoate has been used for individuals with both schizophrenia and paranoid psychosis (where it is licenced) and also occasionally for other indications. A high proportion discontinued the zuclopenthixol within 6 months, this generally being attributed to adverse effects. Those who were still receiving this medication at 6 months were very likely to continue to take it throughout the 18 months. We would therefore recommend robust monitoring for and management of adverse effects in the early phases of treatment."}
+{"text": "Orthopedic conditions include a range of condition varying from traumatic injuries, congenital anomalies, chronic back-pain, arthritis, rheumatologic conditions, and other. In Nepal, approximately 2.35 million people are living with musculoskeletal conditions in which 175,000 people are suffering with MSD from non-traumatic causes. The aim of the study is to observe the clinical and demographic pattern of orthopedic problems presenting in the hospital.A descriptive cross-sectional study was done in All Nepal Hospital Private Limited in the month of November. The data from the medical record section was retrospectively collected. Sample size of 384 was included and convenience sampling technique was used. The descriptive statistical analysis was done.Eight hundred forty four cases were included in the study. Implant removal was the main condition for admission in the hospital 105 (12.44%) followed by Forearm Bone Fracture 84 (9.95%) and Cut Injury 64 (7.58%). Most cases presented during the time 6 PM to 12 AM 312 (36.96%).Most of the orthopedic cases presented in the evening and night time. Implant removal, forearm bone fracture and cut injury form the major bulk of the cases. The burden of musculoskeletal conditions varies from different regions to regions as per their racial, environmental and geographical distribution.6 Study on clinico-demographic pattern of the orthopedic cases is necessary as it assist in identifying areas for primary prevention. A report given by the Ministry of Health and Nepal Health Research Council has already highlights orthopedic cases as the major cause of the disability countrywide.6 This shows that the study on the cases profile of orthopedic cases is necessary to find out the prevalence and pattern of the problem.The statistics of orthopedic cases presenting in the hospital has rapidly rose as the population especially geriatric group rises and there are many challenges to be faced.The main objective of the study is to study the clinico- demographic pattern of orthopedic cases presenting to the hospital.A descriptive cross-sectional study was conducted in All Nepal Hospital Private Limited. The study was conducted in the month of November by collecting the data retrospectively from the medical records section. Ethical clearance was taken from the Ethical Review Board of Nepal Health Research Council (Ref No: 1359). Inclusion criteria included the record of cases presenting with orthopedic complaints whereas incomplete record, repeated case data and record with missing diagnoses were excluded from the study. The sample size was calculated as per the given formula:The sample size of this study is calculated using the formula,n = required sample sizeZ = 1.96 at 95% Confidence Interval (CI)p = prevalence, 50%Margin of error (e) = 5%Where,Therefore, the calculated sample size was 384. Adding the 10% non-response rate, the sample size that will be taken would be 422. Since the convenience sampling technique will be applied the sample size will be doubled to 844 so as to reduce the possible bias such as information bias.Data from the medical records were collected and kept in Microsoft Excel. Statistical Package for Social Services (SPSS) Version 16 was used for the statistical analysis. The descriptive statistical analysis was done.Among the 844 cases included in the study, musculoskeletal conditions comprising of around 44 conditions were recorded. Among them, implant removal was the main condition for admission in the hospital 105 (12.44%). Forearm Bone Fracture 84 (9.95%) and Cut Injury 64 (7.58%) were the second and third most presenting cases. Similarly, road traffic accident 55 (6.51%), Cellulitis 36 (4.26%), Physical assault 34 (4.02%), tibia and fibula fracture 34 (4.02%) Supracondylar fracture 28 (3.31%), phalanx fracture 28 (3.31%) and fall injury 25 (2.96%) are other common presenting conditions.In terms of time of presentation of the cases, most of the cases presented in the time 6 PM-12 AM 312 (36.96%), then the second most influx of cases occurred during 6 AM-12 PM 220 (26.06%) .Regarding the socio-demographic data of the cases presenting in the hospital, male patients 510 (60.42%) were more than female 334 (39.57%). As per caste, Brahmin 182 (21.56%) were the most followed by Chhetri 171 (20.26%), Newar 142 (17%), Gurung 118 (14%), Tamang 108 (13%), Magar 68 (8%) and others 55 (6%).Maximum number of cases presenting came from age group 30-45 215 (25.47%) followed by 15-30 age group 188 (22.27%) . Almost 1 A report given by the Ministry of Health and Nepal Health Research Council has already highlightes orthopaedic cases as the major cause of the disability countrywide.6Orthopedics, as a part of medical science, contribute an immense workload to any kind of tertiary care health centre. Orthopedic cases comprises from cases with fractures, soft tissue injuries, deformities to congenital bone and joint problems. The burden of musculoskeletal conditions varies from different regions to regions as per their racial, environmental and geographical distribution.7 Our study showed that the common age group presenting to the hospital came from 30 to 45 years whereas the most commonly admitted cases were implant removal, forearm bone fracture and cut injury. A study done among orthopaedic road traffic accident cases in a tertiary care hospital of Western Nepal revealed most victims as young, unmarried, pedestrians and drunk drivers.8A study done by Syed et al in a tertiary care centre using the 4-year record data showed that most of the cases presenting comes from age 19-50 years and the most frequent diagnoses belong to lower back pain (25.9%), tendinopathies and enthesopathies (18.3%), bone fractures (11%).5 Similarly, low back pain ranks at the topmost as the cause of disability as per the report submitted by Nepal Health Research Council.6 A previous study on orthopaedic conditions in Nepal implicated that falls were the major cause (43%).5 However our study shows that fall injury comes at 10th most common presenting condition 25 (2.96%).A country-wide cross-sectional survey study done by Chawla et al. showed that approximately 2.35 million people live with musculoskeletal conditions in Nepal.3 As per World Health Organization, more than 90% of the DALYs lost occur in low- and middle-income countries (LMICs), highlighting the disproportionate burden of orthopaedic cases placed on developing countries.4 Our study have highlighted the burden of trauma in orthopedic cases also as 55 (6.51%) cases were found to be admitted secondary to road traffic accident.A study on Global Burden of Disease from 1990 to 2010 reports that non-traumatic orthopaedic cases account for 6.8% of all disability adjusted life years lost whereas traumatic conditions comprises 11%.This is a single-centre retrospective study, our study may not be truly representative of the epidemiology of orthopedic problems prevalent in the community. The cross-sectional nature of the study, does not allow the establishment of causality.Orthopedic cases comprise mostly of young age and the cases presented in the evening and night time more often. Implant removal, forearm bone fracture and cut injury form the major pattern of musculoskeletal conditions presenting in the hospital. Further study is required with larger sample size and probability sampling method for better scientific findings."}
+{"text": "This analysis of a randomized clinical trial examines the efficacy of acyclovir for preventing oropharyngeal HSV reactivation among patients who were mechanically ventilated. NCT02152358),1 preemptive use of acyclovir for patients who were mechanically ventilated with oropharyngeal herpes simplex virus (HSV) reactivation failed to demonstrate a positive impact on day-60 ventilator-free days; however, a trend toward a decreased day-60 mortality rate was found in favor of acyclovir. However, the impact of acyclovir on oropharyngeal HSV reactivation was not assessed. We performed this retrospective study to evaluate the efficacy of acyclovir to suppress HSV oropharyngeal reactivation within the PTH trial.In the recently published Preemptive Treatment for Herpesviridae (PTH) randomized clinical trial (1 which was approved by an independent ethics committee (Comit\u00e9 de Protection des Personnes Sud M\u00e9dit\u00e9ran\u00e9e 5). Written informed consent was obtained from patients or their legally authorized representatives. For the latter, the patient\u2019s follow-up informed consent was obtained when possible. Conduct of the study and reports of results follow the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.This analysis of a randomized clinical trial was planned in the original protocol  at randomization and at days 7, 14, and 21 postrandomization. All patients with at least 1 follow-up swab were included in this study . For categorical variables, between-group comparisons used \u03c72 or Fischer exact tests. All analyses were computed with R software version 3.5.1  at a 2-sided 5% level of significance. Data were analyzed from February through April 2021. Further details regarding statistical analysis are given in eMethods in Data are expressed as median (IQR), mean (SD), or mean with 95% CI, as appropriate. Between-group comparisons used Student Among 239 patients included in the PTH trial, 133 patients were included in the 2 centers participating in this ancillary study; among these patients, 130 individuals (87 patients in Paris and 43 patients in Marseille) had at least 1 follow-up swab and were included in the study. Patient baseline characteristics were comparable between groups; among 66 patients in the acyclovir group and 64 patients in the placebo group, there were 43 (65.2%) men and 46 (71.9%) men, respectively. The groups had a median (IQR) age of 59 (50-66) years and 59 (43-66) years, admission simplified acute physiology score II of 42 (35-54) and 43 (36-50), and admission sequential organ failure assessment score of 10 (7-13) and 9 (7-12), respectively. Median (IQR) body mass index  differed significantly between groups: 29.5 (26.2-34.4) for the acyclovir group vs 26.8 (23.4-31.4) for the placebo group.P\u2009=\u2009.008)  . Subdist1 patients in the acyclovir group had a decreased mortality rate but increased duration of mechanical ventilation.This analysis of a randomized clinical trial found that intravenous acyclovir at a dosing of 15 mg/kg/d for 14 days was effective in decreasing the duration of HSV oropharyngeal shedding compared with placebo among patients mechanically ventilated for 96 hours or more. However, throat HSV shedding was still detected among one-third of patients after 14 days of antiviral treatment. In the parent trial,1 although this drug has been shown to prevent HSV reactivation.2 Although we found here that acyclovir allowed the shortening of HSV shedding duration, this dosing and duration of antiviral treatment do not appear to be sufficient to totally suppress oropharyngeal HSV reactivation and shedding among patients who are mechanically ventilated. Whether increased doses and prolonged duration of treatment may lead to complete suppression of HSV shedding and may improve outcomes remains to be determined. Limitations of our study include the limited number of patients included and missing samples.One hypothesis for the negative result of the PTH trial was the inefficacy of acyclovir to cure HSV oropharyngeal reactivation,"}
+{"text": "Cesarean section is a common obstetric procedure which is done to reduce complications in high risk pregnancies. The aim of study was to find out the prevalence of cesarean section in a maternity unit of a tertiary care center.A descriptive cross-sectional study was conducted among 497 pregnant women presenting in a maternity unit of a tertiary center of Kathmandu, Nepal over a period of six months from March to August 2017 after taking ethical approval from Institutional Review Committee (Ref. 24). In this study, the prevalence of cesarean section, perinatal outcome, maternal and neonatal complications if any were observed. Data and descriptive analysis were done using Statistical Package for the Social Sciences version 22. Point estimate at 95% Confidence Interval was calculated along with frequency and percentage for binary data.The prevalence of cesarean section was 171 (34.4%) at 95% Confidence interval (30.2-38.7). Most common indication for cesarean section was fetal distress 53 (31%). The maternal complications developed in 11 (6.4%) among those who delivered via cesarean delivery; Surgical Site Infection being the most common maternal complication. The neonatal intensive care unit admission rate among the newborns via cesarean section delivery was 48 (27.43%) and neonatal sepsis 14 (8%) was most common adverse neonatal outcome.The cesarean rate at the study center is higher than standard target rate of World Health Organization. Neonatal and maternal adverse outcome in current study were comparable with existing literatures. Therefore, this study was proposed and carried out.In this study we aimed to find out the prevalence of cesarean section in a maternity unit of a tertiary care center.A descriptive cross-sectional study was conducted among pregnant women presenting to the maternity unit of Birendra Hospital, Chhauni, Kathmandu, Nepal over a period of six months from March to August 2017. The study proposal was approved by the local institutional ethical review committee (IRC) of the Nepalese Army Institute of Health Sciences (NAIHS) following which study was conducted (Ref. No: 24).The sample size was calculated using the formula,where,n = required sample sizep = prevalence taken as 50% for maximum sample sizeq = 1-pe = margin of error, 5%Z = 1.96 at 95% Confidence IntervalHence, the required sample size was 384.Adding 10% non-response rate ie. 38.4, the calculated sample size was 422.4.A total of 497 pregnant ladies in labor were enrolled in the study using convenient sampling. With the help of semi-structured questionnaire demographic variables, obstetric history of significance, significant antenatal events, labor events, and postnatal events were recorded. Mode of delivery, perinatal outcome , and maternal and neonatal complications if any were evaluated. Informed verbal consent was taken while enrolling the individual in the study. All pregnant ladies in labor presenting to maternity unit were enrolled excluding spontaneous or induced abortions.The collected data were entered in Statistical Package for Social Sciences version 22 and analyzed. Simple descriptive analysis performed and result were presented in appropriate tables and figures with percentage and frequencies. Point estimate at 95% CI was calculated along with the frequency and proportion for binary data.Total 497 deliveries took place during the study period. Among them, 171 (34.4%) (30.2-38.7 at 95% CI) were CS deliveries with reminder being normal and vacuum deliveries. Out of 171 CS deliveries, 111 (64.9% ) were emergency CS deliveries and rest being elective CS. Of all CS deliveries, 49 (28.7%) were among primi-gravidas women and remaining among multigravida women, with 60 (35.1%) cases having second gravida status. Out of total 171 CS deliveries, 161 (94.2%) having regualar antenatal visits in to the obstretic clinic of the study site and 88 (51.5%) cases had reached their term gestation.Cesarean section was performed for various indications with commonest being fetal distress 53 (31%), following previous CS 44 (26%), Cephalopelvic disproportion (CPD) 20 (12%), failed induction of labor 17 (10%), breech presentation 9 (5%) . Other iOut of total 171 cesarean sections, the maternal complications were developed in 11 (6.4%) cases. The most common maternal complication was surgical site infection (SSI) 6 (3.5%) cases, more among women who had emergency CS ie. 5 (2.9%) cases. The other maternal complications were postpartum hemorrhage (PPH), Peripartum cardiomyopathy and disseminated intravascular coagulation (DIC) .Of total 171 CS deliveries, 95 (54.6%) were male while 79 (45.4%) female and with 3 twin CS deliveries. 148 (84.6%) newborns were having normal weight  rest 24 (13.7%) having low birth weight (1500-2500 grams) and 3 (1.7%) having less than 1500 grams. Neonatal complications were more in cesarean section than normal vaginal delivery, may be reflection cesarean done already among high risk cases and in which there is fetal distress also more so among emergency CS .Forty-eight (27.43%) newborns delivered via CS were admitted to Neonatal Intensive Care Unit (NICU) for various neonatal complications. Among different neonatal complications, the most common was neonatal sepsis (NNS) 14 (8%) followed neonatal jaundice (NNJ) 13 (7%). Other complications were neonatal respiratory distress syndrome (RDS) 9 (5%), low birth weight (LBW)/ preterm delivery 5 (3%), perinatal asphyxia 2 (1%), meconium aspiration syndrome (MAS) 1 (1%) .1 In present study the cesarean rate was 34.4% of the total deliveries with about two-third being emergency ones. The various studies from Nepal showed that the cesarean section in various government and private institutes ranges from 15 % to 81 %, higher among the private institutes.10 Study from Kaski, Nepal showed CS incidence of 13.3% among deliveries and influenced by age, urban residency, high education, and intrapartum symptoms.11 CS rate varies from one hospital to another; 4-year experience from Kirtipur hospital showed 50.9%12 while previous study mentioned it to vary from 10-30%.13 Study from China from 1991 to 2002 showed CS rate has increased from 1%-17% and CS was common among more educated women, with good income, who visited antenatal care, and giving birth equipped hospital leading to demand CS.14 Study showed CS rate has increased from 4.5 to 22.7 per 100 deliveries in 1965 to 1985 in united states (US).15 Sub-Saharan multi country-based study on 2011 showed CS rate of 6.2% (range 4.1-16.8%).2 WHO mentions optimal target range of CS rate to be 5-15%.CS is done to reduce complications in high risk pregnancies and abnormal labor, though study showed no such improvement in perinatal mortality or morbidity.16 Demand CS varied from 0.3 to 14 percent is one the indication which played major role in rising trend of the cesarean section in last two decades in the Nepal also.17 Various studies from the Nepal showed that oligohydramnios (2.22-41 %), Fetal distress (09-30%), Previous CS (11-25%), CPD (6-34%), non-progress of labor (0.7-29%), fetal malpresentation (6-10%), Failed induction of labor (3-9%), PIH/pre-eclampsia/eclampsia (4-8%), Prelabor rupture of membranes (5-6%), ante-partum hemorrhage (1-2%), IUGR (2%), multifetal pregnancy (1-2%) are the common indications for the cesarean delivery.20In this study, we found that the fetal distress (53%) is most common indication for cesarean section and it may be higher rate of its detection resulted from the use of the cardiotocography-incorporated feto-maternal monitoring. Other indications in this study are previous CS (44%), CPD (20%), failed induction (17%), breech malpresentation (9%) and others. There are numbers of maternal, fetal or feto-maternal indications for the cesarean section but the more than 85 % of them are performed for four reasons-prior cesarean delivery, dystocia, fetal jeopardy or abnormal fetal presentation.16 Commonest indication for CS being fetal distress followed by previous CS. Cesarean section is associated with chances of neonatal complications like NICU admission. The neonatal NICU admission rate in this study following Cesarean delivery is 27.43% and most common indications for the NICU admission are: neonatal sepsis, neonatal jaundice, neonatal respiratory distress syndrome, perinatal asphyxia, meconium aspiration syndrome, low birth weight. CS benefit health only in certain health conditions but also has risks like iatrogenic prematurity or respiratory distress of baby and higher maternal mortality (2-4 times) and morbidity (5-10 times) in comparison to vaginal birth.3In present study, the maternal morbidities seen among 6.4% of total cesarean deliveries and those morbidities are: surgical site infection, postpartum hemorrhage, peri-partum cardiomyopathy and DIC. The common maternal morbidities associated with cesarean section are infection of the surgical site, hemorrhage, thromboembolism and higher maternal mortality rate compared to vaginal delivery.Present study has some limiations. Firstly, this study is single institutional experience based on tertiary referral center so result of present study may not be generalizable in every set up. The findings reported in this study need to be further confirmed by replicating similar studies in multiple centers with bigger patient populations. In addition, present study could not explore causality of adverse outcome due to its study design so futher prospective study is advised to confirm and explore the findings.The prevalence of cesarean section is higher than WHO target range may be because this is the only tertiary level referral center for Nepalese Army and their family. Maternal and neonatal complications observed in the center were comparable with existing literatures. In cesarean section case, the NICU admission and neonatal complications is significantly higher than normal deliveries. Careful consideration of cesarean delivery is recommended considering maternal and fetal risk and benefit of doing and not doing cesarean section in a particular case."}
+{"text": "Uncomplicated urinary tract infection (uUTI) is one of the main causes of antibiotics prescription in outpatient setting. Current recommendations, based on studies from pre-antimicrobial resistance era, suggest that diagnosis of uUTI can be made based on clinical symptoms and that urine analysis leads only to a minimal increase in diagnostic accuracy. We analyzed urine cultures (UC) from patients with clinical diagnosis. Prospective and observational study carried out in an Emergency Department during August 2016 to August 2017. Women older than 15 years with 2 or more classic symptoms of uUTI and the absence of vaginal discharge and irritation were included. Those with complicated and recurrent urinary tract infection (UTI) were excluded. Urine cytology and UC were performed in all episodes. A bivariate and multivariate analysis was performed considering the probability of having a positive urine culture according to the different symptomatology variables.We enrolled 208 patients, with a median age of 25 (14-68 years). Previous UTI 6 (2.9%), previous antibiotic (last 3 months) 20 (9.6%). Inflammatory cytology 173 (83.2%), positive UC 109 (52.4%), cystitis 155 (74.5%). Symptoms: dysuria 154 (74%), frequency 111 (53.4%), tenesmus 97 (46.6%), fever 78 (37.5%), hematuria 43 , hypogastric pain 128 (61.5%), back pain 84 (40.4%). Combinations of 3 or more classic symptoms occurred in 52 (25%) episodes. The most frequent association was dysuria, frequency and tenesmus. No statistically significant association was found either in the bivariate or multivariate analysis in relation to presenting positive UC (Tables 1 and 2).The results show that almost 50% of the patients with a clinical diagnosis of UTI had a negative urine culture. We consider it necessary to rethink the prescription of antibiotics without microbiological confirmation in the first episode of uUTI as a strategy to reduce inappropriate use of antibiotics.All Authors: No reported disclosures"}
+{"text": "The study is one of the first to examine both the prevalence of life instability among older adults with HIV (OAWH) in a community clinic and its relationship to their mental health. OAWH (N=623) from a community medical clinic completed an interviewer-administered assessment (English/Spanish) which included an additive Life Instability Index (LII) composed of indicators at the individual  and community  levels. Participants were a mean age of 60 years (SD = 5.90) with the majority identifying as Black-non-Hispanic (65.9%), cisgender male (60.8%), and heterosexual (80.6%). Participants reported an average of 6.08 destabilizing factors (SD = 1.44). In multiple linear regression analyses LII was significantly related to increased substance use among participants , but not with anxiety or depression. An LII is an innovative approach to assess the relationship between OAWH\u2019s mental health and social determinants of health."}
+{"text": "What are the patterns of dexamethasone and prednisolone and methylprednisolone use in extremely preterm infants and are their use associated with 2-year outcomes?In this cohort study including 828 extremely preterm infants from a multicenter randomized clinical trial, 38% of infants were treated with corticosteroids, with exposure rates decreasing as gestational age at birth increased. More infants were treated with dexamethasone, and exposure was shorter and earlier compared with prednisolone or methylprednisolone; longer duration of treatment with dexamethasone, but not prednisolone or methylprednisolone, was associated with worse neurodevelopmental outcomes at corrected age 2 years.These findings suggest that significant practice variation in postnatal corticosteroids treatment was common and that limiting exposure to dexamethasone may be associated with minimizing adverse neurodevelopmental outcomes. This cohort study describes the use of corticosteroids in extremely preterm infants and the association of corticosteroid exposure with neurodevelopmental outcomes at 2 years. Practice variability exists in the use of corticosteroids to treat or prevent bronchopulmonary dysplasia in extremely preterm infants, but there is limited information on longer-term impacts.To describe the use of corticosteroids in extremely preterm infants and evaluate the association with neurodevelopmental outcomes.This cohort study was a secondary analysis of data from the Preterm Erythropoietin Neuroprotection (PENUT) randomized clinical trial, conducted at 19 participating sites and 30 neonatal intensive care units (NICUs) in the US. Inborn infants born between 24 0/7 and 27 6/7 weeks gestational age between December 2013 and September 2016 were included in analysis. Data analysis was conducted between February 2021 and January 2022.Cumulative dose of dexamethasone and duration of therapy for dexamethasone and prednisolone or methyl prednisolone were evaluated.Demographic and clinical characteristics were described in infants who did or did not receive corticosteroids of interest and survived to discharge. Neurodevelopmental outcomes at 2 years of age were evaluated using the Bayley Scales of Infant Development\u2013Third Edition (BSID-III) at corrected age 2 years.P\u2009=\u2009.003) and 5.8  points lower in the language domain (P\u2009=\u2009.03), compared with unexposed infants.A total of 828 extremely preterm infants  born at 19 sites who survived to discharge were included in this analysis, and 312 infants (38%) were exposed to at least 1 corticosteroid of interest during their NICU stay, including 279 exposed to dexamethasone, 137 exposed to prednisolone or methylprednisolone, and 79 exposed to both. Exposed infants, compared with nonexposed infants, had a lower birth weight  and were born earlier . The median (IQR) start day was 29 (20-44) days for dexamethasone and 53 (30-90) days for prednisolone or methylprednisolone. The median (IQR) total days of exposure was 10 (5-15) days for dexamethasone and 13 (6-25) days for prednisolone or methylprednisolone. The median (IQR) cumulative dose of dexamethasone was 1.3 (0.9-2.8) mg/kg. After adjusting for potential confounders, treatment with dexamethasone for longer than 14 days was associated with worse neurodevelopmental outcomes, with mean scores in BSID-III 7.4  points lower in the motor domain (These findings suggest that long duration and higher cumulative dose of dexamethasone were associated with worse neurodevelopmental scores at corrected age 2 years. Potential unmeasured differences in the clinical conditions of exposed vs unexposed infants may contribute to these findings. Improved standardization of treatment and documentation of indications would facilitate replication studies. Multiple small trials and meta-analyses have demonstrated that short courses of low-dose dexamethasone may be useful for earlier weaning and extubation of infants undergoing mechanical ventilation at highest risk of BPD.12 However, the administration of dexamethasone to prevent BPD, especially in the first week of life, has been associated with increased risk for adverse effects, including cognitive, speech, and learning impairments, as well as cerebral palsy (CP).25 Routine dexamethasone therapy in the first week of life is not recommended.28 Currently, most clinicians prescribe low-dose, late-initiated dexamethasone29 of shorter duration than what was previously used30 to maximize benefits and minimize potential risks. Prednisolone and methylprednisolone are synthetic glucocorticoids with similar potency that are used interchangeably in practice to prevent or treat BPD. Their effectiveness has only been evaluated retrospectively.32Bronchopulmonary dysplasia (BPD) is a common complication of prematurity, affecting 20% to 75% of infants born before gestational age (GA) 29 weeks.Given inconclusive evidence regarding the association between dexamethasone and prednisolone or methylprednisolone initiation, dosage, length of exposure, and subsequent outcomes of extremely preterm infants, we have performed an analysis using data from a large contemporary multicenter trial with the following goals: to characterize the use of dexamethasone and prednisolone or methylprednisolone, to identify factors associated with exposure, and to estimate associations between key measures of exposure  and 2-year neurodevelopmental outcomes.NCT01378273) were eligible for this study.33 The PENUT trial was approved by institutional review boards at each site. Parental consent was obtained before or after birth, as permitted by the institutional review board at each site. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.All infants enrolled in the Preterm Erythropoietin Neuroprotection (PENUT) trial  stay. At corrected age 20 to 33 months, infants were evaluated by certified examiners who assessed cognitive, motor, and language development with the Bayley Scales of Infant Development\u2013Third Edition (BSID-III).The population of interest was infants exposed to dexamethasone, prednisolone, or methylprednisolone during their initial NICU course. Exposure to dexamethasone, prednisolone, or methylprednisolone was defined as having at least 1 dose of drug administered at any time during the hospital stay, and no exposure if there were no documented doses administered during that time. The length of exposure was classified by total days of exposure as approximate quartiles of number of days exposed . These quantiles were constructed by determining the quantiles of exposure among the exposed and then rounding them into more clinically relevant quantiles. The association of days of exposure as a continuous variable was also examined for both classes of steroids, as well as total cumulative dose in milligrams per kilogram for dexamethasone. Number of courses and length of each course for both classes of steroid were determined based on number of consecutive days of steroid exposure, with at least 1 day of no exposure determining the start of the next course.P values for 28 comparisons . We aimed to evaluate the association between corticosteroids of interest and neurodevelopmental outcomes measured by BSID-III and CP scores. We used generalized estimating equations (GEE)37 with robust SEs and an independence covariance structure as the statistical model to account for potential correlation of outcomes for same-birth siblings. Specifically, we performed logistic GEE regression to examine differences in infant characteristics between those who were and were not exposed to corticosteroids. We then used linear multivariable GEE analyses using each of the 3 BSID-III scores  as the outcome. We chose to conduct a sequence of outcome regression models that allow characterization of dose associations while accounting for potential confounders. We developed 3 different models to estimate the parallel associations of steroid exposure using quartiles of length of exposure (days) or total cumulative dose; model 1 was adjusted for treatment group (erythropoietin/placebo) and GA at birth in weeks; model 2 was additionally adjusted for potential confounders, ie, being small for gestational age (SGA) and level of respiratory support at 14 days ; model 3 was further adjusted for level of maternal education and in-hospital severe adverse events (SAEs) that are associated with outcomes to improve the accuracy of the estimated association of steroid exposure.We used descriptive statistics to describe the demographic and baseline maternal and infant characteristics and exposure to corticosteroids of interest by study site. Maternal and infant variables were compared in exposed and nonexposed infants individually after adjusting for GA and study treatment group, with Bonferroni correction of P values. Maternal and infant variables were compared in exposed and nonexposed infants individually after adjusting for GA and study treatment group, with Bonferroni correction of P values for 28 comparisons (target P\u2009=\u2009.05/28\u2009=\u2009.0017). All other P\u2009<\u2009.05 were considered statistically significant. All P values were 2-sidedSensitivity analyses included model 3 with further adjustment for clinical site. SAEs included severe BPD , grade 2b to 3 necrotizing enterocolitis, spontaneous intestinal perforation, retinopathy of prematurity requiring intervention, and grade III to IV intracranial hemorrhage at any time during the hospital course. Infants who required any supplemental oxygen at discharge were considered to require respiratory support at discharge. We reported the estimated mean differences in BSID-III scores between groups characterized by amount of exposure, along with their 95% CIs and corresponding When examining exposure to dexamethasone or prednisolone or methylprednisolone as continuous variables by days of exposure or cumulative dose, the models included both any or no exposure as variables, as well as the days and dose of exposure. An example figure depicting the proposed relationship between days of dexamethasone exposure and BSID-III motor score is shown in eFigure 1 in All analyses were conducted using the R statistical package version 3.6.3 . Data were analyzed between February 2021 and January 2022.A total of 828 infants  who survived to discharge were included in this analysis, and 312 infants (37.7%) were exposed to at least 1 corticosteroid of interest (dexamethasone and/or prednisolone or methylprednisolone) . A totalP\u2009<\u2009.001). Similarly, at postmenstrual age 36 weeks, 273 of 312 infants (87.5%) in the exposed group vs 261 of 516 infants (50.6%) in the nonexposed group were diagnosed with severe BPD (P\u2009<\u2009.001). At discharge, 186 of 312 infants (59.6%) in the exposed group and 136 of 516 infants (26.4%) in the nonexposed group required respiratory support (P\u2009<\u2009.001).At age 14 days, more infants who remained intubated received corticosteroids (261 of 312 infants [83.7%]) compared with the nonexposed group (158 of 516 infants [30.6%]) (P\u2009<\u2009.001). Estimated adjusted mean difference in length of stay for infants receiving corticosteroids after adjusting for GA and treatment group was 33  days longer than nonexposed infants.The prevalence of reported SAEs was similar between the exposed and nonexposed groups, except for BPD, which was higher in the exposed group . The mosIn the exposed group, the median (IQR) start day was 29 (20-44) days after birth for dexamethasone and 52 (30-90) days after birth for prednisolone or methylprednisolone. The median (IQR) total days of exposure was 10 (5-15) days for dexamethasone and 13 (6-25) days for prednisolone or methylprednisolone. There was minimal variation based on GA at birth regarding the start day or length of exposure  were exposed by day 7, 31 infants (12.0%) were exposed by day 14, 77 infants (19.8%) were exposed by day 21, and 126 infants (48.8%) were exposed by day 28 after birth. By comparison, of 126 infants exposed to prednisolone or methylprednisolone, 3 infants (2.4%) were exposed by day 7, 8 infants (6.3%) were exposed by day 14, 13 infants (10.3%) were exposed by day 21, 29 infants (23.0%) were exposed by day 28, and 70 infants (55.6%) were exposed by day 56 after birth. The use of corticosteroids varied across the 19 sites, with median (IQR) exposure of 27% (18%-39%) for dexamethasone and 5% (0%-23%) for prednisolone or methylprednisolone .The median (IQR) number of dexamethasone courses per exposed infant was 1 . In 153 infants who received a single course, the median (IQR) duration was 5 (3-11) days . In 105 infants who received more than 1 course, median (IQR) course length was 6 (4-9) days .The median (IQR) number of prednisolone or methylprednisolone courses per infant exposed was 1 . In 76 infants who received a single course, the median (IQR) duration was 8 (5-14) days . In 50 infants who received more than 1 course, median (IQR) course length was 10 (7-19) days .BSID-III assessments were conducted at a median (IQR) age of 24 (22-25) months for infants not exposed to corticosteroids. For infants who were exposed to dexamethasone or prednisolone or methylprednisolone, median (IQR) age at BSID-III assessment was 23 (22-25) months.eFigure 2 in P\u2009=\u2009.003) and language  scores after adjustment for treatment group, GA, SGA, respiratory support at 14 days, in-hospital SAEs, and maternal education (The median (IQR) cumulative dose of dexamethasone exposure was similar among groups at 3 days (1.1 [0.8-1.7] mg/kg), 4 to 7 days (0.8 [0.6-2.0] mg/kg), and 8 to 14 days (1.1 [0.9-1.5] mg/kg) and 3-fold lower than in infants who received dexamethasone for longer than 14 days (3.1 [2.0-5.0] mg/kg). Prolonged exposure among 48 infants with more than 14 days exposure and 2-year outcome data was associated with lower motor . Of 39 infants with CP and dexamethasone exposure, 27 (69.2%) had mild CP and 12 (30.8%) had moderate-severe CP. Of 15 infants with CP and prednisolone or methylprednisolone exposure, 10 (66.7%) had mild CP and 5 (33.3%) had moderate-severe CP.Documentation of CP status was available in 700 infants (84.5%), of whom 85 infants (12.1%) had CP documented. Of 85 infants with CP, 39 (45.9%) had been exposed to dexamethasone, 15 (17.6%) had been exposed to prednisolone or methylprednisolone, and 9 (10.6%) had been exposed to both. Overall, 46 of 490 infants (9.4%) of not exposed to dexamethasone developed CP, compared with 39 of 210 infants (18.6%) with any dexamethasone exposure, 15 of 99 infants (15.2%) with any prednisolone or methylprednisolone exposure, and 9 of 52 infants (17.3%) exposed to both. Exposure to the corticosteroids of interest was not significantly associated with increased odds of CP after adjusting for GA, treatment group, SGA status, respiratory support at 14 days, maternal education, and SAEs .38One third of extremely preterm infants enrolled in our cohort were treated with dexamethasone, and most of them were exposed after the first week of life. The baseline infant characteristics, exposure rate, and timing of exposure are consistent with other recent studies in Europe.42 Although early exposure (age <7 days) has been associated with decreased BPD rates in some studies, it has also been associated with an increased risk of both in-hospital complications as well as neurodevelopmental impairment and CP.22 The associations between later exposure (age >7 days) and neurodevelopmental outcomes are not conclusive, with emerging support for the use of dexamethasone in infants at high risk of developing BPD.9We used timing, total cumulative dose, and duration of treatment to describe dexamethasone exposure and its association with neurodevelopmental outcomes. Prior data from randomized clinical trials evaluating the effect of dexamethasone on neurodevelopment vary, from no effect to severe disability.41Short exposure to dexamethasone in this cohort was not significantly associated with BSID-III scores at corrected age 2 years. Our findings were consistent with 2 other randomized clinical trials evaluating the impact of low dose or short exposure to dexamethasone  that did not find a significant increase in CP or neurodevelopmental impairment compared with placebo.43 in which infants were exposed to corticosteroids for longer periods (up to 75 days) and at higher doses than infants in the PENUT trial, every 1-mg/kg increase in the cumulative dose of dexamethasone was associated with a 40% increased risk of developing disabling CP at every GA.43The incidence of CP in this study was 19% of infants with dexamethasone exposure compared with 9% in infants with no corticosteroid exposure. In a study by Wilson-Costello et al28 In agreement with this recommendation, Ramaswamy et al30 performed a systematic review and network meta-analysis to compare the outcomes and safety of 14 postnatal corticosteroid regimens and concluded that moderately early initiation (8-14 days after birth), medium cumulative dose (2-4 mg/kg), and short duration (<8 days) of systemic dexamethasone might be the most appropriate regimen for reducing the risk of BPD or mortality at postmenstrual age 36 weeks.30 In a commentary on the study by Ramaswamy et al,30 Parikh44 called for more studies evaluating neurodevelopmental impairment outcomes of high-dose dexamethasone regimens before changing clinical practice.While we do not recommend a specific dexamethasone regimen based on the results from our cohort, we found that higher cumulative doses and longer exposures (>14 days) were negatively associated with 2-year neurodevelopmental outcomes. After adjustments for treatment group, GA at birth, SGA status, respiratory support at age 2 weeks, SAEs, and maternal education, BSID-III motor scores showed the biggest difference vs infants with no exposure. The Canadian Pediatric Society suggested in 2020 that clinicians consider a short course of low-dose dexamethasone to prevent or treat BPD (0.15 mg/kg/d to 0.2 mg/kg/d tapered over 7-12 days).45 Our study evaluating the association between the days of exposure to prednisolone or methylprednisolone and BSID-III scores at corrected age 2 years found an association between prolonged (>28 days) exposure and BSID-III motor scores that was not present after additional adjustments for SGA, respiratory support at 14 days, maternal education, and SAEs. We can speculate that an association between prednisolone or methylprednisolone exposure and BSID-III scores was not observed in our cohort owing to the smaller number of infants who received prednisolone or methylprednisolone and the more advanced age and more mature brains at the time of exposure. Further studies designed to evaluate the association between other classes of corticosteroids and neurodevelopment are needed.Although most infants at high risk for developing BPD receive dexamethasone, there is emerging data to support alternative systemic or inhaled corticosteroid therapies that may not carry the same neurodevelopmental sequelae burden.Our study has several limitations. First, the PENUT trial was not designed to primarily evaluate the impact of dexamethasone or prednisolone or methylprednisolone on 2-year neurodevelopmental outcomes. Although we adjusted for known potential confounders, there may still be residual confounding by indication. Infants received the medications based on the attending physician\u2019s clinical judgment, which is reflected in the different clinical characteristics of the groups and the variability among the sites. The indications for use of corticosteroids in each infant were not available. A significant limitation is the lack of data in this data set denoting the exact timing of invasive ventilation and respiratory support weaning strategies, as well as risk for BPD at the time of steroid administration. Additionally, we did not perform an analysis to evaluate the timing of postnatal systemic steroid exposure in association with any morbidity or adverse event. Owing to the relatively small number of infants within each level of prednisolone or methylprednisolone exposure, it is possible that the analysis was underpowered to detect a true association of exposure with outcome. Additionally, our findings do not reflect causal associations and may be due to unmeasured factors associated with exposure to dexamethasone or prednisolone or methylprednisolone and infant neurodevelopmental outcomes.This cohort study found that prolonged dexamethasone treatment was associated with lower BSID-III scores at age 2 years. Each additional day of dexamethasone exposure was associated with significantly lower cognitive and motor scores. There were no linear associations between dexamethasone dose or prednisolone or methylprednisolone exposure duration and BSID-III scores at age 2 years. Prospective studies and longer-term outcomes, including school-age evaluations, are necessary to inform and guide the use of postnatal steroids in this high-risk population."}
+{"text": "This study evaluated the Preparedness for Caregiving Scale (PCS) upon discharge from the hospital. The caregivers reported a mean age of 60.5 years (SD=13.9). The majority of caregivers were female (72%), married (59%), non-Hispanic/Latino (98%) and either white (52%) or African American (48%). Fifty percent were employed outside of the home and averaged 40.7 (SD= 14.4) hours of outside work per week. The average PCS was 24.4 . One-factor structure of the PCS and measurement invariance by race was fully supported. Predicative validity revealed significant association between the PCS and anxiety , p <.001), depression , p <.001), and strain , p <.001). The PCS is a valid and meaningful tool to measure preparedness in African American and white family caregivers of persons with dementia during post- hospitalization transition."}
+{"text": "The diagnosis may not be confidently established based on morphology alone, and immunocytochemistry is mandatory. The choice of the most advantageous immunocytochemical antibodies is critical, as the sample may be scant, and the presence of pigmented histiocytes may be confounding. However, the diagnostic performance of melanocytic markers in this setting is poorly investigated. Moreover, PRAME  recently emerged as a novel marker for the diagnosis of melanoma. The current work aimed to evaluate the sensitivity and specificity of PRAME for the diagnosis of melanoma metastases in cytological samples, compared to other melanocytic markers. (2) Methods: PRAME, S100, Melan-A, HMB45 and SOX10 were tested on cell block sections of 48 cases of melanoma metastases diagnosed from cytological samples, and 20 cases of reactive lymphadenopathy. (3) Results: S100 and SOX10 showed the highest sensitivity (100%), while the sensitivity of PRAME was 85.4%. PRAME, Melan-A, SOX10 and HMB45 showed a specificity of 100%, while the specificity of S100 was lower (85%), as it marked some histiocytes. (4) Conclusion: PRAME immunocytochemistry is highly specific for the diagnosis of melanoma metastasis from a cytological sample, but is less sensitive compared with other melanocytic markers. Cutaneous melanoma (CM) is an aggressive neoplasm with a high rate of metastasis, depending on the stage of the neoplasm and the Breslow thickness . Lymph nThe aim of this study was to investigate the diagnostic performance of PRAME for the diagnosis of CM metastasis in a series of FNAC samples, compared to the other ICC melanocytic markers.All cases with a previous diagnosis of CM, which FNAC had subsequently been performed on, between January 2017 and September 2021, were retrieved from the archives of the Pathology Unit of \u201cVanvitelli\u201d University in Naples. The inclusion criteria were the following: (1) the diagnosis was rendered based on the cytological sample; (2) a cell block (CB) was available; (3) the lesion was subsequently excised and the diagnosis was confirmed histologically. Sixty-eight cases met the inclusion criteria, including 48 cases of CM metastases and 20 cases of reactive lymphadenopathies.FNAC was performed in all cases by a cytopathologist by ultrasound (US) or computer tomography (CT) guidance. Air-dried and alcohol-fixed smears were prepared in all cases and stained by Diff-Quick and Papanicolaou methods, respectively. A dedicated pass was executed in all cases after rapid on-site evaluation and was suspended in 5 mL formalin for the realization of the CB. Formalin-fixed and paraffin-embedded CB sections were used for the ICC evaluations. A CB section was stained with haematoxylin and eosin for adequacy and morphological evaluation of the cytological material.Immunocytochemistry was performed on consecutive CB sections. It was performed on a Ventana platform (Ventana BenchMark ULTRA system) according to the manufacturer\u2019s instructions, using the following antibodies: Melan-A , HMB45 , S100 , SOX10  and PRAME . Immunocytochemistry was interpreted according to the scoring system previously described, considering both the percentage of neoplastic stained cells (score 0\u20133) and the staining intensity (score 0\u20133) [p < 0.05. The statistical analysis was carried out using IBM SPSS statistics V.20.The sensitivity was calculated for each ICC antibody. Furthermore, a two-sided Wilcoxon signed-rank test was used for the comparison of the diagnostic performances of the two most sensitive antibodies (SOX10 and S100). The test compared the final PRAME ICC scores with the final ICC scores of SOX10 and S100 for the 48 cases of CM metastases. The test was considered statistically significant for The present study was retrospectively conducted on archival biological samples. The cytological diagnoses and their histological confirmations had already been rendered in all cases. At the time of the FNAC procedure, written consent, including consent to use the diagnostic data for scientific purposes, had been obtained from each patient. Approval by the institutional ethics board was attained.Our series included 48 cases of CM metastases diagnosed from cytological samples. The diagnosis was subsequently confirmed histologically in all cases. The metastases were in the lymph nodes in 44 (91.6%) cases, in subcutaneous tissues in 2 (4.2%) cases and in the lungs in 2 (4.2%) cases.PRAME was positive in 41 (85.4%) cases and negative in the remaining 7 (14.6%) cases. Strong positivity was observed in 38 out of 41 (92.7%) positive cases, and weak positivity was observed in the remaining 3 out of 41 (7.3%) positive cases. The sensitivity of PRAME ICC was 85.4%.S100 was positive in all 48 cases (100%). Strong positivity was observed in 43 out of 48 (89.6%) cases, moderate positivity was observed in 3 out of 48 (6.2%) cases, and weak positivity was observed in the remaining 2 (4.2%) cases. The sensitivity of S100 ICC was 100%.SOX10 was positive in all 48 cases (100%). Forty-six out of 48 (96%) cases showed strong positivity, 1 out of 48 (2%) cases showed moderate positivity, and the remaining 1 (2%) case showed weak positivity. The sensitivity of SOX10 was 100%.Melan-A was positive in 47 out of 48 (97.9%) cases. One out of 48 (2%) cases was negative. Strong positivity was observed in 23 out of 47 (48.9%) positive cases, moderate positivity in 18 out of 47 (38.3%) cases, and weak positivity in 6 (12.8%) cases. The sensitivity of Melan-A was 97.9%.HMB45 was positive in 43 out of 48 (89.6%) cases. Five out of 48 (10.4%) cases were negative. Twenty-seven out of 43 (62.8%) positive cases showed strong positivity, 11 out of 43 (25.6%) positive cases showed moderate positivity, and the remaining 5 (11.6%) positive cases showed weak positivity. The sensitivity of HMB45 was 89.6%.p = 0.0004) and SOX10 (p = 0.00001).The statistical analysis demonstrated a significantly lower diagnostic performance of PRAME compared with S100 , while S100 marked histiocytes in 3 out of 20 (15%) cases, making the distinction between histiocytes and melanocytes difficult. The specificity of PRAME, SOX10, Melan-A and HMB45 was 100%, while the specificity of S100 was 85%.The results are summarized in Fine-needle aspiration cytology is widely applied for the diagnosis of CM metastases, mainly in patients with a known history of CM. However, the diagnosis of CM from cytological samples may be challenging, as CM may present heterogeneous morphological findings . MoreoveICC is mandatory in the evaluation of cytological samples for the diagnosis of CM metastasis. PRAME showed low sensitivity when compared with other melanocytic markers, but showed high specificity. SOX10 and S100 are confirmed as the most sensitive markers in this specific setting, but S100 was less specific. In conclusion, SOX10 is the most useful ICC marker for the diagnosis of CM metastasis from cytological samples. PRAME is not a suitable ICC marker in this setting, although some data suggest that PRAME may play an important role in the diagnosis of CM in cutaneous samples."}
+{"text": "Performance characteristics were calculated for three screening models: primary HRHPV with p16/Ki67 triage, primary cytology with reflex HPV and primary cytology alone. Primary HRHPV with p16/Ki67 triage was significantly more sensitive in high-grade squamous intraepithelial lesion quantified with cervical intraepithelial neoplasia grade 2 or worse [HSIL(CIN2+)] detection than cytology with reflex HRHPV and cytology alone (83.3% vs. 70.8%/45.8%) and had significantly higher diagnostic predictive values . The number of colposcopies per HSIL(CIN2+) detection indices was 3.4, 4.7 and 4.4, respectively. Primary HPV testing in women <30 years with p16/Ki67 triage of HPV-positive cases might be an effective cervical cancer screening strategy for HSIL(CIN2+) detection with superior diagnostic performance when compared with primary cytology-based models. Women <25 years might also benefit from an introduction to a more sensitive screening approach.Recently, cervical cancer rates elevation has been noted in women aged 20\u201339 years in regions with a very high human development index (HDI). The onset of cancer elevation rates is observed in the age range of 25\u201329 years, which should necessitate effective precancer screening in younger age groups, including those <25 years. From 30.066 liquid-based screening tests results ( The incidence and mortality of cervical cancer vary globally depending on the geographic region and the level of the HDI . In counHuman papillomavirus DNA testing is the globally recommended primary screening strategy for cervical cancer prevention for women 25\u201365 years old in all resource settings ,8. The rDual immunocytochemical staining in cervical cytology specimens with the simultaneous use of anti-proliferative p16 and Ki67 proliferative proteins is a morphologic-independent cell cycle dysregulation biomarker. A diagnostic value profile of p16/Ki67 testing is characterized by high sensitivity and high specificity for histologic high-grade intraepithelial lesions with evidenced effectiveness in HPV-positive women and/or with abnormal cytology results ,18,19,20Data on the use of p16/Ki67 dual-stained cytology in women under 25 years are limited, especially when used as a secondary test in HPV-positive young women undergoing primary HPV screening. Due to increasing cervical cancer rates in women aged 25\u201329 years, we investigated in our study whether primary HPV screening with triage HPV-positive cases with the p16/Ki67 biomarker can be an alternative screening strategy to cytology-based screening in young women under age 30 years. For this purpose, we conducted a retrospective analysis of cytologic\u2013virologic\u2013immunocytochemical reporting rates with histologic correlation at this age range and an evaluation of the diagnostic value of three screening strategies for the HSIL (CIN2+) detection.We conducted a retrospective analysis of cervical cancer liquid-based screening (LBS) tests results, including liquid-based cytology (LBC), 14 types of high-risk human papillomavirus testing (HRHPV14) and p16/Ki67 dual-stained cytology, undertaken at a private-based opportunistic cervical cancer screening at one of the largest Lower-Silesian private outpatient gynecological clinics  from August 2015 to July 2020. There were three cervical cancer screening modalities used in the center over the period considered: cytology with reflex HRHPV14, co-testing (HRHPV14 simultaneously performed with LBC) and co-testing plus (co-testing simultaneously performed with p16/Ki67). The baseline analysis included a total of 30,066 screening tests results, including 20,605 LBC, 8331 HRHPV14 and 1130 p16/Ki67 tests sampled in women aged 15 to 92; mean age of 40.9. From the baseline group, all screening test results in women under age 30 were selected. Following the selection, 3849 LBC results, 1321 HRHPV14 and 316 p16/Ki67 tests results were obtained. The final study group consisted of 121 patients <30 years with available LBC, HRHPV14 and p16/Ki67 tests results who had colposcopy with biopsy and cytologic\u2013virologic\u2013immunocytochemical\u2013histologic correlations could be assessed. Including all the LBS and histology results, in the final group, a retrospective analysis was conducted, and the diagnostic value was evaluated together with assessment numbers of colposcopies needed per detection of HSIL (CIN2+). This analysis comprised 3 screening models (the first screening round with unknown screening history), as follows: (1) model No 1 (M1)\u2014primary HPV with reflex p16/Ki67 for all HPV-positive results; (2) model No 2 (M2)\u2014primary cytology with reflex HRHPV, based on the risk-based management of ASCCP 2019 using a mobile application; (3) model No 3 (M3)\u2014primary cytology alone without any reflex testing, based on the risk-based management of ASCCP 2019 using a mobile application. All analyzed data came from the center\u2019s registry.HPV detection and genotyping were performed by the qualitative in vitro PCR Abbott RealTime High Risk HPV as recommended by the manufacturer, according to a report from the laboratory performing the test. This assay phenotypes 14 types of high-risk HPV DNA, including as follows  and specifically genotypes HPV 16 and HPV 18. If type 16 and/or 18 HPV is detected, the result was categorized as HPV16 or 18 or both positive. If one or more of the other 12 HRHPV14 types were detected, the result was categorized as N16/N18 positive.Liquid-based SurePath slides were obtained using the automatic laboratory PrepStain Slide processor  by a laboratory external to the center, and it was ensured that a laboratory procedure strictly adhered to the manufacturer\u2019s protocol. All cytology samples were reported by a gynecological cytopathologist and classified according to the Bethesda 2014 guidelines. A cytopathologist was aware of the HRHPV14 status of the cervical samples. All residual cervical samples were stored for 6 months in the laboratory under the conditions specified by the manufacturer. This strategy enabled to perform additional tests also ordered later (including the p16/Ki67 triage) and with the patient\u2019s comfort, who did not have to be called for another gynecological visit, and all cervical cancer diagnostics was performed from one cytological sample collection.p16/Ki67 testing was performed in HRHPV14-positive cases and in women who underwent co-testing plus. Dual immunocytochemical staining of cervical samples was carried out using p16 and Ki67 proteins in CINtec PLUS detection kit  processed in an automatic BenchMark XT laboratory system , according to the manufacturer\u2019s protocol, and with one control specimen present in each run. The p16/Ki67 testing was performed from the same LBC sample with residual material stored in a laboratory in the original SurePath vials . An immuno-expression status was assessed by a gynecological cytopathologist specially trained and certified in p16/Ki67 review and classified as positive, negative, or unsatisfactory. A positive result of the p16/Ki67 test was the presence of at least one cell in the preparation meeting the following evaluation criteria: simultaneous red nuclear stain for Ki67 and brown cytoplasmatic stain for p16 in the same epithelial cell. For a morphological evaluation of the cell groups, the positive diagnosis was determined by a strong diffuse p16 stain within the group and the presence of at least one cell with a Ki67 stain in the nucleus and a p16 stain in the cytoplasm at the edge of the assessed group and/or sheet of cells. The negative p16/Ki67 test result was defined when no staining or single staining of p16 or Ki67 was present in the epithelial cell. An unsatisfactory p16/Ki67 test result was determined by features included in the manufacturer\u2019s kit and/or by cellularity criteria, which are consistent with the criteria for a liquid-based cytological preparation.Women with positive p16/Ki67 test result, ASC-US or LSIL HRHP14 positive, with cytologic ASC-H or HSIL regardless of HRHPV14 status, or with ASC-H or HSIL without HRHPV14  were referred for a colposcopy. Indications for the colposcopy were according to Polish guidelines with the extension of the 2012 ASCCP guidelines and 2015 ASCCP interim guidelines. The colposcopy protocol included endocervical sampling as a minimum sampling approach and additional direct or random biopsies if required. Histologic diagnoses of cervical biopsies and endocervical specimens (obtained using curettage with brushing) were reviewed by a gynecological pathologist, according to the LAST 2012/WHO 2014 terminology ,23. Colpp < 0.05 was considered significant.Statistical analysis was conducted using licensed PQStat Software. A diagnostic value of tests, measured with sensitivity, specificity, positive (PPV) and negative (NPV) predictive values, and positive (PLR) and negative (NLR) likelihood ratios, was calculated according to standard definitions. Differences in diagnostic value between the analyzed screening models were evaluated, and the colposcopy number needed for each model was also compared. A In the analyzed period, from August 2015 to July 2020, a total of 5.486 LBS tests were performed in patients aged 15\u201329 years, with a mean age of 25.3 years. A total of 3.849 LBC results were analyzed, with 1.321 HRHPV14 and 316 p16/Ki67 tests results. The following reporting rates were obtained for cytological diagnoses compared to the group of women over 30 years of age, NILM, ASC-US, LSIL and ASC-H+ (% <30 years of age/% \u226530 years of age) 91.3/94.7, 3.9/3.2, 4.2/1.5 and 0.6/0.57, respectively. The biggest difference in the baseline group <30 years of age was for diagnosis of LSIL, which in women <30 years of age was almost three times more frequent than in the 30+ group. In the final study group of 121 women, detected HSIL (CIN2+) cases were 19.83% of all histologic diagnoses. No screening in this group of women would lead to remain these HSIL (CIN2+) lesions undetected, with all the potential consequences. The highest level of the diagnostic value, including sensitivity, PPV, NPV, PLR and NLR, was in screening model 1 of 83.3, 29.4, 91.7, 1.60 and 0.35, respectively. Only in specificity, the highest value of 61.9% was in screening model 3, but it should be remembered that this would be at the expense of not detecting 13 cases of HSIL (CIN2+). In M3, the lowest absolute number of colposcopies needed to perform would also be obtained, but the detection index (number of colposcopies needed per HSIL (CIN2+) detection) is significantly higher in M3 than in M1. The results of the diagnostic value for the analyzed models, a number of HSIL (CIN2+) missing cases and a number of colposcopies performed in each model along with detection of HSIL (CIN2+) vs. colposcopies needed are presented in In this study, we compared the diagnostic value of primary HPV screening with p16/Ki67 triage and cytology-based screening strategies  in women under 30 years of age. The sensitivity of screening model 1 (primary HPV with p16/Ki67 triage) was significantly higher than the sensitivity of cytology with reflex HPV and cytology alone screening models for detection histologic HSIL (CIN2+) in this age range . Moreover, the diagnostic predictive values were significantly higher for primary HPV with p16/Ki67 triage screening model (29.4% for PPV) compared to cytology with reflex HPV and cytology alone . The negative predictive value of primary HPV with p16/Ki67 triage for HPV-positive cases was very high (91.7% at CIN2+ threshold), which suggests the high safety of HPV-positive and p16/Ki67 negative women. The specificity for the detection of HSIL (CIN2+) of primary HPV triaging with p16/Ki67 was statistically significantly higher compared to cytology alone (47.8% vs. 35.1%) but was lower than for cytological screening with reflex HPV testing (61.9%). Our results also indicate a higher level of true screening test results in primary HPV with p16/Ki67 triage compared to cytology with reflex HPV and cytology alone screening models, due to the highest PLR  and lowest NLR (0.35 vs. 0.83 and 0.88) in this screening strategy.Cytology is well known and easily available triaging option for HPV-positive women; however, it is suboptimal due to the lower sensitivity. This requires the use of a secondary screening tool that is more focused on the detection of cervical cancer precursors in HPV-positive patients. This approach was represented in our study by screening model no. 1, in which a highly specific and highly sensitive p16/Ki67 biomarker was incorporated as a triage test in women who had undergone primary HPV screening and had positive HPV status. Our study results are essentially consistent with the data from other reports on the evaluation of the diagnostic performance of p16/Ki67 dual-stained cytology for triaging HPV-positive cases ,20,21,24Similarities with several studies in the sensitivity levels for detection HSIL (CIN2+) obtained in our screening model 1 were noted, including the study of the New Technologies for Cervical Cancer Screening group  (81.8%),High or very high levels of negative predictive value for detecting cervical cancer precursors, regardless of the threshold taken (HSIL(CIN2+) or HSIL(CIN3+)), in most other studies and in our observed at a level higher than 90% or higher than 95% ,21,25, sAs part of our retrospective assessment of diagnostic performance in analyzed screening models was the determination of the HSIL (CIN2+) detection versus colposcopies need index. In screening model 3 with primary cytology alone, the lowest absolute number of colposcopies needed to perform for HSIL (CIN2+) detection was identified. However, the histologic HSIL detection index (CIN2+) per colposcopy rate in this model was higher than in the screening model based on primary HPV testing with p16/Ki67 triaging and based on cytology with reflex HPV. The best rate in the number of colposcopies needed to perform for detection of histologic HSIL was observed in screening model 1 with biomarker triage used. In both analyzed cytology-based screening models, 7 (in M2) and 13 (in M3) cases of HSIL (CIN2+) HRHPV14-positive and p16/Ki67-positive would not be detected.We believe that promoting an effective cervical cancer screening with primary HPV in younger age groups of women, including women below 25, may be associated with building appropriate habits, which may result in a positive change in recently recorded increases in cancers rate among women 25\u201329 years. This may be particularly important in countries with very high HDI and with still too low HPV vaccination coverage and may be a factor making it independent of changes in sexual behavior . FurtherStrengths of this study: (1) One of the few studies evaluating the diagnostic value of p16/Ki67 triage in HPV-positive women <30 years who underwent primary HPV screening, including women below 25 years. (2) A thorough cervical disease ascertainment due to the extended colposcopic protocol used. (3) Our study gives an insight into screening tests results obtained in a private-based opportunistic cervical cancer screening. (4) All diagnostic tests were performed in the same specimen. (5) Immediate histologic correlation results due to the interval between colposcopy and abnormal screening test results not exceeding 3 months. (6) All p16/Ki67 tests were evaluated by a qualified gynecologic cytopathologist. Limitations of the study: (1) This study shows a post-hoc analysis. (2) We currently do not have a large enough group of patients to evaluate a diagnostic value at the CIN3+ threshold in the presented screening approaches. (3) Not all patients with indications for colposcopy decided to do it at the center. Due to different colposcopic protocols used, different histologic terminology and/or lack of p16 stain in cervical histologic specimens, the results of colposcopic biopsies performed outside the center were not included in the study.In conclusion, our study showed that in women under 30 years, cervical cancer screening model based on primary HPV testing with p16/Ki67 dual-staining triage of HPV-positive women can be an effective screening approach in detecting cervical precancers and provide superior diagnostic value when compared with primary cytology with reflex HPV or primary cytology alone models. This investigation also demonstrated that young women below 25 years screened by primary HPV and triage with p16/Ki67 histologic HSIL biomarker might benefit from introducing this more sensitive screening algorithm, especially in the light of new data on the cervical cancer rates elevation in younger groups of women in countries with very high HDI."}
+{"text": "The WHO identified the three most common reasons for worldwide vaccine hesitancy to be safety concerns, lack of knowledge and awareness, and religion and cultural issues. There is limited information on this topic among Arab Americans, a rapidly growing demographic in the US. We sought to determine the reasons for deferral of the coronavirus disease 2019 (COVID-19) vaccine amongst Arab American health professionals living in the US.This was a cross-sectional study utilizing an anonymous online survey. The survey was distributed via e-mail to National Arab American Medical Association members and Arab-American Center for Economic and Social Services healthcare employees. Respondents were considered vaccine hesitant if they selected responses other than a willingness to receive the COVID-19 vaccine.A total of 4,000 surveys were sent via e-mail from December 28 2020 to January 31 2021. The highest group of respondents were between the ages of 18-29 years and physicians constituted 48% of the respondents. Among 515 respondents, 41.9% (n=216) would receive the vaccine within one month of it becoming available to them, and 30.2% (n=156) had already received a vaccine. Among those who would defer the vaccine, 9.3% (n=48) would receive it within 1-3 months, 5.6% (n=29) within 3-6 months and 6.6% (n=34) after over 6 months or longer. 6.2% (n=32) would not receive the vaccine. The three most commonly reported reasons for deferral of vaccine among 75 vaccine hesitant respondents were: \u201cI am worried about the side effects\u201d (65.3%), \u201cI am worried the vaccine moved through clinical trials too fast (54.7%), and \u201cThere is no information about long term side effects of the vaccine\u201d (52%). Data indicate that about a quarter of respondents also expressed distrust of the government and the pharmaceutical industry. The results are summarized in table 1.Reasons cited by this sample of Arab Americans for deferring the COVID-19 vaccine mirror more general concerns about vaccine side effects and need for information. Concerns about clinical trial procedures and distrust have become more prevalent with COVID-19. This data can help inform COVID-19 vaccine advocacy efforts among health care providers, and thus could have substantial impact on vaccine attitudes of the general population.Marcus Zervos, MD, contrafect (Advisor or Review Panel member)janssen (Grant/Research Support)merck (Grant/Research Support)moderna (Grant/Research Support)pfizer (Grant/Research Support)serono (Grant/Research Support)"}
+{"text": "Studies among health care workers from different part of world during the coronavirus disease 19 pandemic have reported substantial impact on their physical, mental and emotional wellbeing. This study measured the impact of coronavirus disease 2019 on the mental health of Nepali healthcare workers in different parts of the world during the pandemic.This cross-sectional survey was carried out from December 25, 2020 to Jan 25, 2021. Ethical approval was taken from the Institutional Review Committee (reference number: 372). Online questionnaire including demographic profiles and Depression, Anxiety, and Stress Scales-21 instrument were sent to Nepali healthcare workers around the world through social media apps using convenience sampling. Data were entered into Microsoft Excel for Mac version 16.49 and analysed.Among 208 who participated in the study, 62 (30%) participants were positive for anxiety, 47 (22.5%) for depression and 25 (12%) for stress. Higher prevalence of depression 18 (30%) and stress 10 (17%) was found in nurses compared to paramedics, among whom depression was seen in 5 (20%) and stress in 4 (16%). Among doctors, depression was found in 24 (19%) and stress in 11 (9%).This study demonstrated that a high proportion of healthcare workers were suffering from depression, anxiety and stress. Our findings are similar to the data from other national and international studies. Coronavirus disease 2019 (COVID-19) pandemic has placed enormous strain on physical and mental health of Healthcare Workers (HCWs). Increased workhour, the risk of infection to self and family members, limited availability of Personal Protective Equipment (PPE), death of fellow health-workers etc. are the stressors affecting the HCWs.1 A study conducted during SARS pandemic demonstrated 18-57% of physician with emotional distress.2 A study from China during COVID-19 pandemic showed 39.1% of HCWs had psychological distress, especially among those working in Wuhan.3Studies done during the pandemic of severe acute respiratory syndrome (SARS) and Ebola have reported significantly high incidence of psychological distress among healthcare workers leading to emergence of PTSD, anxiety, depression and burnout.The aim of this study was to find out the prevalence of depression, anxiety, and stress among Nepali healthcare workers in different parts of the world.This cross-sectional survey was conducted from Dec 25, 2020 to Jan 25, 2021. Ethical approval was taken from the Institutional Review Committee of the Nepalese Army Institute of Health Sciences (Reference no. 372). The study was done among HCWs including doctors, nurses and paramedics . The inclusion criteria consisted of all Nepali healthcare workers, \u226518 years old who gave informed consent. The exclusion criteria were those who were unable to use electronic device. Convenience sampling was done and the sample size calculated as,Where,n = minimum required sample sizeZ = 1.96 at 95% Confidence Intervalp = prevalence taken as 50% for maximum sample sizeq = 1-pe = margin of error, 7%4 instrument were included in the questionnaire.The calculated sample size was 194 but 208 responses were included in the study. An online questionnaire was sent to health care workers currently working in Nepal and also to those originally from Nepal but working in different countries of the world. Google form was used to create the online questionnaire and messaging apps like Viber, Facebook messenger, WhatsApp and also social media like Facebook were used to disseminate the questionnaire. Demographic characteristics, medical history, validated Depression, Anxiety and Stress scales (DASS-21)The collected data were entered and analyzed using Microsoft Excel Sheet. The prevalence of Depression, Anxiety and Stress were calculated and binary data were expressed as frequency and percentage.Out of 208 HCWs who participated in the study, 94 (45.2%) have a private practice, 55 (26.7%) have their practice in government hospitals, 50 (23.8%) in academic settings and 9 (4.3%) in other nongovernment institutes. Our study showed that 170 (81.9%) of HCWs that participated in the study have Urban practice while 38 (18.1%) have Rural practice. The participants were between 18 and 51 years , Table 1Sixty-two (30%) participants screened positive for anxiety, 47 (22.5%) for depression and 25 (12%) for stress. The prevalence of anxiety, depression and stress was higher among female Nepalese compared to males; 41 (42%), 30 (31%), and 17 (17%) respectively .Among the three groups of healthcare workers, 28 (47%) nurses, seven (28%) paramedics and 27 (22%) doctors screened positive for anxiety .Depression was noted to be higher 18 (30%) in nurses followed by paramedics in 5 (20%) and Doctors 24 (19%). Stress was also higher among the Nurses 10 (17%) compared to paramedics 4 (16%) and doctors 11 (9%) .The stress was related to lack of personal protective equipment (PPE) in 159 (76.44%) participants administrative load in 118 (56.73%) participants, taking care of critical patients in 113 (54.32%) participants and lack of hospital resources in 140 (67.3%) participants. The financial stressors in HCWs were also noted. Pay cut and decreased income due to COVID-19 was noted in 102 (49%), job loss in 62 (30%) and stock market loss in 96 (46.15%). The majority 107 (51.2%) of HCW's who responded were single. Married respondents were 95 (45.9%) and rests 6 (2.9%) were divorced, separated or widowed.5 Our study showed a significantly greater male HCWs participation. Out of 208 respondents, 110 (52.8%) were male and 98 (47.1%) were female.Our study showed participation of 208 Healthcare Workers among 300 of those who were invited, roughly equating to 69%, which signifies adequate participation when compared to other studies. Similar study done in the Middle East showed a response rate of 71.9%, which also signifies that, our study participation represented a significant response rate.6 Based on assessment by DASS-21 used in our study, 134 (64.5 %) of the participants suffered either from depression 47 (22.5%), anxiety 63 (30%) or stress related symptoms 24 (12%). This demonstrates that our study result is in accordance with the similar study done in the past in Toronto.A study in 2003 in Toronto, during SARS outbreak, showed that two-thirds of the teaching hospital staff surveyed had increased levels of concerns for personal and family health, and almost one-third of a subset of respondents were emotionally distressed.7 Similar to this, our study demonstrated that 63 (30%) participants screened positive for anxiety, 47 (22.5%) for depression and 24 (12%) for stress.In a meta-analysis conducted with studies from December 2019 to May 2020, most studies reported a higher prevalence of anxiety (30% to 70%) and depressive symptoms (20% to 40%). In those studies, insomnia, burnout, emotional exhaustion or somatic symptoms were also reported.8 Our study had a similar association but lower prevalence of depression, anxiety and stress compared to the Hubei, which was the epicenter of the disease. This may be because of the lesser number of cases and less severe COVID-19 cases taken care by the study respondents in our study.In a study conducted in China (Hubei province), depression (46.9%), anxiety (41.1%), insomnia (32%), and stress (69.1%) were demonstrated among registered nurses and physicians. Moreover, frontline health care providers had clinically significant levels of depression, anxiety, insomnia, and stress compared to the non-frontline health care providers.9 Similarly, an observational study in China of 180 health care workers providing direct care for patients with COVID-19 found considerable levels of anxiety and stress that profoundly affected their sleep quality and self-efficacy.10 Our study did not compare the difference in the emotional well-being among frontline health care workers versus those who were not directly involved in the care of COVID-19 patients. However, 64.5% of the respondents have reported minor to major level of emotional distress as aforementioned, which is noteworthy.Another survey of 1257 nurses and physicians caring for patients with COVID-19 in China found that healthcare providers (41.5% of respondents) had significantly more depression, anxiety, insomnia and distress than providers who did not care directly for the patients.In this study, 159 (76.44 %) reported significant stress secondary to lack of PPE and 140 (67.3 %) reported stress secondary to inadequate hospital resources. These results reflect the need to provide adequate safety and precautionary measures to lessen the probability of the emotional stress among HCWs and prioritize adequate resources including professional support for the well-being of HCWs during pandemic. The pandemic has far reaching effects in the life of HCW's. The psychological well-being is interconnected to the economic effects like pay cut and job loss. Likewise, undue pressure from hospital administration to work without appropriate PPE's and also the severity of the disease they deal with may have acute and chronic mental effects.Our study had certain limitations. It did not compare difference in emotional stress among frontline healthcare workers who were directly involved in the care of COVID-19 patients to those who were not. The study also did not look into the long-term effects on the mental health of HCW's like post-traumatic stress disorder. Similarly, our study did not evaluate the difference of emotional stress among HCWs of different ethnic groups, urban and rural practice and those practicing in Nepal and abroad.Our study demonstrated that a high proportion of healthcare workers were in psychological distress during the COVID-19 outbreak. Proper and effective intervention at a personal and institutional level to mitigate the adverse psychological and emotional effect on HCWs due to COVID-19 is essential to support them from stress, anxiety, depression and burnout. Healthcare workers are the pillars of health delivery of every country; thus, their emotional wellbeing is crucial in delivering adequate health care during the time of pandemic. The early recognition and intervention of psychological stress among HCWs along with the prevention of such stress by adequately addressing perceived factors including availability of PPE and adequate hospital resources are the key factors for successfully handling the pandemic while mitigating the adverse mental effects of the health care workers."}
+{"text": "Superficial veins in cubital fossa vary frequently in their anatomical pattern. The knowledge of variation of the cubital venous pattern is very essential for medical professionals for venous access during different medical procedures. This study aims to find the prevalence of Type A cubital venous pattern among students of a dental college.This descriptive cross-sectional study was conducted among 133 dental students of age 18 to 25 years in the department of anatomy of a dental college from November 2020 to February 2021. This study was conducted after obtaining ethical clearance from the Institutional Review Committee. Convenience sampling used and data was analyzed using Statistical Package for Social Sciences version 20. Point estimate at 95% Confidence Interval was calculated along with frequency and proportion for binary data.Out of 133 dental students, Type A cubital venous pattern was found in 192 arms (72.18%) . Type A cubital venous pattern was seen in 116 (43.61%) left arms and 76 (28.57%) right arms of students. This pattern was observed in 139 (52.26%) females and 53 (19.92%) male arms respectively.This study showed higher Type A cubital venous pattern among dental students than other international studies. Main superficial veins in cubital fossa are cephalic, basilic and median veins. The cephalic vein takes its origin from the lateral aspect of the dorsal venous network of the hand and ends in the axillary vein. The basilic vein starts from the medial end of the dorsal venous network and forms an axillary vein. The medial cubital vein connects cephalic vein to basilic vein.2These veins are commonly used for blood sampling, transfusions, and intravenous injections under emergency conditions. These veins are subjected to variation in their anatomic pattern. According to Del Sol, et al. cubital venous pattern is classified as Type A to Type F.This study aims to find the prevalence of Type A pattern of superficial veins in cubital fossa among dental students. Knowledge of the anatomic variation of these veins will be helpful for health professionals for easy access.This was a descriptive cross-sectional study conducted on 133 students of 18-25 years from November 2020 to February 2021 in the Department of Anatomy, Kantipur Dental College Basundhara, Kathmandu. Ethical approval (reference number-36/020) was taken from Institutional Review Committee of Kantipur Dental College. Students with prominent veins and without any vascular diseases were included in the study.Students with thick subcutaneous tissue and cut and wound in cubital region were excluded. Convenience sampling was done and sample size (n) was calculated as,Where,n = sample sizeZ = 1.96 at 95% Confidence Interval3p = prevalence of Type A venous pattern from the previous study, 33%q = (1-p)e = margin of error, 8%Therefore the minimum required sample size was 133.Type A cubital venous pattern resembles alphabet M. This pattern includes its subdivisions asType A1 in which median antebrachial vein divides into the median cephalic and median basilic veins, which join the cephalic and basilic vein respectively and Type A2 in which the median cephalic vein does not join with the cephalic vein. Venous patterns were recorded on both right and left arm along with name, sex and age of the student on a proforma. Type A venous pattern and its subdivisions Type A1 and Type A2 obtained were carefully studied and analyzed using Statistical Package for Social Sciences version 20. Point estimate at 95% Confidence Interval was also calculated.Out of 133 dental students Type A cubital venous pattern was found in 192 arms (72.18%) (64.56-79.79 at 95% CI). Among 133 students, 30 (22.55%) were male students and 103 (77.44%) were female students. The age range of the students was 18-25 years.Among 103 (77.44%) females Type A pattern was seen in 139 (52.26%) arms, Type A1 pattern in 65 (24.44%) arms and Type A2 in 2 (0.75%). Among 30 (22.55%) males, Type A pattern was seen in 53 (19.92%) arms, Type A1 in 6 (2.25%) arms and Type A2 in 1 (0.37%) arm of students .Type A cubital venous pattern was 116 (43.61%) in the left arm and 76 (28.57%) in the right arm of students. Type A1 pattern was observed in 49 (18.42%) left arms and 22 (8.27%) right arms of students. The distribution of the Type A2 pattern was 2 (0.75%) and 1 (0.37%) in right and left arms respectively .4 The study of variation of cubital venous pattern is essential to assist medical and healthcare professionals to perform safer veni puncture. It helps to make aware of uncommon pattern of cubital veins which can avoid damage to neighbouring cutaneous nerves and arteries. Lack of knowledge can cause multiple punctures, subcutaneous hemorrhage and bruising.5Venous puncture is the commonly done procedure by healthcare professionals in cubital region where superficial veins are observed to be arranged in various pattern.6 Our study showed the higher incidence of Type A venous pattern in both males (19.92%) and females (52.26%) than the study carried out on the students of University of Jordan in which distribution of Type A pattern was 18.2% in males and 16.6% in females.7 The percentage of Type A pattern of our study in right (28.57%) arm was higher and left (43.61%) arm was lower than the percentage of the pattern in right (38.0%) and left (40.0%) arms of Chinese volunteers in a study carried out in Hospital Kuala Lumpur.8 Our study showed the higher incidence of Type A pattern than the study carried by Nicola et al in Department of Anatomy, Faculty of Medicine in Novi Sad, Serbia in which 34% arms of Caucasians with 53 right arms and 62 left arms showed the most common cubital pattern as Type A.9In our study, prevalence of Type A cubital venous patttern was 72.18% with 43.61% in left arm and 28.57% in right arm of students. Female students showed the higher incidence (52.26%) of Type A pattern than males (19.92%). The prevalence of Type A venous pattern of our study was slightly higher than the study conducted by Yammine Eric in which prevalence was 25%.10 Our study was also of medical and paramedical stream of Rama Medical college, Mandhana, Kanpur in which incidence of Type A pattern was only 33.58%. The prevalence of Type A1 (26.69%) and Type A2 (1.12%) pattern of our study was slightly lower than the prevalence of Type A1 (29.54%) and Type A2 (4.04%) of this study.11 Our study showed slightly higher prevalence (72.18%) ofthis pattern than the study conducted on 536 Indian subjects which presented Type A pattern with incidence of 67.5%.12 This study was not similar with the study conducted in 800 upper limbs (200 men and 200 women) of a population in Bucaramanga, Colombiaas in which the distribution of Type A pattern was only 4%.13 This study was in contrast with the study conducted on 300 Chileans of Mapuche ethnic group of both sexes (30 men and 120 women) in which Type A pattern existed with the occurence of only 1%.14In a study conducted on 170 males and 96 females selected from among the staff and students of the University Sains Malaysia's School of Medical Sciences in Kelantan, Malaysia revealed the distribution of Type A cubital patttern as 30.3%. Our study showed higher incidence of Type A pattern than their study. Our study also showed Type A pattern more frequent in females (52.26%) than in males (19.92%) which was in contrast with this study in which 18.8% Malays males and 11.5% Malays females showed this pattern.The limitations of our study includes less number of malesin comparison to females. Larger sample with equal number of male and female students should be in further studies. Newer studies could be the cadaveric study for clear observation of the veins. Radiological techniques such as ultrasound could be used for clear visualization of these veins. It would be better if other parameters like length and diameter of veins could be measured.This study showed higher Type A cubital venous pattern among dental students. Knowledge of uncommon patterns of cubital venous patterns is very helpful for medical and paramedical health personnel to prevent injury to underlying structures and for correct intervention of these veins especially during emergency conditions."}
+{"text": "To determine the association between COVID-19 infection and peripancreatic changes on CT as a sign of acute pancreatic injury.  Retrospective analysis of CT examinations in patients with confirmed COVID-19 infection yielded 103 instances. An age- and gender-matched cohort of patients without COVID-19 was found. CT examinations were evaluated for peripancreatic stranding or edema, fluid collection, or necrosis, without any other explanation. Depicted pulmonary parenchyma was evaluated for possible COVID-19-related changes. Clinical and laboratory data were retrieved from the clinical database. n = 8) or fluid collection (n = 2) without any other cause was found in 10 (10%) patients. Abdominal complaints were reported in 4 (40%) patients. Elevated serum amylase or lipase levels were documented in 5 (50%) patients who also satisfied the diagnostic criteria for acute pancreatitis. From the study sample of 103 patients with COVID-19, pulmonary parenchyma was depicted in 102 (99%), and from these, 57 (55%) had an evidence of pulmonary changes compatible with COVID-19 pneumonia. This proportion was not significantly different between patients with and without peripancreatic changes (p = 0.35). In the matched cohort, we found peripancreatic changes in 2  patients. Patients with pancreatic injury and elevated amylase levels were more likely to require orotracheal intubation .  Peripancreatic fat stranding ( We showed that the prevalence of peripancreatic stranding or fluid collection is higher in patients diagnosed with COVID-19 infection compared to an age- and gender-matched cohort. Patients with pancreatic injury and elevated amylase levels are more likely to require orotracheal intubation. Our findings corroborate the link between COVID-19 infection and pancreatic injury from the perspective of imaging. Data from the 2020 outbreak of SARS-CoV-19 (COVID-19) showed the association between gastrointestinal symptoms and COVID-19 infection in up to 79% of the patients .Although this association has been confirmed by other authors \u20136, the lThe aim of this study was to determine the association between COVID-19 infection and peripancreatic fat edema, stranding, or fluid collection as a sign of acute pancreatic injury.This project was approved by the Ethics Committee of the General University Hospital in Prague (ref. 2221/20 S-IV); it was performed in accordance with the Declaration of Helsinki. Informed consent was waived due to the retrospective nature of the study.We searched the hospital database for patients who were admitted to our tertiary care hospital between April 01 and November 30, 2020, who had a confirmed diagnosis of COVID-19 by real-time reverse-transcriptase polymerase chain reaction (rRT-PCR) assay and underwent CT examination during the hospital stay. The search yielded 225 patients from whom 154 had at least two anatomical parts of the pancreas depicted . From thPatients with other conditions that would induce peripancreatic edema  were not considered.In both cohorts, CT images were evaluated for peripancreatic fat edema and stranding (\u201cstranding\u201d), or (peri)pancreatic fluid collection and/or necrosis (\u201ccollection\u201d) by two radiologists (one junior and one senior) in consensus. In patients with COVID-19, the clinical database was searched for selected items in medical history, laboratory data , and outcome.F test, continuous variables by t-test, or Mann\u2013Whitney test according to their distribution . A p value below 0.05 was considered significant.The statistical analysis was performed in Prism v. 5.0. . Categorical values were compared using the From patients with COVID-19, 58 had CT examinations, where the pancreas was depicted entirely. In 45 patients, at least two anatomical parts of the pancreas  were depicted entirely. Of these 103 patients, 71 (69%) were males. Their age was 66 \u00b1 14 years .n = 8) or fluid collection .From the study sample of 103 patients with COVID-19, pulmonary parenchyma  was depicted in 102 (99%), and from these, 57 (55%) had evidence of pulmonary changes compatible with COVID-19 pneumonia. This proportion was not different between patients with . and without peripancreatic changes  and diabetes (3 of 10 (30%) vs. 24 of 93 (26%), p = 0.70). A more frequent requirement for orotracheal intubation (4 of 10 (40%) vs. 13 of 93 (14%)) did not reach statistical significance by a small margin (p = 0.058). When the group of patients with pancreatic injury was extended to those with elevated amylase levels, the difference (7 of 20 (35%) vs. 10 of 83 (12%)) became significant at p = 0.021. No difference between the groups was observed in the duration of hospital stay (17 (range 5\u201355) vs. 14 (range 1\u201375) days, p = 0.70) or the inhospital mortality (2 of 10 (20%) vs. 15 of 93 (16%), p = 1.0).The clinical characteristics of patients with peripancreatic changes did not significantly differ from those without\u2014notably the body mass index  patients aged 64 and 36 years . Neither of them had amylase or lipase levels sampled and neither reported abdominal pain.In the matched cohort (age 67 \u00b1 15 years), we found peripancreatic changes in 2  in pancreatic islet cells . Apart fIn their series of 52 patients with COVID-19 from the University Hospital in Wuhan, China, Wang et al. identified 9 17%) patients with  pancreatic injury defined as any abnormality in amylase or lipase levels . Barlass% patientOur study, which approached the association between COVID-19 and pancreatic injury from the perspective of clinical imaging, showed that 9.7% of COVID-19 patients had evidence of pancreatic injury of unknown cause on CT. This is in line with the observation of Liu et al., who reported that 5 of 67 (7.5%) patients treated for severe COVID-19 in Wuhan, China, had detectable changes on CT indicating pancreatic inflammation  . The proPatients with COVID-19 infection may exhibit elevation of serum levels of pancreatic enzymes, but they may not develop clinical symptoms or otherwise satisfy the diagnostic criteria for acute pancreatitis . The cliThe clinical characteristics of patients with peripancreatic changes did not significantly differ from those without. Even a more frequent requirement for orotracheal intubation did not reach statistical significance by a small margin. The increased need for mechanical ventilation in patients with pancreatic injury (based on ultrasound and serum enzyme levels) has been reported by Ding et al. with an odds ratio of 10.2 . When weThis is a retrospective study that suffers from the selection bias because only patients with confirmed COVID-19 infection who required hospital admission and CT imaging for any indication that covered the pancreas were included. We assume that the prevalence of peripancreatic changes in an unselected population would be lower. Secondly, the serum levels of pancreatic enzymes were not available in about half of the patients because the pancreatic injury was not suspected. Thirdly, the comparison between patients with and without peripancreatic changes is underpowered due to a small number of subjects with peripancreatic changes. Analysis of clinical, imaging, and laboratory from large multicenter databases will be required to corroborate the link between COVID-19 infection and pancreatic injury and its clinical significance.In conclusion, we showed that the prevalence of peripancreatic stranding or fluid collection is higher in patients diagnosed with COVID-19 infection compared to an age- and gender-matched cohort. Our findings corroborate the link between COVID-19 infection and pancreatic injury from the imaging perspective."}
+{"text": "Burn patients often experience a tremendous amount of pain and anxiety during dressing changes and other procedures, frequently requiring a moderate sedation (MS) or deep sedation (DS) for successful completion. We previously reported our primarily Nurse Practitioner-based model for procedural sedation but recently transitioned to a primarily hospitalist-based sedation service. We evaluated the clinical and financial impact of this transition.Retrospective chart review of patients undergoing MS or DS from June 2019 to June 2020 (burn provider-based [BPB]) and August 2020 to August 2021 . Data included demographics, number and types of sedation, provider type, American Society of Anesthesiology Physical Status Classification (ASA score), complications and relative value units (RVU)/anesthesia units generated. Our hospitalist completed a combined Internal Medicine-Pediatrics residency and is credentialed by the institution for procedural sedation.During the BPB sedation timeframe, 263 patients were admitted to the burn center, of which 55 patients (21%) underwent 203 sedations (average: 3.6 sedations/patient). Twenty-one (10%) were DS. The most common medications used for DS were a combination of Midazolam, Ketamine, Fentanyl, Glycopyrrolate and Ondansetron (81%); and for MS, a combination of Fentanyl and Midazolam (77.5%). Ten percent of patients had an ASA of 3 or greater.During the HB sedation timeframe, 203 patients were admitted, of which 73 patients (36%) underwent 353 sedations for an average of 4.8 sedations/patient (74% increase). Ninety-one (26%) were DS (333% increase). Medication combinations were similar as above for DS (90%) and MS (93%). Nineteen percent of patients had an ASA of 3 or greater.Our hospitalist performed 16% of the sedations in the BPB timeframe and 72% in the HB timeframe. In the BPB group there were 4 desaturation events (0.02%) among all sedations, compared to 8 desaturation and 1 hemodynamic change events (0.025%) in the HB group. Total work relative value units (wRVUs) and anesthesia units of service (for the DS) generated were 599.6 and 133 respectively in the BPB group compared to 1104.2 (84% increase) and 784 (489% increase) respectively in the HB group. During the BPB timeframe 40 patients were taken to the OR for dressing changes for a total of 69.3 hours, compared to zero in the HB timeframe.Transitioning from a BPB to HB sedation service resulted in increased sedation numbers and percentage of patients undergoing a sedation, especially DS, as well as increased RVU generation. Sedations were performed in patients with higher ASA scores without a significant increase in adverse events. There was operating room cost and time savings. HB sedation services can be an efficacious and safe model in a burn center."}
+{"text": "The disease caused by SARS-CoV-2, COVID-19, has caused a global public health crisis. COVID-19 causes lower respiratory tract infection (LRTI) and hypoxia. There is a paucity of data on bacterial and fungal coinfection rates in patients with COVID-19 at low and middle income countries (LMICs). Our objective is to describe the clinical characteristics of critically ill patients with COVID-19 in the Dominican Republic (DR)We performed a retrospective review of patients admitted to the ICU with COVID-19 from March 14th to December 31st 2020, at a 296-bed tertiary care level and teaching Hospital in the Dominican Republic. Demographic and clinical information was collected and tabulated. Laboratory confirmed bacterial and fungal infections were defined as community acquired infections (CAI) if diagnosed within 48 hours of admission and hospital acquired infections (HAI) when beyond 48 hours. Microbiologic data was tabulated by source and attribution. Our cohort had 382 COVID-19 patients. Median age was 64 and most were male (64.3%) and 119 (31.1%) were mechanically ventilated and 200 (52%) had central venous catheters. A total of 28 (7%) laboratory confirmed community acquired infections and 55 (14%) HAIs occurred. Community acquired infections included 13 (46%) bloodstream infections (BSIs), 11 (39%) urinary tract infections (UTI) and 6 (21%) LRTIs. HAIs included 39 (70%) BSIs, 11 (20%) UTIs and 6 (11%) ventilator associated pneumonias (VAP). Causal organisms of community and hospital acquired BSI and UTI are in Figure 1 and Figure 2 respecively. All-cause mortality was 35.3% (135/382) in our cohort, and 100% mortality (76) in those with coinfections. Figure 1. Community acquired and hospital acquired bloodstream infections in COVID-19 patients admitted to the ICUFigure 2. Community acquired and hospital acquired urinary tract infections in COVID-19 patients admitted to the ICUCommunity and hospital acquired infections were common and in the ICU and likely contributed to patient outcomes. More than two thirds of HAIs in the ICU were BSIs. Central venous catheter device utlization and maintenance may play a role in BSIs, along with immunosuppression from COVID-19 therapeutics and translocation from mucosal barrier injury. Mortality in patients with coinfections was higher than those without. Infection prevention strategies to reduce device utilization during COIVD-19 in LMICs may have an impact on HAIs.All Authors: No reported disclosures"}
+{"text": "Quetiapine is an atypical anti-psychotic medication licensed for the treatment of schizophrenia, bipolar disorder and adjunctive use in major depressive disorder. It's off-label use in low doses is increasing, possibly due to its sedative qualities, tolerability, low risk of extrapyramidal symptoms and to limit the unnecessary use of benzodiazepines. However, previous research highlights the risk of metabolic consequences even in low doses. Our aim is to establish the prescribing patterns and off-label use of quetiapine within a complete comminity mental health team population (CMHT).The GR1 CMHT provides care to a population of 25,000 people in a mixed urban and rural area. Multi-disciplinary case notes for all registered patients were reviewed for a one-year period. A database was created to include sociodemographic details, diagnosis, and medication. The proportion of patients prescribed quetiapine was identified and the dosage divided into multiple increments. The team's consultant reviewed and verified all ICD-10 diagnoses. Quetiapine dose by diagnosis was examined using descriptive statistics.Of 246 registered patients, 62 (25% of CMHT caseload) were prescribed Quetiapine. Quetiapine was prescribed across a range of disorders including psychotic 17 (27%), mood 18 (29%), anxiety 14 (22 %), personality disorders 11 (18%) and others 2 (3%). Doses spanned between 25 mg \u2013 800 mg daily. 19 patients (31%) were prescribed less than 25 mg, 20 patients (32%) between 25 mg and 100 mg and 23 patients (37%) above 100 mg. In psychotic and mood disorders, dosage varied widely between the low and high range. Furthermore, of the psychotic disorders, 11 (65%) were prescribed a second antipsychotic medication. For diagnoses in which the prescribing indication was clearly off-label, the dosages were predominantly low (100 mg or less).Quetiapine was commonly prescribed in our patient population. Its frequent off-label use in low doses suggests that its prescription was for its additional qualities. Our findings highlight the importance of assessing the risk-benefit profile for every patient given the potential side effects, involving patients in the consultation of its off-label use and appropriate monitoring."}
+{"text": "TP53 is the most frequently altered gene with approximately 50% of patients harboring mutations. This qualitative study describes the distinct genomic alterations in GCs and GEJs stratified by TP53 mutation status.Gastric cancer (GC) and gastroesophageal junction adenocarcinomas (GEJ) are molecularly diverse. TP53 mutation status was examined using Fisher\u2019s exact test. Functional gene groupings representing molecular pathways suggested to be differentially mutated in TP53 wild-type (TP53WT) and TP53 mutant (TP53MUT) tumors were identified. The association of the frequency of tumors containing a gene mutation in the molecular pathways of interest and TP53 mutation status was assessed using Fisher\u2019s exact test with a P-value of <.01 deemed statistically significant for all analyses.Tumor DNA sequencing results of 324 genes from 3741 patients with GC and GEJ were obtained from Foundation Medicine. Association between gene mutation frequency and TP53 mutations were noted in 61.6% of 2946 GCs and 81.4% of 795 GEJs (P < .001). Forty-nine genes had statistically different mutation frequencies in TP53WT vs. TP53MUT patients. TP53WT tumors more likely had mutations related to DNA mismatch repair, homologous recombination repair, DNA and histone methylation, Wnt/B-catenin, PI3K/Akt/mTOR, and chromatin remodeling complexes. TP53MUT tumors more likely had mutations related to fibroblast growth factor, epidermal growth factor receptor, other receptor tyrosine kinases, and cyclin and cyclin-dependent kinases.TP53 mutation status. These mutational differences can be used when designing future studies assessing the predictive ability of TP53 mutation status when targeting differentially affected molecular pathways.The mutational profiles of GCs and GEJs varied according to  Gastric (GC) and gastroesophageal junction adenocarcinomas (GEJ) are molecularly diverse. TP53 is the most frequently altered gene, with approximately 50% of patients harboring mutations. This article describes the distinct genomic alterations in GCs and GEJs stratified by TP53 mutation status. TP53 mutation status into account in a predictive capacity have yet to be developed. Additionally, there is limited information available assessing its ability to function as a predictive marker in the era of targeted cancer therapy. The mutational differences of GEAs stratified by TP53 mutation status as described in this manuscript can be used as a tool when conceiving future pre-clinical and clinical studies to assess the predictive ability of TP53 mutational status when using molecularly targeted agents.Despite being mutated in approximately 50% of gastroesophageal adenocarcinomas (GEAs), therapeutic interventions taking 1 In the US alone, 26 250 new cases of gastric cancer and 19 260 new cases of esophageal cancer were diagnosed in 2021, with males representing 61% and 79% of these new diagnoses.2 The western population, in particular, has seen the incidence of gastric cancer (GC) and steady increase of gastroesophageal junction adenocarcinomas (GEJs) due to the increasing prevalence of obesity and gastro-esophageal reflux disease.3-5 GCs and GEJs, collectively known as gastroesophageal adenocarcinomas (GEAs), are molecularly diverse. Attempts have been made to molecularly categorize these tumors to organize future studies and create tailored treatment strategies. In 2014, the Cancer Genome Atlas Research Network (TCGA) analyzed 295 GC samples using array-based somatic copy number analysis, whole-exome sequencing, array-based DNA methylation profiling, messenger RNA (mRNA) sequencing, microRNA (miRNA) sequencing, reverse-phase protein array, and microsatellite instability (MSI) testing to propose separating GC into 4 general molecular subtypes.6 The first 2 molecular subtypes were generated on the basis of CpG island hypermethylation (CIMP): Epstein-Barr virus (EBV)+ CIMP tumors (9%) with distinct hypermethylation patterns not associated with the epigenetic silencing of MLH1, and microsatellite instability (MSI) enriched CIMP EBV-tumors (22%) with hypermethylation patterns consistent with MLH1 epigenetic silencing. The remainder of the GCs were then stratified into one of 2 groups based on their relative burden of somatic copy number aberrations (SCNAs): genomically stable (GS) tumors (20%) had less SCNAs as compared to those deemed to have chromosomal instability .6Gastric and esophageal cancer are the third and sixth leading cause of cancer deaths worldwide.ARID1A, PIK3CA, KRAS, and CDH1.7 However, TP53 is the most frequently altered gene with approximately 50% of GEAs and 70% of CIN GCs harboring mutations.8TP53 encodes the tumor suppressor p53 protein that functions as a key member of the G1/S checkpoint to help maintain genetic integrity through the cell cycle.9 In times of cellular stress TP53 expression increases to mediate G1 phase cell cycle arrest to facilitate repair before cellular division or promote apoptosis in cells with an overabundance of molecular derangements that cannot be overcome. When there is a loss of TP53 function, the G1/S checkpoint is effectively lost, and genetically damaged cells have significantly less barriers to unchecked proliferation with negative physiologic consequences. Therefore, it is not surprising that inactivating TP53 mutations have been implicated in the carcinogenesis of a multitude of malignancies, with GEAs being no exception.10 In fact, the Asian Cancer Research Group (ACRG) included TP53 expression as part of their proposed molecular classification of GC.11 Using gene expression panels derived from 300 GCs, the ACRG first separated GCs molecularly into 2 large categories: MSI and microsatellite stable (MSS). MSS tumors were then stratified by the presence of, or lack thereof, an epithelial-to-mesenchymal gene signature (MSS/EMT). The remaining MSS/EMT- tumors were divided into the final 2 categories, MSS/TP53+ and MSS/TP53\u2212, based on levels of TP53 expression with noted differences in patient characteristics between these 2 groups.11Commonly occurring genetic mutations in GEAs include TP53 mutation status into account have yet to be developed, its high prevalence makes it a subject of interest to clinical investigators as a potential predictive marker.12-14 An understanding of commonly co-occurring genetic alterations in TP53 wild-type (TP53WT) and TP53 mutated (TP53MUT) GEAs may help guide clinically practical investigations in the future assessing this potential. This study identified the unique mutational profiles of TP53WT and TP53MUT GEAs by analyzing the DNA sequencing results of 3741 GEA tumor samples.Next-generation sequencing (NGS) is now widely used for most advanced cancers as an aid to elucidate the genomic characteristics of tumors. While therapeutic interventions for GEAs taking 15 The data provided included age at the time of the assay results, gender, tumor mutational burden (TMB), and the distinct genomic alterations noted on DNA sequencing. Information on MSI and PD-L1 status was not available in the dataset. The dataset was sorted by TP53 mutation status. Differences in mutation frequency were detected using Fisher\u2019s exact test of independence with a P-value of <.01 designated as the cutoff value for statistical significance. Statistical significance for continuous data was tested using a 2 samples t-test for mean values and the Mann-Whitney U test for distribution/median values.De-identified data were acquired from Foundation Medicine for all available patients with GEA for whom the FoundationOne CDx (F1CDx) assay was performed within the US. F1CDx is a commercially available NGS diagnostic test developed by Foundation Medicine that uses targeted high throughput hybridization-based capture technology for the detection of substitutions, insertion and deletion alterations, and copy number alterations in 324 genes and select gene rearrangements using DNA isolated from formalin-fixed paraffin-embedded tumor tissue specimens.TP53WT and TP53MUT tumors. After studying these results, 12 predetermined functional gene groupings were created to help elucidate molecular pathways suggested to be differentially affected in TP53WT and TP53MUT tumors. The number of tumors containing a mutation in at least one of the prespecified genes in the molecular pathways of interest was counted. Then, the association of the frequency of tumors containing a gene mutation in the molecular pathways of interest and TP53 mutation status was assessed using Fisher\u2019s exact test of independence with a P-value of <.01 deemed statistically significant.Pathway analysis was completed by first isolating the genes with statistically different mutation frequencies between P < .001). The median patient age was 63, which was similar between TP53WT and TP53MUT patients.The dataset consisted of 3741 patients with GEA: 2946 GCs and 795 GEJs. The entire study population was 65.2% male and 34.8% female. GC patients were 60.6% male and 39.4% female, whereas patients with GEJ were 82.4% male and 17.6% female (TP53 mutations were present in 65.8% of specimens. TP53 mutations were noted in 61.6% of GCs and 81.4% of GEJs (P < .001). The median TMB score was lower in TP53WT as compared to TP53MUT GEAs . The frequency of tumors with a TMB score >10 mutations/megabase  were similar in TP53WT and TP53MUT groups, respectively. The most commonly mutated genes in the entire population other than TP53 were CDKN2A (19.1%), ARID1A (17.4%), KRAS (17.0%), ERBB2 (14.4%), and CDH1 (11.3%)  . Forty-npatients . The genof ERBB3 . Amplifipatients .TP53WT GEAs were more likely to contain a mutation in a gene related to DNA mismatch repair, homologous recombination repair, DNA and histone methylation, Wnt/B-catenin, PI3K/Akt/mTOR, and chromatin remodeling complexes. Furthermore, TP53WT tumors were more likely to contain any mutation in the gene panel as compared to TP53MUT tumors. TP53MUT GEAs were more likely to contain a mutation in a gene related to fibroblast growth factor, epidermal growth factor receptor, other receptor tyrosine kinases, and cyclin and cyclin-dependent kinases. When broken down by tumor type, GCs had pathway analyses results that closely mirrored those of the entire dataset with the only difference being that the frequency of mutations in DNA and histone methylation genes was no longer statistically different between TP53WT and TP53MUT GCs (P = .026). On the other hand, the lone pathway that was differentially affected in TP53WT and TP53MUT GEJs was homologous recombination repair .The pathway analysis results are represented in 17 There are other biomarkers that will soon have therapeutic implications, such as Claudin 18.2 and FGFR2b.19 The use of these predictive biomarkers has helped us tailor treatments for patients with GEA, yet there is still an unmet need to identify additional targets for novel treatment strategies. In our study, we were able to demonstrate that the mutational profiles of GEAs differed when stratified according to TP53 mutation status. TP53 mutations were identified at higher rates in our sample of GEAs as compared to those described by TCGA and other manuscripts reporting such data.21 Genes directly involved in the DNA damage response and epigenetic regulation of DNA were more frequently mutated in TP53WT tumors. Meanwhile, growth factor and receptor tyrosine kinase genes were more frequently mutated in TP53MUT tumors.The most common predictive biomarkers currently used in GEAs are microsatellite instability or mismatch repair deficiency status and expression of human epidermal growth factor receptor 2 (HER2) and programmed death-ligand 1 (PD-L1).TP53MUT than their GC counterparts  in this dataset, which is consistent with DNA sequencing results previously described.23 Given this variability, there was interest in comparing GEJ and GC mutation profiles against one another to assess any further genetic differences stratified by TP53 mutational status that may distinguish the 2 GEA malignancies. Homologous recombination repair genes were more frequently mutated in both TP53WT GEJs and GCs. Additionally, the ratio of mutational involvement of DNA mismatch repair, DNA and histone methylation, epidermal growth factor, and receptor tyrosine kinase genes appeared to be consistent in GEJs and GCs when broken down by TP53 mutation status. The remaining functional gene groupings, however, did not seem to have as much mutational variation between TP53WT and TP53MUT tumors in GEJs as compared to GCs. This can be most readily seen when looking at the involvement of cyclin and cyclin-dependent kinase genes, which play an integral role in the maintenance of the cell cycle in concert with TP53. Twenty-seven percent vs. 44.2% of TP53WT and TP53MUT GCs had cyclin and cyclin-dependent kinase gene mutations. Meanwhile, 54.7% vs. 56.9% of TP53WT and TP53MUT GEJs had cyclin and cyclin-dependent kinase gene mutations. On a gene-specific level, ZNF217 (15.5%) and AURKA (8.1%) amplification mutations were disproportionately seen in TP53WT GEJs as compared to the rest of the dataset . As both ZNF217 and AURKA genes are located on chromosome 20q13, it stands to reason that 20q13 amplification may play a prominent role in the carcinogenesis of TP53WT GEJs.24 These findings suggest that despite their anatomic proximity the genetic makeup of GEJs and GCs are distinct from one another.GEJ tumors were more likely to be TP53 mutations on the outcomes of GEAs have demonstrated conflicting results.25-29 The molecular characterization of GEAs in relation to TCGA subtype, co-occurring mutations, and the type of TP53 mutation itself all seem to influence TP53\u2019s prognostic significance.30 Equally, the ability of TP53 mutation status to function as a predictive marker of treatment response is also unknown. A meta-analysis of 13 studies including 564 cases concluded that GCs with high levels of p53 expression on immunohistochemistry (IHC) have a decreased response to chemotherapy.31 Unfortunately, the correlation of p53 expression on IHC with TP53 mutational status is not consistent, making it difficult to extrapolate the findings of this analysis toward tumor DNA sequencing results.33 More recent studies have attempted to delineate the predictive potential of TP53 mutations in the era of molecularly targeted therapies and immunotherapies. One manuscript supporting its predictive ability in targeting the vascular endothelial growth factor (VEGF) pathway was recently published.34 In 48 patients with GC who received second-line ramicurimab/paclitaxel combination therapy the median OS was 9.5 months for carriers of TP53Inactive mutations, 8.6 months for carriers of other TP53 mutations, 6.0 months for carriers of TP53Active missense mutations, and 4.5 months for TP53WT patients (P = .01). VEGFA was accordingly more mutated in our group of TP53MUT GEAs as compared to TP53WT GEAs  = 6.3). In another review of 356 GCs from the TCGA database, it was found that TP53MUT tumors had lower levels of anti-tumor immunity and a decreased response to immune checkpoint inhibitor therapy as compared to TP53WT tumors.35 On the other hand, sub-group analysis of the phase III GOLD trial investigating olaparib and paclitaxel combination therapy in recurrent and metastatic GC found no difference in therapeutic response based on TP53 mutation status.36 More studies are needed to assess the predictive ability of TP53 mutation in isolation and in conjunction with other molecular alterations.Studies assessing the prognostic impact of 37 This potentially limits the clinical utility of tissue-based mutation analysis as the full mutational landscape of the patient\u2019s tumors may not be elucidated due to the sampling limitations inherent with this method of genetic profiling. This notion, along with the invasiveness of obtaining tumor samples for molecular analysis, has led to the increased use of liquid biopsies assessing circulating tumor DNA (ctDNA) NGS results in conjunction with tissue NGS to guide clinical decision-making. Nonetheless, as tissue-based DNA/RNA sequencing results yet remain standard in clinical practice, the observations of this study could serve as a foundation for practical future preclinical and clinical investigations that can help elucidate the clinical correlations of our findings. For example, genes in the PI3K/AKT/mTOR pathway were significantly more mutated in TP53WT tumors, which was largely driven by the greater presence of PIK3CA mutations in TP53WT as compared to TP53MUT tumors (16.2% vs. 7.9%). Trials are currently underway assessing the role of PI3K inhibitors for PIK3CA mutated tumors in GEAs. It would be useful to perform a subgroup analysis of the results of these trials stratified by TP53 mutation status to determine if these findings signal a pathophysiologic difference that carries predictive relevance in the real-world setting. Similar analyses could be completed for additional studies investigating therapeutic interventions targeting genes and cellular products related to the DNA damage response, epigenetic regulation of DNA, growth factors, receptor tyrosine kinases, cyclins and cyclin-dependent kinases, and the PI3K/AKT/mTOR pathway.The limitations of this study include missing data regarding clinical outcomes, microsatellite instability status, expression of other protein biomarkers, and additional patient characteristics necessary to organize these tumors into one of the 4 molecular subtypes as proposed by the Cancer Genome Atlas Research Network. In addition, while tissue-based assays offer a comprehensive genomic profile, there can be intra- and intertumoral (primary vs. metastatic site) heterogeneity which may not be fully encompassed on tissue NGS.TP53 status. The mutational differences of GEAs stratified by TP53 mutation status as described in this manuscript can be used as a tool when designing and analyzing future pre-clinical and clinical trials to assess the predictive ability of TP53 mutational status when targeting differentially affected molecular pathways.Despite the inherent limitations of this qualitative study, compelling trends within a large database of tumor DNA sequencing results derived from clinically accessible information were identified. A clinical trial assessing the efficacy of berzosertib and irinotecan in TP53 mutant GEA cancers is currently ongoing (NCT03641313) which is the first clinical trial selected for patients based on"}
+{"text": "Specifically, the serostatus terms were inadvertently reversed in the following sentence: \u201cThere was no association between frequency of remission and serostatus, with remission occurring in 196 (69.3%) seropositive patients and 9 (81.8%) seronegative patients (This error has been corrected in the final paginated version of this article."}
+{"text": "M. pneumoniae were not detected. Whether identification of viral nucleic acid represents nasopharyngeal carriage or specific causal etiology of RTI remains to be defined. Large controlled cohort studies  are required to define the carriage rates and the specific etiology and causal roles of specific individual viruses or combination of viruses in the pathogenesis of respiratory tract infections in pilgrims participating in the annual Hajj. Studies of the specific microbial etiology of respiratory track infections (RTIs) at mass gathering religious events remain a priority, especially in light of the novel SARS-CoV-2 pandemic.The aim of our study was to define the spectrum of viral infections in pilgrims with acute respiratory tract illnesses presenting to healthcare facilities around the holy places in Makkah, Saudi Arabia during the 2019 Hajj pilgrimage. During the five days of Hajj, a total of 185 pilgrims were enrolled in the study. Nasopharyngeal swabs (NPSs) of 126/185 patients (68.11%) tested positive for one or more respiratory viruses by PCR. Among the 126 pilgrims whose NPS were PCR positive: (a) there were 93/126 (74%) with a single virus infection, (b) 33/126 (26%) with coinfection with more than one virus (up to four viruses): of these, 25/33 cases had coinfection with two viruses; 6/33 were infected with three viruses, while the remaining 2/33 patients had infection with four viruses. Human rhinovirus (HRV) was the most common detected viruses with 53 cases (42.06%), followed by 27 (21.43%) cases of influenza A (H1N1), and 23 (18.25%) cases of influenza A other than H1N1. Twenty-five cases of CoV-229E (19.84%) were detected more than other coronavirus members (5 CoV-OC43 (3.97%), 4 CoV-HKU1 (3.17%), and 1 CoV-NL63 (0.79%)). PIV-3 was detected in 8 cases (6.35%). A single case (0.79%) of PIV-1 and PIV-4 were found. HMPV represented 5 (3.97%), RSV and influenza B 4 (3.17%) for each, and Parechovirus 1 (0.79%). Enterovirus, Bocavirus, and  Viral respiratory tract infections (RTIs) are one of the most important health problems encountered by pilgrims performing the annual Hajj pilgrimage ,2. The HThe aim of our study was to define the spectrum of viral infections in pilgrims with acute respiratory tract illnesses presenting to healthcare facilities around the holy places in Makkah, Saudi Arabia during the 2019 Hajj pilgrimage.This study was approved by the Research Ethics Committee (REC), Unit of Biomedical Ethics, Faculty of Medicine, King Abdulaziz University (KAU) (Reference No 569-20). Written consent forms were obtained from participants.This was a cross-sectional analytical study, which screened for respiratory viruses in the nasopharyngeal swabs of pilgrims with respiratory tract illnesses presenting to healthcare facilities in the holy places during the 2019 Hajj.Study population and enrolment sites: Pilgrims with severe acute respiratory tract symptoms who presented to, and were initially hospitalized at seven healthcare facilities in Makkah, Arafat, and Mina during the first five days of the 2019 Hajj.Clinical Specimens and patient information: nasopharyngeal swabs (NS) were collected in viral transport media (VTM) and stored at \u221280 \u00b0C in the Special Infectious Agents Unit (SIAU), King Fahd Medical Research Center (KFMRC). Demographic data including nationality, age, and gender from all participants was also obtained.Mycoplasma pneumoniae. Amplification was performed using the QuantStudio 12K Flex Real-Time PCR System .Nucleic acids were extracted using an ExiPrep\u2122 96 Viral DNA/RNA Kit through ExiPrep\u2122 96 Lite   as per the manufacturer\u2019s instructions. Extracted RNA was subjected to multiplex real-time PCR utilizing fast-track respiratory pathogens 21 kit  that enables the detection of influenza A (H1N1) virus; influenza B (Flu B) viruses; human rhinoviruses (HRV); human coronaviruses ; human metapneumoviruses (hMPV) A/B; human parainfluenza viruses ; human bocavirus; human adenovirus; respiratory syncytial virus (RSV) A/B; enterovirus; human parechovirus; and n) and percentages (%). The continuous variable such as age was expressed as mean \u00b1 SD. A non-parametric test (Chi-square test) was applied to compare the proportions and determine the significance of association between categorical variables. p-values less than 0.05 was considered as statistically significant. Graph drawing was performed by using GraphPad Prism software version 9 .The statistical analysis of the data was carried out using the statistical software package SPSS version 25.0 . All categorical variables  presented as numbers  and Africa , followed by Europe , North America for each , then Oceania . Respiratory viruses have been more frequently detected in patients arriving from countries providing annually the highest number of pilgrims [Patients participating in this study descended from 37 countries, mainly from Asia  tested positive for one or more respiratory viruses by PCR , while tM. pneumoniae were not detected (Human rhinovirus (HRV) was the most common detected viruses with 53 cases (42.06%), followed by 27 (21.43%) cases of influenza A (H1N1), and 23 (18.25%) cases of influenza A other than H1N1. Twenty-five cases of CoV-229E (19.84%) were detected more than other coronavirus members (5 CoV-OC43 (3.97%), 4 CoV-HKU1 (3.17%), and 1 CoV-NL63 (0.79%)). PIV-3 was detected in 8 cases (6.35%). A single case (0.79%) of PIV-1 and PIV-4 were found. HMPV represented 5 (3.97%), RSV and influenza B 4 (3.17%) for each, and Parechovirus 1 (0.79%). Enterovirus, Bocavirus, and detected . The numdetected .n = 6), influenza A (H1N1) and CoV-OC43 (n = 3 for each), followed by adenovirus or influenza A not H1N1 (n = 2) (The most common virus detected in multiple virus coinfection cases was HRV with 28 cases out of 33 (84.85%). HRV was commonly accompanied with CoV-229E ( (n = 2) .M. pneumoniae were not detected. As previously described [In our study the human rhinovirus (HRV) was the most commonly detected virus with 53 cases (42.06%), followed by 27 (21.43%) cases of influenza A (H1N1), and 23 18.25%) cases of influenza A other than H1N1. Twenty-five cases of CoV-229E (19.84%) were detected more than other coronavirus members (five CoV-OC43 (3.97%), four CoV-HKU1 (3.17%), and one CoV-NL63 (0.79%)). PIV-3 was detected in eight cases (6.35%). There was one case of PIV-1 and PIV-4 that was found. HMPV represented 5 (3.17%), RSV and Flu B 4 (3.17%) for each, and Parechovirus 1 (0.79%). Enterovirus, Bocavirus, and .25% caseescribed ,11,12, oescribed ,11,12.As per pilgrims\u2019 home country, most cases associated with those arrived from Indonesia, India, and Egypt (10 or more cases) . Cases oRespiratory tract viral infections (RTIs) are the most common infections among pilgrims and represent the leading cause of most hospitalizations ,8,27,28.Transmission and control of respiratory viral infections are critical health challenges, particularly in a country like Saudi Arabia, which receives annually about 3 million pilgrims and more than 20 million religious tourists from more than 180 countries. Overcrowding of individuals with close contact in small areas provide a favorable environment for transmission of respiratory infections. The public and global health concerns increase during Hajj because of the potential of importing and exporting viruses all over the world through pilgrims . Active Importantly, our study showed that 26% of the pilgrims with PCR positive results showed a coinfection with more than one virus (up to four viruses). Of these, 25/33 cases had coinfection with two viruses; 6/33 were infected with three viruses, while the remaining 2/33 patients had infection with four viruses. Whether identification of viral nucleic acid represents nasopharyngeal carriage or specific causal etiology of RTI remains to be defined. The PCR test only detects the presence of nucleic acid and cannot determine whether the virus is alive, or it represents bits of nucleic acid from previous infection. The identification of the virus does not mean it is the causative pathogen since nasopharyngeal carriage of certain viruses is common in most populations. Thus, large controlled cohort studies  are required to define the carriage rates and the specific etiology and causal roles of specific individual viruses or combination of viruses in the pathogenesis of respiratory tract infections in pilgrims participating in the annual Hajj. As Saudi Arabia monitors the global SARS-CoV-2 situation and the numbers of pilgrims allowed to perform the Hajj under strict public health measures of social distancing and wearing of masks, an opportunity to study the effects of stricter infection control measures at mass gathering arises. Studies of the evolution and changes in the viral flora in the nasopharynx of pilgrims and those who develop symptoms of RTI would be appropriate.In summary, respiratory viruses continue to be a possible public health concern for individuals and nations during Hajj seasons. Herein, we demonstrated the pattern of respiratory viruses among pilgrims during the 2019 Hajj Season. There is a need for larger studies to comprehensively determine the pattern of respiratory viruses among pilgrims. Furthermore, implementation of continuous surveillance is of great importance to accurately estimate the potential risk and impose efficient infection control strategies during this annual mass gathering event. Studies of the specific microbial etiology of RTIs at mass gathering religious events remain a priority, especially in light of the novel SARS-CoV-2 pandemic."}
+{"text": "To study the baseline characteristics and clinical outcome of HEV-induced ALF in a recent HEV epidemicTo detect raised ICP clinically and observe response to mannitol infusion.Hepatitis E virus (HEV) is an important cause of acute liver failure (ALF) in Bangladesh with pregnant mothers being more vulnerable. As HEV occurs in epidemics, it limits medical capabilities in this resource-poor country. Cerebral oedema, resulting in raised intracranial pressure (ICP), is an important cause of morbidity and mortality. Practical treatments are currently few.This was a prospective cohort study from June until August 2018 of 20 patients admitted to the intensive care unit (ICU) of a major Bangladeshi Referral Hospital with HEV-induced ALF. We diagnosed HEV infection by detecting serum anti-HEV IgM antibody. All were negative for hepatitis B surface antigen and hepatitis A IgM antibody. Data were collected on 5-day outcome after admission to ICU, monitoring all patients for signs of raised ICP. An intravenous bolus of 20% mannitol was administered at a single time point to patients with raised ICP.Twenty patients were included in the study. Ten (50%) patients, seven (70%) females, received mannitol infusion. HE worsened in eight (40%): seven female and three pregnant. Glasgow Coma scores deteriorated in six (30%): all (100%) females and three pregnant. Consciousness status was not significantly different between pregnant and non-pregnant subjects, nor between those who received mannitol and those who did not. Six patients met King\u2019s College Criteria for liver transplantation.Female patients had a worse outcome, but pregnancy status was not an additional risk factor in our cohort. Mannitol infusion was also not associated with a significant difference in outcome. Every year, more than 20 million people contract hepatitis E virus (HEV) infection, and among them, more than 70,000 die from its complications, including acute liver failure (ALF) . Most ofHEV infection is common in Bangladesh; Sheikh and colleagues found IgM antibodies against HEV in 63.6% of patients with ALF, 83.3% of HBV carriers and in 7.3% of apparently healthy persons in their study . MoreoveStudies in Bangladesh and India have demonstrated that cerebral oedema resulting in raised intracranial pressure (ICP) is an important cause of morbidity and mortality in HEV-induced ALF \u20138. ManniAcharya and co-workers in India found that outcome of ALF in pregnant subjects was similar to that in non-pregnant subjects, and one-third of ALF patients in their study survived with aggressive conservative management . The autExamining the baseline characteristics and clinical outcome of HEV-induced ALF at 5 daysDetecting raised ICP clinically and observing response to mannitol infusion, a key treatment given for HEV-associated cerebral oedema in Bangladeshi patients with ALFWe did this study during an HEV epidemic in a major Bangladesh referral centre to audit treatment given to patients with HEV-induced ALF and to assess the effectiveness of intensive care support in the epidemic. We did this by using the clinical tools available in this resource-poor country:This was a prospective cohort study on baseline characteristics and clinical outcomes of 20 patients admitted to the intensive care unit (ICU) of Chattogram Maa-O-Shishu Hospital (CMOSH) in Chattogram (Chittagong), Bangladesh, with hepatitis E-induced ALF during an epidemic from June 2018 until August 2018 .ALF was diagnosed by clinical detection of encephalopathy and raised INR within 24 weeks of development of jaundice , 19. ALFHE grade was defined by West Haven Criteria as follows: grade 1, any alteration in mentation; grade 2, somnolent or obtunded, but easily rousable or presence of asterixis; grade 3, rousable with difficulty; and grade 4, unresponsive to deep pain , 21.We diagnosed HEV by serum anti-HEV IgM antibody , 23. AllWe selectively intubated subjects with Glasgow Coma Scale (GCS) \u22648 and/or respiratory acidosis in the setting of severe HE  .We collected data regarding treatment, monitoring and hemodynamic and laboratory values daily for the first 5 days after admission to ICU. We monitored all patients for oxygenation, vital signs and raised ICP. A diagnosis of raised ICP was made when neurological examination revealed either decerebrate posture or two of the following four criteria: (1) hypertension (supine blood pressure > 150/90 mmHg), (2) bradycardia (pulse rate < 10/min for the expected pulse rate for the given body temperature), (3) pupillary changes and (4) neurogenic hyperventilation (hyperventilation in the absence of metabolic or respiratory cause) .We infused an intravenous bolus of 20% mannitol in ten patients with a clinical diagnosis of raised ICP. We corrected any metabolic derangement before mannitol infusion, and all patients received standard anti-coma and supportive measures , 26. Onlp value of <0.05 was considered significant. We defined outcomes as HE deterioration and deterioration of GCS after 5-day stay in the ICU.We performed statistical analysis using the STATA software, version 13 , expressing continuous variables as mean, standard error, and confidence intervals, with categorical variables as frequencies and percentages. We compared continuous data using two-sample Wilcoxon rank-sum (Mann-Whitney) test and categorical data using Fisher\u2019s exact test. A A total of 20 subjects were included in the study. Table HE worsened in eight subjects (40%); seven among them (87.5%) were female, and of these, three (37.5%) were pregnant individuals. GCS deteriorated in six (30%); of these, all (100%) were females, and of those, three (50%) were pregnant.The majority (75%) among our subjects were female. Seven (46.67%) out of 15 females and one (20%) out of five male subjects developed HE deterioration. HE deterioration was not significantly different between male and female subjects (Fisher\u2019s exact=0.603).Six (40%) out of 15 female subjects and none (0%) out of five male subjects developed deterioration of GCS. Deterioration of GCS was not significantly different between male and female subjects (Fisher\u2019s exact = 0.260).Seven (35%) out of 20 subjects were pregnant. Three (42.86%) out of seven pregnant subjects and five (38.46%) out of 13 non-pregnant subjects developed HE deterioration. HE deterioration was not statistically significantly different between pregnant and non-pregnant subjects (Fisher\u2019s exact=1.000). Three (42.86%) out of seven pregnant subjects and three (23.08%) out of 13 non-pregnant subjects developed deterioration of GCS. Deterioration of GCS grades was not significantly different between pregnant and not pregnant individuals (Fisher\u2019s exact=0.613).p=0.260). Three (42.86%) out of seven pregnant subjects and three (23.08%) out of 13 non-pregnant subjects met King\u2019s College Criteria for liver transplantation (Fisher\u2019s exact = 0.613). Four (66.67%) among these six subjects developed HE deterioration (p=0.018), and five (83.33%) developed deterioration of GCS (Fisher\u2019s exact=0.002).Six (30%) out of 20 subjects met King\u2019s College Criteria for liver transplantation. Six (40%) out of 15 female and none (0%) out of five male subjects met King\u2019s College Criteria for liver transplantation  out of 20 subjects received mannitol infusion. Two patients  with raised ICP could not be given mannitol infusion because of renal impairment (serum creatinine more than 4.5 mg/dL). Seven (46.67%) out of 15 female and three (60%) out of five male subjects received a mannitol infusion. Three (42.86%) out of seven pregnant subjects received a mannitol infusion.HE deteriorated in 2 (10%) out of 10 patients who received and 6 (30%) out of 10 patients who did not receive mannitol. HE deterioration was not significantly different between patients who received and those who did not receive mannitol (1-sided Fisher\u2019s exact = 0.085).GCS deteriorated in 1 (5%) out of 10 patients that received a mannitol infusion and 5 (25%) out of 10 patients who did not receive a mannitol infusion. Deterioration of GCS was also not significantly different between subjects who received mannitol and those who did not receive mannitol (1-sided Fisher\u2019s exact = 0.070).Seven (35%) out of 20 subjects: three out of five males, four out of 15 females and of these, two out of seven pregnant subjects, received mechanical ventilation on day 1. Nine (55%) out of 20 subjects: three out of five males and six out of 15 females and out of these, three out of seven pregnant subjects, received mechanical ventilation on day 2. On day 3, nine out of 19 subjects: two out of four male subjects and seven out of 15 female subjects and of these, three out of seven pregnant subjects, received mechanical ventilation. On day 4, seven out of 17 subjects: two out of four male subjects and five out of 13 female subjects and of these, one out of five pregnant subjects, were ventilated. On day 5, seven out of 17 subjects: two out of four male subjects and five out of 13 female subjects and of these, one out of five pregnant patients, were ventilated.From day 1 to day 3, a total of seven  subjects received vasopressor support. On day 4 and day 5, six  subjects received vasopressor support.Haemodialysis was started when subjects developed renal failure  with a normal central venous pressure: two subjects\u2014a female, 22 years (creatinine 8.2 mg/dL), second, a female, 60 years (serum creatinine 7.1 mg/dL)). Both received haemodialysis for 5 days in ICU.This study reports the acute outcomes in a typical resource-poor setting in Bangladesh. The majority (75%) of subjects were female. Seven (35%) patients in our study were pregnant. Three (42.86%) out of 7 pregnant subjects and 3 (23.08%) out of 13 non-pregnant subjects had worsening of HE. Deterioration of HE was not statistically significantly different between pregnant and non-pregnant subjects (Fisher\u2019s exact = 1.000).In a previous study on this HEV epidemic in Chattogram (Chittagong), Bangladesh, we found that among 230 of our patients 24 (10.4%) had developed ALF. Four (1.8%) among them died due to multiorgan failure with acute kidney injury, and all were pregnant .Other studies in Bangladesh also found that women, especially pregnant women, were more susceptible to HEV-induced ALF and had worse outcome when they developed ALF , 5. MoreIn prospective studies comparing HEV hepatitis and non-HEV hepatitis in India, the authors observed that 55\u201370% of pregnant subjects with HEV hepatitis and 10\u201320% of pregnant subjects with non-HEV hepatitis developed liver failure , 28. FurP = 0.572). The authors also observed that the clinical and biochemical profile, disease intensity and sequelae were also comparable in those three study groups. Although a significantly higher percentage of ALF was attributable to HEV among pregnant subjects (59.4%) in comparison to both non-pregnant women and girls (30.4%) and men and boys (23.1%), (P < 0.001), the outcome of HEV-induced ALF had no association with the gender and pregnancy status of the subjects (P = 0.103). Furthermore, the mortality of pregnant subjects in HEV-induced ALF of 51% (74/145) and non-HEV-induced ALF of 54.7% (52/95) was not significant (P > 0.1). In addition, the authors also found that the outcome in HEV-induced ALF in pregnant subjects was not associated with the trimester of pregnancy.On the other hand, in a study in India, which included 20 years\u2019 data from a single tertiary centre, the authors observed that pregnant and non-pregnant subjects had equal chances of developing HEV-induced ALF . In thatShalimar and colleagues in their study observed that the increased HEV-induced ALF and resulting mortality might be due to the increased susceptibility of women, especially pregnant women, to HEV infection during an epidemic in affected populations . MoreoveAccording to a study in Bangladesh , cerebrap= 0.085) or GCS deterioration (p= 0.070), the reason for this can be explained by the small sample size of the study.We found that 12 (60%) among our 20 subjects showed clinical features of raised ICP. Ten (50%) subjects received mannitol infusion. HE deteriorated in two (10%) out of 10 subjects who received mannitol and 6 (30%) out of 10 subjects who did not receive mannitol. GCS deteriorated in one (5%) out of 10 subjects who received and 5 (25%) out of 10 subjects who did not receive mannitol. Although the outcome was not found to be statistically significant for either HE worsening (p<0001) [p 0.008).Canalese and co-workers compared the effects of prophylactic dexamethasone and mannitol infusion to revert cerebral oedema in subjects with ALF with HE grade IV in a randomised controlled clinical trial. Cerebral oedema resolved significantly more frequently in 17 among 34 subjects who received mannitol and in 17 among 34 subjects who did not (p<0001) . SurvivaAcharya and colleagues  in IndiaShalimar and his colleagues also observed that MELD, an ALF study group model, and King\u2019s College Hospital criteria failed to predict outcome in HEV-induced ALF. In our study, six patients (30%) met King\u2019s College Criteria for liver transplantation. Four (66.67%) among those 6 patients developed deterioration of their encephalopathy grades (Fisher\u2019s exact =0.018), and 5 (83.33%) developed deterioration of GCS (Fisher\u2019s exact=0.002) [Most of our patients were transferred from different inpatient units\u2014medicine, obstetrics and surgery when they were diagnosed as having HEV-induced ALF. We could not take a detailed history from the patients or look for other causes which could have modified the clinical illness in our subjects owing to cerebral obtundation. Furthermore, we could not test for HEV RNA and detect the HEV genotype in our subjects, owing to resource issues.Moreover, we diagnosed raised ICP, based on clinical parameters, which may not be optimum in some cases, again owing to lack of resources. The sensitivity and specificity of clinical parameters for the diagnosis of raised ICP in the settings of ALF are low. Neurological examination and clinically establishing raised ICP in these patients can be challenging .Most of our patients were female, and many among them were pregnant. Female patients developed worse outcome than male patients. Pregnancy status was not associated with worse outcome in our cohort. More than 50% of our subjects had cerebral oedema, as evidenced by clinical signs of raised ICP. Mannitol infusion, although not found to be statistically significant, was observed to improve outcome in them. Future directions should be early detection of cerebral oedema using more sophisticated imaging techniques and management of cerebral oedema using new therapeutic agents. Finally, HEV infection is common in Bangladesh, and HEV epidemics can result in significant morbidity and mortality in vulnerable populations, which include women and especially pregnant women. Aggressive conservative management with proper ICU protocols of HEV-induced ALF may save many lives."}
+{"text": "This cross-sectional study evaluates measures of health equity in COVID-19 vaccination plans in the 50 US states and Washington, DC. This study aims to determine how every state planned to ensure equitable vaccine distribution.SARS-CoV-2 and the resulting COVID-19 pandemic has affected more than 106 million people worldwide with more than 2.31 million deaths as of February 2021.STROBE) reporting guideline.This cross-sectional study was reviewed by the University of Chicago institutional review board and determined to be exempt. Informed consent was waived because no personal or patient data was used. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (3 Each plan was reviewed by 2 authors (A.H. and T.W.) and evaluated with a focus on how all populations would have equitable access to a COVID-19 vaccine.Investigators analyzed the publicly available COVID-19 vaccination plan for each state and Washington DC, which was accessible on each state\u2019s department of health website. We examined state-specific vaccination distribution models in relation to the US Centers for Disease Control and Prevention COVID-19 Vaccination Program Interim Playbook for Jurisdiction Operations, which was initially created on September 16, 2020.Data were collected using a standardized questionnaire seeking demographic characteristics and vaccine distribution information for each state. This information included the plan publication date, last updated plan version, vaccination plan committee information, number of distribution phases, demographic characteristics and vaccine allotment quantity per phase, conditions listed as high-risk, use of a health equity task force or diversity strategies, vaccine program monitoring techniques, implementation measures, metrics of distribution success, and communication strategies to maximize distribution  created a committee to develop a COVID-19 vaccine distribution plan. A health equity committee was referenced in 20 plans (39%) and not referenced in 31 plans (61%). An implementation committee was referenced in 14 (27%) plans and not referenced in 37 (73%) of the plans. Of the 20 health equity committees, 12 committees reported the types of members involved which included physicians (11 of 12 [92%]), government officials (6 of 12 [50%]), ethicists (4 of 12 [33%]), minority group representations (8 of 12 [67%]), and clergy (5 of 12 [42%]). Of the 51 plans, minority group representatives were present in 8 (16%) of the reported vaccination plans and 26 (51%) of the states collaborating with organizations that serve minority populations. The total number of distribution phases ranged from 3 to 7 with a median of 4. Estimated vaccine allotments per phase and vulnerable patient populations were presented in 14 (27%) and 24 (47%) plans, respectively. High-risk conditions are noted in the 4 States without a health equity committee used partnerships to ensure diversity and equitable vaccine allocation. However, these partnerships also lacked racial/ethnic minority representation, with only 51% of states collaborating with organizations serving minority populations. Additionally, ethicists can identify priority populations during the national allocation of limited COVID-19 vaccines; however, health equity committees were not likely to include an ethicist.5 A limitation of this study is that 41 vaccination plans were not finalized at the time of review and may have been modified after initial distribution phases were completed. Future studies should evaluate whether current protocols may lead to inequities in vaccine distribution during subsequent phases and how inequities will be addressed in future vaccination plan updates.In this cross-sectional study, most COVID-19 vaccination plans were created without advisement from a health equity committee. This is concerning because there is a disproportionate burden of severe COVID-19 disease and mortality among racial and ethnic minority groups. However, minority group representatives were present in only 67% of health equity committees and 16% of all reported vaccination plans."}
+{"text": "The impact of COVID-19 on dementia caregivers is gaining new interest. It is unknown how the pandemic has impacted caregivers\u2019 burden and existential suffering. Analyses were performed on data for dementia caregivers (n=89) enrolled in the Indiana University Telephone Acceptance and Commitment Therapy for Caregivers (TACTICs) pilot trials. Individuals were primary caregivers of a family member with dementia and had clinically significant anxiety measured by a GAD-7 score >10 or between 5-9 with reported interference in life. COVID-19 anxiety was measured using the NIH CoRonavIruS Health Impact Survey (CRISIS) questions. Caregivers were on average 55.2 years of age with 56.2% being child or child-in-law, 71.9% were white and 24.7% were Black. Mean burden scores, measured by the Zarit Burden Index, were higher (44.29) compared to means reported across the literature (26.7) indicating the sample experienced higher than normal levels of burden. Mean existential suffering scores measured by the subscale of Experience of Suffering Scale were lower (9.37) compared to means across the literature (11.5) indicating that overall participants experienced lower levels of existential suffering compared to those in previous studies. A significant relationship was found between COVID-19 anxiety and burden levels , with higher levels of COVID-19 anxiety associated with greater burden. A non-significant relationship was found between COVID-19 anxiety and existential suffering . Results highlight the impact of COVID-19 anxiety as an external stressor on dementia caregiving. and the importance of considering context of external stressors when implementing intervention protocols for caregivers of individuals with dementia."}
+{"text": "Autograft (AG) is the standard of care treatment for deep burns but requires creation of a donor site wound prone to pain and scarring. Treatment with a bioengineered allogeneic cellularized construct (BACC) is an alternative approach that can reduce or eliminate the need for autografting. The BACC is a bilayer construct that was recently approved in the US for the treatment of adult deep partial-thickness (DPT) burns. Here, we report the analysis of pooled safety data from two open-label, randomized, controlled trials (STRATA2011 [NCT01437852] and STRATA2016 [NCT03005106]) that evaluated efficacy and safety of BACC versus autografting in patients with DPT burns.2 (range: 12.0\u2013960.0 cm2). The safety endpoints assessed at each visit included: 1) treatment-emergent adverse events (TEAEs), treatment-related AEs (TRAEs), and serious AEs (SAEs); 2) changes in immunologic responses ; 3) persistence of allogeneic DNA; and 4) laboratory exam and vital signs.The trials enrolled 101 patients aged \u226518 years with 3\u201349% total body surface area (TBSA) thermal burns. In each patient, two DPT areas on the torso or extremities were randomized to receive BACC or AG, where the mean total BACC dosage was 234.8 cmEighty-seven patients (86.1%) experienced TEAEs, 30 patients (29.7%) experienced TRAEs, and 16 patients (15.8%) experienced SAEs. The most frequent TEAEs reported by \u226510% of patients in the pooled analysis were pruritus  and blister, hypertension, and hypertrophic scar . The most frequent TRAEs (\u22655% of patients) were pruritus  and blister . The most common SAEs were transplant (BACC or AG) failure, pneumonia, and deep vein thrombosis , where only one SAE  was possibly related to BACC. One patient (1%) discontinued the trial due to a TEAE (traumatic brain injury). Two patients (2%) experienced SAEs that led to death, neither related to BACC. The number of patients with positive PRA values that were negative at baseline were 36 (38.7%) at Day 28 and 20 (22%) at Month 3. The number of patients with reactivity to HLA I class alleles found in the BACC increased from 4 (4%) at baseline to 39 (40.9%) at Day 28, then decreased to 22 (24.2%) at Month 3. No persistence of allogeneic DNA from the BACC was detected.BACC is well tolerated and is not associated with any unexpected SAEs or TEAEs. The safety profile at BACC treatment sites is similar to that at AG treatment sites. Thus, BACC may offer a safe alternative to autografting for the treatment of DPT burns."}
+{"text": "As of May 2, 2021, U.S. nursing homes (NHs) have reported >651,000 COVID-19 cases and >132,000 deaths to CDC\u2019s National Healthcare Safety Network. Since U.S. COVID-19 vaccination coverage is increasing, we investigate the role of vaccination in controlling future COVID-19 outbreaks. We developed a stochastic, compartmental model of SARS-CoV-2 transmission in a theoretical 100-bed NH with a staff of 99 healthcare personnel (HCP) in a community of 20,000 people. We modeled admission and discharge of residents (parameterized with Centers for Medicare & Medicaid Services data), assuming the following: temporary replacement of HCP when tested positive; daily visits to NH residents; isolation of COVID-19 positive residents; personal protective equipment (PPE) use by HCP; and symptom-based testing of residents and staff plus weekly asymptomatic testing of HCP and facility-wide outbreak testing once a COVID-19 case is identified. We systematically varied coverage of an mRNA vaccine among residents and HCP, and in the community. Simulations also varied PPE adherence, defined as the percentage of time in the facility that HCP properly used recommended PPE . Infection was initialized in the community with 40 infectious cases, and initial infection in the NH was allowed after 14 days of vaccine dose 1. Simulations were run for 6 months after dose 2 in the NH. Results were summarized over 1000 simulations.At 60% community coverage, expected cumulative symptomatic resident cases over 6 months were \u22645, due to low importation of COVID-19 infection from the community, with further reduction at higher coverage among HCP . Uncertainty bounds narrowed as NH resident coverage or PPE adherence increased. Results were similar if testing of staff and residents stopped. Probability of an outbreak within 4 weeks of dose 2 remained below 5% with high community coverage . Figure 1. Drop in symptomatic cases in nursing home (NH) residents with rise in COVID-19 vaccine coverage in the community, increase in personal protective equipment (PPE) adherence, or increase in coverage among NH residents.In each panel, we plotted the mean number of cumulative symptomatic cases of COVID-19 in NH residents after 6 months since vaccine dose 2 (given 28 days after dose 1) and their 90% confidence interval (CI) for three healthcare personnel (HCP) coverage scenarios: 40%, 60%, or 80%. Coverage in HCP was independently modeled of community coverage. The top row is for NH resident coverage of 65%, the middle for 75%, and the bottom row for 85%. The columns (left to right) are for facility-level PPE adherence of 25% (low adherence), 50% (intermediate adherence), and 75% (high adherence). Weekly asymptomatic testing of HCP and twice-weekly outbreak testing in the facility were modeled with an assumed point-of-care test sensitivity of 80% (symptomatic persons) and 60% (asymptomatic persons) and with specificity of 100% and test turnaround time of 15 minutes.Figure 2. Probability of a COVID-19 outbreak in a nursing home (NH) decreased with increase in vaccine coverage in the community or in healthcare personnel (HCP).An outbreak is defined as an occurrence of 2 or more cases within 4 weeks of dose 2. Probability of no outbreak was calculated by counting how many simulations out of a total of 1000 simulations had \u22641 symptomatic case in NH residents or HCP within 4 weeks after dose 2 was administered in the nursing home. The first vaccine dose in residents and HCP was assumed to be given on day 1, and the second dose 28 days later. A probability value and its 90%-confidence interval (CI) at a given community and HCP coverage was calculated by pooling model outputs for 9 sets  of model simulations. Simulations were performed assuming no asymptomatic testing or facility-wide outbreak testing.Results suggest that increasing community vaccination coverage leads to fewer infections in NH residents. Testing asymptomatic residents and staff may have limited value when vaccination coverage is high. High adherence to recommended PPE may increase the likelihood that future COVID-19 outbreaks can be contained.John A. Jernigan, MD, MS, Nothing to disclose"}
+{"text": "The ongoing global pandemic of coronavirus disease 2019 (COVID-19) may cause, in addition to lung disease, a wide spectrum of non-respiratory complications. Among these are thromboembolic complications. The theories that explain the mechanism of thromboembolic complications of COVID-19 are accumulating rapidly, and in addition to the role of imaging for assessment of COVID-19 pneumonia, CT may be useful for identification of these complications, such as pulmonary embolism, ischaemic stroke, mesenteric ischaemia, and acro-ischaemia.Thromboembolic manifestations were diagnosed in 10% of our patients ; 56 patients (45.2%) presented with pulmonary embolism, 32 patients (25.8%) presented with cerebrovascular manifestations, 17 patients (13.7%) presented with limb affection, and 19 patients (15.3%) presented with gastrointestinal thromboembolic complications.Most of our patients had significant comorbidities; diabetes was found in 72 patients (58%), dyslipidemia in 72 patients (58%), smoking in 71 patients (57.3%), hypertension in 63 patients (50.8%), and morbid obesity in 40 patients (32.2%).Thromboembolic events were diagnosed on admission in 41 patients (33.1%), during the first week in 61 patients (49.2%), and after the first week in 22 patients (17.7%).d-dimer levels and those with sudden clinical deterioration.The incidence of thromboembolic complications in COVID-19 patients is relatively high resulting in a multisystem thrombotic disease. In addition to the crucial role of imaging for assessment of COVID-19 pneumonia, CT is important for assessment of the thromboembolic complications, such as pulmonary embolism, ischaemic stroke, mesenteric ischaemia, and peripheral ischaemia, especially in patients with elevated  The ongoing global pandemic of coronavirus disease 2019 (COVID-19) may cause, in addition to lung disease, a wide range of non-respiratory complications due to involvement of organs by the virus or due to direct or indirect complications of this infection , 4.Other organ systems are affected due to the marked affinity of the virus for the angiotensin-converting enzyme 2 (ACE2) receptors , 6. Thusd-dimer correlated with the severity and extent of microthrombosis [Unlike hemorrhagic viruses , Covid-19 is highly prothrombotic causing alterations in the coagulation cascade that leads to a progressive elevation of rombosis .There is increasing evidence that thrombi are a major cause of multisystem organ dysfunction, including respiratory failure . A numbeCOVID-19-associated thrombotic disease is suggested to be caused by various mechanisms including direct effects of COVID-19 through severe illness and hypoxia or severe inflammatory response or an indirect effect of infection related to investigational therapies used for treating COVID-19, which may have adverse drug interactions with antiplatelet agents and anticoagulants .The theories that explain the mechanism of thromboembolic complications of COVID-19 are accumulating rapidly, and in addition to the role of CT chest for assessment of COVID-19 pneumonia, other imaging modalities may be useful for identification of these complications, such as pulmonary embolism, ischaemic stroke, mesenteric ischaemia, and acro-ischaemia.The aim of this study was to estimate the prevalence of thromboembolic manifestations among COVID-19-positive patients and to describe the imaging findings of Covid-19-positive patients who presented with acute arterial or venous thromboembolic events in the pulmonary, cerebral, abdominal, or peripheral circulation.The study protocol was approved by the local Ethics Committee. All study procedures were performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. The ethics committee\u2019s reference number is 9/2020RAD4.All patients included in this study were informed that their clinical, laboratory, and radiological data will be used in the study. A written consent was taken from all patients.Between April and July 2020, we scanned 1245 COVID-19-positive patients, 124 of them (about 10%) had developed thromboembolic manifestations, pulmonary, abdominal, cerebral, or peripheral limbs.The study included 73 males (58.9%) and 51 females (41.1%) with age ranged from 23 to 65 years old, (mean age 43.52 years \u00b1 12.21 years).Inclusion criteria included patients with confirmed Covid-19 infection who presented initially with thromboembolic symptoms or admitted to the hospital and then developed thromboembolic manifestations.Exclusion criteria included patients with thromboembolic manifestations not confirmed to be COVID-19 positive and patients with chronic thromboembolic events.Patients underwent imaging for the suspected region according to the primary manifestations. Patients with suspected stroke underwent MRI brain with DWI according to the routine stroke protocol. Positive patients with acute stroke underwent MR cerebral angiography and venography.The CT pulmonary and abdominal angiogram was performed after intravenous injection of 80\u2013120 cc of iodinated contrast media at a flow rate of 3\u20135 ml/s followed by a 30 ml saline at the same rate. Region of interest was determined, and axial scans were taken during the contrast injection until a threshold enhancement and triggering a diagnostic scan. Indirect venography was done for the patients.Patients with suspected peripheral arterial or venous acute arterial and/or venous thrombosis underwent duplex/Doppler examination of the affected limb followed by CT peripheral angiography for positive cases.All CT scans were performed on a 128-slice multidetector CT scanner.The images were assessed for presence of vascular occlusion either arterial or venous.Pulmonary CT angiography images were evaluated for location and extent of the thrombus, associated pulmonary manifestations of COVID-19, and presence of areas suggestive of lung infarction.Abdominal CT angiography images were evaluated for evidence of arterial and/or venous thrombus (location and extent); involvement of IVC and portal, mesenteric, and iliac veins; and associated manifestations of bowel ischaemia  or intestinal obstruction. Evidence of solid organs infarction was evaluated.Cerebral venogram and angiogram images were evaluated for location and extent of venous sinus thrombosis and evidence of acute arterial thrombosis and its location. Associated cerebral infarctions were evaluated for their extent and presence of hemorrhagic infarction. Evidence of diffusion restriction even with no definite vascular occlusion at angiography was considered thromboembolic events.Duplex studies and peripheral angiography of the upper and lower limbs were evaluated for presence and extent of acute venous thrombosis and presence and extent of acute arterial occlusion.d-dimer values, and ICU admission) were collected from medical records. All data were compiled and analyzed.Demographic and clinical data  developed thromboembolic manifestations  and 47 females (37.9%) with age ranged from 23 to 65 years old (mean age 43.52 years \u00b1 12.21 years). One or more comorbidities were found; diabetes was found in 72 patients (58%), dyslipidemia in 72 patients (58.1%), smoking in 71 patients (57.3%), hypertension in 63 patients (50.8%), and morbid obesity in 40 patients (32.3%).d-dimer level was very high notably in patients with pulmonary embolism (Table The sm Table . ThromboPulmonary embolism presented on admission in 34 patients (60.7%), 13 patients (23.2%) developed symptoms within the first week of admission, and 9 patients (16.1%) had pulmonary embolism after 1 week. The most presenting symptom was shortness of breath (52 patients 92.9%). Fourteen patients were presented with radiological findings that favor the evidence of lung infarction more than the classic features of COVID-19 pneumonia.Three patients (9.4%) were presented with acute stroke. Twenty-four patients (75%) developed cerebrovascular symptoms within the first week of hospital admission for respiratory manifestations. Five patients (15.6) developed cerebrovascular symptoms after 1 week of admission . Twenty-five patients (78.1%) with cerebrovascular manifestations had associated pneumonia.Ischaemic stroke has been associated with arterial thrombosis in 18 patients (40.6%) and venous sinus thrombosis in 9 patients (25%). Seven of them presented with hemorrhagic infarctions. Middle cerebral artery thrombosis was detected in 8 patients, internal carotid artery in 3 patients, anterior cerebral artery in 3 patients, basilar artery in 2 patients, and vertebral artery in 2 patients. Five patients (12.5%) presented with small infarcts identified only on MRI with no definite vascular involvement. Superior sagittal sinus thrombosis was identified in 5 patients, sigmoid sinus thrombosis in 2 patients, one patient presented with isolated straight sinus thrombosis, and one patient presented with internal jugular vein thrombosis.Seventeen patients had peripheral thromboembolic manifestations; 9 patients 52.9%) had deep venous thrombosis of the lower limb, 2 patients (11.8%) had deep venous thrombosis of the upper limb, 5 patients (29.4%) had lower limb ischaemia, and one patient (5.9%) had upper limb ischaemia. All patients with deep venous thrombosis presented with edema of the affected limb  and 2 arterial embolism (10.5%). The most presenting symptom was abdominal pain (18 patients 94.7%). Isolated superior mesenteric vein thrombosis was detected in 4 patients (21%), isolated portal vein thrombosis occurred in 3 patients (15.8%), isolated inferior vein thrombosis was detected in 1 patients (5.3%), and combination of more than one vein thrombosis was detected in 9 patients (47.4%). Arterial thrombosis was detected in the superior mesenteric artery in 2 patients (10.5%), and both presented with bowel ischaemia and intestinal obstruction  have fulminant activation of coagulation and consumption of coagulation factors .In our study, we found 124 patients (about 10%) with thromboembolic manifestations out of 1245 Covid-19-positive patients, 68.5% of them were admitted to the ICU. The rate of thromboembolism reported in the literature is variable. Some studies have reported thromboembolic rates in the range of 20\u201330% while others have reported rates as high as 40\u201370% [s 40\u201370% . The numIn our study, 85 patients (68.5%) were admitted to the ICU.The presence of hypercoagulation and thromboembolic complications had been noted to correlate with disease severity and ICU admission . In our In the current study, pulmonary embolism was the most common complication presented in 56 patients 45.2%) that was similar to Grillet et al.  who stat5.2% thatd-dimer levels were significantly higher in patients with severe COVID-19 than in those with the mild disease. Lorant et al. [d-dimer levels than those without pulmonary emboli and are more likely to be admitted to the ICU. They also reported that d-dimer > 2660 ng/mL has 100% sensitivity and 67% specificity for pulmonary embolism diagnosis prediction in COVID-19 patients, and that was the same in our study which found that highest d-dimer average value was found in patients with pulmonary embolism (average 2765.45 \u00b1 169.11).In a meta-analysis conducted by Xiong et al. , they fot et al.  stated tAs a complication of pulmonary embolism, the lung infarction is rare due to the dual arterial supply of the lung, but it has been described in COVID-19 patients. On CT, lung infarction appears as ground-glass opacities in the early phases in unobstructed lung zones that represents pulmonary haemorrhage and peripheral wedge-shaped pulmonary consolidation , 19.d-dimer levels, haemoptysis, and/or sudden worsening of respiratory function or chest pain should also be considered [Therefore, the radiological findings of lung infarction from pulmonary embolism should be differentiated from GGO as well as consolidations of the COVID-19 pneumonia that may also show reverse a halo sign in about 4% of patients as this will positively impact the patient management. In non-enhanced CT, the presence of peripheral lung opacities with a reverse halo sign, dilatation of pulmonary trunk, and/or increased cardiac volume  indicate risk of PE and may aid in the decision to perform CT pulmonary angiography to confirm or exclude pulmonary embolism . Clinicansidered .d-dimer levels with dilatation of the affected segment of the pulmonary artery. The peripheral wedge-shaped consolidation was associated with thrombus of the related subsegmental artery  of them had evidence of vascular occlusion  presented with small infarcts identified only on MRI with no definite vascular involvement. Figures In our study, 17 patients had peripheral thromboembolic manifestations, 9 patients (52.9%) had deep venous thrombosis of the lower limb, 2 patients (11.8%) had deep venous thrombosis of the upper limb, 5 patients (29.4%) had lower limb ischaemia\u00a0Fig. In a study done by Wichmannet et al.  on autopBhayana et al. , in theiIn the current study, we reported 19 cases with gastrointestinal thromboembolic complications, 17 venous thrombosis (89.5%) and 2 arterial embolism (10.5%). The most presenting symptom was abdominal pain in 18 patients (94.7%). Isolated superior mesenteric vein thrombosis was detected in 4 patients (21%), isolated portal vein thrombosis occurred in 3 patients (15.8%), isolated inferior vein thrombosis was detected in 1 patients (5.3%), and combination of more than one vein thrombosis was detected in 9 patients (47.4%)\u00a0Fig. The incidence of thromboembolic complications in COVID-19 patients is relatively high, and the appropriate mechanism of these complications is the pro-coagulant pattern and the endothelial thrombo-inflammatory syndrome, which may result in multisystemic thrombotic disease.d-dimer level was more than 2600 ng/mL in 83 patients including all 56 patients with pulmonary emboli. So, in patients with high d-dimer levels on hospital admission or sudden clinical worsening, CT pulmonary angiography should be done to exclude pulmonary embolismIn our study, the Also risk factors , clinical parameters, including haemoptysis, sudden worsening of respiratory function, acute abdomen and peripheral limb edema, or chest pain should raise the suspicions of thromboembolic complications.d-dimer levels and those with sudden clinical deterioration.So, in addition to the crucial golden role of CT chest for assessment of COVID-19 pneumonia, other imaging modalities  are also important for the assessment of the thromboembolic complications, such as pulmonary emboli, cerebrovascular strokes, mesenteric vascular ischaemia, and peripheral ischaemia, especially in patients with high"}
+{"text": "Lactococcus species have seldom been considered pathogenic. However, clinically significant infections have been reported, of which few are pediatric cases, all outside the United States.Central venous catheters (CVC), may lead to central line-associated blood stream infections (CLABSIs). In the past, Lactococcus spp. admitted to a tertiary pediatric hospital from January 2018 - December 2020. We reviewed the PubMed database for cases of pediatric Lactococcus spp. infections in English, peer-reviewed literature.We retrospectively identified pediatric patients with bacteremia secondary to Lactococcus spp. bacteremia. The average patient was 17 months old . All had a CVC; two had short bowel syndrome and 1 had nephrotic syndrome. None received probiotics. Empiric treatment for all included vancomycin. Two of 3 patients were de-escalated to ceftriaxone. All isolates were susceptible to penicillin. Duration of treatment was 10-14 days. Two of 3 were managed with CVC retention and none had recurrence of infection. We identified 3 patients with A literature review revealed 9 additional cases (Table 1). The most common source of infection was blood (33%), with 66% (2/3) occurring in patients with central lines. Other sources included liver abscess (11%), brain abscess (11%), cerebrospinal fluid (11%), urine (11%), and endocarditis (22%). Median patient age was 12 months . Five of 9 patients had an underlying risk factor. Duration of therapy ranged from 7-40 days. Most definitive treatment regimens consisted of a third-generation cephalosporin (44%). Of bacteremia, 2/3 received vancomycin as part of their definitive therapy. Five of 9 reported quantitative antimicrobial sensitivity testing (AST) or interpretation of AST to beta-lactam antibiotics; 80% (4/5) were susceptible.Lactococcus infections in the United States and suggests Lactococcus spp. should be considered pathogenic in the appropriate circumstances. This series adds to the limited literature, including AST. Continued accrual of susceptibility data may raise the possibility of using a 3rd generation cephalosporin as empiric therapy for Lactococcus bacteremia.To the best of our knowledge, these are the first reported pediatric cases of All Authors: No reported disclosures"}
+{"text": "Guidelines recommend use of tocilizumab (TCZ), an inhibitor of pro-inflammatory IL-6 signaling, for hospitalized patients with progressive severe or critical Coronavirus disease 2019 (COVID-19). The incidence of infectious complications following the use of TCZ for COVID-19 has not been well-described.2) with a control group who did not receive TCZ, and were hospitalized between 10/12/2020 and 3/6/2021. The primary outcome of the study was diagnosis of a bacterial or fungal infection after day 3 of the index hospitalization. Secondary outcomes included all-cause mortality during the study period and length of stay. We conducted a retrospective, observational matched cohort study of severely ill, hospitalized adult patients with confirmed COVID-19 who were treated with TCZ between 2/24/2021 and 6/1/2021. The intervention group, comprised of patients who received a single dose of TCZ, was matched based on c-reactive protein (CRP) and fraction of inspired oxygen , reflecting the epidemiology of the outbreak during the TCZ and control study periods. 15 bacterial and fungal infections were identified in the TCZ group (20.0%) and 4 (5.3%) infections in the control group (p = 0.012). The majority of infections in both groups were bacterial, with a disproportionate number of bloodstream infections in the TCZ group . 28 patients (37.3%) died in the TCZ group compared to 39 (52.0%) in the matched control (p = 0.068). Median time to discharge was similar between TCZ and control patients .75 patients who received TCZ were identified during the study period, and matched 1:1 with 75 control patients. Baseline CRP and FiOSecondary infections in adult patients with severe and critical COVID-19 were more common in patients who had received TCZ. Prospective studies are needed to confirm and further describe this association.All Authors: No reported disclosures"}
+{"text": "IDSA has published guidelines for the diagnosis and management of prosthetic joint infection (PJI). However, we have observed significant variability in the interpretation and application of these guidelines with respect to the management of those with PJI following debridement and implant retention (DAIR). It is not clear if variations in antimicrobial management are affecting clinical outcomes.We performed a retrospective review at an academic hospital in rural New Hampshire. We included all adult patients from 1/1/2017 to 12/31/2018 with PJI of hip or knee who underwent DAIR. The demographic data, microbiology data, antibiotics treatment and duration were collected. The primary endpoint was overall re-infection rate within 2 years of surgery. Secondary endpoint was re-infection rate stratified by organism and antimicrobial type and duration.A total of 26 patients were included in our study. 65% involved knee joint. 50% had late-onset infection ( >12 months). The top organisms were Streptococcus spp. (34%), CoNS (26 %) and MSSA (18 %). 15% were associated with bacteremia. Ceftriaxone was the most common antibiotic used (54 %). 38 % of patients received Rifampin PO along with IV antibiotics. All patients received PO antibiotic(s) after completing the course of IV therapy, and 7 patients were also on concomitant rifampin PO. The duration of PO antibiotic therapy was varied. 30% of patients received PO antibiotics for 6 months post IV treatment. Life-long suppression therapy were noted in 9 patients. Treatment failure within 2 years occurred in 8 patients (31%). Among those, 75% had Staphylococcal infection. All patients required hardware removal except one patient who required amputation. 2 patients developed recurrent PJI after completing 6 months and one year of PO suppression therapy, one patient had a recurrent infection while on life-long suppression. Staphylococcal infection was significantly associated with treatment failure.Treatment of PJI with DAIR is challenging. Despite long-term IV therapy followed by oral antibiotics, there was a high rate of treatment failure (31% in our study) particularly with Staphylococcal infection. There was no association of variation of treatments and outcomes in our small cohort. All Authors: No reported disclosures"}
+{"text": "Two pneumococcal vaccines are currently recommended for use in U.S. adults: 23-valent pneumococcal polysaccharide vaccine (PPSV23) and 13-valent pneumococcal conjugate vaccine (PCV13). Recommendations for adult PCV13 use were supported by a large randomized-controlled trial (RCT) demonstrating PCV13 efficacy against pneumococcal pneumonia (PnPn) and vaccine-type (VT) PnPn in older adults. New pneumococcal conjugate vaccines are expected to be licensed for adults in late 2021 and recommendations for use among adults will be reviewed and revised, as needed. We conducted a systematic review to summarize evidence on the vaccine efficacy and effectiveness (VE) of PPSV23 and PCV13 against PnPn among adults.We conducted a search of literature published from 1998 to February 2021 on PCV13 and PPSV23 VE studies using eight reference databases. Studies targeting adults with immunocompromising conditions were excluded. VE results with 95% confidence intervals (CI) were abstracted and stratified by vaccine product, outcome evaluated (PnPn and VT PnPn), study design, and effect measure. When applicable, random effects models were used to estimate pooled VE and I-squared statistic was reported to assess heterogeneity.2=0%). Pooled VE of PPSV23 against VT PnPn from three observational studies was 18% . PPSV23 effectiveness against PnPn was limited with a pooled VE of 25%  from nine observational studies.Of 3,422 screened studies, we included 15 studies: three on PCV13 and 12 on PPSV23 (Table 1). In addition to the RCT, we identified two observational studies for PCV13 (Table 1); however, pooled VE of the observational studies was not estimated due to differences in methods for reporting results. Pooled PPSV23 VE against PnPn from two RCTs was 63% (95% CI: 31, 80 IFindings from observational studies supported PCV13 VE against VT PnPn reported in the RCT. Differences in the study design made the magnitude of PPSV23 effectiveness against PnPn and VT PnPn difficult to assess; however, findings from recent observational studies suggest PPSV23 provides limited protection against VT PnPn.All Authors: No reported disclosures"}
+{"text": "This exposes mortuary workers to a variety of health and safety hazards, which include physical, chemical, ergonomics, biological and psychosocial hazards/stressors. The aim of this study was to assess occupational health and safety practices (OHS) among government mortuary workers in Gauteng province.a cross-sectional descriptive study design was conducted between the year 2017 and 2018. A convenient sampling technique was used to sample 11 government hospitals in Gauteng Province. A total of 46 employees participated in the study. Data was collected using structured questionnaires and observational checklists. Ethical clearance and permission to conduct the study were obtained prior to the commencement of the study. Data was analyzed using Statistical Package for the Social Science (SPSS) version 25 software.thirty-one (67%) of the respondents did not know the concept of hazard. Observations indicated that 5 out of 11 (45%) facilities were well maintained with only 2 (18%) of the facilities had the participants wearing the required PPE on duty. There was no association between working experience and having a knowledge of the existing hazards. However, there was a high correlation (P<0.05) between training and adherence to safe practices.the OHS practices were poor amongst operational employees. The study highlights the significance of developing and implementing Occupational Health and Safety programmes. We recommend that these programmes should focus on occupational health and safety education, training, supervision, medical surveillance and monitoring strategies must be developed and implemented. Globally, more than 2.3 million premature deaths are recognized to be due to occupational environments; 2 million deaths result from occupational diseases, with the remaining being work-related occupational injuries . ApproxiIn South Africa, there are limited studies focusing on OHS practices among mortuary workers in a public health facility. Meel  conducteStudy design: a descriptive cross-sectional study was conducted between August 2017 and January 2018.Study population and sampling strategy: a sampling frame in the study was mortuary facilities in the 33 government hospitals based in Gauteng Province, one of South Africa\u00b4s nine provinces. A convenience sampling was used to select 18 facilities. Two hospitals refused to participate and five did not respond; ultimately 11 hospitals participated in the study. The researcher further used purposive sampling to select the participants in the identified health facility  of the study. Private undertakers were excluded from the study. A total of 46 questionnaires were completed.Data collection: to achieve the aims of the study, a semi-structured questionnaire and an observation checklist were developed by the researcher with the assistance of the supervisors. The tools were formulated and base on the requirements of the Occupational Health and Safety Act (OHSA) 85 of 1993 and Environmental Health norms and standards [tandards , 8. The Data analysis: data was captured onto a Microsoft Excel spreadsheet for coding and cleaning. Thereafter, it was transferred to the Statistical Package for Social Sciences (SPSS), version 25 for analysis. Data analysis was conducted with the assistance of a biostatistician. Tables were used to present basic descriptive analysis such as means, percentages and frequencies for the categorical variables. Inferential analyses was kept minimal, only cross tabulation was used for associations and the Fisher\u00b4s exact test was used to analyse the contingency tables.Ethical considerations: the study was granted ethical approval by the University of Johannesburg: Faculty of Health Sciences Research Ethics Committee (REC-01-91-2017). We received permission to conduct the study and approach government hospitals from the Gauteng Department of Health. The management of each hospital gave us permission to access and recruit the participants. Participant gave written consent before participating in the study.Demographic information: forty-six respondents participated in the study, 18 females (39%) and 28 male respondents (61%). Most participants (43%) were in the age group of 45 to 65 years, and there were 13 (28%) in each of the 18 to 35 years and 36 to 44-year age groups. Half of the respondents had Matric (50%), 15 (33%) had grade 11 and 6 (13%) had a certificate; a small number of participants 2 (4%) had a Baccalaureate degree. Among the participants, 15 (33%) were auxiliary workers, 13 (28%) were admin clerks, 12 (26%) were porters and 6 (13%) were cleaners.Knowledge of workplace health and safety hazards: thirty-one (67%) of the respondents did not know the concept of a hazard. Thirty-three (33%) respondents had different opinions and perceived it as something that can cause injuries, danger and or cause diseases as indicated in Thirty-six participants (78%) perceived infectious diseases as a high-risk exposure, four participants (9%) found it to be low risk and six (13%) as no risk. Working conditions were rated as the second-highest risk exposure by 25 participants (54%), 18 (39%) rated manual handling, trips, slips or falls was counted as high-risk exposure by 13 (28%), and awkward posture and chemical exposure were rated high risk by 10 (22%) participants. Most participants (76%) perceived working hours (long shifts) as no risk to their health and safety, 21 (46%) chemical exposure, 18 (39%) awkward posture, 11 (24%) blood exposure, 11 (24%) for manual handling and infectious diseases, whilst 25 (54%) perceived slips, trips or falls as having no risk towards their well-being at the workplace. Twenty-nine participants (63%) reported working conditions did contribute to their personal problems, whereas 17 (37%) said the work conditions could not affect them. Working conditions included facilities, equipment and materials used at work.In order to cope with stressful working conditions, 16 (32%) participants from the study population consulted with the Employee Health and Wellness (EHW) programme, 5 (11%) with supervisors, 4 (9%) absented from work and 4 (9%) smoked. Few participants 2 (4%) drank alcohol and only 3 (7%) would become aggressive at work; 15 (33%) confirmed to do nothing. Those who consulted with EHW listed other measures, such as visiting private doctors, human resources, talking with colleagues as well as consulting with their religious groups.On the high-risk rating scale of contracting occupational diseases, 34 (74%) participants were concerned about being at high risk of contracting occupational Tuberculosis (TB), 22 (48%) Hepatitis B or C, 21 (46%) Meningococcal Meningitis, 19 (41%) Septicaemia and 17 (37%) Human immunodeficiency virus (HIV). Twenty participants (43%) were not at all concerned about contracting HIV at the workplace, 18 (39%) Meningococcal Meningitis, 19 (41%) Septicaemia, 11 (24%) Hepatitis B or C and five (11%) TB. Twenty-five participants (54%) disclosed they were once diagnosed with a medical condition related to work and 21 (46%) said they were never diagnosed. About 25 (54%) of the study population sustained an occupational medical condition. Amongst the 25 participants, 16 (64%) sustained occupational injuries and the remaining occupational diseases.According to Fisher\u00b4s Exact Test, there is no significance between gender and the likelihood of being diagnosed with an occupational medical condition associated with working in the mortuary . However, a little difference was illustrated as 20 (71%) males were diagnosed with an occupational medical condition compared to the 10 (56%) females. When classifying the type of medical conditions by gender, 12 out of 20 (75%) males sustained injuries compared to 4 out of 10 (40%) females. Eight out of 20 (40%) males and 7 out of 10 (70%) females reported for occupational disease. Knowledge of transmission routes of infections: thirty-nine participants claimed to know the routes of exposure. One (2%) identified inhalation, 1 (2%) ingestion, 6 (13%) cuts or abrasion and 16 (35%) identified skin contact as route of exposure. The seven participants who did not know the routes of exposure, three (43%) were diagnosed with a medical condition.Vaccination: all the respondents thought it was important to be vaccinated. About 30 (65%) participants have been vaccinated during their course of employment, whereas 16 (35%) have never been vaccinated in their current employment. The Fisher\u00b4s Exact Test had a p-value of 0.063, which is larger than 0.05, thus there is no correlation between the years of working experience and the likelihood of being vaccinated. The type of vaccination varies depending on the type of microbiological agents and legislative requirements associated with a specific occupational activity. Most of the participants 17 (57%) had been vaccinated against Hepatitis C, 5 (17%) Hepatitis B, 1 (3%) Meningococcal Meningitis, 1 (3%) Tetanus, 1 (3%) all the mentioned vaccines, 4 (13%) were unsure of the type of vaccine received. Twenty-one participants had gone for pre-medical surveillance before employment at their current workplace and 25 (54%) never went. Half of the participants 27 (59%) never went for continuous medical surveillance, 14 (30%) attended yearly and 5 (11%) underwent after more than 5 years.Adherence to health and safety: forty participants (87%) alleged to be knowing the systems of reporting occupational incidences or accidents, 2 (4%) unsure and 4 (7%) did not know them. Eighteen participants (39%) claimed to have access to the summary of OHSA 85 of 1993, 26 (57%) did not have any access, and 2 (4%) unsure. Approximately 36 (78%) participants claimed to have standard operating procedures (SOPs) available at their workplace, 7 (15%) did not have and 3 (6%) were unsure. Twenty-nine participants (63%) had received training on SOPs, whilst 17 (37%) had never been trained. Thirty-four (74%) participants claimed to follow the SOPs, 2 (4%) were not sure and 10 (22%) confirmed to not follow them. All the participants who received training on SOPs followed them, whereas 10 (67%) who did not receive training did not follow the SOP. According to Fisher\u00b4s Exact Test, p = 0.00, which is less than 0.05, Phi=0.754 is greater than 0.5 large effect, thus there is a high correlation between training and adherence.Twenty-six participants (57%) did not receive Personal Protective Equipment (PPE) from the employer and used their own personal clothes; about 20 (43%) were provided with PPE by the employer. It was observed that the participants (100%) had facemasks readily available for use, 45 (98%) had surgical gloves, 27 (57%) cleaning plastic aprons and 24 (52%) waterproof footwear. Few participants (39%) had safety glasses, 16 (34%) cut resistant gloves, 14 (30%) surgical shirts and trousers, only 10 (22%) were provided with long-sleeved gowns. Fit test on PPE was done for the 11 (24%) participants. Less than half the participants (48%) used PPE every time, 13 (28%) sometimes and 12 (26%) never use it. Majority of participants 27 (59%) never took PPE home, 16 (35%) took it every time and three (7%) took it sometimes. There were few challenges associated with the use of PPE. Nine participants (20%) had allergies towards latex, 4 (7%) complained about the sizes and 16 (35%) lacked storage for the PPE. Eleven participants identified other challenges such as staff sharing PPE (2%), 1 (2%) PPE being of poor quality and 9 (20%) confirmed delay in procurement. However, 6 (13%) did not mention any challenges with regards to the use and provision of PPE. Many participants (80%) claimed to their SHE Representatives and 9 (20%) did not. Half of the participants (50%) did not have meetings, five (11%) attended weekly, three (7%) monthly, eight (17%) quarterly and seven (15%) met yearly.Sources of information: few participants (33%) conducted safety talks to visitors or clients, including any staff member that visited their mortuary facilities, whereas 31 (67%) participants do induct the visitors. Twenty-three participants (50%) received information from OHS or EHW staff nurses, 20 (44%) from Environmental Health Practitioners (EHPs), 3 (6%) from other sources such as Safety, Health, Environmental (SHE) Representatives, Human Resource Management (HRM) or supervisors.Summary of observational checklist: the summary of the observations indicates that 5 (45%) facilities have their participants` PPE well-maintained and 2 (18%) have their participants wearing the required PPE on duty. The frequently used PPE set was observed to be facemasks and surgical gloves. Storage places for PPE were provided to 8 (73%) of the facilities. Five facilities (45%) were well maintained structurally, with well-functioning ablution facilities as well as proper safety signages. Three facilities (27%) had a foul smell. Trolleys for transporting corpses were adjustable, clean and in good working conditions in 7 (64%) facilities. Only 2 (18%) of the facilities segregated the infectious from non-infections corpses in storage as well as storing chemicals safely. Temporary storage for waste was kept in good order in 7 (64%) of the facilities. None of the facilities (100%) had evacuation plans available. A summary of the OSHA 85 of 1993 was seen at 1 (2%) facility.Although the dead are not regarded as being a health hazard, mortuary workers are at increased risk of occupational hazards when handling the bodies . The lev\"the internal healthcare practitioners do not regard their illness as work-related and perceive the participants seeks a token of absenteeism, hence the use of private consultation\". This statement indicates there are poor advocacy and awareness towards the mortuary workers regarding EHW services and that there is a need to for EHW practitioners to reach out to the employees in the healthcare sector. An emerging issue shows that OHS challenges do not only contribute to contracting occupational diseases or sustaining injuries but also can have an impact on the morale, health and productivity of employees. This study revealed that they already account for 9% of absenteeism in the study population. They also have an influence on behavioural change, which shifts from healthy behaviour to unhealthy, such as becoming aggressive and addictiveness to smoking. The results revealed that the most likely workers to be vaccinated during their employment are those with less than 5 years\u00b4 experience as compared to the ones with above 5 years. This can be due to some hospitals having just introduced the vaccination programme and other managers mentioned they are yet to develop a programme for vaccination of high-risk employees. Most participants were vaccinated against Hepatitis and few were not sure of the type of vaccines they had received. The OHSA 85 of 1993 requires that workers be taken for medical surveillance before or within 14 days after commencement of employment where any exposure exists, however poor conformance was noted as well as on the frequency of undergoing for periodic assessment [According to reports, low literacy levels have been associated with a high incidence rate ; the stasessment .The results of this study suggests that mortuary attendants are without formal education, which might be a crucial risk factor to have basic knowledge of safe practices and behaviour . SimilarThe findings in this study were consistent with a study in Nigeria, which described mortuaries as abandoned and not considered as a priority in resource allocation , 17. TheThis study identified gaps in the OHS knowledge, practice and implementation of OHS within government mortuaries. Hence, we recommend future research/studies on the following areas: investigating the prevalence and incident of occupational diseases and injuries; compliance of mortuary services to environmental health norms and standards; the effectiveness of OHS policies or control measures in the mortuary workplace; the impact of capacity on the health and safety practices, the impact of temperature on the health of employees, surface contamination in the mortuary; quality of air or efficiency of the ventilation system in the mortuaries, as well as the efficiency of the PPE used by the mortuary workers.Occupational health and safety objectives are to ensure the protection of employees, the public and the environment from the detrimental effects that can arise from working activities. Government mortuaries, as temporary storage for the deceased, harbor all kinds of hazards, which through literature are proven to possess properties that may cause allergy, toxicity or harm to health and safety. Several literatures as referenced in the main body of the manuscript have shown that there is paucity of information on occupational exposure in mortuary settings, especially in developing countries. The summary of the study indicated that harm could occur to both the workers and employers through the loss of time and production due to uncontrolled occupational conditions. As such, mortuary workers in Gauteng Province government mortuaries are not exempt from complying with OHS practice. This study found that workers do have a fair knowledge of OHS but do not adhere to safe work practices. There are gaps identified in the study which may lead to poor practices, and the main gaps include lack of training on workplace safety procedure, provision and maintenance of PPE, as well as ensuring continuous medical surveillance in the workplace. Just as in any profession, some of the risks can be prevented, eliminated, minimized and/or controlled.Current health and safety mitigatory measures in mortuaries are insufficient;There is no formal education relating to safe mortuary practices and behaviour;An unsafe work environment contributes to the incident of acquiring occupational diseases and sustaining injuries on duty.Despite the lack of formal training, a number of gaps are identified which contributes to poor health and safety practices;OHS challenges also have an impact on the morale, health and productivity of employees;Advocacy and awareness on utilization of Employee Health and Wellness Services rendered by employers must be strengthened among mortuary workers and other healthcare practitioners."}
+{"text": "This study aims to describe outcomes of posteriorly-placed glaucoma drainage devices (GDD) with concurrent endoscopic vitrectomy in pediatric patients with glaucoma and corneal opacification.This retrospective case series identified patients under 18 years of age who underwent posteriorly-placed GDD implantation with concurrent endoscopic vitrectomy between 2012 and 2021. Data collected included ocular diagnoses, prior intraocular surgeries, type and position of GDD, surgical complications, and additional surgeries. Preoperative and final visual acuity, intraocular pressure (IOP), number of glaucoma medications, and exam findings were also recorded. Surgical data included type and position of GDD, Success was defined as IOP between 5-21 mmHg without visually devastating complication or need for additional glaucoma surgery.p<0.0001) IOP-lowering medications. Additional complications included retinal detachment (2), chronic corneal graft failure (2), phthisis (1) and band keratopathy (1).Ten patients (14 eyes) with sclerocornea (6), Peters Anomaly (4), corneal decompensation from increased IOP (3), and corneal scar (1) underwent combined endoscopic vitrectomy with posteriorly-placed GDD (Baerveldt (10 eyes), Ahmed (4 eyes)) at 4.6 \u00b1 5.8 years of age. Four eyes of 3 patients remained successful at final follow-up, while 10 eyes of 7 patients required 2.4 \u00b1 1.3 additional surgeries for glaucoma (7) or hypotony (3). Kaplan Meier analysis demonstrated 1- and 2-year survival rates of 36% and 18%, respectively. At final follow-up (3.7 \u00b1 2.4 years), after an average of 4.4 \u00b1 2.4 glaucoma surgeries, 13 of 14 eyes had obtained IOP control on significantly fewer (Management of glaucoma in pediatric eyes with corneal opacification is challenging and often requires multiple surgeries. A combined endoscopic vitrectomy and posteriorly placed GDD is a viable technique to establish aqueous humor outflow. Although the success rate is low, this surgical approach may be useful in ultimately obtaining IOP control and preserving vision in these complex eyes.The online version contains supplementary material available at 10.1186/s12886-022-02373-3. Glaucoma drainage devices (GDD) are a well-established treatment for medication-refractory glaucoma in children \u20134. TubesA retrospective case series identified patients 18 years of age or younger who underwent endoscopic pars plana vitrectomy combined with posteriorly-placed GDD at the University of Michigan between January 2012 and January 2021. This study was approved by the Institutional Review Board at the University of Michigan and adhered to the tenets of the Declaration of Helsinki. As a retrospective study, obtaining informed consent from the patients was waived by the Institutional Review Board at the University of Michigan. Data collection was de-identified and HIPAA compliant.Surgical data collected included age at the time of surgery, ocular diagnoses, previous intraocular surgeries, surgical procedure details, and complications. Preoperative (last recorded before surgery) and final exam details included best-corrected visual acuity (BCVA), intraocular pressure (IOP), slit lamp findings, and number of glaucoma medications . IOP was measured by Icare , Tono-pen  or Goldmann applanation. Change in BCVA was defined as 2 or more line difference in optotype testing or a change between the ability to count fingers, detect hand motion, and distinguish light.The primary outcome measure was GDD success. Success was defined as IOP between 5 and 21 mmHg, no visually devastating complication, and no additional IOP-related surgery. The secondary outcomes were IOP at final follow-up and change in BCVA between final follow-up and initial presentation.All GDD implantations were performed under general anesthesia by the same surgeon (BLB) as previously described , 14. GDDThe surgical technique employed was previously described in Ozgonul et al.  Briefly,For statistical analyses all tests including Wilcoxon Rank Sum test  and Kaplan-Meier survival curves with Log-rank (Mantel-Cox) test and accompanying 95% confidence intervals (CI) were performed with SPSS . All tests were 2-sided, and p-values less than 0.05 were considered statistically significant.Fourteen eyes of 10 pediatric patients underwent an endoscopic vitrectomy with concurrent posterior placement of a GDD. All eyes had corneal opacification and glaucoma due to  were less than 3 years of age and unable to cooperate for quantitative visual testing. Eight of these eyes were reactive to light and 2 could fix and follow. The remaining 4 eyes of 3 patients that were old enough for optotype acuity ranged from light perception to 20/125  and the mean time of follow-up was 3.7 \u00b1 2.4 years . Implanted GDDs included Ahmed FP7 (2 eyes of 2 patients), Ahmed FP8 (2 eyes of 1 patient), BV250 (4 eyes of 3 patients), and BV350 (6 eyes of 5 patients). All plates were positioned in the superotemporal quadrant, with the exception of one Ahmed FP7 which was placed superonasally due to scleral thinning at the site of a previous trabeculotomy. Six eyes of 3 patients underwent concurrent lens extraction and were left aphakic. One eye had cryotherapy for a vitreous tag secondary to persistent fetal vasculature. One eye had explantation of an encapsulated AGV.p=0.0003) than the other 10 eyes . Seven eyes of six patients required additional glaucoma surgery for increased IOP (Table Four eyes (29%) of 3 patients were successful at time of final follow-up, while 10 eyes (71%) of 7 patients required at least 1 additional surgery  for glaucoma or hypotony. Kaplan-Meier analysis demonstrated 1- and 2-year survival rates of 36% with 95% CI and 18% with 95% CI, respectively  compared to preoperative values. A total of 4.4 \u00b1 2.4 surgeries/eye  were performed to obtain pressure control. The most successful approach  combined cycloablation either prior to (5 eyes) or following (3 eyes) endoscopic vitrectomy and posteriorly-placed GDD. Eleven eyes showed improved (7 eyes of 4 patients) or stable (4 eyes of 4 patients) visual acuity at final follow-up. Three eyes had worse vision due to phthisis, chronic graft failure, and band keratopathy.At final follow-up, 1 eye was phthisical, however, IOP control was obtained in the remaining 13 eyes such that final IOP  and number of glaucoma medications  were significantly decreased  and Peters anomaly (29%) were the most common diagnoses in our cohort. While there is minimal information regarding the incidence and treatment of glaucoma in sclerocornea, 50-70% of eyes with Peters Anomaly develop glaucoma, of which more than half require IOP-lowering surgery , 22. In Success of the combined endoscopic vitrectomy and posteriorly-placed GDD approach in adults, such that additional glaucoma surgeries were not required, was 74% in Tarantola et al and 100% in Shaikh et al. , 13 It iThe failures can be divided into 2 groups: increased IOP requiring additional surgery (7 eyes) and hypotony (3 eyes). Of the 7 eyes with increased IOP, 1 had blockage which only required flushing of the tube while all of the others underwent placement of an additional GDD (3 eyes) and/or cycloablation (5 eyes). Five of these 7 eyes had prior glaucoma surgery, although cycloablation had been performed previously in the 1 eye that required a tube flush. An additional 5 eyes  had prior cycloablation, of which 3 eyes had continued IOP control after the endoscopic vitrectomy-GDD surgery. However, caution should be taken as extensive cycloablation prior to GDD placement may lead to either prolonged or temporary hypotony. This was the case in 2 of the eyes which failed due to hypotony, with one eventually becoming phthisical and the second requiring temporary re-ligation of the tube. Nevertheless, it is important to note that IOP control was obtained in 8 of the 14 eyes (57%) at final follow-up with a combination of the GDD placed concurrent with the endoscopic vitrectomy and either prior or sequential cycloablation. This parallels our case series of eyes with Peters Anomaly, suggesting that the combination of GDD and cycloablation is often required in complex pediatric eyes .Additional complications, which were encountered included chronic corneal graft failure (2 eyes) and retinal detachment (2 eyes). It is well established that corneal transplantation has a lower success rate in children than adults. This is attributed to a more robust inflammatory response in young children and limbal stem cell deficiency, which is often present in sclerocornea and Peters Anomaly \u201330. BothTaken together, we present the largest cohort to date of pediatric patients who underwent endoscopic vitrectomy with GDD placement. Limitations of our study include a small sample size, retrospective nature, lack of control population, varying disease etiology and severity, and relatively short follow-up time. A prospective study with potentially greater uniformity of eye pathologies is difficult due to the rarity of these diseases. Although we encountered complications and a high rate of reoperation, these eyes represent a significant challenge for ophthalmologists.The visual prognosis in pediatric eyes with corneal opacification is especially poor when coupled with glaucoma. The inability to obtain IOP control not only causes further vision loss, but can lead to pain and disfigurement. Although these eyes often require multiple glaucoma surgeries, combined endoscopic vitrectomy with posteriorly-placed GDD is a viable surgical option to establish aqueous outflow, achieve IOP control, and preserve vision.Additional file 1:\u00a0Supplemental Table 1.\u00a0Glaucoma Drainage Device Information."}
+{"text": "We conducted a follow up study on patients previously diagnosed with COVID-19 one year ago in an urban community in Paterson, New Jersey. The purpose of the study was to evaluate the socioeconomic impact of COVID-19 as well as assess for receptiveness towards COVID-19 vaccination amongst various ethnic groups. This was a prospective cohort study consisting of patients who had COVID-19 in the months of March and April of 2020. This was a single institutional study conducted at St. Joseph\u2019s Hospital in Paterson, NJ from March to April of 2021. Patients included were either male or female aged 18 years or older. Patients were contacted by telephone to participate to completed the survey. Chi-square testing and multivariable logistic regression analysis were utilized for statistical analysis.Of the 170 patients enrolled in the study, the most common ethnicity was Hispanic (79/170 [46.47%]), followed by African American (46/170 [27.05%]). 83 patients were male (83/170 [48.82%]). Caucasians were the most willing to receive a COVID-19 vaccine (28/30 [93.3%]), followed by Asians (13/14 [92.8%]), Hispanics (63/78 [80.7%]) and African Americans (29/46 [63.0%]). Hispanics had the highest rate of job loss (31/79 [39.24%]), followed by African Americans (16/46 [34.7%]). Hispanics were found to be in the most financial distress (31/79 [39.2%]), followed by African Americans (17/46 [36.9%]). Hispanics and African Americans were more likely to refuse COVID-19 vaccination (p: 0.02). Hispanics were more likely to lose their jobs compared to Caucasians . African Americans were also more likely to lose their jobs when compared to Caucasians .Willingness amongst COVID-19 survivors to get vaccinated based on ethnicityCOVID-19 survivors who lost their jobs following diagnosis with COVID-19 based on ethnicityCOVID-19 survivors who are experiencing financial distress following diagnosis with COVID-19 based on ethnicityHispanics reported the most financial distress and with nearly 40% losing their jobs, the highest in our study group. 37% of African Americans experienced job loss and financial distress following their diagnosis with COVID-19. Only 63% of African Americans and 80.7% of Hispanics were willing to get vaccinated, mostly due to lack of trust in the vaccine. Statistical analysis showed Hispanics and African Americans were more likely to lose their jobs and refuse COVID-19 vaccination following diagnosis with COVID-19. All Authors: No reported disclosures"}
+{"text": "Background: High-impact trauma frequently leads to injuries of the orbit, but literature focusing on the viscerocranium rather than the neurocranium is underrepresented. Methods: Retrospective cohort study (2006\u20132014) at an urban level 1 trauma center assessing the frequency and typical patterns of orbital injuries on whole-body computed tomography (WBCT) with maxillofacial multi-slice CT (MSCT) after severe trauma. (1) Screening of consecutive WBCT cases for dedicated maxillofacial MSCT. (2) Examination by two independent experts\u2019 radiologists for (peri-/)orbital injuries. (3) Case review for trauma mechanisms. Results: 1061 WBCT were included revealing 250 (23.6%) patients with orbital injuries. Less than one-quarter (23.3%) of patients showed osseous and 9.5% showed soft tissue injuries. Combined osseous and soft tissue lesions were present in 39.2% of orbital injuries, isolated soft tissue injuries were rare. Single- or two-wall fractures of the orbit were prevalent, and the orbital floor was affected in 67% of fractures. Dislocated extraocular muscles (44.6%), deformation of the ocular globe (23.8%), and elongation of the optic nerve (12.9%) were the most frequently soft tissue findings. Vascular trauma was suspected in 15.8% of patients. Conclusions: Orbital trauma was confirmed in 23.6% of cases with suspected facial injuries after severe trauma. Concomitant soft tissue injuries should be excluded explicitly in cases with orbital fractures to prevent loss of vision or ocular motility. Orbital injuries pose a serious threat to a patient\u2019s vision and ocular motility. Existent literature describes typical osseous and soft tissue injuries encountered after orbital trauma ,2, but oThe German S3 guideline for the treatment of polytrauma and the severely injured was first published in 2011 in an interdisciplinary effort of 20 different medical societies involved in the care of severely injured patients and revised in 2016 . The guiTherefore, this current study seeks to assess the frequency, typical patterns of osseous and soft tissue injuries of the orbit on WBCT with maxillofacial MSCT after severe trauma, and to evaluate trauma mechanisms in this patient category of a level 1 trauma center.This cohort study was approved by the Ethics committee of University Medicine Greifswald (registration number: BB 115/20) and conducted in accordance with the Declaration of Helsinki of 2013. Informed consent was waived due to the retrospective design of the study.From February 2006 to August of 2014, 6000 WBCT were performed at a large metropolitan trauma center due to suspected polytrauma according to the German S3 guideline for the treatment of polytrauma and the severely injured and screened for additional maxillofacial MSCT . One-tho\u00ae Radiology .The patients received a non-contrast head CT, a contrast enhanced WBCT with arms crossed in front of the abdomen, and an additional maxillofacial MSCT due to suspected facial trauma. Axial images (0.75 mm) were acquired following a standardized polytrauma protocol comprised of arterial scans from the orbital roof to the aortic arch, and another scan from chest to pelvis following a split-bolus protocol . Images Two neuroradiologists with more than twenty years of work experience each  reviewed the images independently. In cases of disagreement, consensus was reached via discussion.During image analysis, the presence of the following criteria was assessed: osseous lesions of the orbit including the optic canal, soft tissue lesions, post-traumatic hemorrhage or edema, and intraorbital foreign bodies.In detail, the number of affected orbital walls and location of fractures was examined and soft tissue injuries were further partitioned into four sub-categories: (1) injuries of the ocular globe and lens , (2) injuries of the extraocular muscles , (3) injuries of the optic nerve , and (4) trauma associated abnormalities of the orbital vessels .\u00ae 9.4 for Windows 10 ) was employed for all statistical analysis by a biostatistician. Descriptive statistics for continuous variables were expressed as arithmetic mean, median, standard deviation (SD), minimum and maximum (range), absolute (n) and relative (%) proportions. Categorical variables were expressed as absolute (n) and relative (%) proportions.CT findings and medical records were documented using an Excel worksheet . The statistical analysis system  Initiative  19]..19].n = 806) with a mean age of 44.5 \u00b1 7.3 years (range: 3 to 98 years). The most common mechanism of injury was road traffic accidents (54.7%). Falls from heights > 3 m (28.8%) and assaults (3.8%) occurred less often. In 26.4% of road traffic accidents patients were inside a car, 10.4% were bicyclists, 9.0% were pedestrians, and 8.9% were motorcyclists  with orbital injuries were identified: 149 (14.0%) suffered from isolated orbital fractures, 3 (0.3%) showed isolated soft tissue injuries, and in 98 cases (9.2%) combined injuries were present. Two-hundred-and-forty-seven patients suffered fractures of the orbit. They occurred in an even distribution on both sides and bilateral fractures were diagnosed in 78 (31.6%) of these patients.Single-wall fractures of the orbit were the most common lesion with 91 cases (36.8%). Injuries involving multiple orbital walls became increasingly rare the more orbital walls were affected, identifying only eight cases (3.2%) with four wall fractures .The orbital floor was affected in 165 patients with orbital fractures (66.8%), the orbital roof in 116 patients (47.0%), the lateral wall in 106 patients (42.9%), and the medial wall in 78 patients (31.6%) of patients showing fractures in this region. Bilateral fractures affected a single wall of each orbit in 12 patients, while the remaining 66 showed a multitude of complex fracture patterns involving two or more orbital walls.One-hundred-and-one patients suffered one or more soft tissue injuries of the orbit. Extraocular muscle injuries were described commonly in 54 (53.5%) of these cases, injuries of the globe and lens in 38 cases (37.6%), and injuries of the optic nerve in 24 cases (23.8%). Orbital vessel damage was suspected in 16 patients with soft tissue injuries (15.8%). A dislocation of orbital muscles occurred in 45 of patients with soft tissue injury (44.6%) a\u2013c. In eIn a single case, muscle trauma was inflicted by a foreign body (1.0%).Deformation of the ocular globe was described in 24 (23.8%) patients a while aSix patients (6.9%) showed a dislocated lens .Thirteen patients (12.9%) were diagnosed with an elongation of the optic nerve compared to the contralateral side, and in 10 cases (9.9%), its shape was otherwise altered .The optic nerve was punctured by a foreign body in one patient (1.0%).The superior ophthalmic vein was enlarged in 10 (9.9%) patients with soft tissue injuries  as an inA direct CCF was identified in six (5.9%) individuals.Intraorbital foreign bodies were identified in extraocular muscles, the optic nerve, and the ocular globe in three individuals (3%) .The frequency of orbital injuries on WBCT with maxillofacial MSCT after suspected facial trauma was 23.6% in this cohort of patients after severe trauma. Among all screened polytrauma patients, orbital injuries were diagnosed in 4.2% cases. This figure is lower than a previously reported prevalence of 7.5% for orbital injuries among polytrauma patients  and consIn the current patient collective, 23.3% of included patients suffered osseous orbital injuries. Most of these fractures (66.8%) involved the orbital floor and most patients (63.2%) showed more than one orbital wall fracture. These findings concur with prior reports about patients with isolated head and orbital trauma ,21,22 anNearly one-tenth 9.5%) of cases of soft tissue injuries were described by the reviewers. Almost all soft tissue injuries were accompanied by various orbital fractures, while isolated soft tissue lesions occurred in only three (0.3%) cases. Even though orbital soft tissue injuries are less common than orbital fractures, they require a swift and precise diagnosis due to their potentially severe complications and long-term consequences . With a .5% of caOne of the major challenges in orbital trauma imaging is identifying injuries that may lead to orbital compartment syndrome (OCS), a condition characterized by elevated intraorbital pressure which can lead to permanent loss of vision in as little as 100 min via retinal or optic nerve ischemia . ImagingIntraorbital foreign bodies were described in only three patients of orbital injuries. Dedicated literature reports much higher frequencies of these injuries of up to 17% in cases of orbital trauma . TherefoFinally, CCF was suspected in 10 patients (9.9%) of patients with soft tissue injuries because of a dilatation of the superior ophthalmic vein. With an incidence of only 0.2%, CCF are very rare vasculopathies after trauma . NeverthIn summary, the likelihood of suffering orbital injuries and the highly disabling consequences of missed injuries demands for specific clinical examinations and a strict surveillance of patients after severe trauma to initiate immediate maxillofacial CT. Delayed or unexplained clinical signs, suspected non-radiopaque foreign objects, suspected cerebrospinal fluid (CSF) leaks, or CCF should prompt imaging  in the subacute phase after polytrauma. Ongoing surveillance for orbital injuries in the intensive care unit could be beneficial in reducing the relevant number of missed orbital injuries . DevelopCertain limitations of this study must be addressed. First, the retrospective study design is susceptible to selection bias. By adhering to the STROBE standards  and compOrbital injuries occur frequently in real-life after suspected polytrauma and should therefore be anticipated by clinicians and radiologists. Periorbital swelling and reduced vigilance of patients often inhibit accurate ophthalmologic testing. Thus, including maxillofacial MSCT into the WBCT protocol plays a crucial role in the diagnostic workup of orbital trauma. Concomitant soft tissue injuries should be excluded explicitly in cases with orbital fractures to prevent loss of vision or ocular motility due to delayed treatment."}
+{"text": "To determine the prevalence of complications of cochlear implant surgery in children with congenital profound sensorineural hearing loss.This study retrospectively & consecutively reviewed charts of children who underwent cochlear implantation from July 2015 to July 2019 at Cochlear Implant Centre of Otolaryngology Department of Capital Hospital, Islamabad Pakistan. These included cases of both genders aged one to 12 years operated at least one year before the time of data collection. Basic demographic data, complications including major and minor complications and treatment received was noted and statistically analyzed using SPSS-23. Results were presented using descriptive statistics.Current study included a sample of N=251 having a mean age of 4.05\u00b12.15 years including 154(61.4%) males and 97(38.6%) females revealed a prevalence of complications of 16(6.4%) with 4(1.6%) major and 12(4.8%) minor complications. Wound infection and acute otitis media with frequency of 3(1.2%) each were the commonest complications, followed by , facial nerve twitching, tinnitus and vertigo, infection and extrusion; and device failure in 2(0.8%) each. However, there was no significant association of complications with age group and gender with P=0.344 and P=0.519 respectively.Present public sector implant program is characterized with a very low prevalence of complications of 16(6.4%) with 4(1.6%) major and 12(4.8%) minor complications. Wound infection and acute otitis media were the commonest complications. Severe to Profound Hearing Loss has a prevalence of 6.7% in clinical population and 0.7% in general population as reported for United Kingdom\u2019s National Health Service clinic5In cases with severe or profound hearing loss (HL), quite a high prevalence of inner ear malformations (IEMs) of around 15 to 20% has been reported in a study.10Cochlear implant surgery started in Pakistan in the year 2000, in the private sector alone and the only available small published study gave a complication rate of 11.5% for private sector program.This study is important since it will cover the local literature gap being the only study of its type in Pakistan and will be helpful in provision of reliable local data regarding complications of cochlear implantation in patients with congenital HL and planning of effective management strategies.th June 2019 were not included in the study. Basic demographic data, complications including major and minor complications and treatment received was noted.This study retrospectively conducted chart reviews of children who consecutively underwent cochlear implantation for congenital sensorineural hearing loss, over a period of four years from July 2015 to July 2019. These included cases of both genders aged one to 12 years who were operated at Cochlear Implant Centre of Otolaryngology Department of Capital Hospital, Islamabad Pakistan. All cases were more than one year postoperative at the time of data collection, hence cases operated after 30Complication of Cochlear Implant surgery was labelled when there was any medical issue arising due to the surgery, which was not expected, resulting in increased morbidity or mandating addition surgical procedure.14th March, 2020. Following data collection, tabulation was done in Microsoft Excel and statistical analyzed performed using Statistical Package for Social Studies (SPSS) Version-23. Statistical analyzed were done using descriptive statistic including frequencies, percentages, mean, and standard deviation. Chi-square test was used for assessment of age and gender association. Data was further examined besides national and international literature and deductions made were finally discussed.Study was initiated after obtaining ethical approval of the research from Ethical Review Committee of Capital Hospital PGMI, Islamabad vide Registeration No. 2020-03-003 dated 10N=251 cases of cochlear implantations performed at this public Cochlear implant Centre rom July 2015 to July 2019, were included in the study. With a mean age of 4.05\u00b12.15 years, the study population comprised 154(61.4%) males and 97(38.6%) females. The prevalence of complications was 16(6.4%) .Minor complications were predominant with frequency of 12(4.8%), followed by major complications 4(1.6%). Wound infection and Acute otitis media predominated with frequency of 3(1.2%) each; followed by facial nerve twitching and Tinitus & vertigo with frequency of 2(0.8%); and Pain/headache & mastoiditis being least common with frequency of 1(0.4%) each . Major cCurrent study being the largest study from Pakistan involving 251 cases of Government funded cochlear implant surgeries in the public sector revealed a prevalence of complications related to cochlear implant surgery among one to 12 year old children being 16(6.4%) with no death report and with 4(1.6%) major complications and 12(4.8%) minor complications. In contrast an Egyptian study by Sefein IK19In a previous study conducted in Pakistan, in the private sector comprised of only 52 cases and revealed much higher prevalence of complications of 11.5% with 3.8% failure rate of the device.Some other complications may also rarely occur. Facial Nerve stimulation occurred in just 0.8% of our cases and was not related to IEM\u2019s, According to Kubo T et al this commonly occurs in ears with anomalies and can be dealt with reprogramming some electrodes, however decrement in speech recognition may occur.28Depending on specific individual anatomical considerations of patient preoperative planning and adoption of soft surgical techniques result in reduction of surgical complications.25Present public sector implant program is characterized with a very low prevalence of complications of 16(6.4%) with 4(1.6%) major and 12(4.8%) minor complications. Wound infection and acute otitis media were the commonest complications.JA: Did the data collection, analysis and interpretation of results.GS: Was responsible for conception of work, writing of manuscript and is responsible for integrity of researchIJK: Did the critical revision of the manuscriptMK: Did the literature review"}
+{"text": "Salmonella which causes infections in various stages of production. In the present study, 182 samples were collected from commercial broiler supply chain, viz., three hatcheries (n = 29), three commercial broiler farms , and three retail meat shops , and used for isolation and identification of Salmonella using three different selective agar media and a selective enrichment medium followed by PCR confirmation targeting the hilA gene. The overall prevalence of Salmonella was 47/182 (25.82%), and a significantly higher (P < 0.05) prevalence was observed in retail meat shops (46.29%), CBF (19.19%), and hatcheries (10.34%). Comparison of three agar media for isolation of Salmonella revealed that all the media were equally selective. However, PCR amplification of hilA gene fragment was significantly higher (P < 0.01) in selective enrichment culture tetrathionate brilliant green bile broth (TTB) as compared to all solid (agar-based) media. Susceptibility pattern against most frequently used antibiotics revealed that 100% of the isolates were resistant to at least one antibiotic. High resistance was observed for doxycycline (94.34%), followed by cefpodoxime (84.91%), ciprofloxacin (72.64%), gentamicin (65.09%), enrofloxacin (61.32%), colistin sulphate (40.42%), amikacin (34.91%), ampicillin (33.96%), neomycin (33.02), cefotaxime (30.19%), ceftazidime (29.25%), trimethoprim-sulfamethoxazole (23.58%), amoxicillin+clavulanic acid (21.70%), and chloramphenicol (12.26%); 16.98% of the isolates were ex-tended spectrum \u03b2-lactamase (ESBL) producers, and 76.41% were multidrug resistant (MDR). MDR Salmonella were significantly higher (P < 0.01) in RMS (91.66%) followed by CBF (82.75%), whereas no MDR isolates were present in the isolates from hatcheries. The results indicated a higher prevalence of Salmonella and AMR for commonly used antibiotics in the complete broiler supply chain, especially RMS and CBF. Also, this study idicated that TTB enrichment followed by PCR and colony PCR was found to be rapid, specific and time-saving method.Antimicrobial resistance (AMR) in poultry production chain is one of the major food safety concerns due to indiscriminate usage of antibiotics and the presence of pathogens such as  Salmonella is recognized as one of the most important zoonotic and foodborne pathogens in broiler production chain , and, andSalmibiotics . Even thSalmonella in integrated poultry supply chain is very complicated, as it involves investigation of all the inputs as well as environmental samples. Therefore, this study was designed to investigate the prevalence and distribution of Salmonella in complete commercial broiler supply chain  and to determine the AMR pattern of these isolates from commercial broiler supply chain in Karnataka, India. One of the major obstacles in detection of Salmonella is the isolation, and hence, the success rate is mainly dependent on the sampling procedure combined with use of selective and sensitive culture method . Si. Si46]. Comparison of different segments of the poultry supply chain revealed higher AMR in retail meat shops followed by CBF and hatcheries. This may be due to the frequent use of antibiotics in the CBF and horizontal gene transfer in the intestine of poultry chicken . Cages, Salmonella from poultry samples. In addition, enrichment of poultry samples in TTB followed by PCR was found to reduce the preenrichment and isolation protocols. The study also revealed higher prevalence of antimicrobial resistant Salmonella in the entire broiler supply chain, which warrants immediate action in terms of reducing the use of antimicrobials as well as biosecurity measures which would help to decrease the emergence of AMR Salmonella.The results of the present study indicated that XLT4 and BGA were found to be specific for isolation followed by colony PCR for identification of"}
+{"text": "Several studies have shown that lung disease is a common extra-articular manifestation of rheumatoid arthritis (RA).To describe the lung manifestations in the RA population in Lom\u00e9, Togo.The study was conducted from October 2018 to July 2019 at the pulmonology unit of the Sylvanus OlympioUniversity teaching hospital, in collaboration with rheumatology centres in Lom\u00e9, Togo. Patientsmeeting the American College of Rheumatology criteria for RA were prospectively enrolled. They underwentclinical examination, spirometry, a 6-minute walk test (6MWT) and a chest X-ray (CXR). All information collected and surveys gathered were subjected to statistical analysis.Twenty-four out of 28 patients were women (85.7%). The mean (standard deviation (SD)) duration of illnesswas 4.1 (2.8) years. Thirteen patients out of 28 (46.4%) had respiratory symptoms. On CXR, interstitiallung disease was the only pleuropulmonary lesion (17.8%). Spirometry was abnormal in 25% of cases, witha predominance of restrictive ventilatory disorder (21.4%). The 6MWT was abnormal in 25% of patients.A total of 20 patients (71.4%) had at least one lung manifestation. We noted that there weresignificantly more patients with respiratory symptoms and no radiographical abnormalities than thosewith both respiratory symptoms and radiographical abnormalities (p=0.013).Lung changes affect a significant proportion of RA patients in Lom\u00e9. Studies conducted with appropriaterespiratory investigations and combining cardiovascular explorations will bring us closer to anunderstanding of the effects of RA-associated lung disease. It is the most common connective tissue disease,[2] while another showeda cumulative incidence of 15 years in 53% of them.[2] Of these, lungdisease is the common extra-articular manifestation of RA detectedin 40 - 70 % of cases5] and a major cause of morbidity and mortalityin RA patients.[6] In some cases, respiratory symptoms may precedethe development of joint symptoms or the diagnosis of RA.[7] This mayinvolve all parts of the lung, including pleura, airways, parenchymaand vasculature.[8] These changes may reflect chronic immuneactivation, increased susceptibility to infection (often related toimmunomodulatory medications) or direct toxicity due to disease-modifying or biological therapy.9]Although it appears primarily as a joint disease, RA is a systemiccondition that can affect several organs, including the heart, lungs,kidneys, eyes, nerves and skin. One study revealed extra-articularmanifestations of RA in a quarter of patients,11] while many have been conducted in NorthAmerican and European white populations.12] The objective of thisstudy was to describe the lung manifestations in the RA population of Lom\u00e9, Togo.Few studies on RA-associated lung diseases have been conductedin black Africans,[13] were included in this study, regardless of diseaseduration and the presence of pulmonary symptoms. They were selectedfrom the outpatient pulmonology clinic of the Sylvanus OlympioUniversity hospital of Lom\u00e9, and from rheumatology clinics in threecentral hospitals in Lom\u00e9 . They were collected overa period from October 2018 to July 2019, and informed oral consentwas obtained from each participating patient. All patients underwentclinical assessment, spirometry test, a 6-minute walk test (6MWT)and a chest X-ray (CXR).Patients meeting the American College of Rheumatology (ACR)criteria for RAA full clinical evaluation of the chest was performed to look for anysymptoms or signs suggesting lung disease. Other extra-articularsymptoms or signs were also noted.[14] Vital capacity, forced vitalcapacity (FVC), forced expiratory volume in 1 second (FEV1), FEV1/FVC ratio with a threshold 70%, total lung capacity and maximumexpiratory flow at 25% of vital capacity, 50% of vital capacity and 75% of vital capacity were found in patients tested in a seated position.The measurements were obtained without the use of bronchodilators.Spirometry was obtained with Spirolab MIR. It was performed inaccordance with the guidelines of the American Thoracic Societyand European Respiratory Society.A 6MWT was obtained with Cosmed Spiropalm. The 6MWT wasabnormal when there was desaturation of 4% and more comparedwith the initial saturation. Patients who did not undergo a 6MWTdue to joint disease were not included in the evaluation of the6MWT results. Those who did not undergo PFTs within 2 monthsof the standard CXR were also excluded from the PFTs outcomeevaluation.The plethysmography and carbon monoxide diffusing capacity(DLCO) tests were not performed due to their absence in our setting.[15] upper-right area (URA),middle-right area (MRA), lower-right area (LRA), upper-left area (ULA),middle-left area (MLA), lower left area (LLA).Chest pain standard radiography was obtained with the YSX500D500 mA digital X-ray machine. A radiologist and a pulmonologist agreedafter discussing each patient\u2019s final report. The lung lesion site on the CXRwas distributed based on the international classification pneumoconiosisX-rays of the International Labor Office (ILO):High-resolution chest computed tomography (HRCT) was notperformed owing to its unavailability in our setting.Data were entered using EpiData 3.1 and analysed using STATA version14 . The \u03c72test (or Fisher\u2019s exact test if the numberswere <5) was used to compare the categorical variables. The significancelimit was set at 0.05.The study considered 28 RA cases, including 4 men (14.3%) and24 women (85.7%). The male:female ratio was 1:6. The mean ageof male patients was 35.2 (6.2) years, that of female patients was46.8 (17.0) years and that of all patients was 45.2 (16.4) years, withextremes of 10 and 75 years. With respect to age, the majority ofpatients (57.1%) were younger than 49 years. Half of them (50%)had a duration of illness between 1 and 3 years. The mean durationof illness was 4.1 (2.8) years, with extremes of 1 and 12 years. Highblood pressure was the most common medical history (14.3%). Asan immunological assessment, only antinuclear antibodies werefound in 5 patients (17.8%). They were high in 1 patient (20%)and normal in 4 (80%). Rheumatoid factor and anticitrullinatedprotein antibodies were not found in any patient. All patients wereon anti-RA therapy at diagnosis. Anti-RA drugs were administeredwith no respiratory examination. The majority of patients (71.4%)were taking oral prednisone associated with methotrexate (MTX),4 (14.3%) only received non-steroidal anti-inflammatory drugs(NSAIDs), 2 (7.1%) took only MTX, 1 (3.6%) took only prednisoneand 1 (3.6%) was given only salazopyrin.Thirteen of the 28 patients had respiratory symptoms (46.4%),including shortness of breath (61.5%), dry cough (38.5%), chest pain(30.7%) and sputum production (7.7%). Under no circumstancesdid respiratory symptoms precede the diagnosis of RA. Only threepatients (10.7%) had clinical evidence of lung involvement in the formof bronchitis and crackles. No other extra-articular symptoms werenoted.In our study, all patients underwent a CXR: 5 (17.8%) had interstitiallung disease (ILD) and none were diagnosed with pleural abnormality.ILD affected lung URA in 2 cases (40%), MRA in 3 cases (60%), LRAin 5 cases (100%), ULA in 3 cases (60%), MLA in 3 cases (60%) andLLA in 4 cases (80%). ILD was bilateral in 4 cases (80%) and localisedin the lower lobe in all cases. Apart from lung damage, 8 patientssuffered from cardiomegaly (28.5%). One case of cardiomegaly wasassociated with ILD.Spirometry was abnormal in 7 of the 28 patients (25%): 1 case ofobstructive ventilatory disorder and 6 cases of restrictive ventilatorydisorder. Abnormalities in the 6MWT were detected in 7 (25%) ofthe 28 patients.Of the 28 patients, 8 had no abnormality in any of the parametersrelated to lung involvement. Consequently, a total of 20 patients(71.4%) had at least a lung involvement.We noticed that patients with respiratory symptoms and noradiographical abnormality were significantly more numerousthan those with both respiratory symptoms and radiographicalabnormalities [16] It is often treated withprednisone or methotrexate.18]As shown in our study, RA is a disease with at least a 3:1 predilectionfor women between 20 and 50 years of age.[19] These symptoms are commonly seen in ILD, which iscommon in RA.[18] This explains why bibasilar crackles are foundin most patients in various studies[19]. However, it is currentlyestimated that ~30% of patients with RA have subclinical ILDnoted on chest high-resolution computer tomography (HRCT).[8]Also, recognition of exertional dyspnoea may be delayed due toexercise limitations associated with joint disease. As in our study,chest pain, which is often a sign of pleural disease, is less present.Pleural disease is also common in RA patients, but only 3 - 5% ofpatients are symptomatic.[8]In RA-associated lung diseases, respiratory symptoms, usuallyinsidious, include dyspnoea on exertion, and a non-productivecough.[20] HRCT was not used in our study, whichconstitutes a limitation. However, the CXR also allowed us torealise that interstitial bibasilar lesions were the most common. Theprevalence of ILD in RA patients is about 20 - 50% depending onthe study method.21] Concerning pleural disease, pleural thickeningand/or effusion was found in between 16 and 24% in chest radiographyof RA patients.[19] Also, RA-associated cardiovascular[22] disease couldexplain the relatively high prevalence of cardiomegaly (28.5%) in ourstudy.Several studies revealed that HRCT is much more sensitive thanCXR in the evaluation of ILD, and that its higher sensitivity shouldallow early diagnosis.[5] Habib et al.[5] found that 32.5% of patientsin their study had abnormal PFTs. This rate was slightly differentfrom ours (25%), most likely due to the systematic use of lungdiffusing capacity for carbon monoxide (DLCO) in their study.The majority of patients with RA-ILD will have a restrictive patternon PFTs, with or without decreased DLCO and hypoxaemia.[23]Decrement of FVC and DLCO is associated with a poorer prognosis.However, a study by Assayag et al.[6] revealed that only decreasedDLCO was statistically significant. PFTs were generally poor predictorsof CXR and HRCT findings.[5]One-third of RA patients usually have abnormal pulmonaryfunction tests (PFTs).[3] whereno respiratory manifestation was found in RA patients. This differenceis certainly due to the lack of systematic searching for respiratorydisorders in the study conducted by Adelowo et al.[3] The prevalenceof pulmonary abnormalities in RA patients varies according to thecharacteristics of the study population, the definition of lung diseaseused, and the sensitivity of the clinical investigations used.[19] Inunselected populations, up to one-third of subjects describe importantrespiratory symptoms, but two-thirds or more may have significantradiographic abnormalities on HRCT.[24]More than two-thirds (71.4%) of our patients had RA-associatedlung disease, contrasting with the results of Adelowo et al.,[22] Indeed, eightpatients (28.5%) had cardiomegaly in our study. Such differences areless important in studies where chest HRCT was systematic[5] becausethe chest HRCT is much more sensitive and specific than CXR inthe evaluation of ILD,[20] and ILD is the most common pulmonarymanifestation of RA-associated lung disease.[18]The present study showed that patients with respiratory symptomsand no radiographical abnormalities were significantly more numerousthan those with both respiratory symptoms and radiographicalabnormalities. This could be explained by the fact that the respiratorysymptoms (dyspnoea and cough) are not specific for pulmonarydamage, but may also be of cardiovascular origin.[12] This prevalenceis undermined by the fact that our study lacks more specificexplorations. Studies with appropriate investigations such as chestHRCT, plethysmography, DLCO and cardiovascular explorationswill bring us closer to the reality.The results of our study indicate that lung changes affect a significantproportion (71.4%) of RA patients in Lom\u00e9, with a predominanceof ILD. These conditions mostly occur in the first 4 - 5 years of thedisease, as revealed in a study by Marigliano et al."}
+{"text": "Microsatellite instability is common in familial colorectal cancers. It can be tested by the molecular and immunohistochemical methods. There are very few studies which address comparing the clinicopathological characteristics of microsatellite stable (MSS) and microsatellite unstable (MSI) colorectal cancers from Iran. In this study, we aimed to evaluate the clinicopathological and immuno-histochemical findings of MSS and MSI colorectal cancers in our Center as the largest Center of gastrointestinal surgery and oncology in the South of Iran. We also compared the immunohistochemical method vs. molecular study using DNA sequencing.For 5 years (2015-2019), 34 patients who underwent operation in the affiliated Hospitals of Shiraz University of Medical Sciences were clinically suspected to microsatellite instability (MSI). The molecular diagnostic tests with DNA sequencing were performed. Clinicopathological and immunohistochemical findings of MSI colorectal cancers were compared with those who were stable. , MSI colorectal cancers were more common in males. These tumors were more common in the right side with more tendencies to produce mucin with lymphocytic infiltration. In the South of IranImmunohistochemistry would be a specific method for diagnosis of MSI colorectal cancers but may be associated with high rate of false negative results and of low sensitivity. Therefore, we recommend performing molecular studies by DNA sequencing in those colon cancers with clinical suspicion for MSI and negative immunohistochemical findings. Colorectal cancer (CRC) is very common in Western countries, and its incidence is being increased in the Eastern Mediterranean countries such as Iran , 2.Sporadic colon cancers are more common and only 5-10% of colorectal cancers are considered hereditary. The most common hereditary colon cancer is hereditary nonpolyposis colorectal cancer (HNPCC) which is secondary to microsatellite instability (MMR)  . ClassifThere is not much information about the prevalence of HNPCC and colon cancers with MSI in Iran . In this study, we evaluated our experience about the clinicopathological findings including demographic, histologic and immunohistochemical findings of colorectal cancers with microsatellite instability in comparison with microsatellite stable colorectal cancers. In the meantime, we tried to compare immunohistochemical method with molecular methods (DNA sequencing) for the diagnosis of microsatellite instability. Tumor SelectionPathology samples were extracted from 34 patients who had operation with the diagnosis of CRC at affiliated Hospitals of Shiraz University of Medical Sciences  from 2015 to 2019. All the tumors were clinically suspected to be microsatellite instable .Histopathological FeaturesHematoxylin-stained slides of the specimens were reviewed by two pathologists (BG and FJ). The following characteristics were evaluated: tumor grade , histological subtype . TumorsImmunohistochemistry MethodThe samples were fixed in 10 % formaldehyde solution, dehydrated, and placed in paraffin for histological analyses. Five-micrometer-thick sections were prepared and mounted on poly-L-lysine-coated slides. Immunohistochemistry (IHC) analysis was performed using the following monoclonal antibodies: anti-MLH1, anti-MSH2, anti-MSH6, and anti-PMS2 . All ant2O2. Heat-induced antigen retrieval was performed using Tris buffer, and the process was performed for 30-60 minutes. After treatment with 10% normal goat serum to block non-specific protein binding, pre-diluted primary antibodies against MLH1, MSH2,MSH6, and PMS2 were applied, followed by incubation with horseradish peroxidase-conjugated multimeric antibody reagent. The antigen-antibody reaction was visualized using diaminobenzidine (DAB) as a chromogen. The slides were counter-stained with hematoxylin. Normal colonic crypt epithelium adjacent to the tumor, lymphocytes and fibroblasts were considered as positive internal control. Loss of expression was recorded when nuclear staining was absent in malignant cells, and present in normal epithelial cells, lymphocytes and fibroblasts. Two observers (BG and FJ) evaluated all cases independently and together. In a few discrepant diagnoses, re-evaluation together solved the issue .Five short tandem repeat (STR) gene markers i.e. NR21, NR24, NR27, BAT25 and BAT26 were analyzed. The related primers were ordered from Macrogene Company . These primers were tagged by Hex or Fam fluorescent dyes at 5* sequences . The reaThe PCR tests were operated in thermal cycler instrument . The PCR condition was adjusted at three steps , of 45 cycles followed by melt curve analysis.After receiving valuable melt curves, all the products were sent to Macrogene Company for fragment analysis. The data of capillary electrophoresis were analyzed by Peak scanner software version 1  . The staClinico-Pathological Features of Colorectal AdenocarcinomasThe patients\u2019 age ranged from 24-88 years (54.8\u00b116.6). Among patients, 14 (41%) were female and 20 (59%) were male. The major location of tumor was rectosigmoid (32.3 %). The cancers were located in the right colon (52 %), the left colon (41%), and the transverse colon (5.8%). The tumoral TNM stage grouping was as follows: I (11.4 %), II (73.5%), III (14.7%), and IV (0%). Sixteen (47%) tumors were well differentiated, 5 (14%) were moderately differentiated, and 13 (38.2%) were poorly differentiated, 30 (88.6%) of cases were non-mucinous, and 4 (11.4%) were of mucinous type. Four tumors (11.4%) showed heavy infiltration of lymphocytes (medullary type). All these data are summarized in IHC AnalysisIHC slides were evaluated based on the positive normal colon mucosa as positive control of the antibody. The frequencies of abnormal results of MLH1, MSH2, MSH6, and PMS2 were 11.7, 2.9, 5.8 and 17.6 %, respectively . At the Frequency of MSI Status Based on DNA Sequencing Using molecular investigation and DNA sequencing, based on the Bethesda criteria, 12 cases (35.2%) were MSI-High and 9 cases (25.7%) showed MSI-low pattern. Three cases showed instability in 4 analyzed markers, 4 in three markers, and 5 in two markers. For the remaining 13 cases, the tumors were MSS.All the 34 cases in this study were clinically or pathologically suspected to MSI based on the Revised Bethesda Guidelines for the testing colorectal tumors .Indeed, among these MSI patients, 13 cases showed conservation of the expression of four MMR proteins by immunohistochemistry. Our results based on the molecular study (gold standard) showed a specificity of 100% and low sensitivity of 38% for the immunohistochemical analysis of microsatellite instability .Association Between Microsatellite Instability and Clinicopathological FeaturesThe association between MSI and clinicopathological characteristics of the tumors is presented in MSI pathway is involved in the pathogenesis of about 10\u201315% of sporadic colon cancers and majority of the cases with HNPCC syndrome. MSI is mutation and somatic inactivation of DNA mismatch repair (MMR) genes, including hMLH1 (human MutL homolog 1), hMSH2 (human MutS homologue 2), hMSH6, and hPMS2 (human post-meiotic segregation 2) (P<0.05). There are controversial reports in the literature, some reported equal incidence in men and women and some has reported male predominance such as our study ..P<0.05).P>0.05). In most of the previous studies, MSI cases have been more common in the ages below 50 from European or African populations . This has also been proved in the previous reports . Therefore, we recommend perfor-ming molecular studies and DNA sequencing in the cases with clinical suspicion for MSI and negative immunohistochemical results."}
+{"text": "C9orf72 are a major cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We aimed to determine the frequency and phenomenology of movement disorders (MD) in carriers of HRE in C9orf72 through a retrospective review of patients' medical records.Hexanucleotide repeat expansions (HREs) in C9orf72 HRE in the pathogenic range and compared the characteristics of patients with and without MD.We retrospectively reviewed the clinical records of patients carrying a C9orf72 HRE had a documented MD. In 6 of 17, MD were the presenting symptom, and in 2 of 17, MD were the sole manifestation of the disease. FTD was present in 13 of 17 patients, ALS in 5 of 17 patients, and 2 of 17 patients did not develop FTD or ALS. Thirteen of 17 patients had more than one MD. The most common MD were parkinsonism and tremor , each one present in 11 of 17 patients. Distal, stimulus-sensitive upper limbs myoclonus was present in 6 of 17 patients and cervical dystonia in 5 of 17 patients. Chorea was present in 5 of 17 patients, 4 of whom showed marked orofacial dyskinesias. The most frequent MD combination was tremor and parkinsonism, observed in 8 of 17 patients, 5 of whom also had myoclonus. C9orf72 patients without MD had shorter follow-up times and higher proportion of ALS, although these results did not survive the correction for multiple comparisons.Seventeen of 40 patients with a C9orf72. They may precede signs of ALS or FTD, or even be present in isolation. Parkinsonism, tremor, and myoclonus are most commonly observed.MD are frequent in  C9orf72 gene is the most frequent genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS).2 Movement disorders (MD) are frequently observed in C9orf72 HRE carriers,3 generally alongside the features of FTD or ALS, with parkinsonism being present in up to 40%.4The GGGGCC hexanucleotide repeat expansion (HRE) in the C9orf72 HRE in other MD has also been investigated. There is no association between C9orf72 HRE and Parkinson disease5 or essential tremor syndrome (ETS).6 Conversely, C9orf72 HRE seems over-represented in corticobasal syndrome (CBS)7 and is the most frequent Huntington disease phenocopy.8The prevalence of C9orf72 gene and compared the characteristics of C9orf72 patients with and without MD.In this study, we sought to define the MD associated with HRE in the C9orf72 tested at the National Hospital for Neurology and Neurosurgery between May 2012 and May 2019 were retrospectively reviewed. Filmed patients provided written informed consent before video recording.All participants were recruited under ethics-approved research protocol (UCLH: 04/N034). Clinical records of all patients with HRE in C9orf72.1 An ABI  3730xl automated sequencer was used for fragment length analysis through capillary electrophoresis. Analysis of RP-PCR electropherograms was performed using Peak Scanner v1.0 (ABI). Expansions with a characteristic sawtooth pattern were put forward for Southern blotting.Repeat-primed fluorescent PCR (RP-PCR) was performed as previously reported in the study by Renton et al. to test for the presence of an expansion in 9 was performed by combining the use of a (GGGGCC)5 probe targeting multiple sites within the expansion and genomic DNA digested with 2 frequently cutting restriction endonucleases whose sites closely flanked the repeat region. Expansion size was estimated by interpolation of autoradiographs using a plot of log10 base pair number against migration distance.Southern hybridizationC9orf72 gene was defined as pathogenic.10 The expansions were classified as \u201csmall\u201d if patients had between 30 and 90 GGGGCC repeats and \u201clarge\u201d if there were >90 GGGGCC repeats.A minimal size of 30 GGGGCC repeats in the U test. Fisher exact test was used to compare proportions. The results were corrected for multiple comparisons using the Benjamini-Hochberg false discovery rate (FDR), with FDR <0.05 deemed a significant result.Quantitative data were not normally distributed after visual evaluation of the data and using the Shapiro-Wilk test. Statistical testing was subsequently performed using the Mann-Whitney Analyses were performed using Stata version 12.0 .Anonymized data not published in this article will be available from the corresponding author on reasonable request.C9orf72 HRE testing. Of these, 53 patients had more than 30 repeats. Clinical data were available in 40 of 53 patients. Among the 40 patients with HRE and available data, 17 had MD according to their clinical notes (links.lww.com/NXG/A394).A total of 501 patients underwent C9orf72 was requested because of the combination of MD and cognitive symptoms (4/17), cognitive symptoms and family history of neurodegenerative conditions (7/17), MD and positive family history (2/17), isolated MD (3/17), and isolated cognitive symptoms (1/17).Patients who developed MD were referred to the neurology clinics because of either MD (7/17) or cognitive symptoms (9/17), or both (1/17). Genetic analysis of C9orf72 testing was requested from consultant neurologists from the cognitive (8/17), MD (6/17) general neurology (2/17), and neuromuscular clinics (1/17). Of the 17 patients with C9orf72 HRE and MD, 2 of 17 had small HREs and the remainder had large expansions in C9orf72. Seven of 17 patients (41.18%) were women. Median age at onset in patients with MD was 58 years (range 8\u201370). A family history of dementia or ALS in first-degree relatives was present in 64.7% of the cases with MD and 69.5% of the cases without MD.Among patients with MD and HRE, Fourteen of 17 patients with MD had available neuropsychological assessments . Among tFifteen of 17 patients had available brain MRI reports. Findings included generalized atrophy in 7 of 15 patients, frontal atrophy in 2 of 15 patients, small vessel disease in 2 of 15 patients, and 1 of 15 patient had midbrain atrophy. The remaining 3 of 15 patients had a normal MRI. No patients exhibited asymmetric atrophy.MD were the initial disease manifestation in 6 of 17 patients: 1 presented with cerebellar ataxia, 1 with hemichorea, 1 with cervical dystonia, and 3 with parkinsonism. Among the other 11 patients, 8 presented with cognitive symptoms (7 with FTD and 1 with learning disabilities) and 3 had a psychiatric onset . In patients who did not present with MD, median time from first symptom to development of MD was 3.5 years (range 0\u201311 years).During the follow-up, 10 of 17 patients developed FTD, 2 of 17 developed ALS, and 3 of 17 developed FTD/ALS overlap. The 2 patients who continued to exhibit solely MD features at the last follow-up had the earliest age at onset (AAO).Most patients (13/17) had more than one MD. The most frequent combination was tremor and parkinsonism (8/17 patients), 5 of whom also had myoclonus.Tremor and parkinsonism were equally prevalent MD manifestations in this cohort, each one affecting 11 of 17 patients . Phenomelinks.lww.com/NXG/A396). DaTscan was performed in 3 of 11 patients and was abnormal in all. Levodopa was administered to all 3 patients with abnormal DaTscan, providing subjective benefit in 2. One patient without available DaTscan did not improve with levodopa.Parkinsonism was mild in 9 of 11 patients and severe and rapidly progressive in the remaining 2 patients, leading them to become bedbound within a year from onset. Parkinsonism was asymmetric in 6 of 11 patients; 3 of 11 patients received a clinical diagnosis of CBS , whereas one patient was considered to have isolated myoclonus of the cheek by a MD specialist.Myoclonus was present in 7 of 17 patients. In most (6/7 patients), this manifested as distal stimulus-sensitive jerks affecting both upper limbs  resembling tardive dyskinesia, although only one patient had a previous history of neuroleptic exposure. One patient had prominent appendicular ataxia.Five patients had chorea, which was limited to the perioral region in 2 patients, to one hemibody in another, and generalized in 2. There were marked orofacial dyskinesias in 4 of 5 patients with chorea (links.lww.com/NXG/A395).Seizures occurred in 4 of 17 patients. Further details are available in the table e-1 (pFDR = 0.05.Patients with HRE and MD (MD+) had a lower proportion of ALS compared with patients with HRE without MD (MD\u2212) (5/17 in MD+ vs 17/23 MD\u2212), a higher proportion of FTD (13/17 MD+ as opposed to 11/23 MD\u2212) and longer median follow-up times (8 years in MD+ compared with 3 years in MD\u2212). Median time from onset to death was longer in the patients with HRE and MD than in those without MD (8 years in MD+ vs 2.5 years in MD\u2212). A family history of neurodegenerative disorders did not differ between cohorts (11/17 MD+ vs 16/23 MD\u2212) . None ofC9orf72 and the differences between HRE carriers with and without MD. Our findings suggest that MD are frequent in patients with HRE in C9orf72 and often precede FTD/ALS. Moreover, MD can be the initial or even the sole manifestation of C9orf72 HRE. Consequently, the spectrum of MD may be significantly more diverse than previously appreciated.This study examined the MD associated with HRE in 8Tremor and parkinsonism were the most frequent MD in our cohort. Although rest tremor has previously been reported in HRE carriers with parkinsonism, postural and intentional tremor, frequently observed in our study, were only mentioned in one previous study as being rare.C9orf72 HRE syndrome, particularly in those with FTD phenotypes. However, in 2 patients, levodopa-unresponsive parkinsonism was the cardinal clinical feature and exhibited a rapidly progressive course, which has not previously been reported.Parkinsonism is a well-recognized feature of the Symmetric, stimulus-sensitive upper limb myoclonus, frequently coexisting with parkinsonism, and chorea with marked orofacial involvement were also a common finding in our cohort.C9orf72 HRE carriers, the phenotypic manifestations do not fall neatly into other syndromic categories, e.g., progressive supranuclear palsy and multiple system atrophy. It is therefore unlikely that misdiagnosis as neurodegenerative entities other than FTD or ALS would occur.2 This perhaps explains the low frequency of C9orf72 HRE among patients with clinical diagnoses of other neurodegenerative conditions.11Despite MD being frequent in C9orf72 HRE with and without MD survived multiple comparisons correction. This may be related to the small sample sizes in both cohorts (MD+ and MD\u2212), which is inherent to the low frequency of C9orf72 expansions. However, MD were less common in those presenting with ALS phenotypes. This may simply reflect shorter follow-up times and difficulty in identifying certain MD in the context of ALS.10 Of note, the 2 sole patients who did not develop FTD or ALS had the earlier AAO, being therefore possible that either of these conditions is developed during the follow-up.None of the contrasts between Our study has several limitations, mainly derived from its retrospective nature. Video recordings were only available in 2 patients, information about previous medications was not systematically recorded in medical notes, and none of our patients had neurophysiologic studies performed. Furthermore, most of the patients were unable to visit our hospital for a clinical review. Clinical data therefore had to be obtained from the medical record and/or discussion with the treating consultant whenever necessary.C9orf72-associated MD are clinically heterogeneous and frequently found in combination. ETS-like tremor, parkinsonism, distal myoclonus, chorea with orofacial involvement, and cervical dystonia in the context of familial neurodegenerative conditions should prompt molecular genetic testing of the C9orf72 gene. Further prospective, systematic studies are needed to accurately assess the phenotypic manifestations of C9orf72-associated MD.Our results suggest that"}
+{"text": "Co-infection of High Risk Human Papillomavirus (HR-HPV) and HIV is thought to favour initiation of intraepithelial squamous cell lesion and subsequent progression to cervical carcinoma.Evaluation of cytological physiognomies in relation to possible age influence and the genotype distribution of human papillomaviruses among HPV/HIV co-infected and HPV monoinfected women in Kisii, Kenya.The case-control study enrolled 42 HPV/HIV co-infected and 42 HPV monoinfected women. Cervical swabs were collected in ThinPrep vials for HPV tying and cytological analysis. HPV subtypes were assayed by Xpert\u00ae HPV system (GXHPV-CE-10).Mono-infected women aged 30\u201339 years had the highest proportion of low grade squamous intraepithelial lesion (LSIL) at 14 (16.67%) while the co-infected aged 50\u201359 years had the highest proportion of high grade squamous intraepithelial lesion (HSIL) at 9 (10.71%). HPV-16 genotype was the most predominant and it increased with age rise. Older coinfected and mono-infected women (>40 years) had HSIL and LSIL as the most predominant cytological grade respectively.The predominance of HPV-16 and HPV-18/45 genotypes in the study setting is a consideration that would benefit targeted prophylactic vaccination programs. HPV testing and cervical cancer screening for young and older women on a regular basis ought to be reinforced. Immunosuppression due to Human Immunodeficiency Virus (HIV) is associated with greater prevalence and broader range of the high risk human papilloma virus (HR-HPV) genotypes in women with cervical cancer Infection with high risk HPV types is closely associated with intraepithelial neoplasia progressively resulting in cervical carcinoma In the case-control study conducted at Kisii Teaching and Referral Hospital (KTRH) located in Kisii County Kenya, participants enrollment inclusion and exclusion criteria was essentially carried out as previously described Briefly, in the one stop sample collection, consented women were recruited into the study. HIV testing was then done according Ministry of Health, National AIDS & STI Control Program (NASCOP) 2018 national testing guidelines using Determine\u00ae rapid test kit , and the positive results confirmed by Uni-Gold\u00ae . There after the participants underwent a preliminary visual inspection with acetic acid (VIA) prior to cervical samples collection with a cyto-broom. Te Pap smears slides were prepared in duplicate for Papanicolaou (Pap) staining. Three independent pathologists read the slides. The cells were classified according to the revised standardized Bethesda classificationDescriptive statistics was applied for cervical lesions and HPV characterization and the significance of their difference tested by chi-square statistics. Significance level was set at P < 0.05.The enrolment of participants was consecutive and purposive which recruited 1854 consented participants. The women first underwent Visual Inspection with 5% Acetic Acid (VIA). There were 410 (22.22%) VIA positive women while 1435 (77.7%) were VIA negative. All the 410 VIA positive samples qualified for cytological analysis and HPV testing. The 121 VIA/HIV positive women had cervical cell exfoliated and smears prepared for cytological evaluation. A portion of the cervical sample was preserved for HPV characterization. Out of the 121 samples, 4 (3.3%) samples/slides were classified as unsatisfactory for cytology while 117 (96.69%) were satisfactory. The satisfactory samples had 79 (67.52%) women with normal cytology and 38 (32.47%) with abnormal cytology. There were 289 VIA positive/HIV negative women. These 289 women had cervical cell samples exfoliated and smears prepared for cytological evaluation. Out of 289 Pap smear samples, 8 (2.76%) were classified as unsatisfactory for cytology while 281 (97.23%) were satisfactory for cytology. The satisfactory samples had 241 (85.76%) women with normal cytology while 40 (14.23%) had abnormal cytology. All the unsatisfactory samples from VIA/HIV positive 4 (3.3%) and those of VIA positive/HIV negative 8 (2.76) were also HPV negative. Abnormal cytology had 38 (32.47%) VIA/HIV positive and 40 (14.23%) VIA positive/HIV negative women who were HPV positive. Only 4 (5.06%) with normal cytology from the VIA/HIV positive and 2 (0.83%) of VIA positive/HIV negative were HPV positive. In total 42 (34.71%) of HIV positive were HPV positive (cases) while 42(14.53%) of HIV negative were HPV positive (controls). The summary of the recruitment process is in Among the women recruited, age categories between HPV/HIV co-infected women (cases) and those in HPV monoinfected women (controls) group were analysed. The highest proportion of cases were in the upper age limit (50 -59 years), with 14 (33.33%) cases. Controls in this age limit were only 5 (11.90%). The highest proportion of controls was in the age category 30 \u2013 39 years where there were 10 (23.81%) cases compared to 15 (35.71%) controls in this age category. Frequencies of the cases and controls in different age categories are represented in The distribution of women required to recruit the adequate sample size of cases (121) compared to that of controls (289), with controls requiring more than twice the population of cases is summarized in Overall mean age for the participants was 37.79 \u00b1 10.21 years. 42 HPV/HIV co-infected women (cases) had mean age of 40.36 \u00b1 11.318 years while 42 HPV mono-infected women (controls) had mean age of 35.21 \u00b1 9.495 years.Prevalence of cytological grades in the study population The overall cytological categories in both co-infection (HPV/HIV) and mono-infections (HPV) combined were classified according to the revised standardized Bethesda classificationThe categorization of cytological grades was done according to the ages of women and the trends presented in The prevalence of HPV types was done in the four age brackets namely; >29, 30\u201339, 40\u201349 and 50\u201359 years . In the The most prevalent HR-HPV subtype was HPV 16 which was consistent with other settings HPV characterization in the current study population showed that HPV type 16 had the highest prevalence of 26 (20.8%) followed by HPV types combination  with 19 (22.6%). HR-HPV type 16 had a higher prevalence of 4 (4.8%) in all ages compared to HPV type (18/45) which had 2 (2.4%) in this population. A similar dimension was observed in the study conducted in the Central Kenya at Thika where the prevalence of HPV type 16 was 4.6% The presented findings had some limitations. The current study was not within reach to evaluate socio-demographic determinants where differences in sexual behaviour and population genetics in a geographical area or ethnicity Low grade lesions were predominant in women aged < 29 with high proportions of HSIL in coinfected and LSIL in monoinfected women aged >40 years and <40 years respectively. Targeted prophylactic vaccines should incorporate HPV-16 and HPV-18/45, due to predominant infection rates in the women in south western Kenya while HPV testing and cervical cancer screening for young and older on a regular basis ought to be reinforced. There was a higher prevalence of HRHPV types in high grade lesions in co-infections which were double that of mono-infections."}
+{"text": "This systematic review aims to summarize 5 key information from non-pharmaceutical intervention studies which adopt Body-Mind-Spirit (BMS) model for older adults: (1) definition of BMS, (2) types and formats of the interventions, (3) background and BMS training of the interventionists, (4) activities included in the interventions, and (5) effect of these interventions on the holistic health of older adults. We conducted a systematic search of 9 databases  for studies published in English or Chinese through May 31, 2021. Inclusion criteria were: (1) Must be empirical studies; (2) Participants must be aged 55 and above; and (3) Must adopt the BMS model or contain BMS in full-text. We found 15 studies . Ten studies (66.67%) adopted Chan\u2019s BMS model. Thirteen studies (86.67%) adopted in-person group interventions. Only five studies (33.33%) provided BMS training to the interventionists. Six articles (40%) categorized the activities as body-, mind- or spirituality-related. Ten studies (66.67%) reported effectiveness in all 3 dimensions of BMS. Of the 7 RCTs, 5 were rated as medium-quality, and 2 were rated as low-quality according to the Cochrane\u2019s Risk of Bias tool. Most interventions based on the BMS model claimed to be effective in improving the holistic health of older adults. In order to improve the internal validity, future RCT studies should be more prudent about the randomization process and adhere to the BMS model when designing the interventions."}
+{"text": "We evaluated disseminated histoplasmosis (DH) in HIV patients over 10 years in southern Brazil. The incidence was 12 cases/1,000 hospitalizations (2010\u20132019); the mortality rate was 35%. Tuberculosis frequently obscured the diagnosis of DH. We emphasize the need in our region to suspect and investigate DH using more sensitive methods. Disseminated histoplasmosis (DH) is an AIDS-defining disease and one of the major causes of death in persons living with HIV/AIDS (PLHIV)  , or both; 2) serologic method: positive immunodiffusion test ; or 3) urinary antigen test: positive immunoenzymatic assay (IMMY). Patients with clinical suspicion of DH and >1 of these diagnostic criteria were included. The study was approved by our university ethics committee .We performed a retrospective study including all DH cases diagnosed in persons with HIV/AIDS at a regional reference service in University Hospital Dr. Miguel Riet Corr\u00eaa Jr. (UH-FURG-Ebserh), a 207-bed tertiary hospital in Rio Grande, Brazil, that serves as reference center for 21 cities in Brazil. The hospital has an average of 257 HIV/AIDS hospitalizations/year (https://www.ibm.com).We analyzed databases from the hospital for clinical and epidemiologic evaluation. In cases in which HIV and AIDS were diagnosed simultaneously, DH was considered the AIDS-defining illness. We calculated the overall incidence rate of DH per 1,000 hospitalizations of persons with AIDS at UH-FURG-Ebserh , 15 cases were diagnosed in 7 years, a rate of 8/1,000 hospitalizations. After more sensitive testing and enhanced physician training were implemented, 16 cases were diagnosed in only 3 years (2017\u20132019), a rate of 24/1,000 hospitalizations, a substantial increase.3 of CD4+ lymphocytes . In 6 (19%), DH was the AIDS-defining illness. A total of 3 persons had DH associated with a systemic inflammatory response syndrome.Most patients were men; mean age was 41 (range 21\u201361) years . Except https://www.cepheid.com). Up to 12 (mean 5) clinical samples/patient were submitted for TB investigations before suspicion of DH.Eight (26%) DH patients were empirically treated for TB  patients, serologic tests in 9 (29%) patients, and urinary antigen assay in 4 (13%) patients. Four (13%) patients had  methods . The diaThe treatment of choice for 81% of patients was intravenous amphotericin deoxycholate  for 14 days, followed by oral itraconazole  for 12 months. A total of 5 (16%) patients were treated only with itraconazole . Twelve months after the DH diagnosis, 35% of the patients had died ; 1 died DH causes severe clinical manifestations in PLHIV that can lead to death . The long investigations for TB delayed the confirmation of the DH diagnosis despite descriptions of the concurrence of these 2 diseases (Histoplasma antibodies have poor sensitivity (30%\u201370%) in immunocompromised patients  was similar to the rate described in a systematic review from Brazil histoplasmosis cases (33%) ("}
+{"text": "Ongoing evaluations of innovative educational programs provide opportunities for quality improvement. This paper reports results from a Project ECHO series on lifelong IDD and dementia. Participant responses (n = 85) were collected from spoke sites in various settings across the US. Using a 5-point (5 very effective) Likert scale, data were collected from assessment items on 4 didactic presentations and 5 case studies representing essential components of the ECHO model. Overall scores by spoke sites for satisfaction with the didactic and case presentations ranged from 3.94 to 4.94; relevance of case studies to the work setting ranged from 4.0 to 4.75. Knowledge gain questions showed consistently positive directionality. As a result of their participation, spokes rated intent to provide better care for patients (57% to 88%), train staff (62% to 81%), and educate family/caregivers (57% to 88%). Implications of findings for the application of quality improvement methods are discussed."}
+{"text": "Encephalitis caused by flaviviruses, Japanese encephalitis virus (JEV) and West Nile virus (WNV) is responsible for significant morbidity and mortality in many endemic countries. Dengue-2 (Den-2) virus is a recent addition to the list of encephalitogenic viruses, after its Central Nervous System (CNS) invasion capability has been established. There is a wide array of laboratory tools that have helped us not only in the diagnosis of these conditions but also in understanding their pathogenesis and pathology. However, there are no reports of Shell Vial Culture (SVC), a centrifuge enhanced tissue culture assay that has revolutionized viral culturing in terms of rapidity and sensitivity being optimized for these flaviviral encephalitic conditions. The present study is an attempt to standardize and evaluate the usefulness of SVC for the laboratory diagnosis of JE, WN and Den-2 encephalitis cases and to compare it with Indirect Immunofluorescence (IIF) technique that detects cell associated virus antigen. Analysis of the various clinical parameters with respect to viral etiology has also been carried out.Pediatric patients constituted the major group involved in the study (92%). Etiological diagnosis of viral encephalitis could be established in twenty nine (58%) patients. JE encephalitis was the commonest with 19 (39%) cases being positive followed by, WN (9 cases-18%) and Den-2 (one case). IIF test could detect antigens of JE, WN and Den-2 viruses in 16(32%), 7(14%) and 1 case respectively. Shell vial culture assay picked up all cases that were positive by IIF test. In addition, SVC assay could detect 3 and 2 more cases of JE and WN encephalitis respectively, that were negative by the IIF test.Shell vial culture is a rapid and efficient tool for the etiological diagnosis of JE, WN and Den-2 encephalitis cases. Early, prompt collection, transport and processing of the CSF samples, would make SVC a better method for the rapid diagnosis of these flaviviral infections. The family flaviviridae encompasses viral agents, which are an important cause of arthropod-borne encephalitis in humans. Japanese Encephalitis (JE) virus is the most common among them in the world . In IndiWest Nile virus, a close relative of JEV, usually causes a mild febrile illness in humans, that may sometime end in encephalitis . High moDengue-2 (Den-2) virus is another flavivirus that is primarily associated with a febrile illness (Dengue fever), Dengue hemorrhagic fever syndrome (DHS) and Dengue shock syndrome (DSS). It is a recent addition to the list of encephalitogenic viruses, after its neurovirulence has been proved by isolation of the virus from CSF, demonstration of specific IgM antibodies and viral genome detection in CSF by RT-PCR .Infections by JE, WN and Den-2 viruses are prevalent in India. Earlier studies from our institution have shown high prevalence of JE infection and also serological evidence of WN and Dengue-2 infections in Pondicherry and surrounding areas .Various techniques have been tried, standardized, evaluated for the laboratory diagnosis of infections due to JE, WN and Den-2 viruses. The rapid laboratory tools that can be of help in clinical situations of viral encephalitis include, demonstration of viral antigen, detection of specific IgM antibody and genome detection . Though Chlamydia trachomatis from the human genital tract [Shell vial culture is a modification of the conventional cell culture technique for rapid detection of viruses in vitro . The tecal tract . Rapid ial tract . The rapal tract .46 (92%) patients were from pediatric age group ranging from 18 months to 12 years with a mean age of 7 years.Predominant sex was male with a M: F ratio of 1.7:1.Fever, Seizures and Altered Sensorium were the clinical symptoms with which most of the patients sought medical help. Fever (98%) was the commonest initial manifestation followed by altered sensorium (92%) and seizures (66%). Headache and Vomiting were present in 4 (8%) and 7(14%) cases respectively.30 (60%) patients stayed only for a week or less period of time in the hospital. Only 8 (16%) patients stayed for 3 weeks or more. Mean duration of hospital stay was 7.5 days.29 (58%) specimens in the study were positive for one of the three flaviviruses studied either by IIF or shell vial culture or both. JEV was the commonest (19 cases-38%), followed by WNV (9cases-18%). Den-2 was detected only in one case.IIF technique could detect the three flaviviruses studied in 24 (48%) cases. Out of this, 16 (32%) were JE, followed by WN and Den-2 in 7 (14%) and 1 (2%) specimens respectively.SVC could pick up all the cases positive by IIF technique. Additional 3 and 2 cases of JE and WNE could be diagnosed by SVC that were negative by IIF test. So, SVC could establish viral etiology in 29 (58%) of the cases studied. JEV was positive in 19 (18%) of cases followed by 9 (18%) WNV and Den-2 virus (one case)Among the four adults (age > 12 years) included, only one case was positive for JE. Rest three were negative for all the flaviviruses studied. Twenty eight (60.8%) patients from pediatric age group (n = 46) were positive for one of the 3 viruses studied. JE was found in 18 (64.3%) cases followed by WN in 9 (32.2%) cases and Den-2 in one (3.5%) case. Seventeen (53.1%) out of 32 male patients studied were positive for one of the three viruses studied. JE was found in 11 (64.7%) cases followed by WN in 5 (29.3%) cases and Den-2 in one (6%) case. Out of the 18 (36%) total female patients in this study, 8 (44.4%) patients were positive for JE and 4 (22.2%) patients for WN. No Den-2 was detected in this group.Three different types of focal neurological deficits (FND) were identified in the patients studied. Commonest was facial palsy, which was seen in 6 (12%) cases, all of them were positive for JEV infection. Hemiparesis was found in 3 (6%) cases that were positive for JEV infection. Hemiplegia was seen in one (2%) patient with JEV infection. Hence, all the FND were associated with JEV infection. No FND were associated with WN and Den-2 viral infections. A total of 9 (18%) patients had an associated FND. One patient was having hemiplegia associated with facial palsy. No FND were found among the patients negative for the 3 viruses studied.Eight patients positive for JEV expired with a case fatality rate (CFR) of 50% and the rest 8 (50%) had a complete clinical recovery. Five patients who were positive for WNV expired (CFR = 62.5%) and the rest 3 recovered. One case, which was positive for Den-2 virus, showed complete recovery. Three (14.3%) among the 21 patients who were negative for all 3 viruses expired, whereas 18 (85.7%) of them showed clinical improvement. Four patients were discharged against medical advice; hence the outcome of these cases could not be analyzed.Japanese encephalitis virus is the most important cause of epidemic encephalitis worldwide with an estimated 30,000\u201350,000 cases annually . The geoConceptually, the most rapid diagnosis of an arbovirus infection can be made by direct detection of virus antigen or nucleic acid in clinical specimens. Rapid serologic diagnostic tests, such as Enzyme Immuno-Assay (EIA) can provide strong presumptive etiologic evidence, if specific IgM is detected in the acute-phase serum or CSF specimen. Detection of IgM is not always evidence of current infection with certain arboviruses, especially flaviviruses, which can induce persistent IgM production ,8. GenomVirus isolation, though more specific compared to antigen detection, is less sensitive and time consuming requiring minimum of 3\u20137 days compared to 5\u20136 hours required for antigen detection by indirect immuno- fluorescent technique . Shell vIn the present study that included 50 patients, males were 32 (64%), and females were 18(36%) with a male to female ratio of 1.7:1. Pediatric age group (0\u201312 years) was the predominant one compared to the adults. This predominant involvement of pediatric age group (92%) and the Male:Female ratio of 1.7:1 are in accordance with the age and sex distribution of the earlier epidemics of viral encephalitis in the endemic areas including Pondicherry and Tamilnadu . Viral eA total of 9 (65.5%) out of 19 patients positive for Japanese encephalitis virus had neurological deficits. Focal neurological deficits occurred in 631.5%) patients who recovered from Japanese encephalitis. The neurological deficits that were noted in the study group were facial palsy (n = 6), hemiparesis (n = 3) and hemiplegia (n = 1). All the neurological deficits were found in patients positive for Japanese encephalitis virus. In one case facial palsy was associated with hemiplegia. No neurological deficits were noticed in patients positive for West Nile or Den-2 virus infections. It is interesting to note the absence of neurological deficits like flaccid paralysis in WN encephalitis cases that is described in outbreaks of WN virus infection in the United States,31..5% patieAmong the 50 patients included in the study, 4 (8%) patients left against medical advice, so the clinical outcome of these cases is not known. Out of the remaining 46 (92%), 16(34.8%) expired and the rest 30(65.2%) had a clinical recovery with or without neurological sequelae. 8 patients positive for Japanese encephalitis virus expired with a case fatality rate (CFR) of 50%. In the present study, West Nile encephalitis had a CFR of 62.5%. Dengue-2 infection was detected only in one patient, who showed complete clinical recovery. This high case fatality rate among children with West Nile encephalitis is in contrast to other published reports where in advanced age is the most important risk factor for morbidity and mortality. It is unclear if this high mortality rate among the children is due to a highly virulent strain of the virus.Indirect immunofluorescence test, the best-studied antigen detection method for the diagnosis of viral encephalitis by flaviviruses especially Japanese encephalitis , could dShell Vial Culture could demonstrate viral etiology in all the 24 cases positive by IIF. In addition shell vial culture could detect the virus in 5(10%) more cases, which IIF failed to detect. Therefore, the technique could establish viral etiology in 29(52%) cases compared to 24(48%) by IIF. The significant reduction in the time taken (36 hours), compared to conventional cell culture technique (3\u20137 days) is an important advantage, which could be due to the hastening of viral entry into the cells of monolayer, as hypothesized. In order to ensure a rapid and precise diagnosis, early, prompt collection, transport and processing of the CSF samples becomes mandatory.Shell vial culture is a rapid and efficient tool for the etiological diagnosis of JE, WN and Den-2 encephalitis cases. It is more sensitive than the Indirect Immunofluorescence technique, which is a widely used rapid diagnostic method for the diagnosis of viral encephalitis. Early, prompt collection, transport and processing of the CSF samples, would make SVC a better method for the rapid diagnosis of these flaviviral infections.Cerebrospinal fluid obtained by lumbar puncture from 50 patients admitted in pediatric and medical wards, JIPMER hospital, Pondicherry with a provisional clinical diagnosis of viral encephalitis constituted the study material. The group included 46 pediatric patients aged between 18 months and 12 years and 4 adults with age ranging from 13 to 40 years. All the patients were from Pondicherry and the neighboring districts of Tamil Nadu State.Porcine Kidney (PS) cells (supply No 3109 A) obtained from National Center for Cell Sciences, Pune, were used in the study. Cells were grown in plastic tissue culture flask  and Roux bottles at 37\u00b0C.3 and antibiotics  was used. L glutamine (3%), vitamin concentrate, glucose (10%), fetal calf serum (10%) and the mixture of antibiotics  were added after the reconstituted Eagle's modified MEM was autoclaved.Eagle's modified MEM  with Earle's salts, NEAA, phenol red without L-glutamine, NaHCOPre-sterilized flat-bottomed cylindrical shell vials (4.5 cm \u00d7 1.5 cm), with a cover slip of 13 mm diameter obtained from Flow Laboratories, Scotland.The lyophilized MAF against JEV , WNV (825605-2) and Dengue virus (M-90450) obtained from National Institute of Virology, Pune were reconstituted with phosphate buffered saline (pH 7.2) and used for staining CSF smears and cell monolayers.Rabbit IgG FITC conjugate (Sigma product No. F7256) was used for secondary staining of the CSF smears and cell line monolayer of the shell vial.JEV (NIV strain P 20778), WNV (NIV strain G 22886), Dengue-2 (NIV strain P 23085) infected mouse brains obtained from National Institute of Mental Health and Neurosciences, Bangalore were blind passaged in suckling mice by intracerebral inoculation.Subsequently the strains were adapted to porcine kidney cell line in the laboratory by serial blind passage. Porcine kidney cell line infected with JE, WN and Dengue-2 viruses stained by indirect immunofluorescence served as positive controls for the IIF study with clinical specimens.Glass slides  were washed with soap water, kept immersed in Teepol solution overnight, washed and autoclaved. Prior to the making of smears, these slides were treated with 1:1 mixture of Methanol-Ethanol for 30 mins in a Coplin jar, air-dried and used.Using a cytospin system  three smears were made on separate glass slides from each of the 50 specimens, one each for JE, WN and Den-2 virus respectively. 150 \u03bcl of CSF specimen was used to prepare one cytospin smear. The cells were sedimented using the cytospin at a speed of 1000 rpm for a time period of 10 mins.Smears were air dried, fixed with chilled acetone for 30 mins. 20 \u03bcl of 1:10 MAF against JE, WN and Den-2 were added to smears 1,2&3 respectively and incubated in a humid chamber at 37\u00b0C for 30 mins, followed by several washes with PBS (pH 7.2). 20 \u03bcl of 1: 10 Rabbit anti-mouse IgG FITC conjugate was added to each of these smears and incubated at 37\u00b0C in a humid box for 30 mins. Smears were washed several times over a period of 10 mins using PBS (pH 7.2). Smears were then dried and mounted with buffered glycerol  and observed under fluorescence microscope  for intracytoplasmic apple green fluorescence.Positive and negative controls were included in every run of the assay for comparison. Smears were examined by two independent examiners and recorded.After adaptation of JE, WN and Dengue-2 viruses (NIV strains) to the porcine kidney cell line, the strains were used for the standardization of shell vial culture. Porcine kidney cell monolayers were grown on the cover slips of shell vials. The NIV strains were used to infect the monolayers. After centrifugation at 1000 rpm for 45 mins, the shell vials were incubated at different time periods of 12, 24, 36 and 48 hrs at room temperature. Cell monolayers were fixed with chilled acetone and stained by indirect immunofluorescence technique as described below. It was found that early best results were obtained after 36 hours of incubation and this served as positive controls for the shell vial assay in this study.5 cells/ml) in growth medium was added to each shell vial and incubated at 37\u00b0C till the confluent monolayer was formed. Shell vials were numbered 1,2 & 3 and the virus growth medium was removed from them. 300 \u03bcl of the specimen was inoculated into each of these shell vials 1,2 & 3 that were later stained by IIF technique for JE, WN and Den-2 viruses respectively. Shell vials were centrifuged at a speed of 1000 rpm for 45 mins at room temperature followed which 1 ml of maintenance medium was added in to each of the shell vials to incubate at 37\u00b0C for 36 hours. Maintenance medium was removed carefully from the shell vials and discarded. Monolayer was rinsed with PBS (pH 7.2) 3\u20134 times dried and fixed with chilled acetone for 30 mins. Coverslips from the shell vials 1,2 & 3 were stained by IIF method for JE, WN and Den-2 viruses respectively as described above. Smears were examined under fluorescence microscope by two independent observers for intra-cytoplasmic apple green fluorescence.1 ml of the porcine kidney cells suspension  declare that they have no competing interestsJSR and RVP designed the study, did the IIF and SVC tests and documented the resultsSS collected CSF specimens, did clinical examination of the patients analysis of clinical outcome in the studied populationJSR and BS analyzed the test results and prepared the manuscript"}
+{"text": "Eighteen patients with advanced breast cancer were commenced on treatment with high dose doxorubicin (100 mg m-2) or doxorubicin (100 mg m-2) and cyclophosphamide (500 mg m-2) at 2 weekly intervals. Three cycles of treatment were planned. rG-CSF was given subcutaneously for 10 days, starting 24 h after each cycle of chemotherapy. Sixteen out of 18 patients responded (89%) of whom six (33%) achieved a complete remission. Twelve (67%) completed the three planned cycles, four (22%) received two cycles and two (11%) received one cycle only. The median time to progression was 5 1/2 months and the median survival was 18 1/2 months. Neutropenia occurred after 89% of courses and 65% of courses were accompanied by a significant (WHO grade III or IV) infection. The duration of neutropenia was short (mean 5.4 days) and mean time to absolute neutrophil count recovery  litre) from the start of treatment was 11 days. Moderate to severe epithelial toxicity (WHO grade 3 or 4) accompanied 43% of courses and was dose limiting. Conclusion: High dose, dose intensive chemotherapy has an excellent initial therapeutic effect in advanced breast cancer but does not prolong duration of remission or overall survival beyond that of standard treatment. Although subcutaneous rG-CSF curtailed the expected duration of neutropenia substantially, the overall incidence of neutropenia and of infections requiring intravenous antibiotics was high. Furthermore, almost half of the courses were complicated by moderate to severe oral mucositis and/or mild to moderate palmar and plantar inflammation. The lack of survival benefit and excess toxicity seriously limits the wider application of this regime. It should not be used in place of standard dose palliative chemotherapy for metastatic breast cancer."}
+{"text": "Even though the majority of patients with bladder malignancies initially present with low stage disease, the clinical epidemiology of these so-called superficial bladder tumours is not well known. In this paper, disease characteristics at initial presentation and during follow-up are described in 1,745 primary cases documented prospectively in the Netherlands. The risk of recurrent disease after primary treatment is very high: in 60% of cases, at least one recurrence is diagnosed within 5 years (95% CI: 58-62%). In patients with a small solitary pTa grade 1 tumour, the 3-year recurrence risk is 37%. In patients with multiple large high grade pT1 tumours, this risk is as high as 77%, despite a significant beneficial effect of adjuvant intravesical chemotherapy. The actuarial risk of disease progression is 10.2% after 3 years (95% CI: 8.6-11.8%). This risk of progression depends on the patient's age at diagnosis, tumour stage, grade, multiplicity and the presence of dysplasia or CIS in random urothelium biopsies. The use of intravesical instillations with chemotherapy or BCG vaccine after TUR does not prevent progressive disease, although this finding is difficult to interpret from a non-randomised study. The 5-year relative survival in patients with superficial TCC of the bladder is 86% (95% CI: 84-88%)."}
+{"text": "A histopathological study was undertaken on breast tissue dissected during the course of 207 consecutive forensic post-mortems on women over the age of 15 years in order to define the frequency and types of lesions found in Australian women. At least 10 blocks were obtained from each breast and a total of 4,738 blocks were examined. A particularly high frequency of atypical hyperplasia (12.6%), carcinoma in situ (13.0%), focal secretory change (24.1%) and perilobular haemangiomas (11.2%) was found. The radial scar, considered by some to be a precursor of infiltrating ductal carcinoma was found in 7.7% of the women."}
+{"text": "This study aimed to assess the safety and efficacy of using high dose melphalan and etoposide followed by autologous, non-cryopreserved marrow rescue in advanced Hodgkin's disease (HD). Seventeen patients with poor risk Hodgkin's disease from a single centre underwent autologous bone marrow transplant (ABMT) using high dose melphalan and etopside conditioning. Two patients had primary progressive resistant disease (PD), two were in fourth relapse, six in second or third complete remission (CR), one patient had good partial response (GPR)  to primary therapy and six were in first complete remission. The patients transplanted in first CR all has a Scotland and Newcastle Lymphoma Group (SNLG) Prognostic Index  which indicated they were in a poor risk prognostic group. Melphalan and etoposide both have a short half life enabling ABMT to be accomplished using unmanipulated marrow stored at 4 degrees C. The marrow was returned to the patient within 56 h of harvest. Complete haematological reconstitution occurred in 16/17 patients, the rate of engraftment reflecting the amount of previous chemotherapy. One patient died of progressive Hodgkin's disease before full engraftment could occur. In patients autografted in first remission, the median number of days with neutropenia (< 0.5 x 10(9) l-1 neutrophils) was 19 (range 9-33) and, in those in subsequent remission, 27 days (range 18-36). The median number of days to 50 x 10(9) l-1 platelets in the same groups were 29 (21-80) and 50 (41-74) respectively. The number of days in hospital post transplant in both groups was similar; median 22 (15-27) and 23 (17-37) respectively. There were no procedural deaths and none of the patients transplanted in first, second or third CR have relapsed (median follow up 21 months). The two patients transplanted with progressive disease showed only temporary responses. The two patients transplanted in fourth relapse went into CR; one is still alive and in CR 15 months post transplant, but the other relapsed 18 months post transplant. This form of intensification therapy with marrow rescue has been shown to be effective and of low toxicity and now forms part of a randomised controlled trial in poor risk Hodgkin's patients as identified by the SNLG index ."}
+{"text": "Between February 1986 and July 1988 a total of 21 children aged 1 to 16 years with malignant germ cell tumours (MGCT), 18 with either metastatic disease or unresectable primary tumour, received the JEB regimen - carboplatin dosage calculated from the EDTA glomerular filtration rate (approximately 600 mg m-2), etoposide 120 mg m-2 daily x 3, and bleomycin 15 mg m-2 weekly. Primary sites were: testis (6), ovary (8), sacrococcyx (4), pineal gland (2) and vagina (1). AFP levels were elevated in 19, beta-HCG in 8. Complete marker response was achieved in 19 out of 19 evaluable patients and complete remission of measurable tumour in 16 out of 19, 12 with chemotherapy alone and 4 with the addition of surgery. A reduction in glomerular filtration rate greater than 10% occurred in 3 of 12 evaluable patients; in none greater than 20%. Sequential audiography was normal in 11 out of 12 evaluated. The regimen was myelosuppressive with WHO grade III or IV myelosuppression occurring in 12 patients. Three patients have relapsed; one with a pineal germinoma who relapsed in the abdomen six months after diagnosis, and two with sacrococcygeal teratomas and lung metastases. Two of these remain in second complete remission after further treatment. There was one death from probable bleomycin pulmonary toxicity. We conclude that this regimen is simple to administer and, apart from myelosuppression, it is well tolerated. It appears to have comparable efficacy to cisplatin-based regimens but with much less nephrotoxicity and ototoxicity and avoids the use of alkylating agents and anthracyclines."}
+{"text": "In 231 colorectal carcinomas, allele variation at four restriction fragments length polymorphisms (RFLP) loci on chromosome 17 have been studied by Southern analysis. Heterozygous loss of the TP53 gene was found in 68% (129/189) of the carcinomas informative on both chromosome arms. In 41% (77/189) of the carcinomas the loss was found only on 17p. Two probes were used to detect alterations on 17p, pBHP53 and pYNZ22. When loss was demonstrated with pYNZ22, pBHP53 also always showed loss (n = 45), whereas when loss was demonstrated with pBHP53, only 45 of 54 (83%) showed loss with pYNZ22. Loss on 17q was found in 34% (64/189) of the carcinomas, and 6% (12/189) had loss on this chromosome arm, only. Loss on 17q was significantly associated with loss on 17p (P < 0.01). These data confirm that the TP53 gene is the target of loss on chromosome arm 17p in colorectal carcinomas, and demonstrate that loss of the TP53 gene is most frequently part of limited, subchromosomal loss. Furthermore, the results do not suggest any additional tumour suppressor gene(s) on chromosome 17 involved in colorectal carcinogenesis."}
+{"text": "A new cancer-associated antigen CA130, recognised by two monoclonal antibodies (moABs) 130-22 and 145-9, was often found to be present at high levels in the sera of patients with ovarian cancer. There was a strong correlation between CA130 and CA125 values. The epitopes recognised by moABs 130-22 and 145-9 were proved to differ from the CA125 epitope, but to exist on the molecule bearing CA125. Unlike OC125, the majority of 130-22/145-9 activity was associated with a much lower molecular mass (less than 200 kDa), indicating that a lower molecular mass immunoreactive determination may be a unique CA130 antigenic determinant within CA125 molecule. Clinical data demonstrate that, (1) elevated levels of CA130 determinant were found in the sera of 91.3% of women with epithelial ovarian cancer, (2) falling or rising levels of CA130 correlated with regression or progression of ovarian cancer in > 95% of cases, (3) normalisation of serum CA130 levels at response does not imply no microscopic residual disease, but CA130 changes during follow-up support the evaluation of recurrence and can be used as a monitoring marker in an individual patient."}
+{"text": "The levels of CA 242, a new tumour marker of carbohydrate nature, were measured in sera of 185 patients with malignancies of the digestive tract and of 123 patients with benign digestive tract diseases. High percentages of elevated CA 242 levels (greater than 20 U ml-1) were recorded in patients with pancreatic and biliary cancers (68%). The sensitivity was somewhat lower than that of CA 19-9 (76%) and CA 50 (73%). On the other hand, in benign pancreatic and biliary tract diseases the CA 242 level was less frequently elevated than the CA 19-9 and CA 50 levels. The serum CA 242 concentration was increased in 55% of patients with colorectal cancer. CA 242 detected more Dukes A-B carcinomas (47%) than CEA (32%), whereas CEA was more often elevated (71% vs 59%) in Dukes C-D carcinomas. CA 242 was slightly elevated (ad 41 U ml-1) in 10% of patients with benign colorectal diseases. CA 50 and CA 19-9 had lower sensitivities than CA 242 using the recommended cut-off values. When cut-off levels based on relevant benign colorectal diseases were used, the sensitivities of these markers were similar and somewhat higher than that of CEA. Less than half of patients with gastric cancer (44%) had an elevated CA 242 serum level. CA 242 is a promising new tumour marker, that may be of additional value in the diagnosis of pancreatic and biliary, as well as colorectal cancer, and may be useful in monitoring cancer patients after radical surgery."}
+{"text": "Decay-accelerating-factor , a phosphatidyl-inositol anchored glycoprotein, is a member of the cell membrane bound complement regulatory proteins that inhibit autologous complement cascade activation. DAF was found expressed on cells that are in close contact with serum complement proteins, but also on cells outside the vascular space and on tumour cells. Using CD55(BRIC110) and CD55(143-30) we show here that DAF(CD55) is only sporadically expressed on the luminal surface of normal colonic epithelium. However, 5/20 adenomas expressed DAF(CD55) on the cell surface of all tumour cells, 5/20 adenomas were completely negative, 10/20 adenomas expressed DAF(CD55) in various amounts. DAF(CD55) was expressed in various intensities on almost all tumour cells of the colon carcinoma cell line HT29. In 5/88 colorectal carcinomas DAF(CD55) was localised on the apical cell surface of all tumour cells, 31/88 were completely negative, 52/88 expressed DAF(CD55) in parts of their neoplastic populations. There was no correlation between the tumour grading, staging and location and the mode of DAF(CD55) expression, but DAF(CD55) was found more often in mucinous carcinomas (P = 0.007). Although the mode of DAF(CD55) expression is not correlated with tumour prognostic parameters, the upregulation of DAF(CD55) in a subset of adenomas and carcinomas needs further investigation concerning protection of tumour cells against complement cytotoxicity."}
+{"text": "The efficacy of high-dose intramuscular MPA therapy in controlling progressive measurable metastatic breast carcinoma was assessed in 32 women. In addition serial measurements of MPA blood levels were carried out in 20 of the patients and subjective effects of treatment were monitored in detail in 18 of the women. Overall 6 patients (19%) gained an objective response and a further 7 (22%) experienced disease stasis from 4-17 months whilst on treatment. Significant differences in serum MPA levels were seen between responders and non-responders, objective tumour shrinkage only being seen in those patients who rapidly attained, and sustained, blood levels in excess of 100 ng ml-1. Subjective assessment showed no evidence of a euphoriant effect of MPA therapy in the non-responders group."}
+{"text": "We report the use of the steroidal aromatase inhibitor, 4-hydroxyandrostenedione , in the management of patients with advanced, hormone resistant, prostatic cancer. Eighteen of 25 patients (72%) showed a subjective response, mainly in the form of pain relief and increased performance. There were no objective improvements. A tumour flare occurred in 17/25 (68%). Detailed endocrine studies were performed during treatment. These showed that suppression of serum oestradiol levels occurred in 19/25 (76%) of patients during treatment with 4-OHA. Serum levels of androstenedione increased in 9/14 patients (64%). Concentration of serum testosterone and 5 alpha-dihydrotestosterone were elevated in 3/14 (21%) and 2/11 (18%) patients respectively. There appeared to be no correlation between response or tumour flare and changes in steroid levels during treatment with 4-OHA. The mechanism of action of 4-OHA in palliating patients with advanced prostatic cancer remains obscure. 4-OHA or its metabolites may be acting on metastatic bone metabolism via effects on oestrogen related osteoclastic and osteoblastic activity. Further investigation of the effects of aromatase inhibitors on prostatic biology, and bone metabolism in patients with metastatic prostate cancer, would appear worthwhile."}
+{"text": "Several studies have suggested that prolonged use of oral contraceptives may increase a woman's risk of developing malignant melanoma. In the Royal College of General Practitioners' Oral Contraception Study, 31 cases of malignant melanoma  have been reported among ever-users and 27 cases among never-users. The risk ratio (RR)  was 0.92  0.55-1.54). There was no significant trend with duration of oral contraceptive use, although those women who had used the pill for at least 10 years had an elevated RR of 1.77 (95% CI 0.80-3.90). The Oxford/Family Planning Association Study has recorded 15 cases among ever-users and 17 cases among never-users; the standardised risk ratio was 0.85 (95% CI 0.42-1.70). None of the rates observed in any duration of use category was materially different from those observed in never-users. The results available so far from the two studies suggest that oral contraceptive use is probably not associated with an increased risk of malignant melanoma."}
+{"text": "This randomised phase II study was performed in order to evaluate the effectiveness of a weekly chemotherapy regimen in advanced prostatic carcinoma patients (stage D2) refractory to hormonal therapy. Seventy-two cases were studied: they were randomised in a 2:1 ratio to receive either epirubicin (30 mg m-2 weekly) or doxorubicin (25 mg m-2 weekly); 48 patients received epirubicin and 24 received doxorubicin. After 12 courses of chemotherapy, the 45 evaluable patients in the epirubicin arm showed a response rate of 37.7% and the 21 evaluable patients in the doxorubicin arm showed a response rate of 33.3% (P = 0.51). Pain intensity, bone and prostatic tumour markers rapidly and significantly decreased in responders. An improvement in physical symptoms, functional conditions and in emotional well-being was observed in the majority of the treated patients. The histological analysis of bone metastases, performed before and after 12 courses of chemotherapy showed a significant reduction in neoplastic invasion and in new bone formation in responders. Cardiac performance worsened in five out of 45 patients and in ten out of 21 during the first 12 courses of epirubicin or doxorubicin respectively (P = 0.014). The median survival was 12.5 months in the epirubicin arm and 8.0 months in the doxorubicin arm (P = 0.042). Our data indicate that in advanced prostatic carcinoma, a weekly epirubicin regimen may give rapid palliative results, similar to that of doxorubicin, but with less side-effects."}
+{"text": "Twenty seven adult patients with newly diagnosed non-Hodgkin's lymphoma localised to either bone (Stage IE) or bone and regional lymph nodes (Stage IIE) were treated between 1967 and 1988. Median age was 53 years and the commonest histology (21 patients) was diffuse histiocytic lymphoma. Twenty-four patients were treated radically: 15 with radiation therapy (XRT) alone and nine with chemotherapy plus radiation therapy (CMT). The cause specific survival for these patients was 56% at 5 years and 40% at 10 years. Survival was significantly better for patients treated by CMT (88% at 5 years) as compared to XRT alone  and for age less than 60 (72% at 5 years) compared to greater than or equal to 60 . Relapse-free rate was 27% at 5 years with XRT alone and 89% with CMT (P = 0.01). Risk factors for loco-regional relapse (seven cases) included: large tumour bulk, treatment by XRT alone and use of 'limited' radiation fields. No radiation dose-response relationship could be identified in this study. Long term local control and survival for localised lymphoma of bone were excellent after treatment by CMT but XRT alone was associated with unacceptably high local and distant failure rates."}
+{"text": "In a retrospective analysis encompassing a 14 year period (1978-92), 22 patients  were identified as having mediastinal large-cell lymphoma with sclerosis on the basis of clinical and pathological features. At presentation, 15/22 had 'bulky' disease and 11/22 had evidence of superior vena caval obstruction. Thirteen patients had stage II disease , nine presented with stage IV disease. Complete remission (CR) was achieved in only 4/22 patients with the initial adriamycin-containing regimen. 'Good partial remission'  was achieved in a further seven patients and 'poor partial remission' (a reduction in measurable disease > 50%) in four, giving an overall response rate of 15/22 (68%). One patient died within 48 h of arrival at the hospital; 16 of the 17 remaining patients in whom anything less than CR was achieved subsequently received additional, alternative treatment  but in only 2/16 did this result in any further degree of response. With a median follow-up of 5 1/2 years, 10/22 patients remain well without progression between 6 months and 14 years . The seven patients in whom the initial treatment demonstrably failed have all died. These results suggest that a proportion of patients with this rare subtype of high-grade B-cell lymphoma may be cured by chemotherapy alone and that the presence of a residual mediastinal mass after treatment does not necessarily imply treatment failure. However, patients in whom the initial chemotherapy fails have a very grave prognosis."}
+{"text": "At a median time of 20 months following high dose melphalan for myeloma, 29 patients relapsed and were treated with induction chemotherapy to maximum response followed by a second course of high dose melphalan. The majority (90%) of patients received 200 mg m-2 with an autologous bone marrow transplant. Sixteen (55%) patients achieved complete remission and 11 (38%) a partial response. The median duration of remission was 17 (4-42) months. The median survival has not been reached, with 50% of patients alive at 58+ months after presentation. The period of neutropenia was similar during both first and second high dose procedures, but the duration of thrombocytopenia was longer in patients receiving melphalan for a second time (median 22 (16-56) days and 41 (18-69) days respectively). There was one treatment-related death due to thrombocytopenic haemorrhage. Repeated administration of high dose melphalan is a feasible approach for patients with relapsed myeloma."}
+{"text": "In an attempt to decrease the risk of second malignancies and future infertility in children with Hodgkin's disease (HD) while retaining acceptable remission rates, an anthracycline based regimen containing no alkylating agent has been devised. VEEP contains vincristine, epirubicin, etoposide and prednisolone given at 3 weekly intervals. Forty-four patients, aged 2-15 years, have been treated: ten relapsed patients and 34 previously untreated with chemotherapy . The median follow up for all patients is 25 months (range 6-52 months). The response rate in previously treated patients was 80% (95% CI 44-97%) and five remain alive in remission. The response rate in untreated patients was 88% (95% CI 72-97%) with 62% CR + CR(u) (uncertain/unconfirmed) (95% CI 44-77%). Of four patients who had a final response of CR(u) three have relapsed at 9, 16 and 38 months. Two of the children in CR have relapsed at 6 and 16 months. The relapse free rate at 3 years is 67% (95% CI 17-82%). In this pilot study the event free survival appears somewhat poorer than conventional combinations and further follow up is required to confirm the salvagability of relapsed patients."}
+{"text": "One hundred and one consecutive patients with newly diagnosed stage I Hodgkin's disease (HD) received treatment at St Bartholomew's Hospital, between 1968 and 1987, with a median follow-up of 12 years. Eleven patients have been excluded from detailed analysis because they either received involved field radiotherapy (RT) or radiotherapy with chemotherapy or were lost to follow-up. Actuarial analysis predicts 78% to be alive and without relapse of Hodgkin's disease at 15 years. Ninety evaluable patients  24; pathological stage (PS) 66) received either mantle or inverted 'Y' RT and form the basis of this analysis. The median age was 33 years . Histology at presentation was nodular sclerosing (39), lymphocytic predominant (27) or mixed cellularity (24). The presenting site was neck (78), axilla (6) groin (4) and mediastinum (2). Complete remission was achieved in all evaluable patients, the actuarial proportion in remission being 75% at 15 years. Factors predictive of a prolonged remission were pathological staging versus clinical staging (P = 0.02) and lymph node size less than 3 cm (P = 0.04). Actuarial overall survival in these 90 patients was 75% at 15 years and none of the above factors correlated with survival. Relapse of HD has occurred in 18 patients . Second remission was achieved in 15/18. The actuarial rate of second remission and survival was 40% at 10 years. Sixteen patients have died, 7 of Hodgkin's disease, 7 of unrelated causes and 2 of second malignancy. A further 3 patients who developed second malignancy are still alive. At 15 years the actuarial mortality related to HD was 12%. These results confirm the importance of long follow up to assess the efficacy of primary therapy."}
+{"text": "Constant denaturant gel electrophoresis (CDGE) was used to screen 179 breast carcinomas for mutations in the conserved regions of the TP53 gene (exons 5 through 8). Mutations were found in 35 of 163 primary tumours (21%) and in 5 of 16 metastases (31%) and resided predominantly in exon 7. The majority of the mutations were G:C-->A:T transitions. Immunohistochemistry demonstrated nuclear accumulation of p53 protein in 35 of 162 primary tumours (22%) and in four of 15 metastases (27%). TP53 mutation was strongly associated with nuclear accumulation of p53 protein. In total 42 of 163 primary tumours (26%) and 5 of 16 metastases (31%) were demonstrated to contain TP53 alterations (mutation and/or nuclear protein accumulation). TP53 alteration in primary tumour was significantly associated with the following parameters: positive node status, T status > 1, negative oestrogen receptor status, negative progesterone receptor status, presence of ERBB2 gene amplification, and invasive ductal histology. Furthermore, there were statistically significant associations, independent of other prognostic factors, between TP53 alterations in primary tumour and disease-free and overall survival."}
+{"text": "Antibodies specific for human p53 were analysed in sera of lung cancer patients. We detected p53 antibodies in the sera of 24% (10/42) of patients with lung carcinoma. The distribution was as follows: 4/9 small-cell lung carcinomas (SCLCs), 2/18 squamous cell lung carcinomas (SCCs), 2/10 adenocarcinomas (ADCs) and 2/5 large-cell lung carcinomas (LCCs). p53 antibodies were always present at the time of diagnosis and did not appear during progression of the disease. Using an original peptide-mapping procedure, we precisely localised the p53 epitopes recognised by p53 antibodies. Immunodominant epitopes reacting with antibodies were localised in the amino and carboxy termini of the protein, similar to those found in breast carcinoma patients or in animals immunised with p53. In light of these data, we suggest that p53 antibodies occur via a self-immunisation process that is the consequence of p53 accumulation in tumour cells. p53 antibodies were also detected in two patients without detected malignant disease. One of these patients died 6 months later of lung carcinoma, suggesting that p53 antibodies may be a precocious marker of p53 alteration."}
+{"text": "Using polymerase chain reaction (PCR) followed by denaturing gradient gel electrophoresis (DGGE), we examined the mutational status of the four 'hotspot' regions of the p53 gene in 47 primary cervical carcinomas. HPV status was determined, also by PCR. In 20 of these cases, we examined for loss of heterozygosity (LOH) on chromosome 17p13. In the 47 carcinomas, and in a further 68 biopsy specimens from normal, premalignant and malignant cervix, we investigated aberrant immunocytochemical expression of p53. Immunocytochemically, abnormal p53 expression was detected in 13 of 115 cases (8/57 carcinomas). Somatic mutation in p53 was detected in 1 of 47 cervical carcinomas; 36 were positive for HPV 16, 18 or 33. A low level of allele loss (3 out of 20 cases) was detected on chromosome 17p, occurring in both HPV-positive and HPV-negative cases, and in cases with and without p53 mutations. We conclude that somatic mutation in the hotspot regions of the p53 gene occurs infrequently in cervical carcinomas; that immunocytochemically detectable levels of p53 are also infrequent; and that there is no consistent correlation between p53 mutational status, LOH on chromosome 17p or HPV status in these cancers."}
+{"text": "Between 1978 and 1983, 44 patients with advanced seminoma were treated with cis-platinum-based combination chemotherapy (39 patients) or with carboplatin (JM8), as a single agent (5 patients). Of the total group, 40 (90%) are alive and disease free. Two of the 4 patients who died relapsed as non-seminomatous germ-cell tumours. Results in previously untreated patients indicate that tumour volume is less important as a prognostic factor than in non-seminomas. Residual masses were present in almost 80% of patients 1 month after chemotherapy; such masses regress slowly and surgery is not indicated. Elective radiotherapy after chemotherapy appears to be inessential since relapse rates are comparable in irradiated (1/15) and unirradiated patients (1/16). Pretreatment serum HCG concentrations did not influence the outcome of chemotherapy. Preliminary results with JM8 suggest that it is an active single agent in the treatment of seminoma."}
+{"text": "Of a total of 307 patients treated with chemotherapy for advanced non-seminomatous germ-cell testicular tumours between 1976 and 1983, 73 (23.8%) had masses excised after treatment. Resected tissue showed residual malignancy in 16 (22%), fibrosis and necrosis in 25 (34%) and differentiated (mature teratoma) in 32 (44%). Of the 16 patients with tumour only 7 (44%) are alive and disease-free compared with 21/25 (84%) and 27/32 (84%) for fibrosis/necrosis and differentiated teratoma respectively. In addition to histological evidence of residual tumour, elevated serum markers at the time of surgery and/or incomplete excision of residual masses were adverse prognostic features. Of 12 patients with differentiated teratoma or fibrosis who had incomplete resections or densely adherent masses excised with difficulty, 7 subsequently relapsed. The majority of differentiated teratoma patients (75%) had evidence of differentiation in their primary tumours; 88% showed cystic change in metastases and almost one-third showed an increase in the size of metastases during chemotherapy. The data suggest that post-chemotherapy surgery may have a therapeutic as well as a diagnostic role and that complete excision of residual disease should be attempted even if resection at one site has shown either fibrosis or differentiated teratoma. The significance of these findings in relation to treatment induced differentiation is discussed."}
+{"text": "ATM) heterozygous deficiency has been proposed to increase susceptibility to breast cancer, some studies have not found excess risk. In experimental animals, increased susceptibility to breast cancer is not observed in the Atm heterozygous deficient mice (Atm+/-) carrying a knockout null allele. In order to determine the effect of Atm heterozygous deficiency on mammary tumourigenesis, we generated a series of Atm+/- mice on the p53+/- background with a certain predisposition to spontaneous development of mammary carcinomas, and we examined the development of the tumours after X-irradiation.Ataxia-telangiectasia is an autosomal-recessive disease that affects neuro-immunological functions, associated with increased susceptibility to malignancy, chromosomal instability and hypersensitivity to ionizing radiation. Although ataxia-telangiectasia mutated  with four genotypes were used in the experiments. The mice were exposed to X-rays  at age 5 weeks.BALB/cHeA-Atm gene on mammary tumourigenesis after X-irradiation in the p53+/- mice of the BALB/cHeA \u00d7 MSM/Ms background. The singly heterozygous p53+/- mice subjected to X-irradiation developed mammary carcinomas at around 25 weeks of age, and the final incidence of mammary carcinomas at 39 weeks was 31% (19 out of 61). The introduction of the heterozygous Atm knockout alleles into the background of the p53+/- genotype significantly increased the incidence of mammary carcinoma to 58% (32 out of 55) and increased the average number of mammary carcinomas per mouse. However, introduction of Atm alleles did not change the latency of development of mammary carcinoma.We tested the effect of haploinsufficiency of the Atm heterozygous deficiency in p53+/- mice. Thus, doubly heterozygous mice represent a useful model system with which to analyze the interaction of heterozygous genotypes for p53, Atm and other genes, and their effects on mammary carcinogenesis.Our results indicate a strong enhancement in mammary carcinogenesis by  ATM (ataxia-telangiectasia mutated) heterozygous deficiency has been proposed to increase susceptibility to breast cancer F1) with four genotypes  were used in the experiments. The conditions for breeding were described previously [The oworkers  was intrboratory . The Atmeviously .Mice were exposed at 5 weeks of age to X-rays  from an X-ray generator . All animal experiments were carried out in accordance with the standards relating to the care and management of experimental animals (Japan) and Osaka Prefecture University's guidelines for animal care and use.Moribund mice were killed by cervical dislocation for autopsy. In cases of thymic lymphoma, the enlarged thymuses were examined as previously described . In tumop53 and Atm genes were determined by analyzing the PCR products for these alleles. Amplification for the p53 alleles was done as described elsewhere [p53 gene were amplified by PCR using primers p53-4F (5'-CGACCTCCGTTCTCTCTCCTCTCTT-3') and p53-6R (5'-AGACGCACAAACCAAAACAAAATTACA-3'), and primers p53-NF (5'-GCCTTCTATCGCCTTCTTGACGAGT-3') and p53-6R, respectively. Similarly, amplification of the wild-type and the targeted allele of the Atm gene were performed by using primers IMR0640F (5'-GCTGCCATACTTGATCCATG-3') and IMR0641R (5'-TCCGAATTTGCAGGAGTTG-3'), and primers IMR0640F and AtmNeo410R (5'-CGGTGGATGTGGAATGTGTG-3'), respectively.Normal and mammary carcinoma tissues were removed. Isolation of DNA, PCR amplification, electrophoresis of PCR products and assessment of allelic losses were performed according to a procedure described previously . Genotyplsewhere . The wil2 analysis and Mann\u2013Whitney U-test, respectively. Comparison of latency in mammary carcinoma development was examined by unpaired Student's t-test.Statistical significance was evaluated for the incidence of mammary carcinoma and number of carcinomas per mouse by \u03c7p53+/- genotype, and tumours of similar macroscopic morphologies were also observed in the (BALB/c \u00d7 MSM/Ms)F1\u2013p53+/- mice. The histological features of these tumours in the mammary glands are shown in Fig. Atm+/- . Fourteen out of 28 p53+/- Atm+/- mice (50%) and seven out of 22 p53+/- Atm+/+ mice (32%) developed mammary carcinomas during the period of observation . Among the tumours that developed in the p53+/- mice, mammary carcinoma were the most common. These mammary carcinomas were mainly observed at 41\u201377 weeks after birth . None of 11 p53+/+ Atm+/- mice and 25 p53+/+ Atm+/+ mice developed mammary carcinomas. Several lymphomas and a few other tumours developed in the four genotypes (Table p53 heterozygous deficiency in (BALB/c \u00d7 MSM/Ms)F1 mice, and p53+/- mice of both Atm+/+ and Atm+/- genotypes developed mammary carcinoma.Twenty-eight Atm gene on mammary carcinogenesis after X-irradiation in p53+/- mice, 55 p53+/- Atm+/-, 61 p53+/- Atm+/+, 47 p53+/+ Atm+/- and 53 p53+/+ Atm+/+ mice  were exposed to X-rays (5 Gy) at age 5 weeks. Only one out of 53 p53+/+ Atm+/+ mice and none of 47 p53+/+ Atm+/- mice developed mammary carcinoma, indicating that almost all p53+/+ mice fail to develop mammary carcinomas, despite X-irradiation and irrespective of Atm gene status. In contrast, 32 out of 55 p53+/- Atm+/- mice (58%) and 19 out of 61 p53+/- Atm+/+ mice (31%) developed mammary carcinomas . A total of 52 mammary carcinomas developed in 55 p53+/- Atm+/- mice (average number of mammary carcinomas/mouse = 0.95), whereas 28 mammary carcinoma developed in 61 p53+/- Atm+/+ mice . Thus, Atm heterozygous deficiency enhanced development of mammary carcinoma in irradiated p53 heterozygous knockout mice. Spring and coworkers [Atm knockout (Atm+/-) heterozygous mice. Mice bearing a knockout allele of Atm and humans carrying a mutant allele of truncated type in the ATM gene have been shown not to have obviously elevated susceptibility to mammary carcinogenesis. Our findings show that heterozygosity for a null knockout allele of Atm enhances mammary carcinogenesis under p53+/- status, although the Atm mutation is not a dominant-negative type. Heterozygous deficiency of p53 might make clear the effect on mammary carcinogenesis of haploinsufficiency in the Atm gene.To test the effect of haploinsufficiency of the oworkers  observedp53+/- Atm+/- and p53+/- Atm+/+ mice, respectively. Thus, X-irradiation at 5 Gy at age 5 weeks considerably shortened the latency period of mammary carcinoma development in these two groups with different genotypes. As shown in Tables p53+/- Atm+/- mice were 58% (32 out of 55) and 50% (14 out of 28) in irradiated and nonirradiated groups, respectively; in p53+/- Atm+/+ mice the incidence in the irradiated group was 31% (19 out of 61) and that in the nonirradiated group was 32% (7 out of 22). The incidence of mammary carcinoma for each genotype was similar between irradiated and non-irradiated groups. Thus, irradiation may not elevate the incidence of the tumours.These mammary carcinomas were observed significantly earlier  than in the nonirradiated group  out of 26 mammary carcinomas from irradiated p53+/- mice and in all of 15 mammary carcinomas from nonirradiated p53+/- mice, regardless of Atm gene status. Only one mammary carcinoma in irradiated p53+/+ Atm+/+ mice  at age 5 weeks developed mammary carcinomas at around 25 weeks of age, and the final incidence of mammary carcinoma at 39 weeks was 31% (19 out of 61). Introduction of the heterozygous Atm alleles into the background of the p53+/- genotype significantly increased the incidence of mammary carcinomas to 58% (32 out of 55) and increased the average number of mammary carcinomas per mouse. However, it apparently did not change the latency of mammary carcinoma development. In nonirradiated mice, introduction of the Atm+/- allele into p53+/- mice also tended to increase spontaneous incidence of mammary carcinoma. In contrast, almost none of the p53+/+ mice developed mammary carcinoma, regardless of the Atm gene status and whether mice were subjected to irradiation. In almost all of the spontaneous and radiation-induced mammary carcinomas, the wild-type p53 allele was found to be lost whereas the wild-type Atm allele was retained, suggesting haploinsufficiency of the latter gene in mammary carcinoma development. Thus, doubly heterozygous mice represent a useful model system with which to analyze the interaction of heterozygous genotypes for p53, Atm and other genes and their effect on mammary carcinogenesis.Tumourigenesis is strongly enhanced in mice with homogeneous deficiency in the PCR = polymerase chain reaction.The author(s) declare that they have no competing interests.SU carried out design of the study, observed mammary carcinoma development and other diseases, and drafted a manuscript. KF prepared tissue specimens and conducted histopathological examinations (veterinarian). SI carried out DNA isolation and genotyping of mice. NM carried out X-irradiation of mice and statistical analysis. MT performed DNA isolation and genotyping of mice. DH carried out production of heterozygous deficient mice. CS participated in designing the study and discussion of data on mammary carcinoma development. SH contributed to histopathological examination. SI conducted histopathological examinations . ON participated in discussion of data and contributed to preparation of the final manuscript. MO carried out design of the study and X-irradiation, and wrote the final manuscript. All authors read and approved the final manuscript."}
+{"text": "To determine whether alterations in oncogenes are associated with tumour progression and metastasis, DNAs from 32 metastatic tumour samples of different sites in 12 autopsy cases of gastric carcinomas were analysed for alterations of ERBB, ERBB2, HST1, INT2 and LMYC genes by Southern blot hybridisation. DNAs from 89 primary gastric carcinomas including 69 advanced carcinomas and 20 early carcinomas were also examined. In primary tumours, no amplification was detected in early carcinomas, while amplification of ERBB and ERBB2 genes was detected in one (1.4%) and four (5.8%) out of 69 advanced carcinomas, respectively. In metastatic tumours, amplification of ERBB gene was detected in three metastatic tumours (9.4%), and all of them had allelic deletion of the LMYC gene. Regardless of histological type, amplification of ERBB2 gene was detected in 8 metastatic tumours (25.0%), out of which three tumours had coamplification of HST1 and INT2 genes. The incidence of ERBB2 amplification in metastatic tumours was significantly higher than that in primary tumours. These results indicate that multi-alterations in oncogenes might occur during tumour progression and metastasis of human gastric carcinomas."}
+{"text": "Monoclonal and polyclonal antibodies against placental alkaline phosphatase (PLAP) were evaluated for tumour immunolocalization of human PLAP-producing Hep 2 tumours in nude mice. The antibodies were labelled with 125I and injected i.p. in mice with developing Hep 2 tumours. The distribution of 125I-anti PLAP in various tissues showed that the labelled antibody was enriched in the tumour, the mean concentration ratio being 7.1 and 6.8 for polyclonal and monoclonal antibodies, respectively. A PLAP negative tumour (RD) showed a mean ratio of 1.2. There was a positive correlation between PLAP content and uptake of labelled antibody in the tumours. Hep 2 tumour cells in tissue culture showed 100% positivity for PLAP, while imprints of the tumour after passage in nude mice showed 40-50% positivity. PLAP offers potential as a useful marker for localizing tumours in humans."}
+{"text": "To identify early symptoms of familial adenomatous polyposis with a view to improve early diagnosis and treatment. Diagnosis on the basis of genetic testing is usually limited to where there is a known family history, so FAP is more usually diagnosed on clinical grounds. Except for those identified via FAP registers, the majority of patients are symptomatic at the time of diagnosis.We undertook a retrospective study of 143 FAP patients treated at the Department of Surgery, University of Erlangen between 1971 and 2000. We identified patterns of symptoms, endoscopic findings and extracolonic manifestations in three age groups.FAP was diagnosed clinically on the basis of symptoms in 84% (120/143) of these patients. Most presented with intestinal symptoms such as colonic bleeding (68%) and diarrhea (42%). All but one of the patients between 20 and 40 years old had rectal polyps , whereas in those over 40 years old the prevalence was 76% (35/46). Non-specific symptoms such as abdominal pain, fatigue and bloating were less frequent and were mainly reported by patients older than 40.The commonest presenting features of FAP are alteration of bowel habit and rectal bleeding, but both are found in many other conditions. Patients with these findings need immediate endoscopy to allow prompt diagnosis and prophylactic surgery. Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited disease and is caused by germline mutations in the adenomatous polyposis coli gene (APC) in chromosome 5q21 . The APCThe incidence of FAP is approximately 1 in 8000 . Early dIn a retrospective analysis, we evaluated all clinical symptoms of FAP prior to surgery. We categorized these according to patient age and into colorectal and extracolonic manifestations of the disease. Our aim was to detect specific characteristics in each age group which could lead to an early clinical diagnosis and prevent the development of colorectal cancer.The diagnosis of FAP was established clinically if more than 100 polyps were detected endoscopically in the colorectum.Between 1971 and 2000, we registered 157 patients  with an endoscopic diagnosis of FAP. The mean age at primary diagnosis was 34 (\u00b1 15 SD) years with a range of 5 to 73 years. In 151 cases, surgery was performed. Sixty-seven patients had colectomy with ileorectal anastomosis, 55 patients underwent restorative proctocolectomy with ileal pouch-anal anastomosis, and 10 had proctocolectomy with an end-ileostomy. Nineteen patients underwent various other surgical procedures. Presently, 83 patients remain alive and 28 patients have been lost to follow-up. Forty patients are known to have died: 20 of colorectal cancer, 5 due to desmoid tumors, 10 of other causes and 5 for unknown reasons.A predominant early symptom could be defined and documented in 143 patients. Family screening revealed that 29 of these patients had affected relatives, while no FAP was detected in the families of the remaining 114 patients.The predominant symptoms of FAP were analyzed and documented retrospectively in all 143 cases. The entire patient population was divided into three age groups according the time of primary diagnosis: less than 20, 20 to 40, and more than 40 years of age. Abdominal pain, pain during defecation, bloating, fatigue and loss of weight were categorized as non-specific symptoms . Diagnosis was incidental in 6% (9/143) and the reasons are unknown in 8% (11/143).Most patients  were between 20 and 40 years of age at primary diagnosis, of whom 75% (58/76) had symptoms. 32% (46/143) of our patients were older than 40 years at primary diagnosis, of whom 65% (30/46) had symptoms. Only 15% of patients (21/143) were less than 20 years old at diagnosis. Within this group five patients were under 10 years old. Only 33% (7/21) of patients under 20 years presented with symptoms.Table Table Carcinomas of the colon were detected in 17% (25/143) and rectal carcinomas in 12% (17/143). No patient younger than 20 years had developed colorectal cancer. In the group between 20 and 40 years old, rectal carcinoma was detected in 21% (10/76) and colon carcinoma in 17% (13/76). In patients older than 40 years of age, 15% (7/143) had rectal carcinoma and 50% (23/46) had colonic carcinoma.Table No patients younger than 20 years suffered from desmoid tumors, but in 20% (3/15) gastric gland polyps and in 13% (2/15) duodenal polyps were discovered. The highest incidence of desmoid tumors  was found in the group between 20 and 40 years of age . In two cases within this age group the diagnosis of FAP was incidental because the patient presented with a desmoid tumor of the abdominal wall. In patients between 20 and 40 years, gastric gland polyps were detected in 52% (27/52), duodenal polyps in 31% (16/52) and polyps of the small bowel in 14% (4/29). Only 14% (5/36) of patients older than 40 years had desmoid tumors at primary diagnosis of FAP . And in this age group 53% (9/17) had gastric gland polyps, 67% (8/12) had duodenal polyps.The commonest non-specific symptom was abdominal pain, found in 16% 21/129) of patients. It was most common in patients between 40 and 50 years of age, 30% of whom had abdominal pain as predominant symptom , no fatigue , no loss of weight , no bloating  and no pain during defecation .In 59% 84/143) tests for fecal occult blood were positive. Microscopic bleeding was detected in 72% (55/76) of patients between 20 and 40 years old and 50% (23/46) of patients older than 40 years of age. In 90% (81/90) more than 100 colon polyps, in 82% (14/17) rectal carcinomas, in 61% (22/36) colon carcinomas, in 73% (19/26) duodenal polyps and in 72% (28/39) gastric gland polyps could be detected in association to fecal occult blood. Colonic bleeding as an early symptom was present in 52% (74/143). This was found in 68% (52/76) of patients between 20 and 40 years old and in 35% (16/46) of patients older than 40 years. Colonic bleeding was found in 80% (72/90) of patients with more than 100 colon polyps, 82% (14/17) of patients with rectal carcinoma, 64% (61/96) of patients with 10\u2013100 rectal polyps, 64% (25/39) of patients with gastric gland polyps and 64% (25/39) of those with duodenal polyps. 23% (33/143) of our patients suffered from anemia, 21% (16/76) of patients between 20 and 40 years, and 17% (8/46) of patients older than 40 years of age. Anemia was found in 44% (16/36) of patients with colon carcinoma, 35% (11/17) of patients with rectal carcinoma and 43% (3/7) of those with polyps of the small bowel. Diarrhea was reported in 31% (45/143). 42% (32/76) of patients between 20 and 40 years but only in 24% (11/46) older than 40 years suffered from this symptom. Diarrhea showed an association to rectal carcinomas in 65% (11/17), more than 100 colon polyps in 49% (44/90), duodenal polyps in 46% (12/26) and polyps of the small bowel in 43% (3/7) (tables 43 tests Most patients with FAP (80%) will be detected by more or less specific symptoms of colorectal disorders which lead to further diagnostic evaluation. Prior to the mid-nineties, when there was no FAP register, families of patients with FAP underwent no routine molecular screening, nor any further specific clinical surveillance. The diagnosis of FAP was verified in 29% of patients by molecular diagnostics, which became available for routine clinical use in the 1990s. The disperson of APC mutations in our study was similar to evaluations concerning other patient populations . Our stuMost patients in our hospital were diagnosed between age 20 and 40 (53%). In 75% (57/76) the diagnosis was made clinically. They mainly presented with fecal occult blood (50%), colonic bleeding (68%) and diarrhea (42%). Rectal polyps were present in 98.7% of patients in this age group. For this reason rectoscopy, which is widely available, should be the first-line investigation in symptomatic patients younger than 40 years of age. Complete colonoscopy should be supplemented if symptoms persist without diagnostic findings during rectoscopy. Some patients presented with extracolonic manifestations such as desmoid tumors. They could be detected in 29% of patients between 20 and 40 years old. In two patients with desmoid tumors, FAP was diagnosed incidentally. In these cases especially, rectoscopy should be performed to exclude polyps. Generally, bleeding and stool disorders were found in cases with severe manifestations in the colon and rectum and colorectal carcinoma. There is an ongoing discussion concerning the benefit of colonoscopy vs. sigmoidoscopy for patients less than 40 years of age with non-acute rectal bleeding . In termNon-specific symptoms were less frequent and occurred in only 0.8\u201316% of our patients. They were associated with pronounced colorectal manifestations and many polyps of the upper gastrointestinal tract. Non-specific symptoms were commonest in patients over 40 years old. The incidence of colonic carcinoma was 42\u201350% in this age group. We conclude that non-specific symptoms can imply a pronounced manifestation of FAP which usually affects patients beyond 40 years of age . Non-speIn summary, we found no symptoms specific for FAP in our patient population. Yet it was possible to correlate several symptoms with disease in our age groups. In a few cases, extracolonic manifestations were the first noticeable changes. Due to their young age and mostly moderate symptoms, patients younger than 40 years of age with FAP are not easily identifiable in routine gastrointestinal practice. In all patients who present with the gastrointestinal symptoms we describe, the first diagnostic step should be rectoscopy, followed by complete colonoscopy to exclude FAP. Patients over 40 years old in whom inherited colorectal cancer is suspected, even without rectal manifestations, should generally undergo colonoscopy earlier than recommended for the general population. In patients of all age groups genetic testing should be recommended in order to allow presymptomatic testing in their sibs and offspring. Family members with positive tests and all persons at risk from families where the mutation could not be identified must be examined and monitored by clinical registers.The author(s) declare that they have no competing interestsRC had the idea for the manuscript, carried out the statistical analysis, collected the details regarding molecular analysis and wrote the manuscript. WB gave information of several patients concerning molecular diagnostics and symptoms and has given final approval of the version to be published. BR checked the manuscript several times for grammer and spelling failures and was involved in revising it critically for important intellectual content. WH is the director of the Department of Surgery at the University of Erlangen where all patients included in the study were treated. He made the data collection of all patients possible. KG selected the patients and collected the symptoms of each patient. He has made substantial contributions to conception and design of the study. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:"}
+{"text": "The association between baseline drug resistance mutations and subsequent increase in viral failure has not been established for HIV-infected children. We evaluated drug resistance mutations at 39 codon sites (21 protease inhibitor (PI) resistant codons and 18 nucleoside reverse transcriptase inhibitor (NRTI) resistant codons) for 92 clinically stable NRTI-experienced, PI-naive HIV-infected children 2 to 17 years of age who were initiating new therapy with ritonavir plus zidovudine (ZDV) and lamivudine or plus stavudine. The association between baseline drug resistance mutations and subsequent viral failure after 12 and 24 weeks of highly active antiretroviral therapy (HAART) was studied.There were few primary PI associated mutations in this PI-na\u00efve population, but 84% had NRTI mutations \u2013 codons 215 (66%), 41 (42%), 67 (37%), 210 (33%) and 70 (32%). None of the specific baseline drug resistance mutations were associated with a higher rate of virologic failure after 12 or 24 weeks of HAART. Median week 12 viral load decreased as the total number of NRTI mutations at baseline increased (P = 0.006). Specifically, a higher level of baseline ZDV resistance mutation was associated with a decrease in viral failure after 12 weeks on a ZDV-containing HAART regimen (P = 0.017).No increase was seen in the rate of viral failure after HAART associated with the presence of resistance mutations at baseline. This paradoxical result may be due to adherence, replicative capacity, or ZDV hypersusceptibility to the new regimen. Nucleoside reverse transcriptase inhibitors (NRTI) were the first antiretroviral drugs available and continue to be a component of anti-retroviral therapy (ART), despite the emergence of drug resistance over time. Few studies have investigated the role of pre-existing drug resistance and response to therapy in children -4 comparThere were very few primary resistance mutations to PIs in this PI-na\u00efve population, although 88% of the children had polymorphisms that included secondary minor resistance mutations. The most frequent secondary PI mutations were at codons 63 (78%), 77 (37%), 36 (17%) and 10 (12%) (data not shown). Only two children had a primary PI resistance mutation (V82A). Other PI mutations  were present in less than 10% of the study subjects. The most common NRTI mutations occurred at codons 215 (66%), 41 (42%), 67 (37%), 210 (33%), 70 (32%), 69 (22%), 118 (21%) and 219 (21%). The median numbers of baseline NRTI, thymidine analog mutations (TAM), PI and total mutations were 3, 3, 2 and 4.5, respectively .After 12 weeks on study, 51 (55%) subjects had viral loads suppressed below 400 copies/ml. The number of subjects with viral suppression dropped to 31 (34%) and 29 (32%) at weeks 24 and 48, respectively.The association between the presence of a specific baseline mutation and virologic failure after 12 weeks of HAART was studied (Table 10 RNA (copies/mL) associated with each additional NRTI resistance mutation (P = 0.006).When the association between the number of baseline resistance mutations and virologic failure after 12 weeks of HAART was investigated, the only significant relationship observed was in the ZDV/lamivudine (3TC)/RTV combination regimen. A higher median number of NRTI mutations at baseline was associated with virologic suppression . There was no apparent association between the number of baseline PI resistance mutations and the level of viral load after 12 weeks of HAART, although as the number of baseline NRTI mutations increased the level of viral load at week 12 decreased , and no suppression. According to this definition, 56 (60%) subjects achieved full viral suppression and an additional 13 (14%) achieved partial viral suppression during the first 24 weeks on HAART. There was no statistically significant (at the unadjusted 5% level) association between any baseline mutation and virologic suppression during the first 24 weeks on HAART.The association between the presence of a specific baseline mutation and virologic suppression during the first 24 weeks on HAART was explored. Viral response was categorized into three ordered levels: full suppression , partial suppression  had a viral rebound. In the three-drug arm children with mutation at the NRTI codon 67 seemed to be less likely to have a viral rebound after virologic suppression (unadjusted P = 0.002). There was also the suggestion of a potential association with virologic failure for the presence of any PI mutation (unadjusted P = 0.020) in the three-drug arm and for mutation at the NRTI codon 69 (unadjusted P = 0.028) in the two-drug arm, but these findings need to be treated cautiously due to the problem of multiple comparisons .For the 69 children with full or partial viral suppression as defined above, the association between the presence of a specific baseline mutation and viral rebound between the suppression and week 48 was evaluated. A rebound was declared if there was an increase in RNA of more than one logWe evaluated the association between resistance mutations and their potential effect on the ability of antiviral medications to reduce the viral burden in children with HIV disease. As expected, there was little PI resistance and considerable NRTI resistance in this PI-na\u00efve, NRTI-experienced population. However, contrary to our expectations, we did not find an increase in the rate of viral failure after HAART associated with the presence of resistance mutations at baseline. The two specific associations identified at week 12 in our study  in combination therapy responded favorably and rapidly. We did not observe an increase in the rate of viral failure after HAART linked to the presence of resistance mutations at baseline. In fact, viral loads at the 12 week time point were inversely correlated with the number of baseline NRTI mutations. It is important to remember that resistance is not an all-or-none phenomenon, and treatment failure is not defined by a resistance test. In order to better understand both the virology of mutated viruses in vivo and their response to anti-retroviral drugs as well as the use of resistance testing, prospective randomized clinical trials linked with pathogenesis-related in vitro analysis should be performed in children.PACTG 338 was a multicenter, randomized clinical trial that enrolled 297 children aged 2\u201317 years. All subjects were HIV-infected, had been receiving continuous, unchanged antiretroviral therapy for the 16 weeks before study entry, and were na\u00efve to protease inhibitors and lamivudine (3TC) or had received no more than 6 weeks of ZDV plus 3TC in the year prior to study entry and none in the 4 months prior to study entry. Children were randomly assigned to receive either ZDV/3TC (n = 100), stavudine (d4T)/RTV (n = 97) or ZDV/3TC/RTV (n = 100). Children initially assigned to the ZDV/3TC regimen were not included in this evaluation of drug resistance and subsequent viral failure as this regimen was demonstrated to result in a suboptimal virologic suppression compared to protease inhibitor-based regimens.3, proportion with CD4 cell count <500 cells/uL was 29%, proportion with CD4 percent <25% was 38%, median plasma HIV-1 RNA was 20,500 copies/mL, and the proportion with HIV-1 RNA copy number > 4 log10 was 75%. The majority of the children were African-American (66%) and 51% were male. Children had received prior treatment with ZDV monotherapy (46%), the combination of ZDV and ddI (37%) or other combination therapy (15%). Baseline characteristics of the children in this resistance analysis were very similar to the baseline characteristics for the overall PACTG 338 study of 297 children, except for minor differences in the CD4 cell count (648 cells/mm3), the proportion of African-American children (51%), and the proportion with HIV-1 RNA copy number > 4 log10 (64%). Children with viral loads <1,000 copies/mL were excluded from this resistance study. For the secondary analyses of viral suppression at weeks 12 or 24 and viral rebound after 48 weeks on HAART, two additional subjects were included, who did not have viral load measured at week 12 but did have information at week 24. The institutional review board at each institution approved the study and informed consent was obtained from all patients or their guardians.A total of 92 children assigned to a RTV-containing regimen had both baseline resistance information and viral load measurement at week 12, and they were included in any analysis involving the primary endpoint of viral failure at week 12. Of these 92 subjects, the median age was 7.3 years, median CD4 cell count was 602 cells/mmSequencing was determined in batch at the conclusion of the study in two laboratories that participated in the National Institute of Allergy and Infectious Diseases (NIAID) Virology Quality Assurance Program. For HIV-1 sequencing, plasma RNA was extracted using the QIAampViral RNA Mini Kit . Reverse transcriptase polymerase chain reaction (RT-PCR) and direct DNA sequencing of protease and reverse transcriptase genes were performed using the TruGene HIV-1 Genotyping Kit  according to the manufacturer's instructions. The International AIDS Society-USA recommended guidelines for resistance to protease inhibitor (PI) and nucleoside reverse transcriptase inhibitors (NRTI) were used ,19.HIV-1 RNA copy number was assessed using the NucliSens Assay  , which hFisher's exact test was used for associations between specific baseline resistance mutations and viral failure, the Kruskal-Wallis test was used to assess the association between the number of resistance mutations and viral failure, and the Mantel-Haenszel test for trend was used to evaluate the association between level of baseline ZDV resistance and viral failure defined as viral load > 400 cp/ml ,24. FurtThe author(s) declare that they have no competing interests.AAW, LMF, RY, KM, SIP, KES and SAN conceived, designed and implemented the primary study (PACTG 338), upon which this secondary resistance study was based. SF organized this secondary study and contributed to its design and implementation along with SAF, AK, LAP and SN. CH performed the statistical analysis. SF drafted the manuscript jointly with KES. All authors provided review comments and textual modifications during manuscript development. All authors read and approved the final manuscript."}
+{"text": "The effects of dietary iron deficiency on induction of putative preneoplastic, gamma-glutamyltransferase (GGT)-positive hepatocyte focal lesions in the liver of rats treated with diethylnitrosamine (DEN) followed by phenobarbital (PB) were investigated. Male Fischer 344 rats of 4 weeks old were placed on an iron deficient (ID) diet containing less than 5 p.p.m. of iron or an iron supplemented (IS) diet containing 180 p.p.m. of iron throughout experimental period of 12 weeks. Both groups of rats were administered 200 mg kg-1 body weight of DEN by a single intraperitoneal injection at Week 4 followed by PB mixed into each diet at a concentration of 0.05% from Week 6 to the final sacrifice at Week 12 when induction of GGT-positive foci was quantitatively analysed. On the ID and IS diets, respective numbers of GGT-positive foci were 6.3 and 14.2 cm-2. The sizes of foci were not altered by the iron content of the diet. The present results indicate that iron plays a role in the development of preneoplastic foci in the livers of rats initiated with DEN and promoted by PB especially in the initiation phase."}
+{"text": "A total of 164 consecutive adults with newly confirmed stage IIIB, IVA or IVB Hodgkin's disease (HD) commenced cyclical combination chemotherapy comprising mustine, vinblastine, prednisolone and procarbazine (MVPP) every 6 weeks (145 patients) or minor variants (19) at St Bartholomew's Hospital between 1968 and 1984. The median follow-up period is 14 years. Complete remission (CR) was achieved in 97/164 (59%) and partial remission (PR) in 23/164 (14%) with lesser responses or death being documented in 44. Achievement of CR correlated with stage, serum albumin and serum beta2 microglobulin level at presentation on univariate and multivariate analysis; 55/97 (58%) remain in continuous CR, the median duration of remission not having been reached. Twelve patients died in first remission; there have been 30 recurrences, one occurring after 13 years. Second remission was achieved in 17/30; 6/17 remain in continuous second remission and two have died in second remission. There have been nine second recurrences, third remission being achieved in 6/9. Two continue in third remission, two patients have died in third remission: 82/164 patients are alive with a minimum follow-up of 6 years. Eighty-two patients have died; 66 with evidence of HD, six with second malignancy, one each of haemorrhage and infection, eight of unrelated causes, the cause of death was unknown in one. The overall median survival from presentation is 14 years, being the same for patients in CR and PR with minimal residual abnormality , and being better for those for whom remission was achieved than those for whom it was not. The median survival following first recurrence is 4 years, being significantly longer for younger patients (less than 50 years). These results emphasise the importance of long-term follow-up to determine the clinical course of HD and are vital for planning experimental chemotherapy at the time of early treatment failure or recurrence."}
+{"text": "Coexistent lung cancer and pulmonary tuberculosis is an urgent problem of thoracic surgery presenting a challenging task for diagnosis and surgical treatment.From 1990 to 2005, 2218 patients with lung cancer underwent surgical treatment in Department of Thoracic Surgery and Oncology, Institute of Oncology, Vilnius University. In 46 (2.1%) patients coexistence of lung cancer and tuberculosis was found. Central lung cancer was diagnosed in 37 (80.4%) and peripheral \u2013 in 9 (19.6%) patients. Epidermoid cancer was diagnosed in 24 (52.2%) patients, adenocarcinoma \u2013 in 10 (21.7%) and adenoepidermoid carcinoma \u2013 in 12 (26.1%) patients. Stage I cancer was diagnosed in 12 (26.1%), stage II \u2013 in 11 (23.9%), and stage IIIA \u2013 in 23 (50%) patients.Pneumonectomy was performed in 18 (39.2%), lobectomy in 10 (21.7%), bilobectomy in 10 (21.7%), segmentectomy in 8 (17.4%) patients. Postoperative surgical complications were observed in 9 (19.5%) patients, non-surgical complications occurred in 19 patients (41.3%). Six patients (13.04%) died. Combined treatment was applied to 23 (50%) patients.Coexistence of tuberculosis and lung cancer in thoracic surgery is fairly rare. This combination was diagnosed only in 46 cases (2.1%) out of 2218 operated lung cancer patients. Epidermoid carcinoma and stage IIIA disease was diagnosed in 50% of patients. Postoperative surgical complications occurred in 9 patients (19.5%) with lung cancer and tuberculosis. Six patients (13%) died in postoperative period. Surgery is the method of choice in treatment of combination of tuberculosis and lung cancer. Median survival of these patients was 28 \u00b1 2 months. Some scientists stated that tuberculosis promotes development of cancer; others assert that tuberculosis and cancer are antagonists. Classics of pathologic anatomy P. Virchov and K. Rokitansky were advocates of latter statement (1854). As the diagnostics of lung diseases improved, scientists began to believe that post tuberculosis sclerotic changes facilitate development of cancer (\"cancer in the scar\") [Coexistence of tuberculosis and lung cancer has remained controversial since the middle of 19e scar\") . At presement 185. As the et al., published analysis of 758 of lung cancer, and coexistence of cancer and tuberculosis was found in 2.1% of cases [Well-known pathologists N. A. Dacosta and G. G. Kinare (1991) on the grounds of numerous autopsies found out that combination of lung cancer and tuberculosis of lung was found in 13.1% of patients . Watanabof cases . Some reof cases .Between 1990 and 2005, 2218 patients with lung cancer underwent surgical treatment in the Department of Thoracic Surgery and Oncology, Institute of Oncology, Vilnius University. In 46 (2.1%) patients coexistence of lung cancer and tuberculosis was diagnosed. Following methods of diagnostics were used: chest X-ray, computed tomography (CT), bronchoscopy, bacterioscopic, bacteriologic and cytological investigation of sputum, pathological investigation.Diagnosis of coexistence of cancer and tuberculosis was established before surgery in 18 (39.1%) patients in other 28 (60.8%) the diagnosis was established after pathological examination of resected specimens. Despite adequate antituberculosis treatment of all 46 pts (4\u20135 months of treatment with drugs of choice) in 15 (32.6%) patients mycobacterium was found in sputum before surgery (TM+).Roentgenological, tomographical and pathological methods revealed coexistence of cancer and tuberculosis in the foci of previous tuberculosis in 32 (69.5%) patients, in 8 17.4%) patients. changes were found unilaterally to tuberculosis, and in 6 (13.0%) changes were in the intact lung. Cases by stage are presented in Table 7.4% patiOperations were performed according to criteria mentioned above and tumor extent is presented in Table It should be noted that such traumatic operations were performed because of clinical situation. Pleural adhesions, fibrosis and sclerosis of lung tissue and scarry changes are usually observed in tuberculosis patients.Pathistological investigation of removed specimen revealed that fibrocavernous tuberculosis in 15 30.5%) patients, infiltrative in 12 (26.0%), disseminated in 5 (10.8%) and pneumosclerosis due to tuberculosis  in 14 (30.6%) patients respectively. Morphological type of cancer is presented in Table 0.5% patiIn 12 (26.0%) patients with progressive lung cancer that was located in the region of post tuberculosis changes we observed destruction of tumor with destruction of lung tissue and tuberculosis dissemination around the tumor. Adjuvant treatment was given to 23 (50%) patients: Of these, 12 (52%) received radiation therapy (42 Gy), 11 (48%) received chemotherapy (etoposide+cisplatinum \u00d7 6 cycles), 5 (21.7%) patients from this group later received antituberculosis treatment because of exacerbation of tuberculosis.Type and extent of operation depended on general status of patient, concomitant disease, extent of cancer and tuberculosis. Clinical type and phase of tuberculosis as well as anatomical, tomographical and histological type of lung cancer were established by roentgenological and morphological investigations.For example this 58-year-old man with the history of chronic bronchitis for about 30 years of duration was diagnosed with tuberculosis 5 months ago. Treatment with five basic antituberculosis medications was started. Treatment was declared ineffective after the bacteriological and bacterioscopical investigations revealed tuberculosis mycobacterium in sputum (TM+). Infiltrative changes in the upper lobe of left lung were found at x-ray examination Figure . Figure Microscopy of the resected specimen showed cancer cells against the background of tuberculosis changes. This specimen confirmed coexistence of tuberculosis and lung cancer, and in this case one process stimulates another. This could explain ineffectiveness of antituberculosis treatment. Exacerbation of tuberculosis influenced incidence of postoperative complications.Postoperative complications occurred in 28 (60.8%) of our patients. From these 9 (19.5%) were surgical complications Table . Rest 19Six patients (13.4%) died due to postoperative complications. Postoperative radiotherapy or chemoradiotherapy was applied in 23 (50%) patients with inactive tuberculosis. From these 12 (52%) patients with pT3N1M0 were treated with regional radiotherapy. The other 11 (48%) patients with T3N2M0 were treated with regional radiotherapy and chemotherapy (6 courses of etoposide + cisplatinum). Tuberculosis specialists and oncologists conducted further follow-up. Median survival of these patients was 28 \u00b1 2 months.Diagnosis of lung cancer in patients with tuberculosis or with residual effects of tuberculosis possesses some peculiarities. These depend on variety of clinical symptoms that occurs due to coexistence of diseases , clinical course and site of cancer (both processes are located in the same region or separately). When cancer develops against the background of active tuberculosis, common symptoms are worsening of patients' general status . Investigations of show that x-ray picture in these cases is different: foci of infiltration of various size, atelectasis, hypoventilation of various parts of lungs, and foci of destruction with formation of caverns is seen. Bacteriological analysis shows presence of tuberculosis mycobacterium, which was not previously detected. As shown earlier in cases, when new signs not typical for tuberculosis occur there should be dynamic analysis of roentgenological signs and bacteriological analysis. In case of ineffective specific treatment coexistence of lung cancer and tuberculosis should be presumed .According to Drent (1994), Tamura (1999), and Watanabe (1999) post tuberculosis scars deform blood and lymphatic vessels ,5,6. LymIn our series of 2218 operated patients, 46 (2.1%) cases of coexistence of lung cancer and tuberculosis were found. It is possible that tuberculosis of lung prepare conditions for the development of lung cancer. We think that patients with coexistence of lung cancer and tuberculosis could be divided into three groups:1. Tuberculosis and lung cancer are unrelated2. There is relation between both processes, post tuberculosis changes, deformation of bronchi and alveoli, epithelial dysplasia are risk factors for lung cancer.3. In lung cancer progression old foci of tuberculosis reactivate and dissemination of tuberculosis mycobacterium occur.We agree with scientists who affirm that in case of new lung symptoms patients with tuberculosis after recovery should undergo follow-up periodically. In order to diagnose lung cancer early, chest x-ray, bronchoscopy and cytological investigation of sputum should be performed. It should be noted that mycobacterium was found in sputum again in part of patients with history of tuberculosis. It was thought to be recurrence of tuberculosis and these patients received recurring antituberculosis treatment. However, when careful checkup was performed in cases of worsening general status in patients with history of tuberculosis, usually lung cancer was diagnosed. Therefore periodic checkup of these patients is necessary.Coexistence of tuberculosis and lung cancer is obvious, although it is rare in the practice of thoracic surgery. In most cases epidermoid cancer was diagnosed (52.2% of patients). Stage IIIA lung cancer was diagnosed in 50% of patients. Postoperative surgical complications occurred for 9 (19.5%) patients. 19 (41.35%) non-surgical complications occurred due to heart and lungs chronic diseases. Six patients (13.04%) died. Surgery is treatment of choice in cases of coexistence of tuberculosis and lung cancer. A good median survival is normally achievable.The author(s) declare that they have no competing interests.SC \u2013 collected number of patients, operated and treated them, used diagnostic methods.VV \u2013 wrote manuscript, send speciments to pathologist, prepared material for publications and operated patients."}
+{"text": "Lumbar bone mineral density (BMD) determination by dual photon absorptiometry was used to study the influence of adjuvant chemotherapy for premenopausal breast cancer on the risk of premature osteoporosis. Six cycles of combination chemotherapy caused ovarian failure in 31 of 44 (71%) women, amenorrhoea mostly already beginning during treatment. In contrast, only seven of 44 (16%) women, who were pair-matched for age and year of breast cancer surgery and had not been treated with chemotherapy, were post-menopausal at the time of measurement. The mean interval after breast surgery was 3.5 years. The significantly decreased BMD in the treated group (1.17 compared to 1.29 g cm-2) could only be explained by the high incidence of menopause in these women, which on average occurred 10 years prematurely. Extrapolation of these findings suggests that adjuvant chemotherapy may precipitate osteoporotic fractures by some 10 years in a considerable proportion of women cured of premenopausal breast cancer."}
+{"text": "Over a 10 year period, between 1974-1984, 257 adult cases of tissue sarcoma have been evaluated in the Department of Medical Oncology, Christie Hospital, Manchester. At registration locally advanced or metastatic diseases was present in 162 (63%). The male/female ratio was 1.5:1 and median age 54 years (range 14-85). The commonest sites were lower limb (33%), visceral (21%), trunk (13%), retroperitoneum (12%) and upper limb (10%). Leiomyosarcoma (27%), liposarcoma (14%) malignant fibrous histiocytoma (10%) and neuro plus fibrosarcomas (15%) were the most frequent histological subtypes. A high proportion of uterine sarcomas (17%) is a point of distinction from many other series. Histological grade was specified in 72% of cases and the distribution  reflected a referral bias towards advanced disease. Local resection of the primary tumour was performed in 76% of cases. In many instances this only amounted to 'shelling out' and true compartmental excisions were rare. Amputation was performed in 31% of patients with limb sarcomas. Ninety-eight patients (38%) had experienced one or more local recurrences prior to referral and the overall local recurrence rate was 56%. Suitable patients (78%) received chemotherapy, 50% entering multicentre trials in collaboration with the EORTC. The commonest regime used in patients with advanced disease was CYVADIC which produced an overall response rate of 37%. Ifosfamide, used as a single agent in 16 patients, induced 3CR and 5PR for an overall response rate of 50%. When used in combination with MTX and VADIC, there was no difference in response rate, but numbers in these pilot studies were small. Seventeen high risk patients received adjuvant chemotherapy with VAC, but the results (11 relapses) were disappointing. An EORTC trial, comparing adjuvant CYVADIC chemotherapy with control has accrued 307 patients, 49 of these from the Christie Hospital. Preliminary results within this centre - 13/25 relapses in the control arm, 5/23 in the chemotherapy arm-suggest an advantage for chemotherapy but the data are statistically not significant. Post-operative radical radiotherapy after resection of the primary tumour or local recurrence was performed in 51 patients, with local control in 65% of cases, although metastases developed in 41%. At the time of analysis (1st April 1984) 98 (38%) were alive, of whom 72 showed no evidence of disease and 52 had never relapsed. Malignant disease was the cause of death in 92%. Overall survival was not influenced by sex, but patients less than 40 years of age fared significantly better (P less than 0.001).(ABSTRACT TRUNCATED AT 400 WORDS)"}
+{"text": "Murine monoclonal antibody CF511, raised against human ovarian clear cell carcinoma, detects a glycoprotein (Mr 600 kDa) called CF511 antigen which is elevated in the serum of many patients with ovarian carcinoma. A competitive enzyme-linked immunosorbent assay was developed to detect CF511 antigen in human serum and used to detected CF511 antigen in subjects with ovarian carcinoma and other diseases. No raised levels (less than 18 unit (U) ml-1) of the antigen were found in the serum of 220 normal individuals or of patients with germ cell tumours (n = 6), granulosa theca cell tumour (n = 1), gastric carcinomas (n = 10) and colo-rectal carcinomas (n = 8). Raised serum levels of CF511 antigen were found in 6/46 patients (13.0%) with benign gynaecological tumours (including endometriosis or ovarian cyst), in 5/7 patients (71.4%) with breast carcinoma and 16/21 (76.2%) lung carcinoma patients. In patients with ovarian carcinoma, 42.3% (11/26) of stage I and II, and 96.0% (24/25) of stage III and IV had levels of greater than or equal to 18 U ml-1. In all patients with serial determination of CF511 antigen levels before and after the surgery, the levels of antigen correlated with the clinical course of disease. Determination of CF511 antigen levels may be useful for detection of ovarian carcinoma as well as lung and breast carcinomas and for monitoring progress of disease and response to therapy."}
+{"text": "We report our approach regarding the technique of endoscopic extraperitoneal radical prostatectomy (EERPE) and analyze the learning curve of two surgeons after thorough technical training under expert monitoring. The purpose of this study was to investigate the influence of expert monitoring on the surgical outcome and whether previous laparoscopic experience influences the surgeon's learning curve.EERPE was performed on 120 consecutive patients by two surgeons with different experience in laparoscopy. An analysis and comparison of their learning curve was made.Median operation time: 200 (110 \u2013 415) minutes. Complications: no conversion, blood transfusion (1.7%), rectal injury (3.3%). Median catheterisation time: 6 (5 \u2013 45) days. Histopathological data: 55% pT2, 45% pT3 with a positive surgical margin rate of 6.1% and 46%, respectively. After 12 months, 78% of the patients were continent, 22% used 1 or more pad. Potency rate with or without PDE-5-inhibitors was 66% with bilateral and 31% with unilateral nerve-sparing, respectively. Operation time was the only parameter to differ significantly between the two surgeons.EERPE can be learned within a short teaching phase. Previous laparoscopic experience is reflected by shorter operation times, not by lower complication rates or superior early oncological data. The initial step towards minimally invasive surgical treatment of localized prostate cancer was made by Schuessler et al. in the early Nineties with his description of a laparoscopic radical prostatectomy (LRP) . HoweverIn view of the satisfactory oncological results of EERPE  and geneTwo surgeons commenced operative training simultaneously. Surgeon 1 (S1) had 7 years of laparoscopic experience, whereas surgeon 2 (S2) had only two years of experience in urological laparoscopy. Details of the laparoscopic procedures performed by both surgeons are given in Table After studying multi media material, both surgeons were trained in a dry lab (pelvic trainer) and on a porcine model for 4 weeks. During one week of training in a high-volume centre, each surgeon attended 6 procedures (camera and assistance) of EERPE. Back at our hospital, 9 consecutive procedures were supervised by experts in the technique. Patient pre \u2013 selection was not made for either surgeons.Between April 2004 and April 2005, 120 consecutive patients underwent EERPE performed by two surgeons. This study was carried out with the approval of the local ethics committee of the University of Regensburg and all patients gave written informed consent before participating in the study. Baseline characteristics are shown in Table All patients were followed up every three months by a self-administered questionnaire sent by mail, including a stamped return envelope addressed to our institution. Erectile function was evaluated by the short form of the international index of erectile function questionnaire (IIEF 5). The possible scores for the IIEF-5 range from 5 to 25, and erectile dysfunction (ED) was classified into five categories based on the following scores: severe (5\u20137), moderate (8\u201311), mild to moderate (12\u201316), mild (17\u201321) and no ED (22\u201325) . ContineEERPE was performed using the technique described by Stolzenburg et al. Pelvic lymph node dissection was performed in patients with PSA \u2265 10 ng/ml and/or a Gleasonscore \u2265 7. Criteria for a nerve-sparing technique were as follows: no preoperative erectile dysfunction, PSA \u2264 10 ng/mL, Gleason score \u2264 6 and no palpable tumour on the nerve-sparing side.After analyzing all important parameters a separate analysis of the learning curve was made according to the specification of three phases. Phase 1: Expert supervision of the first 9 operations . Phase 2: 16 operations performed by the same team with S1 and S2 assisting each other . Phase 3: 95 operations with varying assistants . Thereafter the data of S1 and S2 were compared. Contingency table analysis and two-sided Fisher's exact tests were used to study the association between categorical variables. The two-sided Mann-Whitney U-test was used for the non-parametric comparison of two independent metric variables. Differences between three independent metric variables were tested with the two-sided Kruskal-Wallis test. P values < 0.05 were considered significant. Statistical analyses were completed using SPSS version 10.0 . The closed test principle was used for multiple testing.The median operation time was 200 minutes (range 110 \u2013 415). Pelvic lymph node dissection was performed in 26 (21.7%) patients, unilateral nerve-sparing in 26 (21.7%) and bilateral nerve-sparing in 5 (4.2%) cases. The median aspirated blood/urine mixture was 300 ml (range 100 \u2013 3000). 2 (1.7%) patients received blood transfusion within 24 h post-operatively. There was no conversion to open surgery or early reintervention.The median catheterisation time was 6 days . A routinely performed radiological control showed a leakage of the vesicourethral anastomosis in 9 (7.5%) patients on day 6.A patient with a history of stable coronary heart disease and previous myocardial infarction developed intraoperative cardiac shock due to myocardial reinfarction and died 14 h postoperatively. During the development of the preperitoneal space major bleeding occurred in one patient due to injury of the epigastric vessels, this being stopped immediately by endoclips. Intra-operative rectal injury occurred in 4 (3.3%) patients during the preparation of the prostate apex. Once recognized the defect was closed in two layers (Vicryl 2/0). A rectal catheter was inserted and intravenous antibiotics were administered for 3 days. Food intake was not delayed. No patient required a diverting colostomy.nd degree hydronephrosis one patient required a temporary nephrostomy. No patient developed ileus, deep venal thrombosis, pulmonary embolism or nosocomial pneumonia.After intra-operative deterioration of the respiratory parameters, one patient developed acute respiratory distress syndrome (ARDS) but recovered completely after prolonged intensive-care treatment. Three weeks after regular discharge from hospital one patient presented with a vesicorectal fistula requiring temporary colostomy and suprapubic catheterisation of the bladder for 9 weeks with consecutive spontaneous closure of the defect. Symptomatic pelvic lymphocele occurred in 2 (1.7%) and was treated by laparoscopic intervention. Due to 2Histopathological stage was defined according to the TNM classification (UICC 2002). The distribution is shown in Table In our series, 7 (5.8%) patients experienced PSA failure during the first year. In 4 of these patients, adjuvant therapy was initiated .84 (70%) patients completed the functional follow-up. Of these patients, 62 (74%) patients were completely continent (no pads) 6 months after surgery. 17 (20%) patients reported the daily use of 1 to 2 pads, whereas 5 (6%) patients used more than 2 pads. 12 months post-operatively, 64 (78%) patients were continent, 14 (17%) used 1 to 2 pads and 4 (5%) patients used more than 2 pads.A 12-month functional follow-up was completed by 3 of 5 (60%) patients with bilateral nerve-sparing and by 13 of 26 (50%) patients with unilateral nerve-sparing. In the bilateral nerve-sparing group, 2 of 3 (66%) had an IIEF score > 17 and sexual intercourse was possible with or without PDE 5 inhibitors. 1 of 13 (8%) patients with unilateral nerve-sparing had an IIEF score > 17 and 4 of 13 (31%) reported erectile function sufficient for sexual intercourse with the help of PDE 5 inhibitors.Analysis of the median operation time shows an initial increase from 190 (range 160 \u2013 235) minutes in phase 1 (9 operations under expert supervision) to 234 (range 155 \u2013 350) minutes in phase 2 (16 operations with S1 and S2 assisting each other). Thereafter, median operation time decreased slightly to 195 (range 110 \u2013 415) minutes in phase 3  declare that they have no competing interests.All authors contributed equally to this work and read and approved the final manuscriptThe pre-publication history for this paper can be accessed here:"}
+{"text": "Tyrosine-kinase inhibitors (TKIs) represent the best treatment for advanced non-small cell lung cancer (NSCLC) with common exon 19 deletion or exon 21 epidermal growth factor receptor mutation (EGFRm). This is an observational study investigating epidemiology, clinical features and treatment outcome of NSCLC cases harbouring rare/complex EGFRm.N = 17) achieved median Progression Free Survival (PFS) and Overall Survival (OS) of 53  and 84  weeks respectively, without significant covariate impact. Response Rate and Disease Control Rate (DCR) were 47% and 65%, respectively. Uncommon exon 19 mutations achieved longer OS and PFS and higher DCR compared with exon 18 and 20 mutations. No additional gene mutation was discovered by MassARRAY analysis. TKIs were globally well tolerated.Among 764 non-squamous NSCLC cases with known EGFRm status, 26(3.4%) harboured rare/complex EGFRm. Patients receiving first-line TKIs (A retrospective review of advanced non-squamous NSCLC harbouring rare/complex EGFRm referred to our Center between 2010 and 2015 was performed. Additional molecular pathways disregulation was explored in selected cases, through MassARRAY analysis.Peculiar clinical features and lower TKIs sensitivity of uncommon/complex compared with common EGFRm were shown. Exon 19 EGFRm achieved the best TKIs treatment outcome, while the optimal treatment of exon 18 and 20 mutations should be further clarified. The clinical knowledge of Epidermal Growth Factor Receptor (EGFR) molecular status and its therapeutic application, emerging in the early 2000s , has revMost EGFRm are strong predictors of response to tyrosine-kinase inhibitors (TKIs), with particular reference to the commonest E746-A750 deletion on exon 19 (ELREA) and L858R mutation in exon 21 .Randomized phase III trials showed progression free survival (PFS) and response rate (RR) benefit of EGFR TKIs compared to platinum-doublets chemotherapy as first line treatment of EGFR mutated NSCLC \u20137, with Uncommon or rare EGFRm are all exons 18-21 alterations with the exception of common sensitizing cited above, or all those with a prevalence lower than 5% . These gComplex mutations are characterized by two or more different EGFRm in the same tumor sample, with heterogeneous prevalence reported \u201317in vivo and in vitro data, can be summarized in the principle \u201cthe unit is strength\u201d: when a mutation with a low-intermediate oncogenic potential is not able itself to give rise to cancer, an additional one is required [The hypothetical carcinogenesis pattern of this special subset of EGFR-driven lung cancer, based on few required .in vitro findings addressed this issue, suggesting that uncommon EGFRm respond less to TKIs [So far, no clinical trial has been designed to identify the best treatment for patients with these EGFR molecular variants, and maybe their relatively low incidence could constitute an obstacle to conceive it. Only post-hoc analyses of clinical trials, retrospective studies, case reports and  to TKIs .N = 5) treated with gefitinib showed shorter OS compared to those with common mutations[In a subgroup analysis of the NEJ002 study, the small number of patients with G719X or L861Q mutations  was heterogeneous, with almost half of them carrying a double mutation. An indirect proof of the apparent greater power of second generation TKIs in some uncommon EGFRm is their lower growth inhibitory concentration for in vitro growth arrest of cells transfected with exon 18 EGFR gene mutations [A post-hoc analysis of combined LUX-Lung trials showed that afatinib achieves a median PFS of 10.7 months in patients with at least one of the three above mentioned uncommon mutations , not mucutations .If mutations discussed so far can be catalogued as partially sensitive, exon 20 mutations cluster encloses different types of modifications, , 23 inclA wide subset of exon 20 insertions, whose mechanism of primary resistance are poorly understood, accounts as the third commonest de novo EGFR mutation: no shared consensus exists for treatment of such cases, for which chemotherapy regimens could represent a valid option. On the other hand, specifically designed third generation TKIs have been already proved to work against de novo or acquired T790M mutation, where resistance is principally due to increase in receptor affinity for adenosine triphoshate (ATP) Clinical reports about all other single point-mutations, in-frame deletions, in-frame duplications or insertions are anecdotal, as are those about patients with NSCLC harbouring complex EGFRm, representing the 6% of all EGFR mutated lung adenocarcinoma in a described Asian population .The limited available data don't allow us to draw any conclusions about the optimal treatment of this special class of patients.The aim of our observational retrospective study was to describe epidemiology, clinical features and treatment outcome of uncommon and/or complex EGFRm in a case series of NSCLC patients referring to our Institute. We also explored the coexistence of additional mutations in different genes in a patient subgroup having rare/complex EGFRm.Between 2010 and 2015, 992 patients with non-squamous NSCLC diagnosis referred to our Institute. EGFR mutational status was assessed in 764 patients; among these, no gene alteration was found in 675 (88%) cases, while 89(12%) subjects resulted EGFR mutated; assessment of mutational status was not performed in 228 cases which were excluded from the study.N = 89), 63(71%) presented a common mutation (ELREA or L858R), 24 (27%) a rare isolated mutation and 2(2%) a complex mutation made of at least two rare mutations . Sixteen (62%) patients received adenocarcinoma diagnosis, with histological subtypes mucinous/enteric in 6 (23%), acinar in 4 (15%), papillary in 2 (8%), poorly differentiated in 3 (12%), and lepidic in 1 (4%) cases; not otherwise specified (NOS) non squamous lung cancer was diagnosed in 10 (38%) cases. Smoking history was negative in half of the sample, while 12 patients (46%) have been exposed to smoke, equally divided in still smoker and former-smoker at diagnosis time; in an isolated case (4%) smoking status was unknown. At the diagnosis time, almost all patients presented in an optimal or good Eastern Cooperative Oncology Group (ECOG) performance status (PS), with 6 (23%) and 19 (73%) of them having 0 and 1 score respectively, despite the majority of them  having stage IV. Advanced/metastatic stage was present in 24 patients at the diagnosis  or subsequently to disease relapse ; metastatic spread were mostly in one  or two  sites.Uncommon and complex EGFRm accounted for 3.4% of all non-squamous NSCLC cases. Among patients with EGFRm ( 89), 637% presentN = 15, 58%) received only one systemic treatment line, while 8 (31%) patients received two or more treatment lines. Among the three patients (12%) not receiving any systemic treatment, two had an early stage disease and one had a relapse site suitable of loco-regional treatment  received a systemic treatment. First or second generation TKIs were prescribed in 17 (71%) patients: gefitinib in 11 (46%), erlotinib in 3 (12.5%) and afatinib in 3 (12.5%) cases. A platinum-based chemotherapy with or without an anti-angiogenic drug was administered to 5 (21%) patients; one (4%) patient was treated with an anti-programmed cell death protein 1 (PD-1) monoclonal antibody in the context of a randomized clinical trial  cases of partial response(PR) and 8 (35%) cases of stable disease(SD), 7 (30%) cases of progressive disease(PD) and no case of complete response(CR). RR was 35% , while disease control rate(DCR) was 70% . All patients harboring a resistance exon 20 EGFR mutation, who received first-line chemotherapy, achieved a stable disease.N = 17) we observed 8 (47%) PR, 3 (18%) SD and 6 (35%) PD; RR was 47%  with DCR of 65%   and 84 weeks  respectively  and 3 (p = 0.0045) (See We observed an isolated PR (25%) in the subgroup 1, and 3 (75%) cases of PD at the first radiological assessment; 6 (67%) patients reported PR and 3 (33%) a SD in the subgroup 2; all three patients within the subgroup 3 had PD. No significant differences in terms of RR were observed between subgroups, while higher DCR was shown in subgroup 2 compared with subgroup 1 (045) See . The onlp = 0.037, CI 95%) and subgroup 3   compared with subgroup 1  Figure .p = 0.014, CI 95%) or exon 20   compared with rare mutations in exon 18  Figure Median PFS and OS were not reached in the subgroup 4.No covariate significantly impacts on PFS and OS at the univariate See  and multAn adverse event (AE) of any grade was observed in 13 (76%) patients. Maximum grade (G) of AE was 1 in 5 (33%) patients, G2 in 6 (35%) patients, and G3 in 1(6%) patient receiving gefitinib.Temporary treatment interruption for any cause was registered in 5 (29%) patients, while interruptions due to drug-related AE were 2 (11%), both in patients receiving afatinib. No case of permanent treatment discontinuation was observed.N = 8, 47%), paronychia , asthenia , mucositis  with isolated cases of skin dryness, corneal erosion, urinary tract infection and nausea (See Dose reduction was required only in one patient (5%) taking afatinib. More frequently observed AE were diarrhea , than for gefitinib or erlotinib . No statistically significant difference in terms of AE between patients receiving erlotinib compared to those treated with two other TKIs (p = 1.00), and between first and second generation TKIs (p = 1.00) were observed.The incidence of any drug-related AE was higher for afatinib (N = 6) with complex EGFRm or with rare EGFR mutations not responsive to first-line EGFR TKIs. Analyzed genes by multiplex PCR sequencing (Sequenom) included kras, braf, nras, pi3kca, alk, erbb2, ddr2, mapk1 and ret. MassARRAY analysis confirmed EGFR mutations but did not disclose additional mutations.We searched for additional molecular alterations in other genes as possible driver of tumor progression, in the subgroup of cases , [Looking at results of available phase III clinical trials, EGFRm in NSCLC represent a strong predictive factor to EGFR TKIs. However, most studies consider only more frequent EGFRm, namely the deletion (ELREA) in exon 19 and the point mutation L858R in exon 21. On the contrary, there are no clear data about epidemiology, clinical features and drugs efficacy in patients harboring uncommon mutations. Survival results in patients with uncommon gene alterations, extrapolated from few randomized clinical trials comparing targeted therapies LUNG 6), , 20 provLUNG 6), .Uncommon and complex mutations accounted for less than 4% of all non-squamous NSCLC cases. Among cases carrying EGFRm, 71% had a common mutation and 27% a rare mutation, while 2% a complex mutation. The percentage of rare mutations is slightly higher than in other studies; , 18 simiWe reported a prevalence of G719X and E709X point mutations in exon 18 (7%) and insertions/duplications in exon 20 (4%) in line with previous studies , 31, 32 With regard to the clinical characteristics of studied subjects, we observed a considerable incidence of acinar and mucinous/enteric subtypes (15% and 23% respectively), in contrast with literature data reporting no EGFRm in mucinous subtype., 37 Thisversus chemotherapy in patients harboring common EGFR alterations. Moreover, real-life data from a subset of mutated patients referred to our Institute showed a median PFS in uncommon mutations group not significantly lower than in common mutation group, where median PFS was 14 months   . On the The heterogeneous prevalence of different uncommon mutations might explain such controversial results, as much as the retrospective nature of most case series.We also analyzed the predictive role of different uncommon mutations by dividing patients into four subgroups. We observed higher benefit in terms of DCR, median PFS and OS in the subgroup carrying exon 19, compared with exon 18 and 20 mutations.in vitro and in vivo, thus constituting a new family of sensitizing mutations. [N = 3) cases developing PD as best response. All literature data about exon 20 mutations show a very low RR (about 8%) and poor median PFS (about 2.5 months) with first two generation TKIs [Few data on the exon 19 insertions seem to confirm the positive predictive role of these mutations : as repotations.  Patientstations. , 41 A potations. . In conttations. . SurvivaUnlike the other subgroups, the most appropriate treatment in these patients might be chemotherapy, as confirmed by disease stabilization achieved in our case series. The only patient with complex mutation treated with an irreversible TKI showed a good response and survival. Data about this particular kind of subpopulation are lacking, with an isolated study showing poor RR, however without translating into a survival reduction.Molecular cancer heterogeneity is decisive, since treatment effectiveness appears to depend on the specific mix of carried mutations: RR and PFS seem better  in preseDespite an overall incidence of any grade AE of 78% with TKIs, a single serious AE (G3 diarrhea) was recorded. Even though no significantly different incidence of AE was shown among the three drugs, we confirmed their peculiar safety profile and showed more frequent dose reduction or temporary treatment interruption with afatinib;, 46 anywEven though a prospective multicenter study should be performed in order to propose a treatment algorithm in such uncommon or complex EGFRm, clinical cases or series report acquire their own relevance in the context of clinical practice.th edition Classification of Malignant Tumors (TNM) of NSCLC [Data from patients with histological diagnosis of non-squamous lung cancer have been collected retrospectively from January 2010 to December 2015. Histological samples were obtained with surgical excision, surgical biopsy, trans-bronchial or computerized tomography (CT) scan guided biopsy of primary tumor, surgery or biopsy of metastatic sites. All subjects with at least one rare and/or complex EGFRm were included. A brain-thorax-abdomen CT scan was performed before starting systemic treatment for advanced/metastatic disease with successive radiological assessment every 2-3 months, according to clinical practice. Before study inclusion, all patients signed the informed consent form, according to privacy protective rules for recording clinical data for research and study purposes. The following clinical data were collected: gender, age, smoking status, histology, disease stage at diagnosis according to 7of NSCLC , metastaMutational analysis of exon 18\u201321 of EGFR gene was performed at the time of histological diagnosis and in any case before the start of first line systemic treatment, through Sanger sequencing, PCR-based methods, or pyrosequencing. In the subgroup of patients with complex or rare mutations not responsive to first or second generation TKIs, the mutational status of genes different from EGFR has been investigated by massARRAY (Sequenom) analysis; investigated genes included kras, braf, nras, pi3kca, alk, erbb2, ddr2, mapk1 and ret.plus pemetrexed or gemcitabine or paclitaxel; platinum-based triplet plus gemcitabine and bevacizumab) or were included in clinical trials, when available. TKIs were administered per os daily with initial dose of 150 mg, 250 mg and 40 mg for erlotinib, gefitinib and afatinib respectively, until disease progression or death, unacceptable toxicity or patient refusal. Drug choice was at the physician discretion.First line systemic treatment of patients with advanced/metastatic disease was administered according to national and international guidelines. In particular, a first (erlotinib or gefitinib) or second (afatinib) generation TKI was prescribed in cases with EGFRm with unknown predictive value. Patients harboring EGFRm more frequently associated with resistance to targeted therapy  have been treated with standard chemotherapy  1.1 criteria . Best reProgression free survival (PFS) to first line therapy was measured as the time between diagnosis of advanced disease and first evidence of progression during or after first line therapy, or death for any cause; overall survival (OS) was measured as the time elapsed from diagnosis of advanced/metastatic disease and death for any cause. Best radiological response and survival data were reported for the intention-to-treat population and for the subgroup of patients receiving a first line TKI.We also assessed TKIs best response and survival in four patient subgroups, according to the mutation type: subgroup 1 (rare mutations in exon 18); subgroup 2 (rare mutations in exon 19); subgroup 3 (rare mutations in exon 20); subgroup 4 (complex mutations).All AE were registered and graded through Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.  in patieversus \u2265 70 years old), stage (IIIb versus IV), ECOG PS (0 versus \u2265 1), best response to first line therapy (PR/SD versus PD), number of metastatic sites (< 3 versus \u2265 3), smoking status (exposed versus not exposed), TKI generation (first versus second), histological subtype (mucinous/enteric versus not mucinous/enteric). The same variables were considered in OS analysis, with the addition of data about any subsequent treatment lines (yes versus no). Log-rank test and Cox proportional risk model were used to estimate the impact of such variables on PFS and on OS. Differences of adverse events among different TKIs were analyzed with exact Fisher test. Statistical analyses were performed through SigmaPlot software.RR and DCR binomial proportion confidence interval was calculated with Clopper-Pearson exact test. Different response rates among patient subgroups were analyzed with Fisher exact test. PFS and OS curves were designed with Kaplan-Meier method. PFS was analyzed according to these covariates: age (< 70"}
+{"text": "To describe bacteriological profile, morbidity and mortality of acute bacterial meningitis (ABM) in children and to compare these parameters before and after the introduction of Pneumococcal vaccine in Pakistan National Immunization Program.The present descriptive study was conducted at the Department of Paediatric Medicine of The Children\u2019s Hospital Lahore from January 2012 to December 2015. A total of 503 children one month to five years of age admitted with diagnosis of meningitis were included. Complete blood count, CSF cytology, biochemistry, culture sensitivity and blood culture sensitivity were performed.Streptococcus pneumoniae isolation decreased from 5 (2.5%) in 2012 to 4 (1.3%) in 2013-2015. Refusal to take feed (p=0.002), impaired sensorium (p=<0.001), severe malnutrition (p=0.001), prolonged duration of symptoms (p=<0.001) and incomplete vaccination status (0.005) were associated with mortality. Mortality rate decreased from 20 (10%) in 2012 to 17 (5.6%) in 2013-2015 but more children developed neurological sequelae 2.7% versus 1%.Frequency of meningitis decreased by 50% in 2013-2015 (199 [2012] vs 304 [2013-2015). Most children in both groups were under one year of age. More neurological complications were seen in the group 2, 20% vs 17%. CSF culture positivity decreased from 12% to 6.6%. Streptococcus pneumoniae and mortality of meningitis decreased significantly after PCV but more neurological complications developed in those children who were unvaccinated in 2013-2015 compared to 2012.Acute bacterial meningitis mostly affected children <1 year. Frequency of  Acute bacterial meningitis (ABM) is a severe illness mostly affecting children under the age of five years but people of any age can develop ABM. Despite advances in medical treatment ABM remains an important cause of childhood morbidity and mortality throughout the world.Streptococcus pneumoniae and Haemophilus influenzae type b (Hib).H. influenza as a cause of meningitis after the introduction of vaccine. A step forward is the development of Pneumococcal Conjugate Vaccine (PCV), after which ABM has become an uncommon disease in developed countries.8In children the pathogens responsible for the most cases of meningitis in developing countries are We therefore conducted the study with the aim to describe bacteriological profile, complications and mortality of acute bacterial meningitis in children and to compare these characteristics of the disease before and after the introduction of PCV in our national immunization program.This was a prospective longitudinal hospital based descriptive study, conducted at The Children\u2019s Hospital Lahore over a period of four years from January 2012 to December 2015. All those children (1 month-5 years) who were admitted to General Medical Ward with diagnosis of meningitis on the basis of clinical suspicion and underwent lumbar puncture were included.Inclusion criteria for suspected meningitis as per WHO, was defined as a child aged >1 month to < 5 years with sudden onset of fever  and one of the following signs: neck stiffness or flaccid neck, bulging fontanelle (in children aged <12 months), irritability, drowsiness or convulsion along with CSF showing > 10 WBC. Children with co-morbidities like meningomyelocele, hydrocephalus, acute head trauma and prior central nervous system diseases were excluded. Each patient underwent a detailed history and thorough clinical examination. Relevant laboratory data in all patients including complete blood count, CSF cytology, biochemistry, culture sensitivity (C/S) and blood culture sensitivity (C/S) were performed. Seizures, motor or sensory loss, altered sensorium or any neurological deficit was checked during daily examination. CT scan brain was done in patients having neurological complication. Outcome of patients was noted in form of discharged, died, left against medical advice (LAMA) or shifted to other ward like neurosurgery ward for management of any complication.The data was divided into two groups; Group 1: Patients enrolled from January 2012- December 2012, Group 2: Patients enrolled from January 2013- December 2015. Both groups were compared. For statistical analysis Statistical Package for Social Sciences (SPSS) version 20 software was used.During this four-year study period total 503 patients were hospitalized with ABM. Out of 503 children, there were 199 cases in 2012 and 304 in 2013-2015. Frequency of meningitis decreased to half from 200 cases/ year to 100 cases/year. Maximum numbers of children were in one month to one year of age group 136 (68.3%) and 189 (62%) in both groups. Compared to 2012, relatively more (9.5% vs 5%) children in 2013-2015 were between 3-5 years. .The most common presenting symptom was fever ,  had seizures,  presented with poor feeding and  had impaired consciousness in 2012 vs 2013-2015 respectively. In 2012 presentation with refusal to take feed (p=0.008) and with impaired conscious state were independent predictors of death (p=0.002). CSF culture positivity, severe malnutrition and development of complications also had statistically significant p values of 0.039, 0.037 and <0.001 respectively. In 2013-2015 there were almost similar statistically significant results .Uneventful course was present in . There were significantly more complications in 2013-2015 group  vs . Type of complications are described in .Coagulase negative Staphylococci (CoNS) was the predominating organism 16 (8%) isolated on blood culture followed by Pseudomomas 3 (1.5%), Streptococcus pneumoniae 2 (1%), Acinetobacter 2 (1%), Klebsiella and Staphylococcus aureus 1 (0.5%) in 2012. In 2013-2015 organism isolated were (CoNS) 12 (4%), Staphylococcus aureus 1 (0.3%), Klebsiella 2 (0.7%), Pseudomomas 2 (0.7%) and Citrobacter 1 (0.3%).The blood culture (12.6%vs 6%) and CSF culture positivity was (12% vs 7%) in 2012 vs 2013-2015 group respectively. The common etiology based on CSF culture is shown in . CoagulaOutcome of children is shown in Streptococcus pneumoniae and most of these deaths occurring in developing countries.Worldwide ABM remains a disease with devastating consequences particularly in unvaccinated children and it can cause fatal outcome or severe neurological sequelae especially when there is delay in diagnosis and antibiotic administration. World Health Organization (WHO) estimates that each year, half a million children under 5 years are killed by The disease pattern, bacteriology and mortality associated with ABM were investigated in this study and comparison was done for the children presented before and after introduction of PCV in Pakistan EPI program. The demographic analysis showed a high proportion of patients having male gender (63%). This may signify the male dominance and sex discrimination in South East Asia. A preponderance of males 1.5:1 was noted in an Indian study and in various other studies showing male preponderance.10In our study, 136 (68.3%) and 189 (62%) of our patients were below one year of age confirming that meningitis mostly affect young children as compared to older children. Similar results of meningitis incidence with young age were found in a study published in Niger Med J.11Microbial diagnosis of meningitis based on CSF culture was confirmed in only 24 12%) and 20 (6.6%) of patients in both groups. Our results were comparable with, studies done by Nhantumbo and Rajani in which CSF culture showed positivity in 7.3% and 7.2% respectively.% and 20 CoNS as the most common organism isolated 11/199 (5.5%) followed by Streptococcus pneumoniae 5/199 (2.5%), H. influenzae and Streptococcus pyogenes in 2012. In 2013-2015 the commonest organisms were Klebsiella 7(2.3%). Streptococcus pneumoniae 4/304 (1.3%) and CoNS 3/304 (1%) Considering maximum number of CSF cultures positive for CoNS in 2012, it may be due to skin contamination which was reduced in later years with appropriate sterilization techniques. Second commonest pathogen isolated in our study was Streptococcus pneumoniae and this was consistent with a Korean study in which Streptococcus pneumoniae was the commonest pathogen isolated.Klebsiella was the commonest organism in CSF isolates.17Our study identified In our study acute neurological complications were noted in 34(17%) and 59(19.4%) of our patients. Similar results were seen with 24% complications rate in a study published in Arch Dis Child.10Our case-fatality rate was 10.1% and 5.6% close to that (9.4%) reported in a Korean study and 13.9% in an Indian study.18Streptococcus pneumoniae. Frequency of Streptococcus pneumoniae and mortality of meningitis decreased significantly after introduction of PCV in EPI of Pakistan but more neurological complications developed in those children who were unvaccinated in 2013-2015 compared to 2012. Up-to-date vaccination, early referral and timely appropriate treatment can reduce the morbidity and mortality associated with bacterial meningitis.The frequency and mortality due to ABM was observed mostly under one year of age and the commonest bacterial pathogen isolated in these cases was AB: Main author.FZ &UJ: Data organization, SPSS data compilation, proof reading.AZ: Facilities and technical support for microbiology.HE: Performed microbiological experimental work and manuscript editing.AWR: Final approval of the version to be published."}
+{"text": "Trastuzumab is the backbone of HER2-positive early breast cancer (eBC) and metastatic breast cancer (mBC) treatment, but limited data exist as to re-treatment in relapsed patients. In this prospective, single arm, multicenter trial, we assessed efficacy and safety of trastuzumab and taxane combination in Chinese patients with HER2-positive mBC relapsed after prior (neo)adjuvant trastuzumab. Patients with previous (neo)adjuvant trastuzumab treatment for\u22659 weeks and a relapse-free interval \u22656 months were assigned to trastuzumab treatment with paclitaxel or docetaxel. The primary endpoint was progression free survival (PFS). Secondary endpoints included overall response rate (ORR), clinical benefit rate (CBR), duration of response (DOR), time to progression (TTP), overall survival (OS) and safety profile. Thirty-two patients were enrolled and treated for a median duration of 33.5 weeks. The median PFS was 9.9 months . The ORR was 81.3%  and CBR (CR+PR+SD\u22656months) was 81.3% . The median DOR was 9.8 months  and median TTP was 9.9 months . OS median follow-up time was 20.1 months and 25% OS time was 25.5 months. The safety profile was acceptable with common adverse events including leukopenia (59.4%), neutropenia (56.3%), hypoaesthesia (34.4%) and granulocytopenia (31.3%). In conclusion, re-treatment with trastuzumab plus a taxane as first-line therapy is an effective regimen for patients with HER2-positive mBC relapsed after (neo)adjuvant trastuzumab. The safety profile was good and the adverse reactions were tolerable and manageable. Breast cancer is the most common cancer in women among all racial and ethnic groups by a wide margin . In Chinversus 56% compared with chemotherapy alone in patients with HER2-positive breast cancer  population) are summarized in Table Among the enrolled 32 patients, 28 patients finished the study according to the protocol. Four patients did not finish the study per protocol for reasons of refusing to continue treatment/withdrawing the informed consent form (2 patients), not returning for subsequent treatment (1 patient), or having previous accumulative dose of anthracyclines higher than the range allowed in inclusion criteria (1 patient). During this study, the median treatment duration with trastuzumab in combination with paclitaxel or docetaxel was 33.5 weeks ranging from 1 week to 148 weeks among which 22 patients received paclitaxel for 1-33 weeks, and 10 patients received docetaxel for 3-30 weeks.As shown in Figure In ITT population of the 32 patients, the overall response rate (ORR)  was 81.3 % (26/32), 95% CI (63.6% - 92.8%) and clinical benefit rate (CBR)  was 81.3% (26/32), 95% CI (63.6% - 92.8%). Duration of response (DOR) and OS were analyzed for the studied 32 patients, among which 26 patients (81.25%) had a treatment response (ITT = 26) , neutropenia , hypoaesthesia , granulocytopenia , asthenia , and alopecia . A detailed list of AEs by their severity is shown in Table In the safety set (SS) population of 32 patients, there were a total of 308 cases of adverse event (AE) observed, and 30 subjects experienced at least once AE, resulting in an incidence rate 93.8% , neutropenia , granulocytopenia , and fatigue .The cases of adverse drug reaction (ADR) were also assessed Table . There wThere was one drug withdrawal due to adverse event (3.2%), in which the subject withdrew drug treatment due to grade II headache. There were 5 death cases (15.62%) due to PD totally. In SS, asymptomatic Left Ventricular Ejection Fraction (LVEF) decrease of 10-18% compared to baseline was observed in 8 patients (25.0%), and any case with LVEF less than 40% was not found in this study.This prospective single-arm, multicenter trial demonstrated the efficacy and safety of re-treatment with first-line trastuzumab in 32 HER2-positive Chinese patients who had prior trastuzumab-based therapy in (neo)adjuvant settings.Our efficacy results of trastuzumab re-treatment are comparable to previously reported data from studies involving patients no matter of being trastuzumab naive or of being pre-exposed. In the study H0648g, trastuzumab plus chemotherapy treatment resulted in TTP of 7.4 months, ORR of 50%, DOR of 9.1 months and OS of 25.1 months . In the For re-treatment with first-line trastuzumab in patients previously treated trastuzumab, two retrospective , 18 and versus 6.4 months) and a median OS of 30.9 months (versus 25.1 months)  was first noted until date of documented progression or death), TTP (defined as the number of days from date of registration of enrollment to date of disease progression) and OS (defined as the number of days from date of registration of the enrollment to date of death from any cause).Female patients of at least 18 years old to be included in the study must meet at least the following criteria: diagnosed with recurrent local or metastatic breast cancer; having HER2 positive primary disease; had completed at least 9 weeks of trastuzumab treatment for HER2 positive eBC in adjuvant or neoadjuvant setting; relapsed \u22656 months after discontinuation of last trastuzumab and/or chemotherapy in the (neo)adjuvant setting for HER2 positive eBC; measurable disease according to RECIST criteria 1.0; ECOG performance status of 0-2; life expectancy \u2265 12 weeks; maximum cumulative dose of doxorubicin \u2264360 mg/m2 or maximum cumulative dose of epirubicin \u2264720 mg/m2 or no prior anthracyclines (due to known resistance to prior anthracyclines or toxicity); baseline LVEF \u2265 50% or within normal limits (WNL) at a given institution; no prior history of myocardial infarction within 12 months, or unstable angina pectoris, or cardiac insufficiency (New York Heart Association Class III - IV), or uncontrolled arrhythmia at time of inclusion (Patients with symptomatic congestive heart failure may be included at the investigator's discretion if occurrence was > 6 months prior to enrollment). If there was previous surgery or radiotherapy, patients must have subsequently waited at least 3 weeks. In addition, patients must sign written informed consent obtained prior to any study specific procedures and be able to comply with the protocol.Patients with any of the following were excluded from the study: in pregnancy or lactation; had prior chemotherapy for metastatic breast cancer ; pleural effusions, ascites, or bone lesions as the only manifestation of disease; brain metastatic disease; invasive malignancy (including second primary breast cancer) other than metastatic breast cancer which could interfere with compliance with the protocol or interpretation of results; inadequate bone marrow, hepatic and renal functions; had prior treatment with anti-HER therapies other than (neo)adjuvant trastuzumab; had treatment with any investigational drug within 30 days before the beginning of treatment with study drug; with known allergy or severe reactions to trastuzumab or its constituents; history of uncontrolled seizures, central nervous system disorders or psychiatric disability, which could hinder ability to give informed consent, or compliance with study therapy. Further, patients with serious illness or medical conditions were excluded, including history or current congestive heart failure (New York Heart Association Class III-IV), unstable angina pectoris, myocardial infarction in the last 12 months, poorly controlled hypertension (systolic > 180 mmHg or diastolic > 100 mmHg), clinically significant valvular heart disease, or high-risk uncontrolled arrhythmias, active serious uncontrolled infections, poorly controlled diabetes mellitus, active peptic ulcer or other contraindication to high dose of corticosteroid therapy such as herpes zoster, cirrhosis.Treatment and monitoring were recorded by intervals of periods, in that each period lasted 3 weeks. Trastuzumab was administered once weekly, starting at 4 mg/kg loading dose on day 1 by intravenous infusion over 90 min and followed by subsequent 2 mg/kg intravenous infusion over 30 min as maintenance doses, given once weekly starting on day 8, until disease progression. After initial dose of trastuzumab, the patient was observed for 6 hours. If adverse event did not occur after the initial infusion, the subsequent observation period of administration was shortened to 2 hours after infusion. Body weight was measured before each dose of trastuzumab and it was used for actual dose calculation.The choice of the taxane (docetaxel and paclitaxel) to be used in combination with trastuzumab was made by the investigator's clinical judgement for each patient. Paclitaxel and docetaxel treatment may begin within 24 hours after administration of trastuzumab or on the same day (at least 30 min after trastuzumab infusion). Subsequently administration may be repeated every 21 days up to 6 times as judged by the investigator. Docetaxel (Taxotere) was intravenously infused for more than 1 hour with the initial dose of 100 mg/m2 (\u00b110%), q3w. Paclitaxel (Taxol) was intravenously infused for more than 3 hours with the initial dose of 90 mg/m2 (\u00b110%), q1w. Taxane was first administered for 6 periods (18 weeks) until unacceptable toxicities or the patient's withdrawal from study.Tumor response was evaluated according to RECIST 1.0, anti-tumor efficacy were analyzed approximately 12 months after last enrolled patient. Patients were assessed for disease response or progression every 6 weeks (2 cycles) until disease progression or death being documented. Objective responses were confirmed with a repeat examination within 4 weeks. Survival data were collected after treatment completion or after the progression of disease, and was done once every year and one year after the enrollment of the last patient.Adverse events were continuously monitored, recorded and graded according to the NCI CTC AE v3.0, and for the case of congestive heart failure, according to New York Heart Association (NYHA) classification. Safety profile including changes in LVEF and incidence of symptomatic heart failure of trastuzumab with a taxane in this patient population was determined.Based on the time to disease progression for patients treated with trastuzumab plus taxane being 7.1 months in the H0648g study and 10.6 months in the M77001 study , a PFS o"}
+{"text": "Cellulitis is a frequent soft tissue and skin infection. The lower limbs are affected in 70 to 80% of cases. Cellulitis in aged persons is not yet well described in literature. A retrospective descriptive study conducted in the Internal Medicine Department of Sahloul hospital in Sousse in Tunisia. It included patients whose age was up to 65 years old admitted into hospital for cellulitis of the legs, the arms or the face. One hundred fifty eight patients with a mean age of 73 years old (range: 65 to 94 years old) were included. Female to male sex ratio was 0.68. Among them, we noted diabetes mellitus in 81 cases (50.6%). The infection was located in the lower limbs in 155 cases (98%), in the face in two cases (1.3%) and in the upper limb in one case (0.7%). Twenty one patients (13.3%) presented with severe cellulitis and one presented with necrotizing fasciitis. All patients received intra venous antibiotic therapy. Surgical treatment was indicated in 14 cases. Cefazolin was prescribed in 77 cases (48%). Favorable evolution was noted in 144 patients (91.1%). Forty four patients (27.8%) received prophylactic antibiotics. Prevention of skin and soft tissue infection is a crucial step to preserve health in aged persons. Cellulitis is a skin and soft tissue infection mostly caused by gram stain positive cocci especially streptococcus pyogenes and staphylococcus aureus \u20135. CurreThis retrospective study was conducted at the Internal Medicine and Rheumatology Department in Sahloul Hospital in Sousse in Tunisia over a period of 18 years (1999-2016). It was based on the medical records of patients hospitalized for cellulitis. The study population was made up of all the patients whose age was superior to 65 years old, admitted into hospital for cellulitis of the legs, the arms or the face. The parameters of interest in the study were: epidemiological, clinical, microbial and therapeutic aspects. Data were recorded and analyzed statistically using the software SPSS evaluating free version.One hundred fifty eight patients comprising 94 men (59.5 %) and 64 women (40.5 %) (M/F sex ratio: 0.68) with a mean age of 73 years old (range: 65 to 94 years old) were enrolled. Among them, we noted diabetes mellitus in 81 cases (50.6%), smoking in 51 cases (32.3%), obesity in 52 cases (33%), heart failure in 25 cases (15.8%), recurrent cellulitis in 14 cases (8.8%) and alcoholism in two cases (1.2%). Thirteen patients (8.2%) received corticosteroids and four patients (2.5%) received anti-inflammatory treatment.3 92 mm and 140 mg/l. Blood culture was done in 28 patients and among them only one blood culture was positive and it isolated streptococcus B. Bacteriological superficial samples from the primary lesion were positive in 23 cases (14.5%) , in the face in two cases (1.3%) and in the upper limb in one case (0.7%). Fever was noted in 59 cases (37%) with a mean temperature 38.9\u00b0 (range: 38\u00b0-40.3\u00b0). Satellite lymph node was found in ten patients (6.3%). Twenty one patients (13.3%) presented with severe cellulitis and one presented with necrotizing fasciitis . Inflamm (14.5%) . Risk fa (14.5%) .Evolution Favorable evolution was noted in 144 patients (91.1%). Complicated cases were: diabetic ketoacidosis in three patients (1.8%), necrotizing fasciitis in eight cases (5%), skin abscess and phlebitis in six cases (3.8%) each one. Recurrent cellulitis was retained in 52 cases (33%). It was the second episode in 31 cases (20%), the third episode in 12 cases (7.6%) and more than three episodes in eight cases (5.4%).All patients received intra veinous antibiotic therapy. Different protocols were: cefazolin in 77 cases (48%), Penicillin G associated with Penicillin M in 45 cases (28%), amoxicillin in 20 cases (12.6%), amoxicillin-clavulanic acid associated with fluorquinolone in 11 cases (7%) and Penicillin G in five cases (3%). Antibiotic oral relay was indicated in 52 cases: pristinamycin (31 cases), amoxicillin (10 cases), amoxicillin-clavulanic acid (7 cases) and erythromycin (4 cases). Forty four patients (27.8%) received prophylactic antibiotics. Among them, 43 patients (97.7%) received Benzathine Benzylpenicillin and one patient received erythromycin. The treatment of intertrigo was recommended in all patients having this pathology. Surgical treatment was indicated in 14 cases (8.8%): seven patients (50%) underwent excision of necrotic tissue, four patients (28.5%) underwent flattening of abscess, two patients (14.2%) underwent amputation and one patient (7.1%) underwent coetaneous graft.Our analysis had been particularly interested with aged persons. It is explicated by the fact that this age range in our population is currently important. Few published studies had evaluated this infection in aged persons . The sofIn our study, we had cases of decompensation of chronic diseases and local vascular complications like phlebitis. These results suggest that the decrease in activity due to the infection and the intra venous treatment could cause local vascular complications. Therefore, these data suggest that a simple cellulitis could increase the duration of hospitalization and the costs. The antibiotics were necessary in the management of cellulitis in aged persons . PenicilTo limit the cost of cellulitis and to decrease morbi-mortality in aged patients having cellulitis, health care officials must encourage aged persons to take care of their skin, to treat soft tissue infections and to prevent recurrence. Medical stuff must limit intra venous treatment and promote home care.The frequency of cellulitis in elderly population;The predisposing factors in this age range;The recurrence of cellulitis.Particularities of skin infection in elderly population;Characteristics of severe cellulitis;Promotion of Home Care.The authors declare no competing interest."}
+{"text": "Implant-supported prostheses are currently the standard treatment for the replacement of missing teeth and deficiencies. Implant restorations can either be screw-retained, cement-retained, or both. The implant retention system type is typically chosen during the treatment plan. The primary purpose of this study is to investigate the frequency of implant restoration retention systems.  A five-page questionnaire was sent to private institutes, educational institutes, and governmental hospitals that provide dental services. The data were analyzed using descriptive statistics.  Prior to distribution, the surveys were proofread and pilot-tested at the Faculty of Dentistry at Umm Al-Qura University. The surveys were mailed to three groups: private institutes, educational institutes, and governmental hospitals. In total, 120 surveys were distributed and 87 surveys were returned, for a response rate of 73%. This included thirty-six surveys (41.4%) from private institutes, twenty-two surveys (25.3%) from educational institutes, and twenty-nine surveys (33.3%) from governmental hospitals.  In general, Astra was cited as the most widely used implant system. In addition, cement-retained restorations were more frequently used than screw-retained restorations. However, dental implant failure was more frequently associated with cement-retained restorations than with screw-retained restorations.  Implant-supported prostheses are currently the standard treatment for the replacement of missing teeth and deficiencies to enhance tooth function, for convenience, and for appearance . An implScrew-retained systems are preferred for a prosthesis with multiple abutments, due to the retrievability that allows for the removal of the prosthesis for cleaning and repair. In addition, screw-retained prosthesis tends to have less marginal misfits at the crown implant interface , 5. HoweCement-retained systems are ideal for esthetic purposes. They may provide an advantage in compensating for the unfavorable angulation of an implant. Other advantages include fabrication simplicity, a decrease in laboratory complications, and less stress on bone tissue compared to the screw-retained systems , 8. HoweAs there is currently no consensus about the ideal type of retention system for implant restorations , the priIn April of 2017, a five-page questionnaire was sent to dental institutions, schools, and hospitals that provide dental services in different regions of Saudi Arabia. A total of 120 surveys were sent to 21 dental institutions. The questionnaire asked the respondents for general information, including their city, email address, institution/school, and their specialty. The survey included a total of eleven questions .All questions were of a multiple choice format and allowed the respondent to choose multiple answers. The questions were proofread and pilot-tested at the Faculty of Dentistry at Umm Al-Qura University by a prosthodontic staff member prior to distribution. The surveys were mailed to people in three groups: private institutes, educational institutes, and governmental hospitals. Data were analyzed with descriptive statistics using Microsoft Excel, version 15.19.1.n = 21 (24.14%)), implant surgery (n = 19 (21.84%)), periodontics (n = 18 (20.69%)), prosthodontics (n = 13 (14.94%)), oral and maxillofacial surgery (n = 12 (13.79%)), and general dentistry (n = 4 (4.60%))  from private institutes, twenty-two surveys (25.3%) from educational institutes, and twenty-nine surveys (33.3%) from governmental hospitals. Clinician specialty of the respondents included restorative dentistry ((4.60%)) .n = 10 (28%)), Straumann dental implant system (n = 8 (22%)), Biomet 3i dental implant system (n = 7 (19%)), Anthogyr implants system (n = 6 (17%)), and Noble Biocare implant system (n = 5 (14%))  respondents reported that the role of the clinicians in dental implant treatment was in both surgical and prosthetic treatments. Ten (28%) respondents reported that their role was limited to either surgical or prosthetic treatment .N = 22); 38% (N = 14) reported no limitations (Thirty-one (86%) respondents used cement-retained prosthetics in their practice more than screw-retained prosthetics, while 3 (8%) respondents reported that it depended on the case . Furtheritations .For the access hole filling material, our study revealed that twenty-six (72%) respondents used the light cure composite resin, filled partially with cotton pellets; six (17%) respondents used the resin-modified glass ionomer, partially filled with cotton pellets, and four (11%) respondents used the light cure temporary filling, partially filled with cotton pellets.n = 14 (39%)), followed by a resin-modified glass ionomer (n = 11 (31%)), glass ionomer cement (n = 9 (26%)), and zinc phosphate cement (n = 2 (1%)) (The most frequently used luting agent for the definitive cementation of the implant restorations was resin ( 2 (1%)) .The last survey question asked about the failure rate of the dental implants, in association with the retention system. The results reveal that 28 (78%) respondents reported that the cement-retained restoration more frequently resulted in a dental implant failure, while 6 (17%) respondents reported that the failure was associated with the screw-retained system. Moreover, 2 (6%) respondents reported no association between the retention system and the implant failure .n = 9 (41%)), Astra Tech implant system (n = 6 (27%)), Nobel Biocare implant system (n = 4 (18%)), and Biomet 3i dental implant system (n = 3 (14%)) ) .Twenty (92%) respondents reported that the role of the clinicians in a dental implant treatment was limited to either a surgical or prosthetic treatment. Only two (8%) respondents reported their role in a dental treatment as both surgical and prosthetic .n = 9), while 59% (n = 13) reported no limitations (Fourteen (64%) respondents reported that the retention system they used depended on the case. Six (27%) respondents preferred cement-retained rather than screw-retained prosthetics . Furtheritations . In relan = 10 (45%)), followed by resin (n = 8 (36%)) and glass ionomer cement (n = 4 (18%)) (The most frequently used luting agent for the definitive cementation of implant restorations was the resin-modified glass ionomer (4 (18%)) .The last survey question asked about the failure of the dental implant in association with the retention system. 12 (55%) respondents reported that there was no association between the retention system and the dental implant failure, while 8 (36%) respondents reported that the failure was more frequently associated with cement-retained restorations. Only two (9%) respondents stated that it was more frequently associated with screw-retained restorations .n = 10 (34%)), Straumann dental implant system (n = 8 (28%)), Nobel Biocare implant system (n = 7 (24%)), and Biomet 3i dental implant system (n = 4 (14%)) ) .Eighteen (62%) respondents reported that the role of the clinicians in a dental implant treatment was limited to either surgical or prosthetic treatment. Eleven (38%) respondents reported their role in dental treatment as both surgical and prosthetic treatments .N = 15); 48% (N = 14) reported no limitations (Seventeen (59%) respondents reported that the use of the retention system depended on the case, while nine (31%) respondents preferred cement-retained systems to screw-retained systems . Furtheritations . In termn = 14 (48%)), followed by resin (n = 10 (34%)), glass ionomer cement (n = 3 (10%)), and zinc phosphate cement (n = 2 (7%)) (The most frequently used luting agent for the definitive cementation of implant restorations was the resin-modified glass ionomer ( 2 (7%)) .The last survey question asked about the failure of the dental implant in association with the retention system. 18 (62%) respondents reported that there was no association between the retention system and the dental implant failure. 7 (24%) respondents reported that the failure was more frequently associated with cement-retained restorations. Only four (14%) respondents stated that is was more frequently associated with screw-retained restorations .The results of this study indicate that people working in a variety of specialty areas are involved in implant treatment. In addition, a wide range of implant manufacturer products and a wide range of implant retention protocols and cementation materials are used in their practice. This study also revealed commonly used implant manufacturers and techniques among dental clinicians in Saudi Arabia.Tarica et al.  found thMost dental clinicians in Saudi Arabia followed the American style in implant placement, while the role of the clinicians in implant treatment varied from one institute to another. In a private institute, the role of the clinicians was to perform both the surgical and prosthetic treatment. In an educational institute or governmental hospital, this was not the case. Perhaps this is due to restricted policies in educational and governmental hospitals in Saudi Arabia. In addition, it may be that a variety of specialties exist in governmental hospitals and educational institutes, which limits the clinicians to perform duties beyond their capabilities.In a systematic review, a comparison was conducted between the cement-retained versus screw-retained restoration for marginal bone loss. Overall, the cement-retained restoration provided fewer prosthetic complications and a higher implant survival rate than screw-retained  restoratThe sealing of the access hole of the screw-retained restorations is generally conducted with a partial filling with a cotton pellet and composite resin restoration. In a private institute, they rarely used the amalgam restoration to fill the hole. Most institutions used the resin-modified glass ionomer, resin cement, glass ionomer cements, and zinc phosphate cement. Their agreement in cement materials for definitive cementation indicates that the same cements are selected, due to convenience, familiarity, and cost. Some studies have shown that the cement used for natural dentation does not necessarily correlate with the cement used in dental implant restoration , 15.The last survey question asked about the association between dental implant failure and retention systems. In general, respondents considered the cement-retained dental implant to be more often associated with dental implant failure. The educational institute respondents stated that the dental implant failure was not associated with the retention systems. In a systematic review conducted by Lemos et al. , the cemScrew loosening is a major problem with screw-retained restorations , 17. TheHowever, this study also confirmed further investigation to expand the sample size. This may lead to more in-depth knowledge about the reasons behind implant failure.Within the limitations of this study, the findings illustrate that Astra was cited as the most widely used implant system. In addition, cement-retained restorations were more frequently used than screw-retained restorations. Moreover, resin modified glass ionomer cement was most frequently used for definitive cementation. However, dental implant failures were more commonly associated with cement-retained restoration as compared to screw-retained restorations."}
+{"text": "Toxocara spp. eggs in the public places.Human toxocariasis is contained in the list of neglected diseases. The infection occurs after ingestion of embryonated eggs in contaminated soil. The present study was carried out to estimate the extent of soil contamination with Soil samples were collected randomly from 41 public places in various parts in and around of Ardabil, Iran, between March 2013 and March 2014. Data were examined by microscopy following sodium nitrate flotation.Toxocara spp. were found in 14 (7%) soil samples.Of the 200 collected soil samples, 35 (17.5%) were positive for soil parasites. The eggs of Toxocara spp. eggs in Ardabil city and provides information for local control of toxocariasis.This investigation gives baseline knowledge regarding soil contamination with  Toxocara spp. larval stage, the etiological agent of human toxocariasis, is a significant medical problem worldwide , between Mar 2013 and Mar 2014. The climate of the city is extremely cold, snowy in winter, and temperate in summer with an average annual rainfall of about 304 mm. The mean yearly humidity is approximately 70%.Overall, 200 soil samples were collected from 41 public places in various parts , 40 samples in each parts, of Ardabil City, including sidewalks, public parks, squares, children playgrounds and rubbish dumps by simple random selection .Sampling was done in all 4 seasons of the year.To carry out this, at each sites approximately 150 gram of soil sample was taken with the aid of a small shovel from 8 cm ground depth . The samToxocara spp. eggs, the soil samples were examined by a centrifugal-floatation method with the use of saturated sodium nitrate solution  and one genera of trematode egg (Dicrocoelium spp. egg) were recovered (Toxocara spp. eggs were the most common helminth egg in the public places of Ardabil City (7%) followed by Ascaris spp. eggs (4%) and others  were positive for helminths eggs and nematode larvae . Six genspp. egg , Ascarisecovered . Toxocard others .Toxocara spp. eggs are presented in The contamination of different parts of Ardabil public places with Toxocara spp. eggs and other detected parasites in current research during the whole year showed that in the spring 6 (12%) out of 50 soil samples were positive for Toxocara spp eggs followed by Ascaris spp. Egg 1(2%), Trichuris spp. egg 1(2%) and others. None of the samples was positive for Dicrocoelium spp egg and Nematode larvae.The burden of Toxocara spp. egg was found in 1 (2%) of the soil samples and 1 (2%) of the samples was positive for Trichuris spp. egg.In the summer Ascaris spp. eggs, 4 (8%) of the samples were positive for Nematode larvae, 3 (6%) were positive for Trichuris spp. eggs, 1(2%) for Toxocara spp. egg and 1 (2%) for Dicrocoelium spp. egg.In the autumn 13 out of 50 soil samples were positive for parasitic stages, 4 (8%) out of 200 samples contained Toxocara spp. eggs were found in 6 (12%) of the samples and eggs of Ascaris spp. were found in 3 (6%) and Toxascaris egg was found in 1 (2%) samples , Dublin/Ireland (6%), Utrecht/Netherland (7%), Andhra Pradesh/India (6.5%), Pozani/Poland (6.3%), Assam/India (6.12%), Shiraz/Iran (6.3%), different zones/Costa Rica (7%), Urmia/Iran (7.8%) and Qazvin/Iran (5.8%) (The data obtained on the soil contamination rate with the n (5.8%) , 21\u201329.The rate of contamination in Ardabil City was lower than other studies such as Sao Paulo/Brazil (29%), Kolaczkowwo/Poland (14.5%), Khorram Abad/Iran (22.2%), Erzurum/Turkey 64.28%), Tehran/Iran (10%), Tehran/Iran (38.7%), Bareilly City/India (12.84%), Abadan/Iran (29.2%), Mashhad/Iran (9.2%) and Kermanshah/Iran (18%) 4.28%, Te, 30\u201337.The level of soil contamination found in present investigation was higher than reports from Murcia/Spain 1.24%), Melbourne/Australia (1%), Pondicherry/India (2.21%) and Chennai/India (4.75%) .24%, Mel\u201340.The highest frequency of contamination was found in the southern parts of the city. The influence of the location of the area on the environmental contamination is an ongoing controversial issue . This faToxocara spp. eggs during summer, and autumn was lower than during spring and winter. Our results are in agreement with previous studies showing the seasonal discrepancy influencing in the prevalence of Toxocara spp. eggs in the environment. The differences of contamination rate may be due to culture, geographical parameters, climate condition, seasonal change, soil type, type of population of cat and dog, people\u2019s attitudes toward pets, sample collection, methodology of examination and diagnostic techniques. Thus, the comparison of all such surveys is not reasonable.The frequency of Toxocara spp. eggs and will provide significant information about toxocariasis. Data available about infection in human were limited. Further survey should focus on distinguishing toxocariasis in human in order to develop suitable methods for prevention and control of the disease.Although, this investigation gives baseline knowledge regarding soil contamination with"}
+{"text": "To determine knowledge, attitude and practice (KAP) regarding management of Gestational Diabetes Mellitus (GDM) among Health Care Providers in major cities of Pakistan.A knowledge, attitude and practice (KAP) questionnaire based study was conducted in major cities in Pakistan from health care providers in public and private hospitals and clinics. Questionnaires were provided to the health care providers regarding screening, diagnosis and management of patients with GDM. Data analysis was done using IBM SPSS 20.A total of 210 doctors took part in the study. 55 (26%) reported using fasting blood glucose as screening test for GDM whereas 129(61.4%) respondents used Oral Glucose Tolerance based WHO criteria for diagnosing GDM. Thirty six (17%) and 98(46.7%) doctors referred their patients to Gynecologists. For treating GDM, 64(30.5%) doctors prescribed insulin . 112 (53.5) doctors used combination of capillary glucose by glucometer and plasma blood glucose tests for monitoring of glycemic control of patients with GDM.There is lack of agreed screening tests and criteria for diagnosis and management of GDM patients. Doctors need to be educated to follow evidence based diagnostic and management guidelines so that GDM patients can be effectively managed. Recently released South Asian Federation Societies and Pakistan Endocrine Society guidelines could be much needed consensus guidelines for doctors to apply in their daily practice to improve GDM diagnosis and treatment. Maternal and fetal complications associated with GDM are largely preventable with early recognition and treatment.Gestational diabetes mellitus (GDM) is an endocrine disorder resulting in hyperglycemia with first recognition during pregnancy affecting a significant number of pregnancies each year.Globally there is a lack of consensus regarding diagnosis and further management of GDM and different approaches are adhered to in different region of the world due to lack of a universally accepted protocol. Different protocols used internationally recommend their own patient selection criteria and diagnostic thresholds. Currently the protocols used for diagnosis follow either the 75gm or the 100gm oral glucose tolerance tests (OGTT).6Despite considerable advances in medical approach there have been considerable gaps between disease outcome and acceptable treatment.A nation-wide questionnaire based survey was conducted to study practices regarding screening, diagnosis, treatment and follow-up of GDM in health care practitioners across 21 major cities of Pakistan. Data was collected on a structured self-reported standardized multiple response questionnaire. The questionnaire assessed the knowledge and current practices of health care professionals across following domains of GDM: Timing of screening with respect to trimester of pregnancy, methods and guidelines used for screening and diagnosis of GDM, treatment strategies used for management of GDM and follow-up plan for detection of persistent DM or new onset T2DM.Volunteer medical students from Federal Medical and Dental Medical College, Islamabad, belonging to diverse cities of Pakistan were enrolled in the study. The questionnaire proforma was explained by the lead investigator and the proformas handed over to them just before college summer break. Questionnaires were then taken by them to the practitioners to be filled on the spot and returned. Four hundred (400) health care practitioners including gynecologists, endocrinologists, medical specialists, family physicians and medical officers were contacted. Data was analyzed using IBM SPSS 20. Ethical approval for the study was provided by Ethics Review Board of Shaheed Zulfiqar Ali Bhutto Medical University, PIMS, Islamabad, Pakistan.Two hundred and ten health care practitioners out of 400 hundred contacted from a number of major cities of Pakistan  took parnd and 3rd trimester of pregnancy. Rest of the respondents (n=39 [18.6%]) said that they were screening their patients during routine clinical visits. Although most of the respondents (62.4%) were screening all antenatal patients for GDM, a large number of respondents only screened patients if they either had signs and symptoms suggestive of GDM (n=17 [8.1%]) or were at high risk for GDM (n=51 [24.3%]). Eleven respondents (5.2%) were not screening patients for GDM at all. Most of the respondents (n=90 [42.9%]) were seeing less than five patients of GDM each month. Seventy respondents (33.3%) were seeing between 6 and10 patients, 23(11%) between 11 and 20 patients and 27 (12.9%) more than 20 patients of GDM per month. Only 61 (29.1%) practitioners were using an oral glucose tolerance test (OGTT) for screening purposes; these included 50 gram OGTT by 9 (4.29%), 75 gram OGTT by 51 (24.29%) and 100 gram OGTT by 1 (0.5%) respondent. A venous blood fasting glucose was being used as screening test by 55 (26.19%) respondents. Other screening tests being used included: a random venous blood glucose by 53 (25.24%), a fasting capillary blood glucose using glucometer by 5 (2.85%), a random capillary blood glucose using glucometer by 8 (3.81%) and HbA1c by 20 (9.52%) respondents (Two hundred and two (96.2%) were seeing patients already diagnosed with GDM and 207 (98.6%) were screening their patients for GDM. A large number of respondents (n=82 [39%]) were screening patients for GDM during first presentation to antenatal clinics regardless of timing of pregnancy. Eighty-nine (42.4%) respondents were screening for GDM specifically during 2pondents .There were no uniform criteria used for the diagnosis of GDM. Most of the respondents (n= 129 [61.4%]) reported to be following WHO criteria for the diagnosis of GDM. Other criteria used included ADA guidelines by 26 (12.4%) and IADPSG  criteria by 19 (9%) respondents. Thirty-six (17.1%) practitioners were not sure about the criteria they were using . The repFifty seven (27.1%) respondents were following up their patients by capillary glucose monitoring using glucometer, 41(19.5%) by plasma blood glucose from lab and 112(53.5%) by a combination of both. A significant number of respondents were not aware of right timing of postpartum evaluation for persistent diabetes. Forty one (19.5%) respondents had been asking the patients to visit next day; 58(27.6%) were screening after one month and 111(52.9%) after six weeks of delivery. Investigations done for follow up of persistent diabetes cases by 75(35.7%) was fasting blood sugar, 32(15.2%) by random blood sugar from lab, 6(2.9%) by fasting blood sugar by glucometer, 17(8.1%) by random blood sugar levels (glucometer), 41(19.5%) by HbA1c, 12(5.7%) by 100 gram OGTT, 24 (11.4%) by 75 gram OGTT, 2(1%) by 50 gram OGTT and 1(0.5%) urine for glycosuria.If the initial postpartum follow-up evaluation was negative for persistent diabetes, 103 (49.5%) doctors were screening patients for development of T2DM after 6 months, 35 (16.7%) after one year, 12 (5.7%) after three years. A large number (n=60 [28.6%]) were not screening patients for T2DM at all.nd trimester.4 Timing of screening is important especially in cases of patients who are at higher risk for preexisting DM or GDM. 39% in our study screened patients during first antenatal visit regardless of timing of visit 62% screen all antenatal patients whereas 24% screen only high risk patients. Physicians screening their patients only on the basis of risk factors might miss at least 30% of the cases which may lead to serious pregnancy outcomes.13Our study shows there is clear lack of consensus among health care providers regarding management of GDM. According to our study GDM was mostly managed by gynecologists (51%). Screening was mostly done on first presentation of patient to antenatal clinic as compared to widely adopted timing that is 2In the treatment aspect, again a lack of agreement was seen among the doctors in our study. Most of doctors, about 59% prescribe insulin in either NPH/Regular 70/30 fixed regimen or NPH/Regular split regimen. Gupta et al showed that 79% doctors preferred insulin as the treatment of choice.14During the follow up of GDM patients, in our study 27% preferred glucometer readings while 20% opted for venous blood glucose readings from lab. Divakar showed that 41% clinicians preferred venous blood glucose levels at two weekly intervals and did not recommend home monitoring with glucometer.On follow up post-partum, in our study, again a mixed practice was seen. Fasting blood sugar from lab was the most common investigation, ordered by 36% and OGTT with 75 gm glucose by 12% while an Indian study showed 17% of clinicians recommended 75 gm OGTT at 6 weeks post-partum. The American Diabetes Association (ADA) recommends post-partum follow up at 6-12 weeks and testing with either fasting venous blood glucose or 75 gm OGTT.As ours is a KAP study and we don\u2019t have actual patient data and available data is based on what the doctors can recall so chances of bias cannot be ruled out.Gestational diabetes mellitus is a high-risk state with increased morbidity and mortality in both mother and fetus. Proper knowledge, attitude and practices of health care providers in this regard are needed for early detection and intervention for good pregnancy outcome. There is a lack of agreed screening tests and criteria for diagnosis and management of GDM and health care providers are not abreast with the latest evidence based recommendations internationally. Both maternal and fetal mortality and morbidity can be prevented by establishing well-defined universal criteria to screen, treat, manage and follow-up a patient with GDM and educate and update health care providers concerned with GDM management with the latest practices. The recently launched South Asian Federation of Endocrine Societies Guidelines are indeed very helpful. It is imperative that the GDM guidelines are aggressively propagated among Gynecologists and General Physicians so that diagnosis and treatment are optimized."}
+{"text": "To evaluate new onset epilepsy characteristics, etiology, radiological and electroencephalographic features and to document treatment response in the elderly.This was a retrospective study carried out in King Fahd Medical City, Riyadh, Kingdom of Saudi Arabia, from 2010 to 2013. Medical records were searched to recruit patients. Hundred and nineteen patients were enrolled who fulfill the inclusion criteria. Clinical data with respect to seizure semiology, etiology, electroencephalographic findings, radiological findings, co-morbidities, and anti-epileptic drug (AED) therapy were assessed.Cerebrovascular disease was the most common etiology, followed by occult cerebrovascular disease (oCVD). Focal onset seizures were the most common clinical presentation in this group of cohort. Electroencephalogram (EEG) showed generalized slowing in majority of patients (45.5%), with 21.8% interictal epileptiform activity. Patients required lower doses of AEDs to control seizures, gain better seizure control. Common co-morbidities were hypertension and diabetes mellitus.Patients presenting with LOE, should have search for any other cerebrovascular risk factors. Further research is needed to determine the prevalence of oCVD in LOE, and to investigate whether addressing cerebrovascular risk factors in this cohort of patients can reduce the incidence of stroke. The prevalence and incidence of epilepsies in elderly is high, a third of all diagnoses of epilepsy are made in people over 60.This was a retrospective study. Patients were selected from the hospital records of the epilepsy patients in King Fahd Medical City, Riyadh, Kingdom of Saudi Arabia. After getting institutional review board (IRB) approval, we searched all electronic medical records to identify cases of new-onset epilepsy in elderly. Patient enrolment began on August 2013, and patients presented between 2010 to 2012, who fulfilled the criteria were recruited. We defined elderly population as age 60 years and above. Seizures were classified according to the revised International League against Epilepsy classification into primary generalized, simple partial seizure complex partial seizures and secondary generalized.Figure 1) An etiological diagnosis was possible in 92 (77.3%) of patients, including those with cerebrovascular disease such as ischemic or hemorrhagic 69 (58%), followed by tumors 20 (16.8%) and other etiology including infection, trauma and other inflammatory conditions in 3 (2.5%) patients . Around 27 (22.7%) patients who were labeled as cryptogenic or non-lesional found to have oCVD in the form of small vessel disease, brain atrophy, and subcortical infarcts. Interictal EEG showed; focal epileptiform discharges in 26 patients (21.8%), while slowing in 53 patients (44.5%). Other finding including periodic lateralized epileptiform discharges (PLEDS), and triphasic waves in 7 patients (6.2%), normal record in 20 patients (15.9%) while EEG was not available in 13 patients (8.8%). Seven patients presented with status epilepticus, 5 out of them had ischemic stroke, while one had tumor and one found to have oCVD. Of the 119 patients 107 were on monotherapy and 6 (5%) were on 2 drugs, and 5% were on no medications (Table 1).Hundred and nineteen patients were enrolled in the study; their mean age was 70.12\u00b18.72 years (mean\u00b1SD) and 59 (49.6%) were male. According to seizure classification 73 (61.3%) patients presented with focal onset; with or without secondary generalization, 33 (27.7%) patients with complex partial seizures (CPS) without secondary generalization, 21 (17.6%) CPS with secondary generalization and 19 (16%) with simple partial seizure (SPS), followed by generalized tonic clonic seizure (GTCs) in 41 (34.5%) and status epilepticus in 5 (4.2%) . These findings are in accordance with previous studies reporting that the most frequent type of seizures in the elderly is CPS.%. These 3The IEA in our study was found in 21.8% of patients, while a large number of patients had non-specific findings of generalized or lateralized slowing (46%). Results are controversial; one recent study showed that 72.9% patients had IEA9A limitation of this study may be that only patients from a tertiary care hospital were recruited, that could account for higher percentage of co-morbid conditions. Relationship between stroke and LOE is very interesting; stroke is the most common etiology in LOE while LOE posses an increase risk of subsequent stroke.In conclusion, most common seizure type in our study was focal onset, stroke was the common cause of late onset epilepsy, and even oCVD was prevalent. The HTN and DM were commonly associated co-morbidities. Patients presenting with LOE, should have search for any other cerebrovascular risk factors. Given the small sample size, further research is needed to determine the prevalence of occult CVD in LOE, and to investigate whether addressing cerebrovascular risk factors in this cohort of patients can reduce the incidence of stroke. A prospective study will be of great value in the future."}
+{"text": "The uridine nucleotide analogue sofosbuvir is a selective inhibitor of hepatitis C virus (HCV) NS5B polymerase approved for the treatment of chronic HCV infection with genotypes 1 \u2013 4. The objective of the study was to evaluate the interim results of efficacy and safety of regimens containing Sofosbuvir  among Pakistani population with the rapid virologic response (RVR2/4 weeks) with HCV infections.This is a multicenter open label prospective observational study. Patients suffering from chronic Hepatitis C infection received Sofosbuvir  400 mg plus ribavirin (with or without peg interferon) for 12/24 weeks. The interim results of this study were rapid virological response on week 4. Data was analyzed using SPSS version 21 for descriptive statistics.A total of 573 patients with HCV infection were included in the study. The mean age of patients was 46.07 \u00b1 11.41 years. Out of 573 patients 535 (93.3%) were treatment naive, 26 (4.5%) were relapser, 7 (1.2%) were non-responders and 5 (1.0%) were partial responders. A rapid virologic response was reported in 563(98.2%) of patients with HCV infection after four weeks of treatment. The treatment was generally well tolerated.Sofosbuvir  is effective and well tolerated in combination with ribavirin in HCV infected patients. Hepatitis C virus (HCV) infection is a global health problem, which leads to various complications such as cirrhosis, decompensated liver disease and liver cancer. An estimated 130\u2013150 million people are chronically infected worldwide and 350,000\u2013500,000 HCV-related deaths are reported annually.1HCV infection is responsible for increasing social, economic and health burden worldwide.10Based on sequence homology six major HCV genotypes and numerous distinct subtypes have so far been identified.13Treatment for HCV genotype has evolved from pegylated interferon (peginterferon) and ribavirin to include direct-acting antiviral agents. Treatment with interferon is associated with troublesome side effects, including influenza-like symptoms, depression, fatigue, and cytopenias19There is lack of published national studies about the use of Sofosbuvir in our population. We are presenting here the early results of efficacy and safety of 12/24 weeks of therapy with regimens containing sofosbuvir in patients with HCV infection. This is one of the first open label large scale clinical study of sobosbuvir  under routine clinical practice reporting the initial response on viral load of HCV.This is a multicenter observational study conducted in various secondary and tertiary care hospitals of Pakistan. Before the start of study, it was registered with ClinicalTrials.gov (NCT02804386). Patient were inducted from the out patients department (OPD) after taking informed consent and fulfilling the inclusion criteria. Patients were assigned registration number according to site code and subject number. Screening assessments included standard clinical, laboratory testing, measurement of serum HCV RNA levels, and HCV genotyping.Assessments during treatment included measurement of vital signs, physical examinations, electrocardiography, standard laboratory tests and measurement of serum HCV RNA levels.Sofosbuvir and ribavirin (double regimen) or peg interferon (triple regimen) was prescribed according to international guidelines.The primary efficacy end point of this study was a rapid virologic response (RVR), which was defined as an HCV RNA level below the lower limit of quantification,  at 4 weeks of treatment.This study was approved by the institutional review board and was conducted in compliance with the Declaration of Helsinki, Good Clinical Practice guidelines, and local regulatory requirements.Data was entered and analyzed using Statistical Package for Social Sciences SPSS version 21.0.A total of 573 patients 290 (56.0%) male and 283 (49.3%) female with HCV infection were included in the study. The mean age of patients was 46.07 \u00b1 11.41 years. Out of 573 patients, 535 (93.3%) were treatment na\u00efve, 26 (4.5%) were Relapser, 7(1.2%) were Non-Responders and 5 (1.0%) were partial responders as shown in Patient with double regimen  were 467 (86.7%) however the patient with triple regimen  were 62 (10.8%). Rapid virological response (RVR), with two weeks of treatment was observed in 84.2% patients and by week four of treatment, 563 out of 573 (98.2%) patients . NineteeThe treatment was generally well tolerated and side effects were mild to moderate and included fatigue 136 (23.7%), headache 54 (9.4%), anemia 49 (8.5%) and nausea 6 (1.0%). Only two patients discontinued treatment due to adverse effects. There was one reported death among patients included in this study. This patient had a co infection with hepatitis E virus and died due to acute liver failure. .In this open-label, single-group study of sofosbuvir in patients with HCV infection, more than 98% of patients receiving treatment had a rapid virologic response (RVR) at four weeks which is comparable to other published studies.25In our study 19 out of 23 cirrhotic patients (82.6%) receiving sofosbuvir responded. Response rate in cirrhotic patients varies in different studies. In a phase 3 trial in patients infected with HCV genotype 1, (FISSION study) treatment-naive patients, including a subgroup with compensated cirrhosis, 89% achieved SVR after 12 weeks of treatment with sofosbuvir and peginterferon or ribavirin.25Fatigue, headache, and nausea were the most frequent adverse effects (AEs) as reported in other studies of sofosbuvir in ribavirin-containing regimens.As this is an observational study in real life clinical practice so genotyping and Quantitative RNA levels were not done in all patients though it is very important for HCV treatment analyses and helpful for proper treatment planning. SVR12 is the main efficacy parameter to evaluate success of any treatment of HCV, but in this study we are only reporting interim analysis of EVR2 and EVR4.To the best of our knowledge this is perhaps the first reported experience of Sofosbuvir in our Pakistani population and will help in building confidence regarding use of sofosbuvir  in clinical practice. Hopefully this regimen will address the rising clinical need for effective oral interferon-free treatment options in patients with HCV infections and both to treatment na\u00efve and those who have previously not responded to peg interferon.Sofosbuvir  with ribavirin is effective and well tolerated with and without interferon in patients with HCV infection among Pakistani population."}
+{"text": "Primary varicella-zoster virus (VZV) infection is a benign self-limited disease. In this study, we review our experience in focusing on the outcome and treatment of VZV infection in pediatric malignancy patients. During the study period, a total of 41 patients with pediatric malignancy had been hospitalized with the diagnosis of VZV infection. All the patients were treated with intravenous acyclovir for a median of 7 days (ranging from 5 to 21 days). The calculated attributable delay of chemotherapy due to VZV infections was 8 days (ranging from 2 to 60 days). VZV-related complications were observed in 3 of 41 patients (7%) who suffered from acute respiratory distress syndrome, and one of them with hemophagocytic lymphohistiocytosis died due to respiratory failure despite acyclovir and broad-spectrum antimicrobial treatment plus supportive treatment. VZV infections are still important contagious diseases in pediatric cancer patients, because they cause not only significant mortality but also a delay in chemotherapy. Immunocompromised children are at greater risk of suffering from severe, prolonged, and complicated varicella-zoster virus (VZV) infection . Before A retrospective cohort study design was used to evaluate pediatric cancer patients with VZV infections who were hospitalized in the Pediatric Hematology-Oncology and Infectious Diseases Units of the Dr. Beh\u00e7et Uz Children\u2019s Hospital from December 2008 to March 2015. In this study, the attending physician\u2019s clinical diagnosis of VZV infection was based on case definitions set by the United States Centers for Disease Control and Prevention and the Council of State and Territorial Epidemiologists guidelines reported in 2009 ,7. TheraDuring the study period, a total of 41 patients with pediatric malignancy had been hospitalized with the diagnosis of VZV infection. Among them, 14 (34.1%) were female and 27 (65.9%) were male. The mean age was 58.8\u00b132.4 months (within the range of 8 months to 12 years of age). Of the patients, 29 had acute lymphoblastic leukemia (ALL) (70.7%), followed by 2 cases of acute myeloblastic leukemia (4.9%), 3 cases of Wilms tumor (7.3%), 2 cases of hemophagocytic lymphohistiocytosis (HLH) (4.9%), 2 cases of rhabdomyosarcoma (4.9%), 2 cases of neuroblastoma (4.9%), and 1 case of hepatoblastoma (2.4%). Among the ALL patients, 8 (27.5%) of them were in the induction phase of chemotherapy (ALL REZ-Berlin-Frankfurt-M\u00fcnster protocol), 19 (65.5%) of them were in a maintenance phase, and 2 patients (6.8%) had relapsed ALL. Only 2 children (4.9%) had a known exposure to siblings in the household who had developed chickenpox.Among the 41 patients, neutropenia was present in 18 patients (43.9%), lymphopenia was present in 27 (65.9%) patients, thrombocytopenia was present in 10 patients (24.4%), and anemia was present in 23 (56.1%) patients. Twenty-one patients had associated fever at the time of diagnosis of VZV infection. Active vesicular rashes were present in all of the patients at the time of diagnosis and the median duration of active VZV infection was 7 days (ranging from 5 to 21 days). All patients had been admitted to our hospital within the first day of the onset of rash.All the patients were treated with intravenous acyclovir for a median of 7 days (ranging from 5 to 21 days). During acyclovir treatment, no serious adverse effects including elevation in blood creatinine and urea levels or hematuria were observed, while 2 patients (4.8%) had nausea and vomiting that could not be explained with other reasons.The median hospital stay was 7 days (ranging from 3 to 35 days) and the calculated attributable delay of chemotherapy due to VZV infections was 8 days (ranging from 2 to 60 days). Thirty-eight patients (93%) showed no complications, but 3 patients (7%) suffered from Acute respiratory distress syndrome (ARDS). Two of them required mechanical ventilation and one required noninvasive ventilation; the patient with HLH (1%) died due to respiratory failure despite acyclovir and broad-spectrum antimicrobial treatment plus supportive treatment.Secondary attack rates among susceptible household contacts of people with VZV are as high as 90%; i.e. 9 out of 10 susceptible household contacts will become infected . In thisIn our study, the most common underlying malignant disease was ALL (70.7%), supporting the findings of a previous report . PatientImmunocompromised patients develop serious complications, such as secondary bacterial infection with invasive Streptococcus pyogenes . HoweverOur study showed that the complicated cases were not homogeneously distributed regarding their primary diseases. This visceral dissemination was thought not be related to the type or status of the malignancy or to the duration of specific anticancer therapy. VZV was more likely to disseminate in children with absolute lymphopenia, less than 500 cells per cubic millimeter, than in patients with higher lymphocyte counts. Patients with lymphopenia or poor cell-mediated immune responses during VZV infection are said to be at risk for persistent, severe, or even fatal VZV . Our patImmunocompromised children, particularly those with leukemia, have more numerous lesions, often with a hemorrhagic base, and healing takes nearly three times longer than in healthy children with VZV infections. These patients were reported to suffer from severe progressive VZV infections characterized by continuing eruption of lesions and high fever persisting into the second week of illness . In our In conclusion, VZV infections are still important contagious diseases in pediatric cancer patients because they cause not only significant mortality but also a delay in chemotherapy. Thus, infection control preventions should be taken in hospitals and maximum efforts for preventing possible exposure of pediatric cancer patients to VZV-infected children should be made.Ethics Committee Approval: Retrospective study; Informed Consent: Retrospective study."}
+{"text": "We report here the complete genomic sequence of Japanese encephalitis virus (JEV) strain FC792, isolated from aborted fetuses of sows which were unimmunized with JEV vaccines in Guangxi Province, southern China. The complete JEV genome of strain FC792 had the highest nucleotide homology (99.7%) and amino acid identity (99.4%) with the sequence of JEV strain SA14-14-2 (GenBank accession number AF315119). Phylogenetic analysis showed that strain FC792 had the closest phylogenetic relationship to the sequence of strain YUNNAN0901 (GenBank accession number JQ086762). This study will help us understand the molecular pathogenesis and genetic diversity of genotype III Japanese encephalitis virus in pigs. Flavivirus genus in the family Flaviviridae. It is an enveloped virus, with a positive-sense single-stranded RNA genome that contains a big open reading frame (ORF) flanked by 5\u2032 and 3\u2032 untranslated regions (UTRs)  is a member of the s (UTRs) . The ORFs (UTRs) , 3. JEV s (UTRs) . JEV infs (UTRs) .In May 2016, JEV strain FC792 was isolated from aborted fetuses collected from a pig farm where pigs were administered JEV vaccines in Guangxi Province, southern China. The 5\u2032 and 3\u2032 ends of the viral genome of FC792 were confirmed by a SMARTer Rapid Amplification of cDNA Ends (RACE) cDNA amplification kit . The other parts were generated by 10 overlapping cDNA fragments to encompass the entire genome and were determined by genome-walking sequencing. All PCR products were gel purified using the QIAquick gel extraction kit (Qiagen), cloned into the pMD18-T vector (TaKaRa), and then sequenced on a 3730 DNA analyzer (Applied Biosystems). The genome was assembled using the software program DNAStar (version 7.0).The complete genome sequence of FC792 is 10,977 nucleotides (nt) in length [excluding the poly(A) tail] and includes a 5\u2032 untranslated region (5\u2032 UTR) (nt 1 to 95), structural proteins , nonstructural proteins , and a 3\u2032 UTR (nt 10395 to 10977). Analysis of the full genome sequences demonstrates that the nucleotide sequence homologies between FC792 and the reported JEV full genome sequences vary from 84.6% to 99.7%, while the amino acid identities vary from 96.2% to 99.4%. Strain FC792 has the highest nucleotide homology (99.7%) and amino acid identity (99.4%) to the sequence of strain SA14-14-2 . Phylogenetic analysis showed that JEV strain FC792 has the closest phylogenetic relationship to the sequence of strain YUNNAN0901 .In recent years, JEV strains have been isolated from mummified fetuses or aborted fetuses of sows that have been reported in China with a high nucleotide homology (99.6% to 99.7%) to strain SA14-14-2, such as strain YUNNAN0901 and strain JEV/sw/GD/2008 (GenBank accession number KX965684). This is a very noteworthy problem. It suggests that the safety and immunological effects of JEV strain SA14-14-2 used as a vaccine for pigs need to be reassessed.The genome sequence reported in this study will promote a better understanding of the molecular pathogenesis and genetic diversity of JEV in pigs.MF002373.The complete genome sequence of JEV strain FC792 has been deposited in GenBank under the accession number"}
+{"text": "Residual myocardial ischaemia early after acute coronary syndromes (ACS) is commonly regarded as an adverse prognostic sign and an indication for revascularisation. However, the benefits of revascularisation for improving prognosis are not known.Analysis of 598 consecutive patients with ACS treated with coronary stenting, all of whom underwent adenosine stress cardiac magnetic resonance (CMR) perfusion imaging to guide revascularisation decisions. Follow-up data were obtained from hospital electronic health records.The 598 patients  after coronary stenting with follow-up for 1.4 years (IQR: 0.6-2.7). Inducible perfusion defects were identified in 294 (49%) patients of whom 18 (6%) died during follow-up compared with 6 (2.0%) patients with no perfusion defects (p = 0.01). Of the 294 patients with perfusion defects, 70 (24%) were revascularised  of whom 5 (7%) died during follow-up compared with 13 (6%) who were not revascularised(p = 0.68). K-M survival analysis confirmed that revascularisation was unassociated with survival benefit, regardless of the severity of ischaemia (Figure In our patients with ACS and coronary stenting, inducible ischaemia was associated with increased risk of death during follow-up. Revascularisation did not appear to reduce the risk and should be reserved for improving symptoms in patients on optimal medical therapy."}
+{"text": "Very severe head trauma cases, defined as Glasgow Coma Scale (GCS) scores of less than 6, have a higher mortality rate and poorer outcome. The purpose of this study was to recognize factors associated with survival and 6-month favorable outcome of very severe head trauma patients presenting to emergency department.In this historical cohort study, the authors retrospectively reviewed medical records of head trauma patients who were admitted to the emergency department with post-resuscitation GCS scores of less than 6. Both univariate and multivariate analyses were used to test the association between various parameters with survival and 6-month outcome.103 cases with the mean age of 39 \u00b1 16.5 years were studied . The overall survival rate was 41.7% and the rate of 6-month favorable outcome was 28.2%. In multivariate analysis, brisk pupil light reaction on admission and patent basal cistern on brain computed tomography (CT) scan were significant factors associated with both survival  and favorable outcome , respectively.Based on the results of present study, the survival rate of patients with very severe head trauma (GCS < 6) was 41.7%. The strong predictors of survival and 6-month favorable outcome of these patients were brisk pupillary reactivity and patent cistern on brain CT scan. It seems that very severe head trauma patients still have a reasonable chance to survive and aggressive management should be continued. Accidents are among the top three causes of death in Thailand. The incidence rate of traffic accident mortality in Thailand was 21.61-23.16 per 100,000 people and the trend of mortality gradually increased between 2010 and 2013. Pheunpathom et al. reported that 15.8-29% of trauma patients in the emergency room had head injuries and the most common mechanism of head injury was road traffic accidents  scores, mild head injury (GCS scores 15-13), moderate head injury (GCS scores 12-9) and severe head injury (GCS scores 8-3). Gennarelli et al. reported that patients with GCS scores of 3 to 5 had a higher mortality rate than patients with GCS scores of 6 to 8 . These pA small number of studies have involved patients with GCS scores <6 and have reported that, <60 years of age, adequate spontaneous respiration, brisk pupillary reactivity, increase in GCS score by at least 2 within 24 hours of admission and the appearance of basal cistern on first brain computed tomography (CT) scan were significant predictors of outcome in very severe head injury -8. The purpose of this study was to recognize factors associated with survival and 6-month favorable outcome of very severe head trauma patients presenting to emergency department.Study designIn this historical cohort study, the authors retrospectively reviewed computer-based medical records of all head trauma patients who were admitted to Songklanagarind Hospital between January 1, 2008 and March 31, 2011. Songklanakarind Hospital is the tertiary care center serving both direct transfers from the accident scene and transfer from 14 provinces in the Southern region of Thailand  was used for outcome measurements. GOS consists of good recovery (GR), moderated disability (MR), severe disability (SD), vegetative stage (VS), and death (D) . Finally3), diffuse injury III , diffuse injury IV , evacuated mass (V) , and non-evacuated mass lesion (VI)  , diffuse injury II  .Motor response is one of the three tests in Glasgow Coma Scale. The motor response is comprised of 6 grades: obeys commands (M6), localizes to pain (M5), withdrawal from pain (M4), decorticate posturing (M3), decelerate posturing (M2), and no motor response (M1) . Statistical analysisAll analyses were performed by the R and Epical program 2.9.1 version .Mean andDemographic data103 cases with the mean age of 39 \u00b1 16.5 years (range: 16.5-82) were studied . Survival rate and outcome The overall survival rate in the present study was 41.7%. Twenty-seven patients (26.2%) observed desirable recovery after acute hospitalization and 2 patients recovered to a favorable group by 6 months after injury. On the other side, sixteen patients (15.6%) were dependent and no patient died during the 6-month follow-up. Factors associated with survival rate Factors associated with 6-month favorable outcome Survival classification treeBased on the results of present study, the survival rate of patients with very severe head trauma (GCS < 6) was 41.7%. The strong predictors of survival and 6-month favorable outcome of these patients were brisk pupillary reactivity and patent cistern on brain CT scans. The use of GCS is a universal method to classify the severity of patients with head injury; patients with GCS scores of 3-4-5 have limited survivability. These patients have poor prognosis. Prior studies reported an overall mortality of 42-87.5% . In literature, clinical characteristics and imaging findings have been shown to correlate with outcome in the very severe group. Nevertheless, limited numbers of studies have examined the outcomes of patients with GCS scores of 3-5. Bilateral fixed dilated pupils (BFDP) are a significant predictor in concordance with several studies , 13-16. Lieberman et al. studied 137 trauma patients with a GCS score of 3. Mortality was 100% in the BFDP group whereas the non-BFDP group had 77% mortality . Sakas eGenerally, the neuronal pathway of pupillary light reflex is located in the intrinsic brainstem. Light reflex is conducted by optic tract fibers, which synapse in the pretectal area. The pretectal neurons synapse to the Edinger-Westphal complex. Finally, the ciliary nerve serves pupillary constrictor responses . PupillaIn our study, another factor, the appearance of basal cistern on brain CT scan, has been determined to correlate with survival and outcome. Absence of obliterated basal cistern had an independent association with survival and good outcome. Toutant et al. studied 218 patients with severe head injury and found a strong relationship between mortality rate and death. In detail, death rate in patients with compressed cisterns was approximately twice as high compared with normal cistern  .The strength of the present study includes more detailed assessment of statistically significant factors affecting survival such as pupillary reactivity. However, the present study has limitations including retrospective study design and assessment of early outcome. Firstly, the quality of data and bias may be affected by study design. The second limitation is only assessing early outcome. Long-term outcome is an uncommon aspect to assess in these patients. Interestingly, late outcome assessment of survivors who had very severe head injuries in other studies has shown that physical and psychological impairment remains in many cases . For stuBased on the results of present study, the survival rate of patients with very severe head trauma (GCS < 6) was 41.7%. The strong predictors of survival and 6-month favorable outcome of these patients were brisk pupillary reactivity and patent cistern on brain CT scan. It seems that very severe head trauma patients still have a reasonable chance to survive and management should be continued.All authors passed four criteria for authorship contribution based on recommendations of the International Committee of Medical Journal Editors."}
+{"text": "Coccidioides spp. spores  reported from Kern County and 28%  from six other counties  , compared with rates in persons aged <20 years (5.6), 20\u201339 years (14.9), 60\u201379 years (16.4) and \u226580 years (13.1). However, the sharpest increases in incidence from 2015 to 2016 occurred in persons aged <20 years (134%) and 20\u201339 years (90%); increases were less pronounced in persons aged 40\u201359 years (64%), 60\u201379 years (40%) and \u226580 years (35%). Rates were higher among males  than among females (10.0). Incidence rates by race and ethnicity were not calculated because these data were missing for approximately one third (32.7%) of reports.Although annual coccidioidomycosis incidence rates in California and Arizona typically follow similar trends, Arizona reported a decrease in the rate from 2015 to 2016  (Coccidioides proliferation and airborne release might have contributed, including rainfall after several years of drought and soil disturbance resulting from construction (Coccidioides is endemic, especially those at increased risk for severe disease, should limit exposure to outdoor dust as much as possible, including staying inside and keeping windows and doors closed during windy weather and dusty conditions (Coccidioides is endemic, including construction workers; recommendations for reducing the risk for infection on construction worksites include using personal protective respiratory equipment, dust suppression, and worker education (The reasons for the increased incidence of coccidioidomycosis in California in 2016, particularly in the Central Valley and Central Coast regions, are not known, but climatic and environmental factors favorable to"}
+{"text": "DNM1), encoding the presynaptic protein DNM1, and to investigate possible genotype-phenotype correlations and predicted functional consequences based on structural modeling.To evaluate the phenotypic spectrum caused by mutations in dynamin 1  with DNM1 and a sibling pair who had an inherited mutation from a mosaic parent. Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation. A common phenotype emerged that included severe to profound intellectual disability and muscular hypotonia in all patients and an epilepsy characterized by infantile spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome. Two patients had profound global developmental delay without seizures. In addition, we describe a single patient with normal development before the onset of a catastrophic epilepsy, consistent with febrile infection-related epilepsy syndrome at 4 years. All mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function.We identified 19 patients with de novo mutations in DNM1-related encephalopathy is relatively homogeneous, in contrast to many other genetic epilepsies. Up to one-third of patients carry the recurrent p.Arg237Trp variant, which is now one of the most common recurrent variants in epileptic encephalopathies identified to date. Given the predicted dominant-negative mechanism of this mutation, this variant presents a prime target for therapeutic intervention.The phenotypic spectrum of  DNM1; NM_004408) is located on chromosome 9q34.11 and encodes DNM1, a GTPase involved in synaptic vesicle fission for receptor-mediated endocytosis on the presynaptic plasma membrane.1 DNM1 self-assembles into multimeric spirals around the necks of budding vesicles.2 Functional consequences of Dnm1 mutations have been demonstrated in animal models such as Drosophila temperature-sensitive shibire flies, in which mutations caused depletion of synaptic vesicles due to blocked endocytosis.4 Furthermore, the fitful mouse, heterozygous for a spontaneous mutation in the middle domain of Dnm1, has recurrent seizures.5Dynamin 1 , and Epi4K projects7; from patient reports9; and from diagnostic laboratories. A detailed medical history, including epilepsy, development, and neurologic status, was obtained for each patient. EEG and imaging data were reviewed. Seizures and epilepsy syndromes were classified according to the International League Against Epilepsy (ILAE) classification scheme.10Patients with pathogenic For patients recruited within the EuroEPINOMICS-RES project or the EPGP/Epi4K project, site-specific institutional review boards approved the study. Patients identified by routine clinical genetic testing gave informed consent according to ethics and legal regulations at the individual centers. Signed informed consent was obtained from all study participants or their legal representatives.7; patients 5, 7, and 19 from EPGP/Epi4K6; and patients 1, 2, 15, 17, and 21 by diagnostic whole-exome sequencing or research protocols. Sequencing and data analysis were performed as previously described.11 Sanger sequencing was used in all patients and parents to confirm the mutation and to study the inheritance of the mutation. None of the patients included in this project were found to have additional explanatory genetic findings.Mutations were identified with research or clinical testing using next-generation sequencing: patients 3 and 8 from EuroEPINOMICS12 GDP-AlF4 and magnesium bound to GTPase domain (PDB: 2X2E),12 and DNM3 (PDB:5A3F)13 were downloaded from the protein data bank.14 Graphics were generated with open-source PyMol (www.pymol.org). Variants from the Exome Aggregation Consortium (ExAC) database included only missense changes with \u22652 alleles.15Structures for DNM1 (PDB: 3ZVR),9), resulting in a total of 20 independent mutations (tables 1 and 2). Nine of 20 independent patients (45%) carried recurrent mutations within the DNM1 gene. The most common mutation was the c.709C>T (p.Arg237Trp) mutation, which was found in 6 of 20 independent patients (30%). In addition, mutations affecting the p.Gly359 amino acid residue were identified in 3 of 20 patients , and alterations affecting the p.Lys206 amino acid residue were identified in 2 of 20 patients . All mutations were confirmed to be de novo, except for the affected sibling pair whose father was shown to have 5.5% mosaicism on leucocyte DNA.9 Fourteen of 20 mutations (70%), including the recurrent c.709C>T (p.Arg237Trp) mutation, occurred in the GTPase domain of DNM1.The current study reviewed data from 21 patients, including 19 sporadic patients and a sibling pair . Pregnancy and delivery were unremarkable in all patients with normal birth parameters. Patient 18 died at 2 years of age, before inclusion in this study.For the analysis of DNM1 encephalopathy were nonverbal with severe to profound intellectual disability. In 17 of 21 patients (81%), developmental delay was apparent before seizure onset, while regression started with the onset of seizures in 4 of 21 patients (19%). Except for a single patient (patient 20) who had normal development until the onset of refractory seizures at the age of 4.5 years, all patients had significant developmental delay in the first year of life. Seventeen of 21 patients (81%) were nonambulatory.All patients with Seizures occurred in 19 of 21 patients (90%). Patient 2 did not have seizures, and patient 17 showed only subcortical, nonepileptic myoclonic jerks. Seizures began at a median age of 7.6 months (range 1 month\u20134.5 years). Patient 20 was an outlier with onset at 4.5 years with a febrile infection-related epilepsy syndrome phenotype. In terms of seizure type, 15 of 19 patients presented with infantile spasms, whereas 1 patient each presented with myoclonic seizures, tonic seizures, generalized tonic-clonic seizures (GTCS), and focal seizures; information was not available for 1 patient. Later, spasms occurred in 16 of 19 patients (84%), GTCS in 12 of 19 patients (63%), typical and atypical absence seizures and tonic seizures in 9 of 19 patients (47%), focal seizures in 7 of 19 patients (37%), and atonic seizures in 5 of 19 patients (26%). Five patients had status epilepticus (26%). There were no consistent precipitating factors for seizures: patients 10, 14, and 18 showed sensitivity to higher temperatures and fever; patient 8 had reflex seizures; and patient 17 had nonepileptic myoclonic jerks that were elicited by touch and sound.Abnormal EEG findings were found in all patients with seizures and the patient with nonepileptic myoclonic jerks. One patient (patient 1) had only nonspecific background slowing, while 19 of 20 patients (95%) had epileptiform discharges on EEG and background slowing. Multifocal epileptiform discharges were the most frequent finding, present in 14 of 20 patients (70%). Hypsarrhythmia occurred in 11 of 20 patients (55%). Other epileptiform features observed in a subset of patients included slow spike-wave discharges , generalized spike-wave activity , paroxysmal fast activity , and focal epileptiform discharges .Seizure outcome was assessed in 18 patients: 15 of 18 patients (83%) had refractory seizures. Three patients (17%) became seizure-free on treatment. Patient 19 became seizure-free on the ketogenic diet (KD) at the age of 3.5 years; patient 21 had a dramatic reduction of myoclonic seizures in the second year of life while on the KD and continues to have frequent nonepileptic myoclonic jerks. Seizures in patient 1 were refractory until the age of 6 years, when she became seizure-free on levetiracetam and lamotrigine.Improvement in seizure control, but not seizure freedom, was observed with clobazam or clonazepam in 5 of 20 patients (25%), steroids or adrenocorticotropic hormone in 4 of 20 patients (20%), topiramate or zonisamide in 3 of 20 patients (15%), and the KD in 5 of 20 patients (25%). Worsening of seizures was reported in individual patients with levetiracetam, the KD, and cannabidiol. Nonepileptic myoclonic jerks in patient 17 improved on clonazepam.Neurology.org).A broad range of other neurologic symptoms was observed, including hypotonia in 19 of 21 patients (90%); movement disorders, including choreoathetosis and dystonia, in 11 of 21 patients (52%); and spasticity in 5 of 21 patients (24%). Video recordings of the siblings 2.5 and 4.7 years of age showing their movement disorder and profound hypotonia are available (videos 1\u20133 at Mild dysmorphic features were seen in 8 of 21 patients (38%), but a consistent dysmorphic pattern was not identified. Bitemporal narrowing was found in 3 patients . Eight of 21 patients had microcephaly.Brain MRI was performed in 19 of 21 patients (90%) and was unremarkable in 10 of 19 patients (53%). Six of 19 patients (32%) had cerebral volume loss over time, which was observed as early as 2 years (patient 10). Patient 19 had delayed myelination and a thin corpus callosum.Our cohort included 3 patients with phenotypes that stood out from the overall group. Patient 2  and patient 17  did not have epileptic seizures. Patient 2 was studied at 24 months, an age when 18 of 19 patients had already had seizures. He had profound developmental delay and was nonverbal and nonambulatory; his EEG was normal. Patient 17 had profound developmental delay at 1 year. He had multifocal, low-amplitude myoclonic jerks that were shown to be nonepileptic on several EEG recordings. His EEG showed background slowing and multifocal spikes.16Patient 20  had normal development before the onset of refractory status epilepticus after a mild febrile illness at the age of 4.5 years, a phenotype consistent with febrile infection-related epilepsy syndrome.Seven of 21 patients (33%) had the recurrent p.Arg237Trp mutation and had infantile spasms with developmental delay before seizure onset, progressing to refractory epilepsy with GTCS. Five of 7 patients (71%) had prominent hyperkinetic movements, dystonic posturing of the head and limbs, and/or ataxic gait in patients who achieved independent ambulation. These clinical features were less frequent in the remainder of the patient cohort, with infantile spasms in 9 of 13 patients (69%), GTCS in 5 of 13 patients (38%), refractory epilepsy in 8 of 11 patients (72%), and movement disorder in 6 of 13 patients (46%). Taken together, the patients with the p.Arg237Trp mutation showed a relatively homogeneous phenotype compared with the overall patient cohort.Four patients were \u226516 years of age ; 2 had the recurrent p.Arg237Trp mutation (patients 8 and 10). All had multidrug-resistant epilepsy persisting into adulthood, and their phenotype did not differ from that of the overall cohort. One patient developed severe reflex seizures triggered by actions of personal hygiene such as brushing her teeth. All patients had severe intellectual disability; only one patient was ambulatory.12 Briefly, the position p.Thr65 is present in the switch I motif and coordinates a bound Mg2+ where substitution for an asparagine (p.Thr65Asn) would greatly impair GTP hydrolysis , and all affect GTP binding, hydrolysis, or stability . Two of drolysis . The p.G residue .12 This position is involved in direct contact with the bound nucleotide and likely influences its stabilization and binding. The p.Lys206Asn variant leads to a decrease in protein stability,17 suggesting GTP binding as a stabilization step.The p.Lys206Asn and p.Lys206Glu variants occur in the nucleotide specificity G4 loop of the GTPase domain and interact with the guanosine and ribose moieties of the bound GTP .12 This 18In addition, 2 other variants (p.Gly43Ser and p.Ser45Asn) result in GTP affinity perturbations. Both interact via the oxygen/phosphate backbone with the bound GDP. Point mutations at position 45 are defective in GTP binding.The p.Ala177Pro variant, found in the transstabilizing loop, introduces a severe steric clash near the p.Arg237 switching residue. The proline introduces more steric constraint and affects the dynamics of the arginine in position 237 . The p.S19Four variants are localized to the middle domain of DNM1  . They ocDNM1, encoding a key component of synaptic vesicle recycling. DNM1 initially emerged as a novel disease gene in large-scale genetic studies, but the full phenotypic and genetic spectrum has not yet been described. We show that patients with DNM1 mutations have a phenotype characterized by intellectual disability, hypotonia, and refractory epilepsy typically presenting with infantile spasms. One-third of patients had the recurrent c.709C>T (p.Arg237Trp) mutation and a homogeneous phenotype.Here, we describe the phenotypic spectrum of patients with de novo mutations in DNM1, STXBP1, STX1B, and SNAP25.20\u201322 The DNM1 protein is a key component of vesicle recycling. It is the main driver for invagination of clathrin-coated synaptic vesicles, which occurs through a process of GTP-mediated oligomeric assembly.24 The predominance of intractable epilepsies in patients with DNM1 encephalopathy reinforces the notion that in addition to disrupted synaptic vesicle fusion, disordered vesicle recycling may represent a key step in epileptogenesis.Mutations in genes encoding synaptic vesicle proteins are increasingly recognized as causal for neurodevelopmental disorders, including the epilepsies. Implicated synaptic genes include DNM1 encephalopathy is a disease of vesicle fission, and the mutations in our patient cohort cluster in 2 major functional domains of the DNM1 protein: the GTPase domain and the middle domain. Our structural modeling studies suggest a dominant-negative effect for all mutations studied. Even though all mutations are predicted to impair the process of endocytosis, the locations of the variants indicate disruptions at different stages of vesical invagination  variant, together with localization of mutations to specific domains of the protein. Characterizing DNM1 encephalopathy as a unique condition leading to an intractable epileptic encephalopathy will lay the foundation for the development of targeted therapies.We delineate the phenotypic spectrum of"}
+{"text": "To determine the early surgical outcomes of Tetralogy of Fallot (TOF) repair in children and young adults operated after the age of one year.In this retrospective study, 307 cases of primary repair of Tetralogy of Fallot were done between September 2012 to February 2017, at CPE Institute of cardiology, Multan. Out of 307 operated patients, 4 (1.3%) patients had previous modified Blalock Taussig shunts, 2 (0.6%) associated ASD with TOF, 3 (0.9%) co-association of TOF with PDA, 2 (0.6%) had large conal arterial branch crossing the annulus, 3 (0.9%) had dextrocardia with situs inversus, 12 (3.9%) TOF with double outlet right ventricle (DORV), 2 (0.6%) were associated with complete AV canal defect, 8 (2.60%) with absent pulmonary valve syndrome, 15 (5.5%) with left pulmonary artery stenosis. Data of post-operative complications and operative parameters was recorded for all patients.st surgery. Moderate to severe pulmonary valve regurgitation was diagnosed in 114 (37.1%) patients. Mild to moderate tricuspid regurgitation in 15 (4.8%) patients and moderate right ventricular outflow tract obstruction (RVOT) in 16 (5.2%) patients. Thirty-day mortality was only four (1.3%).Mean age of operated patients was 9.56\u00b14.89 years. Post-operative complications occurred in 7.8% of patients. Most common post-operative complications were pleural effusion with a frequency of 12(3.9%) patients, and complete heart block in one patient. Insignificant small residual VSD was diagnosed in 8 (2.6%) patients. One moderately large VSD was closed surgically after one year of 1Surgical correction of Tetralogy of Fallot (TOF) in children after one year carries good operative outcomes with minimum morbidity and mortality. Tetralogy of Fallot (TOF) accounts for 7-10% of all congenital cardiac defects and has only 24% 10-year survival rate if left untreated.10In developing countries like Pakistan, diagnosis of TOF is often delayed because of limited number of pediatric cardiology and pediatric cardiac surgery departments. Moreover, most of the patients of TOF are diagnosed and treated in later stages of their life, usually after the age of one year. Surgical repair of TOF in older children is associated with more operative complications e.g. bleeding, RV dysfunction, low cardiac output syndrome, arrhythmias and even mortality.In this retrospective analysis, we have shared our experience of surgical repair of TOF of 307 children operated in Ch. Pervaiz Elahi Institute of Cardiology from September 2012 to February 2017. Academic Affairs Department of CPE Institute of Cardiology, Multan approved the study protocol. Data was retrieved from the database of cardiac surgery unit of the institute. No informed consent was taken from guardians of the patients because of the retrospective nature of the study.Out of 307 operated patients, 4 (1.3%) patients had previous modified Blalock Taussig shunts, 2 (0.6%) associated ASD with TOF, 3 (0.9%) had co-association of PDA, 2 (0.6%) large conal arterial branch crossing at the annulus, 3 (0.9%) dextrocardia with situs inversus, 12(3.9%) TOF with double outlet right ventricle (DORV), 2 (0.6%) with associated complete AV canal defect, 8 (2.60%) with absent pulmonary valve syndrome, 15 (5.5%) with left pulmonary artery stenosis.A single pediatric cardiac surgeon (First Author) performed all surgeries through median sternotomy and after establishing cardio-pulmonary bypass at moderate hypothermia. Blood cardioplegia was used to arrest the heart after application of cross-clamp. In 45 (14.6%) patients, surgical repair was done through trans-atrial approach. In rest of cases, we used a combined approach . Infundibular resection was done in all patients. Pulmonary valvotomy with transannular extension was done in patients with small pulmonary valve annulus. In cases of doubly committed sub-arterial ventricular septal defect (DCSA VSD), VSD closure was done by a combined approach through right atrium and pulmonary artery. In patients with left pulmonary artery stenosis, left pulmonary artery was augmented with autologous pericardial patch. In patients with narrowing of pulmonary annulus, trans-annular pericardial patch was applied. Out of two Patients with large conal branch crossing annulus of PV, repair was done with limited transanular extension in one patient and resection of RVOT through right atrium in another.In double-outlet right ventricle (DORV) cases, intra-ventricular tunnel was created by using PTFE graft to commit the left ventricle to aorta. In patients with absent pulmonary valve, pulmonary arteries reduction plasty were done along with pulmonary valve placement by inserting bioprosthetic valve of appropriate size.In patients of TOF with complete AV canal defect, AV canal was repaired using two patch technique along with routine repair of TOF.Criteria for classification of severity of RVOT was;Mild RVOT: pressure gradient 20-40 mmHgModerate RVOT: pressure gradient 41-70 mmHgSevere RVOT: pressure gradient >70 mmHg.Death within 30 day after surgery was labelled as operative mortality. Detailed Morphology of pulmonary valve is given in Out of 307 patients, 230 (74.9%) were male. Mean age of operated patients was 9.56\u00b14.89 years. Peri-membranous VSD was predominant and present in 260 (84.6%) patients .Post-operative complications occurred in 7.8% patients. Most common post-operative complication was pleural effusion that occurred in 12 (3.9%) patients, and complete heart block that occurred in one patient in whom permanent pacemaker was inserted.st surgery.Residual VSD was diagnosed in 10 (3.25%) patients. Out of these 10, 9 VSDs were tiny or small and one was moderate. One moderate VSD was closed surgically after one year of 1Moderate to severe pulmonary valve regurgitation was observed in 114 (37.1%) patients. Moderate tricuspid regurgitation in 15 (4.8%) patients and moderate right ventricular outflow tract obstruction in 16 (5.2%) patients. No postoperative left ventricular outflow obstruction was observed in patients with DORV repair.Only 4 (1.3%) patients expired within 30 days after surgery, 2 (0.6%) of these deaths were due to severe post-operative RV dysfunction, one due to post-operative pneumonia and one due to FFP transfusion related reaction. These patients are under follow up of pediatric cardiologists for onset of cardiac symptoms and any change in echocardiographic finding regarding RV function or RVOT gradient.Tetralogy of Fallot (TOF) in grown up children is still a common presentation in developing countries like Pakistan but in developed countries, it has now become a very rare presentation. And most of the patients of TOF are operated below the age of one year and even at six months. In this study, we have presented our results of repair of TOF in patients of age more than one year at the time of surgery.Vohra et al. concluded that results of late repair of TOF are comparable to early surgery but late repair is associated with increased intensive care unit stay, mechanical ventilation time and inotropic requirements.In our study, the mean duration of ICU stay was 44.12+29.85 hours. In the study of Cabral et al. mean ICU stay of patients was five days,Regarding post-operative complications, the most common complication was pulmonary regurgitation (PR), the incidence of moderate to severe PR was (37.1%). In a study by Khan et al., postoperative incidence of PR was 25%.The results of our study are comparable to the results of other international studies. And from these studies we concluded that late repair of TOF after the age of one year results in good outcomes and hence improved quality of life in these patients.The main limitation is the descriptive design of this study because we did not have the data to compare our results with TOF repair in patients having age less than 1 year. However, we have compared our results with international studies to check the adequacy of the outcomes of our study.Surgical correction of Tetralogy of Fallot (TOF) in children after one year carries good operative outcomes with minimum morbidity and mortality.TW: Conceived, designed the research methodology, prepared this manuscript and is accountable for the originality of the research work.MUR and TM: Did data analysis, helped in writing the manuscript and reviewed the manuscript."}
+{"text": "Enterobacteriaceae and 6 (14%) produced carbapenemase. The high prevalence of multidrug-resistant gram-negative bacteria raises concerns about the empiric treatment of patients with sepsis in Yangon.Among 42 gram-negative bloodstream isolates from inpatients in 3 hospitals in Yangon, Myanmar, admitted during July\u2013December 2014, 16 (38%) were extended-spectrum \u03b2-lactamase\u2013producing  Enterobacteriaceae (CRE) have been reported worldwide (Infections with extended-spectrum \u03b2-lactamase (ESBL)\u2013producing gram-negative bacteria and carbapenem-resistant All bacteria had been isolated at the microbiology laboratories of 3 hospitals in Yangon during July\u2013December 2014. During the study period, 592 blood cultures were processed, 536 from Yangon General Hospital (YGH) and 56 from 2 private hospitals. YGH is a 2,000-bed tertiary referral and teaching hospital in Yangon, providing free hospital care to civilians. The 2 private hospitals have 350 and 100 beds and provide secondary-level medical and surgical services to paying patients. Of the 592 blood cultures, 42 (7.8%) yielded gram-negative bacteria, 28 (67%) from YGH and 14 (33%) from the 2 private hospitals. No clinical information was available about the patients from whom the cultures were taken. The identity and antimicrobial drug susceptibility of isolates were confirmed at Southern Community Laboratories  by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry , disc diffusion testing using the Clinical and Laboratory Standards Institute method  and by comparison with known \u03b2-lactamase gene sequences.We conducted phenotypic confirmation of ESBL production on cefpodoxime-resistant isolates using cefotaxime and ceftazidime with and without clavulanic acid and that of carbapenmase production on meropenem-resistant isolates by modified Hodge test according to Clinical and Laboratory Standards Institute criteria  and 8 (19.0%) were nonfermenting gram-negative bacilli. Of the Enterobacteriaceae, 20 (59%) were multidrug resistant (MDR), with resistance to >3 classes of antimicrobial drugs, and 7 (21%) were extensively drug resistant, with susceptibility to <2 classes of antimicrobial drugs  gene, sequenced as NDM-4 in 5 (83%) and NDM-7 in 1 (17%).Of the 42 isolates, 34 (81%) were olymyxin . PhenotyE. coli isolates and 43% of K. pneumoniae isolates produced ESBLs. This finding is consistent with the high proportion of ESBL production reported in isolates from India (>80%), China (>60%), and other Asia and Southeast Asia countries (>30%) (E. coli and 43% in K. pneumoniae) in this study was comparable to those previously reported from clinical isolates in India  of 6 K. pneumoniae isolates produced either an ESBL or carbapenemase; among these, 3 (20%) of 15 E. coli and 3 (50%) of 6 K. pneumoniae isolates were NDM producers.Two thirds of all isolates included in this study originated from YGH, the largest public hospital in Myanmar. All CRE isolates and 14 (88%) of 16 ESBL producers were isolated from YGH; this may reflect a higher prevalence of colonization with MDR organisms among patients in YGH or they may be healthcare-associated infections. Of concern, at YGH 11 (73%) of 15 Enterobacteriaceae at YGH were susceptible to treatment with colistin, an empiric treatment regimen of meropenem plus gentamicin would have covered only 18 (78%) isolates. This finding highlights the difficulties with designing an effective empiric antimicrobial regimen for patients with suspected gram-negative sepsis in a setting of a high prevalence of antimicrobial resistance, without providing further selective pressure for the spread of CRE and the emergence of colistin resistance.Whereas all 23 (100%) of the Our study has limitations. First, clinical data were not prospectively collected, and it was not possible to obtain data retrospectively because of poor recording systems. Second, we cannot be certain that study isolates represent the population of organisms causing gram-negative sepsis in Yangon. However, the high proportion of ESBL- and carbapenemase-producing gram-negative bacteria among bloodstream isolates from hospitalized patients in Yangon raises concern for the treatment of patients with gram-negative sepsis and suggests a need to reduce selective pressure and control the spread of resistant organisms."}
+{"text": "To determine the clinical outcome of burr-hole aspiration of brain abscess.We analyzed 100 cases of intracranial abscess, treated surgically from January 2015 and October 2016 at Jinnah Postgraduate Medical Centre (JPMC). All patients were treated with burr hole aspiration. Medical records were analyzed for demographics, clinical presentation, predisposing factors, abscess location on imaging and clinical outcomes were charted.The study included 100 patients with 73 (73%) males and 27 (27%) females with a mean age of 36.69\u00b110.96 years. Mean duration of signs and symptoms was 8.50\u00b14.2 days. The most common presenting complaint was altered sensorium in 70 (70%) patients and commonest source of infection was otitis media seen in 27 patients (27%). The GCS on presentation was 13 in 57 (57%) cases. The parietal region was the most common site in 43 patients (43%), followed by frontal region in 33 patients (33%). Complete resolution of abscess with recovery of preoperative neuro-deficit was seen in 77 (77%) patients and recovery with major neuro-deficit was observed in 10 (10%) cases while 13 (13%) patients expired.Early diagnosis, optimum follow-up and timely burr-hole aspiration are the keys in the proper management of brain abscess. Brain abscess is infrequent but potentially life-threatening infection. It involves a focal, intraparenchymal collection of pus4Brain abscess is more common in developing countries with an incidence of 8% compared to 1-2% in Western countries and poses a public health challenge.8The common presenting features are headache, vomiting, fits, fever, focal deficits and impaired consciousness.The study was conducted in the department of neurosurgery at JPMC, Karachi from January 2015 to October 2016, with Institutional Review Board (IRB) approval. One hundred patients were included in this study with ages between 13 to 65 years. Patients with deep-seated or infratentorial abscess, multiple and multiloculated abscesses, recurrent abscess and patients \u2264 12 years old were excluded from the study. Deep seated lesions were managed conservatively if small or aspirated stereotactically.All patients underwent burr-hole aspiration followed by intravenous antibiotics regimen. Significant residual abscess as greater than 50% of original volume (assessed pre operatively) found on postoperative imaging, were reaspirated. Patients were kept on empirical antibiotic regimen till availability of culture reports that was continued after discharge for a total of 12 weeks with six weeks intravenous and six weeks oral therapy. In all of our patients, we have given steroids which were tapered over two weeks. Anti-epileptics were given to all our patients with frontal and temporoparietal abscesses.st month and then at three months. All information was recorded in proformas.Data was collected on the participant\u2019s age, sex, presenting complaints, duration of sign & symptoms, various predisposing factors, location of brain abscess on imaging (CT scan/MRI brain) & outcomes of brain abscess in terms of clinical improvement and mortality. Repeat CT was performed on first postoperative day, one week after surgery and at three months to assess the residual volume of the abscess. Patients were followed up for total of three months at one week, fortnightly for 1Data was analyzed using SPSS version 21. All the data were expressed as mean \u00b1 SD (standard deviation) and percentage (%), as appropriate. The statistical significance of differences between the values was assessed by Chi square test and p value of < 0.05 was considered statistically significant.Among 100 patients, 73 (73%) patients were male and 27 (27%) were female. The ages varied from 15 to 63 years with a mean of 36.69 \u00b110.96 years. Altered sensorium was the most common presentation in 70 (70%) patients, followed by headache in 63(63%) . The durThe commonest location for abscess was the parietal region in 44 patients (44%) followed by frontal in 33(33%), temporal 13 (13%), and occipital regions in 10 (10%). Forty patients (40%) had no residual abscess on post operative CT while 17(17%) patients had significant residual abscesses that were re-aspirated. The remaining 43 patients (43%) had minimal residual abscesses and were managed conservatively . CompletBrain abscess presents with symptoms and signs depending upon its localized and generalized effects. In Gadgil et al. study, presenting complaints at the time of presentation included headache in 14 patients (42%), nausea or vomiting in six (18%), altered mental status in 11 (33%), visual complaints in five (15%), and seizures in three (9%).The common predisposing factors of a brain abscess are Chronic suppurative otitis media (CSOM), congenital cyanotic heart disease, and paranasal sinusitis.13Immunosuppression due to disease or therapy is emerging as an important risk factor for the development of brain abscess.19Brain abscess can occur anywhere in the brain for which CT and MRI brain are the diagnostic tools to confirm its exact location. The most common location for the abscess was the frontal lobe in 24 patients 47.1%) followed by parietal (29.4%), temporal (13.7%), and occipital regions (9.8%) as similar to findings stated by Brook..1% follo14In addition to antibiotic therapy, early surgical intervention fastens recovery provides early improvement in clinical symptoms. The procedure involves performing an initial craniotomy followed by drainage or aspiration of the contents of the abscess or surgical excision. However, inadequate aspiration or drainage is a common failure for deep-seated brain abscesses. The role of image guided surgery is now on the rise. Minimally invasive image-guided keyhole aspiration of cerebral abscesses using per operative neuronavigation with CT or MR guidance are the new alternatives or using stereotaxy. The advantage is decreased intraoperative blood loss, operative duration, and length of incision.In a study by Meng et al.In our study, complete resolution of abscess with recovery of preoperative neuro-deficit was seen in 77 (77%) patients and recovery with major neuro-deficit was observed in 10 (10%). Mortality in our study was 13% which is comparable to Chowdhury et al. studyIt is a single center study with short follow up. Larger trials with comparison of newer image guided procedures are needed but burr hole aspiration remains a viable option especially in emergent settings and in centers where latest imaging facilities are not available.Brain abscess can lead to death of the patient if it is not managed timely. It has excellent results if it is operated in time with proper cover of antibiotics and regular follow-up.LR conceived and designed the study.SA did statistical analysis and editing of manuscript.AA did data collection and manuscript writing.RR did review and final approval of manuscript."}
+{"text": "Escherichia coli (STEC) are important pathogens of global significance. STEC are responsible for numerous food-borne outbreaks worldwide and their presence in food is a potential health hazard. The objective of the present study was to determine the incidence of STEC in fresh seafood in Mumbai, India, and to characterize STEC with respect to their virulence determinants.Shiga toxin-producing E. coli were isolated from 39 fresh seafood samples (18 finfish and 21 shellfish) using culture-based methods. The isolates were screened by polymerase chain reaction (PCR) for the genes commonly associated with STEC. The variant Shiga toxin genes were confirmed by Southern blotting and hybridization followed by DNA sequencing.A total of 368 eaeA (coding for an intimin) and hlyA (hemolysin A) were detected in 43 and 15 seafood isolates, respectively. The variant stx1 genes from 6 isolates were sequenced, five of which were found to be stx1d variants, while one sequence varied considerably from known stx1 sequences. Southern hybridization and DNA sequence analysis suggested putative Shiga toxin variant genes (stx2) in at least 3 other isolates.One or more Shiga toxins genes were detected in 61 isolates. Of 39 samples analyzed, 10 (25.64%) samples harbored STEC. Other virulence genes, namely, stx1d in STEC. This is the first report of stx1d gene in STEC isolated from Indian seafood.The results of this study showed the occurrence of STEC in seafood harboring one or more Shiga toxin genes. The detection of STEC by PCR may be hampered due to the presence of variant genes such as the  Escherichia coli have historically been considered as an indicator of fecal contamination of water and food. More than 700 serotypes of E. coli have been identified and majority of these are non-pathogenic commensals of the human and animal gastrointestinal tract .-27.E. costx2 amplicons obtained with 12 E. coli isolates were subjected to Southern hybridization to determine if they contained Shiga toxin gene sequences. A biotin-labeled probe was prepared using stx2 PCR product from the reference strain USFDA (serotype O157:H7) using Biotin DecaLabel DNA labeling kit . PCR products were separated on a 1.5% agarose gel and Southern blotted onto a positively charged nylon membrane  in an alkaline condition [The non-specific ondition , and hybondition . Followistx1 genes derived in this study have been deposited in GenBank under accession numbers KR632986, KR632985, KR632984, KR632983, and KR632982.The nucleotide sequences of E. coli isolates by biochemical tests and PCR. A total of 10 (25.64%) seafood samples were positive for STEC which comprised 3 fish and 7 shellfish samples  analyzed in this study. When the numbers of isolates from different selective agars were compared, of 368 isolates from seafood samples, 258 (70%) were from SMAC, and 110 (30%) were from HiCrome agar suggesting that SMAC allowed better isolation of E. coli from seafood compared to the chromogenic agar. Further, of 368 E. coli isolates 208 (56.5%) were from fish and 160 (43.5%) were from shellfish.Of 670 isolates screened from 39 samples finfish and shellfish, 368 (54.9%) were confirmed as  samples . E. colistx1 and stx2 genes detected Shiga toxin genes in 61 isolates. Further, seven STEC isolates which included 4 isolates from clams  and 3 from oysters  were among those which yielded specific amplicons with common primers  was obtained using different combination of primers stx1F-PA and BGRID . It was hypothesized that isolates could be harboring sequence variants of Shiga toxin genes which were not amplifiable by existing primers [stx genes using a different pair of stx common primers, MK1 and MK2  consistently yielded faint amplification with stx2 primers stx2F-FA and stx2R-FA [stx2 PCR product of O157:H7 reference strain. The stx2 PCR product of SEHC3 reacted with the probe suggesting the presence of stx2 sequence  seafood samples  and two selective agars (SMAC agar and HiCrome O157:H7 EC agar) were used. Both the selective agars contained antibiotics as selective agents. Pathogenic strains of E. coli occur in very small numbers in a background of large number of other related enterobacteria which may outgrow the pathogenic E. coli when less selective media are used. However, these two selective agars varied with respect to the number of E. coli isolated on them, with SMAC yielding 70% and HiCrome O157:H7 agar yielding 30% of all the isolates of E. coli obtained in this study.The presence of ronments . Since a samples . For thestx1 and stx2 (44.5% of strains), stx2 alone (44.5%) and stx2 and hlyA (19%) [stx genes and were mostly of non-O157 serotypes [Several studies in the past two decades have reported the prevalence of STEC in different types of foods including seafood in India. The first report on the isolation of STEC from India was from non-diarrheic animal sources . STEC weyA (19%) . StudiesyA (19%) . In thisyA (19%) . Seafooderotypes . A studyerotypes . These sE. coli harbored one or more Shiga toxin genes. No single primer pair was able to detect stx genes in all isolates of this study. Sequencing and Southern hybridization were performed to detect stx gene sequences in cases of ambiguity. Nucleotide sequencing enabled detection of stx2 gene sequences in 7 STEC isolates (SST1-SST7) from a fish sample  which consistently yielded faint amplification with stx2 primers stx2F-FA and stx2R-FA [stx2 gene by Southern hybridization using biotin-labeled polynucleotide probe. The stx2 PCR product of SEHC3 reacted with the probe suggesting the presence of stx2 sequence  isolates, while stx2c and stx2d were found in 8 (24.24%) and in 2 (6.06%) isolates, respectively [stx gene in STEC isolates from the animal stool, meat, and human illness reported the presence of stx1d gene [stx1c gene from beef samples of Mangalore, India [stx1c-positive isolates lacked eaeA and hlyA genes [stx1d variant genes in seafood from India.Previous studies from India have shown the presence of in India . Of 187 ectively . A studyx1d gene . Kumar ee, India . These syA genes . The preE. coli with pathogenic potentials such as the STEC is of great concern. As seen in this study, seafood isolates of STEC are very diverse in contrast to clinical isolates which are more or less homogenous. The presence of diverse genotypes of STEC in seafood may be attributed to diverse sources of contamination of seafood. Since some of the virulence genes such as stx and hlyA are phage or plasmid encoded, dissemination of virulence genes in the aquatic environment may result in the emergence of more virulent strains of pathogens. Further, based on the PCR and sequencing results of this study, it may be hypothesized that more variants of Shiga toxin genes may exist in the environment in the region of this study. Probe hybridization and sequencing will help to identify the variant Shiga toxin genes in seafood associated STEC.The results of this study proved the occurrence of STEC in fresh seafood and also STEC with variant Shiga toxin genes. The presence of SK conceived and designed the experiments; SP and PP performed the experiments. SK, BBN, and ML collectively planned and supervised the experiments and analyzed the data. All authors read and approved the final manuscript."}
+{"text": "To assess the biological variability of clinical meaningful molecular markers and their clinical correlations in Chinese patients with colorectal cancer (CRC).In this prospective observational study, frequencies and clinico-pathological features of RAS and BRAFV600E mutations, deficiency of DNA mismatch repair (dMMR) were evaluated in patients with colorectal cancer staged I-IV. The molecular heterogeneity between right-sided and left-sided colorectal cancers was studied in our series by classifying patients with different mutations and dMMR status.Among 400 evaluable patients, mutations in KRAS exon 2, exon 3 or 4, NRAS and BRAFV600E were detected in 36%, 7.5%, 3.5% and 2.5%, respectively. RAS mutations were significantly higher in metastatic CRCs  and right-sided CRCs . In 212 RAS wild-type patients, V600E mutation was higher in older patients , women  and right-sided CRCs . dMMR was detected in 7.75% of all stages of CRCs, with the highest dMMR rate of 40% in stage II right-sided colon cancer.By assessing the mutations and clinical correlations of RAS and BRAF genes, and dMMR status, similar RAS mutation, dMMR frequency and lower BRAF mutation was observed in Chinese patients compared to western patients. A distinct molecular heterogeneity was found between patients with right-sided and left-sided CRCs. Colorectal Cancer (CRC) is a significant cause of cancer-related morbidity and mortality globally. It is the third most common malignancy in China, and the incidence and mortality rates are continuing to rise in recent years. It has been recognized that colorectal cancer is a biologically heterogeneous disease. The carcinogenesis and development involve distinct pathways, which may result in inactivation of tumor suppressor genes and DNA mismatch repair (MMR) genes or activation of oncogenes , 2. In rAmong the heterogeneous genetic alterations in colorectal cancer, the rat sarcoma viral oncogene (RAS) mutation, V-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation and DNA mismatch repair deficiency (dMMR) are the main molecular phenotypes studied most extensively and widely applied in clinical circumstances. The molecular features and association of MMR, RAS and BRAF mutations in colon cancers with prognosis have been reported in previous studies. Although the majority of CRCs show chromosomal instability, approximately 15% of cancers develop via an alternative pathway characterized by defective function of the MMR system. These CRCs are known as dMMR tumors, whereas most CRCs have proficient MMR (pMMR). Colon cancers with dMMR have distinct clinical and pathological features, including tumor site, differentiation, treatment response and survival, etc. The Kirsten rat sarcoma viral oncogene (KRAS) mutation status in codon 12 or 13 of exon 2 has been reported in approximately in 40% of patients with metastatic CRC, and recognized as a predictive marker of resistance to EGFR-targeted antibodies in colorectal cancers. Recently, studies have shown that other KRAS (exon 3 or 4) and NRAS mutations are present in another \u223c11% of patients, and also associated with resistance to anti-EGFR therapy [In this study, we evaluated the frequencies and clinic-pathological characteristics of RAS mutation, BRAF mutation and DNA mismatch repair expression in Chinese patients with sporadic stage I-IV colorectal cancers, and studied the molecular heterogeneity of patients with different tumor site.Of the 400 enrolled patients, 29.5% of patients presented with synchronous metastases, and 31 patients (7.8%) with locally advanced rectal cancer underwent preoperative chemoradiotherapy. The clinicopathological characteristics were shown in Table We detected dMMR in 31 (7.75%) by IHC analysis for MMR proteins expression. Of the 31 dMMR cancers, 29 cases were found to have either loss of MLH1 or MSH2 protein expression; 3 cases had loss of MSH6 expression, all accompanied by loss of MSH2 expression; 5 cases had loss of PMS2 expression, which were accompanied in 3 cases by loss of MLH1 expression. The prevalence of dMMR status was 12.6% (28 patients) of 223 patients with colon cancer, while only 3 (1.7%) out of 177 patients with rectal cancers were detected dMMR status.The frequency of dMMR in patients with stage I-IV CRC is listed in Table Of all 400 patients, 212 patients (53%) had no mutation in KRAS or NRAS gene (RAS wild type). Mutations in KRAS exon 2 (codons 12 or 13) were detected in 144 patients (36%), and mutations in KRAS gene exon 3 and 4 were detected in 30 patients (7.5%); mutations in NRAS gene  were detected in another 14 patients (3.5%). The frequency of all RAS mutation was 47%. The details of mutant exons and codons are shown in Figure In stage I-III patients, mutation rates of KRAS exon 2 and extended RAS mutations were 32.7% and 10.3%; in stage IV patients, mutation rates of KRAS exon 2 and extended RAS mutations were 43.7% and 12.6%. In patients with stage I-III disease, RAS mutation was not related to tumor stage, with the mutations rates were 38.5% in stage I, 42.4% in stage II and 44.6% in stage III, respectively. Univariate analysis found that primary tumor site (right-sided vs. left-sided) and distant metastases (M1 vs. M0) were significantly related to RAS mutation status (Table BRAF mutation (V600E), was mutually exclusive with RAS mutation, and was only detected in 10 patients, which is 2.5% of all patients and 4.7% of 212 patients with RAS wild type. In 212 patients with RAS wild type, BRAF mutation was found significantly related to older age  and female patients , and the BRAF mutation was higher (approaching significance) in right-sided CRC than left-sided CRC .In our series, we classified the patients into five subgroups with different molecular alterations: RAS WT & pMMR (46.8%), RAS MT & pMMR 43.0%), BRAF MT (2.5%), RAS WT & dMMR (3.8%) and RAS MT & dMMR (4.0%). A distinct molecular heterogeneity was observed between patients with right-sided CRC and left-sided CRC . The phenotype is characterized by right-sided location, mucinous cell type and presence of tumor infiltrating lymphocytes. In our study, we also confirmed similar clinicopathological characteristics of colon cancer with dMMR in Chinese patients with sporadic CRCs.vs. 43% of RAS mutation in stage I-III). Roth et. al reported that KRAS exon 2 mutation was related to tumor grade and MSI status in stage II-III colon cancers [The RAS gene is often mutated in metastatic CRC and the most common of these being KRAS gene mutation. Studies have reported \u223c40% of KRAS exon 2 mutation in metastatic CRC, and an additional 10-15% of mutations were detected when extended to all RAS mutation, including KRAS exon 3, 4 and NRAS exon 2, 3, 4 . In non- cancers , but RASBRAF V600E mutation Is associated with poor prognosis in patients with mCRC and resistance to conventional chemotherapy, while the prognostic effect of BRAF V600E in non-metastatic CRC remains controversial , 11, 12,It has long been reported that there are differences in patients' demographic, clinico-pathological features and tumor biology between right-sided and left-sided CRCs , 19. UntThere were limitations of our study. The survival outcomes haven yet to be obtained, and so any correlation between the molecular heterogeneity and patients' survival remains unknown. The limited case numbers is another limitation to the detailed analysis of differences betwee different stages. However, our study further confirms the biological variations of CRCs between different races.Between May 2014 and November 2015, 400 evaluable patients (screened from 431 patients) with sporadic colorectal cancers were prospectively but non-consecutively collected for molecular analysis in the Department of Colorectal Surgery, Fudan University Shanghai Cancer Center. All study patients underwent surgical resection of their primary tumors in our institution. Reasons for excluding 31 patients included hereditary colorectal cancer (15 cases), unavailable tissue for genetic testing (11 cases) and non-adenocarcinoma lesions (5 cases).This study was reviewed and approved by local Institutional Review Boards. All patients gave informed consent for the use of their cancer tissue blocks for molecular analyses.The IHC assay for the MMR proteins expression was performed using the fully automated BenchMark ULTRA platform  using a comprehensive panel of four primary antibodies, including MLH1 (M1), MSH2 (G219-1129), PMS2 (EPR3947) and CONFIRM MSH6 (44) antibodies . Nuclear staining of normal tissue next to the tumor or lymphocytes in the stroma served as internal positive controls. In tumors, dMMR was interpreted as follows - loss of an MMR protein (MLH1 or MSH2 or PMS2 or MSH6) expression was defined as the absence of nuclear staining of tumor cells. Each slide was examined by at least two experienced pathologists.Areas of tumor-rich were scraped from 5-\u03bcm unstained serial sections after confirmation by hematoxylin and eosin-stained slides. Extraction of genomic DNA was carried out using the QIAamp DNA Mini Kit following the manufacturer's protocol . DNA content was quantified using NanoDrop ND-1000 .DNA samples were amplified for regions of KRAS exon 2, 3, and 4, NRAS exon 2, 3, and 4, and BRAF exon 15 by polymerase chain reaction (PCR) using the Real-time PCR master mix . PCR reactions with the primers listed in chi-square test in univariate analyses. Multivariate analysis was performed using logistic regression and the odds ratios were recorded. P value <0.05 was considered statistically significant.The clinicopathological correlations of dMMR, RAS mutations and BRAF mutation were analyzed by Our study assessed the mutation of RAS genes and BRAF gene, dMMR and their clinical correlations in Chinese patients with colorectal cancers. Similar RAS mutation and dMMR frequencies were found in Chinese patients as compared to what has been observed in Western patients, while the frequency of BRAF mutation was lower in Chinese patients. A distinct molecular heterogeneity was found between patients with right-sided and left-sided CRCs. Future studies are required to further understand the mechanism of this biological variability."}
+{"text": "TP53 mutations were found to be significantly more common in DLBCL with MYC translocations . While no gene mutation was found to be more prevalent in patients with DLBCL with bone marrow involvement, MYD88 mutations were more common in primary DLBCL of the CNS or testis. To evaluate the prognostic significance of the abnormalities of these 27 genes, a total of 165 patients with newly diagnosed DLBCL, NOS were included in a multivariate survival analysis. Surprisingly, in addition to the TP53 mutation, CD58 mutation was found to predict poor clinical outcome. Furthermore, copy number loss of CD58 or TP53 was also identified to be an independent negative prognostic factor. Our results have uncovered the previously unknown critical impact of gene mutations on the prognosis of DLBCL and are fundamentally important for the future design of tailored therapy for improved clinical outcomes.The advent of next generation sequencing (NGS) technologies has expedited the discovery of novel genetic lesions in DLBCL. The prognostic significance of these identified gene mutations is largely unknown. In this study, we performed NGS for the 27 genes most frequently implicated in 196 patients. Interestingly,  Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL), accounting for more than 30% of all newly diagnosed NHL . AlthougMYC translocation and/or amplification are poor prognostic factors, independent of the IPI status [MYC+ DLBCL has highlighted the profound impact of molecular aberrations on clinical management for an improved clinical outcome [To date, predictors for the risk stratification of DLBCL include clinical prognostic factors, staging and evaluation of the response to therapy by positron emission tomographic scans (PET-CT), gene expression profiling (GEP) and molecular prognostic factors \u20135. The II status \u20139. The c outcome .TP53 mutation is an independent negative prognostic biomarker in DLBCL [For the past several years, the advances in high-throughput sequencing technologies have made it possible to characterize DLBCL at the whole genome level rather than by using a candidate gene approach. The application of targeted next generation sequencing (NGS) to DLBCL has already yielded many important discoveries in an unbiased and comprehensive manner. The identification of structural alterations and corresponding deregulated signaling pathways has unveiled an unprecedented understanding of DLBCL pathogenesis that will provide invaluable preclinical rationale for a more precise treatment of DLBCL. On the other hand, the biological and prognostic significance of these gene mutations on DLBCL is largely unknown. Previously, several studies have convincingly shown that the in DLBCL . With deIn this study, we performed NGS for the 27 genes most frequently implicated in 196 patients with newly diagnosed DLBCL. A total of 165 patients with newly diagnosed DLBCL, NOS were included in a multivariate analysis to identify the gene mutations having independent prognostic value. Our results have uncovered the previously unknown critical impact of some gene mutations on the prognosis of DLBCL and are fundamentally important for the future design of tailored therapy for improved clinical outcome.A total 196 patients with DLBCL and 6 reactive lymph node samples were successfully analyzed by NGS for the 27 genes most frequently implicated in DLBCL in previous studies , 13. ComFor NGS, each individual sample library was established and sequenced on an eight-lane PicoTiterPlate (Roche) after confirmation of its quality. PIM1 gene were detected in 53 cases (27.04 %),MLL2 in 38 (18.39 %), FAT4 in 34 (15.9 %), TP53 in 29 (14.80 %), CD79B in 29 (14.80 %), MYD88 in 27 (13.78 %), PKD1 in 19 (9.69 %), CARD11 in 17 (8.67%), 2M\u03b2 in 16 (8.16 %), TNFAIP3 in 14 (7.14 %), CIITA in 14 (7.14 %), IRF4 in 12 (6.12 %), MYC in 11 (5.61 %), BCL-6 in 11 (5.61 %), CD58 in 10 (5.10%) and EP300 in 10 (5.10%). The remaining 12 genes, including CD83, BRAF, PRDM1, IRF8, BCL-2, MYOM2, MEF2B, EZH2, PDL2, PDL1 and TNFSF9, had a mutation rate less than 5% , of which 11.73 % were MYC amplification (23/196) and 7.14% MYC translocation (14/196). Among the 14 patients with MYC translocation, 3 cases were shown to concurrently harbor BCL-2 translocation (double hit). When the patient cohort was annotated according to MYC gene amplification and translocation, TP53 mutations were found to significantly correlate with MYC translocations  but not amplification. In DLBCL with MYC translocation, 42.86% patients (6/14) harbored a TP53 mutation, of whom, 2 cases had BCL-2 translocation. In contrast, in DLBCL without MYC translocation, only 11.5% cases (21/182) were detected to harbor TP53 mutation.Among the 196 DLBCL patients, mutations of the % Figure . OverallFAT4 (23.5%), PIM1 (17.6%), CARD11 (17.6%) and MYD88 (17.6%). However, no prevalent gene mutation was detected in this subgroup compared to all the other DLBCL, NOS cases. In our series of 16 patients with primary DLBCL of the CNS or testis, FAT4 mutation exhibited a lower frequency in primary DLBCL of the CNS or testis compared with all the other DLBCL patients analyzed (P = 0.055). Somatic mutations in PIM1 , CD79B  and MYD88  were the most prevalent aberrations. Notably, all 5 MYD88 mutation cases are L265P, which is consistent with the observation of Yamada et al [MYD88 were significantly more frequent in primary DLBCL of the CNS or testis than that of all the other DLBCL, NOS cases  (P = 0.034). In addition to 5 MYD88 mutation cases, 1 more case was detected to have deletion of MYD88 and no copy number gain was found in patients with primary DLBCL of the CNS or testis. To observe the correlation of MYD88 mutations with the activation of associated BCR signaling pathway, the surrogate nuclear factor-\u03baB (NF-\u03baB) and P38-MAPK antigens in primary biopsies were analyzed by immunohistochemical (IHC) staining. The cases with MYD88 L265P showed significantly elevated NF-\u03baB activity compared with wild-type cases . The MYD88 mutation cases also exhibited increased P38-MAPK activity in contrast to MYD88 wild-type cases (P = 0.037).MYC cytogenetic aberration (including translocation and amplification), cell of origin (COO) determined by IHC assessment were selected as candidate parameters. The selected parameters were analyzed by the log-rank test to identify potential prognostic variables related to PFS or OS. The result of the univariate analysis is summarized in Table P = 0.019, P = 0.04, respectively) and bone marrow involvement  were significantly associated with both shorter PFS and OS. Patients with non-GCB subtype had significantly worse PFS (P = 0.033) and OS (P = 0.024) than those with GCB subtype. Ann Arbor stage and MYC aberration were significantly associated with poor PFS  and a non-significant trend towards shorter OS . Elevated LDH was associated with a non-significant tendency towards poor PFS (P = 0.112) and OS (P = 0.059). Interestingly, either of CD58 or TP53 gene mutation was a significant poor prognostic factor for both PFS  and OS   and mutation parameters  for further analysis in a multivariate model. Notably, Ann Arbor stage, bone marrow involvement or MYC cytogenetic aberration was no longer a significant poor independent prognostic factor in the Cox regression model. However, COO as well as B symptoms were found to be an independent factor predicting shorter PFS and OS. Multivariate analysis revealed that poor PFS and OS were present in patients with the TP53 mutation . Interestingly, CD58 mutation was significantly associated with a high risk of progression  and shorter OS   and progression-free survival (PFS) Figure . The mut) Figure . In agreCD58 and TP53 genes in 196 patients with DLBCL. The TP53 gene is a crucial tumor suppressor that acts by transcription-dependent activity (TA) and transcription-independent activity (TIA) in the nucleus and cytoplasm, respectively [TP53 dysfunction has been implicated in lymphomagenesis and disease progression, and either of the normal function of TA and TIA of p53 is crucial for tumor suppression. The DNA-binding domain (DBD) of p53 is the most important domain for its TA and TIA2 [e.g., COSM44656, COSM12005). We observed that exons 4-7 of TP53 were most often mutated  methods based on protein sequence homology. Over 90% missense mutations were predicted to be deleterious (i.e. disrupt the p53 function). Nonsense mutation (n = 1) and frameshift-inducing insertions and deletions (n = 3) led to the production of truncated proteins, indicating a deleterious effect. To examine the functional consequences of TP53 mutations, we analyzed p53 expression in DLBCL biopsy. IHC for p53 revealed that p53 overexpression to be associated with mutational status (P < 0.001). Most tumors with TP53 mutation were shown to express the protein at an elevated level , whereas we detected an elevated p53 expression in fewer tumors with wild-type TP53 (n = 3/23)   . Survivactively) .CD58 gene occurred in DLBCL, NOS. Half of the mutations (n = 5/10) were nonsense mutations (n = 2) and frameshift insertion/deletions (n = 3) that resulted in aberrant transcripts encoding for truncated proteins, all of which lacked the CD58 transmembrane domain  methods. Furthermore, the effect of the in-frame deletions (n = 2) on CD58 protein were predicted to be deleterious using PROVEAN software (http://provean.jcvi.org/seq_submit.php). To confirm the impact of these mutations on CD58 protein, IHC analysis of DLBCL biopsy was performed. Among the cases with CD58 mutation, 80% (n = 2/10) exhibited negative protein expression, while only one wild type sample showed loss of CD58 surface protein expression (n = 15)  , participating in their adhesion and activation . In our n Figure . The mis(n = 15) . Patientctively) . These rCD58 and TP53 gene mutation in the poor prognosis of DLBCL, we investigated the association of CD58 and TP53 copy number variants with the prognosis of DLBCL. Copy number variations of CD58 and TP53 in 196 DLBCL samples were analyzed based on read-depth information and heterozygous sites. A normalized distribution of the mean depth ratio with standard deviation for the CD58 or TP53 gene was generated based on NGS data derived from 203 samples (including 6 reactive lymph node samples and 1 duplicate DLBCL sample). To determine whether a sample had a loss or gain of copy number for a given gene, the depth ratio of the sample was compared with the normalized mean depth ratio of all 203 samples. As shown in CD58 or TP53 genes, was successfully identified. The results showed that copy number loss of TP53 was detected in the majority of cases (16/18), whereas copy number gain of TP53 was found only in 2 out of 18 cases. Considering that both gene mutation and copy number loss of TP53 as well as CD58 would lead to loss of function of these genes, we define both types of gene aberrations as a TP53 or CD58 abnormality. Among patients with TP53 mutations (n = 29) or copy number loss (n = 16), 2 cases were found to simultaneously harbor a TP53 mutation and loss of copy number. Therefore, the total frequency of TP53 abnormalities was detected in 21.94% of cases of DLBCL. When the patient cohort was further annotated according to MYC gene amplification and translocation, no significant correlation was found between copy number loss of TP53 and MYC translocation or amplification . Copy number loss of CD58 occurred in the majority of cases (14/21), whereas gains occurred in fewer cases (7/21). Interestingly, almost all instances of copy number loss and CD58 gene mutations occurred in patients with DLBCL, NOS . Among patients with CD58 mutation (n = 10) or copy number loss (n = 14), two cases were found to simultaneously harbor CD58 mutation and loss of copy number. Therefore, the total frequency of CD58 abnormalities was detected in 12.22% of patients with DLBCL, NOS. To address whether copy number loss of CD58 or TP53 was prognostic, copy number loss of the CD58 or TP53 gene was entered into previous prognostic models as a new potential parameter for further analysis. In univariate analysis  than those without copy number loss. CNV of CD58 was significantly associated with poor PFS (P = 0.002) and a non-significant trend toward shorter overall survival compared with patients without copy number loss of CD58 (P = 0.11). Therefore, copy number loss of CD58 or TP53 was chosen in multivariate model analysis. When adjusted in multivariate Cox regression analysis, independent prognostic factors included COO, B symptoms, CD58 or TP53 mutations and copy number loss of CD58 or TP53. The results of the initial analysis of independent prognostic factors associated with either PFS or OS are shown in Table TP53 was found to be an independent unfavorable prognostic factor for both PFS  and OS . Patients who had copy number loss of CD58 were found to have an independent adverse impact on PFS .In addition to gene mutation, copy number variation (CNV) is another common type of genetic variation. Given the important involvement of PIM1, MLL2, FAT4, TP53 and CD79B, which is consistent with previous reports [MYOM2, PRDM1 and MEF2B, exhibited relatively low mutational incidences in this study compared with those reported by Morin et al [In this study, we performed NGS for 27 genes most frequently implicated in 196 cases of newly diagnosed DLBCL followed by validation using Sanger sequencing. In general, the mutated frequencies of the examined genes were comparable to those reported previously. The most frequently mutated genes identified in our cohort were  reports , 13, 18.MYC cytogenetic aberrations had been reported in 10\u201315% of DLBCL patients, which was generally taken as an independent indicator of poor prognosis [MYC translocation  has remained controversial due to the limited studies with conflicting conclusions [MYC cytogenetic aberrations, of which 11.73 % was MYC amplification and 7.14% MYC translocation. Interestingly, DLBCL with MYC translocation was found to have a significantly higher frequency of TP53 mutation. Numerous studies have demonstrated that MYC abnormalities alone are not sufficient for lymphomagenesis [MYC. The presence of TP53 mutation would likely serve as the secondary event by promoting proliferation and survival of lymphoma cells. Notably, Gebauer, et al had recently performed NGS to investigate the mutational status of TP53 in double hit lymphoma (DHL) and correlated genomic data with immunohistochemical reactivity for p53. They identified TP53 mutations are frequent events in MYC+/BCL-2+ lymphomas. Their findings are very consistent with our clinical data and strongly support our conclusion [MYC translocation with TP53 mutation argues that the presence of MYC cytogenetic aberrations per se may not be the most accurate prognostic factor. Other concurrent cytogenetic aberrations such as BCL-2,BCL-6 translocation as well as TP53 mutation should be simultaneously determined to provide more precise risk stratification when using MYC cytogenetic aberrations as biomarkers.Previously, rognosis \u201310. Neveclusions , 20. In agenesis , 22. Othnclusion . This prPIM1 and the regulators (MYD88 and CD79B) of NF-\u03baB pathway were the most frequently mutated genes, which are consistent with the recent data of Bruno et al [MYD88 mutation in primary DLBCL of the CNS or testis was significantly higher than previously reported studies in the whole DLBCL series ranging from 6.5% to 19.3% but similar to the observation in ABC-DLBCL (39%) [MYD88 has also been recurrently found mutated in majority of lymphoplasmacytic lymphoma (> 90%) [MYD88 L265P with survival in primary DLBCL of the CNS or testis remained unclear, although a worse outcome was raised in DLBCL, NOS. Furthermore, MYD88 L265P mutation cases were found increased activity of associated BCR signaling pathway in primary DLBCL of the CNS or testis. The findings that mutation of MYD88 was almost three times more common in primary DLBCL of the CNS or testis than that detected in DLBCL, NOS and the activation of associated BCR signal pathway in MYD88 mutation cases suggested that MYD88 might be a potential target in primary DLBCL of the CNS or testis.In the current study, mutational profiles were examined in special entities of DLBCL, including DLBCL with bone marrow involvement as well as DLBCL in immune-privileged sites (CNS and testis). In the present study, the BM infiltration was detected in 11.1% of patients with DLBCL, NOS 20/180). No significant difference in mutational frequencies of 27 genes was found between the DLBCL subgroups with or without BM involvement. In primary DLBCL of the CNS or testis, the cell cycle regulator no et al . The pre0. No sigCL (39%) \u201327. MYD8 (> 90%) , 29. TheTP53 and CD58 abnormalities as independent unfavorable prognostic factors based upon a stepwise regression multivariate analysis. The frequency of TP53 mutation was in agreement with previous reports (10\u201323%), while the incidence of TP53 deletion was lower than previously reported as determined by FISH [TP53 mutation in DLBCL has been consistently associated with a poorer clinical outcome among different studies, while the data regarding and the influence of TP53 deletion on prognosis has remained controversial [The most significant finding in the present study was the identification of  by FISH . TP53 muoversial \u201332.TP53 deletion. In this study, copy number loss of TP53 was defined using NGS-based analysis which takes the subclone loading into account. In a multivariate analysis, copy number loss of TP53 was an independent unfavorable predictor of PFS and OS. Nevertheless, a standardized cut-off should be explored in future studies for routine clinical practice. In our patient cohort, the frequency of CD58 mutation detected was in agreement with a previous report, while the rate of CD58 deletion was lower than that reported elsewhere [2M\u03b2, CIITA and CD83, were common in our study, only CD58 abnormality showed prognostic significance. Interestingly, CD58 deletion predicted a poor PFS but only a non-significant trend toward a shorter overall survival (P = 0.11), which is possibly due to a short period of follow-up. These findings strongly support the critical roles of both the adaptive and innate immune evasion in lymphoma prognosis.The conflicting results might be related to inter-observer variability and to differences in methodology and criteria in defining lsewhere . NotablyTP53 or CD58 deletion was independent unfavorable predictor of clinical outcome in a multivariate analysis are encouraging enough to warrant a prospective study of these biomarkers.The accurate detection of somatic CNV is an essential part of cancer genome analysis. Current approaches to identify gene CNVs usually employ cytogenetic technologies, such as karyotyping, FISH and single-nucleotide polymorphism (SNP) array , 34. On Formalin-fixed paraffin-embedded (FFPE) diagnostic biopsies of 235 patients with DLBCL between July 2005 and December 2013 were retrospectively collected from TongJi Hospital and Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences Medical Centers. These tissue samples had been obtained prior to any chemotherapy or radiotherapy. Patient samples were selected based on the following criteria: (1) diagnosis of DLBCL clinical stages I to IV; (2) having completed standard first-line chemotherapy recommended by NCCN; (3) at least 14 years of age at diagnosis; (4) availability of FFPE blocks of the diagnostic biopsies for DNA extraction. Cases were excluded if patients had a history of low grade B-cell lymphoma. The diagnosis of DLBCL for these patients was based on the morphological and immunohistochemical examination of biopsy material according to the WHO classification criteria and confirmed by two hematopathologists. Samples of 6 patients with reactive hyperplastic lymphadenitis were collected as negative controls. Appropriate informed consent was obtained from all donors prior to specimen collection in accordance with the Declaration of Helsinki and under a research protocol approved by the ethics committees of Tongji Hospital and Blood Diseases Hospital, Chinese Academy of Medical Sciences Medical Centers.Genomic DNA was extracted from 3 to 5 \u03bcm thick FFPE sections of these patients with DLBCL and reactive hyperplastic lymphadenitis using the QIAamp DNA FFPE Tissue Kit (Qiagen) following the manufacturer's instructions. The tumor involvement in the FFPE sections was assessed to be at least 90% based on morphology and immunohistochemistry. The concentrations of DNA samples were measured using a NanoDrop spectrophotometer (Thermo Fisher Scientific) and the quality of DNA samples was examined by gel electrophoresis. Eleven samples of DLBCL were excluded due to poor DNA quality (n = 10) or misdiagnosis (n = 1).www.ampliseq.com) to target 27 candidate genes, including 2M, BCL2, BCL6, BRAF, CARD11, CD58, CD79B, CD83, CIITA, EP300, EZH2, FAT4, IRF4, IRF8, MEF2B, MLL2, MYC, MYD88, MYOM2, PDL1, PDL2, PIM1, PKD1, PRDM1, TNFAIP3, TNFSF9 and TP53\u03b2 which are frequently implicated in previous studies [Somatic mutations of selected samples from 224 patients with DLBCL and 6 reactive lymph nodes were identified by next-generation sequencing (NGS) using Ion AmpliSeq technology based on the Ion Torrent PGM platform (Life Technologies). For the detection of somatic mutations, a custom Ion AmpliSeq panel was designed using Ion AmpliSeq designer  based on staining of biomarkers including CD10, BCL-6 and MUM1 was performed to classify DLBCL patients into GCB and non-GCB subtype according to the Hans algorithm. To define bulky disease, we used a maximum diameter of the involved sites \u2265 10 cm. The performance status was assessed using ECOG criteria. The treatment response was assessed after 4 cycles of chemotherapy and classified as Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progressive Disease (PD) according to the International Working Group criteria. DLBCL cases suspected of BM involvement by lymphoma on BM smears were confirmed by bone marrow biopsy, immunohistochemistry and flow cytometry analysis. Primary DLBCL of the CNS (n = 9) or testis (n = 7) were diagnosed based on biopsy pathology and radiographic examination according to WHO classification criteria.log-rank test. All variables with a P value <0.05 in the univariate analysis were included in a stepwise regression multivariate analysis. The Cox model and the generalized Akaike Information Criterion (AIC) in a stepwise algorithm were used to determine hazard ratios (HRs), CIs and whether a variable was an independent prognostic factor for DLBCL. OS and PFS curves of different groups were analyzed using the Kaplan-Meier method. An association was considered statistically significant if P<0.05. All statistical analyses were carried out using free R software (ver. 3.1.1) with the survival, rms, MASS, DMwR, rpart packages along with some base packages.The \u03c72 test, Fisher's exact test and Pearson's correlation were used to determine the correlation between subgroups of patients according to their gene mutational status. Overall survival (OS) was measured from the date of diagnosis to the date of death from any cause, or the latest follow-up. Progression-free survival (PFS) was determined from the date of diagnosis to the date of the first relapse or disease-related death or latest follow-up. To identify potential prognostic factors, the univariate comparison of OS and PFS was made. Differences were assessed using the"}
+{"text": "The 1999 cessation of vaccination against adenovirus types 4 and 7 among US Army trainees resulted in reemergence of acute respiratory disease (ARD) outbreaks. The 2011 implementation of a replacement vaccine led to dramatic and sustained decreases in ARD cases, supporting continuation of vaccination in this population at high risk for ARD. In the past, febrile acute respiratory disease (ARD) was a major cause of illness among military members, especially those in initial entry training (IET [basic training]), a physically and mentally demanding 6- to 12-week program  vaccine began in 1971 and eventually included year-round vaccination, resulting in plummeting ARD rates , partnering with the Naval Health Research Center  Febrile Respiratory Illness (NHRC FRI) Surveillance Program, demonstrated substantial increases in ARD cases, specifically adenovirus-associated ARD. These cases cost \u2248$10\u2013$26 million each year in medical care and lost recruit time  \u00d7 100 trainee weeks, and used SPSS version 21  for analyses.We studied aggregate data from 2010\u20132014 from the ARD-SP and NHRC FRI programs. The Army Public Health Center collected weekly ARD-SP data from the Army\u2019s 4 IET sites . ARD case criteria were oral temperature An ongoing program of year-round administration of AdV-4 and -7 vaccine at Army IET sites began in November 2011. Overall, ARD rates decreased in November 2011 (9% from 2010 rates) and each subsequent year through 2014 . HoweverPrior to implementation of the new vaccine in 2011, adenovirus type 4 was the predominant type at all training sites (86%), followed by types 3 (7%) and 7 (5%). After the reintroduction of adenovirus vaccine, most (71%) adenovirus-positive specimens from 2012\u20132014 were positive for adenovirus types 1 and 2 . HoweverReintroduction of AdV-4 and -7 vaccine had a profound effect at all Army IET sites; the combined ARD rate decreased from 0.43 cases/100 trainee weeks in 2010 to 0.06 cases/100 trainee weeks in 2014 (p<0.001), and adenovirus was identified only sporadically in ill trainees. Although a low level of ARD activity, caused by many different agents, has persisted since reestablishment of the vaccine program, the vaccine has effectively controlled the major cause of ARD at IET sites at the low cost of $150/trainee . In addition to the US military, populations in those and similar settings may benefit from AdV-4 and -7 vaccine ("}
+{"text": "Purpose. Since laparoscopic hepatectomy (LH) became covered by national health insurance in April 2010 in Japan, the numbers of applied cases and institutions performing it have increased and the indication has expanded. We surveyed the current state and safety of LH in Japan. Methods. A questionnaire survey was performed in 41 institutions related to the Japanese Endoscopic Liver Surgery Study Group and 747 institutions certified by the Japanese Society of Gastroenterological Surgery, and responses concerning all 2962 cases of LH performed by August 2011 were obtained. Results. The surgical procedure employed was hemihepatectomy in 234 (8%), segmentectomy in 88 (3%), left lateral segmentectomy in 434 (15%), segmentectomy in 156 (5%), and partial resection in 1504 (51%) cases. The approach was pure laparoscopy in 1835 (63%), hand-assisted laparoscopic surgery in 201 (7%), and laparoscopy-assisted surgery in 926 (31%). Regarding perioperative complications, surgery was switched to laparotomy in 59 (2.0%), reoperation was performed in 4 (0.1%), and surgery-related death occurred in 2 (0.07%). Intraoperative accidents occurred in 68 (2.3%), and postoperative complications developed in 94 (3.2%). Conclusions. When the selection of cases is appropriate, LH for liver diseases can be safely performed. Laparoscopic hepatectomy (LH) was initially performed to resect a benign liver tumor by Reich et al. in 1991 . Based oIn Japan, since LH was initially applied for liver cancer by Hashizume et al. in 1995 and Kaneko et al. in 1996, cases resected by LH have occasionally been reported \u20139. The 4The questionnaire survey has been performed by the Japanese Endoscopic Liver Surgery Study Group since 2009, and this was the 4th survey. The questionnaire was sent by post mail to 41 institutions related to the Study Group and 747 institutions certified by the Japanese Society of Gastroenterological Surgery. The subjects of the survey were all patients who underwent the first laparoscopic hepatectomy at the institutions by August 31, 2011.Four hundred sixty-four institutions (59%) responded to the questionnaire, 113 (14.3%) of these perform LH, and the total number of cases was 2962.The treated disease was hepatocellular carcinoma in 1840 cases (62%), metastatic liver cancer in 762 (26%), intrahepatic cholangiocarcinoma in 50 (2%), other malignant tumors in 27 (1%), hemangioma in 55 (2%), liver cyst in 129 (4%), and other benign diseases in 172 (6%) . The surThe surgical procedure of systematic resection was unilateral lobectomy in 234 (26%), and the approach employed for this unilateral lobectomy was Hybrid-LH in 187 (37%) and Pure-LH in 41 (18%). The number of cases treated with lateral segmentectomy was 434 (48%), being the largest, and the approach was Hybrid-LH in 259 cases (60%). By the disease (HCC and Meta), systematic resection of HCC was performed employing unilateral lobectomy in 91 (16%), segmentectomy in 347 (63%) (including 286 cases (52%) of lateral segmentectomy), and subsegmentectomy in 110 (20%). Of the 286 cases of lateral segmentectomy-treated HCC, the approaches were Pure-LH and Hybrid-LH in 150 (52%) and 122 (43%), respectively. Of the 92 lateral segmentectomy-treated Meta cases, Pure-LH and Hybrid-LH were employed in 77 (84%) and 6 (7%), respectively .Partial resection was performed employing Pure-LH in 986 cases (66%), HALS in 129 (9%), and Hybrid-LH in 389 (26%). The resected region was S6 in 374 (25%), S3 in 315 (20.9%), and S5 in 204 (14%) .Regarding perioperative complications, the procedure was switched to laparotomy in 59 cases (2.0%), reoperation was performed in 4 (0.1%), and surgery-related death occurred in 2 (0.07%). Intraoperative accidents occurred in 68 (2.3%) (hemorrhage in 39 (1.3%) and hypercapnia in 1 (0.03%)). Postoperative complications developed in 94 (3.2%) (hemorrhage in 8 (0.3%), liver failure in 2 (0.07%), bile leakage in 15 (0.5%), thoracicoabdominal fluid in 24 (0.8%), wound infection in 18 (0.6%), liver abscess in 9 (0.3%), hypercapnia in 1 (0.03%), and ileus in 2 (0.07%)) . By the Of the 113 institutions performing laparoscopic hepatectomy which responded to the questionnaire, the annual number of hepatectomy-treated cases (including laparotomy) was 101 or more in 13 institutions (11%), 51\u2013100 in 28 (25%), 31\u201350 in 25 (22%), 11\u201330 in 30 (27%), and 10 or fewer in 12 (11%) .The intraoperative pneumoperitoneum pressure was 12\u2009mmHg or higher in 8 institutions (7%), 10\u201312\u2009mmHg in 29 (26%), 8\u201310\u2009mmHg in 71 (63%), and lower than 8\u2009mmHg in 2 (2%) .LH was partially covered by national health insurance in April 2010 in Japan, and partial resection and lateral segmentectomy are covered, in which the numbers of cases and institutions performing these may be increasing. The questionnaire survey has been performed since 2009 when the Japanese Endoscopic Liver Surgery Study Group was established, and this was the 4th survey. The first and second surveys were performed in institutions related to the study group , 8, but HCC and Meta cases accounted for 60 and 25%, respectively, and HCC cases decreased and Meta cases increased from those in the previous survey   and 863 (30%) of all cases, respectively, these were employed in 398 (43.6%) and 472 (51.8%) cases of systematic resection and 986 (65.6%) and 389 (25.9%) of partial resection, respectively, showing that Hybrid-LH tended to be selected for systematic resection and Pure-LH tend to be selected for partial resection .When systematic resection employing each surgical procedure was analyzed by the approach in HCC and Meta cases , while uPartial resection was performed under complete laparoscopy in 986 cases (66%), and this rate did not change in the HCC and Meta cases. The most frequently resected region was S6  followed by S3  and S5 . When these cases were divided into HCC and Meta, the most frequently resected region was S6 followed by S3 and S5, showing the same order. S6, S3, and S5 are located in the marginal region on the liver foot side considered to be relatively easy to resect, and the findings were as expected. On the other hand, partial resections of S7 and S8 on the dorsal liver head side are considered relatively difficult to resect, but these were performed in 109 (7%) and 167 (11%) cases, respectively, not being markedly low. S1 was resected in 12 (0.8%), showing the lowest rate. Although this region is not necessarily difficult to resect, its resection tended to be avoided, possibly because the visual field is restricted .Regarding perioperative complications, the procedure was switched to laparotomy in 59 (2.0%), reoperation was performed in 4 (0.1%), and surgery-related death occurred in 2 (0.07%). No marked change from those in the previous survey  than thaThe intraoperative pneumoperitoneum pressure was 12\u2009mmHg or higher in 8 institutions (7%), 10\u201312\u2009mmHg in 29 (26%), 8\u201310\u2009mmHg in 71 (63%), and lower than 8\u2009mmHg in 2 (2%). Attention should be paid to it even in laparoscopic hepatectomy because gas embolism by carbon dioxide entering through the hepatic vein is problematic, but carbon dioxide embolism as an intraoperative accident has been reported to be rare in Western countries . ComplicThe mortality was as low as that in the previous survey, and it was much lower than that in Western countries . Not all"}
+{"text": "Cardiac magnetic resonance imaging (cMRI) has recently emerged as a new noninvasive imaging modality that offers superior structural and functional assessment of the heart. cMRI benefits from a large field of view but, consequently, may capture incidental extracardiac findings (IEFs). We aimed to evaluate the frequency and significance of IEFs reported from clinically indicated cMRI scans. 742 consecutive patients  referred to the Cardiac Magnetic Resonance Center of our University Hospital between January 2015 and December 2016 for clinically indicated cMRI were retrospectively enrolled for the evaluation of IEF prevalence and relevance. The median age of the subjects was 51 years (range: 5\u201385 years). A significant number of patients who underwent cMRI had incidental and clinically significant IEFs . cMRI allowed a correct diagnosis in 116/131 cases with a diagnostic accuracy value of 88.5%. IEFs on cMRI are not uncommon and lesions with mild or no clinical significance represent the most frequent findings. cMRI can characterize incidental findings with high accuracy in most cases. Cardiac magnetic resonance imaging (cMRI) has recently emerged as a new noninvasive imaging modality capable of providing high-resolution images of the heart in any desired plane view, without radiation exposure. cMRI consists of several techniques that can be performed separately or in various combinations during a patient's examination. Most frequent indications for cMRI are myocarditis/cardiomyopathies, risk stratification in suspected coronary artery disease/ischemia, and assessment of myocardial viability , 2 and cSignificant parts of neck, thorax, and upper abdomen are imaged at the time of routine clinical cMRI, particularly in the initial multislice axial and coronal images. A careful observation of the surrounding structures may therefore often identify during cMRI incidental extracardiac findings (IEFs) . IEFs ca742 consecutive patients  referred to the Cardiac Magnetic Resonance Center of our University Hospital  between January 2015 and December 2016 for clinically indicated cMRI  were enrCMR examinations were all interpreted by both a radiologist and cardiologist experienced in cMRI. The diagnosis of IEF was made upon images and always included in the report.All incidental findings discovered on cMRI were characterized by means of additional imaging techniques: ultrasound (US), computed tomography (CT), dedicated MR examination, bone scintigraphy with technetium 99m-methylene diphosphonate (99mTC-MDP), and positron emission tomography-computed tomography (PET-CT).IEFs were classified into three categories: (1) findings with mild or no clinical significance, (2) findings with possible clinical significance, and (3) clinically significant findings. The overall prevalence and the sites of extracardiac findings were evaluated and reported.Written informed consent was obtained from all patients; the study was held according to the principles of the Declaration of Helsinki.CMR protocols were based on standardized protocols recommended by the Society for Cardiovascular Magnetic Resonance (SCMR) and the European Society of Cardiology (ESC) Working Group EuroCMR, respectively .CMR was performed using a 1.5\u2009T magnet  with a cardiac phased-array receiver coil with cardiac gating. The standard protocol included multiplane steady-state free precession (SSFP) localizers, transversal T1-TSE black blood, sequences cine steady-state free precession (SSFP) oriented 2, 3, 4 chamber and short axis for the study of the kinetics of the right and left ventricles, T2 short-tau inversion recovery (STIR) black blood for the study of myocardial oedema in short axis and 4 chamber, dynamic sequence T1-TFE in short axis, Phase-contrast to study valvular flow, Phase Sensitive Inversion Recovery (PSIR) sequences for the study of late gadolinium enhancement (LGE) performed after 10\u201315 minutes after intravenous administration of gadolinium (0.1\u2009mmol/kg). Field of view (FOV) of CMR sequences is the determining factor for the highlight of the exhibits around the heart and it is standard according to the international protocols.Continuous variables were reported as mean \u00b1 standard deviation or median and interquartile range, dichotomic as percentages.The median age of the subjects was 51 years (range: 5\u201385 years). Incidental findings were found in 109/742 (14.7%) of examined patients for a total of 131 IEFs; of these, 52 (40%) were intrathoracic and the remaining 79 (60%) were located in upper abdomen. 15 out of 131 incidental findings (11%) were confirmed to be clinically significant, while in the remaining 116 findings 87 were considered to be of mild or no clinical significance (66%); 29 were considered to be of possible clinical significance (22%) based on patient's clinical condition .Of the 131 collateral findings, 15 in 15 patients  were classified as significant and deserving further diagnostic work-up: mediastinal lymphadenopathy/mass (6/15), lung nodule/mass (3/15), aortic coarctation (2/15), breast nodule (1/15), complex renal cyst (1/15), hepatic mass (1/15), and solid renal mass (1/15). Findings with possible clinical significance (29/131) were present in 22 patients : pleural effusion/thickening (9/29), thyroid goitre (6/29), gallbladder lithiasis (5/29), airspace disease (4/29), splenomegaly (2/29), hydronephrosis (2/29), and adrenal nodule (1/29). IEFs with mild or no clinical significance were found in 72 patients : simple renal cyst (31/87), hepatic cyst (24/87), hiatal hernia (8/87), hepatic haemangioma (8/87), thyroid nodule < 1\u2009cm (7/87), bone haemangioma (3/87), paraspinal cyst (2/87), and splenic cyst (1/87) .The most common site of IEFs' localization was the kidney , followed by liver , lung , and thyroid . The lesions found in spleen, pleura, and gallbladder resulted to be with mild or possible clinical significance in all cases and no further diagnostic work-up was deemed necessary. Lung lesions resulted to be malignant in all cases including metastases in 2/3 and lung cancer in 1/3 of cases. Only one of 33 (3%) focal liver lesions resulted to be a metastatic hepatic mass. Two out of 35 (6.7%) kidney lesions resulted to be malignant including 1 case of complex renal cyst and 1 case of renal cell cancer. In two other cases of kidney lesions (6.7%), we observed unilateral hydronephrosis caused by kidney stones, as confirmed by additional imaging. Comparing MR findings with the additional definitive imaging tools, cMRI allowed a correct diagnosis in 116/131 cases with a diagnostic accuracy value of 88.5%. In particular, a lung mass was misdiagnosed as a cancer by cMRI, while it was shown to be a pulmonary atelectasis on chest CT examination.A new/previously unknown diagnosis was made in 74% of cases with IEFs. The most informative sequences for IEFs were surveys , that is, the initial locating sequences in the three planes of space which allow a global view of neck, chest, and abdomen, 90% of IEFs. Further relevant sequences for details were morphological sequences T1-TSE and T1-Fat Sat before and after contrast imaging (5%) and T2-STIR (5%).cMRI is a highly reproducible tool to assess myocardial morphology as well as global and regional heart function. It also provides relevant information regarding tissue characteristics such as viability, myocardial perfusion, storage diseases, and inflammation. cMRI is thus increasingly used in daily practice .In cMRI examinations, a careful assessment of noncardiac structures may also detect relevant noncardiac diseases. The wide FOV used to perform axial/coronal SSFP and BB-FSE sequences at the beginning of the CMR examination allows exploring surrounding cardiac structures including the lungs, upper abdomen, and thoracic spine. This enables detecting possible IEFs that could be clinically significant or require further diagnostic work-up . Few stuIn the present study, images (and not cMRI reports) were analyzed in order to assess the incidence of IEFs. According to Klysik et al. , in our In the present study, clinically significant extracardiac findings were observed in 2% of the population (11.4% of cases), which is consistent with previous studies that reported similar prevalence for \u201cmajor\u201d IEFs during cMRI (range: 1\u201327%) . The moscMRI may be extremely useful in characterizing these incidental findings, with an excellent diagnostic accuracy (88.5%), although further imaging techniques are often necessary to precisely define incidental findings. In particular, CT and fluorodeoxyglucose PET-CT (FDG PET-CT) scan are the first choice to characterize and discriminate the nature of incidental lung parenchymal lesions. Ultrasound (US) or dedicated MRI may be used to further evaluate abdominal and breast lesions. Finally, in all cases of incidental bony lesions, MR with dedicated sequences or bone scintigraphy may improve the characterization of IEFs.A significant number of IEFs can be detected during cMRI, with high accuracy. It is therefore extremely important that whoever reports cMRI should be able to properly assess normal and abnormal thorax and superior abdominal findings. IEFs should be searched, for potentially modifying the clinical management of patients with such findings."}
+{"text": "Rickettsia, designated Rickettsia sp. XY99. Clinical signs resembled those of severe fever with thrombocytopenia syndrome.Only 4 species of spotted fever group rickettsiae have been detected in humans in China. However, phylogenetic analysis of samples from 5 ill patients in China indicated infection with a novel spotted fever group  Rickettsia slovaca (R. aeschlimannii (R. massiliae (Candidatus Rickettsia tarasevichiae (R. sibirica subspecies sibirica BJ-90 (R. parkeri was confirmed to be pathogenic 65 years after its detection in ticks in 1939 (Spotted fever group (SFG) rickettsiae are globally distributed and mostly transmitted by ticks  have been detected in human blood samples  have been detected in ticks, urging a wider search for cases in humans. We report infection of 5 patients with a novel SFG rickettsia in eastern central China.In China, SFG rickettsioses are not listed as reportable diseases, and only 4 species of SFG rickettsiae (ompA) and citrate synthase (gltA) genes were concurrently performed to detect SFG rickettsial DNA (<7 days after illness onset) and convalescent-phase (>14 days after illness onset) serum samples were tested by indirect immunofluorescence assay (IFA) for IgG against R. rickettsii by using a commercially available IFA kit .From March through November 2015, at the People\u2019s Liberation Army 154 Hospital in Xinyang City, Henan Province, China, patients who were acutely symptomatic with fever and had a history of tick bites or animal contact within the past month were screened for SFG rickettsiae infection. At admission, EDTA-anticoagulated samples of peripheral blood were collected. DNA was extracted by using a QIAamp DNA Blood Mini Kit . Nested PCRs selective for outer membrane protein A  of ompA gene (GenBank accession no. KU853020) from each of the 5 patients showed 10-bp differences from that of R. massiliae strain AZT80 (GenBank accession no. CP003319) and 12-bp differences from that of R. rhipicephali strain HJ#5 (GenBank accession no. CP013133). Nucleotide sequences (1150-bp) of gltA gene (GenBank accession no. KU853022) from each of the 5 patients differed from that of R. massiliae strain AZT80 by 4 bp and from that of R. rhipicephali strain HJ#5 by 5 bp  and serologic tests (ELISA or IFA) produced no positive results.Positive amplification of  by 5 bp  Table 2. species . For allkettsiae  Table 3.All 5 patients were farmers who resided in the villages of Xinyang City. Patient median age was 65 (range 62\u201380) years, and 3 were male . Two patComplications included pneumonia (3 patients), hemorrhagic signs (3), hydrothorax (2), and neurologic syndromes (1). For 1 patient, severe complications progressively emerged 6 days after disease onset and included pneumonia and hydrothorax  Figure, Rickettsia sp. XY99 DNA in blood samples collected during the acute period of illness (days 3\u20136 after onset) from 5 patients in the same region of China suggests that this organism was the etiologic agent of the infection. Seroconversion or a 4-fold increase in titers of IgG against R. rickettsii provided supportive evidence of SFG Rickettsia infection. Phylogenetic analysis indicated that Rickettsia sp. XY99 was a novel genotype of SFG rickettsiae.Our detection of R. massiliae infection and many other SFG rickettsioses reported previously  are warranted, according to the guidelines for classification of a new Rickettsia species (Confirmation of the novel Rickettsia sp. XY99. It should be included in differential diagnoses with severe fever with thrombocytopenia syndrome, which causes similar clinical illness and is also endemic to the same area in eastern central China.Physicians in this area of China should be aware of human infections with Rickettsia genotype, China, 2015.Additional materials and methods used in study of Human infection with novel spotted fever group"}
+{"text": "Mycobacterium avium subsp. paratuberculosis infection in cattle has been explored as a promising population strategy We performed paratuberculosis epidemiopathogenic phenotypic and genotypic characterization involving 24 SNPs in six candidate genes  on 502 slaughtered Friesian cows. In the current study, we investigate whether recently proposed paratuberculosis (PTB) epidemiopathogenic (EP) forms  could be associated with some combination of these 24 SNPs. Best EP form grouping was obtained using a combination of 5 SNPs in four genes . These groups were defined according to the level of infection progression risk to patent epidemiopathogenic forms and showed the following distributions: LOWIN (low) with 39 (8%) cases (94.9% AF/5.1% LAT/0% PAT); LATIN (low) with 17 (3%) cases (5.9% AF/94.1% LAT/0% PAT); AVERIN (average) with 413 (82%) cases (52.1% AF/38.5% LAT/9.4% PAT) and PATIN (patent) with 33 (7%) cases (36.4% AF/24.2% LAT/39.4% PAT). Age of slaughter was significantly higher for LATIN (88.3 months) compared to AVERIN  and PATIN , and for LOWIN (73.9 months) compared to PATIN (p = 0.0233), and nearly significant compared to AVERIN (p = 0.0572) These results suggest that some selected genetic polymorphisms have a potential use as markers of PTB EP forms and thus add a new tool for the control of this widespread infection.Control of major mycobacterial diseases affecting livestock is a challenging issue that requires different approaches. The use of genetic markers for improving resistance to  If the Mycobacterium bovis detection has been viewed up to now as an unacceptable effect in eradication of tuberculosis, most bovine tuberculosis eradication programs heavily restrict its use. Although those paratuberculosis (PTB) vaccine cross-reactions could be easily differentiated in most cases by use of the EU-official comparative intradermal test (CIT)  , PTB vacNucleotide Oligomerization Domain 2 (NOD2) (Dendritic Cell-Specific ICAM-3-Grabbing Nonintegrin Dectin-1 (DC-SIGN or CD209) (Toll-like receptor (TLR) (Solute Carrier Family 11 Member 1 (SLC11A1)  gene (SP110 gene (Ipr) has been proposed to control mycobacterial replication in macrophages (Genetic Marker-Assisted Selection (MAS) has been explored after steady advances in identifying genetic effects on resistance to bovine PTB, by both specific candidate gene  and geno2 (NOD2) , Dendritr CD209) , Toll-lior (TLR)  genes, oP1) gene . Moreoverophages  and the rophages .Even so, it seems more plausible that genetic predisposition could be strongly determined by the interaction of more than one candidate gene, and even more after the recent evidence of epistasis among bovine innate immunity genes affecting susceptibility to MAP infection . HoweverIn the current study we propose to follow a similar approach to that accepted for Scrapie infections in small ruminants, in which different Scrapie risk groups are defined according to their prion protein (PrP) genotype for codons 136, 154 and 174 , in orde22.1Genotype data of the 502 Holstein-Friesian animals used in the present study belong to a previous larger study . AnimalsA more detailed description of animals (age and origin), sampling method, compliance with legislation on animal welfare, permission to collect and use the samples has been published elsewhere , 2014a,bCD209 , NOD2 , SLC11A1 , SP110 , TLR2 , and TLR4 . The SNPs were genotyped using the TaqMan\u00ae OpenArray\u00ae technology  according to the manufacturer's indications, and Autocaller v1.1 software  for allele assignation. All individuals and SNP fit the three quality control parameters used elsewhere (Genomic DNA was typed for 24 SNPs in six innate immune related genes previously associated with paratuberculosis : CD209 (lsewhere : sample 2.2-Apparently free EP form risk or low infection progression risk (LOWIN): Over 90% of individuals with this genetic profile were apparently free of infection.-Latent EP form risk or latent infection progression risk (LATIN): Over 90% of individuals with this profile showed latent forms of PTB.-Patent EP form risk or infection progression high risk (PATIN): Patent forms in this group accounted for about 40% of its individuals.The procedure of SNP selection and combination is depicted in SNP combinations that did not fit into any of the above mentioned groups assigned to a fourth group considered of an average risk of infection and named AVERIN.2.3To test whether the genetic risk groups were associated to other variables expected to be modified by PTB, an analysis of variance was run for ELISA optical density (OD) readings and positivity rate, IFN-g OD, MAP isolation frequency and age at slaughter with the GLM procedure of the SAS 9.1 statistical package. Then the risk level means were compared to the control (AVERIN) or the PATIN risk group with the Dunnett test. Statistical analyses resulting in p-values lower than 0.05 were considered to be significant.3rs210748127 (CD209), rs110090506 (SLC11A1), rs41830058 (TLR2), rs136859213 and rs110480812 (SP110) bovine genes were found to comply with the defined criteria. As result, 502 animals without any missing genotype for those 5 SNP were considered for subsequent analyses.A total of five SNPs in A total of 70 genotype combinations were built for those SNP and grouped based on the four established PTB risk levels, as shown in The LOWIN group of 39 animals was finally constituted (94.9%) by animals epidemio-pathologically defined as AF. The 17 cows included in the LATIN were 94.1% LAT forms. The PATIN was the group that had the highest rate of PAT forms, which finally accounted to 40.0% (n = 12/30). The remaining genotypes for which no higher proportions of any PTB EP form could be obtained, were defined as of average risk (AVERIN) and contained the vast majority of cases in the study (n = 416) . About 1Age of slaughter was significantly higher for LATIN (88.3 months) compared to AVERIN  and PATIN , and for LOWIN (73.9 months) compared to PATIN (p = 0.0233), and nearly significant compared to AVERIN (p = 0.0572) .4Our results seem to match what can be expected from a genetically controlled character in a population. Even simplifying into resistant and susceptible, our results show a resistant tail of about 11% (LOWIN and LATIN), and another one of susceptible animals of about 6% animals with the PATIN genotype. The remaining 83% would be a mix of animals with different degrees of resistance or susceptibility. They show a noticeable association between a series of Friesian cattle genotype combinations in several selected innate immunity genes and EP forms of PTB Tables . These fThis study is the first one to show such a definite association and we think that the main reason is the way in which the phenotypes are defined. That is, instead of looking into indirect immune variables or microbiological indicators that might be biased by the widespread presence of MAP in the cattle environments in which the bovine species is bred, we have made an attempt to look into the more direct expression of the innate immunity mechanisms of mycobacterial pathogenesis which is tissue chronic inflammation in agreement with strong recommendations for adequate definitions of disease phenotypes that are found in the literature . Even thFrom an epidemiological view, latent PTB represent a constant and unnoticed threat while patent PTB is a less prevalent form of infection, but with more adverse effects on body condition and productivity rates  of infected animals, as well as on environmental mycobacterial loads , 2014a. CD209, SLC11A1, SP110 and TLR2 genes play a pivotal role in determining risk to MAP infection epidemiopathogenic forms in Spanish Holstein-Friesian cattle. The identification of these four genes as risk markers of bovine PTB confirms previous findings in candidate gene studies  in spite of previous associations between this gene and MAP shedding for this breed  in dairy cattle breeding selection programs as an effective control strategy against paratuberculosis at an affordable cost.In conclusion, although the work reported here has substantial limitations in the number of SNPs and the sample size, that need to be validated in a more specific study, our results open the way to considering an specific combination of SNPs  (projects AGL2006-14315-C02 and RTA2014-00009), Basque Government (GV/EJ) (SAIOTEK program: SA-2010/00102), European Regional Development Fund (ERDF), and European Social Fund (ESF) is also gratefully acknowledged. Patricia V\u00e1zquez was holder of a graduate fellowship award (FPI) (BES-2007-17170) from the Spanish MINECO.This work was supported by the The authors declare no conflict of interest.No additional information is available for this paper."}
+{"text": "This study reports the assembly of a DNA barcode reference library for species in the lepidopteran superfamily Noctuoidea from Canada and the USA. Based on the analysis of 69,378 specimens, the library provides coverage for 97.3% of the noctuoid fauna (3565 of 3664 species). In addition to verifying the strong performance of DNA barcodes in the discrimination of these species, the results indicate close congruence between the number of species analyzed (3565) and the number of sequence clusters (3816) recognized by the Barcode Index Number (BIN) system. Distributional patterns across 12 North American ecoregions are examined for the 3251 species that have GPS data while BIN analysis is used to quantify overlap between the noctuoid faunas of North America and other zoogeographic regions. This analysis reveals that 90% of North American noctuoids are endemic and that just 7.5% and 1.8% of BINs are shared with the Neotropics and with the Palearctic, respectively. One third (29) of the latter species are recent introductions and, as expected, they possess low intraspecific divergences. Occupying 14% of the planet\u2019s land surface, Canada and the continental United States  span envSince its inception in 2003 , DNA barThe present study examines the impact on barcode resolution of increasing both taxon coverage and geographic scale. It examines the performance of a reference library that includes records for 97.5% of the noctuoid species known from Canada and the USA. Aside from comprehensive taxonomic coverage, the present library provides a good sense of geographic variation in many of these taxa as it is based on the analysis of nearly 70,000 specimens. Because of the comprehensive taxon coverage and large sample sizes, the present data also provide a good opportunity to test the performance of the Barcode Index Number (BIN) System \u2014an interThis study recovered DNA barcode records from 69,378 specimens; 43.1%  derived from Canada, 46.2%  from the United States, and 10.7%  from Mexico, and the Neotropical and Palearctic regions . The CanWhenever possible, specimens of each species were analyzed from across its range in North America . HoweverNorth America is often partitioned into 15 terrestrial ecoregions  2]: Arc: Arc2]: ATTCAACCAATCATAAAGATATTGG) and LepR1 (TAAACTTCTGGATGTCCAAAAAATCA) which recovers a 658bp region near the 5\u2032 end of COI including the 648bp barcode region for the animal kingdom . Of the 3671 species known from North America, 102 very rare species lack barcode coverage  are provided in = 19.46) . Only secoverage . They inTests of barcode performance were firstly made at a continental level based on the North American checklist \u20139 and suDNA barcodes were obtained for 3565 of the 3664 valid noctuoid species known from North America. No indels, frameshift mutations or stop codons were detected among the 69,378 sequences recovered from these taxa suggesting that they derive from COI rather than a pseudogene. Considered from a continent-wide perspective, 93% of all noctuoid species possess a diagnostic array of barcode sequences (including those species with deep intraspecific divergence) . Barcode2 = 38.3, p<0.0001). All species of Doidae (2 species) and Euteliidae (17 species) were unambiguously discriminated by barcode sequences, but barcode sharing in the other families ranged from 3.2% (4/125 species) in the Notodontidae to 5.1% (2/39 species) in the Nolidae, 7.1% (173/2452 species) in the Noctuidae, and 8.2% (76/931 species) in the Erebidae  for the Doidae because it was only represented by two species . There wErebidae . BarcodeErebidae .Catocala\u2013 26, Grammia\u2013 18, Cisthene\u2013 5, Haploa\u2013 5) were responsible for 71% (54 of 76 species) of these cases; the other 22 involved 10 genera with two or three species sharing the same barcode. The most striking cases of barcode sharing in this family involved Grammia  and Catocala . The 173 cases of barcode sharing among the 2452 species of Noctuidae involved 38 of its 420 genera  represented 64% (110 out of 173 species) of these cases; the other 63 cases involved 28 genera with two to four species sharing the same barcode. Nine noctuid genera showed a particularly high incidence of barcode sharing with 83% of species in Bellura (5 out of 6), 39% of Copablepharon (9 of 23), 31% of Abagrotis (12 of 39), 26% of Xestia (13 of 50), 23% of Lasionycta (10 of 43) 16% of Acronicta, 14% of Lithophane, 13% of Euxoa, and 10% of Schinia.In total, 255 of 3565 species of noctuoids (~7.1%) shared their barcode with at least one other species . Four ge0 genera . Among tAbagrotis, Acronicta, Anarta, Annaphila, Apamea, Catocala, Copablepharon, Dasychira, Datana, Euxoa, Feltia, Grammia, Hadena, Lacinipolia, Lasionycta, Lithophane, Papaipema, Schinia, Sympistis, Virbia, Zale, Zanclognatha, Xestia) included six or more species with low divergence, but with no evidence of shared sequences (except where noted above). They included seven noctuid genera with many cases of low divergence  and two erebid genera .Cases of low sequence divergence were defined as those involving two or more species with less than 1% sequence divergence, but with no evidence of sequence sharing. In total, 14.7% (525 species) of North American noctuoid species showed from 0.15% to 0.99% divergence from their NN . These sAbagrotis (four species in 11 BINs), Euxoa (ten species in 25 BINs), Grammia (six species in 18 BINs), Idia (three species in 13 BINs), Lacinipolia (eight species in 30 BINs), Sympistis (eight species in 17 BINs), Virbia (two species in 22 BINs), and Xestia (eight species in 20 BINs). One species showed exceptional diversity; specimens of Virbia ferruginosa were assigned to 18 BINs.Deep barcode divergence (>2%) was detected in 135 (3.8%) species, and another 22 species showed sufficient divergence (0.7%\u20131.99%) for their component specimens to be assigned to two or three BINs . These 1When the North American fauna was partitioned into the species assemblages from each of 12 ecoregions , barcodeIt is thought that 35 noctuoid species now found in North America are either migrants or introduced alien species were introduced from Eurasia by human-mediated transport . These sAlthough the BIN count (3816) was just 7% higher than the number of species (3565), this congruence partially reflected the counterbalancing effects of BIN splits and mergers (low-divergence and barcode sharing). In actuality, perfect correspondence between the assignment of specimens to a particular species and their placement in a unique BIN was only evident for 2711 species (76.0%). Another 157 species  were involved in splits with their members assigned to two (102 species), three (31 species), or more (24 species) BINs . AnotherRecords for 3803 BINs were examined for overlap among zoogeographical regions, an analysis which revealed that 284 (7.5%) are shared with the Neotropics while 70 (1.8%) representing 88 species are shared with the Holarctic. Two-thirds of the latter species (59 species) appear to have natural Holarctic distributions while 29 species are believed to have been introduced as a consequence of human activity.Although barcode sequences generally do not provide robust phylogenetic information beyond the species level , most geThe present study provides an average of 20\u00d7 barcode coverage for 97.3% (3565/3664) of the currently recognized noctuoid species in North America. These results indicate that 3310 of these species (92.8%) possess a diagnostic array of DNA barcodes when considered at a continental scale, while barcode resolution rises to 96.0% when examined by ecoregion. About three quarters (76.0%) of these species perfectly coincide with BIN assignments. As reported in other studies , many ofOur results reinforce earlier indications that increased geographic sampling does not seriously diminish the performance of DNA barcodes in specimen identification , 43, 44.High intraspecific divergences (>2%) were present in 135 species (3.8%) of North American noctuoids, a slightly lower incidence than the 5\u20138% reported in other Lepidoptera faunas with well-studied taxonomy , 29, 36.The incidence of barcode sharing in North America uncovered in our study varied among the 747 noctuoid genera, as just 55 genera (7.4%) were involved. Moreover, barcode sharing was highest in Erebidae (8.2%), followed by Noctuidae (7.1%), Nolidae (5.1%) and Notodontidae (3.2%). Our study revealed that 7.15% of North American noctuoid species (255/3565) share their barcode sequence with at least one other species, a pattern that can be explained at least in three ways. First, the lack of divergence may reflect such a recent split that sister taxa lack diagnostic CO1 sequences. Second, barcode sharing can reflect introgression following hybridization between species. Finally, species sharing barcode haplotypes may actually represent only a single polymorphic species as a result of over-splitting, especially in species-rich genera, commonly referred to as \u201cimperfect taxonomy\u201d . DistincOur study indicated that just 284 of 3803 BINs (7.5%) of the noctuoid BINs encountered in Canada and the USA also occur in the Neotropics. Overlap with other zoogeographic regions was even lower with 1.8% are shared with the Palearctic Region (88 species), 0.13% with the Ethiopian Region (5 species), 0.13% with the Oriental Region (5 species), and 0.02% with the Australian Region (1 species) . While tFinally, we consider the correspondence between morphospecies and sequence clusters delineated by the BIN system. The present analysis indicates the strong capacity of the BIN system to estimate species diversity (3816 BINs versus 3565 species with barcode coverage). Our analyses of deep splits suggest that more than 400 undescribed species of Noctuoidea were barcoded in this study. This result suggests the power of BIN analysis to provide rapid estimates of species diversity in poorly studied areas and little known groups, supporting the conclusion of earlier investigations , 31. ThiS1 DatasetSpecimen data  for North American species in the families Notodontidae + Doidae, Euteliidae, Nolidae, Erebidae, and Noctuidae.(XLS)Click here for additional data file.S2 Dataset(XLS)Click here for additional data file.S1 TableThe table represents barcode coverage in terms of the number of specimens analyzed and geographic coverage. Species lacking barcode data are in red.(XLS)Click here for additional data file.S2 TableForty-eight species barcoded from other nations likely share the same barcode as specimens collected in the USA. For species collected in Texas and Arizona\u2014barcodes from Mexican specimens are the best proxy, followed by Guatemala. For species collected in Florida\u2014barcodes from Cuban specimens are best, followed by those from the Dominican Republic or Puerto Rico. Nine species with barcode records from specimens collected from more distant locations  pose a greater risk that their barcode records may not match specimens from the USA.(XLS)Click here for additional data file.S3 TableList of introduced species of noctuoids in North America with the approximate date of their arrival.(XLS)Click here for additional data file.S4 TableData set for the analysis of barcode performance in the discrimination of noctuoid species from the 12 ecoregions of North America.(XLS)Click here for additional data file.S5 TableEach region designated by a numeric code: 1 Arctic (Arctic Cordillera + Tundra); 2 Boreal (Taiga + Hudson plain + Northern forests); 3 Northwestern forested mountains; 4 Marine west coast forests; 5 Eastern temperate forests; 6 Great plains; 7 North American deserts; 8 Mediterranean California; 9 Southern semi-arid highlands; 10 Temperate Sierras; 11 Tropical dry forests; 12 Tropical wet forests.(XLS)Click here for additional data file.S6 Table(XLS)Click here for additional data file.S7 TableList of North American noctuoid species without barcode coverage.(XLS)Click here for additional data file.S8 TableList of North American noctuoid species sharing a barcode haplotype.(XLS)Click here for additional data file.S9 TableList of North American noctuoid species with low sequence divergence from another taxon.(XLS)Click here for additional data file.S10 TableList of North American noctuoid species with deep intraspecific sequence divergence.(XLS)Click here for additional data file.S11 Table(XLS)Click here for additional data file.S1 Treec oxidase I gene for North American species in the families Notodontidae and Doidae.NJ tree based on sequence variation in the barcode region of the cytochrome (PDF)Click here for additional data file.S2 Treec oxidase I gene for North American species in the family Euteliidae.NJ tree based on sequence variation in the barcode region of the cytochrome (PDF)Click here for additional data file.S3 Treec oxidase I gene for North American species in the family Nolidae.NJ tree based on sequence variation in the barcode region of the cytochrome (PDF)Click here for additional data file.S4 Treec oxidase I gene for North American species in the family Erebidae (Arctiinae).NJ tree based on sequence variation in the barcode region of the cytochrome (PDF)Click here for additional data file.S5 Treec oxidase I gene for North American species in the family Erebidae (rest).NJ tree based on sequence variation in the barcode region of the cytochrome (PDF)Click here for additional data file.S6 Treec oxidase I gene for North American species in the family Noctuidae-1.NJ tree based on sequence variation in the barcode region of the cytochrome (PDF)Click here for additional data file.S7 Treec oxidase I gene for North American species in the family Noctuidae-2.NJ tree based on sequence variation in the barcode region of the cytochrome (PDF)Click here for additional data file.S8 Treec oxidase I gene for North American species in the family Noctuidae-3.NJ tree based on sequence variation in the barcode region of the cytochrome (PDF)Click here for additional data file."}
+{"text": "Trichomonas vaginalis, Candida albicans, Neisseria gonorrhea and Actinomyces) among women attending Family Health Option Kenya (FHOK) clinic in Thika.Cervical cancer is the predominant cancer among women in Kenya and second most common in women in developing regions. Population-based cytological screening and early treatment reduces morbidity and mortality associated with the cancer. We determined the occurrence of cervical precancerous changes and cervical microbial infections  diagnosis was based on Pap smear screening test and High Vaginal Swab wet preparation microscopy. Neisseria gonorrhea was diagnosed through Gram staining. Socio-demographic and reproductive health data was collected using a structured questionnaire administered to the study participants and analyzed using Epi Info version 3.5.1.This was a hospital based cross sectional study among women attending reproductive health screening clinic from November 2013 to January 2014. Cervical Intraepithelial Neoplasia (CIN) I, II, III, cervical cancer and microbial infection  participants had no history of Pap smear screening of which 84 (62.7%) were 20\u201340\u00a0years. Use of IUCDs  was associated with cervical inflammation.Of the 244 women screened, 238 (97.5%) presented with cervical inflammation, 80 (32.8%) cervical microbial infections and 12 (4.9%) cervical precancerous changes; 10 (83.3%) with CIN I and 2 (16.7%) CIN II. Of the 80 cervical microbial infections, 62 (77.5%) were yeast cell and 18 (22.5%) CIN I was the predominant cervical precancerous change. There is need to scale up cervical screening test to capture all categories of women. Cervical cancer is a leading cause of morbidity and mortality among women of the reproductive age especially in low resource limited countries. Widespread screening programs, a catalyst for early detection and management of cervical precancerous changes, significantly reduce cervical cancer incidence . HoweverThe recommended cervical cancer screening age is from 25\u00a0years and re-screening period is every 5 years except for at risk population [This was a hospital based cross-sectional study carried out in FHOK Clinic in Thika town. The clinic serves a wide urban and peri-urban population across Kiambu County, Muranga County as well as neighboring outskirts of Nairobi County. The facility is recognized as a centre of excellence in female reproductive health services along with an established quality assured Pap smear screening program.To calculate the sample size, we used a prevalence of 50% estimated by Fisher and Van Belle  as no prStudy participants were consenting women aged 15\u00a0years and above seeking Pap smear test at the health facility from November 2013 to January 2014 who had not taken antibiotics within 72\u00a0h before study enrollment.Candida infection, actinomyces and cervical precancerous changes using Cervical Intraepithelial Neoplasia (CIN) reporting system. High vaginal swabs were processed for wet mount and Gram stain [Trichomonas vaginalis infection was indicated by microscopic observation of motile trichomonads in wet mount, Gram negative diplococci signified gonorrhea infection and presence of pseudohyphae or hyphae or yeast buds denoted Candida albicans infection in Gram stain. Presence of more than 10 white blood cells under microscopic high-power field examination of HVS was classified as cervical inflammation. Both specimens were examined using a light microscope.Study participants were interviewed using a structured questionnaire to collect socio-demographic and reproductive health information. This was followed by collection of Pap smear and High Vagina Swab (HVS) samples. Pap smears specimens were processed and stained through the Papanicolaou staining technique  for deteam stain  examinatData generated was entered in Microsoft Excel 2010 and analysed using Epi info version 3.5.1. Univariate analyses were calculated for both the dependent and independent variables. The association between socio-demographic characteristics and stages of cervical precancerous changes and cervical microbial infections were determined using linear regression for age, age at first sex experience and number of births; Chi square for comparing inflammation among the IUCDs users and non-IUCDs users; and fishers exact for marital status, literacy level, employment status, mode of contraception and history of Pap test.A total of 244 participants were interviewed and their Pap smear and HVS specimens examined. Their mean age was 42 SD: 10.6) years, 134 (55%) had no history of previous Pap smear screening of which 84 (63%) falls within 20\u201340\u00a0years age group; 21\u201330 age group at 27% (36) and 31\u201340 age group at 36% (48). The mean age at first sexual experience was 20 (SD: 3) years, 230 (94%) parous of which 22.1% had 2 children, 159 (65.2%) were using various forms of contraceptives with Intrauterine Contraceptive Devices (IUCDs) being used by majority (23.8%) of the study participants (Table\u00a00.6 yearsFourteen 5.7%) participants presented with cervical cell abnormalities; 12 (4.9%) with cervical precancerous changes and 2 (0.8%) with viral changes. Of the 12 participants with cervical precancerous changes, 10 (83.3%) had CIN I and 2 (16.7%) had CIN II, with a mean age of 46 (SD: 8) years. Six (50%) had attained post-secondary education level, 10 (83%) were married, mean age at first sexual intercourse was 19 (SD: 2.3) years, 4 (33%) had their first sexual experience <18\u00a0years, 10 (83%) had experienced child birth with 8 (67%) having 3\u20135 children. Ten (83%) had observed the five yearly Pap smear screening recommendation in Kenya [.7% partiThere was no difference in the odds  of cervical precancerous changes in women who were married and that of non-married women . No significant association with precancerous changes was found with age, education level, employment status, age at first sexual intercourse, number of births, mode of contraception and history of Pap smear screening on the study participants.T. vaginalis infections. No actinomyces or gonorrhoea infection was identified. The distribution of yeast cell and T. vaginalis infections among study participants was statistically significant (P\u2009<\u20090.05). Among the different techniques employed in this study, HVS wet preparation had the highest positivity rate to inflammatory changes and their causes  while the prevalence of cervical microbial infection was 80 (32.8%). Of the 80 with cervical microbial infection, 62 (77.5%) were yeast cell and 18 (22.5%) were Candida and T. vaginalis were identified as cause of cervical inflammation among the study participants.We observed two levels of cervical precancerous changes; CIN I and CIN II. Cervical intraepithelial neoplasia I (mild dysplasia) was the major dysplasia (83%) observed among the study participants during the study period. This study reported a low prevalence of cervical cell abnormalities 4.9%); 83.3% 10) Low-grade cervical lesions and 16.7% (2) high-grade cervical lesions. The results are comparable to a study done at an outpatient reproductive health clinic in Pakistan whereby 4.6% (32) cases had dysplastic changes of which 56.25% (18) were LSIL and 43.75% (14) HSIL [%; 83.3%  Low-gradMore than half (55%) of the study participant were having their first ever Pap smear screening of which 36% were 31\u201340\u00a0years. This falls within the reproductive age where most of the screening interventions should be done. The Centers for Disease Control and Prevention (CDC) epidemiological study found that 78% of the cervical cancer cases were diagnosed in women 30\u201339\u00a0years . It is tAccording to Burkadze and Gulisa , three oHigh prevalence of inflammatory changes (97.5%) was reported in this study. Cervical microbial infections accounted for 32.8% of the inflammation cases. These results contradict previous findings by a study at National Institute of Health, Islamabad in Pakistan where lower prevalence of inflammatory changes (55.31%) was reported . SimilarVaginal infections are common cause of inflammation of the genital tract in all women; some are associated with sexual activity while others, such as vaginal candidiasis, are not. In this study, Candida (25.4%) and Trichomonas vaginalis (7.4%) were the specific causes of inflammation identified in the High Vaginal Swab wet preparation. Differing findings have been documented in other studies. Bhojani and Garg  reportedTrichomonas vaginalis, a sexually transmitted micro-organism, was suggestive of existence of potential for HIV transmission and the probable explanation would be due to low utilization of barrier method of contraception such as condom, which would provide protection from sexually transmitted diseases as well as cervical cancer. Actinomyces infection is usually detected in IUCD users. The infection was not reported in even among the IUCD users. This can be attributed to the fact that all IUCD users had a history of a previous Pap tests and therefore might have been treated previously. However, inflammation characterized by presence of polymorphonuclear cells (granulocytes) was evident in 26 (44.8%) of the IUCD users through Pap smear examination and with a significant statistical association (OR 2.47 at 95% C.I.). Studies in other parts of the world revealed similar association between vaginitis, and use of IUCDs. Sieber and Dietz [Detection of nd Dietz  and Amsend Dietz  found a Low prevalence of cervical precancerous changes and high prevalence of cervical microbial infection was reported. Majority of the participants were having Pap smear screening for the first time with the most un-screened persons falling within 21\u201340 years. Yeast cell was the predominant microbial organism detected with most causes of inflammation remaining non-specific.There is need to scale up cervical cancer screening awareness in order to capture all categories of women in all age groups in the cervical cancer screening programs. Pap smear screening and high vaginal swab should be offered as one package to identify both precancerous changes and microbial infections not as stand-alone tests. Further studies on the non-specific cause of cervical inflammation should be conducted."}
+{"text": "It is not always possible for endoscopists to differentiate early gastric cancer from adenoma in 0-IIa type neoplasia. The aim of this study was to assess the relationships between images obtained with a narrow band image system combined with magnifying endoscopy (MENBI) and histological findings, especially vascular patterns, to distinguish adenoma from type IIa early gastric cancer (EGC IIa).We postoperatively confirmed and evaluated 46 elevated lesions, 32 adenomas and 14 EGC IIa in patients who had undergone endoscopic submucosal dissection. We randomly selected three sites from each neoplasm. The selected sites were classified as four irregular microvascular patterns (IMVPs). In addition, the selected sites were divided into two groups based on the presence of corkscrews.Regarding IMVP subcategories, (1) slight intrastructural irregular microvascular patterns (ISIMVPs) accounted for 84%, (2) severe ISIMVPs accounted for 6%, (3) fine networks (FNs) accounted for 10%, and (4) corkscrews accounted for 0 of cases in the adenomas. The corresponding proportions in the EGC IIa were (1) 24%, (2) 31%, (3) 45%, and (4) 0. Slight ISIMVPs, severe ISIMVPs, and FNs reliably distinguished the two diseases: P < 0.001 for slight ISMVPs; P < 0.001 for severe ISIMVPs; P < 0.001 for FNs. The presence of corkscrews was observed in 9.5% of EGC IIa and 0 of adenoma cases (P = 0.008).MENBI can be used to differentiate EGC IIa from gastric adenoma based on IMVPs classifications and the presence of corkscrews. It is imperative for an endoscopist to make a differential diagnosis between benign and malignant lesions. For such purposes, magnification endoscopy is a powerful tool for correctly diagnosing superficial neoplasm throughout the entire gastrointestinal tract -3. In adThis study involved retrospective evaluation using our ESD database. Forty-six neoplasms were obtained from patients who had undergone ESD for 0-IIa type lesions according to the Paris endoscopic classification at the Gospel Hospital, Kosin University College of Medicine, Busan, Korea during the period from May 2009 to December 2010. Of these 46 lesions, 32 and 14 lesions, respectively, were postoperatively confirmed to be adenoma and carcinoma. Lesions diagnosed as mucosal low-grade neoplasia of category 3 according to the revised Vienna classification were defined as gastric adenomas . If a whPreoperative endoscopic examinations were performed by conventional endoscopy and chromoendoscopy. The endoscopic examinations and ESD were performed by a single expert endoscopist. Endoscopy was performed using an upper-GI endoscope . The gross findings, such as lesion color, margin, size, and central concavity, of 0-IIa lesions were evaluated by nonzoom endoscopic observation. ESD was performed for all lesions using an insulation tipped diathermic knife  to remove tumors with a minimum lateral margin of 5 mm. Just after removal of the adenomatous lesions, we performed MENBI  on fresh specimens. We screened the complete lesion and picked the three sites, presumably highest grade alteration for MENBI. IMVP cases were subcategorized as (1) slight intrastructual irregular microvascular patterns (ISIMVPs), defined by the presence of thin spiral blood vessels within the fine lobular superficial structure, (2) severe ISIMVPs, defined by the presence of vertical spiral blood vessels within the coarse lobular superficial structure, (3) fine networks, defined by fine tubular structures surrounded by thin microvasculature, or (4) corkscrew patterns, which appear as obliterated surface structures and irregular vascular patterns without loop formation . Adding Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) software . The relationship between IMVP and pathologic diagnosis was evaluated using the 2-sided Fisher exact test. The differences between GA and EGC IIa were assessed by 2-sided Fisher exact test and Student t-test. Diagnostic efficacy was assessed by specificity and sensitivity. Two-tailed P values less than 0.05 were regarded as statistically significant.All lesions were removed by ESD en bloc with a full margin distance to enable subsequent accurate pathologic diagnosis. The average tumor diameter was 1.96 cm in the adenoma group (n = 32) and 2.02 cm in the carcinoma group (n = 14). The majority of lesions in both groups were discolored, although reddish lesions were seen in 9% of cases in the adenoma group and in 14% in the carcinoma group. A central concavity was found in 13% of the adenoma group cases and in 86% of the carcinoma cases  slight ISIMVPs accounted for 84% (81 out of 96), (b) severe ISIMVPs accounted for 6% (6 out of 96), (3) fine networks accounted for 10% (9 out of 96), and (4) corkscrews accounted for 0 (0 out of 96) of cases in the adenoma group. The corresponding proportions in the carcinoma group were (1) 24% (10 out of 42), (2) 31% (13 out of 42), (3) 45% (19 out of 42), and (4) 0 (0 out of 42). Slight ISIMVPs were significant findings for the adenoma group , and severe ISIMVPs and fine networks were significant findings for the EGC IIa group (P < 0.001, sensitivity 30.9%, specificity 93.5%, and positive predictive value 68.4% for severe ISIMVPs; P < 0.001, sensitivity 45.2%, specificity 90.6%, and positive predictive value 67.8% for severe fine networks; The normal patterns of the surface pits and microcirculation are altered in cancerous mucosa , 14. MagAccording to 3 previous studies on the differential diagnosis of gastric carcinoma from adenomatous lesions using MENBI, the investigation of both superficial structure and vascular patterns is useful for the differential diagnosis of adenoma and carcinoma , 16, 17.Apart from the classical categories of IMVPs defined by Nakamura et al, we also assessed the presence of corkscrews and revealed that the presence of corkscrews can be also helpful to draw a sharp line between EGC IIa and adenoma (P = 0.008; In gross findings, it was highly suggested that central concavities may help distinguish between adenoma and EGC IIa . HoweverThe use of ESD for treating adenoma as well as early gastric cancer has currently been popularized with rapid technical progress. Postoperative pathologic evaluation revealed that a few 0-IIa lesions, diagnosed as adenoma by preoperative forcep biopsies, contain carcinomatous components. Adenomatous lesions have often been observed due to the idea that the malignant potential is relatively low from a long-term report . HoweverIn conclusion, MENBI can be used as a highly effective tool to differentiate EGC IIa from gastric adenoma based on IMVP classification and the presence of corkscrews in 0-IIa lesions that are difficult to distinguish by conventional endoscopy. Moreover, it can also be used for precise target biopsies to avoid missing cancerous components. Severe ISIMVPs may reflect more advanced vascular changes than fine networks and slight ISIMVPs. This theory needs to be verified by pathologic evaluation with MENBI examination in the future."}
+{"text": "We found that CAPTEM demonstrated activity in patients with all grades and in pNET and non-pNET. Median progression free survival (mPFS) was 13.0 months (95% CI: 5.6-17.0) and median overall survival (mOS) 29.3 months (95% CI 17.7 - 45.3). Among evaluable patients, there were 11 (38%) partial responses, 15 (52%) stable disease, and 3 (10%) progressive disease for a disease control rate of 90%. A higher rate of partial responses occurred in patients whose tumors had low levels of MGMT expression (63%) compared to intermediate-high (17%) (p=0.19). Our results show that CAPTEM therapy is active in patients with NET including in previously treated patients and in those with poorly-differentiated histology. We observed a trend towards increased response rate, median PFS, and median OS in patients whose tumors had low MGMT protein expression.Recent advances in the treatment of neuroendocrine tumors (NET), including the combination regimen of capecitabine and temozolomide (CAPTEM), have mostly focused on grade 1 and 2 pancreatic neuroendocrine tumors (pNET). We undertook a retrospective review of 38 patients with advanced NET treated with CAPTEM, including patients with non-pancreatic tumors as well as grade 2 and 3 tumors. O Neuroendocrine tumors (NETs) are a diverse group of tumors that range from the indolent typically low grade gastroenteropancreatic neuroendocrine tumors (GEP-NET), thymic and lung NET to the rapidly growing, aggressive type such as small cell lung cancer . NeuroenTreatment options are limited and palliative in nature for patients with all types of metastatic NET. Systemic therapy with somatostatin analogues has been shown to provide control of carcinoid syndrome and improve quality of life in patients with NET, and two prospective randomized trials have shown improvement in progression-free survival compared to placebo, demonstrating the antiproliferative effects of these treatments; however tumor response rates are low \u20136. Gener6-methylguanine DNA methyltransferase (MGMT) levels thereby enhancing the alkylating effect of temozolomide. In-vitro studies showed that 5-FU depletes tumor levels of MGMT [The synergistic activity of 5-FU and TMZ led to the development of temozolomide given in combination with capecitabine (CAPTEM). Capecitabine, which is converted to 5-FU, depletes tumor O of MGMT . Synergi of MGMT . Kulke e of MGMT . Respons of MGMT , 20, and of MGMT , 20\u201324.  of MGMT . Very li of MGMT .In order to further clarify the efficacy and safety of CAPTEM in a wider population of NET patients than previously studied, and to evaluate MGMT IHC as a predictor of response Figure , we repoTable Among all patients, median PFS was 13.0 months and median overall survival (mOS) 29.3 months (Table When stratified by proliferation index (Ki-67%), lower grade was associated with longer overall survival Table . Median All patients had imaging performed at baseline, but several patients did not have imaging performed at our institution during active treatment and were therefore excluded from response analysis. Response to treatment was assessed using RECIST v1.1 criteria, with 29 out of 38 patients having sufficient follow up to assess response to treatment, including 11 patients (38%) with partial response (PR), 15 patients (52%) with stable disease (SD), and 3 patients (10%) with progressive disease (PD), for a disease control rate of 90%  PR observed, 8 (44%) SD, and 1 PD (6%). For the 11 patients with NET not of pancreatic origin, there were 2 (18%) PR, 7 (64%) SD, and 2 (18%) PD, with no statistical difference in response between the two cohorts (p=0.21). Of the patients who had received prior systemic therapy, 16 patients could be evaluated, with a PR observed in 6 (38%), SD in 7 (44%), and PD in 3 (19%). All three patients previously treated with single-agent temozolomide achieved stable disease as best response. For the 13 systemic treatment-na\u00efve patients who had follow-up imaging, PR was observed in 5 (38%), SD in 8 (62%), PD in 0. Of the six patients previously treated with either TKI or MTOR inhibition, 3 PR (50%), 2 SD (33%), and 1 PR (17%) were observed.Thirty-five patients had Ki-67% reported with 10 classified grade 1 (Ki-67 < 3%), 16 as grade 2 (Ki67 3-20%), and 9 grade 3 (Ki67 \u2265 20%). Of the nine patients with grade 3 disease, one patient had well differentiated, two patients had moderately differentiated, and six patients had poorly-differentiated histology. Follow-up information was available for 7, 13, and 7 patients respectively. Of the seven patients with grade 1 tumors, PR were observed in 3 (43%), SD in 4 (57%), and no PD. For grade 2 tumors response rates included PR in 4 patients (31%), SD in 8 (62%), and PD in 1 (8%). For grade 3 tumors rates were PR in 4 (57%), SD in 1(14%), and PD in 2 patients (29%). Patients with grade 3 disease who achieved a clinical benefit from CAPTEM had Ki-67 indices of 20%, 25%, 35%, 40%, and 60%, whereas those that had PD were 50% and 100%.Thirty patients had tumor markers within 30 days of starting treatment and periodically while on treatment . Of these, decrease of at least 50% in one elevated marker occurred in 17 patients (57%) while on therapy. Five patients received CAPTEM for a second time after stopping therapy initially due to achieving best response. Three patients were evaluable for response, 2 had stable disease as best response and 1 had progressive disease at CAPTEM re-challenge. Five patients were eligible for surgical resection following treatment with first-line CAPTEM.Twenty patients had tumor tissue available for MGMT staining, of whom 12 had low and 8 had intermediate-high expression. Fourteen of 20 patients (6 intermediate-high and 8 low expression) had sufficient follow-up to assess response. Of the 8 patients with low MGMT expression by IHC and evaluable response there were 5 PR (63%), 3 SD (38%), and 0 PD. There was a trend toward longer PFS  and longer OS  for patients with low MGMT expression compared to those with high expression. Of the 6 patients with intermediate-high expression MGMT, 1 patient had PR (17%), 4 patients had SD (67%), 1 patient had PD (17%) as best response. Survival rate at 2 years was higher in the MGMT low group (75%) compared to the MGMT intermediate-high group (38%) (p=0.08).MEN1 gene, one patient with pheochromocytoma had a pathogenic VHL mutation in exon 3, and one patient with paraganglioma had a variant of uncertain significance in SDHB c.287-3C>G. One patient with MEN1 gene: c.628_631delACAG mutation had grade 3 pancreatic NET (Ki-67 25%) with high MGMT expression, but still derived benefit from CAPTEM therapy with stable disease burden for 3 years after completion of 8 cycles. A second patient with MEN1 G74fs*45 mutation had grade 1 pancreatic NET had a dramatic response to CAPTEM with 45% response in target lesions. One patient with lung carcinoid with Ki-67 < 5% without evidence of an inherited syndrome had somatic mutations detected including PDGFRB A366T and CDKN1b loss, and had best response of stable disease on treatment.Two patients with NET had mutations in All patients included in analysis received at least one cycle of therapy. Median number of cycles received was 4. Dose reductions or delays occurred in 15 patients (41%). Grade 3 or 4 adverse events were reported in 5 separate patients (14%), with two patients experiencing pancytopenia , a trial comparing temozolomide to combination therapy with capecitabine in patients with advanced pNET. The final results of NCT00869050 are also soon expected to be available. Finally, although low levels of MGMT expression seem to correlate with better responses to CAPTEM, better biomarkers should be sought to assist in predicting which patients will respond to CAPTEM therapy.In conclusion, the results of our retrospective review add further evidence to support the activity of CAPTEM in patients with advanced neuroendocrine carcinomas. Patients with low grade tumors, tumors of pancreatic origin, and tumors with low levels of MGMT expression seemed to have higher response rates. However responses were still observed in patients with high grade tumors, tumors with higher levels of MGMT expression, and in patients with tumors of nonpancreatic origin. Despite A retrospective review of all patients with a diagnosis of metastatic neuroendocrine tumor who received treatment with combination capecitabine and temozolomide between June 1, 2009 and June 1, 2013 at the Ohio State University was performed. The study was approved by the Institutional Review Board at the Ohio State University. A total of 38 patients with any grade metastatic neuroendocrine tumors, medullary thyroid cancer, and pheochromocytoma/paraganglioma were included. Patients were included regardless of prior therapies, including prior chemotherapies and targeted therapies. Patients who had prior systemic therapy were initiated on CAPTEM due to clinical or radiological progressive disease, or intolerance to prior therapy. Newly diagnosed patients were initiated on therapy due to symptomatic disease or high tumor burden, including carcinoid symptoms (n=2) or development of ascites (n=2). Imaging was performed every 2-3 cycles. RECIST v1.1 criteria were used to assess object response to treatment. Temozolomide was dosed at 200 mg/m2/day on days 10-14 and capecitabine at 1500 mg/m2/day in two divided doses on days 1-14 on a 28-day cycle.MGMT protein expression was evaluated using immunohistochemistry in patients who had tissue available in our neuroendocrine tumor tissue bank using MGMT murine antibody . Paraffin-embedded tissue was cut at 4-\u03bcm and sections were placed on positively-charged slides. Slides were then placed in a 60 degree Celsius oven for 1 hour, cooled, deparaffinized and rehydrated through xylene and graded ethanol solutions to water. All slides were quenched for 5 minutes in a 3% hydrogen peroxide aqueous solution to block for endogenous peroxidase. Slides were stained with the Intellipath Autostainer Immunostaining System. All incubations on the Autostainer were performed at room temperature. Slides were counterstained in Richard Allen hematoxylin, dehydrated through graded ethanol solutions, cleared with xylene, and cover-slipped. MGMT expression was determined based on percentage of tumor cells positive for nuclear staining, as per prior studies . Low, inPatient characteristics were summarized using descriptive statistics. Categorical data were summarized as frequency and percentage and continuous variables as medians and ranges. Adverse events were also summarized by grade per the National Cancer Institute Common Terminology for Adverse Events (CTCAE), version 4 criteria using frequency and percentage. Progression free survival (PFS) was measured as time from the start of treatment with temozolomide and capecitabine to clinical or radiologic disease progression or death. Patients who remained alive without disease progression were censored at the date of last follow-up. Overall survival (OS) was calculated from the start of treatment with temozolomide and capecitabine to death from any cause. Patients who were still alive were censored at the date of last follow up. Survivals were estimated using the method of Kaplan-Meier and compared using log-rank test. P values < 0.05 were considered statistically significant. Statistical analysis was performed using SAS version 9.4 for Windows ."}
+{"text": "Purpose. To document the changing clinical presentation of diabetic retinopathy (DR) over a decade, the current knowledge-attitude-practice (KAP) of known type 2 diabetes mellitus (DM) patients, and the current vision related quality of life (VR-QOL) of patients with DR in a tertiary eye care center in Eastern India. Methods. Two hundred and forty patients with known type-2 DM were evaluated. The evaluation included status of DR (n = 240), KAP (n = 232), and VR-QOL (n = 75). International classification of DR was used in the study. The DR status was compared with another cohort (n = 472) examined a decade earlier, in year 2001. The KAP-25 questions were designed after literature review. The National Eye Institute Visual Function Questionnaire  was validated by Rasch analysis. Both KAP and VR-QOL were analyzed according to degree of DR, duration of known DM, and educational qualification. Results. Average age of the current cohort (n = 240) was 57.16 \u00b1 9.03 years; there were 205 (85.4%) male patients and 143 (59.6%) patients had received less than graduate qualification. The mean duration of DM since diagnosis was 10 \u00b1 7.8 months (range 8 months to 30 years); 118 (49.16%) patients had DR. In a decade time, 2001 to 2011, there was a change of retinopathy status at presentation . One-third of NPDR patients had poor vision and half of them were hypertensive. KAP was better in patients with higher education and those having DR. VFQ score was higher in better seeing patients. Conclusion. Patients currently presenting at earlier stage of retinopathy are probably related to poor vision. Early detection and treatment of DR is likely to preserve and/or improve vision. Diabetes mellitus (DM) is a condition of growing concern with increasing prevalence worldwide and associated high morbidity . It is pThe current pattern of diabetic retinopathy at presentation vis-\u00e0-vis a decade earlier.The current knowledge-attitude-practice (KAP).The current vision related quality of life (VR-QOL).DM is related to both genetics and the life style. Awareness of DM and practice to keep it under control depends on the patient and the provider. DR treatment strategy is related to the stage of retinopathy. The status of DR dictates vision related quality of life (VR-QOL). The LV Prasad Eye Institute Eye and Diabetes Study (LEADS) was designed to address some of the common questions related to diabetes care in self-reported type 2 diabetes patients presenting to a tertiary eye care center in the institute's Bhubaneswar (Eastern India) campus. This prospective study addressed the following three issues in patients with DR:The LEADS protocol approved by the institutional ethics committee (LEC 11-093) was a prospective study of the eye and systemic condition of patients with DM presenting to the LV Prasad Eye Institute. Consecutive self-reported type 2 diabetes patients reporting to the institute for the entire period of November (month of World Diabetes Day) 2011 were recruited into the study. The overall study protocol involved a systematic 3-step evaluation as illustrated in The 2nd step involved a repeat fundus photograph by Zeiss fundus camera , fundus fluorescein angiography , and optical coherence tomography . The NEI-VFQ questionnaire  was administered to all patients with DR. The patients who needed further treatment for DR entered into the 3rd step of care .Diabetic Retinopathy at Presentation. We compared our 2011 data with the ones we had collected a decade ago in November 2001 (unpublished) for a similar group of self-reported type 2 DM patients. We compared the DR status (any DR and no DR), DR type (NPDR and PDR), BCVA, and comorbidities (hypertension and cardiac) (p < 0.05 was considered significant.cardiac) . The proThe KAP questionnaire was developed after a review of the literature on guidelines of earlier KAP studies. Our KAP questionnaire consisted of 25 multiple choice questions on both DM and DR. The divisions of questions were as follows: the knowledge questions (1) to (10); the attitude questions (11) to (18); and the practice questions (19) to (25) Tables .A printed copy of the questionnaire in English was given to each enrolled patient within the 1st step of the LEADS after a written consent was obtained. The instructions for completing the questionnaire were provided on the face sheet and were also explained verbally by one of the authors (BW). The non-English speaking or less literate patients were helped in completing the questionnaire by translation from a trained volunteer. The patients were given the option of ticking more than one option for each question should they feel there was more than one correct answer.p < 0.05) for statistical significance.The number of patients providing correct response was calculated for each question. The knowledge questions were also individually analyzed for the number of patients knowing each correct option or factor. With regard to the practice questions an answer was regarded as correct if the patient was compliant with the treating physician or ophthalmologist's instructions. A cut-off value less than 55% was taken as \u201cnot good.\u201d Subgroup analysis was done for each question according to the duration of DM (<20 years and \u226520 years), education (<graduate and \u2265graduate), and DR status (presence and absence of DR). Comparison of KAP was done for each subgroup and analyzed by chi square test   plus optVFQ questions were administered to patients clinically diagnosed to have DR. One of the authors (PS), trained to administer such questions, administered the questionnaire after explaining and obtaining a written consent. All instructions written on the cover page were verbally explained, read, and described; the list of answers was read briefly and the patient was given complete freedom to answer.Rasch Analysis. All statistical analyses were performed using R software (version R 2.14.1). Rasch analysis was performed using R package eRM to determine the validity of the NEI-VFQ 25 [I-VFQ 25 . Initial t-test (p < 0.05). Multiple regression model with stepwise elimination using Akaike information criteria was used to assess the relationship between the vision related QOL and demography  and clinical variable . The final model retained the following factors: age, presence of comorbidity, presence of macular edema, and better eye BCVA.Group analysis was done based on the disease spectrum (NPDR and PDR) and best corrected visual acuity (\u226520/60 and <20/60). Comparison of groups was done using unpairedThe LEADS enrolled 240 patients. This included 205 (85.4%) male and 35 (14.6%) female patients; the mean age was 57.16 years \u00b1 9.03 months (range 31\u201380 years). These recruits were consecutive and surprisingly there were less female patients (no specific reasons). One hundred and forty-three (59.6%) patients had received less than graduate qualification. All patients had type 2 DM. The mean duration of DM since detection was 10 \u00b1 7.8 months (range 8 months to 30 years). DR was detected in 118 (49.16%) patients; 87 (73.7%) had NPDR and 31 (26.7%) had PDR. In patients with DR, 39 (33%) patients had macular edema and 12 (10%) patients had sight threatening retinopathy. Seventy-eight patients with clear media (absence of significant cataract and vitreous hemorrhage) were advised to have FFA and OCT. One or more comorbidities were present in 172 (71.66%) patients and hypertension detected in 126 (52.5%) patients was the commonest comorbidity. Two patients had bilateral poor vision (<20/200).The 2001 cohort had enrolled 472 self-reported type 2 DM patients. There were 368 males and the average age was 57.7 years \u00b1 10.4 months (range 29\u201382). The DR status at presentation in 2001 and 2011 and other demographic details are shown in Two hundred thirty-two patients completed KAP questionnaire (8 patients refused). There were 199 males (85.8%) and mean age was 57 \u00b1 8.9 years (range 31\u201380 years). One hundred forty-three patients (61.6%) were less than graduates.Knowledge  , (2), (4), and (5)) though only two-thirds of patients were aware of necessary life style modification (question (3)). Eye and other organs complications were the commonest known DM complication (question (5)). The overall knowledge of DR was generally poor (questions (7)\u2013(10)) though two-thirds of patients had knowledge that retina is affected in DR (question (6)). In general, there was a trend towards better knowledge in patients with higher education (questions (5) and (8)).Attitude  (Questio. Only two-thirds of patients were aware of the need for life long medication (question (11)). Patients had a good attitude for regular eye check (questions (12) and (16)) though many thought it was required only on experiencing visual symptoms or when advised by treating diabetologist (questions (13), (15), and (18)). Close to half patients thought that blood sugar control is key to prevention of DR (question (14)) and that laser treatment of the eye is a permanent cure of DR (question (17)). Patients with higher education and patients with DR had a comparatively better attitude for eye examination (questions (14) and (17)).Practice  \u2013(22) and (24)) was good. But practice towards foot care and exercise was not good (questions (23) and (25)). In general patients with higher education and patients with DR had a better practice (questions (22) and (23)). p value are given in item-fit statistics.Seventy-eight patients (who were advised for FFA and OCT) were eligible for VR-QOL. Three patients refused to give written consent for the questionnaire; hence NEI-VFQ was administered to 75 patients with DR. This cohort of 75 patients comprised 66 (88%) males; 51 (68%) patients had received less than graduate qualification; mean age was 57.88 \u00b1 7.51 (range 39\u201377 years) years; mean known DM duration was 14.23 (range 10 months\u201330 years) years. Better eye BCVA was <20/60 in 37 (49.3%) patients. Fifty (66.7%) patients had one or more comorbidities, predominantly hypertension . Following FFA and OCT, 54 (72%) patients were confirmed to have NPDR, 21 (28%) patients to have PDR, and 39 (52%) patients to have macular edema. The outfit (unweighted) and infit (weighted) mean square statistics, chi square, andBased on the disease spectrum , NPDR, ax-axis) had difficulty even with the easiest items; subjects with more visual ability (at the right side of x-axis) had no difficulty performing any of the items. The figure shows that the items located at the top of the y-axis such as mental health, near activities, and dependencies required greater visual ability and as such were more difficult items to perform. At the other end, color vision, social functioning, and distance activities located at the bottom of the y-axis required less visual ability and were less difficult items to perform.Person-item map is shown in The comparison between two decades, 2001 and 2011, showed that the patients visited ophthalmologists earlier though there was increasing prevalence of sight threatening retinopathy . This early visit is partly prompted by increasing advocacy and general health awareness and partly due to accessible health care facilities in the vicinity over a decade. Because the patients reported early more often they had no manifest retinopathy or had NPDR. Hypertension was the only significant comorbidity possibly contributing to vision threatening retinopathy. Despite these facts there was overall poor knowledge of DR, particularly regarding life style modification needed to reduce risk of DR and regarding the risk factors for development of eye complications. Though 52.5% were hypertensive, there was little awareness of its association with diabetes related eye complication. Patients with DR and the patients with higher education had positive KAP. Disturbing factors included the belief that medicines could be stopped when diabetes is controlled, that one need not see an ophthalmologist in absence of any visual symptom, and the neglect of foot care and exercise. Three other studies in India have shown poor KAP in both urban and rural population \u201311. ThesNEI-VFQ has been used to assess VR-QOL in a variety of eye diseases \u201320. ThesThere was overall higher VFQ in patients with NPDR than PDR, but it was statistically not significant. This could be rather related to the fact that patients with NPDR had a relatively better vision than patients with PDR. But with increasing number of people with macular edema and vision threatening retinopathy  the QOL Limitations of this study include the following: (1) the cohort comprising patients with self-reported diabetics at a tertiary eye care center may not accurately represent the general population; (2) small sample size and male preponderance may have affected the overall results; (3) the KAP study done in an eye center and in the month of World Diabetes Day (November) might have influenced the knowledge of eye involvement in DM; (4) the KAP questions designed by us were not validated in the same community; (5) the VR-QOL has considered BCVA only as a measure of vision and other clinical measures such as contrast sensitivity, central visual field, and stereopsis were not considered  and incrAt the same time the strengths of the study include (1) standardized measurement of vision using ETDRS chart, (2) clinical diagnosis of retinopathy by fellowship trained retina specialist, (3) accurate measurement of macular edema and macular status with the OCT and FFA, and (4) inclusion of a broader range of questions in KAP questionnaire in both DM and DR.In conclusion this study showed that there is an increase in vision threating retinopathy and more number of people have hypertension, that better knowledge-attitude-practice prevails in people with higher education, and that quality of life is related to best corrected visual acuity, age, and comorbidity. We feel the current advocacy and the information-education-communication (IEC) are inadequate for growing spread of diabetes and related complications in India."}
+{"text": "On February 8, 2017, a suspected case of mumps in a member of a fraternity or sorority at the University of Washington, Seattle campus (UW) was reported to Public Health\u2014Seattle & King County (PHSKC). Additional confirmed and probable mumps cases were subsequently identified among UW students and staff members according to the national case definition.* By July 19, 2017, a total of 42 (16 confirmed and 26 probable) mumps cases were reported among UW students and associated community members, with symptom onset February 6\u2013June 4 .Among the 42 cases, 32 (76%) occurred in UW fraternity and sorority members. Of these, 12 (37.5%) were confirmed cases, and 20 (62.5%) were probable cases. Cases occurred in residents in 20 (38.5%) of 52 fraternity and sorority houses that lodged 2,259 (48.6%) of 4,646 total fraternity and sorority members on the UW campus . All mumps patients had received \u22652 documented doses of measles-mumps-rubella (MMR) vaccine, as is currently recommended  were male. Participants reported the following symptoms during the preceding month, none of which required hospitalization: fever , cough , sore throat , and swelling or pain of the parotid gland or jaw not attributable to dental problems . Specimens were processed at CDC. All 160 buccal swabs were mumps-virus negative by real-time reverse transcription\u2013polymerase chain reaction; positive control testing in the laboratory indicated \u02c399% successful specimen collection and processing.The majority of mumps cases in this outbreak occurred among fraternity and sorority members; other studies have demonstrated that close contact is required for mumps transmission to occur in a population with high mumps vaccination coverage ("}
+{"text": "Living donor liver transplantation (LDLT) in patients with acute liver failure (ALF) has become an acceptable alternative to transplantation from deceased donors (DDLT). The aim of this study was to analyze outcomes of LDLT in pediatric patients with ALF based on our center\u2019s experience.We enrolled 63 children (at our institution) with ALF who underwent liver transplantation between 1997 and 2016. Among them 24 (38%) underwent a LDLT and 39 (62%) received a DDLT. Retrospectively analyzed patient clinical data included: time lapse between qualification for transplantation and transplant surgery, graft characteristics, postoperative complications, long-term results post-transplantation, and living donor morbidity. Overall, we have made a comparison of clinical results between LDLT and DDLT groups.Follow-up periods ranged from 12 to 182 months (median 109 months) for LDLT patients and 12 to 183 months (median 72 months) for DDLT patients. The median waiting time for a transplant was shorter in LDLT group than in DDLT group. There was not a single case of primary non-function (PNF) in the LDLT group and 20 out of 24 patients (83.3%) had good early graft function; 3 patients (12.5%) in the LDLT group died within 2 months of transplantation but there was no late mortality. In comparison, 4 out of 39 patients (10.2%) had PNF in DDLT group while 20 patients (51.2%) had good early graft function; 8 patients (20.5%) died early within 2 months and 2 patients (5.1%) died late after transplantation. The LDLT group had a shorter cold ischemia time (CIT) of 4 hours in comparison to 9.2 hours in the DDLT group (p<0.0001).LDLT is a lifesaving procedure for pediatric patients with ALF. Our experience showed that it may be performed with very good results, and with very low morbidity and no mortality among living donors when performed by experienced teams following strict procedures. Although the first reported case of acute liver failure (ALF) was described in 1946, the definition was introduced in 1970 by Trey and Davidson . AccordiLiving Donor Liver Transplantation (LDLT) for ALF patients was first reported by Matsunami in 1992 . Since tBetween 1990 and 2016 there were 689 LTs performed in pediatric patients in Children\u2019s Memorial Health Institute (CMHI), including 312 LDLTs (45%). Among 689 LT patients, 63 were children transplanted for ALF (9.1%) between 1997 and 2016: 24 (38%) underwent LDLT and 39 (62%) were transplanted with a graft from a deceased donor (DDLT). Patients were qualified for LT based on the King\u2019s College three criteria, or specific criteria in a case of Wilson\u2019s disease.Retrospective analysis was performed to assess recipients and donors data:patients clinical status at admission and at transplantationtotal bilirubin and INR Pediatric End-Stage Liver Disease (PELD)/ Model End-Stage Liver Disease (MELD) scoretime between the recipient listing for transplantation and transplant surgerygraft characteristics recipient and graft postoperative and long- term follow upduration of living donor evaluationperioperative and long- term follow up of living donors .The alternative of a LD donation was proposed mainly to the parents of children with low body weight, in whom a chance of LT from DD was minimal, or in cases of patients with a rapidly deteriorating condition. The potential complications of donor partial hepatectomy were carefully explained. Initial screening took place in our center and consisted of an assessment of basic biochemical and virological parameters. Medical history and interview with a psychologist was carried out. Other performed tests: angio-CT, liver volumetry and accurate internal examination were performed at the center for adults, where the part of liver from LD was harvested. GRWR was estimated and considered to be adequate when between 1% and 4%.Whenever possible the results were compared between LDLT and DDLT groups. Patient and graft survival were analyzed using the Kaplan-Meier method. For statistical analysis the log-rank (Mantel-Cox test) was used to compare survival curves. For continuous variables the Mann-Whitney test and for categorical variables Pearson's chi-squared test was used. A p-value of less than 0.05 was considered to be statistically significant. The statistical software package Graph Pad PRISM 5.0 and Statistica 10.0 were used for statistical analysis. Median values with interquartile ranges were used for numerical data.The research project \u201cAnalysis of indications and results of LT of children with ALF\u201d obtained an approval from the Research Ethics Committee at the Children's Memorial Health Institute, Warsaw, for the realization of our project and included a retrospective analysis of indicated material . At the moment of admission to our hospital a conscious consent allowing the anonymous use of patients\u2019 medical data was signed by Guardians/Parents of children of age \u226416 years. This form of voluntary consent is a standard procedure approved by the ethics committee in our institution and is applicable to all patients treated in our institute. We have obtained all the patients\u2019 data from patients\u2019 medical history documentation and subsequently created an anonymous database as a starting point for our analysis. All the data were anonymized/de-identified prior to analysis. Our research was conducted in accordance to the principles expressed in the Declaration of Helsinki.Among 69 children with ALF, 16 girls and 8 boys were transplanted with liver grafts from LD: their age ranged from one month to 15 years (median 4.0 years); their body weight ranged from 3.1 kg to 46.7 kg (median 19.5 kg). The causes of ALF in our 24 patients are listed in Time between the listing for transplantation and transplant surgery was between 11 and 170 hours (median 25 hours) in patients who received LDLT and between 10 and 168 hours (median 61 hours) in patients transplanted with DDLT. Encephalopathy higher than stage II at the time of hospital admission was observed in 7 (29.1%) patients receiving a LDLT and in 7 (17.9%) patients receiving a DDLT. The number of patients with stages III/IV of encephalopathy immediately prior to transplantation was 15 patients in the LDLT group (62.5%) and 25 patients in the DDLT group (64.1%). Mechanical ventilation at the time of admission was necessary in 4 recipients of LDLT (16.6%) and in 3 recipients of DDLT (7.6%). During pre-transplant treatment the number of patients on mechanical ventilation increased from 4 to 19 (79.1%) among LDLT recipients and from 3 to 24 (61.5%) among DDLT recipients. Renal failure occurred in 3 patients (12.5%) of the LDLT group and in 4 patients (10.2%) of the DDLT group at the time of admission and in 5 patients (20.8%) of the LDLT group and in 10 patients (25.6%) of the LDLT group after transplantation. Altogether 17 patients receiving a LDLT (70.8%) and 26 patients receiving a DDLT (66.6%) underwent hemodialysis (HD) or liver support albumin dialysis\u2014molecular adsorbent recirculating system (MARS) -before transplantation. Hemodynamic failure at admission, requiring catecholamine support, was observed in 3 patients (12.5%) in the LDLT group and in one patient (2.6%) in the DDLT group. After transplantation the hemodynamic support was necessary in 12 patients (50%) of LDLT and 24 patients (61.5%) of DDLT. The LDLT group was characterized by a lower total bilirubin concentration and comparable INR levels. The PELD score in patients from the DDLT group ranged from 17 to 52 (median 36), and from 15 to 45 (median 32) in the LDLT group. The MELD value ranged from 15 to 33 (median 24) in recipients of a LD graft and from 24 to 53 (median 36) in recipients of a DD graft. None of the above results were statistically significant between LDLT and DDLT groups (p = NS) except the total bilirubin concentration  were accepted after the full examination process. Only 2 LDs were excluded due to medical contraindications. The donors\u2019 ages ranged between 21 to 54 years (median 34 years) and body weight was between 44.6 to 92 kg (median 63 kg). Mothers were donors in 14 cases whereas fathers in 8 cases and grandmothers in 2 cases. The detailed donor evaluation was completed within 24 hours in all cases: GRWR ranged from 0.86 to 8.7 (median 1.85) and weight of the graft from 189 g to 617 g (median 319 g). In one case the donor graft was further reduced to a monosegment (segment III) before transplantation. Bisegmental grafts (segments II and III) were transplanted in 15 patients, left liver  in 7 patients and right liver  in one patient. The donor and recipient blood types were identical in 14 patients (58.3%), non-identical but compatible in 5 patients (20.8%), and incompatible in 5 patients (20.8%). The CIT in patients for LDLT ranged between 2.4 and 5.4 hours (median 4.0).The deceased donors\u2019 ages ranged from 15 to 58 years (median 38.5 years) and body weight from 50 to 100 kg (median 70 kg). Only 10 out of 39 DD (25.6%) were categorized as optimal and only 1 was under 18 years old. The majority of 29 DD grafts (74.4%) were harvested from suboptimal donors due to various reasons. The whole liver was transplanted in 31 patients (79.5%), left lobe in 5 patients (12.8%), and left lateral lobe in 3 patients (7.7%). The donor and recipient blood types were identical in 15 patients (38.5%), non-identical but compatible in 9 patients (23%), and incompatible in 15 patients (38.5%). The CIT for DDLT ranged between 5 hours to 15 hours (median 9.2 hours) and was significantly longer than in LDLT  and also from 1 to 15 years (median 9 years) in patients who received a DDLT. There was not a single case of primary non-function (PNF) in patients after LDLT and early graft function was good in 20 out of 24 patients (83.3%). In comparison, PNF occurred in 4 recipients (10.2%) among recipients of a DDLT. Whereas, good early graft function was only present in 20 patients (51.2%). Consequently, LDLT always performed better than DDLT.Three patients out of 24 with a LDLT (12.5%) died within 2 months after transplantation. The causes of death were listed as multi-organ failure (MOF) in 2 patients and neurological complications in one patient. Eight recipients out of 39 (20.5%) died in the early postoperative period after DDLT. The causes of death were listed as: severe post-reperfusion syndrome in onf patient; MOF in two patients; circulatory failure in 3 patients; and, neurological complications in 2 patients. All early deaths occurred within 37 post-operative days. Early mortality after transplantation in patients with ALF was higher in the DDLT group than in the LDLT group. However, this difference was not statistically significant (p = 0.4159). While there was no late mortality observed in the LDLT group, 2 patients died in DDLT group: one within 12 months after transplantation because of sepsis and one within 5 months because of hemophagocytic syndrome. The actual patients\u2019 survival was 83.3% after LDLT and 74.3% after DDLT. However, the Kaplan-Meier comparison did not reach statistical significance .Two patients (8.3%) after LDLT required late re-transplantation: the first on day 58 because of biliary complications and the second on day 157 because of the vascular complications. The following complications occurred in 7 out of 39 DDLT patients (17.9%) requiring re-transplantation: 4 patients required early re-transplantation because of PNF and 3 patients required late re-transplantation because of biliary complications and/or liver fibrosis occurring at 2 months, 2 years, and 4 years. The actual graft survival for this re-transplanted group was 79.1% for LDLT and 53.8% for DDLT  after LDLT and in four patients (10.2%) after DDLT. The detailed clinical outcome for ALF groups after LDLT and DDLT is presented in Follow-up of living donors: a thorough evaluation of liver donor surgery, and living donors was performed. The center performing harvesting from live donors has extensive experience in adult liver surgery and LT. There was no need for blood transfusion during or after operations. None of the living donors required reoperation due to postoperative complications. The hospitalization time due to living donation did not exceed 7\u20138 days in all cases. All donors are alive and no serious early or late complications were observed.In recent years, there has been significant progress in the treatment of ALF. This progress is mainly attributed to dramatic improvements in the quality of medical care, especially in intensive care techniques, including multiple excellent extracorporeal procedures such as hemodialysis and albumin-dialysis. Despite these undisputable successes in patients\u2019 management, the emergency LT (LDLT or DDLT) remains as the only life-saving procedure for patients with ALF. In fact, all of the improved emergency level procedures only help to prolong patients\u2019 temporary survival while awaiting LT . ALF almWhile dealing with ALF patients, one has to remember that meeting the strict requirements for being qualified for LT may change very fast and therefore these patients start a race against the possible irreversible damage inflicted to the central nervous system. Especially in patients with ALF, the scarcity of time becomes very critical for successful LT, as the risk of death in this group reaches up to 90% ,11, 12. Patients with ALF are prone to complications after LT. Because of the fast progress of ALF symptoms and a possible deterioration into MOF, there is a tremendous risk for these undesirable consequences occurring after LT from a marginal donor. These patients are most likely to have initial poor graft function or even PNF. In fact, it was reported that PNF occurred in 16% of ALF patients which was the highest complication rate of any group of LT patients . In our An important problem in LDLT in ALF cases is the need for rapid and efficient evaluation of potential live donors. The benefits for an ALF patient must be carefully weighed against the risk posed to a potential living donor. Based on available data, the risk of complications is small but nonetheless exists . It is aIn our analysis, the actual survival rate in pediatric patients with ALF was 83.3% in LDLT group and 74.3% in DDLT group. The Kaplan-Meier comparison showed that the difference was not statistically significant (p = 0.3975), probably because of a relatively small group of patients. High mortality in ALF patients is mainly attributed to the advanced encephalopathy, toxic edema, hypoxia, and MOF, including renal failure . We suggIn conclusion, our results showed that LDLT is a lifesaving procedure for pediatric patients with ALF. Our experience showed that the LDLT program for children with ALF has very good results with very low morbidity among LDs. Our recommendation is that all operations need to be performed by very experienced teams with strict procedural rules."}
+{"text": "Our study is a retrospective analysis of the clinical data, surgical outcomes, histological finding and prognosis of foramen magnum meningiomas through a serie of 8 cases operated at the department of neurosurgery at Mohammed VI medical university hospital, Marrakesh. From January 2002 to December 2015. There were 3 male and 5 female patients . Cervico-occipital pain (100%) and motor deficit (100%) were the most common presenting symptoms. MRI was the most appropriate diagnostic tool in visualizing tumors of this region. All operations were performed by the posterior approach and gross total resection was achieved in 7 cases. Surgical mortality was 20%. 3 other patients had complications like CSF leak (25%), meningitis  and transient worsening of neurological deficit (12.5%) but made neurological recovery later. Foramen magnum meningiomas have long been regarded as difficult lesions both in terms of diagnosis and management. However, with the availability of MR imaging, newer surgical techniques and skull base exposures, the excision of these lesions is becoming easier and safer. Meningiomas of the foramen magmun (FMM) account for 0.3% to 3.2% of all meningiomas, between 4.2% and 20% of all posterior fossa meningiomas and 8.6% of all spinal meningiomas . FMM havBetween january 2002 and decembre 2015 eight patients were operated for FMM at the department of neurosurgery at mohammed VI medical university hospital, marrakesh, Morocco. Medical charts and records were reviewed retrospectively to determine demograophic data, clinical findings, morphological assessment, surgical approaches and outcomes.Between January 2002 and December 2015, eight patients were diagnosed with foramen magnum meningiomas. 3(37.5%) were male and 5 (62.5%) were female. The median age was 46.75 (ranging from 23 to 60) The mean duration of symptoms was 13 months (ranging from 4 to 36 months). Presenting signs and symptoms were headache and neck pain in all patients (100%), difficulty in swallowing in 2 patients (25%), gait ataxia in 2 patient (25%) brachalgia and arm paresthesias in 2 patients (25%), monoparesis in one patient (12.5%), hemiparesis in 2 patients (25%) and quadriparesis in 5 patients (62.5%). The mean preoperative KPS was 72.5% (ranging from 60% to 80%). 5/8 (62.5%) of the tumors were located anterolateral , 3/8 werth-12th), rostral aspect of the spinal cord, and upper cervical nerves (C1 and C2). arterial structures include the VAs, PICAs, anterior and posterior spinal arteries, and the meningeal branches of the vertebral, external, and internal carotid arteries [The foramen magnum contains several critical neuroanatomical and vascular structures of which the surgeon must be aware. The neural structures include the cerebellar tonsils, inferior vermis, fourth ventricle, caudal aspect of the medulla, lower cranial nerves (9arteries . Meningiarteries , 5. MRI arteries . Tumors arteries . It\u2019s a arteries  and carrarteries . Tumors arteries  for VA aarteries . In our arteries , 11, 12,arteries , GTR canarteries .According to our experience, we think that, the conventional suboccipital midline approach with C1 laminectomy is sufficient to perform safely the adequate microsurgical removal of foramen magnum meningiomas.Meningiomas located in the Foramen magnum are quite uncommon;Their surgical treatments remain a technical challenge;The far lateral approach is widely considered the gold standard approach by many skull base surgeons.The conventional suboccipital midline approach can safely achieve a total resection of foramen magnum meningiomas;A good knowledge of the regional surgical anatomy is sinequanone to achieve a total resection and avoid iatrogenic lesions of the VA and low cranial nerves."}
+{"text": "Background. No predictive or prognostic biomarker is available for patients with locally advanced rectal cancer (LARC) undergoing perioperative chemoradiotherapy (CRT). Members of the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases EGFR , HER2 (ERBB2), HER3 (ERBB3), and HER4 (ERBB4) are therapeutic targets in several cancers. The analysis was performed to assess expression levels and study the potential prognostic impact for disease-free and overall survival in patients with LARC. Patients and Methods. ERBB1\u20134 mRNA expression and tumor proliferation using Ki-67 (MKI67) mRNA were evaluated using RT-quantitative PCR in paraffin-embedded tumor samples from 86 patients (median age: 63) treated with capecitabine or 5-fluorouracil-based CRT within a phase 3 clinical trial. Results. A positive correlation of HER4 and HER2, HER3 and HER2, and HER4 and HER3 with each other was observed. Patients with high mRNA expression of ERBB1  had significantly increased risk for recurrence and death. Patients with high mRNA expression of MKI67 had reduced risk for relapse. Conclusion. This analysis suggests a prognostic impact of both ERBB1 and MKi67 mRNA expression in LARC patients treated with capecitabine or fluorouracil-based chemoradiotherapy. Rectal cancer is the fifth most common type of cancer in adults worldwide . Althoug distant metastases represent the most common type of treatment failure in rectal cancer indicating the need for optimized systemic medical treatment such as modifications of perioperative bolus 5-fluorouracil (5-FU) treatment. However, neither biomodulation of fluorouracil nor combinations with older cytostatic drugs have clearly proved advantage compared to bolus 5-FU  in the capecitabine group versus 14 [7%] in the fluorouracil group, p = 0.67.All patients providing tumor tissue for the current analysis were treated at a single center .Both the clinical study protocol and the molecular investigations reported here were approved by the local ethics committee.\u03bcm section was used for the isolation of RNA according to a fully automated, high-throughput extraction workflow which runs on an Xtract-XL liquid-handling robot . The extraction solutions and chemicals are commercially available in Germany as part of the XTRAKT FFPE kit, which is based on magnetic bead technology (STRATIFYER)  of 89.1, 97.2, 96.0, 92.0, and 99.7%, respectively. A commercially available human reference RNA  was used as positive control. No-template controls were assessed in parallel to exclude contamination.Forty cycles of nucleic acid amplification were applied and the cycle threshold (Cq) values of the target genes were identified. Cq values were normalized by subtracting the Cq value of the housekeeping genehis gene . The lenDetails of the primer/probe sets used for amplification of the target and reference genes are listed in p values were two-sided with p values < 0.05 indicating statistical significance. Statistical analyses were performed with SAS Jmp 10.0  and Graph Pad Prism software . With regard to OS and DFS patient samples with pretherapeutic biopsies (n = 55) were analyzed in order to exclude a possible sampling error.Overall survival (OS) was measured from the date of randomization until death from any cause. Surviving patients were censored at the date of last contact. Disease-free survival (DFS) was measured from the date of randomization until recurrence of tumor, secondary neoplasm, or death from any cause as described . Time-ton = 54) (ERBB1) and HER2  and moderate to high positive correlations between HER4 and ERBB2 (HER2), ERBB3 (HER3) and ERBB2 (HER2), and ERBB4 (HER4) and ERBB3 .Tumor tissue samples were obtained from 86 patients . A total of 52 biopsies and 54 resection specimens from these patients were analyzed as described in the \u201cMaterial and Methods.\u201d Only biopsies deriving prior to treatment were analyzed with regard to OS and DFS. Regarding these biopsies, 30/52 biopsies were derived from the additional neoadjuvant treated patient group and 22/52 biopsies from the solely adjuvant treated patients. Resection specimens were exclusively investigated in patients receiving solely adjuvant chemoradiotherapy to analyze a possible sample effect of biopsies and resected specimens (n = 54) . Basic cn = 54)  using thn = 52) irrespective of treatment modality showed no association between normalized mRNA expression and age (\u226465 versus >65 years) or gender. However, higher EGFR (ERBB1) expression levels were associated with the risk for developing recurrence  or death during follow-up . Furthermore a trend was observed for higher HER3 expression levels among patients still alive during follow-up . No significant association of normalized gene expression was observed in relation to different treatment groups (5-fluorouracil versus capecitabine). Comparison of normalized gene expression in biopsies versus resected specimen in the adjuvant treatment group showed that all markers with the exception of EGFR (ERBB1) displayed higher expression levels in preoperative biopsies than in resection specimens (All biopsies (pecimens . Therefo EGFR (ERBB1) mRNA values the evaluated cut-off (18% high expression) was prognostic for both OS and DFS, while for the ERBB2, ERBB3, and MKI67 no significant prognostic effect was found in the examined cut-offs in terms of OS and DFS. Concerning EGFR (ERBB1), 5/8 deaths (63%) and 7/8 relapses  occurred in patients with high-expressing tumors compared to 8/41 deaths (20%) and 13/41 relapses  in the low-expressing tumors. Patients with high mRNA expression of EGFR (ERBB1) had increased risk for death  and increased risk for relapse  compared to patients with low-expressing tumors. Kaplan-Meier curves for OS and DFS according to the mRNA status of EGFR (ERBB1) are displayed in Figures For the ERBB2 (HER2) mRNA expression (38% high expression) a trend for a prognostic association was observed for OS (p = 0.064) and no correlation for DFS. Furthermore, patients with high MKI67 mRNA expression (82% high expression) showed a trend for a reduced DFS using the Kaplan-Meier method , 2/19 deaths (11%) occurred in patients with high-expressing tumors in comparison to 11/30 deaths (37%) in the low-expressing tumors. Patients with high mRNA expression of ERBB2 (HER2) had reduced risk for death  in the proportional hazard model compared to patients with high-expressing tumors. Kaplan-Meier curves for OS according to the mRNA status of ERBB2 (HER2) are shown in For MKI67, 13/39 relapses (33%) occurred in patients with high-expressing tumors in comparison to 6/9 relapses (67%) in the low-expressing tumors. Patients with high mRNA expression of MKI67 had reduced risk for relapse  in the proportional hazard model compared to patients with low-expressing tumors when adjusting for treatment group. Kaplan-Meier curves for DFS and OS according to the mRNA status of MKI67 are shown in Figures With regard toEGFR (ERBB1), ERBB2 (HER2), HER3 (ERBB3), and HER4 (ERBB4) expression), as well as MKI67 expression in patients with LARC treated at a single center with chemoradiotherapy based on capecitabine or fluorouracil within a phase 3 clinical trial. Expression of EGFR (ERBB1) was prognostic for both, OS and DFS, in this analysis.No molecular markers have been described thus far to identify patients with LARC carrying a high risk for distant metastases. The aim of this study was to assess the potential prognostic value of ERBB family of receptors ( EGFR (ERBB1) expression levels were found more frequently among patients developing metastases. Patients with high mRNA expression of EGFR (ERBB1) also had an increased risk for death compared to patients with low-expressing tumors. In contrast, ERBB3 expression was not prognostic in our analysis. However, both studies are not completely comparable as in the present study analysis for ERBB1\u20134 and MKI67 was based on a standardized RNA extraction method and uniformly staged and treated (5-FU based chemoradiotherapy) patients were investigated in our series. Moreover, Ho-Pun-Cheung and colleagues used two different RNA extraction protocols (TRIzol and Qiagen Columns). These differences may explain the variability in the results. Comparably, both studies used pretreatment specimen and RNA based PCR expression. EGFR (ERBB1) immunohistochemistry and RT-qPCR showed a good overall concordance of 81% in breast cancer patients as described recently [ EGFR (ERBB1) gene expression levels than nonresponders (patients with insignificant tumor regression). The 3-year DFS rates of the patients with lower gene expression levels of EGFR (ERBB1) were significantly higher (90%) than those of the patients with higher gene expression levels (70%) (p = 0.003). These data are in line with the results of our current investigation where patients with high mRNA expression of EGFR (ERBB1) had increased risk for relapse and death compared to patients with low-expressing tumors treated with capecitabine or 5-FU. This provides evidence for the use of EGFR targeted therapies in patients with high expression of EGFR treated with capecitabine or 5-FU.The mRNA expression of the four HER family members has previously been assessed from a series of 100 locally advanced rectal cancers treated with radiotherapy or radiochemotherapy and showed an association for EGFR (ERBB1) and HER3 gene expression with development of distant metastases in LARC . The currecently . This surecently . Respondp < 0.05) as well as in the posttherapeutical resection specimens . Despite obvious differences regarding the aims and methods of both investigations it is surprising that the results appear to be diametrically opposed. Clearly, the number of pretreatment tumor biopsies in the cited publication was relatively small (n = 22). As described in the Results, sampling methods  may explain differences in gene expression levels. However, this does not explain the difference between both data sets. In primary breast cancer, for instance, high MKI67 mRNA expression measured by RT-qPCR is predictive for achieving pathological complete remission (pCR) to neoadjuvant chemotherapy [The predictive value of MKI67 was investigated in a rectal cancer patient cohort treated with neoadjuvant 5-FU based chemoradiotherapy . A smallotherapy . RT-qPCRotherapy . Even th HER2/ERBB2 we found a trend for a reduced risk of death for HER2 high-expressing tumors. The role of HER2/ERBB2 expression in colorectal cancer is very controversial. In a series of 1645 patients using immunohistochemistry and chromogenic in situ hybridization (CISH) with standard protocols an overall positivity rate of 1.6% in CRC patients was described [n = 264). Tumors with an IHC score of 3 or SISH ratios of \u22652.0 were classified HER2 positive. HER2 status was found to be positive in 12.4% of patients with pretreatment biopsies. In this analysis, patients with HER2 positivity showed a trend for better DFS and a significant benefit in cancer-specific survival. Five-year survival rate was 96.0% for patients with HER2 positive tumors (versus 80.0% for HER2 negative tumors) [With regard toescribed . Contrar tumors) . Recentl tumors) . The sam tumors) . Taken tERBB1), normalized gene expression was higher in biopsies than in resection specimens. This difference could be a result of the effect of ischemia. Surgical procedures significantly affect the expression of genes in colorectal cancer tissue seen as a significant difference in the molecular composition of tissue specimens collected after tumor resection compared to specimens collected via colonoscopy before tumor resection [With the exception of EGFR (esection . In the esection  which cl EGFR (ERBB1) mRNA levels had a prognostic significance for DFS as well as for OS. (ii) Differences between pretreatment biopsies and resected specimen underline the importance of standardizing preanalytical procedures in biomarker studies. (iii) High MKI67 mRNA expression correlated by trend with DFS. (iv) A relevant proportion of patients had HER2 positive tumors and therefore a better prognosis. On the other hand, HER2 positivity may offer the possibility for studying trastuzumab-based treatment in this disease.The key findings of our analysis of ERBB family in patients with locally advanced rectal cancer undergoing 5-fluorouracil based chemoradiotherapy are as follows: (i)"}
+{"text": "There is an error in the first sentence of the Results section in the Abstract. The correct sentence is: Completion rates were significantly higher within families with higher education level (82% in tertiary educated families vs. 67% and 56% in secondary and primary educated families respectively) and were strongly correlated within families (ICC = 39.6) and neighbourhoods (ICC = 5.7).There are multiple errors in There is an error in There is an error in S1 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file."}
+{"text": "Stimulant pharmaceuticals are abused among academic students to elevate mood, improve studying, intellectual capacity, memory and concentration, and increase wakefulness. This study was designed to evaluate the current situation of stimulant use among medical students and residents of Babol University of Medical Sciences.This cross-sectional study was conducted among 560 medical students and clinical residents of Babol University of Medical Sciences during the academic year 2014-2015. A self-administered questionnaire was used for data collection.Four hundred and forty-four (79.3%) students filled out the questionnaires. 49 (11%) individuals reported amphetamine and methylphenidate  use. The mean age of the stimulant drug users was 24.6\u00b14.8 years. The main initiator factor was to improve concentration . There were significant statistical correlations between stimulant drugs abuse and male gender, living in dormitor in residence and internship and past medical history of psychiatric disorders  (p<0.05).16 (32%) students started the drug use on their friends\u2019 advice; 15 (30%) due to self-medication and 12 (24%) persons with physician\u00b4s prescription.Because of significant prevalence of stimulant use, regulatory governmental policies and also planning to improve essential life skills, awareness about the side effects and complications of these drugs, screening of at-risk college students and early identification of the abusers are suggested. Medical students are potentially at higher risk of non-medical prescription use of stimulant drugs (methylphenidate and amphetamines) related to their academic conditions such as prolonged wakefulness, series of professional examinations as indicators of their competence, stress, need to enhance their ability to focus and concentrate in writing and studying; and finally, improve their academic performance -3. DrugsThe systematic review literature of Finger  revealedst to the last academic year), studying or working in the hospitals affiliated to Babol University of Medical Sciences, were invited to participate in the study. Data collection was performed with a self-administered questionnaire in which its validity and reliability were confirmed through an expert panel. Demographic characteristics and the condition of stimulant use  were assessed. All of the students were informed about the objectives of the study, and participated voluntarily, as well as confidentiality was assured to them. This study was approved by the Research Committee of Babol University of Medical Sciences. The collected data were analyzed by SPSS package Version 16. Chi-square test was used to assess the correlation between quantitative variables and independent t-test for comparison between the two groups with and without use of stimulant drugs. Results were analyzed at the significant level of 95%. This analytic observational analytical cross-sectional study was performed among medical students and residents of Babol University of Medical Sciences, Babol, North of Iran in the academic year 2014-2015. All clinical residents and medical students ; 260 (58.6%) females and 184 (41.4%) males. 98 (22.1%) in the first 5 semesters of academic year (basic course), 66 (14.9%) in physiopathology, 101 (22.7%) clerkship, 120 (27.0%) internship and 59 (13.3%) individuals in residency course. The mean age of participants was 23.7\u00b14.8 years; most of them (79.5%) were unmarried and 41.2% were living with their family. Their demographic characteristics of studied subjects are presented in Most of the students did not have the past medical history or familial history of psychiatric disorders or past history of referring to a psychiatrist or a psychologist. Forty-nine (11%) individuals reported stimulant use: 29 (6.5%) participants used ritalin while 11 (2.5%) consumed amphetamine. Among the students who recorded the cause, start time, the route and dose of drug administration, 29 (59.2% of abusers) individuals used these drugs for enhancing focus and concentration, 3 (6.1%) for increasing self-esteem and 3 (6.1%) for elevating mood. 16 (32.7% of users) individuals have started the use during recent one year period 11 (22.4%) in the last 6 months, and 3 (6.1%) for the past one month. The route of administration was ingestion in 39 (79.6% of users) students, 3 (6.1%) intravenous and 1 (2%) was inhalation. Out of 29 ritalin users 15 (51.7%) subjects, started on a daily dose of 5mg, 10 mg/day in 3 (10.3%) subjects 2.5 mg/day in 2 (6.9%) individuals; and 9 subjects (31%) recorded a daily dose of more than 10 mg. Most of them (32%) started the use of drugs due to their friends\u00b4 advice. Other reported reasons for stimulant initiation were self-medication (30%) and physician\u00b4s prescription (24%). The correlation of stimulant use with demographic and psychiatric characteristics of medical students is presented in In this research, 11% of medical students and clinical residents had ritalin or amphetamine use. This result is somewhat different with the past similar studies; in the study of Finger , 22% outIn our study, stimulant use was more prevalent in males; a significant difference was observed between two sexes (p=0.009); that is in contrast to Finger\u00b4s study results  in whichThe common ways that medical students started stimulant use were self- medication or friends\u2019 influence. Also, in Valipour\u2019s research in Iran , 50% of The most important limitations of this research are data collection using a self-administered questionnaire, not performing a structured clinical interview for diagnosis of comorbid psychiatric disorders and not examining the current use of stimulant drugs with diagnostic laboratory tests.  considering the significant prevalence of stimulant use in medical students, regulatory governmental policies and also training programs to promote life- skills and educate theim about the adverse effects of these drugs should be implemented to remedy the extension of stimulant use among medical students.In conclusion,"}
+{"text": "This applies particularly to deletion of chromosome 17p13 [del(17p)], found in \u224810% of newly diagnosed MM (ND) and at higher prevalence in advanced disease.TP53 mutations in del(17p) MM remains unresolved.10 We therefore carried out mutational analysis of a series of MM patients who had fluorescence in situ hybridization (FISH)-identified del(17p) to correlate with clinical outcomes.The prognostic impact of 11 Genomic DNA was amplified by polymerase chain reaction and screened for TP53 mutations in exons 4\u201311 using denaturing high-performance liquid chromatography . Mutations were verified by Sanger sequencing. Extended mutation testing was performed on TP53-mutated samples using targeted next generation sequencing  tested at our centre using FISH on CD138+ bone marrow cells (Miltenyi microbead isolation), del(17p) was detected in 10 out of 98 (10.2%) ND and 42 out of 188 (22.3%) relapsed patients. An additional 6 patients were diagnosed with del(17p) at another centre. Material was available for all 16 ND and 35 relapse patients for mutational screening. In 23 patients, samples were available at more than one time point (range 2\u20134). FISH analysis was performed using standard probes.ing NGS; . ClinicaTP53 mutations were identified in 18 del(17p) patients (35%) by DHPLC  were single-nucleotide variants (SNVs), a similar spectrum to that reported previously,10 although others have found deletions or insertions.2 Seventeen SNVs were documented on the International Agency for Research on Cancer TP53 database; 14 (82%) were missense mutations, two nonsense mutations and one altered a splice site. Most were predicted to produce a non-functional protein with <20% transcriptional activity. The remaining mutation was a novel in-frame indel. In 83% of samples, the variant allele frequency of the TP53 mutation was >50%, consistent with the known del(17p) in a significant proportion of cells. In three patients, additional low-level TP53 mutations were detected by NGS.Eighteen different by DHPLC . ConsistTP53 mutations, allowing us to explore the chronology of these genetic events. TP53 mutations were identified at multiple time points in 5 patients  had consistently high mutant levels at both time points. The subclonal nonsense mutation detected in case 3 was only present in the first mutated sample. Thirteen of the 18 TP53-mutated patients (72%) were mutant-positive in the first sample analyzed . However, this frequency may be an underestimate as diagnostic samples were not available from two patients who presented with del(17p), both of whom were TP53-mutated in a subsequent relapse sample (cases 5 and 10). In six patients, it was not possible to determine the chronology of their acquisition as earlier FISH results or stored samples were not available. In cases 1, 3 and 6, TP53 mutations were only detected at relapse despite mutational testing in earlier samples. Two of these patients also only acquired the del(17p) at relapse. Of note, in both the remaining two patients (cases 2 and 7), del(17p) acquisition clearly preceded the TP53 mutation. Case 2 acquired del(17p) at first relapse 34 months post-diagnosis but only acquired a TP53 mutation at their fourth relapse 73 months post-diagnosis. Case 7 presented with del(17p), was mutant-negative at relapse 17 months later, but acquired a TP53 mutation at second relapse 26 months post-diagnosis. The chronology of FISH and mutational testing for the 33 del(17p) patients without TP53 mutations is shown in Twenty-three patients were tested more than once, including 8 patients with patients . In caseanalyzed . In fiveTP53-mutated and non-mutated patients (TP53-mutated patients (56%) also had at least one other high-risk cytogenetic feature detected at some point in their disease , t or 1q gain; TP53-mutated patients . Ten TP53-mutated patients (56%) also had additional mutations in previously reported myeloma driver genes12  and most of these patients  had two or more additional mutations (DIS3 mutations (28%) appears higher.There was no difference in age at diagnosis or disease isotype between patients . Ten TP5utations ; in our TP53-mutated than in non-mutated patients  MM. TP53 haploinsufficiency in MM causes downstream p53 pathway deregulation, altering the delivery of an apoptotic response,6 but the biological consequence of the additional functional loss conferred by mutation of the remaining allele remains unclear. In this cohort, we observed that TP53 mutation usually occurred after, or simultaneously with, allelic loss of 17p13, and conferred a significantly poorer prognosis for those patients with both abnormalities. Bi-allelic inactivation of tumor suppressor genes, including TP53, has been reported to drive relapse in MM. A recent longitudinal study similarly identified that bi-allelic events leading to complete TP53 inactivation resulted in the poorest prognosis at relapse.13 Patients with the lowest levels of TP53 mRNA have also been reported to have the worst clinical outcome.14 There is also evidence of other mechanisms leading to p53 inactivation in MM, including promoter methylation15 thus investigation of TP53 mRNA and p53 protein levels may be warranted. Collectively our results confirm that, in the context of del(17p), acquisition of a TP53 mutation on the other allele confers significantly worse clinical outcomes, and suggest that allelic loss of 17p13 likely precedes such mutations. In the era of genomic medicine, there is a case for routinely screening for TP53 mutations in del(17p) MM to aid management decisions and direct these high-risk patients towards alternative treatment strategies aimed at counteracting the loss of tumor suppressor activity. Finally, the possibility of a different target gene for del(17p) in patients who do not have mutations of TP53 remains to be explored.Median overall survival (OS) from diagnosis was significantly shorter in 5 months , and med5 months . In cont"}
+{"text": "We retrospectively analyzed the risk of recurrence and conditional Disease-Free Survival (cDFS) in 63 patients with complete remission during treatment with tirosin kinase inhibitor (TKI), alone or with local treatment in metastatic renal cell carcinoma.p=0.039).Furthermore the rate of recurrence was higher in patients with brain (88%), pancreatic (71%) and bone metastasis (50%). Patients who continued TKI therapy after complete response had a longer disease free survival than patients who stopped therapy, although the difference was not significant . 2y-cDFS was better in patients treated with multimodal treatment and who continued TKIs than the other patient arms.37% patients achieve CR with TKI alone, while 63% with additional loco-regional treatments. 49% patients recurred after CR, with a median Disease free survival of 28.2 months. Patients treated with multimodal approaches present lower rate of recurrence (40% vs 61%) and longer Disease free survival compared to patient treated with TKI alone . Cessation of TKI should be carefully considered in complete responder patients. Renal cell carcinoma (RCC) is the most frequent type of kidney neoplasm in adults. RCC presents as metastatic a diagnosis in almost 30% of patients and approximately 20% metastasizes after radical or partial nephrectomy  [2]. AltIn 2012, Dr Albiges and her group described the results of a multicenter retrospective analysis including 64 patients who achieved CR during treatment with sunitinib or sorafenib administered alone or with local approaches. In this study, 53 patients (83%) stopped treatment after CR; of them, 29 patients  were still in CR at time of analysis  10]10]. CompAll calculations were conducted by means the R Software v. 3.1.2 (The R Company- Vienna- Austria)."}
+{"text": "Analysis of complete capsid sequences of the emerging norovirus GII.17 Kawasaki 308 from 13 countries demonstrated that they originated from a single haplotype since the initial emergence in China in late 2014. Global spread of a sublineage SL2 was identified. A new sublineage SL3 emerged in China in 2016. Despite the broad genetic diversity, norovirus GII.4 has predominated during the past 20 years  gene sequencing and phylogenetic and haplotype network analyses; list of complete VP1 nucleotide sequences of norovirus GII.17 Kawasaki used in median-joining haplotype network analysis; genomewide identification of 4-aa substitutions that can affect viral fitness of norovirus GII.17 Kawasaki in humans; and maximum-likelihood phylogenetic inference of complete VP1 nucleotide sequences of norovirus GII.17 Kawasaki."}
+{"text": "Bee pollen is a highly nutritive natural foodstuff. Because of its use as a comestible, the association of bacteria with bee pollen is commercially and biologically important. We report here the bacterial diversity of seven bee pollen samples  based on 16S rRNA gene amplicon metagenome sequencing. Apis spp.), bumblebees (Bombus spp.), and syrphids (Sphaerophoria spp.) (Bee pollen has for years been touted as a highly nutritious food . It is aia spp.) , 3. Theria spp.) . One issia spp.) . Microbiia spp.) . The objBee pollen samples were obtained from three different suppliers. We worked with seven such samples, five samples from Europe, one sample from Chile, and one sample from Mexico. DNA extraction for each sample was carried out with a ZymoBIOMICS DNA minikit . Amplicons of the region V3-V4 for 16S rRNA genes were amplified with primers 337F/805R , with 97Cyanobacteria, with a relative abundance of 50% to 76%. The relative abundances of other phyla were 12% to 28% for Proteobacteria, 1% to 3% for Thermotogae, and 1% to 37% for Firmicutes. Bacterial orders with a relative abundance of greater than 1% were as follows: in the sample from Chile, Rhodobacterales (10%), Rhodospirillales (8%), Rickettsiales (1%), Lactobacillales (2%), and Petrotogales (1%); in the sample from Mexico, Rhodospirillales (5%), Rhodobacterales (4%), Rickettsiales (2%), Pseudomonadales (1%), Lactobacillales (10%), and Petrotogales (2%); and in the samples from Europe, Lactobacillales (4% to 37%), Rhodobacterales (6% to 18%), Rhodospirillales (3% to 8%), Pseudomonadales (1% to 3%), Petrotogales (1% to 3%), and Rickettsiales (1% to 2%).Based on the amplicon analysis, the most prevalent phylum in all samples was the These results extend our knowledge of the diversity of bacteria associated with bee pollen and may be useful in developing procedures for microbial control during pollen production.SRP132301 (Chilean sample), SRP132302 (Mexican sample), and SRP132303 .The sequences obtained in the present study were deposited in the Sequence Read Archive (SRA) via the National Center for Biotechnology Information (NCBI) under the numbers"}
+{"text": "The authors found errors in Table\u00a01 after publication of the original article [The correct values for medical history of coronary artery disease (CAD) at baseline are 110 (40%) of all patients, 54(35.5%) of patients categorized as having normoglycaemia, 42(46.7%) of patients categorized as having intermediate hyperglycaemia, and 14 (42.4%) of patients categorized as having DM.All presented numbers and calculations in Table\u00a01 are checked. No other errors were found. The presented errors did not affect results, scientific content or conclusions.The corrected Table\u00a0The authors apologize for having presented this error in the original article."}
+{"text": "Background: The purpose of this study is to analyze the etiology, clinical presentation and outcome of neonatal intestinal obstruction at our institute.Materials and Methods: The medical record of all the patients, presented with intestinal obstruction in neonatal period during 2014 and 2015 was reviewed retrospectively for etiology, clinical features, investigations, management, and outcome.Results: Out of total 53 cases of neonatal intestinal obstruction, 27 were of intestinal atresia (9 cases (17%) were of duodenal atresia, 7 (13%) were of jejunal atresia and 8 (13%) were ileal atresias and 3 cases were found with colonic atresia); 7 were malrotation, 17 were Hirschsprung's disease (HD). All the patients were investigated with abdominal radiography and sonography. All patients were managed surgically. Overall mortality was 10/53 (18.8%). Out of 27 cases of atresia, 9 patients died . Septicemia was the cause of death in 7 patients (58.3%). Anastomotic leak was present in one mortality case. Conclusion: The most common cause of neonatal intestinal obstruction is atresia. Duodenal atresia was the most common atresia in our study followed by ileal atresia. Postoperative complications like septicemia led to most of deaths in our series. Septicemia, wound infection, hypothermia, prematurity need special attention for survival of neonates. Intestinal obstruction is the most common surgical emergency in the neonatal period. Early and accurate diagnosis of intestinal obstruction is paramount for proper patient management. It can be divided into\u2013 High intestinal obstruction like duodenal atresia, jejunal atresia, and malrotation or Low intestinal obstruction like colonic atresia, ileal atresia, Meckel's diverticulum with bands and HD. Vomiting is the chief complaint in high intestinal obstruction whereas abdominal distension with delayed or non-passage of meconium is the predominant complaint in low intestinal obstruction.[1-4] The purpose of this study is to analyze the etiology, clinical presentation, and outcome of neonatal intestinal obstruction at our institute.It is a retrospective case series. The medical record of all the patients, presented with intestinal obstruction in neonatal period during 2014 and 2015 was reviewed retrospectively for etiology, clinical features, investigations, management, and outcome at RNT Medical College. Patients of anorectal malformation and esophageal atresia were excluded from the study. Cases of meconium ileus which were managed conservatively were also excluded.Patients of duodenal atresia were treated with Kimura's duodeno-duodenostomy. Patients of jejuno-ileal atresia, colonic atresia and Meckel's diverticulum were treated by resection and anastomosis. HD was managed with initial colostomy; malrotation was managed by Ladd procedure.A total of 53 cases were treated from January 01, 2014 till December 31, 2015. Among them, 27 patients had intestinal atresia, 7 had malrotation, 17 had HD, and 2 had Meckel's diverticulum (Table 1). There were 40 males and 13 females (M: F- 3:1). Among males, nineteen had intestinal atresia, 14 had HD, 6 had malrotation, and 1 had Meckel's diverticulum. Age of presentation varied from 1 day to 24 days. Median age of presentation for patients with intestinal atresia was 3 days (age range 1-10 days), for HD was 7 days (age range 2-24 days), and for patients with malrotation it was 11 days (age range 2-19 days). Both patients with Meckel's diverticulum presented at day 2 of life. Median weight for patients with intestinal atresia was 2 Kg (1.2-3 kg), and for HD was 2.4 kg (1.6-2.8 kg). Median weight was 2.5 kg and 2 kg for malrotation and Meckel's diverticulum respectively. Forty-two patients (79%) had birth weight <2.5 kg and 15 patients were premature (28%). Twenty eight patients (53%) presented with bilious vomiting as chief complaint of these 24 patients had intestinal atresia. Rest of the 25 patients (47%) had abdominal distension and delayed passage of meconium as chief complaint; out of these 17 cases were found to have HD.Intestinal atresia cohort comprised of 9 cases (17%) of duodenal atresia, 7 (13%) cases of jejunal atresia, 8 (13%) patients of ileal atresia, and 3 cases of colonic atresia. Type I was the most common type of duodenal atresia. In contrast, type III was the most common type in patients with jejunal, ileal and colonic atresia. Out of nine cases of duodenal atresia, 8 (89%) patients had type I while 1 (11%) had type III atresia. Out of 8 cases of ileal atresia, 1 (12.5%) had type I, 5 (62.5%) had type III, and 2 (25%) had type IV atresia. Out of 7 cases of jejunal atresia, 5 (71.5%) had type III and 2 (28.5%) had type IV atresia. All colonic atresia patients had type III atresia. Babies with atresia and Meckel's diverticulum presented earlier after birth while those with HD and other causes of obstruction presented late. Median age of presentation for intestinal atresia, HD, and malrotation was 3 days, 7 days and 11 days respectively. Median age of presentation for Meckel's diverticulum was 2 days. Most atresia patients (12/27- 44.4%) were premature as compared to only three premature patients in other group (3/26- 11.5%). Among these 27 cases of atresia, 8 cases (29.6%) had associated anomalies including anorectal malformation (ARM) in 2, volvulus in 3, tracheo-esophageal fistula in 1, malrotation in 1, and meconium ileus in 1. No associated anomalies were detected among patients having pathologies other than bowel atresia.All patients were investigated with their respective modalities such as abdominal radiograph, ultrasound abdomen, upper and lower GIT contrast studies, laboratory investigations etc. All patients underwent their respective operations depending upon diagnoses. Sepsis (12 patients- 22.6%) and pneumonitis (4 patients- 7.5) were the postoperative non-surgical complications. Anastomotic leak (1 patient- 1.9%) and wound infection (1 patient- 1.9%) were surgical complications seen in this series. Overall postoperative mortality was 10/53 (18.8%); 9 patients died  were of intestinal atresia cohort; in rest of 26 cases, only 1 patient died . The mortality was attributed to only septicemia in 7 patients, pneumonitis in 2 patients, anastomotic leak in one patient and wound infection leading to septicemia in one patient. All the 10 deaths reported in this study also had birth weights <2.5 kg and 9 of these 10 mortality cases were premature . Out of nine patients of intestinal atresia who died, 5 patients had associated anomalies . Hypothermia, metabolic acidosis, and septic shock were main mortality events in our series.This series described our experience of managing neonatal intestinal obstruction over a period of two years. More than half of the patients in the study cohort had intestinal atresia as an etiology of congenital neonatal intestinal obstruction. Other etiologies were HD, Malrotation and Meckel's diverticulum with band obstruction. Duodenal atresia formed the most of cases in the patients with intestinal atresia. The incidence of duodenal atresia has been estimated as 1 in 6000-10,000 live births.[1] Boys are affected more commonly than girls. Eight of the nine patients with duodenal atresia were male in our series. More than 50% patients of duodenal atresia had associated congenital anomalies and classical double bubble sign on X-ray abdomen is enough to conclude the duodenal obstruction.[2] In our study 9 cases (33%) out of 27 were of duodenal atresia, occurring more commonly in boys and 5 cases had associated anomalies which is in agreement to the reported literature. Jejunoileal atresia occurs in approximately 1 in 5,000 live births, it occurs equally in males and females, and about one in three infants is premature.. In our study, 7 cases had jejunal atresia and 8 cases had ileal atresia. Colonic atresia contributes 1.8-15% of all intestinal atresias, with an incidence of 1:40,000 live birth.[5]. In our study, three cases colonic atresia were encountered making an incidence of 11%. Contrast enema study is sometimes required to reach the diagnosis of colonic atresia. In most of the cases, primary resection and anastomosis is not possible due to the presence of distal short/micro colon and ruling out associated HD. If feasible, primary anastomosis is done otherwise staged procedure could be done. We had 3 cases of colonic atresia in which primary anastomosis was done; 1 case died out of 3. Hirschsprung's disease is present concomitantly in at least 2% of population. Some authors believe that it is imperative to rule out HD before reestablishing intestinal continuity in every patient with colonic atresia. We did not rule out HD in our patients with colonic atresia before primary anastomosis but the biopsy of the resected specimen and from the rectum showed presence of ganglion cells in all three cases.HD is a developmental disorder characterized by absence of ganglia in the distal colon, resulting in a functional obstruction.[6] Its incidence is 1 in 5,000 live births. It is the second most common cause of intestinal obstruction after atresia in our study with a total of 17 cases out of 53. Intestinal obstruction due to midgut malrotation in newborns is well known entity. The incidence of malrotation is \u223c1:500 births and the symptomatic incidence is 1:6000. Any neonate presenting with sudden onset of bilious vomiting should be suspected for malrotation and volvulus. In our series, 7 cases had isolated malrotation while 1 case of sigmoid colonic atresia was associated with malrotation. All patients successfully underwent Ladd procedure as advocated by in 1932 by William Ladd.[9] Meckel's diverticulum is a rare cause of intestinal obstruction in neonates, 2 cases were reported in our study both were timely operated and survived.Mortality is higher in atresia cohort in our series (33%). Prematurity, low birth weight, presence of other anomalies, postoperative septicemia, pneumonitis, anastomotic leakage and wound sepsis were considered various causes for mortality in our series.The most common cause of neonatal intestinal obstruction is atresia. Duodenal atresia was the most common atresia in our study followed by ileal atresia. Highest mortality was found in cases of atresia because most of these were premature and had low birth weight. Mortality is higher in patients of atresia with associated anomalies. Septicemia, wound infection, hypothermia, prematurity need special attention for survival of neonates.Source of Support: NoneConflict of Interest: None"}
+{"text": "P < 0.0001; bronchodilators 95% to 82%, P = 0.0024; corticosteroids 81% to 45%, P < 0.0001). Although variability in management remains high, encouragingly significantly fewer doctors are prescribing ribavirin, bronchodilators, and corticosteroids compared to 20 years ago.In 1995, the European Society for Paediatric Infectious Diseases (ESPID) carried out a survey of its members to assess the variation in management of respiratory syncytial virus (RSV) bronchiolitis. The aim of the current study was to carry out a similar survey 20 years later to assess how the management had changed. An electronic, structured, English language survey, based on the United Kingdom National Institute for Health and Care Excellence (NICE) bronchiolitis draft guideline, was sent to ESPID members in March 2015. Questions asked included information on treatment practices of infants with bronchiolitis and doctor demographics. We received responses from 135 doctors (14% of the ESPID members) who worked in 115 hospitals. 56% of the doctors used a written guideline to manage bronchiolitic infants. All doctors stated that they isolated individually or in cohorts all hospitalised bronchiolitis infants. The level of oxygen saturation suggested as an indication to administer supplemental oxygen varied between <89% and <95%. We found significant reductions in the use of ribavirin, bronchodilators, and corticosteroids from 1995 to 2015 (ribavirin 57% to 13%,  Respiratory syncytial virus (RSV) infects almost all children by two years of age. In the UK and other developed nations, between 1 and 4% of the entire birth cohort is hospitalised due to viral bronchiolitis each year, with a large degree of regional variability .The management of RSV bronchiolitis (and that caused by other viruses) is purely supportive with supplemental oxygen and feeding support . RibavirIn 1995, the European Society for Paediatric Infectious Diseases (ESPID) carried out a survey of its members to assess the variation in management of RSV bronchiolitis in infants throughout Europe . The aimn = 970) in March 2015. The questions asked included information on treatment practices in infants with RSV bronchiolitis  and demographics .An electronic, structured, English language survey, based on the United Kingdom (UK) National Institute for Health and Care Excellence (NICE) bronchiolitis draft guideline (the full guideline was published in June 2015 ), was seIn the 1995 survey, high-risk patients were defined as per the 1994 (23rd edition) American Academy of Pediatrics (AAP) Report of the Committee on Infectious Diseases (\u201cRed Book\u201d) and included infants with complicated congenital heart disease, bronchopulmonary dysplasia, cystic fibrosis, and other lung conditions; premature infants; children with immunodeficiency; recent transplant recipients; patients undergoing chemotherapy for malignancy; infants who are severely ill; and all patients mechanically ventilated for RSV infection .In the 2015 survey, we categorised patients by disease severity rather than high-risk categories: any infant with RSV bronchiolitis, infants requiring hospitalisation, or infants requiring high dependency/intensive care.Proportions were compared using Fisher's exact test. Statistical analysis was carried out with IBM SPSS Statistics .This study did not require ethical approval.We received responses from 135 doctors (14% of the ESPID members) who worked in 115 hospitals across the world. Of those, 109 members (12% of the ESPID members) from 95 hospitals fully completed the questionnaire . There were 83 (76%) consultants, 16 (15%) trainees, and 10 (9%) other grades. Of the 83 consultants, 45 (41%) were subspecialists in infectious diseases, 32 (29%) were general paediatricians, 2 (2%) were subspecialists in respiratory medicine, 2 (2%) were in paediatric intensive care, and 2 (2%) listed their specialty as \u201cother.\u201d 67 (61%) worked in university hospitals, 25 (23%) in district hospitals, 7 (6%) in community hospitals, and 10 (9%) in \u201cother\u201d settings. Only 61 (56%) doctors used a written guideline for the management of infants with bronchiolitis.72 (66%) doctors advised respiratory virus testing in all hospitalised bronchiolitic infants, 21 (19%) in only a subset of hospitalised bronchiolitic infants , and 8 (7%) in all infants with bronchiolitis presenting to the emergency department (ED) even if they were discharged home, and 8 (7%) doctors advised against taking respiratory samples from any infants. 50 (46%) doctors worked in hospitals that used point of care tests (POCTs) in the ED to test for RSV infection in infants being admitted to the hospital and 45 (41%) used POCTs to help decide which inpatients to isolate in inpatient wards. Ninety-three (85%) doctors sent respiratory samples to the microbiology/virology laboratory for testing. 57 (61% of those who sent samples to the laboratory) doctors responded that their hospital laboratory routinely tested samples for RSV, influenza, and other respiratory viruses, 25 (27%) only tested samples for RSV and influenza viruses, 8 (9%) only tested samples for RSV, 8 (9%) tested for \u201cother\u201d respiratory viruses, and 1 (1%) only tested for influenza viruses.29 (27%) doctors reported that their hospital isolated infants with RSV infection separately from infants with bronchiolitis caused by other viruses, 25 (23%) doctors put all bronchiolitic infants requiring hospital admission into a cubicle/single room and did not create \u201cbronchiolitis bays\u201d , 22 (20%) isolated infants with the same virus together , 14 (13%) created a \u201cbronchiolitis bay\u201d for all infants with bronchiolitis irrespective of the virus(es) the infants had, and 11 (10%) doctors had another unspecified infant isolation policy.83 (76%) doctors suggested only carrying out a blood gas in hospitalised infants with severe bronchiolitis requiring HDU/PICU, 12 (11%) in all hospitalised infants with bronchiolitis, and 7 (6%) in all infants with bronchiolitis  and 7 (7%) advised against doing blood gas routinely. 65 (60%) doctors suggested only performing a chest X-ray in hospitalised infants with severe bronchiolitis requiring HDU/PICU, 26 (23%) advised against routinely doing chest X-rays, 9 (8%) advised chest X-rays for all hospitalised infants (even if not requiring HDU/PICU) with bronchiolitis, and 9 (8%) advised chest X-rays for all infants with bronchiolitis . The level of oxygen saturation suggested as an indication to administer supplemental oxygen varied between <89% and <95% .90 (83%) doctors reported that they administered supplemental oxygen on general paediatric wards (excluding HDU/PICU) using low flow (\u22642\u2009L/min) nasal cannulae, 55 (50%) used face masks, 41 (38%) used humidified high flow oxygen therapy , 25 (23%) used continuous positive airway pressure (CPAP), 17 (16%) used a headbox, and 9 (8%) used an incubator. The totals add up to more than 100% as most doctors responded that they used more than one method to administer supplemental oxygen.The interventions used to manage infants with bronchiolitis varied considerably .P < 0.0001; bronchodilators 95% to 82%, P = 0.0024; corticosteroids 81% to 45%, P < 0.0001) , corticosteroids , or ribavirin in any patient  and those doctors not using the medication in any patient between 1995 and 2015, we found significant reductions in the use of each of the three medications from 1995 to 2015  .Overall, 43 (39%) doctors gave written advice to parents of bronchiolitic infants: 24 (22%) if discharged from the ED or the inpatient ward, 12 (11%) if discharged from ED (and not if discharged from the inpatient ward), and 7 (6%) if discharged from the inpatient ward (and not if discharged from the ED).We have demonstrated a wide variation in the management of infants with RSV bronchiolitis by members of ESPID, predominantly in Europe. In 2015, fewer doctors prescribed bronchodilators, corticosteroids, and ribavirin than in 1995, but many infants still routinely received inappropriate medications and underwent unnecessary investigations despite a lack of evidence for their efficacy.The 1995 ESPID poll  focussedOur study has several strengths and a number of limitations. We have surveyed a large number of ESPID members covering a range of countries, predominantly within Europe, and received a similar number of completed responses to the 1995 survey (88 in 1995 and 109 in 2015). However, only 12% of the total number of members of ESPID completed the 2015 survey potentially biasing the results as the responses we received may not have been representative of all ESPID members. The 2015 survey included different grades of doctors (trainees and consultants) working in a variety of different hospital settings  and specialties  suggesting that the data are generalizable to other hospitals. There were differences in the questions asked in the two surveys and how infants were categorised, as high-risk or by increased severity of illness, which may have influenced how the respondents completed the questionnaire and could have affected the results. We feel, however, that this is unlikely to have significantly influenced the results of the study and the overall results are in keeping with other studies demonstrating an improvement in care with time [In summary, there remains a wide variation in the management of RSV bronchiolitis in infants by members of ESPID. Although variability in management remains high, encouragingly significantly fewer doctors are prescribing ribavirin, bronchodilators, and corticosteroids compared to 20 years ago. Ongoing education is required to ensure this trend continues."}
+{"text": "Solitary pink lesions in differential diagnosis with hypopigmented/amelanotic melanoma present a diagnostic challenge in daily practice and are regularly referred for second expert opinion. Reflectance confocal microscopy (RCM) has been shown to improve diagnostic accuracy of dermoscopically equivocal pink lesions. No studies have been performed to evaluate the effect of adding a second expert reader and automatic removal of lesions with discordant management recommendations and its potential effect on diagnostic sensitivity and final management of these lesions in retrospective or telemedicine settings.To improve diagnostic accuracy and reduce potential mismanagement of dermoscopically equivocal pink cutaneous lesions by implementing double reader concordance evaluation of RCM images.316 dermoscopically equivocal pink lesions with dermoscopy-RCM image sets were evaluated retrospectively. Accuracy of three readers was evaluated by single reader evaluation of dermoscopy only and dermoscopy-RCM image sets and finally by double reader evaluation of dermoscopy-RCM image sets. Lesions with discordant diagnosis between two readers were automatically recommended for excision.Dermoscopy only evaluation resulted in an overall sensitivity of 95.9% and specificity of 33.6%, with 1 of 12 amelanotic melanomas mismanaged. Dermoscopy-RCM image set single reader evaluation resulted in an overall sensitivity of 93.9% and overall specificity of 54.2%, with 1 of 12 melanomas mismanaged. Dermoscopy-RCM image set double reader concordance evaluation resulted in an overall sensitivity of 98.3% and specificity of 42.7%, with no amelanotic melanoma mismanagement.Evaluation of dermoscopy-RCM image sets of equivocal pink lesions by a single reader in telemedicine settings is limited by the potential for misdiagnosis of dangerous malignant lesions. Double reader concordance evaluation with automatic referral of lesions for removal in the case of discordant diagnosis improves the diagnostic sensitivity in this subset of lesions and reduce potential misdiagnosis in settings where a second expert opinion may be employed. Pink lesion differential diagnosis ranges from inflammatory processes to aggressive skin malignances that may present as pink to red papules, plaques or nodules with little to absent melanin pigmentation ,2. The un tissue . In addin tissue \u201316. Recen tissue .No specific studies have been performed to evaluate the potential effect of double reader concordance evaluation of dermoscopy-RCM image sets to improve accuracy and safety of management of dermoscopically equivocal pink lesions. Our goal in this study was to determine potential improvement of diagnostic accuracy and chosen management of this group of lesions in a telemedicine consultation setting applying double reader concordance evaluation to reduce potential equivocal lesion management mistakes in telemedicine settings where a second expert opinion may be employed.This was an Ethical Committee approved observational retrospective analysis within the European Project DIAGNOPTICS (grant n. 621066) based on 316 consecutive dermoscopically equivocal pink cutaneous lesions collected from 316 different patients that were evaluated with dermoscopy and RCM imaging for diagnostic decision in order to rule out a diagnosis of melanoma during the period of January 2009 to January 2012 at the Dermatology Department at the University of Modena and Reggio Emilia (UNIMORE). All research was approved by IRB  and was conducted according to the principles expressed in the Declaration of Helsinki. Patient consent was obtained in written form. All lesions were evaluated and imaged with digital dermoscopy and with RCM, followed by excision for histopathological analysis. The inclusion criteria for lesions in this study were: (i) lesion detected by clinical naked-eye examination with absent pigmentation or containing less than 10% pigment; (ii) absence of pigment network; (iii) all lesions excised with matching histopathology report; (iv) availability of digital dermoscopy images; (v) availability of a complete standard set of RCM images. We tested the accuracy of an experienced dermoscopy reader (Reader 1) who evaluated only dermoscopy images via telemedicine cloud based server versus two separate experienced RCM readers who individually evaluated dermoscopy-RCM image sets, Reader 2 at UNIMORE and Reader 3 via telemedicine cloud based server. All readers were blind to histopathology diagnosis. Department patient code and private information  was not provided to the readers and the image sets were placed into separate computer folders and numbered (001 to 316) differently than the department patient code to ensure that the evaluations were made in blind.Digital dermoscopy images were obtained with DermLite FOTO System . RCM images were obtained with a reflectance confocal microscope  using a 830 nm laser at a maximum power of 20 mW. RCM images of 0.5 mm x 0.5 mm were acquired with a lateral resolution of 1 \u03bcm and an axial resolution of 3\u20135 \u03bcm and stitched into composite images that covered between 4 to 8 square mm mosaics . A minimum of three mosaics were obtained at different depths, corresponding to the stratum granulosum/spinosum, the dermal-epidermal junction, and the papillary dermis. The cases in this study included the following malignancies: amelanotic/hypomelanotic melanomas (AMM), basal cell carcinomas (BCC), squamous cell carcinomas (SCC) and benign lesions , seborrheic keratosis (SK)), or other benign lesions, and were made available for the evaluation during the time period of January to March 2016. The images were evaluated in blind by 3 readers each with at least two years of dermoscopy and RCM clinical experience. Image sets for Reader 1 and Reader 3 were made accessible on a DICOM and HIPAA compliant secure cloud based server where access to data was only possible with individual login and password. Reader 2 retrospectively evaluated the patient folders at UNIMORE. Each reader was asked to provide their management decision and suspected diagnosis based only on the provided image sets into a Microsoft excel file. Management was grouped into two categories: (i) excision or (ii) no-excision. Management decision confidence level was graded: (i) low or (ii) high. In order to test concordance of double reading, data from the excel files (Reader 2 and Reader 3) were matched and chosen for automatic management with excision when (1) management decision was concordant for excision, (2) management decision was discordant or (3) management decision was concordant for benign diagnosis but with double low confidence.Statistical evaluation was carried out with SPSS statistical package . Diagnostic values of sensitivity and specificity of individual readers were calculated for malignant versus benign lesions. Absolute and relative frequencies of confidence in benign and malignant lesion management were calculated. \u03c7\u00b2 test was used to compare confidence level of management with actual histopathologic diagnosis. Cohen\u2019s kappa coefficient was calculated in order to find association between double reader management and histologic diagnosis, a P-value < 0.05 was considered significant. Receiver Operating Characteristic (ROC) was calculated using binary management values  as the state variable and the overall management decision with confidence level  as the test variable.The study population consisted of 172 histopathology proven malignant cases including AMM , BCC , SCC  and two other malignancy types which included one Kaposi sarcoma and one syringoid eccrine carcinoma . The remaining 144 cases included nevi , SK/SL/LPLK/AK  and other benign lesions including dermatofibromas, angiokeratomas and angiomas classified as other . The evaluations were performed by Reader 1 (dermoscopy only) and by Readers 2 and 3 (dermoscopy-RCM image sets) for a total of 316 dermoscopy evaluations and 632 dermoscopy-RCM image set evaluations. Reader 1 (dermoscopy only) achieved an overall sensitivity of 95.9% and specificity of 33.6%, with 1 of 12 (8.3%) melanomas misdiagnosed.Dermoscopy-RCM image set single reader evaluation resulted in an overall sensitivity of 93.9% (ranging between 91.3% to 96.5%) and specificity of 54.2% (ranging between 53.1% to 55.2%). Sensitivity of AMM diagnosis was 91.7% for Reader 2 and 100% for Reader 3 respectively, with 1 out of 12 MMs (8.3%) mismanaged by Reader 2. Overall diagnostic sensitivity for BCC was 94.2% (ranging between 90.6% to 97.8%) and 100% for SCC. Overall specificity of nevi diagnosis was 57.1% (ranging between 55.3% to 58.9%), 42.5% for SK/SL/LPLK/AK (ranging between 36.4% to 48.5%) and 63.9% (ranging between 61.7% to 66.0%) for other benign lesions. ROC area under the curve for Reader 2 was 0.776 (p < 0.001) and 0.812 for Reader 3 (p < 0.001).Dermoscopy-RCM double reader evaluation utilizing the method of computer automated referral of lesions for removal when two readers had discordant management decisions resulted in an overall sensitivity of 98.3% and specificity of 42.7%; lesions with concordant management decisions for no-excision were considered benign and those with concordant management decisions for excision were considered malignant . CombineIndividual reader confidence was evaluated for Readers 2 (R2) and 3 (R3). For overall malignant lesions R2 managed 143/172 cases (83.1%) and R3 managed 156/172 cases (90.7%) with high confidence. For overall benign lesions R2 managed 54/144 cases (37.5%) and R3 managed 61/144 cases (42.0%) with high confidence. For malignancies present in the study population, high confidence for AMM diagnosis was reported in 7/12 cases (58.3%) by R2 and 11/12 cases (91.7%) by R3. BCC diagnosis with high confidence was reported in 115/138 cases (83.3%) by R2 and 128/138 cases (92.8%) by R3. SCC diagnosis with high confidence was reported 100% of cases by R2 and 17/20 cases (85%) by R3. and   by R2 and 28/56 cases (50.0%) by R3. Spitz naevi diagnosis with high confidence was reported in 2/8 cases (25.0%) by R2 and 1/8 (12.5%) by R3. SK/SL/LPLK/AK diagnosis with high confidence was reported in 13/33 (39.4%) by R2 and 10/33 (30.3%) by R3. For all other benign lesions R2 reported high confidence in diagnosis in 19/47 cases (40.4%) and R3 22/47 (46.8%). R2 and R3 confidence level frequencies are reported in  and  .The purpose of our study was to determine the management safety of equivocal pink cutaneous lesions referred for telemedicine second expert opinion based on dermoscopy-RCM image sets. Since pink lesions present fewer discernable features than their counterparts these lesions are more often referred to colleagues for second opinion or excised at once due to uncertainty. If a clinician excises all equivocal lesions sensitivity will approach 100% but comes at the expense of a significantly decreased specificity and imbalance between patient safety and healthcare expenditures. Our goal in this study was to test a variety of methods of store and forward retrospective evaluation of patient cases and if the addition of a second blind confocal reader has the capability to produce safer management results of equivocal lesions, particularly in telemedicine settings.In the general population AMM accounts for up to 8% of cutaneous melanomas and represents an important diagnostic pitfall for clinicians. AMM also presents a surgical management problem as it can mimic a variety of benign and malignant lesions such as BCC, AK, benign inflammatory plaques and Paget or Bowen disease ,15. The In our study Reader 1 evaluated only digital dermoscopy images via telemedicine access which resulted in an overall sensitivity of 95.9% (BCC: 95.7% and MM: 91.7%) and a specificity of 33.6%, with mismanagement of 1 AMM and 16 BCCs . In a real-world clinical scenario the mismanagement of an AMM can be potentially life threatening since in settings lacking strict follow up control with sequential digital dermoscopy these lesions may go unnoticed for an extended period of time. Our results delineate the limitation of single reader image evaluation specifically in the case of equivocal pink cutaneous lesions where the diagnostic sensitivity may be insufficient to keep the percentage of missed melanomas at a safe level due to the absence of typical criteria in this group of lesions and lower diagnostic confidence level \u201322.RCM has been shown to improve diagnostic accuracy of pink lesions in various settings thanks to the refractive index of melanocytic structures that produce visible reflection in RCM images regardless of their clinical lack of pigmentation ,15. A reRegarding confidence level in diagnosing AMM R2 managed 7/12 (58.3%) correctly with high confidence, 4/12 (33.3%) correctly with low confidence and mismanaged 1/12 (8.3%), reporting the mismanaged lesion as benign with low confidence. R3 managed 11/12 (91.7%) correctly with high confidence and 1/12 (8.3%) correctly with low confidence. The variability of confidence between two readers with similar experience levels suggests that this group of lesions may contain subtle morphologic changes may not be as pronounced as in pigmented MM counterparts and leave more room for potential mistakes in lesion management.For BCC diagnosis R2 managed 115/138 (83.3%) correctly with high confidence, 10/138 (7.2%) correctly with low confidence and mismanaged 5/138 (3.6%) with low confidence and 8/138 (5.8%) with high confidence. R3 managed 128/138 (92.8%) correctly with high confidence 7/138 (5.1%) with low confidence and mismanaged only 3/138 (2.2%) with benign diagnosis and low confidence. These values show that RCM is valid for confident BCC diagnosis even in the case of equivocal pink lesions. The BCC cases mismanaged by both readers were all early superficial types present only on the trunk or legs and away from cosmetically sensitive areas such as the face. Since BCC rarely metastasis these mismanaged false negative lesions would not present significant health risk to these patients and most likely would be diagnosed on a future follow-up visit when dermoscopic features would become mature and more apparent.In our study double reading of dermoscopy-RCM image sets enhanced the overall diagnostic sensitivity (98.3%) and minimized the likelihood to mismanage an invasive melanoma that was otherwise mismanaged with dermoscopy only and dermoscopy-RCM image set single reader evaluations. This previously mismanaged AMM was selected for removal per double reader evaluation due to reader discordance in selected management . Additionally, BCC sensitivity (98.6%) was also improved with double reading evaluation reducing 16 mismanaged BCC by single reader evaluation  to only 2 mismanaged cases. 12/16 of these cases (75.0%) were selected for removal due to reader discordance and 2 cases (12.5%) were removed based on concordant benign diagnosis with both readers reporting low confidence. Overall the improvement of sensitivity resulting for the addition of a second evaluator benefited most from discordant management decision rather than two readers reporting benign management decision with double low confidence. Our results further delineate dermoscopy and RCM as complimentary/synergistic methods for diagnosis of amelanotic/lightly-colored skin lesions as delineated in a recent study by Guitera et al. where RCM sensitivity was 66.6% and 72.9% for melanoma and BCC diagnosis, respectively and its specificity for non-malignant lesion diagnosis was 56.1%. Moreover, RCM is the only clinically applicable tool permitting clear visualization of morphologic features of non-pigmented pink cutaneous lesions that can be applied to both melanocytic and non-melanocytic lesions at the bedside and in a telemedicine setting \u201328.In settings where sequential digital dermoscopy (videodermoscopy) is available we recommend to follow any negative flat lesion that has been referred for confocal teleconsultation and evaluated as benign with no-excision management as videodermoscopy permits objectively controlled follow-up of these lesions referred for consultation and the possibility to identify changes in the lesions over time that can be signs of early malignancy. In the case of any uncertainty in raised or palpable lesions biopsy is advised to reduce the risk of potential mismanagement of a false negative diagnosis/management recommendation ,29. Our Dermoscopically equivocal pink lesions fall into a category of difficult to diagnose lesions that more commonly invoke the need for second expert opinion that is now possible through telemedicine store and forward technology ,31. DistIn conclusion, we showed that the application of a second expert check system in telemedicine settings with an automatic management decision to excise any lesions with discordant management between two readers considerably improved the sensitivity threshold of diagnosis and safety for the patient. Additionally, the use of RCM that permits near histologic non-invasive biopsy enabled the maintenance of an acceptable specificity of lesion diagnosis. With the broadened popularity of RCM and its diffusion into clinical practice the use of telemedicine evaluation will inevitably increase in order to connect patients with experts around the globe particularly in equivocal case presentations. The addition of double reader concordance evaluation of dermoscopy-RCM image sets in this group of lesions may be considered as a safety net for continued spread of the technology and safe management of equivocal pink lesions. Our study should be considered as preliminary and additional studies are warranted to confirm these results."}
+{"text": "Obesity is a condition in which an excess body fat has developed to the point that health is adversely affected.4At a recent World Small Animal Veterinary Association One Health meeting, canine obesity was officially classified as a disease, which is consistent with its classification in people.5The last study to report obesity prevalence in pet dogs in the UK was published in 2010. The study found 59 per cent of dogs were classified as overweight or obese.6Between June 2016 and October 2017, dog owners attending seven different family pet shows in five UK locations  consented to their dog having a body condition score assessment by a team of experienced veterinary nurses. Data from 1100 adult (\u226524 months) and 516 juvenile (<24 months) dogs were available for analysis. In adult dogs, 715 (65 per cent) were overweight (body condition score of 6/9 to 9/9) and 99 (9 per cent) were obese (body condition score of 8/9 or 9/9). Most concerning was the prevalence of obesity in the juvenile dogs examined, where 190 (37 per cent) and 16 (3 per cent) were classified as overweight and obese, respectively. Further, the prevalence increased steadily during the growth phase, from 21 per cent (21/100) in dogs younger than six months of age to 52 per cent (16/31) in dogs 18 to 24 months of age.To date, the veterinary profession has not taken the problem of obesity seriously enough. For example, veterinary surgeons infrequently record weight and body condition during veterinary consultations,9Veterinary surgeons infrequently record weight and body condition during veterinary consultationswww.waltham.com/resources/puppy-growth-charts.Proactive monitoring of body weight and body condition throughout life would be fundamental to any such preventive plan."}
+{"text": "Aspergillus IgG at 6 and 12 months following initiation of therapy in a cohort of 206 CPA patients referred to the UK National Aspergillosis Centre (NAC), Manchester between April 2013 and March 2015. One hundred and forty-two patients (69%) were azole na\u00efve at presentation and 105 (74%) (Group A) were commenced on itraconazole, 27 (19%) on voriconazole, and 10 (7%) were not treated medically. The remainder  had previously trialled, or remained on, azole therapy at inclusion (Group B) of whom 46 (72%) received itraconazole, 16 (25%) voriconazole, and 2 (3%) posaconazole. Initial therapy was continued for 12 months in 78 patients (48%) of those treated; the azole was changed in 62 (32%) patients and discontinued in 56 (29%) patients for adverse reactions , azole resistance , clinical failure  or clinical stability . Azole discontinuation rates were higher in Group B than in Group A . For all patients who survived, weight increased , mean Aspergillus IgG declined from 260 (baseline) to 154 (12 months) and QoL improved from 62.2/100 (baseline) to 57.2/100 (12 months). At 12 months, there was no difference in median survival between Groups A and B . The rate of emergence of resistance during therapy was 13% for itraconazole compared to 5% for voriconazole. Bronchial artery embolization was done in 9 (4.4%) patients and lobectomy in 7 (3.2%). The optimal duration of azole therapy in CPA is undetermined due to the absence of evidenced based endpoints allowing clinical trials to be undertaken. However we have demonstrated itraconazole and voriconazole are modestly effective for CPA, especially if given for 12 months, but fewer than 50% of patients manage this duration. This suggests extended therapy may be required for demonstrable clinical improvement.There is a paucity of evidence surrounding the optimal antifungal therapy for use in chronic pulmonary aspergillosis (CPA) and the duration of therapy remains unclear. We retrospectively evaluated treatment outcomes, including change in quality of life scores (St George\u2019s Respiratory Questionnaire (QoL)), weight and  Aspergillus nodules, chronic cavitary pulmonary aspergillosis (CCPA), sub-acute invasive aspergillosis (SAIA), and chronic fibrosing pulmonary aspergillosis (CFPA) [Chronic pulmonary aspergillosis (CPA) is an uncommon, slowly destructive pulmonary syndrome characterised by progressive cavitation, fibrosis, and pleural thickening. Most common in patients with underlying cavitating lung disease or structural pulmonary anomaly, CPA confers high morbidity and mortality . The spes (CFPA) . Elements (CFPA) .The clinical course of CPA is highly variable between patients as is the associated pulmonary and systemic symptom burden. At present there is no established correlation between symptoms, associated biochemical and serological markers of infection, and disease severity ,4,5. SurThe efficacy of treatment in CPA is not well established but anecdotally reduces symptom burden and may improve prognosis ,11. CurrAt the National Aspergillosis Centre, patients are usually initiated on itraconazole as primary therapy. Reasons for starting an alternative azole such as voriconazole include contraindications to itraconazole use, itraconazole resistance, and high burden of disease, such as presence of multiple aspergillomas. Regardless of the azole initiated, all patients undergo regular therapeutic drug monitoring and dose adjustment.Aspergillus IgG, weight, quality of life assessment questionnaires such as the St George\u2019s Respiratory Questionnaire (SGRQ) and sputum microbiology [Establishing objective therapeutic response in CPA is difficult and at present there is no evidence to support the use of commonly used measures of therapeutic response, including obiology ,14. Crosobiology  NonethelThis retrospective single centre study aims to assess the \u2018real life\u2019 impact of oral triazole therapy on quality of life, body weight and serology over 12 months, specifically comparing itraconazole and voriconazole.A retrospective review of 223 patients referred to the National Aspergillosis Centre (NAC), Manchester, UK over a 24-month period (April 2013 to March 2015) was performed. All patients were assessed against the recent European Society of Clinical Microbiology and Infectious Diseases and European Respiratory Society (ESCMID/ERS) guidelines to confirm the diagnosis of CPA [Aspergillus-specific IgG titer (ImmunoCap (Phadia/ThermoFisher)), SGRQ scores, Medical Research Council (MRC) dyspnea score, weight and prior antifungal therapy. Alterations in azole therapy and the rationale for this were also documented. Survival rates were calculated at 12 months.Data collected at 0, 6 and 12 months included demographics , Aspergillus-specific IgG titers were extracted from electronic medical records. Radiological response to therapy, inflammatory markers, and therapeutic drug monitoring (TDM), culture results, and resistance mechanisms were not collected as part of the study.Date of azole initiation, dose, adverse drug events, and resistance during therapy, alteration or discontinuation of therapy and co-morbid conditions were retrieved from the patients\u2019 case-notes. SGRQ scores, weight and MRC dyspnea scores at 0, 6 and 12 months were extracted from an established prospectively collated patient database established by the NAC. Same therapy\u2014refers to individuals who remained on the primary therapy documented at study inclusion for the entire study period, irrespective of dose or dosage adjustments.Changed therapy\u2014refers to cases where the primary therapy was changed to an alternative azole, and the subsequent therapy continued throughout the study period irrespective of dose or dosage adjustment.Discontinued therapy\u2014refers to cases where treatment was stopped within the study period and no replacement therapy commenced.Being a retrospective study, patients\u2019 informed consent and ethical review were waived. Data was collected as part of a clinical audit and was anonymized prior to analysis.Values are presented as frequencies (%) for qualitative variables and mean \u00b1 standard deviation (SD) for continuous, normally distributed variables or median and interquartile range for non-normally distributed variables. Survival was calculated from the date of initiation of the primary therapy (voriconazole or itraconazole) to the date of death or last follow-up (52 weeks) using the Kaplan\u2013Meier (Mantel-Cox) test; a log-rank test was applied to compare survival curves. Statistical significance was taken as a p \u22640.05. Data analyses were performed with the use of IBM SPSS statistic software, version 23.0  and GraphPad Prism version 7.00 for Windows  was used for graphical illustrations.Of the 206 analysed, 10 (7%) treatment na\u00efve patients were not initiated on any azole : two hadFourteen (7%) patients had no underlying pulmonary co-morbidity. The median number of underlying pulmonary comorbidities per patient was 2 (range 1\u20135). The overall frequency of underlying pulmonary diseases is summarised in Of the 132 Group A patients, 105 (80%) were commenced on itraconazole and 27 (20%) on voriconazole . OverallSixty-four patients were referred with prior or current antifungal therapy (Group B). The duration of prior antifungal therapy for these patients was often uncertain and difficult to ascertain due to patient recollection and commencement of treatment at a peripheral center. The majority of these individuals  had received itraconazole prior to referral although only 6 (13%) remained on it at enrollment. Voriconazole had been prescribed in 25% (n = 16) of individuals; nine (56%) were still on treatment when first seen. Two patients (3%) had previously received intravenous anti-fungal therapy  and micafungin (n = 1)). Posaconazole was given as initial therapy to two patients prior to referral.Forty-nine (47%) patients in Group A were on itraconazole therapy continuously over the 12 month period, 23 (22%) discontinued it and 33 (31%) were changed to a different azole. Twenty (61%) of the 33 patients whose regimen was changed were switched to voriconazole and 13 (39%) to posaconazole. The median duration of itraconazole therapy in Group A was 12 weeks (range 1\u201344) before changing to another triazole and 14 weeks (range: 1\u201348) before discontinuation of therapy. Only 2 (9%) patients had to stop itraconazole therapy before 12 weeks.The median itraconazole dose administered in Group A patients was 400mg per day (range 200-400mg /day). Seventy (67%) patients were on 400mg/day, 19 (18%) on 300mg and 16 (15%) on 200mg per day. Doses were adjusted based on TDM and tolerance in 34 of the 49 (69%) patients who took itraconazole for 12 months. Fifteen (31%) patients remained on the same dose over the 12-month period. Twenty eight (57%) patients had their dose reduced due to persistently elevated therapeutic drug levels which placed them at greater risk of developing itraconazole driven side effects. The median reduction in itraconazole dose was 200mg/day (range 50-300mg lower per day). Six (12%) patients had their itraconazole dose increased by a median dose of 100mg (100-200mg) per day.A. fumigatus and one patient was on anti-TB therapy for non-tuberculous mycobacteria (NTM).The majority of Group B patients were on an itraconazole dose of 400mg (100-600mg) daily . Eighteen (39%) of the 46 patients who were referred while taking itraconazole changed therapy, 7 (15%) remained on the same therapy for 12 months and 21 (46%) had their therapy discontinued. Twelve patients (67%) were changed to voriconazole, five (28%) to posaconazole and one to isavuconazole. The reasons for a change of therapy were: 1) adverse events , 2) lack of improvement , and 3) resistance . Fourteen (67%) of the 21 patients whose therapy had to be discontinued had adverse events, four (19%) had multi- or pan-azole resistant A. fumigatus isolates (5 mono-resistance and 3 pan-azole resistance), and another three (13%) were clinically stable and were followed up off therapy. Adverse events leading to change or discontinuation of therapy are shown in Across both groups, 35 (33%) patients developed adverse events to itraconazole over the 12-month period, with 15 (43%) requiring discontinuation of therapy. Ten (5%) patients had clinical failure, 8 (8%) had itraconazole resistant Aspergillus spp. resistant to itraconazole but sensitive to voriconazole at the time of diagnosis. The median dose of voriconazole prescribed was 400mg/day (range 200-500mg/day). The median duration of voriconazole therapy in Group A was 14 weeks (range: 2\u201340) before change of regimen and 31 weeks (range: 15\u201346) before discontinuation. In no patient was voriconazole discontinued before 12 weeks of therapy.In Group A, the reasons for initiation of voriconazole included a contra-indication to itraconazole (notably heart failure), severe disease (including large aspergilloma), and isolation of Fourteen (52%) of the 27 patients in Group A were on voriconazole therapy for the whole observation period (12 months period). Therapy was switched for seven patients, 5 (71%) of whom were commenced on posaconazole and 2 (29%) on itraconazole. Voriconazole dose was reduced in half of the patients (n = 7) and the other half remained on the same dose for the whole study period. The median reduction in voriconazole dose was 100mg/day (range 100-250mg lower per day). No patient had his/her voriconazole dose increased.Mycobacterium avium complex infection one because of persistently low levels of voriconazole on TDM. Voriconazole therapy was discontinued in 6 (21%) patients. One patient\u2019s therapy was stopped because of resistance.In Group A, five of seven patients who changed therapy (71%) because of adverse events/intolerance (n = 3), in one (14%) to circumvent a drug interaction with therapy for concurrent In Group B, the dose of voriconazole dose was at 400mg daily for 12 (75%) patients (range: 200-400mg). Of the 16 patients in Group B who were on voriconazole, 7 (44%) continued on the same therapy for the 12 months, treatment was discontinued for 5 (31%) patients, 4 (25%) patients changed therapy. Three (75%) of the patients changed to posaconazole and 1 (25%) changed to itraconazole. The reasons for change of therapy were: 1) adverse events (photosensitivity (n = 1) and visual disturbance (n = 1), 2) resistance (n = 1), and 3) lack of clinical improvement. Two (40%) of the 5 patients discontinued treatment due to voriconazole-related adverse events; three (60%) of the patients were clinically stable off therapy.Across both groups, 10 (37%) patients developed adverse events, five (50%) of which were severe enough to need discontinuation of voriconazole  and one A. fumigatus isolate.Two patients were referred on posaconazole. During the 12 months, 26 patients (18 (14%) from Group A and 8 (13%) from Group B) were switched to posaconazole. All Group A and Group B patients who were changed to posaconazole stayed on therapy for the remainder of the 12 months of observation. One of the two patients who were referred while on posaconazole had to discontinue therapy due to isolation of a pan-azole resistant Aspergillus fumigatus isolate, 1 had clinical failure on itraconazole and the third had adverse events to both itraconazole and voriconazole. The indications for IV liposomal amphotericin B were clinical failure on itraconazole (n = 2), multi-azole resistant isolate of A. fumigatus (n = 1) and intolerance to itraconazole (n = 5).Eleven (8%) of the 132 group A patients received at least one course of intravenous (IV) therapy; three received IV micafungin and the remaining 8 received IV liposomal amphotericin B. Only one patient with adverse events to both voriconazole and itraconazole received 2 courses of IV micafungin, the rest received a single course of either IV micafungin or liposomal amphotericin B. Of the 3 patients who received IV micafungin, 1 had a pan-azole resistant Five (8%) of the 64 Group B patients received intravenous antifungal therapy; three patients micafungin and two liposomal amphotericin B. Indications included pan-azole resistance (n = 2), 2, pan-azole drug intolerance (n = 2), and lack of clinical improvement due to failure to achieve therapeutic levels with all available azoles (n = 1).Seven patients underwent surgical resection for treatment of CPA; two of these were among the ten patients who were not initiated on antifungal therapy (they had simple aspergilloma). Nine patients had bronchial artery embolization (BAE) done. Two of the 9 patients who had BAE also required surgery for uncontrolled haemoptysis.Aspergillus-specific IgG at 6 and 12 months following initiation of therapy as summarised in Tables The treatment outcomes evaluated in this study includes change in quality of life scores (St George\u2019s QoL questionnaire), MRC dyspnoea score, weight and The mean baseline SGRQ score for patients who continued on voriconazole for 12 months was 54.0 units (SD = 25.9) and this improved to 50.4 (SD = 26.7) and 44.7 (SD = 25.0) units at 6 and 12 months respectively while on treatment . For patMean weights (Kg) at baseline, 6 and 12 months for patients on voriconazole were 71.6 (SD = 19.8), 71.3 (SD = 20.4), and 73.2 (SD = 14.2) Kg respectively. For patients who were on itraconazole this was 62.7 (SD = 15.9), 65.7 (SD = 15.4), 66.9 (SD = 13.2) respectively . For patBreathlessness improved in those who stayed on therapy for 12 months, and in those who discontinued itraconazole. The median values of MRC dyspnoea score for patients who were on voriconazole for 12 months were 4, 3.5 and 3 units at baseline, 6 and, 12 months respectively and 3, 3 and 2 units at baseline, 6 and, 12 months respectively for patients who were on itraconazole for 12 months. The median values were 4, 4, and 5 units at baseline, 6 months and 12 months respectively for patients who discontinued voriconazole; this was 4, 3, and 3 units at baseline, 6 months and 12 months respectively for those in whom itraconazole discontinued .Aspergillus-specific IgG levels (mg/L) decreased from 250.6 (SD = 239.6) at baseline to 168.8 (SD = 184.1) at 6 months, finally reaching 125.3 (SD = 119.4) mg/L at 12 months for patients who were on itraconazole for 12 months (Mean serum 2 months . A corre2 months . Patient2 months . Contrar2 months . The larA. fumigatus isolates (5 itraconazole mono-resistance and 3 pan-azole resistance) and one (4%) of the 27 patients who was on voriconazole developed a pan-azole resistant isolate of A. fumigatus. For the Group B patients, five (11%) of the 46 patients who were on itraconazole developed resistance and one (6%) of the 16 patients on voriconazole developed resistant isolates of A. fumigatus. One of the two patients who were on posaconazole developed a pan-azole resistant isolate of A. fumigatus. There was no statistically significant difference in the rate of emergence of resistance between Group A and Group B, for either itraconazole  or voriconazole .In Group A, eight (8%) of the 105 patients who were on itraconazole developed azole resistant In Group A, 29 (22%) patients discontinued therapy. 6 were on voriconazole and 23 were on itraconazole. In Group B, 27 (42%) patients discontinued therapy, 21 of these patients were on itraconazole, 5 on voriconazole, and 1 on posaconazole. Azole discontinuation rates were higher in Group B than in Group A (p = 0.003).Overall survival for all patients was 94% (194 of 206). Survival was 95% (140 of 148) in the itraconazole group and 92% (44 of 48) in the voriconazole group as shown in The present study shows that antifungal treatment for at least 12 months in CPA results in improvement in quality of life for patients initiated on voriconazole or itraconazole. This is in keeping with previous observations that long-term triazole therapy is the mainstay of management of CPA ,16. AdveThe SGRQ score measures three main domains related to patient symptomatology, limitation in activities of daily living, and physical and psychological impact of airway disease, reflecting impaired health. It has been validated in a number of respiratory conditions including asthma, COPD, bronchiectasis ,18 and rThe MRC dyspnea scale is a frequently used measure of disability in cardio-respiratory diseases including CPA. However it is insensitive to change and has no definite/precise distinction between the grades . In thisWeight gain is widely used as a clinical marker of response treatment in respiratory infection such as tuberculosis, and is also used as a surrogate marker in CPA. Interestingly, itraconazole use for 12 months was associated with weight gain (median difference in weight of 4.2 Kgs) while this was minimal (median difference in weight of 1.6 Kgs) with voriconazole use. This may reflect clinical improvement but could also be partly explained by peripheral fluid retention which is a common side effect of itraconazole. Some patients may have subtle toxicity with voriconazole, insufficient to stop them taking the drug, but impairing their appetite, as reported verbally in those who stopped therapy. Therefore, we have not been able to demonstrate that weight gain is associated with improvement in SGRQ scores.Aspergillus-specific IgG is fundamental to the diagnosis of CPA [Aspergillus-specific IgG have wide variability with coefficient of variation (CV) between 3.4\u201343.7% [\u00ae assay has a coefficient of variation (CV) of 13%. Overall, the mean baseline IgG levels were well above (5.6\u20139.5 times) the upper reference limit (40mg/L). Patients started on voriconazole had a higher baseline IgG, perhaps reflecting higher initial burden of disease. At 12 months, a decline in the IgG levels was found in all patients. Stopping itraconazole therapy resulted in rising levels of IgG, whereas this effect was not observed in patients stopping voriconazole, in whom Aspergillus-specific IgG levels continued to decline following treatment cessation. There was no correlation between quality of life score and serology. At present, there is no widely accepted consensus on the use of serology to document response to therapy. Our results show that antifungal therapy is associated with a reduction in IgG levels, and stopping therapy may result in a rebound; whether this translates to clinical response or failure of treatment needs further study.An elevated level of s of CPA . The cur.4\u201343.7% . The ImmAspergillus-specific IgG level in patients on voriconazole). The reported efficacy of oral itraconazole is somewhat variable, with a range of 30\u201393%, duration of administration approximately 4\u201312 months, and adverse effects in 16\u201333% of patients [The best antifungal agent for initial treatment of CPA is not known. Itraconazole is often the preferred agent because of cost issues, followed by the newer triazoles. We observed similar improvement in scores in patients started on itraconazole or voriconazole; however, patients on voriconazole typically had a higher burden of disease radiologically and clinically  of the 151 patients who were on itraconazole stopped because of microbiological failure (resistance) compared to 5% n = 2) of the 43 patients on voriconazole. It is possible that voriconazole may have a higher threshold for development of resistance. The presence of azole-resistant ensitive . The devensitive \u201335. Haem of the 4ensitive . PatientA. fumigatus isolates, clinical failure, intolerance and /or adverse events to first and second line agents used in the treatment of CPA, alternative management strategies for CPA such as short or long courses of IV liposomal amphotericin B and micafungin are considered [Sixteen (8%) of our patients were treated with either intravenous micafungin or liposomal amphotericin B therapy. With the increasing incidence of azole-resistant nsidered . About 7nsidered . With shnsidered ,39. The nsidered . There aAspergillus Ig G also improved on treatment, outcomes were similar for both agents, although voriconazole may be preferred for patients with a higher burden of disease, for example multiple aspergillomas or higher Aspergillus serology. However azole toxicity is common and the drugs are poorly tolerated resulting in difficulties in continuing the lifelong therapy these individuals require in order to prevent ongoing lung damage and parenchymal fibrosis. Coupled with the threat of emerging azole resistance and the difficulties associated with defining treatment outcomes in a heterogeneous, multi morbid, CPA population, further prospective studies addressing the impact of azole therapy on CPA, and the identification of appropriate biomarkers with which to measure therapeutic response, are required to fully ascertain the impact of azole therapy on progression of disease.In conclusion, continuous treatment with itraconazole or voriconazole for at least 12 months resulted in the greatest benefit in terms of quality of life scores in CPA. S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S1 File(XLSX)Click here for additional data file."}
+{"text": "Human immunodefiecency virus infected patients did not adhere correctly to their Antiretroviral Therapy because of the drugs adverse effects. Thus, continuous evaluation of the adverse effect of Antiretroviral Therapy will help to make more effective treatment. The aim of this study was to assess the prevalence of Adverse Drug Reaction and associated factors on Antiretroviral Therapy among Human immunodefiecency virus infected Adults at Hiwot Fana Specialized University Hospital, Eastern Ethiopia.A Hospital based retrospective study was conducted among 358 of adult patients clinical records on antiretroviral Therapy from April1 to June30, 2014.The overall prevalence of Adverse Drug Reaction among Human immunodefiecency virus infected patients on antiretroviral Therapy was 17.0%. Of reported Adverse Drug Reaction, 80.3%, 18% and 1.7% occurred in patients on Stavudine, Zidovudine and Tenofovir based regimens respectively. The common Adverse Drug Reaction were lipodystrophy (fat change) (49.2%), numbness/tingling (27.9%), peripheral neuropathy (18%) and (8.2%) anaemia (8.2%). Patients on Stavudine containing regimens were more likely to develop Adverse Drug Reaction compared to Zidovudine  and Tenofovir .The overall prevalence of Adverse Drug Reaction among Human immunodefiecency virus infected patients in this study was 17% and more common on those patients taking Stavudine based regimen. Lipodystrophy and peripheral neuropathy were significantly associated with stavudine-based regimens, while anaemia was significantly associated with zidovudine based regimens. Thus regular clinical and laboratory monitoring of patients on Antiretroviral Therapy should be strengthened. Antiretroviral Therapy (ART) is the cornerstone of management of patients infected with Human immune deficiency virus (HIV). The initiation ART has resulted in significant decreases in HIV-related morbidity and mortality in both the developed and developing countries \u20133. It isStudy area and population: Harari People National Regional State is located in the Eastern part of Ethiopia which is 515 kms away from the capital city- Addis Ababa. It had a projected total population of 203,438 in 2010. It has 36 kebeles , which are the lowest administrative clusters in the region. The health service coverage of the region, which is calculated based on the number of health institutions giving health services per population in the region, is estimated to be about 100%. There were 6 Hospitals and 8 health centers in the region [e region . ART proStudy design and period: A Hospital based retrospective review of ART clinical records were conducted among patients who initiated ART between March26, 2006 and March 26, 2014.Sample size estimation and sampling techniques: The sample size was determined by using single proportion formula by setting 95% confidence interval, P= 0.303 of patients taking ART develop ADRs [lop ADRs , margin Data collection: Data were collected using structured questionnaire which was adopted from routine standard ART monitoring card. Information on patient's details like socio demographic characteristics, WHO clinical staging of the disease at the starting of ART, duration of treatment, drug details, types, severity and outcome of ADRs of reported by patients during clinical examination at time coming to ART unit for their appointment visit were collected by clinical nurses who are working at the hospital ART Clinic. Haematological and metabolic ADRs, which could be done by laboratory examination, were not collected from ART clinical records. The data collection format was checked on daily bases by investigators and supervisors for its completeness and consistency with the patient's clinical records of the hospitals.Data entry and analysis: The collected data were double entered, cleaned and analyzed by using SPSS soft-ware Version16. The finding of this study was presented by using mean, standard deviation and simple frequencies tables. The overall prevalence of ADRs was determined as the proportion of individuals who developed the different ADRs by clinical examination. Odd ratio with 95% confidence interval was used to describe association between the selected study variables (i.e. Outcome and independent variables). Univariate and multivariable logistic regression analysis was performed to explore independent variables that were predictors of adverse drug reactions (ADRs). The criterion for significance was set at P < 0.005. The severity of ADRs were categorized from grade I to IV based on criteria used the WHO severity grading [Ethical consideration: The study protocol was approved by Institutional Health Research and Ethical Review Committee of College of Health and Medical Sciences, Haramaya University. And the patients\u2019 clinical records were reviewed anonymously and all information obtained from clinical records was kept confidential.Characteristics of the study subjects: A total of 358 HIV/AIDS patient ART clinical records were reviewed in this study. The mean age of patients was 34 (SD + 9.8) years, ranging from 18-71 years. Most of the patients were on the age group of 30-39 years (41.4%), female (68.4%), Urban (83%) and elementary school (44.7%). One hundred fifty (41.9%) of the study participants were at WHO clinical stage III. With regards to functional status, most (65.9%) of them were working. Majority (74.6%) of the study participants were on the first line ART regimen. D4T (30)/3TC/ NVP (33.2%) were the most commonly prescribed ART regimen at their initial time initiation of ART. The most frequently used drug other than ART among the study participants were Cotrimoxazole (75.7%) and Isonizide (INH) (14.5%) ( (14.5%) .Antiretroviral treatment (ART) Drug regimen and follow up status of HIV/AIDS patients: At the time of study, 33.2% of the study participants were still on their initial regimen whereas 38% of them had changed one or two drugs during their follow up. Currently (during the study period), most (69.7%) of the HIV/AIDS patients on ART were in the first line regimens. The main reasons for changing initial regimen of ART drugs were new drug availability (45.6%) and adverse drug reaction (41.2%) followed by Immunological failure 10(7.4%), due to new TB 9(6.6%), risk of pregnancy, clinical failure, virological failure, immunological failure and clinical failure, and immunological failure and viral failure each accounts 1(1%). Two hundred fifty eight (72.1%) were still on ART follow up in the hospital ART clinic whereas 48(13.4%), 29(8.15) and 24(6.7%) of the study participants were transferred out to other ART clinic site, died and interrupted their follow up respectively. ART treatment adherence rate among study participants was also reviewed from participant's card. About (5%) had poor adherence. The main reasons for poor adherence were lost / ran out of pills 10(55.6%) and delivery/ travel problems 4(22.2%), followed by nutritional problem 1(5.6%), taking alcohol1 (5.6%), too ill 1(5.6%) and combination of stigma 1(5.6%).Magnitude, clinical symptoms and severity of adverse drug reactions (ADRs): The overall prevalence of ADRs among these study participants was 17.0%. The most frequently identified ADRs clinical symptoms were lipidtropy (Fat change) (44.3%) and Numbness/tingling (4.9%). Most (80.3%) of the patients had grade III ADR. The main management/measure taken to resolve ADRs were one drug change (62.3%), reassurance (18%) and regimen change (14.8%). The majority 27/61 (44.3%) of the study participants with ADRs were died who were on grade III. In addition, most of the study participants, who developed ADRs, were WHO stage III (47.5%) ( (47.5%) . Nausea, (47.5%) .Factors associated with adverse drug reactions: The prevalence of ADRs was higher in those study participants on D4T based ART drug regimen especially D4T/3TC/EFV. This was significantly different when compared to study participants in other treatment regimens (P<0.005). The prevalence of ADRs was higher in those study participants who were more than 50 years of age, in females, ambulatories, in WHO stage III, with initial CD4 count 201-300 cells/\u00b5l and grade III severity level. But the difference was not statistically significant when comparisons were made within each category member (P>0.05). Further analysis with univariate and multivariate was done. In both univariate and multivariate analysis all ART drug users were less likely to develop ADRs as compared to D4T/3TC/ NVP users (p<0.05). It was compared based on the base ART drugs; AZT and TDF based ART drug regimen base users were less likely to develop ADRs when compared to D4T base users  and Cameroon 19.5%)  but it w.5%  but The other common ADR was peripheral neuropathy 18%). This was similar to the study carried out in Cameroon 21.2%) and Kenya (20.7%) %. This w. However.2% and KThe prevalence of ADRs was 17% and more common on those patients taking Stavudine based regimen. Lipodystrophy, peripheral neuropathy and anaemia were the common ADRs. Lipodystrophy and peripheral neuropathy were significantly associated with stavudine-based regimens, while anaemia was significantly associated with zidovudine based regimens. Therefore this study recommends, regular clinical and laboratory monitoring of patients on ART should be strengthened before and after initiation of ART according to guideline of institution particularly for stavudine and zidovudine based regimens. It also recommends further large scale study to assess the magnitude and associated factors ADRs by using clinical and laboratory examination.The prevalence of ADRs was more common on those patients taking Zidovudine -based regimens;Lipodystrophy and peripheral neuropathy were significantly associated with stavudine-based a regimen;Anemia was significantly associated with zidovudine based regimens.The prevalence of ADRs was more common on those patients taking Stavudine based regimen;Lipodystrophy was the common ADRs."}
+{"text": "Indirect immunofluorescence (IIF) using human epithelial cell (HEp-2) substrate is a widely used and the recommended method for screening of antinuclear antibodies (ANA). Dense fine speckled (DFS70) pattern on HEp-2 has been widely reported in various healthy and disease groups. Interpretation of DFS70 pattern can be challenging on a conventional HEp-2 substrate due to its similarity to some of the disease associated patterns. The high prevalence of DFS70 autoantibodies in normal population, lack of association with a particular disease group and a general negative association with systemic and ANA associated autoimmune rheumatic diseases (SARD/AARD) necessitates the confirmation of DFS70 pattern. Results using available commercial assays for confirmation of DFS70 autoantibodies do not always agree with IIF screening results further complicating the lab work flow and ANA algorithms. In this review, we discuss the prevalence of DFS70 antibodies and factors affecting the performance of IIF and DFS70 specific confirmatory assays. Factors that contribute to disagreement between DFS70 suspicion by IIF and confirmatory assays will also be discussed. In addition, we also describe a novel IIF HEp-2 substrate, and its positive impact on DFS70 reporting and ANA screening-confirmation algorithm. ANAs remain a hallmark of systemic autoimmune diseases. Patterns of ANA observed on HEp-2 cells by IIF provide the clinicians with insight into specificity of autoantibodies present, indications of disease likelihood and further implicate or rule out a clinical suspicion . IIF by The DFS70 pattern resulting from autoantibodies binding to the ubiquitously expressed protein called lens epithelium derived growth factor (LEDGF) or p75 or psip1 gene product is frequently observed during routine ANA screening by IIF-HEp-2. DFS70 pattern and autoantibodies were originally described by Ochs et al.  and wereWith the increased demand for ANA testing, many labs have switched to newer solid phase and multiplex methodologies for screening of ANAs . AlthougANA-IIF-HEp-2 is being increasingly requested not only on clinical suspicion of AARD but also for differential diagnosis from AARD. In many clinical laboratories, ANA-IIF referrals come from rheumatologists, hepatologists, neurologists, dermatologists, allergy/immunologists and increasingly from general practitioners to rule out SARD. Based on this trend, the complexity and heterogeneity of ANA screening populations change significantly from one clinical lab to the other. Systematic review for DFS70 autoantibody positivity has been performed by multiple groups , 6, 30. n\u00a0=\u00a015,189; Fig.\u00a0Based on published studies, a great majority of the routine ANA screening population is negative for all ANAs and a large subset of the positive ANA group has DFS70 autoantibodies alone or in combination with other disease associated ANAs. Due to these factors, this review focuses on 20 studies from research group around the world that have reported the frequency of DFS70 suspected cases Fig.\u00a0. The selE. coli vs. Baculo virus system vs. mammalian cells), analytical sensitivity/specificity of the various assay platforms and the established assay cut-off. For a pathologist or a clinical laboratory professional, DFS70 is a distinct pattern that can be differentiated from other similar disease associated patterns. However, depending on the titer levels and presence or absence of other ANA patterns, the interpretation can be challenging [Variations in IIF HEp-2 substrates, screening dilution (1:40/1:80/1:160), inter-observer bias , FITC-conjugate strength and mixed ANA patterns with/without DFS70 impact IIF reporting. It is also possible that the antibodies that produce DFS70 are very heterogeneous and have increased affinity for full length LEDGF presented in its natural form bound to chromatin and/or other proteins. Wide variability in agreements between IIF suspicion and confirmation by DFS70 specific solid-phase assays have been reported , 39, 49.llenging . Expert llenging . Severalllenging . Due to llenging . Users aHere, we introduce a novel HEp-2 IIF substrate  that presents a mixture of natural HEp-2 cells and genetically engineered HEp-2 cells that do not express DFS70/LEDGF/psip1/p75 antigen (referred to as DFS70 KO cells) in 1:9 ratio on glass slide wells. The new IIF substrate retains all the capabilities of conventional HEp-2 substrates for screening of ANAs and further is able to simultaneously detect and confirm with high confidence both mixed and mono-specific/isolated DFS70 patterns Fig.\u00a0. Differe\u00ae DFS70, Inova Diagnostics) and IIF using HEp-2 ELITE/DFS70 KO substrate. The CLIA assay determined 61% (90) of the 148 cases to be positive and 39% (58) as negative. The HEp-2 ELITE/DFS70 KO analysis confirmed 65% (96) of the 148 cases to be positive. New IIF substrate produced a 94% (85) positive agreement with the 90 CLIA positive cases. In addition, the new substrate confirmed approximately a fifth (19%) of the 58 CLIA negative cases to be positive for DFS70 autoantibodies. The new HEp-2 ELITE/DFS KO substrate produced an improved overall sensitivity of 65% compared to 61% obtained with CLIA. The other study cohorts were also tested for DFS70 presence using the HEp-2 ELITE/DFS70 KO substrate. The routine ANA screening population had five cases (2%) identified to be DFS70 positive and the healthy donor population had two cases (2%) as positive. Infectious disease (118) and autoimmune cases (both ANA positive and negative) did not identify any DFS70 positive cases using this improved IIF substrate.The preliminary evaluation of HEp-2 ELITE/DFS70 KO substrate was performed by the Laboratory of Clinical Pathology at the San Antonio Hospital located in Tolmezzo, Italy, using a total of 746 cases across five different cohorts. The study included 148 cases suspected of having DFS70 autoantibodies, which were initially identified by conventional HEp-2 IIF . The other cases evaluated include healthy donors (100), infectious disease positive patients (118), patients diagnosed with an autoimmune disease , and a routine ANA screening population (242) (unpublished results). The 148 cases suspected of DFS70 pattern by conventional HEp-2 IIF were analyzed using a CLIA assay (QUANTA FlashDFS70 autoantibodies have been reported by numerous groups not only in various autoimmune and non-autoimmune disease states but also in healthy population. DFS70 autoantibodies present a unique interpretation challenge for clinical labs that use the recommended HEp-2 IIF for screening of ANAs. Currently available commercial assays for the confirmation of DFS70 autoantibodies do not always agree with DFS70 suspicion by IIF. Over and under estimation of DFS70 pattern using conventional IIF complicates the ANA screening work flow by increasing the number of reflex tests which further increases the cost of implementing the diagnostic algorithm Fig.\u00a0. The nov"}
+{"text": "Women living with HIV are at increased risk to be co-infected with HPV, persistent high-risk (HR) human papillomavirus (HPV) infection and increased HR HPV viral load, which make them more at risk for cervical cancer. Despite their inherent vulnerability, there is a scarcity of data on potential high risk (pHR) and HR HPV genotypes in HIV- infected women with cervical dysplasia and HPV-type specific viral load in this population in Sub Saharan Africa.The aim of this analysis of HIV-infected women was to explore the virological correlates of high-grade cervical dysplasia (CIN 2+) in HIV-infected women, thereby profiling HPV genotypes.This analysis assesses baseline data obtained from a cohort study of 74 HIV-infected women with abnormal cytology attending a Comprehensive Care Centre for patients with HIV infection in Mombasa, Kenya. Quantitative real-time PCR was used for HPV typing and viral load.CIN 2 was observed in 16% (12/74) of women, CIN 3 in 23% (17/74), and, invasive cervical carcinoma (ICC) in 1% (1/74) of women. In women with CIN 3+, HPV 16 (44%), HPV 56 (33%), HPV 33 and 53 (HPV 53 (28%) were the most prevalent genotypes. HPV 53 was observed as a stand-alone HPV in one woman with ICC.p\u2009=\u20090.05; 95%  [CI]:1.03\u201322.5). Women with CIN2+ had a significantly higher viral log mean of HPV 16,  than with CIN 1.A multivariate logistic regression adjusting for age, CD4 count and HPV co-infections suggested the presence of HPV 31 as a predictor of CIN 2+ (adjusted odds ratio [aOR]:4.9; The high prevalence of HPV 53 in CIN 3 and as a stand-alone genotype in the patient with invasive cervical cancer warrants that its clinical significance be further revisited among HIV-infected women. HPV 31, along with elevated means of HPV 16 viral load were predictors of CIN 2\u2009+\u2009. Kenya is home to the world\u2019s fourth-largest HIV epidemic in the world. In 2013, an estimated 1.6 million people were living with HIV and roughly 57,000 people died from AIDS-related illnesses , and 35% had CD4 count of 200 cells/\u03bcl or lower. The median age at first sexual intercourse was 18\u00a0years (IQR\u2009=\u200915.5\u201320), and the median number of sex partners was 2 (IQR: 1\u20134).LSIL was detected in 43/74 (58%), Atypical Squamous cells of undetermined significance (ASC-US) in 12/74 (16%), Atypical Squamous Cells cannot rule Out High-Grade Squamous Intra-epithelial Lesion (ASC-H) in 3/74 (4%), (HSIL) in 15/74 (20%) and 1/74 was inconclusive (1%).Histological results in the 74 women with cytological abnormalities were CIN 1 in 58% (41/74), CIN 2 in 16% (12/74), CIN 3 in 23% (17/74), and one participant (1/74) had invasive cervical carcinoma. Cervicitis was detected in 15% (11/74) and normal histology in 4% (3/74). Two (3%) biopsies were inconclusive. Overall, 30 (40.5%) women had a cytology of CIN2+ .To assess the prevalence of, potential high risk (pHR) and high-risk (HR) HPV genotypes in the 74 HIV+ women with abnormal cytology, we assayed for specific genotypes listed in Table\u00a0Among the 30 women with CIN 2+, over half of women (57%) had either HPV 16 or HPV 18 infection. The combined prevalence of intermediate HPV risk types in CIN 2+ was 30%, of which HPV 53 represented (7/30) 23% and HPV 66 (2/30) 7%. In women with CIN 3+, HPV 16 8/18 (44%), HPV 56 6/18 (33%), HPV 33 and 53 HPV 53 5/18 (28%) were the most prevalent genotypes . No interaction with CD4 count and age was noted  between CIN 2+ and multiple pHR and HR HPV genotypes   than CIN 2 (25%), although our percentage for CIN 3 was higher than the one reported (41%\u201347%) .Contrary to our first hypothesis, our data do not suggest a significant association between multiple pHR/HR HPV infections and CIN 2+. This study suggests that HPV 31 is the only independent predictor of CIN 2+, and an inverse relationship was detected between HPV 66 and CIN 2+. However, in agreement with our hypothesis, our study suggests that HPV 16 viral load correlated with CIN 2+. Our combined HPV 16 and HPV 18 prevalence of 61% in CIN 3+ suggests the need for a wider protection that the nonavalent vaccine would confer.There is a presumed link between HIV-positivity and the prevalence of multiple HPV infections , 11. OurContrary to our hypothesis of required synergistic mechanisms between pHR/HR HPV genotypes for cervical cancer genesis, it may be that in our study population with a low median CD4 count of 236 cells/\u03bcl (IQR: 158\u2013374), single pHR HPV genotypes are capable of inducing cervical cancer genesis.Our lack of association between pHR HPV genotypes and CIN 2+ is in agreement with an observation made by Rahman et al. (2011) that infection with pHR HPV genotypes in HSIL became non-significant when HIV status was included in the multivariate analysis. In women with CIN 3+, HPV 53 was the third most prevalent genotype. (28%) The stand-alone HPV 53 in the only ICC case recorded is incongruent with those from a recent study in Kenya, where pHR HPV genotypes were only detected in low-grade lesion . The womWhen examining associations between specific pHR and HR HPV genotypes and CIN 2+, a multivariate analysis suggested the presence of HPV 31 as an independent predictor of CIN 2+. Furthermore, a high number of concomitant pHR and HR HPV infections in women was observed in the presence of HPV 31.Our finding suggesting that HPV 16 viral load may correlate with the severity of lesions is congruent with those found in the literature pertaining to sub Saharan Africa , 36. NotOur findings can be extrapolated to a HIV population that is moderately to severely immunosuppressed and has had few sexual partners within the region. The relatively high median of concurrent pHR and HR HPV infections suggests an inability to either clear HPV infectious or a propensity to reactivate latent HPV infections. However, it is unknown how many sexual partners their spouses have had, nor can a social desirability bias in reporting sexual behavior be excluded.A major strength of our study is that our samples have been histopathologically confirmed. A recent systematic review suggests that most studies on cervical dysplasia on the continent, have cervical cytology as endpoints,  which onWe recognize that our study has certain inherent methodological limitations. The small sample size compromised our power to assess correlates solely for CIN 3, which is the best proxy for ICC, despite type distribution in CIN 3 not being completely representative of cancer .Additionally, the cross-sectional design, which does not allow the fulfillment of the temporal criterion for causality, bases its analysis on a single measure of pHR and HR HPV viral load for prevalent infections at the baseline screening phase, which may not be able to capture the transient nature of pHR and HR HPV infections. Consequently, it may not be possible to disentangle the risk posed by recently acquired infections along with its elevated viral load from viral load deriving from older infections.A further limitation related to a cross sectional study design may be the lack of data concerning age of acquisition of HIV infection, since it is possible this may have occurred too late in life for some of the women in our study to influence CIN 2+. Moreover, lack of data on HIV viral load and on the recombinant strains present in HIV-1 infected women, precludes us from fully exploring synergistic mechanisms between the two viruses.The epidemiology of pHR HPV genotypes in HIV women is still poorly characterized, as HPV 26, 53, 67, 70,73, and 82 are not included in any HPV DNA screening protocols in sub Saharan Africa. Our findings warrant that the potential carcinogenesis of HPV 53 be better elucidated, especially in severely immunosuppressed women. According to Padalko et al. (2015) the role of pHR HPV genotypes will also need to be assessed in the post vaccine era, in case type replacement leads to pHR HPV genotypes becoming more prevalent in ICC .A systematic review and meta-analysis  found thThe kinetics of different genotype viral load must also be assessed amidst, not only different levels of immunosuppression, but also in the presence of different levels of HIV viral load, multiple pHR and HR HPV infections and other concomitant sexually transmitted infections harbored by HIV-infected women. This would help to elucidate the aetiologic role of pHR and HR HPV viral load in cervical dysplasia pathogenesis and determine virological parameters to predict high-grade lesion in HIV infected women in sub Saharan Africa.Our small sample suggest a high prevalence of HPV 16, 53, 56 and 33 in women with CIN 3+. Furthermore, a HPV 31 was found to be an independent predictor of CIN 2+ and HPV 16 viral load significantly higher in women with CIN 2/+.Whether the available bivalent prophylactic vaccine will be able to meet its objective of reducing cervical cancer incidence by 70% may depend on the efficacy of cross protection against HPV 31 in HIV-infected women and the synergies between HPV genotypes in inducing cervical cancer genesis. The high prevalence of non-HPV 16 and 18 genotypes underscore the benefits of the nonavalent vaccine within this population.Our high prevalence of HPV 53 in CIN 3+ and as a stand-alone HPV genotype in ICC, suggests a need for enhanced HPV 53 detection and its incorporation into a local screening protocol. Given the potential public health impact of pHR HPV in HIV-infected women and its exclusion from prophylactic vaccines, future research efforts are needed to investigate the epidemiology of these genotypes in HIV-infected women in the role of cervical cancer genesis. Moreover, large protective studies assessing the impact of the kinetics on different genotype viral load in HIV infected women in sub Saharan Africa, are needed to elucidate the tripartite relationship between HIV viral load, CD4 count and pHR and HR HPV viral load."}
+{"text": "To evaluate the auditory functions and progress of speech development in children with and without cochlear anomalies who underwent cochlear implantation due to prelingual profound sensorineural hearing loss (SNHL).This study was conducted at Gaziantep University Faculty of Medicine Ear-Nose-Throat Department, between October 2006 and December 2007. A total of 69 children (aged 6 to 24 months) diagnosed with profound SNHL were included. Patients were divided into two groups with respect to the presence of inner ear anomalies: Group-1 consisted of 41 children without inner ear anomaly, whereas Group-2 was composed of 28 patients with inner ear anomalies. The auditory performance was assessed using Listening Progress Profile Test (LPPT) and Monosyllabic Trochee Polysyllabic Test (MTP), the subsections of Evaluation of Auditory Responses to Speech (EARS) test battery.st, 3rd and 6th months were 18.5 (44.1%) and 19 (45.6%); 27 (64.2%) and 28 (67.3%); 31 (75%) and 34 (83%), respectively. Postoperatively, MTP scores in Group-1 and Group-2 were 7.5 (62%) and 7.7 (64%) for 3-words set; 10.4 (58%) and 10.6 (59%) for 6-words set; 14.3 (60%) and 14 (59%) for 12-words set, respectively. The rate of stimulation for electrodes was 1345 q/u (quick/unit) in Group-1 and 1310 q/u in Group-2. No statistically significant difference was detected between groups for variables under investigation.Preoperative LPPT scores were 5 (12%) in both groups. Mean LPPT values after fitting in Group-1 and Group-2 on 1Cochlear implantation is an effective treatment in children with prelingual profound SNHL. Auditory performance and advancement of speech are similar for children with and without inner ear anomalies. Hearing loss is an important disability in our country and over the globe. This problem prevents social harmony and leads to the emergence of individual and social problems. For years, vigorous efforts have been made to help these patients to gain their hearing abilities, and to develop speech. Nowadays, cochlear implant system which has been successfully applied all over the world can recover hearing ability of these patients.In this study, outcomes of the cochlear implant in pediatric patients with very advanced prelingual sensorineural hearing loss (SNHL) with or without congenital inner ear malformations were measured. Hearing functions and development of speech were comparatively evaluated.This study took place in, Gaziantep University Faculty of Medicine Ear-Nose-Throat Department, between October 2006 and December 2007. A total of 69 cases with prelingual bilateral profound SNHL or developed within the first two years of life were included in the study. The cases that underwent cochlear implantation surgery at least six months ago were included. The cases were divided to two groups, those without inner ear anomaly  and with inner ear anomaly . The Gaziantep University Local Ethical Committee approved this study (05-2007/ 17).The cases underwent pure tone/free field audiometry, tympanometry, acoustic reflex measurements, brainstem audiometry (BSA) and auto acoustic emission (OAE) tests before cochlear implantation. All the patients were referred to the departments of pediatric psychiatry and neurology for evaluation. Audiological data of the patients and auditory perception performances were evaluated by an audiologist specialized in this field. Patients who did not benefit from hearing aids, and were prospective cochlear implant candidates, underwent thin-slice axial and coronal computed tomographic (CT) and temporal magnetic resonance imaging (MRI) techniques -4. In thCochlear implant surgery was performed using modified minimal postauricular incision, mastoidectomy, posterior tympanotomy and oval window approach under general anesthesia. A 28 mm- long multi-channel Medel Cochlear Implant Device  electrode was implanted. For patients with inner ear malformations 21mm-long relatively thinner Medel Cochlear Implant Device  electrode was used. Electrodes were controlled intraoperative using telemetric measurement, and acoustic stapes reflex was examined. Telemetric measurements were performed using a fitting device  and these measurements were recorded using Maestro by Medel fitting program. To assess and record the correct placement implant Stenvers and transorbital petrous skiagram were obtained during early postoperative period.Auditory performances of the cases were evaluated after cochlear implantation using Evaluation of Auditory Responses to Speech (EARS) test battery. Auditory performances of both groups were compared with subtest groups of EARS test battery including Listening Progress Profile Test (LPPT) and Monosyllabic Trochee Polysyllabic Test (MTP) scores. MTP test was performed for patients whose Listening Progress Profile Test scores were \u2265 30 points. Pre- and postoperative test results of all patients were compared. Besides EARS test results of the patients with or without inner ear malformations who used cochlear implants for nearly equal time periods were also compared. After wound healing all the cases were referred for rehabilitation program for switch on, programming, speech training and progress evaluation.Velocity values detected in postoperative telemetric measurements, pre-and post-operative EARS test results were statistically compared using Mann-Whitney-U test. p<0.05 values were considered to be significant.In this study, Group-1 consisted of 41  patients with a mean age of 14.24\u00b14.15 months. The Group-2 comprised of 28  patients with a mean age of 12.64\u00b13.85 months. Cochlear implants were applied for the right  and left  ears of the patients. Etiologies of the hearing loss were detected as idiopathic causes  febrile disease , familial genetic disease , difficult labor  and squeal of meningitis  . SuccessLPPT scores of the patients with (Group-2) or without cochlear malformations (Group 1) were evaluated during preoperative period and at one, three and six months after fitting. After first fitting median values were as follows as depicted in Pre- and postoperative 6. month-MTP scores of Groups 1 and 2, were evaluated. Preoperative MTP score was 0 percent. Postoperatively, MTP scores in the 3-words-set were 7.5 (62%) in Group-1 and 7.7 (64%) in Group-2; in the 6-words-set MTP scores were 10.4 (58%) in Group-1 and 10.6 (59%) in Group-2; in the 12-word set MTP scores were 14.3 (60%) in Group-1 and 14 (59%) in Group-2 as depicted in The rate of stimulation for electrodes was 1345 q/u (quick/unit) in Group-1 and 1310 q/u in Group-2. Statistically significant difference was not detected between both groups (p>0.05).There are nearly 250 million people with hearing loss all over the world.Hearing loss can cause sensorial deprivation in the communication skills and regression in the development of language skills and learning ability during infancy. For instance, even children with mild degrees (35-40 dB) of hearing loss can miss 50% of the verbal communication in daily life if they don\u2019t use any hearing aid. Therefore, these types of school age children should use a suitable hearing aid within the first six months and continue their education either by using this device or a cochlear implant dependent on the severity of hearing loss.Etiologies of cases with hearing loss are multifactorial. In a study by Daya et al. on 80 cases with cochlear implants, the idiopathic hearing loss was detected in 62.5% of the patients, while Brookhouser et al. reported the presence of idiopathic hearing loss in 31.5 % of their series consisting of 200 cases.During rehabilitation process after cochlear implantation, EARS test battery is used to follow up developmental levels of the patients. Our LPPT and MTP test results are consistent with the literature.11Literature reviews have shown that speech perception performance and auditory functions in anomalous ears improve at a higher rate during the postoperative period.Successful results were obtained in both groups. Our results obtained were generally consistent with the literature.In conclusion, auditory performance and advancement of speech are similar for children with and without inner ear anomalies. Pediatric cochlear implants can achieve development of hearing and speaking in both groups with similarly higher success rates.MC: Conceived, designed and did statistical analysis & editing of manuscript.MC and EK: Did data collection and manuscript writing.MC and MK: Takes the responsibility and is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved."}
+{"text": "Background: Functional free gracilis muscle transfer is an operative procedure for elbow reconstruction in patients with complete brachial plexus nerve and avulsion injuries and in delayed or prolonged nerve denervation, as well as in patients with inadequate upper extremity function after primary nerve reconstruction. Methods: We retrospectively reviewed our patient records and identified 24 patients with complete brachial plexus nerve injury  whose affected arm and shoulder were totally paralyzed and their voluntary elbow flexion or the biceps function was poor preoperatively (mean M0-1/5 in MRC grade). These patients had undergone the functional free gracilis muscle transfer procedure at our clinic since 2005. Results: Ninety-two percent of all patients showed recovery and improvement. Successful free gracilis muscle transfer is defined as antigravity biceps muscle strength of M3-4/5 and higher, which was observed in 16 (8 obstetric and 8 traumatic) of our 24 patients (67%) in this study at least 1 year after functional free gracilis muscle transfer. This is statistically significant (P < .000001) in comparison with their mean preoperative score (M0-1/5). There was no improvement in motor level of the biceps muscle (M0/5) in 2 patients (1 from each group). The donor site of these 24 patients showed no deficit in motor and sensory functions. Conclusions: Taken together, a significant number (92%) of patients in both obstetric and traumatic brachial plexus injury groups had recovery and improvement and most of these patients (64%) achieved antigravity and elbow flexion at least 1 year after free gracilis muscle transfer at our clinic. Twenty percent of patients with obstetric brachial plexus injury (OBPI) are CBPI, which severely compromises the patient's overall upper extremity functions and growth.10-Functional free muscle transfer (FFMT) with nerve transfer has been commonly adopted for gaining elbow flexion in these patients.1Here, we report the outcomes, in particular, the biceps function/elbow flexion after FFGMT in 24 patients with complete brachial plexus nerve injury (13 obstetric and 11 traumatic) who lost their biceps strength and function.Both OBPI and TBPI patients, who had no visible biceps function and no elbow flexion, were included.We retrospectively reviewed our patient records with brachial plexus nerve injury and identified 24 severely paralyzed patients  who had no elbow flexion and had undergone FFGMT at our clinic since 2005. The median (18), radial (5), and ulnar (1) nerves reinnervated the transferred gracilis muscle in our patients with brachial plexus injury (BPI) in the present study.Results were assessed by the MRC grading system. Mean age at the time of surgery was 10 years  in obstetric patients and 27 years  in traumatic patients. Voluntary elbow flexion or the biceps function was very poor before FFGMT (mean = M0-1/5 in MRC grade) in most of our patients in this study.Written informed consent was obtained from all patients for publication and accompanying images. A copy of the written consent is available for review on request. This was a retrospective study of patient charts, which exempted it from the need for institutional review board approval in the United States. Patients were treated ethically in compliance with the Helsinki declaration. Documented informed consent was obtained for all patients.Taken together, a significant number of patients (92%) in both OBPI and TBPI groups had recovery and improvement .P < .000001) in comparison with their mean preoperative score (M0-1/5). There were some recovery and improvement (M1-2/5) in 6 patients (4 from OBPI and 2 from TBPI), but they did not achieve antigravity. There was no improvement in motor level of the biceps muscle (M0/5) in 2 patients (1 from each group).Successful FFGMT is defined as antigravity biceps muscle strength of M3-4/5 and higher, which was observed in 16 (8 obstetric and 8 traumatic) of our 24 patients (67%) in this study at least 1 year after FFGMT . This isThe donor gracilis muscle of these 24 patients showed no deficit in motor and sensory functions.-18-21,1-Several authors have described a number of functional muscle transfer surgeries involving latissimus dorsi (LD)13Hattori et alHattori et alTaken together, a significant number (92%) of patients in both OBPI and TBPI groups had recovery and improvement and most of these patients achieved antigravity and elbow flexion at least 1 year after free gracilis muscle transfer at our clinic.R.K.N. conceived of the study, R.K.N. and S.G.B. performed all the surgeries and revised the manuscript. C.S. participated in the design of the study, gathered data, performed the statistical analysis, and drafted the manuscript. All authors read and approved the final manuscript."}
+{"text": "Acute erythroid leukaemia (AEL) is a rare subtype of acute myeloid leukaemia (AML), constituting <5% of all the cases of AML. The World Health Organization (WHO) in 2001 classified AEL into two types: (1) erythroid/myeloid leukaemia which required \u226550% erythroid precursors with \u226520% of the non-erythroid cells to be myeloid blasts and (2) pure erythroleukemia (pEL) with \u226580% erythroblasts. The WHO 2008 classification kept these subcategories, but made erythroleukemia a diagnosis of exclusion. There are very few studies on the clinico haematological and cytogenetic profile of this disease, considering the rarity of its occurrence and poor prognosis.This study was done by retrospective analysis of data from 32 case files of patients diagnosed with AEL. Clinical details noted down were the demographic profile, peripheral blood smear details and bone marrow examination details: (1) blasts-erythroblasts and myeloblasts, (2) dysplasia in the cell lineages and (3) cytogenetic abnormalities.The most common presenting symptom was fever. Pancytopenia at presentation was seen in 81.25% of patients. Dysplasia was observed in bone marrow in 100% of erythroblasts and in 40% of myeloblasts in erythroid/myeloid subtype. In pure myeloid subtype, myeloid and megakaryocytic dysplasias were not obvious. Complex karyotype was noticed only in patients of pEL.AEL is a rare group of heterogeneous diseases with many neoplastic and non-neoplastic conditions mimicking the diagnosis. The clinical presentation and cytogenetics are also non-specific, presenting additional challenges to the diagnosis. The defAEL was designated as AML-M6 by the FAB Cooperative Group in 1976 and diagnosis required presence of erythroid precursors \u226530% and dyserythropoiesis \u226510%. Following the amendments brought to the FAB classification in 1985, AML-M6 was to be defined by the criteria: \u226550% erythroblast of all nucleated cells, prominent dyserythropoiesis and \u226530% of myeloblast of the rest of non-erythroid precursors. In this, paradoxically ignored was the rare subtype of pure erythroid leukaemia which was classified under refractory anaemia with excess blasts in transformation . DespiteThere are very few studies on the clinico haematological and cytogenetic profile of this disease, considering the rarity of its occurrence and poor prognosis.2This study was done by retrospective analysis of data from case files of patients diagnosed with AEL at the Kidwai Memorial Institute of Oncology over a period of 19 years from January 1997 to March 2016. A total of 1223 of AML were diagnosed in this period of which 32 patients had AEL (2.6%).Clinical details noted down were the demographic profile: (1) age, (2) gender, (3) presenting symptoms and signs with duration, (4) past history of MDS/MPN or exposure to chemotherapy/radiotherapy and (5) family history. Also noted down were the peripheral blood smear details and bone marrow examination details: (1) blasts-erythroblasts and myeloblasts, (2) dysplasia in the cell lineages and (3) cytogenetic abnormalities. Peripheral smear and bone marrow aspiration slides of all the patients were reviewed, and diagnosis was revisited in view of new amendments to WHO definition of the entity. Diagnosis of AEL was made according to the WHO 2008 definition. Cytogenetic analysis was performed by conventional karyotyping of at least 10 metaphases, and the nomenclature system adopted was the International System for Chromosome Nomenclature (1985 and 1995).33.132 AEL patients were diagnosed in this period in 19 years of which 28 were of myeloid/erythroid subtype (erythroleukemia-M6a) and 4 were of pure erythroid subtype (pEL-M6b). Of these patients, 22(68.75%) were males and 10(31.25%) were females. In the group of patients with pEL, three were males and only one was a female patient. Median age was 36.3 years .The most common presenting symptom was fever seen in 22(68.75%) patients, whereas the most common symptom present was easy fatiguability seen in 28(87.5%) patients. Other prominent presenting symptoms were mild mucocutaneous bleeding seen in 5(15.6%) patients and lymphadenopathy seen in 4(12.5%) patients. Signs on examination were pallor in 25(78.12%) patients, jaundice in 10(31.25%) patients and organomegaly in 10(31.25%) patients: hepatosplenomegaly in 2(6.25%), only hepatomegaly in 5(15.62%) and only splenomegaly in 3(9.3%) patients. Most patients had an ECOG PS of 2. At presentation, most of them required blood/component transfusions. Mean total bilirubin was 2.7 g/dl (0.8\u20134.7) .3.23.2.13 (1800\u201319200) and median platelet count was 92000/mm3 (10000\u20131.8 lacs). Pancytopenia at presentation was seen in 81.25% of patients.Median haemoglobin was 7.8 g/dl (4\u201311.2), median total leucocyte count was 4400/mm3.2.2Bone marrow aspirate morphological examination had a mean erythroblast count of 65%(55\u201395), prominent shift to left with various dysplastic features: megaloblastic forms (22 patients\u201368.75%), nuclear budding (19 patients\u201359.37%), bi and multinucleated forms (21 patients\u201365.6%), cytoplasmic vacuolization (17 patients\u201353.1%), nuclear bridging (12 patients\u201337.5%) and karyorrhexis (7 patients\u201321.8) . Erythro3.2.3Results of cytogenetics by conventional karyotyping is as detailed below. Complex karyotype was noticed only in patients of pEL .4AEL is a hematopoietic neoplasm affecting the erythroid and myeloid precursor cells of bone marrow. The definition of AEL has undergone metamorphoses in accordance with the expanding knowledge of various other disease entities which are pathological mimics of this disease and the biologic and clinical behaviour of the disease. The diagnosis of AEL is one of exclusion. The entities to be excluded are AML-myelodysplasia-related changes (AML-MRC), therapy-related AML (t-AML), AML with erythroblast proliferation and recurrent genetic abnormalities, erythroblast phase of myeloproliferative neoplasms (MPNs) and reactive erythroid hyperplasia after erythropoietin (EPO) treatment .Diagnosis of AML-MRC requires the presence of at least 20% of blasts in the blood/marrow with one of the following: history of MDS/MPN, MDS-related cytogenetic abnormalities and absence of any of recurrent cytogenetic abnormalities, or presence of a minimum of 50% of dysplastic cells in at least two lineages with absence of history of exposure to cytotoxic agents: (1) alkylating agents and (2) topoisomerase II inhibitors . t-AML het al from the same institute [Incidence of AEL in our population of AML patients was 2.6%. This is less than the incidence (4.3%) quoted in Attili nstitute . In thisnstitute \u201318 have nstitute , 16. Somnstitute , 20. Thenstitute . Whethernstitute . The disnstitute , 16, 19.Most common presenting symptom was fever which was similar to that in other studies , 22. AELet al [Bone marrow was hypercellular with prominent dysplasia in erythroid lineage , 27. In et al . ChangesNo cytogenetic abnormality is specific for AEL. Four patients with cytogenetic abnormalities involving deletions in chromosomes 5 and 7, who were earlier classified as AEL from a study at the same institute , were reOf the 32 patients studied, 21(65%) received only the best supportive care; 4(12.5%) received low dose subcutaneous cytarabine; 3(9.3%) received decitabine; 4 received intensive 3 + 7 induction chemotherapy of infusional daunorubicin and cytarabine. The overall survivals in the respective subgroups were 2, 4, 5 and 14 months. The median follow-up period was 7 months.5AEL is a rare group of heterogeneous diseases with many neoplastic and non-neoplastic conditions mimicking the diagnosis. The clinical presentation and cytogenetics are also non-specific offering additional challenges to the diagnosis. Though it has an inherent biological relationship with MDSs, it has a worse clinical behaviour. Amidst the thoughts of phasing out this diagnosis and merging it with MDS, one must appreciate its differences in clinical outcomes. A probable age shift with regard to a younger population calls for more studies in this regard.None."}
+{"text": "Proteobacteria (33.12%), Actinobacteria (14.58%), Acidobacteria (12.81%), and Bacteroidetes (9.89%).We report here targeted deep-sequencing metagenomic data that reveal a high level of diversity in the microbiota residing in the sediment of the Periyar River in a reserve forest of the Western Ghats. Of the 4,674 operational taxonomic units discovered, the dominant phyla represented were  Here, wProteobacteria (33.12%), Actinobacteria (14.58%), Acidobacteria (12.81%), and Bacteroidetes (9.89%) were abundant. Our data provide new insights into the complexity and diversity of microfloral residents of this unique biome. A high OTU discovery rate indicates the existence of highly diverse microbiota among the rich floral and faunal resources in the Western Ghats.OTU binning discovered 4,674 species belonging to 25 major phyla, of which SRP131503.Data for the genome sequence reported here have been submitted to NCBI/GenBank under SRA accession number"}
+{"text": "Fine-needle aspiration cytology is a valuable method for preoperative assessment of head and neck tumors. However, its accuracy in detection of salivary gland masses is controversial compared with other methods. The aim of this work was to evaluate the effectiveness and accuracy of fine-needle aspiration cytology (FNAC) in the diagnosis of parotid gland masses. Over a 10-year period, 126 parotid gland masses were resected. Retrospective chart reviews of 114 patients were performed. The results of FNAC and final histological diagnosis were compared and the accuracy of FNAC was determined. Final histological evaluation revealed 11 malignant tumors and 103 benign lesions. Pleomorphic adenoma was the most common neoplasm (63%), followed by Warthin\u2019s tumor (17.5%). The sensitivity of FNAC in detecting malignant tumors was 73% and the specificity was 97%. Positive predictive value (PPV) was 73% and negative predictive value (NPV) was 97%. The overall accuracy of FNAC in detecting parotid masses was 95%. False-negative diagnosis was found in mucoepidermoid carcinoma, acinic cell carcinoma, and epithelial-myoepithelial carcinoma whereas there was false-positive diagnosis in cases of pleomorphic adenoma and normal parotid gland tissue. FNAC is a reliable minimally invasive diagnostic method with a high sensitivity in diagnosis of lesions in parotid glands. The sensitivity of detection of malignant tumors in parotid glands was low due to the biopsy technique used, and depended on tumor location. Postoperative complications decreased after superficial parotidectomy. In comparison, the overall incidence of salivary gland tumors during the same year was 0.99 in women and 1.49 in men,,,,,,Salivary gland tumors are a morphologically and clinically diverse group of neoplasms, which may present significant diagnostic and management challenges. In the western world, the estimated overall incidence is approximately 2.5\u20123.0 cases Eskilstuna Hospital provides healthcare to more than a quarter of a million inhabitants. Over a 10-year period (January 2003 to December 2014), masses in the salivary gland tumors of 126 patients were resected. Patients treated between January and December 2006 were excluded due to an error in the patients\u2019 electronic medical records. The medical records of 12 patients could not be located, so 114 patients  with a mean age of 56.4 years (range 18-85 years) were included in this study for further investigation. Three surgeons performed the surgical procedures. Intraoperative facial nerve monitoring with a nerve stimulator was used in all cases. We used our department\u2019s electronic database and clinical files to identify all patients who were diagnosed with a mass in the parotid gland. The ICD-10 codes D11.0, D11.9, C08.8, C08.9, and C07.9 were used to identify subjects from the database; this was followed by review of the medical records to confirm the diagnosis.Information regarding patient demographics, FNAC results, and final histological diagnosis results was evaluated. The postoperative outcome, including postoperative infection and hematoma, facial nerve disturbance, and Frey\u2019s syndrome was also registered. The preoperative FNAC results were compared with the final histological diagnosis from the surgical specimens. Data on age, gender, tumor type, and postoperative complications  were collected from the clinical records. Facial nerve disturbance was classified into four categories: (1) none, (2) transient (0\u20122 months), (3) less transient (2\u201212 months), and (4) permanent. Patients with radiologically verified and FNAC-verified cysts in parotid glands were excluded. Patients with inconclusive FNAC results were also excluded.FNAC was performed using a 22-gauge needle attached to a 10-mL plastic syringe mounted on a syringe holder for a single hand grip. The aspirated material was deposited onto five clean glass slides without using local anesthesia. The number of aspirations varied between 2 and 3, depending on the accessibility of the tumor. FNAC air-dried smears were stained with Giemsa stain and the slides were then examined under a light microscope , and results were reported according to the World Health Organization guidelines regarding parotid gland neoplasm.All FNAC samples and tumor specimens were analyzed by the same laboratory . Patients with FNAC-verified malignant tumors were referred to the head and neck cancer center at \u00d6rebro University Hospital for further cancer treatment.The cytology laboratory provided three types of histological results: (1) benign aspiration cytology, (2) suspicious or malignant aspiration cytology, and (3) non-contributory aspiration cytology (indeterminate or inconclusive).FNAC-based diagnoses were compared with diagnoses from histological examination of specimens. We calculated the sensitivity regarding the presence of malignancy , specificity regarding absence of malignancy , positive predictive value (PPV) , negative predictive value (NPV) , and accuracy of FNAC . Confidence intervals were computed at the 95% level. The FNAC and final histological diagnosis results are presented in terms of frequencies and percentages. Kappa value was also used to compare the agreement between the FNAC-based diagnosis and the biopsy-based diagnosis. Statistical analysis was carried out using SPSS (version 12.0).One hundred fourteen patients with parotid masses  with a mean age of 56.4 years (range 18\u201285 years) were included in the study. Mean duration of follow-up was 66 months (range 3\u2012132 months). The female-to-male ratio was approximately 1 to 1.1. Tumors were mainly located in the superficial parotid lobe , but 27 tumors (24%) were in the deep parotid lobe. FNAC of the deep portion of parotid mass was conducted in 7 cases (6%), whereas in 20 cases (17.5%) this procedure was performed using ultrasound-guided biopsy.Parotid tumors were resected via superficial parotidectomy . Total parotidectomy was performed in 18 cases with deep-lobe tumors (15.8%), and enucleation or superficial partial parotidectomy was performed in 2 cases (1.7%). Final histological evaluation revealed 11 malignant tumors (9.6%) and 103 benign lesions (90.3%). Pleomorphic adenoma was the most common neoplasm , followed by Warthin\u2019s tumor .FNAC was performed in 94 patients . In 20 cases (21%) with tumors located in deep parts of parotid glands, FNAC was complemented with ultrasound. In 108 of 114 cases (94.7%), preoperative FNAC and final histopathological findings were conclusive. The overall accuracy of FNAC for parotid masses was estimated to be 95%. False-negative diagnoses were found in mucoepidermoid carcinoma , acinic cell carcinoma , and epithelial-myoepithelial carcinoma  whereas there were false-positive diagnoses in cases of pleomorphic adenoma  and in normal parotid tissue  .FNAC results did not correlate with histology in 6 specimens (6.4%), 3 of which were benign (3%) and 3 malignant (3%). Final histological evaluation showed 11 malignant tumors (8 tumors were diagnosed correctly by FNAC and 3 were classified as benign). Thus, FNAC failed to give a correct cytological result in 3 cases (27.3%). The summary estimates that the sensitivity and specificity were 73% (95% CI 39\u201294) and 97% (95% CI 92\u201299), respectively. The PPV was 73% and the NPV was 97% . The kapIn summary, the study showed low sensitivity for malignant tumors. However, regarding the location of tumors, these three false-negative cases were located in the deep portion of the parotid gland and they were diagnosed by FNAC without ultrasound-guided biopsy.Tumors were mainly located in the superficial lobe , but 27 (24%) were in the deep lobe of the parotid gland. The most common complication of parotid gland surgery was transient facial nerve palsy. Of 114 patients, 39 (34%) had a mild transient palsy, 9 (7.9%) had a transient palsy lasting more than 2 months, and only one patient (0.9%) had permanent facial nerve palsy at 1-year follow-up. Of 39 patients with short-term facial nerve weakness (lasting 0\u20122 months), 21 (53.8%) had tumors located in the deep parotid lobe. Postoperative infection was found in 7 cases (5.8%). Nine patients (7.5%) had a recurrence of the tumor, 1 patient (0.8%) had hemorrhage, and 3 patients (2.5%) developed Frey\u2019s syndrome.,FNAC is a simple, inexpensive, and atraumatic method for preoperative assessment of tumors, lymph nodes, and other lesions in the head and neck. It is a safe procedure requiring minimal equipment, with a very low risk of cancer cell implantation,,,Several imaging modalities have been used for diagnostics of parotid masses, including CT-scan, MRI, and ultrasound-guided core needle biopsy (USCB),The importance of FNAC in distinguishing malignant parotid mass lesions from benign ones has been investigated by several authors,,-,In this study, of 103 cases of benign tumor, 100 cases were diagnosed using FNAC; of 11 malignant cases, 8 were diagnosed with FNAC. The overall accuracy of FNAC for parotid masses was estimated to be 95%, which is in the same range as in previous studies,,,,,,,-,,,A review of the literature showed a FNAC sensitivity ranging from 54% to 92% and a specificity of 86\u2012100%FNAC is a reliable method with high specificity for malignant parotid gland tumors, and provides the surgeon with valuable information in preoperative diagnostics. In this study, the sensitivity of FNAC in detection of malignant tumors was low due to the biopsy technique used, which depended on the location of the tumor. However, in cases where ultrasound guidance was used, 100% accuracy was achieved."}
+{"text": "Further reduction of mother-to-child transmission (MTCT) of HIV requires improved understanding of the reasons for MTCT. We reviewed maternal and infant case notes for HIV-positive infants diagnosed by polymerase chain reaction at Bethesda Hospital. Nineteen cases were analysed. Median gestation at first antenatal consultation (ANC) was 22.5 (interquartile range [IQR] 19.25\u201324). Eleven (57.9%) mothers were HIV positive at first ANC, whilst eight tested negative and later positive . Median maternal CD4 was 408 cells/\u03bcL (IQR 318\u2013531). Six (31.6%) received no antenatal antiretroviral therapy (ART) because they were diagnosed as HIV positive postpartum; 9 (47.3%) received antenatal ART and 3 (15.8%) were never initiated on ART. At 6 weeks postpartum, 5 infants (26.3%) were not on prophylactic nevirapine (NVP) because their mothers had not yet been diagnosed. Maternal seroconversion in pregnancy and breastfeeding, and possibly false-negative HIV tests, were important reasons for prevention of mother-to-child transmission (PMTCT) failure. Seroconversion in pregnancy or breastfeeding, HIV diagnosis in pregnancy compared with diagnosis prior to conception, and health system-related factors have all been found to play a role in PMTCT failure.8In 2010, the South African Department of Health (DoH) prevention of mother-to-child transmission (PMTCT) guidelines recommended World Health Organization Option A .9 HIV polymerase chain reaction (PCR) positivity at 6 weeks postpartum in 2013 was 2.3% for Bethesda Hospital  and its eight peripheral primary healthcare clinics. Our aim was to identify reasons for these PMTCT failures.Bethesda is a rural district hospital serving approximately 115 000 people in Umkhanyakude District, KwaZulu-Natal Province, with an HIV prevalence of 41.1% amongst pregnant women in 2011.We retrospectively reviewed maternal and infant case notes for HIV-positive infants identified by HIV PCR between February and September 2013 at Bethesda Hospital and its clinics.Ethics approval for the study was granted by the University of KwaZulu-Natal Biomedical Research Ethics Committee and the KwaZulu-Natal Health Research Committee.A total of 25 cases of MTCT were identified in the study period. Data were available for analysis in 19 cases . Notes wRegarding infants, 5 (26.3%) were not on NVP at their 6-week postnatal follow-up visit because their mothers had not yet tested HIV positive. Of the remaining 14 subjects, only 8/14 (57.1%) infants were documented to be on NVP prophylaxis, with 6/14 (42.9%) having no record of NVP administered. Two (10.5%) infants were documented as receiving mixed feeding at 6 weeks. One (5.3%) infant died before cART initiation, and 13 (68.4%) were known to have been initiated on cART at a median 5 (IQR 3\u201311) weeks after diagnosis.10 In the present study, we repeat findings elsewhere8 that initially testing HIV negative and subsequently positive in pregnancy or breastfeeding (leading to delays in ART initiation) is a major cause of PMTCT failure, occurring in 8 (42.1%) of the PMTCT failure cases in our study. We could not determine whether this was because of an initial false-negative test, or maternal seroconversion in the majority of cases. Current PMTCT guidelines advocate a confirmatory second HIV rapid test if the initial test is positive. However, there is no confirmatory test if the first test is negative.2 A study of 967 adults presenting for HIV testing in a clinic in Durban found that 2.1% of patients with a negative rapid HIV test had either acute HIV infection  or chronic HIV infection .11 In the context of further reducing MTCT to below 2%, potentially misdiagnosing 2% of mothers living with HIV is significant. Strategies to increase detection of all positive cases could include a second confirmatory rapid test as routine in all pregnant women . Furthermore, regular 3-monthly maternal HIV testing throughout the duration of pregnancy and breastfeeding, in accordance with DoH Guidelines,2 or even reducing the repeat testing interval to 1- or 2\u2013monthly, will be crucial to ensure that maternal seroconversion is detected as soon as possible.Maternal and infant ART have consistently been shown to be highly efficacious for PMTCT; consequently, omitting or delaying ART exposes infants to unnecessary HIV transmission risks.12 Omitting maternal ART when it is known to be indicated occurred in 3 (15.8%) cases (we were unable to ascertain why), and virological failure despite maternal cART occurred in 2 (10.5%) cases. Both these cases had repeated viral loads > 400 copies/mL more than 1 month apart but were not switched to second-line cART. The third case had no viral load sampling during pregnancy.Not documenting infant NVP prophylaxis when it is known to be indicated occurred in 6 (42.9%) cases in our study. However, this is probably higher than the true value as, from clinical experience, we note that infant NVP is often administered but poorly documented. Late booking after 20 weeks\u2019 gestation  occurred in 9 (47%) of cases, although 75% of cases had booked before 24 weeks which should allow time for viral suppression by the time of delivery, assuming ART is initiated promptly.Weaknesses of our study include lack of a control group, small sample size and incomplete or unavailable case notes. Data were too incomplete for analysis of several important variables . Only descriptive analysis was possible and our results must be interpreted with caution.PMTCT remains a focus programme in the South African healthcare sector. Better understanding of the reasons for MTCT can assist further reduction of MTCT rates to the target of less than 2%. Several causes for the failure of PMTCT in our sub-district have been identified. These correspond with reasons for MTCT from previous studies and available literature. Late first ANC, delayed or omission of maternal cART initiation, and poor management of women on cART contributed, amongst other factors, to our MTCT cases. Maternal seroconversion or an initial false-negative HIV test occurs frequently in PMTCT failures in our clinics, with subsequent late maternal ART initiation. This fact highlights the importance of preventing and promptly detecting maternal HIV infection in pregnancy and breastfeeding if MTCT is to be further reduced. Further research is needed to characterise the frequency of false-negative HIV testing in operational PMTCT programmes, and to identify cost-effective testing strategies to ensure early detection of acute maternal HIV infection in pregnancy and breastfeeding."}
+{"text": "Dundee Polyprofessionalism Inventory I: Academic Integrity\u201d, among the faculty and the students\u2019 of two different medical schools in Saudi Arabia.Medical professionalism is an essential aspect of medical education and practice worldwide. Our objective was to explore and compare the perception as recommended sanctions about professionalism lapses, using the \u201cRespondents from the two medical schools in Saudi Arabia, recommended sanctions for the first time, absolute lapses in academic professionalism were determined by using the \u201cDundee Polyprofessionalism Inventory 1: Academic Integrity\u201d.On comparing the faculty and students\u2019 responses  with the published data  we found alignments in recommending sanctions for 14 (46.66%) behaviours among faculty and again concerning the11(36.66%) behaviours among the students of both cohorts.The results can be used to emphasise on the improved teaching and learning strategies in undergraduate medical students\u2019 understanding of professionalism. In the recent past, the professionalism has emerged as a sustained theme, yet medical educators are striving hard to get to uniformly accepted standards concerning the academic integrity. Professionalism has three essential principles, including patient welfare, patient autonomy and social justice. Today\u2019s physicians require to act in accordance with professional standards more than ever before3Professionalism is inevitably associated with a society\u2019s culture9Therefore, this study aimed to explore and compare the perception of professionalism among the faculty and students of two different medical schools in Saudi Arabia which may aid in the teaching and assessment of professionalism in Arabian specific cultural context.This was a cross-sectional study, which took place during the academic year 2015-16 at the Department of Medical Education, College of Medicine, King Saud University (KSU), Riyadh, Saudi Arabia. The responses, collected at KSU were compared with published results from another Saudi medical school.10Dundee Polyprofessionalism Inventory I: Academic Integrity\u201d with 34 survey statements12An anonymous, self-administered, bilingual (English and Arabic), questionnaire \u201cThe obtained data were stored in the computers with password protection and analysed using a statistical computer program (SPSS version 21.0). Respondents were asked to respond about first time lapses in 34 types of behaviours with no mitigating circumstances by undergraduate medical students and to recommend from following list of the10 sanctions, based on a report:13Ignore (None)Reprimand Reprimand (written warning)Reprimand, plus mandatory counsellingReprimand, counselling, extra work assignmentFailure of specific class/remedial work to gain creditFailure of specific year Expulsion from college (readmission after one year possible)Expulsion from college (no chance for readmission)Report to a regulatory body.1431 medical students were contacted and initially 753 responded, but three students declined to participate in the study: response rate was 52%. Out of 750, one hundred and sixty-two (22%) were first-year medical students; 195 (26%) second-year; 160 (21%) third-year; 114 (15%) fourth-year; and 122 (16%) fifth- year students. Of the total agreed participants were (n= 750), there were 441 (58.57%) males and 311 (41.30%) females and 1 (0.1) preferred not to say. There were 166 (22%) students from 17-19 years of age, 518 (68.8%) from 20-24, 69 (9.2%) from 25 or over. Out of total50 participating faculty members, 32 (64%) were male and 18 (36%) were female. 31 (62%) were aged 31-50; 18 (36%) were 51-65 and 1 (2%) were over 65 years. 21 (42%) were primarily clinical faculty members and 29 (58%) were basic medical sciences faculty members.From 103 respondents 8 (7.76%) were aged 17\u201319 years and 95 (92%) were aged 20\u201324 years. 50 (49%) of the respondents were female and 52 (51%) were male and one student opted for \u2018not to say\u2019. Two percent of the respondents were in their first year; 33 (32%) in the second year; 33 (32%) in the third; 32 (31%) in the fourth and 3 (3%) in the fifth year of the course. Of the total 64 participating faculty members, 25 (39%) were male, 36 (56%) were female and 3 (5%) preferred not to give their gender information. 14 (22%) were aged 30 years or under; 40 (63%) were aged 31\u201350 years; 6 (9%) were aged 51\u201365 and 4 (6%) were aged over 65 years. 33 (52%) were doctors and the rest were from other health professions. 47 (73%) were primarily clinical teachers and the remainder non-clinical.Our study compared the median recommended sanctions by the participants from College of Medicine, KSU and from another Saudi medical school.10The sanction Reprimand, plus mandatory counselling as a median recommended sanction was selected from both the groups of KSU and another medical school of Saudi Arabia for a survey statement number (SSN) The responses comparison from faculty of both medical schools in The response similarities between the two student cohorts is shown in Medical professionalism is commonly described as characteristics of professional excellence, integrity and altruism.16\u201ccriminal conviction or caution, drug or alcohol abuse, aggressive, violent or threatening behaviour, persistent inappropriate attitude or behaviour, cheating or plagiarizing, dishonesty or fraud, and unprofessional behaviour of confidentiality or attitude\u201d.The \u201cDundee Poly-professionalism inventory\u201d has questions that help to bring about the perceptions of the faculty and the students in the most common areas of concern related to student fitness to practice. The General Medical Council, UK also outlines these areas as: In the present study, we found congruence in the recommending sanctions for 14 (47%) behaviours between the two cohorts of faculty and 11 (37%) behaviours between the two cohorts of the medical students. There is also only partial congruence between the faculty and students\u2019 responses in the form of median recommended sanctions for professionalism lapses, from the two medical schools in Saudi Arabia. These are reported in a separate paper for KSU by Babelli et al.17Medical professionalism is an essential aspect of medical education and practice worldwide and it must be adopted according to different social and cultural contexts It is also very critical for students to learn and model their professional behaviors, such as having a good attitude, empathy for the patients and also the quality of being honest.Medical professionalism has gained global attention over the past decade, but there still remains a lack of literature on the universal applicability of the leading professionalism framework.The present study is limited to exploring the practicality of an online inventory to \u2018map\u2019 student and faculty understanding of the comparative importance of professional lapses through the proxy of the recommended sanctions.The present study outcomes can be used to emphasise on the improved teaching and learning strategies in undergraduate medical students\u2019 understanding of professionalism."}
+{"text": "Streptococcus pneumoniae isolated from clinical cases and nasopharynx of healthy individuals, 60 erythromycin resistant strains were isolated and characterized using MLST, PFGE, transposon analysis and Quellung reaction. Most of the S. pneumoniae erythromycin resistant (80%) were found to be attributable to the ermB-edncoded ribosome methylase activity which differs from the dominant mechanism of macrolide resistance seen in North America.Amongst 100 1545/6003 (27%), Tn6002 (22%), Tn2009 (20%), Tn2010 (17%). Number of the clinical isolates carrying Tn2010 was more significant than the normal flora. The serotypes found were; 14 (33%), 3 (22%), 23F (15%), 19F (15%), 19A (7%), 6A (3%), 9V (3%) and 6B (2%). The most prevalent serotypes among the clinical (n = 28) and normal flora (n = 32) isolates were serotypes 14 (46%) and 3 (31%), respectively. The most prevalent vaccine serotypes amongst the clinical isolates and the healthy individuals were pneumococcal conjugate vaccines (PCV) 13 and PCV10, respectively. PFGE revealed 34 pulsotypes with 9 common and 25 single types. Significant number of the normal isolates belonged to CT5 and CT6. On the other hand, significant number of clinical isolates belonged to CT8 as compared to the normal flora isolates. MLST showed 2 dominant sequence types. ST3130 (23%) and ST180 (22%) were the most predominant sequence types in the clinical and normal isolates, respectively. There was no significant difference in other sequence types between clinical and normal flora isolates. Three polyclonal complexes including Sweden15A -25, Spain23F-1 and Spain9V-3 constituted 58% of the isolates. Our results suggest that the genetic diversity and transposon distribution were high among S. pneumoniae, particularly in the isolates containing erm(B) and double antibiotic resistant genes (erm/mef). The results presented here could influence the change in the current vaccination practices in Iran which currently calls for vaccination with PCV7 or PCV10.The most predominant transposons were; Tn Streptococcus pneumoniae is a common bacterial pathogen responsible for a numerous community acquired (CA) infections especially among children and elderly [ elderly . The pne elderly  and evenermB (MLSB phenotype) and efflux pump mechanism mediated by mef (M phenotype) genes with various transposons [Macrolides are the most frequently prescribed antibiotic among CA pneumococcal infections . Macrolinsposons \u20136.ermB and mef carried on Tn2010 [similar to Tn2009 with an additional ermB] has been reported , Tn6002 , Tn2010 , Tn3872 , Tn6003/Tn1545  and Tn1116  [3872, Tn6002, and Tn6003/Tn1545, which yield amplicons of 0.8 kb, 3.7 kb, and 7.9 kb, respectively. All primers are listed as The presence of transposons was tested using PCR assay for TnB, tetM) . PCR witSmaI enzyme and electrophoresis was done with ramped pulse times beginning with 5s and ending with 20s at 6 V/cm for 23 h. The banding patterns were read by Dice analysis and clustered by the unweighted pair group method with arithmetic averages (UPGMA) using Gelcompar II version 4.0 .PFGE typing of the isolates was done as described before . BrieflyaroE, gdh, gki, recP, spi, xpt, and ddl [http://eburst.mlst.net/).Multi locus sequence typing (MLST) was done using seven gene targets including  and ddl . The amp\u03c72 test as appropriate. Where needed statistical analysis was performed between the patient and normal flora samples.Differences in the proportions among categorical variables were assessed using Fisher\u2019s exact test or the P<0.05). The rate of ERSP isolates was higher among the invasive (75%) than non-invasive (43%) clinical isolates.In all, 60 (60%) ERSP were isolated with 28 (47%) and 32 (53%) isolates belonging to the clinical and normal flora groups, respectively. The number of ERSP isolates  obtained was significantly higher in the individuals with <15 (76.5%) years old than in adults) \u226515 years, P<0.05) among the invasive (67%) than non-invasive (23%) clinical isolates. On the other hand, serotype 19F was the most prevalent serotype in the non-invasive (38%) clinical isolates. Furthermore, the results showed that the serotypes 19A (13%), 6A (6%) and 6B (3%) were found only in the normal flora which constituted 22% of the isolates (Eight serotypes were identified among the whole isolates. These included serotypes 14 (33%), 3 (22%), 23F (15%), 19F (15%), 19A (7%), 6A (3%), 9V (3%) and 6B (2%) . The mosisolates .All of the ERSP isolates were susceptible to linezolid, vancomycin, imipenem, amoxicillin, cefotaxime, ceftriaxone, and quinupristin/dalfopristin. The highest resistance was found against trimethoprim-sulfamethoxazole (93%) followed by tetracycline (85%), clindamycin (78%), chloramphenicol (48%), penicillin (28%) and kanamycin (25%). In all, 83% of the ERSP isolates were MDR (resistant to 3 or more classes).B phenotype (MIC >256 \u03bcg/ml) (80%) and 12 isolates were assigned to M phenotype (MIC of 1.5 to 16 \u03bcg/ml) (20%)  and clinical isolates (46%) was found. On the other hand, M phenotype was significantly present in the normal (67%) than the clinical isolates (33%).On the basis of the erythromycin-clindamycin double disk test and MIC, 48 ERSP isolates were assigned to MLSl) (20%) . No signermB, ermB/mef and mef were carried in 50%, 36% and 18% of the clinical isolates, respectively. The predominant double resistant genes, ermB/mef, in the clinical isolates were found in serotype 14 (60%) followed by 19F. Amongst the ERSP nasopharynx normal flora, 47%, 28% and 25% were ermB, ermB/mef and mef, respectively. In the normal flora isolates, the major serotypes carrying double resistant genes (ermB/mef) were 19A and 3 (22% each)  .1545/Tn6003 (27%), Tn6002 (22%) and Tn2009 (20%) were the most dispersed transposons . Significant differences between the clinical and normal flora isolates carrying Tn2009 and Tn2010 were observed. The least common type of transposons was Tn1116 and Tn3872+MEGA (3% each) in both clinical and normal flora isolates  constituting 35 isolates and 25 single isolates . With th15A -25) was the most frequent CC constituting 40% of the ERSP isolates  with 10 clonal complexes (CCs) (n = 33) and 27 singletons Figs . Amongstisolates . Amongsthenotype  which weIn the present study, the overall rate of ERSP was 60% which did not significantly differ between the clinical and nasopharynx normal flora isolates. The presence of high number of MDR ERSP isolates (98%) was an indicative of indiscriminate use of antibiotics in general, and macrolide in particular, in clinical practices with eventual dissemination of the resistant strains in Iran.mef), which has been reported to be the dominant macrolide resistant in North American countries [Similar to the results obtained in Asia and some European countries , 14\u201316, ountries \u201318 and Gountries , was fouountries . The preountries , 21 and ountries .mef were found to be associated with 7 different serotypes (out of 8 serotypes identified), suggesting mef to be less discriminative than ermB which was found in 5 different pneumococcal serotypes (mostly in serotypes 3 and 14). Furthermore, it was observed that all isolates carrying Tn2010  also harbored double resistant genes (ermB/mef). On the other hand, no association between the serotypes and transposons or the source of isolation was found. Moreover, we found that many of our isolates could carry wide range of transposons. For examples, serotype 14 in both clinical and normal flora isolates could carry all major transposons including Tn6002, Tn1545/6003, Tn1116, Tn2009 and Tn2010. In contrary to the suggestion by Chancey and colleagues [2010 with Tn2009 and Tn6002 may exist, we did not found any coexistence of transposons in our isolates. 2010 in the clinical as compared to normal flora isolates. On the other hand, significant number of the normal flora carried Tn2009 than the clinical isolates.Some degree of genetic linkage was observed in this study. Our pneumococcal isolates carrying lleagues  that theS. pneumoniae isolated from 11 Asian countries [S. pneumococcus serotypes have disseminated throughout the Far East, South East Asia, Middle East countries. On the other hand, some serotypes are highly localized in parts of Asian countries.Comparative analysis between the report from Asian for Surveillance of Resistant Pathogens (ANSORP) on ountries , which ipneumococcal conjugated vaccine is not routinely used in Iran and it is only given to a limited number of people who are at high medical risks. Our results suggested that PVC13 would be the preferred vaccine over PVC7 or PVC10 and can be implemented in the Iranian national vaccine program.Similar to the other reports from Middle East countries , 25 the 15A-25 ST63 international clone with 57%, 39% and 4% harboring erm(B) alone, mef alone and ermB/mef, respectively. The second most frequent group was Spain23F-1 ST81 clone . Additionally, MLST analysis  revealed nineteen STs with ST3130, ST180, ST81 and ST63 were the frequent STs covering 62% of the total cases. In a study by Calatayud and colleagues in Spain [23F-1 ST81, Sweden15A-25 ST63 and Spain9V-3 ST156 constituting 30% of their invasive isolates, we found the 2 international ST clones  constituting 73% of our invasive isolates. On the other hand, ST81, ST283 and ST236 have been reported as the most frequent STs in some Asian countries [By using Pneumococcal Molecular Epidemiology Network classification,7 international resistant clones, including 19 different STs were identified among our clinical isolates. The most frequent group  was related to the Swedenin Spain , 10 ST countries , 28. Oveountries .S. pneumoniae strains to erythromycin was significantly high and the related isolates were clonally disseminated with majority having MLSB and ermB phenotypic and genotypic characteristics, respectively. Additionally, we showed that within the ERSP isolates, serotypes 14, 3, 19F and 23F constituted majority (85%) of the total ERSP isolates which were belonged to ST3130 (CC63), ST180, ST3130 and ST81 clones, respectively. The data presented here suggest that the use of PVC13 could have a significant protection coverage and should be the recommended vaccine for the Iranian population living in Tehran.The present study showed that the rate of resistance of S1 FigOne spot indicates one ST. The size of one spot relates to the number of pneumococcal isolates with the same ST. The lines designate the presence of single locus variant SLV and DLV links amongst STs.(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file."}
+{"text": "Aim: To study the prevalence of associated anomalies with neonatal duodenal obstruction and factors impacting short-term survival.Material and methods: Records of 31 neonates with neonatal duodenal obstruction could be retrieved and analyzed for a 13.5-year-period (October 2003-May 2016). M:F ratio was 1.58:1. The mean birth weight was 2.15 kg; 12 patients were preterm. Etiologies included duodenal atresia (n=23), duodenal web (n=8) and malrotation of gut (n= 6).Results: Associated anomalies were seen in 19/31: Down's syndrome (n=6), anorectal malformation (ARM) (n=5), annular pancreas (n=5), cardiac anomalies (n=4), esophageal atresia with trachea-esophageal fistula (EA with TEF) (n=3). Mortality in the series was 22.5%; 5 deaths and 2 patients left against medical advice in moribund state . Mortality in associated anomalies group was 5/19; and 2/12 in the no anomalies group, though this difference was not statistically significant (p=0.676). Similarly, low birth weight (LBW) did not have impact on survival (p=0.639) but preterm status had highly significant p value (<0.001).Conclusion: Duodenal atresia was the commonest cause of neonatal duodenal obstruction. Associated anomalies were noted in 61% patients, Down's syndrome being the most frequent. These anomalies did not have any significant impact on the survival, nor did LBW. Preterm status had significant impact on prognosis. Congenital duodenal obstruction (CDO) is amongst the commonest anomalies in newborns. [1] It affects about one in 2500 to 10000 live births, and nearly half of all cases of neonatal intestinal obstruction.  It may be either complete or partial and causes are classified as intrinsic  or extrinsic . [4-7] Survival of neonates has improved commendably because of advances in surgical management, intensive care medicine, and postoperative nutritional support. We reviewed our experience in managing CDO in 31 neonates over 13.5 years.A retrospective study was performed by retrieving the medical records of neonates who underwent surgery for congenital duodenal obstruction in the Department of Pediatric Surgery in a public tertiary-care hospital. This group was studied in detail with respect to the demographic details, antenatal diagnosis, clinical presentation, associated anomalies, surgical procedure, postoperative complications and outcome including mortality of these patients. Demographic Details: A total of 31 neonates with congenital duodenal obstruction including 23 patients of duodenal atresia and 8 patients with duodenal web, were managed over a period of 13.5 years (October 2003 to May 2016). The age distribution of neonate included from day 1 to day 28 of life. Most frequent age of presentation was day 1 of life (12 neonates). Twelve patients (38.7%) were premature (31-36 weeks). There was male sex predilection  with the M: F ratio being 1.58:1.Antenatal Diagnosis: Though majority of the pregnancies were supervised, an antenatal diagnosis of duodenal obstruction on ultrasonography  was made in only two patients. One mother was diagnosed to have polyhydramnios.Clinical Presentation: The commonest presentation was vomiting after breast feeds. Five patients presented with ARM. Three patients with associated EA with TEF presented with frothing from the mouth. The mean birth weight was 2.15 kg. Twenty two neonates were low birth weight (LBW)(70.9%). Associated Anomalies: The frequencies of associated anomalies are shown in Table 1. Radiological Investigation: In all of the cases, plain abdominal roentgenograms were diagnostic (double-bubble appearance). Surgery: Emergency operation was done in 17, while 14 were operated electively. After an initial assessment of associated congenital anomalies and hemodynamic stabilization, the patients underwent laparotomy through a right upper quadrant transverse incision. The etiology for congenital duodenal obstruction was assessed in intra operative period. Etiologies included duodenal atresia (n=23), duodenal web (n=8) and malrotation of gut (n= 6). All patients of duodenal atresia, duodenal webs and annular pancreas underwent exploratory laparotomy with trans-anastomotic tube (TAT) placement at end of procedure. In patient with duodenal atresia and annular pancreas, Kimura's diamond shaped duodeno-duodenostomy was performed. A lateral duodenotomy with excision of the obstructive membrane was done in duodenal web patients . The duodenotomy was closed transversely using 6/0 or 5/0 interrupted delayed absorbable sutures in a single layer. The location of the web was between the first and second parts of duodenum in all except two, in whom the membrane was located at the duodeno-jejunal flexure. Ladd's procedure was done for associated malrotation in six patients. No significant intra-operative surgical or anesthetic difficulties were encountered. It was possible to visualize the exact location of the membrane in the duodenum by careful inspection during surgery. Post operative ventilator support and supportive intensive care were required in seven patients. TAT tube feeds were started on postoperative day (POD) 5 in 10 (32.25%), on POD-6 in 7 (22.58%), on POD-4 in 6 (19.35%) and rest later. In postoperative period, 12 (38.7%) had sepsis and 1 (3.2%) each had intraventricular hemorrhage, congestive heart failure, short bowel syndrome and meningitis. One patient had accidental removal of TAT tube on POD 3 but managed conservatively. Two needed re-operations, 1 for associated large sliding hiatal hernia and 1 for mid ileal perforation. Five patients (16.12%) were expired in postoperative period and 2 (6.45%) left against medical advice in moribund state . Total mortality in series was 22.5 %. Mortality in associated 'anomalies group' was 5/19, and 2/12 in the 'no anomalies' group, though this difference was not statistically significant (p=0.676) .Similarly, low birth weight (LBW) did not have impact on survival (p=0.639) but preterm status had highly significant p value (<0.001).Congenital duodenal obstruction can present at variable age. Complete obstructive lesions like duodenal atresia present earlier as compared to partial obstruction like duodenal web, malrotation and annular pancreas. [3] Most frequent age of presentation for duodenal atresia was day 1 and day 2 for duodenal web. Duodenal atresias (DA) were observed in 23(74.1%) patients and were the most common cause of obstruction. Out of 12 preterm babies, 11 were associated with duodenal atresia and 1 had duodenal web. It could be explained by increase chances of preterm delivery in view of polyhydramnios associated with duodenal atresia. Escobar had similar findings in their study with 169 neonates, where 37% were preterm [5] and Rattan et al study shows out of 38 neonates 10 (26.3%) were preterm.[6]In more than half of the patients with duodenal atresia, associated anomalies and syndromes are present. Down syndrome is present in 30% of cases, malrotation in 20%, and congenital heart diseases in 20% of cases; nevertheless, other congenital anomalies of alimentary tract are also present in these patients[9]. In 2/3rd patients, the associated anomalies occur in isolation, whereas multiple anomalies occur in 1/3rd of patients. Although presence of Down syndrome in patients of duodenal atresia does not affect survival, the presence of multiple anomalies may alter the final outcome.In the current era, majority of cases are diagnosed in antenatal period but in our series only 2 patients had antenatal diagnosis as most of the obstetrics and anomaly scan are still being done by the treating obstetrician thus missing the findings of CDO. Surgical approach is dictated by type of the anomaly. Diamond shaped anastomosis as popularized by Kimura was attempted in all duodenal atresia cases.[10] In patients with duodenal web, lateral duodenotomy was done and web was excised with electrocautery leaving the medial part, avoiding injury to the ampulla of Vater. A proximal 'mega-duodenum'  may require imbrications or a tapering duodenoplasty procedure to avoid prolonged duodenal ileus. [11] Problem faced in initiating the oral feeds due to the gross duodenal dilatation leading to late discharge of pts. In our series though average discharge was at 13 to 14 days but the exact details regarding the oral feed toleration was not mentioned.Escobar et al found 6% of late mortality attributed to associated anomalies, central nervous system bleeding, pneumonia, and anastomotic disruption etc. [5] Rattan et al had reported mortality of 11 (13.5%) out of 81 neonates[6], which is similar to the mortality rate in our group. Zamir et al had reported mortality of 58% in a series from Pakistan. [7] In a review of 287 neonates, Chen et al observed overall mortality of 5.9% .[8] In western counties where antenatal supervision is good and neonates are diagnosed early, postoperative outcome of duodenal obstruction is much better than developing countries.Duodenal atresia was the commonest cause of neonatal duodenal obstruction. Associated anomalies were noted in 61% patients, Down's syndrome being the most frequent. These anomalies did not have any significant impact on the survival, nor did LBW but preterm status did. With increased ICU care and meticulous surgery, most of these patients have good survival. Source of Support: NoneConflict of Interest: None"}
+{"text": "TP53 mutations greatly varies between tumor types; in multiple myeloma (MM) they were rarely detected at presentation, while increased frequency was reported with disease progression. Using next-generation sequencing, we analyzed TP53 exons 4-9 in a large representative cohort comprising patients with MM at diagnosis and more aggressive forms of plasma cell (PC) dyscrasia, identifying mutations in 4/129 (3%) MM, 6/24 (25%) primary PC leukemia, and 2/10 (20%) secondary PC leukemia cases. A similar increase in prevalence associated with disease aggressiveness  was observed for TP53 deletion. Interestingly, in five patients mutations were not concomitant with TP53 deletion. Furthermore, longitudinal analysis revealed the acquisition of TP53 mutations in three of nineteen cases analyzed at relapse. Identified variants were mostly missense mutations concentrated in the DNA binding domain, only partly reflecting the pattern globally observed in human cancers. Our data confirm that TP53 mutations are rare in MM at presentation and rather represent a marker of progression, similarly to del(17p); however, their occurrence even in absence of deletions supports the importance of their assessment in patients with PC dyscrasia, in terms of both risk stratification and therapeutic implications.The prevalence of  TP53 gene at chromosome 17p13, mediates the response to various stress signals , many of which are encountered during tumor development and malignant progression , while its prevalence reached 58% in TP53-mutated subset (P < 0.0001). Overall, TP53 inactivation as a result of gene deletion and/or mutation occurred in 7% of MM, 37.5% of pPCL and 44.4% of sPCL patients; in particular, the two lesions were simultaneously present respectively in 0.8%, 16.7% and 22.2% of cases, causing biallelic gene inactivation. A fraction of TP53 mutations co-occurred with variants affecting other MM driver genes .We also tested the association between the occurrence of ) Tables  and 3. Ir series . HoweverTP53 mutations not visible in the earlier sample, VAFs were of 22.1%, 26.3% and 97%, respectively.Concerning variant allele frequencies, in mutated patients positive for del(17p) VAFs were almost always indicative of the exclusive presence of the mutated allele; on the contrary, in mutated cases at onset and disomic for chromosome 17 VAFs ranged from 2.65% to 100%, suggesting the occurrence of minor mutated subclones in MM-213 and MM-343; the presence of clonal heterozygous mutations in PCL-037; the predominance of mutated allele in PCL-004; and apparent copy number-neutral loss of heterozigosity in MM-262  and 8 primary plasma cell leukemia (pPCL) cases at onset, and 10 secondary PCL (sPCL), admitted to our Institution from July 2001 to April 2014. Additional 16 pPCL patients belonged to a prospective multicenter clinical trial  . All theHighly purified  plasma cells (PCs) were obtained from bone marrow specimens (collected at the time of diagnosis) using CD138 immunomagnetic microbeads as previously described , 38; 19 TP53 exons 4-9  was performed on genomic DNA using the Genome Sequencer Junior instrument , as previously described [TP53 human reference sequence (RefSeq NC_000017.11) and analyzed by the Amplicon Variant Analyzer (AVA) software version 3.0 (454 Life Sciences) to establish the variant allele frequency.NGS of escribed . Furtherhttp://www-p53.iarc.fr). Information about the functional relevance of the detected mutations was obtained from IARC database; specifically, a TP53 mutant was classified as \u201cnon-functional\u201d if the median of its transcriptional activities measured in reporter assays on eight different promoters containing TP53-binding sequences was lower than 20% compared to the wild type protein.The presence of each obtained non-synonymous variant was verified in an independent PCR product by conventional sequencing whenever the sensitivity of the Sanger method was consistent with the VAF. NGS analysis was repeated in case of mutations detected in less than 10% of sequencing reads. To exclude germline variants, we sequenced the matched normal DNA, when available, or consulted the International Agency for Research on Cancer (IARC) Database .Contingency analyses were made using two-sided Fisher's exact test ("}
+{"text": "RA patients receiving TNF inhibitors (TNFi) usually maintain their initial doses. The aim of the Optimizing Treatment with Tumour Necrosis Factor Inhibitors in Rheumatoid Arthritis trial was to evaluate whether tapering TNFi doses causes loss of clinical response.We enrolled RA patients receiving etanercept or adalimumab and a DMARD with DAS28 under 3.2 for over 3 months. Initially (months 0\u20136) patients were randomized to control (constant TNFi) or two experimental groups (tapering TNFi by 33 or 66%). Subsequently (months 6\u201312) control subjects were randomized to taper TNFi by 33 or 66%. Disease flares  were the primary outcome.Two hundred and forty-four patients were screened, 103 randomized and 97 treated. In months 0\u20136 there were 8/50 (16%) flares in controls, 3/26 (12%) with 33% tapering and 6/21 (29%) with 66% tapering. Multivariate Cox analysis showed time to flare was unchanged with 33% tapering but was reduced with 66% tapering compared with controls . Analysing all tapered patients after controls were re-randomized (months 6\u201312) showed differences between groups: there were 6/48 (13%) flares with 33% tapering and 14/39 (36%) with 66% tapering. Multivariate Cox analysis showed 66% tapering reduced time to flare .Tapering TNFi by 33% has no impact on disease flares and appears practical in patients in sustained remission and low disease activity states.https://www.clinicaltrialsregister.eu, 2010-020738-24; ISRCTN registry, https://www.isrctn.com, 28955701EudraCT,  Rheumatology key messagesTapering TNF inhibitors in RA patients by 33% over 6 months did not reduce time to disease flare.By 12 months, 45% of RA patients who tapered TNF inhibitor treatment were able to stop it entirely.Trials and observational studies underpinning the regulatory approval of TNF inhibitors (TNFi) for treating RA patients focus on initial efficacy and long-term safety . What toet al. [et al. [The Optimizing Treatment with TNFi in RA (OPTTIRA) trial was designed when there was limited information about tapering TNF inhibitor in RA patients with good treatment responses. Subsequently several observational studies and trials evaluated tapering. Systematic reviews of reports before 2015  found evet al.  and Edwa [et al.  highlighOPTTIRA is a randomized trial evaluating two tapering regimens in RA. It recruited patients showing EULAR good responses to TNFi  and compOPTTIRA was an open label, 6-month multicentre proof of principle trial with a subsequent 6-month exploratory phase for patients who completed the initial trial. OPTTIRA enrolled RA patients achieving good responses  with lowPatients receiving TNFi had met existing English criteria from the National Institute for Health and Clinical Excellence for these agents. The criteria have changed with time; they included failing to respond to MTX and another DMARD . These cPatients were taking etanercept or adalimumab; their existing TNFi were the trial investigational medicinal products.Rheumatology Online, show reducing etanercept and adalimumab dosing schedules.The proof of principle trial (months 0\u20136) compared three groups: experimental group 1: TNF inhibitor tapered by 33% initial dose; experimental group 2: TNF inhibitor tapered by 66% initial dose; control group: continued standard doses. Rheumatology Online, show the dosing schedules. The tapering schedules reflected standard dosing regimens related to the half-lives of the drugs.In the exploratory phase (months 7\u201312) patients in experimental groups increased times between injections until they stopped. Patients in the control group were further randomized into two groups: control group A had TNFi tapered by 33% initial dose; control group B had TNFi tapered by 66% initial dose. The primary outcome was time to first flare, defined as an increase in DAS28 scores \u2a7e0.6 resulting in a DAS28 >3.2 together with an increase in the swollen joint count; both had to be present on two occasions at least 1 week apart. An increase in DAS28 score \u2a7e1.2 resulting in DAS28 >3.2 was defined as flare irrespective of changes in swollen joints. These criteria reflect the subsequently developed DAS28 flare definitions proposed by OMERACT  and supphttp://www.medscinet.net).HAQ, EuroQol 5-dimension scale (EQ5D-3L), Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) and Functional Assessment of Chronic Illness Therapy were assessed at 0, 3, 6 and 12 months. X-rays of the hands (including wrists) and feet were taken at 0, 6 and 12 months with digitized X-rays read by an experienced observer (D.L.S.) blinded to treatment using modified Larsen scores. Every 3 months disease activity assessments recorded tender and swollen joint counts (28 joints), ESR, patients\u2019 global assessments of disease activity  and DAS for 28 joints together with details of medication and adverse effects. An anonymized electronic data capture system collected clinical data except X-rays  , 24. TheThe randomization algorithm considered patients in both proof of principle trial and the exploratory study taking different biologics. Consequently the randomization ratio generated was 1:1:2; we recruited twice as many to the control group than the initial tapering groups in the proof of principle trial.Potentially eligible patients were screened and reasons for non-entry recorded. The electronic data capture system (MedSciNet) randomized patients using minimization into experimental and control groups, stratified by TNF inhibitor  using randomly permuted blocks. Recruiting staff were blinded to allocation sequences.OPTTIRA was unblinded for assessors because it used treatment-specific algorithms with the adjustment of multiple dosing intervals of the drugs. Disability and quality of life were assessed by patients and X-ray reading was blinded.Randomized patients accepting their allocated treatment were analysed on an intention-to-treat basis. Data management and analyses used Stata . Baseline characteristics were summarized by randomization group as means and standard deviations , medians and interquartile ranges  and frequencies and percentages . Serious adverse event rates in each arm were compared with controls.Rheumatology Online). Kaplan\u2013Meier curves and the log-rank test compared randomized groups. Survival analysis analysed time to flare. The validity of the assumption of proportionality required for Cox regression was investigated graphically  as well as using Schoenfeld residuals in the final Cox models.Separate analysis was performed for the proof of principle phase (0\u20136 months) and the exploratory phase (6\u201312 months). The primary outcome was time to flare (months) for patients randomized to control, 33% taper or 66% taper, defined as the time from study entry to the first flare. Patients without flares, who withdrew or were lost to follow-up, were censored at the time of their last visit. Eight out of 97 patients were lost to follow-up  estimates of precision. All P-values were two sided.The North West London Research Ethics Committee approved OPTTIRA (REC Ref: 10/H0720/69). All enrolled patients gave written informed consent. The trial was registered with the UK Clinical Research Network and other relevant organizations .Rheumatology Online).Between April 2011 and June 2013, 244 patients were screened, 103 randomized and 97 accepted their allocated treatment , HCQ (18), SSZ (11) and LEF (4). All patients received etanercept (43 patients) or adalimumab (54). Two patients were taking prednisolone. The mean baseline treatment duration was 5.8 years (range 0.5\u201315.1 years).Of the patients, 50/97 were randomized to continue biologic at unchanged dosages, 26/97 to taper biologics by 33% and 21/97 to taper by 66%; 74/97 patients completed 6 months\u2019 treatment, 8/97 were lost to follow-up and 15/97 discontinued tapering but were followed up; 13/97 patients stopped treatment for flares, 1/97 stopped for drug toxicity and 9/97 stopped for other reasons including 1/97 for disease progression and 5/97 at the patients\u2019 own request.Of the patients randomized to continue biologics at unchanged doses who completed the 6-month proof of principle trial, 40/50 were re-randomized in the exploratory phase: 22/40 tapered by 33% and 18/40 tapered by 66%; 32/40 patients completed 6 months\u2019 treatment and 8/40 patients discontinued tapering but were followed up; 5/40 stopped treatment for flares, 2/40 had disease progression and 1/40 stopped at the patients\u2019 own request.The 34 patients who had tapered for 6 months and continued on the treatment schedule in the proof of principle trial tapered further until their biologics were completely stopped by 6 months; 21/34 completed 6 months\u2019 treatment, 2/34 were lost to follow-up and 11/34 discontinued tapering but were followed up. All 13/34 patients stopping treatment did so because of flares.Demographic and disease assessments were similar in all patient groups . The patSeventeen patients flared comprising 8/50 (16%) control patients, 3/26 (12%) patients tapering by 33% and 6/21 (29%) patients tapering by 66% . UnivariEleven patients flared: 3/22 (14%) patients tapering by 33% and 8/18 (44%) tapering by 66% . UnivariResults from re-randomized initial controls were combined with the tapering groups in the proof of principle trial to provide a detailed comparison of time to flare in the two tapering regimens over 6 months. Six of forty-eight (13%) patients tapering by 33% flared compared with 14/39 (36%) patients tapering by 66% . MultivaRheumatology Online.Longitudinal analysis of changes within the first 6 months in all treated patients  showed lThe effects of flares, irrespective of treatment group, on 6-month outcomes were assessed in linear regression models adjusted for age, gender and disease duration. DAS28 scores were higher in patients who flared  and EQ5D scores were lower , but HAQ scores were unaffected .Thirty-four patients who tapered biologics in the proof of principle trial  further tapered treatment until they stopped TNF inhibitor over 6 months in the exploratory study. Thirteen of thirty-four (38%) flared and 21/34 (62%) did not flare. Consequently 21/47 (45%) patients who started tapering in the proof of principle trial stopped TNF inhibitor by 12 months; 21/47 (45%) had flared and 5/47 (11%) had stopped tapering for other reasons. The 21 patients who stopped TNF inhibitor without flaring had initial DAS28 score of 1.51  and 12 month DAS28 scores of 2.27 . Their initial HAQ was 0.65  and the 12 month HAQ 0.75 .2 = 3.99, degrees of freedom (DF) = 1, P = 0.050) than for patients receiving etanercept, 23/43 (53%).The flare rate for patients receiving adalimumab, 18/54 (33%), was significantly lower  than for those in remission.At baseline 74 patients were in remission and had DAS28 scores under 2.6; 27/74 (36%) of these patients flared. There were 23 patients with low disease activity (DAS28 score 2.6\u20133.2) and 14/23 (61%) of these flared. The risk of flare was therefore significantly higher for patients with low disease activity at baseline  patients had one or more events; 47/97 (48%) patients had an adverse event in the first 6 months and 29/89 (33%) in the second 6 months ; 4/97  trial  showed Aet al. . More re [et al.  showed c [et al. , 41. TheThe most effective and cost-effective strategy for using biologics in RA patients remains uncertain. As current biologics are not curative in established RA patients, the rationale for their indefinite use in treatment responders is debatable. OPTTIRA shows modest tapering has no negative clinical impacts. We consider there is sufficient evidence for clinicians to reduce TNF inhibitor doses in some treatment responders. This approach may be more cost-effective than their continued use though it risks short-term disadvantages as flares are a burden to patients. Its impacts on disease status and healthcare costs need further evaluation, particularly as we found no evidence that tapering worsened patient-assessed outcomes.Supplementary TablesClick here for additional data file.Supplementary Figure S1Click here for additional data file."}
+{"text": "Delays in seeking timely appropriate care contributes to a large number of deaths from diarrhea in children. This study aimed to identify determinants of delays in seeking timely treatment by mothers/caregivers of under-five children with diarrheal diseases.We used an unmatched case-control study from February\u2014March 2017 among 316 children: 158 cases and 158 controls. Cases were mothers/caregivers with under-five children who had signs/symptoms of diarrhea and sought treatment after 24 hours onset of symptom. Controls sought treatment within 24 hours. Field workers collected data using a pre-tested standardized questionnaire. Multivariate logistic regression was conducted to identify determinants of delay in timely diarrhea treatment seeking. Statistical significance was declared by using a p-value<0.05 and 95% of confidence interval (CI) for an adjusted-odds ratio (AOR).The determinants of delay in timely treatment seeking of mothers/caregivers of under-five children with diarrheal diseases were children <24months ; fail to attend school ; being female children ; preferring government health facility for the treatment of children with diarrheal diseases ; lack of past history taking children to health facility and lack of counseling ; being in the15-25 years age  and taking children to a health facility as a first response to diarrhea .Age of the child, maternal age, and disease related determinants were determinants for seeking timely treatment to diarrheal diseases. Providing skilled based health education and counseling to mothers/caregivers on seeking timely treatment and taking children with diarrheal diseases to a health facility as a first response to diarrhea is a paramount intervention to reduce morbidity and mortality of children. Diarrheal disease is one of the five leading causes of morbidity and mortality among under-five children in the world . ApproxiA large number of children in low-income countries die due to a delay in seeking treatment timely from health care , 12. In We used an unmatched case-control study from February-March, 2017. The study was conducted in Woliso district, which is one of the Zonal towns in the Oromia Region, located 114 km southwest of Addis Ababa. Clean water coverage in the town was above 98% while the coverage of standardized latrine was 94.4% .We obtained a sample from all under-five year children living in Woliso town and surrounding rural kebeles (the lowest administrative unit) who visited under-five clinics with diarrheal diseases. Cases were under-five children with signs/symptoms of diarrhea whose mothers sought treatment after 24-hours of the recognition of diarrhea. Controls were under-five children with signs/symptoms of diarrhea whose mothers sought treatment within 24-hours of the recognition of diarrhea. Children whose mothers/caregivers did not mention the exact dates of onset of diarrhea were excluded.We calculated sample size using two-population proportion-formula by assuming odds ratio of 2, 95%CI, th = 2,3 by lottery method) from the first interval, every Kth individuals at the succeeding intervals were selected separately for cases and controls proportionally based on the number of diarrhea cases reported in February 2017 Ethiopian fiscal year (EFY), same month, of data collection from each health facility. Proportional allocation of the respondents to the five health facilities was conducted. When mothers/caregivers complained of diarrhea in their child completed their consultation with a health professional, they moved to a private room for an interview until the total required sample size obtained.We selected respondents by systematic random sampling techniques. Starting from the first participant selected by random sampling procedures .Table 1).In our study, 316 mothers (158 cases: 158 controls) were interviewed, making a response rate of 100%. The majority, 120 (75.9%) of the cases and 95(60.1%) controls were children <24-months. The mean age of cases was 18.7(\u00b112.5SD) and that of controls was 19.4(\u00b111.6SD) months. More than half of respondents were females, 85(53.8%) among cases and males, 94(59.5%) among controls (Table 1).More than 1/4 61(38.6%) cases and 57(36.1%) control mothers/caregivers were between 15\u201325 years of age. Three-fourths 112(70.9%) cases and 117(74.1%) controls were among the member of the Oromo ethnicity and 147(46.5%) were Orthodox Christian. More than three-fourths of cases 151(95.6%) and controls 151(95.6%) were married. More than 1/4 61(38.6%) cases and 27(17.1%) controls had no education while 77(48.7%) cases and 56(35.4%) controls fathers attended primary education (Table 2).Almost half 71(44.9%) of cases and 89(56.3%) controls were housewives while 49(31.0%) cases\u2019 and 32(20.3%) controls\u2019 father were farmers. The majority, 148(93.7%) of cases and 130(82.3%) controls preferred government health facilities. The cost of treatment 258(81.6%), examination of child 159(50.5%) and distance to health facilities 122(38.6%) were the major reasons for the selection of health facilities (Table 3).Most of the mothers/caregivers 303(95.9%), responded to diarrhea of children by taking them to the health facility. Roughly 80(50.6%) of cases and 102(64.6%) controls took their children immediately when diarrhea of children was complicated with vomiting, 82(51.9) of cases and 85(53.8) controls due to inability to feed, and fever for 81(51.3%) cases and 82(51.9%) of controls. Thirty-five (22.2%) of cases and 53(33.5%) controls mothers/caregivers reported that they seek medical care for any diarrhea. With current diarrhea, 134(42.4%) of respondents complained of vomiting, 92(29.1%), unable to feed and 143(45.3%) had fever. Twenty (12.6%) of cases and 9(5.7%) controls mothers/caregivers believe that diarrhea can be cured by itself. Aproximatly 25(15.8%) of cases and 40(25.3%) controls developed diarrhea within the last six months and visited a health facility  for <5-children with diarrhea than mothers/caregivers between 26\u201335 years age. Mothers/caregivers who did not attend school were more likely to delay seeking treatment for under-five children with diarrhea than mothers/caregivers who attend school .Table 4).Mothers/caregivers who preferred a government health facility for the treatment of children with diarrhea were three times more likely to delay to seek treatment compared with those preferred private health facilities . Mothers/caregivers who take their children to health facilities as a first response to any diarrhea were 90% less likely to delay to seek treatment for children with diarrhea  compared to those did not believe in taking their children to a health facility. Mothers/caregivers who had no history of taking their children to a health facility and being counseled about the importance of timely treatment seeking for diarrhea of children were five times more likely to bring their under-five children late for the treatment of diarrhea than their counterparts  Click here for additional data file.S2 File(ZIP)Click here for additional data file."}
+{"text": "In the Community of Madrid, the 13-valent pneumococcal conjugate vaccine (PCV13) replaced the 7-valent (PCV7) in the fully government-funded Regional Immunization Program (RIP) in May, 2010, but was later excluded in May, 2012, and included again in January, 2015. These unique changes allowed us to assess the impact of the different pneumococcal vaccination policies on PCV13 uptake in infants and on the incidence rate (IR) of invasive pneumococcal disease (IPD) in children <15 years old. In this prospective, active, surveillance study, we estimated PCV13 uptakes, IR and incidence rate ratios (IRR) for total IPD and for IPD caused by PCV13- and non-PCV13 serotypes in children <15 years, stratified by age, in four periods with different vaccination policies: fully government-funded PCV7 vaccination, fully government-funded PCV13, mixed public/private funding and only private funding. Vaccine uptakes reached 95% in periods with public-funded pneumococcal vaccination, but fell to 67% in the private funding period. Overall, IR of IPD decreased by 68% (p<0.001) in 2014\u201315, due to 93% reduction in the IR of PCV13-type IPD (p<0.001) without significant changes in non-PCV13-type IPD. A fully government-funded PCV13 vaccination program lead to high vaccine uptake and dramatic reductions in both overall and PCV13-type IPD IR. When this program was switched to private PCV13 vaccination, there was a fall in vaccine coverage and stagnation in the decline of PCV13-type IPD with data suggesting a weakening of herd immunity. The introduction of pneumococcal conjugate vaccines (PCVs) in childhood immunization programs has markedly decreased the incidence of invasive pneumococcal disease (IPD) \u20134. Data Adherence to recommended vaccine schedules and high uptake are the most important factors for both individual protection and maintaining wider herd immunity in the community . Reductist of May of 2012. Finally, PCV13 was reintroduced in March 2015 for infants born after the 1st of January of 2015. From May, 2012 to May, 2015, the vaccine was available at private markets for purchase by parents.In October 2006, the seven-valent PCV (PCV7) was introduced into the Regional immunization program (RIP)\u2014a public funding immunization program in the Autonomous Region of Madrid (\u22486 million inhabitants). In June 2010, the 13-valent conjugate vaccine (PCV13) replaced PCV7 with a schedule of doses at 2, 4, and 12 months of age but it was later excluded from the RIP in 2012, because of changes in vaccination policies for children born after the 1In the Region of Madrid, IPD in children <15 years of age has been the object of active surveillance since 2007, coinciding with the introduction of PCV7 in RIP. In this study, we aimed to assess the impact of different immunization policies on both vaccine coverage and IPD incidence.A prospective, active, population-based and clinical surveillance study on laboratory-confirmed IPD was carried out in all hospitals with pediatric departments located in the Autonomous Region of Madrid, Spain, from May, 2007 onwards \u201317. A nest period (May 07 \u2013April 08), 2nd period (May 08 \u2013April 09), 3rd period (May 09 \u2013April 10), 4th period (May 10 \u2013April 11), 5th period (May 11 \u2013April 12), 6th period (May 12 \u2013April 13), 7th period (May 13 \u2013April 14), and 8th period (May 14 \u2013April 15). Data from periods 1 to 5 were published [st, 2nd and 3rd periods, with free PCV7 vaccination in RIP), PCV13 period , mixed public/private period , and private period .Data were analyzed annually: 1ublished ; howeverStreptococcus pneumoniae in normally sterile fluids, demonstrated by culture and/or polymerase chain reaction (PCR). Samples were sent to the clinical microbiology laboratory at each center for microbiological culture and/or PCR detection. All pneumococcal isolates were sent to a single reference laboratory  for serotyping by Quellung reaction. When pleural or cerebrospinal fluids from children with meningitis or pleural empyema did not yield positive cultures, samples of these fluids were also sent to the reference laboratory for PCR detection of pneumolysin (ply) and autolysin (lyt) genes [Clinical forms of IPD  and demographic data  were prospectively collected from children <15 years of age with laboratory confirmed IPD. IPD was defined as the presence of t) genes ,19. Pneut) genes , detectiPCV13 serotypes were considered serotypes included in PCV13 and serotype 6C based on previously reported cross-protection data . All othInstituto Nacional de Estad\u00edstica  [Annual population data on children <15 years old and estimated person-years data for different age groups  were obtained from the Spanish  Office) .Details of the number of PCV7 and PCV13 doses delivered per year in Madrid were obtained from IMS Health  as total vaccine sales per year. Yearly estimated vaccine coverage (assuming a 2+1 dose schedule) was calculated by dividing total doses by number of children under 2 years of age and expressed in units/1,000 inhabitants <24 months old/year.Incidence rates (IR) per 100,000 inhabitants of the corresponding age group were calculated for total IPD (children <15 years of age), total IPD stratified by age groups, IPD caused by PCV7 serotypes (PCV7-type IPD), IPD caused by PCV13 serotypes (PCV13-type IPD), and IPD caused by serotypes not included in PCV13 (non-PCV13-type IPD). Incidence rate ratios (IRRs), with their respective 95% confidence intervals, were calculated as ratios between IR in 2011\u201312 (last year of PCV13 in RIP)/IR in 2009\u201310 (last year of PCV7 in RIP), IR in 2013\u201314 (first year of the private period)/IR in 2012\u201313 (mixed public/private funding period), and IR in 2014\u201315 (last year of the private period)/IR in 2009\u201310 (last year of PCV7 in RIP). Comparisons were performed with the EPIDAT version 3.1.The Triple Exponential Smoothing \u201cHolt-Winters\u201d (TES-HW) time-series model  was usedBetween May, 2012 and April, 2015, 113 IPD  were included. When pooling these data with previously reported IPD cases  in all pS. pneumoniae was identified by PCR (25 cases in the Private period); of them, 128 (65.3%) could be serotyped.In a total of 196 (22.8%) cases, Estimated vaccine coverages in the different periods were: 95% (from 2007\u20138 to 2011\u201312), 82% (2012\u201313), 67% (2013\u201314) and 73% (2014\u201315).In children 0-<24 months, the IR of total IPD decreased significantly by 52% in 2011\u201312 due to a significant decrease (76%) in PCV13-type IPD without significant changes in non-PCV13-type IPD. However, when vaccination uptake fell to 67% in 2013\u201314, the IR non-significantly increased compared with 2012\u201313  due to non-significant increases in both PCV13-type  and non-PCV13-type IPD . A similar pattern was observed in children >59 months  .Along the 8-year study period, the most common non-PCV13 serotypes causing IPD  were serotypes 15B (8.6%), 24F (6.8%), 23B (6.1%), 22F (5.7%), and 10A (5.0%). None of the non-PCV13 serotypes stood out for showing increases over time. In the last study period (2014\u201315), 19 different serotypes were identified among 46 non-PCV13 serotypes causing IPD.To the best of our knowledge, this is the first study that, by means of prospective active surveillance, analyses the effects of removing infant pneumococcal immunization with PCV13 from a fully-government funded program. During the two years of free infant universal pneumococcal vaccination with PCV13, infant vaccine uptakes reached 95% and there was a significant overall reduction of IPD (55%) in children younger than 15 years. During the 8-year study period (2007\u201315), all IPD were significantly reduced (68% reduction) through a near elimination of PCV13-type IPD (93% reduction), particularly IPD by serotypes 1 and 19A which, before the introduction of PCV13, accounted for 60.4% of all IPD . The decAfter the exclusion of PVC13 from the fully government-funded vaccination program, vaccine uptake dropped to 67%. Although IR of all IPD and of PCV13-type IPD continued to decrease in children 24-\u226459 months (children vaccinated with PCV13 during the free vaccination program), in children <2 years of age (the target group for vaccination) and children >5 years (children unimmunized with PCV13) the decline in PCV13-type IPD stagnated.Nasopharyngeal colonization, which begins in the first months of age and peaks at 3 years, plays a central role in the epidemiology of pneumococcal infections . ReductiSignificant reduction of nasopharyngeal colonization by vaccine types in unimmunized people appears when vaccine coverage in children reaches 65\u201370% . In the Our data suggest that the drop in vaccine coverage below the threshold from which herd immunity can be expected could lead to a rapid increase in IPD incidence in unimmunized people. The effect of herd immunity on IPD is seen within just a few months after PCV13 introduction . In our It has been reported that the overall reduction of IPD prevented by PCVs is only partly offset by serotype replacement ,32. Our Epidemiologically, according to our forecast data, the vaccination impact would have been greater in the period 2014\u20132015 with >50% IR reduction (versus observed) in PCV13-type IPD, without changes in non-PCV13-types. Clinically, avoidable IPD would have been mostly empyema and bacteremic pneumonia, probably because of the different tropism of pneumococcal serotypes, with serotype 1 linked to respiratory presentations.One study limitation is the estimation of vaccine coverages considering a 2+1 dose schedule instead of the recommended 3+1, which may falsely increase vaccination coverages. However, it seemed appropriate since adherence was probably suboptimal in the private period, as previously reported by other authors in Spain and other European countries . AnotherThe present study strongly suggests the efficacy of a fully government-funded program for universal vaccination against pneumococci, which guarantees high vaccine uptake levels, and consequently a great impact on IPD through both direct and indirect vaccination effects. Lack of completion of vaccination schedules increases when the vaccine is not included in free public immunization programs, making costs an issue for parents , disinclAlthough secular natural trends of serotypes have a potential role that cannot be ignored, the results of our forecast data show that the maintenance of PCV13 in RIP would have reduced the incidence of PCV13-type IPD to a greater degree without significant increased incidences in non-PCV13-type IPD. Therefore, the reintroduction of PCV13 in the RIP in May, 2015 was an appropriate measure, the impact of which warrants future monitoring.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file."}
+{"text": "The objectives were to assess the frequency of hospital acquired pneumonia (HAP) in patients admitted to intensive care unit (ICU) and to determine the frequencies of different etiological organisms in these patients.This was descriptive cross sectional study, which was carried out in medical ICU of Shifa International Hospital Islamabad from January 2013 to January 2014. A total of 1866 patients were admitted in the department of medicine including medical ICU. They were evaluated for HAP and the causative organisms were cultured from these patients. Identification was carried out by standard biochemical profile of the organisms.The total number of patients admitted in medical ICU for any reason were 346. HAP was diagnosed in 88 patients (25.4%). The average age of patients admitted in Medical ICU with HAP was 48 years with the range of 16 to 82 years. 56 were male and 32 females. 42 patients (47.7%) died in medical ICU with HAP. Microbiological analysis showed that Pseudomonas aeruginosa were 27 (30.6%), Acinetobacter spp. were 12 (13.6%), Candida albicans were 12 (13.6%), Klebsiellapneumoniae were 9 (10.2%), Streptococcus spp. were 9 (10.2%), Escherichia coli were 5 (5.6%), Stenotrophomonas spp. were 4(4.5%), Methicillin Resistant Staphylococcus Aureus (MRSA) were 4 (4.5%) others organisms 6 (6.8%).The frequency of HAP in Medical ICU of our hospital is 88 out of 346 (25.4%). The commonest organism identified was Pseudomonas aeruginosa (30.6%) followed by Acinetobacter and Candida albican (13.6% each). Hospital-acquired pneumonia (HAP) is one of the most frequent and most severe medical complications in patients which are hospitalized in intensive care units. It develops mainly in association with invasive airway management and mechanical ventilation.HAP is the infection of lung parenchyma that develops 48 hours after hospital admission6The incidence of HAP in the ICU had been stable in the ranges from 9\u201324% with variation relating to the intensive care and differences in the definitions and diagnostic techniques used.11The pooled incidence density of VAP ranges from two to 16 episodes per 1000 days on ventilator.14Pseudomonas aeruginosa, Enterobacter, Klebsiellapneumoniae, Escherichia coli, Serratia marcescens and Proteus species are the most frequently isolated pathogens causing nosocomial infections15Of all HAP, bacteria such as The rationale of this study was to find out the current frequency of HAP in our population. These studies are the usual method used to identify local identification of microbiological agents causing pneumonia and developing guidelines for the use of antibiotics in intensive care unit.A total of 1866 patients were admitted in the department of medicine including medical ICU from January 2013 to January 2014. They were evaluated for HAP and the causative organisms were cultured from these patients. Total 88 Medical ICU patients out of 346 admissions fulfilled the criteria of HAP and the causative organisms affecting these patients are discussed in this study.Tracheal aspirate (TA): We added an equal volume of Sputasol (Dithiothreitol) to the specimen and digest the sputum by mixing on vortex mixer for 20-30 seconds. Incubated at 37\u00b0C for 15 minutes. When digestion was completed it was diluted 100\u00b5l (0.1ml) of the digested sputum into 9.9ml of \u00bc strength Ringers Solution (sterile) and was mixed properly. From this diluted well mixed sputum, 10\u00b5l was transerred in each plate of Chocolate agar, Sheep Blood Agar, & MacConkey agar (MAC). Sabouraud\u2019s dextrose agar (SDA) was used or fungal culture before adding of sputasol (digestion). Each colony on the plate was equal to 10,000 cfu/mL.Interpretation: Any count of \u2265 105 was considered as significant. Therefore, growth of 5 or more than 5 colonies was identified and reported.Broncho-Alveolar Lavage: Sample was Vortex for 30 seconds from which smear was prepared on clean glass slide for gram stain. Remaining vortexed sample was inoculated on Sheep Blood Agar, Chocolate, & Mac conkey agar using 0.001 loops.Interpretation: Any count of \u2265 104 is considered as significant. Therefore, growth of 10 or more than 10 colonies is identified and reported. Chocolate & Sheep Blood Agar were incubbated in CO2 incubator and MacConkey in atmospheric incubator at 37 \u00b0 C for 24-48 hrs.Culture examination: After 24-48 hours growth was observed and their morphology was done by gram staining. The organisms were further identified by biochemical tests.17Radiological Signs of the definition of clinical diagnosis of HAP are: >2 serial chest radiographs with at least one of the following: (a) New or progressive & persistent infiltrate. (b) Consolidation. (c) Cavitation.Clinical Signs of the definition of clinical diagnosis of HAP are: At least one of the following: (a) Fever (Temperature > 38\u00b0 without other recognized cause). (b) Leukopenia (<4000/mm3 or >12000/mm3). (c) For adults > 70 years of age, altered mental status with no other recognized caused and atleast two of the following (i) New onset of purulent sputum, change in character of sputum, increased respiratory secretions or increased suctioning requirement. (ii) New onset or worsening cough or dyspnea or tachypnea. (iii) Rales or bronchial breath sounds. (iv) Worsening gas exchange (e.g. oxygen desaturation ratio (PaO2-FiO2) < 240, increase oxygen requirement, increase ventilation demand).Statistical analysis was done using the statistical package for social sciences (SPSS) version 17.0 Frequencies and percentages were obtained for categorical variables.All ethical considerations and obligations were duly addressed and the study was conducted after approval of ethical committee.Pseudomonas aeruginosa were 27 (30.6%), Acinetobacter spp. were 12 (13.6%), Candida albicans were 12 (13.6%), Klebsiellapneumoniae were 9 (10.2%), Streptococcus spp. were 9 (10.2%), Escherichia coli were 5 (5.6%), Stenotrophomonas spp. were 4(4.5%), Methicillin Resistant Staphylococcus Aureus (MRSA) were 4 (4.5%). The organisms affecting one patient each included Enterococcus, Aspergillus, Moraxella, Enterobacter specie, Proteus mirabilis and Burkholderia specie.Total 1866 patients were admitted in medicine department for any reason. Out of them 346 were admitted in medical ICU. Out of Medical ICU admissions 188 were admitted with lower respiratory tract infection. Total 88 Medical ICU patients out of 346 admissions fulfilled the criteria of HAP (25.4%). . The avePseudomonas aeruginosa, (30.6%) followed by Acinetobacter specie and Candida albicans (13.6% each), Klebsiellapneumoniae and Streptococcus were 10.2% each.Our study shows that the overall frequency of patients admitted with HAP in Medical ICU was 25.4%. The most frequently isolated organism was Patients admitted to the Intensive Care Units have been shown to be at particular risk of acquiring hospital acquired infection with a prevalence rate as high as 30%. The risk of hospital acquired infection in ICU is 5\u201310 times more than those acquired in general medical and surgical wards.18Overall HAP has accounted for approximately 15% of all hospital acquired infections in USA. it is associated with 11% of Hospital acquired infections other than intensive care units and 26% of Hospital acquired infections in the ICU.20The incidence of HAP varies from hospital to hospital. The incidence of HAP in the ICUs ranges from 9 to 24% with variation relating to care presented in the ICUs and differences in the diagnostic techniques used. A large-scale, prevalence study nosocomial pneumonia arising in the ICU was performed as a part of the European prevalence of infection in Intensive Care (EPIC) study. Among a total of more than 10000 patients in 1417 ICUs across Europe the overall HAP prevalence was 9.6%.et al.,Acinetobacter (20%), Staph. aureus (14.5%) and Klebsiellapneumoniae (75%).In a study done in Beirut in the most commonly identified organism was Acinetobacter anitratus, followed by Pseudomonas aeruginosa and Klebsiella species.spp. (9%)As far as local data is concerned in a study was done in 2009 in Hayderabad Pakistan and out of 50 patients with nosocomial infections 18% were diagnosed as HAPOur study was done in a single center so the data may not be representative of whole population but the age distribution and pattern of organisms have the same trend as previous studies.The frequency of HAP in Medical ICU of our hospital is 88 out of 346 (25.4%). The mortality from HAP is 47.7%. The commonest organism identified was Pseudomonas aeruginosa (30.6%) followed by Acinetobacter and candida albican (13.6% each). Our results are in concordance with international and local data. We recommend that further large scale studies are required and the data needs to be validated regularly to rationalize the use of antimicrobial agents."}
+{"text": "Aqueductal stenosis is the commonest cause of congenital hydrocephalus. The scope of this paper is to highlight the disease burden of hydrocephalus attributed to aqueductal stenosis which still remains unknown in our setting.In a descriptive cross-sectional study, 258 records of patients diagnosed with hydrocephalus were analyzed after ethical approval from Kenyatta National Hospital- University of Nairobi (KNH-UON) ethics and research committee from January 2010 to May 2016. Patients with a diagnosis of hydrocephalus due to aqueductal stenosis were included in this study. Patients age, sex, mode of delivery, associated comorbidities, presenting complaints, neurosurgical intervention performed, Kafarnosky score were recorded. Data were divided into 2 sets based on the patient's age i.e. whether < 1 year or > 12 years. Data were recorded on google data collection form and analyzed using Google spreadsheets.Out of 258 cases of hydrocephalus, 52 had aqueductal stenosis. Male to female sex ratio for this condition was 3:2. There were 25 cases < 1year and 27 cases > 12 years old who were diagnosed with hydrocephalus due to aqueductal stenosis. Associated conditions were bilateral congenital talipes equinovarus, spina bifida, Arnold Chairi malformations, meningitis and HIV. The presenting complaints differed according to the age groups. Neurosurgical interventions included Endoscopic Third Ventriculostomy (ETV) in 21 cases, insertion of Ventriculoperitoneal (VP) shunt and ETV were done in 3 cases while the rest had only insertion of VP shunt. The Kafanosky score improve from < 50 pre-op to 19 cases achieving a score of 100, six months post-op.Aqueductal stenosis contributes a significant burden of morbidity in patients with hydrocephalus. Clinical presentation differs according to patients age. Accurate diagnosis and treatment remain a cardinal to improving patient outcome. Aqueductal stenosis (AS) is a pathological condition causing triventricular obstructive hydrocephalus which requires a clinical and radiological diagnosis. Patients develop symptoms like headache, cognitive and gait impairment, and urinary incontinence . ClinicaIn a descriptive cross-sectional study, 258 records of patients at the Kenyatta National Hospital diagnosed with hydrocephalus were analyzed after ethical approval from Kenyatta National Hospital- University of Nairobi (KNH-UON) ethics and research committee from January 2010 to May 2016. Patients with a diagnosis of hydrocephalus due to aqueductal stenosis were included in this study. The variables collected include: patients age, sex, mode of delivery, associated comorbidities, presenting complaints, neurosurgical intervention performed, Kafarnosky score. Data were divided into 2 sets based on the patient's age i.e. whether < 1 year or > 12 years. Data were recorded on google data collection form and analyzed using Google spreadsheets.In a sample study of 258 cases of hydrocephalus, aqueductal stenosis was identified as a cause of hydrocephalus in 52 cases (20%). The male to female sex ratio for this condition was 3:2. There were 25 cases (9.6%) of aqueductal stenosis in patients < 1year, of which 15 cases presented at birth with only 6 having undergone caesarean section; and 10 cases presented before the age of 6 months. 3 out of the 25 cases of aqueductal stenosis in <1 year old age group were premature. There were 27 (10.4%) cases of patients who were > 12 years old who were diagnosed with hydrocephalus due to aqueductal stenosis.Associated conditions: These were almost exclusively seen in the age group of < 1 years. In 3 cases there was associated bilateral CTEV and spina bifida, 5 cases had associated spina bifida alone, 1 case had bilateral CTEV and 1 case of Arnold Chiari Type 2 malfomation with aqueductal stenosis. Meningitis was a co-morbidity in 6 cases while HIV was present in 3 cases. There was only 1 case of Arnold Chiari Type 1 malformation as an associated co-morbidity in the age group > 12 years.Presenting complaints: For patients who were less than 1 years the main presenting complaints were increase in head circumference, tense anterior fontanelle and sunset eyes in all. Generalized tonic clonic seizures were seen in 5 cases, vomiting in 5 cases, regression of milestones in 5 cases, refusal to breastfeed in 3 cases; hotness of body, nuchal rigidity, and positive Kernings sign were seen in 6 cases. The median head circumference was 48.5cm for neonates who presented at birth and for 48.75cm those who presented before 6 months of age. For patients who were > 12 years the main presenting complaint was headache (19 cases), followed by deterioration of vision (10 cases), abnormal gait (8 cases), convulsions (5 cases), Vomitting ( 5 cases) stool and urine incontinence (4 cases). Other less common presenting complaints were confusion, loss of consciousness, slurred speech, hemiparesis, mutism, abnormal behavior and hiccups  cases of hydrocephalus that had aqueductal stenosis as a cause of hydrocephalus, with a rate off 9.6% having congenital aqueductal stenosis and rate of 10% in adults. This is lower compared to reported cases of 30-40% with a varying prevalence of 15-60% of hydrocephalus in children and 10-40% of cases in adults , 8. TherAqueductal stenosis contributes a significant burden of morbidity in patients with hydrocephalus. Clinical presentation differs according to patients\u00b4 age. Accurate diagnosis and treatment remain a cardinal to improving patient outcome.Aqueductal stenosis has significant morbidity in patients with hydrocephalus;Prevalence and presenting complaints for aqueductal stenosis have been extensively studied in other settings;2 modalities of intervention for aqueductal stenosis include ventriculoperitoneal shunting and endoscopic third ventriculostomy.Prevalence of Aqueductal stenosis in the Kenyan setting;Comparison of Kafarnosky score pre-operatively and post-operatively in Kenyan setting;Prevalence and presenting complaints follow a bimodal distribution of age."}
+{"text": "To the Editor: Surveillance data indicate that tickborne diseases are substantial and increasing global public health problems  samples by using conventional microscopy after Giemsa or Wright staining .Of 75 patients, 42 (56%) were male and 33 (44%) were female. Mean age was 33 (range 14\u201372) years. Nine (12%) patients reported tick bites. The most common symptoms were fever (64 [85.3%] patients), headache (41 [54.6%]), vomiting (26 [34.6%]), muscle ache (22 [29.3%]), and abdominal pain (21 [28%]). At the time of the hospital visit, 9 (12%) patients had signs and symptoms suggesting meningeal involvement; 3 (4%) others had clear meningeal signs. These 12 patients underwent lumbar puncture, and CSF abnormalities were found in the 3 (4%) patients with meningismus. Spirochetes were found in the CSF sample of 1 patient. Of the total 75 patients, this patient was the only 1 with spirochetes, and no patient had facial palsy or other neurologic manifestation. The main laboratory findings were elevated C-reactive protein, found in 74 (98.6%) patients; thrombocytopenia, found in 67 (89.3%); and anemia, found in 37 (49.3%).Preferred treatment was oral doxycycline, which was used for a mean duration of 10 (range 7.3\u201314) days in 55 patients (73.3%). Among 3 TBRF patients with neurologic involvement, 1 was treated with penicillin G (3 million units/4 h for 10 d), and 2 were treated with ceftriaxone (2 g/d for 14 d). Jarisch-Herxheimer reaction occurred in 7 (9.3%) patients, none of whom had meningitis. All patients recovered completely.Currently, TBRF is widely distributed in various foci around the world. In much of sub-Saharan Africa, TBRF is associated with a high number of illnesses and deaths. Indeed, it is reportedly the most common bacterial infection from Senegal and is listed among the 10 leading causes of death in children <5 years of age in Tanzania  patients had meningitis caused by TBRF borreliosis, a finding that accords with the previous report. Reports on TBRF in Spain are scarce. The only previous study involving numerous cases of TBRF in Spain (A recent study conducted among children in southern Spain (B. burgdorferi and Treponema pallidum (B. turicatae and B. duttonii, the agents of TBRF in southwestern North America and sub-Saharan Africa, respectively, cause neurologic involvement as often as B. burgdorferi causes Lyme disease (Neurologic complications are well known features of infection with 2 spirochetes, B. hispanica is among the less severe illnesses caused by the relapsing fever group, serious neurologic complications can occur. With increasing globalization, physicians will likely see increased numbers of travel-related infections and will face imported and emerging TBRF cases. Our study confirms that TBRF is an endemic, underreported disease in many countries and is common in southern Spain. Although the disease caused by"}
+{"text": "Distal femoral fractures account for 3-6% of adult femoral fractures and 0.4% of all fractures and are associated with significant morbidity and mortality rates. As countries develop inter-hospital trauma networks and adapt healthcare policy for an aging population there is growing importance for research within this field.Hospital coding and registry records at the central London Major Trauma Center identified 219 patients with distal femoral shaft fractures that occurred between December 2010 and January 2016. CT-Scans were reviewed resulting in exclusion of 73 inappropriately coded, 10 pediatric and 12 periprosthetic cases. Demographics, mechanism of injury, AO/OTA fracture classification and management were analyzed for the remaining 124 patients with 125 fractures. Mann Whitney U and Chi Squared tests were used during analyses.The cases show bimodal distribution with younger patients being male (median age 65.6) compared to female (median age 71). Injury caused through high-energy mechanisms were more common in men (70.5%) whilst women sustained injuries mainly from low-energy mechanisms (82.7%) (p<0.0001). Majority of fractures were 33-A (52.0%) followed by 33-B (30.4%) and 33-C (17.6%). Ninety-two (73.6%) underwent operative management. The most common operation was locking plates (64.1%) followed by intramedullary nailing (19.6%).The epidemiology of a rare fracture pattern with variable degrees of complexity is described. A significant correlation between biological sex and mechanism of injury was identified. The fixation technique favored was multidirectional locking plates. Technical requirements for fixation and low prevalence of 33-C fractures warrant consideration of locating treatment at centers with high caseloads and experience. The The treatment of distal femoral fractures remains a challenge, in particular AO/OTA type B and C -9. MetapThis paper aims to report the experience of a Central London Major Trauma Center (MTC) in managing adult distal femoral fractures over a five-year period. The complex operative management strategy is also explored.2st of December 2010 and the 31st of January 2016, a period of five years and two months. This generated a total of 219 patient cases , 10 skeletally immature patients and 12 patients with previous total knee arthroplasty were excluded.Patient cases were cross-referenced with their respective radiographs, the Trauma Audit and Research Network Registry (TARN) and the Trauma and Orthopedic Department electronic notes system to ensure homogeneity between the coding records. Seventy-three inappropriately coded cases , mechanism, associated injuries, fracture demographics  and fracture management. The Sex and Gender Equity in Research (SAGER) guidelines were consulted to ensure data collection and design of this study was compliant . ImportaNon-parametric two-tailed statistical tests were used (Mann Whitney U for univariable data and Chi Squared test for multivariable data). Comparisons were made between the age of patients, mechanism of injury and definitive fracture fixation method.33.11). The mean age was 63 years and the median age was 68 years with a range between 15 years and 101 years. There was a classic bimodal distribution with a higher proportion of patients between 15-40 years and 50-90 years sustaining distal femoral fractures . There were a total of 125 fractures with 52.8% (n=66) on the left, 45.6% (n=57) on the right and 0.8% (n=1) bilateral. Although not statistically significant, men were more likely to be younger than women when sustaining these injuries with a median age of 66 years compared with a median age of 71 years (p=0.55). Men had 65.6% (n=21) of the associated injuries cohort.Of the 124 patients, 41.9% (n=52) were male (p=0.072)  or low energy .When unspecified injuries were excluded there was a statistically significant difference between sex and mechanism of injury. High-energy trauma was more likely in men  and low-energy trauma more likely in women  (p<0.0001).3). Of the 60 patients who fell, the majority did so from ground level . Falling from greater than a two meter height occurred in eight patients (13.3%). The 33 motor vehicle incidents were due to pedestrian vs car , cyclist vs car , motorbike vs. car , multicar collision  or unspecified .The most common mechanism of injury was falling  followed by motor vehicle incidents , assaults  and penetrating injuries . Twenty-eight patients had non-specified injuries or other injuries not coded for within our search parameters , 5 (4.0%), 9 (7.2%), 18 (14.4%), 15 (12.0%), 5 (4.0%), 4 (3.2%), 7 (5.6%) and 11 (8.8%) patients respectively . Involvement of the knee joint was present in 60 patients (48.0%).Fracture type consisted of 65 (52.0%) type 33-A, 38 (30.4%) type 33-B and 22 (17.6%) type 33-C configurations as seen in Table 3.45).The majority of patients had an inpatient stay of less than two weeks when censored at either discharge or death. The longest inpatient stay was 95 days  patients. Thirty (93.8%) of these patients had a second fracture elsewhere.3.66). There were 27 (21.6%) fractures managed conservatively for various reasons including undisplaced stable fractures, extreme frailty and poor pre-morbid function. Six (4.8%) patients had missing operative records. Our experience determined the use of locking plates to be the most common intervention occurring in 59 (64.1%) operations. Other operative approaches include IM nailing , screws , IM nail and screws , external fixation  and TKR .In total, 92 (73.6%) fractures underwent operative management  . Accordin France . The mean France , 16. Fif [et al. . Baron e986-1990 . They de4.3Our study determines that high-energy mechanisms dominate the male population 70.5%, n=31) whilst low-energy trauma dominated the female population . This was statistically significant (p<0.0001). These findings are consistent with reported literature elsewhere [1 whilst 4.4et al. determined 33-A1 and 33-C1 to be the most common in their study of 105 distal femoral fractures across four MTCs [et al. also agrees with type 33-A1 being the most prevalent [Our study found that fracture patterns 33-A1, 33-B1 and 33-B2 were the most common. Smith our MTCs . It is drevalent . Our exprevalent , 20.4.5et al. studied 42 elderly patients with displaced distal femoral fractures [The majority of distal femoral fractures are managed operatively in adults. Even in elderly patients, non-operative management of displaced fractures is associated with poor outcomes due to increased risk of pressure ulcers, pneumonia, deep vein thrombosis and knee stiffness . Butt etractures . They coractures . Plate fractures .The link between low-case volume and increased risk of post-operative complications has been shown in the context of total hip arthroplasty . This te4.67 and 8). Fractures around the distal femur are typically shortened and rotated and therefore traction radiographs can be helpful. High-energy injuries mandate radiographs of the pelvis and ipsilateral hip in order to exclude the presence of fractures proximal to the knee.Once operative management has been decided, obtaining the correct imaging is crucial. Initial anteroposterior (AP) and lateral radiographs of the knee and distal femur are important and provides valuable information about the injury  that usually requires independent interfragmentary screw fixation. It also provides invaluable information on fracture configuration, size of bony comminution and bone stock  determining whether internal fixation is achievable. Current implant designs allow internal fixation in increasingly distal fracture configurations and primary distal femoral replacement is rarely performed.All distal femoral fractures with intra-articular comminution and extension should undergo a Computer Tomography (CT) scan with 2D and 3D reconstructions. This will readily identify a coronal plane fracture (Hoffa fracture) , less invasive stabilization systems (LISS) or locked condylar plates (LCP) , 25. Dep13 and 14) [For fractures with intra-articular extension (33-B and 33-C), open reduction and internal fixation with restoration of the articular surface and the relationship of the distal articular segment to the femoral shaft is recommended. Preference is for fixation utilizing an anatomically contoured lateral locking plate for angular stability. This offers a more biomechanically stable construct under physiological loading and is particularly helpful in osteoporotic bone . A combi and 14) .4.8Utilizing a radiolucent table that allows unobstructed fluroscopy of the whole femur is recommended. Place the patient in supine position with a bolster under the ipsilateral hip allowing the leg to lie in neutral rotation. Prepare and drape the entire leg. Use a radiolucent triangle under the thigh to help position the leg. Use a sterile tourniquet to allow access to the shaft of the femur. It is important to ensure unobstructed high quality AP and lateral imaging is achievable before starting the case.Utilize a direct lateral approach for most intra-articular distal femoral fractures. Distally curve the incision anteriorly and incorporate a lateral parapatellar arthrotomy. The advantages of this approach include the ease of plate application, the ability to reduce the metaphyseal component and it\u2019s extensile nature. To visualize the medial articular surface the approach can be extended distally to sublux the patella medially and the option to perform a tibial tubercle osteotomy can allow complete visualization of the articular surface in the complex 33-C2 and 33-C3 fractures.4.9In treating 33-C2 and 33-C3 fractures a pre-operative CT and adequate articular exposure is the key to accurate reduction. Indirect or percutaneous reduction and fixation techniques are not recommended because the goal of treatment is achieving anatomical reduction of the joint cartilage and stable fixation to allow early joint mobilization and rehabilitation. Hoffa fragments are addressed first by placing pointed reduction clamps perpendicularly across the fracture within the exposure. Upon achieving anatomical reduction the fragment is provisionally held with Kirschner wires (K-wires). At least two AP interfragmentary compression screws are used to control rotational forces and should be placed away from the weight bearing area of the articular cartilage. The screw heads must be countersunk below the cartilage surface to avoid impinging on the patella. Use variable pitch headless compression screws or countersunk partially threaded cancellous screws. Following fixation of Hoffa fractures, each condylar segment must be de-rotated and reduced using multiple k-wires or a pointed reduction clamp. Due to the trapezoidal nature of the distal femur and occasional loss of bone the reduction can appear anatomical at one point but mal-reduced at another point. Once anatomical reduction has been achieved, an interfragmentary compression screws should be inserted from lateral to medial to compress the femoral condyles. Care must be taken to place these screws anteriorly or posteriorly to avoid screw conflict with the distal locking screws of the plate.4.1010 and 11) the goals of treatment are to restore length, rotation and alignment of the distal articular surface to the shaft of the femur with minimal disruption to the fracture fragments. This reduces the risk of devascularisation, subsequent non-union and implant failure. Here a pre-contoured lateral distal femoral locking plate is used to bridge the area of metadiaphyseal comminution. Use a plate length that spans three times the length of comminution. In restoring the coronal alignment of the femur the pre-contoured plate can be useful once the plate is \u201creduced\u201d onto the bone. Length, rotation and sagittal alignment can be more difficult to restore and is achieved through manual traction and manipulation of the distal segment with large diameter k-wires or a 5mm Schantz pin to joystick. A femoral distractor placed proximally in the shaft and into the distal articular block can be helpful to maintain traction, restore rotation and maintain sagittal alignment long enough to allow plate application to restore coronal alignment.Once stable fixation of the articular segment has been achieved, it is reduced and fixed to the femoral shaft. In simple fracture patterns direct visualization with lag screw fixation or compression plating can be utilized. In more complex fracture patterns (AO 33-C2 and 33-C3) with metadiaphyseal comminution (Figs. 4.11As with all articular fractures, early range of motion and rehabilitation is key to preserving joint function. Therefore lower extremity range-of-motion exercises and gait training are advocated to commence on the first post-operative day. This rapidly progresses towards a physical therapy exercise program to improve knee range of motion and quadriceps function. Most patients are fitted with a hinge knee brace during the first 6 weeks of ambulation. For the complex 33-C2 and 33-C3 fractures, toe-touch weight bearing is recommended for 10 to 12 weeks. Sutures are removed at two weeks and patients are seen for clinical examination and radiographs at 6 weeks. Patients are radiographically assessed again at 12 weeks for evidence of callous and whether weight bearing can commence. Subsequent review is required every two to three months until clinical and radiographic union is achieved.4.12The use of hospital coding records to derive cases for this study runs the risk of omissions. Incomplete electronic medical records can also affect elements of data collection. To ensure completeness of data capture, several different hospital databases were used to identify and independently confirm cases. As an unblinded observational study, there is risk of unintentional bias in interpreting radiographs. As mentioned previously, sex-based analysis was conducted in disaggregated data. There is the assumption that any differences between gender and biological sex are irrelevant in the context of sustaining distal femoral shaft fractures.This study adds to the existing body of knowledge regarding the epidemiology of distal femoral shaft fractures. It describes an injury that predominantly affects elderly women and younger men in a bimodal distribution. Sex and mechanism of injury are also closely correlated. Intra-articular involvement is common with differing degrees of complexity. Experience suggests the use of locking plates and IM nails are effective operative options. Due to low incidence, it is deemed appropriate to manage these fractures in specialized trauma centers."}
+{"text": "A subset of renal cell carcinoma (RCC) patients has been shown to respond to anti-EGFR therapy. As KRAS and BRAF mutations are associated with poor response to anti-EGFR therapy in some cancers, it has been suggested that screening for KRAS and BRAF mutations in RCC may be a promising strategy to identify patients who might respond to EGFR-targeted therapy. The aim of this study was to investigate the mutation status of EGFR, KRAS and BRAF in RCC patients. Renal tumors and normal renal samples from forty-eight patients who underwent radical or partial nephrectomy for kidney cancer were used in this study. Histological classification of the tumors was performed according to International Union against Cancer (UICC) / American Joint Committee on Cancer (AJCC) classification. Seventeen patients (48%) had clear-cell RCC, 7 (20%) had chromophobe RCC, and 11 patients (32%) had papillary RCC. DNA isolated from the samples was subjected to melting curve mutation analysis for EGFR, BRAF and KRAS using ABI-3130 DNA sequencer. DNA sequencing analysis of RCC samples, when compared with morphologically normal matched regions, did not show any exon mutations. Our results do not support the notion that EGFR, KRAS and BRAF might be mutated in RCC. Renal cell carcinoma (RCC) constitutes 3% of all adult malignancies . AccordioC until use.After obtaining local ethics committee approval, RCC and matched normal samples from 48 patients who underwent radical or partial nephrectomy for kidney cancer were evaluated between June 2009 and June 2011 at the University of Gaziantep, Department of Urology, Turkey. Thirteen patients who had benign and ureteral carcinoma according to the pathological results were excluded from the study. The samples from the remaining 35 patients were used for further study. Portion of the samples were formalin-fixed and processed for histology and the remaining were stored at -80Three micron sections of the formalin-fixed kidney samples were stained with hematoxyline and eosine and the tumor grade was determined according to International Union against Cancer (UICC) / American Joint Committee on Cancer (AJCC) 2009 TNM classification, whereas tumor nuclear grading was performed according to the Fuhrman grading system by a qualified Pathologist.oC (30\u201350 mg tissue) were isolated using Roche High Pure Polymerase Chain Reaction (PCR) Template Preparation Kit  following the protocol of the supplier. DNA samples were stored at -20\u00b0C until further use. DNA sequencing was performed on an ABI 3130 DNA sequencing analysis instrument. The target area was amplified by PCR using primers specific to EGFR, KRAS, and BRAF  had clear-cell RCC, 7 patients (20%) had chromophobe cell RCC, and 11 patients (32%) had papillary RCC. According to 2009 TNM staging of the tumors, 11 patients (31%) were T1a, 8 patients (23%) were T1b, 3 patients (8%) were T2, 9 patients (26%) T3a, and 4 patients (12%) T3b. Twenty-three patients (65%) were evaluated as N0, 8 were (23%) N1, and 4 patients were (12%) N2. According to the Fuhrman grading system, 3 patients (8%) were Grade 1, 15 patients (43%) were Grade 2, and 17 patients were (49%) Grade 3 (Table 2). DNA sequencing analysis of cancer samples and normal tissues did not show any exon mutations in the EGFR, BRAS, and KRAS pathway (data not shown).Nineteen male and 16 female patients  who had RCC were included in the study. The mean age of the patients was calculated as 59.31 \u00b1 12.52 (15\u201377) years. None of the patients were in an occupational group that might play a role in kidney cancer etiology. History of smoking was present in ten male patients (52.6%) and in four female patients (25%). The mean body mass index was 28.31 \u00b1 3.45 (21\u201333) kg/mBRAF and KRAS belong to the RAF proto-oncogene serine / threonine-protein kinase (c-RAF) gene family and their over expression or mutations trigger abnormal cell proliferation. EGFR is believed to be responsible for cell proliferation during carcinogenesis . Kamai e"}
+{"text": "Chronic lymphocytic leukemia (CLL) is a heterogeneous disease in terms of survival with and without treatment. Many chemo and immunotherapeutic agents are available to treat this indolent disease. Aim of this study was to determine the outcomes of patients with chronic lymphocytic leukemia treated with different available chemotherapeutic regimens.All patients with diagnosis of CLL from 2008 to 2013 were included. Data were collected from hospital information system. Objective response rate (ORR) in terms of complete or partial response , stable or progressive disease , overall survival (OS), and progression free survival (PFS) were calculated.Fifty seven patients were included; 42 (74%) male and 15 (26%) were female. Patients with Binet stage A 10 (18%); B 20 (35%) and C were 27(47%). Median age was 50.9 years. Forty six (80%) were treated and 11(20%) remained on watch and wait. Treatment indications were B symptoms 14 (30%), symptomatic nodal disease 18(39%), thrombocytopenia 4(9%), anemia 7(15%) and doubling of lymphocyte count 3 (7%). Chemotherapy regimens used were FC in 38 (83%), FCR 5(11%), chlorambucil 2(4%) and CVP in 1(2%) patient. Twenty two (56%) patients had CR, 13(33%) PR, 3(7.6 %) SD, and 1(2.5%) had PD. ORR was 89%. Median PFS was 23.1 months and median 3 years OS was 55%.Majority of patients was in a relatively younger age group and presented with advanced stage disease requiring treatment. Small number of patients received rituximab due to cost. PFS and OS are comparable with published literature. CLL is a disease of elderly, with male predominance and a median age of more than 70 years. Median age is 58 years in familial cases.6In physically fit patients FCR  is the standard first-line therapy.12In this study, we analyzed objective response rate, progression free survival and overall survival in patients with chronic lymphocytic leukemia treated with different available chemotherapeutic regimens.This is a retrospective study. All patients of CLL from October 2008 to September 2013 were studied. Diagnosis was made according to standard guidelines.Complete and partial response , stable disease (SD), progressive disease (PD) and relapse were defined according to National Cancer Institute\u2013Working Group 1996 guidelines.Meier method and the end point of interest was relapse. The log rank test was applied and considered to be significant at an alpha level of 0.05. The analysis was conducted using SPSS, version 19.Distributions were determined as frequencies and percentages for categorical variables. For continuous variables mean, median, standard deviation and range were computed. Progression free interval survival, interval between dates of treatment ended and relapse in months, was conducted using the Kaplan Fifty seven patients were included. Forty two (74%) patients were male and 15(26%) were female. Median age was 50.9+8.2 years (range 25-72). Patients of Binet stage A, B and C; were 10(18%), 20 (35%) and 27(47%), respectively. Forty six (80%) patients were treated and 11(20%) remained on watch and wait policy. Treatment indications were B symptoms in 14(30%), bulky disease 18(39%), thrombocytopenia 4(9%), anemia 7(15%) and doubling of lymphocyte count in 3 (7%) patients. Chemotherapy regimens used were FC in 38 (83%), FCR 5(11%), CVP 1(2%) and chlorambucil in 2(4%) patients . Two patOutcomes of CLL are variable, some patients have very indolent course while other may have aggressive disease behaviour from the start.17There is a strong evidence that FCR is better than FC, however, former is associated with more side effects.19Our results showed that the onset of CLL is in a relatively younger age group compared to western data.Based on our results, onset of CLL is in a relatively younger age group. Majority of the patients present with advanced stage disease and require treatment at the time of diagnosis. Fludarabine based regimens are affective. Addition of rituximab should be considered where available as it will lead to improved outcomes in CLL."}
+{"text": "Burn trauma is an important public health concern, with increased risk for burns in children. A cross-sectional study was performed to describe the epidemiological characteristics and risk factors for burns in hospitalized Bedouin children in Soroka University Medical Center during the years 2001\u20132002. In a population of 558 hospitalized burn-injured patients, 282 Bedouin children were identified. Two hundred and sixty five patients (94.0%) had burns involving less than 20% of the body surface area. Cause of the burns was scald in 190 patients (67.4%), fire in 80 patients (28.4%), chemical in 8 patients (2.8%), and explosion in 2 patients (0.7%). Two female patients (0.7%) aged 11 and 17 years died of their burns that were caused by fire. The mean length of hospitalization was 9.8 days. Pediatric burn injury has become a significant public health problem in the Bedouin population of the Negev. To reduce the burden of burn injury, it is necessary to increase current efforts in prevention of burns."}
+{"text": "Vitamin D is believed to help in the suppression of malignant cells. Epidemiologic studies suggest that there is an association between vitamin D deficiency and an increased risk of colorectal cancer. The primary aim of this study is to determine if the prevalence of neoplastic polyps is inversely related to serum 25-hydroxyvitamin D levels 25(OH)D.A prevalence study conducted between April 2009 and October 2009 evaluated 651 patients undergoing colonoscopy in order to determine if an association existed between low 25(OH)D levels and the prevalence of neoplastic colon polyps. Multivariate logistic and linear regression analyses were used to establish an association between 25(OH)D levels and histology of colon polyp with gender, race, age and BMI.The presence of tubular adenoma, villous adenoma, tubulo-villous adenoma, or malignancies did not differ (P = 0.5) among the stratified 25(OH)D groups . In addition, despite having more African-Americans than Caucasians in the lowest 25(OH)D category (22.7% versus 7.7%), the presence of neoplastic polyps did not differ significantly (P = 0.8) between the categorized racial groups (Caucasian and African-Americans).Low plasma 25(OH)D levels are not associated with an increased prevalence of neoplastic polyps. Vitamin D has been reported to decrease the risk of colorectal cancer through various mechanisms, including reducing cell proliferation, inhibiting angiogenesis, promoting cell differentiation and stimulating apoptosis . The exaOur study information was submitted to the St. John Providence Hospital and Medical Center Institutional Review Board and was approved with a designated study number of 09127 on April 17, 2009. Patients were then consecutively enrolled by a nurse trained in the study protocol at a community hospital open endoscopy unit from April 2009 to October 2009. A Serum 25(OH)D level was drawn upon patient consent for enrollment in the study. The endoscopist was blinded to the enrolled patients and 25(OH)D levels. Among the 726 patients admitted to the endoscopy unit for colonoscopy, 651 patients were enrolled after exclusion criteria were taken into account. The study included adults age 18 years or older, regardless of gender or ethnicity, who demonstrated a willingness to participate in the study. Exclusion criteria included an inability to visualize the entire colon, history of inflammatory bowel disease, Boston bowel preparation score less than six, or previous history of polyps. Patients undergoing colonoscopy did not receive compensation.Information obtained included the primary indication for colonoscopy, age, gender, BMI and ethnicity. Patients were questioned about known history of previous polyps, previous diagnosis of colon cancer, previous colonoscopy with year and results, if applicable. Additionally, the patients\u2019 use of multivitamin and or vitamin D supplementation with the frequency, dose, and duration were documented. Prior to undergoing colonoscopy, participants\u2019 serum 25(OH)D levels were determined. At the completion of the procedure the Boston bowel preparation score, removal time, and whether the entire colon was visualized were documented. Among participants, all adenomatous and malignant polyps were removed and directly sent to pathology. All lab and pathology specimens were processed and evaluated at St. John Providence Macomb-Oakland Hospital, Oakland Center.The primary aim of this study was to test the null hypothesis that the increased prevalence of neoplastic polyps was inversely related to serum 25-hydroxy Vitamin D levels. Multivariate logistic and linear regression analyses were used to establish an association between 25(OH)D levels and histology of colon polyps with gender, ethnicity, age and BMI. Population studies demonstrate that approximately 30% of middle-aged to elderly individuals possess polyps. Adenomatous polyps constitute about 10% of all polyps. The percentage of polyps obtained throughout this study was 63%. The criterion for significance  was set at 0.050. Statistical significance was set at P < 0.05. Statistical calculations were made using the ANOVA program.Between the 17th of April 2009, and the 26th of October 2009, patients who were referred to our endoscopy center were provided with a detailed description of our study and the opportunity to enroll. If the patient agreed to participate, a screening questionnaire was provided to the patient along with a trained nurse to assist with questions. All patients had the opportunity to ask questions regarding the study prior to signing an informed consent for blood draw. There were three exclusion criteria: entire colon not visualized, patient history of inflammatory bowel disease (ulcerative colitis or Crohns) or a Boston bowel prep score of less than 5. A total of 726 patients were enrolled in the study. Eight patients were excluded secondary to history of inflammatory bowel disease. An additional 42 patients were excluded due to a low Boston bowel prep score, and 25 patients were excluded because the entire colon was not visualized.A total of 651 patients were included in the study. Of these, 429 patients (65.9%) were Caucasian, 128 patients (19.7%) were black and 94 patients (14.4%) were of other ethnicity . The cohort consisted of 324 (49.7%) males and 327 (50.3%) females. Within the cohort 22 (3.9%) patients were under the age of 30 years, 410 (62.9%) patients were between the ages of 31 - 60 years and 219 (33.6%) patients were greater than the 60 years of age (mean age 55.9 and range 17 - 92).Indications for colonoscopy for the 651 participants included routine screening 245 (37.6%), previous GI bleed 136 (20.9%), polyp surveillance 87 (13.4%), family history of colorectal cancer 11 (1.7%), anemia 34 (5.2%), abdominal pain 29 (4.5%), weight loss 6 (0.9%), diarrhea 38 (5.8%), constipation 30 (4.6%), abnormal imaging 10 (1.5%), malignancy 10 (1.5%), and colitis 15 (2.3%). Among the cohort population 128 subjects (19.7%) had a previous colonoscopy, whereas 523 subjects (80.3%) underwent their first colonoscopy. There were 5 trained endoscopists performing colonoscopies on study subjects. All patients were prepped for colonoscopy by ingestion of one gallon of Golytely the evening before the procedure. An Olympus CF-H180 AL/I colonoscope was used on all patients. Narrow band imaging (NBI) and magnification was available for the endoscopist as an accessory tool to evaluate polyps. The minimum size of polyp for polypectomy was 3 mm. Polypectomy with or without electrocautery was performed with Boston Scientific Profile, Captiflex or Captivator II snares. Withdrawal times were documented for each colonoscopy providing a mean time of 9.63 minutes (range 6 - 60 minutes). Evaluation of the cecum with or without terminal ileum intubation constituted complete visualization. The Boston bowel preparation scale was used as a reliable measure of bowel preparation with a score of 0 - 5 indicating inadequate prep and 6 - 9 representing adequate prep [All polyps removed were histologically examined by the institutional site pathologist employing the diagnostic criteria defined by the National Polyp Study . Among tBecause we ascertained the presence of hyperplastic and adenomatous polyps in our study population, we were able to stratify polyps into two groups; cases with non-adenomatous polyps and cases with adenomatous polyps. The histological findings of these polyps were then analyzed statistically for each anatomical location of the colon . Note thSerum 25(OH) vitamin D levels were drawn from each subject prior to colonoscopy. All results were provided by the institutional lab, which defines vitamin D deficiency as < 30 ng/ml. The normal range of 25(OH) vitamin D is 30 ng/ml - 74 ng/ml. Vitamin D supplementation and details of frequency, length of time and dose were assessed on the screening questionnaire. A total of 104 (16%) patients out of 651 patients were currently on vitamin D supplements. Of those, 93 patients (89.4%) took vitamin D daily, 7 patients (6.7%) took vitamin D once weekly and 4 patients (3.8%) did not take vitamin D on a regular basis. The range of intake duration was from 1 month to 180 months with a mean of 22 months. Of the 104 subjects taking vitamin D supplements, 34 (32.7%) were unsure of dose, 16 (15.4%) took 400 IU in a standard multivitamin, 18 (17.3%) took 1000 IU dosage, 7 (6.7%) took 2000 IU dosage, 2 (1.9%) took 5,000 IU dosage and 27 subjects (26%) documented \u201cother\u201d dose of vitamin D. 25(OH) vitamin D levels of all 651 subjects were stratified as severely deficient (< 10 ng/ml), deficient (10.1 ng/ml - 30 ng/ml), and therapeutic (> 30 ng/ml). Seventy-two patients (11.1%) were severely deficient, 407 patients (62.5%) were deficient, and 172 (26.4%) were therapeutic. The mean 25(OH) vitamin D level was 23.9 ng/ml (range 4 - 75 ng/ml).post hoc analysis, the Pearson Chi-Square coefficient did not demonstrate a statistically significant relationship between 25(OH) vitamin D levels and the presence of polyps in the 651 subjects (P = 0.739 CI 95%). In addition, there was no statistically significant relationship between 25(OH) vitamin D levels and the 547 subjects who were not on vitamin D supplements (P = 0.709 CI 95%)  vitamin D with gender, age, and race . In a po CI 95%) . Further CI 95%) .In this prospective cross-sectional study, we found no statistically significant association between 25(OH) vitamin D levels and occurrence of polyps, both adenomatous and non-adenomatous.One of the first studies in the literature to report a relationship between vitamin D and colon cancer was by Garland et al in 1980 . They foAlthough low vitamin D status has long been implicated in colorectal carcinogenesis, we thoroughly investigated the literature after our study findings and have not been able to discern a clear relationship that is consistent with anticarcinogenic effects of vitamin D on colorectal cancer. We found several well-designed studies that have elicited findings that oppose the previous thought that vitamin D is inversely related to colorectal carcinoma. As mentioned previously Morimoto et al. examined diet and lifestyle risk factors for hyperplastic and adenomatous polyps . They foAs mentioned previously, the Women\u2019s Health Initiative results contributed significantly to the vitamin D and neoplasia literature . WatctawEvaluation of the precise delineation of polyp borders and advanced macroscopic analysis of all polyps were performed with the optional application of narrow band imaging (NBI) and magnification. Previous studies have demonstrated no statistically significant benefit of NBI with polyp detection , 25. HowThere were a number of limitations in our study. First, we did not account for aspirin intake which has been shown to be protective against colorectal cancers that overexpress COX-2 . We alsoIn summary, although there were 106,100 new cases or colon cancer and 40,870 cases of rectal cancer in 2009 with a reported 49,920 deaths from both, colorectal cancer remains one of the most preventable malignancies . It has Our study did not provide a statistically significant relationship between 25(OH) vitamin D and adenomatous polyps in average risk individuals. A follow-up meta analysis of all studies in support of our findings should be pursued in an attempt to establish such a relationship in light of the conflicting data pertaining to what role of vitamin D plays in the prevention of colon polyps and colorectal cancer. There is currently a government-supported large patient population study that is investigating the effect of vitamin D on a panel of biomarkers of risk for colorectal cancer. Additionally, the National Cancer Institute is supporting a phase I randomized control trial evaluating vitamin D supplementation in prevention of colon cancer in African Americans with colon polyps. These studies in conjunction with other ongoing trials hold potential to clarify the previous conflicting data with regards to the relationship between vitamin D and neoplasms of the colon. Until then, the role of vitamin D in prevention of adenomatous polyps and colorectal cancer remains controversial and future studies are warranted."}
+{"text": "We report here the complete genome sequence of the human coronavirus NL63 CN0601/14 strain, first isolated from South Korea. It contains 18-nucleotide discontinuous deletions of the open reading frame 1a (ORF1a) and spike regions. This study will aid in our understanding of the complete genome sequences of isolated coronaviruses in South Korea. Coronaviridae in the order Nidovirales (\u2013Human coronavirus (HCoV) NL63 is a member of the family ovirales , 2. The ovirales . HCoV NLovirales , 6. The ovirales \u201311. In SThe strain CN0601/14 was isolated from a patient infected with HCoV NL63 in 2014. Total RNA was extracted from the infected cell supernatant using the QIAamp viral RNA minikit , according to the manufacturer\u2019s instructions. The complete genome of CN0601/14 was generated by first-strand cDNA synthesis from the total RNA (300\u2009ng) with primers consisting of oligo(dT) and 3\u02b9-untranslated region (UTR) reverse primer and performed with PCR using 20 pairs of primers amplifying 10 overlapped fragments. The primers were designed using CLC Main Workbench version 7.0.3 (Qiagen) based on the sequence of the HCoV NL63 isolate CBJ 037 genome (GenBank accession number JX104161). The 10 amplified PCR products were purified and sent to GnC Bio Co. for sequencing. The complete genome of CN0601/14  compared to that of the prototype HCoV NL63 virus (accession number NC005831) by multiple alignment showed that there are 18-nt discontinuous deletions, with a 15-nt deletion in positions 3035 to 3049 of the ORF1a region and a 3-nt deletion in positions 327 to 329 of the spike region. Furthermore, the genome of CN0601/14 showed 98.76% nucleotide homology with that of the prototype HCoV NL63 virus.Altogether, the complete genome sequence data of CN0601/14 indicate that variations in HCoV NL63 occur in South Korea. This information will aid in the understanding of the genetic diversity of HCoV NL63 in South Korea and in manufacturing an infectious CN0601/14 clone construct based on Korean vaccine candidate development.MG772808.The complete genome sequence of the human coronavirus NL63 CN0601/14 strain is available in GenBank under the accession number"}
+{"text": "Scientific Reports7: Article number: 40206; 10.1038/srep40206 published online: 01062017; updated: 04262017.This Article contains an error in Figure 2, where the translation orientation of the hypothetical gene adjacent to CRISPR3 is reversed. In addition, the location of citB and speC beside CRISPR4, along with the sequence logo of CRISPR4 repeats should be reversed. The correct Figure 2 appears below as"}
+{"text": "The study aimed to describe our initial experience with the use of anti vascular endothelial growth factors (anti-VEGFs) in the treatment of retinal diseases.The case records of all patients who had received at least 3 doses of intravitreal anti- VEGF injections between January 2012 to December 2016 were reviewed. Information culled from the data was age, sex, indications for treatment, type of injection, presenting visual acuity, post injection visual acuity, systemic and ocular co morbidities. Results were analyzed using Statistical Package for Social Sciences (SPSS) 20.0 for Windows statistical softwareA total of 190 injections were given during the study period, to 58 eyes of 50 patients. Twenty-eight females (56.00%) and twenty-two males (44.00%) were seen with a mean age of 59.6\u00b1 11.66. Bevacizumab was the most frequently administered anti- VEGF, 142 (74.74%) while only 48(25.26%) injections of Ranibizumab were given. Three eyes had both bevacizumab and ranibizumab (1.58%). Retinal vein occlusion 61(32.11%) was the commonest indication for the injections followed by diabetic macular edema 43(22.63%) and proliferative diabetic retinopathy 42(22.11%). Others were neovascular age related macular degeneration, neovascular glaucoma, vitreous hemorrhage, myopic choroidal neovascularization and cystoid macular edema. There was an association between age and disease, (p = 0.001). There was an improvement in visual acuity after intervention in cases with retinal vein occlusion and diabetic macular edema, and this was statistically significant. Hypertension was the commonest systemic disorder in this series 81(42.36%) and the supero-temporal quadrant 131(68.95%) was the most preferred position to administer the injection. Floaters was the commonest complication seen.Anti VEGFs have become an invaluable tool in the management of a number of retinal diseases in our center. However, the cost implications are a hindrance to an increased uptake of this form of treatment. Cheaper alternative preparations should be made available to encourage the uptake. Government in developing countries should be encouraged to bear the health burden of the old aged pensioner (OAP). They inVEGF is a 40 kDa dimeric glycoprotein that is produced by hypoxic stimulation in different cells of the retina: vascular endothelium, retinal pigment epithelial cells, M\u00fcller cells .Anti-vascular endothelial growth factors (anti-VEGFs) have revolutionized the management of retinal diseases in the past decade. The first VEGF-A inhibitor, bevacizumab (Avastin), was approved by the US Food and Drug Administration (FDA) in 2004 for the first-line treatment of metastatic colorectal cancer. It is a monoclonal antibody (149kDa) that binds to all isoforms of VEGF-A and is now being used as an off label intravitreal drug for the treatment of retinal vascular disorders. The first VEGF-A inhibitors in ophthalmology, pegaptanib (Macugen) and ranibizumab (Lucentis), were approved in 2004 and 2006, respectively. Ranibizumab was formulated for intraocular usage only. It is an Fab fragment of the humanized monoclonal antibody (48kDa) and has an affinity for all VEGF isoforms. The smaller molecule compared to Bevacizumab allows better retinal penetration. Aflibercept (Eylea) is a recent anti-VEGF therapy approved in 2011. It is indicated for use in the treatment of neovascular age related macular degeneration (AMD), macular edema from retinal vein occlusion, diabetic macular edema(DME) and diabetic retinopathy in patients with DME for the treatment of neovascular AMD. These agents have shown significant gain in visual acuity and improvement in morphological outcomes [e.g. Laser photocoagulation and intravitreal steroids), retina specialists now have an armamentarium of antiVegf agents in the treatment of ocular neovascular disorders. The uptake of these agents has increased in developing countries [Together or alone with other conventional treatment . 10% Povidone iodine was used for skin preparation while 5% was instilled into the conjunctival sac before and after injection in all patients. No topical antibiotics were given before and after the procedure.Dosage of intravitreal bevacizumab given was 1.25mg in 0.05ml, while 0.5mg of 0.05ml of ranibizumab was given. Injection site varied between the superotemporal quadrant, inferotemporal and superonasal depending on the surgeon\u2019s access.Injections were given 4mm from the limbus for phakic patients and 3.5mm for pseudophakic patients. Patients were reviewed one day, one week and one month post injection, to assess their visual acuity and check intra ocular pressure. Injections were given every 4 weeks. All patients in this study were followed up for at least 12 months.Information from each subject was entered into a spreadsheet using the Statistical Package for Social Sciences (SPSS) 20.0 for Windows statistical software and analyzed. Comparison of variables was carried out using appropriate statistical tests. P values of <0.05 were considered statistically significant.31). 3 eyes had both bevacizumab and ranibizumab (1.58%).58 eyes of 50 patients were injected. A total of 190 injections were given during this period, consisting of 142 injections of Bevacizumab (74.74%) and 48 injections of Ranibizumab (25.26%), Fig. (1).Ninety- nine (52.11%) females received injections, while 91 males (47.89%) with a mean age of 59.6\u00b1 11.66 years  also shows that the supero-temporal quadrant 131(68.95%) was the most preferred position to administer the injection. The intraocular pressure was raised in 61cases (32.11%). Floaters was the commonest complication seen. Fig. (2) shows an association between age and disease, (p = 0.001). Hypertension was the commonest systemic disorder in this series 81(42.36%), as seen in Table (2).Retinal vein occlusion 61(32.11%) was the commonest indication for the injections followed by diabetic macular edema 43(22.63%) and proliferative diabetic retinopathy 42(22.11%). Others were neovascular age related macular degeneration 26(13.68%), neovascular glaucoma 9(4.74%), vitreous hemorrhage 3(1.58), myopic choroidal neovascularization (1.58) and cystoid macular edema 3(1.58). Table .One hundred and ninety injections were given in this series, with Bevacizumab being the most frequently injected anti Vegf  cases who had short term rise in intraocular pressures received bevacizumab injection. Floaters was the commonest complaint recorded in this series. There was no case of endophthalmitis in this small series; we believe that the strict aseptic conditions as well as 10% Povidone iodine skin prep and 5% drops instillation before and after the injection was effective and contributory.The supero temporal quadrant was the most preferred site for administering the injections. This is most likely because of the ease of access at this position.Anti- VEGFs have become an invaluable tool in the management of a number of retinal diseases in our center. However, the cost implications are a hindrance to an increased uptake of this form of treatment. Cheaper alternative preparations should be made available to encourage the uptake. Government in developing countries should be encouraged to bear the health burden of the old age pensioners (OAP). The National Health Insurance which is still in its infancy could assist such therapies."}
+{"text": "The management of hepatic metastases from colorectal cancer can be understood only as part of a multidisciplinary strategy. Progress experienced by medical treatment, surgical techniques and ways of imaging, has improved the prognosis of patients with liver metastases of colorectal cancers. This work displays the experience of Medical Oncology unit at the Military training hospital in Rabat.From January 2007 to December 2009, 60 patients with liver metastases from colorectal cancer, synchronous or metachronous were supported in the Medical Oncology unit at the Military training hospital in Rabat.Liver metastases were synchronous in 41 (68%) patients and metachronous in 19 (32%). Patients were classified into 3 categories according to their resectability: 14 (22%) were resectable at the outset, 28 (47%) were unresectable and 18 (31%) were considered uncertain resectability. Thirty-five patients (58%) received neoadjuvant chemotherapy before surgical gesture, 25 (42%) received chemotherapy after resection of primary tumor. This chemotherapy enabled the resection of liver metastases in 5 patients initially deemed uncertain resectability. The average objective responses to chemotherapy were in the range of 59% with 4 complete responses and one confirmed histologically. Twenty-three patients (38%) underwent surgery including 15 liver resections with R0 (25%). The median progression-free survival in this series was 15.5 months. Some minor side effects were noted, which have not entered the prognosis of patients.Hepatic resection remains the only potentially curative treatment of liver metastases of colorectal cancers. Perioperative chemotherapy is a promising standard, which has improved the prognosis of patients historically associated with a poor prognosis. Colorectal cancer is the 4th in order of frequency of cancer worldwide . The LivSurgery of liver metastases of colorectal cancer (LMCRC) undeniably improved patient survival, as well as the use of targeted therapies, which has revolutionized the management of LMCRC , which cThis is a retrospective study, conducted over a period of three years from January 2007 to December 2009.Inclusion criteria: any patient with cancer of the colon or rectum, and associated with histologically confirmed liver metastases, whether synchronous or metachronous. The patient\u2019s general condition must be maintained with a performance status score of 0, 1 or 2.Exclusion criteria: any patient with poor general condition.Sixty patients were treated for LMCRC between January 2007 and December 2009, including 34 men and 26 women, with a sex ratio 5M/4W.The average age was 49.5 years. The primary tumor was colon in 35 patients (58%) and rectal in 25 (42%). Identification of K-RAS status was performed in nineteen patients. The results were in favor of K-RAS mutations in 16 patients, the other 3 were K-RAS wild. Twenty-five patients (42%) have undergone an initial surgery on the primary tumor, including thirteen (22%) in emergency under the care of an occlusive syndrome. The Liver metastases (LM) were synchronous in 41 patients (68%) and metachronous in 19 (32%). These (LM) were considered resectable immediately in 14 patients (22%), unresectable in 28 patients (47%), and uncertain resectability in 18 patients (31%). Thirty-five patients (58%) received neoadjuvant chemotherapy before surgery. Twenty-five patients (42%) received chemotherapy after resection of primary tumor.All our patients received chemotherapy with bevacizumab, in combination with fluoropyrimidine intravenously or orally, plus Irinotecan or Oxaliplatin, with cross-over in case of tumor progression. Average objective response was 59%, with 4 complete responses in liver metastases, and one of them was confirmed histologically. Tumor stabilization was observed in 21% of patients, and progression in 34%. The median duration of progression-free survival was 15.5 months. Twenty-three patients received 38% liver surgery. Resection R0 was found in 15 patients (25%) and R1 in eight patients (13%).One patient underwent a radiofrequency on liver damage with good evolution.No patient judged operable immediately progressed under chemotherapy.Five patients (8%) considered unclearly resectable, became operable after chemotherapy. No patient initially considered inoperable could be made on liver metastases after chemotherapy. The rate of carcinoembryonic antigen (CEA) was elevated in twenty-five patients (41%). Normalization of these levels was noted in seventeen patients (28%) after chemotherapy. Some side effects of chemotherapy were identified. Intestinal perforation was noted in one patient (1.7%), it has been assumed in the emergency operating room, with good evolution. A single case of gastrointestinal bleeding had such great abundance of rectal bleeding that led to a blood transfusion without commitment prognosis. Two cases of venous thrombosis (3.5%), presumably due to bevacizumab, have been successfully treated with low molecular weight heparin, and one case of massive proteinuria without impact on renal function. In all these cases, discontinuation of Bevacizumab has been decided. Hand-foot syndrome grade 2 was detected in three patients (5%) and diarrhea grade 2 in 19 patients (32%) were fully managed by medical treatment, and had resulted in no change in dose. Cons by persistent grade 2 neuropathy with functional impairment were registered in seven patients (11.5%) leading to discontinuation of oxaliplatin.Hepatic metastases occur in 25% of patients with colorectal cancers diagnosed advanced stage . There aThis is a young but promising experiment, with results concordant with the literature. Liver metastases surgery remains the cornerstone of treatment. Peri-operative chemotherapy has become a standard treatment. Molecular biology represents a kind of radar for targeted therapies, to detect molecular abnormalities. The future will bring the results of tests that will define the strategic real impact of each treatment sequence."}
+{"text": "There are currently no United States Food and Drug Administration approved molecularly matched therapies for sarcomas except gastrointestinal stromal tumors. Complicating this is the extreme diversity, heterogeneity, and rarity of these neoplasms. Few therapeutic options exist for relapsed and refractory sarcomas. In clinical practice many oncologists refer patients for genomic profiling hoping for guidance on treatment options after standard therapy. However, a systematic analysis of actionable mutations has yet to be completed. We analyzed genomic profiling results in patients referred to MD Anderson Cancer Center with advanced sarcomas to elucidate the frequency of potentially actionable genomic alterations in this population.We reviewed charts of patients with advanced sarcoma who were referred to investigational cancer therapeutics department and had CLIA certified comprehensive genomic profiling (CGP) of 236 or 315 cancer genes in at least 50ng of DNA. Actionable alterations were defined as those identifying anti-cancer drugs on the market, in registered clinical trials, or in the Drug-Gene Interaction Database.Among the 102 patients analyzed median age was 45.5 years (range 8-76), M: F ratio 48:54. The most common subtypes seen in our study were leiomyosarcoma (18.6%), dedifferentiated liposarcoma (11%), osteosarcoma (11%), well-differentiated liposarcoma (7%), carcinosarcoma (6%), and rhabdomyosarcoma (6%). Ninety-five out of 102 patients (93%) had at least one genomic alteration identified with a mean of six mutations per patient. Of the 95 biopsy samples with identifiable genomic alterations, the most commonly affected genes were TP53 (31.4%), CDK4 (23.5%), MDM2 (21.6%), RB1 (18.6%), and CDKN2A/B (13.7%). Notable co-segregating amplifications included MDM2-CDK4 and FRS2-FGF. Sixteen percent of patients received targeted therapy based on CGP of which 50% had at least stable disease.Incorporating CGP into sarcoma management may allow for more precise diagnosis and sub-classification of this diverse and rare disease, as well as personalized matching of patients to targeted therapies such as those available in basket clinical trials. Recurrent and metastatic sarcomas are a rare and heterogeneous group of diseases. With well over 70 subtypes, the exact diagnosis alone can be challenging to make . When saThe promise of personalized medicine has become a realization for many malignancies. Pairing genomic alterations and targeted therapy has transformed diseases like lung cancer, leukemia, and breast cancer \u201312. OutsAll patients in this study had advanced or metastatic relapsed or refractory sarcoma or did not have any other standard care therapies available when they presented for clinical trials. There were 48 men (47%) and 54 women (53%) in this patient cohort with a median age at diagnosis of 45.5 years (range 8-76). There were 36 patients (35%) who had primary site biopsied and sent for next generation sequencing (NGS) and 66 (65%) who had a metastatic site sent for NGS. Of the 102 patients, 38 were metastatic at time of diagnosis. The most common histologies seen in our study was leiomyosarcoma , dedifferentiated liposarcoma (11%), osteosarcoma (11%), well-differentiated liposarcoma (7%), carcinosarcoma (6%), and rhabdomyosarcoma (6%) Table . Ninety-Two of the most common alterations (MDM2 and CDK4 amplifications) are both actionable. MDM2 was altered in 22 patients and all were amplifications. All 22 of these patients also had CDK4 amplifications. One additional patient had a CDK4 amplification without MDM2 amplification. Ten of these co-amplified CDK4/MDM2 cases were dedifferentiated liposarcomas, seven were well-differentiated liposarcomas, two rhabdomyosarcomas (one pleomorphic and one nos), one osteosarcoma, one ewing sarcoma, and one unclassified soft tissue sarcoma. Four of the well-differentiated liposarcoma patients were treated with an investigational MDM2 inhibitor and all achieved at least stable disease, some showing a very durable response.Other notable mutations include three FRS2 and FGF co-amplifications seen in a rhabdomyosarcoma, osteosarcoma, and dedifferentiated liposarcoma. The rhabdomyosarcomas were FOXO1 fusion-negative, hinting at a higher number of mutations . We alsoOf the 102 patients in our cohort, forty (39%) had either no reported mutation (7%) or no actionable mutation (32%). The remaining 62 (61%) patients all had a potentially actionable alteration. Fourteen (14%) patients had an alteration that could be targeted with an approved drug in sarcoma (on-label). This was either an off-target effect of pazopanib or imatinib and included five patients with PDGFR (1 GIST), four with FGFR, three with KIT (2 GIST), and two with KDR gene aberrations.Forty-six (45%) patients had an alteration that could be targeted with a drug approved in another disease (off-label). Sixty-one (60%) patients had an alteration that could potentially be targeted by a drug currently available in clinical trials and, barring particular exclusion criteria, all of them could have been enrolled on a matching trial. Fifty-eight (57%) had an alteration for which a drug currently in pre-clinical development could be used Figure .A subtype analysis of all sarcoma types revealed that the probability of having an actionable mutation was related to histology Figure . NotableClinical response was highly variable. Forty-three patients 42%) only received tumor sequencing, but did not participate in a clinical trial. The remaining fifty-nine patients (58%) chose to participate in a clinical trial. Of these, sixteen (16%) received therapy directed by molecular profile. Of these sixteen patients, eight (50%) had at least stable disease . This is almost certainly driven by the paucity of approved (targeted) therapies in sarcoma. There was a skew toward certain histologic subtypes that harbor more potentially actionable mutations. Well-differentiated and dedifferentiated liposarcomas as well as carcinosarcomas stand out. Almost every patient who was a candidate for an off-label drug also had a drug available in a clinical trial. This speaks to the large variety of compounds available in trials, and the need to get sarcoma patients enrolled early and often.One of the most frequent mutations seen in our cohort was MDM2 amplification. This was exclusively seen co-existing with a CDK4 amplification. This alteration has been reported most commonly in dedifferentiated/well-differentiated liposarcoma  and rareSimilar to the MDM2 and CDK4 co-amplification, we found FGF and FRS2 to be co-amplified. This has previously been observed in dedifferentiated liposarcoma and even found to be co-expressed with MDM2 and CDK4. This co-amplification is not surprising since FRS2 is the receptor substrate for FGF . DespiteWhile MDM2 and FRS2 are enticing for targeted therapy, our finding of MSH2 in leiomyosarcomas presents a potential for immunotherapy. MSH2 is an integral component of the mismatch repair machinery and causes microsatellite instability, creating a target for PD-1 blockade . SuccessPrevious studies have assessed genomic biomarker actionability , 41. TheMDM2 is a negative regulator of the tumor suppressor gene P53 and is a powerful oncogene. MDM2 and CDK4 (12q13-15 amplification) are co-amplified in well differentiated liposarcoma. The response to current therapies is poor. As in . Profiling could have been performed as part of prior care. Otherwise, genomic profiling was performed upon phase 1 clinic presentation.The electronic medical records of 102 diverse sarcoma patients were reviewed and history, laboratory and clinical findings were abstracted. These patients were referred to the Investigational Therapeutics Department at MD Anderson Cancer Center (MDACC). All pathology had previously been reviewed and confirmed by an MDACC pathologist with experience in bone and soft-tissue sarcomas. Therapies differed based on clinical trial opportunities at date of visit. All patients had a commercially available comprehensive genomic panel from Foundation Medicine . Date of death or last follow-up were also noted.Each of the represented clinical trials in this review were independently approved by the MD Anderson institutional review board (IRB) and patients provided written consent to be treated with the corresponding investigational therapy. This retrospective review was also approved by the MD Anderson IRB.http://www.foundationone.com), a clinical grade CLIA-approved NGS test analyzing 236 or 315 cancer-related genes in at least 50ng of DNA from routine formalin-fixed and paraffin-embedded (FFPE) clinical specimens [NGS was performed by Foundation Medicine (FoundationOne, pecimens .Actionable gene alteration was defined as any gene alteration that is either directly targeted or a pathway component of a directly targeted gene by an approved or investigational drug  Table 55.Electronic medical records were reviewed for above mentioned demographic and diagnostic data. The respective molecular diagnostic reports were reviewed for alterations with a potentially actionable mutation either on-label, off-label, or in clinical trials. If patients received treatment with an investigational therapeutic, this was recorded along with the response."}
+{"text": "To evaluate the performance and treatment profile of advanced EML4\u2014ALK positive Non-small cell lung cancer (NSCLC) patients in a developing country with potentially restricted access to Crizotinib.A retrospective analysis of advanced ALK positive NSCLC patients who were treated from June 2012 to September 2015 was conducted. The primary goal was to evaluate outcomes of advanced ALK positive NSCLC in our practice and examine the logistic constraints in procuring Crizotinib.94 patients were available for analysis. 21 (22.3%) patients were started on Crizotinib upfront, 60 (63.8%) on chemotherapy, 10 (10.6%) on Tyrosine kinase inhibitors (in view of poor PS) and 3 (3.2%) patients were offered best supportive care. Reasons for not starting Crizotinib upfront included symptomatic patients needing early initiation of therapy (23.3%), ALK not tested upfront (23.3%) and financial constraints (21.9%). 69 patients (73.4%) received Crizotinib at some stage during treatment. Dose interruptions (> 1 week) with Crizotinib were seen in 20 patients (29%), with drug toxicity being the commonest reason (85%). Median Progression free survival (PFS) on first line therapy for the entire cohort was 10 months, with a significant difference between patients receiving Crizotinib and those who did not ever receive Crizotinib . Median Overall Survival (OS) was not reached for the entire cohort, with 1 year survival being 81.2%. Patients with an ECOG Performance Status (PS) of >2 had a significantly reduced PFS compared to patients with PS < = 2 . 47 patients with financial constraints (68.1%) received Crizotinib completely free via various extramural support schemes.A majority of our ALK positive NSCLC patients were exposed to Crizotinib through the help of various support mechanisms and these patients had similar outcomes to that reported from previously published literature. The discovery of the Anaplastic lymphoma kinase (ALK) gene in non-small cell cancers (NSCLC) and the subsequent use of Crizotinib against this subset of NSCLC has been one of the success stories of precision medicine in lung cancer \u20134. The pst line palliative chemotherapy, cementing its status as the first line option in ALK positive NSCLC [After initial single arm studies and retrospective analysis showed clinical benefit from Crizotinib ,8,9, FDAve NSCLC .However, the potentially prohibitive cost of Crizotinib in a resource constrained setting and additional costs associated with testing for ALK fusion make it mandatory to examine all aspects of therapy before deciding on course of treatment. It is essential to evaluate treatment patterns in such a scenario, where extramural mechanisms are routinely required for optimization of treatment in an economically challenged population. Hence, we carried out a retrospective analysis at our centre to investigate the treatment patterns and outcomes in Indian ALK-positive NSCLC patients, with an emphasis on procurement, use, tolerance and outcomes with Crizotinib.Patients from June 2012 to September 2015 were selected for this analysis subject to the following criteria \u2013Advanced NSCLCPlanned for palliative treatmentPresence of ALK fusion reported as positive, either by immunohistochemistry (IHC) or break-apart Fluorescence In situ Hybridization (FISH)The details of these patients were obtained from the prospective lung cancer audit database that is maintained in the department of medical oncology. The lung cancer audit is an Institutional Ethics Committee (IEC) approved observational protocol, is registered with the Clinical Trials Registry India (registration number: CTRI/2013/01/003335) and patients sign a written informed consent prior to their information being recorded as part of the lung cancer audit.Patients underwent a complete history and physical examination, and routine blood testing  prior to therapy. Demographic data including smoking status and tobacco use was collected. Tumor staging was performed by a contrast enhanced computed tomography of the chest and upper abdomen(CECT) or Whole body FDG PET\u2013CET.Detection of ALK fusion was by either or both of the following methods:\u2019 and 3\u2019 ends of the ALK gene are labelled with red and green fluorescent probes respectively. ALK positivity or rearrangement is reported if the signals are not touching (split). The FISH analysis was performed with the \u2018Abbot Molecular\u2019 platform, according to manufacturer instructions. 100 nuclei were scored to determine the final percentage of ALK positivity. A cut-off of 15% was used to denote samples as positive or negative for ALK.FISH\u2014Formalin-fixed, 4 \u03bcm thick, paraffin-embedded cell blocks were used to evaluate the ALK genetic status with FISH. The slides were deparaffinized, dehydrated, immersed in 0.2 N HCl for 20 min, then washed and incubated in pretreatment solution at 80\u00b0C. In this test, the 5IHC\u2014IHC for ALK was performed with the monoclonal antibody D5F3 .Patients were started on therapy based on age, comorbidities, ECOG Performance status (PS), disease burden requiring emergent initiation of therapy, availability of ALK reports and feasibility for Crizotinib (elucidated separately). Patients were started on either of the following treatments upfront\u2013ChemotherapyCrizotinib 250mg PO twice dailyOral Tyrosine Kinase Inhibitor Best supportive carePatients underwent routine blood investigations, including complete hemogram and biochemistry prior to each cycle of chemotherapy and every monthly or 2 monthly if on Crizotinib. Additionally, ECGs were monitored on Crizotinib at frequent intervals. Dose reduction was considered as per standard criteria.Assessment of radiological response was done every 2\u20133 months and at symptomatic progression. Chemotherapy or targeted therapy was discontinued at disease progression, intolerable side effects, or patient decision. Tumor response was evaluated by RECIST 1.1 criteria. The adverse events during this period were evaluated in accordance with the Common Terminology Criteria for Adverse Events version 4.02 (CTCAE v 4.02). At progression, further therapy was considered based on standard recommendations.Patients were divided into those who received Crizotinib upfront, received Crizotinib at a later time or were never exposed to Crizotinib. Potential reasons for not administering Crizotinib upfront were retrieved. Patients receiving Crizotinib at some later point of their treatment course were examined for reasons of this shift in therapy. The source of financing for patients on Crizotinib was also reported.SPSS version 16 was used for analysis. Descriptive statistics was performed. Median value with interquartile range was provided for continuous variables. Progression free survival (PFS) was calculated in months from the date of start of Crizotinib till the date of progression on Crizotinib. Patients who had not progressed at the time of last follow up were censored. Overall survival (OS) was calculated in months from the date of start of Crizotinib till the date of death. Patients who had not died at the time of last follow up were censored. Kaplan Meier method was used for time to event analysis. Log rank test was used for univariate analysis of PFS and OS. Cox proportional hazard model was used for multivariate analysis.A total of 94 patients satisfied the predefined selection criteria. The median age of the cohort was 51 years (Range 27\u201375 years). The cohort was male predominant, with 53 males (56.4%) and 41 females (43.6%). Eighteen patients (19.1%) were current or previous smokers while history of tobacco use was seen in 24 patients (25.5%). Comorbidities observed included hypertension in 11 (11.7%), diabetes mellitus type 2 in 8 (8.5%), liver dysfunction in 4 (4.3%) and cardiac dysfunction in 3 (3.2%) patients, respectively. The ECOG PS was 0\u20132 in 75 patients (79.8%), and 3\u20134 in 19 patients (20.2%). The median haemoglobin level was 11.4g/dl (IQR: 11.4\u201313.9 g/dl) and the median serum albumin level was 4g/dl (IQR: 3.5\u20135.2 g/dl).All patients 94 had adenocarcinoma or adenosquamous on histopathology of biopsy specimen. Ninety one patients (96.8%) patients were diagnosed with stage IV disease, while 3 patients had stage III disease. The median number of metastatic sites was 2 (range 0\u20137), with commonest sites of metastasis being pleural effusion in 42 (44.7%), opposite lung in 40 (42.6%), bone in 48 (51.1%), liver in 23 (24.5%) and brain in 21 (23.8%) patients, respectively. Disease was purely intrathoracic in 24 patients (25.5%), extrathoracic only in 2 patients (2.1%) and a combination of intra- and extra\u2013thoracic disease was seen in the remainder of patients (72.3%).Sixty patients (63.8%) received chemotherapy as first line treatment, 21 patients (22.3%) were started on Crizotinib upfront, while 10 patients (10.6%) received EGFR TKIs and 3 patients (3.2%) were planned for best supportive care only. The latter 2 categories were started on their respective treatment prior to receipt of ALK positive status.Chemotherapeutic regimens used upfront were Pemetrexed\u2013Platinum, Gemcitabine\u2013Platinum and Paclitaxel-Platinum in 52 (86.6%), 5 (8.3%) and 3 (5%) patients, respectively. Overall, of the 94 patient cohort, 69 patients (73.3%) were exposed to Crizotinib at some point of time, while 25 patients (26.6%) never received Crizotinib.The reasons for patients not being started on Crizotinib on diagnosis were disease burden and being symptomatic necessitating emergent treatment in 17 patients (23.3%), ALK testing not done initially in 17 patients (23.3%), lack of initial financial feasibility in 16 patients (21.9%), delay in final reporting of ALK status (12.3%), patient unwillingness to wait for reports (5.5%), previous treatment in the curative setting (1.4%) and ALK testing done on progression only (1.4%). Reasons were unavailable in 8 patients (11%).Besides patients receiving Crizotinib as first line therapy, a further 48 patients (51%) received Crizotinib at a later point in their treatment course. Reasons for shifting to Crizotinib from prior therapy were receipt of ALK positive status in 26 patients (54.1%), progression on previous treatment in 16 patients (33.3%) and Crizotinib considered as maintenance post response /stabilization of disease after 3\u20136 cycles of chemotherapy in 6 patients (12.5%).Assessment of method of procurement of Crizotinib showed that 31 patients (44.8%) gained access via methods of self-payment. Of these patients, 22 patients (31.8%) purchased Crizotinib by self-financing (including insurance), while the remaining 9 patients (13%) were government supported as part of their employment package. The majority of patients, 38 (55%), received Crizotinib free of cost via support from the Non-governmental Organizations\u2019 (NGOs\u2019).Grade 3/4 adverse events along with other significant toxicities are reported. The common side effects seen in patients include visual hallucinations (26.1%), grade 3/4 anemia (20.3%), and elevation of AST/ALT (8.6%), grade 3/4 vomiting (7.2%), grade 3/4 diarrhoea (4.3%), ECG abnormalities (4.3%) and grade 3/4 fatigue (4.3%). Other rare side\u2013effects included renal insufficiency and Crizotinib induced pneumonitis in 1 patient (1.4%) each.Twenty patients (29%) out of 69 required temporary cessation of Crizotinib for a median of 7 days (range: 2\u201390 days). Drug toxicity, commonly AST/ALT elevation (6 patients), ECG abnormalities (2 patients), and vomiting (2 patients), caused temporary Crizotinib cessation in 17 patients (85%), while drug unrelated causes in 2 patients and lack of compliance in 1 patient required stoppage of Crizotinib.Crizotinib was resumed at full doses in 12 patients (60%) on restarting, while 8 patients (40%) required starting at lower doses. 4 of these patients underwent dose escalation to full doses later.Response rates are reported for patients on Crizotinib. Partial response was seen in 37 patients (53.6%), Stable Disease in 13 (18.8%), with progressive disease in 2 patients (2.8%). Eight patients could not be evaluated by RECIST, while 9 (13%) patients are yet to undergo response evaluation.During the period of analysis, 15 patients progressed on Crizotinib. Their pattern of progression is shown in With a median follow up of 9 months for the entire cohort, median PFS for the entire cohort was 10 months \u201c\u201d. On evaMedian OS was not reached for the entire cohort, with estimated 1 year survival being 81.2% \u201c\u201d. An ECOThe current era of targeted therapy and precision medicine has ushered in a plethora of targeted agents which have shown impressive results in trial settings. However, reproducibility in the real world population is an increasing concern. The applicability of trial data to a non trial population has to take into account the greater incidence of co-morbidities, less stringent monitoring, a more heterogeneous populace and most importantly, issues of access to potentially expensive newer molecules. It is in this scenario that this study assumes importance where besides examining outcomes with Crizotinib, we have attempted to gauge practise patterns associated with the use of this drug as well as throw light on its accessibility to a financially constrained population.The demographic profile and tumor characteristics of our patients was similar to that seen in trials and other large retrospective analysis ,10,11, wA major focus of this study was outlining the treatment patterns in ALK positive NSCLC. A majority of patients were started on chemotherapy (63.8%) upfront, and then later shifted to Crizotinib, such that a significant percentage (73.3%) were exposed to Crizotinib on the whole. Lack of initial exposure to Crizotinib did not seem to affect PFS significantly, as long as patients did get exposed to Crizotinib in their treatment course. One of the potential reasons for this lack of difference is the suggested preferential activity of Pemetrexed in ALK positive NSCLC ,15, whicThe major reasons ascertained for not starting Crizotinib upfront were symptomatic disease requiring urgent treatment, ALK testing not done upfront, lack of initial financial feasibility and a delay in finalization/reporting of ALK positive status. The latter reasons are a reflection of the logistics and financial constraints involved in treating this cohort in the real world with Crizotinib. ALK testing by break-apart FISH probes is an expensive test for the majority of our population and although IHC (less expensive compared to testing by FISH) has shown good concordance with FISH \u201318, it hThere has been considerable debate regarding the cost effectiveness of ALK testing itself and first line therapy with Crizotinib. A Canadian study examined this very issue and concluded that testing for EML4-ALK in stage IV NSCLC and the subsequent treatment with Crizotinib was not cost effective due to the cost of Crizotinib as well as the low frequency of EML4-ALK in the general population . This isWithin the confines of the above constraints, our study confirms the favorable outcomes and tolerability of Crizotinib in the Indian population. A PFS of 10 months, which is commiserate with that seen in the pivotal PROFILE 1014 study ,21. HoweThe profile of adverse events in our patients, while stressing on Grade 3/4 toxicities, seemed higher than quoted in trial data, especially with respect to anemia (20.3%) and ECG abnormalities (5.7%), with lesser frequencies of other adverse events. Although 29% of our patients required dose interruptions, the median duration of cessation was for 1 week, with a majority able to resume Crizotinib at full doses.Our study, while delving into the patterns of treatment of ALK positive NSCLC has certain limitations. The retrospective nature of the study, potential underreporting of subjective adverse events like fatigue, etc. and short duration of median follow-up are lacunae that affect the impact of this study.In conclusion, the treatment of ALK positive NSCLC in the Indian population has its own set of challenges, predominantly socio- economic in nature. Exposure to Crizotinib and ECOG PS appear to be significant predictors of outcomes. However, with active extramural support, a majority of patients are getting exposed to Crizotinib with clinically relevant efficacy, outcomes and tolerability similar to published international data.S1 Table(DOCX)Click here for additional data file."}
+{"text": "In a retrospective review of 614 primary Stage I cutaneous malignant melanomata and 40 nonmelanoma lesions, the diagnostic accuracy(DA) for malignant melanoma was 86.2%. A positive preoperative clinical diagnosis of malignant melanoma was confirmed histologically in 564/604 (93.3%) of lesions. For 614 histologically proven malignant melanomata a correct pre-operative clinical diagnosis had been made in 564/614 (91.9%).An additional 172 patients were referred for wider excisional surgery within 3 months of a biopsy elsewhere. For the total 786 (614+172) patients, the incidence of biopsy of a clinicially unsuspected  malignant melanoma prior to referral to the Plastic Surgery Unit was lowest for lesions of the head and neck (18.3%) and lower limb (19.0%), and highest  for lesions of the hands and fingers.Previous reports of the poor level of clinical diagnostic accuracy in cutaneous malignant melanoma have not been confirmed in the present study."}
+{"text": "The treatments were control (T1) group without supplementation and heat stress, T2 as a heat stress group without supplementation, T3, T4 and T5 groups which were supplemented with 500, 1000 and 1500 ppb CrPic in diet with heat stress, respectively and T6, T7 and T8 groups which were supplemented with 500, 1000 and 1500 ppb nano-chromium in diet under heat stress, respectively. Supplementation of chromium and nano-chromium improved performance including weight gain and feed conversion ratio of heat-stressed chickens. Antibody titers against avian influenza (AI) and infectious bronchitis (IB) at 21 to 42 days of age in broilers fed supplemental chromium and nano-chromium were higher than broiler chickens fed control diet (p < 0.05). Nano-chromium supplementation at level of 1000 ppb and CrPic at level of 1500 ppb improved the antibody titers against AI and IB of broilers under heat stress conditions. It can be concluded from these findings that dietary supplementation of CrPic and nano-Cr can improve performance and antibody titers against AI and IB under heat stress conditions in broilers. This experiment was carried out to investigate the effects of different levels chromium picolinate (CrPic) and chromium nanoparticles (nano-Cr) on the performance and immune function of broilers under heat stress condition. A total of 320 Ross 308 broiler chicks (from 21 to 42 days) were assigned randomly into eight treatment groups  and be reared at either thermoneutral (21 \u02daC) or heat stress (36  Supplementation of organic chromium (Cr) can improve performance of broiler chickens.4-6 Chromium picolinate (CrPic) is an organic source of chromium that has high bioavailability.7,8 The primary role of Cr in metabolism is to potentiate the action of insulin through its presence in an organometallic molecule called glucose tolerance factor (GTF).9 Immunological functions enhance by trivalent Cr and its effects seem to be more pronounced during the times of stress.10 Also, occurrence of reduced bursa weight in broilers subjected to heat stress as well as decreased numbers of lymphocytes in the cortex and medulla areas of the bursa in these animals have been demonstrated previously.11 Organic Cr supplementation has shown be effective in diminishing adverse effects of heat stress in broilers.12,13 It has been observed that broilers under heat stress condition have lower levels of total circulating antibodies as well as lower specific IgM and IgG levels during primary and secondary humoral responses and reduced thymus, bursa, spleen and liver weights.14 Supplementation of chromium methionine (CrMet) at level of 800 ppb can improve immune responses to Newcastle disease and infectious bronchitis (IB) of broiler under heat stress condition.15 It has been reported that antibody production in young broiler chickens decreases in heat stress condition16 and antibody titer against IB improves in broiler chicks fed 400 ppb of CrPic.17 This study was conducted to investigate the effects of CrPic and nano-Cr on performance and antibody titers against AI and IB under heat stress condition in broiler chickens. Heat stress has immunosuppressive effects reducing systemic humoral immune responses.18 Treatment 2 was heat stress group without supplementation. In treatments 3-5 chromium at 500, 1000 and 1500 ppb in the form of CrPic  was added at rates of 418.30, 836.60 and 1254.90 mg per 100 kg of diet under heat stress, respectively. In treatments 6, 7 and 8 nano-Cr at 500, 1000 and 1500 ppb of diet was added at rates of 418.30, 836.60 and 1254.90 mg per 100 kg under heat stress, respectively. Chickens raised under heat stress condition were maintained under environmental temperatures of 36 \u00b1 1 \u02daC from 21 to 42 days of age (from 10:00 to 18:00 hr).A total of 320 day-old Ross 308 broiler chickens fed with corn-soybean meal based diet as shown in Vaccination program. Chickens were vaccinated against Newcastle disease (ND), IB and AI. Vaccination against ND and IB were performed using live vaccines including bivalent ND + IB \u00a0at day one via eye drop method, mono-valent B1  by eye drop at day 9 and monovalent H120  at day 15 by drinking water method as well as a killed vaccine against ND and AI  at day 9 via intra-muscular injection.Nano-chromium preparation. Chromium nanoparticle was processed by a wet polish method in a dry cryo-nanonization grinding system integrated with a size separator . Briefly, 10 g raw CrPic material was added to 250 mL of 95% ethanol. Then, passed through appropriate sized end-plates sieves to collect nano- and micro sized particles of Cr.Nanoparticle size determination. A small amount of nano-Cr powder was added to 5.00 mL of methanol and shaken in a water bath for 5 min. Then, small drop of the sample was added to a 4 mm diameter sample and 100 mesh formvar coated copper grid . Nanoparticles were examined under transmission electron microscope at 75 KV and electron micrographs were taken. The particle size was determined by a transmission electronic microscope  and is shown in Performance evaluation. Feed intake and body weight gain were recorded weekly  during the whole experimental procedure and data were analyzed for growth period (21-42 days of age). Also, protein efficiency ratio and European performance efficiency factors were analyzed for whole experimental period.Sampling. At 21, 28, 35 and 42 days of age, blood samples were collected from the wing vein of birds (eight chicks per treatment).Hemagglutination inhibition test. Serum obtained by centrifugation of samples and subjected to hemagglutination inhibition test (HI) according to OIE protocol.19 Briefly, after two-fold serial dilutions of sera, 4HA AI (H9N2) and same volume (25 \u00b5L) of diluted sera were added in each well of 96 well microplate. After 45 min incubation at room temperature, 25 \u00b5L of 1% chicken red blood cell (RBC) was added and after 30 min incubation at room temperature, the last well which had a complete inhibition was considered as antibody titer.Enzyme linked immunosorbent assay (ELISA). Antibody titers against IB disease virus were determined by ELISA kit  according to the manufacturer\u2019s instructions.Statistical analyses. Data were analyzed by General Linear Models using the PROC GLM procedure of SAS . Significant differences (p < 0.05) among treatment means were determined using Duncan new multiple range test. p < 0.0001). Effects of Cr-Pic and nano-Cr on performance of broiler chickens are shown in Body weight gain, feed conversion ratio (FCR) and European production efficiency factor improved with supplementation of Cr and nano-chromium in heat-stressed chickens. Supplementation of CrPic at level of 1500 ppb and nano-chromium at 1000 ppb had the best performance. The ELISA titers of IB at 21, 28, 35 and 42 days of age are shown in 20 The CrPic supplementation attenuated the decline in performance and antioxidant status resulting from heat stress in quails.21 Increases in lymphocyte counts and decreases in heterophil to lymphocyte ratios in 500 and 3000 ppb Nano-CrPic supplementation in heat-stressed chicks has been reported previously and it has been suggested that Nano-CrPic supplementation exhibits an anti-stress function.22This study was conducted to investigate the effects of different levels CrPic and Nano-CrPic on performance and antibody titers against IB and AI of broiler chickens under heat stress condition. Supplementation of CrPic has beneficial effects on performance and blood biochemical parameters of broiler chickens reared under heat stress conditions.17,23,24 Nano-chromium supplementation at level of 1000 ppb improved European production efficiency factor. It has been reported that dietary supplementation of organic chromium does not improve the production performance of broiler chickens.25 According to previous studies, chromium yeast supplementation to broiler chickens significantly increased protein percentage in the breast and thigh.26 Also, a possibility of better broiler performance through potassium chloride\u00a0supplementation under conditions of severe heat stress (35 to 38 \u00b0C) has been demonstrated.27The supplementation of CrPic and nano-Cr could improve body weight gain and feed conservation rate of broilers, these results are in general agreement with previous reports.28 Disease and stress increase urinary excretion of Cr.29 Thus, stress-associated immunosuppression alleviation may be one of the mechanisms by which Cr acts.30 Results of this study showed that supplementation of Cr can improve hemagglutination titers of AI. These findings are in agreement with the previous reports indicating that supplementation of chromium chloride improves antibody titers of AI.31 Supplemental chromium methionine modulated immuno-suppressive effects of heat stress on cellular and humoral immune responses leading to proportions of heterophils and cytotoxic T lymphocytes reduction.32Vitamins E and minerals such as Cr cause reduction in the serum level of malondialdehyde, the end product of lipid peroxidation, in laying hens.33 Heat stress in broilers causes decreases in CD4+ and CD8+ lymphocytes and antibody production against sheep red blood cells (SRBC).34 Supplementation of nano-Cr improved performance under heat stress condition, but addition of nano-Cr at 1500 ppb did not improve the performance index.The CrPic supplementation through feed or drinking water enhances the\u00a0immune responses\u00a0by up-regulating interferon-gamma expression after vaccination of New-castle disease in broiler chickens.In conclusion, the results of this study indicated that supplementation of Cr and nano-chromium improves performance index and antibody titers against AI and IB under heat stress conditions in broiler chickens."}
+{"text": "Myelodysplastic syndromes (MDS) are clonal stem cell disorders exhibiting cytopenias, ineffective hematopoiesis and morphological dysplasia. Bone marrow cytogenetics, inspite of being incorporated as mandatory tool in diagnosis are done less frequently due to limited availability of this technique in Pakistan. The aim of the study was to study baseline clinicohematological and cytogenetic characteristics of patients presenting with de novo MDS.9/l, platelet count was 82\u2009\u00b1\u200995.7\u2009\u00d7\u2009109/l. Of total 170 (96%) were transfusion dependent. Refractory cytopenias with multilineage dysplasia (RCMD) was the most common world health organization (WHO) category. Karyotype was done in 98 (55%) patients out of which 44 (45%) had abnormal karyotype, complex karyotype (CK) was most commonly observed in 12 (12.2%) followed by monosomy 7 in 7 (7.1%).A retrospective\u00a0cross sectional study was done at National Institute of Blood Diseases and Bone Marrow Transplantation, Karachi, Pakistan from 2010 to 2016. Total of 177 patients were included in the study having median age 51\u00a0years and male to female ratio of 3:1. Pancytopenia was observed in 80 (45%) patients and bicytopenia in 74 (42%). Mean Hb% was 7.8\u2009\u00b1\u20092.18\u00a0g/dl, total leukocyte count (TLC) 8.8\u2009\u00b1\u200913.6 \u00d7 10We found younger median age at diagnosis, higher mean TLC and no significant history of recurrent infections. CK and monosomy 7 carry bad prognostic implications and early disease transformation to acute myeloid leukemia (AML). Monosomy 7 being associated with bad overall survival, such patients must be identified early with close clinical follow up and offered stem cell transplant. This is the largest cohort of patients of MDS evaluated for baseline clinical and cytogenetic characteristics in our country. Myelodysplastic syndromes (MDS) are group of clonal hematopoietic stem cell disorders exhibiting ineffective hematopoiesis, morphological dysplasia and progressive tendency to evolve into acute myeloid leukemia (AML) \u20135. The eThis retrospective cross sectional study was conducted at National Institute of Blood Diseases and Bone Marrow Transplantation, Karachi Pakistan from June 2010 to June 2016. Baseline investigations done included complete blood counts, serum vitamin B 12, serum and RBC folate levels. Clinical parameters were recorded. Bone marrow biopsy samples were taken from posterior superior iliac spine through jamshidi needle and were stained by leishman\u2019s stain. Perl\u2019s (Iron) stain was carried out on each bone marrow sample by commercially provided kits from merck diagnostic according to manufacturer\u2019s instructions. Cytogenetic analysis was performed on overnight, 24-h un-stimulated and 72-h stimulated bone marrow cultures using standard procedures. The GTG (G-bands via trypsin using Giemsa) banding technique was applied, karyotypes were described according to the International System for Human Cytogenetic Nomenclature (ISCN) 2013, karyogram were made using Meta system. Patients were classified according to world health organization (WHO) 2008 classification and IPSS was also calculated. Approval from the Institutional ethics committee was obtained prior to the study.During the study period, patients diagnosed as de novo MDS based on morphological and/or cytogenetic basis were included in the study. Thorough morphological assessment of peripheral smears and bone marrow biopsy was done along with bone marrow cytogenetic analysis.Patients presenting with cytopenias and normocytic/macrocytic anemia due to other non malignant causes, patients having history of prior chemotherapy or irradiation and patients having organomegaly or lymphadenopathy were excluded from the study.Statistical analysis was done by statistical package for the social sciences version 22.0 . Descriptive variables were calculated as mean, standard deviation (SD), frequencies and percentages.A total of 177 consecutive patients diagnosed with MDS were included in the study. The median age of patient was 51 (range 3 to 90\u00a0years). The male to female ratio was 3:1. Frequency of all patients according to WHO classification 2008 is shown in  followed by weakness 141 (80%) and fever 83 (47%). Absolute neutophil count (ANC) of <1.8 was found in 78 (44%) and >1.8 was found in 99 (56%) of patients. Pancytopenia was observed in 80 (45%) and bicytopenia in 74 (42%) (anemia and thrombocytopenia). However, 23 (13%) had cytopenia of one cell lineage. One hundred and seventy (96%) patients were transfusion dependent. History of recurrent infection was found in 21 (12%). Bacterial infections were observed to be the most common cause followed by viral and fungal infections. Co morbidities were observed in 116 (66%) of patients including hypertension in 61 (35%), diabetes mellitus in 55 (31%) while 61 (34%) had no known co morbid. Iron grading was done on all the bone marrow aspirate samples by Perl\u2019s staining method. Grade III iron was found to be frequent, seen in 57 (32%) followed by grade IV in 38 (21.5%) and grade I in 36 (20.3%). Bone marrow myelofibrosis (MF) was done according to WHO 2008 myelofibrosis grading system and found to be MF -0 in 77 (44%), MF -I in 70 (39.5%) and MF-II in 30 (16.9%). Out of all patients, 97 (55%) were alive, 80 (45%) had died by the end of study period. The cause of death for 30 (38%) patients could not be ascertained whereas in rest of the patients the causes of death were septicemia in 19 (23.7%), severe anemia in 10 (12.5%), cardiac arrest in 15 (18.7%) and intracranial bleeding in 6 (7.5%) patients.9/l, which is in concordance with a national study and also seen in India [9/l in our study was higher as compared to other regional and international studies  was the most common encountered WHO sub category of MDS followed by refractory anemia with excess blast (RAEB) as observed in previous study from Pakistan  and the In this study we found abnormal karyotype in 44 (45%), complex karyotype (CK) being most common in 12 (12.2%) followed by monosomy 7 in 7 (7.1%). Monosomy 7 is not commonly observed in previous studies \u201313, 15 eCytogenetic studies are done at limited centers in Pakistan, our study could be helpful to outline cytogenetic characteristics of MDS in our region. Karyotypic abnormalities exhibit a significant role in diagnosis and prognosis of MDS. We observed CK and monosomy 7 frequent in our study which carries poor overall survival and early transformation to AML. Such patients must be identified early in the disease course. Since our study was retrospective, future prospective studies are needed to ascertain the findings.In our study we observed younger median age of disease presentation, higher mean TLC count and no significant history of recurrent infections. RCMD was the most common WHO category and CK was most common abnormal karyotype followed by monosomy 7. Since both carry adverse prognostic implications, early identification of such patients with close clinical follow up and upfront allogenic stem cell transplant must be considered keeping in view the younger age in our cohort at time of presentation. This study was done retrospectively yet represents a large cohort of MDS in our country. In future, prospective studies are needed to be done to further elaborate disease biology and clinical outcome of the baseline adverse disease characteristics observed in our study. Also molecular testing in MDS must be incorporated since nowadays diagnostic spectrum of MDS is moving rapidly towards molecular analysis and its relation to disease outcome."}
+{"text": "P = 0.001) and metastatic breast cancer (P = 0.046) but not for CST6 and BRMS1. In early breast cancer, SOX17 promoter methylation in the EpCAM-positive CTC-fraction was associated with CK-19 mRNA expression (P = 0.006) and worse overall survival (OS) (P = 0.044). In the metastatic setting SOX17 promoter methylation in ctDNA was highly correlated with CK-19 (P = 0.04) and worse OS (\u03a1 = 0.016). SOX17 methylation status in CTCs and ctDNA was comparable and was associated with CK-19 expression but was not reflecting the status of primary tumours in breast cancer. DNA methylation analysis of SOX17 in CTCs and matched ctDNA provides significant prognostic value.Circulating Tumour Cells (CTCs) and circulating tumour DNA (ctDNA) represent a non-invasive liquid biopsy approach for the follow-up and therapy management of cancer patients. We evaluated whether DNA methylation status in CTCs and ctDNA is comparable and whether it reflects the status of primary tumours. We compared the methylation status of three genes, SOX17, CST6 and BRMS1 in primary tumours, corresponding CTCs and ctDNA in 153 breast cancer patients and healthy individuals, by using real time methylation specific PCR. We report a clear association between the EpCAM-positive CTC-fraction and ctDNA for SOX17 promoter methylation both for patients with early ( During the last years, intensive basic research has led to an increasing number of treatment options for cancer patients. This in turn has created an urgent need for biomarkers to predict response to targeted therapy and to monitor emergent drug resistance. Therapy decision for many tumour types is based on biomarkers that are evaluated at the primary tumour by the classic biopsy approach; however, classic biopsy is not allowing monitoring of primary tumours evolution during time, while repeated sampling of metastatic sites is not always possible for practical reasons. \u201cLiquid biopsy\u201d based on minimally-invasive blood-based tests has the potential to be a strong complement to the classic biopsy approach; Circulating Tumour Cells (CTCs) and circulating tumour DNA (ctDNA) are the major players in liquid biopsy analysis, since they can both provide an alternative approach that enables a sensitive, dynamic and specific serial tumour sampling during the course of treatment, and an early marker of response to systemic therapy \u20133. An imNowadays, the detection and molecular characterization of CTCs is one of the most active and hot areas of translational cancer research , 4. TherOn the other hand, the verified presence of extractable amounts of ctDNA circulating in serum and plasma of cancer patients, suggests that ctDNA carrying tumour specific alterations has a very strong potential as a liquid biopsy biomarker as well , 11. TheSOX17 promoter is highly methylated in primary breast tumours, in CTCs isolated both from patients with early and metastatic breast cancer, and in corresponding ctDNA samples [DNA methylation plays a fundamental role in the development and progression of many types of cancer, mainly through the inactivation of certain tumour-suppressor genes . Moreove samples .SOX17), Cystatin M (CST6) and Breast cancer metastasis suppressor 1 (BRMS1) in primary tumours, EpCAM-positive pooled CTC-fractions and ctDNA in well characterized matched clinical samples of breast cancer patients.The primary goal of our present study was to investigate to what extent DNA isolated from CTCs and plasma is representing the primary tumour and whether is carries similar information in terms of DNA methylation biomarkers. To address this question we performed a direct comparison study of the methylation status of SRY (sex-determining region Y)-box 17  and unconverted DNA; no amplification of the SOX17, CST6 and BRMS1 promoter was observed.Evaluation of the analytical sensitivity and specificity of the real time MSP assays used for the evaluation of SOX17 was detected in 26/42 (61.9%) patients diagnosed with early breast cancer and in 21/33 (63.6%) patients that developed metastasis. CST6 promoter methylation was observed in 11/31 (35.5%) patients with early breast cancer and 16/32 (50.0%) patients with metastasis. BRMS1 promoter methylation was detected in 19/42 (45.2%) patients with early breast cancer and 5/32 (15.6%) metastatic patients. There was no correlation between the methylation status of these genes and tumour size, number of lymph nodes, tumour grade, tumour stage, PR and ER receptors, HER2 status and age (data not shown). The diagnostic specificity of real-time MSP assays for each gene was further evaluated in non-cancerous breast tissues (mammoplasties) and fibroadenomas used as controls. SOX17 promoter was methylated in 3/29(10.3%) non-cancerous breast tissues, and in 2/9 (22.2%) breast fibroadenomas. CST6 promoter was methylated in 3/29 (10.3%) non-cancerous breast tissues (mammoplasties) and in 1/10 (10.0%) breast fibroadenomas. BRMS1 promoter methylation was detected neither in 29 non-cancerous breast tissues nor in the 10 fibroadenoma samples tested.FFPE samples were available for 75 out of these 153 patients  patients with early and in 26/61 (42.6%) patients with metastatic breast cancer. CST6 promoter was methylated in 24/92 (26.1%) patients with early, and in 21/61 (34.4%) patients with metastatic breast cancer. BRMS1 promoter was methylated in 20/92 (21.7%) patients with early, and in 31/61 (50.8%) patients with metastatic breast cancer. According to our findings there was no correlation between the promoter methylation status of these genes in the EpCAM-positive CTC-fraction and tumour size, number of lymph nodes, tumour grade, tumour stage, the presence of progesterone (PR) and estrogen receptors (ER), HER2 status, and age (data not shown). The diagnostic specificity of real-time MSP assays for each gene was further evaluated by analyzing the EpCAM-positive CTC-fraction of 23 healthy individuals used as control group revealing that promoter methylation of SOX17 was observed in 1/23 (4.3%), CST6 in 1/23 (4.3%) and BRMS1 in 2/23 (8.7%) healthy individuals.We evaluated SOX17, CST6, and BRMS1 promoter methylation in ctDNA isolated from matched plasma samples from the same 153 patients as above and 49 healthy individuals (Table SOX17 was observed in 24/92 (26.1%) patients with early breast cancer, in 22/61 (36.1%) patients with metastatic disease and in 1/49 (2.0%) healthy individuals. Promoter methylation of CST6 was observed in 33/92 (35.9%) patients with early, 26/61 (42.6%) patients with metastatic breast cancer and 2/49 (4.1%) healthy individuals. Promoter methylation of BRMS1 was observed in 22/92 (23.9%) patients with early and 4/61 (6.6%) patients with metastatic breast cancer and 2/49 (4.1%) healthy individuals. Finally, there was no correlation between the methylation status of these genes in ctDNA and tumour size, number of lymph nodes, tumour grade, tumour stage, the presence of PR and ER receptors, HER2 status, and age (data not shown).We further evaluated the methylation status of SOX17, CST6, and BRMS1 promoter in the EpCAM-positive CTC-fraction, corresponding ctDNA and paired FFPEs and investigated whether there is a direct association.We further directly compared the methylation status of SOX17 promoter methylation but not for CST6 and BRMS1  and metastatic breast cancer .We found a concordance between the EpCAM-positive CTC-fraction and ctDNA in both early and metastatic breast cancer only for S1 Table . There wSOX17 promoter methylation was observed only in 15/42 (35.7%) cases, while the concordances were very low for CST6, and BRMS1. In the metastatic setting, there was a concordance for 21/33 (63.6%) of cases for SOX17 promoter methylation, while there was no concordance for CST6 and BRMS1.In early breast cancer we found no association between the EpCAM-positive CTC-fraction and 42 available paired primary tumours in respect to the promoter methylation status of any of the three genes studied Table ; concordSOX17 promoter methylation was observed in 19/42 (45.2%) cases while the concordances for CST6, and BRMS1 were very low. In the metastatic setting, for SOX17 there was a concordance for 17/33 (51.5%) cases and there was no concordance for CST6, and BRMS1.In early breast cancer, we found no association between ctDNA and 42 available paired primary tumours in respect to the promoter methylation status of these three genes Table ; concordCK-19 mRNA expression in all EpCAM-positive CTC-fractions, since we have extensively used this epithelial marker to verify the presence of CTCs (19\u201321). Using the same procedure, none of 60 healthy individual samples tested (0%) was found positive for CK-19 expression. We further studied the association between CK-19 mRNA expression and SOX17, CST6 and BRMS1 promoter methylation in the EpCAM- positive CTC-fraction. Results are shown in heat maps for each individual patient in all cases . Results are shown as a heat maps for each individual patient in Figure In early breast cancer, CK-19 mRNA while 19/92 (20.6%) samples were positive for SOX17 methylation; 8/92 (8.7%) samples were positive for both SOX17 promoter methylation and CK-19 mRNA and 9/92 (9.8%) samples were positive for CK-19, but were not carrying SOX17 promoter methylation. It is highly remarkable that SOX17 promoter methylation was also identified in the EpCAM-positive CTC-fraction of 11 patients who were negative for CK-19 mRNA expression. However, in the same group CST6 and BRMS1 methylation status was not correlated with CK-19 mRNA expression. More specifically, only 4/92 (4.3%) samples were positive for both CST6 promoter methylation and CK-19 mRNA expression, 13/92 (14.1%) samples were positive for CK-19, but not carrying CST6 promoter methylation, while CST6 promoter methylation was identified in the EpCAM-positive CTC-fraction of 20 patients who were negative for CK-19 mRNA. In the same group only 2/92 (2.1%) samples were positive for both BRMS1 promoter methylation and CK-19 mRNA expression, 16/92 (17.4%) samples were positive for CK-19 but not carrying BRMS1 promoter methylation, while BRMS1 promoter methylation was identified in 17 patients who were negative for CK-19 mRNA expression.More specifically, 17/92 (18.5%) samples were positive for CK-19 expression in the EpCAM-positive CTC-fraction. Results are shown as a heat maps for each individual patient in Figure SOX17, CST6 and BRMS1 promoter methylation were not individually correlated with CK-19 expression. However, in the EpCAM-positive CTC-fraction of the 45 patients who were negative for CK-19 mRNA expression, SOX17 promoter methylation was identified in 18/45 (40.0%), CST6 promoter methylation in 14/45 (31.1%) and BRMS1 promoter methylation in 20/45 (44.4%).In this group 6/61 (26.2%) samples were found positive for CK-19 mRNA expression and SOX17, CST6 and BRMS1 promoter methylation in corresponding ctDNA. Results are shown in heat maps for each individual patient in all cases . Results are shown as a heat maps for each individual patient in Figure CK-19 mRNA expression, while there were only 2/92 (2.2%) cases positive for CK-19 and negative for SOX17, CST6 and BRMS1 promoter methylation. It is highly remarkable that DNA methylation was identified in ctDNA of 43 patients who were negative for CK-19 mRNA expression.In this group, there was a statistically significant association between DNA methylation of one or more of these genes in ctDNA and SOX17 promoter methylation in ctDNA was highly correlated with CK-19 expression (P = 0.040). CST6 and BRMS1 promoter methylation in ctDNA were not individually correlated with CK-19 expression. However samples that were found to have at least two gene promoters methylated in ctDNA were also CK-19 mRNA positive (P = 0.021).Results are shown as a heat maps for each individual patient in Figure SOX17, CST6, and BRMS1 promoter methylation in CTC, ctDNA and corresponding primary tumours and the clinical outcome of patients. Results are shown as a heat maps for each individual patient in Figure We further evaluated whether there is any association between SOX17 gene promoter was found highly methylated in the primary tumour, in the corresponding CTC-fraction and in ctDNA  is shown in Figure BRMS1 promoter , as we have previously reported for a different cohort of breast cancer patients (27). Concerning CTCs, patients with non-methylated SOX17 promoter in the EpCAM-positive CTC-fraction had a significantly better median overall survival (OS) compared to patients with methylated SOX17 promoter .After a median follow-up period of 40 months (range 6\u2013121), 6/92 (6.5%) patients with early breast cancer relapsed and 3/92 (3.3%) of them died as a consequence of disease progression. In 4/6 patients that relapsed A Figure . It is wSOX17, CST6 and BRMS1 promoter methylation in corresponding FFPEs (n = 33) is shown in Figure P = 0.011). It is interesting to note that the Kaplan\u2013Meier estimates of the OS were significantly different in favor of patients with non-methylated SOX17 promoter .During the follow up, 25/61 (40.9%) patients with metastatic disease died as a consequence of disease progression. The direct comparison study of SOX17, CST6 and BRMS1 in primary tumours, corresponding plasma ctDNA and in matched cell pools of EpCAM-positive CTCs, in order to investigate whether the tumour's \u201cliquid phase\u201d reflects the status of the primary tumour. We also wanted to evaluate to what extend these markers yield complementary or additional information about prognosis and disease progression. By using specimens derived from the same patients and identical blood draws, and by applying identical and analytically validated methodologies for the MSP assays used, we minimized most pre-analytical parameters that could affect this comparison. The procedure that we have followed for CTCs enrichment and analysis in the present study has been validated in previous studies and has been compared with commercially available molecular assays [In the present study we performed for the first time a direct comparison study of the DNA methylation status of r assays \u201323.CST6 promoter methylation in primary tissues provides important prognostic information in patients with operable breast cancer [CST6 promoter is methylated in ctDNA and is promising as a highly specific tumour biomarker for early breast cancer patients since it was not detected in plasma of healthy individuals [DNA methylation of these three gene promoters has been extensively studied so far mainly in primary tissues of various types of cancer. We and others have already shown that detection of t cancer , 25. Furividuals .BRMS1 promoter methylation in the primary tumour was associated with poor DFS while our study on BRMS1 protein expression by immunofluorescence revealed CTCs heterogeneity even in the same patient [BRMS1 mRNA expression has been shown to be markedly reduced in melanoma, breast cancer, ovarian cancer and non-small cell lung cancer cell lines, while stable overexpression of BRMS1 in these cell lines significantly inhibited their metastatic potential [We have recently shown that  patient . BRMS1 i patient , 28. BRMotential \u201331.SOX17 promoter is highly methylated in CTCs isolated from patients with breast cancer [SOX17 plays a critical role in the regulation of development and stem/precursor cell function, at least partly through repression of the canonical Wnt/\u03b2-catenin signaling pathway , 33. We t cancer .According to our findings, there was no concordance between the EpCAM-positive CTC-fraction and paired primary tumours in respect to the promoter methylation status of any of the genes studied, neither in early, nor in the metastatic setting. A lack of concordance was also found for the same DNA methylation markers between ctDNA and matched primary tumours. A possible explanation for this finding could be based on tumour heterogeneity and rapid evolution through time, indicating that the liquid biopsy is reflecting the actual phase of tumour evolution. It is now clear that CTCs are not only rare but heterogeneous at the same time, even within the same patient , 35. ThiThere are very few studies so far comparing DNA methylation markers in primary tumours, CTCs and paired ctDNA samples , 18, 22.SOX17 promoter methylation in CTCs and ctDNA in patients with breast cancer. We report for the first time that in the EpCAM-positive CTC-fraction, SOX17 promoter methylation was associated with CK-19 mRNA expression both in patients with early and metastatic breast cancer. In addition, our findings revealed that methylation of SOX17 promoter in ctDNA is associated with unfavorable prognosis in patients with metastatic breast cancer and that in patients with early breast cancer, methylation of SOX17 promoter in the EpCAM-positive CTC-fraction is associated with decreased DFI. We did not find any association between the methylation status of CST6 and BRMS1 in CTCs, ctDNA and corresponding primary tumours. This could be attributed to tumour evolution over time and to the Epithelial Mesenchymal Transition (EMT) phase of CTCs [Our present data indicate a direct association between  of CTCs .SOX17 and CST6 promoter methylation were higher than in the EpCAM-positive CTC-fraction while non-specific methylation was detected at even lower percentages in all cases. This could possibly indicate a release of methylated DNA from apoptotic cells as well. Non-specific methylation events were detected at a very low percentage in all our control samples.In the EpCAM-positive CTC-fraction, we found that all these three genes were methylated at significantly higher percentages in the metastatic setting than in early stages of the disease. This could be explained by the higher tumour load in the metastatic setting. It is also worth mentioning that in plasma the number of samples found positive for SOX17 gene promoter was found highly methylated in the primary tumour, in the EpCAM-positive CTC-fraction and in ctDNA. It is also worth mentioning that the blood specimen of one early breast cancer patient that relapsed very early was found methylated in the EpCAM-positive CTC-fraction, for all genes tested, while it was CK-19 negative. We plan to verify this finding in the future by analysing a larger number of patients. It is also remarkable to note that samples found positive for SOX17, CST6 and BRMS1 promoter methylation in the EpCAM-positive CTC-fraction were negative for CK-19 mRNA expression. If CTCs positivity would be based only on CK-19 expression these samples would have been characterized as CTC-negative. This indicates the importance of multi-parametric testing in CTC analysis.It is also interesting to note that in most early breast cancer patients that relapsed early, In the metastatic setting, much higher detection rates for CK-19 are usually expected, as we have previously shown using the same RT-qPCR assay [ex vivo culture, and characterization of CTCs is a very promising approach to monitor continuously and in a non-invasive way the changing patterns of drug susceptibility in individual patients as their tumours acquire new mutations [Molecular characterization of single CTCs combined with massive parallel sequencing (MPS) technologies performed both in single CTC and paired plasma could elucidate further the association between CTCs and ctDNA , 38. Verutations , 40. Howutations , 42. Recutations . Howeverutations .TM FDA cleared system for the enumeration of CTC. They report an absence of prognostic impact of baseline ctDNA level suggesting that mechanisms of ctDNA release in metastatic TNBC may involve, beyond tumour burden, biological features that do not dramatically affect patient outcome [Concerning the comparison between CTCs and ctDNA, the most important parameter is correlation of the biomarker under evaluation with the clinical outcome. As an example, in a very recent study, Madic et al. used the high prevalence of TP53 mutations in triple negative breast cancer (TNBC) to compare ctDNA and CTCs detection rates and evaluate their prognostic value in metastatic TNBC patients . They us outcome .CTCs molecular analysis when compared to ctDNA and exosomes as a liquid biopsy approach has the clear advantage that its prognostic significance has already been shown through numerous studies \u20139, and tSOX17 promoter methylation in CTCs and ctDNA both in patients with early breast cancer and in patients with metastatic disease but not for the other genes studied. We could not identify a direct association between the methylation status of these genes in primary tumours CTCs and ctDNA, possibly because tumours are evolving and the liquid biopsy is reflecting the actual state of tumour evolution. Combination of DNA methylation analysis of tumour suppressor and metastasis suppressor genes in EpCAM-positive CTCs and matched ctDNA provides significant prognostic value. We plan to extend this direct comparison study and verify these findings in larger cohorts and for a wide range of gene promoters, using Massive Parallel Sequencing technologies. We will evaluate the clinical significance of these findings in an independent study, in respect to the clinical characteristics of the patients and additional markers already studied by our group on CTCs  in a large number of patients with a known clinical outcome and a longer follow up.In conclusion our findings indicate a direct association only between SOX17, CST6 and BRMS1 promoter methylation in ctDNA and in the EpCAM-positive CTC-fraction of 153 breast cancer patients; 92 with early and 61 with metastatic breast cancer. Peripheral blood was isolated from all these patients for CTCs and ctDNA analysis. In early breast cancer cases peripheral blood was collected at least two weeks after surgery and before the initiation of adjuvant chemotherapy, while in the metastasis group samples were collected before the initiation of first line treatment. For 75 of these patients the corresponding FFPEs samples from the primary tumours were available. In all cases the primary tumor of patients that relapsed after several months or years had been analysed. More specifically we analysed: a) EpCAM-positive CTC-fraction samples isolated from peripheral blood of all patients (n = 153); for all these samples, information on the expression of CK-19 in the EpCAM-positive CTC-fraction was also available, b) ctDNA samples isolated from corresponding plasma of the same patients during the same venepuncture (n = 153) and c) 75 corresponding primary breast cancer formalin-fixed paraffin-embedded tissues (FFPE) . As a control population, peripheral blood was collected from 60 healthy individuals, while 29 non-cancerous breast tissues (mammoplasties) and 10 breast fibroadenomas were used as non-cancerous breast tissue controls. All study participants signed an informed consent form to participate in the study, which was approved by the ethics and scientific committees of our institutions.We directly compared SOX17, CST6 and BRMS1 promoter methylation. Genomic DNA (gDNA) from FFPEs was isolated using the QIAamp DNA FFPE Tissue Kit . DNA concentration was determined in the Nanodrop ND-1000 spectrophotometer .Tissue sections of 10 \u03bcm containing 80% tumour cells were used for DNA extraction. DNA 100% methylated  was used as a positive control in MSP for the detection of CK-19 expression studies in CTCs as previously described [The EpCAM-positive CTC-fraction was isolated from 20 mL peripheral blood as previously described , 18, 46.Peripheral blood in EDTA was collected and processed immediately for plasma isolation. All samples were centrifuged at 1600 g (10 min), and plasma was carefully transferred into 2 mL tubes and stored at \u221220\u00b0C until ctDNA isolation. The High Pure Viral nucleic acid kit (Roche Diagnostics) was used to extract ctDNA from plasma (200 \u03bcL) as previously described , 18.Preparation of sodium bisulfite (SB) conversion reaction was performed in a laminar flow hood, in a dedicated separate room. For all clinical samples, before proceeding to SB conversion and MSP reaction steps, the integrity of isolated gDNA was assessed by amplifying exon 20 of the BRCA1 gene as previously described . gDNA exIVD instrument, Roche, Germany). All oligonucleotides were de-novo in-silico designed for each gene by using the PrimerPremier 5 software , and synthesized by IDT  [For high throughput analysis of our samples we designed highly specific and sensitive real Time MSP assays for each gene of interest. All experiments were performed in the LightCycler 2.0  , 48. Fores, USA) , 18, 22.To verify that we could specifically detect only the targeted methylated sequences, in each MSP reaction we used the following controls: a) gDNA not submitted to SB-conversion (unconverted DNA) and placental DNA submitted to SB-conversion , were included as negative controls and b) SB-converted DNA from the DNA methylation standard (100%) were included in every run as positive control. To exclude false negative results, all SB-converted samples found negative by real-time MSP, were checked for DNA quality by using a specifically designed primer set that equally amplifies in the same genomic region both methylated and non-methylated SB-converted target sequences.To evaluate the analytical sensitivity of the developed real-time MSPs we prepared synthetic control mixtures by serial dilutions of SB-converted DNA control samples (0% and 100% methylated). More specifically the SB-converted DNA methylation standard (100%) was spiked in SB-converted placental DNA (0% methylated) in a concentration range of 0%, 1%, 25%, and 50%. For the evaluation of analytical sensitivity, 1 \u03bcL of these synthetic samples were used in the Real- Time MSP reactions.2 test of independence for data analysis and for the evaluation of the significance of differences between groups. We used the Fisher exact test and Cohen's kappa coefficient, for the evaluation of agreement between methylation of each gene in respect to its presence in CTCs and ctDNA and in respect to CK-19 gene expression [P values < 0.05 were considered statistically significant. Statistical analysis was performed by using the SPSS Statistics 22.0 Windows program .We used the \u03c7pression . Correla"}
+{"text": "Modular endoprostheses are commonly used to reconstruct defects of the distal femur and proximal tibia after bone tumor resection. Because limb salvage surgery for bone sarcomas is relatively new, becoming more frequently used since the 1980s, studies focusing on the long-term results of such prostheses in treatment of primary tumors are scarce.\u00ae modular endoprosthesis when used for tumor reconstruction around the knee, and what factors may be associated with mechanical failure? (2) What are the nonmechanical complications? (3) What are the implant failure rates at 5, 10, and 15 years? (4) How often is limb salvage achieved using this prosthesis?(1) What proportion of patients experience a mechanical complication with the MUTARS\u00ae knee replacements in 105 patients; no other endoprosthetic systems were used. Four patients (four of 105 [4%]) were lost to followup, leaving 110 reconstructions in 101 patients for review. The reverse Kaplan-Meier method was used to calculate median followup, which was equal to 8.9 years . Mean age at surgery was 36 years . Predominant diagnoses were osteosarcoma (n = 56 [55%]), leiomyosarcoma of bone (n = 10 [10%]), and chondrosarcoma (n = 9 [9%]). In the early period of our study, we routinely used uncemented uncoated implants for primary reconstructions. Later, hydroxyapatite (HA)-coated implants were the standard. Eighty-nine reconstructions (89 of 110 [81%]) were distal femoral replacements  and 21 (21 of 110 [19%]) were proximal tibial replacements. In 26 reconstructions (26 of 110 [24%]), the reconstruction was performed for a failed previous reconstruction. We used a competing risk model to estimate the cumulative incidence of implant failure.Between 1995 and 2010, endoprostheses were the preferred method of reconstruction after resection of the knee in adolescents and adults in our centers. During that period, we performed 114 MUTARS\u00ae in situ.Complications of soft tissue or instability occurred in seven reconstructions (seven of 110 [6%]). With the numbers we had, for uncemented distal femoral replacements, we could not detect a difference in loosening between revision (five of 17 [29%]) and primary reconstructions (eight of 61 [13%]) . Hydroxyapatite-coated uncemented implants had a lower risk of loosening (two of 42 [5%]) than uncoated uncemented implants (11 of 36 [31%]) . Structural complications occurred in 15 reconstructions (15 of 110 [14%]). Infections occurred in 14 reconstructions (14 of 110 [13%]). Ten patients had a local recurrence (10 of 101 [10%]). With failure for mechanical reasons as the endpoint, the cumulative incidences of implant failure at 5, 10, and 15 years were 16.9% , 20.7% , and 37.9% , respectively. We were able to salvage some of the failures so that at followup, 90 patients (90 of 101 [89%]) had a MUTARS\u00ae modular endoprostheses represent a reliable long-term option for knee replacement after tumor resection, which seems to be comparable to other modular implants available to surgeons. Although the number of patients is relatively small, we could demonstrate that with this prosthesis, an uncemented HA-coated implant is useful in achieving durable fixation.Although no system has yet proved ideal to restore normal function and demonstrate long-term retention of the implant, MUTARSLevel IV, therapeutic study. Various techniques have been described for management of reconstruction of malignant tumors about the knee in adults, including implantation of osteoarticular allografts , 34, all\u00ae system  was introduced in 1992 and has since been widely used in Europe, Australia, and various Asian countries; results of its use in both orthopaedic oncology and revision surgery have been documented ) were lost to followup, leaving 110 reconstructions in 101 patients for review; of these, 64 (64 of 101 [63%]) were alive at final review. The reverse Kaplan-Meier method was used to calculate the median followup, which was equal to 8.9 years   that were implanted for primary reconstruction after tumor resection, 39 (46%) had an extraarticular resection. Twenty-six implants (26 of 110 [24%]) were implanted as a revision of a failed reconstruction, including nine MUTARS\u00ae distal femoral or proximal tibial replacement. A polyethylene locking mechanism connected the femoral and tibial components. Until March 2003, we used the conventional polyethylene lock. From then onward, the PEEK-OPTIMA\u00ae  lock was used. Extension of the implant was possible in 20-mm increments. All stems and extension pieces were equipped with sawteeth at the junctions to allow rotational adjustment in 5\u00b0 increments. The hexagonally shaped stems were available for uncemented (TiAl6V4) or cemented (CoCrMo) fixation. Femoral stems were curved to match the natural anterior curvature of the femoral diaphysis. We generally preferred uncemented fixation, unless we were unable to obtain adequate press-fitting or in cases in which bone quality was deemed insufficient for uncemented fixation. In the early period under study, we routinely used uncemented uncoated implants because at that time, the MUTARS\u00ae system did not come with hydroxyapatite (HA)-coated stems standardly; HA-coated stems were mainly used in cases with a presumed higher risk of loosening such as patients with a failed previous reconstruction. Later, HA-coated implants were the standard for primary reconstruction. The medullary cavity was reamed with a hexagonal rasp to secure optimal contact between the bone and implant. In case of uncemented fixation, the medullary cavity was underreamed by 1 mm. In case of cemented fixation, we overreamed the canal for 2 mm and third-generation cementing techniques were used.A lateral or medial parapatellar approach was used; this depended on the location of the tumor and biopsy tract, which was excised in continuity with the tumor. In all cases, we used a rotating hinged MUTARSIn cases in which an extensor mechanism reconstruction had to be performed, we ran nonabsorbable sutures through the designated holes in the tibial component to fix an attachment tube (implantcast) to the implant; the extensor mechanism was later attached to the tube, again using nonabsorbable sutures. After assemblage of the prosthesis, a trial reduction was performed. A final check was performed to assess knee motion and soft tissue tension and subsequently, the implant was locked.All patients received prophylactic intravenous cephalosporins before surgery; these were continued for 1 to 5 days. Drains were removed after a maximum of 48 hours. Based on pain, patients were mobilized under supervision of a physical therapist, usually on the first postoperative day. Antithrombotic prophylaxis was given until 6 weeks postoperatively.Patients were followed during outpatient visits at 2 and 6 weeks after discharge, after 3 and 6 months, and every 6 months thereafter. Radiographic followup consisted of conventional radiographs and additional imaging (CT/MRI) if complications or recurrence were suspected.Complications and failures were recorded and classified according to Henderson et al. , 18. AseAll data were complete. To estimate the cumulative incidence of revision for different types of failure, a competing risks model was used with patient mortality as a competing event , 30. Fai\u00ae implantation and four (four of 101 [4%]) underwent radiotherapy.Mean age at surgery was 36 years . Predominant diagnoses were osteosarcoma (n = 56 [55%]), leiomyosarcoma of bone (n = 10 [10%]), chondrosarcoma (n = 9 [9%]), giant cell tumor of bone (n = 8 [8%]), and pleomorphic undifferentiated sarcoma (n = 7 [7%]). Sixty-four patients (64 of 101 [63%]) were treated with chemotherapy (according to appropriate protocols) around the period of MUTARSEighty-nine reconstructions 81%) were distal femoral replacements and 21 (19%) were proximal tibial replacements. Eleven distal femoral replacements (11 of 89 [12%]) had a cemented femoral stem. Of 78 uncemented distal femoral replacements (78 of 89 [88%]), 42 were HA-coated (42 of 78 [54%]). All proximal tibial replacements had an uncemented tibial stem, 12 of which were HA-coated (12 of 19 [57%]) . Two patients (two of 101 [2%]) with giant cell tumors had intentional intralesional surgery. Four patients (four of 101 [5%]) had contaminated margins.Complications of soft tissue or instability (Henderson Type 1) occurred in seven reconstructions  after a median of 5 months . These complications included skin necrosis (n = 2 [two of 110 {2%}]), flexion contracture (n = 2 [two of 110 {2%}]), and patellar dislocation (n = 1 [one of 110 {1%}]). One patient underwent surgery for extensor mechanism insufficiency (n = 1 [one of 110 {1%}]). We could not identify factors associated with the occurrence of Type 1 complications. No Type 1 complication resulted in removal or revision of the prosthesis.Aseptic loosening (Henderson Type 2) occurred in 15 distal femoral replacements (15 of 89 [17%]) and two proximal tibial replacements (two of 21 [10%]) after a median of 1.2 years . Both proximal tibial replacements had loosening of the femoral component , for which cemented refixation was undertaken. Of the 15 distal femoral replacements, nine had loosening of the femoral component, three of the tibial component, and three of both components. Treatment consisted of cemented refixation (n = 6), uncemented revision of the femoral component (n = 4), cemented revision (n = 4), and a total femoral replacement (as a result of poor remnant host bone) (n = 1). With the numbers we had, for uncemented distal femoral replacements, we could not detect an association between reconstruction length and the rate of loosening  nor a difference in loosening between revision (five of 17 [29%]) and primary reconstructions (eight of 61 [13%]) . Uncemented HA-coated distal femoral replacements had a lower risk of loosening (two of 42 [5%]) than uncemented uncoated implants (11 of 36 [31%])   occurred in 15 reconstructions (15 of 110 [14%]) after a mean of 3 years . These included six complications of the locking mechanism: three fractures, two instances of wear, and one unlocking of the locking mechanism. Four occurred in PEEK-OPTIMATwo prosthetic fractures and one periprosthetic fracture resulted in revision or removal of the entire implant; others were managed either conservatively or with limited revision procedures such as fixation of the periprosthetic fracture with a small plate, relocking of the locking mechanism, or revision of the locking mechanism. In addition, undisplaced fissure fractures occurred during implantation in 11 reconstructions: nine distal femoral replacements and two proximal tibial replacements. All healed uneventfully. Replacement of the bushings was performed in nine reconstructions (nine of 110 [8%]) after a mean of 6 years .Deep infections (Henderson Type 4) occurred in 15 reconstructions (15 of 110 [14%]). According to the Henderson classification, nine infections were early (< 2 years after implantation [nine of 110 {8%}]) and six were late (six of 110 [5%]). Three early-infected implants were retained. Three late infections occurred after operative intervention for another complication; of these, two were retained.Local recurrences (Henderson Type 5) occurred in 10 patients (10 of 101 [10%]) after a mean of 2 years . All patients who developed a local recurrence had clear surgical margins during the index resection. Two patients had received radiotherapy . Treatment consisted of ablative surgery in seven patients and of a second limb-salvaging resection (without removing the implant) in two. In one patient no further treatment was undertaken as a result of a poor prognosis. Focusing on patients without prior resections, local recurrences occurred in five of 39 patients with an extraarticular resection (13%) and in four of 45 patients with an intraarticular resection (9%) (p = 0.561).With failure for mechanical reasons Types 1\u20133) as the endpoint, the cumulative incidences of implant failure at 5, 10, and 15 years were 16.9% , 20.7% , and 37.9% , respectively . In all, 55 patients (55 of 101 [55%]) required a total of 141 further surgical procedures: 78 (78 of 141 [55%]) for infection and 42 (42 of 141 [30%]) for mechanical reasons. At review, 90 patients (90 of 101 [89%]) had a MUTARS\u00ae in situ. Above-knee amputations were undertaken in seven patients , rotationplasty in two , total femoral replacement in one , and knee disarticulation in one (as a result of a periprosthetic fracture).Limb salvage was achieved in 91 patients (90%). In total, 64 of 101 patients had their original MUTARS\u00ae modular endoprostheses in the treatment of primary tumors, emphasizing on mechanical complications.Modular endoprostheses are frequently used to reconstruct skeletal and knee defects created by resecting a bone neoplasm from the distal femur or proximal tibia. However, they are associated with substantial complication rates on both the short and long term, most notably infection and aseptic loosening , 26, 27.Our study has a number of limitations. Preferably, one would report on proximal tibial and distal femoral replacements separately because they may differ in the types of complications by site. However, we were hampered by a limited number of patients and we therefore chose to report on knee arthroplasty as one group. We grouped patients who had a previous reconstruction together with those reconstructions done for a primary resection and these groups are disparate, which might have influenced our overall risk of loosening. However, we feel that the results as now presented best describe our clinical experiences with this implant system during the period under study. Moreover, as a result of the long retrospective period of our study, we were unable to obtain functional outcome scores and quality-of-life scores. We had no comparison groups so we are unable to determine if this endoprosthesis offers advantages or disadvantages compared with other prostheses or types of reconstruction.All complications of soft tissue and instability (Henderson Type 1) were managed without implant removal. Few studies specified the incidence of complications of soft tissue and instability; however, our results (6%) are comparable with those recently reported by others (7%\u20139%) . Pala etAseptic loosening (Henderson Type 2) occurred in 12% of the primary reconstructions. This is comparable with most long-term followup studies Table\u00a0. The hig\u00ae prostheses after failed allograft reconstructions. We concur with their conclusion that cemented fixation is preferred in case of poor remnant bone quality as may be the case after allograft reconstruction or loosened endoprostheses.Like most modern tumor prostheses, the implants used in our study had a rotating hinge Table\u00a0. Authors\u00ae lock has not resulted in a reduction of long-term structural complication rates. Since 2010, we routinely use the MUTARS\u00ae metal-on-metal locking mechanism because we believe this mechanism should be able to better withstand the high mechanical stresses. Our prosthetic fracture rate (3%) is comparable with the rate reported by Myers et al. (2%) [\u00ae reconstructions, all with a stem diameter of 12 mm or less. We believe that careful reaming and implantation of the largest possible stem diameter are advisable to reduce the risk of stem fractures and recommend using stems of at least 12 mm.Structural complications (Henderson Type 3) occurred in 15%. Introduction of the PEEK-OPTIMAal. 2%)  and comp%  and coal. (2%) , whereasal. (2%)  reportedInfection (Henderson Type 4) occurred in 13% and resulted in removal of the implant in 9%, which is comparable with most previous studies 6%\u201320%) [0% 2, 15\u201328, 32. Failure as a result of local recurrence (Type 5 complication) occurred in 7%. Other long-term followup studies reported comparable rates (5%\u20136%) , 26, 27.As a result of the fact that nearly all studies have used Kaplan-Meier survival analyses to compute implant survival rates, and because different classifications and definitions of failures have been used, it is difficult to adequately compare implant failure rates. Nevertheless, our long-term cumulative incidence rates of failure appear to be comparable to those reported by others , 24, 28 \u00ae  in situ at latest followup, indicating that most complications could be adequately managed.Despite needing more operative procedures for complications, we were able to achieve limb salvage in 90% of our patients. The majority of our patients had a MUTARS\u00ae modular endoprostheses represent a reliable long-term option for knee replacement after tumor resection, which seems to be comparable to other modular implants available to surgeons. The cumulative incidence of implant failure was 20.7% at 10 years with mechanical failure as the endpoint. Aseptic loosening was the most important mechanical complication. HA coating of uncemented implants may reduce the risk of loosening, and we currently use uncemented HA-coated implants believing that it is optimal for durable fixation. We conclude that MUTARS\u00ae represents a reliable system with long-term results comparable to other prostheses and types of reconstructions for tumor resections about the knee.Although no system has yet proved ideal to restore normal function and demonstrate long-term retention of the implant, MUTARS"}
+{"text": "Aspergillusfumigatus; of those treating case-patients, 21% lacked access to susceptibility testing.Of 709 physicians, 348 were familiar with azole-resistant  Aspergillus fumigatus strains have emerged in Europe and recently in the United States. Physicians specializing in infectious diseases reported observing pan\u2013azole-resistant infections and low rates of susceptibility testing, suggesting the need for wider-scale testing.Infections caused by pan\u2013azole-resistant  Aspergillus fumigatus that are resistant to all azole antifungal medications have become common in western Europe and have been documented in other regions since 1998  surveyed US infectious disease physicians to better assess the availability of A. fumigatus; 100 (14%) were aware of the possible link to agricultural or environmental antifungal products. During the previous year, 364 (51%) reported treating >1 patient who had been diagnosed with aspergillosis. Of those, 136 (38%) reported clinical failure of therapy for >1 patient, despite 290 (80%) physicians having used therapeutic drug monitoring to titrate azole therapy. Nine (2%) treating physicians reported observing azole resistance in an azole-naive patient.Of the 709 respondents, nearly half  were familiar with the concept of azole-resistant >1 of their patients had an isolate tested, and 56 (25%) reported that >50% of patients had isolates tested. Forty-one (19%) reported a patient isolate with resistance to >1 azole, and 16 (7%) reported a patient with a pan\u2013azole-resistant isolate.Overall, 224 (62%) treating physicians who responded had access to susceptibility testing; 75 (21%) lacked access; and an additional 65 (18%) were unsure of availability. Of those with access, 182 (81%) reported that testing was physician-prompted; 162 (72%) reported that testing occurred off-site rather than in their hospital. For those reporting off-site testing, 8 (4%) physicians typically received results within 1 week and 42 (19%) reported receiving results \u22653 weeks after request, excluding the minority , who were unsure. Of the 224 physicians who had access to susceptibility testing, 127 (57%) reported that 2\u00a0=\u00a06.3, p = 0.18). Other findings were generally similar across regions, including proportions reporting clinical failure, azole resistance in azole-naive patients, susceptibility testing availability, routine versus physician-prompted testing, and location of testing.Sixteen (8%) physicians practicing in the southern and 14 (9%) practicing in the western US census regions reported seeing >8 patients who had aspergillosis during the previous year, compared with 5 (3%) in the Northeast and 9 (5%) in the Midwest . Of 51 physicians in the South, 13 (26%) reported observing isolates resistant to >1 azole, compared with 9 (14%) of 63 from the Midwest, 5 (14%) of 37 from the Northeast, and 13 (19%) of 70 from the West . Pan\u2013azole-resistant isolates were reported by 4 (8%) of 51 physicians in the South, 7 (11%) of 63 in the Midwest, 2 (5%) of 37 in the Northeast and 3 (4%) of 70 in the West .Of 224 physicians with access to susceptibility testing, 8 (16%) of 51 physicians in the South reported that >50% of their patients\u2019 isolates were tested, compared with 17 (27%) of 63 in the Midwest, 8 (21%) of 37 in the Northeast, and 22 (31%) of 70 from the West (\u03c7A. fumigatus and 14% (100/709) were aware of a possible link to environmental fungicide use. Of physicians who had treated patients diagnosed with aspergillosis within the past year, 21% (75/364) lacked access to susceptibility testing and 57% (127/224) who had access tested an isolate in the previous year. A small proportion of 19% (41/224) reported observing any azole resistance and only 7% (16/224) reported pan-resistance. Of note, physicians in the southern states more commonly observed resistance to >1 azole, compared with physicians from other regions.In summary, approximately 50% (348/709) of surveyed infectious disease physicians were familiar with azole-resistant A. fumigatus is that the Clinical and Laboratory Standards Institute has not established breakpoints for azole susceptibility for A. fumigatus because inadequate clinical data exist to support breakpoints. The institute uses epidemiologic cutoff values, reflecting the minimal inhibitory concentration of 95% of wild-type isolates (Because only a small fraction of patients with invasive aspergillosis have a positive culture (A. fumigatus infections, including those with pan-azole resistance, are occurring in the United States, and that broader susceptibility testing may be warranted to guide patient care. Systematic surveillance for aspergillosis, including collection of clinical data and isolates, could aid in detecting emergence of regional resistance patterns, assessing the role that resistance plays in treatment failure, and determining locally tailored treatment options. Awareness by physicians of azole-resistant aspergillosis and the possible link to environmental fungicide use are essential.Our findings support that azole-resistant"}
+{"text": "We detected a cluster of dengue virus infections in children in Kenya during July 2014\u2013June 2015. Most cases were serotype 1, but we detected all 4 serotypes, including co-infections with 2 serotypes. Our findings implicate dengue as a cause of febrile illness in this population and highlight a need for robust arbovirus surveillance. Due to lack of national surveillance programs, the extent of infection with dengue viruses (DENV) among children is largely unknown in much of sub-Saharan Africa  and Kisumu (an urban city), both located in western Kenya. The cohort is part of a larger ongoing parent study that enrolls additional child cohorts at other study sites or with other study designs and collects vector and environmental data. Details of the parent study are beyond the scope of this report and will be described elsewhere. The study is being conducted under the supervision of the institutional review board of Stanford University  and the scientific and ethics review unit of the Kenya Medical Research Institute . For this study, we enrolled febrile children 1\u201317 years of age. At the enrollment and 1-month follow-up visits, we collected information on demographics and risk factors, performed a physical examination, and obtained blood samples. We tested the blood samples for DENV RNA by reverse transcription PCR (RT-PCR)  by RT-PCR. Of those, 82 (7.4%) were positive for DENV RNA: 58 (70%) were serotype 1 (DENV-1), 2 (2.4%) were serotype 2 (DENV-2), 13 (15.9%) were serotype 3 (DENV-3), and 2 (2.4%) were serotype 4 (DENV-4) . We alsoMost DENV cases occurred during July 2014\u2013June 2015. The likelihood of testing positive for DENV by PCR did not differ by age or sex. The median age of DENV PCR-positive participants was 3.5 years (IQR 2.0\u20135.2 years); 43.9% of participants were female. We did observe a higher likelihood of testing positive by PCR for children from the rural site, Chulaimbo (9.6%), compared with those from the urban site, Kisumu (5.8%) . Continued surveillance is needed to investigate whether DENV is endemic to these areas and if there are differences in regional endemicity.Although reports of DENV infection in Kenya remain sparse, several sero-epidemiologic studies have produced evidence of DENV transmission by demonstrating serum DENV IgG in patients of all ages (DENV viremia during acute infection is known to be transient (Improving efforts to detect DENV infections will raise awareness of DENV and increase the likelihood that healthcare providers will suspect it in patients with AFI. Correct diagnoses improve the ability of public health ministries to detect and react to outbreaks of DENV or other arboviral illnesses, rather than contributing to cycles of missed opportunities for preventive interventions."}
+{"text": "We deeply appreciate the great contributions of many physicians in the registry of esophageal cancer cases. The Comprehensive Registry of Esophageal Cancer in Japan, 2010, was published here, despite some delay. The registry complies with the Act for the Protection of Personal Information. The encryption with a HASH function is used for \u2018\u2018anonymity in an unlinkable fashion\u2019\u2019.We briefly summarized the Comprehensive Registry of Esophageal Cancer in Japan, 2010. Japanese Classification of Esophageal Cancer 10th and UICC TNM Classification 7th were used for cancer staging according to the subjected year. A total of 5878 cases were registered from 280 institutions in Japan. Tumor locations were cervical: 4.3%, upper thoracic: 12.7%, middle thoracic: 48.8%, lower thoracic: 26.5% and EG junction: 6.5%. Superficial carcinomas  were 34.9%. As for the histologic type of biopsy specimens, squamous cell carcinoma and adenocarcinoma accounted for 90.5 and 4.0%, respectively. Regarding clinical results, the 5-year survival rates of patients treated using endoscopic mucosal resection, concurrent chemoradiotherapy, or esophagectomy were 85.5, 27.3, and 55.5%, respectively. Esophagectomy was performed in 3564 cases. Concerning the approach used for esophagectomy, 30.4% of the cases were treated thoracoscopically. The operative mortality (within 30\u00a0days after surgery) was 0.61% and the hospital mortality was 4.29%.We hope that this Comprehensive Registry of Esophageal Cancer in Japan for 2010 will help to improve all aspects of the diagnosis and treatment of esophageal cancer in Japan.I.I. Clinical factors of esophageal cancer patients treated in 2010Institution-registered cases in 2010Patient backgroundTableAge and genderTablePrimary treatmentTableTumor locationTableHistologic types of biopsy specimensTableDepth of tumor invasion, cT (UICC TNM 7th)TableLymph node metastasis, cN (UICC TNM 7th)TableDistant metastasis, cM (UICC TNM 7th)TableClinical Stage (UICC TNM 7th)II.Results of endoscopically treated patients in 2010TableDetails of endoscopic treatmentTableComplications of EMR/ESDTablePathological depth of tumor invasion of EMR/ESD specimensFigureSurvival of patients treated with EMR/ESDFigureSurvival of patients treated with EMR/ESD according to the pathological depth of tumor invasion (pT)FigureSurvival of patients treated with EMR/ESD according to the lymphatic and venous invasionIII.Results in patients treated with chemotherapy and/or radiotherapy in 2010TableDose of irradiation TableDose of irradiation FigureSurvival of patients treated with chemotherapy and/or radiotherapyFigureSurvival of patients treated with definitive chemoradiotherapy according to clinical stage (UICC TNM 7th)IV.Results in patients who underwent esophagectomy in 2010TableTreatment modalities of esophagectomyTableTumor locationTableApproaches to tumor resectionTableVideo-assisted surgeryTableFields of lymph node dissection according to the location of the tumorTableReconstruction routeTableOrgans used for reconstructionTableHistological classificationTableDepth of tumor invasion, pT (JES 10th)TablePathological grading of lymph node metastasis, pN (JES 10th)TablePathological findings of lymph node metastasis, pN (UICC 7th)TablePathological findings of distant organ metastasis, pM (JES 10th)TableResidual tumorTableCauses of deathFigureSurvival of patients who underwent esophagectomyFigureSurvival of patients who underwent esophagectomy according to clinical stage (JES 10th)FigureSurvival of patients who underwent esophagectomy according to clinical stage (UICC 7th)FigureSurvival of patients who underwent esophagectomy according to the depth of tumor invasion, pT (JES 10th)FigureSurvival of patients who underwent esophagectomy according to lymph node metastasis, pN (JES 10th)FigureSurvival of patients who underwent esophagectomy according to lymph node metastasis, pN (UICC 7th)FigureSurvival of patients who underwent esophagectomy according to pathological stage (JES 10th)FigureSurvival of patients who underwent esophagectomy according to pathological stage (UICC TNM 7th)FigureSurvival of patients who underwent esophagectomy according to residual tumor (R)"}
+{"text": "The word \"Blasmacytoid\" is misspelled in the article title. The correct title is: Efficient Sensing of Infected Cells in Absence of Virus Particles by Plasmacytoid Dendritic Cells Is Blocked by the Viral Ribonuclease Erns. The correct citation is: Python S, Gerber M, Suter R, Ruggli N, Summerfield A (2013) Efficient Sensing of Infected Cells in Absence of Virus Particles by Plasmacytoid Dendritic Cells Is Blocked by the Viral Ribonuclease Erns. PLoS Pathog 9(6): e1003412. doi:10.1371/journal.ppat.10034122. In the funding statement, the word \"Immunoprophylaxis\" should instead read \"Immunology\".3. In the legend title of Figure 1, \"INF\" should instead read \"IFN\".4. In the second sentence of the legend body of Figure 4, the IRS661 was employed at 0.7 uM, instead of 1.7 uM. The legend body should instead read, \"IRS661 inhibits pDC activation by direct CSFV or VRP\u0394Erns infection (A) and by VRP-infected cells (B). In A, IRS661 was employed at 0.7 \u00b5M, and in B, at the indicated \u00b5M concentrations. In B, the IFN-\u03b1 levels of the cultures treated with IRS661 were significantly lower (p<0.05) than those receiving control (CTRL) ODN at all concentrations. The bars represent the mean values of three replicates, with error bars showing the standard deviations. The results are representative of three independent experiments.\"The below seven errors do not significantly affect the scientific understanding of the article.5. The Results subheading \"Drugs affecting cytoskeleton and membrane cholesterol prevent stimulation of pDC by infected cells.\" was incorrectly formatted, and should instead be formatted identically to the other Results subheadings.6. In the legend body of Figure 1, the last sentence should include the word \"was\" so that it instead reads, \"The purity of pDC was 2-5%.\"7. In the second sentence of the Figure 6 legend body, \"SK6\" should instead read \"SK-6\".8. In the penultimate sentence of the legend body of Figure S4, \"inoculums\" should instead read \"inocula\".9. In the last sentence of the first paragraph of the Results, \"SK6\" should instead read \"SK-6\".10. In the second paragraph of the Discussion section, in the sentence reading \"Only at this acidic location the RNAse function...\", \"RNAse\" should instead read \"RNase\".11. In the first sentence of the seventh paragraph of the Materials and Methods section, under the subheading \"Stimulation of pDC by infected cells\", \"inoculums\" should instead read \"inocula\"."}
+{"text": "SLC26A4 and GJB2 in 28 children with bilateral severe-to-profound non-syndromic hearing loss (NSHL) without familial history were analyzed using Sanger sequencing. Genetic analysis of individuals without mutations in SLC26A4 and GJB2 was performed by whole exome sequencing (WES). Bi-allelic mutations in SLC26A4 and GJB2 were identified in 12 and 3 subjects, respectively. Of the 13 individuals without mutations in SLC26A4 and GJB2, 2 and 1 carried compound heterozygous mutations in MYO15A and CDH23, respectively. Thus, 64.3% (18/28) of individuals with NSHL were determined to be genetically predisposed. Individuals with sporadic severe-to-profound NSHL were found to mostly exhibit an autosomal recessive inheritance pattern. Novel causative candidate genes for NSHL were identified by analysis of WES data of 10 families without mutations in known causative genes. Bi-allelic mutations predisposing to NSHL were identified in 64.3% of subjects with sporadic severe-to-profound NSHL. Given that several causative genes for NSHL are still unidentified, genetic inheritance of sporadic congenital hearing loss could be more common than that indicated by our results.Discriminating between inherited and non-inherited sporadic hearing loss is challenging. Here, we attempted to delineate genetic inheritance in simplex cases of severe-to-profound congenital hearing loss in Korean children. Variations in  After obtaining informed consent, individuals with hearing loss were enrolled in the Yonsei University Hearing Loss (YUHL) cohort, and their clinical and pedigree data were recorded. The experimental methods were performed in accordance with the approved guidelines. For children, written informed consent was obtained from the parents. From the YUHL cohort, 28 individuals with bilateral severe-to-profound hearing loss without familial history were selected for this study, which was conducted between January 2013 and December 2015 at the Department of Otorhinolaryngology, Severance Hospital, Seoul, Korea. The selected individuals exhibited no other syndromic features except hearing loss and were referred to the Severance Hospital for cochlear implantation. Individuals with a history of non-inherited risk factors for hearing loss, such as perinatal cytomegalovirus infection, neonatal intensive care unit treatment, and middle ear infection, were excluded.SLC26A4 were sequenced using direct Sanger sequencing. In subjects without EVA, GJB2 was sequenced using direct Sanger sequencing. The primer sequences for SLC26A4 and GJB2 are listed in SLC26A4 or GJB2 were analyzed using WES. In case of subjects with cochlear implants, audiological outcomes at 6 months post-surgery were measured in terms of auditory performance (CAP) score and age equivalence based on the sequenced language scale for infants (SELSI)21Physical examination and otoscopy were administered by an otologist. All subjects underwent evaluation for auditory brainstem response (ABR), auditory steady state response (ASSR), and oto-acoustic emission (OAE) for diagnosis of hearing impairment. Subjects who exhibited thresholds <70\u2009dB nHL for ABR were excluded. Average thresholds for ASSR were measured at frequencies of 0.5, 1, 2, and 4\u2009kHz. None of the subjects suspicious for auditory neuropathy were unresponsive in ABR evaluation and presented normal OAE findings. All participants underwent temporal bone computed tomography (TBCT) and magnetic resonance imaging for evaluation of inner ear and temporal bone anomalies. In subjects with unilateral or bilateral enlarged vestibular aqueduct (EVA), all of the exons of Whole blood (3\u2009ml) was collected from the participants and, when available, their siblings and parents for segregation analysis. Genomic DNA was extracted from peripheral leukocytes using red blood cell and cell lysis solutions and a protein precipitation solution (QIAGEN). Whole exome capture was performed using the Agilent SureSelect V5 enrichment capture kit (Agilent Technologies). The enriched library was then sequenced using the HiSeq 2500 sequencing system . Image analysis and base calling were performed with the Pipeline software (Illumina) using default parameters. Sequence reads were mapped to the human reference genome assembly (GRCh37/hg19) using the CLC Genomic Workbench (version 9.0.1) software (QIAGEN). Mapping was performed using the \u201cMap Reads to Reference\u201d function of the CLC Genomic Workbench software with the following settings: mismatch cost, 2; insertion cost, 3; deletion cost, 3; length fraction, 0.5; similarity fraction, 0.9; and map to nonspecific reads, random. Nonspecific reads were ignored for count and coverage. All variants with a minimum coverage of 2 were called using the \u201cBasic Variant Caller\u201d function of the CLC Genomic Workbench and annotated.Variant ranking and calling for disease-causing mutations was performed according to the accepted standard in molecular diagnostics23Analysis of CNV was performed using the paired-end WES data using the EXCAVATOR version 2.2SLC26A4  with sporadic severe-to-profound NSHL and without syndromic features or familial history of hearing impairment. The average thresholds for ASSR in the right and left ears were 103.0\u2009\u00b1\u200924.5\u2009dB and 97.4\u2009\u00b1\u200923.0\u2009dB, respectively. Of the 28 children, 12 exhibited EVA and/or Mondini\u2019s deformity , representing DFNB4 hearing impairment with bi-allelic mutations in SLC26A4 . Direct subjects ; one of subjects .GJB2 and SLC26A4 were further analyzed using WES. On an average, the WES datasets of each of the 13 individuals had 99.2%, 97.7%, and 92.4% of mappable bases represented by coverage of at least 1, 10, and 20 reads, respectively. The mean exome coverage was 71.6.The genetic characteristics of 13 individuals without causative mutations in http://www.ncbi.nlm.nih.gov/SNP/), exome variant server , exome aggregation consortium , and the National Biobank of Korea control databases (NBK) to evaluate the filtered variants. The remaining variants had minor allele frequencies <0.01, and were ranked based on conservation of the affected amino acid residue and the predicted pathogenicity. In addition, we investigated whether the surviving variants had minor allele frequencies <0.005 and 0.0005 for AR and AD genes, respectively; these thresholds were consistent with the minor allele frequency thresholds that Shearer et al. suggested for pathologic variants in NSHLThe 72 known NSHL-associated genes were first examined for the presence of variants 25. WholeMYO15A (YUHL8-21 and YUHL13-21) and CDH23 (YUHL24-21), in three individuals with NSHL; in two of these families, where parental DNA available, segregation was confirmed by Sanger sequencing  and DFNA5 (YUHL44-21)  . ParentaHL44-21) , indicatAs shown in PCDH15 in YUHL14-21, MYO3A in YUHL26-21, and TSPEAR in YUHL36-21  were not covered  bi-allelic variants in recessive genes, (2) hemizygous variants in X-chromosome genes in affected male subjects, and (3) de novo heterozygous variants in families in which trio analysis was possible. Variant filtering reduced the number of candidate genes to one to 13 in 10 families, as outlined in te genes . All mutMUC22  or Concerto , depending on the decision of the patients. These 25 subjects were subdivided into three groups\u2014the SLC26A4 mutation, other gene mutations , and unidentified etiology groups\u2014according to genotype, and preoperative hearing thresholds for ASSR were compared among these groups , which is comparable to that reported in the previous studyIn the present study, we comprehensively evaluated the contribution of genetic predisposition to severe-to-profound sporadic congenital hearing loss by Sanger sequencing and WES. Of the 28 included subjects, 18 (64.3%) carried pathogenic bi-allelic mutations in 1 of 72 genes known to be associated with NSHL. This diagnostic rate is exceptionally higher compared with that reported in a previous study (37%) involving sporadic NSHLSLC26A4 mutations in subjects with sporadic congenital hearing loss in the present study is higher compared that reported in previous studies. Pathogenic variants of SLC26A4 have been previously reported in approximately 10% of cases of severe-to-profound hearing loss in multi-ethnic cohorts11SLC26A4 mutation in Japanese individuals with genetically diagnosed NSHL was reported to be 7.5%, which is comparable to that reported in the two previous studiesSLC26A4 mutations regardless of familial history9SLC26A4 mutations observed in the present study. First, the present cohort only comprised individuals with congenital hearing loss, which usually results from genetic defects. Second, genetic evaluation is convincing and easily agreed to by patients in cases where TBCT findings reveal EVA, which might have resulted in patient selection. Nevertheless, the high rate of bi-allelic mutations in patients with sporadic profound hearing loss implies that sporadic congenital hearing loss is caused in a majority of cases in Korea by SLC26A4 mutations and not by GJB2 mutations. GJB2 mutations account for just 9% of the total frequency observed in this study. Therefore, Korean patients should first be evaluated for SLC26A4 mutations prior to comprehensive genetic analyses such as TES or WES. Because SLC26A4 comprises 21 exons and requires more than 20 primers for Sanger sequencing, TBCT can be more cost-effective for ruling out SLC26A4 mutations. Given that the frequency of SLC26A4 mutations in Korean patients with EVA is >90%, it is reasonable to perform TBCT for discriminating between patients with hearing loss due to SLC26A4 mutations and those with NSHL due to other AR mutationsInterestingly, the frequency of Since the genetic factors associated with hearing loss are extremely heterogeneous, and mutations in nearly 100 genes have been identified as causative factors for NSHL, next-generation sequencing approaches such as TES and WES have been employed for molecular diagnosis of NSHL. Targeted exon sequencing has been used as a cost effective method for genetic diagnosis56101112151618192032GJB2, which is the most common genetic cause of NSHL in the Middle East; in contrast, the present study involved pre-screening for both GJB2 and SLC26A4 mutations. Second, the present cohort only comprised individuals with sporadic hearing loss, whereas the previous study included multiplex cases with at least two affected members. Third, the Korean population is generally outbred, whereas the previous study included only consanguineous families, which exhibit an increased prevalence of AR disordersA previous study involving WES identified causative mutations of NSHL in 60.0% (12 of 20) of the included familiesGRP98/PDZ7)GJB2 mutations or EVA. Their reported frequency of causative mutations (45.4%) is higher compared with that observed in the present study (23.1%) despite the fact that mild-to-moderate hearing loss is less frequently diagnosed by molecular methods than severe-to-profound hearing loss. This discrepancy might be attributable to the relatively small sample sizes of both studies. In the present study, we identified two single heterozygous variants in two AR genes in three families \u2014 YUHL13-21, YUHL20-21, and YUHL44-21  Korean patients with sporadic mild-to-moderate NSHL; the authors also suggested various modes of inheritance, including digenic inheritance  that did not segregate with the affected status in the family .Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations."}
+{"text": "Phase II xenobiotic biotransformation enzymes perform detoxification of hydrophilic and often toxic Phase I products through glutathionetransferase (GST), UDP-glucuronosyltransferase (UDF), N-acetyltransferase (NAT) families and other enzymes. GST protein families metabolize a large number of electrophilic xenobiotics, by conjugating fusing them with glutathione. Arylamine-N-acetyltransferase (NAT) catalyzes the acetylation of the aromatic and heterocyclic amines.This study assesses the frequency of NAT2 and GSTP1 gene polymorphisms in 326 healthy individuals from different regions of Kazakhstan by using Real-Time PCR and direct sequencing methods.The allele frequencies were calculated for NAT2*5 (0.54) and GSTP1 (0.27). GSTP1 alleles were in the Hardy\u2013Weinberg equilibrium (p > 0.05), while NAT2*5 (p = 0.00) were not. The population differences between North, Northeast and South Kazakhstan regions were also analyzed. No statistically significant differences in the frequency of genotypes were found.Allelic polymorphisms of NAT2*5 and GSTP1 genes greatly varied indifferent populations. The Kazakh population was significantly different from the Asian, Caucasoid, African-American and Hispanic populations by NAT2*5 and GSTP1 genes. Allelic variants of the NAT2*5 had a low frequency in Asian populations. Allelic frequency in other world populations varied from 30 to 50%. The differences between Kazakh (0.54) and the world population were statistically significant (p < 0.05). The frequency of GSTP1 (rs1695) in the African American population was 42%. The frequency of GSTP1 in Asian populations varied from 11% to 23%. The frequency in Caucasoid populations was around 30%. The differences between Kazakh population (0.27) and other populations selected were statistically significant (p < 0.05).The study of mutations in GSTP1 and NAT2 genes is necessary in assessing the risk of the development of various diseases, such as cancer. Information on allelic polymorphisms might also be useful for personal perscriptions such as cyclophosphamide, cisplatin, methotrexate, isoniazid, pyrazinamide, and rifampin."}
+{"text": "Conserv Physiol (2016) 4(1): cow068; doi:10.1093/conphys/cow068The article has been updated to correct an error in one of the figures. The publisher wishes to apologize for the mistake."}
+{"text": "The pattern of pediatric stroke displays ethnic and geographical variations. There are few reports from black Sub-Saharan Africa, although relevant data are important in prevention, clinical diagnosis, treatment and prognostication.To describe subtypes, risk factors, localization, age and gender distribution of pediatric stroke in the black Kenyan population.Retrospective cross-sectional study in a single regional referral and teaching hospital.Data were analyzed by SPSS version 13.0 for Windows and presented in tables and bar and pie charts.The study was performed at the Kenyatta National Hospital, a level-6 regional referral health facility with an annual pediatric in-patient turnover of about 40,000 patients. Files of patients aged 1 month to 18 years over a period of 5 years were analyzed for stroke subtypes, localization, risk factors, age and sex distribution. Only those files with complete information were included.Thirty-two of the 712 stroke patients (4.5%) were pediatric. The male:female ratio was 1.7:1. Ischemic stroke comprised 56.3% (n = 18). Mean age was 7.7 years . The most common sites were cortical (51%), lacunar (41%) and brain stem (8%). The most common risk factors were connective tissue disorders (28.1%), heart disease (25%), human immunodeficiency virus (9.4%) and infection (9.4%).Pediatric stroke is not uncommon in the Kenyan population. The risk factor profile comprising connective tissue disorders and infection differs from that reported in other populations, inviting large community-based studies. Pediatric stroke is an important cause of mortality and morbidity.2 Its pat3This was a retrospective study performed at the Kenyatta National Hospital (KNH), a level-6 Eastern and Central African regional referral and teaching hospital in Nairobi, Kenya, with a total pediatric patient population of about 40,000 per year. Ethical approval for the study was granted by the Kenyatta National Hospital/University of Nairobi Ethics and Research Committee (KNH/UoN-ERC). Files of patients aged between 1 month and 18 years with a diagnosis of stroke, seen between January 2004 and December 2008, were retrieved from the hospital registry. Patients were categorized into male and female, and each was sex divided into five year age groups. Only files with complete data were included. Each file was analyzed for presentation, mode of diagnosis, stroke subtype, localization, risk factors and outcome. These data were analyzed using SPSS version 13.0  for Windows and presented by means of tables and bar and pie charts.Thirty-two cases of pediatric stroke out of 712 (4.5%) were retrieved in a pediatric inpatient population of about 200,000 over the study period. Twenty of these (62.5%) were males while 12 (37.5%) were females. Male predominance reduced with age such that by 16\u201318 years, females exceeded males. Mean age was 7.7 years, with the peak occurring in the 6\u201310-year age group .Ischemic and hemorrhagic strokes comprised 18 (56.3%) and 14 (43.7%), respectively. Of these, 17 (53.1%) were cortical types, distributed as eight frontoparietal, four parietal, three temporal, one occipital and one frontal. The remaining 15 cases (46.9%) were subcortical types, located in the basal ganglia (5), internal capsule (4), thalamus (4) and brain stem (2).The most common modes of presentation in younger children (below 5 years) were focal weakness (2), seizures (2), altered mental status (1) and mixed symptoms (3). In older children, it was mixed symptoms (11), hemiparesis (5), altered mental status (3) and other focal neurologic signs, such as aphasia and visual disturbance (5). Nine cases (28.1%) were diagnosed clinically while 23 (71.9%) were confirmed by computed tomography (CT) scan.The major risk/comorbid factors were connective tissue disorders (28.1%), congenital heart disease (25.0%), human immunodeficiency virus (HIV) infection (9.4%), other infections (9.4%) and sickle cell disease (6.3%). In two cases (6.3%), there were multiple comorbid conditions while in five cases (15.6%) no risk/comorbidity was determined . ThirteeThe estimated prevalence of 16 per 100,000 is higher than the 1.29\u201313.0 per 100,000 reported in other populations.[The mean age of 7.7 years observed in the present study is comparable to 7.7 years reported for an American population, but high8As in the literature reports,11 ischemThe most common cause of ischemic stroke among black children is reported to be sickle cell disease. ObservatThese studies reveal that risk factors vary between countries and ethnic groups, suggesting that environmental factors interact with genetic predisposition to determine the overall risk. This implies that there is a need for the evaluation of population-specific factors. A notable observation of the current study is the high prevalence of connective tissue disorders comparable to the Singaporean population. The connHIV was implicated in 9.4% of the cases in the present study. HIV/AIDS increases the risk of both ischemic and hemorrhagic stroke after correcting for other cardiovascular risk factors.20 This i22Observations of the current study reveal that infection was implicated in 9.4% of the cases. This appears to be commensurate with reports that infectious burden index is associated with increased risk of all strokes. In over Pediatric stroke is not uncommon in the Kenyan population. Its characteristics resemble those reported for Caucasian and Asian populations. This risk factor profile comprising connective tissue disorders and infection differ from those reported for other populations, inviting large community-based studies."}
+{"text": "Retroperitoneal lymph node dissection has been advocated for the management of post-chemotherapy (PC-RPLND) residual masses of non-seminomatous germ cell tumors of the testis (NSGCT). There remains some debate as to the clinical benefit and associated morbidity. Our objective was to report our experience with PC-RPLND in NSGCT.We have reviewed the clinical, pathologic and surgical parameters associated with PC-RPLND in a single institution. Between 1994 and 2008, three surgeons operated 73 patients with residual masses after cisplatin-based chemotherapy for a metastatic testicular cancer. Patients needed to have normal postchemotherapy serum tumor markers, no prior surgical attempts to resect retroperitoneal masses and resectable retroperitoneal tumor mass at surgery to be included in this analysisMean age was 30.4 years old. Fifty-three percent had mixed germ cell tumors. The mean size of retroperitoneal metastasis was 6.3 and 4.0 cm, before and post-chemotherapy, respectively. In 56% of patients, the surgeon was able to perform a nerve sparing procedure. The overall complication rate was 27.4% and no patient died due to surgical complications. The pathologic review showed presence of fibrosis/necrosis, teratoma and viable tumor (non-teratoma) in 27 (37.0%), 30 (41.1%) and 16 (21.9%) patients, respectively. The subgroups presenting fibrosis and large tumors were more likely to have a surgical complication and had less nerve sparing procedures.PC-RPLND is a relatively safe procedure. The presence of fibrosis and large residual masses are associated with surgical complications and non-nerve-sparing procedure. In accordance with the last report of The Public Health Agency of Canada (PHAC), the incidence of testicular cancer in Canada is rising and is the most common cancer in young men. The two main histologic subgroups occur with similar frequencies: 54% are seminoma and 41% non-seminoma germ cell tumors; 5% are other types[Testicular cancer has become the model for a curable neoplasm. In treatment of nonseminomatous germ cell testicular tumors (NSGCTT), there have been great improvements in the last 25 years. Cure rates for clinical stage I and low-volume stage II testis tumor patients approach 100%; selecting the best initial modality of treatment and integration of surgery and chemotherapy is critical to optimizing cure and minimizing morbidity. FurtherCurrently, RPLND of residual masses after cisplatin-based chemotherapy is a widely accepted procedure. There are some efforts to limit the extent of surgical resection boundaries to reduce complications. In 40-5Since it appears difficult to predict which patients require PC-RPLND for residual masses that harbor viable cancer or teratoma, there remains significant concern regarding surgical complications. We report our experience with PC-RPLND for residual disease and examine the complications as well as histologic and clinical outcomes.Between 1994 and 2008, three surgeons performed 81 RPLND for a residual mass(es) after cisplatin-based chemotherapy for clinical stages II or III testicular NSGCT. All patients were operated at the Montreal General Hospital . The inclusion criteria were: nonseminomatous tumors, normal postchemotherapy serum alpha-fetoprotein and human chorionic gonadotrophin levels and no prior surgical attempts to resect retroperitoneal tumours. Exclusion criteria were: incomplete data, inadequate follow-up and surgical treatment performed in another hospital. Patients who underwent primary RPLND or radiotherapy were also excluded. PC-RPLND consisted of a full bilateral template limited by the renal vessels, the ureters and the bifurcation of common iliac vessels. Complications were reported according to the relatively new classification of surgical complications proposed by Clavien[Of the 81 cases, 73 fulfilled the inclusion criteria. The mean age was 30.6 years ranging from 16 to 58. Only 6 patients (8.2%) had some preoperative comorbidity including sarcoidosis (1), hypertension (1), chronic renal failure (1), epilepsy (1), atrial fibrillation (1) and duodenal ulcer (1). The patient with chronic renal failure underwent a kidney transplantation before the diagnosis of testis cancer. Chryptorchidism was present in 8 (11%) patients, with two being bilateral.The primary tumor was located on the right side in 34 (46.6%) cases. The most prevalent histology of the primary tumor was mixed germ cell tumor, present in 50 cases (60.8%). Thirty-one patients (42.5%) presented some component of teratoma. Two cases showed burned-out tumours. The testis tumor characteristics are summarized in Table The mean size of retroperitoneal metastasis was 6.3 cm before chemotherapy and 4.0 cm after systemic treatment p < 0.001). The most common sites of retroperitoneal metastasis was paraortic  for 2 to 4 cycles in 57 patients (78.1%). EP (etoposide and cisplatin), VIP  or a combination of regimens were used in 3 (4.1%), 4 (5.5%) and 9 (12.3%), respectively. Additional treatments to normalize the markers were necessary in 7 cases (9.6%) and two patients were submitted to bone marrow transplantation to rescue high dose chemotherapy treatment. The characteristics of post-chemotherapy retroperitoneal disease are described in Table The surgical approach was abdominal in 70 (95.9%) cases and thoracoabdominal in 3 cases. A complete bilateral retroperitoneal dissection was performed in 67 (92.0%) patients. In six (8.0%) patients, right or left unilateral modified template was performed. The surgeon classified the resection as complete or incomplete based on surgical findings. In 8 (10.9%) cases the surgeon's opinion was that an incomplete resection was done. Of these cases, in only 1 (1.4%) viable tumor was identified and the follow-up did not show local disease recurrence. An organ resection was necessary in 18 (24.6%) patients, most often a vascular resection (8 cases) or nephrectomy (5 cases). Vascular resections were composed of aorta replacement in 2 cases, vena cava replacement in 2 cases, iliac artery partial resection in 2 cases, aorta and superior mesenteric artery in 1 case and simultaneous aorta and vena cava replacement in 1 case. The characteristics of surgical procedures are demonstrated in Table The most common surgical complications observed were lymphatic leak or lymphocele (10.9%), requiring treatment with percutaneous drainage in 4.1%. Surgical complications are reported in Table The histology from RPLND specimens demonstrated fibrosis or necrosis in 27 (37.0%), teratoma in 30 (41.1%) and viable carcinoma in 16 (21.9%) cases. Among these 16 cases which presented viable cancer, 4 (25%) had metastasis beyond retroperitoneal, 7 (43.8%) showed retroperitoneal masses larger than 5 cm, 8 (50%) presented initial clinical stage IIC or III and 6 (37.5%) required re-induction chemotherapy. However, only 2 (2.7%) of these 16 patients presented high risk disease according to IGCTC at initial assessment. After PC-RPLND, 7 out of 16 patients with viable cancer received additional chemotherapy (adjuvant).With respect to predictors of surgical complications, we observed a correlation between the presence of fibrosis with non-nerve sparing surgeries and surgical complications (p < 0.05) Figure /2b. In oThe residual tumor size also correlated with complications. The mean size of retroperitoneal disease was 3.2 cm and 2.3 cm, with or without complications, respectively (p = 0.03) Figure .After PC-RPLND there were 7 (9.6%) patients with disease recurrence, with only 2 (2.7%) within the previously dissected field; one after a complete bilateral dissection and another one after a right modified dissection. The first patient died due to disseminated neoplasia and the second one remains alive with active disease. Among the 7 patients with recurrences , the retroperitoneal pathology was: teratoma (3 cases), embryonal carcinoma (1 case), seminoma, (1 case), adenocarcinoma (1 case) and fibrosis (1 case).The estimated 5-year overall survival rate after PC-RPLND was 91.2%. The estimated 5-year disease free survival rate was 89.4% Figure . Median Resection of residual tumor after complete serological remission due to first and/or second line chemotherapy in patients with metastatic germ cell tumors is an established staging and therapeutic procedure. HoweverDefining the patients who actually would benefit the most from this complex surgery is one of the most important issues in the management of this disease. At the moment, there are no reliable methods to select patients with post-chemotherapy residual masses who could be observed without resection ,11. ImagPC-RPLND remains a challenging surgical procedure, especially when large metastases become a fibrotic and adherent to adjacent organs or vital structures. In tertThe concept of reducing the extent of surgery when fibrosis is detected intra-operatively is appealing. One could consider partial resections or limited templates when only fibrosis is suspected. Actually, this approach was specifically addressed and the Although intuitively, many believed that severe fibrosis may be linked with complications, our analysis appears to confirm this correlation. Furthermore, although nerve-sparing procedures are feasible in the post-chemotherapy setting, in our The rational to perform a lymph node dissection in this group of patients is the fact that a significant number of patients will harbor viable teratoma or cancer,15. AlthSeveral authors have been emphasizing the relationship between surgical volume and outcomes. ConsideFinally, we report post-operative complications according to the novel Clavien classification and, as Post-chemotherapy retroperitoneal lymph node dissection is a relatively safe procedure. There remains a significant proportion of patients with teratoma or viable cancer after systemic treatment, justifying surgical resection. The presence of fibrosis and large residual masses is associated with surgical complications and to a non-nerve sparing procedure. There does not appear to be reliable predictors of post-chemotherapy histology of residual masses indicating the continued need for surgical resection in specialized centres.PC-RPLND: Post Chemotherapy Retroperitoneal Lymph Node Dissection; NSGCT: Non-Seminomatous Germ Cell Tumors of the Testis; PHAC : Public Health Agency of Canada; BEP: Bleomycin; Etoposide and Cisplatin; EP: Etoposide and Cisplatin; VIP: Vinblastin; Ifosfamide and Cisplatin; IGCTC: International Germ Cell Consensus ClassificationThe authors declare that they have no competing interests.MAL, AK and SA gathered and compiled data. FB served as pathologist and performed staining and interpretation of slides. AA first conceived of the study and provided valuable input on data evaluation. MAL performed statistical analysis and wrote the manuscript. ST and WK were directly responsible for patient care and data collection. All authors read and approved the final manuscript."}
+{"text": "We analysed the expression of activated (phosphorylated) Akt and MAPK in 98 cases of paired primary colorectal tumours and metastases with the aim to define better the epidermal growth factor receptor (EGFR)-related molecular profile of colorectal cancer as a tool for treatment selection. Among 47 (48%) EGFR-negative primary tumours, 35 cases (74%) were positive for phosphorylated Akt and MAPK. Among 51 (52%) EGFR-positive primary colorectal cancers, 13 (25%) cases were negative for phosphorylated Akt and 15 (29%) were negative for phosphorylated MAPK. In EGFR-negative metastases , phosphorylated Akt was expressed in 41 (73%) and phosphorylated MAPK was expressed in 36 (64%) samples, whereas in EGFR-positive metastases, phosphorylated Akt and MAPK were negative in 14 (31%) and in 10 (22%) cases, respectively. Phosphorylated Akt expression in primary colorectal tumours changed from positive to negative in 16 (16%) paired metastases and from negative to positive in 13 (13%) related metastatic sites. Phosphorylated MAPK expression in primary tumours changed from positive to negative in 13 (13%) paired metastases and from negative to positive in 12 (12%) related metastatic sites. Our findings suggest that phosphorylated Akt and MAPK status in primary tumours does not correlate with Akt and MAPK status in corresponding metastases. EGFR downstream signalling pathway can be overactivated even in the absence of EGFR expression in a considerable proportion of patients. The epidermal growth factor receptor (EGFR) is a tyrosine kinase protein, which plays an important role both in the signal transduction pathway and cellular function .\u03b1 (TGF-\u03b1) to the EGFR, results in the dimerisation of the receptor with the subsequent initiation of the intracellular signalling pathways cascade. A major downstream signalling route is via the Ras-Raf-MAPK. Activation of Ras initiates a multistep phosphorylation cascade that leads to the activation of MAPKs, ERK1 and ERK2, which ultimately regulate transcription of molecules involved in cell proliferation  and transforming growth factor feration . Anotherferation .in vivo\u2019 are still to be investigated fully.The demonstration that EGFR results abnormally expressed or upregulated in 50\u201380% of all cases of advanced colorectal tumours  could be responsible for EGFR aberrant activity even in the absence of a detectable EGFR expression  neutral buffered formalin.The expression of phospho-Akt (Ser437), p44/42 MAP kinase  and EGFR  was evaluated with an immunohistochemistry technique on 5-The sections were deparaffinised and hydrated by passing through xylene and a graded series of ethanol, followed by washing in distilled water.M citrate buffer, pH 6.0. After antigens retrieval, tissues were blocked with 5% normal goat serum for 60\u2009min.The antigens were unmasked for phospho-Akt (Ser437) by heat treatment at 98\u00b0C for 10\u2009min, in EDTA buffer and for p44/42 MAP kinase by microwave treatment at 98\u00b0C for 10\u2009min, in a 10\u2009mSubsequently, the sections were incubated either with phospho-Akt (Ser437) antibody (1\u2009:\u200950 dilution) or MAP kinase antibody (1\u2009:\u2009100 dilution) overnight at 4\u00b0C.Consecutively, immunostaining was performed by the avidin\u2013biotin peroxidase complex technique  for 30\u2009min according to the manufacturer's instructions and using 3\u2032,3\u2032 diaminobenzidine  as a chromogen. Subsequently, the slides were counterstained with Meyer's haematoxylin for 1\u2009min, dehydrated in a graded series of alcohol, treated with xylene and cover slipped.Positive control of phospho-Akt (Ser437) and p44/42 MAP kinase staining was performed on paraffin-embedded human breast cancer in all runs. (Data Sheet of phospho-Akt (Ser437) and p44/42 MAP kinase antibodies, Cell-Signalling Technology.)Negative control for the validation of the phospho-Akt (Ser437), p44/42 MAP kinase assay consisted of sections incubated with secondary antibody alone without primary antibody in all runs. (Data Sheet of phospho-Akt (Ser437) and p44/42 MAP kinase antibodies; Cell Signaling Technology.)All slides were evaluated independently by two pathologists (IB and AM).Epidermal growth factor receptor expression was detected as membranous or cytoplasmic brown staining of neoplastic cells with various intensity. Positivity for EGFR expression was defined as any membrane staining above background level, whether or not completely circumferential. In each case, two stained sections of the tumours were quantified by light microscopy, and a score (range 0\u2013100) expressing the percentage of positive neoplastic cells was obtained.Both the primary and metastatic neoplasm were considered positive when more than 1% of the tumour cells had membranous-complete or -incomplete staining; the neoplasms that showed a specific membrane staining lower than 1% of neoplastic cells were defined negative.The cytoplasmic staining, resulting from either internalised or nascent receptor molecules, without associated membrane staining was reported as negative.1+ weak intensity: faint brown membranous staining;2+ moderate intensity: brown membranous staining of intermediate darkness producing a complete or incomplete circular outline of the neoplastic cell;3+ strong intensity: dark brown or black membranous staining producing a thick outline, complete or incomplete of the neoplastic cell.The intensity of EGFR reactivity was scored using a three-tier system:The percentage of the cells for each intensity staining  was obtained when the intensity EGFR stain was heterogeneous (Phospho-Akt expression was detected as cytoplasmic and nuclear staining of neoplastic cells with various intensity. The intensity of phospho-Akt (Ser473) reactivity was scored using a four-tier system: 0, no staining; 1, weak; 2, moderate; and 3, strong.Positivity for expression of phospho-Akt (Ser473) was defined as cytoplasmatic staining, with score 2 and/or 3; negativity with score 0 and/or 1. Both the primary and metastatic neoplasm were considered positive when more than 1% of the tumour cells had score 2 and/or 3  men and 37 (38%) women, median age at diagnosis was 63 (range 32\u201386) years. Seventy-four (75%) patients had colon and 24 (25%) had rectal cancer. Colorectal adenocarcinoma was the most common histological type as it was observed in 92 (94%) pathological samples from primary tumours; the remaining six (6%) cases were mucinous adenocarcinomas. Histology grades 1\u20132 and 3 were described in 83 (85%) and 15 (15%) tumours, respectively. In 95 cases of primary neoplasm, only a single metastatic site (97%) was available for analysis, three cases had both pulmonary and hepatic metastases (3%) .Globally, pathologic samples from 101 metastatic sites were analysed: 84 (83%), liver metastases; 12 (12%), lung metastases; 4 (4%), brain and 1 (1%) bone metastases .All metastatic samples were obtained from metastasectomies except for the only bone metastasis, which was a biopsy. Liver metastases were synchronous in 42 cases and metachronous in the remaining 41 cases. Seven lung metastases were synchronous, whereas the remaining five were metachronous as they were all brain lesions (four cases). Therefore, globally in 49 cases (50%), the metastatic site analysed was synchronous. The median time elapsed between resection of the primary and corresponding metastatic site was 9 months.In 38 cases (39%), surgical resection of metastases (and consequently specimens collection) was performed after the administration of chemotherapy.Epidermal growth factor receptor expression was positive in 51 (52%) primary tumours and 45 (45%) metastatic sites .In primary tumours phosphorylated Akt and MAPK were positive in 73 (74%) and 71 (70%) cases, respectively, whereas phosphorylated Akt and MAPK were positive in 72 (73%) and 71 (70%) metastatic sites, respectively .Among 47 (48%) EGFR-negative primary tumours, 35 cases (74%) expressed phosphorylated Akt and MAPK . On the Similar to these findings, also in EGFR-negative metastases , phosphorylated Akt was expressed in 41 (73%) and MAPK was expressed in 36 (64%) samples, whereas in EGFR-positive metastases phosphorylated Akt was negative in 14 (31%) cases and MAPK was negative in 10 (22%) cases .Phosphorylated Akt expression in primary colorectal tumours changed from positive to negative in 16 (16%) paired metastases and from negative to positive in 13 (13%) related metastatic sites. Mitogen-activated protein kinase expression in primary tumours changed from positive to negative in 13 (13%) paired metastases and from negative to positive in 12 (12%) related metastatic sites  Figure . InteresAmong the group of patients receiving chemotherapy before resection of metastases, we observed a shift in phosphorylated Akt and MAPK expression in six and four cases, respectively.The introduction of a novel class of targeted antineoplastic agents, such as those directed against the EGFR, have notably expanded the available therapeutic options for patients with advanced colorectal cancer .Unfortunately, available clinical data generally failed to demonstrate a correlation between the level of expression of the target (EGFR in this case) and the global outcome of patients treated, thus making the need for a reliable predictive factor for pretreatment selection of patients as potential candidates to EGFR-targeted therapies even more relevant , metastases were metachronous seems also to suggest the hypothesis that changes in phosphorylated Akt and MAPK expression could have occurred over time with progression of disease. Among patients receiving chemotherapy before specimens collection , it is important to note that phosphorylated Akt and MAPK variation might be hypothetically related to a \u2018selective\u2019 effect of the treatment. Nevertheless, the number of cases observed (six cases for Akt and four cases for MAPK variation) does not seem to confirm this assumption.As EGFR-targeted treatment strategies are employed to treat metastatic disease on the basis of our data, only the EGFR-downstream signalling pathway status in metastases would be relevant. Nevertheless, only a prospective trial including biological assessment of these parameters on metastases could definitely establish whether this could be considered effective in the clinical practice.Taken together, we believe that our observations could bring further insights into the biology of EGFR-expressing colorectal tumours and along with growing clinical data could help clinicians in the future to select better the appropriate anti-EGFR treatment option for the appropriate patient."}
+{"text": "Forty endoscopically proven active variceal bleeds were entered in a prospective trial comparingoesophageal tamponade with SMS 201-995 infusion.\t\tp = 0.15). No significant differences between the groups were seen in time to control ofbleeding, amount of blood transfused or number of patients crossed over to the opposite treatment.Complications in the oesophageal tamponade group were discomfort due to the tube (17 patients) andchest infection (10 patients), while in the SMS 201-995 group 7 chest infections and one episode ofhyperglycaemia occurred, with no symptomatic complaints. The patient survived the admission in 15 ofthe oesophageal tamponade bleeds and all of the SMS 201-995 bleeds (p = 0.047).Oesophageal tamponade controlled 19 of 20 bleeds over the first four hours and 14 of 18 bleeds over48 hours. SMS 201-995 infusion controlled 18 of 20 bleeds over the first four hours and 10 of 20 bleedsover 48 hours (\t\tAn intravenous infusion of SMS 201-995 appears to have comparable efficacy to oesophagealtamponade in variceal bleeding."}
+{"text": "Eleven (1.8%) of 597 patients underwent ophthalmic surgery within 1 month before the onset of prion disease or after the onset. All ophthalmologists reused surgical instruments that had been incompletely sterilized to eliminate infectious prion protein. Ophthalmologists should be aware of prion diseases as a possible cause of visual symptoms and use disposable instruments whenever possible. Visual impairment occurs in 10% to 20% of patients with sporadic Creutzfeldt-Jakob disease (sCJD) during an early stage of the disease (Heidenhain variant) (Sc) was identified in the retina and optic nerve in patients with variant CJD (vCJD) and sCJD  with sCJD; 78 (13.1%) with inherited prion diseases; 48 (8.0%) with infectious prion diseases, including 47 cases of dCJD; and 1 patient with vCJD and 3 patients with unclassified CJD.Thirty-seven patients (6.2%) had a history of ophthalmic surgery at some time in their lives. Among them, 11 patients (1.8%) underwent ophthalmic surgery within 1 month before the obvious onset of prion disease or after the onset. Except for 1 patient with Gerstmann-Str\u00e4ussler-Scheinker disease, all of these patients had sCJD. There have been no reports of the development of prion diseases in patients who underwent ophthalmic surgery after the ophthalmic surgery of patients with prion diseases.Sc  in a report from the United Kingdom (Sc, although the WHO infection control guidelines for prion diseases (Currently, cataract surgery is recommended to improve physical or cognitive function in elderly patients ("}
+{"text": "This retrospective study evaluates the types and incidences of sexual disturbances and fertility distress in patients cured from testicular cancer and examines whether there is an effect resulting from different treatment modalities. A self-reported questionnaire was sent to 124 randomly selected patients who were treated at Hanover University Medical School between 1970 and 1993. Ninety-eight patients were included in the study, representing a response rate of 78%. All patients had been in complete remission (CR) for at least 24 months. The median age at diagnosis was 28 years (range 17\u201344). The median follow-up at the time of study was 12.0 years (range 2.8\u201325.6). Twenty patients (20%) had been treated for seminomatous and 78 patients (80%) for non-seminomatous germ cell tumours. Treatment included surveillance (7%), primary retroperitoneal lymph node dissection (RPLND) (13%), chemotherapy (CT) (33%), CT + secondary resection of residual retroperitoneal tumour mass (SRRTM) (43%) and infradiaphragmatic radiotherapy (4%). Patients receiving two treatment modalities (CT+SRRTM) reported more frequent an unfulfilled wish for children. Inability of ejaculation was clearly associated with RPLND and SRRTM. Subjective aspects of sexuality, like loss of sexual drive and reduced erectile potential, occurred only in a minority of patients after treatment. No abnormalities were observed concerning the course of pregnancies of partners. In conclusion, sexual dysfunction and infertility are common long-lasting sequelae in testicular cancer survivors affecting approximately 20% of patients. The relative risk for infertility appeared to be elevated for patients treated with the combination of CT+SRRTM. Twenty-one of 40 patients were able to fulfil their wish for children, and no congenital abnormalities were observed in these children. \u00a9 1999 Cancer Research Campaign"}
+{"text": "To the Editor: Chikungunya virus (CHIKV) infection is a self-limiting illness characterized by fever, headache, weakness, rash, and arthralgia. Some patients have prolonged weakness or arthralgia lasting several months. In 2006, several Indian Ocean states and India had an outbreak of CHIKV infection . Nine patients (53%) were men. Median age was 43 years (range 31\u201366 years). Several reasons for travel were reported: tourism (64.6%), visits to relatives or friends (11.8%), business (11.8%), and missionary work (5.9%). One patient was a resident in the disease-epidemic area. The median exposure time in the CHIKV-endemic area for the 15 travelers was 15 days (range 9\u201393 days) (missionary and resident patients were excluded). The median delay before being seen at a clinic after return was 2 days (range 0\u201373 days). Only 7 patients (41.2%) were hospitalized. The remainder were outpatients.All patients had fever; arthralgia , weakness , headache , diarrhea , and gum bleeding and epistaxis  were other reported symptoms. The median duration of fever was 5 days (range 2\u201312 days). Only 7 of 16 patients (43.8%) were still febrile when first seen. Physical examination showed diffuse macular erythematous rash in 13 patients (76.5%), a similar rate to that reported among French travelers  was present in 4 patients (33.3%) and thrombocytopenia  in 1 patient (8.3%). This finding may help distinguish CHIKV infection from dengue fever (<12 g/dL) was found in only 1 patient (8.3%). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) determination were available for 12 patients. ALT and AST levels were elevated (>40 IU/L) in 5 (41.7%) and 2 (16.7%) patients, respectively. Seven (46.7%) of 15 patients fully recovered within 1 month; 8 patients (53.3%) reported persistent arthralgia.Twelve acute-phase patients were admitted to the hospital for blood testing within 3 days of the initial examination. In contrast with results of other studies, leukopenia and thrombocytopenia were uncommon in our study. Leukopenia  is difficult, but these are comparatively rare. In contrast, dengue and CHIKV epidemics may overlap, and potential patients should be screened for both.Because the GISPI network provides regional coverage only, the number of imported CHIKV cases in all of Italy in 2006 was likely higher. Moreover, most patients probably did not seek medical care, and when they did, physicians may have failed to recognize the disease because of lack of familiarity with it or limited diagnostic facilities. Differential diagnosis with other arthropodborne viruses of the A. albopictus was first recorded in 1990; it has since quickly spread across the country. Scattered foci are now reported in almost all regions, mainly along the coastal plains, from the sea to the inlands, up to an altitude of \u2248500\u2013600 m (The potential risk for introduction and establishment of CHIKV reservoirs in areas with mosquito vectors was discussed in March 2006 by a multidisciplinary European expert panel (A. albopictus to colonize new areas and its adaptability to the mild Italian climate allow vector populations to be active throughout the year (The ability of Although the same mosquito is a potential vector of dengue, no autochthonous case has been reported as yet, despite annual reports of many imported dengue cases in Italy. On the other hand, the clinical manifestations of both conditions are nonspecific, and a hypothetical autochthonous case would most likely go undiagnosed unless a targeted surveillance system were established. Prompt reporting of imported CHIKV infections is essential for monitoring of potential risk. The possibility of introducing CHIKV into Italy cannot be ruled out on the basis of current evidence."}
+{"text": "Inmice exposed to the standard diet and without Cytreatment (group 1) the insulitis scores increasedslowly until day 11 and then declined slightly at day14 whereas mice exposed to the same diet but givenCy at day 95, showed a sharp decline at day 4followed by a rapid increase between day 7\u201314.However, in mice given either nicotinamide, Prosobeeor both, the insulitis scores at most time-pointswere generally lower than in Cy-teated animals onthe standard diet. In the latter group, CD4 and CD8cells and macrophages were also higher at day 11than all other 4 groups . The number of iNOSlabelled cells increased progressively in mice onthe standard diet and given Cy and were significantlyhigher at days 4, 7 and 11 than in the 3 dietarygroups. Thus, oral nicotinamide or Prosobee, eitheralone or together, prevents Cy induced diabetes inthe NOD mouse. The protective diets suppress Cyinducedintra-islet immune cell influx and iNOSexpression.Spontaneous diabetes in the NOD mouse can beprevented by nicotinamide or by an infant formuladiet in which the protein source is replaced withcasein hydrolysate (Pregestimil) or soy protein(Prosobee). NOD mice maintained on the standarddiet (chow and water) and given cyclophosphamide(Cy) at day 95 develop accelerated and synchroniseddiabetes within 14 days. Here, we compared theability of oral nicotinamide or Prosobee, either givenalone or concurrently, from weaning, in preventingdiabetes in the Cy model. The resulting insulitis andthe expression of intra-islet inducible nitric oxidesynthase (iNOS) were examined at days 0, 4, 7, 11and 14 following Cy administration. Intra-islet CD4and CD8 cells and macrophages were also enumeratedat day 11. In mice given the standard diet andinjected with Cy at day 95 (group 5), diabetesdeveloped in 7/11 mice, 14 days later. Mice exposedto oral nicotinamide (group 2), Prosobee (group 3) orboth (group 4), did not develop the disease duringthis period and until a further 30 days ("}
+{"text": "CYFRA 21-1 assay, measuring cytokeratin 19 fragments, was compared with carcinoembryonic antigen (CEA) assay, as an addition to cytological analysis for the diagnosis of malignant effusions. Both markers were determined with commercial enzyme immunoassays in pleural fluid from 196 patients. Cytological analysis and/or pleural biopsy confirmed the malignant origin of the effusion in 99 patients . Effusions were confirmed as benign in 97 patients . Both markers were significantly higher in malignant than in benign effusions. All the patients with non-epithelial malignancies presented CYFRA and CEA values lower than the 95% diagnostic specificity thresholds (100 and 6 ng ml(-1) respectively). The diagnostic sensitivity in the group of carcinomas and mesotheliomas was similar for CYFRA (58.8%) and CEA (64.7%). However, CEA had a significantly higher sensitivity in carcinomas (72.4% vs 55.3%), while CYFRA had a clearly higher sensitivity in mesotheliomas (89.9% vs 0%). Interestingly, 12 out of the 16 malignant effusions with a negative cytology were CEA and/or CYFRA positive. Regarding their high diagnostic sensitivity and their complementarity, CEA and CYFRA appear to be very useful for the diagnosis of malignant pleural effusions when cytology is negative."}
+{"text": "From 1996 to 1999, the incidence of gastroenteritis in general practices and the role of a broad range of pathogens in the Netherlands were studied. All patients with gastroenteritis who had visited a general practitioner were reported. All patients who had visited a general practitioner for gastroenteritis (cases) and an equal number of patients visiting for nongastrointestinal symptoms (controls) were invited to participate in a case-control study. The incidence of gastroenteritis was 79.7 per 10,000 person years. Campylobacter was detected most frequently (10% of cases), followed by Giardia lamblia (5%), rotavirus (5%), Norwalk-like viruses (5%) and Salmonella (4%). Our study found that in the Netherlands (population 15.6 million), an estimated 128,000 persons each year consult their general practitioner for gastroenteritis, slightly less than in a comparable study in 1992 to 1993. A pathogen could be detected in almost 40% of patients ."}
+{"text": "Two and four treatments of 5 mmol kg-1 of buthionine sulfoximine (BSO) at an interval of 12 h depleted the glutathione (GSH) content in NFSa tumours of C3H/He mice, respectively, to 24.0 and 1.78 percent of the untreated controls. BSO pre-treatments every 12 h enhanced the cytotoxicity of cyclophosphamide (CYC) towards artificial lung micrometastases of NFSa tumours giving enhancement ratios (ERs) ranging from 1.75 to 1.83 and from 2.41 to 2.73, for two and four BSO pretreatments respectively. Large ERs were obtained at low CYC doses . Four BSO pre-treatments at an interval of 12 h did not increase the cytotoxicity of CYC to bone marrow stem cells. Our results suggest a clinical applicability of the combination of BSO and CYC."}
+{"text": "Complicated diverticular disease of the colon imposes a serious risk to patient's life, challenge to surgeons and has cost implications for health authority. The aim of this study is to evaluate the management outcome of complicated colonic diverticular disease in a district hospital and to explore the current strategies of treatment.This is a retrospective study of all patients who were admitted to the surgical ward between May 2002 and November 2006 with a diagnosis of complicated diverticular disease. A proforma of patients' details, admission date, ITU admission, management outcomes and the follow up were recorded from the patients case notes and analyzed. The mean follow-up was 34 months (range 6\u201360 months)The mean age of patients was 72.7 years (range 39\u201387 years). Thirty-one men (28.18 %) and Seventy-nine women (71.81%) were included in this study. Male: female ratio was 1:2.5.Sixty-eight percent of patients had one or more co-morbidities. Forty-one patients (37.27%) had two or more episodes of diverticulitis while 41.8% of them had no history of diverticular disease.Eighty-six percent of patients presented with acute abdominal pain while bleeding per rectum was the main presentation in 14%. Constipation and erratic bowel habit were the commonest chronic symptoms in patients with history of diverticular disease. Generalized tenderness was reported in 64.28% while 35.71% have left iliac fossa tenderness. Leukocytosis was reported in 58 patients (52.72%).The mean time from the admission until the start of operative intervention was 20.57 hours (range 4\u201396 hours). Perforation was confirmed in 59.52%. Mortality was 10.90%. Another 4 (3.63%) died during follow up for other reasons.Complicated diverticular disease carries significant morbidity and mortality. These influenced by patient-related factors. Because of high mortality and morbidities, we suggest the need to target a specific group of patients for prophylactic resection. Complicated diverticular disease is defined as diverticulitis with associated abscess, phlegmon, fistula, stricture or obstruction, bleeding, or perforation -3. HinchMany studies reported variable rates of mortality and morbidities for patients presented with complicated diverticulitis. The morbidity could reach 44%  while thBecause of the high rates of morbidities and mortality, some authors advise prophylactic resection of the affected colonic segment depending on the outcomes and follow-up of people who had recurrent episodes of diverticulitis -12The aim of this study is to evaluate the outcomes of management of complicated diverticular disease of the colon in a district NHS hospital and to explore the current strategies of its treatment.This is a retrospective study of 110 patients who have been admitted to the surgical ward of Princess royal university hospital/Kent between May 2002 and November 2006 with diagnosis of complicated diverticular disease. The spectrum of clinical picture was ranged from stage 1\u20134 according to Hinchey's classification.A proforma of patients' details, mode of presentation, clinical findings, radiographic and laboratory findings, preoperative co-morbidities, type of complicated diverticulitis, operative intervention, morbidity, mortality, length of stay, operative or conservative management outcomes, intensive care admission and the follow up were recorded from the patients' case notes.The exclusion criteria included patients who diagnosed with other bowel pathologies such as cancer, inflammatory bowel disease and mechanical obstruction due to other causes.The diagnosis of the stage of complicated diverticulitis (Hinchey's classification) depended on the history, examination, laboratory findings, imaging (ultrasound &CT scan) and colonoscopy.P < 0.05).The outcomes were specified using statistical analysis. The statistical significance was considered at (The mean age of the patients was 72.76 years (range 39\u201387 years). Thirty-one men (28.18 %) and seventy-nine women (71.81%). Male: female ratio was 1:2.5.Forty-one (37.27%) patients had one or more episodes of diverticulitis.About 20.90% of patients had one episode of diverticular disease. Forty-one patients (37.27%) had two or more episodes of diverticulitis while 41.8% of patients had no history of diverticular disease.Sixty-seven patients (60.90%) had one or more co-morbidities. Cardiovascular disease is the commonest co-morbidity (62 patients-56.36 %). Eight diabetic patients (7.27%), 28 (25.45%) patients with connective tissue and vascular disease and twelve patients (10.90%) had different co-morbidities.Phlegmon was the commonest presentation  followed by perforation , bleeding, stricture and fistula  while left iliac fossa tenderness was reported in 38 patients (34.54 %). Leukocytosis was reported in 58 patients (52.72%). Sigmoid colon was the commonest site for complicated diverticultis in 91%. Other sites in order of frequency were descending colon, transverse colon, ascending colon and the ceacum.The mean waiting time from the admission until the start of operative intervention was 20.57 hours (range 4\u201396 hours). Operative intervention was reported in 57 (51.81%) patients. Hartman's procedure was performed in 32 (56.14%), sigmoid colectomy and ileostomy in 15(26.30%) and proximal colostomy in 5 (8.77%) patients.Segmental resection and division of the fistula was performed for 5 (8.77%) patients while percutaneous drainage was performed in 10(9.09%) patients with pericolic abscesses. Seven (6.36%) patients who were presented primarily with phlegmon and bleeding underwent laparotomy because they were progressed to a worse stage during hospitalization while one of them developed perforation following colonoscopy.Fifty-three (48.18%) Patients were treated by intravenous fluids, analgesia, blood and antibiotics and showed an excellent response.Four (7.01%) patients were admitted to ICU before operation while 25(43.85%) patients were admitted postoperatively. The mean ICU length of stay was 7.36 days (range 1\u201328 days)Perforated diverticular disease was confirmed microscopically in 15(44.11%) out of 34 patients underwent emergency surgery for perforated diverticular disease. The length of the resected colon ranged from 8\u201393 cm with average of 17.59 cm. Diverticular disease was confirmed in all resected specimens.Fifty-four postoperative complications were reported with overall morbidity of 49.09%. Respiratory complications (22.22%) was the commonest morbidity followed by cardiac 16.66%) and wound complications (14.81%). patients with perforation died . Another 4 (3.63%) patients died during follow up because of other reasons.Twenty-three 20.90%) patients had a history of one episode of diverticular disease while forty-one (37.27%) patients had two or more episodes. Fifty-seven (41.81%) patients reported with complicated diverticulitis as their first presentation. (See figure 0.90% patp < 0.05)The mean hospital stay was 16.40 days (range 2\u201361 days). Long stay was associated with perforated diverticulitis and postoperative morbidity.. This was less than other series, which reported a higher morbidity rate . Non-surThe association between high morbidity and perforated diverticultis was confirmed in our study however, no significant association between morbidity and other forms of complicated diverticulitis was found.P value = 0.00) was also confirmed in other studies [Only 21% of perforated diverticulitis had a previous history of diverticular disease while 58.2% of other less severe forms such as phlegmon, bleeding and localized pericolic abscess had such positive history. This statistically significant association , cardiovascular, respiratory problems and immune suppression. Perforation and pericolic abscess were also risk factors for mortality.These parameters and their effects, which have been confirmed in literatures, should be taken in consideration during management of complicated diverticular disease -47.The risk factors for perioperative mortality in our series included the age (about 75% of patients were above 80 year), female patients , cardiovascular disease (75%), Renal and respiratory disease (25%), Immune suppression and diabetes (16% and 08% respectively) , and associated co-morbidities.Our study has defined important risk factors for mortality, and therefore we are advising a more radical approach for management of this disease. However, further larger study is suggested to confirm our conclusions.Complicated diverticulitis carries a significant mortality and morbidity. Identification of high-risk patients to develop complications is important to reduce mortality and morbidity. Preoperative co-morbidities are the major influencing factor for peri-operative mortality and morbidity. Emergency Hartman's operation is the procedure of choice to treat majority of perforated diverticulitis. Prophylactic segmental colonic resection may be suggested for selected group of patients.The author(s) declare that they have no competing interests.A Hussain wrote the article, participated in the sequence alignment and drafted the manuscript. G Subhas carried out the data collection. H Mahmood participated in the sequence alignment, the design of the study and performed the statistical analysis. S El-hsani conceived of the study, and participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript."}
+{"text": "The epidemiological data of a given population on spinal trauma in India is lacking. The present study was undertaken to evaluate the profile of patients with thoracolumbar fractures in a tertiary care hospital in an urban setup.Four hundred forty patients with thoracolumbar spinal injuries admitted from January 1990 to May 2000 to the All India Institute of Medical Sciences were included in the analysis. Both retrospective data retrieval and prospective data evaluation of patients were done from January 1998 to May 2000. Epidemiological factors like age, sex and type of injury, mode of transport, time of reporting and number of transfers before admission were recorded. Frankel's grading was used to assess neurological status. Functional assessment of all patients was done using the FIM\u2122 instrument . Average followup was 33 months (24-41 months).Of the 440 patients, females comprised 17.95% (n=79), while 82.04% (n=361) were males. As many as 40.9% (n=180) of them were in the third decade. Fall from height remained the most common cause . Two hundred sixty (59.1%) patients reported within 48 hours. Thirty-two (7.27%) patients had single transfer, and all 32 showed complete independence for mobility at final followup. 100 of 260 (38.5%) patients reporting within 48 hours developed pressure sores, while 114 of 142 (80.28%) patients reporting after 5 days developed pressure sores.The present study highlights the magnitude of the problems of our trauma-care and transport system and the difference an effective system can make in the care of spinal injury patients. There is an urgent need for epidemiological data on a larger scale to emphasize the need for a better trauma-care system and pave way for adaptation of well-established trauma-care systems from developed countries. Traumatic paraplegia in the young often results in profound change in the life of the injured and also his or her family. These injuries also have tremendous social costs due to prolonged health-care treatment, rehabilitation and productivity loss.1Epidemiology helps us understand the extent of the problem of traumatic paraplegia and the importance of primary care. Epidemiologic studies provide estimates of incidence and prevalence, identify high-risk groups and thus provide insight into priorities for resource allocation, etiologic research and prevention efforts. They also provide a baseline from which to gauge the effectiveness of trauma-care systems involved in transport of the victims to their definitive care in specialized centers. Further, evaluation of the functional outcome of these patients in relation to the modes and timing of transport can provide invaluable insight into the means to improve the existing trauma-care facilities. However, unlike western literature, the epidemiological data of a given population in India is lacking. The present study was undertaken to evaluate the profile of patients with thoracolumbar fractures coming to a tertiary care hospital in an urban setup. This study is not a true epidemiological study as it does not represent the incidence of thoracolumbar injuries in the general population in a geographic area. The study aims to correlate the outcome of spinal cord injury with various epidemiological factors like type of injury, mode of transport, time of reporting, etc.Four hundred forty patients with unstable thoracolumbar spinal injuries admitted from January 1990 to May 2000 to the All India Institute of Medical Sciences constituted the clinical material. Both retrospective and prospective data of the patients from January 1998 to May 2000 were retrived, documented and evaluated. Epidemiological factors like age, sex and type of injury, mode of transport, time of reporting and number of transfers before admission were recorded. Frankel's gradinget al.,Functional assessment of all patients was done using the FIM\u2122 instrumentTwo hundred eighty-eight patients with unstable injuries  or progressive neurological deficit  were managed with surgical decompression and stabilization. Anterior decompression and instrumentation was done when posterior ligamentous complex (PLC) was intact on MRI, and postero-lateral decompression of the cord with posterior instrumentation with interbody support using interbody cages was done with three column injuries with PLC disruption. The rest of the patients were managed conservatively with 4 weeks of bed rest with water/ ripple mattress and log-rolling. Mobilization on wheel chair with thoracolumbar jacket was started after four weeks. Patients were followed up at 3 months, 6 months, 1 year and 2 years for level of rehabilitation and neurological function, along with complications. Average followup was 33 months (24-41 months).Of the 440 patients, females comprised 17.95% (n=79), while 82.04% (n=361) were males (M:F \u2013 4.58:1). 180 (40.9%) of them were in the third decade, 84 (19.09%) of the patients were aged between 11 and 20 years of age, 44 (10%) of the patients belonged to the fourth decade, 72 (16.36%) were between 41 and 50 years, 48 (10.9%) were in the sixth decade and 12 (2.72%) were above the age of 60 years.Fall from height remained the most common cause, with 230 (52.3%) patients, followed by road traffic accident (RTA) , various forms of violence  and gun-shot injuries .Two hundred sixty (59.1%) of the patients reported within 48 hours, 38 (8.6%) reported between two and four days, 52 (11.8%) between five and 10 days and 90 (20.4%) came 10 days after the injury. Two hundred ten (47.7%) patients were transported by ambulance, while the rest were brought by other means .Thirty-two (7.27%) patients had single transfer (32 transfers), 320 (72.7%) patients were transferred 2-4 times  and 88 (20%) patients were transferred 5-7 times  before reaching the definitive care center; the mean transfer rate was 3.4 per person.Frankel grading showed that on admission 294 patients (66.8%) were in Grade-A; 82 patients (18.63%), Grade-B; 28 (6.36%), Grade-C; 16 (3.6%), Grade-D; and 20 (4.54%) were in Grade-E with no deficit. Sixteen (3.63%) patients succumbed to other injuries or complications in few weeks/months of injury. At the final followup, the neurological status was Grade-A in 204 patients, Grade-B in 20, Grade-C in 63, Grade-D in 55 and Grade-E in 82 patients out of remaining 424 patients. Seventy-four patients out of 294 (25.1%) with Frankel-A showed some neurological improvement and 16 patients died; 11 to Frankel-B (3.74%), 36 to Frankel-C (12.24%), 20 to Frankel-D (6.8%) and seven to Frankel-E (2.38%) .Patients with single transfer, ambulance transfers and those reporting within 48 hours showed better neurological recovery , but on P < 0.01). As many as 39 (53.4%) of 260 of patients who reported within 48 hours recovered to either complete or modified independence, while 22 (24.5%) of 90 showed recovery to complete or modified independence on FIS in those who reported after 10 days [P > 0.1).The mobility functional independence staging (FIS) at final followup showed correlation with the mode of transport, time of transport and number of transports. All 32 (100%) patients with single transfer showed complete independence for mobility at final followup, while 190 (59.4%) of 320 patients who were transported between two and four times recovered to either complete or modified independence . Ninety (31.2%) patients undergoing surgery developed pressure sores; of which 44 (48.8%) had reported after five days of injury, as against 102 (67.1%) in the conservative group. Sixty-nine patients (32.9%) transported via ambulance had pressure sores, while 122 (53.04%) out of 230 patients transported by other means developed pressure sores (P > 0.05).In 100 of 260 (38.5%) patients reporting within 48 hours developed pressure sores, while 114 of 142 patients (80.28%) of patients reporting after five days developed pressure sores  of thoracic spine fractures produce complete spinal cord injury.% of thorThe present study shows that thoracolumbar spinal injuries are most common between 21 and 30 years of age. This correlates well with similar findings in most epidemiological studies.491113et al.1115The most common mode of injury was fall from height. This correlates with the previous Indian studies by Chacko There was no significant correlation found between neurological recovery and the time of admission, mode and number of transports, surgical or conservative management; and the initial neurological status largely determined the amount of further recovery, as has been reported widely in the literature.16The most striking difference between the present study and the western literature is seen in the mode of transport of the spinal trauma victim to the definitive care center and the time of patient-reporting. Most developed countries possess an effective trauma-care and transport system, which efficiently transports the victims, usually within the first 12\u201324 hours, to the definitive care centers via well-equipped ambulance.et al. also show a poor ambulance transfer rate of 34% in the rural setup. Most of the victims are transferred by relatives of the patient in cars, rickshaws, jeeps, etc., with little knowledge of the importance of spinal immobilization. In comparison, most developed countries have >90% ambulance transfers of the victim to the definitive care center within 12-24 hours, with trained paramedical personnel.Acute spinal cord injury is a two-step process involving primary and secondary mechanisms."}
+{"text": "Despite the best conservative measures available for the control of major variceal hemorrhage, somepatients either continue to bleed, or rebleed early, and require emergency surgery. One hundred patientswith cirrhosis and uncontrolled bleeding were treated with emergency portasystemic shunts between 1968and 1983. Fifty eight patients had end-to-side portacaval shunts and 42 had Dacron interposition mesocavalshunts. Both groups were comparable with respect to age, sex and prevalence of alcoholism. There was anincreased severity of liver disease as assessed by Child's class in the mesocaval group of patients.Overall in-hospital mortality was 31% with no significant difference demonstrated between themesocaval group (28%) and the portacaval group (33%), nor between alcoholic cirrhotics (34%) and non-alcoholiccirrhotics (21%). Mortality rates based on severity of liver disease were: Child's A (1/6) 17%,Child's B (9/48) 19%, and Child\u2019s C (21/46) 46%. There was a statistically significant difference betweenChild's A & B and Child's C (p < 0.01). Four patients were lost to follow-up. No significant differenceswere found in 5 year survival by life table analysis comparing portacaval (39%) vs. mesocaval (28%) groupsor alcoholic cirrhotics (36%) vs. non-alcoholic cirrhotics (29%). Encephalopathy in survivors was absent in46%, mild in 28% and severe in 26% of patients. There was no significant difference in encephalopathyrates following portacaval or mesocaval shunting.Neither operation was clearly superior and choice of operation can be made on the basis of technical andanatomical factors and surgeon experience. Emergency shunting remains a useful option for patients withvariceal bleeding refractory to other more conservative therapy, and is associated with acceptable earlymortality and long term survival rates."}
+{"text": "Escherichia coli (STEC) in New Mexico increased from 0.9 cases per 100,000 population  in 2004 to 1.7 (95% CI 1.14\u20132.26) in 2007. Non-O157 STEC was more common in nonwhite residents, children <5 years of age, and urban residents.Sporadic infection with Shiga toxin\u2013producing  Escherichia coli (STEC) O157:H7 are well described (The epidemiology of infections and hemolytic uremic syndrome (HUS) caused by Shiga toxin\u2013producing All STEC isolates or broths were sent for confirmation to the Scientific Laboratory Division of the New Mexico Department of Health, where Shiga toxin expression was confirmed by enzyme immunoassay (EIA); the broth was then cultured and preliminarily serotyped. Pulsed-field gel electrophoresis was performed on all isolates. The laboratory submitted non-O157 STEC isolates to CDC for additional serotyping and PCR testing for toxin genes.<0.05 was considered statistically significant.This analysis comprised only sporadic cases of STEC. Negative binomial regression models were used to calculate incidence rates and assess differences in risks for STEC O157 and non-O157 infections. Variables were reporting year, patient age, race/ethnicity, sex, and rural versus urban residence  were STEC O157, and 71 (64%) were non-O157 STEC . Six add1stx (86%), intimin (66%), and enterohemolysin A (81%).Although STEC O157 was the 1 serotype most often identified, infections caused by non-O157 STEC  were diagnosed more frequently. STEC O26 (18%) and O111 (13%) were the most commonly identified non-O157 STEC serotypes. Other STEC O serotypes  were responsible for 33% of all STEC infections. Most isolates were positive for toxin gene STEC O157 infection was significantly more likely to be diagnosed in adults  than in children (<18 years of age) (p = 0.01). Non-O157 STEC serotypes were most commonly identified in children 1\u20134 years of age. STEC O157 infections occurred most commonly in children 5\u201310 years of age, followed by adults >60 years. Sex distributions were similar for patients with STEC O157 and non-O157 infections . White non-Hispanics, which constitute 43% of New Mexico\u2019s population, made up 31% of all confirmed STEC infections in New Mexico; white Hispanics (42%) made up 21% of confirmed STEC cases; and Native Americans (10%) made up 12% of cases .More laboratory-confirmed STEC infections were diagnosed during the summer months than during the rest of the year. STEC O157 cases were diagnosed more frequently in September (10 cases); non-O157 STEC cases were most frequently diagnosed in June and July (9 cases each).Although STEC O157 infections was diagnosed in more persons than were non-O157 STEC infections (28% vs. 16%), the difference was not significant. Patients with STEC O157 infections stayed in the hospital a mean of 6 days (median 4), compared with a mean of 4.5 days (median 3) for patients with non-O157 STEC infections, also not significant. All 5 reported cases of HUS were caused by STEC O157.International travel was related to STEC infection for 12 (11%) patients. Two (5%) STEC O157 cases were travel related, as were 4 (10%) cases each of STEC O111 and O26; and 1 (1%) case each of STEC O128 and O103. Travel to Mexico was documented for 10 of the 12 travel-associated cases.>5 years), and county . More patients with non-O157 STEC infection during this time were nonwhite, <5 years of age, and residents of urban counties. Patients infected with STEC O157 were more likely to be white non-Hispanic, >5 years of age, and residents of rural counties.Most (99 [89%]) persons with STEC were from New Mexico\u2019s urban counties. We calculated incidence rate ratios between STEC O157 and non-O157 infections during 2004\u20132007 , while aThe data collected by New Mexico\u2019s FoodNet surveillance network indicate that sporadic STEC cases increased substantially from 2004 through 2007. Reports of STEC O157 infection doubled from 7 to 14 from 2004 to 2006 but dropped to 9 in 2007. However, the number of non-O157 STEC cases continued to climb and accounted for most of the increase in overall STEC rates in New Mexico during this time, similar to rates in Connecticut and other FoodNet sites  among FoodNet sites for non-O157 STEC incidence in 2007 (As previously reported (Year-to-year increases in numbers of non-O157 STEC infections, both nationally and in New Mexico, must be interpreted with caution because of changes in laboratory testing practices. Although the state\u2019s largest clinical laboratory performed EIAs before active surveillance was implemented in 2004, other laboratories throughout the state might have changed their testing practices.Risk factors for non-O157 STEC infections may be similar to those for STEC O157 infections ("}
+{"text": "Objective: This study was undertaken to determine the prevalence of human papillomavirus (HPV)in loop electrosurgical excision procedure (LEEP) plumes.Methods: Forty-nine consecutive patients with colposcopic and cytologic evidence of cervicalintraepithelial neoplasia (CIN) were tested. Smoke plumes were collected through a filter placed inthe suction tubing. DNA was harvested by proteinase K digest of the filters and prepared forpolymerase chain reaction (PCR) by L1 consensus primers.Results: Thirty-nine (80%) tissue samples were positive for HPV, with types 6/11 in 4, 16/18 in 19,31/33/35 in 2, and other types in 6 patients. The tissue sample was inadequate for typing in 8 patients.HPV DNA was detected in 18 (37%) filters.Conclusions: Although the consequences of HPV in LEEP plume are unknown, it would beprudent to adopt stringent control procedures."}
+{"text": "Aim: This study assessed the causes and incidence of miniplate removal during a 5-year period after Le Fort I osteotomy. Patients and methods: One hundred forty-two patients had plates inserted for fixation of the maxilla after Le Fort I osteotomy between 2001 and 2004. The Le Fort I segment was rigidly fixed with four 2-mm titanium miniplates and 16 screws. They were followed 1 to 5 years for plate complications and need for plate removal. Results: Fifteen of 142 patients (10.6%), 9 females and 6 males, required plate removal. The minimum time period between insertion and removal was 4 months and the maximum period was 18 months. Causes for removal were as follows: infection (40%), pain (13.3%); sinusitis (13.3%); sensitivity to temperature change (13.3%); palpability of plate (13.3%); and phobia (6.8%). Conclusion: In this study, the number of miniplates removed was small and required removal no sooner than 4 months postoperatively (after complete bony union), thus not compromising healing. There is no evidence from this study to support the routine removal of titanium miniplate after Le Fort I osteotomy, rather they should be removed when indicated. Use of rigid fixation in oral and maxillofacial surgery has become a routine for the last 3 decades.One hundred forty-two patients had plates inserted for fixation of the maxilla after Le Fort I osteotomy between 2001 and 2004. Every patient had surgery for similar deformities, with 2 miniplates placed bilaterally (L-form with 4-hole 2-mm diameter miniplates and 7-mm screws were used). The Le Fort I segment was rigidly fixed with four 2-mm titanium miniplates and 16 screws.All plates were inserted in the zygomatic buttress and piriform rim. Age, sex distribution, incidence, and causes for plate removal were recorded during this period. They were followed 1 to 5 years for plate complications and indications for plate removal.Fifteen of 142 patients (10.6%), 9 females and 6 males, required plate removal. The minimum time period between insertion and removal was 4 months and the maximum period was 18 months. Causes for removal were infection (40%), pain (13.3%), sinusitis (13.3%), sensitivity to temperature change (13.3%), palpability of plate (13.3%), and phobia (6.8%).The mean age of patients was 21 years (range = 18\u201332 years). In 15 patients (10.6%), 1 or more plates were removed. Of these patients who had plates removed, 9 (60%) were female (mean age = 24 years) and 6 (40%) were male (mean age = 25 years). Time interval between plate insertion and removal was 13.5 months , pain , sinusitis , sensitivity to temperature change , palpability of the plate , and patient phobia in asymptomatic patients , as shown in Figure During the last 2 decades, plates and screws for rigid fixation in Le Fort I osteotomy has become routine in the treatment of dentofacial deformities worldwide. Rigid fixation with plates and screws, however, is not without complications . The controversy regarding retention of asymptomatic bone plates used for orthognathic surgery is ongoing. Many centersIn this study, the patients were mostly young (mean age = 21 years) and healthy women (63%). In the current study, 10.6% of plates inserted were removed. Several article analyzed the rates of plate removal in a study made up of both orthognathic and trauma patients, and a few analyzed the rates of plate removal in orthognathic surgery, especially Le Fort I osteotomy alone. BruzualThe postoperative time of plate removal is controversial in the literature. In this series, the average interval between plate insertion and removal was 13.5 months. According to Mosbah et al,In this study, infection was the major cause of plate removal (40%). Bhatt et alIn Le Fort I osteotomy, continuity of sinus mucosa is disturbed, the sinus is entered, and possibility of maxillary sinusitis is increased. Kahnberg and EngstromThermal sensitivity was another complication that was reported. Thermal sensitivity commonly accompanied pain. Alpert and SeligsonSeveral authors reported vague pain after surgery. Mosbah et alPalpable plates are among one of the reasons for plate removal; in this study, 2 patients 13.3%) had plates removed for this reason. Rallis et al.3% had pOn the basis of this study, the number of miniplates removed was small and required removal no sooner than 4 months postoperatively (after complete bony union), thus not compromising healing. There is no evidence from this study to support the routine removal of titanium miniplate after Le Fort I osteotomy, rather they should be removed when indicated."}
+{"text": "Objective: This study was undertaken to assess the impact of mycoplasma strains  on the development of chronic endometritis.        Methods: Fifty-eight patients with acute pelvic infection were enrolled in this prospective cohort study. Endometrial cultures and biopsies were obtained on admission and 5\u20137 and 21\u201328 days after completion of treatment.        Results: Of 148 samples, 40 were positive for mycoplasma strains (group A) and 58 were positive for mycoplasma with other pathogens (group B). Twenty-seven samples were positive for other pathogens only (group C). Chronic endometritis was seen in 7 (17.5%), 30 (51.7%), and 10 (37%) in group A, B, and C patients, respectively.         Conclusions: The presence of mycoplasma strains in the endometrial cavity was not found to be associated with an increased incidence of chronic endometritis."}
+{"text": "Information about functional outcome and quality of life after esophagectomy and esophageal reconstruction (ER) for the treatment of esophageal cancer, as evaluated by the patients themselves is limited. We aimed to study the post-surgical outcome of such patients to detect for the development of any complications that may arise from the surgery as well as to evaluate their quality of life following the surgery.From 1993 to 2003, 240 patients with stage I, II, or III esophageal carcinoma underwent esophagectomy at Razi Teaching Hospital located in the north of Iran. Of these, 192 patients filled out a questionnaire during a 2-year period . Among them, there were 134 men (69%) and 58 women (31%), and the mean age at the time of ER was 48 years (ranging from 22 to 75 years). Transhiatal esophagectomy, extended esophagectomy (three field operation), and Ivor-Lewis resection were done in 142 (73.95%), 30 (15.62%), and 20 patients (10.42%), respectively. Intestinal continuity after esophageal resection was established with stomach in 154 patients (80%), colon in 28 patients (14%), and small bowel in 10 patients (5.2%). Cervical anastomosis was established in 172 patients (89.6%), while intrathoracic anastomosis was performed in 20 patients (10.4%).After ER, 66 patients (34.4%) suffered from dysphagia to solids and 50 patients (26%) required at least one or three postoperative dilatations for alleviation of symptoms. Gastroesophageal reflux was seen in 32 patients (16.66%) and was more common in thoracic anastomosis patients than in cervical anastomosis patients. Heartburn was present in 33 cases (17%), 30 of whom required medication (37%). The number of meals per day was three to four in 116 patients (60%), more than four in 51 patients (29%), and less than three in 19 patients (9.82%). The number of bowel movement per day increased in 52 patients (27%), decreased in 60 cases (31%), and unchanged in 80 patients (41%). Weight gain was reported by 38 patients (19.8%), and weight loss was reported by 50 patients (26%). No change in weight occurred in 100 patients (52%). Overall satisfaction was excellent in 29 patients (15%). Overall quality of life  was lower than in general population. Age, sex, and stage of cancer did not affect the functional outcome but affected the quality of life. Also patients who received cervical anastomosis and ER with colon had significantly fewer reflux symptoms. Most of the patients with colon reconstruction gained weight.Self-assessment of postoperative ER by the patients after esophagectomy for malignant disease demonstrates that undesirable symptoms are frequently present at short- and long-term follow-ups. Short- and long-term functional outcome is affected by the type of reconstruction after esophagectomy. Results of this study suggest that colon graft in ER is significantly advantageous compared with other methods because of the ability of patients to gain weight and avoid developing postoperative reflux. Esophageal carcinoma is one of the most common malignancies in Iran and is frequently found in the north of Iran, especially in areas around the Caspian Sea . The incidence of esophageal carcinoma continues to rise in this part of Iran and requires aggressive and timely surgical and oncological treatments. Overall 5-year survival rate at major treatment centers in Iran remains poor. Early de3In our previous unpublished experimental studies, we found that after esophagectomy and esophageal reconstruction (ER), majority of patients complained of dysphagia, reflux, regurgitation, abdominal pain, and cramps. However, little was known about the short- and long-term functional status and quality of life after resection and ER\u20136 in surFrom 1993 to 2003, 240 stage I, II, and III patients with esophageal carcinoma underwent esophagectomy and esophageal reconstruction (ER) at Razi, Aria, and Golsar private hospitals in the city of Rasht located northern part of Iran.Modified standardized questionnaire  is a selThe records of these patients were analyzed for age, sex, sign, symptoms at the time of initial diagnosis, type of operation, organ of reconstruction, operative complications, mortality, quality of life, and finally functional outcome. Factors influencing functional outcome and quality of life were obtained through the patient's medical records and the surveys. Also signs and symptoms of aspiration, frequency of daily meals, and presence of dumping syndrome, bowel habits, and weight changes as well as the patient's overall satisfaction of the operation were all evaluated.Of the 192 patients (80%) completed questionnaire form, there were 134 men (69.80%) and 58 women (30.2%). The mean age at the time of esophagectomy and ER was 48 years (range from 22 to 75 years).Dysphagia was the most common symptom (100 %). Other symptoms are shown in Thirty patients (15/62%) had previous chemotherapy or radiation therapies.Diagnosis and staging were performed by barium swallow, endoscopy, CT scan, and ultrasonography of the chest and abdomen. The operative procedure performed on 142 of the patients (73.95%) was transhiatal esophagectomy. Extended esophagectomy (three field operation) was performed on 30 patients (15.62%) and Ivor-Lewis esophagogastrectomy in 20 patients (10.42%). Intestinal continuity after esophageal resection was reestablished with stomach in 154 patients (80%), colon in 28 patients (14.50%), and small bowel in 10 patients (5.22%). The cervical esophagus anastomosis performed in 172 patients (89.58%) and upper and middle thoracic anastomosis in 20 patients (10.62%). A pyloromyotomy was done in 90 patients (46.87%) and a pyloroplasty in 42 patients (21%).Intraoperative complication occurred in eight patients: tracheal rupture in two, bleeding in three (due to azygos vein rupture), and spleen rupture in three patients. Trachea was repaired by posterolateral thoracotomy and bleeding controlled by reoperation. Postoperative complications occurred in 78 patients (40%), as shown in Feeding jejunostomy was placed in all patients. All cervical and intrathoracic leaks healed with conservative management.Postoperative pathology reports included squamous cell carcinoma in 152 patients (79%), adenocarcinoma in 37 patients (20%), adenosquamous in 2 patients (1/5%), and leiomyosarcoma in one patient (0.5%).Average postoperative hospital stay, after ER, was 22 days (range from 10 to 40days). There were 20 mortalities (10.41%). The time interval between ER and survey ranged from 12 to 48 months. Ninety-eight patients (38 %) were still alive at the time of the last follow-up.One-, two-, three-, and four-year survival rates were 80%, 61%, 52%, and 38%, respectively. Information about functional outcome was obtained from all 192 patients. Dysphagia to solid was mild in 104 patient (61%), severe in 43 patients (25%), and absent in 25 patient (14%). About 104 patients (61%) had dysphagia to pureed foods , and 30 patient (17%) had dysphagia to liquids. Fifty patients (26%) underwent at least two postoperative dilatations, and 40 patients (20.83%) required four to seven dilatations.Eleven patients (6%) had odynophagia, 33 patients (19%) had heartburn that required antacids for relief of heart burn, 33 patients (6%) had chronic cough, 11 patients (6%) complained of dysphonia, and three patients (1.74%) had hoarseness. The number of meals per day is shown in Seventy-nine patients (46%) experienced symptoms of postprandial dumping, including 22 patients (27.5%) with nausea, 36 patients (46%) with cramps and abdominal pain, and 21 patients (26.5%) with diarrhea. Also, 46 patients (27%) failed to regain preesophagectomy weight; 93 patients (54%) maintained preoperative weight, and 33 patients (19%) gained weight compared with their preoperative weight.Overall satisfaction was excellent in 26 patients (15%), good in 103 patients (60%), fair in 26 patients (15%), and poor in 17 patients (10%).Age, sex, and anatomic site of tumor did not influence functional outcome, but ER with colon have better influence on the weight gain and symptoms of esophagitis. Patients with cervical anastomosis had significantly fewer symptoms of reflux when compared with those who received intrathoracic anastomosis. Type or absence of gastric drainage did not significantly affect function outcome.Information of quality of life as assessed by the modified MOS SF-36 was available for 110 patients (63%). Overall physical function score  were decreased significantly compared with national average. Female patients had better quality of life than male patients. Age, time interval from occurrence of tumor to operation, histology, and location of tumor did not significantly affect the quality of life, but the type of the operation, organ for ER, stage of cancer and adjuvant therapy affected the quality of life. Patients who received transhiatal esophagectomy have better quality of life than those with transthoracic esophagectomy. This is because postoperative chest pain is more common when transthoracic approach is used during the operation. Patients with postoperative adjuvant therapy have relatively poor quality of life.Esophageal cancer is one of the most common cancers of gastrointestinal tract in the north of Iran (180 in 100 000 of population). Success Despite continued refinement of operative techniques of esophagectomy, cumulative quality of life after esophagectomy has remained poor in most patients. Until noEsophageal balloon cytology screening is the best approach for early diagnosis of esophageal carcinoma. Surgical resection in the early stage provides excellent long term survival with acceptable quality of live. With thiAlthough the primary objective of ER is to restore normal swallowing with minimal morbidity and mortality, only a minority of our patients (20%) were completely symptom free two or more years after the esophageal resection and reconstruction. Potential complications of dysphagia, aspiration, regurgitation, chronic cough, delayed gastric emptying dumping, and diarrhea can all adversely influence short and long term functional outcome.\u201314 SeverWe are in a region where the esophageal cancer is one of most common cancers of gastrointestinal tract and esophageal surgery is becoming increasingly common. Quality of life and functional outcome is obviously of great importance for these patients after their operation.Health outcome is better measured by using general health measures and traditional biomedical tools synchronously.In the present study, we prepared a questionnaire for upper and lower digestive system functions along with a quality of life survey. Our study demonstrated that the majority of patients were symptomatic for two years (median: 2). Upper gastrointestinal symptoms such as reflux, dysphagia, heartburn, and regurgitation were complains made by most of the patients. More than (35%) complained from reflux symptoms and 66% of these patients used antacids and had difficulties in swallowing, of whom 37% required dilation. In the absence of any anatomic causes of dysphagia after cervical esophagogastrectomy, a functional etiology may be explained by hypertensive peristalsis measured with a manometer, resulting from distention of the remaining cervical esophageal remnant.Thirty two percent of the patients reported some degree of dumping. Moreover, the rate of dumping syndromes was higher in women and young patients. In addition, symptoms of dumping and crampy abdominal pain were also common but only 17% had some degree diarrhea and only 9% used medication. Other researchers have also reported similar results.17 They sugOne significant finding in our study suggests that the incidence of reflux is significantly reduced when the anastomosis is located in the neck. However,19Thirty percent (30%) of our patients regained their preoperative weight and 38 patients (19%) had weight gain. All this eventually prompted us to conclude that for post operative weight gain, ER with colon is superior to other methods . Cough, aspiration, and uncomfortable sleep were seen in 30% of the patients in whom pulmonary complications (abscess/pneumonia) were also more prevalent. In our patients, quality of life  and functional outcome scores were lower than the national average. In addition the type of ER did not affect functional outcome or quality of life.[We concluded that most patients are symptomatic after ER, following esophagectomy due to esophageal cancer, when evaluated through a self assessment questionnaire. Dysphagia, heartburn, reflux, regurgitation, gastric dumping and abdominal cramps are common. Most symptoms are mild to moderate and less than half of these patients require medication and dilatation therapy to tolerate symptoms. Last but not least, quality of life and functional outcome after an ER operation is influenced by age, sex, location of anastomosis, and type of ER performed."}
+{"text": "The World Health Organization (WHO) proposes a successful closure rate for first repair of vesico-vaginal obstetric fistula to be at 85% in each facility, with the continence achievement among the closed cases at 90 %. We are reporting the vesico-vaginal obstetric fistula outcome at the provincial hospital of Maroua-Cameroon from 2005 to August 2007.  Among the overall 32 patients with vesico-vaginal fistula operated, 25 patients were at their first operation. The complete closure of vesico-vaginal fistula (VVF) was 23/25 (92%) and among the 23 patients with complete closure 17(74%) had good continence. When we consider only the 25 patients who were at their first operation, the overall closure of VVF was 23/25 (92%) and among them 17/23 (74%) were continent. Large lesion, bladder neck lesions, vaginal adherence and rigid margin are associated with failure/incontinence. These factors must be taken into consideration when preparing patients for surgery or when assigning them to a surgeon within the surgical team. Some studies present the result of obstetric vesico-vaginal fistula (VVF) repair including repeating operations for the same patient . Other sThis was a case series study at the provincial hospital of Maroua-Cameroon from May 2005 to August 2007. The Maroua Provincial Hospital is a second level referral hospital for the Far North Province of Cameroon.Women consulted in the Maroua provincial hospital for leakage of urine or stools through the vagina. The site and, size of fistulas were confirmed by speculum examination. Transurethral catheter was performed and followed by instillation of 1% methylen blue in the bladder to trace the leakage in small cases. During the study period we identified 48 patients with genital fistulae. We excluded the non obstetrical fistulas (n=6); obstetrical recto-vaginal fistula (n= 3) as the study focused on vesico-vaginal fistulas; and obstetric VVF fistula treated by diversion (n= 7). Finally 32 obstetrical VVF were analyzed.The Surgical technique included an infiltration with adrenaline serum, an incision in V/Y, a v\u00e9sico-vaginal division and a suture without tension in two layers with monofilament and semi-resorbable thread. The V/C incision was done for fistula localized on the uterine cervix. Data were collected on the socio-economic status , reproductive history; circumstance of the occurrence of obstetric fistula; anatomic characteristics of the fistula and the treatment outcome.The data were collected in the standard file prepared for obstetric fistula patients. The information from the file was entered in the Excel software by an assistant nurse with good computer skills. Data was stored in the obstetric fistula database of the Department of Obstetrics and Gynecology of the Maroua provincial hospital. The data of this study was retrieved from the obstetric fistula database of the Department of Obstetrics and Gynecology in the provincial hospital of Maroua-Cameroon between May 2005 and August 2007.Data analysis was performed using EPI Info 3.4. This descriptive analysis includes mean, median, range, standard deviation, 25% quartile (q1), 75% quartile (q3), and proportions. The success rate was calculated as proportion of cure among treated patients. Characteristics from patients who were treated successfully were compared with patients with failure .The mean age of the 32 patients at the time of intervention was 36.2 (SD: 14.3) years; 30(94%) of women had no occupation; 7(22%) were divorced; 4(12.5%) were widows and 28(88%) had no formal education; 18(56.3%) patients did not have antenatal care during the indexed pregnancy; 27(84.4%) of patients had been in labor for more than 12 hours and 28 (87.5%) pregnancies resulted in stillbirth .The patient\u2019s duration of stay with obstetric fistula ranged from 1 month to 33 years, with the median duration at 8.5 years. Among the 32 patients with obstetric VVF, 18 (56%) were at bladder neck region, 26 (81%) were more than 2 cm of size, and 22 (68.8%) had vaginal adhesions .Among the overall 32 patients with vesico-vaginal fistula, closure was observed in 30 (93.5%) patients. The complete closure with good continence was observed in 22 (73.3%) of the 30 patients; closure with residual incontinence observed in 8(26.7%) of the 30 patients repaired and failure of closure was observed in 2 out of the 32 patients (6.2%) patients.Among the overall 32 patients with vesico-vaginal fistula operated, 25 patients were at their first operation. The complete closure of vesico-vaginal fistula was 23/25 (92%) and among the 23 patients with complete closure 17(74%) had good continence. The continence procedure was performed for two patients with the transobturator technique (TOT), but only one of them had a good continence.We compared the overall 22 patients with closure and good continence mentioned above with the 10 patients with failure/incontinence. We found that patients with failure/incontinence have fistula more likely to be localized at the bladder neck region (80% vs. 50%); with size more than 5 cm (30% vs. 9%); with vaginal adherence (80% vs. 64%) and rigid edges (80% vs. 55%) .This study is the first according to our knowledge presenting the quality care in vesico-vaginal obstetric fistula according to the recent WHO recommendations. Among the 32 patients with VVF, the overall closure was observed in 30 93.5%) cases. Our result fit in the WHO target of 85% [% cases. When we consider only the 25 patients who were at their first operation, the overall closure of VVF was 23/25 (92%) and among them 17/23 (74%) were continent. WHO recommends that 90% of the closed fistula should be also continent, and this implies the complete cure of the patient , 7.Large lesion, bladder neck localization, vaginal adherence and rigid margin are associated with failure/incontinence. These factors must be taken into consideration when preparing patients for surgery or when assigning them to a surgeon within the surgical team.There are no competing interests in relation to this manuscript.PMT: study concept, design, data collection, statistical analysis, manuscript writing, and review. JNF: manuscript writing and review. AAM: data collection. JMT: manuscript writing, and review. ASD: manuscript writing, and review. CHR: study concept, design, manuscript writing, and review."}
+{"text": "Dear Editor,The natural history of untreated subretinal neovascular membranes (SRNVM) associated with idiopathic macular telangiectasia (IMT) is generally poor with 81% of eyes in a series of 26 eyes having a final visual acuity of 20/200 or worse.2 Photodyn4A 60-year-old gentleman presented with diminution of vision in the right eye for two months. Best corrected visual acuity (BCVA) was 20/600 in the right eye and 20/60 in the left eye. Fundus examination of both eyes revealed Type 2A IMT with SRNVM in the right eye. Clinicalet al. reported an average of 2.4 PDT treatments for cessation of leakage.[PDT with verteporfin reportedly maintains baseline vision in such eyes. Potter e leakage. Bevacizu leakage. Although"}
+{"text": "A double-blind randomized crossover trial was performed to compare the antiemetic efficacy of two 5-HT3 receptor antagonists, granisetron and ondansetron, in Chinese patients receiving adjuvant chemotherapy  for breast cancer. Twenty patients were randomized to receive chemotherapy with either granisetron on day 1 and ondansetron on day 8 of the first cycle followed by the reverse order in the second cycle, or vice versa. The number of vomiting episodes and the severity of nausea in the first 24 h (acute vomiting/nausea) and the following 7 days (delayed vomiting/nausea) were studied. Acute vomiting was completely prevented in 29 (72.5%) cycles with granisetron and 27 (67.5%) cycles with ondansetron, and treatment failure (>5 vomiting episodes) occurred in two (5%) cycles with each agent (P = NS). Acute nausea was completely controlled in 15 (37.5%) cycles with granisetron and 14 (35%) cycles with ondansetron, whereas severe acute nausea occurred in four (10%) cycles with each agent (P = NS). However, complete response for delayed vomiting was observed in only 21 (52.5%) cycles with granisetron and 22 (55%) cycles with ondansetron (P = NS), and delayed nausea was completely controlled in only 11 (27.5%) and ten (25%) cycles respectively (P = NS). In conclusion, both granisetron and ondansetron are effective in controlling acute nausea and vomiting in Chinese patients, with equivalent antiemetic efficacy. Control of delayed nausea and vomiting is less satisfactory."}
+{"text": "This study examined the association between 17p allelic loss, p53 gene mutation, p53 protein expression and DNA aneuploidy in a series of adenocarcinomas arising in the oesophagus and gastric cardia. 17p allelic loss was detected in 79% (15 of 19) of oesophageal and in 83% (29 of 35) of gastric adenocarcinomas. p53 mutations were detected in 70% (14 of 20) and 63% (26 of 41) of oesophageal and of gastric adenocarcinomas respectively. Both tumour types were associated with a predominance of base transitions at CpG dinucleotides. In five cases of oesophageal adenocarcinoma, the same mutation was detected both in tumour and in adjacent dysplastic Barrett's epithelium. Diffuse p53 protein expression was detected in 65% (13 of 20) and 59% (24 of 41) of oesophageal and of gastric tumours, respectively, and was associated with the presence of p53 missense mutation . DNA aneuploidy was detected in 80% (16 of 20) of oesophageal and in 70% (28 of 40) of gastric tumours. No association was found between p53 or DNA content abnormalities and tumour stage or histological subtype. In conclusion, this study detected a similar pattern of p53 alterations in adenocarcinoma of the oesophagus and gastric cardia--molecular data consistent with the observation that these tumours demonstrate similar clinical and epidemiological features."}
+{"text": "In this study, we examined the potential application of whole-body PET for cancer screening in asymptomatic individuals. PET was performed in conjunction with conventional examinations including physical examination, laboratory study, ultrasonography and chest computed tomography. Between September 1994 and March 1999, 3165 asymptomatic individuals participated in 5575 screening sessions . Follow-up periods were no less than 10 months. PET results were compared with the screening outcomes. Within 1 year after screening, malignant tumours were discovered in 67 of the 3165 participants (2.1%). PET findings were true-positive in 36 of the 67 cancers (54%). Most of the 36 patients underwent potentially curative surgery; thus a wide variety of cancers were detected by PET at potentially curable stages. However, PET findings were false-negative in 31 of the 67 patients (46%). 14 of these 31 (45%) were of urological origin. FDG PET imaging has the potential to detect a wide variety of cancers at potentially curable stages. However, PET imaging is not suited to screening test of general population because PET examination involves substantial cost. \u00a9 2000 Cancer Research Campaign http://www.bjcancer.comWhole-body positron emission tomography (PET) with"}
+{"text": "DNA copy number changes were compared in 29 histologically benign follicular adenomas, of which five were atypical, and 13 follicular carcinomas of the thyroid by comparative genomic hybridization. DNA copy number changes were frequent in adenomas . Most changes were gains, and they always involved a gain of the entire chromosome 7 ; other common gains involved chromosomes 5 (28%), 9 (10%), 12 (24%), 14 (21%), 17 (17%), 18 (14%) and X (17%). Losses were found only in four (14%) adenomas. Two of the five atypical adenomas had DNA copy number losses, and none had gains. Unlike adenomas, gains were rare and losses were frequent in carcinomas. A loss of chromosome 22 or 22q was particularly common in carcinomas , whereas a loss of chromosome 22 was found in only two (7%) adenomas, one of which was atypical (P = 0.002). A loss of 1p was also frequent in carcinomas (31%), but gains of chromosomes 5, 7, 12, 14 or X that were common in adenomas were not found. Loss of chromosome 22 or 22q was present in six of the eight widely invasive follicular carcinomas, but in only one of the five minimally invasive carcinomas. We conclude that large DNA copy number changes are common in thyroid adenomas. These changes are strikingly different from those found in follicular carcinomas consisting of few losses and frequent gains, especially those of chromosome 7. A loss of chromosome 22 is common in widely invasive follicular carcinoma."}
+{"text": "Distinction between non-neoplastic and neoplastic bladder lesions is therapeutically and prognostically important. Our objective is to describe the use of double immunohistochemistry (DIHC) for p53+CK20 as a tool for diagnosing neoplasia in bladder biopsies.p53+CK20 DIHC were examined in 38 reactive atypia, 10 dysplasia, 9 carcinoma in situ (CIS) and 7 invasive carcinoma (IC) cases. CK20 was evaluated according to distribution extent and degree of intensity whereas percentage of positive cells together with staining intensity was taken into account in the evaluation of p53.92% of reactive cases were either CK20(-) or (+) only in the upper 1/3 urothelium. In dysplastic cases CK20 staining distribution was as follows: 60% in 2/3 of the urothelium, 30% full thickness, 10% in the upper 1/3 urothelium. Among CIS cases, 89% had full thickness CK20 positivity, of which 62% were p53(+). 71% of IC cases exhibited strong and full thickness dual staining.This is the first study in the literature to use DIHC of p53+CK20 in distinction of non-neoplastic and neoplastic bladder lesions. Dual staining by p53+CK20 cocktail allows for histologic correlation and diminishes the risk of losing the area of interest in limited biopsy specimens. Further2004 World Health Organization/International Society of Urological Pathology (WHO/ISUP) consensus committee classifies flat urothelial lesions with atypia as reactive urothelial atypia (RUA), atypia of unknown significance (AUS), urothelial dysplasia (UD) and carcinoma in situ (CIS) ,3. UD isPersistent UD or CIS in a background of therapy is considered as therapy failure and may lead to radical cystectomy. Therefore differentiating UD and CIS from RUA in the background of inflammatory/post-therapy changes is critical because of appearent therapeutic and prognostic implications. Other reasons such as small specimen size and interobserver differences may also contribute to difficulties in making the correct diagnosis . MorpholIn the search for reliable markers; p53 and cytokeratin 20 (CK20) are emerging as useful indicators of neoplastic change and prognosis in urothelial proliferations as the reports in favor of them accumulate -12.64 bladder biopsies, consisting of 38 benign/reactive, 10 dysplasia, 9 CIS, and 7 invasive carcinoma (IC)  cases, were retrieved from our surgical pathology files. The samples were fixed in 10% buffered formalin solution and embedded in paraffin blocks. The biopsies were diagnosed according to the 2004 WHO classification of tumors of the urinary system [Sections (4 \u03bcm) from each case were obtained. Deparaffinization, rehydration, and antigen unmasking were achieved by boiling sections in a commercially available steamer. After quenching endogenous peroxidase, slides were incubated with a cocktail of p53+CK20 composed of 10 ul of anti-p53 polyclonal antibody , 50 ul of anti-CK20 monoclonal antibody  and 4,940 ul of Van Gogh Yellow diluent. The detection system used was a double stain polymer detection kit.H&E and double immunohistochemistry (DIHC) of p53+CK20 were examined for each case. Nuclear staining for p53 and cytoplasmic staining for CK20 were interpreted as positive. p53 was evaluated according to the ratio derived from the number of p53-positive cells and staining intensity and scored as: 0 (no staining), 1+ , 2+ , 3+  by semi-quantitative reassortment. CK20 cytoplasmic stain was also semiquantitatively evaluated: 0 (no staining), 1+ , 2+ , 3+ . CK20(+) cells were additionally described by location: Upper 1/3 urothelium including umbrella cells, 2/3 urothelium sparing basal layer and full-thickness staining including the basal layer.35 out of 38 (92%) benign/reactive cases were either CK20(-) or showed CK20 positivity only in the upper 1/3 urothelium including umbrella cells and the majority, 21 out of 35 (60%), of these cases were p53(-). The remaining 3 out 38 (8%) cases showed variable CK20 staining wheras 14 out of 35 (40%) showed weak (1+) p53 positivity  exhibited CK20 positivity in 2/3 of the urothelium sparing the basal layer while 3 cases (30%) showed full-thickness CK20 positivity, only 1 of which was accompanied by 3+ p53 positivity and 1 out 10 dysplastic (10%) cases was CK20(+) only in 1/3 superficial urothelium  CIS cases showed focal or diffuse full-thickness CK20 positivity and 5 out of those 8 (62%) were 3+ p53(+). 1 of the CIS cases (11%) showed CK20 positivity only in the upper 1/3 urothelium accompanied by strong 3+ p53 positivity involving the basal layer  were full-thickness CK20 positive, 2 of those cases 40%) showed 3+ p53 positivity whereas other 2 cases (40%) showed 2+ p53 positivity. The remaining 2 out of 7 (29%) cases showed CK20 positivity other than full thickness whereas 3 out of 7 (43%) cases were p53(-) or showed weak p53 positivity. In dually positive cases, CK20 and p53 occupied the full-thickness urothelium, including the basal layer  may be a useful diagnostic marker in the assessment of bladder biopsies. Two markers, in our opinion, could be used in routine practice, together with careful clinical and morphologic correlation. p53+CK20 DIHC can be considered as a useful innovation in differentiating non-neoplastic vs. neoplastic lesions in bladder biopsies enhancing the credibility of the diagnosis and reducing the number of inconclusive pathology reports of atypia of unknown significance consequently minimizing the need for rebiopsy as the dual staining not only allows for histologic correlation but also diminishes the risk of losing the area of interest in limited biopsy specimens in recut sections.DIHC: Double immunohistochemistry; CIS: Carcinoma in situ; IC: invasive carcinoma; WHO/ISUP: World health organization/international society of urological pathology; RUA: Reactive urothelial atypia; AUS: Atypia of unknown significance; UD: Urothelial dysplasia; IHC: Immunohistochemistry.The authors declare that they have no competing interests.IZY collected the background references, wrote the discussion of the results, created the sequence of alignment and drafted the manuscript. RR obtained the diagnostic material from the archive of the pathology department, carried out the immunohistochemical tests and pathological examination, took the photomicrographs and displayed the results of the study. HBA contributed to the preparation of the manuscript. SB, RD and AVP participated in the design and coordination of the study and gave and reviewed the final histopathological diagnosis. AVP revised the manuscript. All authors read and approved the final manuscript."}
+{"text": "Patients often reach the hospital late after passage of golden hours  after sustaining high-velocity injuries. The decision of internal fixation in Gustilo's Type IIIA and IIIB fractures becomes a formidable challenge in patients reaching late. The purpose of the present study was to find out if internal fixation could be safely undertaken in these patients.Sixty-three patients, having 70 compound fractures (46 Type IIIA and 24 IIIB), which were internally fixed after 6h but within 24h after injury, were included in the present analysis. Follow-up ranged from 18 to 48 months with mean of 28 months.P value < 0.01). Nonunion was seen in five fractures. Functional evaluation using Katenjian's criteria, showed 62.85% (44 fractures of 70) good to excellent results.Overall infection rate noted was (n = 11) 15.71% . The difference in deep infection rate between Type IIIA and Type IIIB was found to be statistically significant (Satisfactory results may be obtained in Gustilo's Type IIIA and IIIB fractures even if fixed after the golden period, provided strict protocol such as aggressive debridement, prophylactic antibiotic coverage, early soft tissue reconstruction and timely bone grafting is followed. The primary coverage of the wound is discouraged. The aim of fracture treatment is the return of the injured extremity to full function in the shortest period of time. Factors such as contamination of wound, major bone or skin loss and nerve or tendon injuries often associated with Gustilo's compound Type III fractures make this a challenging task. The incidence of infection in cases of intramedullary nailing after external fixator removal is noted to be high.2Good to excellent results with primary internal fixation in compound fracture following strict protocol have been described.6The available literature on the subject of internal fixation in compound fractures has not specifically mentioned the exact delay in operation since the time of injury. Only a few articles37With impaired vascularity in the zone of injury, the body's immune system is compromised. During the first two hours, the host defense works to decrease the overall bacterial load. During the next four hours the number of bacteria remains fairly constant, with the bacteria that are multiplying and those that are being killed by the host defense being about equal. These first six hours are thus called the golden period, because after this period, invading organisms, in the presence of abundant necrotic tissues, replicate in logarithmic fashion to establish a clinical infection. A contaminated wound is considered infected after 12h. The time limit is shorter in a severely contaminated wound with severe soft tissue injury. Internal fixation is advocated within 6-8h in majority of their cases, which is considered the golden period for any surgical intervention.Unfortunately, in developing countries due to lack of healthcare facilities, ignorance and poverty, patients often reach the hospital late after the few initial precious hours have passed.In this prospective study of 63 patients (70 fractures), we present our results of internal fixation in Type IIIA and IIIB compound fractures, which were fixed after 6h but within 24h.In this prospective study between February 1996 to October 2000, 63 patients having 70 compound Gustilo Type III fractures  were included. There were 46 males and 17 females, M:F ratio being 2.7:1. Age of the patients ranged from eight years to 65 years with mean age of 37 years. Wounds were classified using Gustilo's classification system.In the emergency room before splinting the extremity, gentle wound toilet with copious amount (3-5 liters) of sterile saline was done and the wound was covered with sterile dressing. All patients received third generation Cephalosporin  and Amikacin  for three days. Oral antibiotic was then continued for 10 to 12 days.The injuries were caused by road traffic accidents in 35 patients (55.55%), industrial accidents in eight (12.69%), fall from height in seven (11.11%), gunshot injuries in five (7.93%), crush injuries in four (6.34%) and others in four patients (6.34%). Associated injuries included ipsilateral and contralateral lower extremity fracture (n=10), fracture of the upper extremity (n=11), clavicle fracture (n=8), thoracic injuries (n=7) and pelvic injuries (n=6).The different fracture patterns noted in our series were transverse fractures (n=17), oblique and spiral fractures (n=10), comminuted fractures (n=22), segmental fractures (n=12) and intercondylar fractures (n=9). Nine fractures reported within 6-10h of injury while 27, 23 and 11 reported after 10-14h, 14-18h and 18-24h respectively. Two fractures were fixed within 6-10h of injury while 23, 29 and 16 were fixed after 10-14h, 14-18h and 18-24h respectively. The patients were taken for surgical debridement and fixation, on an average within 4.7h (range 2-11h) after reaching the hospital. Besides late presentation other causes of delay in fixation were associated injuries to other vital organ requiring operation (n=13), need to perform additional diagnostic procedure (n=9) and unavailability of operation theater (n=6).Aggressive debridement that involved exploration of the wound, excision of devitalized tissues and removal of foreign materials, was performed meticulously. In cases (n=42) where the viability of marginal tissue remained doubtful, repeat debridement was undertaken within 48 to 72h. Soft tissue coverage depended on the operating surgeon's appraisal of the wound. Once the wound looked healthy with sprouting granulation tissues early coverage was planned without delay. The average number of surgeries performed was 4.5 (3 to 8) including debridement and removal of implant.et al.,As recommended by Whittle In this series we divided all diaphyseal fractures (n=32) of the lower extremities into two subgroups. The first subgroup contained 21 fractures that had bone defects less than 2 cm in length and/or cortical apposition more than 50%. Five of these fractures united after primary internal fixation whereas in the remaining 16 additional procedures like dynamization (n=9), exchange nailing (n=5) and cancellous bone grafting (n=2) were undertaken to promote union. Bone grafting was done in two patients after six months where the butterfly fragment was not in contact with either of the major fragments and did not show sign of union. Dynamization (n=9) was performed after 16-20 weeks when it was assessed radiologically that dynamization will permit compression at fracture site without compromising stability. In another five cases of Group 1 where fracture failed to unite even after 10-12 months, closed exchange nailing after thorough reaming was performed.The second subgroup contained 11 patients having bone loss more than 2 cm and/or cortical apposition less than 50%. Bone grafting was done in all of them after the wound was fully re-epithelialized. Three of the 11 cases required two bone grafting procedures. In fractures requiring flap, grafting was undertaken only after three to five weeks of successful coverage of wound.The various wound management techniques used in this series were primary closure (over vacuum suction drain without any tension at the stitch site), delayed closure (n=24) done in three to five days, split-thickness skin graft (5-10 days) and flap cover (within 5 to 15 days). Primary closure was not done in any of Type IIIB fractures. Immediate primary closure (n=18), delayed primary closure (n=6) and split-thickness skin graft (n=12) was done in 36 Type IIIA fractures. Flap cover was performed in 10 cases of Type IIIA and in all the cases of Type IIIB fractures after the appearance of healthy granulation tissue. The gastrosoleus muscle was used as local flap for coverage of open tibial fractures in nine cases.Active and passive physiotherapy of the joints was encouraged as soon as possible. However, mobilization of patients varied depending on the type of fixation, the requirement of plastic surgery and the presence of other injuries. Follow-up of at least 18 months with a mean of 28 months (range 18-48 months) was available at the time of the final evaluation of the result.In this study, KatenjianOverall 44 (62.85%), 30 out of 46 (65.21% in IIIA) and 14 out of 24 (58.33% in IIIB) showed good to excellent results  in our set al.,et al.Davis346P < 0.01). Antibiotics were continued for 10-12 days in our series, the rationale being that wound heals by this time. However, recent reportsThe overall rate of deep infection in our study was 15.71% (n=11) (8.7% in Type IIIA and 29.16% in Type IIIB). Infection rate in compound Type III fractures as reported previously in the literature2378et al.et al.,2et al.,et al.,et al.,Sinclair et al.et al.In our series, we noted that the wounds when covered within a week or 10 days after injury were associated with significantly fewer major complications than the wounds that were covered late. This is in consistence with Fischer et al.,Of the 32 diaphyseal fractures (tibia and femur), reaming was performed in 13 cases and unreamed nailing in 19 patients. As the number of cases were less, the authors cannot draw a definite conclusion regarding the outcome in reamed vis-\u00e0-vis unreamed nailing. Though the grade of compounding did not influence the decision whether to ream or not the authors feel, excessive reaming in compound fractures must be discouraged, as it renders the endosteal surface ischemic and causes further disruption of medullary blood supply in a bone already denuded of periosteum.19After having obtained 62.85% good to excellent results the authors strongly feel that internal fixation can be safely undertaken within 24h of injury in compound Type III fractures. Metallic internal fixation, if judiciously performed gives parallel or superior results than external fixator device or delayed internal fixation after removal of external fixator system.Meticulous and repeated debridement is the key to successful management of the open fractures. Assessment of the viability of damaged muscle in such circumstances is difficult and thus we discourage primary coverage of the wounds at the time of first debridement. However, early wound coverage (within 3-15 days) aids the body in sealing off further entry of bacteria. Furthermore, early flap also enhances healing of fracture by increasing vascularity. Internal fixation reduces hospital stay, achieves better anatomical and functional results and it does not hamper early soft tissue reconstruction."}
+{"text": "Knowledge of the predictors of sustained viral response (SVR) to pegylated interferon (PEG-INF) alfa-2a and ribavirin (RBV) therapy in patients with hepatitis C genotype-4 (HCV-4) is crucial for selecting patients who would benefit most from therapy. We assessed the predictors of SVR to this combination therapy in Saudi patients with chronic HCV-4 infection.This retrospective study included 148 patients with HCV-4 infection who underwent clinical, biochemical and virological assessments before treatment and at 12, 24, 48 and 72 weeks post-treatment.2. Seventy-nine of 148 (60.1%) patients were treatment na\u00efve and 110 (74.3%) underwent pre-treatment liver biopsy. Eighteen (12.2%) patients did not complete therapy because of side effects or they were lost to follow up. Early virological response was achieved in 84 of 91 (92.3%) patients. In the 130 (87.8%) patients who completed therapy, 34 (26.2%) were non-responders and 96 (63.8%) achieved end-of-treatment virological response (ETVR). SVR and virological relapse (24 weeks after ETVR) occurred in 66/130 (50.7%) and 30/130 (31.2%) patients, respectively. Compared to relapsers, sustained responders were significantly younger (P=.005), non-diabetic (P=.005), had higher serum albumin (P=.028), lower alpha-fetoprotein level (P=.026), lower aspartate aminotransferase (AST) (P=.04) levels, and were treatment-naivve (P=.008). In a multivariate regression analysis, the independent predictors of SVR were younger age (P=.016), lower serum AST (P=.012), and being treatment naivve (P=.021).Of the 148 patients, 90 (60.8%) were males. Mean (SD) for age was 48.5 (12.7) years and BMI was 27.9 (7.5) kg/mApproximately half of HCV-4 patients who complete the course of combination therapy achieve an SVR, especially if they are young, treatment naivve and have lower AST levels. Chronic hepatitis C virus (HCV) infects approximately 170 million people worldwide, is a major cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma and represents the most frequent cause for liver transplantation in the US and Europe.2Pegylated interferon (PEG-INF) plus ribavirin (RBV) therapy given for 48 weeks is now established as the standard therapy for patients with chronic HCV infection with genotypes 1 and 4.6610HCV-4 is known to be endemic in Central Africa and in the Middle East.1116This retrospective study included 148 consecutive patients with chronic HCV-4 infection referred to King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh, Saudi Arabia between February 2003 and November 2005. Baseline characteristics of subjects are shown in 37Patients were then treated with PEG-INF alfa-2a  plus RBV  for 48 weeks. Clinical, biochemical and viral parameters were collected both pre-treatment and at weeks 12, 24, 48 and 72 of follow-up.Serum HCV RNA was extracted using an automated extraction system. HCV detection and quantification were performed using an Abbott Real-Time M2000rt PCR assay, which utilized two sets of primers and probes and targeted a conserved region of the 5\u2032 untranslated region of the genome and an internal control. This assay detects and quantifies HCV genotypes (1-6) with a detection limit that ranges from 30 to 100 000 000 IU/mL, where 1 IU/mL=4 copies/mL. Prior to treatment, HCV genotype was performed in all patients  using INNO-LiPA HCV II .Before 2006, viral load testing was performed using the Bayer Quantiplex bDNA System . The lower quantification detection limit was 3200 copies/mL. The highest detection limit was 40 000 000 copies/mL. The average period between the quantitative PCR test and the start of therapy was 2.7 months. The National Institute of Health guidelines state a drop of \u22652 log10 in serum HCV viral load is indicative of response. An early viral response (EVR) was defined as \u22652 log10 drop in serum HCV viral load at 12 weeks after start of treatment. An end-of-treatment virological response (ETVR) was defined as an undetectable serum HCV RNA at 48 weeks. A sustained viral response (SVR) was defined as a persistently undetectable HCV RNA at 72 weeks (6 months after the end of course of treatment). Nonresponse (NR) was defined as a persistent positive HCV (PCR) after 48 weeks of treatment.t tests or non-parametric tests (Wilcoxon and Mann Whitney), as appropriate. The chi-square or Fisher exact tests were used to compare frequencies and proportions. Multivariate stepwise logistic regression analysis was performed to determine the independent predictors of sustained response. An intention-to-treat analysis was used. Patients who discontinued treatment and those who did not complete their course of treatment either due to adverse effects or loss to follow-up were not included in the analysis for ETVR or SVR.Data were collected initially in a specialized data collection form, then introduced into a Microsoft Excel worksheet and finally transferred to the Statistical Package for Social Sciences (SPSS) version 15.0 for Windows  for analysis. Means of continuous variables were compared using 2. Diabetes mellitus, prior interferon-based therapy, and concomitant HBV or HIV infection were present in 45 (30.4%), 59 (39.9%) and 29 (19.6%) patients, respectively . Steatosis in the liver biopsy was similar in the diabetic group (9 of 33) versus non-diabetics (16 of 78) (P=.33). Sustained responders and viral relapsers had similar serum ALT  at time points apart from week 72, in which those who relapsed after ETVR showed significantly higher serum ALT (P=.001)  were males. Mean and standard deviation for age was 48.5 (12.7) years and BMI was 27.9 (7.5) kg/mectively . Pre-tre(P=.001) .P=.016) (P=.157).PCR at 12 weeks post-treatment was done in 131 (91.9%) patients from the whole cohort (n=148) and in 91 (94.8%) of those who completed the full course of treatment (n=96). EVR was achieved in 96 patients (64.9%) in the whole cohort (n=148) and in 84 (92.3%) of those who achieved ETVR. EVR was significantly more common in patients who received treatment for the first time compared to those who previously received treatment  . HoweverP=.008) and lower relapse rate after ETVR (P<.008) compared to those who were previously treated with interferon-based therapy. However, the difference in EVR rate between treatment-na\u00efve patients and those who were previously treated by interferon-based therapies did not reach statistical significance (P=.083) (Eighteen patients (12.2%) failed to complete the 48-week therapy due to side effects or loss to follow up. The full course of therapy was given to 130 (87.2%) patients; 96 (72.9%) achieved ETVR and 34 (26.2%) were non-responders. SVR was achieved in 66 of 130 (50.7%), while the remaining 30 (31.2%) developed virological relapse after ETVR . Virolog(P=.083) . BecauseP=.005), had a lower rate of diabetes mellitus (P=.005), higher serum albumin (P=.028), lower pre-treatment serum aspartate aminotransferase (AST) levels (P=.04), lower serum alpha-fetoprotein (AFP) levels (P=.026), and were more treatment-na\u00efve (P=.008) than patients who developed virological relapse after ETVR   .A total of 158 side effects were encountered in 66 patients (44.6%) during follow-up . EffectsThe present study involved the largest cohort of patients infected with HCV-4 to be reported in the literature after treatment with the combination of PEG-INF alfa-2a and RBV for 48 weeks, and shows that this group of patients can no longer be considered \u201cdifficult to treat\u201d. Indeed, with the use of this regimen, SVR was achieved in 44.6% of the whole cohort, in 50.8% of those who completed treatment and in 68.8% of those who achieved ETVR. These results are similar to the responses achieved in previous studies that involved cohorts with predominantly genotype 1 and are less than the responses in patients infected with genotype 2 or 3.363940Only 18 (12.2%) did not complete their course due to either side effects (n=5) or loss to follow up (n=13) and a total of 34 (26.2%) patients were classified as non-responders. This rate of non-response can be accepted if we put into consideration the tertiary nature of our hospital and the inclusion of many complicated cases such as those who failed previous interferon therapy, cases with organ transplantation, and cases copinfected with HIV and/or HBV. The impression that patients infected with HCV-4 respond poorly to interferon-based therapy and are generally \u201cdifficult to treat\u201d came from many earlier studies where conventional interferon-alfa was used alone or in combination with RBV .242830\u2013324282325Neither the fibrosis stage nor the inflammation grade in the pre-treatment liver biopsy was found to be statistically different between sustained responders and those who developed virological relapse after ETVR. This is contrary to what was previously reported by other studies in patients infected with genotype 1Contrary to other reports,40The safety profile of the combination therapy of PEG-INF alfa-2a and RBV used in the present study is comparable to what was previously described in the literature.2529The significantly lower SVR in our patients who previously received interferon therapy (28.8%) compared to those who were treatment-na\u00efve (55.1%) is consistent with the results of many studies in both genotype 1 and genotype 4.27294446Better identification of the pre-treatment host or viral factors that can identify which patients respond better to therapy is currently attracting more attention. For instance, HCV-4 subtyping has been proposed to affect the response to PEG-INF alfa-2a plus RBV combination therapy.51This study demonstrates for the first time that lower baseline serum AST and not ALT is an independent predictor of SVR to PEG-INF alfa-2a and RBV in patients with chronic HCV-4. We believe that these lower AST levels reflect less severe histological parameters in the sustained responders. A study by Zechini et al showed a statistically significant positive correlation of baseline aminotransferase values with the hepatitis activity index and fibrosis score.Unlike the situation in most randomized controlled trials, the patients included in this study were heterogeneous: 10.1% had previous organ transplantation, 8.1% were positive for liver autoantibodies (classified as overlap syndrome), 19.6% were positive for HBV or HIV serology, 39.9% were non-responders to previous interferon-based therapy and 6.1% had renal impairment. These factors are known to affect the natural history of chronic HCV infection. However, this sample of patients represents what we usually face in real life. If we exclude cases with all the above co-morbidities, our results will only be applicable to patients with isolated HCV infection. As shown in The potential limitations of the current study include the fact that post-treatment biopsy was not done as our main objective was to assess pre-treatment predictors of SVR. There is a solid evidence that SVR is associated with improved outcomes,In conclusion, combination therapy with PEG-INF alfa-2a and RBV, if tolerated and completed, is effective in treating chronic HCV-4 patients especially if they are younger than 40 years of age, have no previous interferon therapy and have lower pre-treatment AST levels. Attempts to improve adherence to therapy and the early detection together with treatment of complications are needed to achieve better response to therapy. Further studies addressing other potential predictors of SVR in chronic HCV-4 patients such as the IP10, insulin resistance, HCV-4 subtype heterogeneity are warranted."}
+{"text": "These 79 preinvasive lesions were found in 34 patients. The respective results of fluorescence bronchoscopy in addition to conventional bronchoscopy and of conventional bronchoscopy alone for detection of preinvasive lesions were: sensitivity 85% (67/79) and 59% (47/79); specificity 60% (351/581) and 85% (493/581); positive predictive values of 23% (67/297) and 35% (47/135); negative predictive values of 97% (351/363) and 94% (493/525). A separate analysis of only the first bronchoscopy of each patient showed similar results. Results of fluoresence bronchoscopy were better in the second part of the patient group. We conclude that after a learning period fluorescence bronchoscopy can increase the yield of finding preinvasive neoplastic lesions when used in addition to conventional bronchoscopy.The aim of the study was to determine whether use of fluorescence bronchoscopy improves the detection of preinvasive neoplastic bronchial lesions. The data of all patients who underwent fluorescence bronchoscopy and in whom bronchial biopsies were taken, were analyzed. Most patients were at risk for preinvasive lesions. A total of 174 bronchoscopies were performed in 95 patients. Of the 681 representative biopsies, 31 were found to be moderate dysplastic, 39 were found to be severe dysplastic and 9 exhibited carcinoma"}
+{"text": "We report the results of our experience on laparoscopic cholecystectomy in sickle cell disease patients in Niger, which is included in the sickle cell belt.A prospective study covering a period of 45 months, from July 2004 to March 2008. We included all sickle cell disease patients that underwent laparoscopic cholecystectomy. Blood transfusion was done for patients with haemoglobin (Hb) levels less than 9g/dl. Homozygous and composite heterozygous patients were admitted in intensive care unit for 24 hours or plus post operatively.The series included 47 patients operated by the same surgeon, 31 females (66%) and 16 males (34%) (Ratio: 0.51). The average age was 22.4 years (range: 11 to 46 years) and eleven (23.4%) of them were aged less than 15 years. The types of sickle cell disease found were 37 SS, 2 SC, 1 S beta-thalassemia and 7 AS. Indications for surgery were biliary colic in 29 cases (61.7%) and acute cholecystitis in 18 cases (38.3%). The mean operative time was 64 min (range: 42 to 103 min). Conversion to open cholecystectomy in 2 cases (4.2 %) for non recognition of Calot\u2018s triangle structures. The postoperative complications were: four (4) cases of vaso-occlusive crisis and one case of acute chest syndrome. The mean postoperative hospital stay was 3,5days (range: 1 to 9 days). No mortality was encountered.Laparoscopic cholecystectomy is a safe procedure in sickle cell patients. It should be a multidisciplinary approach and involve a haematologist, an anaesthesiologist and a surgeon. Sickle cell disease is one of the most common haemoglobinopathies in Africa; it is a serious community health problem in some sub-saharan countries. Its prevalence is varies from 18 to 25% in Niger. Gallstone is a major abdominal complication of chronic haemolysis. General anaesthesia and cholecystectomy can be carried out on sickle cell patients with a very high risks of complications (vaso occlusive crisis and acute chest syndrome). Laparoscopic cholecystectomy (LC) requires expert anaesthesia and a well trained surgeon. Sickling is avoided by preventing hypoxia, hypovolaemia, hypothermia and acidosis; LC is recommended by many authors because of its safety and with a short period of hospital stay [rd generation cephalosporin and metronidazole); blood transfusion for haemoglobin (Hb) levels below 9g/dl. Postoperatively homozygous and composite heterozygous patients were admitted into the intensive care unit for special reanimation during the first 24 hours or more. The American method was used for the surgical operation. The position of trocars depends mainly on the difficulty of the dissection . Our study reviewed the following parameters: age and sex, indication and duration of operation, type of intraoperative incidents and conversion to laparotomy, post operative complications and duration of post operative hospital stay.It\u2019s a prospective study covering a period of 45 months; from July 2004 to March 2008. Were included in the study, sickle cell patients with simple or complicated gallstones admitted in general and digestive surgery unit of the National Hospital of Niamey. Patients with contraindications to pneumoperitonium and those with common bile duct stones were excluded. The preoperative investigations include a hepatic function test, amylasemia; malaria test and ultrasound scan of the hepatobiliary tree. A cardiac echography and lung function test were done depending on the findings on clinical examination. The preoperative management was conducted by the anaesthesiologist and includes hydration, antibiotics  were done on SCD patients with 16 males (34%) and 31 females (66%) (sex.ratio: 0.51). The mean age was 22.4 years (range 11 to 46 years); eleven patients (23.4%) were aged less than 15 years, of whom 7 patients (14.9%) had a past history of surgical operation under general anaesthesia. Haemoglobin electrophoresis showed 37 cases (78.7%) of homozygous HbSS, seven heterozygous (14.9%) Hb AS, 3 composite heterozygous: two cases (4.2%) of HbSC and one case of HbS-beta thalassemia (2.1%). Indications for surgery were biliary colic in 29 cases (61.7%) and acute cholecystitis in 18 cases (38.3%). Preoperatively 27 patients (57.4%) with Hb levels less than 9g/dl were transfused; 7 patients (14.9%) with positive malaria tests were treated with antimalarial drugs .The operations were carried out by the same surgeon. Injuries reported during this procedure included accidental gallbladder perforation in 6 cases (12.8%) and haemorrhage in one case (2.1%). Total cholecystectomy was performed in 44 cases (93.6%) and partial cholecystectomy, leaving a small portion of gallbladder tissue adhered to the liver was performed 3 cases (6.4%). The mean operation time was 64 minutes (range 42 to 103 minutes); the mean anaesthesia time was 96 minutes (range 85 to 157 minutes). Conversion to laparotomy happened in 2 cases (4.2%) due to non recognition of the structures in the Calot\u2019s triangle caused by inflammation and haemorrhage. Drainage was performed in 2 cases (4.2%). Forty patients (85.1%) were follow up in the intensive care unit postoperatively as follows: 35 patients  stayed for the first 24hrs post operatively; 4 patients HbSS (8.5%) stayed for 3 days because of vaso-occlusive crisis (VOC), 1 patient HbSS (2.1%) had acute chest syndrome (ACS) and stayed for 7days under oxygen therapy and antibiotics.The total of these complications were amounted 5 (4 VOC and 1 ACS) representing 10.6% of all LC performed on SCD patients. VOC and ACS occurred in non transfused patients preoperatively. For postoperative analgesia, 10 patients (21.3%) received nalbuphin (morphinic derivative) and the others (78.7%) received intra-venous paracetamol. Feeding was started post operatively at day 0 to day1 for 40 patients (85.1%); day 2 for 4 patients (8.5%) and day 3 for 3 patients (6.4%). The mean post operative length of stay in hospital 3.5 days (range: 1 to 9 days). One patient (2.1%) was seen for follow up on day 12 post-op with complains of fever; an ultrasound scan showed a subhepatic abscess subsequently treated with antibiotics (ceftriaxone and metronidazole). In total, post operative complications were estimated at 12.8% and no mortality occurred.Gallstones are a frequent complication in patients with sickle cell disease (SCD) because of the recurrent episodes of haemolysis leading to an increase in bilirubin excretion and pigment gallstones formation. The incidence of gallstones in patients with SCD increased in these last years due to both the regular use of the non-invasive detection technique (ultrasonography), best follow-up care for patients, and the longer survival of these patients. The prevalence of cholelithiasis in patients with SCD varies between countries. It is estimated at 34 to 70% in USA, 4 to 25% in Africa and 8% in Saudi Arabia . In our The management of SCD is multidisciplinary and involves the anaesthesiologist, the haematologist and the surgeon. Together they assess the patient\u2019s fitness for surgery. Intensive care unit stay postoperatively is recommended by many authors \u20136 for spThe mean duration time for LC is 64 minutes (range 42 to 103 minutes) in our study. Fall and others , 11\u201313. In our study only symptomatic gallstones were operated, but in the future, the surgical management of SCD patients will also handle non symptomatic gallstones. Curro and al  comparedIn our environment, LC is a safe procedure in sickle cell patients with a very low morbidity and mortality rate .It\u2019 s a multidisciplinary approach involving a hematologist, an anesthesiologist and a surgeon. The factors in predisposing to vaso occlusive crisis should be monitored during the pre, intra and post operative management."}
+{"text": "Combination chemotherapy with cytosine arabinoside, cyclophosphamide and L-asparaginase (Asnase) was given to 22 children with acute lymphocytic leukaemia (ALL) with a white-cell count greater than 30 X 10(9)/1, and other features suggestive of poor prognosis. Complete remission was induced in all patients--in 19 after 2 courses of chemotherapy and in the remainder after a third course. During induction, neutropenia occurred in 18 and severe infection in 3. Anaphylaxis to Asnase occurred in 8 patients after the second course and one other had transient Asnase-induced diabetes. All patients received central-nervous-system prophylaxis after achieving remission, during which they were also treated with weekly vincristine and a 2-week course of prednisolone. Continuation therapy consisted of short cycles of intermittent chemotherapy and BCG inoculation or long cycles of intermittent chemotherapy +/- BCG. Life-table analysis shows 46% complete remission rate at 28 months, with 6 patients all in complete remission followed up between 28 and 41 months. There were minimal complications of continuation therapy, and BCG inoculation was well tolerated."}
+{"text": "To the Editor: Hajj pilgrimage is a yearly event in which >2 million Muslims from around the world gather in Mecca, Saudi Arabia. Such high density of crowding presents a risk for local outbreaks and for worldwide spread of infectious agents. Acute respiratory infection (ARI) is the leading cause of admission to Saudi hospitals during the Hajj  2009 virus. A total of 528 persons  who attended a pre-Hajj meningococcal vaccination campaign were invited to participate in a face-to-face interview during which they completed our questionnaire. We achieved a 100% response rate. Mean age of participants was 61 years (range 18\u201394 years). Most pilgrims were born in North Africa (92%), had education above a primary certificate (81%), were unemployed (56% of persons <65 years of age), and were traveling to Saudi Arabia for the first time (78%). Ten percent had chronic pulmonary disease.We assessed knowledge of ARI using 18 questions about symptoms and sources of contamination. Knowledge questions were scored 1 for the correct answer and 0 for incorrect or \u201cdon\u2019t know\u201d answers. Overall, the score of true responses was only 26% (interquartile range [IQR] 21%\u201337%). Scores were higher for respondents <65 years of age . Scores were also higher for female pilgrims . No other demographic or health factor had significant influence.Respondents believed the following were sources of contamination for ARI: sneeze and cough products (58.1%), dirty hands (43.9%), contact with ill persons (40.5%), saliva (17.2%), promiscuity (17.0%), food (12.1%), drink (9.1%), air conditioning (3.4%), and contact with animals (0.4%); 16.7% had no knowledge about ARI sources. When asked about their perceived risk of acquiring ARI during the pilgrimage and contaminating their relatives on returning home, 26% of respondents perceived no or little risk, 20% perceived some risk, and 37% perceived important risk; 17% did not know. Surveyed pilgrims knew the following were symptoms of ARI: cough (64.4% of respondents), dyspnea (45.1%), fatigue (33.3%); expectoration (21.0%), fever (15.2%), rhinitis (8.7%), nasal obstruction (4.0%), and headache and sneeze (3.8% each); 14.4% of pilgrims surveyed did not know any ARI symptoms. Less than 50% of respondents were aware of social distancing, curative treatment, and use of a face mask as precautions to reduce the spread of ARI agents . HoweverSaudi health authorities recommend use of surgical face masks (fatwa allowing use of alcohol-based hand-rubs on skin as a disinfectant (Maintenance of good hand hygiene is also effective in reducing spread of respiratory infection. The World Muslim League has issued a The demonstration of high acceptability of simple physical measures to prevent ARI encourages the education of pilgrims during the pretravel encounter. The results also support conclusion that masks, hand-rubs, and disposable handkerchiefs should be provided to pilgrims, along with strong advice about the risk for ARI, to increase adherence to prevention measures."}
+{"text": "To the Editor: Stockton et al. have reported the detection of human metapneumovirus (HMPV) by using reverse transcriptase-polymerase chain reaction (PCR) in patients with influenzalike illness (We investigated the occurrence of HMPV in children <3 years of age with ARTI during two consecutive winter seasons (November 2000\u2013February 2001 and November 2001\u2013February 2002) as part of a study to detect respiratory viruses  among the pediatric population. The study population comprised 565 children who were brought to Hospital Donostia, San Sebasti\u00e1n, Spain, with reported symptoms of ARTI, most of which (>80%) affected the lower respiratory tract. Of these children, 379 were hospitalized and 186 were discharged without admission. Hospital Donostia belongs to the public health system and is the main referral hospital for a population of 9,500 children <3 years of age. More than 97% of hospitalizations of children in our region occur in this hospital.Nasopharyngeal aspirates were obtained and processed for cell culture by using rapid shell vial techniques on the MDCK, A-549, and LLC-MK2 cell lines. RNA was then extracted from the original samples by using phenol-chloroform  and was converted into cDNA with random primers by using M-MuLV reverse transcriptase . Nested PCR was performed to detect HRSV, influenza, and parainfluenza viruses as previously described (In 411 (72.7%) of the 565 patients studied, at least one of the initially investigated viruses was detected. HRSV was found in 313 (55.4%) children, influenza in 44 (7.8%), parainfluenza in 36 (6.4%), and adenovirus in 32 (5.7%); 14 mixed infections were detected. Of 154 children with a negative result, HMPV detection was performed in 147 (95.5%), with a positive result in six children (4.1%). No HMPV was detected in any of the 100 samples previously positive for the initially studied respiratory viruses. Four of the six HMPV-positive children required hospitalization: a 7-month-old boy with pulmonary bronchodysplasia, rhinitis, and fever of 38.4\u00b0C (patient 1); a 20-month-old girl with previous obstructive pulmonary disease who had acute respiratory insufficiency along with generalized hypoventilation, crackles, wheezing, and radiologic images of air entrapment requiring bronchodilator administration (patient 2); a 16-month-old girl who had a febrile syndrome, basal crackles on pulmonary auscultation, and perihilar infiltrates (patient 3); and an 11-month-old boy with pneumonia of the upper left lobe (patient 4). The two remaining patients, a 7-month-old boy (patient 5) and a 9-month-old girl (patient 6), both with upper respiratory symptoms and clear chest, did not require hospitalization. In all six patients, outcome was favorable.>95% and oscillated from 86% to 88% when compared to those from a different cluster. During the second study season, we observed circulation of both clusters. When we compared these sequences of HMPV F gene obtained in Spain with those recently described in North America (>95% similarity with the isolate CAN97-83 (GenBank accession no. AY145296), and the sequences from the second cluster showed >95% similarity with isolates CAN98-73 to CAN98-79 (GenBank accession nos. AY145287\u2013AY145293), connecting the Canadian isolates to two well characterized groups of HMPV. Our results suggest that in Spain, as well as in other places in the world , and the second was composed of HMPV from patients 2 and 5 (GenBank accession nos. AY152849 and AY152848). The similarity among nucleotide sequences in the same cluster was"}
+{"text": "We aimed to assess whether high-dose preoperative chemoradiotherapy (CRT) improves outcome in esophageal cancer patients compared to surgery alone and to define possible prognostic factors for overall survival.2 on day 1 and 5-fluorouracil 1000 mg/m2/day, from day 1 through day 5 as continuous infusion. One course was given every 21 days. The last two courses were given concurrent with high-dose radiotherapy, 2 Gy/fraction and a median dose of 66 Gy. Kaplan-Meier survival analysis with log rank test was used to obtain survival data and Cox Regression multivariate analysis was used to define prognostic factors for overall survival.Hundred-and-seven patients with disease stage IIA - III were treated with either surgery alone (n = 45) or high-dose preoperative CRT (n = 62). The data were collected retrospectively. Sixty-seven patients had adenocarcinomas, 39 squamous cell carcinomas and one undifferentiated carcinoma. CRT was given as three intensive chemotherapy courses by cisplatin 100 mg/mToxicity grade 3 of CRT occurred in 30 (48.4%) patients and grade 4 in 24 (38.7%) patients of 62 patients. One patient died of neutropenic infection (grade 5). Fifty percent (31 patients) in the CRT group did undergo the planned surgery. Postoperative mortality rate was 9% and 10% in the surgery alone and CRT+ surgery groups, respectively (p = 1.0). Median overall survival was 11.1 and 31.4 months in the surgery alone and CRT+ surgery groups, respectively . In the surgery alone group one, 3 and 5 year survival rates were 44%, 24% and 16%, respectively and in the CRT+ surgery group they were 68%, 44% and 29%, respectively. By multivariate analysis we found that age of patient, performance status, alcoholism and > = 4 pathological positive lymph nodes in resected specimen were significantly associated with overall survival, whereas high-dose preoperative CRT was not.We found no significant survival advantage in esophageal cancer stage IIA-III following preoperative high-dose CRT compared to surgery alone. Patient's age, performance status, alcohol abuse and number of positive lymph nodes were prognostic factors for overall survival. Some studies have also suggested a possible positive effect on local tumor control by increasing the RT dose [Patients with esophageal cancer continue to have a poor prognosis with a 5 year survival rate less than 20%. Several factors contribute to this poor outcome, of which the most important is that the vast majority of patients demonstrate either locally advanced or metastatic disease at the time of diagnosis. Surgery has been relatively unsuccessful in controlling loco-regionally-advanced tumors and preoperative concomitant chemotherapy with radiotherapy (RT) followed by resection has become a treatment option. Several studies -3 have s RT dose . We therThe purpose of this study was to investigate the effect of dose intensification of preoperative CRT on overall survival compared to the outcome of surgery alone and possibly also to identify prognostic factors that might influence overall survival.Two-hundred and one esophageal cancer patients were entered into the database at Haukeland University Hospital, Bergen, Norway during the period 1996 to 2007. In this study we excluded 94 patients due to disease stage 0, I and IV (n = 54), only RT \u00b1 surgery (n = 17), definitive CRT due to medical contraindication of surgery (n = 17), only chemotherapy preoperatively (n = 2), different histology than carcinomas (n = 2), sequential chemotherapy and RT preoperatively (n = 1), and gastric cancer during autopsy (n = 1).The remaining 107 patients were treated with surgery alone (45) or preoperative concomitant high-dose CRT (62). The patients were assigned to surgery alone or CRT followed by surgery according to physician and patient preferences, mainly because survival benefits from preoperative CRT in this study period was considered controversial. Forty-six of 62 patients receiving CRT were deemed resectable before starting CRT and 16 of 62 with T4 tumors deemed resectable pending response to CRT and shrinkage.Staging of the tumors was performed according to UICC classification (2002)  by endos2, intravenous infusion over four hours on day 1, and 5-Fluorouracil 1000 mg/m2/day as intravenous continuous infusion, on day 1 through day 5. The chemotherapy course was repeated on day 22 and 43. RT was given concomitantly with the second and third chemotherapy courses and was applied as 2 Gy per fraction, 5 fractions per week, 33 fractions in 6.5 weeks to a total dose of 66 Gy. RT was given as CT-based conformal 4 fields' treatment in two phases. Phase 1 RT was given with two anterior-posterior parallel-opposed fields and two lateral oblique fields giving 50 Gy, taking into account the normal tissue tolerance of the spinal cord, heart and lungs. The additional 16 Gy were given using the same four fields, but with different angles for the lateral oblique fields. The gross tumor volume (GTV) was drawn directly onto the axial planning CT images using outlines of the defined primary tumor and nodal disease obtained from the EUS and CT scans. The delineated GTV was the macroscopic tumor including possible macroscopic pathological lymph nodes. The cranial and caudal margins were 3 cm from the GTV and the radial margin was 1.5 cm in the first phase of treatment (50 Gy). After treatment with 50 Gy the radial, cranial and caudal margins were reduced to 1 cm and additional 16 Gy to a total dose of 66 Gy were given. There was no time interval between the two RT phases. About one month following the completion of CRT, a chest and abdomen CT scan and EUS were performed to evaluate treatment outcome.The CRT protocol included three intensive chemotherapy courses concurrent with high-dose RT (66 Gy). Each chemotherapy course consisted of cisplatin 100 mg/mToxicities were evaluated and graded according to the National Cancer Institute (NCI) Common Terminology Criteria, version 3.0 .The patients were operated with a right-sided transthoracic or a transhiatal total esophagectomy. All patients had a two-field lymph node resection and left-sided cervical anastomosis, hand-sewn or stapled as of the decision of the surgeon. Most patients had a feeding catheter jejunostomy and feeding was started the day after the operation and continued for 7 - 12 days. All patients had a clinical follow up and underwent radiological and/or endoscopic surveillance when indicated.t tests for nominal and continuous variables, respectively. Exact Mann-Whitney U test was used for comparing ordinal as well as unevenly distributed continuous variables. Univariate assessments of categorical prognostic factors for survival and survival analysis were performed using the Kaplan-Meier method with log-rank tests, while continuous risk factors for survival were analyzed by Cox regression survival analysis.Statistical comparisons between the surgery alone and CRT groups were done with exact chi-square tests and independent samples Variables tested for possible influence on survival in univariate analysis were age, gender, smoking, alcoholism, heart disease, lung disease, diabetes mellitus, performance status, hemoglobin level, histology, histological differentiation, tumor (T)-stage at diagnosis, lymph node (N)-stage at diagnosis, disease stage at diagnosis, tumor length, tumor location in esophagus, preoperative CRT, operation method , number of lymph nodes with metastases in resected specimen .Factors found to be significant at univariate analyses were included in multivariate Cox regression survival analysis.The survival time was calculated from start of treatment (CRT or surgery) to the date of death or to censoring in May 1st 2009.All p-values are from 2-sided tests, p value \u2264 0.05 was considered statistically significant. All statistical analyses were performed by SPSS 15.0 . The study was approved by The Regional Committee for Research Ethics in Western Norway.Of the 107 patients included in the study there were 94 men and 13 women . Thirty-nine had squamous cell carcinomas, 67 adenocarcinomas and one had undifferentiated carcinoma. General pretreatment characteristics are shown in Table There were more smokers in the CRT group than in the surgery alone group  whereas comorbidities  and alcoholism were similar in both groups.Forty-nine patients (79%) received the planned 66 Gy, nine patients (14.5%) received from 60-64 Gy, whereas four patients (6.4%) received between 47.5 and 56 Gy. The mean and median delivered dose-intensities of cisplatin were 84% and 90% of the planned dose, respectively, while mean and median doses of 5-fluorouracil were 86% and 90%, respectively. All chemotherapy dose reductions were due to toxicity.Median time from end of preoperative CRT to surgical resection was 9 weeks (range 4 to 23 weeks) for patients who were operated on.CRT toxicity grade 3 occurred in 30 of 62 patients (48.4%) and grade 4 in 24 of 62 patients (38.7%). Toxicity grade 5 (death) occurred in one patient. This patient had grade 5 leucopenia, grade 5 neutropenia, grade 5 thrombocytopenia and died of neutropenic infection after completed CRT.The following CRT toxicities occurred as both grade 3 and 4: Leucopenia (37 patients), neutropenia (34 patients), neutropenic infection (13 patients), thrombocytopenia (20 patients) and reduced performance status (20 patients).CRT toxicities that occurred as grade 3 only were esophagitis (35 patients), stomatitis (12 patients), anorexia (23 patients), nausea (22 patients), vomiting (5 patients) and anemia in one patient. Each patient might have several types of toxicity.Fifty percent (31 patients) in the CRT group did not undergo the planned surgery. The reason for this was still T4 tumor after response to CRT (8), reduced performance status after CRT (8), cerebrovascular accident during the CRT (1), esophageal fistula and technical difficulties (1) and progression of disease with inoperability (13).In the surgery alone group 25 patients (55.6%) were operated by transthoracic esophagectomy (TTE) and 20 (44.4%) by transhiatal esophagectomy (THE), whereas in the CRT group 29 patients (46.8%) were operated by TTE, 31 (50%) were not operated, one underwent a by-pass operation due to fistula and one underwent abdominal exploration only due to peritoneal carcinomatosis.In the surgery alone group, 38 of 45 patients (84.4%) had a curative resection defined as no macroscopic and microscopic residual tumors and negative resection margins (R0), six patients (13.3%) had microscopic positive margin in the resected specimen (R1) and one (2.2%) had macroscopic residual disease (R2 resection) with infiltration in the trachea.Among the 31 operated patients in the CRT group 26 (84% of 31 patients) had R0 resections, three (10%) had R1 resections and two patients (6.4%) had R2 resections.Comparison of stage of disease before and after treatment in 31 operated CRT patients demonstrated down-staging in 58%, no change in 23% and up-staging in 19% of the patients  had pathological complete response (pCR) and 3 patients demonstrated a T0 tumor with 1 or 2 lymph nodes with residual metastasis.Patients having CRT and not undergoing surgery (31) could only be evaluated clinically. In these patients we found complete response in two (6.4% of 31), partial response in 14 (45.2%) and stable disease in one (3.2%). Progression of the disease was seen in 13 patients (42%) whereof nine had distant metastasis. One patient was not evaluated by CT/EUS after CRT, but had no clinical signs of progressive disease.In the surgery alone group there was a perfect concordance between preoperative clinical staging and the postoperative pathological staging Figure .Postoperative mortality and morbidities occurred during 30 days after operation or during the same hospital stay are listed in Table At time of analysis, 89 of 107 patients had died; follow up time was median 13.6 months for all 107 patients. Dead patients were followed up until death and the alive patients had a median follow-up of 95 months (range 21 - 137 months).Survival rates for surgery alone n = 45) and CRT followed by surgery (n = 31) are listed in Table 5 and CRTBy univariate analysis we found that a favorable overall survival was associated with preoperative CRT  was not reached in both groups Table . The rolOur study has, however, some limitations and the results should be interpreted with caution. The study was retrospective with limited number of patients and the treatment groups included both adenocarcinomas and squamous cell carcinomas. This is because at the time of this study, from 1996, the treatment of both histologies was almost the same and only last years the experts are trying to treat them differently.Another finding in our study was that the high-dose preoperative CRT group had a much higher frequency of serious toxicities compared to other studies applying lower doses of concomitant cisplatin, 5-fluorouracil and RT -25. ThisThe main reason for the inferior survival in esophageal cancer patients generally is the early and frequent occurrence of distant metastases. This was also found in our study, as we found a high proportion of distant metastasis in both treatment groups, and highest in the surgery alone group. It is obvious that refinements of chemotherapy or new and more effective systemic treatments, which are able to treat subclinical metastases, are required for these patients.The observed survival rate in the 31 CRT+ surgery patients in our series was not superior to what is reported in published series which applied lower doses of preoperative CRT ,22,26-30Our high-dose preoperative CRT did not show a significant survival advantage over surgery alone and over what is reported in previous studies applying cisplatin, 5-Fluorouracil and RT in conventional doses. Development of new cytotoxic regimens or other systemic therapies are required in order to cure subclinical distant metastases and significantly improve the prognosis. Age, performance status, alcohol abuse and number of positive lymph nodes are significantly associated with overall survival.The authors declare that they have no competing interests.ORM, MH, and AV assisted in the conception and design of the study. MH assisted in the collection and assembly of the data. MH, TWL, AV and K\u00d8 assisted in data analysis and interpretation. MH, AV, K\u00d8, TWL, ORM and RS assisted in writing the manuscript. All authors read and approved the final manuscript."}
+{"text": "This is a retrospective review of 119 patients who underwent cystocele repair by the same urologist using porcine dermal graft, polypropylene mesh or traditional repair from January 1999 to August 2005. Average follow-up of 13.5 months (range two to 46) was available for 99 patients. Fifty-six (57%) underwent cystocele repair using porcine dermal graft, 25 (25%) received polypropylene mesh and 18 (18%) underwent traditional repair. Twenty-two (22%) patients had cystocele recurrence. Thirty-six per cent patients (20 of 56) with porcine dermal grafts had recurrence compared to 4% (one of 25) and 6% (one of 18) using polypropylene and traditional repair, respectively. Mean time to cystocele recurrence was 4.9 months (range 0.5 to 20). Twelve patients (21%) had extrusion of porcine grafts through the anterior vaginal wall incision compared to one (4%) with polypropylene mesh. Short-term failure rate for anterior vaginal wall prolapse using porcine dermis interposition graft was higher than that for traditional anterior colporrhaphy or polypropylene mesh. In addition, the incidence of vaginal extrusion of porcine graft was unacceptably high. Porcine dermis is a less suitable material for cystocele repair than polypropylene mesh or traditional anterior colporrhaphy.Recurrent anterior vaginal wall prolapse can develop in more than 20% of patients undergoing traditional anterior colporrhaphy. In light of this high recurrence rate many surgeons have been incorporating synthetic or allograft mesh to augment the repair.In this study there are some shortcomings, including retrospective design, short follow-up for a study spanning almost six years and a lack of validated questionnaires. Authors report a negative experience with porcine dermis, both in terms of success and extrusion rate. However, others have reported better outcome which ma"}
+{"text": "The purpose of the study was to delineate the efficacy and toxicity of paclitaxel  in the treatment of drug resistant small-cell lung cancer (SCLC). Patients with SCLC relapsing within 3 months of cytotoxic therapy received paclitaxel 175 mg m(-2) intravenously over 3 h every 3 weeks. The dose of paclitaxel was adjusted to the toxicity encountered in the previous cycle. Of 24 patients entered into the study, 24 and 21 were assessable for response and toxicity respectively. There were two early deaths and two toxic deaths. No complete and seven partial responses (29%) (95%CI 12-51%) were observed and five patients had disease stabilization. The median survival (n = 21) was 100 days. Life-threatening toxicity occurred in four patients; in others (non)-haematological toxicity was manageable. Paclitaxel is active in drug-resistant SCLC. Further investigation in combination with other active agents in this poor prognosis group is appropriate."}
+{"text": "Whereas many patients respond quickly to treatment with tumour necrosis factor (TNF) inhibitors, some patients may experience significant but delayed responses.To evaluate the clinical response between 12 and 24 weeks in subjects with rheumatoid arthritis from the Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes.Clinical response was assessed at 24 weeks in 12-week non-responders, according to American College of Rheumatology (ACR) response criteria. The proportion of subjects who successfully maintained response to 52 weeks was analysed, as were radiographic outcomes.Data from 682 subjects were included in the analysis. Non and partial responders in all three groups  at week 12 showed an improvement in responses at week 24. Over 80% of the week 24 ACR20/50/70 responders in the etanercept plus methotrexate arm sustained their response to 52 weeks. In the etanercept arms, a delayed clinical response was not associated with increased radiographic progression at week 52.A significant proportion of non and partial responders to etanercept with or without methotrexate therapy at week 12 achieved a good clinical response or improved their overall clinical response at week 24. Discontinuing TNF inhibitor therapy at 12 weeks may be premature in some rheumatoid arthritis patients. Tumour necrosis factor (TNF) inhibitors, particularly in combination with methotrexate, have demonstrated excellent symptomatic and radiographic control in rheumatoid arthritis.6In this analysis, we used data from the Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes (TEMPO) to evaluate the extent to which subjects not responding to TNF inhibitor therapy at 12 weeks might respond at 24 weeks. The long-term sustainability of the improvement in response and radiographic outcome at week 52 was also assessed.Data from subjects treated with etanercept, methotrexate and etanercept plus methotrexate from the TEMPO study were used in this analysis.American College of Rheumatology (ACR)20/50/70 responses and Disease Activity Score using 28 joints (DAS28) were assessed at weeks 12, 24 and 52. Based on their clinical response at week 12, subjects were categorised into ACR20 non-responders (no response at week 12), ACR50 non-responders  and ACR70 non-responders .Among the subjects who showed an improvement in clinical response at week 24, the proportion of subjects who successfully maintained the improvement to at least 52 weeks was assessed. The radiographic outcome at week 52 was evaluated using the mean change in total Sharp score (TSS) and the percentage of non-progressors (TSS change \u22640).Frequencies and percentages were provided for improvement and decrease in ACR response and disease activity scores. One-way analysis of variance was used to test the difference in DAS28 scores among groups . The paired-sample t test was used to examine the difference in DAS28 scores between week 12 and week 24 and for week 12 European League Against Rheumatism (EULAR) non-responders who responded at week 24. Fisher\u2019s exact test was used to compare the difference in radiographic progression between the week 12 responders and week 12 non-responders who became responders at week 24 within each treatment group. Bonferroni adjustment was used for multiple comparisons. Logistic regression models were used to identify predictors of response at 12 weeks. Results were considered significant at p\u2a7d0.05 two-sided. Non-responder imputation was used to handle missing clinical and radiographic data. All analyses were performed using the SAS STAT system version 9.1.The TEMPO trial included 682 subjects . Baseline demographic characteristics for TEMPO subjects have been described previously.Results from the analysis of ACR20/50/70 responses at week 24 in week 12 non and partial responders are shown in Of 21 ACR20, 37 ACR50 and 23 ACR70 responders at week 24 in the etanercept plus methotrexate arm, 17 (81.0%), 31 (83.8%) and 19 (82.6%) subjects, respectively, showed a sustained response at week 52 . The susA decrease in ACR20/50/70 response was observed in some subjects between weeks 12 and 24. In the etanercept plus methotrexate arm, 18 out of 175 ACR20 responders (10.3%), five out of 96 ACR50 responders (5.2%) and five out of 51 ACR70 responders (9.8%) decreased their response at week 24 (data not shown). Similarly, 11.5% of ACR20, 23.3% of ACR50 and 4.8% of ACR70 responders in the etanercept monotherapy arm and 16.5% of ACR20, 10.2% of ACR50 and 23.1% of ACR70 responders in the methotrexate monotherapy arm decreased their response between weeks 12 and 24.In subjects from all three treatment arms who were EULAR (moderate or good) non-responders at week 12, but became responders at week 24, their mean DAS28 scores showed a significant decrease from baseline to week 24 and from week 12 to week 24 (p<0.05) . In the To determine if there was a slowing of radiographic progression in subjects who were ACR20 non-responders at week 12, but became responders at week 24 compared with week 12 responders, the mean change in TSS and the percentage of non-progressors were evaluated at week 52. Results are shown in No baseline characteristics or week 12 clinical variables  were significantly associated with a delayed response at 24 weeks.In this retrospective analysis, a substantial improvement in clinical response was observed between 12 and 24 weeks in subjects with rheumatoid arthritis in all three treatment arms from the TEMPO trial, including those who were non or partial responders at 12 weeks. The improvement in response at 24 weeks was most apparent in the etanercept plus methotrexate arm, in which 37.5% of ACR20, 46.8% of ACR50 and 51.1% of ACR70 non-responders became ACR20, ACR50 and ACR70 responders, respectively, at week 24. Similar improvements were observed for DAS28 scores in all three treatment arms.The delayed response observed at 24 weeks was largely sustained in 80% of subjects to 52 weeks and was not associated with an inferior outcome with regard to the inhibition of radiographic progression at 52 weeks in the etanercept and etanercept plus methotrexate arms.\u201312There are no clear guidelines on the appropriate treatment trial duration for TNF inhibitors. Recommendations from international guidelines vary, with most indicating 12 weeks as a time to assess response after TNF inhibitor therapy. Whereas some recommend discontinuing therapy at 12 weeks for non-responders, others allow for doctor\u2019s discretion on whether or not to continue therapy.7Importantly, an analysis of disease variables and patient characteristics failed to identify any predictive factors.\u2013The implications of this assessment are relevant with regard to the subsequent treatment of patients \u201cfailing\u201d TNF inhibitor therapy at 12 weeks. It has been shown that patients who have \u201cfailed\u201d therapy with a TNF inhibitor have somewhat lesser ACR responses to any second-line biological therapy.13Limitations of the current study include the retrospective nature of the analysis. Moreover, these findings are from patients enrolled in a randomised clinical trial who met the specific inclusion criteria and had high disease activity. Therefore, these observations may not reflect patients in a real-world setting.In conclusion, findings from this retrospective analysis suggest that a significant proportion of patients who do not achieve a clinical response 12 weeks after the initiation of etanercept with or without methotrexate therapy may benefit from continuing therapy for up to 24 weeks. Additional benefits of continuing therapy for up to 24 weeks include the sustainability of the 24-week gain in response through at least one year while maintaining radiographic protection."}
+{"text": "In 178 consecutive oesophageal squamous carcinoma cases, 5% (9 cases) had had thyrotoxicosis, hypothyroidism or thyroid carcinoma. The incidence in males was 1% (1 case) and in females 8% (8 cases). This incidence was in excess of other known associations of oesophageal cancer and in this series, it was exceeded only by previous gastric surgery for peptic ulceration."}
+{"text": "To identify chromosomal loci involved in the development of proximal gastric adenocarcinoma, this study delineated the pattern of allelic imbalance in a series of 38 adenocarcinomas arising in the gastric cardia. A total of 137 microsatellite markers covering all autosomal arms, excluding acrocentric arms, were analysed. A mean of 35 out of a total of 39 chromosomal arms studied were informative for each patient. The tumour group demonstrated a high level of allelic imbalance, with an observed median fractional allelic imbalance of 0.47 for the 29 intestinal-type adenocarcinomas and 0.54 for the nine diffuse-type adenocarcinomas. Allelic imbalance was detected in >50% of informative cases in both histological subtypes on a number of chromosomal arms. In the intestinal subtype, these included, 3p (61%), 4q (71%), 5q (59%), 8p (60%), 9p (65%), 9q (83%), 12q (52%), 13q (52%), 17p (78%) and 18q (70%). A higher incidence of allelic imbalance was detected on chromosome 16q in tumours of the diffuse type relative to those of the intestinal type. A more detailed mapping on chromosomes 4q and 6q identified a number of cases with subchromosomal breakpoints. In conclusion, this analysis has indicated regions of the genome potentially involved in the development of proximal gastric carcinomas."}
+{"text": "In 110 consecutive, medicolegal autopsies of young and middle-aged women (range 20-54 years) the breasts were examined by an extensive histopathologic method and by correlative specimen radiography. Malignancy was found in 22 women (20%) of which only one was known to have had clinical invasive breast cancer (IBC). At autopsy 2 women had IBC (2%), the remaining in situ carcinoma (in situ BC) of microfocal type (18%), i.e. 15 (14%) intraductal carcinomas (DCIS), 4 (3%) lobular carcinoma in situ (LCIS) and one (1%) both DCIS and LCIS. Forty-five per cent of the women with malignancy had multicentric and 41% had bilateral lesions. Forty-five per cent of all histologically confirmed malignant lesions were identified by specimen radiography. Adenosis, benign epithelial hyperplasia, papilloma and duct ectasia were positively associated with malignancy. In addition malignancy was significantly more frequent among women aged more than 40 years, with late age at first full-term pregnancy, with alcohol abuse and with steatosis or cirrhosis of the liver. The results suggest that clinically occult in situ BC are frequent in young and middle-aged women."}
+{"text": "The expression of HLA class I antigens was studied in 99 primary tumour  and 57 autologous metastases using immunohistological techniques and monoclonal antibodies against class I monomorphic determinants, HLA-B isotypic determinants and HLA polymorphic determinants. Fourteen per cent of colorectal, 9.6% of gastric and 20% of laryngeal carcinomas completely lacked class I molecules. Selective losses of HLA-B antigens were also detected in 8.8, 3.4 and 5.8% of these tumours respectively. Taking into account complete and selective loss of HLA-B the average alteration in the class I molecules expression totalled 21%. The comparison of class I expression between primary tumours and autologous metastases showed differences in 24% of the patients. These differences consisted mainly in a decrease of class I expression by metastases. Nevertheless, four types of divergence were detected in laryngeal carcinomas, namely: +/-, +/+, -/+, -/-. In addition, a clear correlation between degree of differentiation and class I expression was observed in laryngeal tumours. Finally, when class I gene RFLPs were compared with DNA from 15 tumours and autologous normal mucosa or peripheral lymphocytes, no differences were detected between these samples."}
+{"text": "Enterovirus 71 (EV71) causes life-threatening disease outbreaks in young children in Asia. This cohort study was conducted to understand the dynamics of maternal EV71 antibodies in Taiwanese young infants. Approximately 50% of neonates had detectable EV71 neutralizing antibodies, which declined to almost undetectable levels by 6 months of age. Transplacental maternal antibodies protect young infants from infectious diseases. On the other hand, maternal antibodies in young infants may impede vaccine effectiveness and confound interpretation of vaccine-induced immune responses. Thus, a need exists to understand the dynamics of pathogen-specific maternal antibodies in young infants (Enterovirus 71 (EV71) was first isolated in California, USA, in 1969. Since then, EV71 has been isolated globally and causes life-threatening outbreaks in young children in Asia  are crucial for estimating the seroprevalence in different ages  or SAS software .Neutralization antibody titers were log-transformed to calculate the GMT and 95% confidence intervals. Statistical association between 2 nominal or ordinary variables was tested by using the \u03c7Serum samples from 459 pregnant women and their neonates were obtained from June 2006 to June 2008 and tested for EV71 neutralizing antibody serostatus. Seropositive rates of EV71 neutralizing antibodies in these pregnant women and their neonates were 63% and 51%, respectively. Seroprevalence in mothers was strongly associated with seroprevalence in their neonates, and neonates born to seronegative mothers were all seronegative . In addition, the EV71 antibody titers in seropositive neonates were highly correlated with the EV7 antibody titers in their mothers  .From June 2006 through June 2008, a total of 309 neonates completed follow-up and blood collection at 6 months of age. EV71 neutralizing antibody titers in the serial serum samples from these 309 families were quantified. The seropositive rates of EV71 neutralizing antibodies in the family cohorts were 65% in the mothers, 50% in the neonates, and 1% in the 6-month-old infants, respectively . Only 4 Seroprevalence rates were predicted by making the assumptions that the seropositive rate of EV71 neutralizing antibodies at birth is 50%, that the GMT of these seropositive neonates is 21.8 (SD 0.91), and that the half-life of maternal EV71 neutralizing antibodies is 42 days (1.4 months). Seroprevalence rates of EV71 neutralizing antibodies during each of the first 6 months of age were predicted to be 35%, 25%, 14%, 7%, 3%, and 1%, respectively . The preWe found that \u224850\u201360% of pregnant women had serum EV71 neutralizing antibodies. These maternal EV71 neutralizing antibodies declined to undetectable levels in 99% of the 6-month-old infants. Two cross-sectional studies found similar seropositive rates in 30\u201349-year-old adults and in 6\u201311-month-old infants before the 1998 epidemic in Taiwan .Studies estimating the biologic half-life of EV71 maternal antibodies appear to be new. Theoretically, longitudinal analysis is more reliable and has narrower confidence intervals than cross-sectional analysis  needs to be identified. Several studies have shown that infants 6\u201311 months of age in Taiwan have the highest risk for severe EV71 infection and for death caused by this infection ("}
+{"text": "As part of West Nile (WN) virus surveillance in New York State in 2000, 71,332 ill or dead birds were reported; 17,571 (24.6%) of these were American Crows. Of 3,976 dead birds tested, 1,263 (31.8%) were positive for WN virus. Viral activity was first confirmed in 60 of the state's 62 counties with WN virus-positive dead birds. Pathologic findings compatible with WN virus were seen in 1,576 birds (39.6% of those tested), of which 832 (52.8%) were positive for WN virus. Dead crow reports preceded confirmation of viral activity by several months, and WN virus-positive birds were found >3 months before the onset of human cases. Dead bird surveillance appears to be valuable for early detection of WN virus and for guiding public education and mosquito control efforts."}
+{"text": "The files of the Childhood Cancer Research Group and of the Oxford Survey of Childhood Cancers were scrutinized for all the ovarian neoplasms registered in England, Scotland and Wales in children under age 15 years throughout the period 1962-78. Among 172 cases confirmed as malignant ovarian tumours, 145 (84%) were tumours of germ cell origin , 13 (8%) were epithelial carcinomas , 9 (5%) were sex-cord stromal tumours  and 5 (3%) were other miscellaneous tumour types. Less than 10% of the neoplasms occurred at age less than 5 years, approximately 20% from 5-9, and greater than 70% from 10-14 years. Germ cell neoplasms of greater malignancy  occurred in a significantly higher proportion at younger age (less than 10 years) than dysgerminomas (P = 0.01). The overall incidence (approximately 1.7 cases per 10(6) per annum) did not show any noticeable trend over the 17-year period considered. The clustering of two confined cases and, possibly, a third case, of germ cell neoplasms in three generations of the same family pointed to a genetic component in the aetiology of some of these neoplasms. A large number of sex related and mental or neurological abnormalities was also reported in case children. The 10-year survival rates, determined by the life-table method were: epithelial carcinomas 73%, sex-cord stromal tumours 44%, dysgerminomas 73%, malignant teratomas 33%, endodermal sinus tumours 39%, embryonal carcinomas 25%, other germ cell neoplasms 30% and gonadoblastomas 100%. Apart from cell-type, factors associated with prognosis were clinical stage , size and degree of histological differentiation . The adoption of efficacious polychemotherapy regimens completely changed the prognosis of germ cell tumours other than dysgerminomas (from 29% to greater than 85% disease-free survivors in the present series)."}
+{"text": "We have examined a series of human colorectal adenomas, carcinomas and cell lines derived from human colorectal cancer for loss of heterozygosity (LOH) on chromosome 11q22-23 by polymerase chain reaction (PCR) amplification of a microsatellite polymorphism of the dopamine D2 receptor (DRD2) locus. LOH was demonstrated in 5/30 (16.7%) adenomas and 23/68 (33.8%) carcinomas. Only 2/20 (10%) cell lines showed homozygosity which could potentially be as a consequence of LOH. This moderate level of loss in the tumour samples was probably not an underestimation as a result of excessive stromal contamination because high rates (68-77%) have been detected in the same samples on chromosomes 17 and 18. In contrast to a previous report, LOH in carcinomas at 11q22-23 occurred at a lower frequency and was not associated with Dukes' stage, degree of differentiation, mucin production or the location of the cancer. However, a significant association was found between LOH on chromosome 11 and chromosome 14. Thus, inactivation of any putative tumour-suppressor gene at 11q22-23 by LOH is not a very common event in the development of colorectal tumours, but may be biologically significant if accompanied by chromosome 14 deletions."}
+{"text": "Thymic epithelial tumours are broadly classified into thymomas and thymic carcinomas. Although both tumours occasionally show invasive growth, they exhibit different clinical and biological findings. The oncogene and anti-oncogene in thymic epithelial tumours have not been evaluated fully. We investigated the expression of p53 protein by immunohistochemical analysis using the anti-p53 polyclonal antibody (CM-1) in 17 thymomas and 19 thymic carcinomas. We also examined p53 gene (exon 5-8) mutation in 18 thymic carcinomas by using polymerase chain reaction-single-strand conformation polymorphism methods and direct sequencing. Of the thymoma cases, only one invasive thymoma showed focal nuclear staining. Fourteen of the 19 thymic carcinomas (74%) showed nuclear staining. Point mutations of the p53 gene were recognized in only 2 of the 18 thymic carcinomas (11%). One was the mutation C to T transition in the first letter of codon 222 in exon 6, which results in the amino acid substitution from proline to serine. Another was a silent mutation. p53 protein accumulation is highly frequent in thymic carcinomas but not in thymomas, and gene mutation is uncommon in thymic carcinomas."}
+{"text": "Quantitative real-time PCR assays, which are more rapid and practical than pp65 antigenemia determination, are progressively becoming the preferred method for monitoring Human Cytomegalovirus (HCMV) reactivation. However, the relationship between HCMV DNA and antigenemia levels is still under investigation. The aim of this study was to analyse the relationship between HCMV DNA and pp65 antigenemia levels in order to identify clinically useful threshold values for the management of patients.475 consecutive samples from 156 immunosuppressed patients were tested for HCMV by pp65 antigenemia and Real-time PCR assay.136 out of 475 consecutive samples derived from 48 patients showed evidence of HCMV infection. HCMV DNA was detected in 106 samples, pp65 antigen in 3, and both markers in 27. pp65 antigen detection was associated with higher HCMV DNA levels. The cut-off HCMV DNA level that best predicted pp65 antigenemia in this series of samples was 11,500 copies/ml, but different threshold levels could be observed for specific groups of patients. HCMV disease was observed in 5 out of 48 patients with active HCMV infection. The presence of clinical symptoms was associated with positive pp65 and with higher antigenemia levels. Higher HCMV DNA load at the onset of viral replication was correlated to the development of clinical symptoms.Both pp65 antigenemia and HCMV DNA load can be useful for the prospective monitoring of immunocompromised subjects. Specific cut-off levels capable of triggering preemptive antiviral treatment should be determined in accordance to the type of test used and the characteristics of patients and prospectively validated. Human Cytomegalovirus (HCMV) is the cause of lifelong latent infection in immune competent host. HCMV reactivation is a frequent event and represents a significant cause of morbidity and mortality in immunocompromised patients. The availability of diagnostic assays for the early identification of reactivated HCMV replication has considerably improved the clinical management of immunocompromised patients, thus reducing the risk of HCMV disease and allowing pre-emptive treatment as an alternative to universal prophylaxis. The determination of pp65 antigenemia has long been the reference test for monitoring HCMV reactivation -4, but iFrom June 2004 to March 2005, a total of 475 consecutive blood samples were received by our Laboratory for the simultaneous determination of pp65 antigenemia and quantitative HCMV DNA in plasma. The samples came from 156 patients . The median number of samples per patient was 8 (range: 6\u201328).Patients included 75 (48%) kidney transplant (KT) recipients, 18 (11.5%) bone marrow/stem cell transplant (BMT/HSCT) recipients (including 16 pediatric and 2 adult patients), 34 (21.8%) patients with advanced human immunodeficiency virus (HIV) infection and 29 (18.5%) patients with haematological malignancies.9 /l) and/or thrombocytopenia (platelet count < 100 \u00d7 109/l), gastrointestinal symptoms, artrhalgia, myalgia in KT recipients; fever, leukopenia, hepatitis, enteritis, retinitis or pneumonitis in BMT/HSCT recipients; colitis, oesophagitis, hepatitis, encephalitis or retinitis in patients with advanced HIV infection; fever and neutropenia (< 500 neutrophilis/ul) in haematological patients.Active HCMV infection was defined as the detection of HCMV antigenemia and/or DNAemia. HCMV disease was defined as the association of active infection with clinical symptoms such as: unexplained fever (> 38\u00b0C), leukopenia  before transplantation. In addition the patients received either an anticalcineurin agent or sirolimus. Intravenous ganciclovir or valganciclovir was administered when 50 or more pp65-antigen positive cells were detected. BMT/HSCT recipients underwent standard prophylaxis for bacterial and fungal infections, and received acyclovir 5 mg/kg body weight. Prophylaxis for HCMV infection was not administered. Intravenous ganciclovir  was started when > 1 pp65-positive cells/200,000 PMNL were detected, or after two consecutive HCMV DNA-positive samples. The same criteria were used for pre-emptive treatment of haematological patients. Patients with advanced HIV infection had CD4 cell count < 100 \u00d7 10The donor/recipient serological status was determined before transplantation by a commercially available enzyme-linked immunosorbent assay  according to the manufacturer's instructions.All transplanted patients were monitored for the presence of active HCMV replication for 6 months after transplantation. Determination of HCMV DNA load and of pp65 antigenemia was carried out once (in the absence of HCMV reactivation) or twice a week (during HCMV active replication) until disappearance of antigenemia and/or DNAemia; subsequently, HCMV replication was monitored monthly. HIV-infected and haematological patients were monitored monthly during routine clinical controls. In the presence of clinical signs or symptoms suggestive of HCMV disease monitoring was carried out once a week.Twin blood samples were collected in citrate-anticoagulated tubes for pp65 antigenemia and quantitative real-time PCR. One sample was processed for antigenemia within 4 hours, and the other was stored for quantitative plasma DNA determination. The determination of HCMV antigenemia was carried out using a HCMV BriteTurbo kit (Lagitre U.S.A.) according to the manufacturer's instructions. The number of pp65-positive polymorphonuclear leukocytes (PMNL) was determined after staining with specific fluorescein isothiocyanate-labelled monoclonal antibodies, with results expressed as the number of positive cells per 200,000 PMNL.DNA extraction from plasma (200 \u03bcl) was performed using a QiaAmp DNA Mini Kit  according to the manufacturer's instructions. HCMV DNA quantitation was carried out by a commercially available real-time PCR test: TaqMan Q-CMV Real Time System . This test is based on the simultaneous amplification of the HCMV MIEA (Major Immediate Early Antigen) gene (HCMV UL123-exon 4) and of internal control human beta globin gene DNA, that was added to each sample at a known concentration during specimen processing to monitor DNA extraction and recovery, amplification and detection. Specific TaqMan probes labelled with different reporter molecules (FAM/MGB-NFQ and VIC/MGB-NFQ) were used for target quantitation by interpolation of fluorescent signal intensity with a standard curve derived from the amplification of serially diluted HCMV DNA standards.6 HCMV DNA copies/ml of plasma.The assay was performed according to the manufacturer's recommendations. Briefly, DNA (5 \u03bcl) was added to the PCR mixture containing 5 mM MgCl2, 0.5 \u03bcM of each primer and probe and 0.025 U of uracyl-N-glycosylase (UNG). The PCR conditions were: decontamination at 50\u00b0C for 2 minutes, initial denaturation at 95\u00b0C for 10 minutes followed by 45 cycles of 15 sec at 95\u00b0C and 1 minute at 65\u00b0C. A plasmid containing UL123 gene diluted to give a standard curve of 2 log10 to 5 log 10 copies per reaction was used as a standard for quantification. PCR reactions were performed using an ABI Prism 7300 Sequence Detection System (PE Applied Biosystems). The linear interval of the assay's analytical sensitivity as assessed by the manufacturer was between 316 and 12.5 \u00d7 10The costs of the assays were measured in terms of requirements for time, reagents or kits, and labour.HCMV DNA levels were compared by Mann-Whitney U test. The correlation between HCMV DNA and pp65 antigenemia was analysed using the Spearman correlation coefficient.The differences between groups were analysed using the Chi-square test or the Fisher's exact test, as appropriate. A P value of < 0.05 was considered as statistically significant. Receiver-operating characteristic (ROC) curve analysis was carried out on the MedCalc statistical software, version 7.5.00.To analyse the precision of the real-time PCR assay, inter- and intra-assay variations were calculated by testing three plasma pools containing samples with low , intermediate  and high  viral load value. Intra- assay variation was evaluated by quantifying HCMV DNA load in triplicate for each plasma pool while inter-assay variation was calculated by analysing each plasma pool in four different assays.The mean DNA loads (copies/ml) detected in the low, intermediate and high titre plasma pools, and intra-/inter-assay percent coefficients of variation (CV%) are shown in Table Of the 475 samples analysed, 339 (71.3%) were negative for both HCMV DNA and pp65 antigenemia. The remaining 136 samples, taken from 48 patients , were positive for HCMV DNA , pp65 antigenemia , or both . HCMV assay results were discordant for 109 out of 475 samples (22.95%). Altogether, 51 episodes of active HCMV replication (defined by positive results of HCMV DNA and/or pp65 in at least two consecutive samples) were detected.6) compared to pp65-negative samples  (p < 0.0001) . All samples containing detectable pp65 antigen had significantly higher HCMV DNA levels . When the analysis was focused on single groups of patients, different threshold values between pp65-positive and -negative samples were found in KT recipients  compared to BM/HSCT recipients . The low number of pp65-positive samples in the remaining groups of patients (Table HCMV disease occurred rarely as symptomatic infection was observed in 5 of 48 patients with active HCMV replication (10.4%). HCMV DNA was detected in all 48 patients whereas pp65 was detected in 11, including 5 with symptomatic infection (p < 0.001).Among KT recipients  only one patient  developed symptomatic infection (fever and leukopenia) 44 days after transplantation. In this patient the diagnosis of HCMV infection was based on the simultaneous detection of pp65 and HCMV DNA. In the remaining 23 asymptomatic KT recipients, diagnosis of HCMV reactivation was made due to the detection of HCMV DNA with (4 cases) or without (20 cases) pp65.HCMV disease symptoms, including fever, leukopenia, increased aminotransferase levels, gastritis and pneumonitis, were observed in 4 (66.6%) out of 8 BMT/HSCT D+/R+ recipients during the first two months [range : 20\u201359 days] after transplantation. HCMV DNA preceded the onset of symptoms and pp65 detection in 3 of 4 cases, whereas pp65 and HCMV DNA appeared simultaneously in the last patient. The remaining 4 asymptomatic BMT/HSCT recipients only showed low-level HCMV DNA in the absence of pp65. In the remaining patients asymptomatic HCMV reactivation was diagnosed by the detection of HCMV DNA alone (15 cases) or simultaneously with pp65 (1 case). Altogether, HCMV DNA appeared before antigenemia in 3 out of 5 patients developing symptoms and in none of 6 pp65-positive patients without symptoms of HCMV disease.In symptomatic patients 29.1% of samples were positive for pp65 compared to 11.8% in asymptomatic patients (p < 0.001) Table . MoreoveMedian HCMV DNA level in the first positive sample was 22,400 copies/ml  in the 5 symptomatic patients, and 2677 copies/ml  in the 43 asymptomatic patients (p = 0.029). By contrast, the number of pp65 positive cells in the first positive sample did not differ significantly between symptomatic and asymptomatic patients . A HCMV DNA load > 7880 copies/ml at first detection could predict the onset of symptoms with 80% sensitivity and 79.1% specificity (area under curve: 0.800).HCMV infection responded to ganciclovir in all patients. The clinical monitoring of symptomatic patients during treatment revealed that pp65 became undetectable after 8\u201317 days (median: 12.5 days), whereas HCMV DNA decreased more slowly disappearing 7\u2013105 days (median: 41 days) after the beginning of treatment. Similar results were observed among patients without clinical symptoms: pp65 (detected in 6) disappeared after 7\u201320 days (median: 14 days), whereas HCMV DNA persisted for 3 \u2013 51 days (median: 33 days).HCMV pp65 antigenemia is known to be clinically useful for the management of HCMV reactivation in immunocompromised patients -4. Cut-oReal-time PCR methods for HCMV DNA quantitation could offer a convenient alternative for monitoring HCMV replication which is less influenced by the quality of sample and more suited to standardization and automation, compared to antigen detection tests. In addition, real-time PCR requires a small volume of plasma (200 \u03bcl) compared to 3\u20135 ml of whole blood required for antigenemia, and can be done on neutropenic patients. Finally, despite being considerably cheaper, pp65 requires longer technical labour and longer time for the production of a result and the processing of fresh samples.Although several studies have already addressed this issue ,16,19-23Discrepancies between the two HCMV markers may be linked to the distinct viral components analysed here (protein vs. genome), the different districts considered (PMNL vs. plasma), the sensitivity threshold of the tests. The observation of pp65-positive, HCMV DNA-negative samples could be due to pp65 transfer from endothelial cells to adhering PMNL, in the absence of viral replication ,24. A siProspective laboratory monitoring of patients allows for the timely adoption of therapeutic measures, thus reducing both the incidence and severity of HCMV disease in immunocompromised patients. Some studies describe an earlier rise in HCMV DNA levels, compared to antigenemia, in prospectively monitored patients ,14,17, wHCMV DNA levels were compared between samples with/without evidence of pp65-positive cells, considering pp65 antigenemia > 0 as the lowest possible cut-off level for the prediction of active HCMV infection. Significantly higher HCMV DNA levels were associated with the presence of pp65 antigenemia, while the threshold HCMV DNA value for optimal discrimination of pp65-positive or -negative samples differed according to the risk group. This observation suggests that the level of immune suppression can influence the relationship between HCMV DNA replication and symptomatic HCMV disease. Accordingly, different cut-off HCMV DNA values for risk of disease were detected in solid organ and stem-cell transplant recipients . The ideHCMV disease was observed in only 5 transplant recipients (10.4% of patients showing HCMV reactivation), who developed symptomatic infection shortly after kidney transplantation (1 patient) or BM/HSC transplantation (4 pediatric patients). The detection of pp65 was associated with symptomatic infection, and significantly higher pp65 levels were observed in symptomatic patients. A cut-off antigenemia level of 13 positive cells/200,000 PMNL, comparable to previous results , allowedIn this study pp65 antigenemia, despite lower sensitivity for the diagnosis of HCMV active infection compared to HCMV DNA load, showed better qualitative and quantitative correlation with the presence of symptoms. Only at onset of active replication was the DNA load able to discriminate patients at risk of developing HCMV disease. On technical grounds however pp65 antigenemia, although less expensive, is often difficult to perform in leukopenic samples and suffers from major pitfalls such as labor-intensive manual procedure, requirement for immediate sample processing, subjective interpretation of results. Thus both tests can be useful for the prospective monitoring of immunocompromised subjects. Clinically relevant cut-off levels should be identified for specific groups of patients and assays, and prospectively validated for their predictive value over the development of clinical symptoms of infection.The author(s) declare that they have no competing interests.EC and CPP designed the study, collected clinical data, analyzed the results, and wrote the manuscript; BV carried out experimental work and collected laboratory data; FP and CB contributed to data collection and draft of the manuscript; and NM revised the manuscript. All authors read and accepted the final version of the manuscript.The pre-publication history for this paper can be accessed here:"}
+{"text": "We conducted a case-control study in Wisconsin to determine whether some patients have long-term adverse health outcomes after antibiotic treatment for human granulocytic ehrlichiosis (HGE). A standardized health status questionnaire was administered to patients and controls matched by age group and sex. Consenting patients provided blood samples for serologic testing. Among the 85 previously treated patients, the median interval since onset of illness was 24 months. Compared with 102 controls, patients were more likely to report recurrent or continuous fevers, chills, fatigue, and sweats. Patients had lower health status scores than controls for bodily pain and health relative to 1 year earlier, but there was no significant difference in physical functioning, role limitations, general health, or vitality measures. The HGE antibody titer remained elevated in one patient; two had elevated aspartate aminotransferase levels. HGE may cause a postinfectious syndrome characterized by constitutional symptoms without functional disability or serologic evidence of persistent infection. Ehrlichia that preferentially infects granular leukocytes , 449 HGE cases were identified in the United States, mostly in the Northeast and Upper Midwest, despite limited reporting requirements Ixodes scapularisHuman granulocytic ehrlichiosis (HGE) is a recently identified tickborne infectious disease caused by a bacterium species of the genus Onset of clinical signs and symptoms of acute HGE typically follow a 5- to 10-day incubation period. The acute illness is nonspecific and often includes fever, chills, headache, and myalgia. Abnormal laboratory findings may include leukopenia, thrombocytopenia, and mildly elevated liver enzymes The acute phase of HGE is well characterized. The potential for persistent infection has been suggested but has not been evaluated. We conducted an exploratory case-control study of patients previously treated for HGE to assess health status, symptoms, and changes in serologic status.Ehrlichia equi by immunofluorescence antibody (IFA) test, 2) amplification of specific ehrlichial DNA sequences by polymerase chain reaction (PCR), or 3) demonstration of bacterial microcolonies (morulae) in leukocytes together with a single elevated titer. A probable case was defined as an acute febrile illness with a single elevated antibody titer >1:64 or presence of morulae The Centers for Disease Control and Prevention (CDC) HGE case definition was used. A confirmed case of HGE was defined as any acute febrile illness with laboratory confirmation consisting of 1) a fourfold or greater change in antibody titer to Both confirmed and probable cases of HGE were included in the case-control study. Although HGE officially became a notifiable disease in Wisconsin on April 1, 2000, we identified 111 cases of HGE in northwestern Wisconsin through specific surveillance activities from May 1996 to December 1998 <19, 20-39, and 10-year intervals for persons >40 years old) and gender. A structured questionnaire on health status and symptoms was administered by telephone to patients and controls. The survey consisted of items from six domains of the Medical Outcomes Trust 36-Item Short Form Health Survey (SF-36) We selected 225 controls from a pool of approximately 880,000 living Wisconsin residents who had received medical care from the Marshfield Clinic regional network. Controls were randomly selected from the same zip codes as patients and frequency matched on age group  and fluorescein isothiocyanate-conjugated goat anti-human immunoglobulin  diluted to 1:100. E. equi is closely related or identical to the agent that causes HGE ( Case-patients were asked to provide blood samples for HGE serologic testing and measurement of aspartate aminotransferase (AST). We performed polyvalent IFA on sera using <0.05 were considered statistically significant, and all are two-sided.Data were analyzed by using univariate logistic regression models with calculation of odds ratios (OR) and 95% confidence intervals (CI) by using SAS software ; p values We enrolled 85 (77%) of 111 persons with previously treated HGE (patients) and 102 (45%) of 225 controls. Of the 111 patients, we were unable to contact 13 (12%); 8 (7%) refused participation; 4 (4%) had since died of causes unrelated to HE; and 1 (1%) did not complete the survey. Among the 225 controls, we were unable to contact 56 (25%); 61 (27%) declined to participate; and 6 (3%) surveys were incomplete.There were 73 (86%) confirmed and 12 (14%) probable cases of HGE. Among confirmed cases, 32 (44%) were confirmed by serology alone; 13 (18%) by serology and polymerase chain reaction (PCR); 10 (14%) by PCR alone; 9 (12%) by serology, PCR, and presence of intracytoplasmic morulae; 6 (8%) by serology and presence of morulae; and 3 (4%) by PCR and morulae. Of the 12 probable cases, 9 (75%) had a single IFA serologic titer \u226564, and 3 (25%) had intracytoplasmic morulae identified in blood. The median age of patients was 58 years (range 6-88 years), and the median age of controls was 57 years (range 6-88 years); 66% of patients and 73% of controls were male. Data on coexisting conditions were available for all 102 controls and 39 (53%) of 73 confirmed cases. Comparison of the 39 cases and 102 controls demonstrated no significant difference in the prevalence of cancer (p=0.36), stroke (p=0.49), heart disease (p=0.89), or diabetes (p=0.65).>7 days. The median interval from illness onset to initiation of treatment was 7 days. Nineteen (22%) enrolled patients had evidence of Lyme disease during the acute illness, either the characteristic rash, erythema migrans (14 patients), or seroconversion to Borrelia burgdorferi (7 patients). Six (8%) of 76 enrolled patients tested also seroconverted to Babesia microti after the acute illness.For HGE patients, the median interval from illness onset to telephone interview was 24 months (range 10-40 months). Twelve patients had onset of HGE in 1996, 35 in 1997, and 38 in 1998. The illness was severe enough in 32 (38%) patients to require hospitalization. All 85 enrolled patients received some form of antibiotic treatment for acute illness. Of the 59 patients for whom we have sufficient information, 53 (90%) were prescribed doxycycline for Compared with controls, patients were more likely to report the following constitutional symptoms either continuously or repeatedly during the previous year: fevers, chills, sweats, and fatigue . Patient>512) were no more likely than the other patients to experience one or more of the recurrent or continuous symptoms.The presence of continuous or recurrent constitutional symptoms and the duration of acute illness were not correlated. Patients who were hospitalized or who started antibiotics more than 14 days after onset of illness were no more likely to experience recurrent symptoms than those who received antibiotic treatment within 14 days. Similarly, patients with 1) a preexisting chronic illness, 2) intragranulocytic morulae in an acute-phase blood smear, 3) laboratory evidence of concurrent Lyme disease or babesiosis, 4) anemia, or 5) a high acute- or convalescent-phase reciprocal HGE IFA antibody titer (>1:64) in one (1.4%) of 70 specimens tested. This patient had a very high titer after acute infection , which remained elevated (1:256) 1 year later. He experienced continuous or recurrent fatigue, vomiting, and headaches. Two (2.9%) of 69 patients had elevated (>100 U/L) serum AST levels; one complained of continuous or recurrent chills, sweats, and fatigue.Serum specimens were submitted for serologic testing by 70 (82%) of 85 patients. The HGE IFA antibody titer remained elevated  of 24 patients at 12 months, 4 (44%) of 9 at 18 months, and 2 patients (denominator not reported) at 30 months E. equiFew previous studies have evaluated the long-term serologic profile of treated HGE. Results of one study of treated HGE demonstrated that antibody titers remained elevated 11 to 14 months after onset in 5 of 10 patients tested E. canis and E. equi, respectively, in tissues up to 2 months after treatment with doxycycline (Animal studies and case reports have suggested the possibility of chronic or recurrent HGE. Experimental ehrlichiosis infections in dogs and horses have demonstrated the presence of Our study used current national case definitions for HGE The primary outcome measures in this study were based on self-reported symptoms. Without laboratory confirmation of persistent infection, recall bias should be considered as a possible explanation for the findings. Because of the severity of their past illness and because this was not a blinded study, HGE patients may have been more aware of their constitutional symptoms and had better recall of them than controls. Selection of controls is another potential source of bias if they were less likely to have coexisting chronic diseases compared with cases. However, we found no statistical difference in the prevalence of cancer, stroke, heart disease, or diabetes between cases and controls.Previous studies of various infectious diseases have suggested that convalescence from illness is significantly dependent on the emotional state of the patient. In those studies, as in ours, fatigue was often a persistent symptom (Ehrlichia infection.In summary, we found that a subset of patients with HGE have persistent constitutional symptoms 1-3 years after treatment, without functional disability. Further research is needed to determine whether these symptoms are related to the previous ehrlichial infection or other causes. In the absence of serologic evidence of persistent infection, we believe these symptoms are most likely due to a postinfectious syndrome. Further studies that use PCR testing of convalescent-phase samples would be helpful to exclude the remote possibility of persistent"}
+{"text": "A case-control study of 913 black cancer patients (aged 15-50 years) was undertaken to measure the association between human immunodeficiency (HIV) infection and cancers believed to have an infective aetiology. Controls were patients with cancers believed not to be infective in origin. The prevalence of HIV in the controls of 7.3% (24 of 325) was similar to the background HIV seropositivity in this population. Odds ratios (ORs) and 95% confidence intervals (CI) adjusted for age, year of diagnosis, marital status and sex were calculated. There was a strong association between HIV infection and Kaposi's sarcoma (KS), with 27 of 33 cases being HIV seropositive, OR = 61.8 (95% CI 19.7-194.2) and an elevated association with non-Hodgkin's lymphoma (NHL), with 27 of 40 cases being HIV seropositive [OR = 4.8 (95% CI 1.5-14.8)]. The elevated odds ratio for KS associated with HIV infection accords with the observed increases in the incidence of KS in several sub-Saharan African countries where the prevalence of HIV is high. The odds ratio for NHL associated with HIV infection was lower than that reported in developed countries, and the reason for this is not clear. No other cancers, including cervical and liver cancers, showed significantly elevated odds ratios associated with HIV infection."}
+{"text": "Thoracic hyperkyphosis is a frequent problem and can impact greatly on patient's quality of life during adolescence. This condition can be idiopathic or secondary to Scheuermann disease, a disease disturbing vertebral growth. To date, there is no sound scientific data available on the management of this condition. Some studies discuss the effects of bracing, however no guidelines, protocols or indication's of treatment for this condition were found. The aim of this paper was to develop and verify the consensus on managing thoracic hyperkyphosis patients treated with braces and/or physiotherapy.The Delphi process was utilised in four steps gradually modified according to the results of a set of recommendations: we involved the SOSORT Board twice, then all SOSORT members twice, with a Pre-Meeting Questionnaire (PMQ), and during a Consensus Session at the SOSORT Lyon Meeting with a Meeting Questionnaire (MQ).There was an unanimous agreement on the general efficacy of bracing and physiotherapy for this condition. Most experts suggested the use of 4-5 point bracing systems, however there was some controversy with regards to physiotherapeutic aims and modalities.The SOSORT panel of experts suggest the use of rigid braces and physiotherapy to correct thoracic hyperkyphosis during adolescence. The evaluation of specific braces and physiotherapy techniques has been recommended. Kyphosis can be paradoxically more difficult to treat than scoliosis. There are many types of kyphosis that require various strategies of treatment. Furthermore, there is only a little evidence on the conservative treatment of kyphosis, less than that on scoliosis. With lacking information on the natural history, the difficulties of clinical and radiological assessment, the unclear definition of normal kyphosis and the variety of clinical forms and etiology, vague indications of treatment are allowed for at best. Untreated, kyphosis in the growing child may lead to a progressive deformity of the spine and back pain. At birth, the entire spine shows a slight posterior curve from the occiput to the sacrum. When the baby begins to hold his head up, a cervical lordotic curve develops. However with the sitting position a total kyphosis can be encouraged. With weight bearing and ambulation, the pelvis tilts forward and a lumbar lordosis develops. Staffel  classifiIn the early twentieth century, radiographs allowed Scheuermann  in CopenIn 1939, Schmorl [In 1964, in his monograph Sorenson [Subsequently many authors have proposed normal ranges of posterior sagittal thoracic curves of: 20\u00b0-40\u00b0 for Roaf  and 30 \u00b0The great variance in the range of curve angles in thoracic kyphosis may rely on the radiological position it was taken. In 1982, Stagnara de Mauroy et al.  defined The pathogenesis of Scheuermann's disease was described in 1986 by Aufdermaur [Ippolito  highlighIn 1977, White and Panjabi,  describein 1999, Wenger and Frick  publisheLittle is written on the subject of the lumbar or thoracolumbar patterns of Scheuermann's disease. The Schmorl's nodes and endplate irregularity may be so severe that the lower lumbar Scheuermann's disease can be confused with infection, tumor, or other conditions . The etiThe loss of lordosis in this area of the lumbar or thoracolumbar spine means that Scheuermann's disease can be one of the predictors of developing chronic low back pain in adulthood:Loss of lumbar lordosis correlates well with the incidence of chronic low back pain in adulthood ,20. SedeThis discussion has been opened after the time this consensus paper has been planned, and it has been presented at the SOSORT Lyon meeting at the time the Delphi process was already ongoing. Therefore not all of the latest updates have been included into the questionnaires. Nevertheless the consensus papers are part of a constant process of development and therefore this actual discussion will surely be part of future consensus papers on this topic.The conservative orthopedic treatment with casts and braces was developed in parallel to that of scoliosis 60 years ago. This treatment is intended primarily for normal idiopathic kyphosis or kyphosis developing secondary to Scheuermann's disease. Wearing a brace can prevent the collapse of the anterior wall of the vertebral body and in some cases of Scheuermann's, to help reform this.Due to this lack of understanding a Consensus among experts can at this point give some more understandings about this neglected area of research. Since 2005, SOSORT is developing systematically and yearly Consensuses on the different areas of conservative treatment of spinal deformities -30. The The Delphi method was used which is a systematic, interactive forecasting method which relies on a panel of experts. The experts answer questionnaires in two or more rounds. After each round, a facilitator provides an anonymous summary of the experts' forecasts from the previous round as well as the reasons they provided their comments. Thus, experts are encouraged to revise or clarify their earlier answers in light of the replies of other members of their panel. It is believed that during this process the range of answers will decrease and the group will converge towards the \"correct\" answer. Finally, the process is stopped after a pre-defined stop criterion (Q26 & 27) and the mean or median scores of the final rounds determine the results.Each question (Q) is deemed positive or negative by Consensus. Due to the low Consensus in general on this topic we split the possible Consensus as follows: Strong Consensus (over 90%), Good Consensus (75%-89%), Weak Consensus (51-74%)As some questions were added in the second and third round. the order of questions were modified to make the text easier to read.Q1 Title: Bracing and physiotherapy can be useful for Juvenile Kyphosis and can modify the natural progression.Results: For the Q1 we have 100% positive answers. This point has achieved Consensus.Comment: Restoration of lordosis at the Thoracolumbar area is proven effective.Discussion: In literature [terature  the answQ2 Title: Do you treat Kyphosis conservatively at your Center?Results: For the Q2 we have also 100% of positive answers. This point has achieved Consensus.Discussion: This confirms the previous question.Q3 & 4 Title: What are the therapeutic aims of physical exercise in the treatment of patients at risk of brace and what is the priority?Results: We have given a score according to priority: 3 = high priority, 2 = medium priority, 1 = low priority, 0 = non selected. The results are presented in order of importance of the score.Self control of posture (79), auto-elongation (75), Proprioception (66), Muscular endurance (53), ergonomics (53), Breathing techniques 51), Pectoral stretching (50), Neuromotorial control (50), Muscular strengthening (50), Sport (49), Hamstring mobilization (49), Sensori-motor integration (48), Equilibrium (45), Vertebral mobilization (44), General Motor capacities (40), Coordination (40), Back school (30). [See figure , PectoraComment: The purpose is to correct them in auto-elongation looking for the best 3D correction  and stabilize it isometrically. Then train them to automatically change to this new posture.Discussion: Looking at Q3 and Q4, it appears that self control posture {79/81 = 98%} and auto-elongation {75/81 = 93%} with the use of proprioception are the most used techniques. The back school is rarely used. It is difficult to see a consensus on other physiotherapy techniques, which reflects the diversity of kyphosis.Q15 Title: Do you usually give some \"home exercises\" to practice daily? If yes, how long every day.?Results: Yes (8), No (3), 10 minutes (1), twenty minutes (4), thirty minutes (2), more (2)[See figure Comments: Advised to avoid too much sitting and change their sitting position often. Use the prone position for reading and watching TV. Sit on the edge of a chair with alternative extension on one hip. I encourage them to do more  the level of correction and concentration while they do it because this will be more successful for them.Discussion: This question was added after the comments from the first round. We have a consensus for home exercises and the average time is 20 minutes, which in France is the official duration of a session of physiotherapy exercises in vertebral deviation.Q5 & 6 Title: Why do we treat Kyphosis and the priority of this?Results: Like Q 3 & 4 we have given a score according to priority.91%), Back pain (72/81 = 89%), Quality of life (69/81 = 85%), Aesthetics (67/81 = 83%), Progression in adulthood (58/81 = 72%), Psychological well being (57/81 = 70%), Cobb degree (55/81 = 68%), Disability (43/81 = 53%), Breathing Function (38/81 = 47%).Scheuermann , Anatomical localization (72/81 = 89%), Local pain at the apex of kyphosis (70/81 = 86%), Cobb degree (64/81 = 79%), Disharmony of kyphosis (62/81 = 77%), Family history (49/81 = 60%), Indirect shoulder rigidity (49/81 = 60%), Indirect pelvic rigidity (42/81 = 52%), RMI-scanner (22/81 = 27%) [See figure Direct rigidity of the spine , Custom made (63/81 = 78%), Made to measure (47/81 = 58%), Cad Cam (35/81 = 43%), In day Hospital (32/81 = 39%), Plaster cast before (30/81 = 37%), Plaster cast moulding (29/81 = 36%), in Hospitalization (14/31 = 17%) [See figure  47/81 = 8%, Cad CDiscussion: We have achieved a consensus for physiotherapy before bracing and no hospitalization {67/81 = 83%}.Q16 Title: What are the physiological reasons for the patient to wear the brace and its priority?Results: To avoid hyperflexion on the anterior wall (36/36 = 100%), discourage bad posture (19/36 = 53%), Pain (19/36 = 53%), Stretch(19/36 = 53%), relax (10/33 = 30%) [See figure Comment: To restore proper alignment of muscular forces. To give the thoracolumbar discs space again for proper development by reducing continuous loading.Discussion: We have a consensus with the biomechanical approach of White and Panjabi.Q17 Title: According to your experience and results -- what are the main criteria for an unsuccessful treatment (physiotherapy or brace) and their priority?Results: Rigidity (33/33 = 100%), Angular curve (30/33 = 91%), Cobb degree (27/33 = 82%), High Risser (24/33 = 73%), high thoracic curve (19/33 = 58%), Scheuermann (17/33 = 52%), hypotonia, (15/33 = 45%), Thoraco-lumbar pattern (9/33 = 27%), Family history (9/33 = 27%), Pain (8/33 = 24%), Hypermobility (8/33 = 24%), Excess of sport (7/33 = 21%) [See figure  degree 2/33 = 82%Comment: Compliance is the main criteria. When there is a good compliance results are good regardless of curve rigidity and Cobb angle.Discussion: The hierarchy of factors making the conservative treatment difficult is a valuable indicator to justify early treatment. The clinical examination should come before radiological findings.thoracic kyphosis?Q18 Title: What is your most frequent protocol of wearing the brace in adolescent Results: Permanent (7), Night & school (4) night & after school (4) after school only (1), School only (0), Night only (0) [See figure Discussion: The consensus for night and day wearing means that the intended effect of the brace is not only a mechanical support in the erect position but also concerns the Wolff's laws like scoliosis during nocturnal growth.thoraco-lumbar kyphosis?Q19 Title: What is your most frequent protocol of wearing the brace for adolescent Results: Permanent (3), Night & school (3) night & after school (1) after school only (1), School only (0), Night only (0) [See figure Discussion: For this pattern, there is a consensus with the sitting position.pre-pubertal kyphosis?Q20 Title: What is your most frequent protocol of wearing the brace for Results: Permanent (3), Night & school (2) night & after school (4) after school only (1), School only (0), Night only (0) [See figure Discussion: The majority of respondents are in favor of a part time protocol. Unlike scoliosis there is a consensus to exclude only wearing it at night which confirms the importance of factors related to postural vertical loading in kyphosis.The following three questions were developed for the 3rd round. After the 2nd round, it became impossible to define patterns of braces. We have therefore tried to approach the consensus with the technical descriptors of these orthotics.thoracic kyphosis?Q21 Title: Choose your ideal brace for adolescent Results: material | plexidur (2), polypropylene (2), polyethylene low density (2), polyethylene high density (7)Opening | lateral (5), posterior (2), anterior (4)Level of the brace | Iliac crest (2), lateral pelvis (2), cervical (0), clavicular (3) sternal (5)Pressure points | 3 anterior with pelvis, inferior thorax, and sternum (3), 2 anterior point with pelvis and sternum (7), 2 posterior with sacrum and apex kyphosis (9), one posterior with apex kyphosis only (1) [See figure 11Discussion: There is slight consensus for polyethylene high density material, however no consensus for brace opening and consensus for a sternal support.The biomechanical effects can be:3 points: one posterior, 2 anterior like traumatic kyphosis4 points: two posterior (lordosis control) and two anterior5 points: two posterior and three anterior for better control of lordosis.There is a consensus for a four points system, even if it is easier to control the sagittal posture of the spine with a 5 point system. This point deserves further discussion.thoraco-lumbar kyphosis?Q22 Title: Choose your ideal brace for adolescent Results: material | plexidur (2), polypropylene (1), polyethylene low density (2), polyethylene high density (3)Opening | lateral (2), posterior (2), anterior (2)Level of the brace | iliac crest (1), pelvic lateral (2), cervical (0), clavicular (1) sternal (0)Pressure points | 3 anterior with pelvis, inferior thorax, and sternum (1), 2 anterior point with pelvis and sternum (6), 2 posterior with sacrum and apex kyphosis (5), one posterior with apex kyphosis only (3) [See figure Discussion: There is no consensus for material, no consensus for opening and consensus for a very logical 4 points system.juvenile kyphosis?Q23 Title: Choose your ideal brace for Results: material | plexidur (0), polypropylene (0), polyethylene low density (0), polyethylene high density (2)Opening | lateral (0), posterior (3), anterior (0)Level of the brace | iliac crest (0), pelvic lateral (2), cervical (1), clavicular (0) sternal (0)Pressure points | 3 anterior with pelvis, inferior thorax, and sternum (0), 2 anterior point with pelvis and sternum (2), 2 posterior with sacrum and apex kyphosis (1), one posterior with apex kyphosis only (2) [See figure Discussion: There is consensus for polyethylene posterior opening brace, corresponding to the Milwaukee brace.Q 24 Title: What is the best time for initiating bracing with a rigid kyphosis brace (boy)?Results: < 12 years (0), 12y (3), 13y (3), 14y (1), 15y (1), 16y (0), 17y (0), >17y (0) [See figure Discussion: There is consensus; the best age for bracing seems to be at the beginning of puberty.Q25 Title: What is your minimum period to maintain the brace?Results: 6 months (1), 1 year (2), 18 months (2), 2 years (4), more (0) [See figure Discussion: Taking into account the age of onset to starting treatment (Q22) there is a consensus to maintain the brace till the end of growth but without waiting for definitive bone maturity at Risser 5.Q26 Title: What is the best moment for brace weaning?Results: 6 months (1), 18 months (1), end of growth (7), Risser 5 (3), other (0) [See figure Discussion: This question was asked to verify the consistency of responses. We can confirm that there is a consensus to maintain the brace till the end of growth but without waiting for definitive bone maturity at Risser 5.Q11 Title: Case N\u00b0 1: girl, 13 years, no pain, with idiopathic Kypho-lordotic posture (figure e figure Results: Physiotherapy (25/27 = 93%), Rigid brace (12/27 = 44%), Control (4/27 = 15%), Soft brace (3/27 = 11%), Plaster cast (1/27 = 4%), Surgery (0 = 0%), Nothing (0 = 0%) [See figure Discussion: We have a consensus for physiotherapy and no surgery.Q12 Title: Case N\u00b02: Boy, 15 years, postural pain, idiopathic, low pelvic incidenceResults: Physiotherapy (26/27 = 96%), Rigid brace (18/27 = 67%), Control (2/27 = 7%), Soft brace (1/27 = 4%), Plaster cast (1/27 = 4%), Surgery (0 = 0%), Nothing (0 = 0%) [See figure id brace /27 = 67%Discussion: We have the same consensus for physiotherapy as Q11, but more indications for a rigid brace and consensus to avoid surgery.Q13 Title: Case N\u00b0 3: Boy, 16 years, pain, Scheuermann, Rigid thoracic curveResults: Physiotherapy (21/27 = 78%), Rigid brace (20/27 = 74%), Plaster cast (8/27 = 30%), Surgery (5/27 = 19%), Control (3/27 = 11%), Soft brace (1/27 = 4%), Nothing (0 = 0%) [See figure y 5/27 = %, ControDiscussion: We have a consensus for physiotherapy and rigid brace in this case.Q14 Title: Case N\u00b0 4: Girl, 15 years, thoraco-lumbar kyphosis, pain, low pelvic incidenceResults: Physiotherapy (22/27 = 81%), Rigid brace (17/27 = 63%), Plaster cast (8/27 = 30%), Soft brace (3/27 = 11%) [See figure Discussion: We have a consensus using physiotherapy and a rigid brace. Unlike the case N\u00b03, there is a consensus against surgery, which emphasizes the importance of conservative treatment for this type of kyphosis.Q26 Title: Do you have some suggestions on the questions already prepared?Results: No (14), Yes (1)Comment: \"The treatment of hyperkyphosis should be evaluated according to the aetiology.\"Discussion: Initially, we limited the outset regarding the aetiologies and idiopathic kyphosis. Other causes could require another consensus.Q27 Title: Do you want some more questions?Results: No (15), Yes (0)Discussion: We are at the end of the consensus.Kyphosis and they practice this treatment daily in their clinical practice. Therefore, is there a need for consensus in the treatment of kyphosis.The experts from SOSORT are convinced of the usefulness of conservative treatment for the management of The main rehabilitation techniques used are: self postural control and self-elongation. Back school does not seem useful. These physiotherapy exercises should be repeated at home daily for 20 minutes. It is useful before bracing.The main indications are Scheuermann and pain especially if the kyphosis is rigid.The biomechanical base for conservative treatment is to decrease mechanical stress on the anterior wall of the vertebral body.The main indications for early treatment are: rigidity, size of the curve and the Cobb angle.The best time is at the onset of puberty. The brace should be worn for about 2 years and removed at the end of growth without skeletal maturity at Risser 5.For a Thoracic KyphosisThe brace must be worn all night and for part of the day. The most ideal brace is a 4 point system or a 5 point system in case of muscular imbalance.For a Thoraco-lumbar kyphosisThe brace must be worn during the day in the sitting position and the ideal brace is a 4 point system.For a juvenile kyphosisThe brace must be worn part time, and the ideal brace is the Milwaukee.The four clinical cases:- physiotherapy for muscular idiopathic kypho-lordosis without rigidity.- brace for an idiopathic painful kyphosis- Rigid brace and plaster cast for a rigid thoracic or thoraco-lombar dystrophic curveThe authors declare that they have no competing interests.Written informed consent was obtained from the patients for publication of this report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.JCdM created the initial and successive questionnaires, chaired this consensus paper at the Lyon SOSORT Meeting, May 23--25, 2009, processed the collected data on a web form, collected the literature and contributed in drafting the manuscript. All co-authors contributed in some way to the improvement of the initial questionnaire and in drafting the manuscript. The other members of the SOSORT board contributed by reviewing, text editing and adding certain text files and references. All authors have read and approved the final manuscript."}
+{"text": "To assess the confidence, practices and perceived training needs in diabetes care of post-graduate trainee doctors in the UK.An anonymised postal questionnaire using a validated 'Confidence Rating' (CR) scale was applied to aspects of diabetes care and administered to junior doctors from three UK hospitals. The frequency of aspects of day-to-day practice was assessed using a five-point scale with narrative description in combination with numeric values. Respondents had a choice of 'always' (100%), 'almost always' (80\u201399%), 'often' (50\u201379%), 'not very often' (20\u201349%) and 'rarely' (less than 20%). Yes/No questions were used to assess perception of further training requirements. Additional 'free-text' comments were also sought.82 doctors completed the survey. The mean number of years since medical qualification was 3 years and 4 months, (range: 4 months to 14 years and 1 month). Only 11 of the respondents had undergone specific diabetes training since qualification.4(5%) reported 'not confident' (CR1), 30 (37%) 'satisfactory but lacked confidence' (CR2), 25 (30%) felt 'confident in some cases' (CR3) and 23 (28%) doctors felt fully confident (CR4) in diagnosing diabetes. 12 (15%) doctors would always, 24 (29%) almost always, 20 (24%) often, 22 (27%) not very often and 4 (5%) rarely take the initiative to optimise gcaemic control. 5 (6%) reported training in diagnosis of diabetes was adequate while 59 (72%) would welcome more training. Reported confidence was better in managing diabetes emergencies, with 4 (5%) not confident in managing hypoglycaemia, 10 (12%) lacking confidence, 22 (27%) confident in some cases and 45 (55%) fully confident in almost all cases. Managing diabetic ketoacidosis, 5 (6%) doctors did not feel confident, 16 (20%) lacked confidence, 20 (24%) confident in some cases, and 40 (50%) felt fully confident in almost all cases.There is a lack of confidence in managing aspects of diabetes care, including the management of diabetes emergencies, amongst postgraduate trainee doctors with a perceived need for more training. This may have considerable significance and further research is required to identify the causes of deficiencies identified in this study. Prevalence of diabetes in adults worldwide was estimated to be 4.0% in 1995 and to rise to 5.4% by the year 2025. . People Multiple therapeutic interventions for preventive care make these patients increasingly complex to manage. It is common for patients to be on multiple tablets to address blood glucose control  and InsuThere are many potential barriers to the acquisition of knowledge and skills in management of diabetes by trainee doctors , with thA pre-validated anonymised questionnaire was delivered by post (single mailing) to trainee doctors in three different centres in the UK  with covering letters from the local investigators inviting them to participate.The target sample was defined as all post graduate trainees in general  medicine and related specialties including emergency medicine and intensive care medicine. Specialist trainees in diabetes and endocrinology were excluded. This cohort with day-to-day exposure to the theory and practice of diabetes care provides a representative sample to assess current practice and training. We consulted the local ethics committee was consulted and formal application was considered not necessary. All respondents consented to the use of their responses for analysis. We aimed to approach two hundred trainees expecting a 30% response rate.To assess self-reported confidence among junior doctors, we used the 'Confidence Rating' (CR) scale used by the Royal College of Physicians in the self-assessment of trainees . The scaThe questionnaire was validated in a four-stage process: Initial review by external experts in the field of diabetes, administration of initial draft on a sample cohort, revision of questionnaire based on feedback and final external review.Self-reported answers were tabulated and expressed as number (n) and in percentages rounded off to the next percentage point.82 doctors returned the completed survey, achieving a 41% response rate with 200 questionnaires sent out. 19 were house officers or Foundation Year 1 doctors, 48 were senior house officers or Foundation Year 2 doctors, 11 were specialist registrars and four did not specify their stage of training. The mean number of years since medical qualification was 3 years and 4 months, (range: 4 months to 14 years and 1 month).Only 10 of the respondents had undergone specific diabetes training since qualification. 35 of the doctors had never worked in teams lead by specialists in Diabetes, the rest on average having worked for 10 weeks, with a maximum of 3 years.In diagnosing diabetes, 4 (5%) reported they were 'not confident' CR1), 30 (36%) 'satisfactory but lacked confidence' CR2), 25 (31%) felt 'confident in some cases' (CR3) and 23 (28%) doctors felt fully confident (CR4). Table , 30  who have had specific post graduate training in diabetes, with 50 to 90 percent reporting \"fully confident\" (CR4) across domains. 18 to 51% of trainees without such training (n = 72) achieved \"fully confident\" (CR4) levels.When asked if they would take the initiative to control blood glucose for their patients, 12 (15%) doctors would always take the initiative, 24 (29%) almost always, 20 (24%) often, 22 (27%) not very often and 4 (5%) rarely.Self-reported frequencies of interventions to improve glycaemic control in day-to-day practice in are given in table Only five of our respondents felt their training in diagnosis of diabetes and impaired glucose tolerance was adequate. 59 (72%) would welcome more training in this area. 46 (56%) of our respondents perceive further training to be required in managing diabetes emergencies as well as educating patients.55 (67%) required further training in diagnosis of complications of diabetes while 60 (74%) required further training in modifying diabetes treatment. 46 (56%) reported a requirement for further training in the use of intravenous insulin. 15\u201318 (18\u201322%) did not give an answer to these questions on perceived training needs. Other self-reported learning needs are summarised in table There was no noticeable difference in self-reported training needs of doctors from different training grades. A clear message from the free text comments by respondents was the need for more training.Although the NHS does not lay down standards to benchmark expected knowledge and competencies in diabetes, there appears to be a shortfall.With 40% of our respondents lacking confidence to diagnose diabetes, identifying the estimated half a million undiagnosed people in the UK  would coWith the high prevalence of people with diabetes in hospitals ,19, it iConfidence was also reported to be low in commencing intravenous insulin, titrating intravenous insulin, prescribing intravenous fluids and changing diabetes regime. Our results show doctors are relying on specialist diabetes teams, especially specialist nurses for management of people with diabetes. Though this may help on the short term, it is likely to lead to further erosion of skills, knowledge and confidence among junior doctors. Moreover, many hospitals are yet to establish inpatient specialist nurse service  and concIn the UK, there is a trend towards moving long-term management of diabetes from specialist centres to primary care . This haAppointment to traditional House Officer, Senior House Officer and Specialist Registrar training programs ceased in 2007 . When thOur study demonstrates a lack of confidence in managing many aspects of diabetes care amongst post-graduate trainee doctors, including the management of diabetes emergencies where mortality may be high. Many trainees perceive a need for more training in all aspects of diabetes care, suggesting a need for structured post-graduate training in diabetes. Changes proposed to medical training by the Modernising Medical Careers Enquiry Panel present a unique opportunity to introduce structured postgraduate training in diabetes.CR: Confidence Rating; UK: United Kingdom of Great Britain and Northern Ireland.The author(s) declare that they have no competing interests.JTG came up with the concept for this research projects. JTG, GAM and EBJ designed the questionnaire with input from SX and JA. JTG, KSR and DW undertook the literature review; SX, JTG and EBJ administered the questionnaire. DW, JTG and GM. DW, KSR, JTG carried out data analysis. JTG and GAM drafted this manuscript, which was revised by EBJ. All authors have read and approved the manuscript.The pre-publication history for this paper can be accessed here:"}
+{"text": "A group of 20,358 villagers in two districts of India has been followed for 7 years to study the incidence of oral leucoplakia. The follow-up rate of the population in two districts ranged from 61% to 71%. In one of the districts (Bhavnagar) no new cases of leucoplakia were found among females in the 7-year period. Among males 105 cases developed (4-0/1000/year). The incidence was highest among hookli (clay pipe) smokers. In the Ernakulam district the incidence among males was 3-3/1000/year whereas among females it was 1-9/1000/year. The mixed habits group had the highest incidence of oral leucoplakias ."}
+{"text": "High response rates have been reported in the treatment of advanced gastric cancer with epirubicin, cisplatin and continuous infusion 5-fluorouracil (ECF), including instances of unresectable disease being rendered operable by chemotherapy. We report our experience with ECF as neoadjuvant treatment in gastric and lower oesophageal carcinoma. Twenty-seven patients were treated, of whom ten (37%) had carcinoma of the stomach and 17 (63%) tumours of the lower oesophagus. Histology in the majority of cases, 21 (78%), was adenocarcinoma. Before chemotherapy ten patients (37%) had evidence of initially unresectable locally advanced disease, 16 (59%) had localised disease only and one patient (4%) had a localised primary with a single liver metastasis. Epirubicin (50 mg m(-2) i.v.) and cisplatin (60 mg m(-2) i.v.) were administered every 3 weeks for four cycles together with a continuous 12 week infusion of 5-fluorouracil (200 mg m(-2) day(-1)). Fifteen of 24 assessable patients (62%) had symptomatic improvement on chemotherapy. On combined surgical and/or radiological assessment, 15 of the 27 patients (56%) had objective evidence of tumour response. In all patients assessment for radical surgery was made following chemotherapy. Eighteen patients (67%) proceeded to operation: of these, 11 had complete resection of their disease, one had a histologically incomplete resection and six were found to have unresectable disease. No pathological complete responses were observed. Only one of the ten patients with locally advanced disease achieved complete surgical resection after chemotherapy. At a median follow-up of 36 months from date of diagnosis (range 30-47 months), 19 of the 27 patients (70%) have died. Of 11 patients who had a complete surgical resection, one died post-operatively, three have subsequently relapsed (of whom two have died) and seven remain disease free. Toxicity from treatment was mild and included emesis, myelosuppression, stomatitis and exfoliation. Myelosuppression caused modification of treatment in 14 of 108 chemotherapy cycles (13%). There was one surgical death but no chemotherapy-related deaths. These early results show encouraging symptomatic and objective responses of gastro-oesophageal carcinoma to ECF, but provide no instances of ECF achieving complete pathological response. Only randomised trials can establish the role of neoadjuvant ECF chemotherapy in both initially resectable and unresectable carcinoma of the stomach and lower oesophagus."}
+{"text": "Benign prostatic hyperplasia (BPH) is the commonest disease of the urinary tract afflicting the ageing male and is the commonest neoplastic disease in men aged 50 years and above.Transurethral prostatectomy (TURP) is the ultimate treatment of choice for benign prostatic hyperplasia (BPH) due mainly to the preference of minimally invasive surgery, long term relief of symptoms and cost effectiveness. It is however not available to the majority of Nigerians in need of prostatic surgery in Public Health Institutions.The records of patients who underwent prostatectomy in Aminu Kano Teaching Hospital, over the period June 2001 to July 2007 were examined. The bio data of patients and laboratory investigations performed were retrieved.Five Hundred and forty two patients were operated upon, out of which 40 were excluded due to open prostatectomy (22 patients), bladder neck stenosis (16 patients) or bladder tumour around the trigon (2 patients). The age range of the patients was 47\u2013110 years with a mean of 67.2 years. 289 patients (80.1%) had urethral catheter in situ at presentation and 11 (3%) patients had suprapubic cystostomy of which only 3 (0.85%) had combined urethral stricture and BPH.Only 131 (26%) had their PSA measured which ranged from 2\u2013100 ng/ml out of which 39(29.8% n = 131) patients had more than 4 ng/ml and cancer of the prostate and 1 patient had a PSA level of 4 ng/ml and malignant prostate.Hospital stay was 1\u201332 days (mean 7.9) and the mean follow up period was 5.6 months (range 0\u201360) and there were 17.5% complications comprising of urinary tract infection (UTI) 7.2%, Orchitis 2.2%, urinary incontinence 0.6%, atonic bladder 1%, erectile dysfunction 0.6%, cerebrovascular accident 0.4%, myocardial infarction 0.4%, deep vein thrombosis 0.4% and disseminated intravascular coagulopathy (DIC) 0.6% and 1.2% mortality. The cost of treatment inclusive of pre-admission investigations was US$ 615.00 Despite advances in minimally invasive therapy for LUTH/BPH, TURP is the optimum treatment of choice for the ageing male of sub-Saharan Africa. It is however not available to the majority of patients in this region due to poor health allocation and inadequate facilities and training. Benign prostatic hyperplasia (BPH) is the commonest disease of the urinary tract afflicting the ageing male and is the commonest tumour in men over the age of 50 years. Clinically, BPH has been reported to occur in 8% of men at the age of 40 years rising to 50% and 90% by the ages of 60 and 80 years respectively . AlthougTransurethral resection of the prostate (TURP) is the ultimate treatment of choice of BPH, due mainly to the preference of minimally invasive surgery, long term relief of symptoms and cost effectiveness. It is however not available to the majority of Nigerian patients in need of prostatic surgery in public health institutions, while the high cost in private hospitals is generally prohibitive.This paper reviews our experience with TURP in Aminu Kano Teaching Hospital, Nigeria and examines the prospects of availing the same in other public hospitals despite limited facilities.The records of patients who underwent prostatectomy in Aminu Kano Teaching Hospital, over the period June 2001 to July 2007 were retrieved and examined. The bio data of patients, records of pre-operative biochemistry, haematological and microbiological investigations performed were also retrieved. Mode of clinical presentation, presence of co-morbidity and its treatment outcome, recorded clinical findings particularly digital rectal examination of the prostate, as well as intra- and post-operative complications and histology of resected prostate chips were also extracted and noted from the patients' case notes and Pathology Department Register respectively.Informed consents were routinely obtained from all the patients indicating that data recorded in their files could be used for research purposes. The ethical approval was given to all retrospective studies due to its being a form of audit.2O) was used as irrigation fluid and one set of size 27 FG Olympus continuous flow working sheath with 5\u00b0 telescopes were used for resection of all the prostates.Transurethral procedures were carried out by 2 Urological surgeons. Distilled water at a height of 1 metre from the bladder (exerting a pressure head of 98 cmHAll procedures were abandoned once a capsular perforation was made and 15 (3%) of such cases were identified.Excluded were patients who had open prostatectomy and transurethral bladder neck incisions. SPSS 12.0 was used for statistical analysis of extracted data.A total of 542 patients had prostatectomy out of which 40 were excluded due to open prostatectomy (22 cases), bladder neck stenosis (16 patients) or bladder tumour around the trigon (2 patients). Five hundred and two (502) cases were therefore available for analysis.The age range of the patients was 47\u2013110 years with a mean of 67.2 \u00b1 9.8 SD (Table Two hundred and eighty nine patients (80.1%) had a urethral catheter in situ at presentation, and 11 (3%) patients had suprapubic catheter (SPC) out of which only 3 (0.85%) had combined urethral stricture and BPH, the others had high riding prostate. Seven patients (1.4%) were identified to have had chronic urinary retention of which 3 (0.6%) never recovered detrusor function and remained with urethral catheter more than a year post-operatively.Significant co-morbidity was found in 147 (29.3%) patients in the form of cardiovascular disease (137 [27.3%] patients), chronic obstructive airway disease (5 [0.99%] patients) and chronic renal failure (5 [0.99%] patients).Digital rectal examination revealed benign enlarged prostates in 490(97.6%) patients and 12 (2.4%) patients had suspicious prostate carcinoma, confirmed on biopsy.Prostate specific antigen (PSA) assay and transrectal ultrasound (TRUS) facilities were not available in AKTH until late 2003 and 2007 respectively. One hundred and thirty one (131 [26%]) patients had PSA assay measured  of patients was 5\u201317 g/dl (mean 12.7 \u00b1 2.2 SD) and 154(30.7%) patients with Hb \u2264 10 were transfused pre-operatively. The post operative transfusion rate for all groups was 0.8%.Medical treatment in the form of Prazocin 4\u20138 mg  or alfuzocin 10 mg nocte were given to only 13 patients(2.6%) and of this 3 patients(0.6%) in Prazocin group opted for TURP due to intolerable postural hypotension while remaining 2 patients and those in alfuzocin group opted for TURP due to cost consideration long term.Only 71 patients (14%) had IPSS scored in their files, of which 18 patients (3.6%) had a mean IPPS of 14 \u00b1 3.81 SD and 53 patients (10.6%) had IPSS of 24 \u00b1 7.71 SD. Fourteen patients were not scored for IPSS.Majority of patients (92%) were operated upon under spinal sub-arachnoid block while 6.7% were done under 'saddle' block, using 3 mls of 0.5% bupivacain and 5 patients (1.3%) had general anaesthesia either as conversion (2 patients) or due to sub-arachnoid blockade contra-indications (3 patients).The amount of prostate chips resected weighed between 3\u2013146 gm  over an operation period of 20\u2013120 minutes (mean 64.1 minutes). There was no documented TUR syndrome.Urethral catheters were removed in 0\u201330 days  but 10 patients (2%) needed re-catheterization, with successful trial without catheter in 7 patients (1.4%) after 2 weeks. Persistent irritative symptoms were recorded in 2 patients (0.4%) who did not improve on medical therapy at one year follow up. Re-operation was performed in 5 patients 2 years after initial operation due to intractable haematuria , recurrent adenoma 3 patients (0.6%). All patients had residual urine measured with a urethral catheter before discharge. Satisfactory outcome was recorded in the immediate post-operative period in 483 patients (96.2%).There were 6 peri-operative deaths (1.2%) in the age groups 56\u201360 years (DVT/PE/DIC) and 71\u201375 years (MI). The 2 myocardial infarctions occurred intra-operatively from hypotensive episodes and 3 patients (0.8%) had chronic renal failure due to obstructive uropathy not resolved by TURP.Hospital stay was 1\u201332 days (mean 7.9 \u00b1 5.2 SD) and the follow up period was 0\u201360 months, (mean 5.6 \u00b1 8.3 SD).The average cost of treatment inclusive of pre-admission work-up investigations was US$300\u20131,300, (mean US$617.00 \u00b1 231 SD).Transurethral prostatectomy is still a novel procedure in most government hospitals in Sub-Saharan Africa due mainly to non-availability of equipments and inadequate number of trained personnel conversant with the procedure. Patients' perception of high post-operative morbidity and mortality associated with open prostatectomy in t he locality makes the majority of them reluctant to present early for appropriate therapy as evidenced by the large number presenting with urethral catheter in situ in our series 83.1%) compared with 24% in North America and 42% in the United Kingdom . Detecte.1% compaThe highest incidence of LUTS/BPH was found in the age group 56\u201370 years accounting for a total of 62% of the patients operated in this study. This correlates similar figure reported by Garraway et al of 66% ,4.Co-morbidity is both a strong predictor of length of stay and excess risk of death peri-operatively. Co-morbidities of 29.3% in this study compares favourably to 25% for open prostatectomy in Sicilian-Calabrian region of Italy which may suggest similar standards of healthcare in the 2 regions [2O which is the critical pressure above which fluid is significantly absorbed [Water was used as irrigation fluid during resection due to non-availability of glycine and other irrigation fluids which were expensive to import. Distilled sterile water is cheap, available in abundance and safe as irrigation fluid in transurethral resections and though not proven in this study, the intravesical pressure was likely to be less than 40 cmHabsorbed -8. There10\u201312 sympathetic ganglion blockade and none of these suffered similar complications.The complication rate of 17.5% and mortality of 1.2% in this study Table  are rathTotal blood loss was low with a post operative transfusion rate of 0.8% which is better than the rate of 8.2% for open prostatectomy -12. ThisTURP is associated with a post-operative hypercoagulable state just as in other pelvic surgeries and a deep vein thrombosis (DVT) of 6.8\u201310%  but mostIncidental adenocarcinoma of the prostate of 5.6% Table  is much The predictors of length of stay are: intrinsic patient factors such as co-morbidities, advances in peri-operative care and surgical techniques and extrinsic hospital factors such as resources, capacity and efficient bed management . The lenImpotence is reported to occur, in the literature in 11% of cases post-TURP, but only 0.6% was picked up in this study due to incomplete information, which is one of the draw backs of retrospective study.The cost of treatment is rather high for an average Nigerian as the gross domestic product (GDP) per capita of US$800 is low even within Africa, coupled with poor health allocation from the Budget (2.6%) .The morbidity and mortality of TURP is expectedly higher than what is obtained internationally, but still lower than what was found following open prostatectomy even in European series. The overall cost of TURP was high for an average Nigerian considering the per capita income of US$800:00 but was worthwhile in view of its inherent minimal trauma, short hospital stay and early recovery. Despite advances in minimally invasive therapy for lower urinary tract symptoms/BPH, TURP is the optimum treatment of choice for BPH in the ageing male population of sub-Saharan Africa, but better facilities and skilled medical staff are needed to make it safer and affordable for the majority of patients in public health institutions.The authors declare that they have no competing interests.SUA operated on majority of the patients, conceived of the idea of reviewing the performed prostatectomies over the years and wrote the initial design of the manuscript. SAA operated on some of the patients, collated the data and carried out the statistical analysis as well as critical review of the manuscript AZM reviewed all the histological specimens of the selected patients, participated in the critical review with major corrections of the design of the manuscript. SM reviewed the histology slides with AZM, criticises and made major corrections of the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:"}
+{"text": "Local extension prevents curative resection in more than two-thirds of gastric cancer patients. Unfortunately, resectability is one of the main prognostic factors in these patients, and survival is longer when tumours are completely removed. Preoperative chemotherapy is an attractive concept for obtaining curative resection. Thirty-two locally advanced unresectable gastric cancer patients were enrolled in five Italian Group for the Study of Digestive Tract Cancer (GISCAD) centres. For 16 patients, surgical unresectability was based on computerized tomography scan evaluation of tumour size (four patients) and invasion of adjacent structures (12 patients), whereas in another 16 patients locally advanced disease was confirmed by laparotomy. They received weekly administration of cisplatin 40 mg m(-2), 5-fluorouracil 500 mg m(-2), epidoxorubicin 35 mg m(-2), 6S-stereoisomer of leucovorin 250 mg m(-2) and glutathione 1.5 g m(-2). From the day after to the day before each chemotherapy administration, filgrastim was administered by subcutaneous injection at a dose of 5 microg kg(-1). One cycle of therapy consisted of eight weekly treatments. Fifteen of 32 patients (47%) responded to chemotherapy, whereas 13 (41 %) had stable disease and four (12%) progressed on therapy. Of the 15 responding patients, 13 were completely resected after chemotherapy and two of them had a complete pathological response. Two clinically responding patients were found unresectable at operation because of peritoneal seeding. At a median follow-up from the start of treatment of 24 months (range 11-39 months), 10 of 13 resected patients are alive and eight are relapse free. Three patients died after 11, 12, and 14 months respectively. Toxicity was acceptable: side-effects consisted mainly of grade II National Cancer Institute common toxicity criteria (NCICTC) leucopenia and thrombocytopenia in ten patients. Neither treatment-related death nor surgical complications in patients undergoing surgery were observed. This weekly intensive regimen enabled resection in half of previously inoperable tumours with a moderate toxicity. It can be offered to patients with locally advanced unresectable gastric cancer to obtain curative resection."}
+{"text": "We have compared the expression of somatostatin receptor (sstr) subtypes with the outcome of somatostatin receptor scintigraphy and the effect of somatostatin receptor activation in patients with disseminated carcinoid tumours. Tumour tissues from nine patients with midgut carcinoids  and three patients with foregut carcinoids  were analysed using Northern blotting. Expression of somatostatin receptors was demonstrated in all tumours (12 out of 12), with all five receptor subtypes present in 9 out of 12 tumours. Somatostatin receptor scintigraphy using [111In]DTPA-D-Phe1-octreotide visualized tumours in all patients (12 out of 12). The 111In activity concentrations in tumour tissue (T) and blood (B) were determined in three tumours 1-7 days after injection of the radionuclide. The T/B 111In activity concentration ratios ranged between 32 and 651. Clinically, treatment with the long-acting somatostatin analogue octreotide resulted in marked symptom relief accompanied by a significant reduction in tumour markers, for example urinary-5-HIAA levels (28-71% reduction). Incubation of midgut carcinoid tumours in primary culture with octreotide (10 microM) resulted in a reduction in spontaneously secreted serotonin (45-71% reduction) and 5-HIAA (41-94% reduction). The results demonstrate that carcinoid tumours possess multiple somatostatin receptor subtypes and that somatostatin analogues such as octreotide, which preferentially bind to somatostatin receptor subtype 2 and 5, can be used in the diagnosis and medical treatment of these tumours. In the future, novel somatostatin analogues with subtype specific receptor profiles may prove to be of value for individualizing the treatment of disseminated carcinoid tumour disease."}
+{"text": "Forty-two patients with hepatocellular carcinoma (HCC) were resected and their tumours were analysed for p53 mutations by GC-clamped denaturing gradient gel electrophoresis (DGGE), single-strand conformation polymorphism (SSCP) and gene sequencing. All the exons have been analysed in this study. Eight of 12 HCCs with cirrhosis due to viral hepatitis and the two patients with sarcomatoid changes displayed p53 mutations. In contrast, no mutation was observed in the fibrolamellar variant (n = 9), non-cirrhotics (n = 13) and alcoholic cirrhosis (n = 6). The mutations observed were in exons 5-8. Two mutations were observed in codons 136 and 213 as well as a T insertion between residues 156 and 157 (exon 5) and these are reported for the first time in HCC. Likewise, the silent mutation polymorphism in codon 213 was noticed in 3 of the 42 patients. Survival analysis of these patients after surgery showed the mean and median survival in patients with wild-type p53 to be 60 and 43 months respectively. In the group with p53 mutations, the mean and median survival was 15 and 12 months. The difference was statistically significant (P= 0.003)."}
+{"text": "The National Health Service Central Register (NHSCR) and direct follow-up were used to document ovarian and fallopian tube cancers in 22 000 women from 1986 to 1993. Direct follow-up identified 47/49 cases (96%) and the NHSCR 38/49 (78%). NHSCR ascertainment was incomplete and direct follow-up provided additional information. These findings have implications for interpretation of national cancer statistics and for use of the NHSCR in research trials. \u00a9 1999 Cancer Research Campaign"}
+{"text": "Investigation of transitional cell carcinoma of the urinary bladder (TCC) patients classified by recurrence and/or progression has demonstrated that loss of chromosome 9, as detected by FISH analysis of the pericentromeric classical satellite marker at 9q12, occurs early. A total of 105 TCCs from 53 patients were analysed in situ by two independent observers for loss of chromosome 9 using quantitative fluorescence in situ hybridization (FISH). All 53 primary tumours were evaluated for chromosomes 9, 7 and 17. Normal ranges for chromosomal copy number were defined for normal skin epidermis and bladder epithelium. Values for chromosome 9 copy number outwith the range 1.51-2.10  were significantly abnormal. Twenty-five TCCs were detected with consistent monosomic scores. Of 89 TCCs, in which multiple tumour areas were analysed, 85 tumours (96%) demonstrated the same chromosome 9 copy number in all areas (2-6) analysed; only three tumours demonstrated heterogeneity for this locus. A total of 36% (12 out of 33) of patients with subsequent disease recurrence demonstrated loss of chromosome 9 in their primary and all subsequent TCCs analysed. Only a single patient (n = 20) with non-recurrent TCC showed loss of chromosome 9 (P = 0.0085). Of 53 primary tumours, eight showed significant elevation of chromosome 17. Of these patients, six demonstrated elevation in chromosome 7 copy number. No abnormalities were observed in non-recurrent patients. This study describes rapid quantitation of chromosomal copy number by FISH using a pericentromeric probe for chromosome 9 in TCC of the urinary bladder. Routinely fixed and processed material was evaluated without disaggregation. Strict quality control of FISH demonstrated that this technique was reproducible in a clinical environment and could be used to detect genetic changes relevant to patient outcome. It is proposed that loss of chromosome 9 from primary TCC of the urinary bladder identified patients at high risk of recurrence and possible progression."}
+{"text": "Thirty patients with previously treated metastatic breast cancer were entered in a phase II study with oral lonidamine. Twenty-eight patients are evaluable for toxicity and 25 for response. A partial remission was obtained in four patients (16%) and disease stability in 11 (44%): 10 patients progressed (40%). Toxicity was acceptable, consisting mainly of myalgias (39% of patients) and asthenia (21.4%). No myelotoxicity was observed. The drug is active in previously treated metastatic breast cancer and, because of its peculiar pattern of action and toxicity, deserves to be evaluated in combination with cytotoxic chemotherapy."}
+{"text": "In this phase II study, 39 women (median age 51 years) with advanced breast cancer received docetaxel (75 mg m-2) intravenously over 1 h every 3 weeks as first-line chemotherapy for advanced disease, without routine premedication for hypersensitivity reactions. In 31 evaluable patients, an overall response rate of 52% (95% CI 33-70%) was achieved, including a complete response rate of 13%. The median time to first response was 12 weeks (range 3-35+), the median duration of response was 34 weeks (range 11-42+) and the median time to progression was 24 weeks (range 0-42+). Docetaxel showed considerable activity in patients with visceral involvement (52% response), including lung (67%) and liver (44%) metastases. The safety profile was acceptable. Grade 4 neutropenia occurred in 82% of patients (53% of cycles); febrile neutropenia  occurred in only three (7.7%) patients (1.4% of cycles) and none of these required hospitalisation. Acute adverse events were generally well tolerated, with only two grade 3 events and no grade 4 events reported. Despite no prophylactic premedication, the incidence of acute hypersensitivity reactions was only 13%. Fluid retention was widely experienced (72% of patients) but was severe in only five (12.8%) patients and was the reason for discontinuation of treatment in 16 patients. Nevertheless, patients were able to receive a median cumulative dose of approximately 592 mg m-2 before discontinuing treatment, and the syndrome was slowly reversible after treatment withdrawal. In conclusion, docetaxel, even at a dose of 75 mg m-2, is confirmed to be an active agent in breast cancer. Compared with an earlier study of first-line docetaxel at the usual dose of 100 mg-2, it appears that 75 mg m-2 produces a lower response rate (52% vs 68%), although this still compares favourably with that of doxorubicin monotherapy in a similar patient population (43%). This difference is particularly striking in subgroups of patients with particularly poor prognostic factors, such as liver metastases or involvement of more than two organs. The incidence of fluid retention appears to be similar at the two doses and, it is likely that premedication with corticosteroids will be preferable to dose reduction for managing this adverse event."}
+{"text": "Porcine reproductive and respiratory syndrome virus (PRRSV) is divided into a European and North American genotype. East European PRRSV isolates have been found to be of the European genotype, but form different subtypes. In the present study, PRRSV was isolated from a Belarusian farm with reproductive and respiratory failure and designated \"Lena\". Analyses revealed that Lena is a new East European subtype 3 PRRSV isolate. The main purpose of this investigation was to study the pathogenesis and antigenic characteristics of PRRSV (Lena).Arcanobacterium pyogenes was isolated from lungs of one animal that died, and Streptococcus suis was isolated from lungs of one animal that was euthanized. The difference in viral titres in sera from PRRSV (Belgium A) and PRRSV (Lena)-infected pigs was statistically significant (p < 0.05) at 7, 10, 14 and 21 dpi. The highest viral titres in sera ranged from 104.8 to 106.1 TCID50/ml for PRRSV (Lena) whereas they ranged from 103.1 to 104.8 TCID50/ml for PRRSV (Belgium A).Obvious clinical and virological differences were observed between the animals inoculated with a recent European subtype 1 PRRSV isolate (Belgium A) and animals inoculated with PRRSV (Lena). Three out of six pigs inoculated with PRRSV (Belgium A) had anorexia and low fever at 3, 4 and 5 days post-inoculation (dpi). High fever, anorexia and depression were prominent signs in most pigs inoculated with PRRSV (Lena) between 2 and 28 dpi. Four pigs out of ten died during the experiment. 2.5 TCID50/100 mg to 105.6 TCID50/100 mg in nasal secretions between 3 and 14 dpi and from 102.8 TCID50/100 mg to 104.6 TCID50/100 mg in tonsillar scrapings between 3 and 21 dpi. High viral titres were detected in lungs (102.3-107.7 TCID50/g tissue), tonsils (102.0-106.2 TCID50/g tissue) and inguinal lymph nodes (102.2-106.6 TCID50/g tissue) until 35, 28 and 35 dpi, respectively.The replication of PRRSV (Lena) was further studied in depth. Viral titres ranged from 10To examine the antigenic heterogeneity between the East European subtype 3 isolate Lena, the European subtype 1 strain Lelystad and the North American strain US5, sets of monospecific polyclonal antisera were tested in immunoperoxidase monolayer assays (IPMAs) with homologous and heterologous viral antigens. Heterologous antibody titres were significantly lower than homologous titres (p = 0.01-0.03) for antisera against PRRSV (Lena) at all sampling time points. For antisera against PRRSV (Lelystad) and PRRSV (US5), heterologous antibody titres were significantly lower than homologous titres at 14 and 21 dpi (p = 0.01-0.03) and at 10 and 14 dpi (p = 0.04), respectively.Lena is a highly pathogenic East European subtype 3 PRRSV, which differs from European subtype 1 Lelystad and North American US5 strains at both the genetic and antigenic level. Porcine reproductive and respiratory syndrome virus (PRRSV) is a causative agent of reproductive failure in sows and respiratory disorders in pigs and had been firstly recognized in the USA in 1987 . The PRRThe main purpose of the present study was to investigate the pathogenesis and antigenic characteristics of a recently isolated East European subtype 3 PRRSV isolate.EU909689, EU909690, EU909691, EU909692, EU909693) and North American PRRSV US5 (except ORF2a) . All sequences were compared to the European reference strain Lelystad and the North American reference strain VR-2332  sequences were determined for the Belarusian PRRSV Lena  and the animals inoculated with PRRSV (Belgium A). PRRSV (Lena)-inoculated pigs showed a rapid disease evolution. Anorexia and depression were seen in all animals from 5 to 18 dpi and periocular edema was observed from 3 to 9 dpi. Body temperature and respiratory disease scores are summarized in Figure Arcanobacterium pyogenes was isolated from lungs of one animal that died, and Streptococcus suis was isolated from lungs of one animal that was euthanized. All pigs were negative for porcine circovirus 2, influenza virus, parvovirus and enteroviruses.The results of the postmortem and bacteriological examinations of pigs inoculated with PRRSV (Lena) are presented in Table 4.0 to 106.1 TCID50/ml at 10 dpi and 104.3 to 106.0 TCID50/ml at 14 dpi. A high viremia was observed until 28 dpi. In pigs inoculated with PRRSV (Belgium A), viremia was detected from 3 dpi until 21 dpi. At 28 dpi only one pig out of six was still viremic with low viral titre (101.6 TCID50/ml). The viral titres in this group were significantly lower (p < 0.05) than in PRRSV (Lena)-inoculated animals at 7, 10, 14 and 21 dpi.Viral titres in sera of PRRSV (Lena)-inoculated animals were first detected at 3 dpi in nine pigs out of 10. At 7 dpi, all pigs had viremia which lasted until 28 dpi  was detected in nasal swabs from 3 dpi until 14 dpi and viral titres ranged from 10The results of virus titration of BAL  fluids and PAMs  are represented in Table 2.3-107.7 TCID50/g tissue), tonsils (102.0-106.2 TCID50/g tissue) and inguinal lymph nodes (102.2-106.6 TCID50/g tissue) until 35, 28 and 35 dpi, respectively.High viral titres were detected in lungs -inoculated pigs seroconverted at 7 dpi and antibody titres ranged from 1.7 to 4.7 log4. From 10 dpi until the end of experiment all pigs were seropositive with antibody titres ranging from 4.7 to 7.7 log4. In animals inoculated with PRRSV (Belgium A), the course of anti-PRRSV antibody titres did not significantly differ from that in PRRSV (Lena)-inoculated pigs.All samples collected at 0 and 3 dpi were seronegative regardless of the PRRSV used  is a new East European subtype 3 PRRSV isolate. The main purpose of this investigation was to study the pathogenesis and antigenic characteristics of PRRSV (Lena).To study the pathogenesis, ten 6-week-old conventional pigs were inoculated with PRRSV (Lena). A fever, lasting for several weeks, and a range of respiratory and systemic clinical signs together with gross lesions such as severe fibrinous pleuropneumonia, pericarditis and peritonitis were observed, with four out of ten animals dying within three weeks post-inoculation. The clinical and pathological picture and high mortality are similar to what is seen in the field in Belarus . A comparison of the findings obtained with PRRSV (Lena) with those obtained with other PRRSV strains revealed similarities with some highly pathogenic American strains . Fever, 4.8 to 106.1 TCID50/ml at different dpi. In the present study (European subtype 1 PRRSV isolate Belgium A) and in most previous studies, the highest PRRSV titres ranged from 103.6 to 104.8TCID50/ml. To our knowledge, only few PRRSV strains had been reported to cause abnormally high viremia (105.2-106.0 TCID50/ml) [5.8 and 107.8 TCID50/ml (data not shown).The highest PRRSV (Lena) titres in sera in our investigation ranged from 10ID50/ml) -19. HoweArcanobacterium pyogenes and Streptococcus suis were isolated from lungs of two pigs. It seems that PRRSV (Lena) infection paves the way for other pathogens. Co-infections of certain PRRSV strains with Arcanobacterium pyogenes as well as Streptococcus suis had been shown to increase the severity of the disease in pigs [The severity of the observed clinical signs is most probably not due to a single direct effect of PRRSV (Lena). Secondary infections with other pathogens will have played an important role in the exacerbation of clinical signs. Indeed, in the present study  in pigs ,20. Dama in pigs . Pulmona in pigs . The det in pigs -26. The The appearance of new highly virulent PRRSV strains and absence of effective diagnostic procedures and vaccines create a favorable environment for the emergence of devastating outbreaks. Pivotal examples are the recent atypical PRRSV outbreaks in China and Vietnam . SensitiSince all present commercial kits for serological diagnosis are based on antigens belonging to European subtype 1 and North American PRRSV, it can be assumed that the observed heterogeneity might affect the accuracy of serological assays in geographical regions where East European Subtype 3 PRRSV strains circulate. Therefore, it is of major importance to validate the sensitivity of the current methods for serological PRRSV diagnosis in these regions.Lena is a highly pathogenic East European subtype 3 PRRSV, which differs from European subtype 1 Lelystad and North American US5 strains at both the genetic and antigenic level.Streptococcus suis, Escherichia coli) were regularly found in pigs with respiratory disorders. The lungs from weak-born piglets were collected for virus isolation. PAMs were obtained as previously described [2 atmosphere at 37\u00b0C. Subsequently, PAMs were inoculated with 20% suspensions of the lungs, CPE was observed and cells were fixed for 10 minutes with methanol (100%) at -20\u00b0C. The virus was identified by incubation with PRRSV-specific monoclonal antibodies P3/27 against the nucleocapsid protein [Samples were collected from a nucleus herd of 5000 sows from the Eastern part of Belarus in January 2007. The herd experienced the following problems: abortion, birth of mummified, dead and weak piglets, high mortality rate before weaning, respiratory disorders and mortality (up to 70%) in growing pigs. The herd had been confirmed to be PRRSV positive. Also bacterial pathogens . The primers are listed in Table RNA was extracted using an RNeasy Protect Mini Kit (QIAGEN), according to the manufacturer's protocol. Total RNA was used as template in reverse transcription PCR with reverse transcriptase and random hexamer primers (Invitrogen) at 60\u00b0C annealing temperature and the cycling conditions were used as described by the manufacturer. PCR products were treated with Exonuclease I and Antarctic Phosphatase (New England Biolabs) and used directly for cycle sequencing with a Big Dye Terminator Cycle sequencing Kit V1.1 (Applied Biosystem) and PRRSV primers. Primers were designed based on the alignment of the genome sequences of strains BJ4, MLV, P129, VR2332 and Lelystad  and was demonstrated by a PRRSV-specific staining. Subsequently, three passages on MARC-145 cells were necessary to further adapt PRRSV (Lena) and a virus stock with a titre of 104.6 TCID50/ml was obtained. The alignment of ORF(s) 2a, 4, 5 and 7 of the macrophage-grown and MARC-145 adapted Lena isolates revealed a 100% identity. This virus stock was used for the preparation of IPMA antigens.The use of PAMs in an IPMA for the detection of PRRSV antibodies in sera is difficult and expensive since cells have to be harvested from young pigs . Certain monkey kidney cell lines  can be a replacement for macrophages, but such cell lines do not support the growth of all isolates, particularly European ones. In order to get high virus replication in pigs and generate PRRSV (Lena) quasispecies which might favorably contribute to the adaptation on MARC-145 cells, two 4-week-old piglets from a PRRSV-negative farm were inoculated oronasally with 106 TCID50/pig PRRSV (Lena) in 2 ml of phosphate buffered saline . Six pigs from the same origin were inoculated with 106 TCID50/pig of a recently isolated Belgian PRRSV, designated Belgium A, and served as a reference group for comparison of the clinical picture and virological findings. The Belgian PRRSV had been isolated from lungs and spleen of a stillborn piglet during a PRRSV outbreak in 2007. The herd experienced the following problems: birth of dead and weak piglets, high mortality rate among newborn piglets and respiratory disorders in growing pigs. The herd had been confirmed to be PRRSV positive. Sequencing demonstrated that PRRSV (Belgium A) belongs to the European subtype 1 PRRSV. The animal experiment was approved by the Ethical committee of the Faculty of Veterinary Medicine, Ghent University (EC2008/057).At the age of six weeks, ten conventional pigs from a PRRSV negative herd were inoculated oronasally with 10Clinical signs  were monitored daily in both groups starting from six days before inoculation until the day of death or euthanasia. Respiratory disorders were scored from 0 to 6 , tonsils and inguinal lymph nodes. In the case of death, the same organs were sampled. All samples were frozen and stored at -70\u00b0C for virus isolation and titration. The PAMs and BAL fluids were collected by pulmonary lavage from the left lung as previously described [From the Lena-inoculated pigs, sera and nasal swabs were collected at 0, 3, 7, 10, 14, 21, 28, 35 and 42 dpi and stored at -70\u00b0C for virus titration. Also, sera were stored at -20\u00b0C for PRRSV-specific antibody detection. Seven out of ten Lena-inoculated pigs were anesthetized at 3, 14 and 21 dpi, for collection of tonsillar scrapings and escribed . The othescribed .From the pigs inoculated with PRRSV (Belgium A), only sera were collected at the same time points as from PRRSV (Lena)-inoculated animals. All samples were stored at -70\u00b0C for virus titration and at -20\u00b0C for PRRSV antibody detection.Sera, nasal swabs, tonsillar scrapings, BAL fluids, PAMs and tissue suspensions were titrated on PAMs from PRRSV negative pigs, as previously described . For colStaphylococcus pseudintermedius streak for support of Actinobacillus and Haemophilus spp. growth, and on Columbia CAN agar with 5% sheep blood . Plates were incubated overnight in a 5% CO2-inriched environment at 37\u00b0C and identification of isolated bacteria was performed as previously described [In the case of death or euthanasia, pigs were necropsied, lungs and heart were collected and bacteriological analyses were performed. All samples were inoculated on Columbia agar supplemented with 5% sheep blood  with a escribed . PK-15, 6 TCID50/pig of the PRRSV (Lelystad) [Sera from PRRSV (Lena)-inoculated pigs collected during the pathogenesis study were used. Two other panels of polyclonal antisera were obtained from six-week old pigs inoculated oronasally with 10elystad)  , the pathogenesis study, statistical analyses and antigenic characterization. He drafted the manuscript and participated in the study design, sequencing, phylogenetic analysis and in the adaptation of PRRSV (Lena) on MARC-145 cells. MG carried out the adaptation of PRRSV (Lena) on MARC-145 cells and participated in the pathogenesis study. MV participated in the antigenic characterization study. JVD carried out molecular genetic studies and phylogenetic analyses. TAS participated in the isolation of PRRSV (Lena). HJN conceived the study, coordinated the work and helped in writing the manuscript. All authors read and approved the final manuscript."}
+{"text": "High loads of human papillomavirus (HPV) 16 and HPV 18/45 increase the risk of developing invasive cervical carcinoma, revealing higher risk in percentiles of highest viral loads for HPV 16 (odds ratio (OR) 58.7, 95% confidence interval (CI) 21.9\u2013151.4) compared to HPV 18/45 . Thus, HPV load is a type-dependent risk marker for invasive carcinoma. Controls were selected from the same organised screening programme and have been described in detail elsewhere  and 548 controls (1049 smears) . In all,Our results indicate that increasing viral load of HPV 16 in cervical smears increases the risk of future invasive cervical cancer. For HPV 18/45, a significant OR was only seen for the highest viral-load percentile. The relationship between OR of invasive cancer and viral load of HPV 16 is similar to that previously described for CIS ; consist"}
+{"text": "Allelotypic detection of loss of heterozygosity (LOH) has been used to identify putative tumour-suppressor genes. Loci on human chromosome 11q23 are frequently altered in malignant disease, and LOH has been reported at an anonymous D11S29 locus at 11q23 in a proportion of breast and ovarian cancers and malignant melanomas. Previous studies have reported a high frequency of LOH in cervical carcinoma mapping to 11q23. Using polymerase chain reaction techniques employing probes for a recently described polymorphic dinucleotide microsatellite within this locus, we have searched for LOH in 69 cases of invasive cervical carcinoma. Genomic material was microdissected from sections cut from archival paraffin-embedded material, using the patients' constitutional genotype as a control Sixty-two (90%) of the cases were informative, and LOH occurred in 25/62 (40%) of tumours. Loss of an arm or single chromosome 11 is a well-recognised event in cervical carcinoma, and by employing other microsatellite polymorphisms mapping to 11q13 and 11p11-p12 we excluded those cases with widespread allelic loss. By doing so, LOH at D11S29 was found in 16/53 (30%) of tumours. The findings suggest a putative tumour-suppressor gene on 11q involved in cervical carcinogenesis."}
+{"text": "CEA, CA19-9 and CA50 are tumour associated antigens defined by monoclonal antibodies which havebeen raised against adenocarcinoma cell lines. The aim of this study was to determine whether theircombined use could improve diagnostic accuracy in patients with primary and secondary liver tumours.An immunoradiometric assay was used for the detection of CEA and CA19-9 and the Delfia system forCA50. Serum was collected from 65 normal subjects, 40 with hepatobiliary carcinoma  and 17 with benign hepatobiliary disease. The cut-off levels were calculated as the mean ofthe control group plus 2 standard deviations. All three antibodies contributed to improving the correctclassification of secondary liver tumours , but only CA19-9and CA50 contributed to the diagnosis of primary liver tumours . Thediagnostic accuracy versus benign disease was 81% for primary carcinoma and 91% for secondarycarcinoma. Combined use of CEA, CA19-9 and CA50 helps to differentiate benign from malignanthepatobiliary disease."}
+{"text": "ANA (abundant in neuroepithelium area), a candidate tumour suppressor gene (TSG) located on 21q11.2\u201321.1, was also evaluated for 20 OSCCs and 9 OSCC-derived cell lines. 60% of tumours (12/20) and 88.9% (8/9 cell lines) showed absent or reduced mRNA gene expression; only one OSCC case had a nucleotide substitution in the ANA gene. Interestingly, the frequency of the suppressed ANA mRNA expression was greater in stage IV tumours than in earlier stages. In addition, re-expression of the ANA gene mRNA was induced in 4 cell lines after treatment with 5-aza-2\u2032-deoxycytidine, a DNA demethylating agent. These findings demonstrate that there may be at least 2 distinct TSGs on 21q11.1; loss of ANA gene expression could be involved in the progression of human OSCC; and aberrant methylation of the ANA gene promoter may participate in the transcriptional silencing of the gene in oral cancer cells. \u00a9 2001 Cancer Research Campaign http://www.bjcancer.comLoss of heterozygosity (LOH) on the long arm of chromosome 21 (21q) is observed in several human malignancies. We identified novel tumour suppressor loci on this region in primary oral squamous cell carcinomas (OSCCs). To further determine the role of 21q deletions in oral cavity tumorigenesis, 63 OSCCs were examined for LOH at 21q using 7 microsatellite markers. LOH was observed in 32 of 63 cases (50.8%) that were informative for at least one of the loci analysed. Two distinct deleted regions were identified at chromosomal region 21q11.1. The possible involvement of"}
+{"text": "Tension band wiring (TBW) remains the most common operative technique for the internal fixation of olecranon fractures despite the potential occurrence of subjective complaints due to subcutaneous position of the hardware. Aim of this long term retrospective study was to evaluate the elbow function and the patient-rated outcome after TBW fixation of olecranon fractures.We reviewed 62 patients (33 men and 29 women) with an average age of 48.6 years  who underwent TBW osteosynthesis for isolated olecranon fractures. All patients were assessed both clinically with measurement of flexion-extension and pronation-supination arcs and radiologically with elbow X-Rays. Functional outcome was estimated using the Mayo Elbow Performance Score (MEPS), Visual Analogue Scale (VAS) subjective pain score and VAS patient satisfaction score. Follow up: 6\u201313 years (average 8.2 years).There was a higher prevalence of fractures among men until the 5th decade of life and among women in elderly (p = 0.032). Slip or simple fall onto the arm was the main mechanism of injury for 38 fractures (61.3%) while high energy trauma, such as fall from a height (> 2 m) or road accident, was reported in 24 fractures (38.7%). Hardware removal performed in 51 patients (82.3%) but 34 of them  were still complaining for mild pain during daily activities. The incidence of pin migration and loosening was not statistically decreased when penetration of the anterior ulnar cortex was accomplished (p = 0.304). Supination was more often affected than pronation (p = 0.027). According to MEPS, 53 patients (85.5%) had a good to excellent result, 6 (9.7%) fair and 3 (4.8%) poor result. The average satisfaction rating was 9.3 out of 10  with 31 patients (50%) to remain completely satisfied from the final result. Degenerative changes recorded in 30 elbows (48.4%). However, no correlation could be found between radiographic findings and MEPS (p = 0.073).Tension band wiring fixation remains the \"gold standard\" for the treatment of displaced and minimally comminuted olecranon fractures. In long term, low levels of pain may be evident regardless of whether the metalware is removed and degenerative changes have been developed. Olecranon fractures are common injuries of the proximal ulna which constitute about 10% of all upper extremity lesions ,3. Due tTension band wiring (TBW) which was introduced by Weber and Vasey  remains The purpose of this study was to determine the clinical and radiological outcome after tension band wiring of olecranon fractures and to record the incidence of hardware removal and residual pain or disability.Between 1993 and 2000, 103 patients \u2013 from a rough total of 74200 admitted cases to Orthopaedic Emergency Department \u2013 presented themselves with an olecranon fracture . Isolated fractures without severe concomitant injuries or complex lesions of the affected elbow were recognized in 89 patients and 77 of them were treated with TBW technique. Two patients died, 7 patients were lost despite exhaustive search processes and 6 patients refused examination for different reasons. The remanining 62 patients were identified and formed the study group.The fracture pattern was assessed using the Mayo classification  which taThe postoperative protocol included antibiotics administration (cefuroxime) for 24 hours and progressive mobilization of the elbow joint. In cases of fracture comminution (Types IIB and IIIB) a posterior splint with the elbow in a semiflexed position was applied for a period of 2\u20133 weeks with the aim to prevent fracture collapse and displacement. Anteroposterior and lateral elbow radiographs were repeated at regular intervals until evidence of union was detected. Finally, all the patients were recalled to attend a specially set up clinic for the final assessment with respect to the purpose of the study. Ethics Committee approval was obtained. Flexion-extension arc of the elbow and pronation-supination arc of the forearm were measured with a goniometer. Patient-rated outcomes evaluated with the Mayo Elbow Performance Score (MEPS), Visual Analogue Scale (VAS) subjective pain score (10 = unbearable pain) and VAS patient satisfaction score (10 = complete satisfaction) . The durThe microsoft excel program was used for the creation of the graphs and the SPSS program 12.0  for the creation of statistics. Data analysis was conducted with Chi-square test and Student's t-test. P values less than 0.05 were considered to be statistically significant.From the total of 62 patients who were included in the study, there were 33 men and 29 women with an average age of 48.6 years . The frequency of fractures was higher in men until the 5th decade of life but altered in older decades towards women (p = 0.032) , 13 Type IIB (21%), 8 Type IIIA (12.9%) and 1 Type IIIB (1.6%). The average period of hospitalization was 3.7 days .Wound infection developed in 4 patients (6.5%). In 2 cases intravenous antibiotics proved adequate for the eradication of the infection while in the other 2 elbows wound irrigation and surgical debridement were performed.Reduction was maintained in all elbows until fracture union. No malunions or ulnar nerve palsies complicated the postoperative period. However, non-union was encountered in 2 patients (3.2%) after high velocity injuries who had Type IIB and IIIB fractures accordingly. Re-osteosynthesis in combination with iliac bone graft led to uneventful healing.The anterior ulnar cortex was perforated by both K-wires (group A) in 39 fractures (62.9%), by one (group B) in 5 fractures (8.1%) and by none (group C) in 18 fractures (29%). Hardware removal recorded in 51 patients (82.3%) due to pin prominence, localized pain or direct complaint defined as the patient being \"bothered\" by the metalware VAS 1\u20134). The above event was not significantly affected by pin position as it was found with a frequency of 76.9% (30 fractures) in group A, 100% in group B (5 fractures) and 88.8% in group C (16 fractures) (p = 0.304). It is noteworthy that after metalwork removal, 34 from the 51 patients  were still complaining for mild pain (VAS 1\u20132)  had a significanly reduced flexion arc -50 and 45 degrees respectively- affecting the functional outcome. The rest of cases had some degrees of flexion or extension deficit without being functionally disabled. Supination was more often affected than pronation (p = 0.027) Table .Using the MEPS, 53 patients (85.5%) had a good to excellent result, 6 (9.7%) fair and 3 (4.8%) poor result. The average satisfaction rating was 9.3 out of 10  with 31 patients (50%) to state complete satisfaction of the final result  returned to their original work and no reduction of the level of athletic activitiy was evident among the 16 patients (25.8%) who reported some kind of involvement in sports.Olecranon fractures may be caused by direct injury to the posterior part of the elbow joint or indirectly by forces generated within the triceps muscle during a fall on a partially flexed elbow . The cliIn the herein study, the incidence of olecranon fractures showed a higher prevalence among men until the 5th decade of life and among women in older ages. Similarly, Rommens et al  reportedTension band wiring (TBW) technique, which is relied on the principle of converting posterior tensile forces to articular compressive forces, has gained widespread acceptance for the surgical treatment of olecranon fractures -19. ManyIn spite of the efficacy of TBW fixation even in cases with severe fracture displacement and comminution, many patients express pain or discomfort due to subcutaneous position of the K-wires and the relevant incidence of metalware removal may be raised to 87% . RommensTo avoid hardware problems with TBW technique, some authors have recommended plating osteosynthesis for fracture stabilization ,24. BailVarious degrees of postoperative elbow stiffness and deficit of range of motion have been reported in literature after surgical treatment of olecranon fractures ,26,27. RDegenerative changes are not uncommon after olecranon fractures and they have been related to the length of follow up . KarlssoNon-union, ulnar nerve palsy and wound infection have been described in approximately 2\u201310% of olecranon fractures ,27. EvenTension band wiring fixation for isolated olecranon fractures leads to good elbow function and minimal loss of physical capacity. The technique remains the \"gold standard\" for the treatment of displaced and minimally comminuted olecranon fractures despite the introduction of new implants designed specifically to address the problems of wound irritation and metalware removal. In long term, low levels of pain and elbow degenerative changes may be evident but no clear correlation could be established between radiological and clinical result.The author(s) declare there are no competing intersets.BC wrote the paper. NS and ES collected and statistically analyzed the data. CD and JP conceived, designed and revised the study. Each author read and approved the final manuscript."}
+{"text": "Forty-two oral squamous cell carcinomas (SCCs) were analysed for p53 mutations and human papillomavirus (HPV) infection to examine the prevalency of these factors and correlation with apoptotic index  of the tumour tissue. In polymerase chain reaction (PCR)-Southern blot analysis, HPV DNAs were detected from 22 out of 42 SCCs (52%) with predominance of HPV-16 (68%). p53 mutations in exons 5-8, screened by nested PCR-single-strand conformation polymorphism (PCR-SSCP) analysis, were observed in 16 of 42 tumours (38%). The state of the p53 gene did not show any correlation with HPV infection. The terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labelling (TUNEL) method was used for detection of apoptotic cells. The mean AI was 2.35, ranging from 0.31 to 6.63. SCCs associated with p53 mutation had significantly lower AI than those without p53 mutation (P < 0.01), whereas no difference in AI was found between SCCs with and without HPV infection. The results of this study confirmed that HPV infection and/or p53 mutations are implicated, but are not mutually exclusive events, in carcinogenesis of oral SCC and also showed that decrease in apoptosis is more closely related to p53 mutation than HPV infection."}
+{"text": "Incubation for 20 h in low concentrations of colchicine has been shown to kill the peripheral blood lymphocytes (PBL) of patients with chronic lymphocytic leukaemia (CLL), whereas at least a 10,000 x higher concentration of colchicine is required to kill lymphocytes from a normal donor. This ultrasensitivity of CLL lymphocytes to low doses of colchicine was confirmed in 19/20 PBL samples, 5/6 lymph nodes, and in the one totally replaced marrow studied. PBL from 75 patients with non-Hodgkin's lymphoma (NHDL) were examined for colchicine ultrasensitive (CUS) cells similar to those found in CLL. All the patients had less than 5 x 10(9)/1 morphologically normal circulating lymphocytes. PBL from 45 healthy donors and 39 patients with diseases other than leukaemia or lymphoma were used as controls. CUS cells were detected in 24 (32%) of the 75 patients. The CUS cells were considered to represent blood involvement with malignant lymphocytes for three reasons. First, there was an association with marrow involvement (P less than 0.05) which usually accompanies involvement of the blood with morphologically abnormal cells. Secondly, 23 (77%) of the 30 involved lymph nodes, marrows and spleens studied were CUS. Thirdly, there was a close correlation with the presence of a monoclone of B lymphocytes demonstrated by surface markers (P less than 0.01)."}
+{"text": "Objective: We undertook a microbiological study of purulent specimens from women with symptomatic breast abscesses.Methods: Fifty-one purulent samples were collected in 2 periods (December 1991\u2013April 1992 and January 1994\u2013June 1994) from nonpuerperal breast abscesses in 44 patients attending our hospital.Results: One of the most frequently isolated microorganisms was Proteus mirabilis , present as a pure culture in all but 1 specimen (isolated together with Peptostreptococcus spp.). Staphylococcus aureus was isolated in 10 specimens, 6 of which were post-tumorectomy abscesses. Polymicrobial anaerobic flora were isolated in 11 specimens (21.5%); Staphylococcus epidermidis in 4 (8%); and Streptococcus milleri, Alcaligenes sp., and mixed aerobic-anaerobic flora in 1 specimen each. The 7 remaining samples (13.7%) were negative bacteriological cultures.Conclusions: We draw attention to the frequent isolation of P. mirabilis in recurrent and torpid breast abscesses in 4 women in whom surgery was necessary in addition to antibiotic treatment."}
+{"text": "Forty-three patients with large  but operable carcinoma of the breast have been treated by endocrine manipulation before definitive local surgery. This has allowed the study of the relationship between response to therapy and pretreatment oestrogen receptor (ER) concentration, as measured by a dextran-coated charcoal adsorption method. Premenopausal patients (17) were treated by surgical (4) or medical (13) oophorectomy. Post-menopausal patients (26) received either tamoxifen (10) or an aromatase inhibitor (16). Response was assessed from statistical analysis of the changes in tumour size. On completion of 12 weeks of endocrine therapy, there was significant regression of tumour size in 18 of the 43 patients. All 18 patients had tumours with ER concentrations of greater than or equal to 20 fmol mg-1 cytosol protein. Conversely all patients except one progressing on treatment had tumours with ER concentrations of less than 20 fmol mg-1 cytosol protein. This relationship applied for both premenopausal and post-menopausal patients. The overall response rate of patients with tumours of ER concentration greater than or equal to 20 fmol mg-1 cytosol protein was 60%."}
+{"text": "Therefore, of the 92 patients with residual T1 cancer on restaging TUR, 75 (82%) progressed to muscle invasion within five years compared to 49 of 260 (19%) who had no or non T1 tumor detected on restaging transurethral resection. In a multivariate analysis of risk factors, restaging TUR pathology was the most important single determinant associated with tumor progression  followed by the presence of complete response to BCG at first cystoscopy performed three to six months after TUR , presence of multiple tumors  and high-grade tumors . The authors concluded that restaging transurethral resection identifies patients with T1 bladder cancer who are at high risk for early tumor progression and that this finding justifies an immediate cystectomy in this group of patients to prevent an adverse outcome in the long term.In order to evaluate the impact of pathological findings at restaging transurethral resection (TUR) on tumor recurrence and stage progression, a cohort of 352 patients with T1 bladder cancer underwent a second or restaging TUR after a two to four-week interval. All patients received induction bacillus Calmette-Guerin (BCG) therapy and 88% were followed for five years or more. Maintenance regime for BCG was not instituted in any of the patients. The median (range) follow-up was 7.5 (1-14) years. Pathological findings on restaging TUR were correlated with tumor features, recurrence rates, stage progression frequency and progression-free survival. Of the 352 patients with T1 tumors 203 (58%) had residual tumor on restaging TUR, including 92 (26%) with residual non muscle-invasive (T1) cancer. During the first five years, 66% of cases recurred and 35% progressed in stage. Recurrence and progression rates were 48% and 8% for patients with no residual tumor on restaging TUR, 69% and 37% for those with carcinoma Tumors invading the lamina propria T1) constitute about one-third of all superficial bladder tumors and have recurrence and stage progression rates (with bladder conservation) of 70% and 30-50% respectively within 5-10 years of initial presentation. constituA restaging TUR for patients presenting with T1 tumors detects residual disease in a significant proportion of patients and impr"}
+{"text": "Objective: The objective of this study was to determine whether prophylactic treatment with oral broad-spectrum antimicrobial therapy improves pregnancy outcomes in twin gestations.Methods: Patients with twin gestations between 24 and 32 weeks were randomized to receive amoxicillin/clavulanic acid or placebo. Those patients randomized before 24 weeks received a 1-week course at 24 and at 28 weeks gestation. Those patients entered later than 24 weeks received a 1-week course either at 28 weeks or at enrollment (up to 32 weeks). Other than antibiotic use, the management of the groups was identical and unchanged from the routine care of twin gestations.Results: Of 149 twin pregnancies enrolled, 76 were randomized to the drug group and 73 to the placebo group. There was no significant difference in mean gestational age at delivery (35.9 vs. 35.7 weeks), birth weight , mean neonatal nursery stay (9.9 vs. 11.7 days), or respiratory distress syndrome (6/76 vs. 4/73) in the drug vs. placebo group, respectively.Conclusions: The addition of prophylactic oral broad-spectrum antimicrobial therapy to the standard antepartum management of twin gestations had no demonstrable effect on the gestational age at delivery, birth weight, or neonatal complications. There did not appear to be any beneficial effect of the prophylactic use of amoxicillin/clavulanic acid in this clinical setting."}
+{"text": "To the Editor: Routine vaccination of children with the 7-valent pneumococcal conjugate vaccine , initiated in the United States in 2000, was followed within 2 years by an extensive and rapid decline in invasive pneumococcal disease (IPD)   were broDuring the same period, complicated pneumonia was identified in 7 other inpatients by using the International Classification of Diseases, 9th revision, codes for necrotizing pneumonia and empyema and Current Procedural Terminology codes for thoracoscopic surgery (median age 4.3 years); 2 had asthma, 1 had congenital diaphragmatic hernia with resultant left lung hypoplasia. No causative organism was identified for any of these cases.As illustrated by our 4 cases, serotype 19A is emerging as an increasing cause of severe disease such as complicated pneumonia. Although the incidence of IPD in general has decreased since the introduction of PCV-7, the emergence of nonvaccine serotypes as a cause of severe disease is becoming more prevalent. Among 8 geographic areas in the United States, the incidence of IPD caused by nonvaccine serotypes in children <5 years of age increased from 16.3 cases/100,000 population to 19.9 cases/100,000 population, respectively, from prevaccine years 1998\u20131999 to in 2004 , and a longer course of intravenous antimicrobial drugs (mean 19.2 days vs. 17 days). Although these 7 patients required more video-assisted thoracoscopic surgery than did our 4 patients (100% vs. 75%), those with S. pneumoniae 19A necrotizing pneumonia had a more severe clinical course of illness resulting in more ICU admissions (75% vs. 29%) and intubations (75% vs. 14%).Because organisms were not isolated from the 7 other patients with necrotizing pneumonia during the same period, we are unable to comment on whether All 4 of our patients had completed the PCV-7 series before becoming ill. The emergence of nonvaccine serotypes as a cause of severe disease may be caused by serotype replacement and increased nasopharyngeal carriage of nonvaccine serotypes after receiving PCV-7 ("}
+{"text": "Formestane is a selective inhibitor of oestrogen synthesis by aromatase enzymes and induces disease regression in breast cancer patients. This phase II randomised study was carried out to determine whether there were any differences in the effects of two different doses of formestane on oestradiol (E2) serum levels and to evaluate the corresponding clinical activity in post-menopausal patients with positive or unknown oestrogen receptor status pretreated or not for advanced disease. Furthermore, possible drug interference with adrenal steroidogenesis was assessed by measuring 17-hydroxycorticosteroid (17-OHCS) urinary levels. A total of 143 patients entered the study and were randomly assigned to receive formestane 250 mg (72 patients) or formestane 500 mg (71 patients), both given i.m. every 2 weeks. In comparison with baseline, E2 serum levels decreased by an average of 40% after only 15 days and remained unchanged thereafter, with no difference being observed between the two doses. The values of 17-OHCS remained unchanged during treatment in both groups. Objective responses were 28% (19/69) in the 250 mg and 46% (31/68) in the 500 mg group. In conclusion, the two formestane doses were equally effective in reducing E2 levels without affecting adrenal function, and in inducing a considerable percentage of clinical responses."}
+{"text": "We investigated the incidence of sapovirus (SaV)\u2013associated gastroenteritis in infants and children in Japan during 2007\u20132008 and characterized the diversity of SaV-positive strains. SaV was detected in 19 (4%) of 477 fecal specimens. The leading genogroup  comprised intergenogroup recombinant SaVs (GII/GIV). SaV ORF1 encodes for nonstructural proteins and the major capsid protein (VP1), and ORF2 (VP2) and ORF3 encode proteins of yet unknown functions. On the basis of VP1 nucleotide sequences, SaVs are divided into 5 genogroups (GI\u2013GV), of which GI, GII, GIV, and GV strains are known to infect humans; SaV GIII infects porcine species. We investigated the incidence of SaV-associated gastroenteritis in infants and children in Japan during 2007\u20132008 and characterized the diversity of SaV-positive strains.Sapovirus (SaV) is now considered a notable global enteropathogen of acute gastroenteritis in persons of all ages  during July 2007\u2013June 2008. Of these, 14 specimens were from Tokyo, 30 from Sapporo, 77 from Saga, 91 from Osaka, and 265 from Maizuru. We defined diarrhea as at least 3 passages of unformed (loose and watery) feces a day. We defined acute gastroenteritis as diarrhea and other symptoms, such as vomiting, fever, and abdominal pain. Children studied ranged in age from 1 month to 14 years (median 25 months). The Ethical Committees of The University of Tokyo and Aino University approved the study. A parent or guardian of each child provided informed consent.http://bips.u-strasbg.fr/fr/Documentation/ClustalX), and distances were calculated by using the 2-parameter Kimura method. Phylogenetic trees with bootstrap analysis from 1,000 replicas were generated by using the neighbor-joining method. The sequences of SaV strains detected in the study have been submitted to GenBank under accession nos. FJ445092\u2013FJ445110.RNA was extracted and purified by using the QIAamp Viral RNA Mini kit , according to the manufacturer\u2019s instructions. Reverse transcription (RT) was performed with 5 \u00b5L of RNA template by using SuperScript III reverse transcriptase . By using multiplex RT-PCR, 2 groups of diarrheal viruses were identified: 1) astrovirus, norovirus, and sapovirus and 2) rotavirus and adenovirus , followed by norovirus (19.3%), adenovirus  sapovirus (3.9%), group C rotavirus (0.8%), and astrovirus (0.2%). In addition, we found viral mixed infections in 1.8%.>3 times a day (3 [15%]).Sapovirus was detected in 19 (4%) fecal specimens. The highest incidence of SaV infection was in the 1-year-old group (9 [47%]), and most (13 [68%]) of these infections occurred in infants and children <3 years of age. Infections increased slightly during December through February (12 cases). The most common signs and symptoms in SaV-infected children were diarrhea (19 children [100%]), fever >100\u00b0F (5 [26%]), and vomiting Nineteen SaV sequences were analyzed by phylogenetic analysis and grouped by using the recent SaV capsid region classification scheme .Nucleotide sequence comparison of the identified 15 GIV shared little or almost no divergence among themselves (98%\u2013100% identity), even when they were detected in regions of Japan distant from each other. They are likely to represent a single strain, 8208/Maizuru/08/JP. The 8208/Maizuru/08/JP sequence closely matched Ehime1107 and SW278 . We sugg,\u2013According to the past 5 years of SaV surveillance conducted in the same setting and population in Japan, SaV GI/1 was the most common genotype during 2003\u20132004, and thereafter genotype GI/6 dominated over the GI/1 in 2004\u20132005 (,\u2013Recently, several types of recombinant SaV strains, including intergenogroup and intragenogroup, have occurred frequently in Japan (Our results suggest that recombinant strains may be underestimated. Characterization of SaVs usually is based on the capsid gene sequence only, whereas both the capsid gene and RNA polymerase sequences are needed to identify such viruses. Furthermore, constant surveillance is important to successfully monitor the emergence of these strains."}
+{"text": "We identified enterotoxigenic Bacteroides fragilis in stool specimens of patients with inflammatory bowel disease and other gastrointestinal disorders. The organism was detected in 11 (13.2%) of 83 patients with inflammatory bowel disease. Of 57 patients with active disease, 19.3% were toxin positive; none of those with inactive disease had specimens positive for enterotoxigenic Bacteroides fragilis gene sequences."}
+{"text": "To study the clinical, radiological, and laboratory profile in patients of allergic bronchopulmonary aspergillosis (ABPA).Retrospective analysis of 42 cases of ABPA, diagnosed over a period of 10 years from 1995 to 2005, for their clinical, radiological, and laboratory profiles.Aspergillus antigen, elevated serum titers of total IgE antibody, A. fumigatus specific IgE and IgG antibodies, and serum precipitin against A. fumigatus were positive in majority of patients, who underwent these tests. Thirty eight (90.5%) patients had had history of antitubercular treatment during the course of their illness. All 42 patients met at least four criteria for the diagnosis of ABPA.Of 42 ABPA patients, 27 were men and 17 were women. Their mean age at the time of diagnosis was 31.2 years and mean duration of illness was 12.2 years. Breathlessness was the chief symptom. Other allergic disorders existed in 17 (40.5%) patients, and family history suggestive of allergic disease was present in 22 (52.4%) patients. Most common chest radiographic finding was fleeting pulmonary shadows in 28 (66.7%) patients. High resolution CT thorax revealed central bronchiectasis as predominant finding. Peripheral blood eosinophilia more than 1000 cells/\u03bcl, Type I and type III cutaneous reactivity to Any patient of bronchial asthma, presenting with recurrent shadows in chest radiograph and high peripheral blood eosinophilia, should be investigated for ABPA. Efforts need to be intensified to improve the awareness level among general physicians for early diagnosis and prompt treatment of this disease to avoid misuse of antitubercular drugs. A. fumigatus. This potentially destructive lung disease was first recognized in EnglandAllergic bronchopulmonary aspergillosis (ABPA) is most frequently recognized manifestation of pulmonary aspergillosis occurring worldwide, and is also an important emerging disease in India.Aspergillus antigen; (6) precipitating antibodies to A. fumigatus; (7) elevated specific serum IgE and IgG to A. fumigatus; and (8) peripheral blood eosinophilia.The study is a retrospective analysis of 42 patients with ABPA, diagnosed over a period of 10 years from 1995\u20132005, at Department of Pulmonary Medicine, King George's Medical University, Lucknow. Diagnosis of ABPA was considered if they met four of the following major criteria: (1) history of asthma; (2) radiographic pulmonary infiltrates (fixed/transient); (3) central bronchiectasis on HRCT thorax; (4) elevated total serum IgE antibody; (5) Type I cutaneous reactivity to Aspergillus antigen, serum titers of total IgE antibody, A. fumigatus specific IgE and IgG antibodies, and serum precipitin against A. fumigatus.These ABPA patients were analyzed retrospectively for their clinical, radiological, and laboratory profiles. Clinical evaluation was done by detailed history of present illness, presence of other allergic disorders, history of past treatment, family history of atopic disorder, and physical examination. Radiological examination was done by plain chest radiograph and high resolution computed tomography of thorax. Laboratory profile was analyzed by peripheral blood absolute eosinophil count, skin testing to A total of 42 cases of ABPA were diagnosed in our hospital from 1995\u20132005, including 27 male and 15 female patients. Out of these 42 patients, 29 patients (69%) were in the age group of 20\u201340 years. In our study group the youngest patient was 9-years old and the oldest was 60 at the time of diagnosis. The mean age was 31.2 years.Mean duration of their illness was 12.2 years (1.5\u201330 years). Data for stage of disease were available for 19 patients, which showed that three (15.8%) patients were in stage I; one (5.3%) patient in stage II; ten (52.6%) in stage III; one (5.3%) in stage IV; and one (5.3%) in stage V. Symptom profile of these patients revealed that all 42 (100%) patients had complaint of breathlessness; 24 (57.1%) had cough; 16 (38.1%) were passing mucus plugs in sputum; 11 (26.2%) had fever; 12 (28.6%) had hemoptysis; and 4 (9.5%) had chest pain. History of other allergic disorders, like allergic rhinitis and dermatitis was present in 17 (40.5%) patients, and family history suggestive of allergic diseases was present in 22 (52.4%) patients. Out of 42 patients, 34 (81%) patients frequently needed corticosteroids for control of their symptoms. Past history of antitubercular treatment was present in 38 (90.5%) patients, sometime during the course of their illness.Radiological examination of these patients revealed normal chest radiographs in only two (4.8%) patients. Among the other 40 patients with abnormal chest radiographs, fleeting pulmonary infiltrates were the most common finding and distribution of shadows were mainly in upper zones. Fleeting shadows were present in 28 (66.7%) patients and fixed shadows were seen in remaining 12 (28.6%) patients. Shadows seen were, infiltrates in 29 (69.1%) patients; consolidation in 8 (19.1%); ring shadows in 4 (9.5%); gloved finger appearance in 2 (4.8%); tram track appearance in 1 (2.4%); and prominent bronchovascular markings in 7 (16.7%) patients. Distribution of shadows was unilateral in 14 (33.3%) patients and bilateral in 26 (61.9%) patients. They were in upper zone in 29 (69%) patients and in lower zone in 21 (50%) patients. HRCT thorax showed central bronchiectasis in all 14 patients (100%), who were able to afford it. One patient had cavitation, with aspergilloma, and three patients showed air bronchogram, suggestive of consolidation.Aspergillus antigen. Peripheral blood absolute eosinophil count was raised in all and in 37 (88.1%) patients it was >1000 cells/\u03bcl. Skin test for Type I cutaneous reactivity was positive in 41 (97.6%) patients, while Type III reaction was positive in 29 (69.1%) patients. Sputum culture for fungal elements revealed growth of A. fumigatus in 27/39 (69.2%) patients. Serum titers for specific IgE/IgG were elevated in 30/37 (81.1%) patients. Total serum IgE titers were elevated in all 16 patients who underwent this test (100%). Serum precipitin test against A. fumigatus, done in 18 patients, was positive in all. All patients were not subjected to all laboratory tests, either due to financial constraints or lack of consent. Only 14 patients were subjected to all tests and out of 14 patients, 13 (93%) met all the criteria of ABPA. All 42 patients met at least four criteria for the diagnosis of ABPA [All patients underwent tests like peripheral blood absolute eosinophil count and skin test for Type I and Type III cutaneous reactivity to  of ABPA .ABPA is a syndrome characterized by bronchial asthma, recurrent chest radiographic infiltrates, peripheral blood eosinophilia, frequent need of corticosteroid therapy for control of symptoms, and significant lung destruction. Despite several published series from various parts of the country, this disease is still underrecognized and misdiagnosed as pulmonary tuberculosis.8112-agonists. Itraconazole in doses of 200 mg/day for two years in ABPA is helpful in reducing the need of corticosteroid therapy, along with clinical, biological, and functional improvements.15Oral corticosteroids remain the cornerstone for treatment of ABPA."}
+{"text": "Primary central nervous system lymphoma (PCNSL) is a frequent complication in acquired immunodeficiency syndrome (AIDS). The objective of this survey was to investigate incidence, clinical features, radiological findings, histologic diagnosis, treatment and outcome for all patients with histologically verified AIDS-related PCNSL diagnosed in Norway in 1989\u20132003.We identified the patients by chart review of all cases recorded as PCNSL in The Norwegian Cancer Registry  and all cases recorded as AIDS-related PCNSL in the autopsy registry at a hospital having 67% autopsy rate and treating 59% of AIDS patients in Norway, from 1989 to 2003. Histologic material and radiological images were reviewed. We used person-time techniques to calculate incidence rates of PCNSL among AIDS patients based on recordings on AIDS at the Norwegian Surveillance System for Communicable Diseases .Twenty-nine patients had histologically confirmed, newly diagnosed AIDS-related PCNSL in Norway from 1989\u20132003. Only 2 patients had this diagnosis established while alive. AIDS patients had 5.5% lifetime risk of PCNSL. Their absolute incidence rate of PCNSL per 100 person-years was 1.7 (95%CI: 1.1\u20132.4) and decreased during the consecutive 5-year periods from 3.6, to 2.5, and to 0.4 (p < 0.001). Median survival from initial symptom of PCNSL was 2.3 months, but one patient was still alive 4 years after completed radiotherapy.This is the first national survey to confirm decreasing incidence of AIDS-related PCNSL. Despite dismal survival in most patients, the possibility of long term survival should prompt more aggressive diagnostics in suspected PCNSL. Primary central nervous system lymphoma (PCNSL) has been diagnosed in at least 2% of individuals infected with human immunodeficiency virus (HIV) , and in Few studies on AIDS related PCNSL were population based ,9,15-17.This study complied with the Helsinki Declaration. The Regional Committee for Medical Research Ethics, the Directorate for Health and Social Affairs and The Data Inspectorate approved the study and waived informed consent.Norway (population of 4.2 million in 1989 and 4.6 million in 2003) has mandatory cancer reporting to the Norwegian Cancer Registry. This national registry recorded 180 patients with PCNSL diagnosed from 1 January 1989 to 31 December 2003. Medical records of all patients were reviewed. Histologically verified AIDS-related PCNSL was found in 23 of the 180 patients (98 had non-AIDS PCNSL and 59 no PCNSL) [This study sample thus consisted of 29 AIDS patients with histologically verified PCNSL; 27 were diagnosed and treated at Ullevaal University Hospital. Clinical features, histologic diagnosis, radiological findings, treatment and outcome were registered. HAART was defined as the administration of three or more antiretroviral agents including a protease inhibitor or non-nucleoside reverse transcriptase inhibitor. One pathologist (AKG) re-examined histologic material of all these patients from biopsy (n = 2) or autopsy (n = 27) and reclassified it according to the current WHO-classification (2001). For immunohistochemistry, the antibodies CD3, CD20 and Ki67 were used as a minimum. Epstein-Barr virus hybridization was performed in 25 patients. Twenty-six patients had a complete autopsy of the entire body (excluding systemic lymphoma). The remaining 3 patients underwent biopsy (n = 2) or autopsy (n = 1) of the brain only; none of them had signs of lymphoma at chest- and abdomen imaging (n = 3) or bone marrow biopsy (n = 2). Cause of death was established from medical records, autopsy reports and death certificates.In 14 included patients  images from computed tomography (CT) (in 14) and magnetic resonance imaging (MRI) (in 4) prior to histologic diagnosis were available for review.  A neuroradiologist (JK) and a general radiologist (ISH) reviewed the images, first individually and then together. Results are based on consensus from the joint review.Number of new cases with AIDS and number of AIDS deaths in Norway each year were obtained from MSIS (The Norwegian Surveillance System for Communicable Diseases). Named AIDS reporting from laboratories and clinicians to this national surveillance system has been mandatory in Norway since 1983 [We calculated absolute incidence rates of PCNSL among persons with AIDS based on numbers of newly diagnosed AIDS-related PCNSL and numbers of patients living with AIDS the same year  (data from MSIS). Trend test and 95% confidence interval (CI) for incidence was calculated according to the Poisson distribution.st 2008. Survival curves were calculated and plotted using the method of Kaplan and Meier. All p-values in the analyses are two-sided. The analyses were performed with Stata 9.0  and SPSS 14.0 .Duration of survival was calculated as time between date of first symptom attributable to PCNSL and date of death or January 1In Norway the absolute incidence rate of PCNSL among AIDS patients per 100 person-years in 1989\u20132003 was 1.7 (95%CI: 1.1\u20132.4) and decreased from 3.6, to 2.5, and to 0.4 the consecutive 5-year periods (p < 0.001) , a single lesion in 2 (14%), and multiple (2\u20137) lesions in 11 (79%) patients. In the patient with no lesion, CT one week prior to death indicated hydrocephalus. All together, 37 lesions (36 at CT and 9 at MRI) were identified; involving the lobes in 11 patients (79%) and the deep structures of the brain in 8 patients (57%)  diagnosed after the introduction of HAART in Norway (August 1996). In 3 patients HAART was started mean  4.3  months prior to first symptom of PCNSL and was continued after symptom debut. Only one of these had a favourable clinical and haematological response, with normalization of CD4 cell count; this response was first achieved after PCNSL was diagnosed. In one patient HAART was started after PCNSL was diagnosed and gave no favourable response. Toxoplasma therapy was given to 20/29 (69%) patients; 2 responded with clinical improvement and regress of imaging findings but both died rapidly after their symptoms relapsed 1 and 15 months after initial toxoplasma therapy, respectively.Median survival from first symptom attributable to PCNSL was 2.3 (95% CI: 1.5\u20133.2) months. Only 21% (6/29) and 7% (2/29) were alive at 6 months and 1 year, respectively  of the patients from this time period.Our figures for incidence rate (1.7 per 100 person-years) and lifetime risk (5.5%) of PCNSL among AIDS patients are in the upper range of figures in other studies ,9,15,20.Autopsy in all AIDS patients is needed to truly estimate the incidence of AIDS-related PCNSL. In our study, 93% (27/29) had the diagnosis of PCNSL first established by autopsy. None of these patients had a biopsy performed while alive, and 15% (4/27) of them had no focal brain lesion on imaging  was similar to survival times in other larger materials 1.0\u20132.8 months)  months ,17. Howe. Howe17.Good performance status, higher CD4 count, whole brain irradiation and HAART have favourable impact on survival in AIDS-related PCNSL ,8,22,23.201Tl single-photon emission computed tomography (SPECT). Combining these two methods, a rapid, accurate and minimally invasive diagnosis may be achievable, although the accuracy of this diagnostic approach is not fully clarified in the era of HAART [Delayed diagnosis of PCNSL is a concern with empiric toxoplasma therapy ,22. To rThe present MRI/CT findings are similar to those in toxoplasmosis ,25. MRI This national survey showed decreasing incidence rate of AIDS-related PCNSL in Norway during 1989\u20132003. AIDS patients in Norway had a 5.5% lifetime risk of PCNSL, emphasizing the importance of PCNSL as organ-specific manifestation of AIDS. Despite dismal survival in most patients (median 2.3 months), the possibility of long term survival should prompt more aggressive diagnostics in suspected PCNSL.The authors declare that they have no competing interests.ISH, OM and AE conceived of the study and obtained ethical approvals. ISH collected the data, performed the data analyses and drafted the manuscript. JK and ISH reviewed the imaging material. AKG reviewed the histopathological material. OM, AE and OD contributed in the interpretation of data. All authors have critically revised the manuscript and have given final approval of the version to be published.The pre-publication history for this paper can be accessed here:"}
+{"text": "Twenty-eight patients with progressive symptomatic bone metastases from breast cancer received (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD) 30 mg in 500 ml of 0.9% saline infused over 2 h every 14 days. No other systemic therapy for breast cancer was prescribed. All patients had progressed on at least one previous systemic treatment. APD was continued until the disease progressed. Patients were assessed for objective response by the UICC criteria. In addition, subjective response was determined by a pain questionnaire. Radiological evidence of bone healing with sclerosis of lytic disease  was seen in 4 patients. The median duration of response was 10 months. Eleven patients had stable disease for at least 3 months (median 5 months) and 9 progressed. Symptomatic response occurred in 9 patients and 12 reported an improvement in quality of life. Treatment was tolerated well with no significant toxicity. In conclusion, long-term inhibition of bone destruction is possible with APD therapy alone and both subjective and objective responses are seen."}
+{"text": "Breast cancer is the second most common cancer among women in Madras and southern India after cervix cancer. The Madras Metropolitan Tumour Registry (MMTR), a population-based cancer registry, collects data on the outcome of cancer diagnosis by both active and passive methods. A total of 2080 cases of invasive female breast cancer were registered in MMTR during 1982-89. Of these, 98 (4.7%) cases were registered on the basis of death certificate information only (DCO), and there was no follow-up information for 235 (11.3%). These were excluded, leaving 1747 (84%) for survival analysis. The mean follow-up time was 43 months. The overall Kaplan-Meier observed survival rates at 1, 3 and 5 years were 80%, 58% and 48% respectively; the corresponding figures for relative survival were 81%, 61% and 51%. A multifactorial analysis of prognostic factors using a proportional hazards model showed statistically significant differences in survival for subjects in different categories of age at diagnosis, marital status, educational level and clinical extent of disease. Increasing age at diagnosis was associated with decreased survival. Single women displayed poorer survival (37.4%) at 5 years than those married and living with spouses (50.0%). The survival rate among those who had more than 12 years of education was higher (70%) at 5 years than that of illiterate subjects (47%). An inverse relationship was seen between survival rates and clinical extent of disease. The need for research to determine feasible public health approaches, allied to coordinated treatment facilities to control breast cancer in India, is emphasized."}
+{"text": "CA125 is a tumour marker test based on a monoclonal antibody against an antigen from an ovarian carcinoma cell line. Serum concentrations of CA125 were determined in 95 patients with pancreatic cancer and in 106 patients with benign pancreatic, biliary and hepatocellular diseases. The CA125 concentrations were compared with the CA19-9 and CEA levels. Almost half (45%) of the patients with pancreatic cancer had an elevated CA125 level (greater than 35 U ml-1). Elevated values were also found in benign diseases (24%), especially in patients with pancreatitis and benign hepatocellular diseases, but more seldom in extrahepatic cholestasis. It seems that CA125 is of limited value in the diagnosis of pancreatic cancer. Combination of the CA125 with the CA19-9 test increases the sensitivity only 6% as compared to the CA19-9 assay alone. There may, however, be a use for CA125 in differentiating between obstructive jaundice of benign and malignant origin."}
+{"text": "In the first Rural Cancer Registry in India, 194 cervical cancer cases were registered during 1988-91. The 3 year survival was significantly higher in cases registered in 1990-91 (40.0%), than in those registered in the earlier years (26.6%). This improvement was due to the cancer education activities undertaken by the Registry."}
+{"text": "Surveillance of 2,277 white-tailed deer for antibodies against Ehrlichia chaffeensis in Iowa showed seropositivity rates of 12.5% in 1994 and 13.9% in 1996. From 1994 to 1996, the estimated number of seropositive deer increased to 54,701 (28%). The increasing deer population and expanding tick distribution may increase risk for human monocytic ehrlichiosis."}
+{"text": "Giant cell tumors (GCT) are neoplasms of mesenchymal stromal cells with varied manifestations. There is no uniform accepted treatment protocol for these tumors,49 cases of proven giant cell tumors of appendicular skeleton, 27 prospective and 22 retrospective constituteed this study. The retrospective cases were collected by using computerized data base collection method. The patients were evaluated clinically, radiologically and by histology. Companacci grading and Enneking staging was used in the study. Two treatment modalities were used a) extended curettage (with/ without bone grafting/ cementation) or b) wide excision and reconstruction with a prosthesis or arthrodesis. Functional evaluation was done by Enneking's system. Chi square tests, mann-whitney test and ANOVA were used for statistical analysis.The average age was 26.82 years (16-50 years). 25 patients (51%) were recurrent GCT at presentation. The commonest site was lower end of femur  and upper end of tibia . 40 (81.63%) tumors had less than 5 mm of subchondral bone free of tumor. 35 (71.43%) tumors were Enneking's surgical stage III and companacci grade III. Pathological fractures were seen in 12 (24.49%) cases. Intra-lesional currettage was used in 28 and enbloc excision in 19 patients and 2 (4.08%) underwent amputation. The average follow up period was 18.6 months (range 2-84). One recurrence was seen in a grade III recurrent distal radial lesion in the intralesional curettage group (3.57%) Enneking's functional score with intralesional curettage (25.41) was better than enbloc excision (21.37). Enbloc excision had higher rates of infections (36.84 % Vs 25%) and soft tissue coverage problems (21.05% Vs 0).Intralesional therapy has a better functional outcome and less complications than enbloc excision, albeit with a high recurrence rate which can however be effectively treated with repeat extended curettage. Giant cell tumors (GCT) of bones have been described histologically as neoplasms of undifferentiated mesenchymal stromal cells with the presence of abundant giant cells; radiographically presenting as an eccentric lytic lesion at the ends of long bones and clinically as a benign but often locally aggressive lesion. It has a tendency towards local recurrence and occasionally malignant change.Bloodgood,22The treatment of GCT has changed from amputation at the beginning of century to curettage and excision. The current suggestions have varied from curettage for all lesions1Ours was a combined retrospective-prospective study. Patients treated between January 2000 to January 2006 were included in the study. Patients treated from January 2000 to January 2004 were studied retrospectively from previous hospital records and followed up regularly at regular intervals. Cases from January 2004 to January 2006 were studied prospectively and followed up regularly. A total of 49 patients were studied, with 27 in the prospective and 22 in the retrospective group. Average follow up period was18.6 months (range 2-84 months).Only biopsy proven giant cell tumors of appendicular skeleton were included in the study. Spinal lesions were excluded from study. Evaluation of patients in retrospective group was done by available hospital records using a computerized database. Patients registered during the course of the study were evaluated with clinical examination, radiological evaluation and histopathology. All data was recorded on a prefixed proforma. Radiographs and MR scans were done for all patients. Chest radiographs were done in all patients. Site of lesion,  was carefully evaluated. Size of radiolucent area were recorded as occupying less than one half, one-half and more than one-half diameter of bone in A-P view. Thickness of the subchondral bone at adjacent articular surfaces was measured radiologically and recorded as more than 5 mm, 5 mm or less or zero.Enneking8\u00a9) burr. Phenol  was used as chemical adjuvant in all cases. The subchondral region of cavity was then packed with autogenous bone graft obtained from iliac crest. Either fibular cortical autograft or irradiated corticocancellous allograft bone obtained from bone bank was used. Polymethylmethacrylate (PMMA) was also used in some cases when the size of the intact articular surface after extended curettage needed additional support along with bone grafts. This was to prevent prolonged immobilization. When necessary, standard internal fixation was used. Wide excusion was done when the tumor as assessed by recent X-rays and MR scane had extended to within 2 mm of articular cartilage or when it it had breached the cortex to extend to surrounding soft tissues. Post-operatively, patients were followed up at weekly intervals in first month, fortnightly for next 2 months and monthly thereafter. X-rays were taken at every visit after the eight weeks and then every six weeks. Functional evaluation was done by Enneking's system. This system is applicable in evaluating limb salvage surgeries. This evaluates pain, function and emotional acceptance, besides dexterity as a measure of upper limb functions and walking ability, gait as a measure of lower limb functions. It was done 6 months post surgery or in the last follow up in patients with less than 6 months followup (2 cases). Chi square tests, Mann-Whitney test and ANOVA were used for statistical analysis.Two treatment modalities were used: Extended curettage (with/without bone grafting/cementation) or wide excision and reconstruction with a prosthesis or arthrodesis. The type of reconstruction was decided by a affordability of the patient for prosthesis. Extended curettage was  done wherd decade of life. The male: female ratio was 1.5:1. The commonest site was distal femur in 16 cases (32.65%), followed closely by upper end tibia in 13 cases (26.53%). Eight cases (16.33%) were seen in distal end radius, while 4 cases (8.16%) each were seen in lower end tibia and proximal femur. Lesions were also seen in proximal humerus , lower end humerus  and 2nd metacarpal  Lower limbs accounted for 37 cases (75.51%) while 12 cases (24.49%) involved upper extremity. 25 (51%) of our patients had recurrence on presentation, while the other 24 (49%) were primary. The initial treatment details of recurrent cases were not available accurately in all cases as they were operated in other hospitals. Epiphyseo-metaphyseal was the commonest location in 44 (89.8%) cases. In 39 cases (79.6%) tumors occupied more than half the width of bone on A-P radiographs, while the rest 10 (20.4%) had sizes less than half width of bone. 30 lesions (61.22%) had subchondral tumor free bone of less than 5 mm, while in 11 lesions (22.45%) the tumor had extended right upto articular cartilage. Eight lesions (16.33%) were far away from articular cartilage with more than 5 mm of uninvolved subchondral bone.A total of 49 cases, 22 (44.89%) cases from retrospective group and 27 (55.10%) patients from the prospective group were studied and followed up. The age of the patient at presentation varied from 16 to 50 years. 28 cases (57.14%) were in 3P=0.208) in Campanacci grade or Enneking stage, between the primary or recurrent lesions.Out of 49 patients, 1 was Campanacci grade I (2.04%), 13 were grade II (26.53%) and 35 were grade III (71.43%). Out of 49 patients, 1 was of Enneking stage I (2.04%), 13 were of stage II (26.53%) and 35 (71.43%) were of stage III. There was no statistically significant difference (P=0.404). This may be due to late presentation of primary cases to our clinic. Also, recurrent lesions, when compared to primaries did not have any difference in subchondral tumor free zone.6 of 24 (25%) primary lesions and 3 of 25 (12%) recurrent lesions presented with size less than half the width on A-P radiograph. 18 of 24 (75%) primary and 22 of 25 (88%) recurrent lesions had more than half the width on A-P radiograph. Hence, recurrent lesions, when compared to primary lesions did not have larger sizes at presentation (P=0.935). The mean follow up score in patients with pathological fractures was 22.58, while in those without fracture was 23.76. This was statistically not significant (P=0.564). One out of 12 patients (8.33%) with pathological fracture had recurrence on follow up which however was not significant (P=0.076).Pathological fractures were seen in 12 patients (24.49%) commonly  in lower end femur. It was also seen in lower end radius , upper end femur , upper end tibia  and upper end humerus . Out of 12 patients with pathological fractures, 6 (50%) were primary and 6 (50%) were recurrent lesions; pathological fractures were not commoner in recurrent lesions  were treated with curettage. After curettage, bone grafting alone was used in 23 (82.14%) patients, while one patient, a fourth recurrence in proximal tibia was treated with only bone cement. Four patients were treated with both bone grafting and bone cement after curettage , two of nd metacarpal underwent vascularized toe transfer.Nineteen (38.77%) patients were treated with wide excision and 2 (4.08%) underwent amputation. Out of 19 patients 13 had GCT around the knee joint. Out of which 7 were treated with arthrodesis, six with prosthesis. Four lesions of distal radius were  excised Campanacci grades I  and II  have been predominantly treated with curettage while grade III tumors were treated predominantly with wide excision  . Two undSeventeen of 24 primary cases were treated with curettage and bone grafting (70.83%), while 7 underwent wide excision (29.17%). 11 of 25 recurrent lesions were treated with repeat curettage (44%) and 12 underwent wide excision (48%). Both patients who underwent amputation were recurrent lesions (8%). One patient was amputated at above knee level for recalcitrant infection, while the other was disarticulated at hip for extensive local spread.Out of 14 patients with Campanacci grade I or II, none recurred. One (2.86%) patient out of 35 grade III GCTs recurred. None of Enneking stage I or II recurred. One recurrence in 35 stage III patients (2.86%) was noted. Recurrence was seen in 1 patient (2.04%), who had undergone curettage for a recurrent lesion in distal radius and had fracture at presentation. No recurrences were noted with wide excision .P=0.017). Three patients following wide excision, with complications like exposed plate due to soft tissue coverage problems and recurrent infections had poor scores [P=0.013). Other complications like carpal impingement etc. were seen more frequently in patients of distal end radius treated with wide excision (31.58%).The average follow up was 18.6 months with a median of 19 months. Six patients in curettage group and 5 patients in wide excision group had a follow up of less than 12 months. The average functional score of 47 patients was 23.49. In 28 patients with curettage and bone grafting it was 25.41 while with wide excision it was 21.37, this difference being significant (r scores . Two undLack of a definite treatment protocol in treating GCT has resulted from a highly variable presentation of this ubiquitous bone lesion. Lack of studies from South East Asia has further compounded the problem with a deficient data on outcome of GCTs in Asian population.The mean age of presentation was 26.8 yrs 16-50). Presentation was commonest in third decade. This is in accordance with previous studies.6-50. Pre2521011P=0.564). Fifty one percent of our patients presented to us with first recurrence, following a primary procedure done outside. Recurrence was considered to be present when there was progressive lysis of more than 5 mm at cement-bone or graft-host interface or if there was an absence of a sclerotic rim at the above said interface.P=0.935).Pathological fracture was seen in 12 (24.49%) of our patients, commonly in lower end of femur (5 cases or 41.67%). Similar observations were made by CampanacciAccording to Schajowicz,191114Curettage in GCT is usually followed by adjuvant therapy either to achieve a more thorough tumor kill or to provide enhanced structural support around the joint. We used phenol with curettage. Phenol is known to cause protein coagulation, damages deoxyribonucleic acid and causes necrosis.151351019P=0.017). Joint salvage is known to improve function. Wide excision was associated with more complication rates than curettage.The mean follow up score at the last follow up was 23.5. Curettage had better functional outcome when compared to wide excision  and more loss of productive working hours. Thus for Indian patients extended curettage with bone grafting in giant cell tumors is a cost-effective, easy technology option."}
+{"text": "We examined 46 non-small-cell lung carcinomas (NSCLCs) for the presence of p53 mutations in exons 4-9, positive p53 immunostaining and loss of heterozygosity (LOH) in the TP53 locus. p53 mutations were detected in 13 tumour samples (28.3%), whereas overexpression of the p53 protein was found in 30 of 45 (67%) samples. Allelic loss was found in 9 of 38 (23.6%) informative cases. The statistical analysis revealed no significant correlation between p53 mutations and clinicopathological data, although mutations appear to occur more frequently in squamous cell carcinomas (7 of 18) than in adenocarcinomas (2 of 15). All but three individuals in this study group smoked. In contrast to previous reports, we found a higher prevalence of GC-->AT transitions than of GC-->TA transversions, as expected in a smoking population. A trend was found between p53-positive immunostaining and a history of heavy smoking (76-126 pack-years) and was inversely correlated with allelic deletion (LOH) at the TP53 locus. Eight of the 12 NSCLCs containing p53 mutations also had concomitant p53 overexpression, and it is of specific note that three of the four tumours containing p53 'mutations' with no overexpression of the p53 protein had either insertions or deletions in the p53 gene. No correlation was found between p53 mutations and fractional allele loss or ras mutations. p53 mutations in this Merseyside population in the UK do not appear to be as common as in other reports for NSCLC and exhibit predominance of GC-->AT transitions preferentially at non-CpG sites, suggesting that other carcinogens in addition to those in tobacco smoke may be involved in NSCLC in the Merseyside area of the UK."}
+{"text": "To develop and optimize polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) targeting 18S rDNA and internal transcribed spacer (ITS) region of fungi for rapid detection and identification of dermatophytes.Two PCR-RFLP methods targeting 18S rDNA and ITS regions of fungi were optimized using standard and laboratory isolates of dermatophytes and other fungi. Sixty-eight dermatological clinical specimens (nail clippings (56), material obtained from blisters (8), hair root (2), scraping from scaly plaque of foot (1) and skin scraping (1) collected by the dermatologist were subjected to both the optimized PCR-RFLP and conventional mycological (smear and culture) methods.T. rubrum DNA, respectively. PCR targeting 18S rDNA was specific for dermatophytes and subsequent RFLP identified them to species level. PCR-RFLP targeting the ITS region differentiated dermatophytes from other fungi with identification to species level. Among the 68 clinical specimens tested, both PCR-RFLP methods revealed the presence of dermatophytes in 27 cases (39.7%), whereas culture revealed the same only in 2 cases (7.40%), increasing the clinical sensitivity by 32.3%. Among 20 smear positive specimens, both PCR-RFLP methods detected dermatophytes in 12 (17.6%). Both the methods detected the presence of dermatophytes in 13 (19.11%) smear and culture negative specimens, increasing the clinical sensitivity by 36.1%.PCRs targeting 18S rDNA and the ITS region were sensitive to detect 10 picograms and 1 femtogram of PCR-RFLP methods targeting 18S rDNA and the ITS regions of fungi were specific and highly sensitive for detection and speciation of dermatophytes. However, these procedures generally are either slow or nonspecific and the morphologic and physiologic characteristics depend on too many variables such as slow growth rate, presence of low threshold of organisms in clinical specimens, prior therapy and production of spores.469Dermatophytes are a group of closely related fungi that invade the keratinized tissue  of humans and other animals, resulting in an infection called dermatophytosis. These fungi are the commonest causes of superficial mycoses.Dermatophyte discrimination has met with some success using techniques such as polymerase chain reaction (PCR) targeting 18SrDNA,14Trichophyton rubrum ATCC 34265 and Microsporum gypseum ATCC 26652 supplied by P.G.I Chandigarh and 10 laboratory isolates containing T. rubrum (4), T. mentagrophytes (3), M. gypseum (2) and E. floccosum (1) that were maintained in the laboratory were used in the study.Two standard strains comprising of Sixty-eight dermatological clinical specimens comprising nail clippings (56), material obtained from blisters (8), hair root (2), material obtained from scaly plaque of foot (1) and skin scraping (1) collected by the dermatologist were included in this study. The specimens collected in specially designed sterile paper envelope were transferred onto a sterile Petri plate in a clean air laminar flow work bench. A part of it was processed by conventional investigations and the other part for PCR methods.The clinical specimens were processed for culture with subsequent identification carried out according to standard mycological methods.Hae III enzyme was applied on both the PCR amplicons to identify the species of dermatophytes and other fungi.PCR on the specimens included the extraction of genomic DNA from dermatological specimens, followed by amplification using primers specific for 18S rDNA to detect dermatophytes and ITS primers for detection of fungal genome. PCR based RFLP using DNA from the isolates was extracted by following a modification of the Lee and Taylor protocol as described previously.T. rubrum, specific for dermatophytes,Taq polymerase and 10 \u03bcL of template DNA. The PCR profile consisted of denaturation for 3 min at 95\u00b0C, followed by 35 cycles at 94\u00b0C for 1 min, 58\u00b0C for 1 min and 72\u00b0C for 40 sec and a final extension at 72\u00b0C for 5 min.Uniplex polymerase chain reaction (PCR) was carried out using primers DHIL (5' TGC ACT GGT CCG GCT GGG 3') and DH1R (5' CGG CGG TCC TAG AAA CCA AC 3')  were used in each run.The products were visualized by running the products in a 2% agarose electrophoresis gel incorporated with 8 \u03bcL ethidium bromide at 100V for 20 min using a UV transilluminator (302n m) and documented using gel documentation system . Molecular weight markers  and 2.5 \u03bcL of buffer c were added. The digested products were resolved using 4% agarose gel electrophoresis incorporated with 16 \u03bcL of ethidium bromide at 100 V and documented using The amplified products of dermatophyte-specific PCR were subjected to digestion with T. rubrum. The primers were specific, selectively amplifying all the dermatophyte isolates tested and not amplifying the other nondermatophye fungal DNA.Sensitivity and specificity of PCR assay targeting 18SrDNA (dermatophyte-specific PCR): The analytical sensitivity of PCR Assay targeting 18SrDNA region using dermatophyte specific primers-DH1R and DH1L was 10 picograms of ATCC strain of The application of dermatophyte-specific PCR on dermatological specimens is shown in Hae III enzyme on dermatophyte-specific PCR and ITS PCR amplicons is shown in Figs. The results of application of PCR-RFLP using T. rubrum in 21 specimens (Nail clipping 16 and blister top 5), M. gypseum in 5 specimens (nail clipping 4 and blister top 1) and T. mentagrophytes in 1 specimen (Hair root). In addition, PCR-RFLP on the ITS region detected the presence of DNA of nondermatophytes in 18 (26.4%) clinical specimens that were culture positive and 8 culture negative specimens, increasing the clinical sensitivity by 30.76%. Fungal DNA was not detected in 15 (22.05%) clinical specimens by both PCR methods and smear and cultures were also negative, indicating the specificities of both methods. Overall, the clinical sensitivity of PCR targeting 28s RNA increased by 31.67% over culture method. The fungal etiology associated with dermatomycoses is shown in A. flavus - 5, A. fumigatus - 6, A. niger - 8, Fusarium species - 3, A. terreus - 1, 1 each of C. albicans, C. tropicalis, C. parapsilosis. T. rubrum (dermatophyte) and A. niger (nondermatophyte fungi) were found to be the principal etiological agents that caused dermatomycoses.A comparison of the efficiencies of both conventional and PCR-based mycological methods was performed and the results are shown in the This study was designed to develop PCRs for rapid detection and species level identification of dermatophytes and other fungi that cause dermatomycoses. The results clearly demonstrated not only the specificity but also an increased clinical sensitivity by 36.1% and reliable rapid results within 24 h in contrast to the 21 days of incubation required for the isolation of dermatophytes by culture.PCR targeting the ITS region was considered as the gold standard in this study as application of this PCR indicated the presence of fungus in 77.9% specimens out of which 39.4% were dermatophytes and the rest (38.5%) were nondermatophytes. The superiority of the ITS PCR was also reflected in detection of more number of nondermatophyte fungi involved in causing dermatomycoses and its specificity in proving 15 of the 68 clinical specimens negative for fungal etiology, which were also negative by smear culture and also by dermatophyte specific PCR. In addition, ITS PCR-based RFLP proved to be a confirmatory technique for dermatophyte-specific PCR targeting 18SrDNA gene in detection and identification of the species of dermatophytes with 100% correlation. Based on these factual findings, we consider ITS PCR as the gold standard for this study.et al.28Aspergillus, Candida and Fusarium species as the nondermatophytes that cause dermatomycoses, correlating well with the present study.In the literature, the percentage of dermatophytes isolated by conventional methods range from 30% to 70% in the specimens from clinically diagnosed dermatophytosis patients.26PCR-RFLP has revolutionized diagnostic microbiology and it helps to arrive at a more specific diagnosis by reducing the time, labor and poor isolation rate of conventional culture methods In a diagnostic set up both ITS PCR and dermatophyte-specific PCR can be applied on dermatological specimens since any fungi causing dermatomycoses can be detected. Thus, this study demonstrates the superiority of PCR-based techniques in terms of sensitivity rapidity and reliability when compared to the conventional mycological culture method."}
+{"text": "P< 0.03). Detection of CK-20 and CEA mRNA correlated in nine of 12 cases (75.0%) with the risk of tumour recurrence (not significant) and showed a tendency towards shorter disease-free survival by univariate analysis (not significant). Our data indicate that CK-20 and CEA mRNA detection by RT-PCR may prove useful for the prediction of tumour recurrence of patients with pN0 colorectal carcinoma, although neither reach statistical significance in this series of patients. \u00a9 2000 Cancer Research CampaignThe reported rates for tumour cell involvement in the locoregional lymph nodes of colorectal cancer vary greatly, depending on the method used and case selection. In order to further evaluate the clinical value of molecular biologic detection of tumour cells we investigated 102 histologically tumour-free (pN0) regional lymph nodes from 51 consecutive, completely resected (UICC R0) colorectal carcinoma specimens for the presence of tumour cell mRNA by RT-PCR specific for carcinoembryonic antigen (CEA) and cytokeratin 20 (CK-20). Two lymph nodes located nearest to the primary tumour were investigated in each case. CK-20 mRNA was found in 31 of 51 patients (60.8%) and CEA mRNA in 30 of 51 patients (58.8%), respectively. Identical transcription patterns of CK-20 and CEA mRNA (both positive or both negative) were found in 38 of 51 patients (74.5%). There was a significantly higher proportion of cases with CEA positivity in the lymph nodes of tubulopapillary than of mucinous adenocarcinomas ("}
+{"text": "Microsatellite instability has been observed in a variety of sporadic malignancies, but its existence in sporadic ovarian cancer has been the subject of conflicting reports. We have performed a polymerase chain reaction-based microsatellite analysis of DNAs extracted from the neoplastic and non-neoplastic tissues of 41 ovarian cancer patients. Tumour-associated alterations were observed in seven (17%) of these cases. Clinicopathological correlations revealed that: (1) alterations among tumours classified as serous adenocarcinomas occurred with relatively low frequency (2/24 or 8%); (2) most of the tumours with microsatellite alterations (5/7 or 71%) were of less common histopathological types ; (3) tumour-associated alterations were observed in 3/4 (75%) of the patients with stage I tumours vs 4/37 (11%) of the patients with stage II, III and IV tumours (P = 0.01); (4) tumour-associated microsatellite instability was found to occur with similar frequencies among patients with and without clinical features suggestive of familial disease, including positive family history, early onset, or multiple primary tumours. In summary, we have observed microsatellite alterations in the neoplastic tissues of ovarian cancer patients with diverse genetic backgrounds and clinicopathological features. The pattern of alterations is consistent with the possibility that multiple mechanisms may be responsible for microsatellite instability in ovarian neoplasms."}
+{"text": "EDAcFN enzyme immunoassay (EIA) is a new tumour marker assay measuring the extra domain A-containing isoform of cellular fibronectin (cFN), a component mainly found in extracellular matrices. The concentration cFN was measured in plasma and serum from 468 patients with malignant and benign diseases. The concentrations of cFN were higher in plasma than in serum. Using receiver operating characteristic (ROC) curve analysis, determination from plasma was superior to serum at specificity levels higher than 78% and was chosen for further analysis. The highest frequencies of elevated cFN values were seen in patients with hepato-pancreato-biliary malignancies (50-67%). In pancreatic and bile duct cancers, cFN provided little further information to that obtained by CA 19-9. The greatest advantage over CA 19-9 and CEA was seen in patients with local colorectal cancer and in hepatocellular carcinomas. Four out of nine patients with Dukes' stage B colorectal cancer had an elevated cFn level, but only one had an abnormal CEA level. In hepatocellular carcinomas, cFN was also compared with alpha-fetoprotein. The sensitivity of cFN (72%) was superior to that of AFP (61%), and concomitant use of cFN and AFP raised the sensitivity to 83%. The highest frequencies of elevated values in patients with benign diseases were observed in those with severe liver disease (32%) and biliary (17%) and pancreatic (24%) diseases. A combination of cFN and CA 19-9 showed the highest overall sensitivity of 47%, compared with 31% for cFN and 33% for CA 19-9. The corresponding specificities were 76% for cFN +/- CA 19-9, 85% for cFN and 83% for CA 19-9. The accuracy of a combination of cFN and CA 19-9 or CEA (60% respectively) was higher than that of cFN (55%), CA 19-9 (55%) or CEA (45%) alone. In conclusion, the results of the new cFN test are encouraging and further studies on larger patient materials have been started."}
+{"text": "ARF, frequently inactivated in familial MM), widely reported data suggested the presence within this region of other melanoma susceptibility gene(s). To clearly assess the role of the 9p21 region in sporadic melanoma, we evaluated the presence of microsatellite instability (MSI) and loss of heterozygosity (LOH) in primary tumours as well as in synchronous or asynchronous metastases obtained from the same MM patients, using 9 polymorphic markers from a 17-cM region at 9p21. LOH and MSI were found in 27 (41%) and 11 (17%), respectively, out of 66 primary tumours analysed. In corresponding 58 metastases, MSI was found at higher rate , whereas a quite identical pattern of allelic deletions with 27 (47%) LOH+ cases were observed. Although the CDKN locus was mostly affected by LOH, an additional region of common allelic deletion corresponding to marker D9S171 was also identified. No significant statistical correlation between any 9p21 genetic alteration  and clinicopathological parameters was observed. \u00a9 2000 Cancer Research Campaign http://www.bjcancer.comMalignant melanoma (MM) is thought to arise by sequential accumulation of genetic alterations in normal melanocytes. Previous cytogenetic and molecular studies indicated the 9p21 as the chromosomal region involved in MM pathogenesis. In addition to the CDKN genes (p16/CDKN2A, p15/CDKN2B and p19"}
+{"text": "To describe the clinical features, treatment and outcome patterns in 307 eyes with Coats' disease.Retrospective chart review of patients diagnosed with Coats' disease between January 1996 and January 2006 from a single referral center in southern India.phthisis bulbi (7%), neovascular glaucoma (5%), epiretinal membrane (4.4%) and rubeosis iridis (4.4%).Two hundred and eighty patients (307 eyes) with mean age of 15.67 years (range: Four months-80 years) were included. Decreased vision (77%), unilateral affection (90%) and male preponderance (83.4%) were chief presenting features. Anterior segment involvement was seen in 67 (21.8%) eyes. Retinal telangiectasia were seen in 302 (99%) eyes, exudation in 274 (89%) eyes and retinal detachment in 158 (51.5%) eyes. Four-quadrant disease was seen in 207 (67.2 %) eyes. Visual acuity was < 20/200 in 249 (80.9%) eyes. One hundred and nine of 176 treated eyes (61.93%) had favorable anatomical outcome; 207 of 280 eyes (74%) had an optimal structural outcome. Seventeen (5.3%) eyes were enucleated. Complications following treatment included Indian patients with Coats' disease have a high male predominance, the majority of whom present with severe visual impairment and extensive four-quadrant exudation. Unusual presentations such as pain, vitreous hemorrhage and a high incidence of anterior segment involvement are distinctive to Indian eyes. These courrences. While mourrences. This stuIdiopathic, retinal telangiectasiaWith or without intra or subretinal exudation andTypically seen unilaterally in young males.This study was a retrospective case series which enlisted patients diagnosed with Coats' disease between January 1996 and January 2006. Coats' disease was diagnosed if an eye had:t test) was used for continuous data while non-parametric test  was used for non-parametric data. The SPSS Version 9  was used for analysis.Retinal telangiectasia were defined as dilated, irregular caliber, small to medium-sized retinal vessels; exudative retinopathy as yellow exudation in the sensory retina or subretinal space. Other causes of vasculopathy with evident exudation were excluded. Patient details included age, sex, laterality, duration of symptoms and other vital history. Visual acuity (Snellen's Chart at 6 m), intraocular pressure and anterior segment findings were noted. A thorough fundus examination with binocular indirect ophthalmoscope and a detailed fundus drawing aided with fundus photographs were utilized to enter pertinent data. The disease extent was classified into three zones, the macula  being Zone 1; the mid-periphery, between the retinal vascular arcades and equator being Zone 2 and the peripheral fundus anterior to this being Zone 3. Staging of the disease was done based on the extent and the quadrant(s) of retina involved. TreatmenOver the last 10 years, 280 patients were diagnosed with Coats' disease. The mean age at presentation was 15.67 + 11.6 years (range: Four months to 80 years) with a median age of 11 years. Of the 280 patients, 251 (90%) cases were unilateral and 28 (10%) were bilateral. Males constituted a majority; 256 eyes (83.4%) belonged to male patients, while 51 (17.2%) eyes were that of females. The average duration of complaints was 4.2 months (Range: Four days to six years). The most common clinical symptom at presentation was decrease in visual acuity, seen in 221 (77%) eyes followed by ocular deviation in 69 (22.4%) eyes, pupillary white reflex (leucocoria) in 62 (20.6%) eyes and ocular pain in nine (2.9%) eyes while five (1.6%) eyes were asymptomatic. The distribution of visual acuity recorded at presentation was thus: 20/40 or better in 42 (13.6%) eyes, less than 20/40 and better than 20/120 in 17 (5.5%) eyes, less than 120 and better than 20/2000 in 62 (20.1%) eyes and 186 (60.8%) eyes had hand motion to nil perception of light.All eyes were graded according to the stage of the disease at time of diagnosis . Of the Ultrasound scan was done in 70 eyes (22.7%) while fluorescein angiography was done in 128 eyes (41.5%). A CT scan was required as an additional investigation in four eyes (1.2%) to rule out retinoblastoma. Cytopathologic and biochemical evaluation of the subretinal fluid in 34 eyes (11%) was consistent with the diagnosis of Coats' disease. Eosinophilic foamy histiocytes with cholesterol crystals were typically seen in all 34 samples.Phthisis bulbi in 22 (7%) eyes, glaucoma in 16 (5%) eyes, hypotony in 14 (4.5%) eyes, neovascularization of iris in 13 (4.4%) eyes, epiretinal membrane in 13 (4.4%) eyes, vitreous hemorrhage in 12 (4.2%) eyes and iatrogenic retinal break causing rhegmatogenous retinal detachment in three (1%) eyes.Observation was adjudged appropriate in 163 eyes (53%) while 103 (33.3%) eyes underwent laser photocoagulation. Thirty eP = 0.008), peripheral disease (P = 0.024) and treatment with scleral buckling (P = 0.028).In the analysis of structural outcome, we analyzed patients with at least 12 months of follow-up from presentation. Among those meeting this criterion, 116 eyes (93 patients) were found to have an average follow-up of 14.2 months (range 12-44 months). Univariate analysis  of factoP = 0.794, paired t test. Also, there was no statistical difference between the baseline and final visual acuity according to quadrantic disease distribution [The visual acuity in the eyes with one-year follow-up did not show any significant change in the final visual acuity (mean logMAR 1. 74 baseline and 1.75 at last visit in 116 eyes) ribution .The hallmark lesion of this disease is idiopathic retinal telangiectasia which shows up as \u2018light bulb appearance\u2019 on fluorescein angiography . Other fet al.[et al.,[et al. have reported anatomical benefits from treatment with a yellow-dye laser.[In order to unravel possible differences in the disease manifestation as seen in this part of the world to that reported in the predominantly Western literature available, we compared our findings with several other studies, particularly the one by Shields et al. Anterior.[et al., as compa.[et al.,24 Nucci ye laser. We have Of the 15 eyes of preschool children (<four years) in our study, nine eyes had retinal detachment, while seven eyes had exudation >three quadrants. Stage 3A1 or greater in younger children usually has a poor prognosis.13Twenty-one eyes with advanced Coats' disease were managed with external subretinal fluid drainage and cryo therapy. Retinal reattachment was achieved in 57% eyes while anatomical stabilization was achieved in 85.7% eyes (mean follow-up: 15 months).et al.[We compared the causes of poor visual outcome in the treated eyes with those reported by Shields et al. and founOn an average, Indian patients present at least five years later than their Western counterparts (mean age: 16.5 years versus 11 years) with an average duration of symptoms of 2.5 + 2.8 years. While more than half (55.5% versus 43%) the patients present with diminution of vision, a large majority (80.9% versus 76%) had visual acuity worse than 20/200. Male predominance is even more pronounced (83.2% versus 76%). Bilateral disease is seen twice (10% versus 5%) more commonly. There appears to be a bimodal presentation, the first major peak at a mean age of 16.5 years and the second smaller peak at a mean age of 46.7 years. Anterior segment involvement is more than twice (21.8% versus 10%) more common. Macular telangiectasia is seen five times (5.5% versus 1%) more commonly. Vitreous hemorrhage is a peculiar presenting feature. Almost half (49.2%) the eyes had retinal detachment at presentation, while more than three-fourths of eyes (78.3%) had disease involvement of three quadrants of fundus or more. Extensive four-quadrant retinal exudation is also seen more frequently (67.2% versus 55%). However, exudative (secondary) retinal detachment and retinal macrocysts are seen much less often. Unusual presentations such as pain, vitreous hemorrhage and increased incidence of anterior segment involvement are peculiar to Indian eyes. Treatment in the early stages is often successful in achieving anatomical stabilization. However, advanced cases are difficult to treat and results are disappointing. Visual improvement in classic Coats' disease of childhood onset is usually very minimal and frequently, complications may compromise visual function despite an attached retina."}
+{"text": "Treatment was repeated every 4 weeks for a total of two or three cycles. Among 23 eligible patients (median age: 59 years), three showed complete response (13%), 15 showed partial response (65%), for an overall response rate of 78% . Stable disease was observed in four cases (17%) and progressive disease in one (4%). The median time to failure and median survival time have not yet been reached. Of the 52 treatment cycles administered, diarrhoea and grade 3 or 4 neutropenia were observed in 10% and 75% respectively. There were no therapy-related deaths. The combination of CPT-11 with cisplatin is a promising regimen for neoadjuvant chemotherapy in locally advanced cervical cancer. The toxicities of this regimen are well tolerated. \u00a9 1999 Cancer Research CampaignTo evaluate the response rate and toxicity of the combination of irinotecan (CPT-11) and cisplatin in a neoadjuvant setting, a phase II study was conducted regarding the regimen of this combination in patients with locally advanced cervical cancer. Eligibility included patients with previously untreated stage Ib2, IIb, or IIIb squamous cell carcinoma with good performance status. CPT-11 (60 mg m"}
+{"text": "Low back pain (LBP) is the most prevalent musculoskeletal condition and one the most common causes of disability in the developed nations. Anecdotally, there is a general assumption that LBP prevalence in Africa is comparatively lower than in developed countries. The aim of this review was to systematically appraise the published prevalence studies conducted on the African continent to establish the prevalence of LBP in Africa.A comprehensive search was conducted in April 2006. The following databases PEDro, Psychinfo, Science Direct, SportsDiscus, PubMed, CINAHL, Biblioline Pro-African Wide NiPAD and SA ePublications were individually searched using specifically developed search strategies for epidemiological research conducted on LBP amongst the African population. Two reviewers independently evaluated the methodological quality of the studies reviewed.A total of 27 eligible epidemiological studies were included in this review. The majority of the studies (63%) were conducted in South Africa (37%) and Nigeria (26%). The most common population group involved workers (48%), while scholars comprised 15% of the population. 67% of the studies were found to be methodologically sound, and the LBP prevalence of these were analyzed. The mean LBP point prevalence among the adolescents was 12% and among adults was 32%. The average one year prevalence of LBP among adolescents was 33% and among adults was 50%. The average lifetime prevalence of LBP among the adolescents was 36% and among adults was 62%.The findings support the global burden of disease of LBP, in addition to suggesting that LBP prevalence among Africans is rising and is of concern. Further research into the most effective strategies to prevent and manage LBP in Africa is warranted. The health of Africans is of global concern, as improvement in health outcomes observed in most Western countries over the past few decades has not been achieved in Africa . This haThe global prevalence of general disability is highest in sub-Saharan Africa . The etiLBP is the most prevalent musculoskeletal condition and the most common cause of disability in developed nations . The lifA review of research publications on LBP suggests that most research has been conducted in the developed world, where little racial heterogeneity exists . Racial,The literature on the epidemiology of LBP is accumulating, but for the most part, studies are restricted to high-income countries, therefore little is known about the epidemiology of LBP in the rest of the world . In deveTo our knowledge, no systematic review reporting on the prevalence of LBP on the African continent exists. The aim of this review was therefore to systematically appraise peer-reviewed published disease prevalence studies conducted on the African continent, in order to ascertain whether LBP is of concern among Africans, as it is globally. This review considered the methodological quality of the relevant literature in order to identify opportunities for improvement in research practices, as well as to establish a way forward for high quality research in this area in Africa.This review was part of a larger, more comprehensive study which investigated the prevalence of cervical, thoracic and lumbar spine pain (or LBP) in Africa. The LBP epidemiological findings are reported in this paper.The specific objectives of this element of the review were:1. To determine the prevalence of LBP on the African continent.2. To describe the primary risk factors of LBP among Africans living on the African continent.3. To critically appraise the methodological quality of the prevalence studies with a view to identifying opportunities to improve future research quality.The following terms and definitions were applied to this review:Adolescent: individual aged 11\u201319 years old.\u2022 Adult: individual aged 20 years and older.\u2022 Low back pain: Pain experienced in the lumbar region of the spine.\u2022 Musculoskeletal condition: Affecting the muscles and/or skeleton of the spinal column.\u2022 Africa: All countries located on the African continent.\u2022 Prevalence: the total number of cases of a disease in a given population at a specific time.\u2022 th century to present) and SA ePublications (19th century to present).A comprehensive search was conducted in April 2006 in all accessible library databases of published research reports available at the Stellenbosch University Medical Library. No date limit was applied to any of the databases searched, and thus each database was searched since its inception. The electronic databases included: PEDro (1929 to present), Psychinfo (1806 to present), Science Direct (1823 to present), SportsDiscus (1800 to present), PubMed (1950 to present), CINAHL (1982 to present), Biblioline Pro-African Wide NiPAD  terms were used where possible, with Boolean operators. The search strategies for remaining databases included synonyms of the main search terms. The search strategies are illustrated in Appendix A. Manual searching of journals not indexed in electronic databases was considered, however, all issues of the African journals were not available. This method was thus discarded as it would be difficult to replicate. Secondary searching (or PEARLing) was however undertaken, whereby the reference lists of the selected articles were reviewed for additional references not identified in the primary search.The titles and abstracts of the all identified literature were screened by two reviewers independently (LM and QL) using the inclusion criteria below. The full text of all potentially relevant articles were retrieved and screened by the same two reviewers using the same criteria, in order to determine the eligibility of the paper for inclusion in the review.The inclusion criteria were that the studies reported on epidemiological research, and were conducted on the African continent. The prevalence of LBP should be the study focus, in subjects of adolescent and adult age groups, any race and any gender. Studies could be written in either the English or French language, as these are the primary languages used in African academic publications.The methodological quality critical appraisal tool used in a systematic review into the prevalence of global LBP (reviewing literature from 1966 to 1998) was applied to this review 2. \"Africa\" [MeSH]3. #1 AND #24. \"physical therapy\" [MeSH]5. #3 AND #46. \"prevalence\" [MeSH Major topic]7. #3 AND #68. \"Epidemiology\" [MeSH Major topic]9. #3 AND #810. \"rehabilitation\" [MeSH Major topic]11. #5 AND #812. \"Primary Prevention\" [MeSH Major Topic]13. #3 AND #12ProQuest1. Africa2. back pain3. spinal pain4. #1 AND #2AfricaWide1. back pain2. (#1 AND physiotherapy)3. (#1 AND prevention)4. (#1 AND rehabilitation)5. 6. (#1 AND conditions)7. back conditions8. (spine AND pain)9. spine conditionsSA ePublications1. kw: back pain2. kw: spinal pain3. kw: spine4. kw: physiotherapy5. (kw: back pain) and kw: physiotherapy6. kw: back rehabilitation7. kw: back conditions8. ((((((kw: (spine)) or (kw: (back conditions))) or (kw: (back rehabilitation))) or (kw: (physiotherapy))) or )) or (kw: back pain))Psycinfo1.  or 2. (africa)3. spinal pain4. \"Epidemiology-\" in MJ, MN5. \"Rehabilitation-\" in MJ, MN6. #1 and #27. #1 and 8. #5 and #29.  and #1CiNAHL and ScienceDirect1. (MM \"Back pain+\") or (MM \"Low Back Pain\") or (MM \"Back Injuries+) or (MM \"Back\")2. Africa3. #1 AND #24. 5. #2 AND #46. 7. (MH \"Rehabilitation\")8. #4 AND #7SportsDiscus1. (DE \"BACK PAIN\" OR DE \"LOW BACK PAIN)2. (DE \"AFRICA\")3. #1 AND #24. (DE \"PHYSICAL THERAPY\" OR DE \"BALNEOLOGY\" OR DE \"BATH\" OR DE \"CHIROPRACTIC\" OR DE \"CONTINUOUS PASSIVE MOTION\" OR DE \"DIATHERMY\" OR DE \"ELECTROTHERAPY\" OR DE \"HYDROTHERAPY\" OR DE \"INVERSION THERAPY\" OR DE \"MAGNETIC FIELD THERAPY\" OR DE \"MASSAGE\" OR DE MYOFASCIAL RELEASE\" OR DE \"ORTHOPEDIC MANIPUALTION\" OR DE \"PROPRIOCEPTIVE NEUROMUSCULAR FACILITATION\" OR DE \"ROLFING\" OR DE \"SAUNA\" OR DE \"THERMOTHERAPY\" OR DE \"WATER RUNNING\")5. (DE \"PREVENTION\")6. (DE \"TREATMENT\")7. (DE \"REHABILITATION\")8. (DE \"EPIDEMIOLOGY\")9. (DE \"ETIOLOGY\")10. #3 AND #4The pre-publication history for this paper can be accessed here:"}
+{"text": "The present study was undertaken to examine whether the presence of primary lung cancer could affect the antitumour activities of pleural cavity macrophages (PCM) and peripheral blood monocytes (PBM). PCM by pleural lavage and PBM were simultaneously obtained from 14 lung cancer patients not showing invasion of the pleural cavity. PCM and PBM were isolated by percoll gradient centrifugation and adherence. The lavage method yielded about 16.8 +/- 9.6 (s.e.) x 10(6) cells, which consisted of 80.7% PCM, 17.6% lymphocytes and 1.6% other cells. The cytotoxic activities of PCM and PBM against allogeneic melanoma (A375) cells were assessed by a 72h 125I-IUdR release assay. The lavaged PCM showed spontaneously high tumour cytotoxic activity which was dependent on the effector/target ratio. In 13 out of 14 cancer patients, PCM were significantly more cytotoxic to melanoma cells than PBM. In contrast, there were no significant differences in production of tumour necrosis factor  or interleukin 1 (IL-1) between PCM and PBM. When the abilities of PCM and PBM of the same patient to produce these monokines were compared, PCM produced much more TNF-alpha than PBM, thus indicating a correlation between the expression of spontaneous macrophage-mediated cytotoxicity and spontaneous TNF-alpha production by PCM. These results suggest that PCM may play an important role in host defence against invasion of the pleural cavity by cancer cells."}
+{"text": "Burkholderia pseudomallei infection (melioidosis) were identified in southern Taiwan. Two genotypes that had been present in 2000 were identified by pulsed-field gel electrophoresis. Such a case cluster confirms that melioidosis is endemic to Taiwan.From July through September 2005, shortly after a typhoon, 40 cases of  Burkholderia pseudomallei and is found in northern Australia and tropical countries in Southeast Asia  and PMA-2 (5\u2032-GGT TCG AGA CCG TTT GCG-3\u2032)  with a bacteriophage \u03bb DNA ladder. Gels were stained with ethidium bromide, viewed under UV light, and analyzed by using the Molecular Analyst System (Bio-Rad Laboratories).In addition to the 40 isolates obtained in 2005, a total of 14 Of 40 patients, 30 (75%) were male. Their mean age was 64.6 years (range 38\u201387 years). A total of 37 (92.5%) patients never traveled abroad, and 28 (70%) denied recent contact with mud or dirty water before their illness. Because 3 patients could not walk, infection by cutaneous contact with contaminated dirt or water was less likely. Twenty-seven (67.5%) patients had an underlying debilitating illness, predominantly diabetes mellitus (20 patients).<72 hours before admission were noted in 25 (62.5%) patients, and 13 (32.5%) patients visited hospitals within 24 hours after onset of the illness, which suggests acute illness. The earliest onset of symptoms related to melioidosis was July 20, 2005. This onset was 4 days after the arrival of Typhoon Haitang, which suggests an incubation period of 4 days. Most patients  had B. pseudomallei bacteremia, and 20 of these patients had concomitant pleuropulmonary infections. Of 10 (25%) patients without bacteremia, pulmonary infections remained the predominant foci in 6. Eight (20%) patients died during hospitalization.The most common initial symptoms were fever  and cough . Relevant prodromes lasting XbaI restriction profiles in PFGE provide a level of resolution similar to that obtained with multilocus sequence typing for B. pseudomallei isolates  were identified in SpeI macrorestriction profiles (profiles . These gprofiles .B. pseudomallei infections (Melioidosis became a reportable disease in Taiwan in 2000; through 2004, the Center for Disease Control in Taiwan received reports of 43 cases of B. pseudomallei are likely present in southern Taiwan and that melioidosis is endemic in this country.In conclusion, after widespread flooding caused by a typhoon, an outbreak of melioidosis occurred in southern Taiwan from July 2005 through September 2005. Two genotypic strains were found in clustered cases in 2005 and in sporadic cases found in Tainan and Kaohsiung counties in 2000. These findings confirm that environmental sources of"}
+{"text": "Blood samples collected at 0, 3, 30, 60, 90, and 120 min after zinc administration showed no significant alteration in the plasma levels of TSH, FT3, and FT4 in hyperthyroid patients. There were no changes in the plasma levels of FT3 and FT4 in the control subjects, but TSH levels were acutely depressed by zinc administration. This study suggests that zinc given acutely and in pharmacological doses does not affect thyroid function in hyperthyroid subjects, but affect plasma TSH levels in healthy individuals.Zinc metabolism may regulate thyroid function acting at TRH (thyrotropin-releasing hormone) synthesis, peripheral deiodination of T4 (tetraiodothyronine), and binding of thyroid hormones to nuclear receptors. The aim of this study was to investigate the effect of acute zinc administration on TSH (thyroid-stimulating hormone), FT3 (free triiodothyronine), and FT4 (free tetraiodothyronine) in 10 healthy individuals and 12 hyperthyroid patients with Graves' disease. All these individuals were studied following 25 mg Zn"}
+{"text": "Intestinal parasitic infections are among the most common infections worldwide. Various epidemiological studies indicate that the prevalence of intestinal parasites is high especially in developing countries, although in many of these, the environmental risk factors have not been clearly elucidated. The objective of this study was to determine the risk of pathogenic intestinal parasites infections in Kisii Municipality.Random sampling was used in the selection of the study samples. Stool parasitological profiles of food handlers were done by direct smear and formalin-ethyl acetate sedimentation method. Both vegetable and meat samples were examined for the presence of intestinal parasites. The storage and meat handling practices of the various butcheries were observed.Ascaris lumbricoides and Entamoeba histolytica. Parasites were significantly less likely to be present on meat that was refrigerated during display than meat that was displayed at ambient temperature.Types of samples examined for occurrence of intestinal parasites includes, a total of 84 vegetable, 440 meat and 168 stool samples. Fifty five (65.5%) vegetable, 334 (75.9%) meat and 69 (41.1%) of the stool samples were found positive for intestinal parasites indicating a high overall risk (66.18%) for intestinal parasite infections. Of the parasites detected, the most common parasites infesting the foodstuffs and infecting the food handlers were There is a high risk of infection with intestinal parasites in the sampled Municipal markets. About half of the food handlers surveyed (41.1 %) at the Municipal Hospital had one or more parasitic infections. Furthermore, meat (65.5%) and vegetables (75.9%) sold at the Municipal market were found to be contaminated with parasites hence the inhabitants requires a need for education on food safety, good distribution practices and improvement on sanitary conditions. Ascaris lumbricoides (1.2 billion), Trichuris trichiura (795 million), hookworms  (740 million) [Entamoeba histolytica (50 million) [Giardia lamblia (2.8 million) [Intestinal parasites cause significant morbidity and mortality throughout the world, particularly in developing countries and in persons with comorbidities. The risk of intestinal parasites infections is measured using the DALY (disability- adjusted life year) and one DALY represents the loss of one year of equivalent full health . The resmillion) , Entamoeicanus) 70 millionchiura 79 million,million) . The fecamblia 2. million million)  or ingesmillion) . Intestimillion)  and monemillion) . Additiomillion)  and contmillion) .Ascaris lumbricoides (82%), Trichuris trichiura (60%), Entamoeba histolytica (41%) and Giardia lamblia (30%) [A. lumbricoides (10%), hookworm (4%) and T. trichiura (0.1%) [Epidemiological surveys done in Kenya's poor periurban and urban school children revealed a high prevalence of intestinal parasitic infections with ia (30%) . Recent a (0.1%) . The Kis2 [The study was carried out between December 2004 and June 2005 in Kisii Municipality, which is located at the southern end of the western Kenya highlands at an altitude of 1660 m above sea level. The area receives average rainfall of over 1500 mm per annum distributed almost throughout the year although there are two rainy seasons (March to May and October to November). Temperatures range from 10\u00b0C to 30\u00b0C with relative humidity of 88%. The area is densely populated with a population of 37,531 people and a density of 1295 people/km2 . MajoritBrassica oleracea var. acephala), cabbage (Brassica oleracea capitata), spider flower (Gynandropsis gynandra) and black nightshade (Solanum nigrum)) were collected each day from the vendors by random sampling. The leaves of the four vegetable varieties were chosen because they are the major ones eaten by residents of Kisii Municipality. Twenty two butcheries were randomly selected using lottery method from using a list of the total of 125 butcheries in the Municipality. The asymptomatic adult male and female food handlers from the sampled markets and butcheries were randomly selected by lottery method from a list of attendance at Kisii District Hospital for routine examination of stool parasitological profile according to the Kenyan Ministry of Health Regulations  [A correrational descriptive study design was used to determine the association between various risk factors and the occurrence of intestinal parasites. Two open air markets were randomly selected by lottery method from the list of the five markets of Kisii Municipality. The sample size for foodstuffs and food handlers was calculated on a prevalence of 10%, d = 0.05 at a confidence level of 95%. Each of the four varieties of vegetables commonly sold in the study area was selected by random sampling from the vendors in the open air markets. Samples of vegetables leaves weighing 250 g for each variety  . The meaA 250 g sample of each vegetable or meat sample was examined for intestinal parasite profile (described by ). The saA computer program (SPSS 11.5 for Windows) was used for data analysis. Multiple logistic regression analysis was used. The differences were considered to be statistically significant when the p-value obtained was less than 0.05A total of eighty four vegetable samples comprising of 21 samples for each species were collected, kales cabbage, spider flower and black night shade. In all, 55 (65.5%) vegetable samples were infested with intestinal helminthes. Eleven (52.4%) of kales, 12 (57.1%) cabbages, 17 (81.0%) spider flower and 15 (71.4%) of black night shade tested positive. An average parasite score density of 2.37 was observed in the vegetables (Table The risk factors (independent variables) influencing infection with intestinal parasites (dependent variable) were investigated in 22 butcheries (Table Fifteen (68.2%) butcheries had the same person handling the meat and the cash (no cashier) while seven (31.8%) had a food handler and a cashier. There was a significantly high prevalence of intestinal parasites in meat samples where there was no cashier 154 (59.2%) than where the cashier was present 74 (40.9%) (p = 0.000).The prevalence of intestinal parasites in meat samples collected from (47.1%) whereas those present from butcheries where personnel were not wearing protective clothing were 233 (52.9%).The numbers of butcheries where there were houseflies on the meat samples collected were 13 (59.1%) while those that did not have houseflies were 9 (40.9%). The average parasite score density in the meat samples was ranging from 1.40 to 1.87.Entamoeba histolytica and Ascaris lumbricoides, and 2 (1.2%) had E. histolytica and Giardia lamblia (Table A. lumbricoides 22 (13.1%) and E. histolytica 20 (11.9%). The others were hookworms 13 (7.7%), G. lamblia 6 (3.6%), Trichuris trichiura 2 (1.2%) and Balantidium coli 1(0.6%), in their decreasing order of prevalence. There was a statistically significant difference between the numbers of the various intestinal parasite species among the food handlers (p < 0.010). The parasite score density in the faecal specimens observed ranged between 1.50 for Trichuris trichiura whilst highest parasite score density was found among multiple infections with Entamoeba histolytica and Ascaris lumbricoides with 2.63.Stool specimens were collected from the food handlers attending the Kisii District Hospital. Out of 168 food handlers, 69 (41.1%) were infected with one or more intestinal parasites of whom 27 (16.1%) were infected with one species of protozoan, 37 (22.0%) were infected with one species of helminth, 5(3.0%) had mixed infections, with 3 (1.8%) having The study showed high intestinal parasitic infestation of both meat and vegetable foodstuffs as 65.5 % and 75.9 %, respectively. Additionally, the burden of infection with intestinal parasites among the food handlers was almost half (41%). The presence of moderate parasite score densities in the foodstuffs and food handlers indicate high transmission risks of such parasites to inhabitants of Kisii Municipality. These findings indicate a public health priority and strongly support the need for education on food safety, Good Manufacturing Practice (GMP), Hazard Analysis Critical Control Pint (HACCP), improvement of sanitation conditions in and around the market by waste collection, management and handling of foodstuffs so as to reduce the prevalence of infections in both food handlers and food stuffs sold at the market.Entamoeba histolytica, Giardia lamblia and Balantidium coli and helminthes: Ascaris lumbricoides, Trichuris trichiura and hookworms. The risk of infection with intestinal parasites to the population is increased because these contaminated vegetables are sometimes eaten raw, undercooked to retain the natural taste and preserve heat-labile nutrients, or unclean [Examination of vegetable samples revealed that all were equally highly contaminated with infestation rates of 52.4%, 57.1%, 81.0% and 71.4% respectively for kales, cabbage, spider flower, and black nightshade. This may be attributed to handling techniques of the vegetables . The int unclean . Additio unclean .The type of meat storage practice influenced the prevalence of intestinal parasites, with the refrigerator having least number (7%) while both meat placed in wire mesh and on open surface had higher number of intestinal parasites, 31.4% and 37.5% respectively. This indicates that proper storage methods like refrigeration should be used to minimize risk of contamination as only 18.1% of the butcheries sampled used refrigeration. Poor storage methods expose meat to mechanical vectors like houseflies, cockroaches and rats that transfer eggs, cysts of intestinal parasites to improperly stored meat . AdditioA. lumbricoides (13.1%) and E. histolytica (11.9%), as was observed in Kisii District [A. lumbricoides prevalence of 82% [The most common intestinal parasites affecting the food handlers were District  althoughe of 82% . The pree of 82% . Foods se of 82% .About half of the people surveyed (41.1 %) at the Municipal Hospital had one or more parasitic infections. Furthermore, meat (65.5%) and vegetables (75.9%) sold at the Municipal market were found to be contaminated with parasites. The handlers of meat should employ proper storage methods like refrigeration, employ different personnel to handle money and serve meat to consumers. Additionally, they should use insecticides to kill the houseflies. Media programmes should be launched to enlighten the public on the necessity of good sanitation hygiene and risks of acquiring intestinal parasites.The authors declare that they have no competing interests.RMN designed, performed sampling, parasitological examination and manuscript development. PAA Contributed in planning the research, discussing the results and revising the manuscript. EWK participated in the study design, coordinated the study and revised the manuscript. BON conducted statistical analysis, discussing the results and developing the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:"}
+{"text": "Using a panel of ten polymorphic markers, we examined the frequency of loss of heterozygosity (LOH) on chromosome 17 in 55 sporadic ovarian tumours. LOH on 17p and 17q was observed to be 50% and 62% respectively. LOH at D17S5 was detected in 24/36 (67%) of malignant cases and in 19/43 (44%) at TP53; the marker D17S855 intragenic to the BRCA1 gene showed allele loss in 50% (20/40) cases. The data presented here suggest that loss of the whole chromosome 17 is a relatively frequent event (30%) in ovarian carcinomas and this observation is especially frequent for serous, transitional cell and anaplastic histological subtypes. Mucinous and endometrioid ovarian tumours showed only short interstitial deletions . The overall frequency of the short deletions was relatively low  in our panel of carcinomas. Amplification of c-erbB-2/neu oncogene was detected in 32% (11/34) of the carcinomas tested; the gene was amplified only in those histological subtypes in which high incidence of LOH on chromosome 17 was observed, and was associated with advanced stages of the disease. We conclude that different histological types of tumour may have different aetiological mechanisms, and tumour-suppressor genes on chromosome 17 might be associated specifically with serous and transitional cell ovarian carcinomas."}
+{"text": "Treatment courses were repeated every 4 weeks \u00d7 6 unless prior evidence of progressive disease. Radiation therapy using megavolt irradiation of \u2265 6 MV photons with a 3- or 4-field technique was delivered during the second and third chemotherapy course, that was reduced in dose by 25%. Between October 1994 and July 1996, a total of 38 patients were entered onto this trial, all of whom were assessable for toxicity and survival. Eighteen of these (47%) had objective remissions to combined radiochemotherapy, including four CR (11%), 13 (34%) had stable disease and seven patients (18%) showed tumour progression during treatment. The median progression-free interval of the entire study population was 10 months (range 3\u201332), and median overall survival was 14.0 months (range 3\u201345+ months); 53% of all patients were alive at 12 months, and 18% of patients were alive at 24 months respectively. Severe haematological side-effects comprised neutropenia in 18%, thrombocytopenia in 8% and anaemia in 11%. The most frequent non-haematological side-effects were nausea/vomiting (WHO grade 3: 18%), and diarrhoea (grade 3: 13%). This combined radiochemotherapy regimen was tolerable and effective in patients with locally advanced pancreatic cancer. Since therapeutic results, in fact, compare favourably with other series, including surgical treatment of potentially resectable tumours, further evaluation of combined treatment modalities in the neoadjuvant setting seems warranted. \u00a9 2000 Cancer Research CampaignThe aim of the study was to evaluate the effectiveness and safety of a combined treatment modality including systemic chemotherapy with 5-fluorouracil (FU), leucovorin, cisplatin and external beam radiotherapy in patients with locally advanced pancreatic cancer. Systemic chemotherapy consisted of FU 400 mg m"}
+{"text": "Objective: We prospectively evaluated the rate of adverse reproductive outcomes following pelvic inflammatory disease (PID) in a small cohort of American women.Methods: We enrolled 28 patients having either salpingitis confirmed by laparoscopy or endometritis confirmed by endometrial biopsy. The follow-up was maintained by clinic visits and telephone contact.Results: A median of 15.4 months of follow-up was accomplished for 82.1% of these women. Fifty-two percent (13/25) had unprotected sexual activity without conception for at least 6 months. Fully 55.6% (10/18) of the cohort were involuntarily infertile after at least 1 year of follow-up.Conclusion: In the first prospective cohort study of the reproductive outcomes of American women having had PID, high rates of infertility at 1 year of follow-up were experienced by these women."}
+{"text": "Cardiac function was evaluated in 86 breast cancer patients after standard chemotherapy, followed by ablative chemotherapy and chest irradiation. One patient died of subacute heart failure 3 months after ablative chemotherapy. At a minimum of 1 year's follow-up (range 1-11 years) left vertricular ejection fraction (LVEF) was marginally abnormal in 4 of 27 disease-free survivors. One exceptional patient who received two transplantations is alive, with serious heart failure occurring after the second ablative chemotherapy. Including this patient, the percentage of patients free of clinical and subclinical cardiac dysfunction at 7 years is 78% (95% CI 61-95%). After ablative chemotherapy, cardiotoxicity was rarely life-threatening. The impact of subclinical cardiotoxicity in the long term is not clear and needs continued evaluation."}
+{"text": "KIT aberrations in mucosal melanomas, whereas c-KIT in most types of cutaneous melanomas does not appear to be of pathogenetic importance. However, studies investigating the status of the KIT gene in larger, well-characterised groups of patients with mucosal melanomas are lacking. We analysed 44 archival specimens of 39 well-characterised patients with mucosal melanomas of different locations. c-KIT protein expression was determined by immunhistochemistry, KIT gene mutations were analysed by PCR amplification and DNA sequencing of exons 9, 11, 13, 17 and 18. c-KIT protein expression could be shown in 40 out of 44 (91%) tumours in at least 10% of tumour cells. DNA sequence analysis of the KIT was successfully performed in 37 patients. In 6 out of 37 patients (16%) KIT mutations were found, five in exon 11 and one in exon 18. The presence of mutations in exon 11 correlated with a significant stronger immunohistochemical expression of c-KIT protein (P=0.015). Among the six patients with mutations, in two patients the primary tumour was located in the head/neck region, in three patients in the genitourinary tract and in one patient in the anal/rectal area. In conclusion, KIT mutations can be found in a subset of patients with mucosal melanomas irrespective of the location of the primary tumour. Our data encourage therapeutic attempts with tyrosine kinase inhibitors blocking c-KIT in these patients.Recent data suggested an increased frequency of  Primary mucosal melanomas represent a rare subtype of melanomas that arise from melanocytic cells residing in mucous membranes in various anatomical regions. They account for approximately 1.2% of melanomas  from 1996 to 2007 were retrospectively analysed. A total of 44 archival formalin-fixed and paraffin-embedded tissue samples  were accessible for analysis in this study.Highly sensitive immunohistochemistry for c-KIT with a murine monoclonal antibody  was performed as described earlier , if necessary by micrographic dissection using the PALM Laser-MicroBeam System . DNA extraction was performed with the DNA extraction kit from Qiagen  following the instructions of the manufacturer. Exons 9, 11, 13, 17, 18 of BRAF V600E mutation a LightCycler fluorescence resonance energy transfer (FRET) assay with two fluorescent hybridisation probes was performed as described earlier .All PCR products that showed deviation from the Wt (wild-type) genomic DNA melting peak as well as from the positive control samples were confirmed by direct sequencing of exon 15 of the t-tests were performed.The software SPSS 13.0 was used for statistical analyses. Kaplan\u2013Meier tests and unpaired P=0.44) and overall survival (P=0.82) by Kaplan\u2013Meier analysis during a follow-up of 31.1 months (mean) and 21.1 months . During that follow-up period, 20 patients suffered from melanoma recurrence and 14 patients died due to melanoma metastases.c-KIT expression was determined in 44 tissue samples, 35 primary mucosal melanomas, 4 lymph node metastases, 2 skin metastases and 3 local recurrences . In all,KIT gene were observed in 6 out of 37 (16%) patients, five in exon 11 and one in exon 18  tumours showed strong (++++) and one showed (20%) high (+++) c-KIT protein expression (P=0.015).Alterations in the  exon 18 . Two patpression . In contBRAF V600E mutation could be detected (In 3 out of 27 (11%) mucosal melanomas  the detected .KIT mutations, 61% c-KIT overexpression), acral cutaneous melanomas  and cutaneous melanomas on skin with chronic sun damage  . We could show KIT mutations in 2 out of 12 mucosal melanomas from head/neck, 3 out of 11 from the genitourinary tract and 1 out of 8 from the anal/rectal tract. This is consistent with the findings of Antonescu et al and Rivera et al who detected mutations of the KIT gene in 3 out of 20 (15%) and 4 out of 18 (22%) patients with mucosal melanomas of the anal region and oral cavity, respectively   patients in our series, similarly to other studies with patients suffering from mucosal melanomas who reported 1 out of 17 (BRAF V600E mutations (BRAF mutation suffered from melanoma located in an UV-exposed area of the conjunctiva. In line with this, BRAF mutations in 5 out of 22 patients with conjunctival melanomas.KIT mutations presumably activating the tyrosine kinase activity of c-KIT can be found in a subgroup of patients with mucosal melanomas irrespective of the origin of the primary tumour. This encourages clinical studies with c-KIT blockers in patients with mucosal melanomas and appropriate KIT mutations. Immunohistochemistry for c-KIT expression might be a useful tool to screen for patients who are subjected to mutational analysis but cannot replace genetic analysis.In conclusion, our study supports the finding that"}
+{"text": "Thirty-two patients were enrolled. Major toxicity during induction chemotherapy was haematological: grade III\u2013IV leukopenia was observed in 31% and grade II anaemia in 16% of the patients. The most common severe toxicity during concurrent chemoradiation consisted of grade III leukopenia (21% of the patients); grade III oesophagitis occurred in only two patients and pulmonary toxicity in one patient who died of this complication. Eighteen of 32 patients  had a major response . With a median follow-up of 38.4 months, the median survival was 12.5 months and the actuarial survival rates at 1, 2 and 3 years were 52%, 26% and 19% respectively. The median event-free survival was 8.3 months with a probability of 40%, 23% and 20% at 1, 2 and 3 years respectively. Induction chemotherapy followed by concurrent daily low-dose cisplatin and thoracic irradiation, in patients with locally advanced NSCLC, is active and feasible with minimal non-haematological toxicity. Long-term survival results are promising and appear to be similar to those of more toxic chemoradiation regimens, warranting further testing of this novel chemoradiation strategy. \u00a9 1999 Cancer Research CampaignBoth induction chemotherapy and concurrent low-dose cisplatin have been shown to improve results of thoracic irradiation in the treatment of locally advanced non-small-cell lung cancer (NSCLC). This phase II study was designed to investigate activity and feasibility of a novel chemoradiation regimen consisting of induction chemotherapy followed by standard radiotherapy and concurrent daily low-dose cisplatin. Previously untreated patients with histologically/cytologically proven unresectable stage IIIA/B NSCLC were eligible. Induction chemotherapy consisted of vinblastine 5 mg m"}
+{"text": "Inactivation of the retinoblastoma (RB) gene is known to be implicated in the pathogenesis of several types of human cancers. Since structural alterations of the RB gene have not been well examined in human bladder cancer, we looked for mutations in the entire coding region of this gene using polymerase chain reaction (PCR) and single-strand conformational polymorphism analysis of RNA. We also examined allelic loss of the RB gene using PCR-based restriction fragment length polymorphism analysis. Of 30 samples obtained from patients with bladder cancer, eight (27%) were found to have RB gene mutations. DNA sequencing of the PCR products revealed five cases with single point mutations and three cases with small deletions. These mutations included one (10%) of ten low-grade (grade 1) tumours, four (50%) of eight intermediate-grade (grade 2) tumours and three (25%) of 12 high-grade (grade 3) tumours. Likewise, mutations were found in four (21%) of 19 superficial (pTa and pT1) tumours and four (36%) of 11 invasive (pT2 or greater) tumours. In 15 informative cases, loss of heterozygosity at the RB locus was shown in five cases (33%), three cases with RB mutations and two without them. These results suggest that RB gene mutations are involved in low-grade and superficial bladder cancers as well as in high-grade and invasive cancers."}
+{"text": "An epithelial cell surface antigen is described which is defined by monoclonal antibody HEA125 (IgG1). The antibody was raised against the colon carcinoma cell line HT-29. Under reducing conditions HEA125 immunoprecipitates a surface glycoprotein of Mr 34,000 which was designated Egp34. The antigen does not contain disulfide-linked subunits. A slightly different migration behavior under non-reducing conditions  may be due to intrachain disulfide bonds. After enzymatic cleavage of N-linked carbohydrate residues the apparent molecular weight of the antigen was 29,000. Egp34 is a major cell surface component of HT-29 cells (10(6) molecules per cell). No antigen could be detected in the sera of colorectal cancer patients. A panel of malignant cell lines and normal cells was studied for surface expression of the antigen. 17/17 carcinoma lines of 6 different origins expressed the antigen, whereas 16/16 melanoma, neuroblastoma, sarcoma and lymphoma/leukaemia were unreactive as it was the case for normal fibroblasts and blood cells. Immunoperoxidase staining of frozen tissue sections with HEA125 demonstrated the presence of Egp34 in almost all normal epithelia and tumours derived therefrom. No reactivity with non-epithelial tissues was observed. Undifferentiated carcinomas of various origins homogeneously expressed Egp34. Therefore, HEA125 may become a valuable tool for the immunohistochemical diagnosis of carcinoma."}
+{"text": "To investigate the long-term survival rate of node-positive (pN+) breast cancer treated by locoregional therapy alone, we made an attempt to identify all such patients followed up for at least 15 years after treatment in a defined geographical area  and time period (1945-79) using the files of the local hospitals and the Finnish Cancer Registry. The clinical and autopsy records and histological slides of 1172 women diagnosed with breast cancer in the city were reviewed. From this cohort we identified 339 women with unilateral node-positive breast cancer treated with locoregional therapy without systemic adjuvant therapy. The relative survival rate of the cohort compared with the general female population matched for age and year of follow-up was calculated. The 15- and 30-year survival rates corrected for known intercurrent deaths were 26%  and 21% (16-26%) respectively, and the relative survival rates 23% and 21% respectively. None of the patients with pN2 disease survived for 15 years, whereas the 30-year corrected survival rate in pN1 disease was 24% (18-30%). Women with pT1N1M0 cancer had as high as 59% (43-75%) 15-year survival rate corrected for intercurrent deaths. A trend for improving survival was found by the decade of diagnosis. The results indicate that a considerable proportion of women with pN1 breast carcinoma treated with locoregional therapy alone become 30-year survivors and are probably cured. Adequate locoregional treatment is mandatory in the care of node-positive breast cancer."}
+{"text": "N=372) from a series of 4035 consecutive needle biopsies. We describe the imaging findings, and report excision histology outcomes (N=279) and category-specific PPV for B3 lesions using two approaches including estimates based on subjects who had either excision or follow-up (N=328). B3 represented 9.2% of all CNB results. Excision histology was benign in 181 (64.9%) and malignant in 98 (35.1%) subjects . Positive predictive value for malignancy (based on excision histology) was 35.1% (95% CI: 29.5\u201340.7) and PPV (based on excision or review) was 29.9% (95% CI: 24.9\u201334.8). Lesion-specific PPV (estimates in parentheses for excision or follow-up) was atypical ductal hyperplasia 44.7% (40.6%); lobular intraepithelial neoplasia 60.9% (58.3%); papillary lesion 22.7% (15.9%); radial scar 16.7% (12.3%); phyllodes tumour 12.5% (12.5%); and B3 not specified 20.0%. Approximately one-third of CNB results classified as B3 are malignant on excision, and the likelihood of malignancy varies substantially between specific lesion groups. Whereas cases may be selectively managed without surgery, the majority warrant excision biopsy based on our estimates. Research is needed to improve differentiation between malignant and benign diseases in B3 lesions using diagnostic or predictive methods.Breast core needle biopsy (CNB) is an accurate test but may result in borderline histology . This is an evaluation of the largest series (to date) of B3 histology, which focusses on estimating positive predictive values (PPV) for malignancy. We identified all B3 CNBs over a 10-year period in a single institution ( Percutaneous core needle biopsy (CNB) is an accurate test for sampling breast lesions  core needle histology occurs in a similar (in situ and invasive), and discuss implications for practice and future research.We present a retrospective evaluation of the largest series, to date, of borderline (B3) core needle histology, and report on excision histology outcomes. We provide B3  subcategory-specific positive predictive values (PPV) for malignancy (N=372). We have included all eligible cases in our descriptive evaluation, and for histological outcomes we report on subjects who had excision histology (N=279). To avoid verification bias in estimating category-specific PPV (N=328). Imaging lesions were considered stable on follow-up if unchanged on imaging  review at 6\u201312 months (for masses) or a minimum of 12 months  , we identified eligible subjects as all those with B3 core histology reports  or invasive cancer) (in situ (LCIS)), papillary lesions, radial scar/complex sclerosing lesion, mucocoele-like lesion and phyllodes tumour.One of two breast pathologists reported all core needle histology (without knowledge of outcomes), with one pathologist (SB) interpreting the vast majority (>90%). Results were reported in line with UK and European guidelines  . We haveB3 core needle histology comprised 9.2% 372 from 4035 of all CNB results. To assist in judging generalisability of our series, we have presented in We have reported B3  category-specific PPV for malignancy (DCIS and invasive); B3 core needle histology comprised about 9% of all consecutive CNB performed in the study centre. We are not aware of any published work that estimates PPV for subcategories of B3 lesions in one comprehensive series. Overall, about one-third of borderline lesions on CNB in this study proved to be malignant (PPV 29.9 or 35.1%); however, the PPV for each subcategory within B3 varied substantially . In an oWe have explained the reasons we report two estimates of PPV \u2013 methodologies that include all subjects with known outcomes (and not only those verified on the basis of excision) have been shown to reduce verification bias in calculating measures of accuracy , whereasThe most frequent lesion in our B3 series is ADH, and its frequency within the B3 category is similar to that reported by Our PPV estimates show the highest lesion-specific risk of malignancy in association with LIN (ALH and LCIS) with a higher likelihood of malignancy for this category than reported in other series . The eviUnlike our PPV for papillary lesions (22.7 or 15.9%), one study of screen-detected papillary lesions reported benign excision histology outcomes in all 15 CNB diagnoses of \u2018papillary lesion\u2019 classified as B3  as far as risk of malignancy. Research is needed to help modify our current approach of surgical management for almost all borderline core needle histology, thus minimising unnecessary surgery in the majority of women with B3 on CNB and have benign disease. One example is optimising criteria for reporting lesions as B3 on CNB \u2013 pathologists might work on characterisation of morphological features that potentially allow accurate shifting of some B3 lesions into either the benign or the malignant category. Another area in need of formal evaluation is the selective use of large (vacuum-assisted) core biopsy devices in lesions deemed to be low risk (low PPV) on CNB to either re-sample or remove the imaging lesion, as an alternate to surgical excision. This should only be performed in the context of radiology\u2013pathology correlation and team discussion to ensure appropriate selection of low risk lesions for this form of management.The most relevant research, however, is likely to be in potentially identifying factors or methods that accurately predict outcomes on excision histology for the spectrum of B3 lesions. This may be achieved through two approaches, the first being the evaluation of molecular or genetic markers as indicators of malignancy. Although genetic profiling has indicated that current histological classification of breast cancer does not predict either lymph node metastases or response to therapy, it remains possible that the combination of genetic profile and core needle histology could provide a new diagnostic modality with the greatest discriminatory ability for outcomes. The second approach is the development of predictive systems based on clinical\u2013radiological\u2013CNB correlates with excision histology. We are currently exploring the latter of these approaches."}
+{"text": "In this study we examined the case histories of 163 living and 82 deceased adult Finnish patients with acute hepatic porphyria. There were 184 patients with acute intermittent porphyria and 61 patients with variegate porphyria. Among the 124 of the 163 living patients, who were traced 1984-1985, no hepatocellular carcinoma was found. Among the 82 deceased patients the cause of death was porphyria in 29 (36%), cardiovascular disease in 23 (29%) and hepatocellular carcinoma in 7 (9%). Of the 7 patients with hepatocellular carcinoma, 6 had acute intermittent porphyria and one had variegate porphyria. In acute hepatic porphyria, as compared with the total population, the calculated risk of hepatocellular carcinoma is increased 61-fold."}
+{"text": "Primary carcinomas from 46 patients were screened for TP53 alterations. Immunohistochemistry demonstrated nuclear TP53 protein accumulation in 22 (48%) cases using the polyclonal CM1 antiserum, whereas 15 (33%) cases showed positive nuclear staining with the mononuclear antibody PAb 1801. Constant denaturant gel electrophoresis (CDGE) was used to screen 27 of the vaginal carcinomas for mutations in the conserved regions of the TP53 gene (exons 5-8). Six of these tumours (22%) contained mutations: four were found in exon 5 and two in exon 8. A total of 50% of the primary vaginal carcinomas carried a TP53 alteration. These results indicate that TP53 abnormalities may be involved in the development of these tumours. However, there was no significant association between TP53 abnormalities and survival."}
+{"text": "To evaluate the significance of chromosomal aberrations in renal cell carcinoma, fluorescence in situ hybridization (FISH) was used to determine its prevalence and correlation with clinical parameters of malignancy. In addition, correlation of chromosomal aberration with Ki 67 expression was analysed. We performed FISH with chromosome-specific DNA probes, and the signal number of pericentromeric sequences on chromosomes 3, 7, 9 and 17 was detected within interphase nuclei in touch preparations from tumour specimen. The incidence of loss of chromosome 3 was significantly higher than those of chromosomes 7, 9 and 17 . Hyperdiploid aberration of chromosomes 3 and 17 was significantly correlated with tumour stage , whereas hyperdiploid aberration of chromosome 9 was associated with nuclear grade (P = 0.04). Disomy of chromosome 7 was correlated with venous involvement (P = 0.04). Ki 67 expression was significantly associated with hyperdiploid aberration of chromosome 17 (P = 0.01), but not with aberration of chromosome 3. There was a significant relationship between hyperdiploid aberration of chromosome 7 and Ki 67 expression (P = 0.01). In conclusions, gain of chromosome 17 may reflect tumour development, and aberration of chromosome 7 may affect metastatic potential of malignancy, whereas loss of chromosome 3 may be associated with early stage of tumour development in renal cell carcinoma."}
+{"text": "Infectious complications were responsible for thedeaths by leading to multiple organ failure with pulmonary or renal insufficiency or gastro-intestinalbleeding. The timing of surgery was the only factor that had prognostic significance, i.e. the longer thehospital delay before surgery the higher the mortality, although elderly patients or patients with perforationtended to have a worse prognosis. In conclusion, the results of this study indicated that early surgery isimportant in patients with acute cholecystitis as a means of lowering mortality in bile peritonitis in thiscondition.A review of all patients treated for acute cholecystitis (n=5848) during an 18-year period (1969\u20131986) at twohospitals (one practising early surgery in patients with acute cholecystitis and the other not) disclosed that104 (1.8%) had bile within the abdominal cavity at surgery; 71 with a visible perforation of the gallbladderand 33 without. The bile was infected in 82% of performed cultures (most commonly with Escherichia coli).Mortality was 7.7% (8/104 patients), being 20% (4/20)in the hospital practising delayed surgery and 5% (4/84) in the hospital practising early surgery ("}
+{"text": "Also, normal cervical smears of 114 age-matched control women were analysed. High-risk HPV DNA was detected in 37 of the 57 (65%) baseline smears of the case women, and 7 (6%) of 114 smears of the control women . The HPV positive subsequent smears and cervical cancer biopsies of the case women contained the same HPV type as was detected in the baseline smear. After cytological revision, the baseline smears of 48 case women (84%) were reclassified as abnormal, 33 (69%) of which scored high-risk HPV DNA positive. Ultimately, an undisputable normal baseline smear was found in only 10 case women. In 7 (70%) of them this smear was HPV positive, whereas only 7 (7%) of 104 revised, undisputable normal smears of control women were high-risk HPV positive . The results showed that (1) high-risk HPV presence precedes abnormal cytology in women who develop cervical cancer, and (2) high-risk HPV testing signals false-negative smears of women at risk of cervical cancer. \u00a9 2001 Cancer Research Campaign"}
+{"text": "The aim of this investigation was to examine the possibility of analysing TP53 mutations in archival paraffin-embedded material with the constant denaturant gel electrophoresis (CDGE) method. We extracted DNA from 193 archival primary breast carcinoma samples, diagnosed in 1981-83; further analysis was possible for 186 of these. TP53 mutations in exons 5-8 were detected with CDGE in 30 samples (16.1%) and 17 of these mutations were confirmed by sequencing. Immunohistochemistry demonstrated TP53 nuclear accumulation in 58 tumours (31%). A strong association between the presence of TP53 mutations and TP53 immunostaining was observed (P < 0.001). Our mutation and immunohistochemistry results are in agreement with other findings based on fresh tumour tissue. TP53 abnormalities were significantly related to high S-phase fraction, low oestrogen receptor (ER) content and high tumour grade. Survival of patients with TP53 abnormalities, in the group as a whole, did not differ from patients with normal TP53. Our study did, however, show that patients with abnormal TP53 had a significantly shorter post-recurrence survival (P = 0.005) than patients with normal TP53."}
+{"text": "Loss of phosphatase and tensin homologue deleted in chromosome 10 (PTEN) function in advanced colorectal cancer (CRC) may represent one of the resistance mechanisms to cetuximab by interfering with the epidermal growth factor receptor signal transduction pathway.n=43) and on metastatic (n=24) sites in CRC patients treated with cetuximab.PTEN expression tested by indirect immunofluorescence was evaluated both on primary , PFS  and OS .The loss of PTEN expression tested on metastatic sites was negatively associated with response (100% progressive disease (PD) in PTEN-negative cases A potential role of PTEN in the anti-tumour activity of cetuximab could be hypothesised. Among patients with advanced colorectal cancer (CRC), a small subgroup seems to benefit from the epidermal growth factor receptor (EGFR) inhibitor, cetuximab . EpidermPTEN) is an important tumour-suppressor gene that negatively regulates Akt activities (Phosphatase and tensin homologue deleted in chromosome 10 (tivities  and may tivities .PTEN and EGFR gene copy number assessments by fluorescence in situ hybridisation (FISH). Phosphatase and tensin homologue deleted in chromosome 10 and pAKT IFI assessments were performed on 4-\u03bcm-thick tissue sections of paraffin-embedded specimens by using a PTEN rabbit monoclonal antibody  and a pAKT (Ser 473) rabbit monoclonal antibody , respectively, followed by FITC-conjugated specific secondary antibody . Indirect immunofluorescence-positive tumour cells were recognised by bisbenzimide (Hoechst 33258) (Sigma-Aldrich Corp.) and images were obtained by fluorescent microscopy . Fluorescence intensity was scored as absent, weak, moderate and strong. For both PTEN and pAKT, the percentage of cells expressing antigens was determined by evaluating the number of positive cells in a field with reference to the total number of cells in that field. Samples with an absent or weak expression in <10% of cells were considered as negative.Our experience refers to 50 mCRC patients submitted both to the evaluation of PTEN and pAKT expression by indirect immunofluorescence (IFI) and to \u03bcm paraffin-embedded sections using a hybridisation solution containing both a rhodamine-conjugated probe that is specific for the PTEN locus on chromosome 10q23.21 and a FITC-conjugated control probe specific for 10p11.1\u2013q11.1 . Nuclei were counterstained with DAPI for viewing on an Olympus MX60 fluorescence microscope with a 100-W mercury lamp. Separate narrow band pass filters were used for the detection of Spectrum Orange, Spectrum Green and DAPI. Hemizygous deletion of PTEN was defined as >20% of tumour nuclei containing one PTEN locus signal and by the presence of CEP10 signals. Homozygous deletion of PTEN was exhibited by the simultaneous lack of both PTEN locus signals and by the presence of control signals in >30% of cells (Phosphatase and tensin homologue deleted in chromosome 10 copy number status assessment was performed on 4-EGFR Spectrum Orange/CEP 7 Spectrum Green probe set (Vysis), and counterstaining and viewing were performed as described above for the PTEN gene. An increased EGFR gene copy number was defined as the presence of three or more signals per nucleus  received \u2a7e3 lines of chemotherapy. A total of 36 patients were treated with cetuximab and irinotecan and 14 with cetuximab and oxaliplatin. Patients who obtained a partial response (PR) or a stable disease (SD) were defined as responders. In all, 12 patients (24%) experienced PR, 14 (28%) experienced SD and 24 (48%) experienced a progressive disease (PD). At a median follow-up of 23 months, 49 patients (98%) progressed and 40 (80%) died. In the whole group, median PFS and OS were 4.0 and 9.3 months, respectively.vs 30% PD in PTEN-positive cases; P<0.05)  and OS . Of the paired primary tumours and matched metastases, 25% (5 out of 20) were discordant for PTEN expression. Hemozygous deletion of PTEN was present in 33% (15 out of 45) of primary tumours and all of these had an absent or weak protein expression (P<0.005). The PTEN FISH assessed on primary tumour was neither predictive nor prognostic. No correlation was found between PTEN FISH and PTEN expression on metastatic sites probably because of the low number of cases (n=17). pAKT was not predictive of response, PFS and OS, neither was EGFR.Phosphatase and tensin homologue deleted in chromosome 10-positive staining was mainly localised to the cytoplasm of CRC cells. An example of a PTEN-positive CRC is shown in  P<0.05) , PFS  of cases showed a PTEN primary tumour Epidermal growth factor receptor protein expression is no longer considered as selection criteria for cetuximab sensitivity ("}
+{"text": "India is one of the seven identified countries in the South-East Asia region regularly reporting dengue fever (DF)/dengue hemorrhagic fever (DHF) outbreaks and may soon transform into a major niche for dengue infection in the future with more and more new areas being struck by dengue epidemicsTo study the clinical manifestations, trend and outcome of all confirmed dengue cases admitted in a tertiary care hospital.Record-based study conducted in a coastal district of Karnataka. Required data from all the laboratory confirmed cases from 2002 to 2008 were collected from Medical Records Department (MRD) and analyzed using SPSS 13.5 version.Study included 466 patients. Majority were males, 301(64.6%) and in the and in the age group of 15-44 years, 267 (57.5%). Maximum number of cases were seen in 2007, 219 (47%) and in the month of September, 89 (19.1%). The most common presentation was fever 462 (99.1%), followed by myalgia 301 (64.6%), vomiting 222 (47.6%), headache 222 (47.6%) and abdominal pain 175 (37.6%). The most common hemorrhagic manifestation was petechiae 84 (67.2%). 391 (83.9%) cases presented with dengue fever, 41 (8.8%) dengue hemorrhagic fever, and 34 (7.3%) with dengue shock syndrome. Out of 66 (14.1%) patients who developed clinical complications, 22 (33.3%) had ARDS and 20 (30.3%) had pleural effusion. Deaths reported were 11(2.4%).Community awareness, early diagnosis and management and vector control measures need to be strengthened, during peri-monsoon period, in order to curb the increasing number of dengue cases. Dengue made its debut as early as 1780, when Benjamin Rush described the condition as \u201cbreak bone fever\u201d. This hitherto unfamiliar infection has now grown to demand the attention of all public health care providers. A mosquito borne fast emerging viral infection manifesting in four serotypes capable of causing dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS), poses an increasingly perilous situation due to lack of antiviral drugs or vaccine.India is one of the seven identified countries in the South-East Asia region regularly reporting incidence of DF/DHF outbreaks and may soon transform into a major niche for dengue infection in the near future. The first confirmed report of dengue infection in India dates back to 1940s, and since then more and more new states have been reporting the disease which mostly strikes in epidemic proportions often inflicting heavy morbidity and mortality, in both urban and rural environments. Several During all these epidemics, children <15 years of age were quite severely affected, but majority of infection occurred in active adults in the age group of 16\u201360 years.10 CertaiA record-based descriptive study was undertaken to determine the clinical profile and outcome of all patients admitted to a tertiary care teaching hospital at Manipal, Karnataka  with a diagnosis of dengue, DHF and DSS according to WHO protocol, from JanOf the total 466 cases, admitted to the hospital between 2002 and 2008, 391 (83.9%) had dengue fever, 41 (8.8%) had dengue hemorrhagic fever, and 34 (7.3%) had dengue shock syndrome. The year 2007 had the highest number of reported cases, 219 (47%). Most of dengue cases occurred during the month of September, 89 (19.1%) . Table 1Dengue is an important emerging disease of the tropical and sub-tropical regions today. Since the first confirmed case of dengue in India, during the 1940s, intermittent reports of the infection and its sequelae have come from various parts of the country. These include reports from Ludhiana, Delhi,1\u201319 Luckn20Upon analyzing the year-wise distribution of dengue cases in the study population, steady increase in the number of dengue patients over the past few years was noted. Out of the total 466 cases, 219 (47%) were reported in the year 2007 whereas only 7 (1.5%) cases were reported in 2002. While this may be partially attributed to the rapid unplanned urbanization with unchecked construction activities and poor sanitation facilities contributing fertile breeding grounds for mosquitoes; it is also true that an increase in the alertness among medical fraternity following the initial epidemic and the availability of diagnostic tools in the hospital have contributed to the increased detection of cases. Studies To identify the seasonal variation of the disease, analysis of the data on monthly basis were done. A gradual increase in cases was noticed from June with a peak in September, during all the seven years of the study. Pre-monsoon increase in the number of cases was noted in the months of March and April which could be explained by the stagnation of water, after a few bouts of pre-monsoon rainfall which facilitate vector breeding. The correlation between occurrence of dengue and monsoon season is clearly evident in this study and is further supported by similar findings from Kerala, Ludhiana29The male to female ratio in this study was 1.8:1 respectively. Congruent pattern was also seen in the retrospective analysis of the 2006 North Indian Dengue outbreak. The studHepatomegaly 248 (53.2%), altered sensorium 48 (10.3%), diarrhea 65 (13.9%), and skin rash 101 (21.7%) were not as frequent in our study as compared to other studies. An exclusive study on dengue shock syndrome conducted in Mumbai in 2003 reported hepatomegaly (97.4%), altered sensorium (58%), diarrhoea (50%), rash (42%), and cough (38%) in a significant number of cases. Headache was also seen less frequently compared to other studies. Retro-orThe most common bleeding manifestation in our study was petechiae 84 (18%), whereas during the 2006 outbreak of dengue in North India, malena (50%) and hematemesis (38%) were fouOf the 466 cases, 66 cases showed complications. ARDS was seen among 22 (33.3%) patients and pleural effusion among 20 (30.3%) cases. The overall outcome of patient care was good, with 455(97.6%) patients recovering completely. During the study period, 11 (2.4%) deaths were reported. Maximum number of deaths (4) were seen in 2003. Although there were a greater number of cases 219 (47%) in 2007, there were only two casualties probably owing to early diagnosis and prompt treatment.The present study highlights the importance of dengue fever to clinicians in the areas of epidemiology, manifestations, complications and outcome of the disease. The study has the limitations inherent to a hospital record-based study, so meteorological and entomological data, information, education and communication (IEC) strategies and vector control measures initiated by the government are not correlated."}
+{"text": "Renal allograft recipients suffer from a markedly increased susceptibility to premalignant and malignant cutaneous lesions. Although various aetiological factors have been implicated, little is known of the associated genetic events. In this study we initially employed immunocytochemical techniques to investigate the prevalence and localisation of accumulated p53 in over 200 cutaneous biopsies (including 56 squamous cell carcinomas) from renal allograft recipients and immunocompetent controls. In renal allograft recipients accumulated p53 was present in 24% of uninvolved skin samples, 14% of viral warts, 41% of premalignant keratoses, 65% of intraepidermal carcinomas and 56% of squamous cell carcinomas [squamous cell carcinoma and intraepidermal carcinoma differed significantly from uninvolved skin (P < 0.005) and viral warts (P < 0.01)]. A similar trend was revealed in immunocompetent patients  but with lower prevalence of p53 immunoreactivity: 25% of uninvolved skin samples, 0% of viral warts, 25% of keratoses, 53% of intraepidermal carcinomas and 53% of squamous cell carcinomas. These differences were not statistically significant. Morphologically, p53 immunoreactivity strongly associated with areas of epidermal dysplasia and the abundance of staining correlated positively with the severity of dysplasia. These data suggest that p53 plays a role in skin carcinogenesis and is associated with progression towards the invasive state. No correlation was observed between accumulated p53 and the presence of human papillomavirus (HPV) DNA in any of the lesions. Single-strand conformational polymorphism analysis (exons 5-8) was used to determine the frequency of mutated p53 in 28 malignancies with varying degrees of immunopositivity. p53 mutations were found in 5/9 (56%) malignancies with p53 staining in > 50% of cells, reducing to 1/6 (17%) where 10-50% of cells were positively stained and none where < 10% of cells were stained. These data imply that factors other than p53 gene mutation play a part in accumulation of p53 in skin cancers."}
+{"text": "To the Editor: Accumulating evidence suggests that the degree of serologic cross-reactivity to pandemic (H1N1) 2009 virus varies between populations worldwide. To assess potential serologic cross-reactivity in Singapore, we obtained serum samples during May\u2013June 2009 from 50 randomly recruited, healthy volunteers born mostly before 1958  before widespread transmission of pandemic (H1N1) 2009 virus in Singapore. Standard serologic hemagglutination-inhibition (HI) tests ; 31 (62%) were women, 42 (84%) were born in Singapore , and 26 (52%) had not traveled outside Singapore. None of the 50 participants had HI or MN titers /59/2007 . Use of /59/2007 . Thus, o>80 years of age) in western populations (United States and United Kingdom) /1918\u2013like viruses were widespread in Asia, these contrasting results are a stimulus for additional large-scale studies to assess the effect of these viruses in these populations.Although differences in population demographics and laboratory methods used make comparisons between studies difficult, one of the most striking observations from various studies has been the higher levels of cross-reactive antibody titers in prepandemic serum samples from older persons  2009 virus. Chen et al.  2009 virus originated mainly from swine viruses in North America and Europe (In conclusion, partial cross-immunity and cell-mediated immunity may be present but not detected by HI or MN assays. Thus, results of standard serologic assays may not be providing all relevant data ("}
+{"text": "Serum CA 15-3 values were determined in 177 patients with primary breast cancer and in 41 with non-malignant breast disease. Increased preoperative serum CA 15-3 values (greater than 38 U ml-1) were observed in 7%, 17%, 64% and 67% of patients with stage I, II, III and IV disease, respectively and in none of the patients with benign breast disease. Patients with elevated serum CA 15-3 values had poor 3-year cumulative survival (27%). In the postoperative follow-up 9% of patients with no clinical evidence of disease, 33% with a single metastasis and 67% with two or more metastases had elevated values. Increasing or decreasing serum CA 15-3 values correlated with the clinical outcome in 26 out of 27 cases (96%), whereas serum values remaining in the reference range had no predictive value. At the time of recurrence elevated serum CA 15-3 values were also observed in patients with normal preoperative values. Increased serum CA 15-3 values preceded the clinical detection of tumour recurrence by up to 13 months. In conclusion, serum CA 15-3 levels had prognostic value in breast cancer, reflected the extent of clinically detectable disease and the presence of occult metastatic disease. Further research is warranted on the benefits of CA 15-3 assays in relation to adjuvant chemotherapy as well as the earlier detection and treatment of metastatic disease."}
+{"text": "This study was conducted to review the etiological factors and diseases associated with pediatric noncystic fibrosis bronchiectasis in a tertiary care center in Saudi Arabia.A retrospective review of all patients with confirmed noncystic fibrosis (Non-CF) bronchiectasis by chest X-ray and/or CT chest in a pulmonary clinic during the period 1993\u20132005 at a tertiary care center in Riyadh.P< 0.05).A total of 151 cases were diagnosed as Non-CF bronchiectasis. Seventy-five (49.7%) were male, 76 (50.3%) were female; 148 (98%) are alive and 3 (2%) died. The southwestern regions constituted 72 (50%) of the cases. There was a period of (5 \u00b1 3.2) years between the start of symptoms and diagnosis of bronchiectasis. More than two-thirds of the patients had cough, tachypnea, wheezing, sputum production and failure to thrive. Ninety-one (60%) had associated diseases: Pulmonary diseases in 48 (32%), immunodeficiency in 27 (18%), central nervous system anomalies in 10 (7%), cardiac in 10 (7%) and asthma in 103 (68%) of the patients. Left lower lobe was commonly involved in 114 (76%) patients. Sixty-eight (67%) were found to have sinusitis. More than two-thirds of patients had two or more associated diseases. Forty-nine (32%) developed gastroesophageal reflux. Hemophilus influenza was cultured in 56 (37%), strept pneumoniae in 25 (17%) and pseudomonas aeruginosa in 24 (16%) of the patients. Eighty percent of the patients who had pulmonary function test had abnormal changes. Disease progression was related to development of symptoms before 5 years of age, persistent atelectasis and right lower lobe involvement (Non-CF bronchiectasis should be included in the differential diagnosis of recurrent chest infection in Saudi Arabia. Early diagnosis and identification of associated diseases is needed to prevent progression of the disease. Bronchiectasis was called an orphan disease for the last two decades as its incidence decreased markedly and became an uncommon clinical entity among adults and children in developed countries. It is deet al. from United Arab Emirates[Reports of pediatric bronchiectasis from the Arab world are scarce. Dawson  Emirates reported Emirates Studies  Emirates In anoth Emirates Three ou Emirates In one s Emirates 5% of 81In this report, we present the experience of a tertiary care center in Saudi Arabia on childhood bronchiectasis and review the etiological factors and diseases associated with noncystic fibrosis bronchiectasis.A retrospective review of charts was done for all patients referred to the pulmonary clinic for evaluation of recurrent chest infection during the period January 1993 to August 2005 at King Faisal Specialist Hospital and Research Center (KFSH and RC) in Riyadh region, which is considered a tertiary care center for referral of complicated cases in Saudi Arabia. Only patients with confirmed bronchiectasis on chest X-rays and/or computerized tomography (CT) scan of the chest (CT) were included in the study. The objective of this study was to present the demographic radiological patterns, associated diseases and pulmonary function test (PFT) data that are associated with this disease.All patients with confirmed bronchiectasis had the following tests done: Respiratory cultures from sputum or from nasopharyngeal aspirates if unable to produce sputum for culture and sensitivity; PPD skin test; sputum for acid fast bacilli (AFB) stain and AFB culture, or gastric aspirates instead of sputum for children who are unable to produce sputum; barium swallow to rule out vascular ring or tracheoesophageal fistula (TEF); sinus CT for those who presented with persistent rhinorrhea for more than 3 months.For patients who had family history of bronchiectasis, nasal brush by ear, nose and throat specialist (ENT) or biopsy of airway endothelium for electron microscopy to rule out immotile cilia syndrome was done.  Pulmonary function test was done for patients >5 years of age and able to comprehend to test maneuvers. Associated diseases were investigated according to presenting symptoms or type of referrals. 2) was used to compare categorical variables. Results were presented at a level of significance of P \u2264 0.05SPSS program for Windows (release 11.0.0) was used for data analysis. Chi-square  = 65-75% of predicted values.Moderate lung changes are defined as FEV1 = 55-65% of predicted values.Severe lung changes are defined as FEV1 <55% of predicted values.All confirmed cases of bronchiectasis were screened for cystic fibrosis by sweat chloride test, PPD skin test, respiratory cultures for virology, acid-fast bacilli and other pathogenic bacteria. They were followed every 1-3 month(s) according to the severity of their disease. They were taught how to do regular chest physiotherapy to mobilize secretion and how to take Ventolin and inhaled steroid according to their need. Antibiotic treatment orally or intravenously is advised during exacerbation of their symptoms .Patients who showed clinical deterioration in the form of recurrent fever or increase in sputum or cough or radiological deterioration in the form of involvement of another lobe with bronchiectatic changes or PFT deterioration in all parameters were admitted to the hospital for intensive chest physiotherapy, airway clearance and I.V. antibiotics according to bacterial organism from the respiratory cultures for approximately 7-10 days, in addition to inhalation treatment with albuterol and inhaled steroid.Lobectomy was done when medical treatment failed to stabilize PFT and radiological pictures and to prevent their deterioration. It was usually done in the most severely affected lobe radiologically.Of the total of 900 cases that were referred with recurrent chest infection to pulmonary clinic during the period January 1993 to August 2005, 200 patients were diagnosed to have cystic fibrosis (CF). Of the remaining 700, 151 cases were diagnosed as Non-CF bronchiectasis based on high resolution CT of the chest on 145 (96%) of the patients and chest X-ray in 6 (4%) of the patients due to severe bilateral cystic dilatation of bronchi. Seventy-five (49.7%) were male, 76 (50.3%) were female. One hundred forty-eight (98%) are alive and 3 (2%) died. One hundred forty-four (95%) were Saudi and 7 (5%) were non-Saudi. One hundred forty (93%) were full term. Twenty-two (14.6%) were from the eastern region, 26 (17.2%) from the central region, 39 (25.8%) from the western region, 33 (21.9%) from the southern region and 4 (2.6%) from neighboring countries. Ninety-eight (65%) of the families were consanguineous, while 18 patients (12%) had 1\u20132 sibling(s) with bronchiectasis and 5 patients had 3-4 siblings with similar disease. Age when symptoms began to develop was 2.3 \u00b1 2.2 years. Age at referral to our center was 6.3 \u00b1 4 years. Age at bronchiectasis diagnosis was 7.3 \u00b1 4.1 years. There was a period of 5 \u00b1 3.2 years between the start of symptoms and the diagnosis of bronchiectasis. Period of follow-up was 5.5 \u00b1 3.9 years.More than two-thirds of the patients presented with cough, tachypnea, wheezing, sputum production and failure to thrive. Clubbing was found in 50 (33%) of the patients. Cyanosis and oxygen requirement were reported in 35 (23%) of the patients. Hemoptysis was reported only in 7 (5%) of the cases.Ninety-one (60%) had associated diseases . PulmonaConsolidation of one or two lobes was found in 137 (91%) of the patients, compensatory hyperinflation in 103 (68%), interstitial pattern in 49 (33%), atelectasis in 117 (78%), peribronchial wall thickening in 115 (76%) and lymph node enlargement of the paratracheal region in 33 (22%) of the patients. Left lower lobe (LLL) was commonly involved in 114 (76%), right middle lobe (RML) in 82 (54%)  and righMycobacterium tuberculosis was cultured in 1 patient [Streptococcus pneumoniae in 25 (17%), Pseudomonas aeruginosa in 24 (16%), Branhamella cattarrhales in 13 (9%), Staphylococcus aureus (Staph.) in 11 (7%) and methicillin-resistant Staphylococcus aureus (MRSA) in 3 (2%) of the patients. Candida albicans was cultured in 2 (1%) of the patients. Almost 50% of the patients had more than one organism simultaneously. Viral cultures were done in 33 (22%) of the patients: Respiratory syncytial virus in 3 (9%) patients [Respiratory cultures were done in 105 (70%) of the patients by sputum cultures as the patients were able to do it or by nasopharyngeal aspirates for patients less than 4 years of age.  patient . Hemophipatients  and enteP< 0.05) [Seventy-seven (49%) of the patients were able to do pulmonary function test (PFT). Sixty-eight (88%) of them had abnormal PFT changes. Seventeen (22%) had obstructive lung changes, 14 (18%) had restrictive lung changes and 37 (48%) had combined obstructive and restrictive lung changes . SixteenP< 0.05) .P<0.05). Only 1 case (0.4%) post foreign body aspiration showed marked regression of X-ray changes. The other 78 cases (51.6%) showed clinical improvement but no radiological regression of disease.Disease progression developed in 72 (48%) of the patients, and it was related to development of symptoms before 5 years of age, persistent atelectasis of the affected lobes and involvement of RLL with bronchiectasis (Progression of disease was found in 72 (48%) patients. Associated diseases were found in 71 patients. Asthma was found in 54 patients, ciliary dyskinesia in 9 patients, central nervous system anomalies in 2 patients, immunodeficiency in 21 patients, skeletal anomalies in 5 patients, lipid pneumonia in 7 patients, tracheoesophageal fistula in 2 patients, tuberculosis in 2 patients and cardiac anomalies in 4 patients.Unilateral lobectomy was done in 21 (14%) of the patients, whereas bilateral lobectomies were done in 3 (2%) of them. Follow-up of patients who had lobectomy showed that in 16 of the 21 patients, clinical, radiological and PFT status had improved, while 5 of them had deteriorated due to other associated diseases. Recurrent otitis media was reported in 12 (8%) of the patients. All 3 patients who died had developed acute lung infection in a local hospital that required ventilation and progressed to respiratory failure and death. One of them, who died at 16 years of age, had repair of esophageal atresia and tracheoesophageal fistula with esophageal-colonic anastomosis and recurrent aspiration that required right pneumonectomy. The second patient had type IgM syndrome with lympho-proliferative disorder and CMV infection. The third patient had lipid pneumonia that was complicated with bilateral necrotizing pneumonia, bilateral pneumothoraces, chronic ventilation that required tracheostomy, acute hepatitis, staphylococcal septicemia and recurrent pleural effusion and died at 4 years of age.Published reports from some developing countries suggest that childhood bronchiectasis may not be disappearing and that it represents a more common problem than in developed countries. Karakoc In our report, incidence of bronchiectasis was found to be 1 in 4 cases that presented with recurrent chest infection at our center, which makes it a common problem in this part of the world. In case of bacterial infections, common respiratory organisms such as Staph aureus, H-flue, pneumococcus and pseudomonas were found to be the common bacteria cultured from 51% of the patients. The southwestern region accounted for 50% of the reported cases. Environmental factors such as humidity and crowding during pilgrimage time may have contributed to such increase in its incidence in the western region. Other factors that may have contributed to its high incidence in the southern region could be delayed presentation and treatment as a result of poor living conditions and living in remote areas away from medical facilities.15 Referr12131131131132"}
+{"text": "The association between Ki-ras mutations and proliferation activity was investigated in a comprehensive series of biliary tract carcinomas (BTCs). We precisely microdissected samples of tissue from paraffin-embedded sections of 77 BTCs including 22 intrahepatic cholangiocarcinomas (ICCs), 36 extrahepatic cholangiocarcinomas (ECCs), and 19 gall bladder carcinomas (GBCs). Ki-ras mutations at exons 1 and 2 were determined by the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) method and confirmed by direct sequencing. Proliferation activity was immunohistochemically assessed to generate proliferating cell nuclear antigen labelling indices (PCNA LIs). Ki-ras mutations were detected in 10 of 22 ICCs (45%), 24 of 36 ECCs (67%), and in 16 of 19 GBCs (84%). The frequency of Ki-ras mutations in peripheral type ICCs was 33% (4 of 12) and that in the hilar type ICCs was 60% (6 of 10). In ECCs the highest value of 82% (9 of 11) was found for carcinomas located in the lower part of the biliary tree. Mean PCNA LI in mutation-positive BTCs was significantly elevated compared with the mutation-negative value. These results indicate frequent involvement of Ki-ras mutations in BTCs, especially in GBCs and in distal ECCs, and that carcinomas harbouring a mutation feature high cell proliferation activity."}
+{"text": "Reduced expression of p16 protein, detected by immunohistochemistry, occurred even more frequently, in nine of 33 (27%) cervical and seven of 37 (19%) endometrial tumours. Hypermethylation of a site within the 5\u2032-CpG island of the p16 gene was detected in only one of 32 (3%) cervical tumours and none of 26 endometrial tumours. Homozygous p16 gene deletion, evaluated by differential PCR analysis, was found in four of 40 (10%) cervical tumours and one of 38 (3%) endometrial tumours. Homozygous deletion of p15 was found in three of 40 (8%) cervical tumours and one of 38 (3%) endometrial tumours. PCR-SSCP (single-strand conformation polymorphism) analysis detected point mutations in the p16 gene in six (8%) of 78 uterine tumours (four of 40 (10%) cervical tumours and two of 38 (5%) endometrial tumours). Three were mis-sense mutations, one in codon 74 (CTG\u2192ATG) and one in codon 129 (ACC\u2192ATC), both in cervical carcinomas, and the other was in codon 127 (GGG\u2192GAG) in an endometrial carcinoma. There was one non-sense mutation, in codon 50 (CGA\u2192TGA), in an endometrial carcinoma. The remaining two were silent somatic cell mutations, both in cervical carcinomas, resulting in no amino acid change. These observations suggest that inactivation of the p16 gene, either by homologous deletion, mutation or loss of expression, occurs in a subset of uterine tumours. \u00a9 1999 Cancer Research CampaignThe roles of the"}
+{"text": "To study skin sensitivity to various allergens in patients of nasobronchial allergy.2880 skin prick tests with 60 allergens were performed in 48 patients of nasobronchial allergy.Amaranthus spinosus, Argemone mexicana, Adhatoda vasica, Ailanthus and Cannabis were found to be common allergens. In animal danders common offending allergens were cow dander and dog dander. Among fungi Aspergillus fumigatus, Aspergillus flavus, Alternaria teneis and Fusarium sodani were common allergens. Patients of bronchial asthma had associated allergic rhinitis in 80% cases.Most common offending allergens were insects (21.2%), followed by dusts (12.0%), pollens (7.8%), animal dander (3.1%), and fungi (1.3%). The common insect antigen were locust female (33.3%) followed by locust male (25%), grasshopper (20.8%), cricket (16.7%), cockroach female (16.7%) and cockroach male (14.6%). Common dust allergens were house dust, wheat dust, cotton mill and paper dust. Among pollens, Common allergens in patients of nasobronchial allergy were identified. The data may prove useful in of allergen avoidance and immunotherapy in these patients. Over 20% of the world population suffers from immunoglobulin E (IgE) mediated allergic diseases such as asthma, rhino conjunctivitis, eczema and anaphylaxis. In IndiaThe prevalence of nasobronchial allergy has increased in last two to three decades possibly due to change in indoor and outdoor environment. Allergens are one of the many factors, which can cause and trigger nasobronchial allergy. Prick may be very useful to identify the offending allergen. The present study was done to study the skin sensitivity to various allergens by skin prick test in patients of nasobronchial allergy.The study was conducted among 48 patients suspected to have nasobronchial allergy and attending the Department of Pulmonary Medicine, King George's Medical University, Lucknow, from August 2004 to September 2005. Pregnant and lactating females were excluded from the study. All the patients were subjected to detailed history and clinical examination, TLC, DLC, total serum IgE, stool examination, chest X-ray PA view, spirometry (pre and postbronchodilator) and detailed ENT examination including X-ray of paranasal sinuses.The antigens were obtained from All Cure Pharma Pvt. Ltd., New Delhi. The antigens included 32 types of pollens, 14 types of fungi, 6 types of insects, 4 types of dusts, and 4 types of dander. Oral antihistaminic were stopped two days prior and oral sympathomimetic were stopped for at least 12 hours before skin prick test. If a patient was on oral steroids continuously for more than two weeks, the skin prick test was performed three weeks after the steroid therapy had been stopped.Drop of each allergen was placed 2cm apart and then pricked with 26 gauge needle. Buffer saline was used as a negative control while histamine acid phosphate (1 mg/ml) as a positive control. Grading of skin prick test reaction was done by comparison to histamine positive control, as grade + means 25% of area of wheal induced by histamine, + + means 50% of area of wheal induced by histamine, + + + means 100% of area of wheal induced by histamine, + + + + means 200% of area of wheal induced by histamine. Only 2+,Out of 48 patients, 28 were males and 20 were females. All the patients were between 12 to 45 years of age and majority (56%) were less than 30 years of age. 80% patients of bronchial asthma had associated allergic rhinitis, while 25% patients of allergic rhinitis had associated bronchial asthma.Out of 48 patients 5 patients gave negative skin prick test to all the antigens tested while 43 patients various grades of positive reaction to one or more allergen. In the present study, a total of 2,880 tests were performed with 60 allergens , on 48 patients of nasobronchial allergy. The results of skin reactivity are shown in et al.,[et al.,[Out of 48 patients of nasobronchial allergy, in whom skin prick test was performed, 10.4% of the patients showed negative reaction to all antigens tested, while the remaining 89.6 showed positive reactions of various grades. Markedly, the positive skin reactions (2+ to 4+) were quite common for the various allergens tested. The common offending allergens found in the study were insects (21.8%), followed by dusts (11.9%), pollens 7.8%), dander (3.1%), and fungi (1.3%) . In a pr.8%, dandet al.,[et al.,[In the present study, the markedly positive skin reaction to pollen antigens varied from 0 to 35.4% (average 7.8%) in patients of nasobronchial allergy. The most common among pollens was Amaranthus spinosus (35.4%), followed by Argemone mexicana 22.9%), Adhatoda vasica (18.5%), Ailanthus (12.5%), and Cannabis (8.3%). Gynandropsis gynandra, Eucalyptus, and Typha angusta did not show any markedly positive skin reaction indicating that they are not the common pollen allergens in this part of country. A similar study was done by Agnihotri %, Adhato,[et al., reportedet al.,[et al.,[Among fungi, markedly positive skin reaction varied from 0-4.6% (average 1.3%), and the common fungal antigens were Aspergillus fumigates, followed by Aspergillus flavus, Alternaria teneis, and Fusarium sodani. Also, Aspergillus niger, Candida albicans, Cladosporium herbarum, Helminthosporium, Mucor mucedo, Neurospora, Pencillium, and Tricoderma did not show markedly positive reaction in any patients of nasobronchial allergy. Singh et al., conducte,[et al., found moet al.,[High rates of markedly positive skin reaction were also shown by insects (21.2%), female locust (33.3%), male locust (25%), grasshopper (20.8%), cricket (16.7%), female cockroach (16.7%), and male cockroach 14.6%). Gaur et al., found al.6%. Gauret al.,[et al.,[In the present study, 12% patients of nasobronchial allergy showed markedly positive skin reaction to various dusts. Most common dusts were house dust (25%), followed by wheat dust (12.5%), cotton dust (6.3%), and paper dust (4.2%). Duc et al., found to,[et al., found hoThe differences in incidence of markedly positive reactions in various studies may be due to different flora in different geographical areas and change of flora over a successive time period due to change in the climatic factors. The present study and such studies will definitely be helpful in identifying the allergens causing various allergic disorders including nasobronchial allergy in this part of the country. Furthermore, this study may also be useful in avoidance of allergens causing allergy and allergen immunotherapy. Further studies may be continued from time to time in this part of country to know the newer allergens causing allergic disorders."}
+{"text": "Intraoperative redosing of prophylactic antibiotics is recommended for prolonged surgical procedures, although its efficacy has not been assessed. We retrospectively compared the risk of surgical site infections in 1,548 patients who underwent cardiac surgery lasting >240 min after preoperative administration of cefazolin prophylaxis. The overall risk of surgical site infection was similar among patients with (43 [9.4%] of 459) and without  intraoperative redosing . However, redosing was beneficial in procedures lasting >400 min: infection occurred in 14 (7.7%) of 182 patients with redosing and in 32 (16.0%) of 200 patients without . Intraoperative redosing of cefazolin was associated with a 16% reduction in the overall risk for surgical site infection after cardiac surgery, including procedures lasting <240 min."}
+{"text": "In 1983, we reported results from the Oxford Family Planning Association contraceptive study regarding the association between oral contraceptives (OCs) and cervical neoplasia, after a 10 year follow-up of a cohort of 17,000 women. Further findings from this study are reported here after an additional 12 years of follow-up. A nested case--control design was used in which cases were all women diagnosed under 45 years of age with invasive carcinoma (n = 33), carcinoma in situ (n = 121) or dysplasia (n = 159). Controls were randomly selected from among cohort members and matched to cases on exact year of birth and clinic attended at recruitment to study. Conditional logistic regression analysis was used to determine odds ratios (ORs) and 95% confidence intervals (CIs) associated with various aspects of OC use relative to never users adjusted for social class, smoking, age at first birth and ever use of diaphragm or condom. Ever users of OCs had a slightly elevated OR for all types of cervical neoplasia combined . Odds ratios were highest for invasive carcinoma , intermediate for carcinoma in situ  and lowest for dysplasia . The elevated risk associated with OC use appeared to be largely confined to current or recent (last use in the past 2 years) long-term users of OCs. Among current or recent users, ORs for all types of cervical neoplasia combined were 3.34 (95% CI 1.96-5.67) for 49-72 months of use, 1.69 (95% CI 0.97-2.95) for 73-96 months and 2.04 (95% CI 1.34-3.11) for 97 or more months. These results suggest a possible effect of OC use on later stages of cervical carcinogenesis, although residual confounding due to sexual factors or human papillomavirus (HPV) infection cannot be ruled out."}
+{"text": "Systemic lupus erythematosus (SLE) is an autoimmune disease with multiorgan involvement. The skin is the second most commonly affected organ. SLE with skin lesions can produce considerable morbidity resulting from painful skin lesions, alopecia, disfigurement, etc. Skin lesions in patients with lupus may be specific (LE specific) or may be non specific (LE non specific). Acute cutaneous LE (Lupus specific) has a strong association with systemic disease and non-specific skin lesions always indicate disease activity for which patients present to rheumatologists and internists. Therefore, a thorough understanding of the cutaneous manifestations of SLE is essential for most efficient management.The aims of this study were to evaluate the patterns and prevalence of skin lesions in patients with SLE and to assess the relationship between skin lesions and other systemic involvement.At the Department of Rheumatology and Clinical Immunology, IPGME&R in Kolkata, 150 patients with SLE fulfilling the clinical and laboratory criteria of the American Rheumatology Association (updated 1982) were examined and followed-up for cutaneous manifestations between January 2002 and January 2007.Skin lesions were important clinical features. About 45 patients (30%) presented with skin lesions although all patients had skin lesions during the follow-up period. Skin changes noted were as follows: Lupus specific lesions: malar rash in 120 patients (80%), photosensitive dermatitis in 75 patients (50%), generalized maculopapular rash in 40 patients (26.67%), discoid rash in 30 patients (20%), subacute cutaneous lupus erythematosus (SCLE) in 5 patients (3.34%), lupus profundus in 5 patients (3.34%). The lupus non-specific lesions were non-scarring alopecia in 130 patients (86.67%), oral ulcers in 85 patients (56.67%), vasculitic lesions in 50 patients (33.34%), bullous lesions in 15 patients (10%), Raynaud's phenomenon in 10 patients (6.67%), pyoderma gangrenosum in 2 patients (1.34%), erythema multiforme in 10 patients (6.67%), and nail fold infarcts in 2 patients (1.34%); however, mucosal discoid lupus, lichenoid discoid lupus, livedo reticularis, sclerodactyly, etc. were not detected. Patients having lupus-specific skin lesions e.g., malar rash were associated with systemic involvement, whereas those having lupus non-specific skin lesions were associated with disease flare.Skin lesions in patients with SLE are important disease manifestations and proper understanding is essential for diagnosis and efficient management. SLE is a heterogeneous autoimmune disease marked by diverse patterns of auto-antibody production with multi-organ involvement. The spectrum of disease ranges from minor organ involvement  to life-threatening major organ involvement .Skin is the second most commonly affected organ after joint involvement and skin lesions are the second most frequent way that this disease presents itself. Skin andSkin lesions in patients with SLE are classified as those for lupus-specific disease e.g., malar rash, and those for lupus non-specific disease e.g., alopecia (Gilliam classification). There isCutaneous lesions are important as a diagnostic aid as these account for 4 out of 11 revised ARA criteria for disease classification. Moreover, lupus-specific skin lesions serve primarily as an important diagnostic clue whereas lupus non-specific skin lesions are associated with more active disease and thus require more aggressive therapy and disease monitoring. Thus, a SLE patients (n=150) attending the Rheumatology and Immunology Clinic between January 2002 and January 2007 were evaluated and followed-up. The patients were analyzed according to their age, gender, and clinical features with special attention paid to cutaneous manifestations and disease activity (SLE disease activity index). Laboratory investigations included complete blood count, erythrocyte sedimentation rate, urine analysis, anti nuclear antibody, anti-ds DNA, chest X ray, ultra sonography kidney (biopsy), and echocardiography. Exclusion criteria were skin lesions like folliculitis, cellulitis, candidiasis, tinea infections, scabies, drug rash, etc.Of the 150 patients, 140 (88%) were female and 10 12%) were male. The female to male ratio was 14:1. The mean age at presentation was 30 years. All patients (100%) developed skin lesions during their follow-up period; although, at the time of presentation only 45 patients (30%) had cutaneous lesions and one third of the patients had acute presentation. The lupus erythematosus-specific lesions were noted as malar rash in 120 patients (80%) , photose% were maLE non-specific skin lesions noted were non scarring alopecia in 130 patients 86.67%); scarring alopecia in 10 patients (6.67%); oral ulcers in 85 patients (56.67%) , which w%; scarriOne important observation in a female patient with SLE was generalized maculopapular rash with subsequent denudation of skin simulating toxic epidermal necrolysis (TEN). She stabilized gradually after three episodes of relapse.Other system involvements noted were constitutional symptoms in 145 patients (96.67%) in the forms of fever, anorexia, malaise, etc.; polyarthritis in 135 patients (90%); nephritis in 70 patients (46.67%) with active sediments in urine in 30 patients (20%); proteinuria in 40 patients (26.67%); cardio-pulmonary involvement in 20 patients (13.34%); hematological disturbances in 125 patients (83.34%); neuro-psychiatric involvement in 110 patients (73.34%); and gastro intestinal involvement in 70 patients (46.67%). Lymphadenopathy (20%) mostly showed reactive hyperplasia on histology.All patients were ANA-positive 100%) and anti ds-DNA was detected in 83.34% of the cases [Tables 00% and aet al.[et al.[rd decade in both series.In the present study, the patients\u2019 age ranged from 10-39 years. The median age for disease onset was 25 years. Masi, et al. observedet al.[In this study, the female to male ratio was 14:1 but Malaviya, et al. from Indet al. and Malaviya, et al. reported arthritis as an initial manifestation in 44% and 57% of the patients, respectively.[In the present study, cutaneous involvement was the most common feature (73.34%) in the disease spectrum. Cutaneous lesions were the initial presentation in 25% of the cases as reported by Waston; whereasectively.9 Constitet al.[et al.[Among the LE-specific cutaneous lesions, malar rash was the most common lesion (80%) noted in this study; whereas Wysenbeek, et al. and Vaidl.[et al. from wesl.[et al. and Wysel.[et al.et al. Lesions of subacute cutaneous lupus were detected in this study in 3.34% of the cases; whereas, Wysenbeek, et al. reported the lesions in 13% of the cases. Mucosal DLE, chilblain lupus, etc. were not detected in this study.Diffuse maculopapular rash was noted in 26.67% of the cases in contrast to 59% of the cases as reported by Wysenbeekn, et al. from north India and Vaidya, et al. from Western India noted Raynaud's phenomenon in 32% and 15.5% of the cases, respectively.[Among LE non-specific, skin lesions non-scarring diffuse alopecia was more frequent (86.67%) as compared to 57% noted by Wysenbeek and 82% ectively.13 This vectively. Urticariectively. but we hectively. Bullous ectively. but in tet al.[et al.[Bluish discoloration of the nails as noticed commonly by Kapadia, et al. was not l.[et al.et al.[et al.[In some cases, skin lesions may be associated with the involvement of other organs. Vasculitic skin lesions in some cases are associated with neuropsychiatric manifestations of lupus but in tet al. An assocl.[et al. but no set al.[et al.[In our study group, patients with LE non-specific skin lesions, specially generalized maculopapular vasculitic lesions, and diffuse non-scarring alopecia were associated with more active disease. This was also reported previously by Zeevi, et al. Another l.[et al.Other systemic involvement included constitutional symptoms (96.67%) such as fever, malaise, musculo skelelal (90%), hematological (83.34%) changes.SLE is a multisystem disorder in which cutaneous manifestations can yield valuable diagnostic  as well as prognostic  information. Skin lesions are responsible for increased morbidity. So proper understanding regarding skin lesions of SLE will be helpful for the disease diagnosis and efficient management of patients with lupus. For this reason, more interaction between rheumatologists and dermatologists will lead to more specific diagnosis of cutaneous lesions in patients with SLE."}
+{"text": "Objective: In order to determine the practice habits of obstetricians concerning frequency of prenatalhuman immunodeficiency virus (HIV) testing and management strategies for HIV-seropositive obstetric patients, we conducted a telephone survey of practicing obstetricians over a 3-month period.Methods: In the New Orleans metropolitan area, 71/104 (68%) obstetricians participated and completed the survey.Results: Of these obstetricians, 43/71 (60.6%) test all new obstetric patients for HIV; 64/71(84.5%) routinely ask the patients about risk factors for infection; and 28/71 (39.4%) have actually cared foran HIV-positive patient in their practice. Those obstetricians who routinely tested for HIVwere more likely to have personally managed an infected patient and more likely to ask about riskfactors. The number of obstetricians who would manage infected patients without consultativeassistance was 8/71 (11%).Conclusions: We concluded that obstetricians in this community have largely accepted routinelyoffered prenatal testing and risk assessment, but they have assumed a relatively small role in riskreduction counseling and treatment."}
+{"text": "The expression of the small cell carcinoma (SCLC) antigens cluster-5 (antibody LAM8) and cluster-5A (antibody SWA20) was examined on a panel of routinely processed biopsy or surgical specimens of 290 lung tumours by immunoperoxidase staining. Antigen expression was largely restricted to SCLC. Of over 150 tissue samples evaluated, moderate or strong antigen expression was found in 49% (cluster-5) and 45% (cluster-5A). Concordance in expression of the two antigens was seen in 71% of SCLC samples, with 35% expressing both antigens strongly, 8% moderately and 28% being negative for both antigens. Antigen expression was independent of the morphological subtype of SCLC. Primary lung tumours of other histology, including squamous cell carcinoma, large cell carcinoma, adenocarcinoma, mesothelioma or carcinoid had no significant antigen expression. Of 135 tumours, strong or moderate expression of both antigens was seen only in two cases. 20%, mostly carcinoids, were weakly positive for cluster 5 and 4% for cluster 5A antigen. The remainder were antigen negative. No significant antigen expression was seen in 25 normal lung tissues. The membrane antigens of SCLC cluster 5 and 5A are markers for SCLC and their expression in tissues is tumour-associated."}
+{"text": "Laboratory investigations showed that Shiga toxin\u2013producing Escherichia coli (STEC) infection occurred in 73.1% of patients. STEC O157 was the most common serotype, but a considerable number of cases were from infections by non-O157 STEC.The mean annual incidence of hemolytic uremic syndrome in persons  Stx)\u2013producing Escherichia coli (STEC), especially E. coli O157:H7 and other enterohemorrhagic serotypes; the incidence of HUS represents a robust index of the total incidence of these infections in a population (Hemolytic uremic syndrome (HUS) is the most severe and specific clinical manifestation of infections with Shiga toxin  . We observed the highest incidence  in the northern part of the country; the lowest incidence was reported in the insular regions, Sicily and Sardinia. The incidence was higher in children <5 years of age .The surveillance system was based on all pediatric nephrology centers that perform dialytic treatment in Italy. HUS cases were defined as patients The incidence observed in this study is the lowest among those reported in Europe for the same period . Of 11 (3.2%) patients who died, 6 were in the acute phase of HUS. Among the 274 patients for whom the clinical information was recorded, prodromal bloody diarrhea was reported in 48%, nonbloody diarrhea in 30%, and no diarrhea in 22%. In 21% of cases, diarrhea was reported in other household members before onset of HUS in the child. In addition, diarrhea among schoolmates was reported in 7.3% of cases. These findings suggest that person-to-person transmission may play a major role in the epidemiology of sporadic HUS cases, as described in other studies (Stx by the Vero cell assay and streaked onto MacConkey agar for STEC isolation. Serum samples were collected after diagnosis of HUS and tested for antibodies to the lipopolysaccharide (LPS) of five major STEC serogroups  by enzyme-linked immunosorbent assay as described  of 249 cases examined , a perceWe documented both microbiologic and serologic evidence of STEC infection in a considerable proportion of patients who did not have diarrhea (52.4%), although less frequently than in patients with bloody diarrhea  and nonbloody diarrhea . A similar proportion of patients with STEC infection without diarrhea has also been described in other European studies  of 225 patients examined. Most positive samples contained Stx2 alone (47 samples) or in combination with Stx1 (11 samples). Nineteen STEC strains were isolated from 18 patients (7.9%); these strains were from serogroups O157 (6 strains), O111 (4 strains), O26 (2 strains), O55 (2 strains), O86, O113, O118, O120, and undetermined O (one strain each). The proportion of STEC recovery from stools, similar to that reported in other studies (Stool examination provided evidence of STEC infection in 67 (29.4%) of 228 patients examined. Free fecal Antibodies to LPS were detected in the sera of 144 (61.3%) of 235 patients examined; in 115, this presence was the only evidence of STEC infection. Antibodies were detected to O157 (72 cases), O26 (31 cases), O111 (15 cases), O145 (15 cases), and O103 (8 cases). Three patients had antibodies to two serogroups: O157 and O26, O26 and O145, and O26 and O103.E. coli O157 was the most common STEC serogroup associated with HUS. However, >50% of STEC-positive cases had evidence of infection with non-O157 STEC. This proportion is higher than that reported in studies conducted in the United States  and in 1 (0.8%) of household contacts of STEC-positive and STEC-negative HUS cases, respectively. Two household contacts were infected with STEC strains belonging to a serogroup different from that associated with the HUS case. One of 11 STEC-positive household contacts reported diarrhea. Our findings underscore the potential for person-to-person transmission of STEC infection.The results of this 13-year surveillance indicate that the overall incidence of HUS in Italy is lower than in other European countries, although a small but steady increase has been observed since 1994. As in most countries, STEC O157 represented the most common serotype, but a considerable proportion of cases was due to infections by non-O157 STEC, particularly O26, increasing over the last 5 years. Surveillance of HUS can provide useful information about the trend of STEC infection in the general population and represents an important means to identify STEC serotypes that are highly pathogenic to humans and may emerge as public health threats."}
+{"text": "Long-term outcome of salvage treatment was reviewed in 67 unselected male patients relapsing during or after their primary cisplatin-based chemotherapy for metastatic germ cell tumours. Seven patients underwent only surgery and/or radiotherapy as curatively intended salvage treatment. Thirty-five patients (52%) had a complete or partial response to salvage treatment, 20 (57%) of whom relapsed again. With a median follow-up of 90 months (range 3-143 months) 20 patients (30%) are alive with no evidence of disease, 15 continuously disease-free and five currently disease-free. The 5 year survival from start of salvage treatment is 37% for the group as a whole. Multivariate analysis identified age < or = 35 years, complete response to primary treatment and a relapse-free interval > 3 months as independent predictors of favourable outcome of salvage treatment. A group of patients with these good-risk factors (42%) had a 5 year survival of 72% compared with the remaining patients (58%) with a 5 year survival of only 11%. Whereas patients with good-risk features may be adequately managed by conventional salvage treatment, the remaining patients carry a very poor prognosis and require innovative and more aggressive approaches."}
+{"text": "P< 0.001). Furthermore, 11 (73.3%) of these cases which changed from MSS to MSI also had a change in the expression of hMLH1 from positive to undetectable (P< 0.001). Our data suggest that tumour MSI changes during CDDP-based chemotherapy, and that the loss of hMLH1 expression is one of the factors that has the greatest effect on this transformation. \u00a9 2001 Cancer Research Campaignhttp://www.bjcancer.comTo clarify the mechanism of acquired CDDP resistance in ovarian cancer, we compared the microsatellite instability (MSI) by the amplification of 10 microsatellite loci and immunohistochemical detection of hMSH2 and hMLH1 expression between the primary resected tumours and the secondary resected residual tumours after 5 or 6 courses of CDDP-based chemotherapy in the 24 cases of ovarian cancer. Of the 24 primary resected tumours, 9 (37.5%) showed MSI , while 15 (72.5%) were microsatellite stable tumours (MSS). The primary tumours also had MSI in the residual tumours after CDDP-based chemotherapy. However, all of the cases with MSS in the primary resected tumours exhibited MSI  in the residual tumours after CDDP-based chemotherapy ("}
+{"text": "Breast cancer is the most common cause of cancer death in the western world. The expression differences of many proteins are associated with breast cancer progression or suppression. The purpose of the study was to determine the expression of nm23 protein in the invasion status and metastatic potential of breast cancer by using tissue microarray and to determine its role in breast cancer based on the expression of nm23 gene product.nm23 protein expression was examined by immunohistochemistry (IHC) using commercially available tissue microarray containing malignant and normal breast tissues from 216 patients.a similar percentage of cases showed positive cytoplasmic/nuclear staining for nm23 in normal breast tissue (85.7%), primary breast carcinoma node negative (97.5%) and carcinoma with lymph node metastasis (92.1%). Nuclear localization of staining for nm23 protein was higher in infiltrating ductal carcinoma (IDC) node positive (24.3%) and in matched lymph mode metastasis (18.9%) compared to IDC node negative (4.9%). Strong intensity of cytoplasmic/nucleus staining was observed in IDC node negative (42.6%), in IDC node positive (57.1%), and Infiltrating lobular carcinoma (ILC) node negative (44%) compared to normal breast tissue (16.7%).nm23 protein expression appears widely expressed in normal breast, early and advanced breast cancer stages. Interestingly our study found that strong staining intensity and nuclear localization of nm23 protein may prove to be a useful marker of breast cancer progression. Cancer is characterized by uncontrolled growth (proliferation) of cells -3 and thFormalin-fixed paraffin-embedded tissue microarrays from 188 lymph node negative breast cancer patients, 50 breast cancer patients with lymph node metastasis  and 8 normal breast tissue cores were analyzed by immunohistochemistry for the expression nm23 protein. Included in this study were patients with infiltrating ductal carcinoma, infiltrating lobular carcinoma, normal breast tissue and lymph node metastasis. The final number was 122 tissue cores of node negative infiltrating ductal carcinoma, 41 node negative infiltrating lobular carcinoma, seven normal breast tissue, 40 node positive  and 46 tissue cores of lymph node metastasis. We did not evaluate infiltrating lobular carcinoma node positive because of the low sample size (2 cases). Forty six 3 tissue cores were excluded from statistics because very little cancer cells or no breast cancer tissue were seen. The total number after exclusion was 254 tissue cores (37 matched tissues) of 216 patients.In principle, rabbit Anti-Human polyclonal primary antibody against nm23 protein  was used on deparaffinized tissue microarray slides . A secondary detection system (DAKO Envision) enhanced with conjugated polymer was used to bind with the primary antibody. DAB chromogen was used for permanent color development and detection under microscope.The percentage of carcinoma cells with cytoplasmic/membranous/nuclear staining was recorded on each specimen at 200\u00d7 magnification, using light microscope. The expression of nm23 was scored in all tumors as positive or negative. Positive: \u2265 75% stained cells. Negative: no cells were stained. Also the intensity of staining was categorized into three groups: weak, moderate and strong. This was ascertained by a single qualified pathologist.A tissue section of normal breast was used as positive control for nm23. Rabbit IgG isotype  was used instead of primary antibody in the immunohistochemical technique on a tissue section each of breast cancer and normal breast as negative control Figure .The tissue microarray slides were placed on hot plate at 60\u00b0C for 30 minutes. The slides were immersed in two changes of xylene (10 minutes for each) to remove paraffin. Slides were then immersed in 3 different concentrations of ethanol 100%, 95%, 70% ethanol for 5 minutes each. Slides were rinsed with distilled water to remove ethanol and left for 5 minutes. The slides were then placed in target retrieval solution EDTA buffer pH 9.0 (DAKO) and heated on microwave for 20 minutes at maximum setting. Slides were allowed to cool at room temperature and rinsed with Tris Buffered saline (TBS) mixed with tween 20 (2 changes). Slides were covered with peroxidase blocking solution (DAKO) and left for 15 minutes, followed by rinsing with TBS buffer mixed with tween 20 (2 changes). Then 200 \u03bcl of primary antibody (dilution 1:25) was added on the tissue microarray slides and left for 60 minutes, followed by rinsing with TBS mixed with tween 20 (three changes one minute each change). Two drops of DAKO Envision/HRP, Rabbit/Mouse (secondary antibody) were added on the slides and left for 30 minutes, followed by rinsing with TBS mixed with tween 20 . After that DAB substrate (DAKO) was added on section slides and left for 10 minutes , followed by rinsing, immersion into hematoxylin and 4 different concentrations of ethanol 70%, 80%, 95% and 100% for 2 minutes each. After that slides were immersed in two changes of xylene (2 minutes each) and cover slipped. All incubation steps after heat induced epitope retrieval were carried at room temperature.A majority of positive cases  showed cytoplasmic stained cells with nm23 protein. The immunohistochemical expression of nm23 protein was observed in 97.5% (119/122) of node negative infiltrating ductal carcinoma (IDC). Strong intensity of staining was observed in 42.6% (52/122) and moderate intensity in 35.2% (43/122).Positive expression of nm23 was observed in 61% (25/41) of node negative infiltrating lobular carcinoma (ILC). The strong staining intensity were observed in 44% (11/25) while moderate staining in 16% (4/25). The expression of nm23 protein in normal breast tissues was seen in 85.7% (6/7) cases. Weak staining intensity was observed in 66.7% (4/6) and strong staining in 16.7% (1/6). Different staining intensity had been found in (2/2) tissue cores containing infiltrating lobular carcinoma (strong staining intensity) and normal adjacent breast tissue (weak staining intensity)  was observed in 92.1 % (35/38) with strong staining intensity noted in 57.1% (20/35) cases. The expression of nm23 protein was observed in 89.2% (41/46) of metastatic infiltrating ductal carcinoma (IDC with lymph node metastasis) with strong staining intensity noted in 31.7 % (13/41) cases.It was observed that 89.2% (33/37) of the cases showed positive expression of nm23 protein in both infiltrating ductal carcinoma of breast and its matched lymph node metastasis. Two of 37 cases (5.4%) showed negative expression of nm23 in both sites of infiltrating ductal carcinoma and its matched lymph node metastasis. One case showed positive expression of nm23 at the site of infiltrating ductal carcinoma and negative nm23 expression in its matched lymph node metastasis. Also one case showed negative expression of nm23 infiltrating ductal carcinoma with positive nm23 expression in its matched lymph node metastasis Table .Both nuclear and cytoplasmic staining was seen in 6/122 4.9%) of node negative IDC cases, 2/41 (4.8%) of node negative ILC cases, 9/37 (24.3%) of node positive IDC cases and 7/37 (18.9%)  in the early phases of cancer genesis.In this study we observed a similar percentage of cases with positive staining for nm23 in normal breast tissue, node negative IDC as well as with lymph node metastasis with notable exception ILC. This suggests a relationship between a down regulation of nm23 expression and ILC. It may be possible that, other pathways are involved in progression of metastatic IDC.However, nuclear staining together with cytoplasmic staining was observed in cancer cells in 6/122 (4.9%) of IDC node negative cases, 2/41 (4.8%) of ILC node negative cases, 9/37 (24.3%) of IDC node positive cases and 7/37 (18.9%) in matched lymph node metastasis cases. These results indicate that nuclear localization of nm23 protein is seen more frequently in node positive metastatic cases compared with IDC or ILC node negative cases, suggesting that abnormal nuclear accumulation of nm23 may provide an indication of tumor progression. We cannot be sure whether this nuclear accumulation is due to altered (mutated or truncated form) nm23 with different half-life as up-regulation of nm23 expression is unusual in at least metastatic carcinoma considering its role as tumor suppressor. However, this requires to be proven.In conclusion nm23 protein expression appears expressed widely in normal breast, early and advanced stages of breast cancer, predominantly in ductal carcinoma. It suggests a less significance of nm23 induced pathway of tumor suppression. While, in addition, abnormal cytoplasmic and nuclear localization of this protein in node positive and metastatic cases suggest a possible role of altered nm23 which is functionally inactive with longer half-life. However, this study indicates a complex role of nm23 in breast cancer of different types and in metastatic stages and may not solely function as tumor suppressor as commonly perceive. A larger study with more ILC and metastatic cases may clarify the role and function of nm23 in breast cancer.IHC: Immunohistochemistry; IDC: Infiltrating ductal carcinoma; ILC: Infiltrating lobular carcinoma.NII carried out Immunohistochemical part of the study and lab work, participated in drafting the manuscript. GK carried out the pathological part of the study, participated in drafting the manuscript. HH performed the statistical analysis. MSH initiated the project, participated in drafting the manuscript. All authors read and approved this manuscript."}
+{"text": "In a multicentre trial of the EORTC ECTG we have treated 43 non-pretreated patients with advanced non-small-cell lung cancer (NSCLC) with the new semisynthetic taxoid docetaxel (Taxotere). Six patients were ineligible; of the 37 eligible patients, ten had prior radiotherapy and 18 prior surgery. They received 100 mg m-2 in 1 h i.v. every 3 weeks, usually in an outpatient setting. Prophylactic steroids, antihistaminics or antiemetics were not routinely given. Two patients were not evaluable because they withdrew from the study because of a hypersensitivity reaction after the second cycle. The main toxicity was neutropenia (80% of cycles), although infections were rare (4%). One patient died from sepsis during neutropenia. Hypersensitivity reactions necessitating interruption of docetaxel (Taxotere) infusions were found in only 10% of cycles. The overall response rate was 23% with one complete response, and seven partial responses. Stable disease was found in 16 patients. The median duration of response was 36 weeks, and the median survival of all patients was 11 months. Docetaxel (Taxotere) is among the most active drugs for treatment of NSCLC."}
+{"text": "This retrospective study details 94 patients aftersurgical resection of carcinoma of the ampulla ofVater to determine prognostic factors. The tumourwas limited to the ampulla of Vater in 32%, invadedthe duodenal wall in 34%, infiltrated 2cm or lessinto the pancreas in 22%, and invaded more than2cm into the pancreas and/or other adjacent structuresin 11%. Curative resection was accomplishedin 97% of cases. After exclusion of perioperativedeaths the 1-, 5- and 10-year survival rates were79.6%, 38.2%, and 31.6%, respectively with a mediansurvival of 3.68 years. 26 patients survived more thanfive and 15 patients more than ten years. In anunivariate analysis advanced tumour size, poortumour grading, lymph node metastases and advancedUICC stage significantly decreased survival.Comparison of short and long survivors confirmedtumour size, lymph node status and UICC stage assignificant prognostic factors. In a multivariateanalysis (Cox model), only tumour size was astatistically independent predictor of prognosis.The survival probability increased with each year apatient survived after resection. When a patient hadalready survived five years after resection, theprobability to survive another five years was 83%.Careful clinicopathologic staging is important forthe prognosis after resection."}
+{"text": "The urinary excretion during 24 h of aminoglutethimide (AG) its major metabolite (N-acetylAG) and two minor metabolites (N-formylAG and nitroG) were measured in 10 volunteers given AG who had been typed for acetylator phenotype using sulphadimidine. The slow acetylators of sulphadimidine excreted more AG (mean 28% of the administered dose) than did the fast acetylators (12%), but the latter excreted more of the dose as N-acetylAG (8.8%) than did the former (3.9%). NitroG and N-formylAG were minor urinary metabolites of AG in humans. The former was more abundant in the urine of slow acetylators (0.10% of the dose) than in that of fast acetylators (0.047%), whereas the respective proportions of doses excreted as the N-formyl derivative (0.475 and 0.465%) were not significantly different for the two acetylator phenotypes. These results show that AG is among those drugs that are polymorphically acetylated in humans."}
+{"text": "Expression of periostin is an indicator of epithelial-mesenchymal transition in cancer but a detailed analysis of periostin expression in prostate cancer has not been conducted so far.Here, we evaluated periostin expression in prostate cancer cells and peritumoural stroma immunohistochemically in two independent prostate cancer cohorts, including a training cohort (n = 93) and a test cohort (n = 325). Metastatic prostate cancers (n = 20), hormone refractory prostate cancers (n = 19) and benign prostatic tissues (n = 38) were also analyzed.In total, strong epithelial periostin expression was detectable in 142 of 418 (34.0%) of prostate carcinomas and in 11 of 38 benign prostate glands (28.9%). Increased periostin expression in carcinoma cells was significantly associated with high Gleason score (p < 0.01) and advanced tumour stage (p < 0.05) in the test cohort. Whereas periostin expression was weak or absent in the stroma around normal prostate glands, strong periostin expression in tumour stroma was found in most primary and metastatic prostate cancers. High stromal periostin expression was associated with higher Gleason scores (p < 0.001). There was a relationship between stromal periostin expression and shortened PSA relapse free survival times in the training cohort (p < 0.05).Our data indicate that periostin up-regulation is related to increased tumour aggressiveness in prostate cancer and might be a promising target for therapeutical interventions in primary and metastatic prostate cancer. Periostin (POSTN) is a 93 kDa N-glycoprotein, first described in 1993 in mouse osteoblasts as osteoblast-specific factor 2 (OSF-2). It shows homology with the cell adhesion molecules fasciclin 1 (drosophila) and beta-IgH3 (human), sharing features that are thought to explain some of its functional characteristics [Periostin has been found in several, mainly collagen-rich and fetal tissues as an extracellular matrix protein and is up-regulated by mechanical stress during tissue repair and (re)generation -8. PerioAs a ligand to alpha(V)beta(3) and alpha(V)beta(5) integrin periostin appears to activate the Akt/PKB (protein kinase B) pathway, known to facilitate cell survival and tumourigenesis -15.High expression of periostin protein or mRNA was detected in most solid tumours including breast, colon, head and neck, pancreatic, papillary thyroid, ovarian, lung, gastric and liver carcinoma, as well as neuroblastoma ,13,16-33So far there is only a single report on periostin expression in prostate cancer . IncreasA training cohort was used for the establishment of a periostin evaluation algorithm. The training cohort consisted of tissue of 93 prostate cancer patients diagnosed between 1990 and 2001 at the Institute of Pathology, Charit\u00e9 - Universit\u00e4tsmedizin Berlin. In this cohort cases with and without PSA relapse were selectively chosen to study the relevance of biomarkers for prediction of PSA relapse. The median age was 61 years (range 47-73 years). The pT-status was pT2 in 42 (45.2%) and pT3/4 in 51 (54.8%) cases. The Gleason score was < 7 in 23 (24.7%), 7 in 39 (41.9%) and >7 in 31 (33.3%) cases. Forty-one (44.1%) tumours were judged R1, 50 (53.8%) R0 and 2 (2.1%) Rx. Forty-three (46.2%) patients had a PSA relapse. The median follow-up time was 45 months (range 3-180 months).In a second step, periostin expression was analyzed in a larger test cohort with 325 primary prostate cancers. The test cohort consisted of 325 consecutive patients treated with prostatectomy for prostate cancer between 1993 and 2006 at the Department of Urology, University Hospital Zurich. The median age was 64 years (range 46-79 years). The pT-status was pT2 in 205 (63.1%) and pT3/4 in 120 (36.9%) cases. The Gleason score was < 7 in 50 (15.4%), 7 in 194 (59.7%) and >7 in 81 (24.9%) tumours. Concerning surgical margins, 112 (34.5%) tumours were R1, 207 (63.7%) R0 and 6 (1.8%) Rx. Sixty-eight (20.9%) patients had a PSA relapse. The median follow-up time was 72 months (range 0-163 months). Data on relapse free survival times was available for 211 of the patients. In addition 20 metastatic prostate cancers , 19 hormone resistant prostate cancers and 38 cases of benign prostatic tissue were evaluated. The 19 hormone resistant prostate cancer specimens were from patients undergoing palliative transurethral prostate resection in advanced disease.The study was approved by the the Charit\u00e9 University Ethics Committee (EA1/06/2004) and by the Cantonal Ethics Committee of Zurich (StV 25-2007 neu). In the latter, necessity of patients' informed consent was explicitely ruled out, since this is a retrospective study.The tissue microarrays (TMA) were constructed as previously described . We usedThe TMA blocks were freshly cut (3 \u03bcm) and mounted on superfrost slides . IHC was conducted with the Ventana Benchmark automated staining system  using Ventana reagents and a polyclonal antibody against human periostin  after standard (CC1 m) heat induced antigen retrieval as described before [The periostin protein expression was evaluated by two clinical pathologists  on a multi-headed microscope. The test cohort was subsequently re-evaluated by another pathologist (AS).For evaluation of epithelial and stromal periostin expression, we implemented an immuno-reactive score including intensity and quantity of cells stained. The staining intensity was scored negative (0), weak (1+), moderate (2+) or strong (3+). The quantity of stained cells was scored zero (0), < 10% (1+), 10-50% (2+), 51-80% (3+) or >80% (4+). Intensity and quantity were multiplied (immunoreactive score (IRS), range 0-12).low\" and \"periostin high\" group. Fisher's exact and chi-squared tests were applied to assess associations between categorized periostin expression and clinico-pathological parameters. Correlations were computed using Spearman's bivariate rank order correlation. Univariate survival analysis was carried out according to Kaplan-Meier, differences in survival curves were assessed with the Log rank test. P-values < 0.05 were considered significant.Statistical analyses were performed with SPSS 17.0 . The median value of the IRS was used as cut-off point to dichotomize the tumours into a \"periostin Distinct stromal and epithelial staining characteristics allowed an absolutely certain evaluation of the periostin staining Figure  and 1b. Tumour stroma was positive in all cases of the training cohort and most cases of the test cohort. Only 11 (3.4%) cases of the test cohort were negative. An IRS above 2 was found in the vast majority of primary (82.8%), hormone resistant (78.9%) and metastatic (85%) tumours. Using our periostin score, it was possible to differentiate between low and high periostin expression levels using the median. The median stromal IRS for both primary prostate cancer cohorts was 6 with a mean value of about 5.5.Sixty (18.5%) primary prostate cancer cases showed no epithelial periostin expression and 189 (58.2%) cases had an IRS equal to or below 3 (median 3). In total, 142/418 prostate cancer cases expressed high levels of epithelial periostin. Only 7.4% of cases exhibited an IRS for epithelial periostin expression above 6. Revalidation of the stainings resulted in the same median IRS values.For the 19 hormone resistant prostate cancers the median IRS was 8 for the stromal and 4 for the epithelial periostin expression (means: 6.8 and 5.1). In the 20 samples from prostate cancer metastases the mean and median IRS of epithelial and stromal periostin expression did not differ from that in the primary prostate cancers.In the training cohort, stromal periostin expression showed no correlation (Spearman rank order) with any of the clinico-pathological parameters . A higher pT stage was significantly associated with high epithelial periostin expression  correlated significantly with shortened PSA relapse free survival in both cohorts Table .In the test cohort, neither stromal nor epithelial periostin expression reached prognostic significance  Figure .et al. observing a prostate cancer patient cohort of 77 prostate cancers showing increased periostin expression in early prostate cancer stages as well as in the stroma of advanced prostate cancer cases [et al. and our results may be explained by the sample number (77 versus 418) and differences in grade and stage. Our test cohort was represented by 63.1% pT2 and 36.9% pT3/4 tumours whereas Tsunoda's cohort comprised of 18.2% pT2 and 74.0% pT3/4 tumours. Grade in our test cohort was < 7 in 15.4%, 7 in 59.7% and >7 in 24.9%. Tsunoda's cohort had a much higher percentage of Gleason 8-10 of 55.8%. Altogether, our test cohort might be more representative for early stages of prostate cancer than Tsunoda's which could well explain the observed difference.In this study, we provide evidence for periostin up-regulation during prostate cancer progression. Periostin expression was found in both epithelial cancer cells and in peritumoural stroma. Recently, our group has demonstrated that periostin as a marker for the epithelial-mesenchymal-transition (EMT) programme in lung cancer is prognostically relevant . EMT is er cases . This isWe do acknowledge that a core diameter of 0.6 mm per prostate cancer case might not be fully representative for a given case. This is especially of importance in small cohorts. However, during the preparation of our tissue microarray, we reviewed each case very carefully to choose a representative area of tumour tissue.per se or whether it is actively induced by the tumour cells themselves. The presence of both mRNA and protein in the cytoplasm of tumour cells favours an active or signal transducting role of periostin, respectively. Further functional studies are needed to shed light on the mechanism of periostin up-regulation in prostate cancer.There are several reports on involvement of other EMT markers eg. platelet-derived growth factor-D, hypoxia-inducible factor-1\u03b1 and zinc finger enhancer binding protein 1 in prostate cancer -40. Meanet al. and Castranovo et al. have recently evaluated its therapeutic potential [In our test cohort we could not reproduce the promising results concerning the prognostic value of periostin deduced from the training cohort. A possible explanation is most likely the selection of the training cohort with a very high number of cases with PSA relapse (46%) whereas the consecutive cases of the test cohort show usual relapse rates (21%). The selection of the training cohort was done to identify biomarker for PSA relapse. It is not uncommon to see that prognostic significances are better in trainings cohorts than in tests cohorts. The differing results for relapse free survival of both cohorts are therefore not too surprising for us, also taking into account that the composition of the cohorts is so different. However, this also demonstrates that the prognostic value of periostin is limited in comparison to well established conventional prognosticators of prostate cancer and other potentially prognostic molecular markers ,43. Moreotential ,44. In aotential ,44. It hThis immunohistochemical study describes the periostin protein expression pattern in prostate cancer and benign prostate tissue in a large patient cohort. Its upregulation in primary, metastatic and hormone resistant prostate cancers was related to a more aggressive and advanced tumour biology. These expression characteristics and its proposed drugability make periostin a promising target for an individualized prostate cancer therapy.The authors declare that they have no competing interests.HM, AS, GK and VT designed the study, participated in the statistical analysis and drafted the manuscript. FRF and JG participated in the design of the study and performed the statistical analysis. PJW, PS, TH, HHS and HM designed the \"Zurich\" tissue microarray. GK, FRF, KJ and CS designed the \"Berlin\" tissue micro array. HHS, PJW, AM and MOR participated in collecting clinical data for the \"Zurich\" cohort. HM, GK, AS conceived the study, participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/10/273/prepub"}
+{"text": "The prognostic significance of tumour cell proliferation was investigated in a series of 418 gastric carcinomas using the monoclonal antibody MIB-1. Owing to strong intratumoural heterogeneity of MIB-1 expression three different proliferation indices (PIs) were determined in all carcinomas: (1) PImax in areas of maximal tumour cell proliferation, (2) PIrand in areas randomly distributed over the whole tumour. (3) PIfront in areas exclusively located at the tumour invasion front. There was a strong intertumoral heterogeneity with PImax ranging from 4.9% to 92.2%, PIrand ranging from 3.4% to 81.4% and PIfront ranging from 4.2% to 87.1%. The mean values were 51.3% +/- 19.7 for PImax, 34.2% +/- 18.3 for PIrand and 37.2% +/- 19.5 for PIfront. Whereas no statistically significant correlation could be found between proliferative activity and the clinicopathological parameters depth of invasion, lymph node involvement or grade of tumour differentiation, there was a positive correlation between a high proliferation index at the tumour invasion front (PIfront) and the presence of blood or lymphatic vessel invasion. No significant correlation could be demonstrated between the different proliferation indices and survival, even when different subgroups of patients were analysed separately. The present results suggest that the immunohistochemical evaluation of the proliferation activity has no predictive value for the prognosis of gastric cancer patients or the identification of subgroups of patients who may be at higher risk."}
+{"text": "To investigate the feasibility of thoracoscopic resection, a pilot study was performed in patients with clinically resectable lung tumors. In 40 patients, Video-assisted thoracic surgery (VATS) was performed because of suspicion of malignancy. There were 29 men and 11 women with a median age of 54.8 years (range 18 to 78). Preoperative indications were suspected lung cancer and tumor in 27 patients, assessment of tumor resectability in 7 patients, and probability of metastatic tumors in 6 patients. The final diagnoses in the 27 patients with suspected lung cancer were 12 primary lung cancers, 6 lung metastases, and 9 benign lesions. The success rates for VATS (no conversion to thoracotomy) were 1 of 12 (8.3%) for resectable stage I lung cancer, 8 of 12 (66.7%) for metastatic tumors, and 9 of 9 (100%) for benign tumors. With VATS, 6 of 7 patients (85.7%), possible stage III non-small cell lung cancer, an explorative thoracotomy with was avoided, significantly reducing morbidity. The reasons for conversion to thoracotomy were 1) oncological (N2 lymph node dissection and prevention of tumor spillage) and 2) technical . The ultimate diagnoses were 19 lung cancers, 12 metastatic lung tumors, and 9 benign lung tumors. Our data show the limitations of VATS for malignant tumors in general use. These findings, together with the fact that experience in performing thoracoscopic procedures demonstrates a learning curve, may limit the use of thoracoscopic resection as a routine surgical procedure, especially when strict oncological rules are respected."}
+{"text": "The important role of the p53 gene in tumour progression and cellular response to DNA damage has prompted investigation of the clinical significance of alterations to this gene. We examined both p53 overexpression and mutation of the gene in endometrial carcinoma in order to evaluate the prognostic significance of these changes. Of 122 endometrial carcinomas, 33 (27%) showed overexpression of p53 in the nucleus and 66 (54%) in the cytoplasm. Mutation in the p53 gene was found in 16 (13%) cases but showed no significant association with patient survival. Nuclear p53 overexpression was associated with poor survival . In contrast, cytoplasmic p53 overexpression was associated with better survival . When patients were separated into prognostic subgroups according to established clinical markers, these associations remained significant within most subgroups examined. In multivariate analysis adjusted for surgical stage, histological grade and type and vascular invasion, both nuclear p53 overexpression [hazard ratio 4.9 (95% CI 1.3-17.6). P = 0.016] and cytoplasmic overexpression  were independent prognostic factors. Immunohistochemical assessment of p53 overexpression in the nucleus and cytoplasm could provide useful prognostic information for the management of patients with endometrial cancer."}
+{"text": "Clinical studies have confirmed that renal oncocytoma (RO) is a benign neoplasm with excellent prognosis. In diagnostically challenging cases of renal oncocytic epithelial neoplasms, fluorescent in-situ hybridization (FISH) is increasingly being used and its ability to distinguish RO from chromophobe renal cell carcinoma (ChRCC) has been documented. In this study, we evaluated the differential diagnostic contribution of FISH in cases of RO.Clinicopathologic data and glass slides from 73 patients with RO were reviewed; 20 cases of ChRCC were included for comparison. FISH analysis of formalin-fixed, paraffin-embedded sections was performed using centromeric probes for chromosomes 1, 2, 7 and 17. FISH analysis revealed ROs had frequent loss of signal for chromosome 1 (56%) and 17 (44%). Tumors with more than one loss were common (41%) and 10% cases showed loss of all chromosomes examined. A total of 18% cases did not show any abnormality.Our study shows that chromosomal abnormalities in both ROs and ChRCCs are common with frequent loss of chromosomes 1 and 17. No association was found between overall patient survival and the extent of chromosomal abnormalities. FISH results, even those showing significant chromosomal abnormalities, should not alter the primarily morphology-based diagnosis of RO. Renal oncocytomas (ROs) comprise approximately 3-7% of renal epithelial neoplasms -3. CommoCytogenetic studies of RO revealed genetic heterogeneity of these neoplasms; three distinct subsets were identified: 1) translocation between 11q13 and other chromosomes, 2) loss of 1/1p followed by loss of chromosome Y or 14 and 3) non-recurrent or no detectable aberrations . MoleculBased on the current data on genetic abnormalities occurring in ROs, we have employed an abbreviated FISH panel for chromosomes 1, 2, 7 and 17 in our institution that would aid in their differential diagnosis. In this study, we present our experience with this FISH panel and its contribution in the differential diagnosis along with survival data of 73 patients with RO.The pathology records of the University of Pittsburgh were reviewed to find all patients who underwent primary nephrectomy for renal oncocytoma in the period of 25 years (1981 - 2006). Seventy-three cases of renal oncocytoma were selected from the UPMC archives using conventional histologic examination by two pathologists. For each patient, the data from the final surgical pathology report as well as from the clinical records were retrieved. In addition, 20 cases of ChRCC (11 cases of classic and 9 cases of eosinophilic variant) were included for comparison. Since the previously published FISH results did not show significant difference in observed abnormalities between the classic and eosinophilic variant of ChRCC , the twoFormalin-fixed paraffin-embedded sections were mounted and serially sectioned at 5-mm intervals. H&E section was used by the pathologist to determine the area of the tissue to be targeted for analysis. FISH slides were deparaffinized in xylene twice for 10 minutes, dehydrated twice with 100% ethanol and then pretreated using the Vysis Paraffin Pretreatment Kit. Slides were digested for 18 minutes in protease solution (0.5 mg/ml) at 37\u00b0C. FISH was performed using CEP1, CEP2, CEP7 and CEP17 centromere probes . The target slide was denatured at 75\u00b0C for 5 minutes and dehydrated in 70%, 85%, 100% ethanol. Slides were incubated with probe overnight at 42\u00b0C in a humidified chamber. Post-hybridization washes were performed using 0.4\u00d7 SSC/0.3% Igepal (Sigma) at 72\u00b0C for 2 minutes, followed by a room temperature 2 \u00d7 SSC/0.1% Igepal wash for 30 seconds. Slides were air-dried in the dark and counterstained with DAPI . Analysis was performed using a Nikon Optiphot-2  and Quips Genetic Workstation equipped with Chroma Technology 83000 filter set with single band excitors for Texas Red/Rhodamine, FITC, DAPI (UV 360 nm) . Only individual and well delineated cells were scored, overlapping cells were excluded from the analysis. At least 60 cells were analyzed in the targeted region. Signal loss was considered significant if present in more than 30% of cells, gain if present in more than 20% of cells examined.In the RO group, the study population included 51 males and 22 females  with an average age of 67 (range 29 - 83) years. A total of 32 patients 44%) underwent partial nephrectomy (nephron sparing surgery), the remaining 41 patients (56%) radical nephrectomy with or without ipsilateral adrenalectomy. The mean tumor size was 4.0 cm (range from 1 - 21 cm). Small vessel invasion was present in 4 (5.5%) cases, and invasion into perinephric adipose tissue in 5 (6.8%) cases. None of the patients had evidence of metastatic disease at diagnosis. After a mean follow-up of 64 months (range from 1 to 293 months), a total of 46 (63%) of patients were alive with no evidence of disease; 14 (19%) had died of other causes and no follow up was available for 13 (18%) patients. None of the patients had disease recurrence nor developed metastases. The control ChRCC group consisted of 11 males and 9 females male to female ratio 1.2:1) with a mean age of 64 (range 35 - 88) years (Table 1). Average tumor size was 6.1 cm (range 1 - 14.5 cm). A total of 8 patients (40%) were treated with partial nephrectomy, 12 (60%) with radical nephrectomy. Small vessel invasion was present in 3 (15%) cases, and invasion into perinephric adipose tissue in 2 (10%) cases; one patient had tumor grossly extending into the renal vein. After a mean follow up of 60 months (range from 25 - 87 months), one patient with a tumor extending into the perinephric adipose tissue developed local recurrence 25 months after a radical nephrectomy. Similarly to the renal oncocytoma group, none of the patients with available follow-up died of disease or developed metastases.Characteristic histological features of both RO and ChRCC were observed Figures  and 2. RIn 32 cases, the initial diagnosis of renal oncocytoma was based on histology alone (44%); a total of 41 (56%) cases had some ancillary studies, such as electron microscopy , DNA ploidy analysis , FISH  or histochemistry for Hale's colloidal iron . A total of 68 cases (93%) were initially diagnosed as oncocytoma; however, 5 cases (7%) were diagnosed using descriptive terms such as \"atypical oncocytic neoplasm\" or \"renal cell carcinoma of oncocytic type (oncocytoma)\". In contrast, all of the chromophobe renal cell carcinomas were initially worked-up using ancillary studies such as Hale's colloidal iron histochemical stain  or FISH .The FISH results are summarized in Table 2 and Figure ChRCCs consistently showed multiple chromosomal abnormalities, and 6/20 30%) of cases were abnormal in all chromosomes examined  was observed in papillary renal cell carcinoma ,25 that In our current study, the incidence of chromosomal abnormalities in ROs  was significantly higher than in the previous reports ,12,18. BA total of 3/73 RO cases showed loss of chromosome 1 and gain of chromosome 7 and/or 17; morphologically, 2 cases displayed characteristic alternating nested and organoid growth patterns; the third case had predominantly tubulocystic arrangement of typical oncocytes. All three were initially diagnosed as RO without any ancillary studies. Gains of chromosome 7 and/or 17 without any accompanying chromosomal loss was observed in 4/73 cases; histologic review confirmed the initial diagnosis of RO in all four cases; however, only some of the original histologic sections were available for review in 3 cases precluding a definitive diagnosis. RO cases with extracapsular or vascular space invasion usually showed multiple chromosomal losses or gains; however, one of the cases with perirenal soft tissue extension was normal by FISH. Long term follow-up of patients included in our study confirmed the excellent prognosis of RO as none of the patients died of disease, developed metastases or local recurrence. No association was found between overall patient survival and the extent of chromosomal abnormalities detected by FISH.The incidence of chromosomal abnormalities in ChRCC was in agreement with previous studies ,15,16; 1Our FISH study of ROs, which is largest to date, was based on a series of well-defined oncocytomas diagnosed according to the current morphologic WHO classification criteria . Our resThe authors declare that they have no competing interests.MD carried out the research studies, participated in the drafting of the manuscript. KMC, CRS and TLM carried out the FISH studies. MBA carried out the immunohistochemical studies. RD and SIB participated in the design of the study. AVP conceived of the study, helped draft the manuscript and participated in its design and coordination. All authors read and approved the final manuscript."}
+{"text": "One essential outcome after breast cancer treatment is recurrence of the disease. Treatment decision is based on assessment of prognostic factors of breast cancer recurrence. This study was to investigate the prognostic factors for postmastectomy locoregional recurrence (LRR) and survival in those patients.114 patients undergoing mastectomy and adjuvant radiotherapy in Cancer Institute of Tehran University of Medical Sciences were retrospectively reviewed between 1996 and 2008. All cases were followed up after initial treatment of patients with breast cancer via regular visit  for discovering the LRR. Cumulative recurrence free survival (RFS) was determined using the Kaplan-Meier method, with univariate comparisons between groups through the log-rank test. The Cox proportional hazards model was used for multivariate analysis.The median follow up time was 84 months (range 2-140). Twenty-three (20.2%) patients developed LRR. Cumulative RFS rate at 2.5 years and 5 years were 86%  and 82.5%  respectively. Mean RFS was 116.50 \u00b1 4.43 months . At univariate and multivariate analysis, factors had not any influence on the LRR.Despite use of adjuvant therapies during the study, we found a LRR rate after mastectomy of 20.2%. Therefore, for patients with LRR without evidence of distant disease, aggressive multimodality therapy is warranted. Breast cancer is the main cause of death that affects women worldwide . Women wIn the previous reports, the 10-year local recurrence rates after modified radical mastectomy (MRM) are around 12% to 27% -13.Several studies have reported that young age ,15, largIncidence and outcomes data of LRR after mastectomy are limited by heterogeneous study populations and the different time period studies. Since it is important to know the prognostic factors related with LRR and recurrence-free survival (RFS) of a population of breast cancer patients, we retrospectively investigated the recurrence and survival in patients with breast cancer after MRM. We mainly analyzed the prognostic factors related with LRR to identify the subgroup of patients with higher risk of recurrence for selective treatment .To evaluate the risk of post-surgery recurrence of breast cancer, a historical cohort study was designed. The cases included in this study were selected from the female patients with breast cancer who had received MRM and adjuvant radiotherapy from 1996 to 2008 in Cancer Institute of Imam Khomeini hospital complex. One of major teaching hospitals of Tehran University of Medical Sciences in Iran. Unfortunately patients' records of our center were incomplete. There were 800 complete records that one out of 7 was reviewed. A total of 114 patients were enrolled into this study via systematic random sampling. All cases were followed up  after initial treatment of patients with breast cancer via regular visit  for discovering the LRR. In addition to routine clinical examination, disease assessment included mammography, chest x ray and liver ultrasonography.All patients received postoperatively adjuvant chemotherapy using CMF regimens . Hormonal therapy was given to Sixty-six (57.9%) of the 114 patients. Hormonal therapy was given to all patients with estrogen receptor (ER)-positive or progesterone receptor (PR)-positive tumors by biochemical assay or immunohistochemistry. All patients received postoperatively adjuvant radiotherapy which was usually performed intermittently between courses of chemotherapy. Postmastectomy radiotherapy to the chest wall was only given to high-risk groups showing locally advanced primary tumor and/or metastatic axillary lymph nodes. Irradiation of the axilla, parasternal, subclavicular and supraclavicular lymph node regions was also restricted to these high-risk groups.Cobalt-60 ray was used. The target sites for radiation always included supraclavicular/apical axillary regions. The radiation dose was DT46-50 Gy in conventional fractionations. The 6th edition of the TNM staging system of the American Joint Committee on Cancer (AJCC) was used. The histologic grade of the tumors was scored according to the system of Bloom and Richardson .Patients with distant metastasis detected at the time of diagnosis and those that their surgical margins were positive for carcinoma were excluded.The variables considered in these patients were age, weight, lymph node involvement, size, stage, grade and pathology of the tumor using operative and pathology records. The slides were reviewed by one pathologist.LRR defined as LRR not predated or followed by distant metastases within 6 weeks . The RFSSPSS 16 software was used for statistical analysis.Cumulative RFS was determined by using the Kaplan-Meier method, with univariate comparisons between groups through the log-rank test. The Cox proportional hazards model was used for multivariate analysis.All P-values were tested by two-tailed test, where < 0.05 indicated statistically significant.The total number of patients included in our study was 114. Median age at surgery was 45 years . Twenty-three (20.2%) patients developed locoregional recurrences. The median follow up time was 84 months (range 2-140).In the location of 23 cases with LRR, most 91.29%) were seen at chest wall, 4.34% at internal mammary lymph nodes and 4.34% at axillary lymph nodes (Table .29% werePatients less than 30 years had the lowest rates of LRR (4.34%) and those with 30-40 years had the highest rates (30.43%). Patients with weight of \u2264 50 kg, 90 kg \u2264 had the lowest rates of LRR (4.34%), those with weight of 60-70 kg had the highest rates (34.78%). Patients with tumors \u2264 2 cm had the lowest rates of LRR (21.7%), those with tumors 2 to 5 cm had intermediate rates (34.7%), and those with tumors \u2265 5.0 cm had the highest rates (43.4%). Patients with 4-9 lymph nodes had the highest rates of LRR (52.17%) and those with 10 or more lymph node had the lowest rates (8.6%). Patients with stage I had the lowest rates of LRR (4.34%) and those with stage III had the highest rates (69.56%). Patients with grade 1 had the lowest rates of LRR (8.6%) and those with grade 2 had the highest rates (47.82%). Among the recurrent tumors, 21 (91.30%) were invasive ductal carcinoma and 2 (8.7%) were invasive lobular carcinoma.Kaplan-Meier estimates of cumulative RFS rate at 2.5 years  was 86% 81-91). At 5 year was 82.5% (77-87). Mean RFS was 116.50 \u00b1 4.43 months . .Table According to the results of the multivariate Cox proportional hazards survival analysis, age, weight, tumor size, nodal status, stage, grade and histology of tumor were not significant predictors of LRR after MRM Table .In this study, the median follow up time was 7 years and the LRR rate was 20.2%, a rate similar to those reported for mastectomy performed in large prospective randomized trials. In those trials, local recurrence rate for patients treated with mastectomy ranged from 2% to 19%. The broad range of follow-up time in these studies (6-19 years) may account for the range of recurrence rate -26. The In the present study, most recurrence of breast cancer occurred within 5-20 months. These results support previous data from Saphner et al. who identified a peak of recurrences at 2 years in a large cohort of patients  enrolled in 7 Eastern Cooperative Oncology Group studies of postoperative adjuvant therapy .Similar to previous studies ,28, in tIn this study, RFS rate at 5 - years was 82.5%. Overgaard et al. reported better 5 - year overall survival (OS) and disease-free survival (DFS) rates (72% and 61%) . Ragaz eMany reports suggested that premenopausal and younger age at breast cancer diagnosis were unfavorable prognostic factors for locoregional control and survival ,9,31. InAdditional factors found to be independent predictors of early recurrence include low ER positivity and human epidermal growth factor receptor 2 (HER2) overexpression/amplification ,35.In this report at univariate and multivariate analysis, none of factors reached statistical significance to predict LRR. Patients with tumors \u2265 5.0 cm, 4-9 involved nodes, stage III, grade 2 and ductal tumor were at increased risk of LRR. But no statistical difference was found in our group of patients.About the influence of diet on breast cancer prognosis, the Women's Intervention Nutrition Study found that a low-fat diet reduced breast cancer recurrence , whereasAs reported in another studies ,41, DurnNumber of all cases in this study was limited and we reviewed only complete records and we do not know anything about incomplete records. These were limitations of this study. We hope that more cases accumulation let better comparison in later studies. Also, our results confirmed the previous studies indicated that postoperative adjuvant radiotherapy is mainly applied for patients with four or more metastatic axillary lymph nodes and those with primary tumors at stage T3 or above, who have higher risk of locoregional recurrence.LRR: loco regional recurrence; MRM: modified radical mastectomy; CMF: cyclophosphamide: methotrexate: and fluorouracil; ER: estrogen receptor; PR: progesterone receptor; AJCC: American Joint Committee on Cancer; RFS: recurrence - free survival; DBCG: Danish Breast Cancer Cooperative Group; OS: overall survival; DFS: disease-free survival; HRT: hormone replacement therapy.There is no conflict of interest and any financial and personal relationships with other people or organisations in our study. This study was approved by the medical ethics committee of Tehran University of Medical Sciences.AA participated in the design of the study and conceived of the study. NR drafted the manuscript and acquisition of data and coordination. ZK performed the statistical analysis."}
+{"text": "Extrapulmonary tuberculosis (EPTB) still constitutes an important clinical problem. We aimed to evaluate the incidence and features of extrapulmonary tuberculosis.We retrospectively evaluated 14,266 tuberculosis patients diagnosed between January 1999 and December 2003 in a tertiary care hospital in Istanbul. As many as 2,435 patients (17.1%) with EPTB were evaluated for the incidence and features.Of the 14,266 patients, 4,154 were female (29%) and 10,112 were male (71%) and were aged between 14 and 86 years with a mean age of 35 \u00b1 14 years. As many as 660 (17.9%) patients were diagnosed as EPTB in 1999, 568 (17.8%) in 2000, 357 (13.7%) in 2001, 462 (22%) in 2002 and 388 (14.5%) in 2003. EPTB presented most commonly as pleurisy (66%), followed by lymphadenitis (23%). Lymphadenitis and pleurisy were more commonly observed among female TB patients (60%) and among male TB patients (59%) respectively. EPTB showed a significant female predilection (26.8%) compared to male patients (13.1%). Multi-organ involvement was observed in 37 (1.5%) patients (two organs in 33 and three organs in 4). As many as 197 (8%) EPTB cases had pulmonary tuberculosis simultaneously.EPTB still constitutes an important clinical problem. The rates of EPTB have remained constant despite the decline in pulmonary tuberculosis cases. In the current study, we present our experience of the incidence and features of EPTB patients without HIV infection. In this study, EPTB cases constituted one-fifth of all tuberculosis cases presented to our center in the study period. Tuberculosis (TB) is a serious health problem worldwide and constitutes the main infectious cause of death. It can iIn the current study, we present our experience of the incidence and features of EPTB patients without HIV infection.Mycobacterium tuberculosis through Ziehl-Neelsen acid fast stain and culture in Lowenstein-Jensen or BACTEC media in a tissue or specimen from a site other than lung parenchyma, in association with clinical and/or imaging findings compatible with infection locally, (2) EPTB and pulmonary TB with negative cultures were defined as clinical, laboratory, imaging and/or histopathological evidence of mycobacterial infection in a site other than hilar lymph nodes or lung parenchyma, in association with a positive tuberculin skin test reaction and/or history of exposure to tuberculosis and exclusion of other diseases and response to empirical antituberculosis treatment. We evaluated the clinical presentation of EPTB cases, including demographic features, organ involvement and coexisting pulmonary TB.Of the 14,266 TB patients, 2,435 (17.1%) patients with EPTB were included in the study. Patients presented between January 1999 and December 2003 at SSK Sureyyapasa Center for Chest Disease and Thoracic Surgery, a tertiary care hospital in Istanbul, Turkey, were reviewed retrospectively. Only patients with an extrapulmonary site of infection were included in the study. Miliary TB cases and sole pulmonary TB cases and multidrug-resistant patients' cases were excluded. EPTB and pulmonary TB were defined as follows: (1) Identification of All patients had HIV test in our hospital by macro-eliza method . None of the patients had HIV co-infection. Descriptive statistics  and Chi-square test were used.We identified 2,435 EPTB cases (17.1%) from the 14,266 TB patients who presented to our center during the study period. TB cases included 10,112 (71%) male and 4,154 (29%) female patients aged between 14 and 86 years with a mean of 35 \u00b1 14 years. Table 1The distribution of age and gender in tuberculosis by timeP < 0.001), while pleural disease was significantly higher in men (P < 0.001). EPTB showed a significant female predilection (26.8% vs. 13.1%) (P < 0.001).The most common site of extrapulmonary involvement was the pleura, followed by the lymph nodes. Of the 1,637 (67%) patients with pleural disease, 664 (41%) were female. Of the 567 (23%) patients with lymphadenitis, 342 (60%) were females. Lymph node involvement occurred with significantly higher frequency in women .[Many studies predicted that mostly pleura and regional lymph nodes are likely to be involved. Gonzalez  reported 538 EPTB (31.1%).A study from England showed that lymph node involvement was the most common site in the body. However,vs. 13.1%). In our cases, male-to-female ratio was 71% and 29% respectively. This ratio is consistent with the literature. Gonzalez et al. indicated that EPTB had been more commonly observed in females  as compared to males  in Houston.[et al.[et al. showed that the most common sites in abdomen were small bowel (48%), followed by peritoneum (35%) and lymph nodes (17%).[In our study, EPTB was more common in females than in males . In our sTB of the genitourinary tract was reported as the second most common disease form of extrapulmonary TB. The mostIn this study, we found that 1.5% of EPTB patients had multi-organ involvement. During the primary infection of TB, bacteria can spread to all organs in the body. Therefore, EPTB can be observed in different organs at the same time.In this study, we found one in every five TB patients had extrapulmonary TB. We also found the EPTB was two times more common in females than in males. Clinical signs; laboratory, radiological and endoscopic methods; or bacteriological and histopathological findings help in the diagnosis of EPTB, although laboratory methods might at times be challenging for EPTB compared to pulmonary TB. So clinical suspicion based on chest radiography, localized or systemic symptoms and several laboratory parameters and rapid diagnostic methods expedite the treatment of such cases."}
+{"text": "Abnormal CA 15-3 antigen levels are found in the serum of most patients with advanced breast carcinoma. Elevations of this marker are less frequently seen in other malignancies. Circulating CA 15-3 levels might be useful in the differential diagnosis of the primary site of cancer. We studied the levels of CA 15-3 in 500 patients with different non-mammary cancers. Elevations of CA 15-3 (greater than 40 U ml-1) were observed in all types of epithelial malignancies, especially in ovarian (46%), respiratory (26%) and liver (30%) carcinomas. Abnormal values were observed in some patients with haematological malignancies and sarcomas, but not in melanoma or neurological tumours. CA 15-3 antigen levels correlated with the extent of non-mammary malignant tumours. Patients with locoregional cancer had a significantly smaller proportion of elevations of the antigen than those with distant metastases . In particular, elevated CA 15-3 levels were observed in 70% of patients with metastatic ovarian cancer. Liver involvement by cancer did not produce more elevations of CA 15-3 than metastases to other organs (32% versus 39%). Simultaneous determination of circulating CA 15-3 and CA 125 antigens in 58 patients with cancer of the ovary showed that CA 15-3 is elevated in some cases of ovarian carcinoma with non-elevated CA 125, and that CA 15-3 and CA 125 are distinct antigens. We conclude that circulating CA 15-3 antigen levels can be found elevated in virtually all types of cancer, particularly when distant metastases are present. Therefore, CA 15-3 levels should not be used in the differential diagnosis of the primary site in patients with metastatic malignancies of unknown origin. Evaluation of CA 15-3 levels may enhance the sensitivity of CA 125 in monitoring the course of ovarian carcinoma."}
+{"text": "P=0.31 for difference). Human papillomavirus was detected in 84% (78 out of 93) of patients. In univariate analysis, 80% (12 out of 15) of lesions without HPV regressed compared to 46% (36 out of 78) of lesions with HPV infection (P=0.016). Women without HPV and those who had a resolution of HPV had a four-fold higher chance of regression than those with persistent HPV . Women with five or fewer lifetime sexual partners had higher rates of regression than women with more than five partners (P=0.003). In multivariate analysis, HPV status and number of sexual partners remained as significant independent predictors of regression. In conclusion, HPV status and number of lifetime sexual partners were strongly predictive of regression of untreated CIN 2 and 3.The aim of this paper was to evaluate the factors that predict regression of untreated CIN 2 and 3. A total of 93 patients with colposcopic persistent CIN 2 and 3 lesions after biopsy were followed for 6 months. Human papillomavirus (HPV) types were determined by polymerase chain reaction at enrolment. We analysed the biologic and demographic predictors of natural regression using univariate and multivariate methods. The overall regression rate was 52% (48 out of 93), including 58% (22 out of 38) of CIN 2 and 47% (26 out of 55) of CIN 3 lesions ( Cervical cancer continues to be the most deadly female cancer in developing countries.  infection has been established as the critical step in the development of most cervical cancers . The cerThe aetiology and risk factors involved with cervical carcinogenesis are amenable to study as invasive cervical cancer typically arises after many years from a morphologically defined precancerous lesion. However, since untreated high-grade lesions can progress to invasive cancer, most women with CIN 2 or 3 are treated promptly. Accordingly, there are few reports on the natural history of high-grade dysplasia. On the other hand, not all CIN lesions progress to invasive cancer. In fact, spontaneous regression of moderate dysplasia has been reported in up to 54% of women . Since mWe evaluated the predictors for natural regression of untreated CIN 2 and 3 such as age, race, parity, smoking history, oral contraceptive (OCP) use, marital status, lesion grade, sexual history, and HPV status on all our patients.\u03b2-carotene in the management of women with untreated CIN 2 or 3. Predictors for natural regression, which included age, race, parity, smoking history, OCP use, marital status, lesion grade, sexual history, and HPV status were prospectively analysed. Patients were recruited from the University of California, Irvine, Medical Center, nearby clinics, and colleges. Women greater than 17 years of age with biopsy-proven CIN 2 and 3 were screened. Eligible patients had colposcopic persistence of CIN 2 or 3 one month after initial biopsy and had a negative endocervical curettage. Two pathologists agreed on the cervical histologic diagnosis before enrolment. Based on the guidelines of the Institutional Review Board at University of California, Irvine, written consents were obtained from all patients.We performed an ancillary study to a prospective, double-blinded, randomized, placebo-controlled trial of \u03b2-carotene and placebo arms at the end of the study  method was used to determine HPV genotype as described (\u03c72) and multivariate (logistic regression) analyses performed with Statistical Analysis Systems. All P-values reported are two-tailed.We analysed the age, race, parity, smoking history, OCP use, marital status, lesion grade, sexual history, and HPV status on all our patients. We assessed the impact of various epidemiological risk factors on regression of CIN in all our patients using univariate  patients completed our ancillary study and underwent a 6-month cervical biopsy. The 10 excluded patients did not have a documented persistence of CIN 2 or 3 after initial biopsy. The median age of our patients was 29 years (range 19\u201355). The majority (59%) presented with CIN 3 lesions and 41% had CIN 2 disease. Approximately one-half (46/93) were Hispanic and the others were either Caucasian (n=45) or Asian (n=2). Fifty (54%) women were married or have been married in the past. Twenty-four (26%) women have completed high school or college. The median parity was one. Forty-two (45%) women had a history of OCP use. Twenty-eight (30%) patients were smokers and nine of these women were smoking more than one pack per day. Of the 75 women who completed the sexual history interview, 54 (72%) women had their first sexual intercourse at 18 years or younger (range: 11\u201330) with a median of two lifetime sexual partners (range: 1\u201325). At enrolment, HPV infection was detected in 84% (78 out of 93) of women and most patients had HPV types that were considered high risk for progressing to cancer. The HPV types at baseline included HPV type 16 (42%), type 33 (12%), type 18 (9%), type 31 (8%), type 52 (3%), type 53 (3%), type 35 (1%), type 39 (1%), and mixed/others (22%). Types 16, 18, and 33 were the most prevalent HPV types and 11 patients were infected with multiple HPV types.From 1992 to 1996, 982 patients were screened for our study. We enrolled 124 women into our trial of whom 111 were eligible to be randomized to P=0.31 for difference between grades). Interestingly, 80% (12 out of 15) of lesions without detectable levels of HPV regressed compared to only 46% (36 out of 78) of those infected with HPV (P=0.016). Of the 78 patients who initially tested positive for HPV, 24% (19 out of 78) subsequently developed undetectable levels of HPV. Of the patients who had a resolution of their HPV infection, 63% (12 out of 19) showed regression of their disease compared to a regression rate of only 41% (24 out of 59) in those who had a persistence of their viral infection. After the study, the population was divided into two groups based on the number of lifetime sexual partners: less than or equal to five and more than five. There was a significant inverse relationship (P=0.003) between number of sexual partners and probability of CIN regression , including 58% (22 out of 38) of CIN 2 lesions and 47% (26 out of 55) of CIN 3 lesions (P=0.005), less than or equal to five sexual partners (P=0.003), and Hispanic race (P=0.05) were all significant predictors for regression of high-grade dysplasia. Age, parity, smoking history, OCP use, marital status, lesion grade, and age at first intercourse were not significantly associated with CIN regression (Table 2\u03b2-carotene vs placebo) in the multivariate model did not change the estimates of risk of regression associated with HPV infection or number of sexual partners.In univariate analyses, we found that absence of persistent HPV infection (gression . To furtOver the last 30 years, it has been widely accepted that CIN 1, 2, and 3 represent a continuum in the development of invasive cervical cancer . The bioAfter all 93 patients were analysed in our study, we found that the regression rate of CIN 2 and 3 without conventional therapy was unexpectedly high at 52%. Regression included 58% of CIN 2 lesions and 47% of CIN 3 lesions. In contrast, The presence of cervical HPV DNA often is associated with cytologic and histologic changes of CIN. Indeed, up to 90% of women with CIN are HPV DNA positive depending on the diagnostic method used . In our The role of HPV infection provides only a partial explanation for the high rate of spontaneous regression in our patient population. Sexual risk factors also have been recognised as causative determinants for CIN and cervical cancer. In our study, we found an inverse relationship between the number of sexual partners and CIN regression. Multivariate analyses of our study population showed that the effects of sexual risk factors persist even after controlling for HPV infections; suggesting that the presence of other sexually transmitted disease may also play a role in the natural history of CIN 2 or 3.Our data propose that there may be selected patients with CIN who could be followed for short term in anticipation of spontaneous regression; this group includes those with no evidence of an HPV infection and low sexual risk factors. Indeed, the ASCUS-LSIL Triage Study reached this conclusion for patients with ASCUS Pap smears in whom HPV is not present ("}
+{"text": "Forty-two patients with small cell lung cancer were treated with a combination of carboplatin, ifosfamide and etoposide. Vincristine was given on day 14 of each course, the courses being repeated every 28 days for a maximum of six. Thoracic radiotherapy was given 4 weeks after the last course of chemotherapy but no prophylactic cranial radiotherapy was administered. Thirty patients had clinically limited state disease, the remaining patients having contralateral neck lymphadenopathy and/or pleural effusions. Elevated enzyme levels  were noted in 69% of patients. Twenty-four patients (57%) achieved a complete response (CR) when assessed one month after the end of treatment. A further 21% of patients had a partial response (PR). Median duration of CR was 14 months and of PR 8 months. Cerebral metastases were the sole site of relapse in 13% of the CR patients. Myelosuppression was severe with a median nadir of neutropenia of 0.2 x 10(9) cells 1-1. However, 74% of the patient group received all six courses of chemotherapy and only 16 courses (7%) were delayed because of toxicity. There were three deaths associated with treatment-related neutropenia. The median survival of the total group was 14 months, with an actuarial 2 year survival of 37% and a minimum follow-up of 18 months."}
+{"text": "Carcinomas of the exocrine pancreas respond poorly to most chemotherapy regimens. Recently continuous infusional 5-fluorouracil (200 mg m-(2)day-1) with 3 weekly cisplatin (60 mg m-2) and epirubicin (50 mg m-2) (the ECF regimen) has proven to be an active regimen in gastric and breast cancer and consequently worthy of further study in pancreatic cancer. Thirty-five patients were treated with the ECF regimen as above, of whom 29 were evaluable for response and 32 were evaluable for toxicity. The mean age was 59 years (range 37-75). Sixteen patients had locally advanced disease at presentation and 19 had metastases. Objective tumour responses were documented in five (17.3%) patients who achieved a partial response; in 18 (62%) patients there were no change and six (20.7%) patients progressed on therapy. Patients with either stable disease or partial response had a significantly improved overall survival (median = 253 days) compared with patients who progressed . Grade 3/4 (WHO) toxicity  included alopecia in 18 (56%) patients, nausea/vomiting in eight (25%) stomatitis in three (9%) and diarrhoea in seven (22%) patients, with rhinorrhoea and excessive lacrimation in one patient each. Neutropenic sepsis occurred in 13 cycles in ten patients, and there was one toxic death due to sepsis. There were eight other episodes of non-neutropenic sepsis requiring hospital admission. Fourteen patients (40%) experienced complications with their Hickman lines, including thrombotic episodes (six patients) or their line falling out (five patients). ECF can prolong survival in patients with locally advanced or metastatic pancreatic cancer who demonstrate a response or stabilisation of their disease. However, this is associated with considerable toxicity."}
+{"text": "In conjunction with rehydration, the bisphosphonates are the treatment of choice for hypercalcaemia of malignancy. Single infusions of either pamidronate or clodronate are usually effective, but a direct comparison of the two agents given at the highest doses commonly used has not been performed. Forty-one patients  with hypercalcaemia of malignancy  persisting after 48 h of saline rehydration were randomly allocated to receive a 4 h intravenous (i.v.) infusion of either pamidronate 90 mg or clodronate 1500 mg. No other systemic anti-cancer treatment was prescribed. There were no significant differences in the post-hydration serum calcium values (mean 3.17 mmol l-1 for pamidronate and 3.06 mmol l-1 for clodronate), tumour type or frequency of bone metastases between the two treatments. One patient on each treatment died within 2 days and was not assessable for response. A total of 19/19 (100%) patients achieved normocalcaemia following pamidronate and 16/20 (80%) with clodronate. The median time to achieve normocalcaemia was 4 days (range 2-14) for pamidronate and 3 days (range 2-6) with clodronate. The median duration of normocalcaemia was 28 days (range 10-28+ days) after pamidronate and 14 days after clodronate (range 7-21 days) (P < 0.01). Two patients who failed to respond to clodronate were successfully treated with pamidronate and achieved normocalcaemia for 14 and > 28 days respectively. Two patients experienced fever after pamidronate but no significant toxicity was observed with either treatment. We conclude that both agents are effective in the management of hypercalcaemia of malignancy. At the doses studied, the effects of pamidronate are more complete and longer lasting than those of clodronate."}
+{"text": "To the Editor: Identified in 1935 by Lancefield and Hare, group G streptococci (GGS) are part of the normal flora of the pharynx, gastrointestinal tract, genital tract, and skin , methicillin-resistant S. aureus (MRSA) (9 [12%]), and gram-negative or anaerobic organisms (13 [18%]).A total of 73 persons with GGS were admitted to the hospital during the 5-year study period; the number of patients admitted increased yearly . Mean agThe spectrum of GGS infections ranged from mild skin and soft tissue infection (34 [46%]) to invasive diseases, including urogenital infection (7 [10%]); lower respiratory tract infection (7 [10%]); pharyngitis (6 [8%]); endocarditis and catheter infection (5 [7%]); and others (14 [19%]), such as peritonitis, pelvic abscess, rectal abscess, and septic arthritis. Four of the 6 persons with pharyngitis were assumed to be colonized with the organism. Eight (24%) of 34 skin and soft tissue infections were associated with bacteremia, 5 (15%) with osteomyelitis, and 20 (59%) with polymicrobial infections. Six persons with lower respiratory tract infections and 1 each with endocarditis, genital tract infection, pelvic abscess, and dental abscess also had polymicrobial infections.Eighteen persons had bacteremia, the trend of which also increased yearly. Of these, 8 had skin and soft tissue infections, 4 had endocarditis, 2 had urinary tract infections, 1 had possible spontaneous bacteria peritonitis, and 1 had hemodialysis catheter infection; 2 were of unknown source. Of the patients with endocarditis, 2 had vegetations on the native valves, 1 had a pacemaker infection, and 1 had prosthetic valve vegetation. One case of native valve endocarditis occurred in a tricuspid valve in an injection drug user. Another case occurred in a patient in which an epidural abscess was associated with an aortic valve vegetation.Most of the patients had underlying medical conditions; 34% had diabetes mellitus. In contrast to previous reports, which stated that malignancy was the most common underlying disease (Three (4%) patients died; their deaths were unlikely to be attributable to GGS because all were elderly (78\u201392 years) and had underlying coexisting conditions and co-infections. All 4 persons with endocarditis and the patient with the catheter infection survived. Five patients who were co-infected with MRSA were treated with vancomycin or daptomycin; the remainder were treated with \u03b2-lactam antimicrobial drugs and had the sources of infection (catheter or pacemaker) removed. When infections caused by gram-negative or anaerobe organisms were identified, they were also treated with appropriate antimicrobial drugs. The overall average length of stay for all patients with GGS was 9.4 days, with longer stays for those with underlying diabetes mellitus (14.6 days) than for those without diabetes (6.7 days).GGS was an important etiologic agent for a wide spectrum of infections. Its impressive increase in our institution during the past 5 years raises concerns because other types of \u03b2-hemolytic streptococcal infection have increased recently. Group A and B ("}
+{"text": "Lymphocyte sensitivity to encephalitogenic factor (EF) was measured with the macrophage migration inhibition (MMI) test in 60 women with dysplasia or carcinoma in situ of the cervix, in 10 women with invasive cervical carcinoma, and in 20 women with a variety of benign gynaecological conditions. Significant migration inhibition with EF (P less than 0.01) was seen with lymphocytes taken from 7/13 (54%) women with mild and/or moderate dysplasia, from 22/47 (47%) women with severe dysplasia and/or carcinoma in situ, from 6/10 (60%) women with invasive cervical carcinoma and from 3/20 (15%) women with benign gynaecological conditions. Autologous serum was seen to abrogate EF-mediated migration inhibition in 3/4 sensitized women with mild and/or moderate dysplasia, in 5/7 sensitized women with severe dysplasia and/or csrcinoma in situ and in 2/3 sensitized women with invasive cervical carcinoma. Autologous serum from 2 sensitized women with benign gynaecological conditions did not abrogate the response of their lymphocytes to EF."}
+{"text": "Between January 1984 and December 1999, 467 (341 non-relapsed and 126 metastatic) breast cancer patients were followed-up postoperatively. Among the 126 metastatic patients 36 showed thoracic (19 patients) or liver (17 patients) metastases, alone or in conjunction with other organs as the first evidence of distant spread. We focused on this series of 377 patients including 341 non-relapsed plus 36 with liver or thoracic metastases. The patients were followed-up after mastectomy with serial determinations of a panel of CEA-TPA-CA15.3 tumour markers, bone scintigraphy, CXR and LE. Up to December 1999, equivocal CXR occurred in 23 (6.1%) patients of whom 11 (47.8%) developed thoracic metastases; 14 (3.7%) patients showed an equivocal LE of whom 5 developed liver metastases. In the 37 patients with equivocal CXR or equivocal LE prolonged clinical and imaging follow-up over 41 \u00b1 36 months  was used to ascertain the presence or absence of thoracic or liver metastases. In the 23 patients with equivocal CXR the negative and positive predictive values of the tumour marker panel to predict thoracic metastases were 92% and 100% respectively. In the 14 patients with equivocal LE the negative and positive predictive values of the tumour marker panel for prediction of liver metastases were 90% and 100% respectively. This study shows that in breast cancer patients the CEA-TPA-CA15.3 tumour marker panel has a high value for selecting those patients at high risk of developing clinically evident pulmonary or liver metastases from amongst those subjects with equivocal CXR or equivocal LE. \u00a9 2000 Cancer Research Campaign"}
+{"text": "The development of effective strategies against cervical cancer in Africa requires accurate type specific data on human papillomavirus (HPV) prevalence, including determination of DNA sequences in order to maximise local vaccine efficacy. We have investigated cervical HPV infection and squamous intraepithelial lesions (SIL) in an unselected cohort of 1061 women in a rural Gambian community. Squamous intraepithelial lesions was diagnosed using cytology and histology, HPV was typed by PCR-ELISA of DNA extracts, which were also DNA sequenced. The prevalence of cervical HPV infection was 13% and SIL were observed in 7% of subjects. Human papillomavirus-16 was most prevalent and most strongly associated with SIL. Also common were HPV-18, -33, -58 and, notably, -35. Human papillomavirus DNA sequencing revealed HPV-16 samples to be exclusively African type 1 (Af1). Subjects of the Wolof ethnic group had a lower prevalence of HPV infection while subjects aged 25\u201344 years had a higher prevalence of cervical precancer than older or younger subjects. This first report of HPV prevalence in an unselected, unscreened rural population confirms high rates of SIL and HPV infection in West Africa. This study has implications for the vaccination of Gambian and other African populations in the prevention of cervical cancer. It is well established, on a cellular and epidemiological basis, that the sexual transmission of high oncogenic risk (HR) human papillomavirus (HPV) types is the essential prerequisite for cervical carcinogenesis . ConsequSamples were collected during a large reproductive morbidity survey in rural Gambia between January and July 1999 as described elsewhere  or knife cone biopsy. Histology and cytology results were subjected to clinical review to decide on a final diagnosis viz low- or high-grade squamous intraepithelial lesions (LSIL or HSIL) , microin\u03b2-globin gene in order to verify the presence of an adequate DNA sample and the absence of PCR inhibitors. The presence of HPV and \u03b2-globin DNA was visualised on an agarose gel. Human papillomavirus typing was preformed by enzyme linked immuno-sorbent assay (ELISA) using streptavidin coated microtitre plates to capture PCR product  (http://www.ncbi.nlm.nih.gov/BLAST/) search was carried out for each of the consensus strands produced by sequencing at least twice in each direction. Alignment analysis was carried out using the Lasergene suit of software . The sequences most homologous to the Gambia samples are listed in Samples that could not be identified by ELISA were characterised by DNA sequencing. Selected HPV positive samples were also sequenced to confirm typing accuracy and to detect any relevant sequence variations in known HPV types. Sequencing was carried out on a Beckman Coulter CEQ2000 Automated Sequencer, using protocols and reagents supplied by the manufacturer. Human papillomavirus DNA sequencing utilised the MY09/MY11 consensus primer pair as the product of these (\u2248455\u2009bp) is a more suitable target for sequencing than that of GP5+/6+ (\u2248140\u2009bp). Furthermore, MY09/11 primers amplify a region containing highly conserved amino acids, which simplifies sequence alignment in HPV classification . Frequency distributions of HPV infection and different HPV types were calculated. Socio-demographic characteristics and other morbidities were examined as risk factors for HPV infection by cross tabulation and c groups . An adju\u03b2-globin human housekeeping gene was amplified in 710 out of 934 (76%) samples; consequently, only these samples were suitable for HPV analysis. The \u03b2-globin negative samples may have been incorrectly stored or damaged during transfer to the UK, prevalence figures are therefore based upon the 710 \u03b2-globin positive samples. Of the three main ethnic groups, Wolof women were slightly under-represented (38.7% of eligible population vs 32.1% of those with adequate cytology and 34.1% of those with adequate HPV samples) and Mandinka women were slightly over-represented (43.9% of eligible population vs 49.5% of those with adequate cytology and 46.2% of those with adequate HPV samples). Younger women aged 15\u201324 years were under-represented .Of 1871 eligible women, 1348 (72%) participated in the study  and 1061Human papillomavirus infection was present in 95 of 710 adequate samples ). Adjusting HPV prevalence for under-representation of Wolof subjects reduced prevalence slightly to 13.0%. Human papillomavirus typing by PCR-ELISA was successful in 84 samples revealing 6 different LR and 13 different HR types . Dual ceHuman papillomavirus DNA was amplified with the GP5+/6+ primers in 11 samples but were negative by ELISA, and therefore contained HPV types not included in the probe cocktails. These samples were sequenced with the MY 09/11 primers; five had either degenerated in storage or would not amplify, two contained multiple templates and were impossible to sequence, while four were successfully sequenced and identified but none were infected with novel types, merely types not included in the ELISA probe cocktail .DNA sequencing was conducted on samples successfully identified by ELISA as HPV types associated with HSIL. All HPV-16 samples sequenced showed DNA homology in the amplified region with a variant of HPV-16 African type 1  . Both HPn=22; 16 confirmed by histology), LSIL were found in 3.3%  and atypical squamous cells of uncertain significance (ASCUS) in 1.1% (n=10). A single case of invasive cervical cancer was diagnosed by clinical and cytological criteria but the woman sadly died before the histology could be confirmed; it was included in the HSIL analysis.The overall crude prevalence of cervical precancer was 6.7% (63/946 adequate smears (95% CI: 5.2\u20138.4%)), or 6.5% after adjusting for the under-representation of Wolof women Cytological abnormalities were confirmed by histology in 55.6% (35/63) of cases with HSIL present in 2.3% (\u03c72P=0.03) and cervical HPV infection. Rates of SIL were highest at ages 25\u201334 years (22 out of 265 (8%)) and 35\u201344 years (24/268 (9%)), intermediate at ages 45\u201354 (9/150 (6%)) and lowest at ages 15\u201324 (8/263 (3%)). In subjects where both adequate cytology/histology and HPV analysis were available, 574/612 (93%) had normal cytology, 38 out of 612 (6%) had SIL and seven out of 612 (1%) had ASCUS. Of the subjects with normal cytology 525/574 (91%) were negative for HPV while in those with SIL/ASCUS 20/38 (53%) had HR HPV types. Of subjects with HSIL, 13/15 (87%) had HR HPV types, although the other two were negative for HPV. Among subjects with HSIL, HPV-16, HPV-33 and HPV-58 were most common, each found in 3/15 (20%). HPV-16 was found in the single invasive cancer case. HPV-18, -31, -35, -39 and -45 occurred once each among subjects with HSIL. Of 30 subjects with LSIL/ASCUS, seven were infected with HR HPV types; of subjects with normal cytology 66/576 (12%) had HPV infection.Risk factors for cervical precancer included age  . Moderatet al was urban  and the higher HPV prevalence may be explained by differing sexual behaviour as well as the much higher prevalence of LR HPV types in the Nigerian study than in our study.This first unselected study of cervical HPV and SIL in an unscreened, rural West-African population of its kind shows HPV infection to be common at 13.4% (adjusted=13.0%) with the majority HR types. Although younger subjects were under-represented, such an age profile is comparable with other studies. The high cervical HPV infection prevalence and SIL are in agreement with Gambian Cancer Registry data  in this study and meta-analysis of worldwide HPV prevalence studies shows low overall prevalence of HPV-35 (\u22482%), even in Africa . No HPV samples in this study were found to be novel types after identification by sequencing, although some were unusual subtypes or variants . The DNAHistologically confirmed cervical neoplasia prevalence in our study was 6.7% (adjusted=6.5%). Diagnostic accuracy was improved by classifying subjects with abnormal cytology but normal histology as \u2018normal cervix\u2019. The prevalence of abnormal cytology alone was slightly higher at 7.4% (70/946 adequate smears). Other investigators have used a cytological screening to identify cervical disease providing a less accurate prevalence of SIL (In this study, HPV infection was not associated with age, parity or concurrent STI. The even distribution of HPV prevalence at different ages is unusual though observed in other developing countries such as India  and ArgeThe ideal treatment strategy for this rural Gambian population would involve the use of a prophylactic vaccine to prevent cellular viral entry. Current prophylactic vaccine formulations require three needle injections, cold storage and offer only type specific protection (The ethnic groups in our study population have not previously been studied using these methods. Other studies in African populations using the same methods to those used in our study ("}
+{"text": "Thyroid cancer may have a familial predisposition but a specific germline alteration responsible for the disease has not been discovered yet. We have shown that familial papillary thyroid cancer (FPTC) patients have an imbalance in telomere-telomerase complex with short telomeres and increased telomerase activity. A germline mutation (A339V) in thyroid transcription factor-1 has been described in patients with multinodular goiter and papillary thyroid cancer. In this report, the presence of the A339V mutation and the telomere length has been studied in FPTC patients and unaffected family members. All samples analyzed displayed a pattern typical of the homozygous wild type revealing the absence of the A339V mutation. Shortening of telomeres was confirmed in all patients. We concluded that the A339V mutation in thyroid transcription factor-1 (TITF-1/NKX2.1) is not correlated with the familial form of PTC, even when the tumor was in the context of multinodular goiter. Familial non-medullary thyroid cancer (FNMTC), most frequently of papillary hystotype (FPTC), recurs in two or more members of the same family in about 10% of the patients. The clinical form of PTC may be part of a clinical syndrome such as the Adenomatous polyposis of colon (FAP) , GardnerIn light of these evidences, we investigated the presence of A339V mutation in patients with the occurrence of FPTC and short telomeres. Out of 408 patients affected by differentiated thyroid carcinoma (DTC), followed in the Section of Endocrinology of University of Siena  from 1978 to 2009 , 63 patients (15.4%), belonging to 38 kindred, showed the familial recurrence of the disease possibly configuring the features of familial thyroid cancer (FTC). All patients with FTC had the papillary hystotype (FPTC), 15 of them (23.8%) presented the follicular variant and 1 (1.6%) the warthin-like variant. Of these patients, 40 (63.4%) had a parent-child relationship (22 kindred), 19 (30.2%) had a sibling relationship (13 kindred) and 4 (6.4%) had an uncle-niece relationship (3 kindred). Age at diagnosis of FPTC group was 46 \u00b1 15.5 yrs (range: 15-78 yrs). Age at diagnosis of probands was 54.3 \u00b1 9.3 (range 25-77 yrs) and that of affected familial members was 42.9 \u00b1 15.7 (range 15-73 yrs). No thyroid cancer associated syndrome was present clinically in our patients. Clinical features of FPTC patients are reported in Table In conclusions, in this study we analyzed 63 FPTC patients for the presence of the A339V mutation in thyroid transcription factor-1 (TITF-1/NKX2.1) in order to correlate that mutation with the predisposition to develop familial form of thyroid cancer demonstrated by shorter telomere length which may contribute to genetic instability and thyroid cancer development. Our results confirmed that FPTC patients have significantly short telomeres compared to unaffected family members. The reason of the predisposition to develop thyroid cancer in patients displaying the imbalance in telomerase complex has not been identified yet. The A339V mutation in thyroid transcription factor-1 (TITF-1/NKX2.1) might be a candidate gene in view of recent findings [The authors declare that they have no competing interests.SC carried out the molecular genetic studies and wrote the manuscript, SC contributed to perform the experiments, CF helped to collect clinical patient's data, MP helped with DNA extraction, MC revised the clinical data and FP revised the manuscript and coordinated the experiments.All authors read and approved the final manuscript."}
+{"text": "Survival in squamous cell carcinoma of the head and neck (HNSCC) was compared with overexpression and mutation of the p53 gene. Archival tissue from 77 tumours was analysed for protein expression using immunohistochemistry (IHC) with the monoclonal antibody Do-7, and for the presence of mutation in exons 5-8 using single-stranded conformation polymorphism (SSCP), followed by DNA sequencing in SSCP-positive cases. p53 expression was scored as high (>70% nuclei stained) in 25 (32%) tumours, as intermediate (10-70% nuclei stained) in 19 (25%) tumours and as low (<10% nuclei stained) in 33 (43%) tumours. Twelve (18%) tumours exhibited gene mutation (ten missense and two nonsense mutations) and an additional five tumours contained changes that could not result in amino acid substitution or protein truncation. There was no correlation between gene expression and mutation, mutations being equally frequent in tumours with either high (4/25), intermediate (4/19) or low protein expression (4/33). Fifty-eight patients were eligible for survival analysis. There was a strong correlation between p53 mutation and cause-specific survival; median survival among mutated cases was 12.5 months compared with >160 months among non-mutated patients (P < 0.005). There was no correlation between p53 overexpression and survival. The results suggest that p53 mutation status is an important prognostic factor in HNSCC, and that IHC analysis of protein overexpression is an inadequate measure of gene mutation in these tumours."}
+{"text": "STXBP1) encephalopathy.Researchers from the University of Antwerp, Belgium, and numerous international collaborators report a comprehensive overview of the phenotypic and genetic spectrum of Syntaxin-binding protein 1 ( STXBP1) encephalopathy. The article provides a phenotypic summary of 147 patients with STXBP1-E pathogenic variants, including 45 previously unreported patients with 33 novel STXBP1 variants. Researchers used statistical analysis to further classify variant type (missense vs truncating) and cognitive outcome  and cognitive outcome and seizure outcome (seizure-free vs not seizure-free). Age of inclusion criteria ranged 6 months to 56 years with a mean of 5.75 years. At the onset of seizures, 53% of patients were diagnosed with EOEE, 20% with Ohtahara Syndrome (most with evolution to West Syndrome), 9% with West Syndrome, 6% with intellectual disability with non-syndromic epilepsy, and 2% with Dravet Syndrome. One additional patient was reported to have early myoclonic encephalopathy and one patient reported to have intellectual disability with two possible seizures.Researchers from the University of Antwerp, Belgium, and numerous international collaborators report a comprehensive overview of the phenotypic and genetic spectrum of Syntaxin-binding protein 1 , focal seizures (57.9%), and tonic seizures (41.3%). Seizure freedom was attained in 1 in 3 patients while 1 in 3 remain therapy resistant. Intellectual disability was found in all patients, with 88% of these patients classified in the severe to profound range. Greater than 60% of patients had focal or multi-focal epileptic activity on EEG. Other common EEG findings were burst suppression (35%) and hypsarhythmia (40%). Behavioral problems associated with Autism or autistic features was seen in 1 in 5 patients. Other common phenotypic symptoms include axial hypotonia, ataxia or ataxic gait, tremor, spasticity and dyskinesia, or dystonia. MRI findings were normal in almost half, with abnormal findings consistent with cerebral atrophy (33%), thinning of the corpus callosum (16%), or hypomyelination (16%).Regarding epilepsy associated with STXBP1 should furthermore be classified as a complex neurodevelopmental disorder vs primary epileptic encephalopathy due to the high incidence of intellectual disability associated with STXBP1 with little correspondence to age of seizure onset or severity. [There was a higher incidence of severe to profound intellectual disability associated with missense variants 91%) compared to truncating variants (86%). Out of the 9 patients without epilepsy, 6 carried truncating variants and 3 carried missense. The authors noted that % compareSTXBP1 pathogenic variants. Although most patients with STXBP1-related disease present with epilepsy, others may have primarily movement disorders such as an ataxia-tremor-retardation syndrome [STXBP1 variants, autism spectrum disorder is rarely seen [COMMENTARY. This paper provides a comprehensive phenotypic and genetic analysis of individuals with syndrome . In somesyndrome ,3. AlthoThe authors have declared that no competing interests exist."}
+{"text": "The objective of this study was to classify the various types of odontogenic tumours (OTs) using the newly updated 2017 world health organization (WHO) histological typing and to analyze the prevalence of these tumours among Nigerians as well as to compare the results obtained with reports from world-wide studies.The records of four major tertiary hospitals in Nigeria were reviewed over a 12-year (2004-2015) period. Lesions diagnosed as odontogenic tumours were classified into four groups according to the 2017 WHO histological typing. Data which consisted of age, sex and site were analyzed using SPSS for Window  and frequency tables were computed.A total of 582 OTs were recorded and reviewed, benign OTs were 573 (98.5%) cases and malignant OTs were 9 (1.5%) cases. Of the benign OTs, the epithelial OTs were the commonest  while the benign mixed OTs were the least frequent . The mean age was 30\u00b114 years (age range of 3\u201377years) and the peak age was in the third decade  of life. There was slight male gender and strong mandibular site predilection. Ameloblastoma, was the most frequent OT and it accounted for 75.5% of the OTs, followed by adenomatoid odontogenic tumour (8.1%) and odontogenic myxoma (7.2%). Malignant OTs accounted for 1.5% of the OTs.OTs show a geographic variation with tendency for prevalence of the epithelial OTs in Africa. Ameloblastoma has a high prevalence among Nigerians and is the most common OTs in Africa. Prevalence of odontoma is relatively low in developing African countries like Nigeria when compared to the prevalence in developed countries. Key words:Odontogenic tumours, WHO classification, Nigerians. Odontogenic tumors (OTs) constitute a heterogeneous group of diseases arising from the tooth-forming tissues or their remnants . They poThe first internationally accepted classification system for OTs was published in 1971  by the WSeveral world-wide reports on OTs were based on the 1992 WHO histological classifications . ReportsAlthough many studies -9,12,14 A 12-year (2004-2015) retrospective review of OTs was carried out. Information from case files and histopathology records of patients with OTs were retrieved from 4 major tertiary hospitals in Nigeria . Information retrieved consisted of demographic data on age, sex, site, radiological presentation and definitive histological diagnosis. OTs were further re-classified according to the 2017 WHO histological typing. The benign OTs were categorized into three groups; group I (Odontogenic epithelium), group II (Odontogenic mesenchyme) and group III (Mixed odontogenic tumors) while the malignant OTs were categorized into Ameloblastic carcinoma, Primary intraosseous carcinoma and odontogenic sarcoma. Data was analyzed using SPSS for Window  frequency tables were computed.A total of 582 OTs were recorded over a 12-year period. Benign OTs accounted for 98.5% (573 cases) while malignant OTs (9 cases) accounted for 1.5% in this series. Of the benign OTs, the epithelial OTs (benign histologic group I) were the most frequently observed (500 cases) and accounted for 86%, while the benign mixed OTs (benign histologic group II) were the least frequently observed (21 cases) and accounted for 3.6%. Ameloblastoma which was the most frequently observed lesion accounted for 75.5% of OTs and 76.6% of benign OTs followed by adenomatoid odontogenic tumour (8.1% of OTs and 8.2% of benign OTs) Several studies -9,12,14 Ameloblastoma 75.5%) was the most common type of OT observed followed by AOT 8.1%) and odontogenic myxoma (7.2%). Nigerian studies .1% and o,12 based5.5% was et al.  is a relatively rare, locally invasive benign tumour of mesenchymal origin. It is reported to account for between 4.7\u201317.7% of OTs ,33,36,39Our series further confirms that malignant OTs are rare especially among Nigerians. Perusal of the scientific literature shows that previous African studies ,16 reporConclusionsOTs show a geographic variation with tendency for prevalence of the epithelial OTs in Africa. There was a slight male gender and strong mandibular site predilection for OTs among Nigerians. Ameloblastoma is the most common OTs in Nigerians and odontomas are rare among Africans but have been reported to occur more in Europe and America. Malignant tumours derived from odontogenic tissues rarely occur in Nigerians."}
+{"text": "The results showed that high risk- (HR) HPVs were detected in 37/189 (19.6%) PCa specimens compared to 16/167 (9.6%) of BHP specimens . These data suggest HR-HPV may play a role in PCa. HPV 52 and 58 were the most frequent genotypes  detected in the population studied. Koilocytes were detected in all in situ PCR-HPV-positive samples, representing a pathognomonic feature of infection, and we observed the overexpression of p16-INK4A in HPV-positive samples compared to HPV-negative samples, indirectly suggesting the presence of HR-HPV E7 oncoprotein. These results suggest that HPV infection plays an important role in prostate cancer development.The aim of this study was to evaluate the association between prostate cancer (PCa) and Human papillomavirus (HPV) infection in the Mexican population. We studied 356 paraffin-embedded tissues from unrelated Mexican men with PCa or benign prostatic hyperplasia (BPH), with the latter serving as control. HPV detection was performed by polymerase chain reaction (PCR) using universal primers, and viral genotypes were detected using sequencing or multiplex PCR. Light microscopy analyses enabled the identification of koilocytes in samples subsequently analyzed for HPV detection by  Prostate cancer (PCa) is the second most common cancer and the fifth leading cause of death from cancer in men (Human papillomavirus (HPV) infection is one of the most common sexually transmitted infections (STIs) worldwide .HPV infection is also one of the causes of intraprostatic inflammation, and there is evidence showing that chronic inflammation is involved in the regulation of cellular events in prostate carcinogenesis  tissue samples, and the case group comprised 189 tissue samples from men diagnosed with PCa, which was confirmed by histological analysis. The Institutional Human Research Ethical Committee approved the protocol.DNA was extracted from paraffin-embedded tissue samples using the DNeasy Blood and Tissue Kit  according to the manufacturer\u2019s protocol. DNA concentrations were spectrophotometrically determined at 260 nm. The integrity of the DNA samples was assessed by electrophoresis in 1% agarose gels, with the human beta-globin gene being amplified by polymerase chain reaction (PCR) as internal control. HPV detection was performed using consensus primers to amplify part of the L1 gene HPV region, following the previously demonstrated efficacy of PCR amplification from a variety of genital HPV types (All HPV-positive tissue samples were stained with hematoxylin and eosin (HE). Briefly, the tissues were incubated with Harris\u2019 hematoxylin for 15 min and subsequently washed with distilled water, followed by acid alcohol, running water, and 2% sodium bicarbonate. Subsequently, the samples were fixed in 80% ethanol for 2 min, placed in alcoholic eosin solution for 10 min, and then the samples were decolorized with 90% ethanol to remove excess dye. Finally, the samples were analyzed using a light field optical microscope at 20\u00d7 magnification.in situ PCR was performed using E6/E7 specific primers, as previously described . The amplification of DNA was accomplished using a hot start method with two consensus sequence primer pairs within E6 and E7 of high-risk HPV (pU-1M and pU-2R primers) . The cycling conditions were 2 min at 94 \u00baC and 18 cycles of 94 \u00baC for 1 min, 60 \u00baC for 1 min and 72 \u00baC for 1 min. Clips and AmpliCover discs were removed and the slides were washed in PBS, followed by 5 min in 100% EtOH prior to air drying.To identify the high-risk HPV (HR-HPV)  E6/E7 viral genes, ications . Brieflyications . NegativWe used an indirect immunolabeling method with a primary anti-digoxigenin antibody  conjugated to alkaline phosphatase to detect the PCR product. Briefly, blocking was performed in 5% BSA  in PBS for 30 min. The slides were subsequently drained and an anti-DIG antibody  was applied (100 mL per sample) for 2 h at room temperature. The detection of alkaline phosphatase was performed for 10 min using an NBT/BCIP kit (Roche). After detection, the slides were rinsed in distilled water for 5 min and counterstained with Fast Green. The slides were air-dried and subsequently mounted in Permount histological mounting medium .Images were obtained using a DFC290 HD digital camera . The image files were opened with PhotoImpact software  and digitally processed to obtain a more homogeneous signal.Sections of 5 \u03bcm in thickness were obtained from the paraffin blocks and mounted on electrocharged slides. Subsequently, the tissues were de-paraffinized and rehydrated as previously described , as a measure of the association between HPV infection and the risk of PCa.p=0.01).In this study, we examined the presence of HPV in paraffin-embedded tissue samples from unrelated Mexican men with PCa or BPH. Using three pairs of degenerate primers targeting the L1 late gene, HPV was detected in 14.9% (53/356) of all tissues analyzed, showing higher levels in tissues with PCa (37/189 or 19.6%) than in tissues with BPH (16/167 or 9.6%), suggesting that HPV infection could be a risk factor for PCa , which is much higher than the occurrence of the low-risk (LR) HPV genotypes at 19% (17% in the BPH group and 21% in the PCa group). The viral genotypes observed in the samples in order of decreasing prevalence were HPV 52 (33.3%), HPV 58 (17.17%), HPV 11 (12.7%), HPV 18 (10.8%), HPV 16 (7.8%), HPV 33 (6.9%), HPV 6 (5.9%), and HPV 31 (4.0%) . The detWith respect to HPV genotype distribution in the study groups, in HPV infections involving a single genotype, HPV 52 was the most common genotype found in both groups, while in HPV infections with multiple genotypes, the most common genotypes were HPV 58 and 52 for the PCa group, and HPV 52, followed by HPV 11 and 58, for the control group . The mosAdditionally, we identified koilocytes, cells containing an acentric, hyperchromatic nucleus displaced by a large perinuclear vacuole. Although the genesis of the cytoplasmic vacuole remained unclear, particularly because both HPV DNA replication and virion assembly exclusively occur in the nucleus, in clinical biopsies from cervical cells, koilocytosis is observed in both LR and HR HPV infections . MoreoveIn this study, we examined the presence of HPV in two study groups: a control group comprising BPH tissues and a case group comprising cancerous tissues. We found HPV in 53 (14.9%) of the 356 tissues analyzed, which is similar to the findings in other reports of tissue analysis from Latin America (18.63%)  development of diagnostic assays; (ii) evaluation of the impact of vaccination in cancer prevention strategies, especially since many HPV genotypes are not covered by the current quadrivalent HPV vaccine used in Mexico; and (iii) description of highly prevalent genitourinary tract HPV infections in sexually active men in M\u00e9xico (In conclusion, the high frequency of detection of HPV in PCa, combinations of genotypes with oncogenic potential that dominated in the PCa group, identification of HPV associated koilocytes, and overexpression of p16INK4A in prostate cancer specimens constitute evidence suggesting the association of HPV with PCa and a potential role for the virus in the etiology of PCa."}
+{"text": "Medication safety in cancer patients receiving complex medication regimens is an important problem in various settings. Medication related events, interceptions and interventions are not well described in this area. We intended to study incidence, types, settings and stages involved, root cause analysis, medication classes involved and the level of harm cause by medication errors in two hospitals providing oncology services comparatively. The severity of incidents and interventions are studied.It was a prospective cross sectional study among cancer in-patients of two tertiary care hospitals of KPK. Scale by NCC-MERP was used for evaluation of all medication related incidents. The data obtained was analyzed by IBM SPSS statistics 22 with 95% confidence interval and used the same for other descriptive statistics.All medication orders were reviewed at both sites (Computerized Prescription Order Entry and HWP systems). Potential ADEs incidence was found high at site 2 (97.5%) while medication errors without harm was high at site 1 (97.5%). Most events occur at prescribing level 87.6 and 81.7% at both sites 1 and 2. Types highly reported involved improper dose 31.4 and 15.5%, monitoring error 14.6 and 15.2% at site 1 and 2. Medications involved in these incidents were antibiotics 44 and 12.7%, antiemetic 7.5 and 15.8% and antineoplastic 2.9 and 9.4% at site 1 and 2. Severity of 3.6 and 36.5% incidents had potential to cause harm at site 1 and 2. Root causes were human factors 62.6 and 72.3%, drug selection 33.6 and 38.8%, and dose selection 39.6 and 15.3% at sites 1 and 2. Contributing factors including staff training 33.6 and 24.3%, system for covering patient care 14.9 and 36.6%, communication system 2.4 and 20.3%, interruptions 9.7 and 7.3% and others 78.8 and 68.6% were highly reported. Preventability of medication errors was 99% at both sites. Intervention was taken in 90.5% events at site 1 (CPOE system) while the incidence lowest at site 2 (HWP system).Medication related events are high among cancer in-patients at the site lacking updated electronic system for medication prescribing. Proper training about medication safety, reporting and interventions are required. Premium non nocere\u201d or \u201cfirst, do no harm\u201d is one of the main part of the oath the physicians take during practicing medicine. It is because of the complex and human nature of medicine management [According to the Latin phrase \u201cnagement . But onenagement \u20134. Thesenagement . Patientnagement  became anagement . The mednagement . MEs amonagement \u20139. The snagement .Attitudes like hiding errors or punitive approach causes difficulty in creating safe culture and patient safety among HCPs . A changCancer patients are more prone to medication errors like prescription errors with over dosage. Anti-neoplastic medicines have several toxic effects at their therapeutic doses as well because of the narrow therapeutic index, complex regimes and the vulnerability of cancer patients to potential harms , 11\u201313. In this study we tried to evaluate the incidence of medication errors among cancer inpatients along with humanistic and system related causes and contributing factors. The medication errors were evaluated according to the scale established by National Coordinating Center for Medication Errors Reporting and Preventions (NCC-MERP).The study was approved by the scientific committee of the institute and both hospital sites. The study design was cross-sectional and extended over the period of nine months at both sites. The medical records were directly observed by the principal investigator for all in-patients receiving chemotherapy.Both study sites were non-government health institutes. The pharmacy services at both institutes differed on the basis of system operation. Site 1 used highly upgraded software with computer order entry system (CPOE)/computer decisions supportsystem (CDSS). While at Site 2 all medication orders were handwritten by the oncologists. The medication orders were forwarded by nurses through software to in-patient pharmacies while dispensed by pharmacists.Medication orders were reviewed after prescription by the principle investigator. Data collection tool was designed by the criteria of NCC-MERP. While medication orders were reviewed with several approved medical guidelines and literature such as Medscape, British National Formulary (BNF), National Comprehensive Cancer Network (NCCN) guidelines and other drug indices which were followed at the settings., More than one type, stage, causes and contributing factors were included for a medication order where needed. Where a number of causes and contributing factors lead to the occurrence of incident, these were reported separately.Medication orders of in-patients (both adults and pediatrics) with breast, ovarian, prostrate, blood and gastric cancer receiving chemotherapy and/or supportive care medications were reviewed. Patients receiving radiotherapy or anti-neoplastic drugs for indications other than cancer were excluded. Patients visiting multiple times for chemotherapy were included again.We calculated the rate of incidents per 1000 medication orders. Mean with 95% confidence interval was obtained for the types, causes and contributing factors of incidents along with rate and a two-tailed significance via IBM SPSS statistics 22. Further descriptive analysis for the stages and medication classes involved in medication related events.n\u2009=\u20094852). A rate of 0.25 incidents per 1000 orders occurred.In this study, 75 charts (in CPOE system) with 2925 medication orders at site 1 and 76 charts (in HWP system) with 1657 medication orders at site 2 were reviewed. A total of 1195 incidents were found during review of all medication orders (P\u2009=\u20090.000) showed improper dose, 133 incidents  of potential problems with the lack of treatment effectiveness, 116 incidents  of wrong drug, 86 incidents  of monitoring errors including contraindications and drug interactions, 69 incidents  of wrong time or schedule of drug administration and 229 other types of incidents  such as not highlighting administration considerations in 33 incidents , wrong indication for drug in 61 incidents  and missing information about the drugs in 18 incidents  (Table\u00a0At site 1 (CPOE system) approximately 185 incidents  showed improper dose, 92 incidents  of monitoring errors including contraindications and drug interactions, 52 incidents  of wrong time or schedule of drug administration, 51 incidents  of no or improper labeling, 53 incidents  of potential problems with the lack of treatment effectiveness, and 345 other types of incidents  such as missing information about the drugs in 107 incidents , 68 incidents  of unnecessary medications including many others including product unavailability, medications without need and no entry in records (Table At site 2 (HWP system) approximately 94 incidents  which further includes performance deficit of staff in 137 incidents , Dosage and rate miscalculations in 108 incidents , transcribing error in 26 incidents  and confrontational behavior of the staff in 43 incidents . Other causes included lack of monitoring and cross checking practices in 61 incidents  and prescribing unnecessary medicines in 30 incidents  (Table\u00a0Among many causes leading towards incidence occurrence the highly reported cause/s at site 1 (CPOE system) were dose or dosage selection in 233 incidents , drug selection in 198 incidents , human factors in 369 incidents , human factors in 438 incidents  which further includes performance deficit of staff in 162 incidents , confrontational behavior of the staff in 135 incidents , transcribing error in 51 incidents . Among other causes the most common were lack of monitoring practices i.e. 155 incidents  (Table While at site 2 (HWP system) causes leading highly towards incidence occurrence were drug selection in 235 incidents , dose or dosage selection in 93 incidents , communication barriers caused 58 incidents , System covering patient care in 88 incidents , frequent interruptions in 57 incidents  along with other factors in 464 incidents . Other factors further included highest rate of prescribing practices in 261 incidents , lack of updated knowledge in 126 incidents  and staff attitude in 92 incidents  as factors which played role in the occurrence of incidents at different levels (Table\u00a0Among the contributing factors leading towards occurrence of incidents the highly reported factors at site1 (CPOE system) included staff training in 198 incidents , system covering patient care in 222 incidents , Communication system in 123 incidents , assignment of inexperienced personnel in 99 incidents , policies and procedures in 61 incidents  along with other factors in 416 incidents  which lead to the occurrence of these incidents. Among other factors prescribing practices in 248 incidents , staff attitude in 95 incidents , lack of interdisciplinary approach in 78 incidents , cross checking practice in 57 incidents  and lack of updated knowledge in 23 incidents  resulted in the occurrence of these incidents (Table At site 2 (HWP system) the presence of factors like staff training in 147 incidents  and 376 incidents  at site 2 (HWP system). Among no harm events the Category C events were highly reported at site 1 (CPOE system) with an occurrence of 334 incidents (56.7%) and Category D events were highly reported at site 2 (HWP system) with an occurrence of 189 incidents (31.2%).Patient outcome analysis according to the severity index (NCC-MERP) showed many incidents caused no harm at both sites with a figure of no harm events at site 1 (CPOE system) of 554 incidents  with an incidence of 221  and at site 1 (CPOE system) an incidence of 21 . The Category E events were reported highly at site 1 (CPOE system) with an occurrence of 21 incidents (3.6%) and 115 incidents (19%) at site 2 (HWP system). While occurrence of Category F events reported were 90 incidents (14.9%), and Category G events reported were 15 incidents (2.5%) only at site 2 (HWP system) (Table At site 1 (CPOE system) setting of initial incident showed greater incidence at the level of ward in 287 incidents 48.7%) and prescribers\u2019 office in 285 incidents (48.4%). Site 2 (HWP system) also showed greater incidence of setting of initial incident at the level of ward in 294 incidents (48.5%) and at prescribers\u2019 office in 269 incidents (44.4%) , pharmacist at incident rate of 39 (6.6%), nurse at incident rate of 25 4.3%), patient care giver at incident rate of 14 (2.4%) and others at incident rate of 2 (0.3%) at site 1 (CPOE system). At site 2 (HWP system) initial error showed higher occurrence at the level of physician at incident rate of 495 (81.7%), pharmacist at incident rate of 21 (3.5%) followed by nurse at incident rate of 75 (12.3%), patient care giver at incident rate of 5 (0.8%) and others at incident rate of 4 (0.7%)  at a rate of 482 incidents (81.8%) followed by physician at a rate of 48 incidents (8.1%), nursing at a rate of 15 incidents (2.6%) and others at a rate of 44 incidents (7.5%). At site 2 ((HWP system) the primary investigator among others  discovered and intercepted greater number of incidents at a rate of 536 incidents (86.9%) followed by nursing at a rate of 30 incidents (5%) and pharmacy at a rate of 14 incidents (2.3%) (Table The medication review process identified incidence rate of 574 (97.5%) medication errors without harm at site 1 (CPOE system) and 20 (3.3%) at site 2 (HWP system) among all reported incidents. The preventability analysis showed a rate of prevention of 582 incidents (98.8%) and 7 incidents (1.2%) were not preventable at site 1 (CPOE system). At site 2 (HWP system) 601 incidents (99.2%) showed preventability and 5 incidents (0.8%) were not preventable.Medical interventions were done and reported at site 1 (CPOE system) by all HCPs involved with an incidence rate of 533 incidents (90.5%) as compared to site 2 (HWP system) with an incidence rate of 48 incidents (8%) (Table The medication classes involved in the occurrence of medication related events reported at site 1 (CPOE system) highly reported antibiotics in 259 incidents (44%), analgesics and antipyretics (NSAIDs and Opiates) in 67 incidents (11.4%), and antiemetic in 44 incidents (7.5%) along with other classes including antihistamines, antineoplastic agents, anti-diabetic agents, coagulants and drugs acting on central nervous system. At site 2 (HWP system) the medication classes highly reported included antiemetic in 96 incidents (15.8%), antibiotics in 77 incidents (12.7%), dietary supplements in 72 incidents (11.9%), antineoplastic agents in 57 incidents (9.4%), analgesics and antipyretics (NSAIDs and Opiates) in 55 incidents (9.1%) along with other classes like replacement solutions, human albumin, coagulants and cathartics and laxatives  was also same as the patient profile was mostly incomplete lacking basic medical and/or medication information of the patient . Watts aOur study provided a detailed overview of severity of all medication related events including medication errors without harm and the potential ADEs which are mostly not done in many studies. This study categorized outcome on the basis of medication error index presented by NCC-MERP. Our study showed that at the setting working on CPOE/CDSS electronic system most of the incidents are intercepted before reaching the patient. Many errors which reached the patients were intercepted by the pharmacist\u2019s rounds along with medical practitioners at each unit. During ward rounds and during medication review electronically medical interventions were done and discussed with the practitioners which if approved was applied. While at the setting with a limited access to drug databases a lot of incidents reached the patients without interception. A large number of incidents reached the patients which needed evaluation for harm. This lack of updated system and least involvement of clinical pharmacist during ward rounds and during dispensing from pharmacies reduced the chances of medical interventions which could lead to permanent patient harm, increasing length of stay, and medication cost. Ranchon et al. provided almost similar results on the severity of outcomes. The study suggests that the toxic nature of cytotoxic drugs, patient condition and comorbidities, complex regimens and frequent dose adjustments and calculations makes the outcomes severe. The outcome evaluation though requires close observation which may affect the results of such studies.The errors were highly reported at the level of prescription at prescriber\u2019s office and oncology ward. Error discovery was higher at pharmacy level at site 1 working on electronic system with CPOE and CDSS as compared to site 2 with most of the work done manually and least updated electronic system. It elucidates that pharmacy department is efficiently involved in the medication utilization review process at site 1 with complete access to patient medication and medical record based electronic system which makes it easier to detect any medication related event as compared to site 2. The pharmacist\u2019s involvement during medication use process greatly reduces the occurrence of medication errors in chemotherapy patients. Ranchon et.al showed an incidence of 5.2% prescription errors in cancer patients which is quite low as compared to the rate at site 2 in our study and almost equal to site 1. The hospital reported by Ranchon et al. had a same electronic system as at our study\u2019s site 2 and a handwritten prescription approach but the prescriptions were sent to pharmacy department before administering to the patients for complete review which greatly reduced the number of medication errors reaching the patient. The study showed a low percentage of administration (0.02%) and dispensing (0.16%) errors as compared to our study. Both; our study and the Ranchon et al. study; has under-reported errors at administration and pharmacy level due to blame and shame approach and lack of time and observation strategies. Watts et al. showed similar results while studying chemotherapy medication errors at a pediatric hospital at a low rate of 6/1000 patient visits while 3.9/1000 dispensing orders. After implementation of a pharmacy surveillance system the error rate was further reduced by 50% at both ends. The study focused on the need of multidisciplinary review of policies and procedures to ensure patient safety .Our study found a higher incidence of medication related events  at site 2 (HWP system) while rate of medication errors without harm and interventions was reported highly at site 1. The higher incidence of potential ADEs at site 2 might be due to the absence of clinical pharmacists, lack of staff training, less updated software and communication among HCPs. Errors nature was preventable mostly concluding that proper cross checking could prevent a greater incidence before reaching the patient.Drugs highly at risk of medication errors in our study were antibiotics the most commonly prescribed class of drugs in our health care settings, anti- analgesics and antipyretics supplements, antacids, anti-cancer drugs, and electrolytes because of less consideration while prescribing these classes of drugs. Tang et al. found similar results in his study. Antibiotics were the leading class of drugs (38.9%) subjected to errors due to its prescribing pattern and confusion with other drugs having similar names. Other drugs reported were analgesics (6.9%), electrolytes (8.4%), antidiabetics (6.9%) and other classes (38.9%). Ranchon et al. predictors of prescribing errors among cancer patients showed a 3.15% error rate among all antineoplastic prescriptions .A detailed study by Richard J. Fitz Gerald showed the importance of accurate medication and medical history in the prevention of medication errors. Errors were more common when patients admitted at hospitals because of incomplete medication histories. Many drugs can cause or mask many conditions like preventing tachycardia by beta adrenoceptor antagonists in hemorrhagic patients, abdominal pain by corticosteroids in perforated duodenal ulcers and/or masking the effects of investigations as thyroid function tests by amiodarone. It also showed that to prevent such errors pharmacists can perform much better roles as compared to physicians and nurses due to their ability to take detailed medication histories and compliance records .Our study revealed many issues of concern at cancer care settings working on different systems. CPOE with CDSS will greatly reduce the occurrence of medication errors by decreasing the workload of every member involved in pharmaceutical care. Regular staff training and incorporation of pharmacist at different checkpoints will improve health care provision. Regular root cause analysis by a health care team will greatly improve the system making better utilization of resources. The limitation of this study was the less number of data collection members. The handwritten prescriptions, lack of ward pharmacists, under-reporting of mediation errors and time constraints at site 2 may affect the actual number of errors.This study has focused on the root causes and contributing factors in two systems working on different approaches of prescribing, dispensing and administration. The incidence and prevalence of medication related incidents are mostly studied without considering the factors involved which are leading to their occurrence. For improvement in our health system and patient safety more studies like this are needed to be done on a broader level.Time limit as the study was done only for few months. It is needed to be done for a period of a year at least to better understand the occurrence rates of medication related events.The sample size needed to be increased which was limited because of lack of data collection personnel.All the health care team members including prescribers, pharmacists and nurses are need to be a part of such research team to avoid any biasness and misinterpreting any medication order.Many of the events may go un-reported due to lack of personnel.A more strong statistical analysis is needed for handling such a huge data with so many variables.The limitations of this study includes"}
+{"text": "Commitment to Change (CTC) has been shown to be an effective performance measure of continuing professional development (CPD) training, in that 50-67% of providers choosing CTC also made behavioral changes in clinical practice . However, very little is known about the factors that are associated with a learner committing to practice change. This study presents findings from a retrospective observational study that compared trends across various health profession, demographics, and activity-type categories to identify learner characteristics that may lead to higher CTC responses. Learner data from 2014 -2017 was obtained from two different continuing education office databases. The combined dataset contained 68,365 evaluations from 26,508 learners, of which 22.8% wrote a CTC. At both sites, CTC was more likely if the activity was enduring or charged a fee and less likely for an RSS (p<0.001). Results indicate that CTC varies based on provider demographics, such as profession and specialty. Allied health providers (32.4-37.5%) and health educators (36%) were most likely to make a commitment, followed by nurses (28.6%), physicians (23.9%), pharmacists (14.9%), and dentists (9.1%). Physician specialties and provider region also varied with the highest CTC by geriatricians (50%) and occupational medicine providers (42.3%) and the lowest rates of CTC found in the southeast region. Results of the study will help inform the development and implementation of future CPD in order to successfully engage learners in committing to change clinical practices."}
+{"text": "BRCA1/2 mutation (BRCAm). Our aim was to present real-world experience with olaparib in Korea. Method: We included HSROC patients with BRCAm treated with olaparib maintenance at four institutions in Korea between 2016 and 2018. Medical records were reviewed for clinico-pathologic characteristics, objective response, survival outcomes, and safety. Results: One hundred HSROC patients with BRCAm were included. BRCA1 mutation was present in 71 patients (71.0%), and BRCA2 mutation was present in 23 patients (23.0%). In terms of the best objective response with olaparib maintenance in 53 patients with partial remission from most recent chemotherapy, complete remission occurred in 12 (22.6%) and partial remission in four (7.5%), while 33 patients (62.3%) had stable disease. The 24 month progression-free survival was 42.4%, and 24 month overall survival was 82.1%. Grade 3 or more adverse events were as follows: anemia in 14 patients (14.0%), neutropenia in seven patients (7.0%), thrombocytopenia in two patients (2.0%), oral mucositis in one patient (1.0%), and soft tissue infection in one patient (1.0%). Conclusions: The safety and effectiveness of olaparib maintenance treatment in a real-world study were consistent with those reported in previous clinical trials.Background: Olaparib maintenance therapy has shown efficacy and tolerability in patients with platinum-sensitive, high-grade serous recurrent ovarian cancer (HSROC) with  Ovarian cancer is the second most common cause of death related to gynecologic malignancy and the eighth leading cause of death from cancer in women worldwide . The proBRCA1/2-deficient tumor cells [p < 0.0001) [BRCA1/2 mutation (BRCAm) revealed significantly improved PFS in the olaparib-treated group compared to the placebo group  [Olaparib (Lynparza\u2122) is a poly (adenosine diphosphate\u2013ribose) polymerase (PARP) inhibitor that induces synthetic lethality in or cells ,6. Previ 0.0001) . The PhaBRCAm. The Korean Food and Drug Administration (KFDA) has permitted the use of olaparib in a maintenance setting based on the results of Study 19 since August 2015, and olaparib has been widely used clinically since January 2016\u2014the date from which reimbursement for this treatment was initiated by the National Health Insurance Service of Korea. In Korea, olaparib is approved for the maintenance treatment of patients with platinum-sensitive HSROC with BRCAm treated at four major tertiary institutions in Korea. Safety data from previous trials indicate that olaparib monotherapy is generally well tolerated by recurrent ovarian cancer patients ,8. This BRCAm who were treated with olaparib maintenance therapy at four institutions in Korea  between January 2016 and December 2018. In general, eligibility criteria were designed to recruit a patient population similar to the one enrolled in Study 19. All patients older than 18 years with platinum-sensitive histologically confirmed HSROC with BRCAm were eligible if they had received at least two previous lines of platinum-based chemotherapy, were in objective response  to their most recent regimen, and had platinum-sensitive disease following their penultimate line of chemotherapy. All patients were monitored until December 2018 for survival and discontinuation of olaparib. This study was approved by the institutional review boards of the participating centers in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines .This was a retrospectively reviewed observational study of Korean women with HSROC with Olaparib maintenance monotherapy  was administered orally and continued until disease progression if toxicities were manageable. Modification of olaparib dosage was performed at the clinicians\u2019 discretion. Patients were advised to visit every month for prescriptions, symptom check-up, and laboratory tests  and every 3 months for tumor assessment  until objective disease progression or intolerable toxicities. Safety and tolerability were assessed throughout the follow-up period by reviewing medical records of adverse events , physical examination results, vital signs, and laboratory findings. Endpoints of this study were safety, tolerability, duration of, and reasons for discontinuing therapy and objective response, PFS, and overall survival (OS). PFS was defined as the interval between the day olaparib was started and the first radiologically documented progression of disease or last follow-up. OS was defined as the interval between the day olaparib started and death from any cause or last follow-up. Best overall response to olaparib maintenance was defined as the best response recorded from the start of treatment until disease progression/recurrence in patients with measurable or evaluable disease. Only patients with measurable disease and a PR at entry could achieve a best overall response of complete remission (CR) or partial remission (PR). Confirmation of response (CR or PR) was performed at the next scheduled response evaluation criteria in solid tumors (RECIST) assessment and \u2265 4 weeks following the date that the criteria for response were first met .Summary statistics were used to describe patient characteristics. Median (range) or mean (standard deviation) were used for continuous variables. Categorical variables are presented as frequency (percentage). The Kaplan\u2013Meier method was used to estimate PFS and OS. All statistical analyses were accomplished using IBM SPSS ver. 21.0 .BRCA1/2 mutation were treated with olaparib maintenance therapy at four institutions . Data cutoff for final analysis was December 2018; the median duration of follow-up was 10.2 months . Between January 2016 and December 2018, 100 HSROC patients with BRCA mutations; 69 patients (69.0%) had BRCA1 mutations and 24 patients (24.0%) had BRCA2 mutations. Somatic BRCA mutations were present in six patients (6.0%): three patients had BRCA1 mutations, one had BRCA2 mutations, and two had BRCA1/2 mutations. Altogether, 71 patients (71%) had BRCA1 mutations, 23 patients (23%) had BRCA2 mutations, and three patients (3%) had BRCA1/2 mutations. International Federation of Gynecology and Obstetrics (FIGO) stage IIIC at initial diagnosis was most common (47.0%) among the patients. Most patients had undergone two chemotherapy regimens before olaparib , while some patients had undergone three regimens . Four patients had undergone five or more previous regimens. Platinum-free interval was > 12 months in 68 patients (68.0%) and 6\u201312 months in 32 patients (32.0%) (median 14.6 months (6.0~86.3 months)). There were 16 patients (16.0%) with previous bevacizumab exposure. In terms of objective response to most recent chemotherapy, complete response was shown in 46 patients (46.0%) and partial response in 53 patients (53.0%).Baseline characteristics are summarized in At the median follow-up duration of 10.2 months , 62 patients were still being treated with olaparib. Percentages for the number of olaparib users per total patients for different time periods are shown in In terms of best overall response to olaparib maintenance in 53 patients with measurable or evaluable disease  from most recent chemotherapy, complete remission (CR) was shown in 12 patients (22.6%), partial remission (PR) in four (7.5%), and stable disease in 33 (62.3%) . Among tAEs are shown in Time to first AE (event rate per patient-years) is shown in Information regarding 41 cases with dose reduction (DR) due to AEs is provided in BRCA1/2 mutation is consistent with that reported in previous studies [Our real-world experience of the safety and effectiveness of olaparib maintenance treatment in HSROC patients with  studies ,4,10 witBRCAm (n = 74) in Study 19 and patients in our study [BRCA mutation status was similar between Study 19  and our study . In Study 19, 18 of 136 patients with BRCAm (13.2%) had definite somatic BRCAm [BRCA mutation. Platinum-free interval and objective response to the most recent chemotherapy were similar in the two studies [BRCAm in Study 19). There were also differences in observed numbers of AEs between our study and Study 19. Among patients with BRCAm in Study 19, 97% had AEs. The most common non-hematologic AE was nausea (73%), while the most common hematologic AE was anemia (26%). In our study, 64 total episodes (64.0%) of AEs were observed, with 13 cases (13.0%) of nausea/vomiting and 24 cases (24.0%) of anemia. The percentage of anemia was similar in the two studies (26% vs. 24%), but grade \u2265 3 anemia was observed in only 5% of patients in Study 19 compared to 14% of our patients. There were some differences between olaparib-treated patients with ur study . Median ic BRCAm , while w studies . DespiteBRCA status, the number of previous chemotherapy regimens, and platinum-free intervals in our study were similar to those reported by the SOLO2 study [O2 study . Median O2 study  comparedO2 study . HoweverDifferences in AEs between our study and Study 19 might have been caused by different treatment patterns in a real-world setting and biases caused by the retrospective nature of the study. Randomized controlled trials (RCTs) should adhere strictly to the study protocol, but in the real world, treatment can vary depending on the physician . In StudReal-world data are important as they involve circumstances and conditions outside the scope of highly controlled clinical trial settings . RCTs foBRCAm. Inclusion criteria, treatment, and follow-up protocols were relatively consistent among institutions and physicians because medical practices in Korea are performed under the guidelines and recommendations of the KHIRA. Olaparib has to be prescribed every month based on laboratory tests by physician appointment, and image evaluations (mostly CT scans) are required every 3 months.To the best of our knowledge, this study is the first to describe a real-world experience with olaparib maintenance in HSROC patients with There are several potential limitations to the current study. First, it was based on retrospectively collected data. Therefore, our study may have had biases, especially due to incomplete data collection, and the lack of specific protocols and safety profiles in a real-world setting may have interfered with the accurate interpretation of data. The use of multi-institutional study data could also be considered a limitation of our study because, in a retrospective setting, multiple physicians from different institutions may not have used identical management protocols for each clinical situation. Also, the patient number was not large enough for more specific subgroup analysis, and observation time was not long enough to determine survival outcomes.BRCA1/2 mutation in a real-world clinical practice, as has been demonstrated in clinical trials. However, a longer follow-up period is needed for survival analysis.In summary, results from this multi-institutional, retrospective, observational study indicate that olaparib maintenance treatment is both effective and safe for HSROC patients with"}
+{"text": "People with dementia and carers may be vulnerable to loneliness and isolation. The IDEAL study includes two loneliness measures: 6 item de Jong Gierveld (DJG) scale (range 0-6) and a single-item self-report measure and the six-item Lubben social network scale (range 0-30). Full data are available for 1533 people with dementia for self-rated loneliness and for 1455 for the DJG scale and 1232 and 1195 carers respectively. For isolation complete data are available for 1489 people with dementia and 1252 carers. The prevalence of severe loneliness for people with dementia were 10% (self-rated) and 5% (DJG score 5+), approximately the population norm, and 15% and 18% respectively for carers. Most people with dementia or carers did not rate themselves as lonely ((79% and 71%) compared with 65% and 39% using the DJG scale. One third, 35%, of people with dementia were at risk of isolation compared with 18% of carers."}
+{"text": "When the Global Polio Eradication Initiative (GPEI) began in 1988, cases of poliomyelitis were reported from 125 countries. Since then, only Afghanistan, Nigeria, and Pakistan have experienced uninterrupted transmission of wild poliovirus (WPV). The primary means of detecting poliovirus is through surveillance for acute flaccid paralysis (AFP) among children aged <15 years with testing of stool specimens for WPV and vaccine-derived polioviruses (VDPVs) in World Health Organization (WHO)\u2013accredited laboratories of the Global Polio Laboratory Network (GPLN)  rate ; an NPAFP rate \u22652 is considered sufficiently sensitive to detect circulating poliovirus. The second indicator is the collection of adequate stool specimens  and arrival at a WHO-accredited laboratory by reverse cold chain and in good condition  from \u226580% of persons with AFP, which ensures sensitivity and provides the specificity to track poliovirus circulation (Among the 47 countries in the WHO African Region (AFR), the NPAFP rate in 2017 was 7.0 per 100,000 children aged <15 years, and 92% of AFP cases had adequate stool specimens; in 2018, the NPAFP rate was 5.4 per 100,000 children aged <15 years, and 89% of the AFP cases had adequate stool specimens. Among the 18 high-priority AFR countries assessed, 15 (83%) met both surveillance indicators nationally in 2018, compared with 13 (72%) in 2017 . HoweverAmong the 21 WHO Eastern Mediterranean Region (EMR) countries, the NPAFP rates in 2017 and 2018 were 8.4 and 9.5 per 100,000 children aged <15 years, respectively, and the respective percentages of AFP cases with adequate stool specimens in 2017 and 2018 were 88% and 90%. In the two countries with endemic WPV transmission, the number of WPV1 cases increased in Afghanistan (from 14 in 2017 to 21 in 2018) and Pakistan (from eight in 2017 to 12 in 2018). In 2017, Syria accounted for all 74 reported cVDPV2 cases in EMR. In 2018, 12 cVDPV cases were reported in Somalia, including five cVDPV2 cases, six cVDPV type 3 (cVDPV3) cases, and one coinfection of both cVDPV type 2 and type 3. Among the 11 high-priority EMR countries evaluated, nine (82%) countries in 2017 and 10 (91%) countries in 2018 met both surveillance indicators nationally; however, as in AFR, national indicators masked subnational underperformance  Figure)Figure).In the WHO Western Pacific Region, 26 cVDPV type 1 (cVDPV1) cases were reported in Papua New Guinea in 2018. Papua New Guinea did not meet either surveillance indicator nationally in 2017, and although the NPAFP rate improved in 2018 (mainly related to implementation of enhanced AFP surveillance as part of the outbreak response), collection of adequate stool specimen remained low. In the WHO South-East Asia Region, one cVDPV1 case was reported in Indonesia in 2018. Although Indonesia met both surveillance indicators nationally in 2017 and 2018, subnational weaknesses in surveillance were substantial  Figure)Figure).Environmental surveillance (testing of sewage samples) supplements AFP surveillance by identifying poliovirus transmission in the absence of detected AFP cases  isolate and identify polioviruses; 2) conduct intratypic differentiation (ITD) to identify WPV, Sabin (vaccine) poliovirus, and VDPV; and 3) conduct genomic sequencing. Poliovirus transmission pathways are monitored through analysis of the viral capsid protein (VP1) coding region sequences from isolates. Standard timeliness indicators specify that laboratories should report \u226580% of poliovirus culture results within 14 days of specimen receipt, \u226580% of ITD results within 7 days of isolate receipt, and \u226580% of sequencing results within 7 days of ITD result. The combined field and laboratory performance indicator is to report ITD results for \u226580% of isolates within 60 days of paralysis onset in AFP cases. The accuracy and quality of testing at GPLN laboratories are monitored through an annual accreditation program of onsite reviews and proficiency testing  was detected in Afghanistan and Pakistan, with frequent cross-border transmission between the two countries. Compared with the previous report  of the 31 countries met acute flaccid paralysis surveillance indicators nationally; however, subnational variation in surveillance performance was substantial, and no improvements were noted from 2017 to 2018.Surveillance systems need continued strengthening through monitoring, supervision, and improvements in specimen collection and transport to provide sufficient evidence for interruption of poliovirus circulation."}
+{"text": "GJB2, as the most common cause of ARNSHL, is only <20% in the Iranian population. Here, we aimed to determine the relative contribution of several apparently most common loci in a cohort of ARNSHL Iranian families that were negative for the GJB2 mutations.Autosomal recessive non-syndromic hearing loss (ARNSHL), one of the global public health concerns, is marked by a high degree of genetic heterogeneity. The role of GJB2 gene via Sanger sequencing, 60 negative samples (30 families from each province) were analyzed using homozygosity mapping for 10 ARNSHL loci.Totally, 80 Iranian ARNSHL families with 3 or more affected individuals from Isfahan and Hamedan provinces, Iran were enrolled in 2017. After excluding mutations in the Fourteen families were found to be linked to five different known loci, including DFNB4 (5 families), DFNB2 (3 families), DFNB7/11 (1 family), DFNB9 (2 families) and DFNB3 (3 families).Despite the high heterogeneity of ARNSHL, the genetic causes were determined in 23.5% of the studied families using homozygosity mapping. This data gives an overview of the ARNSHL etiology in the center and west of Iran, used to establish a diagnostic gene panel including most common loci for hearing loss diagnostics. Over 70% of prelingual HL cases can be classified as non-syndromic HL (NSHL), where the hearing deficit is the only sign (http://hereditaryhearingloss.org). However, more than seventy different DFNB loci have been mapped for ARNSHL by homozygosity mapping, an effective method to locate genes causing ARNSHL in large consanguineous families (Hearing loss (HL) is the most frequent form of sensory impairment in humans, with approximately 1\u20132 in 1000 infants being born with a serious HL (https://GJB2), as the most common cause of HL all over the world (GJB2 (NM_004004.5) could explain the etiology of ARNSHL in 4% to 35% of patients from different origin, suggesting that GJB2 gene mutations account for a part of ARNSHL in Iran.  confirmation of HL by Pure tone audiometry (PTA) from 250\u20138000 Hz 2) the autosomal recessive inheritance deduced through pedigree analysis 3) existence of three or more affected members within the pedigree. A complete clinical investigation was performed to exclude environmental exposures and to determine the presence of syndromic findings in each family.Genomic DNA was extracted using Prime Prep Genomic DNA Extraction kit from blood  according to the manufacturer\u2019s instruction. Qualitative and quantitative assessment of genomic DNA was checked using 1.2% agarose gel and Nanospec cube biophotometer .http://www.ncbi.nlm.nih.gov). Primers for STR markers of each locus were mostly obtained through the Probe database (https://www.ncbi.nlm.nih.gov/probe). STR markers of each locus and their primer sequences are listed in Power of the pedigrees for linkage analysis was simulated by calculating SLINK, using FastSLink (ver.2.51) option of Easy linkage plus version 5.05 software to predict the potential LOD score in a given family . Based o2 (4 mM), 2.5 \u03bcl Taq PCR buffer (10X), 0.12 \u03bcl of each of the primers (10 PM), 0.15 \u03bcl Taq DNA polymerase (5U/ul), 0.9 \u03bcl dNTP mix (10 mM) and 1.2 \u03bcl DNA (about 70 ng). The reaction was adjusted to the volume of 25 ul by ddH2O. Standard cycling was done in a thermocycler . STR markers were selected based on their physical distance found at NCBI UniSTS. The criteria for selecting these markers are as follows: greater heterogeneity values, and lying near or at the known loci. At least 4 STR markers were selected for linkage analysis. PCR of STR markers was conducted according to the standard procedure. The touchdown program was used for markers amplification. Thermal cycling conditions for amplifying markers were in accordance with previous protocols . PCR conGJB2 gene, 60 Iranian families segregating (ARNSHL), from Isfahan and Hamedan provinces (30 families from each province) in the center and west of Iran, were screened for 10 ARNSHL loci. Totally, 634 individuals were studied 245 of whom were patients, with ages ranging from 6 months to 52 yr. For 45 families, PTA was consistent with profound HL (\u226580 dB), 12 families showed severe HL (61\u201380 dB), whereas the 3 remaining families showed moderate HL (41\u201360 dB).After excluding mutations in the MYO7A), DFNB3 (MYO15A), DFNB4 (SLC26A4), DFNB7/11(TMC1), DFNB9 (OTOF), DFNB21 (TECTA), DFNB24 (RDX), DFNB59 (PJVK), DFNB63 (LRTOMT) and DFNB53 (COL11A2). The family members were individually genotyped for these markers. After genotyping of STR markers and linkage analysis, 14 out of the 60 families, negative for GJB2 mutations, showed linkage to five different loci  among the studied families.GJB2 mutations. We have obtained 20% and 26% involvement of GJB2 mutations in ARNSHL in Hamedan and Isfahan provinces, respectively (unpublished data).We determined the contribution of 10 DFNB loci to HL in 60 Iranian families affected with ARNSHL and negative for the GJB2 negative families in the west and center of Iran. DFNB4 was found to be the mostly linked locus among the studied families, with 3 out of 30 (10%) and 2 of 30 (6.6%) showing linkage to it in Isfahan and Hamedan provinces, respectively.For the first time, we investigated the role of 10 other loci in the etiology of HL in SLC26A4) are the second most common cause of ARNSHL, after GJB2, all over the world  Iranian families with 2 or more ARNSHL patients were linked to DFNB4 locus  from Isfahan province and two out of 30 families (6.6%) from Hamedan were linked to DFNB3. The DFNB3 locus was first identified in the village of Indonesia, Bengkala, with a frequency of 9.4% among the inbred population . Since t(OTOF). Mutations in the OTOF gene (named as homology to Ferlin (Fer-1)) encoding otoferlin at DFNB9 results in ARNSHL which is sometimes associated with auditory neuropathy. Otoferlin is a member of the ferlin protein family; its role is in vesicle recycling and efficient and linear encoding of low-intensity stimulate the synapse between inner hair cells and auditory nerve fibers .In the present study, one family (3.3%) from every single province was linked to DFNB9 e fibers . OTOF muspectrum , 27. The in Iran . It was Our study involves 3 families with moderate to severe HL highlighted by a \u201cU\u201d shaped audiogram. DFNB21 and DFNB93 are related to this audio profile , 29. IntTMC1 (Transmembrane channel-like gene I) is required for postnatal hair cell development. TMC1 might be an ion channel or transporter which mediates K+ homeostasis in the inner ear . In the study on 144 GJB2-negative subjects, using linkage analysis and direct sequencing, 4 out of 144 families (2.7%) were linked to DFNB7-11(The contribution of DFNB7/11 in Hamedan Province was found to be 3.3% (1/30), in line with the prevalence figures of 4% in Pakistan, and 3.4% in Turkey. The related gene nner ear . The TMC DFNB7-11. Moreove DFNB7-11, using hThe next step of the study involves DNA sequencing of the corresponding genes of the DFNB loci in the linked families to identify the pathogenic mutations. Until now, 4 homozygous mutations have been identified in the related families, including 3 missense and 1 splice site mutations , 33. TheGJB2 mutations, from Isfahan and Hamedan provinces, respectively. Thus, nearly 23.5% of ARNSHL families negative for GJB2 mutations are linked to 5 loci including DFNB4, DFNB2, DFNB3, DFNB9 and DFNB7/11. The remaining genes and loci could be either rare or yet to be identified  and 8 out of 30 (26.6%) ARNSHL families, negative for 0% and 8 entified . The stuGJB2- mutation negative ARNSHL in Isfahan and Hamedan provinces. This finding is interesting in view of the extreme genetic heterogeneity of ARNSHL (with over 50 genes discovered so far). Investigation of a limited number of genes could lead to an acceptable level of diagnostic yield.Using homozygosity mapping, we detected 23.5% of the genetic etiology of Ethical issues  have been completely observed by the authors."}
+{"text": "Studies have reported that invasive ductal carcinoma (IDC) with coexisting ductal carcinoma in situ (DCIS) show lower metastatic potential and recurrence and better overall survival than pure IDC. In this study, we assessed F-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) images of patients with newly diagnosed IDC to determine if there is any difference in PET findings in IDC-DCIS and pure IDC cases.max and SULmax), other hypermetabolic foci in the breast, and ipsilateral normal breast were measured. Presence of axillary and distant metastases was noted. FDG PET/CT images of patients with newly diagnosed IDC of the breast who subsequently underwent breast surgery and had histopathology result in our records were further evaluated. Tumor grade, pathological staging, and presence of DCIS were noted from the histopathology results. Standardized uptake value (SUV) of the primary tumor . Pathology showed axillary metastasis in all 13 pure IDC (100%), and 27 IDC-DCIS (61.4%) cases. PET showed axillary uptake in 25 IDC-DCIS (56.8%), and 8 pure IDC (61.5%) cases, and abnormal/questionable distant uptake in 12 IDC-DCIS cases and 1 pure IDC case.Fifty seven (57) patients with IDC were included. Coexisting DCIS was present in 44 (IDC-DCIS) and not present in 13 (pure IDC) cases. Per histopathology, the primary tumor was unifocal in 33 IDC-DCIS (75%) and 12 pure IDC (92.3%) cases, and multifocal in 11 IDC-DCIS cases (25%), and 1 pure IDC case (7.7%). FDG uptake was multifocal in 20 IDC-DCIS cases (45.5%) and 1 pure IDC case (7.7%), and unifocal in 24 IDC-DCIS (54.5%), and 12 pure IDC (92.3%) cases. There was no significant difference in patient age, size of the primary tumor, SUVIn our preliminary findings, multifocal breast FDG uptake and multifocal tumor appear to be more common in IDC-DCIS than pure IDC. There is no significant difference in SUV and size of the primary tumor in IDC-DCIS and pure IDC cases. Axillary metastases appear to be more common in pure IDC than IDC-DCIS cases. F-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) is commonly used in the detection of distant metastases in high-risk patients with locally advanced disease or inflammatory breast cancer . FDG PET Ductal carcinoma in situ (DCIS) is a preinvasive/non-invasive breast cancer, where proliferations of malignant ductal epithelial cells remain confined within intact breast ducts. DCIS often coexist with invasive ductal carcinoma (IDC) . DCIS isIn this study we aimed to further assess F-18FDG PET images of newly diagnosed IDC patients to determine if there is any difference in PET findings in IDC-DCIS and pure IDC cases. In this study, FDG PET/CT images of newly diagnosed and untreated breast cancer patients who subsequently underwent breast surgery and had histopathology result in our records were further evaluated. This retrospective study was approved by Kuwait Ministry of Health and Health and Ethics Committee at Trakya University Faculty of Medicine.  FDG PET/CT images were obtained at Philips Gemini Time of Flight  and GE discovery 8  PET/CT cameras. PET images were obtained 60 min following intravenous injection of 222-296 MBq (6-8 mCi) of F-18 FDG. Prior to PET image acquisition, a low dose CT was obtained for attenuation correction and anatomic localization purposes. PET acquisition was 3 min/bed from top of the head to mid thighs. PET images were corrected for attenuation on the basis of the CT data and reconstructed using a standard iterative algorithm (ordered subset expectation maximization) and reformatted into transaxial, coronal and sagittal views. Maximum intensity projection images were also generated. Both attenuation corrected and uncorrected PET images as well as PET/CT fusion images were reviewed. max) of the primary tumor(s), focal hypermetabolic areas other than the primary tumor , and ipsilateral normal appearing breast tissues by placing circular region of interests. We also normalized SUVmax to lean body mass (SULmax) in primary tumors. We calculated patient\u2019s lean body mass via an online calculator which uses an equation using patients\u2019 height and weight  and away from primary tumor. Histopathology results were reviewed mainly to obtain information about pathological stage of the tumor, grade of the primary tumor, presence of multifocal tumor, and presence of DCIS. In patients with partial surgery, such as wide local excision, lumpectomy, or segmental mastectomy, DCIS adjacent/around the tumor was searched pathologically. Statistical Analysismax, SULmax and mean size of the primary tumor, mean SUVmax of multifocal uptake and mean SUVmax of the ipsilateral normal breast in IDC-DCIS and pure IDC cases. To compare means and calculate p values, the two-sample t test was used if normality holds or the non-parametric Mann\u2013Whitney U test for non-normal data. P< 0.05 was considered statistically significant. Statistical analysis was performed using SPSS software version 25 (IBM Corp.). The goal was to determine if there was any significant difference in mean SUV Fifty seven (57) female patients with newly diagnosed IDC from Mubarak Al-Kabeer (29 patients) and Trakya University (28 patients) hospitals were selected for further analysis (mean age 57.1\u00b112.2 year). Thirty four (34) patients had underwent mastectomy , 14 had breast preservation surgery , and 9 had wide local excision. All the patients had undergone sentinel lymph node (SLN) biopsy and/or axillary clearance/ dissection. max and SULmax of primary tumor. Coexisting DCIS was present in 44 patients with IDC (IDC-DCIS). There was no coexisting DCIS in 13 patients (pure IDC). Histopathologically, the primary tumor was multifocal in 12 patients (in 11 IDC-DCIS cases and in 1 pure IDC case) and unifocal in 45 patients . max and SULmax of primary tumor and SUVmax of normal breast) and pathology findings of IDC-DCIS and pure IDC patients and statistical results.  In IDC-DCIS group (44 patients), FDG PET showed multifocal uptake in 20 patients (45.5%) and unifocal uptake in 24 patients (54.5%). Multifocal FDG uptake was present in 9 of 11 patients with multifocal tumor, and in 11 of 33 patients with unifocal tumor on pathology. max of multifocal uptake was 4.3\u00b12.3, ranging from 2 to 10.4. Number of multifocal uptake (foci of uptake in addition to primary tumor) was 1 in 10 patients (5 adjacent to primary tumor and 5 away from primary tumor), 2 in 3 patients (adjacent to primary tumor), 3 in 3 patients  and \u2265 5 in 3 patients .In IDC-DCIS group, mean SUVmax of 4.4) adjacent, around and away from the primary tumor (SUVmax of 12)  and in these patients multiple foci of uptake were around the primary tumor in 4, around and away from the primary tumor in 1 and away from the primary tumor in 2 cases . In 4 ofx of 12) . max of 5.4) and also another focal uptake adjacent to primary tumor (SUVmax of 2). In a patient with multifocal tumor on pathology and multifocal breast uptake on PET , coexisting lobular carcinoma in situ (LCIS) was also detected in addition to DCIS. In this group, 25 patients had mastectomy and 19 had partial surgery. In patients with partial surgery, DCIS was available around the tumor and other parts of the breast were not examined.  In another case with microscopic multifocal tumor and lumpectomy, PET showed uptake in the primary tumor (SUVmax of 3.9) in addition to primary tumor. There was coexisting LCIS in this patient. In a patient with multifocal tumor on pathology, PET showed uptake in the primary tumor only. In 4 patients in this group, surgery was partial and DCIS was negative around the tumor but whole breast was not examined to search for DCIS in other parts of the breast.  In pure IDC group, pathology showed unifocal tumor in 12 patients (92.3%) and multifocal tumor in 1 patient (7.7%). PET showed unifocal uptake in 12 patients (92.3%) and multifocal uptake in 1 patient (7.7%). In a case with unifocal tumor in pathology, PET showed focal uptake , and in 27 IDC-DCIS cases (61.4%). PET showed uptake in the axillary nodes in 25 IDC-DCIS patients (56.8%), and in 8 pure IDC patients (61.5%). PET was false negative for axillary metastases in 5 cases with IDC-DCIS and 5 cases with pure IDC. PET was false positive for axillary metastases in 3 cases with IDC-DCIS. PET showed findings suggestive of/consistent with distant metastases in 6 IDC-DCIS cases , and 1 pure IDC case (in bone). In 6 other cases with IDC-DCIS there was questionable or suspicious uptake: mildly hypermetabolic mediastinal and abdominal lymph nodes (3 cases), mild uptake in lung nodules (2 cases), and questionable uptake in a rib (1 case). In 3 cases with IDC-DCIS there was abnormal uptake in thyroid which was likely due to thyroid pathology. Results of statistical analysis There was no significant difference in mean age of patients in IDC-DCIS (57\u00b112.5) and pure IDC (60.4\u00b110.4) cases (p=0.519).max of the primary tumor in IDC-DCIS (7.7\u00b14.1) and pure IDC (7.0\u00b12.3) cases (p=0.739). There was no significant difference in mean SUVmax of the primary tumor in IDC-DCIS (4.8\u00b12.7) and pure IDC (4.4\u00b11.6) cases (p=0.902). There was no significant difference in mean SUL There was no significant difference in mean greatest dimension of the primary tumor in IDC-DCIS (3.3\u00b12.2) and pure IDC (3.9\u00b12.7) cases (p=0.617). There was no significant difference in mean ipsilateral normal breast uptake in IDC-DCIS (1.2\u00b10.5) and pure IDC (1.2\u00b10.6) cases (p=0.753).max of 2.18\u00b11.16   . In thei16-5.49) . FDG-PET16-5.49) . PET was16-5.49) . FDG upt16-5.49) .max and mean SULmax of the primary tumor in IDC-DCIS and pure IDC cases. We did not have an opportunity to obtain more PET parameters such as metabolic tumor volume (MTV) and total lesion glyclolysis (TLG) to compare in IDC-DCIS and pure IDC cases. Significantly increased Tc-99m V-DMSA uptake was reported in patients with IDC-DCIS as compared to pure IDC  or due to pregnancy/lactation , 31. Uni One of the limitations of our study was the small number of pure IDC cases which might affect statistical results when comparing various parameters in IDC-DCIS and pure IDC cases. As the majority of IDC patients have coexisting DCIS, we had only small number of pure IDC patients. Studies in larger number of patients may provide more accurate results. The other limitation of our study was partial surgery to be performed in some of our patients. Although this was not a major problem for IDC-DCIS patients, it may cause false negative DCIS result in pure IDC group. However, in pure IDC group, partial surgery was done only in 4 of 13 patients and in other 9 patients with mastectomy whole breast was examined pathologically. Although our study has some limitations, it is the only study reporting/comparing FDG PET findings in IDC-DCIS and pure IDC cases. In our preliminary findings, multifocal breast FDG uptake and multifocal tumor appears to be more common in patients with IDC-DCIS than pure IDC cases. There is no significant difference in SUV and size of the primary tumor in IDC-DCIS and pure IDC cases. Axillary lymph node metastases appear to be more common in pure IDC cases than IDC-DCIS. No potential conflict of interest relevant to this article was reported."}
+{"text": "What are the clinical outcomes among Medicare patients with atrial fibrillation undergoing left atrial appendage closure with an implanted device?2DS2-VASc scores in the absence of anticoagulation therapy. The 1-year mortality rate (7.5%) was higher than that in previous randomized clinical trials, likely because of the inclusion of older patients with more comorbidities who were ineligible to receive warfarin.In this cohort study of 13\u2009627 patients with atrial fibrillation who underwent left atrial appendage closure, the rate of hospitalization for stroke at 6 months (1.2%) was significantly lower than expected according to their CHALeft atrial appendage closure via an implanted device was associated with a decreased risk of stroke in patients with atrial fibrillation. This cohort study of patients with atrial fibrillation who underwent left atrial appendage closure with an implanted device evaluates postprocedural mortality rates and rates of readmission and ischemic stroke. Left atrial appendage closure (LAAC) has emerged as a nonpharmacological alternative for stroke prevention in patients with nonvalvular atrial fibrillation. Contemporary data regarding the characteristics and outcomes of patients undergoing this procedure are limited.To determine the characteristics, postprocedural mortality rate, and rates of readmission and ischemic stroke among Medicare beneficiaries who underwent LAAC via implanted device.This population-based cohort study used Medicare inpatient claims from January 2015 to December 2017 for 13\u2009627 patients aged older than 65 years with a diagnosis of atrial fibrillation who underwent LAAC with an implanted device from January 2015 to November 2017. Data analyses were conducted from January through August 2019.Left atrial appendage closure.Mortality rates during the index admission and for 1 year after LAAC were assessed. The 30-day readmission rate and the primary reasons for readmission were also examined. In addition, the likelihood of hospitalization for ischemic stroke within 180 days among 9231 patients for whom 6 months of follow-up data were available was evaluated.2DS2-VASc score was 4.3\u2009(1.4). Twenty-eight patients (0.2%) died during the index admission. Mortality rates were 0.6% (80 patients) at 30 days, 1.9% (262 patients) at 90 days, 4.0% (547 patients) at 180 days, and 7.5% (1027 patients) at 365 days. The 30-day readmission rate among 13\u2009599 patients discharged alive was 9.4% (1284 patients). Among 9231 patients with 6 months of follow-up data, 111 (1.2%) experienced readmission for ischemic stroke or transient ischemic attack within 180 days of discharge.Among the 13\u2009627 patients undergoing LAAC, the mean (SD) age was 78.0\u2009(6.3) years, 9406 (69.0%) were older than 75 years, 11\u2009980 (87.9%) were white, and 5630 (41.3%) were women. The mean (SD) CHA2DS2-VASc scores in the absence of anticoagulation therapy. Mortality at 1 year was higher than that reported in previous randomized clinical trials, likely because the patients in the present study were older, had a higher number of comorbidities, and were ineligible to receive warfarin.In this cohort study of patients older than 65 years with atrial fibrillation who underwent LAAC with an implanted device, readmission rates for ischemic strokes over the course of 6 months were lower than expected given the patients\u2019 CHA Anticoagulation therapy is the cornerstone for stroke prevention in patients with AF, according to their CHA2DS2-VASc  risk scores.2 Left atrial appendage closure (LAAC) devices have emerged as nonpharmacological alternatives for stroke prevention in patients with AF.3 The Watchman device (Boston Scientific) was the first LAAC device that was compared with warfarin in 2 randomized clinical trials: PROTECT AF 4 and PREVAIL .5 The device received US Food and Drug Administration approval in 2015 for stroke prevention in patients with nonvalvular AF who are at high risk of stroke and are deemed suitable for short-term oral anticoagulation therapy but have appropriate rationale to seek nonpharmacologic alternatives to warfarin. To date, the real-world data outside clinical trials regarding the use and outcomes of LAAC devices are limited. To address this gap in knowledge, in this study, we describe the characteristics of patients undergoing LAAC via implanted device and examine the postprocedural outcomes of mortality, hospital readmissions, and ischemic stroke using Medicare data.Atrial fibrillation (AF) has emerged as a cardiovascular epidemic, with prevalence estimated to approach 12.1 million individuals in the United States by 2030.STROBE) reporting guideline.6The study was approved by the University of Iowa institutional review board, and the need for consent was waived because of the use of encrypted patient identifiers. This study follows the Strengthening the Reporting of Observational Studies in Epidemiology  procedure code 02L73DK . Currently, Watchman is the only intraluminal LAAC device approved by the US Food and Drug Administration for this procedure code. We obtained patient dates of death from the Beneficiary Summary File, with mortality information available up to 1 year after the LAAC. We only included patients older than 65 years who had at least 1 year of Medicare enrollment to identify comorbidities from the inpatient claims preceding LAAC.The study used Centers for Medicare & Medicaid Beneficiary Summary (enrollment) and Medicare Provider and Analysis Review (inpatient claims) files from January 2015 through December 2017. Patients aged 66 years and older who underwent LAAC with the Watchman device during January 2015 through November 2017 were identified in hospital discharge records in the Medicare Provider and Analysis Review files according to 2DS2-VASc score were identified using an established algorithm according to International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and ICD-10 diagnoses on the LAAC hospital discharge record, as well as inpatient claims during the year preceding the LAAC admission.9Patient demographic characteristics  were identified on the Beneficiary Summary File. Comorbid conditions included in the CHA9 which collapses individual ICD-9-CM and ICD-10 codes into approximately 200 meaningful clinical categories. In addition, we evaluated the likelihood of admission for ischemic stroke or TIA within 180 days and the rate of admission for ischemic stroke or TIA per patient-year among patients discharged alive for whom at least 6 months of follow-up data were available. Admissions for ischemic stroke were identified by primary diagnosis on inpatient claims using ICD-10 codes starting with I63, I65, and I66 for ischemic stroke and G45 for TIA.The primary outcome was mortality during admission and within 1 year of LAAC. The secondary outcomes were readmissions within 30 days after LAAC discharge and reasons for readmission among patients discharged alive. To assess reasons for readmission, all first readmissions within 30 days of discharge were categorized according to the primary diagnosis code using the US Agency for Healthcare Research and Quality Clinical Classification System,2DS2-VASc score). Mortality was expressed as the percentage of patients who died within 30, 90, and 180 days. Readmission rates for ischemic stroke and TIA were reported as the percentage of patients admitted for stroke or TIA within 180 days , as well as the rate of stroke or TIA admissions per patient-year of follow-up. In the latter estimate, patients were censored because of death or end of the observation period . Confidence intervals around the rate of stroke admissions were generated assuming a Poisson distribution. Stroke admission rates were reported for a composite representing ischemic stroke or TIA, as well as separately for TIA and ischemic stroke. Finally, we assessed trends in mortality and readmission rates over time and by CHA2DS2-VASc score using the Cochran-Armitage test for trend. Statistical analyses were performed using SAS statistical software version 9.4 (SAS Institute). All statistical testing was 2-tailed, with P\u2009<\u2009.05 designating statistical significance.Data analyses were conducted from January through August 2019. Summary statistics for patient characteristics were described as proportions for categorical variables , or using mean and SD for continuous variables (patient age and CHA2DS2-VASc score was 4.3\u2009(1.4), which would yield an expected annual ischemic stroke risk of 4.8%, according to previous work.10 There were 11\u2009980 white patients (87.9%), 455 black patients (3.3%), and 523 Hispanic patients (3.8%). 5 Compared with the randomized trials, the patients in the current study were older ; with a higher percentage of women; higher prevalence of congestive heart failure (41.9% vs 26.8% and 23.4%), hypertension (91.8% vs 89.6% and 88.5%), and diabetes (37.1% vs 24.4% and 33.8%); and a higher mean (SD) CHA2DS2-VASc score (4.4 [1.4] vs 3.4 [1.5] and 3.8 [1.2]).Overall, 13\u2009627 patients with AF underwent LAAC with Watchman implantation from January 2015 through November 2017. The mean (SD) age was 78.0\u2009(6.3) years, 7997 (59.7%) were men, 5630 (41.3%) were women, 9406 (69.0%) were older than 75 years, and their mean (SD) CHADuring the hospital admission for LAAC, 28 patients (0.2%) died. Over the observation period, mortality rates were 0.6% (80 patients) at 30 days, 1.9% (262 patients) at 90 days, 4.0% (547 patients) at 180 days, and 7.5% (1027 patients) at 1 year . The 30-14 are shown in The mortality and stroke readmission rates in the present study compared with those of previous studies2DS2-VASc score , within 180 days , and within 365 days . We compared the observed rates of ischemic stroke after LAAC via implanted device in our study with expected stroke rates in the absence of anticoagulation therapy according to CHA2DS2-VASc scores, using data from prior studies.10 We noted a 60% to 69% relative reduction in stroke risk after LAAC, compared with the risk in the absence of anticoagulation therapy , hypertension with complications (111 patients [0.8%]), cardiac dysrhythmias (103 patients [0.8%]), complications from a device or surgical procedure (84 patients [0.6%]), and septicemia (68 patients [0.5%]). There were 28 readmissions (0.30%) for hemorrhagic stroke within 180 days after LAAC via implanted device.5 our study had a higher percentage of women, and the patients had higher numbers of comorbidities and higher CHA2DS2-VASc scores. The risk of readmission for stroke (1.2% at 6 months) was significantly lower than that expected according to the mean (SD) CHA2DS2-VASc score of 4.3 (1.4) in the absence of anticoagulation therapy, which would yield an expected annual ischemic stroke risk of 4.8%, according to previous work.10To our knowledge, this is the largest study outside clinical trial to assess the characteristics of patients with AF undergoing LAACs and the associated outcomes of mortality, readmissions, and stroke. We noted that, compared with previous randomized clinical trials,11 of the PROTECT AF4 and PREVAIL5 randomized clinical trials compared 5-year outcomes for the 732 patients who underwent LAAC with the Watchman device with 382 patients in the control group treated with warfarin. In the LAAC groups of those studies,5 the incidence of ischemic stroke or systemic embolism was 1.6% per 100 patient-years, and the overall mortality rate was 3.6% per 100 patient-years. Left atrial appendage closure was associated with lower risk of all-cause mortality, as well as cardiovascular or unknown death, compared with warfarin. In the present study, readmission for ischemic stroke occurred in 111 of 9231 patients (1.2%) within 180 days after LAAC implantation. We observed a mortality rate of 7.5% at 1 year, and 28 patients (0.2%) died during the index admission for LAAC. There can be several explanations for the slightly higher rates of stroke and mortality in our study compared with the randomized clinical trials.5 Our study included an older patient population (aged >65 years) with higher numbers of comorbidities and higher CHA2DS2-VASc scores. Patients in the randomized clinical trials had to be eligible to receive warfarin to participate, which would likely preselect a healthier population. In contrast, eligibility for long-term anticoagulation therapy is not a requirement for the device implantation in clinical practice.A recent meta-analysis13 150 patients with AF who were not eligible for oral anticoagulation therapy underwent LAAC. Patients received aspirin and clopidogrel for 6 months after implantation and aspirin thereafter. The annualized ischemic stroke and systemic embolization rate was 1.8%, and the mortality rate at 1 year was 4.6%. Another long-term nonrandomized prospective real-world study from Europe, EWOLUTION ,14 reported 1-year outcome data for 1025 patients undergoing LAAC. The annual rate of ischemic stroke was 1.1% (15 of 1325 patient-years), and the 1-year mortality rate was 9.8%. Many of these patients were not eligible for anticoagulation therapy and underwent LAAC as a last resort option for stroke prevention. In both studies,14 the rate of stroke was lower than that in the present study. However, as observed in the present study, the 1-year mortality rate was significantly higher than those in the randomized studies,5 possibly because of the inclusion of patients with higher numbers of comorbidities.In the ASAP  nonrandomized study,This study is retrospective and based on Medicare claims data, which have inherent limitations. We only included patients aged older than 65 years; therefore, our results cannot be extrapolated to younger patient populations. Specific details regarding LAAC via device implantation, immediate complications, preimplantation and postimplantation antithrombotic therapy, or postimplantation left atrial appendage imaging results were not available. The exact cause of death and whether it was related to the Watchman implantation procedure were unclear.2DS2-VASc scores. Although LAAC provides an attractive nonpharmacological option for stroke prevention in patients with AF who are not candidates for long-term anticoagulation therapy, further prospective long-term real-world studies are needed to monitor its safety and efficacy.In this retrospective real-world study of Medicare patients aged older than 65 years with AF, LAAC via implanted device was associated with a decreased risk of admission for stroke compared with the expected risk without anticoagulation therapy. The risks of 1-year mortality and stroke at 6 months were higher than those in previous randomized clinical trials, likely because the population in the current study was older and had more comorbidities and higher CHA"}
+{"text": "Arthropodborne viruses (arboviruses) are transmitted to humans primarily through the bites of infected mosquitoes and ticks. West Nile virus (WNV) is the leading cause of domestically acquired arboviral disease in the continental United States , La Crosse virus (86), Jamestown Canyon virus (41), Powassan virus (21), St. Louis encephalitis virus (eight), eastern equine encephalitis virus (six), and unspecified California serogroup virus (four). Cases were reported from all states except Hawaii and New Hampshire. Of the 3,142 U.S. counties, 858 (27%) reported one or more arboviral disease cases.Overall, 2,647 WNV disease cases were reported from 787 counties in 48 states and DC. Of these, 1,658 (63%) cases were neuroinvasive and 2,435 (92%) patients had illness onset during July\u2013September . In 2018Among the 1,658 WNV neuroinvasive cases, 908 (55%) were reported as encephalitis, 542 (33%) as meningitis, 70 (4%) as acute flaccid paralysis, and 138 (8%) as an unspecified neurologic presentation. Of the 70 patients with acute flaccid paralysis, 25 (36%) also had encephalitis or meningitis. Among patients with neuroinvasive disease, 1,541 (93%) were hospitalized and 165 (10%) died. The incidence of WNV neuroinvasive disease in the United States was 0.51 per 100,000 population . The higLa Crosse virus disease cases (86) were reported from seven states, primarily in the East North Central and South Atlantic divisions . La CrosJamestown Canyon virus disease cases (41) were reported from eight states, primarily in the East North Central and West North Central divisions . JamestoPowassan virus disease cases (21) were reported from eight states, primarily in the New England and Middle Atlantic divisions . PowassaEight cases of St. Louis encephalitis virus disease were reported from four states  . The medSix cases of eastern equine encephalitis virus disease were reported from four states  . The medAs in previous years, WNV was the most common cause of neuroinvasive arboviral disease in the United States, accounting for 92% of reported neuroinvasive disease cases. The incidence of WNV neuroinvasive disease in 2018  was nearly 25% higher than the median incidence of 0.41 during 2008\u20132017 (range\u00a0=\u00a00.13 [2009]\u20130.92 [2012])  is consistently the leading cause of domestically acquired arboviral disease, but other arboviruses cause sporadic cases and outbreaks of neuroinvasive disease.WNV neuroinvasive disease incidence was nearly 25% higher in 2018 than the median incidence during 2008\u20132017. WNV transmission via organ transplantation was reported for the first time since 2013. The first documented case of Powassan virus transmission via blood transfusion was reported.Health care providers should consider arboviral infections in patients with aseptic meningitis or encephalitis, perform appropriate diagnostic testing, and report cases to public health authorities. Surveillance helps to identify outbreaks and guide prevention strategies."}
+{"text": "Deterioration of sediment quality has been found in the Nakdong River Estuary after large-scale reclamations. Here, I report microbial diversity in sediments of Nakdong River Estuary in the Republic of Korea based on 16S rRNA gene sequencing by next-generation sequencing (NGS) techniques. Proteobacteria, Firmicutes, Bacteroidetes, and Planctomycetes.Deterioration of sediment quality has been found in the Nakdong River Estuary after large-scale reclamations. Here, I report microbial diversity in sediments of Nakdong River Estuary in the Republic of Korea based on 16S rRNA gene sequencing by next-generation sequencing (NGS) techniques. The dominant bacterial phyla were  Nakdong River Estuary is the largest estuary in the Republic of Korea, and it has been protected by law since the 1960s to maintain a natural ecosystem because this estuary is of great value as seaweed and shellfish grounds. The estuary is a critical stopover site for migratory birds because of its location in the center of the East Asia-Australia flyway . Howeverde novo clustering the sequences by a 97% sequence identity cutoff using QIIME software (v1.8.0)  at Jinudo (sandbar), which is located in the northern part of Nakdong River Estuary , in July 2017 and stored at 4\u00b0C for further analysis. The sediment properties after sampling are shown in Proteobacteria (37.3%), Firmicutes (7.2%), Bacteroidetes (6.5%), Planctomycetes (5.3%), Chlamydiae (2.8%), Cyanobacteria (2.3%), Verrucomicrobia (1%), Arthropoda (0.7%), Spirochaetes (0.6%), Bacillariophyta (0.6%), and Chloroflexi (0.3%). This diverse microbial abundance denotes that multifaceted mechanisms are proceeding in Nakdong River Estuary. These results provide expanded knowledge of the microbial community of Nakdong River Estuary and aid in developing appropriate strategies and management tools for Nakdong River Estuary.The taxonomic classifications at the phylum level were as follows: SRP157404.The 16S rRNA gene amplicon sequences obtained from this study have been deposited in the Sequence Read Archive (SRA) of the NCBI database under the project accession number"}
+{"text": "Background: Metastatic renal cell carcinoma is chemoresistant and radioresistant disease with poor survival historically, but outcome has improved in past decade after introduction of tyrosine kinase inhibitors like sunitinib and sorafenib. Sorafenib has not been tested in Indian patients with metastatic RCC till now. Material and Methods: This is a single arm, prospective, observational study done in unselected population of 60 patients with metastatic RCC treated with sorafenib as first- line therapy to assess efficacy and safety. Results: Twenty three out of 60 patients (38.33%) continued sorafenib by the end of the study. Overall response rates (ORR), stable disease (SD) and disease control rates (DCR) were 35%, 43.33% and 78.33%, respectively. Median progression- free survival (PFS) and overall survival (OS) were 6 and 8 months, respectively and associated with histopathology, Memorial Sloan Kettering Cancer Centre (MSKCC) risk groups, Heng risk groups and performance status. Best tolerated dose was 400 mg per day which was half of standard dose. Fatigue, diarrhea, rashes and hand foot syndrome were common side effects while hypertension was rare. Conclusion: Sorafenib, as first-line therapy, is an effective and safe treatment in Indian patients with metastatic RCC with poor tolerance to dose more than 400 mg per day. Side effects are mostly manageable. However, 5-year survival for the 30% patients who present with advanced and metastatic disease3 and another 25% patients who undergo localized resection and relapse with metastases5, is less than 10%3. Chemotherapy is not effective and cytokine therapy with interleukins or interferon-alfa produce modest response at the cost of significant toxicities in metastatic RCC5-7.  Renal cell carcinoma (RCC) accounts for 3% of adult malignancies globally8,9. Prognosis of metastatic RCC has improved significantly in recent time due to understanding of its molecular pathways. Von-Hippel-Landau (VHL) gene, a tumor suppressor gene which is regulator of platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and other hypoxia-inducible factors (HIF) are found to be deleted, mutated, or altered in up to 80% of the patients with clear cell carcinoma, the most common subtype of RCC accounting for more than 80% of cases10. In placebo controlled trials, sorafenib has shown to improve progression-free survival (PFS) versus placebo in the treatment of naive patients and improvement both PFS and overall survival (OS) in treatment refractory patients11,12. It is relatively cheap, so suitable for Indian patients. Sunitinib and pazopanib, the other tyrosine kinase inhibitors which have shown to improve progression-free survival in phase III trials in patients with metastatic RCC as first-line therapy are beyond reach of most patients at our institute because of financial constraints13,14. Moreover, recent analysis showed no significant difference in PFS and OS between sorafenib and sunitinib as first-line therapy15,16. Data regarding use of tyrosine kinase inhibitors in Indian patients with metastatic RCC is sparse and sorafenib was never tested before among Indian patients with metastatic RCC to our best knowledge. So, this single arm, prospective, observational study was conducted at Gujarat Cancer & Research Institute to determine efficacy and safety of sorafenib among Indian patients with metastatic RCC.Sorafenib is a multikinase inhibitor which inhibits tumor proliferation and angiogenesis by inhibiting vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3, platelet-derived growth factor receptor \u03b2 (PDGFR\u03b2); FMS-like tyrosine kinase 3 (Flt-3) c-Kit protein (c-Kit), Raf and RET receptor tyrosine kinasesStudy designThis is prospective, single arm, single centre, observational study done at Gujarat Cancer & Research Institute over a period of three and half years (42 months) from January 2013 to June 2016.The study included patients at least 18 years of age with histologically confirmed metastatic renal-cell carcinoma (RCC) with adequate bone marrow, liver, pancreatic, and renal function treated with sorafenib as first-line treatment. Patients with performance status within the range of the Eastern Cooperative Oncology Group (ECOG) criteria also entered the study.Dose modificationsStarting dose of sorafenib was determined based on performance status, comorbidity and biochemistry profile. Doses were delayed or reduced if patients had clinically significant adverse events that were related to sorafenib. In such cases, doses were reduced to 400 mg once daily, and then to 200 mg once daily. If further reductions were required, sorafenib was permanently stopped. If adverse events resolved to a grade of 1 or less, the dose could be escalated to the previous level. Baseline evaluation This included medical history and physical examination, tumor imaging with computed tomography (CT) or magnetic resonance imaging (MRI) scans of the chest, abdomen and pelvis as well as bone scan, assessment of ECOG performance status, laboratory measurements , cardiac function with electrocardiogram and two- dimensional echocardiography. Primary end pointProgression-free survival (PFS) was calculated as the time between the start of therapy and the date of progression or death from any cause.Secondary end pointObjective response rate (ORR), overall survival (OS) and safety. ORR defined as the proportion of patients with confirmed complete response (CR) or partial response (PR). Clinical response {CR, PR, stable disease (SD)} and progressive disease (PD) were assessed according to response evaluation criteria in solid tumors (RECIST) using CT scans, MRI and bone scans (if bone metastases were present at baseline). Evaluations were done at regular intervals usually every 2 to 4 months. OS was calculated as the time between the start of therapy and the date of death due to any cause.Toxicities were documented using the National Cancer Institute\u2013Common Toxicity Criteria version 4.0 .Statistical analysisData were analysed using SPSS. Survival was calculated using Kaplan-Meir method. Between January 2013 and June 2015, a total of 70 patients with metastatic RCC were included in the study. All study participants received sorafenib and followed- up for a minimum of one year. Ten patients were lost at follow up and were therefore subsequently excluded from the study.Baseline characteristics18 and Heng risk groups19. Based on these prognostic schemes, seven patients (11.67%) with no risk factor were in favourable risk group, twenty-nine patients (48.33%) with one or two risk factors in intermediate risk group and twenty-four patients (40%) with three or more risk factors in poor risk group. . Most common sites of metastasis were lung (66.67%) followed by bone (36.67%) and liver (20%). There was 100% concordance between Memorial Sloan Kettering Cancer Centre (MSKCC) risk groupsk group.  Patients with ECOG performance status 1 without comorbidity and good nutritional status were started with 600 mg of sorafenib once daily, while patients with ECOG performance status 1 with comorbidity or poor nutritional status and ECOG performance status 2 without comorbidity and good nutritional status were started on 400 mg of sorafenib once daily. Sorfenib in dose of 200 mg once daily was offered as starting dose to patients with ECOG performance status 2 with comorbidity or poor nutritional status and ECOG performance status 3. Among the 60 evaluable patients, starting dose of sorafenib was 600 mg in 11 patients (18.33%), 400 mg in 39 patients (65%) and 200 mg in 10 patients (16.33%).EfficacyIn this study, the median PFS with sorafenib was 6 months (range: 0.5 to 27 months), and the median OS was 8 months (range of 0.5 to 42 months). ORR (CR+PR) with sorafenib as first-line was 35% , and disease control rate (DCR=CR+PR+SD) was 78.33% (SD=43.33%). One- year PFS was 23.33%, and one-year OS was 43.33% in this study. The median PFS and OS were significantly longer in patients with clear cell carcinoma than patients with non-clear cell carcinoma histology . Median Table 5).SafetyToxicity profile of sorafenib is shown in Discontinuation and Dose modifications: Twenty- three out of 60 patients (38.33%) were continued with sorafenib at the end of study. Among the remaining 47 patients (61.67%), the reason for discontinuation was progression in majority of patients . Only 3 patients (6.38%) discontinued sorafenib due to tolerance issue. Patients had very poor tolerance to 600 mg daily dose of sorafenib. Among the 11 patients treated with 600 mg daily dose of sorafenib, two toxic deaths (18.18%) were seen and 8 patients (72.72%) required dose reduction to 400 mg once daily mostly due to rashes and hand foot syndrome. Dose reductions were not required in patients treated with daily dose of 400 mg and 200 mg and no toxic death was noted in these patients. Dose escalations from starting dose were never possible due to tolerance issues.3,4,6,7. With increase understanding of its molecular pathway and realizing importance of VHL gene, tyrosine kinase inhibitors were developed for treatment of metastatic RCC8,9. Treatment of metastatic RCC was challenging in the past as chemotherapy and radiotherapy were not much effective and cytokine therapy with interleukin-2 or interferon alfa had limited efficacy and considerable toxic effects11. These results were comparable to our study.Sorafenib was the first tyrosine kinase inhibitor which was approved by the United States Food and Drug Administration (US-FDA) in December 2005. It was considered as monotherapy by Ratain MJ et al for advanced RCC based on phase II trial in untreated patients of metastatic RCC. The results found an ORR of 36% (73 out of 202 patients) and SD of 32 % (65 out of 202 patients) with significant PFS advantage of 24 weeks for sorafenib versus 6 weeks for placebo in the 65 patients with stable disease at 12 weeks postrandomization12. The median OS was 19.3 months in sorafenib group and 15.9 months in placebo group which did not reach prespecified boundaries for statistical significance. A subsequent phase III, randomized, placebo controlled trial of sorafenib in dose of 400 mg twice daily demonstrated significant PFS advantage of 5.5 months in sorafenib group versus 2.8 months in placebo group in treatment refractory patients of metastatic RCC20. CR, PR and disease control rates (DCR) were 0%, 5.2% and 79.4%, respectively for sorfenib versus 1.1%, 7.6% and 64.1%, respectively for interferon alfa-2a. Only patients with ECOG performance status 0 and 1 and clear cell histology were included. In our study, we found almost similar PFS, but better PR and DCR with sorafenib in unselected patients with metastatic RCC. In a recently published PREDICT study performed on unselected patients of metastatic RCC, ORR and DCR were 23.4% and 70.4%, respectively overall and 31.4% and 94.6%, respectively after excluding patients with no radiological assessment21. The median PFS was 7.6 months in patients with no prior therapy and 7.1 months in patients who received one or more prior therapies. These results are similar to those obtained in our study.First-line therapy with sorafenib was compared with interferon alfa-2a and it was found that both treatments were similar (5.7 months versus 5.6 months) with regard to PFS, but patients treated with sorafenib had greater tumor shrinkage (68.2% versus 39%), better quality of life and improved tolerability22,23. Sorafenib was found to be effective in Asian patients as well. In a Chinese study, CR, PR, ORR, SD, DCR median PFS and 1-year PFS were 1%, 23.5%, 24.5%, 63.3%, 87.8%, 60 weeks and 58.4%, respectively, while in a Korean study, ORR, DCR and median PFS in patients with metastatic RCC treated with with sorafenib as first-line therapy were 23.2%, 56% and 7.4 months, respectively. PFS data in these studies were better than those of our study24,25,16. Sorafenib is useful first-line therapy even after introduction of sunitinib in treatment of metastatic RCC. Though an indirect comparison meta-analysis of 6 trials showed superiority of sunitinib over sorafenib and bevacizumab plus interferon alfa, a Korean study and a retrospective analysis in Chinese patients reported no difference in PFS and OS between sunitinib and sorafenib as first-line therapy25, 26. This is the first study establishing efficacy and safety of sorafenib in Indian patients with metastatic RCC. Further studies are required to compare sorafenib with sunitinib as first-line treatment in Indian patients. We also validated prognostic schemes by MSKCC and Heng in Indian patients18, 19.Data regarding the use of tyrosine kinase inhibitors are sparse. Only sunitinib was tested in Indian patients with PFS of 11.4 months in a study from Tata Memorial Hospital and PFS of 7.5 months in another study from our institute12. This study showed higher incidence of fatigue, diarrhea, skin rashes and hand-foot syndrome but lower incidence of hypertension compared to Chinese and Korean studies22,23. Different polymorphisms in genetic profile and different metabolism might be responsible for this difference which needs to be further investigated.In this study, it was shown that Indian patiets have very poor tolerance to standard dose of sorafenib. No patient in our study could be escalated to standard dose of 800 mg per day and 72.72% receiving dose of 600 mg per day required dose reduction with two toxic deaths (18.18%). However, patients receiving 400 mg or 200 mg daily dose tolerated well with no dose reduction or toxic death in these groups. Four hundred milligram daily dose was best tolerated dose of sorafenib in this study which was half of that given in the above- mentioned study. Still, our results were comparable to most of studies. Most common toxicities related to sorafenib were fatigue followed by diarrhoea, rash, hand foot syndrome and myalgia. The most common grade 3 or higher toxicities related to sorafenib requiring dose modifications were rash, hand foot syndrome and diarrhoea. Toxicity profile was different in this study. Our patients reported more fatigue, similar diarrhea, rash and hand foot syndrome and less hypertension than western patients Sorafenib is one of the several agents that target proangiogenic growth factor pathway in the pathogenesis of metastatic RCC and is shown clinical activity in clinical trials so it is a viable option. This is the first study establishing its safety and efficacy in Indian patients with comparable response rates and PFS to most of studies. In the present study, a half dose of Sorafenib was better tolerated by patients compared to other studies. Toxicity profile was different and most of the side effects were easily manageable. Careful patient selection, dose adjustment, counselling and follow- up are required to get optimal results."}
+{"text": "In 2013, the 66th session of the Regional Committee of the World Health Organization (WHO) South-East Asia Region (SEAR)Before 2000, only two of the 11 SEAR countries (Sri Lanka and Thailand) included RCV in the routine infant immunization schedule. By the end of 2016, eight (73%) countries had introduced RCV . India, Rubella cases and outbreaks were reported by three countries  in 2000, by nine countries  in 2010, and by all 11 countries in 2013. By 2016, case-based measles-rubella surveillance had been initiated in all SEAR countries and included rubella immunoglobulin M (IgM) antibody testing for all suspected measles casesThe number of SEAR countries reporting CRS cases through the WHO-UNICEF Joint Reporting Form (JRF)From 2010 to 2016, reported annual rubella incidence in SEAR decreased 37%, from 8.6 to 5.4 cases per 1 million population. Five countries reported <1 rubella case per 1 million population in 2016, including four  that reported a decrease in incidence of \u226595% since 2010 . In 2016Substantial progress was made toward rubella and CRS control in SEAR during 2000\u20132016, with a 37% decline in reported rubella incidence. Momentum for rubella and CRS control was accelerated by the Regional Committee with the establishment of a regional goal in 2013 to achieve measles elimination and rubella and CRS control by 2020  and to verify progress toward rubella and CRS control goals. As countries progress toward elimination of endemic rubella virus transmission, elimination-standard surveillance will be required  had achieved \u226595% reduction in rubella cases since 2010  countries had introduced rubella-containing vaccine (RCV) into routine immunization programs.During 2000\u20132016, six additional SEAR countries introduced RCV, and first dose RCV (RCV1) coverage increased from 3% (2000) to 15% (2016). During 2010\u20132016, reported rubella incidence decreased 37%, from 8.6 to 5.4 cases per 1 million population. Bangladesh, Maldives, Sri Lanka, and Thailand likely have controlled rubella and congenital rubella syndrome (CRS).Rubella and CRS elimination in the region might be considered with investment in high routine RCV coverage, periodic high-quality supplementary immunization activities, and improved rubella and CRS surveillance. With the introduction of RCV in India and Indonesia beginning in 2017, regional RCV1 coverage is expected to increase rapidly."}
+{"text": "Cochrane generates and disseminates high-quality systematic reviews through the cochrane library. We surveyed Ethiopian health professionals' knowledge and experience with cochrane, the cochrane library and Evidence Based Medicine (EBM).A cross-sectional survey was conducted using a convenient sample of health professionals in DebreBerhan Referral hospital in Ethiopia. Participants completed a pre-tested self-administered survey before EBM training. Data were analyzed using Fisher's exact or Chi-Squared test with Yates' correction. The strength of association between variables was quantified using odds ratios with 95% confidence intervals.The response rate was 71.4% (35/49). Over half (54.3%) of the sample were males; 68.6% aged \u2264 30 years; 54.3% were physicians and 37.1% were nurses. Up to 65.7% had heard about Cochrane and only two knew cochrane South Africa as their reference centre. Nearly 48.6% were aware of the cochrane library, of whom 46% accessed it however; none used it for lacking awareness, search skills, access to internet and time constraints. Majority had a positive attitude towards EBM; 45.7% had heard of EBM; 74.3% rated their EBM knowledge as low; 74.3% lacked EBM training; and 88.6% were keen to attend EBM course. Adequate EBM knowledge was correlated with prior training , male gender (P = 0.04), a positive attitude towards EBM (P = 0.001) and awareness of Cochrane (P = 0.004).Ethiopian health professionals have unmet training needs and want support through professional development workshops and an improved education system to provide high-quality evidence-based healthcare. Evidence Based Medicine (EBM) is the integration of clinical expertise with the best research evidence and patient values and preferences to formulate the right decisions to care for individual patients . The EBMStudy setting and design: A cross-sectional survey was conducted in September 2014 at DebreBerhan Hospital in Ethiopia. It is the only public regional referral hospital in the area serving about 2.4 million population. The hospital has 130 beds, 366 employees , treats about 450 patients daily and provides curative and preventive services at inpatient and outpatient departments [artments .Participants: They were mainly practicing physicians and nurses who were nominated to participate in EBM training, which was funded by the American International Health Alliance [Alliance . The traAssessment, collection and data management: The survey was designed by Cochrane South Africa (CSA) and used in the 2004 study of people in developing countries on the challenges they face to contribute to Cochrane, and has been described previously [eviously , 24. AftData analysis: The Shapiro-Wilk test showed the total EBM knowledge scores was normally distributed  but not the total attitude scores . Using the mean value of 4.26, the participants' total knowledge score was classified as inadequate or adequate. To categorize their overall attitude towards EBM score as negative or positive, the median score of 2 was applied. The association between categorical parameters were tested by Fisher's exact or Chi-Squared tests with Yates' correction. An odds ratio with 95% confidence interval was calculated to assess the strength of association. All statistical tests were two tailed and a P value of less than 0.05 was applied for statistical significance. The IBM SPSS Statistics for Windows (Version 20.0) was used for data analysis.Participants: Out of 49 participants who attended EBM training, 35 (71.4%) completed the survey. The median time to complete the survey was 11 min (Interquartile range 9-20). Sixteen (46%) of the participants were females and 19 (54.3%) were males; 24 (69%) were \u2264 30 years old and 11 (31.4%) between 31-40 years of age; 19 (54%) were physicians, 13 (37%) nurses, and 3 (9%) were in other profession . Of the total 19 physicians, 15 (79%) were general practitioners and four (21%) specialists . All were very comfortable or comfortable in reading and writing English language. The study participants (n = 35) and nonparticipants (n = 14) were comparable on a range of socio-demographic variables. For easy of analysis and clarity, the responses from three other professionals and 13 nurses was combined and presented in this report.Knowledge of Cochrane and evidence based medicine: Twenty-three (65.7%) of the participants have heard about Cochrane and 12 (34.3%) did not. Awareness of Cochrane was 68.8% for nurses and 63.2% for physicians with no significant difference between the two groups (P = 0.73). Most gained their awareness of Cochrane from conferences or internet sites (43.5%), followed by colleagues (39%) and other sources (17.4%) such as journal articles, supervisors and training. Overall awareness of Cochrane was not associated with gender (P = 0.14). Asked whether Ethiopian health professionals were familiar with Cochrane, 19 (54.3%) stated that they were. When asked to identify the Cochrane Reference Centre for Ethiopia, only two (5.7%) participants identified Cochrane South Africa and the large majority  did not know. Of the total participants, 16 (45.7%) had heard of EBM and 19 (54.3%) had not. Awareness of EBM among physicians (68.4%) was significantly higher than nurses (18.8%) . Similarly, significantly more male participants (68.4%) than females (19%) had awareness of EBM . Awareness of EBM was not associated with age group (P = 0.26). When asked if they had attended EBM training, only 9 (25.7%) indicated that they had and 26 (74.3%) had not attended any training. The level of EBM training was comparable between nurses (31.3%) and physicians (21.3%) (P = 0.07). Attitude towards evidence based medicine: The large majority approved that the use of EBM in clinical practice was beneficial  of the participants were judged to have adequate knowledge and 19 (54.3%) inadequate knowledge of EBM. The rate of adequate knowledge of EBM was comparable between nurses (43.8%) and physicians (47.4%) (P = 0.83). Similarly, 13 (37.1%) were considered having a positive attitude and 22 (62.9%) a negative attitude towards EBM. The proportion of nurses (25%) and physicians (47%) with a positive attitude was comparable (P = 0.31). The participants with adequate knowledge of EBM were more likely to show a positive attitude towards EBM (P = 0.001) (= 0.001) . Adequat= 0.001) .Knowledge of the Cochrane library: Of the total 35 participants, 17 (48.6%) reported awareness of the Cochrane Library and knew it was free online access in Ethiopia. Yet, 18 (51.4%) were unaware and had no idea how to access it. This result did not differ between nurses (50%) and physicians (47.4%). A follow-up question asked if the general population of Ethiopian health professionals had awareness of the Cochrane Library. Fifteen (42.9%) of the participants believed that they were aware whereas 20 (57.1%) were unsure.Use and factors associated with accessing the Cochrane library: Twenty-four (68.6%) of the participants had accessed the Cochrane Library while 11 (31.4%) did not. None of the 24 who indicated accessing the resource had used it because of difficulties. Their two most common individual barriers were unawareness of the resource (54.2%) and lack of search skills (45.8%). They also reported system barriers involving the lack of access to reliable internet (45.8%), inadequate facilities or resources relating to computers and library services (12.5%), poor access to the Cochrane Library and insufficient time at work (8.3%).The study participants also proposed enablers to overcome their barriers. The majority (80%) wanted hands-on training to develop information searching skills; 45.7% suggested raising awareness of the Cochrane Library; 14.3% proposed easy access to internet; and 8.6% sought more computers to be accessible at the point of care.In the present survey, most health professionals have heard of Cochrane from various sources. This finding is consistent with evidence from India  but loweEqually, 8.5% of Sri Lankan doctors  and 4.3%Ethiopian practicing health professionals have unmet training needs to provide evidence-based healthcare. A focused strategic plan of action should be developed to overcome their personal and organizational barriers to practice EBM. Establishing a hospital committee that develops a framework and policy for EBM program must be considered. Awareness sensitization campaign, in-service training and upgrading the health infrastructure, including the internet service are critical to promote the use of Cochrane Library among clinical staff. The set up of EBM journal club in hospitals also helps an increased awareness and use of evidence, as well as assist clinical staff to keep up-to-date with the medical literature.Major barriers to awareness of Cochrane, the Cochrane Library and evidence-based practice exist in Africa;Strong political commitment, leadership and policy are lacking for evidence-based practice in Africa.Medical  institutions in Africa can have positive impact in fostering awareness about Evidence Based Medicine and use of the Cochrane Library among future cohorts of health workers;The importance of integrating Evidence Based Medicine into continuing professional development program and medical  education in Africa.The authors declare no competing interest."}
+{"text": "PGR and ESR1) were common to four cancers of women. From network analysis, we identified a novel linker gene, C3AR1, which had not been implicated previously in endometriosis. The shared genetic mechanisms of endometriosis and cancers in women identified in this study provided possible new avenues of multiple disease management and treatments through early diagnosis.Endometriosis is a chronic disease occurring during the reproductive stage of women. Although there is only limited association between endometriosis and gynecological cancers with regard to clinical features, the molecular basis of the relationship between these diseases is unexplored. We conducted a systematic study by integrating literature-based evidence, gene expression and large-scale cancer genomics data in order to reveal any genetic relationships between endometriosis and cancers in women. We curated 984 endometriosis-related genes from 3270 PubMed articles and then conducted a meta-analysis of the two public gene expression profiles related to endometriosis which identified Differential Expression of Genes (DEGs). Following an overlapping analysis, we identified 39 key endometriosis-related genes common in both literature and DEG analysis. Finally, the functional analysis confirmed that all the 39 genes were associated with the vital processes of tumour formation and cancer progression and that two genes ( Endometriosis is a chronic disease of women occurring at the reproductive stage of their lives. Worldwide, approximately 176 million (6\u201310%) women are affected by this disease  diagnoseEndometriosis, along with breast cancer, are estrogen-dependent chronic gynecological disorders and have similar risk factors associated with reproduction and the use of hormone replacement therapy . In addiCervical cancer is the abnormal growth of cells in the lining of the cervix. The most common cervical cancer is squamous cell carcinoma . On the Although endometriosis and endometrial cancer are two separate diseases, epidemiological, biological, and molecular data suggest that there could be links between the two disorders . EndometTherefore, a detailed investigation on the genetic control of the different cancer types along with endometriosis is necessary in order to explore the relationships between these two diseases. Over the last few decades, a large number of genetic data have been generated using next generation sequencing (NGS) technology and these can be used to decipher the genetic relationships between the two types of diseases. Therefore, we have conducted a meta-analysis of NGS data to explore evidence concerning the genomic and functional relationships of endometriosis and cancers in women.To explore the genetics of endometriosis, we conducted a literature search and extracted 3270 records from the GeneRIF (Gene Reference into Function), a database providing lists of genes and their functions . We curaGSE2339 and GSE5108) related to endometriosis that were collected from the gene expression omnibus (GEO) database, a repository of high-throughput gene expression data of original submitter-supplied records and curated records. Using GEO2R, we compared endometriosis samples with that of healthy individuals and, using the data filtering criteria of adjusted P values <0.05 and an absolute fold change >2, identified genes that are differentially expressed  state set presenting the molecular mechanisms underlying the pathology of endometriosis  genes  genes  shared aGO:0042127; P-value: 1.03E\u201341), growth , apoptotic process , and cell adhesion  , five  to progesterone  and 45 to cytokine . Thirty-one genes were associated with cytokine production  and 17 genes involved in the ERK1 and ERK2 cascades   and MAPK cascade  play important roles in cell development processes related to cancer progression.Functional enrichment analysis of the 165 genes shared by our curated endometriosis-related gene list and at least one GEO dataset was conducted using Gene Ontology (GO) terms as functional units . The res.47E\u201317) . All the.27E\u201310) . In addiGO:0006915; P-value =3.47E\u201306), the regulation of the cell cycle , cell proliferation , cell death , and cell differentiation . Our study also found that five genes are also involved in the enrichment of estrogen  and four in the enrichment of progesterone . Ten genes were found to be associated with angiogenesis , twelve genes in responses to cytokine  and seven genes in cytokine production . Eleven genes were involved in the MAPK pathway  and five genes were involved in ERK1 and ERK2 cascade   .C3 is common in both estrogen, progesterone, angiogenesis, cytokine production, MAPK pathway, ERK1, and ERK2. Pleiotrophin (PTN), a member of a highly conserved human gene family , VCAM1 (61), DAPK1 (54), CD14 (53), HLA-DRA (53), TFAP2C (51), CCR1 (50), CDH3 (47), CXCL12 (46), TIMP1 (46), BGN (45), CSF1R (43), MMP9 (43), CNN1 (41), LIPC (41), CDH1 (40). From the derived network, we identified novel linker genes showing functional links with the endomitriosis related genes. Among the identified linker genes, twenty genes  have more than >20 connections. Results suggested that these linker genes can be used in prognostic studies of endometriosis.The network analysis of the 165 endometriosis related genes showed that most of the genes has more than 20 connections. We found maximum connections (75) in TAGLN had highest number of connections (23) followed by CSF1R (17), ESR1 (16), THBS1 (16), IRF6 (14), PLA2G2A (12), BDNF (10), and PLCB1 (10). We also revealed 20 novel linker genes  connected with the 39 genes. Among the linker genes, 16 genes had 10 or more connections with highest in CFI (25) followed by C3AR1 (24), IGFBP1 (21), VEGFA (19), IRF8 (18), IGFBP5 (18), CSF1 (15), PARD3 (15), FEZ1 (14), FOXF1 (14), OVGP1 (13), PARD6A (13), CD47 (12), PGF (12), IRF5 (10), and PAX2 (10).A network analysis of 39 genes is presented in . By focuy=axb, where a = 2.684 and b is an exponent with an estimated value of \u22120.110. The correlation between the given data point and the corresponding point on the fitted curve is 0.195 (R2\u00a0=\u00a00.014). Topological analysis on the shortest path length distribution analysis shows that the average length of the shortest path is 2, which indicates that the number of nodes which instantly connected  genes with >4% of genetic alterations frequency. IRF6 showed 6% and SOX17, MSR1, PTGIS showed 3% in the TCGA breast invasive carcinoma tumor samples. In TCGA uterine corpus endometrial carcinoma samples, there were nine  genes with >5% alteration frequency. Three genes  showed >7% alteration frequency in the TCGA cervical squamous cell carcinoma. Most of these alterations were related to amplification. MME, SOX17, AGTR1, PGR, and ESR1 had the highest amplifications frequency ranging from 4% to 11% in ovarian serous cystadenocarcinoma. We observed similar features in the uterine corpus endometrial carcinoma dataset: the genes with the highest frequency included SOX17 and C3 (8%), PAX8, MME and ESR1 (7%). In breast invasive carcinoma, IRF6 showed the highest rate of alteration (6%) followed by SOX17 and MSR1 (3%). In the case of cervical squamous cell carcinoma, alteration frequency was greatest in MME (10%), followed by PGR (9%) and AGTR1 (8%). Therefore, all these endometriosis-related genes are associated with gene amplification events across the four cancers of women TCGA samples.In addition to the sample analysis, we explored the genomic alterations in multiple genes across several tumor samples \u20133D. We uC3AR1) is within the 165 full gene list, which was identified by overlapping analysis between literature-based endometriosis-related genes and one set of GEO datasets.We applied the network analysis and constructed a gene network to identify the global connections of the 39 genes identified by overlapping analysis between endometriosis-related genes and two GEO datasets. The derived network comprised 20 linker genes that were shown to connect with core genes. Interestingly, one of those linker genes (C3AR1 (PARD3 and C3AR1 (both 3%), followed by CD47 (2.6%) and IRF8 (2.4%). The graphical presentation of expression result from cBioportal  followed by BRCA1 (4%), PGR (4%) and ESR1 (4%). IGF2 had the lowest rate of alteration (1%). TCGA data sets collected from the eleven studies provided 7,462 samples in which the maximum rate of genetic alteration occurred in endometrial carcinoma (36.86% of 529 cases), followed by ovarian epithelial tumor (27.69% of 585 cases), invasive breast carcinoma , and ovarian cancer   .GO:0050847; P-value =2.90E\u201303); the hormone-mediated signalling pathway ; and the intracellular receptor signalling pathway   . Among tEndometriosis is the hormone-dependent abnormal growth of endometrial epithelial and stromal cells outside the uterine cavity which may cause chronic pelvic pain, subfertility and result in an increased risk of ovarian cancer . In a prIn this study, functional analysis of endometriosis-related genes revealed shared mechanisms of endometriosis concerned with four cancers of women. This was particularly the case for cell proliferation, growth, apoptotic process, cell adhesion, regulation of cell cycle, regulation of cell death, and regulation of cell differentiation. The control of cell proliferation and apoptosis are the key regulatory mechanisms of cancer progression. The apoptotic process is highly regulated in human cells and essential for maintaining the physiological balance between cell death and cell growth . DiffereMAPK (mitogen-activated protein kinases), ERK1 and ERK2, are activated in endometriosis. MAPK act as integration points for many biochemical signals and are involved in a variety of cellular processes, including cell proliferation, differentiation, transcription regulation and development , which is a zinc-dependent endoprotease and also involved in ECM re-modulation and conversion of plasminogen to angiostatin  with high amplification frequency compared to other genes across the cancer types. These genes are all involved in endometriosis suggesting their involvement in the progression of cancers in women.We identified that the alteration frequency was highest (5%) in ignaling . Gene IRectoderm , also shiostatin . FinallyPGR and ESR1) were common to four cancers of women. Mutational analysis proved that eight endometriosis genes had a higher rate of alterations across the four cancers in women. Finally, we explored a novel linker gene, C3AR1, which had not been implicated previously in endometriosis. The evidence of shared genetic mechanisms of endometriosis and cancers in women may be an avenue of future disease management and treatment through early diagnosis. This article provides a catalogue of genetic links between endometriosis and cancer as a guide for further investigation and analysis.Using integrated bioinformatic analysis we discovered evidence of genetic link between endometriosis and women\u2019s cancers. We utilized information from next generation sequence data and compiled a list of a large number of endometriosis related genes. Functional analysis confirmed that 39 genes were associated with the processes of tumour formation and cancer progression of which two  genes shared at least one GEO dataset, 39 genes shared between two GEO dataset and 52 genes common in four women specific cancer.Click here for additional data file.10.7717/peerj.8135/supp-3Table S1Click here for additional data file.10.7717/peerj.8135/supp-4Table S2Click here for additional data file.10.7717/peerj.8135/supp-5Table S3Click here for additional data file.10.7717/peerj.8135/supp-6Table S4Click here for additional data file."}
+{"text": "In light of recurrent outbreaks of circulating vaccine-derived poliovirus 2 (cVDPV2) in Nigeria, we describe the genome sequence of a coxsackievirus A20 strain (CVA20). JX275140 and KX162716) found in Nigeria were from indigenous enterovirus species Cs (EV-Cs).In light of recurrent outbreaks of circulating vaccine-derived poliovirus 2 (cVDPV2) in Nigeria, we describe the genome sequence of a coxsackievirus A20 strain (CVA20). The nonstructural region (NSR) of this CVA20 genome showed that the enigmatic NSRs in recombinant cVDPV2s (GenBank accession numbers  Enterovirus, family Picornaviridae, and order Picornavirales. The genus has 15 species, and poliovirus (the best characterized member of the genus) belongs to species C. Several coxsackie A viruses  and some numbered EVs are nonpolio enterovirus members of species C (NPEV-C).Enteroviruses (EVs) belong to the genus In 2016, we detected a CVA20 strain from a child with acute flaccid paralysis (AFP) in Nigeria (The genome of the isolate was amplified in overlapping fragments 2 to 3 kb each) as previously described  kb each  with defMH785183), with 7,091 nucleotides , was assembled from 865,833 (24.4%) of the 3,548,364 reads generated. The genome has a G+C content of 45% and encodes two proteins  in overlapping open reading frames (ORFs) (JX275140) (87.09%) and NIE1519325 (GenBank accession number KX162716) (86.70%). NIE0811456 and NIE1519325 are recombinant circulating vaccine-derived poliovirus 2 strains (cVDPV2s) with a nonstructural region of unknown origin recovered in Nigeria in 2008 (The genome for CVA20 strain NGR_2016 (GenBank accession number 865,833 2.4% of th in 2008 . It also in 2008 . TherefoMH785183. The raw reads have also been deposited in the SRA with the BioProject accession number PRJNA554498.The genome described here has been deposited in GenBank under the accession number"}
+{"text": "Journal of Experimental Botany, (2012) 63(13): 4887-4900, doi: 10.1093/jxb/ers163f and anti TRXs m) were inadvertently duplicated. The experiment was repeated and In the above article several bands of the western blottings of figures 4 and 5 (anti TRXs The figures now appear as below:The authors apologize for these errors which have been corrected online."}
+{"text": "Quantifying interference of maternal antibodies with immune responses to varying dose schedules of inactivated polio vaccine (IPV) is important for the polio endgame as IPV replaces oral polio vaccine (OPV).Type 2 poliovirus humoral and intestinal responses were analyzed using pre-IPV type 2 seropositivity as proxy for maternal antibodies from 2 trials in Latin America. Infants received 1 or 2 doses of IPV in sequential IPV\u2013bivalent oral polio vaccine (bOPV) or mixed bOPV-IPV schedules.Among infants vaccinated with bOPV at age 6, 10, and 14 weeks of age and IPV at 14 weeks, those with type 2 pre-IPV seropositivity had lower seroprotection rates than seronegative infants at 4 weeks  and 22 weeks  post-IPV. A second IPV at age 36 weeks resulted in 100% seroprotection in both groups. Among infants vaccinated with 1 IPV at age 8 weeks followed by 2 doses of bOPV, pre-IPV type 2-seropositive infants had lower seroprotection at age 28 weeks than those who were seronegative . A second dose of IPV at 16 weeks achieved >97% seroprotection at age 24 or 28 weeks, regardless of pre-IPV status. Poliovirus shedding after challenge with monovalent OPV, serotype 2, was higher in pre-IPV seropositive infants given sequential IPV-bOPV. No differences were observed in the mixed bOPV-IPV schedule.The presence of maternal antibody is associated with lower type 2 post-IPV seroprotection rates among infants who receive a single dose of IPV. This impact persists until late in infancy and is overcome by a second IPV dose. The global effort to eradicate polio has resulted in near-complete interruption of wild polio virus transmission . After tWe analyzed data from 2 recently published studies to evaluate the impact of type 2 poliovirus seropositivity before IPV administration\u2014as a surrogate of maternally derived antibodies\u2014on serotype 2 humoral and intestinal immunity from IPV and implications for optimal timing and number of IPV doses in low- and middle-income countries in the final stages of global polio eradication.Two phase IV, multicenter, randomized controlled, observer-blinded vaccine trials (IPV001 and IPV002) were conducted in 5 countries in Latin America , 13. ForThe IPV002 study took place in Santiago de Chile. We included in this analysis infants who received 1 dose of IPV at aged 8 weeks, bOPV at 16 and 24 weeks, and mOPV2 challenge at 28 weeks, and infants who received 2 doses of IPV at 8 and 16 weeks, 1 dose of bOPV at 24 weeks, and mOPV2 challenge at 28 weeks  titers, seroconversion rates at different time points, and mucosal shedding of mOPV2 after oral challenge.Detailed serum and stool sample processing and laboratory assays are described in the articles reporting the primary study , 13. BloBoth studies were approved by the relevant country authorities and institutional review boards. Written informed consent was obtained from all parents or guardians , 13.For both studies, the per-protocol population was used, which required receipt of all scheduled vaccinations. Seroprotection was defined as a NAb titer \u22658. Seroconversion in IPV001 was defined in the study protocol as either seroprotection in subjects who were previously seronegative or a minimum 4-fold increase over the expected titer level, accounting for decay of maternally derived antibody . For seroconversion measured at week 14, the titer at week 6 was used as the baseline; for seroconversion measured at weeks 18, 36, and 40, the 14-week titer was used as baseline.10 viral titers at days 7, 14, 21, and 28 after the challenge [In IPV001 subjects, 4 combinations of pre-IPV serostatus were possible based on NAb measurements at age 6 and 14 weeks ; median NAb, seroprotection and seroconversion rates were assessed for each group. For the primary objective, however, rates of post-IPV seroprotection were compared between subjects who were seropositive and those who were seronegative at the time of first IPV (age 14 weeks), but with the exclusion of the subset of subjects who seroconverted between 6 and 14 weeks because of potential of inadvertent environmental exposure to type 2 vaccine strain in these infants . In IPV002 the primary analysis was based on serostatus at the single 8-week pre-IPV time point. Intestinal immunity was assessed by extent of shedding after mOPV2 challenge using a composite quantitative shedding index end point, computed as the arithmetic mean of stool loghallenge , 13.P values provided by the Fisher exact method, with mid-P correction.All analyses were performed with R software . NAb titThe per-protocol cohort was composed of 823 subjects from IPV001 and 359 from IPV002 . Rates oFrom IPV001, distribution of the 4 possible combinations of pre-IPV serostatus was as follows: 330 subjects (40.2%) were seronegative at both 6 and 14 weeks of age, 223 (27.2%) were seropositive at both time points, 232 (28.3%) went from seropositive at 6 to seronegative at 14 weeks , and 34 (4.1%) changed from seronegative to seropositive . The depP = .04). Log2 NAb titers were 5.17  in the pre-IPV seronegative versus 4.17 (3.66\u20134.83) the pre-IPV seropositive group (P = .0037). Among the infants receiving 2 IPV doses in IPV001, seroprotection rates at age 36 weeks  were 82.7%  in the pre-IPV seronegative compared with 60.4% (51.1%\u201369.0%) in the pre-IPV seropositive groups.Among infants assessed after 1 dose of IPV, there were notable differences in type 2 seroprotection rates and NAb titers between infants who were pre-IPV seronegative versus those who were pre-IPV seropositive in both studies . In the P = .002). The median titer was 7.17  in pre-IPV seronegative infants, compared with 3.83 (3.83\u20134.50) in pre-IPV seropositive infants (P < .001).A similar relationship was found among IPV002 infants in whom the seroprotection rate among pre-IPV seronegative infants at 28 weeks (after the complete regimen of 1 IPV and 2 bOPV doses and 20 weeks after IPV dosing) was 93.0% , compared with 73.9% (65.0%\u201381.1%) in pre-IPV seropositive infants .In the IPV001 study population, a second dose of IPV given at age 36 weeks (22 weeks after dose 1) seemed to overcome any potential interference of maternal antibody present prior to the initial IPV dose . Among bPost-IPV seroconversion was analyzed according to 6- and 14-week serostatus combinations . Among i10 higher  in pre-IPV seropositive subjects.Mucosal type 2 immunity, as measured by shedding of virus after mOPV2 challenge, was compared between pre-IPV seropositive and seronegative infants (again excluding subjects who seroconverted between 6 and 14 weeks in IPV001) . In IPV0This exploratory analysis of 2 parallel studies conducted in Latin America affirms the interference of maternally derived antibodies with polio type 2 immune responses to IPV in healthy children vaccinated according to vaccine schedules endorsed in current World Health Organization guidelines [The biologic mechanisms of maternal antibody interference and correlation in human trials have been well characterized , 17. AmoIn previously reported results, we noted 80% type 2 seroconversion after the single dose of IPV at age 14 weeks and nearly 98% seroprotection after the full 3 bOPV-1 IPV schedule, plus mOPV2 challenge . AlthougAlthough previous data have demonstrated that delayed multiple-dose priming IPV regimens can overcome higher levels of maternal antibody, further study is warranted to determine whether the use of single-dose IPV in delayed schedules  has a similar effect . An impoOur data demonstrate an unexpected relationship between type 2 pre-IPV seropositivity and decreased intestinal mucosal protection against subsequent mOPV2 challenge among infants in the IPV002 study vaccinated with sequential IPV-bOPV schedules starting at 8 weeks of age. This phenomenon does not seem to derive directly from the effect of maternal antibody on post-IPV serum titers, because this effect was not observed among IPV001 infants, and previous analyses have shown only weak or no correlation between prechallenge NAb titers and stool poliovirus shedding after mOPV2 challenge , 25. RatIrrespective of underlying mechanism, our observations may be important for policy making in polio eradication. Polio vaccine schedules similar to that of the IPV002 study subjects have the advantage of reducing the burden of vaccine-associated paralytic poliomyelitis and are thus particularly relevant in countries where this is the predominant form of paralytic polio . HoweverSeveral limitations in our study should be acknowledged. Because this was an exploratory objective, the original studies were not powered or specifically designed for this analysis. No birth blood sample was available, resulting on our dependence on 8- or 6- and 14-week infant serum samples to represent maternal immunity. The findings from these 2 studies conducted in Latin American countries may not be generalizable to all geographic locations, particularly those where OPV has been less effective and maternal antibody levels may be higher and driven by wild or vaccine virus exposure. Passive exposure to type 2 vaccine virus could have played a role in the serologic and mucosal responses noted in the study, despite our efforts to exclude such infants from the analysis. Finally, some comparisons in this study arose from contrasts of groups across studies, which may be confounded by many other factors.In conclusion, observations in this combined analysis of 2 large vaccine trials provide important data to inform vaccine policy for global polio eradication. The presence of type 2 maternally derived antibodies was associated lower rates of seroprotection in infants who received a single dose of IPV, an effect that was still prominent at 36 weeks of life. This interference can be overcome by adding a second IPV dose. Future research to further describe this phenomenon, and establish whether the pattern of such interference is also observed with newer and future formulations of IPV currently under development, will be important , 29.Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.Supplementary materials are available at Supplemental_TableClick here for additional data file."}
+{"text": "We detected Chuzan virus (CHUV) in domestic yaks from the Qinghai-Tibetan Plateau, western China, indicating CHUV probably has been transmitted to yaks in recent years. Awareness for CHUV surveillance and transmission and livestock health management in these special regions should be raised to avoid outbreaks and animal loss. Orbivirus, family Reoviridae. A CHUV outbreak, first reported in Japan in 1985, was the causative agent of disease that resulted in many reproductive disorders in cattle, including abortion, stillbirth, and congenital malformation (Chuzan virus (CHUV) belongs to the Palyam serogroup of genus \u2013,,Bos grunniens) on China\u2019s Qinghai-Tibetan Plateau.Like other orbiviruses, CHUV consists of 10 double-stranded RNA segments (Seg-1 to Seg-10), which encode 7 structural viral proteins (VP1\u2013VP7) and 4 nonstructural proteins (NS1\u2013NS4)  infection, also belonging to genus During August 2016\u2013April 2017, we randomly collected 208 blood samples from apparently healthy domestic yaks, 71 yaks from Gansu Province (46 <1 year of age), 64 yaks from Qinghai Province (23 <1 year of age), and 73 yaks from Sichuan Province (29 <1 year of age). Soon after sampling, total RNAs were extracted and used as templates to amplify full-length cDNA by reverse transcription PCR . One pair of specific primers was designed based on VP2 genome sequence of CHUV  Table 1 For phylogenetic and identity analysis of genome sequence of 10 segments from CHUV, we designed 10 pairs of primer based on known sequences deposited in GenBank  Table 1 ,,Five (7%) of the 71 samples were positive for CHUV in Gansu Province, 4 of which were <1 year of age  Table 2.,Orbivirus . Identity analysis showed that genome sequences for Seg-1 to Seg-10 of CHUV shared >98.38% nt identities and >98.09% aa identities with CHUV strain KT887181/GX871/China in previous studies (The yaks that were positive for CHUV were located in 2 cities of Gansu Province \u2248600 km apart, which indicates that transmission of CHUV has spread rapidly around the Qinghai-Tibetan Plateau. Further studies are needed to determine the epidemiology and evolution of CHUV in livestock with concomitant virus isolation and phylogenetic analysis. The awareness of livestock health management in these special regions should also be raised.Additional methods and results for study of Chuzan virus in yaks, Qinghai-Tibetan Plateau, China, 2016\u20132017."}
+{"text": "Extra-pulmonary tuberculosis (EPTB) is defined as any bacteriologically confirmed or clinically diagnosed case of TB involving organs other than the lungs. It is frequently a diagnostic and therapeutic challenge with paucity of data available. The aim of this study was to assess the prevalence of bacteriologically confirmed EPTB; to determine the most affected organs and to evaluate the therapeutic outcome of EPTB patients treated under program conditions in the littoral region of Cameroon.A descriptive cross-sectional laboratory-based epidemiological survey was conducted from January 2016 to December 2017 and 109 specimens from 15 of the 39 diagnosis and treatment centers in the littoral region were obtained.Two diagnostic methods (Gene Xpert MTB and culture (LJ and MGIT) were used for EPTB diagnosis. Determine HIV1/2 and SD Biolinewere used for HIV diagnosis. Confirmed EPTB cases were treated following the national tuberculosis guide.p\u2009=\u20090.442). Therapeutic success was better (71.7%) in HIV negative EPTB patients (p\u2009=\u20090.787).The prevalence of bacteriologically confirmed EPTB was 41.3% (45). All 45 cases were sensitive to rifampicin. Males were predominately more infected [26 (57.8%)] likewise the age group 31\u201345\u2009years with 15 (33.3%) cases. The overall prevalence for HIV was 33.6% (36). HIV infection was present in 28.9% (13) of patients with EPTB. The most affected sites with EPTB were: Lymph nodes (66.5%), pleural cavity (15.6%), abdominal organs (11.1%), neuromeningeal (2.2%), joints (2.2%) and heart (2.2%). Overall, 84.4% of the study participants had a therapeutic success with males responding better 57.9% (The prevalence of bacteriologically confirmed EPTB patients treated under program conditions in the littoral region of Cameroon is high with a therapeutic success of 84.4% and the lymph nodes is the most affected site. Tuberculosis (TB) is a leading cause of morbidity and mortality worldwide, accounting for about 9.6 million new cases and 1.5 million deaths annually  this was closely followed by the pleural cavity 7 (15.6%) as illustrated on Fig.\u00a0The most affected site were the lymph nodes 31/109 (68.9%) and there was a statistically significant different between the positivity of lymph node aspirates and all other EPTB specimens tested  was better in HIV negative EPTB patients compared to HIV positive [11(28.1)] patients (p\u2009=\u20090.787). With respect to site, treatment completion rate was observed as follows: lymph node 25 (83.3%), pleural effusion 7 (100%), abdominal organs 4(80%), joints 1(100%), neuromeningeal 1(100%) and the heart 0(0%) as shown on Table\u00a0Overall, 84.4% of these participants had a therapeutic success with males responding better 22 (57.9%) as oppose to females16 (42.1%) , we still thing these findings are of epidemiological importance.Mycobacterium tuberculosis out of the lungs and the reactivation of infection in extra-pulmonary organs [The prevalence of bacteriologically confirm EPTB in this study was high (41.3%). This finding is similar to those of Luma , were thy organs . Bacteriy organs , lack ofy organs . All they organs .The maley organs  in MorocWe found that lymph node involvement was the most common site of infection. This was different from recent studies , 15 wherEven though culture is considered the gold standard in TB diagnostics, growth on solid culture media requires four to six weeks. This delay would negatively affect patient care. To overcome this problem, we opted for automated cartridge-based molecular nucleic acid amplification (NAA) techniques, which offer a rapid diagnosis of life-threatening disease such as TB meningitis with a turnaround time of 24\u2009h. This method is said to be very sensitive as it can detect as few as 10 mycobacteria . There wEPTB treatment success rate in this study was high and identical to the nationwide pulmonary TB therapeutic success rate of 75 to 84% reported in 2006 to 2015 , 20. ThiThis study established that treatment success of EPTB patients co-infected with HIV was lower (28.1%) compared to TB-HIV negative patients (71.7%) and this is in line with Atekem, et al  in the SThe prevalence of bacteriologically confirmed EPTB patients treated under program conditions in the littoral region of Cameroon is high with a therapeutic success of 84.4% and the lymph nodes is the most affected site."}
+{"text": "In Tanzania, malaria ranks number three among the top ten causes of deaths in all age groups, however little is known about the utilisation of emergency department by patients with complications of malaria. We describe clinical presentation, resource utilization, and outcomes of acutely ill patients with complications of malaria presenting to an urban emergency department (ED) in Tanzania.We screened 405 patients which physicians had a clinical suspicion or diagnosis of malaria at ED. We enrolled 184 (45.5%) patients meeting WHO clinical and laboratory definition of malaria. The median age was 22\u00a0years (interquartile range 22\u201333\u00a0years), 105 (57%) were male, and overall 124 (67.4%) were self-referral. The use of insecticide treated nets (ITNs) in this group was 125 (67.4%). Fever 125 (67.9%), headache 56 (30.4%) and general body malaise 41 (22.2%) were the top three frequent complains, while tachycardia 83 (42.9%) was the most frequent abnormal vital sign. Overall, 21 (11.4%) patients had severe anaemia and 21 (11.4%) had abnormal renal function test. In ED 121/184 (65.8%) patients received antimalarial, 74/184 (40.2%) received antibiotics, 6/184 (3.3%) received antipyretic/analgesic and 5/20 (25%) patients with severe anaemia received blood transfusion. Overall, 99/184 (53.8%) patients were hospitalized, 3 (1.6%) died at the ED, and the overall hospital morality was 3.8%. Overall we found a substantial burden of patients with complications of malaria presenting in the largest public ED in Tanzania.The online version of this article (10.1186/s13104-019-4388-8) contains supplementary material, which is available to authorized users. Malaria is still a major health problem across the lower and middle income countries accounting for up to 40% of public expenditure in Africa . In AfriIn Tanzania, as in other SSA countries, malaria is among the top health problems, affecting particularly the children below age of 5-years and pregnant women. Over 90% of the population in Tanzania lives in Malaria zones, and 60% of the country population lives in the malaria endemic zones , 4. In TThe complications of malaria, including but not limited to hypoglycemia, anemia, acute kidney injury (AKI), acidosis, sepsis, hypoxia, shock, disseminated intravascular coagulopathy (DIC), respiratory distress and cerebral malaria have all been associated with poor outcomes . In TanzThe establishment of a full capacity Emergency Medicine Department at Muhimbili National Hospital (EMD-MNH) in Dar es salaam, Tanzania has provided an opportunity to improve and standardize care in the management of critically ill patients including acute complication of malaria. While most of these patients present in a critically ill stage and requires emergency interventions to abate death and improve long-term morbidity, the exact burden and outcome of patients with complications of malaria presenting to EMD remains unknown. We aimed to describe clinical presentation, resource utilization, and outcomes of acutely ill patients with complications of malaria presenting to an urban EMD in Tanzania.This prospective study enrolled a consecutive sample of patients presenting to the EMD-MNH in Dar es salaam, Tanzania from 1 January 2017 to 31 September 2017.The EMD is a full capacity acute public emergency department of Muhimbili National Hospital (MNH), the National referral hospital located in Dar es Salaam, the commercial city of Tanzania. MNH has a 1500 bed capacity, receives an average of 1000\u20131200 outpatients per day, and the EMD has an annual volume of approximately 60,000 patients . The depThe study investigator and research assistant prospectively screened and enrolled eligible patients using an electronic structured data sheet to record study information, including demographics, clinical presentation, management and EM diagnosis and final disposition. We followed up each patient to final hospital disposition, and recorded length of hospital stay, need for intensive care unit (ICU) or high dependency unit, final hospital diagnosis and clinical outcome (discharge or death).Data from hand-written case report forms were transferred to Excel spreadsheet , and imported to IBM SPSS Statistics v 23 for analysis. Demographic data is summarized by means and standard deviation (SD), we used Chi-square test to compare categorical variables, and Mann\u2013Whitney U-test for comparison of continuous variables. In both comparisons, a two-tailed p-values of\u2009<\u20090.05 was considered statistically significant.We screened 405 100%) patients who were clinically diagnosed to have malaria at EMD-MNH by the treating physician. Among 405 patients, 132 (32.5%) tested positive for malaria . In those who tested negative, 52 (19.4%) presented with at least one feature of severe malaria as defined by the WHO and National guidelines  were followed up . Among those followed up, 105 (57.1%) were male, and the overall median age was 22\u00a0years [interquartile range (IQR) of 22\u201332\u00a0years]. Overall 124 (67.4%) were self-referral from home, and the ITNs use among these patients was 125 (67.4%) (Table\u00a0Tachycardia 83 45.1%) was the most frequent abnormal vital sign among enrolled patients; hypoxia 8 (4.3%) was least. Fever 125 (67.9%), headache 56 (30.4%) and general body malaise 41 (22.3%) were the top three presenting complaints  tested positive . Among patients who received complete blood cell counts order 25 (13.5%) had elevated white blood counts and 21 (11.4%) had severe anaemia (Hb\u2009<\u20097\u00a0g/dL) of who 5 (2.7%) received blood transfusion in EMD  was the most frequent complication, followed by renal failure 15 (8.2%) while disseminated intravascular coagulopathy (DIC) was the least frequent complication  were hospitalized for inpatient care and 3 patients (1.6%) died in the EMD. The overall in-hospital mortality rate was 3.8% (Table\u00a0.8% were The establishment of a full capacity EMD at MNH in Tanzania manage provided an opportunity of early stabilization of acutely ill and injured patients, including those with acute complication of malaria. In this study over half of patients who were clinically suspected to have malaria by providers had neither laboratory evidence of malaria no features of severe malaria, a similar finding from what has been observed from other studies . While wNearly half of patients in this study had features of complications of malaria. Hypokalaemia requiring replacement was observed found in 20% of patients however only 1% of patient in this study received hypokalemia management at EMD or in the wards. While we didn\u2019t pursue the reasons for lack of treatment of hypokalemia, at the time of the study the department was quipped with management guidelines for hypokalemia, which calls for provision of supplemental potassium for these patients.Anaemia was the most frequent complication of malaria observed in this study population, with over 10% of patients presenting with severe anaemia. Despite this presentation only one quarter of these patients received blood as part of care. This finding further complement the observation made by Shari et al. in a prospective observation of anaemic children presenting to same EMD in which only 23% of children with indications received transfusion . None ofMost patients were admitted to the wards for the inpatient care, nine patients with uncomplicated malaria were also admitted to the wards, indicating the potential for other illnesses and complications that might have been associated with current malaria diagnosis. The observed mortality rate in our study low compared to other studies of malaria done in similar settings, and this is despite the relatively short duration of hospital stay compared to other settings .There is a substantial burden of patients with complications of malaria presenting in the largest public ED in Tanzania. We have described their clinical presentation, management, outcomes and gaps in care provision. Future studies should focus on factors affecting delivery of appropriate care in patients with complications of malaria.This was a single-centre study and our results may not necessarily be generalizable to other settings, however the EMD at MNH is the largest tertiary referral hospital in Tanzania, and receives acutely ill and injured patients from all over the country.Additional file 1: Figure S1. Study flow diagram: patient enrollment results and outcomes.Additional file 2: Table S1. Investigations ordered in the emergency department."}
+{"text": "Utilizing eight waves (2002-2016) of data from the Behavioral Risk Factor Surveillance System (BRFSS), this study examines the disparities and trend of dental care utilization among dentate adults aged 50 years or older in the U.S. Findings reveal that there was a significant increase of dental care utilization among Asians and Blacks in older adults. The rates increased from 73% (95%CI: 69%-78%) to 81% (95%CI: 79%-84%) and 54% (95%CI: 52%-56%) to 60% (95%CI: 69%-62%) for Asians and Blacks respectively in the 75-79 age-group. Early in 2002, there was a linear decreasing pattern of dental care utilization with age. However, the 65-69 age-group became a turning point in 2018 with a lower rate of dental care utilization before 65-69 years of age and higher rate in the older age groups. Overall, Hispanics and Blacks had much lower rates of dental care utilization than that of Whites and Asians."}
+{"text": "BRCA1 and BRCA2 genes. The aim of this study was to describe BRCA1 and BRCA2 gene variants in Mexican patients with ovarian cancer. Sequencing of BRCA1 and BRCA2 genes from tumors of 50 Mexican patients with ovarian cancer was made in a retrospective, non-randomized, and exploratory study. We found genetic variants in 48 of 50 cases. A total of 76 polymorphic variants were found in BRCA1, of which 50 (66%) had not been previously reported. Furthermore, 104 polymorphic variants were found in BRCA2, of which 63 (60%) had not been reported previously. Of these polymorphisms, 5/76 (6.6%) and 4/104 (3.8%) were classified as pathogenic in BRCA1 and BRCA2, respectively. We have described the genetic variants in BRCA1 and BRCA2 of tumors from Northeast Mexican patients with sporadic ovarian cancers. Our results showed that the use of genetic testing helps recognize patients that carry pathogenic variants which could be beneficial for personalized medicine treatments.Gynecologic cancers are among the leading causes of death worldwide, ovarian cancer being the one with the highest mortality rate. Olaparib is a targeted therapy used in patients presenting mutations in  Gynecologic cancers are among the leading causes of death worldwide, ovarian cancer being the one with the highest mortality rate, registering an incidence of 238,719 patients and 151,905 deaths in 2012, as reported by the World Health Organization (WHO) [. CA-125 is not a specific biomarker for ovarian cancer, it can be increased in other types of cancer and other specific non-malignant women\u2019s conditions, such as pregnancy, pelvic inflammatory disease, and infectious disease [Mortality is attributed to the absence of a sensitive and specific test that allows diagnosis in early stages ,5. To da disease ,10,11. HBRCA1 and BRCA2 [BRCA1 and BRCA2 mutations in phase II clinical trials and retrospective multicenter studies [Beyond a specific diagnostic test, the lack of success for chemotherapy strategies plays a key role in ovarian cancer mortality. Recently, the Food and Drug Administration (FDA) approved a targeted therapy with the use of olaparib  that shows benefits in patients who carry mutations in any genes of homologous recombination, but mainly in nd BRCA2 ,14. Olapnd BRCA2 ,16,17. T studies ,19.BRCA genes and their dysfunctions have helped drive clinical trials for olaparib administration in ovarian cancer patients [The refinement and cost reduction in Next Generation Sequencing technologies have allowed the expansion of genetic knowledge of human diseases ,21. Nextpatients . Genomic variation findings of tumor driver genes are making it possible to personalize the treatment of cancer patients. Personalized cancer treatment includes early diagnosis, targeted therapy, monitoring response to treatment, tracking resistance, and prediction of disease-free survival. More recently, it has benefited from the isolation and analyses of circulating tumor DNA and Circulating Tumor Cells from plasma (liquid biopsies) ,25,26. BRCA1 and BRCA2 genes in tumors from Northeast Mexican patients with sporadic ovarian cancer and to detect the percentage of potential eligible patients for future olaparib clinical trials.The aim of this study was to describe genetic variants in the BRCA genes. The research protocol was approved by the Ethics Committee in Research of the Hospital Universitario at the Universidad Autonoma de Nuevo Leon (HU-UANL), with the registration number Bl13-005.We conducted a retrospective, non-randomized, and exploratory study to search genetic variants in We collected cases from the Pathology Departments of public and private hospitals that participated in the study. Pathologists selected tumors from paraffin embedded tissues blocks for the identification of tumor cellularity of >80%. We ensured quality by avoiding areas of inflammation and necrosis. The patients have sporadic ovarian cancer. Tumor samples were obtained from 10 mg tissues and DNA was extracted using the AllPrep DNA/RNA FFPE kit . DNA concentrations and quality  were evaluated by the NanoDrop 8000 Spectrophotometer .BRCA1 and BRCA2 genes was performed in the Ion Torrent Personal Genome Machine (PGM) Sequencer . Sequence reads were mapped to the hg19 reference genome and used to generate BAM files; variants were predicted using the both Torrent Suit Variant Caller  and the Genome Analysis Toolkit .Complete sequencing of the exons of BRCA1 and BRCA2 Panel . The panel amplifies 167 amplicons that cover about 16.3 kb and result in coverage between 98\u2013100% of the coding regions of both genes. The libraries were designed according to the manufacturer by the platform Ion AmpliSeq Library Preparation Protocol . Each sample was labeled individually and added to the emulsion and subsequently sequenced using a P1 chip. Each run of that protocol produced about 10 Gb of information and each sample had an average depth of 500X [The sequencing process started with 30 ng of DNA, which was processed according to the standard protocol Multiplex Ion AmpliSeq  of 500X . http://www.ncbi.nlm.nih.gov/clinvar). For missense variants, predictions of pathogenicity were generated using Align-GVGD (http://agvgd.iarc.fr/). Variants passing quality control and filtering were visually confirmed using the Integrative Genomics Viewer (IGV) . Rare vaWe included 50 tumors with a mean age of 51 years; the range was 33\u201386 years. The histological tumor subtypes were distributed as follows: 10 high-serous grade (20%), 13 endometrioid (26%), 7 papillary, 6 mucinous (13%), 1 low-serous grade (2%), 10 clear cell (20%), 1 transitional cell (2%), 1 dysgerminoma (2%), and 1 borderline (2%).BRCA1 of which 26 (34%) had been previously reported. In BRCA2, we found 104 polymorphic variants of which 41 (39.4%) had also been reported previously, these variants are showed in BRCA1 and BRCA2 variants found (66% and 60% respectively) had not been previously reported. Our samples have an average coverage of 650X.We identified, in 48 of 50 (96%) cases, 76 polymorphic variants in BRCA1 and BRCA2, 5/76 (6.6%) and 4/104 (3.8%), respectively. We found pathogenic variants in For samples with pathogenic variants, the histological subtype and age at diagnosis are shown in In Mexico, the Federal Health Secretary\u2019s prevention campaign directed for women focuses on breast and cervical cancers. Ovarian cancer is an urgent health problem for screening campaigns, taking advantage of new genomic technologies, such as Next Generation Sequencing methods, can help with better diagnoses and suggest new treatment approaches, such as personalized medicine ,30,31.BRCA1 and BRCA2 pathogenic variants found in our study have been reported in patients with breast cancer or ovarian cancer patients [BRCA1 and BRCA2 pathogenic variants in ovarian cancer because they are therapeutic targets for olaparib therapy. The information reviewed in the Clinical Variation database showed that the patients . It is iBRCA1 variants because rs1060915 (40%), rs16941 (40%), rs16940 (40%), rs1799966 (40%), rs16942 (36%), rs799917 (44%), rs1799949 (38%), rs3765640 (30%) are mostly present in samples with endometrioid and clear cell types. An unusual finding was the detection of 26 variants (four of them pathogenic) in endometrioid sample 36 (BRCA2 with variants rs144848 (100%), rs206075 (100%), rs206076 (97.9%), rs169547 (95.8%), rs953426 (70.8%). Mutations in BRCA genes are rarely detected in the endometrioid histological type according to the COSMIC database [BRCA1 are reported in the high-grade serous carcinoma samples [We can see similarities in the ample 36 . All hisdatabase . The maj samples . BRCA mutations. Patients can expect a better therapeutic response if they are platinum sensitive and are treated with combination therapy with inhibitory PARPs [BRCA1 mutations have a better prognosis than those with epigenetic events [The standard treatment for ovarian cancer is surgery and/or chemotherapy with platinum or taxanes, depending of the tumor phase; however, treatment with inhibitory PARPs can be improved if the genetic test reveals ry PARPs ,35. Patic events .BRCA mutation carriers and only 7 patients (41%) had a positive response to treatment. On the other hand, 11 of 46 non-BRCA mutation carriers responded to olaparib[BRCA1 mutation carriers and 6 cases had BRCA2 mutations (4.4%) [Gelmon (2011) directed a phase 2, multicenter, open label, non-randomized study with 65 high-grade serous ovarian cancer patients: 17 were  olaparib. Anothers (4.4%) .Compared with a previous Mexican study of breast/ovarian hereditary cancer patients, we found six variants in common between the studies, all of them benign. These results are shown in BRCA mutations in ovarian and breast cancer patients with hereditary cancer history. They found BRCA mutations in 26 of 98 ovarian cancer patients (28%), also reporting the Mexican founder mutation BRCA1 ex9-12del in 35% of their patients from central Mexico [BRCA genes in 12% of selected patients. This percentage is important because it corresponds to patients with sporadic cancer and shows the importance of molecular screenings in all patients for better diagnosis and therapy strategies.Villarreal-Garza (2014) reported the clinical significance of l Mexico . In compBRCA genes. For example, we used Multiplex Ion AmpliSeq BRCA1 and BRCA2 Panel that includes primers for the entire coding region, whilst Villarreal-Garza and colleagues used HISPANEL for Sequenom MassARRAY  and end point PCR for BRCA1 ex9-12del mutation. Nevertheless, the founder mutation BRCA1 ex9-12del was absent in our study likely because we have samples from sporadic cancer patients from the Northeast of Mexico, in comparison with other studies that include patients with hereditary history of cancer and are from central Mexico (Mexico City and Puebla State), the region of origin of this founder mutation [BRCA1 because this is a large rearrangement and our samples are from FFPE tissues with degraded DNA.Another important aspect to highlight is the difference in the molecular test for screening the genetic variants in the mutation ,40,41. ABRCA (olaparib), NF1 (temsirolimus), PI3K/RAS (sorafenib), or that exhibit HER2 over expression (trastuzumab) [Mutation screenings in druggable driver genes are of great value for medical treatment decisions in over 50% of ovarian cancer patients. For example, there are therapies for patients that carry mutations in tuzumab) . The nexCYP2D6, CYP3A5, CYP2C8, and IL-10 genes in breast cancer patients from Mexico and Spain and classified them by metabolic activity for chemotherapy but no specific function has been described for these polimorphisms [The Mexican population is genetically diverse, consisting of peoples of Amerindian, European, African and Asian descent and detailed ancestry studies have been described by other Mexican research groups . We haveorphisms . Previouorphisms . BRCA1and BRCA2 genes in tumors from Northeast Mexican ovarian cancer patients. In addition, we report pathogenic variants in these genes according to the ClinVar database .Our study reports for the first time the genetic diversity of This work raises the need to implement molecular genetic testing with high specificity, sensitivity, and low cost for all ovarian cancer patients. Test results may help oncologists offer more precise molecular diagnosis and better personalized therapies. In this case, 12% of patients could be candidates for olaparib therapy. BRCA genes in Hispanic populations. These populations have limited economic resources to access genomic medicine for better prognosis and treatment of ovarian cancer [Dean et al. showed the importance of performing screening of genetic variants along n cancer .Comprehensive studies that include high-quality samples from biobanks, complete clinical records, and better bioinformatics analyses are very important to identify key factors for the diagnosis, treatment, and follow-up of the therapeutic response of ovarian cancer patients ,47. BRCA1 and BRCA2 from tumors of Northeast Mexican patients with sporadic ovarian cancer. Our results showed that the use of genetic testing helps identify patients that carry pathogenic variants that could beneficial for personalized medicine treatment. We have described genetic variants in"}
+{"text": "Bacteroidales markers were detected in all water and sediment samples , however, the detection of host-associated MST markers varied. Human and avian markers were the most frequently detected in water samples , whereas in sediment samples, only human-associated markers were detected more often (86%) than swine (64%) and avian (8.8%) markers. The results indicate that several locations in the Tiaoxi River are heavily polluted by fecal contamination and this correlated well with land use patterns. Among the five bacterial pathogens tested, Shigella spp. and Campylobacter jejuni were the most frequently detected pathogens in water  and sediment samples . Shiga toxin-producing Escherichia coli (STEC) and pathogenic Leptospira spp. were less frequently detected in water samples  and sediment samples , whereas E. coli O157:H7 was only detected in sediment samples (11%). Overall, the higher prevalence and concentrations of Campylobacter jejuni, Shigella spp., and STEC, along with the MST marker detection at a number of locations in the Tiaoxi River, indicates poor water quality and a significant human health risk associated with this watercourse.Taihu Lake is one of the largest freshwater lakes in China, serving as an important source of drinking water; >60% of source water to this lake is provided by the Tiaoxi River. This river faces serious fecal contamination issues, and therefore, a comprehensive investigation to identify the sources of fecal contamination was carried out and is presented here. The performance of existing universal (BacUni and GenBac), human , swine (Pig-2-Bac), ruminant (BacCow), and avian (AV4143 and GFD) associated microbial source tracking (MST) markers was evaluated prior to their application in this region. The specificity and sensitivity results indicated that BacUni, HF183-TaqMan, Pig-2-Bac, and GFD assays are the most suitable in identifying human and animal fecal contamination. Therefore, these markers along with marker genes specific to selected bacterial pathogens were quantified in water and sediment samples of the Tiaoxi River, collected from 15 locations over three seasons during 2014 and 2015. Total/universal  Bacteroidales are often used as the target, as they are obligate anaerobic bacteria found in the human and animal gut at higher levels than E. coli  assays tested, but the most widely used MST makers, such as HF183 Taqman and BacHum qPCR assays were not included. They also reported that the Pig-2-Bac assay  showed a higher accuracy than other mitochondrial DNA based swine FST markers. Bacteroidales assay (Pig-2-Bac) to assess the levels of swine fecal pollution in the Hongqi River, and Bacteroidales-like sequences present in pig fecal samples. Although MST methods provide information on the source of fecal pollution, they do not provide evidence for, or confirm the presence of, bacterial pathogens. Determining the correlation between MST data and direct pathogen detection has been addressed in relatively few cases  and composite fecal sources from ducks and geese  were collected from farms, pet stores and the backyards of households located near the Taihu Lake/Tiaoxi River watershed region in the Huzhou area. All fecal samples were transported to the laboratory on ice and stored at -20\u00b0C within 6 h of collection. Primary effluents  were collected from a wastewater treatment plant (WWTP) located in Suzhou and brought to the laboratory on ice. Biomass from primary influents was collected by centrifugation at 4,000 \u00d7 g for 10 min at 4\u00b0C, and DNA was extracted immediately. Ethical approval for handling fecal samples in this study was acquired from Xi\u2019an Jiaotong-Liverpool University (XJTLU) Research Ethics Committee.The preliminary selection of MST assays for this study was based on the identity of the livestock population in Zhejiang Province and as per the data released by the National Bureau of Statistics, PR China in 2015 . The MST\u00ae DNA isolation kit that uses Inhibitor Removal Technology\u00ae (IRT) , following the manufacturer\u2019s instructions. The quality and quantity of extracted DNA was confirmed by NanoDrop ND 2000C  and extracts were stored at -20\u00b0C prior to further analysis. Further quality assurance of extracted DNA samples and the details of plasmid standard construction for MST qPCR assays are provided in Supplementary Note DNA extraction from the fecal/sewage samples was performed using the PowerFecalAll qPCR reactions (20 \u03bcl) were performed in triplicate and the reaction mixture for all Taqman chemistry-based qPCR assays included 10 \u03bcl of TaqMan Environmental Master Mix 2.0 , 2 \u03bcl of the probe/primer set with a final concentration as shown in For each MST assay, the limit of detection (LOD) was determined from the standard curve. The lowest concentration of standard gene copies that could be confidently detected in all triplicates was considered as the LOD . All theInitially, 25 sampling locations were selected covering the East and West, and junctions of the Tiaoxi River with other tributaries, extending to approximately 100 km of the mainstream river ; samplesThe current study incorporates microbiological assessment data published in our previous study . The enuBacteroidales, and one SYBR green-GFD assay was selected for detection of avian associated fecal markers  in each qPCR assay. All the TaqMan qPCR assays (20 \u03bcl of master mix), contained 10 \u03bcl of TaqMan Environmental Master Mix 2.0 , 2 \u03bcL of template DNA, 6 \u03bcl nuclease-free water and 2 \u03bcL of primers and probes at the final concentrations shown in Bacteroidales , and final assessment of qPCR results for each of the MST and pathogen quantification assays are provided in All the qPCR assay results were processed based on the Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE) guidelines ; if the Reliable quantification and specific detection of genetic markers by qPCR poses many challenges, therefore assays should be carefully designed and optimized to obtain maximum achievable specificity and sensitivity . The quar2) values were \u22650.98. The detailed performance characteristics of all the qPCR assays are provided in the r2) values. The details of master standard curves and LOD for each tested MST assay are presented in The amplification efficiencies of all MST qPCR assays tested were in the range 86\u2013102% and the correlation coefficient  of DNA] than the GenBac3 assay in all of the tested samples.Both BacUni and GenBac3 assays, targeting universal/general 10 gene copies per ng of DNA and showed cross reactivity with chicken (7/10), cow (3/10), duck (1/3), dog (2/10), and goose (1/3) fecal DNA samples identifying it as the least specific (69.5%). The BacHum marker had the highest specificity (80.4%) among the tested human-associated markers, along with HF183 Taqman. The BacHum assay had a sensitivity of 73.3% (6/10 human feces and 5/5 sewage samples) at an average concentration of 3.19 log10 copies per ng of DNA and was detected (above LOD) in three different host fecal DNA samples \u2013 chicken (6/10), cow (1/10), and dog (2/10). Similar to BacHum, the HF183 Taqman marker was highly specific (80.4%) among human-associated assays and was found in 73.3% of target sources (6/10 human feces and 5/5 sewage samples) at an average concentration of 3.63 log10 copies per ng of DNA. However, HF183 Taqman marker was found in only two different host fecal DNA samples, chicken (7/10) and dog (2/10). The final human-associated assay, Hum2 was the least sensitive marker and was detected in only 53% of samples of human origin (7/10 human feces and 1/5 sewage samples) at an average concentration of 2.52 log10 copies per ng of DNA. It was also detected in chicken (4/10), cow (2/10), pig (2/10), dog (1/10), and goose (1/3) fecal DNA samples, making it less specific (78%). In general, chicken (40\u201370%) and dog fecal samples (10\u201320%) had cross-reactivity with all of the human-associated assays. Overall, HF183 Taqman was the only assay that did not exhibit any cross-reactivity with cattle or swine fecal DNA samples, while HF183 SYBR, Hum2, and BacHum showed cross-reactivity with either cattle or swine fecal DNA samples  was evaluated with 10 pig fecal samples and the target was found in 90% of samples (9/10) at an average concentration of 3.03 logg of DNA . The Pigg of DNA , but sho10 copies per ng of DNA in chicken feces. Those human and cow samples for which there was cross reactivity comprised ca. 3 log-fold fewer gene copies than chicken feces. The GFD markers were only detected in 7 of the 10 chicken feces samples and cross-reacted with dog fecal DNA samples (3/10). The mean concentration of GFD markers was 2.20 log10 copies per ng of fecal DNA sample, so ca. 100-fold less than AV4143.The avian associated MST assays performed very distinctively on the tested fecal DNA samples . The AV4FC count data was used for an initial assessment of fecal contamination at these sampling locations and the results reported in our previous study . The FC DNA samples tested for PCR inhibition did not show any major difference in concentration values (based on mean Cp and percentage of coefficient of variation) for undiluted and 1:4 diluted DNA extracts, indicating that the samples were free of potential PCR inhibitors. The range and compiled values of amplification efficiencies and linear range of quantification for all qPCR assays are provided in Bacteroidales marker was detected in all water and sediment samples at the 15 locations. In water samples, the mean concentration of total Bacteroidales marker was 6.22 log10 gene copies/100 ml with concentrations ranging from 4.62 to 7.63 log10 gene copies/100 ml  and sediment samples (P > 0.003). In relative terms, the total Bacteroidales concentration was high during winter for both water and sediment samples. Based on the quantification of total Bacteroidales, the water samples from location 16 and sediment samples from location 15 were found to be the most fecally polluted, regardless of the fecal source . Locations 15 and 16 are suburban areas, which are close to a WWTP. For the host associated MST marker analysis in water samples, human-associated markers were the most frequently detected (97%), followed by avian (89%) and swine (84%). In sediment samples, human-associated MST marker was detected more often (86%), followed by swine (64%). The avian markers were positive for several sediment samples but were always below the LOD.Data on the presence and distribution of MST markers in water and sediment samples at 15 sampling locations, determined by qPCR, are presented in s/100 ml . For sedies/gram . Signifi10 gene copies/100 ml (range 2.91\u20135.6 log10 gene copies/100 ml) (10 gene copies/gram (mean 3.91 log10 gene copies/gram) (P > 0.004) but not in the water samples. Based on the HF183 Taqman assay, water samples collected from locations 12 and 16, and sediment samples collected from location 15 had the highest concentration of human-associated marker during the three seasons. Location 12 is very close to Huzhou city and as stated above, locations 15 and 16 are suburban areas close to a WWTP, and the sampling was carried out at the junction of Tiaoxi River and a canal that enters Taihu Lake  in all three seasons with a mean concentration of 3.75 log/100 ml) . For sedes/gram) . During es/gram) . There wihu Lake  (Supplemihu Lake .10 gene copies/100 ml (range 2.77\u20135.56 log10 gene copies/100 ml) (10 gene copies/gram (range 3.6\u20134.7 log10 gene copies/gram) (P > 0.001) and sediment samples (P > 0.001) was statistically significant. Higher concentrations of swine associated marker were observed in water samples at location 1 during summer and in sediment samples at location 10 during winter. The samples at location 1 were collected 1 km inside the Taihu Lake from the junction with the Tiaoxi River, and runoff during the summer was probably a contributory factor. Location 10 was close to a rural area where the agricultural input to the river upstream was likely to enhance the swine marker content.With respect to swine fecal contamination, the swine associated marker was detected less often in water (38/45) and sediment samples (29/45) than human markers. The mean concentration of swine marker in water samples was 2.96 log/100 ml) . The meaes/gram) . The var10 gene copies/100 ml (mean 2.70 log10 gene copies/100 ml)  at concentrations of 2.30\u20135.56 log/100 ml) . There wCampylobacter jejuni (62% and 53%) and Shigella spp. (60% and 91%), followed by STEC (55% and 51%) and pathogenic Leptospira spp. (33% and 13%). The E. coli O157:H7 marker was detected only in sediment samples (11%). The concentrations of marker genes of bacterial pathogens detected in water and sediment samples at each location are provided in Campylobacter jejuni (mapA) was present in a quantifiable range in 20 out of 45 water samples (2.31\u20132.88 log10 gene copies/100 ml) and 13 of 45 sediment samples (3.30\u20133.86 log10 gene copies/gram)  with concentrations of 2.32 and 2.35 log10 gene copies/100 ml, respectively. In sediments, the ipaH gene was quantified in 14 samples with concentrations ranging 3.32\u20133.47 log10 gene copies/gram (stx2 (Shiga toxin-producing E. coli) was quantified in only 2 out of 45 water samples (locations 5 and 21) with a concentration of 2.31 and 2.42 log10 gene copies/100 ml, respectively. In sediments, it was quantified in 14 out of 45 samples with a concentration range of 3.32\u20133.65 log10 gene copies/gram (stx2 genes was observed at location 14. The LipL32 gene (Pathogenic Leptospira spp.) was quantified in 15 out of 45 water samples with the concentration ranging from 2.43 to 3.13 log10 gene copies/100 ml, with the highest levels recorded at location 21. The LipL32 gene was quantified in 6 (out of 45) sediment samples at a concentration of 3.32\u20133.65 log10 gene copies/gram  . The higation 20 . In the ies/gram  and the ies/gram  and the ies/gram  and highation 20 .r) and p-values were >0.5 and <0.05, respectively (r = 0.667 and p < 0.01) and HF183 Taqman (r = 0.572 and p < 0.05) but not with Pig-2-Bac and GFD markers (r = 0.832 and p < 0.01), suggesting humans as the major contributor to the total Bacteroidales content. BacUni also showed positive correlation with stx2 gene (r = 0.6 and p < 0.05). HF183 Taqman showed negative correlation with GFD marker (r = -0.582 and p < 0.05) and positive correlation with stx2 gene (r = 0.593 and p < 0.05). Since there are multiple fecal sources  of stx2 gene presence in the environment, it is difficult to draw conclusions on the stx2 gene correlation with BacUni and HF183 Taqman. No significant correlation was observed for Pig-2-Bac and GFD markers with the marker genes of bacterial pathogens addressed in this study.All the correlations in this study were considered as significant only when Rho marker for human and animal feces, excluding avian sources, has frequently been reported in Asian countries such as India  of the 90 water and sediment samples tested . Shiga toxin-producing E. coli (STEC) can cause gastrointestinal disease leading to mild or severe bloody diarrhea  was not detected in any of the water samples, but detected at low frequency (33%) in sediment samples (during autumn season)  . It has  O157:H7  and the  O157:H7 . OverallBacteroidales marker was detected in all of the water and sediment samples at these 15 monitoring locations, confirming the presence of fecal contamination. Although human-associated markers were frequently detected at several locations, locations 3, 12, and 16 had high concentrations on one or more occasions, indicating that they are major human fecal contaminated sites of the Tiaoxi River region. The swine associated marker was frequently detected in samples from locations 13 and 21 and the avian associated marker was detected with high concentrations at locations 6, 15, 20, and 21, matching the land use pattern and pointing to the entry of swine and avian fecal sources to the Tiaoxi River. Among five bacterial pathogens monitored, Campylobacter jejuni was frequently detected at locations that are primarily polluted with avian fecal material  and high concentrations were detected at locations 6 and 13 (on one or more occasions) indicating that these sites pose potential human health risks. Similarly, Shigella spp. were frequently detected at higher concentrations in two locations (locations 3 and 12) that are highly contaminated with human fecal sources, and the Shiga toxin-producing E. coli (STEC) at two locations (locations 5 and 21), which are contaminated with either human or pig fecal sources. The bacterial pathogen quantification results correlate with the findings of host-associated fecal markers, and the data generated here are valuable for water quality monitoring authorities responsible for minimizing the health risks associated with pathogens, by identifying sites where intervention is required.In summary, our MST qPCR validation study demonstrates that BacUni, HF183 Taqman, Pig-2-Bac, and GFD assays are the most suitable for differentially identifying and monitoring human and animal fecal contamination in the Taihu watershed. In the case of fecal pollution monitoring at the Tiaoxi River, 15 out of 25 monitoring locations were identified as hotspots of fecal contamination based on FC enumeration, and samples collected from those 15 locations were further used for the quantification of MST and pathogenic bacterial gene markers. The total Ethical approval for this study was provided by XJTLU Research Ethics Committee (EXT-16-07-01).RS, AM, and RR conceived and designed the experiments. RS and KV carried out the field sampling. KV performed the experiments and data analyses and prepared the manuscript with the directions of his supervisors RS, AM, and RR. RS and AM contributed to the revision of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Increase in the evidence of global occurrence of Zika viral infection suggests that in Africa the circulation of the virus which causes 80% of asymptomatic infection could be undetected and/or overlooked. We sought to serologically detect Zika virus infection in febrile patients at Greater Accra Regional Hospital, Ghana.Of the 160 patient serum samples analyzed, 33 were found to have antibodies against Zika virus infection. Among the sero-positives 30 (91%) of the cases were anti-Zika virus IgM with the 21\u201330-year age group recording the highest number of 8 (26%) and 2 (7%) cases being the least for the 61\u00a0years and above age group. All sero-positive febrile patients developed at least one symptom consistent with Zika virus infection: 33 (100%) fever, 25 (76%) muscle pain, 24 (73%) joint pain, and conjunctivitis 2 (6%). Digestive symptoms recorded include 16 (49%) nausea, 12 (36%) vomiting and diarrhea 18 (55%). In addition, 28 (85%) loss of appetite, 14 (75%) rapid respiration and chest pain 15 (42%) were reported by seropositive febrile patients. Our data indicates exposure to Zika virus which suggests the possible circulation of the virus among febrile patients in Ghana with a sero-prevalence rate of 20.6%. Aedes africanus mosquito in 1948 Aedes sppted more . The higted more . The comted more . In thisThe limitation of this study was the absence of plaque neutralization reduction test and PCR for confirmation."}
+{"text": "Residents of long-term acute care hospitals (LTACHs) are considered important reservoirs of multidrug-resistant organisms, including Carbapenem-resistant Enterobacteriaceae (CRE). We conducted this study to define the characteristics of CRE-infected/colonized patients admitted to an LTACH and the molecular characteristics of the CRE isolates.This retrospective study was conducted to collect information on demographic and comorbid conditions in CRE-colonized/infected patients admitted to a 77-bed LTACH in Detroit between January 2011 and July 2012. Data pertaining to hospital-related exposures were collected for 30 days before positive CRE culture. Polymerase chain reaction (PCR) gene amplification, repetitive sequence\u2013based PCR, and multilocus sequence typing (MLST) were performed on 8 of the CRE isolates.blaKPC-3 sequence.The study cohort included 30 patients with CRE-positive cultures, 24 (80%) with infections, and 6 (20%) with colonization. The mean age of cohort was 69 \u00b112.41 years; 19 (63%) patients were ventilator-dependent, and 20 (67%) were treated with at least 1 antibiotic. Twenty-three (77%) patients had CRE detected following LTACH admission, and the median days from admission to CRE detection in these patients (interquartile range) was 25 (11\u201343). Seven more patients were already positive for CRE at the time of LTACH admission. Molecular genotyping and MLST of 8 CRE isolates demonstrated that all isolates belonged to the same strain type (ST258) and contained the The majority of patients with CRE presented several days to weeks after LTACH admission, indicating possible organism acquisition in the LTACH itself. The genetic similarity of the CRE isolates tested could further indicate the occurrence of horizontal transmission in the LTACH or simply be representative of the regionally dominant strain. Klebsiella pneumoniae Carbapenemase (KPC)\u2013producing Enterobacteriaceae, an increasingly common type of CRE at LTACHs, express serine \u03b2-lactamases that are only sometimes susceptible to last-resort antimicrobials such as tigecycline, colistin, and gentamicin ) was 5 (3.75\u20137). The top 5 comorbid conditions reported among our cohort included hypertension (86%), diabetes mellitus (70%), chronic obstructive pulmonary disease (57%), end-stage renal disease (55%), and congestive heart failure (54%).During the 30-day period before positive CRE culture, 19 (63%) patients were ventilator-dependent, 6 (20%) patients had an indwelling central venous catheter, 8 (27%) had an indwelling urinary catheter, and 9 (30%) had undergone surgery. Twenty patients (67%) were treated with at least 1 antibiotic within the prior 30 days, among whom 19 (95%) had been exposed to 2 or more antibiotics. Twenty-one of 30 (70%) patients had overlapping stays in the same unit of the LTACH. Five patients died during their hospitalization within 30 days of the CRE culture date , 4 (80%) of whom had bloodstream infection with CRE.Of all CRE-positive cultures, 24 (80%) represented CRE infection and 6 (20%) CRE colonization. The source of CRE samples in infected patients included 17 (71%) blood samples, 4 (17%) urine samples, 2 (8%) sputum samples, and 1 (4%) wound discharge sample . Five (8Twenty-three patients had CRE detected following admission to an LTACH. The median number of days from admission to CRE detection in these patients (IQR) was 25 (11\u201343) . The remblaKPC-3 sequence  . This inOn the other hand, some of these patients  might have been colonized for long periods before developing infection, and thus might have already been colonized with CRE when they were admitted to the LTACH. As active surveillance was not done at the time of admission, such \u201cpresent on admission\u201d CRE cases might have gone unnoticed, potentially leading to CRE spread within the LTACH. Identifying asymptomatically colonized patients early in their LTACH stay through active surveillance, followed by prompt institution of infection control measures for colonized patients, might have decreased opportunities for horizontal transmission. Such infection control measures, which have been proven to prevent CRE spread in the LTACH setting, include rigorous adherence to hand hygiene, contact precautions using gloves and gowns, use of private rooms for colonized patients or cohorting of colonized patients on dedicated floors or units, appropriate environmental cleaning, chlorhexidine bathing of patients, and use of dedicated equipment such as stethoscopes, blood pressure cuffs, thermometers , 19, 25.blaKPC-3 sequence). These 8 strains were evenly distributed during the study period and were identified in patients admitted from 7 different acute care hospitals. Although all this could indicate horizontal transmission, it could also simply be representative of the regionally dominant strain ST258 found in Michigan [Our study also demonstrated genotypic similarity between all 8 of the CRE isolates tested  should be considered among subjects at the time of LTACH admission, and possibly throughout their LTACH stay , 27. In"}
+{"text": "Little is known about the relationship between sleep duration and activities of daily living (ADLs) in those with mild dementia. We sought to examine the independent relationship between objective and subjective sleep duration and ADLs in community-dwelling older adults with mild dementia. Analyses were conducted on baseline data from participants enrolled in the Healthy Patterns Clinical Trial . Measures included 24-hour wrist actigraphy for objective sleep duration, proxy-reported Pittsburgh Sleep Quality Index  for subjective sleep duration and the Barthel Index for performance of ADLs. We used Spearman\u2019s correlation and multivariate linear regression. A total of 30 individuals  aged 74.6 (SD 7.4) with mean Clinical Dementia Rating (CDR) scores of 1 (SD 0.5) were enrolled. Objective sleep duration ranged from 2.7 to 11.5 with mean 6.7 (SD 2.4) hours; subjective sleep duration ranged from 4 to 13.5 with mean 7.9 (SD 2.4) hours. Longer objective and subjective sleep duration were significantly associated with worse ADL scores  in bivariate analyses. After controlling for age, CDR, and depression, subjective sleep duration was independently associated with ADLs  and objective sleep duration trended toward significance . These preliminary results suggest self-reported longer sleep could be indicative of declines in ADLs in older adults with mild dementia. Further prospective studies are necessary to determine the independent association between objectively assessed sleep duration and ADLs in patients with mild dementia."}
+{"text": "The development of a vaccine for group A streptococcus (GAS) is of paramount importance given that GAS infections cause more than 500,000 deaths annually across the world. This prospective passive surveillance laboratory study evaluated the potential coverage of the M protein-based vaccine currently under development. While a number of GAS strains isolated from this sub-Sahara African study were included in the current vaccine formulation, we nevertheless report that potential vaccine coverage for GAS infection in our setting was approximately 60%, with four of the most prevalent strains not included. This research emphasizes the need to reformulate the vaccine to improve coverage in areas where the burden of disease is high. iGAS) and invasive group A streptococcal (iGAS) infections. Information about the emm type variants of the M protein causing GAS disease is important to assess potential vaccine coverage of a 30-valent vaccine under development, particularly with respect to how they compare and contrast with non-iGAS isolates, especially in regions with a high burden of GAS. We conducted a prospective passive surveillance study of samples from patients attending public health facilities in Cape Town, South Africa. We documented demographic data and clinical presentation. emm typing was conducted using CDC protocols. GAS was commonly isolated from pus swabs, blood, deep tissue, and aspirates. Clinical presentations included wound infections (20%), bacteremia (15%), abscesses (9%), and septic arthritis (8%). Forty-six different emm types were identified, including M76 (16%), M81 (10%), M80 (6%), M43 (6%), and M183 (6%), and the emm types were almost evenly distributed between non-iGAS and iGAS isolates. There was a statistically significant association with M80 in patients presenting with noninvasive abscesses. Compared to the 30-valent vaccine under development, the levels of potential vaccine coverage for non-iGAS and iGAS infection were 60% and 58%, respectively, notably lower than the coverage in developed countries; five of the most prevalent emm types, M76, M81, M80, M43, and M183, were not included. The emm types from GAS isolated from patients with invasive disease did not differ significantly from those from noninvasive disease cases. There is low coverage of the multivalent M protein vaccine in our setting, emphasizing the need to reformulate the vaccine to improve coverage in areas where the burden of disease is high.Group A streptococcus (GAS) is responsible for a wide range of noninvasive group A streptococcal (non-IMPORTANCE The development of a vaccine for group A streptococcus (GAS) is of paramount importance given that GAS infections cause more than 500,000 deaths annually across the world. This prospective passive surveillance laboratory study evaluated the potential coverage of the M protein-based vaccine currently under development. While a number of GAS strains isolated from this sub-Sahara African study were included in the current vaccine formulation, we nevertheless report that potential vaccine coverage for GAS infection in our setting was approximately 60%, with four of the most prevalent strains not included. This research emphasizes the need to reformulate the vaccine to improve coverage in areas where the burden of disease is high. Streptococcus pyogenes) the ninth leading single-organism cause of human mortality due to infectious diseases, with the majority of deaths attributable to invasive group A streptococcal (iGAS) diseases and rheumatic heart disease  ranked group A \u03b2-hemolytic streptococcus (GAS)  and iGAS diseases  was established to collect epidemiological data on GAS in Africa, where surveillance information is largely lacking  in Cape Town, so as to inform the development of M protein-based vaccines. Additionally, we investigated how iGAS isolates compare and contrast with non-iGAS isolates with respect to their respective molecular characteristics.By means of a prospective surveillance laboratory study, under the auspices of AFROiGAS and iGAS infection are listed in iGAS accounted for 46% of GAS cases. Patients with iGAS infection were older, with a median age of 36\u2009years , than patients who had non-iGAS infection, with a median age of 29\u2009years . The proportion of patients with iGAS infections was higher for newborns and patients \u226565\u2009years old than for the other patients.From February 2016 to March 2017, 488 laboratory-confirmed GAS cases were identified at the National Health Laboratory Service (NHLS) based at GSH in Cape Town. Characteristics of patients with non-iGAS cases, the most common clinical manifestations were wound infections (34%), abscesses (11%), and hand sepsis (11%). For iGAS infections, the most common clinical presentations were bacteremia (33%), septic arthritis (18%), and abscesses (7%). emm 80 was significantly associated with patients presenting with non-iGAS abscesses (P\u2009=\u20090.007).Clinical information was available for 460 (94%) isolates . Among niGAS and iGAS infections were based on clinical data and additional information recorded in the notes section of the case report form (CRF).Information on the site of sampling was available for 475 isolates (97%); data were recorded as detailed on the laboratory requisition form. In addition to those listed in emm types were identified in 233 non-iGAS and iGAS isolates , M81 (10%), M80 (6%), M43.7 (6%), M183.2 (6%), M44 (5%), M53 (5%), M92 (5%), M184 (4%), and M116 (3.0%). Twenty different emm types accounted for 86% of GAS isolates. Twenty emm types were represented only once, including STG1750.0, previously thought to be group G streptococcus , failed PCRs, and isolates awaiting sequencing. Forty-six isolates . The 10 tococcus . Analyseemm types that were included in the 30-valent GAS vaccine currently being developed (emm types among our cohort are included in the vaccine and were represented by 54 GAS isolates (23%) (emm types representing 100 isolates (43%) have shown cross-protection, demonstrating >50% bactericidal killing in the presence of rabbit antisera generated after vaccination with the 30-valent vaccine (emm type (M76) most commonly identified by us is not included in the 30-valent vaccine but is among the emm types that evoked bactericidal antibodies. Of 233 GAS isolates, 54 were vaccine types (VT) and 100 were non-vaccine types, indicating cross coverage (identified in the figures as \u201cNVT-K\u201d [non-vaccine type\u2014killed]). No information regarding potential vaccine coverage was available for 40 (17%) isolates (\u201cNo killing data\u201d). This vaccine could cover 65% of emm types, corresponding to 66% of GAS cases in our setting.We assessed the proportion of eveloped . Fifteenes (23%) . Fifteenemm types were identified in 126 non-iGAS isolates , M81 (12%), M80 (8%), M43.7 (6%), M184 (6%), M183.2 (6%), M44 (5%), M53 (5%), M92 (5%), and M49 (3%). The 10 most prevalent emm types accounted for 71% of the isolates; 20 different emm types accounted for 90% of non-iGAS isolates. No new emm types were observed. Twelve emm types were presented only once.A total of 32 isolates . Of thesiGAS emm types are included in the 30-valent vaccine, representing 11 different emm types. An additional 47 non-iGAS isolates (37%), representing 7 emm types, were included among the cross-protection isolates. The most commonly isolated emm type for non-iGAS infection, M76, was not included in the 30-valent vaccine. The potential coverage for non-iGAS infection in our setting is 60%. No information regarding potential vaccine coverage (\u201cNo killing data\u201d) was available for 28 (22%) isolates.A total of 29 (23%) non-emm types were identified in 107 iGAS isolates , M81 (8%), M183.2 (7%), M43.7 (6%), M44 (6%), M53 (6%), M92 (6%), M80 (5%), M116.1 (4%), M33 (4%), and M8 (3%). The 10 most prevalent emm types accounted for 66% of the isolates; 20 different emm types accounted for 84% of the GAS cases isolated. STG1750.0 was identified in 1 isolate. Seventeen emm types were represented only once.Thirty-five isolates . Among tiGAS emm types are included in the 30-valent vaccine, representing 11 different emm types. An additional 39 iGAS isolates (36%) representing 9 more emm types were included among the cross-protection isolates. The most commonly isolated emm type for iGAS infection (M76) was not included in the 30-valent vaccine. The potential coverage for iGAS infection in our setting is 58%. No information regarding potential vaccine coverage was available for 27 (25%) isolates (\u201cNo killing data\u201d).A total of 24 (22%) emm cluster designation (from the CDC website) to 231 isolates . Non-iGAS infections showed a peak in the winter months. iGAS infections reached a trough in the winter months and peaked in the summer months .There was an association between the type of GAS infection and the season of the year; however, the data did not reach statistical significance  and iGAS (84%) cases. The proportion of iGAS cases was remarkably high, accounting for almost half (46%) of GAS infections in our surveillance study.This is the first report of a prospective study describing the molecular types of both noninvasive and invasive GAS infections in South Africa. The most prevalent emm types in our study (15/46), were included, translating to levels of vaccine coverage (vaccine type and non-vaccine type killing) for non-iGAS and iGAS infection of 60% and 58%, respectively. Notably, the strains identified by us as the most prevalent, in both the non-iGAS and iGAS groups, were not included in the 30-valent vaccine. Interestingly, one emm type, STG1750.0, was obtained from one patient presenting with bacteremia.Compared with the 30-valent vaccine, only one-third of the 46 emm types, a result similar to others found in high-income countries  were not represented in our study.We found a lower diversity of ountries . In our ryngitis , and 48 mm types ; 74% of mm types . Their 2emm type and GAS disease manifestations. emm types 1, 3, 5, 6, 12, 14, 17, 44, and 61 have been reported previously to be associated with superficial GAS disease     and ARF  and 41) . Our stuiGAS infections in our study are in keeping with this observation; however, for iGAS infection, a higher number of cases were observed in the summer months.Seasonal variations in the frequency of GAS cases have been observed in studies conducted in the United States. GAS infections have been shown to peak in the winter and early spring months and to reach a trough in the summer and autumn months . Similaremm cluster typing system classifies >200 emm types into 48 emm clusters containing closely related M proteins that share structural and binding properties  and non-iGAS and iGAS groups . We also considered age group analysis and found no differences among patients between the ages of 13 to 18  and 19 to 64 years  and those older than 64 years . There was a difference in the younger population, among the newborns  and those 6 to 12 years of age . This difference could have been due to the small sample size in these age categories.Our study had a number of limitations. (i) We were unable to assess the variation in the distribution of  studies , 25, sinemm types  identified by us, accounting for 45% of our cases, are not included in the current 30-valent vaccine formulation, there is evidence of cross-protection based on detection of bactericidal antibodies that recognize shared epitopes in the N-terminal region of the emm types .We conducted a prospective passive surveillance laboratory study among samples submitted from February 2016 to March 2017 to the National Health Laboratory Service (NHLS) from inpatients and outpatients attending Groote Schuur Hospital (GSH) in Cape Town. GSH is a tertiary-level hospital serving a catchment population of approximately one and a half million people (6) and forms part of a network of clinics and hospitals that are affiliated with the University of Cape Town. GSH  provides care to more than 560,000 referrals and inpatient admissions every year, including adults (>12 years) and neonates; the NHLS also receives specimens from external primary health care clinics. We documented demographic data and clinical presentation and laboratory data from non-Strep laboratory.At the time of a laboratory-confirmed GAS diagnosis, a standardized case report form was completed by a study microbiologist. Clinical information was obtained by accessing the patient\u2019s medical record. A total of 122 isolates were collected and stored at \u221280\u00b0C until transfer to the AFROiGAS was defined as GAS isolated from a sterile source such as blood, cerebrospinal fluid, or pleural fluid .GAS isolates were stored in the AFROeviously . BrieflyS. pyogenesemm sequence database center at the CDC, which assigned all the emm types and subtypes  at Stellenbosch University, South Africa. The sequences generated were analyzed using BioEdit v7.0.9 . The sequences were submitted electronically to the subtypes .emm type and clinical symptoms using the chi-square test or Fisher\u2019s exact test. A P value of <0.05 was considered to be statistically significant. All statistical analyses were performed using Stata . The sample size was calculated using a prevalence of 21% for GAS pharyngitis as reported in a previous study conducted in Cape Town .We evaluated the association between ape Town . The min"}
+{"text": "Cushing\u2019s disease (CD) is a rare cause of hypercortisolemia presenting a major diagnostic and therapeutic challenge. Data on pituitary function in long-term follow-up after CD treatment in childhood is limited.Long-term assessment of patients of the Children\u2019s Memorial Health Institute (CMHI) after CD treatment in childhood.Retrospective analysis of 29 CD patients, mean age at the time of diagnosis 13.46 yrs. The long-term follow-up (FU) was done by: 1) obtaining the data from a patient\u2019s questionnaire (75% of adult patients); 2) using the data from the last clinic visit for patients who did not respond to the questionnaire and for current CMHI patients. The average long-term FU from transsphenoidal pituitary surgery (TSS) was 10.23 yrs.At the latest FU: 18 patients (62%) had long-term disease remission after TSS1, 2 patients (6.9%) after TSS2, 1 patient (3.4%) after the post-TSS radiotherapy (XRT) cycle and 3 patients (10.3%) after bilateral adrenalectomy (BA). One patient (3.4%) died after TSS2 due to postoperative complications, 1 patient (3.4%) had persistent disease at latest FU, in 1 patient (3.4%) the long-term FU was not possible to perform. CD recurrence occurred in 4 out of 28 patients (14%) at an average time 3.6 yrs. from definitive treatment. One patient (3.4%) after BA was operated because of Nelson's syndrome. Two patients (6.9%) were suspected of relapse at latest assessment. At the time of the last evaluation, 17 patients (63%) were on levothyroxine therapy since definitive treatment, 16 patients (59%) were on hydrocortisone treatment, 10 patients (37%) were taking sex hormones replacement, 4 patients (15%)\u2014antidiuretic hormone.Relatively large number of patients after CD treatment in childhood have hormonal pituitary deficits as well as mood and cognitive disorders. CD recurrence can occur even after a long time post effective treatment. Cushing\u2019s disease (CD) is characterized by excess production of adrenocorticotropic hormone (ACTH) by a pituitary corticotroph adenoma, which results in hypercortisolemia. As CD is extremely rare in the pediatric population, the disease is often challenging for physicians of different specialties.. Thus, cTwenty-nine patients (15 girls and 14 boys) were diagnosed with CD and/or treated at Children\u2019s Memorial Health Institute (CMHI), Warsaw, Poland between 1993 and 2018.All patients underwent TSS as a primary treatment for CD . Data was retrospectively collected and therefore some data is missing. The average age of all patients at surgery was 13.49 yrs. (5.42\u201317.25). All but one patient were admitted to the Department of Endocrinology CMHI before surgery. Informed consent was obtained from all patients who completed the questionnaire and Institutional Bioethical Commission (48/KBE/2018) gave permission for the release of anonymized data for publication.The latest FU of adult patients (previous patients of CMHI) was done using the data from the patient\u2019s questionnaire  completed by each patient. Answers to the questionnaire were obtained either by mail, telephone, or electronically and were verified with the patient by the doctor conducting the study. From 24 adult patients, 18 patients responded, so the response rate was 75%. FU of patients who did not respond to the questionnaire was finished during the last assessment at CMHI. In case of 1 patient there was no FU after TSS. The long-term FU of current CMHI patients was performed based on the data from the last clinical evaluation at CMHI and their/their parent\u2019s consent was also obtained. In order to present the outcome confirmed by clinical evaluation, a long-term analysis of 27 patients (93%) was performed also on the basis of data from the latest clinical assessment at CMHI ).Serum cortisol, triiodothyronine and thyroxine  were determined by immunochemical or radioimmunoassay method. Thyroid-stimulating hormone was measured by immunochemical or by radioimmunometric method. Serum ACTH, luteinizing hormone (LH) and follicle-stimulating hormone levels were determined by immunoradiometric assay and serum testosterone and estradiol\u2014by radioimmunoassay. Cortisol levels in the morning and at night were defined as the mean values of 2 measurements respectively: cortisol level at 0800H and 0830H and cortisol level at 0000H and 0030H.Bilateral inferior petrosal sinus sampling (BIPSS) was done by blood sampling from each inferior petrosal sinus for measurement of ACTH concentration simultaneously with peripheral venous sampling. ACTH was measured at baseline and at 3\u2019, 5\u2019, and 10\u2019 after ovine corticotropin-releasing hormone (CRH) administration (1 \u03bcg/kg). Central ACTH secretion was confirmed by an inferior petrosal sinus  to peripheral ACTH ratio >2.0 at baseline and >3.0 after oCRH stimulation . LateralResected tissues were analyzed using hematoxylin and eosin staining, as well as reticulin staining and ACTH immunohistochemistry.The pituitary function of adult patients was assessed at 2 time points: at the last clinical assessment at CMHI and at the latest FU, while the pituitary function of 4 children was assessed based on the information from the last visit at CMHI. At the latest FU adult patients gave information in the questionnaire about their drug therapy due to hormonal deficits since the definitive CD treatment. The evaluation of pituitary function at the last visit at CMHI was based on the following rules: secondary hypothyroidism was defined as a reduced (below the lower limit of the assay) level of free thyroid hormones with low, inappropriately normal or even slightly elevated (but inappropriate) thyroid-stimulating hormone concentration; secondary adrenal insufficiency was diagnosed on the basis of a reduced level of morning cortisol (<5 \u03bcg/dl) with low (most commonly) or inappropriately normal ACTH levels (ACTH reference range 10\u201360 pg/ml) and/or insufficient cortisol response in the exogenous ACTH test (an intravenous administration of 1 \u03bcg or 250 \u03bcg corticotropin), e.g. a cortisol level after stimulation below 18 \u03bcg/dL in the 30th or 60th minute of the test. Hypogonadotropic hypogonadism was diagnosed according to a lack of signs of puberty after the age of 13 in girls and 14 in boys accompanied by low levels of sex hormones (estradiol/testosterone) at low gonadotropin concentrations and/or based on an insufficient LH response in the LH-releasing hormone test (according to obligatory laboratory standard). The central diabetes insipidus (DI) was diagnosed on the basis of polyuria in patients with urine osmolality below 300 mOsm/kg with serum osmolality above 300 mOsm/kg or on the basis of a water deprivation test results. Short-term assessment of GH secretion was performed in accordance with current recommendations. The following stimulation tests were used to assess growth hormone secretion: with glucagon, with L-dopa, with clonidine and with arginine. GH deficiency (GHD) was defined as peak GH <10 ng/ml in 2 stimulation tests .The obtained anthropometric parameters  were presented as standard deviations (SDS) for body height and BMI using the LMS method ,22. Z-sce and sex, 24. Adue and sex. Pubertae and sex and pubeThe distribution of continuous variables was checked for normality. The Student t-test was used to determine significant differences, when variables had the normal distribution. The Mann-Whitney test was used to compare groups with non-normal variable distribution. The exact Fischer test, one-proportion z-test and two-proportion z-test for small sample size were used to compare two groups where the checked variables were expressed in a dichotomous scale. Significance was assumed if P<0.05. Data were analyzed using Statistica 13.0 PL for Windows.The mean age at the disease onset was 10.20 yrs. . The disease onset was defined as the moment when the first symptom of the disease occurred\u2013e.g.: time of weight gain or height deceleration at the growth chart and other. There was no significant difference between the patients regarding sex (P = 0.85). Detailed characteristics of anthropological parameters at presentation and at the latest FU are detailed in Mean age at diagnosis was 13.46 yrs. (range 5.50\u201317.30). The most common symptoms are presented in Mean morning serum cortisol (at 0800H and 0830H) was 30.05 \u03bcg/dl . Mean sleeping serum cortisol (at 2400H and 2430H) was 21.67 \u03bcg/dl (range 8.20\u201352.14). Mean maximum morning serum ACTH (at 0800H) was 111.70 pg/ml . The following protocol of dexamethasone (Dx) administration was used: 30 \u03bcg/kg/dose  every 6 hours for 48 h (low dose dexamethasone suppression test) and 120 \u03bcg/kg/dose (max. 2 mg/dose) every 6 hours for 48 h after low dose dexamethasone suppression test (high dose dexamethasone suppression test) . In 18 pMagnetic resonance imaging (MRI) of the hypothalamo-pituitary region showed abnormalities consistent with a pituitary adenoma in 20/29 cases (69%). Concordance between the site of the adenoma in MRI and at surgery was 9/17 (53%) . Localization of a tumor in preoperative imaging raised the cure rate for CD to 70% when MRI detected pituitary tumor vs. 30% when there was no tumor in MRI, but the difference was not significant (P = 0.68).Thirteen out of twenty-nine patients (45%) who had negative preoperative MRI or unclear endocrine diagnosis underwent BIPSS, which was performed with general anesthesia in all patients. The mean age of patients at the time of BIPSS was 11.70 yrs. (range 5.17\u201317.00). Positive BIPSS results were found in all 13 patients (100%). BIPSS showed lateralization of ACTH secretion in 8 patients . There were no data about lateralization in BIPSS in Patient 8\u2019s medical record, in case of Patient 19 the BIPSS results were ambiguous, in case of Patient 26 BIPSS gave no results because of abnormal venous system . Concordance between lateralization of the tumor on BIPSS and during surgery was 5/8 (63%). One out of five patients (20%) with this concordance did not have remission after TSS1. The remission rate (after TSS1) in patients who underwent BIPSS preoperatively was 84.5% (11/13 patients) and 80% in patients who did not undergo this procedure (12/15 patients); (1 patients excluded because of no FU); the difference was not statistically significant (P>0.5). Localization of a microadenoma by BIPSS agreed with surgical location in 62.5% of cases. The results of the imaging investigations are shown in Treatment of CD consisted of TSS as the first definitive therapy in all patients. Regarding surgeries performed at CMHI, an endoscopic technique was used only in individual cases due to the weak sinuses aeration in prepubertal children, hence the main technique was transnasal microsurgical transsphenoidal resection. Twenty-three out of twenty-eight patients (83%) were operated at CMHI by the same neurosurgeon. Twenty-three out of twenty-eight patients (83%) had the initial biochemical remission after a single TSS procedure (post-operative serum cortisol <1.8 \u03bcg/dl ) and 2/2Histopathological examination confirmed a corticotroph adenoma in 23/25 (92%) patients. In 4 patients  operated outside CMHI there were no data in the medical record about the result of histopathological examination. Positive histology (pituitary adenoma) was present in all 19/19 patients (patients with available data) with remission after TSS1 and in 4/4 patients without remission . HistopaTwo patients (7%) (Patients 8 and 20) had persisting postoperative hypercortisolemia after two TSS and received external beam direct pituitary irradiation outside our center. Pituitary irradiation in patient 20 was performed using a 6-MV linear accelerator and a dose of 4.500 cGy (rad) in 25 fractions was delivered every weekday for 5 weeks. There were no detailed data on XRT in Patient 8\u2019s medical record.At latest clinical assessment at CMHI, 77.8% of patients were in remission, 2 patients (7.4%) had recurrence of disease, while 1 patient (3.7%) had the suspicion of recurrence. One patient (3.7%) died after TSS2. Two patients (7.4%) were before TSS. The median period of FU from TSS for all patients except two (Nos. 12 and 25) from TSS was 3.87 yrs. (range 0.17\u201310.17).At the moment of the end of FU: 86% of patients were in remission, 2 patients (7%) had the suspicion of recurrence, 1 patient (3.5%) was uncured, 1 patient (3.5%) died after TSS. Three patients underwent bilateral adrenalectomy. The median FU from TSS for all patients except one (No. 25) was 10.23 yrs. (range 0.67\u201324.50). Clinical and biochemical recurrence of hypercortisolemia was seen in 4 (15%) patients  . The cliTwenty-six out of twenty-nine (90%) patients required hydrocortisone (HC) substitution after definitive treatment (TSS1/TSS2 or XRT). Fifty nine percent of patients were on HC substitution at the time of the final FU. Time of recovery of pituitary adrenal axis post-TSS in patients who required HC substitution (8 patients) after successful treatment was 1.66 yrs. (range 0.33\u20133.25).Short-term growth hormone (GH) assessment was performed in 12 patients at a mean interval of 1 year (range 0.08\u20138.33) after the last definitive treatment for CD which was TSS for all patients . From other patients: 1 patient (No. 14) had been treated with recombinant growth hormone (rGH) before TSS and the treatment was continued after surgery, 1 patient (No. 26) was undergoing evaluation for GHD at the last assessment, in 1 patient GH assessment has been performed before definitive treatment (XRT). GHD was present in 11/12 (92%) tested patients . In total, rGH therapy was administered in 13/15 patients . In 3 patients rGH therapy was discontinued because of the disease recurrence. 1 patient (No. 3) was before start of rGH therapy at the last assessment. At latest assessment none of the surveyed patients were treated with rGH (there is no reimbursement for rGH therapy in Poland after growth completion). The rGH therapy was finished at the mean age 17.69 yrs. (range 10.83\u201322.40).On the basis of available data from the last visit at CMHI, 19/25 patients  were undergoing pubertal development and 5/25 patients  were pubertally adults . One patEighteen out of twenty-nine patients (62%) developed central DI after TSS1. The mean time of DI duration after TSS1 was 38.40 months (range 0.03\u2013287.00). Normal production of antidiuretic hormone recovered in 13/18 patients (72.2%) with a mean time 5.76 months (range 0.03\u201319.00). At latest evaluation 4 patients  were taking desmopressin as vasopressin substitution therapy. In 1 patient (Patient 11) DI lasted 6 days, after that symptoms of syndrome of inappropriate antidiuretic hormone hypersecretion occurred, which disappeared after fluid restriction.The evaluation of the long-term pituitary function was performed in 27 out of 29 (93%) patients. Patient 21 was excluded from the analysis because post-TSS2 complications resulted in the patient\u2019s death 1 months after surgery. Patient 25 was referred to post-TSS care to her place of residence and did not respond to the questionnaire. The mean FU of patients included to the analysis was 10.52 yrs. (range 0.67\u201324.50). At the time of the last clinical assessment at CMHI pituitary thyroid-stimulating hormone deficiency was diagnosed in 73.9% of patients, adrenocorticotropin deficiency in 56.2% of patients, gonadotropin deficiency in 43.4% and antidiuretic hormone deficiency in 21.7% of patients. At the time of the last FU, 63% of patients were on levothyroxine therapy since definitive treatment, 59% of patients were on hydrocortisone treatment, 37% of patients were taking sex hormones replacement, 15% were taking antidiuretic hormone. At latest FU, 6 patients (22%) had a single pituitary hormone deficiency. Seven patients did not take any substitution therapy for pituitary deficiency.At diagnosis, 5 (17%) patients  had hypertension, which resolved in all of them (the mean time of FU of 7.23 yrs. (range 0.67\u201322.83)). Patient 16, who did not suffer from high blood pressure at diagnosis, reported at latest FU to take ramipril due to primary hypertension.At diagnosisAt diagnosis, low mood was found in 3 (10%) patients  and emotional lability in 6 (20%) patients . Patient 1 developed clinical depression diagnosed before TSS and he was treated with fluoxetine. Two patients (Nos. 10 and 11) had problems with concentration. Patient 6 presented very strong anxiety, a sense of threat of disease and distrust immediately after TSS. From the day 3 after TSS she had visual and tactile hallucinations. She was taking chlorprothixene for 2 weeks and the psychotic episode resolved (resolution of the hypercortisolemia was observed 1 month later).Follow-upPatients 10 and 12 reported in the questionnaire having depression and being under constant psychiatry care (FU 6 and 16.17 yrs.) but they do not require anti-depressant therapy. None of these two patients had any psychiatric problems before TSS. Thirty-eight percent of 18 surveyed adults reported low mood, 33%\u2014depressive states, 44%\u2014memory problems, 50%\u2014emotional lability, 39%\u2014problems with concentration, 61%\u2014mood swings and 67%\u2014irritability.This research supports previous findings on clinical presentation of CD in the pediatric population, however, it also indicates different aspects of the disease in comparison with other studies. Comparing to studies on adult population, there were identified both similarities and differences in clinical presentation of CD. Similar to the results of the study by Devoe et al. on 41 children  and the On the basis of data on adult patients, the localization of a tumor in preoperative MRI raises the cure rate of CD: up to 90% (if MRI detects pituitary tumor) vs. 50\u201370%, when there is no tumor in MRI , 32, 33.The remission rates in pediatric population vary largely due to the lack of agreement on definition of post-operative remission, with reported rates between 45 and 95% , 7, 8, 9The limitation of the data obtained from the patient\u2019s questionnaire is the fact that the pituitary function was not assessed on the basis of the results of hormonal tests. However, this information is valuable and the knowledge about pituitary function after a long period from TSS is important both for patients and for doctors, while limited number of pediatric studies report this kind of data. However, the FU based on biochemical evidence  was shorter but still long-term . High percentages of patients on ongoing levothyroxine therapies in the presented study may result from the fact that other thyroid disorders may be a reason for needing drug supplementation. In each patient levothyroxine therapy lasted from start of drug therapy (after TSS) until latest FU, which indirectly suggests the persistence of the pituitary deficiency, although there is a possibility of a different cause than the central one. The patients were asked in the questionnaire about other chronic diseases and none of them gave the primary thyroid disease as the potential reason of hypothyroidism. These results are a bit controversial as in other studies on patients after TSS in childhood the thyroid-stimulating hormone deficiency was reported to be between 6.7% . ObtaineMost patients did not have the evaluation of GH secretion at latest FU so our results cannot be comparable with for example Devoe et al.\u2019 or Yordanova et al.\u2019 results, where GHD was the most common pituitary deficiency , 15. DesCD recurrence can occur even a long time after effective treatment. Long-term observation of patients after CD treatment in childhood indicates the presence of a large number of patients with hormonal pituitary deficits, as well as a significant problem of mood and cognitive disorders that may be the result of hypercortisolemia in the past.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S1 Appendix(PDF)Click here for additional data file."}
+{"text": "Background: Insight into health conditions associated with death can inform healthcare policy. We aimed to cluster 27,525,663 deceased people based on the health conditions associated with death to study the associations between the health condition clusters, demographics, the recorded underlying cause and place of death. Methods: Data from all deaths in the United States registered between 2006 and 2016 from the National Vital Statistics System of the National Center for Health Statistics were analyzed. A self-organizing map (SOM) was used to create an ordered representation of the mortality data. Results: 16 clusters based on the health conditions associated with death were found showing significant differences in socio-demographics, place, and cause of death. Most people died at old age (73.1 (18.0) years) and had multiple health conditions. Chronic ischemic heart disease was the main cause of death. Most people died in the hospital or at home. Conclusions: The prevalence of multiple health conditions at death requires a shift from disease-oriented towards person-centred palliative care at the end of life, including timely advance care planning. Understanding differences in population-based patterns and clusters of end-of-life experiences is an important step toward developing a strategy for implementing population-based palliative care. The National Vital Statistics System of the National Center for Health Statistics uses death certificates in the United States (US) to register daily how people die in the US (since 1959). This allows clinicians and policy makers to better understand the death rates over time, but also permits study of associations between cause of death, place of death, age, gender, ethnic background, and known health conditions associated with death. Each death record consists of 117 attributes, most of them categorical with up to 7500 different categories per attribute. Although the data set from 2006 to 2016 consists of only 6 GB of data, the number of categorical attributes makes analyses by traditional processing application software challenging.Self-organizing maps (SOMs) have been used to create an ordered representation of multi-dimensional data, to simplify complexity and to reveal meaningful associations. This method has been applied in various fields, like biology ,2, bioteWe aimed to cluster 27,525,663 deceased people based on entity codes  that were associated with death using the data-mining tool Viscovery SOMine. This approach permitted study of the associations between health conditions clusters, demographics, the underlying cause of death, and the place of death. This can provide important knowledge to inform healthcare, including palliative care policy in the US. Indeed, the need for palliative care services will increase because of the ageing population and the increase in non-communicable diseases . In 2015For this study we analyzed the Multiple Cause-of-Death Mortality Data from 2006 to 2016 of the National Vital Statistics System of the National Center for Health Statistics, which provides data obtained from death certificates in the US . Data File Documentations, Multiple Cause-of-Death, 2006\u20132016 , National Center for Health Statistics, Hyattsville, Maryland). Data records without data in the health conditions ) were omitted, resulting in a total number of 27,525,663 usable records. See additional file for details and Health conditions associated with death and underlying primary cause of death were coded using the International Classification of Diseases (ICD)-10 coding scheme . These codes were aggregated into 346 disease categories . A multiwww.viscovery.net; Vienna, Austria). A SOM was used to create an ordered representation of the mortality data. SOMs are a form of unsupervised artificial neural network and can be viewed as a non-parametric regression technique that converts multi-dimensional data spaces into lower dimensional abstractions. A SOM consists of units on a grid (nodes), where each node represents a group of very similar data records. Thereby, the SOM generates a nonlinear representation of the data distribution, which can be used to identify homogenous data groups and perform statistical analyses on them [p-value <0.01 was considered statistically significant.Statistical analyses were performed using Viscovery SOMine 7.1 by Viscovery Software GmbH  years) . At deatSixteen clusters were identified , which aThe top-five most prevalent health conditions associated with death in this cluster were (1) heart failure (34.1%); (2) atherosclerotic heart disease (22.5%); (3) cardiac arrest (21.8%); (4) hypertension (16.6%); and (5) diabetes mellitus (14.8%). The top-five most prevalent underlying primary causes of death were: (1) atherosclerotic heart disease (15.8%); (2) heart failure (10.0%); (3) hypertensive heart disease (6.2%); (4) diabetes mellitus (5.2%); and (5) myocardial infarction (4.8%). Compared to the whole population, the deceased in this cluster had a significantly higher mean age at the time of death and were more often men, black, widowed, and local residents. 43.5% died in the hospital and 28.6% died at home. The deceased in this cluster had a higher prevalence of multi-morbidity than the whole population.The top-five most prevalent health conditions associated with death in this cluster were (1) other cancer (15.8%); (2) breast cancer (13.6%); (3) prostate cancer (10.9%); (4) lung cancer (9.9%); and (5) cardiac arrest (9.6%). The top-five most prevalent underlying primary causes of death were: (1) breast cancer (12.1); (2) other cancer (9.6%); (3) prostate cancer (8.4%); (4) lung cancer (6.3%); and non-Hodgkin lymphoma (6.2%). Compared to the whole population, the deceased in this cluster had a significantly lower mean age at the time of death; were more often men, white, married, local resident; and were more likely to have tertiary education level. They more often died at home or in a hospice facility, and died due to a natural cause. Moreover, the deceased had a lower prevalence of multimorbidity than the whole population.The top-five most prevalent health conditions associated with death in this cluster were (1) other sepsis (29.7%); (2) unspecified kidney failure (16.1%); (3) cardiac arrest (14.3%); (4) respiratory failure (13.9%); and (5) diabetes mellitus (11.7%). The top-five most prevalent underlying primary causes of death were: (1) other sepsis (8.0%); (2) dementia (4.6%); (3) atherosclerotic heart disease (4.6%); (4) diabetes mellitus (4.2%); and (5) unspecified kidney failure (3.9%). Compared to the whole population, the deceased in this cluster had a significantly higher mean age at the time of death; were more often women, black or American Indian, widowed or never married, non-local US resident, more often had only primary education, and were more likely to die in the hospital . Moreover, the deceased had a higher prevalence of multi-morbidity than the whole sample.The top-five most prevalent health conditions associated with death in this cluster were (1) chronic obstructive pulmonary disease (46.8%); (2) pneumonia (35.3%); (3) respiratory failure (28.2%); (4) nicotine dependence (23.7%); and (5) cardiac arrest (12.2%). Moreover, the top-five most prevalent underlying primary causes of death were (1) chronic obstructive pulmonary disease (37.7%); (2) pneumonia (16.7%); (3) other interstitial pulmonary disorder (6.2%); (4) atherosclerotic heart disease (5.3%); and (5) lung cancer (2.5%). Compared to the whole population, the deceased in this cluster had a significantly higher mean age at the time of death; were more often women; were more often white; were less likely to have tertiary education level; were more likely to be a non-local US resident; more often died in the hospital ; and more often died due to a natural cause. Moreover, the deceased had more health conditions associated with death, and a higher prevalence of multimorbidity.The top-five most prevalent health conditions associated with death in this cluster were (1) dementia (65.6%); (2) hypertension (19.5%); (3) pneumonitis (17.9%); (4) atherosclerotic heart disease (14.5%); and (5) cardiac arrest (12.3%). Moreover, the top-five most prevalent underlying primary causes of death were: (1) dementia (47.7%); (2) atherosclerotic heart disease (7.8%); (3) pneumonitis (7.0%); (4) unspecified stroke (6.0%); and (5) chronic obstructive pulmonary disease (4.1%). Compared to the whole population, the deceased in this cluster had a significantly higher mean age at the time of death; had a higher proportion of women; were more often white; more often had received only primary education; were more often widowed; were more likely to be a local resident; more often died in a nursing home (50.4%); and more often died due to a natural cause. Moreover, the deceased had more health conditions associated with death; and a higher prevalence of multimorbidity.Significant differences in socio-demographics, place of death, and the primary underlying cause of death were found after clustering 27,525,663 death records based on the health condition(s) associated with death. Generally, most people died at old age and had multiple health conditions associated with death. The lowest proportion of subjects died in a hospice facility, and most people died in the hospital or at home.This analysis showed that death record data from more than 27 million deceased subjects can be clustered based on one or more of the possible 346 health conditions associated with death using the data-mining tool Viscovery SOMine. Clustering data sets of this size and dimensionality is not an easy task for many conventional cluster algorithms due to computational load. The Viscovery SOMine suite allows to represent large data sets on a SOM calculated from a random sample and uses this low-dimensional representation to conduct cluster analysis and group profiling on the entire data. The SOM allows a visualization of the findings in an intuitive way. For example, Chronic life-limiting diseases are highly prevalent among both causes of death as well as among the health conditions associated with death. The deceased had a mean of three health conditions associated with death, and about three quarters had \u22652 health conditions associated with death. This corroborates the GBDS 2017 findings that improvements in premature mortality for select conditions have led to older populations with complex diseases . Indeed,n = 20,132,389) were aged 65 years or older; and 30.7%  were aged 85 years or older at death. Healthcare organizations and healthcare professionals need to be prepared to offer palliative care to this growing number of dying elderly. Indeed, projections from mortality statistics of England and Wales from 2006 to 2014 predict an increase in the proportion of people dying above 85 years from 38.8% in 2014 to 53.2% in 2040 [In line with global mortality data , the curThe mean age at death in the cluster \u2018Geriatric disease\u2019 was 85 years and dementia was the most prevalent cause of death within this cluster. Previous studies have shown that dementia is a life-limiting illness and persons with dementia are in need of palliative care . Howevern = 1,497,487) had an age of 40 years or younger. The clusters \u2018Open wound/suffocation\u2019, \u2018Poisoning\u2019, and \u2018Other physical harm\u2019 had the highest proportion of younger people: 52.0%, 41.8%, and 27.8%, respectively. This is most probably related to the manner of death  associated with the death causes constituting these clusters. However, younger people were also represented in the other clusters . This is important to realize, as palliative care needs of younger people with life-limiting illnesses may differ from palliative care needs from the elderly [In the current sample, 5.4% of the deceased , \u2018Lung cancer\u2019 (49%), and \u2018Other cancer\u2019 (50%) were more often married at time of death, while subjects in the clusters \u2018Geriatric disease\u2019 (58%) and \u2018Neurodegenerative disease\u2019 (50%) were more often widowed. A study performed in the United Kingdom showed that older people live years  with substantial care needs . PartnerDying at the place of preference is seen as one of the key principles of a good death . Home isThe strength of the current study does not lie in the novelty of any disease specific findings. The novelty of our manuscript lies in our approach and the strong statistic confirmation of many more or less known facts, derived from findings of often smaller or specialized studies. Indeed, we included data of 27,525,663 death records that represent a complete population-based sample of death in the US. The strength of this Big Data approach is seeing the \u201cgrand picture\u201d. This is also why we chose not to stratify the data with respect to gender, race, or any other attribute, since we wanted to keep the focus on the entire population, instead of specific subgroups.n2) or worse.The Viscovery software provided innovative data representation and visualization SOMs, clustering as well as statistical profiling of these death records. The use of SOMs in general and the Viscovery software in particular has several advantages for the analysis of this mortality data set. Since the data is large in quantity as well as complexity we wanted a high-performance method to accurately represent the data distribution, while reducing complexity to a handleable degree, which is one of the strengths of SOMs. In addition, this approach allows for innovative visualization to study interdependencies between diseases and other information. Furthermore, the map representation can be used to apply hierarchical clustering methods to this huge data set, which would be impractical with classical methods because of their high running time complexity of O  at the time of death. Healthcare organizations and professionals need to be prepared to offer interdisciplinary palliative care to a growing number of people dying with multiple health conditions. Indeed, the high prevalence of multiple health conditions requires a shift from primarily disease-oriented care towards person-centred palliative care at the end of life, including timely advance care planning . Underst"}
+{"text": "Unlike the already well-documented human serum proteome, there are still limitations regarding analyzing and interpreting the various physiological changes and disease states of the serum proteomes found in duck. Serum proteome in duck under the condition of mycotoxin contamination in feed has not yet been examined. This study aimed to introduce the characterization of the circulating proteomes in duck serum during exposure to aflatoxin B1 (AFB1).Duck serum samples were collected from four experimental groups, gel-based mass spectrometry was then applied, and finally, 445 proteins were identified in pulled serum sample.Gallus gallus] was up-regulated in the group with the highest AFB1 contamination.Among these 445 proteins, 377 were present in at least one group from all. There were 35 proteins which were expressed when the duck was exposed to AFB1. The protein library that allows the identification of a large number of different proteins in duck serum will be enhanced by the addition of these peptide spectral data. It is noteworthy that chromodomain-helicase-DNA-binding protein 7 (CHD7) [CHD7 protein might be somehow relative to aflatoxicosis in the duck that causes poor performance and economic loss. Moreover, other proteins present in duck serum were also added in the protein library. Mycotoxin is commonly found in poultry feed. Incidence of mycotoxicosis could potentially cause several diseases associated with poor performance, impair immune or organ function and results in severe economic loss in the poultry industry. Poultry feeds in Thailand that is located in tropical zone are commonly contaminated with low level of aflatoxin. Aflatoxin B1 (AFB1) is known as a hepatotoxic and carcinogenic agent in human and several animal species.Other reports have mentioned the ways in which poultry performance and serum profiles are affected by aflatoxin . Among pEimeria spp. or avian pathogenic Escherichia coli exposure and hen physiology during growth were reported .Duck serum samples were collected from four experimental groups, following gel-based MS approached, amount of 445 proteins were identified in pulled serum sample . Of thosAnasplatyrhynchos], protein Wnt-9b [G. gallus], AT-rich interactive domain-containing protein 4A [G. gallus], stAR-related lipid transfer protein 8-like [Meleagris gallopavo], CHD7 [G. gallus], zinc finger matrin-type protein 1-like [A. platyrhynchos], OTU domain-containing protein 7B-like [M. gallopavo], BTB/POZ domain-containing protein 3, partial [A. platyrhynchos], and C-C motif chemokine 4-like [M. gallopavo].Venn diagram shows the number of differentials expressed proteins found between groups of duck after day 5  and day G. gallus], putative interleukin 17 receptor E-like, partial [A. platyrhynchos], CHD7 [G. gallus], and sodium bicarbonate cotransporter 3-like [M. gallopavo].As shown in The preliminary results of five ontology classifications including molecular function, biological process, cellular components, protein class, and pathway class were classified. Functional protein classifications by molecular function were composed of catalytic activity (44%), binding (30%), receptor activity (17%), and structural molecule activity (9%). The categorization of biological function of protein expression provided 12 different component ratios which were a majority group of cellular process (30.60%), followed by metabolic process (26.50%), multicellular organismal process (10.20%), cellular component organization or biogenesis (8.20%), developmental process (6.10%), response to stimulus (6.10%), biological regulation (6.10), immune system process (4.10), and localization (2.00%). Categorization of the most abundant proteins by cellular components composed of membrane (20%), followed by organelle (27%), cell part (26%), macromolecular complex (13%), cell junction (7%), and extracellular region (7%), respectively.In case of distribution of the proteins by protein class, a majority protein function was nucleic acid binding (17%) while other minor classes were receptor (13%), hydrolase (7%), cell junction protein (7%), enzyme modulator (7%), lyase (7%), cytoskeletal protein (7%), transferase (7%), transcription factor (7%), transfer/carrier protein (3%), ligase (3%), calcium-binding protein (3%), oxidoreductase (3%), isomerase (3%), transporter (3%), and signaling molecule (3%). There were five categories which equally abundant proteins shown under pathway class; Ras Pathway (20%), integrin signaling pathway (20%), CCKR signaling map (20%), TCA cycle (20%), and vasopressin synthesis (20%).http://stitch.embl.de/). The summary of the biological interaction of the proteins that were identified involved the construction of a protein-protein functional network with the use of the online software Stitch4.0 ; ADNP homeobox protein two isoform X1 [observed . The ADNobserved .G. gallus], was found in the AFB1 contaminated group at the level of 250 \u00b5g/kg feed (Gr4). Interestingly, two proteins were downregulated in the group orally supplemented with AFB1 at the dose of 25 \u00b5g/kg BW (Gr1); ADNP homeobox protein 2 isoform X1 [A. platyrhynchos], and mitochondrial ornithine transporter 1 [G. gallus].As illustrated in the Venn diagram , a singlG. gallus], has been identified in this study and has been found upregulated in only Group 4 (the highest AFB1 concentration). A class of ATP-dependent chromatin remodeling enzyme that functions in the invoking changes in the interaction between DNA and nucleosomes is represented by the CHD. It is a factor in cellular processes, for example, replication, transcription, recombination, repair, and development [It is interesting to note that one protein, CHD7 [elopment .The CHD7 is an ATP-dependent chromatin-remodeling link that regulates polymerase II transcription as well as the specific step of polymerase I transcription termination. In addition, it may regulate negatively DNA replication (UNIPORT). Mutation of the CHD7 gene has been reported to be linked to \u201cCHARGE\u201d syndrome in human embryo which \u201cR\u201d refers to retardation of growth and development when other abbreviation letters are ignorable .One group of heme-thiolate monooxygenases is comprised of cytochromes P450. CYP3A4  is involved in aflatoxin metabolism as observed in the networks of the protein-protein interactions . In addiTherefore, CHD7 might be somehow relative to aflatoxicosis in the duck that results in poor performance and economic loss. In this study, the low resolution of the 1-D analysis may cause the failure to detect these proteins. Thus, increased enhancement of the resolution of 2-D analysis will be necessary for future studies. Furthermore, because the proteome is dependent on context, defining the precise state of the animals that the plasma is extracted from is critical.In the future, further independent validation of these biomarkers should be confirmed using greater number of samples and more techniques including Western blot to obtain the greatest diagnostic power for the assessment of aflatoxicosis in duck from the healthy duck.In summary, this is the first study to achieve the establishment of a database of serum proteins of duck following exposure to AFB1. The information that is necessary in case of the additional exploration of the levels and patterns of duck serum proteins using different forms of administration and with various concentrations of the toxin is provided by this database. Based on the changes in the protein levels that occur during development, it is suggested that there is the possibility that they have an effect on the stage of exposure to aflatoxins. At present, evaluation of these proteins as candidates for uses in future investigations of markers for aflatoxicosis in duck is being conducted.NT designed the experimental study and wrote the manuscript. JR supported to prepare pre-fractionation protein by SDS-PAGE and samples for MS analysis. SR was responsible for proteomics part and assisted for data analysis. All authors contributed to the submitted manuscript."}
+{"text": "The very high sanitary risk scores were 32 (47.1%) and 21 (31.3%) for FC (p\u2009>\u20090.05); 25 (36.8%) and 3 (4.5%) for FS (p\u2009<\u20090.001), respectively. Contamination of the stored drinking water samples with FS was significantly higher in households with diarrhetic U5 children in the low- and medium-risk ranges (p\u2009<\u20090.05). Water turbidity of 47 (69.1%) and 23 (34.3%) in households with U5 children with and without diarrhea, respectively, was above the permissible level (p\u2009<\u20090.001). The residual free chlorine (RFC) in all the household-stored drinking water samples was below the World Health Organization (WHO) permissible level and temperatures of all the household-stored drinking water samples were permissible. Promotion and advocacy of good stored drinking water handling practices are essential for decreasing the high risk of microbial contamination in both study areas. We recommend education interventions targeting personal hygiene and drinking water handling at the household level.Contamination of drinking water in household water storage containers and inadequate water supplies are common public burdens in low- and middle-income countries, including towns in Wegera District, Ethiopia. Our study aimed to assess the quality of drinking water and identify factors associated with diarrhea in households with under-five (U5) children with and without diarrhea in Ambagiorgis and Gedebge towns in Wegera District. Stored drinking water samples from households with U5 children with and without diarrhea had fecal coliform (FC) counts of 59 (86.8%) and 55 (82.1%) ( About 28 in 100 people lack access to sufficient and quality drinking water globally  with and without diarrhea in Ambagiorgis and Gedebge towns of Wegera District in Amhara Region, Ethiopia. The findings of this study may assist Ethiopian water officials, primary health-care institutes, and health policymakers in designing programs for increasing awareness about household water handling practices, hygiene, sanitation, and protection and treatment of household-stored water.A community-based survey was conducted in Ambagiorgis and Gedebge towns of Wegera District from June to October 2016 with the aim of assessing the quality of household-stored drinking water in households with U5 children with and without acute diarrhea. Wegera District is located in northwestern Ethiopia Fig.\u00a0. The maiBased on a similar study, we assumed that minimal prevalence of the fecal indicator among diarrhetic U5 children would be 71% and among non-diarrheic 90% , hypochlorous acid (HOCl), or hypochlorite ion (OCl\u2212).Stored drinking water: water that is intended for drinking and is stored in a container.p\u2009>\u20090.05). Significantly more caregivers in households with U5 children without diarrhea were literate (p\u2009<\u20090.05) and had higher monthly incomes than those in households with diarrhea cases (p\u2009<\u20090.05). The use of tap water was also associated with the absence of diarrhea (p\u2009<\u20090.01) (Table The ages of the caregivers in households with diarretic and non-diarrhetic U5 children were similar (1) Table .p\u2009>\u20090.05). However, FS concentrations of water samples were significantly higher in households with diarrhetic children in the low and medium sanitary risk categories (p\u2009<\u20090.05) (Table The contamination of 59 (86.8%) of the drinking water samples from households of U5 diarrhetic children with low (16.2%), medium (47.1%), high 13.2%), and very high (10.3%) risk of FC concentrations and 55 (82.1%) of the samples from households of U5 non-diarrhetic children with low (22.4%), medium (44.8%), high (9.0%), and very high (6.0%) risk of FC concentrations was similar  and 22 (32.8%), 22 (32.8%), 11 (16.4%), and 0 (0.0%) of the samples from households with U5 children without diarrhea (p\u2009<\u20090.01) had very high, high, medium, and low sanitary risk scores for FC, respectively (Table p\u2009<\u20090.001) and 4 (6.0%), 3 (4.5%), 17 (25.4%), and 0 (0.0%) of the samples from households of U5 children without diarrhea (p\u2009<\u20090.001) also had very high, high, medium, and low sanitary risk scores for FS, respectively , 6 (8.8%), 10 (14.7%), and 2 (2.9%) of the drinking water samples from households with U5 children with diarrhea . Five (7.4%) of the drinking water samples from households with U5 children with diarrhea and 4 (6.0%) of the samples from households with U5 children without diarrhea had pH above the WHO permissible level (p\u2009>\u20090.05). None of the household drinking water samples had permissible amounts of residual free chlorine, but the temperatures of all the household-stored drinking water samples were in conformity with the WHO standards.Forty-seven (69.1%) of the drinking water samples from households with U5 children with diarrhea and 23 (34.3%) of the samples from households with U5 children without diarrhea had turbidity values above the WHO permissible level  due to the high altitude of the study sites .Our study showed that almost 70% of the studied households with U5 children with diarrhea and 23 (34%) of the households with U5 children without diarrhea had turbid stored water that exceeded the WHO permissible limit for turbidity. A study in Jimma Zone in Ethiopia recorded turbidity of drinking water samples up to 65\u00a0NTU  of the water samples examined to have very high levels of FC (Abdelrahman and Eltahir p\u2009<\u20090.05) within the context of inadequate supply and poor water quality conditions that are typical of Wegera District.It is possible that microbial qualities and physicochemical indicators of drinking water quality are differentially informative of diarrhea risk in various settings (Strauss et al. -risk categories and turbidity of household-stored drinking water were significantly higher in households with U5 children with diarrhea than in households with U5 children without diarrhea. No permissible amounts of RFC were detected in any of the water samples tested. Frequent exposure to stored drinking water that does not conform to WHO standard may result in diarrhea among under-five children. We recommend that the local authorities implement interventions focused on the provision of safe water supplies, behavioral change in personal hygiene and drinking water handling practices, and the protection and treatment of household-stored water. These measures can improve the microbial quality by effectively preventing coliforms and pathogenic contaminants from entering the ready-to-drink water supply. We recommend that further research be carried out on health aspects of household-stored drinking water handling and use in communities with different water sources and socioeconomic situations and that the WASH and other water/sanitation programs consider this issue in their behavioral intervention programs.This study found that household-stored drinking water was grossly contaminated with FC and FS in both households with U5 children with diarrhea and households with U5 children without diarrhea in the northwestern Ethiopian highlands. FS contamination at low- and medium"}
+{"text": "There is lack of information on the proportion of new smear\u2014positive pulmonary tuberculosis (PTB) patients treated with a 6-month thrice-weekly regimen under Revised National Tuberculosis Control Programme (RNTCP) who develop recurrent TB after successful treatment outcome.To estimate TB recurrence among newly diagnosed PTB patients who have successfully completed treatment and to document endogenous reactivation or re-infection. Risk factors for unfavourable outcomes to treatment and TB recurrence were determined.Adult (aged \u2265 18 yrs) new smear positive PTB patients initiated on treatment under RNTCP were enrolled from sites in Tamil Nadu, Karnataka, Delhi, Maharashtra, Madhya Pradesh and Kerala. Those declared \u201ctreatment success\u201d at the end of treatment were followed up with 2 sputum examinations each at 3, 6 and 12 months after treatment completion. MIRU-VNTR genotyping was done to identify endogenous re-activation or exogenous re-infection at TB recurrence. TB recurrence was expressed as rate per 100 person-years . Regression models were used to identify the risk factors for unfavourable response to treatment and TB recurrence.Of the1577 new smear positive PTB patients enrolled, 1565 were analysed. The overall cure rate was 77% (1207/1565) and treatment success was 77% (1210 /1565). The cure rate varied from 65% to 86%. There were 158 of 1210 patients who had TB recurrence after treatment success. The pooled TB recurrence estimate was 10.9% [95%CI: 0.2\u201321.6] and TB recurrence rate per 100 person\u2013years was 12.7 [95% CI: 0.4\u201325]. TB recurrence per 100 person\u2013years varied from 5.4 to 30.5. Endogenous reactivation was observed in 56 (93%) of 60 patients for whom genotyping was done. Male gender was associated with TB recurrence.A substantial proportion of new smear positive PTB patients successfully treated with 6 \u2013month thrice-weekly regimen have TB recurrence under program settings. Each dose during IP was to be given under direct observation; during CP, the first weekly dose was given under direct observation and the remaining two doses of the week were self-administered . There were 759 (48%) non/never-alcohol users, 779 (50%) past users and 27 (2%) current users.Of the 1565 patients, 1506 (96%) were non-reactive for HIV, 48 (3%) reactive and HIV status was unknown for remaining 11. Of the 48 HIV reactive patients, 38 (79%) were put on anti-retroviral treatment.Two hundred and ninety three (19%)were found to have diabetes. Details of anti-diabetic medications were available for 276 (94%): 183 (65%) were on oral drugs, 54 (19%) on insulin and 39 (14%) on both insulin and oral drugs.Distribution of study population by sputum smear, culture and DST results is given in M. tuberculosis. There were 166 (11%) with negative sputum cultures, 8 (<1%) with cultures positive for Non-tuberculous mycobacteria, 18 (1%) with culture contamination and 5 (<1%) with insufficiency of specimens.Of the 1565 patients, 860 (55%) had sputum smear grading of 2+/3+. A total of 1368 (87%) had at least one baseline culture positive for Information on drug susceptibility test was available for 1304 (95%) of 1368 culture positive patients. of them, 1173 (90%) were susceptible to H, R and E while the remaining 131 (10%) had resistance to one or more drugs. H mono-resistance was observed in 77 (6%), E mono-resistance in 27 (2%), EH resistance in 6 (<1%), and resistance to R/HR was present in 20 (1.5%).st care seeking was 2 weeks [IQR: 1\u20136 weeks]. The median duration from 1st care seeking to anti-TB treatment initiation was one week [IQR: 1\u20135 weeks]. Overall, the median duration from the onset of symptoms to anti-TB treatment initiation was 6 weeks [IQR: 3\u201312 weeks].The median duration from the onset of symptoms to 1Sputum smear status at the end of IP was available in 1442 (92%) of 1565 patients. Of them 1241 (86%) had converted to smear negative by 2 months of IP and additional 146 (10%) converted by 3 months of IP; the information on month of conversion was missing for one patient; while the remaining 54 had not converted.Of 1565 patients, 1210 (77%) were successfully treated  . TreatmeThere were 18 (1%) of the total who were switched over to MDR-TB treatment. Treatment was modified for 15 (1%) patients: for diabetes (n = 8), clinical indication (n = 6) in whom continuation phase was extended and in one for medical indication . There were 7 (<1%) patients who were not evaluated for treatment outcome.Of 1210 successfully treated patients, 950 (79%) had recurrence free survival at 12 months follow-up, 158 (13%) had recurrence at variant time points during the period of follow-up, 73 (6%) were lost to follow-up by 12 months and 29 (2%) had died . The weiPulmonary TB constituted 155 (98%) of the 158 TB recurrences, and 3 had TB lymphadenitis. Of PTB patients, 150 were bacteriologically positive .A total of 87 (55%) patients had TB recurrence within 3 months post-treatment and a total of 122 (77%) occurred within 6 months.M.tb and were eligible for genotyping. Genotyping details were available for 60 (49%) of 123 patients while the DNA could not be extracted in the remaining 63 patients. Endogenous reactivation was observed in 56 (93%) patients. Two HIV positive patients with recurrence had endogenous reactivation. Genotyping could not be done in 63 patients since DNA could not be extracted due to inadequate growth or contamination.Of the 150 patients who had bacteriologically confirmed TB recurrence, 123 had available baseline and recurrent sputum cultures positive for The factors analyzed for unfavourable response at the end of treatment included sex, age-group, BMI, initial sputum smear grade, culture grade, drug susceptibility profile, diabetes and anti-diabetic medications, HIV and ART status, smoking, alcohol, duration of intensive phase of treatment, place of treatment, duration from symptoms to treatment initiation and missed doses in intensive phase . None ofThe factors analysed for TB recurrence included sex, age-group, BMI, baseline sputum smear grade, culture grade, drug susceptibility profile, diabetes and anti-diabetic medications, HIV and ART status, duration of intensive phase of treatment, type of DOT, smoking and alcohol use during treatment and / or follow-up, respiratory symptoms at the end of treatment, duration of anti-TB treatment, weight gain during treatment and missed doses in intensive phase . Of all A higher proportion of HIV reactive patients had recurrence compared to HIV non-reactive patients; however, this difference was not significant due to small numbers of HIV reactive patients.This is the first study which has attempted to determine the TB recurrence rates of 6 month thrice-weekly regimen under program settings in India, among new smear positive patients distributed across different geographical locations. We observed a TB recurrence rate of 12.7 per 100 person-years within first year after being declared as successfully treated. In terms of proportions, 10.9% experienced recurrence, which was similar to earlier studies carried out in different geographical locations in the country at different time points. A systematic review reported 10% recurrence after successful treatment among patients treated under DOTS regimen in India . StudiesBeing male was more likely to be associated with TB recurrence in our study. Our finding was contrary to an earlier systematic review from India which reported that sex was not a risk factor for TB relapse . Risk faTB recurrence was mainly due to endogenous reactivation as suggested by genotyping findings in our study. This reflects poorly on the efficacy of the regimen under program settings in its ability to offer a relapse free cure. Previous molecular study from India has documented that most (88%) of TB recurrences in HIV-infected patients were due to exogenous re-infection while most (91%) of recurrent TB cases in HIV uninfected were due to endogenous reactivation . SimilarThe cure rate in our study was 77%. This is lower compared to the RNTCP target of 90% . The posSputum conversion of 96% at the end of intensive phase of treatment is according to the RNTCP target of >90% . In addist care seeking was 19.4 days in the systematic review compared to 2 weeks observed in our study [We observed a median delay of 6 weeks from onset of symptoms to treatment initiation. A systematic review on delay in diagnosis and treatment of pulmonary TB patients in India reported a median delay of 57.5 days from onset of symptoms to treatment initiation . The medur study . The varThe study has few inherent limitations. We did not collect data on the radiological extent of disease. The details of smoking and alcohol were self reported. We were unable to do genotyping on all positive recurrent TB cultures due to insufficient growth.Our findings suggest that a significant proportion of new smear positive pulmonary TB patients successfully treated with 6-month thrice-weekly regimen have TB recurrence under program settings. The RNTCP has now revised the regimen and the current recommendation is a daily 6-month regimen with Fixed dose combination (FDC) drugs.S1 File(DOCX)Click here for additional data file."}
+{"text": "To determine the frequency of mycobacterium tuberculosis detection, in bronchial washing in sputum-scarce cases of suspected pulmonary tuberculosis.A descriptive cross-sectional study was conducted at the Ojha Institute of Chest Diseases, Dow University of Health Sciences, Karachi, during July 2016 to December 2017. Sputum-scarce patients with suspicion of pulmonary tuberculosis were selected and underwent for bronchoscopy, detailed examination of bronchial tree was performed, and bronchial washing collected for testing of mycobacterium tuberculosis with Gene Xpert.A total of 120 patients were included. In this study 55 (45.8%) patients were female and 65 (54.2%) were male with mean\u00b1SD of age was 39.9 \u00b114.7 years. Bronchial washing Gene Xpert for mycobacterium tuberculosis was detected in 83 (69.2%) sputum-scarce cases of suspected pulmonary tuberculosis patients.Bronchial washing Gene Xpert has an excellent diagnostic yield for detection of mycobacterium tuberculosis in sputum-scarce cases of suspected pulmonary tuberculosis. Mycobacterium tuberculosis (MTB); a type of airborne bacterium is a causative agent for PTB.4Pulmonary Tuberculosis (PTB) is a major public health problem, affecting the population world widely. PTB diagnosis is based on isolation of the organism from respiratory specimens, especially sputum samples. WHO suggests the bacteriological identification and confirmation of PTB by means of acid-fast bacilli (AFB) in respiratory specimens.Smear microscopy is still gold standard in many developing countries, but up to 22.8% cases are smear negative and has higher mortality as compared with smear positive.10The rational of this study was to determine the frequency of detection of Mycobacterium tuberculosis in bronchial washing Gene Xpert in sputum-scarce cases of suspected PTB. The utilization of this study is to identify the number of cases that are sputum-scarce yet having PTB. If the frequency of MTB on BW found to be high, not only complications related to MTB can be reduced but so is the associated morbidity and mortality. Early screening of sputum-scarce cases will help to prevent the associated complications and early management can be practiced. Local data is scarce regarding this study in the population of Sindh. This research was designed to find out the current magnitude of MTB in sputum-scarce cases. Our objective was to determine the frequency of mycobacterium tuberculosis detection, in bronchial washing in sputum-scarce cases of suspected pulmonary tuberculosis.This cross-sectional research was designed and conducted at a tertiary care teaching hospital, during July 2016 to December 2017. Non-probability consecutive method was used for selection of patients. The ethical approval of study was done from Institutional Review Board of our University.Patients having age between 18 to 60 years, either male or female, with suspected PTB with sputum-scarce as per operational definitions, taking anti-TB medications less than 1 week, and naive were included in the study.Patients with disseminated or extra pulmonary tuberculosis, HIV positive and immunocompromised patients were excluded from the study.A written informed consent was obtained from the patient undergoing bronchoscopy procedure. Patients fulfilling the inclusion criteria were selected. Taking detailed history regarding cough, fever and loss of weight, thorough physical examination and routine investigations, assessment for the fitness of patients for the bronchoscopy procedure was performed. Details regarding educational status were recorded. Bronchoscope was introduced through trans-nasal route after proper lubrication with xylocaine ointment. Detailed examination of bronchial tree was performed, and BW was collected and sent to the laboratory for Gene Xpert, and presence or absence of MTB was recorded. For data analysis Statistical Package for Social Science (SPSS) software version 22 was used. P-value of \u22640.05 was taken as significant.Sample size was calculated by using the proportions as reported by Khalil KF et al.PTB diagnosis is suspected from a combination of:Cough with sputum, fever (more than 98.4 \u00b0F), sweating and shortness of breathing5% of body weight over 6 to 12 months)Respiratory rate more than 20 per minute, weight loss  patients were female and 65 (54.2%) were male. Selected patients were segregated into following age groups; 18-30 years 44 (36.7%) patients, 31-40 years 18(15%) patients, 41-50 years 21 (17.5%) patients and 51-60 years 37 (30.8%) patients. Socio-economic status of selected patients was; lower class 45 (37.5%) patients, middle class 69 (57.5%) patients and upper class 6 (5%) patients. Educational status was; illiterate 29 (24.2%), primary 10 (8.3%), middle 5 (4.2%), matric 22 (18.3%), intermediate 36 (30%) and graduate/post graduate 18 (15%).Duration of symptoms in selected patients was; 2-8 weeks in 107 (89.2%) patients and 9-16 weeks in 13 (10.8%) patients. Duration of Anti Tuberculosis Therapy (ATT) in selected patients was; Naive 51 (42.5%) patients, 1-4 days 7 (5.8%) patients and 5-7 days 62 (51.7%) patients. Gene Xpert MTB was detected in 83 (69.2%) patients. Thus, PTB was confirmed in 69.2% of patients who were sputum-scarce. 4 (3.3%) patients were found to have rifampicin resistant.2 test. No significant difference was observed in frequency according to the effect modifiers. Details are given in Bronchial Wash Gene Xpert for MTB results were cross tabulated with different effect modifiers such as gender, age, socio-economic status, educational status, duration of symptoms and ATT. Differences in frequency according to these effect modifiers was assessed by \u03c7Tuberculosis is still a major global health problem, affecting millions every year in developing countries. TB is ranked as the second leading cause of death worldwide from an infectious cause, after HIV. TB mortality remains unacceptably high given that most deaths are preventable, if they have access to health care for a timely diagnosis and the proper treatment.12et al and Shin JA et al reporting detection of TB in 30-48% in smear negative patients.In our study, we determined the frequency of detection of Mycobacterium tuberculosis in BW Gene Xpert in sputum-sarce cases of suspected pulmonary tuberculosis. Many sputum smear negative patients are reported to have progressive disease.Bronchoscopy with BW under local anesthesia is a relatively safe procedure and well tolerated by most of the patients. Complications are rare in occurrence.Bronchial washing Gene Xpert has an excellent diagnostic yield for detection of MTB in sputum-scarce cases of suspected PTB. In our study we were able to make diagnosis of PTB in 69.2% of patients who were not able to produce sputum.SHu did data collection; initial manuscript write up.FFZ conceived and designed study, manuscript editing and final approval.SHa did data collection and data analysis and initial manuscript write-up.BFZ did manuscript corrections, revision and statistical analysis."}
+{"text": "This cohort study describes patterns of development, management strategies, and long-term vascular consequences of hypertension associated with ibrutinib in the non\u2013clinical trial setting. Thus, we aimed to describe patterns of development, management strategies, and long-term vascular consequences of hypertension associated with ibrutinib in the non\u2013clinical trial setting.Hypertension is a commonly noted adverse event for patients with chronic lymphocytic leukemia who are treated with ibrutinib in the clinical trial setting .STROBE) reporting guideline.This multicenter cohort study took place at the Memorial Sloan Cancer Center in New York, New York; the Lombardi Cancer Center, Georgetown University Hospital, in Washington, DC; and the Abramson Cancer Center, University of Pennsylvania, in Philadelphia. It included patients treated with 420 mg of ibrutinib daily for at least 6 months outside of clinical trials; patients requiring dose reductions were excluded. Baseline cardiovascular comorbidities and medication regimens, sequential blood pressure (BP) measurements before and after ibrutinib exposure, adjustments to cardiovascular medication regimens, and development of cardiovascular complications were collected. Institutional review boards at all institutions approved the study, and informed consent was not required because of minimal risk to participants. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology .The We identified 247 patients at 3 institutions treated with ibrutinib. Before initiation of ibrutinib, baseline cardiovascular comorbidities included hypertension (107 [43.3%]), hyperlipidemia (87 [35.2%]), diabetes (40 [16.2%]), coronary artery disease (24 [9.7%]), heart failure (5 [2.0%]), valvular heart disease (7 [2.8%]), atrial fibrillation (11 [4.5%]), other arrhythmia (16 [6.5%]), stroke (7 [2.8%]), and smoking history (104 [42.1%]). Details regarding baseline cardiovascular medication profiles are available in the P\u2009<\u2009.001), with a median (range) time to peak BP of 6 (0 to 35) months. Systolic BP changed more than diastolic BP . Incident hypertension  was observed in 86 participants (34.8%), with grade 3 or higher systolic hypertension observed in 82 (33.2%). Of those without baseline hypertension, new systolic hypertension developed in 92 participants (65.7%), and new diastolic hypertension developed in 25 (17.9%). For those with baseline hypertension, 53 (49.5%) experienced systolic hypertension of grade 3 or higher according to the Common Terminology Criteria for Adverse Events, and 5 (4.7%) experienced diastolic hypertension of grade 3 or higher according to the Common Terminology Criteria for Adverse Events. New atrial fibrillation was observed in 16 participants (6.4%), and coronary artery disease was diagnosed in 4 participants (1.6%). Preexisting cardiovascular comorbidities, smoking history, and diabetes were not associated with the development of hypertension in a univariate analysis.The A total of 51 patients (20.6%) had a change in their cardiovascular medication regimen in the first year after ibrutinib exposure. Of these, 15 (29.4%) increased the dose of an existing hypertensive medication, and 41 (80.4%) started at least 1 new antihypertensive medication. Of the 41 patients who started a new medication, 8 (19.5%) started at least 2 new agents. The most common new classes of agents selected were \u03b2-blockers (18 participants [43.9%]), diuretics (9 participants [30.0%]), angiotensin-converting enzyme inhibitors (8 participants [19.5%]), angiotensin receptor blockers (8 participants [19.5%]), and calcium channel blockers (7 participants [17.1%]).4 We found that median time to peak BP was 6 months, suggesting the need for ongoing and close monitoring of BP in patients treated with ibrutinib for several months after drug initiation. The observed rate of incident hypertension and grade 3 or higher systolic hypertension was higher than that observed in clinical trials,3 perhaps reflecting the inclusion of a more comorbid population with potentially less stringent monitoring or different management strategies used in practice vs clinical trial settings. The discrepancy between the proportion of patients experiencing new or worsening hypertension and those with a change in their antihypertensive regimens suggested a potential opportunity for care optimization as well as patient and clinician education. This study is limited by its retrospective design. This study, combined with available clinical trial data on hypertension incidence, may be influenced by natural variation in BP, emphasizing the importance of measuring the variability of BP before and after ibrutinib exposure. Because ibrutinib is given continuously and hypertension prevalence is cumulative, ongoing study of long-term vascular consequences of ibrutinib-associated hypertension is needed.Ibrutinib-associated hypertension is a common adverse event affecting those with and without preexisting hypertension."}
+{"text": "Human metapneumovirus is an emerging pathogen that causes upper and lower respiratory illness. Nursing home outbreaks of infection with this virus can cause severe illness and lead to poor patient outcomes. We report an outbreak investigation in a nursing home during 2018 and infection control guidelines to assist in disease control. Almost all children are infected by 5 years of age, but reinfection can occur throughout life, especially in older adults and immunocompromised persons  provides long-term care, short-term rehabilitation, skilled nursing services, and dementia care. The New Mexico Department of Health initiated an investigation to determine the cause of the illness, characterize the clinical manifestations, and limit transmission.>1 of the following signs and symptoms: cough, fever, shortness of breath, or hypoxia (oxygen saturation <90%). A total of 49 (62%) of 79 residents were identified as case-patients (>99.1\u00b0F (72%), hypoxia (33%), shortness of breath (27%), sore throat (8%), nasal congestion (8%), myalgia (6%), headache (6%), and wheezing (4%).A case of respiratory illness was defined as illness in a nursing home resident with onset during February 15\u2013March 31, 2018, and comprising patients ; 17 , dementia (63%), other neurologic disease (25%), diabetes (18%), chronic lung disease (14%), and cancer (10%). Eighteen case-patients (37%) were in hospice or receiving palliative care. Pneumonia was clinically diagnosed in 9 (18%) case-patients and confirmed by chest radiograph. Three case-patients (6%) visited an emergency department and 9 (18%) were hospitalized (median length of stay 7.3 days); none were intubated or admitted to the intensive care unit.https://www.biofiredx.com). No other pathogens were detected. Thirty-one additional nasopharyngeal/oropharyngeal specimens were sent to the Centers for Disease Control and Prevention  and tested by using a singleplex real-time RT-PCR for HMPV  of the 49 case-patients within a median of 3 days of symptom onset. Testing at a commercial laboratory detected HMPV in 5 (71%) of 7 nasopharyngeal specimens by using the BioFire Respiratory Panel (20 targets), a reverse transcription PCR (RT-PCR) kit ; suspending new admissions; restricting visitation; canceling group activities, including serving meals in the dining hall; intensifying hand hygiene and environmental cleaning; and extensive education for facility staff. Among staff, 8 (<7%) of 120 self-reported respiratory symptoms during the outbreak. Staff who reported respiratory symptoms were furloughed. No laboratory testing was performed for symptomatic staff. Staff illnesses resulted in an average of 3 days of work missed per ill employee. Challenges identified during the outbreak response included maintaining adequate staffing, maintaining supplies necessary for implementation of infection control precautions, the psychological hardship of restricting residents to their rooms, and difficulties controlling the movement of residents with dementia. The last reported case was on March 16, 2018.Prompt identification of the pathogen within 2\u20133 days of specimen collection assisted providers and the facility in coordinating an effective response. Anecdotally, facility staff noted that pathogen identification also promoted credibility. Although diagnostic laboratory testing can be an additional expense, pathogen identification can be invaluable and cost can be reduced by not testing every case-patient once a pathogen has confidently been identified and other pathogens have been ruled out.We report a large outbreak of HMPV-associated severe respiratory illness in a nursing home that affected 62% of residents. Respiratory illness outbreaks in nursing homes present unique challenges because of needs of the residents and structural configuration of the facility, which must be considered when implementing infection control measures. This outbreak demonstrates the need for considering and testing for HMPV during respiratory outbreaks in nursing homes and other residential care settings. Prompt recognition of respiratory outbreaks and institution of outbreak control measures are key to preventing disease spread, hospitalizations, and deaths."}
+{"text": "Presented is a two-group RCT evaluating a multi-component exercise program for hip fracture patients to determine if it is effective in improving the ability to walk independently in the community. Hip fracture patients age \u226560 years (N=210) were assessed and randomized within 26 weeks of hospitalization, and reassessed 16 and 40 weeks later. The primary outcome was ability to walk 300m in six minutes. PUSH (active treatment) included aerobic conditioning, strengthening, balance and functional training. PULSE (attention control) included transcutaneous electrical nerve stimulation, flexibility and active range of motion exercises. Both groups received 2-3 visits per week for 16 weeks in their residences from a physical therapist. 22/96 in PUSH (22.9%) and 18/101 in PULSE (17.8%)  became community ambulators. We conclude that advancing substantial proportions of hip fracture patients to community ambulation will require more than the intervention evaluated in this study."}
+{"text": "One of the most important etiologies in pretermpremature rupture of membranes (PPROM) is cervical bacterial colonization.This study evaluated cervical bacterial colonization in women with PPROM and the pregnancy outcomes.In this cohort study, 200 pregnant women with PPROM at 27-37 wk of gestation who were admitted in an academic hospital of Mashhad University of Medical Sciences from March 2015 to July 2016 were studied. samples were obtained from endocervical canal for detection of routine bacteria and Gram staining. Also, we obtained one blood culture from neonates. Maternal endocervical culture, chorioamnionitis, neonatal intensive care unit admission, neonatal positive blood culture, neonatal sepsis, and mortality were documented. Most common isolated microorganism of endocervical culture were Escherichia coli (24.2%), Coagulase negative Staphylococci (27.2%), Enterococcus and candida each one (11.7%). The prevalence of GBS was only 2.2%. Simultaneous positive blood cultures were seen in 3% of neonates. Among them, Gram-negative bacilli accounted for (66.6%), while Gram-positive cocci and candida made up only (16.7%). Endocervical colonization was associated with a higher admission rate (p=0.004), but there was no significant correlation between endocervical colonization and chorioamnionitis, positive blood culture and neonatal mortality rate.With regard to low GBS colonization rate, appropriate antibiotic regimens should be considered in PPROM cases according to the most prevalent micro organisms of endocervical bacterial colonization. Maybe cervical bacterial colonization had some effects on neonatal outcomes. There was no significant association between endocervical bacterial colonization and chorioamnionitis, positive neonatal blood culture and neonatal mortality. Premature rupture of membrane (PROM) is defined as membrane rupture before the beginning of labor contractions and if it happens before 37 wk of gestation, it is called preterm premature rupture of membrane (PPROM) which is one of the main cause of preterm labor and neonatal death in about 2.3% of newborns , 2. AlthPROM can cause maternal complications like chorioamnionitis, sepsis, placenta abruption, and endometritis. Prematurity as the most important neonatal complication increased the neonatal morbidity and mortality. In some studies, there were relationships between PPROM and intraventricular hemorrhage, periventricular leukomalacia and cerebral palsy -12. WithGroup B streptococcus (GBS) is the main pathogen which its colonization has been observed in lots of western maternal genital tract in PPROM cases, also this is the main cause of early neonatal sepsis in these countries -18. So, With regard to the importance of maternal genital tract colonization as an etiologic factor in PPROM, appropriate antibiotic therapy has a cardinal role in prevention and treatment of maternal and neonatal complications. The aim of this study was the evaluation of bacterial colonization in genital tract of pregnant women with PPROM and its relationship with maternal and neonatal complications.In this cohort study, 200 pregnant women with PPROM between 27-37 wk of gestation were studied in an academic Hospital in Mashhad University of Medical Sciences, Mashhad, Iran from March 2015 to July 2016. Diagnosis of membrane rupture was accomplished by speculum examination to see amniotic fluid leakage from cervical os and nitrazin test was done to confirm the diagnosis if needed. Inclusion criteria were PPROM, gestational age between 27-37 wk, no symptom or sign of chorioamnionitis at admission, and no antibiotics use before culturing. Exclusion criteriawas: patients\u2019 refusal for being in the study. After exposing the cervix by sterile speculum, two samples were obtained with soft cotton swabs from endocervical canal; first swab was placed in Trypticase Soy Broth media and send immediately to the laboratory for detection of routine bacteria and Gram staining. This swab was cultured on sheep blood agar and Eosin methylene blue and evaluated after 24 incubation period. 2 at 35oC for 24-48 hr. After incubation, the enrichment broth is subcultured to blood agar plates and GBS like colonies are identified by the CAMP test and hydrolyzing ability for hippurate  + intravenous Ampicillin 2 gr every 6 hr until 48 hr and the oral antibiotics (amoxicillin 500 mg every 8 hr) were administered up to 5 days if labor was not happened and two doses of 12 mg intramuscular betamethasone was also administered (12 mg every 24 hr for 2 doses). For cases between 34-36 wk of gestation, Ampicillin was administered as mentioned before and if labor didn\u2019t start, pregnancy termination was planned after patient\u2019s stabilization. Chorioamnionitis was defined as: temperature more than 381) Maternal tachycardia more than 100/min, 2) fetal tachycardia more than 160/min, 3) uterine tenderness, 4) malodor uterine discharge, 5) Maternal leukocytosis (WBC White blood cells >15000), and pregnancy termination was planned in these cases. Maternal chorioamnionitis, neonatal intensive care unit (NICU) admission, neonatal positive blood culture, neonatal sepsis (at first 3 days after delivery) and mortality were documented. With regard of the most frequent microorganism which growth in endocervical culture of PROM cases according to the study which performed in this academic hospital , StaphylEthical considerationThis study was approved by the Ethics Committee of Mashhad University of Medical Sciences, Mashhad, Iran  and an informed written consent was taken from all the participants.Statistical analysisData were analyzed by SPSS . With regard of the sample size in this study, parametric tests were used, so data analyzing was performed by Chi-square and Fisher Exact tests. p\u22640.05 was considered statistically significant.In this study, the age of participants was 15-42 yr with mean age of 27.6\u00b12.3 yr. The mean gestational age was 31.5\u00b12 wk. From 200 women; 101 women were primigravid (50.5%), 99 women were multi gravid (49.5%). The history of PROM in previous pregnancy was reported in 43.3% of cases. 21% of cases had comorbidities which diabetes  was the most frequent.Evaluation of endocervical culture showed that 64 cases (32%) were culture negative and 136 cases (68%) were culture positive; which in 62 cases (31%) they were gram negative and in 58 cases (29%) they were gram positive microorganisms .in 16 cases (8%) fungal species were found. the endocervical cultures showed the most frequent pathogen was Escherichia coli (E. coli) 33 cases (24.2%) and after that Staphylococci epidermis (20 cases =14.7%); Staphylococci saprophyticus (17 cases =12.5%); Enterococcus saprophyticus and Candida species (16 cases in each group=11.7%) were the main pathogens. Just 3 cases (2.2%) of GBS were detected . There were 12 cases (12%) of maternal chorioamnionitis during expectant management, but Chi-square test didn\u2019t show any significant relation between maternal chorioamnionitis and endocervical culture (Relative Risk (RR)=1.41, 95%CI: 0.39-5.3, p=0.59). From 12 chorioamnionitis cases; endocervical culture was negative in 3 cases (25%) and was positive in 9 cases (75%). Culture results showed the growth of Klebsiella pneumonia in 3 cases (24%), E. coli in 2 cases (17%), Enterococcus, Pseudomonas and Staphylococci epidermis and saprophyticus each in 1 case (8%). There was significant relation between chorioamnionitis and duration of PPROM (p<0.001) . In this study, we also evaluated the antibiogram for cultured microorganisms which showed that 54.4% of them were sensitive to at least one antibiotic group. The most sensitivity was related to penicillin (12.5%) and cefotaxime (11.7%). Just 2 microorganisms were sensitive to both penicillin and macrolide. About 50.8% of cultured microorganisms were resistant to at least one group of routine antibiotics which administered in PPROM cases  which the most resistant (15.4%) was related to both penicillin and macrolide .In this study, mean neonatal weight was 1500\u00b1200 gr. 95 neonates (47.5%) were admitted at NICU and 105 cases (52.5%) didn\u2019t need NICU admission. NICU admission was significantly higher in women with positive endocervical culture (p=0.004) . Also, t1) Multiple congenital anomaly in 6 cases (30%); 2) Respiratory distress syndrome in 5 cases (25%);3) Sepsis in 5 cases (25%); 4) Severe asphyxia in 2 cases (10%); and5) unexplained in 2 cases (16%). There wasn\u2019t any significant relation between bacterial colonization of cervical sampling and neonatal death by using Chi-square test . Also, there was no relation between chorioamnionitis and neonatal death by using Chi-square test . But, there was a significant relationship between neonatal blood culture and neonatal death . Blood culture was positive in 25% of live and 0.6% of dead neonates. There wasn\u2019t any significant relationship between positive neonatal blood culture and duration of PPROM until endocervical sampling (p=0.151). All the mothers who delivered neonates with positive blood culture had positive endocervical culture too . The causes of neonatal sepsis were gram-negative bacillus in 5 cases (66.6%), gram-positive cocci in one case (16.7) and Candida in one case (16.7%).Results of this study showed that 136 cases (68%) of PPROM patients had a positive endocervical culture which mainly consists of gram-negative (31%) microorganisms and then, 29% gram-positive and 8% fungal species. The most frequent pathogens in endocervical culture were E. coli (24.2%) and then Staphylococci epidermis 14.7%), Staphylococci sapraphitices (12.5%), Enterococus (11.7%) and Candida (11.7%). just 3 cases of GBS were identified. So, the results of current study were totally different from some studies of western countries like the study of Lajos in Brazil %, Staphy which GBIn the study of Loeb and colleagues, they evaluated 300 PPROM cases between 20-25 wk of gestation ; may be In the similar study of Dechen and colleagues which was done in India ; the posIn the current study, coagulase negative Staphylococcus had a rare prevalence and it was positive just in one case (0.7%), but in the study which was done in Saudi Arabia about 24.2% of cultures was positive in terms of this micro organism but similar to current study the prevalence of klebsiela pneumonia and Enterococcus were about 12.9% and 11.3% respectively .In one study which performed in Kerman (another city of Iran) prevalence of GBS and anaerobic pathogens in vaginal culture of PPROM women were about 5% and 1% respectively which the prevalence of these pathogens were about twofold higher compared to the results of current study ; these dIn terms of drug sensitivity of colonized bacteria in the study of Zeng and colleagues which performed a systematic review in this field, they reported that most staphylococcus species (areus and epidermis) were resistant to penicillin (66-100%), except for cloxacilin . In the In the current study, blood culture was positive in about 6 neonates (3%) which 66.6% of these cases were gram-negative bacillus (klebsiella and E. coli) and just in one case gram-positive cocci and Candida (16.7%) were seen. In the study of Stoll and colleagues in USA; the most common pathogen of blood culture in preterm neonates (delivered from PPROM mothers) was E. coli which was consistent with the result of current study .These results were different from the result of Zeng which 7.6% of neonates had positive blood culture and gram-positive pathogens were responsible for about 58.5% of these results and gram-negative bacillus existed in about 33.8% of neonatal blood cultures . VariousLimitationOne of the limitations of current study was that we didn\u2019t evaluate the frequency of Chlamydia and mycoplasma in the patients, however, it was due to some important reasons; first, these microorganisms are not the normal genital flora, and second, the detection method for these two microorganisms are so complex and different and their culture media were not available for us. With regard to different bacterial genital Flora in different society even in the same country, it might be better than in PPROM cases, prophylactic antibiotics administered according to the most prevalent genital tract bacterial colonization and especially environmental pathogens of each community that the last factor  may have a cardinal role in neonatal sepsis. It is recommended that more studies should be performed to support the best choice of prophylactic antibiotics in PPROM patients according to the most prevalent bacterial colonization and neonatal blood culture.Although high prevalence of genital tract bacterial colonization was seen in the PPROM pregnant women; the GBS colonization wasn\u2019t prevalent in this study. So, it might be better that prophylactic antibiotic administration is considered according to the most prevalent microorganism of endocervical bacterial colonization. Although vaginal bacterial colonization could increase the NICU admission, it had no effect on the prevalence of chorioamnionitis, neonatal sepsis and mortality. Important factors in neonatal mortality were positive neonatal blood culture and neonatal sepsis."}
+{"text": "Juniperus (fam. Cupresaceae). In this review we briefly describe their distribution and different biological activities . This paper also includes a detailed explanation of their use as chiral building blocks for the synthesis of bioactive natural products. Among other uses, communic acids have proven useful as chirons for the synthesis of quassinoids , abietane antioxidants, ambrox and other perfume fixatives, podolactone herbicides, etc., featuring shorter and more efficient processes.Communic acids are diterpenes with labdane skeletons found in many plant species, mainly conifers, predominating in the genus  Of these, the most abundant in Nature is 1.Communic acids are a group of diterpenic natural products ,2,3,4 wiCupresaceae species, especially in the genus Juniperus. Although there are species that contain several of them, the most common case is the presence of only one. A tertiary mixture of 1\u20133 is found in Juniperus nana Willd. , antitumoral quassinoids [bruceantin (52)], antifungal podolactones [nagilactone F (63) and oidiolactone C (69)], and abietanes [19-hydroxyferruginol (76) a target for tolerance after transplant and in autoimmune diseases], and sugikurojin (80)] ] .30) and ambracetal (40) are perfume fixatives with a powerful amber-type aroma. Their syntheses were carried out alternatively from methyltrans-communate (1a) or methyl cis-communate (2a) or a mixture of the two .,97.69) w1 and subsequent oxidation with Jones reagent, double esterification with diazomethane and allylic oxidation with SeO2/t-BuOOH yielded 36% of the hydroxydiester 64. Elimination of the trifluoroacetate of 64 with Pd(PPh3)4 led to diene 56, whose hydrolysis with sodium propanethiolate afforded diacid 65. Two different procedures were employed to carry out the double lactonization. First, the selective methylation of the carboxyl group at C12 with MeOH in the presence of 1,1\u2032-carbonyldiimidazole and then iodolactonization under Barrett\u2019s conditions after strict deoxygenation of the reaction medium furnished the iodo derivative 67 (80% yield) along with a 20% yield of dilactone 66. Iodo derivative 67 was exclusively converted in dilactone 66 by reaction with AgNO3/H2O/acetone (84% yield). Dilactone 66 was directly obtained from diacid 65 through a novel dilactonization process by treatment with substoichiometric Pd(II) (25%) and p-benzoquinone in a mixture of acetic acid and acetone as solvent (56%). The 9,11 double bond in diene-dilactone 68 was obtained, via the corresponding lithium enolate of 66 after adding phenylselenenyl chloride, and oxidation of the 11\u03b1-phenylseleno derivative to corresponding selenoxide by hydrogen peroxide with concomitant syn-elimination. Treatment of 68 with dimethyldioxirane afforded the natural oidiolactone C (69). Additionally, 62 was prepared by allylic oxidation as indicated in The selective ozonolysis of 76), isolated from Podocarpus ferrugineus [80), isolated from Cryptomeria japonica [trans-communic acid (1) is shown in Synthesis of the phenol abietane diterpenes 19-hydroxyferruginol 3\u00b72H2O (4.0 equiv.) and LiCl (3.0 equiv.) in Ac2O at 120 \u00b0C for 12 h led to the methyl O-acetyl salicylate 73 (74% yield). Transformation of 73 in abietane 74 was carried out by the addition of MeMgBr in excess. When this compound was treated with Et3SiH and CF3COOH was obtained silylether 75, whose treatment with LiAlH4 in THF at reflux afforded 19-hydroxyferruginol (76) (Epoxidation of ester nol (76) .75 with Na2CrO4 and NaOAc in Ac2O-AcOH led to 7-oxoderivative 77. Compound 77 was refluxed with LiAlH4 in THF giving sugikurojin A (80). An alternative route to compound 80 from 75 involved the removal of the silyl group and further acetylation and oxidation to obtain ketone 79, which was then transformed into 80 (Heating of silylether  into 80 .Cupresaceae especially in genus Juniperus. Furthermore they constitute appropriate building blocks for the efficient preparation of interesting bioactive natural products as ambrox, nagilactone F, bruceantin, 19-hydroxyferruginol and others.This paper reveals the occurrence of the communic acids in fam."}
+{"text": "Fecal incontinence frequently occurs after total mesorectal excision for rectal cancer. This prospective study analyzed predictive factors and the impact of pelvic intraoperative neuromonitoring at different follow-up intervals.Fifty-two patients were included undergoing total mesorectal excision for rectal cancer, and 29 under control of pelvic intraoperative neuromonitoring. Fecal incontinence was assessed using the Wexner Score at 3 and 6\u2009months after stoma closure (follow-ups 1 and 2) as well as 1 and 2 years after surgery (follow-ups 3 and 4). Risk factors were identified by means of logistic regression.p = 0.014); follow-up 2: 3 of 29 (10%) vs. 9 of 23 (39%), (p = 0.017); follow-up 3: 5 of 29 (17%) vs. 11 of 23 (48%), p = 0.019; follow-up 4: 6 of 28 (21%) vs. 11 of 22 (50%), p = 0.035).New onset of fecal incontinence was significantly lower in the neuromonitoring group at each follow-up (follow-up 1: 2 of 29 patients (7%) vs. 8 of 23 (35%), (Non-performance of neuromonitoring was found to be an independent predictor for fecal incontinence throughout the survey. Neoadjuvant chemoradiotherapy was an independent predictor in the further course 1 and 2 years after surgery.Performance of pelvic intraoperative neuromonitoring is associated with significantly lower rates of fecal incontinence. Neoadjuvant chemoradiotherapy was found to have negative late effects. This became evident 1 year after surgery. Bowel dysfunction after total mesorectal excision (TME) for rectal cancer occurs frequently. It seriously impacts patients\u2019 daily lives leading not only to physical but also to emotional suffering with persistent feelings of insecurity. The dysfunction rate ranges from 50 to 90%. Anorectal dysfunction includes fecal incontinence (FI), urgency, frequency, and stool clustering, a symptom complex summarized under \u201clow anterior resection syndrome\u201d (LARS) \u20133.Several instruments were used for evaluation of postoperative bowel dysfunction. This resulted in substantial variations in the reporting of the abovementioned symptoms. The most frequently used instrument is the validated Wexner Score focusing on FI .A variety of risk factors for FI have been reported such as low rectal cancer, radiotherapy, and pelvic autonomic nerve damage \u20137. In paThe present prospective study investigated the potential impact of related risk factors and pIONM on the incidence of FI within a 2-year follow-up (FU) period.ClinicalTrials.gov: NCT01585727) were also excluded [Out of a consecutive series of 187 prospectively investigated patients undergoing elective TME for primary rectal cancer between January 2008 and October 2015, 52 were included. Of those 52 patients, 29 underwent pIONM-controlled surgery  . The stuexcluded .In the present study, all patients underwent standardized nerve-sparing TME with dissection in front of Denonvilliers\u2019 fascia carried out by a colorectal surgeon. Those patients with indication for neoadjuvant chemoradiotherapy were treated using 50\u2009Gy in 5 weeks with accompanying chemotherapy followed by surgery after 6 to 8 weeks.The pIONM was performed using the standard methodological setup . MedicalFor assessment of the anorectal function, patients were asked to complete the validated Wexner Score. The scoring system ranges from 0 to 20 points and consists of five items, including incontinence of flatus, incontinence of liquid, incontinence of solid, wearing a pad, and lifestyle alteration requirements . AnorectThe median time interval between TME and stoma closure was 3 months. Preoperative data was compared to functional outcome at 3 and 6 months after stoma closure (FU1 and FU2). Further, FU were performed at 12 and 24\u2009months after surgery (FU3 and FU4).U test was used. Statistical significance was defined as p < 0.05.The data was analyzed using SPSS 22.0 software . The influence of predictor variables on the risk of new onset of FI following surgery was calculated using univariate analysis. Functional data was transformed into a binary outcome (new onset of FI vs. no new onset of FI). Variables significantly associated with FI in the univariate analysis were included in a logistic regression analysis in order to examine their independent influence. For comparison of function between the non-pIONM and pIONM group, the chi-square test or Mann-Whitney p = 0.461)).Table n = 2), cystoprostatectomy (n = 1), and hysterectomy (n = 1)).No death occurred within 30\u2009days following surgery. During the further follow-up, two patients died of rectal cancer. Four patients had a history of pelvic surgery  reported onset of FI after 3 months following stoma closure (FU1). Six months after stoma closure (FU2), 12 patients (23%) developed FI. One year after surgery (FU3), 16 of 52 (31%) suffered from onset of FI. After 2 years (FU4), 17 of the remaining 50 patients (34%) reported disturbed function.In the univariate analysis, non-performance of pIONM was associated with an increased risk for onset of FI at short-term FU. At the 1- and 2-year FU, neoadjuvant chemo-radiotherapy, absence of pIONM, and tumor site in the lower rectal third were found to significantly increase the risk for FI Table .Table 2p = 0.014). At second FU, 3 of 29 (10%) had onset of FI in the pIONM group and 9 of 23 (39%) in the non-pIONM group (p = 0.017). After 1 and 2 years, 5 of 29 (17%) and 6 of 28 patients (21%) undergoing pIONM reported onset of FI while in the non-pIONM group 11 of 23 (48%) and 11 of 22 (50%) had developed FI (p = 0.019 and p = 0.035).At each FU, the pIONM group had significantly lower rates of newly developed FI than the non-pIONM group Fig. . After tThe present study demonstrated that up to one third of the patients undergoing TME for rectal cancer suffer from FI with a diminished quality of life even 2 years after surgery. This is in accordance with the data of a previous meta-analysis on long-term gastrointestinal functional outcomes following curative anterior resection for rectal cancer. This meta-analysis revealed a pooled incidence of FI of approximately 35% ranging from 3.2 to 79.3%. The reported variations might be explained by the use of modified instruments in the vast majority of the analyzed 48 studies despite the availability of validated scoring systems .Emmertsen and Laurberg developed a valid scoring system, the LARS Score, measuring in addition to FI further functional components such as urgency, frequency, and stool clustering in order to determine the true impact of bowel dysfunction . HoweverTME under pIONM was found to result in significantly lower rates of FI compared to those undergoing surgery alone Fig. . SimilarThis present study further highlights the effect of pIONM on functional preservation not only being significant in the short course, but also in the subsequent FU, which revealed its sustainability even after 2 years (21% vs. 50%). This finding is in accordance with a recent study analyzing pIONM-controlled TME vs. TME alone for preservation of urinary and sexual function  .. 45%) [The positive effect of pIONM on function might result from improved identification of the pelvic autonomic nerves compared to visual assessment alone. A previous study revealed identification rates to be almost twice as high under the use of pIONM (~ 80% vs. 45%) . Without. 45%) , 20.Several studies demonstrated the negative impact of neoadjuvant radiotherapy on ano(neo-)rectal function. Pollak and colleagues revealed FI rates to be more than twice as high in patients undergoing preoperative short-course radiotherapy than in those undergoing surgery alone (57% vs. 26%) . The DutIn the present study, localization of cancer in the lower rectal third was also found to predict for FI Table , which iLimitations of the present study are the relatively small sample size, the non-randomized design, and the resulting potential for selection bias. Moreover, the patients\u2019 responses to the questionnaires may have been influenced by the information that surgery was carried out with pIONM. The evaluation of ano(neo-)rectal function was based on the validated Wexner Score, which is suitable for the assessment of the degree of FI, but does not provide information on frequency, urgency, and stool clustering. The LARS Score was not used. In addition, this report is limited to the investigation of the impact of long-course radiotherapy.The striking finding of the present study is that performing pIONM reduces the incidence of FI not only in the short course, but also in the further course 2 years after TME. The negative impact of neoadjuvant long course radiotherapy became evident 1 year after surgery and remained an independent predictor in the long run.Rectal cancer patients need to be informed about potential functional deterioration and side effects of neoadjuvant radiotherapy in order to carefully weigh up the risk of local recurrence and bowel dysfunction. The patients\u2019 expectations on post-treatment quality of life should thus be considered during the decision-making process in the multidisciplinary tumor board. Further investigation could focus on the value of pIONM in patients selected for radiotherapy and how this would affect the functional outcome."}
+{"text": "Early ante-mortem laboratory confirmation of human rabies is essential to aid patient management and institute public health measures. Few studies have highlighted the diagnostic value of antibody detection in CSF/serum in rabies, and its utility is usually undermined owing to the late seroconversion and short survival in infected patients. This study was undertaken to examine the ante-mortem diagnostic utility and prognostic value of antibody detection by rapid fluorescent focus inhibition test (RFFIT) in cerebrospinal fluid (CSF)/serum samples received from clinically suspected human rabies cases from January 2015 to December 2017.Samples collected ante-mortem and post-mortem from 130 and 6 patients with clinically suspected rabies respectively, were received in the laboratory during the study period. Ante-mortem laboratory confirmation was achieved in 55/130 (42.3%) cases. Real time PCR for detection of viral nucleic acid performed on saliva, nuchal skin, brain tissue and CSF samples could confirm the diagnosis in 15 (27.2%) of the 55 laboratory confirmed cases. Ante-mortem diagnosis could be achieved by RFFIT (in CSF and/or serum) in 45 (34.6%) of the 130 clinically suspected cases, accounting for 81.8% of the total 55 laboratory confirmed cases. The sensitivity of CSF RFFIT increased with the day of sample collection (post-onset of symptoms) and was found to be 100% after 12 days of illness. Patients who had received prior vaccination had an increased probability of a positive RFFIT and negative PCR result. Patients who were positive by RFFIT alone at initial diagnosis had longer survival  than patients who were positive by PCR alone or both RFFIT and PCR.Detection of antibodies in the CSF/serum is a valuable ante-mortem diagnostic tool in human rabies, especially in patients who survive beyond a week. It was also found to have a limited role as a prognostic marker to predict outcomes in patients. Ante-mortem diagnosis of human rabies is essential for patient management and public health measures. The detection of virus specific antibodies in the CSF/serum of patients with suspected rabies is thought to have a limited diagnostic role owing to late seroconversion and short survival in rabies. We examined the diagnostic and prognostic utility of antibody detection by rapid fluorescent focus inhibition test (RFFIT) in CSF/serum samples received from clinically suspected human rabies cases (2015\u20132017). RFFIT (in CSF and/or serum) could confirm ante-mortem diagnosis in 45 (34.6%) of the 130 clinically suspected cases, accounting for 81.8% of the total 55 laboratory confirmed cases. The sensitivity of CSF RFFIT increased with the day of sample collection (post-onset of symptoms) and was found to be 100% after 12 days of illness. Patients who had received prior vaccination had an increased likelihood of a positive RFFIT and negative PCR result. Patients who were positive by RFFIT alone at initial diagnosis had longer duration of survival, although with poor functional outcomes. Antibody detection by RFFIT in CSF/serum was found to have a diagnostic utility especially in patients who survived beyond a week and a limited prognostic role in human rabies. Mononegavirales, Family Rhabdoviridae). Rabies lyssavirus (RABV), the prototype virus of the Lyssavirus genus is the most common causative agent of rabies, usually transmitted through the bite of an infected mammal. Dog-transmitted rabies accounts for most of the human cases reported worldwide. This zoonotic disease causes an estimated 61,000 human global deaths annually, mostly in Asia and Africa; India accounts for a third of the global disease burden . PCR (on single or multiple samples) could therefore confirm the diagnosis in 15 (27.2%) of the 55 laboratory confirmed cases. Of these, PCR alone could confirm the diagnosis in 10 (18.1%) patients.Of the 15 patients who were positive by PCR on single or multiple samples, 5 had received no prior vaccination and 3 had received partial/complete vaccination; history of vaccination was not known in 7 patients.Ante-mortem diagnosis of rabies could be done by RFFIT (in CSF and/or serum) in 45 (81.8%) of the 55 laboratory confirmed cases. Of these 45 cases, RFFIT (in CSF and/or serum) alone could confirm the diagnosis in 40 (72.7%) cases, while the rest of the 5 cases were also positive by PCR (in a single or multiple samples) .124 CSF samples were received for RFFIT from 100 patients. A single CSF sample was received from 79 patients, 2 CSF samples each from 20 patients and more than 2 (five samples) from one patient. RVNA was detected in CSF samples of 41/100 (41%) patients tested, which contributed to the ante-mortem diagnosis in 74.5% of the 55 laboratory confirmed cases. Titres ranged from 0.1 to 240 IU/ml (mean 32.48 IU/ml). Of these 41 patients positive for RVNA, a single CSF sample was positive in 24 patients, two consecutive CSF samples in 16 patients and more than 2 (5 samples) were positive in one patient.Of the 41 patients positive for CSF RFFIT, 34 (82.9%) had received prior vaccination , one (2.4%) had not received any prior vaccination and vaccination status was unknown in 6 (14.6%) patients. 17 patients were also positive by serum RFFIT and 3 patients were PCR positive . Therefore, CSF RFFIT alone could confirm a diagnosis of rabies in 21 patients (i.e 38% of the 55 laboratory confirmed cases)A total of 111 sera were received for RFFIT from 84 patients. A single serum sample was received from 63 patients, paired sera from 19 patients and more than 2 samples from 2 patients each. RFFIT was positive in sera of 22/84 (26.1%) patients tested. Titres ranged from 0.937 to >960 IU/ml (mean 140 IU/ml).Of these 22 patients, 5 patients did not receive any prior vaccination (a single serum sample was received from 2 and paired sera were received from 3 patients each), 16 patients had received partial or complete vaccination (paired sera were received from 14 and >2 sera were received from 2 patients each), vaccination status was unknown in 1 patient (paired sera received).Of the 22 patients who were positive by serum RFFIT, 17 patients were also positive for CSF RFFIT, 2 patients were positive by PCR (in single /multiple samples) and 1 patient was positive by both CSF RFFIT and PCR. Therefore, serum RFFIT alone could confirm a diagnosis of rabies in 2 patients.The age of patients ranged from 1 to 76 years (mean 24.08 years) and 32/55 (58.1%) were male. Children up to 12 years of age accounted for 26/55 (47.2%) of the cases. The presenting clinical features were known in 49/55 laboratory confirmed cases. Based on the manifestations in the acute neurological phase the cases were broadly classified into three clinical forms: encephalitic , paralytic  or atypical  rabies ,16. BaseDetails on post-exposure prophylaxis (PEP) were available in 43/55 (78.1%) cases; 36/55 (65.4%) cases received vaccination, 7/55 (18.1%) did not receive any vaccination and vaccination status was unavailable in 12 (21.5%) cases. Of the 36 cases who received vaccination, 25 (69.4%) received a complete course of vaccination and 11(30.5%) received partial vaccination. Details on rabies immunoglobulin (RIG) received were available in 37/55 (67.2%) cases. 10/55 (18.1%) received equine or human RIG, 27/55 (49%) did not receive RIG and in 18 (32.7%) cases details were unavailable. The incubation period could be ascertained in 42 cases and ranged from 12 to 90 days (mean 34.6 days). Duration of survival and outcome was known in 39 (70.9%) of the 55 laboratory confirmed cases. Post-mortem brain tissue was not received for testing from any of the 55 cases where confirmation of rabies was done on ante-mortem samples.In 46/55 laboratory confirmed cases, where details of sample collection were available, the day of collection of samples post-onset of symptoms ranged from 1 day to 64 days (mean 11.06 days). The time from collection of samples to communication of results to the treating physician (including time for transportation of samples to the laboratory) ranged from <1\u20135 days; mean 3.08 days [1.28 days (range <1\u20133 days) for PCR results and 3.8 days (range 2\u20135 days) for RFFIT results].PCR gave the earliest positive result in 14/46 (30.4%) laboratory confirmed cases and was the only ante-mortem test positive for rabies in 10/46 (21.7%) cases. 7/46 (15.2%) patients were confirmed positive for rabies up to 3 days (post-onset of symptoms); the earliest positive sample was at 1-day (in 1 patient) followed by 2 days (1 patient) and 3 days (5 cases) post-onset of symptoms, respectively. CSF RFFIT was the earliest positive diagnostic test result in 36/46 (78.2%) laboratory confirmed cases and the only ante-mortem test that was positive for rabies in 21/55 (38%) . CSF RFFIT was positive by 7 days (post-onset of symptoms) in 12 patients and the earliest positive sample was at 4 days post-onset of symptoms (in 4 patients).Serum RFFIT was the only test positive in 2 patients; both these patients had received no prior vaccination. Their samples had been collected on day 8 and 13 (post-onset of symptoms) respectively.Post-mortem brain tissue was received from 6 patients. All brain tissues were positive for rabies by FAT and PCR. No ante-mortem clinical samples were received from any of these six patients.Early laboratory confirmation of rabies can help avoid unnecessary costs and aid in prognostication, decisions regarding treatment or palliation, infection control to limit exposures in healthcare settings, public health measures to investigate the source of infection and provide risk assessments of contacts with potential exposures, and case closure and grief counseling of family members ,18.The RFFIT is considered the gold standard assay and has been used to estimate the post-vaccination titres of RVNA for several years. However, the diagnostic utility of antibody detection in CSF/serum in rabies is usually underestimated/ undermined owing to the late seroconversion and short survival in infected patients. Few studies have highlighted the diagnostic utility of antibody estimation in clinically suspected human rabies cases , 19.As evident from the results of this study, detection of antibodies in CSF and/or serum samples was found to be a valuable ante-mortem diagnostic tool in clinically suspected cases of human rabies. Ante-mortem diagnosis of rabies could be achieved by RFFIT (in CSF and/or serum) in 45 (34.6%) of the 130 clinically suspected cases, accounting for 81.8% of the total 55 laboratory confirmed cases. Of these 45 cases, RFFIT (in CSF and/or serum) alone could confirm the diagnosis in 40 (72.7%) cases, while the rest of the 5 cases were also positive by PCR (in a single or multiple samples).CSF RFFIT was the earliest positive diagnostic test result in 36/46 (78.2%) laboratory confirmed cases and the only ante-mortem test that was positive for rabies in 21/55 (38%). CSF RFFIT was positive by 7 days post-onset of symptoms in 12 (26%) patients and the earliest positive sample was at 4 days post-onset of symptoms in 4 (8.6%) patients. Serum RFFIT was the only test positive in 2 patients; both these patients had received no prior vaccination. Their samples had been collected on day 8 and 13 (post-onset of symptoms) respectively.Ante-mortem laboratory confirmation of rabies infection could be achieved in 18 of the 20 clinically suspected and previously unvaccinated cases of human rabies diagnosed in the United States from 1980 to 1996. Antibody to RABV was detected in the sera of 10 50%) patients; it was the earliest positive diagnostic test result in 7 (35%) patients and the only ante-mortem test that was positive for rabies in 3 (15%) cases. Antibody in CSF was detected in 2 (15.3%) of the 13 patients for whom CSF was submitted for ante-mortem diagnosis of rabies [0% patienSerum antibody to rabies virus is not present until several days after the onset of clinical signs and appears even later in CSF. Therefore, antibody detection is of limited value for diagnostic confirmation early in the course of illness , 21. HowAs observed in this study , the senA majority 65.3%) of the cases in our study had paralytic or atypical features and a protracted course of illness. Paralytic rabies is more frequently observed in patients who are partially vaccinated, possibly resulting from an immunopathologic attack on virus infected cells in the brain and spinal cord . The dur% of the Another factor which may contribute to the low sensitivity of antigen or nucleic acid detection (e.g PCR) and increased sensitivity of antibody detection is the vaccination status of the individual prior to development of symptoms. Though the association between vaccination status and the result of RFFIT was not found to be statistically significant (p = 0.118), a majority of patients 94.4%) who had received prior vaccination  were positive by RFFIT (in CSF and/or serum). In contrast, most of the vaccinated patients (91.7%) tested had a negative PCR. A significant association was observed between the vaccination status and result of PCR (p = 0.002), reinforced by the unadjusted odds ratio (OR = 0.04) indicating a lesser likelihood of PCR being positive in vaccinated patients as compared to unvaccinated patients . An inve.4% who hResults of serological assays have to be interpreted with caution when the test is performed on a single CSF or serum sample, especially when the history of vaccination is unavailable or unreliable. Recent intravenous immune globulin (IVIG) administration is known to confound serologic diagnosis of rabies . Though Individuals who develop neutralizing antibodies in the serum or CSF early during the disease course are considered potentially favourable candidates for aggressive management . In patiIn our study, the duration of survival and outcome of illness was known in 39 (70.9%) of the 55 laboratory confirmed cases. 16 of the 39 (41%) patients survived beyond 3 months and RFFIT (in CSF and/or serum) was the only test positive at initial diagnosis in 15 (93.7%) of them, while 1 (6.2%) patient was positive by both RFFIT and PCR. In contrast, all 4 patients (100%) who were positive by PCR only at initial diagnosis died within a week. Patients who were positive by RFFIT alone at initial diagnosis had longer survival  than patients who were positive by PCR alone or patients who were positive both by RFFIT and PCR .All the patients in this study who had longer survival were managed with supportive measures with or without intensive care. The longer duration of survival can be attributed to vaccination prior to onset of illness , increased awareness about rabies, ante-mortem laboratory confirmation and better access to critical care facilities in India in recent years. However, tragically, as observed in this study too, most of the reported human survivors in India are left with poor functional outcomes, with serious long-term repercussions for care-givers .These cases re-emphasize the importance of timely, appropriate and adequate PEP to prevent rabies and draws attention to the serious repercussions of incomplete PEP or deviations as observed in this study. Though recovery from rabies is consistently associated with the presence of neutralising antibodies in the blood and CSF, family members of previously vaccinated patients diagnosed with rabies must be made aware that although intensive care can prolong life, the patient is most likely to survive with multiple disabilities. These cases also underscore the urgent need for formulation of national guidelines for management of rabies cases in rabies endemic countries and the imperative of humane palliative care to minimize the suffering of those dying of this agonizing disease .Current medical outcomes, however dismal, do not predict future medical outcomes, as evident by the commendable strides in medicine over the last few decades . Though There are several challenges associated with neutralization assays like the RFFIT- cumbersome testing procedure and extended turn-around-time (2\u20133 days), requirement of cell culture facility, fluorescent microscope and biosafety measures. Therefore, in laboratories which do not have facilitates to perform RFFIT, an adequately validated ELISA for antibody detection against RABV G protein can be used. An ELISA is an easier, faster, cheaper and safer (use for live virus not required unlike RFFIT) alternative and been shown to correlate well with virus neutralization assays like RFFIT , 35. RapThis study highlights a critical observation with serious public health implications-an increasing number of vaccinated individuals continue to develop and die of rabies and a few survive with serious disabilities . There wOur study has some limitations. The details of ARV included information about vaccination only as a part of the recent PEP for all patients. Reliable data on any other past history of rabies pre-exposure or post-exposure prophylactic vaccination could not be obtained. Since the diagnostic tests for the clinically suspected cases were performed as requested by the referring physicians, not all tests were performed for all patients. Moreover, since our laboratory receives samples from various hospitals across the country, serial sampling and testing of multiple clinical samples which could have increased the overall sensitivity of ante-mortem diagnosis, was not feasible for all patients. Post-mortem brain tissue was received only from six suspected cases and in none of the 130 patients where ante-mortem clinical samples were sent, re-iterating the challenges in post-mortem confirmation of human rabies. Therefore, post-mortem confirmation by the \u2018gold standard\u2019 FAT on brain tissue could not be done on any of these cases. Once a diagnosis of rabies is made, family members often opt to take the patient home to avoid health care costs. Therefore, the outcome of several patients was not known/documented. Laboratory tests for rabies were negative on ante-mortem clinical samples in 75/130 (57.6%) patients with clinically suspected rabies. Rabies could not be ruled out in these patients-a well-recognized limitation of ante-mortem diagnostic testing.In conclusion, this study highlights the challenges of ante-mortem rabies diagnosis and re-iterates that the best approach for maximizing the sensitivity and accuracy of ante-mortem diagnosis of rabies is through testing of multiple/serial samples using multiple modalities. Despite the challenges in interpretation, detection of specific antibodies in the CSF and/or serum is a valuable adjunctive/confirmatory ante-mortem diagnostic tool in human rabies, especially when other tests may be non-contributory, particularly in the context of a changing clinical profile of rabies (vaccinated cases with protracted course of illness) in rabies endemic countries in recent years- which may not conform to the clinical and laboratory profile of rabies described several years ago, that the scientific community even today largely identifies with. Early presence of CSF neutralizing antibodies in previously vaccinated/unvaccinated rabies cases can also potentially be used to help guide decisions regarding intensive /supportive /palliative care in patients along with several other factors  and as aS1 Table(DOCX)Click here for additional data file."}
+{"text": "New HIV infections in Tanzania have been decreasing, however some populations remain at higher risk. Despite of that, evidence on the magnitude of HIV infection and the associated factors and HIV/AIDS services uptake among fisherfolk in Tanzania are inadequately explored. This study therefore aimed at determining prevalence of HIV infection and utilization of HIV/AIDS services among fishfolk in selected Islands of Lake Victoria for evidence-based interventions.n\u2009=\u2009456) and retrospective review of voluntary counselling and testing (VCT) registry (n\u2009=\u20091744) were done in Buchosa and Muleba districts. Structured questionnaire and HIV rapid test kits with the standard testing protocol were used as research tools.Cross-sectional study determining status of HIV infection among fisherfolk (p\u2009<\u20090.001]. Participants employed in fishing related employment had higher odds of being HIV infected (5.4 times) than those practiced fishing and farming . Lack of formal education , being older  and using alcohol  predicted the likelihood of contracting HIV infection. Approximately three quarters (76%) of respondents had ever tested for HIV infection within past 1\u00a0year. Moreover, about half of the study participants had used condom inconsistently and 5 out of 14 (37.5%) of participants who knew their status had never started treatment. Despite the low uptake of most HIV preventive services, majority (88%) of male fisherfolk were circumcised.A total of 269 (58.9%) male and 187 (41.1%) female fisherfolk were recruited during the community survey. Prevalence of HIV infection was 14% in all surveyed landing sites with a site variation from as low as 7.2% to as high as 23.8%. Participants employed in fishing related employment had higher odds of being HIV infected (5.4 times) than those who practiced fishing and partly farming [OR\u2009=\u20095.40; 95%CI 1.88\u201315.61; The magnitude of HIV infection among fisherfolk was up to 3 times higher than that of the general populations in Muleba and Buchosa districts. Higher age, using alcohol and lack of formal education predicted increased likelihood of HIV infection. The uptake of key HIV/AIDS curative and preventive services was generally low.The online version of this article (10.1186/s12913-018-3784-4) contains supplementary material, which is available to authorized users. HIV pandemic is the major public health challenge of the present decade with about 36.7 million people lived with HIV/AIDS globally in the year 2015 with only 17 million on antiretroviral treatment (ART) . Table\u00a0A total of 456 study participants were recruited in this study with more men than women (58.9% vs 41.1%). Mean age of participants was 32.97\u2009\u00b1\u20099.68\u2009years ranging from 15 to 80\u2009years. Majority of the study participants (43.9%) were fishermen and minority (15.1%) being employed in different fishing related activities . Three-quarters of the respondents were mobile population conducting fish related activities and the rest as permanent residents fully or partly engaged in fishing. The distribution of residence in terms of being permanent or mobile was comparable between the two studied Districts [\u03c7p\u2009<\u20090.05]. The infection was lower among men than women (12% vs 17.1%) and yet statistically not different . In Buchosa District, the odds of contracting HIV among men was lower compared to women  whilst comparable in Muleba District . Prevalence of HIV infection was highest (29.3%) among the combination of the widowed, divorced and cohabiting participants and lowest (9.5%) among the married respondents. Participants employed in fish related employment had higher odds of being HIV infected (5.4 times) than those who practiced fishing and partly farming . During the survey however, all respondents accepted HIV testing with exception of only 2%.This study found 14% prevalence of HIV infection among fisherfolk with a variation from as low as 7.2% at Lunyanja to as high as 23.8% at Kasalazi  of male fisherfolk had never tested for HIV within past year before the survey in landing sites located in Buchosa as compared to 16.8% of their counterparts in Muleba. The highest uptake of VCT was among women in Muleba with 90.1% (73/81) whereas in Buchosa only 70% (70/100) of women had ever tested. Only half of all study respondents practiced consistent use of condom and 35.7% (5/14) of respondents found already living with HIV infection and knew their status were not on antiretroviral drugs (ARVs). Moreover, uptake of male circumcision was satisfactory with a coverage of 89%"}
+{"text": "In closed chest CPR an end-tidal carbon dioxide (EtCO2) value of >16.5 mmHg was associated with a 75% sensitivity and 64% specificity for achieving ROSC. Since publication of the RECOVER guidelines, CPR practice did not clinically significantly change at our institution and no improvement of already high ROSC rates was noted. The percentage of cats surviving to hospital discharge was higher than previously reported and the reason for this improvement is not evident with these results. Euthanasia remains a major confounding factor in assessing intermediate and long-term CPR outcomes in dogs and cats.Cardiopulmonary resuscitation (CPR) outcomes have not been prospectively described since implementation of the Reassessment Campaign on Veterinary Resuscitation (RECOVER) guidelines. This study aimed to prospectively describe CPR outcomes and document arrest variables in dogs and cats at a U.S. veterinary teaching hospital since implementation of the RECOVER guidelines using the 2016 veterinary Utstein-style CPR reporting guidelines. One-hundred and seventy-two dogs and 47 cats that experienced cardiopulmonary arrest (CPA) underwent CPR following implementation of the RECOVER guidelines and were prospectively included. Supervising clinicians completed a data form for CPR events immediately following completion of CPR from December 2013 to June 2018. Seventy-five (44%) dogs and 26 (55%) cats attained return of spontaneous circulation (ROSC), 45 dogs (26%) and 16 cats (34%) had ROSC \u2265 20 min, 13 dogs (8%) and 10 cats (21%) were alive 24 h after CPR, and 12 dogs (7%) and 9 cats (19%) survived to hospital discharge. The most common cause of death in animals with ROSC \u2265 20 min was euthanasia. Patient outcomes were not significantly different since publication of the RECOVER guidelines except for a higher feline survival to hospital discharge rate. Dogs ( In 2012, the Reassessment Campaign on Veterinary Resuscitation (RECOVER) initiative responded to the growing recognition of the importance of veterinary cardiopulmonary resuscitation (CPR) and published evidence-based consensus guidelines for the performance of CPR in dogs and cats (The two largest prospective U.S. studies describing the outcome of dogs and cats suffering from cardiopulmonary arrest (CPA) to date were published in 2009 and 2014 and data for both studies was collected prior to the publication of the RECOVER guidelines . A recenUtstein-style guidelines on uniform reporting of in-hospital cardiopulmonary arrest (IHCA) and CPR in dogs and cats were released by the RECOVER initiative in 2016 . These vThe main purpose of this study was to prospectively describe CPR outcomes and document arrest variables in dogs and cats at a U.S. veterinary medical teaching hospital since implementation of the RECOVER guidelines using the 2016 veterinary Utstein-style CPR reporting guidelines . The secAll dogs and cats that suffered from CPA and underwent CPR during the time period from December 2013 through June 2018 were prospectively enrolled in this study. During the study period, CPR was conducted by rescuers trained in CPR according to the RECOVER clinical guidelines for veterinary CPR  for the duration of at least 30 s  or pre-and post-arrest functional capacity by the Modified Glasgow Coma Scale (MGCS) was conducted retrospectively as previously described \u201320.This manuscript is part of a two-manuscript series, factors associated with improved CPR outcomes are described in the companion paper.2 values measured in patients undergoing closed chest CPR only were calculated with the Wilson/Brown method. P-values of < 0.05 were considered statistically significant with post-hoc Bonferroni corrections applied to adjust for multiple comparisons where appropriate.All statistical analyses were performed using commercially available software . Normality testing was performed on continuous variables using the Shapiro-Wilk test. None of the data sets were found to be normally distributed and non-parametric tests were used for further analyses. All continuous data is reported as median (range). Mann-Whitney U testing was used to compare variable distributions between patients achieving ROSC and those not achieving ROSC, between patients with a shockable and non-shockable first documented arrest rhythm, and to compare variables between the current study and a previous study conducted at the same facility prior to publication of RECOVER guidelines. Categorical data were compared between patients achieving ROSC and those not achieving ROSC and between patients with a shockable and non-shockable first documented arrest rhythm with the Fisher's exact test. Area under the receiver operating curve (AUC) analysis and 95% confidence interval (CI) for EtCODuring the study period, 177,125 dogs and cats presented to the hospital, and 46,874 were admitted to the hospital as inpatients. A total of 18,726 dogs and cats were presented to the small animal emergency service and the number of small animal cases anesthetized was 17,997. The total number of annual CPA events could not be determined since events without attempted CPR are not uniformly recorded in the electronic medical record. Time of day during which CPA occurred and training status of the CPR team leader were associated with patient outcome and are described in the accompanying manuscript.Out of 177,125 canine and feline visits to the hospital during the study period, a total of 219 CPR episodes were recorded (0.12%) in 172 dogs and 47 cats. Of the dogs and cats that underwent CPR, 44% of dogs (75/172) and 55% of cats (26/47) achieved ROSC. Seventeen percent of dogs (30/172) and 21% of cats (10/47) had ROSC ranging from 30 s to <20 min, 26% of dogs (45/172) and 34% of cats (16/47) had survived events (sustained ROSC that continued for \u226520 min) and 7% of dogs (12/172) and 19% of cats (9/47) survived to hospital discharge.Of the animals that achieved ROSC for <20 min, 57% of dogs (17/30) and 80% of cats (8/10) were euthanatized. Of the 17 dogs euthanatized within 20 min of ROSC, 71% (12/17) were euthanatized due to poor prognosis, 12% (2/17) due to financial concerns, 12% (2/17) due to a combination thereof, and in one dog (6%) the reasons for euthanasia were not clear. Of the 8 cats euthanatized within 20 min of ROSC, 50% (4/8) were euthanatized due to poor prognosis and 50% (4/8) due to a combination of poor prognosis and owner financial constraints. The animals that did not achieve sustained ROSC and were not euthanatized (13 dogs and 2 cats) all experienced another CPA, of which none survived. The median duration of ROSC until euthanasia or rearrest was 4.75 (0.5\u201318) min.Of the animals that had sustained ROSC (\u226520 min), 27% of dogs (12/45) and 56% of cats (9/16) survived to hospital discharge. Of the animals that achieved sustained ROSC but that did not survive to hospital discharge, 58% of dogs (26/45) and 44% of cats (7/16) were euthanatized. The remaining 16% of dogs (7/45) suffered repeat CPA, none of which survived. Twenty-nine percent of dogs (13/45) that achieved sustained ROSC were alive at 24 h after CPA. Thereof, one dog  was euthanatized due to relapse of spontaneous tension pneumothorax that led to the first episode of CPA and the associated poor prognosis. The remaining 12 dogs  that were alive at 24 h post-CPA all survived to hospital discharge. Sixty-three percent of cats (10/16) that achieved sustained ROSC were alive at 24 h post-CPA. One cat  was euthanatized 4 days post-CPA due to poor prognosis associated with progressive multiorgan dysfunction. The remaining 9 cats  that were alive at 24 h post-CPA all survived to hospital discharge.p = 0.12), canine (p = 0.07), and feline rates (p = 0.89) for achievement of any ROSC were not significantly different (p = 0.64), canine (p = 0.09), and feline (p = 0.12) sustained ROSC were also not significantly different. The overall rate of patients surviving to hospital discharge was not different between studies (p = 0.28) and neither was the canine survival to hospital discharge rate (p = 0.99). The feline survival to hospital discharge rate was statistically significantly higher in the present study compared to the study conducted prior to publication of the RECOVER guidelines (p = 0.0004).Compared to a study conducted at our institution prior to implementation of the RECOVER guidelines, overall  were purebred and 17% (30/172) were mixed breeds. Of the 47 cats, 51% (24/47) were domestic shorthair cats, 32% (15/47) were domestic medium or longhair cats, and 15% (7/47) were purebred cats. Breed could not be determined for one cat . Further information regarding gender distribution and weight of animals included in this study can be found in the accompanying manuscript investigating factors associated with improved CPR outcomes. Chest conformation of dogs and cats was not recorded in the present study.Disease categories at the time of hospital admission are summarized in n = 1), and dopamine (n = 3) in dogs achieving ROSC. One dog not achieving ROSC received norepinephrine and vasopressin simultaneously. Medication constant rate infusions to support cardiovascular function were not in place in any cats that did not achieve ROSC and one cat that achieved ROSC had been receiving dopamine at the time of CPA.Forty-three percent of dogs that did not achieve ROSC (42/97) had no supportive, basic life support (BLS), or advanced life support (ALS) measures in place at the time of CPA. One or more CPR measures were already in place in 85% (64/75) of dogs that did achieve ROSC. Thirty three percent (7/21) of cats that did not achieve ROSC did not have any CPR measures in place at the time of CPA. One or more CPR measures were already in place in 77% of cats (20/26) that did achieve ROSC. An overview of all CPR measures in place at the time of CPA in all dogs and cats is provided in fast scores could only retrospectively be calculated in 27 dogs  and 6 cats . Median APPLEfast score in dogs not achieving ROSC was 29 (16\u201340) and in dogs achieving ROSC was 30 (17\u201333). In cats not achieving ROSC, median APPLEfast score was 24.5 (23\u201326) and in cats achieving ROSC was 31.5 (14\u201337). Prearrest functional capacity as assessed by the modified Glasgow coma scale (MGCS) could be calculated for 11 dogs and 4 cats that achieved ROSC. The median score of dogs with ROSC was 16 (7\u201318). Median MGCS for cats achieving ROSC was 18 (17\u201318). No statistical associations with patient outcome were performed due to the low numbers of patients in which MGCS and Applefast scores were available.Prearrest severity of illness as assessed using the canine and feline APPLECPA was witnessed in 66% of dogs (64/97) not achieving ROSC and in 89% (67/75) of dogs achieving ROSC. In cats, CPA was a witnessed event in 52% (11/21) of patients not achieving ROSC and in 85% (22/26) of cats that achieved ROSC.n = 68, 31%) of animals, and suffering CPA due to an unknown cause was significantly associated with not achieving ROSC (p = 0.0012). Suffering CPA due to a drug overdose or toxicity was significantly associated with ROSC (p < 0.0001).Suspected causes of CPA are summarized in In-hospital CPA was more common in both dogs and cats in this study compared to OHCA. The majority of dogs and cats receiving CPR in this study were categorized as emergency room outpatients at the time of CPA . ICU inpatients were the second most common group of animals receiving CPR  The specific location of IHCA is summarized in p = 0.5). The time to CPR in patients with and without ROSC was not significantly different in this study compared to a study at the same facility prior to publication of the RECOVER guidelines (p = 0.33).Median time to CPR initiation after CPA recognition in the present study was 12 s (immediate\u221221 min) in patients with ROSC and 12 s (0.2\u201313 min) in patients without ROSC, which was not significantly different (RECOVER guideline compliance for BLS and ALS execution in this study was variable. p = 0.66). At a median of 120 (60\u2013225) compressions per minute, chest compression rates in this study were significantly higher than chest compression rates employed at our facility prior to introduction of a RECOVER based CPR approach [median of 105 (65\u2013230) compressions per minute (p < 0.0001)].Median chest compression rates for dogs not achieving ROSC were 120 (70\u2013160) per minute and 120 (60\u2013225) per minute for dogs achieving ROSC. Median chest compression rate in cats that did not achieve ROSC was 150 (120\u2013200) per minute and in cats that did achieve ROSC was 120 (80\u2013190) per minute. Median chest compression rates between animals with and without ROSC were not significantly different (2 was monitored in 59% (129/219) of patients and a reading could be obtained in 84% (109/129) thereof. Excessive airway fluid was noted in 45% (9/20) of patients in which an EtCO2 reading could not be obtained. In dogs and cats that did not achieve ROSC, the median EtCO2 was 15 (0\u201354) mmHg and in those that achieved ROSC was 23 (9\u201361) mmHg, which was significantly different (p = 0.0004). EtCO2 demonstrated a fair accuracy at discriminating between patients undergoing closed chest CPR that did and did not achieve ROSC with AUC (95% CI) of 0.715 (0.618\u20130.811), p = 0.0002. The optimal cutoff for the performance of EtCO2 as an outcome discriminator was 16.5 mmHg with a sensitivity (95% CI) of 75% (60\u201386%) and specificity (95% CI) of 64% (52\u201375%).EtCOp = 0.064) between patients not achieving ROSC [1 (<0.5\u201314) min] and in patients achieving ROSC [1 (<0.5\u201315) min]. The median ventilatory rate in patients not achieving ROSC was 10 (5\u201340) per minute and in patients achieving ROSC was 10 (5\u201360), p = 0.07) per minute. The distribution of ventilatory rates recorded in this study [10 (5\u201360) per minute] was significantly different compared to that recorded in our previous study .Endotracheal intubation was performed in 99% (96/97) of dogs not achieving ROSC, and 93% (70/75) of dogs achieving ROSC. Of cats not achieving ROSC, 100% (21/21) were intubated, as were 92% (24/26) of cats that achieved ROSC. A minority of dogs not achieving ROSC  and dogs achieving ROSC  were already intubated at the time of CPA. One cat that did not achieve ROSC  and 11% (3/26) of cats that achieved ROSC were already intubated at the time of CPA. Mouth to snout ventilation was performed until endotracheal intubation could be achieved in 1 dog achieving ROSC  and 1 dog not achieving ROSC . Mouth to snout ventilation was never employed in cats. Ventilation was never provided using a tight-fitting face mask in either species. Median time to intubation was not different (Cardiac rhythms were monitored during CPR efforts in 95% of dogs (161/172) and 98% of cats (46/47); and in 32% of dogs (55/172) and 13% of cats (6/47), an ECG was already in place at the time of CPA. Median time to first rhythm diagnosis was 3 (0.5\u201313) min in dogs and 3.5 (1\u201310) min in cats. A rhythm diagnosis at the time of CPA or during CPR efforts was available for 77% of dogs (124/161) and 70% of cats (32/46). In the remainder of the animals, the first obtained rhythm diagnosis occurred only at the time of ROSC. Individual rhythm diagnoses obtained at the time of CPA or during CPR are summarized in p = 0.12) when analyzing canine and feline rhythms collectively. When comparing rhythms of dogs and cats achieving ROSC and not achieving ROSC separately, the presence of a shockable first documented rhythm in dogs was significantly associated with ROSC (p = 0.02), whereas in cats, there was no association of first documented rhythm and ROSC (p = 0.63). Median number of comorbidities present at the time of CPA (categories of comorbidities listed in p = 0.17).The presence of a shockable first documented arrest rhythm vs. a non-shockable one was not statistically significantly associated with achieving ROSC (p = 0.3).Throughout the course of CPR, 22% (22/98) of all non-shockable rhythms in dogs became shockable, as did 7% (2/27) of initially non-shockable rhythms in cats. The development of a subsequent shockable rhythm compared to never having a shockable rhythm was not associated with ROSC  and 5 cats were defibrillated at least once. Median time from start of CPR to defibrillation was 8 (1\u201323) min and initial defibrillation was successful in 52% of cases (22/42), to a perfusing rhythm in 41% (9/22) and to a non-perfusing rhythm in 59% (13/22).p = 0.0116).Defibrillation in patients with an initially shockable rhythm was successful in 71% (17/24) of cases, whereas defibrillation in patients developing a shockable rhythm during CPR was only successful in 28% (5/18) of cases. This was statistically significantly different (p > 0.99). The proportion of unsuccessfully defibrillated to successfully defibrillated patients in those that received epinephrine prior to rhythm diagnosis  and those that received epinephrine after rhythm diagnosis was not significantly different . Patients with initial or subsequent shockable arrest rhythms were administered lidocaine in 5 cases, amiodarone in 2 cases and magnesium sulfate in 3 cases.Information on epinephrine administration timing, time to first arrest rhythm, and ECG diagnosis was available in 135 animals. Administration of epinephrine occurred prior to obtaining a rhythm diagnosis in 51% of patients (69/135). In 19% of these animals (13/69) the first documented arrest rhythm subsequently diagnosed was shockable and in 16% of animals (11/69), the first documented arrest rhythm was non-shockable but converted to a shockable rhythm throughout the course of CPR. This was not different to the numbers of initial non-shockable rhythms that converted to shockable rhythms in 15% (10/66) of animals in which epinephrine was administered only after confirming a non-shockable rhythm (Ninety percent of patients in this study received epinephrine as part of ALS efforts (197/219), whereas vasopressin was only administered to 5% of patients (11/219). Atropine was given in addition to epinephrine in 81% of patients (177/219), atropine alone was given in 4% (9/219) of patients. Reversal agents were used in 5% of cases (11/219), two patients received two reversal agents. A total of 7 patients received naloxone, 4 patients received flumazenil, and two patients received atipamezole. Of the 11 patients, 4 received reversal agents due to arrest under general anesthesia, constituting 25% (4/16) of the general anesthesia patient population. Of those 4 patients, 2 received naloxone only and 2 received both naloxone and flumazenil. Sodium bicarbonate therapy was instituted in 4% (9/219) of cases. Forty-five percent of patients (98/219) received isotonic crystalloids, 2% (4/219) synthetic colloids, and 10% (21/219) 7.2% sodium chloride during CPR efforts. Blood products were administered to 5% of patients during CPR, packed red blood cells to 4% (8/219) and plasma products to 1% (3/219).A total of 222 CPR complications were reported in 143 patients (65%) and multiple complications occurred in 55 patients (32%). Complications included difficulties with intubation (62), ETT dislodgement (12), excessive airway fluid hampering ventilation (40), loss of IVC (9), loss of ECG leads (22), defibrillator malfunction (4), inability to deliver shock (8), safety concerns precluding shock delivery (1), and incorrect drug dosages (64). Out of the incorrect drug dosages, atropine was administered at too high a dose (>0.1 mg/kg) in 3 cases, at too low a dose (<0.02 mg/kg) in 18 cases, and epinephrine was administered at too high a dose (>0.1 mg/kg) in 10 and at too low a dose (<0.01 mg/kg) in 33 cases.In this study, 44% of dogs and 55% of cats achieved initial ROSC, which is comparable to the outcomes reported by the previous study at our institution and a further improvement in patient outcomes could not be confirmed since publication of the RECOVER guidelines . OverallWith approximately 39,000 cases admitted to the hospital per year, the annual small animal case load increased approximately 30% in this study period compared to a previous study conducted at the same institution , whilst a similar percentage of patients were euthanatized per species, leaving more cats to survive to hospital discharge. The body conformation of cats likely makes chest compressions more effective than in most dogs and may account for the higher survival rate of cats in this study. Survival to hospital discharge is also dependent on the severity of the underlying illness and it remains possible that the cats included in this study were less severely ill than dogs. In our accompanying manuscript, being a cat was associated with increased odds for survival to hospital discharge even after controlling for being under general anesthesia at the time of arrest, making a general anesthesia related CPA as an explanation for higher survival unlikely. Illness severity scoring and prearrest functional capacity assessment could only be performed in a minority of patients and therefore differences in prearrest illness severity and patient neurologic function remain factors that could explain the higher feline survival to hospital discharge rates.Even though veterinary ROSC rates in North America have become comparable to ROSC rates in people, the rate of survival to hospital discharge in veterinary medicine overall remains significantly lower , 24, 25.Cardiopulmonary arrest in patients with an unknown underlying etiology was associated with lower likelihood of ROSC, whereas CPA due to drug overdose or toxicity was associated with achieving ROSC. We were not able to confirm the previously reported lower likelihood of ROSC in patients suffering CPA due to hemorrhage, shock, multiorgan dysfunction syndrome, or neurologic disease , 3. PatiThe median chest compression rates in our study were not different between patients with and without ROSC and fall into the rates recommended by the RECOVER guidelines . Even th2 monitoring has been recommended to assess the efficacy of chest compressions and predict CPR outcomes in people and the RECOVER initiative has adopted the recommendation of its routine monitoring during CPR  or written at patient admission to the hospital.KH and SE designed the study and generated the CPR questionnaire and critically revised the manuscript. SH compiled and analyzed the data and wrote the manuscript. Results were interpreted by SH, KH, and SE. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "CIRT was applied either alone  or in combination with intensity modulated radiotherapy (IMRT) . The toxicity was assessed according to the Common Toxicity Terminology Criteria for Adverse Events (CTCAE) v4.03. (3). Results: the median follow-up was 24 months (range 5\u201361 months). Overall, the therapy was tolerated very well. No grade >3 acute and chronic toxicity could be identified. The most reported acute grade 3 side effects were acute dysphagia  and acute odynophagia , making supportive nutrition via gastric tube  and via high caloric drinks  necessary due to swallowing problems . Overall, chronic grade 3 toxicity in the form of chronic hoarseness occurred in 7% of the patients . At the last follow-up, all the patients were alive. No local or locoregional recurrence could be identified. Only one patient with laryngeal ACC developed lung metastases three years after the first diagnosis. (4) Conclusions: the accelerated hypofractionated active raster-scanned carbon ion radiotherapy for radioresistant laryngeal malignancies is feasible in practice with excellent local control rates and moderate acute and late toxicity. Further follow-ups are necessary to evaluate the long-term clinical outcome.(1) Background: The authors present the first results of active raster-scanned carbon ion radiotherapy (CIRT) for radioresistant laryngeal malignancies regarding efficacy and toxicity. (2) Methods: 15 patients with laryngeal adenoid cystic carcinoma (ACC;  In recent years, more aggressive therapy regimes in the treatment of head and neck cancers (HNC) were established to achieve improved tumor control and prolonged survival, with the consequence of high toxicity rates due to the close proximity of organs at risk and increased doses applied ,2,3. Thun = 15, 100%). No local or locoregional recurrence could be identified. The total laryngectomy was applied in one patient before radiotherapy (6.7%). Thus, in all other patients, we could provide organ-sparing . Complete remission (CR) could be detected in three patients (20%), partial remission (PR) in five patients (33.3%), and stable disease (SD) in seven patients (46.7%). Before radiotherapy, the tracheostomy was obligatory for severe airway obstruction in 33.3% of the cases (n = 5). At the follow-up, these patients were no longer dependent on a tracheostoma due to a good tumor response. Lung metastases occurred three years after the first diagnosis (DC at last follow-up of 93%) in only one patient ), who received bimodal radiotherapy (RT.)The median follow-up was 24 months (range: 5\u201361 months). At the last follow-up, all patients were still alive (n = 5) and 40% from acute grade 2 toxicity (n = 6). The most identified acute grade 1/2 toxicities were dysphagia , odynophagia , dermatitis , hoarseness , xerostomia , and mucositis . Acute grade 1 alopecia was detected in five cases (33.3%) and dry cough in two cases (13.3%). Acute toxicity was equally distributed between CIRT alone and bimodal RT with IMRT and C12 boost. Supportive nutrition via a gastric tube was obligatory in two patients (13.3%) and via high caloric drinks in one patient (6.7%).Treatment was well tolerated by the patients without any severe treatment-related side effects . No gradn = 5) and grade 2 toxicity in 20% (n = 3) of the patients. Chronic grade 1 toxicity in the form of xerostomia  and hoarseness  dominated. Chronic grade 2 hoarseness was reported by three patients (20%), xerostomia by three patients (20%), and dysphagia by one patient (6.7%). According to the chronic toxicity, no relevant differences between CIRT alone and bimodal RT could be assessed. At the last follow-up, acute odynophagia, dermatitis, alopecia, and dry cough resolved in all the patients. No patient was dependent on supportive nutrition 12 months after therapy.Chronic toxicity was rare. No chronic grade 4 and 5 toxicity could be identified. A chronic grade 3 toxicity in the form of hoarseness occurred 12 months post RT in only one patient (6.7%) with chondrosarcoma who received CIRT alone with doses up to 60 Gy )/3 Gy (RBE). Chronic grade 1 toxicity could be observed in 33%  rates and OS despite limitations in the patient number, short follow-ups, and the retrospective character of the current study. Lung metastases occurred three years after therapy in only one patient with ACC. Larynx-preservation could be achieved in all patients who had not received prior laryngectomy before RT.Treatment was tolerated well without any severe grade 4 or 5 acute and late side effects. Although a longer follow-up was needed to make a clear statement, late treatment-related side effects remained low. Thus, only one patient (7%) reported a chronic grade 3 toxicity in the form of hoarseness. We could not identify the major differences between CIRT alone and bimodal RT in the small study cohort. Both methods seem equally safe regarding toxicity. In a systematic research of the literature including the PubMed, Embase, and Cochrane Library databases, we could identify only a few retrospective analyses reporting the HNC patients who were treated with carbon ions ,25,26,27Dose-escalated radiotherapy with active raster-scanned carbon ions and intensity-modulated radiotherapy is an advanced method in the treatment of radioresistant tumors ,15,28. LHigher prescribed doses to optimize tumor control for laryngeal malignancies are associated with increased swallowing dysfunction, stricture, and feeding tube dependence. These functional disorders correlate with the radiotherapy dose and the volume of surrounding irradiated tissue. Thus, an increase of the irradiated pharyngeal constrictor muscle volume >30% which receive >70 Gy lead to higher swallowing dysfunction and an irradiated pharyngeal constrictor muscle volume >50%, which receive more than 65 Gy to a higher aspiration rate ,32. DyspIt is difficult to compare our results with other carbon ion experiences for head and neck cancers because of the missing data for laryngeal malignancies, different tumor sites, and various dose calculation models for CIRT reported in the current literature. Nevertheless, several authors describe similar toxicity rates for CIRT in the head and neck regions with insignificant high-grade acute and chronic side effects ,28,29,34Medical records of fifteen patients who received CIRT either alone or in combination at the Heidelberg Ion Beam Therapy Center (HIT) and the Department of Radiation and Oncology of the University Hospital Heidelberg were identified and analyzed retrospectively. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of the University Hospital Heidelberg (S-421/2015).Before radiotherapy, a clinical examination, the Eastern Cooperative Oncology Group (ECOG) performance status, as well as preserving symptoms, were assessed in all patients by an otorhinolaryngologist. Endoscopy, computed tomography (CT), and magnetic resonance imaging (MRI) were performed to determine the tumor, nodal, and metastasis stage according to the 8th edition of the Union for International Cancer Control (UICC) TNM classification guidelines.n = 7; 47%) up to 60 Gy  in 3 Gy (RBE) single dose fractions. Tumors of ACC histology  received bimodal RT with IMRT doses of 50 Gy to 54 Gy in 2 Gy single dose fractions to the CTV2 and a carbon ion boost to the CTV1 with 18 Gy (RBE) to 24 Gy (RBE) in 3 Gy (RBE) single dose fractions. CTV2 received at least 90% and CTV1 received at least 95% of the prescription isodose. CIRT was applied in 5\u20136 fractions per week at the Heidelberg Ion Beam Therapy Center (HIT) or at the Marburg Ion Beam Therapy Center (MIT) with active raster-scanning and daily position correction. IMRT was applied in 5 fractions per week with a daily portal image guidance and weekly performed MV-CT scans for position correction. Dose constraints to the constrictor muscles and to the esophageal constrictor were defined as low as reasonably available. Doses for the spinal cord were limited to 45 Gy (EQD2). A treatment plan showing active raster-scanned radiotherapy alone for a patient with chondrosarcoma of the left vocal cord is depicted in Treatment planning was performed based on a non-contrast CT scan with a slice thickness of 3 mm in the irradiation position. For immobilization, an individual thermoplastic head mask with a shoulder fixation was used. Target delineation based on a contrast-enhanced CT or MRI was performed for image correlation . The gross tumor volume (GTV) was defined as the delineated primary tumor. CTV1  involved the macroscopic tumor with a safety margin of 5 mm including areas of possible microscopic spread for definite radiotherapy or the whole larynx for postoperative radiotherapy. In case of ACC histology, CTV2 for the lymphatic drainage was delineated. The planning target volume (PTV) included the CTV with a safety margin of 3\u20135 mm. Chondrosarcomas were irradiated with carbon ions only  . CompletStatistical analyses were performed with IBM SPSS Statistics version 24  using the Kaplan\u2013Meier method for survival analysis. OS, LC rate, and treatment-related acute (up to 3 months after treatment), as well as chronic toxicity (>3 months after treatment), were analyzed. Local control was assessed from the day of commencement of RT to the day of local progressive disease (PD). OS was considered as the time period between the first diagnosis and last follow-up or death. DC was assessed from the day of therapy commencement to distant tumor progression.n = 8) and CS in 46.7% (n = 7) of the patients. The most common tumor sites were the supraglottic  and the glottic larynx . In only one case was the tumor located in the subglottic larynx (6.7%). Initial symptoms at the time of the first diagnosis were hoarseness , dyspnea  and dysphagia . The majority of the tumors were locally advanced with the T3 stage having been reached by two patients (13.3%), the T4a stage by six patients (40%), and the T4b stage by two patients (13.3%). At the time of the first diagnosis, no patient showed lymph node involvement (N0) or distant metastases (M0). According to the grading, three patients could not be staged for grading (20%), five patients were staged G1 (33.3%), three patients were G2 (20%), and four patients were G3 (26.7%). According to the patient and disease characteristics, no significant differences between CIRT alone and bimodal RT could be detected.Fifteen patients with a laryngeal malignancy treated with CIRT at our department were identified using the National Center for Tumor Disease (NCT) cancer registry. Patient, disease, and treatment characteristics are shown in n = 4). Overall, 53.3% of the patients received CIRT in combination with IMRT (n = 8) and 46.7% received CIRT alone (n = 7). The prescribed doses were 50 Gy in a 2 Gy single dose fraction for IMRT and 18 Gy (RBE)  or 24 Gy (RBE)  in a 3 Gy (RBE) single dose fraction for the C12 boost and 60 Gy (RBE) in a 3 Gy (RBE) single dose fraction for CIRT alone. The median EQD2  was 75 Gy for all patients (range: 72.5\u201380 Gy). The median PTV volume prescribed on the primary tumor was 110 cc (range: 59\u2013150 cc) for C12 alone and 500 cc (range: 387\u2013731 cc) for the bimodal RT with a median boost volume of 118 cc (62\u2013138 cc) for the C12 boost. The median follow-up was 24 months (range: 8\u201361 months).Radiotherapy was applied postoperatively in six cases (40%) and definitely in nine cases (60%). Overall, one patient received laryngectomy  and five patients received a larynx-sparing laser surgical partial tumor resection  before radiotherapy. Negative resection margins could be achieved in only one patient with a total laryngectomy (6.7%), R1 in another patient (6.7%) and R2 in four patients (26.7%). Functional neck dissection was applied in three patients (20%). Only one patient with laryngeal ACC received concomitant cetuximab 75 mg/m\u00b2 weekly (6.7%); 7 cycles. The majority of the patients who received prior surgery were treated with CIRT alone (57%; Accelerated hypofractionated active raster-scanned carbon ions radiotherapy for laryngeal malignancies seemed to be feasible and safe in practice with excellent local control rates and moderate side effects. Especially for radioresistant tumors of the head and neck, carbon ions seem to be an effective method for dose escalation. Further follow-ups are necessary to evaluate the long-term clinical outcome."}
+{"text": "Kawasaki disease (KD) can be associated with concomitant viral or bacterial infections. Children with persistent or recurrent fever 36 hours after the end of intravenous immunoglobulin (IVIG) are considered to be resistant to treatment and are at increased risk for coronary complications. Although concomitant infection does not affect coronary outcome, it is unknown how it influences the response to IVIG treatment.Retrospective cohort study between 2008 and 2016 in a tertiary pediatric university hospital, including 154 children, of which 59 (38%) had concomitant infection.Children with concomitant infection were more likely to have fever 48 hours after initial IVIG treatment  and to be treated with a second dose . Children with infection had higher C-reactive protein at the time of diagnosis , and 48 hours after IVIG administration . Nevertheless, there was no statistically significant difference in the prevalence of coronary complications (Z-score > 2.5) between children with and without concomitant infection .Children with KD and concomitant infection are more likely to have persistent fever and elevated inflammatory markers after treatment. This association increases the likelihood of receiving a second dose of IVIG but not the risk of coronary complication. Accordingly, prospective studies to distinguish true IVIG resistance from infection induced persistent fever is warranted. Kawasaki disease (KD) is an acute systemic vasculitis mostly affecting children younger than 5 years old. It is the most important cause of acquired heart disease in children in developed countries . ConcomiThis retrospective study included children with a diagnosis of KD between 2008 and 2016 followed at the Sainte-Justine\u2019s University Hospital Center . Inclusion criteria were a diagnosis of KD maintained at discharge based on current clinical practice and recommendations [Medical charts were reviewed for demographic characteristics, clinical course, laboratory values and infectious workup. Clinical KD criteria were reviewed and children classified as complete or incomplete KD, in the presence of fever and \u22643 clinical criteria for the latter. Delay in IVIG administration was defined as > 10 days between onset of fever and IVIG administration; and IVIG resistance as persistent or recrudescent fever (> 38.5\u00b0C) 36 hours after the end of IVIG infusion. Concurrent infection was defined as a clinical diagnosis and proven concurrent infection as patients with a positive microbiologic testing or imaging study in the presence of clinical symptoms. Testing for concomitant infection was based on clinical symptoms. Urinary tract infection was diagnosed according to current American Academy of Pediatrics guidelines . GastroeEchocardiographic CA size was reviewed for all children at onset of the disease, with follow-up studies for a minimum of 3 months and up to one year after diagnosis of KD. CA Z-scores were calculated for the right coronary artery, left main coronary artery, left anterior descending artery and circumflex artery. CA aneurysm was defined as a localized dilatation of a portion with adjacent normal measurements, or an obvious saccular deformation of the CA. CA dilatation of non-aneurysmal segments was defined as a CA Z-score > 2.5 , calcula2 tests were used for comparison of categorical variables. Logistic regression was used to examine the association between concomitant infection and CA complications, controlling for confounder variables (IVIG resistance). All analyses were performed with SPSS Statistics version 23 . A two-tailed p value of <0.05 was deemed significant.Quantitative variables were summarized as mean \u00b1 SD and categorical variables as frequencies and percentages. The Shapiro-Wilk test was used to test for normal distribution. Comparison of clinical and laboratory data between patients with and without concurrent infection was performed using the student\u2019s t-test for continuous variables with normal distribution or the Mann-Whitney U test for continuous variables with non-normal distribution. ANOVA for repeated measures was used to describe the variation of temperature and laboratory values over time. The Fisher or the \u03c7The study included 154 children  aged 3.4\u00b12.8 years. The median number of diagnostic criteria was 5 (range 2\u20136), with 59 (38%) children having incomplete KD criteria. IVIG were administered to 150 (97%) patients, 6.7\u00b12.6 days after onset of fever. Delay in IVIG administration occurred in 10 (7%) patients, and IVIG resistance in 36 (23%).Concurrent infections were diagnosed in 59 (38%) patients, of which 20 (34%) were viral and 39 (66%) bacterial. URTI was diagnosed in 19 (32%) children, caused by respiratory syncytial virus (n = 3), parainfluenza (n = 3), rhinovirus (n = 4), influenza (n = 2), enterovirus (n = 2) and adenovirus (n = 4). Three children had multiple viruses detected. Two (7%) children were diagnosed with viral gastroenteritis. Three (5%) children had a clinical and biological profile suggestive of acute CMV infection (positive IgM and negative IgG), and 2 (3%) of acute mycoplasma infection. Otitis media was diagnosed in 7 (12%) of patients, and pneumonia in 8 (14%) children. Group A streptococcus pharyngitis was diagnosed in 13 (22%). Four (7%) patients had bacterial adenitis, complicated by retropharyngeal pharyngitis in one child. One child was diagnosed with perforated appendicitis and underwent surgery, with pathology confirming the diagnosis. One child had Escherichia Coli pyelonephritis. Concomitant infection was proven by microbiologic testing and/or imaging in 48 (81%) of patients. Characteristics of patients with viral versus bacterial infections are described in During hospitalization, antibiotics were empirically initiated in 95 (62%) children, and completed in 36 (23%). Antibiotics were initiated on average 2\u00b15 days prior to IVIG treatment, with antibiotics initiated prior to IVIG treatment in the majority of cases . Only a minority  were started on antibiotics after non-response to initial IVIG treatment.Age was similar between children with and without infection , with a similar proportion of male (34 (58%) versus 67 (71%) patients, p = 0.10). There was a similar proportion of children with incomplete clinical criteria among children with and without infection (20 (34%) versus 39 (41%), p = 0.38). There were 50 (58%) children with infection who received antibiotics compared to 45 (47%) without infection who received antibiotics (p<0.001). Of the former, 29 (58%) completed antibiotic treatment versus 7 (16%) of the latter (p<0.001). Most children with and without concurrent infection received IVIG (57 (97%) and 93 (98%) patients; p = 0.63). Delay in diagnosis and IVIG administration occurred in 4 (7%) children with concurrent infection versus 6 (7%) without concurrent infection, p = 0.89 . FinallyOverall, IVIG resistance occurred in 36 (24%) patients. Children with concurrent infection had higher rates of IVIG resistance (19 (33%) versus 17 (18%) patients, p = 0.04), and higher temperature at 48 hours . They weIVIG resistance was higher in patients with proven infection on microbiologic testing and/or imaging than those without (16 (35%) versus 20 (19%) patients, p = 0.04). There was no difference in response to treatment between patients who had a proven infection on microbiologic testing and/or imaging study versus those with clinical diagnosis of infection (16 (35%) versus 3 (27%) patients, p = 0.64). Resistance to initial IVIG treatment in patients with bacterial infection was nearly double that in patients with viral infection, although not reaching statistical significance (12 (46%) versus 4 (24%) patients, p = 0.12). There was no difference in response to treatment between patients with complete and incomplete clinical criteria (25 (28%) versus 10 (17%) patients, p = 0.12).Patients who received antibiotics during their hospital course, independent of infection status, were at higher risk of IVIG resistance than those who did not (27 (29%) versus 9 (16%) patients, p = 0.05). However, neither receiving antibiotics prior to IVIG therapy (15 (27%) versus 11 (41%) patients, p = 0.22) nor completing antibiotic course (13 (36%) versus 14 (25%) patients, p = 0.25) were associated with response to treatment.There was no significant difference in coronary artery complications  between In this retrospective series, the presence of a concomitant infection was associated with a higher rate of resistance to IVIG treatment. Patients with concomitant infection were more likely to have persistent fever and slower normalization of inflammatory markers after IVIG treatment. The administration of antibiotics did not decrease this risk of resistance to IVIG therapy. However, concomitant infection was not associated with an increased risk of coronary artery complications.More precisely, the higher likelihood of repeated IVIG treatment when concurrent infection was present is defined as recrudescence of fever 36 hours after the end of IVIG infusion based on expert opinion . Our resAnother hypothesis would be that the presence of infection triggers an additional inflammatory response at the molecular levels that impact response to treatment and outcomes. IL-1\u03b1 and IL-1\u03b2 have been shown to be essential in the development of KD . The IL-Persistence of fever after IVIG treatment is a strong risk factor for development of coronary aneurysms ,17. In tIn general, patients who are resistant to initial treatment receive a second dose of IVIG (2 g/kg) . NotwithThere are limitations to this study essentially related to the retrospective methods, and the diagnosis of concomitant infection. On one hand, in the absence of systematic testing for infections there is a potential underestimation of the actual concurrent infection rate, as some infections could not be identified. On the other hand, inclusion of only children with infectious workup at time of initial KD diagnosis could have falsely increased the rate of concurrent infection. However, the rate of concomitant infection in this series was similar to those previously published . MoreoveIn this study, patients with concomitant infection had a higher rate of resistance to IVIG treatment. Patients with concomitant infection had longer duration of fever and slower normalization of inflammatory markers after initial treatment. However, the presence of infection was not associated with an increased risk of CA complication. Accordingly, the persistence of fever in KD and the definition of resistance to IVIG should be regarded speculatively when concurrent infection is present. Decision to intensify treatment in patients with concurrent infection should not only be based on persistent fever. Coronary artery dimensions may be a more useful indication for treatment in this patient population. Prospective studies are needed to better refine which children truly require additional therapies."}
+{"text": "MECP2 is the major causative gene. In addition, CDKL5 and FOXG1 mutations have been reported in Rett patients, especially with the atypical presentation. Each gene and different mutations within each gene contribute to variability in clinical presentation, and several groups worldwide performed genotype-phenotype correlation studies using cohorts of patients with classic and atypical forms of Rett spectrum disorder. The Rett Networked Database is a unified registry of clinical and molecular data of Rett patients, and it is currently one of the largest Rett registries worldwide with several hundred records provided by Rett expert clinicians from 13 countries. Collected data revealed that the majority of MECP2-mutated patients present with the classic form, the majority of CDKL5-mutated patients with the early-onset seizure variant, and the majority of FOXG1-mutated patients with the congenital form. A computation of severity scores further revealed significant differences between groups of patients and correlation with mutation types. The highly detailed phenotypic information contained in the Rett Networked Database allows the grouping of patients presenting specific clinical and genetic characteristics for studies by the Rett community and beyond. These data will also serve for the development of clinical trials involving homogeneous groups of patients.Rett spectrum disorder is a progressive neurological disease and the most common genetic cause of intellectual disability in females.  MECP2 gene located in the X chromosome [MECP2 typically results in severe neonatal encephalopathy and early lethality [Rett syndrome  is a severe neurodevelopmental disorder that affects predominantly females with an incidence of approximately 1 in 10,000 female births mainly caused by mutations in the ethality .MECP2 gene, additional genes have been associated with the RTT phenotype. In particular, mutations in CDKL5, located on the X chromosome, have been reported in the infantile seizure onset type of RTT, while mutations in FOXG1, located on chromosome 14, have been reported in patients with the congenital presentation. It is still an object of debate if CDKL5 and FOXG1 mutations are responsible for atypical RTT or for a different neurodevelopmental phenotype [Beyond the classic form of RTT, a number of atypical forms with different degrees of severity have been described: the Zappella variant (formerly known as the preserved speech variant) , 6, the henotype \u201312.https://www.rettdatabasenetwork.org [Different RTT databases have been generated in the past and recent years. Among them are the International Rett Syndrome Association (IRSA) North American database and the InterRett , 14. Thework.org . Althougwork.org . The pubMECP2, CDKL5, or FOXG1 mutation to better understand the typical and atypical forms of RTT and provide information of RTT cohorts for the development of clinical trials.Here, we describe the first 1007 records contained in the registry and discuss the content of RND on the basis of the published guidelines for RTT clinical diagnosis , 17. We RND contains clinical files for 1958 patients affected by classic or atypical RTT . Clinical data originates from Croatia (29 patients), Denmark (64 patients), France (252 patients), Hungary (82 patients), India (3 patients), Israel (93 patients), Italy (605 patients), Romania (15 patients), Serbia (50 patients), Spain (398 patients), United Kingdom (255 patients), USA (96 patients), and Russia (16 patients).Patient clinical and genetic data were provided and inserted by the expert clinician through direct patients' evaluation, as described in Grillo et al. . The sysMECP2, FOXG1, or CDKL5 has been identified. Enrolled patients either met the diagnostic criteria for RTT or had a mutation in MECP2. All participants had complete mutation testing including MECP2 sequencing and deletion/duplication testing. Clinical diagnosis utilized the 2002 consensus criteria [CDKL5- and FOXG1-mutated patients were included whenever the diagnosis of RTT was achieved according to the 2002 consensus criteria or 2010 revised RTT criteria.Data analysis is presented for the first 1007 patients aged over 5 years and for whom a pathogenic mutation in criteria  or the rcriteria . CDKL5- MECP2 mutation types were grouped as Arg106Trp, Arg133Cys, Thr158Met, Arg306Cys, Arg168\u2217, Arg255\u2217, Arg270\u2217, Arg294\u2217, C-terminal deletion, early truncating mutations (mutations interrupting the MECP2 protein before amino acid 310), and large deletions. Those not falling in any of the above listed categories were grouped as \u201cother.\u201d CDKL5 mutation types were clustered on the basis of early truncating mutations, late truncating mutations, large deletions, and missense mutations. FOXG1 mutation types were grouped as early truncating mutations, late truncating mutations, gene deletions, and missense mutations.Descriptive statistics were used to summarize the characteristics of the RND dataset. P < 0.05 was considered as significant.Differences in clinical characteristics between groups of patients were tested by Fisher's exact test or by chi-squared analysis when the normal approximation was appropriate. R tool version 3.5.1 was used for statistical analyses, and MECP2 mutation.Among the 1007 RTT patients analyzed in this study, 806 were classified as classic, while the remaining 201 as atypical. Among this latter group, 46 had the congenital form of RTT, 36 patients the early-onset seizure variant, and 54 the Zappella variant (formerly known as the preserved speech variant). For the remaining 65 patients, the type of atypical form was not specified. All cases were sporadic except for 2 pairs of sisters and 5 pairs of monozygotic twins affected by RTT and carrying a MECP2 was mutated in 949 patients (94.2%), while 32 patients carried a mutation in CDKL5 (3.2%) and 26 patients in FOXG1 (2.6%).MECP2-mutated patients, 804 have a diagnosis of classic RTT (84.7%), 24 the congenital variant (2.5%), five the early-onset seizure variant (0.5%), and 54 the Zappella variant (5.7%) and the remaining 62 have an atypical form of RTT not better specified in categories (6.5%). All mutation types are present in this population with p.Arg255\u2217, p.Thr158Met, and C-terminal deletions being the most frequent mutations despite significant difference between classic and atypical forms  had never learned to walk independently. Epilepsy before 5 years of age was present in 63.0% of patients; in 3.9% of seizures, onset was before 1 year of age, and seizures were not controlled or barely controlled by therapy in 21.4% .MECP2-mutated patients [MECP2 point mutations on median clinical severity. The cumulative distribution plots of patients positive for the MECP2 mutations showed that the missense mutation Arg133Cys and late truncating mutations are associated to the less severe phenotype  and large deletions are associated with the \u201cmost severe\u201d form of RTT syndrome , while the other individual could speak and walk and had a moderate intellectual disability (Zappella variant). The five monozygotic twin pairs reported in RND were much more concordant than the sister pairs. Among the twin pairs, only two out of five had an identical clinical score, indicating that at least at this level of investigation, they were phenotypically identical. The remaining three twin pairs differed in specific fields such as epilepsy and weight (twin pair 1), level of speech and level of phrases (twin pair 2), or height, age of regression, and voluntary hand use (twin pair 3).The cohort of CDKL5 mutation-positive cases. Thirty-one patients had a diagnosis of the early-onset seizure variant of RTT, while one was diagnosed as atypical RTT. The most frequent mutations, representing the 50% of CDKL5-mutated patients, were truncating mutations (28.1% of late truncating and 21.9% of early truncating mutations) followed by missense mutations (31.2%) and large deletion (18.8%). In our cohort, the majority of patients had a normal head circumference at birth (93.8%), a deficient sphincter control (96.0%), feeding difficulties (97.4%), IQ < 40 (100%), and presence of hand stereotypies (85.7%) and had never spoken (82.6%) (RND contains 32 records for  (82.6%) .MECP2 mutations, it was possible to compute the total score for the CDKL5-mutated patients. However, no correlation was observed between type of mutation and clinical severity (data not shown).As for patients with FOXG1 mutation-positive cases. Twenty-two patients had the congenital form of RTT, 2 patients had the classic form, and two patients were classified as atypical. The cumulative distribution of the patients positive for FOXG1 mutations showed a clear trend toward a less severe phenotype for FOXG1 late truncating mutations , since it was present in 63% of MECP2-mutated patients, in 96.9% (31 out of 32) of CDKL5 cases, and in 87.5% of FOXG1-mutated patients. The epilepsy that started before 1 year of age was present in 96.9% of CDKL5 patients with epilepsy, versus 3.9% of MECP2-mutated patients and 37.5% of FOXG1-mutated patients. Epilepsy was not controlled by therapy in 84% of CDKL5-mutated cases versus 21.4% of MECP2-mutated patients and 58.8% of FOXG1-mutated patients  rather than in CDKL5  or FOXG1  patients  and walk (91.3%) compared to MECP2  and CDKL5 .Breathing dysfunction and eye pointing were statistically more frequent in patients . ConversMECP2, CDKL5, or FOXG1 mutation , as reported in MECP2-mutated patients included in the RND dataset. It is however known that behind midline and exuberant hand stereotypies, many patients with MECP2 may show more varied stereotypies or subtle stereotypes, like pill rolling or tapping [MECP2-positive patients have feeding difficulties, only 43.3% have gastrointestinal disturbances. This would suggest that part of the feeding difficulties arise from abnormal muscle tone and oropharyngeal dysfunction [MECP2  and large deletions are among the \u201cmost severe\u201d form of RTT syndrome , while the other individual could speak and walk and had a moderate intellectual disability (Zappella variant) [Interestingly, the cohort of variant) .CDKL5 and classified as having atypical RTT is much less documented than the classic RTT phenotype caused by MECP2 mutations. A report in 2013 described 86 patients with a mutation in CDKL5 with data originating from family questionnaires recorded in InterRett [CDKL5. Expectedly, for the early seizure variant of RTT caused by CDKL5 mutations, the majority of patients experienced at least one episode of epilepsy . The proportion of patients with a mutation in CDKL5 that never learned to walk in the three cohorts is also very similar , together with the proportion of patients displaying hand stereotypies  [CDKL5 mutation acquired early speech skills in the InterRett cohort and 39/172 (22.7%) had the simplest level of communication in the International CDKL5 Disorder Database while only 17.4% females harboring a CDKL5 mutation had shown a somewhat level of speech in RND [The phenotype of the patients carrying a mutation in nterRett , and mornterRett . RND pro in RND) , 27. Theh in RND , 27.FOXG1 and classified as having atypical RTT is even less documented than the phenotype caused by CDKL5 mutations. The cumulative distribution in FOXG1 late truncating mutations. The cumulative overall distribution in MECP2 to CDKL5 and FOXG1 mutation. CDKL5 patients lie in the most severe range in comparison to MECP2 patients with FOXG1 patients even more shifted than CDKL5 patients towards a worse clinical phenotype and a very minimum overlap with MECP2 patients.Regarding CDKL5-mutated patients, no significant genotype-phenotype correlation was observed. The phenotype of the patients carrying a mutation in MECP2-mutated patients; epilepsy and reduction in eye pointing capability are statistically more frequent in CDKL5-mutated patients, while the large majority of FOXG1 patients have never learned to walk, sit, and speak. Moreover, we observed that the majority of MECP2-mutated patients have the classic form of RTT, the majority of CDKL5-mutated patients have the early-onset variant, and the majority of FOXG1-mutated patients have the congenital form, with some exceptions (In conclusion, the Rett Networked Database is a registry for patients with RTT where clinical data are validated by experienced clinicians upon direct examination of the affected individuals. One of the unique features of this database is its ability to collect a huge amount of clinical details, the collected clinical items being almost 300 with different levels of completeness, and genetic data \u201315. RND ceptions . RND pro"}
+{"text": "The objective was to compare medium-term efficacy and safety of a partially absorbable mesh kit and native tissue repair in pelvic organ prolapse (POP).Women with primary POP stage \u2265 II were randomized to transvaginal trocar-guided partially absorbable mesh (81 women) or native tissue repair (82 women). Primary outcome was overall anatomical success (POP < stage II) at 24\u00a0months. Secondary outcomes were composite success, global improvement, and adverse events.Sixty-nine (85%) of the women allocated to partially absorbable mesh underwent mesh surgery; 8 (10%) crossed over to native tissue repair and 4 women (5%) withdrew from the study. Eighty (98%) of the women allocated to native tissue repair underwent the assigned treatment and 2 (2%) withdrew. Twenty-four months later, 140 surgically treated women (89%) demonstrated an overall anatomical success of 39%; 45% (32 out of 71 women) for mesh, and 32% (22 out of 69) for native tissue repair . Composite success was 88 and 73% respectively . There was global improvement in 86% (48 out of 56 women) in the mesh group and in 77% (47 out of 60 women) in the native tissue group . Four women were diagnosed with mesh exposure at 2\u00a0years (6%).At 24\u00a0months, no significant anatomical or composite benefit of partially absorbable mesh over native tissue repair could be demonstrated in women who had been surgically treated for primary POP. Pelvic organ prolapse (POP) occurs in up to 50% of parous women . The lifclinical.gov, number NCT 02231099. Consecutive women with symptomatic POP (\u2265 stage II) were asked to participate and underwent a systematic work-up, which included medical history, completion of urogynecological questionnaires , that comprised the Dutch validated Urogenital Distress Inventory (UDI), Defecatory Distress Inventory (DDI), Incontinence Impact Questionnaire (IIQ), Pelvic Organ Prolapse/Urinary Incontinence Sexual Function questionnaire (PISQ12), and routine gynecological investigation including pelvic organ prolapse quantification (POP-Q)  and the risk for de novo dyspareunia [3 out of 60\u2009=\u20095%]). The difference was nonsignificant .p value of 0.04; Table Peri- and postoperative characteristics were not significantly different Table . Median In 4 out of 71 women treated with mesh (6%), a mesh exposure was detected, in 3 of them at the 6-month follow-up and in 1 other woman at 24\u00a0months. All exposures were seen in the anterior compartment. Two of the 4 women were asymptomatic; the other 2 had symptoms of vaginal discharge. Two women were treated successfully with local estrogens. One woman needed supplementary surgery, which was performed in the operating theater, and the exposure was successfully excised. One asymptomatic woman did not want any treatment. Three of these 4 women completed the PGI-I and mentioned much or very much improvement compared with the situation before the initial POP surgery.Forty-two out of 75 women (56%) in the mesh and 35 out of 73 women (48%) in the native tissue group had reported pain in the lower abdomen or in the genital area at baseline. Thirteen out of 67 women (16%) in the mesh group and 19 out of 66 women (29%) in the native tissue group reported pain in the lower abdomen or genital region at 24\u00a0months  in the mesh group and 55 women (69%) in the native repair group had reported that they were sexually active and completed the PISQ-12 questionnaire. Seven women in the mesh group (12%) versus 3 women (6%) in the native tissue repair group reported dyspareunia at baseline. Twenty-four months after surgery, in 8 of these women, dyspareunia had resolved. At 24\u00a0months, 1 woman in the mesh group was no longer sexually active for unknown reasons and 1 woman was lost to follow-up. At 24\u00a0months, dyspareunia and de novo dyspareunia rates did not significantly differ between groups , and a reduced surface area, which may have led to a reduction in fibrotic reaction around the individual mesh fibers, which could have resulted in a more physiological integration of the mesh [Mesh exposure was seen in 4 out of 71 women (6%). In a randomized controlled trial with non-absorbable mesh after 1\u00a0year follow-up, an exposure rate of 17% was reported and published 7-year exposure rates were 42% , 26. Thethe mesh , 27. Thithe mesh .Although the occurrence and stage of descent in the apical compartment did not differ between the groups, treatment in this compartment did differ: 48 women 62%) in the mesh group versus 74 women 91%) in the native tissue repair group . In all other scenarios, however, this statistical significance would disappear.The strength of the study is that this is the only randomized controlled trial on a partially absorbable mesh (kit) in POP surgery. The last update of the Cochrane review included 37 studies on the effectiveness and safety of mesh, with a total of 4,023 women . There wImportant additional research would also involve a better selection of women who could potentially benefit from  mesh, e.g., selecting those with an increased risk for recurrence for POP. A prediction model for POP recurrence may facilitate this selection .In conclusion, at 24\u00a0months\u2019 follow-up, no anatomical or subjective benefit of partially absorbable mesh over native tissue repair could be demonstrated in women who were surgically treated for primary POP."}
+{"text": "Discrimination impacts functional health outcomes of African Americans and other racial/ethnic minorities in the United States; yet this is understudied in African immigrants whose population has risen by 137% since 2000. We examined the relationship between discrimination and physical function with a convenience sample of first-generation African immigrants age 50+ recruited through community-based organizations (N=124). Discrimination was measured with the Everyday Discrimination scale with higher scores indicating more experiences of discrimination (range=0-23). High versus low levels of discrimination were categorized at the mean. Physical function was measured using the PROMIS Physical Function measure with high scores indicating greater functional ability (range=11-50). Raw function scores were converted to standardized T-scores with a population mean of 50 and standard deviation (SD) of 10. Linear regression was used for analyses. Mean age of the sample was 61.4(SD=7.9) years. About two-thirds (63%) were female, more than half (52.4%) immigrated in search of better opportunities and half of the sample had high levels of discrimination. The mean function score was 44.2(SD=8.3) indicating that this sample had functional ability 6 points less than the population average. After adjusting for demographic and migration factors, the mean physical function score was 2.5 points lower  for participants with more experiences compared to those with fewer experiences of discrimination. In conclusion, discrimination was associated with poor physical function in African immigrant older adults after adjusting for covariates. Longitudinal studies of discrimination and physical functioning should be pursued in more diverse, larger samples of African immigrants."}
+{"text": "Among the patients clinically diagnosed with endophthalmitis, 29 of the 40 culture proven samples (72.5%) and 42 out of 63 (66.6%) of culture-negative samples were positive for presence of TTV/TLMV. Interestingly, 51 of the 102 (50%) samples in the control group were also positive for TTV/TLMV. Comparing the clinical outcome among patients diagnosed with endophthalmitis, we observed no significant association in the final visual acuity of patients who were positive for presence of TTV/TLMV, however, these patients had significantly higher repeat antibiotic injections (p = 0.03). Further evidence is however needed to correlate TTV / TLMV with a particular pathology or group of pathologies in the eye.Human anelloviruses (Torque Teno Virus (TTV) and TTV Like Mini Virus (TLMV)) are now being reported at a high prevalence across the world, with a controversial disease-inducing potential. The aim of this study was to investigate the role of these anellovirus in vitreous of patients with presumed infectious endophthalmitis. After informed consent, vitreous fluid from patients with endophthalmitis ( Torque Teno Virus in the vitreous humor of patients with panuveitis and culture negative endophthalmitis [Anellovirus might have a role in the pathogenesis of endophthalmitis, thereby suggesting a detailed investigation on the possible role of TTV in the pathogenesis of endophthalmitis in different populations. Human anelloviruses, namely Torque teno virus (TTV), and TTV-like mini virus (TLMV), species are characterized by their staggering worldwide prevalence, with conflicting opinions on their pathogenic role in the literature. [Endophthalmitis is a serious intraocular inflammation caused usually by bacterial or fungal infection. Most cases are medical emergencies, and delay in administration of treatment may result in permanent loss of vision . The abihalmitis ,6, has serature. \u20139 Severaerature. \u20139, for eerature.  At preseerature. A previous report by Emre et al.  reportedA total of 103 vitreous samples from patients who presented to the institute between December 2017 and June 2018 and diagnosed clinically as infectious endophthalmitis, after vitrectomy were included in the study group. Similarly the control group included 102 samples from patients undergoing vitrectomy for non-infectious retinal disorders. Informed consent was obtained from all patients and approved by the Institutional Review Board, L V Prasad Eye Institute, Hyderabad, India. The microbiology work up of the samples from the study group was performed as described previously.  Approx. DNA was extracted from the vitreous samples using the QIAamp DNA minikit . Presence of both TTV and TLMV was then assessed by q-PCR using SYBR green method to detect the presence of TTV and TMLV in all samples, on the Quant studio 3 (Applied Biosystems) system. The primers for q-PCR were chosen to amplify a distinct conserved region of TLMV upstream of the ORF 2, and within the ORF2 in TTV. ,16 \u03b2-ActThe study included 103 vitreous samples in the infectious group and 102 samples in control group of which the mean age was 50.54 \u00b1 16.23 years (range 9\u201377 years) in the control group and 42.44 \u00b1 21.95 years (range 1\u201388 years) in the study group, respectively. These included 68 (66.6%) males and 34 (33.4%) females in the control group and 75 (72.8%) males and 28 (27.2%) females in the study group. The clinical diagnosis of patients diagnosed with infectious endophthalmitis included post-trauma in 50 (48.5%) and post-operative in 29 (28.1%) while 15 patients (14.5%) were diagnosed as endogenous endophthalmitis .Of these 103 presumed infectious samples, 63/103 (61.1%) samples were culture negative while 40/103 (38.9%) samples were culture positive and included bacterial growth in 35/40 (87.5%) while 5/40 (12.5%) grew fungus. Human anellovirus was detected in 71/103 (68.9%) infectious samples which included TTV in 23/103 and TLMV in 20/103 samples while 28/103 samples showed presence of both TTV and TLMV. Comparatively, 51/102 (50%) samples in the control group also showed presence of TTV and/ or TLMV in the vitreous fluid .5 copies /reaction among all the groups tested and there was no significant correlation between copy number and culture proven infection.The melting curve (melting temperature 84.04 \u00b1 0.24 (mean \u00b1 SD)  analysisp = 0.532) compared to patients with culture negative endophthalmitis. The visual outcome after two months of follow up was further assessed in patients that showed presence of anellovirus and it was found that 49/71 (69%) patients diagnosed with infectious endophthalmitis had unfavorable (>20/200) visual outcomes compared to patients who did not show presence of these viruses, although the difference was not statistically significant (p = 0.56). Further we investigated the number of surgical interventions required or attempted in all patients and compared it with the presence or absence of allenovirus. We observed that patients who were TTV and /or TLMV positive patients had significantly higher repeat antibiotic injections (p = 0.03) as shown in Comparing the two groups, we found a significant association of anellovirus with endophthalmitis . No significant difference was observed in the distribution of TTV and/or TLMV in men and women participating in this study. Also the mean age, and clinical diagnosis were similar in TTV/TLMV positive and TTV/TLMV negative patients. Comparing detection of TTV and/or TLMV in culture negative and culture positive samples in the presumed infectious endophthalmitis group, we observed presence of TTV and/or TLMV in 29/40 (72.5%) culture positive samples and in 42/63 (63.4%) culture negative vitreous samples. This association of TTV and/or TLMV as a co-infection in patients with culture positive endophthalmitis was however not significant .(PDF)Click here for additional data file."}
+{"text": "Bioscience Reports (2018) 38, BSR20180942; https://doi.org/10.1042/BSR20180942The following source of funding was not acknowledged in the published version of the article:This work was supported by grants from the key program of Tianjin Health Bureau (Grant NO.14KG104).The online version was corrected on 20 December 2018."}
+{"text": "IntroductionOcular involvement in leukemia may occur because of direct leukemic infiltration or because of secondary ophthalmic involvement as a result of abnormalities related to blood like anemia, thrombocytopenia, and leukocytosis. In some patients with leukemia, ophthalmic signs can precede the systemic features and can help in early diagnosis of systemic leukemia. Due to the scarcity of data on this topic from Pakistan, we conducted this study to determine the pattern of ocular involvement in patients with leukemia presenting in our settings.MethodsThis cross-sectional study was conducted in a tertiary care hospital of Pakistan over a period of one year. The study comprised of both newly diagnosed and follow-up patients of acute leukemia of age more than 15 years. Patients underwent detailed ophthalmic anterior and dilated posterior segment examination. Patient\u2019s demographic profile, type of leukemia, chemotherapy status, and hematologic findings were also documented.ResultsThere were 97 leukemic patients in the study with 55 (56.7%) males and 42 (43.3%) females. Various ophthalmic manifestations were observed in 47 (48.45%) patients. Forty-two (43.3%) were diagnosed cases with acute lymphocytic leukemia (ALL) and 55 (56.7%) suffered from acute myelogenous leukemia (AML). Ophthalmic manifestations were present in 29 patients of AML (52.7%) and 18 patients of ALL (42.85%). Ocular involvement was significantly more common in newly diagnosed (n=32) as compared with follow-up patients (n=15) . Posterior segment (n=48) was the most common site of ocular involvement  with retinal hemorrhages seen in 40 patients (41.2%) and papilloedema in seven cases (7.2%). Thirty-three (70.2%) out of 47 patients with ophthalmic manifestations were asymptomatic while 14 (29.8%) had ocular symptoms at the time of initial presentation.ConclusionOphthalmic manifestations were present in about half of the patients with leukemia. Ocular involvement was more prevalent in newly diagnosed cases and in patients with AML. Leukemia is a malignant neoplasm of the bone marrow which results in abnormal production of white blood cells and affects multiple organs of the body. It is one of the most common neoplasms . LeukemiOcular involvement in leukemia may occur due to direct leukemic infiltration or because of secondary ophthalmic involvement as a result of abnormalities related to blood like anemia, thrombocytopenia, and leukocytosis or because of chemotherapy or immunosuppression . Direct Leukemia-related ophthalmic manifestations can adversely affect vision and have an important role in indicating the survival prognosis of systemic leukemia . TherefoThis cross-sectional study was conducted in the Department of Ophthalmology, Jinnah Hospital, Lahore, Pakistan, a tertiary care multi-disciplinary hospital affiliated with Allama Iqbal Medical College, University of Health Sciences, Lahore, Pakistan. The study was approved by the Ethical Review Board of the Allama Iqbal Medical College and was conducted following the ethical principles laid down in the Declaration of Helsinki. The study was conducted from February 2017 to January 2018 and included patients with acute leukemia of age greater than 15 years, admitted in the Oncology department of Jinnah Hospital, Lahore. Both newly diagnosed and follow-up patients were included in this study. Informed written consent was obtained from all the patients. Patients with opacities in the ocular media and with a history of diabetes mellitus, acquired immunodeficiency syndrome (AIDS), sickle cell disease and retinal vascular disease were excluded from the study. Leukemia was diagnosed by consultant hematologist on the basis of bone marrow biopsy. Immunophenotyping by flow cytometry was performed on all bone marrow samples to differentiate AML from ALL.The ophthalmic examination consisted of a Snellen chart for best corrected visual acuity and anterior segment evaluation by slit lamp biomicroscope. Direct and indirect ophthalmoscopes and slit lamp biomicroscopes with fundus lens were used for detailed dilated fundus examination. Bedridden patients were evaluated on the bedside using direct and portable indirect ophthalmoscopes.The data was analyzed using Statistical Package for Social Sciences (SPSS) version 20.0 . Descriptive variables were calculated as frequencies and percentages whereas quantitative variables were analyzed as mean (SD). Chi-square test was used to analyze the effect of qualitative variables whereas student's t-test was used to see the effect of quantitative variables on leukemic findings with p-value <0.05 considered as statistically significant.There were 97 patients in the study with 55 (56.7%) males and 42 (43.3%) females with a female to male ratio of 1:1.31. Forty-two patients (43.3%) were diagnosed with ALL and 55 (56.7%) patients suffered from AML. Forty-seven out of 97 patients (48.5%) had ophthalmic manifestations at the time of presentation. Out of these, 27 (49.1%) were males and 20 (47.6%) were females (p=0.886) (Table Thirty-two (68.1%) patients were newly diagnosed and 15 42.3%) were follow-up patients (p=0.045). Ophthalmic manifestations were more common in patients with AML (52.7%) as compared to ALL (42.85%) and in newly diagnosed (57.1%) as compared to follow-up patients\u00a0(36.6%)  was the most frequent site of ocular involvement. Most common findings in the posterior segment included retinal hemorrhages (41.2%) followed by papilloedema (7.2%). A total of nine patients (16.7%) showed direct leukemic and 45 83.3%) showed secondary leukemic changes. Thirty (70.2%) patients with ophthalmic manifestations were asymptomatic while 14 (29.8%) had ocular symptoms at the time of presentation (Table .3% showeThe most commonly observed symptoms were decreased vision (n=12) and red eyes n=4). Eighty-five patients (87.6%) had good vision ranging from 6/6-6/18 on the Snellen\u2019s chart. Eight patients (8.3%) had impaired vision ranging from 6/24-6/60 whereas four patients (4.1%) had severe loss of vision <6/60  , Khadka Majority of patients included in our study were males 56.7%). This pattern of male majority in patients with acute leukemia is comparable to that reported in the studies of Bitirgen et al. (60%) , Koshy e6.7%. ThiPosterior segment ocular findings 88.9%) were significantly more common than anterior segment manifestations. Most common posterior segment manifestations were hemorrhages, that included pre-retinal hemorrhages, intra-retinal hemorrhages, and retinal hemorrhages with Roth spots. Ophthalmic manifestations were more commonly seen as a consequence of secondary changes in systemic leukemia (83.3%) as compared to the direct ocular involvement in acute leukemia (16.7%). These findings were statistically significant and supported by the studies of Koshy et al. , Khadka 8.9% wereEight patients had impaired vision (8.2%) with four patients having papilloedema, two having pre-retinal hemorrhages over the pre-macular area, while two having intra-retinal hemorrhages over macula. A total of four patients had severe loss of vision (4.1%). Of these four patients, one had optic nerve infiltration with intra-retinal hemorrhages, one had papilloedema and two had pre-retinal hemorrhages over the premacular area. Out of the 47 patients with ophthalmic manifestations, 70.2% presented without symptoms while only 29.8% had at least one or more ocular symptoms. Absence of any ocular signs symptoms in patients with acute leukemia has major implications. Studies have shown that ocular involvement in patients with lymphocytic and myelogenous leukemia may be associated with poorer prognosis of systemic leukemia . It can Ocular involvement is seen in almost half of the patients of acute leukemia. Acute leukemia is more common in males and ophthalmic manifestations related to this disease are more prevalent in newly diagnosed patients with AML as compared to ALL. As a majority of the patients with ocular signs have no ocular symptoms, it is recommended to conduct a mandatory ophthalmic examination in all leukemic patients, at the time of diagnosis, to detect ocular complications at an early stage."}
+{"text": "Objective: To present the genetic causes of patients with primary immune deficiencies (PIDs) in Kuwait between 2004 and 2017.Methods: The data was obtained from the Kuwait National Primary Immunodeficiency Disorders Registry. Genomic DNA from patients with clinical and immunological features of PID was sequenced using Sanger sequencing (SS), next generation sequencing (NGS) of targeted genes, whole exome sequencing (WES), and/or whole genome sequencing (WGS). Functional assays were utilized to assess the biologic effect of identified variants. Fluorescence in situ hybridization (FISH) for 22q11.2 deletion and genomic hybridizations arrays were performed when thymic defects were suspected.Results: A total of 264 patients were registered during the study period with predominance of patients with immunodeficiencies affecting cellular and humoral immunity (35.2%), followed by combined immunodeficiencies with associated syndromic features (24%). Parental consanguinity and family history suggestive of PID were reported in 213 (81%) and 145 patients (55%), respectively. Genetic testing of 206 patients resulted in a diagnostic yield of 70%. Mutations were identified in 46 different genes and more than 90% of the reported genetic defects were transmitted by in an autosomal recessive pattern. The majority of the mutations were missense mutations (57%) followed by deletions and frame shift mutations. Five novel disease-causing genes were discovered.Conclusions: Genetic testing should be an integral part in the management of primary immunodeficiency patients. This will help the delivery of precision medicine and facilitate proper genetic counseling. Studying inbred populations using sophisticated diagnostic methods can allow better understanding of the genetics of primary immunodeficiency disorders. Primary immunodeficiency diseases (PIDs) comprise a heterogeneous group of monogenic inborn errors of immunity with a wide spectrum of clinical manifestations. Due to international collaborative efforts and the availability of advanced functional and genetic testing, our knowledge of the underlying causes of PIDs has tremendously increased in the last decades . HoweverThe evaluation of patients suspected to have PIDs starts with reviewing the clinical presentation, followed by phenotypic and functional immunologic studies. Because of the vast clinical and immunologic heterogeneity of patients' mutations in known causative genes , and theIn this report, we present the results of genetic studies performed in a large cohort of PIDs patients from Kuwait between 2004 and 2017.The data was obtained from the Kuwait National Primary Immunodeficiency Disorders Registry (KNPIDR) which was approved by The Research and Ethics Committee of the Ministry of Health in Kuwait in accordance with the Declaration of Helsinki. An informed written consent was obtained from patients and/or families for whom the genetic testing was done for research purposes, but such consent was not taken for tests done for clinical purposes. PIDs were classified according to the International Union of Immunological Societies, Primary Immunodeficiency Diseases Committee report on Inborn Errors of Immunity 2017) (7 (1). A in situ hybridization (FISH) for 22q11.2 deletion and genomic hybridization array were performed when thymic defects were suspected  findings, targeted Sanger sequencing (SS) of gene(s) of interest was performed on genomic DNA according to standard protocols . Fluorescence uspected . For whouspected . Reads wA total of 264 patients were registered in KNPIDR from January 2004 to December 2017 and distributed as follows: immunodeficiencies affecting cellular and humoral immunity, 93 patients (35.2%); combined immunodeficiencies (CID) with associated syndromic features, 64 patients (24.3%); predominantly antibody deficiencies, 33 patients (12.5%); diseases of immune dysregulation, 46 patients (17.5%); congenital defects of phagocyte number or function, 16 patients (6.1%); autoinflammatory disorders, 1 patient (0.3%%); and, complement deficiencies, 11 patients (4.1%). The diagnosis was established in four patients based on lack of protein expression as assessed by flow cytometry (three patients with MHC II deficiency and one patient with LAD-1 deficiency). Parental consanguinity and family history suggestive of PID were reported in 213 (81%) and 145 patients (55%), respectively  with an overall diagnostic yield of 70% (184 patients) Figure . Five paRAG1 (n = 9), RAG2 (n = 6), DCLRE1C (n = 7), JAK3 (n = 5), AK2 (n = 5), CD3D (n = 3), ADA (n = 2). Only two of these 37 patients had compound heterozygous variants, while 35 had homozygous variants.Genetic testing was performed in 83 out of 93 patients with immunodeficiencies affecting cellular and humoral immunity. The disease-causing mutation was identified in 75 patients (90%). Among those, 37 (49%) carried defects in genes that cause severe combined immune deficiency (SCID) (1). Causes of SCID included mutations in DOCK8 (n = 10), DOCK2 (n = 3), TFRC deficiency (n = 8), ICOS deficiency (n = 2), RFXANK resulting in MHC class II deficiency (n = 12 mutations), ZAP-70 (n = 1), IKBKB (n = 1). No cases of hyper-IgM syndrome (HIGM) due to X-linked CD40 ligand (CD40L) deficiency were reported. A patient with clinical features of Omenn syndrome (OS) who did not harbor defects in genes known to be associated with OS, had a homozygous 691 kb deletion at 5q33.1 encompassing the GM2A gene associated with GM2-gangliosidosis, which was detected by chromosomal microarray. Interestingly, large deletions were reported in all DOCK8 deficient patients and two patients with Artemis deficiency. All the diseases reported in this category have autosomal recessive (AR) pattern of transmission.The remaining 38 subjects with a definitive genetic diagnosis in this group had defects in genes that results in other forms of combined immunodeficiencies (CID), less profound than SCID. The following gene defects were identified: ATM mutations while no genetic testing was attempted for the other four patients. Four patients had immunodeficiency with centromeric instability and facial anomalies (ICF) due to a mutation in either DNMT3B or ZBTB24, while two patients have no identifiable mutations in ICF-causing genes despite satisfying clinical, immunologic, and cytogenetic diagnostic criteria. No Nijmegen breakage or Bloom syndrome patients were identified. Eight out of 64 (12.5%) patients in this group carried the clinical diagnosis of hyper IgE syndrome (HIES). In four of them, the molecular diagnosis of STAT3 loss-of-function was obtained. No patients with TYK2 or PGM3 deficiency were identified. Three patients were diagnosed with Wiskott-Aldrich syndrome (WAS) on the basis of genetic testing and clinical phenotype, while 30 patients were diagnosed with DiGeorge syndrome and carried the typical 22q11.21 microdeletions. Nine patients were categorized as having other syndromic immunodeficiencies, in particular: hepatic veno-occlusive disease with immunodeficiency (n = 2 with SP110 mutations), STAT5B deficiency (n = 2), MYSM1 deficiency (n = 2) cartilage hair hypoplasia (n = 1 with RMRP mutation), TTC7A deficiency (n = 1), and HOIP deficiency (n = 1 with RNF31 mutation). Aside from the patients with DiGeorge syndrome, only four patients of the remaining 24 (16.6%) in this category had an autosomal dominant (AD) disease while three (12.5%) had X-linked (XL) disorders. The remaining 17 subjects (70.8%) had diseases due to biallelic mutations.Among the 64 individuals who were diagnosed with combined immunodeficiencies (CID) with associated syndromic features, a molecular defect was identified in 54 patients (84%). The diagnosis of a DNA repair defect syndrome was made in 14 out of 64 patients (21.8%). Ten of them were diagnosed with ataxia telangiectasia, of whom six were confirmed to have BTK (n = 4), AICDA (n = 9), NFKB2 (n = 2). One patient had \u03bc heavy-chain deficiency likely due to a large deletion as shown by lack of amplification of the whole gene. Also in this group of patients, AR inheritance was predominant (n = 10 patients), whereas gene defects with AD and XL inheritance were identified in two and four patients, respectively.Thirty-three patients were diagnosed with predominantly antibody deficiency. Seven of these had transient hypogammaglobulinemia of infancy, 5 had IgA deficiency, and four were diagnosed with common variable immunodeficiency. Among the 19 patients in whom genetic testing was performed, a disease-causing mutation was identified in 16 subjects (84.2%). The following genes were found to carry pathogenic mutations: LYST mutation was identified while one subject carried a donor splice site mutation. Four patients had ALPS due to FAS (n = 2) or FASL (n = 2) biallelic mutations. Early-onset IBD due to IL10 deficiency was found in four siblings. Familial hemophagocytic lymphohistiocytosis (FHL) with or without hypopigmentation was identified in a relatively high number of patients in this category (24/46). In 13 out of the 24 (52%) a genetic diagnosis was achieved: PRF1 n = 4 (FHL2), STX11 n = 2 (FHL4), and STXBP2 n = 4 (FHL5), RAB27A n = 2 (Griscelli syndrome type 2), BIRC4 n = 1 (XIAP). Three individuals were diagnosed with autoimmune polyendocrinopathy syndrome-1 (APS-1) and were confirmed to harbor AIRE gene mutations. Only 1 case with XL inheritance and 2 cases with AD disease belonged to this group.Diseases of immune dysregulation were identified on the basis of clinical and immunologic phenotype in 46 patients. Genetic studies were performed in 40 patients. A disease-causing mutation was found in 31 of the 40 studied (67%). Four patients were diagnosed with Chediak-Higashi syndrome. In three of these, an exonic CYBA, 1 in NCF1, and 1 in NCF2. Of note, no CGD patients with the XL form of the disease were identified. Three patients with pulmonary alveolar proteinosis were found with mutations in the GM-CSF receptor. One patient with severe congenital neutropenia carried compound heterozygous mutation in the JAGN1 gene. One patient with cyclic neutropenia, 1 with leukocyte adhesion deficiency type 1 (LAD1) and 3 subjects with glycogen storage disorder type 1 b that had early onset neutropenia, were diagnosed by immunologic/metabolic studies without further genetic evaluation. All patients were affected by AR disorders.Sixteen individuals in the registry were affected by congenital defects of phagocyte number, function or both, and genetic testing successfully identified a causative mutation in nine of them. Among the 6 patients with a diagnosis of CGD based on positive DHR testing, 5 received genetic testing. Of these, 3 had mutations in n = 5) followed by hereditary angioedema (n = 2) and four patients had impaired complement function, not well charactrerized. None of the subject belonging to this group received genetic testing.One case of Blau syndrome was identified in the category of autoinflammatory disorder based on clinical findings, but genetic testing was not performed. Finally, 11 patients were identified with complement deficiencies, with the most common being C4 deficiency . The patients were cured with hematopoietic stem cell transplantation.First, using Whole Genome Sequencing we were able to diagnose multiple members of the same family with ficiency . This neDOCK2 (OMIM 603122) mutations cause a novel T\u2212B+ CID  mutations in two siblings who presented with congenital bone marrow failure and myelodysplasia  that abolished enzymatic activity in three siblings from a consanguineous family  and family history of PIDs (55%), including early deaths, similar clinical phenotype, and/or previously identified PIDs. Another important finding is the high percentage of AR diseases accounting for more than 90% of all PIDs where a genetic diagnosis was achieved, while XL and AD pattern of transmission were detected in only eight patients and six patients (excluding Di George syndrome), respectively. Similarly, molecular studies confirmed that the AR mode of inheritance is the most common in Tunisian patients accounting for 73% of all PIDs entities investigated . This isIL2RG deficiency were detected. In line with previous data on CGD from consanguineous populations  and China (40%) , 37, 38.n = 88, 57%) followed by 26 frameshift mutations, 16 splice-site defects, 10 non-sense mutations, and 14 large deletions. It is worth mentioning that large deletions mainly clustered in DOCK8 deficiency (n = 10), while the other types of mutations were more uniformly distributed among the different categories. The finding that missense mutations were the most common type resulting in PIDs was also documented in the Tunisian population (38%) while deletions accounted for almost 22% of all mutations  and five previously undescribed genetic defects. The vast majority of the mutations were missense  in our registry. Families from areas with high rate of consanguineous marriages have been important for the identification of novel and complex phenotypes associated with PIDs , and to standardize and possibly simplify the language used in the genetic reports.WA-H: development of the research concept and goals, design of methodology, data collection, writing the initial manuscript draft, approval of the submitted manuscript, and agreement to be accountable for the content of the work. MM, WB, and RC: performance the genetic testing, critical review of the manuscript, approval of the submitted manuscript, and agreement to be accountable for the content of the work. CK, YB, RG, and LN: supervision of genetic testing, critical review of the manuscript, approval of the submitted manuscript, and agreement to be accountable for the content of the work. JC and OMD: performance the genetic testing, contributed to the writing of the manuscript, critical review of the manuscript, approval of the submitted manuscript and agreement to be accountable for the content of the work.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Substance use has a terrible impact on health, behavior and country\u2019s economy because the number of people particularly the youngsters being involved in this practice is increasing rapidly. However, the prevalence, determinants and consequence of substance use in the study area has been overlooked.2) test was considered to examine the nonparametric association of factors with ever substance use.A descriptive quantitative cross-sectional study was conducted among 254 health science students of Haramaya University. The respondents were selected randomly after double stratification based on their department and batch respectively. A pre-tested self\u2013administrable anonymous questionnaire was used. The collected data were entered into epidata version 3.1 and exported to SPSS version 23. Descriptive statistical analysis was done to examine findings. Besides, chi-square . From the overall ever substance users, 31.6% had undesirable health consequences. Among these consequences, anorexia [40 (35.1%)] accounted for the highest percentage followed by insomnia [29 (25.4%)], depression [25 (22%)], gastritis [25 (22%)], dental caries [23 (20.2%)] and increased sexual activity [12 (10.5%)].Prevalence of ever substance use for at least one substance was found to be 114(45.4%). Ever khat chewers take the highest percentage [107(93.9%)] followed by ever smokers 45(39.5%) and ever drinkers 44(38.6%). Among these ever substance users, 80(70.2%) were found to be current substance users. Being a preparatory student (26.3%) and freshman at university (57.9%) were critical times to initiate substance use. Sex, monthly income, sexual risk behavior and family history of substance use were found to be significantly associated with being ever substance user as witnessed by their respective XPrevalence of ever substance use in the study area was relatively high. Therefore attention should be given to the major reasons for substance use mainly orientation of freshman students about better stress coping mechanisms and expansion of adequate recreational activities. Substance use has become one of the rising major public health and socio-economic problems worldwide. Hard drugs like cocaine are rarely available in Ethiopia where as Khat, alcohol and cigarette are commonly available and used substances . Khat isThis study has been conducted from January 16\u201330, 2018 at Haramaya University. Haramaya University was established in 1954 next to Addis Ababa University in Ethiopia. It is located about 510\u2009km away from Addis Ababa in Oromia national regional state, East Hararghe administrative zone. The study programs of the university range from undergraduate (Diploma and first degree) to post graduate levels  in its 3 campuses and 13 colleges. Among these colleges, College of Health and Medical Science is one of the colleges which was established in September 1996 with the objective of training health professionals who contribute to filling the gap of health need of the country, especially the rural population. It had 8 training programs: Medicine, Pharmacy, Comprehensive Nursing, Public Health, psychiatric Nursing, Midwifery, Medical laboratory technician and Environmental health science.A descriptive institution based quantitative cross-sectional study design was conducted to determine the prevalence, associated factors and consequences of substance use among students of the college of health and medical science at Haramaya University. All regular health and medical science students of the college were included for the study. Students who were critically ill (unable to read and write) and physically impaired (had a hearing and speaking problem) at the time of data collection were excluded.n\u2009=\u2009(Z\u03b1/2)2 p (1-p)/d2)); where n\u2009=\u2009the required minimum and feasible sample size, Za/2(1.96): significance level at \u03b1 =0.05 with 95% confidence interval, p: proportion of substance use in Mekelle University (21%)  followed by public health [44 (17.5%)] and Nursing [27(10.8%)] students. Based on batch (class year), third-year students accounted for the highest percentage [81(32.3%)] followed by second-year [57 (22.7%)] and first year [52 (20.7%)] students  were ever substance users of whom 94(82.5%) were males. Out of these 114 ever substance users, the most majority were from the department of medicine [54 (47.4%)] and public health 20 (17.5%). Ever khat chewers take the highest percentage [107(93.9%)] of substance use. Furthermore, males were found to be more ever Khat chewer [92(86.0%)], ever smoker [43(95.6%)] and ever drinker [36(81.8%)] than females  were found to be current substance users and 72 (87.8%) of whom were males. Among the total of 80 current substance users, current chewers account for the highest percentage [7593.8%)] (Table\u00a0.8%] (TabMost of the ever substance users [5147.6%)] used substance once a day. It was found that nearly half of the ever substance users [47(44%)] practiced using substance for more than 4\u2009years duration. Majority of the substance users cost 15\u201325 Ethiopian birr per day to use substances ] started using substances after 15\u2009years of old. About 49% of the ever substance users started using substance before joining university whereas nearly 51% of them after joining university. Out of those 49% students who started substance use before joining university, the most majority [23(20.2%)] began substance use at preparatory school whereas from those students who started substance use after joining university (51%), being freshman (32.5%) was found to be a critical time to initiate substance use at university ] was the leading reason enumerated by students. The others were to be free from psychological stress [63(23.3%)], peer pressure [35(13%)], role modeling of families and teachers [29(10.7%)], religious purpose [22(8.1%)], socialization purpose [21(7.8%) and lack of adequate recreational area [20(7.4%)].Among all the 251 respondents, 23091.6%) were aware of all the undesirable health effects of substance use. Out of 114 ever substance users, 31.6% of them had undesirable health effect that may be correlated with their substance use behavior. Anorexia [40 (35.1%)], insomnia [29 (25.4%)], depression [25 (22%)], gastritis [25 (22%)], dental caries [23 (20.2%)] and increased sexual activity [12 (10.5%)] were the major undesirable health effects reported by the students thought to result from their substance use . Similarly, those students who have sexual risk behavior were twenty-nine times more likely to be substance user than students who had no sexual risk behavior . Regarding monthly income and family history of substance use, students who had monthly income more than 540 Ethiopian birr were seventy-two times more likely to be substance user than students who earned a monthly income less than 540 Ethiopian birr . Likewise, students who had a family history of substance use were one hundred forty times more likely to be substance user than students who had no family history of substance use   is to strengthen the prevention and treatment of substance use, including narcotic drug use and harmful use of alcohol. Therefore, this study is aimed to show the prevalence and associated factors of substance use in the study area after the launch of SDG by 2015 that involves the implementation of different preventive and therapeutic measures. Prevalence of ever substance use for at least one substance was found to be 45.5%. This finding is almost consistent with a study in many African universities which was 69.8% , 19, 21.As compared to other studies, this study showed a higher magnitude of ever substance use and majority of whom are still using substance. This indicates the number of youngsters being involved in this practice is increasing despite the different preventive and therapeutic interventions that have been taken into action since 2015. Male sex, sexual risk behavior, average monthly income and family history of substance use were significantly associated with increased odds of ever substance use. The study also found that the leading reason for substance use was to keep alert while studying followed by psychological stress, peer pressure, role modeling of families and teachers, socialization purpose and lack of adequate recreational activities. Since all of these reasons are modifiable, every health preventive, promotive and rehabilitative action can be considered of paramount significance. Therefore, families and teachers should be role models in disliking substance use. Moreover, freshman students should be told and oriented of better stress coping mechanisms so that they can adapt themselves to the new university environment. Lastly, the authors would like to extend their recommendation to the college of health and medical science itself to expand more recreational activities so that students can prefer these services instead of substance use during their break time.As this study focused on undergraduate health science students, the findings would be helpful to initiate effective substance use control programs in health science schools. Likewise, it can also be used as a blueprint to conduct an interventional study in the particular area. However, it was not possible to establish a temporal relationship between the exposure and outcome variable as this study design was a cross-sectional study. The result may not be representative of entire university students in Ethiopia due to a small sample size of the study.Additional file 1: Questionnaire A structured questionnaire used for interviewing selected health and medical science students of HU, 2018."}
+{"text": "Despite the highest population, the productivity of Ethiopian livestock is low, and the direct contribution to the national economy is limited. Poor genetic potential, shortage of feed in quantity and quality, poor health care and management practices are the main contributors to low productivity and production. Data on animal disease and management practices are not in place, in this regard; we estimate the burden of animal health ailments and management practices in ruminants via simple cross-sectional study design in randomly selected peasant associations in western Tigray of northern Ethiopia.A preliminary disease survey in ruminants and their management practices comprising of cattle, sheep and goats was undertaken to evaluate the existence, burden of ruminant diseases and management practices. A total of 121 randomly selected household respondents of Maikhadrah and Bakhar (26.2%), Dansha (19.7%), Adi-Hirdi (18.0%), Adi-Remets and Inda-Selassie (36.1%) sub-districts were inspected throughout the study period. Most (81%) of farmers feed their animals on free grazing in the open environment travelling from highlands and midlands to lowlands in search of adequate feed (different species of grasses) and crop residues during the wet season up to the beginning of the dry season. Majority of farmers (43.8%) had veterinary access from governmental veterinary officers. Thirty-four (33.9%) of the respondents got veterinary access from illegal drug dealers in mini shops or market. Among the major disease constraints identified; Tick infestation (89.3%), lice infestation (68.6%) mange mite infestation (77.7%) lumpy skin disease (LSD) (42.1%), trypanasomiasis (62.8%) bovine pasteurellosis (52.1) mastitis (13.2%), sheep and goat pox (15.7), abortion (19.0%), dystocia (24.8%), retained fetal membrane (25.6%), prolapsed uterus (13.2%) delayed heat period (38.8%) were most endemic ailments directly affecting livestock production and farmers livelihood.In conclusion management practices in livestock production is poor to a large extent. Burden and endemicity of livestock diseases are substantially higher. The data obtained could be the source of facts for planners in animal health service delivery system in this sub region.The online version of this article (10.1186/s12917-018-1621-y) contains supplementary material, which is available to authorized users. Among all the livestock that constitute Ethiopian farm animals, ruminants comprising of cattle, sheep and goats are among the main source of draft power (cattle), wealth accumulation purposes and income generation . Sheep aEthiopia is endowed with the largest livestock population of an estimated 53.4 million cattle 55.2% are female and 44.8% are males) 23.6 million sheep and 18.6 million goats [Literatures indicate that livestock production and productivity are hindered by poor nutritional value both in quantity and quality, poor livestock husbandry practices, animal health ailments and husbandry constraints . The afo and despite poorly designed housing shelter is provide by their owners around their home stead areas to protect from predators [Livestock husbandry practices are extensively managed on free grazing range/extensive system, specifically in the central part of Ethiopia where crop farming dominates the agricultural practices and with farmers keeping an average of 5 to 15 cows/shoats/household (HH) under the free range system, the animals move about freely to feed on forages/grasses, which are abundantly available during the raining season. Hardly are the animals provided supplementary feeds redators . [In Ethiopia, where livestock agriculture is merely practiced; cattle are raised in an extensive way in small-holder production systems. As a result of extensive livestock production, productivity is hindered by losses due to animal health problems of which; anthrax, blackleg, lumpy skin disease (LSD),trypanosomiasis and other major health problems experienced are parasites, with liver fluke being the major internal parasites,followed by ticks and biting flies. Animal health is recognized to be significant source of production losses such as low weight gain, draught, fertility and lactation performances rvation) , 10. In rvation) . Farmersrvation) .Major animal health constraints and efficient livestock husbandry practices are yet to be identified and developed respectively. Therefore; the aim of this scenario was to recognize livestock ailments and management practices for further investigation and as decision-making tool for livestock agriculture development. Based on literatures and personal observations from need assessments, it is possible to hypothesize that the management practices in livestock agriculture is poorly practiced resulting in high densities of livestock disease burden.A cross-sectional study design was conducted in Western Zone of Tigray, Northern Ethiopia. This area is bordered by Sudan and Eritrea in the west and north respectively and Amhara regional state in the South. The study area includes three districts; Tsegede and Welkayte being highland agro ecological characteristics and lowland characteristics in Kafta-Humera. Six peasant associations were randomly selected per each districts identified as Adi-remets, Adi-hirdi, Inda-selassie, Dansha, Baekhar and Maikhadrah Fig.\u00a0.Fig. 1Ge3 to 1800\u00a0mm3 per annum. Humera is one of Ethiopia\u2019s most fertile agricultural zones, with large-scale farming of cash crops such as sesame, maize, cotton, okra, and sorghum [Western Tigray (Humera) positioned at an elevation of 600\u00a0m above sea level; is characterized by a very harsh environment with an annual temperature ranging from 27 to 45\u00a0\u00b0C and rainfall ranges from 900\u00a0mm sorghum . AgriculTigrigna regional language (farmers) and finally translated in to English during data entry and analysis soon after collection of raw data. The questionnaire was pre-tested before administration to the interviewees. Farmers have responded to different animal diseases as they recognize via their grass rooted knowledge of vernacular /local names of different diseases affecting their cattle, sheep and goats on the basis of different disease symptoms and pathognomonic signs. However, animal health personnel\u2019s (Vets and para-vets) from respected veterinary officers were involved during house to house visits to boost further disease classification and identification on the basis of physical examination.Simple random sampling technique was applied after dividing districts in to peasant associations and then at household level via multistage sampling procedure. Overall 121 randomly selected respondents comprising of household (HH) farmers, agricultural development agents (ADA) and veterinarians were involved during face to face interview. Structured and semi-structured questionnaire comprising of both qualitative and quantitative data was deliberately developed for this study [Additional file Raw data were entered, edited, checked and managed in to Microsoft Excel Spread Sheet Access. Data organization, summarization and analyses were performed after coding and rechecking, in SPSS Statistics for Windows, Version 20.0..Simple descriptive analysis was generated  level of significance was considered as cut point.The mean average number of cattle, sheep and goats per household were 15.58, 11.11 and 13.94 in that order. Mean age at first calving for cattle, sheep and goats was 55.82, 12.03 and 12.37\u00a0months respectively. House design for cattle was poorly designed non concrete/natural earthen floor open air around homestead (58%) whereas non concrete fenced with stone wall and wood wall near homestead (45%) housing design was practiced for small ruminants to protect from predators. Most (81%) of farmers feed their animals free grazing from the open environment travelling from highlands and midlands to lowlands in search of adequate feed (different species of grasses) and crop residues during the wet season up to the beginning of the dry season (Table\u00a0Majority of farmers (43.8%) had access for services from governmental veterinary officers. Thirty-four (33.9%) of the respondents got veterinary access from illegal drug dealers in mini shops or market. Nearly 7 % of farmers (6.6%) sought veterinary diagnosis and medication from private veterinary drug venders. In terms of disease prevention and control over their ruminant animals, farmers are not fully aware of taking/hardly take up to veterinary vaccination and treatment centers due to beyond their cost affordability, traditional beliefs that awaiting the sick animal for self-recovery; taking to traditional healer or long distance reasons. The nearest distance to veterinary service delivery center ranges from one kilometer (5%) to beyond ten kilometers (34.5%). Forty two percent of respondents (42.1%) could afford the cost for vaccination and treatment; nearly 10 % of the farmers (10.7%) treat personally with modern medicine; 14 % (14%) of them take their sick animal to traditional healers and 18 % of the respondents (18.2%) treated their sick ruminants personally from traditional and herbal medicines.Livestock diseases are significant challenges to the livestock production sub-sector in Ethiopia. Main risk factors for livestock losses in the study sub-region were disease (61.2%), predators (5%), drought (4.1%), poisoning/grass toxicosis (4.1%) and theft (2.5%). Morbidity rates of cattle, sheep and goats were determined as 8, 12.5, and 15.5% in that order. Ninety one percent of all ailments identified were communicable diseases consisting of bacterial, viral, protozoal and parasitic infections.The major ruminant disease constraints limiting livestock production in the study setting were lumpy skin disease (LSD) 42.1%), trypanasomiasis (62.8%) bovine pasteurellosis (52.1) mastitis (13.2%), sheep and goat pox (15.7%) foot rot (11.7%). Among the reproductive disorders; abortion (19.0%), dystocia (24.8%), retained fetal membrane (25.6%), uterine prolapsed (13.2%) delayed heat period/prolonged anestrous (38.8%) were the ailments identified. Grass toxicosis (21.5%), bloat (18.2%) and hyena byte (8.3%) were among the non-communicable ailments and injuries identified. Parasitic diseases of ticks (89.3%), lice (68.6%) and mange mite (77.7%) infestation were among the devastating health problems in livestock production system. Detail burden and frequency of endemic diseases are reported in agro ecological zone wise in"}
+{"text": "The following study employs secondary data from the Money Follows the Person Rebalancing Demonstration (MFP) in Connecticut (CT) to assess relationships between rural and urban living on loneliness and reinstitutionalization among an older adult (65+) sample. MFP is a federal initiative to help states transition people from institutional settings to the community. Older adults  who transitioned from institutional care to the community between 2009 and 2015 were surveyed 6, 12 and 24 months after transition. Rurality was determined according to the CT State Office of Rural Health and US Census Bureau definitions: urban area (UA), urban cluster (UC) and rural, utilizing 2017 CT Population data. SPSS was used to conduct chi-square tests and one-way ANOVAs to examine relationships. Almost half of participants (48%) resided in UAs, another 43% lived in UCs and 8% lived in rural towns. A statistically significant relationship was found between rural and UC groups and loneliness, indicated by a three-item modified version of the R-UCLA loneliness scale. Rural residents reported lower rates of loneliness (3.84 out of 9) than did UC (4.61) or UA (4.64) residents. However, a significantly higher percentage of rural residents (44%) reported at least one instance of reinstitutionalization at 24 months compared to UC (36%) or UA (30%) residents. Multivariate analyses seek to clarify these contradictory results. The findings of this study have the potential to further inform the literature regarding loneliness and connections between reinstitutionalization among older adults living in rural and urban environments."}
+{"text": "The blood group of Malagasy patients with cancer have never been the subject of previous publications. Our objective was to determine the blood group of Malagasy patients with cancer followed in the Medical Oncology Unit of the Soavinandriana Teaching Hospital, Antananarivo. This was a one-year retrospective study (November 2012 to October 2013) in patients over the age of 15 with histological or pathological evidence of their cancer. One hundred and thirty of the 258 patients identified had an ABO blood group determination (50.39%). Among these 130 patients, 114 patients (87.69%) had solid tumors and 16 patients (12.31%) had hematologic malignancies. Thirty seven (28.49%) patients were transfused and 93 (71.54%) not transfused. There were 57 men and 73 women (sex ratio = 0.78), the average age was 55.11 +/- 14.76 years. With regard to their blood group, 52 patients (40%) were blood group B, 44 (33.84%) group O, 27 (20.76%) group A and 7 (5.38%) group AB. The order of blood group frequency of cancer patients in our series differs from other studies. This study has allowed us to know the proportion of each blood group in our Unit and thus help us in the management of stocks of labile blood products in our hospital. One hundred and thirty of the 258 patients identified had an ABO blood group determination (50.39%). Among these 130 patients, 114 patients (87.69%) had solid tumors and 16 patients (12.31%) had hematologic malignancies. Thirty seven (28.49%) patients were transfused and 93 (71.54%) not transfused. There were 57 men and 73 women (sex ratio = 0.78), the average age was 55.11 +/- 14.76 years. With regard to their blood group, 52 patients (40%) were blood group B, 44 (33.84%) group O, 27 (20.76%) group A and 7 (5.38%) group AB (Few studies on the Malagasy blood group have been conducted in the general population and among certain categories of population , 2. For group AB .This is the first ABO blood group study in Malagasy patients with cancer. It allow us determine the blood groups' repartitions of some Malagasy patients suffering from cancer. Although in the Malagasy population, knowing the blood group is not common , 2, the The order of blood group frequency of cancer patients in our series differs from other studies. The possible biases of our study remind us of the need to carry out studies determining the association between blood groups ABO and the risk of developing cancers in our country. Nevertheless, this study has allowed us to know the proportion of each blood group in our Unit and thus help us in the management of stocks of labile blood products and awareness of donations of blood in our hospital.The authors declare no competing interests."}
+{"text": "Chronic myeloid leukemia (CML) is characterized by hyperproliferation of myeloid precursors, increased fibrosis, and neoangiogenesis in the bone marrow. Imatinib inhibits BCR-ABL tyrosine kinase produced due to reciprocal translocation t in neoplastic CML cells. It reduces hyperproliferation of myeloid precursors and has been found to affect bone marrow fibrosis and angiogenesis. This study was done to assess the effect of imatinib on bone marrow morphology and angiogenesis in CML. 31 newly diagnosed CML patients were evaluated before and after 3 months of imatinib therapy. A marrow morphological response (MMR) score was used to assess marrow cytological and histological features including grade of fibrosis. Mean microvessel density (MVD) was also assessed. Hematological parameters and BCR-ABL transcript levels were assessed in the peripheral blood. 86.21% of patients showed decrease in marrow cellularity with normalization of M:E ratio. 72.42% of patients had decrease in grade of fibrosis and 17.24% showed no change while 10.34% of patients showed progression of fibrosis grade. Patients with MMR score \u2265 2 (n=4) and those with progression of fibrosis grade (n=3) showed suboptimal molecular response (BCR-ABL transcripts > 10%). Pretherapy mean MVD of patients (14.69 \u00b1 5.28) was higher than that of controls (6.32 \u00b1 1.64). A significant reduction of 66.51% was observed in posttherapy mean MVD (4.98 \u00b1 2.77) of CML patients (p<0.001). Imatinib therapy in CML not only decreases marrow cellularity, but also helps towards normalization of bone marrow microenvironment by reducing fibrosis and angiogenesis. Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by excessive accumulation of apparently normal myeloid cells in the bone marrow and peripheral blood. It is associated with the presence of Philadelphia chromosome, which is the result of a reciprocal translocation between chromosomes 9 and 22 resulting in the formation of BCR-ABL chimeric protein which has uncontrolled tyrosine kinase activity . BesidesThis was a prospective study done over a period of one year between July 2016 and June 2017. The study was approved by the Institutional Ethics Committee. A total of 31 patients of CML were enrolled in this study. Written informed consent was taken from all the patients. Detailed history was obtained from each patient. Detailed clinical examination and blood and bone marrow examination were done in all patients. BCR-ABL status estimation was done by FISH or real-time PCR (RT-PCR). All patients showed presence of BCR-ABL translocation at the time of diagnosis.Hematological response was graded as follows:9/L, platelet count < 450 x 109/L, no immature cells in peripheral blood, and no splenomegaly.Complete hematological response (CHR): WBC count < 10 x 10Partial hematological response (PHR): \u2265 50% reduction of WBC count, presence of immature granulocytes in peripheral blood, and persistence of splenomegaly.Nil hematological response (NHR): response worse than partial.Molecular response was assessed by quantitative RT-PCR from peripheral blood samples and graded as per European LeukemiaNet Response Definitions and Monitoring Recommendations (2013)  evaluated sequential hematological parameters at \u2264 1 month, 3 months, 6 months, and 12 months after imatinib therapy and observed that 80% of patients achieved CHR at 3 months. Srinivas BH et al. [51.7% of patients evaluated in this study achieved CHR after 3 months of imatinib therapy. Narang N et al.  evaluateSignificant improvement in bone marrow morphology was seen after imatinib therapy in this study. In our study, all patients showed some degree of marrow fibrosis at presentation. The pre therapy grade of fibrosis of majority of patients 61.29%) was Grade 2, followed by Grade 3 (25.81%) and Grade 1 12.9%). The occurrence of myelofibrosis at the time of presentation has been observed in 30-96.15% of CML patients in various studies , 12. Thi.9%. The % was Gra\u03b1 and were then put on imatinib therapy. They observed some degree of myelofibrosis in all patients (100%) prior to the start of imatinib therapy, Grade 1 in 1 patient (2%), Grade 2 in 8 patients (20%), Grade 3 in 16 patients (40%), and Grade 4 in 15 patients (37%). Posttherapy fibrosis grades could be evaluated at follow-up at 3 months in 23 patients, at 6\u20139 months in 1 patient, at 11\u201312 months in 8 patients, at 14\u201318 months in 4 patients, and after 24 months in 4 patients. They observed reduction in grade of fibrosis by at least one grade in 85% of patients [In this study, 72.42% of patients had decrease in grade of fibrosis at 3 months of follow-up and 17.24% did not show any change in grade of fibrosis while 10.34% of patients showed progression of fibrosis grade. Bueso-Ramos CE et al. (2004) evaluated pre and post-imatinib therapy bone marrow fibrosis grades in 40 patients who had treatment failure with interferon-Several mechanisms have been proposed for myelofibrosis in CML patients. Marrow fibrosis in CML may be mediated by platelet derived growth factor (PDGF) released by megakaryocytes which stimulates fibroblasts . A role We observed erythroid hyperplasia in 2/29 (6.89%) of our patients after imatinib therapy. 2 (6.89%) patients showed marrow hypoplasia, 1 (3.45%) showed marrow necrosis, and 4 (13.79%) patients showed presence of lymphoid aggregates in bone marrow biopsy. Erythroid hyperplasia after imatinib therapy has also been observed in other studies with an incidence range of 13.51%-36.7% , 21. MarIn this study, we observed a statistically significant correlation between MMR score and hematological response  and betwThe mean MVD of 10 control samples in this study was 6.32 \u00b1 1.64, which was significantly lower (p<0.001) than mean MVD of 30 CML patients (14.69 \u00b1 5.28) at the time of diagnosis. This suggests that the MVD may have an important role in the formation of tumor microenvironment and pathogenesis of tumor. We observed a statistically significant  drop of 66.51% in post treatment mean bone marrow MVD levels in CML patients after 3 months of imatinib therapy. This suggests an antiangiogenic role of imatinib. Lokeshwar NM et al.  also obs in vivo studies in mice retina demonstrated that neuropilin 1 (NRP1) which is a receptor on endothelial cells for VEGF regulates angiogenesis in a VEGF independent fashion via ABL1 tyrosine kinase [In CML patients, increased angiogenesis is the result of BCR-ABL oncogene induced increased expression of VEGF gene . Reductie kinase .Apart from hyperproliferation of myeloid precursors, the bone marrow microenvironment in CML is also altered. There is significant increase in marrow fibrosis and neovascularization. Imatinib mesylate therapy not only decreases the marrow cellularity, but also helps towards normalization of the bone marrow microenvironment by reducing fibrosis and angiogenesis."}
+{"text": "West Nile virus (WNV) lineage 2 is associated with neurologic disease in horses and humans in South Africa. Surveillance in wildlife and nonequine domestic species during 2010\u20132018 identified WNV in 11 (1.8%) of 608 animals with severe neurologic and fatal infections, highlighting susceptible hosts and risk for WNV epizootics in Africa. All specimens were subjected to 1-step nested real-time reverse transcription PCR (RT-PCR) targeting WNV  , during February 2010\u2013June 2018. We extracted RNA from the samples using the QIAamp viral RNA , 1 (2%) of 54 African buffalo (Syncerus caffer), 1 (5%) of 22 domestic dogs (Canis lupus familiaris), 1 (33%) of 3 exotic fallow deer (Dama dama), 1 (9%) of 6 giraffes , 1 (9%) of 11 domestic goats (Capra aegagrus hircus), 1 (11%) of 9 lions (Panthera leo), 1 (2%) of 45 domestic sheep (Ovis aries), and 2 (7%) of 28 roan antelope (Hippotragus equinus) (Eleven (1.8% [95% CI 0.8%\u20132.9%]) of the 608 animals tested positive for WNV. A total of 519 (84.5%) specimens were from animals that died, of which 78 were found dead and classified as sudden unexpected death. WNV was detected in 6 (1.7% [95% CI 0.3%\u20133.0%]) of 361 wildlife and 5 (1.5% [95% CI 0%\u20133.3%]) of 196 nonequine domestic animals but in 0 of 51 birds . We deteequinus) . Only 2 \u2013Virus isolation identified African horse sickness virus as a co-infection in the WNV-positive dog (ZRU358_17), confirmed by the Equine Research Centre . WNV neuPositive WNV infections were detected in the Free State , Gauteng , North West , Limpopo , and Mpumalanga provinces  . Most poWe detected WNV in lung , brain , and spleen  tissue and in blood  . Clinicahttps://www.inqababiotec.co.za) and conducted sequence analysis with CLC-genomic workbench (https://www.qiagenbioinformatics.com), MAFFT (Multiple Alignment using Fast Fourier Transform) version 7 , and MEGA6.06 (https://www.megasoftware.net). We used RAxML (https://cme.h-its.org/exelixis/web/software/raxml) for maximum-likelihood phylogenetic analysis of the partial nonstructural protein 5 gene region (215 nt) and confirmed the RT-PCR results and WNV lineages  collected by the South African National Parks in March 2014 and 45 African buffalo in June 2016, all from KNP, and from 34 Nile crocodiles (Crocodylus niloticus) collected from northern KwaZulu-Natal during 2009\u20132012. We coated flat-bottom 96-well microtiter plates  with 1:800 dilution of WNV cell lysate antigen, prepared according to (https://www.cdc.gov/ncezid/dvbd/specimensub/arc) diluted 1:400 and horseradish peroxidase\u2013conjugated rabbit antimouse IgG  (1:2000 dilution). We calculated the percentage inhibition of antibody binding with a cutoff value of 40% and confirmed positive reactions by microtiter virus neutralization test using a 103 50% tissue culture infectious dose stock culture  (We used an epitope-blocking ELISA (We recorded WNV (lineages 1 and 2) in wildlife and nonequine domestic animals in South Africa. Seroconversion to WNV was demonstrated in asymptomatic white rhinoceros from KNP. The data suggest severe disease and neurologic signs occur in species other than horses; these signs may be used for surveillance in areas of Africa where horses are less common to predict WNV outbreaks and predict spillover events into the human population. Wildlife and nonequine domestic animals are not as closely monitored for WNV as horses, and early detection is less likely. The short viremia associated with WNV infection may result in underreporting of positive animals if only RT-PCR is used for diagnosis, but a lack of conjugates for wildlife species complicates development of IgM ELISA. The epitope-blocking ELISA and microtiter virus neutralization test can be used for seroprevalence studies in animals other than horses because they are species-independent but do not differentiate between IgM and IgG and are not quantitative. Future work should focus on assay development for species other than horses.Seasonality of West Nile virus in wildlife, nonequine domestic animals, and birds, South Africa, 2010\u20132018."}
+{"text": "The aim of the study was to examine common sequences of causes of readmissions among those patients with multiple hospital admissions, high-impact users, after abdominal aortic aneurysm (AAA) repair and to focus on strategies to reduce long-term readmission rate.  The patient cohort (2006\u20132009) included patients from Hospital Episodes Statistics, the national administrative data of all NHS English hospitals, and followed up for 5 years. Group-based trajectory modelling and sequence analysis were performed on the data. n=3055) were high-impact users. The high-impact users among ruptured abdominal aortic aneurysm (rAAA) repair constituted 17.3% of the patient population (n=4144). There were 2 subtypes of high-impact users, short-term (7.2%) with initial high readmission rate following by rapid decline and chronic high-impact (10.1%) with persistently high readmission rate. Common causes of readmissions following elective AAA repair were respiratory tract infection (7.3%), aortic graft complications (6.0%), unspecified chest pain (5.8%), and gastrointestinal haemorrhage (4.8%). However, high-impact users included significantly increased number of patients with multiple readmissions and distinct sequences of readmissions mainly consisting of COPD (4.7%), respiratory tract infection (4.7%), and ischaemic heart disease (3.3%).  From a total of 16,973 elective AAA repair patients, 18% ( A significant number of patients were high-impact users after AAA repair. They had a common and distinct sequence of causes of readmissions following AAA repair, mainly consisting of cardiopulmonary conditions and aortic graft complications. The common causes of long-term mortality were not related to AAA repair. The quality of care can be improved by identifying these patients early and focusing on prevention of cardiopulmonary diseases in the community. Repair of abdominal aortic aneurysm (AAA) has been associated with very high readmission rates . It is oThe general patient population has a small subgroup of patients, the high-impact users, who have significantly higher rates of unplanned hospitalisations . They arUnderstanding the temporal order of the causes of readmissions may help us assess any repeated chain of events that occur in high-impact users. Previous studies have shown that order of events have significant impact on the outcomes of patients . For exaHospital Episode Statistics (HES) data were used to extract information on patients diagnosed with AAA repair . The datAll adult patients over the age of 18 who had primary AAA repair from the year 2006 to 2009 were included in the study. Patients who died during the follow-up period were included in the study as well. The patient cohort comprised two main types of repair, EVAR (endovascular aneurysm repair) and open repair. Initially, specific ICD-10 codes were used to identify AAA patients, as used in previous studies: elective AAA I714, I719) and ruptured AAA I713, I718) , 12. Aft, I718 , , I719 anp < 0.05). These criteria are usually chosen to test for the model with best estimate of number of groups and predictors associated with them [The trajectory model was applied to the modified dataset which categorised individuals into different subgroups. The outcome was the annual number of emergency readmissions for each patient for each successive year during the 5-year follow-up. In order to determine the optimum number of subgroups within a population, the choice of model was based on the following criteria: smallest value of Bayesian Information Criteria (BIC), largest value for average posterior probability for each group, odds of correct classification (OCC) >5, and each trajectory with significant parameter estimates  into 2 groups based on their nonelective readmissions: Group 1 (82.0%) and Group 2 (18%)  classified the patient population ( 2 (18%) . Group 1n=748, 7.7%), chest pain , aortic graft complications , gastrointestinal haemorrhage , and external injuries . Of the total population, 57.6% had emergency readmission (n=9791). Within low-impact users, 49.7% of them had emergency readmission (n=6918), none of these patients had multiple readmissions but had similar common causes of emergency readmissions. Of the high-impact users, 82.8% of them had emergency readmissions (n=2531). The common causes and sequences of readmissions are mentioned in Within the patient population, the common causes of nonelective readmissions over 5-year period were respiratory tract infection  showed that 10.2% of the patients were high-impact users. The most common causes of readmissions were respiratory tract infection (n=379 (9.1%)), aortic graft complications (n=214 (5.1%)), gastrointestinal haemorrhage (n=206 (4.9%)), unspecified chest pain (n=166 (3.9%)), and exacerbation of COPD (n=158 (3.7%)). The common sequences of readmissions are mentioned in Subanalysis of elective open repair (n=6172) showed that 13.5% of the patients were high-impact users. The most common causes of readmissions were respiratory tract infection (n=394 (9.2%)), exacerbation of COPD (n=248 (5.8%)), aortic graft complications (n=221 (5.1%)), heart failure (n=199 (4.6%)), and gastrointestinal haemorrhage (n=196 (4.5%)). Common sequences of readmissions are mentioned in Subanalysis of elective EVAR (n=4144) into 3 subgroups based on their nonelective annual readmission rates: Group 1 (82.7%), Group 2 (10.1%), and Group 3 (7.2%)  classified the patient population (3 (7.2%) . Group 1n=127, 8.4%), COPD (chronic obstructive pulmonary disease) , hypotension , gastrointestinal haemorrhage , and chest pain . Within low-impact users, the common causes of readmissions were respiratory tract infection , chest pain , hypotension , gastrointestinal haemorrhage , and external injury . No common sequences of multiple readmissions were identified among low-impact users. The common causes of readmissions and their distinct sequences among high-impact users are mentioned in Within patient population, the common causes of nonelective readmissions over 5-year period were respiratory tract infection (n=3877) showed that 6.6% of the patients were high-impact users. The most common causes of readmissions were exacerbation of COPD (n=36 (10.0%)), respiratory tract infection (n=30 (8.4%)), aortic graft complications (n=21 (5.8%)), and external injuries (n=16 (4.5%)). The common sequences of readmissions are mentioned in Subanalysis of open repair for rAAA (n=267) showed that 21.9% of the patients were high-impact users. The most common causes of readmissions were exacerbation of COPD (n=68 (17.5%)), aortic graft complications (n=44 (11.3%)), respiratory tract infection (n=32 (8.2%)), gastrointestinal haemorrhage (n=20 (5.1%)), and ischaemic heart disease (n=14 (3.6%)). The common sequences of readmissions are mentioned in Subanalysis of EVAR for rAAA (Following AAA repair, high-impact users follow a distinct pathway of hospital care use. They have persistently high readmission rate as compared with low-impact users. They have significant number of patients with multiple emergency hospital admissions. Within rAAA repair patients, there was a third group, short-term high-impact, that initially had very high readmission rate followed by rapid decline. These patients were those with poor prognosis and did not survive after initial high readmission rate. High-impact users following AAA repair had repeated hospital admissions for cardiopulmonary conditions. The common causes of long-term readmissions in patient populations were respiratory tract infection, exacerbation of COPD, external injuries, and aortic graft complications.There has been a debate about the proportion of emergency readmission that can be prevented in the community. The implementation of penalty for hospitals with higher than expected 30-day all-cause readmission rate among medical patients sparked research into preventative measures for causes of readmission. However, it was found that most of the readmissions were not preventable , 22. It All causes of emergency admissions during the 5-year period following rAAA repair were examined. Common causes of readmissions were cardiopulmonary conditions, aortic graft complications, and external injuries: these were common in all subgroups. Similar causes of readmission were found in earlier studies evaluating causes of short-term readmissions following AAA repair, but most of them are based on patients with elective repair . The comSince cardiopulmonary conditions are prevalent among sequences of multiple readmissions in high-impact users, a need for improved care to prevent exacerbation and progression of chronic cardiopulmonary conditions and infections in the community may be required to prevent multiple readmissions in high-impact users following AAA repair. The sequence analysis identified that multiple readmissions mainly consisted of a vicious cycle of COPD, respiratory tract infection, and ischaemic heart disease. It may suggest that the primary care team should be vigilant to assess patients once they are discharged back to the community after AAA repair. Meticulous preventative measures such as regular flu vaccination to prevent chest infection, secondary preventative medical therapy for ischaemic heart disease, and regular follow-up for COPD should be followed in these patients to prevent them from becoming high-impact. Moreover, the high-impact users had higher readmissions for aortic graft complications than the other group. In contrast, majority of low-impact users did not have any multiple readmissions.All subgroups had similar common causes of readmissions, but high-impact users had significantly higher proportion of patients with multiple readmissions compared to other groups. The common sequences of causes of multiple readmissions in these patients consisted of exacerbation of COPD and chest infections. This was particularly important since it indicated that mere observation of common causes of readmission were similar in all subgroups. However, sequence analysis identified distinct sequences of readmissions that can be targeted by policymakers to prevent patients from having multiple readmissions.Sequence analysis is a novel approach to study chronological order of events which can impact clinical outcome. This technique had been used in social science and psychology to understand pattern of events during the life-course of participants in the study. Previous studies have not evaluated temporal sequence of readmissions but only provided cross-sectional crude analysis of the common causes of readmissions. This technique can be applied to other adverse events or health-care services to assess deterioration in patient's health status. Hospital data did not contain information on the community events which led to hospital admissions. Further studies using primary care data will be helpful to understand all factors that lead to hospital readmissions among high-risk users.This study had certain limitations despite the efforts to understand trends in readmission rates among subgroups of the patient population. The study was limited by the use of ICD and OPCS for identification of patient cohort, which is prone to coding errors in the administrative data collection . With anIn conclusion, high-impact users form a significant number of patients who follow a distinct pathway of hospital care use following AAA repair. They mainly suffer from certain cardiopulmonary conditions in the community that lead to their recurrent hospital admissions. Prevention of these conditions can improve their health status. The potential role of cardiac rehabilitation after aneurysm repair and separate management pathway from the rest of the patient population should be further explored."}
+{"text": "Sound knowledge and good practice on insulin injection technique are essential for nurses in order to administer insulin correctly and to educate patients or their relatives adequately. This study aimed to assess the insulin injection practice through the use of insulin pen among nurses working in a tertiary healthcare center of Nepal. Results. The median (IQR) insulin injection practice score of nurses was 11 (9-12) out of 16. Thirty-seven (55.2%) nurses store insulin pen filled with insulin cartridge at room temperature while 57 (85.1%) nurses store unopened cartridge at refrigerator (2-8\u00b0C). The practice of hand washing and injection site cleaning was mentioned by 92.5% and 82.1% of the nurses, respectively. However, just over half of the nurses mix the premix (cloudy) insulin and prime insulin pen before each injection. Thirty-four (50.7%) nurses do not lift skin during injection and more than half of the nurses keep needle beneath the skin for less than 5 seconds after completely injecting the required dose of insulin. One out of ten nurses massage injection site after injecting insulin. Most of the nurses (86.6%) use single needle more than once and the median (IQR) frequency of needle reuse was 6 (3-12). Similarly, systematic site rotation was performed by 59 (88.1%) nurses and twenty (29.9%) nurses claim that they use single insulin pen for two different cartridges. A cross-sectional descriptive study was conducted among 67 nurses working in one of the tertiary healthcare centers of Nepal. Demographic information and insulin injection practice of nurses through the use of insulin pen were assessed using self-administered questionnaire. Each correct practice was scored \u201c1\u201d and incorrect practice was scored \u201c0.\u201d The insulin injection practice of nurses assessed through the use of insulin pen was suboptimal and highlights the need for urgent educational intervention. Diabetes mellitus (DM) affects 425 million people worldwide and about three-quarters of them live in low- and middle-income countries . PrevaleAssessment of nurses' insulin injection practice is important to ensure the safe and effective use of insulin pens. Therefore, it is necessary to assess the insulin injection practices of nurses from Nepal where an evidence of such practice is lacking. The appropriately collected data will provide useful information for developing interventional strategies in order to improve current practice. The objective of this study is to assess the insulin injection practice through the use of insulin pen among nurses working in a tertiary healthcare center of Nepal.This was a cross-sectional descriptive study conducted among nurses working in one of the tertiary healthcare centers of Nepal in April 2018. Ethical approval of this study was obtained from the Institutional Review Committee of the participating hospital. Two hundred eighty-five nurses were working in different departments/units of hospital during this study period. Among them, eighty-five nurses working in Operation Theater, Pediatric ward, Neonatal Intensive Care Unit, Pediatric Intensive Care Unit, and Emergency Department were excluded because these nurses do not usually administer insulin subcutaneously using insulin pen. Out of 200 nurses, 68 of them who were working on morning shift during the day of data collection were selected purposefully to reduce bias. One of the nurses refused to participate, therefore providing only 67 valid sets of data. Self-administered questionnaire was developed to assess insulin injection practice of nurses through insulin pen and was based on new insulin delivery recommendation . The recOf 68 nurses, 67 (98.52%) nurses gave consent to participate in this study. The median (IQR) age of the participants was 23 (21-24) years (ranged from 18 to 35 years). Majority of the nurses had completed Proficiency Certificate Level in Nursing (61.2%) while 19 (28.4%) nurses had completed Bachelor of Science in Nursing (28.4%) and seven (10.4%) nurses had completed either Bachelor of Nursing or Bachelor of Nursing Sciences. Thirty-four nurses (50.7%) were working in general wards and the remaining nurses were working in critical care units. The overall median (IQR) working experience of the participants was 1 (0.75-2) year (ranged from 0.25 to 6 years). About four-fifth of the nurses claimed that they had not attained any formal class or training to use insulin pen.The median (IQR) insulin injection practice score was 11 (9-12) out of 16. Assessment of insulin injection practice of nurses using insulin pen revealed that 37 (55.2%) nurses store insulin pen filled with insulin cartridge at room temperature while 57 (85.1%) nurses store unopened cartridge at refrigerator (2-8\u00b0C). Fifty-four (80.6%) nurses told that they were familiar with different types of insulin and their administration schedule with respect to meal. Hand washing and injection site cleaning were practiced by 62 (92.5%) and 55 (82.1%) nurses, respectively. However, mixing of premix (cloudy) insulin and priming of insulin pen prior to each injection was performed by 35 (52.2%) and 34 (50.7%) nurses, respectively. Abdomen and thigh were the most common sites chosen for injection and arms were also used by five (7.5%) nurses. Thirty-four nurses (50.7%) do not lift skin during injection. Forty-four (65.7%) nurses inject insulin nearly at 90\u00b0 and thirty-five (52.2%) nurses keep needle beneath the skin for less than 5 seconds after injecting required dose of insulin. One out of ten nurses reported that they massage injection site after injecting insulin. Only eight nurses mentioned the appropriate length of needle for insulin pen. Fifty-eight nurses (86.6%) used one needle more than once and median (IQR) frequency of needle reuse was 6 (3-12). Similarly, 59 (88.1%) nurses claimed that they do systematic site rotation while injecting insulin. Twenty (29.9%) nurses mentioned that they use single insulin pen for two different cartridges. The median (IQR) practice score for nurses who completed Proficiency Certificate Level in Nursing, Bachelor of Science in Nursing, and Bachelor of Nursing or Bachelor of Nursing Sciences was 10 (9-12), 11 (9-12), and 11 (9-14), respectively. However, this difference was not statistically significant (p = 0.347).As key frontline healthcare professionals, nurses are responsible for proper insulin administration for hospitalized patients with diabetes. Therefore, their knowledge, practice, and commitment are key factors for controlling patients' blood sugar levels and for educating patients and their relatives for correct insulin injection technique through insulin pen. However, present study showed inconsistency between insulin injection practice of nurses using insulin pen and new insulin delivery recommendation . This isIt is recommended that unopened insulin cartridge should be stored in a refrigerator (2-8\u00b0C) while insulin pen in use can be stored at room temperature (15-30\u00b0C) for up to 30 days . HoweverTo our knowledge, this is the first study to report the insulin injection practice of nurses through insulin pen from Nepal. However, this study was limited to a single center, conducted on limited number of nurses, and thus the findings might not be generalizable. This study used self-administered questionnaire, therefore the results might defer from actual practice. Also, this study did not investigate nurses' rationale for their practices.The insulin injection practice of nurses was suboptimal and highlights the need for urgent educational intervention among younger nurses and those with limited work experiences, though practice in senior nurses needs further exploration. Moreover, workplace-based learning and point-of-care interventions need to be considered for improving current practice."}
+{"text": "Rotavirus causes severe-diarrheal diseases in infants. An estimation of 138 million rotavirus-associated diarrheal cases and 215,000 deaths occur every year globally. In December 2016, West-Shewa zone in Ethiopia reported unidentified gastrointestinal diarrhea outbreak. We investigated to identify the causative agent of the outbreak to support response operations.Medical records were reviewed, and the daily line list was collected from health facilities. Descriptive data analysis was done by time, person and place. Stool specimens were first tested by antigen capture enzyme immunoassay (EIA) technique and further confirmed by reverse-transcription polymerase chain reaction (RT-PCR) as a gold standard. The product of RT-PCR was genotyped for each gene using G1-G4, G8-G9 and G12 primers for VP7 gene and P(4), P(6), P(8) and P(14) primers for VP4 gene.A total of 1,987 diarrheal cases (5.7 per 1000) and five deaths  were identified and epidemiologically-linked to confirmed rotavirus from December 2016 to February 2017. Among the cases, 1,946 (98%) were < 5 children. Fourteen (74%) of the 19 tested stool specimens were positive for rotavirus by EIA and RT-PCR. Majority of strains detected were G12P(6) (25%) and G-negative P(8) (25%) followed by G9P(8) (19%), G1P(8) (13%) and G3/G2 P(8), G12P(8), and G-negative P(6) (6% each).Diarrheal outbreak which occurred in West-Shewa zone of Ethiopia was associated with rotavirus and relatively more affected districts with low vaccination coverage. Routine rotavirus vaccination quality and coverage should be evaluated and the surveillance system needs to be strengthened to detect, prevent and control a similar outbreak. Rotavirus in the family Reoviridae and causes severe diarrhea and vomiting in infants [Rotavirus is a genus  infants . Rotavir infants , 3. Most infants . Rotavir infants -6. Indiv infants . Followi infants . Rotavir infants . An esti infants -12. Rota infants . Diarrhe infants . Rotavir infants  which ma infants , 17.nd week of December 2016, West Shewa zone of Oromia regional state reported rotavirus suspected acute diarrhea outbreak. As the number of daily cases increasing the investigation was warranted and conducted to identify the underlying causative agent of the outbreak to support outbreak management and response operations.Diarrheal diseases caused by rotavirus cannot be clinically differentiated from that caused by other enteric pathogens; specific diagnosis needs testing of fecal specimens with commercially available assays . ELISA, West Shewa zone is one of the zones in Oromia regional state of Ethiopia to the west of Addis Ababa. Based on the 2007 Census conducted by the Central Statistical Agency of Ethiopia (CSA), this Zone has a total population of 2,058,676, of which 1,028,501 are men, and 1,030,175 are women. The investigation was warranted by the Ethiopian Public Health Institute as part of outbreak response and management. Subsequent permissions obtained from Oromia Regional Health Bureau, West Shewa Health Department, Nono, Danno and Jibat districts health offices to investigate the outbreak. The outbreak case definition for rotavirus was \u201cany person presenting to a health facility with acute diarrhea and/ or vomiting or any person in which clinician suspected rotavirus in Nonno, Danno, Jibat districts after December 16, 2016.\u201d Clinicians were reported cases met the case definition for the duration of the outbreak. Medical records were reviewed and all cases were line listed up on getting verbal permission from medical directors of health facilities. Patients' age, outbreak area setting, contact history, and date of symptoms of onset were used to epidemiologically link gastrointestinal diarrheal cases with laboratory-confirmed rotavirus cases. The descriptive cross-sectional study design was employed, and data analysis was done by time, person and place using Microsoft Excel. The incident rate was calculated by dividing the number of the case to the population (Source: 2007 Census) and expressed per 1,000. The age-specific incident rates were also calculated by dividing the number of cases within a specific age group or sex to respective age group population and multiplying by 1,000. Three years of routine rotavirus vaccination coverage data were received from West Shewa Health Department and compared with suspected rotavirus incidence rate. Incident rate and vaccination coverage were depicted on the map using the Arc Geographic Information System (Arc GIS) 10.4.1 version to illustrate the most affected districts.TMRotavirus kit, Oxoid Ltd, United Kingdom) on the collected 19 fecal specimens at the national laboratory of the Ethiopian Public Health Institute (EPHI). RT-PCR was used as a gold standard for further confirmation and genotyping. All positive samples were further characterized by molecular methods at the Rotavirus Regional Reference Laboratory (RRRL): South Africa Medical Research Council (SAMRC) Diarrheal Pathogens Research Unit, Department of Virology, SefakoMakgatho Health Sciences University, Pretoria, South Africa. As described before, the VP7 and VP4 genes were amplified by reverse transcription polymerase chain reaction (RT-PCR) using the outer primer sets sBeg/End9 and Con2/Con3 [Rotavirus infection was determined by using an antigen capture enzyme immunoassay . A total of 19 stool specimens were collected during the diarrhea outbreak in the affected districts. All children sampled were with unknown rotavirus vaccination history. Among the collected samples, 14 (74%) were positive for rotavirus by EIA. Male and female contribute 7 (50%) each of the positive cases  and five deaths  were identified and epidemiologically linked to confirmed rotavirus from 16 December 2016 to 21 February 2017. Among the cases, 1121 (56%) were male, and the rest of 866 (44%) cases were female . Only 32ve cases . With reve cases . The outary 2017 . Among tary 2017 . Routineary 2017 . The 201This is first reported and investigated rotavirus-associated diarrheal outbreak occurred in three districts of West Shewa Zone of Oromia Region in Ethiopia. The diarrheal outbreak affected the health of many children is associated with rotavirus where 62% of the cases were not vaccinated. In sub-Saharan Africa 45.5% in 2000 and 38.9% in 2013 deaths of diarrheal diseases attributed to rotavirus . Childrend dose of rotavirus vaccine was 81% in 2015/2016 and 67% in 2016/2017 which was less than the World Health Organization's minimum requirement [G-P combinations such as G1P(8), G2P(4), G3P(8), G4P(8) and G9P(8) contribute about 90% of all human rotavirus infections in which G1P(8) is the most prevalent combination worldwide. Surveillance studies indicate that G1P(8) strain contribute 52.2% of rotavirus strains globally and 17.4% in Africa . Severaluirement , 43. Simuirement . We alsoThe diarrheal outbreak occurred in three districts of South West Shewa zone of Oromia region in Ethiopia was associated with different rotavirus strains and relatively more affected districts with low vaccination coverage. The existing routine rotavirus vaccination needs to be evaluated and the surveillance system needs to be strengthened to detect, prevent and control a similar future outbreak.Rotavirus is the most common cause of severe gastroenteritis and responsible for more than one-third of diarrheal diseases related to hospitalizations and deaths in infants under five years old. Currently, there is a safe and effective vaccine to prevent rotavirus infections.Rotavirus caused diarrheal disease outbreak and mostly affected under five years children in West Shewa Zone of Oromia Region of Ethiopia. The occurrence of the outbreak suggested there is an inadequate rotavirus vaccination coverage in the area.All Authors declared no competing interests."}
+{"text": "OBJECTIVES/SPECIFIC AIMS: Sudden death in the young (SDY) occurs in people between 1 and 40 years of age who do not have a known premortem risk factor for early death. Cardiovascular diseases account for the majority of causes of SDY. Sequencing of genes associated with congenital arrhythmia susceptibility and familial cardiomyopathy reveals pathogenic variants in 30% of postmortem cases . However, better data are needed to determine the prevalence of phenotype and genotype abnormalities in surviving relatives. METHODS/STUDY POPULATION: A retrospective cohort study was performed at a tertiary pediatric center including all subjects with a family history of SDY. Cases were identified using ICD-9 codes , search of cardiology databases, and by recursive identification of all family members of a subject. Phenotype data was independently reviewed by a pediatric cardiologist. Genotype results were available when obtained by the original treating physician. RESULTS/ANTICIPATED RESULTS: Cardiac evaluations were performed in 279 subjects from 175 families, of whom 117 subjects (42%) were first-degree relatives of the proband. Mean age of the subject at time of evaluation was 9 years (SD 5.9). Most probands were over 18 years at the time of SDY: 1\u20134 years of age (9%); 5\u201312 (5%); 13\u201317 (16%); 18\u201324 (18%); 25\u201340 (42%). A final diagnosis was determined in 55 families (20%), and a variant in a gene potentially causative of SDY was discovered in 20/55 (36%) of those families. Variants were classified as 50% pathogenic/likely pathogenic, 50% variants of unknown significance. Cardiac testing  was abnormal in 124/279 subjects (44%). Among those with abnormal studies, 57/124 (46%) were from a family where a final diagnosis could be determined . However, 67/279 of total subjects (24%) had at least 1 abnormal study and a final diagnosis was not determined in the family. DISCUSSION/SIGNIFICANCE OF IMPACT: An abnormal phenotype is common among relatives referred for cardiac evaluation after SDY. While testing identifies a family diagnosis in 20% of families, many patients have abnormal cardiac testing and no clear diagnosis can be made. An improved postmortem protocol for phenotype testing in relatives of a SDY victim and improved postmortem genetic testing may lead to a higher diagnosis rate and improved risk determination in surviving family members."}
+{"text": "Trichomonas muris is one of the most common protozoa diagnosed in rodents. The trichomonads are generally described as presenting only trophozoite form while pseudocyst is another morphological form of trichomonads identified among gastrointestinal and genitourinary trichomonads. We identified and described different shapes of T. muris pseudocysts and trophozoite in stool samples were collected from rodents including Merinos persicus, Mus musculus and Cricetulus migratorius.In this cross-sectional study, stool samples from 204 trapped rodents were collected from Meshkin Shahr during Mar to Dec 2014. Samples were preserved in formalin 10% and PVA solution and transferred to Department of Medical Protozoology and Mycology, School of Public Health, Tehran University of Medical Sciences. Formalin-ether concentration method was used for the samples. The slides were stained with tri-chrome staining method and observed under light microscope.T. muris based on size (18 to 24 \u03bcm), presence of three anterior flagella, recurrent flagellum, undulating membrane, and axostyle in direct examination and stained slides with trichrome staining method. Fifty-five out of 204 (27%) rodents were infected with T. muris in which 51(25%) samples pseudocysts form were observed. The spherical bodies of pseudocyst with almost 8 \u03bcm size, contained internalized flagella, an undulating membrane with recurrent flagellum, axostyle, and costa were seen. The pseudocysts were more prevalent than trophozoite form and pseudocysts were found with different shapes in this study.The trophozoites were classified as T. muris pseudocysts were found in stool samples of caught rodents for the first time in northwestern Iran. Trichomonas muris is one of the most common protozoa diagnosed in rodents , Mus musculus (no.63) and Cricetulus migratorius (gray hamster) (no.24) were collected by Sherman method, live animal traps from Meshkin Shahr area, northwest of Iran from Mar to Dec of 2014  in accordance with Helsinki Declaration and guidelines.T. muris including Merinos persicus 40/117 (34.2%), Mus musculus 7/63 (11.1%) and C. migratorius 8/24 (33.3%), in which 51/204 (25%) samples pseudocysts form were observed. The most common frequency of T. muris was found in Merinos persicus including 21/69 (30.4%) male and 19/48 (39.6%) female followed by C. migratorius including 8/16 (50%) male and then Mus musculus including 5/42 (11.9%) male and 2/21 (9.5%) female. Frequency of T. muris infection in male rodents 34/127 (26.8%) was almost equal with female rodents 21/77 (27.3%)  of them were male and 77(37.7%) were female. In general 55 out of 204 (27%) rodents were infected with  (27.3%) .T. muris. Trophozoites were classified as T. muris on the basis of size (18 to 24 \u00d7 12 to 14 \u03bcm), presence of three anterior flagella, recurrent flagellum, undulating membrane, and axostyle in direct examination and stained slides with tri-chrome staining method  of pseudocysts could be distinguished in fresh feces that stage A is infective form but stage D or aged pseudocyst is not . Some chT. muris demonstrated that pseudocyst formation is a reversible phenomenon and pseudocyst has normal morphology of internal structure and ability of division and it is infective form of parasite. Furthermore pseudocysts were observed as ameboidal or spherical form presenting intense flagella beating inside the cell  have been completely observed by the authors."}
+{"text": "To determine the safety and efficacy of N-butyl 2-cyanoacrylate in bleeding gastric varices in children.This retrospective observational study was conducted in the Department of Gastroenterology and Pediatric Surgery in Liaquat National Hospital Karachi between January 2010 and January 2017. Gastric fundal varices were obliterated in pediatric population with single shot of N-butyl-2 Cyanoacrylate 0.50ml diluted with 0.50ml of Lipoidal with use of forward-viewing video endoscope with 22-gauge needle. The primary outcome was primary hemostasis, Secondary outcome was complications, re-bleeding and mortality.Thirty patients was included in the study, 18(60%) were male with mean age of 7.12\u00b1 2.9 years. Non cirrhotic portal hypertension was the most common etiology in 15 (50%) patients, followed by liver cirrhosis secondary to hepatitis B and D co-infection in 6(20%) patients. Primary hemostasis was achieved in 29 (96.7%), while 3(10%) patients developed re-bleeding after 48 hours, and hemostasis was achieved after second session of endoscopic obliteration. Abdominal pain and fever developed in 3(10%) patients which was managed conservatively. Mortality was observed in 1(3%) of cases due to sepsis after shunt surgery.Endoscopic fundal varix obliteration with N Butyl-2 cyanoacrylate was safe and effective in treatment of gastric variceal hemorrhage in children. Portal hypertension is a pathological entity which indicates elevated pressures in the hepatic portal system. It is an outcome of increased vascular resistance or increased blood flow in portal system, it is technically stated in terms of portal pressure gradient or a hepatic venous pressure gradient (HVPG) equal to or greater than 5 mmHg in children.5Acute variceal hemorrhage is a catastrophic and fatal event in children resulting from the rupture of esophageal and gastric varices (GV), which stipulate urgent intervention. An adequate and safe approach in managing esophageal varices is endoscopic variceal ligation (EVL), it is highly recommended and standard of care first line treatment in the management in both adults and children.9Different treatment modalities for treating gastric variceal hemorrhage in adults include endoscopic gastric varix obliteration with directly injecting N-butyl-2-cyanoacrylate into the varix, Transjugular Intrahepatic Portosystemic Shunt (TIPS) and balloon-occluded retrograde trans venous obliteration (B-RTO) requiring skillful radiological expertise and finally portosystemic shunt surgeries. The Baveno VI consensus guidelines propose the use of N-butyl-2-cyanoacrylate (histoacryl) as a treatment of choice in endoscopic obliteration of gastric varix in adults.10The Baveno V consensus statement on portal hypertension in children suggest the use of N-butyl-2-cyanoacrylate (histoacryl) for isolated gastric varices and gastro esophageal varices Type-II (GOV2) but there are no definite recommendations, as it requires more controlled trials for validation.11Historically Soehendrain in 1986 proposed for the first time, the use of N-butyl 2-cyanoacrylate, a tissue adhesive agent, which was endoscopically injected into the bleeding gastric varices.14N-butyl, 2-cyanoacrylate is glue like substance with adhesive properties, it induces the process of polymerization and solidifies when in contact with water or blood promoting obliteration of the vessel and also promotes local thrombosis. The American Society of gastrointestinal endoscopy guidelines on tissue adhesives recommend the mixing of cyanoacrylate with lipoidal with a standard ratio of 1:1 up to 1:1.6 in adults. Appropriate dilution delays fast polymerization of cyanoacrylate and allows adequate endoscopic administration with injector and prevents its adherence to catheters and endoscopes. Data on safety and efficacy of N-butyl-2-cyanoacrylate in managing bleeding gastric varices in children is scarce.15Our main objective was to observe the safety and effectiveness of N-butyl 2-cyanoacrylate injection in bleeding gastric varices in pediatric population and also observe its outcomes which include achievement of hemostasis, re-bleeding and complications.The study was conducted in Department of Gastroenterology and Pediatric Surgery at Liaquat National Hospital, Karachi Pakistan. Patients medical record were reviewed extensively from January 2010 to January 2017after receiving an approval from the institution`s ethical review board.Pediatric population up to 14 years of age manifesting acute upper gastrointestinal bleeding or malena as a consequence from the rupture of GV were included for study analysis. We included patients of both liver cirrhosis and EHPVO. Diagnosis was made on the basis of laboratory investigations complete blood count liver function tests, prothombin time, albumin, ultrasonography of liver and abdomen, computerized tomography (CT) scan abdomen and endoscopic findings and in some cases liver biopsy was also done. EHPVO was confirmed with contrast enhanced CT angiography.The patients presenting with malena and /or hematemesis were admitted in high dependency unit for resuscitation. Hemodynamic stability was achieved with intravenous fluids, antibiotics, andoctreotide1 microgram/kg bolus dose and then 1 microgram/kg/hour in continuous infusion for at least 3 days with transfusion of packed red blood cells if required.Endoscopy was performed after informed consent within 24 hours of hemodynamic stability. Endoscopic criteria to label hemorrhage from GV was integrated, if anyone of the following was present:Spurting or oozing of fresh blood from varixPresence of blood clot or ulcer on varixOccurrence of discrete large varix with no other source of hemorrhage and with no evidence of esophageal varices.8We used Sarin classification to classify gastric varices. Gastro-esophageal varices Type-1 (GOV1)is extension of esophageal varices along the lesser curve of the stomach, gastro-esophageal varices Type-2 (GOV2) is continuation of EV to the gastric fundus along greater curvature of stomach, isolated gastric varices Type-1 (IGV1) are present in fundus of stomach and lastly isolated gastric varices Type-2 (IGV2), are also labeled ectopic varices, they can be present anywhere in the pylorus antrum, or corpus, of stomach.Primary homeostasis is defined as endoscopic homeostasis, with normalization of vital signs and no hemoglobin drop or re-bleeding within 48 hours of gastric varix obliteration. Early re-bleeding is defined as hypotension or 2gm /dl drop in hemoglobin from base line requiring blood transfusion or history of hematemesis or malena within 48 hours of gastric varix obliteration whereas late re-bleeding was defined as recurrence of bleeding after 48 hours up to 30 days.Technical failure is defined as failure to achieve hemostasis or stop bleeding from the varix during endoscopy. After discharge all patients were closely monitored in outpatient department for 24 months, till the time they went for liver transplant or shunt surgery.Thirty patients were enrolled in this study which were managed as acute gastric variceal hemorrhage. The mean age was 7.12\u00b1 2.9 years. Out of 30 patients 18(60%) were males. Non-cirrhotic portal hypertension which included extra hepatic portal vein obstruction was the most common etiology of portal hypertension comprising 15(50%) patients and other causes illustrated in . MajoritThe mean Pediatric End-stage Liver Disease (PELD) score was 7.81 \u00b11.28 in cirrhotic patients. Among children, 26 (86.7%) experienced primary gastric variceal hemorrhage (hemorrhage from rupturing of gastric varices for the first time) whereas 4 (13.3%) patients encountered secondary gastric variceal hemorrhage . Urgent need of blood transfusion was considered necessary in 19(63.3%) patients whereas 11(37.7%) did not require any blood products.Most common type of gastric varices on endoscopic findings was isolated gastric varix Type-1 (IGV1) in 18(60.0%) children and gastro esophageal varices Type-2 (GOV2) in 12(40%) patients. About 12(40%) of patients underwent both EVL and FVO.Technical success and primary homeostasis was accomplished in 29(96.7%) patient. One (3.3%) patient had ongoing hemorrhage which was not controlled endoscopically so the patient was referred for emergent shunt surgery who later died due to sepsis.Rebleeding was observed in 3(10.0%) patients after 48 hours and required second session obliteration with of N-butyl, 2-cyanoacrylate. No major complications were observed in patients, only 3(10%) patient developed fever and abdominal pain and managed conservatively.The patients with liver cirrhosis and bilary atresia 4(13.3%) were followed and referred to liver transplant centre. Out of 15(50%) patients with extra hepatic portal vein obstruction (EHPVO) 9(29.7%) patients underwent distal splenorenal shunt surgery, while 2(6.6%) patients were lost to follow-up. The other three patients had complex hepatoportal anatomies who did not meet criteria for shunt surgery. They were kept on secondary prophylaxis with non-selective beta blockers. Mean follow-up of these patients were 12.66\u00b10.44 months.Portal hypertension and its complications are difficult to manage, as gastric variceal hemorrhage is life threatening and options are limited in pediatric population. Gastric varices are mostly prevalent in patients with portal hypertension particularly with extra hepatic portal venous thrombosis (EHPVO) in children.vs. 17%, P<0.01)and isolated gastric varix (IGV1) have intense risk to bleed as compared to gastro esophageal varix (GOV) in adults.P<0.001) and are more likely to bleed.Sarin et al has also concluded that patients with EHPVO frequently had gastric varices as compared with patients with cirrhosis 31% vs. %, P<0.01In published studies fever and abdominal pain are the most frequent complains after cyanoacrylate injection reported in 90% of patients which resolves spontaneously with antibiotics and analgesics.17In our study, fortunately none of our patients had life threatening complications; only 3(10%) patients had fever and abdominal pain post procedure conservatively managed with analgesics and broad spectrum antibiotics resolved spontaneously.Special safety precautions should be undertaken by the endoscopy technicians and the endoscopist to protect eyes and endoscopy biopsy channel. Huang et al. revealed damage to the endoscopy channel after the use of histoacryl and underwent costly repair. In our study, we strictly followed the protocol and no endoscopy equipment was damaged and endoscopist conducted the procedure without complications.20In adults the volume of N-butyl, 2-cyanoacrylate injected into the varix varies between 0.5 to 1ml as by experts, but further studies are needed to validate ideal volume to obliterate varix. Some experts suggest volume can be modified to the size of varix.Primary hemostasis was achieved in 96.7% of patients in our study, these results are quite comparable to results in adult population.25Rebleeding is an established complication accounting 0.1 to 6.3% in adults.In adult population the severity of gastric variceal hemorrhage is more intense, with increase chances of rebleeding (25%-55%) and with significantly higher fatality rate (26%-89%) as compared to pediatric population(0%-8%), and it needs further validation.29Baveno VI pediatric satellite symposium for portal hypertension recommended transjugular intrahepatic portosystemic shunt (TIPS) procedure and portosystemic shunt surgery (MesoRex) for primary and secondary prophylaxis of variceal bleeding.Our study proposes endoscopic fundal varix obliteration using N-butyl-2-cyanoacrylate is safe and effective in children for the initial hemostasis from bleeding gastric varices especially in center\u2019s where emergency shunt surgery service and transjugular intrahepatic portosystemic shunt (TIPS) is not available.LK conceived, designed, editing and is responsible for integrity of the study.BSA did data collection and manuscript writing, statistical analysis, integrity of the research work.MA and PA did review and final approval of manuscript to be published."}
+{"text": "We deeply appreciate the great contributions of many physicians in the registry of esophageal cancer cases. The Comprehensive Registry of Esophageal Cancer in Japan, 2011, was published here, despite some delay. The registry complies with the Act for the Protection of Personal Information. The encryption with an HASH function is used for anonymity in an unlinkable fashion.We briefly summarized the Comprehensive Registry of Esophageal Cancer in Japan, 2011. Japanese Classification of Esophageal Cancer 10th and UICC TNM Classification 7th were used for cancer staging according to the subjected year. A total of 6993 cases were registered from 300 institutions in Japan. Tumor locations were cervical: 4.5%, upper thoracic: 13.0%, middle thoracic: 47.8%, lower thoracic: 27.2%, and EG junction: 7.1%. Superficial carcinomas  were 36.4%. For the histologic type of biopsy specimens, squamous cell carcinoma and adenocarcinoma accounted for 88.3 and 5.3%, respectively. Regarding clinical results, the 5-year survival rates of patients treated using endoscopic resection, concurrent chemoradiotherapy, radiotherapy alone, or esophagectomy were 86.0, 28.1, 26.5, and 54.5%, respectively. The endoscopic submucosal dissection accounted for 78.1% of endoscopic resection. Esophagectomy was performed in 4147 cases. Concerning the approach used for esophagectomy, 33.5% of the cases were treated thoracoscopically. The operative mortality (within 30\u00a0days after surgery) was 0.65% and the hospital mortality was 3.76%. The 5-year survival rate of patients with pStage IV in UICC classification (including patients with supraclavicular node metastasis) was better than that of patients with pStage IVb in JES classification (not including patients with supraclavicular node metastasis).We hope that this Comprehensive Registry of Esophageal Cancer in Japan for 2011 will help to improve all aspects of the diagnosis and treatment of esophageal cancer in Japan.I.Clinical factors of esophageal cancer patients treated in 2011Institution-registered cases in 2011Patient backgroundTableAge and genderTablePrimary treatmentTableTumor locationTableHistologic types of biopsy specimensTableDepth of tumor invasion, cT (UICC TNM 7th)TableLymph node metastasis, cN (UICC TNM 7th)TableDistant metastasis, cM (UICC TNM 7th)TableClinical stage (UICC TNM 7th)II.Results of endoscopically treated patients in 2011TableDetails of endoscopic treatment for curative intentTableComplications of EMR/ESDTablePathological depth of tumor invasion of EMR/ESD specimensFigureSurvival of patients treated with EMR/ESDFigureSurvival of patients treated with EMR/ESD according to the pathological depth of tumor invasion (pT)FigureSurvival of patients treated with EMR/ESD according to the lymphatic and venous invasionIII.Results in patients treated with chemotherapy and/or radiotherapy in 2011TableDose of irradiation TableDose of irradiation FigureSurvival of patients treated with chemotherapy and/or radiotherapyFigureSurvival of patients treated with definitive chemoradiotherapy according to clinical stage (UICC TNM 7th)FigureSurvival of patients underwent radiotherapy alone according to clinical stage (UICC TNM 7th)IV.Results in patients who underwent esophagectomy in 2011TableTreatment modalities of esophagectomyTableTumor locationTableApproaches to tumor resectionTableVideo-assisted surgeryTableFields of lymph node dissection according to the location of the tumorTableReconstruction routeTableOrgans used for reconstructionTableHistological classificationTableDepth of tumor invasion, pT (JES 10th)TablePathological grading of lymph node metastasis, pN (JES 10th)TablePathological findings of lymph node metastasis, pN (UICC 7th)TablePathological findings of distant organ metastasis, pM (JES 10th)TableResidual tumorTableCauses of deathFigureSurvival of patients who underwent esophagectomyFigureSurvival of patients who underwent esophagectomy according to clinical stage (JES 10th)FigureSurvival of patients who underwent esophagectomy according to clinical stage (UICC 7th)FigureSurvival of patients who underwent esophagectomy according to the depth of tumor invasion, pT (JES 10th)FigureSurvival of patients who underwent esophagectomy according to lymph node metastasis, pN (JES 10th)FigureSurvival of patients who underwent esophagectomy according to lymph node metastasis, pN (UICC 7th)FigureSurvival of patients who underwent esophagectomy according to pathological stage (JES 10th)FigureSurvival of patients who underwent esophagectomy according to pathological stage (UICC TNM 7th)FigureSurvival of patients who underwent esophagectomy according to residual tumor (R)"}
+{"text": "Young people under the age of 40 with colorectal cancer represent a distinct subgroup with a more aggressive disease behaviour compared to older patients. This study aim to provide an updated overview on clinicopathological features, treatment and outcome of colorectal cancer in young adults under the age of 40. In our retrospective study, we reviewed 32 cases of colorectal cancer in young adults aged less than 40 years that were diagnosed at the pathology department of Mongi Slim hospital over a fifteen-year period (April 2000 - November 2014). Our study group included 13 male and 19 female patients  between 17 and 39 years of age . The presenting clinical symptoms were dominated by altered bowel habits (n=17), followed by bleeding per rectum (n=16). Histopathological examination of the surgical and biopsy specimens established the diagnosis of mucinous adenocarcinoma in nine cases, well-differentiated adenocarcinoma in 11 cases, moderately differentiated adenocarcinoma in six cases, poorly differentiated adenocarcinoma in four cases and signet ring cell carcinoma in two cases. The tumours were classified after surgery as stage I (n = 2) (6%), stage IIA (n = 7) (22%), stage IIB (n=4) (13%), stage IIC (n=1) (3%), stage IIIB (n=8) (25%), stage IIIC (n= 4) (12%), stage IVA (n=4) (13%) and stage IVB (n=2) (6%). During the follow-up period which ranged between one month and 9 years, local recurrence of the tumour occurred in six cases, seven patients had hepatic metastases and seven patients died after a mean follow-up period of seven months. Molecular genetic studies are increasing the understanding of the pathobiology of colorectal cancer and may ultimately allow at-risk patients to be identified at an earlier stage. Colorectal cancer (CRC) arises predominantly in the older population, with more than 90% occurring after the age of 55 years . ColorecWe undertook a retrospective study of 32 young patients under 40 years of age who were operated on for colorectal cancer at the surgery department of Mongi Slim hospital of Tunis between April 2000 and November 2014. The cases were retrieved from the files of the registry of the surgery department of the same hospital. Medical records were scrutinized for epidemiologic characteristics, initial manifestations of the disease, methods of diagnosis, laboratory findings, surgical or palliative therapy and overall morbidity and mortality. Diagnosis of colorectal cancer was based upon histopathological findings. All patients underwent imaging evaluation during the preoperative period. All specimens were surgically obtained. Tissues were fixed in 10% phosphate buffered formaldehyde, embedded in paraffin and sections were prepared for routine light microscopy after staining with haematoxylin and eosin. Disease stage was determined according to the seventh edition of the TNM classification of the Union Internationale Contre le Cancer (UICC). Tumours were histologically classified according to the 2010 World Health Organisation Classification Of Tumours of the Digestive System. Patient confidentiality was maintained.Patient characteristics: Patients under 40 years of age with CRC diagnosed between April 2000 and November 2014 represented 7,53% of all CRC (n=425). There were 13 male and 19 female patients  between 17 and 39 years of age . Five patients presented with co-morbidities namely Crohn\u00b4s disease (n=2), duodenal ulcer (n=1), chronic gastritis (n=1) and celiac disease (n=1). Five patients had a family history of CRC, one patient had a family history of familial adenomatous polyposis and one patient had a family history of renal and bladder cancer.Presenting symptoms: The presenting clinical symptoms were dominated by altered bowel habits (n=17), followed by bleeding per rectum (n=16), abdominal pain (n=15), altered general health (n=11), occlusive syndrome (n=8), rectal syndrome (n=6), abdominal mass (n=4), vomiting (n=1) and weight-loss (n=1).Biological tests: Preoperative serum carcinoembryonic antigen levels were performed in 12 cases. They were elevated in four cases (> 5ng/ml) and within normal range in eight cases (< 5ng/ml). Preoperative serum carbohydrate antigen CA 19-9 levels were performed in three cases. They were elevated in one case ( > 37 U/ml) and within normal range in two cases ( < 37 U/ml).Localization of colorectal cancer, endoscopic and radiological findings : The tumour localisation was classified in four groups: rectal cancers  included tumours within a distance of 16 cm or less from the anal verge, measured with a rigid sigmoidoscope. All tumours above 16 cm from the anal verge were declared as colon cancers  and subdivided in tumours of the sigmoid colon (n= 10), left colon (including descending colon (n=2), left flexure (n=3) and transverse colon (n=1)) and right colon , cecum (n=2) and appendix) according to the operation protocol. Colonoscopy and / or rectoscopy were performed in all cases. Postoperative computed tomography scan showed adrenal metastases in two cases, hepatic metastases in seven cases , left hemicolectomy (n=5), sigmoidectomy (n=4), total colectomy (n=2), anterior resection (n=13), abdominoperineal amputation (n = 2), total procto-colectomy (n=1). Postoperatively, 20 patients received adjuvant chemotherapy. One patient with peritoneal carcinomatosis discovered peroperatively had only palliative chemotherapy.Pathologic findings: Grossly, carcinomas of our series had variable macroscopic appearances : exophytic or fungating with predominantly intraluminal growth (n = 6) ( (n = 6) , exophyt (n = 6) . Associa (n = 6) , well-dithedition)Staging of colorectal carcinoma according to UICC  (6%), stage IIA (n = 7) (22%), stage IIB (n=4) (13%), stage IIC (n=1) (3%), stage IIIB (n=8) (25%), stage IIIC (n= 4) (12%), stage IVA (n=4) (13%) and stage IVB (n=2) (6%).Operative morbidity and postoperative complications: Postoperative course was uneventful in 17 cases. Postoperative complications  occurred in 14 patients (44%).Surgical complications: Colorectal anastomotic leakage (n=2) and rectovesical fistula (n=1).Non surgical complications: Hemorrhagic shock (n=7), sepsis (n=1), bilateral pleural effusion (n=1), oligoanuria (n=1), and hypokalemia (n=1).Follow-up and evolution: The mean follow-up period of our patients was 29 months (range: 1 month - 9 years). Local recurrence of the tumour occurred in six cases. In the control examination, CT scan revealed liver metastases in seven cases. Seven patients died after a mean follow-up period of 7 months (range: 1-13 months).The current definition of young CRC patients remains controversial. Some studies used the cutoff age of 50 years, while others used 30 years or 45 years. But to date, majority of studies in the literature used the cutoff age of 40 years to denote a young patient with CRC. This lack of a standard definition makes it difficult to make meaningful comparisons between different studies. In our study, we defined young patients using an upper limit of 40 years as most studies reported. The Surveillance, Epidemiology and End Results (SEER) database estimates showed that the incidence of CRC in young adults has been increasing over the last 25 years, while the overall incidence has remained relatively stable for older adults .et al. published a detailed systematic review of 55 articles pertaining to CRC in adults less than 40 years old in 2004 [The majority of CRC cases in young adults are sporadic in nature and the aetiology remains unclear. Several factors, however, have been proposed to contribute to the increasing rate of CRC in young adults, specifically unhealthy dietary choices and red meat consumption, physical inactivity and obesity , 19. Whe in 2004 . The com in 2004 . Many au in 2004 , 25. In In our study, the mucinous tumours constituted 28% of young CRC and 13% of tumours were found to have poor differentiation. Previous studies have shown the presence of signet ring carcinoma in 1,7- 11,1% of young CRC . In our In summary, this retrospective study from Tunisia provides an overview on clinical symptoms, radiological features, treatment and outcome in 32 patients under 40 years of age with CRC. Outcome of younger patients could be improved if screening colonoscopy would start at 40 years as young patients could be diagnosed at an earlier tumour stage. The early detection of CRC followed by a sufficient oncologic treatment is crucial regardless of age. Molecular genetic studies are increasing the understanding of the pathobiology of colorectal cancer and may ultimately allow at-risk patients to be identified at an earlier stage. Future interventions tailored to this young population may help achieve improvements in their overall prognosis.Colorectal cancer is infrequent before 40 years of age and is associated with a poor outcome due to advanced stage at diagnosis, delayed diagnosis and poor differentiation;Accurate diagnosis and staging of colorectal cancer is critical for optimal treatment planning and for determining prognosis.This is the first retrospective study from Tunisia that provides an overview on clinical symptoms, radiological features, treatment and outcome in 32 young Tunisian patients under 40 years of age with colorectal cancer.The authors declare no competing interests."}
+{"text": "Dengue fever is prevalent in the world; in recent years, several outbreaks occurred in West Africa. It affects pregnant women. We aimed to assess the consequences of dengue fever on pregnant women and their fetuses during dengue epidemic in Burkina Faso.We conducted a cross-sectional study from November 1, 2015 to January 31, 2017 in 15 public and private health facilities in Ouagadougou, using secondary data. Immunochromatographic rapid test Duo detecting specific antibodies, immunoglobin M/G and /or dengue non structural antigen1 virus was used to diagnose dengue cases.Out of 399 (48%) women registered during the study period, 25 (6%) were pregnant. The average age of pregnant women was 30\u2009years, with 18 and 45\u2009years as extremes. The main symptoms were fever (92%) and headache (92%). Nine patients (36%) had severe dengue characterized by bleeding (16%), neurological symptoms (16%) and acute respiratory distress (8%). Eight (32%) of the 25 women had early miscarriage and 8 (32%) women gave birth to viable fetuses. Among those with viable babies, 5 (20%) presented post-partum hemorrhage and 3 (12%) presented early delivery. The main fetal complications included 3 cases of acute fetal distress (12%). One case of maternal death (4%) and 4 cases of neonatal mortality (44.5%) were notified.Dengue fever occurring during pregnancy increases maternal and neonatal mortality. Its severe complications require specific monitoring of pregnant women until delivery. Aedes [Dengue is an arboviral infection transmitted by mosquitos of the genus Aedes , 2. The Aedes \u20133. The dStudies on the reciprocal influence between dengue and pregnancy are quite rare. The fetal consequences of dengue are neither well understood nor well documented . Few datThis was a descriptive cross-sectional study involving 15 health facilities in the city of Ouagadougou: 4 District hospitals and 3 Teaching hospitals with packages of healthcare services corresponding to the secondary and tertiary levels of the health pyramid in Burkina Faso. In addition, eight private health facilities were selected according to their capacity of diagnosing dengue to be part of the study. We obtained the authorization of the General Director of Healthcare in Ouagadougou for data collection. The diagnosis of dengue was performed using rapid diagnostic tests (RDTs), which are immuno-chromatographic tests detecting Non Structural Antigen 1 (NS1Ag) and immune-globulin M and G (IgM and IgG). We used the World Health Organization classification of dengue (WHO 2009) to classify the women according to the severity of dengue.The study population consisted of all the patients  diagnosed with dengue in these healthcare centers from November 1, 2015 to January 31, 2017, using dengue RDTs.The sample consisted of all the pregnant women treated for dengue in these healthcare centers. The inclusion criteria were the positivity of the NS1 antigen and/or IgM and/or IgG. Isolated IgG positivity was considered a serological scar of dengue but we could not titrate this antibody.Serotype 2 of dengue virus (DENV-2) was identified by Polymerase chain reaction (PCR) in the Pastor Institute of Dakar, as the causal agent of the epidemic during the study period .The diagnosis of malaria was performed using malaria RDTs Histidine Rich Protein 2 and / or blood smears.The data were collected from the consultation records, laboratories and the clinical records of the patients. The collected data were analyzed using EPI INFO version 3.5.In this study, 835 patients were screened for dengue, using rapid diagnostic tests (RDTs). Among them, there were 399 women (48%), including 25 (6.5%) pregnant women. Sixty-eight percent of the pregnant women were between the ages of 25 and 35\u2009years. The average age of pregnant women was 30\u2009years with 18 and 45\u2009years as extremes, and 92% of pregnant women lived in Ouagadougou. Forty four percent (44%) had university degrees and 36% high school level. Thirty-wo percent (32%) were public and private sectors workers. Students accounted for 24%, as did housewives, and 20% of women were informal sector workers. Dengue frequency distribution during the study period showed a peak in October with 10 cases (40%), which corresponds to the peak in all the patients. Eight cases (32%) were notified in November 2016 , asthenia (64%) and painful symptoms (84%) including headaches (92%), arthralgia (72%) and lumbago/myalgia (64%). Hemorrhagic signs (32%) included epistaxis (24%) and metrorrhagia 16%). Four women (16%) presented neurological symptoms such as consciousness disorders (coma stage I\u2009=\u20091 case and coma stage II\u2009=\u20093 cases). Two cases of malaria-dengue co-infection were notified. The clinical characteristics of women are shown in Table\u00a06%. Four Twenty-one of the 25 pregnant women (84%) had early dengue with positive NS1Ag. Sixteen pregnant women (64%) presented with primary dengue and 6 others (36%) with secondary dengue fever. Three patients were carriers of IgG alone.Fifteen pregnant women (52%) had anemia with hemoglobin level less than 10\u2009g/dl. Two of them were transfused with packed red blood cells. Thrombocytopenia defined as platelet count less than 150,000 / mm3, was observed in 12 patients (48%). Six of them had platelet count less than 50,000 / mm3 and 5 women received transfusion of platelets. Six women (24%) had elevated levels of aspartate aminotransferase (ASAT) ranging from 2 to 15 times the normal value. Two patients had a serum creatinine higher than 120\u2009\u03bcmol/l.Sixteen women (64%) had dengue fever with warning signs while 9 women (36%) had severe dengue fever, according to the 2009 WHO classification.Maternal complications were present in 6 cases. There was early delivery in 3 cases (12%) and intra partum hemorrhage in 5 cases (20%). Three women gave birth vaginally while 3 others underwent caesarean section. Two women expelled macerated fetuses. Seventeen women were always pregnant while they were discharged, and 8 women gave birth, with one of them having twins. A death was recorded in a context of liver failure and postpartum hemorrhage, which stands for 4% of lethality. Lethality was 12.5% among those who gave birth.Fetal complications were observed in 6 cases including 3 cases 12%) of fetal distress and 3 cases (12%) of prematurity. Four cases of neonatal deaths (44.5%) were notified, 3 of which were due to prematurity and one case to neonatal infection. Women and fetal consequences are summarized in Table\u00a0% of fetaDuring the study period, 25 pregnant women were infected by dengue virus in Ouagadougou. The monthly epidemiological curve showed a maximum number of cases in October and November. The proportion of pregnant women with dengue was probably underestimated during our study as we only described the cases present in our database and as the survey was conducted in facilities not frequented by all pregnant women. Dengue surveillance should be instituted in pregnant women in order to distinguish it from malaria, since the two diseases share many common symptoms. The patients\u2019 average age was 30\u2009years, close the result of a descriptive survey conducted in Rio de Janeiro , and lowUnlike the common situation in developing countries where most of women suffering from infectious diseases are unemployed, housewives or farmers, most of pregnant women in our series were public and private sectors workers. Therefore, most of them could afford for the rapid diagnostic test cost (15 to 25 euros). This fact shows that pregnant women from low socioeconomic categories  suffering from dengue but unable to afford for RDTs cost could not be diagnosed. The dengue frequency in pregnant women was underestimated, regarding the 2016 dengue outbreak in the city of Ouagadougou .Out of the 25 pregnant women infected by dengue in our study, 84% were at phase of viremia. In Colombia, a reverse situation was observed in two studies with an acute viremic phase of 29.9 and 27.3% , 10. In In our study, the reported cases showed an upward distribution according to the trimester of pregnancy, with a doubling of the number of cases from the 1st to the 3rd trimester. Similar findings were reported in Colombia . HoweverIn our study, we recorded only 3 cases of Caesarean section out of the eight deliveries. Most of the studies reported as many cases of Caesarean section as natural deliveries; for instance, Alvarenga and Leon reported 50 and 53.8% respectively . ConsideWe recorded one maternal death out of 25 cases. Maternal mortality is significant in most studies: 17/78 in Sudan, 2/13 in Rio de Janeiro, and 3/16 in South Asia . The recOur study showed that pregnant women are at high risk of complications when they catch dengue fever. The usual bleeding during delivery may be aggravated by this disease. On the other hand, some of the complications noted in this study cannot be exclusively attributed to dengue fever. Nevertheless, these complications should be taken into account in order to prevent the risk of bleeding and preterm delivery."}
+{"text": "Capecitabine-temozolomide (CAPTEM) has significant activity in patients (pts) with metastatic low grade pancreatic neuroendocrine tumors (NETs). However, there is limited data regarding its activity in pts with metastatic well-differentiated intermediate and high grade pancreatic and nonpancreatic NETs. The objective of this study was to assess the functional imaging response, survival, and tolerability of CAPTEM in this population.2 orally twice daily (bd) from days1 to 14 and temozolomide 100 mg/m2 bd from days 10 to 14 every 28 days. Data regarding functional imaging response, progression-free and overall survival, and toxicities was collected. A retrospective audit of pts with metastatic well-differentiated intermediate (WHO grade 2) or high grade (WHO grade 3) NETs treated at Peter MacCallum Cancer Centre between March 2013 and March 2017. Pts received capecitabine 750 mg/m Thirty-two pts received a median of 6 cycles (range: 2-16) of CAPTEM for grade 2  or grade 3 , Ki67 <55%  or Ki67 \u226555%  NET. Primary site included gastroenteropancreatic , lung , and unknown origin . Twenty-two percent received CAPTEM as first-line therapy. After a median of 31 months of follow-up, the two-year overall survival (OS) was 42%, with a median OS of 24 months. There was a trend towards improved median progression-free survival (PFS) in pts with low grade 3 (Ki67<55%) versus high grade 3 (Ki67 \u226555%) NETs . Ten (31.3%) experienced grade 3/4 toxicity, with nausea (15.6%), thrombocytopaenia (12.5%), and fatigue (9.4%) the most common toxicities reported. CAPTEM has significant activity in patients with metastatic grades 2 and 3 NETs with manageable toxicity. The PFS benefit observed in the grade 3 subgroup with Ki67<55% warrants further evaluation in a larger randomized trial. Neuroendocrine tumors (NETs) are a rare, heterogeneous group of tumors classified according to their site of origin, histology, Ki-67 index, and mitotic count .Metastatic well-differentiated low and intermediate grade NETs are typically managed with long-acting somatostatin analogues (SSAs) or biological agents (everolimus and sunitinib) , 3. In cThe role of cytotoxic chemotherapy for patients with well-differentiated intermediate to high grade NETs has evolved over time, though the ideal regimen remains uncertain. Consensus guidelines from the European Neuroendocrine Tumor Society (ENETS) and North American Neuroendocrine Society (NANETS) do not include specific recommendations for a particular chemotherapy regimen. Historically, streptozocin (STZ) regimens (STZ \u00b1 doxorubicin or 5-fluorouracil) were the only approved regimens for patients with metastatic pancreatic NETs (pNETs) \u201313. RespCapecitabine and temozolomide (CAPTEM) has demonstrated significant activity in patients with metastatic well-differentiated pancreatic NETs , 26. HowPeter MacCallum Cancer Centre is the largest comprehensive cancer centre in Australia, a state and national referral centre for NETs patients as well as an ENETS Centre of Excellence. We present our experience with the CAPTEM regimen in patients with metastatic intermediate  and high grade  NETs, including responses based upon functional imaging, survival, and toxicity.This study was a retrospective audit of all patients with metastatic intermediate (WHO grade 2) or high (WHO grade 3) grade NETs who were treated with CAPTEM between March 2013 and March 2017. All patients were deemed ineligible for peptide receptor radionuclide therapy (PRRT) due to the presence of disease sites that lacked sufficient somatostatin receptor expression. Fluorine-18 fluorodeoxyglucose positron emission tomography combined with computed tomography (FDG PET/CT) was routinely performed in the pretreatment evaluation of all patients in addition to SSTR imaging, generally using gallium-68 DOTA-octreotate PET/CT. FDG-avidity or objective evidence of progression of unresectable disease on functional or anatomic imaging was considered adequate indications for active treatment according to treatment pathway guidelines established within the NET Service.Demographic, clinical, and radiological data was collected from patients' electronic medical records. Demographic data included the patient's age, gender, and Eastern Cooperative Oncology Group (ECOG) performance status. Clinical data included date of diagnosis, site of primary NET, Ki67 index, tumor grade, site of metastases, prior therapies received, and date of progression and/or death. Data regarding CAPTEM administration  was als2 bd orally on days 1\u201314 and temozolomide 100 mg/m2 bd orally on days 10\u201314 on a 28 day cycle as per standard schedule with premdications and antiemetics . Baseline characteristics are shown in The best functional imaging response achieved was complete metabolic response in four patients (12.5%) while 11 (34.4%) achieved a partial metabolic response and five (15.6%) had stable disease. The overall objective response rate was 46.9% and the objective disease control rate was 62.5%.After a median of 31 months of follow-up, the median OS for the entire cohort was 24 months (95% CI: 17.1- 30.8) and the two-year OS was 42% . The medPatients with low grade 3 (Ki67 20-55%) had a higher OS compared to those with high grade 3 NETs (Ki67 \u2265 55%)  , as did The median PFS for the entire cohort was 10 months (95% CI: 3.7- 16.2) . The medThe toxicity profile of CAPTEM is shown in The optimal treatment for patients with metastatic intermediate and high grade NETs is not established. A few retrospective and prospective studies have demonstrated activity of CAPTEM in patients with advanced pancreatic neuroendocrine tumors (PNETs) and non-PNETs. There has been considerable difference among the reports with regards to the line of therapy, site of primary (pNET or non-PNET), response evaluation , and even dosing schedule of CAPTEM regimen. Although the numbers are small, this study highlights the improved survival with CAPTEM in first line which needs to be further evaluated in a prospective manner. We observed an objective response rate of 46.9% and a disease control rate of 62.5%. The median PFS was 10 months with a 2-year OS of 42%. In an exploratory analysis of patients who received CAPTEM in the first line, we demonstrated a median PFS of 17 months.This is consistent with previously reported data. In a series of 30 patients with metastatic well- or moderately-differentiated tumors pancreatic neuroendocrine tumors who received CAPTEM in the first-line setting, the response rate was 70% with a median PFS of 18 months . SimilarThere is a wide variation in the clinical course and outcomes of patients with Ki-67 values greater than 20%. This is consistent with the results of our study which suggests that patients with Ki 67 20-55% had improved survival outcomes as compared to patients with Ki 67> 55%.A single prospective phase II study has examined CAPTEM in patients with a variety of metastatic NETs . An inteCAPTEM appears to be relatively well tolerated, with nausea, thrombocytopenia, and anaemia the most common grade 3 or 4 toxicities. Being a retrospective study, the toxicities might not have been adequately captured so it may not be representative for the chemotherapy regimen. However out results are consistent with previous retrospective reports of CAPTEM toxicity , 18, 25.The audit has its limitations of being retrospective and of a small sample size as expected of uncommon tumors. Conversely, the selection of patients for treatment on the basis of functional imaging and, specifically, the requirement for sites of disease with FDG-avidity that lack SSTR expression is likely to have biased the population of G3 NEN towards a poorer prognostic group given the adverse outcomes in such patients , 33. It CAPTEM is an oral chemotherapy regimen which is associated with objectives responses and promising survival outcomes in metastatic well-differentiated intermediate and high grade NETs, including in non-pNET tumors. In particular, survival outcomes in the first-line setting and the low grade 3 (Ki67<55%) subgroup are promising and require further investigation. The toxicity profile of CAPTEM is favorable compared to streptozocin-based regimens and other targeted agents and comparable to other chemotherapy regimens. The ENETs guidelines currently recommend this regimen for patients with intermediate and high grade NETs as a second line therapy . Randomi"}
+{"text": "Although the US has one of the highest per-capita health expenditures in the world, it noticeably lags behind a number of other industrialized countries in terms of life expectancy (LE). These disparities remain unexplained by individual demographic, socioeconomic, and healthcare factors. Analysis of death certificates for 1999-2016 revealed that diseases contributed most to LE variability are myocardial infarction , heart failure (10.6%), stroke (8.2%), lung cancer (7.5%) and COPD (7.2%). Analysis of histories of diseased patients in Medicare records showed that septicemia (15.7%), low weight (13.8%), renal disease (13.3%), disorders of electrolyte and fluid balance (9.0%) and heart failure (7.3%) contributed most to the disparities. Diseases that substantially contribute to disparities in LE in the US include both common and less-often-discussed diseases. Future studies of variations in treatment patterns, access-to and quality-of medical care for these diseases could provide important insight in observed patterns."}
+{"text": "The study investigated the prevalence of stillbirth at the Buea regional hospital, by taking cases of pregnant women who attended antenatal clinic(s) and those who did not attend but had their deliveries at the Buea regional hospital. The study specifically estimated the prevalence of stillbirths; identified possible risk factors associated with stillbirths, and determined whether the number of antenatal clinic visits is related to the occurrence of stillbirths-because during antenatal clinic visits, pregnant women are educated on risk factors of stillbirths such as: preterm deliveries; sex of the stillbirth; history of stillbirth; history of abortion(s); what age group of mothers are more likely to have a stillbirth.st, 2014 to April 30th, 2017. With the aid of a checklist data was collected, analysed and presented with the use of tables, pie-charts and bar charts.The study was a hospital based retrospective study at the maternity in which there were 3577 deliveries registered at the Buea regional hospital dated May 1The prevalence of stillbirths was 26\u2030; possible risk factors associated with stillbirths included: preterm deliveries; women aged 20-29 years; history of abortion(s); a history of stillbirth; sex of stillbirths were more of females than males; and insufficient antenatal clinic attendance  had more stillbirths.The study established that stillbirths can occur in any woman of child-bearing age. possible risk factors associated with stillbirths included: preterm deliveries; women aged 20-29 years; history of abortion(s); a history of stillbirth; gender of stillbirths were more of females than males; and insufficient antenatal clinic attendance  had more stillbirths. Stillbirth is defined as \u201ca baby born with no signs of life at or after 28 weeks of gestation\u201d . It is aStudy design: this study was a hospital based retrospective study. Records at the maternity unit were studied dated from 1st May 2014 to 30th April 2017.Settings and population: all women who gave birth  at the Buea regional hospital.Inclusion criteria: all deliveries at the Buea regional hospital within the time frame. Deliveries dated from May 1st, 2014 to April 30th, 2017.Exclusion criteria: transferred cases of deliveries. Incomplete documented files where not assessed.Sample size and sampling: all delivery files at the Buea regional hospital dated May 1st, 2014 to April 30th, 2017. This study was a hospital based retrospective study of records at the maternity unit.Data collection: the data for this study was collected using a checklist which had two parts; SHEET ONE for the outcome of all deliveries  and SHEET TWO for only women who had stillbirth(s). The checklist was divided into rows and columns which had demographic variables, preterm deliveries, term deliveries and post term deliveries, sex of the stillbirth, history of stillbirth, history of abortion and number of ANC's attended. As well as various age groups . The data obtained was tallied under the various columns with different colours of ink to indicate the various parameters under each age group. This helped facilitated the interpretation of results, for example: a preterm delivery was indicated in black ink, term deliveries in blue ink, post term deliveries in green ink and stillbirths in red ink.Ethical consideration: ethical clearance was obtained from the Faculty of Health Sciences (FHS), University of Buea and was presented at the Regional Delegation of Public Health to seek for authorization to collect the research data and it was approved. A copy of the authorization letter was presented to the director of the Buea regional hospital for approval and a letter of permission was obtained from the director as well as from the general supervisor of the Buea regional hospital.Data analysis: after data was collected, it was entered into a software version where it was checked for its completeness, cleaned and analyzed accordingly. Frequency tables and graphs were used to describe some variables.Presentation and analysis of data: during the period of study, there were 3577 deliveries at the Buea regional hospital, of which 93 were stillbirths giving a prevalence of 26 per thousands. With respect to age, patients were divided into four groups:< 20years; 20-29years; 30-39years; \u226540years.Age range of parturients: among the 3563 parturients, of those less than 20 years (<20years): had 46(1.2%) preterm babies, 160(4.47%) term babies, and 10(0.28%) post term babies. Of those parturients between 20 and 29 years (20-29years); had 237(6.63%) preterm babies, 1812(50.66%) term babies and 66(1.85%) post-term babies. Parturients between 30-39years: had 80(2.24%) preterm babies, 1071(29.94%) term babies and 46(1.29%) post term babies; while for those \u226540years, had 6(0.16%) preterm babies, 40(1.12%) term babies and 3(0.07%) post term babies (m babies .Civil status of parturients: two thousand and ninety one (61.49%) of the women were married and 1372 (38.51%) were unmarried giving a total of 3563 (100%) women.Employment status of parturients: one thousand and fifty eight mothers were employed which gave 52.15% as compared to 1705 mothers who were unemployed which gave 47.85% (e 47.85% .Gender of the babies: there were 2013(56.27%) females and 1564(43.72%) males of the 3577 deliveries  were preterm, 3083 (86.19%) term and 125 (3.49%) post-term deliveries , followed by mothers aged 30-39years, 20(21.5%) and trailed by mothers aged \u226540years 3(3.2%) ( 3(3.2%) .Time of occurrence  of stillbirth: stillbirth occurred most in pre-terms 56(60.2%), followed by term births - 31(33.3%) and lastly 6(6.5%) stillbirth in post-term (ost-term . 53(57%)ost-term .History of stillbirths: of the 93 stillbirths, 3(3.20%) mothers had a history of stillbirth as compared to 90(96.86%) who had no history of stillbirth  have had an abortion in the past as compared to 86(92.5%) mothers who did not have an abortion  was recorded by parturients with \u22641 ANC; 21 stillbirths (22.6%) recorded by parturients with 2 ANC; 10 stillbirths (10.8%) recorded by parturients with 3 ANC and 3 stillbirths (3.2%) recorded by parturients \u22654 ANC  had 46(1.2%) preterm babies, 1604.47%) term babies, and 100.28%) post term babies. Those aged between 20 and 29 years (20-29years); had 237(6.63%) preterm babies, 1812 (50.66%) term babies and 66(1.85%) post-term babies. Parturient aged between 30-39years: had 80(2.24%) preterm babies, 1071(29.94%) term babies and 46(1.29%) post term babies; while for those aged \u226540years, had 6(0.16%) preterm babies, 40(1.12%) term babies and 3(0.07%) post term babies. There were 3577 deliveries at the Buea regional hospital, of which 93 were stillbirths giving a prevalence of 26 per thousands. The stillbirth rate of 26 per thousand in this study equals that reported in the year 2009 in Cameroon [% term ba% post teStillbirths occurred more in mothers who had attended fewer antenatal clinic. It occurred more in mothers who attended \u22641 ANC which was 59 stillbirths (63.4%); 2 ANC attendance which was 21 stillbirths (22.6%); 3 ANC after which accounted for 10 stillbirths (10.8%) and those with \u22654 ANC attendance had the least number of 3 stillbirths (3.2%). Furthermore, other reported risk factors for stillbirths were: maternal syphilis, maternal malnutrition; and lack of antenatal care: which improving the use of antenatal care, and nutritional status of the mother could effectively contribute towards reducing the unacceptably high burden of stillbirths in developing countries . ResultsLimitation of the study: records were not well organized, making the task of data collection difficult.It was concluded that, the prevalence of stillbirths was 26 per thousand, possible risk factors associated with stillbirth includes: the gestational age of the baby - prevalent in preterm deliveries; age (20-29years); females are more prone to stillbirths than males; a history of abortion; and insufficient ANC attendance (\u22641 ANC attendance) are at high changes of having a stillbirth.The prevalence of stillbirth;Possible risk factors associated with the occurrence of stillbirths;Which areas of the globe have the least or highest occurrence of stillbirths.Educates health personnels and researchers about the prevalence of stillbirths;It also educates health personnels and the population at large on some possible risk factors of stillbirth and what can be done to lower it;It reveals an estimate on what the present occurrence of stillbirth might be in our setting and helps to fight against some cultural beliefs in our setting because when pregnant women come for ANC, they are educated for example on their feeding habits because some of them say when they eat roasted plum, it makes the baby to be dark in complexion when delivered.The authors declare no competing interests."}
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+{"text": "S-Cong Jiang. The correct spelling is Si-Cong Jiang. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.An author name was incorrectly spelled as"}
+{"text": "Ninf. Please view the complete, correct equation here:In the Time to the most recent common ancestor subsection of the Results, there is an error in the equation. The notation N in parentheses is incorrect. It should read"}
+{"text": "The Editor-in-Chief and the publisher have retracted this article . An inveAdas Darinskas and Thomas E. Ichim disagree with this retraction. The other authors did not respond to any correspondence about this retraction."}
+{"text": "The third author\u2019s name is spelled incorrectly. The correct name is: Chenyang Cai.An additional affiliation is missing for the sixth author. Jiabin Cai is also affiliated with Co-innovation Center of Efficient Processing and Utilization of Forest Resources, Nanjing, Jiangsu, China.The publisher apologizes for the errors."}
+{"text": "Data Availability statement. The original statement is as follows:In the original article, there was an error in the https://db.cngb.org/cnsa/). Data of this project could be accessed after an approval application. Please refer to https://db.cngb.org/, or email: CNGBdb@cngb.org for detailed application guidance. The accession code CNP0000425 should be included in the application.\u201d\u201cThe datasets that support the findings of this study are deposited under supervision and control in the China National Genebank , no additional data are available at this time. Data of this project can be accessed after an approved application to the Ministry of Science and Technology of the People's Republic of China (http://www.most.cn/bszn/new/rlyc/fwzn/). Please refer to https://fuwu.most.gov.cn/html/bszx/xzxkl/20190630/2907.html for detailed application guidance. The accession code CNSA-CNP0000425 should be included in the application.\u201d\u201cAccording to national legislation/guidelines, specifically the Administrative Regulations of the People's Republic of China on Human Genetic Resources (The authors apologize for this error and state that the revision does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "The funding details of ADNI can be found at: Alzheimer's Disease Neuroimaging Initiative (ADNI) was not included as an author in the published article. The corrected Statement appears below.http://www.adni-info.org/ for up-to-date information).The ADNI project that provided Caucasian data was launched in 2003 as a public-private partnership, led by Principal Investigator Michael W. Weiner (see The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "Supplementary Figure 1 and Supplementary File as published. The MoCA-Hil instructions were erroneously published as Supplementary Figure 1. This is supposed to be the MoCA-Hil tool. MoCA-Hil is under copyright of Z. Nasreddine MD and is reproduced with permission. Copies are available atwww.mocatest.org. Supplementary File did not follow the prescribed format for reproductionIn addition, the published MoCA-Hil instructions which appear under . The corrected Supplementary Figure 1 and Supplementary File have been published.In the original article, there was a mistake in The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "In the original article, the incorrect names were indicated as the last name for the three authors for Fang et al. 2017. They should be \u201cHwu, F. Y., Lai, M. W., and Liou, R. F.\u201d and so the reference should now change to Hwu et al. 2017.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "Following the review of the open source data file mentioned in the Data Availability Statement (S1 Data), there are discrepancies with some of the variables provided in the open source data, meaning that the results in the published manuscript cannot be re-produced from the open source data file. The data available on Figshare has been updated.https://doi.org/10.25392/leicester.data.9860807.v1).The Data Availability Statement should therefore read: Data to reproduce the analysis are available on Figshare ("}
+{"text": "Drosophila model). Evgenii is a PhD student in the lab of Dmitry Afonnikov at the Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, investigating information technologies in genetics.First Person is a series of interviews with the first authors of a selection of papers published in Biology Open, helping early-career researchers promote themselves alongside their papers. Evgeniya Karpova and Evgenii Komyshev are co-first authors on \u2018 Evgeniya Karpova and Evgenii KomyshevWhat is your scientific background and the general focus of your lab?E.K.K.: I am a postdoctoral researcher in the laboratory of stress genetics led by Nataly Gruntenko at the Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, investigating genetic and physiological basis of stress response to Drosophila as a model.E.G.K.: I am a PhD student in the sector of Bioinformatics and Information Technologies in Genetics led by Dmitry Afonnikov at the same research center.E.K.K. & E.G.K.: We work in different areas, and the combination of experimental and technical expertise allowed us to develop a method for automation of imago quantifying and fecundity assessment in Drosophila with the use of mobile devices running the Android operating system.How would you explain the main findings of your paper to non-scientific family and friends?E.K.K.: The synthetic theory of evolution understands fitness as reproductive success, i.e. the ability of an individual to produce offspring and thus transfer its genes. This is why fecundity is the most frequently used parameter for the estimation of fitness in insects. Although offspring calculation is conceptually simple, in practice it is a laborious task. We optimized, tested, and introduced a new method of automated count of Drosophila adults using the SeedCounter mobile application. The application is available on all mobile devices based on the Android system, and it does not require any additional equipment. It makes accurate calculations and can seriously save time for anyone who faces the unenviable task of counting fecundity in flies.E.G.K.: This application allows users to quickly and accurately calculate the number of offspring in a wide range of values. The estimates of flies fecundity obtained with the use of the mobile app were compared with the results of manual counts of the same samples. The data show a good correspondence of the number of flies obtained manually and with the help of the mobile app, which indicates its high accuracy and efficiency.What are the potential implications of these results for your field of research?E.K.K.: The traditional manual method of counting the progeny takes a long time and limits the opportunity of making large-scale experiments. A development of computer methods that would allow us to automatically make a quantitative estimate of Drosophila melanogaster fecundity is an urgent task. With the use of the mobile application SeedCounter that analyzes images of objects placed on a standard sheet of paper, we would be able to study D. melanogaster fecundity in large samples. The method would also be useful for quantifying numbers of adult flies in longevity or viability experiments.E.G.K.: Surprisingly, the SeedCounter application, which was originally developed for counting and measuring wheat grains, performed well in the task of counting D. melanogaster flies. The changes made to the application to process D. melanogaster images were quite small. This gives us reason to believe that our application can be used to count other biological objects of the similar size.What has surprised you the most while conducting your research?E.K.K.: I was amazed at how much modern technique can facilitate the work of an ordinary biologist. You must always try to find opportunities to use new techniques to improve the efficiency of scientific work and never stop there.E.G.K.: I was surprised that in the digital images we captured, you can estimate the body shape of D. melanogaster, which in turn could be used to determine their gender in the future.\u201cI was amazed at how much modern technique can facilitate the work of an ordinary biologist.\u201dWhat, in your opinion, are some of the greatest achievements in your field and how has this influenced your research?E.K.K. & E.G.K.: Recently the methods using mobile devices for analyzing the images of biological objects have developed rapidly. Modern mobile devices (smartphones and internet tablets) have high resolution digital cameras and multi core processors with enough processing power for image processing and analysis. These functions allow users to take and process images where it is necessary and make a rapid and accurate count. We have taken this as our inspiration to suggest a method that helps us to measure fecundity by adult progeny emergence in Drosophila with the use of mobile devices.What changes do you think could improve the professional lives of early-career scientists?E.K.K.: In my opinion, the main thing for a young scientist is to choose an interesting topic that will inspire him or her to research and benefit all of humanity. However, early career researchers lack experience. A friendly team and effective communication with colleagues can help young researchers learn a lot and move in the right direction.E.G.K.: In my opinion, the professional lives of early-career scientists could improve the expanding introduction of new technologies and the use of modern tools, which are currently appearing more and more. Modern technologies allow you to measure and evaluate what was previously impossible, or too labor-intensive. These innovations can significantly facilitate routine operations, as well as improve the accuracy, objectivity and efficiency of modern experiments.What's next for you?E.K.K.: I hope the new method will increase the quality and speed of my research in the field of adaptation to adverse environmental conditions. In particular, the detection of long-term effects of regular stress exposure in the D. melanogaster model. In the future, these studies can help to find the way to improve stress resistance in different biological objects including humans, which is very important in our time.E.G.K.: We plan to improve our app: expand its functionality and availability, and improve its usability. We hope that as many researchers as possible will discover SeedCounter as a useful tool in their work."}
+{"text": "The authors wish to make a change to this published paper . In the https://www.mdpi.com/2218-273X/10/3/416.The authors apologize for any inconvenience caused, and we wish to stress that this change does not affect the presented scientific results and statistical analyses. The manuscript with be updated and the original will remain online on the article webpage at"}
+{"text": "Detecting the existence of SARS-CoV-2 in the indoor atmosphere is a practical solution to track the prevalence and prevent the spread of the virus. In this work, a thermophoretic approach is presented to collect the novel coronavirus-laden aerosols from the air and accumulate to high concentrations adequate for the sensitivity of viral RNA detection. Among the factors, the density and particle size have negligible effects on particle trajectory, while the vertical coordinates of particles increase with the rise in heating source temperature. When the heating temperature is higher than  I.et al.et al.The outbreak of Coronavirus disease 2019 (COVID-19) pandemic has caused a dramatic impact on healthcare services and economies in the affected countries.et al.An aerosol is defined as a suspension system of solid or liquid particles in the air or another gas.Keeping social distancing is expected to be effective to prevent infection via bioaerosol contact.II.Due to a study conducted in Singapore,In this study, a 2D model of the device is considered to investigate the performance of thermophoretic separation and collection of virus-laden aerosols. The main component of the device is a channel, and the bottom wall of which is connected with a heating source. Driven by the thermophoretic force, the particles will move upward and exit the channel through the upper outlet. The length of the channel is 415\u2009mm, including an inlet region of 160\u2009mm, a thermophoresis region of 220\u2009mm, and an outlet region of 35\u2009mm. The geometric structure of the device is shown in In the evaluation of RNA stability of SARS-CoV-2 under thermal treatment, the virus was inactivated after being heated at III.A.et al.Thermophoresis is an important transport mechanism of small particles in a non-isothermal carrier fluid driven by the temperature gradient. Particles suspended in a non-isothermal mixture subject to a force pushing them in the direction of the temperature drop. The driving mechanism behind this force is the collision of gas molecules on the particles\u2019 surface. Collisions are more likely to occur on the hotter side of the particle where the average molecular velocity of the gas is greater. This results in a net force toward colder regions of the gas. Particle with different physical properties exhibit different responses to the force, which realizes sorting and separation. In gas media, the thermophoretic force acting on a suspended particle depends on the flow regime characterized by the Knudsen number B.This model is composed of flow field, temperature field, and particle tracing. The flow field is characterized by Navier\u2013Stokes equations,Heat transfer in fluids is characterized byet al.The trajectory of the particle in the fluid flow is characterized byBrownian motion is the random, uncontrolled movement of particles in a fluid as they constantly collide with other molecules, which leads to spreading of particles from regions of high particle density to low density.mm, with temperature 293.15\u2009K. The boundary condition of the outlet has a relative pressure Air and aerosols are injected into the domain, carried by an air flow of 2000 IV.A.The numerical simulation is conducted on a desktop PC with Intel(R) Core(TM) i7-6700 CPU and 32 GB physical RAM. et al.The validation of the model presented in this study is investigated by comparing with the results of Eslamian B.In this study, the numerical simulations are conducted to investigate the particle trajectories of aerosols in a laminar flow of carrier fluid in a channel shown in The real-time trajectories of aerosol particles are shown in Due to the thermal gradient, aerosols are driven by thermophoretic force to move upward and then exit the channel through the upper outlet. On the horizontal direction, the particles are carried by the inertia force and move right with the carrier fluid. On the vertical direction, the particles are driven by buoyancy and thermophoretic forces to move upward, whereas the gravity acts downward. Gravity and buoyancy forces are proportional to the particle diameter cubed, while the thermophoretic force is linearly proportional to the particle diameter. Since the density of aerosol particles is close to the carrier fluid, the buoyancy can be almost balanced by gravity. Therefore, the trajectories of particles with varying sizes showed a tiny divergence on the vertical direction, while the density and particle size have negligible effect on particle trajectory. According to Eq. According to V.In this study, thermophoresis is adopted as a novel technique to collect and accumulate virus-laden aerosols from indoor air. Numerical simulations were conducted by coupling the transfer equations of heat and mass transfer with particle tracing for the fluid flow. The availability of this device was verified and suitable operation conditions were determined based on the simulation and the parameters acquired from articles and experiments. It has been acquired that thermophoretic force is significant to drive the virus-bearing aerosols to move upward and accumulate at the cold side. When the heating temperature is higher than 355\u2009K, all the particles exit the channel through the upper outlet, thus achieving the collecting of virus-laden aerosols. Considering the stability of viral RNA, a suitable range (A.X.Z. and F.Y.R. proposed the research and designed the numerical work; A.X.Z. conducted the simulation; A.X.Z. and F.Y.R. wrote the manuscript; and B.J.W., C.C.W., D.Z.L., E.Y.S., and G.Y.Y. contributed to the discussion of the data and review of the manuscript."}
+{"text": "This Retraction follows an Expression of Concern relating to this article previously published by Portland Press.This article is being retracted from Bioscience Reports at the request of the authors following receipt of a notification from a reader, alerting the authors to the duplications in Figure 4A as well as duplicated figures from another published article by the same authors in Zhongguo Shi Yan Xue Ye Xue Za Zhi (10.19746/j.cnki.issn1009-2137.2019.02.046).The authors wish to retract the article. The Editor-in-Chief and Editorial Board agree with the retraction."}
+{"text": "Conflicts of Interest: F.U. and C.M. are co-founders of an academic spin-off of the University of Eastern Piedmont called noiVita s.r.l.s. None of the authors have obtained any commercial profit from this paper. The rest of the authors declare no conflicts of interest.The authors would like to publish this addendum to their recent publication  to declaWe apologize for any inconvenience to the readers this oversight may have caused."}
+{"text": "The authors wish to make a change to the published paper . We wishhttps://www.mdpi.com/2073-4360/12/7/1592.The authors apologize for any inconvenience caused and the change does not affect the scientific results. The manuscript will be updated, and the original will remain online on the article webpage at"}
+{"text": "Zhai Y and Chen Q performed the experiments. Wang YZ and Li X analyzed the data. Zhai Y and Li LN contributed analysis tools. Zhai Y, Li LN and Chen Q provided critical inputs on design, analysis, and interpretation of the study. All the authors had access to the data. All authors read and approved the final manuscript as submitted."}
+{"text": "Indirect support was provided through salaries by the home institutions of all co-authors. Inertia-Technology B.V. provided support in the form of salary for author SB. Rosmark Consultancy provided support in the form of salary for author JPV. The specific roles of these authors are articulated in the \u2018author contribution\u2019 section. The funders did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.There are errors in the Funding statement. The correct Funding statement is as follows: Swedish-Norwegian Foundation for Equine Research ("}
+{"text": "The authors wish to make a change to the published paper . In the https://www.mdpi.com/2073-4360/11/9/1490.The authors apologize for any inconvenience caused and the change does not affect the scientific results. The manuscript will be updated, and the original will remain online on the article webpage at"}
+{"text": "Dr. Luigi Boccuto was not included as an author in the published article. The corrected Author Contributions Statement appears below.HH, CT, and LW contributed to the writing of the manuscript. LW and CT supervised the project and provided clinical images. LB contributed to the conceptualization, design, and editing of the manuscript. All authors contributed to the article and approved the submitted version.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "Dear Mr. Editor,The cervical ectopic pregnancy is a very rare condition that accounts for less than 1% of all ectopic pregnancies  is priceIn fact, fertility preservation is a major and common demand of most patients suffering from cervical ectopic pregnancy. Recent studies have shown that 75% of these patients desire future fertility . MoreoveThere were no sources of funding.No ethical approval was needed.No consent was needed.Antoine Naem: Reviewed the literature and wrote the manuscript.Bashar Al-Kurdy: Supervised the writing process and revised the manuscript.N/A.Mr. Antoine Naem.All of the authors declared that they have no conflict of interest."}
+{"text": "Beibei Wu was not included as an author in the published article. The corrected Author Contributions Statement appears below.ME designed the study and prepared the first draft, figures, and tables. HP, ME, and BW did the data analysis. ZJ collected the samples and did the microbiological isolation. SB and YL reviewed the manuscript. MY and ME finalized the manuscript and managed the project. All authors contributed to the article and approved the submitted version.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "Sci., 2019, DOI: ; 10.1039/c9sc04060a.Correction for \u2018Synergistic catalysis on Fe\u2013N The Royal Society of Chemistry regrets that the email addresses for the corresponding authors were not included in the original article.songtao@qibebt.ac.cn.The email address for Tao Song is Email: yangyong@qibebt.ac.cn.The email address for Yong Yang is Email: The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "In the published article, the order of the first name and the surname of the authors was incorrect. The first name of the first author was swapped with his middle name.Mosoi A. Alexandru, Beckmann J\u00fcrgen, Mirifar Arash, Martinent Guillaume and Balint Lorand.The names of the authors were incorrectly spelled as Adrian A. Mosoi, J\u00fcrgen Beckmann, Arash Mirifar, Guillaume Martinent and Lorand Balint.The correct spelling of the authors' names is The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "The authors wish to make a change to the published paper . In the https://www.mdpi.com/2076-2615/10/12/2380.The authors apologize for any inconvenience caused and the change does not affectthe scientific results. The manuscript will be updated, and the original will remain online on the article webpage at"}
+{"text": "A. lumbricoides incidence was associated with mean minimum temperature of the state, the state-wide rate of households without access to piped water and toilet, explaining 77% of the incidence of A. lumbricoides infections. Mean minimum precipitation in the state, the rate of households without access to a toilet, piped water and sewage system best explained (73%) the incidence of E. histolytica infections. G. lamblia infections were only explained by the latitude of the state (11%). In addition to the well-known socioeconomic factors contributing to the incidence of A. lumbricoides and E. histolytica we found that temperature and precipitation were associated with higher risk of infection.The aim of this study is to provide an overview of the geographical distribution of Ascariasis, Amebiasis and Giardiasis, and to identify specific geographical, socioeconomic and environmental factors that are associated with the incidence of these infections in Mexican children. We made use of publicly available data that was reported by federal organizations in Mexico for the year 2010. The contribution of geographical, socioeconomic and environmental factors to the incidence of infections was assessed by a multivariable regression model using a backwards selection procedure.  Ascaris lumbricoides (A. lumbricoides) with a prevalence between 16% and 33% depending on the region of the country and Giardia lamblia (G. lamblia) on the other hand, are responsible for malabsorption, diarrhea, blood loss and reduced growth, and thus SINAVE requires case notification for these two pathogenic intestinal protozoa , in which all the relevant variables were publicly available.A. lumbricoides, E. histolytica and G. lamblia) were obtained from the SINAVE from children aged 5 to 9\u00a0years. The data is publicly available at: http://www.epidemiologia.salud.gob.mx. Medical doctors of all health facilities of the country report laboratory confirmed cases of A. lumbricoides, E. histolytica/dispar and G. lamblia infections by age group through the SINAVE webpage, which is a national reporting system following standard procedures to ensure the quality of the data .We selected all the available geographical and environmental variables that are known to be associated with intestinal parasitic infections  were selected to be used in a multivariable linear regression model, one for each parasite. The best multivariable model was obtained with a backward procedure with an with an entry level of 0.15 and a threshold for inclusion into the final model of 0.1 . For internal validation we obtained bootstrapped estimates  and compared these changes to the empirical dataset . The unit of mapping was \u201cthe state\u201d the largest administrative unit of Mexico. The maps were generated using R studio ggplot2 package .A. lumbricoides was of 153.1 (SD\u2009=\u2009211.1), the incidence of E. histolytica/dispar was of 549.3 (SD\u2009=\u2009325.1) and the incidence of G lamblia was of 35.2 (SD-35.8). The incidence of A. lumbricoides and E. histolytica was highest in the southern states of Veracruz, Tabasco, Yucatan and Oaxaca and the incidence of G. lamblia was highest in the northern states of Baja California and Sinaloa and the southern state of Yucatan , showed that the mean minimum temperature of the state, the state-wide rate of households without access to piped water and the rate of households without access to a toilet are the variables that best fit the incidence of A. lumbricoides incidence , increasing the likelihood of infection(Bray and Harris Environmental factors showed to be important predictors for the incidence of G. lamblia infection incidence in Mexican children was the latitude of the state. However, the model only explained 11% of the incidence of this parasite. In contrast to our results, other studies assessing the risk factors for G. lamblia at individual level have shown that low education, lack of sewage system and toilets are associated with this parasite as well (Cifuentes et al. G. lamblia. G. lamblia incidence is influenced by unpredictable outbreaks, usually associated with contaminated food and water sources, these outbreaks could potentially change the geographical distribution of the parasite despite the socioeconomic and environmental risk factors (Wearing et al. The only factor associated with This study has limitations that need to be addressed for proper interpretation of the results. There are other factors that are known to affect the incidence of intestinal parasites and were not measured, such as malnutrition and migration (Buonsenso et al. A. lumbricoides and E. histolytica/dispar we found that temperature and precipitation were associated with higher risk of infection. More research is needed to evaluate the effect of climate change on the incidence of A. lumbricoides and E. histolytica/dispar.In addition to the well-known socioeconomic factors contributing to the incidence of"}
+{"text": "Qin QX and Wang JJ performed the experiments. Qin QX and Wang JJ analyzed the data. Qin QX and Wang JJ contributed analysis tools. Qin QX, Wang JJ and Wang H provided critical inputs on design, analysis, and interpretation of the study. All the authors had access to the data. All authors read and approved the final manuscript as submitted."}
+{"text": "Correction to: Archives of Osteoporosis (2020) 15: 15410.1007/s11657-020-00814-4The authors were made aware of the misuse of references and erroneous work by Sato and colleagues in our paper. Therefore, the reference as well as any citation of the reference has been removed. This erratum does not affect the findings in our research paper. The authors and the journal regret the error.We wish to thank Jose Moran et al. for bringing this to our attention."}
+{"text": "In the original published version of this article, the text did not cite the following source as a reference: Alobayli, F.Y., 2019. Factors influencing nurses' use of local anesthetics for venous and arterial access. J. Infusion Nurs. 42 (2), 91. The authors apologize for this error. Both the HTML and PDF versions of the article have been updated to correct the error."}
+{"text": "Instituto de Salud Carlos III, RETICS  INVICTUS PLUS and FEDER is RD06/0019/0010. The corrected Funding statement appears below.There is an error in the Funding statement. The correct number for Instituto de Salud Carlos III, RETICS  INVICTUS PLUS and FEDER. The corrected Funding statement appears below.There is an error in the Funding statement. The correct Name for the Funder is The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "Ulex europaeus in two different habitats, and discuss the driver of the differences, including rhizobia. The magnitudes of leaf allelopathy of the samples collected in two different habitats were assessed by comparing the hypocotyl and radicle lengths of the lettuce seeds tested on the samples. One habitat was in and adjacent to an Acasia koa forest, while the other was more than 50 m away. A. koa is indigenous to Hawaii and known to have a close symbiotic relationship with Bradyrhizobium for nitrogen-fixing. Within the past three years, U. europaeus has newly invaded both sampling sites, whereas the A. koa forest has been there for several decades. The combined result of both hypocotyl and radicle lengths of the lettuce seeds tested on both sites by linear model and multicomparison analyses showed no significant difference. But the radicle lengths of the lettuce seeds tested on U. europaeus sampled in and adjacent to the A. koa forest were significantly longer than those of the samples more than 50 m away, as measured by t-test (p = 0.05). This result suggested that the magnitude of the leaf allelopathy of U. europaeus depended on the distance of the habitat from the A. koa forest.The objective of this study was to assess the magnitudes of the leaf allelopathy of  Ulex europaeus L., which belongs to Fabaceae, is a common native species in the Atlantic coast of Europe, e.g., in the United Kingdom, France, Spain, or Portugal [Gorse, Portugal . It was Portugal , and hasPortugal . It has U. europaeus, which belongs to the Fabaceae family, is known to have a symbiotic relationship with the rhizobia Bradyrhizobium [Bradyrhizobium in soil is key to the successful invasion of U. europaeus [Plant legume species are known to have symbiotic relationships with rhizobia, i.e., soil-inhabiting bacteria in the root nodules . Rhizobihizobium , and theuropaeus . U. europaeus differs significantly according to the habitat [U. europaeus to compete with other species. Bertin et al. [U. europaeus; specifically, on its activities in the rhizosphere.In addition, allelopathy is known as another strategy used by invasive species to adapt to new environments ,8. Allel habitat , allelopn et al.  stated tU. europaeus bushes are often seen adjacent to Acacia koa forests. A. koa, indigenous to Hawaii and belonging to the Fabaceae family, is known to have a symbiotic relationship with Bradyrhizobium [U. europaeus in the A. koa forest, the forest has been greatly diminished, and the lone A. koa tree left in the epicenter of U. europaeus bushes seems to have been weakened and disappeared in the future . In brief, our hypothesis of the prioritized invasion sequence of U. europaeus in relation to A. koa is that it weakens the allelopathy against A. koa at the beginning to utilize the Bradyrhizobia on its root, and starts expelling A. koa by strong allelopathy after gaining Bradyrhizobia in the nodules that start fixing enough nitrogen for adaptation. Leary et al. [Bradyrhizobium used by A. koa in Hakalau Forest on Hawaii Island, which is far from the U. europaeus-infested area, and those used by U. europaeus in the periphery and epicenter of the infested area. Two same box-PCR fingerprint types of Bradyrhizobium used by the two plant species were found, and one common type used by A. koa was also used by U. europaeus; this was the dominant type in A. koa. The chemical structure of nod factor receptors (NFRs) released from the rhizobium enables the rhizobium and the plant species to identify each other; the relationship mutually recognizes the rhizobium and the plant [U. europaeus is thought to find the three box-PCR fingerprint types of Bradyrhizobium by the unique NFRs at the beginning of the invasion. If the dominant types of Bradyrhizobia used by U. europaeus are ubiquitous in the soil, U. europaeus does not need to rely on the three types of Bradyrhizobia, which are common in A. koa, to adapt to the new habitats on Hawaii Island. However, it is thought to be a natural process for U. euroapeus to start using the three box-PCR fingerprint types of Bradyrhizobium, which are known to be used by both A. koa and U. europaeus at the beginning of the invasion if there is the little dominant type of Bradyrhizobia available for U. europaeus. The aim of this study was to discuss our hypothesis by comparing the results of the assessment related to the magnitudinal difference in the leaf allelopathy according to the habitats.In the southeast flank of Mauna Kea on Hawaii Island, hizobium . After ty et al.  reportedhe plant . U. euroA. koa forest, altitude: 1888 m) and 19\u00b041\u203214.0\u2033 N and 155\u00b026\u203246.2\u2033 W  on March 8, 2018  and partially covered by Kikuyu grass (Pennisetum clandestinum). The A. koa forest is several decades old, and grows on the substrate called \u201ckipuka,\u201d similar to a sandbank made by the lava flows from Mauna Loa eruption in 1843 [U. europaeus trees in and adjacent to the kipuka are sparsely distributed in A. koa forest. Each mother tree of U. europaeus away from the A. koa forest is isolated and is growing in the middle of the lava flow of the Mauna Loa eruption [The leaf samples were obtained from seven mother trees on Hawaii Island at coordinates 19\u00b041\u203213.6\u2033 N and 155\u00b026\u203244.2\u2033 W  of cv. Great Lakes is universally used as a test plant because its seeds germinate rapidly and grow uniformly [A. koa forest, and more than 50m away from the forest . By comparing the combined results of the hypocotyl and radicle lengths of the lettuce seeds tested on two different habitats, no significant difference was found (A. koa forest and those tested on the leaves sampled more than 50m away from the A. koa forest were not significantly different (A. koa forest were significantly longer than those tested on the leaves sampled more than 50 m away (p = 0.05, The radicles and hypocotyls of the lettuce seeds tested on the leaves from the two different habitats were both significantly shorter than those of the control (by as found . The hypifferent , but theU. europaeus against other species, maybe including A. koa, was strong. Focusing on the relationship of the leaf allelopathy and the distance from the A. koa forest, the magnitude of the leaf allelopathy was weaker in the leaves in and adjacent to the A. koa forest compared to those from the other sampling site, because the leaf litter leachate normally strongly enhances the growth of radicles [U. europaeus greatly depends on the existence of Bradyrhizobium [A. koa, which has a symbiotic relationship with Bradyrhizobium. Specifically, U. europaeus of the sampling sites, which are located in the new invasion area, is suggested to lack a common Bradyrhizobia type for both species, because it is still in the early stages of adaptation. However, A. koa seemed to be a competitive target for U. europaeus because the allelopathy of the leaves of U. europaeus grown in and adjacent to the A. koa forest was suggested to be stronger compared to the control (A. koa and U. europaeus, U. europaeus may outcompete A. koa to obtain sunlight for photosynthesis. As mentioned, three common types of Bradhyrhizobia for both species have been reported [U. europaeus may rely on the common symbiont of A. koa until it obtains its dominant type of Bradyrhizobia in the early stages of adaptation. Given that there was the abundant dominant type of Bradyrhizobium for U. europaeus except for in the U. europaeus-infested area in the study covering all genetic types of Bradyrhizobia of Hawaii Island, the hypothesis may be different. However, study to identify all the genetic types of Bradyrhozobia in the soil of Hawaii Island has not been done yet, and it could be even impossible. Furthermore, the magnitude of allelopathy of U. europaeus leaves of the mother trees, which have invaded areas in and adjacent to the A. koa forest in the past three years, should be tested and compared to the data of this study. If the magnitude of the leaf allelopathy of the leaves of the mother trees older than three years and grown in and adjacent to the A. koa forest is significantly stronger than that of the leaves sampled in the same habitat for this study, U. europaeus may have proceeded to the next sequence of adaptation in relation to A. koa. In addition, the interaction between other types of symbiotic nitrogen fixation, such as the genera of the bacterial group Frankia and Myrica faya, which are also seriously invasive in Hawaii, should be investigated in terms of invasion strategies to better understand our hypothesis in general.The results suggest that the leaf allelopathy of radicles . As the hizobium , the all control . After oreported . U. euroA. koa forest were significantly shorter than those tested on the samples from more than 50 m away. This may be related to multigenic factors, including allelochemicals exuded from many parts of U. europaeus. However, the symbiotic relationship of U. europaeus with Bradyrhizobia in the new invasion sites is important because it causes a magnitudinal difference in the leaf allelopathy, depending on the habitats.To conclude, the results of this study show that the radicle lengths of the lettuce seeds tested on the leaf samples obtained from the mother trees in and adjacent to the"}
+{"text": "The authors wish to make a change to their published paper . In the The strain developed as a response to the applied electrical field results from the diffusion of the ions and migration to the positive (anions) and negative (cations) electrode layers, and subsequent accumulation close to the electrodes.https://www.mdpi.com/2073-4360/12/5/1187.The authors apologize for any inconvenience caused, and the change does not affect the scientific results. The manuscript will be updated, and the original will remain online on the article webpage at"}
+{"text": "Establishment of a CRISPR/Cas9-based strategy for inducible protein dimerization. microPublication Biology. In the version of the microPublication originally published online, the last name of the first author was misspelled. The correct spelling is Zielich. This mistake has been corrected online. The spelling was correct in the original PDF version."}
+{"text": "The Supporting Information can be accessed at https://asanchez-tojar.github.io/code_in_ecology/supporting_information.html.The Data Availability Statement is missing from this paper. The publisher apologizes for this error. The correct Data Availability Statement is as follows: Data and code to reproduce the results are available from"}
+{"text": "In this regard, Aylward et al.  utilizedshrinkage.Visual inspection of parameter estimates  has been criticized in the literature because it biases the results toward an alternative hypothesis .All codes used in the analysis are available on the Open Science Framework (https://doi.org/10.17605/OSF.IO/UB6J7).Datasets used in this study are reuse of open datasets on the Open Science Framework (MS and KK provided theoretical input and designed this study. MS analyzed the data. MS and KK wrote the manuscript. Both authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The authors wish to make a change to the published paper . In the https://www.mdpi.com/2073-4360/11/11/1822.The authors apologize for any inconvenience caused, and this change does not affect the scientific results. The manuscript will be updated, and the original will remain online on the article webpage at"}
+{"text": "In the original article, there was an error. Specifically, the Data Availability Statement was incorrect.A correction has been made to the Data Availability Statement. The correct statement should read:aqjones@uoguelph.ca).The datasets generated for this article are not readily available because of ethical restrictions. Requests to access the datasets should be directed to Dr. Andria Jones-Bitton (email: The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "The authors wish to make a change to the published paper . In the https://www.mdpi.com/2073-4360/11/9/1487.The authors apologize for any inconvenience caused and the change does not affect the scientific results. The manuscript will be updated, and the original will remain online on the article webpage at"}
+{"text": "Indirect support was provided through salaries by the home institutions of all co-authors. Inertia-Technology B.V. provided support in the form of salary for author SB. Rosmark Consultancy provided support in the form of salary for author JPV. The specific roles of these authors are articulated in the \u2018author contribution\u2019 section. The funders did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.There are errors in the Funding statement. The correct Funding statement is as follows: Swedish-Norwegian Foundation for Equine Research ("}
+{"text": "Cell Death & DiseaseCorrection to: 10.1038/s41419-020-03231-0 published online 30 November 2020The original version of this article unfortunately contained a mistake. The authors omitted to include the acknowledgement section. The authors apologize for the mistake. The original article has been corrected.Acknowledgments.We thank Mr. Gilles Dubuis for his expert technical assistance. We also thank, at the University of Lausanne, the Cellular Imaging Facility for its support in image acquisition, the Genomic Technologies Facility for its support in sequence generation and analyses, and the Biostatistics platform for its counseling and statistical method validation."}
+{"text": "In the original publication of the article, the name of one of the authors is incorrect. The author's name is Eiso AB, but was modified to A. B. Eiso. The correct name is given in this Correction."}
+{"text": "Catanese Jr, which was incorrectly given as Daniel J. Catanese. This has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Correction to:Oncogene10.1038/s41388-019-0712-y; published online 11 February 2019.The original version of this article contained an error in Fig. 5a where the colours of the labels representing the Hinge and LBD of the AR were incorrect and did not match the corresponding exons. The corrected version of this Figure now appears in the article. The conclusions of this paper were not affected. The authors apologise for this error and any confusion caused."}
+{"text": "The authors wish to make a change to the published paper . In the https://www.mdpi.com/2073-4360/11/11/1855.The authors apologize for any inconvenience caused and the change does not affect the scientific results. The manuscript will be updated and the original will remain online on the article webpage at"}
+{"text": "In the original article, there was an error in the URL provided in Data Availability Statement. The updated statement appears below.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.http://flowrepository.org/id/FR-FCM-Z2XE.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. Debarcoded files are uploaded to Flow Repository"}
+{"text": "Following a reassessment of the contribution of Dr. Dalit Barkan to discussions on the database presented in the manuscript, the authors came to the conclusion that her name should be included in the author list.SB and SS isolated macrophages extracted RNA and performed bioinformatics analysis of the sequences obtained. SB also performed the transfer, monocytic ablation, and MDSC characterization experiments, and wrote the manuscript. SS and SA performed the myeloid cell characterization. SS-Z and NS assisted in RNA isolation and data analysis. DB assisted in data analysis and discussion. AA designed the study and wrote the manuscript.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "The authors wish to make a change to the published paper . In the https://www.mdpi.com/1420-3049/25/5/1249.The authors apologize for any inconvenience caused, and the change does not affect the scientific results. The manuscript will be updated, and the original will remain online on the article webpage at"}
+{"text": "In the original article, an author name was incorrectly spelled as Andrew J. Predergast. The correct spelling is Andrew J. Prendergast.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "E. Celis and K. Ryan, and John Wiley & Sons Ltd. The withdrawal has been agreed because the authors were unable to obtain approval to publish the final version from all authors.The above article, published online on 28 February 2020 in Wiley Online Library (wileyonlinelibrary.com) as an Accepted Article ("}
+{"text": "This article has been retracted: This paper is retracted because as of this writing, the authors are not able to correct an erroneous negative control in Figure 6B with an original image. Nevertheless, the conclusions of the paper are correct as when the concern was raised after publication, the authors repeated the experiments and confirmed the original results. The authors are deeply sorry for the error.1238-1249. https://doi.org/10.18632/oncotarget.26664Original article: Oncotarget. 2019; 10:1238\u20131249."}
+{"text": "In the original publication, the equal contribution information was not available in first page of the article.The correct information is provided in this correction.M.-c. Kim, S. Jang contributed equally to this work."}
+{"text": "Materials [Journal of Clinical Medicine have checked the case, and the Editor-in-Chief has approved the retraction.In the published paper , Figure aterials . After taterials . The autJournal of Clinical Medicine. MDPI is a member of the Committee on Publication Ethics and takes the responsibility to uphold strict ethical policies and standards very seriously.We apologize to readers of"}
+{"text": "The objective is to assess if the effect of diabetes on cognition differs by race/ethnicity in the U.S. and how this association differs between older Hispanics in the U.S. and older Mexicans in Mexico. Data comes from a sample of older adults 50 and older with direct interviews from the 2012 waves of the Health and Retirement Study  and the Mexican Health and Aging Study . Cognition was measured as a total cognition score. OLS regressions were used to test the association between diabetes and cognition by race/ethnicity in the U.S. and among older Mexicans in Mexico. Results showed that Non-Hispanic Whites (NHW) had the highest cognition scores in the U.S., followed by Hispanics and non-Hispanic blacks (NHB). Mean cognition score of older Mexicans was higher than for NHB and Hispanics in the U.S. but lower than NHWs. The prevalence of diabetes was highest among Hispanics (32.3%), followed by NHB (30.6%) and NHW (19.9%). The prevalence of diabetes in Mexico was like those NHW in the U.S. (19.9%). In the U.S., the effect of being NHB and Hispanic (compared to white) on cognition was equivalent to having 5.3 and 2.4 fewer years of education, respectively. However, the effect of diabetes on cognition did not differ by race/ethnicity. The final analysis will include a direct comparison between Hispanics in the U.S. and a matched sample of older adults in Mexico with similar sex and age to test differences in the effect of diabetes on cognition between these two samples."}
+{"text": "The following information is missing from the Competing Interests statement: A preliminary patent application was filed by McMaster University on behalf of SMP and GP prior to publication. The rights to this patent are now assigned to Exerkine Corporation for the multi-nutrient supplement used in this study. This patent is now published as International Patent No. WO/2018/157258, September 7, 2018.10.17605/OSF.IO/H35QC.Additionally, the Data Availability statement for this paper is incorrect. The correct statement is: Data underlying the study are available on the OSF repository at DOI:"}
+{"text": "The authors wish to make a change to the published paper . In the https://www.mdpi.com/2073-4360/10/9/1043.The authors apologize for any inconvenience caused and the change does not affect the scientific results. The manuscript will be updated, and the original will remain online on the article webpage at"}
+{"text": "Chen JH and Zhao H conducted the histological evaluation and immunohistochemical evaluation. Zhao H collected the data. Zhao H analyzed and interpretated the data. Zhao H drafted the manuscript. Chen JH reviewed and revised the manuscript. All the authors had access to the data. All authors read and approved the final manuscript as submitted."}
+{"text": "The authors wish to make a change to the published paper . In the https://www.mdpi.com/2073-4360/12/10/2371.The authors apologize for any inconvenience caused and the change does not affect the scientific results. The manuscript will be updated, and the original will remain online on the article webpage at"}
+{"text": "Hannah K. Heywood was not included as an author in the published article. The corrected Author Contributions Statement appears below.CT, HH, and ST reviewed and evaluated the literature and drafted the manuscript. MK was involved in the conception of the review and critically revised the manuscript. SF provided pre-clinical data. All authors contributed to manuscript revision and approved the submitted version.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "In the original article, the authors were incorrectly ordered as Ayelet Ben-Sasson and Tamar Y. Podoly. The correct order is Tamar Y. Podoly and Ayelet Ben-Sasson.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "The Funding statement for this paper is incorrect. The correct statement is: AAS and SA were supported by the Research to Prevent Blindness, Inc. (unrestricted grant). MGH was supported by the L.K. Whittier Foundation."}
+{"text": "The authors wish to make a change to the published paper . In the \u03b8: contact angle of liquid on solid surfacehttps://www.mdpi.com/2073-4360/11/6/935.The authors apologize for any inconvenience caused and the change does not affect the scientific results. The manuscript will be updated, and the original will remain online on the article webpage at"}
+{"text": "D.E.R.B.B.I. intervention\u201d was expanded to \u201cDevelopment Emotional Relation Body-Based Intervention\u201d.In the original article, there was an error. The acronym \u201cAn error was also made, referring to \u201cthe Institute of -Blinded for Peer Review-\u201dConclusion, Paragraph Number 1:A correction has been made to The results presented in this study provide some insights into potential clinical work with the mothers and fathers of children with ASD. Studying the parental ability of insightfulness and acceptance of a child diagnosis of ASD has enriched our understanding of the processes underlying the interactions of these parents with their children. These aspects should be addressed through intervention programs for parents. At the Institute of Orthophonology (IdO) support for parents has been incorporated into the D.E.R.B.B.I. intervention  within the Turtle Project (Di Renzo et al., The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "Scientific Reports 10.1038/s41598-020-60246-5, published online 21 February 2020Correction to: The Acknowledgements section in this Article is incomplete.\u201cWe thank Dr. Ronald Zhu and Dr. Falk Poenisch for their support and guidance in the proton dosimetry. We thank Dr. Sang Hyun Cho for the support in the dosimetry of the Cs-137 irradiator. We thank Dr. David Volk and Mr. Paul Wisdom for fabricating the high-throughput irradiation device and its supporting and protection system. We thank Dr. Aimee McNamara for sharing her knowledge in RBE modelling. We thank Ms. Christine Wogan for the editorial assistance. This work was supported by the National Cancer Institute [Grant No. U19 CA021239] and by the Radiation Oncology Strategic Initiative Boot Walk Award from The University of Texas MD Anderson Cancer Center.\u201dshould read:\u201cWe thank Dr. Ronald Zhu and Dr. Falk Poenisch for their support and guidance in the proton dosimetry. We thank Dr. Sang Hyun Cho for the support in the dosimetry of the Cs-137 irradiator. We thank Dr. David Volk and Mr. Paul Wisdom for fabricating the high-throughput irradiation device and its supporting and protection system. We thank Dr. Aimee McNamara for sharing her knowledge in RBE modelling. We thank Ms. Christine Wogan for the editorial assistance. This work was supported by the National Cancer Institute [Grant No. U19 CA021239], the Cancer Prevention and Research Institute of Texas (CPRIT) [RP150578], and by the Radiation Oncology Strategic Initiatives Boot Walk Award from The University of Texas MD Anderson Cancer Center. JY was supported by the CPRIT Research Training Program [RP170067].\u201d"}
+{"text": "Fraser R. Hughson was not included as an author in the published article. The corrected Author Contributions Statement appears below.FH undertook initial experiments to electrospin magnetic nanofibers. VB undertook the electrospinning, SEM, and XRD measurements. GW did the XRD and magnetic analysis and interpretation. SC did the magnetic measurements and assisted in the magnetic interpretation. TN conceived and helped to oversee the research. All authors were involved in the data interpretation.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "The Joseph T. Freeman Award lecture will feature an address by the2020 Freeman Award recipient Cynthia Brown, MD, MSPH. The Joseph T. Freeman Award is a lectureship in geriatrics awarded to a prominent physician in the field of aging, both in research and practice. The award was established in1977 through a bequest from a patient\u2019s estate as a tribute to Dr. Joseph T. Freeman."}
+{"text": "The authors wish to make a change to the published paper . In the https://www.mdpi.com/2073-4360/12/1/131.The authors apologize for any inconvenience caused and the change does not affect the scientific results. The manuscript will be updated, and the original will remain online on the article webpage at"}
+{"text": "Data pertaining to the GO-FORWARD study are available from the Yale University Open Data Access Project at https://yoda.yale.edu/request-data.The Data Availability statement for this paper is incorrect. The correct statement is: All de identified data required to replicate the results in this paper are either already available in the technical appendix or are available at The publisher apologizes for the error.The Acknowledgments section is missing from the paper. The correct Acknowledgments section is: This study, carried out under YODA Project # 2017\u20132326, used data obtained from the Yale University Open Data Access Project, which has an agreement with JANSSEN RESEARCH & DEVELOPMENT, L.L.C.. The interpretation and reporting of research using this data are solely the responsibility of the authors and does not necessarily represent the official views of the Yale University Open Data Access Project or JANSSEN RESEARCH & DEVELOPMENT, L.L.C."}
+{"text": "There is information missing from the Competing Interests statement. The correct Competing Interests statement is as follows: N.A. was a consultant for Cepheid, and has licensed a biomarker for early detection of pancreas cancer to Cepheid (PATENT # 10167513). N.A also has grant funding from Astex Pharmaceuticals (GRANT # 120039). N.A. has served as a consultant to Johnson and Johnson, as an advisor to Celgene, and as a member of the Scientific Advisory Council to the No Stomach for Cancer Foundation. H.K. reviewed the manuscript; he is a scientific contributor and Vice President at Astex Inc. This does not alter our adherence to PLOS ONE policies on sharing data and materials."}
+{"text": "Wang JY, Lu L and He X analyzed the data. Ma LJ provided critical inputs on interpretation of the study. All authors had access to the data. All authors read and approved the final manuscript as submitted."}
+{"text": "In the original publication  there waE. coli and S. aureus, respectively.Due to this correction in Figure 6, the reported values of the released AgNPs in the original publication  from hydThe authors state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."}
+{"text": "The rationale for the treatment of long-COVID symptoms\u2014a cardiologist\u2019s view By Schieffer E and Schieffer B. (2022) Front Cardiovasc Med. 9:992686. doi: 10.3389/fcvm.2022.992686A Corrigendum on In the published article, there was an error in the article type. It was incorrectly published as a Systematic Review. The correct article type is: Perspective.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "The corrected figure is shown here. The error appears in print and in PDFs downloaded before April 10, 2023. The authors apologize for the error and any confusion.After publication, it was discovered that the image in"}
+{"text": "The published article  has beenPolymers Editorial Office and the authors, the paper has been retracted and will be marked accordingly. https://www.mdpi.com/2073-4360/13/19/3354.Following its publication, the authors contacted the Editorial Office regarding legal issues related to confidentiality and a copyright issue. Zhengzhou University was not aware that the article had been submitted for publication and did not agree to the publication of the paper in its current form. Thus, in agreement with the This retraction has been approved by the Editor-in-Chief of the journal.The authors agree to this retraction."}
+{"text": "Yu JX and Yuan DD carried out data curation. Li L and Wang YJ provided critical inputs on design, analysis, and interpretation of the study. All the authors had access to the data. All authors read and approved the final manuscript as submitted."}
+{"text": "Error in Conflicts of InterestConflicts of Interest was described inaccurately. Please replace it with the following paragraph under the heading of Conflicts of Interest:In the original publication , Conflic\u201cThe publication presents the results of an industry collaborative research project. The project involves students and staff from Griffith University , Central Queensland University  and Bioproton Pty Ltd. . C.T. is supported by a PhD scholarship from Bioproton Pty Ltd.\u201d The authors state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."}
+{"text": "The Funding statement is incomplete. The complete statement is: X.Z. was supported by the NNSF of China under Grant No. 12105117, the Fundamental Research Funds for the Central Universities (Grant No. 21621007), Guangdong Basic and Applied Basic Research Foundation (Grant No. 2022A1515010523), the Science and Technology Planning Project of Guangzhou (Grant No. 202201010360), and E.D. was supported by NSF grant SES-1919494. A.P. was supported by the Pinhas Sapir Center for Development and the Foerder Institute for Economics Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."}
+{"text": "BJGP Open 2022; DOI: https://doi.org/10.3399/BJGPO.2022.0126, there was an omission from the competing interests paragraph. The text should read: \u2018Nicholas Panay is the founder of a private menopause clinic and has received funds for research and speaking from pharmaceutical companies. He was not involved in the analysis of this study. The other authors have no competing interests.\u2019 The online version has been corrected.In the article by Alsugeir"}
+{"text": "Zygomaturus keanei from northern South Australia. This is only the third partial skeleton of a late Cenozoic diprotodontid described in the last century, and the first displaying soft tissue structures associated with footpad impressions. Whereas it is difficult to distinguish Z. keanei and the type species of the genus, Z. trilobus, on dental grounds, the marked cranial and postcranial differences suggest that Z. keanei warrants genus-level distinction. Accordingly, we place it in the monotypic Ambulator gen. nov. We, also recognize the late Miocene Z. gilli as a nomen dubium. Features of the forelimb, manus and pes reveal that Ambulator keanei was more graviportal with greater adaptation to quadrupedal walking than earlier diprotodontids. These adaptations may have been driven by a need to travel longer distances to obtain resources as open habitats expanded in the late Pliocene of inland Australia.Diprotodontids were the largest marsupials to exist and an integral part of Australian terrestrial ecosystems until the last members of the group became extinct approximately 40 000 years ago. Despite the frequency with which diprotodontid remains are encountered, key aspects of their morphology, systematics, ecology and evolutionary history remain poorly understood. Here we describe new skeletal remains of the Pliocene taxon  Most o tonnes \u201314, witho tonnes . Diprotoistocene \u201318, and ustralia \u201318. Thison, 1967  from theMeniscolophus mawsoni Stirton, 1955 [Z. keanei [Euowenia grata  [Euryzygoma dunense  [Euo. grata have hitherto been ascribed to a species [The Tirari Formation is located in the Tirari Sub-basin of the Lake Eyre Basin  and repron, 1955 , Z. kean. keanei , Euowenis, 1887)  and Eurys, 1888) . Diproto species .Z. keanei was collected by A.B.C. and T.H.W. in September 2017 from the Main Body of the Tirari Formation, exposed at the Keekalanna East Waterhole on the Warburton River, South Australia  describe the footpad impressions associated with the pes and (iii) make inferences about its functional morphology in relation to locomotion.The primary aims of this paper were to (i) provide a revised diagnosis, description and comparison of . 2. 2.1et al. [Serial designation of the marsupial cheek dentition follows Stirton et al.  and Lucket al. ; upper cet al. [et al. [Diprotodon optatum and Zygomaturus trilobus, in which a postcingulid is found behind it.Upper premolar cusp morphology follows Stirton et al. . Some feet al. ,11,14,25et al. , we refe [et al.  as the p [et al. . In addi [et al.  as the \u2018et al. [Cusp terminology for the molars follows Stirton et al. , and Tedet al. , where tet al. . In dipret al. ,30,31. Cet al.  or as thet al. ,30,33\u201335et al. , parastyet al. ,9,34 or et al. ,35. A deet al.  or midliet al. . We follet al.  in referNomina Anatomica Veterinaria [The descriptions of postcranial material follow the erinaria , supplemerinaria ,34,38. Merinaria , Tschirnerinaria , Argot [erinaria , Warburterinaria , Harvey erinaria  and unpu. 2.2Z. keanei and examined here was collected prior to this study [SAMA P54742 was collected from Keekalanna East, lower Warburton River, Kalamurina Station, South Australia, in the Main Body of the Tirari Formation by A.B.C. and T.H.W. in 2017. Permissions for fieldwork and fossil collection were granted by the Australian Wildlife Conservancy. The partially articulated skeleton had been eroded by the river when discovered but carbonate concretions preserved the skull and protected feet and other joints from further disarticulation. The material was prepared at the Flinders University Palaeontology laboratory and stabilized with Paraloid B-72. The near-complete, articulated pes was manually prepared out of its enclosing concretion with a micro-jack. Other material referred to is study ,16.Z. keanei and comparative material were observed from the following institutions, with the most complete material digitized for direct comparisons: Flinders University, Adelaide (FU); Museum and Art Gallery of the Northern Territory, Alice Springs (NTM); Papua New Guinea National Museum and Art Gallery, Port Moresby (PNG); the South Australia Museum, Adelaide (SAMA); Queensland Museum, Brisbane (QM); Australian Museum, Sydney (AM); Museums Victoria, Melbourne (NMV); Queen Victoria Museum and Art Gallery, Launceston (QVM); Smithsonian Institution, Washington DC (USNM); University of California Museum of Palaeontology (UCMP); Natural History Museum, London (NHMUK); Tasmania Museums and Art Gallery (TMAG). Key specimens were digitized using an Einscan Pro + 3D surface scanner at between 0.24 mm and 0.7 mm resolution.Specimens of . 2.3The near-complete pes of SAMA P54742 was scanned using computed tomography (CT) with a SOMATOM Force scanner by Dr Jones and Partners Medical Imaging at the South Australian Health and Medical Research Institute before the pes was completely prepared out of its concretion. Specimens were scanned with a 0.4 mm slice thickness to produce 2729 slices. The CT scans were imported into image processing software Mimics 22.0 where segmentation, thresholding and smoothing of the materials were carried out. The outline of the soft tissue was manually segmented at dorsal, lateral and anterior planes to ensure the accuracy of segmentation. The pedal elements were segmented using the \u2018split mask\u2019 function in Mimics v. 22. The matrix encasing the pes made it difficult for the X-rays of the CT scanner to penetrate and so high-resolution differentiation of the bone surfaces was not possible. Consequently, it was also manually prepared out of the concretion to allow the observation of the pedal morphology of the bones in detail. The structures resembling soft tissue within the matrix were not recognized in the scan images until after the bones were prepared and, as such, are no longer represented by a physical object.. 2.4All specimen comparisons were undertaken using a mixture of .stl files in the software programs 3-matic v. 14.0 and Blender 2.93, photos and observation of physical specimens. Three-dimensional meshes of specimens were aligned in the same plane/axis to enable consistent comparisons and then figured in orthographic view in the descriptions. All comparisons regarding proportions between taxa are relative to the element and not absolute unless stated otherwise. Comparisons were made with all the material listed in the electronic supplementary material. Comparisons were primarily restricted to taxa found in mainland Australia during the late Miocene to the Late Pleistocene with some exceptions mentioned in the text.The late Miocene Alcoota Local Fauna contains four species of diprotodontid described on the basis of craniodental remains, but articulated or associated elements of individual skeletons are rare . NeverthNototherium tasmanicum Scott, 1911 [Zygomaturus trilobus, which is in line with previous studies [N. tasmanicum is beyond the scope of this study.We refer specimens formerly attributed to tt, 1911  to Zygom studies ,47\u201349. ANototherium mitchelli Owen, 1845 [Kukaodonta robusta  [Kukaodonta robusta as a junior synonym of Nototherium mitchelli on the grounds that features displayed in the type of Nototherium mitchelli allow it to be distinguished from all other diprotodontids.The taxonomy of en, 1845  and Kukas, 1891)  is still. 2.5Am. keanei were made using the minimum humerus circumference using the equation in Richards et al. [Body size estimates of s et al. .LogKg = ) \u2212 0.108Body size was also calculated using humeri from Alcoota diprotodontids for comparison with late Miocene taxa.. 3. 3.1Class: Mammalia Linnaeus, 1758 Superorder: Marsupialia Illiger, 1811 Order: Diprotodontia Owen, 1877 Superfamily: Diprotodontoidea Archer & Bartholomai, 1978 Family: Diprotodontidae Gill, 1872 Ambulator gen. nov.Genus: Zoobank registrationZooBank LSID of this publication: urn:lsid:zoobank.org:pub:949A693F-B15A-4552-AF51-CEB2B3299827Zoobank LSID of genus: urn:lsid:zoobank.org:act:853C952C-66DB-4B8A-ADCC-1DCA3EFA9948Ambulator keanei Type species: Ambulator keanei  comb. nov.Species: . 3.1.1\u2018Ambulator\u2019 is Latin for \u2018walker\u2019. This is in reference to the taxon's many postcranial adaptations that to plantigrade, graviportal walking. The gender of the genus is masculine.. 3.1.2As for the species until another species is described.. 3.1.3None. 3.1.4Named for Mr Vincent P. Keane, who provided heavy equipment for the excavations in the Tirari Desert in 1962 conducted by Ruben A. Stirton, Paul F. Lawson, Richard H. Tedford and Michael O. Woodburne ,57.. 3.1.5SAMA P13844, partial lower mandible with both ascending rami missing; right and left I1; left and right P3; left M1; right M4, partial maxilla containing left M2\u2013M4. Collected by R. A. Stirton in 1962.. 3.1.6Keane Quarry, Lake Palankarinna, South Australia . Palanka. 3.1.7UCMP 70121, right M1 (Keane Quarry); UCMP 70120, right M2 (Keane Quarry); UCMP 44622, left I1 (Woodard Quarry); UCMP 45409, left I1 (Woodard Quarry). UCMP 44622 and UCMP 45409 were previously identified [entified  as right. 3.1.8Ambulator keanei is distinguished from all other diprotodontids by the following unique combination of traits.Kolopsis torus and differs by having an anterodorsally taller septum relative to the nasals.The shape of the cranium is most similar to that of Ma. ronaldi, Kolopsis yperus, Kolopsis rotundus and Z. trilobus. The P3 differs from Ma. ronaldi by being similar in size to the M1. The P3 further differs from those of Kolopsis yperus, Kolopsis rotundus and Z. trilobus by the parastyle being slightly broader relative to the other cusps on the tooth. The upper molars can be confidently differentiated from all other diprotodontids except those of Z. trilobus and H. tomasettii by the absence of a forelink; a separated parastyle that is variably present on all molars; clear separation between the precingulum, lingual cingulum and postcingulum on all molars; a distinct mesostyle/buccal cingulum; low midlink; high postparacrista and postmetacrista; mesostyle partially connected to the postmetacrista; and a broad postmetaconulecrista.The upper incisors differ from all other diprotodontids through the combination of the hypsodont, laterally diverging I1; a triangular I3 that is anteroposteriorly longer than the I2 and two dorsoventrally aligned buccal grooves on the I3. The P3 has five main cusps and is most similar to those of Euowenia grata and Pyramios alcootense; a distinct digastric process positioned below the hypolophid of the m4; no clear separation of the digastric sulcus and the pterygoid fossa; the posterior masseteric eminence is positioned at the posteroventral edge of the masseteric fossa; and the coronoid process arises almost vertically above the mandibular corpus unlike that of Z. trilobus.The dentary can be differentiated from all other diprotodontids by having: a shallower symphysis than in those of Meniscolophus mawsoni, Ma. ronaldi, Nototherium mitchelli and Z. trilobus. The lower incisors can be further differentiated from those of Z. trilobus and N. mitchelli by being less dorsally curved. The p3 is most similar to those of Z. trilobus, No. mitchelli, Kolopsis rotundus and M. ronaldi. The protoconid on the p3 is broader relative to length than in that of Z. trilobus. The lower molars can be identified to the exclusion of all other diprotodontids except those of Z. trilobus and H. tomasettii by the combination of being lower crowned than those of D. optatum and Eur. dunense; wide, U-shaped interlophid valleys; the presence of the midlink and buccal cingulid; a low cristid obliqua; and low midlink.The i1 is most similar to those of Am. keanei are most similar to those of D. optatum and Z. trilobus. The scapula lacks the large infraspinous process seen in that of D. optatum and is less medially curved than that of Z. trilobus. The deltopectoral crest of the humerus is straight, similar to that of D. optatum and unlike that of Z. trilobus. The supracondylar bridge is present, unlike in that of D. optatum.The forelimbs of D. optatum and Z. trilobus, differing by an hourglass-shaped pisiform. The triquetrum is smaller relative to the rest of the manus; the hamatal facet is mediolaterally narrow and angled almost parallel with the styloid facet. The styloid facet on the triquetrum is crescent shaped. A scaphoid facet is present on the hamatum but is not nearly as extensive relative to the hamatum in that of D. optatum. The hamate process is larger and projected more plantarly. The hamatal and scaphoidal facets on the capitatum converge to a point unlike in that of Z. trilobus. The radial facet on the scaphoid is concave similar to those of Z. trilobus and D. optatum. Unlike that of D. optatum, there is no differentiated hamatal facet that is larger than the capitatum facet on the scaphoid. The metacarpals are similar to those of D. optatum and unlike those of Z. trilobus with metacarpal 5 being the largest and triangular in dorsal view. The manual proximal and middle phalanges are smaller and taper more distally, and the manual ungual phalanges are narrower and taller than in Z. trilobus.The manus is most similar to those of Am. keanei is most similar to those of D. optatum and Z. trilobus. The lateral trochlear crest is larger than that of Z. trilobus and similar to that of D. optatum. The femoral condyles are asymmetrical with the medial condyle extending more caudally. There is no step in the lateral condyle such as those observed in D. optatum and Z. trilobus. There is no medial projection of the medial femoral facet on the tibia like in that of D. optatum. The femoral facet on the fibula is triangular and one-tenth the size of the tibial facet.The hindlimb of Z. trilobus, Euo. grata and D. optatum. The tibial facet on the talus is oval and takes up a smaller portion of the dorsal surface, unlike the larger rectangular tibial facet in those of Z. trilobus, Euo. grata and D. optatum. The calcaneal facet on the talus is more concave than in that of Z. trilobus, resulting in the posteromedial corner of the talus being deeper. The cuboid facet of the navicular differs from that of Z. trilobus by tapering dorsally to a thinner point, causing the facets for the talus and ectocuneiform to nearly meet. The cuboid is pentagonal in the dorsal aspect, similar to that of Z. trilobus. The medial plantar tubercle of the cuboid is larger than in that of Z. trilobus and is anteriorly hooked, similar to that of D. optatum. The mesocuneiform is fused with the entocuneiform but not with the ectocuneiform like in those of Euo. grata. Metatarsal 5 is triangular in dorsal view and curves medially, most similar to that of Z. trilobus and differs from those of D. optatum and Euo. grata by the lack of distinctly separate insertion points for the mm. peroneus on the lateral edge of metatarsal 5.The pes is most similar to those of . 3.1.9SAMA P52377, a partial right and left manus with radius and ulna and right and left pes, initially assigned to Euowenia grata [UCMP 70126, right maxilla (preserving M2\u2013M4). Stirton [Am. keanei. As the premolar was not known, Stirton [Z. trilobus specimens, we consider UCMP 70126 to be a variant of Am. keanei;UCMP 70124, right I3 previously identified as an I3 of Me. mawsoni, based on how it differs from the paratypes UCMP 44622 and UCMP 45409. However, as there is no material to suggest Me. mawsoni is represented in Keane Quarry, we re-identify UCMP 70124 as belonging to Am. keanei making the latter the only known diprotodontid taxon from the site; UCMP 70131, right I3 identified as Am. keanei for the same reasons as UCMP 70124.ia grata ; UCMP 70 Stirton  identifi Stirton  did not . 3.1.10Woodard Quarry Lake Palankarinna, Tirari Formation, Mampuwordu member, approximately 3.9Ma [y 3.9Ma ,21UCMP 44633, partial left and right parietal; UCMP 44626, right calcaneus; UCMP 44627, right tibia; UCMP 44401, partial left dentary with m4 present.Lawson\u2013Daily Quarry, Lake Palankarinna, Tirari Formation, Mampuwordu member, approximately 3.9 MaUCMP 70125, highly worn, left I1; UCMP 70126, right maxilla with M2.Keane Quarry,Lake Palankarinna, Tirari Formation, Mampuwordu member, approximately 3.9 MaUCMP 71387, partial maxilla with right incisors; right M2\u2013M4, left M2 and M4, and left masseteric process; UCMP 70121, right M1; UCMP 70123, left p3, left m1; UCMP 70120, right M2; UCMP 70124, right I3; UCMP 70131, right I3.Mullet Locality, Lake Palankarinna, Tirari Formation, Mampuwordu member, approximately 3.9 MaUCMP 297918, left maxilla, right maxilla with right M3\u2013M4, right P3, right M1\u2013M2, right I1, left and right I1, a partial epitympanic; UCMP 322914, mandible.Keekalanna East, Warburton River, Tirari Formation, Main Body, 3.6\u20133.9 Ma [6\u20133.9 Ma ,21SAMA P54742, partial skeleton consisting of a cranium, left dentary, atlas, axis, three other cervical vertebrae, four thoracic vertebrae, right clavicle, manubrium, rib fragments, right and left scapula, left humerus, partial right humerus, partial left and right radius, distal left ulna, complete left manus , left femur, left tibia, left fibula and near-complete left pes, with ungual phalanges 2 and 3 missing; SAMA P52377, partial left and right articulated manus with distal radii and ulnae attached, right manus , left manus (missing the trapezoid), a fragmentary distal right tibia, the left pes , a right pes .Lake Kanunka, Tirari Formation, Pompapillina Member, 3.6 Ma [, 3.6 Ma ,21UCMP 66917, right M4.. 3.2. 3.2.1Ambulator keanei. It consists of an adult cranium, although the right half and most of the basicranium are damaged or missing. The cranium is anteroposteriorly elongate , tapering anteriorly over the length of the rostrum in dorsal view. A bony septum arises from the premaxilla, projecting anterodorsally from above the I1. Although damaged, it appears to have been triangular in lateral view. The nasals extend dorsal of the incisors and have a concave anterior border in lateral view. In dorsal view, the nasals terminate anteriorly in a sharp medial tip above the septum, and broaden posteriorly, with an anteriorly concave margin, to meet the edge of the frontals above the orbits. The diastema is 52.5 mm long, with the palatal surface of the premaxilla being considerably narrower than that of the maxilla.SAMA P54742  is the mIn dorsal view, the frontals project laterally above the orbit before tapering anteriorly towards the nasals. The frontals are arched slightly dorsally when viewed from the lateral aspect. The left parietal plate is present, but only the posterior section adjacent to the occiput remains. The parietal plate is convex in vertical cross-section and meets medially with the other plate to form a weak sagittal crest. The maxilla is slightly convex at the buccal margin, tapering anteriorly towards the premaxilla. The orbit is crushed and slightly distorted, and situated below the border of the nasofrontal suture. The transverse palatine foramen is strongly concave with the apex level with the protoloph of the M4. The anterior half of the pterygoid cavity is present in SAMA P54742; it is located below the optic foramen, tapers anteriorly, and the surface is buccally concave. The anterior half of the basioccipital crest is present; it is located posterior to the pterygoid cavity with strong oval depressions on buccal sides. A deep, transverse canal extends from the posterior face of the orbit along the maxilla to a large foramen that presumably includes the optic foramen and the rostral alar canal. The masseteric process extends ventrally to be level with the molar occlusal surface and terminates level with the interloph valley of the M4. The zygomatic arch is arched dorsally in lateral view. The glenoid fossa is flat and located at the base of the jugal. Most of the basicranium is cracked and slightly distorted, obscuring many of the sutures. The posterior epitympanic fossa is located between the postglenoid process and the mastoid. The paroccipital process is directly posterior to the epitympanic fossa and is buccolingually compressed and slightly hooked anteriorly. The paroccipital process tapers ventrally, before terminating level with the tooth row. The mastoid is confined to the occiput and is angled slightly anteriorly to the rest of the occiput. The occipital condyles are dorsoventrally elongate, having near-equal depth to the paroccipital process. They taper slightly ventrally and have a convex articular surface. The foramen magnum is oval and slightly dorsoventrally compressed.Kolopsis torus, with a relatively shallow zygomatic arch and masseteric process, than to those of Zygomaturus trilobus and Maokopia ronaldi. The prominent septum is similar to that observed in Z. trilobus and Diprotodon optatum, and is unlike the smaller/absent bony septum in Neohelos stirtoni, Kolopsis torus, Plaisiodon centralis and Pyramios alcootense. In contrast with those of D. optatum, no nasal fossa is present in Am. keanei, which is similar to that seen in Z. trilobus. The nasals are positioned close to the incisor arcade, which is more similar to the state in Kolopsis torus and Pl. centralis and unlike the extremely posteriorly positioned nasals in Euowenia grata. The nasals of Am. keanei are not as laterally flared as those of Z. trilobus. The masseteric process is similar to that of Kolopsis torus, as opposed to the more extensive and anteroposteriorly flattened masseteric process observed in those of Euo. grata, Euryzygoma dunense and Z. trilobus. The orbit faces more laterally than in those of Z. trilobus and Ma. ronaldi. The frontals arise less steeply above the nasals than in those of Z. trilobus, Ma. ronaldi and Hulitherium tomasettii. The basicranium is aligned close to level with the tooth row, similar to that seen in those of Kolopsis torus and Pl. centralis, but unlike in those of Eur. dunense, D. optatum and the more extreme Z. trilobus, which are more dorsally angled relative to the tooth row. The occiput is more similar in both size and angle to that of Kolopsis torus than the broad, anteriorly oriented occiput of Z. trilobus. The paroccipital process is more similar in shape and size to that of Pl. centralis (NTM P7333) than that of any other diprotodontid.Overall, the shape of the cranium is more similar to that of . 3.2.2The I1 is anteroventrally curved and tapered in buccal view. Enamel of the I1 is restricted to the buccal side. The I2 is the smallest incisor and is circular in cross-section. There are two dorsoventrally aligned grooves on the buccal side of I3, as observed in UCMP 70124, that form a single prominent groove when worn (UCMP 70131). The triangular occlusal outline on the relatively unworn I3 in UCMP 70124 and UCMP 70131 becomes square with wear, as seen in SAMA P54742 figures .Am. keanei is identical to that of Z. trilobus. The I2 of SAMA P54742 is too worn for adequate comparison but is larger relative to the I1 than that of Z. trilobus. The I2 and I3 are larger in proportion to the I1 than in those of Z. trilobus (observable between SAMA P54742 and QVM1990GFV115). The triangular I3 (SAMA P13844) is most similar to those of Eur. dunense and Alkwertatherium webbi. The incisors of Am. keanei differ from Euo. grata by the presence of the I3; a proportionately larger I2 and the enamel being more restricted to the buccal side of the I1. The incisors of Am. keanei differ from those of D. optatum by the I1 being rooted (i.e. not hypselodont) and splayed, tapering to a point; and the occlusal surface of the I3 is triangular with a buccal groove, as opposed to the rounded occlusal surface in that of D. optatum. The incisors of Am. keanei differ from those of Kolopsis torus, Py. alcootense, Al. webbi and Pl. centralis in that the I1s are larger relative to the I2 and I3; are anteroventrally curved; and tapered to a point.The I1 of The P3 has a roughly pentagonal occlusal outline, has five cusps and is slightly smaller than the M1 . The lenAmbulator keanei is most similar to those of Z. trilobus and Z. gilli. However, the morphology of the P3 is quite variable . The buccal groove in the parametacone is slightly shallower in that of Z. gilli (NMV P209962) but this seems to be highly variable in both Am. keanei and Z. trilobus, with the variation in Z. trilobus encompassing what is observed in those of Am. keanei and Z. gilli . Given the range of intraspecific variation observed within the upper molars of Am. keanei and other taxa, it is difficult to find definitive features that differentiate Am. keanei from those of Z. trilobus, H. tomasettii and NMV P194569. However, the presence of the buccal cingulum/mesostyle differentiates Am. keanei from NMV P194569. This cannot differentiate Am. keanei from H. tomasettii, as in the latter, the cingulum is variable; the buccal cingulum is absent in the M2 of PNG MR25077 and present in the M4 of PNG MR25191. There is also overlap with some specimens of Z. trilobus  which have a distinct buccal cingulum, though other specimens of Z. trilobus lack any buccal cingulum . The postprotocrista appears to be larger and more distinct than that of Z. trilobus and broader than that of NMV P194569. The variable presence of the larger kinked postparacrista observed in UCMP 70126, SAMA P54742 and UCMP 6617 can occasionally be used to distinguish Am. keanei from those of Z. trilobus, H. tomasettii and NMV P194569.The upper molars of . 3.2.3The mandibular corpus is high and narrow, with both the tooth row and ventral margins straight and level. The symphysis is oval and anteroposteriorly elongate, extending below the posterior extremity of the p3. The diastema is narrow and straight, comprising approximately 13% of the dentary length. The mental foramen is positioned below the anterior extremity of p3; a pathology obscures the foramen in SAMA P54742. The digastric sulcus is long and deep, extending from below the coronoid process to below the m3. The digastric process is abraded but appears to be positioned directly below the hypolophid of the m4. No clear separation between the pterygoid fossa and the digastric sulcus was observed . The angKolopsis torus, Pl. centralis, Eur. dunense and Z. trilobus; this is unlike the deeper symphysis in those of Euo. grata, Me. mawsoni, Py. alcootense and D. optatum. The digastric process, while most similar in size and position to that of Z. trilobus, differs by being slightly weaker and positioned closer to the tooth row. The digastric process is larger and more pointed than in that of Kolopsis torus. No clear separation of the digastric sulcus and pterygoid fossa was observed in Am. keanei, Kolopsis torus, Py. alcootense, Pl. centralis, Me. mawsoni or D. optatum. The coronoid process is less anteriorly angled than in that of Z. trilobus (NMVP 232053). The posterior masseteric eminence is positioned at the base of the masseteric fossa, unlike in those of D. optatum and Euo. grata.The symphysis is shallow and slightly dorsally inflected, similar to those of . 3.2.4The i1s diverge anterobuccally, and curve dorsally. The i1 in cross-section is taller than its width, with enamel mostly confined to the ventral surface and the ventral half of the lateral surface.Am. keanei is most similar to those of Z. trilobus, Me. mawsoni and Nototherium mitchelli and can only be differentiated from Ma. ronaldi by its larger absolute size. The I1 is less dorsally curved than those of Z. trilobus and No. mitchelli.The i1 of The p3 is triangular and anterodorsally elongated in occlusal view . The lenAm. keanei is most similar to those of Z. trilobus, Ma. ronaldi, Kolopsis rotundus and No. mitchelli. It differs from Ma. ronaldi by the presence of the buccal cingulum, similar to those of Ma. ronaldi and No. mitchelli. It differs from Z. trilobus by having a more bulbous protoconid in proportion to the length of the tooth.The p3 of All molars are rectangular and anteroposteriorly elongate in occlusal view. When viewed in occlusal aspect, all lophids slope posteriorly, are bowed such that they are anteriorly concave; low crowned with broad U-shaped interlophid valleys in buccal view. Molar size varies between specimens, with the smallest being SAMA P54742 and the largest being SAMA P22914 . A low pAm. keanei are most similar to those of Z. trilobus and H. tomasettii, differing only by the postcingulid being slightly less posteriorly extended, the paracristid terminating in the midline of the m1 as opposed to in the buccal quarter, and having a larger anterobuccal basin on the m1.The lower molars of . 3.2.5. 3.2.5.1m. longissimus dorsi, m. obliquus capitis caudalis and m. obliquus capitis cranialis. The lateral vertebral foramen is 9.5 mm wide and positioned just dorsolateral to the centrum. The spinous process  is small, forming a slight raised surface on the dorsal centrum. The ventral arch is unfused but converges on the midline. The caudal articular fovea is obscured by the axis in SAMA P54742, but in UCMP 297918, it is less concave than the cranial articular fovea and more dorsoventrally compressed.The atlas and axis of SAMA P54742 could not be separated from each other during preparation without risking further damage . The craZ. trilobus (e.g. WAM 96.3.386) by tapering slightly anteriorly. The transverse foramina are mediolaterally narrower than in those of Eur. dunense (SAMA P23346), with a deeper and more oval cranial articular surface and narrower transverse processes. The transverse processes are mediolaterally narrower relative to length than in those of D. optatum (UCMP 60870). The atlas of Am. keanei lacks the large caudal tubercles on the ventral processes seen in those of Z. trilobus (WAM 96.3.386).The cranial articular fovea differs from that in . 3.2.5.2The axis of SAMA P54742 is robust  and is arrow shaped in ventral view. The cranial articular surfaces of the axis are oval and concave to mirror the convex articular facets on the atlas. Most of the spinous process and the transverse processes have been broken off. Small foramina occupy the centre of the ventral surface of the centrum. The spinous process appears to have been narrow. Two large foramina penetrate the dorsal surface of the centrum. The caudal extremity of the centrum is circular with a flat articular facet.Z. trilobus. The dorsal centrum foramina vary in Z. trilobus from fused (WAM 65.4.150) to separated (WAM 96.3.402), which may be ontogenetic.The spinous process is craniocaudally narrower relative to the axis than in those of . 3.2.6Three post-axis cervical vertebrae are included in specimen SAMA P54742. All three are highly damaged with only the centrum remaining, making it difficult to determine their order.. 3.2.7Four partial thoracic vertebrae were found with SAMA P54742. Due to their damage, we could not identify them to position, but we have made an attempt to describe them broadly. All possess a large semicircular centrum with flat cranial and caudal extremities . A large. 3.2.8m. pectoralis major. The facet for the manubrium is oval, with the articular surface being somewhat concave.SAMA P54742 preserves one partial clavicle, which is cylindrical and tapers towards the acromial end . The sha. 3.2.9The manubrium of SAMA P54742 is highly damaged with part of the right clavicle and the first rib crushed into it . The croTwo sternebrae were found with SAMA P54742, both are rectangular and dorsoventrally compressed.. 3.2.10Nine rib fragments are included in SAMA P54742. The first rib is flat and curves medially, and tapers proximally. The sternal ribs are elongated and medially curved, tapering slightly distally; they are flat in section, but are not as broad as the first rib. The articular process of the head is elongated with a spherical articular surface at the proximal end and transitions to posterodistally concave at the distal end. The neck of the ribs is pinched between the head and the tubercle (transverse process facet). The tubercle is located on the medial face of the rib and is small compared to the head. The body varies in thickness and size, but all are curved and taper distally.. 3.2.11mm. rhomboids form a distinct, rounded tip, positioned anterocaudal to the scapular spine. No distinct caudal angle is present, and the dorsal border is rugose with a large insertion scar for m. serratus posterior on the proximocaudal face of the spine. The edges of both supraspinous and infraspinous fossae are partially missing, but most of the borders can be inferred. The scapular notch is concave on the medial edge. The oval glenoid cavity is 49 mm \u00d7 83 mm and tapers cranially. The glenoid cavity is a concave articular surface, particularly deeply concave when viewed from the lateral aspect. The supraglenoid process is a small tubercle on the craniolateral tip of the glenoid fossa. The large laterally projecting coracoid process hooks medially. A large infraglenoid tubercle/process extends 64.5 mm from the glenoid fossa, expanding in width to form a rugose surface for attachment of the mm. triceps brachii caput longum and mm. teres major.The scapula is triangular when viewed from the lateral aspect, being broadest distally and tapering proximally . The scaZ. trilobus than to Kolopsis torus. It differs from those of Kolopsis torus, Pl. centralis and Ne. stirtoni by possessing a large infraglenoid process, a rugose cranial angle projecting slightly cranial of the scapula spine, and a large caudolaterally hooked coracoid process. It differs from that of Z. trilobus by being less medially curved around the ribs and possessing a larger hooked coracoid process. It differs from that of D. optatum by lacking an infraspinous process on the caudal border of the scapula.The scapula is more similar to that of . 3.2.12m. deltoideus pars clavicularis. The deltoid tuberosity for attachment of the m. deltoideus pars spinalis/acromialis is on the lateral side, perpendicular to the deltopectoral crest, and tapers gradually both proximally and, more abruptly, distally in a concave slope. The tuberosity for m. latissimus dorsi and m. teres major projects 1/3 of the way down the medial humeral shaft, forming a small ridge that hooks slightly caudally. A shallow groove for the origin of the m. brachialis is situated below the humeral head and wraps below the deltoid tuberosity to meet the cranial face of the lateral supracondylar crest. The olecranon fossa is shallow. The radial fossa is moderately indented above the midline of the trochlea with two very weak convex ridges. The medial and lateral epicondyles extend outward, making the humerus the widest at the distal end. The supracondylar bridge is broken off but the ends show it was 68.45 mm in length. The capitulum is circular on the cranial aspect and projects further cranially than the trochlea. The articular facet of the trochlea is craniocaudally narrower than the capitulum and the lateral aspect is shallowly concave.The left humerus of SAMA P54742 is highly abraded on the cranial face of the humeral head and the proximal 1/3 of its length. The lateral supracondylar crest and the greater tubercle are abraded off on SAMA P54742. The humerus is relatively gracile for a diprotodontid, with a total length of 324 mm from the distal trochlea to the humeral head, and it has a minimum circumference of 117.6 mm at the distal part of the diaphysis. The humeral head projects slightly caudally. The lesser tubercle is positioned directly below the humeral head, covering the medial and caudomedial sides of the proximal humerus. The deltopectoral crest is relatively straight, extends over more than half of the proximal humerus and terminates level with the deltoid tuberosity just over half-way down the shaft. The maximum height of the deltopectoral crest is on the distal end parallel to the deltoid tuberosity and appears to be an attachment for the Z. trilobus and D. optatum. The caudal projection of the humeral head is similar to those of Z. trilobus and is less caudally projected and more ovoid from the proximal aspect than in those of Ne. stirtoni and all diprotodontid humeri from Alcoota except NTM P7250. The greater tubercle is damaged and consequently cannot be compared to other diprotodontids. The lesser tubercle is relatively large and positioned more cranially than observed in most diprotodontids but is similar to the condition of diprotodontid humeri from Alcoota. The origin of the m. brachialis leaves a rugose lump below the caudolateral side of the humeral head which is similar to, but not as rugose as, that seen in D. optatum and Z. trilobus. A large insertion scar for mm. latissimus dorsi and teres major is positioned more proximally than the deltoid tuberosity, similar to that of Z. trilobus; this is unlike that of D. optatum that has a very weak insertion scar in approximately the same location, and also those of Ne. stirtoni, Ngapakaldia tedfordi, Nimbadon lavarackorum and diprotodontid humeri from Alcoota that possess a large insertion scar level with the deltoid tuberosity. The deltopectoral crest is straight, similar to that seen in D. optatum. The deltoid tuberosity is large, similar to those of D. optatum and Z. trilobus. The supracondylar bridge is present, differentiating it from that of D. optatum in which the supracondylar bridge was cartilaginous or ligamentous. The full extent of the lateral supracondylar crest cannot be determined, but it appears to be better developed than that observed in D. optatum. The medial epicondyle is relatively large, similar to those of D. optatum, Z. trilobus and Kolopsis torus, providing a greater attachment area for the anconeus medialis, m. palmaris longus, m. flexor carpi radialis, m. flexor carpi ulnaris and m. flexor digitorum profundus. The trochlea is rounded and angled slightly cranially, similar to in D. optatum, as opposed to the flatter trochlea observed in Ngapakaldia (UCMP 69814 and UCMP 75968), or the rounded but less spherical trochlea in that of Z. trilobus  than it is to the more spherical styloid in those of Z. trilobus or D. optatum. The styloid process of Am. keanei differs from those of all Alcoota diprotodontids by being proportionally larger in comparison to the diameter of the shaft.The styloid process of the ulna is most similar to those of . 3.2.14m. pronator quadratus is triangular and deeply concave, on the medial face of the shaft widening distally before terminating at the distal epiphysis. The carpal surface is sub-triangular when viewed from the distal aspect, with the scaphoid facet extending between the styloid process and the posterior scaphoid process. The scaphoid facet is oval and anteroposteriorly elongate from the distal aspect and deeply concave from lateral aspect. The styloid process tapers to a rounded point in lateral aspect and is anteroposteriorly compressed, forming a sharp point in caudal aspect. A large, rugose distal radial tuberosity is positioned above the styloid process, at the epiphyseal border. The posterior scaphoid process is rounded to a bulb that is slightly deflected medially. The hamatum process extends medially from the scaphoid facet towards the hamatum; the surface is relatively flat compared to the scaphoid facet and forms a wide rounded medial edge. A small barrel-shaped concavity lies on the medial face between the styloid and hamatum facet, possibly for insertion of a ligament. The groove for the m. extensor pollicis longus is on the medial face of the styloid facet and is very shallow.The capitular facet is circular and deeply cupped . The ulnZ. trilobus and smaller than in those of all diprotodontids from Alcoota. The notch for the m. pronator quadratus is more similar to that of Z. trilobus and smaller than in some diprotodontid radii from Alcoota, such as NTM P7319 and NTM P6141, but not others, such as NTM MP1328. The diaphysis cross-section is similar in shape to that of Z. trilobus. The distal articular surface of the radius is also more similar to that of Z. trilobus than to any other diprotodontid observed in this study. The hamatum process is proportionally larger than in most diprotodontid radii from Alcoota, especially NTM P7325 and NTM P6141, but is not that much larger than in NTM MP1328. The extensive hamatum process results in a triangular appearance on the distal aspect of the shaft, similar to that of Z. trilobus. The size and shape of the scaphoid facet, anterior scaphoid process, and the styloid process, appear to be within the range of variation of Z. trilobus TMAGZ 3554 and WAM 68.1.29.The ulnar facet is similar in size and shape to that of . 3.2.15The carpals and metacarpals are very large relative to the digits . The pisa) is hourglass shaped in dorsal view, with a rugose, caudally projecting tuber for attachment of the m. flexor carpi ulnaris and a concave cranial surface. It is anteroposteriorly elongated, widest at the tuber, pinches to a thin waist at the centre and widens again at the stylar facet. The tuber is wide and is positioned at an approximately 45\u00b0 angle relative to the ground; it also has a large, flat, palmar component. The stylar facet is large and cup shaped, covering most of the cranial face; it is angled craniodorsally, supports the majority of the styloid process of the ulna, is widest on the lateral side and tapers medially. Two triquetral facets are present on the cranial face: one is small and triangular, confined to the craniomedial face, palmar to the styloid facet; the other is a small and oval, on the craniolateral face. The triquetral fossa is large, deep and oval, positioned on the antero-palmar face, caudal to the triquetral facet. The pisiform of SAMA P52377  is small compared to most other carpals; it is thin and dorsoplantarly elongated. The pisiform facet is small and triangular on the posterior face. The styloid facet is large (approx. 2/3 the size of the pisiform stylar facet), crescent shaped and cups the anteroplantar surface of the styloid process, being largely concave on the medial side. The hamatal facet is dorsoplantarly elongated and split into two parts covering most of the anterior face; the dorsal facet is larger and shallowly saddle shaped and the palmar facet is smaller and flat.The triquetrum b is smalZ. trilobus (WAM 2023.4.14). The crescent-shaped styloid facet is similar to that seen in NTM P7268 from Alcoota.The triquetrum differs from those of all other diprotodontids by being smaller in proportion to the rest of the manus. It has a narrower hamatal facet that is angled at approximately 45\u00b0 to the styloid facet, as opposed to nearly 90\u00b0 as observed in that of c) is triangular in dorsal view with a rugose palmar face. The triquetral facet is large and bean shaped, covering most of the caudolateral face; the dorsal surface of the facet is slightly saddle shaped, which restricts the mediolateral slippage of the triquetrum. The scaphoid facet continues from the dorsomedial border of the triquetral facet and slopes anteriorly along the dorsal surface of the hamatum. The capitatal facet covers the entire medial face and is deeply concave to lock and restrict the movement of the capitatum. The capitatal fossa is large and positioned in the centre of the capitatal facet. The hamate process is restricted to the cranial end of the palmomedial face, is short, wide and bulbous and does not project cranially below the metacarpal 5 facet. The entire dorsal half of the anterior face is composed of facets for metacarpal 4 and metacarpal 5; the metacarpal 5 facet is the larger of the two, with both facets having a saddle-shaped surface with the border between them being comparatively concave. A shallow fossa is located palmar of both facets.The hamatum c is triaZ. trilobus and Ne. stirtoni. The triquetral facet is relatively smaller in proportion to the hamatum than in that of Z. trilobus and more similar in shape to those of diprotodontid hamata from Alcoota. A scaphoid facet is present unlike in those of Z. trilobus and NTM P7272 from Alcoota and is similar to those of D. optatum and NTM P4469 from Alcoota but much smaller relative to the hamatum than in D. optatum. The hamate process is larger and more plantarly projected than in those of Z. trilobus and D. optatum, but smaller than those of Ni. stirtoni and diprotodontid hamata from Alcoota , restricting movement between the hamatum and the capitatum, similar to diprotodontid hamata NTM P4469 and NTM P4469 from Alcoota. The stepped separation of the metacarpal 4 and metacarpal 5 facets that are restricted to the dorsal half of the distal end is more similar to the state in Alcoota diprotodontids than in that of Z. trilobus.The hamatum\u2013capitatum ligamental fossa is larger than in that of  Alcoota . The capd) is triangular in dorsal and ventral aspects, and it tapers plantarly to a rugose face. The hamatal facet is located on the lateral face and mirrors the capitatal facet on the hamatum, which dramatically restricts movement between the two carpals; fossae are located anteroplantar and posteroplantar of the hamatal facet. The scaphoid facet takes up the caudodorsal third of the medial face; it is convex, oval and anteroposteriorly elongated. The trapezoidal facet begins at the anterior border of the scaphoid facet and is the smallest facet on the medial face of the capitatum; its surface is distinctly concave, to contrast the convex surface of the scaphoid facet, and it terminates at the posterior border of the metacarpal 2 facet. The scaphoid fossa is located on the medial face palmar to the trapezoidal facet and posterior of the metacarpal 2 facet. The metacarpal 2 facet takes up the entire anterior border of the medial face; its surface is concave and pinched in the centre. The anterior face is composed of facets for metacarpal 3 and metacarpal 4. The metacarpal 3 facet takes up the majority of the anterior face with a distinct mediolaterally convex surface. The metacarpal 4 facet is comparatively flat and only occupies the dorsolateral corner of the anterior face. A shallow fossa is located ventral to the metacarpal 4 facet and lateral to the metacarpal 3 facet.The capitatum d is triaAm. keanei is craniocaudally shorter than that of Z. trilobus. The capitatum is mediolaterally broader than those of diprotodontid capitata NTM P4011 and NTM P4034 from Alcoota. The hamatal and scaphoidal facets converge to a ridge, unlike in that of Z. trilobus (WAM 2023.4.18). The hamatal and scaphoidal facets are smaller than in that of Z. trilobus and only cover the dorsal halves of both faces. It greatly differs from the state in that of Z. trilobus by lacking a plantar extension/process in the metacarpal 3 facet, and in the lack of a ligamental fossa on the metacarpal 4 facet. The facet for metacarpal 2 is much larger than in that of Z. trilobus (WAM 2023.4.18).The capitatum of e) is long, is widest proximally and tapers palmomedially to a rounded bulb. It articulates with the capitatum, trapezium and the trapezoid. The capitatal facet is located palmolaterally, extending along the entire lateral edge of the scaphoid; it is oval with a concave surface. The capitatal fossa is located distal of the capitatal facet, midway along the lateral face, extending the entire length of the lateral face. The radial facet is a highly convex surface, forming a ball and socket joint with the scaphoid facet of the radius; it occupies entire dorsal surface. The trapezoidal facet is cranially oriented and bean shaped and flat. The trapezium facet is flat and covers the mediodorsal face of the palmar process.The scaphoid e is longAm. keanei and those of Z. trilobus is concave, unlike the convex facets seen in diprotodontid scaphoids from Alcoota. The trapezoidal facet is noticeably smaller than in that of Z. trilobus and is approximately equal in size/slightly larger than in those of all diprotodontid scaphoids from Alcoota. It lacks the large, differentiated hamatal facet that is observed in that of D. optatum.The radial facet of the scaphoid of both The trapezoid is crushed in both manus of SAMA P52377 and cannot be described.f) is present in each of SAMA P54742 and SAMA P52377. It articulates with the scaphoid, trapezoid, metacarpal 1 and metacarpal 2. It is roughly hourglass shaped in plantar view and widest at the trapezoid articular border. The trapezoidal border is triangular, narrowing dorsally, with a flat articular surface and is located on the lateral face. The metacarpal 2 facet is small and triangular, located on the dorsomedial corner at the convergence trapezoidal facet and metacarpal 1 facet. The metacarpal 1 facet takes up the entire medial face, has a mediolaterally concave articular surface and is hourglass shaped. The scaphoidal facet is located on the lateral face; it is circular in shape with a weakly convex articular surface.A partial right trapezium f is presZ. trilobus is known for comparison. That of Am. keanei differs from NTM P6730 from Alcoota in having a small scaphoid facet and the metacarpal 1 trapezoidal facets converging to a sharp triangular point.No trapezium for Metacarpal 1 is the broadest and shortest of the five metacarpals in SAMAP 52377. It is noticeably rectangular in dorsal aspect and is craniodorsally flattened. It articulates with the trapezoid, metacarpal 2 and proximal phalanx 1. The proximal articular surface is broad and dorsoplantarly concave.Metacarpals 2 to 5 are more elongated than metacarpal 1, and the distal articular surfaces end in a spherical phalangeal facets.d) is the second shortest metacarpal and articulates with the trapezoid, trapezium, capitatum, metacarpal 3 and proximal phalanx 2. The metacarpal 3, capitatal and trapezoidal facets converge to form a pointed proximal articular surface. The capitatal facet is separated into two parts (upper and lower), with an articular surface mirroring the metacarpal 2 facet on the capitatum with little movement between the two. The metacarpal 3 facet is small and indistinguishable from the dorsal section of the capitatal facet. The trapezoidal facet is small, circular and located dorsomedially on the proximal end. The diaphysis is kinked laterally, triangular in cross-section, and arched in the lateral aspect.Metacarpal 2 d is the c) is straight, elongate and cylindrical. It articulates with the metacarpal 2, metacarpal 4, the capitatum and the proximal phalanx 3. The capitatal facet is the largest, taking up all of the proximal articular surface; it is a palmarly tapering trapezoid that is slightly concave and angled caudomedially so that it is convergent on a sharp edge with the metacarpal 4 facet. The metacarpal 2 and metacarpal 4 facets are on opposing edges of the capitatal facet, facing medially and laterally, respectively; both have flat articular surfaces, with that for metacarpal 4 being larger than that for metacarpal 2. The diaphysis is roughly square in cross-section and elongate, resembling a rectangular prism.Metacarpal 3 c is strab) is straight, elongate and cylindrical. It articulates with the metacarpal 3, metacarpal 5, capitatum, hamatum and proximal phalanx 4. The hamatal facet is large, taking up most of the proximal articular surface; it is deeply concave, forming a valley between the dorsal and plantar edges. The capitatal facet is small and slightly convex; it extends down the medial edge of the hamatal facet/proximal edge of the metacarpal 3 facet. The facets for metacarpal 3 and metacarpal 5 are on opposing edges of the proximal articular surface, facing medially and laterally respectively; both are flat, with the facet for metacarpal 3 being broader than that for metacarpal 5, but unlike in metacarpal 5, they are restricted to the dorsal half of metacarpal 4. The diaphysis is cylindrical and elongate.Metacarpal 4 b is straa) is the largest metacarpal and articulates with the hamatum, metacarpal 4 and proximal phalanx 5; it is triangular with a slightly convex lateral edge in dorsal aspect. The hamatal facet takes up most of the proximal articular surface; the articular surface is palmodorsally convex and mediolaterally concave. The metacarpal 4 facet is on the medial edge of the hamatal facet and forms an articular surface that is flat and faces medially. The diaphysis is broad and plantar-dorsally flattened, the medial edge is flat, while the lateral edge is convex, and it tapers distally.Metacarpal 5 a is the Z. trilobus. They differ from those of all diprotodontid metacarpals from Alcoota by lacking a keel for separation of the sesamoids on all distal articular facets  is broader than all other phalanges, with a wider proximal articular facet and shallow median keel; it is hourglass shaped and oval in cross-section. The distal articular surfaces are saddle shaped; this indicates more dorsoventral movement occurs between the ungual and middle phalanx than between the middle phalanx and proximal phalanx.The middle phalanx 5 a is broaThe ungual phalanges figures  are relaZ. trilobus, similar to that seen in D. optatum. The ungual phalanges of Am. keanei are narrower and taller relative to length than in those of Z. trilobus and do not display any of the characteristic dorsopalmar flattening seen in the latter with the exception of ungual phalanx 1.The proximal and middle phalanges are relatively shorter and taper more anteriorly than in those of . 3.2.16m. vastus lateralis. The proximal half of the trochanteric fossa is partially missing, but the remnant is broad and faces medially.A partial left femur of SAMA P54742  is brokem. gastrocnemius medialis is separated into two indentations on the border of the lateral epicondyle. The lateral condyle is broader than the medial condyle and aligned in the sagittal plane; it possesses a flatter articular surface, for articulation with the tibia, than the more rounded medial condyle; a small articular facet for the fibula is on the lateral border. The medial condyle is abraded on the medial face, but its full width still appears substantially narrower than the lateral condyle. When viewed from the distal aspect, the medial condyle extends far more caudally than the lateral condyle and is rotated laterally out of the sagittal plane; the articular surface is more rounded. The trochlea surface is deeply concave on the cranial face. The medial trochlea crest is cone shaped and protrudes substantially cranially in comparison to the rest of the trochlea. The lateral surface of the trochlea is partially abraded but does not appear to extend to the same extent as the medial trochlear crest.The distal femoral fragment is broken at the diaphysis, with the edges of most features being abraded to some extent. The attachment for the Am. keanei is most similar to that of D. optatum and differs by lacking the slight step in the lateral condyle seen in D. optatum. The large medial trochlear crest is most similar in shape to that in D. optatum. That Am. keanei lacks a large distinct step in the lateral condyle for separation of the tibial and fibular facets is most similar to that in some diprotodontid femora from Alcoota, such as NTM P4130, in contrast with those of Z. trilobus. The femur of Am. keanei differs from that of Z. trilobus in the absence of the lateral step for the fibula on the lateral condyle and a weaker medial crest. The lateral crest is broken in all specimens of Z. trilobus, but the base is proportionally larger in Am. keanei. The trochlear surface extends less cranioproximally than in Z. trilobus.The femur of . 3.2.17m. popliteus forms a large, slightly curved ridge travelling down the caudal face below the fibula facet. The insertion scar of m. semimembranosus forms a small indentation on the craniomedial face just below the border of the medial condyle facet and the tibial tuberosity. The insertion scars for the m. semitendinosus and m. gracilis are faint and share an indentation distal of the insertion scar for the m. semimembranosus 1/3 further down the shaft.Only the proximal end of the tibia is known (SAMA P54742) . It is bAm. keanei is morphologically very similar to that of Z. trilobus. The tibial tuberosity is less laterally extensive than in that of Z. trilobus. The surface of the lateral femoral facet is angled more dorsally relative to the medial femoral facet similar to those of D. optatum and Euo. grata and unlike the more caudally angled lateral femoral facet in that of Z. trilobus. No medial projection of the medial femoral facet like in that of D. optatum is observed in Am. keanei. The attachment for m. popliteus is positioned slightly more laterally on the diaphysis below the apex of the fibula/lateral femoral condyle facet than in that of Z. trilobus.The proximal tibia of . 3.2.18m. peroneus brevis is large and rugose, taking up the entire craniolateral corner of the fibular head. The ridge for the attachment of m. extensor digitorum longus is below the cranial corner of the fibular facet and is rugose.Only the proximal portion of the fibula is known (SAMA P54742) ; it is tAm. keanei is in stark contrast to the large concave one in that of Z. trilobus. The femoral facet is smaller than any other diprotodontid examined in this study, and only those of Ni. lavarackorum, Ng. tedfordi and some diprotodontid femora from Alcoota such as NTM P92756 and NTM P4827 are close to it in such small size relative to the rest of the fibular head. The relatively larger tibial facet in Am. keanei, covering half of the fibula head and with a more laterally extended process for attachment of m. peroneus digiti quartus, differentiates it from all Alcoota material and that of Z. trilobus. The fabellar facet is smaller than that of Z. trilobus and more similar in size to diprotodontid fibulae from Alcoota.The comparatively tiny femoral facet of the fibula of . 3.2.19The pes is angled in such a way that the metatarsals and phalanges curve medially relative to the orientation of the talus, resulting in a crescent-shaped lateral edge . The phab) is small compared to the rest of the pes. It is located in the centre of the tarsus, is longer than it is wide and dorsoplantarly thick. The tibial facet is oval in dorsal aspect; anteroposteriorly elongated; and is flat, apart from the raised medial crest. The medial crest occupies the posterior half of the medial edge and is concave in lateral view. The fibular facet is 1/5 the size of the tibial facet. The fibular facet is triangular with a plantar point and the flat articular surface is angled dorsolaterally at 125\u00b0 relative to the tibial facet. The talar neck extends craniomedially from the tibial facet as a depressed surface. The talar head bears the cuboid and navicular facets, which both extend anteromedial of the tibial facet, and is rounded and anteroposteriorly elongate. The cuboid facet occupies 1/4 of the talar head but 3/4 of the cranial face, and has a rounded articular surface; a faint raised border separates it from the navicular facet. The navicular facet is directed medioplantarly and takes up 3/4 of the talar head; its articular surface is convex, which increases the range of possible movement between the talus and the navicular. The calcaneal facet is square with concave edges and a deeply concave articular surface. No clear border is present between the cuboid and calcaneal facets. A large ligamental pit/groove is present between the craniomedial border of the calcaneal facet and the planto-lateral border of the navicular facet.The talus b is smalZ. trilobus, D. optatum and Euo. grata  is craniocaudally long, mediolaterally narrow and dorsoplantarly deep and broader at the posterior end. The tuber makes up more than half of the length of the calcaneus and curves medially. The talar facet is L-shaped in dorsal view and widest at the posterior end, covering the entire width of the anterior projection on the medial side, which meets up with the border of the cuboid facet; the articular surface is saddle shaped with a convex caudal portion and concave cranial portion, restricting the craniocaudal movement of the talus. A deep fossa for the calcaneo-talar ligament is caudal to the talar facet. The cuboid facet is a deep, concave depression on the anterior face of the calcaneus, projecting much further on the lateral side. The lateral talar ligamental fossa is shallow and broad. The plantar tubercle is positioned on the lateral face and is anterodorsally elongated, running the length of the tibial facet. The distolateral process on the most anterior point of the calcaneus is pointed from the dorsal aspect and globular on the lateral side.The calcaneus a is cranZ. trilobus but is mediolaterally narrower and dorsoplantarly deeper relative to the length of the calcaneus. The calcaneal tuber is also similar to that of diprotodontid calcaneus NTM P4009 from Alcoota but is longer; however, it is substantially different from the other two morphs observed in Alcoota (e.g. NTM P4008 and NTM P7300). The deep, narrow cross-section of the tuber is reminiscent of those observed in Pitikantia dailyi, Ne. stirtoni and Ni. lavarackorum. The talar facet does not extend onto the distolateral process in contrast with that seen in Z. trilobus. Like in that of Z. trilobus, the fossa for the calcaneal talar ligament is relatively shallow compared to those observed in Euo. grata and D. optatum. The cuboid and navicular facets are similar to those of Z. trilobus and are plantodorsally shorter than in Ni. stirtoni.The calcaneal tuber is most similar to that of c) is C-shaped in dorsal aspect, with a large posteromedial process. It articulates with the talus, calcaneus, cuboid, ectocuneiform and meso-entocuneiform. The talar facet takes up approximately 2/3 of the lateral face and is deeply concave, forming a ball and socket joint, allowing some movement between both tarsals. The calcaneal facet is small and located on the cranioplantar edge of the talar facet. The posteromedial process is broadly square and plantarly deflected, resulting in a concave plantar surface; the medial edge is dorsoplantarly narrow and anteroposteriorly elongate with a rounded surface. The meso-entocuneiform facet is thin and extends across most of the anteromedial face, terminating just dorsal of the ectocuneiform facet. The ectocuneiform facet is small, with a flat, rectangular articular surface. The dorsal half of the cuboid facet is a thin surface located on the mediodorsal edge of the navicular between the talar and ectocuneiform facet; the plantar half is rectangular with a flat surface.The navicular c is C-shAm. keanei is more similar to those of Z. trilobus, D. optatum and Euo. grata than those of diprotodontids from Alcoota. The talar facet is similar to that of Z. trilobus but tapers more posteriorly and is more concave. The cuboid facet was slightly obscured in the CT scan (by articulated elements) but appears to be similar to that of Z. trilobus, differing by tapering dorsally to a thinner point, causing the facets for the talus and ectocuneiform to nearly meet. The calcaneal facet was too obscured (by articulated elements) for adequate comparison. The morphology of the medial process is most similar to that of D. optatum but has a stronger plantar curve and tapers dorsally; although this does vary in D. optatum (e.g. SAMA P58516 and SAMA P5121). The entocuneiform facet is mediolaterally long and dorsoplantarly narrow, similar to those of D. optatum and Z. trilobus, but extends the same length as the talar facet, as in D. optatum. The ectocuneiform facet is also identical to that of D. optatum, except in that it nearly comes into contact with the talar facet.The navicular of d) articulates with the calcaneus, talus, navicular, ectocuneiform and metatarsal V. It is pentagonal in dorsal aspect with a concave medial edge. The talar facet is oval and deeply concave. The navicular facet is positioned craniomedially to the talar facet; the lower half is flat and is approximately half the size of the talar facet while the upper half is a thin surface between the talar and ectocuneiform facets. The calcaneal facet is positioned plantolateral to the talar facet and is around the same size; it is circular and convex. The plantar tuberosity is large, rugose and hooks anteriorly. A shallow groove is present on the plantolateral face of the cuboid between the plantar tubercle and the calcaneal facet. A deep groove is present between the plantar tuberosity and the metatarsal 5 facet. It is possible that either of the previous grooves may provide passage for the m. peroneus longus tendon. The lateral tuberosity extends along the lateral edge of the cuboid. A smooth surface on the anterior face of the lateral plantar tuberosity is present. The ectocuneiform facet is triangular and deeply craniocaudally concave. The metatarsal 5 facet is oval and saddle-shaped.The cuboid d articulAm. keanei is more similar in shape to that of Z. trilobus than any other compared diprotodontid. The talar facet is more concave, and smaller than in that of Z. trilobus. The medial plantar tubercle is larger than in that of Z. trilobus, similar to that in the Alcoota diprotodontid (NTM P7286) but is more anteriorly hooked, as in that of D. optatum. The lateral tubercle extends anteroposterior, as in that of Euo. grata. The ectocuneiform facet is more concave than in that of Z. trilobus. The metatarsal 5 facet is smaller and more concave than in that of Z. trilobus.The cuboid of f) is the smallest of the tarsals. It is pyramidal, narrowing to a plantar point. It articulates with the cuboid, navicular, meso-entocuneiform and metatarsals 2, 3 and 4. The navicular facet takes up the entire posterior face, the flat articular surface restricting rotational movement. The mesocuneiform facet takes up the entire medial face; its surface is slightly concave, allowing for some rotational movement. The cuboid facet takes up the majority of the lateral face; it is split into a dorsal and plantar facet that is separated by the cuboid-ectocuneiform ligamental fossa in the centre. The anterior face is slightly pointed causing metatarsal 2, metatarsal 3 and metatarsal 4 to be angled medially from the sagittal plane. The facet for metatarsal 4 is the largest of the three metatarsal facets on the anterior face and is restricted to the dorsal section of the ectocuneiform. The facet for metatarsal 3 is small and triangular and is the second smallest facet on the anterior face. The metatarsal 2 facet is a very small triangular facet located on the anteromedial corner.The ectocuneiform f is the D. optatum (UCMP 5735 (right), SAMA P5121, UCMP 57350 (left)), precise details of their shape may not be important. Their overall morphology appears to be more similar to that seen in D. optatum than that in the ectocuneiforms NTM P2999, NTM P2998 and NTM P2997 from Alcoota.Due to the poor resolution of surfaces in the CT scan, detailed comparisons of the articular facets are not possible; the specimen is bound together by a hard calcareous matrix, which prohibits disarticulating the specimen without damage and loss of preserved relationships. Given that the morphology of the articular facets appears to vary between specimens of e) is fused with the mesocuneiform. The combined tarsal is thin and mediolaterally elongated; it is dorsoplantarly concave; and is most robust at the medial end. It articulates with the navicular, hallux, metatarsal 2 and the entocuneiform. The navicular facet is elongated and extends across the entire posterior face. The entocuneiform facet is small and flat. The CT scan does not reveal details of the metatarsal 2 facet but it appears to be small and located on the dorsolateral corner of the anterior face. The hallucal facet is deeply mediolaterally concave and occupies most of the anterior face. Two tubercles, one dorsal and the other plantar, protrude from the medial extent of the body.The entocuneiform e is fuseAm. keanei differs from those of all diprotodontid entocuneiforms from Alcoota by being fused to the mesocuneiform. It differs from that of Euo. grata by not also being fused with the ectocuneiform. Is more similar to that of Z. trilobus than that of D. optatum. The body is craniocaudally narrower relative the mediolateral length than in those of Z. trilobus, and the metatarsal 1 facet is larger and more concave. The plantar and dorsal tubercles on the medial extremity of the body are found in NTM P4005, NTM P4006 and NTM P4007 from Alcoota, but are more prominent in Am. Keanei.The entocuneiform of The hallux  is square in dorsal view, 25.5 mm/30.0 mm, articulating with the entocuneiform and rotated in the transverse plane. The plantar face is concave with a small ligamental fossa in the centre. The entocuneiform facet is anterodorsally concave. A small ligamental fossa is present on the plantar face. A large, rounded sesamoid on the proximal anterior corner of the plantar face may indicate the presence of a phalanx that has been disarticulated and separated; although this sesamoid may have shifted from another location on the pes throughout the taphonomic process, since this is not observed in any other diprotodontid.Metatarsal 2 is the smallest of the five metatarsals and articulates with the ectocuneiform, mesocuneiform and metatarsal 3. It is cylindrical, being widest on the distal end and tapers proximally. The proximal articular end is triangular in dorsal view and composed of three facets. The mesocuneiform facet is on the posterior side and is the largest of the three. The entocuneiform facet is the smallest and is situated on the proximal-most tip. The metatarsal 3 facet is on the cranioproximal edge. The distal articular surface is globular.Metatarsal 3 is the second smallest metatarsal; it is cylindrical in overall shape and widest distally, and tapers proximally. It articulates with the entocuneiform, metatarsal 4 and metatarsal 2. The distal articular surface is globular.Metatarsal 4 is cylindrical and widest distally, and tapers proximally. It articulates with the entocuneiform, metatarsal 5 and metatarsal 3. The distal articular surface is globular with a slight keel on the plantar surface.mm. peroneus extends laterally from the cuboid facet. The distal articular surface is globular with a flat plantar surface.Metatarsal 5 articulates proximally with the cuboid and metatarsal 4. It is relatively flat and triangular in dorsal view with a convex lateral edge, similar to metacarpal 5, and curves medially to take up approximately half the anterior surface area of the pes. The cuboid facet is circular and mediolaterally concave. A large process for attachment of the A lateral pedal digital sesamoid is lateral of the distal articular facet. It is large, rounded and articulates with metatarsal 5 and proximal phalanx 5. The other sesamoid that would be on the medial side of the distal articular facet of metatarsal 5 has been displaced to the centre of the plantar surface of the metatarsal 5 .Z. trilobus, differing from those of D. optatum and Euo. grata by the lack of distinctly separate insertion points for the mm. peroneus on the lateral edge of the metatarsal 5. The metatarsal 2 is straighter and less arched than in those of D. optatum and Euo. grata. The metatarsal 1 is wider than in those of D. optatum and Euo. grata. The distal articular processes on metatarsal 2 to metatarsal 5 differ from those of Ng. tedfordi, Ni. lavarackorum, Ne. stirtoni and all Alcoota diprotodontids, except NTMP 4991 by the absence of a keel for sesamoids.Metatarsal 5 is most similar to that of Four digits project craniomedially from the craniodorsal distal articular facets of metatarsals 2\u20135 in the pes. All proximal phalanges are widest at the proximal end before tapering to a waist at 2/3 their length distally and then widen at the distal articular facet. The distal articular facets are saddle shaped with the articular surface being dorsoplantarly concave and slightly mediolaterally concave. Proximal phalanx 5 is the largest, with proximal phalanx 3 being the smallest and 2 and 4 are approximately equal in size; this same pattern applies to the middle phalanges. The plantar faces of proximal phalanges 5 and 4 have grooves for flexor tendons and this groove is largest in phalanx 5. The distal articular surfaces are only slightly rounded, allowing for little movement between the proximal and middle phalanges and restricting them to a permanently partially flexed position.The middle phalanges are shorter than the proximal and ungual phalanges. All middle phalanges are cylindrical (except the fifth) and constricted in width at mid-length. The proximal articular surfaces are oval and mediolaterally wide, shallowly concave, and form a weak ball and socket joint with the proximal phalanges. The distal articular facets are barrel shaped with the surface being dorsoplantarly slightly concave.Ungual phalanges 5 and 4 are present in SAMA P54742, with the distal ends broken off. Both have large, arch-shaped articular facets. The surface is saddle shaped and slightly raised at the medial keel. A flexor tubercle is present on the proximoplantar end of ungual phalanges and is largest in ungual phalanx 5. The flexor tubercles are triangular in plantar view, tapering anteriorly; a deep fossa is present on the medial and lateral sides. Both unguals are broken at the distal ends making the shape of the unguis difficult to determine.Am. keanei differ from those of Euo. grata by being more robust; the distal articular surfaces of the proximal phalanges are less plantarly deflected; the articular facets for sesamoids are larger in proximal phalanges 5 and 4; and a distinct median keel is present on the unguals. A large sulcus is present on the proximal phalanx 5. Phalanges of Am. keanei differ from those of D. optatum by a large groove for flexor tendon on proximal phalanx 5.Phalanges of . 3.2.20D. optatum footpad impressions from Lake Callabonna  and therefore are interpreted as fossilized/replaced soft tissue structures that may have been replaced during rapid anaerobic decay of organic matter [The description of footpad morphology is based on observations of the images derived from the CT scan . The CT c matter , more spc matter ,59. TherThe outer perimeter of the footpad impression is oval in overall shape (in plantar aspect) with five distinguishable sections which we refer to as pads figures  and 27; The navicular pad is medial to the calcaneal pad and terminates below the proximal half of the navicular, but most of the pad sits between the posterior border of the navicular and the medial curve of the calcaneal tuber. The plantar surface is populated with dorsoplantarly elongate outer chambers. A majority of the plantar surface is plantarly convex, as is the calcaneal pad.The hallucal pad is rectangular and rose abruptly dorsally of the navicular pad. The outer chambers were plantar-dorsally elongated.The metatarsal pad is the second largest pad, making up the entire anterolateral border of the pes. It extends unbroken from under the posterior border of the calcaneus to the distal end of metatarsal 5 and is sickle shaped. The outer chambers are oval and mediolaterally elongated in the anterior cross-section. The plantar surface of the footpad rises dorsally at near 90\u00b0 from the plantar surface of the metatarsal pad below the border of the phalanges and metatarsal.b,c).The dermal papillae on the phalangeal pad are closest to the bones of the foot and nearly contacting the phalanges. The outer chambers are oval in dorsal and anterior cross-sections b,c.. 3.3Am. keanei is 262 kg, with an upper bound of 334.1 kg and a lower bound of 190.0 kg.The mean body size estimate of . 4Ambulator keanei was described solely from tooth-bearing portions of the skull and isolated teeth. The partial skeleton described here  were found  from the type locality of Z. gilli  differs sufficiently from that of Am. keanei to warrant specific distinction ; howeveAm. keanei, Z. trilobus and Hulitherium tomasettii. Yet these taxa differ markedly in cranial and limb morphology. Some characters that were previously hypothesized to be diagnostic for Am. keanei, such as the mesostyle [Am. keanei. Our observations suggest that caution should be implemented when identifying diprotodontid taxa to species level from the dentition alone.There are also few characters of the molar dentition that can consistently be used to distinguish some diprotodontid taxa, including esostyle , vary inesostyle ; we advoMaokopia ronaldi, Euryzygoma dunense, Meniscolophus mawsoni, Kolopsis torus, Pyramios alcootense and Plaisiodon centralis). The postcranial material of the Alcoota diprotodontids was referred to as a collective here, but future studies should endeavour to find element associations within the sample that can be tied to the craniodental remains from which Alcoota species have hitherto been named. A method could be to associate the elements through phylogenetic inferences for other taxa, i.e. associating more material with features only found in diprotodontines or zygomaturines. However, the higher level systematics of the Diprotodontidae is in urgent need of review, particularly with the inclusion of postcranial characters. Another method may be to associate elements by size, abundance and functional groups. Postcranial material from the Lawson\u2013Daily Quarry may belong to Me. mawsoni, since it does not appear to belong to Am. keanei or Euo. grata, which are both found in the same deposit . Through our comparisons, we found that a humerus (NMV P232193) ascribed to a species of Zygomaturus, from Batesford Limestone Quarry, was slightly different in the termination of the deltopectoral crest from those of Am. keanei and Z. trilobus; yet, the dentition from Batesford Limestone Quarry could not be differentiated from those of Am. keanei and Z. trilobus. The specimens were found from an in situ bedded stratum of the Moorabool Viaduct Sand; 2.2 m above the underlying Fyansford Clay and Moorabool Viaduct Sand . The excavation of more material may lead to a new species being described from the deposit.Undescribed postcranial elements are known for a range of diprotodontids , because they are shared with D. optatum and Euo. grata. Leaving Am. keanei within Zygomaturus would also effectively mean that the genus would include other diprotodontids such as Hulitherium tomasettii.The stability of other genera is also in need of reassessment. For example, phyletic , while Mngeneric . We susp 4.2.Am. keanei is very similar to that of Z. trilobus, which led to its previous placement in the same genus. However, the cranium is markedly different. It is more elongate and most similar overall to that of Kolopsis torus. The incisors of Am. keanei consist of a large I1 with a smaller I2 and I3, unlike the broad, chisel-shaped I1 of D. optatum or the wide I3 and I2 of Neohelos stirtoni. Herbivores that consume large amounts of tougher, low-nutrient food (e.g. grazers) usually possess broader incisors and a larger incisor arcade, while those that eat lower quantities of softer, more nutritious food (browsers) usually have smaller, narrower, more selective incisors [Am. keanei may have consumed a higher proportion of browse than D. optatum, which is hypothesized to have been a mixed feeder [Am. keanei are splayed and pointed similar to those of Z. trilobus, not scooped as in Py. alcootense or bladed as in Kolopsis torus, and may have been less suitable for cutting and procuring food. This tusk-like lower incisor morphology may also have had a secondary function, e.g. in defence or intraspecific competition, similar to Rhinoceros unicornis (Indian rhinoceros) [The dental morphology of incisors ,70. Consd feeder \u201373. The noceros) ,75. It inoceros) .Am. keanei are low crowned, bilophodont, and characterized by wide interlophid valleys and low crests, similar to those of H. tomasettii and Z. trilobus, but unlike the high-crowned molars of D. optatum. Previous analyses of molar microwear and \u03b413C isotopes of both H. tomasettii and Z. trilobus have shown values expected in those of browsers [\u03b413C values typical of browsers have also been observed in dental material from Eur. dunense, which has a very different molar morphology [Eur. dunense, Me. mawsoni and Euo. grata, the lower crown height of Am. keanei may indicate that it was adapted to a less abrasive diet. The extremely worn teeth of SAMA P54742 may, for this individual, reflect old age or a high-wear diet to which Am. keanei was not expressly adapted. In addition, the smaller crests and wider interloph(id) valleys compared with those of Eur. dunense, Me. mawsoni and Euo. grata may have provided a greater surface area for crushing and grinding food than cutting, which is also consistent with less abrasive food [The molars of browsers ,77. Howerphology . Higher rphology ,79\u201381. Bive food ,82.Am. keanei would have provided less attachment area for the masseter than in Z. trilobus, Euo. grata and Eur. dunense. The size and proportions of jaw adductor muscles have been shown to differ between different dietary groups of extant marsupial herbivores [Am. keanei are proportionally smaller compared to the cranium and positioned more posterior to the tooth row than to those of Z. trilobus. This suggests that Am. keanei primarily fed on softer material that required less processing than the diets of Z. trilobus and D. optatum.The smaller zygomatic arch and masseteric process in rbivores ,84. Exparbivores ,85. Massrbivores ,87. The . 4.3. 4.3.1Am. keanei is morphologically more similar to that of D. optatum than to those of Z. trilobus, Ne. stirtoni, Ng. tedfordi, H. tomasettii, Kolopsis torus, Pl. centralis and Py. alcootense. The humeral head of Am. keanei is more ovoid and less caudally projected than that of Ne. stirtoni. This is thought to stabilize the shoulder and reduce movement to the anteroposterior plane during locomotion [m. latissimus dorsi and m. deltoideus in Am. keanei indicate restricted adduction and abduction of the arm. The large m. deltoideus attachment site also suggests the deltoids acted to extend and stabilize the shoulder during locomotion.The forelimb of comotion ,89. A lecomotion . The larAm. keanei superficially resemble that of the Loxodonta africana (African elephant), as Murray [D. optatum. The prominent infraglenoid process observed in the scapulae of Am. keanei, Z. trilobus and D. optatum would provide a large attachment area and leverage for the m. triceps brachii caput longum, which originates in this area in other marsupials [Lasiorhinus latifrons (southern hairy-nosed wombat) and Phascolarctos cinereus  by J.D.v.Z. and A.B.C.). The structure of the infraglenoid tubercle resembles the hooked angulus caudalis in Lo. africana, which provides an attachment area for a range of muscles, including the m. triceps brachii caput longum [The forelimb morphologies of Pleistocene diprotodontids and s Murray  observedrsupials ,40,42 (ut longum .Lo. africana) provides attachment for the m. rhomboids and likely was antagonistic to the m. triceps brachii caput longum. The large, caudally hooked coracoid process provides a larger lever for the m. biceps brachii, which may have been important for weight bearing by preventing flexion of the shoulder joint and countering the m. triceps while standing, similar to that in extant horses [Am. keanei, Z. trilobus and D. optatum, but absent from late Miocene taxa . They suggest that Am. keanei was capable of strong extension of the elbow and shoulder to support its weight during locomotion. Similarities in forelimb morphology to Lo. africana have previously been hypothesized by Murray [D. optatum (and by extension Am. keanei) may have walked by swinging its forelimbs in a pendulous, low-energy form of locomotion. This is supported by trackway evidence of Pliocene and Pleistocene diprotodontids, where the footprint for the manus and pes overlap [The robust, medially deflected cranial angle of the scapula  and absence from Pliocene and Pleistocene diprotodontines (D. optatum and various humeri that could be Eur. dunense or Euo. grata). The proximal ulna is not known for Am. keanei.The morphology of the distal humerus of f motion . The supf motion ,97. HoweAm. keanei appears to be primarily adapted to weight bearing as opposed to other functions such as grasping. The large styloid process on the ulna and hamatum process on the radius indicates more weight being distributed across the manus than in earlier diprotodontids . The large ball and socket joints (radius-scaphoid and ulna-pisiform-triquetrum) also provide additional bracing against lateral stresses when compared to pre-Pliocene diprotodontids . The large size of the carpals relative to the metacarpals suggests that a substantial portion of the weight-bearing role has been shifted from the phalanges to the carpus, including a significant portion of weight on the pisiform, as seen in D. optatum  similar to the calcaneus in the pes [Ne. stirtoni, Ng. tedfordi, Ni. lavarackorum, Kolopsis torus, Pl. centralis and Py. alcootense), making Am. keanei the earliest diprotodontid species observed to possess it , but larger than in D. optatum or Z. trilobus  with an enlarged metatarsal 5 and calcaneus is superficially reminiscent of that seen in ground sloths, in which it has been termed \u2018pedolateral rotation\u2019 and hypothesized to allow for their upright bipedal position . The out humans . Furthermore, the manus appear to be more specialized for quadrupedal locomotion than in earlier diprotodontids and Z. trilobus, with greatly reduced grasping and food manipulation ability. The late Miocene to Pliocene saw the climate of Australia becoming cooler and drier, which drove the expansion of C4 grasslands and grassland-adapted herbivores [Am. keanei, needing to travel further for food and developing more efficient means of travelling between locations. The more open grassland habitats may have facilitated the specialization of limbs for increased vagility. Some adaptations in the limbs may also reflect increased body size among diprotodontids. However, size estimates based on humeral circumference for Am. keanei are smaller than those estimated for Alcoota diprotodontids  and Z. trilobus, the latter displaying a morphology indicating its forelimb was adapted to a different function.Many aspects of the postcranial morphology of rbivores ,106\u2013108.rbivores . This maodontids , which migratory  and perhmb bones , and the. 5Ambulator keanei. This is only the fourth species of post-Miocene diprotodontid for which postcranial material has been described and includes the first three-dimensional description of the footpad morphology for the family. We found that Am. keanei expresses the earliest evidence for specialized graviportal locomotion within diprotodontids, suggesting that it may have been relatively vagile, which may correlate with late Pliocene grassland expansion. We also found evidence that the phalanges of graviportal diprotodontids were not used in weight bearing during locomotion. Systematic comparisons of established diprotodontid taxa indicate that inclusion of postcranial morphology in phylogenetic analyses is needed in order to resolve both species- and the higher-level taxonomy for the Diprotodontidae. Rare, well-preserved skeletal and soft tissue material found in the Main Body of the Tirari Formation indicates considerable potential for discovery of additional material. Future efforts should target collecting more vertebrate material from this formation. This may lead to not only a better understanding of marsupial diversity but a better understanding of the faunal change of Australia through time.We describe the first postcranial material known for"}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-023-36363-2, published online 05 June 2023Retraction of: The Editors have retracted this Article.After publication, it was brought to the Editors\u2019 attention that the methods used to determine the sensitivity, specificity, and cut-off values presented in Table 5 are not described in sufficient detail to allow reproduction of the analyses. The Editors contacted the Authors to request clarifications and the raw data underlying the study. The Authors were not able to provide a clear and valid description of the methodology. They did provide some of the data; however, these were not the original raw data and the Editors were not able to confirm their veracity.The Editors therefore no longer have confidence in the results and conclusions presented in this Article.Khalid M. Mohany disagrees with the retraction. Mona A. H. El-Baz and Ahmed F. Amin did not respond to the correspondence about this retraction."}
+{"text": "Funding statement. The Shenzhen City project support was omitted. The correct Funding statement appears below.In the published article, there was an error in the"}
+{"text": "This is a correction of Biochem Med (Zagreb) 2023;33(2):020704. DOI: https://doi.org/10.11613/BM.2023.020704 Since the publication of the article, the authors have noticed that their first names and surnames in the by-line were listed in reverse. The correct by-line is presented above. We apologize to the authors for any inconvenience caused to the readers."}
+{"text": "Cucumis melo L.) has a long history of cultivation worldwide. During cultivation, domestication, and selection breeding, the sugar content of mature melon fruits has been significantly increased. Compared with unsweet melon and wild melon, rapid sucrose accumulation can occur in the middle and late stages of sweet melon fruit development. The phloem unloading pathway during the evolution and development of melon fruit has not been identified and analyzed. In this study, the phloem unloading pathway and the function of related sugar transporters in cultivated and wild melon fruits were analyzed by CFDA [5(6)-carbofluorescein diacetate] and esculin tracing, cytological pathway observation, qRT\u2013PCR, and gene function analysis, etc. Results show that the phloem unloading pathway of wild melon fruit is largely symplastic, whereas the phloem unloading pathway of cultivated melon fruit shifts from symplastic to apoplasmic during development. According to a fruit grafting experiment, the fruit sink accumulates sugars independently. Correlation analysis showed that the expression amounts of several sucrose transporter genes were positively correlated with the sucrose content of melon fruit. Furthermore, CmSWEET10 was proved to be a sucrose transporter located on the plasma membrane of the phloem and highly expressed in the premature stage of sweet melon fruits, which means it may be involved in phloem apoplast unloading and sucrose accumulation in sweet melon fruits. Finally, we summarize a functional model of related enzymes and sugar transporters involved in the apoplast unloading of sweet melon fruits during enlargement and sucrose accumulation.Melon ( Sugar is transported from sources to sinks through three steps: loading into the phloem of source leaves, long distance flow within the phloem, and unloading to sink organs. During the past decade, phloem transport research has focused on phloem loading and unloading . Phloem Cucumis melo L.) is one of the most widely grown crops of the Cucurbitaceae family and is consumed worldwide  (Melon [a (MPG)] . During et al.  were analyzed from the database of Cucurbit Genomics  for providing melon seeds and thank Professor Chunlong Li  for providing yeast strain CSY4000. We thank Muhammad Mohsin Kaleem for his critical reading and editing of the manuscript. We also thank Jianbo Cao and Limin He  for transmission electron microscope support. This work was supported by the National Natural Science Foundation of China (31972435), the National Key Research and Development Program of China (2019YFD1000300), the Fundamental Research Funds for the Central Universities (2662018QD062), and the China Agriculture Research System of MOF and MORA (CARS-25).J.C., Y.Z., and Z.B. conceived and designed the experiments. Y.Z. performed most of the experiments and analyzed the data. K.L. identified the functional characteristics and subcellular localization of SWEET protein. D.Y., P.Z., and J.C. performed the CFDA and tracing experiment. S.W. measured the sugar content. Z.W. and Y.Z. performed the qRT\u2013PCR. Y.Z. and J.G. conducted the fruit grafting experiment. Y.Z. prepared the figures and tables and wrote the first draft of the manuscript with assistance from S.W. J.C. revised the manuscript and figures.Relevant data can be found within the paper and its supporting materials. All data from this study are available from the corresponding author upon reasonable request.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.Horticulture Research online.Web_Material_uhad123Click here for additional data file."}
+{"text": "A predictive model based on ground glass nodule features via high-resolution CT for identifying invasiveness of lung adenocarcinoma By Yan B, Chang Y, Jiang Y, Liu Y, Yuan J and Li R. (2022). Front. Surg. 9:973523. doi: 10.3389/fsurg.2022.973523A Retraction of the Original Research Article The journal and Chief Editors retract the 26 August 2022 article cited above.This article is retracted by Frontiers. The publisher has discovered that the authors provided false information for the peer-review process. As the scientific integrity of the article cannot be guaranteed, and adhering to the recommendations of the Committee on Publication Ethics (COPE), the publisher therefore retracts the article.The authors have not responded to this retraction.This retraction was approved by the Chief Editors of Frontiers in Surgery and the Chief Executive Editor of Frontiers."}
+{"text": "Error in Figure, as published. The corrected  appears below. The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated.In the original publication , there w"}
+{"text": "Hymenoptera as published. The figure shows pictures of members of the Vespidae family. Two of these images were wrong. Polistes picture showed a Vespula, and contrariwise Vespula picture presented a Polistes. The corrected Taxonomy of Hymenoptera appears below. The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. The original article has been updated.In the original article , there w"}
+{"text": "The authors regret that in the caption of Fig. 1, ref. 36 was wrongly attributed as the original source of the figure. The correct figure caption is shown here:Fig. 1 The assembly of a sandwich-type carbon nanotube (CNT) immunosensor and its detection method is depicted schematically. The antibodies are attached onto CNTs through a poly layer. This figure has been adapted/reproduced from ref. 117 with permission from Wiley, copyright 2014.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "In the published article, there was an error in the author list as published. The Parkinson's Progression Markers Initiative was erroneously excluded. The author list has now been updated.In addition, an Author's note was missing from the published article. The updated Author's note appears below:Author's noteMembers of Parkinson's Progression Markers Initiative (PPMI) are listed in the Supplementary material.In addition, a Supplementary material file listing the members of The Parkinson's Progression Markers Initiative was erroneously excluded from the publication. The Supplementary material has now been published alongside the original article.In addition there was an error in the Acknowledgments statement as published. The date of data download, the full address of the PPMI database and the RRID number was missing. The updated Acknowledgments statement appears below.Acknowledgmentswww.ppmi-info.org/access-data-specimens/download-data), RRID:SCR_006431. For up-to-date information on the study, visit www.ppmi-info.org.Data used in the preparation of this article were obtained on September, 2nd 2022 from the Parkinson's Progression Markers Initiative (PPMI) database (The authors apologize for these errors and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "The authors wish to make the following corrections to this paper .S. aureus 3515 were prepared by a Ph.D. student who is not a co-author of this paper. Thus, these images involve copyright issues and need to be corrected. The corrected In the original publication, there were mistakes in"}
+{"text": "Relationship with the diaphragm to predict the surgical outcome in large and giant pituitary adenomas By Harel E, Cossu G, Daniel RT and Messerer M. (2022) Relationship with the diaphragm to predict the surgical outcome in large and giant pituitary adenomas. Front. Surg. 9:962709. doi: 10.3389/fsurg.2022.962709An Erratum on An omission to the funding section of the original article was made in error. The following sentence has been added: \u201cOpen access funding was provided by the University of Lausanne\u201d.The original version of this article has been updated."}
+{"text": "In the original version of our article, there was an error in Figure 2E. Specifically, the representative images of TPC-1 cell line were incorrect. The correct image is provided below. This correction will not affect the results and conclusions. The authors apologize for any inconvenience this may have caused."}
+{"text": "R. Soc. Open Sci.10, 230402. (Published online 19 July 2023) (https://doi.org/10.1098/rsos.230402)Owing to an error in the code, the activity-level data used in the linear-mixed model was incorrect changing the quantitative results of the model. All other activity measures used throughout the publication were unaffected and remain correct. Here we correct the values in table 1.In the Discussion of the original paper, we compared the effect size of distance and activity: \u2018The estimated coefficients for the scaled activity level and scaled distance show that the effect of the distance was stronger\u2019. With the corrected values, the impact of these factors is comparable."}
+{"text": "In this article , James JThe Authors\u2019 Contributions section has been revised to:ECH performed the data analysis and wrote the manuscript. MS and KB calculated and validated the dose-voxel kernels. DL provided editorial review. JNB and ACG contributed to the protocol development, execution of the experiments, and interpretation of the data. CM performed structure delineation in rabbit CT volumes. JJK performed the interventional procedures. RJA contributed to the protocol development, data analysis, and interpretation of the data. SCK contributed to the data analysis and interpretation of the data. AS and GM contributed to the conceptualization and review of the study. All authors contributed to the drafting and revision of the manuscript. All authors read and approved the final manuscript.The original article  has been"}
+{"text": "Look to the stars\u2014Is there anything that public health and rehabilitation can learn from elite sports? By Millet GP and Chamari K. (2023) Front. Sports Act. Living. 4:1072154. doi: 10.3389/fspor.2022.1072154An Erratum on An omission to the funding section of the original article was made in error. The following sentence has been added: \u201cOpen access funding was provided by the University of Lausanne\u201d.The original version of this article has been updated."}
+{"text": "Her medical history is pertinent for C3-C6 anterior cervical fusion 19 years before and surgical myotomy 12 years ago for reported ZD that presented with similar symptoms. Barium esophagram showed a left lateral diverticulum of the cervical esophagus without serosal perforation and cervical hardware near it  is an uncommon disease mostly of the elderly male population. Other types of pharyngoesophageal diverticula have also been reported as a rare complication of anterior cervical spine surgery. Figures . Once thAuthor contributions: K. Modi: review of literature, substantial contributions to the conception and design of the work, and drafting and revising the work. C. Eke: substantial contributions of the conception and design of the work and drafting and revising work. D. Lee, P. Tarnasky: analysis and interpretation of data for the work and revising the work critically for important intellectual content. K. Modi is the article guarantor.Financial disclosure: None to report.Informed consent was obtained for this case report."}
+{"text": "In the published article, an author name was incorrectly written as Qiyu Wang. The correct spelling is Xinyu Wang.In the published article, there was an error. The author's initials in the Author contributions section were written incorrectly.A correction has been made to Author contributions. This section previously stated:XW conceived and designed the experiments. JR wrote the manuscript. QW, QC, and YJ performed the data analyses. WF and HH collected data and information. SL and LS helped to perform the analysis and followed up patients. All authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication.The corrected section appears below:XWu conceived and designed the experiments. JR wrote the manuscript. XWa, QC, and YJ performed the data analyses. WF and HH collected data and information. SL and LS helped to perform the analysis and followed up patients. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors apologize for these errors and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "The author list of this article has been corrected to include Dr. Bibhu D. Mohanty, who was mistakenly omitted by the authors. This omission was not discovered until after publication. The authors regret the error. Dr. Bibhu D. Mohanty is now listed as the 10th author."}
+{"text": "The original publication of this article contained an incorrect funding section. The correct and incorrect information is listed in this correction article, the original article has been updatedIncorrectNot applicable.CorrectThis study was based on data from Fatemeh Jahanjoo\u2019s Ph.D. thesis, which was financially supported by the Research Deputy of the Tabriz University of Medical Sciences (TUOMS) under Grant No. 64041 and approved by the Institutional Review Board of TUOMS with ethics code: IR.TBZMED.REC.1398.1244."}
+{"text": "Acknowledgements statement. Support received by CR from the Canada Research Chair program was omitted from the statement.In the published article, there was an error in the The corrected Acknowledgements statement appears below.The authors would like to acknowledge the technical assistance of Dr. Aja Rieger, Mariana Juarez-Platas, Dhruvesh Patel, Nicole Coursen, Marnie Newell, and Audric Moses. We express our gratitude to the undergraduate students that worked on the project. CR was supported by the Canada Research Chair program (CRC-2018-00081).The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "Caption: A Svalbard reindeer grazing on the summer tundra in Adventdalen, Svalbard. In the background are the mountains and glaciers on the north side of Isfjorden, wherereindeer were reintroduced to from Adventdalen.Credit: Hamish Burnett."}
+{"text": "Kinesin family member 2A serves as a potential biomarker reflecting more frequent lymph node metastasis and tumor recurrence risk in basal-like breast cancer patients By Yang H and Liu Y. (2022) Front. Surg. 9:889294. doi: 10.3389/fsurg.2022.889294A Retraction of the Original Research Article The journal and Chief Editors retract the 16 June 2022 article cited above.This article is retracted by Frontiers. The publisher has discovered that the authors provided false information for the peer-review process. As the scientific integrity of the article cannot be guaranteed, and adhering to the recommendations of the Committee on Publication Ethics (COPE), the publisher therefore retracts the article.The authors have not responded to this retraction.This retraction was approved by the Chief Editors of Frontiers in Surgery and the Chief Executive Editor of Frontiers."}
+{"text": "In the published article, there was an error in the Funding statement and funding from the Italian Ministry of Health was omitted. The correct Funding statement appears below.The Me.Me.Me. study was funded by an advanced grant from the European Research Council (ERC-AdG-2012 n. 322752). This research was also supported by Italian Ministry of Health \u201cRicerca Corrente\u201d funds.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "In the published article, an author name Eliseu Verly-Jr. was incorrectly written as Eliseu Velry-Jr.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "J. Cell Sci. (2022) 135, jcs259586 (doi:10.1242/jcs.259586).There was an error in The name of the author Kai Tang was spelled incorrectly (Kai Tan). The correct name appears above, and both the online full-text and PDF versions of the article have been updated. We apologise to the authors and readers for this error."}
+{"text": "Guest EditorLawrence L. SprietHuman Health and Nutritional Sciences,University of Guelph,Guelph, ON,Canadalspriet@uogelph.caDisclosures: This supplement is supported by the Gatorade Sports Science Institute (GSSI), a division of PepsiCo, Inc.Guest Editor Conflicts of Interest: This supplement was guest edited by Dr. Lawrence L. Spriet, who attended a meeting of the GSSI Expert Panel in October 2022 and received honoraria from GSSI for his participation in the meeting and the writing of the preface for the supplement. Dr. Spriet received no honorarium for guest editing the supplement. Dr. Spriet has no potential conflicts of interest that are directly relevant to the content of this supplement."}
+{"text": "There was an error of omission in the original publication , in the A correction has been made to the Conflicts of Interest section. The revised text is: \u201cThe author N.N. declares no conflict of interest as an independent researcher. R.M. and S.M.-v.S. are the inventors of the DASD device, full-time staff members of the University of the Western Cape and joint patent holders with the University of the Western Cape. The DASD device was licensed for manufacture and sale to Amplitude Consulting PTY (LTD) between October 2021 and December 2022. R.M. and S.M.-v.S. are shareholders of Amplitude Consulting PTY (LTD).\u201dThe authors state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."}
+{"text": "In the original published version of this article, the acknowledgements section omitted some information. This has now been corrected to \u201cG.P. Marquez and R.B. Salonga would like to acknowledge Ritsumeikan University and Nagoya City University, respectively, for their internal research grant support.\u201d The authors apologize for these errors. Both the HTML and PDF versions of the article have been updated to correct the error."}
+{"text": "Jin TY and Li ZH analyzed the data. Jin TY, Tang JW and Xu J contributed analysis tools. Chen L and He ZC provided critical inputs on design, analysis and interpretation of the study. All the authors had access to the data. All authors read and approved the final manuscript as submitted."}
+{"text": "In the published article, there was an error in the Funding statement. The funding statement was forgotten. The correct Funding statement appears below.FUNDINGThis work was supported by grants from the National High Level Hospital Clinical Research Funding of China (No. 2022-PUMCH-A-194).The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "Fan L performed the experiments and analyzed the data. Qin JL contributed analysis tools. Lin XD contributed immunohistochemical techniques. Wu Y and He ZZ collected the data. He P provided critical inputs on design, analysis, and interpretation of the study. All the authors had access to the data. All authors read and approved the \ufb01nal manuscript as submitted."}
+{"text": "Migratory birds have long been implicated in the spread of avian influenza . They arHPAIV is also infectious to mammals. Mammal-to-mammal transmission has been reported regularly . In JapaLarge-scale industrial-level poultry-rearing practices need to be reviewed across the country. Japan's livestock administration has promoted large-scale industrial overcrowding. However, this production system makes livestock vulnerable to infectious diseases and fails to ensure sustainability. Awareness of animal welfare has increased over the recent years, especially in European countries, adding various regulations in farming practices. Limiting the number of animals raised per square foot is such an example . As for In Japan, the measures taken in response to avian influenza are positioned as an area of \"Disaster Response and Recovery Assistance.\"  In this Conception and designing of the study; KY.Data collection; OA and TT.Data analysis and interpretation; KY.Writing this paper; KY.Critical revision of the paper; OA, GT and TT.All the authors read the final draft and approved submission.None.Medical Network Systems Inc. and Kyowa Kirin co. ltd. outside the submitted work. Dr Tanimoto reported personal fees from Medical Network Systems Inc. and Bionics co. ltd., outside the submitted work. No other disclosures were reported.Dr Ozaki reported personal fees from"}
+{"text": "Adams, The Physiological Society and American Physiological Society, and John Wiley and Sons Ltd. The retraction has been agreed at the authors' request. Since publication, the authors have identified that the calculation of microcirculatory resistance does not require a correction factor. This invalidates several figures in the paper and the overall conclusions. The editors have no ethical concerns about the paper. The authors have prepared a Letter to the Editor (10.14814/phy2.15807) explaining, in detail, the error and their decision to retract the paper.The above article, published online on 10 March 2023 in Wiley Online Library ( Adams, The Physiological Society and American Physiological Society, and John Wiley and Sons Ltd. The retraction has been agreed at the authors' request. Since publication, the authors have identified that the calculation of microcirculatory resistance does not require a correction factor. This invalidates several figures in the paper and the overall conclusions. The editors have no ethical concerns about the paper. The authors have prepared a Letter to the Editor (10.14814/phy2.15807) explaining, in detail, the error and their decision to retract the paper.The above article, published online on 10 March 2023 in Wiley Online Library ("}
+{"text": "Tu M, Jia HX and Liu HP performed the experiments. Wang XJ and Wang Y analyzed the data. Wang YB and Jiang N contributed analysis tools. Lu CY provided critical inputs on design, analysis, and interpretation of the study. All the authors had access to the data. All authors read and approved the final manuscript as submitted."}
+{"text": "A grant was incorrectly added in the Funding Statement. The first sentence of the Funding Statement should read: \"This research was supported by grants from the National Natural Science Foundation of China (No. 91217301 to B.K.H.).\""}
+{"text": "In the author list, the spelling of the name Wladmir J. Alonso is incorrect.The correct spelling is Wladimir J. Alonso."}
+{"text": "Journal of Cellular and Molecular Medicine , \u2018Differential proteomic profiling to study the mechanism of cardiac pharmacological preconditioning by resveratrol\u2019 by Karel Bezstarosti, Samarjit Das, Jos. M. J. Lamers and Dipak K. Das, and published in the October 2006 issue in Wiley Online Library (http://onlinelibrary.wiley.com), has been retracted by agreement between the authors, the journal Editor-in-Chief, Professor LM Popescu and Blackwell Publishing Ltd. The retraction has been agreed due to findings of data fabrication in the western blot data in Figure 6 that occurred in the laboratory of Dipak K. Das in an investigation into the work of Dipak K. Das by the University of Connecticut Health Center. Although no questions have been raised concerning the data generated by Karel Bezstarosti and Jos M J Lamers, these authors fully support the retraction.The following article from"}
+{"text": "A funding organization and grant were incorrectly omitted from the Funding Statement. The following sentence should be read after the first sentence of the Funding Statement: \"P.J.C. is funded by the US Public Health Service grant GM098629.\""}
+{"text": "A patient with anaplastic meningioma and lung metastases resistant to conventional treatment underwent radiopeptide therapy with 177Lu- DOTA-octreotate in our institute. The treatment resulted in significant improvement in patient's quality of life and inhibition of tumor progression. This case may eventually help to establish the value of radiopeptide therapy in patients with this rare condition. Meningiomas are generally slow-growing lesions that arise from intracranial and spinal meninges. They are usually perceived as benign tumours for which radical surgery is the treatment of choice . HoweverA 62 year old female with intracranial anaplastic meningioma was referred to our department for a restaging with 18F-fluorodeoxyglucose (FDG)-PET/CT. The patient suffered from a protrusio bulbi of the left eye and progressive facial pain. No conventional treatment option could be offered to the patient, who had undergone multiple surgical resections and percutaneous radiation before.The fused PET/CT images  manifested multifocal accumulation in the left temporal region with local bone infiltration. Furthermore, they demonstrated multiple pulmonary metastases in the upper lobe of the left lung Figure . In viewThe local recurrence rate of meningioma is determined by the extent of the resection, histopathological grade and biological aggressiveness of the tumor ,9. Once The presented case may help to establish the value of PRRT in patients with the rare condition of anaplastic meningioma.The authors declare that they have no competing interests.Conception of the case report: A.S., S.E., HJ.B.; Collection and assembly of data: H.A., W.W., U.H.; Literature review and interpretation of data: A.S. S.E., H.A.; Drafting of the article: A.S., HJ.B., S.E.; Critical revision of the article for important intellectual content: U.H., H.A. W.W. All authors have read and approved the final manuscript.Written informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal."}
+{"text": "Published 09 July 2013Derbyshire ER, Clardy J. 2013. Closing in on a new treatment for sleeping sickness. Trypanosoma brucei.The title of the related research article was incorrect in two locations, next to the accompanying image in the key information box and in the reference list. The correct title of the related research article is: Hypothemycin, a fungal natural product, identifies therapeutic targets in The article has been corrected accordingly."}
+{"text": "In the Methods section of our published article , the evoMoreover, the experimental results contained in this paper were obtained by the first author in cooperation with Dr. U. Welzel, Dr. E. Bischoff and Prof. Dr. E.J. Mittemeijer  during the stay of the first author in the department of Prof. Dr. Mittemeijer. Thus the authors would like to express our gratitude to them in the Acknowledgements section of this published article ."}
+{"text": "Frankel and colleagues have compared Israel and the U.S.\u2019s experiences with health information exchange (HIE). They highlight the importance of institutional factors in fostering HIE development, notably the influence of local structures, experience and incentives. Historically, information infrastructure in the U.S. has been limited due to lack of standards, fragmented institutions and competition. The Health Information Technology for Economic and Clinical Health (HITECH) Act of 2009 authorized billions of dollars for the adoption and \u201cMeaningful Use\u201d of electronic health records. HITECH programs and Meaningful Use incentives target the advancement of HIE through 1) building blocks, 2) local support and 3) payment incentives. Meaningful Use requirements create a roadmap to broader electronic exchange of health information among providers and with patients. Ultimately, successful HIE in the U.S. will depend on whether Meaningful Use can address institutional needs within local markets.http://www.ijhpr.org/content/2/1/722This is a commentary on  Health information technology  has the potential to improve the safety, efficiency and quality of patient care . Health The Israel Journal of Health Policy Research the authors analyze the role of institutional factors in the development of HIE initiatives in Israel and the U.S. [In Frankel and colleagues\u2019 article published recently in the U.S. . In bothIn the U.S., HIE strategy has evolved over time within a competitive, fee-for-service environment with fragmented providers. Early policies focused on development of a nationwide health information network, an architecture that sought to connect community-level HIE entities within regional markets . RegionaIn 2009, the national strategy for the advancement of HIE shifted with the Health Information for Economic and Clinical Health (HITECH) Act of 2009. HITECH authorized the Office of the National Coordinator for Health Information Technology to implement programs and created the Medicare and Medicaid Electronic Health Records Incentive Programs to award incentive payments to physicians and hospitals to adopt and meaningfully use interoperable electronic health records (EHRs) ,11. HITEWidespread information sharing requires the technical ability to securely and reliably send and receive structured data from disparate sources. In the U.S., the national HIE strategy focuses on standards, policies and services as building blocks to enable the exchange of health information through regional HIOs and/or through interoperable EHRs . The StaStarting conditions and institutional context may vary across communities resulting in unique barriers to HIE. For example, a key barrier to sharing health information is limited existing infrastructure to connect unaffiliated providers and hospitals. The provision of technical assistance can aid stakeholders in overcoming these barriers. HITECH created three programs at the local-level to develop infrastructure and assist with Meaningful Use . The StaBeyond building blocks and local support, national policies in the U.S. have focused on aligning Meaningful Use with payment incentives to create a business case for information sharing outside the organization. Meaningful Use incentives require providers and hospitals to exchange health information with outside providers and with patients through certified EHR technology. Stage 2 requirements include the exchange of transitions of care summaries and the capability to share standards-based data across vendor platforms . Beyond Institutional factors highlighted by Frankel and colleagues will continue to shape the context and incentives for broader electronic exchange of health information. In the U.S., the national strategy leverages Meaningful Use as a roadmap to advance HIE through regional HIOs and interoperable EHRs. Policies and programs address institutional challenges through building blocks, local support and payment incentives. Standards and certification enable providers, hospitals, and patients to share health information through interoperable EHRs. State designated entities and regional extension centers provide technical assistance to meet the Meaningful Use requirements for electronic exchange. Finally, the alignment of Meaningful Use with payment incentives creates a business case for information sharing outside the organization. Ultimately, the future success of HIE in transforming patient care and empowering consumers in the U.S. will depend on whether Meaningful Use can address the needs of institutions within local markets.The author declares that they have no competing interests.Michael F. Furukawa is the Director of the Office of Economic Analysis, Evaluation and Modeling at the Office of the National Coordinator for Health Information Technology (ONC) in the U.S. Department of Health and Human Services in Washington D.C. Previously, he was an Assistant Professor in Health Management and Policy at Arizona State University.Frankel M, Chinitz D, Salzberg CA, Reichman. Sustainable Health Information Exchange: The Role of Institutional Factors. The Israel J of Health Policy Research 2013, 2:21."}
+{"text": "The World Allergy Organization Journal on page 62, the name Arthur Eisen is incorrect. This should appear as Herman Eisen.In the article \"Memories: Failures and Dreams by Alain de Weck. A Book Review,\" which appeared in volume 2 of http://www.waojournal.org.This error has been noted in the original version of the article, which is available at"}
+{"text": "Irish Veterinary Journal with BioMed Central, The Open Access Publisher, as part of their increasing veterinary portfolio. This is indeed an historical moment in the history of Irish Veterinary Journal, which was first published in November 1946. In this electronic age that we live in, it is interesting to note that the publication of the first issue was delayed by a post-war shortage of paper.As Editor-in-Chief, I am delighted to announce the re-launch of Irish Veterinary Journal was a study of blood serum parameters in cattle, horses, sheep and pigs in Ireland by W. Burke McAleer; a paper that emerged from his PhD thesis in the Veterinary College in Dublin. In its early years an editorial committee managed the journal and there was no mention of an individual Editor until the mid-1960s when J.K. Kealy was listed officially as Editor. B.T. Farrelly, who presided over the IVJ until 1980, soon followed him. Dr. Pat Hartigan became Editor in 1981 and worked tirelessly as peer-review Editor for many years until 2006. Management of publishing over this period was carried out by Irish Veterinary Publications Ltd. and more recently by IFP Media Ltd. for the new Veterinary Ireland organisation.The first scientific paper published in the Irish Veterinary Journal, with the support of Veterinary Ireland - the Irish professional representative organisation, is delighted to become part of the greater BMC publishing family and hopes to offer a new voice for high quality veterinary research internationally. Along with my Deputy Editors, Simon More, John Mee and Grace Mulcahy and expert editorial board, I would like to wish the new Irish Veterinary Journal every success.The move to Biomed Central heralds an exciting chapter in the history of the journal. Gu\u00edm gath rath ar Iris Tr\u00e9idliachta \u00c9ireann nua!Michael DohertyEditor-in-ChiefIrish Veterinary Journal"}
+{"text": "B2011106 (W.P.X.) from the Medical Science Foundation of Guangdong Province (http://www.gdwst.gov.cn); [^] grant No. S2011040004327 (W.P.X.) from the Doctor Initiating Project of the National Science Foundation of Guangdong Province; and the Fundamental Research Funds of the State Key Laboratory of Ophthalmology. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of this manuscript.\" There was an error in the funding statement. The correct funding statement is: \"This research was supported by grant No. 30973246 (W.Z.C.) from the National Natural Science Foundation of China ("}
+{"text": "The study of membranes and embedded proteins represents an advanced task in the field of molecular simulation. While nowadays a profound selection of sampling techniques, molecular topologies and theoretical approaches is available, the analysis of actual simulation data remains a difficult endeavour.For homogeneous lipid bilayer simulations, the calculation of the bilayer thickness or area per lipid is directly accessible. For lipid mixtures, e.g. with cholesterol or embedded proteins, this is no longer the case. To face this challenge, APL@Voro has been developed . The opehttp://www.aplvoro.org.Even phase transitions within a bilayer can be tracked and visualised in an instructive and convenient way. APL@Voro represents a major improvement for the analysis of complex membrane simulations. The application is available at"}
+{"text": "The published Financial Disclosure is missing funding information. The following is the correct funding information:We gratefully acknowledge the ongoing contribution of the parents and children in the Twins Early Development Study (TEDS). TEDS is supported by a program grant  from the U.K. Medical Research Council (MRC), with additional support from the US National Institutes of Health . Genome-wide genotyping was made possible by grants from the Wellcome Trust Case Control Consortium 2 project . RP is supported by a Medical Research Council Research Professorship award [G19/2] and a European Advanced Investigator award [295366]; O.S.P.D. is supported by a Sir Henry Wellcome Fellowship from the Wellcome Trust [WT088984]; C.M.A.H. is supported by a research fellowship from the British Academy. We also thank the Wellcome Trust Case Consortium 2 team for their help with genotyping and quality control of our data."}
+{"text": "After publication of this work , we noteThe authors declare that they have no competing interests.in vitro experiments, data analysis and drafted the manuscript. SL carried out the in vitro experiments, data analysis and drafted the manuscript. ShY participated in data analysis and drafted the manuscript. HA carried out the in vitro experiments. KO participated in experimental design and discussion. TJA conceived of the study, participated in its design and performed in vivo and in vitro experiments. He also helped to draft the manuscript. All authors read and approved the final manuscript.HVV participated in the"}
+{"text": "Acta Cryst. (2010), E66, o2004.Corrigendum to  et al.  are corrected.The chemical diagram and the title of the paper by Hou  The revised scheme is shown below.         In the paper by Hou"}
+{"text": "Cholangiopathy is pathologically and pathogenetically heterogeneous and presents a broad spectrum of clinical manifestations. A majority of them are known for many years, while some are newly emerging diseases. Recent advances in biology and medicine have introduced new technologies to study the cholangiocyte biologies and physiologies and the genetics, and the pathogenesis and pathology of cholangiopathy is now being evaluated from the aspects of experimental and clinical studies. Several animal models have been developed for autoimmune and genetic cholangiopathy such as primary biliary cirrhosis and polycystic disease of the liver and biliary tract. Knowledge and understanding of these conditions have led to the development of promising therapies and novel tools to characterize these clinical conditions.  In this special issue of cholangiopathy, several important aspects of cholangiophany are addressed with respect to recent progress. First, in the tutorial review, the anatomy and physiology of the biliary tree and physiologic functions of biliary epithelial cells are briefly introduced for better understanding of cholangiopathy. Several important and basic mechanisms and clinicopathological features of cholangiopathy are also described. Then, Drs. M. Harada and Y. Nokanuma describe the immunological aspects of biliary tree itself and also cholangiopathy with respect to innate immunity. Several biliary diseases, particularly biliary atresia, are now being discussed from the aspect of innate immunity. Then, Dr. Zen et al. introduce a newly emerging disease of IgG4-related disease with respect to biliary tract. Many clinicians and pathologists try to categorize this disease family showing a well response to steroid therapy and involving several organs. Dr. Shimoda et al. and Dr. Sasaki et al. focused on the pathogenesis of primary biliary cirrhosis from aspects of fractalkine and cellular senescence, respectively. Dr. Shimoda et al. stress the importance, of innate and acquired immunity and Drs. K. Sasaki and Y. Nakanuma notice the participation of autophagy in the induction of cellular senescence of biliary epithelial cells. Drs. K. Tsuneyama et al. discuss the animal models of primary biliary cirrhosis which are available. Dr. Ninomiya et al. introduced a new animal model of primary biliary cirrhosis. These models will contribute to the understanding of the pathogenesis of primary biliary cirrhosis in near future. Dr. Y. Sato et al. report their accumulating data on unique animal model of Caroli's disease and discuss its molecular mechanism. This animal model resembles the autosomal-recessive polycystic disease of the kidney and liver. Lastly, Drs. G. Fava and I. Lorenzini discuss molecular pathogenesis of cholangiocarcinoma, another topic of neoplastic cholangiopathy. New biomarker and molecular targeting therapies are now rapidly evolving in this field. We are sure that this special issue will contribute to the further progress of understanding and treatment of cholangiopathy.Yasuni NakanumaYasuni NakanumaAnthony J. DemetrisAnthony J. DemetrisYoshiyuki UenoYoshiyuki UenoAlberto QuagliaAlberto Quaglia"}
+{"text": "Due to errors in the typesetting process, the version of Table 1 in the article was incomplete. The complete, correct version is available here: The corresponding author's email address was incorrect, and should be: daqifu@cau.edu.cn"}
+{"text": "We are currently in an era where the international scientific publication is highly valued, acting as a strong parameter for evaluation mechanism in ranking universities in the competitive scientific world. In this context, writing the editorial of this special issue gives us a great responsibility. After a cautious revision of the several articles submitted for publication in this special issue by the Editorial Board of this journal, the accepted papers translate the commitment of the authors to the scientific research. This special issue is a sample of the current research efforts addressing issues related to the interaction between the light and the oral tissues, highlighting subjects such as the treatment of pathologies associated with high intensity laser for better healing and welding, the use of high intensity laser treatment for cosmetic dentistry, evaluation of adhesive systems and dentin hypersensitivity, the detection and treatment decision of caries lesions with laser fluorescence, the treatment of root perforation using high intensity laser, and also the low level laser therapy for improving wound healing.We hope that the readers can enjoy this special issue and improve their knowledge about the light interaction with the hard and soft oral tissues.S. Nammour S. Nammour H. S. LohH. S. LohR. De MoorR. De MoorC. P. EduardoC. P. Eduardo"}
+{"text": "Hypothenemus hampei (Ferrari) (Coleoptera: Curculionidae) is endemic to Africa and is the most devastating pest of coffee worldwide. The female bores a hole in the coffee berry and deposits her eggs inside. Upon hatching, larvae feed on the seeds, thus reducing both quality and yields of the marketable product. The coffee berry borer was found in the district of Kona on the island of Hawaii in August 2010 and appears to be restricted to that area.The coffee berry borer,  Hypothenemus hampei (Ferrari) .Among the usual pest management options that can be implemented against a et al. . In addia et al. . Removin"}
+{"text": "There was an error in the Funding statement. The correct funding is:\"Supported by the NIH grants R01 AR047825 and R01 AI07055. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\""}
+{"text": "There was an error in the Acknowledgments. The spelling of the name \"Dr. Yuro Guo\" is incorrect. The correct spelling is \"Dr. Yiru Guo\"."}
+{"text": "This publication is supported by the project 'BIOCEV - Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University - http://www.biocev.eu/en/' (CZ.1.05/1.1.00/02.0109), from the European Regional Development Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\" A grant number and the initial provider of the funding for the grant from BIOCEV were incorrectly omitted from the Funding Statement. The Funding Statement should read: \"This work was supported by the Academy of Sciences of the Czech Republic grant no. IAA601110908 ("}
+{"text": "This method applies random swaps between two taxa connected to the same node, without changing the topology of the tree. The evaluation of a new tree is based on different distance matrices, representing non-phylogenetic information such as other types of genetic distance, geographic distance, or combinations of these. To test our method we use published trees of Vesicular stomatitis virus, West Nile virus and Rice yellow mottle virus.Phylogenetic trees are an important tool for representing evolutionary relationships among organisms. In a phylogram or chronogram, the ordering of taxa is not considered meaningful, since complete topological information is given by the branching order and length of the branches, which are represented in the root-to-node direction. We apply a novel method based on a  were used.Our innovative method makes phylogenetic trees easier to interpret, adding meaning to the taxon order and helping to prevent misinterpretations. Phylogenetic trees are an important tool in evolutionary biology for representing the history of evolution of organisms. They are composed of nodes, representing hypothetical ancestors, and branches or edges, reflecting the relationship between nodes. Terminal nodes or taxa represent the taxa whose evolution has been investigated, and they can represent extant or extinct organisms . In phylPrevious work has already accepted the challenge of ordering the taxa to add a meaning according to the genetic distance. The software Neighbor-Net  is shown\u03bc) - Evolutionary Algorithms (EAs) .We reconstructed the tree presented by Perez et al. using the maximum-likelihood optimality criterion as implemented in PAUP* version b10  and the The tree is from Bertolotti et al.  and contRYMV is a positive-sense single-stranded RNA virus belonging to the genus Sobemovirus and it is considered to be among the most important rice pathogens within sub-Saharan Africa ,18. We cmaptools [shape [http://www.census.gov/geo/www/cob/st2000.html in ESRI Shapefile (.shp) format for all 50 States, D.C., and Puerto Rico; Mexico shapefile was downloaded from http://www.vdstech.com/map_data.htm and Africa shapefile was downloaded from http://www.maplibrary.org/index.php. Collection site coordinates for VSV were kindly provided by L. Rodriguez, A. Perez and S. Pauszek. WNV collection site coordinates were already available. RYMV collection site coordinates were extracted from the shapefile using GRASS-GIS software [Data on country borders were obtained from shapefiles available online, managed and plotted with R software  and the maptools  and shaps [shape . In partsoftware ; specifisoftware ), and coAlgorithms were written in R, using the package 'ape' . The runFC implemented the computational model, carried out the simulations, and participated in the interpretation of the results. LB conceived the design of the study, implemented the computational model, and participated in the interpretation of the results. TLG conceived the design of the study and participated in the interpretation of the results. MG conceived the design of the study, participated in the interpretation of the results, and coordinated the participants' contributions. All authors participated in writing the manuscript and approved it."}
+{"text": "There is a sentence missing from the Acknowledgments:The authors thank David A. Leopold and Brian E. Russ for helpful discussions. This research was supported by the NIMH and NINDS Intramural Research Programs of the NIH."}
+{"text": "Most of the current biophysical models designed to address the large-scale distribution of malaria assume that transmission of the disease is independent of the vector involved. Another common assumption in these type of model is that the mortality rate of mosquitoes is constant over their life span and that their dispersion is negligible. Mosquito models are important in the prediction of malaria and hence there is a need for a realistic representation of the vectors involved.Anopheles gambiae s.s. and Anopheles arabiensis. Sensitivity analysis highlight the importance of relative humidity and mosquito size, the initial conditions and dispersion, and a rarely used parameter, the probability of finding blood. We also show that the assumption of exponential mortality of adult mosquitoes does not match the observed data, and suggest that an age dimension can overcome this problem.We construct a biophysical model including two competing species, An. gambiae s.s. and An. arabiensis and their interaction. This new mosquito model, OMaWa, can improve our understanding of the dynamics of these vectors, which in turn can be used to understand the dynamics of malaria.This study highlights some of the assumptions commonly used when constructing mosquito-malaria models and presents a realistic model of  Anopheles arabiensis and Anopheles gambiae s.s. Our aims in this article are 1) to formulate recent research on the Anopheles gambiae complex in a mathematical framework, and 2) to show how the new formulations influence the dynamics of malaria and mosquito populations.This is the first of two papers describing a dynamic model  of In this paper, we describe a model of the dynamics of the two species and then show how parameters can influence the success of the two species, and how temperature, humidity and mosquito size can influence malaria transmission.An. arabiensis and An. gambiae s.s. has been observed in Kenya , \u03b2I,E is the induced mortality rate for eggs (not specified) and \u03c4E is the inverse of development time from eggs to first instar larvae.where BL/K is used as a scaling factor to modify the growth rate. When the population is low compared to the breeding sites available, its growth is high. As the population grows, there is more competition for food, predators become more abundant, and the growth slows. In the egg compartment this represents the idea that the mosquitoes will lay fewer eggs when breeding sites are already occupied , m2 =  or induced (I) mortality and the second subscript denoting the age group (mn) of the mosquitoes. \u03a6 represents the mosquito flux (transport) and subscripts \u0131 and \u0237 define which boundaries are evaluated. This is discussed in the section \u201cMovement of mosquitoes\u201d.Again, mn-1, as well as the flux to and from the point of interest mn+1, and mortality due to lack of food (P(B)). Parametrization schemes related to mortality are discussed later.The number of adult mosquitoes of a specific age in a grid point is controlled by new mosquitoes from This results in the following equation for the first age group: n =  are The equations for age groups msize) is important for the efficiency of mosquito multiplication. There are also some indications that increased body size is a strategy for survival in arid environments . This experiment explores how the dynamics of malaria is sensitive to temperature, relative humidity and mosquito size (measured as mm). We assume that no births occur to isolate the effect of the transmission process, and consequently constant mosquito body size in the course of integration, but include mortality and the biting rate. In this experiment we assume that only one species is present (since the main competition occurs in the aquatic stages). This sensitivity test is designed to observe how the proportion of mosquitoes becomes infected as a function of temperature, relative humidity and mosquito size, given that we start with 1000 newly emerged mosquitoes, with ribed in .The rate of sporozoite development within mosquitoes is expressed as b = 0.0051029, c = 0.7349, and d = 17.0325. This expression was derived from the figure in MacDonald page 119 [where a = 9.5907, page 119 , and fitpage 119 .The gonotrophic cycle and biting rate are defined in Eq. (26).The integrations are repeated with different combinations of temperature and relative humidity. This is a simple representation of gametocyte transmission to mosquitoes and is an idealized approach for exploring the proportion of mosquitoes  that would become infected under different temperature, RH and mosquito size. Figure These results should be viewed in light of recent findings by Paaijmans et al. that optimal transmission occurs at lower temperatures .Sensitivity to temperature and carrying capacity (TempCar)An. arabiensis and An. gambiae s.s. We set the relative humidity to 80% and the probability of getting a blood meal to one. We assumed that the soil was saturated and we varied the temperature between 16 and 38\u00b0C (with corrections over 33\u00b0C for water temperature) and the carrying capacity between 0.0625 and 125 mgkm-2.The aim of this sensitivity test was to investigate how carrying capacity and temperature determine the relative proportion of An. arabiensis invests more time in growth than An. gambiae s.s., the former develops a larger body, and consequently has the potential to oviposit more eggs than the latter. If the two species experience the same mortality rate in the aquatic stages, more An. gambiae s.s. will emerge, but over time An. arabiensis can face this challenge by outnumbering the eggs of An. gambiae s.s. in the habitat. Thus, we are interested in testing how the carrying capacity in the aquatic stages alters the relative proportion of each of the adult species. In this model we only consider the competition between these two species, and hence neglect other competing species [Carrying capacity in the aquatic stages influences larval growth and adult survival. While  species .An. gambiae s.s. dominates between 27 and 30\u00b0C. This is the effect of the development rate modifications described by Kirby et al. [An. arabiensis is most pronounced in the drier simulations, meaning that high competition, compared to adult survival, is favourable for this species. This can be attributed to the strategy of larger body size and higher egg production. Lehmann et al. found that An. arabiensis dominated during the dry season, while An. gambiae s.s. dominated in the rainy season [An. arabiensis in crowded breeding places might be one factor contributing to the shift in species composition as the surface area of puddles starts to shrink.As observed in Figure y et al.  and Paaiy et al.  An. arabiensis will potentially use less energy per batch of eggs and will also be able to utilize breeding sites at a higher rate than An. gambiae s.s. It is also possible that An. arabiensis uses cattle for navigation [P(B), for An. arabiensis from zero to one, as well as varying the temperature as described for TempCar.This experiment shows how the model responds to changes in the probability of finding a blood meal, which influences the rate at which mosquitoes can oviposit and increases energy consumption if hosts are hard to locate. If, for example, cattle are easier to find compared to humans, vigation . Over tiAn. gambiae s.s., independent of the probability of An. arabiensis finding a blood meal. This is a purely theoretical experiment designed to demonstrate a concept. The probability of finding blood is varied between zero and one for An. arabiensis. The scenario in which P(B) = 1 for An. gambiae s.s. and zero for An. arabiensis is not a realistic scenario, but the difference in P(B) is grounded in differences in their feeding behaviour, whereby An. arabiensis can utilize cattle more efficiently than An. gambiae s.s., for example.We set the probability of finding blood to one for An. arabiensis. In addition to the pattern observed in Figure P(B) is low for An. arabiensis, An. gambiae s.s. dominates. P(B) can be interpreted as a parameter that describes both the probability of finding blood for reproduction and survival, and the energy spent in the search for a blood meal. For example, easy access to cattle might give An. arabiensis an advantage in exploiting breeding sites, which could lead to suppression of the number of An. gambiae s.s. if increased use of bed nets reduces the effective human population or causes higher mortality of anthropophilic species. This mechanism might help to explain the decline in An. gambiae s.s. observed by Bayoh et al. [Figure h et al. .P(B) similar to Figure P(B)=1 over all land areas for both species. The population density is space-invariant at 400 humans/km2 (remember that the number of mosquitoes is limited by the number of hosts). Thus, the only limitation in this experiment is the physical environment , which is updated every 3 h. The initial conditions for the mosquito populations were the same for the two runs.This experiment is similar to pBlood1D, but this time we integrate the model for 5 years over the African domain. The experiment consists of two runs, for which the first has P(B) is an expression of the cost of finding a host, it might well be that P(B) also includes a component that describes the environment shaped by cattle and humans. Therefore, it should be noted that it is difficult to distinguish between the true probability of finding blood and the environmental changes caused by the presence of humans or cattle.Even though we have stated that the probability of finding blood An. gambiae s.s. loses the competition after 5 years  limits the distribution of An. gambiae s.l. to approximately 17\u00b0N in the Sahel, the experiment with P(B)=1 (P1) has a distribution up to 22\u00b0N in Mali, Niger, Chad and Sudan. This is in line with observations of the northerly limit of An. gambiae s.l. [An. gambiae s.l. north of 17\u00b0 in the original set-up (P0) might be a result of the way the model is formulated. The population density is calculated within a box of approximately 50 km\u00d750 km. It might well be the case that pockets of higher population/cattle densities within this box could sustain a mosquito population. This is not resolved in the model. It is also worth mentioning the study by De Meillon [An. gambiae s.l. is present in large parts of the country. The original set-up (P0) allows sustainable mosquito populations in Namibia, while the density of An. gambiae s.l. in P1 is more comparable to the observations of De Meillon. The problems of capturing the distribution of An. gambiae s.l. in Namibia may originate from the problems of resolving pockets of high host density or changes in cattle density and distribution at the time of the study compared to the present day [Under the scenario of equal probability of finding blood for the two species,  Figures  and 13, iae s.l. -150. The Meillon  of the asent day ,44,152.An. gambiae s.l. in South Africa is not very sensitive to the probability of finding a blood meal. Hence, the distribution of An. gambiae s.l. is mainly restricted by climate according to the model.It is also worth mentioning that the density of An. arabiensis and An. gambiae s.s. under realistic (P0) and space-invariant (P1) P(B) after 6, 12, and 18 months. The integration was started on January 1 and the model was run for 5 years.Figures An. gambiae s.s. and An. arabiensis. To explore the theoretical dispersion distance and the influence of the initial conditions, we set up a simple experiment. In mosqTran(a) the model was initialized with An. arabiensis at -4.494381\u00b0E, 14.0154\u00b0N (Sahel), and An. gambiae s.s. at -4.494381\u00b0E, 6.502846\u00b0N  on January 1, 1989. The second experiment, mosqTran(b), had the same setup, but without An. arabiensis.The purpose of this experiment was to demonstrate how the initial conditions and competition influence the distribution of The purpose of this demonstration was to show the importance of mosquito movement and how new areas can or cannot be colonized. In a model in which movement is restricted, the vector range would also be restricted by the initial model conditions. For example, if only one point was specified for mosquitoes at the beginning of the integration, only the same point would have mosquitoes after 100 years. With dynamic movement the mosquitoes could colonize new areas if the environmental conditions, or the probability of finding blood, change over time.An. gambiae s.s. distribution in the two experiments. It is evident that in the presence of An. arabiensis, An. gambiae s.s. fails to colonize large parts of Mali and Burkina Faso. It can be argued that this is not a result of the initial conditions, but of competition. Additional file Figure mosquitoes/km2. It is interesting to note that dispersal occurs in pulses. The dispersal of An. arabiensis is slower than that of An. gambiae s.s., probably because of the drier conditions in the Sahel and An. gambiae s.s. reached the area before An. arabiensis  humidity ,157 and An. gambiae s.l. is not exponential, and that inclusion of an age dimension alters the expected outcome of interventions targeted to reduce the vector population [An. arabiensis and An. gambiae s.s. The true carrying capacity is hard to estimate on a continental scale and thus relies on qualified guesswork taking into account rainfall, groundwater and soil saturation, for example. Carrying capacity influences not only the relative distribution of the two species but also the total number of mosquitoes. To correctly estimate the biting rate, a correct estimate of carrying capacity is required, and thus more work is needed to parametrize puddle formation. It should also be noted that no current large-scale models can describe the formation of puddles as rivers retreat, as described by Animut et al. [Assumption of exponential mortality has several advantages , the probability of finding a blood meal. P(B) is important in describing a realistic distribution of An. arabiensis and An. gambiae s.s. Thus, we hypothesize that the large-scale distribution of bovines is key to the success of An. arabiensis. Likewise, large-scale human density favours the presence of An. gambiae s.s.Experiment pBlood2D showed how the model responds to the parameter An. gambiae s.s. (and An. arabiensis). The distribution of An. gambiae s.s. changes dramatically with the presence of An. arabiensis, and thus the initial model conditions are highly relevant for correct description of the distribution of the two species. When rainfall is highly seasonal, the first come, first served principle seems to be important for the success of a species in drier conditions. Whether or not this plays a role in the evolution of aestivation in An. gambiae s.s. M form [Finally, experiment mosqTran showed how the initial conditions influence the dispersal of . M form  is a queAn. gambiae complex is not irrelevant when assessing the impact of climate change, since vectorial capacity varies between species.The strong influence of initial conditions on dispersal of the An. gambiae complex in malaria transmission. We hope to refine the model as new data on mosquito biology become available, and to incorporate the effects of interventions.The availability of mosquito models allows researchers to build on and improve our understanding of the role of the The authors declare that they have no competing interests.The work presented here was carried out as a collaboration between all the authors. BL and AS defined the research theme. TML designed methods and mosquito experiments, performed the model runs, analysed the data, interpreted the results and wrote the paper. DK, AS and TML designed and evaluated the regional climate simulations. EL provided input with respect to the malaria situation in Ethiopia, which in turn was used in the model formulation. All the authors have contributed to, seen and approved the manuscript.Density of mosquitoes under different predation regimes and temperatures.Click here for fileIdealized puddle modelClick here for fileThe functional form of of equation 42.Click here for fileA note on how initial conditions can influence the spatial distribution ofAn. gambiae s.l.Click here for file"}
+{"text": "The authors wish to advise our readers that Anita Marinelli was omitted from the original author list in error. The correct list and order of authors should be: Katelyn L. Conant, Anita Marinelli, and Johnan A. R. Kaleeba. All authors support this change and heartily apologize for any inconvenience that the error may have caused."}
+{"text": "The following details were mistakenly excluded from the published Funding statement: R.B was supported by NIH NS052574. Additional support in the early phases of this project was provided by a grant from the Milken Family Foundation/Epilepsy Research Foundation to A.L.B."}
+{"text": "S. Marcescens in patients on a Postoperative Cardiosurgery Unit (PCU), and describe the epidemiological investigations and control measures undertaken.We report an outbreak of infections with S. macescens in cultures from patients admitted to the PCU, active surveillance through clinical and microbiological results was initiated. Retrospectively, we searched for S. marcescens positive microbiological results from patients that had been admitted to the PCU in the preceding months. All patients staying on the PCU were screened for S. marcescens colonization. Environmental samples were taken from the PCU as well as from the operating room where the patients had been operated. S. marcescens strains were identified.After the identification of various microbiological results positive for S. marcescens. One of them died from a septic shock due to bacteremia secondary to central line infection with S. marcescens. The other two patients presented bacteremic ventilator-associated pneumonia. Specific precautions based on contact transmission were implemented and the staff was instructed about hand hygiene with alcohol-based hand rub. Retrospectively, two more patients with S. marcescens positive cultures were identified. One of them, who had had a diagnosis of bacteremic mediastinitis, had been discharged from the original PCU location. The second patient, who had been admitted in the same period, had a wound culture positive for S. marcescens. This second patient had been moved to the new location and was still staying in the PCU. Neither the environmental samples  from the PCU, nor the samples taken from the operating room were positive for S. marcescens. It was confirmed that in all of the cases it was the same S. marcescens strain.In the month of August, after moving the PCU and the cardiac surgery operating room to temporary locations due to renovation works, three patients, admitted to the PCU, were identified to have cultures positive for Data suggested that the mode of transmission was most likely due to the transfer of organisms from person to person by cross transmission.None declared"}
+{"text": "This special issue is aimed at collecting together recent developments in the field of natural product analysis. This issue covers methodologies and applications as diverse as secondary metabolite identification to the detection of metals in food stuffs. The chemistry of natural products has gained prominence not only due to the on-going search for new bioactive substances but also in related areas such as food chemistry and chemical ecology.We feel that this special issue represents some of the wide ranging research currently performed in this diverse area and this is exemplified by the affiliations of the authors of the papers included which is made up of chemists, biochemists, biologists, physicists, toxicologists, physiologists, pharmaceutists, and geochemists. What all of these researchers have in common, despite their wide ranging backgrounds, is the need to make use of the powerful techniques of analytical chemistry to analyze natural compounds in complex matrices. Thus, this special issue is dedicated to all the readers that would like to apply analytical chemistry for natural products analysis.This issue presents ten papers, which describe either a specific analytical method for specific types of natural products, the use of natural compounds to aid analytical developments, or modern techniques for the analysis of metals in food stuffs and food quality control (a growing area of interest). The article by L. de S. Ferreira et al. describes the use of hyphenated techniques to determine fatty acids in a species of seaweed from the Fernando de Noronha archipelago. In addition, a second paper has used SRTXRF analysis as a technique to determine several inorganic species within the same archipelago. Both papers contribute to an increased understanding of adsorption and accumulation of such natural elements by algae in that specific area.V. S. A. Devi and V. K. Reddy's paper presents a methodology for spectrophotometric determination of iron(II) and cobalt(II) using 2-hydroxi-1-naphthaldehyde-p-hydroxybenzoichydrazone which can then be applied for the analyses of biological and water samples that contain these metals. Guazuma ulmifolia Lam. (\u201cMutamba\u201d). Thermogravimetry analysis along with HPLC were used in the study. The results can be used as a chemical marker in the quality control of dried extracts of G. ulmifolia. The paper by G. C. Lopes et al. reports the preliminary estimation of the stability of the dried extract from the bark of Phyllomedusa hypochondrialis frog and its incorporation into nanostructured layered films in conjunction with nickel-tetrasulfonated phthalocyanines. The film was used as a biosensor to detect dopamine, a neurotransmitter associated with diseases such as Alzheimer's and Parkinson's. The study by M. F. Zampa et al. is the first report of the antimicrobial peptide from the skin of the Anacardium occidentale L.), found in northeast Brazil, as a component of a nanocomposite electrode. The performance of the electrodes was evaluated by the determination of dopamine. S. B. A. Barros et al. demonstrate the exploitation of the polyelectrolytic behavior of natural cashew gum  mass spectrometry for the confirmation of the hapten number in synthesized antigens. Two unique applications using MAb, Eastern blotting, and knockout extract have been introduced in this paper. The Eastern blotting method has great potential applications for the wide range of natural products. Lippia sidoides Cham. , native to northeastern Brazil and northern Minas Gerais, and their essential oils. The oxygenated monoterpene 1,8-cineole was the major constituent, followed by isoborneol and bornyl acetate. The chemical composition of essential oils described in this paper differs from that described in the literature for L. sidoides found in its native environment. The article of S. R. de Moraes et al. highlights the use of Virola surinamensis, during germination and seedling development. The authors conclude that the germination of V. surinamensis seeds and the seedling development are processes in which both fatty acids and secondary metabolites  are equally consumed in the seeds indicating their potential physiological role as energy and carbon sources.The paper of M. J. Kato et al. demonstrates the GC-MS monitoring of the major secondary metabolites and fatty acids occurring in the seeds of The article of P. J. Gates and N. P. Lopes describes the application of negative ion chip-based nanospray tandem mass spectrometry for the analysis of flavonoid aglycones. The methodology is tested by the analysis of a crude green tea extract, where the expected flavonoids were readily identified.Norberto P. LopesNorberto P. LopesErnani PintoErnani PintoMichael NiehuesMichael NiehuesPaul J. GatesPaul J. GatesRicardo VessecchiRicardo Vessecchi"}
+{"text": "The treatment of discogenic lumbar disease is a major challenge faced by physicians throughout the world. This condition affects many patients and will inevitably become more prevalent with a rapidly aging population. Disc degeneration tends to increase rapidly with age so that 10% of 50-year-old and 60% of 70-year-old discs are severely degenerated [\u201cMeasurement of intervertebral motion using quantitative fluoroscopy: report of an international forum and proposal for use in the assessment of degenerative disc disease in the lumbar spine\u201d presents the case for using quantitative fluoroscopy application to the measurement of intervertebral motions and degenerative disc diagnosis. In the second article, M. W. Hasz provides a review of the diagnostic procedures for degenerative disc disease. He also provides a succinct explanation of how radiography, computed tomography, magnetic resonance, and discography are utilized in degenerative disc disease diagnosis.The mechanism of lumbar disc disease is elucidated in an article by V. K. Goel et al. which outlines the molecular processes involved in disc degeneration and the physical and chemical changes reducing disc integrity. The diagnosis of this condition is extensively explored in two related articles. The first article by A. C. Breen et al. Disc disease treatment is extensively addressed in four articles. The articles by D. Kok et al. and by L. Marchi et al. explore the application of interbody fusion as treatment for severely degenerated discs. V. Popov and D. G. Anderson provide an insightful review of treatments for lumbar disc degeneration and the application of ipsilateral and bilateral decompression with a tubular retractor system under microscopy. D. Drazin et al. provide a review of stem cell injection therapy for the intervertebral disc. Evaluation of the outcomes of patients with lumbar disc disease is critical to the assessment of treatment efficacy. C. Lozano-Alvarez et al. describe the use of the Core Outcome Measures Index (COMI) in daily clinical practice for assessing patients with degenerative lumbar disease. The current issue covers disc disease from several angles. Our intention is to provide a resource which can enlighten readers as to the mechanism, diagnosis, and the present state of intervertebral disc disease therapy and its treatment advances.Brian R. SubachThomas C. SchulerMark R. McLaughlinPaul J. SlosarChristopher H. ComeyNajeeb M. Thomas"}
+{"text": "There is an error in the Funding Statement. The correct Funding Statement is the following:This work was supported by Presidential grant for Scientific Schools (5638.2010.4) and grant from the Molecular and Cellular Biology Program of the Presidium of the Russian Academy of Sciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.The following statement is missing from the Acknowledgments:The authors are grateful to Dr. M. Pikunov  for providing us with fibroblasts IVL 11NS (NLF), to Dr. V. Korobko  for providing us a PhTERT-pGL3 construct and to Dr. M. Zinovyeva for aid in preparation of RNA and cDNA samples."}
+{"text": "In the author byline, name of the fourth and ninth authors were incorrect.The correct name is: Elisabetta Gennaro.The correct name of the ninth author is: Giovanni Guidotti.The ninth author was also affiliated with the incorrect institution. The correct institution is:DREAM Program Department, Community of Sant\u2019Egidio, Blantyre, Malawi"}
+{"text": "GRAM09) (http://www.nefu.edu.cn). [^] The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. There was an error in the published funding statement. The correct funding is: This work was financially supported by the Forestry Science and Technology Supporting Program of China (No. 2011BAD37B01) ("}
+{"text": "Cognitive adaptation training (CAT) improves functional outcome in outpatients with schizophrenia living in the United States of America. The efficacy of CAT has never been demonstrated for patients living in a residential facility. We describe how CAT was delivered to two chronically hospitalized patients with schizophrenia living in The Netherlands. CAT was delivered for 8 months, and consisted of weekly home visits by a psychiatric nurse. Both patients improved on measures of functional outcome used in the US studies. These results indicate that CAT may improve outcomes, even in patients that have been hospitalized for several years. Cognitive impairments in schizophrenia substantially contribute to long-term functional disability . CognitiWe then share the results of the assessments with the patient. Specific problem areas the patient wants to work on are prioritized. CAT has proven to successfully improve functional outcomes for patients living in the United States of America \u20139. A recMr. C. is 54 years old and hospitalized for over 20 years, living in a group home with 6 other patients. Clinical symptoms included auditory hallucinations, social withdrawal, anxiety, and stereotypical behaviours. Mr. C.'s performance on neuropsychological testing indicated fair executive functioning. The FrSBe revealed behavioural apathy. Results of the assessments of executive function and clinical symptoms are given in Personal hygiene was the first area that the patient agreed to work on. The CAT therapist gave him a comic on brushing teeth, to make the discussion of the activity easier. Mr. C. admitted the relevance of brushing teeth but was afraid to throw up from the taste of the toothpaste. A soft brush and an own desired toothpaste flavour (strawberry) were provided on trial. Mr. C. began to carry out the activity on a daily basis. A checklist containing brushing teeth every day was used to compensate for apathy. Later on, other hygiene activities were added to this list. Initially, we reinforced improvement in hygiene, by providing a new comic. Mr. C. did not have a number of household items , so the CAT therapist provided them. Starting from the second month of CAT, sessions also consisted of activities outside the home. A map of the village was provided to improve Mr. C's orientation to the neighbourhood. The CAT therapist gave him the task of finding a specific location  on the map, and then Mr. C. showed her the route. After visiting a number of activity centres, Mr. C. was more enthusiastic about these services and asked to participate in wood crafting 8 hours a week. One month later, Mr. C. asked to work another 4 hours per week at a framing center. The tasks at the latter location were more varied and cognitively demanding, and the new colleagues of Mr. C. were less impaired than he was. Therefore, the CAT therapist visited the workplace and worked with staff to adapt the working environment by giving Mr. C. only one type of task at a time. This enabled him to successfully complete assigned tasks. Every morning Mr. C. was scheduled for work; a voice cue from a personalized alarm prompted him to wake up. This alarm was also used to prompt him to take his medication, which was previously administered by staff. This made Mr. C. independent in taking his medication for the first time in 20 years. Due to the physical nature of his job he began to experience physical complaints. Therefore, during work, he was instructed by the staff when to take a break. After a few weeks, Mr. C. was able to initiate this himself. In addition, swimming was introduced as a new physical exercise with the goal to reduce muscle stiffness. He was reminded to engage in this activity by adding it to his calendar.By the end of the treatment, Mr. C. had increased his participation in work-related activities from 0 days to 4 partial days per week. The staff no longer observed a body odor, and Mr. C. was more easygoing in personal contact. The interventions were explained and gradually transferred to his case manager after 6 months. After 8 months, the case manager visited Mr. C. to evaluate his checklist and to monitor his medication adherence and hygiene and participation in work-related activities all of which remained substantially improved from baseline.Mr. J. is a 24-year-old male with early-onset schizophrenia, hospitalized for 4 years. Current clinical symptoms included auditory hallucinations, disorganization, and blunted affect. Neuropsychological task performance revealed fair executive functioning. The FrSBe revealed behavioural disinhibition. Results of the assessments of executive function and clinical symptoms are given in Interventions started with reorganizing belongings. Most items strewn around consisted of clothing or paperwork. Mr. J. was provided with a file folder for his paperwork. In his clothing cabinet, we attached labels to shelves for several clothing items . In a similar way, we organized his DVDs, comics, and computer games. Next, he was provided with a weekly checklist, with activities that he wanted to carry out more frequently. The first items on this list contained catheterizing and brushing teeth. We attempted to improve social contact by introducing Mr. J. to other patients with similar interests. A young patient living at a neighbouring apartment reacted positively to this. This patient and Mr. J. agreed to meet on a weekly basis and cook a meal. The CAT therapist trained Mr. J. in meal preparation. In the first session, he was provided with a recipe, consisting of easy sentences for every subtask which Mr. J. followed. The therapist intervened only when necessary. Mr. J. needed help with cooking times and measuring quantities. Since Mr. J. did not have a timer and a measuring cup, these were provided. The next session was used to rehearse the same meal, using the supports provided. After three sessions, Mr. J. was able to prepare this meal using the instructions of the recipe and without interventions from the CAT therapist. In a similar way, the CAT therapist and Mr. J. worked on a second and third recipe. Mr. J. needed more support to carry out the activities on his checklist more regularly. A voice-cue alarm was put in his room to remind him of brushing his teeth at the end of the day. Gradually, the voice-cue alarm was used to prompt him carrying out a larger repertoire of activities . This intervention was explained to nursing staff members of his group, and they were asked to evaluate the items on his checklist at the end of the evening. Such evaluations started with \u201clet's look at your checklist together.\u201d For catheterization, an important event was appearing on his checklist that he had to carry out multiple times a day Mr. J. was also provided with an alarm-watch. With the help of the CAT therapist, Mr. J. wrote down tasks and appointments that occurred less often than daily on a calendar that he and the therapist placed on the bathroom door. These interventions increased the target behaviors.After 6 months of treatment, Mr. J. visited his neighbour multiple times a week, he took a shower at least every other day, and he spent more hours on leisure activities. He was also able to increase his participation in work-related activity. His case manager became more closely involved in the process. She created brief weekly contact to discuss the interventions with him, and this made it possible to sustain Mr. J.'s improved functioning on a longer term.The current case reports describe how CAT was delivered to chronically hospitalized patients with schizophrenia in the Netherlands. This is a different population than treated with CAT in efficacy studies in the US and Denmark, where CAT participants lived in the community or in minimally supervised board and care homes \u201310. Chro"}
+{"text": "There was an error in the funding statement. The correct funding statement is: \"This work was supported in part by NIH grants R01DK44073, R01DK56210, and R01DK076023 to R.A.P. and a Scientist Development Grant (0630188N) from the American Heart Association to W.D.L. Genome-wide genotyping was funded in part by an Institutional Development Award to the Center for Applied Genomics (H.H.) from the Children's Hospital of Philadelphia. Follow-up genotyping after the initial GWAS was funded in part by the Center for Inherited Disease Research (CIDR). CIDR is funded through a federal contract from the U.S. National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. No additional external funding was received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\""}
+{"text": "Neonates suffer more severely and die more often than adults from a wide range of infections . AlthougThe neonatal intestinal tract faces a particular challenge in adapting to the complex microbial ecosystem that develops immediately after birth. Host immunity and the microbiome develop through reciprocal interactions. The review by E. Tourneur and C. Chassin shows how aberrant development of the mucocutaneous intestinal barrier contributes to inflammatory disorders, such as NEC. This paper and that of D. J. Hackam et al. highlight the specific contribution of the receptor for bacterial endotoxin, Toll-like receptor 4 (TLR4), and related signaling events in normal development and NEC pathogenesis. Intestinal epithelial cells are innate immune competent and shape the development of intestinal immunity. Bacterial toxins have also been appreciated as critical effectors of several pathogens that threaten newborn infants. Their role in invasive neonatal infections is reviewed by A. F. Sonnen and P. Henneke. Given recent advances in toxin structure and membrane action, appreciating changes in immune cell signaling in newborns will be an essential step to understand pathogenic mechanisms of neonatal disease.L. monocytogenes. And K. V. Driessche et al. highlight that the diminished proinflamatory cytokine capacity of the newborn following infection with M. tuberculosis allows bacterial spread. The reviews by M. R. P. Coombs et al. for Staphylococcus species and E. A. Marchant et al. for coagulase-negative Staphylococcus emphasize that the inability for preterm and full-term newborns to localize infection leads to high morbidity and mortality early in life.While barriers such as skin and mucous membranes are more readily breached in the newborn compared to the adult, the infectious risk in early life is higher irrespective of route of infection , 3. The The paper by S. Gantt and W. J. Muller reviews the immunologic basis for severe neonatal herpes disease and potential strategies for therapeutic intervention. They then explore differences between the immune system of newborns and those of older children and adults, which predispose them to severe infections. Two papers focus on another major viral pathogen, cytomegalovirus (CMV). In the first, M. Schleiss reviews the present state of knowledge on the immune responses of the fetus and newborn infant to CMV. With this as a background, the reader can better understand the rationale for the novel vaccine strategy proposed by M. Leviton et al. to prevent congenital infection, using an attenuated CMV vaccine. It is our hope that this series of reviews and important new information will provide the reader with a clearer understanding of newborn host defense mechanisms and potential therapeutic strategies.Robert BortolussiPhilipp HennekeTobias Kollmann"}
+{"text": "Cardiopulmonary exercise testing (CPET) allows the clinician to objectively evaluate symptoms and important functions. CPET also arms the investigator with a powerful tool to better understand the respiratory system role as an engaged participant of a fully integrated physiologic system in humans. The insights gained mean that CPET can aid in the assessment of activity limitation and dyspnea, in evaluating disability and disease severity, in judging risk and prognosis, and in considering the suitability for specific interventions such as transplantation. In the research laboratory, CPET can contribute to the complete evaluation of new therapeutic or management agents, provide physiologic understanding for various hypotheses and new-found research results, and aid in discovery to further our understanding of the complex behaviour and interaction of the human respiratory system. While these benefits are well known to those working closely in the field, the need for greater and more effective dissemination of these benefits is required. Hence, this special issue focuses on cardiopulmonary exercise testing. We begin with M. K. Stickland et al. reviewing normal exercise physiology, as well as providing guidelines for the understanding of cardiopulmonary exercise test results. Techniques to ensure valid measurements of inspiratory capacity permitting a learned assessment of ventilatory constraint are outlined by J. A. Guenette and colleagues, while R. Ramos and others review the clinical usefulness of rapid incremental testing protocols. J. C. da Silva et al. examine the best criteria to determine ramp exercise testing speed in their original research study. Meanwhile, I. Vogiatzis and colleagues undertake a detailed review of varied mechanisms contributing to activity limitation in chronic lung diseases. B. Borel et al. explore the responsiveness of different exercise testing protocols to therapeutic interventions in COPD. A. Apostolo et al. review the interaction and consequences for the lungs in the setting of chronic heart failure, while C. H. Kim and colleagues report original research assessing the validity of a new multivariate index for grading gas exchange severity in patients with pulmonary arterial hypertension and with heart failure. Finally, D. E. O'Donnell et al. review the respiratory consequences of obesity and its impact on exercise performance in both health and in COPD.We hope you find these articles both interesting and useful. We are confident that they will become meaningful resources in this field."}
+{"text": "The emergence of emergency medical services (EMS) as a realm within emergency medicine (EM) has recently been completed, with EMS gaining status as a boarded subspecialty. While there are excellent journals and a rich literature addressing EMS and out-of-hospital care, we embraced, with enthusiasm, the invitation of the editors to coordinate an EMS-related special issue on prehospital Care. The open access and online nature of the offers a unique chance for widespread attention to EMS, at a time when that attention is particular  As guest editors, we bring to the issue's review process over a century of experience in ground EMS, air transport, and disaster operations. Our backgrounds include experience with urban and rural ground and air EMS systems all over the U.S. and abroad. Our responsibilities include involvement with ground and/or air EMS care in the USA east coast , the USA west , and the U.S. southwest (J. Goodloe and Stephen Thomas of the University of Oklahoma). International experience comes from J. Deslandes (France's Urgence Pratique Formation).The breadth of interests from our collective background has translated into a similarly broad range of topics covered in this special issue on prehospital care. The solicitation of manuscripts allowed for virtually any topic within prehospital and out-of-hospital care, and the manuscripts received were a testament to the excellence of work around the world, in our chosen fields. We believe that the papers that were ultimately approved for publication in this special issue represent important contributions to the state of the evidence in EMS as follows. A paper focuses on an EMS angle of a subject that has become one of the most important rooms in the house of medicine: quality. In his review of clinical performance indicators, M. J. El Sayed outlines EMS's place in the dialogue about quality measurement. His overview provides background discussion, education, and practical direction for EMS services. Another article takes on a clinical conundrum facing acute care providers every day: what's causing this patient's dyspnea? J. E. Gough and K. L. Brewer address the differentiation of various causes of dyspnea-differentiation that can be tricky even in the hospital setting. The divergence of therapeutic approaches to varying dyspnea etiologies means that the earlier the true causes can be identified, the more rapidly patients can receive appropriately tailored therapy. In their pilot study, J. E. Gough and K. L. Brewer suggest that peak expiratory flow rate may provide useful clues to allow earlier differentiation of two major causes of dyspnea. Air medical transport is one of the more controversial aspects of EMS. Unfortunately, both sides of the HEMS debate frequently mischaracterize the existing evidence, with the statement \u201cthere is very little data addressing HEMS outcomes.\u201d In an attempt to provide an overview of the existing evidence, so that those with HEMS outcomes interest can get the original research and judge quality and impact for themselves, J. Hatfield et al. provide an annotated bibliography of HEMS outcomes research since 2007. Another paper addresses patient safety. C. T. Crowder et al. provide a look into a matter which has managed to elude attention despite the recent increased emphasis on patient safety. Rather than examine issues related to medical care, the study assesses the safety of patient transport. Specifically, F. J. Crowder et al. focus on stretcher-related problems and patient (and EMS crew member) safety issues related to stretcher misadventures. A different paper is a review of a potentially interesting possibility for improving drug and fluid delivery in the prehospital and disaster settings. Hyaluronidase, used a half-century ago for \u201chypodermoclysis,\u201d fell out of favor decades ago due to immune reactions to the animal-based enzyme. With the relatively new availability of human recombinant hyaluronidase, the early literature suggests there might be a potential role for subcutaneous fluid administration in some prehospital settings. A. O. Arthur et al. outline the current state of the evidence and provide some directions for potential future research. In the paper of B. King et al., they continue the focus on disaster and mass casualty situations. In their report on a wind-caused collapse of a large tent at a city festival, the authors outline the benefits of planning and provide some important lessons learned for future planning. The review by L. J. Hamilton et al. changes focus to another area of importance in EMS: pediatric care. While most of the literature addressing pediatric prehospital care has understandably focused on general pediatrics and trauma situations, Hamilton et al. narrow the discussion to children with complex chronic conditions. While there are (thankfully) relatively few of these patient numbers, transports of children with chronic complex medical conditions can occupy a disproportionately large percentage of an EMS service runs. The experience and insights of L. J. Hamilton et al. should assist those EMS services and providers who care for this special patient population. A study by A. O. Arthur et al. changes focus to the other end of the age spectrum. With the aging of the population , any suggestive trend of a problem regarding older adults can be a harbinger of a major upcoming issue. Arthur et al. identify such a potential trend, potentially related to economic concerns, of a rise in the proportion of \u201ctransport refusal\u201d patients who are geriatric. It is of course unknown whether economic or other identifiable factors are responsible for this finding, but the authors' preliminary findings should prompt further analysis of the issue. The special issue wraps up with an overview of HEMS research endpoints and potential benefits. The summary is intended not so much to make the case for (or against) HEMS as having outcomes benefits, as it is intended to highlight specific areas of investigation and focus for future efforts to define HEMS role in prehospital care. It has been our pleasure to bring this special issue to the readership of this journal. We hope that the literature in the edition helps to move the EMS world forward or at least inform debates and discussions regarding how to provide the best possible care in the out-of-hospital setting. Of course, we would be delighted to hear from you, the readers, as to comments or questions about any of the articles.Stephen H. ThomasStephen H. ThomasChristopher ColwellChristopher ColwellJean-Claude DeslandesJean-Claude DeslandesSophia DyerSophia DyerJeffrey M. GoodloeJeffrey M. Goodloe"}
+{"text": "Quantum information technology has been recognized as one of the most promising future technologies . The de18 papers have been received for this special issue and 9 among them have been accepted for publication. The paper by C. Chen et al. presents a survey on the recent development of closed-loop control strategies in quantum control including closed-loop learning control and quantum feedback control as well as an introduction to quantum robust control. The paper by S. Cong and F. Meng presents a survey on Lyapunov control of quantum systems which is a \u201cfeedback design\u201d and \u201copen-loop control\u201d strategy. The paper by S. N. Khonina et al. develops an algorithm for solving the steady-state Sch\u00f6dinger equation for a class of potentials. The paper by S. Zhao et al. proposes a hybrid impulsive control method combined with Lyapunov control to achieve a more accurate convergence for a class of nonideal quantum systems. The paper by V. Tiporlini and K. Alameh investigates the principles of operation and the optimal design of an optically pumped quantum magnetometer. The paper by W. Yang and J. Sun investigates the Lyapunov control of finite-dimensional quantum systems with impulsive control fields. The paper by M. Li et al. proposes a feedback control scheme through Rabi oscillation stabilization to preserve the coherence in cavity QED. The paper by Y. Xing and J. Wu presents a quantum control method to control the Shannon entropy of quantum systems. The paper by M. Li proposes a numerical simulation algorithm for stochastic process of direct photodetection of a driven two-level system."}
+{"text": "Culex sp. bridge vectors. The mosquito Culex modestus is widespread in southern Europe, where it acts as the principle bridge vector of WNV. This species was not previously thought to be present in the United Kingdom.The risk posed to the United Kingdom by West Nile virus (WNV) has previously been considered low, due to the absence or scarcity of the main Cx. modestus at two sites in marshland in southeast England. Host-seeking-adult traps placed at a third site indicate that the relative seasonal abundance of Cx. modestus peaks in early August. DNA barcoding of these specimens from the United Kingdom and material from southern France confirmed the morphological identification.Mosquito larval surveys carried out in 2010 identified substantial populations of Cx. modestus appears to be established in the North Kent Marshes, possibly as the result of a recent introduction. The addition of this species to the United Kingdom's mosquito fauna may increase the risk posed to the United Kingdom by WNV. Culex modestus is a competent laboratory vector of West Nile virus  and regus  using a Mosquito Magnet trap . This site is 5 km from Cliffe and 18 km from Elmley  and the Camargue (3 adults) were generated. A 709 bp fragment of the cytochrome c oxidase subunit I (COI) was amplified by PCR [Cx. modestus COI barcodes were compared to those obtained from Cx. pipiens specimens from the North Kent Marshes (n = 3) and Somerset (n = 6) as well as 35 COI sequences downloaded from GenBank. Phylogenetic analyses were carried out using MEGA5 software [Larval and adult mosquitoes were identified morphologically using a range of keys ,7-9. To software .Cx. modestus of all stages were collected, along with Anopheles maculipennis s.l., Cx. pipiens s.l. and Culiseta annulata. At both sites Cx. modestus was the second most abundant species after Cx. pipiens s.l., making up 44% and 23% of the overall larval population sampled at Cliffe and Elmley respectively (Table In larval surveys 850 ly Table .Cx. modestus were captured at Northward Hill between 12 July and 10 September, with a peak of 325 adults in the second week of August (Table Cx. modestus comprised 75% of the mosquitoes collected at Northward Hill. Morphological identification of Cx. modestus was confirmed by DNA barcoding and phylogenetic analyses. All the COI sequences from Cx. modestus specimens form a discrete clade with high bootstrap support (Figure A total of 649 adult female Cx. modestus have been reported from the Camargue and Dombes wetlands in southern and central France [Cx. modestus are present in the United Kingdom and provides further support for the existence of northern populations of the species.Established populations of l France ,12 as wel France  but the l France . Howeverl France . Our finCx. modestus could have been present in the North Kent Marshes for a long time without being detected. The mosquito fauna of the North Kent Marshes are among the most well sampled in the United Kingdom, both by amateur entomologists and by professionals engaged in mosquito control [It seems unlikely that  control .An. maculipennis s.l. but did not detect Cx. modestus. In the present larval survey Cx. modestus were found to be strongly associated with An. maculipennis s.l.; being present in 73% of sites containing An. maculipennis s.l. larvae. This suggests Cx. modestus was absent from this site in 2003. However the 2003 survey did not record any Cx. pipiens s.l. in An. maculipennis s.l. positive sites, whilst they were present in 20% of such sites in the present study; suggesting that the sampling strategy employed in 2003 may not have been sensitive to Culicines.An extensive larval survey was carried out at Elmley in 2003 . This suCx. modestus populations were established recently, international shipping may well have been the route of introduction. International shipping has previously been implicated in the introduction of mosquito species; including Cx. modestus to China [If these to China  and therCx. modestus is extending its distribution in Europe, with speculation that this may be driven by weather events or changes to wetlands [A number of vectors and vector-borne diseases have undergone changes in their geographic ranges in recent years, in response to varied biotic and abiotic environmental factors . There iwetlands ,13. WithCx. modestus populations exist alongside the potential WNV maintenance vector Cx. pipiens s.l. at sites hosting many migratory and resident birds. Since human population numbers in the North Kent Marshes are relatively low and little is known of the dispersal range or host preferences of Cx. modestus in the United Kingdom, it is difficult to quantify the significance of any change in risk to humans. It does seem likely, however, that the risk posed to horses, which are often grazed in the North Kent Marshes, will have increased. In light of this, and until the national distribution of Cx. modestus is established, surveillance for WNV in the United Kingdom should now focus on this part of Kent.A recent review of the potential vectors of WNV  concludeCx. modestus in southern England suggests a recent introduction of this species and provides further evidence for expansion of its geographic range. There is an associated increased risk posed to the United Kingdom by WNV and other pathogens transmitted by Cx. modestus.In summary, the discovery of populations of The authors declare that they have no competing interests.Cx. modestus, carried out the phylogenetic analysis and contributed to revision of the manuscript. JMM and AGCV designed and carried out the adult trapping, identified the adults and contributed to revision of the manuscript. MAN and BVP contributed to the design of the larval survey, interpretation of the results and revision of the manuscript. All authors read and approved the final manuscript.NG designed and carried out the larval surveys, identified the larvae and drafted the manuscript. SMS initially identified the larvae as"}
+{"text": "There was an error in the Funding statement. The correct Funding is:http://www.ntnu.no/dmf/rad/samorg. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.This work was supported by a grant from the Liaison Committee between the Central Norway Region Health Authority and the Norwegian University of Science and Technology (to T.S.M. and I.S.). URL:"}
+{"text": "The tenth author's name was spelled incorrectly. The correct name is: Garrett T. Kenyon.This error was introduced in the preparation of this article for publication."}
+{"text": "There was an error in the funding statement. The correct funding statement is: This research was supported, in part, by the U.S. Department of Energy (award DE-SC0004601). The Emory Genome Center acknowledges the Georgia Research Alliance and the Atlanta Clinical and Translational Sciences Institute for funding for major equipment purchases. DT acknowledges the support of the Onassis Scholarship Foundation. The work conducted by the U.S. Department of Energy Joint Genome Institute is supported by the Office of Science of the U.S. Department of Energy under Contract No. DE-AC02-05CH11231. No additional external funding was received for this study. The sponsors of this research had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."}
+{"text": "We are delighted to present a special issue on the subject of functional residues of proteins. Finding focused articles within the time frame of a special issue is always challenging, which is further compounded by authors' reluctance in making their contributions to new journals. We have been fortunate enough that some leading researchers in the field agreed to support this special issue and contributed their work at our request. We present here nine articles on various aspects of the subject. We received some more submissions, which could not be accommodated because of a strict quality control, we tried to maintain. Finally compiled special issue starts with a very interesting commentary on posttranslated modifications leading to normal and disease-associated biological functions, contributed by T. M. Karve and A. K. Cheema. This is followed by the analysis of a specific biological system of ATP synthetase, contributed by Z. Ahmad et al., exploring its catalytic sites and focusing on charged residues. R. Prasad et al. then describe a related system of ABC transporters and review the state of the knowledge on its functional residues. Functional residues in a protein do not always follow a universal pattern, and this is demonstrated by R. Kumar et al. in describing the dynamic structure of estrogen receptors. This paper is then followed by a special group of functional residues, that is, cysteins in sulfurtransferases by N. Nagahara. Viola et al. present an excellent study of catalytic machinery in the biosynthesis of amino acids. Subsequntly, K. M. Fukasawa et al. then present their analysis of functionally relevant zinc-binding sites in metalloproteases. Subsequently, M. S. Khan et al. provide an elaborate discussion on the mechanism of serpin inhibition, specially focusing on the role of polymerization. Finally, M. A. Kabir et al. present an investigation of a eukaryotic chaperon, involved in protein-folding.Thus, the special issue covers a wide range of systems and describes an overview of some of the most significant studies on the subject of finding functional residues in proteins. We would like to express our most sincere gratitude to the authors who agreed to contribute and referees who provided useful feedback, allowing the papers to meet the high standards of publication.We hope that the readers of Journal of Amino Acids will find these articles of great interest and look forward to any comments to improve our future efforts.Shandar AhmadShandar AhmadJung-Ying WangJung-Ying WangZulfiqar AhmadZulfiqar AhmadFaizan AhmadFaizan Ahmad"}
+{"text": "There was an error in funding information regarding the year the PRIN grant was granted to FS. The correct financial disclosure should be: \"This work was supported by the National Institutes of Health Conte Center grant MH77970 (M.M.M.), the John C. and Edward Coleman Memorial Fund (M.M.M.), and the Italian Ministry of University and Research, PRIN 2008 (F.S.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\""}
+{"text": "There was information omitted from the Funding statement. The correct version is available below.This study was supported by Stiftelsen Kempe-Carlgrenska Fonden. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."}
+{"text": "Anopheles gambiae s.l. insecticide-resistance monitoring programme was established in four sentinel sites in Burkina Faso. For three years, between 2008 and 2010, WHO diagnostic dose assays were used to measure the prevalence of resistance to all the major classes of insecticides at the beginning and end of the malaria transmission season. Species identification and genotyping for target site mutations was also performed and the sporozoite rate in adults determined.A longitudinal An. gambiae s.l. from the south-west of the country but mosquitoes from the two sites in central Burkina Faso were largely susceptible. Within three years, DDT and permethrin resistance was established in all four sites. Carbamate and organophosphate resistance remains relatively rare and largely confined to the south-western areas although a small number of bendiocarb survivors were found in all sites by the final round of monitoring. The ace-1R target site resistance allele was present in all localities and its frequency exceeded 20% in 2010 in two of the sites. The frequency of the 1014F kdr mutation increased throughout the three years and by 2010, the frequency of 1014F in all sites combined was 0.02 in Anopheles arabiensis, 0.56 in An. gambiae M form and 0.96 in An. gambiae S form. This frequency did not differ significantly between the sites. The 1014S kdr allele was only found in An. arabiensis but its frequency increased significantly throughout the study (P\u2009=\u20090.0003) and in 2010 the 1014S allele frequency was 0.08 in An. arabiensis. Maximum sporozoite rates (12%) were observed in Soumousso in 2009 and the difference between sites is significant for each year.At the onset of the study, resistance to DDT and pyrethroids was already prevalent in An. gambiae s.l. throughout Burkina Faso. Results from diagnostic dose assays are highly variable within and between rounds of testing, and hence it is important that resistance monitoring is carried out on more than one occasion before decisions on insecticide procurement for vector control are made. The presence of 1014S in An. gambiae s.l., in addition to 1014F, is not unexpected given the recent report of 1014S in Benin but highlights the importance of monitoring for both mutations throughout the continent. Future research must now focus on the impact that this resistance is having on malaria control in Burkina Faso.Pyrethroid and DDT resistance is now established in  Insecticide resistance monitoring should be an essential component of any malaria vector control programme. Vector control activities have been dramatically scaled up in recent years across much of sub-Saharan Africa with a concomitant reduction in malaria cases. In orde1014F, conferring resistance to pyrethroids and DDT, increased during this time period. At the beginning of the century, 1014F was found only in the south-western region and largely restricted to the Anopheles gambiae S form) mosquitoes positive in 2009. The sporozoite infection rate differed significantly between sites and a significant difference between years was observed in the south-western sites (Kuinima and Soumousso) . Preliminary analysis of intron data  suggest that the 1014S allele in An. arabiensis in Burkina Faso has an independent origin and has not arisen by introgression from An. gambiae, contrary to the prediction in Kenya[1014S and 1014F may differ and perhaps the former allele is more closely associated with DDT selection than pyrethroids[1014S allele. However, recent functional characterization of the alternative sodium channel alleles supports the importance of DDT in selecting for 1014S by demonstrating that the L1014S substitution had a much greater impact on sensitivity to DDT than to pyrethroids[In . gambiae,27,28. Iin Kenya. The souethroids. The samethroids.An. gambiae s.s. in Burkina Faso is at least partially explained by the high frequency of 1014F in this species. However, undoubtedly other resistance mechanisms are contributing towards the resistance phenotype. Indeed, pre-exposure to the synergist PBO for one hour increased permethrin mortality to >90% in all sites when tested in 2010 (data not shown). This is strongly indicative of metabolic resistance mechanisms and work is ongoing to investigate this further.The very high probability of surviving permethrin or DDT exposure in ace-1R allele, which is associated with resistance to this carbamate insecticide, is already present in An gambiae s.s and appears to be spreading rapidly throughout the country. Although the bio-assay data do not indicate high frequencies of bendiocarb resistance at present, this situation should be closely monitored.The expanding geographical range and prevalence of pyrethroid resistance in Burkina Faso may impact on the efficacy of malaria control activities. There is already limited evidence that the level of resistance to pyrethroids in Soumousso is impacting on the efficacy of LLINS in use in the field. In lighThe authors declare that they have no competing interests.HR and NFS conceived and designed the study. AB, NFS and HR drafted the manuscript. AB and CMJ analysed the data. AB, AT, CMJ, GMW, AS, LF oversaw field collections, bio-assays and conducted laboratory work. All authors read, corrected and approved the final manuscript.Pyrethroid bio-assay results for Anopheles gambiae s.l. in four localities after exposure to PBO 4%. An. gambiae mosquitoes, collected from four sentinel sites in 2010 have been exposed to PBO 4% for xxmin, prior to an exposure deltamethrin Permethrin for 1 hour. This table presents the mortality and standard error for each insecticide and locality.Click here for fileSpecies composition of An gambiae s.l between the mid and end of the malaria transmission season. The data provided represent the statistical comparison of An. gambiae complex species and molecular forms composition between the mid and end of malaria transmission season during the three years of the study in the four localities. An. gambiae M form (M), An. gambiae S form (S), hybrid of S and M form, (H) and An. arabiensis (B) proportions are given by collection round, the mean and confidence limits (CL) of the proportion are given for each species and locality. The total number of mosquitoes PCR-tested is given for each round  and the P value comparing species composition between rounds is given.Click here for file"}
+{"text": "There were errors in the Funding statement.http://www.singhealth.com.sg), National Medical Research Council (http://www.nmrc.gov.sg), Biomedical Research Council of Singapore and The Singapore Millennium Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The correct statement is \"This work was supported by grants from the SingHealth Foundation ("}
+{"text": "Parkinson's disease (PD) is the second most common neurodegenerative disorder, and increasing age is a major risk factor for development of PD. As such, PD is expected to become increasingly prevalent in coming years as the aged population grows in number. PD is typically treated with pharmacological and sometimes surgical approaches, but these treatments do not adequately address many aspects of the disease. As such, rehabilitation may play a key role in the management of PD. The nine articles in this special issue illustrate the broad spectrum of important rehabilitation issues for people with PD. M. H. Nilsson et al. report relationships between health and housing in very old individuals with PD, examining the impact of environmental barriers and accessibility problems on daily life. A. Letanneux et al. focus on the psychosocial impact of speech impairment in PD, presenting a French version of the Dysarthria Impact Profile. K. B. Foreman et al. also address speech issues, examining the effects of concurrent performance of a speech task and a postural control task in individuals with PD. Postural control is also addressed by G. Vervoort et al., who present evidence of differences in specific aspects of postural control in people with PD who experience freezing of gait compared to those with PD who have no history of freezing of gait. S. T. Nemanich et al. also focus on gait in PD, examining utility of walking speeds for identifying fallers and determining predictors of preferred and fast pace walking speeds. A. Williams et al. examine the relationships between gait and upper extremity movements in PD, studying the effects of amplitude and cadence manipulations. B. K. Randhawa et al. also examine upper extremity performance as assessed by handwriting, demonstrating the acute changes in handwriting following a single intervention session using transcranial magnetic stimulation. L. A. King et al. examine two different exercise interventions, focusing on which outcome measures were most effective for measuring change following agility boot camp or treadmill training. Finally, G. Frazzitta et al. report the effects of a four-week multidisciplinary inpatient rehabilitation program on gait and balance function after completion of the intervention and one year later. The broad scope of work in this special issue is reflective of the far-reaching impact that rehabilitation may have on many aspects of PD, from the individual to the environmental level. Last but not least, the presented work will provide a multilevel understanding of PD motor problems which will feed into the clinical care and optimal rehabilitation for patients with this complex disease. Gammon M. EarhartGammon M. EarhartLeland E. DibbleLeland E. DibbleTerry EllisTerry EllisAlice NieuwboerAlice Nieuwboer"}
+{"text": "Notes of Allergy Watchers\", which appeared in volume 2 of The World Allergy Organization Journal on page 61, the name Doctor Arthur Eisen is incorrect. This should appear as Doctor Herman Eisen.In the article \"Introduction to the New Editorial Series, http://www.waojournal.org.This error has been noted in the original version of the article, which is available at"}
+{"text": "Acta Cryst. (2007), E63, i194.Corrigendum to  et al.  are corrected.The title and formula in the paper by Zhou  The Crystal data in the original paper are correct apart from the formula.In the paper by Zhou"}
+{"text": "This special issue of the International Journal of Microbiology focuses on global health. More specifically, our aim is to establish whether there is a role for microbial ecology in global health. \u201cGlobal health\u201d is often defined as the \u201chealth of populations\u201d a problem that transcends geographic boundaries and exists at the intersection of demography, economics, epidemiology, political economy, and sociology. Conspicuously absent from this definition is microbial ecology. Is there, after all, a role for microorganisms in health of populations or is \u201cglobal health\u201d defined strictly by its human dimensions? We argue that the analyses of the factors that led to the emergence and reemergence of pathogens, expansion of vector-transmitted diseases into the new areas of the planet, and recent zoonotic outbreaks highlight an important role for microbial ecology in the health of human populations. Original research and review articles within this special issue contribute to the scientific scaffolding, upon which the risk assessment and management framework is to be built.Nowhere on this planet are issues of microbial and human ecology more important than in large urban slums. There, humans and microbes do not only intersect, they collide, and the consequences of this collision are often catastrophic. A review by Abraham traces pathogenic, often drug-resistant microbes from inadequate sanitation facilities in megapolises through rivers toward downstream consumers of tainted waters. The review addresses persistence of pathogens in rivers running through the world's major cities, interactions of waterborne pathogens with highly diverse aquatic microbiota, their survival in favorable environmental niches, in biofilms, and in association with amoeba. The author then comments on the utility of indicator organisms in assessing quality of waters in megacities and offers his vision of the pressing research needs for science-based solutions for the water quality and sanitation crisis in the world's urban population centers.'s review contains a thoughtful analysis of the methods for the detection and quantification of viable but non-culturable (VBNC) pathogens and Cryptosporidium oocysts, estimating virulence potential of the pathogens in the VBNC state and developing risk assessment models that take into consideration viable but non-culturable as well as drug-resistant pathogens. N. J. Rowan also offers a critical analysis of the efficacy of new water sanitation technologies and the potential impacts of their byproducts on water quality. A critical review by N. J. Rowan, builds a case for the need to adapt risk assessment and management framework to accommodate viable but nonculturable (VBNC) pathogens. N. J. RowanIssues associated with the usefulness of indicator organisms arise again in the review by Bienfang et al. The first part of the review by P. K. Bienfang et al. contains a thorough survey of marine dinoflagellates and cyanobacteria that produce toxic secondary metabolites, and comments on the hypotheses which link production of toxins with various environmental factors. The second part of their review is dedicated to infectious marine microorganisms. This discussion is framed by the five dilemmas associated with the use of indicator organisms to estimate the presence of infectious (introduced and autochthonous) pathogens in seawater. Francisella tularensis. This study demonstrates that culturable F. tularensis is widely distributed in the environment. It tests the utility of certain genetic markers for the discrimination between potentially pathogenic and nonpathogenic environmental isolates of Francisella. S. A. Sousa et al. provide a thorough review of the epidemiological, comparative, and, functional genomics studies carried out with environmental and pathogenic members of the Burkholderia cepacia complex. The latter part of the review by S. A. Sousa et al. contains a critical analysis of the methods that are currently available to the researchers for the identification of virulence determinants in isolates of B. cepacia and for the determination of mechanisms which these pathogens use to proliferate in the different environments and infect its vertebrate and invertebrate hosts. Autochthonous opportunistic pathogens take the center stage in the review by S. A. Sousa et al. and the environmental survey of T. Broman et al. Over a 3-year period, T. Broman et al. tested nearly six hundred water and sediment samples and almost one hundred wild rodents for the presence of endemic strains of E. coli and Salmonella can persist in soils and in association with plants for extended periods of time. Consumption of fruits and vegetables, which harbor these human pathogens has already resulted in dozens of large international outbreaks of gastroenteritis. Not surprisingly, therefore, there has been an explosion in research aimed at understanding behavior of Salmonella and enterovirulent E. coli outside of their human or animal hosts. Research articles by A. D. Duffit et al. and A. M. Ibekwe et al. further contribute to our understanding of the ecology of enterohemorrhagic E. coli O157:H7 in soils and water by defining gene expression associated with the persistence in these environments, in the presence (or absence) of fumigants or native soil microbiota. A. A. Mafu et al. correlate attachment of Salmonella and other human pathogens to abiotic surfaces with culture conditions and surface properties, thus furthering our understanding of persistence of human pathogens outside of their hosts.One of the most disturbing realizations to which scientists and lay people came within the last decade is that human pathogens, like enterovirulent A review by S. Schj\u00f8rring and K. A. Krogfelt and a research article by S. S. Hussey et al. address the impact of antibiotics on human gut-associated microbiota. The study by S.S. Hussey et al. demonstrates that a short-term parenteral antibiotic administration to human neonates can affect the composition and diversity of the gut associated microbiota. The focus of S. Schj\u00f8rring and K. A. Krogfelt's review on antibiotic-resistance gene transfer between native gut microbiota and enteric pathogens echoes the reviews by R. Abraham and N. J. Rowan, which appear earlier in the issue, although ecological scales of these three reviews are decidedly different. S. Schj\u00f8rring and K. A. Krogfelt also tackle the issue of antibiotic resistance in the food production environment, further contributing to our understanding of the ecology of human enteric pathogens outside of their animal hosts. Microorganisms are abundant on this planet. Microbial processes like photosynthesis and nitrogen fixation continue to shape this planet. The Plague, Irish Potato Famine, cholera\u2014no textbook is complete without these events that shaped human history. Our history textbooks, however, never mention by name the microorganisms that reshaped continents and almost halted civilizations. In trying to understand these events, we exile their culprits into anonymous infamy and thus diminish the role of ecology of common soil and water microorganisms in the health of human populations. Each year throughout the past century, humans were more and more assertive in defining our global environment. We rarely, however, reflect on the question of how global climate change, population dynamics, methods of food production, crowding in megacities, changes in life styles, and dietary habits affect the ecology of planet's microbiota, the microbiota that shaped this planet, affected global health and often defined the course of human civilizations.Max TeplitskiMax TeplitskiJorge H. Leit\u00e3oJorge H. Leit\u00e3oShlomo SelaShlomo Sela"}
+{"text": "The authors note that two baseline traces in Figure 6A (right panel) appeared incorrectly. Due to a copy and paste error while processing the original current traces for the preparation of the figure, the first and third traces and the eleventh and twelfth traces were duplicated. This error does not affect scientific results or the conclusions of the article. The authors apologise for this error and are providing the corrected figure via this Correction.http://www.plosone.org/corrections/pone.0001511.006.cn.tif [^] The revised version of Figure 1 can be seen here:"}
+{"text": "There was an error in the corresponding author designation. Michael C. James is the only corresponding author. His email address is mcjames@dal.ca."}
+{"text": "In response: We thank Dr. Behr for her comment (Tenrecidae and not Erinaceidae) and are unlikely to be kept as pets (Leptospira bratislava in the Netherlands and Denmark and the main host of L. canicola in Israel (Capillaria, no report of a human infection transmitted by hedgehogs has been published to our knowledge. comment . The intn Israel . Finally"}
+{"text": "To the Editor: The article on hedgehog zoonoses  and are unlikely to be kept as pets (Leptospira bratislava in the Netherlands and Denmark and the main host of L. canicola in Israel (Capillaria, no report of a human infection transmitted by hedgehogs has been published to our knowledge. comment . The intn Israel . Finally"}
+{"text": "In the Funding statement, multiple funding organizations and grants are incorrectly omitted.The following paragraph should be read with the Funding statement:http://www.bric.ed.ac.uk/) [^] and the University of Aberdeen Biomedical Imaging Centre (http://www.abdn.ac.uk/ims/imaging/). [^] Both centres are part of the Scottish Imaging Network, A Platform for Scientific Excellence (SINAPSE)collaboration (http://www.sinapse.ac.uk/), [^] funded by the Scottish Funding Council, Scottish Executive Chief Scientist Office, and the six collaborator Universities. Professor Joanna M. Wardlaw was funded by the Scottish Funding Council and Scottish Executive Chief Scientist Office through the SINAPSE collaboration. David Alexander Dickie was funded by a SINAPSE industrial collaboration (SPIRIT) PhD scholarship with TMVSE, a Medical Research Council (MRC) scholarship, and the Tony Watson Scholarship bequest to The University of Edinburgh. Dr Dominic E. Job was funded by Wellcome Trust Grant 007393/Z/05/Z. Dr Trevor S. Ahearn was funded by SINAPSE and the University of Aberdeen. Professor Alison D. Murray was funded by NHS Grampian via the University of Aberdeen.\"\"The authors would like to acknowledge and thank the following centres and funders. This work was carried out in The University of Edinburgh Brain Research Imaging Centre (BRIC;"}
+{"text": "He should also be noted as the corresponding author, whose email address is: shan.lu@umassmed.eduIn the online version of this article, author Dr. Shan Lu was not included in the author byline. He should be listed as the eighth author and affiliated with: This information is present in the PDF version of the article."}
+{"text": "Glutamate is converted to ornithine. Many enzyme reactions are involved in the inter-conversion of glutamate and ornithine by intestinal mucosa . The mod"}
+{"text": "This special issue on the overactive bladder deals with specific aspects of OAB with respect to pathophysiology, specific patient populations, and treatments. The editorial board selected 8 papers that address these special angles of the OAB spectrum.In the basic research section, Y. Kubota et al. describe the role of KIT-positive cells in the urinary bladder. KIT staining is used as a marker for interstitial cells. Latest publications suggest that KIT is not only a detection marker of these cells but also may play a crucial role in the control of bladder function.T. Antunes-Lopes et al. relate about the latest developments of biomarkers like nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) and how useful they are at this moment to be as biomarkers. It seems that BDNF is the best future candidate for this goal.With respect to medical treatment, three papers are presented. The first is from A. Athanasopoulos and K. Giannitsas. In an overview about antimuscarinics, they conclude that the differences are small and that individuals respond differently to the various available drugs. A. Matsumori et al. illustrate that it is possible to prescribe other antimuscarinics when the first one fails. They present data about the effect of propiverine in patients who failed other antimuscarinic treatments for OAB. A special group of patients who are treated with OAB is presented by F. van Rey and J. Heesakkers. In a group of MS patients with OAB, the highly beneficial effect of solifenacin is presented based on bladder diaries and patient-reported outcome measures.Another well-established treatment for OAB is pelvic electrical neuromodulation presented by T. F. Al-Shaiji et al. They review the indications, possible mechanisms of action, surgical aspects and possible complications, and safety issues of this technique.A completely different type of neurostimulation for OAB is described by F. M. J. Martens et al. They relate about the results of the Finetech-Brindley neurostimulator in patients with a complete spinal cord injury. This difficult and time-consuming surgery has various beneficial effects on as well the urinary and the gastrointestinal tract. Moreover, the sexual functions and the lower limb spasms may change to the good with this exciting technique.The last contribution in this special issue on OAB is from J. Neuhaus et al. They present about a fairly difficult and special kid on the block: those suffering from bladder pain syndrome or interstitial cystitis. They propose a new diagnostic model that includes extended diagnostics with molecular markers. Differential diagnosis and tailored therapy according to them should be based on three diagnostical columns: clinical diagnostics, histopathology, and molecular diagnostics. The future will tell whether this is way to go in this difficult-to-treat disturbance of the lower urinary tract.The editorial board of this special issue hopes that these topics give you more insight in the OAB spectrum and that it gives new ideas to implement in basic research as well as clinical practice.John P. F. A. HeesakkersFrancisco CruzYasuhiko IgawaErvin Kocjancic"}
+{"text": "There is an error in the seventh sentence of the Abstract. It should read: SSWD was disproportionally higher in individuals in tidepools.There are errors in the fourth paragraph of the Results. It should read: In the early summer, adult sea stars in different sub-habitats were differentially susceptible to SSWD . Purple"}
+{"text": "There is an error in the Acknowledgements of the published article. The Acknowledgements should read:This study was supported by UM/MOHE/ HIR Project No. D000014-16001. The authors are grateful to Dr. Mohammadtaghi Amiri-Khorasani for expert guidance during the early stage of this project and Dr. Jos Vanrenterghem for his valuable comments. The authors also acknowledge the expert guidance of Nafiseh Khalaj, who contributed to biomechanics data collection and manuscript preparation (related to data collection)."}
+{"text": "There is an error in the funding statement that was introduced during the preparation of this manuscript for publication. Please refer to the correct funding statement here:This work was supported by the Chicago Biomedical Consortium with support from the Searle Funds at the Chicago Community Trust (to T. L. Vanden Hoek and A.R. Leff), and by a grant from GlaxoSmithKline Center of Excellence (to A. R. Leff). The co-author Dr. Alan Leff has received research grant support from GlaxoSmithKline. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."}
+{"text": "To the Editor: Tortoli et al.  region. The 16S rRNA gene sequence of these isolates showed 100% similarity with those of M. yongonense and M. marseillense. The isolates were more closely related to M. yongonense than to M. marseillense in terms of the hsp65 gene and ITS1 region; however, the rpoB gene sequence showed a higher degree of similarity to that of M. intracellulare (99.4%) than to that of M. marseillense (97.4%). The authors did not mention the similarity of the isolates with M. intracellulare in these sequences except for the rpoB gene. However, because these sequences showed high similarity to M. yongonense, a high degree of similarity to M. intracellulare could be inferred.M. yongonense highlighted its unique molecular character . No consensus guidelines are available for mycobacterial identification, but the rpoB gene has been used widely as a target gene; multilocus sequence analysis also has been used recently (M. yongonense preceded the acquisition of the rpoB gene from M. parascrofulaceum by a lateral gene transfer event (M. intracellulare than to M. yongonense on the basis of the rpoB gene sequence and multilocus sequence analysis. It is also possible that the isolates are a M. yongonense strain that preceded the acquisition of the rpoB gene but that are not the same as the initially described M. yongonense.The initial description of"}
+{"text": "The list of authors in the original article has been modified to include Nina L. Reislev and affiliations have been modified accordingly. Dr. Reislev was originally listed in the Acknowledgment section, and has now been added to the list of authors. The Acknowledgment section in the original article has been updated.Author contributions: RK and MP designed the study. NR recruited participants, collected psychometric and brain imaging data. LH, MB, CC, and AS analyzed the rsfMRI data. LH, RK, and MP wrote the manuscript. SL and AS edited the manuscript and provided scientific expertise.All the other files remain unchanged. This error does not change the scientific conclusions of the article in any way.The original article has been updated.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "There is an error in the Competing Interests section. The number of authors that have affiliations with Datasio and Collecte Localisation Satellites should be four. The complete, correct competing interests information is as follows: While four authors have affiliations with the commercial companies Datasio and Collecte Localisation Satellites, this does not alter their adherence to PLOS ONE policies on sharing data and materials.ReichertM@dnr.sc.gov).Additionally, there is an error in the final sentence of the Funding section. The last sentence should read: Data from the South Carolina Department of Natural Resources may be requested from Dr. Marcel Reichert (John.Neilson@dfo-mpo.gc.ca). Data from the US National Marine Fisheries Service may be requested from Dr. Clay Porch (Clay.porch@noaa.gov). Data from the South Carolina Department of Natural Resources may be requested from Dr. Marcel Reichert (ReichertM@dnr.sc.gov).Please view the complete, correct Funding section here: The authors confirm that, for approved reasons, some access restrictions apply to the data underlying the findings. Data are not owned by the authors of the paper but may be obtained from the relevant government agencies. Data from Fisheries and Oceans Canada may be requested from Dr. John D. Neilson ("}
+{"text": "The publisher apologizes for this error.The email address for the first author, Corinna E. Dreher, is incorrect. The correct email address is:"}
+{"text": "The correct second sentence is as follows: The software  can be downloaded from http://figshare.com/articles/SynPAnal_Program/1285116.In the Materials and Methods section of the article, in the second sentence of the Software Requirement subsection, the link from which SynPAnal can be downloaded is incorrect. The correct link is:"}
+{"text": "Due to a typesetting error, the Funding section is missing in this article. The Funding section should read as follows: \"The work was supported by NIH grant NS051255 (A.B.) and grants from the Swedish Cultural Foundation in Finland (J.A.) and Magnus Ehrnrooth Foundation (J.A.).\" The publisher apologizes for this error."}
+{"text": "Head and neck cancer clinical research is thriving. Infrastructure for clinical research is supported through the National Institute for Health Research Clinical Research Network with operates through 15 local clinical research networks for studies within the UK Clinical Research Network Portfolio. The National Clinical Research Institute is a partnership of UK cancer research funders that support high-quality cancer research, although the National Institute for Health Research also has funding streams that will fund cancer-related research. Their websites provide up-to-date information regarding ongoing research projects. Other specialty organisations such as the British Association of Head and Neck Oncologists play important subsidiary roles in supporting research. Clinical research into head and neck cancer is an active and increasing area of activity in the UK. Several active research centres where clinical trials are underway are distributed evenly through the UK. \u00a0The framework for the organisation and infrastructure support of clinical cancer research is supported through the National Institute for Health Research (NIHR) Clinical Research Network (CRN). The NIHR CRN is the clinical research delivery arm of the National Health Service (NHS) in England, tasked with supporting the rapid set up and effective conduct of studies in the UK Clinical Research Network Portfolio, so that researchers can gather the robust evidence needed to improve treatments for NHS patients. The CRN operates across the NHS through a national coordinating centre and comprises 15 local clinical research networks (LCRNs) that cover the length and breadth of England. Each LCRN delivers research across 30 clinical specialties. At a local level the LCRN is responsible for the provision and allocation of research infrastructure including research nurses in collaboration with each partner organisation \u2013 each NHS Trust. The clinical specialties within each LCRN are managed across six divisions. Clinical research in head and neck cancer falls under \u2018division 1\u2019 \u2013 Oncology.The National Cancer Research Institute (NCRI) is a partnership of UK cancer research funders, government, charity and industry. In addition to the NCRI, the NIHR has several funding streams that support cancer trials. The NCRI comprises both clinical and managerial leadership. For each tumour type there are clinical studies groups (CSGs) and there are also modality CSGs, which cross cut the tumour site specific groups (e.g. radiotherapy CSG). The head and neck CSG is a group of approximately 20 individuals. All the specialties related to clinical cancer research are represented \u2013 e.g. surgical specialties of head and neck surgery , clinical and medical oncology, oral medicine, head and neck pathology, radiology, clinical trials and statistics, consumer representatives and administrative support. The head and neck CSG is also attended by representatives of the NCRI infrastructure as well as the main funders \u2013 Cancer Research UK. Over the last two years, the CGG has invited trainee representatives from the relevant specialties to attend meetings for a year, with the clear aim of growing tomorrow's research leaders. The membership of the CSG rotates regularly and advertisements for positions on the group are advertised both on the NCRI website as well as in the national press. The current chairman is Professor Hisham Mehanna at the University of Birmingham.http://www.ncri.org.uk) or search cancer \u2018head and neck\u2019 on the UK Clinical Trials Gateway: https://www.ukctg.nihr.ac.uk/A broad range of national studies is currently open, including trials of surgery, radiation, chemotherapy and other topics. For an up-to-date list of the current research protocols please consult the head and neck section of the NCRI website  stream of the NIHR.http://www.mrc.ac.uk).For feasibility studies Cancer Research UK remains the main funder and they also support translational research in relation to clinical trials. It is important to engage with a pathologist during the development of studies that might involve collecting and storing human tissue and to be aware of the requirements of the Human Tissue Authority. The role of pathology in research is addressed on the NCRI website and the MRC Data and Tissues Tool kit is being developed as a signpost to good guidance (A number of other funding streams are available including those coming direct from the department of Health who put out regular calls for research proposals via the NIHR. For smaller research projects in single centres or pump priming grants the Royal College of Radiologists and the British Association of Head and Neck Oncologists are sources of potential funding. Both of the above and also the Royal College of Surgeons are sources of short-term research grants for individuals. Useful web addresses for individuals looking for research funding are given below.http://www.cancerresearchuk.org/http://csg.ncri.org.uk/http://www.rcr.ac.ukhttp://www.rcseng.ac.ukhttp://www.bahno.org.ukhttp://www.hta.ac.ukhttp://www.nihr.ac.uk/funding-opportunities/http://www.nihr.ac.uk/funding/funding-for-research.htm"}
+{"text": "This article was republished on June 12, 2015, to correct an omission in the Editor section of the article. The Editor of this article was Ann M. Powers. The publisher apologizes for this error. Please download this article again to view the correct version."}
+{"text": "Soojin Park's affiliation was not originallyrecorded. Dr. Park is affiliated with the Graduate Scool of MOT/Sogang Institute ofAdvanced Technology, Sogang University, Seoul, Korea. The article has since been correctedonline.In the article \u201cFlexor Tendon Entrapment at the Malunited Base Fracture of theProximal Phalanx of the Finger in Child: A Case Report\u201d"}
+{"text": "Recently, a new journal, JEAAS  has been launched. The goal of this new interdisciplinary journal is to advance the field of animal sciences. A particular focus is the establishment and application of animal models for basic and clinical research . Theref"}
+{"text": "Heikki Summala). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.There are errors in the Funding section. The publisher apologizes for the errors. The correct funding information is as follows: Mr. Jami Pekkanen received funding from a personal grant from Finnish Cultural Foundation (grant no. 00140724). Mr. Jami Pekkanen and Mr. Teemu Itkonen were employed in MULSIMCO project funded by the Finnish Academy ("}
+{"text": "There is an error in the Funding section. The complete, correct funding information is as follows:Dr. Bond's contribution was supported in part by NIAAA-funded Center Grant P50 AA005595."}
+{"text": "Dr. Giuseppe Gargiulo is not included in the author byline. He should be listed as the fourteenth author and affiliated with Federico II University, Naples, Italy. The contributions of this author are as follows: Performed the experiments."}
+{"text": "Nucl. Acids Res. 43 (18): 8694\u20138712. doi: 10.1093/nar/gkv865The authors wish to make the following corrections to Figure In Figure The results and conclusion of the article are not affected and remain valid. The authors apologise to the readers for the inconvenience caused."}
+{"text": "May is National High Blood Pressure Education Month. High blood pressure, also known as hypertension, is the leading risk factor for stroke and a major cause of morbidity and mortality . In the To control hypertension, patients can take medications as directed, measure their blood pressure, and eat a lower-sodium diet and more fruits and vegetables . Health-http://www.cdc.gov/bloodpressure and http://www.cdc.gov/stroke.CDC\u2019s Division for Heart Disease and Stroke Prevention focuses on promoting cardiovascular health and improving quality of care for all and eliminating disparities associated with heart disease and stroke. Additional information is available at"}
+{"text": "The Data Availability Statement appearing with the published article is incorrect. The correct Data Availability Statement should read:http://www.legislation.gov.uk/uksi/2013/218/pdfs/uksi_20130218_en.pdf) which state that outside of Department of Health and Public Health England, data can only be disclosed in a form in which no individual child can be identified. Cleaned and anonymised NCMP data has subsequently been made available by the HSCIC through the UK Data Service. Please see below for the contact information of this third party. The food outlet data from the local councils of West Berkshire are provided in supplemental files. All food outlet data are attributed to their respective local councils: Bracknell Forest Council (http://www.bracknell-forest.gov.uk), Reading Borough Council (http://beta.reading.gov.uk/home), Slough Borough Council (https://www.slough.gov.uk/), The Royal Borough of Windsor and Maidenhead (http://www.rbwm.gov.uk/contacts.htm), Wokingham Borough Council (http://www.wokingham.gov.uk/), West Berkshire Council. To apply for individual-level NCMP data, please contact the Health and Social Care Information Centre,enquiries@hscic.gov.uk.There are legal restrictions on the student outcome data. National Child Measurement Programme data was used as determined by the data sharing agreement with the then Information Centre of the National Health Service (NHS IC), now Health and Social Care Information Centre (HSCIC). The data sharing agreement stated that all record level data must be treated in accordance with the Data Protection Act 1998 and individual level data must not be made available without agreement of the NHS IC. Access to data from the National Child Measurement Programme was granted to Nick Townsend during his previous employment with the National Obesity Observatory . All analysis of the data was undertaken then and the data was not seen by any other authors of this paper. Sharing of the NCMP data is governed by a set of regulations ("}
+{"text": "The publisher apologizes for this error.The first and last names for the second and the fifth authors were inadvertently switched. The first name appears as the last name and the last name appears as the first name. Zhao Xinwang should be Xinwang Zhao and Tu Jinxing should be Jinxing Tu. The correct citation is: Bu SH, Zhao X, Yi C, Wen J, Tu J, Zhang YM (2015) Interacted QTL Mapping in Partial NCII Design Provides Evidences for Breeding by Design. PLoS ONE 10(3): e0121034. doi:There are errors in the author contributions. The initials for Xinwang Zhao should be XZ and the initials for Jinxing Tu should be JT.soyzhang@mail.hzau.edu.cn.An additional email address for the corresponding author is missing. The additional email address is:"}
+{"text": "The image for r between the two subpopulations in this regime.There is an error in the first sentence of the seventh paragraph of subsection \u201cElementary model: two-phenotype cell population dynamics\u201d of section \u201cCell Population Model for Transition and Growth Dynamics: Two-Phenotypes\u201d. The correct sentence is: We can determine the population ratio The image for The image for There are errors in the Author Contributions. The correct contributions are: Conceived and designed the experiments: JZ, HQ and SH. Performed the experiments: JZ and AOP. Analyzed the data: JZ and AOP. Contributed reagents/materials/analysis tools: HQ and AOP. Wrote the paper: JZ and AOP. All authors participated in editing the manuscript."}
+{"text": "In the original manuscript, there is an error in the author list and Dr. Yoel R. Petashnick was incorrectly given as Dr. Yoel Potachnik in the original publication. This is now corrected to Dr. Yoel R. Petashnick. This error does not change the scientific conclusions of the article in any way. The original files of the article have been updated.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Hepatozoon invade the blood cells of many mammalian species, being transmitted by range of arthropods. In domestic carnivores, three species of Hepatozoon were described to date: H. canis and H. americanum in dogs and H. felis in cats. The classification of Hepatozoon in wild carnivores is still not complete due to lack of field and experimental data as well as phylogenetic studies. The aim of this study is to carry out a survey on the prevalence and diversity of Hepatozoon sp. in red foxes Vulpes vulpes. Samples of tissues were collected from dead foxes in 11 counties of Romania; 91 samples of liver tissue were examined in total. DNA extraction was performed with commercial kit according to the manufacture's protocol. Hepatozoon sp. DNA was detected by PCR using primers amplifying 400-600 bp long part of 18S rRNA gene. These primers are commonly used for diagnostic purposes in dogs and in some studies also for detection of Hepatozoon sp. in wild carnivores. PCR products were sequenced to validate positive results of reaction. DNA of parasite was confirmed in 55% of examined samples. Recent findings classified Hepatozoon sp. in foxes and other wild canids in Europe as H. canis. However, Rhipicephalus sanguineus, the only known vector of H. canis in Europe, is absent in most of our sampling sites. Moreover, this tick is typical for the dogs but rare or even absent in foxes. In order to clarify the identity of the parasite, the next step of our study is to focus on amplification of longer or full segment of 18s rRNA gene to allow more accurate phylogenetic analyses and comparison with H. canis sequences from dogs and Hepatozoon isolates from other carnivores.Apicomplexan parasites of genus This study was supported by IGA UVPS Brno, project 115/2013/FVL."}
+{"text": "This article was republished on May 26, 2015, to correct an omission in the Editor section of the article. The Editor of this article was Joseph M. Vinetz. The publisher apologizes for this error. Please download this article again to view the correct version."}
+{"text": "Reason for erratum:The name for the author Md. Abdul Hye Khan was listed as Abdul Hye Khan and the citation as Khan, AH instead of Hye Khan, MA, due to a typesetting error. This mistake does not change the scientific conclusions of the article in any way. The publisher apologizes for this error.The original article has been updated."}
+{"text": "In the Author Contributions section, Eric. E. M. Wohlford should be listed as EMW as being one of the persons who performed the experiments."}
+{"text": "The complete, correct Data Availability section should read as follows:In the Data Availability section, there is an error in the DOI for the data uploaded to the Harvard Dataverse Network. The correct DOI is http://thedata.harvard.edu/dvn/, doi: 10.7910/DVN/O239GQ).All files are available from the Harvard Dataverse Network ("}
+{"text": "Nucl. Acids Res. 43 (14): 6919\u20136933. doi: 10.1093/nar/gkv613de Broek to Bram van den Broek.The name of one of the authors has been misspelled in the article and should be changed from Bram van The authors apologise to the readers for the inconvenience caused."}
+{"text": "In Fig. In Fig. Unfortunately, after publication of the original version of this article , it was The corrected Fig."}
+{"text": "The Academic Editor field is missing from this paper. The Academic Editor is James P. Meador, Northwest Fisheries Science Center, NOAA Fisheries, UNITED STATES. The publisher apologizes for the error."}
+{"text": "Crassostrea), Saccostreinae subfam. nov. (including Saccostrea and tentatively Striostrea) and Ostreinae (including Ostreinae and Lophinae taxa) are recognized.There is an error in the seventh sentence of the Abstract. The subfamily name is misspelled. The correct sentence is: Therefore, the subfamily Crassostreinae  is entirely located in the second segment.There is a typographical error in the second sentence of the second paragraph in the \u201cDataset, DNA extraction, amplification and sequencing\u201d section of the Methods. The correct sentence is: It is worth mentioning that, despite some oysters show a split of the 16S rRNA gene into two segments, e.g. in the Asian"}
+{"text": "The following information is missing from the Competing Interests statement: Calciscon AG holds a patent for the T50-Test and markets the T50-Test. The publisher apologizes for this error. The complete, correct Competing Interests statement is: The authors have the following interests. This study was supported by an unrestricted grant from Fresenius MC, Bad Homburg, Germany. Bernard Canaud is employed by Fresenius MC and holds shares in this company. Andreas Pasch is a part-time employee of Calciscon and holds shares in this company. Mauro Dionisi and Matthias Meier are both employed by Calciscon. Calciscon AG holds a patent for the T50-Test and markets the T50-Test. There are no other patents, products in development or marketed products to declare. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials."}
+{"text": "Mesacanthus is a common and speciose genus of acanthodian fish from Lower Old Red Sandstone and Middle Old Red Sandstone assemblages (representing the Lower Devonian and Middle Devonian respectively) and is well represented in many palaeoichthyology collections in the UK. Based upon descriptions given during the 19th century, specimens of the genus Mesacanthus from the Orcadian Basin and Midland Valley areas of Northern and Central Scotland have historically been referred to a number of different species; of these, the most frequently discussed in the literature are M. mitchelli, M. peachi and M. pusillus. In order to test the validity of these three species, traditional morphometric analyses were carried out on over 100 specimens of Mesacanthus, from both the Lower Devonian and the Middle Devonian, that cover the full range of known localities for these taxa in Northern and Central Scotland. Based upon morphological and morphometric comparisons, this investigation has found that at least two species of Mesacanthus are valid (M. mitchelli and M. pusillus) as specimens from the Lower Devonian and Middle Devonian have been shown to differ significantly in a number of important ways. However, no evidence has been found for the validity of the second and distinct Middle Devonian species, M. peachi. Mesacanthus  are important early representatives of Gnathostomata  and haveacanthus  is foundacanthus . The faurmations .Mesacanthus having recognised that some of the species of Acanthodes . These spines are small and delicate structures and are not always well preserved, making this particular character a difficult one to use on its own in diagnosing specimens. Prior to this work, Mesacanthus pusillus (Acanthodes pusillus) in which he stated that the species is extremely small, has short anal spines, triangular scales with raised keels on their top edge and a distinct tail in which the upper lobe extends to a sharp point and the lower lobe forms a small triangle. Using this description for comparison, other authors erected new species of Mesacanthus, but often without providing any new information on the overall anatomy of the genus , the National Museum of Scotland (NMS), the Natural History Museum, London (NHMUK) and the Hunterian Museum (GLAHM). Images of specimens housed in the Elgin Museum (ELGNM), the collections of the British Geological Survey (GMS) and the Royal Ontario Museum, Canada (ROM) were also looked at during the course of this investigation. The specimens include representatives from all three of those species that are most commonly discussed in the literature and cover all of the known localities for All of the specimens used in the analyses were studied first hand by the author. A number of key measurements were taken from each of the specimens and these measurements are laid out in The data set was subjected to a series of statistical analyses that included multivariate analysis of variance (MANOVA) canonical variate analysis (CVA) and principle component analysis (PCA), as well as a number of other simple comparisons . These aMesacanthus was carried out as part of this investigation. This was done because one of the few distinctions between M. mitchelli, M. pusillus and M. peachi that can be found in the current literature is a supposed difference in \u2018robustness,\u2019 with M. peachi purportedly being \u2018more robust\u2019 i.e., having a smaller length to width ratio than M. pusillus and M. mitchelli . Specimens of M. mitchelli, M. peachi and M. pusillus do not appear to differ to drastically in these plots, although the 95% confidence ellipses for specimens from the Lower Old Red Sandstone plot marginally higher, meaning that these specimens have on average slightly greater length to width ratios. This difference was investigated further through the application of a t-test . M. peachi and M. pusillus were found not to be significant . On the other hand, the length to width ratios of the specimens of M. mitchelli did show a significant difference to the length to width ratios of the specimens of M. peachi, and also of the specimens of M. pusillus  and comparing their length to width ratios with those of M. mitchelli also recovered a significant difference between these two groups . It is also worth noting that, of the other combinations of measurements that were subjected to t-tests, the sum of the distance between the pectoral and pelvic fin spines divided by the overall length of the specimen ((PP + PA)/L) was found to be significantly different between M. mitchelli and M peachi  and M. mitchelli and M. pusillus , but, importantly, not significant between M. peachi and M. pusillus . Again, a significant difference was found between groups of Middle Devonian and Lower Devonian specimens . A significant difference was also recovered between the length to anal fin spine and overall length ratio between specimens from the Lower Old Red Sandstone and Middle Old Red Sandstone .The bivariate plots produced for length and width  show thaM. mitchelli, M. pusillus and M. peachi were treated as separate groups, a priori, show that M. peachi and M. pusillus cannot be distinguished from one another based upon the measurements taken, but specimens of M. mitchelli can be distinguished from both M. peachi and M. pusillus. M. mitchelli) does appear to be more separated from the two Middle Devonian species, which overlap with one another to a greater degree; the Middle Devonian specimens plot more along the negative half of Axis 2 whereas the Lower Devonian specimens plot predominantly in the positive half. While this plot may not be completely clear in showing how these groups separate, the numerical results obtained in these analyses show to a much greater degree the amount of overlap and separation between the groups and, crucially, whether or not this type of multivariate analysis recovered any significant differences between the groups based upon the measurements taken. The confusion matrix from this MANOVA test demonstrates the high level of overlap between specimens of M. peachi and M. pusillus and the relatively low levels of overlap between specimens of these taxa and specimens of M. mitchelli . This shows a high degree of similarity between specimens of M. peachi and M. pusillus. Conversely 37 out of 48 of those specimens currently identified as M. mitchelli were recovered as such by this analysis (77%). The results of uncorrected and Bonferonni corrected pairwise comparisons between these specimens show that a significant difference exists between specimens of M. mitchelli and specimens of both M. peachi and M. pusillus , but show no that significant difference exists between specimens of M. peachi and M. pusillus . Importantly, the difference between each of these groups (\u2018more robust\u2019 and \u2018less robust\u2019) and the Lower Old Red Sandstone specimens was found to be significant  also showed that, based upon the measurements in this study other than length and width, no significant difference exists between the two groups from the Middle Old Red Sandstone i.e., those that appear \u2018more robust\u2019 and \u2018less robust\u2019 . This suggests that these differences in fin spine curvature are not specific differences, but are more likely to be a result of intraspecific variation or even preservation.Comparison of the morphologies of the various fin spines of Mesacanthus under a light microscope and using high resolution photographs also showed that there were no differences between specimens of different species. The scales in all specimens had a similar morphology; small, tightly packed and unornamented and diamond shaped  plotted well within the standard range for the species; it did not plot close to specimens of M. peachi and M. pusillus  but in terms of the measurements used in this study the only observed differences are in the total body length and width (specimens of Mesacanthus are on average approximately 35% the average length of specimens of Cheiracanthusand only 25% the average width) and the relative positions of the attachments for the dorsal and anal fin spines. In terms of the latter character, specimens of Cheiracanthus differ in the fact that the attachment of their dorsal fin spine is located anterior to the attachment of their anal fin spine, and not the other way around, as is the case in all species of Mesacanthus . Given how similar these genera are overall, the results of the various bivariate and multivariate analyses that included specimens of Cheiracanthus showed a clear distinction between the two taxa. Because of the results of these additional analyses the author feels that this method does have potential when it comes to being used for discrimination between similar and morphologically conservative taxa such as acanthodians.The strength of these methods in discriminating between anatomically similar acanthodians, using the measurements outlined in M. mitchelli is currently said to be distinguishable from M. peachi on the basis of how \u2018robust\u2019 the two species are (M. peachi being supposedly more \u2018robust\u2019 than M. mitchelli) then a difference in the XY scatters of length and width between specimens of M. mitchelli and M. peachi should be expected. Simple comparison of these features shows that such a difference does exist and that it is significant  found a significant differences between this group and the specimens of M. mitchelli .Additionally, multivariate analyses which grouped all of the Middle Devonian specimens into a single group  for the existence of two distinct Middle Devonian groups within the specimens, the current taxonomic distinctions within M. pusillus was in use first  were \u2018more robust\u2019 than M. mitchelli. Despite the fact that M. peachi and not M. pusillus when he gave that diagnosis, and also went on the try and discriminate between the two Middle Old Red Sandstone taxa using the same character, the fact that the chosen discriminating character has been shown to not be sufficient and that no other differences could be found between the specimens from the Middle Old Red Sandstone either, it must be concluded that all specimens from the Middle Old Red Sandstone should be regarded as belonging to one species, M. pusillus. From this evidence, it seems reasonable to retain the names M. mitchelli and M. pusillus for specimens from the Lower Old Red Sandstone and Middle Old Red Sandstone respectively. Further investigation of these taxa may yield more differences in their anatomy but provisionally this study diagnosis them using the same character as M. mitchelli has a greater length to width ratio than M. pusillus.Seeing as the name se first  it must M. mitchelli (NHMUK PV P560) was studied first hand by the author and data taken from it was used in the analyses of this investigation. The current whereabouts of the holotype specimens of M. peachi and M. pusillus, however, remain uncertain, despite an exhaustive search of the literature and collections. M. pusillus lost but also went on to state that certain specimens in the collections of the Royal Ontario Museum and in the Elgin Museum could possibly be the counterparts to the syntype material. This investigation and has identified two specimens in the collection of the Royal Ontario Museum and one specimens in the Elgin Museum that could be the missing syntype material (or the counterpart of it) of M. pusillus. Acanthodes pusillus and two of these figured specimens, although the figures are not very clear, closely resemble specimens ROM 25872, ROM 25846 and ELGNM 1978.191.1  than Mesacanthus pusillus, from the Middle Devonian. This study has also concludes that M. pusillus should provisionally be considered the only valid species name for specimens from the Middle Devonian, as no evidence was found for a second, distinct Middle Devonian species, M. peachi, as was originally stated by We conclude that the genus 10.7717/peerj.1331/supp-1SOM S1The figure shows the large amount of ovelap between specimens from the Middle Devonian (pink squares) and Lower Devonian (grey inverted triangles) recovered by the PCA. Specimens from the Middle Devonian occupy a greater range of positions within the morphospace but oveall do not differ drastically from the specimens from the Lower Devonian in this analysis.Click here for additional data file.10.7717/peerj.1331/supp-2SOM S2M. peachi and M. pusillus. As in M. pusillus falling within the same space as the specimens of M. peachi.The PCA scatter shows the morphospace occupied by the 2 Middle Devonian species Click here for additional data file.10.7717/peerj.1331/supp-3SOM S3Mesacanthus and Cheiracanthus. Again, this lends evidence to thestrength of this method and its potential for use in future studies of other similar taxa.As in Click here for additional data file.10.7717/peerj.1331/supp-4SOM S4Mesacanthus are divided into 2 groups (Middle Devonian specimens and Lower Devonian specimens) and analysed alongside specimens ofCheiracanthus. The confusion matrix produced in this analysis and the uncorrected and Bonferonni corrected Hotelling\u2019s p-values are shown in Table 6.The figure shows the CVA scatter that is produced when the specimens of Click here for additional data file.10.7717/peerj.1331/supp-5SOM S5p-values show how each of these groups was found to be significantly different from the others. This is important because this shows that when M. peachi and M. pusillus are synonymised the single taxon is found to still be significantly different from other acanthodian taxa. Red = not significant; Green = significant.The confusion matrix shows the relatively low amount of confusion between specimens from the 3 groups in this particular analysis. The uncorrected and Bonferroni corrected Hotelling\u2019s Click here for additional data file.10.7717/peerj.1331/supp-6SOM S6M. peachi. (B) Specimen GSM 21448, which is very likely the specimen figured by (A) Figure from Click here for additional data file.10.7717/peerj.1331/supp-7SOM S7M. pusillus. (B) Specimen ROM 25846, which is possibly one of the specimens (or counterpart to) that was figured by (A) One of three figures given by Click here for additional data file.10.7717/peerj.1331/supp-8SOM S8Click here for additional data file.10.7717/peerj.1331/supp-9Supplemental Information 1The table records all of the measurements taken for each specimen looked at in this study.Click here for additional data file."}
+{"text": "In the XML and PDF versions of the article, the corresponding authors\u2019 email addresses are duplicated. Please see below for the authors\u2019 correct email addresses:zaravinos.apostolos@ucy.ac.cyApostolos Zaravinos, Deltas@ucy.ac.cyConstantinos Deltas, In the PDF version of the article, the corresponding author\u2019s name is spelled incorrectly in the footnote containing the author\u2019s current address. The correct name is: Apostolos Zaravinos.The journal apologizes for these errors, which were introduced during the preparation of the article for the publication."}
+{"text": "Worldwide, health care systems are increasingly highlighting the importance of traditional medicines. The World Health Organization (WHO) plans to introduce traditional medicine into the international classification of diseases (ICD) for the first time since it started in 1900. Kampo medicine is a traditional Asian medical system that is unique in many ways. Kampo was transferred from the ancient Han Chinese dynasty and uniquely developed in Japan, especially during the Edo period (1603\u20131867). The theoretical understanding and the use of the abdominal examination \u201cFukushin\u201d to assess the patient's constitutional state are particular to Kampo.After the Meiji restoration in 1867, Japan's new government accepted only Western medicine from Europe and founded one medical licensure system. The result was suppression of acquired wisdom and insights with marginalization of practitioners until 1976. At that time, the Japanese Medical Association promoted its coverage by Japan's National Health Insurance program by physicians who were trained in Western medicine. And now, all of Japan's 80 medical schools teach Kampo medicine. As a result, roughly 90% of physicians use Kampo medicine in their daily practice. This is a very unique model of integration of traditional medicine and modern biomedicine. To better understand the promise of this integration, this special issue features Kampo medicine in the context of modern biomedicine.\u03b2 gene can be the predictive biomarker of the effectiveness of Kampo medicine for the treatment of the climacteric syndrome. T. Yoshino et al. and H. Tokunaga et al. describe hie (cold sensation) and hiesho (cold disorder). Hie and hiesho are very important concepts in Kampo treatment. T. Yoshino et al. characterized hie and hiesho. H. Tokunaga et al. characterized the differences of male hie, female hie with menstruation, and female hie after menopause by data mining method. To conclude, S. Yakubo et al. summarize the history and pattern diagnosis of Kampo medicine.Many provocative articles are included in this special issue. To begin, K. Katayama et al. address the current situation of Kampo use in the National Health Care program. The authors analyzed 67,113,579 health care claim records and found that only 1.34% represented Kampo prescriptions. This suggests that a very small portion of conventional practice includes Kampo treatment even though many physicians use Kampo. H. Okamoto et al. present us with a case series of patients with refractory glossodynia. Among 39 patients, 69.2% of patients reported a beneficial effect. This is one of the examples in which Kampo treatment is effective even for the difficult cases in the Western biomedicine. K. Ogawa et al. show the usefulness of daiobotanpito for the treatment of acute diverticulitis. Y. Tanaka and T. Sakiyama report the case series of the usefulness of the Kampo treatment for pediatric emotional and behavioral disorders which were also refractory to the modern biomedicine. M. A. Bahar et al. reported that goshajinkigan prevents paclitaxel induced peripheral neuropathy without interfering with the anticancer action of paclitaxel in the basic research. Kampo medicines are often used for the purpose of the reduction of the side effects of chemotherapy for malignancies. K. Watanabe et al. report the potentially preventive effect of diabetic complications. Goshajinkigan is often used for the neuropathy from diabetes mellitus. Additionally, this Kampo medicine may be beneficial for the blood glucose control. K. Katayama et al. report a computer-based diagnostic way of Kampo patient patterns termed \u201cSho.\u201d This represents a promising blend of modern technology for a new world of traditional medicine in the future. Y.-C. P. Arai et al. reported about Fukushin, Kampo's unique diagnostic procedure. Certain Fukushin findings are related to the anxiety-depression levels. T. Namiki et al. report that cytosine-adenine (CA) repeat polymorphism of the estrogen receptor Together, these articles represent the promise and challenges present in the scientific understanding of Japan's herbal medicine tradition. We hope these articles help the readers to understand and appreciate the potential power of Kampo medicine outside of Japan. We invite you to explore Kampo.Kenji WatanabeKenji WatanabeGregory A. PlotnikoffGregory A. PlotnikoffTakeshi SakiyamaTakeshi SakiyamaHeidrun Reissenweber-HewelHeidrun Reissenweber-Hewel"}
+{"text": "The affiliation for the tenth author is incorrect. Philip J. McCall is affiliated with the Liverpool School of Tropical Medicine, Liverpool, United Kingdom."}
+{"text": "Operational research (OR) includes a wide range of problem-solving techniques and methods applied in the pursuit of improved decision-making and efficiency. OR involves the construction of mathematical models that attempt to describe the system. Because of the computational and statistical nature of most of these fields, OR also has strong ties to computer science and analytic. Operational researchers faced with a new problem must determine which of these techniques are most appropriate given the nature of the system, the goals for improvement, and constraints on time and computing power. The main focus of this special issue will be on the new research ideas and results for the OR. Considering the wide applications of OR, it seems natural that this journal selected it as the theme of its special issue.This special issue is composed of ten research papers; the covered subjects include topics such as ranking, congestion, fuzzy numbers and system, supply chain, and optimization problems. Below, a very brief overview of the featured works is given.M. Rostami-Malkhalifeh et al. in their paper deal with evaluating congestion in free disposal hull (FDH) models. In the DEA literature, there exist many methods dealing with theory and application of congestion in convex technologies. Considering nonconvex technologies, this paper discusses congestion in free disposal hull. The presented method shows the sources of congestion and estimates its amounts and also detects the losses amounts of output due to congestion. In a paper by M. Fallah and A. Mohajeri, green supply chain management is considered. Nowadays, due to global warming and climate changes, it is an important issue. Here, the authors formulate a comprehensive closed-loop model for the logistics planning considering profitability and ecological goals. They noted that the profitability criterion supported the cyclic network with the minimum costs and maximum service level. In the work provided by M. Rostami-Malkhalifeh et al., a new method is presented for solving fuzzy system of linear equations with crisp coefficients matrix and fuzzy or interval right hand side. The authors derived conditions for the existence of a fuzzy or interval solution of linear system. A work by M. Rostami-Malkhalifeh et al. discusses calculating superefficiency and then ranking the units based on it. The authors noted that most of the existing models do not provide the projection of Pareto efficiency. Thus, they introduced a model based on which the projection of Pareto-efficient can be achieved. The presented model is unit invariant and feasible and makes the amount of inefficiency effective in ranking. In a paper by M. Rostami-Malkhalifeh et al., a procedure is provided for ranking DMUs in DEA technique considering ideal and anti-ideal points. They formulated a model which is introduced to compute the performance of units for these two points through using common set of weights. The important feature of this model is that it can rank all DMUs by solving only three programs and it can rank all the extreme and nonextreme efficient DMUs. In the work by L. G. Moazam and T. Allahviranloo, a new concept of the 2nd power of a fuzzy number is introduced. The authors noted that this method is exponent to production (EP) method that provides an analytical and approximate solution for fully fuzzy quadratic equation (FFQE). The work by M. Rostami-Malkhalifeh et al. studies the inverse DEA technique while the nonradial enhanced Russell model is being used. They also introduced necessary and sufficient conditions for extra inputs or lack outputs determination and also investigated for showing the extra input or lack output. In the work by M. R. Abu Bakar et al., a new method is provided for the directional slack-based measure for the inverse DEA. The authors noted that the presented method elucidates the inverse directional slack-based measure model within a new production possibility set and noted that this approach was investigated in this study with reference to a resource allocation problem. It is possible to simultaneously consider any alterations of certain outputs associated with the efficient decision-making unit. In the paper by S. Kim, it is mentioned that gamification means the use of various elements of game design in nongame contexts including workplace collaboration, marketing, education, military, and medical services. This paper suggested the decision criteria for selection of gamification platform to support a systematic decision-making process for managements. They noted that the criteria are derived from previous works on gamification, introduction of information systems, and analytic hierarchy process.A. Grilo and J. Santos noted that there exists a shortage in the literature regarding the efficiency evaluation and productivity evolution of the new technology-based firms (NTBFs) in the incubation scope. Thus, they provided a model considering DEA analysis in order to incubate NTBFs for assessment and improvement in the efficiency. Moreover, they also used Malmquist index.F. Hosseinzadeh LotfiF. Hosseinzadeh LotfiA. AmirteimooriA. AmirteimooriBarnett ParkerBarnett ParkerMohammad KhodabakhshiMohammad KhodabakhshiJie WuJie WuM. Vaez-ghasemiM. Vaez-ghasemi"}
+{"text": "Through an oversight the author list of the published version of this paper failed to reflect the important contributions of Amir Shmuel. For all aspects of scientific attribution he should be considered to be the final author on the paper, so that the appropriate author list is: Richard B. Buxton, Valerie E. M. Griffeth, Aaron B. Simon, Farshad Moradi, and Amir Shmuel.2 may be driven differentially by excitatory and inhibitory activity and formulated experiments to test the idea. Valerie E. M. Griffeth, Aaron B. Simon, and Farshad Moradi conducted experiments and contributed ideas on how their results could be interpreted within the hypothesis. Richard B. Buxton wrote the manuscript, and all authors contributed to editing the final version.Richard B. Buxton and Amir Shmuel conceptualized the hypothesis that CBF and CMROThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "After the publication of the article, readers raised concerns about several aspects of the presentation as well as the methodological aspects of the study and the conclusions drawn. Follow-up with the authors and consultation with editorial board members, identified the following concerns:The manuscript was copyedited on submission at the request of the editorial office yet language errors were reintroduced during the evaluation process. The quality of the language of the published article is not in line with the criteria for publication in the journal.https://en.wikipedia.org/wiki/Hospital-acquired_infectionFragments of text overlap with text from the \"Hospital-acquired infection\" entry on Wikipedia: http://wonder.cdc.gov/wonder/prevguid/p0000419/p0000419.aspTable 1 was reproduced without attribution from: Julia S. Garner: Guidelines for Isolation Precautions in Hospitals Hospital Infection Control Advisory Committee. 01/01/1996, http://onlinelibrary.wiley.com/doi/10.1034/j.1600-0668.2001.110203.x/abstractTable 2 was adapted without attribution from: Pasanen, A.L., A review: Fungal exposure assessment in indoor environments. Indoor Air, 2001. 11(2): p. 87\u201398, http://metagenomics.anl.gov/?page=MetagenomeOverview&metagenome=4555914.387.7% of sequences in the MG-RAST dataset are noted as failing QC: Evidence that pathogens were detected in the samples is not sufficient.Data from MG-RAST have not been validated, either via other bioinformatics methods or independent approaches such as PCR or culture. How the potential non-specificity in the matching to taxons was addressed is not clear.For certain genera and species, metagenomics abundance is compared to CFU/mL. No information is provided on how the different species on the agar culture plate were counted or confirmed, or how the normalization steps in library preparation and sequencing were accounted for when measuring metagenomics abundance.Whether the results for PhiX174 originate from library preparation or contamination from elsewhere is not reported. The human endogenous retroviruses that are reported are likely reads from the human genome and should be classified as such.The accuracy of the taxonomic assignments for the metagenomics reads In Table 7 is unclear. Several of the bacteria listed should not be classified as pathogens.The Editors consider that the concerns outlined above compromise the integrity of the work and the validity of the conclusions reported and as a result retract this publication."}
+{"text": "Lejla Ferhatovic was supported by the Croatian Foundation for Science (HRZZ) grant no. 02.05./28. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.There are errors in the Funding section. The correct funding information is as follows: This study was funded in part by the VA Rehabilitation Research and Development grant 3690-03 ("}
+{"text": "In our recent article [1], we did not declare potential competing interests relevant to this work, and there are additional details relating to the funding statement and affiliations. We apologize for these omissions and would like to disclose the following information.The competing interests statement should read:Dr. Susan M. Johnson was a primary developer of Emotionally Focused Couples Therapy (EFT) and is the founding Director of the International Centre for Excellence in Emotionally Focused Therapy (ICEEFT). Dr. Paul S. Greenman is an EFT therapist and supervisor.The Funding statement should read:This research was supported in part by the International Centre for Excellence in Emotionally Focused Therapy (ICEEFT), a not-for-profit corporation whose mission includes the scientific evaluation of EFT. The director of the ICEEFT, Dr. Susan M. Johnson, had a role in study design and preparation of the manuscript. Additional funding was provided by a National Institute of Mental Health grant, Award Number R01MH080725, awarded to JAC. No additional external funding received for this study. The NIMH had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.The affiliations should have additionally included:Susan M. JohnsonInternational Centre for Excellence in Emotionally Focused Therapy, Ottawa, Ontario, Canada"}
+{"text": "Biol. Open 2013, 10:981\u2013989.This Correction relates to Unfortunately, there were errors in the first published version of this article. These errors are detailed below and the original article has been changed accordingly.The statements regarding funding were incomplete and the following text has now been included in the Acknowledgements section:D.R. is supported by the Academy of Finland, The Sigrid Jus\u00e9lius Foundation and Helsinki University Central Hospital Research Foundation.We apologise for any confusion caused."}
+{"text": "This article  has beenHowever, the estimate of the association between folate intake and spontaneous preterm delivery did not change the conclusions after the error was corrected.In consultation with the Journal\u2019s editors we decided to retract the article from BMC Pregnancy and Childbirth.A corrected manuscript will be resubmitted to the Journal at the time of retraction.On behalf of all authors,Verena Sengpiel and Bo Jacobsson.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2393/14/202/prepub"}
+{"text": "Nucl. Acids Res. 42 (18): 11642\u201311656. doi: 10.1093/nar/gku666The authors wish to make the following corrections to Figure In the original figure, panels A and B were accidently duplicated. A corrected Figure is provided below.The results and conclusion of the article are not affected and remain valid. The authors apologise to the readers for the inconvenience caused."}
+{"text": "Leishmania major and Leishmania tropica are the known aetiological agents. In 2011, more than 58,000 cases were reported in the country by the Ministry of Health. The central region of the country harbors 20\u00a0% of the reported cases. However, the epidemiology of the disease in this area is not well understood. An epidemiological survey was conducted in 2010 to identity the circulating parasite and the sand fly vector in the central provinces of Edlib and Hama.Cutaneous leishmaniasis is a disease transmitted by sand fly bites. This disease is highly prevalent in Syria where Leishmania parasites were first identified by sequencing the ITS1 gene amplicons. Then polymorphism analysis was performed using the RFLP technique.Sand fly specimens were collected using CDC light traps and identified morphologically. Total DNA was extracted from the abdomens of female specimens and from Giemsa-stained skin lesion smears of 80 patients. Phlebotomus sergenti and Phlebotomus papatasi were the most predominant.A total of 2142 sand flies were collected. They belonged to eight species, among which L. tropica ITS1 gene was amplified from two pools of P. sergenti specimens and from skin smears of cutaneous leishmaniasis patients. This suggests that P. sergenti is the potential vector species in the study area. The digestion profiles of the obtained amplicons by TaqI restriction enzyme were identical for all analysed L. tropica parasites. Moreover, L. infantum ITS1 gene was amplified from two pools of Phlebotomus tobbi in the relatively humid zone of Edlib.L. tropica is confirmed to be the aetiological agent of cutaneous leishmaniasis cases in the central provinces. RFLP technique failed to show any genetic heterogeneity in the ITS1 gene among the tested parasites. The molecular detection of this parasite in human skin smears and in P. sergenti supports the vector status of this species in the study area. The detection of L. infantum in P. tobbi specimens indicates a potential circulation of this parasite in the humid zone of Edlib. Further epidemiological studies are needed to evaluate the burden of this visceral parasite in the study region. Leishmania parasites and transmitted to humans by sand fly bites in more than 70 countries around the world, in climates ranging from tropical to desert. Syria is considered one of the most endemic countries for CL . Moreover, analysis of ITS1 gene sequences amplified from the two pools of P. tobbi from Edlib showed that the parasite belongs to L. infantum and is identical to the Iranian strain ITOB/IR/2009/Bilesavar [GenBank: HQ535858.1], which was also isolated from P. tobbi.All the obtained amplicons were sequenced. Their analysis revealed that the gene segments amplified from the two pools of L. tropica from the skin smears of CL patients and from P. sergenti pools were digested by Taq1 restriction enzyme in order to detect potential genetic polymorphism. Digestion products showed that all isolates displayed two DNA bands of approximately 140 and 190\u00a0bp  among 51 tested samples [L. tropica isolate characterized by a specific digestion pattern using Taq 1 enzyme, in addition to two other types of isolates with different digestion patterns, reflecting the existence of a genetic polymorphism at the level of the ITS1 gene. Moreover, our results suggest that the sand fly vector responsible for L. tropica transmission in the study area is P. sergenti. Two pools of sand flies belonging to this species were positive for Leishmania ITS1 gene. PCR-RFLP analysis of the amplified gene produced the same digestion pattern as that observed for all L. tropica isolates from skin lesions. Besides, P. sergenti is the dominant sand fly (43\u00a0%) in our collections. This species is known to be the vector of L. tropica in several countries [L. tropica is an anthroponotic parasite; nevertheless, zoonotic transmission has been documented in certain foci in the Middle East. The rock hyrax (Procavia capensis) is the main reservoir of L. tropica in certain Israeli and Palestinian foci [Leishmania species in Morocco, Iran and Israel [L. tropica in the central provinces in Syria suggests an anthroponotic transmission pattern of this parasite. However, the involvement of dogs as reservoirs should be investigated. It is worth noting the absence of L. major, the agent of zoonotic CL, among the tested skin smears, despite the important spread of its specific vector, P. papatasi. The rodent reservoir of this species (Psammomys obesus) does not occur in the central provinces, while it is found mainly in the desert area, east of Damascus [The objectives of the current study were to identify the sand fly vectors and rn Syria , 36 and rn Syria , 38. PCR species , 22. Thi samples . Whereasountries \u201330. L. tian foci . In addid Israel \u201343. The Damascus .L. infantum seems to circulate in the study area, as it was detected in two pools of female specimens of P. tobbi collected in the humid area of Edlib. L. infantum is the known agent of visceral leishmaniasis in the Mediterranean basin. Few cases of VL are reported annually in Syria. Recent reports showed an incidence of VL of 14 cases per year, based on a 2\u20134-fold underreporting ratio [P. tobbi in the transmission of visceral Leishmania parasites was also recorded during a study conducted in the province of Lattakia that borders the western side of the study zone [L. infantum was also proven to be a causative agent of CL in the Mediterranean basin [L. infantum as the causative agent of cutaneous lesions [P. tobbi as the vector of this dermotropic form. We expect a similar epidemiological situation in the humid zones west of Syria. Analysis of skin smears of patients originating from these zones is required to confirm the circulation of dermotropic L. infantum.udy zone . Neverthan basin \u201350. In t lesions . These a, L. tropica was identified as the parasitic agent responsible for the high number of CL cases in the central provinces of Syria. RFLP analysis of the ITS1 gene amplicons obtained from skin lesions and from the sand fly vector did not reveal any polymorphism among the circulating parasites. Entomological data showed that P. sergenti and P. papatasi are the most dominant species in our collections. The detection, for the first time in Syria, of L. tropica ITS1 gene in two pools of P. sergenti, supports the vector status of this species. The amplification of L. infantum ITS1 gene from two pools of P. tobbi in the humid part of Edlib suggests an active circulation of this parasite. Further studies in humans, vectors and potential reservoirs are needed to determine the burden of L. infantum in the study area and in other parts of Syria.Using PCR-ITS1 method"}
+{"text": "Antibiotic resistance of bacteria and other microorganisms is one of the most serious and grievous challenges of the twenty-first century. The life-saving drugs, which held a great deal of promises during the 1940s to eradicate all the infectious life-threatening diseases in the world, have ceased to work, because of the increasing emergence of microbial strains invulnerable to them. Many of the previously efficacious antibiotics are no longer usable because of widespread occurrence of multiresistant microbial strains. Lately, discovery of new antibiotics is failing to keep pace with the emergence of (multi)resistance of pathogenic and also environmental bacterial strains. Consequently, the prospect of chemotherapy looks bleak. The trepidation that we might be pushed back to a situation analogous to the preantibiotic era, when no chemotherapeutic agent was available to contain and combat deadly bacterial infections, does not appear to be an overblown imagination. Helicobacter pylori isolated from vegetables and salad samples, picked up from groceries and supermarket in a province of Iran. The high similarity in the genotype pattern of the isolates obtained from vegetables and humans indicates transmission. A. B. Fl\u00f3rez et al. reveal tetracycline and erythromycin-resistant bacteria and genes conferring resistance to these antibiotics in 10 Spanish and 10 Italian samples of commercial cheese. P. Krupa et al. report on the population structure (based on spa typing) of oxacillin-resistant Staphylococcus aureus isolated from nasal swabs of pigs, collected from two slaughter houses of Poland. Some meat samples bought from the shops were also included into their studies. D. De Vito et al. characterize multidrug-resistant clinical isolates of Salmonella typhimurium for resistance genes in an area of southern Italy by pulsotyping and phage typing. C. Zhang et al. report on the resistant phenotype and genotype of Streptococcus suis serotype 2, isolated from 62 clinically healthy sows and 34 diseased pigs reared in different farms of China. Antibiotic resistance in the nosocomial isolates is a matter of serious concern. F. Lombardi et al. look into the molecular epidemiology of carbapenemase-producing strains of Klebsiella pneumoniae isolated from the surgery unit at a cardiovascular centre of Italy. D. Ojdana et al. demonstrate the ability of an E. coli strain obtained from a hospital of Poland to produce carbapenemase enzymes and also the presence of genes responsible for the production of carbapenemases and other \u03b2-lactamases. Extended-spectrum-\u03b2-lactamase (ESBL) is a bacterial enzyme having the ability to hydrolyse even the third-generation cephalosporins and aztreonam. Besides Klebsiella pneumoniae some strains of Escherichia coli are also known to produce this enzyme. This is indicated by M. S. Rezai et al. who performed genotyping of ESBL-producing strains of E. coli, obtained from a paediatric hospital of north Iran. The authors also show the association of ESBL-positive E. coli strains with resistance to various other antimicrobials. Occurrence of ESBL-producing Enterobacteriaceae in iceberg lettuce obtained from the retail market of Rochester (US) is described by N. Bhutani et al. A wide spectrum of diseases is caused by the virulent strains of ESBL-positive isolates of E. coli. Regional difference in the prevalence of virulence genes in 432 phenotypically ESBL-positive patient-isolates of E. coli  is shown by J. Lillo et al. Keeping in mind the tremendous challenge posed by drug-resistant tuberculosis, a number of relevant articles are included in this collection. The susceptibility profile of M. tuberculosis isolates to various antitubercular antibiotics varies significantly depending on the test system as revealed by Z. Mei et al. They have also shown that changes in bacterial susceptibility are further caused by mixed infection with particular genotypes of M. tuberculosis strains. Resistance-profile of 100 strains of M. tuberculosis, isolated from patients in northeast Iran, is reported by A. T. Sani et al. Occurrence of nontuberculosis Mycobacterium, in 25 out of 125 patients (20%) surveyed, underscores the need of proper diagnosis before the onset of chemotherapy.Based on this backdrop, this special issue appears to be an aptly undertaken and well-timed endeavour to address this global problem. The articles contributed by investigators from various research laboratories with different scientific backgrounds have not only portrayed the width of the problem but also displayed some silver lining in the management of the looming crisis. Rapid detection of the profile of resistance is essential for timely application of the right antibiotic to a patient. H. Frickmann et al. summarize the efficacy and limitations of various molecular and mass spectrometric methods for the detection of resistance. The omnipresent nature of the resistant organisms is revealed in a number of articles. F. B. Atique and Md. M. R. Khalil report on the occurrence of antibiotic resistance among bacteria  isolated from allogenic bone samples for grafting, collected from different hospitals of Bangladesh. Food materials are believed to serve as a vehicle for transmission of resistance. This issue is addressed by F. S. Dehkordi et al. who report on the genotype and resistance-profile of Pseudonocardia. The antibacterial compound produced by it is effective against Staphylococcus aureus. They have also purified and partially characterized this compound. R. D. Wojtyczka et al. demonstrate high antibacterial activity of two new quinoline derivatives of a structure of 3-thioacyl 1-methyl 4-arylaminoquinolinium salts against some nosocomial strains of staphylococci in both planktonic and biofilm form. In view of the widespread nature of the problem caused by inefficacy of the antibiotics produced by fermentation and chemical synthesis, it is necessary to tap alternative sources  for novel antibiotics. P. Del Serrone et al. demonstrate antibacterial activity of Neem seed oil (Azadirachta indica A. Juss.) against enteropathogenic strains of E. coli and indicate that some of the ciprofloxacin-resistant isolates lost their virulence following treatment with Neem seed oil. Antimicrobial peptides are considered potential candidates for the management of multidrug-resistant infections. M. Singh and K. Mukhopadhyay evaluate the antimicrobial potential of an anti-inflammatory neuropeptide whereas C. Chen et al. report on the efficacy of recombinant lysostaphin against methicillin-resistant S. aureus (MRSA) in a mouse model. Widespread use of carbapenems is associated with emergence of resistance. The polymyxin antibiotic colistin is not used at present because of its nephrotoxicity. H.-J. Tang et al., however, demonstrate the efficacy of a combination of colistin and imipenem against carbapenem-resistant Klebsiella pneumoniae. Bacteriophages could be suitable alternatives for antibiotics, which currently have lost efficacy because of the emergence of resistant strains. N. Shivshetty et al. demonstrate the potential of a bacteriophage isolated from sewage to protect diabetic mice against Pseudomonas aeruginosa-induced bacteremia. Reversal of bacterial resistance to antibiotics is essential to restore the efficacy of the existing antimicrobials. C. Santiago et al. claim to achieve an increase in susceptibility of a MRSA strain to ampicillin when it was combined with a plant extract. A number of computerized models have been developed during the recent past to assist the physicians with the necessary information to enable prescription of the right antibiotic in the right moment. M. Rodriguez-Maresca et al. report on the efficacy of a new electronic device based on laboratory data on the most probable susceptibility profile of pathogens responsible for infections and also on local epidemiology.Discovery of new drugs and strategies to circumvent antibiotic resistance is the need of the hour to contain the problem. N. Jafari et al. report on the isolation of an antibiotic-producing strain of a soil Actinomycetes belonging to the genus"}
+{"text": "I read with great interest the recent article reporting the relation between skeletal muscle mass and dysphagia in cancer patients by Hidetaka Wakabayashi et al.Insufficient dietary intake and decreased appetite are major factors for loss of muscle mass.We acknowledge support by the German Research Foundation and the Open Access Publication Funds of the G\u00f6ttingen University. The authors certify that they comply with the ethical guidelines for publishing in the Journal of Cachexia, Sarcopenia and Muscle: update 2015.M. Saitoh, J. Ishida, M. Konishi, and J. Springer declare that they have no conflict of interest."}
+{"text": "There are errors in the Author Contributions. The correct contributions are: Conceived and designed the experiments: ESG ADM. Analyzed the data: ESG ADM. Contributed to the writing of the manuscript: ESG ADM.Additionally, there is an error in"}
+{"text": "Jean.Nakamura@ucsf.edu).The corresponding author for this article is not listed. The corresponding author is Jean L. Nakamura (The editor\u2019s affiliation is missing. Bruce Korf\u2019s affiliation is: University of Alabama, Birmingham School of Medicine, United States of America."}
+{"text": "The publishers regret to announce that the symbols in et al.1. Fig. The figures as they should have appeared, along with their correct captions, are printedbelow. The publishers apologise for this error."}
+{"text": "The affiliation for the fourteenth author is incorrect. Anna Chrostek is not affiliated with #5 but with #6, Department of Psychiatry, Institute of Psychiatry and Neurology, Warsaw, Poland.In addition, the eleventh author\u2019s name is misspelled in the PDF version of the article. The correct name is: Piotr \u015awitaj. The publisher apologizes for the error."}
+{"text": "The establishment of a DNA synthesis and construction foundry at Imperial College in London heralds a new chapter in the development of synthetic biology to meet new global challenges. The Foundry employs the latest technology to make the process of engineering biology easier, faster and scalable. The integration of advanced software, automation and analytics allows the rapid design, build and testing of engineered organisms. The publication of the Roadmap for Synthetic Biology in 2012 and its recommendations resulted in significant U.K. Government investment in synthetic biology. Over \u00a3100 million was invested through the Research Councils U.K. and Innovate U.K. to establish six new Synthetic Biology Research Centres , four Doctoral Training Centres  and an Innovation and Knowledge Centre  to drive the commercial translation of synthetic biology research. The U.K. Government's commitment to the commercialization of synthetic biology was further reinforced with an additional \u00a310 million investment in the Rainbow Seed Fund for synthetic biology spinouts and start-ups. One of the more innovative initiatives to come out of this investment was the creation of a U.K. DNA synthesis capability to support synthetic biology academic research and commercial translation. In total, five DNA Synthesis Foundries were established .The DNA Synthesis and Construction Foundry at Imperial College (the Foundry) is located at SynbiCITE, which operates from the Imperial Incubator. SynbiCITE as the national centre for the translation and commercialization of synthetic biology provides a number of innovation programmes to its academic and industrial partners. These innovation programmes are specifically designed to provide early-stage business support and include: education and training, funding for proof of concept and development of prototypes and business support. An important element in the innovation programmes SynbiCITE provides is access to its laboratory facilities, including\u2013the Foundry. This access provides scientists and researchers with a maker space for the rapid translation of ideas and designs: producing a prototype or generating critical data\u2013all geared towards advancing technology, removing the technical uncertainty and risk in the process. This facility is available to SynbiCITE's extensive network of partners including 17 U.K. universities and over 50 industrial and commercial partners, made-up of multinational companies, SMEs and start-ups.SynbiCITE with its specific focus on commercial translation employs the Foundry to provide a suite of state-of-the-art robotic and analytical equipment supplying end-to-end design, construction and characterization capability to its partners. Work is focused on industry-led projects with commercial or practical applications, which can benefit from the Foundry's automated higher throughput and capacity.Build a state-of-the-art DNA Synthesis and Construction Foundry. Operated as a series of modular automated workstations the Foundry provides an integrated, flexible assembly platform capable of delivering biological design automation at scale.Develop the U.K. capability and infrastructure for synthetic biology. The creation and operation of standardized workflows and software for DNA synthesis, assembly and verification of large DNA assemblies (>50\u00a0kb), including chromosome synthesis at scale.Support the U.K. industrial base in synthetic biology. The Foundry as part of SynbiCITE, the national IKC for Synthetic Biology, will provide access, collaboration and training opportunities to U.K. companies interested in synthetic biology.Provide support and training programmes. The Foundry, in collaboration with its partners, act as a focal point for the training of researchers  in the synthesis and construction of DNA, at scale, in relation to synthetic biology applications.www.synbicite.com. To keep abreast of the fast pace of technology development in synthetic biology, the facilities and resources available at the Foundry will evolve to meet demand. The Foundry has continued access to the latest cutting edge technology, required to stimulate innovation in synthetic biology, is made possible through a number of special collaborations with industrial partners supplying resources and expertise.The Foundry's facilities and resources are available to all SynbiCITE academic and industrial partners\u2013providing access to both equipment and expertise. A list of all the equipment is available at People with the correct skills are key to the successful adoption of synthetic biology by industry. We also recognize that this new industry depends on people with the right skill-set to translate their ideas. SynbiCITE is therefore committed to sharing new approaches and discoveries in synthetic biology with its partners by providing scientific workshops and technical training on all equipment and platforms.A major aim of the Foundry (and synthetic biology) is to make the design and engineering of biological systems systematic and standardized around a \u2018design-build-test-report-learn\u2019 cycle. The Foundry has been specifically built to support and exploit this framework.design of transgenes and experiments.A range of commercial and proprietary BioCAD/CAM tools for the rapid and scalable build and assemble multiple DNA components in parallel. Supported by software for programming and scheduling automation.Conventional and acoustic liquid handling robotic platforms to test equipment for metadata acquisition allowing characterization and quantification across the range of biological products.A suite of high-throughput analytical/report on the tracking of the workflow for any assembly or experiment. The LIMS tracks the users\u2019 specifications containing the product design, the entire construction sequence including replicating reagents, PCR and assembly; and the sample reagent lineage, location and availability.A web-based Laboratory Information Management System (LIMS) to learn capability with statistical interpretation and modelling which can feedback into the design loop.The engineering-design cycle is completed with data analytics, providing the The facilities and accompanying capabilities include:The Foundry and SynbiCITE, both represent a unique public\u2013private collaborative effort to accelerate and promote business exploitation of emerging research and technology around synthetic biology. The Foundry intends to deliver a key resource to the U.K. synthetic biology industrial and academic community seeking to commercialize their ideas and research."}
+{"text": "Unfortunately, after publication of this article  it was nLT and RZ designed the study and developed the database. LT and RZ performed the statistical analyses and drafted the manuscript. RZ wrote the manuscript. AG critically revised the statistical analysis, the study design and the manuscript. AM critically revised the manuscript in cooperation with the co-authors and interpreted the data. HH critically revised the microbiological findings. RA, as the department chair, supported this study and participated in designing the study. RA and JS critically revised the manuscript. RZ collected the patient data. All the authors have read and approved the submitted version of the manuscript."}
+{"text": "There is an error in the Author Contributions. The third author, Kejhal Khursheed, should be noted as contributing equally to this work along with the first and second authors, Abigail L. Savage and Thomas P. Wilm. The publisher apologizes for this error."}
+{"text": "We theoretically and numerically analyze thermal invisibility based on the concept of scattering cancellation and mantle cloaking. We show that a small object can be made completely invisible to heat diffusion waves, by tailoring the heat conductivity of the spherical shell enclosing the object. This means that the thermal scattering from the object is suppressed, and the heat flow outside the object and the cloak made of these spherical shells behaves as if the object is not present. Thermal invisibility may open new vistas in hiding hot spots in infrared thermography, military furtivity, and electronics heating reduction. The realization of electromagnetic invisibility cloaks12378111314152318et al.35363839414243The concept of invisibility has been extended to other realms of physics. Cloaks capable of hiding objects from acoustic waves2324283032In this paper, we propose to use the concept of scattering cancellation to generate the invisibility effect for heat diffusion waves. The peculiarity of our cloak is that, unlike earlier designs, we consider both static and time-harmonic dependence ), it is possible to suppress the dominant multipolar scattering in the quasistatic limit.Following the procedure described in the previous section, with these new boundary conditions, one can show that the In conclusion, we have proposed an original route towards designing thermal cloaks based on the scattering cancellation technique. This technique is inspired by the plasmonic cloaking, which makes use of shells with induced negative polarization to suppress scattered electromagnetic fields. And contrary to invisibility cloaks based on transformation optics, SCT offers simple cloaking designs .One may envision that using this design may further make the thermal cloaking closer to its practical and feasible realization. We believe that such a structured cloak could be manufactured within current technology, having in mind some potential applications in invisibility, sensing and thermography. The range of industrial applications is vast, and our proof of concept should foster research efforts in this emerging area of thermal cloaks and metamaterials.Analytical methods based on scattering Mie theory of spherical thermal scatterers are used to obtain the results presented in M.F. and P.-Y.C conceived the idea of this study. M.F. performed numerical simulations and wrote the manuscript. P.Y.C., H.B., C.A., S.G., and A.A. contributed to the analysis of the results and reviewed the manuscript. S.G. and A.A. supervised the project."}
+{"text": "S. mansoni worms. We are grateful to all villagers in Senegal for their cooperation and thank the Senegalese field team  for their dedicated help with the fieldwork.There is an omission in the Acknowledgments section. Please see the corrected Acknowledgments here: We thank Prof. J. Webster, together with Drs. Polydor Ngoy Mutombo, Moussa Sacko and Charlotte Gower, for access to the raw microsatellite data of Kokry-Bozo , and the Schistosomiasis Collection team at the Natural History Museum in London (SCAN) for providing"}
+{"text": "There was an error in the funding statement. The correct funding information is:This research is supported by the Japan Society for the Promotion of Science throughthe \u201cFunding Program for World-Leading Innovative R&D on Science and Technology(FIRST Program),\u201d initiated by the Council for Science and Technology Policy (CSTP).The funders had no role in study design, data collection and analysis, decision topublish, or preparation of the manuscript.The legends for the Supporting Information figures were omitted. The full titles andlegends for the Supporting Information Figures are as follows:Fig. S1. Annual variation in daily tweet activity. Mean tweetprobability distribution in 2010 (P) and 2011 (Q). JS=0.0009.Fig. S2. Collective attention related to multiple events. Tweetprobability distribution, and the rankings of the popularity and the enhancement ofkey terms in Japanese tweets on Jun 13, 2010. Each black bar in the figure denotesthe time range during which tweets were considered for calculating term frequency.The red text in the tables denotes terms related to (A) an earthquake and (B)Hayabusa's return to the Earth. (C) in the figure is related to Twitter outage. Thetext in parentheses denotes the English translation.Fig. S3. Collective attention related to new year holidays. Tweetprobability distribution, and the rankings of the popularity and the enhancement ofkey terms in Japanese tweets on January 1, 2011. The black bar in the figurerepresents the time range during which tweets were considered for calculating termfrequency. The red text in the table represent terms related to new year holidays,and the text in parentheses denotes the English translation."}
+{"text": "There is an error in the byline of the article. Dr. Tingting Li is not the Corresponding Author and is solely a co-author. Please direct all correspondence to Dr. Jinghang Chen and Dr. Le Zhang."}
+{"text": "Reason for Corrigendum:There was a mistake in the accession number as published. The accession number in the published version is referred to as E-MTAB-2072 while the correct accession number is E-MTAB-3375. The authors apologize for the mistake. This error does not change the scientific conclusions of the article in any way.JM led the project and performed the bioinformatic analysis. DP conducted the electrophysiology experiments. SP contributed to electrophysiology. KW extracted the RNA and conducted qPCRs. IS contributed to RNA extraction. DK prepared the samples for RNA-sequencing. KW, JM, and MD designed the study. JM, KW, CB, and MD wrote the manuscript.This work was supported by the Research Council of Norway (grants 204861 and 199355), Bergen Medical Research Foundation, and the University of Bergen (KW).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "This does not alter adherence to all the PLOS ONE policies on sharing data and materials.The following information is missing from the Competing Interests section: The authors have read the journal's policy and have the following conflicts: M.L., D.S. and G.G. are inventors of the polyfunctionality index (patent number: WO2013127904) and M.L. is proprietary owner of the Funky Cells ToolBox software ("}
+{"text": "Bacillus anthracis, the highly dangerous zoonotic bacterial pathogen species is currently composed of three genetic groups, called A, B and C. Group A is represented worldwide whereas group B is present essentially in Western Europe and Southern Africa. Only three strains from group C have been reported. This knowledge is derived from the genotyping of more than 2000 strains collected worldwide. Strains from both group A and group B are present in France. Previous investigations showed that the majority of sporadic French strains belong to the so-called A.Br.011/009 group A clade and define a very remarkable polytomy with six branches. Here we explore the significance of this polytomy by comparing the French B. anthracis lineages to worldwide lineages. We take advantage of whole genome sequence data previously determined for 122 French strains and 45 strains of various origins.B. anthracis lineage in North America, called WNA for Western North American, is derived from one branch of the A.Br.011/009 polytomy predominant in France.A total of 6690 SNPs was identified among the available dataset and used to draw the phylogeny. The phylogeny of the French B group strains which belongs to B.Br.CNEVA indicates an expansion from the south-east part of France (the Alps) towards the south-west . The relatively small group A strains belonging to A.Br.001/002 results from at least two independent introductions. Strikingly, the data clearly demonstrates that the currently predominant B. anthracis, in agreement with its ecology and in contrast with some other pathogens. The population structure of the six branches A.Br.011/009 polytomy identified in France, diversity of branch length, and comparison with the WNA lineage, suggests that WNA is of post-Columbian and west European origin, with France as a likely source. Furthermore, it is tempting to speculate that the polytomy\u2019s most recent common ancestor -MRCA- dates back to the Hundred Years' war between France and England started in the mid-fourteenth century. These events were associated in France with deadly epidemics and major economic and social changes.The present work extends the range of observed substitution rate heterogeneity within  Bacillus anthracis, the causative agent of anthrax, is a spore-forming bacterium present worldwide. The bacterium mainly affects wild and domesticated herbivores, causing a serious, often fatal disease. Spores which are the infectious form of the bacteria can remain in soil for decades before being ingested by animals while browsing or grazing . Th. Th17]. In order to maximize the resolution of the SNP analysis, the SNP screen was applied to the subset of A.Br.011/009 and A.Br.WNA strains. Less SNPs are excluded when less strains are taken into account, mostly due to deletions, partial genome assemblies in public WGS data and/or sequence quality issues in some data sets. Within this subset of strains, 1934 SNPs are identified as compared to 1451 in the corresponding portion of B. anthracis. The previously proposed pre-columbian Bering Strait hypothesis for the importation of the WNA branch in North America was prompted by the very long branch length of the WNA lineage [B. anthracis, was highly sensitive, and in which B. anthracis benefited from a much increased number of generations per year.Along this line, the presence in this polytomy of a very short branch (17 SNPs for the lineage 5) found in France has a great impact on previous propositions for the evolution of  lineage . The predepartment formed a single clonal cluster differing by a maximum of two SNPs and they belong to the same branch as the Sterne vaccine strain. They will together be subsequently called the Sterne lineage. The three additional A.Br.001/002 strains are older samples  isolated in other departments of France. They are clearly unrelated to the recent Doubs outbreak [B. anthracis isolates from China, 74 of which were canSNP typed as A.Br.001/002 and 8 were A.Br.Ames. The authors estimate from historical records that the Ames lineage present in the Texas/Louisiana Gulf region split from its Chinese progenitor lineage in the early to middle 1800s. Since the USA-import, the USA specific Ames lineage expanded between 4 and 12 SNPs. The most part of the Ames lineage expansion occurred while in China, before the USA-import.Sequence analysis identified 231 chromosomal SNPs that differentiate the 24 A.Br.001/002 French strains. The length from the purple star to the tips is similar and varies from 131 for one Georgian strain to 198 . All 21 outbreak  strains outbreak  investigB. anthracis would have been introduced to North America from Europe, perhaps France. The WNA lineage is believed to have been present in North America at least since 1770: anthrax was present in Haiti at that time according to historical records [B. anthracis strains in others countries. French settlements were established in Eastern North America (\u201cNouvelle France\u201d) since the beginning of the seventeenth century  and in Western Africa because of the slave trade almost at the same period (1600\u20131650). The trade of textiles could have been a source of introduction of the disease in North America and Africa. Later on, the better understanding of the disease, and the strong prophylactic and control measures applied in France since the end of the nineteenth century have probably slowed down the turn-around of B. anthracis during the twentieth century. We can consequently reasonably hypothesize that the French lineage kept expanding at an unaffected rate after the WNA split for approximately 300 years i.e. from year 1600 until 1900 corresponding to two-thirds of the French lineage length. 1300\u20131500 is consequently a likely estimate for the dating of the outbreak which gave birth to the A.Br.011/009 polytomy. In France, years 1350\u20131450 corresponds to the \"One hundred years war\" with England (1337\u20131453). It was characterized by major epidemics (including the Black Death plague due to Yersinia pestis), civil war events, and major economic changes. At that time, South-West France was occupied by England. Uncontrolled armed groups were travelling across large regions of France. The associated events would have favored the geographic spreading and subsequent fixation across most of France. This period is thus a good candidate for the dating of the root of the A.Br.011/009 polytomy observed in France.Under the hypothesis of a French emergence of the A.Br.011/009 polytomy, as implied by the very short French branch . In agreement with these historical records, the Carbosap branch is the longest presumably as a result of more extensive cultivation. Three chromosomal deletions of 29, 24 and 3.5 kb relative to virulent strains have been described in Carbosap . InteresB. anthracis population in France in the broader context of the worldwide diversity of this species. France is one among a few countries where both the A and B branches are represented [B. anthracis would be faster after introduction in a previously B. anthracis free environment. This would fit with the present observations, and, conversely, suggest that lineage expansion rates may provide indications on the origin of a lineage. In this view, short lineages  would tend to be closer to their birth place. Because of the recent introduction of A.Br.011 SNP typing, the distribution of the A.Br.011/009 lineage in the world is poorly known. In order to test the hypotheses proposed here, it will be necessary to more precisely investigate the presence and genome sequence of A.Br.011/009 in neighboring European countries and elsewhere.In this report, we position the genetic diversity found within the resented . The A.Bresented  previousS1 TableThe geographic origin and year of isolation are indicated when known.(XLSX)Click here for additional data file.S2 TableThe position given refers to Ames ancestor genome accession number NC_007530.2. canSNPs are indicated.(XLSX)Click here for additional data file."}
+{"text": "The copyright statement appearing with the published article is incorrect. The correct copyright is: 2016 Crown Copyright. This is an open-access article distributed under the terms of the Re-use of Public Sector Information Regulations 2005, which permit unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.The Funding statement in the published article is incorrect. The correct Funding statement should be: Agriculture and Agri-Food Canada and Canadian Poultry Research Council through the Poultry Cluster II Program .There are errors in the Acknowledgements of the published article. The Acknowledgements should read: FY and XY were NSERC Visiting Fellows to the Canadian Federal Government Laboratories. JH was a visiting graduate student financially supported by the China Scholarship Council through the MOE-AAFC Ph.D. Research Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."}
+{"text": "BMC Medicine 2015, 13:59, highlighting previously undeclared competing interests and including more information in the acknowledgements section.This is an Erratum to http://www.biomedcentral.com/1741-7015/13/59Please see related article:  There was missing information in the competing interests and acknowledgements sections of our published article . The errThe statement in the competing interests should read as follows: This study is funded by unrestricted research fund from NutraSource. Susan Cho is founder and owner of NutraSource and Albert Lee is an employee of NutraSource. The other authors declare that they have no competing interests.The following information should be included in the acknowledgements section: The authors also thank Dr. Yi K Park at National Cancer Institute for her guidance in the study design."}
+{"text": "Ae. Albopictus should be Ae. albopictus and all instances of Ae. Cretinus should be Ae. cretinus. The publisher apologizes for the error.In the Abstract, the names of the species are incorrectly listed. All instances of"}
+{"text": "A psychosocial exploration of body dissatisfaction: a narrative review with a focus on India during COVID-19 By Ahuja KK and Banerjee D. (2021) Front. Glob. Womens Health 2:669013. doi: 10.3389/fgwh.2021.669013A Retraction of the Mini Review article Following publication, the publisher has discovered that the corresponding author submitted false information that compromised the peer-review process. As the scientific integrity of the article cannot be guaranteed, and adhering to the recommendations of the Committee on Publication Ethics (COPE), the publisher therefore retracts the article.The authors do not agree to this retraction.This retraction was approved by the Chief Editors of Frontiers in Global Women\u2019s Health and the Chief Executive Editor of Frontiers."}
+{"text": "In the above article, one of the co-author's surnames was spelled incorrectly. Claire de Oliviera should have been printed as Claire de Oliveira. This has now been updated in the original article online.The publisher apologises for this error."}
+{"text": "Due to a production error, author Bonny Yee-Man Wong was referenced incorrectly in the citation.In the original version, they were incorrectly written as Wong B-M. The correct version is Wong BY.The publisher apologizes for this mistake. The original version of this article has been updated."}
+{"text": "The Joseph T. Freeman Award lecture will feature an address by the 2022 Freeman Award recipient Neil M. Resnick, MD, FGSA, of the University of Pittsburgh. The Joseph T. Freeman Award is a lectureship in geriatrics awarded to a prominent clinician in the field of aging, both in research and practice. The award was established in 1977 through a bequest from a patient's estate as a tribute to Dr. Joseph T. Freeman. The Excellence in Rehabilitation of Aging Persons Award lecture will feature an address by the 2022 Excellence in Rehabilitation Award recipient Patricia C. Heyn, PhD, FGSA, FACRM, of Marymount University. The Excellence in Rehabilitation of Aging Persons Award is designed to acknowledge outstanding contributions in the field of the rehabilitation of aging individuals."}
+{"text": "Rypticussubbifrenatus was incorrectly identified as that of its similarly colored congener R.carpenter. Hence the latter was deleted from the St. John-Thomas inventory. In addition, an image of the blenniid fish Hypsoblenniusexstochilus was obtained from St. Thomas, and it is now added to that inventory. These two changes did not substantially affect data on the ecological structure of the St. John-Thomas fauna.Review of the image plates shows that an image of  Prompt publication of corrections to faunal inventories helps ensure the accuracy of biogeographical data. Here we correct the erroneous occurrence of a misidentified serranid fish in the St. John-Thomas inventory. In addition, a newly available photograph of a blenniid taken at St. Thomas provides a voucher for its addition to that inventory.Rypticuscarpenteri\u201d is incorrect and should read \u201cRypticussubbifrenatus\u201d. The distributions of large dark spots on the interorbital areas and the colors of the fins of those two species differ  at St. Thomas. That species is easily recognized by its diagnostic pair of orbital cirri, each of which consists of a very large, branched stalk, and the color pattern of its head. This image represents the sole-source record for the addition of this species to the St. John-Thomas faunal inventory.Fig. R.carpenteri from and addition of H.exstochilus to the St. John-Thomas inventory had very little effect on data in Tables 3-6: In Table 3 the only change is the addition of one to the number of uncommon shallow species. The only changes in Table 5 are small increases (< 0.5%) in the percentages of Core Coral Reef Fishes. There are no changes to Tables 4, 6.The combination of the removal of"}
+{"text": "PLOS ONE journal was notified about the omission of the original questionnaire and the corresponding coding key from the Supporting Information. The missing information can be viewed under DOI: https://doi.org/10.5683/SP3/7AOEQS. The files have been assessed by senior members of the journal staff. With this correction, all relevant data are now provided.After publication of , the PLO"}
+{"text": "There is an error in the Correction published on December 9, 2021. The incorrect figures were published again by mistake in the original Notice of Correction. The publisher apologizes for the error. Please see the complete, correct Figs"}
+{"text": "Nguyen Minh  The authors regret that in the original article the authorship was incorrect. J. Baggerman and S. P. Pujari were not included in the original author list. Additionally, J. F. van der Bent was spelled incorrectly in the original article. The correct author list is as presented above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "Phytophthora species and other soilborne pathogens. In this context, isolation from tissues and soil of ornamental and forest plants from nurseries in four regions of Spain was carried out. A high diversity of Phytophthora species was confirmed. Fourteen Phytophthora phylotypes  were isolated from over 500 plant samples of 22 species in 19 plant genera. Nine species were detected in water sources, two of them (P. bilorbang and P. lacustris) exclusively from water samples. P. crassamura was detected for the first time in Spain. This is the first time P. pseudocryptogea is isolated from Chamaecyparis lawsoniana and Yucca rostrata in Spain.The plant nursery industry has become an ideal reservoir for  Phytophthora and Pythium  to avoid spore liberation), moderate nitrogen fertilisation, and routine tool disinfection [A high priority should be placed on the production of pathogen-free propagating material by appropriate sanitary practices . The micium spp. . Nurserynfection .Phytophthora species into natural habitats worldwide [Phytophthora [It has long been known that nursery stock is the most common pathway for the introduction of new orldwide . Supplyiophthora ,62,100 wPhytophthora phylotypes were isolated from tissues and rizosphere soil of 22 plant species in 19 genera and from water samples. The presence of Phytophthora mixed infections is noteworthy. It is also relevant reporting, for the first time, the presence of P. crassamura, P. pseudocryptogea, P. sansomeana, and Phytophthora sp. tropicalis-like 2 in the Spanish nursery industry. The need for preventing Phytophthora dispersion to natural ecosystems must be translated in implementing new policies at the global scale. Good biosecurity practices in nurseries and early detection are critical to mitigate the risk of spread of these pathogens.This study confirms the widespread presence of pathogens in plant nursery stocks and the risk posed by the plants for the planting pathway. Seventeen"}
+{"text": "The authors of Magwood et al.  have supOne of the coauthor names was incorrectly spelled in the article as \u2018Tom Concannon\u2019. The coauthor's name is being corrected to \u2018Thomas W. Concannon\u2019.https://doi.org/10.1002/cl2.1237. The authors apologise for the error.The original version is also corrected and can be found on the below link:"}
+{"text": "Frontiers in Medicine. As of 21 October 2022 this manuscript has now been transferred to Frontiers in Microbiology with the doi: 10.3389/fmicb.2022.922894.The authors and publisher would like to note that this article was originally published in"}
+{"text": "In the published article, there was an error in the Acknowledgments statement. The mistake was related to the part referring to the ER acknowledgments, and more precisely in the Grant Agreement No. of the European xAIM , which was incorrectly written as INEA/CEF/ICT/A2020/2265375. The correct Acknowledgments statement appears below:"}
+{"text": "Due to a publisher error, the below statement was not included:The reviewer OH declared a past co-authorship with the authors JD, CR to the handling editor.The publisher apologizes for this mistake. The original version of this article has been updated."}
+{"text": "Bioengineered, have retracted the following article:We, the Editors and Publisher of the journal 10.1080/21655979.2020.1870320.Yu-Bin Ji & Fu-Ling Wang. Optimization of trypsin extraction technology of Allium cepa L. polysaccharide by response surface methodology and the antitumor effects through immunomodulation. Bioengineered; 2021. 12(1):382-391. doi: Since publication, concerns have been raised about the integrity of the data in the article. When approached for an explanation, the authors have been unable to address the concerns raised and have not provided their original data in the appropriate format. As verifying the validity of published work is core to the integrity of the scholarly record, we are therefore retracting the article. The corresponding author listed in this publication has been informed.We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines on retractions.The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as \u2018Retracted\u2019."}
+{"text": "H. pylori) screening and eradication treatment in an asymptomatic population in China and to explore the most cost-effective screening protocol for H. pylori. Method We used TreeAge 2019 to construct Markov models to assess the direct healthcare costs and quality-adjusted life years (QALYs) and the cost per year of life saved (YoLS) of three therapies, i.e., annual, triennial and five-yearly H. pylori screening. Excess probabilities were derived from published high quality studies and Meta-analyses, and costs and utilities were derived from the Chinese Yearbook of Health Care Statistics and published studies. Incremental cost-effectiveness ratios (ICERs) were used to describe the results. The willingness-to-pay threshold was set at China\u2019s Gross National Product per capita. Result In the asymptomatic population, the ICER per QALYs gained was US$1238.47 and US$1163.71 for every three and five years of screening compared to the annual screening group; the ICER per YoLS gained was US$3067.91 and US$1602.78, respectively. Conclusion Screening for H. pylori in asymptomatic populations in China and eradicating treatment for those who test positive is cost-effective. Increasing screening participation in asymptomatic populations is more effective than increasing the frequency of screening. From a national payer perspective, it is cost-effective to screen the general asymptomatic population in China for H. pylori and to eradicate those who test positive. Individuals need to choose a screening programme that they can afford according to their financial situation.Objective The aim of this study was to investigate the cost-effectiveness of Helicobacter pylori ( H. pylori) is a Gram-negative microaerobic bacterium that can be transmitted from person to person and is a major causative agent of gastric diseases such as chronic gastritis, peptic ulcers and gastric cancer [H. pylori infection and also has the highest number of peptic ulcers and gastric cancer cases [H. pylori-related disease in China is enormous. The global consensus on H. pylori recommends that all people with H. pylori infection should receive eradication treatment unless there are clear circumstances that make eradication inappropriate [Helicobacter pylori  and the cost per year of life saved (YoLS). A Markov decision model was developed to evaluate three H. pylori screening regimens i.e., annually, every three years and every five years. Screening is carried out by the urea breath test (UBT) and those who screen positive receive 14 days of bismuth quadruple therapy. The model includes the development and treatment status of two diseases, peptic ulcer, and gastric cancer, to assess the cost-effectiveness of different screening strategies for H. pylori-related disease. The end of the model depends on the life expectancy of the Chinese population (78 years).This study used a Markov model to conduct a cost-effectiveness analysis to assess the economic benefits of an H. pylori infection and without associated digestive disorders.The study assumed a cohort population of 10,000 people and set their initial age at 20 years, with a cohort maximum year of 80 years (the average life expectancy of the Chinese population in 2020). It is assumed that they are initially healthy individuals, free of All variables used in our Markov models were derived from published studies  or authorities , as shown in S is the five-year survival rate of gastric cancer, t is time, and P in Equation (2) is the probability of metastasis after transformation (In Equation (1), ormation .H. pylori eradication treatment regimen, which selected a proton pump inhibitor, bismuth and two antibiotics . The therapy is recommended by the Chinese H. pylori guidelines and the report of the 5th Maastricht Conference [In this study, a 14-day bismuth quadruple therapy was chosen as the nference ,9. The enference . Mortalinference .H. pylori infection and asymptomatic H. pylori infection were in a healthy state . The health utility values for PUD and gastric cancer are from a study conducted in 2017 [In this study, parameters regarding the cost of treatment were obtained from reports published by the National Health and Family Planning Commission or the State Food and Drug Administration of China. The cost of bismuth in quadruple therapy is the market retail price of the drug. We assumed that people with no  in 2017 . In the The total cost is accumulated by multiplying the cohort size with the sum of the costs for each health state. The QALYs for each cycle are calculated using the utility value associated with each health state multiplied by the proportion of years lived in that state. Each cycle of the model is one year in length, so the model runs for a total of 60 cycles. The total QALY and life year is the accumulation of the QALY and life year values over all cycles.Notably, the following is according to the recommendation of the World Health Organization (WHO) for the evaluation of pharmacoeconomic . ICER < Many of the parameters used in this study have considerable uncertainty. For this reason, one-way sensitivity analysis and probabilistic sensitivity analysis were conducted to assess the effect of uncertainty on the robustness of the resultsThe impact of each input parameter on the results was assessed by a deterministic sensitivity analysis (DSA) with a one-way sensitivity analysis (\u00b120% of the input parameter), using tornado plots to present the results for each parameter.Probabilistic sensitivity analysis (PSA) was used to determine the uncertainty of the input parameters. PSA was performed using Monte Carlo simulation simulations with 1000 iterations. Each parameter was specified a certain distribution, where the mean of the distribution is typically equal to the point estimate.H. pylori screening in two scenarios, as follows.By varying the assumptions for scenario analysis, this study examines the cost-effectiveness of H. pylori is initiated at different ages in asymptomatic people. This hypothesis is used to explore the optimal screening regimen for different age groups.It is assumed that screening for Compare the cost effectiveness of no repeat screening with that of no screening. This scenario examines the cost-effectiveness of increasing screening participation in asymptomatic people who are not screened.The cost-effectiveness acceptability curve (CEAC) and the incremental cost and incremental quality adjusted life year cost-effectiveness (CE) plane are used to present the results of the probabilistic sensitivity analysis.H. pylori screening regimens in people not infected with H. pylori. There was no significant difference in the number of gastric cancer cases between the three cohorts; the difference in the incidence of PUD between the three groups was also not significant.H. pylori screening, subjects survived an average of 45.43 years at an average total cost of $2487.08. In the cohort screened for H. pylori every three years, subjects survived an average of 45.01 years at an average total cost of US$2266.06. In the cohort screened for H. pylori every five years, subjects spent an average of 45.01 years at an average total cost of US$2241.19. Compared to the annual H. pylori screening regimen, the ICERs per QALY gained were US$1317.48 and US$1277.92, and the ICERs per YoLS gained were US$516.41 and US$522.05 for subjects using the every-three-year and every-five-year screening regimens, respectively. There was no significant benefit in terms of total QALYs, or number of gastric cancers, for subjects using an annual H. pylori screening programme compared to those screened several years apart. The annual screening programme for H. pylori did not show a significant cost benefit over the other two screening programmes.Baseline data are reported in The results of the one-way sensitivity analysis are presented using a tornado diagram. The impact of extreme variations in each key parameter on ICER for different screening and treatment strategies is shown in the tornado diagram. In the Markov model, the cost-effectiveness of screening and treatment programmes is not sensitive to any of the variables . From thThe results of the scenario analysis are shown in The older the age of screening initiation, the more advantageous the annual screening programme is compared to other screening programmes. When the cost of screening is halved, the annual screening strategy is more cost effective over the whole time.H. pylori screening regimen over a no-screening regimen. In the CE plane, the scatter is concentrated in the fourth quadrant, meaning that subjects in the no-repeat screening strategy gained more QALYs and spent less compared to the no-screening cohort (The results in g cohort .H. pylori screening programmes in asymptomatic populations and assists Chinese health policy makers and digestive disease specialists in developing more cost-effective screening programmes and recommendations. Markov models are applicable to chronic disease research and effectively bridge the gap between real-world clinical observations. The use of Markov models to study the cost-effectiveness of different H. pylori screening programmes effectively fills a gap that is difficult to achieve in the real world. Our study used Markov models to conduct a health economic assessment of H. pylori screening and treatment programmes in an asymptomatic population and to determine the cost-effectiveness of different H. pylori screening programmes for the asymptomatic Chinese population.This study provides new evidence for the development of H. pylori in China is very high [H. pylori infection is therefore a very serious public health problem in China. The need for interventions to reduce the prevalence of H. pylori infection in China is very urgent for the public health sector in China. In the results of this study, we found that screening for H. pylori and eradication of patients who screened positive had a significant effect on improving the health and economic benefits of the asymptomatic population. The comparison cost $218.96 less per QALY obtained for H. pylori screening than for subjects who were not screened for H. pylori. This is consistent with the findings of previous studies. It is well known that China is currently facing a very serious threat of antibiotic resistance, which is also the main reason for the failure of H. pylori eradication treatment [H. pylori eradication treatment, but also affects the effectiveness of antibiotics for other diseases [H. pylori and also prevent patients from developing resistance to other antibiotics commonly used in clinical practice [In the 2018 study, it was noted that the prevalence of reatment . The rigdiseases . For thiH. pylori eradication therapy with PPI therapy alone in terms of short-term efficacy and lifelong prevention. The incidence and recurrence of PUD after H. pylori eradication was significantly reduced and more cost-effective than PPI treatment alone [H. pylori screening in asymptomatic people comes mainly from the prevention of PUD. A programme of screening at intervals of several years can reduce expenditure compared to a programme of annual screening. Past studies have shown that reinfection after successful H. pylori eradication therapy is rare, so the benefits of eradication therapy for infected individuals are long-term [H. pylori in the asymptomatic population for high-stakes testing are not significant. High frequency screening for H. pylori is therefore of limited effectiveness in preventing PUD in patients who have already been screened and successfully eradicated.Previous Markov model studies have compared the cost-effectiveness of nt alone ,40. In tong-term . In contH. pylori infection and the development of gastric cancer. According to a study by the Cancer Research Centre of Sun Yat-sen University, there are about 450,000 new cases of gastric cancer in China each year, of which at least 64.84% are caused by H. pylori infection [H. pylori infection in China recommends screening for H. pylori in communities at high risk of gastric cancer or in individuals at high risk of gastric cancer in China and the eradication of H. pylori in screen-positive patients. In previous Markov model studies, it has been shown that annual screening is more cost effective than no screening [H. pylori screening compared to the cohort without H. pylori screening.There is a strong association between nfection . The concreening . Howevercreening ,13. In cH. pylori. Large-scale screening for H. pylori in asymptomatic populations entails significant economic and labour costs [H. pylori [China has a huge number of people infected with ur costs . And witur costs ,40. Base. pylori , we recoH. pylori screening has a very limited effect on the prevention of H. pylori-related disease. The triennial and quinquennial screening programmes cost $1238.47 and $1163.70 more per QALY gained compared to the annual screening programme, respectively. The incremental QALYs and reduction in H. pylori-associated disease obtained with the annual screening programme did not show an absolute advantage over the triennial and quinquennial screening programmes. However, the benefit that the cohort without repeat screening could obtain compared to the group without screening was highly significant. We therefore believe that it is more cost-effective to increase the participation rate of unscreened asymptomatic people in screening than to increase the frequency of screening.In terms of screening frequency, increasing the frequency of H. pylori infection that can be prevented by screening, unlike most previous studies that were limited to the primary outcome of gastric cancer. The design of this study is closer to the real world situation [H. pylori infection and associated disease. Second, we did not model gender and region separately to discuss cost-effectiveness, and H. pylori-related disease varied significantly by gender and region. This study remedies this problem through uncertainty-sensitive analysis, and in terms of the results, the results of this study are sufficient to evaluate the bias introduced by these differences.The strength of this study is that our study design includes two major diseases caused by ituation . An addiH. pylori screening strategies for asymptomatic populations in China, and the results can be used as a reference for digestive disease prevention policies developed by health administrations. The generality of this study is worth discussing. The study findings should be applied to developing countries and regions similar to China. The rates of H. pylori infection and recurrence, the cost of screening and eradication treatment, and patient compliance vary greatly due to the actual situation in different countries and regions [This study provides a comprehensive analysis of the cost-effectiveness of different  regions ,21. TherH. pylori and to eradicate treatment in patients with positive screening results. H. pylori eradication treatment has significant benefits for the prevention of stomach cancer and peptic ulcers. Therefore, from a national payer perspective, we recommend screening for H. pylori in asymptomatic Chinese populations and eradication treatment for those who test positive. We also recommend but not the participation rate of screening in asymptomatic people, increasing the frequency of repeat screening. From an individual payer\u2019s perspective we also recommend screening and eradication of H. pylori for asymptomatic people, who can choose a screening programme they can afford according to their financial situation. High-frequency repeat screening has not been shown to improve the effectiveness of peptic ulcer and gastric cancer prevention in Chinese asymptomatic populations.In summary, it is cost-effective to screen asymptomatic Chinese populations for"}
+{"text": "RSC Advances article due to concerns with the reliability of the data.The Royal Society of Chemistry hereby wholly retracts this Part of the image in Fig. 1g  panel) is a scaled, rotated and inverted version of the image in Fig. 3d .The authors also informed the editor that incorrect H&E staining images, labelled with bpV(pic)/PLGA-ASC, were used in Fig. 4c.Given the significance of the concerns about the validity of the data in the article, the findings presented in this paper are not reliable.The authors do not agree with the decision to retract the article.RSC AdvancesSigned: Laura Fisher, Executive Editor, Date: 22nd December 2022"}
+{"text": "Global Evidence-to-Policy (E2P) Summit. This summit brought together different stakeholders from all WHO Regions to identify common challenges, share lessons learned, and provide recommendations to support evidence-informed decision-making as a catalyst for policy and societal changes.In response to the challenges created by the COVID-19 pandemic to the role of evidence in policymaking, the World Health Organization (WHO) in collaboration with the Pan American Health Organization (PAHO) convened the first The E2P summit was organized by the Evidence-Informed Policy Network (EVIPNet), a global initiative with strong experience in promoting the use of evidence in policymaking.an EVIPNet Americas regional meeting to discuss the processes for using scientific evidence for the COVID-19 pandemic response and the challenges faced in translating this knowledge into policies in Latin America and the Caribbean (LAC). The event contributed to strengthening the EVIPNet Americas network. Three different panels were convened that provided insights into the use of evidence during the COVID-19 pandemic, experiences of Ministries of Health, and shared strategies and mechanisms for institutionalizing the use of evidence. The panels and participants shared important insights and lessons from different institutions in different countries . They reflected on several experiences of encouraging the use of evidence by public institutions to effectively respond to the COVID-19 pandemic, such as the need to better communicate evidence, to strengthen the relationship between evidence producers and decision makers, and for greater capacity-building in non-pandemic times to ensure better preparedness.As part of the Summit, PAHO convened Call for ActionEVIPNet Americas and PAHO have used their experience in supporting LAC countries to encourage collaboration between stakeholders and to use evidence better in responding to the COVID-19 pandemic see . The E2PConceptualization: L.R., C.M., J.B. and T.P., Writing \u2013 original draft: C.M., E.C., J.B., T.P., M.H., AND L.R., Writing \u2013 review & editing: M.M., D.F., L.K., R.B., C.C., C.V.M.A., and S.G. All authors reviewed and agreed with this final version of the paper.No individual data was used for this manuscript. The resources mentioned are all publicly available under the URLs reported in the table.This commentary did not have any source of funding.The author is a staff member of the Pan American Health Organization. The author alone is responsible for the views expressed in this publication, and they do not necessarily represent the decisions or policies of the Pan American Health Organization.The authors have declared that no competing interests exist. Authors hold sole responsibility for the views expressed in the manuscript, which may not necessarily reflect the opinion or policy of the Pan American Health Organization."}
+{"text": "Prevention of preterm birth:a randomized trial of vaginal compared with intramuscular progesterone. Acta ObstetGynecol Scand 2012; 92:215\u2013222: DOI: wileyonlinelibrary.com), and has been published byagreement between the journal's Editor\u2010in\u2010Chief and John Wiley and Sons, Ltd. The notehas been agreed due to concerns raised regarding the authenticity of the data presentedwithin the article. The authors have provided a response to the journal regarding theseallegations. The journal has requested an investigation from the author's institution,University of Menoufia, and an investigation is on\u2010going. As a result, the journal isissuing this note to readers. A subsequent note will be published depending on theoutcome of the investigation.This note is for the above article, published online on 27 September 2012in Wiley Online Library ("}
+{"text": "A. Mirghni  Sekhar C. Ray was incorrectly spelled in the published article; the corrected version is shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "Chrysopidia (s. str.) from China is presented. Based on the examination of type specimens of the genus reported by previous Chinese scholars and the line drawings of Chrysopidiamanipurensis provided by Ghosh (1990), I proposed five new combinations: Apertochrysaplatypa , comb. nov., Apertochrysayangi , comb. nov., Apertochrysashennongana , comb. nov., Apertochrysazhaoi , comb. nov., and Apertochrysamanipurensis , comb. nov. As for Chrysopidiasinica Yang & Wang, 1990, I still treat it as a valid species until supplementary specimens are available because the gonarcal complex of the type specimen is missing. A new species Chrysopidia (Chrysopidia) tjederisp. nov. is also described based on new materials. A key to all known species of this subgenus is also provided.A taxonomic study of the green lacewing subgenus  The paper has been retracted by the publisher due to evidences of misconduct.The removed version is archived for the purpose of resolving nomenclatural questions and is available from the publisher upon request."}
+{"text": "Helicobacter pylori can be responsible for the development of otitis media with effusion.It is proposed that H. pylori in the adenoid tissue and fluid of the middle ear in patients who suffer from adenoid hyperplasia and otitis media with effusion in comparison with those who suffer from adenoid hyperplasia without otitis media with effusion.The aim of this study is to investigate the prevalence of This is a case\u2013control study that was carried out in 50 children of age 2\u20137 years old who were admitted with adenoid hyperplasia. Patients were divided into case and control groups. The study group included 25 patients with adenoid hyperplasia and otitis media with effusion and the control group included 25 patients with adenoid hyperplasia without otitis media with effusion. The patients in both groups underwent surgical adenoidectomy. For the case group we carried out myringotomy and placement of tympanostomy tube, and fluid samples were collected under sterile conditions. The samples were sent to the laboratory for polymerase chain reactions.H. pylori was found to be positive in 18 samples of the middle ear fluid (70%) and in 1 polymerase chain reaction adenoid tissue sample (4%). In the control group H. pylori was positive in 3 samples of adenoid tissues (12%). There was no gender difference.In the case group H. pylori is one of the important bacteria that plays a role in the pathogenesis of otitis media with effusion. Whether adenoid tissue may be a reservoir for H. Pylori is unclear. Haemophilus influenzae was the single most common pathogen, and other common bacteria included Streptococcus pneumonia and Moraxella catarrhalis. Other bacteria account for a small percentage of cases.Helicobacter pylori (H. pylori) in the middle ear.H. pylori. Many body regions other than the gastrointestinal tract have been investigated for the presence of this microorganism. In recent years, H. pylori has been found in adenoid tissue, nasal polyp tissue and the middle ear.H. pylori has also been shown to be present in high ratios in nasal polyps, laryngeal samples, and vocal cord lesions using real-time polymerase chain reaction (PCR) method.H. pylori presence separately.H. pylori. It has been shown that PCR method has almost 100% sensitivity and specificity in the detection, identification and quantitation of H. pylori in biological samples.H. pylori in adenoid tissue of patients with adenoid hyperplasia without OME in comparison with patients who have adenoid hyperplasia with OME.Otitis media with effusion (OME) is defined as middle ear effusion without signs and symptoms of acute inflammation found in acute otitis media.Our study is a case\u2013control study that was performed on 50 children between the ages 2 and 7 years old with adenoid hyperplasia, with median age of 4.5 years, who were admitted to the ENT department of Shafa hospital  between October 2013 and March 2015. The patients were enrolled in the study by non-random easy sampling method.Inclusion criteria were signs and symptoms of adenoid hyperplasia that were confirmed by lateral neck radiography in the extension position. The patients have been divided into two groups of case and control, based on the presence or absence of signs and symptoms of OME. After history taking and clinical examination including otoscopy, diagnosis of OME was confirmed as well as tympanometry for confirmation of OME. The patients in the case group had OME but the patients in the control group did not.H. pylori, genomic isolation kit was used.Exclusion criteria included patients who did not consent to enter the study, a history of previous adenoidectomy, neurological disorders, genetic syndromes, craniofacial abnormalities such as Down syndrome, and other causes of airway obstruction such as deviated septum, nasal polyps, and turbinate hypertrophy. In addition patients with active infection were excluded. We described objectives and methods of the study to parents of the patients and they were asked questions to ensure that they understood the procedure. Afterwards, they were allowed to ask their possible questions. Later, written permissions were obtained from all parents. Then all patients underwent surgical adenoidectomy under the same conditions, and adenoid samples were prepared with curette. A core biopsy specimen was taken from each adenoid tissue; collected samples were placed immediately in PSB buffer. In addition, for the case group, samples from the middle ear effusion were taken. For this purpose, outer ear canal was cleaned with 70% alcohol solution, then an incision was made at the anterior inferior quadrant of the eardrum. Samples were collected from middle ear fluid and were placed in the PSB transmission medium. The effusion and adenoid tissue samples were transported to microbiology laboratory. The samples were frozen immediately after removal and stored at \u221220\u00a0\u00b0C; when required, specimens were thawed, and supernatants of centrifuged specimens were assayed. To measure the DNA of H. pylori was determined in the bands of 260\u2013280\u00a0nm by absorption rate. At the end, all patients\u2019 information was entered the checklist. Data was reported by descriptive statistics and analysis was done by chi-square and Fisher exact tests and SPSS software was applied.Measurement was performed by a spectrophotometer. Thus the existence of the DNA of The ethical code of this article is IR.KMU.REC.1395.344.H. pylori in the middle ear fluid, 3 patients (12%) in the control group had H. pylori in adenoid tissue and 1 patient (4%), in the case group had H. pylori in adenoid tissue. Thus the frequency of H. pylori in the middle ear fluid in the case group is more than it's frequency in adenoid tissues of both case and control groups  in the control group had H. pylori in adenoid tissue and none of the boys in case group had bacteria in adenoid tissue. Eight girls (30.8%) in the case group had H. pylori in the middle ear fluid samples and 10 boys (41.7%) in the case group had H. pylori in the middle ear fluid. Results are reported in The number of patients who entered the study was 50 children who were studied in two groups of 25 cases and 25 controls. 24 patients (48%) were male and 26 (52%) were female. Out of 50 patients, 18 patients (70%), in the case group had l groups . Out of H. pylori and the pathogenesis of various upper aerodigestive tract problems have been shown. H. pylori for reproduction needs a microaerophilic environment. This environment is present in the middle ear of OME patients. The mechanism of the colonization of these bacteria in the gastric mucosa is still unclear. It is said this bacteria grows by implanting inside the mucosal epithelium of the stomach, protected by impermeable mucus layer to the gastric acid. The PH of the luminal side of the mucus layer is 1.0\u20132.0 and the PH of the mucosal side is approximately 7.4. The PH of the middle ear effusions is also between 7.0\u20139.0. In H. pylori infections mucosal metaplasia and goblet cell hyperplasia occurs, a similar situation in OME.H. pylori by specimen collection from middle ear. We calculated H. pylori positivity rate not on the basis of the number of ears, but the number of patients because we would like to know the existence rate of H. pylori in each individual. We found H. pylori in 70% of the middle ear effusions is positive, and this is relatively high in comparison with other studies such as Chul Von et al.H. pylori was 30%), so we suggest that H. pylori could be an important etiologic factor for development of OME. Agirdir et al.H. pylori positivity was 66.6% in effusion of 30 patients with OME and the adenoid of the patient group and the control group showed no significant difference in the prevalence of H. pylori. Yilmase et al.H. pylori in 45% of the patients with OME. In another study by Yilmaz et al.H. pylori was positive in 67% of children. None of the tissue samples obtained from adenoids of study group and only one of the tissue samples in the control group was positive with PCR. There are two possible explanations for why H. pylori has been discovered in the effusion of the middle ear. The first is that the tonsil and adenoid act as a reservoir for H. pylori. Since the tonsil, adenoid, and Eustachian tube are anatomically close, this can allow for H. pylori to spread directly.H. pylori that is mixed in with the gastric fluid can then be detected in the middle ear. There is an association between chronic middle ear problems and gastroesophageal reflux. Higher concentration of pepsin/pepsinogen in the middle ear than serum of patients with OME has been reported by Tasker et al.OME is one of the most common causes of hearing loss among children in developed countries. OME is characterized by fluid accumulation in the middle ear with no active infection; if the disease persists for more than three months, it is called chronic OME. In several studies, the relationship between In a study that published in 2008 by Fancy et al.H. pylori in patients with OME was studied. Eighty-four patients who were subjected to adenoidectomy and myringotomy were included in the study group. Ninety-one patients who had only adenoidectomy were selected as the control group. Adenoid samples were positive for H. pylori in 25% patients in the study group and 19.8% patients in the control group. In the study group, 42.8% effusion samples (Otitis Media) of the patients were positive for H. pylori. They showed that the colonization of H. pylori in adenoid tissue and in the middle ear may be involved in the pathogenesis of OME.In another study by Saki et al.H. pylori in adenoid samples of study group was 4% and in control group was 12%; this finding is not significant in comparison of H. pylori positivity of patients with OME that was 70% indicating that adenoid tissue is not a reservoir for H. pylori. We hope future studies will be done on the relationship between OME and H. pylori in the world population.In the present study, we found that the presence of H. pylori presence in middle ear of the children with chronic OME, indicating H. pylori have a possible role in OME pathogenesis. In addition we detected H. pylori presence in 4 of 50 adenoid specimens, supporting the idea that adenoid tissue does not act as a reservoir for H. pylori.Our study showed that there is significant The authors declare no conflicts of interest."}
+{"text": "Fusarium oxysporum f. sp. lactucae. The Fusarium oxysporum f. sp. lactucae is the scientific name of the studied fungus. Therefore, it must be written according to the scientific rules. Therefore, the style of this scientific name has to be corrected throughout the whole manuscript. The E-mail address of Mohamed S. Sedeek that was sent previously is now corrected to mohamed.sedeek@pharma.cu.edu.eg. The previous E-mail address used by Hanaa is now replaced by the official one hanaa.omar@agr.cu.edu.eg, as very recently required by Cairo University. This would positively reflect the actual citation record of our university accordingly. The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. The original publication has also been updated.The authors of this paper  have agr"}
+{"text": "The authors wish to make a correction to the published version of their paper .Conflicts of Interest: The authors declare no conflict of interest.should beConflicts of Interest: M.K. is a shareholder-CEO in Wellnas Co., Ltd. K.N. is an inventor of pending (WO2015147251 and WO2018070545) and awarded (Japanese Patent No. 6192167 and Indonesia Patent No. P000063624) patents regarding this work and a shareholder in Wellnas Co., Ltd.We apologize for this error. The change does not affect the scientific results. The published version will be updated on the article webpage, with a reference to this correction notice."}
+{"text": "In the original published version of this article, the article was incorrectly stated as having been submitted to the journal in January 2020. This has now been corrected to August 2020. The publisher apologizes for this error. In addition, the original published version of this article stated the incorrect institutional review board reference number as IR.QUMS.REC.1399.260 in the Methods section. This has now been corrected to IR.QUMS.REC.1398.375. The authors apologise for this mistake. Both the HTML and PDF versions of the article have been updated to correct the error."}
+{"text": "Echinops kebericho Mesfin (60), Hagenia abyssinica (Bruce) J.F.Gmel (60) and Laggera tomentosa (A.Rich.) Sch.Bip. ex Oliv. & Hiern (58). The present study is the first systematic, qualitative, and quantitative ethnobotanical analysis and documentation done on the use of the medicinal plants from GBG for traditional medicine. In addition, our study reveals that E. kebericho is endemic and endangered plant and is highly used in traditional medicine. Therefore, GBG authorities should take steps for the propagation and restoration of this plant. Further it is suggested that the pharmacological properties of the roots and leaves of E. kebericho should be compared to find the possibility of use of leaves in place of roots for the preparation of traditional medicine which would help in conserving this endemic plant of Ethiopia.Gullele Botanical Garden (GBG) in Addis Ababa, Ethiopia is a joint venture of Addis Ababa government and the university. The garden has been built mainly to conserve the endemic plants and to advance the research on the endemic and non-endemic plants collected from different part of Ethiopia. Many traditional healers from the environs of GBG and different subcities of Addis Ababa depend on the garden for their practice of traditional medicine but there is no systematic documentation of the traditional medicinal knowledge of these healers. The main objective of the present study is to comprehensively document the ethnobotanical and ethnomedicinal information from the traditional healers of different ethnic and cultural groups depending on GBG and to create a database of the endemic plants used by these healers. The ethnobotanical and ethnomedicinal data obtained from 60 traditional healers have been analyzed both qualitatively and quantitatively. A total of 81 medicinal plants belonging to 47 families have been identified. Majority of the plants used belonged to Asteraceae (12) family. The most frequently used plant form and plant parts are herbs and leaves. The major method adopted by the healers for preparation and administration of traditional medicine is crushing and topical, respectively. Skin and general diseases are the most important ailments treated by the healers. The three most cited plants used to treat diseases are  In Ethiopia, the use of medicinal plants to cure and heal diseases has been practiced for a long time and traditional medicine is one of the important components of health care . The couin situ management techniques. This increase in the GBG\u2019s flora can mainly be attributed to the propagation and planting, reforestation, natural regeneration of endemic plants and limited and sustainable use of the medicinal plants by the traditional healers.The high cost of the drugs and modern healthcare have led the people of Ethiopia to heavily depend on the age-old traditional medicinal systems. The practise of traditional medicine is carried in many regions of Ethiopia. One of such regions in Ethiopia is Gullele Botanical Garden (GBG) in Addis Ababa. Addis Ababa city is the capital of Ethiopia and is divided into ten subcities. Gullele is a subcity with an area of nearly 30\u00a0sq.km and with a population density of nearly 9,500\u00a0per sq.km. There are many ethnic groups that resides in Gullele among which the major groups are Amhara, Oromo, Gamo and Guragie. Botanical gardens are one of the key places for the conservation of a variety of plants. It is known that botanical gardens around the world help to conserve \u223c41% of the threatened species . GulleleGBG provides a greener environment to the Addis Ababa city and provides an ecosystem for carbon storage, habitat conservation and prevention from soil erosion. Most of the Ethiopian population heavily depend on the use of traditional medicine because of its low cost and high cultural acceptance. As per the garden authorities, traditional healers in Ethiopia have been providing several medical services, treatments and remedies for a long time in Ethiopia. Hence, the people around the garden and in Gullele subcity heavily depend on the plant medicines given by the traditional healers living in the garden\u2019s vicinity. Therefore, the garden\u2019s authorities collaborate closely with the traditional healers or traditional physicians to collect, protect and propagate the medicinal plants species in GBG. Inside GBG there is a medicinal garden which contains and propagates the medicinal important plants which are overharvested. The medicinal garden and the forest section of GBG has a total of 166 medicinal plants which are sustainably used by the certified traditional healers around Gullele and Addis Ababa city. For bio-prospecting and optimum use of the medicinal plant\u2019s proper survey and documentation are required .A significant number of traditional healers from different ethnic groups with different culture and tradition depend on the medicinal plants of GBG to practise traditional medicine but there is no systematic documentation of this traditional medicinal knowledge used by the healers. Although, GBG is playing a vital role of transferring the traditional medicinal knowledge from one generation to other there are still many instances where the indigenous knowledge that is available among traditional healers is lost or diluted due to word-to-mouth teaching to the next generation of healers. Therefore, GBG has been selected for the current study and to maximize the documentation the help of the GBG authorities have been taken to identify traditional healers from different ethnic groups. The main objective of the present study is to comprehensively document the ethnobotanical and ethnomedicinal information from the traditional healers of different ethnic and cultural groups depending on GBG and to create a database of the endemic plants used by the healers. Thereafter to quantitatively analyze the data obtained with various ethnobotanical indexes and to uncover the plants which are mostly used in the treatment of diseases by the healers. Identifying the endemic plants mostly used by the healers will help the GBG\u2019s authorities to cultivate and propagate the endemic plants with priority over the others. A secondary objective of this study is to identify the important endemic medicinal plants used by the healers as obtained from the quantitative ethnobotanical analysis and use it for bio-prospecting and discovery of new drug leads.Eucalyptus globulus and Juniperus, respectively. As this is the first botanical garden in Ethiopia and has a diverse flora and fauna, it is a major destination for eco-tourism and educational outreach. The garden contains around 100\u00a0hectares of cultivated plants which harbors nearly 1,600 indigenous plants. Amongst them, around 64 plant species are endemic species, 189 are exotic plants, 900 are indigenous plant species and about 65 are critically endangered species .This study has been conducted following the guidelines for best practices in ethnopharmacological research . During The qualitative ethnobotanical data analysis has been done with the aid of Origin Pro 2021 software. To analyze and summarize the data reported on the medicinal plants, parts and life form used, preparation mode and administration mode, descriptive statistics have been used. The therapeutic uses of the medicinal plants collected from the informants in the local languages are translated to English. These diseases, as reported by the informants, are classified into different categories according to the International Classification of Primary Care .To quantify the collected data, different ethnobotanical indices have been employed. Four ethnobotanical indices have been employed to assess the collected data.ur\u201d is the number of citations for a particular ailment category and \u201cNt\u201d is the number of species used for that particular ailment category. The ICF value mainly states the homogeneity present in the ethnobotanical knowledge. A high value of ICF means the informants agree on the use of the medicinal plant species to treat the ailment, while a lower value shows that the informants are secretive about their plant uses or the medicinal plants are chosen at random.Trotter and Logan developed the ICF and readapted by Heinrich to analyze if there is a consensus between the medicinal plants used by the informants and the various ailment categories . The infRelative frequency of citation is used to measure the agreement among the traditional healers with the documented plants in a particular study area . The relp\u201d is the number of informants that have cited the medicinal plant used for a particular disease. \u201cN\u201d is the total number of informants citing that particular medicinal plant species used for any diseases.Fidelity level index is mainly used to find out the most preferred medicinal plant species used to treatany ailment . The forJaccard\u2019s similarity (JI) index is used to find out the similarity between the operational taxonomic units. It is mainly calculated by comparing the published data from similar taxonomical units by analyzing the medicinal plant species and their uses. The Jaccard\u2019s similarity index is calculated with the aid of the following formulae :JI=C\u2009A+The demographic characteristics of the traditional healers have been documented as per the information provided by the healers in face-to-face discussion . A totalThe educational level of the healers as from the collected data has been divided into three categories, i.e., modern education, religious education and uneducated. Most of the informants, i.e., \u223c58% are literate and have contemporary education. Ten traditional healers are religiously educated, and they constitute \u223c17% of the total informants. The rest 25% did not have any formal education, but the traditional medicinal knowledge has been handed over to them through ancestry . In mosthttps://powo.science.kew.org/). The data collected from the field documentation showed that the traditional healers used 81 plant species for which the specimens\u2019 samples have been collected and documented. The 81 medicinal plant species belonged to 47 families  Kuntze from our study used by the traditional healers to treat wart, is also found to have anti-cancer, anti-microbial, anti-inflammatory and antioxidant activities  Kuntze is also known to exhibit anti-plasmodial and antiprotozoal activities  H.Rob is mainly used by the traditional healers in Gullele Botanical Garden to treat snake bites and menstrual problems. In addition, it is widely used for the treatment of cancer (Laggera tomentosa (A.Rich.) Sch.Bip. ex Oliv. & Hiern is frequently being used by the healers to treat tonsils and headache in and around Gullele Botanical Garden. The antioxidant and the bactericidal activities of the essential oil of this plant have been documented  C.Jeffrey  R.M. King and H. when applied topically to the incision wound of Sprague-Dawley rats for 8 days, there is an overall healing of the wound by 60%  Pers. when applied to the excision wound infected with Staphylococcus aureus of Wistar rats healed the wound by nearly 40 percent (Ageratina pichinchensis (Kunth) R.M. King and H. Rob. The topical application of the extract with carboxymethyl cellulose in a randomized trial in treating the chronic venous leg ulcers of 17 patients showed an ulcer size reduction of around 79 percent in the second month of treatment and it healed completely by the eighth month  has been used to the highest extent by the traditional healers followed by the medicinal plant Hagenia abyssinica (Bruce) J.F.Gmel (60 citations) and Laggera tomentosa (A.Rich.) Sch.Bip. ex Oliv. & Hiern (58 citations), respectively  Hochst ex Baker, Spiniluma oxyacantha (Baill.) Aubr\u00e9v., Urtica simensis Hochst. ex A.Rich, Pentanema confertiflorum (A.Rich.) D.Gut.Larr., Santos-Vicente, Anderb., E.Rico & M.M.Mart.Ort. and Kalanchoe petitiana A. Rich plants have also been found to be used by traditional healers to treat a variety of diseases  followed by shrubs (\u223c26%), trees (\u223c12%), stem (\u223c11%), climber (\u223c6%) and lianas (\u223c3%) the least used by the traditional healers . Herbs aIn the current study, the traditional healers have used different parts of the medicinal plant to prepare the medicines. Among all the plants parts, the most commonly used is leaves (46 citations) followed by roots (26 citations) and whole plant (11 citations) . BesidesIn the present work, the healers have adopted various preparation modes to prepare the medicine, as represented in The most common route for administration of the traditional medicine prepared are dermal/topical and oral, having a citation of 43 and 28, respectively . In addiHagenia abyssinica (Bruce) J.F.Gmel., Echinops kebericho Mesfin and Laggera tomentosa (A.Rich.) Sch.Bip. ex Oliv. & Hiern. The use of these three plants may be because of its abundance and ease of availability in the place. Those plants having high citations against the various diseases should be further explored for their biological activities   Figure . The contivities . In linetivities . The higThe diseases cited by traditional healers have been divided to 16 categories . The higTaxus brevifolia and Catharanthus roseus, respectively and anti-malarial drugs quinine from Cinchona spp. and Artemisinin from Artemisia annua are well known drugs isolated from plant extracts for treating the respective diseases (The relative frequency of citation (RFC) mainly reveals the importance of the medicinal plant species with the reference to the citations provided by the traditional healers . In the diseases . The natdiseases . In courdiseases . In our Echinops kebericho Mesfin, Galium abaujense Borb\u00e1s and Laggera tomentosa (A.Rich.) Sch.Bip. ex Oliv. & Hiern has 100 percent fidelity and is used to treat snakebite, eczema and leech would heal, respectively (Cyathula uncinulata (Schrad.) Schinz, Jasminum abyssinicum Hochst. ex DC., Linum usitatissimum L., and Olinia rochetiana A.Juss. has 90 percent fidelity level in treating wounds  Kuntze and Phytolacca dodecandra L\u2019He\u2019r. having 90% FL, is used for the treatment of skin disease i.e. wart. Other plants such as Carissa spinarum L., Clematis simensis Fresen., Lactuca inermis Forssk. and Sparrmannia ricinocarpa (Eckl. & Zeyh.) Kuntze is used for the treatment of evil eye, tonsillitis, impotency and hepatitis, respectively (The fidelity level (FL) of the medicinal plants used to treat various diseases in this study varies from 50 to 100% . The datectively . Ten medg wounds . Similarectively . Nearly ectively . The higectively . Fidelitectively . It is gectively . In the ectively . The lowectively . The maiectively .The similarities and differences in the ethnobotanical studies in a region reveal the indigenous knowledge of the medicinal plants based on the historical, phytochemicals, and ecological factors that govern the selection of medicinal plants . The curEchinops kebericho Mesfin and Laggera tomentosa (A.Rich.) Sch.Bip. ex Oliv. & Hiern has the highest fidelity of 100 percent and is also being explored for many of their pharmacological and bioactivities. In many other ethnobotanical and ethnomedicinal studies carried out in Ethiopia, Echinops kebericho Mesfin is used by the traditional healers to treat many other diseases such as black leg, respiratory and liver diseases, cough, headache, scabies, toothache, stomach ache, common cold, sunstroke, tonsillitis, vomiting, gonorrhoea etc  Sch.Bip. ex Oliv. & Hiern also has a fidelity of 100 percent. This medicinal plant is endemic to Ethiopia and is used by many traditional healers in Ethiopia. The plant\u2019s crushed juice is taken for the treatment of migraine while the vapor of the boiled leaves is taken to treat cold  Kuntze and Lactuca inermis Forssk. have a fidelity of 90 percent. Dichrocephala integrifolia (L.f.) Kuntze in addition to Ethiopia is used all over Africa as a traditional medicinal plant to treat schizophrenia, diarrhoea, amebiasis, epilepsy, worm infections, dementia, asthma, malaria, inflammation, hepatitis and gastrointestinal diseases  Sch.Bip. a native of Africa has been extensively used in traditional medicines for treating several diseases such as constipation, wounds, scabies, tonsillitis, fever, worms infection etc  Sch.Bip. ex Schweinf. is also less explored which is used for treating skin wounds and has a fidelity of 75 percent. Tagetes minuta L. has a fidelity of 70 percent and is used to treat a number of diseases. It is also used in food and aromatherapy because of the unique composition of its essential oil -\u03b2-ocimene, L-verbenone and limonene (Solanecio gigas (Vatke) C.Jeffrey is an endemic plant of Ethiopia and has been used to treat many diseases such as diarrhoea, wounds, skin and liver diseases  H.Rob. is plant which is mainly used in the middle east countries to treat diseases like cough and skin. The pharmacological and bioactivities of this plant has not been explored extensively. It is seen that the extract from this plant exhibits antiprotozoal, cytotoxic and antimicrobial activities (Pentanema confertiflorum (A.Rich.) D.Gut.Larr., Santos-Vicente, Anderb., E.Rico & M.M.Mart.Ort has the least fidelity of 50 percent among all the Asteraceae plants. Pentanema confertiflorum is used in various regions of Ethiopia for traditional medicine (S. aureus and T. mentagrophytes (In the current study, the traditional healers have used the maximum number of medicinal plants belonging to the family of Asteraceae. Some of these plants are endemic and are being used extensively by the traditional healers in Ethiopia . Among thoea etc . In mosthoea etc . The safl models . Severalhe roots . In addihe roots . It is she roots . It alsoalbicans . The extalbicans . The essalbicans . Deyno ealbicans . In the eat cold . The aereat cold . It is seat cold . The esseat cold . The majneumonia . Dichrocdiseases . Several. brucei . Fankem eactions . It is seactions . Lactucais plant . Althoug inermis . Gymnanttion etc . G. amygll lines . The flall lines . The ethP. ovale . In the P. ovale . In addiP. ovale . The ext E. coli . In the . mutans . In othe. mutans . In addi. mutans . Inula atial oil . The essbacteria . It is sbacteria . In the of fungi . The essof fungi . In addiof fungi . It alsoof fungi . T. minuarasites . In addilimonene . Similarlimonene . Solanecdiseases . As thisll lines . In anotnd HIV-2 . Bidens he world . Many rel models . Kumari l models . The extl models . In the l models . B. pilohe world . It is she world . In addiactivity . In the activity . The metactivity . In addixysporum . The plaxysporum . Orbivestivities . Pentanemedicine . The metrophytes . In anotrophytes . TherefoTo the best of knowledge, this is the first systematic qualitative and quantitative ethnobotanical and endemism study conducted in Gullele Botanical Garden in Addis Ababa, Ethiopia. The medicinal plant species documented in the current study are used to treat a variety of human ailments. Most of the medicinal plants are herbs and shrubs and for preparing the traditional medicine by the healers. Mostly the leaves of the medicinal plants are used. Most herbal preparation is made from fresh medicinal plants, majorly by crushing and pounding. This study also reveals that the most treated ailments by the healers are skin and, as expected, the most cited route of administration of the medicine is dermal/topical. This study also reveals that there are several endemic plants in the garden, which are still unexplored by the traditional healers. The medicinal plants used by the traditional healers around Gullele Botanical Garden to treat the patients in the area through traditional healthcare systems significantly complement the modern healthcare systems, as the later are considerably costlier. The use of these medicinal plants by the healers lowers the cost of the traditional medicines, which can be easily accessed by the ethnic groups around the garden. In addition, the use of the plant-based medicines by the healers helps in the continuation of the practice of the traditional medicinal knowledge as well as transfers this information of the traditional medicine to the young generation. There are various medicinal plants with high citations for which further phytochemical, pharmacological, microbiological, and toxicological investigations are needed. In addition, this study reports many endemic plants in GBG having medicinal value but are either endangered or vulnerable. To conserve these endemic medicinal plants the GBG authorities should propagate and conserve these endemic plant species. Besides this, due to increasing modernization, the traditional medicinal knowledge is eroding at a very fast pace and will be extinct soon. Hence, endless, and tireless efforts are needed to conduct more ethnobotanical and ethnomedicinal studies both in Ethiopia and throughout the world to document and preserve the precious and invaluable traditional medicinal knowledge."}
+{"text": "The correct email address should be hongmei.hu@uol.de.In the published article, there was a mistake in the email address of the correspondence. The email address of the corresponding author is"}
+{"text": "Acknowledgments Section:There was an error in the original publication . A correAcknowledgments: We thank K. Shashok for editing the use of English in this manuscript. The authors state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."}
+{"text": "After the publication of  it was nA. alternata and contains two histone-fold-containing proteins.In the Data Analysis section of the Material and Methods, there is an error in the second sentence of the first paragraph. The correct sentence is: Histone H3 sequences of PresA_alt and PresA_ten isolates were compared to reference sequence Accession number NW_017306216.1. This is the genomic scaffold of"}
+{"text": "Dear Dr. Rujittika Mungmunpuntipantip,Thank you for your letter and comments on the paper. The paper described by Ong et al. focuses on the safety and adverse events among the PWE following COVID\u201019 immunization. Some of the recruited subjects in the paper have other comorbidities, which do not deter them from being vaccinated. Some adverse events are inevitable, which are not proven to be more frequent or more severe compared with the general population. All in all, the benefits of COVID\u201019 vaccination outweigh its potential risks.We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Neither of the authors has any conflict of interest to disclose for this letter.Thank you.Best regards,Corresponding author:Ching Soong Khoo.Department of Medicine,Universiti Kebangsaan Malaysia Medical Centre.chingsoongkhoo@gmail.comEmail: Lead author:Marjorie Jia Yi Ong.The National University of Malaysia.marjorieongjiayi@gmail.comEmail:"}
+{"text": "This article has been retracted: In July of 2020, the Academic Committee of Jiangsu Normal University launched an investigation into this paper and requested that the authors provide the original experimental records and data for verification. To date, however, the authors have failed to provide the requested documents. The committee has concluded that this paper displays signs of academic fraud. In light of this, the paper is retracted. The University and Oncotarget thank the Pubpeer community for raising the concerns.100227-100241. https://doi.org/10.18632/oncotarget.22151Original article: Oncotarget. 2017; 8:100227\u2013100241."}
+{"text": "This article has been corrrected at the request of the authors to include Dr.\u00a0Syed Rehan H. Daimi as last author. Dr. Daimi was erroneously omitted from the author list by the submitting author and instead included in the Acknowledgements section of the article. Upon realizing their error, the authors contacted Cureus to request that Dr. Daimi be added. Dr. Daimi also contacted the journal with this request. Upon reaching a consensus, Dr. Daimi was added as last author, the corresponding Acknowledgement removed, and the formal correction issued. The authors deeply regret this error and apologize to Dr. Daimi for the omission."}
+{"text": "Singh  The author regrets that the funding information was incorrectly shown in the acknowledgements section of the original manuscript. The corrected funding acknowledgement is as shown below.All authors acknowledge support for this work, in part, from the National Science Foundation under Grant No. 1609303. A. S. and S. K. S. also acknowledge support, in part, from the National Science Foundation under Grant No. 1655496 and 1661038. The electrokinetics module used in the presented NanoMagnetoElectrokinetic modeling framework was developed with support from these grants.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "This Retraction follows an Expression of Concern relating to this article previously published by Portland Press.Bioscience Reports at the request of the Editor-in-Chief and the Editorial Board following receipt of a notification from a reader, alerting the Editorial Board to image duplications between Figures 1E and 1F in the Bioscience Reports article, and Figure 4B by Liu et al. 2019 (https://doi.org/10.1016/j.dld.2018.08.021).This article is being retracted from Bioscience Reports paper was also flagged in Labb\u00e9 et al. 2019  due to incorrectly listed sequence codes. The Editorial Office approached the authors for a response to this concern and did not receive a response.The The authors have been contacted with regards to the retraction, and have not responded to the Journal's queries and the concerns raised. Given the extent of the issues raised, the Editorial Board stand by the decision to retract the article."}
+{"text": "In the original published version of this article, Md. Abdul Halim was not included as a co-author. This has now been corrected, with Md. Abdul Halim added as the first co-author. The corrected version of the Author Contribution Statement can be found below. The authors apologize for the errors. Both the HTML and PDF versions of the article have been updated to correct the errors.Author contribution statement:Md. Abdul Halim, Md. Mominur Rahman: Conceived and designed the experiments; Performed the experiments; Analyzed and interpreted the data; Contributed reagents, materials, analysis tools or data; Wrote the paper.Declaration of interest's statement:The authors declare no conflict of interest."}
+{"text": "Bioscience Reports at the request of the Editor-in-Chief and the Editorial Board following receipt of a notification from a reader, alerting the Editorial Board to duplications that appear in the article and between papers from unrelated authors. Specifically, the mouse tumour images from Figure 3A seem to appear as those in Figure 7A of Zhao et al. 2018 (doi: 10.1111/jcmm.13688) and in Figure 7A of Xue et al. 2018 (doi: 10.1111/jcmm.13604). The Editorial Office also identified a duplication between the Figure 5B BGC-823/NC and BGC-823/mimics+linc00152 images. The authors have been contacted with regards to the retraction and have not responded to the Journal's queries or the concerns raised. Given the extent of the issues raised, the Editorial Board stand by the decision to retract the article.This Retraction follows an Expression of Concern relating to this article previously published by Portland Press. This article is being retracted from"}
+{"text": "Posterior fossa high-grade arteriovenous malformations (AVMs) are challenging diseases. This video presents the treatment of a patient with a diffuse, high-flow AVM of the posterior fossa on the tonsil and cerebellopontine angle (4 cm in diameter) and deep draining veins. The patient had an intraventricular and cerebellar hemorrhage. After conservative treatment, total resection of the AVM was performed with embolization and surgery. The authors resected the nidus after the endovascular embolization, on the same day. The postoperative course was uneventful, and the patient was discharged with almost full recovery.https://youtu.be/logCCn3uKUcThe video can be found here:  Therefore, the treatment for posterior fossa AVM is recommended only for hemorrhage cases. However, most posterior fossa AVMs are associated with an increased hemorrhage rate.Posterior fossa high-grade arteriovenous malformations (AVMs) are challenging diseases.This video presents the treatment of a patient with a posterior fossa AVM on the tonsil and cerebellopontine angle, 4 cm in diameter , and deep draining veins. This AVM was Spetzler-Martin grade III and located on the tonsil and cerebellopontine angle.The patient had intraventricular and cerebellar hemorrhage. After conservative treatment, total resection of the AVM was performed with embolization and surgical resection. We resected the nidus on the same day after the endovascular embolization. Postoperative course was uneventful, and he was discharged almost fully recovered.0:21 Introduction. This video describes the surgical treatment of a large, high-flow, and diffuse AVM of the posterior fossa.0:31 Clinical History. The patient was a 37-year-old male. He presented with a loss of consciousness, headache, and dizziness. Neurological examination revealed ataxia. He was found to have intraventricular and cerebellar hemorrhage. After conservative treatment and observation, he was transferred to our institution.0:53 Preoperative Imaging. Computed tomography (CT) demonstrated left cerebellar and intraventricular hemorrhage. Magnetic resonance imaging (MRI) demonstrated the AVM at the tonsil and cerebellopontine angle. The nidus measured 4 cm in diameter.Supplemental Fig. 1).Angiography of the left vertebral artery (VA) demonstrated a large, high-flow, and diffuse AVM of the posterior fossa. 3D digital subtraction angiography demonstrated that the nidus was fed from the left anterior inferior cerebellar artery (AICA), left posterior inferior cerebellar artery (PICA), and several feeders around the occipital sinus. The deep draining veins enter the bilateral superior petrosal sinus (SPS), and the superficial draining veins enter the occipital sinus (In terms of the Spetzler-Martin grade, this AVM was grade III and located on the tonsil and cerebellopontine angle.1:48 Feeding Arteries and Draining Veins of the AVM. There are three major groups of arterial feeding arteries supplying the AVM: one group from the AICA, the second group from the PICA, and many feeders around the occipital sinus. All feeders are intradural feeding arteries. The AVM has three draining veins. Deep draining veins align to the bilateral SPS, and the superficial draining vein terminates to the occipital sinus.2:16 Operative Procedure. Preoperative embolization is useful to reduce the flow of the AVM. In this procedure, the AICA and PICA were embolized using endovascular treatment with Onyx. It is hard to identify the AICA on the operative field because it is derived from the ventral side of the nidus. After obliteration of the AICA and PICA, the AVM was operated on in the operating room on the same day.At first, the main feeder of the PICA was identified and the feeders around the superior surface of the nidus and the occipital sinus were dissected. Then, from the suboccipital surface to the petrosal surface was dissected. The drainer to the left SPS was identified. The main feeders of the AICA and PICA were separated. After all feeders were separated, the drainers were dissected and separated, and thereafter the nidus was removed.3:13 Endovascular Treatment. The patient underwent multiple embolization procedures in which the AICA and PICA were embolized before surgical resection. Onyx was injected through the microcatheter. The angiogram before surgery revealed continued slowing and thrombosis of the nidus.3:38 Positioning, Skin Incision, and Craniotomy. The patient was put in the park-bench position. The head was slightly turned with the contralateral side downward. A hockey-stick incision was made. The craniotomy was extended to the condylar fossa. The foramen magnum was opened and C1 laminectomy was carried out.3:57 Operative Video. The resection of the AVM was performed by the left transcondylar fossa approach on the same day of the endovascular treatment 35 days after the onset. The posterior fossa AVM resection is recommended 4\u20136 weeks after the onset due to mass effect.4:00 Pial and parenchymal dissection was carefully undertaken around the superior surface of the nidus.4:12 The main feeder of the PICA was identified.4:18 The feeders around the main draining vein to the occipital sinus and the superior surface of the nidus were individually dissected, coagulated, and separated. The arachnoid and pial dissection was carefully performed.4:46 The deepest part of the nidus was the hematoma cavity. We can see the hematoma cavity. The bleeding artery was coagulated and Surgicel cotton balls were used for hemostasis.5:01 The medial side of the main draining vein was dissected. A Weck clip was used when necessary to occlude and separate the feeders.5:15 The area from the occipital surface to the petrosal surface was also dissected. We can see the vertebral artery. The arachnoid around the lower cranial nerves was dissected, and the draining vein going to the SPS was exposed. We used the operative view from the transcondylar fossa to identify the vertebral artery and dissect the arachnoid around the lower cranial nerves.5:35 After separating the feeding arteries, the PICA was exposed and clipped. ICG angiography was used to ascertain blood flow. Having checked the flow of the AVM, the PICA was clipped, coagulated, and separated.5:58 Feeding arteries were separated on the ventral side of the nidus. We can see the AICA. The AICA was embolized by cast Onyx. The intravascular Onyx was then dissected.6:17 The draining vein going to SPS was separated, and the last feeder was separated.6:27 After the complete occlusion of all arteries, the nidus was movable. The draining vein going to the occipital sinus was separated.6:39 The AVM was totally resected.6:50 Postoperative Course. The postoperative course was uneventful. The patient experienced no other neurological deficit. He was discharged 3 weeks after surgery.6:58 Postoperative Imaging. Postoperative MRI demonstrated a minor cerebellar contusion but no cerebral ischemia. Postoperative angiography demonstrated total removal of the AVM and preservation of the passing artery.7:17 Patient Walking on Postoperative Day 10. The patient was able to move independently without any assistance. He could walk smoothly and returned to normal life.Primary surgeon: Torihashi. Assistant surgeon: Ogura, Kadowaki, Sakamoto, Kurosaki. Editing and drafting the video and abstract: Torihashi. Reviewed submitted version of the work: Torihashi. Approved the final version of the work on behalf of all authors: Torihashi. Supervision: Kurosaki. Endovascular surgeon: Sakamoto, Kadowaki.Supplemental Fig. 1"}
+{"text": "Article no. 898, 2021; DOI: 10.3892/etm.2021.10330Exp Ther Med 22:Subsequently to the publication of the above article, an interested reader drew to the authors\u2019 attention that an error was made during the compilation of The authors have re-examined their raw data and identified the data that should have been included in the figure. The corrected version of"}
+{"text": "NCBI's Sequence Read Archive BioProject associated with this work is PRJNA543399. The Data Availability Statement should read:There is an error in the Data Availability Statement. The correct number for PRJNA484227 and PRJNA543399. All raw counts and translation events used in this study are available as Supporting Information. RP-BP is publicly available at https://github.com/dieterich-lab/rp-bp under the MIT License. The code for generating co-expression networks is available as Supplementary Information.The data generated for this study have been deposited in NCBI's Sequence Read Archive through the BioProject accession numbers The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "Following publication of the original article (Wang et al. AcknowledgementsThe authors would like to thank Dr. Kevin J. Tracey, Dr. Ravi Sitapara and Ms. LeeAnne Daley for the insightful discussion, Dr. Sarah Oelsner for critical reading of the manuscript, and Dr. Douglas David Thomas for contributing to the concept and the protocol on the involvement of NO in this project and for providing numerous feedback on the presentation of this manuscript. A portion of the publication fee was defrayed by Chimerix Inc.The original article has been corrected."}
+{"text": "Dr Andreas Karas presents the key clinical data for this new antibiotic for MDR Gram-negative infections, followed by reflections from Professor Jonathan Edgeworth on the potential use of the new agent in UK clinical practice. Included in the latter is a case study example of a compassionate use case using cefiderocol.  This article is part of a promotional Supplement developed and sponsored by Shionogi B.V. The accompanying video formed part of an educational webinar for which the author received a speaking honorarium. The material underwent peer review by the Supplement Editors. Editorial assistance to Shionogi Europe was provided by Page Medical. J.E. received personal fees for the preparation of this article.JAC-AMR Online.The video transcript is available as dlab053_Supplementary_DataClick here for additional data file."}
+{"text": "In the original article, there were errors. The authors made typographical errors.Page 3, Statistical Analyses/Voxel-Level Analysis:In the third and fourth lines, both SMA should be replaced by AG.The authors apologize for these errors and state that these do not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "De la Rosa and John Wiley & Sons Ltd. The retraction has been agreed following several concerns brought to the journal\u2019s attention relating to duplicated elements between some of the figures in this article and those in an article published in FEBS Letters https://doi.org/10.1016/j.febslet.2014.11.031, but these two articles have different corresponding authors.In addition, the same email address for correspondence was provided for the above article and for The paper has been retracted on the basis of the above duplications."}
+{"text": "Health research and knowledge translation for achieving the sustainable development goals: tackling the hurdleshttps://doi.org/10.1093/eurpub/ckaa032), published on 23 March 2020.This is a correction notice for article ckaa032 (doi.org/10.1093/eurpub/ckaa032). The Publisher apologizes for this error.Some final author corrections to the publisher\u2019s proof had not been implemented. The changes in wording are of stylistic nature and do not affect the content of the article. The corrected version of the paper is now available here ("}
+{"text": "Following publication of the original article , the autAmanda Y. Wang is funded by RACP Jacquot Research Establishment Award, Australia.The original article  has been"}
+{"text": "These have been corrected and appear below. The Publisher apologizes for the errors. Author Vera Ripoll\u2019s middle initial M has also been added.Funding: This work was carried out at a centre supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. BTS was supported by the Spanish Foundation of Rheumatology (FER). CW and VR were supported by LUPUS UK. CW is supported by Versus Arthritis Clinical Research Fellowship 21992. VR is supported by the Louise Gergel Fellowship. TM was supported by MRC grant MR/P017371/1.Acknowledgements: We thank Rekha Lopez for assistance with collecting damage data.Disclosure statement: The authors have declared no conflicts of interest."}
+{"text": "Int J Obes 10.1038/s41366-021-01025-8Correction to: The original version of this article unfortunately contained a mistake. The following statement was missing in the article: Disclaimer Statement: The content is solely the responsibility of the authors and does not represent the official views of the NIH or federal government.AcknowledgementsThe workshop entitled \u201cNeuroimaging and Modulation in Obesity and Diabetes Research 10th Anniversary Meeting\u201d, that served as an important foundation for this review article, was supported by the NIDDK of the NIH. We would like to thank the authors for their service on the workshop planning committee. BC, ML, and LES were lead authors. All other listed authors contributed equally to the workshop report. All listed speakers contributed to authorship for their section of the report.The authors apologize for the mistake. The original article has been corrected."}
+{"text": "Due to a processing error, this article was initially published including the wrong Abstract. The correct Abstract is shown below, and the original article has been corrected.http://www.fusfoundation.org.The Focused Ultrasound Foundation was created to improve the lives of millions of people worldwide by accelerating the development of this noninvasive technology. The Foundation works to clear the path to global adoption by organizing and funding research, fostering collaboration, and building awareness among patients and professionals. Since its establishment in 2006, the Foundation has become the largest nongovernmental source of funding for focused ultrasound research. For more information, visit"}
+{"text": "Saccharomyces cerevisiae, it is highly conserved throughout the ascomycetes. The work described here touches on many aspects of the process including control of entry, formation and dissolution of the limiting membrane, and construction and function of the spore wall in a variety of ascomycetes.I wish to thank all of the authors who contributed papers to this Special Issue on the Formation and Function of Ascospores. While the process of ascospore formation is most extensively studied in Ashbya gossypii. Wendland provides a timely review of spore formation in A. gossypii, highlighting similarities and the differences with S. cerevisiae [A. gossypii and Aspergillus flavus, respectively [Ascospore formation is usually linked to meiosis. However, it is not clear if this is the case in revisiae . The envectively ,3.Schizosaccharomyces pombe cells undergo \u2018virtual nuclear envelope breakdown\u2019 (vNEBD) in Meiosis II, in which nuclear proteins equilibrate into the cytoplasm [S. pombe name for the prospore membrane) and spore formation [S. cerevisiae, Durant et al. demonstrate that the transient localization of the MAP kinase Smk1 to the lip of the prospore membrane is required for proper membrane closure and spore morphogenesis [S. pombe [Earlier work has shown that ytoplasm . Yang etormation . In S. cogenesis . Captureogenesis . Zhang eS. pombe .S. pombe spore wall [S. cerevisiae contains an outer layer consisting of a polymer of the di-amino acid dityrosine. Basiony et al. characterize the product of the Dit1 enzyme, responsible for the first step in dityrosine synthesis [S. cerevisiae is composed of chitosan and a third, uncharacterized component [Cryptococcus neoformans [Talaromyces macrosporus are highly stress resistant and will not germinate unless first exposed to extremes of heat or pressure. Dijksterhuis et al. identify a small protein that is released from the spore wall under germination conditions and characterize the phenotype of spores lacking this key spore wall component [The spore wall is the defining feature of the ascospore, and four studies added to our understanding of the organization of this remarkable extracellular matrix. Tahara et al. have used a quick-freeze deep etch electron microscopy technique to reveal the architecture of the surface layers of the ore wall . The spoynthesis . In addiomponent . Chrissioformans . The ascomponent .The papers of this Special Issue highlight the fascinating cell biology of this highly conserved developmental process. My thanks again to all of the contributors."}
+{"text": "In the original article, there was a mistake in Figure 8 as published. The picture of His-TF-RcMEP2 at 60 min was confused by L.J.P. because the sample container marker was blurred . Thus, FThe correction does not change the scientific conclusions of the article in any way. The authors apologize for any confusion this error may have caused to the readers."}
+{"text": "Materials and Methods section, subsection Step 2: Model Selection and Supervised Training of the Classifier Algorithm. The correct formulas are provided below.Due to a production error, two formulas were incorrectly published in the The publisher apologizes for this mistake. The original article has been updated."}
+{"text": "In the original publication, the given name and surname of the author Blal Adem Esmail was swapped in one of the references and hence incorrectly cited as Blal and Geneletti (2017) in the article.The correct reference is provided below.Environmental Impact Assessment Review 62: 1\u201313.Adem Esmail, B., and D. Geneletti. 2017. Design and impact assessment of watershed investments: An approach based on ecosystem services and boundary work. The original article has been corrected."}
+{"text": "The British Journal of Social Work (2020). https://doi.org/10.1093/bjsw/bcab099Some minor updates have been made to this paper to improve clarity and readability. No factual academic content has been changed. The publisher apologises for the errors in the previous version"}
+{"text": "Translational Psychiatry 10.1038/s41398-021-01482-9, published online 26 June 2021Correction to: The original version of this article unfortunately contained a mistake. Due to a typesetting error, the following funding information was omitted: This work was supported in part by the Swiss National Research Foundation . The funding sources had no role in the writing of the manuscript or in the decision to submit it for publication. We apologize for the error. The original article has been corrected."}
+{"text": "RSC Advances article due to concerns with the reliability of the data.The Royal Society of Chemistry hereby wholly retracts this 1The images in the article were screened by an image integrity expert. Images published in Fig. 4 of the article have also been published in another article by a different set of authors.Furthermore, the left and right panels in Fig. 4A show duplicated images. In addition, the left and right panels in Fig. 4B are also identical.The authors were unable to provide raw data for any of the images published in Fig. 4.Given the significance of the concerns about the validity of the data, the findings presented in this paper are not reliable.The authors do not agree with the retraction.RSC AdvancesSigned: Laura Fisher, Executive Editor, th January 2021Date: 19"}
+{"text": "Tasserkidriluscf.americanus found in a channel near the Te\u0161mak swamp in Slovakia  and to compare its morphological features and habitat requirements with those of populations occurring in North America and Europe. The new specimens are similar to those found in The Netherlands and Belgium, but dissimilar to previously reported North American material of T.americanus, reopening the question of whether the European form is a separate species. The European form has the penis sheaths approximately twice as long as and wider than the North American form and may inhabit slow-flowing or standing waters of a eutrophic character, which is in conflict with the current knowledge on the morphology and ecology of North American populations. Further investigation is necessary to solve the questions about the origin and taxonomic relationship of the European population to other populations.The main objective of this study is to present a new record of  Tasserkidrilus Holmquist, 1985 includes 14 freshwater species, all in the Holarctic Region  and T.kessleri , which have a more scattered distributional pattern, occurring in several countries in both Eurasia and North America.At present, the genus Tasserkidrilus is Tubifexkessleri, which was described by Tasserkidrilus, which was later accepted as the correct genus assignment for many species previously classified in Tubifex . The information provided by Aulodrilusamericanus Brinkhurst & Cook, 1966 as the type species of Tasserkidrilus, is incorrect.T.americanus date back to studies carried out more than 30 years ago  have a longer upper tooth and several are equipped with an intermediate tooth, which can sometimes be doubled   Fig. d. All chT.cf.americanus in streams have been documented from Belgium and The Netherlands  from the Estuary of the Elbe River (Germany), described by T.americanus, based on the length and shape of the penis sheaths , as stated by T.americanus, since it is a medium-sized river inappropriate for navigation and the species has not been documented there at all. Based on those arguments, the presence of T.cf.americanus in Slovakia remains inexplicable and requires further investigation.Another question that arises from the occurrence of DCE863AD-2455-5EAC-87E6-CC3BF7BCDE0D10.3897/BDJ.9.e72846.suppl1Supplementary material 1T.cf.americanus occurrence in SlovakiaData associated to Data typeoccurrencesBrief descriptionTasserkidriluscf.americanus in SlovakiaExcel table filled with required and recommended DwC data linked with the occurrence of File: oo_570563.xlsxhttps://binary.pensoft.net/file/570563Igor Kokavec"}
+{"text": "The lecture will be given by the 2020 Baltes Award recipient, William Chopik, PhD, of Michigan State University. The recipient of the 2021 Baltes Award is Laura B. Zahodne, PhD, of the University of Michigan. The Margret M. and Paul B. Baltes Foundation Award in Behavioral and Social Gerontology recognizes outstanding early-career contributions in behavioral and social gerontology. The award is generously funded by the Margret M. and Paul B. Baltes Foundation."}
+{"text": "Dr. Jones will discuss the work of the NIA Office of Special Populations. Dr. Jones will also be available for small group discussion."}
+{"text": "Article no. 261, 2020; DOI: 10.3892/etm.2020.9391Exp Ther Med 20:Following the publication of the above article, the authors have realized that they inadvertently included data derived from the same original source for the invasion and migration assay Vector control experiments shown for the HCT116 cells in Experimental and Therapeutic Medicine for allowing them the opportunity to publish this. They also apologize to the readership for any inconvenience caused.The corrected version of"}
+{"text": "Some offunction . Howeverfunction . On the function . All of function . Reducinfunction . Iran, l This research was approved by the Ethics Committee of Hormozgan University of Medical Sciences (IR.HUMS.REC.1399.030). Hereby, we highly appreciate the cooperation of the personnel of Mother and Child Welfare Research Center and Hormozgan University of Medical Sciences The authors declare that they have no conflict of interest."}
+{"text": "S-Curve Adoption Tool for EVs to forecast the future proportion of electric vehicles in these Counties. Two data tables are presented: the reformatted historic data and the data from the S-curve analysis. Data is also presented for the collective UK.Regional data from the UK Government's Department for Transport has been analyzed to produce a forecasted dataset of the uptake of electric vehicles (EVs) within Counties of England to the first quarter of the year 2100 using an S-curve methodology. This data includes all vehicles, not just cars. The historic proportion of electric vehicles in the fleets of these regions is calculated using data from 2011 Q4 to 2021 Q1. This data is then analyzed using SCATE, the  This includes the total number of vehicles, the number of EVs, and the calculated historic percent of vehicles which are battery electric for each quarter (between 2011 Q4 and 2021 Q1) in each County.Percent_cumulative_EVs_S_curve_2021_Q1.xlsx is the simulated S-curve data, i.e. the original data presented. This shows the forecast S-curve data based on the historic data for each County in England up to 2100 Q1.Files relevant for running the analysis tool SCATE:main.py is the primary code file to be run in python. This is where the files containing the primary data and look-up tables described below are defined and the analysis period for SCATE is set. This file then calls on other sub-modules to re-structure the primary data and to perform the S-curve analysis.dataextract.py is a sub-module to main.py. This module extracts data from the primary data sources and uses the look-up tables to group the historic data by County.analyzer.py is a sub-module to main.py. When this module Is called, the S-curve analysis is conducted, to assess future adoption of EVs in each County.analyservaribales.py is a sub-module to main.py. This file defines variables necessary for analyzer.py to run.LA2County.xlsx is the look-up table used to convert the primary data that is grouped by Local Authority to instead be grouped by County, derived from Office for National Statistics data CountyDistricts.xlsx is the look-up table used to convert the primary data that is grouped by Postcode District to instead be grouped by County, derived from data available on doogal veh0132.xlsx (May 2021) and veh0122.xlsx (May 2021) which are included and can also be downloaded from the UK Government's Department for Transport website To run SCATE 2S-Curve Adoption Tool for EVs and is available on GitHub at: https://github.com/EPGOxford/SCATE.The primary data files from the UK Government's Department for Transport were processed using the python analysis tool named SCATE, developed by the authors. SCATE is the The primary data files were veh0122.xlsx (May 2021), the total number of licensed vehicles at the end of the quarter, and veh0132.xlsx (May 2021), the total number of battery EVs licenced at the end of each quarter. The data in the files is aggregated in two different ways: by Postcode District and Office of National Statistics Local Authority Code, respectively. In order to regroup the data into County categories, the look-up tables CountyDistricts.xlsx and LA2County.xlsx were used as keys to group Postcode Districts and Local Authorities by County. The number of EVs in each County is then divided by the total number of vehicles in that same County to give the percentage of EVs. Where a postcode spans two Counties, the total number of registered vehicles within that postcode are assigned to both counties. This ensures that when data for each County is assessed, the proportion of EVs will be an underestimate. However, it means that this data cannot be summed to represent England and users should be aware. Thus, the historic proportion of EVs in a County were calculated.Once the historic proportion of EVs in a County had been calculated, this data was used as an input for S-curve analysis, conducted in python. The following equation was used:S-curve analysis was considered appropriate as it is the uptake pattern often seen for emerging technologies, as was the case for the initial adoption of the internal combustion engine vehicle.The acquisition of this data conformed to Elsevier's ethics in publishing.Katherine A. Collett: Methodology, Software, Investigation, Validation, Writing \u2013 original draft, Writing \u2013 review & editing. Sivapriya M. Bhagavathy: Conceptualization, Methodology, Software, Funding acquisition. Malcolm D. McCulloch: Conceptualization, Supervision, Funding acquisition.The authors declare that they have no known competing financial interests or personal relationships which have or could be perceived to have influenced the work reported in this article."}
+{"text": "Streptococcus mutans  and Enterococcus faecalis  from human saliva with the engagement of high school students in scientific research.The microbiome of the human oral cavity is composed of numerous and diverse bacteria, archaea, eukarya and viruses . BacteriSaliva samples were collected from 61 healthy donors, undergraduate students from Valsassina College, Lisbon, Portugal. All samples were examined for the presence of phages using the agar overlay method. The study was approved by the Egas Moniz Ethics Committee  and written informed consent was obtained from all subjects.E. faecalis, uniform turbid lysis zones were generated by saliva samples collected from 6 of 61 individuals (9.8%). No plaques for S. mutans were evident after direct plating of the material.Three to five days after inoculation with E. faecalis, but not S. mutans bacteriophages. Our data is similar in prevalence to previous studies who also attempted to isolate lytic bacteriophage from oral E. faecalis [E. faecalis phages in the saliva of healthy individuals suggests that they may play a role in the control of this bacterium in the oral cavity.It was possible to isolate faecalis . The pre"}
+{"text": "The original version of this article, published on July 6, 2021, contained a mistakes.The affiliation of Dr. Laudi was assigned incorrectly. The correct information is given below.The title and subtitle of the article were displayed incorrectly. The correct information is given above.The original article has been corrected."}
+{"text": "Salmonella spp. and some helminth coinfections. In this study, S. typhimurium and Ascaridia galli coinfections were analyzed, and the consequences on therapy were proposed. In a first experiment where the effect of the bacteria on the nematode was evaluated, thirty 42-day-old broiler chickens were divided into 3 groups and coinfected with both parasites. The rate of A. galli egg inoculum was kept constant at 500/ml while that of S. typhimurium varied as follows: T0 , T104 , and T106 . EPG and parasitic load were measured using the McMaster technic, and number of worms and their length were also measured. We observed that T106 containing 106 CFUs of Salmonella significantly reduced the EPG values, and this group recorded the lowest worm load ranging from 18 to 21 worms. Likewise, the length of the worms obtained with T104 and T106 appeared to be shorter than those of the control (T0). In a second experiment to assess the effects of the nematode on the bacteria, thirty 42-day-old broiler chickens were divided into 3 groups and coinfected with both parasites. The rate of S. typhimurium inoculum was kept constant at 106 CFUs while that of A. galli varied as follows: T0 (106CFUs), T500 , and T750 . Bacterial load was measured using Voogt technique. We observed that T500 increased the colonization time and prolonged the duration of S. typhimurium secretion. Salmonella appears to be a hyperparasite considering the deleterious effect on A. galli. Due to this, it may be prudent to combine anti-Salmonella treatment with anthelmintic so as to effectively treat pathologies caused by these two pathogens.Previous studies have reported interactions between  Strongyloides can drag Escherichia coli during their migration from the intestine to other organs of the host. Other nematodes such as Trichinella spiralis and A. galli have been identified as direct vectors for Salmonella transmission  dem demStronia galli . In thisathogens . This stathogens .S. typhimurium) and the helminth . These studies focused not only on the pathogenic effects on the host but also the consequences in terms of therapy  coxcretion , 31 The vaccines .Salmonella typhimurium has deleterious effects on A. galli by reducing the nematode length and load in broiler chickens. This is in agreement with other studies that demonstrated that Salmonella interacts with gastrointestinal nematodes when they live together in a common environment. Moreover, the effects of this interaction between S. typhimurium and A. galli have been shown to be harmful both for the A. galli. This is manifested in the reduction in pathogenicity of A. galli. In view of these bacteria, deleterious effect on A. galli and Salmonella appears to be a hyperparasite. It would be wise to recommend the association of anti-Salmonella treatment with anthelmintic for the treatment of pathologies caused by these two pathogens. This needs to be considered in the future to augment other control strategies in poultry."}
+{"text": "Here we report a fatal and uncommon case of esophageal variceal bleeding secondary to the presence of a Tapeworm in the upper digestive tract in a patient coming back from North Africa. A 54 year-old man with a history of liver cirrhosis (Child-Pugh B8) was admitted to the intensive care unit for hemorrhagic shock due to hematemesis. The patient promptly received intravenous colloid fluids and red blood cell transfusions. Due to hemodynamic instability, immediate gastroduodenal endoscopy was performed. Acute esophageal variceal bleeding was observed. Surprisingly, we identified a segmented tapeworm extending from the esophagus through the cardia to the duodenum  as well The authors report no declarations of interest.Authors have no funding sources.\"Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request\u201d.E.F and M.D. were physicians in charge of patient.E.F. wrote the manuscript.E.F. and M.D. reviewed manuscript.Consent to publish was obtained from the patient\u2019s relative."}
+{"text": "The original version of this article, published on May 12, 2021, contained a mistake.The columns of the graphical abstract were incorrect. The correct information is given below.The original article has been corrected."}
+{"text": "The authors have requested that the following changes be made to their paper .M. longifolia. The updated \u201cAuthor Contributions\u201d and \u201cFunding\u201d are provided below.The original authors wish to add Dr. Kelly J. Vining and Dr. Bernd Markus Lange as coauthors of this paper. The author contributions were: K.J.V. and B.M.L. contributed to this paper by providing the genome data of We would like to apologize for any inconvenience caused to the authors and readers by this mistake. The published version will be updated on the article webpage, with a reference to this notice."}
+{"text": "The lecture will be given by the 2020 recipient, Sara Czaja, PhD, FGSA of Weill Cornell Medicine. The 2021 M. Powell Lawton Award recipient is David Roth, Phd, FGSA, of Johns Hopkins University. The M. Powell Lawton Award is presented annually to an individual who has made outstanding contributions from applied research that has benefited older people and their care. The Lawton Award is generously funded by the Polisher Research Institute of Abramson Senior Care."}
+{"text": "Carlos Contreras was not included as an author in the published article [ article . The corThe contributions as an author were Investigation and Resources.cjcontreras@ucam.edu.The affiliation is Innova, Health and Sport Institute, 30100 Murcia, Spain, and e-mail is The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. The original article has been updated."}
+{"text": "A new Supplementary Information file has been uplodaded with the correct information.In the Supplementary Information for this article, the equations e, i and j in section IV. Ionic flows and currents were incorrect. The descriptions of Supplementary Information"}
+{"text": "Dr. Nielsen will discuss research priorities for the Division of Behavioral and Social Research. Dr. Nielsen will also be available for small group discussion."}
+{"text": "The data DOI in this article  is incorhttps://doi.org/10.5518/945.Data supporting this work can be accessed via the University of Leeds repository: This change does not affect the results, discussion and conclusions presented in the article. The published article has been updated."}
+{"text": "This approach allows us to share our observations with stakeholders and participants, enabling us to protect the culture of mass gathering events, minimize the risk of infection and restore a sense of well-being in daily life.During the COVID-19 pandemic, it has been important to both minimize the risk of infection and restore daily life. As a typical example, mass gathering events, such as sporting events, are gradually becoming more common, thanks to the measures taken to contain COVID-19. Some pilot studies have been launched at governments\u2019 initiative to investigate the risk of infection without measures such as face masks and physical distancing at mass gathering events, but the ethics of these studies should be carefully considered. On the other hand, it is still beneficial to implement infection control measures at mass gathering events and, in parallel, to estimate the risk of infection with measures in place, especially under a lack of vaccination progress or the spread of mutant strains possibly resistant to vaccines. To help improve compliance with measures taken by spectators and organizers and to ensure their effectiveness, we have conducted quantitative evaluations of the implementation of such measures by monitoring CO Various measures were taken to stop the spread of COVID-19, including lockdowns, but daily life must be gradually restored while continuing to minimize the risk of infection.Mass gathering events, such as sporting events, are an opportunity to restore a sense of normalcy. While mass gathering events are a pathway of infection, they are also essential for bringing joy into daily life. Mass gathering events, which were restricted during the pandemic, are gradually becoming more common, thanks to the measures taken to contain COVID-19. In the UK, the Events Research Programme was launched at the government\u2019s initiative with the progress of the vaccination programme.It is still important and beneficial to implement infection control measures at mass gathering events and, in parallel, to estimate the risk of infection with these measures in place and to follow up on the subsequent infection situation, especially given a lack of progress in vaccination and the spread of mutant strains possibly resistant to vaccines. The infection routes of COVID-19 include droplet transmission (direct exposure to the virus in the vicinity of infectors), airborne transmission  and contact transmission . It has been estimated by quantitative microbial risk assessment that the implementation of measures according to the route of infection, such as physical distancing and wearing of face masks for droplet transmission, ventilation for airborne transmission and decontamination and hand washing for contact transmission, is useful for controlling the risk of infection at mass gathering events.2 concentrations, assessing the proportion of people wearing face masks and analysing human flows at professional events, such as sports games, leading to the improvement of the measures.,2 measurements can be used to monitor human crowding and ventilation (2 concentrations were observed when people gathered in restrooms during a break in events; in subsequent events, real-time CO2 observation was implemented in several stadiums to reduce human crowding. The proportion of people wearing face masks can be estimated without collecting personal information by analysing video footage with artificial intelligence (We have conducted quantitative evaluations of the implementation of these measures by monitoring COtilation . In praclligence . The avelligence .Sharing these observations and the effects of public health measures with participants will be essential to controlling the risk of COVID-19 and preserving the culture of mass gathering events. For example, real-time feedback on the proportion of people wearing face masks can be expected to help participants maintain high adherence, hopefully without any psychological burden and with enjoyment. The culture of mass gathering events is fostered not only by athletes, artists and their associates but also by fans. Understanding and mitigating the health risks of mass gathering events will protect the culture, minimize the risk of infection and restore a sense of well-being in daily life.No external financial support is used for this article.Conflict of interest. This research project comprises other members from two private companies, Kao Corporation and NVIDIA Corporation, Japan. K.F. is affiliated with Kao Corporation. W.N. received financial support from the Kao Corporation until March 2020 in context outside the submitted work. T.Y., M.O., W.N., N.S. and T.O. have received financial support from the Kao Corporation for a collaborative research project in the context of measures at mass gathering events. T.Y., M.O., W.N. and N.S. have received financial support from Yomiuri Giants, Japan Professional Football League and Japan Professional Basketball League. M.M., T.Y., M.O., N.S., W.N. and S.I. attend the new coronavirus countermeasures liaison council jointly established by the Nippon Professional Baseball Organization and Japan Professional Football League as experts without any rewards. T.Y., M.O., W.N., N.S. and K.F. are advisors to the Japan National Stadium. Other authors declare no competing interests. The findings and conclusions of this article are solely the responsibility of the authors and do not represent the official views of any institution."}
+{"text": "Scoliidae occur predominantly in tropical and subtropical regions and are ectoparasitoids of Scarabaeoidea larvae  which are immobilised, parasitised by the female wasp in their terrestrial larval gallery and buried deeper in a special cell by the female wasp. Herein, we provided, for the first time, illustrated keys to 11 genera and 52 species of Scoliidae from China, based on specimens in the Naturalis Biodiversity Center  and additional specimens from the Chinese Academy of Insect Science (Beijing), Zhejiang University  and Sun Yat-sen University  and it is a first attempt to make keys available for all the Scoliidae species in China.The  Hymenoptera, Scoliidae) form a medium-sized family with approx. 560 species worldwide and occur predominantly in tropical and subtropical regions  subspecies and varieties. The systematics is in a state of confusion, which is well summarised by Scoliinae. For the present key, we examined Chinese specimens of four major collections: Naturalis Biodiversity Center , Chinese Academy of Insect science , Zhejiang University  and Sun Yat-sen University . In this paper, we provide illustrated keys for all taxa of Scoliidae from China for the first time. This paper is part of an on-going project on the revision of the Chinese Scoliidae.Scoliid wasps , Chinese Academy of Insect Science (IOZ), Zhejiang University (ZJUH) and Sun Yat-sen University (SYSU).This work is based on specimens in the collections of the Naturalis Biodiversity Center . Detailed images of specimens were taken and processed using a digital camera Zeiss Stereo Discovery V12 and with the software Axiovision SE64 Rel.49.1. Habitus images were taken with a Nikon D600 camera coupled with a Nikon 60 mm Macro lens and processed with the software Combine ZM. All images were further processed using Adobe Photoshop CS5. Morphological terms for body structures and measurements followed Betrem et al. (1972). Wing venation nomenclature followed a modified version of the Comstock-Needham  and BetrThe genitalia were removed, cleaned and pinned under the specimen in a genitalia tube as described by Notes. Only the male holotype of Campsomeriellailanensis from Taiwan is known. According to the description and drawings by C.ilanensis is very similar to C. (C.) collarisquadrifasciata  and it could be a synonym of the latter.Notes. Males of this genus are difficult to recognise, the key above is a practical key to the males present in the material we have studied and is just a first attempt. The male of M.farrenwhitei Betrem, 1928 is here recorded for the first time worldwide. However, males identified as M.szetschwanensis  could be the male of M.stoetzneri Betrem or another species, since the female of M.szetschwanensis and the males of M.bella , M.grossa  and M.stoetzneri  are unknown and the forma A (in C.szetschwanensis) specimen of M.szetschwanensis carries an identical collection label as the holotype female of M.stoetzneri (Schulten 2011).Notes. The name Scoliaquadripustulata Fabricius was misapplied for a long time to another species now known as Scoliabinotata Fabricius  binotata Fabricius. All reported records of S.quadripustulata from China concern S.binotata; therefore, we delete S.quadripustulata from the Chinese fauna.abricius . We chec"}
+{"text": "Healthcare for any inconvenience. Please see updated information as follows:The correct name of the fourth author is Latifah Alqasem.5 Department of Economics, Institute for Economics and Finance, 00118 Rome, Italy; luigi.guiso@tin.itAffiliation number five is corrected in this form:v_prasad@yu.edu.sa.The correct email address of Madhusudhan Varanasi is as follows: The information that needs to be added to the funding and acknowledgment sections are included below.Some details of the authors\u2019 names, affiliations, and email addresses were incorrect in the original version of the article . Additio"}
+{"text": "Dear colleagues,Anais Brasileiros de Dermatologia (ABD),http://www.consort-statement.org/consort-statement/checklist);http://prisma-statement.org/prismastatement/Checklist.aspx).https://www.strobe-statement.org/index.php?id=available-checklists).https://www.care-statement.org/checklist). Articles that do not meet the profile of those mentioned above can be viewed and are reported on the EQUATOR website (http://www.equator-network.org/).As stated in the Editorial of the previous issue of the In addition to these changes, which will certainly require the authors\u2019 qualification and commitment, there are new instructions regarding other sections and the Research Ethics Commission\u2019s protocol. As for the illustrations, special consideration is requested for the illustrations in the Dermatopathology section.http://www.anaisdedermatologia.org.br/ to get acquainted with these new guidelines.We invite the readers to access the ABD website at Finally, to make it easier for the authors, the Consent to Use in Publication and the Conflict of Interest Declaration forms have been modified, in which signatures are now restricted to a single document and are entirely presented online.Accordingly, we are on this path together, in search of increasing qualification, which will result in an increase in the Impact Factor for ABD, in line with the quality of the Ibero-Latin American Dermatology.None declared.Silvio Alencar Marques: Approval of the final version of the manuscript; preparation and writing of the manuscript.Ana Maria Roselino: Approval of the final version of the manuscript; preparation and writing of the manuscript.Hiram Larangeira de Almeida Junior: Approval of the final version of the manuscript; preparation and writing of the manuscript.Luciana P. Fernandes Abbade: Approval of the final version of the manuscript; preparation and writing of the manuscript.None declared."}
+{"text": "Unfortunately, the surname of the co-author T. R. W. Herrmann was misspelled in the original publication of the article. It is correctly spelled as Herrmann and not Hermann.The original article has been corrected."}
+{"text": "In the original article, there was an error. Dr. Gopal Pramanik was acknowledged without his agreement. As per his request, we are removing his name and contribution from the acknowledgment paragraph.Acknowledgments. The corrected paragraph is shown below.A correction has been made to the \u201cWe sincerely thank Drs. Stefan Heller and Marta Milo for help with data analysis, and Dr. Walter Marcotti for helpful discussion. We also thank Dr. Kathleen J. Millen for generously providing the Lmx1a-cre mice and Dr. Theresa Zwingman for answering the many questions we had concerning these mice . We thank Dr. Joseph P. Sarsero  for sharing Peripherin-GFP mice with us and Dr. Lin Gan  for sharing Bhlhb5-cre line.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "PLoS Biology, volume 4, issue 4: DOI: 10.1371/journal.pbio.0040095In C. symbiosum to a conserved homolog identified in the crenarchaeal soil clone (AJ627422) was misplaced. This box should be drawn from the C-terminal region of the larger open reading frame immediately upstream of the amoA subunit of C. symbiosum.There were errors in Figure 4. In (A), the shaded box connecting the hypothetical protein adjacent to the amoB subunit of N. europaea amo subunits were mislabeled and misplaced. Their orientation should be reversed such that the amoC subunit appears in opposite orientation to the far left, followed by the A subunit and then the B subunit. This results in the inversion of the shaded boxes connecting the N. europaea and C. symbiosum amo subunits with respect to the original image. The color coding of the unlinked amoC3 subunits is also incorrect. They should appear as pink colored boxes.In (B), the In the figure legend for both (A) and (B), the amoB and amoC sunbunits were inadvertently juxtaposed. The amoC subunit is represented by the pink colored box and the amoB subunit is represented by the orange colored box.The corrected Figure 4 is attached."}
+{"text": "The number of sequenced eukaryotic genomes is rapidly increasing. This means that over time it will be hard to keep supplying customised gene finders for each genome. This calls for procedures to automatically generate species-specific gene finders and to re-train them as the quantity and quality of reliable gene annotation grows.We present a procedure, Agene, that automatically generates a species-specific gene predictor from a set of reliable mRNA sequences and a genome. We apply a Hidden Markov model (HMM) that implements explicit length distribution modelling for all gene structure blocks using acyclic discrete phase type distributions. The state structure of the each HMM is generated dynamically from an array of sub-models to include only gene features represented in the training set.Acyclic discrete phase type distributions are well suited to model sequence length distributions. The performance of each individual gene predictor on each individual genome is comparable to the best of the manually optimised species-specific gene finders. It is shown that species-specific gene finders are superior to gene finders trained on other species. Ab initio HMM gene finders for eukaryotes include Genscan -AG position producing the same coding sequence. These unambiguous splice sites are found using a tailored Smith-Waterman algorithm similar to EST_GENOME  but allo elegans  and H. s sapiens . Coding  sapiens . This re sapiens  DNA leveThe final model is trained as a Class Hidden Markov model . This alFor many new genomes, not enough full-length mRNAs are available to generate a UTR annotated training set of sufficient size. In these cases the training set is supplemented with gene structures without UTR annotation. This presents a problem in training because unspecific training on un-annotated UTR sequence pollutes the signal contributed by annotated UTRs. To solve this problem two parallel UTR sub-models are introduced . For the M. musculus version the subsets 0% \u2264 42% \u2264 46% \u2264 51% \u2264 100% are used. Genscan was run locally with default settings. Augustus and GenelD where run on their respective web servers with \"forward strand only\" settings. Table To assess the performance of Agene we have tested it on a diverse set of eukaryotes. For a subset of these species-specific C. glabrata to 53% for U. maydis. To illustrate the variation of sequence signals, sequence logos [C. elegans version of Agene on a few of the other test species. The differences in performance between the C. elegans version and the versions created for each species are shown in Table The set of species listed in Table ce logos  for donoD. rerio and 700 for U. maydis to 7152 for N. crassa and 7914 for A. nidulans. The training sets are available as additional files [see Additional file U. maydis version of Agene was generated using different sized training sets. Performance as a function of training set size is shown in Figure The sizes of the training sets used range from 266 for H. sapiens and M. musculus. Our specificity for these species is comparable to that of the remaining test species but the sensitivity is lower. Though important, this category of species does not represent the type of species where automated gene finder generation is most in demand. Species such as H. sapiens and M. musculus are subject to so much attention that several high quality gene finders already exist. Our focus is on the large number of eukaryotes that do not receive the same attention. The performance of our gene finders are much higher for the genomes they are customised to than for other genomes. These results emphasise the value of a species-specific approach.For the majority of test species the performance of Agene is comparable or slightly better than the alternative gene finders we have tested. We have aimed at developing a method as flexible as possible to accommodate a large variety of genome characteristics and to work with typical sized training sets. This choice, however, does not seem to allow for an effective modelling of gene structures in species with very long introns like ab initio gene prediction methods require a training set limits their use in cases where no mRNA has been sequenced yet. The SNAP gene finder [The fact that e finder  addressee finder  uses an H. sapiens genes have at least one completely non-coding first exon [A. thaliana, D. malanogaster, and M. musculus. For this reason, Agene returns UTR predictions as an integral part of the gene predictions. This is only possible, however, if the training set used to generate the gene finder contains sufficient UTR annotation. The modelling of the UTR component of the first and last coding exons improves predictions slightly by helping to delineate the start and end of the coding region. We expected that including UTR exons in the model would improve predictions by ensuring that the model does not wrongly predict UTR exons as coding exons. We have tested to what extent this is the case (data not shown) and found the effect on performance is not significant.It has been reported that 40% of rst exon . Among tThe length modelling approach taken in this paper has proved to be an effective way to implement the powers of GHMMs. By integrating length modelling into the HMM state structure computational complexity is linear in the sequence length. This allows for full length modelling of all gene structure elements, including introns.A problem in evaluating gene predictions stems from the fact that gene finders only predict one full transcript at a time whereas the majority of genes have multiple transcripts. This may account for many of the inconsistencies in predictions. The N-best algorithm, used by Agene, is able to return a number of sub-optimally scoring paths together with the optimal one. It is likely that alternative transcripts are among these sub-optimal predictions. For genes with many alternative exon borders, however, the number of combinations of these is so large that only a subset of these are likely to be be real transcripts. In considering such suboptimal paths a post-processing step is required where the biological sensibility is evaluated.A procedure to automatically generate species-specific gene finders for novel genomes is presented. This includes generation of a training set from a set of mRNAs as well as dynamic building and training of an HMM that fits the organism gene structure and the amount annotation available in the training set. Acyclic discrete phase type distributions implemented as HMM state structure are well suited to model sequence length distributions and are very cost effective in terms of complexity. The automatically customised gene finders perform as well or better than most existing manually customised gene finders.A. gambiae. The file is in Fasta format and packed using bzip2.The sequence part of the training set for Click here for fileA. gambiae. The file is in GFF format and packed using bzip2.The annotation part of the training set for Click here for fileA. nidulans. The file is in Fasta format and packed using bzip2.The sequence part of the training set for Click here for fileA. nidulans. The file is in GFF format and packed using bzip2.The annotation part of the training set for Click here for fileA. thaliana. The file is in Fasta format and packed using bzip2.The sequence part of the training set for Click here for fileA. thaliana. The file is in GFF format and packed using bzip2.The annotation part of the training set for Click here for fileC. elegans. The file is in Fasta format and packed using bzip2.The sequence part of the training set for Click here for fileC. elegans. The file is in GFF format and packed using bzip2.The annotation part of the training set for Click here for fileC. glabrata. The file is in Fasta format and packed using bzip2.The sequence part of the training set for Click here for fileC. glabrata. The file is in GFF format and packed using bzip2.The annotation part of the training set for Click here for fileD. hansenii. The file is in Fasta format and packed using bzip2.The sequence part of the training set for Click here for fileD. hansenii. The file is in GFF format and packed using bzip2.The annotation part of the training set for Click here for fileD. melanogaster. The file is in Fasta format and packed using bzip2.The sequence part of the training set for Click here for fileD. melanogaster. The file is in GFF format and packed using bzip2.The annotation part of the training set for Click here for fileD. rerio. The file is in Fasta format and packed using bzip2.The sequence part of the training set for Click here for fileD. rerio. The file is in GFF format and packed using bzip2.The annotation part of the training set for Click here for fileH. sapiens. The file is in GFF format and packed using bzip2.The annotation part of the training set for Click here for fileH. sapiens. The file is in Fasta format and packed using bzip2.The sequence part (sub-file 1) of the training set for Click here for fileH. sapiens. The file is in Fasta format and packed using bzip2.The sequence part (sub-file 2) of the training set for Click here for fileH. sapiens. The file is in Fasta format and packed using bz2.The annotation part (sub-file 3) of the training set for Click here for fileK. lactis. The file is in Fasta format and packed using bzip2.The sequence part of the training set for Click here for fileK. lactis. The file is in GFF format and packed using bzip2.The annotation part of the training set for Click here for fileM. musculus. The file is in Fasta format and packed using bzip2.The sequence part of the training set for Click here for fileM. musculus. The file is in GFF format and packed using bzip2.The annotation part of the training set for Click here for fileN. crassa. The file is in Fasta format and packed using bzip2.The sequence part of the training set for Click here for fileN. crassa. The file is in GFF format and packed using bzip2.The annotation part of the training set for Click here for fileU. maydis. The file is in Fasta format and packed using bzip2.The sequence part of the training set for Click here for fileU. maydis. The file is in GFF format and packed using bzip2.The annotation part of the training set for Click here for file"}
+{"text": "Although the sequence requirements for translation initiation regions have been frequently analysed, usually the highly expressed genes are not treated as a separate dataset.To investigate this, we analysed the mRNA regions downstream of initiation codons in nine bacteria, three archaea and three unicellular eukaryotes, comparing the dataset of highly expressed genes to the dataset of all genes. In addition to the detailed analysis of the nucleotide and codon frequencies we compared the N-termini of highly expressed proteins to the N-termini of all proteins coded in the genome.The most conserved pattern was observed at the amino acid level: strong alanine over-representation was observed at the second amino acid position of highly expressed proteins. This pattern is well conserved in all three domains of life. Escherichia coli) E. coli aWe used two-tailed Fisher's exact test (FET) to compare observed frequencies of nucleotide, codon or amino acid in HEG dataset and all genes dataset . FET examines whether the frequencies in two datasets are different enough to reject the null hypothesis . In all figures and tables the P-values of 0.01 or less were considered significant. No correction for multiple testing was applied to any of the analyses.AT performed the data analysis. MR participated in the study's design and choice of methods. TT conceived the study and participated in its design and coordination. All authors read and approved the final manuscript.E. coli and to 80 HEG of S. cerevisiae.The list of orthologues to 80 HEG of Click here for file0: there is no difference in nucleotide frequency between all genes and HEG. . \u2191: frequency is increased in HEG compared to all genes. \u2193: frequency is decreased in HEG compared to all genes. -: no difference between HEG and all genes datasets.P-values for U, C, A and G in nucleotide positions 4\u201330. HClick here for fileJustifying the method of using orthologues.Click here for fileJustifying the selection of organism.Click here for file"}
+{"text": "Each year, March is designated National Kidney Month to raise awareness about the prevention and early detection of kidney disease. In the United States, kidney disease is the ninth leading cause of death  to document and monitor the burden of chronic kidney disease and its risk factors in the U.S. population and to track progress in chronic kidney disease prevention, detection, and management (https://www.nkdep.nih.gov and about diabetes prevention and control at https://www.cdc.gov/diabetes.In collaboration with partners, CDC supports and maintains the Chronic Kidney Disease Surveillance Project website ("}
+{"text": "In the original version of this article , publishJoseph H. GormanRobert C. Gorman IIIOriginally the author names have been published as:Joseph H. Gorman IIIRobert C. GormanThe correct author names are:The original publication of this article has been corrected. The publisher apologizes to the readers for the inconvenience caused."}
+{"text": "We also acknowledge the Fly EM Project Team technicians who assisted R.D.F in imaging the serial sections with the statement: \u201cWe thank the Fly EM Project Team for assisting R.D.F. with imaging the serial sections of the larval central nervous system with transmission electron microscopy.\u201d This has been corrected both online and in print.We regret and hereby correct the omission of Richard D. Fetter as an author, who performed sample preparation, serial sectioning and electron microscopy imaging of the whole"}
+{"text": "The Funding section is incorrect. The correct funding information is as follows: R. Bierings and J. Voorberg were supported by funding from the Dutch Thrombosis Foundation."}
+{"text": "A total of 52 schools (n = 8679 students) participated in the experimental implementation phase of the project P.A.T.H.S. . After completion of the Tier 1 Program, students were invited to respond to the Subjective Outcome Evaluation Form (Form A) to assess their views of the program, instructors, and perceived effectiveness of the program. Based on the consolidated reports submitted by the schools to the funding body, the research team aggregated the consolidated data to form a \u201creconstructed\u201d overall profile on the perceptions of the program participants. Results showed that high proportions of the respondents had positive perceptions of the program and the instructors, and roughly four-fifths of the respondents regarded the program as helpful to them. The present study provides additional support for the effectiveness of the Tier 1 Program of the P.A.T.H.S. Project in Hong Kong."}
+{"text": "Biochemia Medica 2018;28(1):010703. DOI: https://doi.org/10.11613/BM.2018.010703This is a correction of Since the publication of this article, the authors have noticed that the surname of the last author in the byline was published incorrectly. The correct byline is presented above. The authors apologize for any inconvenience caused to the readers."}
+{"text": "A total of 546 students participated in the Tier 1 Program of the P.A.T.H.S. Project responded to the Chinese Positive Youth Development Scale (CPYDS) at pretest and posttest and the Subjective Outcome Scale (SOS) at posttest. Result showed that the SOS was internally consistent. The SOS total scores were significantly related to measures of global satisfaction and the participants' degree of sharing with others, thus giving support to its construct validity. Factor analysis revealed that there were three dimensions of the scale and the related subscales were significantly correlated among themselves. Based on the significant relationships between the SOS measures of perceived program effectiveness and posttest CPYDS scores as well as changes in CPYDS scores, the present study revealed the convergence of subjective outcome evaluation findings and objective outcome evaluation findings in the P.A.T.H.S. Project."}
+{"text": "In the original article, we have neglected to thank our funder, Novartis Farma S.p.A. The Funding Statement appears below.Novartis Farma S.p.A. supported publication of this article.The authors apologize for this oversight. This error does not change the scientific conclusions of the article in any way.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Reason for Corrigendum:In the original article, a term \u201cwrote the paper\u201d appeared in the Author Contributions. This was unintentionally vague and did not differentiate between writing and correcting the manuscript. The authors apologize for the lack of clarity. This error does not change the scientific conclusions of the article in any way.The corrected Author Contributions are as follows:PS and MK designed the paradigm. PS collected the data and BR, MK, and DW helped acquiring the data. PS analyzed the data. YK, CR, and KM supported data analysis and interpretation. PS wrote and all co-authors corrected the manuscript. All authors gave final approval of the version to be published.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Scientific Reports 10.1038/s41598-018-19182-8, published online 15 January 2018Correction to: The original version of this Article contained a typographical error in the spelling of the author Paul Bastian, which was incorrectly given as Paul Bastain.In addition, the Acknowledgements section in this Article was incorrect:\u201cWe thank Dr. Shambhu Bhat for performing correspondence analysis in this study and also for critical reading of the paper. We thank Dr. Girnun for providing HIF1\u03b1 construct and valuable suggestions for our study. We thank Dr. Elin Lehrmann and Dr. Kevin Becker for assistance with microarray data. We are grateful to Drs. Tony Passaniti and Michele Vitolo for critical reading of the manuscript. The research in R.B.G laboratory was supported in part by a Merit Review Award from the Department of Veterans Affairs and RO1-10019169 and RO1-10018832 from the NIH.\u201dnow reads:\u201cWe thank Dr. Girnun for providing HIF1\u03b1 construct and valuable suggestions for our study. We thank Dr. Shambhu Bhat for performing correspondence analysis in this study and also for critical reading of the paper. We thank Dr. Elin Lehrmann and Dr. Kevin G. Becker  for undertaking microarray experiments, data analysis, and GEO data submission. We are grateful to Dr. Tony Passaniti and Dr. Michele Vitolo for critical reading of the manuscript. The research in R.B.G laboratory was supported in part by a Merit Review Award from the Department of Veterans Affairs, RO1-10019169 and RO1-10018832 from the NIH. This research was also supported in part by the Intramural research Program of the NIH, National institute on Aging.\u201dThese errors have now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Data are from the Adaptive Interaction study whose authors may be contacted at the University of St Andrews: mpe2@st-andrews.ac.uk.One point has been amended in the raw data file, and the authors have uploaded the corrected data set under a different figshare DOI. The correct Data Availability statement is: Data are available from figshare  in Intervention sessions.There are multiple errors in There are multiple errors in Please see the complete, correct Tables"}
+{"text": "This paper reports a qualitative evaluation study conducted to explore the perceptions of students who joined the Tier 1 Program of the Project P.A.T.H.S. A total of 92 students were randomly selected to participate in 10 focus groups, which provided qualitative data for the study. With specific focus on how the informants described the program, the descriptors used were primarily positive; the metaphors named by the informants that could stand for the program were basically positive. Program participants also perceived the program to be beneficial in different psychosocial domains. The present study lends further support to the effectiveness of the Tier 1 Program of the Project P.A.T.H.S. in promoting holistic development in Chinese adolescents."}
+{"text": "Nine focus groups comprising 23 program implementers recruited from nine schools were conducted to evaluate the Tier 1 Program (Secondary 2 Program) of the Project P.A.T.H.S. . Qualitative findings showed that a majority of the program implementers regarded the program as beneficial to the program participants in different psychosocial domains. The program implementers also described the program positively and positive metaphors were used to represent the program. In conjunction with the previous research findings, the present study provides further support for the effectiveness of the Tier 1 Program of Project P.A.T.H.S. in promoting holistic development among Chinese adolescents in Hong Kong."}
+{"text": "There is an error in the seventh sentence of the Results section. The correct sentence is: Respondents were predominantly Mende , or mixed Mende , or Kono , and either Muslim , Christian  or of unknown religion .https://dx.doi.org/10.5255/UKDA-SN-852917. Due to the emergency conditions under which research was conducted, and the incriminating nature of some of the information collected, transcripts are not open access but can be disclosed upon request to the authors if particular conditions are met.The Data Availability statement for this paper is incorrect. The correct statement is: The qualitative data from which this article draws is deposited in the UK Data Service ReShare repository"}
+{"text": "The Project P.A.T.H.S.  is a positive youth development program in Hong Kong. After completion of the program, program implementers were required to draw five conclusions based on the subjective outcome evaluation findings collected from the program participants and implementers as reported in the evaluation report. Secondary analyses of the data collected from 48 schools that had joined the Secondary 3 program showed that most of the conclusions concerning perceptions of the program, instructors, and effectiveness of the program were positive in nature. There were also conclusions indicating strengths and possible improvement of the program. The present findings are consistent with the previous findings that suggest that the Project P.A.T.H.S. is well received by the stakeholders and the program is beneficial to the development of Chinese adolescents in Hong Kong."}
+{"text": "Reason for Erratum:In the final publication, the first names of the last two authors have been shortened to initials only (R. J. Pasterkamp and J. P. H. Burbach). The names should appear as follows: R. Jeroen Pasterkamp and J. Peter H. Burbach.The publisher apologizes for the error. This error does not change the scientific conclusions of the article in any way and the original article has been updated."}
+{"text": "In charitable foundations throughout the world, different approaches are used to allocate funding. As many projects with good will  actually fail to help those who really need it, it is argued that the evidence-based approach  represents the best strategy to support projects that can really help the needy. Using this approach, scientific research findings are systematically used to (1) understand the nature of the problem and/or social needs, (2) design appropriate intervention programs based on the best available evidence, and (3) systematically evaluate the outcomes of the developed program. Using the Project P.A.T.H.S. funded by the Hong Kong Jockey Club Charities Trust as an example, the characteristics underlying this approach are outlined. The systematic use of scientific evidence in the Project P.A.T.H.S. is exemplary in different Chinese societies. This project provides much insight for charitable foundations and funding bodies locally and globally."}
+{"text": "Classroom observations based on the Co-Walker Scheme were conducted in 34 schools in order to examine the implementation quality of the Tier 1 Program (Secondary 3 Program) of the Project P.A.T.H.S.  in the Experimental Implementation Phase. Results showed that the overall level of program adherence was generally high (with an average of 82.8%) and the mean ratings of the 13 items examining the implementation quality were all on the high side. Student participation and involvement, and the degree of achievement of the objectives, were the two significant predictors of both overall implementation quality and success of implementation, whereas lesson preparation was the third significant predictor of overall implementation quality. In conjunction with other process evaluation findings, the present study supports that the implementation quality of the Project P.A.T.H.S. is good."}
+{"text": "The Director is the legal representative and public face of the European Centre for Disease Prevention and Control (ECDC) and is accountable to the ECDC Management Board. She/he will lead and manage ECDC and take overall responsibility for its operations, ensuring the achievement of ECDC\u2019s objectives.http://ecdc.europa.eu/en/aboutus/jobs/Pages/JobOpportunities.aspxFor detailed information on the job description, requirements and the application procedure, please visit the ECDC website at: The deadline for applications is 9 November 2016 at 12:00 noon Brussels time."}
+{"text": "The following information is missing from the Funding section: This work was supported by Chinese Academy of Sciences grant XDPB05 to SXY and YMH.yangshixia@ivpp.ac.cn.The first email address listed for Shi-Xia Yang is incorrect. The correct address is"}
+{"text": "Saprospiria was incorrectly indicated (and in conflict with the etymology paragraph) within the description of the class. A correction has accordingly been made to Discussion, Taxonomic Consequences, Description of Saprospiria, class. nov.:In the Taxonomic Consequences section of the Discussion chapter of the original article the type of the newly proposed class Saprospiria, class. novDescription of .Saprospira, type genus of the type order of the class, -ia ending to denote a class; N.L. fem. pl. n. Saprospiria, the class of the order Saprospirales).Sa.pros.pi'ri.a (N.L. fem. n. Saprospirales.The description is the same as for the order Saprospirales.This class is described on the basis of 16S rRNA gene and whole-genome phylogenetic analysis. The type and currently sole order of the class is The authors apologize for this error and state that this does not change the scientific conclusions of the original article in any way.The original article has been updated.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "AbstractMicrodon (Chymophila) katsurai Maruyama et Hironaga 2004 was speculated to be a myrmecophilous species associated with the ant Polyrhachislamellidens based on observations of adults near the ant nest. However, there have been no reports regarding the observation of immature stages of this species in association with P.lamellidens.The hoverfly M.katsurai larvae inside a P.lamellidens nest and conducted rearing experiments on the larval M.katsurai. P.lamellidens workers did not show any inspection or attack behavior against the M.katsurai larvae under rearing conditions, suggesting that M.katsurai larvae can survive inside a P.lamellidens nest. Although no predatory behavior by the M.katsurai larvae was observed, all the M.katsurai larvae pupated and emerged in a rearing environment. The dorsal surface of the larval M.katsurai has a distinct pale green color with a uniform reticular structure. The puparium of M.katsurai shows several morphological features that are characteristic of the subgenus Chymophila. We conclude that M.katsurai is likely a myrmecophilous species that utilizes P.lamellidens as a specific host and that classification of M.katsurai based on puparium morphology is concordant with that based on adult morphology.For the first time, we found three  Microdontinae  spend their larval and pupal periods in ant nests. Several papers reported that larvae of some microdontine species prey on ant eggs, larvae, and pupae  from the end of May to the beginning of July , in the city of Nirasaki, Yamanashi Prefecture, Japan. We found a P.lamellidens nest in several rotten Pinusdensiflora Siebold et Zuccarini 1842 trees that had fallen and were piled up , and wood flakes taken from the P.lamellidens workers were removed before the microdontine adults emerged to avoid any attack behavior of ant workers against adult hover flies  from a piece of bark flake and placed it to the side wall of the transparent container. The ventral surface of the larva is sticky enough to attach onto the container wall. er flies .We conducted observations on the morphology of the microdontines at the larval and adult stages. The body color and morphology of the dorsal surface were recorded in individual larvae, prepupae (this stage lies between the moment when the cuticle of the larva hardens and the appearance of the anterior spiracles ) and pupP.lamellidens larvae throughout the rearing experiments. Neither was any attack behavior of P.lamellidens workers against the microdontine larvae and pupae observed. One of the larvae (No. 2) started pupation 24 d after collection in the field, and the other two (No. 1 and 3) began pupation 16 d after that , 8.6-8.8 mm in width (N = 3) and 6.0 mm in height . The thick marginal band consisted of both dorsal fringe and ventral fringe  and that on the left side was 410-465 \u03bcm in height and 484-497 \u03bcm in width (N = 3). In addition, protruding pores were observed on the surface of the anterior spiracles in each individual  fulgens, such as dorsal surfaces that have a uniform reticular structure, a thick marginal band consisting of both a dorsal fringe and a ventral fringe, and anterior spiracles with a height that is shorter than its width  in Japan  as well, is decreasing from the influence of recent residential and industrial development (M.katsurai and P.lamellidens. It is necessary to protect the P.lamellidens habitats immediately to conserve not only P.lamellidens but also the very rare species M.katsurai.in Japan . Furtherelopment . The pre"}
+{"text": "J. Cell Sci.129, 2651-2659.There was an error published in In the abstract of this paper, there was a typographical error in the protein name CAMSAP3. The correct sentence should read:Core apical-basal polarity determinants polarise the spectrin cytoskeleton to recruit the microtubule-binding proteins Patronin  and Shortstop  to the apical membrane domain.The online version of the article has been corrected accordingly.We apologise to the authors and readers for any confusion that this error might have caused."}
+{"text": "The Funding section is incorrect. The correct Funding information is: This work was supported by the Korea University Grant 2016.http://science.aci-llc.net/prostate.The URL in the first sentence of the \u201cPurpose\u201d section of the Abstract is incorrect. The correct URL is: The publisher apologizes for the errors."}
+{"text": "The affiliation for the first author is missing. Milad Adibi is affiliated with: LifeGlimmer GmbH, Markelstrasse 38, 12163 Berlin, Germany.The following information is missing from the Funding section: LifeGlimmer GmbH provided funding in the form of salary to MA. The specific role of this author is articulated in the 'author contributions' section. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.The following information is missing from the Competing Interests section: MA is affiliated with LifeGlimmer GmbH. This does not alter our adherence to PLOS ONE policies on sharing data and materials."}
+{"text": "Eumeninae, we overlooked the paper by Eumeninae in China. It was kindly brought to our attention by Dr A.V. Fateryga and we are glad to correct the omissions here and are grateful to use some additional comments by Dr Fateryga.In our recently published illustrated key to the genera and checklist of the species of Chinese The following couplets should be changed or added to accommodate two missing genera:Cholordynerus and Stenancistrocerus.The following species and subspecies should be added to the checklist. The omitted genera are Ancistrocerus Wesmael, 1836][Symmorphusallobrogus  (Dr A.V. Fateryga in litt.: reported as S.bifasciatus in S.bifasciatus was reported as S.mutinensis)Symmorphuscrassicornis Correction (by Dr A.V. Fateryga):Brachyodynerusperrarus (not \u201cperarrus\u201d) Kurzenko, 1977"}
+{"text": "We report two cases that demonstrate not only rare presentations of a rare disease, but accepted methods of hydatid management and the use of C.A.T. scanning in diagnosis and follow-up. They also confirm the value of operative cholangiography and perhaps introduce the use of a new anthelminthic agent, mebendazole, in association with surgery."}
+{"text": "Scientific Reports7: Article number: 41125; 10.1038/srep41125 published online: 01242017; updated: 10202017.The original version of this Article as well as the previous Corrigendum contained a typographical error in the spelling of the author Hicham El Costa which was incorrectly given as Hicham E.L. Costa.This error has now been corrected in the PDF and HTML versions of the Article, as well as the previous Corrigendum that accompanies the Article."}
+{"text": "There are two tiers of programs in the Project P.A.T.H.S. . In the Tier 1 Program, teaching units based on different positive youth development constructs are covered. A total of 24 experimental schools  and 24 control schools  were randomly selected to participate in a randomized group trial. Analyses of covariance and linear mixed models controlling for differences between the two groups in terms of pretest scores, personal variables, and random effects of schools showed that participants in the experimental schools had significantly higher positive youth development levels than did participants in the control schools at post-test based on different indicators derived from the Chinese Positive Youth Development Scale. In conjunction with other evaluation findings reported previously, the present study suggests that the Tier 1 Program of P.A.T.H.S. promotes the positive development of Chinese adolescents in Hong Kong."}
+{"text": "Eucricetodon from this region. Eucricetodontinae are the most abundant fossils in the Oligocene Valley of Lakes faunas. The present\u00a0study consists of the description of five species of cricetid rodents from 43 localities ranging in age from the early Oligocene to the early-late Oligocene. In addition to Eucricetodon asiaticus described in Mongolia in 1923, we have found Eucricetodon bagus and Eucricetodon jilantaiensis that were described from Nei Mongol and Eucricetodon occidentalis discovered in Kazakhstan. This taxonomical study provides new information regarding the evolution of the Cricetidae in Central and Eastern Asia during the Oligocene and, more particularly, regarding their phylogenetic relationships and the evolutionary trends.The Oligocene fossil deposits from Valley of Lakes in Central Mongolia have provided a wealth of rodent fossils. Among these, cricetids are a very important part. To date, only the Miocene genera have been described in detail. Here, we focus on the Oligocene genus  Eucricetodon Thaler, 1966. It was firstly described as a subgenus within Cricetodon, and Thaler did not include any original diagnosis on the description. Later, it was erected as genus by Mein and Freudenthal . The fossils are stored in the collections of the Geological-Paleontological Department at the Museum of Natural History of Vienna (Austria). Table The studied material includes 542 upper and lower molars, from 43 localities of Oligocene age, belonging to five species of the genus Order Rodentia Bowdich, 1821Superfamily Muroidea Illiger, 1811Family Cricetidae Brandt, 1855Subfamily Eucricetodontinae Mein and Freudenthal, 1971Eucricetodon Thaler, 1966Genus Eucricetodon asiaticus Fig.\u00a0SynonymyEucricetodon aff. asiaticus\u2014Maridet et al. Table 3. p. 264. 2014 Original type locality: Hsanda Gol Formation, near Loh, MongoliaStratigraphic range: Early Oligocene Geographical range: Central AsiaMaterial: See Table Measurements: Given in Table DescriptionM1 (27 specimens): The enamel is thick. The molar has three roots, two on the labial part and a wider one on the lingual side. Its crown is high: the cusps are stout and rounded. The prelobe is present in only one specimen (SHG-C/1). The anterocone is mostly simple and wide, but it can be rounded  or even slightly split . The anterocingulum is present in only one case (SHG-C/1). The anterocone spur is usually present : The enamel is thick : Both lingual and labial anterolophs are present, but the lingual is less developed than the labial, in some specimens is difficult to distinguish : This molar has an elongated shape. The anteroconid is situated on the longitudinal axis of the occlusal surface; it is transversally elongated. The labial anterolophid is a well-developed ridge that connects the anteroconid with the protoconid : Both labial and lingual anterolophids are present and well developed : The labial anterolophid is long and it reaches the protoconid. The lingual anterolophid is also long and connected to the metaconid Fig.\u00a0SynonymyEucricetodon aff. bagus\u2014Maridet et al. Table 3. p. 264. 2014 Eucricetodon asiaticus\u2014Maridet et al. Table 3. p. 264. 2014 Eocricetodon cf. meridionalis\u2014Maridet et al. Table 3. p. 264. 2014 Original type locality: Akespe, Aral Formation, Kazakhstan (early Oligocene)Stratigraphic range: Early Oligocene Geographical range: Central AsiaMaterial: See Table Measurements: Given in Table DescriptionIncisor: The buccal surface of the lower incisor presents three parallel lines and there is no oblique ornamentation.M1 (25 specimens): The cusps are stout and rounded. The anterocone is anteriorly enlarged and clearly simple; it can be rounded on the apex or can be labial-lingually elongated (DEL-B/7). It is situated on the labial side of the occlusal surface. There is no prelobe nor anterocingulum. The labial and lingual anterolophs are well developed and long; they reach the paracone and protocone, respectively. The anterocone spur is present in some specimens; it is long and connected to the anterior arm of the procotone in some molars . The anterolophule is missing; it can be mistaken for the anterior arm of the protocone when is connected to the spur of the anterocone. The protolophule I is always absent. The protolophule II is always present, and it is joined to the entoloph. Some teeth display a protostyle  with a protostyle spur that ends on the protocone. The posterior arm of the protocone ends freely in the sinus and the entoloph is attached to the middle part of the protocone. In some cases (TGR-A/14), the posterior arm of the protocone is connected to the entoloph. The posterior spur of the paracone is always present, but an anterior spur is present as well (TAT-D/1). All teeth display a short mesoloph. The second mesoloph is present in some specimens : Both lingual and labial anterolophs are well developed. The protolophule I, present in all but one : The labial anteroloph is present and long whereas the lingual one is weak and in some specimens is absent (TAT-D/1). The protolophule I is present and connected to the anterolophule. The protolophule II is absent. The entoloph is present; it can be curved and connected to the middle part of the protocone or connected to the protolophule : This molar has an elongated shape. The anteroconid is situated on the longitudinal axis of the occlusal surface; it is transversally elongated and simple. The labial anterolophid is a well-developed ridge that connects the anteroconid with the labial part of the protoconid. The lingual anterolophid is present and reaches the metaconid in its anterior part. The anterolophulid is present in some molars and connected to the middle part of the anteroconid : Both labial and lingual anterolophids are present and well developed. The metalophulid I is present and is connected to the anterolophulid. The metalophulid II is absent. The posterior arm of the protoconid is connected to the ectolophid. Most of the cases present a prolongation of the protoconid hind arm that can reach the metaconid (TAT-D/1). The mesolophid is always present and it is short. The ectomesolophid is not present, but some specimens have an enlargement of the ectolophid in its labial part . The ectolophid is horizontal. The sinusid is wide, transversal, and open. The mesostlylid is present in some cases : The labial anterolophid is long and it reaches the protoconid. The lingual anterolophid is also long and connected to the metaconid. The metalophulid I is present and it is connected to the anterolophulid. In one case, it is connected to the lingual anterolophid. The metalophulid II is absent, but one molar (TAT-D/1) presents a spur on the metalophulid I that is connected to the ectolophid. The ectolophid is long and thin; it bears a mesolophid in some fossils 2014 Eucricetodon aff. bagus\u2014Maridet et al. Table 3. p. 264. (Only for IKH-A/1)2014 Eucricetodon sp. 1\u2014Maridet et al. Table 3. p. 2642014 Eucricetodon sp. 2\u2014Maridet et al. Table 3. p. 2642014 Eocricetodon cf. meridionalis\u2014Maridet et al. Table 3. p. 264. (Only for IKH-A/3-4 pro parte)2014 Original type locality: UTL4 (Ulan II), early late Oligocene, Ulantatal, Inner Mongolia, ChinaNew localities: See Table Stratigraphic range: Early-late Oligocene Geographical range: Central AsiaMaterial: See Table Eucricetodon bagus NHMW2015/0260-262; NHMW2015/0264-274. Eucricetodon cf. bagus NHMW2015/0259/0001; NHMW2015/0263/0001-2; NHMW2015/0246/0001)Measurements: Given in Table DescriptionM1 (nine specimens): The anterocone is rounded and large; it is usually simple, but it can be slightly split. A labial anterocingulum sometimes present : Both lingual and labial anterolophs are well developed. The protolophule I is usually present  and curved forward : The labial anteroloph is present and long, and the lingual is absent. The protolophule I is present and connected to the short anterolophule. The protolophule II is absent. Some molars have a small paracone spur : This molar has an elongated shape. The anteroconid is situated on the longitudinal axis of the occlusal surface; it is transversally elongated and simple. The labial anterolophid is a well-developed ridge that connects the anteroconid with the labial part of the protoconid. The lingual anterolophid is missing or very short. The anterolophulid is present in some molars and connected to the labial part of the anteroconid : The molars are squared. Both labial and lingual anterolophids are present but the lingual one is weaker than the labial. The metalophulid I is present and it is connected to the point where the labial anterolophid and the anterolophulid are joined. The metalophulid II is always absent. The posterior arm of the protoconid is connected to the ectolophid. The protoconid hind arm is not prolonged. The mesolophid is always present and it is short. The ectomesolophid is absent. The ectolophid is horizontal. The sinusid is wide, transversal, and is closed by a small cingulid in some cases : The labial anterolophid is long and it reaches the protoconid. The lingual anterolophid is shorter and it does not reach the metaconid. The metalophulid I is present and is connected either to the anterior part of the anterior arm of the protoconid or to the lingual anterolophid . The lingual anterolophid is less developed than in E. caducus; the protoconid hind arm is not prolonged as E. asiaticus and E. caducus. In general, the cingular formations are not as developed as in E. caducus or E. asiaticus on the m2. The lingual anterolophid on the m3 is shorter than in E. caducus. The metalophulid I is lingually connected, and the mesolophid is more developed than is E. caducus on the m3.s et al. . M1 has s et al. . HoweverE. bagus possesses in general derived traits according to the trends described for the genus 2014 cf. Aralocricetodon aff. schokensis\u2014Maridet et al. Table 3. p. 264. 2014 E. bagus\u2014Maridet et al. Table 3. p. 264. 2014 Original type locality: UTL4 (Ulan II), early Late Oligocene, Ulantatal, Inner Mongolia, ChinaStratigraphic range: Early Oligocene Geographical range: Central AsiaMaterial: See Table Measurements: Given in Table DescriptionM1 (nine specimens): The enamel is thick : Both lingual and labial anterolophs are well developed. The anterolophule is thick. Only one molar (TGW-A/2b) has a protolophule I that is connected to the anterolophule. The protolophule II is present on the rest : The labial anteroloph is present and long, and the lingual is absent. The protolophule I is present and connected to the anterolophule. The protolophule II is absent. The paracone spur is absent. The entoloph is complete; it is curved and connected to the protocone. The mesoloph is long and reaches the labial border. The posterior part of the entoloph is present and joined to the metalophule. The neoentoloph is present but incomplete. The sinus is narrow, long, and proverse. The hypocone is reduced. The posteroloph is always present and long. The mesosinus is closed by a cingulum.m1 (17 specimens): The anteroconid is large and situated on the longitudinal axis of the occlusal surface; it is rounded. The labial anterolophid is present but thin. The lingual anterolophid is absent in some specimens (TGW-A/2a). The anterolophulid is present only in three cases : Both labial and lingual anterolophids are present and well developed.The metalophulid I is present and it is connected to the anterolophulid. The metalophulid II is absent. The posterior arm of the protoconid is well-developed and in some molars Fig.\u00a0 ends frem3 (three specimens): The labial anterolophid is short but reaches the protoconid. The lingual anterolophid is also short and connected to the metaconid. In two specimens, the lingual anterolophid is absent. The metalophulid I is present and is connected to the lingual anterolophid. The metalophulid II and metalophulid spur are absent. The ectolophid is long and thin, oblique in two molars , we have realised that the size ranges are wide enough to represent more than one species. The high intraspecific variability seems to correspond to two species. Therefore, we suggest the revision of the fossils ascribed to E. jilantaiensis and we compare here only with the material from the type locality . Mongolian and Ulantatal material share the size, the absence of anterior protocone arm, the presence of both anterolophids, the short mesoloph, the straight sinus, and the posterior metalophule on the M1. Also, they share the presence of metalophulid II and short ectomesolophid on the m1.us Table . The greE. jilantaiensis was only known previously in China, and it is morphologically close to E. asiaticus. They have been phylogenetically related 2014 Original type locality: Altynshokysu, Aral Formation, Kazakhstan (Early Oligocene)Stratigraphic range: Early Oligocene Geographical range: Central AsiaMaterial: See Table E. occasionalis NHMW2015/0335/0001-4 and Eucricetodon cf. occasionalis NHMW2015/0334/0001-5)Measurements: Given in Table DescriptionM1 (three specimens): The anterocone is large and crescentic; it is always simple. The labial anteroloph is well developed and it reaches the paracone : Both lingual and labial anterolophs are present, but the labial one is longer than the lingual one  is too worn and no structure can be appreciated.m2 (one specimen): The molar is rectangular. Both labial and lingual anterolophids are present but the labial one is weaker than the lingual one. The metalophulid I is present and it is connected to the anterolophulid. The metalophulid II is absent. The protoconid hind arm is long and ends freely in the mesosinusid. The ectolophid is connected to the protoconid and it bears a mesolophid. The ectomesolophid is absent. The sinusid is wide, transversal, and short; it is closed by a small cingulid. The mesosinusid is open. The hypolophulid is anterior and connected to the posterior part of the ectolophid, clearly before the hypoconid. The hypoconid hind arm is present. The posterolophid is long and it does not display a constriction : Both labial and lingual anterolophids are well developed and reach the protoconid and metaconid, respectively. The metalophulid I is present and it is connected to the anterior arm of the protoconid. The metalophulid spur is absent. The metalophulid II is always absent. The ectolophid is oblique and bears a short mesolophid that ends freely in the mesosinusid m1: NHMW2015/0264/0001. The molar has two roots. The anteroconid is rounded and well developed. The anterolophulid is not present. The metalophulid I is present and is connected to the anteroconid. The metalophulid II is also present and connected to the ectolophid. The mesosinusid is closed by a small cingulid. The sinusid is wide and short. The mesolophid is not visible, possibly due to the strong wear. The posterolophid is well developed and it reaches the entoconid. The hypoconid hind arm cannot be distinguished.Remarks: Given the small size (1.42\u2009\u00d7\u20090.99), this specimen could be assigned to E. occasionalis. However, the tooth is strongly corroded and the measurements might be slightly underestimated, the molar is strongly worn, prohibiting identification, and a taxonomical assignation cannot be done.Eucricetodon. There are 11 new occurrences of Eucricetodon in comparison to previous studies . However, the distribution of the different species has changed. E. asiaticus was known with certainty in biozone A and E. aff. asiaticus in biozone B (Maridet et al. E. asiaticus. E. caducus was known only in biozone A and is now present also in biozone B. E. bagus was found in biozone C and C1, but the presence in biozone B was dubious (E. aff. bagus on Maridet et al. E. jilantaiensis and E. occidentalis are described in Mongolia for the first time.Both morphological and metrical features of the studied fossils led us to identify five species belonging to Eucricetodon display a combination of characters that can be used as environmental indicators. For instance, the biozone A is characterised by large-sized species with brachydont/bunodont crowns; oblique/blunt cusps, simple occlusal pattern, and low crown heights, such as E. asiaticus and E. caducus. The dental microwear analysis made in E. asiaticus from Ulantatal (Gomes Rodrigues et al. E. jilantaiensis and the smaller E. occasionalis and E. bagus. The species found here show more complicated patterns and a size decrease that, according to Bergman\u2019s rule, could indicate an increase of temperature. The microwear analysis performed in E. jilantaiensis from Ulantatal reflects a diet without fruit and an increase of the potential consumption of abrasive and fibrous plants. These are more frequently found in open habitats (Gomes Rodrigues et al. Eucricetodon diversity decreases, E. bagus shows a trend towards size decreases for the specimens from biozone B, and the larger species disappeared. This is again consistent with Bergman\u2019s rule and would coincide with the Late Oligocene Warming Event, recorded since 26.7\u00a0Ma (Zachos et al. The species of"}
+{"text": "Anti-HIV medication is the standard treatment for the HIV infected patient. An important concern of anti-HIV drug use is the adverse effects. The kidney problems due to anti-HIV is widely mentioned. Indinavir and atazanavir are the two drugs with many reports on renal toxicity. Here, the authors use the standard chemoinformatics technique for predicting properties of both drug and compare the derived result. Based on this study, atazanavir seems to be more problematic than indinavir considering the induction of renal problem.HIV infection becomes the present problematic infectious disease worldwide. The pathogenic HIV virus will destroy immune system of the patients and result in several clinical problems. Anti-HIV medication is the standard treatment for the HIV infected patient. An important concern of anti-HIV drugs use is the possible adverse effects . The kid-Activity\u00a0Relationships \u2013 GUSAR\u201d used. The online prediction tool is available at http://cactus.nci.nih.gov/. The technique is used in previously published article , respectively. The viscosity of indinavir and atazanavir are equal to 2.675 and 3.302 log10 (CP), respectively.Based on this study, the predicted melting points of indinavir and atazanavir are equal to 186.8 and 205.34\u00baC, respectively. The solubility of indinavir and atazanavir are equal to -3.208 and -3.719 loghttp://www.thaiceramicsociety.com/). This implies the change of higher risk of needle shape crystal formation than indinavir.The main pathogenesis of renal problem due to antiretroviral drug is the crystal formation . Based oBased on this work, the authors use the standard chemoinformatics technique for predicting properties of both drug and compare the derived result. Based on this study, atazanavir seems to be more problematic than indinavir considering the induction of renal problem. In fact, both drugs can cause the renal problem and the problem is not uncommon ,5. HowevVW and BJ wrote the manuscript equally.The author declared no competing interests.Ethical issues  have been completely observed by authors.None."}
+{"text": "Following publication of the original article , the autAllessia Castellino. The correct author name is:Alessia Castellino.Originally, the author name was published as:"}
+{"text": "It is with great sadness that we announce the death of Dr. Eugene Garfield. Dr. Garfield died on Sunday 26 February 2017. He was 91. Dr. Garfield is credited as the inventor of the journal impact factor . Dr. Gar"}
+{"text": "A total of 49 schools participated in the Secondary 2 Program of the Experimental Implementation Phase of the Project P.A.T.H.S. . After completion of the program, 7,406 students completed a Subjective Outcome Evaluation Form (Form A) designed by the research team to reveal their comments about the program, instructors, and perceived effectiveness of the program. Based on the consolidated reports submitted by the schools, the research team aggregated the data to form a \u201creconstructed\u201d overall profile on the perceptions of the program participants. Results showed that high proportions of the respondents had positive perceptions of the program and the instructors. About 80% of the respondents were satisfied with the program and regarded it as helpful to their overall development. The present findings provide support to the effectiveness of Secondary 2 Program of Project P.A.T.H.S. from the perspective of the program participants."}
+{"text": "In the published article, Pamela Nicholson was not included as an author. In addition, author names were incorrectly spelled as Saria InAlbon and Piklu R. Chowdhury. The correct spellings are Saria In-Albon and Piklu Roy Chowdhury.The authors apologize for these errors and state that they do not affect the scientific conclusions of the article in any way.The original article has been updated.JF, LF, and SD conceived the study and performed the genomic analyses. PN performed strain isolations and DNA preparations. Bioinformatic analyses was made by SI-A and LR. PC established the phylogenic relationship using by PhyloSift. RZ and AdV provided strains and metadata from strains of Brazil.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "N-oxide from phosphatidylcholine and other forms of choline and carnitine were associated with CVD  no. 26461257, and Yokohama Foundation for Advancement of Medical Science. L.C. is supported by MEXT Government Scholarship no. 122229. These funding sources had no role in the study design; in the collection, analysis and interpretation of data; in the writing of the manuscript; or in the decision to submit the paper for publication.T.I. is supported by a Grant-in-Aid for Scientific Research from the The authors declare no conflict of interest."}
+{"text": "It is almost axiomatic that international standards facilitate trade. The sale of products by one country to another is certainly made easier when the buyer country knows that the goods it is purchasing conform to established standards; standards which both the buyer and seller countries may well have helped to formulate. It is for just this reason that the U.S. Department of Commerce strongly advocates the acceptance of international technical standards based on U.S. technology. The effects of international standards on testing services may not be as obvious as they are on products but they are just as significant.Although the producer in a seller country and the user in a buyer country may both be cognizant of the international standards for a given product, there is often disagreement on the means for verifying the conformance of the product to the standards. Clearly, the producer must test the product before it leaves his plant in order to be sure that it satisfies the standards (or any other provisions that were made part of the contract). The buyer, however, may be unwilling to accept the seller\u2019s assurances. He may opt to have the product retested in his own country. He may charge the costs of these tests to the manufacturer; but whether or not he does this, these costs raise the total cost of the product in the buyer country. Situations such as this make it difficult for a foreign producer to compete against a domestic producer for a share of the market in any given country, aside from any import tariffs that might be imposed by the buyer country.In an effort to promote the sale of American products abroad, the Office of the U.S. Trade Representative has been active in international negotiations to alleviate this situation. Most of the proposals seek agreements whereby test data generated in the seller country would be accepted in the buyer country, provided that the tests were carried out in an accredited laboratory. The conditions for accreditation are still to be formulated, but it is quite clear that they will have to be contingent upon mutual agreements regarding the test methods and the qualifications of the individuals who perform the tests. In short, international standards for test methods and personnel qualifications are a prerequisite to international acceptance of test data.For many products, tests to evaluate quality are destructive. That is, the quality of the product is evaluated, at least in part, by sampling tests of a mechanical or chemical nature which destroy the usefulness of the samples. There are numerous products, however, for which sampling and destructive testing are inappropriate and for which the quality of each and every item must be verified nondestructively. Such products are either too expensive and unique to be destroyed, or else they impact directly upon public safety. Examples include airplanes, nuclear reactors, refineries, metals processing equipment and steam generators. International agreements regarding the acceptance of test data on such products must necessarily await international standards for nondestructive test methods and for the certification of nondestructive testing personnel.The development of such standards is the responsibility of Technical Committee 135 on Non-Destructive Testing in the International Organization for Standardization (ISO/TC 135). The technology of NDT is generally newer than that of mechanical testing, and the development of standards for NDT, accordingly, is not as far advanced as it is for mechanical testing. Although there is a large variety of NDT methods, seven are in comparatively wide use: ultrasonics, x-ray radiography, eddy currents, magnetic particles, liquid penetrants, visual examination and leak testing. Two other methods, acoustic emission testing and neutron radiography, might be classed as \u201crapidly emerging.\u201dTC 135 is organized into subcommittees (SCs) along similar lines. SC 2 on Surface Methods deals with liquid penetrant and magnetic particle testing. SC 3 on Acoustic Methods is responsible for ultrasonic and acoustic emission testing. SC 4 on Electromagnetic Methods is chiefly concerned with eddy current testing. SC 5 on Radiation Methods is responsible for x-ray, gamma ray, and neutron radiography, and SC 6 is on Leak Detection Methods. SC 7 was established only a few years ago to develop an international standard for the qualification and certification of NDT personnel for all of the methods.At the invitation of the host country, the Sixth Plenary Meeting of ISO/TC 135 was held in Yokohama, Japan, during the week of May 11\u201315, 1987. Meetings of SC 2 and SC 3 were also scheduled during the same time frame, as was a meeting of Working Group 1 (WG 1) of SC 3, which is concerned with ultrasonic reference blocks.Eight countries were represented at the meetings: The U.S.S.R., which serves as the secretariat for both TC 135 and SC 2; the U.S., which is the secretariat for SC 3; Italy, whose delegate to the meetings is the convenor for SC 3/WG 1; plus Canada, France, Federal Republic of Germany, Republic of Korea and, of course, Japan. The U.S. delegation of six members was exceeded in size only by the Japanese delegation; the Soviet delegation had four persons.The U.S. delegation was headed by Dr. Leonard Mordfin of the National Bureau of Standards, who chairs the U.S. Technical Advisory Group for ISO/TC 135 (\u201cthe TAG\u201d).  Other members of the U.S. delegation included Dr. Donald G. Eitzen of NBS, who was chairman-elect of SC 3, plus four representatives from the private sector: W. E. Lawrie, the U.S. member of SC 3/WG 1; J. D. Marble, the secretary of SC 3; C. W. McKee, vice chairman of the U.S. Technical Advisory Group; and Dr. M. C. Tsao, who is the principal developer of a working document on the characterization of search units and sound fields for ultrasonic nondestructive testing. This document is based upon ASTM standards. One of the U.S. delegation\u2019s principal objectives at the meeting was to advance this document toward international acceptance. The U.S. delegation had, in fact, several objectives which it had set for itself prior to the ISO meetings. As things turned out, all of these objectives were attained. There were two occurrences, both unexpected, which may have contributed to this successful record. The first was the absence of a delegate from the United Kingdom. The U.K.\u2019s position in recent years has run somewhat counter to the main thrust of ISO/TC 135 activities, and this has tended to cause delays and to limit progress. The second occurrence was even more surprising and it took place, or at least it began, prior to the meeting itself.About two hours before the scheduled opening of the plenary meeting on May 11, a member of the host Japanese delegation notified Drs. Mordfin and Eitzen that the Soviet delegation wished to meet with them immediately. The Americans assented. At the meeting, the spokesman for the Soviet delegation announced that the chairman of TC 135, Professor V. V. Kljuev, had resigned from this position because\u201d \u2026 he was no longer working in NDT\u201d and had not come to Yokohama. Professor Kljuev is an eminent Soviet scientist with considerable expertise in NOT, so this development was quite unexpected. Even more unexpected was the Soviet spokesman\u2019s next remark, which was a request that Dr. Mordfin chair the week\u2019s meetings of TC 135. For a secretariat to appoint someone other than one of its own countrymen to chair an ISO committee meeting may well be unprecedented. To the other delegates at the meeting it was certainly unheard of. Needless to say, Dr. Mordfin accepted the invitation. Although the chair is a nonpartisan position, Dr. Mordfin\u2019s appointment unquestionably eased the U.S. delegation\u2019s attainment of its objectives at the meetings.In retrospect, the Soviet move was a wise one. The Soviet nominee to replace Professor Kljuev as permanent chairman of TC 135 is Dr. Y. K. Fedosenko. His qualifications for the position are impeccable but his English is poor \u2026 and TC 135 meetings are conducted in English. Hence Dr. Fedosenko\u2019s appointment was delayed until the end of the TC 135 meetings at which time he pledged to improve his English before the next TC 135 meeting in 1989.Aside from this, it is a matter of record that the positions of the U.S. and the U.S.S.R. in ISO TC 135 have been generally similar and quite compatible over the last few years. In fact, in matters under debate in TC 135, the U.S. finds itself allied with the Soviet Union more often than with, for example, the U.K. or France. The parallel objectives of the U.S. and the U.S.S.R. were quite evident in the Yokohama meetings. It is apparent, therefore, that the Soviet appointment of Mordfin benefited both countries.Other notable appointments during the meeting were Mr. A. P. Degtjarev as the new permanent chairman of SC 2 on Surface Methods and Dr. Eitzen as the new permanent chairman of SC 3 on Acoustic Methods. Both men are highly acclaimed in their fields. However, Mr. Degtjarev, like Dr. Fedosenko, is new to TC 135 whereas Dr. Eitzen has been a member of the U.S. delegation to the last three plenary meetings. With this background Dr. Eitzen has, in fact, been fulfilling the chairman\u2019s responsibilities for SC 3 since September 1986, when the previous chairman resigned. Under his deft leadership in Yokohama, the subcommittee reviewed international comments which had been submitted on the U.S. working document on the characterization of ultrasonic search units and sound fields, and a resolution was adopted elevating the next revision of the document to formal ISO Draft Proposal status.During the year prior to the Yokohama meetings, seven proposals for new work items were letter balloted through TC 135 for addition to the committee\u2019s Program of Work. All were accepted. Five of the seven proposals had been submitted by the U.S. One of these proposals was for the development of a standard for ultrasonic reference blocks; this was the basis for the establishment of Working Group 1 in SC 3. Another proposal was for a secondary calibration method for acoustic emission transducers; it is the U.S. intent that this be compatible with the acoustic emission measurement system developed at NBS. The other three new work items proposed by the U.S. deal with the standardization of neutron radiography. A team of U.S. experts in this field is already preparing drafts for ISO consideration, based on ASTM standards. In an effort to expedite this activity, the U.S. delegation sought and obtained a resolution directing the German secretariat of SC 5 on Radiation Methods to poll its members regarding the establishment of a new working group on neutron radiography with an American convenor.The U.S. delegation was also successful in securing a resolution relating to personnel qualification and certification. An ISO Draft Proposal on this topic is at considerable variance with American practices. Hence, the U.S. delegation sought to invite the Canadian secretariat of SC 7 on Personnel Qualification to hold its next meeting in the United States. The American Society for Nondestructive Testing, which has offered to host this meeting, feels that the two approaches to NDT personnel qualification could, perhaps, be harmonized more effectively in an American venue.It is not at all uncommon at technical meetings for significant accomplishments to be recorded outside of the meeting rooms. This was true in Yokohama as well. Informal discussions between members of the U.S. delegation and Mr. E. Julliard of the French delegation led to a tentative agreement for the exchange of draft nondestructive testing standards which are under development in the two countries. The proposed agreement, which would involve AFNOR standards in France and ASTM and ANSI standards in the United States, is expected to facilitate the standards development process by reducing duplication of effort and by drawing the two countries into closer alignment in TC 135. Detailed procedures for implementing the agreement remain to be worked out but preliminary exchanges have already been effected. These involved French and English vocabularies for liquid penetrant testing and ultrasonic testing as a first step toward standard ISO vocabularies for these two nondestructive test methods.Many working drafts dealing with nondestructive test methods were furthered during the week of meetings in Yokohama, most of them with significant U.S. input. It is not practical to describe this progress here in detail, but some of the drafts which were advanced in this way include documents dealing with procedures and equipment for magnetic particle testing, vocabulary for liquid penetrant inspection, ultrasonic reference blocks, ultrasonic inspection of forgings, and x-ray radiography of castings. It was also resolved that the U.S. will submit proposals for new work items to develop ISO vocabularies on magnetic particle testing and acoustic emission testing. In addition, procedures for updating three existing ISO standards, dealing with surface methods of nondestructive testing, were reaffirmed.Subject to approval by the German member body of ISO, the next meeting of TC 135 will be held in Berlin in 1989. Meetings that may be arranged in the meantime include SC 4 on Electromagnetic Methods in Bulgaria; SC 7 on Personnel Qualification in the United States; working group on radiography of castings in Germany; and working group on neutron radiography in Japan.All of the delegates were uniformly complimentary about the outstanding arrangements which had been made by the Japanese hosts for these meetings. The International Conference Center in Yokohama is an exceptional facility for meetings of this kind, the banquet at the grand Hotel New Grand was exquisite, and the city of Yokohama itself proved to be thoroughly delightful."}
+{"text": "In the original article, there was an error. There is no Appendix. A correction has been made to the Discussion: Recommendations for Assignment Framework, paragraph two.https://scholarworks.montana.edu/xmlui/handle/1/14090.The final infographic assignment is available at The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.The original article has been updated.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Due to an oversight, the link used to list authors and grant authorship to Alzheimer's Disease Neuroimaging Initiative (ADNI) members was incorrect. The correct link is appearing below:http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdfAuthorship of ADNI members has been corrected.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.The original article has been updated.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Priscila B. S. Serpa (from full name Priscila Beatriz da Silva Serpa). The authors apologize for the mistake. This error does not change the scientific conclusions of the article in any way.The spelling of Priscila B. D. Serpa is wrong. The correct is The original article has been updated.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Therefore, we wish to replace the figure with the correct one below (The authors wish to make a change to their published paper . The unine below C. http://www.mdpi.com/1999-4923/9/3/27), with a reference to this addendum.The authors apologize for any inconvenience caused. The changes do not affect the scientific results. The manuscript will be updated and the original will remain online on the article webpage ("}
+{"text": "Dis. Model. Mech.9, 685-696.There was an error concerning The wrong figure was used for The authors and DMM office apologise to the readers for this error."}
+{"text": "The publisher apologizes for the error.The last two authors, Haiyang Yu and Xueqi Gan, should be noted as co-corresponding authors of this work. The email address for Haiyang Yu is"}
+{"text": "To the Editor: The article by Virk et al.  in Mexico. The authors then concluded that M. lepromatosis lepromatous leprosy is a travel-related hazard for travelers to Mexico or other disease-endemic areas. We note that the exact source of acquiring the M. lepromatosis infection by the patient in this study was entirely uncertain, and experimental evidence was not enough to prove M. lepromatosis to be a travel-related hazard.M. lepromatosis infection and leprosy-like illness in a patient in Canada who had no history of contact or travel to leprosy-endemic areas. Jessamine et al. indicated that transmission dynamics of M. lepromatosis infection is complex, and undiscovered mechanisms or unknown reservoir interactions may exist in such areas of nonendemic regions. Previous studies have also reported the roles of subclinical cases and environmental reservoirs in the transmission of leprosy (M. lepromatosis to the study patient in his vicinity. Thus, the assertion of Virk et al. (M. lepromatosis when traveling to Mexico or other leprosy-endemic areas as tourists is misleading and demands extensive research to prove it.In contrast, Jessamine et al. (In addition, it is intriguing to note that host genetic determinants can influence the acquisition and onset of leprosy ("}
+{"text": "Qualitative evaluation was carried out to understand the perceptions of the students participating in the Tier 1 Program of the P.A.T.H.S. Project. Five focus groups based on 43 students recruited from four schools were conducted to generate qualitative data to evaluate the program. With specific focus on how the informants described the program, results showed that the descriptors used were mainly positive in nature. When the informants were invited to name three metaphors that could stand for the program, the related metaphors were basically positive in nature. Finally, the program participants perceived many beneficial effects of the program in different psychosocial domains. Intra- and inter-rater reliability analyses revealed that the coding of the positive or negative nature of the responses was reliable. The present study provides qualitative support for the effectiveness of the Tier 1 Program of the Project P.A.T.H.S. in promoting holistic development in Chinese adolescents in Hong Kong."}
+{"text": "Due to an oversight, Sally Andrews was not included in the author list. The updated author contributions statement appears below. The authors apologize for the mistake. This error does not change the scientific conclusions of the article in any way.The original article has been updated.Conception of the initial idea behind the Perspective: LP, DE. Revisions of consecutive drafts and writing up of final version: LP, DE, SA. Design of Figure 1 diagram: LP.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Upon publication of the original article , the autAn updated version of Fig. The publisher apologises for this error.Corrected Fig."}
+{"text": "Due to a mistake, Dr. A. G. Amico, Dr. G. Larosa, Dr. R. Leanza, and Dr. G. Milluzzo were not included as authors in the published article. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.The corrected Author Contributions appears below.GC is the main proposer of the CATANA activity. GAPC and DM are the main proposers of the ELIMED activity and GAPC is responsible of the CATANA proton therapy room. GAPC, GPetringa, and FR contributed on the relative dosimetry and on the Monte Carlo simulations. FR and VScuderi contributed in the experimental and dosimetric part of the paper with particular regard to the laser-driven activities. FS and AntonioR are the main responsible of the ELIMED transport beamline. VSalamone and LR contributions are on absolute dosimetry, dosimetry tests, and patients positioning. They are the medical physicists following the treatments. CS and GPrivitera are the oncologists and radiotherapist dedicated to the treatments. TA and AndreaR are the oculists who follow the patients after the treatment producing the follow-up results. VP, MS, and LV are the medical physicists involved in the use of TLD detectors in the laser-driven proton beams. GL, RL and AA contributed to the ELIMED dosimetry working on the Faraday Cup tests. GM contributed on the diagnostic and, partially, on the Monte Carlo activities of ELIMED.The original article was also updated.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "A total of 52 schools (n = 8679 students) participated in the experimental implementation phase of the Project P.A.T.H.S. . After completion of the Tier 1 Program, 344 instructors completed the Subjective Outcome Evaluation Form (Form B) to assess their views of the program, instructors, and perceived effectiveness of the program. Based on the consolidated reports submitted by the schools to the funding body, the research team aggregated the consolidated data to form a \u201creconstructed\u201d overall profile on the perceptions of the program implementers. Results showed that high proportions of the workers had positive perceptions of the program and their own performance, and roughly 90% of the workers regarded the program as helpful to the program participants. The present study provides additional support for the effectiveness of the Tier 1 Program of the P.A.T.H.S. Project in Hong Kong."}
+{"text": "The following acknowledgments were missing from the original article.BD was supported by the Hereditary Disease Foundation, the Beckman Institute and the Resource Center for CLARITY, Optogenetics and Vector Engineering, which supports technology development and dissemination at the California Institute of Technology. The AAV-PHP.B plasmid was distributed from the Gradinaru Laboratory at the California Institute of Technology. The authors thank Viviana Gradinaru for her help in providing the AAV-PHP.B plasmid.The authors apologize for this mistake. This error does not in any way change the scientific conclusions of the article.BED is listed as an inventor on a patent application related to AAV-PHP.B. KLJ, RDD and RLK have no conflicts of interest to disclose."}
+{"text": "H. Wingenbach is incorrect. The correct email address to reach the corresponding author is tanja.wingenbach@bath.edu). All other data are available within the paper and supporting information files.The data availability statement is also incorrect. Please see the correct Data Availability Statement here: Some restrictions to data apply. Due to legal restrictions, the ADFES-BIV video set must be made available upon request to the corresponding author, Dr. Tanja Wingenbach ("}
+{"text": "Glioblastoma (GBM) is the most aggressive brain tumor in adults. Due to the high degree of heterogeneity, little is known about the molecular events underpinning GBM genesis and the disease is already advanced at clinical presentation, thus complicating the efficacy of therapies.This special issue provides an update on novel basic and translational advances, which are expected to impact on patient treatment and improve survival.On the translational front, the review by F. A. Chowdhury et al. focuses on the cytotoxic and antiapoptotic potential of Thymoquinone for GBM treatment by affecting key signaling pathways that promote tumor cell proliferation. Another two reviews by V. Desai and A. Bhushan and M. N. Park et al. highlight the potential of natural compounds in the treatment of this devastating disease both individually and in combination with the standard of care for GBM patients, that is, chemo- and radiotherapy, and their mechanism of action in promoting apoptosis and suppressing invasion. Another novel therapeutic strategy based on recombinant immunotoxins is described by S. Zhu et al. in their review. Importantly, this work also highlights the challenges associated with the use of immunotoxins, for instance, delivery to the brain and immunogenicity.\u03b3 inhibition using its ligands and its inhibitor that results in downregulation of stem cell markers and sphere-forming ability and the other on sodium valproate that acts by blocking the proliferation, migration, and angiogenesis of human glioma cells.Finally, the original papers by C.-N. Im and by D. Kavaliauskait\u0117 et al. propose two experimental strategies to inhibit GBM growth. One is based on PPAR Drosophila. The review by L. Ryskalin et al. addresses the role of the mammalian Target of Rapamycin (mTOR) in the brain and in particular how mTOR activation is critical in GBM development. H. Alfardus et al. examine the key role of microRNA in the regulation of glycolytic metabolism and oncogenic signaling pathways in GBM. Finally, a review by S. A. Vald\u00e9s-Rives et al. provides an overview of all the signaling pathways that negatively control apoptosis and how these could be targeted to trigger an apoptotic response in GBM.As part of the basic advances in GBM research, we solicited the submission of manuscripts that could help deepen our understanding of the signaling pathways underlying malignant growth and ultimately lead to the development of new therapies. The research article by S. Paglia et al. focuses on alterations in the PTEN/aPKC/Lgl axis that are implicated in gliomagenesis in in vitro models. Another interesting approach for screening of different antiglioma compounds is shown by D. W. Lee et al. This group implemented a 3D cell-based, high-throughput screening method that allows mimicking the microenvironment using a micropillar and microwell chip platform. Using this system, they evaluate cytotoxicity and efficacy of 70 compounds.In an elegant and alternative strategy, using mathematical algorithms M.-E. Oraiopoulou et al. modelize not only overall proliferation but also the intratumor heterogeneity. Moreover, these in silico data are further validated usingIn line with the notion that the microenvironment plays an important role in sustaining the pathogenesis of glioma, I. A. W. Ho and W. S. N. Shim investigated the contribution of the microenvironment to GBM heterogeneity. In their work they try to understand how the different types of stromal cells that surround the tumor such as endothelial cells, microglia, and others may impact angiogenesis, invasion, proliferation, and stemness of GBM cells. Understanding this crosstalk would aid to better tailor therapeutic interventions.Finally yet importantly, the work by N. Senhaji et al. characterizes the EGFR amplification and IDH mutations in GBM patients from the Northeast of Morocco. In this work the authors, using a specific population, aim to determine the prevalence of those genetic aberrations and how this relates to the frequency seen in other ethnic groups.We hope that this special issue will help investigators interested in GBM biology to familiarize with the recent therapeutic advances in this field and to better understand the role of key signaling pathways in the oncogenic process leading to this disease. We also hope that the content of this special issue will stimulate discussion and inspire future basic and translational studies.Sara G. M. PiccirilloMarta M. AlonsoFrancesco Pasqualetti"}
+{"text": "Dr. Ciro Casanova is not included in the author byline. He should be listed as the last author as Ciro Casanova on behalf of the CHAIN study. He is affiliated with the Department of Respiratory Medicine, Hospital Ntra. Sra. de Candelaria, Tenerife, Spain. The contributions of this author are as follows: Recruited patients and reviewed the manuscript.The publisher apologizes for the error."}
+{"text": "All compounds were assessed for their in vitro activity against promastigotes of three Leishmania species The most lipophilic aminoalcohols bearing an aliphatic moiety with eight to 12 carbon atoms displayed a good activity against L. amazonensis and L. major, and two of them also showed antiproliferative activity against L. chagasi. The best results were obtained for the N-dodecanoyl ethylenediamine derivative and for N-decyl aminoalcohol .In this work, we report on the preparation and evaluation of the"}
+{"text": "The original submission of this manuscript included a citation of one of the authors' patents . During In the interests of fairness, we cite the other patent in question in this Correction .We fully acknowledge that this was an editorial error and apologize to the authors and reviewers for any inconvenience this has caused them.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2334/10/291/prepub"}
+{"text": "A 35-year-old woman presented with a history of productive cough and fever for a week. The fever was high grade and associated with chills. The sputum was yellowish and viscid. The patient had a history of recurrent episodes of cough and expectoration since childhood, which had needed frequent hospitalizations. Fifteen years after her marriage, she had no children. She was a nonsmoker. On examination her blood pressure was 126/80, pulse rate was 116/minute and respiratory rate was 36/minute. She had clubbing in all her digits. Her heart sounds were best heard on the right side of the chest, and the apex was best felt in right fifth intercostal space. The examination of the chest revealed bilateral crackles and rhonchi. Her chest roentgenogram revealed dextrocardia . ECG shoWhat is the diagnosis?http://www.saudiannals.net"}
+{"text": "Dear Reader,It is indeed a pleasure to present you with the Volume 12 Year 2008 issues of the Journal of the Indian Society of Periodontology.The ISP is really fortunate to have a wealth of experienced academicians who have painstakingly reviewed and corrected the articles that the diligent, young and energetic minds across the country have toiled to bring to your purview. I do hope you will relish the scholarly fare.www.jisponline.com. You can submit articles directly from www.journalonweb.com/jisp.I would like to particularly thank the Publishers, Medknow Publications and specifically Dr. D. K. Sahu, its Director for their painstaking work in the short time that we have had this year to bring out the 3 issues. Thanks to their efforts, the JISP is now online at The President Dr Praveen Kudva and the Honorary Secretary Dr. M. M. Dayakar deserve a special mention here for their help and encouragement in bringing out the JISP this year. A special thanks to Dr. D. G. Pol for the persistent stimuli he provided is seeing all the three issues Jan, May and Nov 2008 released before this years annual conference at Chandigarh.I welcome your comments and suggestions on the JISP and as its Editor, I am fully committed to bringing about a JISP that reflects the quality and character of professional excellence of periodontology in India and the world today.Sincerely yours,Editor,Journal of Indian Society of PeriodontologyE-mail: smilesindia@gmail.comD. Arunachalam"}
+{"text": "IFSES is a Federation of Societies representing laparoscopic surgeons in Continents or Countries with large M.A.S. input. Acceptance of Societies is on application which is carefully scrutinised and voted on by ballot at Executive Committee Meetings \u2013 the latest Society to be accepted in this International Federation  is I.A.G.E.S. Members of the various Societies which form the Federation have representation in and dialogue with IFSES through two nominated Representative Members of each Society, who represents that Society in the IFSES Executive Committee.The Member Societies are: 1) European Association for Endoscopic Surgery (EAES), 2) Canadian Association of General Surgeons (CAGS), 3) Federation Latinoamericana de Cirugia (FELAC), 4) Association Latinoamaericana de Cirujanos Endoscopistas (ALACE), 5) Japan Society for Endoscopic Surgery (JSES), 6) Society of American Gastrointestinal Endoscopic Surgeons (SAGES), 7) Endoscopic and Laparoscopic Surgeons of Asia (ELSA), 8) Indian Association of Gastrointestinal Endo-Surgeons (IAGES), 9) Chinese Society for Laparo-Endoscopic Surgery (CSLES), and 10) General Surgeons of Australia (GSA).The only continent not yet part of IFSES is Africa and it is expected that a Pan African Society of M.A.S. will take its place in IFSES.A unique concept of IFSES was that these surgeons from several Endoscopy Societies sought and obtained the partnership of Industry, so that leading manufacturers joined IFSES as Corporate Members and are part of the Executive Committee making this the only Federation where surgeons integrate with and actively involve Industry to help achieve the mutual goal of the growth and spread of M.A.S. The current Corporate Partners are: 1. Aesculap AG. C.O KG, 2. Ethicon Endo-Surgery, 3. Karl Storz GmbH and Co, 4. Olympus, 5. Tyco-US SurgicalM.A.S. is so encompassing in its spread, so varying in its complexity and instrumentation, the spectrum of surgical care in the world so disparate, from the opulent to the deprived, that to state that the IFSES mission through the activities of its Member Societies and Corporate Members is the growth and spread of M.A.S. all over the world may appear idealistic and futuristic. IFSES is aware of the magnitude of the problems, but is evolving a strategy to try, as best, to achieve its mission to ensure that the cutting edge of surgical progress is made available to all people in all placesIFSES is rich in the quality, diversity, capability, activity and culture of each one of its Member Societies and the ethical and professional excellence of its Corporate Members and acts as a meeting point, unifying force, melting pot, apex body of all its Member Societies, for harmonious interaction and cooperative efforts of the Societies, to help facilitate the spread of M.A.S. world wide. The current President of IFSES comes from a developing country and it has been his constant thrust to channelise the efforts of all Member Societies and Corporate Partners towards helping ensure optimal surgical care through M.A.S. to the developing world. With this view a Training Centre is being set-up in Accra, Ghana with the support of Industry. Other Training Centres in the developing world are under evaluation.One important function is the Biennial World Congress of Endoscopic Surgery. IFSES designates the venue of the World Congress after debating and voting on bids from Member Societies. The next World Congress will be in September 2006 in Berlin under the Chairmanship of Professor Gerhard Buess. The commitment of IFSES towards the developing world is evident from the fact that a full day session on Low-Cost M.A.S. will be he held at this Congress with participation from Governments, the World Health Organisation, Health Care administrators and Surgeons.Record current details of all Member Societies and Corporate Members, their Presidents / Chairmen, contact persons with addresses, representatives in the IFSES Executive Committee, dates of future conferences, publications, websites etc.Maintaining and posting a complete calendar of dates of all surgical endoscopic meetings world wide over the next few years, not only of Member Societies but also of National Societies of its Europe [EAES], Asia [ELSA], India [IAGES], Latin America [FELAC and ALACE] Member Societies. This would enable National and International Societies to plan meeting without clash or conflict and give surgeons prior notice of these meetings. Moreover, it would provide Industry an opportunity to exhibit their products with proper planning. Greater participation of industry would give financial support to the Conferences. For this it is very imperative that EVERY Member Society exert to post this information on the Website early and with complete details of conferences venue, dates, host organization, contact persons, registration and abstract dates. Under the leadership and initiative of Ms. Lynn Farrar of Ethicon Endosurgery a comprehensive new website is under preparation.Creating an International Data Base of:Surgeons and institutions desiring to receive the benefit of M.A.S. training programmes.Surgeons of good standing willing to travel and teach in neighbouring areas.Surgeons willing to absorb some of these trainees into their Fellowship/ Observer programmes.Stockpile of equipment ready for donation when required by Corporate Partners/Member Societies/Hospitals.International Fellowship opportunities list \u2013 Universities, Hospitals could give date of Fellowship in M.A.S. open to all countries, particularly in the developing World.International Reporting of Research Grants in terms of Fellowship Opportunity.International job registering in terms of the above. This could include Bio-Engineering, nursing, O.R. technician opportunities in M.A.S.A few aspects which IFSES can contribute to spread of M.A.S. worldwide are:To maintain and update this information it is mandatory that each Member Society and Corporate Partner transmit all relevant data to the IFSES Secretary to keep the IFSES website IFSES.org informative and vibrant. A conspicuous absentee from the Member Societies is representation from Africa. A Committee has been set-up with Professor J. Perissat who has several years of commitment and experience in developing M.A.S. in that Continent as Chairman to correct this inequity and as also embrace and support countries in Africa which have their own active Endoscopy Surgical Societies.All the above and much more has for the International Federation of Societies of Endoscopic Surgeons basically only one mission \u2013 to ensure safe M.A.S. by well trained surgeons, at affordable cost, world-wide."}
+{"text": "Calcium signals are involved in a large variety of physiological processes. Theirversatility relies on the diversity of spatio-temporal behaviors that thecalcium concentration can display. Calcium entry through inositol1,4,5-trisphosphate (IP The calcium . They couldapproximately describe the distribution with a model that assumes a weakcooperativity among channels. Inter-channel cooperativity is mediated by the CaThe quantal properties of CaIn the present paper we introduce a simple model that takes into account both thestochasticity due to IPPercolation in connection with Cae.g.The aim of the simple model that we introduce in this paper is to characterize thebasic mechanisms that shape the distribution of the number of channels that openduring puffs. In particular, we identify the competition between two stochasticprocesses as the main determinant of the form of the distribution. Therefore, ananalysis of this form may give information on the relative weight of the twocompeting processes. The model does not include a detailed description of thedynamics that takes place during or between events. For some time most models ofintracellular Casee e.g..The obsi.e., of IPi.e., the distance We introduce here a simple model to describe the distribution of puff sizes thatoccur at sites with similar numbers of IPThe two stochastic components of the model are evident in the expression of i.e., i.e., on the realization. In those cases,the dominant stochastic component of The relationship between We first illustrate how the distribution, A transition from Cai.e.i.e.In the Cae, , see . We plotWe can think of the Ca of  see . The arri.e., the transition to the IPi.e. on the maximum distance for whichCICR-coupling can work effectively. Therefore, it should be possible to estimate i.e., to infer a biophysical parameter thatcharacterizes the intra-cluster dynamics from statistical information on theemergent collective behavior of the channels of the cluster.The results of puff see . Thus, tith  see , taking  of  see  we conclWe now discuss how we can estimate We now describe how to estimate The procedure is illustrated in Intracellular CaRecent experiments In this paper we have presented a simple model that includes a description of theintra-cluster spatial organization with which we can reproduce the observeddistribution over all event sizes. In the model the distribution, e.g.There are two limiting cases in which one of the two stochastic processes consideredin the model is the main determinant of the distribution shape. If the mean distancebetween IPGiven that Each term of the sum that defines Eq. (1) is the product of two functions. We have ananalytic expression for one of them, omly see . We onlya priori. Namely, we fix at the beginning the values of For each value,  of  see .We define two quantities,"}
+{"text": "It was also eventful for the Indian Journal of Urology. For the first time we organized an independent evening function to celebrate the journal's achievements. It also provided an opportunity to thank all the people who have participated and helped us in our endeavor. The IJU best paper first prize award was bestowed to Dr. S. Sriram for his paper titled \u201cDetection and Management of post transplant renal artery stenosis\u201d at the hands of USI President Dr. Ganesh Gopalakrishnan. The second best paper award was awarded to Dr. (Mrs) P. Rekha for her paper \u201cHistological reclassification, histochemical characterization and c-kit immunoexpression in renal cell carcinoma\u201d by Dr. S.V. Kotwal, the President Elect.The 43The editorial board took this opportunity to acknowledge the contribution of all peer reviewers and Professor Robert Pickard, Freeman Hospital, Newcastle, UK was selected as the best international peer reviewer. While Dr. Gagan Gautam was considered as the best reviewer from India for the year 2009. I congratulate both of them and hope that they would continue to help the Indian Journal of Urology.This issue carries a symposium on \u201cTesticular cancer\u201d edited by Dr. Hemant Tondgonkar, the Head of Urology Department, Tata Cancer Hospital, Mumbai. Testicular cancer is a remarkable success story and a fine example of multidisciplinary management of malignancy.I would like to take this opportunity to personally express gratitude to the outgoing chairman of the Indian Journal of Urology Dr. Mahesh Desai. He has been a source of great strength and was always available in times of crisis. It was his dream to make the Indian Journal of Urology one of the best and to make it visible in the international arena. I hope that he will continue to guide us in future.The editorial board welcomes Professor Dr. Ganesh Gopalakrishnan as the new chairman of the Indian Journal of Urology and we all look forward to working with him.With best wishes."}
+{"text": "The high diversity of ornamentation type in pollen grains of angiosperms has often been suggested to be linked to diversity in pollination systems. It is commonly stated that smooth pollen grains are associated with wind or water pollination while sculptured pollen grains are associated with biotic pollination. We tested the statistical significance of an association between pollen ornamentation and pollination system in two families of the monocotyledons, the Araceae and the Arecaceae, taking into account the phylogenetic framework.Character optimization was carried out with the Maximum Parsimony method and two different methods of comparative analysis were used: the Concentrated-Change test and the Discrete method. The ancestral ornamentation in Araceae is foveolate/reticulate. It is probably the same in Arecaceae. The ancestral flowers of Araceae were pollinated by beetles while ancestral pollination in Arecaceae is equivocal. A correlation between ornamentation type and pollination was highlighted in Araceae although the results slightly differ depending on the method and the options chosen for performing the analyses. No correlation was found in palms.In this study, we show that the relationships between the ornamentation type and the pollination system depend on the family and hence vary among taxonomic groups. We also show that the method chosen may strongly influence the results. The exine wall of the pollen grains of flowering plants displays patterns of ornamentation  that are highly diversified. The reasons accounting for such variation in the ornamentation of pollen grains in flowering plants still remain unclear. Among the different types of relationship implying pollen ornamentation that have been suggested, the existence of a link between exine sculpturing and pollinator type has often been proposed and was even evidenced in certain situations Character optimization was carried out with the Maximum Parsimony method implemented in the Mesquite software .Two PCMs were used: the Concentrated Changes Test or CCT  and DiscTo our knowledge, there is little data in the literature concerning the evolution of ornamentation of pollen grains in monocots . ConcernArisaemateae+Areae clade . The interpretation of the results may then be strongly influenced by the method chosen, as already shown . In our In spite of the important literature on pollen ornamentation available for the Arecaceae , no steaThe Pollination type appeared as a very variable character and consequently, no clear evolutionary trend emerged from the character optimisation Figure . The ancThe reason why Angiosperms display such a large diversity of pollen ornamentation remains to date rather unclear. Several studies addressing this question have been produced, often leading to conflicting, or at least different, conclusions. Most studies however examine the hypothesis of a link between pollen ornamentation and the pollination system. The underlying idea is that since pollen grains need a vector (biotic or abiotic) to reach the female parts, the pollen surface may play a role in the efficiency of the interaction either with the pollination agent or with the receptive area of the female organs. A relationship between abiotic pollination (wind and water) and smooth (or nearly) pollen grains has been proposed in many studies ,22 but cThe fact that no correlations could be detected in the palm family may be due to various reasons. First, it has to be stressed that the sampling was sparser for palms than for the Araceae. In particular, there was a poor overlap at the species level between the pollen and the pollinator datasets. This led us to combine information from different species for the ornamentation type, which we are aware may be questionable considering the high lability of the character even at the intraspecific level. We tried to overcome this problem by attributing polymorphic character states whenever intrageneric diversity was recorded, and by applying two different treatments to polymorphic species in the comparative analyses but we cannot exclude that the choices made here  may have biased the results. However, there is a possibility that our results indeed reflect the reality and that pollen ornamentation is not involved in the pollination syndrome in palms. In this family, the traits linked to pollinator identity still remain almost unknown. Palm flowers are relatively poorly diversified in morphology when compared to the spectacular flowers of other groups . In manyIn conclusion, it is our feeling that there is little to be gained from seeking a general tendency concerning the relationship between the type of pollen ornamentation and the pollination system across the angiosperms. The ornamentation of the pollen wall is only one of the numerous elements that constitute the pollination syndrome and certainly not the most important . Like thThe authors declare that they have no competing interests.JS performed the coding and the optimization of the reconstruction of the characters, carried out all the comparative analyses, interpreted the data and contributed to writing the manuscript. WJB provided the phylogenetic framework for the Arecaceae. MCA assembled the dataset on the pollination type in Arecaceae. SN supervised the study and contributed to writing the manuscript. All authors read and approved the final manuscript.Studies published about relationship between the ornamentation of pollen grains and others characters in angiosperms. Studies previously published about relationship between the ornamentation of pollen grains and others characters in angiosperms.Click here for fileDetailed information on the methods used. Detailed information on the material and the methods used in the study.Click here for fileEvolution of the ornamentation and of the pollination in Araceae when polymorphic species are duplicated and with the coding 'Psilate/Verrucate' vs. 'Other Ornamentation' and 'Beetle' vs 'Other Pollination'. A. Optimization of the ornamentation type coded as 'Other-O' (white) and 'Psilate/Verrucate' (black). B. Optimization of the pollination type coded as 'Other-P' (white) and 'Beetle' (black). The bicoloured branches indicate an equivocal inference of the ancestral character state. The transitions towards 'Beetle' pollination and 'Psilate/Verrucate' ornamentation are indicated by full crossbars and the reversals towards 'Other-P' pollination and 'Other-O' ornamentation are indicated by open crossbars (red and blue crossbars correspond respectively to the ACCTRAN and DELTRAN optimizations). Species names are coloured according to the subfamilies .Click here for fileEvolution of the ornamentation and of the pollination in Araceae when polymorphic species are removed and with the 'Echinulate' vs. 'Other Ornamentation' and 'Fly' vs 'Other Pollination'. A. Optimization of the ornamentation type coded as 'Other-O' (white) and 'Echinulate' (black). B. Optimization of the pollination type coded as 'Other-P' (white) and 'Fly' (black). The bicoloured branches indicate an equivocal inference of the ancestral character state. The transitions towards 'Fly' pollination and 'Echinulate' ornamentation are indicated by full crossbars and the reversals towards 'Other-P' pollination and 'Other-O' ornamentation are indicated by open crossbars (red and blue crossbars correspond respectively to the ACCTRAN and DELTRAN optimizations). Species names are coloured according to the subfamilies .Click here for fileEvolution of the ornamentation and of the pollination in Araceae when polymorphic species are duplicated and with the coding 'Echinulate' vs. 'Other Ornamentation' and 'Fly' vs 'Other Pollination'. A. Optimization of the ornamentation type coded as 'Other-O' (white) and 'Echinulate' (black). B. Optimization of the pollination type coded as 'Other-P' (white) and 'Fly' (black). The bicoloured branches indicate an equivocal inference of the ancestral character state. The transitions towards 'Fly' pollination and 'Echinulate' ornamentation are indicated by full crossbars and the reversals towards 'Other-P' pollination and 'Other-O' ornamentation are indicated by open crossbars (red and blue crossbars correspond respectively to the ACCTRAN and DELTRAN optimizations). Species names are coloured according to the subfamilies .Click here for fileDetailed results about the comparative analyses conducted with the Concentrated-Changes Test in Araceae. Pollen ornamentation was coded as 'Psilate/Verrucate' vs. 'Other Ornamentation', pollination system was coded as 'Beetle' vs 'Other Pollination'. A \u2013 Distribution of events in the character 'pollination type' on branches reconstructed as having 'Psilate/Verrucate' and 'Other-O' ornamentation, respectively. B \u2013 Distribution of events in the character ornamentation type on branches reconstructed as having 'Beetle' and 'Other-P' pollination, respectively. O: Other-P or Other-O depending on the context; B: Beetle; P/V: Psilate/Verrucate; 1: Pollination and ornamentation type reconstructed with ACCTRAN; 2: Pollination and ornamentation type reconstructed with DELTRAN. The Fisher exact test was computed for the columns with numbers in bold .Click here for fileDetailed results about the comparative analyses conducted with the Concentrated-Changes Test in Araceae. Pollen ornamentation was coded as 'Echinulate' vs. 'Other Ornamentation', pollination system was coded as 'Fly' vs 'Other Pollination'. A \u2013 Distribution of events in the character 'pollination type' on branches reconstructed as having 'Echinulate' and 'Other-O' ornamentation, respectively. B \u2013 Distribution of events in the character ornamentation type on branches reconstructed as having 'Fly' and 'Other-P' pollination, respectively. O: Other-P or Other-O depending on the context; F: Fly; E: Echinulate; 1: Pollination and ornamentation type reconstructed with ACCTRAN; 2: Pollination and ornamentation type reconstructed with DELTRAN. The Fisher exact test was computed for the columns with numbers in bold .Click here for fileEvolution of the ornamentation and of the pollination in Arecaceae when polymorphic species are duplicated and with the coding 'Echinulate' vs. 'Other Ornamentation' and 'Fly' vs 'Other Pollination'. A. Optimization of the ornamentation type coded as 'Other-O' (white) and 'Echinulate' (black). B. Optimization of the pollination type coded as 'Other-P' (white) and 'Fly' (black). The bicoloured branches indicate an equivocal inference of the ancestral character state. The transitions towards 'Fly' pollination and 'Echinulate' ornamentation are indicated by full crossbars and the reversals towards 'Other-P' pollination and 'Other-O' ornamentation are indicated by open crossbars (red and blue crossbars correspond respectively to the ACCTRAN and DELTRAN optimizations). Species names are coloured according to the subfamilies .Click here for fileDetailed results about the comparative analyses conducted with the Concentrated-Changes Test in Arecaceae. Pollen ornamentation was coded as 'Psilate/Verrucate' vs. 'Other Ornamentation', pollination system was coded as 'Beetle' vs 'Other Pollination'. A \u2013 Distribution of events in the character 'pollination type' on branches reconstructed as having 'Psilate/Verrucate' and 'Other-O' ornamentation, respectively. B \u2013 Distribution of events in the character ornamentation type on branches reconstructed as having 'Beetle' and 'Other-P' pollination, respectively. O: Other-P or Other-O depending on the context; B: Beetle; P/V: Psilate/Verrucate; 1: Pollination and ornamentation type reconstructed with ACCTRAN; 2: Pollination and ornamentation type reconstructed with DELTRAN. The Fisher exact test was computed for the columns with numbers in bold .Click here for fileDetailed results about the comparative analyses conducted with the Concentrated-Changes Test in Arecaceae. Pollen ornamentation was coded as 'Echinulate' vs. 'Other Ornamentation', pollination system was coded as 'Fly' vs 'Other Pollination'. A \u2013 Distribution of events in the character 'pollination type' on branches reconstructed as having 'Echinulate' and 'Other-O' ornamentation, respectively. B \u2013 Distribution of events in the character ornamentation type on branches reconstructed as having 'Fly' and 'Other-P' pollination, respectively. O: Other-P or Other-O depending on the context; F: Fly; E: Echinulate; 1: Pollination and ornamentation type reconstructed with ACCTRAN; 2: Pollination and ornamentation type reconstructed with DELTRAN. The Fisher exact test was computed for the columns with numbers in bold .Click here for file"}
+{"text": "After publication of this work , US EnviAll authors have been notified of, and agree with this decision.The authors declare that they have no competing interests.in vitro experiments, analyzed the data and wrote the manuscript. LWY and HN performed Taq Man\u00ae real time RT-PCR and gene expression array experiments, respectively. MJE assisted with in vitro experiments. KTM participated in planning the studies and analysis and interpretation of the data. All authors have read and approved the final manuscript.LMC designed the study and carried out the"}
+{"text": "M. tuberculosis and E. coli genomes, and identify biologically interpretable rules which predict protein functional class from information only available from the sequence. These rules predict 65% of the ORFs with no assigned function in M. tuberculosis and 24% of those in E. coli, with an estimated accuracy of 60\u201380% . The rules are founded on a combination of detection of remote homology, convergent evolution and horizontal gene transfer. We identify rules that predict protein functional class even in the absence of detectable sequence or structural homology. These rules give insight into the evolutionary history of M. tuberculosis and E. coli.The analysis of genomics data needs to become as automated as its generation. Here we present a novel data-mining approach to predicting protein functional class from sequence. This method is based on a combination of inductive logic programming clustering and rule learning. We demonstrate the effectiveness of this approach on the"}
+{"text": "Am J Trop Med Hyg 82: 838\u2013845, the financial support section should have stated that Dr. Ruiz is a member of the Research Career of the National Council of Scientific and Technical Research (CONICET) from Argentina. The journal regrets this omission.In Am J Trop Med Hyg 66: 605\u2013610, one of the author's last names is misspelled. The correct spelling of the sixth author's name is Ippolytos Kalofonos. The journal regrets the error.In"}
+{"text": "Stepping into New Year, let me wish you all \u2018A Very Happy New Year\u2019 along with my team. It is also the time worth looking into what has been achieved and what you can look forward to in the coming year.All the issues of 2008, special supplement of January on Dementia and the January \u2013 March 2009 issue are already in our website and hard copies are being distributed to members at ANCIPS. The posting of copies will commence after ANCIPS 2009 conference. Possibly this is happening for the first time in the history of our journal. But this is a necessity rather than anything special because the above scheduling is essential if we are serious about getting the journal indexed. However, the general body has to look into this issue next year in view of elections due then. As the new editor needs time to settle, if changes do come about, a provision has to be made to the publication of the Jan-march issue by the previous editor himself, preferably before ANCIPS. I seek the permission of the esteemed EC and the members.I am very happy to present a DVD containing:All the published issues of IJP since 1958-2008. A powerful search engine has been embedded to data mine based on titles, authors, abstracts and keywords. Many people have supplied the issues of the past journals but some names deserve a special mention. I am grateful to Dr. O. Somasundaram, who supplied majority of the issues, Dr. Chittaranjan Andrade from Bangalore and Dr. Smita N. Deshpande from New Delhi for supplying the journals from their private collections.All the published issues of Indian Journal of Neurology & Psychiatry for the years 1949- 1953 edited by Dr. N.N. De and Dr. A.K. Deb respectively. It had stopped publication between 1954-1957 and it came out with the current name of Indian Journal of Psychiatry in 1958. I am grateful to Dr. Haque Nizamie, Director & Dr. D. Ram, Professor, Central Institute of Psychiatry, Ranchi for all the interest and effort in getting these copies scanned and transmitted to us for processing. The Commemorative Volume featuring 50 golden years was published in January 2008 and for those still missing the issue and interested in it, it is available as a supplement at our website.As a service to the society, we have also included the clinical practice guidelines edited and published by Dr. Shiv Gautham & Dr. Ajit Avasthi for the Indian Psychiatric Society. It contains:First Publication of 2004 covering 6 major disorders \u2013 Schizophrenia, Depression, Bipolar disorders, Obsessive compulsive disorders, Generalized anxiety disorder and panic disorderSecond Edition covering - substance abuse disorders, sexual dysfunctions & sleep disorders (2005)Third Edition covering \u2013 Geriatric Psychiatry (2006)Fourth Edition covering \u2013 Child Psychiatry (2007)I am grateful to Dr. Shiv Gautham & Dr. Ajit Avasthi for all the help and effort in getting the CPGs.We have also included free the photo-directory containing the updated membership codes, names, addresses and photos of all the members in PDF format. I must thank our treasurer Dr. Asim Kumar Mallick from Kolkata and his team for all the effort and help.The preparation of the DVD was a mammoth task and I will be failing in my duty if I do not thank the whole team that put up their heart and soul in the task. I must thank in addition to Dr. O. Somasundaram, from Chennai, the PGI group led by Dr. P. Kulhara, Dr. Ajit Avasthi and Dr. Sandeep grover for the input which changed our archiving ways dealing with digitalization. Dr. Swaminath G. & Dr. Ajit Bhide have spent many hours and days to beat the deadline. My thanks to the PGs in our department - Dr. Abhijith H., Dr. Kiran Kumar K, Dr. Smitha T., Dr. Nimisha Mishra and Dr. Saraswathi N. I also thank the other staff in the department - Dr. Dushad Ram, Asst. Professor, Dr. L. Sam S. Manickam, local coordinator, Dr. VST Krishna, PSW and Prof. P. Kalaiah, Dr. Rajesh Raman, Associate Professor and Dr. Bindu. A for their active involvement. My thanks to Mrs. Renuka B.S of Vijaya foundation, Mysore and Roopa N. from Bangalore for review and editing. My thanks are also due for Dr. Ajit Bhide and Dr. Chittaranjan Andrade for reviewing the DVD. I am grateful to Mr. Madhushetty, CEO and Mr. Srinath and Mr. Raghu of Indigo Informatics at Bangalore for the excellent job executed with aplomb. I also thank Mr. Vasudev Bhatt from Ramya creations, Mysore for the work and help all through. My sincere thanks to M/s. Sun Pharmaceuticals, Mumbai, who have sponsored it fully under a special educational grant and I am specifically grateful to Mr. Dilip Sanghvi, CEO, Mr. T.K. Roy, Senior vice president & Mr. K. Nanda Kumar, Vice President who personally took interest in the whole project.I am very happy to present the special issue of Dementia, truly a collectors' volume to all the members. Dr. Shaji K.S from Trissur was the guest editor and all the credit must go to him for his very systematic effort in getting the invited and original articles numbering 21 in time and setting it in order. In view of the space constraint some of the articles and the original articles received for the supplement have appeared in this issue. The supplement is already available at our website and hard copies are available for distribution at ANCIPS 2009 at Agra. I am grateful to Mr. Vivek Seth, CEO of Intas Pharmaceuticals, Ahmedabad for sponsoring the issue fully. I also thank Mr. Ravi Prasad L., Sales Manager and Mr. Shivakumar T. M. of Intas Pharmaceuticals for their personal interest.I am confident the New Year will usher in many new changes so also many new faces. We intend to approach NHS for indexing purposes early this year. Dr. Mohan Das, incoming president has promised to lead the process. Many national and international academicians and researchers have promised their helping hand. Journal will have new sections like Psychiatric Pearls, the section under Dr. Vikram Yeragani and many more. Dr. Ajit Bhide is doing excellent service so also Dr. Vikram Patel, Dr. Chittaranjan Andrade and others. I am confident the new year will be a milestone year in the annals of IPS.I have one dream fulfilled of what I had expressed in my first editorial \u2013 golden jubilee, 2008 of digitalizing and archiving of IJP. Luckily with every one contributing the DVD contains much more than that. For the future, as I know there are excellent publications available at Zonal, State and Local branch levels which are not accessible to many members and as such lost to the society. How about digitalizing all these publications? I am confident that it could be done by ANCIPS 2010! If society wills, budgetary constraint can be overcome one way or other."}
+{"text": "Salmonella Enteritidis emerged as a major egg-associated pathogen in the late 20th century. Epidemiologic data from England, Wales, and the United States indicate that S. Enteritidis filled the ecologic niche vacated by eradication of S. Gallinarum from poultry, leading to an epidemic increase in human infections. We tested this hypothesis by retrospective analysis of epidemiologic surveys in Germany and demonstrated that the number of human S. Enteritidis cases is inversely related to the prevalence of S. Gallinarum in poultry. Mathematical models combining epidemiology with population biology suggest that S. Gallinarum competitively excluded S. Enteritidis from poultry flocks early in the 20th century."}
+{"text": "An. arabiensis was the predominant species observed in all regions whereas An. pharoensis and An. funestus were observed along the south border in the Senegal River valley where extensive irrigation schemes are present. The distribution limits of anopheline species were observed from the Senegal River basin in the Trarza region up to the south limit of the Saharan desert in Tidjikja city. Overall, all An. funestus and An. pharoensis were fed respectively on human and ovine hosts whereas the mean anthropophilic rate of An. gambiae s.l. was 53%. A low Plasmodium falciparum infection rate was observed for species of the An. gambiae complex (0.17%) represented mainly by An. arabiensis. Because of the specific nature of this investigation, longitudinal studies are essential to better characterize the malaria vectors and their respective role in malaria transmission.This study reports for the first time on the distribution, host preference and infection rates of malaria vectors in Mauritania. It was conducted during an outbreak of Rift valley fever. Three anopheline species were reported.  In Mauritania, malaria is a major public health concern in southern and south-eastern regions. In fact, it is clearly on the increase and significantly contributes to the increase in illness and mortality, especially in children under 5 years of age and pregnant women . In spitAn. gambiae s.l. and An. funestus appear to be the dominant vectors of malaria. Their limits of distribution throughout the country are however unknown. This situation makes impossible the determination of the origin of malaria suspected cases in areas where malaria vectors are thought to be absent. One of the principal explanations for such suspected cases is that they have been imported. However, this hypothesis seems to be speculative with regards to some autochthonous cases observed [observed . The hypobserved .Plasmodium falciparum, P. malaria and P. ovale CS antigen [An. gambiae complex and molecular forms of An. gambiae s.s. were identified by PCR according to Scott et al. [Our survey covered 21 localities in 5 administrative regions during October and November 2003: Trarza , Brakna , Assaba  Tagant  and Hodh El Garbi (Tintane)  followed by An. pharoensis (5%) and An. funestus (3%). An. gambiae was collected in all localities visited except in Moudjeria (Tagant region) where no mosquito was collected. All three species were collected in Trarza region, but An. pharoensis was observed only in Trarza and Brakna regions. The molecular identification of the species of the An. gambiae complex has revealed the predominance of An. arabiensis. An. gambiae M form was observed only in Assaba , Brakna  and Hodh El Garbi . The distribution limits of anopheline species ranged from the Senegal River Valley in Trarza region up to the south limit of the Saharan desert in Tidjikja city.In total, 647 anopheline specimens belonging to three species were collected. An. arabiensis in the Mauritanian context is in agreement with the general distribution of this species in Africa [An. funestus was observed only in Brakna region adjacent to the Senegal River basin where its comeback was recently reported [An. funestus in this area. An. pharoensis whose vectorial role in malaria transmission was already suspected in the Senegal River delta [The predominance of n Africa . An. funreported , as it ireported . The dever delta  was founAn. gambiae s.l. among the five regions . All An. funestus and An. pharoensis had fed on human and ovine hosts respectively  cannot be excluded. Moreover, because of the specific nature of this investigation, longitudinal entomological studies are essential in order to better characterize the malaria vector populations and to identify their respective roles in the transmission of human Plasmodium.To our knowledge, this study reports, for the first time, on the distribution, host preference and infection rates of malaria vectors in Mauritania. With regard to these findings, and most notably the very low mosquito infection rates, it is clearly necessary to differentiate febrile cases attributed to malaria from other febrile infections, including the hemorrhagic fevers in the light of their recurrent emergence. However, the possibility that there is transmission of uritania  and tranThe authors declare that they have no competing interests.HB, SAOM and DD contributed to sample collections and laboratory processing, BL participated to the study conception and coordination, ID and MD conceived, coordinated the study and drafted the manuscript. All authors read and approved the final manuscript."}
+{"text": "After his initial schooling and intermediate at Indore, he joined Medical College, Nagpur, and completed his M.B.B.S in 1952. For the next 2\u20133 years, he served as a House Surgeon and a Registrar at Medical College, Indore. In 1955, in pursuit of higher specialized education, he moved to the USA. He completed his 4-year residency in Urology at Kansas City Hospital, Kansas, and cleared FRCS in Urology at the Royal Canadian College of Surgeons. He decided to return to his motherland in the hope of initiating Urology, which hardly existed as a speciality then.One of the founding fathers of Indian Urology, Professor B. C. Bapna, was born on 1On his return to India in 1961, he visited few places, but in the absence of a suitable opportunity and his ardent love for Urology, he joined as a Registrar in the Department of General Surgery at the All India Institute of Medical Sciences (AIIMS), New Delhi. He started performing endoscopic urological procedures with his own set of ACMI instruments, which he had brought from the USA. This made him very popular at AIIMS. The speciality of Urology started at AIIMS in 1963 with Late Prof. S. M. Singh as Associate Professor and Dr. B. C. Bapna as Assistant Professor. In 1969, he was promoted as Associate Professor of Urology and headed a separate unit.In 1971, after the sudden demise of Late P. N. Katawa, Dr. Bapna was selected as Professor and Head of Urology at the Postgraduate Institute of Medical Education and Research, Chandigarh (PGIMER). He was joined by Dr. M. S. Rao as Assistant Professor in 1972 and myself as a Lecturer in 1975. Dr. S. Vardyanathan, who passed his M.Ch under Professor Bapna, became a Lecture later on.Prof. Bapna was a strict disciplinarian; a hard task master and brooked no non-sense. A reprimand to the defaulting Senior Resident and even to the faculty members would come in the choicest words that would put them in place. He trained scores of specialists, both at AIIMS and at PGIMER, who occupied coveted and places of pride not only in India but in the other countries too. Prof. Bapna, besides being a great teacher, was also a master craftsman as an endoscopic surgeon. Before the advent of the fiber optic light sources, he practiced his art with battery-cell-operated lamps. It was always a pleasure to watch him operate.He established probably one of the best centers of Urology training and research at PGI, Chandigarh, that it became the envy of the best brains in the country, who longed to get admission for M.Ch Urology. Under his leadership, a number of research projects under the aegis of the Indian Council of Medical Research (ICMR), Department of Science and Technology (DST) and Indian National Science Academy (INSA) and a generous funding from the Institute were initiated. These encompassed the endemic renal stone disease in this region: national highway trauma and neurogenic bladder and complicated vesico-vaginal fistulae as a consequence of neglected labour in poor rural areas. All these efforts resulted in the publication of a very large number of articles in reputed and peer-reviewed national and international journals. The center at PGI came on the world map of Urology.The speciality of urology started in India in 1960\u20131 as a section of Urology in the larger ambit of the Association of Surgeon of India. Dr. Bapna played a stellar role in the formative years as its Secretary- cum-Treasurer for a long time. He gave it a definite direction as well as monitored its growth. He was elected as President of the Urological Society of India for a 2-year term in 1979\u201380. Prof. Bapna also became a fellow of the National Academy of Medical Sciences in India.He superannuated in June 1986 and moved to Indore a year later. He practiced for some time in the beginning only. At the age of 83 years, Prof. Bapna continues to be in the pink of health and has a wonderful time in the company of his children and grandchildren. I have probably had the longest association with Prof. Bapna, first as his student and later on as his colleague. It was indeed a great pleasure and a challenge. I learnt a lot from him, which enabled me to wade through comfortably in troubled situations. I wish Mrs. and Prof. Bapna many more years of a healthy and peaceful life."}
+{"text": "The authors declare the following competing interest, which should have been declared at the time of publication. M.L. discloses consulting income from the Avian/Pandemic Flu Registry  and from Novartis Vaccines and Diagnostics. The other authors declare no competing interests."}
+{"text": "Sir,et al. have reviewed the recent advances in drug resistant tuberculosis.(Grover, rculosis. In this rculosis. The caserculosis. This strrculosis. In this rculosis. The impoThe objective for us, however, is to prevent the emergence and transmission of such a strain. The most important risk factor implicated in the occurrence of XDR cases is inadequate or inappropriate management of tuberculosis. Hence, there is an urgent need to strengthen services of DOTS and DOTS-Plus under RNTCP. Only an efficient first-line therapy in the form of DOTS can stop XDR tuberculosis from being a major public health concern in the days to come."}
+{"text": "Honorable Shri U. C. Sharma, Director of Medical Education, Government of Assam, and chief guest of the evening; Shri M. M. Deka, Principal, Guwahati Medical College, and guest of honor; Dr. H. K. Borah, Chairman, organizing committee; Dr. Nirmal Bhattacharyya, Organizing Secretary; members of the executive committee; past Presidents and Secretaries of this association; invited guests; faculty; delegates; and ladies and gentlemen.th annual conference at this beautiful city of Guwahati. The terrorist attack of October 30th and its aftermath forced us to postpone our meeting by a month. Such cowardly acts of terrorism shock us, but do not deter our sprits and commitment toward love, justice, mercy, and working towards the progress of our country and our specialty.I feel honored to be here as the President of our august association on the inaugural function of the 34As I stand here talking before you, I still remember the mid-70's when I returned back to Ahmedabad after my pediatric surgical training in the United Kingdom. I started pediatric surgery in Gujarat with four beds in a busy 1000-bedded Municipal Hospital in Ahmedabad. We have progressed from those days when vascular access used to be the first and major challenge for any neonatal or pediatric surgical problem to advanced neonatal and pediatric minimally invasive surgery. Today, I can proudly state that many centers in India including Ahmedabad are doing a huge amount of excellent work which is at par with many leading centers across the world.th year as a separate association. As is characteristic of Indians, we have made a lot of progress in not only on the national but also on the international scene. We have now reached a stage where we can put forward our views and experiences with confidence and authenticity and can be sure that pediatric surgeons across the globe listen to us with conviction.It has been almost 53 years since IAPS branched out from general surgeons as a separate group of people who were not only interested but also dedicated to deal with surgical problems of children. We are in our 15However friends, it is still too early to pat our backs at this point of time. India won a much awaited individual gold medal and two bronze medals at the recent Beijing Olympics, but countries like Ethiopia, Turkey, Uzbekistan, and Zimbabwe have been winning more medals than us for years. As per UNICEF 2007 records, India registers the highest number of child deaths across the globe. Of the estimated 9.7 million children in the world dying before completing five years of age, 21% (i.e. 2.1 million) are in India. Also, 50% of child mortality is due to neonatal reasons, as opposed to 37% across the world. As we all know, neonatal anomalies account for almost 10% of the total neonatal mortality rates and this is where we pediatric surgeons would be playing a major role. There are still many pediatric surgical centers across India which are managing a phenomenal amount of pediatric surgical workload with meager resources, lack of trained manpower, and poor backup facilities leading to a high morbidity and mortality. Training of paramedical personnel, nurses, and technical staff should be made priority if we want to come out with good pediatric surgical results.Female feticide though legally banned in India is not so successful. Feticide should be legally banned but it should not be a sex-biased law. Lots of male fetuses are also aborted for minor defects which are easily correctable postnatally in India. Is this legally permissible? I want that we should raise our voice of banning feticide as a whole and not a sex-biased law.Over the past year, there has been a lot of exchange of knowledge and clinical experience in the form of CME's, seminars, conferences, and workshops across the country. Details of the same are there in the Secretary's report and I will avoid repetition of the same. My congratulations to all the organizers. Over and above all these meetings, many state chapters and subchapters of IAPS have been diligent and have carried out their academic activities with precision. Special congrats to the Tamilnadu and Pondicherry chapter of IAPS, headed by Prof. Sathappan and Dr. Raveenthiran, which organized its seventh annual conference and preconference workshop at Vellore in July. Quality of workshop organization was taken to a higher level by Dr. Srimurthy, Dr. Ramesh, and their team at Bangalore when they organized the International Workshop on Advanced Pediatric Laparoscopy in August. The urodynamics workshops organized by Pediatric Urology subchapter of IAPS across different centers of the country have also been generating a lot of interest. I request other subchapters of IAPS to catch up.th birthday at New Delhi. I felt proud to see the amount of respect this great stalwart received from senior colleagues from across the world who had come all the way specially to greet him.We are proud that our fellow member and past President Dr. D. K. Gupta is presently the President of the Asian Association of Pediatric Surgeons (AAPS) and also President of Federation of Association of Pediatric Surgeons of SAARC (FAPSS). He has also been given the responsibility to organize the World Congress of Pediatric Surgeons in 2010 at Delhi. I had the honor and privilege to meet Prof. P. Upadhyaya, the recipient of this year's R. K. Gandhi gold medal, at a meeting organized to honor him on his 80Honorary member of IAPS Prof. Prem Puri has been elected as the President of the World Federation of Associations of Pediatric Surgeons (WOFAPS). He also received Honorary Fellowship from the American Academy of Pediatrics for his work on VUR.The year gone by has been shocking for our association in that we lost a dear friend Dr. K. K. Sharma. This is the first time in the history of our association that we have faced such a calamity. Dr. Sharma was a dynamic and efficient person. He had set himself high goals for the betterment and progress of IAPS during his tenure as Secretary cum Treasurer. As a tribute to the departed soul, we have named the session on GI surgery at this conference on his name. Dr. V. Sripathi needs special mention for the way in which he has shouldered the responsibility of Secretary cum Treasurer after the sudden demise of Dr. Sharma. He has been immaculate, prompt, and also very considerate in carrying out his duties. A special word of thanks to Venkat!I would like to sincerely thank Dr. H. K. Borah, Dr. N. C. Bhattacharyya, and the entire team of IAPSCON 2008 for their dedicated hard work to put up a fantastic show at Guwahati in spite of all the odds. This year's IAPSCON is unique for it is a 'complete Indian affair'. All our CME speakers, orators, paper presenters, and even delegates are Indians. I am sure you all will agree that they have put up an excellent show. The next IAPSCON will be held in the historic city of Lucknow. Dr. S. N. Kureel, Dr. R. K. Tandon, Dr. Ashish Wakhlu and their team will leave no stone unturned to make it a memorable event for you all.I would like to thank all my friends and seniors who have helped me in the times of need during my tenure as President of this august association. Thanks to all my executive committee members and past President Dr. Biswanath Mukhopadhyay for their support. I now pass the baton to my successor Dr. V. K. Raina who I am sure will take the association to further heights. Finally, I would like to thank my wife Nita and my son Dr. Amar Shah who have been a constant source of inspiration and whole-hearted support.Thank you all for giving me this opportunity to serve you all as President, IAPS.Wishing you all a happy and fruitful time in GuwahatiLong live IAPSJai Hind"}
+{"text": "Cis-regulatory modules (CRMs) are distinct, genomic regions surrounding the target gene that can independently activate the promoter to drive transcription. The activation of a CRM is controlled by the binding of a certain combination of transcription factors (TFs). It would be of great benefit if the transcriptional output mediated by a specific CRM could be predicted. Of equal benefit would be identifying in silico a specific CRM as the driver of the expression in a specific tissue or situation. We extend a recently developed biochemical modeling approach to manage both prediction tasks. Given a set of TFs, their protein concentrations, and the positions and binding strengths of each of the TFs in a putative CRM, the model predicts the transcriptional output of the gene. Our approach predicts the location of the regulating CRM by using predicted TF binding sites in regions near the gene as input to the model and searching for the region that yields a predicted transcription rate most closely matching the known rate.eve gene, MSE2. A model trained on the MSE2 in D. melanogaster was applied to the surrounding sequence of the eve gene in seven other Drosophila species. The model successfully predicts the correct MSE2 location and output in six out of eight Drosophila species we examine.Here we show the ability of the model on the example of one of the CRMs regulating the D. melanogaster to other Drosophila species and accurately predicts the location and transcriptional output of MSE2 in those species. However, we also show that the current model is not specific enough to function as a genome-wide CRM scanner, because it incorrectly predicts other genomic regions to be MSE2s.The model is able to generalize from  Each CRM responds independently to a particular set of TFs, and causes a particular level of transcription to occur at the promoter it controls. CRMs might therefore be involved in \"situation-specific\" gene expression (e.g. tissue specificity). To understand what role CRMs are playing in \"situation-specific\" gene expression, we need computational models that predict the genomic location of the CRM responsible for triggering the expression of the target gene in a specific situation. Similarly important are computational models that predict the transcription rate mediated by a given DNA sequence. Those models can be applied to identify DNA regions with regulatory functions.Understanding transcriptional regulation is one of the main goals of the post-genomic era. Transcriptional regulation is a very complex biological phenomenon that is controlled by many factors . Here, wD. melanogaster. Our approach is distinct from previously reported CRM predictors  becauseD. melanogaster)  bp in steps of 100 bp. We use the same log-odds PWMs in training and CRM prediction. In particular, we use the background model, B, for D. melanogaster, even when predicting CRMs in other organisms. We do this because changing the background model would change the log-odds scores of sites, and predicted site association constants, Ks, would then be different for identical sites in different organisms.To test the specificity of the model, we apply the model to the predicted TFBS-map of all windows surrounding et al. [To measure the specificity of the model predictions, we compute the PC as defined by Pevzner et al. . For a gK are the \"known\" genomic regions in the MSE2  and P(r) are the \"predicted\" genomic regions predicted by the model using an RMS threshold of r. . A base-pair is considered as predicted if it is part of a \"minimal\" window whose RMS error is equal or below the threshold r. A window is only \"minimal\" if there is no other, smaller window contained within it, whose RMS error is equal or better.where Meta-MEME: eve: Even-skipped gene; D. mel: D. melanogaster; D. pse:  D. pseudoobscura; D. an: D. ananassae. D. moj: D. mojavensis; D. wil:  D. willistoni; D. gri: D. grimshawi. D. vir: D. virilis; D. per:  D. persimilis.DCB researched and carried out the experimental work under the supervision of TLB. The initial manuscript draft was written by DCB, and refined by TLB.Comparison of parameters from different models. Table containing the parameters for the TFs after training was performed.Click here for fileComparison of TFBS-maps in predicted MSE2 regions. Table containing a visualization of the TFBS-maps from the predicted MSE2 regions using our predictor.Click here for fileComparison of TFBS-maps in homologous MSE2 regions. Table containing a visualization of the TFBS-maps from homologous MSE2 regions.Click here for fileSequence conservation of homologous MSE2s. Multiple alignment of the homologous MSE2 region in the eight different Drosophila species.Click here for fileThe Reinitz model and PWMs. Additional detail on the Reinitz model.Click here for fileCount matrices and logos of the used TFs. Table containing the count matrices and logos of the TFs used in this study.Click here for file"}
+{"text": "P. falciparum. However the parasite species P. ovale curtisi, P. ovale wallikeri and P. malariae occur across the continent at population prevalences ranging from negligible, up to ~9% for P. ovale sp. and up to ~15% for P. malariae. All three species are able to recur in the successfully treated patient months or years after exposure, even if successful clearance of blood-stage infections has occurred through antimalarial therapy. We present some recent data from surveys in several African localities as well as analyses of Malaria Reference Laboratory data for patterns of presentation of these parasite species among imported malaria cases in the UK, and consider the possibility that a substantial hidden burden of infection exists. The public health implications and challenges posed by these malaria species to malaria eradication programmes will also be considered.The elimination of malaria in Africa is sensibly focused on the challenge of"}
+{"text": "Patient. We report a 51-year-old male presenting with Grade            III rhabdomyosarcoma.            Discussion. A case of rhabdomyosarcoma which developed in            proximity to a metal surgical implant is described. Few cases have been reported in            the world in humans.The therapeutic approach to the disease is presented, together            with a brief review of literature."}
+{"text": "The 8th and 13th authors' names were spelled incorrectly. The correct name of the 8th author is Jonathan M. Tomaszewski. The correct name of the 13th author is Ivan Bertoncello."}
+{"text": "Quercus complex is one of the systems which can offer such an opportunity. To investigate the contemporary pattern of hybridization we sampled and genotyped 320 offspring from a natural mixed forest comprising four species of the European white oak complex: Quercus robur, Q. petraea, Q. pubescens, and Q. frainetto.Few studies address the issue of hybridization in a more than two-species context. The species-rich Q. petraea and Q. robur, showed a high propensity to hybridize with Q. pubescens and Q. petraea, respectively. Significant structure of the effective pollen pools  was detected in our sample. However, no support was found for the isolation by distance hypothesis. The proportion of hybrids was much higher (79%) in the seed generation when compared to the adult tree generation.A total of 165 offspring were assigned unambiguously to one of the pollen donors within the study plot. The minimum amount of effective pollen originating from outside the plot varied markedly among the seed parents, ranging from 0.18 to 0.87. The majority of the successful matings (64.1%) occurred between conspecific individuals indicating the existence of reproductive barriers between oak species. However, the isolation was not complete since we found strong evidence for both first-generation (8.4%) and later-generation hybrids (27.5%). Only two out of eight seed parents, belonging to First-generation hybrids were observed only between three out of six possible species combinations. Hybrids between one pair of species preferred to mate with one of their parental species. The observation of first and later-generation hybrids in higher frequency in acorns than in adults might be explained by selection against hybrid genotypes, the history of this uneven-aged forest or past introgression between species. Natural hybridization and subsequent introgression provide opportunities for alleles to travel between species within a genus . The preQuercus was suspected for a long time  and oakong time  and confong time -12. Hybrong time  and relaong time . However petraea .Q. robur and Q. petraea . The st stricto .Q. frainetto within the core plot was very small (15 trees) the sampling for this species was extended to the nearby area  with one of the inferred genetic clusters (e.g. 'robur'). In this study we classified each tree with a high probability to belong to one of the four genetic clusters  as pure species and Q < 0.90 as hybrid . However, as in the recent study of Lepais and his colleagues . We ass\u03a6pt, an analogous of Fst, was tested by 9999 random permutations. This analysis was conducted for the total effective pollen pools and for the separate effective pollen pools originating from inside and outside of the study plot. By using the same software we then tested the isolation by distance hypothesis. The association between the two matrices, pairwise \u03a6pt between the effective pollen pools of single tree progenies and pairwise physical distances between the maternal parents, was analyzed using the Mantel test statistics  and seethe area . Accordithe area  the effe reserve . In cont species ,16,37. A1 hybrids between three out of twelve possible species combinations, including reciprocal crossings, which suggest that hybridization at this site is not restricted to one species pair  with thQ. petraea, Q. pubescens and intermediate individuals between both species in Italy [Our results indicate that hybrids participate at reproduction both as pollen donor and receptor (the case of seed tree Fra-102). Similar situations were reported in a mixed stand with in Italy . MoreoveQ. petraea to Q. robur revealed by paternity analysis in our sample is consistent with the outcome of the Bayesian analysis in the adult generation [Q. petraea is very common in the study area while Q. robur is frequent only in a small marginal part of the reserve. Higher success rates of the combination Q. robur  \u00d7 Q. petraea  were also observed in artificial crosses [Q. petraea and Q. robur [Q. pubescens and Q. petraea was mainly from Q. pubescens towards Q. petraea (20/4 matings) in our sample. The opposite direction was observed between the two species in a hybrid zone in Italy [The asymmetric gene flow from neration . A possi crosses ,40. Our Q. robur . Moreovein Italy . The ecoin Italy . These dQ. robur seed parent and the majority of Q. robur adult trees and an overlap of the flowering time with most of the Q. petraea individuals can be advocated as one of the causes to explain the high propensity for hybridization of this seed tree. Differences in flowering time may lead to a preponderance of pollen coming from Q. petraea relative to the pollen coming from its conspecific individuals. Phenological observations at this site are needed to validate this hypothesis. Furthermore, the present results are based on only one flowering season and the patterns of pollen movement may certainly vary from year to year [Q. cerris trees might have been also hindered the pollen coming from the eastern part of the study plot, where Q. robur is predominant (Figure The level of hybridization may be higher for one individual or another because of an overlap in flowering time with most of the individuals of other species. Almost no differences in flowering time between oak species have been reported in different mixed forests ,43. For  to year . Hence, t Figure .Q. robur seed parent which was very similar to the effective pollen pool of Q. petraea trees. The low amount of genetic differentiation between the effective pollen pool received by the Q. robur seed parent and the three other Q. petraea neighboring trees is consistent with the result of the paternity analysis that indicated a high rate of hybridization with Q. petraea trees. In contrast to the study of Streiff and her colleagues [The low amount of genetic differentiation among the effective pollen pools for seed parents which belong to the same species may be due to the limited number of sampled maternal parents. Genetic heterogeneity of effective pollen pools was reported in other studies based on larger sample sizes ,37. Genelleagues  a signiflleagues . The higBy using paternity analysis and a set of six highly polymorphic microsatellite loci we have traced patterns of contemporary gene flow within and between oak species in a natural reserve. Our results confirm that introgressive hybridization between different pairs of species is quite common and play a significant evolutionary role within the white oak species complex. Selection against hybrids over years might contribute to the maintenance of species identity despite considerable amounts of interspecific gene flow. However, the differences between the proportion of hybrid acorns and the proportion of hybrid adults may also be explained by the stand history or past introgression. Further phenological investigations and a larger sample size are required for a better understanding of the hybridization events taking place in this four-oak-species stand.ALC conceived the idea, collected the seed samples, did the laboratory work, performed the paternity analysis, and wrote the majority of the text. OG helped to analyze the data and to draft the manuscript. RF participated in the design and coordination of the study, data interpretation and made substantial contributions to writing this paper."}
+{"text": "Dear ISP members,Greetings from Head Office,It is my pleasure to pen a few words as secretary of ISP for the Journal of Indian Society of Periodontology. Publication of the Journal is an essential part of any scientific professional organization. In the true spirit of our founders and distinguished eminent past office bearers, the new team has taken all the necessary steps to keep our organization in track. ISP has always carved its own image among the dental professional bodies. Journal of our society has a vital role in building up a positive image for an eminent scholar and a dedicated person with enthusiasm and strength Dr. D. Arunachalam has been elected as the editor of JISP. I am sure under his stewardship the journal is going to search its newer heights selecting the image of our society. Our Head Office takes all the measures and lends a helping hand to all the members who want to contribute to the journal. I request co-operation from our members in all our activities including the JISP.I wish Dr. D. Arunachalam and his team all the success ahead in their venture.Thanking You,Yours at Sincere,Secretary,Journal of Indian Society of PeriodontologyE-mail: smilesindia@gmail.comM. M. Dayakar"}
+{"text": "Following publication of the original article , the autC. Neal Stewart Jr. was not included as an author during production process. The publishers apologise for this error. The full author list is given in this correction article. The original article  has been"}
+{"text": "In the original article, there was an error. The link of sequencing data was not attached in Supplementary Material section.A correction has been made to the Supplementary Material section:https://datadryad.org/). All the data can be downloaded from DRYAD by searching for doi: 10.5061/dryad.hm5vs13 or by directly accessing the link: https://doi.org/10.5061/dryad.hm5vs13.The genome assembly and annotation data were deposited in the DRYAD digital repository (The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.The original article has been updated."}
+{"text": "N,N\u2032-diamidocarbene\u2019 by Kelly M. Wiggins et al., Chem. Sci., 2012, 3, 2986\u20132992.Retraction of \u2018Homonuclear bond activation using a stable  Chemical Science article with the agreement of Christopher W. Bielawski, Jonathan P. Moerdyk, and Kelly M. Wiggins due to data fabrication as detailed below. This retraction supersedes the information provided in the Expression of Concern related to this article.The Royal Society of Chemistry hereby wholly retracts this S-methyl thiobenzoate and the compound denoted 7a* did not occur as reported. No reaction occurred and compound 8a was isolated. The characterization data for the two reported compounds was fabricated from other spectra. The signing authors would like to apologise for this and any consequent inconvenience to authors and readers.The Royal Society of Chemistry has been contacted by the corresponding author of this article and the Research Integrity Officer at The University of Texas at Austin regarding concerns of scientific misconduct affecting this article. The Research Integrity Officer has informed us that an investigation to ascertain the validity of the work reported has found that scientific misconduct by one of the article's co-authors has taken place as follows: Scheme 5 and the last paragraph under the heading \u201cDisulfides\u201d in the Results and Discussion section discusses fabricated data. The NMR spectra figures on page S36 were also fabricated. The synthesis of Signed: Christopher W. Bielawski, Jonathan P. Moerdyk, and Kelly M. Wiggins, March 2015.Chemical Science.Retraction endorsed by May Copsey, Executive Editor,"}
+{"text": "Plasmodium vivax malaria from western Africa are reported annually in the Russian Federation. Infected native African people moving from western Africa for different purposes  or Russian citizens  incubate the pathogen until reaching their Russian destination. Imported cases of Plasmodium species recorded over the past twenty years throughout the Russian Federation were inventoried. These data were included in the national register. The data of imported malaria cases were analysed according to the species of Plasmodium, case origin, dates of importation, and patient nationality. All imported and other confirmed malaria cases and the associated P. vivax-infected patients who contracted the disease in western Africa were diagnosed in the Russian Federation from 1984 to 2017. Among them, 3 cases had mixed infections . Conclusion. Our data reveal an existing risk of contracting P. vivax infections in towns of West sub-Saharan Africa despite the absence of local P. vivax infection records. A total of 267 Plasmodium vivax occupies the largest malaria-endemic region of the world, followed by P. ovale [ P. vivax is almost absent in western sub-Saharan Africa, the epicentre of global malaria endemicity, due to genetic resistance of the local human population, which is in contrast with East Africa where P. vivax malaria is distributed mainly in Ethiopia, but infrequent further south too. P. ovale is distributed throughout sub-Saharan Africa and South-East Asia, and in the western Pacific. It is responsible for 1-5% of all malaria cases in West Africa [P. ovale . P. vivat Africa . P. vivax. One of them is Duffy negativity, which is present in western sub-Saharan African populations. The Duffy antigen is located on the surface of red blood cells. The protein encoded by this gene is a glycosylated membrane protein. It is general receptor but has some specificity for chemokines. This genetic aberration is the only one among malaria genetic protection mechanisms without known negative affects to the health of human beings. Duffy negativity as a susceptibility factor had been speculated from epidemiological data before its function was discovered in the 1970s [There are several known genetic resistance mechanisms againsthe 1970s . Duffy n vivax malaria that several investigators in the United States failed to intentionally infect volunteers with P. vivax [ P. vivax, and heterozygous individuals experienced partial protection [Nearly 100% of West Africans and their New World descendants, including the majority of Afro-Americans, have Duffy negativity in the form of heterozygotes; and the only place in the world with homozygotes for Duffy negativity are present. This genetic aberration is extremely rare in other ethnic groups. Duffy negativity is so effective in the protection againstP. vivax . A recenotection . P. vivax almost disappeared from West Africa, but complete elimination was not achieved [ P. vivax absence in West Africa and the lack of local records of the pathogen in western sub-Saharan countries, sporadic cases of P. vivax malaria imported from the region have been registered in countries where malaria has been eliminated [ P. vivax malaria cases in West Africa are absent from WHO documents from the last 10 years [ P. vivax malaria among Duffy negative subjects had been detected by PCR in West Cameroon recently [ P. vivax malaria cases in Ethiopia, Eritrea, Somalia, Sudan, and Madagascar appeared in these documents, and some authors perceived the data as a recent development [Therefore,achieved . Despiteiminated . Data on10 years , 9. Sporelopment . P. vivax in West Africa and imported cases of P. vivax malaria recorded from that region would be surprising. Unfortunately, the wheel is too often reinvented and history is continually rewritten when there is a clear set of events to look back on, to get to know better, and to understand [ P. vivax were undertaken in 2012 only [A confirmation of the presence ofderstand . The fir P. vivax infection, even during a short stay, in towns of West sub-Saharan Africa despite the absence of local records of P. vivax infection.The aim of this paper is to call attention to an existing risk of contracting P. vivax malaria from West sub-Saharan Africa to the Russian Federation (1994-2017) and retrospective data (1984-1992) of the USSR.We present data regarding the importation of vivax malaria and operating at the Martsinkovsky Institute of Medical Parasitology & Tropical Medicine of the Ministry of Health Russian Federation in Moscow since 1982. In addition to scientific research, the centre conducts epidemiological monitoring and the evaluation of antimalarial measures [The WHO Collaborating Centre for Research has been studyingmeasures .Each diagnosed malaria case is required to be reported by any medical establishment in the Russian Federation to a local Rospotrebnadzor Department  using the official form \u201cCard of Epidemiological Investigation\u201d that contains clinical, laboratory, entomological, and epidemiological information. In addition to reporting to local Rospotrebnadzor Department, thin and thick blood films together with a copy of the Card of Epidemiological Investigation for each identified malaria case are sent to the Reference Centre on Tropical Diseases at the Martsinkovsky Institute (Moscow) for microscopic confirmation by experts in malaria diagnoses. These data have been accumulated in the National Surveillance Register at the Martsinkovsky Institute since 1978. All imported cases are mapped to a country of origin.The information derived from standard cards is entered into a database and analysed annually. The annual report presents data on the aggregate of cases from all parts of the Russian Federation. The reports are distributed to all 85 administrative territories of the country as analytical information.detection of malaria patientsepidemiological investigation of cases and focientomological monitoring of breeding places and resting siteslarviciding with ecologically safe methods (according to the transmission season)indoor residual spraying of pyrethroids environmental measures, including hydroengineering and environmental control of breeding habitatsmedical personnel traininghealth education of the foci population.The scope of malaria surveillance as a part of the general state surveillance system is as follows: malaria case reports are entered into a database; data is analysed and disseminated through an annual published analytical letter called \u201cThe Malaria Situation in the Russian Federation\u201d; and planning, monitoring, and analysis of the efficacy of antimalarial measures are conducted. Malaria surveillance measures are carried out in all potential foci whenever imported malaria cases occur, as well as in new active foci when local transmission of malaria emerges. These measures include the following:Data on registered cases of malaria in Russia are published in a table with all the reportable pathogens that are transmitted each year, produced by the CISID (WHO/EURO). P. vivax malaria to Russia from the countries of sub-Saharan Africa occurs almost annually by foreigners  and Russian citizens . According to the \u201cNational Register of Malaria in the Russian Federation\u201d and the \u201cQuestionnaire of Epidemiological Survey of Malaria Foci,\u201d 319 patients from sub-Saharan Africa with P. vivax malaria were identified from 1984 to 1992. Among them, 159 Russian citizens and foreigners were infected in 10 western African countries, with the majority infected in Nigeria  [ P. falciparum + P. vivax infections .Apart from imported malaria cases in Russia, Dr. G. Suleymanov  detected three Russian citizen patients with91-1992) . Two of  P. vivax malaria cases from West African countries to the Russian Federation decreased.After the disintegration of the USSR, the number of travellers and persons working under contracts from the USSR/Russia decreased, and subsequently, the number of imported 135 imported cases of P. vivax malaria from Africa were registered; among them, 104 were from West Africa [ P. falciparum + P. vivax and 1 - P. vivax + P. ovale   was reported in 2012 and occurred in a Russian resident visiting Sierra Leone.From 1994 to 2008,t Africa , includimalaria) . There w P. vivax malaria cases presented a fever, but none had severe and life-threatening conditions. All patients with P. vivax malaria received chloroquine for a 3-day period followed by a 14-day course of primaquine.AllOnly twenty subjects reported compliance with malaria chemoprophylaxis (mefloquine or atovaquone/proguanil). All of them had visited West Africa and did not complete the drug regimen. No history of individual chemoprophylaxis was available for the remaining cases. P. vivax cases in 2009-2010 and 2013 originating in West African countries were not registered. One case from Guinea was recorded in 2011, one case from Cameroon was recorded in 2012, and two cases  were recorded in 2014. Imported P. vivax cases from West African countries were not registered in 2015-2017. Thus, the total number of imported malaria cases from western sub-Saharan African countries for 1984-2017 is 267. The West African countries that served as the source of imported malaria cases are presented in Imported P. vivax to Russia from the countries of sub-Saharan Africa differed from those of the Newly Independent States (NIS) countries by clinical manifestation. Among the latter were a higher number of manifestations after long-term incubation of the pathogen (45% of imported cases from Tajikistan and 50% from Azerbaijan) [Imported cases ofrbaijan) .P. vivax) by Russian citizens from sub-Saharan Africa presented the first clinical manifestation of the disease on the 12th-14th day after arrival in Russia. None of the imported P. vivax cases were followed by \u201cintroduced cases,\u201d despite the susceptibility of endemic Russian mosquitoes to P. vivax from foreign countries [Most imported cases of tertian malaria  were located in cities where the conditions for transmission were not favourable and medical care was easily accessible, i.e., early detection of patients was possible. In addition, the return of foreign students and Ph.D. students after their summer vacations occurs in October, when the transmission season of P. vivax infection. Data of each case been collected for the last three years period, but we could not exclude that any individual presented his/her information incorrectly due to memory or other problems.The limitation of the study is travel histories of patients with P. vivax infection in towns of West sub-Saharan Africa by local residents and foreigners despite the absence of local records of P. vivax infection. The appearance of imported cases of P. vivax malaria from that region of Africa should be considered in Russia and other countries.The results of the research analysis reveal an existing risk of contracting P. vivax distribution and by clinicians for the timely and correct diagnoses and treatment of malaria patients who arrive each year from African countries.This article can be used by epidemiologists to refine the global area of P. vivax is far less developed than that for P. falciparum, representing a barrier to rational strategies for control and elimination of the disease. This communication may be considered important for studies on P. vivax distribution in sub-Saharan African countries.A current understanding of the spatial epidemiology and geographical distribution of"}
+{"text": "Nature Communications 10.1038/ncomms1845, published online 22 May 2012.Correction to: The original version of this Article did not acknowledge Mark de Bruyn as part of the FishPopTrace consortium. This has not been corrected in the PDF and HTML versions of the Article."}
+{"text": "Background: Cultural factors influence how individuals define, evaluate, and approach their quality of life (QoL). The CushingQoL is a widely used disease-specific questionnaire to assess QoL in patients with Cushing's syndrome. However, there is no information about potential cross-country differences in the way patients interpret the items on the CushingQoL. Thus, the current study examined if the CushingQoL is interpreted in the same way across nationalities.Methods: Patients from the U.S. (n = 260) and the Netherlands (n = 103) were asked to fill out the CushingQoL and a short demographics survey. Measurement invariance testing was utilized to explore whether or not the patient samples from the U.S. and the Netherlands interpreted items on the CushingQoL in the same way.Results: A two-subscale scoring approach was used for the CushingQoL. Model fit was good for the U.S. sample , as well as the Dutch sample . Invariance testing revealed that three of the 12 items on the CushingQoL were interpreted differently across the groups. These items are all related to psychosocial issues . Items assessing physical aspects of QoL did not vary across the U.S. and Dutch samples.Conclusions: Interpreting results from the CushingQoL requires careful consideration of country of residence, as this appears to impact the interpretation of the questionnaire. Cushing's syndrome (CS) is a rare disease that is characterized by chronic overexposure to elevated cortisol levels . CS can interpretation of individual items across nationalities. There is a statistical process that can be used to assess whether or not different groups are interpreting items in the same way, and this process is referred to as measurement invariance testing. If a questionnaire is measurement invariant (MI) across groups, then this result indicates that the items on a questionnaire are interpreted the same across the groups. In other words, the items are tapping into the same underlying construct  across groups.The U.S. Surgeon General has emphasized the importance of measuring the same construct across nationalities . CulturaFollowing the guidelines of the U.S. Surgeon General , the aimParticipants were recruited from the United States (U.S.) and the Netherlands. The study protocol was approved by the University of California, Merced Institutional Review Board. All patients provided digital informed consent in accordance with the Declaration of Helsinki before filling out the survey.n = 239). Participants were on average 49.6 years old (SD = 13.02).For the U.S. sample, participants were 260 patients who were invited to participate through the Cushing's Support and Research Foundation's (CSRF) listserv and Facebook page. Patients were eligible for the current study if they were over 18 years of age, in remission from CS, and living in the U.S. at the time of completing the survey. Patients were asked to complete the CushingQoL (English version) and a demographics survey. The majority of participants were female . Participants were on average 53.17 years old (SD = 12.57).For the Dutch sample, participants were 103 patients recruited through the Dutch Adrenal Association (NVACP). NVACP members received an email through the NVACP listserv, with a short description of the study and a link to the online survey. Patients were eligible for the current study if they were over 18 years of age, in remission from CS, and living in the Netherlands at the time of completing the survey. Patients were asked to complete the CushingQoL (Dutch version) and a demographics survey. The majority of participants were female , but this level of correlation was not severe enough to cause problems in the invariance phase. Therefore, all models were estimated using all CushingQoL items.All analyses were conducted in Msion 7.4 , and thesion 7.4  were higTo test whether a questionnaire is MI, an analysis called multiple-group confirmatory factor analysis (MGCFA) can be used. MGCFA assesses whether or not items are related to constructs in the same way across the groups. An iterative modeling approach is implemented, where several phases of the model are estimated . The firThe initial estimation of the factor structure followed Tiemensma et al. , where tIn the next phase, measurement invariance was evaluated by estimating several multiple-group CFA models. This process was used to compare the U.S. and Dutch samples and assess whether the same subscale structure and model results exist across the groups. Following the guidelines prescribed by Meredith , three m2 difference test  to In summary, the CushingQoL is a valuable tool for assessing the QoL of patients with CS. Interpreting results from this tool requires a careful consideration of country of residence, as this appears to impact the interpretation of the questionnaire.All authors wrote and edited the manuscript and approved the final draft. In addition, SW performed the data analysis and interpreted the results, JT conceived the study and collected the data, and SD assisted with data analysis and interpretation.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "We were interested in the letter by Hengartner and Pl\u00f6derl  which waadmetan and bayesmh commands in Stata 15. We took a number of different analytical approaches: the DerSimonian and Laird model with 0.5 continuity correction, the inverse variance heterogeneity model with 0.5 continuity correction , the Peare rare ), the Maare rare ), the reare rare .Our results are presented in Table The main conclusion of Khan et al.  is that Joseph F. Hayes and Gemma Lewis have no conflicts of interest to declare. Glyn Lewis has acted as an expert witness for litigation concerning antidepressants.J.F.H. is funded by the Wellcome Trust (211085/Z/18/Z). All authors are supported by the NIHR UCLH Biomedical Research Centre. These funders played no role in the preparation of the manuscript.Joseph F. Hayes and Gemma Lewis wrote the first draft of this correspondence. All authors edited the correspondence and agreed to submit it."}
+{"text": "The authors of \u201cImportance-Performance Analysis of Personal Health Records in Taiwan: A Web-Based Survey\u201d :e131) overlooked omissions in the metadata. Two of the article's authors should have been designated as having made an equal contribution. The authors are Dr. Yu-Lung Chiu and Dr. Hsyien-Chia Wen. Their contributions to this paper were significant, and we apologize for the omission in the original article.This correction has been made in the online version of the paper on the JMIR website on June 9, 2017, together with the publication of this corrigendum.A correction notice has been sent to PubMed, and the publication was resubmitted to Pubmed Central and other full-text repositories."}
+{"text": "There is an error in the Materials and methods section, under the Animals subsection. The correct IACUC approval numbers are: NO. 2010051101 and 2009121507."}
+{"text": "Supplementary Figure 1 as published. The Supplementary Figure that was submitted at the time of publishing was mislabeled. The corrected Supplementary Figure 1 appears below. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.In the original article, there was a mistake in The original article has been updated.ZB-J is CEO of MAP Corporation Pte., Ltd. and will receive income from MAP Corporation Pte., Ltd. MAP Corporation Pte., Ltd. developed and owns the MAP technology. MAP is offered as not-for-profit product for individuals and for-profit for enterprises with financial interest for ZB-J as stockholder. PC is Director of Sciens Pty. Ltd., with 50% ownership in the company. JG is a stockholder in MAP Corporation Pte., Ltd. No authors received payment from MAP Corporation Pte., Ltd. for this work. WY declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The authors wish to make a change to the published paper . In the https://www.mdpi.com/2073-4360/6/12/2974.The authors apologize for any inconvenience caused. The change does not affect the scientific results. The manuscript will be updated, and the original will remain online on the article webpage"}
+{"text": "Optimization of the microwave-assisted Knoevenagel-Doebner condensation on vanillin at 50 W. as published. The values in the Eq. of base column for lines 2 to 8 are not accurate. The corrected Table 2. Optimization of the microwave-assisted Knoevenagel-Doebner condensation on vanillin at 50 W. appears below. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.In the original article, there was a mistake in Table"}
+{"text": "This is a correction of Biochem Med (Zagreb)2019;29(3):030704. DOI: https://doi.org/10.11613/BM.2019.030704Since the publication of the article, the authors have noticed that their first names and surnames in the byline were listed in reverse. The correct byline is presented above. We apologize to the authors for any inconvenience caused to the readers."}
+{"text": "Edwardsiella tarda (E. tarda). Endoscopy showed features of moderate inflammation similar to exacerbation of Crohn's disease. The patient was treated simultaneously with intravenous steroids and antibiotics, and his symptoms resolved. This case report highlights the importance of clinicians being able to promptly recognize and treat concurrent bacterial infections in Crohn's disease exacerbations.Crohn's disease exacerbations can often be associated with bacterial infections causing gastroenteritis. We report a child who experienced exacerbation of his Crohn's disease associated with a positive stool culture for  Clostridium difficile . Th (22.7%) \u20138. The mnfection . The orgnfection .E. tarda [To our knowledge, this is the second documented case of a CD flare with E. tarda  and the"}
+{"text": "Cystoisospora was created in 1977  cells  cells . Developexamined . DevelopC. canis was examined in MDCK cells and primary cells from embryonic canine kidneys, and embryonic canine intestine as well as embryonic bovine trachea and kidney (C. canis sporozoites using bovine turbinate and African green monkey kidney (CV-1) cells provided remarkedly different findings of no asexual multiplication but rather MZTC formation in both host cell types (C. belli MZTC in the tissues of humans (C. canis in mice (C. ohioensis in mice (C. felis in mice (C. canis using two canine, four human, one monkey, and one bovine cell lines (C. canis isolates by different research groups. It suggests that two different genetic types of C. canis exist and that one divides by endodyogeny in culture and the other produces MZTC. How this would translate to in vivo development and pathogenicity in dogs is also an interesting area needing research.Development of sporozoites of d kidney . Developll types . Examinaf humans , 18, C.  in mice , C. ohio in mice . The orgll lines . No asexll lines  and Houkll lines  with drall lines . AdditioC. suis in five types of mammalian host cells in culture indicated that development was by endodyogeny (C. suis development of Type I meronts by endodyogeny in these cell cultures (in vitro (C. suis was observed in a swine testicular cell line (The initial studies on the development of odyogeny  and stagodyogeny . Similarodyogeny . Howeverodyogeny . The ultcultures  was examcultures . Notablyin vitro . Completell line . Developell line . Oocystsell line . The stuell line .C. suis conforms to all other reported features of the genus.No evidence of MZTC formation has been reported in cell cultures. Similarly, studies in pigs and potential paratenic hosts have been negative , 29. ThiC. belli in human and other mammalian cell cultures (C. belli as are present in C. suis (in vitro but otherwise the structural findings were similar to those reported for C. suis. Stages of C. belli obtained from macrophage cell cultures were infectious for RMK cells upon subinoculation and development by endodyogeny occurred (Four studies have examined development of sporozoites obtained from oocysts of cultures \u201333. The cultures . The aut C. suis  while unoccurred  but MZTCCystoisospora species from mammals and to provide insight into future research directions. Development will occur in many host cell types but studies with C. suis illustrate that selection of the proper host cell type can lead to complete development thus increasing the utility of an in vitro system. Studies with C. canis suggest that genetic differences in Cystoisospora species exist that are reflected by the phenotype of development expressed in vitro. I look forward to seeing what advances in our knowledge of this group are revealed in the future.I have attempted to point out the similarities and important differences in the development of The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Cara H. Haney was not included as an author in the published article. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.New Author Contribution Statement:LS and CL cultivated plant lines and harvested nodules. LS, CL, and CH constructed bacterial reporter strains. CL carried out cryosectioning, nodule staining, and microscopy. SL, CL, and CH conceived the study and designed experiments. SL and CL wrote the manuscript.The original article has been updated.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In the funding statement the following sentence was omitted:http://archive.most.gov.il/English/Pages/default.aspx).YZ also gratefully acknowledges the support of the Israeli Ministry of Science, Technology and Space ("}
+{"text": "Tetrahymena pyriformis at the interface were investigated. The synergy of the ellipsoidal shape of the cell body and the mechanosensing feature of the cilia allow for cells to slide on interfaces, and the sliding behavior leads to cell accumulation on the interfaces. Here, to examine the generality of the sliding behavior of ciliates, we characterized the behavior of Paramecium caudatum, which is a commonly studied ciliate. Our experimental and numerical results confirmed that P. caudatum also slid on the solid/fluid interface by using the same mechanism as T. pyriformis. In addition, we evaluated the effects of cellular ellipticity on their behaviors near the wall with a phase diagram produced via numerical simulation.Some types of ciliates accumulate on solid/fluid interfaces. This behavior is advantageous to survival in nature due to the presence of sufficient nutrition and stable environments. Recently, the accumulating mechanisms of  P. caudatum was observed and recorded using a dark-field inverted microscope  with an sCMOS camera . To observe side views of P. caudatum, a smaller cover glass  was placed in a disposal cuvette with observation solution containing P. caudatum, and the interface between the glass and the observation solution was observed from an angle parallel to the ground using a free-angle observation system .To prevent nonspecific binding between the cells and glass during observations, the glass  was coated with MPC polymer  according to Ohmura et al. . Brieflyhttps://fiji.sc/), and the calculation of statistical analyses were performed using Igor Pro 6.37 (WaveMetrics). In the PIV analysis, Python (https://www.python.org/) with OpenPIV (http://www.openpiv.net/) was used. Numerical calculation was performed according to Ohmura et al. [The cellular speeds and steady angles were acquired using Fiji ("}
+{"text": "Scientific Reports 10.1038/s41598-019-43655-z, published online 13 May 2019Correction to: The Author Contributions section of this Article in incorrect.\u201cG.F. participated to the experimental campaigns, coordinated the data analysis through the integration of different techniques and contributed to the interpretation of the results. T.C. performed UV/NIRR imaging experiment and data analysis, contributed the theoretical discussion of the results and to the writing of the manuscript. V.T. participated to the experimental campaigns and was responsible of transport of the artefacts from Turin to Oxfordshire and their handling at the ISIS pulsed neutron source. M.B. participated to the experimental campaigns and contributed to the theoretical discussion. J.K. contributed to the interpretation of the neutron results and to the writing of the manuscript. L.A. participated to the PGAA measurements and performed the PGAA data analysis. L.C. performed XRF measurements and contributed to the discussion of XRF data analysis. R.C.P. performed the Raman experiment and relative data analysis and participated to the PGAA measurements. C.S. analysed the XRF data and performed the Principal Component Analysis and Box Plot Analysis. R.S. coordinated the PGAA measurements, contributed to the discussion of the PGAA results and to the writing of the manuscript. C.A. proposed and coordinated the experimental measurements and participated to the writing of the manuscript.\u201dshould read:\u201cG.F. participated to the experimental campaigns, coordinated the data analysis through the integration of different techniques and contributed to the interpretation of the results. T.C. contributed the theoretical discussion of the results and to the writing of the manuscript. V.T. participated to the experimental campaigns and was responsible of transport of the artefacts from Turin to Oxfordshire and their handling at the ISIS pulsed neutron source. M.B. participated to the experimental campaigns and contributed to the theoretical discussion. J.K. contributed to the interpretation of the neutron results and to the writing of the manuscript. L.A. participated to the PGAA measurements and performed the PGAA data analysis. L.C. performed XRF measurements and contributed to the discussion of XRF data analysis. R.C.P. performed the Raman experiment and relative data analysis and participated to the PGAA measurements. C.S. analysed the XRF data and performed the Principal Component Analysis and Box Plot Analysis. R.S. coordinated the PGAA measurements, contributed to the discussion of the PGAA results and to the writing of the manuscript. C.A. proposed and coordinated the experimental measurements and participated to the writing of the manuscript.\u201dIn addition, the Acknowledgements section of this Article is incomplete.\u201cThis research is partially supported by CNR, within the CNR-STFC Agreement 2014\u20132020 (N. 3420), concerning collaboration in scientific research at the ISIS Spallation Neutron Source, and by the ARKHA (ARchaeology of the invisible: unveiling the grave-goods of KHA) project. Our thanks go out to Christian Greco and Stephen Hull for fruitful discussions and suggestions, to Tea Ghigo of the Bundesanstalt f\u00fcr Materialforschung und \u2013pr\u00fcfung (BAM) in Berlin for providing us with UV and NIR images of the textiles, and to the ISIS team of IMAT. Financial support by the Access to Research Infrastructures activity of E-RIHS.it (www.e-rihs.it) is also gratefully acknowledged.\u201dshould read:\u201cThis research is partially supported by CNR, within the CNR-STFC Agreement 2014\u20132020 (N. 3420), concerning collaboration in scientific research at the ISIS Spallation Neutron Source, and by the ARKHA (ARchaeology of the invisible: unveiling the grave-goods of KHA) project. Our thanks go out to Christian Greco and Stephen Hull for fruitful discussions and suggestions, and to the ISIS team of IMAT. We are very grateful to Tea Ghigo of the Bundesanstalt f\u00fcr Materialforschung und \u2013pr\u00fcfung (BAM) in Berlin who performed the UV/IRR experiments and data analysis and provided us with the images published in fig. 2. Financial support by the Access to Research Infrastructures activity of E-RIHS.it (www.e-rihs.it) is also gratefully acknowledged.\u201d"}
+{"text": "Marion Dolezel and Marianne Miklau were not included as authors in the published article. The corrected Author Contributions Statement appears below. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.ME conducted the study and drafted the manuscript. MD and MM contributed to data acquisition and analysis. AH, WR, RS, and FW contributed to the study design and implementation and edited the manuscript. All authors read and approved the manuscript for publication."}
+{"text": "Listeria monocytogenes (L.m), Listeria innocua (L.i), and Escherichia coli to form biofilms on polystyrene support under different parameters by performing crystal violet (CV) staining technique.The present study was conducted to evaluate the capacity of IIa and IIb), L.i, and E. coli strains at different microbial load. Selected strains and combinations were grown in biofilms for 6 days attached to polystyrene microplates under aerobic and microaerophilic conditions. The evaluation of the power of adhesion and biofilm formation was determined by CV staining followed by the measurement of optical density at 24 h, 72 h, and 6 days incubation time with and without renewal of the culture medium.Different suspensions were prepared with single strains and with multiple combinations of strains including two serogroups of L.m (All the strains tested, presented more or less adhesion power depending on the variation of the studied parameters as well as the ability to form multispecies biofilms. Their development is more important by renewing the culture medium and increasing the initial load of bacteria. The ability to adhere and form biofilms differs from one serogroup to another within the same species. In bacterial combination, strains and species of bacteria adopt different behaviors.E. coli could adhere to polystyrene and form biofilms under different conditions. More researches are necessary to understand the mechanisms of biofilm formation and the influence of different parameters in their development.The ability to form biofilms is a key factor in the persistence of tested strains in the environment. Our study showed that L.m, L.i, and  Salmonella, Staphylococcus . The method of assessing biofilm formation was based on the technique described by Stepanovi\u0107 et al. et al. [S [et al. . They dederstood .IIa) showed a moderate adhesion after 24 h of incubation. This slow adhesion could be linked to the presence of L.m 038 strain which has already shown a moderate adhesion at 24 h when it has been tested alone (biofilm monospecies). The combination of L.m 023+L.m 026+L.i (L.m/IIa+L.i) has shown a moderate adhesion after 72 h of incubation, knowing that when tested alone, each strain showed a strong adhesion at 24 h. This suggests that bacterial strains may show different behavior when they are simultaneously present in a multispecies biofilm, either by increasing or decreasing the adhesion capacity. This difference in behavior of L.m was reported by Giaouris et al. [et al. [Our study showed some particularities. The combination of L.m 038+ L.m 026 + L.m 043 .All the strains tested showed a more or less adhesion power depending on the variation of the studied parameters as well as an ability to form multispecies biofilms. Strains of L.m, L.i, and The ability to adhere and form biofilms is different from one serogroup to another within the same species. In bacterial combination, strains and species adopt different behaviors. The ability of bacterial species to form biofilms poses a real problem in different areas. The study of the ability of strains to adhere to surfaces and to form biofilms remains complex. Several parameters can influence the adhesion, such as the nature of the surfaces, the bacterial species, the number of bacteria, the presence of a single bacterial genus or multi-genus, and many other parameters.Recent advances in the understanding of the biofilm development cycle have indicated that, in most cases, it is a dynamic process in which factors such as nutritional conditions, temperature, oxygen tension, and osmolarity can have big influences on biofilm formation. The variation of these parameters can influence the adhesion power of bacteria as well as the extent of biofilm formation.More researches are still necessary to understand the mechanisms of biofilm formation and the influence of different parameters in their development. The next stage of our research will involve testing the effect of some biocides on the viability of species forming biofilms and their sensitivity to antibiotics with the aim of studying the probable correlation between sensitivity toward biocides and antibiotics.SLA planned the study and drafted the manuscript under the supervision of LB and TMH. SLA designed the experiment protocol under the supervision of LB and TMH. SLA collected and analyzed samples did the statistical analysis and revised the manuscript under the supervision of LB and TMH. All authors read and approved the final manuscript."}
+{"text": "There is an error in the Funding statement. The grant number is incorrect and should be 15K06725 instead of 15K06715.https://www.jsps.go.jp/english/e-grants/).\u201dThe full correct statement should read: \u201cThis work was supported by funding from the Okinawa Institute of Science and Technology Graduate University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. SH was supported by the Japan Society for the Promotion of Science, KAKENHI Grant Number 15K06725 ("}
+{"text": "This notice describes a correction to the above mentioned paper. The first two authors of this paper, Katie F. M. Marwick and Anna J. Stevenson, contributed equally to this paper and are joint first authors. The publisher apologises for this omission on the original publication of the paper."}
+{"text": "Due to an editorial error, the Data Availability Statement containing the accession numbers were erroneously omitted from the article. The Data availability Statement appears below. The publisher apologizes for the mistake. The original article has been updated.https://www.ncbi.nlm.nih.gov/) under Bioproject PRJNA490743 with Sample IDs SAMN10056964\u2013SAMN10057130.The datasets generated for this study can be found in the National Center for Biotechnology Information ("}
+{"text": "Scientific Data, 10.1038/sdata.2017.163, Published online 31 October 2017Correction to: The authors regret that Luba M. Pardo was omitted in error from the author list of the original version of this Data Descriptor. This omission has now been corrected in the HTML and PDF versions.The authors also regret that Anemieke Rozemuller was omitted in error from the Acknowledgements of the original version of this Data Descriptor. This omission has now been corrected in the HTML and PDF versions."}
+{"text": "Dear EditorWe appreciate the comments. Currently the erection in our patient is complete without restrictions. However, we are aware of the possibility of problems with growth. Hence, we have informed the parents regarding these possible problems in the future. Intra-operatively, we considered using scrotal flaps for the coverage of penile shaft. However. The diameter of the penile shaft was so small and the scrotal flap was thought to be too thick and hence would hide the definition of the shaft at this age. The excellent myo-cutaneous flap described by the authors still remains an option if needed in the future. We promise the readers to write a letter to the Editor in the future to document if such problems would arise.None.None.The original study was approved by the research committee, National Hospital (Care), Riyadh, Saudi Arabia. The current reply does not require this.Not applicableReply is from the senior author on behalf of all authors.NA.M M Al-Qattan."}
+{"text": "Journal of the Belgian Society of Radiology, 99(1), pp. 1\u201320, DOI:  Fig. 2 on page 3: part of the caption (from C-D) should be replaced by:C.The meniscus homologue (thick arrow) is interposed between the ulnar styloid and disc proximally and the cartilage of the triquetral bone distally.D.The volar and dorsal part of the RUL  are fixed between the radial notch and the base of the ulnar styloid. The m. extensor carpi ulnaris lies within his sulcus .E.The m. extensor carpi ulnaris lies on the ulnar styloid . The central disc (TFC)  is attached at the radial side to the cartilage of the radial sigmo\u00efd notch and at the ulnar side to the styloid.2. Fig. 27 on page 14: the grey zone in the center of the figure 27 fails. Correct figure infra ."}
+{"text": "Nature leads with a story about the suspected double-whammy packed by bullets made of depleted uranium. A slew of new appointees in both houses of the U.S. Congress leads the news in Science this week."}
+{"text": "Due to a production error, the last name of the fourth author was incorrectly spelled as Amy K. Beatty. The correct form is Amy K. Beattie. The publisher apologizes for this mistake. The original article has been updated."}
+{"text": "The accusations were really flying this week. At global warming negotiations in The Hague, Nature's lead story reports the Europeans accused the U.S. of intransigence in the face of a looming catastrophe and the U.S. shot back that the Europeans are ignoring solid environmental science. Science leads with a group of scientists who are accusing their own community of  misconduct."}
+{"text": "Trichinella spiralis in beaver meat (Castor fiber) in Poland and Europe. In Poland, the beaver is a strictly protected animal species, except the few regions where high population density leads to economic losses. In these areas, the reduction culling of the animals was introduced. This uncommon hunting game animal is consumed and treated as a delicacy by hunters. However, currently, there is a lack of knowledge on possible risk factors for humans associated with the consumption of beaver meat. This paper presents the result of the study on the occurrence of nematodes of the genus Trichinella in beavers.This is the first report of the finding of Trichinella spp. The 50g samples were taken from each animal and digested separately, according to a procedure based on the EU reference method. The larva DNA was examined by PCR and sequencing.In total, 69 beavers were examined for the presence of Trichinella larva was detected by the digestion method. The result of PCR confirms the presence of T. spiralis in beaver meat.One of the 69 examined beavers was infected. Only one Trichinella spp. This is the second confirmed case of Trichinella spp. infection in beavers in Europe and the first of T. spiralis.This case further confirms the ability of these typical herbivores to be infected with   \u2022Trichinella spiralis larva in beaver meat.First report of the presence of \u2022Trichinella spiralis by digestion method and confirmed by PCR and sequencing.Detection of \u2022New parasitic risks factor for humans associated with consumption of beaver meat. Multiplex PCR. The recognition of species was provided by the multiplex PCR method according to the protocol given by the European Reference Laboratory for Parasites . The PCR for amplification of 5S rDNA and CO1 was performed according to previously described methods  were taken from the rear left leg from 749/2011 . Digesti015/1375 . Examinaarasites  (EURLP). methods . The PCR methods .3T. spiralis . The Regional Veterinary Laboratory in Krosno (Subcarpathian voivodeship) provided a positive sample. The density of invasion was 0.02 larva per gram (lpg). Based on the morphological characteristic larva was recognized as belonging to genus Trichinella . Additionally, analysis of the alignment of CO1 sequence amplified from examined samples show 100% identity with reference sequence CO1 of T. spiralis  No 749/2011.M. R. - main idea and work organization.E. B-Z. and M.K. carried out the molecular study.K. G-K. and J. Z. performed a magnetic stirrer digestion method.J. K. and J. W. - sample collection from hunters, transport samples to laboratory and contribution to the final version.T. C. - helped supervise the project.The authors declare that there is no conflict of interest regarding the publication of this article."}
+{"text": "The Data Availability statement for this paper contains inactive web links. The updated statement with active web links is as follows:https://www.marchofdimes.org/research/ohio-collaborative-overview.aspx) and access will be approved by the Leadership Committee through its director of operations, Joanne Chappell (joanne.chappell@cchmc.org). Some restrictions may apply for the protection of privacy. Any use of the Danish Replication WES data must be approved by the Danish National IRB and the Danish Data Protection Agency through an application facilitated by the Danish Principal Investigator  at the University of Southern Denmark. Some restrictions may apply for the protection of privacy.For the Discovery whole exome data, the requests of the data underlying the findings reported in this study of the families from northern Finland (Oulu), as well as individual-level phenotype and SNP genotype data from the Finnish (Helsinki) birth cohort , are available through the March of Dimes Prematurity Research Center Ohio Collaborative , and summary statistics of the complete data set are available on request from 23andMe. Access to the DNBC individual-level data can be obtained through dbGaP Authorized Access portal (https://dbgap.ncbi.nlm.nih.gov/dbgap/aa). The Norwegian cohort data underlying this study was obtained from a third party and is a subject to some legal restrictions. The data originates from the Norwegian Mother Child cohort (MoBa), which is controlled by the MoBa Scientific Management Group. The research data can be accessed via electronic application forms at https://www.fhi.no/en/studies/moba/. Data can be requested of all interested researchers qualifying for the requirements established by the MoBa Scientific Management Group. For more information please contact datatilgang@fhi.no.For the validation GWAS datasets: the summary statistical outcomes of the top 10,000 SNPs for the 23andMe data have been deposited in the GeneStation repository ("}
+{"text": "The correct name of Dr. De Carvalho is Ricardo A. Pontes de Carvalho.The corresponding author of the article has changed to Ricardo A. Pontes de Carvalho.Email: rcarvalho@3tophthalmics.comFollowing publication of the original article , the aut"}
+{"text": "The authors wish to make a change to the published paper . In the http://www.mdpi.com/2073-4360/9/8/375.The change does not affect the scientific results. The manuscript will be updated and the original will remain online on the article webpage"}
+{"text": "Benjamin E. J. Spurgeon was not included as an author in the published article. The updated Author Contributions statement appears below.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.The original article has been updated.JK performed the statistical analysis, researched data, and wrote the paper. BS performed and interpreted the platelet function tests. AQ, TS, RA, LM, KM, AG, and EK reviewed and edited the manuscript. SA reviewed and edited the manuscript and is the guarantor of the manuscript. All authors approved the final submission of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The authors wish to make a change to the published paper . In the https://www.mdpi.com/2073-4360/11/2/229.The authors apologize for any inconvenience caused and the change does not affect the scientific results. The manuscript will be updated and the original will remain online on the article webpage"}
+{"text": "The corresponding author's name is spelled incorrectly. The publisher apologizes for this error. The correct name is: Kurtis Jai-Chyi Pei.hhsu@mail.npust.edu.tw.In the Data Availability statement, there is an error in the email address provided for Dr. Hsiu-Hui Su, the Director of the Institute of Wildlife Conservation. The correct email address is:"}
+{"text": "This article has been retracted: After re-analyzing the original data for this article, the authors found discrepancies between the published data and the ones recently analyzed. This raises serious concerns about the accuracy of the data. The authors believe that further research is needed to confirm these findings, and are no longer confident about some of the data published in the original publication. As a result, all authors have agreed to the retraction of this paper from Oncotarget.60885-60895 . https://doi.org/10.18632/oncotarget.11659Original article: Oncotarget. 2016; 7:60885\u201360895."}
+{"text": "The authors wish to make the following erratum to this paper . In the paper, the second author\u2019s name Chengyang Zhao should be Chenyang Zhao and his e-mail, 220171151@seu.edu.cn, has been changed to cyzhao@seu.edu.cn.The errors were introduced as a result of author oversight. We apologize for any inconvenience caused to the readers by these mistakes. The manuscript will be updated, and the original will remain online on the article website."}
+{"text": "In the original article, there was an error. The \u201cCorrespondence emails\u201d are listed in the incorrect order.Correspondence.A correction has been made to the *Correspondence:Wang Madoctormawang@126.comTengfei Zhangfcczhangtf@zzu.edu.cnZhaoyuan Fangfangzhaoyuan@sibs.ac.cnThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "The corrected Figure In the original article, there was a mistake in Figure The original article has been updated.NO owns stock of CLINO Co. Ltd. NO and SF are scientific consultants for the CLINO Co. Ltd. RH and KY have no conflict of interest."}
+{"text": "AbstractVernoniaincana Less. and V.echioides Less. are two semi-aquatic species from southern South American that are referred to as \u201cthe semi-aquatic Vernonia of South America\u201d and they have been, until now, retained as members of Vernonia mostly because each had some unusual characters that made them hard to place. Based on an ongoing molecular study, we can now say that V.incana is the sister taxon to all true Vernonia and can therefore be responsibly left in Vernonia but, because of its morphological and geographic differences, it is now assigned to its own subgenus: Vernonia subg. Austrovernonia. Vernoniaechioides is not closely related to V.incana and is now part of a separate investigation. This placement of V.incana as sister to the true Vernonia species brings up the possibility of a South American root for the Vernonia clade and perhaps indicates a propensity in the lineage for growing in or near water. The species V.incana is lectotypified. Vernonia Schreb. during the last 30 years, as summarised in the treatments of American Vernonieae . Due to the shared habits and similarity in pollen, there was no reason to remove the two species from Vernonia. However, the question of where to place these two somewhat odd South American species continued to puzzle students of the tribe. The situation remained unchanged as attention turned to the greater problems found in the Old World Vernonieae  and was recognised in the Vernonieae. The feature was found in the corolla lobes of Vernonia, Vernonanthura H.Rob. and Trepadonia H. Rob. and was illustrated schematically in the Robinson (1999a)PageBreak treatment and with photographs in the Vernonia typical group. However, in the study by Vernoniaechioides and V.incana, as seen at that time, did not show the multiple longitudinal ducts. Thus, on the basis of the remote geographical location, details cited below and the apparent lack of multiple ducts in the species, it was suggested that the species are not closely related to Vernonia and needed further study.Recently, this relationship was called into question as a result of a study of corolla lobe anatomy in which a brief observation of the two species was included . The corVernoniaincana and V.echioides inhabit hydromorphic soils always growing along river banks in open patches of Coleataeniaprionitis (Nees) Soreng and other grasses forming tall grass associations locally known as \u201cpajonales\u201d . We were even more fortunate that they were willing to share their published  and the sequences from these two species were combined with 125 taxa from Keeley et al. (in prep.), mostly from the Americas. Extractions were made from one specimen of V.incana housed in the U.S. National Herbarium (US). The 5pt8s marker was not informative within the true Vernonia so its use was not continued.We were fortunate that our colleagues Sterling Keeley, Tim Gallaher and Jason Cantley were just finishing a project that included an updated molecular phylogeny of the entire ublished  and unpuSamples were prepared by hand grinding leaf material with liquid N in a mortar and pestle followed by extraction using DNeasy Plant Mini Kit following the manufacturer\u2019s protocols .ndhF and the non-coding spacer region trnL-F were used for the analyses. Sequencing was done at the Laboratory of Analytical Biology, NMNH, Smithsonian Institution. The resulting sequences were added to the previously selected taxa from the existing nexus file generated by Keeley et al. (in prep) and aligned by eye. Preliminary phylogenetic trees were produced using RAxML  of the data. The placement of Vernoniaincana are listed in Table The GenBank numbers and voucher information for PageBreakVernoniinae, they are not in the same clade. Vernoniaincana is the sister group of the clade consisting of the true Vernonia. Although the phylogeny cannot be presented until the Keeley et al. paper is published, it is possible to visualise the placement of V.incana by examining the published trees of Vernonia, the same ones that are used in the current Keeley et al. (in prep) article. The placement of V.incana in our phylogeny was in clade number 1 in V.incana is placed.The results show that while both species remain in the sub-tribe V.incana is in conflict with the findings of Vernonia. The nearest relatives in the subtribe Vernoniinae, Vernonias.s., Vernonanthura and Trepadonia, all have obvious multiple longitudinal ducts in the corolla lobes. A careful re-examination of the corolla lobes of V.incana confirmed that ducts were not evident under the microscope in whole mounts of the corollas. If any ducts are present, they are too obscure to be seen in this way. It is possible that the more semi-aquatic habitat of these species has somehow suppressed the production of the ducts. Thus, while being a character of some value, the ducts are not 100% reliable for defining the subtribe Vernoniinae.The suggested placement of Vernonieae .Pollen morphology, that is so helpful in many other members of the rnonieae , is not PageBreakV.incana cite: gallery forest, inundated savannah, flooded field, laguna margin, marsh or emerging from water. One specimen,  has an additional label in the packet stating: \u201cCoastal for nearly all marshes \u2013 common \u2026 leaves emerge above water level, often dense\u201d. The rhizomes of the species have fleshy lateral roots apparently a specialisation for their habitat . The semi-aquatic habit of the South American species is especially interesting because the North American species of the true Vernonia are all spatially related to water in that they grow near water  but not in standing water as do many of the South American collections. This propensity PageBreakPageBreakto grow in or near water may indicate a prope aquam origin for the genus which is in contrast with the other members of the subtribe Vernoniinae: Vernonanthura is often in open areas requiring fire-survival strategies and Trepadonia is a climbing plant.One of the features that the two South American species share is semi-aquatic habit. The habit is clearly stated in the label data of many of the specimens. Labels for tat Fig.  and are Vernoniinae. Of the two species, the position of V.incana is separate from V.echioides and is the sister group of Vernonias.s. but geographically remote from the rest of the genus, without obvious corolla lobe ducts and also without a basal node on the style. The basal node has been observed on the style in all examined species of Vernonias.s., Vernonanthura and Trepadonia , P 00682761 and P 00682762. None of the isosyntypes has the collecting number so they cannot be considered isolectotypes. A photograph of a specimen of this gathering from B is mounted and filed at F 0BN014552. There may be other isosyntypes that are not available on line .The single species is as follows: Vernoniaimmunis Griseb., Symb. Fl. Argent. 163. 1879.Cacaliaimmunis (Griseb.) Kuntze, Revis. Gen. Pl. 2: 970. 1891.Cacaliaincana (Less.) Kuntze, Revis. Gen. Pl. 3(2): 138. 1898.Compositae in that herbarium were destroyed during WWII . In 1959, after his death, the Blake family sold his personal herbarium and library to C.L. Lundell (1959) who later transferred it to TEX [all of the Lundell specimens should be cited as LL]. The K specimen and one of the P specimens have a larger portion of the root than the others but they have less label information than the LL sheet. According to Lessing worked at Berlin (B) and all of the ing WWII . There aing WWII  because PageBreakPageBreakThe collection date and location were determined by consulting th Century, Brazil had control of Uruguay and some collections made at that time (from what is now southern Brazil and Uruguay) were labelled as \u201cBrasilia meridionalis\u201d.According to J. Mauricio Bonifacino (MVFA), in the early 19"}
+{"text": "Following publication of the original article , the autM. van Hague.Originally the author name was published as:M. van Hage.The correct author name is:"}
+{"text": "There is information missing from the Data Availability section. The publisher apologizes for this error.ying.wang@duke.edu, Data Manager) or the Corresponding Author (cynthia.moylan@duke.edu).The complete, correct Data Availability section is: Gene expression and methylation data are available through GEO at GSE31803. Clinical data are available to researchers who meet the criteria for access to confidential data through the Duke NAFLD Biorepository ("}
+{"text": "Following the publication of the above article, the name of one of the authors was incorrectly presented. E. M. Flier should be shown as E. Maratos\u2010Flier.The authors sincerely apologize to the readers for this error."}
+{"text": "Rhipicephalus microplus, a known vector of bovine babesiosis and bovine anaplasmosis, is of great concern in the cattle industry. For this reason, detailed knowledge of the distribution of R. microplus is vital. Currently, R. microplus is believed to be associated mainly with the northern and eastern Savanna and Grassland vegetation in South Africa. The objective of the study was to record the distribution of R. microplus, and the related endemic Rhipicephalus decoloratus, in the central-western region of South Africa that comprises Albany Thicket, Fynbos and Savanna vegetation. In this survey, ticks were collected from 415 cattle in four provinces  and from the vegetation in the Eastern Cape province of South Africa between October 2013 and September 2015. More than 8000 ticks were collected from cattle at 80 localities of which R. microplus was present at 64 localities and R. decoloratus at 47 localities. A total of 7969 tick larvae were recorded from the vegetation at 20 localities of which 6593 were R. microplus and 1131 were R. decoloratus. Rhipicephalus microplus was recorded in each of the regions that were sampled. Rhipicephalus microplus is now present throughout the coastal region of the Eastern Cape province and at multiple localities in the north-eastern region of the Northern Cape province. It was also recorded in the western region of the Western Cape province and one record was made for the Free State province. The observed range changes may be facilitated by the combined effects of environmental adaptability by the tick and the movement of host animals.The Asiatic blue tick,  Rhipicephalus decoloratus (the African blue tick), which is endemic to Africa and transmits Babesia bigemina (African redwater) and R. microplus (the Asiatic blue tick), which is originally from southern Asia and acts as a vector for B. bigemina and B. bovis, the causative organism of Asiatic redwater in cattle. Rhipicehalus microplus is of greater concern in the cattle industry mainly because of the greater pathogenicity of B. bovis  significantly impact domestic animal health and the livestock farming industry globally . Thereafter, Howell, Walker and Nevill  in the districts of Humansdorp, Knysna, George, Mossel Bay, Heidelberg, Swellendam and at a few inland localities. Since then, R. microplus has successfully become established in the mesic Grassland and Savanna interior regions and is now widely distributed throughout the provinces of Limpopo, Mpumalanga, North West, Gauteng and KwaZulu-Natal . However, to date it is uncertain whether and how widely R. microplus is distributed in the predominant Albany Thicket vegetation. Recent studies suggest that R. microplus might be expanding its range further westwards, across South Africa, with isolated records in the western region of the ECP   and Grassland (predominantly grass layer) vegetation because of the perception that the tick does not occur in drier regions and/or in predominantly woodland and shrub vegetation. This study was conducted in an attempt to address the paucity of information regarding the geographic distribution of R. microplus and the related endemic R. decoloratus, largely in the Eastern Cape, Northern Cape and Western Cape provinces of South Africa.In general, current distribution maps for the tick species in South Africa are in need of revision. This is mainly because of the fact that most of the locality data for ticks are either based on historic data Spickett  or biasen = 5) were also provided by private cattle farmers in response to radio interviews, articles in newspapers and popular magazines.In this study, two methods were mainly used to obtain ticks: (1) active tick removal from cattle (by the authors N.N. and S.M.) and (2) sampling of ticks on vegetation using drag sampling (by N.N.) , mainly the south-western region of the WCP and at one locality in the north-eastern region of the FSP between October 2013 and March 2015 . The vegR. microplus and R. decoloratus and not their prevalence or intensity of infestation, none of the collections that were made from cattle were intended to be complete. The ticks from each animal were preserved separately in labelled sample bottles containing 70% ethanol. Information on date, farm, breed, sex and age of the host was recorded. In addition to on-host tick collections, ticks were collected from the vegetation at 20 localities in the ECP (five in each of the four above-mentioned vegetation types) using drag sampling during October 2012\u2013February 2013. The drag sampling method is described in detail in Nyangiwe et al.  as R. decoloratus. Overall, the two species were sympatric at 40 (50%) localities, with R. microplus present at more localities (80%) than R. decoloratus (58.8%)  were identified as  (58.8%) .R. microplus was recorded from cattle at more localities (n = 51) compared to R. decoloratus (n = 33). In particular, R. microplus was recorded at most of the sampling localities (51 of 53) in the predominantly Albany Thicket vegetation in the western region of the ECP (R. microplus larvae was higher (6593) than that of R. decoloratus larvae (1131) and larvae suspected of being hybrids were recorded at each of the 20 sampling localities  than R. decoloratus (n = 10). Rhipicephalus microplus was specifically recorded in the furthest north-eastern region of the province close to Van Zylsrus, Kuruman and Kimberley . In the WCP, R. microplus was found on cattle at more localities (n = 4) than R. decoloratus (n = 3). Specifically, R. microplus was recorded close to Kuilsriver, Wellington and Swellendam (map not shown). Ticks were obtained from cattle at a single locality (close to Heilbron) in the FSP (map not shown) and both tick species were recorded .R. microplus is widely distributed along the western region of the ECP and has established its presence in the north-eastern region of the NCP.The study provided evidence that R. microplus was commonly found on cattle and vegetation  in the region west of east London. In addition, R. microplus was present on cattle at more localities than R. decoloratus  and in higher abundance on the vegetation . Albany Thicket vegetation is dominated by shrubs and succulents, although several C3 and C4 grass species are also present  in the communal grazing areas in the western region of the ECP. The present study therefore provides evidence for further expansion of the geographic range of R. microplus in this region, as the tick was recorded at 51 novel localities. Prior to Nyangiwe et al.  on the vegetation at two communal areas in the ECP.In the ECP, e et al.  and the e et al. . Counts R. microplus in the NCP. The fact that R. microplus was present at only some of the localities (8 of 18) that were sampled suggests that its presence in the NCP reflects a recent introduction. This hypothesis is supported by the fact that the localities that were positive for R. microplus were situated close to the border with NWP . Spickett et al.  and climatic conditions  in this province. Previous studies recorded low numbers of R. microplus from cattle at localities close to the border of already infected provinces, for example, in the north-western region (Hoopstad) close to the border of NWP , it is the fourth study that recorded R. micoplus has increased its distribution range in South Africa and can now be found throughout the Albany Thicket vegetation of the ECP, in the Bushveld vegetation of the NCP and in isolated patches in the Fynbos vegetation of the WCP. It is predicted that the establishment of the Asiatic blue tick in na\u00efve environments will result in higher disease incidence and tick-related deaths. This is supported by the fact that several B. bovis-related deaths have recently been recorded among na\u00efve cattle in the WCP.This study provides evidence that"}
+{"text": "Sci., 2015, DOI: 10.1039/c5sc02231b.Correction for 'Visualising mouse neuroanatomy and function by metal distribution using laser ablation-inductively coupled plasma-mass spectrometry imaging' by Bence Paul  In the original manuscript, the name of one of the authors was published incorrectly. The correct name of the author is Megan M. Niedzwiecki.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "This is a correction of of Biochem Med (Zagreb)2019;29(2):020711. DOI: https://doi.org/10.11613/BM.2019.020711Since the publication of the article, the authors have noticed that one of the authors in the byline was missing an affiliation. The correct byline is presented above. The authors apologize for any inconvenience caused to the readers."}
+{"text": "Nature Communications 10.1038/s41467-018-04120-z, published online 3 May 2018.Correction to: In the original version of the Article, the authors stated they had no competing interests to declare. They omitted to declare that Dr. Ye is a shareholder of Wuhan Yuanzheng Pharmaceuticals Inc. and Shanghai Braegen Pharmaceuticals Inc. This has now been corrected in the PDF and HTML versions of the article."}
+{"text": "Addition of an Author\u201cJisha Antony\u201d was not included as an author in the published article. The corrected Author Contributions Statement appears below. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.in situ hybridization and the siRNA assays. HS isolated and cloned the rs4077450_rs4077451 minor and major allele fragments into the plasmid constructs and was supervised by JM. AD carried out the luciferase assay and was supervised by JA. RT carried out the conditional analysis. WS and TF carried out the CoDeS3D analyses. ML, JH, and TM wrote the manuscript with input from JO and WW.ML, JH, JO, and TM designed the study. ML performed the functional annotations, the eQTL analyses, the enhancer assays, the"}
+{"text": "Corrigendum:After publication, the authors noticed that the fourth author's name is written incorrectly. Robert Steinert is now corrected to Robert E. Steinert in the author list and contributions."}
+{"text": "Table 2 has two typographical errors. The number of control and carcinoma samples from the Geng et al. study should be 8 rather than 16. The analysis used the correct number of samples. The number of samples in the Sanapareddy et al. study was incorrectly placed in the carcinoma column and should have been in the adenoma column. The analysis for unmatched tissue and adenoma tissue was rerun with this correction and did not meaningfully change the results. An updated version of the analysis can be found at https://github.com/SchlossLab/Sze_CRCMetaAnalysis_mBio_2018.Volume 9, no. 3, e00630-18, 2018,"}
+{"text": "The original version of this paper contained an omission in the conflict of interest statement. The correct version of the conflict of interest statement is below:D.Mu. is employed by Combat Stress, a national UK charity that provides clinical mental health services to veterans. D.MacM. is the lead consultant for an NHS Veteran Mental Health Service. N.G. is the Royal College of Psychiatrists\u2019 Lead for Military and Veterans\u2019 Health, a trustee of Walking with the Wounded, and an independent director at the Forces in Mind Trust; however, he was not directed by these organisations in any way in relation to his contribution to this paper. N.J. is a full-time member of the armed forces seconded to King's College London. N.T.F. reports grants from the US Department of Defense and the UK MoD, is a trustee (unpaid) of The Warrior Programme and an independent advisor to the Independent Group Advising on the Release of Data (IGARD). S.W. is a trustee (unpaid) of Combat Stress and Honorary Civilian Consultant Advisor in Psychiatry for the British Army (unpaid). S.W. is affiliated to the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Emergency Preparedness and Response at King's College London in partnership with Public Health England, in collaboration with the University of East Anglia and Newcastle University.All authors are based at King's College London which, for the purpose of this study and other military-related studies, receives funding from the UK Ministry of Defence (MoD). S.A.M.S., M.J., L.H., D.P., S.M. and R.J.R. salaries were totally or partially paid by the UK MoD. The UK MoD provides support to the Academic Department of Military Mental Health, and the salaries of N.J., N.G. and N.T.F. are covered totally or partly by this contribution. This paper represents independent research part funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London.The views expressed are those of the author(s) and not necessarily those of the National Health Service, the NIHR, the Department of Health and Social Care, Public Health England or the UK MoD."}
+{"text": "There are several errors in the article.The fifteenth author's name is spelled incorrectly. The correct name is: Stephen J. Sowerby.There is an error in the affiliation for author Stephen J. Sowerby. The affiliation should be: Department of Biochemistry, University of Otago, Dunedin, New Zealand.There is an error in the Competing Interests section. The correct Competing Interests should read: The FECPAKG2 technology was produced and distributed by Techion Group Ltd, of which HM is an employee, and GM is a Managing Director. GM and SSo hold stock in Techion Group Ltd. These affiliations however did not play any role in the preparation and submission of this manuscript. All other authors declare that they have no competing interests."}
+{"text": "An author name was incorrectly spelled as Charlotte L. C. J. de Bree. The correct spelling is L. Charlotte J. de Bree. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.JD is currently employed by Aduro Biotech, but was employed by Triskelion when the studies were performed. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Streptococcus pyogenes. Sci. Rep. 7:1129. doi: 10.1038/s41598-017-01267-5. The correct reference appears in the Reference List below. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.In the original article, the reference for Sugimoto et al.  was incoThe original article has been updated.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Urochloa arrecta (Poaceae) on the early colonization of two native species (Pontederia cordata and Leersia hexandra) of aquatic macrophytes. Our hypotheses were (i) the competitive effects of U. arrecta on the native species P. cordata and L. hexandra are density-dependent and that (ii) these species respond differently to competitive interactions with the invasive species. We conducted the experiments in a greenhouse and in the field, in a tropical reservoir. The biomass of U. arrecta (ranging from 206.2 to 447.1 g) was manipulated in the greenhouse in trays with different densities. After the establishment of the invasive species, we added P. cordata and L. hexandra propagules to each tray. In the field, a propagule of P. cordata was planted in 36 sites with different densities of U. arrecta. The biomass and length of the natives and the biomass of the invasive species were measured in the greenhouse and in the field experiments. The biomass and length of the native plants decreased with increasing biomass of the exotic species in both experiments, showing that the competition between U. arrecta and native species depends on the density of the exotic species. The root:shoot ratio of L. hexandra decreased with increasing U. arrecta biomass, but the opposite occurred for P. cordata. These results indicate that native species exhibit different strategies of biomass allocation when interacting with U. arrecta. The strong competitive effects of U. arrecta and the different responses of the native species help to explain the reduced diversity of native macrophytes observed in sites colonized by U. arrecta. The results also suggest that in a scenario of dominance of exotic species, recolonization by native macrophytes is unlike to occur naturally and without human interventions that reduce the biomass of the exotic species.The responses of native plants to competition with invasive plants depend mainly on the density of the invasive plants and on the ability of the native plants to compete for resources. In this study, we tested the influence of the invasive exotic  In general, only a small fraction of introduced species become successfully established and exhibit population growth to the point of becoming \u201cinvasive\" . When thThe impacts of invasive species on native species depend largely on the abilities of interacting species to compete for resources . CompetiCompetition among plants occurs predominantly by nutrient (\u201croot competition\u201d) and/or light acquisition (\u201cabove-ground competition\u201d). The roots and shoots of the plants acquire different resources from the environment, and some studies therefore try to separate the effects of the competition of each plant part . One of Coexistence between species under natural conditions can be facilitated by several mechanisms, such as disturbances and trade-offs between competitive and dispersal abilities . HoweverUrochloa arrecta (Hack. ex T. Durand & Schinz) Morrone & Zuloaga, a species native to Africa, which has colonized tropical and subtropical aquatic ecosystems. In particular, this species is invading and causing ecological impacts in various Brazilian aquatic ecosystems  and tested whether the competitive effects on them differ. First, we developed a greenhouse experiment to test the effects of U. arrecta on the biomass and on the root:shoot ratio of the two native species. Then, we repeated the experiment in the field, using P. cordata as a focal species, to test the generality of our results obtained in the greenhouse. We tested the hypotheses that (i) the competitive effects of U. arrecta on P. cordata and L. hexandra depend on the invasive biomass and (ii) that native species respond differently to these effects. These hypotheses were postulated because previous studies in the field showed that the native macrophyte biomass decreases in the presence of U. arrecta  and the other in situ in the Rosana Reservoir .We performed two experiments employing an additive design  to assesUrochloa arrecta (exotic), P. cordata, and L. hexandra (natives) were used in our greenhouse experiment. The native species were selected based on different levels of co-occurrence with U. arrecta (details about this selection in L. hexandra (Poaceae species often found to co-occur with U. arrecta) is a perennial species that can grow vigorously in aquatic ecosystems  that were filled halfway with sediment and maintained with a 3\u20135 cm water layer. The water was replaced with tap water whenever necessary. To create a gradient of U. arrecta (0\u2013450 g DW m\u22122). Then, we added one propagule of P. cordata and one of L. hexandra at the opposite extremes of each tray (separated from each other by ca. 30 cm). These propagules of P. cordata and L. hexandra were collected in the Rosana Reservoir and brought to the greenhouse, where we removed their leaves and roots in order to allow all plants to start to grow at similar conditions. In addition, we selected propagules with similar weights. The distance between the native species in the microcosms (ca. 30 cm) was assumed to be enough to avoid interaction between them. Although we did not measure the survival rates of the propagules of the native species during the course of the experiment, all propagules survived in our experiment and even those planted in more dense microcosms formed small individuals.A clear gradient in biomass, a necessary condition to test our hypotheses, was formed by 200 days after planting P. cordata and the average length of shoots generated by L. hexandra were measured with a tape (cm). Afterward, the biomass of each species was washed to remove sediment and was separated into shoots and roots. After drying in an oven , the dry mass of roots and shoots of each species was measured on a scale with a precision of 0.01 g. We emphasize that the experimental design of this study simulates a situation in which the recolonization by native aquatic macrophyte species occurs after the occupation of an invasive exotic species that is dominant in an ecosystem, a common situation in several Neotropical aquatic environments.The experiment was completed 3 months after the introduction of the native species. The length of 2\u20130.3 m \u00d7 0.3 m) with different densities of U. arrecta. These sites were identified and demarcated with stakes, and a propagule of P. cordata was planted in each site. The P. cordata propagules were treated the same way as those used in the greenhouse (see details above for the greenhouse experiment). We monitored the field experiment at every week and observed that the propagules of P. cordata were consumed by herbivores in 14 sites. Thus, 3 months after the establishment of the native species, only 36 sites were used in this study.The field experiment was conducted in one arm of the Rosana Reservoir , near the sites where the native macrophytes were collected for the greenhouse experiment. We first selected 50 sites (squares of 0.09 mP. cordata and the shoots of U. arrecta in an area of 0.09 m2 (0.3 m \u00d7 0.3 m) around the native species were collected. For each site, the species were separated and washed, packed and placed in an oven at 70\u00b0C until reaching a constant weight. The dry shoot biomass of U. arrecta and the shoot and root biomass of P. cordata were obtained by using a precision scale with an accuracy of 0.01 g.At the end of the experiment (90 days), the individuals of U. arrecta and the native species identity (L. hexandra and P. cordata), respectively. The response variables were standardized to the values of these variables expected in the absence of U. arrecta. Thus, we expressed them as log response ratios, lnRR = ln(Yu/Yc), where Yc was the value of a response variable without U. arrecta and Yu was the value of this response variable under the influence of U. arrecta. To estimate Yc, we used the mean values of the response variables in the control experimental units. Thus, lnRR is equal to 0.0 in the absence of competitive effects, and the more negative lnRR is, the higher the effect of U. arrecta in limiting the growth of the natives. As our objective was to analyze the competition between the invasive and native species and to evaluate whether they responded differently to the competition effect in a scenario of exotic dominance, we chose to remove the sites with the absence of the invasive species .Following U. arrecta biomass on P. cordata biomass was tested using a second-order polynomial regression due to the non-linearity of the data. All statistical analyses were performed in R  between the total biomass of the invasive species and the total biomass of the native species into Cohen\u2019s d using: d =2r/d (dV) is given by: dV = 4rV/(1 \u2212 r2)3, where rV is the variance of r (rV = (1 \u2212 r2/n \u2212 1) and n is the sample size. Finally, d was transformed into Hedges\u2019 g after multiplying d by a correction factor j  and 36 native species . However, the coefficient of determination of the model for L. hexandra  was substantially higher than that observed for P. cordata .We found that the total biomass of both native species significantly decreased with the increase in the biomass of U. arrecta . However, the slope of the relationship between the biomass of U. arrecta and length of L. hexandra  was significantly steeper  than that for P. cordata .Similar to what we found for biomass, the native species\u2019 length decreased significantly with the increase in the biomass of U. arrecta biomass on the root:shoot ratio clearly differed between the two native species , being positive for P. cordata  and negative for L. hexandra . Despite the opposite effects, the magnitudes of the slopes were similar. These results indicate that L. hexandra invests more in shoots, while P. cordata invests more in belowground structures (roots), with an increasing degree of competition with U. arrecta.The effects of the P. cordata followed the pattern found in the greenhouse. The biomass of U. arrecta negatively affected the biomass of P. cordata . The root:shoot ratio of the biomass of this native species was positively and significantly affected by the biomass of the invasive species .The results obtained in the field experiment with U. arrecta on native species was substantially larger than the effects reported in the meta-analysis of U. arrecta on L. hexandra was greater than that estimated for P. cordata in the greenhouse experiment. However, the largest effect size was estimated for P. cordata when the experiment was carried out in the field, despite the high overlap between the confidence intervals .The effect of U. arrecta on P. cordata and L. hexandra are biomass-dependent, corroborating our first hypothesis. Most importantly, in accordance with our second hypothesis, we showed that the native species responded differently to the competitive interaction with the invader, at least in terms of plant height and root:shoot ratios. In addition, it is likely that the increase in U. arrecta biomass increases the competition for nutrient acquisition more in P. cordata than in L. hexandra, given that the former species invested more in root growth when in greater competitive interaction with U. arrecta than the latter. However, although these native species responded differently to the competitive interaction with the invader, L. hexandra was not the most negatively affected by U. arrecta (as suggested by similar responses in terms of biomass production), which contradicts our prediction in this regard.We found that the competitive effects of U. arrecta on native species were even stronger in the field experiment, where the growth of P. cordata was nearly suppressed at high densities of U. arrecta . These results, along with those obtained in the greenhouse, indicate that high densities of the invasive species decrease recolonization success by native species, which may explain the pattern of reduced macrophyte diversity with the increase of U. arrecta biomass at small spatial scales .The negative effects of l scales . Our finl scales . Thus, iU. arrecta . Thus, our results agree with other studies showing that not all species are able to etiolate in the face of light competition. For example, L. hexandra, is that the light limitation was offset by the increased investment in the biomass of the shoots, as shown by the results for the root:shoot ratio (see below). By contrast, P. cordata has broader leaves than L. hexandra, and thus, increased light acquisition may be obtained by increases in leaf area instead of etiolation. These factors may also explain the steeper reduction in length for L. hexandra than for P. cordata along the invasive biomass gradient.Macrophytes respond to competition  and otheU. arrecta biomass in terms of investment in belowground or aboveground structures , revealing different strategies to overcome competition with the invasive species. The increase in plant density exacerbates competition, which may occur for space, nutrients and/or light (L. hexandra growth becomes increasingly limited by light availability over a gradient of U. arrecta biomass, while P. cordata growth becomes increasingly limited by nutrients and space over the same biomass gradient. The largest investment in shoots by L. hexandra at high densities of the invasive probably occurs because Poaceae are, in general, highly sensitive to shading conditions. Allocation to shoot biomass, relative to root biomass, is likely to be a response to light limitation under high competition, as observed for other herbaceous species (P. cordata indicates a response to root competition (for other examples, see The native species responded differently to the increase in or light . Increasor light . Based o species . On the U. arrecta, and the reduction was even higher for P. cordata in the field. The significant reduction in the growth of native species when exotic species are dominant, as simulated in our experiments, supports the model of preemptive competition, as found in other studies (U. arrecta is unlikely and that their success can only occur if the invasive species is manipulated, reducing its occupation.Despite the changes in biomass allocation of the native species over the competition gradient, there was a reduction of approximately 90% of the native species biomass at high biomass of  studies . In prac studies , our res studies . In summP. cordata demonstrate that at least the direction and intensity of the competitive effects exerted by U. arrecta were similar to those found in the greenhouse. This congruence suggests that the data obtained experimentally in the greenhouse can be extrapolated to field situations, as the results obtained in the latter also indicate the importance of density-dependent effects of an invasive species on native species.Experiments in greenhouses and controlled conditions are criticized for using small spatial and temporal scales and for not replicating the complexity found in natural environments . ExperimU. arrecta possesses higher competitive effects than other invasive species. The consistent negative effect of exotic plants on the biomass of native plants, according to Finally, we believe that the larger effect sizes in our experiment compared to those estimated by U. arrecta and native macrophytes are density dependent and that P. cordata and L. hexandra respond differently to this competitive interaction were corroborated. Our results suggest that in a scenario of dominance of invasive Poaceae, recolonization by native macrophytes is unlike to occur naturally. Our results also indicate that the reduction of the diversity of native macrophytes observed in sites colonized by U. arrecta can be explained by the competitive effects of this invasive species. In practical terms, due to the density-dependent competitive effects, when it is not possible to eliminate the invasive species, a strategy to maintain it at low density would be required to allow recolonization by natives and to maintain local biodiversity. Also in this context, we believe that increasing the number of propagules to analyze the capacity of native species to recolonize environments densely colonized by exotic species would be an interesting avenue for further research.In short, our hypotheses that the effects of competition between TM and ST conceived the ideas and designed the experiments. TM, ST, and FB conducted the greenhouse and field experiments. TM and LB analyzed and interpreted the data. TM led the writing of the manuscript. ST and LB gave major input into the first draft. All authors contributed critically to the final version of the manuscript and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In the Funding statement, the grant number from Vietnam National Foundation for Science and Technology Development is incorrect. The correct grant number is: 105.08\u20132017.11."}
+{"text": "In the New GFR Estimating Equation for SCD subsection of the Results, there is an error in the equation. The text inside the fourth set of parentheses is incorrect. It should read: . The publisher apologizes for the error. Please view the complete, correct equation here:"}
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+{"text": "Our review aims to delineate the psychiatric spectrum of autoantibody-associated autoimmune encephalitis over time through its discoveries of antibodies. We searched in PubMed for appropriate articles depicting the first appearance and spectrum of psychiatric symptomatology in autoantibody-positive encephalitis for this narrative review. Memory impairment was first associated with autoantibodies against intracellular antigens such as anti-HuD antibodies in 1993. 8\u00a0years later, autoantibodies against cell membrane surface antigens such as voltage-gated potassium channels were described in conjunction with memory dysfunction. The spectrum of psychiatric syndromes was amplified between 1990 and 2020 to include disorientation, behavior, cognitive dysfunction, obsessive compulsive behavior and suicidality in encephalitis patients occurring together mainly with antibodies against surface antigens, less so against intracellular antigens. In general, we found no specific psychiatric symptoms underlying specific autoantibody-associated encephalitis. As fundamental data on this issue have not been systemically assessed to date, we cannot know whether our specific findings would remain from systematic studies, i.e., on the association between cerebrospinal fluid N-methyl-D-aspartate receptor antibodies in catatonia. The psychiatric symptomatology overlaps between psychiatric domains and occurs frequently in antibody-positive encephalitis. No specific psychiatric symptoms imply an underlying, specifically autoantibody-associated encephalitis. The psychiatric phenotypology associated with antibody-positive encephalitis has evolved tremendously recently, and this new evidence reveals its relevance for future diagnostic and treatment aspects of autoimmune encephalitis patients. Autoimmune encephalitis is a disorder that can dynamically alter its phenotypical appearance over time. It is often characterized by an initial psychiatric manifestation, or reveals predominant or isolated psychiatric features /Amiphiphysin/AMPAR (\u0251-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor)/ BRSK2 (BR serine/threonine kinase 2)/CASPR2 (contactin-associated protein 2/CRMP3/4 (collapsing reponse mediator protein 3/4)/CV2/CRMP5 (cronveinten 2/collapsing response mediator protein 5), debrin/ DPPX (dipeptidyl aminopeptidase-like protein 6), GABAAR (gammaaminobutyric acid protein A receptor)/GABABR (gammaaminobutyric acid protein B receptor)/GAD65 (glutamic acid decarboxylase 65)/GlycinR/HuD/KLP11 (Kelch like 11 protein)/LGI1 (Leucine rich glioma inactivated protein 1)/Ma/Ta/mGluR5 (metabotropic glutamate receptor 5)/Neurexin3alpha/NMDAR (N-methyl-D-aspartate receptor)/Ri, Ro, SOX1/Synapsin/VGKC (voltage gated potassium channel)/Zic4, AND psychiatry\u201d. We elucidate the autoantibodies\u2019 discoveries via their first psychiatric presentation. Our classification of psychiatric features relies on the analysis strategy of Al Diwani et al. , categorNeuroimmunological researchers suggest 1) develoIn contrast, the clinician should assume a possible autoimmune encephalitis with psychiatric features according to Graus et al.  if threeThe differential diagnosis of autoimmune encephalitis is often demanding, and other diseases must be carefully ruled out in every patient. Several other disease entities need to be considered, such as the neuropsychiatric phenotype of lupus erythematosus often associated with double-stranded deoxyribonucleic acid antibodies, anti-antiphospholipid antibodies, anti-\u00df2-glycoprotein-I, lupus anti-coagulant or anti-ribonucleoprotein antibodies  encephalitis is associated with NMDAR antibodies. In NMDAR encephalitis, the psychiatric symptoms even precede the appearance of neurologic symptoms  and postsynaptic ADAM metallopeptidase domain 22 (ADAM22). LGI1 antibodies might induce neuronal apoptosis, as recently demonstrated in hippocampal neurons  was reported to be associated with a paraneoplastic encephalitis associated with a depressive syndrome, incoherent thoughts, insomnia, panic, personality changes and psychotic symptoms such as delusional thinking and auditory hallucinations , glutamic acid decarboxylase 65 (GAD65), glycine- or leucine-rich glioma-inactivated 1 (LGI1) or NMDAR autoantibodies have demonstrated that neural transmission on the cellular level with consecutive, altered signal cascades could induce psychiatry symptoms and cognitive anomalies on the behavioral level (Haselmann et al. As psychiatric symptoms and syndromes have been less intensively investigated than neurological deficits and symptoms in autoimmune encephalitis patients, these symptoms may be underdiagnosed in patients with autoimmune encephalitis: There is thus a great need for more detailed descriptions of psychiatric syndromes and symptoms in patients with autoimmune encephalitis to enable the psychiatric features of this disease to be better characterized, thereby ensuring these patients receive more effective therapy following a psychiatric onset or predominantly psychiatric manifestation of autoimmune encephalitis."}
+{"text": "Associations of obesity and cardiovascular health with neighborhood walkability have been observed in the literature; however, limited research has evaluated self-selection that may underlie associations. We measured accessibility to parks and trails using geospatial measurements as well as self-reported activity-friendliness of neighborhoods  in 1140 participants (ages 28-49 years) in the ongoing Colorado Adoption/Twin Study of Lifespan behavioral development and cognitive aging (CATSLife). Physical health indicators included BMI, resting heart rate, and mean arterial blood pressure. The relative similarity of siblings\u2019 accessibility was evaluated to consider self-selection; all models were adjusted for sociodemographics including education. BMI was associated with accessibility to parks, with each increasing log(mile) distance associated with 1.2 BMI unit increase . Self-reported neighborhood activity-friendliness was comparable in prediction of BMI (p<0.01). Greater trail accessibility was associated with lower resting heart rate  and mean arterial pressure , whereas self-reported neighborhood activity-friendliness was not associated (p>0.40). Measures of park accessibility tended to be more similar among identical twins (median ICC = 0.30) than fraternal twins or siblings (median ICC = 0.15) or siblings in adoptive families (median ICC = 0.12), excluding siblings who live together. Measures of trail accessibility were consistent across sibling types (median ICCs = 0.25-0.27). Sibling similarity for park accessibility modestly increased with genetic relatedness suggesting potential heritable contributions, whereas comparable similarity was apparent for trail accessibility. Altogether, small associations were observed for park and trail access with physical health, with indications of environmental selection."}
+{"text": "Staphylococcus aureus characterized with multi-antibiotic resistance and regulated by high level agr functionalities in several communities in southwest Nigeria was investigated and evaluated for infection control. Staphylococcus aureus pathotypes recovered from 256 cases including purulent pus from skin infections, soft tissue aspirates, wounds, otorrhea, eye, throat and endocervical infections were assayed for biofilm and antibiogram. Further genotyped with micro-array, mapped for geospatial distribution and evaluated for clonal diversity and functional accessory gene regulators (agr). Significant Staphylococci infection among the ages  and female gender with prevalence rate of MSSA (53.0%) and MRSA (1.5%)  were observed. More than 52.5% resistance rates to tetracycline and amoxicillin with significant median resistance were observed in all the infection cases (p = 0.001). Resistance rate of 78.8% at MIC50 32\u03bcg/ml and MIC90 128\u03bcg/ml to amoxicillin-clavulanate, and more than 40% resistance to ceftazidime, ciprofloxacin and tetracycline of MIC90 and MIC50 at 32 \u03bcg/ml were observed. Strains with multi-antibiotic resistance index above 0.83, high beta-lactamase and strong biofilm clustered into separate phylo-group. Heterogeneous t442 (wound and pus), t657 (wound), t091 (ear) and t657 (ear and wound) revealed high phylogenetic diversity. Only 4.6% pvl+ MSSA-CC1 agrI, pvl+ MSSA-CC5 (13.6%) and pvl+ MRSA-CC7 agrII (4.6%), expressed enterotoxin, leukocidins, proteases and resistance gene determinants. Livestock clonal types clustered with identified community-associated strains. Clonal dissemination of resistant pvl+ MSSA-CC1 and MRSA-CC5 encoding agr were predominant in several peri-urban communities where adequate geno-surveillance, population-target antimicrobial stewardship, extensive community structured infection control programs are needed to prevent further focal dissemination.Spread of genetically diverse  Several strains . In addiactivity .agr), which encodes a two-component signal transduction system that could down-regulate surface proteins metabolism and up-regulate secreted proteins during in vitro growth [agr groups were reported to enhance persistent staphylococci bacteraemia and soft tissue tropism with low antibiotic susceptibility to penicillin, cephalosporin and vancomycin [Staphylococcus aureus) and MSSA (methicillin-susceptible Staphylococcus aureus) is becoming pandemic in several communities in Africa, mostly Nigeria where animal husbandry, behavioural responses and declined demographic factors enhance continuous dissemination of staphylococcal infection with high degree of antibiotic resistance [Severity of staphylococci infection correlates with virulence expression which is regulated through the functionality of accessory gene regulators , skin aspirates and effusions (n = 34), wounds (n = 55), otorrhea (n = 36), eye infection (n = 14), throat (n = 35) and endocervical (n = 24), collected between June 2017 and August 2018 from overall 12,654 outpatients. This included patients from neighbouring states attending three major health facilities which serve as referral clinics in southwest Nigeria. Ethical permission for the study was granted by the Federal Medical Centre Abeokuta Health Research Ethics Committees with protocol approval: FMCA/470/HREC/09/2017; NHREC/08/10-2015 with permission from other health facilities but data on their gender, age, disease conditions and subjects\u2019 location of residence were not fully retrieved. Each sample were cultured for Staphylococci strains and phenotypically characterized on Baird-Parker agar and Mannitol salt agars, Gram stained for cellular morphology, tested for catalase and coagulase production as previously discussed [Beta-lactamase production was assayed with modified starch-acidometric method  and MiniStaphylococcus aureus.Phenotypic assessment of biofilm production was done in micro-broth bioassay . BrieflymecA and pvl as described by Acevedo et al [mec5 (AAAATCGATGGTAAAGGTTGGC) and mec6 (AGTTCTGCAGTACCGGATTTGC) and pvl gene with primers pvl-F (AATGAAATGTTTTTAGGCTCAAGACA) and pvl-R (TGGATAACACTGGCATTTTGTGA) with DNA template (1\u03bcl) and water (18 \u03bcl) for each reaction following previous described multiplex protocol [For detection of pathogenic MRSA, isolates were genotyped for do et al . Brieflydo et al  and amplprotocol . AmplifiS. aureus protein A (spa gene). PCR assay was performed in constituted reaction mixture of 2x MyTaq HS Mix (10\u03bcL), containing spa primers; spa1095F (5\u2019-AGACGATCCTCCGGTGAGC-3\u2019), spa1517R (5\u2019-GCTTTTGCAATGTCATTTACTG-3\u2019) of 5\u03bcL each and 1\u03bcL template DNA through 30 cycles of denaturation at 94\u00b0C for 30 seconds, annealing at 60\u00b0C for 30seconds and elongation at 72\u00b0C for 30 seconds, with final extension at 72\u00b0C for 5minutes [S. aureus DSM 1104L strain served as a positive and distilled water as negative control. Quality of amplicon products was examined on electrophoresed agarose gel and positive strains were purified with GFX PCR DNA and Gel Band Purification Kit . Purified PCR products were sequenced with forward primer spa1095F using BigDye 3.1 terminator sequencing and analyzed on ABI Genetic Analyzer 3500Dx . Categorisation of spa types was carried out with Based Upon Repeat Pattern (BURP) algorithm of the Ridom Staph Type software version 1.4  to cluster all spa types in the database according to spa clonal complexes [spa types with other meta-spa sequences were analysed with MEGA software (version 6.0).Extracted genomic DNA obtained from overnight culture, was typed for 5minutes ,24. DNA omplexes . Clonal S. aureus strains with mecA and pvl were further genotyped with StaphyType DNA microarray  for other virulence genes. Approximately 170 distinct genes and their allelic variants were targeted for PCR amplification and hybridization on Microtiter strip-mounted DNA microarrays following manufacturer\u2019s instruction and the image of the array was recorded and analysed using a designated reader and software  [Encoded ologies) .Geographical coordinates of individual subjects with staphylococcal infection were identified and recorded with differential global positioning system (GIS) and interpolated for analysis in ArcGIS 10.5.1 programme with respect to land division according to boundary marks in southwest Nigeria .th percentile resistance were evaluated with Boxplot analysis. Significance of resistance level of staphylococci strains was determined with chi-square and staphylococcal infectivity was calculated with multiple comparison using Kruskal-wallis test.To identify variables and risk factors that could influence staphylococcal infection rate among dependent variables , univariate logistic regression analyses was performed to calculate the odds ratio and corresponding 95% confidence intervals. Resistant rates was analysed with radar plots while Median and 75Staphylococcal infection was significant among the ages  while higher prevalence rate of MSSA (53.0%) and MRSA (3.0%) infection were recorded among female and male subjects respectively. MSSA (37.9%) and MRSA (1.5%) infection rates were significant in wound infection as other clinical conditions presented by the subjects (p<0.05) while MSSA (42.2%) were observed in other conditions  as shown in S. aureus from different sources as shown in th) and median resistance were observed in wound strains than others. Overall resistance rate of 78.8% to AMC at MIC90 (128\u03bcg/ml) was recorded for strains obtained from aspirates, while strains recovered from pus, ear and wound infections showed more than 30% resistance at MIC50 (8\u201316\u03bcg/ml). S. aureus strains (59.3%) recovered from pus and aspirate were resistant to CRO at MIC90 (64\u03bcg/ml) and MIC50 (8\u03bcg/ml), respectively. More than 40% of S. aureus strains obtained from aspirate had high resistance to TET (MIC90 and MIC50 at 64\u03bcg/ml), while strains recovered from pus were resistant to GN (MIC90 and MIC50 at 128\u03bcg/ml and 16\u03bcg//ml), respectively , t657 (wound), t091 (otitis media) and t657 (otitis media and wound) clustered into clade F1 with other spa types from blood stream and soft tissue infection (red rectangular). High phylogenetic relatedness of spa sequences of livestock-associated S. aureus strains  clustered with the human strains (Heterogeneous  strains .pvl+ MSSA-CC1 (4.6%) obtained from wound samples, of spa t1839, majorly encoded exfoliative toxin , proteases  and resistant determinants; bla (beta lactamase repressor (inhibitor) and beta-lactamase regulatory protein); fosB ; sdrM (tet efflux protein) and Q2YUB3 (Multidrug resistance transporter) , leukocidins  and proteases . In addition, agrII was also recorded in 4.6% pvl+ MRSA-CC7 strains of spa t091 characterized with LukF-PV, lukD, lukE, proteases and aphA3, ; sat (Streptothricine-acetyltransferase); tetK (Tetracycline resistance markers); msr (A) (Macrolide efflux); and mph(C), (lysylphosphatidyl-glycerol synthetase). Most MSSA strains were observed to be prevalent at urban communities showing focal dissemination to other nearest suburbs while identified MRSA was observed to be spreading together with other MSSA strains  , express strains .S. aureus infections are now commonly observed among the children with high risk of sores, blood stream and scalded skin infections which are recorded due to low immunity, poor hygiene and possible transmission from staphylococci-carrier mothers [S. aureus and animals strains [Continuous spread of staphylococcal infection in several communities is now becoming a threat to the populace and mostly the children. Methicillin susceptible  mothers . Occupat mothers . Nosocom mothers . A signi strains ,32.in-vitro biofilm production reflects acute systemic infection severity and pathology that could progress to high morbidity [mecA gene and beta-lactamase production which is a major factor to be considered towards achievable control of MRSA spread [The ability to treat multi-antibiotic resistant staphylococci strain characterized with biofilm is a challenging situation  and deteorbidity ,36, makiorbidity . High biorbidity . In addiA spread .spa types in extra-intestinal infections clearly showed high phylo-diverse spa strains clustering into various different clades. In spite of this strain-diversity, profound relatedness with other meta-spa types suggests high level dissemination of similar clonal groups [spa types in single or multiple staphylococcal infections having high substantial impact through localization and distribution in soft tissue for adaptation, colonization and pathogenesis thereby initiating severe infection [In addition, identification of heterogeneous l groups . This isnfection ,42.spa sequences from various skin and soft-tissue infections , is an evidence of genetic recombination of spa repeats from livestock-associated staphylococci particularly bovine milk [spa strains [spa types to human and high prevalence of these associated livestock spa types. It is also necessary to evaluate the emerging animal clonal spa types vis-a-vis animal husbandry and antibiotic residue in milk in order to safeguard the populace and drastically reduce dissemination and risk of contracting antibiotic resistant strains. Findings on animal related MRSA and MSSA spa types in humans, illustrates livestock involvement in continuous spread and distribution of Staphylococcal pathotypes in many communities. To control the prevalent, milk hygiene and animal waste management would enhance reduction in spread and skin infectivity particularly among children.Identified phylo-diverse MSSA from Nigerian communities indicates active transfer of clonal strains to other locations . Detectiine milk . This fu strains . It is aS. aureus encoding functional agr is known to have well-characterised operons controlling and regulating exfoliative toxin and protease genes in pvl+ MSSA-CC1 strains which are in wound infections [agrI and agrII in MSSA and occurrence of agrII in pvl+ MRSA-CC7 clonally differ from agrIII that were reported in Tunisia [agrII in resistant pvl+ MSSA-CC5 and pvl+ MRSA-CC7 clones in pus, wound and abscess would further intensify invasiveness through action of enterotoxin genes , leukocidins  and proteases . Furthermore, bloodstream, skin and soft-tissue infections would be more severe in agr controlled staphylococcal diseases and could result in longer hospital stay, increase debilities and therapeutic failure. In rural and semi-urban settings with poor health facilities and hygiene awareness, dissemination of these resistant clonal pathotypes would exacerbate infection burden, mostly among the vulnerable elderly. Major limitations to the study were inadequate provision of demographic data, low retrieval of residence locations of the recruited subjects and their level of closeness to livestock around the households.Resistant fections ,46, woul Tunisia ,48. Expragr encoded pvl+ MSSA-CC1 and pvl+ MRSA-CC5 strains characterised with very high antibiotic resistance would require aggressive implementations of antibiotic stewardship, public health regulation, hygiene practice and extensive community health care intervention coupled with well-structured strategic infection control programs. Periodic geno-surveillance and investigation of multi-antibiotic resistant zoonotic MSSA and MRSA needed to be implemented concurrently with formulated health policy to prevent imminent outbreak of these clonal pathotypes.Control of skin and soft tissue staphylococcal infections predominantly caused and spread by S1 Table(DOCX)Click here for additional data file."}
+{"text": "Bone-active medications (BAM) [prescriptions (RxBAM) and supplements. The sample included frequency-matched males and females 65 years or older from the Baltimore Hip Studies\u2019 seventh cohort. Differences in baseline characteristics between males and females with complete data(n=313) were assessed using t-tests and chi-square tests. Generalized estimating equations(GEE) predicted the probability of RxBAM use by sex among participants(n=270) with outcome data during follow-up adjusted for baseline characteristics. Prior to fracture, there were sex-differences in BAM use, with fewer men than women taking RxBAMs(9% versus 26%), calcium(18% vs. 57%) and vitamin D (55% vs. 68%). These differences remained over the year post-hip fracture. Only 12(3.5%) participants took RxBAM the entire study period. Of RxBAM users n=70(26%), there were few new-users (n=35), and many participants stopped or never started treatment. Unadjusted GEEs showed that men were less likely to use RxBAM , during the hip fracture recovery period compared to females. However, after controlling for differences in baseline characteristics between males and females, particularly pre-fracture BAM medication use, the observed association . RxBAM use was low, especially in men and may contribute to the high rates of preventable subsequent osteoporotic fractures and post-fracture mortality."}
+{"text": "Adoption of an observation unit (OU) strategy in patients with chest pain at intermediate-risk for ACS has been hampered by limitations of traditional cardiac testing. As a result, most intermediate risk patients are admitted to the hospital for their evaluation. CMR demonstrates superior accuracy compared to other testing modalities. Additionally, CMR is with highly sensitive to recent or ongoing infarction which may allow stress imaging to be performed without waiting for the results of serial cardiac markers. These advantages of CMR make it well suited for use in OUs. An OU-CMR strategy may be resource saving compared to hospital admission.To compare resource consumption between an observation unit stress cardiac MRI (OU-CMR) strategy and hospital admission when used to evaluate emergency department (ED) patients with chest pain at intermediate risk for acute coronary syndrome (ACS).Patients meeting intermediate risk criteria  underwent stratified blocked randomization to OU-CMR or hospital admission. OU-CMR participants underwent cardiac markers at 0, 4, and 8 hours with adenosine or dobutamine CMR imaging performed at the first available time after the return of the first two cardiac marker results. CMR imaging included resting wall motion, T2 weighted imaging, and perfusion, stress wall motion and perfusion, and delayed enhancement. Hospital admission participants underwent evaluations as determined by their treating physician. Participants were contacted at 30 days to determine events occurring after hospital discharge. Primary outcomes included direct cost of the index hospitalization and length of stay. Cost was calculated using cost:charge ratios and physician work-RVUs. The results of the first 50 participants are reported in this interim analysis.Participants had a mean age of 56 years, a median TIMI risk score of 2 , 25 (50%) were female, and 10 (20%) reported prior coronary disease. Participants were equally randomized with 25 participants in each treatment group. Protocol adherence was high among both groups . Stress CMR imaging was obtained in 24/25 (96%) OU-CMR participants during the index visit; 11/25 (44%) received imaging the same day as presentation. In the OU-CMR group, 20/25 (80%) of participants were discharged from the OU without admission. Five participants were admitted from the OU and underwent continued monitoring (n = 1) or cardiac catheterization (n = 4). Of the 4 undergoing cardiac catheterization, 1 was diagnosed with a non-ischemic emergent cardiac condition and 3 were not found to have an emergent cause of chest pain. There were no complications related to CMR testing. Among standard care participants, all patients were admitted, 21/25 (84%) had cardiac imaging with 14 undergoing stress echocardiography, 3 stress cardiac MRI, 3 cardiac catheterizations, and 1 resting echo exam.ACS criteria were met in 3/50 (6%) participants due to revascularization (n = 2) and myocardial infarction (n = 1), all in the hospital admission arm during the index hospitalization. Two participants had repeat hospitalizations for chest pain within 30 days, both in the hospital admission arm, and neither met ACS criteria. The OU-CMR group had a trend towards same day discharge more frequently than standard care participants (7/25 (28%) vs 3/25 (12%), p = 0.29). Cost of index hospitalization demonstrated a near significant trend towards favoring OU-CMR before adjustment  and after adjustment for covariates . Length of stay demonstrated a trend towards favoring OU-CMR before  and after adjustment .An OU-CMR approach among ED patients with chest pain at intermediate risk for ACS is feasible. OU-CMR decreases hospital admissions and has demonstrated a strong near-significant trend towards decreasing index hospitalization cost."}
+{"text": "Most adults have experienced traumatic events . Late-life traumas may compound upon trauma histories , accentuating the risks confronting older adults. Per CMS\u2019 updated Requirements for Participation, nursing homes (NHs) must implement trauma-informed care (TIC) approaches, effective November 2019. Many NHs do not staff Masters of Social Work (MSWs), despite their expertise in providing mental health care. Notwithstanding, employed MSWs feel unprepared to help their NHs implement TIC. This presentation discusses findings from a national survey of NH social service directors (N = 932). Results showed 71% (n = 650) reported moderate to strong interest in TIC training. A Kruskal-Wallis H test revealed a statistically significant difference in TIC training interest \u03c72(1) = 43.690, p < .001, such that MSWs reported higher interest (M = 486.47) than non-MSWs (M = 375.23). There was no difference between those with and without a Bachelor of Social Work."}
+{"text": "We report the genome sequence of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) isolate obtained from a patient with symptoms of coronavirus disease 2019 (COVID-19) who was infected in Cali, Colombia. The patient had no recent travel record and did not require hospitalization. The virus genome was obtained using Oxford Nanopore MinION sequencing. We report the genome sequence of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) isolate obtained from a patient with symptoms of coronavirus disease 2019 (COVID-19) who was infected in Cali, Colombia. The patient had no recent travel record and did not require hospitalization. The virus genome was obtained using Oxford Nanopore MinION sequencing. Coronaviridae, genus Betacoronavirus) is spreading in the Americas and causing coronavirus disease 2019 (COVID-19) (Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) . The assembly was performed in two steps (using default parameters). First, for quality control and filtering of reads (fragments of 400 to 700\u2009bp), we used the gupplyplex script of the ARTIC Network bioinformatics protocol (https://artic.network/ncov-2019/ncov2019-bioinformatics-sop.html), followed by a reference assembly with minimap2 (MN908947.3). The consensus sequence was quality checked using Qualimap v2.2.1 . The alignment was performed using MAFFT (github.com/nextstrain/augur)   . A maximn/augur)  with a Gn/augur) . We detef8 gene) . The CalThis work obtained institutional review board/ethics committee exemption from the Facultad de Salud of the Universidad del Valle because it relies on laboratory results that did not involve experimentation with humans. The required documentation is available upon request.EPI_ISL_445219 and MT470219, respectively. Raw reads were deposited in the GenBank Sequence Read Archive (SRA) under accession number SRX8341156 (BioProject number PRJNA632678 and BioSample number SAMN14917563).The genome sequence of SARS-CoV-2 isolate Cali-01 was deposited in GISAID and GenBank under accession numbers"}
+{"text": "Correction to: BMC Health Serv Res 20, 124 (2020)https://doi.org/10.1186/s12913-020-4967-3Following publication of the original article , the autThe updated content in the Competing interests is shown below:Carlos Qui\u00f1onez receives consulting income for dental care related issues from Green Shield Canada. All other authors declare no competing interests.The original article has been corrected."}
+{"text": "Psidium guajava L.) is an important fruit crop of tropical and subtropical areas of the world. Genomics resources in guava are scanty. RNA-Seq based tissue specific expressed genomic information, de novo transcriptome assembly, functional annotation and differential expression among contrasting genotypes has a potential to set the stage for the functional genomics for traits of commerce like colored flesh and apple color peel.Guava (cv. Allahabad Safeda to understand important genes and pathways controlling fruit development. Tissue specific RNA sequencing and de novo transcriptome assembly using Trinity pipeline provided us the first reference transcriptome for guava consisting of 84,206 genes comprising 279,792 total transcripts with a N50 of 3603\u2009bp. Blast2GO assigned annotation to 116,629 transcripts and PFam based HMM profile annotated 140,061 transcripts with protein domains. Differential expression with EdgeR identified 3033 genes in Allahabad Safeda tissues. Mapping the differentially expressed transcripts over molecular pathways indicate significant Ethylene and Abscisic acid hormonal changes and secondary metabolites, carbohydrate metabolism and fruit softening related gene transcripts during fruit development, maturation and ripening. Differential expression analysis among colored tissue comparisons in 3 cultivars Allahabad Safeda, Punjab Pink and Apple Color identified 68 candidate genes that might be controlling color development in guava fruit. Comparisons of red vs green peel in Apple Color, white pulp vs red pulp in Punjab Pink and fruit maturation vs ripening in non-colored Allahabad Safeda indicates up-regulation of ethylene biosynthesis accompanied to secondary metabolism like phenylpropanoid and monolignol pathways.Development of fruit from flower involves orchestration of myriad molecular switches. We did comparative transcriptome sequencing on leaf, flower and fruit tissues of Benchmarking Universal Single-Copy Orthologs analysis of de novo transcriptome of guava with eudicots identified 93.7% complete BUSCO genes. In silico differential gene expression among tissue types of Allahabad Safeda and validation of candidate genes with qRT-PCR in contrasting color genotypes promises the utility of this first guava transcriptome for its potential of tapping the genetic elements from germplasm collections for enhancing fruit traits. Psidium guajava L.) fruit is a berry with edible pericarp tissue as flesh and has excellent antioxidant properties [Guava  is the chief pollinator [Fruiting branches in guava bear three terminal flower buds and the central floral bud develop faster into fruit compared to other two lateral buds. In Northern India subtropics, there are two flowering seasons Staphyloccocus, scavenge cancer causing free radicals and helps in the structural protein, collagen synthesis which maintains integrity of blood vessels, skin, organs, and bones [Guava is India\u2019s fourth most important fruit crop after mango, banana, citrus and is popularly known as poor man\u2019s apple because of low cultivation cost and high nutritive value. Guava is a climacteric fruit and contains reducing sugars, indigestible lignin fiber and carotenoids that increase as the fruit ripens  with majnd bones .Colored fruits are preferred by the consumer owing to higher nutraceutical properties. Color in fruits and vegetables are controlled by secondary metabolism pathway genes mainly phenylalanine ammonia-lyase (PAL), chalcone synthase (CHS), dihydro- flavonol 4-reductase (DFR), flavanol synthase/flavanone 3-hydroxylase (F3H), UDP-glucose:flavonoid 3-O-glucosyltransferase (UFGT), anthocyanidin synthase (ANS) and transcription factors (TFs) of myeloblastosis (MYB), basic helix-loop-helix (bHLH), tryptophan- aspartic acid (WD) repeats, NAC  and MADS  domain \u201319. For No such studies have so far been conducted in guava. Also, there exists enormous gene sequence variation among species that generating consensus sequence-based markers and validation is labor intensive and non-targeted. Developing new colored genotypes with desirable agronomic traits by hybridization without marker assisted selection for color related genes is a time-consuming process. So, generating expressed genic sequence information at genome wide level is important to expedite gene cloning and tapping in color trait controlling loci from agronomically less preferred colored guava cultivars (owing to low yields and/or lesser shelf life). Tissue specific comparative gene expression within a genotype and comparison to contrasting genotypes by RNA-Seq is an alternate targeted approach in the absence of gold standard genome assembly.To generate a global gene expression landscape in guava we generated RNA-Seq libraries from leaf, flower buds and fruit tissue of green skinned/white pulped table purpose guava cv. Allahabad Safeda (AS). In another cv. Apple Color (AC) fruit peel color changes from green to apple color (reddish) at fruit picking stage and peel becomes leathery within 3\u20135\u2009days in winter season. Pink pulp cv. Punjab Pink (PP) is commercially grown for red nectar and the color develops during maturation process (immature fruits have white pulp) probably owing to the chromoplast development as found in other similar genotypes . ComparaWe have developed the first de novo reference transcriptome assembly of guava, performed gene annotations, compared different fruit development stages to understand molecular pathway (s) in fruit ripening and compared 3 different genotypes with variable coloration in pulp and fruit skin/peel to understand the fruit color development pathway in guava Fig.\u00a0 & Fig.\u00a0250 of 3603\u2009bp were obtained  vs mixed flower buds (MFb), mixed fruit vs leaf & shoot tip (LSt) and mixed flower bud vs leaf & shoot tip  in MFr compared to LSt, with 971 being up and 1154 down regulated. In MFr and MFb comparison, 1445 DETs were found, of which 719 were up-regulated and 726 down regulated. However, 660 DETs were identified between MFb and LSt, with 447 up and 213 down-regulated  represented by six transcripts Hydroxycinnamoyl CoA shikimate  belonging to BAHD family of acyl-CoA-dependent acyl-transferases controls lignin , 31 and 1_c1 reprhttp://mapman.gabipd.org) with all DETs at FDR\u2009<\u20090.001. Differential 2125 transcripts were found significantly regulated in fruit compared to leaf  and Salicylic acid (SA) signal transduction pathways were up-regulated whereas Jasmonate (JA), Auxin, and Brassinosteroid (BR) were down-regulated with few transcripts showing up-regulation Fig.\u00a0b. EthyleWe identified 40 TF families with multiple transcripts belonging to MYB, MADS, HB, WRKY, ARF, bHLH, AP/EREBP, bZIP, NAC, AUX/IAA, B3, Jumonji and, Polycomb. These families showed both up and down regulation, indicating their importance in modulation of fruit development. Sucrose cytosolic invertase 2 (CINV2), responsible for conversion of sucrose to monosaccharides like fructose and glucose showed up-regulation and is in line with increase in sucrose catabolism in developing fruits.Cellular response analysis depicts down regulation of transcripts belonging to biotic stress and is in line with fruits being more prone to pathogen and insect damage in comparison to leaves Fig.\u00a0c. PhytoeWe compared RNA-Seq at different fruit maturity and ripening stages in AS. Comparison of mature fruit 0DF to immature fruit ImF identified 220 differentially regulated transcripts, with 75 showing up-regulation and 145 showing down regulation -reticuline 7-O-methyltransferase-like  showed high homology, so common primers were designed for qRT-PCR. Results show that expression of -reticuline 7-O-methyltransferase Like (RML) transcripts increases to 100X at 0DF_AS compared to ImF_AS set to unity . Process of ripening is accelerated by the conversion of complex polysaccharides into simple sugars leading to increased sugar to acid ratio concomitant with textural and color changes. Conversion of l-aminocyclopropane-l-carboxylic (ACC) acid from S-adenosylmethionine (SAM) is catalyzed by ACC synthase and is the rate limiting step in ethylene biosynthesis [Climacteric fruits show increased rate of respiration and ethylene biosynthesis which in turn triggers the activity of enzymes like PGs, PeLs and, ynthesis , 45. Expynthesis . We obseynthesis . ExpressGuava is rich in secondary metabolites. Expression of genes controlling secondary metabolites like isoflavone reductase (IFR) is maximum in immature fruits, flavanone 3-hydroxylase (F3H) is high in leaf, flower and immature fruits and flavonoid 3, 5 -hydroxylase (F3\u20195\u2019H) 2-like in leaf and flower tissue , 4CL, HCT, Caffeoyl CoA 3-O-methyltransferase (CCoAOMT), Cinnamoyl CoA reductase (CCR), Caffeic acid 3-O-methyltransferase (COMT) and CAD genes. Several CAD family members generally show up-regulation in the fruit flesh and respond to ABA, ethylene and various biotic and abiotic stresses as observed in melon . HoweverTranscript FPKM value and qRT-PCR  in chloroplast and help relieving the oxidative stress by reactive oxygen species (ROS) evolving from the photosynthesis reactions . OverexpMethionine not only acts as a building block for protein synthesis but also serves as immediate precursor of S-adenosylmethionine, a major methyl-group donor in transmethylation reactions and as an intermediate for biosynthesis of polyamines and ethylene . Up-reguForsythia intermedia, a precursor for the biosynthesis of antiviral and anticancer agent, podophyllotoxin [SlBEL1- like 11 in tomato increased the chlorophyll content [Eucalyptus grandis uncharacterized LOC104449412.SDH converts (2)-secoisolariciresinol into (2)-matairesinol in llotoxin , 56. Altllotoxin  and overllotoxin  leads to content  and delaUp-regulation of Mannan endo-1,4-beta-mannosidase (\u03b2-mannanase) indicates utilization of mannans in producing mannose oligosaccharides from lignocellulosic polysaccharides . KinesisEscherichia coli, Saccharomyces cerevisiae, Pseudomonas putida and Streptomyces spp. to synthesize a wide range of phenylpropanoid-derived compounds like flavanones, naringenins, kaempferol, quercetin, stilbenes and many more [Anthocyanin biosynthesis genes like F3H , Isoflavany more . Prelimiany more . IncreasTissue specific and genotypic comparative transcriptome analysis of guava reported here corresponds to the metabolic changes expected and observed in climacteric fruit crops. The transcriptome assembly generated in this study will set the stage for functional genomics in guava, the second most important fruit crop of Northern India. Comparative transcriptome sequence analysis of non-colored vs colored guava cultivars will lead to identification of simple sequence repeat, Insertion-deletion and single nucleotide polymorphism-based markers and be utilized in linkage mapping and other genetic studies. Notably, identification of candidate gene-based markers for red color will aid in generating polymorphic markers and prove a boon for marker assisted breeding for color trait in guava.Punjab Pink is a hybrid between Portugal x L-49\u2009=\u2009F1 x Apple Color and was developed by Punjab Agricultural University, Ludhiana and released in year 2009. CISH-G5/Lalima is an apple color selection of Central Institute of Sub-tropical Horticulture, Lucknow, Uttar Pradesh, India. Allahabad Safeda is an open pollinated seedling selection from Uttar Pradesh, India. The three cultivars were clonally propagated and raised in the mother block of Regional Fruit Research Station - PAU, Bahadurgarh, Patiala, Punjab, India. The 10\u2009years old clonal propagated trees growing in fruit research orchards of PAU, Ludhiana, India have been used in current study.Psidium guajava L. local cultivars Allahabad Safeda (AS), Apple Color (AC: CISH-G5) and Punjab Pink (PP) 10\u2009years old trees growing in Orchards of PAU, Ludhiana, India. Allahabad Safeda is the most prominent cultivar grown throughout India for table purpose. AS fruits are green skinned at immature and harvesting stage , starts turning yellow and skin turns completely yellow within 3\u2009days after picking  and becomes over-ripe thereafter. Foliage and flower buds of AS, PP and AC are all green however pulp of PP turns to deep pink on maturity (0DF), whereas immature fruit pulp is white. Fruits of AC turn their skin color from green (\u22125DF) to reddish (0DF) in winter season  without seed (ImF_PP), mature fruit without seed (0DF_PP) and AC green peel  and red peel  were also harvested, similarly.In AS, we collected actively growing immature young leaves, fully expanded mature leaves, actively growing shoot tips, flower buds at six different developmental stages from immature to mature (1\u2009day before anthesis) and 0D opened flower, 80DPA (immature fruit) with seeds and without seed (ImF), fully mature ready to harvest fruit tissue with seeds and without seeds (0DF), fruit tissue 3\u2009days after harvesting without seeds (3DF) and fruit tissue 7\u2009days after harvesting without seeds (7DF) in three replicates. All the tissues were flash frozen in liquid NTotal RNA was extracted from all the tissues using Spectrum\u2122 Plant Total RNA Kit (Sigma-Aldrich) followed by on-column DNase I digestion (Sigma-Aldrich) for removing DNA contamination. RNA integrity was analysed on 1.2% agarose denaturing gel as described before . High quBioanalyzer (Agilent) was used to asses RNA quality before preparing RNA-Seq libraries. Libraries were constructed with ribo-zero treated RNA from 3 biological replicates of AS LSt, MFb, MFr and a single sample for AS ImF, 0DF, 3DF, 7DF, ImF_PP, 0DF_PP, AC_GP & AC_RP. RNA had RIN value \u22658.3 and TruSeq Stranded RNA Library Prep kit (Illumina) was used with an insert size of ~\u2009300\u2009bp. The paired end (PE) libraries were sequenced on Illumina HiSeq2500. 100\u2009bp high quality PE reads were generated. All the libraries were run in a single lane to avoid any discrepancies while calculating differential expression (FPKM). Read quality was assessed using FASTQC toolkit , 76. Ada\u2212\u20093. Gene ontology (GO) terms associated with transcripts were determined using BLAST2GO program [The assembled transcripts were annotated on the basis of corresponding homologs identified from BLASTX  program  program . GO enri program . KEGG an program . DatafilThe trimmed reads were mapped to reference transcriptome and abundance of transcripts was measured in FPKM values using RSEM estimation tool, for each sample . Trimmedhttp://mapman.gabipd.org) [DETs in tissues/genotypes were put together in a fasta file and pathway annotation were determined using online Mercator analysis tools (ipd.org) . DETs weipd.org)  was usedipd.org) .http://frodo.wi.mit.edu/).Two micro grams of RNA was reverse transcribed by reverse transcriptase (Maxima First Strand cDNA Synthesis Kit for RT-qPCR containing oligo (dT)18 and random hexamer primers; Thermo-Scientific, Surrey, UK), in a 25\u2009\u03bcl reaction further diluted to 100\u2009\u03bcl with nuclease free water. Diluted cDNA template (2\u2009\u03bcL) was used for a 15\u2009\u03bcl PCR reaction. Gene-specific primers , Mixed Flower bud (MFb) and Mixed Fruit (MFr) tissue samples and the replicates.Additional file 3: Table S3. Expression of top 20 co-up regulated transcripts in Allahabad Safeda fruit tissue compared to leaf and flower with FDR <\u20090.001.Additional file 4:Table S4. FPKM value of top differentially regulated transcripts of red peel vs green peel of Apple Color (AC) and Punjab Pink (PP) mature red fruit vs Allahabad Safeda (AS) mature fruit in development stages of AS, PP and AC.Additional file 5: Table S5. Primer Sequences for candidate genes/internal control for qRT-PCR analysis.Additional file 6: Figure S1. Summary of conserved orthologous genes (BUSCO) in the assembled guava transcriptome.Additional file 7: Figure S2. Blast2GO distribution of assembled transcripts into A) Biological processes B) Cellular component C) Molecular function.Additional file 8: Figure S3. Metabolic overview with MAPMAN analysis of differentially expressed transcripts of mature fruit (0DF) vs Immature fruit (ImF) of cv. Allahabad Safeda. Up- and Down- regulated DETs are represented with blue and red squares, respectively with log2 transformed values.Additional file 9: Figure S4. MAPMAN analysis of differentially expressed transcripts of ripe fruit (3DF) vs mature fruit (0DF) of cv. Allahabad Safeda A) Metabolic Overview B) part of regulation overview C) proteasome and autophagy. Up- and Down- regulated DETs are represented with blue and red squares, respectively with log2 transformed values.Additional file 10: Figure S5. MAPMAN analysis of differentially expressed transcripts of apple color skin vs green skin of Apple Color \u2013 CISH-G5, shows up-regulation of the secondary metabolism pathway. Up- and Down- regulated DETs are represented with blue and red squares, respectively with log2 transformed values.Additional file 11 : Figure S6. Cluster analysis of differentially expressed transcripts among fruit stages of Allahabad Safeda (AS), Apple Color (AC) and Punjab Pink (PP) immature fruit (ImF), mature fruit (MF), 3\u2009days after harvesting (3DF), 7\u2009days after harvesting (7DF), green peel and red peel.Additional file 12: Figure S7. Gene Ontology enrichments between A) red and green peel of Apple Color B) mature fruit of Punjab Pink and Allahabad Safeda.Additional file 13. Guava_Reference_Transcriptome_Data files. Data S1. Functional Annotation of Allahabad Safeda Transcriptome Assembly. Data S2. Differential expression among different tissue types, mixed flower buds vs leaf & shoot tip (MFb vs LSt), mixed fruit stages vs leaf & shoot tip (MFr vs LSt) and mixed fruit stages vs mixed flower buds (MFr vs MFb) of Allahabad Safeda. Data S3. Differential expression between mature but unripened fruit (0DF) vs immature fruit (ImF) of Allahabad Safeda. Data S4. Differential expression between 3\u2009days ripe fruit (3DF) vs mature unripened fruit (0DF) of Allahabad Safeda. Data S5. Differential expression between 7\u2009days over-ripe fruit (7DF) vs 3\u2009days ripe fruit (3DF) of Allahabad Safeda. Data S6. Differential expression between red peel vs green peel of Apple Color. Data S7. Differential expression between Punjab Pink mature fruit (PP_0DF) vs Allahabad Safeda mature fruit (AS_0DF). Data S8. FPKM values of DETs among fruit and peel stages of 3 genotypes. Data S9. Expression of genes involved in\u00a0important pathways for fruit maturation, ripening and pathogenesis in different tissues of 3 guava genotypes."}
+{"text": "The eutherian fibroblast growth factors were implicated as key regulators in developmental processes. However, there were major disagreements in descriptions of comprehensive eutherian fibroblast growth factors gene data sets including either 18 or 22 homologues. The present analysis attempted to revise and update comprehensive eutherian fibroblast growth factor gene data sets, and address and resolve major discrepancies in their descriptions using eutherian comparative genomic analysis protocol and 35 public eutherian reference genomic sequence data sets.Among 577 potential coding sequences, the tests of reliability of eutherian public genomic sequences annotated most comprehensive curated eutherian third-party data gene data set of fibroblast growth factor genes including 267 complete coding sequences. The present study first described 8 superclusters including 22 eutherian fibroblast growth factor major gene clusters, proposing their updated classification and nomenclature.The integrated gene annotations, phylogenetic analysis and protein molecular evolution analysis argued that comprehensive eutherian fibroblast growth factor gene data set classifications included 22 rather than 18 homologues. FGF gene data sets. Specifically, Belov and Mohammadi [The eutherian fibroblast growth factors or FGFs were implicated as key developmental regulators \u20133. Firstohammadi  and Beenohammadi  argued tohammadi  and OrniUndoubtedly, the public eutherian reference genomic sequence data sets advanced biological and medical sciences \u201334. IndeFGF gene data sets, and address and resolve major disagreements in their descriptions using eutherian comparative genomic analysis protocol and 35 public eutherian reference genomic sequence data sets.Therefore, the present analysis attempted to revise and update comprehensive eutherian FGF complete coding sequences among 577 FGF potential coding sequences , FGF1B (9 FGF14 or FGF4 genes), FGF1C (11 FGF13 or FHF2 genes) and FGF1D (15 FGF11 or FHF3 genes)  and FGF2B (20 FGF1 genes)  , FGF4B (16 FGF9 genes) and FGF4C (14 FGF16 genes) , FGF5B (16 FGF7 genes), FGF5C (7 FGF3 genes) and FGF5D (9 FGF22 genes) , FGF6B (12 FGF17 genes) and FGF6C (7 FGF8 genes)  and FGF7B (17 FGF6 genes) , FGF8B (12 FGF23 genes) and FGF8C (16 FGF21 genes)  or 3 coding exons (17 other major gene clusters). The eutherian FGF coding exon numbers were constant within major gene clusters, and there was no evidence of differential gene expansions indicating that 22 eutherian FGF major gene clusters respectively included orthologues. For example, whereas the human FGF1A gene included 5 coding exons along 264,215\u2009bp  [FGF major gene clusters respectively, there were nucleotide sequence identity patterns of very close eutherian orthologues , close eutherian orthologues , typical eutherian orthologues  and distant eutherian orthologues (FGF8B). In comparisons between eutherian FGF major gene clusters within superclusters, there were nucleotide sequence identity patterns of very close eutherian homologues , very close and close eutherian homologues (supercluster FGF6), close and typical eutherian homologues (supercluster FGF5) and typical eutherian homologues (supercluster FGF8). Finally, in comparisons between eutherian FGF major gene clusters between superclusters, there were nucleotide sequence identity patterns of close, typical, distant and very distant eutherian homologues.Indeed, the calculations of pairwise nucleotide sequence identity patterns confirmed present phylogenetic classification of eutherian =\u20090,094) , 25\u201328. FGF genes.Therefore, the present phylogenetic analysis proposed updated classification of eutherian The protein molecular evolution analysis used protein primary structure features as major alignment landmarks in eutherian FGF protein amino acid sequence alignments, including common cysteine amino acid residues, common exon-intron splice site amino acid sites and common predicted N-glycosylation sites Fig.\u00a0 Additio. There wR) of eutherian FGF gene data set using 267 FGF complete coding sequences . The protocol then deposited FGF complete coding sequences in European Nucleotide Archive as curated third-party data gene information [FGF gene classification and nomenclature. Third, the protocol used new genomics tests of contiguity of eutherian public genomic sequences in eutherian FGF gene annotations. Using multiple pairwise genomic sequence alignments of eutherian genomic sequences harbouring FGF complete coding sequences, the tests of contiguity analysed numbers of coding exons in FGF genes and their relative orientation. The tests discriminated between FGF genes not including coding exon misassemblies in eutherian genomic sequence assemblies and FGF genes including coding exon misassemblies. The tests used mVISTA AVID option in multiple pairwise genomic sequence alignments, using default settings [Homo sapiens) were 95% nucleotide sequence identity along 100\u2009bp , 90% along 100\u2009bp , 85% along 100\u2009bp , 80% along 100\u2009bp , 75% along 100\u2009bp , 65% along 100\u2009bp (Rodentia) or 70% along 100\u2009bp in other pairwise alignments [FGF complete coding sequences.The protocol used gene identifications in 35 public genomic sequence assemblies, tests of reliability of eutherian public genomic sequences and new genomics tests of contiguity of eutherian public genomic sequences in eutherian equences . The Natata sets \u201353, as wata sets , 55. Sec Archive , 56, theormation \u201360. The ormation  and guidormation  in updatsettings , 64. Theignments \u201346. In pFGF gene data set. First, using BioEdit 7.0.5.3, the protocol translated FGF complete coding sequences, and aligned them at amino acid level using ClustalW implemented in BioEdit 7.0.5.3. After manual corrections of FGF protein primary structure alignments, the FGF nucleotide sequence alignments were prepared accordingly. Second, the MEGA 6.06 program was used in phylogenetic tree calculations, using minimum evolution method that was applicable in phylogenetic analysis of very close, close, typical, distant and very distant eutherian FGF homologues  [FGF complete coding sequences that were used in statistical analyses. The Microsoft Office Excel common statistical functions were used in calculations of pairwise nucleotide sequence identity patterns of eutherian FGF gene data set. Using pairwise nucleotide sequence identities of FGF nucleotide sequence alignments including 267 FGF complete coding sequences, the protocol calculated average pairwise nucleotide sequence identities (\u0101) and their average absolute deviations (\u0101ad), and largest (amax) and smallest (amin) pairwise nucleotide sequence identities.The protocol used protein and nucleotide sequence alignments, calculations of phylogenetic trees, calculations of pairwise nucleotide sequence identities and analysis of differential gene expansions in phylogenetic analysis of eutherian  method) , 66. ThiFGF nucleotide sequence similarities with FGF protein primary structures in protein molecular evolution analysis. The protocol used complete FGF nucleotide sequence alignments in tests of protein molecular evolution, including 267 FGF complete coding sequences and 58,533 codons. Among eutherian FGF complete coding sequences, the average number of codons was 219. Using MEGA 6.06, the relative synonymous codon usage statistics were calculated as ratios between observed and expected amino acid codon counts (R\u2009=\u2009Counts / Expected counts). The protocol then described 20 amino acid codons including R\u2009\u2264\u00a00,7 as not preferable amino acid codons, viz.: TTA, TTG, CTT, CTA, ATA, GTT, GTA, TCA, TCG, CCG, ACG, GCG, TAT, CAT, CAA, GAT, TGT, CGT, CGA, GGT  or compensatory amino acid sites .The protocol used analysis of FGF protein amino acid sequence features and tests of protein molecular evolution integrating patterns of Additional file 1. Third-party data gene data set of eutherian fibroblast growth factor genes.Additional file 2 Multiple pairwise genomic sequence alignments of eutherian fibroblast growth factor genes. The FGF coding exon sequence regions in base sequences (Homo sapiens) were displayed as indigo rectangles, and grey arrows indicated their relative orientation (top). The genomic sequence regions including sequence identity levels above empirical cut-offs of detection of common genomic sequence regions were shown accordingly in multiple pairwise alignments.Additional file 3. Pairwise nucleotide sequence identity patterns of eutherian fibroblast growth factor genes.Additional file 4. Protein amino acid sequence alignments of eutherian fibroblast growth factors. The amino acid positions were labelled using white letters on black background (100% sequence identity level), white letters on dark grey background (\u2265 75% sequence identity level) or black letters on grey background (\u226550% sequence identity level). The 19 invariant amino acid sites were shown using white letters on violet backgrounds and 3 forward amino acid sites were shown using white letters on red backgrounds in reference human FGF1A protein primary structure (top). The stop codons were indicated by &s."}
+{"text": "Certain cognitive tasks, such as those involving inhibition, can influence an older adult\u2019s dual-tasking ability more than others. This study aimed to manipulate cognitive task difficulty to evaluate age-associated differences in brain activity and behaviour during walking. Nineteen younger  and 20 older  adults completed four cognitive-auditory tasks: simple reaction time , Go-no-Go , N-back  and Double number sequence  with or without self-paced walking. Trials took place under single cognitive (SC), single motor (SM) and dual-task  conditions. Throughout each condition, cerebral oxygenation changes (\u0394HbO2) in the prefrontal cortex were acquired using functional near-infrared spectroscopy (fNIRS). Behavioural measures including response time (ms), accuracy (%) and gait speed (m/s) were also calculated. Repeated measures ANOVAs revealed that OAs exhibited greater \u0394HbO2 than YAs in the left hemisphere during the GNG inhibition task (p = 0.04). Activation in the right hemisphere also increased compared to the left during DNS DT (p = 0.05). Response times increased with increasing task difficulty and YAs were faster than OAs during NBK SC (p = 0.09). Neural findings revealed age-associated changes in prefrontal activation at the GNG inhibition difficulty level. Behavioural results indicated poorer performance with increasing task difficulty including slower response times in OAs. Moreover, gait speed and accuracy only decreased within task and difficulty. Therefore, understanding the neural and behavioural changes across task difficulty may help monitor cognitive decline and distinguish normal aging from disease states."}
+{"text": "In summary, our findings point to Nur77 as an important regulator of CS-induced inflammatory responses and support the potential benefits of Nur77 activation for COPD treatment.Cigarette smoke (CS) contains multiple gaseous and particulate materials that can cause lung inflammation, and smoking is the major cause of chronic obstructive pulmonary disease (COPD). We sought to determine the mechanisms of how CS triggers lung inflammation. Nur77, a nuclear hormone receptor belonging to the immediate-early response gene family, controls inflammatory responses, mainly by suppressing the NF-\u03baB signaling pathway. Because it is unknown if Nur77\u2019s anti-inflammatory role modulates COPD, we assessed if and how Nur77 expression and activity are altered in CS-induced airway inflammation. In lung tissues and bronchial epithelial cells from COPD patients, we found Nur77 was downregulated. In a murine model of CS-induced airway inflammation, CS promoted lung inflammation and also reduced Nur77 activity in wild type (WT) mice, whereas lungs of Nur77-deficient mice showed exaggerated CS-induced inflammatory responses. Our findings in  Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease characterized by persistent airflow limitation and impaired gas exchange . It invoTo discover mechanistic insights into the molecular pathophysiology of CS-induced lung inflammation and COPD, in this study, we tested the potential mediating roles and actions of Nur77 , 11  cells from COPD patients (COPD HBE cells), suggesting a link between Nur77 downregulation and COPD pathogenesis. Furthermore, we found that CS downregulated Nur77 expression and activity and also exacerbated inflammatory responses, both in mice 2. Monolayer cultures at 90% confluence were deprived of growth factors before treatment.HBE cells  obtained from Lonza  were grown and maintained in bronchial epithelial cell medium (Lonza) supplemented with growth factors and hormones, according to the manufacturer\u2019s instructions. H292 cells were obtained from ATCC  and maintained in RPMI medium supplemented with FBS, penicillin, and streptomycin . Cells were cultured at 37\u00b0C in a humidified atmosphere of 5% COHuman lung tissue sampling was done as reported previously . COPD luCytosporone B , SB203580  and PD98059  were dissolved in DMSO to prepare stock solutions (100 mM). Working concentrations were prepared by further dilution with DMSO. Cells deprived of growth factors were treated with the indicated concentrations as previously described \u201332.Nr4a1 (Nur77) knockout (KO) mice (006187) acetate (PDNPA), similarly disrupted LPS-induced p38 MAPK-mediated interaction and phosphorylation of Nur77, which restored Nur77\u2019s ability to inhibit NF-\u03baB signaling and pro-inflammatory cytokine production [Our data that CSE induces Thr-phosphorylation of Nur77 in human airway epithelial cells provide a new mechanism via which CS/CSE triggers Nur77 downregulation. This is an important finding because discovery of a new pathological process offers a novel target for therapeutic interventions. Furthermore, we found that the p38 MAPK inhibitor SB203580 selectively suppressed CS/CSE-induced Thr-phosphorylation of Nur77, suggesting that p38 MAPK is likely the kinase responsible for this post-translational modification. CS activates the MAPK pathway that regulates activities of several transcription factors in multiple cell types . Nur77 coduction . AdditioSubcellular localization represents a key mechanism of Nur77 functional control , 44. SpeCOPD progression is a key driver of its morbidity and mortality. Because no current therapy effectively prevents disease progression, novel therapies are urgently needed. Therefore, it will be important to further extend our findings of short-term CS exposure effects upon airway inflammation, that often triggers COPD pathogenesis. Future studies using disease models with prolonged (6 to 12-month) CS exposure may provide further valuable insights about Nur77\u2019s role in COPD progression.In conclusion, by showing that CS reduces Nur77 expression and activity and that a Nur77-specific agonist can reverse such Nur77 downregulation and counter exaggerated inflammatory responses in the lungs of mice and human airway epithelial cells, our study demonstrates potential therapeutic benefits of Nur77 activation for the treatment of COPD.S1 Checklist(PDF)Click here for additional data file.S1 Table(PDF)Click here for additional data file.S1 DatasetFigure A) Western blot images and densitometry data for Figure B) Western blot, EMSA images and densitometry data for Figure C) Cell count data for Figure D) Western blot images for ((PDF)Click here for additional data file."}
+{"text": "Extraintestinal manifestations (EIM) in inflammatory bowel disease (IBD) are common including cutaneous manifestations that either precede or follow manifestations of IBD. Cutaneous manifestations of IBD include erythema nodosum, pyoderma gangrenosum, oral lesions, and Sweet\u2019s syndrome.\u00a0Cutaneous manifestations of IBD tend to recur and extensive cases may require maintenance management with immunomodulators or biologics. However, the complications and adverse effects of long-term therapy with immunosuppressive agents are numerous and need to be considered before their initiation. We report a case of a Crohn\u2019s disease patient with recurrent and debilitating cutaneous manifestation of lupus panniculitis that had sustained remission with hydroxychloroquine. Both Crohn\u2019s disease (CD) and ulcerative colitis (UC) are systemic disorders that often affect other organs in addition to the gastrointestinal tract. Extraintestinal manifestations (EIM) associated with inflammatory bowel disease (IBD) are common, occurring in up to 40% of patients with IBD . The extA 46-year-old black female presented with multiple painful skin ulcers that had developed over a one-month period. Her medical history included bipolar disorder, migraine headache, iron deficiency anemia, and episodic watery diarrhea. Physical examination showed multiple deep ulcers with irregular borders, surrounding erythema, induration, and purulent material. Five ulcers were on her right thigh, and two on her right calf. Erythematous nodules on her left leg and abdomen were also noted which the patient reported would progress to ulcers. She was previously treated with multiple courses of antibiotics with no benefit.Laboratory examination showed elevated WBC (White blood cell) 12.6 K/\u03bcL (reference range: 3.8-10.5 K/\u03bcL), CRP (C-reactive protein) 76 mg/L (reference range: \u22645.0 mg/L), ESR (Erythrocyte sedimentation rate) 98 mm/hr (reference range: 0-20 mm/hr), positive ANA (Anti-nuclear antibodies) 1:2560 (reference range <1:80), anti-dsDNA (Double stranded DNA) antibody 104 IU/mL (reference range \u226430 IU/mL), ASCA Ab (anti-Saccharomyces cerevisiae\u00a0antibodies) IgA 43 U (reference range: \u226420 U), and ASCA Ab IgG 65 U (reference range: \u226420 U). The colonoscopy showed multiple colonic ulcers, discontinuous inflammation, and crypt distortion findings supportive of Crohn\u2019s disease. Dermatopathology of skin biopsy revealed inflammation, fibrosis, and fat necrosis consistent with lupus panniculitis (Figure Extraintestinal manifestations usually parallel the disease activity of IBD, but the course of some EIMs such as ankylosing spondylitis, primary sclerosing cholangitis, and pyoderma gangrenosum can be independent of intestinal inflammation . Mild cuRecurrent cutaneous manifestations of IBD often result from severe underlying IBD and may require systemic immunosuppression for maintenance therapy. Immunomodulators and biologics can cause many adverse effects including, but not limited to, pulmonary toxicity, neutropenia, hepatotoxicity, infections, and myelotoxicity. Hydroxychloroquine should be considered as a treatment option for cutaneous manifestations in IBD given its safety profile when compared to those of immunomodulators and biologics."}
+{"text": "AcP & AlP), fluorescein diacetate hydrolases (FDH), cellulase, urease and aryl sulphatase in rhizosphere and bulk soil after 8 years of different management regimes. Soil organic carbon (SOC), moisture content and few enzyme indices such as enzymatic pH indicator (AcP/AlP), alteration index three (Al3) and geometric mean (GMea) were also measured. The treatments were conventional rice-wheat system (termed as scenario (Sc1), CT system), partial conservation agriculture (CA)-based rice-wheat-mungbean system , partial climate smart agriculture (CSA)-based rice-wheat-mungbean system (Sc3), partial CSA-based maize-wheat-mungbean system (Sc4), full CSA-based rice-wheat-mungbean system (Sc5), and full CSA-based maize-wheat-mungbean system (Sc6). Soil samples were collected from rhizosphere and away from roots (bulk soil) at 0\u201315\u00a0cm soil depth before sowing (from rhizosphere of previous crops), at maximum tillering, flowering, and after harvesting of wheat crop. Results showed that DHA activity was higher before sowing (59.8%), at maximum tillering (48.4%), flowering (8.6%) and after harvesting (19.1%) in rice based CSA systems (mean of Sc3 and Sc5) over maize based CSA systems (mean of Sc4 and Sc6) in rhizospheric soil. On average, \u03b2-glucosidase activity was significantly higher in rhizospheric soils of rice based system over maize based CSA system. Before sowing of wheat, significantly higher (21.4%) acid phosphatase activity was observed in rhizosphere over bulk soils of maize based CSA system. Significantly higher alkaline phosphatase activity was observed before sowing of wheat in bulk soils of rice (25.3%) and maize (38.5%) based CSA systems over rhizospheric soils. Rice based CSA systems showed 27% higher FDH activity than maize based systems. Significant interaction effect was observed between the managements and enzymes. SOC played an important role in regulating the enzymes activity both in rhizosphere and bulk soil. Significant variation in AcP/AlP, Al3 and GMea was observed among the managements. Therefore, CSA managements are beneficial in improving enzyme activities not only in rhizosphere but also in bulk soil where residues are retained thereby may help in improving nutrient cycling.In agriculture production system, soil enzymes are important indicators of soil quality. Measurements of soil quality parameter changes are essential for assessing the impact of soil and crop management practices. Keeping this in view, an experiment was conducted to evaluate the enzyme activities namely dehydrogenase (DHA), \u03b2-glucosidase, acid and alkaline phosphatase ( \u2022Soil enzyme activities in rhizosphere and bulk soil were carried out with climate smart agriculture practices.\u2022Residue retention and zero tillage improves enzyme activities in bulk soil.\u2022Dehydrogenase and \u03b2-glucosidase activities were higher in rhizospheric soils of rice based system.\u2022Urease activity was not affected by growth stages and climate smart agriculture practices.\u2022SOC played an important role in regulating the enzymes activity in soil. During Climate Smart Agriculture (CSA) practices are based on conservation agriculture (CA) principles of zero tillage (ZT), residue management and sustainable crop rotation along with precision irrigation and N-management using sub-surface drip irrigation (SDI) system. There are number of advantages of CSA practices such as higher soil organic carbon, improved soil physical properties, nutrient availability, and crop productivity as reported by researchers all over the world .Several studies have been done on the effect of different agriculture management practices on soil enzyme activities in cereal based systems . While s2 fertilization effect and volatile organic compounds released by roots . So. SoAlP/A content . LemanowSignificant interactions among the scenarios, crop growth stages and rhizosphere and bulk soils on the soil enzymes might be due to the effect of Climate Smart Agriculture practices followed. Residue retention increases microbial population  by provi5The enzyme activities are strongly influenced by tillage and crop establishment, crop rotation, and crop residues and water management practices. In bulk soil, enzymes activities were higher under CSA practices over conventional managements and activities of some of the enzymes were similar or comparable to rhizospheric soils. Rice based CSA systems showed higher enzyme activities over maize based systems. The CSA based systems has shown higher DHA and alkaline phosphatase activities before sowing rather than at maximum tillering, flowering and after harvesting of wheat. FDH activity in rice based CSA systems was 27% higher than maize based systems. Higher SOC was observed under CSA based systems which also influenced soil moisture availability due to crop residue retention. Crop management practices under a specific agro-ecosystem has important implications in nutrient availability to plants because upon decomposition, crop residues release nutrients which could help in savings of precious nutrients applied externally besides improving overall soil quality and carbon enrichment. Therefore, future studies should consider nutrients availability and priming effect at different crop growth stages in rhizosphere and bulk soils under CSA based cereal systems.The authors declare no competing interests."}
+{"text": "Organ ischemia reperfusion injury (IRI), associated with acute hepatocyte death, remains an unresolved problem in clinical orthotopic liver transplantation (OLT). Autophagy, an intracellular self-digesting progress, is responsible for cell reprograming required to regain post-stress homeostasis.Methods: Here, we analyzed the cytoprotective mechanism of pituitary adenylate cyclase-activating polypeptide (PACAP)-promoted hepatocellular autophagy in a clinically relevant mouse model of extended hepatic cold storage (4 \u00b0C UW solution for 20 h) followed by syngeneic OLT.Results: In contrast to 41.7% of liver graft failure by day 7 post-transplant in control group, PACAP treatment significantly improved graft survival (91.7% by day 14), and promoted autophagy-associated regeneration programs in OLT. In parallel in vitro studies, PACAP-enhanced autophagy ameliorated cellular damage (LDH/ALT levels), and diminished necrosis in H2O2-stressed primary hepatocytes. Interestingly, PACAP not only induced nuclear cAMP response element-binding protein (CREB), but also triggered reprogramming factor Kruppel-like factor 4 (KLF4) expression in IR-stressed OLT. Indeed, CREB inhibition attenuated hepatic autophagy and recreated hepatocellular injury in otherwise PACAP-protected livers. Furthermore, CREB inhibition suppressed PACAP-induced KLF4 expression, whereas KLF4 blockade abolished PACAP-promoted autophagy and neutralized PACAP-mediated hepatoprotection both in vivo and in vitro.Conclusion: Current study documents the essential neural regulation of PACAP-promoted autophagy in hepatocellular homeostasis in OLT, which provides the emerging therapeutic principle to combat hepatic IRI in OLT. Liver ischemia reperfusion injury (IRI), an innate immunity-mediated sterile inflammation, represents a major complication in liver transplantation, hemorrhagic shock and partial hepatectomy Autophagy, an intracellular self-digesting progress degrading damaged organelles and malformed proteins by lysosomes, provides essential supply  to starved cells for energy metabolism and biosynthesis Although liver IRI is considered as a local sterile innate response, both immune and nervous systems are integrated to maintain dynamic communication. IR-triggered inflammation was shown to activate systemic neuroendocrine hypothalamus and regional neural-hormonal-stress responses PACAP, encoded by the ADCYAP1 gene, is a member of vasoactive intestinal peptide (VIP)/glucagon/secretin family CREB, binding to cAMP response elements, is a critical cellular transcription factor in neuroregulation and neuron survival KLF4, the crucial self-renewal transcriptional factor of KLF family, exerts diverse modulation in proliferation, differentiation, and somatic cell reprogramming This study elucidated the cytoprotective role of PACAP-mediated autophagy in a clinically authentic mouse model of extended hepatic cold storage and followed syngeneic OLT. First, we determined whether and how PACAP neuropeptide protected liver grafts against extended cold storage in an autophagy-dependent manner. The question then arose whether PACAP-mediated autophagy could preserve hepatocyte viability, and promote hepatic regeneration/repair. Finally, we addressed whether PACAP-mediated CREB and KLF4 coactivation was essential for hepatic autophagy in liver IRI.Liver grafts from C57BL/6 mice were stored in 4\u00b0C UW solution for 20 h, and then transplanted orthotopically into syngeneic C57BL/6 mice  The artery and portal vein of cephalad lobes (70% of whole liver) were clamped by an atraumatic clip for 90 min Serum alanine transaminase (sALT) indicated liver function was assessed by IDEXX Lab . Hematoxylin and eosin-stained liver sections and electron microscopy imagine were analyzed blindly for liver histology.Quantitative PCR was performed by using Platinum SYBR green quantitative PCR kit and QuantStudio3 Real-time PCR system (ThermoFisher). The used primer sequences were published Ischemic liver tissue proteins, after electrophoretic separation and transfer, were detected by monoclonal antibodies of Atg5 (12944), LC3 (4108), p62 (39749), proliferating cell nuclear antigen (PCNA) (13110), Ki67 (9129), pCREB (9198), KLF4 (12173), and \u03b2-actin (4970) . in situ, primary hepatocytes were separated by Percoll gradient centrifugation, and then cultured in collagen-coated plate for 24 h. Pre-treatment with PACAP38 (10 nM), with 3-MA (10 \u03bcM), CREB inhibitor (10 \u03bcM), KLF4 inhibitor (10 \u03bcM), DMSO for 1 h, KLF4 siRNA or NC siRNA , hepatocellular necrosis was triggered by hydrogen peroxide . Cells were processed for immunofluorescence and PI staining after 6 h, whereas supernatants were assessed by ALT/LDH kit (ThermoFisher).After liver collagenase perfused digestionStressed hepatocytes were stained with LC3 (4108), pCREB (9198) and KLF4 (12173) monoclonal antibodies  followed with Alexa Fluor 488 secondary antibody (A11008), Alexa Fluor 555 F-actin conjugate (A34055) for cellular skeleton, and DAPI counterstain (P36931) (ThermoFisher).PI staining (ThermoFisher) was used to detect dead cells by binding DNA. Red fluorescence images were merged with bright-field images for blindly evaluation.Liver graft survival curves were plotted by Kaplan-Meier survival analysis and Log-rank comparison test. All results were indicated by mean \u00b1 standard deviation, and analyzed with Student's t test and ANOVA test. Statistical significant was identified as P<0.05.First, we studied whether administration of PACAP neuropeptide protected liver against extended cold storage-mediated IRI and prolonged graft survival in a mouse syngeneic OLT model. Compared with 41.7% survival in PBS control group, 91.7% of recipients conditioned with PACAP remained alive at 14 days post-OLT , as compared with controls , a system designed to mimic liver IRI in vivo. PACAP pre-treatment preferentially enhanced LC3 induction and accumulation in hepatocellular nucleus and cytoplasm  and reperfusion (6 h) to study the mechanism of PACAP-CREB axis-mediated autophagy in IR-damage. In agreement with our previous results in vivo , which otherwise are diminished after CREB inhibition  and proKLF4 suspension significantly diminished otherwise abundant hepatic autophagy related components Figure A and hepIn a murine model of warm IRI, we have previously shown that treatment with PACAP neuropeptide controlled innate immunity-mediated macrophage function and modulated hepatic homeostasis In a warm hepatic IRI model, PACAP treatment diminished macrophage inflammation response in PKA-dependent manner and prevented hepatocellular necrosis/apoptosis through YAP signaling in vivo, we then analyzed PACAP modulation in a well-controlled hydrogen peroxide (H2O2) stimulated primary hepatocyte cultures. To further determine whether PACAP-exerted cytoprotection was autophagy-dependent, we first monitored the autophagy activity in PACAP treated primary hepatocytes by immunofluorescence staining. Markedly increased LC3 accumulation was found in hepatocellular nucleus and cytoplasm of PACAP-treated hepatocytes. Hyperoxidative hepatocellular necrosis is typically featured as loss of cell membrane integrity and releasing of cellular enzymes. As PI dye is unable to permeate through the intact cell membrane of live cells, PI stains dead cell DNA as diffusion into the porous membrane. Interestingly, PACAP prevented oxidation stressed hepatocellular death, while control group exhibited notable PI-indicated dead cells and hepatocellular release of ALT/LDH in supernatants. Consistently, autophagy inhibition eliminated LC3 accumulation in PACAP-treated hepatocytes, and recreated hyperoxidative cell death, evidenced by massive PI staining and elevated ALT/LDH levels.To mimic liver IR-mediated hepatocellular hyperoxidation insult Activation of CREB signaling preferentially promoted autophagy-mediated neuroprotection in a rat model of Alzheimer's disease KLF4, a pleiotropic transcription factor, regulates cellular differentiation, proliferation and oncogenesis In conclusion, this study documented PACAP attenuated liver IR-injury and prolonged graft survival in a clinically relevant cold IR stressed OLT model. Exogenous PACAP neuropeptide-enhanced autophagy controls hepatic cytoprotection, while proficient PACAP-CREB-KLF4 signaling is essential for regaining hepatocellular homeostasis. Consistent with the emerging function of autophagy-mediated cytoprotection against IR-stress Supplementary figures and table.Click here for additional data file."}
+{"text": "In this study, we compared the gene expression induced by two different types of metal oxide nanoparticles, titanium dioxide nanoparticles (TNP) and cerium dioxide nanoparticles (CNP) using microarray analysis. About 50 genes including interleukin 6, interleukin 1, platelet-derived growth factor \u03b2, and leukemia inhibitory factor were induced in cultured BEAS-2B cells treated with TNP 40 ppm. When we compared the induction levels of genes in TNP-treated cells to those in CNP-treated cells, the induction levels were very correlated in various gene categories (r = 0.645). This may suggest a possible common toxic mechanism of metal oxide nanoparticles.Recent publications showed that metal nanoparticles which are made from TiO"}
+{"text": "Nigella sativa (NS) oil supplementation on the outcomes of patients with mild Coronavirus Disease 2019 (COVID-19).To investigate the potential efficacy of Prospective, two-arm, parallel-group, randomised , open-label, controlled, exploratory phase II clinical trial of oral NS oil in patients with mild COVID-19.Inclusion Criteria:- Patients with mild COVID19 .- Adult (18 - 65 years old).- Written informed consent by the patient  prior to initiation of any study procedures.- All patients should understand and agree to comply with planned study procedures.- Polymerase chain reaction (PCR)-confirmed infection with Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) from throat swab.Exclusion Criteria:- Patients with pneumonia or severe illness requiring admission to intensive care unit.mL/min) or end stage renal disease requiring dialysis- Severe chronic kidney disease .- Pregnancy or breast feeding.- Anticipated transfer within 72 hours to another hospital that is not a study site.- Allergy to the study medicationThe trial is currently conducted on patients recruited from King Abdulaziz University Hospital, Jeddah, Saudi Arabia.Nigella sativa oil (MARNYS\u00ae Cuminmar) 500 mg softgel capsules, one capsule orally twice daily for 10 days plus standard of care treatment .Intervention group: Comparator group: standard of care treatment.Proportion of patients who clinically recovered (defined as 3 days of no symptoms) within 14 days after randomisation.http://www.randomization.com.Patients will be randomly assigned to treatment or control groups in a 1:1 ratio using a computer-generated randomization scheme (Random permuted blocks of 10) developed using the web-based program: No blinding.Up to 200 eligible patients will be randomly assigned to either treatment or control groups.Protocol version 1, as of July 14, 2020. Recruitment was started on May 21, 2020. The intended completion date is December 31, 2020.NCT04401202. Date of trial registration: May 26, 2020.ClinicalTrials.gov Identifier: The full protocol is attached as an additional file, accessible from the Trials website (Additional file  Additional file 1."}
+{"text": "Correction to: BMC Med Educ 19, 339 (2019)https://doi.org/10.1186/s12909-019-1754-0Incorrect: A quantitative study was conducted in an academic hospital , a large merged medical center (Noordwestgroep Alkmaar and OLVG Amsterdam), and two affiliated hospitals (Westfriesgasthuis Hoorn and Rode Kruis Ziekenhuis Beverwijk).Correct: A quantitative study was conducted in an academic hospital , two large merged teaching hospitals  and two affiliated teaching hospitals (Westfriesgasthuis Hoorn and Rode Kruis Ziekenhuis Beverwijk).In the original publication of this article  there ar"}
+{"text": "Kinase drug discovery represents an active area of therapeutic research, with previous pharmaceutical success improving patient outcomes across a wide variety of human diseases. In pancreatic ductal adenocarcinoma (PDAC), innovative pharmaceutical strategies such as kinase targeting have been unable to appreciably increase patient survival. This may be due, in part, to unchecked desmoplastic reactions to pancreatic tumors. Desmoplastic stroma enhances tumor development and progression while simultaneously restricting drug delivery to the tumor cells it protects. Emerging evidence indicates that many of the pathologic fibrotic processes directly or indirectly supporting desmoplasia may be driven by targetable protein tyrosine kinases such as Fyn-related kinase (FRK); B lymphoid kinase (BLK); hemopoietic cell kinase (HCK); ABL proto-oncogene 2 kinase (ABL2); discoidin domain receptor 1 kinase (DDR1); Lck/Yes-related novel kinase (LYN); ephrin receptor A8 kinase (EPHA8); FYN proto-oncogene kinase (FYN); lymphocyte cell-specific kinase (LCK); tec protein kinase (TEC). Herein, we review literature related to these kinases and posit signaling networks, mechanisms, and biochemical relationships by which this group may contribute to PDAC tumor growth and desmoplasia. Pancreatic endocrine tissue contains distinct populations of hormone-producing pancreatic islet cells. Islet \u03b1 cells synthesize glucagon; islet \u03b4 cells synthesize somatostatin; islet \u03b2 cells synthesize insulin. Pancreatic exocrine tissue contains acinar cells that synthesize digestive enzymes subsequently carried toward the duodenum by branched tubes lined by ductal epithelial cells. Most pancreatic cancers (approximately 95%) develop from these ductal cells. These cancers are generally called pancreatic ductal adenocarcinomas (PDAC) and present notoriously poor prognoses.PDAC accounts for approximately 90% of all pancreatic cancers and remains resistant to treatment, in part, due to its extensive desmoplastic stroma . PDAC maThe mortality rate of pancreatic cancer is high; more than four decades of research have improved 5-year survival rates from 4 to 7% . RadiothRecently, our group undertook the identification of novel target kinases for PDAC using patient-derived pancreatic cancer cell lines and wild-type pancreatic tissue specimens . During Initially pursued as a potential tumor suppressor, more recent experimental results support the characterization of Fyn-related kinase (FRK) as an oncogene. Indeed, the emerging narrative suggests that FRK functionality is determined in an organ-specific manner . In breaTransgenic mice with a gene of interest operating under the control of insulin promoters are frequently used to drive site-specific expression in the pancreas. The transcription factor Pancreatic and Duodenal Homeobox 1 (PDX1) is a primary activator of insulin promoter regions. While this transcription factor likely plays a role in the kinomic regulation of pancreatic cancer cells (discussed below), genetically engineered insulin promoter sequences often rely upon PDX1 to drive the expression of their downstream genes. Transgenic mice expressing FRK in this manner ,25,26 de1173 [1173 is associated with subsequent downregulation of EGFR signaling pathways associated with tumorigenesis [Early evidence suggests the tumor suppressor activity of FRK involves direct binding to retinoblastoma (Rb) proteins inside cellular nuclei  Figure . Later s1173 . Phosphoigenesis ,32,33,34igenesis  analysesigenesis . While tigenesis ,37,38.B lymphoid kinase (BLK) is a nonreceptor tyrosine kinase that is preferentially expressed in B cells, and ectopically expressed in T-cell malignancies ,40. PrecIn normal adult pancreatic tissue, BLK is expressed by beta cells. BLK kinase activity enhances the synthesis and secretion of insulin by upregulating the transcription factor PDX1  Figure . While PEndocrine and diabetes research provides complementary evidence of the relationship between BLK, PDX1, and pancreatic pathophysiology. PDX1, formerly known as Insulin Promoter Factor 1 (IPF1), is a transcriptional activator of insulin and plays a major role in normal glucose metabolism. Loss-of-function BLK mutations attenuate PDX1 expression to decrease insulin expression and compromise downstream signaling mechanisms . In thisLike BLK, hemopoietic cell kinase (HCK) can be found in B lymphocyte lineages . AlthougData concerning HCK and pancreatic cancer are not abundantly represented in the literature, although one study demonstrates that gain of the HCK locus in PDAC patient biopsy predicts decreased patient survival . InteresRenal fibrosis is a common sequela of chronic renal allograft injury and recent work identifies HCK as an important driver of this fibrosis, with HCK overexpression activating fibrotic pathways, and HCK knockdown inhibiting fibrotic pathways . AdditioLeukemogenic ABL proto-oncogene 2 kinase (ABL2) fusion proteins RCSD1-ABL2 and ZC3HAV1-ABL2 have been reported in Philadelphia chromosome-like acute lymphoblastic leukemia patients ,85. In vAs discussed above, PDAC is characterized by large-scale desmoplasia. In addition to receptor tyrosine-kinase signal transduction pathways, signals from the extracellular environment may be transduced by integrin molecules that bind and activate nonreceptor tyrosine kinases. Collagens are well represented in the tumor stroma of PDAC and play significant roles in pancreatic tumor progression ,100,101.Another collagen receptor, discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase that belongs to a family of nonintegrin signal transducers . Of all An insightful review by Moll and colleagues documents additional points that highlight the atypical landscape of current DDR1 research . In brieDesmoplasia restricts oxygen and nutrient delivery; decreased vascularization results in hypoxic collections of cells with abnormal, compensatory metabolic processes that allow surviving tumor cells to overcome otherwise uninhabitable environmental conditions . WithoutSerotonin demonstrates vasoactive properties and promotes fibroblast activation and collagen deposition in select fibrotic contexts . SerotonAlternatively, another signaling node of LYN in pancreatic cancer involves the megakaryocyte-associated tyrosine kinase (MATK) . This kiEphrin receptor (EPH) family kinases are receptor tyrosine kinases integral to normal human development. During development, members of the EPH kinase family participate in the generation and maintenance of early vasculature and coordinate cell segregation and positioning in the gastrointestinal tract ,160,161.In fibroblasts, kinase-independent EPHA8 signaling may proceed through phosphatidylinositol 3-kinase (PI3K) mechanisms  Figure . In neurKRAS and TP53 mutational profiles [FYN regulates downstream serine-threonine kinase activity modulating fibroblast\u2013epithelial cell interactions and promoting organ fibrosis ,186. FYNprofiles ,202.TP53 tumor suppressor gene. PDAC presents with approximately 90% KRAS mutation frequency [KRAS mutations. However, PDCL5 cells express dysfunctional, mutant TP53, while PDCL15 cells express wild-type TP53. This is significant because FYN kinase is identified as a lead candidate kinase only in PDCL15 cells with functional p53 tumor suppressor proteins [Foremost among potential therapeutic targets in pancreatic cancer stand cancer\u2019s most frequently mutated oncogene family, the RAS genes ; and therequency . While tproteins .KRAS mutant cells than in KRAS wild-type cells [TP53 mutant pancreatic tumors, FYN-mediated AMPK suppression would impart insignificant cancer cell survival advantage. Correspondingly, FYN is not identified as a lead candidate kinase in our analyses of PDCL5 cells; these cell lines already have functionally deficient TP53. In contrast, our analyses did identify FYN as a candidate kinase in PDCL15 cells which express wild-type, fully functional TP53. Perhaps FYN demonstrates increased enzymatic activity in this cell line in order to subvert AMPK-dependent p53 tumor suppressive activity. When PIKE-A binds AKT, it enhances AKT\u2019s antiapoptotic properties [KRAS and wild-type TP53.Mechanistic studies exploring the signaling axis of FYN in pancreatic cancer suggest significant modulation of cell cycle and apoptotic behaviors ,157,158.pe cells . Other cpe cells . In the pe cells . In somepe cells . This suoperties . When fuoperties ,209. In The lymphocyte cell-specific kinase (LCK) is an important regulator of T-cell functionality. Activation of the T-cell receptor (TCR) induces conformational change  and phosTEC family kinases are conspicuous in the development and treatment of hematogenous  and soliDesmoplastic stromal reactions create a biophysical barrier to drug delivery, whilst also directly promoting tumor growth and contributing to treatment resistance . In the Many of the inhibition studies referenced above rely upon genetic knockdown, rather than targeted inhibition of kinase activity. For pancreatic cancer, highly specific pharmaceuticals targeting single kinases (rather than families or groups of kinases) remain underdeveloped. Currently, Bosutinib , 7f 251251, DapaOverall, kinase inhibitors continue to show great promise in many cancers, but their contribution to improved pancreatic cancer survival has not been significant. Kinase inhibitors that attenuate the antitherapeutic characteristics of desmoplasia may play a crucial role in realizing future therapeutic efficacy. Such inhibitors may not be clinically efficacious on their own, however. Kinase inhibitors that simultaneously target desmoplastic processes and oncogenic processes would be ideal. While highly specific monotherapies have great utility as research chemicals, many kinase-controlled molecular mechanisms have robust compensatory pathways that limit the clinical impact of targeted kinase inhibition. Few absolute-selective  small molecule inhibitors have been identified, although many dual- or multiple-target inhibitors are in use ,260. PolThese studies provide support for the validity of ongoing drug development strategies targeting protein tyrosine kinases. Our identification and contextualization  of 10 ki"}
+{"text": "A 49-year-old asymptomatic man presents for a vasectomy evaluation. His past medical history is noncontributory, and his family history is remarkable for prostate cancer in his father. On genitourinary examination, his left testicle is notably larger than his right testicle, with concern for a firm, nontender upper pole mass palpated on the left side. Scrotal ultrasound is performed and reveals numerous hypoechoic masses within the left testicle  and a noThere is no evidence of angiolymphatic invasion or extension of this pathology beyond the tunica albuginea. Pre-operative tumor markers are as follows: lactate dehydrogenase (LDH) 204 IU/L [normal range 120\u2013240 IU/L], alpha-fetoprotein (AFP) 3.3 ng/mL [normal range <7.9 ng/mL], \u03b2-human chorionic gonadotropin (\u03b2-hCG) <2 mlU/mL [normal <5 mIU/mL]. Chest x-ray and CT scan of the abdomen and pelvis reveal no lymphadenopathy or evidence of metastases.A. Leydig cell tumorB. Non-seminomatous germ cell tumor (NSGCT)C. SeminomaD. Testicular lymphomaB. Non-seminomatous (mixed) germ cell tumor (NSGCT)Testicular neoplasms are uncommon, with 8,820 new cases estimated to arise nationwide in 2014 .This patient\u2019s pathology revealed 80% seminoma  and 20% The clinical stage of NSGCT holds prognostic value and directs management. The American Joint Committee on Cancer (AJCC) staging criteria rely on histopathology, tumor markers, and nodal or metastatic involvement on imaging.5 Tumor markers are useful in diagnosing GCTs and monitoring for inadequate treatment or recurrence; however, normal levels do not exclude GCTs. In this patient, the lack of angiolymphatic invasion or extension beyond the tunica albuginea classifies his pathologic stage as pT1 [The optimal post-orchiectomy management for clinical stage I NSGCT remains controversial. While orchiectomy is curative in 70\u201380% of stage I NSGCT , retropeThe patient recovered uneventfully from his orchiectomy. He opted for active surveillance and demonstrated no evidence of relapse on CT imaging with normal serum tumor markers one year following his surgery."}
+{"text": "A 24-year-old female patient without cardiac symptoms underwent preoperative echocardiography before correction of severe pectus excavatum. Echocardiography was difficult to perform because of the funnel chest, nevertheless, hypertrabeculated apical segments were diagnosed. To confirm the suspicion of non-compaction cardiomyopathy (NCCM) cardiac magnetic resonance imaging (MRI) was performed. For better visualization of non-compacted and compacted myocardium of the left ventricle (LV) a 3-dimensional (3D) whole heart sequence  covering the entire heart and adjacent thoracic structures was performed. The 3D whole heart sequence revealed a severe funnel chest Fig.\u00a0a with Ha"}
+{"text": "Gastric cancer is among the most lethal human malignancies. Previous studies have identified molecular aberrations that constitute dynamic biological networks and genomic complexities of gastric tumors. However, the clinical translation of molecular-guided targeted therapy is hampered by challenges. Notably, solid tumors often harbor multiple genetic alterations, complicating the development of effective treatments.To address such challenges, we established a comprehensive dataset of molecularly annotated patient derivatives coupled with pharmacological profiles for 60 targeted agents to explore dynamic pharmacogenomic interactions in gastric cancers.ALK-mutant tumors, a significant association between PIK3CA-E542K mutation and AZD5363 response, and transcriptome expression of RNF11 as a potential predictor of response to gefitinib.We identified lineage-specific drug sensitivities based on histopathological and molecular subclassification, including substantial sensitivities toward VEGFR and EGFR inhibition therapies in diffuse- and signet ring-type gastric tumors, respectively. We identified potential therapeutic opportunities for WNT pathway inhibitors in Collectively, our results demonstrate the feasibility of drug screening combined with tumor molecular characterization to facilitate personalized therapeutic regimens for gastric tumors. Cancer is a complex disease, with profound genomic alterations and diverse cellular hierarchy \u20134. AdvanGastric cancer is the third leading cause of cancer-induced mortality worldwide \u201316. The g for 10\u2009min, followed by washing with Dulbecco\u2019s phosphate-buffered saline. Patient-derived tumor cells (PDCs) were cultured in neurobasal medium with N2 and B27 supplements  and human recombinant basic fibroblast growth factor and epidermal growth factor . Human gastric cancer cell-lines were purchased from the Korean Cell Line Bank. All cell lines were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum and Antibiotic-Antimycotic  at 37\u2009\u00b0C in a humidified atmosphere with 5% CO2. PDCs and all cancer cell-lines were tested for mycoplasma contamination.After receiving informed consent, gastric tumor specimens or malignant ascites were obtained from patients undergoing surgery at Samsung Medical Center (SMC) in accordance with the Samsung Medical Center Institutional Review Board. This study was conducted in compliance with all relevant ethical regulations for human specimen research. Portions of the surgical samples were enzymatically dissociated using Liberase\u2122 (Roche) and tumor cells from malignant effusions were collected by centrifugation at 300Tumors were subjected to target exome sequencing using CancerSCAN, a targeted sequencing platform designed at Samsung Medical Center. CancerSCAN covers a range of exonic regions of specific genes that are associated with cancer progression. Genomic DNA was sheared in Covaris S220 sonicator (Covaris) to construct a sequencing library using the SureSelect XT Reagent Kit, HSQ (Agilent Technologies), enriched for target genes. The library was purified and amplified with a barcode tag, and library quality and quantity were determined. Sequencing was carried out using the 100-bp paired-end mode of the TruSeq Rapid PE Cluster kit and TruSeq Rapid SBS kit on a HiSeq 2500 sequencing platform (Illumina). The target exome sequencing data of previous gastric cancer cases were downloaded from the European Genome-phenome Archive (EGAS00001002515).The sequenced reads in FASTQ files were aligned to the human genome assembly (hg19) using the Burrows-Wheeler Aligner. The initial alignment BAM files were subjected to sorting (SAMtools), removal of duplicated read (Picard), local realignment of reads around potential small insertions/deletions, and recalibration of the base quality score . MuTect was used to generate high-confidence mutation calls. Variant Effector Predictor was used to annotate the called mutations.ONCOCNV was used to generate estimated copy number alterations in tumor specimens.RNA-seq libraries were prepared using the Illumina TruSeq RNA Sample Prep kit. Sequenced reads were mapped onto hg19 using the Burrows-Wheeler Aligner. The initial BAM files were sorted and summarized into BED files using SAMtools and bedTools. The BED files were used to calculate the reads per kilobase of transcript per million reads (RPKM)\u00a0value for each gene, using the DEGseq package.z-factor scores, comparing both negative and positive control wells ). Protein concentrations were determined using micro-BCA protein reagent (Pierce Biotechnology). Thirty micrograms of total proteins were separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis and transferred onto nitrocellulose membranes with 0.2-\u03bcm pore size (Whatman). The membranes were incubated with antibodies against phospho-AKT (Ser473) ; RRID: AB_2315049), AKT , phospho-mTOR (Ser2448) , mTOR , phospho-S6 ribosomal protein (Ser2235/236) , S6 ribosomal protein , phospho-4E-BP1 (Thr70) , 4E-BP1 , phospho-EGFR (Tyr1068) , EGFR , RNF11 , or\u00a0\u03b2-actin . The ECL method (Invitrogen) was used for protein detection.Total cell extracts were prepared using lysis buffer . All statistical analyses were conducted by either Wilcoxon rank-sum test (two-sided), Pearson\u2019s correlation coefficient test, or Fisher\u2019s exact test (two-sided) as relevant. All statistical analyses were conducted using the R software (https://www.r-project.org) or GraphPad Prism.TP53 mutation, whereas LCNA and EBV-positive tumors were marked by high prevalence of CDH1 and PIK3CA mutations, respectively  and PI3K inhibitors . Somatic mutation in FGFR2 conferred increased sensitivity to multi-targeted tyrosine kinase inhibitors, including FGFR- and VEGFR-targeting compounds  gene was significantly associated with global resistance to a broad range of therapeutics, including those targeting the PI3K-AKT-mTOR (PAM) pathway   consistently demonstrated upregulation of the WNT signaling pathway  complex, have been detected in a broad spectrum of tumor types, including gastric cancer [PIK3CA mutation is a key molecular determinant to AKT inhibition response in gastric cancer cell-lines [PIK3CA mutation, the \u201chot-spot\u201d mutations are located within the helical (exon 9) or kinase (exon 20) domains [PIK3CA mutations and clinical prognosis [PIK3CA-mutant tumors, we found that SNVs that lead to E542K amino acid substitution induced the most robust susceptibility to an AKT inhibitor (AZD5363) compared to other PIK3CA mutations  conferred increased sensitivities to gefitinib  tumors. We also identified lineage-specific drug associations, for example, between EGFR inhibitors and signet-ring tumors, and VEGFR compounds and diffuse-type tumors. Consistent herewith, the recent REGARD clinical trial revealed that the VEGFR2 antagonist ramucirumab showed prominent clinical benefits in diffuse tumors compared with intestinal-type tumors based on subgroup analysis [BRCA2 mutations. Targeting BRCA1/2-deficient cancers using PARP inhibitors has been the archetype of synthetic lethality based on the inhibition of DNA damage repair (DDR) pathway. The first-in-class PARP inhibitor, olaparib, has been the most extensively studied compound of DDR inhibitors, and the therapeutic landscape of olaparib has been rapidly expanding [BRCA2 mutation could potentially benefit from olaparib treatment.The fundamental principle of precision oncology is that molecular characterization of the tumor enables optimal patient-tailored therapy , 58. Witanalysis . Furtherxpanding . Previouxpanding . Unfortuxpanding . The curALK-mutant tumors. Furthermore, we found significant therapeutic vulnerabilities of PIK3CA-E542K mutant tumors to AKT inhibition therapy. Of note, we have previously performed the first and largest prospective molecular-guided targeted therapy in patients with gastric cancer, aligned with eight pre-specified genomic biomarkers and ten independent biomarker-associated clinical trials  [PIK3CA-E542K mutant tumors demonstrated the most robust response to AKT inhibitors when compared with patients harboring E545K, E545G, E453K, or other mutant type tumors. Our findings were further experimentally validated where AZD5363 demonstrated potent cytotoxic activities in PIK3CA-E542K-mutant gastric cancer cell-lines, subsequently downregulating PI3K pathway encoding molecules, including phosphorylation of mTOR, S6K, and 4E-BP1. These results collectively suggest that the current pharmacogenomic atlas of PDC models support the clinical feasibility of molecular-guided targeted therapy in hopes of expediting personalized treatment.Moreover, through large-scale pharmacogenomic analyses, we suggested inhibition of WNT signaling as a therapeutic option for a Trial) . ConsistRNF11, of the therapeutic response to gefitinib treatment. RNF11 has been presented as a proto-oncogene, delaying the degradation of EGF-activated EGFR signaling pathway components. Previous phase II and III clinical trials using EGFR-targeted agents  in gastric cancer were terminated due to insignificant survival advantage [EGFR amplification in gastric tumors, and revealed potential mechanisms underlying EGFR therapeutic resistance [RNF11 sensitized tumor cells, including tubular-type tumors to gefitinib. These results suggest a potential combinational strategy to circumvent EGFR-mediated therapeutic resistance.Lastly, we identified molecular determinants, including dvantage , 67\u201369. sistance . NotablyIn conclusion, integration of tumor genome and drug sensitivity data is the next step towards precision oncology therapy. As molecular target agents, including trastuzumab and ramucirumab, are currently being used in combination with cytotoxic chemotherapeutic compounds  to treat gastric cancer patients , 19, we PIK3CA-E542K mutation with AKT inhibition therapy. Furthermore, we suggested RNF11 expression as a predictive biomarker for gefitinib treatment in gastric cancer.In summary, we have established a systematic framework for genetic prediction of anticancer drug response using patient-derived resources that are molecularly, clinically, and pharmacologically annotated. Through comprehensive pharmacogenomic analyses, we identified lineage-specific drug sensitivities and gene-drug interactions that are well represented within clinical context, including VEGFR inhibitors with diffuse-type tumors and Additional file 1: Table S1. List of 60 drugs that were used in the drug sensitivity analysis. Drugs have been annotated based on their chemical and/or generic name, target molecule and clinical phase.Additional file 2: Table S2. Clinical annotations of 131 gastric cancers used in the drug screening and/or genomic characterization.Additional file 3: Table S3. List of major cancer-driver genes and sequencing library information for CancerSCAN.Additional file 4: Table S4. Mutational landscape of gastric cancer.Additional file 5: Figure S1. Unsupervised clustering of gastric cancers. Figure S2. Frequency of major gastric cancer-driver gene alterations. Figure S3. Pharmacological landscape of gastric cancers for 60 molecular-targeted compounds. Figure S4. Subgroup-specific drug sensitivity among gastric cancers. Figure S5. Gene-drug associations among gastric cancers. Figure S6. Pathway enrichment analysis between ALK-mutant and ALK wild-type tumors. Figure S7. Pharmacological effects of PIK3CA mutations on AZD5363 and Taxol combination treatment. Figure S8. Correlations between RNF11 mRNA expression level and EGFR inhibitors. Figure S9. siRNA-mediated knockdown of RNF11 promotes therapeutic sensitivity to gefitinib.Additional file 6: Table S5. Area Under the Curve (AUC) values for 60 drugs in 129 PDCs.Additional file 7: Table S6. Tumor type-specific drug associations. Wilcoxon rank-sum test was applied to determine the relative difference of drug sensitivity between individual tumor type and the rest.Additional file 8: Table S7. Pharmacogenomic interactions using integrative analysis of drug sensitivity results (AUC) and genomic alterations. The statistical significance was calculated using Wilcoxon rank-sum test."}
+{"text": "Gut microbiome datasets comprise microbial taxa relative abundances that necessarily sum to 1; analysis ignoring this feature may produce misleading results. We assessed 163 genera from the first batch of Microbiome Ancillary Study (n=530) stool samples and examined associations between microbiota and body weight. We compared conventional Bayesian linear regression (BLR) and network analysis to their compositional counterparts, adjusting for past weight and other covariates. Conventional BLR identified Roseburia and Dialister (positive association) and Coprococcus-1 (negative association) after multiple comparisons adjustment(P<.0125). No conventional network module was associated with weight. Using compositional BLR, men with higher Coprococcus-2 and Acidaminococcus had higher weight, whereas men with higher Coprococcus-1 and Ruminococcus-1 had lower weight (P<.05), but findings were non-significant after multiple comparisons adjustment. Two compositional network modules with respective hub taxa Blautia and Faecalibacterium were associated with weight(P<.01). Findings depended on analytical workflow; compositional analysis is advocated to appropriately handle the sum-to-1 constraint."}
+{"text": "Legionella and Streptococcus pneumoniae urinary antigens and PCR for other respiratory viruses on nasopharyngeal swabs were all negative. A bronchoalveolar lavage excluded pulmonary aspergillosis. On day 3, the patient developed severe dyspnea with decreased oxygen saturation (90%). Unenhanced chest computed tomography (CT) imaging showed diffuse bilateral peribronchial consolidations surrounded by ground-glass opacities  and serum lactate level was 274 U/L ; other blood tests showed normal results. COVID-19 was detected in two oropharyngeal swab samples by RT-PCR on consecutive days; pacities  and 2.1 However, less common imaging findings have also been reported. A pattern of peribronchial infiltrate with surrounding GGO is not well described in COVID-19, let alone to this extent.2 Radiologists should be aware of the wide spectrum of CT manifestation of this infection.The typical CT pattern of COVID-19 pneumonia consists of ground-glass opacities (GGO) with bilateral and peripheral distribution."}
+{"text": "Ageism negatively impacts hiring and electability success, as well as intergenerational relationships . The current study sought to examine whether personality cues influenced performance ratings of older adult (OA) speakers whose behavior had been modified by an embodiment intervention . One-hundred-and-three young adults  rated the performance of 9 OA speakers performing 5-minute campaign speeches, and reported the cues that influenced their ratings. Two independent raters coded the cues . Participants also completed the Refined-Aging Semantic Differential  as a measure of ageism endorsement. Greater ageism was associated with lower performance ratings =15.97, p<.001, R2=.14); performance was reduced by .12, 95%CIs for each additional point of ageism endorsement. Next, we investigated whether personality cues would modify this relationship using Hayes PROCESS Model 1 (2018). A significant interaction emerged between ageism and introverted cues , suggesting that greater perceived introversion was negatively associated with performance ratings. Additionally, individuals lower in ageism were more likely to calibrate their performance judgments based on the pose condition of the speaker, with participants lower in ageism exhibiting greater variability across pose conditions (Ms=3.96-4.37), than individuals higher in ageism (Ms=4.21-4.31), suggesting that individuals lower in ageism were attending to nuances in the speech , while higher ageist individuals relied more heavily on age-related judgments."}
+{"text": "Cine DENSE (Displacement Encoding with Stimulated Echoes) MRI offers high resolution circumferential, radial, and longitudinal strain assessment. Dyssynchrony assessment using midwall circumferential strain corresponds to the predominant physiologic orientation of myofibers, and its effectiveness for cardiac resynchronization therapy (CRT) patient selection has recently been demonstrated . CurrentTo test the hypothesis that cine DENSE circumferential strain analysis most effectively distinguishes between HF patients referred for CRT (HF/CRT) versus HF patients not candidates for CRT (HF/no CRT) and normal volunteers.2, matrix = 128 \u00d7 128, slice thickness = 8 mm, flip angle = 20\u00b0, TR = 17 ms, TE = 1 ms, number of spiral interleaves = 6, fat suppression, temporal resolution = 17 ms, and displacement encoding frequency = 0.1 cycles/mm. Images were exported to a PC and analyzed using custom-developed segmentation, tissue tracking, and strain analysis methods that have been described previously [MRI and echocardiography were performed in 21 subjects separated into 3 groups as defined above: HF/CRT patients (N = 9), HF/no CRT patients (N = 8), and normal volunteers (N = 4). All MRI studies were performed on a 1.5 T system . An ECG-gated spiral cine DENSE pulse sequence was used to acquire images with displacement encoding applied in two orthogonal in-plane directions. Separate 14-heartbeat breath-hold acquisitions were used for each displacement encoding direction. Short-axis images were acquired at basal, mid-ventricular, and apical levels. Additional imaging parameters included field of view = 340 \u2013 400 mmOf the 21 patients , 17 had a cardiomyopathy, 6 (35%) of which had an ischemic etiology. For all 252 segments, DENSE circumferential and radial peak timing correlated modestly . Patient-level circumferential timing measures for onset of circumferential contraction and peak circumferential contraction correlated closely . As shown in Figure MR cine DENSE assessment of circumferential strain timing using contraction onset and peak contraction effectively distinguished CRT candidates from HF patients not candidates for CRT and normal volunteers. The better discrimination of circumferential versus radial strain dyssynchrony measures has important implications for identifying the optimal imaging modality to identify CRT candidates."}
+{"text": "Acute myocarditis may mimic acute ST-segment elevation myocardial infarction (STEMI) and result in unnecessary invasive coronary angiography. Cardiac magnetic resonance (CMR) can differentiate myocarditis from acute ischemic myocardial injury and provide a basis for adoption of an appropriate treatment strategy in such patients.The aim of this observation was to determine the diagnostic value of CMR in assessment of patients with acute non-rheumatic streptococcal myocarditis.We evaluated 6 young adults  with acute non-rheumatic streptococcal myocardits following recent (mean 4.8 days prior to presentation) pharyngitis . All patients presented with non-pleuritic chest pain and focal ST segment elevation on admission electrocardiogram. Cardiac enzymes (creatine phosphokinase and troponin T) were elevated and emergent coronary angiography revealed normal coronary arteries. Two-dimensional transthoracic echocardiography showed regional wall motion abnormality (RWMA) with wall motion score index (WMSI) ranging from 1.12\u20131.24 and left ventricular ejection fraction (LVEF) ranging from 40\u201357%, and contrast-enhanced CMR demonstrated characteristic subepicardial late gadolinium enhancement (LGE) involving 4.8 \u00b1 2.4 myocardial segments without an early perfusion defect , laboratory evidence of acute streptococcal infection and characteristic CMR findings can distinguish these patients from those with acute STEMI who benefit from primary coronary intervention."}
+{"text": "GABA) and glutamatergic (VPGlu) neurons, and a subpopulation of GABAergic neurons co-express enkephalin (VPPenk). Rabies tracing reveals that VPGlu and VPPenk neurons receive preferential innervation from upstream D1- relative to D2-expressing accumbens neurons. Chemogenetic stimulation of VPGlu neurons inhibits, whereas stimulation of VPGABA and VPPenk neurons potentiates cocaine seeking in mice withdrawn from intravenous cocaine self-administration. Calcium imaging reveals cell type-specific activity patterns when animals learn to suppress drug seeking during extinction training versus engaging in cue-induced cocaine seeking. During cued seeking, VPGABA neurons increase their overall activity, and VPPenk neurons are selectively activated around nose pokes for cocaine. In contrast, VPGlu neurons increase their spike rate following extinction training. These data show that VP subpopulations differentially encode and regulate cocaine seeking, with VPPenk and VPGABA neurons facilitating and VPGlu neurons inhibiting cocaine seeking.Projections from the nucleus accumbens to the ventral pallidum (VP) regulate relapse in animal models of addiction. The VP contains GABAergic (VP Heinsbroek et al. show that glutamate and GABA neurons in ventral pallidum differentially regulate cued cocaine seeking. Calcium activity in glutamate neurons increases when mice refrain from cocaine seeking. Activating glutamate neurons inhibits cocaine seeking. Calcium activity increases in GABA neurons during cocaine seeking, and activating GABA or enkephalin neurons induces cocaine seeking.  Glu) and GABAergic (VPGABA) neurons  neurons is necessary for motivated drug seeking in animal models of addiction for all known drugs of abuse . Recent  neurons , and verand GABA . Activataversion , whereas seeking . These e seeking .GABA neurons may be composed of multiple neuronal subtypes. For example, some globus pallidus GABAergic neurons expressing NK2 homeobox 1 project to canonical output structures, while other GABAergic neurons express enkephalin and forkhead box P2 and preferentially innervate the striatum  in cue-induced drug seeking (which models the ability of drug-associated stimuli to drive drug craving and relapse) remains unexplored.Recent studies suggest that VPstriatum . These pstriatum . Althougstriatum  and thatstriatum . HoweverThe main input to VP neurons arises from the nucleus accumbens, and this pathway is composed of dopamine D1 and D2 receptor-expressing GABAergic medium spiny neurons (D1- and D2-MSNs) . D1 and Penk, VPGlu, and VPGABA subtypes on cocaine seeking after extinction training in self-administering mice.Here we describe the results form a series of experiments conducted to dissect the subcircuit connectivity and functional roles of the VPin situ hybridization (RNAscope) to quantify neuron subtype density in subcommissural dorsal VP (dVP)\u2014VPGlu (23%), VPGABA (73%), and VPPenk (16%)\u2014and found that >90% of VPPenk and <5% of VPGlu neurons co-expressed the vesicular GABA transporter (Vgat) . Although we did not distinguish between enkephalin-expressing and non-enkephalin-expressing VPGABA neurons, given that 22% of VPGABA neurons are VPPenk neurons  innervated by D2-MSNs.We used r (Vgat)  and 1B. r (Vgat) , and we r (Vgat) . Rabies  neurons , and tha neurons , the remGlu and VPPenk neurons , suggesting that VPGlu neurons may directly innervate other VP neurons or indirectly activate the VP through an extended circuit mechanism. Compared with the other cell types, a significantly larger proportion of VPPenk neurons were Fos activated by CNO , indicating that this subpopulation may be more excitable or responsive to Gq pathway signaling than VPGlu or VPGABA neurons. All VP subpopulations  were not randomly distributed and formed clusters based on k-nearest neighbor analysis . Inactive responses were also augmented, indicating non-selective behavioral activation . However, mice made significantly more active (previously cocaine rewarded) than inactive (unrewarded) responses during CNO facilitated cue-induced cocaine seeking indicating that stimulating the VP elicits drug seeking rather than non-specific motor activation . Active and inactive responding was not different during CNO-driven extinction responding, indicating potential nonspecific motor activation .All mouse strains acquired stable cocaine self-administration and extinguished responding in the absence of cocaine reward and drug-conditioned cues see . StimulaGABA neurons would recapitulate the effects of global VP stimulation and transduced VPGABA neurons with a Cre-dependent Gq DREADD in Vgat-IRES-Cre mice prior to cocaine self-administration training . Unexpectedly, although both CNO- and Veh-treated mice reinstated to cocaine-paired cues compared with extinction baseline, stimulating VPGABA neurons with CNO did not potentiate reinstated cocaine seeking . There was no effect by CNO on inactive nose poking during cued cocaine seeking . Thus, although stimulating VPGABA neurons produced a drug-seeking response in mice after extinction, it did not further potentiate drug seeking in the presence of conditioned drug cues.Given that the majority of VP neurons are GABAergic, we hypothesized that stimulating VPPenk neurons using Penk-IRES-Cre mice that were trained to self-administer cocaine . Stimulating VPPenk neurons did not affect inactive responding during either the cue-induced cocaine seeking or extinction tests . These data show that VPPenk neurons constitute a subpopulation of VPGABA that can facilitate cocaine seeking.We next expressed Gq DREADD in the GABAergic subpopulation of VPGlu neurons on cocaine seeking by expressing Gq-DREADD in Vglut2-IRES-Cre mice  and active nose poking during extinction . Stimulating VPGlu neurons did not affect inactive nose-poke responding .We also investigated the effect of stimulating VP2+ events in the different VP cell types. An AAV harboring a Ca2+ reporter (AAV1-hSyn-DIO-gCaMP6f) was microinjected into the VP of the different Cre mouse lines, and a GRIN lens (7.3 by 0.6 mm) was implanted above the microinjection site. Calcium-driven changes in fluorescence were visible within 3\u20134 weeks , when nose poking was extinguished to <40% of Ext1 after 10 d of extinction training (Ext10), and during cue-induced cocaine seeking (cue seeking). Mice underwent active nose-poke responding and cocaine infusions during self-administration when wearing a \u201cdummy\u201d miniature microscope  for habituation .We used a gradient index (GRIN) lens and miniature microscope strategy to quantify single-cell Ca\u20134 weeks  and S4, ituation . Althougituation  and 2C, 2+ events across cell types and sessions . This increased number of Ca2+ events in VPGlu neurons was most marked during Ext10, when the VPGlu event rate (2.88 events/min) was >2-fold higher than that observed in VPPenk or VPGABA neurons. Comparing sessions within the VPGlu population revealed that the VPGlu Ca2+ event rate was increased after extinction learning had occurred (comparing Ext1 with Ext10 and Reinst). In VPGABA neurons, the frequency of Ca2+ events was instead selectively increased during Reinst. By contrast, the frequency of VPPenk Ca2+ events did not change across the sessions. Although the average calcium event rate across all recorded cells (1.58 events/min) was low compared with reported average basal electrical firing rates of VP neurons in vivo (282 spikes/min) (2+ event rates reported for the nucleus accumbens (We examined the effects of extinction training and cued cocaine seeking on the frequency and amplitude of Casessions . Becausekes/min) , our finccumbens  and lateccumbens .2+ events would emerge within each cell type by plotting cumulative Ca2+ events over time  and 27 min (Ext1 versus Reinst). Similarly, the increased Ca2+ event rate in VPGABA neurons during Reinst  emerged at 27 min (Ext1 versus Reinst) and 30 min (Ext10 versus Reinst). Consistent with a lack of difference in the average VPPenk Ca2+ event rate, analyzing cumulative Ca2+ events failed to identify an overall difference between sessions for VPPenk neuron activity . However, a significant interaction was found , which post hoc tests confirmed was mediated by VPPenk neuron activity around nose pokes during Reinst , and this effect was mediated by population activity around nose pokes during Ext1  and VPGlu neurons (23%), as well as a subpopulation of VPGABA neurons co-expressing proenkephalin (16%). We found that stimulating VPGABA and VPPenk neurons facilitated cocaine seeking and that cued seeking differentially activated these cells, by increasing in the number of Ca2+ events in VPGABA and by changing Ca2+ population activity around nose pokes for VPPenk neurons. Conversely, activating VPGlu inhibited cocaine seeking, and VPGlu Ca2+ events occurred more frequently following extinction learning. Moreover, VPGlu population activity around nose-pokes was elevated selectively during early extinction when seeking responses no longer produced cocaine reward. Together, these data support a hypothesis that VPGlu activity reduces motivation, that this process is recruited during extinction learning, and that VPGABA and VPPenk activity facilitates the motivation to seek cocaine in response to cocaine-associated cues.Activity in VP neurons is necessary for motivated drug seeking in rodent models of drug addiction , but lit2+ activation of VPPenk and VPGlu neurons, chemogenetic VPGABA stimulation did not alter cocaine seeking elicited by cocaine-conditioned cues, and Ca2+ population activity was not significantly organized around nose pokes during cued seeking. This more complex portrait of activity likely resulted from VPGABA neurons\u2019 being a larger  and more heterogeneous cell group than VPGlu and VPPenk neurons. However, despite the lack of changes in Ca2+ activity around nose pokes in these cells, VPGABA neurons strongly increased their overall Ca2+ event rate during cued seeking, indicating that these cells may mediate the overall increased motivated state associated with cue-induced drug seeking. Indeed, activation of VPGABA cell bodies or VPGABA projections to the VTA is rewarding  and discrete (non-extinguished) cues. Following extinction, the context-coding cells may no longer have been reflected in VPPenk Ca2+ events , resulting in a reduced number of cells recruited by nose pokes during cue seeking. It is interesting to note that despite a reduction in the size of the VPPenk population recruited by nose pokes, overall VPPenk population responses were recruited by nose pokes only during cue seeking. This may be explained by a sharpening of the population response to nose pokes when only cue-activated VPPenk neurons were responsive, but this hypothesis requires further testing in future studies. It also remains possible that the differences observed between early extinction and cue seeking in VPPenk neurons are mediated by subsets of VPPenk neurons defined by distinct projection targets. In line with this idea, enkephalin-containing globus pallidus neurons project to the striatum and encode a stop signal for ongoing movement patterns This study did not generate new unique reagents. Further information and requests for resources and reagents should be directed to and will be fulfilled by the Lead Contact, Peter Kalivas  and every other generation new mice were introduced into the colonies to prevent inbreeding   For anatMice were implanted with a chronic jugular vein catheter as described previously  and infuThree to four days after surgery, mice were food deprived overnight and trained to self-administer cocaine  for 12 days, during which operant responses for cocaine were paired with the presentation of a compound cue (tone + light). Throughout self-administration catheter patency was assessed periodically using the intravenous infusion of the short acting barbiturate Brevital. Afterward, mice underwent 7 days of home cage abstinence, followed by at least 10 days of extinction training with neither cocaine nor cocaine-associated cues present, followed by cue seeking tests  into the VP, followed by the implantation of a GRIN lens  above the VP. Mice were allowed to recover for 3 weeks, and underwent a second surgery during which a base-plate was installed for miniature microscope attachment. Videos of Ca2+ mediated fluorescence changes in individual neurons were acquired using a miniature microscope system and acquisition software . Videos were recorded at a 15 Hz framerate under constant low light illumination < 1 mW. Data files were decompressed, downsampled by a special factor of four, motion corrected using a rigid body translation algorithm (TurboReg), and \u0394F/F normalized . Afterward, temporal and spatial components were extracted using principal/independent component analysis (PCA/ICA). The quality of individual temporal and spatial components was examined manually for each cell using Mosaic software (Inscopix). Changes in Ca2+ fluorescence around behaviorally meaningful events (nose-pokes for cocaine) and the frequency and amplitude of Ca2+ transients (Ca2+ events) were analyzed separately. Ca2+ events were identified using a peak-finder algorithm  and frequency (spikes/min) and amplitude (a.u.) data were processed using custom-written code in MATLAB (Mathworks).Mice were injected with the Cre dependent genetically encoded Ca12 GC/ml, Salk vector core; AAV8-CA-DIO-RG, titer: 2.5*1012 GC/ml, UNC Vector core). Three weeks later mice were injected with G-Deleted EnvA pseudotyped replication deficient Rabies SAD\u0394G-B19-mCherry . Ten days after rabies injection, animals were perfused for histology.For cell-type specific monosynaptic retrograde rabies tracing, D2-eGFP x Cre recombinase expressing double transgenic mice were injected with a cocktail of Cre dependent helper viruses mixed in 1:1 ratio , mCherry , dsRed , substance P , and Ser32-phospho-cFos , as well as Alexa-conjugated secondary antibodies . Cell counting and co-localization studies were performed using the cell counting plugin in ImageJ (NIH). For immunohistochemical validation of DREADD function, mice were injected with CNO or vehicle 2 h prior to perfusion.in situ hybridization protocol (ACDbio) based on manufacturer recommendations, without epitope retrieval or protease pretreatment steps. Images were taken using a Zeiss LSM880 confocal microscope at 40x and cell counts and co-localization analyses were performed in ImageJ using the Cellcounter plugin (NIH).Wild-type C57BL/6J mice were euthanized, and brains were rapidly extracted and flash frozen in isopentane solution on dry ice. Brains slices (15 \u03bcm) were stained for mRNA expression using the RNAscope 2+ fluorescence around active nose-pokes were analyzed as described previously  within a session for each cell. During extinction, only nose-pokes separated by at least 20 s from each other were used in analyses to prevent cross-contamination of signals between responses. During cued seeking, only nose-pokes occurring outside of the 20 s time-out between cue presentations  were evaluated. For the analysis of changes in population activity around nose-pokes, Ca2+ fluorescence signals were transformed to absolute values to incorporate both increased and decreased responses (2+ activity was compared before (\u22122 to 0 s) and after (0 to 2 s) a nose-poke for each cell. To calculate the proportion of cells with increased or decreased responses to nose-pokes, non-absolute transformed Ca2+ signals within these same time-windows were compared and significantly modulated cells were defined as having average activity > 2 s.d. higher (increased) or > 2 s.d. lower than baseline prior to a nose-poke.Changes in Caeviously . Fluoresesponses . To quanin situ hybridization for the different VP cell markers. The k-nearest neighbor value (Euclidian distance) for all cells was compared to the k-nearest neighbor values of a shuffled dataset .To investigate whether the different neuronal populations were organized as clusters or randomly distributed throughout the VP, we used a k-nearest neighbor algorithm (k = 10) on the centroids (ImageJ Cellcounter) of neurons identified by either virus expression (in Cre mouse lines) or 2+ event rate and amplitude comparisons as specified in the results. Chi-square tests with Bonferroni correction for repeated-measures was used for rabies tracing data and Ca2+ population fraction comparisons. Statistical significance was set at 0.05.All data are presented as mean \u00b1 sem. Statistical analyses were performed using Prism . Paired Student\u2019s t tests were used for extinction tests. One sample t tests were used for clustering analyses. One-way and two-way repeated-measures analysis of variance (RM-ANOVA) with Greenhouse-Geisser correction and Neumann-Keuls post hoc tests were used for cue seeking tests and CaThe published article includes all data generated or analyzed during this study. MATLAB code written by J.A.H. was used to process and analyze all calcium imaging datasets. Code, and data are openly available upon request.12"}
+{"text": "The aim of this study was to predict driving behavior based on emotional intelligence & driving risk perception.This research was descriptive & correlational. The sample size consisted of 400 drivers from 5 taxi terminals of different areas of Tehran megacity by convenience sampling. The tools which used in this study were as follows: Manchester driving behavior questionnaire, Ulleberg & Rundmo driving risk perception questionnaire, Shrink emotional intelligence questionnaire. Data analysis was based on Pearson correlation & multiple simultaneous regression.Analysis revealed that the relationship between driving behavior & driving risk perception was significant & negative (r = -0/34) (\u0251 = 0/01). The relationship between driving behavior & emotional intelligence was significant & negative (r = -0/28) (\u0251 = 0/01). Emotional intelligence & driving risk perception could predict 16% of driving behavior. That means by increasing emotional intelligence & promote driving risk perception among taxi drivers, the risky driving behavior could be decreased. In the other words drivers who do risky driving behavior and commit driving offenses, their emotional intelligence is less than other drivers.Risky driving behavior, Driving risk perception, Emotional intelligence"}
+{"text": "Mealtime difficulties are common in residents with dementia, leading to negative outcomes. Interaction with staff are critical to engage residents in eating. This study characterized dyadic verbal interactions (descriptive statistics), and relationships among verbal behaviors and between verbal behaviors and individual characteristics . This secondary analysis of 110 videotaped mealtime observations involved 25 residents and 29 staff (42 unique dyads) in 9 nursing homes (NH). Verbal behaviors (utterances) were coded using the Cue Utilization and Engagement in Dementia mealtime video-coding scheme, addressing 8 positive behaviors and 4 negative behaviors. Staff spoke three times more frequently (76.5%) than residents (23.5%). Nearly all staff utterances were positive (99.2%). 85.1% of residents\u2019 utterances were positive and 14.9% negative. Staff positive utterances were associated with staff negative utterances (p=.02), and resident positive (p<.001) and negative (p<.001) utterances. Staff negative utterances were associated with resident negative utterances (p=.02), but not with resident positive utterances (p=.39). Resident positive and negative utterances were associated (p<.001). Staff positive utterances were associated with staff race (p=.01), and resident age (p=.01), dementia stage (p<.001), and eating function (p<.001). Resident positive utterances were associated with years staff worked as caregivers (p=.02) and in the current NH (p=.01), resident age (p=.04), comorbidity (p=.04), dementia stage (p=.01), and eating function (p=.003). Resident negative utterances were associated with dementia stage (p=.01). Dyadic mealtime interactions were dynamic, interactive and complex. Multiple resident and staff characteristics were related to mealtime verbal interactions. Findings may inform development of individualized, person-centered mealtime care interventions."}
+{"text": "Level\u00a0of\u00a0Difficulty: Intermediate.)We describe the case of a degenerative, sutureless bioprosthetic valve (BPV) with deformation and stent infolding in a patient with elevated surgical risk. Following discussion among the heart team, balloon valve fracture was performed to facilitate deployment of an aortic valve-in-valve transcatheter heart valve. Post-procedural imaging demonstrated BPV frame protrusion and contained annular rupture, which required operative intervention.  with deformation and stent infolding in a patient with elevated\u2026 An 81-year-old female presented with New York Heart Association functional class III symptoms of breathlessness. She had undergone implantation of a 19-mm Perceval  sutureless bioprosthetic valve (BPV) 2 years previously for high-risk severe native aortic stenosis. Computed tomography (CT) demonstrated stent infolding and collapse . Transth"}
+{"text": "The superscan appearance in the FDG PET/computerized tomography (CT) imaging might be because of benign diseases or malignant infiltrations. This case report presents lymphomatous blastic infiltration as a cause of superscan appearance in 18F-FDG PET/CT.The"}
+{"text": "To develop effective fall prevention intervention, it is necessary to understand how older adults respond to challenges that demand cognitive-motor dual-tasking capability, an important capability in the daily lives. The purpose of this study is to investigate how older adults adjust their motor responses when encountering cognitive and walking perturbations simultaneously. We recorded kinematic data as subjects walked on a treadmill with or without 1) continuous random-amplitude treadmill platform sways ; and 2) each of the four cognitive tasks: Paced Auditory Serial Addition test (PASAT), clock test, visual color-word incongruent test (V-stroop), and auditory pitch-word incongruent test (A-stroop). We computed dynamic margins of stability (MOS), gait variability, and short-term local divergence exponent (LDE) of the trunk motion . Data of ten older subjects (age: 72.2\u00b14.9) show that cognitive performance did not differ between standing, Perturbed or No-perturbed walking. Subjects demonstrated significantly greater local instability and variability in step measures, joint angle and MOS during Perturbed than No-perturbed walking (p<0.001). During dual-task conditions, subjects walked with significantly larger medio-lateral MOS (MOSML) compared to walking only, especially during early phase of the trial. During Perturbed walking, subjects had significantly larger MOSML during PASAT and Vstroop than walking only. Our data showed that subjects tried to increase their dynamic MOS during Perturbed walking or a cognitive task more difficult or taxing visual attention. However, the adjustments do not sustain throughout the trial. These findings suggest older adults tend to prioritize cognitive over walking tasks even when encountering walking perturbations."}
+{"text": "The toxicity test of ammonium persulfate was conducted to ensure of its potential toxic effects according to the single-dose acute oral toxicity study (OECD Guideline 423) and 90-day repeated dose sub-chronic oral toxicity study guideline (OECD Guideline 408) for establishing national chemical management system, and matching in the Globally Harmonized Classification System (GHS) category. In acute oral toxicity study, pasty stool, perineal contamination and temporary body weight decrease were observed after dosing 1st and 2nd challenge (300 mg/kg body weight). All test animals were dead within 6 hours after dosing at 3rd challenge (2000 mg/kg body weight). Therefore, the GHS class of test substance is considered class 4. In sub-chronic toxicity study, body weight changes, food consumptions, hematological, biochemical and pathological examination did not show any noticeable and significant differences between the administered  and control (vehicle only) group animals. Based on these results, the no observed adverse effect level (NOAEL) is considered above 80 mg/kg body weight."}
+{"text": "We sequenced four severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes from Malaysia during the second wave of infection and found unique mutations which suggest local evolution. Circulating Malaysian strains represent introductions from different countries, particularly during the first wave of infection. Genome sequencing is important for understanding local epidemiology. We sequenced four severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes from Malaysia during the second wave of infection and found unique mutations which suggest local evolution. Circulating Malaysian strains represent introductions from different countries, particularly during the first wave of infection. Genome sequencing is important for understanding local epidemiology. Coronaviridae and the genus Betacoronavirus and has caused a pandemic of coronavirus disease (COVID-19). As of 31 March 2020, Malaysia had 2,766 confirmed cases with 43 deaths (Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) belongs to the family se COVID-9. As of 3 deaths .Viral RNA was extracted from the samples using a QIAamp viral RNA minikit  and amplified according to the ARTIC nCoV-2019 protocol (MN908947) with the Geneious mapper. About 94% of the reads were mapped, except for strain 186197 (25.2%). The average depth of coverage for iSeq was 5,000\u00d7, except for strain 186197, which had only 1,000\u00d7 coverage (www.gisaid.org), including six other previously deposited Malaysian strains .The iSeq raw FastQ files were analyzed using Geneious Prime 2020 . The average number of raw paired reads obtained from iSeq was 1.8 million . Paired coverage . Therefocoverage . Multiplcoverage . PhylogeThe four complete genome sequences reported here date from the main second wave of infections in Malaysia . Strain Our data showed that current circulating strains in Malaysia represent introductions from different countries and local evolution. More genomic data will clarify virus spread in Malaysia, particularly with respect to the role played by the mass gathering.MT372480 to MT372483), BioProject (PRJNA616147), BioSample , and SRA .These sequences have been deposited in the GISAID EpiCoV newly emerging coronavirus SARS-CoV-2 platform under identifiers EPI_ISL_417917 to EPI_ISL_417920. The sequences were also deposited in the following NCBI databases: GenBank (accession numbers"}
+{"text": "Expressed sequence tags (ESTs) provide an imprint of cellular RNA diversity irrespectively of sequence homology with template genomes. NCBI databases include many unknown RNAs from various normal and cancer cells. These are usually ignored assuming sequencing artefacts or contamination due to their lack of sequence homology with template DNA. Here, we report genomic origins of 347 ESTs previously assumed artefacts/unknown, from the FAPESP/LICR Human Cancer Genome Project. EST template detection uses systematic nucleotide exchange analyses called swinger transformations. Systematic nucleotide exchanges replace systematically particular nucleotides with different nucleotides. Among 347 unknown ESTs, 51 ESTs match mitogenome transcription, 17 and 2 ESTs are from nuclear chromosome non-coding regions, and uncharacterized nuclear genes. Identified ESTs mapped on 205 protein-coding genes, 10 genes had swinger RNAs in several biosamples. Whole cell transcriptome searches for 17 ESTs mapping on non-coding regions confirmed their transcription. The 10 swinger-transcribed genes identified more than once associate with cancer induction and progression, suggesting swinger transformation occurs mainly in highly transcribed genes. Swinger transformation is a unique method to identify noncanonical RNAs obtained from NGS, which identifies putative ncRNA transcribed regions. Results suggest that swinger transcription occurs in highly active genes in normal and genetically unstable cancer cells. Systematic nucleotide exchanges, also called swinger transformations, systematically exchange specific nucleotides with other specific nucleotides during DNA replication and/or RNA transcription. DNA or RNA molecules corresponding to systematic nucleotide changes are called swinger DNAs or swinger RNAs. Only 23 systematic nucleotide exchanges Figure 1Systematic nucleotide exchange analyses identify genomic origins of unknown DNA/RNA sequences. Several types of RNAs with no sequence homology to template genomes exist. This includes RNA-DNA differences , post-trMitogenomic human swinger RNA reads produced by Illumina confirmed corresponding EST data . The swiThe Encyclopedia of DNA Elements (ENCODE) project concluded that a human genome includes approximately 20,000 protein-coding genes and predicts that 80% of non-coding regions regulate gene expression . HoweverExpressed sequence tags (ESTs) are short DNA sequences (100\u2013600 bp) generated from the sequencing of cDNA libraries. The ESTs represent RNAs derived from a particular cell irrespective of sequence similarity or dissimilarity to its template genome, unlike transcriptomes, in which sequencing reads with sequence similarity are considered as true reads while ignoring non-homologous reads. This underlines a major limitation in identifying and studying non-canonical RNAs and their association with various genetic diseases like cancers. Therefore, here we apply swinger transformations to identify unknown expressed sequence tags (ESTs) occurring in the FAPESP/LICR Human Cancer Genome Project . We expeThe FAPESP/LICR Human Cancer Genome Project corresponds to 891,011 published  and 55,2The unknown 149,500 ESTs were then swinger-transformed according to the 23 bijective transformations Figure 1In total, 347 ESTs (0.23%) were identified using swinger transformation analyses 3. This These 347 swinger-transformed RNAs matched 205 known and two uncharacterized genes 3. TheseTwo A \u2194 T-transformed swinger RNAs detected in the colon and head-neck cancer lines mapped on the adenylate kinase 1 (AK1) coding gene Table 2.Among the detected swinger RNAs, 51 swinger RNAs match mitochondrial genes 2. It isInterestingly, detection of swinger transformed DLGAP1 mRNAs  of the mitochondrial genome (NC_012920.1), while two mapped on the 5' terminal of ND2  gene. Interestingly, for MT-ND4, among the three ESTs identified across three different biosamples for three different swinger transformations, two ESTs mapped on the same 3' terminal ND4 region i.e. 11,610\u201311,801 bp on the mitochondrial genome (NC_012920.1). For Nuclear gene poly(A) binding protein cytoplasmic 1 (PABPC1), all the 33 identified ESTs preferentially mapped on the mid-region  of PABPC1 gene.\u22126) swinger RNAs map either on the mid or the 3' regions of the gene. These tests assume that the probability of mapping randomly on these regions is 2/3. One tailed sign tests are justified by the working hypothesis that polymerase enzyme fatigue (occurring more downstream from transcription initiation) causes swinger transcription. These observations indicate that the mid and 3' regions of highly expressed genes are more prone to produce swinger transformed RNAs than the 5' region, for each nuclear and mitochondrial genes. Similarly, swinger transformed ESTs (from only one biosample) mapping on identified genes, preferentially mapped on the same region  and 33 among 33 . This result suggests that these 15 regions are transcriptionally active, with potential roles in nerve cells and possible associations with carcinogenesis. However, these specific cancer tissue samples are unavailable, preventing further in-vitro and in-vivo tests and analyses.Seventeen and two identified swinger RNAs were transcribed from 15 non-coding genomic regions and two uncharacterized genomic regions, respectively Table 3.The identified swinger RNAs were mapped on human nuclear chromosomes. No compartmentalizations on any chromosomal arm, region or band of a chromosome were detected in relation to swinger expressed regions. Swinger RNAs produced by transformations that are more conservative at the amino acid level are also more abundant than swinger RNAs produced by transformations that cause more amino acid changes . This efWe report genomic origins of 347 previously unidentified ESTs generated by the FAPESP/LICR Human Cancer Genome Project . These rAll datasets generated for this study are included in the article/GW conducted design, analysis, observation and writing. P-EF contributed to result assessments. HS designed the systematic nucleotide exchange framework. P-EF and HS contributed to writing and supervising this study.This work was supported by the A*MIDEX project (no ANR-11-IDEX-0001-02) funded by the \u00ab Investissements d'Avenir \u00bb French Government program, managed by the French National Research Agency (ANR).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Here, we extend this approach by examining changes in the urinary metabolome in a hematopoietic (HP) resistant mouse model (p53\u2212/\u2212) after IR exposure. As p53 is a primary regulator in radiation response and apoptosis, limited hematopoietic stem cell apoptosis leads to reduced mortality at doses of ~8\u201310 Gy but increased mortality at higher doses (>15 Gy) due to mitotic catastrophe in gastrointestinal (GI) crypt cells. Urine was collected from mice (wild-type (WT), p53+/\u2212, and p53\u2212/\u2212) pre-irradiation and at 4 and 24 h after total body irradiation (TBI)  for metabolic phenotyping using an ultra-performance liquid chromatography mass spectrometry (UPLC-MS) platform. Minimal differences were detected between unirradiated WT, p53+/\u2212, and p53\u2212/\u2212 mice. While similar perturbations were observed for metabolites involved in tryptophan, vitamin B6, and histamine pathways, glycine conjugation, and redox metabolism for WT and p53\u2212/\u2212 mice after TBI, an overall dampened response was observed in p53-deficient mice. Despite comparable metabolite patterns between genotypes, differentiation was achieved through receiver operating characteristic curve analysis with high specificity and sensitivity for carnitine, N1-acetylspermidine, and creatine. These studies highlight that both attenuated and dampened metabolic responses due to genetic variability in the general population need to be addressed in biodosimetry frameworks.Due to risks from potential exposures to ionizing radiation (IR), improved radiological countermeasures are required, as well as rapid high-throughput biodosimetry. Genotypic variation in the general population contributes to differences in radiosensitivity that may affect biodosimetry accuracy. Previous studies utilized radiosensitive mutant mouse models (Parp1 The need for rapid biodosimetry, radiological countermeasures, and mitigation efforts has arisen from the ongoing risks of potential exposures to ionizing radiation (IR), including through accidental (nuclear power plants or stored waste) or malicious  events. Concerning biodosimetry, practical biomarkers are needed that can classify the clinical severity of acute radiation syndrome (ARS), or the absence thereof, to administer appropriate medical care. While lower exposure levels <2 Gy) would require minor medical treatment in the absence of secondary conditions, higher exposure levels may lead to hematopoietic syndrome (2\u20134 Gy) that may be treated with supportive care such as cytokine therapy . Potenti Gy would1H-NMR) or gas chromatography (GC)-mass spectrometry (MS)) to thousands -MS) of compounds or spectral features in a given sample \u2212) as Lockspray\u00ae to calibrate accurate mass.Samples were injected (2 \u03bcL) and analyzed by an ACQUITY UPLC  coupled to a Xevoescribed  using le+, M + H = 176.1188) or 4-nitrobenzoic acid ) as previously described [+/\u2212, and p53\u2212/\u2212 mice) [\u2212/\u2212 mice were assessed using a Welch\u2019s t-test  corrected p-values determined with a classical Benjamini-\u2013Hochberg step-up correction procedure) or a Barnard\u2019s test (< 70% presence in a single group) using the software MetaboLyzer [Data files were inspected in MassLynx v.4.1 , pre-processed in Progenesis QI , and normalized to internal standards (debrisoquine (ESIescribed . The res/\u2212 mice) . PositivaboLyzer . HeatmapaboLyzer , and volaboLyzer , the KyoaboLyzer , and theaboLyzer . Ions weaboLyzer ,29. ValiaboLyzer . Pathway+/\u2212, and p53\u2212/\u2212) were observed and only irradiated WT and p53\u2212/\u2212 were further explored   slightly decreased at 4 h. Pathway enrichment showed primary perturbations to fatty acid \u03b2 oxidation, tryptophan, vitamin B6, and histamine pathways, amino acid metabolism, glycine conjugation, and redox metabolism (\u2212/\u2212 mice at 4 h for carnitine and N1-acetylspermidine combined (AUC = 0.91) at the equitoxic dose (8 Gy) and fair values for the equidose   . The gretabolism , Table 1tabolism . ROC cur = 0.73) . At 24 h = 0.73) .\u2212/\u2212 (10 Gy) mice with IR induced hematopoietic injury. Similarities in metabolic responses after IR exposure between genotypes suggest presence of in vivo compensatory mechanisms and highlight the utility of genetically engineered mouse models in biodosimetry studies compared to in vitro models [\u2212/\u2212 genotype compared to WT, likely due to decreased hematopoietic stem cell apoptosis [In the present study, we compared changes in the urinary metabolome at 4 and 24 h post-irradiation in WT (8 and 10 Gy) and p53o models ,31. Aftepoptosis . Perturb\u2212/\u2212 was observed compared to WT mice [\u2212/\u2212 mice, including the resultant p53 response  [\u2212/\u2212 mice) and in TCA cycle intermediates (Parp1\u2212/\u2212 mice) [While genetically engineered knockout mouse models are an extreme example of genetic variability in the general population, they provide vital information on possible effects to biodosimetry accuracy. Considering the current study, IR exposure will quickly elicit p53-mediated apoptosis in sensitive WT tissues along with a cascade of downstream gene activation in other tissues (see review ). Mutati WT mice . Conversnd Mdm2) . The uri/\u2212 mice) ,12.\u2212/\u2212), kynurenic acid (Atm\u2212/\u2212), and 4-pyridoxic acid (Parp1\u2212/\u2212). Decreased urinary levels of kynurenic acid have been consistently reported in murine models after IR exposure [Some common metabolites identified between genetic mutant mouse studies include hippuric acid  deacetylation and converted to 1-methylnicotinamide through nicotinamide N-methyltransferase (NNMT). While p53 is a well described target of SIRT1 deacetylation [4, was detected in the current study. MHPG-SO4 is a major metabolite of norepinephrine, which is a major catecholamine neurotransmitter along with dopamine and epinephrine. Increased catecholamine excretion has been observed in humans after accidental irradiation [Three additional compounds  have been previously identified in radiation exposure studies and show similar fold changes between p53tabolism . Histamitabolism . Histamitabolism  and histtabolism . The pos WT mice . Disrupt WT mice  and may tylation , the ubiadiation  but litt\u2212/\u2212 genotype may complicate prediction of IR toxicity. Three metabolites  identified in the current study are involved downstream of p53-targeted pathways (see below) and show high to fair classification performance across time points. Elevated carnitine levels may indicate fatty acid \u03b2 oxidation perturbation, as carnitine palmitoyltransferase 1 (CPT1) binds carnitine to a corresponding fatty acid to form an acylcarnitine for transportation across mitochondrial cell membranes. Deficiency of p53 may affect both substrate concentration and enzymatic conversion, as it upregulates CPT1C, a brain specific isoform, by phosphorylating activated protein kinase (AMPK) [\u2212/\u2212 genotype may distinguish from WT mice, similar patterns for N1-acetylspermidine and creatine do suggest compensatory pathways in p53-deficient mice. For an example considering N1-acetylspermidine, acetylated and non-acetylated spermine and spermidine steady-state levels were found to remain unchanged in radiosensitive shSAT cells, possibly through altering ornithine decarboxylase activity [While similar patterns emerge for metabolite perturbation between genotypes, classification models show how false negatives in the p53e (AMPK)  and alsoe (AMPK)  (see reve (AMPK) ). Increae (AMPK)  and has e (AMPK) . Similare (AMPK) . Muscle e (AMPK) , but p53e (AMPK) ,58. Hereactivity . In term\u2212/\u2212 and Atm\u2212/\u2212), demonstrates how genetic variability in the general population may affect predictive performance in small molecule-based biodosimetry. As there is likely no single metabolic biomarker indicative of IR exposure and ARS severity, the goal is to combine small molecules with other targets  to increase the predictive performance of biodosimetry models for complex exposures. However, both attenuated and dampened metabolite responses pose challenges with false positive or negative rates, respectively. These challenges may be further exacerbated when moving from rather simple exposures (whole-body photon irradiation) to more complex exposures . Future work will continue to assess genotypic independence in complex exposure and further biodosimetry marker panel development.Differences in tissue and cell response to IR exposure in p53-deficient mice will result in decreased mortality due to hematopoietic injury compared to WT. Conversely, at higher doses (>15 Gy) increased mortality from GI injury occurs due to lack of cell arrest and mitotic catastrophe in crypt cells. Identification of IR induced hematopoietic injury biomarkers is extremely relevant in a radiological emergency, as significant reduction in mortality may be achieved with proper supportive care. This study, along with previous examples of radiosensitive genotypes (Parp1"}
+{"text": "Macrophages are important imaging targets for identifying and monitoring high-risk atherosclerotic plaque. Human protein cages and graphite/FeCo core-shell nanocrystals are unique, multi-functional nanoparticle platforms for cellular imaging.in vivo.To evaluate 7 T MRI using human ferritin protein cage nanoparticles (HFn) and graphite/FeCo core-shell nanocrystals (CN) for detecting macrophage accumulation in mouse carotid atherosclerosis A macrophage-rich carotid lesion in FVB mice (N = 6) was induced as follows: high fat diet for 4 weeks then diabetes induction by 5 daily intraperitoneal injections of streptozotocin. Two weeks later, we performed carotid ligation of the left common carotid artery. Either one of two different nanoparticles, HFn or CN, was injected into mice via tail vein 2 weeks after carotid ligation (N = 3 for each nanoparticle).1) HFn-Fe are human ferritin protein cages chemically modified to contain an iron oxide core (dose \u2013 25 mgFe/kg).2) CN have a FeCo core with a graphite shell, with Cy5.5 also attached for fluorescence imaging .in vivo MRI, both in situ and ex vivo fluorescence imaging was performed using Maestro\u2122 in vivo imaging system . Perl's iron and immunofluorescence staining was also performed to confirm co-localization of nanoparticles with macrophages.MRI at 24 and 48 hours was performed on 7 T MRI scanner  using a gradient echo sequence . Accumulation of nanoparticles on MRI was measured as the size of susceptibility artifacts (% reduction of lumen area). After final In vivo MRI showed the accumulation of HFn-Fe and CN in the ligated left carotid arteries (Figure s Figure , with T2s Figure  and 2. Fs Figure  with no s Figure .Figure 1Both iron oxide protein cage nanoparticles and graphite/FeCo core-shell nanocrystals allow noninvasive MRI of macrophage accumulation in mouse atherosclerosis. These powerful, multi-functional nanoparticles may allow improved noninvasive characterization of vascular inflammation and atherosclerosis."}
+{"text": "Nibbling 405 kb off the X: Viable deletion alleles eliminating 50 protein coding genes, including a chromatin factor involved in neuronal development. microPublication Biology. ser-2::gfp (otIs138 transgene) and dat-1:rfp (vsIs33 transgene) .\u201dvsIs33 is incorrectly reported in the following sentence: \u201cThe harsh touch sensory neuron PVD, generated by the postdeirid lineage, can been labeled with two transgenically expressed fluorophores, vsIs33 to [dop-3::rfp]. In addition sentence has been corrected.Authors have corrected the genotype of The sentence now reads:ser-2::gfp (otIs138 transgene) and dop-3:rfp (vsIs33 transgene) .\u201cThe harsh touch sensory neuron PVD, generated by the postdeirid lineage, can be labeled with two transgenically expressed fluorophores, These errors have been corrected online as well as in future PDF versions of this article."}
+{"text": "Despite the high prevalence of sensory impairment in older adults, there are no standard practices for its consideration in cognitive studies. We conducted a systematic review to identify and survey prospective cohort studies collecting cognitive data in older adults in order to determine whether and how hearing and vision were considered. Among 81 cohorts that responded, 30 (37%) objectively assessed hearing, with audiometry as the most frequently-used method; 61 (75%) used patient-report and 12 (15%) used provider-report to subjectively assess hearing. Forty-one (51%) cohorts objectively assessed vision, half of which measured distance or near visual acuity; 55 (68%) used patient-report and 10 (12%) used provider-report to subjectively assess vision. Nineteen (23%) cohorts offered hearing accommodations and 30 (37%) offered vision accommodations during cognitive testing. Findings indicate variation in methods used to assess hearing and vision as well as in accommodation practices that could impact estimates of cognition among older adults."}
+{"text": "To the Editor: Jin and Tong described a patient with severe coronavirus disease (COVID-19) in whom rhabdomyolysis developed on day 9 of hospitalization  (Clinicians treating rhabdomyolysis concurrent with COVID-19 must assess the many differential diagnoses, including severe acute respiratory syndrome coronavirus 2\u2013induced myositis, reactions to medication, cytokine storm, hypoxia, or a thromboembolic event. This differential diagnosis is crucial because each condition has a distinct therapeutic approach."}
+{"text": "The PET/CT scan with 18F-choline demonstrated highly increased tracer incorporation within a gross lesion in the hepatic dome coupled with diffuse activity in bone marrow, this latter aspect was probably due to the compensatory hematopoiesis stimulation induced by chronic hemolysis. This pattern of skeletal 18F-choline uptake should be considered as a peculiar PET/CT finding in thalassemic patients.A 57-year-old male with history of thalassemia intermedia and hepatocellular carcinoma underwent a positron emission tomography/computed tomography (PET/CT) scan with"}
+{"text": "To compare peripapillary retinal nerve-fiber\u2013layer (pRNFL) thickness, total retina macular volume, and ganglion-cell-layer (GCL) macular volume and thickness between persons living with HIV (PLHIVs) with well-controlled infections and good immune recovery, and sex- and age-matched HIV-uninfected controls (HUCs).www.clinicaltrials.gov identifier: NCT02003989) included 56 PLHIVs, infected for \u226510 [median 20.2] years and with sustained plasma HIV-load suppression on combined antiretroviral therapy (cART) for \u22655 years, and 56 matched HUCs. Participants underwent spectral-domain optical coherence tomography (SD-OCT) with thorough ophthalmological examinations and brain magnetic resonance imaging (MRI). Their overall and quadrant pRNFL thicknesses, total macular volumes, and GCL macular volumes and thicknesses were compared. Cerebral small-vessel diseases (CSVD) complied with STRIVE criteria.This prospective cross-sectional study  PLHIVs and 14 (25%) HUCs was associated with overall thinner pRNFLs, and smaller total retina and GCL macular volumes, independently of HIV status.SD-OCT could not detect pRNFL thinning or macular GCL-volume reduction in well-sustained, aviremic, cART-treated PLHIVs who achieved good immune recovery. However, CSVD was associated with thinner pRNFLs and GCLs, independently of HIV status. Combined antiretroviral therapy (cART) ensures human immunodeficiency virus (HIV) suppression and immunological recovery in a majority of persons living with HIV (PLHIVs), dramatically improving life expectancy ,2. As a The concept of the retina being an anatomical and functional central nervous system surrogate is increasingly recognized . NotablySpectral-domain (SD)-OCT detected significant pRNFL thinning in severely immunodeficient PLHIVs  \u201323. In PWe undertook this concurrent cohort study to investigate pRNFL and GCL thicknesses in PLHIVs with well-sustained, cART-controlled, immunovirological parameters and HIV-uninfected controls (HUCs). Because we wanted to examine the role of chronic HIV infection itself, we selected PLHIVs with cART-sustained, immunovirological control for at least 5 years, without hepatitis C virus (HCV) infection, past or ongoing acquired immune deficiency syndrome (AIDS)-defining neurological events (ADNEs), and/or alcohol or illicit drug abuse.This study, approved by the CPP \u00cele-de-France VI Ethics Committee, adhered to the tenets of the Declaration of Helsinki. Written informed consent was obtained from all participants.In this cross-sectional study (NCT02003989), we prospectively included PLHIVs followed in two Infectious Diseases Departments in University Hospitals, caring for about 8,000 PLHIVs in the Paris area (France). Inclusion criteria were: (1) HIV seropositivity known for \u226510 years; sustained CD4+ T-cell count \u2265350/\u03bcL and plasma HIV load (plVL) <20 copies/mL for \u22655 years on cART. plVL was quantified using the Amplicor monitor assay , which has a lower detection limit of 20 HIV-1 RNA copies/mL. Exclusion criteria were: (1) transient low-level viremias \u226520 but \u2264200 copies/mL  once within the previous 5 years; (2) history/concomitant ocular trauma or diseases; (3) family history of glaucoma; (4) prior/current treatment with drugs associated with toxic optic neuropathy or retinopathy; (5) prior/current neurological/psychiatric disorders, including ADNE; (6) prior/current diabetes mellitus; (7) prior/current alcohol or illicit substance abuse ; (8) HCV infection. Cognitive decay was not sought prior to inclusion and was not an exclusion criterion.Age (\u00b15 years)- and sex-matched (1:1) HUCs were selected on a voluntary basis; exclusion criteria were the same as for PLHIVs. The absence of HIV infection was confirmed by ELISA or rapid HIV test.All participants underwent the same comprehensive neurological and ophthalmological examinations. All SD-OCT were obtained with a Spectralis OCT, which generates four sectoral pRNFL thicknesses and an overall value that is the average of the four quadrants, using the new Nsite Axonal Analytics software . Overall and sectoral pRNFL thicknesses were recorded for each eye. The total retinal macular volume was calculated with the Heidelberg software using the Early Treatment for Diabetic Retinopathy Study (ETDRS) grid. We used the Iowa Reference Algorithm to segment the GCL and calculated the GCL thickness for each of the 9 ETDRS-grid subfields and the total GCL macular volume within the ETDRS grid  29\u201331].\u201331.29\u201331The main outcome measure was the overall pRNFL thickness. Previous studies found a standard deviation of ~9 \u03bcm for it with the OCT machine used herein . With th2 or Fisher\u2019s exact test were used as appropriate to compare groups. Analysis of variance (ANOVA) of repeated measures was used to detect differences among the different pRNFL quadrants and among the different GCL ETDRS-grid subfields.Only one eye of each participant was randomly selected for analysis. The non-parametric Mann-Whitney U-test and chiLinear-regression models were used to test associations between OCT measurements  and visual function measurements, axial length and age (predictor variables). HIV status was included in all these linear-regression models to test a possible HIV effect on an association.For the PLHIV group, associations between overall and temporal pRNFL thicknesses, total retinal macular volumes, GCL macular volumes (outcome variables) and duration of HIV infection (predictor variable) were tested with a multivariate model including age as a covariate. Univariate regression analyses were used to identify associations between PLHIVs\u2019 overall and temporal pRNFL thicknesses, total retinal macular volumes or GCL macular volumes (outcome variables) and CD4+ T-cell nadirs (predictor variable).Significance was defined as p<0.05. All analyses were computed with Statistica software  and no statistical correction was made for multiple comparisons.Among 71 PLHIVs initially included, 15 were secondarily excluded because of bilateral glaucoma (n = 1), bilateral high ametropia (n = 6), previous bilateral ocular surgery (n = 3), alcoholism (n = 1), diabetes (n = 2), HCV infection (n = 1) or missing MRI (n = 1). Among 65 HUCs initially included, nine were secondarily excluded because of bilateral high ametropia (n = 4), bilateral glaucoma (n = 1), diabetes (n = 1), HCV infection (n = 1), missing MRI (n = 1) or MRI-detected meningioma (n = 1). A total of 56 PLHIV-eyes and 56 HUC-eyes were included in the statistical analyses. Participants\u2019 characteristics are summarized in The median CD4+ T-cell nadir was 249 cells/\u03bcL and median CD4/CD8 T-cell ratio was 0.95. All PLHIVs had plVLs <20 copies/mL for 11\u00b14 years and achieved immune recovery on cART, including aviremia and CD4+ T-cell counts >350 cells/\u03bcL for 10\u00b13 years.pRNFL thicknesses, total retinal macular volumes and GCL macular volumes and thicknesses  did not Among the functional parameters , high coAssociations between structural measures and other variables are reported in MRIs did not reveal a lesion that could cause optic neuropathy or trans-synaptic retrograde degeneration within the optic nerves. MRI detected CSVD in 21 (38%) PLHIVs and 14 (25%) HUCs (p = 0.15); it mainly reflected WMHs of presumed vascular origin . Documented CSVD was associated with overall thinner pRNFLs, smaller whole retinal macular volumes and smaller GCL macular volumes for all participants, with HIV status having no significant effect .Our results showed that overall and 4-quadrant  pRNFLs, total retinal macular volumes, GCL macular volumes and EDTRS-grid\u2013defined GCL regional thicknesses were not smaller in long-term\u2013sustained, immunovirologically controlled PLHIVs compared to age- and sex-matched HUCs.Our results agree with those of two studies ,24 that According to Invernizzi et al. , the GCLSignificant overall pRNFL thinning was found in other studies, but affected only PLHIVs with CD4+ T-cell count nadirs <100 cells/\u03bcL for \u22656 months, compared to PLHIVs with nadirs >100 cells/\u03bcL ,22 or HUThe higher frequency of CVSD-surrogate WMHs in aviremic, cART-treated PLHIVs compared to HUCs, not related to any ART classes, was recently reported ,47. We fDespite being the first combined OCT\u2013MRI study in middle-aged, cART-treated PLHIVs with well-sustained immune restoration, our study might suffer from a lack statistical power. Although our study-sample size might be considered relatively small, it is in accordance with previous similar publications  and is sAlthough our series is not representative of the entire HIV+ population, it is representative of PLHIVs receiving care in northern Europe, where >90% are successfully treated . HoweverIn addition to the OCT evaluation of visual pathway structures, most visual evaluation and ocular parameters were similar for PLHIVs and HUCs, with the exception of visual field MDs and IOP. Decreased visual field MD is a classic sign of HIV\u2013NRD but in our study it cannot be explained by pRNFL thinning or decreased GCL macular volume. That decline could however be explained by functional changes without structural damage of the retinal ganglion cells or other cells implicated in vision. Indeed, decreased cone-photoreceptor density in HIV+ participants was found using an adaptive optics camera  and SD-OOur results showed that cART-treated PLHIVs who successfully achieved sustained immunovirological control, even with HIV infection lasting 20 years, do not have pRNFL thinning. That is an optimistic finding in terms of PLHIVs aging. However, in line with recent results from a study on HIV-infected children , as in tS1 Fig1, fovea; 2, parafovea superior; 3, parafovea temporal; 4, parafovea inferior; 5, parafovea nasal; 6, perifovea superior; 7, perifovea temporal; 8, perifovea inferior; and 9, perifovea nasal.(JPG)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 TablePLHIVs, persons living with HIV: HUCs, healthy uninfected controls.(DOCX)Click here for additional data file.S1 File(XLSX)Click here for additional data file."}
+{"text": "Approximately 50% of older adults receiving care at VA are Veterans with chronic pain (V-CP). While physical activity can reduce chronic pain and increase mobility, little is known about group exercise (GE) effects for V-CP. We hypothesized that attrition may limit GE effectiveness. In this study, we retrospectively compared program attrition and participant mobility at three-months of Gerofit GE. At baseline, Older V-CP (N=21) had lower mobility assessment scores  compared to unaffected Veterans. Three-month attrition was higher for older V-CP (54% vs 39%). For those completing three months GE, gains in mobility were similar. We conclude that Veterans with chronic pain are less likely to persist in group exercise but those who persist benefit much like those without pain. Further study is needed to understand successful exercise adherence."}
+{"text": "Motor vehicle crashes represent a significant public health problem. Efforts to improve driving safety are multifaceted, focusing on vehicles, roadways, and drivers with risky driving behaviors playing integral roles in each area. As part of a study to create guidelines for developing risky driving countermeasures, 480 drivers  completed online surveys measuring driving history, risky driving , and psychosocial characteristics. A cluster analysis using frequency of the risky behaviors and seat belt use identified five risky behavior-clusters: 1) rarely/never distracted-rarely/never reckless/aggressive (n=392); 2) sometimes distracted-rarely/never reckless/aggressive (n=33); 3) sometimes distracted-sometimes reckless/aggressive (n=40); 4) often/always distracted-often/always reckless/aggressive (n=11); 5) no pattern (n=4). Older drivers were more likely in the first/lowest cluster . Fifteen older drivers participated in a follow-up study in which their vehicles were equipped with a data acquisition system that collected objective driving and video data of all trips for three weeks. Analysis of video data from 145 older driver trips indicated that older drivers engaged in at least one distracted behavior in 115 (79.3%) trips. While preliminary, this suggests considerably more frequent engagement in distracted driving than self-reported and that older drivers should not be excluded from consideration when developing risky driving behavior countermeasures. Full study results and implications will be presented."}
+{"text": "Approximately 12-18% of family caregivers to older adults in the U.S. are emerging adults (aged 18-25), yet minimal research focuses on this subgroup of caregivers . Although several theories have developed to explain the growing number of emerging adults assuming informal caregiving roles , the reasons why emerging adults become caregivers have not been studied. In the current study, a sample of 248 emerging adult caregivers were asked to describe the circumstances that led to providing unpaid care to an older adult. Using discovery-oriented coding methodology, 11 themes emerged within participants\u2019 responses: care-recipient illness (35.5%), familial relationship (35.5%), care-recipient became dependent (23.8%), proximity (13.7%), only option (10.1%), reciprocal care (8.9%), availability (8.5%), age-related decline (6.9%), monetary restrictions (6.9%), care-recipient desire (6.0%), and community service (4%). Follow-up analyses found that participants who identified familial relationships  were less likely to endorse willingness to provide nursing care in the future compared to those who did not identify familial relationships (p=.032). Participants who identified care-recipient dependency as a circumstance leading to caregiving  were more likely to endorse willingness to provide instrumental (p=.034) and emotional (p=.047) care in the future than those who did not identify care-recipient dependency. These results demonstrate the unique reasons that may lead emerging adults to begin caregiving and how these reasons relate to future willingness to care for an older adult."}
+{"text": "Single-cell RNA sequencing (scRNA-seq) provides high-dimensional measurements of transcript counts in individual cells. However, high assay costs and artifacts associated with analyzing samples across multiple sequencing runs limit the study of large numbers of samples. Sample multiplexing technologies such as MULTI-seq and antibody hashing using single-cell multiplexing kit (SCMK) reagents (BD Biosciences) use sample-specific sequence tags to enable individual samples to be sequenced in a pooled format, markedly lowering per-sample processing and sequencing costs while minimizing technical artifacts. Critically, however, pooling samples could introduce new artifacts, partially negating the benefits of sample multiplexing. In particular, no study to date has evaluated whether pooling peripheral blood mononuclear cells (PBMCs) from unrelated donors under standard scRNA-seq sample preparation conditions  results in significant changes in gene expression resulting from alloreactivity . The ability to demonstrate minimal to no alloreactivity is crucial to avoid confounded data analyses, particularly for cross-sectional studies evaluating changes in immunologic gene signatures.Here, we applied the 10x Genomics scRNA-seq platform to MULTI-seq and/or SCMK-labeled PBMCs from a single donor with and without pooling with PBMCs from unrelated donors for 30\u2009min at 4\u2009\u00b0C. We did not detect any alloreactivity signal between mixed and unmixed PBMCs across a variety of metrics, including alloreactivity marker gene expression in CD4+ T cells, cell type proportion shifts, and global gene expression profile comparisons using Gene Set Enrichment Analysis and Jensen-Shannon Divergence. These results were additionally mirrored in publicly-available scRNA-seq data generated using a similar experimental design. Moreover, we identified confounding gene expression signatures linked to PBMC preparation method , as well as SCMK sample classification biases against activated CD4+ T cells which were recapitulated in two other SCMK-incorporating scRNA-seq datasets.We demonstrate that (i) mixing PBMCs from unrelated donors under standard scRNA-seq sample preparation conditions  does not cause an allogeneic response, and (ii) that Trima apheresis and PBMC sample multiplexing using SCMK reagents can introduce undesirable technical artifacts into scRNA-seq data. Collectively, these observations establish important benchmarks for future cross-sectional immunological scRNA-seq experiments.Supplementary information accompanies this paper at 10.1186/s12915-020-00941-x. By avoiperiment \u201310 or arperiment , 12 genoperiment \u20135  from unrelated donors are pooled during scRNA-seq sample preparation. Co-culturing human leukocyte antigen (HLA) mismatched PBMCs causes a rapid and potent allogeneic response wherein T lymphocytes are stimulated through T cell receptor binding to \u201cnon-self\u201d major and minor histocompatibility complex proteins \u201316. For Here, we performed scRNA-seq using the 10x Genomics platform on PBMC samples isolated from eight unrelated healthy donors pooled under conditions where cells from a single donor were processed in isolation or after donor pooling. Donor identities for each cell were assigned using SCMK and MULTI-seq data, as well as the in silico genotyping pipeline, souporcell . We obseTo assess whether mixing PBMCs from unrelated donors causes alloreactivity during scRNA-seq, we performed a cross-sectional study of PBMCs isolated from 8 unrelated healthy donors Fig.\u00a0. To recoWe first assessed the performance of MULTI-seq and SCMK by comparing the results of three distinct demultiplexing workflows on donor A-H PBMCs from microfluidic lane #3: (i) deMULTIplex, (ii) demuxEM, and (iii) souporcell. deMULTIplex  and demuTo assess whether cells that remained unclassified following SCMK demultiplexing were randomly distributed throughout the scRNA-seq data, we computed the frequency of unclassified cells for each PBMC cell type. This analysis revealed that T lymphocytes and NK cells were especially likely to remain unclassified in SCMK data Fig.\u00a0b. MoreovIt is conceivable that the presence of LMOs and/or sub-optimal SCMK labeling buffer conditions caused the observed classification biases in PBMCs. To address whether LMOs interfere with SCMK labeling, we generated scRNA-seq data where cells from 7 PBMC donors were pooled after labeling with SCMK reagents but not LMOs. As was observed previously, SCMK classifications were similarly biased against T lymphocytes and NK cells  or did not undergo (donors A\u2013C) apheresis using Trima filtration, a method to enhance leukocyte yield during sample preparation , 21. IniTo assess whether mixing PBMCs from unrelated donors induces alloreactivity during multiplexed scRNA-seq, we compared the expression profiles of mixed and unmixed donor A PBMCs. Mapping the densities of mixed and unmixed donor A sample classifications onto PBMC gene expression space Fig.\u00a0a, bottomNext, we focused on CD4+ T cells because of their known involvement in alloreactivity \u201316. MixeExpanding our analysis to other PBMC cell types, we next applied two unbiased approaches to measure any putative allogeneic response signature. First, we used the dissimilarity metric Jensen-Shannon Divergence (JSD)  to compuTo determine the likelihood of observing elevated mixing status JSD scores relative to technical replicates by chance, we repeated this workflow after permuting donor A classifications. Specifically, we reasoned that if permuted JSD scores were greater than the difference between observed mixing status and technical replicate JSD scores, then the observed differences are not significant. To this end, JSD scores after donor A label permutation were larger than the experimental JSD score differential in all cell types except CD14+ classical monocytes Fig. c.The second unbiased approach we utilized to look for allogeneic response signatures was Gene Set Enrichment Analysis (GSEA) , 27. SpeIt is conceivable that the presence of LMOs and antibody-DNA barcodes could delay or block any allogeneic response between PBMCs from unrelated donors. To explore this possibility, we repeated our analytical workflow on a publicly-available scRNA-seq dataset where PBMCs from two unrelated healthy donors were sequenced in isolation and after pooling and incubation on ice for 30\u00a0min . MirroriCollectively, these targeted and unbiased quantitative comparisons across all PBMC cell types in two, independently-generated scRNA-seq datasets demonstrate that mixing PBMCs from unrelated donors under standard multiplexed scRNA-seq sample preparation conditions  does not result in a detectable allogeneic transcriptional response.Sample multiplexing approaches for scRNA-seq are being increasingly utilized by the single-cell genomics field to reduce assay costs while improving data breadth and quality. However, the impact of pooling PBMCs from unrelated donors during scRNA-seq sample preparation on gene expression patterns has not yet been adequately quantified. Here, we used the 10x Genomics scRNA-seq platform to directly compare the gene expression profiles of PBMCs prepared for sequencing alone or after mixing with PBMCs from unrelated donors for 30\u2009min at 4\u2009\u00b0C. We found no evidence of global changes in gene expression profiles in any PBMC cell type (quantified using JSD and GSEA), PBMC cell type proportions, or alloreactivity marker gene expression in CD4+ T cells linked to PBMC mixing status. Although PBMCs actively participating in an allogeneic response were not included in this study, these observations were mirrored in an independently-generated, publicly-available PBMC scRNA-seq dataset , demonstIn addition to the alloreactivity analysis, we found that Trima apheresis can introduce confounding variables into scRNA-seq data, which suggests that this PBMC preparation method should be avoided in future experiments. Moreover, we found that SCMK demultiplexing results were biased against activated CD4+ T cells and other lymphoid cell types. This observation was mirrored in two scRNA-seq datasets generated (i) in the absence of LMOs and (ii) with optimized SCMK antibody-DNA labeling conditions. These findings are in contrast to the original Cell Hashing report , where PCollectively, this study proposes three critical benchmarks for future sample-multiplexed scRNA-seq analyses of PBMCs. First, we demonstrate that alloreactivity can be disregarded as a potential confounder when analyzing scRNA-seq data from PBMCs of unrelated donors pooled under standard multiplexed scRNA-seq sample preparation conditions. These conclusions may not, however, be generalizable to all single-cell genomics assays or sample preparation workflows. Second, we demonstrate that Trima apheresis of PBMCs introduces artifactual gene expression signatures which can confound downstream scRNA-seq data analyses. Third, we demonstrate that SCMK reagents are biased against certain PBMC cell types, which illustrates the importance of validating antibody-based sample multiplexing technology performance.++ and Mg+ free, Corning, Cat#21-031-CV) before counting cells (Nexcelom K2). Live cells were then enriched using a dead-cell removal kit . Live cells were then washed with PBS and labeled with LMOs, as described previously [PBMCs were provided by the Vitalant Research Institute. PBMCs were thawed at 37\u2009\u00b0C and washed one time with warm media , supplemented with 10% FBS  and Benzonase ) and one time with 2% FBS in PBS  to account for the increased probability of random sequencing errors.The same quality-control workflows were applied to the 8-donor  LMO labeling and (ii) SCMK antibody-DNA labeling conditions on SCMK demultiplexing performance. More stringent quality-control steps were not employed because these datasets were not being used to assess alloreactivity gene expression signatures. Briefly, raw gene expression matrices were parsed as described above before the data was log2-transformed, centered, and scaled. Following unsupervised clustering, the top 2000 variable genes (selection.method\u2009=\u2009\u201cvst\u201d) were then used for dimensionality reduction using PCA and UMAP. Finally, low-quality cells were removed as described above. Summary statistics for each dataset following quality-control are as follows:We annotated cell types within each PBMC dataset using literature-supported cell type marker genes , 33, 35 We additionally annotated three CD4+ T cell subsets in the 8-donor , an alternative sample classification pipeline [k\u2009=\u20098) [k\u2009=\u20092), as MULTI-seq/SCMK barcode count matrices were unavailable. For the 2-condition PBMC dataset, classifications were provided from the supplier.For the 8-donor PBMC dataset, cells were classified into donor groups using three different workflows. First, MULTI-seq and SCMK barcode count matrices were fed into the \u201cclassifyCells\u201d and \u201cfindThresh\u201d functions in the deMULTIplex R package . Second,pipeline . Third, p values for donor A cell type proportions. Statistically-significant shifts were never identified between donor A cells from microfluidic lane 1 (A1) and A2/A3 cells, although shifts were detected between A1/A2/A3 and A4, perhaps due to technical variability. This workflow was additionally repeated for CD4+ T cell subsets  vs B2/B3/C2/C3), between mixed and unmixed donor A cells (A1/A4 vs A2/A4), and between technical replicates (A1 vs A4). We then quantified the magnitude of variability due to algorithm performance by repeating this entire workflow after permuting donor A classifications 100 times. Finally, we contextualized the significance of differences in JSD scores associated with mixing status and technical noise via comparison to the average and standard deviation of permuted JSD scores  in Seurat to compute Additional file 1: Figure S1. Analysis of SCMK classification bias on PBMC scRNA-seq datasets  generated without LMOs. Figure S2. Analysis of gene expression signatures associated with Trima apheresis. Figure S3. Analysis of PBMC cell type proportions across different experimental conditions. Figure S4. Analysis of PBMC cell type proportions and gene expression states linked to alloreactivity in Zheng et al. scRNA-seq dataset. Figure S5. scRNA-seq quality-control and cell type annotation workflow, 8-donor PBMC dataset. Figure S6. scRNA-seq quality-control and cell type annotation workflow, Zheng et al. PBMC dataset. Figure S7. CD4+ T-cell subset classification workflow for 8-donor, 7-donor, and Zheng et al. scRNA-seq datasets. Figure S8. PBMC cell type annotation workflow, 7-donor PBMC and resting/stimulated PBMC datasets.Additional file 2: Supplemental Table\u00a01. List of enriched gene sets amongst PBMC cell types as determined by GSEA for 8-donor PBMC scRNA-seq dataset. Supplemental Table\u00a02. List of enriched gene sets amongst PBMC cell types as determined by GSEA for Zheng et al. PBMC scRNA-seq dataset."}
+{"text": "P = 0.002], and de-novo AML  were independently associated with a favorable response. Patients who attained a complete remission had a median survival of 43.7 months compared with 5.2 months for refractory patients (p < 0.0001). Neither the FLT3-ITD and NPM1 mutational status nor the indication for salvage therapy significantly impacted on the response to HiDAC/MITO salvage. NGS analysis identified 20 different mutations across the myeloid gene spectrum with a distinct TP53 signature detected in non-responding patients. HiDAC/MITO is an effective salvage regimen in R/R AML, however patients with adverse cytogenetics or secondary disease may not benefit as much from this approach.A substantial segment of patients with acute myeloid leukemia (AML) will relapse following an initial response to induction therapy or will prove to be primary refractory. High-dose cytarabine and mitoxantrone (HiDAC/MITO) is an established salvage therapy for these patients. We studied all adult patients with relapsed/refractory (R/R) AML who were treated with HiDAC/MITO in our center between the years 2008-2017. To determine whether responding patients harbored a unique molecular signature, we performed targeted next-generation sequencing (NGS) on a subset of patients. The study cohort consisted of 172 patients with a median age of 54 years (range 18\u201377). The composite complete remission rate was 58%; 11 patients (6%) died during salvage therapy. Median survival was 11.4 months with a 1-year survival rate of 48%. In multivariate analysis favorable risk cytogenetics [Odds ratio (OR)=0.34, confidence interval (CI) 95%, 0.17\u20130.68;  FLT3-ITD ) or thrombocytopenia  ) . InductiUsing bone marrow samples obtained at the time of diagnosis we performed targeted next-generation sequencing (NGS) of 54 myeloid cancer associated genes with the Illumina TruSight Myeloid Sequencing Panel, following the manufacturer\u2019s protocol. Briefly, high quality DNA was extracted using the QIAcube . DNA concentration was measured by Qubit Fluorometric Quantitation . The NGS libraries were sequenced on an Illumina MiSeq System . Reads were aligned to the human reference genome version 19 (hg19) to create BAM files. The somatic variant caller was then performed for variant analysis of the specific regions in the manifest. Single nucleotide variants (SNVs) and insertions-deletions (indels) at diagnosis were analyzed using the Illumina MiSeq Reporter software and subsequently with Ingenuity software (Qiagen). Variant allele frequencies (VAF) of mutations were calculated as the ratio between the number of mutant and total reads."}
+{"text": "C. elegans genome engineering. Following the discovery that the Drosophila mariner element Mos1 could mobilize in the C. elegans germline , tools for efficient Mos1-mediated transgene insertion have been developed and widely adopted (Robert and Bessereau 2010). In parallel, the establishment of effective antibiotic selection in C. elegans offered increased versatility for genetic crosses and the advantage of injecting into phenotypically wild-type animals .Insertion of single-copy transgenes is an important tool in Mos1-mediated single-copy insertion (mosSCI) system is a toolkit of choice for this approach . The ttTi5605(mos1)II insertion site in particular has been used for stable germline expression, and plasmids targeting ttTi5605 are also compatible with the \u2018universal\u2019 mosSCI insertion sites .Reliable, site-specific, single-copy transgene insertion remains a key technique for applications such as synthetic reporters and rapid testing of genetic rescue constructs, especially when germline expression is required. The highly developed ttTi5605, we constructed two modified mosSCI plasmids , however existing ttTi5605-mosSCI plasmids use unc-119(+) selection. Our plasmid allows use of the ttTi5605 site without the need for injection into unc-119(ed3) mutants, which are more challenging to grow than wild-type animals and do not have optimal germline health on standard E. coli OP50 as a food source.To add to the suite of tools for targeting plasmids . First, unc-119 selection-based ttTi5605-mosSCI plasmid (pCFJ151) by adding loxP recombination sites flanking the unc-119(+) selection cassette (unc-119(+) selection cassette using an existing Cre recombinase protocol . Since unc-119(+) is a frequently used selection marker, this new feature will add flexibility for construction of strains with multiple transgenes.Second, we modified the standard cassette . This chet al. 2009). We performed three independent test injections using different transgenes and found both of our plasmids to be effective for mosSCI (unc-119(+) cassette (unc-119(+) excision, which can be easily screened for using a visible phenotype, excision of NeoR would require screening by PCR or by loss of drug resistance. Overall, we hope that these excisable unc-119(+) and NeoR mosSCI plasmids will be useful companions to the extensive mosSCI plasmid and strain toolkit .For increased versatility, both of the plasmids described here are minimal and do not encode additional tags or fluorescent proteins. Multiple-fragment transgenes can be seamlessly fused and cloned into these plasmids using the Gibson isothermal assembly technique by designing PCR amplicons, synthetic dsDNAs, restriction fragments or oligos with overlapping homologous ends  was constructed in two steps from pCFJ151 (Addgene # 19330). Briefly, the C. briggsae unc-119(+) selection cassette was removed, leaving a modified minimal multiple cloning site (MCS) between the ttTi5605 insertion homology arms. A PCR amplicon containing C. br. unc-119(+) flanked by loxP sites was cloned into the BssHII(PteI)/BglII sites. To construct plasmid pALS297 , the loxP::C. br. unc-119(+)::loxP selection cassette was excised from pALS186 by BssHII(PteI)/BglII digestion and replaced by an MluI/BglII-digested PCR amplicon containing the NeoR selection cassette flanked by loxP sites. The NeoR selection cassette (Prps-27::NeoR::unc-54-3\u02b9utr) was amplified from pCFJ910 (Addgene # 44481).unc-119(ed3) allele. Segregation of unc-119(ed3) was followed by the unc phenotype. The ttTi5605(mos1) insertion site was followed using a three-oligo PCR  modified from the Wormbuilder site (http://www.wormbuilder.org/) to simultaneously amplify the ~720 bp product from the mos1 insertion allele and the 455 bp product from the wild-type allele. PCRs were performed with DreamTaq Green 2X PCR Mastermix (Thermo #K1081) using 1 uL of single worm lysate in a 20 uL reaction at an annealing temperature of 57\u00b0C.To create strain ALS344, strain EG6699  was backcrossed 4X to wild-type N2 animals to remove the Cloning transgenes into mosSCI plasmids. Transgenes of interest were assembled from multiple PCR amplicons with ~20 nucleotide overlapping ends into mosSCI plasmids by Gibson Isothermal assembly  using a home-made enzyme mix or a kit (NEB #E2621S). For assembly into AvrII(XmaJI)/XhoI-digested pALS297 or pALS186, the first fragment of the transgene is amplified using the forward primer op297-p186AvrIIF (Table 1) and a transgene-specific reverse primer. The last fragment of the transgene is amplified using a transgene-specific forward primer and the reverse primer op297XhoIR or op186XhoIR (Table 1) for assembly into pALS297 or pALS186, respectively.Microinjection and screening. Worm mosSCI transgenesis was performed according to the direct injection protocol  as described in detail on the Wormbuilder site (http://www.wormbuilder.org/). Transgene-containing mosSCI plasmids were purified by ZymoPURE plasmid miniprep (Zymo #D4209). Co-injected plasmids were purified by HiSpeed Plasmid Midi kit (Qiagen #12643). For unc-119(+)selection, plasmids were injected into strain EG6699 , which was grown on E. coli HB101. For NeoRselection, plasmids were injected into strain ALS344 (Table 1) and G418 was added to plates the day after injection as described  (125 uL of 25 mg/mL G418 per 35 mm plate).Following heat-shock and counter-selection for co-injection markers, inserts were verified by PCR using pairs of primers where one primer hybridized to genomic DNA flanking the insertion site and outside of the vector homology arms  and the second primer hybridized either within the transgene or selection cassette (Table 1). Amplification was carried out using either DreamTaq Green 2X PCR Mastermix  or Phusion polymerase , respectively, according to the manufacturer\u2019s instructions in 20 uL reactions containing 1 uL of a 6uL single worm lysate as the template.Excision of the unc-119(+) selection cassette. The C. br. unc-119(+) selection cassette was excised using Cre recombinase as described  using pDD104 . Briefly, 15-20 animals were injected and moved onto 5-6 plates (3 P0 worms/plate). Approximately 15 F1 animals expressing the mCherry co-injection marker were singled. From the progeny of these animals, unc F2 animals were singled to establish excised lines. At least two independent lines were recovered from each of two independent trials. Cre-mediated excision of the NeoR selection cassette has not been tested.Table 1: List of plasmids, strains and oligonucleotides. Oligonucleotides with NM or JL designations were described by or adapted from Dr. M. Nonet (Washington University School of Medicine in St. Louis) or Dr. J. L. Bessereau (Universit\u00e9de Lyon), respectively, based on protocols referenced on the Wormbuilder site (http://www.wormbuilder.org/). *, N20-22  represents 20-22 transgene-specific nucleotides."}
+{"text": "Chenopodium quinoa) have been developed because seeds high in saponins taste bitter. The aim of this study was to elucidate the role of saponin in resistance of quinoa to Cucumber mosaic virus (CMV). Differential gene expression was studied in time-series study of CMV infection. High-throughput transcriptome sequence data were obtained from 36 samples (3 varieties \u00d7 +/- CMV \u00d7 1 or 4 days after inoculation \u00d7 3 replicates). Translation, lipid, nitrogen, amino acid metabolism, and mono- and sesquiterpenoid biosynthesis genes were upregulated in CMV infections. In \u2018Red Head\u2019 (bitter), CMV-induced systemic symptoms were concurrent with downregulation of a key saponin biosynthesis gene, TSARL1, four days after inoculation. In local lesion responses (sweet and semi-sweet), TSARL1 levels remained up-regulated. Known microRNAs (miRNA) (81) from 11 miR families and 876 predicted novel miRNAs were identified. Differentially expressed miRNA and short interfering RNA clusters (24nt) induced by CMV infection are predicted to target genomic and intergenic regions enriched in repetitive elements. This is the first report of integrated RNASeq and sRNASeq data in quinoa-virus interactions and provides comprehensive understanding of involved genes, non-coding regions, and biological pathways in virus resistance.Saponins are secondary metabolites with antiviral properties. Low saponin (sweet) varieties of quinoa ( Chenopodium quinoa Willd.) is a pseudocereal crop with high nutritional value . Samples times were chosen because in preliminary studies, no symptoms were observed at 24 h and symptom development typically began by Day 4 (data not shown). Excised leaf samples were immediately frozen in liquid nitrogen and kept at -80\u00b0C until RNA extraction. To verify successful inoculation, virus- and mock-inoculated tissues were tested by CMV AgriStrips  according to manufacturer\u2019s instruction.Seed from three arieties , \u2018JessieTotal RNA was extracted from individual samples by Direct-zol RNA MiniPrep Plus kit  according to manufacturer\u2019s protocol. Concentration of DNA-digested RNAs was measured by NanoDrop\u2122 One Microvolume UV-Vis Spectrophotometer . The cDNA library preparation for RNASeq and small RNASeq, and sequencing on illumina HiSeq 4000 was performed by GENEWIZ .C. quinoa reference transcripts by Salmon v0.12.0 -2way\u201d means individual variety-specific model while considering time and treatment effect, whereas \u201cVariety--treatment means individual variety-specific model by considering main effect of treatment only. upregulated and downregulated indicates comparison of CMV-inoculated and mock-inoculated samples.(XLSX)Click here for additional data file.S4 TableFor tab descriptions refer to (XLSX)Click here for additional data file.S5 Table(XLSX)Click here for additional data file.S6 TableSince characterization of DEmiRNA was followed as the DEGs from RNASeq, thus, for description of the tabs refer to (XLSX)Click here for additional data file.S7 TableGenome coordination, length, number of reads mapped in million (RPM), unique reads, cleaved sizes, and abundance of cleaved nucleotide of the clusters are shown.(TXT)Click here for additional data file.S8 Table(XLSX)Click here for additional data file.S9 TableFor tab descriptions refer to (XLSX)Click here for additional data file."}
+{"text": "It was highlighted that the original article  containeIncorrect sentenceThe same search of 970 million PubChem fingerprints averages 220\u00a0ms/query, making chemfp one of the fastest CPU-based similarity search implementations.Correct sentenceThe same search of 97 million PubChem fingerprints averages 220 ms/ query, making chemfp one of the fastest CPU-based similarity search implementations."}
+{"text": "PD-L1) expression, and higher tumor mutation burden (TMB). The high-risk subtype also harbored significantly elevated cell cycle modulators CDK4/CDK6 and TP53 mutation. These observations were validated in 9 independent LUAD cohorts. Our findings suggest that immune checkpoint blockade therapy may be efficacious for high-risk subtype of LUAD patients.Immune checkpoint blockade (ICB) therapies have revolutionized the treatment of human cancers including lung adenocarcinoma (LUAD). However, our understanding of the immune subtyping of LUAD and its association with clinical response of immune checkpoint inhibitor remains incomplete. Here we performed molecular subtyping and association analysis of LUAD from the Cancer Genome Atlas (TCGA) and validated findings from TCGA cohort in 9 independent validation cohorts. We conducted consensus molecular subtyping with nonnegative matrix factorization (NMF). Potential response of ICB therapy was estimated with Tumor Immune Dysfunction and Exclusion (TIDE) algorithm. We identified 2 distinct subtypes of LUAD in TCGA cohort that were characterized by significantly different survival outcomes . The high-risk subtype was featured by lower TIDE score, upregulation of programmed death-ligand 1 ( Lung adenocarcinoma (LUAD) is a leading cause of cancer related death worldwide and accounts for about 40% of lung cancer patients . Over thProgrammed cell death protein 1/programmed cell death-ligand 1 (PD-1/PD-L1) axis is a critical immune checkpoint pathway that could downregulate response of immune system in lung cancer . EnhanceTumor mutation burden (TMB) is an indicator implicated in better response to ICB treatment, which is independent of PD-L1 expression level , 11. An Tumor Immune Dysfunction and Exclusion (TIDE) algorithm is a computational method using gene expression profile to predict the ICB response in NSCLC and melanoma . TIDE usIn this study, we performed consensus clustering analysis for LUAD based on immune gene expression signatures and identified 2 subtypes. These 2 subtypes were characterized by significantly different survival outcomes , TIDE scores, PD-L1 expression, TMB and enrichment of cell cycle signaling. The high-risk subtype is presumably efficacious towards ICB treatment.n = 502). Using this 433-gene panel, we identified 2 distinct LUAD subtypes  was compiled, 433 of which were significantly associated with overall survival  showed a consistent trend although did not reach statistical significance  in TCGA LUAD cohort . TP53, NPD-L1 expression and higher TMB. Pathway analysis suggested that high-risk group was featured by activated cell cycle signaling. TP53 mutation was more frequently mutated in the high-risk subtype.We uncovered 2 prognostic subtypes of LUAD by analyzing 2,300 LUAD samples from TCGA LUAD cohort and 9 independent validation cohorts. The high-risk subtype has significantly lower TIDE score, higher n = 85) as compared with the other LUAD cohorts. These findings suggested that patients of high-risk subtype may be more sensitive to ICB treatmentWe observed that TIDE score was significantly lower in high-risk subtype than low-risk subtype via univariate regression analysis in TCGA LUAD cohort and 9 validation cohorts. The difference remained statistically significant in multivariate analysis among these cohorts except GSE30219, this is probably due to smaller sample size of GSE30219 cohort  and 1,798 samples from 9 cohorts in Gene Expression Omnibus (GEO) repository (https://www.ncbi.nlm.nih.gov/geo/) (We collected gene expression profiles of 502 LUAD samples from TCGA-LUAD cohort (ov/geo/) . In totaov/geo/) . We alsoR package caret (version 6.0-82).We obtained 2,995 immune-related genes from 160 immune signatures curated in the TCGA pan-cancer immune landscape project , which wA that contained prognostically significant immune-related genes aforementioned. Matrix A was factorized into 2 nonnegative matrices W and H . Repeated factorization of matrix A was performed and its outputs were aggregated to obtain consensus clustering of LUAD samples. The optimal number of subtypes was selected according to cophenetic, dispersion, and silhouette coefficients [R package NMF (version 0.21.0) [R code was available in Supplementary Materials and Methods.We used nonnegative matrix factorization (NMF) to perform molecular subtyping , 56. Speficients . The con 0.21.0) . The NMF 0.21.0) . The R cPotential ICB response was predicted with TIDE algorithm .R package limma (version 3.38.3) [DESeq2 (version 1.22.2) [t statistics for microarray and RNA sequencing data. We used t statistic as input to R function fgsea that implemented in fgsea package (version 1.6.0) to perform gene set enrichment analysis (GSEA). Signaling pathways in Molecular Signatures Database (MSigDB) were used in GSEA [The  3.38.3)  and DESe 1.22.2)  were use in GSEA .Significantly mutated genes (SMGs) were identified using MutSigCV algorithm . The sigR software 3.5.1 was applied in this study for the statistical analyses. Univariate and multivariate Cox proportional hazards model were used to analyze the association between subtypes and prognosis with Rsurvival package. Survival curve was drawn with Kaplan-Meier method and Log-rank test was used to evaluate difference between survival curves. Association between mutation rate of SMGs and 2 subtypes was evaluated by Fisher\u2019s exact test. Multivariate logistic regression was performed to test the association between SMGs and identified LUAD subtypes by taking into account confounding factors. The continuous and categorical variables between 2 subtypes were compared using two-sided Wilcoxon rank-sum test and chi-square test, respectively. Benjamini-Hochberg method was used to adjust for multiple hypothesis testing [ testing .Supplementary MaterialsSupplementary FiguresSupplementary TablesSupplementary Table 1"}
+{"text": "In previous studies, caregiver (CG) stress, substance use, poor physical health, poor mental health, financial problems, and social isolation have been associated with increased risk of elder mistreatment (EM) for older care recipients (CR). This study aimed to assess how the COVID-19 pandemic has impacted these CG-related risk factors for EM in a community sample of CGs. A non-probability sample of 433 CGs caring for adult CRs age \u226560 years with physical (76%), cognitive (34%) and mental health (14%) conditions completed a survey on COVID-19 impacts in April-May 2020. CGs had mean age 61 (range 21 \u2013 91), were 75% female and 92% non-Hispanic White. Over 40% of CGs reported doing worse financially since COVID-19. Compared to before COVID-19, 15% reported drinking more alcohol and 64% reported somewhat or greatly increased feelings of social isolation and loneliness. CGs reported that COVID-19 had made caregiving more physically (18.7%), emotionally (48.5%) and financially (14.5%) difficult, interfered with their own healthcare (19%), and led to family conflict over caring for CR (13.2%). Younger CGs (age <65) and those with annual income <$50,000 were more likely to report negative COVID-19 impacts. This study suggests CGs of older adults may be experiencing increased stress, alcohol use, social isolation and negative impacts on their own health and financial situation. Healthcare and social service providers should assess for these EM risk-factors in caregivers and connect them and their care recipients with resources and services to address these stressors to reduce risk of EM during the COVID-19 pandemic."}
+{"text": "EWSR1-FLI1, is toxic or unstable in most primary tissues. Consequently, attempts to model Ewing sarcomagenesis have proven unsuccessful thus far, highlighting the need to identify the cellular features which permit stable EWSR1-FLI1 expression. By re-analyzing publicly available RNA-Sequencing data with manifold learning techniques, we uncovered a group of Ewing-like tissues belonging to a developmental trajectory between pluripotent, neuroectodermal, and mesodermal cell states. Furthermore, we demonstrated that EWSR1-FLI1 expression levels control the activation of these developmental trajectories within Ewing sarcoma cells. Subsequent analysis and experimental validation demonstrated that the capability to resolve R-loops and mitigate replication stress are probable prerequisites for stable EWSR1-FLI1 expression in primary tissues. Taken together, our results demonstrate how EWSR1-FLI1 hijacks developmental gene programs and advances our understanding of Ewing sarcomagenesis.Ewing sarcoma is an aggressive pediatric cancer of enigmatic cellular origins typically resulting from a single translocation event t  . The resulting fusion gene,  EWSR1) to Friend leukemia integration 1 transcription factor (FLI1) (85%) or E-twenty-six-related (ETS-related) gene (ERG) (15%) . Fi. Fi44]. ble here .t test with an alternative hypothesis of \u201cgreater\u201d implemented via the stat_compare_means function of the ggpubr package. Finally, the peaks which passed q value filtering were overlapped to create a consensus peak set for each cell type using the findOverlapsOfPeaks function of the ChIPpeakAnno package v3.20.0. Then the consensus peak sets for iPSCs and MSCs were overlapped and plotted.ssDRIP-Seq (strand-specific DNA : RNA immuno-precipitation sequencing) data was obtained from a recently published public repository . Publicly available data sets used in this study are listed in Recent years have yielded powerful insights into the molecular mechanisms by which EWSR1-FLI1 controls gene expression and cellular behavior. However, it is still unclear what cellular characteristics are required for stable EWSR1-FLI1 expression in primary tissues. Consequently, successful spontaneous models of Ewing sarcoma do not yet exist. To address this gap in knowledge, we mined publicly available transcriptomic profiles of Ewing sarcoma and normal tissue types. This allowed us to identify a population of Ewing-like normal tissues belonging to developmental processes such as gastrulation. Additional analysis and experimental validation revealed stable expression of EWSR1-FLI1 likely requires factors which resolve R-loops and replication stress. Taken together, our findings suggest that Ewing sarcomagenesis likely occurs in tissues which already tolerate high proliferation and transcriptional activity because of their capacity for resolving R-loops and mitigating replication stress."}
+{"text": "Exertional heat stroke (EHS) is a life-threatening medical condition involving thermoregulatory failure and is the most severe condition along a continuum of heat-related illnesses. Current EHS policy guidance principally advocates a thermoregulatory management approach, despite growing recognition that gastrointestinal (GI) microbial translocation contributes to disease pathophysiology. Contemporary research has focused to understand the relevance of GI barrier integrity and strategies to maintain it during periods of exertional-heat stress. GI barrier integrity can be assessed non-invasively using a variety of in vivo techniques, including active inert mixed-weight molecular probe recovery tests and passive biomarkers indicative of GI structural integrity loss or microbial translocation. Strenuous exercise is strongly characterised to disrupt GI barrier integrity, and aspects of this response correlate with the corresponding magnitude of thermal strain. The aetiology of GI barrier integrity loss following exertional-heat stress is poorly understood, though may directly relate to localised hyperthermia, splanchnic hypoperfusion-mediated ischemic injury, and neuroendocrine-immune alterations. Nutritional countermeasures to maintain GI barrier integrity following exertional-heat stress provide a promising approach to mitigate EHS. The focus of this review is to evaluate: (1) the GI paradigm of exertional heat stroke; (2) techniques to assess GI barrier integrity; (3) typical GI barrier integrity responses to exertional-heat stress; (4) the aetiology of GI barrier integrity loss following exertional-heat stress; and (5) nutritional countermeasures to maintain GI barrier integrity in response to exertional-heat stress. Whilst classic heat stroke (CHS) primarily impacts incapacitated individuals  whose thermoregulatory responses are insufficient to compensate against increased ambient temperatures  or D-mannitol [182 kDa] ~1\u20132 g) that freely transverses the GI tract transcellularly independent of barrier integrity ) versus mild hyperthermic (30 \u00b0C/35% RH) conditions resulted in comparable DSAT responses  strain . Later st e.g., ,110,111),1112max)% e.g., ,115,116),1162max)% e.g., ,118; and; and2max% e.g., ,122,123.,123.2max% . Howeve 38.4 \u00b0C ). A follmax) in temperate conditions (~22 \u00b0C), which was sufficiently intense to induce detectable small intestinal barrier integrity loss using the DSAT. Similarly, gastroduodenal integrity, measured using a single sugar-probe (sucrose) has been shown to be unaltered following one hour of moderate intensity treadmill running (40\u201380% VO2max) in temperate conditions  CHO intake) to improve CHO tolerance during exercise does not appear to strengthen the GI barrier ; from three strains) blunted DSAT ratios (8%) and circulating endotoxin concentrations (~12%) following a ~35-min fatiguing run (80% ventilatory threshold) in the heat (35 \u00b0C/40% RH) [11 CFU\u00b7day Lactobacillus Casei) was associated with an increased rise in endotoxin concentrations, compared with placebo, following two hours moderate-intensity running (60% VO2max) in the heat (34 \u00b0C/32% RH) [9 CFU Bifidobacterium longum) had no effect on resting endotoxin concentrations following six weeks of pre-season training in collegiate swimmers [9 CFU; from five strains) had no influence on either DSAT, I-FABP or sCD14 responses following a simulated 42.2 km marathon in temperate conditions [8 CFU Lactobacillus Salivarius) had no influence on DSAT responses, , following two hours of moderate intensity running (60% VO2max) in temperate conditions [Probiotic supplementation is increasingly popular in athletic populations, despite inconsistent effects of their use for either maintaining immune health or improving exercise performance . With re/40% RH) . A follo/40% RH) . In cont/32% RH) . Similarswimmers . Likewisnditions . Finallynditions . It is uThe present data indicate that probiotic supplementation has little for supporting GI barrier integrity in response to exercise. It is not possible to elucidate whether inconsistent responses are attributable to the specific probiotic strain, duration of supplementation or another factor. Future research is required to develop probiotic supplementation regimes and will need to address factors such as strain(s), timing and dose. It will also be necessary to verify potential efficacy using relevant exercise (heat stress) protocols. Global metabolomics approaches have linked exercise-induced GI barrier function loss with alterations in GI microbiota composition during a four-day military arctic training exercise , and suPolyphenols are natural compounds that defend plants against damage from radiation and pathogens. Over 8000 polyphenols have been identified, which are classified into four major groups: flavonoids; phenolic acids; stilbenes; and lignans. Quercetin is the most abundant dietary flavonoid polyphenol , and in \u22121 in 46 \u00b0C/20% RH) heat acclimation regime was assessed [2max) in the heat .There are no practical recommendations supporting polyphenol use to protect the GI tract during strenuous exercise. Despite promising in vitro observations, more work is required to determine the optimal formulation, time-course and polyphenol dose to support GI barrier function across different exercise-modalities. No studies have successfully measured the effect of polyphenols on secondary GI MT post-exercise and clearly future studies should attempt to control for dietary polyphenol intake.L-carnosine [L-carnosine is a cytoplasmic dipeptide of beta-alanine and L-histidine [\u22121) with a patented zinc amino-acid complex animal feed, reduced GI MT  during 12\u201314 h of cyclic heat stress [\u22121) on other livestock  when raised under cyclic heat stress [Zinc-Carnosine (ZnC) is a pharmaceutical chelate of zinc and arnosine . It is warnosine , and morarnosine . Zinc isarnosine , whilst istidine . Daily Zistidine ,291. Theistidine . In vitristidine ,294 and istidine  upon damt stress ,296. Simt stress ,298. Mect stress ; antioxit stress ; and stat stress .\u22121) to prevent deficiencies, and to supplement with large oral doses (~75 mg\u00b7day\u22121), when suffering from acute upper respiratory tract infection to accelerate recovery [L-Carnosine supplementation is uncommon, supplementing \u03b2-alanine (~65 mg\u00b7kg\u00b7day\u22121) the rate-limiting precursor for muscle L-carnosine synthesis, has been shown to increase muscle carnosine stores [\u22121) attenuated a 3-fold rise is DSAT ratio by 70% after short-duration (20 min) high-intensity running (80% VO2max) [\u22121 for 14 days) in the same study, and when the two-treatments were combined the benefits appeared synergistic (85% reduction DSAT ratio). Furthermore, the combination of ZnC and BC blunted the exercise-induced increase in DSAT ratio by 30% after only two-days, whilst no protection was offered by either ingredient alone at this point [No guidelines exist concerning ZnC supplementation in athletic populations. Athletes are recommended to ensure sufficient dietary zinc ingestion (EU RDA = 10 mg\u00b7dayrecovery . Though e stores . To date VO2max) . This efis point .\u22121 for 14 days to protect the GI tract during moderately demanding exercise. Further work is needed to substantiate existing findings and verify the potential benefits of ZnC during more strenuous exercise. No studies have successfully measured the influence of ZnC on secondary GI MT post-exercise. Research is required to determine the optimal time-course and dose of ZnC to support GI barrier function with chronic and acute supplementation. Larger doses of ZnC (150 mg\u00b7day\u22121) appear well-tolerated in GI disease patients in the short-term [\u22121) appears to prevent zinc inhibiting copper absorption [Practical recommendations support ZnC use at a dose of 75 mg\u00b7dayort-term , and dosort-term . Co-ingesorption .Investigation of nutritional countermeasures that support GI barrier integrity during strenuous exercise is an important and expanding area of research. Preliminary observations indicate that some diet regimens and dietary supplements could benefit exercising populations. Optimal supplementation strategies should be safe, well-tolerated, practical , fast acting and effective in a wide range of scenarios . It is also important that they are without secondary adverse responses, especially those relating to skeletal muscle adaptation, thermoregulation, immune function, bone health etc. Whilst there are numerous examples of well-conducted studies reporting beneficial effects from diet regimens and individual supplements on GI barrier integrity, it is currently not possible to provide definitive guidance. In part this is due to limitations and variations in study designs and in some instance\u2019s incomplete characterisation of the bioactive nutrients.Future research should address diet regimens/nutritional supplements that satisfy the above requirements when tested in the most demanding scenarios . It would appear very worthwhile to assess the synergy between ingredients that maintain GI integrity, especially if they are considered to act via different biochemical pathways. Further supplements that warrant future exploration include: omega-3 polyunsaturated fatty acids ; vitaminFrom a methodological perspective, it is recommended that future studies assess a battery of relevant GI barrier integrity markers  and monitor alterations in the proposed mechanistic pathways  underpinning any functional benefits. Key extraneous variables should be controlled, including: prandial state ; hydratiEHS is a life-threatening disease involving thermoregulatory failure, which sporadically arises in otherwise healthy individuals following performance of strenuous exercise or occupationally arduous tasks. Current EHS management policy primarily takes a thermoregulatory management approach despite evidence of MT following loss of GI barrier integrity being an important process in the disease pathophysiology. A range of techniques are available to assess GI barrier integrity in vivo, and a battery approach monitoring multiple measures in both field and research settings is recommended. The severity of GI barrier integrity loss following exertional-heat stress appears to be intensity and duration-dependent, with thermoregulatory strain being an additional risk factor. Considerations for the specific GI barrier integrity assessment technique must be made when interpreting individual study\u2019s conclusions, whereby I-FABP responses typically provided the greatest sensitivity. The specific aetiology of exertional-heat stress induced GI barrier integrity loss is poorly defined, but likely relates to the direct effects of localised hyperthermia, ischemia-reperfusion injury and neuroendocrine-immune alterations.\u22121 liquid multi-transportable CHO), and acute L-glutamine ingestion two hours pre-exercise (0.25\u20130.9 g\u00b7kg\u00b7FFM\u22121). Benefits from BC, and probiotics likely relate to the specific supplement formulation, and hence require further investigation. Despite a sound rationale for the use of NO precursors and polyphenols to limit exercise-induced GI barrier integrity loss, substantive supporting evidence is currently absent. ZnC requires further verification, where short-term (1\u20133 days) high-dose supplementation appears an attractive consideration. Further well-controlled research in nascent areas could elucidate potential treatment options for exercise-induced GI barrier integrity loss.A range of nutritional countermeasures have been shown to positively affect GI barrier integrity following strenuous exercise and exercise-heat stress. However, despite rapid advancements in this field, definitive recommendations cannot be provided due to the heterogeneity of experimental designs. Nevertheless, promising effects have been associated with following general sports nutrition CHO supplementation guidelines during exercise (30\u2013100 g\u00b7h"}
+{"text": "The US federal government mandates nursing homes (NHs) provide preference-based, person-centered care for residents. Yet only 2% of NHs successfully implement person-centered care. The Care Preference Assessment of Satisfaction (ComPASS) is a 16-item tool that facilitates residents\u2019 preference fulfillment . This study examines barriers/facilitators to preference fulfillment from the perspective of residents who completed ComPASS. Secondary data analysis from an R21 (NR011334-01) provided qualitative data from 196 residents across 28 NHs on why residents were satisfied (or not) with the fulfillment of their individual preferences. Most residents were female (70.4%) and white (80.1%) with a range of cognitive/physical abilities. Content analysis revealed six thematic codes classifying barriers/facilitators to preference fulfillment: resident agency, values, and physical characteristics; social support systems; staff competence; communication success; built environment; access to resources. Discussion will include implications for ameliorating barriers to preference fulfillment while meeting government mandates. Part of a symposium sponsored by the Research in Quality of Care Interest Group."}
+{"text": "Declining energy may indicate homeostatic dysregulation and predict adverse health outcomes. We hypothesized that declining energy would predict greater frailty (1-10), greater mortality, and faster mood (CES-D) and cognition (3MS) decline over time. This observational cohort studies included 2,443 older adults  from the Health ABC Study with up to eight years of data. Energy was assessed using a single-item question about prior month\u2019s energy . We used linear mixed models to create energy change scores . In regression models adjusting for baseline outcome performance and energy and demographics, declining energy predicted greater frailty , greater mortality , and faster CES-D  but not 3MS decline. Energy changes are easy to assess and predict clinically-relevant outcomes. Future work should consider mechanisms of declining energy on disability-related outcomes. Part of a symposium sponsored by Brain Interest Group."}
+{"text": "Risk stratification in dilated cardiomyopathy (CMX) patients with advanced heart failure remains a growing clinical challenge. A simple manner to non-invasively risk stratify this difficult cohort would have obvious advantages.Utilizing cardiovascular MRI (CMR), recently demonstrated to identify abnormal myocardial substrate, typically infarct or more recently infiltrative pathology via the delayed hyperenhancement technique (DHE), we hypothesize that +DHE will represent an adverse prognosis as defined by need for urgent cardiac transplantation (TX), LVAD or death in a dilated cardiomyopathy patients.Over 24 consecutive months, 13 patients with a dilated CMX and NYHA class III-IV heart failure underwent standard 3D CMR  to interrogate the pattern, distribution and extent of DHE . Patients were categorized into: 1) + DHE/+midwall Stripe 2) +DHE/-midwall Stripe and 3) -DHE/-Stripe. LVAD, Tx need, major adverse clinical events (MACE) and event free survival were evaluated over the next 6 months.2 = 5, p < 0.05). Specifically, all 5 pts requiring LVAD and/or urgent Tx by 6 months had +DHE/+Stripe while no -DHE/-Stripe pts experienced the need for LVAD or urgent Tx. Similarly, a +DHE/+Stripe strongly predicted MACE . Any +DHE pt with + or -Stripe, in general, predicted a more egregious course, meeting a MACE, worsening LVEF, or non-improved/worsening NYHA class. No -DHE/-Stripe patient had a major adverse clinical event, see Table All patients were alive at 6 months for folow-up while 5 required Tx. All pts completed the CMR exam in 50 \u00b1 10 minutes. Of 11/13 pts (85%) with +DHE, 9/11 pts (82%) had +Stripe and 2/13 pts were -DHE/-Stripe. DHE/Stripe categorization positively strongly correlated with NYHA class  while only weakly correlating with 3D LVEF  and EDV . However, DHE/Stripe categorization strongly predicted the need for LVAD and/or urgent Tx surgery over the ensuing 6 months (X+DHE/+Stripe is highly predictive of LVAD and Tx need over the ensuing 6 months. Those +DHE/-Stripe patients have intermediate risk but no LVAD/Tx use, while those -DHE/-Stripe have a good prognosis. Thus, incorporating this approach into routine clinical practice may help manage CMX patients more expectantly and effectively.CMX patients with advanced heart failure require an improved risk stratification policy. We believe this observation represents the first attempt to risk stratfiy systematically for those with a dilated CMX. Specifically, a simple observation of the binary nature of DHE/Stripe predicated early morbidity and mortality. Herein, using standard CMR, the presence of"}
+{"text": "Scientific Reports 10.1038/s41598-018-28986-7, published online 17 July 2018Correction to: This Article contains an error in the Acknowledgements section, where\u201cSequencing datasets generated for this study have been submitted to Gene Expression Omnibus (GEO) repository (accession number GSE888888).\u201dshould read:\u201cSequencing datasets generated for this study have been submitted to Gene Expression Omnibus (GEO) repository (accession number GSE88888).\u201d"}
+{"text": "Using time-lapse imaging and RNAseq, we found that the differences in anthracycline cardiotoxicity are closely linked to extent of cardiomyocyte uptake and magnitude of activation/inhibition of several cellular pathways such as death receptor signaling, ROS production, and dysregulation of calcium signaling. The results provide molecular insights into anthracycline cardiac interactions and offer a novel assay system to more robustly assess potential cardiotoxicity during drug development.Anthracyclines are a class of chemotherapy drugs that are highly effective for the treatment of human cancers, but their clinical use is limited by associated dose-dependent cardiotoxicity. The precise mechanisms by which individual anthracycline induces cardiotoxicity are not fully understood. Human-induced pluripotent stem cell\u2013derived cardiomyocytes (hiPSC-CMs) are emerging as a physiologically relevant model to assess drugs cardiotoxicity. Here, we describe an assay platform by coupling hiPSC-CMs and impedance measurement, which allows real-time monitoring of cardiomyocyte cellular index, beating amplitude, and beating rate. Using this approach, we have performed comparative studies on a panel of four anthracycline drugs  which share a high degree of structural similarity but are associated with distinct cardiotoxicity profiles and maximum cumulative dose limits. Notably, results from our hiPSC-CMs impedance model (dose-dependent responses and ECThe online version contains supplementary material available at 10.1208/s12248-021-00576-y. Anthracyclines are a class of chemotherapies that are widely prescribed for the treatment of human cancers , 2, whicDoxorubicin may induce cardiotoxicity through inhibition of topoisomerase II, oxidative stress, dysregulation of intracellular calcium signaling, mitochondrial impairment, and apoptosis , 6. Our Animal models are commonly used in preclinical evaluation of drug cardiotoxicity, which are low throughput and exhibit species differences in cardiac structure and function , 10. Dat50 values that agreed well with their clinical dose limits. Genomic analysis identified several dysregulated pathways that are conserved across anthracyclines, but the extent to which each pathway was activated or inhibited was product specific. Notably, anthracyclines displayed significant differences in their ability to enter into hiPSC cardiomyocytes which were associated with their distinct cardiotoxicity profiles.Here, we describe an assay system that couples hiPSC-CMs and cellular impedance measurement. The assay can detect functional alterations such as beating rate, beating amplitude, and cellular index of hiPSC cardiomyocytes mimicking physically relevant conditions. We evaluated the assay suitability by testing a panel of four anthracyclines . All agents elicited cytotoxic effects in hiPSC-CMs in a dose-dependent manner, yielding differential EC2) were obtained from Fujifilm Cellular Dynamics, Inc., utilizing a validated iCell differentiation protocol that consistently produces hiPSC-CMs of high quality and purity. The hiPSC-CMs were routinely monitored for uniform plating confluency and consistent beating profiles using the CardioExcyte 96 platform , epirubicin hydrochloride (E9406), and idarubicin hydrochloride (I1656) were purchased from Sigma-Aldrich. Daunorubicin hydrochloride (1467) was from Tocris Bioscience.Human-induced pluripotent stem cell\u2013derived cardiomyocytes  was used.hiPSC-CMs  were seeded onto CardioExcyte96 sensor plates (Nanion) and were cultured as described above. Cardiomyocyte beating profiles and cellular index were recorded in real-time at 20-s intervals using the CardioExcyte 96 impedance system (Nanion). After anthracycline addition (0\u20135 \u03bcM), impedance signals were recorded every 90 min for 48 h. Cellular index and contractility data were normalized to pre-treatment values and were plotted against time for each anthracycline dose. ECThe hiPSC-CMs were cultured for 5 days and treated with individual anthracycline at 500 nM for 48 h. The resultant cells were collected by cell-scraper and centrifugation, followed by RNA extraction using the miRNeasy Micro kit (Qiagen). RNA content was estimated by UV spectrophotometry (Thermo Fisher Scientific), and quality was assessed using an Agilent BioAnalyzer RNA Nano Kit. Only samples with a RNA integrity number (RIN) \u2265 8 were proceeded for further analyses.versus control groups. Gene transcripts with greater than 0 RPKMs per sample, with greater than twofold change in expression compared to control groups, and with a p value significance of < 0.05, as determined by a two-tailed paired t-test, were further analyzed. Ingenuity pathway analysis (IPA) was used to analyze entire dysregulated mRNA gene sets. Using the HIVE and R Heatmap function, principal component analysis (PCA) and hierarchical clustering were performed using RPKM values of genes identified in select IPA cardiotoxicity pathways. To be included in the analysis, mRNA gene expression had to be significantly dysregulated across the entire panel of anthracyclines. Hierarchical clustering heat maps were generated by taking the logarithm base 10 of RPKM + 1 values and scaling by row.RNA sequencing (RNAseq) was performed as previously described . The IllWhole cell lysates from hiPSC-CMs were subjected to immunoblotting analysis for protein expression. Briefly, cells were cultured onto 6 well plates for 5 days and treated with 150 or 500 nM anthracycline for 48 h. The resultant cells were collected by centrifugation and cell pellets were lysed in RIPA buffer. Protein content was determined using Pierce BCA Protein Assay Kit (Thermo Fisher Scientific). Equal amounts (30 \u03bcg per lane) of total proteins were resolved by NuPAGE 4\u201312% gradient Bis-Tris gels (Thermo Fisher Scientific) and were transferred to PVDF membranes. Membranes were immunoblotted with specified antibodies and were visualized using Immobilon Western Chemiluminescent HRP Substrate (Millipore) and an ImageQuant LAS 4000 imager (GE). Monoclonal antibodies against DR4 (D9S1R), DR5 (D4E9), TNFR1 (C25C1), and S15 phospho p53 (16G8) were purchased from Cell Signaling Technology. Anti-Fas antibody (C-20) was purchased from Santa Cruz Biotechnology. Anti-p53 antibody conjugated to HRP (cat # HAF1355) was purchased from R&D systems. Anti-GAPDH antibody (2D4A7) was purchased from Novus. Horseradish peroxidase\u2013conjugated goat anti-rabbit IgG1 (sc-2054) and goat anti-mouse IgG1 (sc2969) were purchased from Santa Cruz Biotechnology.5 cells/cm2 to form a beating monolayer. hiPSC-CMs were treated with 5 \u03bcM anthracycline for 24 h and were imaged using a Leica SP8 confocal microscope (Leica Microsystems) with PLAPO objective lens 40\u00d7 (NA1.3). An excitation laser line of 488 nm (Emission 550-650 nm) was used to detect anthracycline fluorescence.hiPSC-CMs were cultured on a Nunc Lab-Tek II chambered cover glass (Thermo Fisher Scientific) at 1.56 \u00d7 10For colocalization imaging, hiPSC-CMs were first incubated with 100 nM MitoTacker Deep Red (Thermo Fisher Scientific) for 30 min, a mitochondria marker, followed by treatment with 5 \u03bcM anthracycline for 2 h. Live cell imaging was performed using an LSM 510 Meta Confocal Microscope attached to an Axiovert 200 Inverted Microscope (Carl Zeiss). An oil immersion 40\u00d7 objective lens was used for optical imaging. Excitation laser lines of 488 and 633 nm were respectively used to detect anthracycline and mitochondria.2 control allowing images to be captured every 10 min for 200 min. A 60\u00d7 water immersion objective lens (NA 1.2) was used for confocal imaging with excitation at 488 nm (Em 600 \u00b1 37 nm) to detect anthracycline fluorescence.hiPSC-CMs were seeded onto CellCarrier Ultra 96 well black plates with an optically clear cycl olefin bottom (Perkin Elmer Inc.) to form beating monolayers. Upon addition of anthracycline (5 \u03bcM), cells were immediately imaged using the Cell Voyager CV8000 High Content Screening system (Yokogawa Electric Corp.). The Cell Voyager stage incubator is equipped with temperature and CO50 values  and was therefore anticipated to be the most toxic to hiPSC-CMs. Indeed, idarubicin was found to be the most cytotoxic agent among the tested drugs, displaying the lowest EC50 value (0.25 \u03bcM) in the hiPSC-CMs model. Epirubicin exhibited the greatest hiPSC-CMs EC50 value (1.1 \u03bcM), corresponding to the highest allowable cumulative clinical dose (900 mg/m2). EC50 values for daunorubicin and doxorubicin also followed the pattern of the recommended cumulative doses in cancer patients . hiPSC-CMs monolayer cultures were treated with 500 nM anthracycline for 48 h. The assay conditions were chosen based on impedance results which showed a notable decrease in cellular index Figs.  and 2. IZ-score values (quantifies a match between predicted and observed expression patterns) for each anthracycline treatment condition . In addition, the top upstream regulators predicted to be activated based on mRNA gene expression changes are shown . This data demonstrates that the signaling pathways affected in hiPSC-CMs are well conserved across the panel of anthracyclines. However, idarubicin and daunorubicin displayed higher activation Z-scores compared to doxorubicin and epirubicin for many canonical pathways including ROS, calcium signaling, necroptosis, cardiac hypertrophy, and cardiac repair . Doxorubicin and epirubicin displayed the highest activation Z-scores for G2/DNA damage checkpoints and inhibition of oxidative phosphorylation. This data suggests that each anthracycline drug can activate or inhibit specific cellular mechanisms to different extents.Dysregulated mRNA gene sets were compared using ingenuity pathway analysis (IPA) . We highp value < 0.05) across the entire panel of anthracyclines. PCA and hierarchical clustering clearly demonstrate good replicate reproducibility and that anthracycline treatments clustered separately from vehicle controls. Interestingly, doxorubicin and epirubicin frequently clustered together and separated from idarubicin and daunorubicin which also clustered together. In hierarchical clustering data, this was observed for pathways of death receptor (DR) signaling, cardiac hypertrophy, calcium signaling, ROS, and oxidative phosphorylation  Figure  and hierion Fig. . We haveion Fig. , 8. Simiion Fig.  and protion Fig. . ImmunobAnthracyclines share a high degree of structural similarity; however, they differ in methoxy and hydroxyl groups rendering differences in lipophilicity  that mayConfocal microscopy analysis revealed that doxorubicin and epirubicin were primarily localized to the nucleus, while idarubicin and daunorubicin exhibited substantial non-nuclear localization Fig. . AnthracWe developed a novel assay system to assess drug cardiotoxicity utilizing physiologically relevant hiPSC-CMs coupled with cellular impendence measurement. After testing a panel of four anthracyclines, we show that the assay is robust in capturing functional attributes of hiPSC-CMs in response to drug treatment Figs.  and 2. SDespite numerous efforts by the scientific community, the precise mechanisms by which anthracyclines induce cardiotoxicity are not fully understood. Previous studies on doxorubicin linked several cellular processes to its action in hiPSC-CMs . HoweverWe further showed a unique pattern of anthracyclines in cellular uptake into hiPSC-CMs. This was done by tracing the intrinsic fluorescence of anthracyclines Figs.  and S3. Coupling hiPSC-CMs with impedance measurement offers a robust, high-throughput platform for assessing drug cardiotoxicity. The anthracycline family elicits dose-limiting cardiotoxicity through deregulation (inhibition or activation) of several conserved pathways in cardiomyocytes. The extent of pathway dysregulation was product specific and associated with their ability to enter hiPSC-CMs Fig. .Fig. 8A ESM 1(DOCX 393 kb)"}
+{"text": "Fusarium graminearum. Previous study showed that the numerous F. graminearum genes including regulatory factors were differentially expressed upon FgV1 infection, however, we have limited knowledge on the effect(s) of specific transcription factor (TF) during FgV1 infection in host fungus. Using gene-deletion mutant library of 657 putative TFs in F. graminearum, we transferred FgV1 by hyphal anastomosis to screen transcription factors that might be associated with viral replication or symptom induction. FgV1-infected TF deletion mutants were divided into three groups according to the mycelial growth phenotype compare to the FgV1-infected wild-type strain (WT-VI). The FgV1-infected TF deletion mutants in Group 1 exhibited slow or weak mycelial growth compare to that of WT-VI on complete medium at 5 dpi. In contrast, Group 3 consists of virus-infected TF deletion mutants showing faster mycelial growth and mild symptom compared to that of WT-VI. The hyphal growth of FgV1-infected TF deletion mutants in Group 2 was not significantly different from that of WT-VI. We speculated that differences of mycelial growth among the FgV1-infected TF deletion mutant groups might be related with the level of FgV1 RNA accumulations in infected host fungi. By conducting real-time quantitative reverse transcription polymerase chain reaction, we observed close association between FgV1 RNA accumulation and phenotypic differences of FgV1-infected TF deletion mutants in each group, i.e., increased and decreased dsRNA accumulation in Group 1 and Group 3, respectively. Taken together, our analysis provides an opportunity to identify host\u2019s regulator(s) of FgV1-triggered signaling and antiviral responses and helps to understand complex regulatory networks between FgV1 and F. graminearum interaction.The Fusarium graminearum virus 1 (FgV1) causes noticeable phenotypic changes such as reduced mycelial growth, increase pigmentation, and reduced pathogenicity in its host fungi,  Virus divert many cellular resources to produce virus-specific components and counteract to host defense responses during virus infection . This viTranscription factors (TFs) are DNA-binding proteins responsible for modulating gene regulatory systems by cooperating with a range of proteins, including other upstream or downstream TFs, transcription initiation complex, and epigenetic regulators . During Fusarium graminearum causes Fusarium head blight of major cereal crops, such as wheat, barley, and rice , nivalenol, and zearalenone that are considered threat to the animals and human health  of TFs and their target genes in gene regulatory network using diverse computational and experimental approaches  is a single-stranded RNA (ssRNA) virus and closely related to the proposed family \u201cviridae\u201d . FgV1 inminearum . Previouminearum . FgHex1 minearum . FgHal2 of virus . Transcrnfection . Howevernfection . Recent response . This prF. graminearum. Based on this library, we analyzed phenotype of virus-infected mutants and the relationship between FgV1 RNA accumulation and phenotypic differences of FgV1-infected TF deletion mutants. To our knowledge, this is the first description of phenome-based association study in characterizing effects of Fusarium graminearum transcription factors on FgV1 infection.Here, to gain new insights on the role(s) of host transcription factors that might be associated with viral RNA replication or symptom development following FgV1 infection, we transferred FgV1 to gene-deletion mutant library of 657 putative TFs in Fusarium graminearum GZ03639 WT strain and 657 TF deletion mutant library were provided by the Center for Fungal Genetic Resources . All fungal isolates were stored in 20% (v/v) glycerol at \u221280\u00b0C and TF deletion mutants were reactivated at 25\u00b0C on potato dextrose agar (PDA) with geneticin (50 \u03bcg/ml). TF deletion mutants were subcultured on complete medium (CM) agar containing geneticin for further experiment. Fungal colonies incubated on CM agar at 25\u00b0C for 120 h were photographed. Fungal cultures used for extraction of RNA were prepared as previously described (escribed . BrieflyF. graminearum GZ03639 (WT-VI) was generated by using protoplast fusion method  to remove genomic DNA according to the manufacturer\u2019s instructions. As described previously, 4 M LiCl was added to total RNA extract to a final concentration of 2 M to isolate ssRNA fraction  according to the manufacturer\u2019s protocols. All synthesized cDNAs were diluted to 20 ng of mixture with nuclease-free water.For nucleic acid extraction, frozen mycelia were pulverized using liquid nitrogen and a mortar and pestle. Total RNAs were extracted with RNAiso Plus reagent  followed by treatment with fraction . SamplesTM Real-time PCR system using gene-specific internal primers as described previously with slight modification , and 10 pmoles of each primer. The thermal profile was as follows: 3 min at 95\u00b0C and 40 cycles of 10 s at 95\u00b0C, 30 s at 59\u00b0C, and melting curve data obtained by increasing the temperature from 55 to 95\u00b0C. Two endogenous reference genes, i.e., ubiquitin C-terminal hydrolase  and elongation factor 1\u03b1 , were used as internal controls to normalize qRT-PCR results. Data were analyzed using the Bio-Rad CFX Manager V1.6.541.1028 software (Bio-Rad). RNA samples were extracted from at least two independent, biologically replicated experiments, and each PCR product was evaluated in at least three independent experiments, including three technical replicates. All primer sets used in this study are listed in Real-time quantitative RT-PCR (qRT-PCR) was performed with a Bio-Rad CFX384fication . Each reDNaseI-treated total RNAs from all virus-infected TF deletion mutants were treated by 30 units of S1 Nuclease (Takara Bio). Samples were loaded into 1% agarose gel for analysis of viral double-stranded (dsRNA) accumulation. After separation on agarose gel, dsRNA was visualized in a UV transilluminator. To measure relative accumulation of FgV1 viral dsRNA in TF deletion mutants, 3 \u03bcg of total RNA from all virus-infected mutants were loaded and separated on 1% agarose gel. Ethidium bromide-stained gels were visualized in a UV transilluminator. Band intensity were measured using ImageJ software  motif and heteromeric CCAAT-binding factor showed relatively high phenotypic variation following FgV1 infection compared to that of other TF families (Approximately 88% of FgV1-infected TF deletion mutants (Group 2) showed similar phenotype and mycelial growth regardless of phenotype of virus-free TF gene deletion mutants. Among FgV1-infected TF deletion mutants in Group 3, which growth reduction rate was lower than 10%, colony morphology of most mutants in this group showed recovery phenotype and viral accumulation level was as low as 10% of WT-VI although FgV1 infection might still affect colony morphology. In this regard, comparisons of colony morphology including mycelial growth of TF deletion mutants following hypovirulence-associated FgV1 infection help screening host gene(s) that might attribute or affect development of virus-derived symptom and FgV1 replication. We observed that families .FgNHP6A (FGSG_00385) deletion mutant that showed pH 4-resistance. Among these 35 TF deletion mutants, most of gene deletion mutants showed decreased mycelial growth compared to WT. Colony morphology of virus-free deletion mutants including FgSWI6 (FGSG_04220), FgNOT3 (FGSG_13746), GzC2H090 (FGSG_10517), GzWing019 (FGSG_08572), and FgCrz1A (FGSG_13711) showed similar phenotypes to those of WT-VI such as reduced aerial mycelia, reduced mycelial growth, and increased pigmentation (GzC2H003 (FGSG_00477) and FgNHP6A (FGSG_00385) TF deletion mutants showed slow mycelial growth after FgV1 infection compared to WT-VI (FgCrz1A (FGSG_13711), GzZC108 (FGSG_08769), GzMADS003 (FGSG_09339), and FgStuA (FGSG_10129) showed little reduction of mycelial growth compared to WT-VI. Six out of those 35 TF deletion mutants including GzAPSES004 (FGSG_10384) and FgFSR1 (FGSG_01665) mutants were not able to uptake FgV1 via hyphal anastomosis method, this result might be explained as growth defect in those deletion mutants , GzC2H048 (FGSG_07075), and ZIF1 (FGSG_01555) deletion mutants showed more damaged virus-infected phenotype compared to WT-VI though they were belong to the Group 2. The other pH 11 responsive gene FgPac1 (FGSG_12970) deletion mutant showed similar phenotype to WT-VI. \u0394GzC2H048 and \u0394ZIF1 also showed osmotic stress response. Between two pH 4-resistance TF deletion mutants, \u0394GzC2H005 (FGSG_00653) and \u0394GzMyb008 (FGSG_02719), they showed different phenotype. FgV1-infected \u0394GzC2H005 deletion mutant showed very weak and low density of colony morphology. In contrast, FgV1-infected \u0394GzMyb008 (Group 3) showed much faster mycelial growth and formed rhombus-shape of red line at the outside region of colony. In case of GzDHHC003 (FGSG_06542) and GzZC086 (FGSG_8924), related with oxidative stress response, showed normal growth but with relatively reduced mycelia growth compared to WT-VI. FgFlbA (FGSG_06228) showed increased transcript level following FgV1 infection and deletion mutant showed resistance phenotype in all stress factors except for pH 11 stress response. The virus-infected \u0394FgFlbA (Group 2) colony grow normally but contain clustering region around fungal colony. In contrast, while \u0394GzWing020  showed sensitive responses to all stress responsive factors in phenome data, FgV1-infected colony showed increased aerial mycelia production and hyphal growth compared to WT-VI. Obtained results indicated that some of F. graminearum TF candidates that showed sensitive response in pH, fungicide or ROS stress alone also involved in response to FgV1 infection as well as TF candidates that response in broad range of environmental stress factors.TF phenome analysis described phenotypic change under diverse abiotic stresses, including osmotic stress, reactive oxygen species (ROS) stress, fungicide, cell wall stress, and acidic (pH = 4) or basic (pH = 11) conditions . We compnfection . In resuFgARS2 (FGSG_01106), GzC2H075 (FGSG_09368), FCT1 (FGSG_01182), and FCT2 (FGSG_05304) were divided in Group 1. FgV1-infected \u0394GzGATA007 (FGSG_09565) belong to Group 2, however, showed retarded growth compared to WT-VI or to the typical colony morphologies of FgV1-infected TF deletion mutants belonging to Group 2 (GzC2H075 (FGSG_09368) and GzGATA007 (FGSG_09565) deletion mutants, which showed apparent reduction in mycelial growth following FgV1 infection, exhibited sensitive response only to DNA damage reaction in phenome data. Individual mycelial growth value of RFX1  deletion mutant was slightly higher than that of WT-VI, however, virus-infected mutant showed strong inhibition of mycelial growth phenotype so we are unable to process further experiment. FHS  deletion mutant that showed oxidative stress and ROS response along with DDR did not show significant change of colony morphology following FgV1 infection. The colony morphology of GzZC302  and GzZC303  deletion mutants showed similar reduced aerial mycelia, increased pigmentation, and responded to multiple stress factors include oxidative, ROS and pH, however, their virus-infected phenotypes were not significantly different compared to WT-VI. \u0394Gzscp , which exhibit multiple defects along with DDR, showed little reduction of mycelial growth compared to WT-VI.Previous study identified 16 putative TFs involved in DNA damage responses (DDRs) . In this Group 2 . GzC2H07Although all DDR-related putative TF genes exhibited different sensitivity to DNA damaging agent include methyl methanesulfonate, hydroxyurea, bleomycin, and camptothecin , we coulGzZC252 (FGSG_05370) and GzZC311 (FGSG_00217) were grouped into 1 and 3, respectively, following FgV1 infection (GzZC252 (FGSG_05370) and GzZC311 (FGSG_00217) genes were up-regulated upon FgV1 infection , GzbHLH007 (FGSG_02814) GzC2H006 (FGSG_00764), TRI15 (FGSG_03881), and GzGATA003 (FGSG_04626) that showed significant changes of gene expression levels upon FgV1, Fusarium graminearum virus 2 , FgV3 (a Fusagravirus), and Fusarium graminearum hypovirus 1 infections , GzZC040 (FGSG_13828), GzZC086 (FGSG_8924), TRI15 (FGSG_03881), FgFlbB (FGSG_03597), GzDHHC003 (FGSG_06542), and GzZC267 (FGSG_01669) deletion mutants. Among them, dsRNA accumulation level was also significantly increased in FgV1-infected GzZC086 deletion mutants. \u0394GzZC021 (FGSG_03873), GzZC252 (FGSG_05370), and \u0394GzZC303 (FGSG_00573) in Group 3 showed significant decrease in viral dsRNA accumulation level. FgV1-infected \u0394GzZC252 showed significant reduction in dsRNA accumulation but not in viral ssRNA accumulation level compared to that of WT-VI. In addition, we observed dsRNA patterns of these TF deletion mutants (GzZC021 (FGSG_03873), \u0394GzZC252 (FGSG_05370), and \u0394GzZC197 (FGSG_03892) showed decreased dsRNA accumulation compared to those of WT-VI and other mutants classified into Groups 1 and 2 (GzbZIP015 (FGSG_09286), \u0394GzC2H024 (FGSG_04083), and \u0394GzZC033 (FGSG_13652) produced fluffy but low density of aerial mycelia  as shown in F. graminearum, further studies are needed.We observed different phenotype change in fungal colony color which turns yellow after virus infection without greater reduction of mycelial growth in some TF deletion mutants. Those genes were not listed in phenome data as pH sensitive responsive mutants that showed reduced mycelial growth at pH 4 or pH 11 . However pH drop . Because pH drop , change F. graminearum. We expected it would provide information for identifying host factor(s) or characterizing signaling pathway that related with hypovirulence-associated traits of FgV1 regardless of phenotype observation of FgV1-infected TF deletion mutant. As mentioned above, several TF deletion mutants showed WT-VI like colony morphology. Some of these TFs might play central roles in reprogramming transcriptional network or function as an important downstream regulator, which results in pleiotropic effects by gene deletion. For example, FgSWI6 and GzAPSES004 were suggested as hub regulators of virulence, mycotoxin synthesis, and sexual reproduction-associated networks , \u0394GzZC303 (FGSG_00573), and \u0394GzZC302  and GzZC197  showed reduced gene expression level in FgDICERs or FgAGOs double knockout mutant strains compared to WT (GzbHLH011 (FGSG_06262) and GzHOMEL018 (FGSG_07243) showed reduced gene expression level in both \u0394FgGCN5 and \u0394FgSAS3 that are putative histone acetyltransferase (HATs) in F. graminearum (GzbHLH011 and \u0394GzHOMEL018 belong to Group 3 (GzZC086 (FGSG_08924), involved in oxidative stress in F. graminearum (GzZC086 (Group 1) showed significantly increased viral RNA accumulation level  and GzZC252 (FGSG_05370) that were grouped into 1 and 3, respectively, showed increased gene expression level following FgV1 infection but result of FgV1 transmission into each gene deletion mutant showed different colony morphology. GzZC311 and GzZC252 encoded hypothetical protein contain fungal-specific regulatory protein domain, however, their cellular functions have not been identified yet. \u0394GzZC252 negatively affects FgV1 dsRNA accumulation but not for ssRNA accumulation. Further investigation with complementation or overexpression mutant is required to confirm whether this gene is required for FgV1 RNA accumulation. Among Group 2, FgV1 infections in \u0394GzbZIP015 (FGSG_09286) and \u0394GzZC050 (FGSG_12597) mutants showed similar colony morphology like WT-VI  and argonaute-like 2 (agl2) in Cryphonectria parasitica . Interestingly, Cryphonectria hypovirus 1 (CHV1) and FgV1 exhibit suppression activity against host antiviral response through suppression of RNAi component-related gene transcription . Previourasitica . We atte of RNAi . Furthervia hyphal anastomosis into several TF deletion mutants including \u0394GzZC030 (FGSG_06380), \u0394GzZC032 (FGSG_00153), \u0394GzZC044 (FGSG_12094), \u0394GzZC060 (FGSG_08808), \u0394GzZC232 (FGSG_07067), \u0394FgArt1 (FGSG_02083), \u0394GzZC301 (FGSG_00404), and \u0394GzZC316 (FGSG_00125). Most of those gene deletion mutants did not show specific alteration in mycelial growth. Among them, we confirmed gene expression levels of 9 TFs by qRT-PCR  of novel TF genes that showed distinguishable phenotypes following FgV1-infection. Further study will explore the roles of these TF genes and their putative target genes during FgV1 infection.Kinases and phosphatases also contribute to the regulation of gene expression by interacting with transcription factors . Both pheviously , applyinThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.JY and K-HK designed the experiments, analyzed the data, and wrote the manuscript. JY performed the experimental work. Both authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Scientific Reports 10.1038/s41598-018-27222-6, published online 13 June 2018Correction to: The original version of this Article contained errors in the Abstract.\u201cThe independent sonographic features for the TN subgroup included regular shape , no spiculated/angular margin , posterior acoustic enhancement , and no calcifications .\u201dnow reads:\u201cThe independent sonographic features for the TN subgroup included regular shape , no spiculated/angular margin , posterior acoustic enhancement , and no calcifications .\u201dAdditionally, this Article contained an error in section (B) of the Figure 6 legend.(B) The uncircumscribed margin with cellular prominence .\u201d\u201cnow reads:(B) The uncircumscribed margin with cellular prominence .\u201c"}
+{"text": "Isospora species causing systemic coccidiosis in Superb Glossy Starlings (Aves: Sturnidae). The A/T rich (34.7% G/C) genomes were 6223\u2009bp in length for Isospora greineri and 6217\u2009bp for Isospora superbusi. Each encoded 3 protein-coding genes,  plus 18 LSU and 14 SSU rDNA fragments. Arrangement of protein- and rRNA-coding regions was identical to known Eimeria sp. mt genomes; start codon usage was conventional. The mitochondrial genome structures of Isospora and Eimeria species are conserved and reflect the close phylogenetic association between these eimeriid genera of apicomplexan parasites.Complete mitochondrial genomes are reported for two  Isospora  and other birds are commonly parasitized by coccidia transmitted via the fecal-oral route Box . More thdia Long . Levine dia Long  generaliIsospora species possess morphologically indistinguishable oocysts  held at the Toronto Zoo .Specific identification based on microscopy is almost impossible because some Isospora greineri (6223bp) and Isospora superbusi (6217bp) assembled using de novo sequence assembly within Geneious software . The mitochondrial genomes of I. greineri  and I. superbusi  had three protein-coding genes  as well as 18 LSU and 14 SSU rDNA fragments but no regions encoding tRNAs. The two Isospora spp. had 99.2% pairwise sequence identity with the majority of differences within the protein-coding or intergenic regions  as described (Hafeez et\u00a0al.  regions . Genome  regions . Our amp"}
+{"text": "Sufficient physical activity is crucial to maintaining independence, health and wellbeing during ageing, yet physical inactivity is common in older people. Identifying factors associated with physical activity engagement is essential to develop novel approaches to increase activity in older people. Automatic, context-dependent habits may play an important role in physical activity behaviour. The current study aimed to investigate the relationship between physical activity behaviours and their automaticity in older people. 123 community dwelling Australians aged over 65 \u2013 88 years , recruited from participant registries, hospital noticeboards and community groups, completed an online questionnaire. Current physical activity levels were measured using the Incidental and Planned Exercise Questionnaire, and automaticity of those physical activity behaviours were measured using the Self-Report Habit Automaticity Index. Participants also reported demographic information, body mass index (BMI), medical history and current mood symptoms. Participants reported an average of 2.28 hours planned walking (SD=2.33), 5.81 hours planned moderate/vigorous exercise (SD=4.02), and 20.5 hours incidental activity (SD=15.52) per week. Multiple regression analyses revealed that after controlling for age, gender, BMI and depression symptoms, higher automaticity scores were associated with more hours per week of planned walking (p=.012), moderate/vigorous exercise (p=.038), and incidental activity (p=.017). Supporting older people to make their physical activity more habitual could therefore be an effective approach to increase levels of physical activity in this population."}
+{"text": "EML4) is the canonical anaplastic lymphoma kinase (ALK) fusion partner in non-small cell lung cancer (NSCLC), and ALK-positive patients showed promising responses to ALK tyrosine kinase inhibitors (TKIs). However, studies that comprehensively investigate ALK TKI treatment in patients with different ALK fusion patterns are still lacking.Echinoderm microtubule-associated protein-like 4 (ALK-positive patients with advanced NSCLC were retrospectively studied for their response to crizotinib and subsequent treatments. Comprehensive genomic profiling (CGP) was conducted to divide patients into different groups based on their ALK fusion patterns. Non-canonical ALK fusions were validated using RNA-sequencing.Ninety-eight EML4-ALK fusions, 19.4% carried only non-canonical ALK fusions, and 26.5% harbored complex ALK fusions with coexisting canonical and non-canonical ALK fusions. The objective response rate and median progression-free survival to crizotinib treatment tended to be better in the complex ALK fusion group. Notably, patients with complex ALK fusions had significantly improved overall survival after crizotinib treatment (p = 0.012), especially when compared with the pure canonical EML4-ALK fusion group (p = 0.010). The complex ALK fusion group also tended to respond better to next-generation ALK TKIs, which were used as later-line therapies. Most identified non-canonical ALK fusions were likely to be expressed in tumors, and some of them formed canonical EML4-ALK transcripts during mRNA maturation.54.1% of patients had pure canonical ALK fusions could potentially have better treatment outcomes to ALK TKIs therapy. Also, diagnosis using CGP is of great value to identify novel ALK fusions and predict prognosis.Our results suggest NSCLC patients with complex  ALK) gene rearrangements (ALK. Echinoderm microtubule-associated protein-like 4 (EML4)-ALK is the canonical and most common ALK gene arrangement found in NSCLC, by which multiple EML4 breakpoints fuse in frame with the kinase domain of ALK  include kinesin family member 5B (KIF5B)-ALK, TRK-fused gene (TFG)-ALK, kinesin light chain 1 (KLC1)-ALK, striatin (STRN)-ALK, and TNFAIP3 interacting protein 2 (TNIP2)-ALK -ALK fusion was almost exclusively found in large cell lymphomas  accounts for more than 80% of all diagnosed cases , 2. Apprngements , 4, leadn of ALK . Indeed,variants . Some ALIP2)-ALK \u201310, whilymphomas .-positive NSCLC. Crizotinib, showed improved objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) in ALK-positive NSCLC patients compared with chemotherapy  versus non-canonical (non-EML4-ALK) fusions in NSCLC. Rosenbaum et al. compared 14 canonical ALK fusions with 3 non-canonical ALK fusions and concluded that patients with canonical ALK fusions had better overall survival (OS)  are becoming the standard of care for oncogeneotherapy \u201314. Subsotherapy \u201317. Nevehibitors , 19, altvariants . In contval (OS) . Howeverin situ hybridization (FISH) and immunohistochemistry (IHC), which only give the positivity/negativity of ALK fusion, comprehensive genomic profiling (CGP) is able to separate different ALK fusion variants and identify rare fusion partners that may be associated with different sensitivities to ALK TKIs. In the current study, we used CGP to characterize 98 ALK-positive NSCLC patients and grouped them based on the presence of canonical and/or non-canonical ALK fusions. We aimed to study the crizotinib response in patients with different ALK fusion patterns and sought to correlate the clinical outcomes with different patient/treatment characteristics and genomic profiling results.Unlike traditional diagnosis methods, such as break-apart fluorescence ALK-positive patients with advanced NSCLC were retrospectively studied. Hybridization capture-based CGP using next-generation sequencing (NGS) was performed with (FFPE) or plasma samples collected at baseline (n = 43) or progressive disease  to characterize their ALK fusion patterns. Crizotinib clinical response was evaluated via computed tomography scans six weeks after the first crizotinib administration and every 6/8 weeks thereafter according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. PFS was measured from the date of initiation of crizotinib treatment until disease progression or death. Overall survival (OS) was calculated from the date of initiation of crizotinib treatment to death resulting from any causes or was censored at the last follow-up on November 30, 2019.This study was approved by the institutional ethics review board of Guangdong Provincial People\u2019s Hospital [Ethics number: No. GDREC2019323H (R1)]. All patients signed informed consent forms prior to sample collection and consented for publication of related clinical information and any accompanying image. Ninety-eight http://adtex.sourceforge.net) was used to identify copy number variations (CNVs) with default parameters.Tumor genomic DNA was extracted from FFPE samples with a tumor content >50% using a QIAamp DNA FFPE Kit  to detect somatic mutations. Genomic DNA from white blood cells was extracted using DNeasy Blood & Tissue kit . Hybridization capture-based CGP using NGS was performed at two genetic testing centers. Brie\ufb02y, the KAPA Hyper Prep Kit  was used for DNA library preparation. Customized xGen lockdown probes  were used for hybridization enrichment. All procedures were conducted according to the manufacturers\u2019 instructions. The overlapping 279 cancer-relevant genes from the two testing centers were included for CGP analysis . The fusALK break-apart probes  and/or IHC staining with Ventana anti-ALK (D5F3) rabbit monoclonal primary antibody , following the manufacturers\u2019 instructions.Unstained FFPE sections from tumor specimens collected at diagnosis were subjected to FISH with Total RNA from FFPE samples was extracted using RNeasy FFPE kit (QIAGEN). Reverse transcription was performed with Superscript Vilo mastermix (Life Technologies). Gel-puri\ufb01ed DNA was sent for Sanger sequencing to identify the sequence in cDNA.Poly(A) fractions from the globin depleted RNA samples (1.0 \u03bcg) were purified by oligo-dT purification beads  and then used to construct cDNA libraries following the TruSeq RNA Sample Preparation Guide . Sequencing was performed on the HiSeq 2000 System  using the TruSeq Paired-End (PE) 100 bp Kit . Real-time analysis and base calling were conducted using the Control software in the instrument. The initial processing of reads from the HiSeq instrument used the Illumina CASAVA (v1.8).ALK fusion groups was done using Fisher\u2019s exact test, and genes with p values smaller than 0.1 were included for further analysis. For survival data, Kaplan-Meier curves were analyzed using the log-rank test; for the pairwise log-rank test, the p values were adjusted by Benjamini and Hochberg method; the censored points were marked in the figure when the patient loss to follow-up during the study. The univariate and multivariate analyses were performed using the Cox regression model. For analyzing the next generation TKIs, only patients who had known next generation TKI treatment history were included. Two-sided p values of less than 0.05 were considered as statistically significant. All statistical analyses were done in R (v.3.6.0).The comparison of mutation frequency between different ALK-positive using break-apart FISH and/or IHC. Ninety-eight ALK-positive patients with advanced NSCLC were retrospectively studied for their clinical response to crizotinib after excluding patients with early staging, unacceptable crozotinib toxicitiesor unclear clinical history, as well as patients without crizotinib treatment  and 55 patients being sequenced at PD after crizotinib treatment  19 patients (19.4%) carried only the non-canonical ALK fusions; 3) 26 patients (26.5%) who harbored both canonical and non-canonical ALK fusions were classified as the complex ALK fusion group. As shown in ALK fusion groups, with majorities of the ALK-positive patients in our cohort were never smokers (81.6%) with lung adenocarcinoma . Also, most patients received crizotinib as the first line (63.3%) or second-line (28.6%) treatment. After disease progression to crizotinib treatment, more than 60% of the patients used next-generation ALK inhibitors and about 40% of patients received palliative treatment  were detected to be patterns 2B, we cALK-positive patients with baseline CGP. As shown in ALK fusion group, we found that DCR was similar among all groups while the complex ALK fusion group had improved ORR compared with other groups  than other ALK fusion patterns , especially when comparing the complex ALK fusion group with the pure canonical EML-ALK fusion group  and analysis based on the combination of baseline and post-crizotinib CGP (n = 98) gave similar results in terms of the frequency of various ALK fusion patterns and the clinical results, we used the data of all 98 ALK-positive patients for the later on analysis.We further examined the post-treatment patient survival in these ALK fusions and post-crizotinib ALK inhibitor treatment were the only 2 factors that were significantly associated with improved OS . By multivariate analysis, we found complex ALK fusions and post-crizotinib ALK inhibitor treatment still significantly correlated with OS  mutation/deletion and MYC amplification were found to be the most frequent genomic alterations in each ALK fusion group, followed by genomic changes in SET domain containing 2 (SETD2), CREB binding protein (CREBBP), epidermal growth factor receptor (EGFR), and cyclin D1 (CCND1)  and CCND1 amplification  were the top 2 genomic alterations enriched in complex ALK fusion groups compared with the pure canonical EML4-ALK fusion group , we included the mutation/CNV status of EGFR and CCND1 into the multivariate Cox regression analysis. We also included the oncogenic/loss-of-function TP53 mutations given that they have been shown to be associated with unfavorable treatment outcomes in ALK-positive NSCLC. Complex ALK fusions and post-crizotinib ALK inhibitor treatment could still predict post-crizotinib OS after including these genomic alterations ; EGFR mutation/amplification was not significantly associated with OS, whereas CCND1 amplification was likely to be a hazard factor for OS , 5 patients took brigatinib (median PFS = 5.2 months), 9 patients received ceritinib (median PFS = 5.8 months), and 7 patients received foritinib (median PFS = 5.2 months). The remaining 3 pure canonical EML4-ALK fusion patients received ensartinib (PFS = 4.5 months), lorlatinib (PFS = 5.0 months), and foritinib plus chemotherapy (PFS = 8.7 months), respectively. In the pure non-canonical ALK fusion group, 3 patients switched to alectinib (median PFS = 9.0), 2 patients took brigatinib (median PFS = 1.1 months), 1 patient received foritinib (median PFS = 11.6 months), 1 patient received ceritinib (PFS = 14.0 months), and 1 patient was treated with apatinib (PFS = 1.2 months). Among the complex ALK fusions cohort, 2 patients switched to brigatinib , 2 patients took ceritinib , 3 patients received aletinib , 5 patients treated with foritinib , and 1 patient received foritinib and concurrent chemotherapy (PFS > 18.2 months). As shown in ALK fusion group tended to have better response to next-generation ALK TKIs than other groups, although the PFS was not statistically significant . Similarly, these patients also seemed to have a better OS , transmembrane protein 178A (TMEM178A), spectrin repeat containing nuclear envelope protein 1 (SYNE1), zinc finger CCCH-type containing 8 (ZC3H8), acireductone dioxygenase 1 (ADI1), AF4/FMR2 family member 3 (AFF3), protein kinase C epsilon (PRKCE), CUGBP Elav-like family member 4 (CELF4), mal T-cell differentiation protein-like (MALL), SET binding factor 2 (SBF2), proteasome 20S subunit alpha 8 (PSMA8), potassium voltage-gated channel modifier subfamily G member 3 (KCNG3), peroxidasin (PXDN), and ring finger protein 10 (RNF10)  Table 2.ALK fusions for further studies. Patient P64 had a rare ALK fusion, linking ALK intron1 with ALK intron19 (EML4-ALK (v3b) mRNA using RNA-seq , and mRNA expression level of EML4 exon1-6 and ALK exon20-29, which corresponds to v3b variant of EML4-ALK fusion, was also significantly higher than other exons of these two genes -ALK fusion simultaneously . We detected both EML4 intron13-GALNT14 fusion and GALNT14-ALK exon19 fusion in pre-mature mRNA by RNA-seq , and we also found EML4 exon13-ALK exon20 (v1) fusion in mature mRNA (GALNT14-ALK fusion was indeed EML4 intron13-GALNT14-ALK exon19 fusion that can be spliced to form EML4-ALK mature mRNA (SLC19A3 (IGR)-ALK fusion might be non-productive. Similarly, EML4-ALK mature mRNA were observed in patient P73, who harbored SETD2-ALK fusion at the DNA level  As this study was initiated many years ago, we used crizotinib as the major ALK TKI treatment in our cohort; however, crizotinib was no longer used as the front-line therapy in ALK-positive patients in many countries given the promising therapeutic response of next-generation TKIs. Within the 150 ALK-positive NSCLC patients dragonized in our hospital, 30 of them used second generation ALK inhibitors as the first TKI treatment  Due to the limited availability of patient samples and the instability of RNA within the samples, we only performed RNA-seq validation for a few rare ALK fusions. Although the IHC positivity implies their expression in cancer cells, future studies were needed to confirm whether these rare ALK fusions could form functional products in the tumor. 4) The median OS in our patient cohort was significantly shorter than that in the previous studies  The  studies . PossiblALK fusions in advanced NSCLC patients, and we showed that some of the non-canonical ALK fusions could form canonical EML4-ALK transcripts during mRNA splicing. We are also the first group to comprehensively investigate the therapeutic effects of crizotinib in NSCLC patients with different ALK fusion patterns and demonstrated that the complex ALK fusions were associated with improved post-ALK TKI patient survival. Therefore, our results suggest that the determination of ALK fusion pattern using CGP has great clinical potentials to identify novel ALK fusions and make better prediction about patient prognosis.Overall, we identified multiple novel non-canonical http://www.biosino.org/node), accessions OEP001261 and OEP001269.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: NODE , National Natural Science Foundation of China , Natural Science Foundation of Guangdong Province , National Key Technology R&D Program of the Ministry of Science and Technology of China: Prevention and Control of Major Non-communicable Diseases , Key Lab System Project of Guangdong Science and Technology Department-Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer , and Strategic Priority Research Program of the Chinese Academy of Sciences . XZ and YS are the employees of Nanjing Geneseeq Technology Inc.; YX and XW are the employees of Geneseeq Technology Inc.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Staphylococcus aureus sequence type 72 (ST72) is prevalent in South Korea and has shown resistance to multiple antimicrobials. ST72 isolates display different levels of resistance to the antistaphylococcal lysostaphin. Draft genome sequencing of ST72 human isolates exhibiting lysostaphin resistance or susceptibility was performed to better understand the mechanism of lysostaphin resistance using subtractive genomics.Methicillin-resistant  Staphylococcus aureus sequence type 72 (ST72) is prevalent in South Korea and has shown resistance to multiple antimicrobials. ST72 isolates display different levels of resistance to the antistaphylococcal lysostaphin. Draft genome sequencing of ST72 human isolates exhibiting lysostaphin resistance or susceptibility was performed to better understand the mechanism of lysostaphin resistance using subtractive genomics.Methicillin-resistant  Staphylococcus aureus (MRSA) sequence type 72 (ST72) has emerged as a nosocomial infection that causes pneumonia, endocarditis, and skin and soft tissue infections (SSTIs) in South Korea  used in the study were originally isolated by the Asia Pacific Foundation for Infectious Diseases, in South Korea . These hde novo using IDBA-UD (v.1.1.1)  (A single colony was inoculated in 10\u2009ml of tryptic soy broth (TSB) under orbital shaking culture conditions (200\u2009rpm) at 37\u00b0C for 16 h. The cells were harvested by centrifugation. Genomic DNA from K07-204 and K07-561 was isolated by the phenol-chloroform extraction method  under BioProject/BioSample accession numbers PRJNA637991/SAMN15163378 and PRJNA637996/SAMN15163770, respectively.The draft genome sequencing data for K07-204 and K07-561 are available in the GenBank database under the accession numbers"}
+{"text": "International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) diagnostic codes related to maternal dependence on opioids (F11.20) or benzodiazepines (F13.20) and to newborns affected by maternal use of drugs of addiction (P04.49) or experiencing withdrawal symptoms from maternal drugs of addiction (P96.1) separately.Opioid use disorder and neonatal abstinence syndrome (NAS) increased in Massachusetts from 1999 to 2013  of the following ICD-10-CM code combinations to assess substance-exposed newborns were calculated: 1) those related to maternal dependence on opioids (F11.20) or benzodiazepines (F13.20) and 2) those related to newborns affected by maternal drug exposure (P04.49) or experiencing withdrawal from drug exposure (P96.1). To identify NAS, the validity of codes P04.49 or P96.1 and P96.1 alone were assessed. Analyses conducted using P96.1 alone included infants from 12 of the 15 hospitals (69.5% of the weighted sample) that reported individual ICD-10-CM codes to MDPH. Substance-exposed newborns and NAS that were confirmed using abstracted clinical record data served as the diagnostic standard. Identification of substance-exposed newborns was confirmed using either a documented history of maternal substance use during pregnancy or laboratory confirmationRecords for 1,123 mother-infant pairs were abstracted; six infants were excluded because there was insufficient information in the clinical chart to confirm that the birth mother and infant were linked correctly. The data included information from four complete sets of twins and 33 other infants who constituted one member of multiparous births. Most infants were born at term (92%) and weighed >2,500 g at birth (91%) . ApproxiICD-10-CM codes can be used to monitor the prevalence of several conditions, including substance-exposed newborns and NAS. Evaluating the sensitivity and PPV of these codes can inform how well they identify actual cases. The MDPH surveillance system reports selected maternal drug dependence codes and newborn exposure codes for monitoring substance-exposed newborns separately, and this analysis found the newborn exposure codes to have higher  sensitivity than do maternal drug dependence codes within each substance exposure scenario; specificity for both types of codes was consistently high.These data demonstrate opportunities for improvement in identifying substance-exposed newborns. Implementing universal maternal screening protocols with validated screening tools to help identify maternal drug use, executing standardized facility protocols around screening and assessing newborns for substance exposure, and improving communication between patients and maternal and infant health care providers might lead to improvement in identifying substance-exposed newborns (State surveillance definitions of NAS vary widely across the United States (Using exposure (P04.49) in addition to withdrawal (P96.1) codes might be more sensitive for identifying NAS than using P96.1 alone because P04.49 might identify newborns exhibiting signs of NAS who have not received a diagnosis of withdrawal (P96.1) by providers. Because these codes provide different information, they should be selected based on the surveillance purpose. In Massachusetts, many hospitals have programs to support mothers with substance use disorder and infants with a diagnosis of NAS  diagnostic codes to surveil substance-exposed newborns and neonatal abstinence syndrome (NAS), but the ability of these codes to identify substance-exposed newborns and NAS is unknown.Massachusetts uses independent combinations of Whereas ICD-10-CM codes performed relatively well for surveillance of NAS in the sample for this study , surveillance for substance-exposed newborns using ICD-10-CM codes missed more cases (sensitivity range = 16%\u201361%).In Massachusetts, ICD-10-CM codes are effective for NAS surveillance but should be applied cautiously for surveillance of substance-exposed newborns."}
+{"text": "A community based, peer volunteer-driven educational program was developed to empower older adults to improve health behaviors through health literacy. A community needs assessment determined the curricula which included classes on chronic disease management and issues impacting older adult health. Volunteers were recruited and trained on the curricula by health educators using a train-the-trainer module. 173 volunteers convened 302 workshops, and trained 2,065 unique older adults who account for 5000 attendees. Using a pretest posttest design, an outcome evaluation found statistically significant increases in knowledge among older adult workshop attendees on 6 of the 7 health topics (p<.01). Eighty-three percent of attendees reported positive health behavior changes at 3-month follow-up. The most commonly cited changes were increased physical activity and improved nutrition. Program challenges included volunteer scheduling and retention. Building a sustainable community-based, peer volunteer-driven health education program for older adults will be discussed."}
+{"text": "Hordeum vulgar L. var. nudum) is one of the staple foods for Tibetans and an important livestock feed in the Tibetan Plateau. We report the complete mitochondrial genome of Tibetan hulless barely. The complete mitochondrial genome size is 416,675\u2009bp. Hulless barely mitochondrial genome encode 34 protein-coding genes, 19 tRNA genes and three rRNA genes. The mitochondrial genome has 50 forward and palindrome repeats totally. Nucleotide sequence of coding region takes over 13.60%, GC content is 44.33%. The maximum-likelihood (ML) phylogenetic tree based on 11 protein-coding genes common to seven plant mitochondrial genomes using Arabidopsis thaliana as out-group support that hulless barely is close to Triticum species.Hulless barley ( Mitochondrial DNA is the extra-nuclear genome in plant cytoplasm except the chloroplast DNA, most likely through the taming of an \u03b1-proteobacterial endosymbiont. Lots of evidences support that a single origin of mitochondria for all eukaryotes originated about 1.5 billion years ago (Gupta & Golding ftp://ftp.ncbi.nlm.nih.gov/refseq/release/mitochondrion) by blastn    common to seven plant mitochondrial genomes for our phylogenetic analysis. Totally 11 protein-coding genes were aligned using the MAFFT version 5 (Katoh et\u00a0al. We used 11 protein-coding genes (Sequencing the mitochondrial genome of hulless barley will provide essential genomic information for breeding, together with its nuclear and chloroplast genomes is essence to understanding the diversification and evolution of hulless barely."}
+{"text": "The chromatin insulator CCCTC-binding factor (CTCF) displays tissue-specific DNA binding sites that regulate transcription and chromatin organization. Despite evidence linking CTCF to the protection of epigenetic states through barrier insulation, the impact of CTCF loss on genome-wide DNA methylation sites in human cancer remains undefined.Here, we demonstrate that prostate and breast cancers within The Cancer Genome Atlas (TCGA) exhibit frequent copy number loss of CTCF and that this loss is associated with increased DNA methylation events that occur preferentially at CTCF binding sites. CTCF sites differ among tumor types and result in tissue-specific methylation patterns with little overlap between breast and prostate cancers. DNA methylation and transcriptome profiling in vitro establish that forced downregulation of CTCF leads to spatially distinct DNA hypermethylation surrounding CTCF binding sites, loss of CTCF binding, and decreased gene expression that is also seen in human tumors. DNA methylation inhibition reverses loss of expression at these CTCF-regulated genes.These findings establish CTCF loss as a major mediator in directing localized DNA hypermethylation events in a tissue-specific fashion and further support its role as a driver of the cancer phenotype. Primary prostate cancer (PC) is a common age-related disease with low overall mutation rates compared to other cancers . ProstatCCCTC-binding factor (CTCF), a zinc finger DNA-binding protein, is largely responsible for bridging this gap between expression and chromatin organization. CTCF functions in gene transcription and repression and as an insulator that interferes with enhancer-promoter interactions , 5. CTCFIgf2-H19 locus experiences DNA hypermethylation with CTCF downregulation at a series of intergenic CTCF sites resulting in imprinting loss during aging and cancer development . Therefore, we sought to determine whether decreased CTCF expression via CN loss in prostate and breast tumors was principally associated with hypermethylation at CTCF binding sites. Publicly available CTCF ChIP-Seq data in LNCaP was used to define putative prostate CTCF binding sites (GEO: GSE33213) and MCF7 CTCF ChIP-Seq (GEO: GSE30263) employed to define breast cancer CTCF sites. Comparing CTCF binding sites identified by ChIP-Seq against HM450 methylation data of TCGA samples demonstrates a significant enrichment for differentially methylated regions at putative CTCF binding sites  events were located within 2\u2009kb of these CTCF binding sites   of CTCF copy number alteration in primary tumors Fig. . AdaptatTo date, an instructive mechanism for the targeting of DNA hypermethylation events in aging and cancer has yet to be elucidated. It has been proposed that the evacuation of transcription factors leaves DNA vulnerable to de novo DNA methyltransferase activity (DNMT) . In addiP = 1.72e\u221215). Recent work finds that CTCF binding sites are located at the prostate cancer-specific topologically associating domains boundaries for AR loci both in normal and cancer cells which we speculate in human tumor samples may alter expression . Samples were divided by CTCF copy number alteration status to compare RNA expression and DNA methylation. Deletion samples involved over 100,000\u2009kb of the CTCF region. Analyses were conducted in R using TCGA biolinks package from Bioconductor. Boxplots and volcano plots are created using ggplot2 (Bioconductor) in R.NspI digested fragments to predict enrichment regions. Analysis was restricted only to those fragments containing CpG sequences as defined by CpG density > 2.5% [P values < 0.01 as significant; several probe regions identified by this cut point were further validated using Combined Bisulfite Restriction Analysis (COBRA) assay and MeDIP-qPCR  was performed using the HOMER package . SignifiNspI fragment or Illumina 450k Methylation array probe genomic location using BedTools.Hg19 genome annotation data was obtained from Ensembl. CTCF binding sites for prostate cells were obtained from CTCF ChIP-Seq in LNCaP cells (GEO: GSE33213). For breast cancer data, CTCF binding sites were obtained from CTCF ChIP-Seq in MCF7 cells (GSE30263). Transcribed regions including introns, exons and untranslated regions, CpG island locations, and CTCF binding sites were matched to Cytoscan HD array Additional file 1: Figure S1. Combined Bisulfite Restriction Analysis (COBRA) and MeDIP-qPCR Validation of Six Differentially Methylated Identified Probes Two different methods were used to validate probes identified by MeDIP-chip analysis in biological replicates after 5 day shRNA induction. Detailed information of array probes . Arrows denote uncut bands. (A) COBRA using TaqI (left) and MeDIP-qPCR (right) of Cytoscan HD probe C-4QPFF region. (B) COBRA using TaqI (left) and MeDIP-qPCR (right) of Cytoscan HD probe C-6LWFW region. (C) COBRA using TaqI (left) and MeDIP-qPCR (right) of Cytoscan HD probe C-4QXQN region. (D) COBRA using TaqI (left) and MeDIP-qPCR (right) of Cytoscan HD probe C-3GEQV region. (E) COBRA using BstUI restriction enzyme of Cytoscan HD probe C-3GEQV region. (F) COBRA using TaqI (left) and MeDIP-qPCR (right) of Cytoscan HD probe C-6XOOB region. Figure S2. Quantitative PCR Validation of Differentially Expressed Genes Identified by Transcriptional Array Following CTCF Knockdown (A) Six genes identified by transcriptional array profiling as down regulated following CTCF knockdown were validated using qPCR in biological replicates. Significant downregulation was confirmed in two independent shRNAs targeting CTCF following 5 days of doxycycline induction. Data shown are mean\u00b1SD of technical triplicates representative of multiple experiments . (B) Three genes identified by transcriptional array profiling as up regulated following CTCF knockdown were validated using qPCR in biological replicates. Significant upregulation was confirmed in two independent shRNAs targeting CTCF following 5 days of doxycycline induction. Data show are mean\u00b1SD of technical triplicates representative of multiple experiments . Figure S3. Expanded Results of ChIP-qPCR and meDIP-qPCR in Immortalized HPECs Following 10 days of shRNA Induction (A) ChIP-qPCR Results for TNFAIP3 promoter CTCF binding site. (B) ChIP-qPCR Results for FGF5 promoter CTCF binding site. (C) ChIP-qPCR Results for AMIGO2 promoter CTCF binding sites. (D) ChIP-qPCR Results for EPHA3 promoter CTCF binding sites. (E) MeDIP-qPCR Results for TNFAIP3 promoter CTCF binding sites. (F) MeDIP-qPCR Results for FGF5 promoter CTCF binding site. (G) MeDIP-qPCR Results for AMIGO2 promoter CTCF binding sites. (H) MeDIP-qPCR Results for EPHA3 promoter CTCF binding sites. All data are presented mean \u00b1SD of technical triplicates, one representative experiment of three. *P < 0.05; **P < 0.01. Figure S4. Methylation Quantification of LTBP2 Promoter CTCF binding site by Quantitative Pyrosequencing of Bisulfite Converted DNA to Validate meDIP-qPCR Results (A) Methylation quantification of HPECs +Dox in shCTCF2 after 10 days of shRNA induction (Data represent mean+SE of two independent experiments). (B) Methylation quantification of HPECs +Dox in shNSC after 10 days of shRNA induction (Data represent mean+SE of two independent experiments). (C) MeDIP-qPCR demonstrating increased methylation at LTBP2 promoter CTCF binding site after 10 days of shCTCF induction. Data shown are mean+SD of technical triplicates from one representative experiment of three. *P < 0.05 and *P < 0.01. Figure S5. Correlation analysis of promoter methylation vs. mRNA expression in TCGA prostate cancer samples. Methylation B-values and mRNA (log2 RSEM) expression levels compared for (A) LTBP2, (B) TNFAIP3, (C) FGF5, (D) EPHA3, and (E) AMIGO2 genes. Pearson correlation R-value shown. Data was downloaded from cBioPortal for PRAD TCGA samples (Cell 2015). Figure S6. Comparison of hypermethylated versus hypomethylated probes with proximity to CTCF binding sites in TCGA tumor samples (A) Prostate cancer cell line LNCaP CTCF ChIP-Seq (GSE33213) identified putative CTCF binding sites. The percentage of hypermethylated probes and percentage of hypomethylated probes were calculated with respect to proximity to CTCF binding sites. (B) Breast cancer cell line MCF7 CTCF ChIP-Seq (GSE30263) identified putative CTCF binding sites. The percentage of hypermethylated probes and percentage of hypomethylated probes were calculated with respect to proximity to CTCF binding sites. Figure S7. Correlation analysis of CTCF mRNA expression vs. DNMTs or AR/ER mRNA expression in TCGA prostate or breast cancer samples. CTCF mRNA (log2 RSEM) expression levels compared for (A) DNMT1, (B) DNMT3A, (C) DNMT3B in prostate cancer; (D) DNMT1, (E) DNMT3A, (F) DNMT3B in breast cancer; (G) AR in prostate cancer and (H) ER in breast cancer. Pearson correlation R-value and p-values are shown. Data was downloaded from cBioPortal for PRAD TCGA samples (Cell 2015).es Table , COBRA ces Table , and MeDes Table  are provAdditional file 2: Table S1. Significantly altered genes that contain a CTCF binding site in the TSS and significant hyper- or hypomethylation on methylation array. Table S2: Common hypermethylation CGs containing CTCF binding sites in both prostate and breast tumors. Table S3. Differentially methylated CGs in both prostate and breast tumors. Table S4: Cytoscan Probes\u2019 Characteristics Used in Array Validation. Table S5: Combined Bisulfite Restriction Analysis (COBRA) Assay Characteristics (Related to Additional file Table S6: Primer sequences of COBRA and MeDIP-qPCR used for Validation of Cytoscan Array (Related to Additional file Table S7: MeDIP-qPCR Performed region and methylation values after CTCF knockdown. Table S8: Primers Used for ChIP-qPCR and MeDIP-qPCR in Extended Knockdown Studies (Related to Fig."}
+{"text": "Background: Frailty assessment has often been performed only at baseline in cohort studies. Little is known regarding factors associated with changes in frailty indices over follow up in patients with coronary artery disease (CAD). Methods: Between 11/2008 - 8/2012, 142 community-dwelling adults \u226565 years of age with prior history of CAD (angina or revascularization) participated in a study of frailty assessment at Mayo Clinic Health System in La Crosse, WI. A sample of participants (n=45) were included for frailty re-assessment using the Fried frailty criteria approximately 5 years after their baseline measures. Frailty classification was based on absence of deficits (non-frail), 1-2 deficits (intermediately frail), or 3 or more deficits (frail). Factors associated with a change in frailty indices were studied. Results: There were 45 patients that had a second assessment of frailty indices. At baseline, 24 patients (60%) were not frail while 16 patients (40%) had at least 1 frail feature. At follow up, 20 patients (50%) were not frail while 20 patients (50%) had a frail feature. Those improving were more often being married, had prior revascularization, and were without angina. Interval development of slower gait speed  and decreased grip strength  were associated with worsening frailty. Conclusions: Older adults with CAD are not often frail by standard criteria; however, incident deficits develop during long term follow-up. Spousal support, absence of angina, and change in functional indices are less often associated with frailty features."}
+{"text": "Glioblastoma is the most common and deadly form of primary brain cancer, accounting for more than 13,000 new diagnoses annually in the USA alone. Microglia are the innate immune cells within the central nervous system, acting as a front-line defense against injuries and inflammation via a process that involves transformation from a quiescent to an activated phenotype. Crosstalk between GBM cells and microglia represents an important axis to consider in the development of tissue engineering platforms to examine pathophysiological processes underlying GBM progression and therapy.This work used a brain-mimetic hydrogel system to study patient-derived glioblastoma specimens and their interactions with microglia. Here, glioblastoma cells were either cultured alone in 3D hydrogels or in co-culture with microglia in a manner that allowed secretome-based signaling but prevented direct GBM-microglia contact. Patterns of GBM cell invasion were quantified using a three-dimensional spheroid assay. Secretome and transcriptome (via RNAseq) were used to profile the consequences of GBM-microglia interactions.Microglia displayed an activated phenotype as a result of GBM crosstalk. Three-dimensional migration patterns of patient-derived glioblastoma cells showed invasion was significantly decreased in response to microglia paracrine signaling. Potential molecular mechanisms underlying with this phenotype were identified from bioinformatic analysis of secretome and RNAseq data.The data demonstrate a tissue engineered hydrogel platform can be used to investigate crosstalk between immune cells of the tumor microenvironment related to GBM progression. Such multi-dimensional models may provide valuable insight to inform therapeutic innovations to improve GBM treatment.The online version contains supplementary material available at 10.1186/s12974-020-02026-6. Glioblastoma (GBM) is the most common and deadly form of central nervous system cancer , 2. In tMicroglia (MG) are resident immune cells of the CNS , 20. In We previously developed a gelatin-based hydrogel model platform to investigate pathophysiological processes underlying GBM cell invasion and therapeutic response. Notably, we observed that biophysical  and metabolic (hypoxia) transitions in the GBM tumor microenvironment both significantly alter GBM invasion \u201332. MoreEGFROE) and displays medium invasive potential in vivo. GBM39 possesses an EGFR variant III mutation (EGFRvIII) and displays low invasive potential in vivo [2 environment. PDCs were shipped by overnight courier and seeded into hydrogel cultures immediately upon arrival.Patient-derived GBM cells (PDCs) were obtained from Mayo Clinic . All specimens used in this study (GBM12 and GBM39) were derived from tumors from different patients then maintained as patient-derived xenografts in nude mice , 35. All in vivo , 35. GBM2 and passaged upon reaching confluence.HMC3 microglia cells  were cultured in DMEM supplemented with 10% FBS and 1% P/S. Cells were incubated at 37 \u00b0C in 5% COAll animal care protocols were in accordance with NIH Guidelines for Care and Use of Laboratory Animals and were approved by the University of Illinois Laboratory Animal Care and Use Committee. Both male and female C57BL/6J mice  were used to obtain primary microglial cultures as described previously . In brie1H NMR spectroscopy .Methacrylamide-functionalized gelatin (GelMA) macromers and GelMA hydrogels were synthesized and prepared as previously described , 37. GelThe compressive modulus of GelMA hydrogels was measured using an Instron 5943 mechanical tester . HydrogeCell-containing hydrogels were made similarly but with addition of cell suspensions (5000 cells per 25 \u03bcL hydrogel) or cell spheroids (5000 cells per spheroid per 25 \u03bcL hydrogel) to the pre-polymer solution prior to being placed into Teflon molds  and then photopolymerized.Hydrogel identification: To distinguish hydrogels containing PDCs versus microglia, all hydrogel specimens containing microglia were cut into half-disks before being placed into culture while GBM seeded hydrogels were maintained as full disks.Proteins from HMC3 microglia cultured in hydrogels (cell suspensions) were isolated using protocols described previously \u201332. WestImage-iT\u2122 Fixative Solution  was used to fix HMC3 microglia seeded hydrogels (cell suspensions). Cells were permeabilized with 0.1% Triton X-100 (Sigma-Aldrich) in PBS and stained with Alexa Fluor\u2122 488 Phalloidin (Invitrogen) for F-actin and Hoechst 33342 (Invitrogen) for nuclei following the manufacturer\u2019s protocol. Stained samples were imaged using a Zeiss LSM 700 confocal microscope.Total RNA of GBM cell-seeded hydrogels (cell suspensions) was extracted using an RNeasy Plant Mini Kit  with an additional step using an RNase-free DNase set (Qiagen) for DNase digestion. RNA integrity number (RIN) was determined using an Agilent 2100 bioanalyzer with all samples exhibiting a RIN > 8.Libraries for RNA sequencing were prepared using the TruSeq Stranded mRNAseq Sample Prep Kit . The libraries were quantitated by qPCR and sequenced on one lane for 101 cycles from one end of the fragments on a NovaSeq 6000 (Illumina) using a NovaSeq SP reagent kit and yielded 400 to 500 million single reads per lane. Library quality check was done using FastQC (version 0.11.8). Salmon version 0.13.1 was used to quasi-map reads to the transcriptome and quantify the abundance of each transcript. Filtering was set with the threshold of 0.5 counts per million and resulted in 15,901 genes to be analyzed for differential expression that contained > 99.5% of the reads. After filtering, trimmed mean of M values (TMM) normalization in the edgeR package was performed and log2-based count per million values (logCPM) were calculated \u201341. Diffg for 1 min to assist spheroid formation then placed into incubator  for 24 h. Plates were then incubated for additional 24 h with horizontal shaking at 60 rpm. Spheroids were then transferred and mixed with pre-polymerized GelMA solution and photopolymerized into hydrogels. Spheroid images were acquired using a Leica DMI 400B florescence microscope  at days 0 (immediately upon seeding), 1, 3, 5, and 7. Invasion was then quantified via ImageJ and invasion distance reported as fold change of their average radius compared to day 0 as described previously [We have previously reported a robust, three-dimensional assay to quantify GBM cell invasion in three-dimensional hydrogels \u201350; GBM eviously , 31.GBM12 cell proliferation in cell suspension hydrogels was determined using a commercial Vybrant\u00ae MTT Cell Proliferation Assay Kit (Invitrogen) adapted from the manufacturer\u2019s protocol as described previously , 32, 51.g, 10 min) to remove any debris. As an additional control, we created a 1:1 mixture of GBM single and MG single media (Mix) that would not account for any GBM-MG crosstalk mediated shifts in secretome. The secretome for each specimen was profiled using a Proteome ProfilerTM Human Angiogenesis Array Kit  following the manufacturer\u2019s protocol. Blots were imaged using an Image Quant LAS 4010 chemiluminescence imager . Dot intensities were quantified with the ImageJ macros toolset Protein Array Analyzer (Table SCell culture media was collected from the following group: GBM-MG co-cultures (co-culture), GBM cells alone (GBM single), or MG cells alone (MG single). The media were spun down 300\u00d7g, 0 min to t test. Analysis of MTT was performed via one-way ANOVA followed by Tukey\u2019s HSD post hoc test. Analyses of invasion were performed via two-way ANOVA followed by Tukey\u2019s HSD post hoc test. Significance level was set at p < 0.05 unless stated otherwise (p < 0.01 and p < 0.0001). A minimum of n = 3 samples was used for all analyses and specified in each result section. Error bars are plotted as the standard error.Statistical analysis for Western blot was performed via n = 14; Fig. GBM single, MG single) cultures were generated as either GBMWe have previously developed a family of gelatin hydrogels to investigate pathophysiological processes underlying glioblastoma invasion and progression. Extensive biophysical performance data has previously been reported including network architecture and mechanical performance , 53, watco-culture), allowing exchange of secreted factors between hydrogel disks but not allowing direct cell-cell contact  exhibited the characteristic elongated shape of quiescent MG. However, in response to co-culture with GBM12-seeded hydrogels (GBM-MG co-culture), MG adopted a rounded ameboid shape associated with activation . While CD68 is normally expressed at low levels in quiescent microglia, CD68 expression was increased in microglia co-cultured with GBM cells  a GBM single culture specimen containing RNA isolated from GBM-seeded hydrogels cultured independently (n = 3 for each group). This comparison allowed investigation of global shifts in GBM gene expression profiles only due to GBM-MG crosstalk  analysis for biological process ontology showed upregulated genes were associated with proliferation and RNA/DNA replication and proliferation, while downregulated genes were associated with motility, adhesion, and invasion  a co-culture downregulated multiple immune response-related pathways in GBM cells including nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs), tumor necrosis factor (TNF) signaling, nuclear factor kappa-beta (NF-\u03baB) signaling, toll-like receptor signaling (TLRs), and mitogen-activated protein kinase (MAPK) signaling. GBM-MG co-culture decreased focal adhesion pathway activation. Upregulated KEGG pathways included those involved in cell proliferation and survival included thyroid hormone signaling, Janus kinase-signal transducer and activator of transcription pathway (JAK-STAT) signaling, central carbon metabolism, forkhead box transcription factors (FOXO) signaling, and adenosine monophosphate-activated protein kinase (AMPK) signaling. Intriguingly, EGFR tyrosine kinase inhibitor resistance was also increased, indicating that the co-culture might also alter the therapeutic response to classes of drugs targeting receptor tyrosine kinase inhibitors. iRegulon analysis of upregulated genes showed high normalized enrichment scores for SUZ12 (NES = 7.021), RCOR1 (NES = 5.834), and REST (NES = 5.475). iRegulon analysis also showed high normalized enrichment scores for downregulated genes STAT1/2/3 (NES = 15.831/13.455/3.002) and IRF1/5/8 . Together, these analyses indicate that co-culture with microglia induces significant shifts in GBM transcriptome linked to increased proliferative behavior and decreased invasive potential.KEGG pathway analysis was used to identify the top 20 up- and downregulated pathways Table Sc. GBM-MGco-culture strongly inhibited GBM12 invasion over the course of a seven-day spheroid-based invasion assay, with effects observed as early as after 24 h . GBM39 show reduced invasive potential in vivo compared to GBM12, but nonetheless GBM39 invasion was again significantly inhibited in the multi-dimensional hydrogel model in response to nMG co-culture, with effects observed as early as day 3 , increased significantly in response to GBM-MG co-culture Fig. a. MG co-y 3 Fig. .Fig. 4Sco-culture versus GBM or MG monocultures  and a Mix media ; insulin-like growth factor binding protein 3 (IGFBP-3); angiogenin (ANG); heparin-binding epidermal growth factor-like growth factor (HB-EGF); dipeptidyl peptidase-4 (DPP4); Serpin F1; and coagulation factor III (F3). Six factors were expressed at levels greater than 0.75 of the positive reference intensity value within each secretome array  and pentraxin-related protein (PTX3) were both highly expressed in cultures containing MG  media but lowly expressed in GBM-single hydrogels. Serpin E1, tissue inhibitor of metalloproteinase-1 (TIMP-1), and vascular endothelial growth factor (VEGF) were expressed across all culture conditions.A secretome screen was performed to compare cell culture media from GBM-MG ray Fig. c. Of theCellular crosstalk within the tumor microenvironment provides a powerful avenue of interaction that may significantly shape disease progression. Tools to interrogate cellular crosstalk offer an opportunity to identify novel therapeutic compounds to improve treatment of glioblastoma. This work demonstrates the use of a tissue engineering platform to investigate the role of crosstalk between patient-derived GBM specimens and microglia on shifts in the phenotypic, proteomic, and transcriptomic signatures of GBM. GBM-MG crosstalk is bidirectional and induces microglia activation along with shifts in GBM cell activity consistent with the go-or-grow phenomenon . This woboth morphological changes and increased CD68 expression as a result of GBM-MG co-culture. These results are consistent with hallmarks of microglial activation seen in cases of disease and histopathological analysis of GBM tumors [While microglia display a quiescent phenotype in single culture, hallmarks of microglial activation were observed via M tumors , 62. TheM tumors . Indeed,co-culture upregulated genes in a patient-derived GBM specimen associated with cell cycle, RNA/DNA division and metabolic activity. However, genes involved in cell adhesion/migration showed significant downregulation as a result of GBM-MG co-culture. These findings indicate tradeoffs in GBM proliferation versus invasion due to MG crosstalk consistent with the go-or-grow dichotomy of GBM cells [NLR, TNF, NF-\u03baB, MAPK, and TLR pathways in GBM specimens in response to MG co-culture. NLR and TLR signaling pathways are involved in pathophysiological responses to inflammation and tumor progression [NF-\u03baB signaling pathway is known to be sensitive to TNF signaling [TLR and MAPK signaling involved in cell migration and tumor invasion. These pathways contribute to heightened immune responsiveness and are involved in angiogenesis and cell migration [While advanced sequencing techniques such as RNA sequencing offer the opportunity to define the transcriptomic signature of cells to aid treatment planning and outcome prediction , 44, 63,BM cells , 64, 65.gression \u201368. Of tignaling \u201371 whichignaling , 73, breignaling , and driigration , 69\u201371, TH and STAT3 signaling, indicating that secreted factors from microglia may promote GBM proliferation, reduce apoptosis, and enhance chemotherapeutic resistance [co-culture upregulated FOXO signaling, which has been linked to therapeutic resistance due to its contribution to DNA repair as well as mediation of oxidative stress. iRegulon analysis showed GBM-MG crosstalk increased enrichment for SUZ12, previously shown to be increased in high grade astrocytoma and involved in pathways that regulate glioma proliferation and metastasis [REST and RCOR1, known to regulate the oncogenic properties of GBM stem cells [IRF family has been shown to be significant tumor suppressors, inhibit tumor proliferation and loss of IRF genes may contribute to tumor metastasis and invasion [KEGG analysis also showed strong upregulation in sistance \u201377. Recesistance , 78. Mortastasis , 80. iReem cells  that assem cells , 83. Theinvasion , 85. Toginvasion , 86\u201388. EGFROE GBM12 cells co-cultured with HMC3 microglia and EGFRvIII GBM39 cells co-cultured with primary mouse neonatal microglia.The hydrogel platform was subsequently used to experimentally interrogate the influence of GBM-MG crosstalk on GBM proliferative and invasive phenotypes in patient-derived GBM12 cells. GBM12 cells exhibited significantly increased proliferation and significantly inhibited invasion in response to MG co-culture. Strikingly, MG-induced inhibition of GBM12 invasion was observed for multiple combinations of patient-derived GBM specimens and microglia: co-culture (vs. GBM-single or MG-single cultures) but also compared to the Mix control, consistent with synergistic activation of CCL2 secretion due to GBM-MG crosstalk. IGFBP-3, known to regulate cell proliferation, was also increased in GBM-MG crosstalk, though its role in cancer progression remains to be fully understood [co-culture, as was ANG, well-known for its role in angiogenesis and cell proliferation [Analysis of the combined GBM-MG secretome revealed multiple targets driving the observed shifts in functional and transcriptomic activity. CCL2 and CCL3 are associated with monocyte and macrophage recruitment \u201391 and mderstood \u201394. DPP4derstood , 96) andderstood \u201397) wereferation , 99, andferation \u2013103. Preferation  also indferation  secretomThe immune system and immune cells and their relationship with cancer have been a hot topic in recent years. Tumor-associated macrophages/microglia, or GBM-associated macrophages/microglia here, has drawn a large amount or research efforts \u201321. Whil., collagens, laminins) and hyaluronic acid (HA), complex perivascular niches, regions of hypoxia [Finally, we note the value and limits of a tissue engineering approach described herein. Glioblastoma tumors contain a heterogeneous mix of cells, including a subpopulation of tumor initiating cells  \u2013110, cri hypoxia , and mul hypoxia . We also hypoxia . While wThis study describes a tissue engineering platform to examine the role of GBM-microglia crosstalk on processes associated with GBM progression. It also shows the ability to use bioinformatic tools to identify transcriptomic shifts underlying these responses. We show dynamic, two-way interactions between patient-derived GBM cells and microglia via paracrine signaling influence both microglia and GBM cell phenotype. Microglia in the presence of patient-derived GBM cells showed morphological shifts associated with activation. Microglia co-culture significantly inhibited GBM invasion but enhanced proliferation that could be captured via three-dimensional spheroid invasion assays and transcriptomic analyses. Future efforts will seek to understand the contribution of GBM-microglia crosstalk on tumor resistance to therapeutics, to reveal candidate signaling axes for rational combinatorial targeting.Additional file 1:Figure S1. Raw images for \u03b2-actin Western blot samples . Figure S2. Raw images for CD68 Western blot samples . Table S1. Selected gene ontology (GO) biological process terms that showed significant differences in overrepresented test of GBM co-culture compared to single culture. Table S2. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways that showed significant differences in overrepresented test of GBM co-culture compared to single culture. Table S3. Secretome profiling pixel intensities for individual blots."}
+{"text": "Saccharum spp.). In response to various stresses, plants have evolved a variety of complex defense systems of signal perception and transduction networks. Transcription factors (TFs) that are activated by different pathways of signal transduction and can directly or indirectly combine with cis-acting elements to modulate the transcription efficiency of target genes, which play key regulators for crop genetic improvement. Over the past decade, significant progresses have been made in deciphering the role of plant TFs as key regulators of environmental responses in particular important cereal crops; however, a limited amount of studies have focused on sugarcane. This review summarizes the potential functions of major TF families, such as WRKY, NAC, MYB and AP2/ERF, in regulating gene expression in the response of plants to abiotic and biotic stresses, which provides important clues for the engineering of stress-tolerant cultivars in sugarcane. Increasing vulnerability of crops to a wide range of abiotic and biotic stresses can have a marked influence on the growth and yield of major crops, especially sugarcane ( Saccharum spp.) plays a crucial role in sugar and biofuel production, accounting for 80% of sugar production in the world. Genetic improvement of modern sugarcane cultivars hits a bottleneck through conventional hybrid breeding as a result of sugarcane complex genome, heterogenous and polyploid-aneuploid nature [During the life cycle of plant species, abiotic  and biotic  stresses are major threats to global crop productivity . To coped nature . cis-elements of target gene, which might be influenced by genomic features, DNA structure and TF interactions [Oryza sativa (2389), Hordeum vulgare (2620), Triticum aestivum (3437) and Saccharum spp. (672). It is noteworthy that, to date, 39 WRKY, 44 NAC, 38 MYB and 73 AP2/ERF gene families of TFs in sugarcane have been identified.Under unfavorable environmental conditions, various stress-response mechanisms have been evolved by plants at different layers, such as cellular signal perception and transduction, inducing expression of specific sub-sets of defense genes, and therefore activating the overall defense reaction, ultimately contributing to phenotype . Transcrractions . In planractions . Variousractions . AccordiIn last decade, numerous TFs involved in response to abiotic and biotic stress in different crops including sugarcane were investigated using modern molecular tools, such as functional genomics, transcriptomics and proteomics . This reIpomoea batatas in 1990s [Arabidopsis thaliana) [Saccharum spontaneum) [Hordeum vulgare) [Oryza sativa) [Jatropha curcas) [Zea mays) [Triticum aestivum) [Gossypium hirsutum) [WRKY being as one of the most characterized class of plant TFs, regulate diverse plants developmental, physiological and metabolic processes . The firin 1990s , but WRKin 1990s . A myriain 1990s . Numerouhaliana) , sugarcantaneum) , barley vulgare) , rice (O sativa) , physic  curcas) , maize (ea mays) , wheat (estivum) , cotton Arabidopsis, the most authenticated and widely accepted classification system stipulates that plant specific WRKY TFs are denoted by 60 amino acids in their highly conserved DNA binding region  [4-5-C-X22-23-H-X-H or C-X7-C-X23-H-X-C at the C-terminus having affinity towards DNA binding [4-5-C-X22-23-H-X-H) adjacent to atypical. Group II and III WRKYs have one WRKY domain. WRKYs in group I and II have the same type of finger motif, whereas group III WRKYs consists of a C-X7-C-X23-H-X-C motif at the C-terminus. WRKYs in Group II can be further categorized into five sub-groups , while WRKYs in Group III can be categorized into two groups, IIIa (C-X7-C-X23-H-X-C) and IIIb , based on the zinc-finger motif structure [S. spontaneum, as evidenced by these genes containing an incomplete domain (only the WRKYGQK motif was identified), which indicated they may have lost their function as WRKYs [Based on the genomic characterization of  domain) . Further binding . WRKY prtructure . Howeveras WRKYs . Taking AtWRKY25, AtWRKY26 and AtWRKY33) contributed to significantly higher thermo-tolerance. While double (wrky25/26) and triple (wrky25/26/33) mutants depict poor seed germination, decreased membrane integrity and increased susceptibility to temperature stress [TaWRKY1 and TaWRKY33 in Arabidopsis [TaWRKY70 [T. aestivum exhibits enhanced tolerance to heat stress. Furthermore, overexpression of TaWRKY008, TaWRKY122 and TaWRKY45 in T. aestivum also enhanced tolerance to extreme temperature stress [VaWRKY12 that was localized in the nucleus inhibited the cellular damage in Arabidopsis and grapevine after cold stress [ZmWRKY106 in Zea mays showed higher activities of antioxidants under heat stress and improved vigor of transgenic plants [High or low temperature stress has significant influence on a myriad of processes including physiological, enzymatic, metabolic, growth and developmental in plant system, hence leading to low yield with poor quality of produce . More spTaWRKY70  in T. aee stress . Overexpd stress , while oc plants .WRKY22 in Arabidopsis, by targeting genes encoding a toll/interleukin-1 receptor (TIR) domain\u2013containing protein, lead to cope the threat associated with excess soil moisture [HaWRKY76 was upregulated in Arabidopsis transgenic plants in response to excess soil moisture, imparting enhanced resistance through the repression of fermentation pathways that ensue to carbohydrates reservation [PlWRKY70, a Paeonia lactiflora TF, was considerably suppressed under waterlogging stress [Waterlogging is one of the serious threats to agriculture, as it affects the aeration ability of roots and alters the physical and chemical nature of soil, thus triggering the adverse effects on productivity of crop species worldwide . Overexpmoisture . A sunflervation . In contg stress . AtWRKY28 in Arabidopsis, positively regulated in response to drought stress [WRKY46/54/70 acted as negative regulators under drought stress [ScWRKY3 played positive regulation by sodium chloride (NaCl), polyethylene glycol (PEG), and abscisic acid (ABA), but it was suppressed by salicylic acid (SA) and methyl jasmonate (MeJA) [TaWRKY93 [ZmWRKY40 [TaWRKY2 [GhWRKY91 [GmWRKY54 [2+-mediated signal transduction pathways and osmotic adjustments. Drought, due to reduced potential water content in plants, can directly limit the normal functioning of crop plants by averting the enzymatic activities, accumulation of soluble matters, formation of ROS (reactive oxygen species) multiplexes and restricted metabolic pathways, thus making the agricultural efficiency at risk . WRKY TFt stress , whereast stress . In sugae (MeJA) . In otheTaWRKY93 , ZmWRKY4ZmWRKY40 , TaWRKY2GhWRKY91  and GmWRGmWRKY54  conferreOsWRKY89, a group III TF, through direct or indirect activation of SA mediated signal transduction pathway, not only intensified the plants resistance against UV irradiation but also imparted tolerance counter to insect pests and fungal infection [WRKY4, WRKY5, WRKY11 and WRKY46 were observed during the exposure of oxidative stress in Salvia officinalis and play a pivotal role in the signaling mechanism during plant responses [Ultraviolet (UV) light plays a crucial role from germination to the growth and development in plants . Howevernfection . Oxidatinfection , while pnfection . Overexpesponses .CsWRKY50 plays crucial role against infection stress of Pseudopernospora cubensis in Cucumis sativus [VvWRKY1, JA pathway-related gene, positively regulates the stress tolerance response to downy mildew in Vitis vinifera [CaWRKY27, confers the resistance against Ralstonia solanacearum infection in tobacco (Nicotiana tabacum) [GhWRKY44, a significant TF in cotton-pathogen interaction, it provides an enhanced tolerance in tobacco against bacterial and fungal pathogens. The plants exhibited a lower level of ROS accumulation in experimental units having overexpression of GhWRKY44 through SA and JA signal transduction pathways of disease resistance [TaWRKY70 transcription factor, through SA and ET mediated signal transduction pathways, was noted in plants when exposed to pathogen (Puccinia striiformis sp. tritici) infection [WsWRKY1 [AcWRKYs [GmWRKY31 [ScWRKY3 was stably expressed in the smut-resistant cultivar, whereas it was suppressed in the smut-susceptible cultivar at early stages (0\u201372 h) of infection with the smut pathogen (Sporisorium scitamineum). Meanwhile, this gene was proposed to act as a negative regulator under the pathogen infection either Fusarium solani var. coeruleum or Ralstonia solanacearum in N. benthamiana [WRKY33 alleles were significantly upregulated in sugarcane against the Xanthomonas albilineans attacks [During biotic stress, plants undergo the partial or complete modulation of multiple signal transduction pathways such as plant hormones, which subsequently resulted in the induction of several related transcriptional genes, thus resulting in positive response to stressful environment . Plant W sativus . VvWRKY1vinifera . In additabacum) . GhWRKY4[WsWRKY1 , AcWRKYs[AcWRKYs  and GmWRGmWRKY31  TFs in dthamiana . More re attacks . CollectNAM from Petunia hybrida [Ataf1/2 from Arabidopsis [NAC  is one of the most important and largest family of plant-specific stress-responsive TFs . NAM fro hybrida  and Atafbidopsis  were thebidopsis ,59. The bidopsis . NTLs  pathway [OsNAP exhibit improved resistance in rice against cold stress at the vegetative stage through ABA-mediated signal transduction pathway [LlNAC2 with LlZHFD4 and LlDREB1 from tiger lily enhanced the tolerance in Arabidopsis against cold, salinity and drought stresses by maintaining its membrane integrity [CaNAC064 was found a positive modulator of plant resistance to cold stress by interacting with haplo-proteins that were induced by low temperature [Crop plants employ various molecular mechanisms such as chaperon signaling, ROS scavenging, various compatible solutes accumulation, transcriptional activity, antioxidant production and induction of mitogen-activated protein kinase (MAPK) and calcium-dependent protein kinase (CDPK) cascades against heat stress ,65. NAC bidopsis . In sugae stress . ANAC019ne COR47 . Transfo pathway . Various pathway . Notablyntegrity . CaNAC06perature .Arabidopsis as overexpressing ANAC019, ANAC055 and ANAC072 genes bind specifically to drought responsive cis-element [OsNAC10 (root-specific) exhibited to improve root dynamics and to enhance drought tolerance, which ultimately leading towards sustainable plants physio-morphological and yield related attributes in rice under field conditions [OsNAC6 TF was proven to be effective for enhanced drought tolerance and root development in rice [EcNAC67 upon drought stress displayed higher seedling vigor, lower spikelet sterility and enhanced tolerance to drought stress [TaNAC47 and ONAC066 enhanced drought tolerance in wheat [GhNAC2 [Arabidopsis. In Pyrus betulifolia, overexpression of PbeNAC1 imparted resistance against chilling and drought stress by interacting with PbeDREBs [NAC016 in Arabidopsis [ShNAC1 in tomato [Aquaporins expression, stability of cell membrane, accumulation of osmo-protectants and scavenging of ROS are modulated in plants when exposed to drought stress . NAC TFsnditions . Another in rice . In trant stress . Overexpin wheat  and ricein wheat , respect [GhNAC2  showed tPbeDREBs . Few ovebidopsis  and ShNAn tomato  were alsANAC092 for higher rate of seed germination, salinity inducing lower chlorophyll loss at later stages, and the delay of leaf and flower senescence in Arabidopsis. Significantly enhanced tolerance to osmotic stress in rice was attributed by OsSRO1c gene. This gene imparts stomatal closure and hydrogen peroxide (H2O2) accumulation by interacting with several stress responsive functional and regulatory proteins [GmNAC20. Stress alleviation by GmNAC20 was regulated by the activation of the DREB/CBF\u2013COR pathway. Overexpressing GmNAC11 only led to decreased sensitivity towards salinity [TaNAC67 conferred significantly enhanced multi-abiotic stresses  tolerance in transgenic Arabidopsis [TaNAC29 in transgenic Arabidopsis plants, grown under greenhouse conditions, showed decreased sensitivity towards drought and salinity stresses with increased activity of antioxidants and lower accumulation of harmful malondialdehyde (MDA) and H2O2 contents [ThNAC7 in Tamarix hispida seedlings [Balazadeh et al.  demonstrproteins . In soybsalinity . A nuclebidopsis . Overexpcontents . Enhanceeedlings .TaNAC8 has a positive role to protect plants against the stripe rust pathogen infection [ZmNAC41 and ZmNAC100 genes were induced by JA and SA pathways, respectively, to ensure tolerance in maize against Colletotrichum graminicola [TaNAC30 [TaNAC2 [SlNAC61 against infection stress caused by the Tomato yellow leaf curl virus (TYLCV) [ONAC122 and ONAC131 TFs have imperative roles in diseases tolerance responses through the regulated expression of defense- and signaling-related genes such as OsLOX, OsPR1a, OsWRKY45 and OsNH1 [JA2 and JA2L) differentially regulated stomatal closure and reopening under pathogen attack through. Namely, JA2 played a positive role in stomatal closure by regulating the expression of an ABA biosynthetic gene, whereas JA2L served as a positive role in JA/COR (JA/coronatine)-mediated stomatal reopening by regulating the expression of genes involved in the JA metabolism [NAC4 in Arabidopsis [LsNAC069-silenced lettuce lines showed non-significant alteration in susceptibility to Bremia Lactucae, but increased resistance to Pseudomonas cichorii bacteria [Many studies showed that a number of NAC TFs play dual roles in plant immunity against various pathogens through the hypersensitive responses and ETI . A wheatnfection . ZmNAC41minicola . In cont[TaNAC30  and TaNA [TaNAC2  negative (TYLCV) . In ricend OsNH1 . In tomatabolism . Interesbidopsis . The LsNbacteria . The chacolored1 (c1)\u201d was identified in Zea mays, which encodes a MYB-protein domain involved in anthocyanin biosynthesis in aleurone layer of maize seed [The MYB family is a major and functionally diverse protein class of eukaryotes. The proteins of this family as TFs are majorly associated with protein-protein interaction, DNA binding and regulatory activity management of proteins . Severalize seed . Based on the number of repeats (varying from 1\u20134) in sequence, MYB family proteins have been classified in four groups, i.e., 1R-MYB (one repeat), R2R3-MYB (two repeats), 3R-MYB (three repeats) and 4R-MYB (four repeats) . Each reLeAN2 improved the resistance of plants against heat stress through a high level of antioxidants activity (non-enzymatic) and a low level of ROS accumulation [OsMYB1 gene can increase the tolerance of plants to both heat and salinity stresses [OsMYB55 proved to be effective in enhancing tolerance against high temperature and drought stress with improved growth and development of seedlings [TaMYB80 was effective for resistance against heat and drought stresses in transgenic Arabidopsis [PbrMYB5 from Pyrus betulaefolia imparted tolerance against cold stress by modulating the ascorbic acid biosynthesis in tobacco [Plants regulate the stress related genes and signaling networks to overcome abiotic stresses . Many ofmulation . In ricestresses . While ieedlings . In wheabidopsis . Similar tobacco .Arabidopsis. Approximately 51% MYB proteins were upregulated (such as AtMYB2/74/102) and 41% were downregulated as a result of drought stress [AtMYB44 (a member of R2R3-MYB TF subfamily) has been observed to enhance the tolerance against drought/salt-stress in soybean [BcMYB1, another member of R2R3-MYB TF subfamily, was induced strongly during water deficiency, high polyethylene glycol contents and salinity stress in Boea crassifolia. However, only marginal induction of BcMYB1 was observed in the case of low temperatures [MYB TFs have been observed to be involved in ABA signaling pathways in response to drought stress  in variot stress . Overexp soybean . Similareratures . Arabidopsis, overexpression of AtMYB37 could increase seed yield and tolerance of transgenic plants against drought stresses [PScMYBAS1 promoter was involved in positive regulation under abiotic stresses  and hormone (SA and MeJA) treatments [ScMYBAS1-3 was associated with drought resistance and biomass accumulation in rice transgenic lines [ScMYB2 was participated in an ABA-mediated leaf senescence signaling pathway and acted as a positive regulator in respond to PEG-mediated drought stress [OsMYB3 from rice was observed to enhance tolerance against cold, while OsMYB2 was observed to enhance tolerance against dehydration, cold and salt stresses [OsMYB48-1 can be distinctly induced through PEG, ABA, H2O2 and dehydration, whereas only slight induction was observed after cold and high salinity stresses. However, overexpression of OsMYB48-1 could enhance the drought and salinity tolerance in rice [TaMYB1D was proven to be effective to enhance the tolerance against drought and oxidative stresses through regulating phenylpropanoid metabolism [In stresses . In sugaeatments . Recentlic lines . Anothert stress . OsMYB3 stresses . Express in rice . Similartabolism .Arabidopsis [AtMYB4-mutated Arabidopsis plants showed enhanced tolerance to UV-B exposure because MYB4 represses the function of gene producing cinnamate 4-hydroxylase enzyme, which is involved in biosynthesis of hydroxycinnamate ester, while another protein AtMYB7 had a positive effect in producing phenylpropanoid compounds to absorb UV-B radiation [AtMYB4 and AtMYB7 are involved in regulating the balance for the production and accumulation of sunscreen compounds for radiation tolerance of Arabidopsis [GmMYB12B2, a soybean R2R3-MYB TF, rendered tolerance to UV radiation and salt stress in transgenic Arabidopsis [Among secondary metabolite, flavonoids and sinapate esters are key compounds in absorbing UV-B and enhance tolerance of plants from harmful UV-radiation effects in UV-B impaired mutant of bidopsis . Initialbidopsis ,120. Manadiation . Thus, ibidopsis . In addibidopsis .Arabidopsis, AtMYB102 was observed to enhance susceptibility against GPA (green-peach aphids) infestation [AtMYB96 acts as important molecular link between SA and ABA crosstalk, through which it can enhance the resistance against pathogens in Arabidopsis [MYB72 (root specific) act as signaling pathways convergence node in Arabidopsis [TaRIM1 increased the resistance against infestation of Rhizoctonia cerealis in transgenic wheat [y1 (yellow seed 1) of sorghum produced the 3-deoxyanthocyanidin phytoalexins against the attack of Colletotrichum sublineolum in maize [GmMYB12B2, a soybean R2R3-MYB TF, rendered tolerance to UV radiation and salt stress in transgenic Arabidopsis [CmMYB15 through lignin accumulation, which can reduce the aphid proliferation [MdMYB30, could enhance disease resistance through the regulation of wax biosynthesis in apple [CaPHL8, a novel MYB TF, was proven to be effective for increasing pepper plants immunity against Ralstonia solanacerum infection [VdMYB1, a member of R2R3-MYB TF, was observed as a positive activator of the defense response by activating the expression of stilbene synthase gene2 (VdSTS2) against infection stress caused by Erysiphe necator fungus of grapevine [In addition to abiotic stress response, MYB TFs were also observed to be involved against biotic stresses. In estation . AtMYB96bidopsis . Beneficbidopsis . Overexpic wheat . A MYB Tin maize . Overexpbidopsis . Moreoveferation . Similarin apple . CaPHL8,nfection . VdMYB1,rapevine . Overallcis-element [Arabidopsis (The AP2/ERF (APETALA2/Ethylene response element binding factors) superfamily genes are characterized by the presence of highly conserved DNA-binding domain with 60\u2013-70 amino acids in each domain . In addi-element . However-element . Until nbidopsis .Arabidopsis [TaDREB3-A1 gene displayed the enhanced tolerance in transgenic Arabidopsis plants against heat, drought and salt stresses [Arabidopsis plants overexpressing RAP2.1 showed an enhanced sensitivity to cold and drought stresses, as evidenced that RAP2.1 acting as an active transcriptional repressor in defense responses to these stresses in Arabidopsis through the down-expression of the desiccation/Cold-regulated (RD/COR) genes [BnaERF-B3-hy15mu3 mutant gene from a modified AP2/ERF TF from Brassica napus enhances freeze tolerance in transgenic Arabidopsis, as resulted from this mutant gene encoded for a factor exhibiting more binding activity with the GCC box element than the wild-type gene [Brassica napus regulated synergistically the drought-responsive element (DRE)-mediated signaling pathway by trans-active and trans-inactive at different stages of cold stress in a competitive manner [Arabidopsis lines, also exhibiting low electrolyte leakage with improved root architecture [VaERF080 and VaERF087) in Arabidopsis [BpERF13 in birch [OsDREB1G overexpressed in rice exhibited strong cold tolerance, but did not exhibit significant increase in drought or salt tolerance [AP2/ERF TFs play a significant role in several abiotic stresses tolerance most probably through ET mediated signaling cascade. The identified AP2/ERF TFs, known to be involved in abiotic tolerance, belonged to bidopsis . Overexpstresses . An obseR) genes . Anotherype gene . Two Groe manner . Expressitecture . Similarbidopsis . A recenin birch . OsDREB1olerance . Arabidopsis AtRAP2.12 is a key transcriptional regulator of the core anaerobic response controlled hydraulic conductivity of root 1 (HCR1), thereby regulating hydraulic conductivity (Lpr) and hypoxia responsive genes hence modulating the resilience of plants to multiple flooding scenarios [ZmERFB180 [TaERFVII.1 [ThRAP2.3/15/39 genes also played a vital role to cope with the waterlogging stress in the Taxodium hybrid [AP2/ERF TFs have been identified and characterized for waterlogging in many plant species. Sugarcane aerial roots developed under waterlogging stress, contribute to maintaining higher root activity and a higher ethylene concentration that increased the sensitivity of adventitious root-forming tissues and plays a principal role in aerenchyma formation . Transcrcenarios . SimilarmERFB180  and TaERERFVII.1  conferrem hybrid .Populus euphratica depicted that upregulated expression of PeDREBa exhibited significantly higher values for physio-morphological traits and signal responsive regulation of drought and salt stress [GmDREB2 overexpressed in Arabidopsis alleviated the drought stress and salt toxicity through binding specifically to the cis-element [GmDREB1 activated the expression of numerous soybean-specific stress-responsive genes i.e., an ABA receptor family protein (GmPYL21) and translation-related genes such as ribosomal proteins under diverse abiotic stress conditions [AP2si6 appeared to be more dynamically expressed in transgenic Sesamum indicum to cope with signal responsive water deficiency [OsDREP1 [AtDREB2A CA [Dreb2 genes were differentially upregulated in the presence of ABA responsive cis-element to cope with drought stress [TaDREB1 genes were induced as a result of DRE-binding protein (a transcript activator), thereby improving the tendency of wheat plants to tolerate the osmotic variations [TaDREB3 and TaCBF5L under the stress-responsive promoters HDZI-3 and HDZI-4 showed enhanced tolerance towards frost in wheat and drought resistance in barley [SodERF3 was induced by ABA, salt stress and wounding in sugarcane and overexpression of this gene in transgenic tobacco plants increased tolerance to drought and osmotic stresses [The expression analysis in t stress . A soybe-element . Anothernditions . Transcrficiency . Overexp[OsDREP1  and AtDRREB2A CA  conferret stress . TaDREB1riations . Transgen barley . Expressstresses TaPIE1 [OsEREBP1 [Soly106 [GmERF113 [OsERF83 [HvRAF, a novel AP2/ERF TF in barley, had dual regulatory functions under biotic (R. solanacearum) and abiotic  stresses [TaPIEP1 was significantly induced in response to Bipolaris sorokiniana infection. The transgenic plants with TaPIEP1 overexpression were exhibited significantly higher resistance against fungal pathogen [CaERF5 played a crucial role in protecting transgenic tobacco plants against R. solanacearum infection [Arabidopsis was observed by ectopic expression of an apple MdERF11 in response to Botryosphaeria dothidea [AP2/ERF TFs were associated with the regulation of disease resistance in plants. Overexpression of TaPIE1 , OsEREBPOsEREBP1 , Soly106[Soly106 , GmERF11GmERF113  and OsER[OsERF83  genes, istresses . In wheapathogen . In addipathogen . A peppenfection . More redothidea . CollectSaccharum species at a genome wide level due to its complex polyploid genome. There is an urgent need for employing molecular breeding tools to improve sugarcane cultivars, a vegetative propagation crop, with narrow genetic pools and a complicated genome. In addition, plant epigenetics, which is a conserved regulatory mechanism in gene expression, includes DNA methylation, histone modification, chromatin remodeling and noncoding RNA etc., which is an emerging tool to better understand the biological processes in sugarcane environmental responses.TFs play pivotal roles at transcriptional level by either suppressing or activating genes under diverse stresses. Approximately 7% coding capacity of vascular plant genome is attributed to TFs for regulating genes at transcriptional level . Thousan"}
+{"text": "We determined the ability of machine learning-based analysis of quantitative [18F]DCFPyL PET-CT. Primary tumors were delineated using 50\u201370% peak isocontour thresholds on images with and without partial-volume correction (PVC). Four hundred and eighty standardized radiomic features were extracted per tumor. Random forest models were trained to predict lymph node involvement (LNI), presence of any metastasis, Gleason score \u2265\u20098, and presence of extracapsular extension (ECE). For comparison, models were also trained using standard PET features . Model performance was validated using 50 times repeated 5-fold cross-validation yielding the mean receiver-operator characteristic curve AUC.In a prospective cohort study, 76 patients with intermediate- to high-risk PCa scheduled for robot-assisted radical prostatectomy with extended pelvic lymph node dissection underwent pre-operative [p\u00a0<\u20090.01), nodal or distant metastasis , Gleason score , and ECE . The highest AUCs reached using standard PET metrics were lower than those of radiomics-based models. For LNI and metastasis prediction, PVC and a higher delineation threshold improved model stability. Machine learning pre-processing methods had a minor impact on model performance.The radiomics-based machine learning models predicted LNI  contains supplementary material, which is available to authorized users. In primary prostate cancer (PCa), risk stratification is crucial to determine prognosis and treatment strategies. Extended pelvic lymph node dissection (ePLND) is the current standard for identification of lymph node metastases \u20133. This Prostate-specific membrane antigen (PSMA) is a type-II transmembrane protein known to be highly overexpressed on PCa cells . KaittanPSMA expression may be quantified non-invasively using PSMA ligand positron emission tomography computed tomography (PET-CT). A novel approach for quantification is to use radiomics analysis, which entails high-throughput image data mining aiming to capture a tumor\u2019s phenotype and perhaps its metastatic tendency \u201314. Mach18F]DCFPyL PET-CT data predicts metastatic disease and high-risk tumor features in patients with intermediate- and high-risk primary PCa scheduled to undergo robot-assisted radical prostatectomy and ePLND. Predictions using a full radiomics feature set were compared to those based on standard PET metrics only, and the influence of tumor delineation and partial-volume correction (PVC) was evaluated.We investigated whether machine learning-based analysis of quantitative [18F]DCFPyL PET-CT for staging purposes in a prospective cohort study (NL6754). We analyzed patients included between November 2017 and August 2019. Inclusion criteria were (1) biopsy-proven prostate adenocarcinoma and (2) clinical indication for robot-assisted radical prostatectomy with ePLND based on either an \u2265\u20098% risk score of LNI based on the Memorial Sloan Kettering Cancer (MSKCC) nomogram or any high-risk feature . Patients with distant metastases on PET for whom surgery was omitted were only included in case of histopathological confirmation. Only patients who underwent [18F]DCFPyL PET-CT at the Amsterdam UMC were included. Surgical tissue specimens (prostate and lymph nodes) were reviewed according to international guidelines by uropathologists DCFPyL, from mid-thighs to skull base, at 4\u00a0min per bed position. Images were reconstructed using iterative ordered subset expectation maximization reconstruction  with 4-mm voxel dimensions, with corrections for decay, scatter, random coincidences, and attenuation correction. Lucy-Richardson iterative deconvolution (10 iterations) was applied for PVC [Patients were scanned on a time-of-flight PET-CT system  with European Association of Nuclear Medicine Research Ltd. (EARL) accreditation . A CT sc for PVC . The ful18F]DCFPyL PET-CT scans for intra-prostatic tumor localization. A mask was manually drawn around PET avid intra-prostatic tumor volumes to constrain region-growing and prevent inclusion of bladder activity. All masks were reviewed by a second observer. If needed, consensus was reached through joint revision. Next, tumors were delineated using a region-growing algorithm with a background-adapted peak threshold DCFPyL PET-CT metrics predict disease risk in primary PCa patients, indicating that PSMA expression detected on PET is related to both local tumor histopathology and metastatic tendency. Therefore, these data could be leveraged in clinical practice to identify low-risk patients for whom ePLND will be unnecessary  and GS is not fully evident PSMA PET radiomics (without machine learning) for prediction of GS \u2265\u20098 and LNI, observing similar validation AUCs for GS (AUC 0.84) and LNI prediction (AUC 0.85) [68Ga]PSMA could predict LNI, and observed AUCs of 0.70\u20130.76, similar to the AUCs we observed for standard PET metrics [18F]- and [68Ga]-labeled PSMA ligands.Zamboglou et al. similarly investigated use of [UC 0.85) . However metrics . Combine18F]FDG PET in esophageal cancer, PVC and delineation method did not affect the predictive value of textural features, despite an effect on absolute reads [18F]DCFPyL in primary prostate cancer, we observed that PVC had a substantial impact on most radiomics features and that delineation threshold mainly affected morphological features . External and multicenter validation of the models trained on the current dataset is needed to determine the net benefits of using radiomics versus standard PET metrics in clinical practice.Machine learning-based analysis of quantitative [ESM 1(PDF 45\u00a0kb).ESM 2(PDF 570\u00a0kb).ESM 3(PDF 135\u00a0kb).ESM 4(PDF 136\u00a0kb)."}
+{"text": "Brain-derived neurotrophic factor (BDNF) signals through its cognate receptor tropomyosin receptor kinase B (TrkB) to promote the function of several classes of inhibitory interneurons. We previously reported that loss of BDNF\u2013TrkB signaling in cortistatin (Cort)-expressing interneurons leads to behavioral hyperactivity and spontaneous seizures in mice. We performed bulk RNA sequencing (RNA-seq) from the cortex of mice with disruption of BDNF\u2013TrkB signaling in cortistatin interneurons, and identified differential expression of genes important for excitatory neuron function. Using translating ribosome affinity purification and RNA-seq, we define a molecular profile for Cort-expressing inhibitory neurons and subsequently compare the translatome of normal and TrkB-depleted Cort neurons, revealing alterations in calcium signaling and axon development. Several of the genes enriched in Cort neurons and differentially expressed in TrkB-depleted neurons are also implicated in autism and epilepsy. Our findings highlight TrkB-dependent molecular pathways as critical for the maturation of inhibitory interneurons and support the hypothesis that loss of BDNF signaling in Cort interneurons leads to altered excitatory/inhibitory balance. Mounting evidence suggests that brain-derived neurotrophic factor (BDNF) signals through its receptor TrkB to promote inhibitory interneuron function, including a subpopulation of cortistatin-expressing (Cort) neurons. This study identifies how TrkB depletion in Cort neurons impacts the Cort interneuron transcriptome as well as gene expression in the surrounding cellular milieu of mouse cortex. Our findings highlight TrkB-dependent molecular pathways in the maturation of inhibitory interneurons and further implicate BDNF signaling as critical for regulating excitatory/inhibitory balance. We identified BDNF regulation of a number of genes expressed in Cort neurons that are implicated in both autism and epilepsy, which is of note because these conditions are highly comorbid, and are hypothesized to share underlying molecular mechanisms.Signaling of brain-derived neurotrophic factor (BDNF) via its transmembrane receptor tropomyosin receptor kinase B (TrkB) plays a significant role in the maturation and function of inhibitory neurons in the cortex and hippocampus . AlthougBDNF\u2013TrkB signaling plays an important role in the development of several classes of inhibitory interneurons. For example, BDNF regulates the differentiation and morphology of hippocampal interneurons , and BDNIH  has been used to identify molecular profiles for many cell types in the mouse brain, including Cort interneurons . Here, wCort promoter (Corttm1(cre)Zjh/J; referenced in text as CortCre; stock# 010910, The Jackson Laboratory; RRID:IMSR_JAX:010910; loxP-flanked TrkB allele  and CortCre;TrkBflox/flox . As seizure onset begins at P21  under control of Cre-recombinase. For RiboTag experiments in Cort neurons, the groups were adult CortCre; Rpl22HA Input versus CortCre; Rpl22HA immunoprecipitation (IP). For RiboTag experiments in TrkB-deleted versus TrkB-intact Cort neurons, the groups were P21 CortCre; Rpl22HA mice and CortCre;TrkBflox/flox;Rpl22HA mice .For bulk homogenate RNA-seq experiments, the groups were postnatal day 21 (P21) Corts at P21 , mice maad libitum access to standard laboratory chow and water. Mice were group housed based on genotype. All experimental animal procedures were approved by the SoBran Biosciences Institutional Animal Care and Use Committee. Male and female mice were included and analyzed for all experiments.All mice were housed in a temperature-controlled environment with a 12 h light/dark cycle and Cre;TrkBflox/flox mice, RNA was extracted using Life Technologies TRIzol (Thermo Fisher Scientific), purified using RNeasy minicolumns (Qiagen), and quantified using a Nanodrop spectrophotometer (Agilent Technologies). RNA concentrations were normalized and reversed transcribed using Life Technologies Superscript III (Thermo Fisher Scientific). Quantitative PCR (qPCR) was performed using a Realplex Thermocycler (Eppendorf) with Life Technologies GEMM mastermix (Thermo Fisher Scientific) and 40 ng of synthesized cDNA. Individual mRNA levels were normalized for each well to Gapdh mRNA levels. For validation of genes differentially expressed in control and experimental Ribotag samples, cDNA was synthesized using the Ovation RNA Amplification System V2 Kit (described below), and qPCR was performed as above. TaqMan probes were commercially available from Thermo Fisher Scientific  or as described in the study by t test. Data are presented as the mean \u00b1 SEM and statistical significance was set at *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.Mice were cervically dislocated, and cortices were flash frozen in isopentane. For bulk homogenate experiments in P21 control and CortCre;TrkBflox/flox P21 mice were cervically dislocated and the brains were removed from the skull, flash frozen in isopentane, and stored at \u221280\u00b0C. Brain tissue was equilibrated to \u221220\u00b0C in a cryostat (Leica), and serial sections of cortex were collected at 16 \u03bcm. Sections were stored at \u221280\u00b0C until completion of the RNAScope assay. We performed single-molecule fluorescent in situ hybridization using the RNAscope Fluorescent Multiplex Kit version 2  according to the study by Wt1  and Cre  probes. Probes were fluorescently labeled with orange , green , or far red  fluorophores using the Amp 4 Alt B-FL. Confocal images were acquired in z-series at 63\u00d7 magnification using a Zeiss 700LSM confocal microscope. Images were blinded, and transcript colocalization was quantified using custom MATLAB functions. Briefly, cell nuclei were isolated from the DAPI channel using the cellsegm toolbox  and CortCre;TrkBflox/flox (n = 5) mice were collected and flash frozen in isopentane. RNA was extracted from one hemisphere of each animal using Life Technologies TRIzol (Thermo Fisher Scientific), purified with RNeasy minicolumns (Qiagen), and quantified using Nanodrop. The Nextera XT DNA Library Preparation Kit was used to generate sequencing libraries according to manufacturer instructions. Samples were sequenced on the HiSeq2000 (Illumina).Cortices of control  were collected and flash frozen in isopentane. For each sample , one hemisphere of the cortex from each animal was homogenized according to previously described protocols (AB_2565334) and Pierce A/G magnetic beads . RNA from Input and IP samples was purified using RNeasy microcolumns (Qiagen) and quantified using the Invitrogen Ribogreen RNA Assay Kit . Sequencing libraries were prepared using the SMARTer Stranded RNA-Seq Kit (Clontech) and sequenced on the HiSeq2000 (Illumina).Cortices of Cortrotocols . An aliqn = 6) or CortCre;TrkBflox/flox;Rpl22HA (n = 6) mice were collected and flash frozen in isopentane. One hemisphere of the cortex from each animal was homogenized according to previously described protocols  according to manufacturer instructions from 10 ng of RNA. Library concentration was quantified using the KAPA Library Quantification Kit . Libraries were sequenced using the MiSeq Reagent Kit v3  and NuGEN Custom SoLo primer.Cortices of control , (3) only genes that were syndromic or had gene scores of 1 or 2 , and (4) only genes that had gene scores of 1 or 2, ignoring syndromic genes (N = 91 genes). All RNA-seq analysis code is available on GitHub: https://github.com/LieberInstitute/cst_trap_seq. Raw RNA-seq reads are available at BioProject Accession PRJNA602667.Cross-species enrichment analyses of the human SFARI  and HarmWe used paired end read alignment and gene counting for these 10 samples (5 per genotype group). We analyzed 21,717 genes with reads per kilobase per million counted/assigned  >0.1. We performed differential expression analysis with limma voom using genotype as the main outcome of interest, further adjusting for the gene assignment rate (measured by featureCounts), the chrM mapping rate, and one surrogate variable.We used paired end read alignment and gene counting for these six samples (three input and three IP). We analyzed 21,776 genes with RPKM > 0.1. We performed differential expression analysis with limma voom using fraction (IP vs Input) as the main outcome of interest, further adjusting for the gene assignment rate (measured by featureCounts) and also using the duplicateCorrelation function in limma to treat each mouse as a random intercept by using linear mixed-effects modeling.We used single end read alignment and gene counting for these 12 samples (6 per genotype). We analyzed 21,187 genes with RPKM > 0.1. We performed differential expression analysis with limma voom using genotype as the main outcome of interest, further adjusting for the gene assignment rate (measured by featureCounts).Cre;TrkBflox/flox; Cre;TrkBflox/flox (n = 5) and littermate controls (n = 5). Among the 21,717 expressed genes (at RPKM > 0.1), we identified 33 differentially expressed between CortCre;TrkBflox/flox and controls at FDR < 0.1 including 15 genes with absolute fold changes >2 . We also observed decreased expression of ATPase plasma membrane Ca2+ transporting 4 (Atp2b4), matrilin 2 (Matn2), and cholinergic receptor nicotinic alpha 4 subunit . These genes encode proteins that are important for intracellular calcium homeostasis, formation of filamentous networks in the extracellular matrix, and acetylcholine signaling, respectively  and neuronal pentraxin II (Nptx2), additional genes of interest due to their roles in packaging neuropeptides into secretory vesicles and excitatory synapse formation, in CortCre;TrkBflox/flox mice compared with control mice , logFC , t [moderated t statistic ], P.Value , adj.P.Val , B , gene_type (gencode class of gene), EntrezID (Entrez Gene ID), AveExpr [Average expression on the log2(counts per million + 0.5) scale], Length (coding gene length), and ensemblID (Ensembl gene ID). Download Figure 1-1, CSV file.Differential gene expression analysis of Cort10.1523/ENEURO.0310-19.2019.f1-2Figure 1-2Cre and CortCre;TrkBflox/flox bulk cortex. Columns represent Cluster , ONTOLOGY , ID (gene ontology ID), Description (gene ontology set description), GeneRatio , BgRatio , Pvalue , p.adjust [Benjamini\u2013Hochberg-adjusted p value (FDR)], qvalue , geneID [gene symbols corresponding to the differentially expressed genes in the GO set ], and Count [number of differentially expressed genes in the GO set ]. Download Figure 1-2, CSV file.Gene ontology analysis of differentially expressed genes between CortCre;TrkBflox/flox cortex compared with control, we performed gene ontology (GO) analysis on the subset of 269 marginally significant (at p < 0.005) genes with Entrez gene IDs, stratified by directionality , neuron projection terminus (p = 2.63 \u00d7 10\u22124), and collagen-containing extracellular matrix (p = 3.06 \u00d7 10\u22128). Analysis with the molecular function category showed terms such as calcium ion transmembrane transporter activity (p = 4.75 \u00d7 10\u22124), glutamate receptor activity (p = 1.35 \u00d7 10\u22123), and excitatory extracellular ligand-gated ion channel activity (p = 1.52 \u00d7 10\u22123). Analysis with the biological processes category showed terms such as positive chemotaxis (p = 3.07 \u00d7 10\u22124), calcium ion-regulated exocytosis (p = 6.67 \u00d7 10\u22124), and neurotransmitter-gated ion channel clustering (p = 4.55 \u00d7 10\u22124). Together, GO analysis of differentially expressed genes supports the hypothesis that the disruption of BDNF\u2013TrkB signaling in Cort interneurons impacts signaling pathways that control excitatory/inhibitory balance and network excitability.To identify signaling pathways impacted by differentially expressed genes in CortCre) to mice expressing a Cre-dependent HA peptide tag on the RPL22 ribosomal subunit , logFC , t [moderated t statistic ], P.Value , adj.P.Val , B , gene_type (gencode class of gene), EntrezID (Entrez Gene ID), AveExpr [average expression on the log2(counts per million + 0.5) scale], Length (coding gene length), and ensemblID (Ensembl gene ID). Download Figure 2-1, CSV file.Differential gene expression analysis of Cort10.1523/ENEURO.0310-19.2019.f2-2Figure 2-2n = 100) found to be enriched in our IP samples from Cort neurons. Box highlights Cort-positive neurons. Download Figure 2-2, TIF file.CSEA of IP-enriched genes in Cort neurons. CSEA of IP-enriched genes identifies Cort interneurons. Bullseye plot of the output of CSEA reveals a substantial over-representation of Cort-positive neuron cell transcripts at multiple pSI levels among those transcripts , ONTOLOGY , ID (gene ontology ID), Description (gene ontology set description), GeneRatio , BgRatio , Pvalue , p.adjust [Benjamini\u2013Hochberg-adjusted p value (FDR)], qvalue , geneID , Count ]. Download Figure 2-3, CSV file.Gene ontology analysis of differentially expressed genes between CortCort transcripts in IP compared with the Input fraction  and depletion of glial fibrillary acidic protein (Gfap) and Bdnf exon IV-containing transcripts , including 627 genes with absolute fold changes >2  and significant depletion of transcripts for Gfap, Mal (T-cell differentiation protein), Slc25a18 (solute Carrier Family 25 Member 18) and Bdnf, genes enriched in astrocytes, oligodendrocytes, and excitatory neurons, respectively (Nxph1), synaptotagmin 2 (Syt2), tetratricopeptide repeat domain 9B (Ttc9b), and S100 calcium binding protein A10 (S100a10). These genes are of particular interest given their role in synapse function and calcium signaling  to allow for HA tagging of ribosomes in control Cort interneurons  or TrkB-depleted Cort interneurons , tagged ribosomes were selectively immunoprecipitated (IP) from cortical homogenate tissue (Input) using an anti-HA antibody. Ribosome-associated RNA was isolated from IP samples and total RNA was isolated from Input samples.To better understand signaling pathways and cellular functions modulated by BDNF\u2013TrkB signaling in Cort cells, we performed TRAP followed by RNA-seq in TrkB-depleted Cort interneurons. We intercrossed Cort10.1523/ENEURO.0310-19.2019.f3-1Figure 3-1Cre IP vs CortCre;TrkBflox/flox IP for all expressed genes. Columns represent Symbol (mouse gene symbol), logFC , t [moderated t statistic [with empirical Bayes)], P.Value , adj.P.Val , B , gene_type (gencode class of gene), EntrezID (Entrez Gene ID), AveExpr [average expression on the log2(counts per million + 0.5) scale], Length (coding gene length), and ensemblID (Ensembl gene ID). Download Figure 3-1, CSV file.Differential gene expression analysis of Cort10.1523/ENEURO.0310-19.2019.f3-2Figure 3-2Cre IP vs CortCre;TrkBflox/flox IP. Columns represent Direction , Cluster , ONTOLOGY , ID (gene ontology ID), Description (gene ontology set description), GeneRatio , BgRatio , Pvalue , p.adjust [Benjamini\u2013Hochberg-adjusted p value (FDR)], qvalue , geneID , and Count [number of differentially expressed genes in the GO set ]. Download Figure 3-2, CSV file.Gene ontology analysis of differentially expressed genes between Cort10.1523/ENEURO.0310-19.2019.f3-3Figure 3-3Cre vs CortCre;TrkBflox/flox bulk cortex; CortCre Input vs IP; or CortCre IP vs CortCre;TrkBflox/flox IP). TRUE indicates that gene was significant in that particular \u03c72 enrichment test for that dataset and SFARI gene set. The first column indicates the Gencode ID. Download Figure 3-3, CSV file.Cort-enriched and TrkB-dependent genes in SFARI. Rows indicate SFARI genes  that were differentially expressed in at least one dataset , adj.P.Val , setSize (number of genes in the disease gene set), numSig , ID (Harmonizome ID), and sigGenes [genes significantly differentially expressed and in the disease set (i.e. those genes driving the enrichment)]. For the \u201cIP vs Input\u201d tab, columns represent Harmonizome disease set description, Enrich_OR (odds ratios from genes significantly more highly expressed in Cort neurons than in Input), Enrich_Pval , Deplete_OR (odds ratios from genes significantly more highly expressed in Input vs Cort neurons), Deplete_Pval , and setSize (number of genes in the disease gene set). Download Figure 3-4, XLSX file.Cort-enriched and TrkB-dependent genes in Harmonizome database. Each Excel tab indicates the enrichment analyses from each disease gene set in the Harmonizome database. For \u201cBulk\u201d and \u201cIP genotype\u201d tabs, columns represent Harmonizome disease set description, OR , p.value , we identified 444 differentially expressed between IP RNA fractions at FDR < 0.05, including 75 genes with fold changes >2  of Wilms tumor 1 (Wt1), synaptotagmin 6 (Syt6), and G-protein subunit gamma 4 (Gng4) transcripts . We observed significant depletion of transcripts for the transient receptor potential cation channel subfamily C member 6 (Trpc6), calbindin 1 , and galectin 1  transcripts . Several of these genes are of interest due to their involvement in calcium signaling/homeostasis . Furthermore, we showed significant depletion of Trpc6, Calb1, and Lgals1 transcripts  compared with control Cort neurons . Similarly, of the 937 genes in the \u201cHuman gene\u201d SFARI database (which contains genes with rare variations associated with ASD from sequencing studies) with homologs expressed in our data, 93 were differentially expressed . These enrichments were preserved in the more stringent subset of ASD genes, either with  or without  syndromic genes . We further found significant enrichment for the overlap of genes differentially expressed in TrkB-depleted Cort cells compared with control Cort cells with those identified in both human and animal models of ASD as identified by SFARI . Similarly, of the 917 genes in the Human gene SFARI database with homologs expressed in our data, 66 were differentially expressed , which were preserved in the smaller subset of more stringent ASD genes with  or without  syndromic genes .Finally, we explored the potential clinical relevance of deficits in Cort neuron function using predefined genes sets from autism-sequencing studies [using Simons Foundation Autism Research Initiative (SFARI)] and disease ontologies (using Harmonizome). We found no significant enrichment in our bulk RNA-seq data with those identified in both autism spectrum disorder (ASD) and animal models relevant for ASD by the SFARI . Howeverp = 1.93 \u00d7 10\u221212; Extended Data In addition to the overlap of ASD-relevant genes with those important for Cort identity and function, there was significant enrichment of many gene sets related to psychiatric disorders (at both the diseases and endophenotype levels) in the Harmonizome database  with thoCre;TrkBflox/flox and control mice and identified significant differential expression of genes important for excitatory neuron function. Pathway analysis of these differentially expressed genes revealed functions associated with glutamatergic synapses and synaptic membranes , which encodes a synaptic protein implicated in excitatory synapse formation and neural plasticity  that influences cortical excitability by reducing excitatory transmission onto neurons in the lateral habenula . Because TrkB receptors were selectively depleted from Cort interneurons, which do not synthesize BDNF , mild seizures may have already have begun and could be influencing gene expression. In summary, depletion of TrkB receptors from Cort inhibitory interneurons may disrupt inhibitory signaling, leading to disinhibition of cortical excitatory neurons and disruption of network activity. This imbalance may push the cortex toward elevated excitation and increased expression of activity-regulated genes such as Bdnf, Nptx2, and Npy.ize BDNF , Bdnf inpression . Alternaseizures , and incseizures . TherefoSyt2, a synaptic vesicle membrane protein (Nxph1, a protein important for dendrite\u2013axon adhesion (Mal, which is implicated in myelination (Apoe, which is synthesized in astrocytes (Cort promoter in a bacterial artificial chromosome, and gene expression data were obtained using a microarray approach combined with TRAP. Here, we used a mouse that expresses Cre from the endogenous Cort promoter, and gene expression data were obtained using a Ribotag/RNA-seq approach. Reassuringly, there is significant overlap between the Doyle microarray dataset and our RNA-seq analysis (Extended Data Translatome profiling in Cort neurons showed enrichment of neuron-relevant genes such as  protein  and Nxphadhesion . We alsolination , and Apotrocytes . These dCre;TrkBflox/flox mice, we compared the translatomes of intact Cort interneurons and Cort interneurons depleted of TrkB receptors. TrkB-depleted Cort neurons show dysregulation of genes associated with calcium ion homeostasis (Calb1, calcium binding protein; Syt6, calcium dependent exocytosis; Robo1, axon guidance; Lgals1, plasma membrane adhesion molecule; To identify putative molecular mechanisms that contribute to Cort interneuron dysfunction in CortCxcr4, a chemokine receptor, is reduced in TrkB-depleted cortistatin interneurons by a factor of 4, which supports previous work showing modulation of CXCR4 expression and receptor internalization by BDNF\u2013TrkB signaling (Cxcr4, calcium signaling is important for stimulating (Cre;TrkBflox/flox mice show decreased expression of genes in calcium-related GO categories compared with control mice (Calb1. Importantly, exogenous application of BDNF induces the elevation of intracellular calcium (During development, cortical interneurons are generated in the ventral subcortical telencephalon and travel long distances to reach their final destination in cortical circuits, both tangentially from their birthplace in the ganglionic eminences and radially to their correct laminar position . Chemokiignaling . Degradaignaling . Deletioignaling  and mutaignaling , prematuignaling . The facignaling  providesmulating  and haltmulating  neuronalrol mice , such as calcium , and end calcium . AdditioIn summary, we provide evidence that the loss of BDNF\u2013TrkB signaling in Cort interneurons leads to alterations in calcium signaling and axon development in these cells, which may contribute to altered excitatory/inhibitory balance in the cortex. Several of the genes enriched in Cort neurons and differentially expressed in TrkB-depleted neurons are implicated in both ASD and epilepsy. These data shed light on the role of BDNF\u2013TrkB signaling in the function of Cort-expressing interneurons and provide the rationale for further functional studies of these interneurons."}
+{"text": "In patients with ascending aortic (AA) aneurysms, prosthetic graft replacement yields benefit but risk for complications in the descending aorta persists. Longitudinal impact of AA grafts on native descending aortic physiology is poorly understood.Transthoracic echocardiograms (echo) in patients undergoing AA elective surgical grafting were analyzed: Descending aortic deformation indices included global circumferential strain (GCS), time to peak (TTP) strain, and fractional area change (FAC). Computed tomography (CT) was used to assess aortic wall thickness and calcification.46 patients undergoing AA grafting were studied; 65% had congenital or genetically-associated AA : After grafting (6.4\u00b17.5 months), native descending aortic distension increased, irrespective of whether assessed based on circumferential strain or area-based methods (both p<0.001). Increased distensibility paralleled altered kinetics, as evidenced by decreased time to peak strain (p = 0.01) and increased velocity (p = 0.002). Augmented distensibility and flow velocity occurred despite similar pre- and post-graft blood pressure and medications , and was independent of pre-surgical aortic regurgitation or change in left ventricular stroke volume (both p = NS). Magnitude of change in GCS and FAC was 5\u201310 fold greater among patients with congenital or genetically associated AA vs. degenerative AA (p<0.001), paralleling larger descending aortic size, greater wall thickness, and higher prevalence of calcific atherosclerotic plaque in the degenerative group . In multivariate analysis, congenital/genetically associated AA etiology conferred a 4-fold increment in magnitude of augmented native descending aortic strain after proximal grafting  independent of age and descending aortic size.Prosthetic graft replacement of the ascending aorta increases magnitude and rapidity of distal aortic distension. Graft effects are greatest with congenital or genetically associated AA, providing a potential mechanism for increased energy transmission to the native descending aorta and adverse post-surgical aortic remodeling. Prosthetic graft replacement is a well-established interventional therapy for patients with ascending thoracic aortic aneurysms (AA), in whom it provides potential lifesaving benefits and is recommended by consensus guidelines , 2. WhilOne reason for heightened risk following prosthetic graft surgery may be due to altered vascular tissue properties of the native aorta. An added factor may stem from the impact of grafts on aortic physiology. Prosthetic grafts differ from the native aorta with respect to geometry and distensibility \u201312, and This study examined temporal changes in descending aortic mechanics among patients undergoing prosthetic graft replacement of the ascending aorta. To do so, transthoracic echocardiography (echo) was used to quantify descending aortic distension (strain) and flow pre- and post-operatively, together with input variables including left ventricular function and aortic size. Goals were to (1) determine impact of AA graft implantation on descending aortic distension post-operatively; and (2) identify pre-operative clinical, hemodynamic, and imaging variables associated with graft-induced effects on the native descending aorta.This entailed a retrospective review of pre-existing  data; informed consent for study participation was not obtained given the retrospective nature of this protocol. The study protocol was approved by the Weill Cornell Institutional Review Board, which approved analysis of pre-existing data for research purposes, approved query of institutional databases to identify eligible patients for this study (prior to data de-identification), and waived the requirement for informed consent. A pre-designated study investigator (JWW) oversaw access to patient identifiers for data query purposes prior to data de-identification for image/research analyses.The population comprised patients who underwent surgical prosthetic graft replacement of the AA, in whom transthoracic echo was performed pre- and post-operatively. Patients were included based on availability of echo datasets inclusive of descending aortic images of adequate quality to assess distension pre- and (within two years) post-operatively. CT (available in 74%) was used to further test whether descending aortic wall thickness modified graft response. To examine the primary impact of prosthetic grafts on descending aortic physiology, patients with concomitant conditions known to affect aortic distension  were excluded.Patients underwent prosthetic graft surgery and imaging at New York Presbyterian Hospital/Weill Cornell Medicine : Aortic reconstruction was performed using polyethylene terephthalate (Dacron) grafts. Demographic indices were compiled via review of electronic medical records. AA etiology  and diagnostic categories were classified based on review of clinical/records and images by a dedicated study investigator (JK) blinded to strain analyses.Transthoracic echoes were performed in accordance with consensus  guidelines  using coChest CT imaging was performed in accordance with standard clinical protocols. The imaging field of view varied based on body habitus, with adjustments made to encompass the thoracic aorta. Images were acquired using both ECG gated and non-gated algorithms. In 81% of exams, iodinated contrast was intravenously infused in conjunction with image acquisition with contrast timing tailored to opacify the thoracic aorta.Aortic size and deformation were assessed on echo using short axis images . Strain analyses were performed using commercial software . In brief, multiple (~10) seed points were placed equidistantly throughout the circumference of the aorta. Automated speckle tracking was then performed such that seed points were tracked throughout the cardiac cycle. Automated tracking analyses were visually inspected: If deemed suboptimal , seed points were manually adjusted to optimize vessel tracking. Consistent with prior studies by our group and others \u201317, the Global Circumferential Strain (GCS)\u2013peak circumferential deformation of the aortic wall between systole and diastole (measured as the relative (%) difference between these two time points; [end-systole\u2013end-diastole] / end-diastole * 100).Pulse Pressure Adjusted GCS\u2013GCS normalized for pulse pressure (systolic\u2013diastolic blood pressure), the latter of which was based on brachial measurements at time of echo [ of echo .Time to peak (TTP) strain\u2013calculated as the time interval between initial LV systolic contraction (R wave onset) and maximal circumferential aortic strain.Aortic analyses also included quantification of end-systolic luminal area (ESA) and end-diastolic area (EDA) as well as corresponding linear diameters. Aortic area measurements were used to calculate fractional area change (FAC = [ESA\u2013EDA]/EDA). In addition, aortic distensibility (AD) was calculated via an established equation (AD = [ESA\u2013EDA] / [EDA x PP]), for which PP represents pulse pressure, and EDA and ESA the area of the descending aorta at end systole and end diastole .Aortic regurgitation (AR) was assessed based on 2D and Doppler indices of severity, including jet width, vena contracta, pressure half-time, and calculated regurgitant volume/ fraction: Aggregate data was used to assess AR severity, which was graded in accordance with consensus guidelines .LV chamber size and function were quantified on echo based on standardized linear dimensions measured in parasternal long axis orientation, concordant with established methods validated in prior research , 22. LV Aortic wall thickness was measured on CT using (double oblique) reformatted short axis images in the mid descending thoracic aorta. CT datasets were also reviewed for presence of calcific atherosclerotic plaque in the aortic arch and descending thoracic aorta, which was graded in a binary (present/absent) manner.Comparisons between groups were made using Student\u2019s t-test (expressed as mean \u00b1 standard deviation) for continuous variables. Categorical variables were compared using chi-square or Fisher\u2019s exact test (when < 5 expected outcomes per cell). Bivariate correlation coefficients were used to evaluate associations between continuous variables. Univariable and multivariate modeling was performed via linear regression. Reproducibility of GCS was assessed based on mean difference and limits of agreement (mean \u00b1 1.96 standard deviation) between repeated measurements, as well as intra-class correlation coefficients (ICC). Statistical calculations were performed using SPSS 22.0 . Two-sided p<0.05 was considered indicative of statistical significance.The population comprised 46 patients with AA aneurysms who underwent elective surgical prosthetic graft repair. Aneurysms were attributable to congenital or genetically associated conditions in over half (63% [n = 30]) patients, including 30% (n = 14) with bicuspid aortic valve, 22% (n = 10) with Marfan syndrome and 13% (n = 6) with other conditions. In the remaining 37% (n = 16) of patients, AA was deemed sporadic (degenerative) in etiology.Echo was performed at median [inter-quartile range] intervals of 1.9 [0.6\u20134.5] and 2.4 [0.7\u201312.4] months pre- and post-operatively. Alterations in descending aortic distensibility primarily occurred in patients with congenital or genetically associated aneurysms: As shown in Of note, time to peak strain decreased across the study population (p = 0.01), reflecting similar patterns in patients with congenital or genetically associated and degenerative AA aneurysms. Similarly, pulsed wave Doppler derived velocity (assessable in 59% of patients) increased post-operatively . Despite differences in imaging-evidenced temporal indices, non-invasive pulse pressure was similar pre- and post-operatively , possibly reflecting imprecision of brachial arterial blood pressure measurements.\u0394 = 0.39, limits of agreement [LOA] = -3.40, 2.62), and inter-observer reproducibility .Reproducibility of strain indices was tested in 15 random exams (33% of study population), among whom descending aortic GCS strain yielded good intra-observer  or vascular tissue properties. Second, it is important to recognize that whereas current analyses demonstrated good reproducibility of GCS within our dataset, further research is warranted to establish reproducibility across vendor platforms and in larger epidemiologic cohorts. It should also be noted that our study examined native aortic distension as an endpoint rather than actual clinical events, and that our study entailed longitudinal imaging comparisons in patients undergoing surgery: Although lack of a  control group prohibited us from fully excluding disease evolution as a cause for change in descending aortic distensibility, descending aortic size was similar (p = NS) before and after surgical grafting\u2014supporting the notion that changes in aortic strain were not attributable to localized aortic remodeling (dilation) as would be expected in the context of disease progression. Moreover, our current results build upon prior work by our group in which intra-operative transesophageal echo data demonstrated that descending aortic strain increased near immediately after graft implantation\u2013supporting the notion that graft effects on aortic biomechanics were primarily responsible for our observed longitudinal changes in strain on serial transthoracic echo. Last, it is important to recognize that whereas our data showed native descending aortic distension to similarly increase in patients with genetic and BAV-associated AA, clinical studies have shown that risk for dissection after graft surgery is elevated in Marfan syndrome patients whereas risks in patients with BAV is predominantly (if not exclusively) limited to recurrent aneurysmal dilation . In thisIn conclusion, findings of this study suggest that prosthetic graft replacement of the ascending aorta increases magnitude and early timing of distal aortic distension in patients with congenital or genetically associated AA. Future studies are warranted to test whether post-operative changes in native aortic distensibility varies based on extent of grafting or genetic etiology of AA, and whether graft-induced effects are modifiable based on graft design or predictive of long-term event risk.S1 FileA de-identified data set encompassing key variables used for analysis has been included.(XLSX)Click here for additional data file."}
+{"text": "Pulmonary vein antrum isolation (PVAI) has become an effective therapy in patients with paroxysmal atrial fibrillation (AF). Extension and location of ablation lesions often remain unclear during the procedure.We evaluated a new approach on visualization of myocardial injury using cardiac magnet resonance imaging (CMR) during PVAI procedure.Patients who underwent PVAI, received CMR before and at the terminal phase of PVAI using the Miyabi-MRI system . Delayed enhancement (DE-CMR) free breathing sequences were applied, and maximum intensity projections (MIP) obtained. Myocardial injury size was then measured on manually segmented 3D images by a computer algorithm using dynamic thresholding.30 patients received PVAI from February to July 2008. In a subset of 14 patients, CMR was performed before and during the procedure. Using DE-CMR, the increase in average lesion to healthy myocardium ratio was 10.3 \u00b1 4.1% during PVAI. Figure Using CMR is feasible in the course of ablation procedures. In PVAI patients, DE-CMR allowed identification of location and extension of myocardial injury. Therefore, this new CMR approach might improve ablation techniques, and thus long-term success of PVAI."}
+{"text": "Dear Sir:I read with interest the article \u201cNafamostat mesylate treatment in combination with favipiravir for patients critically ill with Covid-19: a case series\u201d by Doi et al. [We treated 24 laboratory-confirmed coronavirus disease 2019 (COVID-19) patients admitted to the ICU during March 19 to April 30, 2020, in Tokyo. We encountered several complication cases associated with COVID-19 medications, including nafamostat mesylate and favipiravir (not their combination), and recently reported them in emergency medicine journals [Two COVID-19 cases diagnosed with neuroleptic malignant syndrome (NMS) and received favipiravir treatment (not the combination nafamostat mesylate + favipiravir) were recently published. In the letter for our manuscript, Prakash speculated that favipiravir induces serotonin syndrome (SS) probably due to its serotonergic properties . AlthougAnother complication case was diffuse microbleeding in brain treated with nafamostat mesylate and venovenous extracorporeal membrane oxygenation (VV-ECMO) . A 56-yeTherefore, although all three complication cases recovered well, serious adverse events, such as CNS and bleeding complications, require careful consideration when using these drugs in COVID-19 patients. Both efficacy and adverse events should be discussed simultaneously whenever providing new therapy."}
+{"text": "The decreasing number of family/friend caregivers available to help the rising number of older adults is creating a critical family care gap. For this reason, there is a growing need for interventions that reduce family/friend caregiving time. We systematically reviewed five electronic databases to identify randomized trials, case control, quasi-experimental, and cross-sectional studies that evaluated a modifiable element that could be targeted for interventions with care recipients 65+ and/or their family/friend caregivers and reported on an outcome of time spent caregiving. We excluded studies without a comparison, broadly defined. The initial search included 1,812 unique records. Following abstract and title screening 311 full-texts were reviewed. Fifty-five studies published between the years of 1990 and 2019 met inclusion criteria. Studies predominantly focused on care recipients with dementia (58%) and were largely conducted in western countries (91%). The categories of interventions reviewed included pharmaceuticals (25%), public long-term care financing (7%), case management (7%), care setting (16%), technology (7%), multi-component interventions (9%), skills building (15%), additional formal expertise/care (9%), and other (5%), with one study falling into multiple categories. Pharmaceuticals, case management, care setting, and multi-component interventions demonstrated promising evidence to reduce family/friend caregiving time. Methodologically, studies were inconsistent in measurement and ascertainment of caregiving time. Given the public health concerns of reduced availability of family/friend caregivers for older persons in the upcoming decades, caregiving interventions should consider measurements of caregiving time as key outcomes."}
+{"text": "To determine whether chemoprophylaxis with hydroxychloroquine versus placebo increases time to contracting coronavirus disease 2019 (COVID-19) in frontline healthcare workers.To determine whether chemoprophylaxis with daily versus weekly dosing of hydroxychloroquine increases time to contracting COVID-19 disease in frontline healthcare workers.To compare the number of COVID-19 cases between each trial arm on the basis of positive tests To compare the percentage of COVID-19 positive individuals with current testing methods versus serologically-proven COVID-19 in each trial armTo compare COVID-19 disease severity in each trial armTo compare recovery time from COVID-19 infection in each trial armTo determine compliance (as measured by trough pharmacokinetic hydroxychloroquine levels) on COVID-19 positive testsTo determine if genetic factors determine susceptibility to COVID-19 disease or response to treatmentTo determine if blood group determines susceptibility to COVID-19 diseaseTo compare serum biomarkers of COVID-19 disease in each armDouble-blind, multi-centre, 2-arm (3:3:2 ratio) randomised placebo-controlled trialNational Health Service (NHS) workers who have direct patient contact delivering care to patients with COVID-19.Participants in the trial will be recruited from a number of NHS hospitals directly caring for patients with COVID-19.Have given written informed consent to participateBe aged 18 years to 70 yearsNot previously have been diagnosed with COVID-19Work in a high-risk secondary or tertiary healthcare setting  with direct patient-facing careTo be included in the trial the participant MUST:Known COVID-19 positive test at baseline (if available)Symptomatic for possible COVID-19 at baselineKnown hypersensitivity reaction to hydroxychloroquine, chloroquine or 4-aminoquinolinesKnown retinal diseaseKnown porphyriaKnown chronic kidney disease Known epilepsyKnown heart failure or conduction problemsKnown significant liver disease (Gilbert\u2019s syndrome is permitted)Known glucose-6-phosphate dehydrogenase (G6PD) deficiencyCurrently taking any of the following contraindicated medications: Digoxin, Chloroquine, Halofantrine, Amiodarone, Moxifloxacin, Cyclosporin, Mefloquine, Praziquantel, Ciprofloxacin, Clarithromycin, Prochlorperazine, FluconazoleCurrently taking hydroxychloroquine or having a clinical indication for taking hydroxychloroquineCurrently breastfeedingUnable to be followed-up during the trialCurrent or future involvement in the active treatment phase of other interventional research studies  before study follow-up visitNot able to use or have access to a modern phone device/web-based technologyAny other clinical reason which may preclude entry in the opinion of the investigatorThe presence of any of the following will mean participants are ineligible:A)Daily hydroxychloroquine orB)Weekly hydroxychloroquine orC)PlaceboInterventions being evaluated are:The maximum treatment period is approximately 13 weeks per participant.Hydroxychloroquine-identical matched placebo tablets will ensure that all participants are taking the same number and dosing regimen of tablets across the three trial arms. There is no variation in the dose of hydroxychloroquine by weight.The dosing regimen for the three arms of the study  are described in further detail below.Arm A: Active Hydroxychloroquine (\u2013 daily dosing and placebo-matched hydroxychloroquine - weekly dosing). Form: TabletsRoute: Oral. Dose and Frequency:Active hydroxychloroquine:Days 1-2: Loading phase - 400mg (2 x 200mg tablets) taken twice a day for 2 daysDays 3 onwards: Maintenance Phase - 200mg (1 x 200mg tablet) taken once daily, every day for 90 days (~3 months)th day) for 90 days (~3 months)Days 3 onwards: Maintenance Phase - 2 tablets taken once a week on the same day each week (every 7Matched Placebo hydroxychloroquine:Arm B: Active Hydroxychloroquine (- weekly dosing and placebo matched hydroxychloroquine \u2013 daily dosing.) Form: TabletsRoute: Oral. Dose and Frequency:Days 1-2: Loading Phase - 400mg (2 x 200mg tablets) taken twice daily for 2 daysth day) for 90 days (~3 months)Days 3 onwards: Maintenance Phase - 400mg (2 x 200mg tablets) taken once a week on the same day each week (every 7Active hydroxychloroquine:Days 3 onwards: Maintenance Phase - 1 tablet taken once daily for 90 days (~3 months)Matched Placebo hydroxychloroquine:Arm C: Matched placebo Hydroxychloroquine (- daily dosing and matched placebo hydroxychloroquine - weekly dosing.) Form: Table. Route: Oral. Frequency:Days 1-2: Loading Phase - 2 tablets taken twice daily for 2 daysDays 3 onwards: Maintenance Phase - 1 tablet taken once daily for 90 days (~3 months)Matched placebo hydroxychloroquine - daily dosing:Days 3 onwards: Maintenance Phase - 2 tablets taken once a week on the same day each week (every 7th day) for 90 days (~3 months)Matched placebo hydroxychloroquine \u2013 weekly dosing:A schematic of the dosing schedule can be found in the full study protocol Participants will be randomised to either hydroxychloroquine dosed daily with weekly placebo, HCQ dosed weekly with daily placebo, or placebo dosed daily and weekly.Randomisation will be in a 3:3:2 ratio , using stratified block randomisation. Random block sizes will be used, and stratification will be by study site.Participants and trial investigators consenting participants, delivering trial assessments and procedures will be blinded to intervention.A sufficient number of participants will be enrolled so that approximately 1000 participants in total will have data suitable for the primary statistical analysis. It is anticipated that approximately 1,200 participants will need to be enrolled in total, to allow for a 20% dropout over the period of the trial. This would result in approximately 450:450:300 participants randomised to hydroxychloroquine daily, hydroxychloroquine weekly+daily matched placebo or matched-placebo daily and weekly.th April 2020V 1.0, 7EU Clinical Trials RegisterEudraCT Number: 2020-001331-26th April 2020Date of registration: 14th May 2020. It is anticipated that the trial will run for 12 months. The recruitment end date cannot yet be accurately predicted.Trial registered before first participant enrolment. Trial site is Cambridge University Hospitals NHS Foundation Trust. Recruitment started on 11The full protocol is attached as an additional file, accessible from the Trials website  guidelines (Additional file  Additional file 1.Additional file 2."}
+{"text": "The correct citation is: Viana BF, Trajano GS, Ugrinowitsch C, Pires FO (2020) Caffeine increases motor output entropy and performance in 4 km cycling time trial. PLoS ONE 15(8): e0236592. The first author\u2019s initials are also indexed incorrectly in PubMed. The correct initials are: Viana BFThe fourth author\u2019s initials are also indexed incorrectly in PubMed. The correct initials are: Pires FO."}
+{"text": "CSF1R-related leukoencephalopathy is an adult-onset leukoencephalopathy with axonal spheroids and pigmented glia caused by colony stimulating factor 1 receptor (CSF1R) gene mutations. The disease has a global distribution and currently has no cure. Individuals with CSF1R-related leukoencephalopathy variably present clinical symptoms including cognitive impairment, progressive neuropsychiatric and motor symptoms. CSF1R is predominantly expressed on microglia within the central nervous system (CNS), and thus CSF1R-related leukoencephalopathy is now classified as a CNS primary microgliopathy. This urgent unmet medical need could potentially be addressed by using microglia-based immunotherapies. With the rapid recent progress in the experimental microglial research field, the replacement of an empty microglial niche following microglial depletion through either conditional genetic approaches or pharmacological therapies (CSF1R inhibitors) is being studied. Furthermore, hematopoietic stem cell transplantation offers an emerging means of exchanging dysfunctional microglia with the aim of reducing brain lesions, relieving clinical symptoms and prolonging the life of patients with CSF1R-related leukoencephalopathy. This review article introduces recent advances in microglial biology and CSF1R-related leukoencephalopathy. Potential therapeutic strategies by replacing microglia in order to improve the quality of life of CSF1R-related leukoencephalopathy patients will be presented. CSF1R-related leukoencephalopathy, a subgroup of adult-onset leukodystrophy, is a progressive neurodegenerative white matter disease caused by mutations in the colony stimulating factor 1 receptor (CSF1R) gene . Ho. HoCSF1RCSF1R-related leukoencephalopathy cases [CSF1R gene donors in two CSF1R-related leukoencephalopathy patients [CSF1R-related leukoencephalopathy were noted in another case [Empiric trials of glucocorticoids did not show obvious clinical improvements in reported hy cases . Hematophy cases . This mepatients . These ppatients . During patients . More impatients . Furtherpatients . In bothpatients . Satisfaher case . This paher case .+ cells from a sex-mismatched donor was noted in post-mortem brains after HSCT through observation of Y-chromosomes using chromogenic in situ hybridization [Graft-derived ramified Iba1dization . In an edization . These ldization . In addidization . The fundization . Transpldization .CSF1R-related leukoencephalopathy in clinical practice by providing brain-engrafting microglia-like cells with donor wild-type CSF1R to repopulate the microglial niche [All major brain cell types including microglia can be generated and differentiated from stem cells . Althougal niche . HoweverCSF1R gene mutation [CSF1R-related leukoencephalopathy patients did not show clinical symptom improvement following HSCT [Repopulating microglia from a human leukocyte antigen-matched donor could perform normal functions such as phagocytosis and cytokine production, while altered functions such as an increased release of cytokines after stimulation were noted in microglia-like cells derived from either a patient donor or a family member who also carried the mutation . Worseniing HSCT , suggesting HSCT . RecreatCSF1R-related leukoencephalopathy to date, and development of a potential microglia-based treatment is warranted. A detailed understanding of the microglial niche, and potential regulating factors such as epigenetic markers, novel pharmacological therapies to remove microglia by targeting CSF1R, emerging genomic engineering tools and stem cell treatments, may all facilitate the selective replacement of dysfunctional microglia with healthy microglia in CSF1R-related leukoencephalopathy patients. While still relatively novel, microglial replacement therapy is a scientifically sound strategy and presents an exciting research opportunity that could lead to clinical translation, alleviation of symptoms and improving the life quality of individuals who are suffering from currently incurable CSF1R-related leukoencephalopathy.There are no available specific therapies for"}
+{"text": "To assess the effects of age and refractive status on anterior segment anatomical structures, including the ciliary body, using a new swept-source anterior segment optical coherence tomography (AS-OCT) device.This prospective observational study included 63 healthy volunteers (mean age: 44.2 years). Images of the anterior segment were obtained using a new swept-source AS-OCT  with tracking and image averaging from the right eye of all participants. Repeatability as well as inter- and intra-observer reliability of biometric measurements were evaluated. The impact of image tracking and averaging on ciliary muscle measurements was tested. Univariate and multivariable statistical models were developed to evaluate the relationship of age and refractive status on anterior segment biometric measurements.p<0.001 and p = 0.006, respectively). Nasal and temporal CMTMAX  and lens thickness (p<0.01) increased with age. Nasal and temporal SSMAX decreased with older age and increasing hyperopia . Image averaging resulted in improved ciliary muscle measurements (p = 0.008 to 0.02). Lens vault increased with older age and increased hyperopia (p<0.01). OCT measurements of the angle decreased with older age and increased hyperopia (p<0.001 to 0.03). Aqueous depth decreased with older age and increased hyperopia (p<0.01). Pupil diameter decreased with older age (p<0.01).For all test-retest repeatability and inter- and intra-observer reproducibility of swept-source AS-OCT measurements, high intraclass correlation (ICC) was noted (0.88\u20131.00). The nasal maximum ciliary muscle thickness (CMTMAX) and distance between scleral spur to the thickest point of the ciliary muscle (SSMAX) were larger than those on the temporal side (Repeatability and reproducibility of biometric measurements using the ANTERION AS-OCT were excellent. Image averaging improved the accuracy of ciliary muscle measurements. The device produced measurements of biometric parameters that described superficial and deep structures including the ciliary body and full lens thickness from a single image. Optical coherence tomography (OCT) was described over 20 years ago , now witTracking refers to the process by which OCTs can monitor the position or orientation of the eye based on a reference point or structure to ensure that OCT B-scans are acquired from the same location across or within imaging sessions . High-qu2]: > 100 square millimeters; and depth of imaging: ~8 mm [from the anterior cornea to the posterior lens]). Based upon commercially available lasers at the time of development, initial time-domain OCTs scanned at a wavelength of ~1300 nm which provided adequate depth of imaging (including the ciliary muscle) but lacked in resolution and speed ) . Bland-Altman analyses were also performed for CMTMAX and SSMAX showing a tighter 95% limits of agreement comparing Averaging 8 compared to Averaging 1 and center bias lines closer to zero for higher averaging . Thus, univariate linear regressions were first conducted to evaluate the relationship between different anterior segment biometric parameters  to age and refractive status. Then, a multivariable linear regression analysis was carried out to further clarify the effects of age and refractive status on each of the above biometric parameters. Discrepancies between the results of univariate and multivariable analyses were likely due to the effect of variable co-variation in the univariate analyses.Subjects were recruited based on a distribution of ages. Given the attention to age, it was noted that younger volunteers were more likely to be myopic compared to older volunteers. Statistically, there was significant covariation between age and refractive status . In terms of CMTMAX, univariate analysis showed positive linear relationships between both nasal and temporal values to age . For univariate analysis against refractive status, there was no statistically significant relationship . Multivariable analyses linear regression analyses confirmed these results (p<0.001\u20130.004 and refractive status p = 0.22\u20130.84). The above results suggested that the nasal and temporal CMTMAX sized increased with increasing age.The mean values of CMTMAX and SSMAX on the nasal side were significantly greater than those on the temporal side  and more hyperopic refractive status . In multivariable linear regression analysis, both nasal and temporal SSMAX still showed independent negative linear relationships with age (p<0.001\u20130.01) and more hyperopic refractive status (p = 0.005\u20130.03). These results suggested that the ciliary muscle apex was positioned more anteriorly in older and more hyperopic subjects.In terms of SSMAX, in univariate analysis, both nasal and temporal values showed negative linear relationships with age , and a positive linear relationship with refractive status . Multivariable linear regression analysis showed that increased age was still related to a thicker crystalline lens (p<0.01), whereas the lens thickness was no longer significantly associated with refractive status (p = 0.24). These results suggested that age had an impact upon lens thickness while refractive status did not.For lens thickness, univariate analysis showed a positive linear relationship with age , and a positive linear relationship with refractive status . Multivariable linear regression analysis confirmed that lens vault was independently and significantly associated with both age (p<0.01) and more hyperopic refractive status (p<0.01).As for lens vault, univariate analysis showed a positive linear relationship with age , scleral spur angle (SSA750), angle-opening distance (AOD750), and trabecular-iris space area (TISA750) on the temporal and nasal sides (p = 0.1\u20130.33).Eight anterior chamber angle biometric endpoints were analyzed: anterior chamber angle . Multivariable linear regression analyses confirmed the results of univariate analyses showing that there were independent and significant negative linear relationships between all angle metrics on both nasal and temporal sides with increased age and more hyperopic refractive status (p<0.001\u20130.03).Univariate analyses showed a negative linear relationship between all of these end-points with increased age and more hyperopic refractive status  and more hyperopic refractive status . The result of multivariable linear regression analyses was consistent with the result of univariate analyses showing significant and independent relationships between decreased aqueous depth and increased age (p = 0.01) and more hyperopic refractive status (p = 0.01).For aqueous depth, univariate analyses showed negative linear relationships with age , while there was no relationship with refractive error . Multivariable linear regression analyses confirmed the above results showing a positive linear relationship with age (p<0.01) but not refractive status (p = 0.83).For pupil diameter, univariate analysis showed negative linear relationships between pupil diameter and age  or refractive status . Mean ACA distance did not correlate with age  or refractive status . Mean spur-to-spur distance did not correlate with age  or refractive status .Not every measured endpoint demonstrated a statistically significant relationship to age or refractive status in univariate analyses. Mean CCT did not correlate with age Click here for additional data file.S1 Fig(A) Lens thickness versus age. (B) Lens thickness versus spherical equivalent refractive error. (C) Lens vault versus age. (D) Lens vault versus spherical equivalent refractive error.(TIFF)Click here for additional data file.S2 Fig(A) Nasal and temporal ACA750 versus age. (B) Nasal and temporal ACA750 versus spherical equivalent refractive error. (C) Nasal and temporal SSA750 versus age. (D) Nasal and temporal SSA750 versus spherical equivalent refractive error. (E) Nasal and temporal AOD750 versus age. (F) Nasal and temporal AOD750 versus spherical equivalent refractive error. (G) Nasal and temporal TISA750 versus age. (H) Nasal and temporal TISA750 versus spherical equivalent refractive error.(TIFF)Click here for additional data file.S3 Fig(A) Aqueous depth versus age. (B) Aqueous Depth versus spherical equivalent refractive error.(TIFF)Click here for additional data file.S4 Fig(A) Pupil diameter versus age. (B) Pupil diameter versus spherical equivalent refractive error.(TIFF)Click here for additional data file.S1 Data(XLSX)Click here for additional data file."}
+{"text": "Gata6 in genetically engineered mouse models reduces the proliferation and increases the differentiation of Kras mutant LUAD tumors. These effects are influenced by the epithelial cell type that is targeted for transformation and genetic context of Kras-mediated tumor initiation. In LUAD cells derived from surfactant protein C expressing progenitors, we identify multiple genomic loci that are bound by GATA6. Moreover, suppression of Gata6 in these cells significantly alters chromatin accessibility, particularly at distal enhancer elements. Analogous to its paradoxical activity in lung development, GATA6 expression fluctuates during different stages of LUAD progression and can epigenetically control diverse transcriptional programs associated with bone morphogenetic protein signaling, alveolar specification, and tumor suppression. These findings reveal how GATA6 can modulate the chromatin landscape of lung cancer cells to control their proliferation and divergent lineage dependencies during tumor progression.Lineage selective transcription factors (TFs) are important regulators of tumorigenesis, but their biological functions are often context dependent with undefined epigenetic mechanisms of action. In this study, we uncover a conditional role for the endodermal and pulmonary specifying TF GATA6 in lung adenocarcinoma (LUAD) progression. Impairing  Lung epithelial differentiation is coordinated by a network of transcription factors (TFs) whose activities are cell lineage specific. The contextual regulation of these networks is required for pulmonary development and homeostasis while their perturbations are linked to chronic diseases of the airways  and lungGata6 blocks terminal differentiation, whereas Gata6 gain of function impairs alveolarization [GATA6 favor lung epithelial specification and proliferation, whereas increased GATA6 levels may activate more mature markers of the distal lung epithelium [The GATA family of zinc finger DNA binding TFs is conserved mediators of cell fate. During endodermal patterning, GATAs can activate or repress transcription . GATAs mrization . In adulrization . In humaithelium .GATA6 is rarely mutated, but its expression is increased in early stage non small cell lung cancer (NSCLC) relative to normal tissue and may correlate with tumor promoting genes [GATA6 is decreased in high-grade NSCLC [In human lung cancers, ng genes , 11. Howde NSCLC , 13, andde NSCLC . The mecKRAS mutations [KRAS mutations in human lung cancers [KrasLSL-G12D genetically engineered mouse model (GEMM) (referred to herein as K), low-grade adenomas, and lung adenocarcinoma (LUAD) arise by expression of a mutant Kras allele (KrasLSL-G12D) in the proximal-distal airways [KrasLSL-G12D expression in conjunction with loss of Tp53 using a floxed null allele (exon 10) of p53  (referred to herein as KP) generates more heterogeneous disease with higher grade tumors [Gata6 [KrasLSL-G12DGata6fl/fl (KG) and KrasLSL-G12Dp53fl/flGata6fl/fl (KPG) mice, respectively, with impaired GATA6 expression  of GATA6 in KP mice, which can generate higher grade LUADs. KPG mice harbored reduced tumor burden and number of tumors Fig. . These tKrasG12D alone can transform surfactant protein C positive (SPC+) alveolar type II (AT2) cells, which generate LUADs in the distal airways [KrasG12D in CC10 positive (CC10+) club cells at the proximal duct junctions results in hyperplasia, which can progress to SPC+ tumors at later stages [CC10 or SPC promoters [Gata6 specifically in these different progenitor cell populations  did not cause tumor regression  and the cell of origin in which it is expressed. Expression of  airways . Alternar stages . GATA6 eromoters  to targeCell lineage specification is ultimately controlled by epigenetic mechanisms and chromatin dynamics , 22. HenGata6 was impaired , suggesting that loss of GATA6 can also indirectly induce activation of chromatin at other distal loci  in KPG cells included stem cell differentiation and BMP signaling Fig. . In the Bmp7  were coactivated   activated multiple mediators of BMP signaling, such as mp7 Fig. . Also, tmp7 Fig.  and someted Fig. . In KPG ted Fig. . Moreove1b) Fig.  and rendion Fig. . Analogolls Fig. . Despitells Fig. . Moreovells Fig. . The outlls Fig. . Howeverlls Fig. , consistIn summary, our study identifies novel epigenomic mechanisms by which GATA6 modulates LUAD proliferation, differentiation, and the activation of lineage-specific tumor suppressive pathways.Apc-null mouse model of colorectal cancer, GATA6 is required for tumor initiation [GATA6 is amplified [Kras mutations, GATA6 inhibits tumor progression by regulating epithelial differentiation [By combining GEMMs with progenitor-specific gene targeting and integrated epigenomic analysis, we uncovered a novel requirement for GATA6-mediated transcriptional programming in lung cancer. GATA6 can also regulate tumorigenesis in other endodermal tissues and has seemingly paradoxical functions in the same cancer type, which parallels the dose and temporal requirement of this TF during development. In the itiation . In humamplified , 35 and ntiation . We demoKrasG12D-mediated transformation of SPC+ progenitors in the presence or absence of p53. It has been suggested that Kras-mediated transformation of CC10+ cells involves the differentiation of CC10+ progenitors into SPC+ tumor cells, and that loss of p53 accelerates tumor progression in this context [Gata6 in CC10-derived tumors that also have lost p53. A prior study concluded that GATA6 inhibits the expansion of double SPC+/ CC10+ cells in the proximal airway following loco-regional injury [Gata6 loss of function may also perturb the differentiation of progenitors within this region when mutant Kras is activated, but this effect was not sufficient to alter the reduced tumor burden when compared with control mice.Although GATA6 may be expressed in several epithelial progenitor cell types in the lungs, GATA6 deficiency significantly reduced  context . While Gl injury . InteresGata6 sensitized tumor cell organoids to BMP-mediated growth inhibition. Mesenchymal BMP signaling is required for AT2 differentiation [The mechanisms by which GATA factors regulate transcription during mammalian development are contextual as these TFs have nonredundant genomic targets. The molecular activities of GATA6 during pulmonary specification and lung cancer in particular are not fully understood. We demonstrate that GATA6 binding predominantly correlates with enhancer activation in SPC+ progenitor derived cancer cells, consistent with it being a key regulator of epithelial lineage identity. Our epigenomic analysis also revealed that the loss of GATA6 indirectly influences chromatin accessibility at a broad range of aberrantly activated enhancers associated with novel gene networks. Although several of these genes are likely to contribute to intrinsic cell proliferation, responses to stromal- and/or autocrine-derived signals may also account for the ability of GATA6 to enhance Kras-mediated tumorigenesis in vivo. For instance, suppression of ntiation , and thentiation .Hopx and Nkx2-1, which encode for TFs that are essential for alveolar cell identity but can constrain LUAD progression [GATA6 partially inversely correlated with NKX2-1 and HOPX. The compensatory activation of HOPX and NKX2-1 may also explain the increased latency and differentiation of tumors initiated by Kras when GATA6 is inhibited. It is also possible that precocious activation of EMT TFs in this context supports a tumor suppressive state as reported in pancreatic cancer [de-novo tumor suppressive gene networks. Paradoxically, in late stage human LUAD, GATA6 is repressed along with other lineage TFs such as NKX2-1 and HOPX [GATA6 is also rarely mutated in human lung cancers. Consequently, although GATA6 expression is initially required for the proliferation of LUAD cells, reducing GATA6 at later stages of tumor progression in conjunction with other epigenetic alterations may activate invasive programs and metastatic dissemination. Altogether, our findings demonstrate how a lineage TF can reprogram the chromatin landscape of lung tumor cells in a manner that potentiates seemingly divergent functions during malignant progression.Inhibiting GATA6 in KP cells also induced the expression of several EMT associated TFs, but these cells did not display overt mesenchymal phenotypes despite GATA6 directly targeting E-cadherin in other cell types . In LUADgression , 30. Morc cancer . Aberranand HOPX , 13, andand HOPX , 39. GATAdditional experimental procedures are provided in KrasLSL-G12D (JAX #008179 (ref. [p53flox (JAX #008462 (ref. [KrasLSL-G12Dp53flox (gift from F. Slack), and Gata6flox (JAX #008196 (ref. [79 (ref. )) (Jacks62 (ref. )), FVB K96 (ref. )) mice wMycoplasma every 6 months using the ATCC Universal Mycoplasma Detection Kit . Prior to injection into mice, cells were tested for Mycoplasma and murine viral contamination by the Yale University Molecular Diagnostics Laboratory.Cell lines from SPC-Cre KP and KPG and Lenti-Cre KP were isolated from bulk lung of tumor-bearing mice 13\u201316 weeks after tumor initiation, sorted by EpCAM positive expression, and grown in RPMI media. All cell lines were tested for SPC-Cre KP and KPG cells lines were grown in plates for 3 days. Three biological replicates were collected. Total RNA was extracted using the RNeasy kit  with an on-column DNase treatment. Samples were sequenced on a HiSeq 2500  with single-end 76 base reads. Data were analyzed using HISAT2 and Deseq2.SPC-Cre KP and KPG cells lines were grown for 3 days. Two biological replicates were collected. For ChIP-seq, 20\u2009\u03bcg of chromatin was subjected to immunoprecipitation overnight with corresponding antibodies listed in All sequencing data are deposited in NCBI\u2019s Gene Expression Omnibus under accession number GSE124604.For Western blotting, total protein lysate was harvested from cells using RIPA lysis buffer. For immunostaining, tissue was fixed overnight in 4% PFA at 4\u2009\u00b0C and embedded into OCT or paraffin. Images were acquired using a Keyence  or Olympus microscope  and analyzed using ImageJ (NIH). All antibodies and concentrations are listed in b-actin and represented as mean\u2009\u00b1\u2009SEM. Relevant primers are listed in SPC-Cre K and KG tumor nodules were macrodissected and immediately flash frozen in liquid nitrogen. Tissue was grinded by mechanical dissociation using a motor/pestel instrument. Total RNA was extracted using RNeasy Mini Kit for mRNA (QIAGEN) with an on-column DNase treatment. 1\u2009\u03bcg of mRNA was reverse transcribed into cDNA using the iScript cDNA Synthesis Kit . cDNA qRT-PCR was performed using SYBR Green Master Mix . Reactions were run in quadruplicate. Data were normalized to housekeeping genes P values were calculated by two-tailed Student\u2019s t test, or by Mann\u2013Whitney if samples did not follow Gaussian distribution. Variation was estimated using F test, and if variances were significantly different, P value was calculated using Welch\u2019s t-test. Tumor burden was analyzed by Mann\u2013Whitney test using specific time points or area under the curve. Grading of KP and KPG tumors was analyzed using chi-square. Quantification of SPC and CC10+ tumors was analyzed using Fisher\u2019s exact test. All statistics were performed using Prism software .In vivo and in vitro experimental data were presented as mean\u2009\u00b1\u2009SEM. Supplementary MaterialSupplementary Table 1Supplementary Table 2Supplementary Table 3Supplementary Table 4Supplementary Table 5"}
+{"text": "PCR of upper respiratory specimens is the diagnostic standard for severe acute respiratory syndrome coronavirus 2 infection. However, saliva sampling is an easy alternative to nasal and throat swabbing. We found similar viral loads in saliva samples and in nasal and throat swab samples from 110 patients with coronavirus disease. Sampling technique proficiency also varies, especially during self-sampling , which can result in false negatives. Furthermore, shortages of swabs, transport media, and personal protective equipment limit healthcare capacity to conduct SARS-CoV-2 tests that rely on swab sampling.Quantitative reverse transcription PCR (qRT-PCR) is the diagnostic standard for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease (COVID-19)  at the Royal Liverpool University and Aintree University Hospitals . We recruited participants who had provided written informed consent and had COVID-19 symptoms. The National Health Service Research Ethics Committee (20/SC/0169) approved the study under Integrated Research Application System no. 282147.https://www.copanusa.com). We also asked participants to funnel their saliva into a sterile cryotube . We immediately extracted RNA from the swab samples; we stored saliva samples at \u201380\u00b0C until processing. We extracted viral RNA using the QIAamp Viral RNA Mini Kit  and tested 8 \u03bcL of extracted RNA using the genesig Real-Time Coronavirus COVID-19 PCR . We quantified viral loads using the manufacturer\u2019s positive control (1.67 \u00d7 105 copies/\u00b5L) as reference.Within 24 hours after patient consent, we collected nasal and throat swab specimens containing 1.0 mL of Amies transport medium  were women. Most participants were hospitalized; 21 (19.1%) were discharged to home directly from the emergency department. Overall, 12 (10.9%) saliva and 14 (12.7%) nasal and throat swab specimens of 110 paired samples tested positive for SARS-CoV-2 RNA. Viral loads for all samples ranged from 36 to 3.3 \u00d7 10 samples .Insignificant viral load discrepancies existed among all positive samples (p = 0.1955 by Wilcoxon signed-rank paired test). Two patients tested positive (<10 copies/mL) on nasal and throat swab samples and negative on saliva samples; the discrepancies might have resulted from the different processing times of the 2 specimens because freeze-thawing can reduce the stability of RNA (Saliva sampling can improve SARS-CoV-2 diagnostic techniques. Saliva samples are easier to collect than nasal and throat samples; the technique is noninvasive, presumably preferred by the participant, and does not require sampling proficiency. In addition, saliva sampling does not require swabs and transport media, which have limited availability during the pandemic. Our technique uses a funnel which, although helpful, might not be necessary for sample collection. Our study focused on symptomatic hospitalized participants; further research is needed on saliva sampling for patients with mild and asymptomatic SARS-CoV-2 infection.Further studies should document the effects of storage and transport on RNA and viral loads. Rapid processing of saliva samples might benefit patients in low- and middle-income countries, where the pandemic is still accelerating and swab availability is limited (As rates of SARS-CoV-2 infection increase, we must continue to investigate efficient diagnostic strategies. Easy and effective diagnostic techniques, such as saliva sampling, should be evaluated in certified clinical laboratories."}
+{"text": "For detection and quantification of myocardial infarction, delayed enhancement cardiovascular magnetic resonance imaging (CMR) has emerged as the new gold standard. Furthermore, CMR has the unique advantage of visualization of even microinfarctions at very high spatial resolution.Some patients who receive prompt reperfusion do not have a significant enzyme rise, but do exhibit typical ECG changes, which are consistent with an aborted myocardial infarction (MI). These patients are presumed that myocardial necrosis has been avoided. However, this has not been studied systematically with CMR.The aim of this research was therefore to study CMR-parameters for the identification of aborted MI.To investigate the extent of aborted MI we examined 421 consecutive patients undergoing primary percutaneous coronary intervention (PCI) in acute STEMI within 12 h after symptom onset. Aborted MI was defined as maximal creatine kinase \u22652 upper limit of normal coupled with typical evolutionary electrocardiographic changes (ST-segment resolution > 50% within 2 h). All patients with aborted MI underwent CMR within 2\u20134 days using a 1.5 T MRI scanner. Left ventricular function was assessed by a standard steady-state free precession technique. For acute infarct determination, 3 short-axis slices using a T-2 weighted turbo spin-echo sequence were obtained. Early and delayed enhancement images covering the whole ventricle were acquired \u22481 and 15 minutes after intravenous administration of 0.15 mmol/kg body weighted gadobutrol  with an inversion recovery gradient echo sequence.Of the 421 STEMI patients 53 patients (12.6%) fulfilled aborted MI criteria, with the highest frequency (22.4%) occuring in patients treated with primary PCI < 2 h after symptom onset.In patients with aborted MI, CMR detected no delayed enhancement (DE) in 22 patients (41.5%), consistent with the absence of myocardial necrosis and infarction. In 31 (58.5%) patients CMR revealed transmural (27.3%) or non-transmural (31.2%) DE in the distribution of a coronary artery compatible with MI. As compared with true MI patients, patients with aborted MI had a significant lower infarct size  shorter pain-to-balloon time and a significant better left ventricular ejection fraction .CMR can distinguish between patients with true aborted MI with absence of myocardial scar and patients with fulfilled criteria of aborted MI but detected scar formation. Therefore CMR should be established as a diagnostic criteria for true aborted MI."}
+{"text": "Physical resilience (PR), which denotes one\u2019s ability to resist functional physical decline, can be operationalized through longitudinal assessments on the Short Physical Performance Battery (SPPB). Dual-task walking (DTW) is predictive of adverse outcomes but its role in predicting incident PR has not been assessed. Herein, we determined whether velocity during Single-Task-Walk (STW) and Dual-Task-Walk (DTW) conditions predicted incident loss of PR and identified moderators of this relationship. Participants were 163  non-demented, community-dwelling older adults with baseline SPPB scores of 10-12. At baseline, individuals completed neuropsychological testing, the SPPB and DTW paradigm. Cognitive reserve was evaluated using the Wide Range Achievement Test (WRAT-3) and speed of processing was assessed using the Symbol Digit Modalities Test (SDMT). Individuals with SPPB scores < 10 were categorized as not physically resilient. Those with scores of 10 or higher were categorized as physically resilient. At three-year follow up 75.4% (n=123) of participants remained physically resilient while 24.5% (n=40) lost PR. Binary logistic regression revealed that slower DTW , but not STW velocity , was a significant predictor of PR loss. Moreover, moderation analyses revealed that DTW velocity predicted PR loss only among individuals who had lower baseline scores on the WRAT-3  and SDMT . We propose that cognitive reserve and speed of processing influenced the utility of DTW velocity in predicting PR loss among community-residing older adults."}
+{"text": "Research examining the illness experience from the perspective of individuals with dementia (IWDs) has gained increased attention. Previous studies suggest many IWDs experience unmet needs and behaviors that can impact their well-being. Most research has assessed these constructs using caregiver proxy-reports, resulting in underestimation of the amount and type of unmet needs. Additionally, no published studies have assessed self-reported behavioral expressions. As part of a larger study conducted in a memory care unit, the current pilot study examined the reliability of these measures along with examining how IWD\u2019s experienced unmet needs, behaviors, and behavioral distress. Results found that individuals with mild to moderate dementia (n=12) were able to provide reliable self-report data about their own unmet needs (\u221d=.96), unmet need-related distress (\u221d=.98), and behavioral expressions (\u221d=.91). Nearly all participants identified at least one unmet need (74.8%). The highest reported unmet needs concerned health information (75.0%) and findings/arranging services (41.7%). The least reported unmet needs concerned daily living activities (16.7%) and legal/financial services (33.2%). The highest unmet needs related-distress concerned emotional support (41.7%) and the least distressing concerned daily living activities (16.7%). The most frequently reported behaviors included agitation (66.7%) and complaining/criticizing things (58.3%) while the least reported behaviors were refusing to be left alone (8.3%) and yelling/swearing (8.3%). The highest behavioral distress reported was agitation (58.3%) while the least was wandering (8.3%). Discussion will highlight how these results fit within current literature, recommendations for future research in exploring these constructs using self-report methodology, and how well-being outcomes may be impacted."}
+{"text": "Correction to: BMC Infect Dis 20, 726 (2020)https://doi.org/10.1186/s12879-020-05444-2After publication of the original article , the autThe incorrect author name is:<GivenName>Ritter</GivenName><FamilyName>Manuel</FamilyName>The correct author name is:<GivenName>Manuel</GivenName>.<FamilyName>Ritter</FamilyName>.The original article has been corrected."}
+{"text": "Scientific Reports 10.1038/s41598-018-30508-4, published online 13 August 2018Correction to: This Article contains typographical errors in the Materials and Methods section under subheading \u2018Accession Numbers\u2019.\u201cThe nucleotide sequences of the ORF1119, ORF4395 and ORF4971 genes have been deposited in the DDBJ/EMBL/GenBank under the accession nos. LC306881, LC306883 and LC306885, respectively.\u201dshould read:\u201cThe nucleotide sequences of the ORF1119, ORF4395 and ORF4971 genes have been deposited in the DDBJ/EMBL/GenBank under the accession nos. LC317050, LC317052 and LC317053, respectively.\u201d"}
+{"text": "Activating the Stimulator of Interferon Genes (STING) adaptor incites antitumor immunity against immunogenic tumors in mice, prompting clinical trials to test STING activators. However, STING signaling in the tumor microenvironment (TME) during development of Lewis lung carcinoma (LLC) suppresses antitumor immunity to promote tumor growth. We hypothesized that local immune balance favoring suppression of antitumor immunity also attenuates antitumor responses following STING activation. The purpose of this study was to evaluate how STING activation impacts antitumor responses in mice bearing LLC tumors.Mice bearing established LLC tumors were treated with synthetic cyclic diadenyl monophosphate (CDA) to activate STING. Mice were monitored to assess LLC tumor growth, survival and protective antitumor immunity. Transcriptional and metabolic analyses were used to identify pathways responsive to CDA, and mice were co-treated with CDA and drugs that disrupt these pathways.CDA slowed LLC tumor growth but most CDA-treated mice (77%) succumbed to tumor growth. No evidence of tumor relapse was found in surviving CDA-treated mice at experimental end points but mice were not immune to LLC challenge. CDA induced rapid increase in immune regulatory pathways involving programmed death-1 (PD-1), indoleamine 2,3 dioxygenase (IDO) and cyclooxygenase-2 (COX2) in the TME. PD-1 blockade enhanced antitumor responses to CDA and increased mouse survival but mice did not eliminate primary tumor burdens. Two IDO inhibitor drugs had little or no beneficial effects on antitumor responses to CDA. A third IDO inhibitor drug synergized with CDA to enhance tumor control and survival but mice did not eliminate primary tumor burdens. In contrast, co-treatments with CDA and the COX2-selective inhibitor celecoxib controlled tumor growth, leading to uniform survival without relapse, and mice acquired resistance to LLC re-challenge and growth of distal tumors not exposed directly to CDA. Thus, mice co-treated with CDA and celecoxib acquired stable and systemic antitumor immunity.STING activation incites potent antitumor responses and boosts local immune regulation to attenuate antitumor responses. Blocking STING-responsive regulatory pathways synergizes with CDA to enhance antitumor responses, particularly COX2 inhibition. Thus, therapy-induced resistance to STING may necessitate co-treatments to disrupt regulatory pathways responsive to STING in patients with cancer. During tumor development local inflammation establishes immune checkpoints (ICPs) that suppress antitumor immunity in primary lesions and tumor-draining lymph nodes (TDLNs), which together constitute the immune tumor microenvironment (TME). Blocking cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and programmed cell death-1 (PD-1) interactions that contribute to ICPs generated promising clinical responses in some cancers.Resistance to PD-1 blockade (nivolumab) therapy in patients with advanced melanoma and renal cell carcinoma correlated with elevated oxidative tryptophan metabolism mediated by indoleamine 2,3 dioxygenase (IDO) following PD-1 blockade, suggesting that adaptive therapy resistance may be a barrier to inciting effective and durable clinical responses to immunotherapy.Stimulator of Interferon Genes (STING) led to long-term tumor-free survival of mice with relatively immunogenic tumors such as B16 melanoma.Direct introduction of innate immune adjuvants into the TME is an alternative strategy to boost antitumor immunity. Intratumoral treatment with a synthetic cyclic diadenyl monophosphate (CDA) derivative to activate the signaling adaptor 3) mice were given a short course of direct  CDA treatment . CDA treatment did not slow tumor growth immediately (day 3) but after the final CDA treatment tumor growth was reduced significantly  in this prior study, we next tested if CDA treatment was more effective in mice with smaller LLC tumors. Mice were treated with CDA as before, except that treatment was initiated when LLC tumors were first detected (90\u2013120 mm3), 4\u20135 days earlier than in our initial study on mice with more established tumors. Earlier CDA treatment prevented progression of small LLC tumors, leading to rapid tumor regression and uniform survival  induce T cells expressing PD-1 to become functionally exhausted and/or undergo apoptosis. Like many patients with cancer, mice with LLC tumors are poorly responsive to blockade of PD-1/PD-L1 signaling.Next, we tested if direct CDA treatment induced IDO enzyme activity in tumor lesions and TDLNs by assessing production of kynurenine (Kyn), a tryptophan catabolite made by cells expressing IDO, in TME tissues from mice with LLC tumors. LLC tumor cells do not express IDO but IDO activity induced in TDLN DCs via STING/IFN-I signaling during LLC tumor growth suppresses antitumor immunity to promote optimal LLC tumor growth.To test if CDA-induced PD-L1 expression reinforces ICP potency mice were co-treated with CDA and anti-PD-1 monoclonal antibodies (mAbs) to block PD-L1/PD-1 interactions that inactivate effector T cells. Consistent with LLC tumors being refractory to PD-1 blockade, anti-PD-1 mAb monotherapy  did not slow LLC tumor growth , and hadNext, we tested if three different proprietary IDO inhibitor (IDOi) drugs with distinct pharmacological characteristics enhanced therapeutic responses to direct CDA treatment in the LLC tumor model. Indoximod (1-methyl-D-tryptophan (1MT)), navoximod (NLG-919) and lindrostat (BMS-986205) have all been tested in patients with cancer as monotherapies, or in combination with other anticancer treatments, with varying effects on clinical outcomes.Co-treatment with 1MT did not enhance CDA-mediated tumor control or increase survival significantly, relative to outcomes with CDA monotherapy . NavoximDCs expressing IDO in the TME suppress effector T cells and activate regulatory CD4 T cells (Tregs) to attenuate T cell immunity via PD-1-dependent mechanisms.Next, we tested if a COX2-selective inhibitor, celecoxib, boosted antitumor responses to CDA. Mice with established LLC tumors were co-treated with CDA (dosing as before) and celecoxib . Celecoxib monotherapy had no effect on tumor growth or survival, while (as before) CDA monotherapy slowed tumor growth and improved survival outcomes but did not prevent most mice from succumbing to tumor growth . Co-treaSince celecoxib and CDA co-treatments induced potent and robust antitumor immunity, we tested if this drug combination induced abscopal immunity that prevented growth of distal tumors not directly exposed to CDA. Accordingly, mice were inoculated to seed dermal LLC tumors (day 0) and a second bolus of LLC cells was administered 5 days later via intravenous injection to seed distal tumors in other tissues, including lungs. Celecoxib and CDA co-treatments were initiated when dermal tumors were established (as before) and 8/9 mice survived until experimental end points on day 30 . On inspTo investigate how celecoxib impacts immune responses following STING activation, we analyzed expression of immune response genes in tumor lesions from CDA-treated mice with established LLC tumors. As expected, CDA treatment stimulated local transcription of genes encoding pro-inflammatory cytokines, IFN-\u03b2, IFN-\u03b3, tumor necrosis factor (TNF)-\u03b1 and interleukin (IL)-6 . CelecoxIn summary, inhibiting COX2 activity was more effective in unleashing the antitumor potential of CDA than simultaneous disruption of the PD-1 and IDO pathways that commonly contribute to ICPs and promote therapy resistance in many patients with cancer and mouse tumor models. To assess if celecoxib impacts other STING-responsive immune regulatory pathways, we assessed PD-L1 transcription and IDO activity in tumor lesions and TDLNs after CDA treatment. Celecoxib co-treatment completely blocked CDA-induced IDO activity in tumor lesions and TDLNs , as IDO In this study, we show that robust resistance to the antitumor effects of STING is an adaptive feature of the TME in mice with established LLC tumors. STING activation3). Resistance to CDA therapy was not an intrinsic attribute of LLC tumors, as initiating CDA monotherapy when small LLC tumors were first detected (~100 mm3) led to uniformly protective responses against primary tumors and secondary LLC challenge, indicating that mice acquired stable antitumor immunity. Therapy resistance in mice with established LLC tumors was mediated by TME pathways that rapidly increased in potency following CDA treatment. Independent co-treatments to disrupt three distinct immune regulatory pathways increased tumor control and enhanced survival significantly following CDA treatment. Thus, adaptive resistance to CDA therapy increased as LLC tumors matured, reflecting higher resistance to immunotherapy in patients diagnosed with advanced cancers.We selected the LLC model for this study because LLC tumors depend on intrinsic STING signaling for optimal growth because STING/IFN-I signaling elevated IDO activity in TDLN DCs that suppress antitumor immunity.While PD-1 blockade monotherapy did not promote antitumor responses, PD-1 blockade synergized with CDA to reduce therapy resistance and promote uniform survival. However, surviving mice did not clear primary tumor burdens, as all mice harbored invasive residual tumors emanating from primary tumor lesions, and some mice had metastatic tumors. Two proprietary IDO inhibitor drugs with distinct pharmacological characteristics,Metabolic adaptations, including elevated IDO activity, emerged as correlative markers of poor survival of patients with cancer with advanced melanoma and renal cell carcinoma following nivolumab treatments to block PD-1 interactions.Min intestinal tumors.34The COX2-specific inhibitor celecoxib was more effective in disrupting adaptive resistance to CDA therapy than PD-1 blockade or lindrostat co-treatments, even if these co-treatments were combined. Mice co-treated with CDA and celecoxib survived uniformly and acquired systemic antitumor immunity that protected mice from growth of distal LLC tumors not exposed directly to CDA  and acquired long-term (memory) immunity that prevented growth of LLC tumors after secondary challenge. These outcomes revealed that the COX2 pathway is a major factor contributing to therapy resistance, and that inhibiting COX2 activity restored the full range of antitumor responses to CDA monotherapy observed in mice with smaller B16 tumorsIn clinical settings, the requirement for direct CDA administration into tumors may be challenging, although improved image-guided drug delivery makes this approach increasingly feasible. Some STING activators may be effective when given systemically. 5,6-Dimethylxanthenone-4-acetic acid (DMXAA), which activates murine but not human STING, blocked growth of small LLC tumors when given via the intraperitoneal route, although (as for CDA) DMXAA was less effective in controlling growth of larger LLC tumors and survival was not reported.In summary, adaptive therapy resistance is a major barrier to achieving effective antitumor responses following direct activation of STING, particularly when the TME is mature. Our findings suggest that STING agonist monotherapy may not provoke durable and abscopal antitumor immunity in settings of clinical cancer, unless treatment is given directly to relatively small tumors. Our findings in the LLC tumor model testify to the remarkable physiological plasticity of the mature TME, and identify potential strategies to reduce therapy resistance by targeting STING-responsive pathways that suppress antitumor immunity and inflammation. For these reasons, the LLC model offers novel insights into robust barriers that preclude successful clinical immunotherapy, as mice with established LLC tumors reflect high resistance to immunotherapy in patients diagnosed with advanced cancers.C57BL/6 (B6) mice were bred in a barrier facility at the Comparative Biology Centre, Newcastle University. STING-KO mice (fully backcrossed to B6 background) were described previously.385 cells/mouse) into the right flank of female B6 mice and tumor growth was monitored. Tumor sizes were calculated using the formula V=(d1\u00d7d2)3/2\u00d7(\u03c0/6), where d1 and d2 are perpendicular tumor diameters. Mice were treated with mixed linkage CDA ammonium salt  or vehicle (deionized water), as described previously.5 cells/mouse  and 5 days later with 5\u00d7105 cells/mouse (intravenously).LLC (ATCC) tumor cells were injected intradermally (2\u00d710IDO activity was measured in TDLN or tumor lesions as described previously.RNA was extracted using Tri reagent (Sigma-Aldrich), using the manufacturer\u2019s recommended procedure. RNA was then reverse-transcribed using a random hexamer cDNA RT kit (Clontech), and quantitative RT-PCR was performed using SsoFast EvaGreen supermix (Bio-Rad). PCR primers (murine) were as follows ;\u03b2-actin: TACGGATGTCAACGTCACAC & AAGAGCTATGAGCTGCCTGA;COX2: ATCATAAGCGAGGACCTGGG & CTGCAGGTTCTCAGGGATGT;PD-L1: TGCGGACTACAAGCGAATCA & CTTCTCTTCCCACTCACGGG;Granzyme B: GAAGCCAGGAGATGTGTGCT & GCACGTTTGGTCTTTGGGTC;MMP3: CTATACGAGGGCACGAGGAG & CCACCCTTGAGTCAACACCTMMP13: GGAGCCCTGATGTTTCCCAT & ATCAAGGGATAGGGCTGGGT;TNF-\u03b1: TCGTAGCAAACCACCAAGTG & GGAGTAGACAAGGTACAACCIL-6: AGACAAAGCCAAGT CCTTCAGAGA & GCCACTCCTTCTGTGACTCCAGCIFN-\u03b3: CCTTCTTCAGCAACAGCAAGGCG & CCCACCCCGAATCAGCAGCGIFN-\u03b21: GCAGCTGAATGGAAAGATCA & GTGGAGAGCAGTTGAGGACAThreshold cycle (Ct) values were set in the early linear phase of amplification; relative expression of target genes were calculated as 2Ct(\u03b2-actin)\u2212Ct(target gene).Data were analyzed using GraphPad Prism. For tumor growth, two-way analysis of variance with Bonferroni post hoc multicomparison tests were performed. Unpaired two-tailed non-parametric Mann-Whitney U tests were performed for two group comparisons. Statistical significance for survival curves was evaluated using the log-rank test."}
+{"text": "There is a reporting error in the figure legend of The Cortex panels for CD11b WT Veh and APP/PS1 SS in To improve the reproducibility of this study, the authors have provided additional details regarding the ingredients used to prepare the Smart Soup:\u201cThe CFDA-approved single-herb granules of Rhizoma Acori Tatarinowii (AT), Poria cum Radix Pini (PRP) and Radix Polygalae (RP) were obtained from Tianjiang Pharmaceutical, Jiangyin, China:AT product name: Shi Chang Pu, lot number: 1112134;PRP product name: Fu Shen, lot number: 1103019;RP product name: Zhi Yuan Zhi, lot number: 1102028.\u201dThe authors have provided the underlying individual level data for their manuscript, which have been uploaded as Supporting Information Files. The original images underlying S1 File(PDF)Click here for additional data file.S2 File(PDF)Click here for additional data file.S3 File(PDF)Click here for additional data file.S4 File(PDF)Click here for additional data file.S5 File(XLSX)Click here for additional data file.S6 File(XLSX)Click here for additional data file.S7 File(XLSX)Click here for additional data file.S8 File(XLSX)Click here for additional data file.S9 File(XLSX)Click here for additional data file.S10 File(XLSX)Click here for additional data file.S11 File(XLSX)Click here for additional data file."}
+{"text": "These results suggest that ZIKV can serve as an adjuvant to subcutaneous tumor vaccines that enhance long-term survival and generate protective tissue-resident memory CD4+ T-cells.Zika virus (ZIKV) exhibits a tropism for brain tumor cells and has been used as an oncolytic virus to target brain tumors in mice with modest effects on extending median survival. Recent studies have highlighted the potential for combining virotherapy and immunotherapy to target cancer. We postulated that ZIKV could be used as an adjuvant to enhance the long-term survival of mice with malignant glioblastoma and generate memory T-cells capable of providing long-term immunity against cancer remission. To test this hypothesis mice bearing malignant intracranial GL261 tumors were subcutaneously vaccinated with irradiated GL261 cells previously infected with the ZIKV. Mice also received intracranial injections of live ZIKV, irradiation attenuated ZIKV, or irradiated GL261 cells previously infected with ZIKV. Long-term survivors were rechallenged with a second intracranial tumor to examine their immune response and look for the establishment of protective memory T-cells. Mice with subcutaneous vaccination plus intracranial irradiation attenuated ZIKV or intracranial irradiated GL261 cells previously infected with ZIKV exhibited the greatest extensions to overall survival. Flow cytometry analysis of immune cells within the brains of long-term surviving mice after tumor rechallenge revealed an increase in the number of T-cells, including CD4 Glioblastoma multiforme (GBM) is a highly aggressive malignant brain tumor whose treatment options currently offer little chance of long-term survival or cure. Patients with GBM typically undergo surgical resection followed by treatment with chemotherapy and temozolomide , with a Oncolytic viruses offer a promising avenue for treating GBM. Viral tropism can be exploited to target tumor cells with greater efficiency and fewer side effects when compared to treatment with chemotherapy and temozolomide . Recentlin vitro, we observed no significant improvement in OS following intracranial (i.c.) injections of ZIKV in glioma-bearing mice or rats, unlike the survival improvements in a previous publication which used a mouse-adapted Dakar ZIKV to treat GL261-bearing mice , myeloid cells [CD45(hi) CD11b(+)], lymphoid cells [CD45(hi) CD11b(-)], and microglia [CD45(int) CD11b(+)]. CD45(hi) CD11b(-) cells were sub-gated to identify CD19(+) B cells and CD3(+) T cells. Effector memory and memory CD4 T cells were identified as CD44(hi) CD62L(lo) cells and activated CD4 T cells were identified based on CD69 expression. (B) Representative flow cytometry plots showing expression of memory and activation markers in different groups of mice. Isotype specific antibodies were used to control for nonspecific antibody binding and to determine positive gating. T:V:T- long-term survivors 7 days following (TIF)Click here for additional data file.S2 FigFlow cytometry gating strategy to analyze immune cells in the brain following rechallenge of long-term survivors of second vaccine treatment study. Mononuclear cells isolated from brain were analyzed by flowcytometry as described in materials and methods. Debris (SSC-A vs FSC-A) and doublets (SSC-H vs SSC-A) were excluded and live cells were gated to identify CD19(+) B cells and CD3(+) T cells. Memory CD4 T cells were identified as CD44(hi) CD62L(lo) cells, which are sub-gated based on CD103 expression as tissue resident memory T cells. Isotype specific antibodies were used to control for nonspecific antibody binding and to determine positive gating.(TIF)Click here for additional data file.S1 FileExcel spreadsheet of raw data from mouse and rat survival studies, IFN\u03b3 secretion by lymphocytes, and CT values from qRT-PCR.(XLSX)Click here for additional data file.S1 Raw imagesUncropped images of PCR gels related to (TIFF)Click here for additional data file."}
+{"text": "Age is the dominant risk factor for infectious diseases, but the mechanisms linking the two are incompletely understood1,2. Age-related mosaic chromosomal alterations (mCAs) detected from blood-derived DNA genotyping, are structural somatic variants associated with aberrant leukocyte cell counts, hematological malignancy, and mortality3-11. Whether mCAs represent independent risk factors for infection is unknown. Here we use genome-wide genotyping of blood DNA to show that mCAs predispose to diverse infectious diseases. We analyzed mCAs from 767,891 individuals without hematological cancer at DNA acquisition across four countries. Expanded mCA (cell fraction >10%) prevalence approached 4% by 60 years of age and was associated with diverse incident infections, including sepsis, pneumonia, and coronavirus disease 2019 (COVID-19) hospitalization. A genome-wide association study of expanded mCAs identified 63 significant loci. Germline genetic alleles associated with expanded mCAs were enriched at transcriptional regulatory sites for immune cells. Our results link mCAs with impaired immunity and predisposition to infections. Furthermore, these findings may also have important implications for the ongoing COVID-19 pandemic, particularly in prioritizing individual preventive strategies and evaluating immunization responses."}
+{"text": "Assimilate evidence for interventions to ameliorate negative changes in physical performance, muscle strength and muscle quantity in hospitalised older adults.We searched for articles using MEDLINE, Embase, CINAHL and Cochrane library using terms for randomised controlled trials, older adults, hospitalisation and change in muscle quantity, strength or physical performance. Two independent reviewers extracted data and assessed risk of bias. We calculated standardised mean differences for changes in muscle function/quantity pre- and post-intervention.n\u00a0=\u20093,417) involved physical activity interventions; a variety were trialled. Eleven studies involved nutritional interventions (n\u00a0=\u2009676). One trial involved testosterone (n\u00a0=\u200939), two involved Growth Hormone (n\u00a0=\u200953), one involved nandrolone (n\u00a0=\u200929), and another involved erythropoietin (n\u00a0=\u2009141). Three studies (n\u00a0=\u2009206) tested Neuromuscular Electrical Stimulation. Evidence for effectiveness/efficacy was limited. Strongest evidence was for multi-component physical activity interventions. However, all studies exhibited at least some concerns for overall risk of bias, and considering inconsistencies of effect sizes across studies, certainty around true effect sizes is limited.We identified 9,805 articles; 9,614 were excluded on title/abstract; 147 full texts were excluded. We included 44 studies including 4,522 participants; mean age 79.1. Twenty-seven studies (There is currently insufficient evidence for effective interventions to ameliorate changes in muscle function/quantity in hospitalised older adults. Multiple interventions have been safely trialled in heterogeneous populations across different settings. Treatment may need to be stratified to individual need. Larger scale studies testing combinations of interventions are warranted. Research aimed at understanding pathophysiology of acute sarcopenia will enable careful risk stratification and targeted interventions. A variety of interventions have been trialled for outcome measures relevant to acute sarcopenia.There is currently insufficient evidence for effective interventions to treat acute sarcopenia.Trials involving a combination of interventions in stratified individually are warranted.Sarcopenia is defined by low muscle strength with low muscle quantity/quality; additionally demonstrated low physical performance defines severe sarcopenia. Cut-offs are two standard deviations (SDs) below means of young healthy reference populations . Acute sIt is unknown whether chronic sarcopenia interventions can treat acute sarcopenia. Mechanisms differ, which may affect treatment efficacy. Acute sarcopenia is associated with greater systemic inflammation and immune-endocrine dysregulation. Inflammation (acute or chronic) may blunt response to exercise or protein challenges (anabolic resistance), but this may be acutely/severely upregulated in acute sarcopenia . Acute sProtocol was agreed by all researchers and registered with Prospective Register of Systematic Reviews\u2014CRD42018112021. Reporting is consistent with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidance.We included randomised controlled trials (RCTs) and quasi-RCTs involving hospitalised patients \u226565\u00a0years-old, where pre- and post-intervention measurements of muscle quantity, strength or physical performance were available. Post-intervention measures until 28\u00a0days post-intervention were included. We included physical activity, nutritional, pharmaceutical or Neuromuscular Electrical Stimulation (NMES) trials. Exclusion criteria were: degenerative neuromuscular disorders; acute stroke; trials of parenteral nutrition, surgical technique/invasive procedure, chemotherapy/radiotherapy, or anaesthetic agents/techniques; no control group; lengths of stay less than 2\u00a0days. We included studies that measured muscle quantity using computed tomography (CT), magnetic resonance imaging (MRI), dual energy X-ray absorptiometry (DXA), bioelectrical impedance analysis (BIA), or ultrasound, muscle strength using handgrip strength, knee flexion, or knee extension, or physical performance using short physical performance battery (SPPB), gait speed, timed up and go (TUG), or 6-Minute Walking Test (6MWT). There were no date or language restrictions.Clinicaltrials.gov, article references and protocol citations. We contacted authors for information where necessary, including requesting age breakdown of data. If no response was obtained, a decision was made to include studies where mean age was one SD\u2009>\u200965.We searched electronic databases  on 16 January 2019; search repeated on 3 April 2020. Grey literature was identified through Web of Science, Google Scholar, We used published and unpublished terms for study design (RCTs), population  and outcome measures  in our search. Full search strategy is available in the online supplement; this was reviewed and agreed with an information specialist.Citations were imported into Microsoft Excel 2016. Duplicates were removed automatically/manually. Two reviewers independently screened titles and abstracts for inclusion . Disagreements were resolved through discussion. Full texts were reviewed independently by the same reviewers; disagreements were resolved through discussion or third review (TAJ).Data were extracted independently by two reviewers  using a template (Microsoft Excel 2016). Extracted data were country, study design, sample size and dropouts, sample characteristics , speciality, intervention description , intervention characteristics , control group, outcome data, length of stay and adverse events. Outcome data at baseline and follow-up to include muscle quantity, muscle strength and physical performance were extracted.Two reviewers  independently assessed risk of bias using Cochrane risk of bias tool. Conflicts were resolved by discussion. Risk of bias was collated using RevMan version 5.3 .We summarised study and participant characteristics, and outcome data at baseline and follow-up using means/SDs in text and tables. Interventions were grouped by subtype and outcomes. All studies were included in narrative synthesis. If sufficient information was available to estimate standardised mean differences (SMDs) of change scores, effect sizes were evaluated as described in statistical analysis section. Certainty of interventions with large effect sizes was evaluated using Grading of Recommendations, Assessment, Development and Evaluations .Correlations for outcome measures were calculated from studies reporting SDs of change scores and baseline/follow-up measures . Mean con\u00a0=\u200956), no control group (n\u00a0=\u200910), follow-up over 28\u00a0days (n\u00a0=\u200912), no baseline measures (n\u00a0=\u20096), no measures meeting inclusion criteria (n\u00a0=\u200920), duplicate data (n\u00a0=\u200911), unable to obtain necessary data from authors (n\u00a0=\u200924), other intervention type (n\u00a0=\u20092), and non-hospitalised population (n\u00a0=\u20096)  . We inclThis review included 4,522 participants . Sample size per arm ranged from 7 to 232. Most studies were small; 52% (23/44) [17\u201340] included 30 or fewer participants per arm; only 9% (4/44) [41\u201343] included over 100 participants in both arms. Mean age across all studies was 79.1\u00a0years; 59% female. Of studies reporting BMI, 74% (20/27)  reported mean overweight (\u226525) BMI; three studies reported mean obese (\u226530) BMI in at least one arm . One study reported data on ethnicity [38]. Two studies  reported frailty prevalence in control and intervention arms by recognised definitions; a third reported mean frailty indices [37]. Most studies  reported physical activity interventions. Eighty-nine percent (24/27) included physical performance  and 44% (12/27) included muscle strength . One study reported muscle quantity change [38], a multi-arm trial including nutritional and pharmaceutical interventions. Trials were conducted in various settings including elective orthopaedic , colorectal , orthopaedic rehabilitation , vascular [17], and cardiac surgery , and geriatric , respiratory [23] and general medicine .A range of physical activity interventions were trialled; evidence for effect was limited. Interventions included strength and balance training , early and/or increased mobilisation , group exercise [42], water exercise/physiotherapy [18], chair-based exercise , seated side-tapping [47], pedal exercisers  and progressive weight-bearing exercise in orthopaedic rehabilitation , using specialised harnesses where appropriate. An individualised multimodal physical training programme involving resistance exercise using machines and/or weights and gait/balance training substantially improved physical performance (gait speed and SPPB) and muscle strength in one of the largest studies [43]. Other trials of individualised physical training programmes  showed small effects on physical performance . Differences may relate to how interventions were delivered or adherence. The trial with the largest effect size reported adherence rates of 83.4\u201395.8% (\u226590% exercises successfully performed each session) [43] compared to 59.7%  in another [57].Interventions that ameliorated reductions in physical performance in trial populations included backward walking [17], progressive exercises stratified by frailty [55], resistance and balance training [44], chair-based resistance exercise [38], individually progressed lower limb and core strengthening exercise [45], individualised progressive resistance, balance, and walking exercises [43] and seated side-tapping [47]. Interventions that ameliorated reductions in muscle strength included pedal exercise [23], individualised progressive resistance, balance and walking exercises [43] and early mobilisation with enhanced recovery after surgery [25]. A high-intensity physiotherapy-led group exercise programme was as efficacious as individual sessions; group exercise resulted in improved therapist efficiency [42]. Group exercise was embedded into a multimodal physical training trial [43].Eleven nutrition trials were identified. Populations included orthopaedic surgery , geriatric , general , and respiratory medicine  and critical care [39]. Six studies reported physical performance change , seven muscle strength change  and four muscle quantity change . Most studies were small; only one included more than 45 patients per arm. Interventions included protein-enriched foods  or supplements , \u03b2-Hydroxy-\u03b2-MethylButyrate [59], oral nutritional supplementation [28], eicosapentaenoic acid [29], citrulline [30], nitrate-rich beetroot juice [49] and nutritional consultation [27]. Three trials combined nutritional consultation to reach specified caloric/protein intake) with strength/resistance training . One study of progressive strength training followed by immediate protein supplementation showed statistically significant improved handgrip strength [51]. Statistically significant improvements in physical performance were demonstrated comparing all interventions in a multi-arm study to placebo, including whey protein with/without exercise [38].Five trials involved pharmaceuticals; four in orthopaedic surgery populations. Pharmaceuticals included growth hormone (GH) , steroid (nandrolone) [33], testosterone [38] and erythropoietin injections [60]. All studies measured muscle quantity  and both GH trials measured muscle strength. The only study that measured physical performance was the multi-arm study including physical activity and nutritional interventions [38]. One GH trial showed statistically significant amelioration in muscle quantity loss by DXA [32] and the other showed statistically significant amelioration in knee flexion strength loss [31]. Adverse events were similar between control and intervention arms [31]; one study showed slightly higher peripheral oedema rates amongst GH recipients [32]. The nandrolone trial did not report statistically significant results [33]. Erythropoietin induced a small statistically significant amelioration in muscle quantity loss after orthopaedic surgery, not related to haemoglobin changes. Testosterone was safe in the multi-arm study, with statistically significant amelioration in physical performance demonstrated comparing all intervention groups to placebo [38].Three trials involved NMES ; all combined NMES with exercise. One trial (geriatric medicine population) tested functional training alone against functional training with NMES [34]. No statistically significant different change in gait speed between groups was demonstrated. Another trial (respiratory medicine population) showed significant lesser decline in knee extension strength with NMES [35]. The third trial  resulted in significant improvements in physical performance with NMES [52].Physical activity interventions were investigated more commonly than others. However, this mostly relates to studies with physical performance outcomes; only four trials not involving physical activity interventions measured physical performance . Conversely, many physical activity trials reported muscle strength change but only one measured muscle quantity change, a multi-arm study also involving nutritional/pharmaceutical interventions. Nutritional and pharmaceutical trials focused on muscle strength and quantity changes rather than physical performance. This suggests disconnect in how physical activity interventions are trialled compared to other interventions; physical performance declines may not be prioritised as organ insufficiency markers in need of urgent treatment.Only nine trials reported muscle quantity change. This relates to historical reduced availability of feasible serial assessment tools; DXA, CT and MRI remain gold-standard, but ultrasound is increasingly utilised ,16. As sWe identified several physical activity interventions that stratified treatment protocols individually (e.g. by frailty) . Most substantial and significant effects on muscle strength and physical performance were demonstrated in the highest reported adherence trial [43]. Although this demonstrates high adherence of hospitalised older adults to complex trial designs is possible, effectiveness is expected to be reduced in clinical environments with limited compliance. Increasing mobilisation alone may be insufficient to prevent/treat acute sarcopenia , although this is safe to do when possible and should be commended . Physical activity interventions can be multidimensional and include resistance exercise ; it is safe and feasible to use machines/weights during acute phase of illness in hospitalised older patients . Pedal exercises  and seated side-tapping [47] are simple, cheap, feasible and potentially effective; these may be implemented as part of multidimensional stratified interventions. Group exercise may be as effective as individual exercise but more cost-effective [42]. Group exercise has additional benefits of improving social interaction, and potentially improving motivation  and adheSeveral nutritional interventions were trialled. Although few trials showed statistically significant results, all trials were small and may have been under-powered for efficacy. Three trials combined nutritional intervention with physical activity 27, 38, 51]. Research in chronic sarcopenia suggested additional protein supplementation may be most effective when combined with targeted physical activity i.e. resistance exercise . As infl8, 51. ReFew studies tested pharmaceuticals. There is suggestion from GH trials that this may be effective in ameliorating reductions in muscle quantity and strength . Further research is needed, including longer term outcomes. Benefits of GH supplementation need to be balanced against adverse effects, although supplementation was safe in dosages used in these small studies. Research is ongoing into novel pharmaceutical agents for use in acute and chronic sarcopenia . StudiesTrials of NMES showed conflicting results. NMES involves delivery of controlled electrical stimuli to superficial muscles via self-adhesive skin electrodes. These stimuli evoke muscle contractions, recruiting motor units and activating muscle fibres . NMES haThis review included hospitalised adults over 65\u00a0years-old. We excluded younger adults to focus towards most vulnerable patients, who are most likely to benefit from targeted interventions. More studies were excluded for participant age than were included (56 versus 44). This suggests persistent bias against involvement of older people in clinical trials, particularly those with frailty. Considering we included search terms for older people in our search, it is likely more trials involving younger adults were not identified, as well as trials excluded through abstract screening. Trials conducted in younger adults may be useful when developing interventions for acute sarcopenia in older adults, but caution should be taken extrapolating results from younger less heterogeneous populations.It is important to consider only three studies reported frailty status in both control and intervention arms . Frailty was measured in intervention arms but rates were not reported in studies that stratified by frailty . Although important measures, handgrip strength and gait speed alone may be insufficient to diagnose pre-morbid frailty during acute illness [42]. Recording levels of frailty prior to hospitalisation can ensure control and intervention arms are matched and enable sub-group analysis assessing treatment effect in individuals with and without frailty [45]. Only one study reported ethnicity amongst participants [38]. Normative values of muscle quantity may vary according to ethnicity , and musAs described, majority of trials were small; many may have been underpowered to detect changes. Due to high heterogeneity in populations, interventions, and outcome measures, it was not possible to conduct meta-analyses. Some interventions that were not shown to be effective in small individual trials may be effective in larger powered studies. Additionally, most studies exhibited some concerns for risk of bias overall, and due to inconsistencies in effect sizes across different studies, there is limited certainty around true effect sizes. Many different outcome measures were also assessed across different RCTs. We consider that standardisation of assessment and outcome measures within geriatric medicine research will enable greater ease of knowledge transfer, sharing of datasets and future meta-analyses of RCTs in ageing.It is important to consider that none of the included trials specifically included the presence of (acute or chronic) sarcopenia as inclusion criteria, or stratified treatment by sarcopenia. However, we consider that results of identified RCTs identified will be pivotal towards designing trials for prevention and/or treatment of acute sarcopenia. Acute sarcopenia is a rapidly progressing research area and therapeutic target. Twenty-two percent of studies (10/44) included in this review were published in the last 18\u00a0months. This demonstrates how rapidly progressive this area is, with increasing numbers of studies measuring muscle quantity and function as outcome measures.Deteriorations in muscle quantity, strength and physical performance are problematic in older adults following hospitalisation. However, insufficient evidence exists to enable targeted prevention/treatment strategies. A number of interventions have been trialled and shown to be safe for heterogeneous populations across various settings. Multidimensional physical activity interventions which are individually tailored (e.g. for frailty) have been trialled ; the trial with most substantial effect size reported excellent adherence [43]. Large scale multi-arm studies assessing effectiveness of combined interventions including physical activity , NMES [34], nutrition [59] and pharmaceuticals  are warranted. Treatment may be most effective when stratified according to individual need. Treatment is likely to be guided by a combination of clinical and biological factors (e.g. immune-endocrine markers). Further research aimed at understanding pathophysiology of acute sarcopenia will enable risk stratification and targeted interventions.aa-20-0102-File002_afaa209Click here for additional data file."}
+{"text": "It is aimed to determine the prevalence of suicidal behaviors regarding to epidemiological and psychosocial characteristics among Bruneian school-student adolescents.The cross-sectional study of 2599  school-student adolescents aged between 13-17 years was based on the Global School-based Health Survey in Brunei. Data on suicidal behaviors, psychosocial and demographic characteristics were analyzed using multiple logistic regression model.The prevalence of suicidal behaviors was 9.3%, 6.5% and 5.9% for suicidal ideation, suicidal plan and suicidal attempt respectively. Female adolescents reported more attempts (61.2%). It was found that some characteristics including suicide ideation (69%), anxiety (28%), loneliness (30%) were statistically different between the attempters of suicide and non-attempters among Bruneian school-student adolescents . Also, some suicide-related behaviors like planned suicide (52%), bullying victimization (21%), physical fight (29%), serious injury (28%), early sexual debut (8.5%), alcohol use at early age (20%), alcohol use in the past 30 days (12%) and physically attacked (30%) showed different rates between two groups of participants . Compared to those who did not report attempting suicide, the attempters were more likely to have suicide ideation ; planned suicide ; and sustained serious injury . The revealed suicidal behaviors, including being lonely, anxious, bullied, attacked physically, alcohol use among school students should be considered by parents and school and counselling service staff in order to prevent selectively.Suicide, Adolescents, Brunei Darussalam"}
+{"text": "Drosophila Plc21C is involved in calcium wave propagation during egg activation. microPublication Biology. 10.17912/micropub.biology.000235For Hu, Q; V\u00e9lez-Avil\u00e9s, AN; Wolfner, MF (2020). Authors requested to correct an omission in their funding acknowledgement:\u201cNIH grant R21-HD088744 (to MFW). NSF Grant 1428922 funding (for the shared Zeiss Elyra Super Resolution Microscope).\u201dThe authors correct the funding report to read:\u201cNIH grant R21-HD088744 (to MFW). NSF Grant 1428922 funding (for the shared Zeiss Elyra Super Resolution Microscope). For ANVA: partial support from Cornell\u2019s Department of Molecular Biology and Genetics and its NSF-funded REU program (funded on NSF REU DBI-1659534), and partial support from the Society of Developmental Biology\u2019s Choose Development! Program, which is funded by NSF .\u201dThis omission has been corrected online."}
+{"text": "Cancers are a large group of diseases that mostly emerge because of the uncontrollable action of many different genes in human cells. There are possibilities of gene fusions, deletions, amplifications, overexpression, and other abnormalities that lead to the development of cancers. One group of culprits in cancer development are protein kinases, a large family of enzymes catalyzing protein phosphorylation. The human genome contains more than 500 protein kinase genes. Kinases regulate various cellular functions, such as proliferation, cell cycle, apoptosis, differentiation, etc. . DeregulAvapritinib (BLU-285) (brand name Ayvakit) a was appSelumetinib  (brand name Koselugo) a was appTucatinib  (brand name Tukysa) a was appPemigatinib (INCB054828) (brand name Pemazyre) a was appCapmatinib (INC280) (brand name Tabrecta) b was appSelpercatinib (LOXO-292) (brand name Retevmo) b was appRipretinib (DCC-2618) (brand name Qinlock) b was appPralsetinib (BLU-667) (brand name Gavreto) b was app(brand name Margenza) was approved by the FDA on December 16, 2020, for the treatment of HER2-positive breast cancer. It is a chimeric IgG monoclonal antibody medication against HER2 receptor tyrosine kinase. The decision was made based on evidence from a clinical trial (NCT02492711) of 536 patients 27 to 86 years old with HER2-positive metastatic breast cancer who had been previously treated for their metastatic disease [Margetuximab  disease .(brand name Ibrance), a CDK4/6 inhibitor for advanced (metastatic) breast cancer (2015); lenvatinib (brand name Lenvima), a VEGFR1/2/3 inhibitor for progressive, differentiated thyroid cancer (2015); cobimetinib (brand name Cotellic), a MEK inhibitor for melanoma in combination with vemurafenib, a BRAF inhibitor (2015); osimertinib (brand name Tagrisso), an EGFR inhibitor for non-small-cell lung carcinomas with specific mutations (2015); necitumumab (brand name Portrazza), an EGFR antibody for advanced (metastatic) squamous non-small cell lung cancer (2015); alectinib (brand name Alecensa), an ALK inhibitor for non-small-cell lung cancer (2015); olaratumab (brand name Lartruvo), a PDGFRA inhibitor for certain types of soft tissue sarcoma (2016); ribociclib , a CDK4/6 inhibitor for advanced breast cancer (2017); brigatinib (brand name Alunbrig), an ALK and EGFR inhibitor for non-small-cell lung cancer (2017); copanlisib (brand name Aliqopa), a PI3K inhibitor for relapsed follicular lymphoma (2017); abemaciclib , CDK4/6 inhibitors for advanced or metastatic breast cancers (2017); acalabrutinib , a BTK inhibitor for mantle cell lymphoma (2017); binimetinib (brand name Mektovi), a MEK inhibitor for unresectable or metastatic melanoma (2018); encorafenib (brand name Braftovi), a MEK inhibitor for unresectable or metastatic melanoma (2018); duvelisib (brand name Copiktra), a PI3K inhibitor for refractory chronic lymphocytic leukemia, small lymphocytic lymphoma, and follicular lymphoma (2018); dacomitinib (brand name Vizimpro), an EGFR inhibitor for metastatic non-small-cell lung cancer (2018); lorlatinib (brand names Lorbrena and Lorviqua), an ALK and ROS1 inhibitor for metastatic non-small cell lung cancer (2018); gilteritinib (brand name Xospata), an AXL inhibitor for relapsed or refractory acute myeloid leukemia (2018); erdafitinib , an FGFR inhibitor for locally advanced or metastatic bladder cancer (2019); alpelisib (brand name Piqray), a PI3K inhibitor for breast cancer (2019); pexidartinib , an inhibitor of CSF1, KIT, and FLT3 for symptomatic tenosynovial giant cell tumor (2019); entrectinib (brand name Rozlytrek), an inhibitor of ALK, ROS1, TKI, and TRKA/B/C for metastatic non-small cell lung cancer (2019); and zanubrutinib (brand name Brukinsa), an inhibitor of BTK for mantle cell lymphoma (2019).Other notable drugs approved by the FDA since 2014: ramucirumab (brand name Cyramza), a VEGFR2 inhibitor for advanced stomach cancer or gastroesophageal junction carcinoma (2014); palbociclib Current progress in the field of small-molecule inhibitors of kinases has led to the development of a number of compounds, with various choices for each target molecule, as well as antitumor potencies and specificity for different types/stages of cancers. On the other hand, there are already a lot of antibodies targeting kinases available. Nevertheless, there is still ample room for additional development. Hopefully, there will be a lot of new anti-kinase drugs that can be used either as monotherapy or combined with other anti-cancer medications in the future."}
+{"text": "Triatoma (Meccus) pallidipennis (Hemiptera: Reduviidae)\u201d (Bioscience Reports (2018) 38, https://doi.org/10.1042/BSR20180988) would like to add the following Acknowledgements to their study:The authors of the original article \u201cVariability of defensin genes from a Mexican endemic Triatominae:"}
+{"text": "Scientific Reports 10.1038/s41598-020-61247-0, published online 16 March 2020Correction to: This Article contains a typographical error in the Methods section where,23.\u201d\u201cWe performed the hematologic analysis using Mindray BC-6800  automated hematology analyzer that yielded CPD including CBC, leukocyte differentiation and reticulocyte count with information on volume, conductivity and different scatter measuresshould read:23.\u201d\u201cWe performed the hematologic analysis using Mindray BC-6800 plus  automated hematology analyzer that yielded CPD including CBC, leukocyte differentiation and reticulocyte count with information on volume, conductivity and different scatter measuresAlso, the Article contains an error in Table 6 where the row entitled \u2018Ramdom Forest (RF)\u2019.should read:\u2018Random Forest (RF)\u2019."}
+{"text": "The role for hormone therapy in the maintenance of diastolic function upon ovarian senescence has not been clinically tested due to concerns for off-target health risks. We developed a cell-based hormone therapy (cHT) approach that recapitulates native cell\u2013cell interactions between ovarian granulosa and theca cells in a 3D bioengineered construct to mimic the dynamic release of sex hormones. Our first report in ovariectomized (OVX) rats shows that cHT ameliorates various adverse somatic effects of hormone deficiency (e.g. bone loss). To extend these findings to cardiac health, we sought to determine the efficacy of cHT in preserving diastolic function in OVX-spontaneously hypertensive rats (SHR). 14 SHRs underwent bilateral OVX while 5 SHRs received sham surgery at 12 weeks of age. Following an 8-week washout, OVX rats were randomized to cHT or pharmacologic hormone therapy (pHT: E2 (10 mcg/kg/day) and P4  for 10 weeks and compared to OVX-vehicle and Sham. While uterine atrophy by OVX was minimized by cHT and pHT, hormone levels across OVX groups were not overtly different. Systolic blood pressure increased progressively over time (P<0.01), without a treatment effect. Even so, cHT and pHT prevented OVX-related reductions in myocardial relaxation and increases in Doppler-derived filling (P<0.05); paralleling the diastolic profile of Sham. Alongside superior diastolic function, 25% increases in cardiac interferon regulatory factor-4 (Irf-4) gene expression levels occurred in both hormone-treated OVX groups and Sham when compared to OVX-vehicle, suggesting a link between sex hormones and local immune modulation in the regulation of female cardiac health."}
+{"text": "A novel coronavirus designated as SARS-CoV-2 in February 2020 by World Health organization (WHO) was identified as main cause of SARS like pneumonia cases in Wuhan city in Hubei Province of China at the end of 2019. This been recently declared as Global Pandemic by WHO. There is a global emergency to identify potential drugs to treat the SARS-CoV-2. Currently, there is no specific treatment against the new virus. There is a urgency to identifying potential antiviral agents to combat the disease is urgently needed. An effective and quick approach is to test existing antiviral drugs against. Whole genome analysis and alignment carried out using BLASTn, SMART BLAST and WebDSV 2.0 had shown more than 238 ORF\u2019s coding for proteins mostly origin from Bat SARS coronavirus and root genomic origin from Archaea. Molecular docking results against protein targets Furin, papain like proteases, RdRp and Spike glycoprotein had shown paritaprevir, ritonavir, entecavir and chloroquine derivatives are the best drugs to inhibit multi targets of coronavirus infection including natural compounds corosolic acid, baicalin and glycyrrhizic acid with minimal inhibitory concentrations. Thus we propose use of paritaprevir, entecavir, ritonavir and chloroquine derivatives as best drug combination along with niacinamide, folic acid and zinc supplements to treat novel coronavirus infection. We also propose use of plant protease inhibitors (PI\u2019s) and Anti-IL8, IL-6, IL-2 as future drug models against coronavirus. A novel coronavirus designated as SARS-CoV-2 in February 2020 by World Health organization (WHO) was identified as main cause of SARS like pneumonia cases in Wuhan city in Hubei Province of China at the end of 2019. This been recently declared as Global Pandemic by WHO. There is a global emergency to identify potential drugs to treat the SARS-CoV-2. Currently, there is no specific treatment against the new virus. There is a urgency to identifying potential antiviral agents to combat the disease is urgently needed. An effective and quick approach is to test existing antiviral drugs against SARS-CoV-2. Spike protein recognize and bind host receptors like ACE-2 and whose conformational changes facilitates fusion of viral envelop and host membrane leading viral entry into host cells. Replication of viral RNA occurs through RNA polymerase activity by n unique mechanism. Targeting protease like Spike protein for viral entry and polymerase for replication of virus in host cell can bring effective treatment against novel SARS-CoV-2.Coronavirus are enveloped with a positive RNA genome. Coronaviridae family of the order Nidovirales, having four genera . sThe SARS-CoV-2 seems be \u03b2 genus and probable origin from bat and suspected to have an intermittent host. Structurally coronavirus contain spike (S) protein, envelope (E) protein, membrane (M) protein and nucleocapsid (N) protein. Viral entry through host receptor attachment promoted by spike protein leading to viral fusion to cell membrane of the host and leading to infection. Incubation period may range from 7 days to 21 days with flu like symptoms or sometimes go asymptomatic. Spike protein determines the viral entry and infection. Antiviral therapies targeting human immune system and direct coronavirus are the primary methods of treating the viral infection. Innate immunity of human immune system plays important role as primary defence mechanism against coronavirus infection and its replication. Interferon plays key role in controlling viral replication and immune presentation of viral antigens and to enhance immune responses. Viral entry and replication require human cell signal pathways, by blocking such signal pathways can bring anti-viral effect. Previously known coronavirus infections SARS and MERS causing virus used angiotensin converting enzyme 2 (ACE2) and DPP4 human receptors of human cells independently. Targeting RNA-dependent RNA polymerase (RdRP) of coronavirus is second line of treatment itself include preventing the synthesis of viral RNA through acting on the genetic material of the virus inhibiting virus replication. Activation of the viral spike protein (S) by host cell proteases is essential for viral host cell attachment and entry and the responsible enzymes are potential therapeutic targets. The cellular proteases like furin, cathepsin and receptors like C-type lectins are Ca++-dependent glycan-binding proteins (GBPs) a functional receptor-mediated endocytosis in Golgi bodies plays important role viral infection, replication and maturation as shown in .Different strategies for developing drugs and treatment against SARS-CoV-2 include viral protein inhibitors and human cell receptor inhibitors to be studied extensively. Some interferon inhibition like ribavirin and cyclophilin were studied to treat coronavirus pneumonia. Interferon inhibition alone cannot treat the SARS-CoV-2, multi target therapy to be considered as effective way of treating which includes inhibition of receptor proteases like furins, viral proteins like spike (S) and Nsp12, a coronavirus, is an RNA-dependent RNA polymerase (RdRp) protein vital enzyme for coronavirus replication/transcription complex, which can inhibit both viral host cell entry and replication. As designing of novel molecules at present is time consuming and no present therapies existing to treat SARS-CoV-2, we propose use of existing antiviral and other drugs to treat the coronavirus infection. High-throughput screening, bioinformatics and AI based tools and methods to screen existing drug database is the fastest approach to discover drug leads against SARS-CoV-2 for example anti-retro viral drugs like Lopinavir and Ritonavir.After determining the efficacy, the drugs can be approved through proper hospital based clinical trials for clinical treatment of patients. Viral encoding proteins and human cell proteins aiding viral host cell entry and replication were analysed by bioinformatics tools like Molecular docking and Swiss Dock protocols by conducting homology modelling and ligand preparations. SARS-CoV-2 Viral papain like protease, main protease, spike and RNA-dependent RNApolymerase (RdRp) and human furin human ACE2 and type-II transmembrane serine protease proteins were extensively used for targeted drug discovery. Virtual screening of proposed protein targets was docked against anti-HIV and anti-Hepatitis drugs were selected as ligands from drug database including some natural phytochemicals known for antiviral properties. The present study predicts wide range of drug leads that may inhibit this study predicts a variety of compounds that may inhibit novel SARS-CoV-2 coronavirus. Validation of successful drug leads should be studies for complete efficacy using proper in-vitro and in-vivo methods further to continue clinical studies.Whole genome of SARS-CoV-2 was obtained from NBCO Nucleotide database with reference number NC_045512.2. The nucleotide sequences were aligned using BLASTn sequence aligner and similarity search analysis with SARS-CoV-2 viral genomes submitted at NCBI from different samples of infected Cluster. MN908947 (complete genome) NC_045512 (reference sequence), LC522350 (gene region coded for RdRp), LC523807 (coded for N), LC523808 (coded for N), LC523809 (coded for N), LC528232 complete, LC528233 complete, LC529905 complete, LR757995 complete, LR757996 complete, LR757997 complete, gapped, LR757998 complete, MN938384 complete, MN938385RdRP, MN938386 RdRP, MN938387 S, MN938388 S, MN938389 S, MN938390 S, MN970003 RdRP, MN970004 RdRP, MN975262 complete, MN975263 RdRP, MN975264 RdRP, MN975265RdRP [ORF finder searches for open reading frames (ORFs) in the DNA sequence you enter. The program returns the range of each ORF, along with its protein translation. Use ORF finder to search newly sequenced DNA for potential protein encoding segments, verify predicted protein using newly developed SMART BLAST or regular BLASTP ,4,5.After genome alignment, the whole genome was searched for ORF domains using SMART BLAST. Quality parameters like minimal ORF length 75 with standard genetic code having ATG and initiation codons been set.dockingserver.com. 3D structure structures are aligned by Autodock and pymol structure alignment tools.Nucleotide sequence editing was conducted using WebDSV 2.0. Protein alignment was done using Clustalw and protein to DNA sequence comparison done using pairwise alignment EMBL EBI tools ,7. The hDocking calculations were carried out using Docking Server. Gasteiger partial charges were added to the ligand atoms. Non-polar hydrogen atoms were merged, and rotatable bonds were defined \u201310.Docking calculations were carried out on selected ligands to SARS-CoV-2 main protease PDB ID 6LU7, Human furin PDB ID6HZD, PDB ID 3E9S papain like protease and PDB ID 6NUR Nsp12 of SARS virus. Essential hydrogen atoms, Kollman united atom type charges, and solvation parameters were added with the aid of Autodock tools . AffinitDocking simulations were performed using the Lamarckian genetic algorithm (LGA) and the Solis & Wets local search method . InitialGenetic ID MN908947 SARS-CoV-2 isolate Wuhan-Hu-1, complete genome after BLASTn similarity search had shown more similarity with many bat coronaviruses, some unknown virus and for some synthetic recombinant virus with genetic ID FJ211859.1 see SMART BLAST analysis shows more than 283 open reading frames shown in supplementary file orf finder-NCBI and in Selected paritaprevir, entecavir, ergotamine tartrate, telaprevir, dihydroergotamine, simeprevir, ergotamine alkaloid, telmisartan, ritonavir tartrate, fgi 106, corosolic acid, chloroquine, darunavir, nelfinavir, glycyrrhizic acid, baicalin, ritonavir, quilajja saponin, lopinavir, amprenavir, fosamprenavir, quercetin, remdesivir, pemetrexed, raltitrexed, sofosbuvir were docked against proteins SARS-CoV-2 main protease PDB ID 6LU7, Human furinPDB ID6HZD, PDB ID 3E9S papain like protease and PDB ID 6NUR Nsp12 (RdRp) in selective manner as mentioned in , 3 and 4Paritaprevir, chloroquine and ritonavir had shown strong multi target inhibition like spike proteins, proteases and furin. Natural compounds like baicalin, corosolic acid had shown multi target inhibition properties against spike proteins, proteases and furin.At present world is facing pandemic situation because of SARS-CoV-2 infection. There is an urgency to address this situation as no present treatment protocols are not been established. The only way to develop quick treatment protocols can be achieved by studying detailed case studies of SARS infections caused by influenza and non-influenza viruses and also studying existing antiviral drugs.Computational and high throughput screening tools are the best aids to design and study the efficacy of existing antiviral drugs along with some anti-inflammatory drugs against SARS-CoV-2 targeted sites. Antiviral drugs like oseltamivir used against neuraminidase of SARS in last decade, favilavir an RNA-Dependent RNA polymerase (RdRp) inhibitor also showed effective against the SARS influenza virus. Recently Japan also proposed use of favipiravir and Avian flu drug to treat SARS-CoV-2 infection. Remdesivir a proposed drug to treat Ebola virus also been proposed to test against SARS-CoV-2. DNA and RNA inhibitors like sofosbuvir and anti-HIV drug compositions also been proposed at present to treat the present global pandemic caused by novel coronavirus. Most of the proposed drugs had shown either less efficacy or effective in some patients but not achieved complete success. In order to develop complete treatment protocol, one should understand the disease pathogenesis. As per case reports available study indicates respiratory outburst due to various inflammatory study indicates severe diarrhoea and respiratory outburst due to inflammatory factors causing death among novel coronavirus infected patients. As per our study we found CD4+ activation leading to TH1 and TH2 cytokines outburst in excessive leading to severe respiratory illness in patients affected by SARS-CoV-2. This virus has Orf zone indicating C lectin type binding receptors of host , 5 and 6The present used carried out using computational and high throughput screening tools in order to evaluate the whole Genome analysis of SARS-CoV-2 and identifying potential drugs to treat novel coronavirus influenza. Gene sequence was obtained from NCBI genome database ,3 and Mosupplement1DISTANCE TREE RESULT OF SARS COV 2 GENOMEREVERSE PRIMERS IN WHOLE GENOME OF SARS CoV 2supplement3orf best hitssupplement5SEQUENCE SIMILARITY HOMOLOGYsupplement4ORFfinder - NCBIsupplement7FORWARD PRIMERS IN WHOLE GENOMEsupplement8SARS COV2 ALIGHNED WHOLE GENOME TO TRANSALTED ALIGHTMENTsupplement8SARS COV2 WHOLE GENOME ALIGHMENT AND SITESsupplement9Taxonomysupplement2Factsheet_SmartBLASTsupplement10GenBank_ MN908947.3supplement6Smart BLAST orf whole genome"}
+{"text": "We describe 2 cases in coronavirus disease patients in France involving presumed thrombotic stroke that occurred during ongoing anticoagulation treatment for atrial fibrillation stroke prophylaxis; 1 patient had positive antiphospholipid antibodies. These cases highlight the severe and unique consequences of coronavirus disease\u2013associated stroke. Coronavirus disease (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Evidence increasingly shows that SARS-CoV-2 is not always confined to the respiratory tract but can induce neurologic diseases  sought care for respiratory symptoms, including dyspnea and cough. At admission, physical examination revealed a blood pressure of 120/70 mm Hg, irregular heartbeat (100 beats/min), fever (39\u00b0C), and bilateral crackling sounds on pulmonary auscultation. Laboratory findings revealed low leukocyte count and lymphopenia . Chest rSupportive treatment began  infusion/d], and hydroxychloroquine [200 mg orally 2\u00d7/d]), and the same dosage of apixaban was continued. On April 3 , dysarthria, left hemiplegia, and alteration of consciousness developed. Brain magnetic resonance imaging revealed acute ischemic stroke in multiple vascular areas . We switOn April 3, a 74-year-old man with a history of multiple cardiovascular diseases, such as atrial fibrillation treated with rivaroxaban , sought care for influenza-like illness and confusion. His work colleagues had noticed disorientation during his activity as a truck driver. At admission, physical examination revealed hypertension (230/70 mm Hg) and irregular heartbeat (86 beats/min). He was febrile (38.3\u00b0C) and had crackling sounds on pulmonary auscultation. Neurologic examination showed nonfluent aphasia. COVID-19 was diagnosed from results of real-time reverse transcription PCR, microbiologic testing, and computed tomographic thoracic imaging . Brain cTreponema pallidum, Mycobacterium tuberculosis, and Aspergillus spp.; acute bacterial meningitis has also been implicated (Several factors can cause acute ischemic stroke, but the primary ones are arterial and cardiac embolism, arterial wall disease, and variants of those conditions. Both of these patients had concurrent cardiovascular conditions, particularly atrial fibrillation, although both were adequately treated with anticoagulants. Hematologic derangements, including lymphopenia and leukopenia, are associated with ischemic stroke and are predictors of worse prognosis with stroke (In this rapidly emerging epidemic, several cases have reported strokes in SARS-CoV-2\u2013infected patients (2-glycoprotein I antibodies might rarely lead to multiple thrombotic cerebral events (Other authors suggest that the presence of antiphospholipid antibodies, such as anticardiolipin antibodies, as well as anti\u2013\u03b2The association between cerebral stroke and COVID-19 requires more attention. Coagulability dysfunction and possibly antiphospholipid antibody syndrome may contribute to thromboembolic events in the central nervous system. Further investigation is required to determine the prognostic role of the presence of antiphospholipid antibodies in COVID-19.Additional data for 2 coronavirus disease patients with acute cerebral stroke, France 2020."}
+{"text": "Salmonella enterica serotype Typhi isolated from a returned traveler from Pakistan who developed sepsis. Whole-genome sequencing revealed relatedness to a previously reported outbreak in Pakistan and identified the blaCTX-M-15 and qnrS resistance genes.We report a draft genome sequence of extensively drug-resistant (XDR)  Salmonella enterica serotype Typhi isolated from a returned traveler from Pakistan who developed sepsis. Whole-genome sequencing revealed relatedness to a previously reported outbreak in Pakistan and identified the blaCTX-M-15 and qnrS resistance genes.We report a draft genome sequence of extensively drug-resistant (XDR)  Salmonella enterica serotype Typhi (S. Typhi) is a significant public concern due to the potential for severe disease with few antimicrobial treatment options (S. Typhi and other pathogens (S. Typhi isolate from a traveler who had visited Pakistan (The emergence of extensively drug-resistant (XDR)  options . Whole-gathogens , 2. HerePakistan  and deveN50 value of 204,170\u2009bp and a draft genome size of 4,757,010\u2009bp. The GC content (52.04%) was comparable to that of other S. Typhi strains from Pakistan (Blood cultures were performed using Bactec (BD) culture bottles and the Bactec FX instrument. Susceptibility testing was performed using the MicroScan WalkAway 96 plus instrument (Beckman Coulter). DNA extraction was carried out using the Zymo Quick-DNA fungal/bacterial kit according to the manufacturer\u2019s instructions, followed by library preparation using the NEBNext Ultra II DNA kit. Illumina sequencing was carried out on a MiSeq instrument to yield 6,805,326 150-bp reads (https://github.com/czbiohub/Spid.jl) with a previously reported Pakistan chromosomal reference sequence for alignment  detection pipeline SPID v0.4.0  protocol number 17-24056.PRJNA588448. The short reads are available under SRA accession number SRX7117257. The genome assembly is available under GenBank accession number GCA_009724275.1.All the data are available under BioProject number"}
+{"text": "Fusarium graminearum is a global fungal pathogen of wheat and other small grains, causing Fusarium head blight (FHB) disease, also known as wheat scab. We report here the annotated genome of a deoxynivalenol/15-acetyl-deoxynivalenol-producing Brazilian strain called CML3066, isolated from FHB-symptomatic wheat spikes collected in 2009. Fusarium graminearum is a global fungal pathogen of wheat and other small grains, causing Fusarium head blight (FHB) disease, also known as wheat scab. We report here the annotated genome of a deoxynivalenol/15-acetyl-deoxynivalenol-producing Brazilian strain called CML3066, isolated from FHB-symptomatic wheat spikes collected in 2009. Fusarium graminearum is the main pathogen causing Fusarium head blight (FHB), an important cereal disease worldwide , isolated in 2009 in Rio Grande do Sul state, Brazil . This strain was isolated from a symptomatic wheat spike with 21.5% FHB incidence (The ascomycete fungus orldwide . The F. F. graminearum CML3066 was extracted from mycelia grown for 3 days in potato dextrose broth (PDB) medium using a cetyltrimethylammonium bromide (CTAB) protocol  and the SMRT analysis portal using the PacBio data. The PacBio assembly was manually gap filled and further scaffolded using Lastz v1.04.03 alignments with the complementary Illumina assembly, resulting in four complete chromosomes from telomere to telomere with no gaps or N bases. Reference sequence statistics were extracted from Geneious v8.1. The genome annotation of CML3066 was done using the MAKER v2.30  calling was performed with SAMtools using default settings. SNP effects were predicted using SnpEff 4.2. Comparison of SNP frequencies along all four chromosomes of both CML3066 and PH-1  revealed11\u2013PRJEB12819. The accession numbers for the assembled chromosomes and mitochondrial genome are LT222053 to LT222057. The secretome and effector predictions can be found at https://github.com/ana321wood/Secretome_CML3066_Feb2020/blob/master/Secretome_CML3066_Feb2020_AMW.txt.The raw data and assembled/annotated sequences have been deposited in the European Nucleotide Archive (ENA). The study accession number is"}
+{"text": "Lachinospiraceae bacterium NBRC 112778. This anaerobic bacterium, isolated from a sweet potato-digesting mesophilic methanogenic bioreactor, represents a new genus related to the genus Anaerosporobacter. The 4.52-Mb circular genome harbored many genes involved in carbohydrate utilization, suggesting its adaptation to a saccharolytic environment.Here, we report the draft genome sequence of  Lachinospiraceae bacterium NBRC 112778. This anaerobic bacterium, isolated from a sweet potato-digesting mesophilic methanogenic bioreactor, represents a new genus related to the genus Anaerosporobacter. The 4.52-Mb circular genome harbored many genes involved in carbohydrate utilization, suggesting its adaptation to a saccharolytic environment.Here, we report the draft genome sequence of  Lachinospiraceae bacterium NBRC 112778 was obtained from a mesophilic methanogenic bioreactor digesting sweet potato. The methanogenic sludge was inoculated onto reinforced clostridial medium (RCM) (Anaerosporobacter mobilis (GenBank accession no. AY534872)  of cells obtained from ca. 1.5 liters of culture using an Isoplant II genomic extraction kit , and its quality was assessed by using a NanoDrop spectrophotometer (Thermo Scientific) and a Qubit fluorometer (Invitrogen). DNA was then sheared to an average size of 10 kb using g-TUBEs (Covaris). The genomic library was constructed using DNA template prep kit 1.0 and DNA/polymerase binding kit P6 (Pacific Biosciences [PacBio]). Size selection and quality analysis of the genomic library were performed using a BluePippin system  and a 2100 Bioanalyzer (Agilent), respectively. A PacBio RS II sequencer was used to sequence the 10-kb library of the NBRC 112778 genome using P6-C4 chemistry. For the following analysis, default parameters were used for all software.De novo assembly for 112,408 PacBio subreads  was performed successfully to closure by HGAP2, yielding a single contig. The assembled genome data were circularized and subjected to annotation using the Rapid Annotations using Subsystems Technology (RAST) server  implemented with SMRT Analysis software v2.3.0 (PacBio) . De novoA single contig generated from the assembly consisted of 4,521,945\u2009bp with a G+C content of 36.6%. The sequence assembly did not contain any plasmid. RAST predicted 4,174 genes for protein-coding sequences, 24 rRNA genes, and 69 tRNA genes. A whole-genome survey using the SEED Viewer (SAMD00112399). The 16S rRNA gene sequence and complete genome sequence of NBRC 112778 have been deposited in DDBJ/GenBank under accession no. LC330916 and AP018794, respectively. We submitted the raw sequencing reads to DRA under accession no. DRR198068.The conditions for the isolation and cultivation of NBRC 112778 are available in the BioSample database (accession no."}
+{"text": "Efficacious HIV-1 vaccination requires elicitation of long-lived antibody responses. However, our understanding of how different vaccine types elicit durable antibody responses is lacking. To assess the impact of vaccine type on antibody responses, we measured IgG isotypes against four consensus HIV antigens from 2 weeks to 10 years post HIV-1 vaccination and used mixed effects models to estimate half-life of responses in four human clinical trials. Compared to protein-boosted regimens, half-lives of gp120-specific antibodies were longer but peak magnitudes were lower in Modified Vaccinia Ankara (MVA)-boosted regimens. Furthermore, gp120-specific B cell transcriptomics from MVA-boosted and protein-boosted vaccines revealed a distinct signature at a peak (2 weeks after last vaccination) including CD19, CD40, and FCRL2-5 activation along with increased B cell receptor signaling. Additional analysis revealed contributions of RIG-I-like receptor pathway and genes such as SMAD5 and IL-32 to antibody durability. Thus, this study provides novel insights into vaccine induced antibody durability and B-cell receptor signaling. In the case of experimental HIV vaccines, efficacy is correlated with Envelope (Env)-specific antibody responses4. In particular, Env IgG3 titers that mediate antibody-dependent cellular phagocytosis (ADCP) and antibody dependent cellullar cytotoxicity (ADCC) are correlated with decreased risk of infection6. However, these responses decay more than 10-fold 6-months post-vaccination, paralleling the decline in vaccine efficacy7. Estimates of HIV-1 specific IgG half-lives range from 25-213 days, depending on the vaccine regimen and antigen (excluding gp41)9. Interestingly, the Vaccine-Induced HIV Seropositivity/Reactivity (VISP/VISR) in non-infected HIV vaccine recipients is commonly observed for vaccines with a Gag or Env component10, indicating that antibody responses can remain detectable for several weeks to a year post-vaccination. However, positive results on diagnostic tests are qualitative in nature and thus not quantitative in estimating antibody longevity. Hence, in this study, we measured antibody responses in the VISP cohort by a quantitative assay, the Binding Antibody Multiplex Assay (BAMA), across vaccine regimens. Furthermore, we model antigen-specific antibody decay kinetics and immunoglobulin subclasses necessary to inform rational design of HIV-1 vaccines with improved durability.While vaccine-elicited antibody durability has been achieved for licensed vaccines such as yellow fever, measles, smallpox, and Hepatitis B, elicitation of long-lived, functional antibody responses with candidate HIV-1 vaccine regimens remains elusive12. Env-specific antibodies after gp120 protein vaccination correlate with the number of circulating short-lived memory B-cells13; however, in participants who control HIV without treatment, memory B cell responses did not correlate with plasma antibody titers14. Since memory B cells differentiate into plasma cells upon boost and studying the plasma cell compartment in human participants is difficult, memory B cells provide the best window into signaling underlying the generation of antibody responses.Vaccine induced antibodies are secreted by plasmablasts within days of exposure, followed by memory B cells and plasma cells. These B cell dynamics are noticeable in analyses of half-lives using antibody-titers24. Specifically, analysis of early innate PBMC signatures associated with antibody levels after one dose of recombinant HIV gp140 with TLR-4 agonist adjuvant revealed a negative correlation of mitotic cell division modules with antibody production and upregulation of plasma cell surface markers a week after vaccination23. Further, a recent study identified a B cell (CD14\u2212CD20+) gene signature that predicts protection from infection after vaccination with Ad26-prime and gp140-boost in Rhesus Macaques and in RV-14424. Collectively, these results suggest that gene expression profiling, particularly from sorted B cells may unveil important insights into mechanisms of B cell differentiation across vaccine types.Additional insights into drivers of vaccine induced antibody responses from genome-wide transcriptional profiling have revealed gene signatures of B cell differentiation and early innate signaling. Early studies of gene expression showed type I interferon, inflamasome, and complement signaling in peripheral blood mononuclear cells (PBMCs) upon vaccinationIn the present study, we assessed the longevity of HIV-1 Env-specific IgG and IgG3 responses across 10 HIV vaccine regimens and quantified the effects of each vaccine type on durability using both linear and nonlinear mixed effects modeling (see Table 10. IgG or IgG3 in serum were assessed by a Binding Antibody Multiplex Assay (BAMA) for binding to a panel of consensus HIV Env proteins including gp120, gp140, gp41, and the V1V2 region of gp120 at peak (2-4 weeks post-last vaccination) at multiple post-vaccination time points. Vaccine immunogens varied by trial with DNA-MVA (HVTN 094 and 205) utilizing a gp150 immunogen, and Canarypox-protein (HVTN 097) and DNA-protein (HVTN 105) utilizing a gp120 immunogen.Five phase I or phase IIa HVTN trials 077 (DNA/Ad35 or Ad5), 094 (DNA/ HIV62B MVA), 097 (ALVAC/AIDSVAX B/E), 105 (DNA/AIDSVAX B/E), 205 (DNA/HIV62B MVA) were investigated in this study. Broadly, HVTN 094 and HVTN 205 were MVA-boosted trials with or without DNA priming, utilizing DNA expressing VLPs displaying gp160 in the prime and matched MVA-expressing VLPs displaying gp150 in the boost, HVTN 077 was Adenovirus (Ad)-boosted, and HVTN 097 and HVTN 105 were protein-boosted with subtype B MN gp120 and subtype A/E A244 gp120. HVTN 097 was primed with canarypox containing clade E 92TH023 gp120 while 105 was primed with DNA containing clade C ZM96 gp140. HVTN 094-T3 and 105-T2 were each primed twice with DNA followed by two MVA or protein boosts, respectively  window of the model.Robust responses against gp140 were elicited in both MVA  and protein-boosted trials . For gp140 and gp120 IgG as well as gp140 IgG3 antibody responses, MVA-boosted trials  displayed longer half lives than protein-boosted trials   baseline Net MFI at peak and 6 month timepoints. Post vaccination data points that were less than (pre-vaccination) baseline were not included. Only viral-boosted trials HVTN 077 (Ad5), HVTN 094 (MVA), and HVTN 205 (MVA) had sufficient post-vaccination data to be modeled. Newer trials  have not yet sampled for a sufficient period post-vaccination to observe long-lived responses, and other trials did not have sufficient participants with maintained antibody responses. DNA/MVA vaccination in HVTN 205 resulted in an asymptote between 103 Fig. . Uniquel103 Fig. , indicatnge Fig.  for MVA nge Fig. , panel DWe next investigated molecular signatures of durable responses in 26) was used with and without addition of FCRL genes to evaluate the role of FCRL genes in the regulation of BCR signaling. The FCRL genes were incorporated in BCR signaling pathways by mining\u00a0primary literature28. Boolean Omics Network Invariant-Time Analysis (BONITA), which performs discrete-state modeling identified BCR pathway with FCRL genes to be significant at p\u00a029 between MVA and protein boosted groups. PTPN6 and PTPN11 inhibit BCR signaling and were identified to have low impact on regulation of BCR pathway by BONITA irrespective of FCRL genes. The regulation identified by BONITA suggests that FCRL2 and FCRL3, which have very high impact scores, are required for activation of PTPN11 and PTPN6 while LYN can be activated by either Fig. Discrete dynamic modeling was employed to better understand changes in BCR signaling and how they relate to changes in FCRL genes. A network of BCR signaling , in agreement with previous vaccine studies33. IL32, shown to act as an immunosuppressant during HIV infection34, was accordingly identified as negatively correlated in both MVA- and protein-boosted trials  genes in B cells40. Taken together, this analysis shows that the durability of antibody responses is induced by a coherent transcriptional signature supported by previous studies of B cell gene expression.An association of B cell gene expression at peak antibody magnitude with antibody half life suggests potential molecular mechanisms responsible for long-lived antibody responses. This association could be dependent on the vaccine type used in each trial, and thus MVA- and protein-boosted\u00a0trials were analyzed separately (see methods). Twenty-four genes were significantly associated with half-life in MVA  and in protein-boosted trials (HVTN 105) . These genes included tetraspanins (SNX13 and TSPAN33) which are involved in several signal transduction events required for B cell activationials Fig . Additio18. Genes highly expressed after MVA-boosted vaccination  were enriched in genes downregulated after LAIV compared to pre-vaccination. Further, genes highly expressed in durable vs transient subjects in protein-boosted 105-T2 (DDPP) were also enriched for genes downregulated after LAIV. Further, a signature of many immunoglobulin genes, TNFSF13B, and FCRL5 was observed seven days after vaccination with TIV or diphtheria toxoid22 as well as in protein-boosted HIV vaccines in our study. Thus, protein-boosted vaccination induces genes regulating BCR signaling.To compare gene signatures identified in this study with previous vaccine signatures we investigated influenza and diphtheria toxoid vaccine response. Comparison between live attenuated (LAIV) or protein (TIV) influenza vaccination revealed that LAIV produced lower magnitudes of HA-specific antibodies and gene expression at 1 week than TIV24 derived two gene signatures of HIV vaccine efficacy, one of 53 genes and the other of 200 genes from B cells following Ad26-gp140 vaccination in non-human primates. These signatures were validated in PBMCs from RV-144. Both signatures were enriched in genes with higher\u00a0expression upon MVA boost than protein boost , which results in responses of the size of those in protein-boosted trials but with extended half lives in multiple years and decades.This study describes differences in half life of antibody response between MVA-boosted and protein-boosted HIV vaccinations. MVA-boosted vaccinations  lead to longer half life with lower-magnitude of antibody responses than protein-boosted HIV vaccines . Nevertheless, protein-boosted vaccines elicited a greater time-averaged mean antibody response to gp120. Promisingly, MVA-boosted vaccines led to half lives longer than those for immunoglobulin molecules53. When gp41 is included in the boost (i.e. gp150 boost vs gp120 boost), gp41 responses were as robust as gp140 responses, with increased response longevity vs gp120 responses. High epitope similarity to gut bacteria may contribute to rapid, large gp41 responses and persistence of gp41-specific antibodies in early HIV infection and HIV vaccination55. Inconclusivity of this study with regard to V1V2 along with putative efficacy of V2-specific antibodies calls for a higher powered study of V2-specific antibody responses57, including ongoing efficacy trials.Antibody responses observed here and in primary trials vary considerably by antigen-specificity. We found responses to gp140 are most frequent and robust followed by gp41 (when included in boost) and gp120 with few responses to V1V260. Taken together, this evidence demonstrates that vector and priming strategies, independent of immunogen, play a critical role in determining the magnitude of the gp120-specific antibody response.In the current study, effects of immunogen on vaccine-elicited antibody durability was not explicitly tested because MVA and protein boosted regimens used gp150 and gp120 respectively. Moreover, protein-boosted regimens (HVTN 097 and HVTN 105) included in this study were boosted with AIDSVAX B/E (gp120 immunogen) whereas MVA-boosted regimens (HVTN 094 and HVTN 205) analyzed in this study were boosted with MVA/HIV62 (gp150 immunogen) matched to the DNA prime. Despite the differences in gp120 sequences previous studies suggest a stronger response regardless of the immunogen used. Moreover, viral-prime, protein-boost vaccine trials have demonstrated robust gp120-specific antibody response following both gp120 and gp140 boost61. Despite the caveats of the HVTN 910 (VISP/VISR) cohort , we have added further evidence that long-lived vaccine-induced antibody responses are achievable with current HIV vaccine regimens. Moreover, this evidence makes clear that future experimental vaccines studies should investigate persistence of antibody responses and underlying B cell transcriptional programs.The nonlinear model demonstrated that two different viral vectors (vaccinia and adenovirus) can lead to long-lasting antibody responses. Nonetheless, 62, their lifespan is likely imprinted at the time of differentiation12. Long term survival of antibodies has been shown to correlate to memory B cell numbers following meningitis vaccine63. Moreover, gp120-specific antibodies correspond to memory B cells following HIV vaccine13. Therefore, study of gene expression in memory B cells is an attempt to understand responses that might have led to lasting memory B cell and plasma cell responses. Though our study can not differentiate into responses driven by specific B cell types, it demonstrates the state of memory B cells that emerge from germinal centers at the same time as longer-lasting MVA-induced plasma cells. Given the difficulty of sampling lymph nodes in human participants and pre-selection of participants, memory B cell signaling provides the most expedient window into germinal center dynamics.Our study profiled gene expression in memory B cells, which develop upon multiple rounds of vaccinations and whose predecessors, at the minimum, would have contributed to the development of long-lived plasma cells. Although plasma cells develop distinct transcriptional programs from memory B cells67. Markedly high FCRL2, FCRL3, and FCRL5 were identified in the context of Hepatitis C vaccination68. T-bet and FCRL5+ memory B cells correlate with longevity of antigen-specific antibody responses69, however there are conflicting data on longevity and FCRL5+ memory B cells71. We found a weak negative correlation between Tbet and half life in MVA trials  and no other correlations. Finally, discrete state modeling shows that FCRL2 and FCRL3 can independently activate LYN which leads to downstream activation of the BCR signaling pathway27. Thus, the current study provides mechanistic insights into regulation of BCR signaling by FCRL.The current gene expression analysis indicated a clear and strong signature of difference between protein and MVA boosted trials including differences in FCRL genes. FCRL molecules have an excitatory role in marginal zone (B2) B cell signalling74. Unfortunately, dendritic cell-based therapeutic HIV vaccination studies demonstrated decreased immunogenicity with TLR4 activation75. Another adjuvant, MF59, used in HVTN 702 (NCT02968849) with gp120-boost following canarypox prime, increases strength, breadth, and durability of response to Influenza vaccine by activating the early innate response76. Thus, the data shown here calls for careful understanding of how TLR4 agonists affect antibody responses on their own and in the context of MF59.The transcriptomic signature of enhanced durability of MVA-boosted regimens  consisted of RUNX1, RUNX2, and TLR4 as well as higher levels of Toll-like Receptor and IL-1R signaling. Thus, use of TLR4 agonists could increase antibody durability. Indeed there are safe TLR4 adjuvants that have already been tested in HIV vaccination24 in MVA-boosted trials along with increased gp120 half-lives is encouraging for the development of MVA as a vector for HIV vaccination. Moreover, enrichment of this signature in subjects with durable responses in AIDSVAX B/E protein-boosted 105-T2 suggests that protective HIV vaccine signatures may also be associated with durable responses. The Ehrenberg et al. gene signatures was identified by measuring gene expression at varied time points in human PBMCs (RV144) and in B cells from non-human primate Ad26-gp140 efficacy studies24. However, there are many differences between our study and Ehrenberg et al24, including antigen specificity , timepoints assessed (2 weeks and 6 months vs multiple), and prime (DNA vs Ad26 or canarypox). Nonetheless, MVA-boosted regimens  produced a B cell gene signature associated with protection, but at lower levels of antibody production than the protein-boosted regimens in Ehrenberg et al. Thus, our data present a rationale for continued investigation of MVA+ protein regimens, including testing immunogen to improve magnitude and durability of antibody responses.Enrichment of HIV vaccine signatures associated with protection47, HVTN 09448, HVTN 09749, HVTN 10550, HVTN 20553 were previously acquired and data were used in this analysis with approval from the HVTN77. Analysis of Levey-Jennings charts indicate the comparability of historical controls across trials and time for positive controls including HIVIG and CH58 mAb. All methods were carried out in accordance with relevant guidelines and regulations, and informed consent was obtained from all subjects.Antibody levels measured by binding antibody multiplex assay (BAMA) were either acquired from the primary analysis or obtained de novo for the current study. We tested serum samples from HVTN trial 910 retrospectively with IRB approval . Longitudinal samples from HVTN 105 at month 12 were obtained with informed consent . Primary data for trials HVTN 07780, Con6 gp120, and gp70_B.CaseA_V1V2 at primary and longitudinal timepoints as described previously82. Briefly, samples were incubated with antigen-coated beads in BAMA assay diluent , 1% milk blotto (w/v), 0.05% Tween-20 (v/v) in PBS), washed, then incubated with either biotinylated anti-human IgG (Southern Biotech) or biotinylated anti-human IgG3  followed by washing and incubation with Streptavidin-PE (BD Biosciences). Binding peak magnitude (Median Fluorescence Intensity) was measured in duplicate using a Bio-Plex 200 (Bio-Rad) and averaged to obtain Mean Fluorescence Intensity (MFI). Positive controls included titrated HIV positive IgG (HIVIG), CH58 mAb  and Purified IgG3 human myeloma protein (Sigma) coupled beads. All experiments were conducted following Good Clinical Laboratory Practice (GCLP) guidelines with tracking of antigen performance through historical Levey-Jennings control charts.Serum samples were tested for IgG and IgG3 binding Ab responses to gp41, Con S gp140lme4 and statistical properties  computed using emmeans which estimates a reference grid based on the factors in the model then averages over other factors and propagates error so that confidence intervals and p-values can be computed for the factor of concern84. Residuals were well-distributed across time . Covariates such as BMI and sex were not included in the model since systematic bias was not observed in these variables , and insufficient sample size existed to consider covariates in our mixed effects models. Time-averaged means were obtained by dividing the area under the response curve by 540 days as log(magnitude) and Antibody decay was assessed by both linear and nonlinear mixed effects modeling of log-transformed or raw Net MFI values from BAMA respectively. Models used random effects to account for inter-individual variability but did not control for demographic variables. Linear mixed effects models included participants with at least two non-zero  was used during cell labeling to prevent gp120 from binding T cells. On average 350 gp120+ cells were obtained per sample.Participants were selected for B cell bulk RNA-sequencing by matching durable 89. BONITA was additionally used to assess the B Cell Receptor Signaling Pathway from which was taken from Wikipathways26 but originally created in NetSlim25. This pathway was manually converted into the format necessary for use with BONITA29. FCRL genes interact through immunoreceptor tyrosine-based activating motif (ITAM) and immunoreceptor tyrosine-based inhibitory motifs (ITIM) with LYN and PTPN molecules, respectively28. To recapitulate this behavior, activating edges were added from FCRL2-5 to LYN and activating edges were added from FCRL1-5 to PTPN6 and PTPN11. Note that PTPN6 and PTPN11 have inhibitory connections to downstream genes; activating them inhibits the rest of the pathway. The resultant networks (with and without FCRL genes) were then subjected to BONITA pathway analysis. Edge sets (.txt) and network files (.graphml) of these BCR networks are now available at https://github.com/Thakar-Lab/BONITA.Genes implicated in durable response were evaluated by measuring association between gene expression at the peak and half-life estimates from linear model by Spearman correlation. The genes with coefficient of variation Supplementary Data\u00a0Table S1.Supplementary Data\u00a0Table S2.Supplementary Data\u00a0Table S3.Supplementary Data\u00a0Table S4.Supplementary Information."}
+{"text": "Among 200 patients developing hospital-acquired pneumonia (HAP) outside the intensive care unit, 61% were treated empirically without broad-spectrum Gram-negative coverage, with clinical cure in 69.7%. Lower disease severity markers  and the absence of diabetes mellitus and prior doxycycline treatment (but not the time to HAP onset) identified patients not requiring broad-spectrum Gram-negative coverage. Pseudomonas aeruginosa are considered canonical HAP pathogens and international guidelines recommend empiric broad-spectrum Gram-negative antimicrobial coverage [P. aeruginosa, and Acinetobacter baumanii; thus, its usage provides an opportunity to address the unanswered question of the requirement for broad-spectrum Gram-negative coverage in non-ICU HAP. The aims of this study were to (1) identify and characterize a representative cohort of patients with non-ICU HAP; and (2) report treatment outcomes without broad-spectrum Gram-negative coverage.Hospital-acquired pneumonia (HAP) occurring outside the intensive care unit (ICU) is a relatively understudied nosocomial infection (non-ICU HAP). Gram-negative bacilli (GNB) such as Enterobacteriaceae and coverage , 2. Howecoverage . Therefocoverage . DoxycycAn electronic search identified all inpatient ward chest X-rays (CXR) performed in 2 tertiary care hospitals in Edinburgh, United Kingdom, over 13 months (June 2018\u2013July 2019) where the request or report included the terms \u201cconsolidation\u201d or \u201cpneumonia\u201d (n = 4250). These reports were reviewed to identify those cases with radiological evidence of infective consolidation (n = 728). The electronic patient records for these patients were reviewed to determine whether the case definition was met. Non-ICU HAP was defined as new/progressive CXR consolidation occurring (1) \u226548 hours after hospital admission; (2) in a non-intubated adult; (3) in a non-ICU ward (and \u226548 hours since ICU discharge if relevant), ; (4) with documentation of consistent symptoms  or chest auscultation findings ; and (5) a clinical diagnosis of pneumonia. Patients were excluded if pneumonia occurred following a frank aspiration event or if a clinical diagnosis of aspiration pneumonia was made.Relevant clinical, laboratory, and microbiological details for the first HAP episode were recorded from the electronic patient records. Clinical cure was defined as the treatment of HAP without a requirement for antimicrobial escalation and without mortality attributable to HAP (treatment failure refers to the occurrence of 1 or both outcomes). Mortality was considered attributable to HAP if pneumonia was recorded on the death certificate.t-test if normally distributed or a Mann Whitney test if not. Categorical variables were compared using Fisher\u2019s exact test. Following a receiver operator characteristic analysis, Youden\u2019s J statistic was calculated to determine cut-offs for the association between continuous variables and outcomes. Variables identified by univariate analysis were included in multiple logistic regression after assessing multicollinearity. We reported 2-tailed P-values, and a P < .05 was considered statistically significant. The statistical analysis was performed using Prism, version 8.0 .Continuous variables were compared using an unpaired A favorable ethical opinion was provided by the West of Scotland Research Ethics Service (19/WS/0152) and Caldicott approval was provided by National Health Service Lothian Research and Development (2019/0242).Staphylococcus aureus carriage was identified in 4/132 screens performed. 11.5% of patients were colonized with other antimicrobial-resistant organisms .We identified 200 patients with non-ICU HAP . Patient9/L), but the median C-reactive protein was elevated (94 mg/L) and lymphopenia was common (70%). Microbiological evaluation consisted of a sputum sample in 18.5% of patients, a respiratory pathogen polymerase chain reaction throat swab in 27%, and blood cultures in 47.5%. It was not known whether samples were obtained prior to antimicrobials. Pathogenic bacteria were identified in 19/37 sputum samples and respiratory viruses were identified in 18/54 swabs (Escherichia coli bacteremia (1/95 blood cultures). There were 12 patients who had microbiological evidence of HAP caused by Enterobacteriaceae or P. aeruginosa. This was associated with the number of comorbidities  and specifically with chronic obstructive pulmonary disease , but not with time to HAP onset, prior hospitalization, or prior antimicrobials.HAP was diagnosed a median of 9 days after admission. Sepsis  was pre54 swabs . There wThe most common first-line empiric antimicrobial used was doxycycline (59.5%), followed by amoxicillin and gentamicin (14%), vancomycin and gentamicin (6.5%), and then piperacillin-tazobactam 5.5%; . AntimicP = .0002) and urea >5.5 mmol/L  as being associated with treatment failure. Undergoing surgery prior to developing HAP was associated with a reduced likelihood of treatment failure . A further episode of HAP during the same admission occurred in 16.5% of patients, and there were 2 cases of Clostridioides difficile infection following HAP treatment. A HAP diagnosis was recorded on discharge documentation for coding in 42.5% of cases.Clinical cure was achieved in 70% of patients. Mortality attributable to HAP occurred in 16% of patients. Logistic regression identified a new/increased supplemental oxygen requirement , consistent with institutional antimicrobial guidelines recommending amoxicillin and gentamicin for HAP with \u22652 SIRS criteria or doxycycline for patients with <2 criteria. There was no difference in the time to HAP onset or qSOFA scores between the groups. Empiric therapy constituted doxycycline (95.9%), amoxicillin (2.5%), or amoxicillin plus clarithromycin (1.6%). In all 29 instances of antimicrobial escalation, this represented changing to a regimen with broader Gram-negative coverage.Overall, 61% of patients were treated without empiric broad-spectrum Gram-negative coverage, with clinical cures in 69.7%. These patients had lower SIRS scores when compared to patients treated empirically with such coverage , prior doxycycline treatment , diabetes mellitus , a neutrophil count >6.2 \u00d7 109/L , and a respiratory rate >18/minute  as being associated with treatment failure in patients treated without empiric broad-spectrum Gram-negative coverage.Logistic regression identified new/increased supplemental oxygen requirements , an absence of diabetes mellitus, and prior doxycycline treatment (but not time to HAP onset) identify this subgroup.Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.Supplementary materials are available at ciaa391_suppl_Supplementary_MaterialClick here for additional data file."}
+{"text": "Hieracium subgenus Pilosella species are self-incompatible. Some undergo facultative apomixis where most seeds form asexually with a maternal genotype. Most embryo sacs develop by mitosis, without meiosis and seeds form without fertilization. Apomixis is controlled by dominant loci where recombination is suppressed. Loci deletion by \u03b3-irradiation results in reversion to sexual reproduction. Targeted mutagenesis of genes at identified loci would facilitate causal gene identification. In this study, the efficacy of CRISPR/Cas9 editing was examined in apomictic Hieracium by targeting mutations in the endogenous PHYTOENE DESATURASE (PDS) gene using Agrobacterium-mediated leaf disk transformation. In three experiments, the expected albino dwarf-lethal phenotype, characteristic of PDS knockout, was evident in 11% of T0 plants, 31.4% were sectorial albino chimeras, and the remainder were green. The chimeric plants flowered. Germinated T1 seeds derived from apomictic reproduction in two chimeric plants were phenotyped and sequenced to identify PDS gene edits. Up to 86% of seeds produced albino seedlings with complete PDS knockout. This was attributed to continuing Cas9-mediated editing in chimeric plants during apomictic seed formation preventing Cas9 segregation from the PDS target. This successful demonstration of efficient CRISPR/Cas9 gene editing in apomictic Hieracium, enabled development of the discussed strategies for future identification of causal apomixis genes.Most  Pennisetum squamulatum [Increasing seed yields in major crops requires new insights into the function of genes that regulate plant reproduction. Plants typically form seeds via a sexual pathway requiring meiosis to form male and female gametes and fertilization to initiate seed formation A. A numbamulatum .Citrus [Targeted genomic deletions, together with mutations in genes at apomixis loci would facilitate identification of additional apomixis genes. However, CRISPR/Cas9-mediated genome editing, which takes advantage of the cellular DNA double-strand break repair pathways to generate small indels, targeted substitutions and multiplex genome modifications , has notCitrus ,9, whereCitrus . HoweverHieracium subgenus Pilosella species, members of the Asteraceae, have been developed as a eudicot model for the molecular analysis of gametophytic apomixis. Sexual and apomictic species are self-incompatible, therefore seeds formed in the absence of fertilization are easily identified. In characterized apomicts, more than 95% of seed is formed via the facultative apomictic pathway [Hieracium praealtum (R35) and Hieracium piloselloides (D36) the dominant, LOSS OF APOMEIOSIS (LOA) locus regulates AI cell formation, suppression of the sexual pathway and aposporous embryo sac formation. In R35 the dominant LOSS OF PARTHENOGENESIS  have shown phenotypic reversion to the sexual mode of reproduction. This indicates that sexual reproduction is the default reproductive mode [LOA and LOP loci from chromosome walking would conceivably enable the functional characterization of apomixis genes. Importantly, unlike many apomict model species, the characterized sexual and apomictic subgenus Pilosella species can be efficiently transformed using Agrobacterium mediated leaf disc transformation [Interestingly, \u03b3 irradiation-induced deletions of the ive mode ,12. Targormation .NCED4 was successfully edited using CRISPR/Cas9 in diploid, self-compatible lettuce (Lactuca sativa) with editing stability and Cas9 segregation demonstrated in the next seed generation [Tragopogon porrifolius and tetraploid Tragopogon mirus, a low-efficiency Agrobacterium-mediated transformation system was developed to examine CRISPR/Cas9 gene editing efficiency in T0 calli and regenerated shoots, however plants were not taken to the next generation [Chrysanthemum morifolium, low-efficiency editing of an introduced fluorescent marker gene was observed [Taraxacum kok-saghyz), a sexual relative of Hieracium, however due to self-incompatibility the analyses did not progress to the T1 generation [Cas9 gene should be retained in progeny derived via the apomictic pathway and not segregate as typically occurs among sexually derived progeny. A knowledge of the efficiency of CRISPR/Cas9 gene editing is therefore required in apomictic Hieracium before embarking on large scale editing approaches to identify and characterize apomixis genes.CRISPR/Cas9 gene editing has been assessed in a small number of sexual Asteraceae species. The thermoinhibition gene neration . In bothneration . In hexaobserved . CRISPR/neration . The CasHieracium piloselloides, D36 to assess CRISPR/Cas9 gene editing efficiency. PDS catalyzes the desaturation of phytoene to \u03b6-carotene during carotenoid biosynthesis and loss of PDS function in Arabidopsis results in a visible albino dwarf seedling-lethal phenotype [PDS has been used to develop and evaluate CRISPR/Cas9 gene editing in crops including rice [PDS knockout in all tissues can be phenotypically identified, in addition to chimeric plants exhibiting albino sectors. Agrobacterium-mediated leaf disk transformation was used to introduce constructs targeting Hieracium PDS (HPDS). T0 regenerants and subsequent T1 progeny derived via apomictic reproduction in flowering chimeric T0 plants were analyzed. Editing events were assessed using amplicon deep sequencing. Albino seedlings increased in frequency in T1 progeny suggesting that editing continues during apomictic seed formation due to non-segregation of Cas9.In this study, we targeted knockout of the endogenous phytoene desaturase (PDS) enzyme in tetraploid self-incompatible apomictic henotype . PDS hasing rice , cassavaing rice , wheat [ing rice  and banaing rice . Due to Hieracium piloselloides (4x = 2n = 36) was maintained by vegetative micropropagation in vitro and grown in a glasshouse, as described previously [eviously .H. piloselloides, D36 is closely related to diploid lettuce and shares the same base chromosome number (n = 9). Comparative genomic analysis between Hieracium species and lettuce has revealed partial macrosynteny for six linkage groups [Arabidopsis PDS amino acid sequence (NCBI accession AF360196) [Arabidopsis PDS. The amino acid sequence of lettuce PDS was then used in TBLASTN analysis against the Hieracium diploid plant D18 genomic DNA scaffold and tetraploid apomictic Hieracium D36 transcriptomes at http://hieracium.csiro.au [Hieracium PDS . The RNA was treated with Turbo DNAse I  to remove contaminating genomic DNA, ethanol precipitated and resuspended in nuclease-free water. First-strand cDNA was synthesized from 5 \u03bcL of RNA using SuperScript\u00ae III First-Strand Synthesis SuperMix . The predicted full-length coding sequence of the HPDS gene was amplified by polymerase chain reaction (PCR) using 0.5-\u03bcM forward (SWH12) and reverse (SWH13) primers  in a 20-\u03bcL reaction. The PCR product was purified using the Illustra GFX PCR DNA and Gel Band Purification Kit  and Sanger sequenced.The tetraploid e groups . To idenF360196)  against cium PDS . The ide primers , 1 \u03bcL ofHieracium diploid D18 genome sequence [HPDS.Three 20-nucleotide guide RNAs, beginning with a guanidine and binding directly upstream of an NGG protospacer adjacent motif (PAM), were designed using Geneious v. 11.0.4 . Guides were analyzed for offsite targeting against the sequence . Complemsequence  and to pHPDS was screened in vitro using the Guide-it Complete sgRNA Screening System . The forward primers used for amplifying the templates for in vitro transcription of the sgRNAs are shown in HPDS gene generated using the primers SWH44 and SWH46  was used as the plant selectable marker instead of kanamycin for selecting positive transformants. To confirm the presence and integrity of the T-DNA in the phosphinothricin-resistant primary T0 transformants, the Extract-N-Amp Kit  was used to amplify a 906 bp fragment of the Cas9 coding sequence by PCR using primers SWH190 and SWH191 . PCR fragments were Sanger sequenced at the Australian Genome Research Facility (AGRF). Sequence chromatograms with mixed spectra were analyzed using the Inference of CRISPR Edits (ICE) web tool at https://ice.synthego.com/.Genomic DNA was extracted from emerging leaves of young T0 plantlets using the Extract-N-Amp Kit  for sequencing. Primers (SWH186 and SHW187), surrounding the predicted editing sites , were usHieracium leaf tissue using the DNeasy Plant Mini Kit (Qiagen), following the manufacturer\u2019s protocol. Libraries were prepared using a two-step PCR protocol. For the first round PCR, primers were designed to generate two amplicons of ~200 bp each. The primers SWH200/201/202/203 spanned sgRNA1 and sgRNA2, while the primers SWH204/205/206/207 spanned sgRNA3 (For next generation sequencing (NGS), 18 independent T0 transformants and an untransformed D36 control, were analyzed. Genomic DNA was isolated from d sgRNA3 . First-rIllumina paired-end reads were imported into Geneious (Biomatters) as fastq files. The sequences were paired, trimmed and then aligned to the amplicon reference sequence using Geneious Read Mapper with fast sensitivity. All sequence variants occurring at a frequency \u22651% from the reference amplicon were selected for analyses. These variants were further analyzed using CRISPResso  and CRISv/v) Triton X-100 for 5 min. Seeds were washed 4 times in sterile water and then plated onto media consisting of 0.5 \u00d7 Murashige and Skoog Basal Salts, 3% (w/v) sucrose, pH 5.7 (KOH), 0.8% (w/v) plant agar and 1 \u00d7 Gamborg\u2019s vitamins (Sigma-Aldrich) without selection. Whole seedlings were harvested 10 days after germination. DNA was extracted from whole seedlings using the method described by Edwards et al. [Seeds were harvested from mature plants and surface-sterilized with 12.5 g/L sodium hypochlorite and 0.05%  transgenic plants containing the construct targeting eriments . All trapigments . Their rpigments A,B. Elevpigments C\u2013E and ppigments F. In sompigments B\u2013D. The pigments .HPDS-edited plants contained a mixture of green and white capitula, as well as sectorially mutated capitula that displayed a mixture of white and green tissues  were found, including single base deletions and insertions, plus a 49 base deletion between guides sgRNA1 and sgRNA2 . A 540 bp region of the ic lines A, lane 3ic lines B. Alignmic lines B. Converic lines B. Similaic lines . Analysiic lines C,D. Thred sgRNA2 B,D. ThesHPDS gene, amplicon deep sequencing was performed on 18 independent T0 transformants . The 7 albino lines included those shown in Brassica napus [Hieracium transgenics were large deletions between two distant guide RNAs  with confirmed edits were screened by PCR for the presence of the Cas9, showing that 98.7% (78/79) of seedlings contained the Cas9 cassette  was present 1 base upstream of the PAM of the sgRNA3 site  and, in chimeric plants, albino sectoring continued through floral development. The absence of Cas9 segregation . It would be interesting to test the efficiency of CRISPR/Cas9 within dihaploid (D18) Hieracium. The type of explants used may also influence regeneration efficiencies. Like our study, leaf discs were used to generate transgenic apple plants that carried CRISPR/Cas9-induced mutations in PDS [Recovery of fully albino mutants in the T0 generation occurred at an average frequency of 11.4%, with a maximum observed frequency of 16.7% in Experiment 2 . The effalbinism , while falbinism . Differes in PDS . In thatHieracium using a genome editing strategy together with a seed screening approach used in a prior \u03b3-mutagenesis screen to identify apomixis loci in Hieracium [LOA locus in both apomictic H. praealtum (R35) and H piloselloides (D36) resides on the long arm of a single hemizygous chromosome. The chromosomal location of the LOP locus in H. praealtum (R35) remains unknown, and the exact sizes of LOA and LOP loci are unclear. Gene sequences, SNPs, and molecular markers linked to both loci are known [Hieracium transgenics were 51 bp deletions between two guides (Hieracium could therefore deploy pairs of sgRNAs that generate large (Kb) fragment deletions via the NHEJ repair pathway, which would enable the functional analysis of large cis-regulatory domains or gene clusters within apomixis loci.Results presented here pave the way for the identification of key genes involved in apomixis in ieracium . The LOAre known ,19,22,33re known . In thiso guides D, and lao guides A,B. FutuLOA locus could be a good initial focus for use of CRISPR/Cas9 to target multiple candidate apomixis genes simultaneously in this manner in Hieracium. LOA controls AI cell formation, sexual suppression and the formation of aposporous embryo sacs. If LOA were successfully deleted by CRISPR/Cas9, in tetraploid H. piloselloides, then the LOP locus would segregate in half of the progeny. Chromosomally reduced gametophytes containing LOP would develop into viable dihaploid (n + 0) seeds without fertilization  gene in allotetraploid cotton (Gossypium hirsutum) [LOA function would enable Cas9 segregation in the progeny, which would facilitate rapid genetic screening. Candidate apomixis genes identified in this approach could then be transformed into characterized apomictic mutants deficient in LOA and LOP function to determine whether activity was restored [The better characterized lization A. If LOPd ploidy B. If botenotypes A,B beforirsutum) . Similarrestored ."}
+{"text": "Hypertrophic cardiomyopathy (HCM) is a prevalent and complex cardiovascular condition. Despite being strongly associated with genetic alterations, wide variation of disease penetrance, expressivity and hallmarks of progression complicate treatment. We aimed to characterize different human isogenic cellular models of HCM bearing patient-relevant mutations to clarify genetic causation and disease mechanisms, hence facilitating the development of effective therapeutics.AAVS1 locus into these disease models resulted in calcium reporter lines.We directly compared the p.\u03b2-MHC-R453C and p.ACTC1-E99K HCM-associated mutations in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and their healthy isogenic counterparts, generated using CRISPR/Cas9 genome editing technology. By harnessing several state-of-the-art HCM phenotyping techniques, these mutations were investigated to identify similarities and differences in disease progression and hypertrophic signaling pathways, towards establishing potential targets for pharmacological treatment. CRISPR/Cas9 knock-in of the genetically-encoded calcium indicator R-GECO1.0 to the CALM1, CASQ2 and CAMK2D, and downregulation of IRF8 in p.\u03b2-MHC-R453C mutants, whereas the opposite changes were detected in p.ACTC1-E99K mutants. Contrasting profiles of nuclear translocation of NFATc1 and MEF2 between the two HCM models suggest differential hypertrophic signaling pathway activation. Calcium transient abnormalities were rescued with combination of dantrolene and ranolazine, whilst mavacamten reduced the hyper-contractile phenotype of p.ACTC1-E99K hiPSC-CMs.Confocal line scan analysis identified calcium transient arrhythmias and intracellular calcium overload in both models. The use of optogenetics and 2D/3D contractility assays revealed opposing phenotypes in the two mutations. Gene expression analysis highlighted upregulation of Our data show that hypercontractility and molecular signaling within HCM are not uniform between different gene mutations, suggesting that a \u2018one-size fits all\u2019 treatment underestimates the complexity of the disease. Understanding where the similarities  and differences  lie will allow development of therapeutics that are directed towards common mechanisms or tailored to each disease variant, hence providing effective patient-specific therapy.  \u2022Isogenic models of hiPSC-CMs bearing sarcomeric mutations address HCM complexity.\u2022Calcium reporter lines and optogenetics enabled refined phenotypic analyses of HCM.\u2022Different mutations showed phenotypic and mechanistic similarities and differences.\u2022Arrhythmias in both models were rescued by combining ranolazine and dantrolene.\u2022Variable phenotypes support mechanism-driven development of effective therapeutics. PatieMYH7, encoding for the beta myosin heavy chain (\u03b2-MHC) thick filament. A lower incidence (1\u20135%) involve ACTC1, encoding the alpha cardiac actin thin filament , Britain Israel Research and Academic Exchange Partnership (BIRAX) [04BX14CDLG], Medical Research Council (MRC) [MR/M017354/1], Engineering and Physical Sciences Research Council (EPSRC) [DM's Doctoral Prize Research Fellowship], National Centre for the Replacement, Refinement, and Reduction of Animals in Research (NC3Rs) , Heart Research UK, German Research Foundation , European Research Council [ERC-AG-IndivuHeart], European Commission [FP7- Biodesign], German Centre for Cardiovascular Research (DZHK), German Ministry of Education and Research, and the Freie und Hansestadt Hamburg."}
+{"text": "Although there are many clinical and molecular biomarkers in acute myeloid leukemia (AML), the novel and reliable biomarkers are still required to predict the overall survival at the time of disease diagnosis.In order to identify independent predictors, we firstly selected 60 cytogenetically normal AML (CN-AML) patients using the propensity score analysis to balance the confounders and performed circular RNA (circRNA) sequencing. Next, one outcome related to circRNA was selected and validated in the independent cohort of 218 CN-AML patients. We then constructed circRNA-miRNA-mRNA regulated network and performed cellular metabolomic analysis to decipher the underlying biological insights.PRDM16 was validated by the dual luciferase report assay, fluorescence in situ hybridization, and ShRNA interference assay.We identified 308 circRNAs as independent candidate predictors of overall survival. Hsa_circ_0075451 expression was validated as an independent predictor with a weak predictive ability for overall survival. The regulated network of this circular RNA indicated 84 hub genes that appear to be regulated by 10 miRNAs sponged by hsa_circ_0075451. The regulatory axis of hsa_circ_0075451 -| miR-330-5p/miR-326 -| Our data demonstrates that hsa_circ_0075451 expression may independently contribute to the poor prognosis of AML and present a novel therapeutic target.The online version contains supplementary material available at 10.1186/s12916-020-01898-y. FLT3-ITD, NPM1, and CEBPA mutations . FigS2. [Sequences inserted into pmirGLO reporter plasmid confirmed by Sanger sequencing]. FigS3. [Flowchart of constructing circRNA-miRNA-mRNA regulatory network]. FigS4. [Hazard ratios of altered hsa_circ_0075451 expression on overall survival by stratified analyses]. FigS5. [The predictive power of CircRNA (hsa_circ_0075451) and clinical and molecular factors]. FigS6. [Differentially expressed genes between high and low hsa_circ_0075451 expression]. FigS7. [In silico analysis of 15 miRNAs potentially interacted with hsa_circ_0075451 in the CircInteractome database]. FigS8. [Correlation relationship between hsa_circ_ 0075451 and microRNAs in 9 AML cell lines]. FigS9. [Dual luciferase reporter assays to test the interactive relationship between hsa_circ_0075451 and miRNAs]. FigS10. [Dual luciferase reporter assays to test the interactive relationship between 3\u2019-UTR of PRMD16 and miRNAs]. FigS11. [ShRNA interference assay was used to further confirm the regulated relationship of hsa_circ_0075451 -| miR-326/ miR-330-5p -| PRDM16]. FigS12. [RNA FISH for hsa_circ_0075451(circGMDS) and miR-330-5p/miR-326 was detected in OCI-AML2 cells]. FigS13. [Metabolic changes in patients with aberrant hsa_circ_0075451 expression]. Table S1. [ Clinical characteristics of patients in the training group]. Table S2. [Primers of cRNA /miRNAs]. Table S3. [The sequences using for dual luciferase reporter assay]. Table S4. [Aberrantly expression of the circular RNA signatures between favorable and unfavorable group]. Table S5. [CircRNAs related to outcome validated by Cox regression analysis]. Table S6. [Gene Ontology and pathway analysis of survival associated circRNAs]. Table S7. [Different expression of circRNAs which encoding genes enriched in the GO:0016835 term]. Table S8. [Characteristics of CN-AML patients with high and low hsa_circ_0075451 expression in the validated cohort]. Table S9. [Landmark analysis of CN-AML patients]. Table S10. [Clinical characteristics of patients for mRNA profiling analysis]. Table S11. [mRNAs expression between high and low hsa_circ_0075451]. Table S12. [Gene enrichment analysis of the differentially expressed genes]. Table S13. [KEGG pathways and GO enrichment analyses in the 84 hub genes.]. Table S14. [Clinical characteristics of patients for the metabolomic analysis]. Table S15. [Pathways enriched analysis].Additional file 2. : Dataset 1.Additional file 3. : Dataset 2.Additional file 4. : Dataset 3."}
+{"text": "To the Editor,Most patients requiring intensive care unit (ICU) admission for Coronavirus disease 2019 (COVID-19) presented acute respiratory distress syndrome (ARDS) . The patHere, we report on clinical and echocardiographic features together with serum levels of cytokines in a monocenter prospective study of critically ill COVID-19 patients admitted to the medical ICU of Henri Mondor Hospital, Cr\u00e9teil, France, between March 8th and March 30th, 2020. The study has received the approbation of an institutional review board . Informed consent was obtained from all patients or their relatives. Reverse-transcriptase polymerase chain reaction (RT-PCR) assays of nasopharyngeal swabs were positive for SARS-CoV-2 in all patients. Blood samples were drawn within 48\u00a0h of ICU admission to measure cytokines concentrations using Luminex\u00ae multiplex bead-based technology  on serum diluted \u00bd. Echocardiographies were performed within the same time frame to characterize cardiac dysfunction  and categorize patients according to LVEF tertiles. Patients were not receiving dobutamine at the time the first echocardiography was performed, except for one patient. Principal component analysis (PCA) was used to summarize cytokines profiles information and assess its relation with LVEF tertiles  tertiles.Additional file 3: Figure S1. Serum troponin concentrations as a function of tertiles of left ventricle ejection fraction (LVEF) in critically ill COVID-19 patients."}
+{"text": "Non-alcoholic fatty liver disease (NAFLD), which affects both adults and children, is the most common liver disorder worldwide. NAFLD is characterized by excess fat accumulation in the liver in the absence of significant alcohol use. NAFLD is strongly associated with obesity, insulin resistance, metabolic syndrome, as well as specific genetic polymorphisms. Severe NAFLD cases can further progress to cirrhosis, hepatocellular carcinoma (HCC), or cardiovascular complications. Here, we describe the pathophysiological features and critical genetic variants associated with NAFLD. Recent advances in genome-engineering technology have provided a new opportunity to generate in vitro and in vivo models that reflect the genetic abnormalities of NAFLD. We review the currently developed NAFLD models generated using clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) genome editing. We further discuss unique features of CRISPR/Cas9 and Cas9 variants, including base editors and prime editor, that are useful for replicating genetic features specific to NAFLD. We also compare advantages and limitations of currently available methods for delivering genome-editing tools necessary for optimal genome editing. This review should provide helpful guidance for selecting \u201cgood fit\u201d genome-editing tools and appropriate gene-delivery methods for the successful development of NAFLD models and clinical therapeutics. Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease with a worldwide prevalence of approximately 25% . NAFLD iRecent genome-wide association studies (GWAS) with single nucleotide polymorphism (SNP) analysis and independent cohort studies have revealed several key genetic variants associated with NAFLD . StudyinPNPLA3 encodes a 481-amino acid protein that is abundantly expressed in human liver and mouse adipose tissue [PNPLA3  that is highly associated with NAFLD [PNPLA3 rs738409 variant confers increased risk of NASH, fibrosis, and hepatocellular carcinoma (HCC) [Patatin-like phospholipase domain-containing protein 3 (PNPLA3), also called adiponutrin, is a triglyceride (TG) lipase that mediates TG hydrolysis in fat cells. e tissue . GWAS ofth NAFLD . This sima (HCC) ,13.(TM6SF2) encodes a 351-amino acid protein that resides in the endoplasmic reticulum (ER) and the ER-Golgi intermediate compartment of human hepatocytes [TM6SF2 has not been fully elucidated, small hairpin RNA (shRNA)-mediated knockdown of TM6SF2 in mice impairs hepatocyte secretion of very low-density lipoprotein (VLDL) [TM6SF2  that is significantly associated with NAFLD. This single mutation is predominantly found in individuals of European ancestry. The TM6SF2 rs58542926 variant is highly associated with increased levels of hepatic TGs and serum ALT. Additional case-control studies confirmed that the TM6SF2 rs58542926 variant is strongly correlated with the severity of NASH, fibrosis, and HCC [TM6SF2 variant  that is associated with reduced expression of TM6SF2. In vitro siRNA studies revealed that knockdown of TM6SF2 increased TG levels and lipid droplet area, whereas overexpression of TM6SF2 reduced lipid droplet content. These data suggest that TM6SF2 plays a critical role in TG metabolism and provide indirect evidence of an association of the TM6SF2 variant (rs10401969) with NAFLD.Transmembrane 6 superfamily 2 atocytes . Althougn (VLDL) . An exom and HCC ,16. An eGCKR (rs1260326 and rs780094) that are closely related to histological features of NASH [GCKR variants are associated with increased levels of TG and serum low-density lipoprotein (LDL)-cholesterol, but lower fasting glucose. A separate cohort study further verified the correlation of the GCKR rs780094 (C > T) variant with high levels of TG and serum glucose as well as with the severity of liver fibrosis [Glucokinase regulator (GCKR) is primarily expressed in the liver and plays a key role in controlling glucose metabolism by binding and transporting glucokinase . A recen of NASH . These Gfibrosis .(MBOAT7) is highly expressed in hepatocytes and encodes an enzyme involved in reacylation of phospholipids in the context of phospholipid remodeling [MBOAT7  that is associated with increased hepatic TG levels and NAFLD severity in patients of European descent [MBOAT7 rs641738 variant show increased serum ALT levels [Membrane-bound O-acyltransferase domain-containing 7 modeling . GWAS id descent ,21. AnotT levels . GWAS ofT levels .HMOX1 show increased serum ALT levels [Heme oxygenase (HMOX1) is a key enzyme that protects the liver from oxidative stress caused by excessive heme . PediatrT levels . On the T levels ,25.Recent advances in genome-editing technology have provided unprecedented opportunities for establishing various disease models for biomedical research. Starting from zinc finger nucleases (ZFNs), researchers have developed transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) genome-editing techniques . To dateCRISPR/Cas9 was originally identified as the molecular basis of a prokaryotic immune system that confers protection against foreign pathogenic DNA . Doudna Although recent GWAS have identified genetic variants that are significantly associated with NAFLD, causal links between specific SNPs and NAFLD must be verified by functional analyses. Advances in genome-editing tools, particularly CRISPR/Cas9, have enabled the development of several in vitro and in vivo NAFLD models . RepresePNPLA3 rs738409 (I148M) variant is one of the best-characterized NAFLD-associated SNPs. To determine the biological function of this specific SNP, Luukkonen et al. introduced two different types of PNPLA3 mutations into a human cell line using CRISPR/Cas9 genome editing [The  editing . They suTM6SF2 rs58542926 (C > T) variant is closely associated with elevated hepatic TG and serum AST levels [TM6SF2, Fan et al. disrupted TM6SF2 in mice using CRISPR/Cas9 genome editing [TM6SF2 mutant mice containing a C/G-bp insertion immediately after the start codon. TM6SF2 mutant mice exhibited a slight increase in serum TG levels, but showed no significant differences in hepatic TG accumulation or serum ALT and AST levels compared with wild-type mice\u2014phenotypic features that did not correspond to those observed in human carriers of the TM6SF2 rs58542926 variant [TM6SF2 plays a critical role in cholesterol metabolism. Another group disrupted TM6SF2 in zebrafish using CRISPR/Cas9 by co-injecting larvae with Cas9 mRNA and gRNA targeting either exon 3 or exon 4 of TM6SF2 [An earlier GWAS study revealed that the T levels ,15,16. T editing , obtaini variant . Instead variant . These df TM6SF2 . Both muGCKR and MBOAT7 variants. Codner et al. established GCKR P446L mice by HDR-mediated CRISPR/Cas9 genome editing using long single-stranded DNA templates [MBOA7-deleted human liver cell lines containing 31-, 101-, or 917-bp deletions using NHEJ-mediated CRISPR/Cas9 genome editing [MBOA7 gene and exhibited the most dramatic increase in fat accumulation, particularly saturated and mono-unsaturated TGs. These results indicate that MBOA7 plays a critical role in hepatic fat accumulation.CRISPR/Cas9 genome editing has also been used to investigate functional roles of NAFLD-associated emplates , althoug editing . All thrAlthough CRISPR/Cas9 has opened a new era in genome editing, it still has some limitations in generating target-specific point mutations or precise sequence replacements. Indeed, the efficiency of HDR-mediated nucleotide insertion is very low (<5%) . NHEJ-meTM6SF2 rs58542926 (C > T), TM6SF2 rs10401969 (C > T), GCKR rs1260326 (T > C), GCKR rs780094 (C > T), and MBOAT7  variants.A base editor for generating specific point mutations without the need for donor DNA templates was first developed by Liu and colleagues using a Cas9 variant . The resPNPLA3 rs738409 (C > G) and HMOX1 rs2071746 (A > T).Although base editors allow a specific single nucleotide to be mutated, replacement of a short stretch of DNA is still technically difficult. Liu and co-workers further developed a prime editor that enables insertions and point mutations without the need for DSBs and donor DNA templates . The uniRecent advances in genome-editing tools have been accompanied by investigations of various gene delivery methods for improving gene-editing efficiency . gRNA anVarious types of viral vectors for gene editing have been used to further improve the efficiency of gene delivery. One widely used viral vector is adeno-associated virus (AAV) , which cNAFLD, a multifactorial disease influenced by both environmental and genetic factors, is an increasingly common liver disorder worldwide, especially in developing countries . AlthougCRISPR/Cas9 and various Cas9 variants have revolutionized the genome-editing field; however, unwanted off-target events have been problematic from both basic research and clinical application standpoints ,90. It iRecent progress in genome engineering has revolutionized the establishment of various disease models that mimic genetic variants. In vitro and in vivo models of NAFLD have also been generated using CRISPR/Cas9 genome editing. In addition to CRISPR/Cas9, which primarily generates deletion mutations, Cas9 variants, such as base editors and prime editors, are available for specifically generating point mutations or sequence replacements. Selection of the most suitable genome-editing tool together with an efficient gene delivery method will lead to the successful establishment of NAFLD models for the development of therapeutics."}
+{"text": "Numerous neuropsychiatric inventories have been created for behavioral and psychological symptoms of dementia (BPSD). These inventories are seldom used in long-term care (LTC) settings due to questionable psychometrics, lengthy administration, and reliance on knowledgeable informants. The Columbia Behavior Scale for Dementia (CBS) is a rapidly administered BPSD rating tool that was developed for LTC residents. The 11-item CBS can be completed in less <5 minutes independently, with nursing staff, or in conjunction with interdisciplinary care teams. LTC residents (N = 350) participated in a validation study in Maryland, USA . Internal consistency (\u237a = 0.75) and inter-rater reliability (r = 0.99) for the CBS were strong. CBS scores were not biased by informant type (p > 0.05): GNAs/CNSs (40.69%), nurses (36.10%), other facility staff (23.21%). Diagnostic validity was confirmed by significantly higher CBS scores  for LTC residents with dementia  versus those without dementia . Higher CBS scores were significantly associated with greater impairment on cognitive instruments  and increased mood dysfunction , indicating convergent validity. Principal components analysis produced three CBS factors, psychosis, aggression, and non-aggressive motor disinhibition, which significantly identified LTC residents with greater odds for antipsychotic use. Results will be discussed in terms of right-sizing antipsychotic utilization, improving nonpharmacological behavior management, and enhancing the dementia literacy of nursing staff."}
+{"text": "TSE).US manufacturers, concerned about bovine spongiform encephalopathy (BSE), ceased marketing bovine heparin in the 1990s. Recent short supplies of safe porcine heparin suggest that reintroducing bovine heparin might benefit public health. We purified heparin from crude bovine extract spiked with BSE agent, removing substantial infectivity and abnormal prion proteins (PrP Heparin is a widely used injectable anticoagulant. In the 1990s, bovine-derived heparin was withdrawn from the US market because of concerns about possible contamination of bovine tissues with the agent of bovine spongiform encephalopathy (BSE), the causative agent of variant Creutzfeldt-Jakob disease (vCJD) in humans  and infectivity. We assayed BSE infectivity using intracerebral inoculations of 30-\u03bcL volumes into BSE-susceptible transgenic mice (TgBo110) overexpressing the bovine prion-protein\u2013encoding (PRNP) gene  , washed the pellets, resuspended them in inoculation buffer, and inoculated mice as described. We tested brains of all mice for PrPTSE as reported previously (5). We detected residual infectivity in all aliquots, including the final product. NaOH treatment removed 1.5 log10 of BSE infectivity. We estimated removals by other steps. DE filtration removed \u22651.4 log10 of BSE infectivity. The hydrogen peroxide bleaching and methanol precipitation  steps each removed <1 log10 of infectivity, considered negligible. Thus, cumulatively, scaled-down heparin purification removed a total of >2.9 log10 of BSE infectivity; NaOH treatment and DE filtration were the only effective steps.We ended the study 2 years after inoculations, testing brains of all mice for PrPexx.com) . We deteTSE in each sample using the real-time quaking-induced conversion (RT-QuIC) assay with hamster\u2013sheep chimeric prion protein (10 50% seeding doses (SD50), as reported previously . To increase sensitivity and remove heparin interfering with RT-QuIC at low concentrations of PrPTSE, we centrifuged all samples as we did previously. To quantify PrPTSE, we resuspended pellets and serially diluted each sample in phosphate-buffered saline 0.05% sodium dodecyl sulfate, adding 2 \u00b5L of each dilution to seed RT-QuIC, each dilution into quadruplicate wells (see log10 SD50 values in 10 of PrPTSE and DE filtration steps removed 1.3 log10 of PrPTSE. Hydrogen peroxide bleaching and methanol precipitation reduced PrPTSE by only negligible amounts. Thus, processing from crude heparin to final pharmaceutical heparin cumulatively removed 3.7 log10 of spiked PrPTSE.We also quantified residual PrP10 of scrapie infectivity and 3.4 log10 of PrPTSE (10 of PrPTSE. We could demonstrate only >2.9 log10 reduction in infectivity, because the starting titer of the BSE-infected brain homogenate was low. However, we detected both residual BSE infectivity and PrPTSE seeding activity after final steps of processing, so our model process did not yield sterile heparin. We found NaOH treatment and DE filtration to be the most effective steps for removing both BSE infectivity and PrPTSE seeding activity, consistent with previous results using scrapie agent.We showed previously, using a rodent-adapted scrapie agent, that heparin processing removed 3.6 logOverall, our data suggest that typical heparin manufacturing is likely to remove substantial amounts of BSE agent. Furthermore, a probabilistic model assessing the vCJD risk for bovine heparin sourced from cattle in the United States and Canada estimated the risk to be very low ("}
+{"text": "For an older patient, transitioning back into the community after an acute health incident is a critical juncture. Avoidable acute-care readmissions are expensive for hospitals and federal programs. Negative health outcomes for patients and negative financial outcomes for hospitals and federal programs have focused attention on effective discharge interventions to improve care transitions and decrease avoidable acute-care readmissions. This study compares cost and readmissions outcomes from peer-reviewed publication data for three discharge interventions: Care Transitions Intervention (CTI), Project RED (ReEngineered Discharge), and the Transitional Care Model (TCM). This study adjusted costs to 2015 rates and compared cost savings per patient, return on investment (ROI) and percent reduction of readmissions. Cost savings per patient (2015-adjusted) were found for all interventions: CTI ($152.89); Project RED ($327.03); TCM ($1565.84). ROI was positive for all interventions: CTI (832%); Project RED (535%); TCM (232%). Compared to control groups, intervention group readmissions were 3.6% lower for CTI (n.s.), 5.5% lower for Project RED (p<.05), and 13.2% lower for TCM (p<.05). These three discharge interventions differ in scale and intensity, but they all show cost savings and reductions in readmissions. The lower-cost intervention shows cost savings and ROI (CTI), and the more resource-intensive interventions (Project RED and TCM) reduce costs and statistically significantly reduce rates of readmission. Even with small budget dollars, hospitals have options for finding an effective discharge intervention to reduce costs and readmission rates."}
+{"text": "Ischemic cardiomyopathy (ICM) is one of the most usual causes of death worldwide. This study aimed to find the candidate gene for ICM.We studied differentially expressed genes (DEGs) in ICM compared to healthy control. According to these DEGs, we carried out the functional annotation, protein-protein interaction (PPI) network and transcriptional regulatory network constructions. The expression of selected candidate genes were confirmed using a published dataset and Quantitative real time polymerase chain reaction (qRT-PCR).From three Gene Expression Omnibus (GEO) datasets, we acquired 1081 DEGs (578 up-regulated and 503 down-regulated genes) between ICM and healthy control. The functional annotation analysis revealed that cardiac muscle contraction, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy and dilated cardiomyopathy were significantly enriched pathways in ICM. SNRPB, BLM, RRS1, CDK2, BCL6, BCL2L1, FKBP5, IPO7, TUBB4B and ATP1A1 were considered the hub proteins. PALLD, THBS4, ATP1A1, NFASC, FKBP5, ECM2 and BCL2L1 were top six transcription factors (TFs) with the most downstream genes. The expression of 6 DEGs  were consistent with our integration analysis and GSE116250 validation results.The candidate DEGs and TFs may be related to the ICM process. This study provided novel perspective for understanding mechanism and exploiting new therapeutic means for ICM. Three series of datasets, GSE46224 [The expression profile of ICM and healthy control were downloaded from GEO database  were used to modulate the http://genecodis.cnb.csic.es/analysis). The terms with FDR\u2009<\u20090.05 was significant results.Gene Ontology (GO) classification and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were structured by using GeneCodis (http://thebiogrid.org/), and then the PPI network was visualized by Cytoscape (3.6.1) (http://www.cytoscape.org/). The nodes represent proteins and edges connect the nodes to show their relationship.The top 50 DEGs in ICM were applied to construct the PPI network by using Biological General Repository for Interaction Datasets (BioGRID) (http://genome.ucsc.edu). The TF that regulates these DEGs comes from the matching tool in TRANSFAC. The ICM -specific transcriptional regulatory network was built by Cytoscape.The corresponding promoters of the top 20 up-regulated or down-regulated DEGs were obtained by UCSC  of \u226440% and fulfilling one of the following criteria: patients with history of myocardial infarction or revascularization (cardiac bypass surgery or percutaneous coronary intervention), patients with \u226575% stenosis of left main or proximal LAD, or patients with \u226575% stenosis of two or more epicardial vessels . SubjectTen patients diagnosed as ICM and 10 controls were enrolled in this study. The detailed characteristics of the patients were listed in Table Three datasets  were obtained from GEO Table . CompareBase on the GO enrichment analysis, signal transduction FDR\u2009=\u20093.04E-12), apoptotic process (FDR\u2009=\u20097.64E-08), cytoplasm (FDR\u2009=\u20093.40E-67) and protein binding (FDR\u2009=\u20096.06E-70) were most significantly enriched GO terms. After the KEGG pathway enrichment analysis, we found that ECM-receptor interaction (FDR\u2009=\u20098.23E-06), MAPK signaling pathway (FDR\u2009=\u20094.96E-05), Cardiac muscle contraction (FDR\u2009=\u20090.021418), hypertrophic cardiomyopathy (FDR\u2009=\u20090.003907), arrhythmogenic right ventricular cardiomyopathy (FDR\u2009=\u20090.00204) and dilated cardiomyopathy (FDR\u2009=\u20090.005789) were significantly enriched pathways in ICM. The top 15 most significantly enriched GO terms and KEGG pathways of DEGs in ICM were listed in Fig. .04E-12, The PPI network of top 50 DEGs in ICM was consisted of 208 nodes and 194 edges  were identified. ICM-specific transcriptional regulatory network was built, which consisted of 104 nodes and 290 edges Fig.\u00a0. Among oSix DEGs  were selected to verify in GSE116250 dataset. Among them, BCL6, BLM and IPO7 were the hub gene of ICM-specific PPI network. THBS4 was top TFs covering the most downstream DEGs. MYH6 and SERPINA3 were top 40 DEGs in ICM. As displayed in Fig.\u00a0Six DEGs validated in GSE116250 were chose for qRT-PCR verification  for qRT-PCR confirmation might affect the quality of our results. Although the validation based on GSE116250 suggested that our qRT-PCR results were generally convincing, studies with larger sample size need to be conducted to confirm this conclusion. The identification of DEGs of ICM is a pilot study and further model systems or cell lines experiments are needed to reveal their biological functions in ICM.The functional annotation, PPI network and ICM-specific transcriptional regulatory network were performed to identify DEGs, TFs and pathways in ICM which provides perspective to reveal the pathology and develop therapeutic targets for the ICM.Additional file 1. All differentially expressed genes between ICM and healthy control."}
+{"text": "Wolbachia pipientis to restrict RNA viruses is presently being leveraged to curb global transmission of arbovirus-induced diseases. Past studies have shown that virus replication is limited early in arthropod cells colonized by the bacterium, although it is unclear if this phenomenon is replicated in mosquito cells that first encounter viruses obtained through a vertebrate blood meal. Furthermore, these cellular events neither explain how Wolbachia limits dissemination of viruses between mosquito tissues, nor how it prevents transmission of infectious viruses from mosquitoes to vertebrate host. In this study, we try to address these issues using an array of mosquito cell culture models, with an additional goal being to identify a common viral target for pathogen blocking. Our results establish the viral RNA as a cellular target for Wolbachia-mediated inhibition, with the incoming viral RNA experiencing rapid turnover following internalization in cells. This early block in replication in mosquito cells initially infected by the virus thus consequently reduces the production of progeny viruses from these same cells. However, this is not the only contributor to pathogen blocking. We show that the presence of Wolbachia reduces the per-particle infectivity of progeny viruses on na\u00efve mosquito and vertebrate cells, consequently limiting virus dissemination and transmission, respectively. Importantly, we demonstrate that this aspect of pathogen blocking is independent of any particular Wolbachia-host association and affects viruses belonging to Togaviridae and Flaviviridae families of RNA viruses. Finally, consistent with the idea of the viral RNA as a target, we find that the encapsidated virion RNA is less infectious for viruses produced from Wolbachia-colonized cells. Collectively, our findings present a common mechanism of pathogen blocking in mosquitoes that establish a link between virus inhibition in the cell to virus dissemination and transmission.The ability of the endosymbiont  Wolbachia pipientis is associated with virus inhibition in multiple mosquito vectors. Furthermore, Wolbachia is inherited transovarially and spreads across the vector population like a natural gene drive, making it an attractive vector control agent. In this study, we examine how the presence of the bacterium in arthropod cells prevents initial establishment of vertebrate cell derived viruses. Our results indicate rapid turnover of incoming viral RNA very early during infection in Wolbachia-colonized cells, thus establishing it as a cellular target for pathogen blocking. Additionally, upon evaluating how these events might further limit virus spread, we find that infectivity of progeny viruses belonging to multiple RNA virus families are reduced on a per-particle basis. This aspect of virus inhibition is independent of any particular Wolbachia-host association and affects how these viruses replicate in na\u00efve mosquito and vertebrate cells, thus providing a collective basis of reduced virus dissemination and transmission in Wolbachia-colonized mosquitoes.Viruses transmitted by arthropod vectors pose a significant global health risk. Incidence of diseases caused by these viruses can thus be reduced by implementing effective vector control strategies. This need is further exacerbated due to the lack of commercially available vaccines and antivirals. Presence of the intracellular bacteria  Wolbachia pipientis makes it an exciting biocontrol agent that is currently being used to limit transmission of arboviruses around the world [Wolbachia-host associations and is dependent on the Wolbachia strain and the arthropod host species [Wolbachia-host association, giving the impression that different Wolbachia-host permutations involve distinct mechanisms of inhibition [Wolbachia-colonized cells ultimately limit virus dissemination within mosquito tissues, and transmission from mosquitoes to vertebrates. To this end, the goal of this study was to utilize an array of mosquito cell culture models representing different Wolbachia-host combinations to identify a common viral target for pathogen blocking and to determine the link between intracellular virus inhibition, restricted virus dissemination and virus transmission. Our results identify the viral RNA genome as a target for pathogen blocking in arthropods, which include both fruit flies and mosquitoes. In Wolbachia-colonized cells, viral RNA targeting occurs at multiple stages of the replication cycle, notably in the very early stages following virus internalization and genome delivery, that lead to a shortened half-life of the incoming viral RNA. Additionally, we demonstrate that viral RNA present within viruses produced from Wolbachia-colonized cells are less infectious in vertebrate cells, contributing to the overall reduced infectivity of the progeny viruses. We provide evidence that this aspect of pathogen blocking is likely independent of any particular Wolbachia strain and arthropod host association and affects members of at least two + ssRNA virus families. Finally, we show that two major aspects of pathogen blocking i.e. limited virus dissemination and transmission occur due to the inability of these less infectious viruses to propagate in na\u00efve arthropod and vertebrate cells.The pathogen blocking ability of the arthropod endosymbiont he world . The imp species \u20135. Colle species , 6\u20139. Ea species , 10\u201314. hibition , 10\u201313. Wolbachia is associated with reduced viral gene expression in arthropod cells. This widely reported aspect of virus inhibition can be observed both in vivo, in Aedes aegypti mosquitoes colonized with wAlbB  colonized with and without Wolbachia derived from the planthopper host, Laodelphax striatellus (wStri). It should be noted that throughout this study, multiplicity of infection (MOI) was calculated in terms of viral genome equivalents (particles) instead of infectious units (PFUs), given that the former is independent and the latter is dependent on a single host/tissue cell line (e.g. vertebrate or arthropod) that the viruses are assayed on to determine virus \u201cinfectivity\u201d. Spread of Chikungunya viruses derived from BHK-21 (Baby Hamster Kidney fibroblast cells) expressing a fluorescent reporter protein (CHIKV-mKate) was thus assessed in these mosquito cells following a synchronized infection at a low MOI (1 particle/cell) that involved virus adsorption at 4\u00baC. Cell monolayers were then extensively washed with 1XPBS to remove any unbound viruses and warm media (37\u00baC) was added to cells to initialize virus internalization and infection. Virus spread was then measured over 50 hours by quantifying mean virus-encoded fluorescent reporter expression observed over four distinct fields of view taken per well every 2 hours (wStri) and/or time on virus spread. Virus growth was significantly reduced over time in cells colonized with wStri compared to cells without the bacterium; Ordinary Two-way ANOVA with Sidak\u2019s multiple comparisons test, Wolbachia: p < 0.0001, Time: p < 0.0001, Time X Wolbachia: p < 0.0001  or without Wolbachia (w/o wStri) and JW18 Drosophila melanogaster cells with (wMel strain) or without Wolbachia (w/o wMel) were grown overnight in media containing the cross-linkable nucleoside analog 4-thiouridine (4SU) at 50 \u03bcM  = 0.0469, JW18 fly cells, Time: p = 0.0042, Wolbachia (wMel) = 0.021. , 65.58 minutes (w/ wStri). In comparison, half-life was reduced approximately 2.2-fold in fly cells; 53.7 minutes (w/o wMel), 24.4 minutes (w/ wMel)  . Based oolbachia . Howeverolbachia .Wolbachia-colonized fly cells on vertebrate BHK-21 cells [wStri-colonized C710 mosquito cells in combination with their inability to propagate in na\u00efve C710 mosquito cells might explain why virus dissemination is reduced in mosquitoes carrying Wolbachia. Additionally, the observed loss in transmission could occur as a result of these viruses being unable to spread and kill vertebrate cells. But given that Wolbachia-mediated reduction of virus dissemination and transmission has been observed against multiple RNA viruses across multiple Wolbachia-host associations, we first wanted to expand our previous findings to determine whether our previous observation regarding the loss in per-particle infectivity is limited either to any particular virus or certain Wolbachia-host associations [It is unclear how the aforementioned cellular events lead to reduced virus dissemination within the mosquito vector as well as reduced transmission into vertebrate hosts. In our previous study, we reported reduced infectivity of Sindbis viruses derived from 21 cells . In lighciations \u20139, 12.Aedes albopictus-derived or Drosophila melanogaster-derived cells with and without Wolbachia. Infectious viruses present in the same cell supernatant were assayed by quantifying plaque-forming units on vertebrate cells. Following independent quantification these attributes in tandem, we then calculated per-particle infectivity or specific infectivity ratio (SI) of progeny viruses as the ratio of infectious virus to total virus  and the native fruit fly (Drosophila melanogaster JW18 cells). Mosquito cells were challenged with a panel of arboviruses, including alphaviruses Sindbis (SINV) and Chikungunya (CHIKV) and one flavivirus, Zika (ZIKV) to determine the breadth of this phenotype against multiple arboviruses. In all cases, viruses grown in the presence of Wolbachia (W+ viruses) exhibited a lower SI ratio than viruses grown in cells without the endosymbiont (W- viruses). Degree to which infectivity (SI) was reduced varied depending on the virus type; Welch-corrected unpaired two-tailed t-test on log-transformed values, SINV: 3-fold reduction , CHIKV: 5-fold reduction , ZIKV: 32-fold reduction  (Drosophila melanogaster cells with and without Wolbachia (wMel); Welch-corrected unpaired two-tailed t-test on log-transformed values, SINV , CHIKV , ZIKV   , S2 Fig.= 2.629) . PresencWolbachia strains are capable of reducing progeny virus infectivity in the context of a single arthropod host  cell type. A panel of three Aedes albopictus derived mosquito cells were obtained, each colonized by a distinct Wolbachia strain, including Wolbachia strain wAlbB (Aa23 cells) derived from the native Aedes albopictus and non-native strains wStri (C710 cells) derived from a planthopper, Laodelphax striatellus and wMel (RML12 cells), derived from Drosophila melanogaster [Wolbachia strains classify them into two distinct clades, with wAlbB and wStri representing Supergroup B and wMel Supergroup A  versus low (MOI = 0.1 particle/cell) starting virus titers on infection outcome in the presence of Wolbachia. We found starting MOI to influence progeny SINV infectivity for both W- and W+ viruses, as a lower starting MOI = 0.1 particle/cell (Wolbachia background (RML12-wMel) . Extent to which SINV infectivity was reduced seemingly varied between cells colonized with different Wolbachia strains, which could be a result of either the genotype of the cells, Wolbachia strains or both. We observed differences in relative Wolbachia titers between the three cell lines. Notably, titers of both Supergroup B strains , that had a more pronounced effect on SINV (wMel strain (RML12 cells) . It is unclear whether these moderate differences in endosymbiont titer are in any way correlated with the extent to which virus infectivity is reduced, given the considerable variation in Wolbachia titers across passaged cell lines. Based on these results, we conclude that presence of pathogen-blocking Wolbachia strains are commonly associated with a concomitant reduction in progeny virus infectivity.All cells, regardless of the cle/cell  resulted12-wMel) . However on SINV , were onWolbachia to propagate in na\u00efve mosquito cells. CHIKV expressing a fluorescent reporter protein (CHIKV-mKate) was grown in C710 Aedes albopictus cells with and without Wolbachia (wStri strain), purified and subsequently used to infect na\u00efve mosquito cells at equal MOIs (MOI = 5 particles/cell) following a synchronous infection. Virus infection and spread was then monitored over a period of 50 hours using a live-cell imaging system by quantifying mean virus-encoded fluorescent reporter expression observed over four distinct fields of view taken per well every 2 hours (Wolbachia) and/or time, on virus spread. Our results show significant effects of all three variables on virus growth, both on their own as well as in combination with each other; Three-way ANOVA with Tukey\u2019s post-hoc test, Source: p < 0.0001, Wolbachia: p < 0.0001, Time: p < 0.0001, Source X Time: p < 0.0001, Source X Wolbachia: p < 0.0001, Wolbachia X Time: p < 0.0001, Source X Time X Wolbachia: p = 0.0016 (Wolbachia compared to those without (Wolbachia (wStri strain). Importantly, these results indicate that reduced infectivity of W+ viruses might contribute to their inability to spread to new mosquito cells regardless of whether or not these cells are colonized by Wolbachia. Assuming that the mechanism of cellular inhibition of virus replication is cell-autonomous, this model might help explain why limited virus dissemination occurs within tissues with both high and low Wolbachia densities. As evident from the results from wMel-colonized Aag2 cells [wMel-colonized mosquitoes fail to establish systemic infections in na\u00efve mosquitoes following intrathoracic injection, demonstrating a quantifiable loss in infectivity in vivo [We next monitored the ability of progeny viruses derived from mosquito cells colonized with (W+ virus) and without (W- virus)  2 hours . Three-w= 0.0016 . As expeWolbachia (wStri strain) was subsequently used to infect na\u00efve BHK-21 cells at an MOI of 5 particles/cell. Infection was synchronized as before and virus spread was measured over 42 hours by quantifying mean virus-encoded fluorescent reporter expression observed over four distinct fields of view taken per well every 2 hours  and measured luciferase activity as a proxy for viral structural protein expression over time ; Two-tailed Welch\u2019s t-test, p = 0.0196, t = 4.883, df = 2.774 , suggesting that inhibition occurs early in the infection process [in vitro transcribed virus replicon reporter, which indicates that inhibition of virus replication is independent of virus entry into Wolbachia-colonized cells and therefore might involve an intracellular viral target [Wolbachia-mediated inhibition of mosquito cell (C6/36) derived DENV-2 in wMel-colonized Aag-2 cells involve degradation of the viral RNA [wMel cells as early as 1h post infection, following synchronized binding (4\u00baC) and internalization (25\u00baC) of DENV-2 viruses. It is important to note that this reduction likely represent a loss of incoming viral RNA, due to low amounts of nascently synthesized viral RNA being present in the cell this early in infection. Here using metabolic labelling, we determined the half-life of the incoming vertebrate cell-derived viral RNA to show that virus inhibition occurs very early during infection, with the incoming viral RNA undergoing faster turnover in Wolbachia-colonized cells. This likely involves one or more cellular RNA degradation pathways, including perhaps orthologs of the RNA exonuclease Xrn1, whose role in pathogen blocking of flaviviruses has been demonstrated in Aedes aegypti derived Aag2-wMel cells [Togaviridae (SFV) and Flaviviridae (DENV-2) families, suggesting perhaps a common mechanism of action across different cell types and RNA viruses [Uptake of viruses occur as the mosquito takes an infectious bloodmeal from a vertebrate animal. As the blood meal is digested, these viruses infect midgut cells before escaping the midgut barrier and disseminating to other mosquito tissues, which become persistently infected. Therefore, it is important to note that the viruses initially establishing infection in the vector are of vertebrate origin, while those that undergo dissemination and eventually transmission, are derived from mosquito cells. Prior studies have shown that initial infection of viruses in mosquito midguts is reduced in the presence of nfection , 18. In infected \u201314. Usinl target \u201314. Moreiral RNA . Interesel cells . Taken t viruses \u201314.Wolbachia in mosquitoes has been shown to also reduce the rate of virus infection in different mosquito tissues. These include tissues proximal to the midgut like Malpighian tubules and fat bodies, as well as distal tissues like salivary glands, implying limited virus dissemination in the presence of the endosymbiont [Wolbachia-density or its role in innate immunity. In fact, viral RNA levels are dramatically reduced in the mosquito head, which is poorly colonized by Wolbachia [Wolbachia-colonized mosquitoes [Wolbachia-colonized mosquitoes, reduced transmission is thought to likely occur as a result of reduced virus growth in salivary gland tissues. Interestingly, however, previous studies have found that although salivary gland secretions from Wolbachia-colonized mosquitoes contain detectable levels of Zika viral genome copies , these levels far exceed the actual number of infectious viruses that can be assayed on either vertebrate or mosquito cells, implying a reduction in per-particle infectivity [Presence of symbiont . Interesolbachia . These rolbachia . In addisquitoes , 7\u20139. Itectivity .Drosophila melanogaster cells colonized with wMel on vertebrate BHK-21 cells [Aedes albopictus mosquito cells, colonized with both native (wAlbB) and non-native (wMel and wStri) Wolbachia strains. Additionally, Wolbachia reduces the infectivity of progeny viruses belonging to two distinct families of + ssRNA viruses, Togaviridae  and Flaviviridae (ZIKV) in both mosquito and fly cells. Using growth assays we clearly demonstrate the inability of progeny W+ viruses to replicate in na\u00efve vertebrate cells, thus linking virus infectivity to loss in transmission. Importantly, we demonstrate that reduced infectivity of these progeny viruses also limits their ability to grow in na\u00efve mosquito cells. Remarkably, limited virus growth is independent of whether or not these na\u00efve cells are colonized with Wolbachia, thus providing an explanation for why viral RNA levels are reduced in tissues with low Wolbachia titers. Therefore, while it is unclear whether virus production is abrogated completely from Wolbachia-colonized cells, as Wolbachia infection rates are known vary significantly between different cell lines and across passages, it is possible that the small proportion of infectious W+ virus progeny is produced from sub-populations of cells with very low/no Wolbachia.We have previously shown reduced per-particle infectivity of Sindbis virus grown in 21 cells . In thisWolbachia strain and/or host cell species, we expect this phenotype to remain consistent in Wolbachia-host associations where pathogen blocking have been reported previously. However, it would also be interesting to explore this phenotype in particular Wolbachia-host combinations that lack pathogen blocking abilities against susceptible viruses e.g. Dengue Virus  in Aedes aegypti mosquitoes with wPip, West Nile Virus  in Culex tarsalis mosquitoes systemically infected with wAlbB and Cricket Paralysis Virus  in Drosophila pandora infected with wPanCI [While further investigation is required to determine whether these results are limited to single virus type, h wPanCI \u201323.Wolbachia, our data does not exclude the possibility of an additional block in progeny virus binding that might exacerbate this inhibitory effect. One notable limitation of our experimental system is the use of a limited number of mammalian epithelial cell lines as a generalized vertebrate model of infection. While cultured fibroblast and epithelial cells like BHK-21 and Vero, respectively, are physiologically relevant and have been regularly used towards the study of alphavirus and flavivirus pathogenesis, further studies using a diverse set of tissue-specific cell lines is required to fully understand the effect of Wolbachia on virus transmission [Finally, we demonstrate that loss in virus infectivity occur at the level of the encapsidated virion RNA and affects its ability to replicate following direct delivery into vertebrate cells. Further work is required to determine the exact fate of W+ virus derived viral RNA in vertebrate cells in terms of its stability, localization and translation. Given the absence of information regarding potential structural differences between viruses derived from mosquito cells with and without smission .Wolbachia\u2019s ability to restrict viruses is seemingly limited to positive-sense single-stranded RNA (+ssRNA) viruses, as inhibition of neither negative-sense single-stranded RNA (-ssRNA) nor DNA viruses have been observed either in the field, or under laboratory conditions. It is therefore likely that factor(s) regulating virus inhibition affect this particular genomic feature shared by all susceptible viruses [Drosophila melanogaster RNA methyltransferase Dnmt2 as a host determinant of pathogen blocking [Wolbachia.Notably, our findings support the hypothesis of viral RNA being the target for pathogen blocking.  viruses , 25\u201326. blocking . Interesblocking . FurtherAedes albopictus cells with and without Wolbachia wMel  were grown at 24 \u00baC in Schneider\u2019s insect media (Sigma-Aldrich) supplemented with 10% (v/v) heat-inactivated fetal bovine serum (Corning), 1% (v/v) each of L-Glutamine (Corning), non-essential amino acids (Corning) and penicillin-streptomycin-antimycotic (Corning). C710 Aedes albopictus cells with and without Wolbachia wStri  were grown in 1X Minimal Essential Medium (Corning) supplemented with 5% (v/v) heat-inactivated fetal bovine serum (Corning), 1% (v/v) each of L-Glutamine (Corning), non-essential amino acids (Corning) and penicillin-streptomycin-antimycotic (Corning). Aa23 Aedes albopictus cells with and without Wolbachia wAlbB  were grown at 24 \u00baC in Schneider\u2019s insect media (Sigma-Aldrich) supplemented with 20% (v/v) heat-inactivated fetal bovine serum (Corning), 1% (v/v) each of L-Glutamine (Corning), non-essential amino acids (Corning) and penicillin-streptomycin-antimycotic (Corning). JW18 Drosophila melanogaster cells with and without Wolbachia wMel were grown at 24 \u00baC in Shields and Sang M3 insect media (Sigma-Aldrich) supplemented with 10% (v/v) heat-inactivated fetal bovine serum, 1% (v/v) each of L-Glutamine (Corning), non-essential amino acids (Corning) and penicillin-streptomycin-antimycotic (Corning). Aedes albopictus C636 cells and mammalian BHK-21 (Baby Hamster Kidney Fibroblast) and Vero  cells were grown at either 28\u00baC (C6/36) or 37 \u00baC (BHK/Vero) under 5% ambient CO2 in 1X Minimal Essential Medium (Corning) supplemented with 10% (v/v) heat-inactivated fetal bovine serum (Corning), 1% (v/v) each of L-Glutamine (Corning), non-essential amino acids (Corning) and penicillin-streptomycin-antimycotic (Corning).RML12 Aedes albopictus derived cells  or Drosophila melanogaster derived cells (JW18) with or without Wolbachia  by infecting na\u00efve cells with virus at an MOI of 10 particles/cell. In all cases, serum-free media was used for downstream virus purification. Media containing virus was collected 5 days post-infection for alphaviruses SINV (SINV-nLuc), CHIKV (CHIKV18125-capsid-mKate), and 7 days post-infection for flavivirus ZIKV (MR766 Uganda Strain). Virus stocks were subsequently purified and concentrated by ultracentrifugation (43K for 2.5 h) over a 27% (w/v) sucrose cushion dissolved in HNE buffer . Viral pellets were stored and aliquoted in HNE buffer before being used for all subsequent experiments. Viral titers were determined using standard plaque assay on vertebrate cells . Cells were fixed either 48 hours post infection  or 72 hours post infection (ZIKV) using 10% (v/v) formaldehyde and stained with crystal violet to visualize plaques. Virus particles were determined by quantifying viral genome copies via quantitative RT-PCR using primers listed in the primer table (Virus stocks were generated from er table  and stanAedes aegypti mosquitoes either -infected and -uninfected with Wolbachia (wAlbB strain) , were reared in an insect incubator  at 28\u00b0C and 75% humidity with 12 h light/dark cycle. Four to six-day old mated female mosquitoes were allowed to feed for 1h on approximately 108 PFUs of SINV (TE12-untagged) containing citrated rabbit blood (Fisher Scientific DRB030) supplemented with 1mM ATP (VWR) and 10% sucrose using a Hemotek artificial blood feeding system  maintained under constant temperature of 37\u00b0C. Engorged mosquitoes were then isolated and reared at 28\u00b0C in the presence of male mosquitoes. Infected mosquitoes were harvested 5\u20137 days post blood meal before being snap frozen in liquid nitrogen and stored at \u221280\u00b0C before further processing. Samples for qPCR and qRT-PCR were homogenized in TRiZOL (Sigma Aldrich) reagent and further processed for nucleic acid extractions using manufacturer\u2019s protocols.5 copies), quantified using qRT-PCR, were transfected into BHK-21 cells in serum-free Opti-MEM (Gibco). To maximize production of infectious units, equal mass (1 \u03bcg) of virion (SINV-nLuc) isolated RNA derived from JW18 fly cells was transfected into BHK-21 cells. Transfection was carried out for 6 hours before the transfection inoculum was removed and overlay was applied. Cells were fixed 48 hours post transfection using 10% (v/v) formaldehyde and stained with crystal violet to visualize plaques.Virion encapsidated RNA was extracted from viruses (SINV-nLuc) were purified over a 27% sucrose cushion using TRiZOL reagent (Sigma Aldrich) using manufacturer\u2019s protocol. Post extraction, RNAs were DNase  treated using manufacturer\u2019s protocol to remove cellular contaminants and viral RNA copies were quantified via quantitative RT-PCR using primers probing for SINV nsP1 and E1 genomic regions  and vertebrate (BHK-21) cells were monitored using Incucyte live cell analysis system . Cells were grown under standard conditions as described earlier under 5% ambient COAedes albopictus cells with (w/ wStri) or without Wolbachia (w/o wStri) and JW18 Drosophila melanogaster cells with (w/ wMel) or without Wolbachia (w/o wMel) were grown overnight (~12h) in media supplemented with 50 \u03bcM nucleoside analog 4-thiouridine (Sigma). These 4SU-treated cells were synchronously infected with Sindbis virus (SINV) derived from vertebrate BHK-21 cells at an MOI of 10 particles/cell. At indicated times post infection, tissue culture supernatants were removed, and cell monolayers were washed with 1XPBS prior to RNA extraction using TRiZOL reagent (Sigma Aldrich) using manufacturer\u2019s protocols. A total of 1\u03bcg of total RNA per sample was biotinylated using HPDP-Biotin (Pierce) and all 4SU-labelled RNA was separated from the total RNA pool using streptavidin cleanup and levels of unlabeled RNA at each time point was measured relative to that present at 0 minutes post internalization. RNA half-life was extrapolated using non-linear, exponential decay model as described previously [C710 eviously , 28.Quantification of viral protein translation was performed using cellular lysates following synchronized infections with reporter viruses (SINV-nLuc), or transfections with virion-derived RNA from the aforementioned viruses. At indicated times post infection, samples were collected and homogenized in 1X Cell Culture Lysis Reagent (Promega). Samples were mixed with NanoGlo luciferase reagent (Promega), incubated at room temperature for 3 minutes before luminescence was recorded using a Synergy H1 microplate reader (BioTech instruments).Total DNA and RNA from samples were extracted using TRiZOL reagent (Sigma Aldrich) using manufacturer\u2019s protocols. Complementary DNA (cDNA) was synthesized using MMuLV Reverse Transcriptase (NEB) with random hexamer primers (Integrated DNA Technologies). Negative (no RT or no gDNA) controls were performed for each target. Quantitative PCR or RT-PCR analyses were performed using Brilliant III SYBR green QPCR master mix (Bioline) with gene-specific primers according to the manufacturer's protocol and with the Applied Bioscience StepOnePlus qPCR machine (Life Technologies). All primer sets, except for ZIKV_MR766 Env and CHIKV_18125 E2 were designed based on information present in existing literature , 20. ForWolbachia sequences comprising five MLST genes coxA, gatB, ftsZ, hcpA and fbpA. The resulting alignment was used to perform Maximum-likelihood analyses in MEGA X with a bootstrap value set to 1000. The resulting newick (.nwk) file was used to construct a phylogenetic tree using FigTree v1.4.4.MUSCLE alignment was performed on concatenated All statistical analyses were conducted using GraphPad Prism 8 .S1 FigAedes aegypti mosquitoes with and without Wolbachia (wAlbB strain) using qRT-PCR at 7-days post infectious blood meal with SINV. Error bars represent standard error of mean (SEM) of biological replicates (n = 6). Welch\u2019s t-test performed on log-transformed values. *P < 0.05 (B) Viral RNA replication in mosquito cells colonized with Wolbachia. RML12 mosquito cells with or without Wolbachia (wMel strain) were infected with SINV at an MOI of 10 particles/cell. Total cellular RNA was harvested 48 hours post infection and assayed for viral RNA levels using quantitative RT-PCR. Error bars represent standard error of mean (SEM) of biological replicates (n = 6). Welch\u2019s t-test performed on log-transformed values. ****P < 0.0001.(A) Viral RNA levels were quantified in individual adult female (TIF)Click here for additional data file.S2 FigAedes albopictus RML12 cells colonized with (w/ Wolb) or without (w/o Wolb) Wolbachia (wMel strain) (n = 6). Corresponding specific infectivity ratios are presented in Mean percentage of total CHIKV (A) and ZIKV (B) particles produced from (TIF)Click here for additional data file.S3 FigWelch\u2019s t-test performed on log-transformed values. Error bars represent standard error of mean (SEM) of biological replicates (n = 5\u20136). *P < 0.05; **P < 0.01.(TIF)Click here for additional data file.S4 FigKruskal-Wallis test of multivariate comparisons with Dunn\u2019s post-hoc test. Error bars represent standard error of mean (SEM) of biological replicates (n = 4). **P < 0.01, ns = non-significant.(TIF)Click here for additional data file.S5 FigMicrograph images presented here represent of one out of four fields of view collected per replicate/time point (n = 6) every 4 hours (A-L). For each set, left and right images represent BHK-21 cells infected with W- virus (derived from C710 cells without wStri) and W+ virus (derived from C710 cells with wStri) respectively. Infected cell populations are visible as red cells, outlines of which are masked in blue to allow automated quantification using Incucyte Base Analysis Software (quantified in (TIF)Click here for additional data file.S6 FigWolbachia (wMel strain). 1 \u03bcg of total virion RNA was transfected into BHK-21 cells and infectious titer was determined by counting the number of plaques produced after 48 hours post transfection. Details of the assay can be found in Materials and Methods. Error bars represent standard error of mean (SEM) of biological replicates (n = 3). Welch\u2019s t-test on log-transformed data. *P < 0.05.Viruses were derived from JW18 fly cells with (W+ virus) or without (W- virus) (TIF)Click here for additional data file.S1 TableAll primers were used at a final concentration of 10\u03bcM for quantitative RT-PCR reactions. All primer sets, except for ZIKV_MR766 Env and CHIKV_18125 E2 were designed based on information present in existing literature , 20. For(DOCX)Click here for additional data file."}
+{"text": "COVID-19 has created challenges for staff in promoting resident activity. To better understand the pandemic-related challenges that Activity Professionals are facing, we asked COVID-19 specific questions as part of a larger survey. The overall survey focused on identifying challenges and potential technology solutions  to assist Activity Professionals in their job duties. Activity Professionals (N=19) completed the online questionnaire. Respondents  were highly educated/experienced: 68% had a Bachelor\u2019s degree or above, and 53% had 10-35 years of experience. Respondents worked in Independent Living (68%), Assisted Living (37%), Memory Care (26%), Skilled Nursing (21%), or Personal Care (11%). All Activity Professionals reported impact by COVID-19, as follows: 1) Cancelled activities: Group activities/gatherings; hosting outside entertainment; fewer volunteers, vendors, paid sources. 2) New restrictions: Number of people in elevators, rooms; no contact with residents. 3) Unexpected new tasks: More 1:1 meetings; video conferencing; additional phone calls with residents, staff, and families; ordering groceries online. Daily duties changed significantly with less help and limited availability of technology. 4) Effect: Fewer activities and new delivery models . Concerns about potential negative effects on residents while trying to meet the creativity challenge: \u201cThis has caused lots of \u201cout of the box\u201d thinking for ways to engage residents and keep things upbeat despite the challenges.\u201d Results illustrate the breadth of challenges that staff are facing, some of which can be addressed by technology."}
+{"text": "Dear Sirs,Whether COVID-19 can trigger Guillain\u2013Barr\u00e9 syndrome (GBS) is currently controversially discussed. Recent studies in this and other journals \u20134 indicaNotably, several case series already conveyed a rapid sequence and even significant overlap of COVID-19 pneumonia and GBS \u20136. We alThe first patient, a 76-year-old male, presented with a reduction of his general condition and dyspnoea. Thoracic CT revealed pneumonic infiltrates typical for COVID-19. PCR analysis for SARS-CoV-2 were equivocal. Four days after hospitalization, the patient showed a rapidly evolving flaccid tetraparesis with general areflexia and phrenicobulbar involvement with consecutive requirement of intensive care. Cerebrospinal fluid (CSF) showed albuminocytologic dissociation and IgM autoantibodies against sulfatide were detected in serum (Table The first and the third patient fulfilled Brighton level 1 diagnostic criteria for GBS , the secPrototypic GBS usually arises two to four weeks after an infection \u201311. We w"}
+{"text": "Brain atrophy and cognitive deficits persist among individuals with suppressed HIV disease. The impact of cannabis use is unknown.HIV+ and HIV\u2212 participants underwent cross-sectional magnetic resonance imaging and neuropsychological testing. Lifetime frequency, duration (years), and recency of cannabis use were self-reported. Relationships of cannabis use to resting-state functional connectivity (RSFC) and to 9 regional brain volumes were assessed with corrections for multiple comparisons. Peripheral blood cytokines and monocyte subsets were measured in the HIV+ group and examined in relation to cannabis exposure.+CD16++ monocyte count.We evaluated 52 HIV+  and 55 HIV\u2212 [54.0 \u00b1 7.5 years old] individuals. Among HIV+ participants, recent cannabis use (within 12 months) was associated with diminished RSFC, including of occipital cortex, controlling for age. Duration of use correlated negatively with volumes of all regions (most strikingly the nucleus accumbens) independently of recent use and intracranial volume. Recent use was associated with larger caudate and white matter volumes and lower soluble vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1 concentrations. Duration of use correlated positively with psychomotor speed. Use > 10 times/lifetime was linked to more somatic symptoms, better executive function, and lower CD14+CD16++ monocytes that facilitate HIV neuroinvasion. HIV-specific cannabis studies are necessary.HIV+ individuals demonstrated opposing associations with cannabis. Recent use may weaken RSFC and prolonged consumption may exacerbate atrophy of the accumbens and other brain regions. More frequent or recent cannabis use may reduce the inflammation and CD14 Use. Use2]. 9-tetrahydrocannabinol (THC) and cannabidiol (CBD) generally having opposing neurophysiological effects [Acutely impairing effects of cannabis on cognition are well known . Functio effects . Finding effects  16] [18 [189-tet effects  [16] [19 effects  20]-  [37 [37et alet al.  39] [40 [40et alet al.  41] . Ho. Ho68]. More evidence of HIV-specific cannabis effects was revealed by RSFC. Cannabis use within the past year was associated with decreased RSFC in the HIV+ and comparison groups alike; but HIV+ recent users, unlike their HIV\u2212 counterparts, demonstrated involvement of occipital cortex. HIV+ individuals exhibit visual processing/attention deficits  77] and and77] aWe also observed associations between recent cannabis use and enhanced RSFC (caudate-precuneus and hippocampus-motor cortex) in the HIV+ group. These findings, while not achieving strict statistical significance, add to data indicating the complexity of cannabis effects on the brain. Functional MRI has pointed to neuroadaptive processes that may mitigate cannabis-induced impairment  82]: lo: lo82]: +/lowCD16++ monocyte counts in our HIV+ participants in agreement with published findings [+CD16+ monocytes can differentiate into macrophages that constitute CNS viral reservoirs [In vitro THC treatment of monocytes lowers macrophage susceptibility to HIV [Cannabis possesses anti-inflammatory properties and is under investigation for its therapeutic value . It has findings . Non-clafindings  98], se, se+/lowfindings  100]. H. H+/lowCservoirs . In vitry to HIV  and may y to HIV . We founy to HIV . Reducedy to HIV . Comprehy to HIV  104]..+/lowCD1It is worth noting that medical marijuana may not produce the adverse neurocognitive consequences often seen in recreational users. Individuals who sought cannabis treatment for anxiety, sleep disturbance, etc. have reported better executive functioning after three months . While cOther limitations of this work include the cross-sectional design which precludes causal inference. The lack of brain volumetric associations with cannabis use in HIV\u2212 individuals may reflect the relatively few HIV\u2212 recent users. Cannabis use information was self-reported; unknown variables included age of onset, periods of abstinence, cumulative lifetime exposure, and whether participants met Diagnostic and Statistical Manual of Mental Disorders criteria for any current substance use disorder or lifetime dependence diagnosis. Notoriously difficult to quantify, cannabis consumption presents a major challenge to research  105]. G. G105]. The current report provides evidence that cannabis use in suppressed HIV disease may exert an adverse long-term impact on the brain that competes with protective (possibly shorter-term) effects. Prolonged exposure may cause or exacerbate brain volumetric loss. Future investigations should confirm and explore the consequences of the weaker RSFC observed in our recent users. Anti-inflammatory cannabis actions may inhibit viral CNS entry, attenuate brain atrophy, and perhaps elicit compensatory RSFC mechanisms. HIV-specific research is needed as the drug\u2019s effects may differ by HIV serostatus. Although the higher number of somatic complaints among our HIV+ frequent or recent cannabis users may signify self-medication, host and viral factors potentially associated with this outcome should be investigated. Knowledge of how cannabis may compound or counteract the damaging consequences of HIV will likely have implications for cannabinoid-based interventions. Additional research is necessary to determine interrelationships among cannabis use, cognition, and brain integrity in individuals with HIV."}
+{"text": "Salmonella enterica serovar Typhimurium. The RcsC and RcsD proteins form a phosphorelay that activates their cognate regulator RcsB in response to outer membrane stress and cell wall perturbations, conditions Salmonella experiences during infection. Surprisingly, the non-cognate phosphorelay protein BarA activates RcsB during logarithmic growth in Luria-Bertani medium in three ways. That is, BarA\u2019s cognate regulator SirA promotes transcription of the rcsDB operon; the SirA-dependent regulatory RNAs CsrB and CsrC further increase RcsB-activated gene transcription; and BarA activates RcsB independently of the RcsC, RcsD, and SirA proteins. Activation of a regulator by multiple sensors broadens the spectrum of environments in which a set of genes is expressed without evolving binding sites for different regulators at each of these genes.To survive an environmental stress, organisms must detect the stress and mount an appropriate response. One way that bacteria do so is by phosphorelay systems that respond to a stress by activating a regulator that modifies gene expression. To ensure an appropriate response, a given regulator is typically activated solely by its cognate phosphorelay protein(s). However, we now report that the regulator RcsB is activated by both cognate and non-cognate phosphorelay proteins, depending on the condition experienced by the bacterium  Salmonella enterica serovar Typhimurium. The phosphorelay proteins RcsC and RcsD activate RcsB upon cell envelope perturbations, whereas the non-cognate phosphorelay protein BarA activates RcsB during rapid growth in Luria-Bertani medium. Our findings establish that BarA controls gene expression via both its cognate regulator SirA and the non-cognate regulator RcsB. In addition, they demonstrate that RcsB controls gene expression in response to multiple signals detected by the RcsC, RcsD, and BarA proteins.The phosphorelay is a form of signal transduction used by organisms in all three domains of life. Typically, a phosphorelay consists of sensor proteins that respond to specific signals by activating a cognate regulatory protein that alters gene expression. Phosphorelays exhibit specificity towards their cognate regulators, thereby ensuring that any changes in gene expression help an organism cope with the experienced stress (and not with an unrelated stress). However, we now report that the regulator RcsB is activated by both cognate and non-cognate phosphorelay proteins in the bacterium  Salmonella enterica serovar Typhimurium.Survival in a hostile environment requires gene products that protect an organism from the particular stresses present in that environment. Phosphorelay systems allow bacteria to respond to environmental insults by activating a regulatory protein that alters the expression of a subset of genes , 2. To eBacteria and cell wall-containing eukaryotes utilize two-component systems to alter behavior in response to changes in environmental or cellular conditions , 7. The Enterobacteriacae is Rcs, which consists of the RcsC, RcsD and RcsB proteins ATP (PerkinElmer) for 30 minutes at room temperature. Purified RcsB, SirA or PhoP proteins were then added to the mixture at final concentrations of 4 and 7 \u03bcM  and the incubation was pursued for 15 min. Reactions were stopped by the addition of 10 \u03bcl of 2X LDS sample buffer and samples were run, without heating, on NuPAGETM 4\u201312% bis-tris protein gels (ThermoFisher Scientific). The gels were dried at 80\u02daC for 30 min and exposed to a phosphor screen overnight.Phosphorylation assays were performed as previously described  with somTM LDS sample buffer (ThermoFisher Scientific) and normalized according to the OD600. Protein samples were run on NuPAGETM 4\u201312% bis-tris protein gels (ThermoFisher Scientific) and transferred to nitrocellulose membrane using iBlot Gel Transfer Device (ThermoFisher Scientific). Membranes were blocked with 5% milk solution in TBST for 1 h. Membranes were probed with 1:5000 dilution of mouse anti-FLAG (Sigma), rabbit anti-HA (Sigma) or mouse anti-RpoB (BioLegend). Secondary horseradish peroxidase-conjugated anti-rabbit  or anti-mouse (Promega) was used at 1:5000 dilution. The blots were developed with the Amersham ECL Western blotting detection reagents  or SuperSignal West Femto chemiluminescent system (Pierce). Images were acquired with LAS-4000 imager . Images were quantified using ImageLabTM software (Biorad).Cells were grown in LB broth media with or without NaCl. To extract total proteins, cells were precipitated with trichloroacetic acid  and washed with 80% acetone. Samples were resuspended in NuPAGECells were grown in LB broth media with or without NaCl. Whole-cell extracts were prepared as previously described . SamplesrcsD coding region. Primer extension reactions were run together with a template-specific sequencing ladder generated with primer W4171 and a DNA template corresponding to rcsD -228 to +38 region (relative to rcsD ATG start codon) amplified with primers W3228-W3229 using Salmonella 14028s genomic DNA as template.Cells were grown in LB broth and total RNA was extracted using the hot phenol procedure as previously described . Primer S1 FigrcsC rcsD (HS1383) Salmonella harboring plasmid pRprA-GFP (rprA-gfp) and of isogenic mutants with Tn10dTc insertion in the barA and rcsB genes. The genomic location in the Salmonella enterica serovar Typhimurium 14028S genome of each Tn10dTc insertion is indicated below each strain. A derivative of the rcsC rcsD parental strain with a Tn10dTc is also shown.Fluorescence from (TIF)Click here for additional data file.S2 FigbarA) Salmonella harboring plasmid pRprA-GFP (rprA-gfp) and pBarA or pVector (empty pACYC184 vector) following 24 h of growth on LB solid medium without (-NaCl) or with (+NaCl) NaCl. Data are representative of two independent experiments, which gave similar results.Fluorescence from wild-type (14028s) and HS1520 ((TIF)Click here for additional data file.S3 FigrcsBD56Q (HS1483) Salmonella harboring plasmid pRprA-GFP (rprA-gfp) with pBarA or pVector (empty pACYC184 vector) following 24 h of growth on LB solid medium without (-NaCl) or with (+NaCl) NaCl. Data are representative of two independent experiments, which gave similar results.Fluorescence from wild-type (14028s) and (TIF)Click here for additional data file.S4 FigbarA (HS1520), sirA (HS1565) and csrB csrC (HS1651) Salmonella harboring plasmid pRprA-GFP (rprA-gfp) with pCsrB or pVector (empty pACYC184 vector) following 24 h of growth on LB solid medium without (-NaCl) or with (+NaCl) NaCl. Data are representative of two independent experiments, which gave similar results.Fluorescence from wild-type (14028s), (TIF)Click here for additional data file.S5 FigrcsBD56Q (HS1483) Salmonella harboring plasmid pRprA-GFP (rprA-gfp) with pCsrB or pVector (empty pACYC184 vector) following 24 h of growth on LB solid medium without (-NaCl) or with (+NaCl) NaCl. Data are representative of two independent experiments, which gave similar results.Fluorescence from wild-type (14028s) and (TIF)Click here for additional data file.S6 FigcsrB csrC (HS1651) and csrB csrC rcsC (HS1654), Salmonella harboring plasmid pRprA-GFP (rprA-gfp) with pCsrB or pVector (empty pACYC184 vector) following 24 h of growth on LB solid medium without (-NaCl) or with (+NaCl) NaCl. Data are representative of two independent experiments, which gave similar results.Fluorescence from (TIF)Click here for additional data file.S7 FigrcsB-FLAG (HS717) and rcsB-FLAG csrB csrC (HS1778) Salmonella grown in LB NaCl-free broth. Samples were analyzed with antibodies directed to the FLAG epitope or the RpoB protein. (B) Western blot analysis of crude extracts prepared from rcsD-HA (HS1309) and rcsD-HA csrB csrC (HS2276) Salmonella grown in LB NaCl-free broth. Samples were analyzed with antibodies directed to the HA epitope or the RpoB protein. Data are representative of two independent experiments, which gave similar results.(A) Western blot analysis of crude extracts prepared from (TIF)Click here for additional data file.S8 FigrcsC (HS1350), barA rcsC (HS1521), sirA rcsC (HS1566) and csrB csrC rcsC (HS1654) Salmonella harboring plasmid pRprA-GFP (rprA-gfp) following 24 h of growth on LB solid medium without (-NaCl) or with (+NaCl) NaCl. Data are representative of three independent experiments, which gave similar results. Quantification of the fluorescence is provided on the right panel of the figure. Values derived from three independent experiments (mean \u00b1 standard deviation) were statistically analyzed by Prism 8 using two-tailed unpaired t test. Statistical significance is indicated by *P<0.05, ** P<0.01, *** P<0.001, **** P<0.0001; ns, not significant. Error bars indicate standard deviation.Fluorescence from (TIF)Click here for additional data file.S9 FigrcsB (EG12925) Salmonella harboring plasmid pRprA-GFP with pSirA or pVector (empty pACYC184 vector) following 24 h of growth on LB solid medium without (-NaCl) or with (+NaCl) NaCl. Data are representative of two independent experiments, which gave similar results.Fluorescence from wild-type (14028s) and (TIF)Click here for additional data file.S10 Fig-293-GFP (rcsD-gfp), pRcsD-270-GFP, pRcsD-235-GFP, pRcsD-220-GFP or pRcsD-110-GFP with pSirA or pVector (empty pACYC184 vector) following 24 h of growth on LB solid medium without (-NaCl) or with (+NaCl) NaCl was monitored. The numbers -293, -270, -235, -220 and -110 refer to locations relative to the rcsD start codon. Data are representative of two independent experiments, which gave similar results.Fluorescence from wild-type (14028s) harboring pRcsD(TIF)Click here for additional data file.S11 FigrcsD start codon (indicated in bold green letters).Underlined nucleotides represent the putative SirA binding site based on the results of (TIF)Click here for additional data file.S12 FigrcsD (HS1382), barA rcsD (HS1522), sirA rcsD (HS1567) and csrB csrC rcsD (HS1655) Salmonella harboring pRprA-GFP (rprA-gfp) following 24 h of growth on LB solid medium without (-NaCl) or with (+NaCl) NaCl. Data are representative of three independent experiments, which gave similar results. Quantification of the fluorescence is provided on the right panel of the figure. Values derived from three independent experiments (mean \u00b1 standard deviation) were statistically analyzed by Prism 8 using two-tailed unpaired t test. Statistical significance is indicated by *P<0.05, ** P<0.01, *** P<0.001; **** P<0.0001; ns, not significant. Error bars indicate standard deviation.Fluorescence from (TIF)Click here for additional data file.S13 Fig198-918  was first incubated with [\u03b3-32P]ATP for 30 minutes at room temperature. SirA, RcsB or PhoP were then added at the indicated concentrations and the incubation was pursued for 15 min at room temperature before being stopped by the addition of 2X LDS-sample buffer. Data are representative of two independent experiments, which gave similar results.Purified BarA(TIF)Click here for additional data file.S14 FigbarA (HS1564), ackA-pta (MP1238) and barA ackA-pta (HS1987) Salmonella harbouring plasmid pRprA-GFP following 24 h of growth on LB solid medium without (-NaCl) or with (+NaCl) NaCl. Data are representative of two independent experiments, which gave similar results.(A) Fluorescence from wild-type (14028s), (TIF)Click here for additional data file.S15 FigrcsC rcsD sirA barA (HS1796) Salmonella harboring pRprA-GFP (rprA-gfp) with pSirA or pVector (empty pACYC184 vector) following 24 h of growth on LB solid medium without (-NaCl) or with (+NaCl) NaCl. Data are representative of two independent experiments, which gave similar results.Fluorescence from wild-type (14028) and (TIF)Click here for additional data file.S16 FigrcsB (EG12925), barA (HS1520), arcA (MK71) and arcB (EG16900) Salmonella harboring pLldP-GFP (lldP-gfp) following 24 h of growth on LB solid medium without (-NaCl) or with (+NaCl) NaCl. Data are representative of two independent experiments, which gave similar results.Fluorescence from wild-type (14028s), (TIF)Click here for additional data file.S17 FigrcsB (EG12925), barA (HS1520), phoP (MS7953s) Salmonella harboring pRstA-GFP (rstA-gfp) or pVector (empty pMS201) following 24 h of growth on LB solid medium without (-NaCl) or with (+NaCl) NaCl. Data are representative of two independent experiments, which gave similar results.Fluorescence from wild-type (14028s), (TIF)Click here for additional data file.S18 FigrcsB (EG12925), barA (HS1520), ompR (EG14379) Salmonella harboring pOmpC-GFP (ompC-gfp) following 24 h of growth on LB solid medium without (-NaCl) or with (+NaCl) NaCl. Data are representative of two independent experiments, which gave similar results.Fluorescence from wild-type (14028s), (TIF)Click here for additional data file.S19 FigrcsC mRNA. Vertical lines mark the residues in the predicted site that match those in the consensus.The CsrA binding site consensus sequence is shown above the predicted CsrA binding site in (TIF)Click here for additional data file.S1 DataStatistical analysis details are also included.(PZFX)Click here for additional data file.S2 DataStatistical analysis details are also included.(PZFX)Click here for additional data file.S3 DataStatistical analysis details are also included.(PZFX)Click here for additional data file.S4 DataStatistical analysis details are also included.(PZFX)Click here for additional data file.S5 DataStatistical analysis details are also included.(PZFX)Click here for additional data file.S6 DataStatistical analysis details are also included.(PZFX)Click here for additional data file.S7 DataStatistical analysis details are also included.(PZFX)Click here for additional data file.S8 DataStatistical analysis details are also included.(PZFX)Click here for additional data file.S9 DataStatistical analysis details are also included.(PZFX)Click here for additional data file.S10 DataStatistical analysis details are also included.(PZFX)Click here for additional data file.S11 DataStatistical analysis details are also included.(PZFX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file."}
+{"text": "Risk stratifications for endometrial carcinoma (EC) depend on histopathology and molecular pathology. Histopathological risk stratification lacks reproducibility, neglects heterogeneity and contributes little to surgical procedures. Existing molecular stratification is useless in patients with specific pathological or molecular characteristics and cannot guide postoperative adjuvant radiotherapies. Chromosomal instability (CIN), the numerical and structural alterations of chromosomes resulting from ongoing errors of chromosome segregation, is an intrinsic biological mechanism for the evolution of different prognostic factors of histopathology and molecular pathology and may be applicable to the risk stratification of EC.By analyzing CIN25 and CIN70, two reliable gene expression signatures for CIN, we found that EC with unfavorable prognostic factors of histopathology or molecular pathology had serious CIN. However, the POLE mutant, as a favorable prognostic factor, had elevated CIN signatures, and the CTNNB1 mutant, as an unfavorable prognostic factor, had decreased CIN signatures. Only if these two mutations were excluded were CIN signatures strongly prognostic for outcomes in different adjuvant radiotherapy subgroups. Integrating pathology, CIN signatures and POLE/CTNNB1 mutation stratified stageIendometrioid EC into four groups with improved risk prognostication and treatment recommendations.We revealed the possibility of integrating histopathology and molecular pathology by CIN for risk stratification in early-stage EC. Our integrated risk model deserves further improvement and validation. Endometrial carcinoma (EC) is the sixth most common malignant tumor in females worldwide and the second most common in the female reproductive system . The risIn the former system, prognostic factors of histopathology, such as histopathological type, grade, stage, myometrial invasion (MI) and lymphovascular space invasion (LVSI), constitute indications for risk assessment and adjuvant radiotherapy . NumerouExisting molecular prognostic factors, such as POLE mutation, copy number variation (CNV) and abnormal expression of mismatch repair proteins, classify EC into four molecular subtypes: POLE-mutant, microsatellite instability (MSI), low copy number variation (CNV-L) and high copy number variation (CNV-H) . In addiChromosomal instability (CIN), which originates from ongoing errors of chromosome segregation and eventually manifests as both numerical and structural aberrations of chromosomes, including aneuploidy, polyploidy, and CNV , 12, exiTo investigate the CIN reflected by CIN signatures in EC, we first confirmed the difference in CIN signatures between benign and malignant endometria. In the TCGA Uterine Corpus Endometrial Carcinoma (UCEC) cohort, 23 cancer samples had notably increased CIN25 and CIN70 expression levels compared to matched adjacent normal tissues  subgroup, vaginal brachytherapy (VBT) subgroup and external beam radiation therapy (EBRT) subgroup; \"Prognostic factors of molecular pathology became the focus of our investigation. Among the TCGA molecular subtypes of EC except POLE-mutant, CNV-L, MSI and CNV-H had the lowest, intermediate and highest risks of recurrence, respectively, and correspondingly had the lowest, intermediate and highest CIN25 and CIN70 , mutation profiles, FGA and Aneuploidy Score of the TCGA UCEC cohort are available at cBioPortal for Cancer Genomics . RNAseq There were three adjuvant therapeutic strategies after surgery for stage I EC patients, namely, observation (OB), vaginal brachytherapy (VBT), and external beam radiation therapy (EBRT). Indications for the three adjuvant radiotherapies in the guidelines of ESMO-ESGO-ESTRO were based on six established clinicopathological risk factors, including age, histologic type, grade, stage, MI, and LVSI . LVSI waIn the OB, VBT, EBRT and EBRT EEC subgroups, AUC and optimal cutoff values based on CIN25 and CIN70 signatures, FGA and Aneuploidy Score were determined by the time-dependent receiver operating curve using the \u201csurvivalROC\u201d package on the R platform. Kaplan\u2013Meier curves and log-rank tests were carried out to predict 5-year DFS and 10-year OS based on the optimal cutoff values or mutation status of different subgroups. Cox proportional hazards models were used to evaluate the prognostic value of mutations and CIN signatures. Covariates violating the proportional hazards assumption were added as time-dependent covariates in the Cox regression models.If not specified otherwise, comparisons among clinicopathological features and among molecular alterations were tested using the Chi square test for categorical variables and using the Mann\u2013Whitney test or one-way analysis of variance (ANOVA) in continuous cases. SPSS 21.0 and GraphPad Prism 8 software programs were used to perform statistical and survival analyses and to plot graphs. Meta-analysis was performed using STATA 12.0. Data in this article are presented as the mean\u2009\u00b1\u2009S.D., and p values were based on two-sided tests with\u2009<\u20090.05 considered statistically significant.Additional file 1: Figure S1. Comparison of CIN signatures among prognostic factors of histopathology. a Paired scatter plots of CIN25 (left) and CIN70 (right) expression profiles comparing endometrial carcinomas (red) with paired adjacent normal tissues (blue) from TCGA dataset (n\u2009=\u200923). Each pair of dots indicates the amount of CIN25 or CIN70 expression for a particular patient. P values represent paired t test calculations. b Boxplots of CIN25 (left) and CIN70 (right) expression in normal endometria (blue) and endometrial carcinomas (red). Each dot indicates the amount of CIN25 or CIN70 expression for a particular sample in the GSE63678 dataset. (c) Same as (b) but comparing benign lesions (blue) with endometrial carcinomas (red) from the GSE17025 dataset. P values presented in (b) and (c) are Mann\u2013Whitney test calculations. d Forest plot comparing CIN70 expression in Grade 1 & 2 versus Grade 3 patients. e Forest plot comparing CIN70 expression in EEC versus non-EEC samples. f Forest plot comparing CIN70 expression in Stage I & II versus Stage III & IV patients. In (d), (e) and (f), an inverse variance (IV) fixed effects method was used to meta-analyze the data; squares (blue) represent standardized mean difference (SMD); square size is proportional to weights used in the analysis; bars (gray) represent 95% confidence intervals (CI); diamonds (yellow) represent overall SMD with associated 95% CI . P values: *p\u2009<\u20090.05, **p\u2009<\u20090.01, ***p\u2009<\u20090.001.Additional file 2: Figure S2. Relationships between CIN and molecular prognostic factors. a Boxplot of CIN25 and CIN70 expression in PTEN wild-type (blue) versus mutant patients (red) from the OB, VBT and EBRT groups. b Boxplot of CIN25 and CIN70 expression in PIK3CA wild-type (blue) versus mutant patients (red) from the OB, VBT and EBRT groups. c Boxplot of CIN25 and CIN70 expression in FGFR2 wild-type (blue) versus mutant patients (red) from the OB, VBT and EBRT groups. d Boxplot of CIN25 and CIN70 expression in PPP2R1A wild-type (blue) versus mutant patients (red) from the OB, VBT and EBRT groups. e Boxplot of CIN25 and CIN70 expression in wild-type POLE, CTNNB1, PTEN, PIK3CA, FGFR2 and PPP2R1A (blue) versus mutant patients (red) from the PCAWG EEC cohort. P values in (a)\u2013(e) are Mann\u2013Whitney test calculations .Additional file 3: Figure S3. Kaplan\u2013Meier plot for DFS and OS in Stage I EEC from TCGA based on Guidelines, FGA, Aneuploidy Score and TCGA subtypes. a 5-year PFS. b 10-year OS. Patients are grouped by quartiles of FGA and Aneuploidy Score. P values for (a) and (b) are calculations of the log-rank test.Additional file 4: Table S1. Genes in CIN25 and CIN70."}
+{"text": "Here, we report on the diagnostic precision of this approach that provides both a rapid neuro-oncology tumor board decision tool and a safe fallback method at affordable cost.Despite recent advances in targeted diffuse glioma therapy, temozolomide still remains a therapeutic mainstay that rests on MGMT promoter methylation state as key predictor. Despite its importance in clinical decision making, MGMT testing has neither been standardized nor is it rapidly available. We, therefore, implemented an integrative diagnostic pipeline, comprising a methylation-specific PCR (MSP) complemented by a STP-27-based MGMT promoter assessment2), methylation array data, and the MSP result were available.Anonymized diagnostic and quality control data from 113 brain tumor patients from two centers  were analyzed. For each tumor, an integrated morphomolecular diagnosis (2016 WHO classificationDNA from natively frozen (FF), formalin-fixed (FO), or formalin-fixed/paraffin-embedded (FFPE) biopsies was extracted using Maxwell FFPE DNA Purification (Promega) or Qiagen FFPE Tissue (Qiagen) kits. DNA was quantified photometrically  for methylation array and by a Qubit Fluorometer 2.0 (Thermo Fisher) for MSP. Two hundred to 400 ng of DNA was modified with sodium bisulfite  according to the manual with exception of the last elution step (15 \u00b5L).3 were used to amplify methylated and unmethylated sequences, yielding DNA products of 83bp (unmethylated) and 91bp (methylated). Twenty-five nanograms of DNA was amplified with HotStart Taq polymerase , visualized by gel electrophoresis . Methylated MSP products only or both methylated and unmethylated bands were scored as \u201cmethylated\u201d; unmethylated band only as \u201cunmethylated\u201d and samples negative for both reactions as \u201cfailed.\u201d Controls: Meningioma samples (MGMT unmethylated) and universal methylated human DNA .MSP primers targeting the DMR2 region of the MGMT promoterMethylation arrays  were performed by a service provider (Life&Brain) according to the manufacturer\u2019s protocols.4 Unclear cases were verified by dimension reduction (http://www.epidip.org). Results were interpreted by board-certified neuropathologists in correlation with histology.Classification, tools, and integrated diagnoses: Methylation classes, copy number profiles, and MGMT promoter methylation were determined from array data as reported.Methylation and coarse copy number data do not contain information traceable to individuals. According to local ethics and legal boards, such data are not classified as \u201cpersonal health-related data\u201d and are exempt from ethical permits for scientific evaluation.1 approaches to assess MGMT promoter methylation resulted in identical interpretation in 107/113 of cases (94.7%), with comparable concordance levels in both laboratories . Relative to STP-27, MSP produced false-positive (5/113) and false-negative (1/113) results (Methylation-specific PCR-based (MSP) and STP-27 (tumor methylome-based) results . With th5 implementable in most laboratories in developed countries, can drastically minimize temporal gaps between intraoperative consultations and diagnostic methylation classification, separate MGMT testing\u2014not yet achievable by selective nanopore sequencing6\u2014remains necessary. The application of MSP for MGMT testing in conjunction with the nanoDx pipeline now enables high-precision molecular brain tumor diagnostics as well as neuro-oncological decision within 48 h.We present an easy-to-implement approach to fast and precise brain tumor diagnostics. Whereas nanopore sequencing-based tumor methylation profiling (nanoDx),"}
+{"text": "Resident soil microbiota play key roles in sustaining the core ecosystem processes of terrestrial Antarctica, often involving unique taxa with novel functional traits. However, the full scope of biodiversity and the niche-neutral processes underlying these communities remain unclear. In this study, we combine multivariate analyses, co-occurrence networks and fitted species abundance distributions on an extensive set of bacterial, micro-eukaryote and archaeal amplicon sequencing data to unravel soil microbiome patterns of nine sites across two east Antarctic regions, the Vestfold Hills and Windmill Islands. To our knowledge, this is the first microbial biodiversity report on the hyperarid Vestfold Hills soil environment.Our findings reveal distinct regional differences in phylogenetic composition, abundance and richness amongst microbial taxa. Actinobacteria dominated soils in both regions, yet Bacteroidetes were more abundant in the Vestfold Hills compared to the Windmill Islands, which contained a high abundance of novel phyla. However, intra-region comparisons demonstrate greater homogeneity of soil microbial communities and measured environmental parameters between sites at the Vestfold Hills. Community richness is largely driven by a variable suite of parameters but robust associations between co-existing members highlight potential interactions and sharing of niche space by diverse taxa from all three microbial domains of life examined. Overall, non-neutral processes appear to structure the polar soil microbiomes studied here, with niche partitioning being particularly strong for bacterial communities at the Windmill Islands. Eukaryotic and archaeal communities reveal weaker niche-driven signatures accompanied by multimodality, suggesting the emergence of neutrality.We provide new information on assemblage patterns, environmental drivers and non-random occurrences for Antarctic soil microbiomes, particularly the Vestfold Hills, where basic diversity, ecology and life history strategies of resident microbiota are largely unknown. Greater understanding of these basic ecological concepts is a pivotal step towards effective conservation management. East Antarctica constitutes up to two-thirds of the continent and is home to some of the oldest, coldest and most oligotrophic soils on Earth . Apart fClimate and soil age abiotic factors such as pH, moisture and nutrient content exert a strong influence on Antarctic species distribution and life histories , 11\u201313. However, our ability to unravel these basic ecological concepts in cold regions has been limited by the small number and depth of studies available . Moreoven = 837), eukaryotic 18S (n = 162) and archaeal 16S (n = 144) rRNA gene amplicon sequencing data from soil samples spanning nine east Antarctic sites between the Vestfold Hills (n = 5) and Windmill Islands (n = 4). By taking a multivariate, exploratory network and modelling approach using fitted SADs we aim to (1) elucidate the previously unknown soil microbial biodiversity of the Vestfold Hills, (2) determine the driving processes  underlying the microbial communities of east Antarctica and (3) clarify whether they differ between the Vestfold Hills and Windmill Islands.Projected twenty-first century expansion of ice-free habitats across eastern Antarctica means that tools for rapidly assessing soil ecosystem health, such as species abundance distributions (SADs), are gradually becoming more important in managing microbial biodiversity loss, especially in regions where survey data is scarce , 30. In We recovered a total of 60,495,244 high-quality bacterial 16S rRNA gene sequences, which clustered into 36,251 operational taxonomic units (OTUs) at 97% identity cut-off. Our micro-eukaryotic and archaeal runs yielded a total of 1,299,519 18S rRNA and 13,373,072 16S rRNA gene sequences after read-quality filtering, which respectively clustered at 97% into 1511 and 589 OTUs Table . SubsampActinobacteria (30.5%) and Proteobacteria (14.6%). Bacteroidetes (24.9%) and Gemmatimonadetes (8.0%) were more prevalent at the Vestfold Hills, whereas Chloroflexi (17.8%) and Acidobacteria (13.6%) were present in greater relative abundances throughout the Windmill Islands. With the exception of Rookery Lake (RL = 4.2%), Browning Peninsula (BP = 10.9%) and Herring Island (HI = 3.1 %), Cyanobacteria abundance was relatively low across all sites. At Mitchell Peninsula (MP) and Robinson Ridge (RR), rare candidate phyla namely Candidatus Eremiobacteraeota (WPS-2) and Candidatus Dormibacteraeota (AD3) were present in higher relative abundances  compared to the other sites. At lower taxonomic levels, bacterial sequences classified into 169 classes, with members largely belonging to Flavobacteria (10.9%) and Actinobacteria (9.0%), followed by similar proportions (6.0%) of Thermoleophilia, Chloracidobacteria, Gamma-proteobacteria and Alpha-proteobacteria , Archaeplastida , Excavata (Euglenozoa = 5.4%), Opisthokonta  and Amoebozoa (Cercozoa and Tublinea = 4.4%) , Crenarchaeota phylum (84.5%), whilst members of Euryarchaeota (15.0%) were mainly exclusive to the Vestfold Hills  and Halobacteriaceae (15.0%), followed by unclassified, SAGMA-X, Cenarchaeaceae and TMEG families, collectively accounting for 0.01% of total relative archaeal abundance.Archaeal diversity was predominantly distributed within the rchaeota 5.0% wereR = \u2212\u20090.23, P = 0.0034) and archaeal  communities. However, no significant correlation was found between micro-eukaryotic and archaeal richness .Non-metric multidimensional scaling (NMDS) ordination of microbial OTU communities and corresponding environmental metadata revealed that soils were conserved within sites and broadly by geographic region Fig. . Apart fDomain-level networks displaying the co-occurrence of OTUs provided new insights on the potential sharing of niche spaces or interactions between co-existing taxa, many of which are understudied Fig. . The resSaccharibacteria (TM7), a parasitic bacterium, and Actinobacteria. Also noted was the lack of co-occurrent micro-eukaryotic species. Crenarchaeota were more strongly embedded within the Windmill Islands network suggesting different life histories or niche preferences between the two regions. Similarly, rare candidate bacterial phyla Candidatus Eremiobacteraeota (WPS-2) and Candidatus Dormibacteraeota (AD3) only formed strong visible associations in this region. The astounding taxonomic diversity of Actinobacteria .Notable associations within the Vestfold Hills network included positive associations between ria Fig.  and S2 w2O3) and gravel content  and the amount of mud but displayed a positive relationship with total carbon content (TC) and conductivity . Only micro-eukaryotes demonstrated a significant  difference between the two regions.Generalised additive models (GAMs) were fitted to test the ability of a range of soil parameters to explain the variation in Chao1 richness of bacteria, eukarya and archaea. A stepwise model selection process (based on the lowest AIC) was used to identify the \u2018best model\u2019 and thereby identify the key environmental drivers. These models explained a moderate percentage of variation (45.0\u201366.8%) in richness for all three microbial communities at the regional scale Table , S5,S6. ent Fig. . Micro-ewPLN&gt;wNB), likely attributable to these Antarctic communities being substantially more heterogenous than expected . By contrast, eukaryotic and archaeal communities demonstrated multimodal distributions accompanied by relatively weaker PLN-fits, particularly for eukaryotic communities at the Vestfold Hills . These trends remained consistent at the local scale  than negative binomial (NB) distributions  and Dormibacteraeota (AD3), previously implicated in a novel mode of primary production using atmospheric energy sources [Ochrophyta and Ciliophora , this extensive survey of the east Antarctic soil microbiome reveals that whilst bacterial diversity is rich, both micro-eukaryotic and archaeal phylogenies were comparatively low Figs. . Overallpacities , 31. Howds Table , manifes sources , were noora Fig. . In contbilities , therebyStrong niche partitioning appear to be driving the establishment and maintenance of contemporary microbiomes of the arid-to-hyperarid east Antarctic soils analysed here Fig. ; Table 2Rhizocarpon lichens and invasive grass Poa annua across the Antarctic Peninsula  and Candidatus Dormibacteraeota (AD3) who are comprised of members genetically capable of atmospheric chemosynthesis, a novel process proposed to be contributing to primary production in these nutrient poor desert soils [In an era of progressively rapid natural and anthropogenic change, communities demonstrating strong niche-driven responses may have increased susceptibility to disturbance events such as large-scale colonisation, like those observed by al. 2012 , 37, 38.rt soils .Nitrososphaera  soils reported the presence of ammonia monooxygenase [Crenarchaeota at the Windmill Islands and micro-eukarya in general at the Vestfold Hills  from the top 10 cm were taken along three parallel transects following a geospatially explicit design [n = 837) included in this study were previously submitted for extensive chemical and physical attributes (Table S2) [Sampling was performed by expeditioners via the Australian Antarctic Program (AAP) across nine polar desert sites spanning two ice-free regions (the Vestfold Hills and Windmill Islands). All nine sites were within the vicinity of Casey  and Davis  research stations in Eastern Antarctica   n = 837) targeting the 16s rRNA gene using the 27F/519R [n = 18) at each site was selected for the sequencing of micro-eukarya (n = 162) and archaea (n = 144) targeting the 18S and 16S rRNA genes using the 1391f/EukBr  and A2F/519R [DNA was extracted in triplicate from soil samples using the FASTDNA\u2122 SPIN Kit for Soil  and quantified using the Qubit\u2122 4 Fluorometer  as described in van Dorst et al. 2014. Diluted DNA (1:10 using nuclease-free water) was submitted to the Ramaciotti Centre for Genomics  for amplicon paired-end sequencing on the Illumina MiSeq platform  with negative and positive (mock) controls in accordance to protocols from Bioplatforms Australia (BPA) . All 93 A2F/519R  primer shttps://qiime2.org) feature-table merge option. These were rarefied using the qiime feature-table rarefy function to generate random subsamples .We followed the UPARSE OTU algorithm  endorsedq = 0) were generated using the iNEXT package. Non-metric multidimensional scaling (NMDS) ordinations  and Chao1 richness estimates were calculated in vegan v2.5-3 [All multivariate and statistical analyses were carried out in the R environment (R Core Team 2018) using the subsampled datasets for bacteria, micro-eukarya and archaea. Subsampled rarefaction curves , and one of each correlated pair was removed from the list of potential predictors. Models were then fitted with all predictors (saturated models) using each of the Chao1 richness variables  as the response variable. Starting with this saturated model, the best model (i.e. the most parsimonious\u2014as indicated by the lowest AIC) was then identified using the stepAIC function in the MASS v7.3-51.4 package [To try and better understand the relationship between a range of environmental co-variates, we first constructed a Pearson correlation matrix to identify co-correlated variables ( package  in R. WeMIC) in the MINE software package [P &lt; 0.001) co-occurrence relationships between pairs of OTUs were uploaded into the CYTOSCAPE software [MIC &gt; 0.8). Statistical inferences of network topology were calculated using the Network Analyser algorithm (treatment = \u2018undirected\u2019) in CYTOSCAPE  were calculated for PLN- and NB-fits on each dataset to provide a measure of the relative goodness for fit [As described in , PLN and for fit .Additional file 1: Figure S1. Rarefaction curves of subsampled bacterial, eukaryotic and archaeal communities between sites. In all cases, data was approaching asymptote indicating that sufficient sampling depth was achieved. A particularly rich number of bacterial, eukaryotic and archaeal species were observed at MP (Mitchell Peninsula), TR (The Ridge) and RR (Robinson Ridge), respectively. Figure S2. Top 15 most genus of bacterial, eukaryotic and archaeal communities between sites. As taxonomic levels decrease, the number of unclassified taxa increase substantially. Interestingly, archaeal communities were dominated by Nitrososphaera, a genus of ammonia oxidising archaea possibly implicated in nitrogen cycling within these nutrient starved soils. Figure S3. NMDS plots of microbial OTU communities and environmental soil parameters. In all cases, soil samples clustered according to site and broadly by geographic region. Although TR (The Ridge) is more environmentally similar to the Windmill Island sites, it\u2019s soil bacterial and eukaryotic communities cluster more strongly with the Vestfold Hills. Figure S4. GAM model output of negative binomial distributions of best environmental predictor variables against estimated bacterial Chao1 richness based on AIC, where \u2018*\u2019 indicates a significant  correlation. A positive relationship is generally observed between bacterial richness and copper (CU), phosphorous , aluminium , sodium ion concentrations (CECNA) and the amount of gravel (GRVL) but displayed a negative relationship with titanium dioxide (TIO2). Figure S5. GAM model output of gaussian distributions of best environmental predictor variables against estimated eukaryotic Chao1 richness based on AIC, where \u2018*\u2019 indicates a significant  correlation. A negative relationship is generally observed between eukaryotic richness and dry matter fraction (DMF), soil pH, nitrite concentrations (NO2) and mud content but displayed a positive relationship with total carbon (TC) and conductivity (COND). A significant correlation is observed against random regional effects. Figure S6. GAM model output of gaussian distributions of best environmental predictor variables against estimated archaeal Chao1 richness based on AIC, where \u2018*\u2019 indicates a significant  correlation. Archaeal richness displayed positive relationships with conductivity (COND), total nitrogen (TN), phosphorous  and sodium ion concentrations (CECNA), whilst a negative relationship was observed against titanium dioxide (TIO2). Figure S7. Local scale PLN- (blue) and NB-fitted (orange) SADs of the nine sites studied. These trends remain consistent with those observed for the regional fitted SADs, where bacterial communities display strong niche-driven signatures across all sites whilst eukaryotic and archaeal communities demonstrated weaker PLN-fits and multimodality. Table S1. Summary of amplicon sequencing output and OTU pipeline analysis. Table S2 CYTOSCAPE network topology analysis between regions at the domain-level. Table S3. Environmental soil parameters averaged between sites. Table S4. Akaike weights calculated from local-scale PLN- and NB-fitted SADs. Where NA indicates that the fitting procedure did not converge, which is usual for small datasets."}
+{"text": "To ensure conceptus fitness, epiblast cells must undertake this proliferative feat while maintaining genome integrity. How epiblast cells maintain genome health under such an immense proliferation demand remains unclear. To illuminate the contribution of genome stability pathways to early mammalian development we systematically reviewed knockout mouse data from 347 DDR and repair associated genes. Cumulatively, the data indicate that while many DNA repair functions are dispensable in embryogenesis, genes encoding replication stress response and homology directed repair factors are essential specifically during the peri-implantation stage of early development. We discuss the significance of these findings in the context of the unique proliferative demands placed on pluripotent epiblast stem cells.Murine development demands that pluripotent epiblast stem cells in the peri-implantation embryo increase from approximately 120 to 14,000 cells between embryonic days (E) 4.5 and E7.5. This is possible because epiblast stem cells can complete cell cycles in under 3 h  Pluripotent cells in early mammalian embryos proliferate at a phenomenal rate. This is necessary to maintain embryo growth and reach critical developmental milestones within defined temporal windows. Because all somatic tissues are derived from these early pluripotent precursors, it is critical that genome integrity is maintained during early development. Embryonic pluripotent stem cells are thus subjected to unique challenges to maintain their DNA health. To elucidate which genome stability pathways are essential for early development we probed the Mouse Genome Informatics Gene Ontology Project (MGI-GO) database . Within Embryonic development consists of a series of events occurring in chronological progression. Murine development takes 19 to 20 days depending on mouse strain . PreimplPotency states. Totipotent cells are present in the embryo between fertilization and morula formation. They can give rise to any cell type from any stage of the animal\u2019s life, including germ and placental cells. Pluripotent cells exist in the inner cell mass (ICM) and epiblast region of the developing embryo from the blastocyst stage to immediately prior to organogenesis. Pluripotent cells can give rise to any cell of dermal lineage  but not placental or germ cells. Multipotent cells exist in newly formed tissues or organs and can develop into a limited number of cell types within their original dermal lineage.Peri-implantation is the developmental period from implantation to organogenesis (E4.0 to E8.5). Implantation begins at E4.0 when the free-floating embryo contains 64 cells . At thisBetween E6.5 and E7.5 the rate of epiblast proliferation is exceptionally pronounced, with some cell cycles completed in 2.2 h . Elongatin vivo appears to be specific to the epiblast as embryos with tetraploid trophoblast cells and diploid epiblast cells can generate live pups  plays a central role regulating stem cell outcomes following genomic insult. p53 orchestrates growth arrest or apoptosis following activation of the DNA damage response  . AdditioDSBs are a major threat to genome stability because a failure in repair may result in loss of an entire chromosome arm . AdditioHomology directed repair utilizes the homologous sister chromatid as a template for repair and is thus limited to the S and G2 cell cycle phases . HDR iniConversely, EJ involves the covalent ligation of broken DNA ends to repair DSBs and thus does not require an additional chromatid template. End-joining mechanisms function in S and G2, but notably are the only DSB repair pathway available in G1 . ClassicIn addition to DNA breaks, cells must also contend with damage to nucleotide bases, base mismatches, and bulky DNA lesions that distort the DNA double helix. Base excision repair (BER) mends small non-distorting DNA lesions such as oxidized DNA bases , while nKu70 (Ku80 (Prkdc (DNA-PKcs) (Nhej1 (XLF)  , Nhej1 (j1 (XLF) ] or onlyF)   . Additio (53BP1) . In vivost cells . While Ton cells .Consistent with a greater tolerance of genome instability in preimplantation cells, only 10 knockouts of genome stability factors that we reviewed were lethal during preimplantation . FactorsErcc2 deletion did not permit morula generation. Ercc2\u2013/\u2013 embryos fail to develop past the 2-cell stage in vitro and there is no evidence of embryo implantation in vivo  complex. TFIIH opens DNA and anchors the cdk-activating kinase (CAK) complex to facilitate transcription (Ercc2 knockouts are compromised during embryonic genome activation (EGA), a reasonable conclusion is that preimplantation lethality is associated with a loss of XPD transcriptional activity. Likewise, Xab2 is a TFIIH and NER component and Xab2 deletion is lethal prior to the blastocyst stage  codes for the 70 kDa subunit of the heterotrimeric RPA ssDNA binding complex that participates in replication, but which also functions in ATR activation, replication fork repair, HDR and NER  (Atr (Topbp1 (Hus1 (Chek1 (CHK1)  protein complex . 9-1-1 iPrpf19) , also fu19)  , Cdc25A  (Cdc25A , TimelesTimeless , and Prp (Prpf19  are all Atr null embryos form blastocysts that in vitro display widespread apoptosis within the ICM but not in the trophoblast, and which are eventually compromised by day three of culture (Chek1 null embryos also form blastocysts, but unlike Atr null embryos, are unable to attach to the culture vessels in outgrowth experiments (In somatic tissues, ATR or CHK1 inhibition coupled with replication stress induces replication catastrophe and S-phase apoptosis . Similar culture . ATR acteriments . The moreriments .Brca1 (Brca2 (Rad51 (Bard1 (Palb2 (Rad51C (Ctip (Ptip (Dna2 (Mre11, Rad50, and Nbs1 (Common HDR factors manipulate DNA substrates at two-ended DNA breaks and stressed replication forks . During Brca1 , Brca2 (1 (Brca2 , Rad51 (2 (Rad51 , Bard1 (1 (Bard1 , Palb2 (1 (Palb2 , and Rad (Rad51C . Similar (Rad51C . This in1C (Ctip ; Ptip (Cip (Ptip ; Dna2 (Lip (Dna2 , and theand Nbs1 .Brca2 null mESCs is rescued when fork protection is facilitated by inhibiting PARP activity to protect replication forks from MRE11 nuclease (In vivo, deleting factors that participate in both canonical HDR-dependent DSB repair and fork remodeling or resection, typically confers reduced cell proliferation and embryo failure during gastrulation. For example, Brca1\u2013/\u2013 embryos are severely malformed with an underdeveloped pro-amniotic cavity and mesoderm (Brca1 null embryos display a significant reduction of DNA synthesis by E6.5, increased p21 , and a e arrest . Similarnockouts . Loss ofApex1 (Rnaseh2B (Rif1 (Blm (Rev3L (Usp7 (Ino80 (Apex1 does not directly function in replication, but is critical for the repair of abasic DNA sites that if left unresolved confer replication stress (Rnaseh2B resolves RNA within RNA-DNA hybrids, including mis-incorporated ribonucleotides, which if not resolved can impede replication (Rif1 also coordinates replication timing (Blm encodes a helicase that functions in homologous recombination, the replication stress response (Rev3L encodes the catalytic subunit of POL \u03b6 which facilitates translesion synthesis to enable replication forks to negotiate lesions within DNA without stalling (Usp7 is a deubiquitylating enzyme that promotes efficient DNA replication (Ino80 encodes a chromatin remodeling factor that functions in both replication and HDR (Peri-implantation development additionally requires several genes that are functionally linked to HDR or replication stress mitigation. Such genes include Apex1 , Rnaseh2Rnaseh2B , Rif1 (C2B (Rif1 , Blm (Chif1 (Blm , Rev3L (m (Rev3L , Usp7 (K3L (Usp7 , and Ino7 (Ino80 . Apex1 dn stress . Similarlication . In addin timing . Blm encresponse , promoteresponse , and parresponse . Rev3L estalling . Usp7 islication  and Ino8 and HDR .in vitro culture of peri-implantation murine epiblast stem cells are now established (While HDR and replication associated genes are not the only genome stability factors required for peri-implantation development, their predominance on the list of genes essential for this developmental window is compelling. Conditions enabling ablished . HoweverThe fastest cell cycles in the lifetime of a mouse are likely during the brief window of epiblast development. Outside of the embryo, rapid proliferation contributes to replication stress in hematopoietic and cancerous tissues by robbing cells of the time to properly execute DNA polymerization . For exaPluripotent cells in the early embryo display almost non-existent G1 phases and appear to use unique mechanisms to ensure S-phase progression is not impeded. For example, human ESCs counter G1 brevity by loading MCM proteins faster than cultured non-pluripotent cells . RetinobDespite these efforts, human and mouse ESCs display endogenous replication stress in unperturbed cultures . It is nin vivo, and it is feasible that pre-implantation embryos simply tolerate under-replication for this brief period. Tolerance of replication defects is consistent with observations that preimplantation embryonic cells are more resistant to genomic insult than peri-implantation cells. Compromising the replication stress response should confer similar DDR activation, chromosomal segregation errors, and aneuploidy in both pre- and peri-implantation cells. However, cells with supernumerary chromosomes persist in the blastocyst before elimination during peri-implantation (In vivo, activating p53 through deletion of its negative regulator Mdm2 leads to lethality during peri-implantation (in vivo.Under-replication due to endogenous stress is described in mESCs and human iPSCs . Lengtheantation . This maantation . This suParp1 has roles preventing the trans-differentiation of extraembryonic trophoblast cells (Additionally, it is important to recognize that genome stability factors may possesses cryptic essential functions during early development. For example, PARP1 is DDR factor involved in multiple aspects of genome integrity . Howeverst cells . This plst cells . Additiost cells .Blm promotes BIR at chromosome ends in human cancer cells that maintain telomere length through the alternative lengthening of telomeres mechanism suggesting that Blm may promote BIR elsewhere in the genome following replication stress (Pold3 is also implicated in vertebrate BIR (Rad52 also functions in vertebrate BIR casting doubt on the requirement for BIR in early development and indicating the need for future studies (It is possible the canonical G1-phase c-NHEJ DSB repair pathway is dispensable during peri-implantation because cells rapidly transition through their brief G1 phase and engage alt-NHEJ or HDR in S-phase. Conversely, c- and alt-NHEJ remain active in HDR-deficient embryos, and in principle EJ functions could provide redundant DSB repair activity. An explanation why c- or alt-NHEJ cannot rescue HDR during peri-implantation may stem from the diversity of substrates repaired by HDR. While two-ended DSBs are readily repaired by EJ, collapsed replication forks present as one-ended DNA breaks which c- or alt-NHEJ cannot process . One-endn stress . Additiorate BIR . Convers studies .Brca1/2, Bard1, Rad51 and Rad51C, Ctip, Ptip, Dna2, and genes encoding the MRN complex. Interestingly, the helicases and translocases that promote fork regression, including Smarcal1, are not essential for peri-implantation (Multiple HDR factors essential for peri-implantation also play central roles in replication stress management. This includes HDR factors that regress, stabilize, or resect stalled replication forks including antation . This maantation . Given tWhile most DDR and repair factors are non-essential, this does not exclude non-essential genome stability pathways from playing an important role in healthy development. Deletion of non-essential DDR and repair genes commonly results in the birth of live pups exhibiting a wide array of deleterious phenotypes . AdditioThe critical genome stability pathways required for cell survival are determined by the type of genomic lesions the cell encounters and when in the cell cycle those lesions arise. Early embryonic development is largely protected from exogenous influence. Preimplantation embryos are wholly contained, and maternal blood supply begins at E9.5 . The criin vitro. Co-culture of ICM derived ESCs, trophectoderm derived trophoblast stem cells, and extraembryonic endoderm stem cells results in the spontaneous self-assembly of a structure remarkably like the gastrulating embryo. These structures, termed \u201cETX embryos\u201d will enable directed gene deletion within specific embryonic cell types (Another caveat of reports reviewed here is that many were pioneering studies that utilized the newly developed technology of gene targeting in mice. In the intervening decades, our understanding of early development and experimental capability has blossomed. Development of new stem cell culture technologies now enables mechanistic study of peri-implantation development within three-dimensional gastrula structures ll types . Coupledhttp://www.informatics.jax.org/go/term/GO:0000077; nucleotide excision repair: http://www.informatics.jax.org/go/term/GO:0006289; mismatch re- pair: http://www.informatics.jax.org/go/term/GO:0006298; base excision repair: http://www.informatics.jax.org/go/term/GO:0006284; DSB repair via homologous recombination: http://www.informatics.jax.org/go/term/GO:0000724; DSB repair via non-homologous end joining: http://www.informatics.jax.org/go/term/GO:0006303.MGI-GO designations discussed in this review can be found at the following. DNA damage checkpoint: GK and AC conceived of the review manuscript. GK compiled the information presented in The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Linguatula serrata isolated from nasal cavity of a dog was characterized for the first time. The total size of the circular mitogenome was 15,328\u2009bp consisting of 37 genes including 13 protein coding genes, 22 tRNA genes, two rRNA genes and two control regions. Phylogenetic tree was constructed based on 17 closely related species and their genetic relationship with Linguatula serrata was analysed.The complete mitogenome of  Linguatula serrata is an aberrant arthropod of the class Pentastomida (Hendrix  Hendrix . The adu Hendrix . The lar Hendrix . Linguat Hendrix . Human b Hendrix . Human i Hendrix .Linguatula serrata adult worm (Accession No. IR-17-Dog-Urmia) as described before , Armillifer armillatus (AY456186), Armillifer agkistrodontis (KX686568), Abacion magnum (JX437062), Nobia grandis (KF720334), Lepas australis (KM017964), Pollicipes polymerus (AY456188), Squilla empusa (DQ191684), Scutigerella causeyae (DQ666065), Rhipicephalus microplus (KP143546), Ixodes ricinus (KF197115), Ammothea carolinensis (GU065293), Hutchinsoniella macracantha (AY456189), Argulus americanus (AY456187)) and three Nematoda (Trichinella trichuria (GU385218), Trichinella spiralis (AF293969), Trichuris ovis (JQ996232)) available in the GenBank, were retrieved and aligned with draft Linguatula serrata sequence. The Fasciola gigantica (KF543342) complete mitochondrion genome (Trematode) was included as out group. The sequences were analysed using ClustalW  were genetically closer to Nematods compared to Arthropods. Among the three pentastomida,  serrata . The com"}
+{"text": "As cases of coronavirus disease 2019 (COVID-19) mount worldwide, attention is needed on potential long-term neurologic impacts for the majority of patients who experience mild to moderate illness managed as outpatients. To date, there has not been discussion of persistent neurocognitive deficits in patients with milder COVID-19. We present two cases of non-hospitalized patients recovering from COVID-19 with persistent neurocognitive symptoms. Commonly used cognitive screens were normal, while more detailed testing revealed working memory and executive functioning deficits. An observational cohort study of individuals recovering from COVID-19 (14 or more days following symptom onset) identified that among the first 100 individuals enrolled, 14 were non-hospitalized patients reporting persistent cognitive issues. These 14 participants had a median age of 39\u00a0years (interquartile range: 35\u201356), and cognitive symptoms were present for at least a median of 98\u00a0days (interquartile range: 71\u2013120 following acute COVID-19 symptoms); no participants with follow-up evaluation reported symptom resolution. We discuss potential mechanisms to be explored in future studies, including direct viral effects, indirect consequences of immune activation, and immune dysregulation causing auto-antibody production. Viral infections can cause cognitive symptoms through direct viral effects on the central nervous system (CNS) or through indirect phenomena. For SARS-CoV-2 infection, current descriptions of cognitive issues focus on hospitalized patients with severe disease  diagnosed 12 years prior by neuropsychological testing, and took no scheduled psychoactive medications. She holds a master\u2019s degree, and there were no issues with substance use. She denied any depressive symptoms impairing functional abilities. A comprehensive neurologic evaluation 149\u00a0days after symptom onset revealed improving left whole arm parasthesias and dysesthesias and 4+/5 strength in the left 5th digit abduction. She scored 30/30 on the Montreal Cognitive Assessment (MoCA). Detailed neuropsychological testing revealed mild disorganization and inefficient, error-prone task execution Table . Other cA 56-year-old otherwise healthy, high-functioning White woman was evaluated by telemedicine 37\u00a0days after symptom onset for PCR-confirmed COVID-19. She initially developed loss of smell and taste, fatigue, diarrhea, and dyspnea; these symptoms later improved. During acute COVID-19 she experienced 2 days of a neurogenic bladder, persisting symptoms of a lower limb radiculopathy or neuropathy, and difficulty focusing. With return to work she noticed word finding difficulties, inefficient learning, and decreased organization leading to missed deadlines. She scored 30/30 on the Mini-Mental State Exam (MMSE). Digit span forward was 7 , and digit span backwards was 3 . Letter and category fluency were normal. Neurocognitive symptoms have persisted at least 72\u00a0days after symptom onset; further work up is pending. She was not prescribed any medications, there were no issues with substance use, and she holds a bachelor\u2019s degree. She denied any depressive symptoms impairing functional abilities.The Long-term Impact of Infection with Novel Coronavirus (LIINC) study in San Francisco, CA, prospectively enrolls adults in recovery from COVID-19 at least 14\u00a0days from symptom onset with a documented positive SARS-CoV-2 nucleic acid amplification test (\u201cLong-term Impact of Infection with Novel Coronavirus\u201d In addition to reported symptoms, we identified measurable executive functioning deficits in young and middle-aged adults who were never hospitalized during acute COVID-19. The observational study data suggests cognitive symptoms may be common in patients recovering from COVID-19 and last months or longer after acute illness. Interestingly, these cognitive deficits were not captured by the MMSE or MoCA, common cognitive screens, suggesting neuropsychological testing is warranted (Folstein et al. Several hypothesized mechanisms may contribute to COVID-19-associated neurocognitive symptoms. Not all COVID-19 patients with severe neurologic sequelae have evidence of SARS-CoV-2 in cerebrospinal fluid, suggesting both direct viral and indirect mechanisms contribute to CNS dysfunction (Esp\u00edndola et al.\u00a0We observed COVID-19-associated neurocognitive symptoms in young and middle aged adults who were not hospitalized. Further work is needed to establish symptom prevalence, affected populations, spectrum of clinical involvement, natural history, and underlying mechanisms."}
+{"text": "Midline gliomas like diffuse intrinsic pontine glioma (DIPG) carry poor prognosis and lack effective treatment options. Studies have implicated amplifications in the phosphatidylinositol 3-kinase (PI3K) signaling pathway in tumorigenesis; compensatory activation of parallel pathways  may underlie the resistance to PI3K inhibition observed in the clinic.Three patient-derived cell lines  and a mouse-derived brainstem glioma cell line were treated with PI3K (ZSTK474) and MEK (trametinib) inhibitors, alone or in combination. Synergy was analyzed using Chou-Talalay combination index (CI). These agents were also used alone or in combination in a subcutaneous SU-DIPG-XIII tumor model and in an intracranial genetic mouse model of DIPG, given via convection-enhanced delivery (CED).P = .038). No significant short- or long-term neurotoxicity of ZSTK474 and trametinib delivered via CED was observed.We found that these agents abrogate cell proliferation in a dose-dependent manner. Combination treatments were found to be synergistic (CI < 1) across cell lines tested. They also showed significant tumor suppression when given systemically against a subcutaneous DIPG model  or when given via direct intracranial injection (CED) in a intracranial DIPG mouse model (combination only, median survival 47 vs 35 days post-induction, Our data indicate that ZSTK474 and trametinib combinatorial treatment inhibits malignant growth of DIPG cells in vitro and in vivo, prolonging survival. These results suggest a promising new combinatorial approach using CED for DIPG therapy, which warrants further investigation. PI3K and MEK inhibitions act synergistically against DIPG.CED of ZSTK474 and trametinib is safe and beneficial against a DIPG mouse model.This study demonstrates an actionable deregulation of the PI3K and MEK signaling pathways in DIPG. Targeting both pathways with ZSTK474 and trametinib, respectively, results in synergistic inhibition of cell viability. Treatment with each agent alone, albeit beneficial, resulted in upregulation of the nontargeted pathway. Novel intracranial delivery of ZSTK474 and MEK via CED, a drug delivery approach currently used in clinical trials for DIPG, resulted in a significant survival benefit in mice. Concurrently, we demonstrate that CED of these two agents resulted in no neurotoxic effects in a murine model and has potential for rapid clinical translation.1 External beam radiation is the standard of care. However, treatment only prolongs survival by a median of 3 months.2 This stagnating prognosis is due, in part, to the failure of most chemotherapeutics to cross the blood\u2013brain barrier (BBB) and achieve high concentrations in the tumor.3 Local delivery strategies, such as convection-enhanced delivery (CED), in which a cannula is surgically placed in the tumor, can circumvent this problem. In a phase I clinical trial of DIPG patients, CED achieved both high regional concentrations of the therapeutic agent and minimal systemic exposure and toxicity.4\u20136Pediatric midline gliomas, of which diffuse intrinsic pontine glioma (DIPG) is the most common variant, are universally lethal malignancies with a median survival of less than 1 year.8 Similarly, a recent molecular meta-analysis of 1000 high pediatric glioma and DIPG samples identified common alterations in the PI3K-MAPK and mitogen-activated protein kinase (MEK) signaling pathways.9 Previously, we reported that inhibitors of RTKs and their downstream effectors, including dasatinib (RTK inhibitor), everolimus (mTOR inhibitor), and perifosine (PI3K/AKT inhibitor) had effective inhibition patient-derived DIPG cells growth.11CED allows for a wide array of non-BBB-crossing therapeutics to be used. Recently, platelet-derived growth factor receptor, a receptor tyrosine kinase (RTK), has emerged as a possible target as it is estimated to be overexpressed in 80% of DIPG cases. Moreover, nearly 50% of DIPGs exhibit amplifications in the RTK/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway.13 Besides poor BBB penetration, resistance may be due to activation of alternative signaling pathways that compensate for PI3K/AKT/mTOR inhibition and allow tumor cells to evade the antiproliferative effects of monotherapy.14 Combination therapy targeting multiple pathways may thus be a more effective strategy.However, monotherapy using PI3K inhibitors or upstream RTK targeting has thus far proven to be insufficient in clinical trials for DIPG and other cancers.15 DIPG,10 and other solid cancers.17 Crosstalk between the two pathways occurs at multiple points, including the ability of ERK and the downstream kinase ribosomal S6 protein kinase to compensate for AKT in the activation of mammalian target of rapamycin complex 1 (mTORC1) via inhibitory tuberous sclerosis complex 2 phosphorylation, MEK suppression of PI3K signaling by promoting membrane localization of phosphatase and tensin homolog, and AKT suppression of RAF via phosphorylation, as schematized in 18 Unfortunately, the BBB penetration of agents targeting RAS\u2013ERK pathway and PI3K/AKT/mTOR pathway inhibitors is poor or not fully characterized and thus these agents necessitate the use of CED.19Co-inhibition of the RAS\u2013ERK pathway has shown promise against glioblastoma,In this study, we evaluate novel PI3K agents for use against DIPG and demonstrate synergistic effects by targeting both PI3K and MEK/ERK pathways. We show that ZSTK474, a PI3K inhibitor, and trametinib, a MEK inhibitor, synergistically inhibit DIPG cell proliferation in vitro and in vivo, prolonging survival in a genetically engineered mouse DIPG model following CED administration.21 SU-DIPG-IV and SU-DIPG-XIII were obtained from Dr. Michelle Monje . SF8628 cells were obtained from Dr. Rintaro Hashizume and the Gupta Laboratory . Mouse-derived brain stem glioma cells were established from the genetically engineered mouse model (GEMM) of DIPG generated by our group and using methodology previously described.21 Cells were grown as previously described.11Three patient-derived  and a mouse-derived (mBSG) cell lines were used for in vitro experiments.50 values, defined as treatment dose at which cell viability was decreased to 50% of vehicle treatment condition, were estimated from log (agonist) versus response including variable slope (four parameters) statistics in GraphPad Prism. Separate cell viability assays were performed to analyze whether any of four novel PI3K agents\u2014ZSTK474 (LC Laboratories), BKM120, GDC-0032, and BYL719 \u2014demonstrated more potent inhibitory effects on DIPG. In addition, assays were used to determine whether combination therapy with ZSTK474 and trametinib  would result in synergistic inhibition of DIPG. Each cell line was treated with each drug either individually or in combination. Combination index (CI) was calculated using Compusyn software (Combosyn) using the Chou-Talalay method.22Cells were seeded in 96-well plates at 5000 cells per well 24 hours prior to treatment. Cell viability was assessed 48 and 72 hours after treatment using CellTiter-Glo (Promega). Luminescence was normalized to vehicle treatment. All cell viability assays were done in triplicate for each experiment and repeated at least three times. GI50 concentrations  and harvested after 24 hours. Lysates were prepared by washing treated and nontreated cells with cold phosphate-buffered saline (PBS) followed by lysis with modified RIPA buffer  supplemented with protease and phosphatase inhibitor cocktail . Protein concentrations were assessed using Bradford assay (Alfa Aesar). SDS-PAGE was used to resolve lysates using 4%\u201320% polyacrylamide gels (Bio-Rad Laboratories). These were then transferred to PVDF membranes (Thermo Fisher) and blocked with 5% blotting-grade blocker (Bio-Rad) in TBS/0.1% Tween-20. Membranes were probed using several primary antibodies from Cell Signaling Technology: pAKT Ser473 , pAKT-Thr308 , pERK1/2Thr202/Tyr204 , total ERK1/2 , and GAPDH . Total AKT1 (#60203-1-lg) diluted at 1:1000 was obtained from Proteintech. Appropriate secondary antibodies conjugated with horseradish peroxidase (Abcam) were incubated in blocking buffer. Western blot detection was performed with Amersham ECL kit . Each experiment was repeated independently three times. Semi-quantification of western blots was completed using ImageJ software .Protein levels of phosphorylated and total AKT and ERK  were quantified by immunoblotting to determine PI3K and MEK activity. Cell lines were cultured until 70% confluence, treated with ZSTK474 and trametinib individually or in combination at GI6 GFP and luciferase-expressing SU-DIPG-XIII cells re-suspended in 100 \u03bcL Matrigel (BD Biosciences).All procedures conducted in mice are approved by the Weill Cornell Medicine Institutional Animal Care and Use Committee and are consistent with the recommendations of the American Veterinary Medical Association and the National Institutes of Health Guide for the Care and Use of Laboratory Animals. SU-DIPG-XIII cells were transfected with lenti-viral CAG-Luciferase (firefly), (GFP-Puro) according to manufacturer recommendations . Four-week-old females NOD.CB17-Prkdcscid/NcrCrl mice  were injected subcutaneously with 4.0 \u00d7 10n = 6), trametinib (n = 7), ZSTK474 and trametinib (combination) (n = 6), and vehicle (n = 6). Animals were treated via intraperitoneal (IP) injection once daily, for 10 days with either trametinib (3 mg/kg/day), ZSTK474 (400 mg/kg/day), or the combination of trametinib and ZSTK474 dissolved in DMSO and then diluted in PBS  to the desired concentration . The change in tumor volume was assessed with bioluminescence, measured immediately before treatment and posttreatment once weekly until day 60 after which animals were killed. Most mice showed some sign of systemic toxicity in the form of weight loss or food avoidance. No animal, however, reached euthanasia endpoints. Notably, animals with undetectable luciferase signaling at any time point were removed from two-way analysis of variance (ANOVA) analysis .Treatment was started 2 weeks post implantation of tumor cells and confirmation of tumor establishment with bioluminescence imaging. Mice were separated into four treatment groups: ZSTK474 (Nestin-Tv-a (Ntv-a);p53fl/fl mice. Induction of brainstem gliomas (BSGs) in mice was accomplished using DF1 virus-producing cells transfected with replication-competent avian sarcoma (RCAS) plasmids , as previously described.21 Injections were performed on postnatal (P) day 3\u20135 after using hypothermia for anesthetizing animals on ice. Bioluminescent imaging was used to confirm initial transfection. Mice with confirmed initial transfections were separated into combination treatment (n = 11) and vehicle (n = 10) groups, monitored daily, weighed at least twice weekly and killed upon onset of brain tumor symptoms . Treatments were performed at days 21 and 28 post tumor induction under isoflurane anesthesia. Animals were treated with CED of either ZSTK474 or trametinib via microinjection infusion (CED) in to brainstem at GI90 concentrations (1.9 \u03bcM for both drugs) in 1% DMSO in PBS, or 1% DMSO in PBS alone as control. Injection site was 1-mm posterior, 0.8-mm lateral, and 4-mm deep to lambda. A Nanofill 10 \u03bcL syringe  with a 32-gauge needle was used. Mice were placed in a Kopf small animal stereotactic frame. Infusion volume was 5 \u03bcL over 10 minutes.Survival experiments used d-luciferin  as per manufacturer\u2019s protocol.Mice were imaged once weekly using a Bruker In-Vivo Xtreme small animal imaging system . For imaging, mice were isoflurane anesthetized (2% in oxygen) and examined for tumor bioluminescence 10 minutes following IP injection of To assess for treatment-related neurotoxicity or neuroinflammation, adult (6\u20138 weeks old) na\u00efve mice were used. They were injected via CED twice as described earlier and monitored regularly following CED for difficulties with ambulation, eating, drinking, defecating, urinating, or grooming. A total of eight animals were divided into four groups \u2014treatment with the combination of ZSTK474 and trametinib versus vehicle, and killed at 2 days versus 14 days after the last CED. Animals were treated under the same protocol as GEMM survival experiments. No animals displayed any immediate or delayed neurological deficits postoperatively.Mouse brains were harvested after formalin perfusion and cryopreserved using Optimal Cutting Temperature compound . Sections were cut 5-\u03bcm thick using Thermo Scientific Cryotome FSE cryostats. Tumors were confirmed using hematoxylin & eosin (H&E) staining, Ki67 (D3B5) , H3.3K27M (D3B5T) , and luciferase  staining. Neurotoxicity was assessed via H&E and immunohistochemistry for glial fibrillary acidic protein (GFAP) , Ionized calcium binding adaptor molecule 1 (Iba1) , and cluster of differentiation 3 (CD3) . Staining and immunohistochemistry were performed by the Weill Cornell Pathology Core. Slides were reviewed by D.J.P., a board-certified neuropathologist, for neurohistopathological changes observed in the treatment group against vehicle-treated animals.50 for PI3K inhibitors  , lowest GIZSTK474)  and C or23 BKM120,24 GDC-0032,25 and BYL71926) to determine effect on cell proliferation. Each of these agents has different cytostatic and cytotoxic effects and isoform specificity, summarized in 50 values   after Bonferroni correction for multiple comparisons . No difference in relative cell viability was found when treating SU-DIPG-XIII cells  ; Table 1II cells ; Table 110 resulted in a more potent inhibition of cell viability in patient- and mouse-derived DIPG cells compared to each drug individually ,vidually . Analysin tested . The mut50 concentration  = 1.69, P = .21). However, there was a significant main effect for time F = 5.04, P = .0045) and a trend for interaction effect  = 1.82, P = .09.  over vehicle (n = 11), with median survival 47 days versus 35 days, respectively (log rank P = .038)  . Histolo = .038)  and B. I = .038) .Treatment of na\u00efve animals with CED of the combination therapy (ZSTK474 and trametinib) protocols used in the GEMM survival experiment revealed no acute or chronic features of inflammation or neurotoxicity beyond that observed in vehicle-treated animals Tissue was processed and stained with markers of gliosis (GFAP), T-cell lymphocytic infiltration (CD3), and microglia (Iba1) either 2 days  and B or13 We have previously shown how combinatorial therapy resulted in increased caspase-dependent apoptosis.10 In this study, two CED injections were used to best approximate our clinical experience, where one or two CED injections are used in patients.5In this study, we demonstrated how dual PI3K and MEK inhibition synergistically inhibits DIPG cell growth in vitro while reducing tumor burden and prolonging survival in vivo. Although prior studies have demonstrated RTK and downstream PI3K/AKT/mTOR amplifications in DIPG, monotherapy against the PI3K pathway has failed to show a significant tumor response in various malignancies including DIPG and other CNS tumors.29 mitochondrial function,30 PIM kinase,31 and neuroligin.32 Of these, MEK inhibition has shown promise in preclinical work for dual therapy with PI3K inhibitors.33 Studies have shown how MEK signaling is often co-activated along PI3K in many types of cancers,17 including gliomas.34 In recent early-phase studies, two trials using PI3K inhibitors used in this study and one trial using PI3K/mTOR inhibitors PF-04691502 and gedatolisib, examined dual PI3K and MEK inhibition in advanced solid tumors.36 Partial responses were observed particularly in ovarian and endometrial KRAS mutant cancers, including 29% of ovarian cancers with BKM120 and trametinib.35 Moreover, frequent toxicity-related dose delays and reductions may have prevented sustained therapeutic drug levels across all trials. These issues emphasize not only potential problems in tolerating systemic dual PI3K and MEK treatment, but also a potential advantage of CED.Numerous pathways have been synergistically targeted along PI3K, such as histone deacetylase complex (HDAC),38 Previous reports on selective PI3K inhibitors demonstrated rebound activation of non-inhibited PI3K isoforms, a possible mechanism behind resistance.40 Pan-PI3K inhibition may have theoretical advantages and disadvantages related to their antiangiogenic and immunomodulatory properties\u2014while PI3K \u03b1 and \u03b2 isoforms are expressed in various tissues, \u03b4 and \u03b3 isoforms are largely expressed in leukocytes and affect neovascularization and immune signaling.41 However, reported pan-PI3K inhibitor adverse effects from clinical trials are more related to off-target effects  and general dose-related toxicity than isoform-specific toxicity.18 ZSTK474 was chosen among novel PI3K inhibitors currently in phase I or II clinical trials  because of both its profile as a pan-PI3K inhibitor and high oral maximum tolerated dose in mice.39 Immunoblot analysis of downstream effectors of PI3K/AKT and MEK/ERK pathways confirmed presence of mutual feedback inhibition and redundant signaling , our experiments were not adequately powered for the level of variability we observed between individual animals\u2019 tumor volumes. The numerous side effects we observed ultimately convinced us to use a direct drug delivery approach instead. Nevertheless, prior studies, our current in vitro data, and our GEMM in vivo results present a strong rationale for dual PI3K and MEK inhibitor therapy for cancer treatment and is thus being exploited in the clinic at the early-phase clinical trial level in other malignancies.44Ultimately, a more comprehensive multiple dosing regimen coupled with pharmacokinetics/pharmacodynamics studies will be required for correlating in vitro synergistic effects with effects in animal models. Although our GEMM experiments demonstrated prolonged survival with PI3K and MEK treatment via CED, our subcutaneous xenograft studies showed no significant difference between treatment groups. However, there was a trend toward an interaction with the other main effect of time. Differences in tumor volume over time dependent on treatment group would suggest that treatment did affect tumor growth. Owing to decreased number of animals in the trametinib group secondary to poor luciferase signal  was instead observed when the drugs were given via systemic routes, consistently with clinical evidence suggesting that the development of dose-limiting toxicities for these agents is common and potentially increased by their combination.49 These findings are consistent with the results of both preclinical work and clinical trial results demonstrating the safety of CED in DIPG patients, and emphasize the strengths of a local delivery approach in the treatment of brain malignancies.50Moreover, trametinib has been reported to have poor BBB penetration; as such, CED was used to maximize intratumoral concentration.This research was supported in part by Cristian Rivera Foundation, McKenna Claire Foundation, The Lyonhearted Foundation, Christian Koehler Foundation, Brooke Healey Foundation, Fly a Kite Foundation, Children\u2019s Brain Tumor Family Foundation, Joshua\u2019s Wish, Lily LaRue Foundation; and Alex Lemonade Stand Foundation\u2019s Pediatric Oncology Student Training Grant (U.T.); and American Brain Tumor Association Medical Student Summer Fellowship in honor of Collegiate Charities Dropping the Puck on Cancer and Super Lucy (R.C.).vdz004_suppl_Supplementary_FiguresClick here for additional data file.vdz004_suppl_Supplementary_Figures_LegendsClick here for additional data file."}
+{"text": "Arterial blood gases (ABG) demonstrated metabolic acidosis. Computed tomography revealed a giant hiatal hernia with stomach, ileum and colon in thoracic cavity. The patient was immediately started intravenous (IV) fluids of 2l in 6 hours, Foley and jugular catheter vein cannulation to support main arterial pressure and urine output. The patient was discussed for surgical operations.A Giant hiatal hernia (GHH) is a type III hernia with a sliding and para esophageal component such as > 30% of the stomach, colon, spleen or pancreas due a chronic positive pressure on the diaphragmatic hiatus. Surgical repair requires hernia sac excision, tension-free repair and Nissen fundoplication. Recurrence rates range between 2% and 12%. A 77 years old Caucasian woman presented to the ED with significant thoracic pain, vomiting and bradycardia (<50 bpm). She presented a medical history of atrial fibrillation and anticoagulant therapy. She reported a traumatic rupture of the sternum 5 years ago. Her vital signs were: blood pressure 130/70 mmHg, respiratory rate 40 breaths/minute, heart rate 129 beats/minute and temperature superior of 36 C. Oxygen saturation was 85% on room air. The abdominal examination was normal. Thoracic examination reported reduced vesicular murmur. Laboratory evaluation revealed high leukocytosis with a white blood cell (WBC) count of 16 per mm"}
+{"text": "Background: To investigate the diagnostic performance of simultaneous 18F-fluoro-deoxyglucose ([18F]-FDG) PET/MR enterography in assessing and grading endoscopically active inflammation in patients with ulcerative colitis. Methods: 50 patients underwent PET/MR 24 h before ileocolonoscopy. Inflammatory activities of bowel segments were evaluated with both Mayo endoscopic subscore and Nancy histologic index. MR, DWI (Diffusion-weighted imaging) and PET were utilized as qualitative parameters for detecting endoscopically active inflammation. SUVmaxQuot in each segment  was calculated to quantify inflammation. Results: In the study arm without bowel purgation, combined reading of PET and MR resulted in significantly increased specificity against each submodality alone  and highest overall accuracy. In the study arm with bowel purgation, the significantly lower specificity of PET (0.595) could be markedly improved by a combined reading of PET and MR. Metabolic conditions in bowel segments with both endoscopic and histological remission were significantly lower than in segments with endoscopic remission but persistent microscopic inflammation . SUVmaxQuot correlated highly with Mayo endoscopic subscore (\u03c1 = 0.718 and 0.606) and enabled grading of inflammatory activity. Conclusions: Simultaneous [18F]-FDG PET/MR may be considered as an alternative to endoscopy in clinical trials. Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) with relapsing\u2013remitting courses. According to expert consensus-based recommendation, the selected treatment-target for UC was clinical and endoscopic remission (Mayo endoscopic subscore [MES] of 0\u20131) . Persist18F-fluoro-deoxyglucose ([18F]-FDG) Positron Emission Tomography (PET)/MR have been demonstrated in the assessment of IBD [18F]-FDG PET/MR in predicting histologically active inflammation in 50 patients with UC -FDG PET/MR enterography in detecting endoscopically active inflammation and predicting complete (endoscopic and histologic) remission in patients with UC. Our study included three key findings that we considered important. First, [18F]-FDG PET/MR enabled detection of endoscopically active inflammation and grading of disease activity with high diagnostic accuracy. Second, the newly proposed PET-MR as combined reading of both PET and MR parameters resulted in the highest diagnostic specificity regardless of bowel cleansing. Third, metabolic conditions in bowel segments with complete remission was significantly lower than in segments with only endoscopic remission but persistent microscopic inflammation. Therefore, SUVmaxQuot facilitated prediction of endoscopic remission and complete remission with different cutoff values. Evaluation of disease activity and extent is of crucial importance for clinicians in choosing the proper treatment. In acute attack of UC, ileocolonoscopy is associated with increased rate of complications. The alternative diagnostic test should be non-invasive, easy to perform and correlate well with disease activity. Our study aimed to investigate the superior diagnostic value of -FDG PET/MR enterography not only facilitated detection of endoscopically active inflammation but also enabled grading of inflammatory activity by means of SUVmaxQuot, which correlated highly with MES . Based on higher cutoff values, SUVmaxQuot might predict bowel segments with severe ulcerative inflammation (MES 3). This result was supported by a former study with 15 UC patients utilizing PET/CT, which demonstrated significantly increased FDG-uptake (SUVmaxQuot between 1 and 3) in segments with endoscopically severe inflammation  -FDG PET/MR may serve as a non-invasive alternative to endoscopy without the need of bowel purgation. For detecting endoscopically active inflammation, PET-MR as combined reading of PET and MR provides higher diagnostic accuracy than each sub-modality alone. With lower cutoff-value, SUVmaxQuot facilitated to differentiate bowel segments with complete remission from those with endoscopic remission.Simultaneous ["}
+{"text": "False positive radioiodine uptake following thyroidectomy for differentiated thyroid cancer has been reported in some cases. A 57-year-old female patient was referred for ablative radioiodine treatment four weeks after undergoing total thyroidectomy for papillary thyroid carcinoma. Posttherapeutic I-131 scintigraphy showed uptake in the neck and large focus in the lower abdomen and pelvis. Pathology revealed a mucinous adenocarcinoma of the right ovary. Radioiodine is used for treating differentiated thyroid carcinoma . The preA 57-year-old female patient underwent total thyroidectomy. Histopathology revealed a follicular thyroid carcinoma (pT1bNxMx). Four weeks later she received, with thyroid hormone withdrawal, 3.7 GBq of 131I as a treatment. At this time, the serum thyroglobulin level was 2.7 ng/mL, TSH was 73 \u00b5IU/ml and antithyroglobulin antibody level was less than 20 IU/mL. Five days after the treatment, WBS  showed mstruma ovarii) [Ovarian radioiodine uptake at post-therapy WBS may occur in benign or malignant conditions -4. Patho ovarii) , a benig ovarii) , 6 and a ovarii) . The mal ovarii) . To our  ovarii) .It is important to recognize the physiological and pathological aetiologies (unrelated to thyroid) that demonstrate 131 I uptake and may lead to false positif 131 I scan in patients of DTC."}
+{"text": "Dual sensory impairment (DSI) affects 11.3% of adults aged \u226580 years. Hearing and vision impairments are each associated with cognitive decline and dementia, but DSI\u2019s impact is unknown. All-cause dementia and mild cognitive impairment (MCI) were adjudicated using longitudinal cognitive information. Ten neurocognitive tests were summarized using latent variable methods. Hearing was measured using pure tone better-ear thresholds (0.5-4 kHz) and vision with better-eye presenting distance visual acuity and/or contrast sensitivity. In 881 adults , DSI (vs. no hearing or vision impairment) was cross-sectionally associated with -0.17 standard deviations (SD)  lower global cognitive score and an 87% increased odds  of combined MCI/dementia, after full adjustment for demographic and clinical factors. Future longitudinal research should elucidate the mechanism underlying this association to determine if treatment can delay cognitive decline and MCI/dementia in older adults."}
+{"text": "Finally, drug-target network analysis reveals several potential druggable genetic interactions by targeting tumor vulnerabilities. This study offers a powerful network-based methodology for identification of candidate therapeutic pathways that target tumor vulnerabilities and prioritization of potential pharmacogenomics biomarkers for development of personalized cancer medicine.Tumor-specific genomic alterations allow systematic identification of genetic interactions that promote tumorigenesis and tumor vulnerabilities, offering novel strategies for development of targeted therapies for individual patients. We develop an Individualized Network-based Co-Mutation (INCM) methodology by inspecting over 2.5 million nonsynonymous somatic mutations derived from 6,789 tumor exomes across 14 cancer types from The Cancer Genome Atlas. Our INCM analysis reveals a higher genetic interaction burden on the significantly mutated genes, experimentally validated cancer genes, chromosome regulatory factors, and DNA damage repair genes, as compared to human pan-cancer essential genes identified by CRISPR-Cas9 screenings on 324 cancer cell lines. We find that genes involved in the cancer type-specific genetic subnetworks identified by INCM are significantly enriched in established cancer pathways, and the INCM-inferred putative genetic interactions are correlated with patient survival. By analyzing drug pharmacogenomics profiles from the Genomics of Drug Sensitivity in Cancer database, we show that the network-predicted putative genetic interactions  are significantly correlated with sensitivity/resistance of multiple therapeutic agents. We experimentally validated that afatinib has the strongest cytotoxic activity on BT474  methodology for quantifying the putative genetic interactions in cancer. Trained on over 2.5 million nonsynonymous somatic mutations derived from 6,789 tumor exomes across 14 cancer type, we found that genes identified in the cancer type-specific genetic subnetworks were significantly enriched in established cancer pathways. The network-predicted putative genetic interactions are correlated with patient survival. By analyzing drug pharmacogenomics profiles, we showed that the network-predicted putative genetic interactions  were significantly correlated with sensitivity/resistance of anticancer drugs  and we experimentally validated it in breast cancer cell lines. Finally, drug-target network analysis reveals several potential druggable genetic interactions  by targeting tumor vulnerabilities. This study offers a generalizable network-based approach for comprehensive identification of candidate therapeutic pathways that target tumor vulnerabilities and prioritization of potential prognostic and pharmacogenomics biomarkers for development of personalized cancer medicine. Recent exponential advances in genome sequencing technologies have enabled a detailed map of genomic alterations identified in human cancer populations. Several multi-center cancer exome/genome projects, such as The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC), have significantly improved our understanding of the landscape of somatic alterations that promote tumorigenesis and tumor evolution \u20134. Yet, KRAS and c-Myc) and the emerging drug resistance. In addition, restoring the function of TSGs that are highly mutated or deleted in tumor cells by traditional small molecular drug is not feasible. Recent efforts to map genetic interactions  in tumor cells have suggested that tumor vulnerabilities from evolutionary medicine perspective can be exploited for development of novel molecularly targeted therapies , S6B Fig) for HRAS in breast cancer. Interestingly, breast cancer patients harboring nonsynonymous somatic mutations on BCL2L1-HRAS reveals poor survival rate compared to the wild-type status on both BCL2L1 and HRAS . BCL2L1, encoding two specific isoforms (Bcl-xL or Bcl-xS), has been shown to have functional roles in multiple cancer types, including breast cancer  and TP53 mutant [p.E285K]), MCF7 (both BRCA2 and TP53 wild type), and MDA-MB-231 (BRCA2 wild-type but TP53 mutant [p.R280K]). Cell viability assay  compared to MCF7  and MDA-MB-231 , consistent with drug response analysis from the GDSC database .t cancer . Recent n cancer  and brean cancer . We founafatinib . Afatiniafatinib , is undeafatinib . To expessay see  reveals BRCA2 and TP53 (BRCA2-TP53) are sensitive to JQ1 . Clinical studies showed that mutations on TP53 reduce responsiveness to first-line tyrosine kinase inhibitors in EGFR-mutated non\u2013small cell lung cancer (NSCLC) patients  group) on both genes of BCL2L1-HRAS (C) or XRCC1-HRAS (E) are significantly correlate with poor survival rates comparing to wild-type [WT] group on both genes. P-value in B and D was computed by permutation set. P-value in C and E was computed by log-rank test.((PDF)Click here for additional data file.S7 Fig(PDF)Click here for additional data file.S1 Table(PDF)Click here for additional data file.S2 TableAll genetic interactions were identified by experimental assays in organisms or human cells or models.(XLSX)Click here for additional data file.S3 Table(PDF)Click here for additional data file.S4 Table(XLSX)Click here for additional data file.S5 Table(XLSX)Click here for additional data file.S6 TableThe P values are calculated by the Wilcoxon rank-sum test over the corresponding gene set and human essential genes identified in cancer cell lines.(PDF)Click here for additional data file.S7 Table(XLSX)Click here for additional data file.S8 Table(XLSX)Click here for additional data file."}
+{"text": "Opioids are an important tool for managing Medicare Hospice beneficiaries\u2019 pain and symptoms. Little is known about the prevalence of opioid dependence among patients discharged alive from hospice. Using 100% Medicare hospice, acute inpatient, and Part B claims from Federal Fiscal Years (FY) 2017-2018, we identified hospice beneficiaries that were discharged alive during FY2017-2018 and associated with diagnosis codes in subsequent health care incidents indicating opioid dependence. We used a crosswalk from the Agency for Healthcare Research and Quality to determine which codes represented opioid dependence. We characterized beneficiaries and their hospice providers using information from the Medicare Enrollment Database and Provider of Services file. There were 468,204 live hospice discharges during FY2017-2018, among which 9,282 (2.0%) were associated with subsequent health care events including a diagnosis code signifying opioid dependence. Post-hospice opioid diagnoses were more frequent among beneficiaries who were younger ; dual-eligible ; and relative to cancer, diagnosed with lung , heart , or liver diseases . Beneficiaries with opioid incidents tended to have survived much longer after hospice (150.9 days with opioid incidents vs. 13.6 days no opioid-related incidents). The states with the highest rates of post-hospice opioid-incidents per 10,000 live discharges were Kentucky (435.2), Wyoming (386.0), Tennessee (359.3), Washington (345.6), and Idaho (342.9). Further monitoring can ensure that hospice beneficiaries receive appropriate care during and after hospice enrollment."}
+{"text": "Major sources of false positive findings were PSMA-expressing residual adenocarcinoma with marked post-radiotherapy treatment effect. False negative interpretation occurred in 8 regions of 6/79 (8%) patients with histopathology validation, including prostate (bed) (n\u2009=\u20095), pelvic nodes (n\u2009=\u20091), and extra pelvic lesions (n\u2009=\u20092). Lesions were missed mostly due to small metastases or adjacent bladder/urine uptake.Consensus reads were false positive in 20 regions of 17/217 (8%) patients with lesion validation. Majority of the false positive interpretations  occurred in the context of suspected prostate (bed) relapse (T) after radiotherapy  contains supplementary material, which is available to authorized users. Biodistribution of the radiotracer and PSMA expression level of prostate cancer and normal tissues may lead to false clinical interpretations. Here we present details for false PET interpretations of the blinded consensus reads.Our recent prospective trial reports 84 to 92% [68Ga]Ga-PSMA-11 PET at biochemical recurrence resulted in less than 10% false positive interpretations. About two-thirds of all documented false positive interpretations occurred in the context of suspected recurrence in the prostate post-radiotherapy. Following radiation therapy, cancer and prostate tissue undergo considerable molecular and histologic change over time. Effects vary with dose and duration of therapy, interval from onset, and addition of systemic treatment [[reatment . Prostatreatment . In a prreatment . Risk foreatment . Residua68Ga]Ga-PSMA-11 PET. However, residual prostate cancer with severe treatment effect, even without conversion into progressive disease, is another possible source of PSA Ga-PSMA-11 PET imaging, we anticipate that the frequency of imaging detected potential local failures after prostate radiotherapy will increase. This in turn will increase the number of post-radiation biopsies requiring careful pathologic evaluation prior to initiation of salvage therapy.Accuracy of biopsy for the diagnosis of prostate cancer is somewhat limited as demonstrated by previously reported discordance with whole-gland pathology . Sample 68Ga]Ga-PSMA-11 PET/MRI interpretation resulted in two false positive lung findings. One patient demonstrated focal tracer uptake of right upper lobe lung cancer. Focal uptake was interpreted as prostate cancer lung metastasis by all three readers. This interpretation accounts for a false positive finding with respect to prostate cancer detection; however, subsequent diagnosis of lung cancer considerably altered oncologic management. Another patient demonstrated focal uptake in a bronchogenic cyst with prominent peribronchial glands  patients [68Ga]Ga-PSMA-11 uptake in the prostate post-radiotherapy was a major source of false positive findings. Uptake was noted in PSMA-expressing benign tissue or tumor remnants with successful treatment response by histopathology. Previous studies report limited prognostic relevance of these remnants underlining the importance of additional pathologic evaluation [68Ga]Ga-PSMA-11 PET.A prospective multi-center trial with blinded reads and lesion validation revealed false positive [patients . Faint taluation , 14. OthESM 1(DOCX 641 kb)"}
+{"text": "Cognitive impairment  and malnutrition (~38.7%) are common concerns among older adults \u226565 years. CI and malnutrition may be used as predictive risk factors for poor surgical outcomes. The 2012 ACS NSQIP/AGS Best Practice Guidelines for the preoperative assessment of geriatric surgical patients classify severe nutritional risk as either having a BMI < 18.5 kg/m2, serum albumin (SA) < 3.0 g/dL and/or unintentional weight loss > 10%-15% within 6 months. Using SA as a surrogate marker for malnutrition, we evaluated the relationship between CI, malnutrition, and risk for poor surgical outcomes in a geriatric population. Electronic medical record chart reviews of patients (\u226565 years old) undergoing elective intermediate or high-risk surgery (IHRS), between 2016 and 2019 in Tucson, AZ, were conducted. Pre-and-post assessment factors such as cognitive status via mini-cog, laboratory markers (SA), and hospital complications were examined. Multivariate regression analyses were performed to determine the association between cognitive status, SA levels, and hospital complications. Of the 173 patients undergoing IHRS included in this assessment , 42.8% experienced hospital complications. Multivariate regression analysis revealed cognitive impairment and low SA levels were significantly associated with this outcome (p<0.05), adjusted for age and gender. We demonstrated MCI and low SA levels are risk factors of postoperative hospital complications among older patients undergoing elective IHRS. Increased understanding of predictive factors can help enhance prevention efforts, aiding in improving patient experiences and reducing patient and hospital costs."}
+{"text": "This study presents the whole CBT-CS11 dataset discussed in [1] including sedimentological  analyses), geochemical  analyses) as well as palynological (dinoflagellate cyst and pollen assemblages from [1]) data. The present study also describes the different statistical tests from which ecological groups have been established from palynological indicators in [1].The high-time resolution (\u223c70 years in average) multi-proxy analysis conducted on the mid-shelf core CBT-CS11  revealed the complexity of the palaeohydrological and palaeoclimatic signals recorded over the last 7 kyrs in the recently published paper: \u201cOceanic  On thWe have plotted the D50 from the total grain-size measurements with Sr-XRF counts . Both arversus finer (Al) sediment composition, while Ca/Fe and Sr/Ti ratios discussed in [versus terrigenous (Fe and Ti) fractions, with the biogenic component characterized by finer (Ca) or coarser (Sr) biogenic clasts.The Zr/Al ratio discussed in  allows dussed in  allow diOperculodinium centrocarpum and Spiniferites elongatus) percentages [3-free grain-size data from [Subpolar North Atlantic dinocyst  that typify both continental and marine studied communities .2.1-O. centrocarpum and S. elongatus) is explained by grain-size proxies .North Atlantic subpolar gyre grouping (-Echinidinium spp. and Selenopemphix quanta-Protoperidinium nudum) are explained by heavier \u03b418O Cibicides refulgens [Pentapharsodinium dalei in the biplot.Coastal heterotrophic taxa  that may explain the proportion of these foraminiferal taxa first fixed on plants and then transported by fluvial currents.The estuarine taxon minifera  explain 2.2-Quercus and Corylus) grouping covaries mainly with oceanic sedimentological tracers (Zr/Al and D50), suggesting a distal signature .The mixed oak forest (-Alnus mainly) signature is explained by enhanced freshwater microalgae  and L. machaerophorum percentages.The alluvial forest  are explained by higher dinocyst (L. machaerophorum excluded) concentrations.Anthropic pollen signature  can be distinguished while the third mode characterizes the strongest human impacts on the environment. Fluvial/proximal signature, with finer (Ca) or coarser (Sr) biogenic sediments, characterized by fine detritic sediments, is characteristic of the \u201cL. machaerophorum - alluvial forest\u201d pole (top right of L. machaerophorum excluded) concentrations.Two natural modes  were measured at the PSO  using the IRMS platform (MAT253 mass spectrometer coupled with a KIEL IV preparation line for benthic species) for [13C and \u03b418O, respectively.beccarii  (101 anaefulgens  (113 ana3.33 of dry sediments were first treated at room temperature by hydrochloric acids (cold HCl: 10-25-50% until the reaction is over and the effervescence disappears) and hydrofluoric acids (cold HF: 45% for 4 hours followed by 70% for 30h) to remove carbonates and silicates, respectively, then sieved through 10 \u03bcm nylon mesh screens.Palynological treatments  were conducted on the <150 \u03bcm fraction under the following protocol [Lingulodinium machaerophorum for dinocyst assemblages), counts were prolonged until at least 100 other specimens were found.Palynomorph  determinations were made using a Leica microscope DM2500 at X630 magnification. A minimum of 300 dinocysts and 200 pollen grains were counted per level. In case of over-representation of a taxon  for XRF data and Detrended Correspondence Analysis (DCA) for palynological data  thanks to the \u201cPast version 1.75b\u201d software ."}
+{"text": "Although research has shown mental health and substance use problems (MHSUPs) are fairly prevalent in older adults (OAs), less research has considered MHSUPs in hospice beneficiaries and their families. This secondary analysis filled this gap using the Health and Retirement Study\u2019s Core survey wave from 2014 and Exit wave data from 2016. These data are nationally-representative of OAs aged 50+. Each biennial wave introduces an experimental module to a random 10% of Core survey participants. One Core 2014 experimental module included self-report indicators assessing past MHSUPs, like depression and anxiety, using single items. Exit 2016 proxy-reported information about respondent deaths was used to create a decedent subsample. Descriptive statistics established MHSUP prevalence rates in OAs and their family. The self-report depression indicator was validated against the 8-item Center for Epidemiological Studies Depression Scale (CESD-8) at the \u22653, \u22654, and \u22655 cut points using \u03c72 analyses. The full sample\u2019s  average age was 68 years. Participants were mostly non-Hispanic (87.5%), White (72.8%), and female (59.7%). The decedent subsample (n=64) was bifurcated by hospice (54.7%) versus nonhospice (45.3%) utilization. Most participants in the full sample (63.9%), hospice decedent subsample (77.1%), and nonhospice decedent subsample (75.9%) endorsed at least one MHSUP. Depression and anxiety were the most common MHSUPs in each study sample. The CESD-8 was associated with the self-report depression indicator across all cut points (p<.001). Practitioners, policymakers, and researchers should consider the high prevalence rates of MHSUPs found in OAs and their families when designing programs, policies, and research."}
+{"text": "Scientific Reports 10.1038/s41598-020-59797-4, published online 20 February 2020Correction to: This Article contains an error in the Data Availability section.https://github.com/giorgiaauteri/LittleBrownBats_WNSSurvivorsVsNonsurvivors).\u201d\u201cGenomic data (raw reads) will be made available on GenBank (SRA accession PRJNA563655). All commands  and scripts  used for analyses are available on GitHub (should read:https://github.com/giorgiaauteri/LittleBrownBats_WNSSurvivorsVsNonsurvivors).\u201d\u201cGenomic data (raw reads) will be made available on GenBank (SRA accession PRJNA563455). All commands  and scripts  used for analyses are available on GitHub ("}
+{"text": "SPOP mutations , TMPRSS2-ERG fusions , and PTEN deletions/losses . Differentially expressed genes (DEGs) between AAs and EAs showed significant enrichment for prostate eQTL target genes (p = 8.09\u00d710\u221248). Enrichment of highly expressed DEGs for immune-related pathways was observed in AAs, and for PTEN/PI3K signaling in EAs. Nearly one-third of DEGs (31.3%) were long non-coding RNAs (DE-lncRNAs). The proportion of DE-lncRNAs with higher expression in AAs greatly exceeded that with lower expression in AAs (p = 1.2\u00d710\u2212125). Both ChIP-seq and RNA-seq data suggested a stronger regulatory role for AR signaling pathways in DE-lncRNAs vs. non-DE-lncRNAs. CaP-related oncogenic lncRNAs, such as PVT1, PCAT1 and PCAT10/CTBP1-AS, were found to be more highly expressed in AAs. We report substantial heterogeneity in the prostate tumor genome and transcriptome between EA and AA. These differences may be biological contributors to racial disparities in CaP incidence and outcomes.Men of predominantly African Ancestry (AA) have higher prostate cancer (CaP) incidence and worse survival than men of predominantly European Ancestry (EA). While socioeconomic factors drive this disparity, genomic factors may also contribute to differences in the incidence and mortality rates. To compare the prevalence of prostate tumor genomic alterations and transcriptomic profiles by patient genetic ancestry, we evaluated genomic profiles from The Cancer Genome Atlas (TCGA) CaP cohort (n = 498). Patient global and local genetic ancestry were estimated by computational algorithms using genotyping data; 414 (83.1%) were EA, 61 (12.2%) were AA, 11 (2.2%) were East Asian Ancestry (EAA), 10 (2.0%) were Native American (NA), and 2 (0.4%) were other ancestry. Genetic ancestry was highly concordant with self-identified race/ethnicity. Subsequent analyses were limited to 61 AA and 414 EA cases. Significant differences were observed by ancestry in the frequency of  SPOP mutations, TMPRSS2-ERG fusions, PTEN deletions/losses, immune signaling, and expression of non-coding RNAs were identified as potential contributors to prostate cancer racial disparities. Our comprehensive characterization of genetic ancestry and genomic/transcriptomic alterations would provide new insight into the biology of prostate cancer racial disparities in the AA population.Disparities in cancer defined by self-identified race or ethnicity have been a long-standing and persistent challenge. It is well documented that certain racial and ethnic populations in the US experience higher incidence of specific cancer types, higher incidence of aggressive cancers, and higher mortality. The Cancer Genome Atlas (TCGA) data resource contains multi-omic profiles and clinical annotations of large-scale samples, and therefore serves as an excellent resource for the evaluation of the relationship between genetic ancestry and genomic alterations in cancers. In this study, we performed a cancer type specific analysis of the influence of genetic ancestry on genomic alterations in prostate cancers\u2013a malignancy for which there are some of the largest cancer disparities by race and ethnicity in the US. We found that there is substantial heterogeneity in the genomic alterations and transcriptomic dysregulation occurring in men of African (AA) and European (EA) ancestry in the TCGA prostate cancer cohort.  Prostate cancer (CaP) is the second leading cause of cancer death in US males, accounting for an estimated 31,620 deaths in 2019 . While shttp://52.25.87.215/TCGAA/) [TP53 mutations and lower frequencies of genomic alterations affecting genes in the PI3K pathway than EA patients [The Cancer Genome Atlas (TCGA) contains data on multidimensional genomic profiles including gene expression, copy number alterations, mutations, transcript fusions, and epigenetic aberrations for 33 common adult cancers, including CaP . Given t/TCGAA/) , which ppatients . To furt\u221205) (\u221206) (Among the 498 patients with genotyping information (SNP Array) in the TCGA CaP cohort, 83.1% self-identified as White, 11.4% Black, 2.4% Asian, 0.2% American Indian/Alaska Natives. Race was unavailable for 2.8% of patients . In the \u221205) , and 13.5) (\u221206) . The dis5) (\u221206) .\u221203), while the SPOP subtype was more prevalent among AAs  (SPOP mutations differed significantly between EAs and AAs (p = 5.6\u00d710\u221203) , as estimated by the ABSOLUTE algorithm [TMPRSS2-ERG fusion was more frequently observed in EAs than AAs  (TMPRSS2-ERG breakpoint sites was similar between EA and AA men. Comparison of the weighted Genome Instability Index (wGII) [PTEN (10q23.31) was less frequently deleted/lost among AAs (p = 3.5\u00d710\u221203) (KMT2C and FOXA1 were significantly higher in AAs with high grade tumors compared to EAs (The distribution of the seven CaP molecular subtypes defined by the TCGA consortium  was comp7\u00d710\u221203) . Next, t7\u00d710\u221203) . We fit 7\u00d710\u221203) , but the6\u00d710\u221203) . SPOP mu% of EAs . SPOP mulgorithm . The tot4\u00d710\u221202) . The disx (wGII)  suggestex (wGII) . After c5\u00d710\u221203) . Finallyd to EAs .SPINK1, a gene defining a molecular subtype of CaP with more rapid progression in an at-risk, natural history radical prostatectomy sample [\u2212205).The Wallace et al [\u221217). The DEGs identified in TCGA tumor tissue were enriched with genes regulated by normal prostate tissue eQTLs  Project [\u221248) (\u22123) by ancestry showed greater enrichment with eGenes than those with lesser statistical significance. The identified DEGs did not show enrichment for genes whose expression levels were associated with CaP risk through a large-scale TWAS [et al [\u22124)   with RNA-seq profiling, 3,787 of 60,483 genes (including protein-coding and non-coding genes) were identified as differentially expressed among AAs and EAs using DESeq2 (FDR corrected p<0.1). Upon adjustment for age and Gleason score using a propensity score, 5,964 genes were differentially expressed between AAs and EAs (FDR corrected p<0.1), of which 3,015 were also differentially expressed in the unadjusted analysis . For exay sample , 42, wasct [\u221248) . Moreoveale TWAS   . Additio al [\u22124) . In conc.8\u00d710\u22123) .\u2212125) (\u221210)  (\u221227), with greater enrichment for eGenes among the lncRNAs than the protein coding genes   , 1,868 (11.7%) lncRNAs were identified as differentially expressed (DE-lncRNAs) between AAs and EAs by DESeq2 (FDR corrected p<0.1) . In cont\u2212125) . The DE-\u2212125) . The rem5) (\u221210) . The DE-)   . The enrR = 1.4) . HoweverR = 1.4) , suggest)  .PVT1, PCAT1, and PCAT10/CTBP1-AS have been previously studied and implicated in prostate tumorigenesis [PVT1, PCAT1, and PCAT10 were significantly overexpressed in prostate tumors relative to tumor-adjacent normal tissues (PCAT1 and PCAT10 were significantly enriched in a CaP-specific manner relative to enrichment in other cancer types (PVT1 was highly expressed across multiple cancer types without specificity to CaP. Both PCAT1 and PCAT10 have been reported to be AR-regulated [PCAT1 and PCAT10 in cell lines treated with synthetic androgen agonists (DHT and R1881)   and PCAT1  (PVT1 and PCAT1 in AA relative to EA patients.A PubMed search returned one or more related results only for 200 (10.7%) of the 1,868 DE-lncRNAs, suggesting that a clear majority of the DE-lncRNAs are unstudied , even amigenesis \u201370. Thes tissues . PCAT1 aer types . In contegulated , 68. Thid R1881) . Moreove)  . There w0\u00d710\u221213) . This exTo further understand how tumor molecular changes may contribute to CaP racial disparities, we comprehensively analyzed the multi-dimensional omics profiles of CaPs by genetic ancestry in TCGA. Our findings buttress existing evidence that patterns of genomic and transcriptomic alterations in prostate tumors differ by patient genetic ancestry \u201342. For PVT1, PCAT1, and PCAT10/CTBP1-AS, were further studied in the TCGA CaP dataset. PVT1 and PCAT1, located in the vicinity of the MYC oncogene, are encompassed by the 8q24.21 protein-coding gene desert\u2013a region harboring many cancer risk variants [PVT1/PCAT1 and their copy numbers. It suggests that variation in gene copy numbers may partially explain the higher expression of these two DE-lncRNAs in AA patients. Consistently, expression of PVT1 has been found to be higher in a sample of African Caribbean CaP patients [PVT1 promotes tumorigenesis by stabilizing the MYC protein and encoding microRNAs. Additionally, the promoter of the PVT1 gene regulates MYC transcription independently of PVT1 RNA through competition for shared enhancers [PCAT1 is regulated by the PRC2 and is highly expressed in a subset of aggressive CaP in which it has a predominantly repressive effect on gene expression [PCAT1 promotes CaP proliferation and growth by interacting with AR and LSD1 [PCAT1 is also a potential repressor of BRCA2, leading to downstream impairment of DNA damage repair [PCAT1 and PCAT10 may be regulated by AR signaling [Our interrogation of the lncRNA transcriptome revealed 1,868 DE-lncRNAs in CaPs between AAs and EAs. Interestingly, nearly 85% of these DE-lncRNAs had higher expression in AAs. Nearly half of the DE-lncRNAs were intergenic, mirroring results from CaP GWAS that identified risk loci in non-coding regions , 75. Thevariants , includivariants . We founpatients . As a wenhancers . PCAT1 ipression . It has e repair . Finallyignaling , 68, 78,de novo identification of AA population-specific recurrent genomic alterations. The sample size of the TCGA dataset is also insufficient to compare the frequency of uncommon genomic alterations between genetic ancestry groups. For example, although ERF was previously identified as recurrently mutated in the tumors of AAs [ERF mutations did not differ by genetic ancestry in the TCGA cohort. Our analyses adjusted for age and Gleason score, but residual confounding by additional clinicopathological factors is possible. Moreover, information regarding patient socioeconomic status is not available in TCGA, and thus we were unable to account for these important drivers of CaP disparities in our analyses. Racial minority patients are underrepresented in the TCGA CaP cohort and the proportion of AA men with high risk tumors is lower than that among the EA men. Additional genomic data resources designed to address disparities-related questions are still urgently needed to yield a more accurate assessment of the impact of African ancestry, and genetic ancestry generally, on CaP genomic alterations profiles.As we and others have reported before , 79, alts of AAs , the preTMPRSS2-ERG fusions, PTEN deletions/losses, and SPOP mutations differed between AAs and EAs. Few of the identified genomic aberrations with differential prevalence across genetic ancestry groups can be therapeutically targeted, and accordingly, future functional characterization is necessary to understand how these factors contribute to prostate tumorigenesis and cancer progression. Moreover, genomic profiling of tumors across racial/ethnic populations is paramount for fulfilling the potential of precision medicine.In summary, interrogation of the transcriptome in the TCGA CaP dataset revealed that dysregulation of the non-coding transcriptome and genes regulated by prostate eQTLs may contribute to CaP racial disparities. The tumor transcriptome among AAs showed relative enrichment for immune-related pathways. Frequencies of common genomic alterations in CaP including https://gdc.cancer.gov/, October 9, 2018). Affymetrix SNP Array 6.0 data in CEL format (n = 498) were downloaded from the TCGA Cancer Genomic Cloud (http://www.cancergenomicscloud.org/). Genotype-calling and subsequent estimation of genetic ancestry was performed as described before [The genomic profiles and clinical annotations for the TCGA CaP samples were retrieved from the Genomic Data Commons  or Fisher\u2019s exact test for categorical variables . For overall survival and disease-free survival analysis, the log-rank test was used to compare Kaplan-Meier survival curves and the Mantel-Haenszel method was used to estimate hazard ratios comparing AAs and EAs. All statistical tests were two-sided.Clinical factors were accounted for in all analyses comparing genetic characteristics between AA and EA patients. Age at diagnosis  and Gleason score , 29.8%; 7(4+3), 20.2%; > = 8, 41.0%) were comprehensively annotated  and theiThe methods used to estimate global and local genetic ancestry for the TCGA CaP sample have been described previously . BrieflyThe prevalence of the seven molecular subtypes previously identified in the TCGA CaP sample was compared between men of AA and EA ancestry . The subhttps://portal.gdc.cancer.gov/ using the Genomic Data Commons (GDC) Data Transfer Tool (gdc-client_v1.2.0_Ubuntu14.04_x64). Single nucleotide variants (SNVs) of somatic mutations generated by the MuTect2 pipeline were identified using the MAFs. All SNVs of somatic mutations that passed quality control were included in mutational signature analyses. Each mutation was classified into one of six base substitution categories  and the sequence context in which a mutation occurred  was also considered. Thus, the mutational spectrum of a tumor can be summarized as a vector of length 96, where each element represents the mutation count at one of the 96 mutated trinucleotides. A set of consensus mutational signatures identified from de novo extraction across 10,250 samples was published by the Wellcome Trust Sanger Institute (WTSI) Mutational Signature Framework [Mutation annotation files (MAFs) were downloaded from the GDC Data Portal  for 494 patients (including 61 AA and 410 EA). For each patient, a pair of segmentation files of tumor and matched control (if available) was selected for somatic copy number alteration analysis. If multiple aliquot barcodes existed for one patient, one single pair of tumor/matched control samples was selected with the following hierarchy: (1) sample type: for tumor tissues, primary > recurrent > metastatic (Sample Type code: 01 > 02 > 06); for normal control tissues, blood > solid (Sample Type code: 10 > 11); (2) molecular type of analyte for analysis: prefer D analytes (native DNA) over G, W, or X (whole-genome amplified); (3) order of sample portions: higher portion numbers were selected; and (4) order of plate: higher plate numbers were selected. Recurrent focal SCNAs (peak regions) were identified using GISTIC 2.0 (ftp://ftp.broadinstitute.org/pub/GISTIC2.0/) [Segmentation files for somatic copy number alteration (SCNA) analysis were obtained from the TCGA Cloud (TIC2.0/) . After eX\u2208n\u00d7mR denoting the recurrent focal SCNA profile across all tumors, where n is the number of tumors, m is the total number of recurrent focal SCNAs and the th element of the matrix ijX, X is determined following: ijc is the actual change in copy number for thj recurrent focal SCNA in thi tumor. We created 10,000 permutations of the matrix using the function permatswap in the R package vegan. The genomic disruption level of each tumor (row-wise sum of the matrix) as well as each recurrent focal SCNA (column-wise sum of the matrix) were maintained in the permutations by supplying the parameters: method = \"quasiswap\", fixedmar = \"both\", shuffle = \"both\" and mtype = \"prab\". Permutation was performed within amplifications and deletions separately. A test statistic for the association with AA patients relative to EA patients for each recurrent focal SCNA was generated using a logistic regression model for each permutated recurrent focal SCNA profile. This model used AA ancestry status  as the dependent variable and the binary alteration status as the independent variable, adjusting for the propensity score as a covariate. Subsequently, the significance  of the association between each recurrent focal SCNA and genetic ancestry was determined by examining the position of the observed test statistic among the distribution of all statistics generated from the permutated recurrent focal SCNA profiles. The Benjamini and Hochberg (BH) procedure [The relative frequency of focal SCNA events at each peak region was compared between AA and EA men using logistic regression adjusting for age and Gleason score. To control the overall level of genomic disruption when comparing the alteration frequencies for each SCNA event across ancestry groups, we performed a controlled permutation test in which both the fractions of the genome affected by each of the amplifications and deletions in each sample (column-wise) and the alteration frequency of each recurrent focal SCNA (row-wise) were maintained in the permuted data. We first created a binary matrix rocedure  was thenTo assess chromosomal instability, the weighted Genome Instability Index (wGII) was calculated using segmentation files . First, https://portal.gdc.cancer.gov/). In the GDC RNA-seq analysis pipeline, reads were aligned to the GRCh38 reference genome, and then gene level expression was measured from HT-Seq raw read count using GENCODE v22 for gene annotation. For tumor expression analyses, one single aliquot barcode was selected for each patient with the following selection hierarchy: (1) sample type: primary > recurrent > metastatic (Sample Type code: 01 > 02 > 06); (2) molecular type of analyte: prefer R analytes (RNA) over T ; (3) order of sample portions: higher portion numbers were selected; and (4) order of plate: higher plate numbers were selected. Differential gene expression analysis between tumor samples from AA and EA patients was performed using the DESeq2 package [et al [Gene-level RNA-Seq data were downloaded using the Genomic Data Commons (GDC) Data Transfer Tool (gdc-client_v1.2.0_Ubuntu14.04_x64) from the GDC Data Portal . GWAS-related genes were defined as those located within 1Mb of GWAS SNPs. GWAS SNPs associated with CaP risk were retrieved from the NHGRI-EBI GWAS Catalog [http://www.biocarta.com/) and the CaP disparity-related gene sets previously reported by Wallace et al [https://genepattern.broadinstitute.org/). A gene list ranked by the Wald statistic calculated by DESeq2 was used. Visualization of significantly enriched gene sets was performed using Cytoscape (v3.5) [Genes regulated by normal prostate tissue eQTLs (eGenes) were identified by the Genotype-Tissue Expression (GTEx) Project . The lis Catalog . TWAS-re Catalog . Enrichmce et al . GSEA wae (v3.5) .In an effort to classify lncRNA genes and reveal their potential biological roles, we determined their genomic distribution patterns relative to protein-coding loci. We first defined two classes of lncRNA genes, intergenic and genic, according to whether their boundaries overlapped with any protein-coding genes. The set of genic lncRNAs was further classified into three locus biotypes. First, we identified lncRNAs transcribed in an antisense direction and designated them as the \u201cantisense\u201d biotype. For lncRNAs transcribed in the same direction as the nearest gene, they could overlap protein-coding genes, sharing exonic regions (the \u201cexonic\u201d biotype) or intronic regions (the \u201cintronic\u201d biotype). LncRNAs were evaluated at a transcript level. In cases where a lncRNA gene had multiple transcripts that could be classified into different types, the hierarchy of types used to classify lncRNAs was: exonic > intronic > antisense > intergenic.t-test. Annotation of the genomic position also facilitates the functional interpretation of lncRNAs. Applying ChromHMM [et al [et al [et al, among differentially expressed and non-differentially expressed lncRNAs was assessed by Fisher\u2019s Exact test. The Benjamini and Hochberg (BH) procedure [The subcellular localization of lncRNAs can provide insight into their molecular function and we therefore compared the relative concentration index (RCI) between lncRNAs differentially expressed and non-differentially expressed with respect to genetic ancestry. RCI values were downloaded from the lncATLAS database . A lowerChromHMM , Valdes-M [et al  partitiol [et al  previousrocedure  was applhttp://cistrome.dfci.harvard.edu/NR_Cistrome/). Wig profiles (assembly GRCh37/hg19) were also downloaded. The AR binding signal across lncRNAs of interest was visualized using the UCSC genome browser. The aggregation plot of ChIP-seq signals across transcriptional start sites (TSS) of differentially-expressed and non-differentially expressed lncRNAs was generated by agplus [AR ChIP\u2013seq data performed on the VCaP and LNCaP CaP cell lines from published datasets were downloaded from the GEO (GSE55064) and Nuclear Receptor Cistrome , a method adapted from Gene Set Enrichment Analysis (GSEA). Tumors within TCGA were ordered according to the expression level of a specific lncRNA while a sample set was defined by a specific cancer type. Enrichment scores (ES) and normalized enrichment scores (NES) were calculated in the same way as in GSEA. Thirty-three SSEA analyses were performed for every lncRNA comparing each cancer type to the others within TCGA. Finally, we ranked genes within each cancer type by normalized enrichment score (NES) and assigned fractional ranks  to assess cancer type specificity.S1 Fig(A) Censoring rates of OS, DSS, DFI, and PFI. (B) Forest plot showing the association between African ancestry and prostate cancer survival outcomes. Dots and horizontal lines represent HR values and their 95% CIs, respectively. Arrows indicate where the CI values extend outside the range indicated. P-values were calculated from the Wald test of the coefficient for genetic ancestry in the Cox PH models. (C-F) Genomic alterations associated with (C) OS, (D) DSS, (E) DFI, and (F) PFI. The bar plots show the significance (y axis) for each genetic event of somatic mutations, transcript fusions, recurrent focal amplifications, and recurrent focal deletions. Orange and green bars represent the genetic events that had significantly higher or lower alteration frequencies among patients with worse survival outcomes, respectively. Genomic alterations with non-significant results are colored in gray.(TIF)Click here for additional data file.S2 FigSPOP, KMT2C, and FOXA1 stratified by genetic ancestry. (C) Frequency of TMPRSS2-ERG fusion stratified by genetic ancestry in high risk prostate cancer patients. (D) Frequency of 2q22.1 (SPOPL), 10q23.31 (PTEN), 6q14.3 (ZNF292) and 21q22.3 (TMPRSS2) copy number alterations stratified by genetic ancestry. (E) Gene sets identified through gene set enrichment analysis that were significantly activated  and repressed  in tumors of AA men (FDR corrected p<0.1 through permutation test). Candidate gene sets were identified from the BioCarta pathway database and Wallace et al. Many gene sets pertaining to immune-related signaling were activated in AA tumors. (F) Enrichment plots of the Wallace Prostate Cancer Race (Up), T Cytotoxic Cell Surface Molecules, Wallace Prostate Cancer Race (Down), and CARM1 and Regulation of the Estrogen Receptor gene sets.(A) Comparison of genomic alterations by genetic ancestry. The bar plots show the significance (y axis) for each genetic event of somatic mutations, transcript fusions, recurrent focal amplifications, and recurrent focal deletions. Orange and green bars represent the genetic events with alteration frequencies that were significantly higher or lower in patients of AA ancestry, respectively. Genomic alterations with non-significant results are colored in gray. (B) Mutation frequency of (TIF)Click here for additional data file.S3 FigClinical and genomic data were retrieved for 498 patients. EIGENSTRAT and a k-nearest neighbors (k-NN) classifier were applied to classify individuals as: European American (EA), African American (AA), East Asian American (EAA), Native American (NA), or other ancestry (OA). Genomic and transcriptomic analyses were limited to 475 men classified as EA or AA who had data available for the analysis of interest.(TIF)Click here for additional data file.S1 Table(XLSX)Click here for additional data file.S2 Table(XLSX)Click here for additional data file.S3 Table(XLSX)Click here for additional data file.S4 Table(XLSX)Click here for additional data file.S5 Table(XLSX)Click here for additional data file.S6 Table(XLSX)Click here for additional data file.S7 Table(XLSX)Click here for additional data file.S8 Table(XLSX)Click here for additional data file.S9 Table(XLSX)Click here for additional data file.S10 Table(XLSX)Click here for additional data file.S11 Table(XLSX)Click here for additional data file.S12 Table(XLSX)Click here for additional data file.S13 Table(XLSX)Click here for additional data file."}
+{"text": "Pteris vittata rhizosphere soils are reported. The following phyla were recorded in arsenic-rich soils: Actinobacteria (59%), Proteobacteria (26%), Chloroflexi (17%), and Acidobacteria (9%). Actinobacteria (45%), Proteobacteria (22%), Chloroflexi (10%), and Acidobacteria (11%) were in natural-mineral soils.Data on the 16S rRNA gene amplicon sequences from  Pteris vittata, which is also known as Chinese brake, can accumulate large amounts of arsenic (As) in its above-ground biomass, up to 27,000\u2009mg/kg  in Perak, Malaysia , and three samples were from Penang, Malaysia . Soil tightly attached to the roots of P. vittata was removed using sterile forceps . Locus-specific sequence primers containing overhang adapters were used to amplify a specific segment (V3 to V4) of the bacterial 16S rRNA gene (https://www.drive5.com/usearch) (de novo clustering process with a 97% similarity threshold. The rare OTUs with <2 reads (referred to as doubletons) are often considered spurious and were removed from further analysis. Once the OTUs were created and filtered, PyNAST  extraction kit  according to the manufacturer's instructions. The purity of the extracted DNA was examined using a 1% Tris-acetate-EDTA (TAE) agarose gel . The 16SRNA gene . With thusearch) . Using Ual phyla .PRJNA882671 (The amplicon data from this work have been deposited in the Sequence Read Archive (SRA) of the National Center for Biotechnology Information (NCBI) with BioProject accession number NA882671 ."}
+{"text": "A 3-year-old female child was brought to the outpatient department with 1.5\u2009months of progressive gait difficulty and neck pain. Physical examination showed grade 3/5 strength of the upper and lower extremities and hyperactive deep tendon reflexes. Laboratory tests exhibited a normal white cell count, an increased erythrocyte sedimentation rate , an elevated C-reactive protein level , and a positive interferon-gamma release assay (T-spot test). Lateral cervical plain radiograph showed an abnormal cervical alignment . ComputeThe imaging examinations and laboratory tests supported the diagnosis of cervical tuberculosis (TB). The child underwent surgical treatment with one-stage posterior internal fixation followed by anterior-approach debridement and bone grafting. Histopathological examination showed extensive granulomata mixed with caseous necrosis. The child\u2019s symptoms significantly improved after surgery . The hisUpper cervical TB in young children is rarely reported. Without timely and proper treatment, affected individuals may suffer from progressive neurological deficits and disability."}
+{"text": "Endoscopic submucosal dissection (ESD) has become the gold standard for superficial colorectal neoplasia resection. As recently reported, diagnostic ESD is also feasible and safe for colorectal lesions with a focal deep invasive pattern of less than 15 mmWe report here the case of a 73-year-old patient with a 12-mm pseudodepressed non-granular laterally spreading tumor (LST) in the left colon, with a 6-mm Kudo Vn, Sano 3b demarcated area highly suspicious of deep invasion . After Diagnostic endoscopic submucosal dissection of the non-granular laterally spreading tumor with focal degeneration area.Video 1The final histology was an adenocarcinoma with 1500-micron submucosal invasion without lymphovascular invasion or budding. In view of the low risk of lymph node recurrence, monitoring was proposedEndoscopy_UCTN_Code_TTT_1AQ_2AC"}
+{"text": "Background: Carbapenem-resistant Acinetobacter baumannii (CRAB) has emerged as a major cause of bloodstream infection among hospitalized patients in low- and middle-income countries (LMICs). CRAB infections can be difficult to treat and are devastating in neonates . CRAB outbreaks are hypothesized to arise from reservoirs in the hospital environment, but outbreak investigations in LMICs seldom incorporate whole-genome sequencing (WGS). Methods: WGS (Illumina NextSeq) was performed at the National Institute for Communicable Diseases (South Africa) on 43 preserved A. baumannii isolates from a 530-bed referral hospital in Gaborone, Botswana, from March 2021\u2013August 2022. This included 23 blood-culture isolates from 21 unique patients (aged 2 days\u201369 years) and 20 environmental isolates collected at the 36-bed neonatal unit in April\u2013June 2021. Infections were considered healthcare-associated if the culture was obtained >72 hours after hospital arrival (or sooner in inborn infants). Blood cultures were incubated using an automated system  and were identified using manual methods. Environmental isolates were identified using selective or differential chromogenic media (CHROMagarTM). Taxonomic assignment, multilocus sequence typing (MLST), antimicrobial resistance gene identification, and phylogenetic analyses were performed using publicly accessible analysis pipelines. Single-nucleotide polymorphism (SNP) matrices were used to assess clonal lineage. Results: All 23 blood isolates and 5 (25%) of 20 environmental isolates were confirmed as A. baumannii; thus, 28 A. baumannii isolates were included in the phylogenetic analysis. MLST revealed that 22 (79%) of 28 isolates were sequence type 1 (ST1), including all 19 healthcare-associated blood isolates and 3 (60%) of 5 environmental isolates. Genes encoding for carbapenemases  and biocide resistance (qacE) were present in all 22 ST1 isolates; colistin resistance genes were not identified. Phylogenetic analysis of the ST1 clade demonstrated spatial clustering by hospital unit. Related isolates spanned wide ranges in time (>1 year), suggesting ongoing transmission from environmental sources . An exclusively neonatal clade (0\u20132 SNPs) containing all 8 neonatal blood isolates was closely associated with 3 environmental isolates from the neonatal unit: a sink drain, bed rail, and a healthcare worker\u2019s hand. Conclusions: WGS analysis of clinical and environmental A. baumannii revealed the presence of unit-specific CRAB clones, with evidence of ongoing transmission likely driven by persistent environmental reservoirs. This research highlights the potential of WGS to detect hospital outbreaks and reaffirms the importance of environmental sampling to identify and remediate reservoirs  and vehicles  within the healthcare environment.Disclosures: None"}
+{"text": "Implementing effective antimicrobial stewardship interventions is an important component of antimicrobial stewardship programs. Recently, stewardship research has shown that clinician characteristics may have an impact on antimicrobial stewardship intervention methods and acceptance rates.A multisite health system antimicrobial stewardship prospective audit and feedback program interventions performed by stewardship staff using a standardized electronic medical record (EMR) tool were compared by stewardship clinician profession  from 7/1/2017 to 6/30/2022. Outcomes assessed were intervention rates, communication methods, and intervention acceptance by patient age and intensive care unit (ICU) status of patient. Generalized estimating equations utilizing logistic regression were used to assess for associations between staff. Associations were assessed both univariately and after adjusting for other factors.Of 69,503 prospective audit and feedback EMR based rules, there were 14,699 rules associated with an intervention. The majority of rules were reviewed by pharmacists (90.7%) followed by physician (9.2%) and APP (< 1%). Of 9,034 interventions with an outcome documented, 7326 (85.5%) pharmacist interventions were accepted and 360 (77.3%) physician interventions were accepted (adjusted p=0.047). \u202fPharmacists intervened by direct action  in 6.6% of interventions; whereas, physicians did so rarely (0.4%). Pharmacists were more likely to use synchronous communication than physicians in the adjusted model . Patients in the ICU had a significantly lower intervention acceptance rate .*% are reported as row % **Multivariable model was also adjusted for day of week and time of day APP-Advanced practice provider; ICU-intensive care unit*% are reported as row % **Multivariable model was also adjusted for day of week and time of day APP-Advanced practice provider; ICU-intensive care unitAntimicrobial stewardship pharmacists and physicians are both effective at prospective audit and feedback but used different intervention styles. Advanced practice providers were vastly underrepresented. Patients in the ICU may benefit from tailored ASP efforts.Sara Ausman, PharmD, Gilead: Honoraria Caitlin Brown, PharmD, Alexion: Grant/Research Support|Trevena: Advisor/Consultant Christina G. Rivera (O'Connor), Pharm.D, Gilead Sciences: Advisor/Consultant|Gilead Sciences: Board Member|Gilead Sciences: Grant/Research Support|Gilead Sciences: Honoraria"}
+{"text": "Seven hit compounds were further examined via cell-based antiviral and intracellular protease assays, in which two compounds (NSC116640 and NSC332670) strongly inhibited FMDV, with EC50 values at the micromolar level of 2.88 \u00b5M (SI = 73.15) and 5.92 \u00b5M (SI = 11.11), respectively. These compounds could inactivate extracellular virus directly in a virucidal assay by reducing 1.00 to 2.27 log TCID50 of the viral titers in 0\u201360 min. In addition, the time-of-addition assay revealed that NSC116640 inhibited FMDV at the early stage of infection (0\u20138 h), while NSC332670 diminished virus titers when added simultaneously at infection (0 h). Both compounds showed good FMDV 3Cpro inhibition with IC50 values of 10.85 \u00b5M (NSC116640) and 4.21 \u00b5M (NSC332670). The molecular docking of the compounds on FMDV 3Cpro showed their specific interactions with amino acids in the catalytic triad of FMDV 3Cpro. Both preferentially reacted with enzymes and proteases in physicochemical and ADME analysis studies. The results revealed two novel small molecules with antiviral activities against FMDV and probably related picornaviruses.Foot-and-mouth disease (FMD) is a highly contagious disease in cloven-hoofed animals, caused by the foot-and-mouth disease virus (FMDV). It is endemic in Asia and Africa but spreads sporadically throughout the world, resulting in significant losses in the livestock industry. Effective anti-FMDV therapeutics could be a supportive control strategy. Herein, we utilized computer-aided, structure-based virtual screening to filter lead compounds from the National Cancer Institute (NCI) diversity and mechanical libraries using FMDV 3C protease (3C Aphthovirus genus within the Picornaviridae family .While NSC116640 and NSC332670 exhibited promising anti-FMDV potential, it is important to note that these findings stem from an in vitro study using optimal concentrations of both viruses and compounds. Such carefully selected concentrations were utilized to facilitate a clear observation of the inhibitory effects. However, the micromolar concentrations at which these compounds manifest antiviral activity may not necessarily translate to effective dosages when administered to animals. In addition, the predictive interaction between the compounds and 3CSaccharomyces cerevisiae and Schizosaccharomyces pombe [NSC79451 (2-hydroxy-N-(2-methyl-5-nitrophenyl)-3-nitrobenzamide) and NSC681744 (N-[6-[benzoyl-[cyano(phenyl)methyl]amino]hexyl]-N-[cyano(phenyl)methyl]benzamide) are diverse chemical compounds in the mechanical diversity sets of the NCI library. Both NSC79451 and NSC681744 were investigated using high-throughput yeast halo assays; however, none of them could inhibit es pombe . Additioes pombe .pro, which could inhibit FMDV infection in vitro. NSC116640 and NSC332670 presented promising results as anti-FMDV candidates based on our biological assay and in silico computational data, which could pave the way for further antiviral development.Conclusively, FMD is a picornavirus that infects cloven-hoof animals and causes severe losses in livestock production worldwide. The disease widely spreads in endemic areas where vaccination is implemented. Effective antiviral agents for FMD control are needed to minimize the shed virus and protect the infected animals from clinical signs. This study discovered two novel chemical compounds targeting FMDV 3C"}
+{"text": "Geographically associated Antimicrobial Stewardship Programs (ASPs) may benefit from working in collaboration. Independent ASPs can coordinate efforts with other programs to address high-yield targets for quality improvement and share in experience and knowledge to meet both local goals and fulfill national regulatory standards.In 2016 ASPs from six neighboring urban/rural VA Medical Centers serving 800K veterans agreed to target fluoroquinolone (FQ) use with shared messaging on preferred indications and reducing avoidable FQ toxicity. All sites had an established ASP and dedicated ASP Champions; two sites lacked FT ID trained MD and ASP FTE allocation varied per site. Sites pooled antibiograms 2018-22 and national metrics for FQ use in outpatient (OP) 2017-22, inpatient (IP) 2020-22 and the pandemic period (PP). Electronic platforms sustained communication and regular teleconferences facilitated planning and coordination. Local decisions determined interventions to target based on resources and patterns of use. FQ-targeted prospective audit/feedback, peer-peer reports and modified EMR- order entry were supplemented with shared educational materials. Messaging with reinforced with bi-annual regional events used targeted email campaigns and teleconferenced talks, including throughout the PP.Over six years FQ total OP fills sustainably fell 13.6K to 4.3K with annual pharmacy visits 25K (1.5-7K site/year) and DOT/1,000 unique OP visits fell by nearly 70% in the same period across all sites urban/rural (P=.01). In the 522 (28-175) acute, 594 (50-275) LTC beds FQs fell 22.3 to 10.8 DOT/1,000 patient days by 2022. Regional-trends did not increase in PP, but decline slowed. In the region E. coli resistance was unchanged but in sites reporting FQs, suscepblity improved for isolates of MRSA (n 1294) and MSSA (n 1931); with sustained gains in the PP.Despite differences in hospital size, settings and resources, sustained outcomes can be achieved through efforts developed with regional partners. Coordinated regional stewardship initiatives facilitated by shared metrics are effective, support local efforts, allow for program autonomy and lessen the overall workload through shared experience.All Authors: No reported disclosures"}
+{"text": "Fusarium isolates cultured from diseased and healthy citrus trees were sequenced, assembled, and annotated. Isolate species identification was confirmed using single marker  phylogenetic assessment. Studies of the traits and genotypes of plant-associated isolates are important to understanding the fungal contribution to phytobiomes of citrus.The genomes of eighteen  Citrus sp. scions grafted onto Citrus aurantium and \u00d7 Citroncirus species rootstocks. California trees had low Huanglongbing (HLB) disease pressure; Florida trees had high HLB pressure. Fungal taxonomy was initially assigned by internal transcribed spacer (ITS) sequencing  and Florida  citrus trees. Samples were taken from quencing  and confFusarium oxysporum CF00159 and Fusarium falciforme CF00175) were additionally sequenced with Oxford Nanopore Technologies (ONT) (Strains were grown on potato dextrose agar (PDA) for 1 week, collected by scraping fungal mycelial tissue from the medium, and frozen in liquid nitrogen. High-molecular-weight DNA was extracted from fungal tissue based on reference es (ONT)  at MiGS.es (ONT) .Genome assembly of Illumina reads was performed using AAFTF \u20138 for pe\u201315\u2013MG183712) sequences of each genome assembly for species identification (\u2013FUSARIUM-ID v 3.0 (Fusarium species (BLASTN was used to capture translation elongation factor 1 (TEF1) (fication \u201335. A muID v 3.0  was creaID v 3.0 , and theID v 3.0 . The 18  species , and thePRJNA855134. The individual SRA read accession numbers and genome accession numbers for each isolate are listed in This whole-genome project has been deposited at DDBJ/ENA/GenBank under the BioProject accession no."}
+{"text": "It would be highly advantageous to reformatselection outputs to \u201done-bead-one-compound\u201d solid-phaselibraries, unlocking activity-based and cellular screening capabilities.Here, we describe hydrogel-encapsulated magnetic beads that enablesuch a transformation. Bulk emulsion polymerization of polyacrylamidehydrogel shells around magnetic microbeads yielded uniform particles(7 \u00b1 2 \u03bcm diameter) that are compatible with diverse in-gelfunctionalization  and transformationsassociated with DNA-encoded library synthesis . In a case study of reformatting mRNA display libraries,transcription from DNA-templated magnetic beads encapsulated in gelparticles colocalized both RNA synthesis via hybridization with copolymerizedcomplementary DNA and translation via puromycin labeling. Two controlepitope templates  were successfully enriched  from an NNK Bead-templatedgel particles via emulsion polymerizationcan scalably transform display-type encoded libraries into one-bead-one-compoundlibraries suitable for functional screening. These \u201dbeyond ruleof 5\u201d (bRo5)6 libraries are proving highly productivefor discovering ligands of transcription factors, protein\u2013proteininteractions, and other difficult targets.10 However, encoded library analysisis almost exclusively limited to binding affinity selections againstthe purified target and achieving cellular activity starting fromaffinity selection hits frequently requires intensive additional roundsof optimization.Combinatorial synthesis offers unprecedentedaccess to novel, expansivechemical spaces. Encoded combinatorial library technologies, suchas DNA-encoded libraries (DEL)12 yield combinatorial librariesthat are spatially isolated, clonal populations of a single librarymember that can be individually assayed. The OBOC principle was appliedto DEL technology,13 and the resultinglibraries could be functionally screened using biophysical, biochemical,or cellular assays.16 For biophysical and biochemical screening, microfluidiccompartmentalization was critical for scalably isolating single librarybeads for activity assay; however, there are high entry barriers toimplementing these approaches.Implementation of solid-phase tactics for librarysynthesis hasproven effective for expanding into other functional screening modalities.\u201cOne-bead-one-compound\u201d (OBOC) split-and-pool synthesisprocedures18 Water-in-oil-in-water (w/o/w) emulsions similarly dodge the needfor microfluidic sorting by enabling emulsion screening via commerciallyavailable FACS instruments, which has found use in enzyme engineering,high-throughput enzymology, and other important applications.21 Droplets themselves are difficult to manipulate and can be replacedwith hydrogels,22 which exhibit solution-and solid-like properties, a key property that spurred their use insingle-cell sequencing workflows,23 bacterialmicrocultures,24 directed evolution,22 and other applications25 that require the delivery and confinement of reagents in small volumes.These properties collectively suggested that hydrogel particles couldbe highly useful for expanding solid-phase OBOC encoded library synthesiscapabilities.Significant recent technologydevelopment efforts have aimed toreduce these barriers. For example, particle-templated emulsions eliminatethe need for local droplet microfluidics capabilities.28 Templated library preparation via in vitro transcription/translation(IVTT) was particularly advantageous because RNA transcripts and translatedpeptides localized to their host particle, generating monoclonal beadsfor screening without further emulsification or other partitioning.We applied this approach to library screening using fluorescence-activatedcell sorting (FACS) instrumentation, successfully isolating two controlepitopes translated using the conventional 20 biogenic amino acidsand library members translated from a recoded genetic table containingthe unnatural amino acid azidolysine. This new particle format introducesimportant handling advantages that will enable encoded library synthesisautomation while also unlocking functional screening capabilitiesby way of a polyvalent encoded library member display.Here, we describe a versatile hydrogel-based particlethat supportsboth chemical and biochemical synthesis. Particle preparation viabulk magnetic microbead-templated emulsion polymerization is straightforward,scales well, and yields unusually uniform products. The hydrogel layercan display diverse chemical functionality commonly used in both conventionalsplit-and-pool combinatorial chemical synthesis or templated enzymaticbiosynthesis.29 yieldedP1-functionalized gel particles , and all bead sizes yielded populations readily gated by forwardand side scatter in flow cytometry for comparison of hydrogel fluorescenceupon probing .Hydrogel particles were preparedvia emulsification of an acrylamide:bis-acrylamidemonomer solution and magnetic microbeads. Magnetic beads were suspendedin a monomer solution and combined with catalyst (TEMED)-containingoil, the suspension was emulsified using a bead mill homogenizer andpolymerized on ice, and magnetic-bead-containing particles were isolatedon a magnet 1A. Copolarticles 1B, whicharticles 1C. Over articles 1D. Flow articles 1E. Hydro5 to 108 particles in microtube-compatible reactions and using standardlaboratory equipment. Magnetic isolation post curing ensured thatonly microbead-containing emulsion droplets were retained, the mostlikely factor enhancing particle uniformity. The gel layer combinedwith magnetic handling also proved to be very useful for rapid andpotentially automatable reagent exchange and bead washing. We chosepolyacrylamide specifically because it is easily synthesized and inhibitsaggregation and adherence to tube walls. Polyacrylamide is also inertand thus compatible with a range of different chemical and biochemicalreactivities.Microbead-templated emulsion polymerization yieldedsurprisinglyuniform particles that did not require microfluidics for either preparationor analysis, and the particles exhibited superb handling and biocompatibility.The particle preparation scale ranged from 10Figure S3), alkynes using propargyl methacrylate(PMA), or primary amines using 3-(aminopropyl)methacrylamide (APMA).Particle functionalization was detected by flow cytometry with theaddition of the appropriate fluorescent-dye-labeled substrates, includingcomplementary oligonucleotide, double-stranded oligonucleotide ligationmodule, azide, or succinimidyl ester, respectively. Depending on reactivity,the relative fluorescence increased between 5- and 25-fold comparedto naive gel particles. Hybridization and amine acylation resultedin the largest shift; all functionalization reactions yielded baselineseparation of product and starting material by flow cytometry. Hydrogelswith escalating amine loading capacity were prepared by copolymerizingincreasing concentrations of APMA (0.02\u201320 mM); acylation withFAM-OSu resulted in log-linear increases in gel particle fluorescenceover the 4 order of magnitude serial dilution . Here, we show that particle loading capacityis quantitative over 4 orders of magnitude. At the highest site density(20 mM), each median diameter (7 \u03bcm dia) particle harbors \u223c4fmol amine sites. If this gel particle were used as a vehicle to dosea microfluidic droplet (40 pL),30 the resultingmaximum concentration would be 100 \u03bcM. For in-gel assays,31 the same 100 \u03bcM concentration is on thelower end of the [APMA] particles tested. Increasing [APMA] > 20mMinhibited emulsion formation and [oligonucleotide] > 20 \u03bcMwouldbe both impractical and unnecessary for routine biochemical transformations.Hydrogels were diversely functionalized by includingsubstoichiometricmethacrylamide-modified additives in the acrylamide:bis-acrylamidemonomer solution for copolymerization. Incorporation of the synthetichairpin headpiece DNA (HDNA) and subsequent proof-of-concept enzymaticoligonucleotide ligation reaction demonstrate the viability of standardDEL synthesis workflows using these particles.32 DNA-templated 2.8 \u03bcm magnetic beads weremixed with untemplated, dye-labeled  beadsas negative controls  fused to a HiBiT luciferase complementation sequenceop codon 4A. Folloop codon 4B; only op codon 4C. Transop codon 4D. In-gecking P4 4E.Orthogonal detection of multiple epitope tags demonstratedsuccessfultranslation of gel-immobilized RNAs and subsequent immobilizationof the translation product in the gel particle. Immunofluorescencemeasurements confirmed the presence of each epitope by specific epitopelabeling, also demonstrating a proof-of-concept for conducting in-gelprotein binding assays. HiBiT detection quantitatively confirmed thepresence of captured peptide with high sensitivity. Because the HiBiTtag is C-terminal, quantitation reflects the minimum concentrationof translated peptide retained in the hydrogel particle; N-terminaltruncates or other translation byproducts would not be detected. In-gelpeptide capture yields were sufficient for robust detection in bothimmunofluorescence and HiBiT assays, but they fell well short of theRNA capture oligonucleotide P1 concentration (50 \u03bcM), whichis the limiting reagent for translation product capture; we wouldexpect a 50 \u03bcM maximum concentration if all capture sites wereoccupied by translation product.5) fused to theHiBiT tag was used to template magnetic beads via limiting dilutionemulsion PCR (emPCR). Single-bead qPCR analysis36 of the templated library beads indicated 42000 DNA templatesper bead with \u223c30% of beads templated . DNA-templated beads were next encapsulated inhydrogels copolymerized with oligonucleotide P1. Library beads (5\u00d7 106) were combined with control epitope beads (1%HA or V5), translated in the presence of puromycin oligonucleotideP4, probed with dye-labeled antibodies ,and sorted by FACS into four populations  degenerate codons  similar to those of theall-natural peptide epitopes previously tested  was used to template magnetic beads via emPCR, resultingin particles with an average of 2 \u00d7 104 template moleculesper bead. The NNT degeneracy excludes GAC codons in the NNU5 transcripts. After gel encapsulation, we combined NNT5 library beads (3 \u00d7 106) with AzK-templating beads(\u223c0.1% of beads) and performed in-gel transcription/translationusing the \u0394Gln/AzK engineered IVTT mix in the presence of P4.After translation, we performed in-gel CuAAC on the entire librarymixture with 647AF-alkyne to label AzK-presenting particles and thensorted the 647AF-high population (\u223c2%) via FACS. After sequencingand decoding, we observed an \u223c6-fold enrichment of GAC-templatingsequences in the sorted population compared to the starting librarypool (Table S2).We also sought to establish the compatibility oflibrary-scalesynthesis and sorting with engineered genetic codes. Beads were functionalizedwith a DNA template that encodes a single GAC codon (native Gln codon)fused with the HiBiT tag and encapsulated in P1-functionalized gels.An engineered IVTT mix, which lacked glutamine and GlnRS and containednoncanonical amino acid azidolysine (AzK) charged onto CUG-tRNAy tested 4E.35 NexThese experimentsestablished the feasibility of FACS-based high-throughputscreening of gel particle libraries. Using standard PCR protocolsfor library generation, magnetic beads templated with several controlepitope-coding sequences and doped into a conventional library asbackground were successfully sorted as hits and exhibited substantialenrichment compared to library input. Importantly, coupled transcriptionand translation of the mixed library and epitope particles withoutadditional compartmentalization yielded sufficiently pure in-gel epitopedisplay for immunofluorescence-based screening. The translation products,like the RNA transcripts, are concentrated in the gel matrix of theDNA-templated magnetic bead, proving that all enzymatic steps areproximity driven.41 PEG diacrylate-derived polymers resemble supports for synthesisof hydrophobic peptides, and polymers of N-isopropylacrylamideexhibit interesting thermally induced phase transitions.42Magnetic core hydrogel particles support diversefunctionalizationvia copolymerization and subsequent chemical and biochemical proceduresanalogous to solid-phase synthesis. Particle preparation involvescommercially available chemicals, materials, and laboratory apparatus,and particle analysis using widely available flow cytometry equipmentwas sufficient for assay development and screening. Radical-mediatedpolymerization is mild and amenable to incorporating a variety ofacryloyl and methacryloyl moieties. We demonstrated some of the mostcommon functionalities deployed in chemical library synthesis, butthe scope of available materials and applications is vast. For example,methacrylated gelatins and collagens promote cellular adhesion,23The magnetic hydrogel particles also alleviatesolid support handlingissues, introducing important advantages for automating encoded librarysynthesis and screening. Split-and-pool tactics underpin the currenton-DNA DEL synthesis workflow, which is readily automated using routineliquid handling of interleaved aqueous building block coupling andethanol precipitation steps. Solid-phase split-and-pool synthesis,however, is notoriously fraught; the particles aggregate and suspensionhandling is difficult due to settling and clogging. Magnetic particlemanipulation, like robotic liquid handling, is established automationscience and is routinely employed in genomic analysis workflows. Additionally,hydrogel particle deformability and freedom from aggregation couldalso be highly advantageous for microfluidic automation, such as droplet-scalesample preparation and screening.While prototypingthe more complex mRNA display encoded libraryparadigm, we discovered that gel particles uniquely enable proximity-drivenbiochemical synthesis. Products of transcription from bead-bound DNAtemplates and subsequent translation of these gel-bound RNA transcriptsare synthesized and remain concentrated only in the origin particle.High effective concentration of both DNA and RNA species in concertwith the greatly reduced diffusion coefficient afforded by in-gelRNA hybridization and puromycin trapping were sufficient; no additionalcompartmentalization was necessary.12 Also, like OBOC technology, it is not possibleto purify the bead-bound synthesis products for screening. Thus, itmay be advantageous to contemplate quality control (QC) bead strategies,wherein larger and higher-capacity QC beads are doped into the librarysynthesis, then harvested by filtration and individually analyzedto match DNA sequences with corresponding translated peptide massspectra, analogous to our solid-phase OBOC DEL QC strategy.13The proximity-driven reformattingof selection-type mRNA displaylibraries to bead libraries introduces well-known advantages and disadvantagesof the OBOC approach. The resulting monoclonal particles are analogousto OBOC-type library beads, unlocking the possibility of functionalassays. Functional screening could be advantageous for mRNA displayand other enzymatically synthesized or templated libraries. Like DEL,affinity selection is the exclusive mode of ligand discovery; targetbinding is assumed to be a proxy for biological activity, which canonly be determined after synthesis and evaluation in a formal activityassay. Unlike DEL hits, synthesis of such library members  can be intensive; thus, upfront functionalscreening would be highly useful for hit triaging alone. The possibilityof directly evaluating more complex cellular activity is also highlydesirable and uniquely the purview of the OBOC approach.6 hit finding requires higher concentrations. However, cyclic peptidesand oligonucleotides tend to emerge directly from selection with \u223c1\u201310nM affinities;4 a screening concentrationof 100 nM would be sufficient to identify active species, particularlyif the assay were conducted in the bead itself.31 Moreover, the templated OBOC synthesis approach disclosedhere makes selection-to-screen workflows experimentally tractableas selection output can be used directly as input to emPCR for gellibrary production.OBOC library screening typically involveshigh-capacity synthesisresin to achieve requisite local concentrations of one library memberfor assay. Chemical synthesis methods applied to the gel particlesresulted in high loads over a wide range (0.02\u201320 mM). Evenincomplete conversion of RNA templates (50 uM) yielded translatedpeptide product concentrations of \u223c100 nM. For chemotypes likeconventional DEL members, which tend to be Rule-of-5 compliant,8\u2013109 particles) and analysis scale (106 particles)suitably bridge the divide between affinity selection library sizesand conventional microplate-based functional screening, which wouldordinarily require costly and low-throughput library member synthesisat scale. Although the numerical diversity is lower, the OBOC formatcould unlock functional screening capabilities and simultaneouslyenable SAR profiling of smaller scaffolds that would otherwise bedifficult or impossible to isolate in affinity maturation. Key nextexperiments will deploy activity-based probes43 to detect biochemical or cellular activity perturbation with anenzymatically synthesized ligand in the hydrogel environment, whichis distinct from either surface presentation or dilute solution ofligand and perhaps closer to the macromolecular crowding of the cytoplasm.Such screening capabilities could greatly expand and accelerate hit-to-leadoptimization for encoded libraries.In conclusion, we describe a straightforwardand scalable approachto generating hydrogel particles for encoded library synthesis. Theselibrary particles do not require additional compartmentalization inplates or droplets and are directly screened using commercial flowcytometry instrumentation. Preparation scale (10"}
+{"text": "Mitragyna speciosa Korth.) is widely use worldwide despite its addictive potential. Although psychostimulant use has been linked to occurrence of endoplasmic reticulum (ER) stress, data is lacking on how regular kratom use affects ER stress. This case-control study first determined differences in ER stress sensor protein expression  between regular kratom users and healthy controls. Second, it evaluated the association between kratom use characteristics, targeted ER stress sensor protein expression, and \u201ckratom use disorder\u201d diagnosed with Diagnostic and Statistical Manual for Mental Disorders 5th Edition (DSM-5) among regular kratom users.Kratom  and p-JNK  increased the odds of kratom use disorder occurrence. Kratom use characteristics and other ER stress sensor protein expression were not associated with kratom use disorder.The study\u2019s findings revealed first that kratom users registered significantly higher protein expression in all targeted ER stress sensors compared to the control group. Second, higher protein expression of CHOP (Regular kratom use may induce protracted ER stress, leading to the decompensation of the unfolded protein response to maintain ER homeostasis. This effect may be linked to kratom use disorder occurrence. Mitragyna speciosa Korth.) is traditionally used in remedies for various illnesses in Southeast Asia. Currently, it is widely used around the world to improve mood and anxiety, enhance endurance, manage opioid dependence as a self-prescribed replacement, and serve as an analgesic for chronic pain   by compaS1 Appendix(DOCX)Click here for additional data file.S2 Appendix(DOCX)Click here for additional data file.S3 Appendix(DOCX)Click here for additional data file.S1 Fig(PDF)Click here for additional data file.S1 Checklist(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file."}
+{"text": "Reactive oxygen species(ROS) that cause PTMs of mitochondria-associated membrane (MAM)proteins determine these intertwined MERC functions. Chronic changesof the pattern of these PTMs not only control physiological processessuch as the circadian clock but could also lead to or worsen manyhuman disorders such as cancer and neurodegenerative diseases.Cells must adjust their redox state to an ever-changing environment thatcould otherwise result in compromised homeostasis. An obvious way toadapt to changing redox conditions depends on cysteinepost-translational modifications (PTMs) to adapt conformation,localization, interactions and catalytic activation of proteins. SuchPTMs should occur preferentially in the proximity of oxidative stresssources. A particular concentration of these sources is found nearmembranes where the endoplasmic reticulum (ER) and the mitochondriainteract on domains called MERCs (Mitochondria-Endoplasmic ReticulumContacts). Here, fine inter-organelle communication controls metabolichomeostasis. MERCs achieve this goal through fluxes of Ca This in2+ flux .Accordi2+ flux , as wellilibrium . Within aperones , while waperones .Moreoveaperones , in autoaperones  and as aaperones . Consist, Rab32) . The MER, Rab32) .MERC-localized proteins can undergo posttranslational modifications (PTMs) suchas phosphorylation or palmitoylation, which have functional implications.For instance, calnexin phosphorylation dependent on protein kinase CK2 andERK determines its interaction with phosphofurin acidic cluster sortingprotein 2 (PACS-2), a critical regulator of MERC formation  that conCysteines account for 2% of the total amino acid content of cells, which is thelowest number for all amino acids, but they are highly conserved and undergooxidation and reduction . Thissu2H) and irreversible sulfonic acid(-SO3H). The partial reversibility of these oxidation-basedPTMs highlights the labile aspect of these modifications, but also theirrole as on/off switches ,sulfinic acid  to yield peroxynitrite, a major RNS  links ER andmitochondrial membranes, mediating a regulated lipid conduit . As is tchondria .The first characterized MERC protein that controls tethering is mitofusin-2, adynamin-related GTPase. Mitofusin-2 can form proteinaceous bridges betweenthe ER and mitochondria ,but thi2+ release that thenactivates mitochondrial oxidative phosphorylation (OXPHOS) associated with aburst of ROS entering the interorganellar cleft  and remain much lower than the typical extracellular medium thatis usually situated at about 2\u2009mM . Thiscompartment contains large amounts of ROS-consuming or generating enzymessuch as superoxide dismutase 1 (SOD1), peroxiredoxins (PRDX) and glutathioneperoxidases (GPx) that are able to buffer ROS generated from mitochondrialOXPHOS  transfers Ca2+ into thematrix  -localized mitochondrialCaematrix . TheMCUematrix . The MCUoverload . The MCUd MICU2) , and thed MICU2) . We namelmatrix . The oxi2+ entry .Therefom the ER . Increas complex . Regardl complex . Moreove complex .2+ content determines the extent ofCa2+ flux towards mitochondria (2+ entry (SOCE) (2+ import by sarco/endoplasmic reticulumCa2+-ATPase (SERCA) pumps combine to store Ca2+ withinthe ER (2+-handling proteins (2+ (The extent of ER Cachondria . Storeoy (SOCE)  andCa2+nthe ER . Althougnthe ER , truncatnthe ER . Like moproteins , SERCA iproteins .SERCA aproteins  and thisproteins . ER-locaproteins . While tproteins  and, henproteins , the redeins  or IP3Rs  and one additionalcytosolic residue (cysteine 1394) in addition to 5 cysteines that arealready oxidized under basal conditions , an ER chaperone with a limited number of substrates  . Consisttabolism . PERK antabolism  and Ire1tabolism . HoweverThe originally discovered function of MERCs is the production of specificlipids, as unveiled by the biochemical isolation of MAMs by Jean Vance. Indeed,Upon establishment of their raft-like structure, MERCs also supplymitochondrial phosphatidylcholine (PC), phosphatidylinositol (PI), andphosphatidylserine (PS) . AfterP2+ import  is under the control oftwo diacyglycerol acyltransferases (DGAT1/2), of which DGAT2 is MERCenriched . The act2O2produced from oxygen consumption and uses it for PDI oxidation , pyruvate dehydrogenase (PDH), isocitrate dehydrogenase(IDH) and oxoglutarate dehydrogenase (OGDH)  . ATP syne (OGDH)  and \u03b2-oxe (OGDH)  also appd OXPHOS. Upon a chondria . Such a chondria .2+ uptake leads to anoverload, which further increases the production of ROS by the respiratorychain, especially if associated with the depolarization of the IMM and theopening of the mitochondrial permeability transition pore , which reduces ATPproduction and thus compromises SERCA pumping on the ER side of MERCs,highlighting additional connections between the ER and mitochondrial ATP regulates ROS production by controlling the activation ofthe antioxidant response transcription factor nuclear factor erythroid2-related factor 2 (Nrf2) . Since Nllations .Given the many known mechanisms that compromise or alter the functioning of theER and mitochondria, as well as cellular metabolism based on cysteineoxidation at MERCs, it is not surprising that this mechanism malfunctions inmany metabolic disease settings.2+, lipids and sterols tomitochondria, which is indeed found in patient tissue, but it remainsto be determined whether cysteine PTMs of MERC proteins are behindthese observations  oramyotrophic lateral sclerosis (ALS) also show increased oxidativestress. Relevant for MERC regulation, a clear increase of nitrosylatedPDI was observed in ALS . Within2+fluxes, redox status and cysteine modifications is strong incardiovascular diseases, especially upon myocardial ischemia andreperfusion. Under this condition, myocardial cells frequently undergocell death due to an excessive flux of Ca2+ from thesarcoplasmic reticulum (SR)/ER to the mitochondria, causingmitochondrial Ca2+ overload and cell death that eventuallytriggers heart failure (Cardiovascular diseases are highly correlated with increased levels ofROS . A well- failure .The MCU failure . In the case of insulin resistance in diabetes, increased mitochondrialROS levels are a potential causative mechanism . Aknown3R-mediatedCa2+ flux towards mitochondria, in its absence ROSincrease (3Rs isnecessary to prevent energy depletion of cancer cells (3Rs again suggests a cancer-promoting role (3Ractivity (A plethora of cancer-relevant proteins controls metabolic MERC signaling,including p53 , PTEN B, thekinincrease . Similarincrease . At MERCincrease .Severalincrease .While tincrease , MERC foincrease . Similarer cells . High exing role . Howeveractivity . The comactivity , butin activity . In summactivity .To conclude, MERCs are a central cellular hub in metabolic andaging-related diseases. Redox control of MERC tethering and regulatoryproteins is a key mechanism to control their roles in metabolism. Muchof the information gathered on cysteine PTMs controlling MERCs hasbeen gathered before their significance for this organellar contactsite was known, suggesting that future research may reveal additionalfunctional connections."}
+{"text": "UK improvement initiatives3 encourage hospitals to align with UKHSA guidance. UTI is a common infection in the emergency department (ED) and diagnosis can be challenging in the elderly.5UKHSA urinary tract infection (UTI) diagnostic guidance uses presence/absence of specific symptoms/signs to guide decisions on urine culture and antibiotic treatment.1 Identify ED patients aged 65 years+ (65+) with primary diagnosis of UTI. Limit to non-admitted for manageable sample. Complete retrospective chart review to elicit documented UTI symptoms/signs and associated: (i) urine dipstick testing; (ii) urine sampling for microscopy, culture and susceptibility (MC&S); and (iii) antibiotic treatment. Assess alignment with relevant UKHSA guidance. Estimate time taken.To explore retrospective chart review to quantify UTI treatment alignment with UKHSA UTI guidance.1 urine dipstick test; urine for MC&S; and UTI antibiotic treatment. Findings were mapped to illustrate if UKHSA diagnostic pathway and intended antibiotic prescribing decisions followed.Electronic patient record search for key terms  identifiTwenty-seven of 40 patients matched UKHSA criteria for lower UTI/pyelonephritis. Three of 27 followed recommended pathway of: no dipstick; urine for MC&S; and antibiotic. Twenty of 27 had urine dipstick test (not recommended); 16/27 had urine sample for MC&S (recommended); 26/27 received an antibiotic (recommended). Twenty-three who received antibiotics had dipstick testing, no urine for MC&S or both. One patient did not receive indicated antibiotic treatment. Documented symptoms/signs did not indicate UTI/pyelonephritis in 13/40 patients. Two of 13 followed the recommended pathway of: no dipstick; no urine for MC&S; and no antibiotic. Seven of 13 received a dipstick test; 6/13 had urine for MC&S; 9/13 received antibiotics which were not indicated. Five of 40 followed the recommended pathway; 30/40 received the recommended treatment. The time cost was around 30 min/patient.UKHSA guideline alignment was low. Testing in asymptomatic patients appeared to result in unnecessary antibiotic use. Retrospective chart review generated detailed data to assess alignment, however results may represent poor documentation not poor alignment. Retrospective chart review time cost too high for large numbers and assumes accurate documentation."}
+{"text": "In this Special Issue, \u201cMolecular Mechanism of Chronic Viral and Non-viral Liver Diseases\u201d, invaluable articles have been published. Alcohol-associated liver disease (ALD) is one of the major liver diseases, and alcohol promotes hepatic fibrosis and hepatocarcinogenesis . During Hepatitis B virus (HBV) infection causes acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Oncogenic potential of HBV is associated with the X gene product (HBx), which may be able to activate a cellular transcription factor at both viral and cellular promotor sequences in hepatocytes . HBx mayadenosine triphosphate-binding cassette subfamily C member 2 (ABCC2) [Qiu et al. examined the role of autoantibodies to paired box protein Pax-5 (PAX5), protein patched homolog 1 (PTCH1), and guanine nucleotide-binding protein subunit alpha-11 (GNA11) in the sera of Hispanic American patient with HCC . They co (ABCC2) .mitochondrial amidoxime reducing component 1 (MTARC1) rs2642438 and hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) rs72613567 polymorphisms had protective effects on nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) [Hepatic steatosis is common among patients scheduled for bariatric surgery, and steatohepatitis and liver fibrosis have been reported as potential complications of traditional jejunoileal bypass surgery . Kalinows (NASH) , althougThe prevalence of NASH in morbidly obese patients was extremely high, and early intervention is recommended . BariatrInterferon-free direct-acting antivirals against hepatitis C virus (HCV) are readily available, and their efficacy is higher, with fewer adverse events and a shorter duration, resulting in the decrease of HCV-related hepatic diseases; although, there are several problems . However"}
+{"text": "Dear Editor,1 Stress-triggered dysfunctions of microglia have been identified as a commonly occurred pathological feature of MDD.3 Microglial dysfunction contributes to the pathogenesis of MDD via immunoresponses/neuroinflammation-mediated neural damage and pathological synapse loss-mediated neural circuit disruption.1 Although the involvement of microglia in MDD has been widely investigated, the molecular mechanisms underlying microglial dysfunction remain largely unknown. Recently, we identified glutaminase 1 (Gls1) as one key protein that participates in microglial dysfunction.6 Gls1 catalyzes the hydrolysis of glutamine to produce glutamate in the brain.4 Besides its well-known role in excitatory neurotoxicity, we found Gls1 up-regulation in microglia in animal models of Alzheimer\u2019s disease and ischemic stroke.7 Gls1 activates microglia to overproduce cytokines and release inflammatory extracellular vesicles, therefore leading to neuroinflammation in animal models of Alzheimer\u2019s disease and ischemic stroke.6 More importantly, Gls1 has been found to be up-regulated in the brains of MDD patients, and microglial Gls1 deficiency mitigated LPS-induced depression-like behaviors.8 However, LPS exposure is not an appropriate model to mimic MDD phenotypes, leaving the involvement of Gls1 in MDD an undetermined question.Major depressive disorder (MDD) is one of the most common psychiatric illnesses that significantly increase the risk of suicide.9 CRS mice were more immobile in the forced swimming test (FST) and tail suspended test (TST), and less desired to sucrose solution in the sucrose preference test (SPT), displaying typical depression-like behaviors .ues Fig. . ImmunohcreER\u2009\u00d7\u2009Gls1-loxp) mice (Gls1-cKO mice)  between CRS-induced Gls1-cKO and CRS control mice  of Gls1 inhibitor CB839 via intraperitoneal injection (3 injections every other day) right after CRS exposure (Supplementary Fig. mpi Fig.  and prefmpi Fig.  of CRS mmpi Fig. . Hence, In summary, we demonstrated a significant increase in microglial Gls1 expression levels in CRS mouse brains. The microglial Gls1 knockout reversed depression-like behaviors presumably through inhibiting microglial activation and abnormal engulfment of synaptic structure (Supplementary Fig. Supplemental materialsT & F-values for all figures"}
+{"text": "Dear Editor,Saphnelo (anifrolumab-fnia) has been approved in 2021 by the Food and Drug Administration (FDA) in the US. The launch of Saphnelo marked the only new treatment approved for systemic lupus erythematosus (SLE) in more than 10 years.Hyperactivation of the type I interferon (IFN) signature has been observed in several systemic autoimmune conditions, and the type I IFN receptor antagonist 1 the link between IRGs regulators and systemic autoimmune conditions is poorly characterized. Interferon regulatory factors (IRFs) are a family of transcription factors that modulate immune responses through IFN signaling pathway. Among the nine mammalian members (IRF1-IRF9), IRF4 expression is restricted in immune cells and is required for their proper maturation and differentiation. A previous study using blood samples from SLE patients demonstrated that the differential expression of IRF4 and IRGs can delineate gene expression signatures associated with clinical features and treatment outcomes.2 However, prior research has not been aimed at clarifying the association among focal IRF4 expression, target organ pathology, and therapeutic benefits in lupus nephritis (LN).Albeit several studies have been focused on the role of IFN-responding genes (IRGs) and IFN signature in rheumatic conditions,We initially investigated gene expression features in human kidney samples. By analyzing two transcriptome datasets  by GEO2R online tool, we found 85 overlapped differentially expressed genes (DEGs) between the two datasets, including 60 upregulated genes and 25 downregulated genes Fig. . Kyoto E21H33NO9, a drug candidate for SLE treatment )3 that prevented progression of lupus nephritis  and the artemisinin derivative SM934  and 0.73 (P\u2009<\u20090.05), respectively for GSE112943 and GSE113342 dataset) , while moderately correlated with antinuclear antibody (ANA), IL-17A levels, and percentage of Th17 cells (0.4\u2009<\u2009r\u2009<\u20090.59) in MRL/lpr mice  T cells in spleens from aged MRL/lpr mice  was conducted. Unlike SCID mice transferred with IRF4 intact cells, the ones transferred with AAV-shIRF4-knockdown (AAV-IRF4) cells did not exhibit aggravating proteinuria, renal pathology or elevating circulating autoantibodies  Fig.  implied rin Fig. . In lighice Fig. . A similice Fig. .lpr mice and normal C57BL/6 mice. Flow cytometry analysis demonstrated that PNS, SM934, Enzastaurin, and Trametinib abated IRF4 expression in T and B cells in a dose-dependent manner, rather than in macrophages or dendritic cells. However, IRF4 suppression was not present in cultures containing artemisinin and its derivatives  Hyperactivation Restricts MurineOriginal and uncropped films of Western blots"}
+{"text": "People with HIV (PWH) and substance use (PWSU) have demonstrated inferior HIV care continuum outcomes, including lower retention in care (RIC), poorer ART adherence, and lower rates of viral suppression (VS) relative to peers without substance use within the literature. We compared 3-year outcomes among people with and without substance use who are enrolled in a smartphone intervention, PositiveLinks (PL), to determine the relative impact of PL for this subgroup of PWH.We performed retrospective chart review of clinical encounter and laboratory data and ICD-diagnoses for 600 PWH enrolled in PL from 2017-2020. Substance use was categorized by diagnoses of illicit substance use and/or substance use-related visits conducted at the UVA Ryan White Clinic. Patients with no documented substance use, or documented tobacco or reported alcohol use with no criteria for a substance use disorder were considered non-substance using. We analyzed HIV clinical outcomes  for PL members in each group at baseline (April 2017) and three years later .p< .01) while among PWH without substance use, RIC increased from 47% to 69% (p< .01). VS increased significantly among PWSU from 71% to 90% (p< .01), while among PWH without documented substance use, VS increased from 70% to 87%, (p< .01). Differences between groups for RIC and VS were not statistically significant at either time point.Chart review for the 3-year period of interest for 600 PWH enrolled in PL revealed 117 PWH meeting criteria for substance use and 483 not meeting criteria. A mean of 13 Ryan White Clinic visits were conducted per person among 117 PWSU, compared to 8 visits each among 483 PWH without documented substance use (p< .01) over 3 years. Among PWSU, RIC increased from 56% to 79% (A sample of 600 PWH using PL demonstrated comparable HIV clinical outcomes across 3 years regardless of substance use status. This sample selects for PWSU who stayed enrolled in PL at 3 years, and may not reflect outcomes expected for a broader population of variably engaged PWSU offered non-tailored mobile health interventions for HIV care. Further analysis is planned to determine whether covariates including demographic characteristics and PL usage patterns influence outcomes observed.Sylvia Caldwell, MPH, DHSc, Warm Health Technology: Advisor/Consultant Ben Elliott, MSW, Warm Health Technology: Advisor/Consultant Ava Lena Waldman, M.H.S., CHES, CCRP, Warm Health Technology: Advisor/Consultant Rebecca Dillingham, MD MPH, Warm Health Technology: Advisor/Consultant"}
+{"text": "Immunocompromised patients (ICP) are at higher risk of infection, but are often excluded from trials for community-acquired pneumonia (CAP). Due to limited data on CAP treatment in ICP, the IDSA/ATS CAP guideline omits recommendations for ICP. We aimed to assess predictors and outcomes associated with empiric broad-spectrum antibiotic (BSA) use versus standard CAP treatment in ICP hospitalized with CAP without IDSA risk factors for drug-resistant organisms (DRO).We collected data from non-ICU adult ICP hospitalized with CAP [Table 1] between 1/2017 to 12/2022 at 69 Michigan hospitals who received either BSA on hospital day 1 or 2 or a standard CAP regimen. BSA included anti-MRSA and anti-Pseudomonal antibiotics. We excluded patients with moderate/severe COPD, structural lung disease, pulmonary complications, and IDSA risk factors for DRO. Collected data included patient characteristics, laboratory results, antibiotic data, and 30-day outcomes via phone follow up. Logistic regression was used to assess predictors of empiric BSA accounting for hospital-level clustering. We assessed the association of empiric BSA vs. empiric standard CAP treatment with 30-day outcomes using regression models adjusted for variables associated with probability of treatment and known predictors of each outcome.Pseudomonas (2.0% (22/1115) standard CAP vs 2.5% (40/1604) BSA) [Table 3]. Of ICP started on BSA, median duration of BSA was 4.4 days [SD 3.4]. After adjustments, receipt of empiric BSA was associated with increased readmission, transfer to ICU and longer hospitalization compared to standard empiric CAP coverage [Table 4].Of 40,882 patients with CAP, 2719 were ICP. Of 2719 ICP with CAP, 41% (N=1115) received standard empiric CAP coverage. Compared to ICP who received standard empiric CAP coverage, those who received empiric BSA had a higher incidence of severe sepsis, higher Pneumonia Severity Index, and hospitalization or IV antibiotics in prior 90 days [Table 2]. The most common CAP pathogen identified was ICP hospitalized with CAP often received empiric BSA but few had identified DRO. Empiric BSA use for CAP in ICP without IDSA risk factors for DRO was associated with worse patient outcomes compared to standard empiric CAP coverage.Elizabeth McLaughlin, MS, RN, Blue Cross Blue Shield of Michigan: Support provided through the Value Partnership Program"}
+{"text": "Serratia Marcescens causes serious infections. Carbapenems were preferred due to fear of inducible AmpC resistance. IDSA guidance now recommends ceftriaxone, and in high-burden cases, cefepime. Evidence on Serratia bacteremia treatment is limited. This study compares outcomes of cefepime or carbapenem (CPCT) vs. non-cefepime non-carbapanem containing definitive therapy (NCPCT) in non-ESBL Serratia bacteremia.Serratia Marcescens bacteremia hospitalized in seven Massachusetts acute care hospitals (2015 - 2022) . Demographics, clinical course characteristics, and antibiotic therapy choices were obtained. Primary outcome was 30-day mortality, and secondary composite outcome was antimicrobial failure (Definitions in Table 1 and 2). Chi Square and Mann-Whitney U tests were computed using SPSS statistical package.We retrospectively reviewed adults (\u226518 years) with (Table 1). CPCT patients had longer definitive therapy and more prolonged hospital stay, while more patients in the NCPCT group were switched to oral therapy (Table 2). Neither 30-day mortality rate  nor antimicrobial failure rate  was significantly different.69 out of 128 patients were included in the study. The mean age was 59.23 and 27.53% had IVDU disorder. 21.9 % of patients received CPCT while 78.1% were treated with NCPCT. Notably, more patients in the CPCT group received antibiotics in preceding 3 months, and had more ventilator associated pneumonia (VAP). Other baseline characteristics, bacteremia sources and severity of infection were similar between both groups Our study found no significant difference in 30-day mortality or antimicrobial failure between CPCT and NCPCT groups. Furthermore, longer hospital stay was observed in CPCT patients, possibly due to cefepime and meropenem\u2019s less suitability for outpatient antimicrobial therapy (OPAT). Our study is limited by its small size and the overlap in definitive antibiotic therapy. Our findings suggest narrower Beta-lactam therapy may be appropriate which may help early hospital discharge and less days of broad spectrum therapy. Prospective studies are needed to confirm these conclusions and contribute to safe antimicrobial stewardship.All Authors: No reported disclosures"}
+{"text": "Racial and ethnic minority burn patients often face barriers to longitudinal psychosocial support after injury. Studies utilizing the Burn Model System (BMS) National Database show adult minority patients report worse psychosocial outcomes during burn recovery in domains such as body image or social re-integration. No study to date has investigated differences in psychosocial outcomes by racial or ethnic category in the pediatric population using the BMS database. This study examines eight outcomes in minority pediatric patients to better characterize potential differences in the pediatric patient population.Patients under 18 years old treated for burn injury between 2009 and 2019 consented to participate in a multi-center longitudinal study were included in the current sample. We analyzed eight outcomes using the National Institute of Health Toolbox and PROMIS-25 measures with higher reported scores indicating worse symptom severity. Multi-level, linear mixed effects, regression modeling analyzed associations between race/ethnicity and outcomes at three time points  and on average 8.78 years old (range: 3-18 years at time of injury). When surveyed 12 months after injury, pediatric Hispanic patients reported a mean fatigue score of 45.8 : 41.6, 49.9) compared to pediatric non-Hispanic patient score of 43.0 . At 12 months, Hispanic patients reported a mean anxiety score of 46.1 , compared to 41.4  reported by non-Hispanic patients. At 12 months after injury, Hispanic patients reported a mean peer relationship score of 51.1  compared to non-Hispanic patients' score of 55.5 . Hispanic patients also reported a mean pain interference score of 44.7  compared to non-Hispanic patients' score of 38.3  at 12 months after injury.Following burn injury, pediatric Hispanic patients report worse outcomes in several psychosocial domains compared to pediatric non-Hispanic patients, although differences were not statistically significant. However, as significant differences in outcomes exist in adult Hispanic/Latino patients, this study supports the need for further evaluation into potential factors that lead to worse outcomes in Hispanic populations.Although pediatric Hispanic patients do not report significantly worse outcomes than non-Hispanic patients in short term burn recovery, these patients may benefit from further counseling and psychosocial support after injury."}
+{"text": "The COVID-19 pandemic may affect sexual intimacy and have implications for overall sexual well-being.This study comprised two main objectives: 1) To explore the influence of COVID-19 pandemic on older couples\u2019 sexual intimacy; and 2) To assess how older couples\u2019 sexual intimacy during the COVID-19 pandemic influences mental health.The sample of this qualitative study consisted of 391 older participants (between 65 and 87 years of age).For the first objective, semi-structured interview data yielded five main themes: (1) Less sexual satisfaction (68%); (2) Less sexual desire (67%); (3) Stronger affective relationships (34%); (4) Fear of contracting physical illness (29%); and (5) Less attractiveness (23%). Three main themes concerning mental health were reported by participants: (1) Less anxiety and distress (78%); (2) Greater attention to negative emotional states (55%); and (3) Less emotional outbursts (41%).The pandemic affected older adults\u2019 sexual intimacy, mostly negatively. Less sexual satisfaction and desire were felt by these older couples. Conversely, stronger affective relationships were reported. In spite of these mostly negative influences, existing sexual intimacy was mostly linked to less perceived anxiety and distress, greater attention to negative emotional states, and less emotional outbursts. Sexual intimacy during COVID-19 has received little attention; however, these results highlight its positive contribution to mental health and therefore a relevant approach to this topic should be taken, especially in later life.None Declared"}
+{"text": "Methicillin Resistant Staph aureus (MRSA). Consequently, it is often over-prescribed. Antimicrobial stewardship programs (ASP) have used time-outs to ensure therapies are tailored to the patient with proper indication and coverage.Vancomycin is often started empirically for its reliability with gram-positive pathogens, particularly Enterococcus), purulent cellulitis without culture data, and pending or negative cultures for deep-seated infections  with ID consult.Between November 2022 and February 2023 provider discontinuation of IV vancomycin was prospectively reviewed when it was no longer needed at a 298 licensed bed community teaching hospital in Chicago. Results of culture sensitivities including MRSA nares screen, blood, and wound cultures were used to analyze appropriateness. Appropriateness was defined as having a positive MRSA culture, positive MRSA nares for treatment of PNA only, gram positive infections with a true and severe beta-lactam allergy, gram positive infections with beta-lactam resistant pathogens  consult.Of the 107 patient encounters, pharmacists intervened and discontinued 62 (57.9%), ID discontinued 16 (14.9%) and the primary medical team discontinued 29 (27.1%).30% (46/153) of patients studied continued an inappropriate vancomycin regimen. There is room for improvement in regards to proper education surrounding antimicrobial stewardship. An antimicrobial time-out can help further decrease inappropriate vancomycin use.All Authors: No reported disclosures"}
+{"text": "Mycetohabitants rhizoxinica was associated with bacteriemia in an immunocompromised individual where its host Rhizopus microsporus caused mucormycosis. Our data demonstrate the endosymbiont Ralstonia pickettii can impact virulence of its R. microsporus host. Together, these data suggest Mucorales endosymbionts can influence both fungal and bacterial infections; however, their frequency and diversity in Mucormycosis is unknown. This project investigates the frequency and diversity of bacterial endosymbionts in Mucorales clinical isolates.Soil-associated Mucorales fungi frequently host bacterial endosymbionts that produce damaging endotoxins important for plant pathology. Our work and clinical reports suggest an important and unanticipated role for endosymbionts in human disease. The endosymbiont oC) were subjected to phenol/chloroform DNA extraction. Bacterial presence was assessed by 16s RNA PCR, and resulting bands identified by nanopore sequencing. In parallel, WGS of total DNA confirmed bacterial presence and identity. Bacteria were also physically isolated from homogenized fungal mycelia  harvested under sterile conditions. Bacteria from supernatants  were identified by 16s RNA PCR and Nanopore sequencing.Mucorales isolates from mucormycosis patients via the UK National Mycology Reference Laboratory and the Instituto Nacional de Rehabilitacion, Mexico, were identified by ITS1/2 PCR or MALDI-TOF. Fungal isolates  were evaluated for bacteria presence. 17/27 (62%) were 16s RNA positive. Culture identified 6 bacterial species . Mucorales isolates originated from cutaneous 11/27 (41%); respiratory 8/27 (29%); and sinus-orbital diseases 7/27 (26%).In total, 27 Mucorales isolates (The presence of bacterial endosymbionts in clinical isolates of Mucorales is frequent, diverse and can potentially influence fungi in causing disease among individuals at risk.All Authors: No reported disclosures"}
+{"text": "Clostridioides difficile (C. difficile) infection (CDI) is a leading cause of nosocomial infection that can range from mild diarrhea to life threatening pseudomembranous colitis and death. Aging as well as defects in the host immune response including failure to develop antibody response against C. difficile antigens increases the risk of bacterial colonization, hospitalization, mortality and developing recurrent CDI. The present study aimed to investigate the differences in the B cell response between young and aged C. difficile infected mice.3 spores of C. difficile R20291 strain . The young (3-4 months) and aged (22-24 months) mice were euthanized at 14 days post infection (dpi). The germinal center response and IgA+ antibody-secreting cells (ASCs) were studied using multicolor flow cytometry.C57BL/6 mice were rendered susceptible to CDI via the administration of oral cefoperazone for 10 days and then the mice were challenged with 10C. difficile infected aged mice exhibited greater weight loss at 4 dpi compared to young C. difficile infected mice. The gut germinal center response studied at 14 dpi showed mild changes in T follicular helper cells (CXCR5+PD-1+ of CD4+) and germinal center B cells (GL7+CD95+ of CD19+B200+) of young C. difficile infected mice, whereas the response was dampened in the aged C. difficile infected mice . Further, at 14 dpi ASCs (CD138+CD98+) were seen in the lamina propria of the cecum and colon of the C. difficile infected mice, but the frequencies of CD138+CD98+ ASCs as well as IgA+ ASCs were significantly lower in the C. difficile infected aged mice compare to young mice .The defect in B cell response during CDI may be responsible for more severe infection and recurrent CDI among aged individual compared to young individuals. It remains to be seen if age-related changes impact antibody production and whether the antibody production during primary CDI provides long-term immunity.Vincent B. Young, MD, PhD, ASM: Senior Editor for mSphere Journal|Debiopharm: Consultant|mSphere: Senior Editor|Vendanta Biosciences: Consultant"}
+{"text": "Neuroinflammation is a multifactorial process occurring in the central nervous system (CNS) that is intimately linked to temporal and spatial regulation of gene expression mediated by noncoding RNAs (ncRNAs). ncRNAs are present at high concentrations in the CNS and show specific multidimensional expression, exerting immunomodulatory effects via direct or indirect interactions with various effector proteins or other molecules to form complex networks that regulate downstream immune response pathways , 2. NextMaruyama et\u00a0al. report that lncRNA Neat1 (Neat1) is upregulated in DRG following peripheral nerve injury via Neat1-mRNA interaction-dependent and independent mechanisms, which promotes spinal neuroinflammation  mediating peripheral neuropathic pain. Neat1 is causally involved in neuropathic pain and regulates spinal microglia activation through neuro-immune communication. Further investigation of Neat1\u2019s function could lead to novel treatment options for neuropathic pain. Advances in high-throughput sequencing over the last decade have revolutionized transcriptome research, propelling drug discovery for neurological disorders  gene, a regulator of peripheral immune cell migration expressed in spinal cord astrocytes -induced astrocyte injury. They show that the CCL2 level in cerebrospinal fluid from neuromyelitis spectrum disorder (NMOSD) patients is significantly higher than in other non-inflammatory neurological disease groups and that blocking astrocyte CCL2 gene expression effectively attenuates AQP4-IgG-induced injury and reduces inflammatory cytokine release (interleukin 6 and 1 beta). The findings support that CCL2 is involved in initiating astrocyte damage via AQP4-IgG, making it a promising candidate target for the treatment of neuroinflammatory diseases.Peripheral neuropathic pain caused by primary damage or injury to the peripheral nervous system is a complex and debilitating condition. Few treatments are currently available for neuropathic pain, partly due to incomplete understanding of the underlying mechanisms. Recent evidence has revealed dysregulated expression of lncRNA in damaged nerves, dorsal root ganglion (DRG), and spinal dorsal horn following peripheral nerve injury . Maruyamisorders \u201310. Marutrocytes . Wang etDracocephalum moldavica L., exerts neuroprotective effects by inhibiting calcium/calmodulin-dependent protein kinase II (CaMKII)-dependent apoptotic and inflammatory pathways in dementia , demonstrating that tilianin inhibits inflammation and apoptosis dependent on the miR-193b-3p/calmodulin (CaM) and miR-152-3p/CaMKII\u03b1 co-initiated p38 mitogen-activated protein kinase (MAPK)/nuclear factor kappa B (NF-\u03baB) p65 and BCL2 apoptosis regulator (Bcl-2)/BCL2 associated X, apoptosis regulator (Bax)/caspase-3/poly(ADP-ribose) polymerase (PARP) pathways. These findings provide insights into the potential use of tilianin for treating VaD, highlighting its role as a promising small-molecule regulator of miRNA-associated inflammatory responses. The potential role of miRNAs in regulating neuroinflammation has been widely demonstrated  signaling pathways, which are closely associated with pro-inflammatory responses. Therapeutic approaches targeting miRNAs in CNS diseases are also addressed, proposing that the combination of drug therapy and specific miRNAs could play a broader and prospective role in treatment.Another contribution focuses on ncRNA-based drug molecule discovery for the treatment of CNS disorders. Tilianin, the main active ingredient in the traditional Chinese medicine dementia , 13. Sunnstrated . Zhang eOverall, this Research Topic explores the functions and molecular mechanisms of ncRNAs in immune-inflammatory responses in CNS disorders, especially neuropathic pain, NMOSD, VaD, and spinal cord brain injury. Since inflammatory ncRNAs are differentially expressed with biological regulatory effects in the peripheral circulation of CNS patients, we hope that highlighting these recent advances in ncRNA-oriented innovative pathogenesis, candidate targets, and active compounds and summarizing drug development targeting ncRNAs and neuroinflammation will motivate further research leading to diagnostic and therapeutic discovery in CNS diseases. This Research Topic was achieved by the diligent work of the Editorial Office of Frontiers in Immunology, the participating authors, and the reviewers, and we sincerely appreciate their valuable contributions to this Research Topic.ZC: Writing \u2013 original draft. FG: Writing \u2013 review & editing. JC: Writing \u2013 review & editing. GB: Writing \u2013 review & editing. RL: Conceptualization, Writing \u2013 original draft."}
+{"text": "Dried blood spot (DBS) PCR sensitivity for congenital cytomegalovirus (cCMV) screening ranges from 34% to 86%, but it is unclear whether a negative DBS PCR reflects an absence of CMV DNAemia or a technical limitation in viral detection by DBS PCR. The objective of this study was to determine the agreement between CMV DNA PCR tests in plasma and DBS among cCMV infected infants.This single center retrospective cohort study evaluated infants diagnosed with cCMV infection by urine CMV PCR at age \u2264 21 days due to clinical symptoms, failed newborn hearing screen, or NICU admission screening. Subjects with a plasma CMV PCR test performed within the first month after birth and a newborn CMV DBS PCR test were included in the study. Agreement between the plasma and DBS PCR tests was calculated using Cohen\u2019s kappa coefficient. Clinical characteristics and viral loads were compared between groups with concordant and discordant DBS and plasma PCR tests using the Kruskal-Wallis or Mann-Whitney U test.70 cCMV infected infants were included in the study. 30 (43%) were female, 51 (73%) were white, 13 (19%) were black, 6 (8%) were other/multiracial, 3 (4%) were Hispanic, and 54 (77%) had symptomatic cCMV infection. 49 (70%) had DBS+/plasma+ PCR; 1 (1.4%) had DBS+/plasma- PCR; 14 (20%) had DBS-/plasma+ PCR; and 6 (9%) had DBS-/plasma- PCR. Groups had similar distributions of sex, race, ethnicity, gestational age, birthweight, birth length, birth head circumference, and symptomatic infection. DBS sensitivity was 71%. Agreement between the tests was fair . Of the 20 subjects with DBS- tests, 70% had plasma+ PCR and 30% had undetectable CMV DNA in plasma. Infants with DBS+/plasma+ PCR had significantly higher plasma viral loads compared to those with DBS-/plasma+ PCR  (p < 0.0001).In this predominantly symptomatic cohort, DBS PCR identified the majority (71%) of infants with cCMV infection. A negative DBS PCR was associated with either low-level plasma CMV DNAemia that was seen in 20% of cCMV infected infants, or no plasma DNAemia in 9% of infants. These findings may impact the use of DBS as a screening test for cCMV infection.Alexandra Katherine Medoro, MD, Merck: Grant/Research Support Amy Leber, PhD, Biomeriux: Grant/Research Support|BioRad: Advisor/Consultant|Cephied: Grant/Research Support|Diasorin: Grant/Research Support"}
+{"text": "Leishmania (Mundinia) procaviensis is a parasitic kinetoplastid that was first isolated from a rock hyrax in Namibia in 1975. We present the complete genome sequence of Leishmania (Mundinia) procaviensis isolate 253, strain LV425, sequenced using combined short- and long-read technologies. This genome will contribute to our understanding of hyraxes as a Leishmania reservoir. Leishmania parasites have been isolated from hyraxes (family Procaviidae) in Ethiopia (Leishmania (Mundinia) procaviensis (Procavia capensis) in Namibia in 1975  supplemented with 10% fetal calf serum (FCS), 2% stable human urine, 1% basal medium Eagle vitamins, and 25\u2009\u03bcg/mL gentamicin sulfate, with subpassage to fresh medium every 4 days to sustain parasite growth and viability (Short-read library construction and sequencing were contracted to (i) BGI  (paired-end reads [270\u2009bp and 500\u2009bp] sequenced using the Illumina HiSeq platform) and (ii) Aberystwyth University  (paired-end reads [300\u2009bp] sequenced using the Illumina MiSeq platform). We performed long-read library preparation and sequencing according to the Nanopore protocol (SQK-LSK109) on R9 flow cells (FLO-MIN106). Read quality was assessed using MultiQC .Leishmania major Friedlin strain genome (GenBank assembly accession number GCA_000002725.2)   as a refThe analysis workflow for assembly and annotation was performed using Snakemake  and is aEuglenozoa, which contains 130 single-copy orthologues from 31 species; we found that 123 of the orthologues were present (94.6% completeness). We carried out functional annotation and prediction using the MAKER2 annotation pipeline (We assessed assembly completeness with BUSCO , using tpipeline  in combiGCA_017918225.1. The master record for the whole-genome sequencing project is available under GenBank accession number JAFNID000000000.1. Raw sequencing reads are available under BioProject accession number PRJNA689706.The assembly and annotations are available under GenBank assembly accession number"}
+{"text": "Nature uncovered how pepper NLR Tsw detects phytohormone receptors\u2019 interference caused by tomato spotted wilt virus (TSWV) effector, triggering a robust immune response, showcasing a new manner of NLR guarding.Plant intracellular nucleotide-binding domain leucine-rich repeat (NLR) receptors play crucial roles in immune responses against pathogens. How diverse NLRs recognize different pathogen effectors remains a significant question. A recent study published in  Capsicum chinense, was known to confer resistance against tomato spotted wilt virus (TSWV). This Tsw-mediated immunity is activated by the effector NSs, a gene-silencing suppressor protein encoded by TSWV  proteins represents a major group of immune receptors in higher plants that evolved to detect the presence of pathogen effectors delivered into host cells. Although a few studies reported direct recognition of effectors by NLRs, indirect recognition such as guard, decoy, or integrated decoy models, seems to occur more prevalently  receptor Coronatine-insensitive 1 (COI1), auxin (AUX) receptor Transport inhibitor response 1 (TIR1), and strigolactone (SL) receptor partner More Axillary Growth2 (MAX2), exhibit great structural similarities to part of the Tsw LRR domain, which was then named as phytohormone receptor-like (PRL) domain. The phytohormones JA, AUX, and SL have central roles in regulating various physiological processes, not only in plant growth and abiotic stress, but also in regulating immune responses against different pathogens  members were identified. Among them, TCP21 not only showed interaction with NSs, but also with COI1, TIR1, and MAX2, suggesting that NSs targets these receptors through TCP21  and RPS2 (resistance to P. syringae 2) guard the effectors targeting guardee RIN4 (RPM1 interacting protein 4)  carries an integrated WRKY domain to capture the effectors, activating defense (Le Roux et al. In addition, this study offers a new model for NLR activation during plant defense response. Previous studies suggested some indirect recognition models. In the guard model example, Arabidopsis NLRs RPM1 (resistance to In summary, Chen and colleagues identified how NLR Tsw detects the interference of phytohormone receptors by TMSV effector NSs through the structurally similar PRL domain. This discovery improves our understanding of how NLRs are activated by pathogens. The novel PRL domain in NLR could potentially be employed to engineer NLRs to improve crop disease protection."}
+{"text": "The test-negative design is common in studies of influenza vaccine effectiveness. However, estimates are biased when there is heterogeneity in healthcare seeking behavior by vaccination or case status, both influenced by presence of high risk comorbidities. This study sought to examine potential differences in case rate and vaccination status by patterning of these comorbidities among hospitalized patients enrolled during the 2018/19 influenza season.Participants were hospitalized with acute respiratory illness during the 2018/2019 influenza season in three major hospital systems in southeast Michigan within the US Hospitalized Adult Influenza Vaccine Effectiveness Network (HAIVEN). Influenza was confirmed by molecular testing of respiratory specimens. Latent class models with 4 classes were constructed from 17 ICD-10 diagnostic code defined high risk conditions to assess clustering among individuals; this analysis assumes latent similarities exist among those within a class defined using known conditions. Individuals were assigned the class with the highest membership posterior predicted probability. Chi-square tests were used to compare classes.Figure 1 (n=840). There were statistically significant differences between classes for all conditions; Class 2 had highest prevalence of comorbidity with high frequencies of cardiometabolic and lung disease, and Class 3 had lowest prevalence of comorbidity with only modest frequency of lung disease. Influenza cases represented 18.4%, 13.6%, 20.5%, and 18.3% of those in each class, respectively . Vaccination rates were 77.6%, 77.3%, 55.8%, and 67.6%, respectively, with statistically significant differences between all classes except Classes 1 and 2 .Characteristics of latent classes are in Latent class analysis identified significant variation in influenza vaccination rates by patterning of high risk comorbidity among adults hospitalized with acute respiratory illness. Care should be taken to examine such differences within test-negative studies of vaccine effectiveness in hospitalized populations, with particular concern during circulation of multiple vaccine-preventable respiratory viruses.Arnold Monto, MD, Roche: Advisor/Consultant|Roche: Honoraria Emily T. Martin, PhD, MPH, Merck: Grant/Research Support"}
+{"text": "Sub1 Indica rice cultivars.The increased frequency of heavy rains in recent years has led to submergence stress in rice paddies, severely affecting rice production. Submergence causes not only hypoxic stress from excess water in the surrounding environment but also osmotic stress in plant cells. We assessed physiological responses and Ethylene-Response AP2/ERF Factor regulation under submergence conditions alone and with ionic or nonionic osmotic stress in submergence-sensitive IR64 and submergence-tolerant IR64-Sub1 exhibited shorter plant heights and root lengths under submergence with nonionic osmotic stress than normal condition and submergence alone. IR64-Sub1 seedlings exhibited a significantly lower plant height under submergence conditions alone and with ionic or nonionic osmotic stress than IR64 cultivars. IR64-Sub1 seedlings also presented lower malondialdehyde (MDA) concentration and higher survival rates than did IR64 seedlings after submergence with ionic or nonionic osmotic stress treatment. Sub1A-1 affects reactive oxygen species (ROS) accumulation and antioxidant enzyme activity in rice. The results also show that hypoxia-inducible ethylene response factors (ERF)-VII group and alcohol dehydrogenase 1 (ADH1) and lactate dehydrogenase 1 (LDH1) genes exhibited different expression levels under nonionic or ionic osmotic stress during submergence on rice.Our results indicate that both IR64 and IR64-Together, these results demonstrate that complex regulatory mechanisms are involved in responses to the aforementioned forms of stress and offer new insights into the effects of submergence and osmotic stress on rice.The online version contains supplementary material available at 10.1186/s12870-023-04380-y. Oryza sativa) is the staple food of more than half the world\u2019s population. In 2019, global rice production was 755.5 million tons; in the same year, rice production in Asia was 677.2 million tons, constituting 89.6% of global production and highlighting the importance of rice as a food crop in Asian countries . Using membrane-anchored ubiquitin-fold (MUB) proteins as the internal control, this study performed quantitative real-time (qRT) PCR with specific primer pairs (Supplementary Table Additional file 1. Primers used for quantitative RT-PCR experiments."}
+{"text": "To systematically evaluate the efficacy and safety of FDA-approved isocitrate dehydrogenase (IDH) inhibitors in the treatment of IDH-mutated acute myeloid leukemia (AML).We used R software to conduct a meta-analysis of prospective clinical trials of IDH inhibitors in the treatment of IDH-mutated AML published in PubMed, Embase, Clinical Trials, Cochrane Library and Web of Science from inception to November 15th, 2022.A total of 1109 IDH-mutated AML patients from 10 articles (11 cohorts) were included in our meta-analysis. The CR rate, ORR rate, 2-year survival (OS) rate and 2-year event-free survival (EFS) rate of newly diagnosed IDH-mutated AML (715 patients) were 47%, 65%, 45% and 29%, respectively. The CR rate, ORR rate, 2-year OS rate, median OS and median EFS of relapsed or refractory (R/R) IDH-mutated AML (394 patients) were 21%, 40%, 15%, 8.21\u00a0months and 4.73\u00a0months, respectively. Gastrointestinal adverse events were the most frequently occurring all-grade adverse events and hematologic adverse events were the most frequently occurring\u2009\u2265\u2009grade 3 adverse events.IDH inhibitor is a promising treatment for R/R AML patients with IDH mutations. For patients with newly diagnosed IDH-mutated AML, IDH inhibitors may not be optimal therapeutic agents due to low CR rates. The safety of IDH inhibitors is controllable, but physicians should always pay attention to and manage the differentiation syndrome adverse events caused by IDH inhibitors. The above conclusions need more large samples and high-quality RCTs in the future to verify.The online version contains supplementary material available at 10.1186/s13148-023-01529-2. Acute myeloid leukemia (AML), a highly aggressive and heterogeneous hematological malignant tumor, is the most common type of acute leukemia affecting adults and has caused a large number of leukemia-related deaths , 2. The Mutations in isocitrate dehydrogenase genes (IDH1 and IDH2) occur in about 20% of AML patients . This muIDH inhibitors are very promising drugs for AML patients with IDH mutations, especially for the elderly and R/R AML patients with IDH mutations. However, there are some concerns about IDH inhibitors. For example, Elihu Estey et al.  doubted This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.We searched Web of Science, Embase, Cochrane Library, PubMed, and ClinicalTrials.gov databases to identify relevant prospective clinical studies published from inception to November 15, 2022, without language restrictions. We searched for the following keywords: acute myeloid leukemia, AML, acute myelogenous leukemia, enasidenib, AG221, ivosidenib, AG120. In addition, we have reviewed the references of the retrieved literature to identify any possible relevant studies.We searched for prospective clinical studies of IDH inhibitors in the treatment of AML patients with IDH mutations. Inclusion criteria were based on the PICO-framework. Population (P): AML patients with IDH mutations. Intervention (I): Treatments containing IDH inhibitors (enasidenib or ivosidenib). Comparison (C): Placebo or treatments without IDH inhibitors (enasidenib or ivosidenib). Response outcome (O): complete remission (CR) rate; overall response rate (ORR) included complete remission, complete remission with incomplete hematologic or platelet recovery, partial remission, and morphologic leukemia-free state; Survival Outcome (O): 2-year overall survival (OS) rate; 2-year event-free survival (EFS) rate, median overall survival, median event-free survival. Safety outcome (O): all grade adverse events during the whole treatment period; grade\u2009\u2265\u20093 adverse events during the whole treatment period.The following are our criteria for excluding literature: (a) retrospective studies; (b) review and guideline; (c) with unavailable study data; (d) investigation; (e) conference articles; (f) repeated reported articles; (g) bridging studies; (h) maintenance therapy after allogeneic hematopoietic cell transplantation. When there is a dispute between two reviewers, the decision is made by the third reviewer (YL).Two reviewers (XC and XX) independently extracted the following information: author/year, national clinical trial (NCT) number, study design, nation, stage, IDH mutations type, median age, sample size, interventions, median follow-up, outcomes.We assessed the quality of included RCTs and non-randomized prospective cohort studies according to the modified Jadad scale and the Methodological Index for Non-Randomized Studies Trials (MINORS) , respectI2 statistic were used to examine the heterogeneity across studies. If I2 indicates that there is no statistical heterogeneity between the studies (I2\u2009<\u200950%), we use the fixed effect model for analysis. Otherwise, we use random effect model for analysis. For the subgroup analysis results with high heterogeneity (I2\u2009>\u200975%), we comprehensively analyzed the sources of heterogeneity. Publication bias was evaluated by Egger\u2019s and Begg\u2019s tests. P\u2009<\u20090.05 indicates statistical significance, and there may be publication bias.R software version 4.2.0 was used to statistically analyze treatment response, survival, and safety results in newly diagnosed and R/R AML patients with IDH mutations treated with IDH inhibitors. We analyzed these results separately for newly diagnosed IDH-mutated AML and R/R AML with IDH mutations, and subsequently performed subgroup analyses according to medication regimen (IDH inhibitor combination therapy and IDH inhibitor monotherapy). The effect size of all pooled results were expressed by 95% confidence interval (CL), which has an upper limit and a lower limit. Both random-effects and fixed-effects models were used to draw forest plots. The Cochrane Q chi-square test and According to the search strategy, a total of 1202 articles were identified. First, we removed 546 duplicate articles with EndNote software. Then, we excluded 641 articles after screening the title and abstract, and excluded 5 articles after reading the full text. Ultimately, 10 articles (11 cohorts) were eligible for analysis , 21\u201329. This meta-analysis involved 1109 IDH-mutated AML patients from 3 RCTs , 23, 25 We assessed the quality of three , 23, 25 I2\u2009=\u200986%] and 65% , respectively. Subsequent subgroup analyses showed that both CR and ORR rates were significantly higher in the IDH inhibitor combination therapy group  than in the IDH inhibitor monotherapy group . There is a high heterogeneity in ORR among newly diagnosed IDH-mutated AML patients receiving combination therapy with IDH inhibitors (I2\u2009=\u200982%), which derives from the different drugs combined with IDH inhibitors . And the heterogeneity was greatly reduced when a cohort of IDH inhibitors combined with intensive chemotherapy was excluded (I2\u2009=\u200935%). See Additional file Seven , 26, 29 I2\u2009=\u20090%]. Venugopalet et al. [I2\u2009=\u20090%]. Therefore, we estimate that the CR rate of IDH inhibitor combined therapy may be slightly higher than that of IDH inhibitor monotherapy. See Fig.\u00a0Four , 27, 28 t et al.  reportedt et al. , the CR I2\u2009=\u20090%]. No cohort reported ORR in R/R IDH-mutated AML patients treated with IDH inhibitor combination therapy. See Fig.\u00a0Three , 27, 28 I2\u2009=\u200990%]. Subsequent subgroup analysis showed that the 2-year OS rate was significantly higher in the IDH inhibitor combination therapy group  than in the IDH inhibitor monotherapy group . There is a high heterogeneity in 2-year OS rate among newly diagnosed IDH-mutated AML patients receiving combination therapy with IDH inhibitors (I2\u2009=\u200985%), which derives from the different drugs combined with IDH inhibitors . And heterogeneity disappeared when IDH inhibitors combined with standard treatment cohort were excluded (I2\u2009=\u20090%). See Additional file Five , 26, 29 I2\u2009=\u200975%]. The 2-year EFS rate for IDH-inhibitor combination therapy in newly diagnosed IDH-mutated AML patients was 31% , and the 2-year EFS rate for IDH inhibitor monotherapy in newly diagnosed IDH-mutated AML patients was not pooled due to only one relevant article. Because only Pollyea et al.  and 8.21 months , respectively. No article reported the OS results of IDH-inhibitor combination therapy in IDH-mutated AML patients. See Fig. Three , 27, 28 I2 = 0%]. Only 1 article [Two , 28 arti article  reportedWe performed a single-arm meta-analysis of 7 \u201327, 29 ap\u2009=\u20090.0432) and therefore should be interpreted cautiously in conjunction with other results. For other results, the Egger\u2019s test and Begg\u2019s test did not suggest the possibility of publication bias. See Additional file We performed publication bias analysis of all results using Egger\u2019s and Begg\u2019s tests. Eegger\u2019s test suggests there may be publication bias in the 2-year OS rate in newly diagnosed IDH-mutated AML patients treated with IDH inhibitors  in two populations (newly diagnosed IDH-mutated AML patients and R/R IDH-mutated AML patients) based on treatment response and survival. This is the first systematic review and meta-analysis to evaluate the efficacy and safety of IDH inhibitors in IDH-mutated AML patients. At present, other drug regimens for the treatment of AML patients with IDH mutations mainly include cytarabine and anthracycline induction/consolidation, and venetoclax alone or in combination . We aimeSince Mardis et al. first reported AML patients with IDH1 and IDH2 mutations in 2009 , researcOur meta-analysis showed that IDH inhibitors combined with other agents were approximately twice as effective as IDH inhibitors alone . It has been reported that IDH1 mutations may be associated with worse prognosis in AML patients and IDH2 mutations may be associated with better prognosis in AML patients , 41. In The studies included in our manuscript involved two combination strategies: IDH inhibitors combined with azacitidine with or without other anticancer agents, and IDH inhibitors combined with intensive chemotherapy. Impaired cellular differentiation and leukemic development in IDH-mutated AML patients are associated with 2-hydroxyglutarate (2-HG) production and DNA hypermethylation caused by IDH gene mutations. In addition, AML patients with IDH mutations may have concomitant mutations in DNMT3A . TherefoR/R AML Patients have been a major challenge in AML treatment. Patients with refractory or relapsed AML (R/R AML) have a very poor prognosis with a median survival of less than 6\u00a0months and a 3-year overall survival (OS) of no more than 10%. In the subgroup analysis of three clinical studies \u201345, the Most AML patients are elderly, and adverse events associated with anticancer drugs are important because they generally tolerate anticancer drugs poorly due to poor physical fitness. Our detailed meta-analysis of adverse events associated with IDH inhibitors showed that all grades of adverse events commonly (>\u200915%) occur in IDH-mutated AML patients treated with IDH inhibitors are nausea (30%), blood bilirubin increased (24%), diarrhea (24%), constipation (23%), vomiting (21%), thrombocytopenia(20%), neutropenia(18%), anemia (17%) and\u00a0decreased appetite (17%), most of which are gastrointestinal adverse events. Common (>\u20095%) grade\u2009\u2265\u20093 adverse events were neutropenia (24%), thrombocytopenia (21%), anaemia (14%), febrile neutropenia (12%), sepsis (10%), blood bilirubin increased (8%), pneumonia (8%) and\u00a0electrocardiogram QT prolongation (6%), most of which are haematological adverse events. Differentiation syndrome is a potentially fatal worrisome adverse event that manifests clinically as dyspnea, fever, weight gain, unexplained hypotension, acute renal failure, and pulmonary infiltrates or pleural pericardial effusion on chest radiography . ApproxiThis meta-analysis has five limitations. First of all, our meta-analysis of survival outcomes in newly diagnosed AML patients with IDH mutations and R/R AML patients with IDH mutations lacked long-term survival  analyses. Future clinical studies are expected to provide long-term survival outcomes. Second, differences in follow-up time and age between studies may have some impact on the results. Third, The sample size of some articles included was small. Forth, too few R/R AML patients with IDH1 mutations (0% or 22.20%) were included for efficacy analysis of IDH inhibitors in IDH-mutated R/R AML. See Additional file IDH inhibitor is a promising therapy for R/R AML patients with IDH mutations, which is of great significance for individualized and precise treatment of R/R AML patients with IDH mutations. IDH inhibitors alone and in combination with other drugs have not been significantly more effective than other current therapies (e.g. venetoclax-based drug regimen) in the treatment of newly diagnosed AML patients with IDH mutations. For newly diagnosed AML patients with IDH mutations, clinicians should avoid using IDH inhibitors alone and pay attention to the low CR rate that IDH inhibitors may cause. When IDH inhibitors are used, clinicians should pay high attention to the occurrence of differentiation syndrome, and make early diagnosis and timely treatment. However, we need more large samples and high quality RCTs in the future to prove and supplement our conclusions.Additional file 1. Figure S1: Forest plot of all grades adverse events related to IDH inhibitors. Figure S2: Forest plot of grade \u2265 3 adverse events related to IDH inhibitors. Figure S3: The ORR rate of newly diagnosed AML patients with IDH mutation treated by IDH inhibitor combined therapy(excluding IDH inhibitors combined with intensive chemotherapy). Figure S4: The 2-year OS rate of newly diagnosed AML patients with IDH mutation treated by IDH inhibitor combined therapy(excluding IDH inhibitors combined with intensive chemotherapy). Table S1: Quality evaluation of RCTs according to modified Jadad scale. Table S2: Quality evaluation of non-randomized prospective cohort studies according to Methodological Index for Non-Randomized Studies Trials. Table S3: Egger\u2019s and Begg's tests of all results. Table S4: IDH gene mutation in AML patients involved in efficacy analysis."}
+{"text": "Ventilated hospital-acquired bacterial pneumonia (vHABP) is a major source of morbidity & mortality in hospitalized patients. Clinical risk scores and systemic biomarkers have limited clinical & prognostic utility in vHABP. Alveolar biomarkers\u2014specifically alveolar neutrophilia (AN), the percentage of polymorphonuclear cells (PMN%) present in bronchoalveolar lavage (BAL) fluid\u2014gauge the host inflammatory response directly at the site of infection, offering an attractive but untested predictive risk biomarker in vHABP. We aimed to generate preliminary data exploring AN as a vHABP biomarker.We performed a retrospective cohort study of intensive care unit (ICU) patients with vHABP from 2010-2023. vHABP was defined as development of acute hypoxic respiratory failure requiring invasive mechanical ventilation, clinical suspicion of pneumonia by treating teams prompting performance of BAL respiratory culture, and BAL PMN% > 50%. Patient demographic characteristics, comorbidities and acute severity of illness metrics were abstracted via chart review. PMN% values were dichotomized using median split rounded to the nearest PMN% decile ( > or < 80% PMN% in BAL fluid). Study outcomes included ventilator-free days, ICU length of stay and vHABP-directed antibiotic treatment duration within 30 days of vHABP.44 patients met study inclusion criteria. 30 (68%) had a BAL neutrophil of > 80%. Patients with BAL PMN > 80% had a numerically higher use of tracheostomy and trend towards lower P/F ratio at the time of vHABP diagnosis [Table 1]. BAL PMN > 80% was associated with a 15% decrease in ventilator-free days (p < 0.01) and a 25% longer ICU length of stay (p < 0.01) than those with BAL PMN < 80% [Figure 1]. There was no significant difference in post-BAL vHABP-directed antibiotic duration in patients with and without BAL PMN > 80%.Though limited by low sample size, this exploratory study suggests AN may be a potentially useful predictive risk biomarker in vHABP. Larger-scale, prospective studies of alveolar biomarkers\u2014including AN\u2014in vHABP are warranted.Owen Albin, MD, Charles River Laboratories: Advisor/Consultant|Shionogi: Advisor/Consultant"}
+{"text": "Correction: BMC Trials (2022) 23:986https://doi.org/10.1186/s13063-022-06907-4Following publication of the original article , we haveOriginally published:Consecutive patients presenting with suspected acute coronary syndrome between July 2022 and Apr 2024 were included.Corrected phrase (2022 becomes 2021):Consecutive patients presenting with suspected acute coronary syndrome between July 2021 and Apr 2024 were included.The original article has been corrected."}
+{"text": "Studies consistently show that patients with prescription opioid use disorder (OUD) respond to buprenorphine treatment. Few studies have followed these patients in the long-term. Our longitudinal research has shown opioid abstinence to be associated most strongly with opioid agonist/partial agonist treatment. We also found that many patients used agonist treatment inconsistently; questions remain about the benefits of intermittent opioid agonist treatment.We examined patients during the 3.5 years following their entry into a 3-month trial of treatment for prescription OUD. The current analysis compared opioid use outcomes among patients who reported receipt of agonist treatment consistently, inconsistently, or never.This secondary analysis (N=309) of a U.S. multi-site randomized controlled trial of treatment for prescription OUD assessed variability in receiving opioid agonist treatment during the 3.5-year follow-up period, and the association between agonist treatment and opioid abstinence. Assessments were collected at months 18, 30, and 42 following treatment entry; patients were asked if they were currently taking agonist treatment and whether they had used other opioids in the previous month. Patients with only one follow-up assessment (n=29) were excluded from this analysis.Most patients reported current opioid abstinence on at least one follow-up visit: 38% were always abstinent, 41% sometimes, and 21% never. Twenty-three percent always reported currently using agonist treatment, 26% sometimes, and 51% never. Patients consistently reporting agonist use were most likely to always be opioid-abstinent in the past month (69%), with 25% sometimes and 6% never abstinent. Patients who never reported agonist use were equally likely to be abstinent never (32%), sometimes (35%), and always (32%). Patients who sometimes reported receiving agonists were most likely to report abstinence sometimes (65%); 14% never reported abstinence, and 21% always did.Those consistently receiving agonist treatment were more likely to always be opioid-abstinent (69%) than those sometimes (21%) or never (32%) receiving agonists. Those never receiving agonist treatment were more likely to never report opioid abstinence (32%) than were those sometimes (14%) or always (6%) receiving agonists. Interestingly, those who sometimes received agonists were more likely to be abstinent than those who never received agonists: those who sometimes received agonists were more likely to be abstinent sometimes than those who never received agonists (65% vs. 35%) and less likely to never be abstinent than were those who never received agonists (14% vs. 32%).Receiving opioid agonist treatment has been shown to be associated with opioid abstinence during long-term follow-up. This study shows that even those who only inconsistently receive agonists are also likely to benefit.R. Weiss Consultant of: Alkermes, M. Griffin: None Declared"}
+{"text": "Objectives: To estimate the public health impact of annual vaccination of children with a quadrivalent live-attenuated influenza vaccine (QLAIV) across Europe.Methods: A deterministic, age-structured, dynamic model was used to simulate influenza transmission across 14 European countries, comparing current vaccination coverage using a quadrivalent inactivated vaccine (QIV) to a scenario whereby vaccination coverage was extended to 50% of 2\u201317 year-old children, using QLAIV. Differential equations described demographic changes, exposure to infectious individuals, recovery and immunity dynamics. For each country, the basic reproduction number (R0) was calibrated to published influenza incidence statistics. Assumed vaccine efficacy for children was 80% (QLAIV) and 59% (QIV). Symptomatic cases cumulated over 10 years were calculated per 100 000 person-years. One-way sensitivity analyses were conducted on QLAIV efficacy in 7\u201317 year-olds (59% instead of 80%), durations of natural  and QLAIV vaccine-induced immunity , and R0 .Results: Across countries, annual QLAIV vaccination additionally prevents 1366\u20133604 symptomatic cases per 100 000 population . Among children (2\u201317 years), QLAIV prevents 551\u20131555 cases per 100 000 population . Among adults, QLAIV indirectly prevents 726-2047 cases per 100 000 population . The most impactful drivers of total protection were duration of natural immunity against influenza A, R0 and QLAIV immunity duration and efficacy. In all evaluated scenarios, there was a large direct and even larger indirect protection compared with the reference scenario.Conclusions: The model highlights direct and indirect protection benefits when vaccinating healthy children with QLAIV in Europe, across a range of demographic structures, contact patterns and vaccination coverage rates."}
+{"text": "Since September 2022, bivalent mRNA COVID-19 vaccines have been recommended in the United States, but the variants these vaccines were designed to protect against are no longer circulating widely. In September and October 2023, the Food and Drug Administration approved and authorized updated 2023\u20132024 Formula monovalent XBB.1.5 component\u2013containing COVID-19 vaccines, formulated to target current variants more closely, specifically Omicron variant XBB.1.5, for persons aged \u22656 months.On September 12, 2023, the Advisory Committee on Immunization Practices recommended vaccination with updated COVID-19 vaccines for all persons aged \u22656 months.The updated COVID-19 vaccines are meant to broaden vaccine-induced immunity and provide protection against the currently circulating SARS-CoV-2 XBB-sublineage variants including against severe COVID-19\u2013associated illness and death.COVID-19 vaccines protect against severe COVID-19\u2013associated outcomes, including hospitalization and death. As SARS-CoV-2 has evolved, and waning vaccine effectiveness has been noted, vaccine formulations and policies have been updated to provide continued protection against severe illness and death from COVID-19. Since September 2022, bivalent mRNA COVID-19 vaccines have been recommended in the United States, but the variants these vaccines protect against are no longer circulating widely. On September 11, 2023, the Food and Drug Administration (FDA) approved the updated (2023\u20132024 Formula) COVID-19 mRNA vaccines by Moderna and Pfizer-BioNTech for persons aged \u226512 years and authorized these vaccines for persons aged 6 months\u201311 years under Emergency Use Authorization (EUA). On October 3, 2023, FDA authorized the updated COVID-19 vaccine by Novavax for use in persons aged \u226512 years under EUA. The updated COVID-19 vaccines include a monovalent XBB.1.5 component, which is meant to broaden vaccine-induced immunity and provide protection against currently circulating SARS-CoV-2 XBB-sublineage variants including against severe COVID-19\u2013associated illness and death. On September 12, 2023, the Advisory Committee on Immunization Practices recommended vaccination with updated COVID-19 vaccines for all persons aged \u22656 months. These recommendations will be reviewed as new evidence becomes available or new vaccines are approved and might be updated.By the end of 2022, COVID-19 vaccines had prevented 18.5 million COVID-19 hospitalizations and 3.2 million COVID-19 deaths in the United States  and infants aged <6 months are at highest risk for COVID-19\u2013associated hospitalization. During January 1\u2013August 26, 2023, COVID-19\u2013associated hospitalization rates among adults aged \u226575 years were two to three times as high as those among the next youngest age group (adults aged 65\u201374 years). Rates among infants aged <6 months are similar to those among adults aged 65\u201374 years  that the true effect lies close to that of the estimated effect. Evidence that includes only randomized controlled trials begins at high certainty, whereas evidence that includes observational data begins at low certainty.Among adolescents and adults, benefits of bivalent vaccination were assessed using pooled observational VE data for three outcomes: medically attended COVID-19,www.cdc.gov/vaccines/acip/recs/grade/covid-19-2023-2024-Monovalent.html.Studies from the Vaccine Safety Datalink (VSD), a postauthorization vaccine safety monitoring system, were used to assess rates of serious adverse events  that have been associated with vaccination Additional, updated CDC VE data were also reviewed, including data showing patterns of waning bivalent vaccine\u2013induced immunity against infection and COVID-19\u2013associated hospitalization during a period with increased Omicron XBB sublineage circulation . Among adults aged 50\u201364 years, the incremental cost-effectiveness ratio of updated COVID-19 vaccines was estimated to be $25,787 per quality-adjusted life year, with estimates in those aged \u226550 years robust to input changes across plausible ranges  COVID-19 vaccine for all persons aged \u22656 months.Infants and children aged 6 months\u20134 years are recommended to receive a multidose initial series (previously referred to as the primary series) and at least 1 updated mRNA COVID-19 vaccine dose depending on vaccination history as defined herein. Infants and children aged 6 months\u20134 years who are unvaccinated are recommended to receive either 2 updated Moderna COVID-19 vaccine doses or 3 updated Pfizer-BioNTech COVID-19 vaccine doses . InfantsFor those receiving updated mRNA COVID-19 vaccines, persons aged \u22655 years without immunocompromise are recommended to receive 1 updated COVID-19 vaccine dose, irrespective of previous COVID-19 vaccination history . For thoUnvaccinated persons aged 6 months\u201311 years who are moderately or severely immunocompromised are recommended to receive an initial vaccination series of 3 homologous updated (2023\u20132024 Formula) mRNA COVID-19 vaccine doses. Unvaccinated persons aged \u226512 years who are moderately or severely immunocompromised can complete an initial vaccination series with 3 homologous doses of updated mRNA or 2 doses of updated Novavax COVID-19 vaccine.https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vaccines-us.html.Persons who are moderately or severely immunocompromised, have completed an initial series, and have received \u22651 updated COVID-19 vaccine dose, may receive additional updated COVID-19 vaccine doses, guided by the clinical judgment of a health care provider and personal preference and circumstances. Any further additional doses should be administered \u22652 months after the last COVID-19 vaccine dose. Additional clinical considerations, including detailed schedules and tables by age and vaccination history for those who are and are not moderately or severely immunocompromised, are available at COVID-19 vaccines are transitioning from federal procurement and distribution into the commercial marketplace during fall 2023. Under the Affordable Care Act (ACA), ACIP recommendations for routine immunization that have been adopted by CDC and are listed on CDC Immunization Schedules are required to be covered by group health plans and health insurance issuers offering group or individual health insurance coverage without cost-sharing requirements. The Coronavirus Aid, Relief, and Economic Security (CARES) Act expedited coverage for COVID-19 vaccines; since January 5, 2021, ACA-covered insurers must cover, without cost sharing, any COVID-19 vaccine FDA authorized under an EUA or FDA approved under a Biologics License Application immediately upon authorization or approval of the vaccine (https://vaers.hhs.gov or by telephone at 1-800-822-7967.Adverse events after vaccination should be reported to the Vaccine Adverse Event Reporting System (VAERS). Reporting is encouraged for any clinically significant adverse event even if it is uncertain whether the vaccine caused the event. Information on how to submit a report to VAERS is available at"}
+{"text": "Avibacterium paragallinarum (AP) strains isolated from chickens in the absence of clinical signs. The availability of these genomes can aid scientists in improving current diagnostics and increase our understanding of AP epidemiology and pathogenicity in chickens.We report the complete genome sequences of two non-typical  Avibacterium paragallinarum (AP) is a primary pathogen and causes infectious coryza (IC) disease in chickens , Ohio Department of Agriculture. The two isolates were sequenced by both Illumina and Oxford Nanopore Technologies (ONT).chickens \u20133. Therehickens \u2013\u20136. HowevSRR17662949. This strain (AG21-0333) was sent to ISU to conduct the nanopore sequencing. For ONT sequencing, DNA extraction was prepared using the Circulomics Nanobind CBB Big DNA Kit , the gram-negative bacteria high molecular weight DNA extraction protocol. Nanopore libraries were prepared using the Ligation Sequencing (SQK-LSK109) and native barcoding (EXP-NBD104) kits according to the manufacturer\u2019s protocol . The library was loaded onto an FLO-MIN106 R9.4.1 flow cell and sequenced with the MinION device . FastQC v0.11.9 was used to assess read quality for both strains   as previously described . The extherwise) . Bases bg SQK-LSK9 and natGenomic features of the ntAP genomes confirmed their classification as AP; however, the genomic analysis showed meaningful differences from typical AP isolates."}
+{"text": "Invasive pulmonary mucormycosis (IPM) is a common and deadly mold infection in patients (pts) with hematological malignancies (HM). Comparing chest x-ray (CXR) to computed tomography (CT) in IPM offers the opportunity to evaluate the concordance of these two imaging studies and the clinical significance of discordant imaging.We reviewed all HM pts with CT-positive probable/proven IPM at MD Anderson Cancer Center (2000-2020) who had a concurrent CXR performed within 5 days of the reference CT. Concordant imaging was defined as a consolidation or mass-like lesion on CXR matching the suspicious CT lesion. In addition to survival curve analysis, a multivariate Cox's proportional hazard model was used to identify independent predictors of 84-day all-cause mortality after IPM symptom onset.Among 44 included pts, 31 (70%) were neutropenic (< 500/\u00b5L). Only 24 pts (55%) had a matching lesion on CXR while the remaining 20 (45%) had discordant imaging. 20/29 pts (69%) with consolidation on CT and 9/12 pts (75%) with reverse halo sign or nodules with cavitary lesions had concordant CXR findings, whereas nodules without these features were rarely associated with concordant CXR findings . Although infection severity at baseline (APACHE II scores 15 vs. 16) was comparable, pts with concordant CXR lesions tended to have higher rates of intensive care unit admission during IPM therapy  and higher 84-day mortality  than those with discordant imaging. This difference was corroborated by survival curve analysis , even when restricted to the 31 neutropenic pts . APACHE II score > 18 at IPM diagnosis , neutrophil recovery , and presence of a concordant CXR lesion  were independent predictors of 84-day mortality (Table 1).Figure 1Table 1Even when accounting for neutropenia status, a known confounder of radiographic imaging in IPM pts, visualization of IPM on CXR concordant to CT was an independent predictor of poor outcomes, possibly as a surrogate of extensive lesions and high fungal burden. If confirmed in larger cohorts, CXR might be used as a supportive prognostic staging tool in IPM pts, especially in resource-poor settings.Dimitrios P. Kontoyiannis, MD, MS, ScD, PhD, AbbVie: Board Member|Astellas: Grant/Research Support|Cidara: Board Member|Gilead: Grant/Research Support|Merck: Advisor/Consultant|Scynexis/MSGERC: Board Member"}
+{"text": "Nereididae is among the most familiar of marine annelid families, common and well-studied in most marine environments but paradoxically no recent key or identification guide exists to the world\u2019s genera. Here updated generic descriptions, a list of characters, a linear key to genera, and minimal diagnoses that distinguish each genus from all others in the family are provided. This information is generated from a Delta database of 186 morphological characters and a link is provided to downloadable software allowing the same data to be interrogated using the open-source Delta program Intkey \u2013 a nonlinear multiple entry point computerised interactive key. For each genus the recent literature is also summarised, comments on taxonomic status provided, and published keys to species cited. Nexus format matrices are provided for all 45 genera and 158 Nereididae species, representing all genera, scored for 146 multistate characters from the same character list to facilitate future phylogenetic studies. Nereididae is probably the best-known of all the families of marine annelids (\u201cpolychaetes\u201d) \u2013 the family includes many species that are commonly encountered world-wide, intertidally, and also in diverse habitats from ephemeral freshwaters to abyssal depths . Nereididae are almost invariably used as exemplars of marine Annelida in invertebrate zoology textbooks  and a downloadable interactive identification tool (= Taxonomic Information System) using the Delta Intkey software ;to discriminate all genera based on minimal diagnoses (see Systematic account of genera);to provide a character list (see Nereididae characters) and Nexus format data matrices  for inclNereididae taxa (CSIRO)is still available as Windows only software via We used the Delta (Descriptive Language for Taxonomy) suite of programs to create and manage taxonomic data to support objective and quantitative description and discrimination of dae taxa . The oriNereididae genera), linear keys (see below and Key to genera of Nereididae), interactive keys and Nexus files .Delta comprises several separate applications: the Delta Editor manages taxon by character data and generates outputs via scripts . For the purposes of this paper, principal outputs are natural language descriptions and diagnoses of taxa .We concur with RBASE = 2.00 ABASE = 1.00 REUSE = 1.01 VARYWT = 0.80; Number of confirmatory characters = 2. Following the recommendation of RBASE), evenness of subdivisions based on abundance indices, , minimising re-use of characters (REUSE) and treatment of variable characters (VARYWT); The key was generated by the Delta Confor program with the following settings: Characters and character states are described and illustrated in the following section. The downloadable Intkey interactive key associated with this paper includes a more comprehensive set of character state illustrations. Two Nexus files are provided as Suppl. materials Nereididae are available as a separate download  andMuseum Victoria (NMV),or derived from the literature as credited in the figure captions. Some characters are included even though their potential to inform higher level relationships are not yet tested, for example: palpophore surface (character 4), and prostomium longitudinal groove (character 9). We have also included some characters useful for distinguishing species . Meristic characters, in particular paragnath counts, are thus far rarely used to characterise nereidid genera \u2013 typically such characters require data from large numbers of specimens if they are to be the basis of robust taxonomic conclusions  and Unanereiszghali). Nereididae specimens, in which case both species of Unanereis may be referable to Ceratonereis or Solomononereis.All 2. Palps [NEXUS: palp orientation]anteriorly directed.ventrally directed.Nereisagulhana. However, in some taxa, e.g., Micronereis and some Kainonereis and Platynereis species, the palps are distinctly ventrally directed and not fully visible in dorsal view. Examples of ventrally directed palps are Micronereisbansei, Kainonereisalata and Platynereisaustralis. Caution is required utilising this character alone for identification since, at least in Kainonereis and Platynereis, this condition seems to be expressed in epitokes and not always confirmed for atokes. Furthermore, it is plausible that palps which may have been ventrally directed in live epitokes may be distorted into an anteriorly directed palps orientation as an artefact caused by preservation with pharynx extended  sub-ovoid , obtusely conical , and subconical  ). The present 2-state system is an attempt to describe more effectively the variation in the family. Thus, barrel-shaped palpophores (most genera) have an approximately equal width from base to palpostyle. They are not overly large compared to the size of the palpostyle, and in some cases may be of similar length and usually they have a transverse groove  , b. Howeove Fig. . Variabi4. Palpophore surface [NEXUS: palpophore surface]without grooves or striae .Nereididae except members of the genus Micronereis which have an undivided roughly spherical palp that is also ventrally located on the anterior prostomium; see Micronereisbansei).A biarticulate palp with a distinct distal palpostyle is present in all 6. Palpostyles for m [NEXUS: palpostyles form]spherical.subconical.acutely conical.Micronereis) are recognised as having three shapes: spherical, subconical , and acutely conical. The palpostyles are spherical in members of the Namanereidinae, as illustrated by Namalycastisabiuma). Some members of the genera Ceratocephale and Gymnonereis have palpostyles that are acutely conical e.g., Ceratocephaleaureola), Gymnonereisminyami), Perinereiscaeruleis). This character is also useful for species separation across several unrelated genera of Nereididae.Palpostyles  and Neanthesbioculata).Two pairs of eyes are present in most 8. Prostomium anterior margin [NEXUS: prostomium anterior margin]entire Fig. .indented , Namalycastisborealis) and Ceratonereis spp.).The prostomium in 9. Prostomium longitudinal groove [NEXUS: prostomium longitudinal groove]present  distinguishes Namalycastis and Namanereis from most other nereidids.Terminology for characters 10 and 11 follows 11. Tentacular belt [NEXUS: tentacular belt divided]fused, separate segments not recognisable.represented by two distinct segments each carrying a pair of tentacular cirri.12. Tentacular cirri comprising [NEXUS: tentacular cirri number]four pairs.three pairs.13. Tentacular cirrophores [NEXUS: tentacular cirrophores]1. present.2. absent (cirri undivided).14. Tentacular cirri extending to chaetiger (number)Ceratonereis spp. and Platynereis spp.). Generally the posterodorsal pair is the longest.Small variations in the length of these cirri on the tentacular belt is often not a useful statistic, but may assist in recognising taxa which have very long tentacular cirri  are a pair of organs that are prominent and easily visible if present, but only by dissection. The oesophageal caeca are located immediately posterior to the muscular pharynx. at the start of the oesophagus. Their utility in taxonomy was first suggested by 18. Jaws [NEXUS: jaw dentition]with smooth or slightly crenulate cutting edge Fig. .with dentate cutting edge Fig. .Neanthes spp., Perinereis spp.), while others have finer, translucent jaws . However, many taxa are intermediate between these conditions, and abrasion may falsely result in the appearance of \u201csmooth\u201d jaws. Differences in the chemical composition of nereidid jaws may offer the best opportunity to distinguish taxa, but these studies have yet to be undertaken systematically.Variation in jaw morphology is as yet not well understood. Some taxa have jaws with smooth or faintly crenulate cutting edge, while others have distinctly or indistinctly toothed jaws. In some taxa the jaws are robust and dark  and Neanthescapensis).These are the smooth bar paragnaths of Thus, bar-like paragnaths are distinct from \u201cmelted paragnaths\u201d described and illustrated by 42. Area IV smooth bar-like paragnaths: numberNeanthes and Perinereis, in addition to cones a separate patch of bar-shaped paragnaths occurs at the maxillary end of Area IV; these bars are counted separately.Paragnaths on Area IV are typically roughly conical in shape, though variations range from flattened domes of irregular shape to tooth-like paragnaths. In some taxa, particularly species of 43. Area IV rod-like paragnaths [NEXUS: Area IV rodlike paragnaths]present.absent.44. Area IV rod-like paragnaths: number45. Oral ring papillae [NEXUS: oral ring papillae]present.absent.46. Oral ring papillae: number47. Oral ring papillae arrangement [NEXUS: oral ring papillae arrangement]solitary.arranged in tufts.48. Area V papillae [NEXUS: Area V papillae]present.absent.49. Area V papillae: numberCeratocephale spp., Area V and VI contain up to three papillae in total; these are here interpreted as all occurring in Area V, with VI = 0,0.In 50. Area VI papillae [NEXUS: Area VI papillae]present.absent.51. Area VI papillae: number52. Areas VII-VIII papillae [NEXUS: Areas VIIVIII papillae]present.absent.53. Areas VII-VIII papillae: number54. Areas VII-VIII papillae arranged [NEXUS: Areas VIIVIII papillae rows]in a single row.in a double row.nd (posterior) row may be hard to see unless the pharynx is completely everted.Where a double row of papillae is present, the 255. Oral ring paragnaths [NEXUS: oral ring paragnaths]present.absent.56. Oral ring paragnaths (discrete or continuous) [NEXUS: oral ring paragnaths arranged]with Areas V, VI and VII-VIII discrete.comprising a continuous ring dorsally and ventrally, discrete groups not recognisable.57. Oral ring paragnaths on Areas V and VI (discrete or continuous) [NEXUS: Areas VVI paragnaths]form discrete groups.continuous, not recognisably distinct.58. Oral ring pyramidal paragnaths Fig.  [NEXUS: present.absent.Pyramidal paragnaths have a quadrangular base and taper to a pointed apex : 309.59. Crown-shaped oral ring paragnaths Fig.  [NEXUS: present.absent.60. Crown-shaped oral ring paragnaths: number61. Area V conical paragnaths [NEXUS: Area V conical paragnaths]present.absent.62. Area V conical paragnaths: number63. Area V conical paragnaths arranged [NEXUS: Area V cones arranged]in a triangle.in a longitudinal line.irregularly.64. Area VI paragnaths [NEXUS: Area VI paragnaths]present.absent.65. Area VI paragnaths arranged [NEXUS: Area VI paragnaths arranged]in a roughly circular group.in lines or arcs.Neanthes, an alternative arrangement of cones occurs: a distinct line or arc.Area VI paragnaths are usually arranged in a circular or irregular compact group (sometimes of only one or two paragnaths). In some species of 66. Area VI conical paragnaths [NEXUS: Area VI conical paragnaths]present.absent.67. Area VI conical paragnaths: number68. Area VI smooth bars Fig.  1. present.2. absent.73. Area VI rod-shaped paragnaths: number of rows74. Areas VII-VIII paragnaths [NEXUS: Areas VIIVIII paragnaths]present.absent.75. Areas VII-VIII conical paragnaths [NEXUS: Areas VIIVIII cone paragnaths]present.absent.76. Areas VII-VIII conical paragnaths: numberAreas VII-VIII typically forms a continuous ventro-lateral band of paragnaths and is recorded as such. In a few taxa the Areas VII-VIII band of paragnaths is extended through the dorsal region and encircles the oral ring of the pharynx; in this case even though the band nominally extends through the dorsal Areas V and VI, they are indistinguishable and the count is recorded for Areas VII-VIII.77. Areas VII-VIII conical paragnaths arranged [NEXUS: Areas VIIVIII cones arranged]in isolated patches.in one or more irregular lines forming a continuous band.Cheilonereisperistomialis Benham, 1916, the paragnaths on Areas VII-VIII are arranged in distinct isolated patches. In other nereidids the arrangement is an irregular but continuous band made up one or more rows deep.In a few nereidid species, e.g., 78. Areas VII-VIII conical paragnaths (size distribution) [NEXUS: Areas VIIVIII cones sizes]similar in size, or irregular mix of large and small paragnaths in a single band.differentiated, with a separate band of minute paragnaths also present.Typically the paragnaths on Areas VII-VIII comprise a variety of sizes irregularly arranged. However, in some taxa there is differentiation into an anterior band of paragnaths similar in size to elsewhere on the proboscis, and a separate band of minute paragnaths.79. Areas VII-VIII P-bar paragnaths Fig.  [NEXUS: present.absent.80. Areas VII-VIII P-bar paragnaths (interspersed/discrete) [NEXUS: Areas VIIVIII Pbar arrangement]interspersed with conical paragnaths.forming a separate band.81. Areas VII-VIII rod-shaped paragnaths Fig.  present.absent.Ceratocephaleloveni) and by Ceratocephaleandaman) that presence/absence of mid-dorsal papilla is variable and likely to be related to size or sexual maturity. However, the description of Ceratocephalepapillata de Le\u00f3n-Gonz\u00e1lez & G\u00f3ngora-Garza, 1992 is based on 155 specimens, all of which have mid-dorsal papilla. In other species of Ceratocephale, observations on mid-dorsal papillae should be interpreted with caution.It has been shown by 87. Transverse dorsal lamellae mid-dorsal papilla commencing chaetiger88. Notopodium [NEXUS: notopodium development]with at least one distinct ligule or lobe.strongly reduced, without distinct lobes or ligules.According to nautical wisdom, boats are defined as vessels able to be carried on ships. Parapodial lobes and ligules are distinguished according to a similar logic: lobes can be carried on ligules, but not vice versa. In general, ligules are larger and flatter than the smaller, conical lobes.89. Dorsal notopodial ligule Fig.  chaetiger 1.chaetiger 3.chaetiger 4.chaetiger 5.91. Dorsal notopodial ligule, length on anterior chaetigers [NEXUS: dorsal notopodial ligule anterior]markedly elongate.not markedly elongate.markedly reduced.92. Dorsal notopodial ligule, length on posterior chaetigers [NEXUS: dorsal notopodial ligule posterior]markedly elongate Fig. .not markedly elongate.93. Dorsal notopodial ligule, breadth on posterior chaetigers [NEXUS: dorsal notopodial ligule posterior width]markedly broader Fig. .not markedly broader.94. Dorsal notopodial ligule, reduction on posterior chaetigers [NEXUS: dorsal notopodial ligule posterior size]absent Fig. .markedly reduced.not markedly reduced Fig. .95. Dorsal notopodial ligule (divided into branchiae or not) [NEXUS: dorsal notopodial branchiae]divided into numerous branchial filaments Fig. .not divided into numerous branchial filaments.Dendronereides is the dorsal notopodial ligule divided into numerous branchial filaments. The branchial structures of Dendronereides and Dendronereis are therefore not homologous.Only in 96. Prechaetal notopodial lobe Fig.  smaller than dorsal notopodial ligule on anterior chaetigers, usually reduced or absent posteriorly.approximately equal to length of dorsal notopodial ligule at least on anterior chaetigers (thus notopodium of three similar sized ligules/lobes).98. Prechaetal notopodial lobe distribution [NEXUS: prechaetal noto lobe location]present on all chaetigers (may be reduced in size on posterior chaetigers).restricted to a limited number of anterior chaetigers.99. Prechaetal notopodial lobe, reducing in size posteriorly, last present at approx. chaetiger100. Notopodial acicular process .101. Notopodial acicular process reducing in size posteriorly, last present on chaetiger102. Notopodial acicular ligule Fig.  similar to or shorter than neuropodial acicular ligule.prolonged, distinctly longer than neuropodial acicular ligule.reduced, much shorter than neuropodial acicular ligule.104. Dorsal cirrus (divided into branchiae or not) [NEXUS: dorsal cirrus branchiae]divided into numerous branchial filaments Fig. .not divided into numerous branchial filaments.Dendronereis does the dorsal cirrus form numerous branchial filaments. The branchial structures of Dendronereides and Dendronereis are therefore not homologous.Only in 105. Dorsal cirrus Fig.  length o106. Dorsal cirrus: sub-terminally attached to dorsal notopodial ligule on posterior chaetigers, or not [NEXUS: dorsal cirrus subterminal]sub-terminally attached to dorsal margin of dorsal notopodial ligule on posterior chaetigers Fig. .not sub-terminally attached to dorsal notopodial ligule on posterior chaetigers.107. Dorsal cirrus terminally attached to dorsal notopodial ligule on posterior chaetigers, or not [NEXUS: dorsal cirrus terminal]terminally attached to dorsal notopodial ligule on posterior chaetigers.not terminally attached to dorsal notopodial ligule on posterior chaetigers.108. Dorsal cirrus terminally attached, or not [NEXUS: dorsal cirrus terminal all]terminally attached throughout, so that dorsal notopodial ligule has appearance of a cirrophore for the dorsal cirrus.not terminally attached throughout all chaetigers.109. Dorsal cirrus (with/without cirrophore) [NEXUS: dorsal cirrophore]simple, lacking basal cirrophore  [NEXUS: dorsal cirrophore expanded]expanded and leaflike , for example in some species of Ceratonereis but we contend that these are misinterpretations.Terminology after 115. Neuropodial prechaetal lobe present on chaetigers116. Neuropodial prechaetal lobe development [NEXUS: neuropodial prechaetal lobe form]projecting beyond postchaetal lobe (at least in anterior chaetigers).not projecting beyond the postchaetal lobe.117. Neuropodial postchaetal lobe .absent.127. Accessory ventral cirrus commencing chaetiger128. Relative length of paired ventral cirri [NEXUS: accessory ventral cirri length]superior ventral cirrus of chaetigers 10\u201320 longer than inferior cirrus Fig. .superior ventral cirrus of chaetigers 10\u201320 and inferior cirrus similar in length Fig. .superior ventral cirrus of chaetigers 10\u201320 shorter than inferior cirrus.Ceratocephale the superior cirrus is always the longer of the pair, especially on the first few chaetigers. However, in at least one species, Ceratocephalepapillata, the superior cirrus is shorter than the inferior cirrus on anterior-most 10\u201320 chaetigers.In most 129. Notoaciculae on chaetigers 1 and 2 [NEXUS: notoaciculae chaetigers 1 2]present.absent.Ceratonereismirabilis and related species, notoaciculae of chaetigers 1 and 2 are present, but are short and translucent even though those of subsequent chaetigers are dark and extend to the tip of the acicular ligule. Namalycastis and Namanereis have notoacicula in chaetigers 1 and 2, although like notoaciculae in remaining chaetigers, they sit just above the neuroaciculae in the upper part of the neuropodium.Presence of notoaciculae in chaetigers 1 and 2 is difficult to observe and failure to mention this character in published descriptions cannot be taken as evidence of absence. It is necessary to manipulate the parapodia with transmitted light, or, preferably in small specimens, to remove and mount parapodia on slides. In 130. Notochaetae of chaetigers 3 and 4 [NEXUS: notochaetae chaetigers 3 4]present.absent.131. Notochaetae: heterogomph spinigers [NEXUS: notochaetae heterogomph spinigers]present.absent.Chaetal shaft with heterogomph articulation is illustrated in Fig. 132. Notochaetae: homogomph spinigers [NEXUS: notochaetae homogomph spinigers]present.absent.Chaetal shaft with homogomph articulation is illustrated in Fig. 133. Notochaetae: sesquigomph spinigers [NEXUS: notochaetae sesquigomph spinigers]present.absent.Nereididae species before adopting new terms and a revised assessment of their taxonomic significance.Chaetal shaft with sesquigomph articulation is illustrated in Fig. 134. Notochaetae: homogomph falcigers Fig.  distally bifid  Fig.  [NEXUS: present.absent.157. Neurochaetae dorsal fascicle: simple chaetae  present from chaetiger158. Neurochaetae dorsal fascicle: homogomph falcigers in anterior chaetigers [NEXUS: neurochaetae dorsal fascicle homogomph falcigers anterior]present.absent.159. Neurochaetae dorsal fascicle: homogomph falcigers on posterior chaetigers [NEXUS: neurochaetae dorsal fascicle homogomph falcigers posterior]present.absent.160. Neurochaetae ventral fascicle: sesquigomph falcigers [NEXUS: neurochaetae ventral fascicle sesquigomph falcigers]present.absent.161. Neurochaetae ventral fascicle: sesquigomph falcigers blade [NEXUS: neurochaetae ventral fascicle sesquigomph falcigers bifid]distally bifid.with a single distal tooth.162. Neurochaetae ventral fascicle: heterogomph spinigers [NEXUS: neurochaetae ventral fascicle heterogomph spinigers]present.absent.163. Neurochaetae ventral fascicle: heterogomph spinigers in anterior chaetigers with blades [NEXUS: neurochaetae ventral fascicle heterogomph spinigers anterior serrated]evenly serrated throughout.coarsely serrated proximally.164. Neurochaetae ventral fascicle: heterogomph spinigers on posterior chaetigers with blades [NEXUS: neurochaetae ventral fascicle heterogomph spinigers posterior serrated] /finely serrated proximally.coarsely serrated proximally.165. Neurochaetae ventral fascicle: homogomph spinigers [NEXUS: neurochaetae ventral fascicle homogomph spinigers]present.absent.166. Neurochaetae ventral fascicle: sesquigomph spinigers [NEXUS: neurochaetae ventral fascicle sesquigomph spinigers]present.absent.167. Neurochaetae ventral fascicle: heterogomph falcigers [NEXUS: neurochaetae ventral fascicle heterogomph falcigers]present.absent.168. Neurochaetae ventral fascicle: heterogomph falcigers blade [NEXUS: neurochaetae ventral fascicle heterogomph falcigers bowed]tapering, with straight margin Fig. .bowed, with convex margin Fig. .Composetia and similar taxa. Other Nereididae, for example many species illustrated in This character was introduced by 169. Neurochaetae ventral fascicle: anterior chaetigers heterogomph falcigers with long blades Fig.  [NEXUS: present.absent.Definitions of blade length of falcigers were introduced by 170. Neurochaetae ventral fascicle: anterior chaetigers heterogomph falcigers with extra-long blades Fig.  [NEXUS: present.absent.The term \u201cextra-long blades\u201d is equivalent to \u201cType 1\u201d of 171. Neurochaetae ventral fascicle: anterior chaetigers heterogomph falcigers with short blades Fig.  [NEXUS: present.absent.The term \u201cshort blades\u201d is equivalent to \u201cType 2\u201d of 172. Neurochaetae ventral fascicle: posterior chaetigers heterogomph falcigers with long blades [NEXUS: neurochaetae ventral fascicle heterogomph falcigers posterior long]present.absent.173. Neurochaetae ventral fascicle: posterior chaetigers heterogomph falcigers with extra-long blades [NEXUS: neurochaetae ventral fascicle heterogomph falcigers posterior xlong]present.absent.174. Neurochaetae ventral fascicle: posterior chaetigers heterogomph falcigers with short blades [NEXUS: neurochaetae ventral fascicle heterogomph falcigers posterior short]present.absent.175. Neurochaetae ventral fascicle: heterogomph falcigers blade [NEXUS: neurochaetae ventral fascicle heterogomph falcigers tendon]with recurved terminal tooth and distinct tendon.lacking distinct tendon on terminal tooth.176. Neurochaetae ventral fascicle: heterogomph falcigers blade [NEXUS: neurochaetae ventral fascicle heterogomph falcigers bifid]terminally bifid.with a single terminal tooth.177. Neurochaetae ventral fascicle: homogomph falcigers in anterior chaetigers [NEXUS: neurochaetae ventral fascicle homogomph falcigers anterior]present.absent.178. Neurochaetae ventral fascicle: homogomph falcigers on posterior chaetigers [NEXUS: neurochaetae ventral fascicle homogomph falcigers posterior]present.absent.Namanereis while other Namanereidinae, and some Nicon species, have a bilobate pygidium. Other nereidids are commonly described as having a funnel-shaped pygidium, which may be crenulated or multi-incised (perhaps indicating specimens approaching epitoky). For the majority of Nereididae the form of the pygidium is unknown, often because specimens were incomplete posteriorly. Thus, we have not included a character describing the form of the pygidium.A trilobate pygidium is present in 179. Anal cirri form [NEXUS: anal cirri form]cirriform or conical.short, stout and appearing as an extension of the pygidium.flattened, resembling posterior dorsal cirri.Although some epitokal features may be diagnostic at the genus level , they ar180. Dorsal cirrophores of chaetigers 5\u20137 of epitokes [NEXUS: dorsal cirrophores chaetigers 5 7]unmodified.modified into flattened elytriform discs.modified into spherical globular structures.181. Natatory region in males commences chaetiger182. Natatory region in males comprises number of chaetigers183. Natatory region in females commences chaetiger184. Natatory region in females comprises number of chaetigers185. Pygidium of male epitokes [NEXUS: pygidium of male epitokes]unmetamorphosed.with pygidial rosette.Male epitokes may have the pygidium modified to form a pygidial rosette with multiple rows of short papillae. The unmodified form is illustrated by 186. Oocyte shape [NEXUS: oocyte form]spherical.ovoid.Nereididae but in many Namanereis species they are ovoid.Oocytes are typically spherical in Nereididae genera are widely recognised as likely para- or polyphyletic groups. They are polymorphic for characters which distinguish other nereidid genera and therefore key out in more than one couplet.It is easy to reach an incorrect identification using a linear  key \u2013 one always reaches a name, irrespective of errors that may have been made. Thus, it is wise to doubt, and some form of verification is highly desirable. Our recommendation is that after reaching a genus determination using the key below, the next step should be to compare the specimen at hand with the diagnosis of the genus that has been tentatively identified; if specimen and diagnosis match, the user can have increased confidence in the identification. See Methods above for further discussion. As discussed in the Introduction, several Taxon classificationAnimaliaPhyllodocidaNereididae\ufeffKinberg, 18654014296E-D3B4-5F7C-AE98-5B931F1C5C2DNereis (Alitta) auctt.Nereisvirens Sars, 1835.https://www.marinespecies.org/polychaeta/aphia.php?p=taxdetails&id=234848.Dorsal notopodial ligule markedly broader on posterior chaetigers; palpophore massive subconical, flattened ; ventral peristomial flap absent; notochaetae sesquigomph spinigers absent .Palpophore massive subconical, flattened . Palpophore surface with a single transverse groove  or with several oblique grooves or striae ; palpostyles subconical. Prostomium anterior margin entire. Tentacular belt greater than length of chaetiger 1. Tentacular cirri cirrophores present.Jaws with dentate cutting edge.A.virens species complex); II conical paragnaths present; III conical paragnaths present; III rod-like paragnaths absent; IV paragnaths present; IV conical paragnaths present; IV smooth bar-like paragnaths absent. Oral ring papillae absent. Oral ring paragnaths present; with Areas V, VI, and VII-VIII discrete. Oral ring pyramidal paragnaths absent, or present. Area V conical paragnaths present, or absent; arranged in a longitudinal line, or irregularly. Area VI paragnaths present; paragnaths arranged in a roughly circular group, or in lines or arcs; conical paragnaths present. Areas VII-VIII paragnaths present; conical paragnaths present; P-bar paragnaths absent, or present.Maxillary ring of pharynx with papillae absent. Maxillary ring paragnaths present. Area I conical paragnaths present ; present on all chaetigers. Notopodial acicular process absent. Dorsal cirrus sub-terminally attached to dorsal margin of dorsal notopodial ligule on posterior chaetigers; not terminally attached to dorsal notopodial ligule on posterior chaetigers.Neuropodial prechaetal lobe absent. Neuropodial postchaetal lobe present; projecting beyond end of the acicular ligule; present throughout all chaetigers; digitiform. Ventral neuropodial ligule of anterior chaetigers present. Ventral neuropodial ligule of anterior chaetigers approx. as long as acicular neuropodial ligule. Ventral neuropodial ligule on posterior chaetigers present. Ventral neuropodial ligule on posterior chaetigers similar to length of acicular neuropodial ligule, or short, up to half length of acicular neuropodial ligule.Notoaciculae on chaetigers 1 and 2 present, or absent. Notochaetae of chaetigers 3 and 4 present. Notochaetae: homogomph spinigers present. Neurochaetae dorsal fascicle: heterogomph spinigers absent; homogomph spinigers present; dorsal fascicle heterogomph falcigers in anterior chaetigers present; on posterior chaetigers present, or absent. Neurochaetae ventral fascicle: heterogomph spinigers present; spinigers in anterior chaetigers with blades evenly serrated throughout; on posterior chaetigers with blades finely serrated proximally; heterogomph falcigers present; anterior chaetigers heterogomph falcigers with long blades absent; anterior chaetigers heterogomph falcigers with extra-long blades present; anterior chaetigers heterogomph falcigers with short blades absent; posterior chaetigers heterogomph falcigers with long blades absent; posterior chaetigers heterogomph falcigers with extra-long blades present; posterior chaetigers heterogomph falcigers with short blades absent; ventral fascicle heterogomph falcigers blade with recurved terminal tooth and distinct tendon, or lacking distinct tendon on terminal tooth; ventral fascicle heterogomph falcigers blade with a single terminal tooth.Anal cirri form cirriform or conical.Alitta is due to Alitta now contains eight species all occurring in either the North Pacific or North Atlantic Oceans. Alittasuccinea  has been reported as a supposed introduced species from numerous cosmopolitan localities but as summarised by The modern concept of Alitta but the four species in the A.virens species complex can be identified using the keys to atokes and to epitokes in There is no identification guide for all species of Taxon classificationAnimaliaPhyllodocidaNereididae\ufeffHartman, 19548974DE78-DD2F-5644-B6AF-320764DC6F52Nereis (Leonnates) ehlersi Augener, 1913.https://www.marinespecies.org/polychaeta/aphia.php?p=taxdetails&id=324844.Ventrum of anterior chaetigers with rows of tubercles extending to the base of each neuropodium . Dorsal notopodial ligule commences chaetiger 1; prostomium anterior margin entire; maxillary ring of pharynx with papillae present (secondary diagnosis).Palpophore barrel-shaped, approximately equal width from base to palpostyle . Ventrum of anterior chaetigers with rows of tubercles extending to the base of each neuropodium.Maxillary ring of pharynx with papillae present (sometimes with horny tips); solitary; 50\u2013110 papillae in total. Maxillary ring paragnaths absent. Oral ring papillae absent. Oral ring paragnaths absent.Dorsal notopodial ligule present; commences chaetiger 1; not markedly elongate on posterior chaetigers; not markedly broader on posterior chaetigers; not markedly reduced on posterior chaetigers. Prechaetal notopodial lobe present; smaller than dorsal notopodial ligule on anterior chaetigers, usually reduced or absent posteriorly; restricted to a limited number of anterior chaetigers. Notopodial acicular process absent. Dorsal cirrus not sub-terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached throughout all chaetigers.Neuropodial prechaetal lobe absent. Neuropodial postchaetal lobe present; projecting beyond end of the acicular ligule; digitiform. Ventral neuropodial ligule of anterior chaetigers present.Notoaciculae on chaetigers 1 and 2 absent. Notochaetae: homogomph spinigers present. Neurochaetae dorsal fascicle: heterogomph spinigers absent; homogomph spinigers present; sesquigomph spinigers present. Neurochaetae dorsal fascicle: sesquigomph falcigers present; blades serrated; heterogomph falcigers in anterior chaetigers absent; on posterior chaetigers absent. Neurochaetae ventral fascicle: sesquigomph falcigers present; heterogomph spinigers absent; homogomph spinigers absent; sesquigomph spinigers present; heterogomph falcigers absent.Anal cirri form cirriform or conical.Australonereis is a monotypic genus. The single species A.ehlersi  occurs only in southern Australian estuaries where these large and often locally abundant worms are instantly recognisable by the conspicuous rows of tuberculae on the ventral surface; living specimens are also much more fragile than those belonging to other genera of Nereididae and readily fragment in the field.Taxon classificationAnimaliaPhyllodocidaNereididae\ufeffMalmgren, 1867749B279B-4CAE-58B9-B050-FACE11B61DB7Chaunorhychus Chamberlin, 1919.Pisionura Hartman & Fauchald, 1971.Ceratocephaleloveni Malmgren, 1867.https://www.marinespecies.org/polychaeta/aphia.php?p=taxdetails&id=129371.Transverse dorsal lamellae present; dorsal notopodial ligule absent . Dorsal cirrus arising from basal cirrophore; dorsal notopodial ligule commences chaetiger 3 (secondary diagnosis).Palpophore barrel-shaped, approximately equal width from base to palpostyle . Palpostyles subconical, or acutely conical. Eyes present, or absent. Prostomium anterior margin indented. Tentacular belt equal to or less than length of chaetiger 1.Jaws with dentate cutting edge.Ceratocephale spp., Areas V and VI contain up to three papillae in total; these are here interpreted as all occurring in Area V, with VI = 0,0.Maxillary ring of pharynx with papillae absent. Maxillary ring paragnaths absent. Oral ring papillae present. Oral ring papillae arrangement solitary. Area V three papillae present (close together); VI papillae present, or absent; VII-VIII seven papillae present, arranged in a single row. Oral ring paragnaths absent. In C.abyssorum); commencing chaetiger 4\u201310.Transverse dorsal lamellae present  based on C.bansei Khlebovich, 1966 may be the only species of Ceratocephale with papillae on Area VI of the pharynx.The definition of Ceratocephale currently includes 12 accepted species recorded from all oceans except the Arctic Ocean and from intertidal to abyssal depths  auctt.Ceratonereismirabilis Kinberg, 1865.https://www.marinespecies.org/polychaeta/aphia.php?p=taxdetails&id=129372.Notochaetae: sesquigomph falcigers present; dorsal cirrus sub-terminally attached to dorsal margin of dorsal notopodial ligule on posterior chaetigers . Neurochaetae dorsal fascicle: sesquigomph falcigers present; palpophore barrel-shaped, approximately equal width from base to palpostyle  (secondary diagnosis).Palpophore barrel-shaped, approximately equal width from base to palpostyle  (elongate). Palpophore surface with a single transverse groove . Prostomium anterior margin indented.Oesophageal caeca absent.Jaws with dentate cutting edge.Maxillary ring of pharynx with papillae absent. Area I conical paragnaths absent; II conical paragnaths present; III conical paragnaths present; IV paragnaths present; IV conical paragnaths present. Oral ring papillae absent. Oral ring paragnaths absent.Dorsal notopodial ligule not markedly elongate on posterior chaetigers; not markedly broader on posterior chaetigers; markedly reduced on posterior chaetigers, or not markedly reduced on posterior chaetigers. Prechaetal notopodial lobe absent. Notopodial acicular process absent. Dorsal cirrus sub-terminally attached to dorsal margin of dorsal notopodial ligule on posterior chaetigers; arising from basal cirrophore; cirrophore of dorsal cirrus short, at most as long as ventral notopodial ligule, or much longer than ventral notopodial ligule; cirrophore of dorsal cirrus not enlarged and vascularised; cirrophore of dorsal cirrus cylindrical throughout.Neuropodial postchaetal lobe present; projecting beyond end of the acicular ligule; restricted to anterior chaetigers; digitiform or flattened. Ventral neuropodial ligule of anterior chaetigers present. Ventral neuropodial ligule of anterior chaetigers approx. as long as acicular neuropodial ligule, or short, up to half length of acicular neuropodial ligule. Ventral neuropodial ligule on posterior chaetigers present. Ventral neuropodial ligule on posterior chaetigers similar to length of acicular neuropodial ligule, or short, up to half length of acicular neuropodial ligule.Notoaciculae on chaetigers 1 and 2 present. Notochaetae: homogomph spinigers absent; sesquigomph spinigers present; sesquigomph falcigers present; blade distally bifid, or with a single distal tooth. Neurochaetae dorsal fascicle: heterogomph spinigers absent; homogomph spinigers absent; sesquigomph spinigers present; sesquigomph falcigers present; heterogomph falcigers in anterior chaetigers present. Neurochaetae ventral fascicle: heterogomph spinigers present; homogomph spinigers absent; heterogomph falcigers present; anterior chaetigers heterogomph falcigers with short blades absent; heterogomph falcigers blade lacking distinct tendon on terminal tooth; heterogomph falcigers blade terminally bifid, or with a single terminal tooth.Anal cirri form cirriform or conical.Ceratonereis as currently defined follows the concept of Ceratonereis sensu lato\u201d) had included unrelated nereidid species with superficially similar paragnath configuration. Those disparate species (none of which have the indented prostomium characteristic of Ceratonereis sensu stricto) are now moved to genera ComposetiaSimplisetiaCeratonereis is probably monophyletic . Areas VII-VIII conical paragnaths differentiated, with a separate band of minute paragnaths also present; dorsal notopodial ligule markedly broader on posterior chaetigers (secondary diagnosis).Palpophore massive subconical, flattened . Tentacular belt greater than length of chaetiger 1. Ventral peristomial flap present.Oesophageal caeca present.Jaws with dentate cutting edge.C.peristomialis).Maxillary ring of pharynx with papillae absent. Maxillary ring paragnaths present. Area I conical paragnaths present; II conical paragnaths present; IV paragnaths present; IV conical paragnaths present. Oral ring papillae absent. Oral ring paragnaths present; with Areas V, VI and VII-VIII discrete; on Area V and VI form distinct groups. Area V conical paragnaths absent. Area VI paragnaths present; paragnaths arranged in a roughly circular group; conical paragnaths present; smooth bars absent. Areas VII-VIII paragnaths present; conical; arranged in isolated patches, or in one or more irregular lines forming a continuous band; conical paragnaths differentiated, with a separate band of minute paragnaths also present  from the NW Pacific and C.peristomialis Benham, 1916 from the SE Pacific; both species are commensals of hermit crabs. Cheilonereis species are characterised by the presence of a ventral collar or flap that partly covers the ventral paragnaths of the oral ring when the pharynx is extended  Hartmann-Schr\u00f6der, 1985.Nereiscostae Grube, 1840.https://www.marinespecies.org/polychaeta/aphia.php?p=taxdetails&id=324848.Neurochaetae ventral fascicle homogomph spinigers present; maxillary ring paragnaths present; oral ring paragnaths absent; Neurochaetae dorsal fascicle: heterogomph falcigers in anterior chaetigers absent; oesophageal caeca present .Palpophore barrel-shaped, approximately equal width from base to palpostyle . Palpophore surface with a single transverse groove . Prostomium longitudinal groove present; anterior region entire, sub-quadrangular, longitudinal groove present; prostomial posterior region subequal to or longer than anterior region. Tentacular belt greater than length of chaetiger 1.Oesophageal caeca present.Jaws with dentate cutting edge.Maxillary ring of pharynx with papillae absent. Maxillary ring paragnaths present. Area I conical paragnaths present; II conical paragnaths present; III conical paragnaths present; IV paragnaths present; IV conical paragnaths present. Oral ring papillae absent. Oral ring paragnaths absent.Dorsal notopodial ligule not markedly broader on posterior chaetigers; not markedly reduced on posterior chaetigers. Prechaetal notopodial lobe present; smaller than dorsal notopodial ligule on anterior chaetigers, usually reduced or absent posteriorly; present on all chaetigers, or restricted to a limited number of anterior chaetigers. Notopodial acicular process absent. Dorsal cirrus not sub-terminally attached to dorsal notopodial ligule on posterior chaetigers.Neuropodial postchaetal lobe present; projecting beyond end of the acicular ligule; restricted to anterior chaetigers. Ventral neuropodial ligule of anterior chaetigers present. Ventral neuropodial ligule of anterior chaetigers approx. as long as acicular neuropodial ligule. Ventral neuropodial ligule on posterior chaetigers present. Ventral neuropodial ligule on posterior chaetigers similar to length of acicular neuropodial ligule.Notoaciculae on chaetigers 1 and 2 absent. Notochaetae: homogomph spinigers present. Neurochaetae dorsal fascicle: heterogomph spinigers absent; homogomph spinigers present; heterogomph falcigers in anterior chaetigers absent; on posterior chaetigers absent. Neurochaetae ventral fascicle: heterogomph spinigers absent; homogomph spinigers present; heterogomph falcigers present; falcigers blade tapering, with straight margin; anterior chaetigers heterogomph falcigers with long blades absent; anterior chaetigers heterogomph falcigers with extra-long blades present; anterior chaetigers heterogomph falcigers with short blades absent; posterior chaetigers heterogomph falcigers with long blades absent; posterior chaetigers heterogomph falcigers with extra-long blades present; posterior chaetigers heterogomph falcigers with short blades absent; heterogomph falcigers blade lacking distinct tendon on terminal tooth; homogomph falcigers on posterior chaetigers present, or absent.Anal cirri form cirriform or conical.Composetia of Composetia sensu Hartmann-Schr\u00f6der, 1985 to two new genera: Parasetia and Potamonereis. Composetia currently includes 11 species which collectively are widely distributed around the globe; however, many species have not yet been re-evaluated against the revised concept of The description here follows the revised concept of The only identification guide is the tabular comparisons of Taxon classificationAnimaliaPhyllodocidaNereididae\ufeffSouthern, 1921DF13E0A3-B540-593F-9BB4-3AAC46C1AD2EDendronereidesheteropoda Southern, 1921.https://www.marinespecies.org/polychaeta/aphia.php?p=taxdetails&id=206894.Dorsal notopodial ligule divided into numerous branchial filaments .Ventral neuropodial ligule of anterior chaetigers absent; maxillary ring of pharynx with papillae present; prostomium anterior margin entire (secondary diagnosis).Palpophore barrel-shaped, approximately equal width from base to palpostyle . Palpophore surface with a single transverse groove .Jaws with dentate cutting edge.Maxillary ring of pharynx with papillae present; solitary. Maxillary ring paragnaths absent. Oral ring papillae present. Oral ring papillae arrangement solitary. Area V papillae present; VI papillae present; VII-VIII papillae present. Oral ring paragnaths absent.Dorsal notopodial ligule present. Dorsal notopodial ligule divided into numerous branchial filaments. Dorsal cirrus not sub-terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached throughout all chaetigers.Ventral neuropodial ligule of anterior chaetigers absent. Ventral neuropodial ligule on posterior chaetigers absent.Notochaetae: homogomph spinigers present; sesquigomph spinigers present, or absent. Neurochaetae dorsal fascicle: heterogomph spinigers present, or absent; homogomph spinigers present; sesquigomph spinigers present, or absent; heterogomph falcigers in anterior chaetigers present, or absent; homogomph falcigers in anterior chaetigers present, or absent. Neurochaetae ventral fascicle: heterogomph spinigers present, or absent; homogomph spinigers present, or absent; heterogomph falcigers present, or absent; heterogomph falcigers blade lacking distinct tendon on terminal tooth; homogomph falcigers on posterior chaetigers present, or absent.Dendronereides is the only nereidid genus in which the dorsal notopodial ligule is transformed into \u201cbranchial\u201d filaments; the genus contains three species which occur in tropical estuaries of the Indo-Pacific. There is no taxonomic review or identification guide for the species of Dendronereides.Taxon classificationAnimaliaPhyllodocidaNereididae\ufeffPeters, 18541A17B1DC-9FC4-5F1C-87C5-87884ACDA302Dendronereisarborifera Peters, 1854.https://www.marinespecies.org/polychaeta/aphia.php?p=taxdetails&id=206700.Dorsal cirrus divided into numerous branchial filaments . Ventral neuropodial ligule on posterior chaetigers absent; palpophore massive subconical, flattened ; prostomium anterior margin indented (secondary diagnosis).Palpophore massive subconical, flattened . Prostomium anterior margin indented.Maxillary ring of pharynx with papillae present, or absent. Maxillary ring paragnaths absent. Oral ring papillae present. Oral ring paragnaths absent.Dorsal notopodial ligule not markedly elongate on posterior chaetigers; not markedly broader on posterior chaetigers; not markedly reduced on posterior chaetigers. Prechaetal notopodial lobe present; smaller than dorsal notopodial ligule on anterior chaetigers, usually reduced or absent posteriorly. Dorsal cirrus divided into numerous branchial filaments. Dorsal cirrus not sub-terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached throughout all chaetigers.Ventral neuropodial ligule of anterior chaetigers present. Ventral neuropodial ligule of anterior chaetigers approx. as long as acicular neuropodial ligule. Ventral neuropodial ligule on posterior chaetigers absent. Neuropodia of branchial chaetigers divided into five lobes, plus ventral cirrus, plus two smaller cirri on ventral neuropodial lobe . Posteriorly becoming simpler, eventually with a single neuropodial lobe and ventral cirrus.Notochaetae: homogomph spinigers present. Neurochaetae dorsal fascicle: heterogomph spinigers absent; homogomph spinigers present; heterogomph falcigers in anterior chaetigers absent; on posterior chaetigers absent. Neurochaetae ventral fascicle: heterogomph spinigers absent; homogomph spinigers present; heterogomph falcigers absent.Dendronereis are easily recognised as this is the only genus of Nereididae in which the dorsal cirrus is transformed into branchial filaments. Species belonging to Dendronereis are known, all occurring in shallow waters of the Indo-Pacific. Five species of Taxon classificationAnimaliaPhyllodocidaNereididae\ufeffMalmgren, 18652D3814AB-6658-59B9-99B3-E5B5DDB85B41Nereis (Eunereis) Malmgren, 1865.Nereislongissima Johnston, 1840.https://www.marinespecies.org/polychaeta/aphia.php?p=taxdetails&id=129373.Oral ring paragnaths present; maxillary ring paragnaths absent .Palpophore barrel-shaped, approximately equal width from base to palpostyle . Palpophore surface with a single transverse groove . Tentacular belt greater than length of chaetiger 1.Jaws with dentate cutting edge.Maxillary ring of pharynx with papillae absent. Maxillary ring paragnaths absent. Oral ring papillae present, or absent. Oral ring paragnaths present; with Areas V, VI, and VII-VIII discrete, or comprising a continuous ring dorsally and ventrally, discrete groups not recognisable; on Areas V and VI form distinct groups. Area V conical paragnaths present, or absent. Area VI paragnaths present; arranged in a roughly circular group; conical paragnaths present, or absent; smooth bars present, or absent. Areas VII-VIII paragnaths present, or absent; conical paragnaths present; conical paragnaths arranged in isolated patches, or in one or more irregular lines forming a continuous band; conical paragnaths similar in size, or irregular mix of large and small paragnaths in a single band; rod-shaped paragnaths absent.Dorsal notopodial ligule not markedly elongate on posterior chaetigers; not markedly broader on posterior chaetigers; markedly reduced on posterior chaetigers, or not markedly reduced on posterior chaetigers. Prechaetal notopodial lobe present, or absent; smaller than dorsal notopodial ligule on anterior chaetigers, usually reduced or absent posteriorly; restricted to a limited number of anterior chaetigers. Notopodial acicular process present, or absent. Dorsal cirrus not sub-terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached throughout all chaetigers; simple, lacking basal cirrophore.Neuropodial prechaetal lobe absent. Neuropodial postchaetal lobe absent, or present; projecting beyond end of the acicular ligule; restricted to anterior chaetigers; digitiform. Ventral neuropodial ligule of anterior chaetigers present. Ventral neuropodial ligule of anterior chaetigers approx. as long as acicular neuropodial ligule. Ventral neuropodial ligule on posterior chaetigers present. Ventral neuropodial ligule on posterior chaetigers similar to length of acicular neuropodial ligule.Notoaciculae on chaetigers 1 and 2 absent. Notochaetae: homogomph spinigers present; homogomph falcigers present, or absent. Neurochaetae dorsal fascicle: heterogomph spinigers absent; homogomph spinigers present; heterogomph falcigers in anterior chaetigers present; on posterior chaetigers present; blades serrated. Neurochaetae ventral fascicle: heterogomph spinigers present; homogomph spinigers absent; heterogomph falcigers present; falcigers blade tapering, with straight margin; anterior chaetigers heterogomph falcigers with long blades absent; anterior chaetigers heterogomph falcigers with extra-long blades present; anterior chaetigers heterogomph falcigers with short blades absent; posterior chaetigers heterogomph falcigers with long blades present, or absent; posterior chaetigers heterogomph falcigers with extra-long blades present, or absent; posterior chaetigers heterogomph falcigers with short blades absent; heterogomph falcigers blade lacking distinct tendon on terminal tooth.Anal cirri form cirriform or conical.Composetia) by The description here follows Eunereis is the only Nereididae genus with paragnaths present only on the oral ring. Eunereis includes species which in other respects, especially chaetal characters, are similar to either of the genera Neanthes or Nereis suggesting a review is necessary.Eunereis includes ten accepted species which encompass wide geographic and bathymetric distributions. There is no published identification guide to all species.Taxon classificationAnimaliaPhyllodocidaNereididae\ufeffHorst, 19193018967B-9FEF-5D04-B384-F9791C2CB15BGymnorhynchus Horst, 1919 (replaced homonym).Gymnorhynchussibogae Horst, 1918.https://www.marinespecies.org/polychaeta/aphia.php?p=taxdetails&id=324851.Accessory ventral cirrus present; neurochaetae ventral fascicle sesquigomph spinigers present . Notochaetae sesquigomph spinigers present; dorsal notopodial ligule present (secondary diagnosis).Palpophore barrel-shaped, approximately equal width from base to palpostyle . Palpophore surface with a single transverse groove ; palpostyles subconical, or acutely conical. Prostomium anterior margin indented.Jaws with smooth or slightly crenulate cutting edge or with dentate cutting edge.Maxillary ring of pharynx with papillae absent. Maxillary ring paragnaths absent. Oral ring papillae present. Oral ring papillae arrangement solitary. Area V papillae present; VI papillae present; VII-VIII papillae present. Oral ring paragnaths absent.Transverse dorsal lamellae absent, or present.Dorsal notopodial ligule present; commences chaetiger 1; not markedly elongate on posterior chaetigers; not markedly broader on posterior chaetigers; markedly reduced on posterior chaetigers . Prechaetal notopodial lobe present; smaller than dorsal notopodial ligule on anterior chaetigers, usually reduced or absent posteriorly; present on all chaetigers. Notopodial acicular process present. Dorsal cirrus not sub-terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached throughout all chaetigers; arising from basal cirrophore.Neuropodial prechaetal lobe present; extending beyond postchaetal lobe (at least in anterior chaetigers). Neuropodial postchaetal lobe present; not projecting beyond end of the acicular ligule; present throughout all chaetigers; flattened. Ventral neuropodial ligule of anterior chaetigers present. Ventral neuropodial ligule of anterior chaetigers approx. as long as acicular neuropodial ligule. Ventral neuropodial ligule on posterior chaetigers present. Ventral neuropodial ligule on posterior chaetigers similar to length of acicular neuropodial ligule, or short, up to half length of acicular neuropodial ligule. Accessory ventral cirrus present.Notoaciculae on chaetigers 1 and 2 absent. Notochaetae: homogomph spinigers present, or absent; sesquigomph spinigers present. Neurochaetae dorsal fascicle: heterogomph spinigers absent; homogomph spinigers present, or absent; sesquigomph spinigers present. Neurochaetae dorsal fascicle: sesquigomph falcigers present, or absent; blades serrated; heterogomph falcigers in anterior chaetigers absent; on posterior chaetigers absent. Neurochaetae ventral fascicle: sesquigomph falcigers present, or absent; heterogomph spinigers absent; homogomph spinigers present, or absent; sesquigomph spinigers present; heterogomph falcigers absent.Anal cirri form cirriform or conical.Gymnonereis is diagnosed by the presence of accessory dorsal and ventral cirri and notochaetae comprising sesquigomph spinigers . There is no published key to all species although several regional keys exist  Malmgren, 1867.Nereisdiversicolor M\u00fcller, 1776.https://www.marinespecies.org/polychaeta/aphia.php?p=taxdetails&id=146968.Neurochaetae dorsal fascicle simple chaetae  present; palpophore massive subconical, flattened  .Palpophore massive subconical, flattened . Palpophore surface with a single transverse groove . Tentacular belt greater than length of chaetiger 1.Jaws with dentate cutting edge.Maxillary ring of pharynx with papillae absent. Area I conical paragnaths present; II conical paragnaths present; III conical paragnaths present; III rod-like paragnaths absent; IV paragnaths present; IV conical paragnaths present; IV rod-like paragnaths absent. Oral ring papillae absent. Oral ring paragnaths present; with Areas V, VI, and VII-VIII discrete; on Areas V and VI form distinct groups. Area V conical paragnaths absent. Area VI paragnaths present; paragnaths arranged in a roughly circular group, or in lines or arcs; conical paragnaths present; smooth bars absent. Area VII-VIII paragnaths present; conical paragnaths present; conical paragnaths arranged in one or more irregular lines forming a continuous band; conical paragnaths similar in size, or irregular mix of large and small paragnaths in a single band; rod-shaped paragnaths absent.Dorsal notopodial ligule not markedly elongate on posterior chaetigers; not markedly broader on posterior chaetigers; not markedly reduced on posterior chaetigers. Prechaetal notopodial lobe present; smaller than dorsal notopodial ligule on anterior chaetigers, usually reduced or absent posteriorly; restricted to a limited number of anterior chaetigers. Notopodial acicular process absent. Dorsal cirrus not sub-terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached throughout all chaetigers.Neuropodial postchaetal lobe absent, or present; projecting beyond end of the acicular ligule; restricted to anterior chaetigers; digitiform. Ventral neuropodial ligule of anterior chaetigers present. Ventral neuropodial ligule of anterior chaetigers approx. as long as acicular neuropodial ligule. Ventral neuropodial ligule on posterior chaetigers present. Ventral neuropodial ligule on posterior chaetigers similar to length of acicular neuropodial ligule.Notoaciculae on chaetigers 1 and 2 absent. Notochaetae: homogomph spinigers present. Neurochaetae dorsal fascicle: heterogomph spinigers absent; homogomph spinigers present; heterogomph falcigers in anterior chaetigers present; on posterior chaetigers present; blades serrated; simple chaetae  present. Neurochaetae ventral fascicle: heterogomph spinigers present or absent; homogomph spinigers absent; homogomph falcigers present or absent; heterogomph falcigers present; anterior chaetigers heterogomph falcigers with long blades absent; anterior chaetigers heterogomph falcigers with extra-long blades present; anterior chaetigers heterogomph falcigers with short blades absent; posterior chaetigers heterogomph falcigers with long blades absent; posterior chaetigers heterogomph falcigers with extra-long blades present; posterior chaetigers heterogomph falcigers with short blades absent; heterogomph falcigers blade lacking distinct tendon on terminal tooth.Anal cirri form cirriform or conical.Hediste species are characterised by the \u201csimple\u201d neuropodial falcigers (with fused articulation) which are present in posterior chaetigers and by having paragnaths on both rings of the pharynx. The most recent taxonomic treatments are Hediste is a genus of estuarine nereidids which occur in the northern hemisphere. Seven species of Hediste are currently described but despite recent publications, the most widespread species, H.diversicolor  still contains cryptic species not yet described . Neurochaetae dorsal fascicle heterogomph falcigers in anterior chaetigers absent; Area VI papillae absent; palpophore barrel-shaped, approximately equal width from base to palpostyle  (secondary diagnosis).Palpophore barrel-shaped, approximately equal width from base to palpostyle . Tentacular belt greater than length of chaetiger 1.Jaws with dentate cutting edge.Maxillary ring of pharynx with papillae absent. Area I conical paragnaths present; II conical paragnaths present; III conical paragnaths present; III rod-like paragnaths absent; IV paragnaths present; IV conical paragnaths present; IV rod-like paragnaths absent. Oral ring papillae present. Oral ring papillae arrangement solitary. Area V papillae absent; VI papillae absent; VII-VIII papillae present. Oral ring paragnaths present; with Areas V, VI, and VII-VIII discrete; on Areas V and VI form distinct groups. Area V conical paragnaths absent. Area VI paragnaths present; paragnaths arranged in a roughly circular group; conical paragnaths present; smooth bars absent. Areas VII-VIII paragnaths present; conical paragnaths present; conical paragnaths arranged in one or more irregular lines forming a continuous band; conical paragnaths similar in size, or irregular mix of large and small paragnaths in a single band; rod-shaped paragnaths absent.Dorsal notopodial ligule not markedly elongate on posterior chaetigers; not markedly broader on posterior chaetigers; not markedly reduced on posterior chaetigers. Prechaetal notopodial lobe present; smaller than dorsal notopodial ligule on anterior chaetigers, usually reduced or absent posteriorly. Dorsal cirrus not sub-terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached throughout all chaetigers.Neuropodial postchaetal lobe present. Ventral neuropodial ligule of anterior chaetigers present. Ventral neuropodial ligule of anterior chaetigers approx. as long as acicular neuropodial ligule. Ventral neuropodial ligule on posterior chaetigers present. Ventral neuropodial ligule on posterior chaetigers similar to length of acicular neuropodial ligule.Notoaciculae on chaetigers 1 and 2 absent. Notochaetae: homogomph spinigers present. Neurochaetae dorsal fascicle: heterogomph spinigers present; homogomph spinigers present; heterogomph falcigers in anterior chaetigers absent; on posterior chaetigers present; blades serrated; blades with teeth only slightly longer proximally than distally. Neurochaetae ventral fascicle: heterogomph spinigers present; homogomph spinigers present; heterogomph falcigers present; anterior chaetigers heterogomph falcigers with long blades absent; anterior chaetigers heterogomph falcigers with extra-long blades absent; anterior chaetigers heterogomph falcigers with short blades absent; posterior chaetigers heterogomph falcigers with long blades absent; posterior chaetigers heterogomph falcigers with extra-long blades present; posterior chaetigers heterogomph falcigers with short blades absent.Imajimainereis contains a single species, I.pacifica de Le\u00f3n-Gonz\u00e1lez & Sol\u00eds-Weiss, 2000, which differs from all other Nereididae by having both papillae and paragnaths on the oral ring and neurochaetae including heterogomph spinigers.Imajimainereis is recorded from the Gulf of California, eastern Pacific Ocean . Notochaetae homogomph falcigers present; maxillary ring paragnaths absent; oral ring paragnaths absent; dorsal notopodial ligule not markedly reduced on posterior chaetigers (secondary diagnosis).Palps anteriorly directed, or ventrally directed. Palpophore barrel-shaped, approximately equal width from base to palpostyle . Prostomium the antennae are separate but sometimes basally fused in male epitokes. Tentacular cirri articulated.Jaws with dentate cutting edge.Maxillary ring of pharynx with papillae absent. Maxillary ring paragnaths absent. Oral ring paragnaths absent.Dorsal notopodial ligule commences chaetiger 3, or chaetiger 4 ; not markedly elongate on posterior chaetigers; not markedly reduced on posterior chaetigers. Prechaetal notopodial lobe present . Dorsal cirrus not sub-terminally attached to dorsal notopodial ligule on posterior chaetigers.Neuropodial prechaetal lobe absent. Neuropodial postchaetal lobe present; present throughout all chaetigers. Ventral neuropodial ligule of anterior chaetigers present. Ventral neuropodial ligule of anterior chaetigers approx. as long as acicular neuropodial ligule. Ventral neuropodial ligule on posterior chaetigers present.Notoaciculae on chaetigers 1 and 2 absent. Notochaetae: homogomph spinigers present; homogomph falcigers present ; homogomph falcigers with multidentate blade with two or more small lateral teeth, first and subsequent lateral teeth much smaller than terminal tooth present. Neurochaetae dorsal fascicle: heterogomph spinigers absent; homogomph spinigers present; heterogomph falcigers in anterior chaetigers present. Neurochaetae ventral fascicle: heterogomph spinigers present; homogomph spinigers absent; heterogomph falcigers present; falcigers blade bowed, with convex margin.Pygidium bilobate. Anal cirri form cirriform or conical.Dorsal cirrophores of chaetigers 5\u20137 of epitokes modified into flattened elytriform discs. Natatory epitokal modifications in males commence chaetiger 15. Natatory epitokal modifications in females commence chaetiger 15.Kainonereis was originally described for an epitokous specimen in which dorsal cirri of chaetigers 5\u20137 were expanded into elytra-like structures. Unless epitokes are available Kainonereis is not separable from Nicon and Websterinereis . A revision by Taxon classificationAnimaliaPhyllodocidaNereididae\ufeffPettibone, 1971A548C2F2-63AF-5B86-936E-156FC2B5648DNereis (Leptonereis) inermis Hoagland, 1920.https://www.marinespecies.org/polychaeta/aphia.php?p=taxdetails&id=843657.Neurochaetae ventral fascicle heterogomph spinigers in anterior chaetigers with blades coarsely serrated proximally; oral ring papillae present; maxillary ring of pharynx with papillae absent . Prostomium anterior margin indented; prechaetal notopodial lobe approximately equal to length of dorsal notopodial ligule at least on anterior chaetigers (thus notopodium of three similar sized ligules/lobes); antennae form cirriform ; maxillary ring paragnaths absent (secondary diagnosis).Palpophore barrel-shaped, approximately equal width from base to palpostyle  (elongate). Prostomium anterior margin indented.Jaws with dentate cutting edge, 20 teeth.Maxillary ring of pharynx with papillae absent. Maxillary ring paragnaths absent. Oral ring papillae present. Oral ring papillae number two in total; arrangement solitary. Area V papillae absent; VI papillae present, one papilla (a single fleshy nob on each side); VII-VIII papillae absent. Oral ring paragnaths absent.Dorsal notopodial ligule present; markedly reduced on posterior chaetigers. Prechaetal notopodial lobe present; approximately equal to length of dorsal notopodial ligule at least on anterior chaetigers (thus notopodium of three similar sized ligules/lobes); present on all chaetigers. Dorsal cirrus not sub-terminally attached to dorsal notopodial ligule on posterior chaetigers.Neuropodial prechaetal lobe present. Neuropodial postchaetal lobe present; projecting beyond end of the acicular ligule; flattened. Ventral neuropodial ligule of anterior chaetigers present. Ventral neuropodial ligule of anterior chaetigers approx. as long as acicular neuropodial ligule. Ventral neuropodial ligule on posterior chaetigers present. Ventral neuropodial ligule on posterior chaetigers similar to length of acicular neuropodial ligule.Notoaciculae on chaetigers 1 and 2 present. Notochaetae: homogomph spinigers present. Neurochaetae dorsal fascicle: heterogomph spinigers absent; homogomph spinigers present; heterogomph falcigers in anterior chaetigers absent; on posterior chaetigers absent. Neurochaetae ventral fascicle: heterogomph spinigers present; spinigers in anterior chaetigers with blades coarsely serrated proximally; homogomph spinigers absent; heterogomph falcigers absent.Kinberginereis is the original description of Kinberginereis is most similar to Kainonereis, atokes differing only in that Kinberginereis has an indented prostomium but the prostomium of Kainonereis is entire. Epitokes of Kainonereis are distinctive in having elytriform expansion of dorsal cirrophores of chaetigers 5\u20137 but epitokes of Kinberginereis are unknown.The most recent taxonomic treatment of Kinberginereis includes a single species, K.inermis  described from a single specimen from shallow water in the Philippines; the only subsequent reports are unverified occurrence records now in the Smithsonian National Museum of Natural History from the Gulf of Mexico.Taxon classificationAnimaliaPhyllodocidaNereididae\ufeffHartman, 19458C7A0D76-6047-5EB7-B63D-A6B04E21F426Nereisculveri Webster, 1879.https://www.marinespecies.org/polychaeta/aphia.php?p=taxdetails&id=181592.Maxillary ring of pharynx with papillae in tufts . Dorsal notopodial ligule commences chaetiger 1; neurochaetae ventral fascicle homogomph falcigers on posterior chaetigers present (secondary diagnosis).Palpophore barrel-shaped, approximately equal width from base to palpostyle . Prostomium anterior margin indented; longitudinal groove present.Jaws with dentate cutting edge.Maxillary ring of pharynx with papillae present; in tufts. Maxillary ring paragnaths absent. Oral ring papillae present. Oral ring papillae arrangement solitary. Area V papillae absent; VI papillae present; VII-VIII papillae present or absent (may be absent in juveniles). Oral ring paragnaths absent. Papillae triangular or conical on Area VI, rounded on Areas VII-VIII.Dorsal notopodial ligule present; commences chaetiger 1; not markedly elongate on posterior chaetigers; not markedly broader on posterior chaetigers; not markedly reduced on posterior chaetigers. Prechaetal notopodial lobe present; smaller than dorsal notopodial ligule on anterior chaetigers, usually reduced or absent posteriorly; restricted to a limited number of anterior chaetigers. Notopodial acicular process absent. Dorsal cirrus not sub-terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached throughout all chaetigers.Neuropodial prechaetal lobe absent. Neuropodial postchaetal lobe present; projecting beyond end of the acicular ligule; restricted to anterior chaetigers. Ventral neuropodial ligule of anterior chaetigers present. Ventral neuropodial ligule of anterior chaetigers approx. as long as acicular neuropodial ligule. Ventral neuropodial ligule on posterior chaetigers present. Ventral neuropodial ligule on posterior chaetigers similar to length of acicular neuropodial ligule.Notoaciculae on chaetigers 1 and 2 absent. Notochaetae: homogomph spinigers present. Neurochaetae dorsal fascicle: heterogomph spinigers absent; homogomph spinigers present; heterogomph falcigers in anterior chaetigers absent; on posterior chaetigers absent; homogomph falcigers in anterior chaetigers present, or absent; on posterior chaetigers present, or absent. Neurochaetae ventral fascicle: heterogomph spinigers absent; homogomph spinigers present; heterogomph falcigers absent; homogomph falcigers on posterior chaetigers present (with long blades).Pygidium funnel-shaped, crenulated, or multi-incised, with ventral incision. Anal cirri cirriform or conical.Laeonereis here is derived from the revision of Laeonereis. Simultaneously with the publication of the morphological revision of Laeonereis by Laeonereis  and revealed seven or nine molecular OTUs. It is tantalising that The description and diagnosis of Laeonereis are recognised, largely confined to the Atlantic coasts of North and South America; they can be identified using the key of Currently eight species of Taxon classificationAnimaliaPhyllodocidaNereididae\ufeffKinberg, 1865C3644EC1-EA46-55DC-A616-A86BEEAC1EA8Nereis (Leonnates) auctt.Laevispinereis He & Wu, 1989.Leonnatesindicus Kinberg, 1865.https://www.marinespecies.org/polychaeta/aphia.php?p=taxdetails&id=129374.Oral ring papillae present; maxillary ring paragnaths present; oral ring paragnaths absent; ventral neuropodial ligule on posterior chaetigers similar to length of acicular neuropodial ligule; neurochaetae dorsal fascicle homogomph spinigers present .L.persicus and L.stephensoni); longitudinal groove present; anterior region sub-quadrangular or sub-rectangular. Tentacular belt greater than length of chaetiger 1.Palpophore barrel-shaped, approximately equal width from base to palpostyle , or massive subconical, flattened . Palpophore surface with a single transverse groove . Prostomium anterior margin entire or indented ; present on all chaetigers, or restricted to a limited number of anterior chaetigers. Notopodial acicular process absent. Dorsal cirrus not sub-terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached throughout all chaetigers.Neuropodial prechaetal lobe absent. Neuropodial postchaetal lobe present; projecting beyond end of the acicular ligule; present throughout all chaetigers or restricted to anterior chaetigers; digitiform. Ventral neuropodial ligule of anterior chaetigers present. Ventral neuropodial ligule of anterior chaetigers approx. as long as acicular neuropodial ligule. Ventral neuropodial ligule on posterior chaetigers present. Ventral neuropodial ligule on posterior chaetigers similar to length of acicular neuropodial ligule.L.fujianensis); homogomph spinigers present; sesquigomph spinigers present, or absent (present in L.fujianensis); sesquigomph falcigers present, or absent; heterogomph falcigers in anterior chaetigers present, or absent; on posterior chaetigers present, or absent; homogomph falcigers in anterior chaetigers present, or absent; on posterior chaetigers present, or absent. Neurochaetae ventral fascicle: sesquigomph falcigers present, or absent; blade with a single distal tooth; heterogomph spinigers present, or absent; homogomph spinigers present, or absent; sesquigomph spinigers present, or absent; heterogomph falcigers present, or absent; falcigers blade bowed, with convex margin; heterogomph falcigers blade lacking distinct tendon on terminal tooth; homogomph falcigers in anterior chaetigers present, or absent; on posterior chaetigers present, or absent. Ventral fascicle neuropodial falcigers apparently vary considerably between species.Notoaciculae on chaetigers 1 and 2 absent. Notochaetae: homogomph spinigers present; homogomph falcigers present, or absent. Neurochaetae dorsal fascicle: heterogomph spinigers present, or absent , 5E , 7B , 9D  all show sesquigomph articulation as accepted by other authors, e.g. Parasetiairritabilis ), Leonnatescrosnieri de Le\u00f3n-Gonz\u00e1lez & Salazar-Vallejo, 2003).The current description and diagnosis follow Leonnates includes 13 species with the greatest diversity in the tropical Indo-Pacific. Taxon classificationAnimaliaPhyllodocidaNereididae\ufeffKinberg, 1865BD8300F9-84E4-5EEF-A4DA-55C68B821E5BNereis (Leptonereis) auctt.Leptonereislaevis Kinberg, 1865.https://www.marinespecies.org/polychaeta/aphia.php?p=taxdetails&id=152401.Dorsal cirrus terminally attached to dorsal notopodial ligule on posterior chaetigers; maxillary ring paragnaths absent . Dorsal notopodial ligule markedly broader on posterior chaetigers; prostomium anterior margin entire; maxillary ring of pharynx with P-bar paragnaths absent (secondary diagnosis).Palpophore barrel-shaped, approximately equal width from base to palpostyle .Maxillary ring of pharynx with papillae absent. Maxillary ring paragnaths absent. Oral ring papillae absent. Oral ring paragnaths absent.Dorsal notopodial ligule present; markedly elongate on posterior chaetigers; markedly broader on posterior chaetigers; not markedly reduced on posterior chaetigers. Dorsal cirrus not sub-terminally attached to dorsal notopodial ligule on posterior chaetigers; terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached throughout all chaetigers.Neuropodial postchaetal lobe absent. Ventral neuropodial ligule of anterior chaetigers present. Ventral neuropodial ligule of anterior chaetigers approx. as long as acicular neuropodial ligule. Ventral neuropodial ligule on posterior chaetigers present. Ventral neuropodial ligule on posterior chaetigers similar to length of acicular neuropodial ligule.Notochaetae: homogomph spinigers present. Neurochaetae homogomph and heterogomph spinigers and heterogomph falcigers, but their distribution in dorsal and ventral fascicles is unknown.Leptonereis given here follows the most recent treatment  . Neurochaetae dorsal fascicle homogomph falcigers on posterior chaetigers present; maxillary ring paragnaths absent; prostomium anterior margin entire (secondary diagnosis).Palpophore barrel-shaped, approximately equal width from base to palpostyle . Palpophore surface with a single transverse groove . Prostomium anterior margin entire. Tentacular belt greater than length of chaetiger 1. Tentacular cirri three pairs.Jaws with dentate cutting edge.Maxillary ring of pharynx with papillae present. Maxillary ring paragnaths absent. Oral ring papillae present. Oral ring papillae arrangement solitary. Area V papillae absent; VI papillae present; VII-VIII papillae present, arranged in a single row. Oral ring paragnaths absent.Dorsal notopodial ligule markedly reduced or absent on posterior chaetigers. Prechaetal notopodial lobe present; restricted to a limited number of anterior chaetigers.Neuropodial prechaetal lobe absent. Neuropodial postchaetal lobe present; not projecting beyond end of the acicular ligule; digitiform. Ventral neuropodial ligule of anterior chaetigers present. Ventral neuropodial ligule of anterior chaetigers approx. as long as acicular neuropodial ligule. Ventral neuropodial ligule on posterior chaetigers present. Ventral neuropodial ligule on posterior chaetigers short, up to half length of acicular neuropodial ligule.Notoaciculae on chaetigers 1 and 2 absent. Notochaetae: homogomph spinigers present. Neurochaetae dorsal fascicle: heterogomph spinigers absent; homogomph spinigers present; dorsal fascicle heterogomph falcigers in anterior chaetigers absent; on posterior chaetigers absent; dorsal fascicle homogomph falcigers in anterior chaetigers present; on posterior chaetigers present; ventral fascicle heterogomph spinigers absent; homogomph spinigers present; sesquigomph spinigers present. Neurochaetae ventral fascicle: heterogomph falcigers absent; homogomph falcigers in anterior chaetigers present; on posterior chaetigers present.This easily diagnosed genus from estuaries in India includes a single species. Taxon classificationAnimaliaPhyllodocidaNereididae\ufeffDay, 19630FD2B90F-6BE2-5215-9ADB-53D8CB09F980Micronereidescapensis Day, 1963.https://www.marinespecies.org/polychaeta/aphia.php?p=taxdetails&id=324861.Tentacular belt represented by two distinct segments each carrying a pair of tentacular cirri . Dorsal notopodial ligule absent; neurochaetae ventral fascicle sesquigomph spinigers present (secondary diagnosis).Palpophore barrel-shaped, approximately equal width from base to palpostyle . Eyes absent. Prostomium with eyes, if not absent, indistinct and likely to be missed. Tentacular belt equal to or less than length of chaetiger 1; represented by two distinct segments each carrying a pair of tentacular cirri.Jaws with dentate cutting edge, seven teeth.Maxillary ring of pharynx with papillae absent. Maxillary ring paragnaths absent. Oral ring papillae absent. Oral ring paragnaths absent.Dorsal notopodial ligule absent. Prechaetal notopodial lobe absent. Notopodial acicular process absent.Neuropodial prechaetal lobe absent. Neuropodial postchaetal lobe absent. Ventral neuropodial ligule of anterior chaetigers present. Ventral neuropodial ligule of anterior chaetigers short, up to half length of acicular neuropodial ligule. Ventral neuropodial ligule on posterior chaetigers present. Ventral neuropodial ligule on posterior chaetigers similar to length of acicular neuropodial ligule. Dorsal notopodial ligule elongate, exceeding length of dorsal cirrus.Notochaetae: homogomph spinigers present. Neurochaetae dorsal fascicle: heterogomph spinigers absent; homogomph spinigers present; heterogomph falcigers in anterior chaetigers absent; on posterior chaetigers absent; ventral fascicle heterogomph spinigers absent; homogomph spinigers present; sesquigomph spinigers present .Micronereides was erected to contain M.capensis Day, 1963 a small nereidid lacking pharyngeal papillae or paragnaths and in which tentacular cirri arise from two distinct anterior segments (unique among Nereididae). A revised diagnosis was provided by Gymnonereidinae.M.capensis, recorded from shelf depths in the South Atlantic Ocean.The genus is still only known from a single species, Taxon classificationAnimaliaPhyllodocidaNereididae\ufeffClapar\u00e8de, 1863B54F0B95-D187-5F51-B03F-00845FCB5AD9Notophycus Knox & Cameron, 1970.Phyllodocella Fauchald & Belman, 1972.Quadricirra Banse, 1977.Micronereisvariegata Clapar\u00e8de, 1863.https://www.marinespecies.org/polychaeta/aphia.php?p=taxdetails&id=129375.Palpostyles absent  . Maxillary ring of pharynx undivided (secondary diagnosis).Antennae absent. Palps ventrally directed. Palpophore surface with a single transverse groove ; palpostyles absent .Jaws with dentate cutting edge.Maxillary ring of pharynx undivided.Maxillary ring of pharynx with papillae absent; undivided maxillary ring with two paragnaths in total. Oral ring papillae absent. Oral ring paragnaths present; on Areas V and VI not recognisably distinct. Crown-shaped oral ring paragnaths present. Area V conical paragnaths absent.Dorsal notopodial ligule absent. Prechaetal notopodial lobe absent. Notopodial acicular process absent. Acicular notopodial ligule absent.Neuropodial postchaetal lobe absent. Ventral neuropodial ligule of anterior chaetigers absent. Ventral neuropodial ligule on posterior chaetigers absent.M.bansei). Notochaetae: homogomph spinigers present; homogomph falcigers present or absent; homogomph falcigers with multidentate blade with two or more small lateral teeth, first and subsequent lateral teeth much smaller than terminal tooth present. Neurochaetae dorsal fascicle: heterogomph spinigers absent; homogomph spinigers present; heterogomph falcigers in anterior chaetigers absent; homogomph falcigers in anterior chaetigers present; on posterior chaetigers present. Neurochaetae ventral fascicle: heterogomph spinigers absent; homogomph spinigers present; heterogomph falcigers absent.Notoaciculae on chaetigers 1 and 2 absent  marine waters. Micronereis species differ from other Nereididae in lacking antennae and having a pharynx that is not fully eversible. They are sexually dimorphic and males have distinctive neurochaetae that function as copulatory hooks not found in other Nereididae.Micronereis currently includes ten accepted species which collectively have a wide global distribution. Taxon classificationAnimaliaPhyllodocidaNereididae\ufeffHartman, 1959C39C0DA3-0F57-5783-89CE-D206253F0F3CLycastisabiuma Grube, 1872.https://www.marinespecies.org/polychaeta/aphia.php?p=taxdetails&id=129376.Palpophore surface without grooves or striae ; antennae form subconical  . Prostomium anterior margin indented (secondary diagnosis).Palpophore barrel-shaped, approximately equal width from base to palpostyle . Palpophore surface without grooves or striae  or with a single transverse groove ; palpostyles spherical. Prostomium anterior margin indented; longitudinal groove present. Tentacular belt equal to or less than length of chaetiger 1.Jaws with dentate cutting edge.Maxillary ring of pharynx with papillae absent. Maxillary ring paragnaths absent. Oral ring papillae absent. Oral ring paragnaths absent.Notopodium strongly reduced, without distinct lobes or ligules. Dorsal cirrus arising from basal cirrophore .Neuropodial postchaetal lobe absent. Ventral neuropodial ligule of anterior chaetigers absent. Ventral neuropodial ligule on posterior chaetigers absent.Notoaciculae on chaetigers 1 and 2 present. Notochaetae: homogomph spinigers absent; sesquigomph spinigers present, or absent. Neurochaetae dorsal fascicle: heterogomph spinigers present (rarely), or absent; homogomph spinigers absent; sesquigomph spinigers present; heterogomph falcigers in anterior chaetigers present, or absent (rarely); on posterior chaetigers present, or absent; blades smooth, or serrated; blades with teeth only slightly longer proximally than distally. Neurochaetae ventral fascicle: heterogomph spinigers present; spinigers in anterior chaetigers with blades evenly serrated throughout, or coarsely serrated proximally (rarely); on posterior chaetigers with blades finely serrated proximally, or coarsely serrated proximally; homogomph spinigers absent; heterogomph falcigers present, or absent (rarely); anterior chaetigers heterogomph falcigers with long blades absent; anterior chaetigers heterogomph falcigers with extra-long blades present; anterior chaetigers heterogomph falcigers with short blades absent; posterior chaetigers heterogomph falcigers with long blades absent; posterior chaetigers heterogomph falcigers with extra-long blades present; posterior chaetigers heterogomph falcigers with short blades absent.Pygidium with three incisions marking lateral and dorsal lobes. Anal cirri form cirriform or conical, or flattened, resembling posterior dorsal cirri.Oocyte spherical.Namalycastis currently includes 33 accepted species recorded mainly from intertidal and supralittoral areas, including freshwater, of the tropics and subtropics. Together with sister-group Namanereis, they are one of only a few polychaetes to be found in association with riparian vegetation. Because they have an unadorned pharynx and a simplified parapodia, distinguishing species relies heavily on differences in chaetae, form of sensory organs of the head, and pigmentation patterns in living specimens. The modern concept of the subfamily and genus was introduced by Namalycastiscaetensis Alves & Santos, 2016, Namalycastisglasbyi Fernando & Rajasekaran, 2007, Namalycastisjaya Magesh, Kvist & Glasby, 2012, Namalycastisocculta Conde-Vela, 2013 and Namalycastisrhodochorde Glasby, Miura, Nishi & Junardi, 2007; however, Namalycastisocculta Conde-Vela, 2013 is now accepted as Namanereisocculta . Taxon classificationAnimaliaPhyllodocidaNereididae\ufeffChamberlin, 1919E4E1CB01-7AE5-5147-9A46-E3FB005E109ECryptonereis Gibbs, 1971.Lycastella Feuerborn, 1932.Lycastilla Sol\u00eds-Weiss & Espinasa, 1991.Lycastoides Jakubova, 1930.Lycastopsis Augener, 1922.Lycastisquadraticeps Blanchard in Gay, 1849.https://www.marinespecies.org/polychaeta/aphia.php?p=taxdetails&id=129377.Palpophore surface without grooves or striae ; prostomium anterior margin entire . Palpostyles spherical; dorsal cirrus simple, lacking basal cirrophore (secondary diagnosis).Antennae present, or absent (rarely). Palpophore barrel-shaped, approximately equal width from base to palpostyle . Palpophore surface without grooves or striae  or with a single transverse groove ; palpostyles spherical. Eyes present, or absent. Tentacular belt equal to or less than length of chaetiger 1. Tentacular cirri four pairs, or three pairs.Jaws forms with a crenulate cutting edge have 2 teeth proximally, with smooth or slightly crenulate cutting edge or with dentate cutting edge.Maxillary ring of pharynx with papillae absent. Maxillary ring paragnaths absent. Oral ring papillae absent. Oral ring paragnaths absent.Notopodium strongly reduced, without distinct lobes or ligules.Neuropodial postchaetal lobe absent. Ventral neuropodial ligule of anterior chaetigers absent. Ventral neuropodial ligule on posterior chaetigers absent.Notoaciculae on chaetigers 1 and 2 present. Notochaetae: homogomph spinigers absent; sesquigomph spinigers present (rarely), or absent. Neurochaetae dorsal fascicle: heterogomph spinigers present (rarely), or absent; homogomph spinigers absent; sesquigomph spinigers present, or absent; heterogomph falcigers in anterior chaetigers present; on posterior chaetigers present; blades serrated; blades with teeth only slightly longer proximally than distally, or much longer proximally than distally. Neurochaetae ventral fascicle: heterogomph spinigers present (rarely), or absent; spinigers in anterior chaetigers with blades evenly serrated throughout; on posterior chaetigers with blades finely serrated proximally; homogomph spinigers absent; heterogomph falcigers present (some forms with very long blades = pseudospinigers); anterior chaetigers heterogomph falcigers with long blades present; anterior chaetigers heterogomph falcigers with extra-long blades present; anterior chaetigers heterogomph falcigers with short blades absent; posterior chaetigers heterogomph falcigers with long blades present, or absent; posterior chaetigers heterogomph falcigers with extra-long blades present, or absent; posterior chaetigers heterogomph falcigers with short blades absent.Pygidium with three incisions marking lateral and dorsal lobes. Anal cirri form cirriform or conical, or short, stout and appearing as an extension of the pygidium.Oocyte spherical (rarely), or ovoid.Namanereis currently includes 27 accepted species recorded mainly from intertidal, supralittoral and terrestrial areas, including the freshwaters of streams, caves, and underground aquifers. Although mainly found in the tropics and subtropics one species, Namanereisquadraticeps (Blanchard in Gay 1849), has a circum-subantarctic/temperate distribution. Together with sister-group Namalycastis, they are one of only a few polychaetes to be found in association with riparian vegetation. Because they have an unadorned pharynx and a simplified parapodia, distinguishing species relies heavily on differences in chaetae and form of sensory organs of the head. The modern concept of the subfamily and genus was introduced by Namanereiscanariarum N\u00fa\u00f1ez, Glasby & Naranjo, 2020, Namanereischristopheri Conde-Vela, 2017, Namanereisgesae Fiege & Van Damme, 2002, Namanereisllanetensis N\u00fa\u00f1ez, Glasby & Naranjo, 2020, Namanereisocculta , Namanereispilbarensis Glasby, Fiege & Van Damme, 2014, and Namanereissocotrensis Glasby, Fiege & Van Damme, 2014, making this genus one of the most studied in the last 20 or so years. As noted by Lycastoidesalticola Johnson, 1903 is also part of the Namanereis clade, but the species cannot take the name Namanereis, as Lycastoides is the senior genus  auctt.Nereis (Neanthioides) Rioja, 1918.Praxithea Malmgren, 1867.Neanthesvaalii Kinberg, 1865.https://www.marinespecies.org/polychaeta/aphia.php?p=taxdetails&id=129378.Maxillary ring paragnaths present; neurochaetae dorsal fascicle heterogomph falcigers in anterior chaetigers present; dorsal notopodial ligule not markedly broader on posterior chaetigers; oral ring papillae absent; notochaetae homogomph falcigers absent; notochaetae sesquigomph falcigers absent; neurochaetae dorsal fascicle simple chaetae  absent; Area VI smooth bars absent; notoaciculae on chaetigers 1 and 2 absent .Palpophore barrel-shaped, approximately equal width from base to palpostyle , or massive subconical, flattened  (rarely). Palpophore surface without grooves or striae or with a single transverse groove  or with several oblique grooves or striae . Eyes present, or absent. Tentacular belt greater than length of chaetiger 1.Oesophageal caeca present, or absent.Jaws with dentate cutting edge.Maxillary ring of pharynx with papillae absent. Maxillary ring paragnaths present. Area I conical paragnaths present; II conical paragnaths present, or absent; III conical paragnaths present, or absent; III rod-like paragnaths absent; IV paragnaths present, or absent; IV conical paragnaths present, or absent; IV smooth bar-like paragnaths present, or absent; IV rod-like paragnaths absent. Oral ring papillae absent. Oral ring paragnaths present, or absent; with Areas V, VI, and VII-VIII discrete, or comprising a continuous ring dorsally and ventrally, discrete groups not recognisable; on Areas V and VI form distinct groups, or not recognisably distinct. Area V conical paragnaths present, or absent. Area VI paragnaths present, or absent; paragnaths arranged in a roughly circular group, or in lines or arcs; conical paragnaths present; smooth bars absent. Areas VII-VIII paragnaths present, or absent; conical paragnaths present; conical paragnaths arranged in one or more irregular lines forming a continuous band; conical paragnaths similar in size, or irregular mix of large and small paragnaths in a single band, or differentiated, with a separate band of minute paragnaths also present; rod-shaped paragnaths absent.Dorsal notopodial ligule markedly elongate on anterior chaetigers, or not markedly elongate on anterior chaetigers; markedly elongate on posterior chaetigers, or not markedly elongate on posterior chaetigers; not markedly broader on posterior chaetigers; markedly reduced on posterior chaetigers, or not markedly reduced on posterior chaetigers. Prechaetal notopodial lobe present, or absent; smaller than dorsal notopodial ligule on anterior chaetigers, usually reduced or absent posteriorly, or approximately equal to length of dorsal notopodial ligule at least on anterior chaetigers (thus notopodium of three similar sized ligules/lobes); present on all chaetigers, or restricted to a limited number of anterior chaetigers. Notopodial acicular process present, or absent; reducing in size posteriorly, last present on chaetiger 5\u201325. Dorsal cirrus sub-terminally attached to dorsal margin of dorsal notopodial ligule on posterior chaetigers, or not sub-terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached throughout all chaetigers.Neuropodial prechaetal lobe absent. Neuropodial postchaetal lobe absent, or present; projecting beyond end of the acicular ligule, or not projecting beyond end of the acicular ligule; present throughout all chaetigers, or restricted to anterior chaetigers; digitiform. Ventral neuropodial ligule of anterior chaetigers present. Ventral neuropodial ligule of anterior chaetigers approx. as long as acicular neuropodial ligule, or short, up to half length of acicular neuropodial ligule. Ventral neuropodial ligule on posterior chaetigers present, or absent. Ventral neuropodial ligule on posterior chaetigers similar to length of acicular neuropodial ligule, or short, up to half length of acicular neuropodial ligule.Notoaciculae on chaetigers 1 and 2 absent. Notochaetae: homogomph spinigers present. Neurochaetae dorsal fascicle: heterogomph spinigers present, or absent; homogomph spinigers present; heterogomph falcigers in anterior chaetigers present; on posterior chaetigers present, or absent; blades serrated. Neurochaetae ventral fascicle: heterogomph spinigers present, or absent; homogomph spinigers present, or absent; heterogomph falcigers present; anterior chaetigers heterogomph falcigers with long blades present, or absent; anterior chaetigers heterogomph falcigers with extra-long blades present, or absent; anterior chaetigers heterogomph falcigers with short blades present, or absent; posterior chaetigers heterogomph falcigers with long blades present, or absent; posterior chaetigers heterogomph falcigers with extra-long blades present, or absent; posterior chaetigers heterogomph falcigers with short blades present, or absent; heterogomph falcigers blade lacking distinct tendon on terminal tooth.Anal cirri form cirriform or conical.Neanthes, even after removing some species to Alitta and Pseudonereis, was found by N.gisserana  and N.glandicincta ) and with elongate dorsal notopodial lobe on all chaetigers , and N.mossambica Day, 1957) or only on posterior chaetigers . Furthermore, Neanthes includes a subset of species having well-developed prechaetal notopodial lobes, giving the notopodia a tri-lobed appearance, which differs from the majority of bilobed species  oxypoda Marenzeller, 1879.https://www.marinespecies.org/polychaeta/aphia.php?p=taxdetails&id=324862.Dorsal notopodial ligule markedly broader on posterior chaetigers; notochaetae sesquigomph spinigers present . Palpophore massive subconical, flattened ; neurochaetae dorsal fascicle heterogomph spinigers present (secondary diagnosis).Palpophore massive subconical, flattened .Jaws with dentate cutting edge.Maxillary ring of pharynx with papillae absent. Area I conical paragnaths present; II conical paragnaths present; III conical paragnaths present; III rod-like paragnaths absent; IV paragnaths present; IV conical paragnaths present; IV rod-like paragnaths absent. Oral ring paragnaths present; with Areas V, VI and VII-VIII discrete; on Areas V and VI form distinct groups. Area V conical paragnaths present. Area VI paragnaths present; paragnaths arranged in a roughly circular group; conical paragnaths present; smooth bars absent. Areas VII-VIII paragnaths present; conical paragnaths present; conical paragnaths arranged in one or more irregular lines forming a continuous band; conical paragnaths similar in size, or irregular mix of large and small paragnaths in a single band; rod-shaped paragnaths absent.Dorsal notopodial ligule markedly elongate on posterior chaetigers; markedly broader on posterior chaetigers. Prechaetal notopodial lobe present; approximately equal to length of dorsal notopodial ligule at least on anterior chaetigers (thus notopodium of three similar sized ligules/lobes); present on all chaetigers. Dorsal cirrus sub-terminally attached to dorsal margin of dorsal notopodial ligule on posterior chaetigers; not terminally attached to dorsal notopodial ligule on anterior or posterior chaetigers.Neuropodial prechaetal lobe absent. Neuropodial postchaetal lobe present; projecting beyond end of the acicular ligule; present throughout all chaetigers; digitiform. Ventral neuropodial ligule of anterior chaetigers present. Ventral neuropodial ligule of anterior chaetigers approx. as long as acicular neuropodial ligule. Ventral neuropodial ligule on posterior chaetigers present. Ventral neuropodial ligule on posterior chaetigers similar to length of acicular neuropodial ligule. Notopodial dorsal ligule with prominent ovoid lobe medial to the dorsal cirrus in middle and posterior parapodia.Notoaciculae on chaetigers 1 and 2 present. Notochaetae: homogomph spinigers present; sesquigomph spinigers present. Neurochaetae dorsal fascicle: heterogomph spinigers present; homogomph spinigers present; sesquigomph spinigers present. Neurochaetae ventral fascicle: heterogomph spinigers present; homogomph spinigers present; heterogomph falcigers present ; falcigers blade tapering, with straight margin; anterior chaetigers heterogomph falcigers with long blades absent; anterior chaetigers heterogomph falcigers with extra-long blades present; anterior chaetigers heterogomph falcigers with short blades absent; posterior chaetigers heterogomph falcigers with long blades absent; posterior chaetigers heterogomph falcigers with extra-long blades present; posterior chaetigers heterogomph falcigers with short blades absent.Anal cirri form cirriform or conical.Nectoneanthes was treated as a synonym of Neanthes by Nectoneanthesoxypoda  as an epitokal form and resurrected Nectoneanthes and described a second species for the genus. The description by Nectoneanthes; both species occur on the north-west Pacific coast, with N.oxypoda also recorded by Taxon classificationAnimaliaPhyllodocidaNereididae\ufeffLinnaeus, 175806161371-38D6-527E-A638-D12FF23784E8Heteronereis \u00d6rsted, 1843.Johnstonia Quatrefages, 1850.Lycoris Lamarck, 1818.Naumachius Kinberg, 1865.Nereis (Nereis) auctt.Thoosa Kinberg, 1865.Nereispelagica Linnaeus, 1758.https://www.marinespecies.org/polychaeta/aphia.php?p=taxdetails&id=129379.Notochaetae homogomph falcigers present; maxillary ring paragnaths present; Area II rod-like paragnaths absent; dorsal notopodial ligule not markedly elongate on posterior chaetigers; antennae present; oral ring papillae absent .Palpophore barrel-shaped, approximately equal width from base to palpostyle . Palpophore surface with a single transverse groove . Eyes present, or absent. Tentacular belt greater than length of chaetiger 1.Oesophageal caeca present, or absent.Jaws with smooth or slightly crenulate cutting edge or with dentate cutting edge.Maxillary ring of pharynx with papillae absent. Maxillary ring paragnaths present. Area I conical paragnaths present, or absent; II conical paragnaths present, or absent; III conical paragnaths present, or absent; III rod-like paragnaths absent; IV paragnaths present; IV conical paragnaths present; IV smooth bar-like paragnaths present, or absent; IV rod-like paragnaths absent. Oral ring papillae absent. Oral ring paragnaths present, or absent; Areas V, VI, and VII-VIII discrete, forming distinct groups. Area V conical paragnaths present, or absent; arranged in a triangle, or in a longitudinal line. Area VI paragnaths present, or absent; paragnaths arranged in a roughly circular group; conical paragnaths present; smooth bars absent. Areas VII-VIII paragnaths present, or absent; conical paragnaths present; conical paragnaths arranged in one or more irregular lines forming a continuous band; conical paragnaths similar in size, or irregular mix of large and small paragnaths in a single band; rod-shaped paragnaths absent.Dorsal notopodial ligule not markedly elongate on posterior chaetigers; not markedly broader on posterior chaetigers; markedly reduced on posterior chaetigers, or not markedly reduced on posterior chaetigers. Prechaetal notopodial lobe present, or absent; smaller than dorsal notopodial ligule on anterior chaetigers, usually reduced or absent posteriorly; restricted to a limited number of anterior chaetigers. Notopodial acicular process absent. Dorsal cirrus not sub-terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached throughout all chaetigers.Neuropodial prechaetal lobe absent. Neuropodial postchaetal lobe absent. Ventral neuropodial ligule of anterior chaetigers present. Ventral neuropodial ligule of anterior chaetigers approx. as long as acicular neuropodial ligule. Ventral neuropodial ligule on posterior chaetigers present. Ventral neuropodial ligule on posterior chaetigers similar to length of acicular neuropodial ligule, or short, up to half length of acicular neuropodial ligule.Notoaciculae on chaetigers 1 and 2 absent. Notochaetae: homogomph spinigers present; homogomph falcigers present. Neurochaetae dorsal fascicle: heterogomph spinigers absent; homogomph spinigers present; heterogomph falcigers in anterior chaetigers present, or absent; on posterior chaetigers present; blades serrated; blades with teeth only slightly longer proximally than distally. Neurochaetae ventral fascicle: heterogomph spinigers present, or absent; spinigers in anterior chaetigers with blades evenly serrated throughout; on posterior chaetigers with blades finely serrated proximally; homogomph spinigers absent; heterogomph falcigers present, or absent; anterior chaetigers heterogomph falcigers with long blades present, or absent; anterior chaetigers heterogomph falcigers with extra-long blades present, or absent; anterior chaetigers heterogomph falcigers with short blades absent; posterior chaetigers heterogomph falcigers with long blades present, or absent; posterior chaetigers heterogomph falcigers with extra-long blades present, or absent; posterior chaetigers heterogomph falcigers with short blades present, or absent; heterogomph falcigers blade lacking distinct tendon on terminal tooth.Anal cirri form cirriform or conical.Nereis is the type taxon of the family Nereididae. It is a large assemblage of species, currently with 226 species attributed to the genus, many that probably belong in other genera. There are no revisions of the genus, or parts of it, or any that delineate species into informal subgroups. The description here follows Nereis have been found from the littoral zone to abyssal areas, and from a wide range of habitats.Species of N.falsa de Quatrefages, 1866.No complete identification guide to species is available but several useful keys of restricted scope have been published: Taxon classificationAnimaliaPhyllodocidaNereididae\ufeffKinberg, 1865C0A85013-959C-5B78-B1A0-AD0552B97E0ANiconpictus Kinberg, 1865.https://www.marinespecies.org/polychaeta/aphia.php?p=taxdetails&id=173735.Maxillary ring paragnaths and papillae absent; neuropodial postchaetal lobe present; dorsal notopodial ligule commences chaetiger 3; dorsal notopodial ligule not markedly reduced on posterior chaetigers; oral ring paragnaths absent; notochaetae homogomph falcigers absent .Palpophore barrel-shaped, approximately equal width from base to palpostyle . Palpophore surface with a single transverse groove . Eyes present, or absent. Tentacular belt greater than length of chaetiger 1.Jaws with dentate cutting edge.Maxillary ring of pharynx with papillae and paragnaths absent. Oral ring papillae and paragnaths absent.Dorsal notopodial ligule present, or absent; not markedly elongate on posterior chaetigers; not markedly broader on posterior chaetigers; not markedly reduced on posterior chaetigers. Prechaetal notopodial lobe present, or absent; smaller than dorsal notopodial ligule on anterior chaetigers, usually reduced or absent posteriorly; restricted to a limited number of anterior chaetigers. Notopodial acicular process absent. Dorsal cirrus not sub-terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached throughout all chaetigers.Neuropodial prechaetal lobe absent. Neuropodial postchaetal lobe present; projecting beyond end of the acicular ligule; present throughout all chaetigers, or restricted to anterior chaetigers; digitiform. Ventral neuropodial ligule of anterior chaetigers present. Ventral neuropodial ligule of anterior chaetigers approx. as long as acicular neuropodial ligule. Ventral neuropodial ligule on posterior chaetigers present. Ventral neuropodial ligule on posterior chaetigers similar to length of acicular neuropodial ligule.Notoaciculae on chaetigers 1 and 2 absent. Notochaetae: homogomph spinigers present. Neurochaetae dorsal fascicle: heterogomph spinigers present, or absent; homogomph spinigers present; heterogomph falcigers in anterior chaetigers present, or absent; on posterior chaetigers present, or absent; blades serrated; simple chaetae  present, or absent; homogomph falcigers in anterior chaetigers present, or absent. Neurochaetae ventral fascicle: sesquigomph falcigers present, or absent; heterogomph spinigers present, or absent; homogomph spinigers present, or absent; heterogomph falcigers present; anterior chaetigers heterogomph falcigers with long blades absent; anterior chaetigers heterogomph falcigers with extra-long blades present; anterior chaetigers heterogomph falcigers with short blades absent; posterior chaetigers heterogomph falcigers with long blades present, or absent; posterior chaetigers heterogomph falcigers with extra-long blades present, or absent; posterior chaetigers heterogomph falcigers with short blades absent; heterogomph falcigers blade with recurved terminal tooth and distinct tendon, or lacking distinct tendon on terminal tooth; homogomph falcigers in anterior chaetigers present, or absent.Pygidium bilobate. Anal cirri form cirriform or conical.Nicon is not a species-rich genus: of the 700+ species of Nereididae, only ten belong to the genus Nicon and those ten species are from diverse habitats and widespread regions . Ventral neuropodial ligule of anterior chaetigers short, up to half length of acicular neuropodial ligule; oral ring papillae present; prostomium anterior margin entire; Area V papillae absent (secondary diagnosis).Palpophore barrel-shaped, approximately equal width from base to palpostyle . Tentacular belt greater than length of chaetiger 1.Jaws with dentate cutting edge.Maxillary ring of pharynx with papillae present; solitary. Maxillary ring paragnaths absent. Oral ring papillae present. Oral ring papillae arrangement solitary. Area V papillae absent; VI papillae present; VII-VIII papillae present. Oral ring paragnaths absent.Dorsal notopodial ligule present; commences chaetiger 3; not markedly elongate on posterior chaetigers; not markedly broader on posterior chaetigers; markedly reduced on posterior chaetigers.Neuropodial prechaetal lobe present. Ventral neuropodial ligule of anterior chaetigers present. Ventral neuropodial ligule of anterior chaetigers short, up to half length of acicular neuropodial ligule. Ventral neuropodial ligule on posterior chaetigers present. Ventral neuropodial ligule on posterior chaetigers similar to length of acicular neuropodial ligule.Notochaetae: homogomph spinigers present. Neurochaetae dorsal fascicle: heterogomph spinigers absent; homogomph spinigers present; heterogomph falcigers in anterior chaetigers present; on posterior chaetigers present; blades serrated; blades with teeth only slightly longer proximally than distally. Neurochaetae ventral fascicle: heterogomph spinigers present; spinigers in anterior chaetigers with blades evenly serrated throughout; on posterior chaetigers with blades finely serrated proximally; homogomph spinigers absent; heterogomph falcigers present; falcigers blade bowed, with convex margin; heterogomph falcigers blade with recurved terminal tooth and distinct tendon.Anal cirri form cirriform or conical.Ceratocephalaedmondsi Hartman, 1954  was separated into the new genus Olganereis by Ceratocephale species).Olganereis is monotypic and the sole species O.edmondsi  occurs in estuaries in southern Australia. The only other Australian nereidid with papillae on both rings of the pharynx is Dendronereidesheteropoda Southern, 1921 from tropical estuaries and in which the dorsal notopodial ligule is divided into 'branchial' filaments.Taxon classificationAnimaliaPhyllodocidaNereididae\ufeffKhlebovich & Wu, 19622AF17D19-1FA0-5B81-BE0E-F9C5A8A432D0Ganganereis Misra, 1999.Periserrula Paik, 1977.Paraleonnatesuschakovi Chlebovitsch & Wu, 1962.https://www.marinespecies.org/polychaeta/aphia.php?p=taxdetails&id=324866.Neurochaetae dorsal fascicle homogomph spinigers absent; oral ring papillae present; prostomium anterior margin entire .Palpophore barrel-shaped, approximately equal width from base to palpostyle . Palpophore surface with a single transverse groove .Jaws with dentate cutting edge.Maxillary ring of pharynx with papillae absent. Maxillary ring paragnaths present. Area I conical paragnaths present, or absent; II conical paragnaths present; III conical paragnaths present; III rod-like paragnaths absent; IV paragnaths present; IV conical paragnaths present; IV rod-like paragnaths absent. Oral ring papillae present. Oral ring papillae arrangement solitary. Area V papillae present, or absent; VI papillae present; VII-VIII papillae present. Oral ring paragnaths absent.Dorsal notopodial ligule not markedly elongate on posterior chaetigers; not markedly broader on posterior chaetigers; not markedly reduced on posterior chaetigers. Prechaetal notopodial lobe present; approximately equal to length of dorsal notopodial ligule at least on anterior chaetigers (thus notopodium of three similar sized ligules/lobes). Dorsal cirrus not sub-terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached throughout all chaetigers.Neuropodial postchaetal lobe present; projecting beyond end of the acicular ligule. Ventral neuropodial ligule of anterior chaetigers present. Ventral neuropodial ligule of anterior chaetigers approx. as long as acicular neuropodial ligule. Ventral neuropodial ligule on posterior chaetigers present. Ventral neuropodial ligule on posterior chaetigers similar to length of acicular neuropodial ligule.Notochaetae: homogomph spinigers present. Neurochaetae dorsal fascicle: heterogomph spinigers present; homogomph spinigers absent. Neurochaetae ventral fascicle: heterogomph spinigers present; homogomph spinigers absent; heterogomph falcigers present, or absent; heterogomph falcigers blade lacking distinct tendon on terminal tooth; homogomph falcigers in anterior chaetigers present, or absent; on posterior chaetigers present, or absent.Anal cirri form cirriform or conical.Paraleonnates are those of Paraleonnates is a genus of four species which occur in shallow muddy habitats, typically estuaries and mangroves, in the Indo-Pacific.The most recent taxonomic treatments of Paraleonnates but omits Paraleonnatestenuipalpa  which had been moved to Paraleonnates by P.tenuipalpa may be a senior synonym of Paraleonnatesbolus .Taxon classificationAnimaliaPhyllodocidaNereididae\ufeffVillalobos-Guerrero, Conde-Vela & Sato, 20223FAA02AD-6AE1-5EC6-8533-F6B145884B80Nereisirritabilis Webster, 1879.https://www.marinespecies.org/polychaeta/aphia.php?p=taxdetails&id=1600661.Neurochaetae dorsal fascicle sesquigomph falcigers present; palpophore massive subconical, flattened ; oral ring papillae absent . Neurochaetae ventral fascicle sesquigomph falcigers present; neuropodial postchaetal lobe not projecting beyond end of the acicular ligule (secondary diagnosis).Palpophore massive subconical, flattened . Prostomium longitudinal groove present; anterior region entire, hemispherical, longitudinal groove present; prostomial posterior region as long as anterior region. Tentacular belt greater than length of chaetiger 1.Oesophageal caeca absent.Jaws with smooth or slightly crenulate cutting edge.Everted pharynx a truncate cone, tapering, greatest width at margin of tentacular belt.Maxillary ring paragnaths present. Area I conical paragnaths absent; II conical paragnaths present; III conical paragnaths present; IV paragnaths present; IV conical paragnaths present. Oral ring paragnaths absent.Dorsal notopodial ligule not markedly reduced on posterior chaetigers. Prechaetal notopodial lobe present; restricted to a limited number of anterior chaetigers. Notopodial acicular process present, or absent.Neuropodial prechaetal lobe absent. Neuropodial postchaetal lobe present; not projecting beyond end of the acicular ligule; restricted to anterior chaetigers; digitiform. Ventral neuropodial ligule of anterior chaetigers present. Ventral neuropodial ligule of anterior chaetigers approx. as long as acicular neuropodial ligule. Ventral neuropodial ligule on posterior chaetigers present. Ventral neuropodial ligule on posterior chaetigers similar to length of acicular neuropodial ligule.Notoaciculae on chaetigers 1 and 2 absent. Notochaetae: homogomph spinigers present. Neurochaetae dorsal fascicle: heterogomph spinigers absent; homogomph spinigers present; sesquigomph falcigers present; heterogomph falcigers in anterior chaetigers absent; on posterior chaetigers absent. Neurochaetae ventral fascicle: sesquigomph falcigers present; heterogomph spinigers present; homogomph spinigers absent; heterogomph falcigers absent; falcigers blade bowed, with convex margin.Anal cirri form cirriform or conical.Parasetia was established by Nereisirritabilis Webster, 1878, removed from Composetia due to absence of oesophageal caeca and other morphological differences from a redefined Composetia. Parasetiairritabilis  occurs on the Atlantic coast of North America down to a depth of ~ 50 m.Taxon classificationAnimaliaPhyllodocidaNereididae\ufeffKinberg, 1865085C72C3-6E60-56C1-9E89-8E6F7C7C3512Arete Kinberg, 1865.Gnatholycastis Ehlers, 1920.Lipephile Malmgren, 1867.Nereis (Lipephile) Malmgren, 1867.Nereis (Perinereis) auctt.Perinereisnovaehollandiae Kinberg, 1865.https://www.marinespecies.org/polychaeta/aphia.php?p=taxdetails&id=129380.Palpophore massive subconical, flattened ; oral ring paragnaths present; Area VI smooth bars present; antennae present .Palpophore massive subconical, flattened . Palpophore surface with a single transverse groove . Tentacular belt greater than length of chaetiger 1.Jaws with smooth or slightly crenulate cutting edge or with dentate cutting edge.Maxillary ring of pharynx with papillae absent. Maxillary ring paragnaths present. Area I conical paragnaths present or absent; II conical paragnaths present or absent; III conical paragnaths present; III rod-like paragnaths absent; IV paragnaths present; IV conical paragnaths present or absent; IV smooth bar-like paragnaths present, or absent; IV rod-like paragnaths absent. Oral ring papillae absent. Oral ring paragnaths present; with Areas V, VI, and VII-VIII discrete; on Areas V and VI form distinct groups. Area V conical paragnaths present, or absent; arranged in a triangle, or in a longitudinal line. Area VI paragnaths present, arranged in lines or arcs; conical paragnaths present, or absent; smooth bars present. Areas VII-VIII paragnaths present, or absent; conical paragnaths present; conical paragnaths arranged in one or more irregular lines forming a continuous band; conical paragnaths similar in size, or irregular mix of large and small paragnaths in a single band; rod-shaped paragnaths absent.Dorsal notopodial ligule markedly elongate on posterior chaetigers, or not markedly elongate on posterior chaetigers; not markedly broader on posterior chaetigers; not markedly reduced on posterior chaetigers. Prechaetal notopodial lobe present, or absent; smaller than dorsal notopodial ligule on anterior chaetigers, usually reduced or absent posteriorly; restricted to a limited number of anterior chaetigers. Dorsal cirrus sub-terminally attached to dorsal margin of dorsal notopodial ligule on posterior chaetigers, or not sub-terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached throughout all chaetigers.Neuropodial prechaetal lobe absent. Neuropodial postchaetal lobe absent, or present; projecting beyond end of the acicular ligule; present throughout all chaetigers, or restricted to anterior chaetigers. Ventral neuropodial ligule of anterior chaetigers present. Ventral neuropodial ligule of anterior chaetigers approx. as long as acicular neuropodial ligule. Ventral neuropodial ligule on posterior chaetigers present. Ventral neuropodial ligule on posterior chaetigers similar to length of acicular neuropodial ligule, or short, up to half length of acicular neuropodial ligule.Notoaciculae on chaetigers 1 and 2 absent. Notochaetae: homogomph spinigers present. Neurochaetae dorsal fascicle: heterogomph spinigers absent; homogomph spinigers present; heterogomph falcigers in anterior chaetigers present; on posterior chaetigers present; blades serrated; blades with teeth only slightly longer proximally than distally, or much longer proximally than distally. Neurochaetae ventral fascicle: heterogomph spinigers present, or absent; spinigers in anterior chaetigers with blades evenly serrated throughout, or coarsely serrated proximally; on posterior chaetigers with blades finely serrated proximally; homogomph spinigers absent; heterogomph falcigers present; anterior chaetigers heterogomph falcigers with long blades present, or absent; anterior chaetigers heterogomph falcigers with extra-long blades present, or absent; anterior chaetigers heterogomph falcigers with short blades present, or absent; posterior chaetigers heterogomph falcigers with long blades present, or absent; posterior chaetigers heterogomph falcigers with extra-long blades present, or absent; posterior chaetigers heterogomph falcigers with short blades present, or absent; heterogomph falcigers blade lacking distinct tendon on terminal tooth.Anal cirri form cirriform or conical.Perinereis contains 97 species and is thus one of the most species-rich in the family  auctt.Platynereismagalhaensis Kinberg, 1865.https://www.marinespecies.org/polychaeta/aphia.php?p=taxdetails&id=129381.Areas VII-VIII rod-shaped paragnaths present . Notochaetae homogomph falcigers with terminal tendon present (secondary diagnosis).Palps anteriorly directed, or ventrally directed. Palpophore barrel-shaped, approximately equal width from base to palpostyle . Palpophore surface with a single transverse groove . Tentacular belt greater than length of chaetiger 1.Jaws with dentate cutting edge.Maxillary ring of pharynx with papillae absent. Maxillary ring paragnaths present. Area II rod-like paragnaths present; III conical paragnaths absent; III rod-like paragnaths present; IV paragnaths present; IV conical paragnaths absent; IV rod-like paragnaths present. Oral ring papillae present, or absent. Oral ring paragnaths present; on Area V and VI form distinct groups. Area V conical paragnaths absent. Area VI paragnaths present; conical paragnaths absent; rod-shaped paragnaths present. Areas VII-VIII paragnaths present; conical paragnaths absent; conical paragnaths arranged in isolated patches, or in one or more irregular lines forming a continuous band; rod-shaped paragnaths present.Dorsal notopodial ligule not markedly elongate on posterior chaetigers; not markedly broader on posterior chaetigers; not markedly reduced on posterior chaetigers. Dorsal cirrus sub-terminally attached to dorsal margin of dorsal notopodial ligule on posterior chaetigers; not terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached throughout all chaetigers.Neuropodial postchaetal lobe absent. Ventral neuropodial ligule of anterior chaetigers present. Ventral neuropodial ligule of anterior chaetigers approx. as long as acicular neuropodial ligule. Ventral neuropodial ligule on posterior chaetigers present. Ventral neuropodial ligule on posterior chaetigers similar to length of acicular neuropodial ligule.Notoaciculae on chaetigers 1 and 2 absent. Notochaetae: homogomph spinigers present; homogomph falcigers present; with terminal tendon present; articulation fused on some chaetigers (present as a simple chaeta), or with blade free throughout. Neurochaetae dorsal fascicle: heterogomph spinigers absent; homogomph spinigers present; heterogomph falcigers in anterior chaetigers present; on posterior chaetigers present; blades serrated; blades with teeth only slightly longer proximally than distally. Neurochaetae ventral fascicle: heterogomph spinigers present; spinigers in anterior chaetigers with blades evenly serrated throughout; on posterior chaetigers with blades finely serrated proximally; homogomph spinigers absent; heterogomph falcigers present; anterior chaetigers heterogomph falcigers with long blades absent; anterior chaetigers heterogomph falcigers with extra-long blades present; anterior chaetigers heterogomph falcigers with short blades absent; heterogomph falcigers blade lacking distinct tendon on terminal tooth.Anal cirri form cirriform or conical.Platynereis are easily recognised by the small rod-like paragnaths in tight rows on the pharynx; 36 species are recognised. No revisions have been published, but regional studies using molecular data to revise species to resolve the complex taxonomy, and taxonomic history of this genus have been appearing .Palpophore barrel-shaped, approximately equal width from base to palpostyle . Prostomium longitudinal groove present; anterior region entire, hemispherical, longitudinal groove present; prostomial posterior region shorter than anterior region. Tentacular belt greater than length of chaetiger 1.Oesophageal caeca absent.Jaws with dentate cutting edge.Everted pharynx a truncate cone, tapering, greatest width at margin of tentacular belt.Maxillary ring paragnaths present. Area I conical paragnaths present, or absent; II conical paragnaths present; III conical paragnaths present; III conical paragnaths isolated lateral groups absent; IV paragnaths present; IV conical paragnaths present. Oral ring paragnaths absent.Prechaetal notopodial lobe absent. Dorsal cirrus not sub-terminally attached to dorsal notopodial ligule on posterior chaetigers.Neuropodial prechaetal lobe absent. Neuropodial postchaetal lobe present; not projecting beyond end of the acicular ligule; restricted to anterior chaetigers; digitiform. Ventral neuropodial ligule of anterior chaetigers present.Notoaciculae on chaetigers 1 and 2 present. Notochaetae: homogomph spinigers present. Neurochaetae dorsal fascicle: heterogomph spinigers present, or absent; homogomph spinigers present; heterogomph falcigers in anterior chaetigers present; on posterior chaetigers present. Neurochaetae ventral fascicle: heterogomph spinigers present; homogomph spinigers absent; heterogomph falcigers present; falcigers blade tapering, with straight margin.Anal cirri form cirriform or conical.Potamonereis was established by Composetia in which oesophageal caeca are absent and which have a truncate-conical pharynx, and other morphological differences (at the same time those authors redefined Composetia). Both species of Potamonereis occur in the North-west Pacific in Japanese estuaries.Taxon classificationAnimaliaPhyllodocidaNereididae\ufeffKinberg, 1865CB56277D-22CA-5D26-8542-5AED85FC6614Phyllonereis Hansen, 1882.Pseudonereisgallapagensis Kinberg, 1865.https://www.marinespecies.org/polychaeta/aphia.php?p=taxdetails&id=129382.Maxillary ring of pharynx with P-bar paragnaths present, usually in regular comb-like rows . Area VI shield-shaped bars present (secondary diagnosis).Palpophore barrel-shaped, approximately equal width from base to palpostyle . Palpophore surface with a single transverse groove . Tentacular belt greater than length of chaetiger 1.Jaws with dentate cutting edge.Maxillary ring of pharynx with papillae absent. Maxillary ring paragnaths present; of pharynx with P-bar paragnaths present, usually in regular comb-like rows. Area I conical paragnaths present; II conical paragnaths present; III conical paragnaths present; III rod-like paragnaths absent; IV paragnaths present; IV conical paragnaths present; IV rod-like paragnaths absent. Oral ring papillae absent. Oral ring paragnaths present; with Areas V, VI and VII-VIII discrete; on Area V and VI form distinct groups. Area V conical paragnaths present, or absent. Area VI paragnaths present; paragnaths arranged in lines or arcs; conical paragnaths present, or absent; smooth bars present, or absent; shield-shaped bars present. Areas VII-VIII paragnaths present; conical paragnaths present; conical paragnaths arranged in one or more irregular lines forming a continuous band; conical paragnaths similar in size, or irregular mix of large and small paragnaths in a single band; P-bar paragnaths absent, or present.Dorsal notopodial ligule markedly elongate on posterior chaetigers; markedly broader on posterior chaetigers; not markedly reduced on posterior chaetigers. Prechaetal notopodial lobe present, or absent. Notopodial acicular process absent. Dorsal cirrus not sub-terminally attached to dorsal notopodial ligule on posterior chaetigers; terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached throughout all chaetigers.Neuropodial prechaetal lobe absent. Neuropodial postchaetal lobe absent, or present; projecting beyond end of the acicular ligule; restricted to anterior chaetigers; digitiform, or flattened. Ventral neuropodial ligule of anterior chaetigers present. Ventral neuropodial ligule on posterior chaetigers present. Ventral neuropodial ligule on posterior chaetigers similar to length of acicular neuropodial ligule, or short, up to half length of acicular neuropodial ligule.Notoaciculae on chaetigers 1 and 2 absent. Notochaetae: homogomph spinigers present; homogomph falcigers present, or absent. Neurochaetae dorsal fascicle: heterogomph spinigers present, or absent; homogomph spinigers present, or absent; heterogomph falcigers in anterior chaetigers present; on posterior chaetigers present; blades serrated; blades with teeth only slightly longer proximally than distally. Neurochaetae ventral fascicle: homogomph spinigers absent; heterogomph falcigers present; heterogomph falcigers blade lacking distinct tendon on terminal tooth.Anal cirri form cirriform or conical.Pseudonereis species are characterised by presence of both P-bars and comb-like rows of paragnaths in Areas II-IV .Palpophore barrel-shaped, approximately equal width from base to palpostyle . Tentacular belt greater than length of chaetiger 1.Jaws with dentate cutting edge.Maxillary ring of pharynx with papillae absent. Maxillary ring paragnaths absent. Oral ring papillae present, or absent. Oral ring paragnaths absent.Dorsal notopodial ligule present; commences chaetiger 3; not markedly elongate on posterior chaetigers ; not markedly broader on posterior chaetigers; markedly reduced on posterior chaetigers. Dorsal cirrus not sub-terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached throughout all chaetigers.Ventral neuropodial ligule of anterior chaetigers present. Ventral neuropodial ligule of anterior chaetigers approx. as long as acicular neuropodial ligule. Ventral neuropodial ligule on posterior chaetigers present. Ventral neuropodial ligule on posterior chaetigers similar to length of acicular neuropodial ligule.Notochaetae: homogomph spinigers present; homogomph falcigers present (on posterior chaetigers). Neurochaetae dorsal fascicle: heterogomph spinigers absent; homogomph spinigers present; heterogomph falcigers in anterior chaetigers present; on posterior chaetigers present; blades serrated; blades with teeth only slightly longer proximally than distally. Neurochaetae ventral fascicle: heterogomph spinigers absent; homogomph spinigers absent; heterogomph falcigers present; anterior chaetigers heterogomph falcigers with long blades absent; anterior chaetigers heterogomph falcigers with extra-long blades present; anterior chaetigers heterogomph falcigers with short blades absent; posterior chaetigers heterogomph falcigers with long blades present; posterior chaetigers heterogomph falcigers with short blades present.Anal cirri form cirriform or conical.Rullierinereis is a genus with similarities to Nicon and Typhlonereis but differing in having notopodial homogomph falcigers . alcigers . FifteenTaxon classificationAnimaliaPhyllodocidaNereididae\ufeffHartmann-Schr\u00f6der, 198571B0A9D9-6CCE-55CB-A33B-8A5C0828603ACeratonereis (Simplisetia) Hartmann-Schr\u00f6der, 1985.Nereis (Ceratonereis) aequisetis Augener, 1913.https://www.marinespecies.org/polychaeta/aphia.php?p=taxdetails&id=324869.Neurochaetae dorsal fascicle simple chaetae  present; palpophore barrel-shaped, approximately equal width from base to palpostyle ; maxillary ring paragnaths present .Palpophore barrel-shaped, approximately equal width from base to palpostyle . Palpophore surface with a single transverse groove .Jaws with dentate cutting edge.Maxillary ring of pharynx with papillae absent. Maxillary ring paragnaths present. Area I conical paragnaths present, or absent; II conical paragnaths present; III conical paragnaths present; III rod-like paragnaths absent; IV paragnaths present; IV conical paragnaths present; IV rod-like paragnaths absent. Oral ring papillae absent. Oral ring paragnaths absent.Dorsal notopodial ligule not markedly elongate on posterior chaetigers; not markedly broader on posterior chaetigers (rarely markedly reduced on posterior chaetigers). Prechaetal notopodial lobe present, or absent; smaller than dorsal notopodial ligule on anterior chaetigers, usually reduced or absent posteriorly; restricted to a limited number of anterior chaetigers. Notopodial acicular process present, or absent. Dorsal cirrus not sub-terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached throughout all chaetigers.Neuropodial postchaetal lobe absent, or present; projecting beyond end of the acicular ligule; restricted to anterior chaetigers; digitiform. Ventral neuropodial ligule of anterior chaetigers present. Ventral neuropodial ligule of anterior chaetigers approx. as long as acicular neuropodial ligule. Ventral neuropodial ligule on posterior chaetigers present. Ventral neuropodial ligule on posterior chaetigers similar to length of acicular neuropodial ligule, or short, up to half length of acicular neuropodial ligule.S.lizardensis); homogomph spinigers present; heterogomph falcigers in anterior chaetigers present; on posterior chaetigers present; simple chaetae  present. Neurochaetae ventral fascicle: heterogomph spinigers present; homogomph spinigers present (only in Simplisetia sp. from Phuket), or absent; heterogomph falcigers present; anterior chaetigers heterogomph falcigers with long blades absent; anterior chaetigers heterogomph falcigers with extra-long blades present; anterior chaetigers heterogomph falcigers with short blades absent; posterior chaetigers heterogomph falcigers with long blades present, or absent; posterior chaetigers heterogomph falcigers with extra-long blades present, or absent; posterior chaetigers heterogomph falcigers with short blades present, or absent; heterogomph falcigers blade lacking distinct tendon on terminal tooth.Notoaciculae on chaetigers 1 and 2 absent. Notochaetae: homogomph spinigers present. Neurochaetae dorsal fascicle: heterogomph spinigers present, or absent . Dorsal notopodial ligule commences chaetiger 4; dorsal notopodial ligule not markedly elongate on posterior chaetigers; notochaetae homogomph falcigers absent (secondary diagnosis).Palpophore barrel-shaped, approximately equal width from base to palpostyle .Jaws with dentate cutting edge.Maxillary ring of pharynx with papillae absent. Maxillary ring paragnaths absent. Oral ring papillae absent. Oral ring paragnaths absent.Dorsal notopodial ligule present; commences chaetiger 4; not markedly reduced on posterior chaetigers. Prechaetal notopodial lobe present; present on all chaetigers. Notopodial acicular process absent. Dorsal cirrus not sub-terminally attached to dorsal notopodial ligule on posterior chaetigers.Neuropodial prechaetal lobe absent. Neuropodial postchaetal lobe present; not projecting beyond end of the acicular ligule; present throughout all chaetigers; digitiform. Ventral neuropodial ligule of anterior chaetigers present. Ventral neuropodial ligule of anterior chaetigers approx. as long as acicular neuropodial ligule. Ventral neuropodial ligule on posterior chaetigers present. Ventral neuropodial ligule on posterior chaetigers similar to length of acicular neuropodial ligule.Notoaciculae on chaetigers 1 and 2 absent. Notochaetae: homogomph spinigers present. Neurochaetae dorsal fascicle: heterogomph spinigers absent; homogomph spinigers present; heterogomph falcigers in anterior chaetigers present; on posterior chaetigers present. Neurochaetae ventral fascicle: heterogomph spinigers present; homogomph spinigers absent; heterogomph falcigers present; falcigers blade tapering, with straight margin.Anal cirri form cirriform or conical.Dorsal cirrophores of chaetigers 5\u20137 of epitokes modified into spherical globular structures. Natatory epitokal modifications in males commence chaetiger 22. Females without natatory modifications.Sinonereis Wu & Sun, 1979 is a monotypic genus originally based on a single epitokous specimen. An emended description including atokous characters was provided by Taxon classificationAnimaliaPhyllodocidaNereididae\ufeffGibbs, 1971B069DACD-C9CC-5050-B536-4D41B71D7E34Solomononereismarauensis Gibbs, 1971.https://www.marinespecies.org/polychaeta/aphia.php?p=taxdetails&id=324870.Area II rod-like paragnaths present; prostomium anterior margin indented . Notochaetae homogomph falcigers present; dorsal notopodial ligule markedly reduced on posterior chaetigers (secondary diagnosis).Palpophore barrel-shaped, approximately equal width from base to palpostyle . Prostomium anterior margin indented. Tentacular belt greater than length of chaetiger 1.Jaws with dentate cutting edge.Maxillary ring of pharynx with papillae absent. Maxillary ring paragnaths present. Area I conical paragnaths present; II conical paragnaths absent; II rod-like paragnaths present; III conical paragnaths absent; III rod-like paragnaths present; IV paragnaths present; IV conical paragnaths absent; IV rod-like paragnaths present. Oral ring papillae absent. Oral ring paragnaths absent.Dorsal notopodial ligule not markedly elongate on posterior chaetigers; not markedly broader on posterior chaetigers; markedly reduced on posterior chaetigers. Prechaetal notopodial lobe absent. Notopodial acicular process absent. Dorsal cirrus not sub-terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached throughout all chaetigers.Neuropodial postchaetal lobe absent. Ventral neuropodial ligule of anterior chaetigers present. Ventral neuropodial ligule of anterior chaetigers approx. as long as acicular neuropodial ligule. Ventral neuropodial ligule on posterior chaetigers present. Ventral neuropodial ligule on posterior chaetigers short, up to half length of acicular neuropodial ligule.Notoaciculae on chaetigers 1 and 2 present. Notochaetae: homogomph spinigers absent; sesquigomph spinigers present; homogomph falcigers present; homogomph falcigers with multidentate blade with 2 or more small lateral teeth, first and subsequent lateral teeth much smaller than terminal tooth present; sesquigomph falcigers present, or absent. Neurochaetae dorsal fascicle: heterogomph spinigers absent; homogomph spinigers absent; sesquigomph spinigers present; heterogomph falcigers in anterior chaetigers absent; on posterior chaetigers present; blades serrated. Neurochaetae ventral fascicle: heterogomph spinigers present; homogomph spinigers absent; heterogomph falcigers absent.Anal cirri form cirriform or conical.Solomononereis is a genus of Nereididae sharing some similarities to members of the larger genus Ceratonereis. Solomononereis, however, can be distinguished by the presence of rod-like paragnaths on the maxillary ring. Solomononereis contains two species, both occurring in the tropical Indo-Pacific to a depth of ~ 30 m. Taxon classificationAnimaliaPhyllodocidaNereididae\ufeffWesenberg-Lund, 1958974DE7F1-99C0-5F83-8A37-6CE966A79210Stenoninereismartini Wesenberg-Lund, 1958.https://www.marinespecies.org/polychaeta/aphia.php?p=taxdetails&id=324872.Dorsal cirrus arising from basal cirrophore; ventral neuropodial ligule of anterior chaetigers absent; palpophore surface with a single transverse groove  . Oral ring papillae absent; maxillary ring paragnaths absent; palpostyles subconical (secondary diagnosis).Palpophore barrel-shaped, approximately equal width from base to palpostyle . Prostomium anterior margin indented; longitudinal groove absent. Tentacular belt equal to or less than length of chaetiger 1.Jaws with dentate cutting edge.Maxillary ring of pharynx with papillae absent. Maxillary ring paragnaths absent. Oral ring papillae absent. Oral ring paragnaths absent.Dorsal notopodial ligule present; commences chaetiger 3; markedly reduced on posterior chaetigers. Prechaetal notopodial lobe absent. Notopodial acicular process absent. Dorsal cirrus not sub-terminally attached to dorsal notopodial ligule on posterior chaetigers; arising from basal cirrophore; cirrophore of dorsal cirrus much longer than ventral notopodial ligule (and ciliated); cirrophore of dorsal cirrus cylindrical throughout.Neuropodial prechaetal lobe absent. Neuropodial postchaetal lobe present; not projecting beyond end of the acicular ligule; present throughout all chaetigers; flattened (rounded). Ventral neuropodial ligule of anterior chaetigers absent. Ventral neuropodial ligule on posterior chaetigers absent.Notoaciculae on chaetigers 1 and 2 present. Notochaetae: homogomph spinigers absent; sesquigomph spinigers present. Neurochaetae dorsal fascicle: heterogomph spinigers absent; homogomph spinigers absent; sesquigomph spinigers present; heterogomph falcigers in anterior chaetigers absent; on posterior chaetigers absent. Neurochaetae ventral fascicle: heterogomph spinigers present; homogomph spinigers absent; heterogomph falcigers present; falcigers blade tapering, with straight margin; anterior chaetigers heterogomph falcigers with long blades absent; anterior chaetigers heterogomph falcigers with extra-long blades present; anterior chaetigers heterogomph falcigers with short blades absent; posterior chaetigers heterogomph falcigers with long blades absent; posterior chaetigers heterogomph falcigers with extra-long blades present; posterior chaetigers heterogomph falcigers with short blades absent. Neuropodial heterogomph spinigers with blades basally serrate, coarse teeth, larger teeth longer than blade width, 2/3 of the blade edentate and subulate. Neuropodial heterogomph falcigers with very long blades, increasing their length from upper to lower positions in the same fascicle; falcigers with blades smooth.Anal cirri form cirriform or conical.Stenoninereis Wesenberg-Lund, 1958 was described for a single species, S.martini Wesenberg-Lund, 1958. The genus now includes four small species, all occurring in sinkholes in the Caribbean-Mexico-central America region. Species of Stenoninereis can be identified using the key of Taxon classificationAnimaliaPhyllodocidaNereididae\ufeffPillai, 1961E4A27572-88EA-56FD-8C0A-F206C7991603Tambalagamiafauveli Pillai, 1961.https://www.marinespecies.org/polychaeta/aphia.php?p=taxdetails&id=324873.Transverse dorsal lamellae present; neurochaetae dorsal fascicle sesquigomph spinigers absent . Dorsal cirrus arising from basal cirrophore; tentacular belt greater than length of chaetiger 1; notochaetae sesquigomph spinigers absent (secondary diagnosis).Palpophore barrel-shaped, approximately equal width from base to palpostyle . Prostomium anterior margin indented. Tentacular belt greater than length of chaetiger 1.Jaws with smooth or slightly crenulate cutting edge.Maxillary ring of pharynx with papillae absent. Maxillary ring paragnaths absent. Oral ring papillae present. Oral ring papillae arrangement solitary. Area V papillae present; VII-VIII papillae present. Oral ring paragnaths absent.Transverse dorsal lamellae present.Dorsal notopodial ligule present; commences chaetiger 1. Prechaetal notopodial lobe present. Dorsal cirrus arising from basal cirrophore; cirrophore of dorsal cirrus enlarged and vascularised; cirrophore of dorsal cirrus cylindrical throughout.Ventral neuropodial ligule of anterior chaetigers present. Accessory ventral cirrus present.Notoaciculae on chaetigers 1 and 2 absent. Notochaetae: homogomph spinigers present. Neurochaetae dorsal fascicle: heterogomph spinigers absent; homogomph spinigers present; heterogomph falcigers in anterior chaetigers absent; on posterior chaetigers absent. Neurochaetae ventral fascicle: heterogomph spinigers absent; homogomph spinigers present; heterogomph falcigers absent.Tambalagamia Pillai, 1961 is similar to Ceratocephale and, especially to Gymnonereis, with double ventral cirri being shared characters. Tambalagamia to be a junior synonym of Gymnonereis. We follow Tambalagamia as separate pending phylogenetic analysis with better taxon sampling of both genera. Tambalagamia currently includes three species which can be identified using the tabular comparison of Taxon classificationAnimaliaPhyllodocidaNereididae\ufeffFauvel, 1911D2A469FC-05F5-5D2A-A397-E5D6C969B09DTylonereisbogoyawlenskyi Fauvel, 1911.https://www.marinespecies.org/polychaeta/aphia.php?p=taxdetails&id=324874.Dorsal notopodial ligule markedly broader on posterior chaetigers; prostomium anterior margin indented . Maxillary ring of pharynx with papillae present; dorsal notopodial ligule markedly elongate on posterior chaetigers (secondary diagnosis).Palpophore barrel-shaped, approximately equal width from base to palpostyle . Prostomium anterior margin indented.Jaws with smooth or slightly crenulate cutting edge.Maxillary ring of pharynx with papillae present; in tufts. Maxillary ring paragnaths absent. Oral ring papillae present. Oral ring papillae arrangement solitary. Area V papillae absent; VI one papillae present; VII-VIII papillae present (in a single row). Oral ring paragnaths absent. Maxillary ring papillae absent on Areas I and II, with double rows on Areas III and IV.Dorsal notopodial ligule present; commences chaetiger 3; markedly elongate on posterior chaetigers; markedly broader on posterior chaetigers; not markedly reduced on posterior chaetigers. Dorsal cirrus not sub-terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached throughout all chaetigers.Ventral neuropodial ligule of anterior chaetigers present. Ventral neuropodial ligule of anterior chaetigers approx. as long as acicular neuropodial ligule. Ventral neuropodial ligule on posterior chaetigers present. Ventral neuropodial ligule on posterior chaetigers similar to length of acicular neuropodial ligule. The neuropodial acicular ligule has three or four distinct lobes; homology of these is unclear, therefore these structures are not scored in this description.Notoaciculae on chaetigers 1 and 2 absent. Notochaetae: homogomph spinigers present. Neurochaetae dorsal fascicle: heterogomph spinigers absent; homogomph spinigers present; heterogomph falcigers in anterior chaetigers absent; on posterior chaetigers absent. Neurochaetae ventral fascicle: heterogomph spinigers absent; homogomph spinigers present; heterogomph falcigers absent.Tylonereis is one of several genera of Nereididae from tropical estuaries which have papillae on both maxillary and oral rings of the pharynx. The genus contains three species, all known from coastal lagoons and lakes of the tropical Indo-Pacific. Taxon classificationAnimaliaPhyllodocidaNereididae\ufeffGrube, 18668F549577-311C-549F-8E5C-EC4B8603F712Nereisheterocheta Quatrefages, 1866.https://www.marinespecies.org/polychaeta/aphia.php?p=taxdetails&id=324876.Dorsal cirrus terminally attached throughout, so that dorsal notopodial ligule has appearance of a cirrophore for the dorsal cirrus . Acicular notopodial ligule reduced, much shorter than neuropodial acicular ligule; maxillary ring of pharynx with papillae present (secondary diagnosis).Palpophore barrel-shaped, approximately equal width from base to palpostyle . Prostomium anterior margin indented. Tentacular belt greater than length of chaetiger 1.Jaws with dentate cutting edge.Maxillary ring of pharynx with papillae present. Maxillary ring paragnaths absent. Oral ring papillae present. Oral ring paragnaths absent.Dorsal notopodial ligule absent. Prechaetal notopodial lobe absent. Notopodial acicular process absent. Acicular notopodial ligule reduced, much shorter than neuropodial acicular ligule. Dorsal cirrus length ~ 5\u00d7 acicular notopodial ligule at chaetigers 10\u201320; not sub-terminally attached to dorsal notopodial ligule on posterior chaetigers; terminally attached throughout, so that dorsal notopodial ligule has appearance of a cirrophore for the dorsal cirrus.Ventral neuropodial ligule of anterior chaetigers absent. Ventral neuropodial ligule on posterior chaetigers absent. The single notopodial ligule  and the nearby north-east Pacific Ocean . Dorsal notopodial ligule commences chaetiger 5; dorsal notopodial ligule not markedly elongate on posterior chaetigers (secondary diagnosis).Tentacular belt greater than length of chaetiger 1. Tentacular cirri extend to chaetiger 2 (longest cirrus).Jaws with dentate cutting edge.Maxillary ring of pharynx with papillae absent. Maxillary ring paragnaths absent. Oral ring papillae absent. Oral ring paragnaths absent.Dorsal notopodial ligule present; commences chaetiger 5; not markedly elongate on posterior chaetigers; not markedly broader on posterior chaetigers; markedly reduced on posterior chaetigers. Prechaetal notopodial lobe absent. Notopodial acicular process absent. Dorsal cirrus length ~ 1\u00d7 acicular notopodial ligule at chaetigers 10\u201320; sub-terminally attached to dorsal margin of dorsal notopodial ligule on posterior chaetigers; not terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached throughout all chaetigers.Neuropodial prechaetal lobe absent. Neuropodial postchaetal lobe absent. Ventral neuropodial ligule of anterior chaetigers present. Ventral neuropodial ligule of anterior chaetigers approx. as long as acicular neuropodial ligule. Ventral neuropodial ligule on posterior chaetigers present. Ventral neuropodial ligule on posterior chaetigers similar to length of acicular neuropodial ligule.Notoaciculae on chaetigers 1 and 2 absent. Notochaetae of chaetigers 3 and 4 absent. Notochaetae: homogomph spinigers present. Neurochaetae dorsal fascicle: heterogomph spinigers absent; homogomph spinigers present; heterogomph falcigers in anterior chaetigers absent; on posterior chaetigers absent. Neurochaetae ventral fascicle: heterogomph spinigers present; homogomph spinigers absent; heterogomph falcigers present; anterior chaetigers heterogomph falcigers with long blades absent; anterior chaetigers heterogomph falcigers with extra-long blades present; anterior chaetigers heterogomph falcigers with short blades absent; posterior chaetigers heterogomph falcigers with long blades absent; posterior chaetigers heterogomph falcigers with extra-long blades present; posterior chaetigers heterogomph falcigers with short blades absent.Typhlonereis is known from a single species represented by six specimens from 2222 m in the far North-east Atlantic Ocean . Notochaetae sesquigomph falcigers present; prostomium anterior margin entire (secondary diagnosis).Antennae present . Tentacular belt greater than length of chaetiger 1.Jaws with dentate cutting edge.Maxillary ring of pharynx with papillae absent. Maxillary ring paragnaths present. Area II conical paragnaths present; III conical paragnaths present; III rod-like paragnaths absent; IV paragnaths present; IV conical paragnaths present; IV rod-like paragnaths absent. Oral ring papillae absent. Oral ring paragnaths absent.Dorsal notopodial ligule markedly elongate on posterior chaetigers; not markedly broader on posterior chaetigers; not markedly reduced on posterior chaetigers. Dorsal cirrus not sub-terminally attached to dorsal notopodial ligule on posterior chaetigers; terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached throughout all chaetigers.Neuropodial prechaetal lobe present; extending beyond postchaetal lobe (at least in anterior chaetigers). Neuropodial postchaetal lobe present; projecting beyond end of the acicular ligule; flattened. Ventral neuropodial ligule of anterior chaetigers present. Ventral neuropodial ligule of anterior chaetigers approx. as long as acicular neuropodial ligule. Ventral neuropodial ligule on posterior chaetigers present. Ventral neuropodial ligule on posterior chaetigers short, up to half length of acicular neuropodial ligule.Notochaetae: homogomph spinigers present; sesquigomph falcigers present; blade distally bifid. Neurochaetae dorsal fascicle: heterogomph spinigers absent; homogomph spinigers present; heterogomph falcigers in anterior chaetigers present; on posterior chaetigers present. Neurochaetae ventral fascicle: heterogomph spinigers present; homogomph spinigers absent; heterogomph falcigers present; heterogomph falcigers blade terminally bifid.Unanereis Day, 1962 was described from a single specimen found in the tube of a species of Terebellidae. A second species, U.zghali Ben Amor, 1980, from a vertical rocky substrate including dendrophyllid coral Astroidescalycularis and algae Corallinamediterranea but without an obvious host, has been described from the Mediterranean .Palpophore barrel-shaped, approximately equal width from base to palpostyle . Palpophore surface with a single transverse groove . Tentacular belt equal to or less than length of chaetiger 1, or greater than length of chaetiger 1.Jaws with dentate cutting edge.Maxillary ring of pharynx with papillae absent. Maxillary ring paragnaths absent. Oral ring papillae present. Oral ring papillae arrangement solitary. Area V papillae absent; VI papillae present; VII-VIII papillae present. Oral ring paragnaths absent.Dorsal notopodial ligule present; commences chaetiger 3; not markedly elongate on posterior chaetigers; not markedly broader on posterior chaetigers; not markedly reduced on posterior chaetigers. Prechaetal notopodial lobe present; smaller than dorsal notopodial ligule on anterior chaetigers, usually reduced or absent posteriorly; restricted to a limited number of anterior chaetigers. Notopodial acicular process absent. Dorsal cirrus not sub-terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached to dorsal notopodial ligule on posterior chaetigers; not terminally attached throughout all chaetigers.Neuropodial postchaetal lobe present; projecting beyond end of the acicular ligule; present throughout all chaetigers; digitiform. Ventral neuropodial ligule of anterior chaetigers present. Ventral neuropodial ligule of anterior chaetigers approx. as long as acicular neuropodial ligule. Ventral neuropodial ligule on posterior chaetigers present. Ventral neuropodial ligule on posterior chaetigers similar to length of acicular neuropodial ligule.Notoaciculae on chaetigers 1 and 2 absent. Notochaetae: homogomph spinigers present. Neurochaetae dorsal fascicle: heterogomph spinigers absent; homogomph spinigers present; heterogomph falcigers in anterior chaetigers present; on posterior chaetigers present; blades serrated; blades with teeth only slightly longer proximally than distally. Neurochaetae ventral fascicle: heterogomph spinigers present; homogomph spinigers absent; heterogomph falcigers present; anterior chaetigers heterogomph falcigers with long blades absent; anterior chaetigers heterogomph falcigers with extra-long blades present; anterior chaetigers heterogomph falcigers with short blades absent; posterior chaetigers heterogomph falcigers with long blades present, or absent; posterior chaetigers heterogomph falcigers with extra-long blades absent; posterior chaetigers heterogomph falcigers with short blades present, or absent; heterogomph falcigers blade lacking distinct tendon on terminal tooth.Anal cirri form cirriform or conical.Websterinereis is similar to Rullierinereis in having the anterior margin of prostomium entire, the maxillary ring bare and papillae on the oral ring; Websterinereis differs from Rullierinereis in lacking notopodial homogomph falcigers. There are five species of Websterinereis which are known from the Atlantic, Indian, and Pacific Oceans, mostly from shallow water (less than ~ 130 m) except for W.glauca, which is recorded to a maximum depth of 3310 m. The genus was revised by Taxon classificationAnimaliaPhyllodocidaNereididae\ufeffKhlebovich, 1996B6C3393C-54F5-5646-8ECF-8E9D5FEEE89DLeonnatessimplex Monro, 1939.https://www.marinespecies.org/polychaeta/aphia.php?p=taxdetails&id=1039985.Oral ring papillae present; maxillary ring paragnaths present; ventral neuropodial ligule on posterior chaetigers short, up to half length of acicular neuropodial ligule .Palpophore barrel-shaped, approximately equal width from base to palpostyle . Tentacular belt greater than length of chaetiger 1.Jaws with dentate cutting edge.Maxillary ring of pharynx with papillae absent. Maxillary ring paragnaths present. Area I conical paragnaths present; II conical paragnaths present; III conical paragnaths present; III conical paragnaths isolated lateral groups absent; IV paragnaths present; IV conical paragnaths present. Oral ring papillae present. Oral ring papillae arrangement solitary. Area V papillae present; VI papillae present; VII-VIII papillae present; VII-VIII papillae arranged in a double row. Oral ring paragnaths absent.Dorsal notopodial ligule not markedly reduced on posterior chaetigers.Ventral neuropodial ligule of anterior chaetigers present. Ventral neuropodial ligule of anterior chaetigers approx. as long as acicular neuropodial ligule. Ventral neuropodial ligule on posterior chaetigers present. Ventral neuropodial ligule on posterior chaetigers short, up to half length of acicular neuropodial ligule.Notoaciculae on chaetigers 1 and 2 absent. Notochaetae: homogomph spinigers present. Neurochaetae dorsal fascicle heterogomph spinigers absent; homogomph spinigers present; heterogomph falcigers in anterior chaetigers present; on posterior chaetigers present. Neurochaetae ventral fascicle: heterogomph spinigers present; homogomph spinigers absent; heterogomph falcigers present; falcigers blade tapering, with straight margin.Wuinereis was established by Leonnates. The two genera  are similar in having only paragnaths on the maxillary ring and only papillae on the oral ring. Wuinereis can be separated by chaetal and parapodial characters as per the diagnosis given here. The sole species, W.simplex  is known only from Aldabra Atoll in the Indian Ocean."}
+{"text": "Scientific Reports 10.1038/s41598-023-42426-1, published online 15 September 2023Correction to: The original version of this Article contained errors in affiliations of Lorenzo Benvenuto and Eugenio Realini. Their affiliations were inadvertently switched.The correct affiliation for Lorenzo Benvenuto is listed below:\u2018algoWatt S.p.A., 16149 Genoa, Italy.\u2019The correct affiliation for Eugenio Realini is listed below:\u2018Geomatics Research & Development srl (GReD), 22074 Lomazzo, Italy\u2019.The original Article has been corrected."}
+{"text": "Prostate cancer (PCa), the second most prevalent solid tumor among men worldwide, has caused greatly increasing mortality in PCa patients. The effects of lipid metabolism on tumor growth have been explored, but the mechanistic details of the association of lipid metabolism disorders with PCa remain largely elusive.The RNA sequencing data of the GSE45604 and The Cancer Genome Atlas-Prostate Adenocarcinoma (TCGA-PRAD) datasets were extracted from the Gene Expression Omnibus (GEO) and UCSC Xena databases, respectively. The Molecular Signatures Database (MSigDB) was utilized to identify lipid metabolism-related genes. The limma R package was used to identify differentially expressed lipid metabolism-related genes (DE-LMRGs) and differentially expressed microRNAs (DEMs). Moreover, least absolute shrinkage and selection operator (LASSO), extreme gradient boosting (XGBoost), and support vector machine-recursive feature elimination (SVM-RFE) were applied to select signature miRNAs and construct a lipid metabolism-related diagnostic model. The expression levels of selected differentially expressed lipid metabolism-related miRNAs (DE-LMRMs) in PCa and benign prostate hyperplasia (BPH) specimens were verified using quantitative real-time polymerase chain reaction (qRT\u2012PCR). Furthermore, a transcription factor (TF)-miRNA\u2012mRNA network was constructed. Eventually, Kaplan\u2012Meier (KM) curves were plotted to illustrate the associations between signature miRNA-related mRNAs and TFs and overall survival (OS) along with biochemical recurrence-free survival (BCR).Forty-seven LMRMs were screened based on the correlation analysis of 29 DE-LMRGs and 56 DEMs, in which 27 LMRMs were stably expressed in the GSE45604 dataset. Subsequently, receiver operating characteristic (ROC) curves and machine learning methods were employed to develop a lipid metabolism-related diagnostic signature, which may be of diagnostic value for PCa patients. qRT\u2012PCR results showed that all seven key DE-LMRMs were differentially expressed between PCa and BPH tissues. Eventually, a TF-miRNA\u2012mRNA network was constructed.These results suggested that 7 key diagnostic miRNAs were closely related to PCa pathological processes and provided new targets for the diagnosis and treatment of PCa. Moreover, CLIC6 and SCNN1A linked to miR-200c-3p had good prognostic potential and provided valuable insights into the pathogenesis of PCa.The online version contains supplementary material available at 10.1186/s12944-023-01804-4. Prostate cancer (PCa) is the most prevalent urological tumor . ProstatRecent studies have shown that abnormal metabolic reprogramming, particularly in glycolysis , fatty aThe present study sought to identify key diagnostic miRNAs related to lipid metabolism and establish a potential TF-miRNA\u2012mRNA network using the RNA sequencing data of PCa, which might serve as clinically significant biomarkers and provide a reference for PCa diagnosis and prognosis.https://xenabrowser.net/datapages/), and 495 PCa samples with complete corresponding survival information were utilized for prognostic analysis. The GSE45604 dataset was acquired from the GEO database (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE45604). MSigDB was utilized to extract lipid metabolism-related genes (LMRGs) [The RNA sequencing data of the TCGA-PRAD dataset, including 499 PCa and 52 normal samples, were obtained from the UCSC Xena database ( (LMRGs) .2fold change (FC)|>\u20091 and P\u2009<\u20090.05. The expression levels of DEGs were displayed by heatmap and volcano plot via the pheatmap (version 4.1.0) and ggplot2 (version 3.3.2) R packages, respectively. DE-LMRGs were then identified by obtaining the intersection between LMRGs and DEGs, and DE-LMRG expression was assessed by the Wilcoxon test and visualized using a heatmap plotted using the pheatmap package (version 4.1.0).DEGs between 499 PCa and 52 normal samples from the TCGA-PRAD dataset were selected by the limma R package (version 3.44.3) based on the threshold of |logn\u2009=\u200910) and BPH tissues (n\u2009=\u200910) were collected from prostate biopsy specimens from patients admitted to The Second Affiliated Hospital of Xi\u2019an Jiaotong University from December 2021 to May 2022. The Ethics Committee of the Xi\u2019an Jiaotong University Health Science Center approved the research design on December 27, 2021 (protocol #: 2021\u20131700). Written consent was obtained from the patients before they donated their tissue samples.PCa tissues  was used to isolate total RNA from tissues. The M-MLV Kit  was used to reverse transcribe (RT) total RNA (290\u00a0ng). The SYBR\u00ae Green qPCR Kit (Accurate Biology) was utilized for qPCR. U6 was the internal control. Fig. S\u00a0t method .Table 1S2FC|>\u20091 and P\u2009<\u20090.05 as the screening criteria [P\u2009<\u20090.05 were considered screening criteria. The overlapping DE-LMRMs and miRNAs expressed in samples from the GSE45604 dataset were used to identify stably expressed DE-LMRMs.To identify LMRMs, DEMs between 52 normal and 499 PCa samples of the TCGA-PRAD dataset were first screened using the limma R package, considering |logcriteria . Next, DP\u2009<\u20090.05) and visualized using violin plots drawn using the ggplot2 (version 3.3.2) package to investigate the correlation between the key diagnostic miRNAs and different clinical characteristics.To assess the diagnostic utility of stably expressed DE-LMRMs, diagnostic miRNAs were identified from stably expressed DE-LMRMs (area under the ROC curve (AUC)\u2009>\u20090.8) by ROC curves constructed using the pROC package (version 1.17.0.1)  and wereTo investigate the potential regulatory mechanism of key miRNAs, the StarBase and miRNET databases , 24 wereA total of 519 DEGs were derived from the TCGA-PRAD cohort, comprising 157 upregulated and 362 downregulated mRNAs  and miR-148a-3p (P\u2009=\u20090.03) showed a high correlation with age . Of these, only 3 mRNAs  exhibited significant correlations with the OS of 495 PCa samples (P\u2009<\u20090.05)  and BPH (n=10) tissue samples. B Analysis of the expression levels of U6 in PCa (DU145 and 22Rv1) cells and non-tumorigenic prostate epithelial (RWPE-1) cells. Supplementary Table 1. Receiver operating characteristic analysis for 27 differentially expressed lipid metabolism-related miRNAs."}
+{"text": "Neuroblastoma is the most frequent extracranial childhood tumour but effective treatment with current immunotherapies is challenging due to its immunosuppressive microenvironment. Efforts to date have focused on using immunotherapy to increase tumour immunogenicity and enhance anticancer immune responses, including anti-GD2 antibodies; immune checkpoint inhibitors; drugs which enhance macrophage and natural killer T (NKT) cell function; modulation of the cyclic GMP-AMP synthase-stimulator of interferon genes pathway; and engineering neuroblastoma-targeting chimeric-antigen receptor-T cells. Some of these strategies have strong preclinical foundation and are being tested clinically, although none have demonstrated notable success in treating paediatric neuroblastoma to date. Recently, approaches to overcome heterogeneity of neuroblastoma tumours and treatment resistance are being explored. These include rational combination strategies with the aim of achieving synergy, such as dual targeting of GD2 and tumour-associated macrophages or natural killer cells; GD2 and the B7-H3 immune checkpoint; GD2 and enhancer of zeste-2 methyltransferase inhibitors. Such combination strategies provide opportunities to overcome primary resistance to and maximize the benefits of immunotherapy in neuroblastoma. Neuroblastomas are the most common extracranial solid tumour in children, with 90% of cases occurring in children less than 10 years of age.reg) exert highly immunosuppressive effects through functions including secretion of inhibitory cytokines, such as interleukin (IL)-10, which attenuate cytotoxic T-cell responses and inhibit antigen presenting cell maturation.High-risk neuroblastomas are classified as immunologically \u201ccold\u201d due to limited T-cell infiltration, major histocompatibility complex class I (MHC-I) downregulation and low mutational burden leading to an immunosuppressive tumour microenvironment (TME).This review will address the shortcomings and advances in the use of immunotherapy for the treatment of neuroblastoma. The clinical characteristics and risk classifications for neuroblastoma have been extensively discussed elsewhere.MYCN oncogene, which is frequently seen in patients with high-risk neuroblastoma, is a major driver of poor prognosis and is associated with decreased tumour immunogenicity.MYCN amplification is responsible for the suppression of interferon activity as well as the expression of chemokines, and its overexpression enhances tumour cell resistance to immune-mediated cytotoxicity via multiple mechanisms, including MHC-I downregulation and inhibition of NK cell activation.Amplification of the GD2 is a disialoganglioside highly expressed in melanomas and neuroblastomas, implicated in tumour progression by modulating cancer cell proliferation, migration and tumour invasiveness.19The murine IgG3 antibody 3F8 is the first anti-GD2 antibody developed and studied for effectiveness in treating neuroblastoma. An early phase I study of anti-GD2 monotherapy showed anti-tumour responses, ranging from complete clinical remission to mixed tumour regressions, in 7 of the 17 patients with neuroblastoma and melanoma treated. Typical acute side effects of severe pain and urticaria were prevalent throughout this study, thought to be the result of 3F8 interaction with pain sensory fibers, but long-term effects were not observed.25Naxitamab (Hu3F8) is a humanized IgG1 antibody being tested clinically as both a monotherapy and in combinations with immunogenic cytokines . A phaseSeveral anti-GD2 antibodies have been generated and characterized over the past decade, with dinutuximab Ch14.18/SP2/0) being the first to receive marketing approval in 2015 for the treatment of high-risk neuroblastoma./SP2/0 be29Dinutuximab beta (Ch14.18/CHO) is a dinutuximab analog produced by the International Society of Paediatric Oncology European Neuroblastoma Group (SIOPEN) using Chinese hamster ovary (CHO) cells to optimize protein glycosylation patterns and reduce rapid drug clearance by endogenous antibodies which recognize non-human sialic acid epitopes in antibodies derived from SP2/0 cells.Other anti-GD2 antibodies in development have followed a similar approach of humanization to counteract dose-limiting toxicities and HAMA responses. Indeed, phase I clinical testing of humanized 14.18  demonstrated reduced pain and other toxicities associated with ch14.18 treatment, while still inducing an objective response in 18% of patients with refractory neuroblastoma.38Overall, multiple anti-GD2 antibodies have undergone molecular revision and refinement to reduce immune-related toxicities and severe neuropathic pain associated with CDC and HAMA responses. Despite the attractive tissue expression and restricted distribution of GD2 as a target, the ADCC-based mechanism of anti-GD2 induces often intolerable toxicity made worse by combination with activating cytokines such as IL-2. Alternative methods of enhancing anti-GD2 efficacy are required, since of the three clinically approved antibodies available, currently dinutuximab is the only one deemed effective for standard therapy.Immune checkpoint proteins are expressed by a range of immune cell types and perform critical functions in maintaining tolerance and preventing autoimmunity.The fully human IgG4 antibody nivolumab was evaluated in two phase II trials designed to assess the toxicity and pharmacokinetics of anti-PD-1 monotherapy in patients with refractory neuroblastoma . The first study demonstrated that nivolumab is well-tolerated in children with similar pharmacokinetics to those seen in adults, however objective responses were not observed and benefit was limited to stable disease only.Preclinical studies have sought to overcome the challenge of low-sensitivity to anti-PD-1 in neuroblastoma by inducing target cell PD-L1 expression. One provocative study demonstrated that targeting GD2 in LA-N-1 neuroblastoma cells with ch14.18/CHO in co-culture with primary leukocytes induced strong PD-L1 expression in what is usually a PD-L1 negative model.50Ipilimumab is a first-in-class human monoclonal antibody targeting the immune checkpoint CTLA-4. A phase I clinical trial (NCT01445379) assessing pharmacokinetics and immunogenicity in a mixed cohort off refractory solid tumours showed that it is tolerated in children, although immune-related adverse events (irAEs) consistent with those seen in adults were observed. Despite the lack of tumour regressions following single-agent ipilimumab, patients who exhibited irAEs had an increased OS relative to those who did not, suggesting that disruption of immunological tolerance with ipilimumab was beneficial in terms of survival outlook.51Poor clinical responses to single-agent ICB have motivated preclinical investigations into combination strategies. One such study showed that the murine syngeneic NB-SQ neuroblastoma model exhibits an immunosuppressive TME characterized by a high frequency of myeloid-derived suppressor cells and Tregs.The importance of TAMs in TME of neuroblastoma and other cancers is well established.61 62In contrast to GD2, the transmembrane integrin-associated protein CD47 is ubiquitously expressed throughout a range of different tissue types. Being frequently overexpressed in tumours, CD47 enrichment is strongly associated with worse prognosis in both haematological and solid cancers.MYCN model of high-risk neuroblastoma demonstrated significant growth-limiting effects after treating established tumours.+ myeloid infiltration predicts poor neuroblastoma outlook and PD-L1 is strongly associated with CSF-1R expression in human neuroblastomas, this may represent a promising therapeutic avenue.74Colony stimulating factor-1 (CSF-1)/CSF-1R interactions can also be targeted to modulate TAM migration and accumulation in tumour sites.Clinical trials aiming to validate the therapeutic benefit observed with preclinical CSF-1R-PD-1 dual inhibition using both small molecule (NCT02452424) and monoclonal antibody inhibitors (NCT02526017 and NCT02323191) are assessing responses in patients with neuroblastoma.+ and GD2\u2013 target neuroblastoma cells in vitro.81NK cells can target tumour cells for cytolytic killing and are known to produce pro-inflammatory cytokines and chemokines which attenuate tumour progression and metastasis.Cell-based therapies involving the adoptive transfer of chimeric-antigen receptor (CAR) T cells has revolutionized the treatment of haematological cancers, inducing striking and durable regressions of B-cell acute lymphoblastic leukaemia.A first-in-human phase I clinical trial (NCT03294954) administered chimeric antigen receptor NKT (CAR-NKT) cells to children with refractory neuroblastoma.The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is an intracellular DNA sensing pathway and integral innate immune defense mechanism to viral infection or cellular transformation. On detection of pathogen-associated molecular patterns, such as cytoplasmic DNA (cDNA), STING signaling drives IFN-I production which can boost anti-tumour effector T-cell function .90 9190 91The effect of STING agonism on tumour-immune interactions has been studied in multiple cancer types, including pancreatic cancer, breast cancer, head and neck cancer, lung cancer and leukaemia.94STING activation and poly-ADP ribose polymerase (PARP) inhibition was investigated in breast cancer gene (BRCA)-deficient breast cancer models; the combination significantly improved anti-tumour responses by driving IFN-I production, T-cell recruitment and DC activation, while inducing immunological memory and reducing adaptive resistance to PARP inhibitors (PARPi).97+ T-cell recruitment and anti-tumour effector responses, while synergising with ICB to inhibit tumour growth significantly more than irradiation alone.Radiotherapy also induces STING activation through the accumulation of DNA damage and triggering of DNA damage responses.MYCN amplificationMYCN amplified neuroblastoma tumours. A study using genetically engineered mouse models of neuroblastoma used the STING agonist DMXAA to evaluate the anti-tumour effect of dual STING activation and MYCN inhibition.MYCN-amplified tumours are associated with reduced IFN-I pathway activity in primary metastatic neuroblastomas and established cellular models, depletion of N-Myc potently augmented IFN pathway activity in response to DMXAA treatment.Around 50% of high-risk neuroblastomas exhibit Targeting neuroblastoma with immunotherapies has been challenging because of its highly immunosuppressive TME, with some promising treatments not translating successfully (see Outstanding questions). The use of checkpoint inhibitors as a treatment for neuroblastoma has not been successful in the clinic and any studies that have been conducted only proved the safety of using these inhibitors in children, suggesting that they might need to be administered in combination with other treatments. The most widely studied and successful immunotherapy is the use of anti-GD2 antibodies and approaches to overcome resistance to GD2 treatments and improve response are currently being explored. Combination of anti-GD2 and anti-CD47 antibodies showed promising results in mouse models and has now been evaluated in a first-in-human clinical trial.Many questions still remain for the use of immunotherapies in neuroblastoma treatment. Combination strategies involving anti-GD2 have been successful in clinical trials, but have not yet received approval for clinical use. Furthermore, the limited impact of ICIs in the clinic and strategies to improve patient responses need further investigation. The possibility of using radiotherapy in combination with STING agonists also needs to be explored. Moreover, possible combination treatments to enhance responses need to be tested and the safety and efficacy of dual CAR-T cells needs to be tested in a clinical setting in paediatric oncology.https://www.clinicaltrials.gov/ct2/show/NCT03363373NCT03363373: https://clinicaltrials.gov/ct2/show/NCT01757626NCT01757626: https://clinicaltrials.gov/ct2/show/NCT00072358NCT00072358: https://clinicaltrials.gov/ct2/show/NCT00492167NCT00492167: https://clinicaltrials.gov/ct2/show/NCT02914405NCT02914405: https://clinicaltrials.gov/ct2/show/NCT01704716NCT01704716: https://clinicaltrials.gov/ct2/show/NCT04751383NCT04751383: https://clinicaltrials.gov/ct2/show/NCT03189706NCT03189706: https://clinicaltrials.gov/ct2/show/NCT04501757NCT04501757: https://clinicaltrials.gov/ct2/show/NCT03033303NCT03033303: https://clinicaltrials.gov/ct2/show/NCT02650648NCT02650648: https://clinicaltrials.gov/ct2/show/NCT01662804NCT01662804: https://clinicaltrials.gov/ct2/show/NCT01419834NCT01419834: https://clinicaltrials.gov/ct2/show/NCT03332667NCT03332667: https://clinicaltrials.gov/ct2/show/NCT01711554NCT01711554: https://clinicaltrials.gov/ct2/show/NCT02573896NCT02573896: https://clinicaltrials.gov/ct2/show/NCT03786783NCT03786783: https://clinicaltrials.gov/ct2/show/NCT01857934NCT01857934: https://clinicaltrials.gov/ct2/show/NCT04385277NCT04385277: https://www.clinicaltrials.gov/ct2/show/NCT00026312NCT00026312: https://clinicaltrials.gov/ct2/show/NCT01445379NCT01445379: https://clinicaltrials.gov/ct2/show/NCT02813135NCT02813135: https://clinicaltrials.gov/ct2/show/NCT02304458NCT02304458: https://clinicaltrials.gov/ct2/show/NCT02914405NCT02914405: https://clinicaltrials.gov/ct2/show/NCT04412408NCT04412408: https://clinicaltrials.gov/ct2/show/NCT04730349NCT04730349: https://clinicaltrials.gov/ct2/show/NCT05302921NCT05302921: https://clinicaltrials.gov/ct2/show/NCT02541604NCT02541604: https://clinicaltrials.gov/ct2/show/NCT00877110NCT00877110: https://clinicaltrials.gov/ct2/show/NCT03209869NCT03209869: https://clinicaltrials.gov/ct2/show/NCT03294954NCT03294954: https://clinicaltrials.gov/ct2/show/NCT03242603NCT03242603:"}
+{"text": "Correction to: Acta Neuropathologica (2023) 146:451\u2013475 10.1007/s00401-023-02611-yThe wrong Supplementary files  were originally published with this article; it has now been replaced with the correct file.The original article has been corrected.Supplementary file1 (PDF 5870 KB)Supplementary file2 (XLSX 3302 KB)Below is the link to the electronic supplementary material."}
+{"text": "Bifidobacterium. We hypothesized that the association between yogurt intake and colorectal cancer incidence differed by Bifidobacterium status in tumor tissue.Although epidemiological evidence is limited, experimental data indicated a tumor-suppressive effect of yogurt containing Bifidobacterium status.We utilized data from two prospective cohort studies: the Nurses\u2019 Health Study and the Health Professionals Follow-up Study. Inverse probability weighted multivariable Cox proportional hazards regression was used to assess differential associations of yogurt intake with the incidence of colorectal carcinomas subclassified by tumor Bifidobacterium data. The association between yogurt intake and colorectal cancer incidence differed by Bifidobacterium status (Pheterogeneity = 0.03). This differential association became stronger in a subgroup analysis of proximal colon cancer (Pheterogeneity = 0.003). Multivariable hazard ratios in individuals who consumed \u2265 2 servings/week (vs. < 1 serving/month) of yogurt were 0.43  for Bifidobacterium-positive proximal colon cancer, and 1.40  for Bifidobacterium-negative proximal colon cancer.During follow-up of 132,056 individuals, we documented 2,950 incident colorectal cancer cases, including 1,191 with available Bifidobacterium-positive (but not Bifidobacterium-negative) proximal colon cancer, suggesting an interactive influence of yogurt intake and intestinal microbiota on tumor development.Yogurt intake was inversely associated with the incidence of All Authors: No reported disclosures"}
+{"text": "Clostridioides difficile infection (CDI). The CD treatment algorithm was revised in April 2022 to reflect updated national clinical practice guidelines and disseminated to TMC providers. Our study aimed to assess provider compliance to TMC\u2019s CD treatment algorithm.Tufts Medical Center\u2019s (TMC) Antimicrobial Stewardship Team (AMT) in collaboration with gastroenterology (GI) developed an institutional treatment algorithm to guide appropriate inpatient management of CD was conducted. We collected patient demographics, white blood cell count, serum creatinine (SC), length of stay, CD treatment, Infectious Diseases (ID) & GI consult, occurence of severe CDI (defined as white blood cell > 15 K/uL or SC > 1.5 mg/dL), occurrence of recurrent CDI, and immunocompromised status . A 2-step Clostridioides difficile (CD) testing algorithm was used. For CD toxin A/B & glutamate dehydrogenase antigen (GDH) indeterminate results, reflex to nucleic amplification test (NAAT) was performed only with AMT approval.A retrospective study of adult patients hospitalized from April 15, 2022 to October 31, 2022 and tested for CD toxin/GDH stool testing; 70 (63%) positive and 41 (37%) indeterminate. Of patients who had an indeterminate CD toxin/GDH, none had subsequent CD NAAT testing, and none receive CDI treatment. Of the others, 81 (73%), 23 (21%), and 7 (6%) were diagnosed with non-severe, severe, and fulminant CDI, respectively. The overall adherence to the institutional CD treatment algorithm was 58% (figure 1). More patients were appropriately treated with oral vancomycin  compared to those who were appropriately treated with fidaxomicin . Guidance adherence was (3) 38% among patients who had one or more recurrent episodes of CD, and none received suggested ID or GI consultation for additional CDI treatment consideration.A total of 111 inpatients had CD treatment algorithm was low. This study highlights opportunities to improve prescription of first line CDI therapy, especially among patients who are at higher risk for recurrence.Adherence to institutional Maureen Campion, PharmD, BCIDP, Shinoigi: Speaker"}
+{"text": "Multisystem inflammatory syndrome in children (MIS-C) is an uncommon but severe hyperinflammatory syndrome occurring weeks after SARS-CoV-2 infection. Presentation can vary and overlap with other conditions, including acute COVID-19 and Kawasaki disease. Identifying clusters of MIS-C phenotypes informs efforts to reduce misclassification, characterize pathogenesis, and tailor treatments. Here we describe clusters of presentation using the largest collection of U.S. MIS-C cases to date.poLCA R package; the number of clusters was selected based on decreasing information criteria and automated variable selection.We analyzed 9131 MIS-C cases reported to CDC from 55 U.S. health departments; onset dates ranged from February 2020\u2013October 2022. Thirty-one dichotomous clinical variables were selected for clustering after excluding ones with high (\u2265 15%) missingness or rare (\u2264 10%) or high (\u2265 90%) prevalence. We excluded 595 cases with \u2265 5 missing variables and conducted multiple imputation on the remaining 8536 cases. Latent class analysis (LCA) was run using the LCA identified five clusters, two of which were characterized by distinct organ system involvement: a respiratory symptom-driven cluster primarily affecting older children , and a mucocutaneous symptom-driven cluster primarily affecting young children  . The remaining three clusters delineated a spectrum of clinical severity, with clinically mild and moderate clusters with infrequent shock , and a severe cluster (N = 1881 [22.0%]) with shock and ICU admission for nearly all cases . The proportion of cases belonging to this clinically severe cluster decreased over time as proportions of the mild/moderate clusters increased . The case fatality ratio was highest in the respiratory (5.0%) and clinically severe clusters (1.6%) compared with other MIS-C cases .MIS-C cases reported to CDC national surveillance clustered into five groups with distinct symptoms and severity. Use of MIS-C phenotypic clusters in future studies may inform treatment decisions and assist with prognosis.All Authors: No reported disclosures"}
+{"text": "Our method was validated by analyzing methyl-tert-butyl ether extracts of reference human plasma, whichenabled a direct comparison of 48 phosphatidylcholine and 27 sphingomyelinspecies previously reported in an interlaboratory lipidomics harmonizationstudy. The potential for plasma PL quantification by MSI-NACE-MS viaa serial dilution of NIST SRM-1950 was also demonstrated based onestimation of relative response factors using their reported consensusconcentrations. Moreover, lipid identification was supported by modelingpredictable changes in the electrophoretic mobility for cationic PLsin conjunction with MS/MS. Overall, this work offers a practical derivatizationprotocol to expand lipidome coverage in CE-MS beyond the analysisof hydrophilic/polar metabolites under aqueous buffer conditions.Orthogonal separationtechniques coupled to high-resolution massspectrometry are required for characterizing the human lipidome, givenits inherent chemical and structural complexity. However, electrophoreticseparations remain largely unrecognized in contemporary lipidomicsresearch compared to established chromatographic and ion mobilitymethods. Herein, we introduce a novel derivatization protocol basedon 3-methyl-1- Precolumn chemical derivatization strategieshave been developed to introduce or switch charge states on specificlipid classes to modify their chromatographic retention, reduce isobaricinterferences, and improve ionization efficiency with lower detectionlimits in ESI-MS.41 For instance, Smithet al.44 have used diazomethane for charge inversion on modifiedcationic PLs via quantitative methylation. However, given the explosiveand toxicity hazards of diazomethane that is generated insitu,45 safer methylating agentsare required in routine MS-based lipidomic workflows without blastshields and other personal protective equipment. Herein, we introducea novel two-step chemical derivatization strategy for the quantitativemethylation of PLs based on 9-fluorenylmethyoxycarbonyl chloride (FMOC),followed by 3-methyl-1-p-tolyltriazene (MTT) thatoffers a practical way to expand lipidome coverage in MSI-NACE-MS.For the first time, we demonstrate that this procedure enables therapid identification and quantification of PCs and sphingomyelins(SMs) as their cationic phosphate methyl esters, which was validatedon a standard reference human plasma sample previously analyzed inan interlaboratory harmonization study.15Recently, we have introduced multisegment injection (MSI)-NACE-MSas a multiplexed separation platform for the quantitative determinationof fatty acids from blood specimens,sn-glycero-3-phosphocholine(PC 36:0[D70]), 1,2-dipalmitoyl-d62-sn-glycero-3-phosphocholine(PC 32:0[D62]), methyl-tert-butyl ether (MTBE), MTT,FMOC and all other chemical standards were purchased from Sigma-AldrichInc.  unless otherwise stated. All lipid standardspurchased were either as a powder or dissolved in solution (1:1) ofchloroform and methanol. Stock solutions for lipids were then dilutedin chloroform and methanol and stored at \u221280 \u00b0C priorto further use. The reference material from the National Instituteof Standards and Technology (NIST) SRM-1950 pooled human plasma waspurchased from the NIST . While certified referencevalues for NIST SRM-1950 have been reported for several polar metabolites,plasma PLs measured in this study were compared to the median of meanconcentrations reported for NIST SRM-1950 in an international studyacross 31 laboratories that adopted various LC-MS/MS lipidomic workflows.In this case, consensus plasma PL concentrations required measurementsfrom a minimum of five laboratories having a sample coefficient ofdispersion (COD) < 40%.15Ultra LC-MSgrade methanol,acetonitrile, water, and 2-propanol were used to prepare the sheathliquid and the background electrolyte (BGE). Ammonium formate, formicacid, 1,2-distearoyl-d70-38 Briefly, 50 \u03bcL of an NIST SRM-1950 plasma aliquot was mixedwith 100 \u03bcL of methanol containing PC 32:0[D62] as a recoverystandard and shaken for 10 min. Then, 250 \u03bcL of MTBE was added,and the mixture was subjected to vigorous shaking for 10 min. To inducephase separation, 100 \u03bcL of deionized water was then added priorto centrifugation at 10 min at 4000g. Next, 200 \u03bcLof the lipid-rich MTBE upper layer was transferred into another vialand dried at room temperature using an Organomation MULTIVAP nitrogenevaporator . For underivatized lipids, dried plasma extractswere then reconstituted to a volume of 50 \u03bcL containing acetonitrile/isopropanol/water(70:20:10) with 10 mM ammonium formate containing internal standardsPC 36:0[D70] (5 \u03bcM), benzyltriethylammonium chloride (BTA) (1\u03bcM), and PC 32:0[D62] (5 \u03bcM) prior to analysis by MSI-NACE-MS.Plasma samples andlipid calibrant solutions were extracted using a modified MTBE-basedliquid extraction procedure previously described for fatty acids andanionic lipids using MSI-NACE-MS in negative ion mode.p-toluidine). After centrifugation for 10 min at 4000g, 200 \u03bcL of hexane as the supernatant was transferredout to a separate glass vial and then evaporated to dryness undernitrogen. Lastly, derivatized extracts were then reconstituted in50 \u03bcL of acetonitrile/isopropanol/water (70:20:10) with 10 mMammonium formate containing internal standards PC 36:0[D70] (5 \u03bcM),BTA (1 \u03bcM), and of PC 32:0[D62] (5 \u03bcM) prior to analysisby MSI-NACE-MS. Derivatization yields for methylated PLs from plasmaextracts were calculated based on the integrated relative peak area(RPA) for each native (untreated) PL relative to PC 36:0[D70] as aninternal standard using All plasma ether extracts and PL calibrantswere subject to a two-step chemical labeling procedure using FMOCand MTT. In 2 mL amber glass vials, 100 \u03bcL of 0.85 mM FMOC inchloroform was added to dried ether plasma extracts, and the mixturewas shaken vigorously for 5 min. Then, samples were blown down todryness using nitrogen at room temperature prior to reconstitutionin 50 \u03bcL of MTBE containing 450 mM MTT. Vials were next sealedwith Teflon tape and vortexed for 30 s prior to derivatization at60 \u00b0C for 60 min (unless otherwise stated). Afterward, 100 \u03bcLof methanol, 250 \u03bcL of hexane, and 200 \u03bcL of deionizedwater was added to back extract polar byproducts of the reaction  following voltage application, with the ion sourceoperating at 300 \u00b0C with a drying gas of nitrogen that was deliveredat 4 L/min. The TOF-MS was operated in a 2 GHz extended dynamic rangeunder positive mode detection. A Vcap was set at 3500 Vwhile the fragmentor was 120 V, the skimmer was 65 V, and the octopolerf was 750 V. All separations were performed using bare fused-silicacapillaries with 50 \u03bcm internal diameter, a 360 \u03bcm outerdiameter, and 100 cm total length .A capillary window maker  was used to remove7 mm of the polyimide coating on both ends of the capillary to preventpolyimide swelling with organic solvents in the background electrolyte(BGE) or aminolysis under alkaline nonaqueous buffer conditions.46 An applied voltage of 30 kV was used for CEseparations at 25 \u00b0C together while using a forward pressureof 5 mbar (0.5 kPa). The BGE was 35 mM ammonium formate in 70 vol% acetonitrile, 15 vol % methanol, 10 vol % water, and 5 vol % isopropanolwith an apparent pH of 2.3 adjusted with the addition of formic acid.Derivatized plasma extracts and lipid standards were introduced in-capillaryhydrodynamically at 50 mbar (5 kPa) alternating between 5 s for eachsample plug and 40 s for the BGE spacer plug for a total of sevendiscrete samples analyzed within a single run.38 Prior to the first use, capillaries were conditioned byflushing at 950 mbar (95 kPa) with methanol, 0.1 M sodium hydroxide,deionized water, and BGE sequentially for 15 min each. The BGE andsheath liquid were degassed prior to use. For analysis of NIST SRM-1950by MSI-NACE-MS in negative ion mode to verify acidic lipids not amenableby the FMOC/MTT labeling, an alkaline BGE with the same organic solventcomposition was used, but with ammonium acetate and ammonium hydroxideas the BGE and pH modifier respectively as described elswhere.36 In this case, the same MTBE extraction protocolwas applied for the direct analysis of fatty acids and anionic lipids,but the extract was concentrated 2-fold without FMOC/MTT chemicalderivatization. Plasma PLs were annotated by MSI-NACE-MS based ontheir sum composition, mass error, and relative migration times (RMTs)or apparent electrophoretic mobilities (Tables S1 and S2) with selected PLs from NIST SRM-1950 ether extractsfurther characterized by MS/MS for confirmation of molecular PC andSM species.An Agilent 6230 time-of-flight(TOF) mass spectrometer with a coaxialsheath liquid electrospray (ESI) ionization source equipped with anAgilent G7100A CE unit was used for all experiments . An Agilent 1260 Infinity isocraticpump and a 1260 Infinity degasser were utilized to deliver an 80:20methanol:water with 0.1 vol % formic acid at a flow rate of 10 \u03bcL/minusing a CE-MS coaxial sheath liquid interface kit. For mass correctionin the real time, the reference ions purine and hexakisphosphazine(HP-921) were spiked into the sheath liquid at 0.02 vol % to provideconstant mass signals at 44 In this case, MSI-NACE-MS under alkaline buffer conditionsand negative ion mode can directly analyze native PEs and other acidiclipids without chemical derivatization.38 FMOC reacts not only with PE species from plasma ether extractsbut also with excess MTT byproducts to form a neutral adduct as shown in the proposed reaction mechanism. The reaction of p-toluidine with FMOC  contributesto a reduction of ion suppression for closely migrating methylatedphospholipids in MSI-NACE-MS in conjunction with back extraction intohexane that was found to be superior to MTBE as an organic solvent. Overall, methylation of phosphoricacid moieties expands the separation window in MSI-NACE-MS by improvingthe resolution within PL class species, as shown in e.g., diacylglycerides,cholesteryl esters, etc.). In all cases, a serial injection of sevenindependent plasma extracts was analyzed rapidly within a single analyticalrun by MSI-NACE-MS (\u223c3.5 min/sample) under positive ion modewith full-scan data acquisition. This method also analyzed methylatedSM species, which also undergo a distinct mobility and mass shift(+14 Da) as shown in their MS/MS spectra acquired under positive andnegative ion mode detection .SMs have been reported to undergo methylation with a second equivalenton their hydroxyl moiety when using diazomethane, which leads to signalsplitting and lower sensitivity gain.42 In our case, dimethylated SM species were not detected likely dueto the lower reactivity of MTT compared to diazomethane that requiresspecial safety precautions when handling, given its explosive hazardsand toxicity.44A two-step chemicallabeling strategy using FMOC/MTT was firstdeveloped to generate a positive charge on methylated PLs to increasetheir electrophoretic mobility, as depicted in echanismS1. The r47 that allowed forthe analysis of acidic metabolites in urine by GC-MS.48 Similarly, Furukawa et al.49 reported using MTT to methylate oligosaccharides containing sialicacid residues in glycoblotting experiments prior to MALDI-MS analyses.However, this reagent remains unexplored to date, with sparse informationrelated to its reaction mechanism and applicability to routine lipidomicanalyses. Initial studies were performed to optimize reaction conditionsfor the formation of methylated PCs as a function of three experimentalfactors, namely, the reaction time (0\u2013180 min), MTT concentration(50\u2013900 mM), and reaction temperature (20\u2013100 \u00b0C).A maximum yield for methylated PCs was achieved using 450 mM MTT witha reaction time of 60 min at 60 \u00b0C corresponding to an averageyield of \u223c70%. This apparent reaction yield was lower thanfirst anticipated without the use of FMOC due to ion suppression effectsfrom p-toluidine formed as a byproduct when usingexcess MTT (data not shown). A kinetic study was next performed todetermine the minimum reaction time needed when using a two-step chemicalderivatization strategy based on FMOC/MTT, where the reaction progresswas reflected by a more intense golden/amber hue, as shown in 38 Similarly, plasma lipidomicprotocols that rely on more polar organic solvent mixtures for single-phaseextraction often suffer from limited recovery and poor solubilityfor nonpolar lipids that prevents their accurate quantification.50MTT was previously introduced as a methylation agent for esterificationof carboxylic acids31 the electrophoretic mobility represents an intrinsicphysicochemical parameter for characterizing ionic lipids in solutionby MSI-NACE-MS.38 Zwitterionic PC speciesthat migrate close to the EOF under alkaline BGE conditions overlapsubstantially, resulting in a narrow separation window as comparedto acidic lipid classes, such as PEs, phosphatidylinositols (PIs),lysophosphatidic acids (LPAs), and free/nonesterified fatty acids(FAs). This scenario was suboptimal for PCs and SMs as it can contributeto false discoveries from isobaric interferences when performing untargetedlipidomics. n = 48) andSMs (n = 27). These plasma PLs were annotated basedon their sum composition, mass error (<10 ppm), and relative migrationtimes (RMTs) or apparent electrophoretic mobilities (Tables S1 and S2).Similar to the use of collisional cross-sectionalareas for classifying lipid structures as gas-phase ions in IMS,38 which were also independently verified as consensus plasmalipids in an interlaboratory harmonization study using NIST SRM-1950.15 In general, methylated SMs migrated with a slowerpositive mobility than PCs due to differences in their chemical linkagebonding that impact their conformational size in solution. Among methylatedPC and SM species having similar masses , the SMs migrated later due to their longer acyl chains,resulting in a slower overall electrophoretic mobility in solution.Also, there were characteristic mobility shift patterns evident withinboth PL subclasses38 since a longer fattyacyl backbone (C30\u2013C44) and greater degrees of unsaturation(n = 0\u20138) predictably reduce or increase theapparent mobility for methylated PCs and SMs, respectively, as previouslyshown for various acidic lipids and FAs.38 The separation resolution of native zwitterionic PLs under theseconditions was otherwise poor in MSI-NACE-MS as they comigrate closewith the EOF. The steepness of the slope for underivatized PLs reflectstheir inadequate within-class separation, which are also prone toion suppression effects. The benefit of methylation of plasma PLsis more clearly illustrated in R2 > 0.930).Despite their similar charge state, more highly unsaturated methylatedPCs in this case have smaller hydrodynamic sizes in solution thanless unsaturated or fully saturated homologues.Moreover, these cationic phospholipids also satisfiedour selectioncriteria when using temporal signal pattern recognition in MSI-NACE-MSto reject spurious signals and background ions,m/z 198.0982)corresponding to a mass shift of m/z 14 compared to the native PC (m/z 184.0773). Also, annotation of the MS/MS spectra acquired undernegative ion mode (at 30 V) confirmed that both methylated PC 40:6and native PC 40:6 contained stearic acid (18:0) and docosahexaenoicacid  with the latter likely from an sn-2 position whencomparing the signal fragment ratio for the two fatty acyl chains.Interestingly, a double formate adduct anion [M + 2OOCH3]\u2212 was detected as the molecular ion for methylatedPC 40:6 (PC 18:0_22:6) when acquiring MS/MS spectra in negative ionmode since formic acid was included as an electrolyte in the BGE andsheath liquid solution. This was reflected by a characteristic neutralloss of m/z 60 (methylformate) thatoccurred twice compared with only once for native PC 40:6. Moreover,methylated PC 40:6 generated a unique base peak product ion at m/z 761.5081 in negative ion mode unlikenative PC 40:6. However, not all methylated PC isomers from NIST SRM-1950plasma extracts were comprised of fully resolved species in MSI-NACE-MSas highlighted for methylated PC 38:5 after acquiring MS/MS spectraunder negative ion mode , whichcomprised a mixture of two comigrating PL species, namely, PC 16:0_22:5and PC 18:1_20:4. Distinctive MS/MS spectra were also acquired formethylated SM 34:1;O2 under positive and negative ion mode conditions that confirmed the same methylatedphosphorylcholine headgroup but lacked diagnostic fatty acyl chains,which may be better achieved as their lithiated adducts to lower theenergy barrier in collision-induced dissociation.51 Other approaches are needed to confirm the exact stereochemistryof methylated PL molecular species and their potential isomers fromhuman plasma extracts, such as the location of unsaturation and/orgeometric configuration when using MS/MS in conjunction with ozone-induceddissociation experiments52 or photochemicalderivatization.53 Nevertheless, mobilityplots generated separately for a series of methylated PCs and SMsprovide complementary information to deduce the probable chemicalstructure of plasma PLs and reject potential isobaric candidates comparedto relying on accurate mass alone . Overall, MSI-NACE-MS combines the selectivity of HILIC  and reversed-phase  chromatography, which is optimal forthe rapid analysis of ionic classes of lipids from volume or mass-limitedsamples.3815 reported the use of NIST SRM-1950 as a reference sample when comparingthe performance of untargeted lipidomic platforms across 31 internationallaboratories, each using their own analysis data workflows, LC-MSmethodology, and hardware/software configuration. Although 1527 uniquelipid features were measured quantitatively across all sites, only339 of these plasma lipids were reported consistently from at leastfive or more laboratories with adequate precision based on a minimumcoefficient of dispersion threshold (COD < 40%). We next aimedto validate our two-stage chemical derivatization protocol using MSI-NACE-MSfor a panel of methylated PCs and SMs measured consistently from NISTSRM-1950 plasma extracts compared to various standardized LC-MS protocols.Overall, 75 plasma PLs reported in the harmonization study were annotatedbased on their sum composition from NIST SRM-1950 ether extracts ina targeted manner, including 48 PCs and 27 SMs as their cationic phosphatemethyl esters (Tables S1 and S2). Overall,MSI-NACE-MS was able to measure 90% of reported consensus PCs (48out of 53) and SMs (27 out of 30) from NIST SRM-1950, respectively,based on the combined PL annotations used by Bowden et al.,15 which also included mass resolvable plasmanyland plasmenyl species. However, the latter lipid species were confirmednot to be detected in our case. An analysis of acidic lipids fromNIST SRM-1950 was also performed when using MSI-NACE-MS under negativeion mode without chemical derivatization to expand lipidome coverageto include more polar classes of acidic lipids under alkaline conditions.38 This also includes LPCs that have poor recoveryafter hexane back extraction and PEs that generate isobaric interferenceswith PCs after methylation if FMOC was not used as a protecting agent.In this case, we were able to reliably measure 11/14 (79%) bile acids(BAs) and 19/25 (76%) of LPCs but only 24/35 (69%) PE and 7/13 (54%)PI species from the consensus plasma lipids reported by Bowden etal.15 The reduced coverage was likely dueto the lower ionization efficiency of polar/acidic lipids under negativeion mode detection in conjunction with the much smaller sample volumesintroduced in-capillary (\u223c10 nL) in MSI-NACE-MS than LC-MSmethods. Although only 8 FA species satisfied the selection criteriain the lipidomics harmonization study, MSI-NACE-MS can quantify morethan 20 FAs from blood extracts as described elsewhere.53Figure S7 depicts a Venn diagram forconsensus PLs from NIST SRM-1950 that were measured by MSI-NACE-MSunder both positive and negative ion mode. As expected, a larger fraction(\u223c50%) of methylated PCs and SMs were measured consistentlyby MSI-NACE-MS in positive ion mode relative to negative ion modewithout chemical derivatization. This was due to the improved separationresolution and greater ionization response achieved for cationic PCsand SMs following FMOC/MTT derivatization and hexane back extraction.Overall, our work highlights that >150 ionic lipids can be measuredin reference plasma by MSI-NACE-MS under two complementary configurations,including phosphatidylserines (PSs) and PAs that were not reportedas consensus plasma lipids when using LC-MS methods.15 For comparison, large-scale CE-MS metabolomic studies usingaqueous BGE conditions typically measure <90 polar/hydrophilicmetabolites consistently in blood specimens under positive and negativeion modes when using a coaxial sheath liquid flow interface.54Previously, Bowden et al.38 which reduces mass ambiguitieswhen credentialing ionic lipids in an untargeted manner.55n = 5).In all cases, methylated PCs and SMs were normalized to a single deuteratedinternal standard, given the lack of ion suppression or enhancementeffects in MSI-NACE-MS after sample workup. The potential for reliablequantification of methylated PCs was evaluated by comparing relativeresponse factors  generated from the slopes ofthe calibration curves for each lipid standard with those derivedfor the same lipid following a serial dilution of NIST SRM-1950 humanplasma. In the latter case, consensus (median of mean) PL concentrationsreported in a lipidomics harmonization study15 were used to construct calibration curves. R2 > 0.980). Thiscomparison also confirmed the lack of matrix-induced ion suppressionin MSI-NACE-MS, given minimal differences (bias <2%) in the apparentsensitivity measured from calibrant standards relative to referenceplasma extracts.A major analytical challenge in contemporarylipidomic research remains reliable quantification, given the lackand/or high costs of lipid standards and matching stable-isotope internalstandards. However, a key advantage of MSI-NACE-MS is that ionic lipidsmigrate with a steady-state mobility under isocratic BGE conditionswhile using a continuous sheath liquid solution during ionization,unlike LC-MS methods that rely on gradient elution for optimal separationperformance. Multiplexed separations in MSI-NACE-MS not only improvesample throughput but also enable versatile serial sample injectionconfiguration to encode mass spectral information temporally withina separation,Table S3 summarizesthe performanceof MSI-NACE-MS for reliable quantification of four representativeplasma PCs when external calibration curves were used compared toa serial dilution of NIST SRM-1950. As expected, good accuracy wasachieved when quantifying methylated PC 34:0, PC 38:6, and PC 40:6in both spike recovery studies as well as unspiked reference plasma(mean bias <10%) when using calibration curves by MSI-NACE-MS whencompared to untargeted LC-MS methods.15 A slightly higher bias (<25%) was found for PC 38:6 and PC 40:6concentrations in NIST SRM-1950 when compared to a targeted shotgunlipidomic interlaboratory comparison study by DI-MS/MS using a commerciallipid kit under standardized operating conditions.17 The latter discrepancy may arise due to isobaric interferencewhen high-efficiency separations are not used in lipidomic analyses.Overall, poor accuracy (mean bias \u223c\u221250%) was noted primarilyfor PC 30:0 after hexane sample cleanup since this procedure favorsa quantitative recovery of more lipophilic PLs having longer totalcarbon acyl chain lengths.15 As expected, this strategy was better suitedto more abundant plasma PLs (>10 \u03bcM), given the serial dilutionprocess unlike lipid standards that permitted PL quantification overa wider linear dynamic range (n = 14)and SM (n = 7) species were measured in at least4 concentration levels with adequate precision (CV < 20%) and linearity(mean R2 = 0.987) as summarized in Table S4).In cases where a direct measurement of a response factor was not feasibleby MSI-NACE-MS due to inadequate dynamic range, the closest PL analoguein terms of mass and lipid class from n = 27) having reported consensusconcentrations >5.0 \u03bcM in contrast to a larger average biasof 104% for PLs < 5.0 \u03bcM (n = 17). The lattergroup of PLs comprised mostly lower abundance SMs and PCs that reliedon surrogate PLs to estimate their response factor with greater uncertainty(Table S4). Further work is needed to evaluatethe quantitative accuracy and long-term analytical performance ofMSI-NACE-MS for plasma PLs when using FMOC/MTT derivatization. Nevertheless,this approach offers a higher-throughput approach for quantitativelipidomic analyses even in cases when standards are not available,which was recently applied to identify two specific circulating PCsas surrogate biomarkers of the omega-3 index following high-dose fishoil, docosahexaenoic acid, or eicosapentaenoic acid supplementation.55We also explored an alternative strategyfor semiquantitative estimationof other plasma PLs lacking chemical standards via response factorsderived from the serial dilution of NIST SRM-1950 when using the medianof mean consensus lipid concentrations reported by Bowden et al.ic range 5b. OveraIn summary, expanded lipidome coveragewas achieved in MSI-NACE-MSwhen using a two-step precolumn chemical derivatization strategy toconvert zwitterionic PLs into their corresponding cationic methylphosphate esters. This labeling procedure is quantitative and moreconvenient to use than diazomethane for PL methylation, which resultsin improved separation performance and ionization efficiency. Overall,75 cationic PCs and SMs were characterized from reference human plasmawith adequate precisionby MSI-NACE-MS following FMOC/MTT derivatizationand hexane back extraction when compared to an international lipidomicharmonization study. Additionally, more than 69 other acidic and polarPLs from NIST SRM-1950 plasma extracts can also be measured by MSI-NACE-MSunder negative ion mode without chemical derivatization. Additionally,polar lipid classes poorly retained in reversed-phase LC-MS  are well resolved in MSI-NACE-MS. This strategy greatlyexpands conventional CE-MS metabolomic protocols that rely on aqueousbuffer systems and thus have been limited to the analysis of hydrophilic/polarmetabolites. Lipid annotation and structural classification were alsosupported based on predictable trends in the electrophoretic mobilityfor methylated PCs and SMs that are dependent on polar headgroup/chemicallinkage, total fatty acyl chain length, and degrees of unsaturation.Advantages of MSI-NACE-MS include greater throughput and minimal ionsuppression effects that allow for unique data workflows for dataacquisition and lipid authentication in comparison to other separationmethods that utilize single sample injections. MSI-NACE-MS is alsomore amenable to standardization since it operates using only a barefused-silica capillary under an isocratic nonaqueous buffer systemunlike LC-MS that relies on different column types and gradient elutionprograms when using reversed-phase and HILIC separations. However,MSI-NACE-MS with a coaxial sheath liquid interface suffers from higherdetection limits and lower concentration sensitivity for ionic lipidscompared to LC-MS protocols due to the smaller sample volume introducedon-capillary. Also, electrically neutral lipid classes are not resolvedor reliably measured even after methylation, such as diacylglyceridesand cholesteryl esters. Future studies are underway to better characterizeother methylated PL subclasses in MSI-NACE-MS with improved sensitivitywhile developing accelerated data workflows and automated data processingtools for biomarker discovery in lipidomic studies.In this work, we introduce a two-step chemicalderivatization strategyusing FMOC/MTT for the methylation of zwitterionic PLs to expand lipidprofiling coverage by MSI-NACE-MS under positive ion mode conditions.FMOC was used as a compatible protecting agent to prevent generationof PE isobaric species to PCs that also reduced ion suppression effectsfrom excess MTT byproducts prior to hexane back extraction. We optimizedthe efficacy of this reaction to generate quantitative yields of 75cationic methylated PCs and SMs verified in reference human plasmawhen using MSI-NACE-MS, which comprised 90% of consensus plasma lipidswithin these two classes, as reported in an international lipidomicsharmonization study. Overall, PL methylation resulted in improvedseparation resolution, faster analysis times, and reduced ion suppressionwhile allowing for better lipid structural classification based onchanges in their electrophoretic mobility. This method is optimalfor lipidomic studies requiring higher sample throughput and loweroperating costs with stringent quality control while consuming minimalvolumes of the sample and organic solvent. Complementary analysisof other polar or acidic lipid classes can be achieved by their directanalysis using MSI-NACE-MS under negative ion mode without chemicalderivatization. We also demonstrated good precision and accuracy whenquantifying methylated PCs and SMs in reference plasma samples, includingthe potential for use of serial dilution of NIST SRM-1950 to estimaterelative response factors for lipids lacking chemical standards, providedthey are present at concentrations >5 \u03bcM. This methylationstrategyis anticipated to offer a practical alternative to diazomethane forimproved lipid analysis when using other MS instrumental platformswithout excessive hazards and safety precautions, including directinfusion-MS, ion mobility-MS, and LC-MS/MS methods."}
+{"text": "Gram-negative bloodstream infection (BSI) in hospitalized children is associated with significant morbidity and mortality. It is unclear whether bacterial clonality of isolates during BSI in a unique patient is associated with clinical characteristics such as immunocompromise. We hypothesized that genomic diversity of BSI isolates would be higher in immunocompromised patients due to mucosal barrier injury and therefore larger translocation bottleneck.E. coli, Klebsiella spp., or Pseudomonas aeruginosa. An aliquot from the blood culture bottle was plated on agar, and at least 24 colonies were picked randomly and subjected to whole-genome sequencing (WGS). Patient-specific reference genomes were constructed using long-read sequencing of at least 1 isolate on the PacBio platform. All isolates were sequenced using Illumina (MiSeq or NextSeq). Single nucleotide variant (SNV) calls were made using the WideVariant pipeline (github). Clinical characteristics were obtained retrospectively from the electronic medical record. We defined immunocompromise as neutropenia (ANC< 500) on the day of BSI or prior solid organ or stem cell transplant. The proportion of BSI episodes with clonal blood isolates (defined as 0 SNV) was compared between immunocompromised and non-immunocompromised patients using Fisher\u2019s exact test.We prospectively enrolled patients with a central venous catheter who were hospitalized at Boston Children\u2019s Hospital and had a positive blood culture that grew E. coli, 14 Klebsiella spp.) and 9 from Pseudomonas aeruginosa. Immunocompromised patients had a significantly higher proportion of Enterobacterales BSI episodes with clonal isolates compared with non-immunocompromised patients [13/18 (72%) vs. 1/7 (14%) respectively, P=0.021). This was not seen with Pseudomonas BSI, which had clonal isolates in 3/5 (60%) vs. 2/4 (50%) respectively (P=1).We enrolled 34 patients , 25 having BSI from Enterobacterales (11 Contrary to our hypothesis, immunocompromised patients were more likely to have clonal Enterobacterales BSI isolates compared with non-immunocompromised patients, perhaps due to lower host pressures for bacterial population diversification in immunocompromised patients.Arolyn Conwill, PhD, Day Zero Diagnostics: current employee|Day Zero Diagnostics: Stocks/Bonds"}
+{"text": "Sr) are being used in wheat breeding programs, new emerging stem rust pathotypes are a challenge to important Sr genes. In recent years, multiple studies on leaf and yellow rust molecular mechanism have been done, however, for stem rust such studies are lacking. Current study investigated stem rust induced response in the susceptible wheat genotype C306 and its Near Isogenic Line (NIL) for Sr24 gene, HW2004, using microarray analysis to understand the transcriptomic differences at different stages of infection. Results showed that HW2004 has higher basal levels of several important genes involved in pathogen detection, defence, and display early activation of multiple defence mechanisms. Further Gene Ontology (GO) and pathway analysis identified important genes responsible for pathogen detection, downstream signalling cascades and transcription factors (TFs) involved in activation and mediation of defence responses. Results suggest that generation of Reactive Oxygen Species (ROS), cytoskeletal rearrangement, activation of multiple hydrolases, and lipid metabolism mediated biosynthesis of certain secondary metabolites are collectively involved in Sr24-mediated defence in HW2004, in response to stem rust infection. Novel and unannotated, but highly responsive genes were also identified, which may also contribute towards resistance phenotype. Furthermore, certain DEGs also mapped close to the Sr24-linked marker on Thinopyrum elongatum translocated fragment on wheat 3E chromosome, which advocate further investigations for better insights of the Sr24-mediated stem rust resistance.Stem rust of wheat is a deleterious fungal disease across the globe causing severe yield losses. Although, many stem rust resistance genes ( Puccinia graminis f. sp. tritici (Pgt)), is estimated to cause up to 50% loss in yield or even higher if infection starts at an early stage . Re. Re20 prt method . The RT-T. elongatum chromosomal region harbouring the Sr24-linked marker using the following approach. Chromosome 3E of T. elongatum genomic sequence (NCBI genomes reference genome number ASM1179987v1), was used for mapping of Sr24 tightly linked SSR marker Xbarc71 (NCBI GenBank id BV211796.1) and stem rust responsive DEGs using NCBI-BLAST tool. The mapped DEGs were filtered to 70Mbp region from end terminal of 3E chromosome . The mapped gene coordinates were visualized using ChromoMap Ver 4.1.1 , 5150, 5In case of susceptible genotype C306, response at early infection stage (10 hpi) was characterized by, upregulation of relatively lower number of genes than HW2004 . Lower nAt late stage (72 hpi) the downregulated genes included BHLH, PDZ6 and NBS-LRR domain-proteins, RING-type E3 ubiquitin ligase, Myb TF, glycosyl transferase and . As, theR\u2019 gene family and involved in resistance to leaf and stripe rusts [R\u201d gene mediated resistance. Such basal expression differences of defence related genes has also been reported to contribute towards resistance to Xanthomonas infection in rice [The two NILs showed minor differences at basal levels . In the pe rusts . In addipe rusts , 54. Hig in rice , 55. PreR\u2019 gene is a hallmark of specific defence response in plants [Comparative analysis at early stage of infection (10 hpi) revealed upregulation of candidates involved in pathogen recognition, defence signalling, TFs involved in activation of defence responsive genes in HW2004 , Table 5n plants . The gen2O2 catabolism, and detoxification) were relatively reduced, indicative of their importance in the early infection stage  showed that their trend was consistent with microarray data . RT-qPCRPgt infection, identified several key aspects mediating stem rust resistance response, including pathogen detection , activation of defence TFs and downstream induction of multiple defence processes, collectively helping in restricting pathogen growth.Differential expression analysis of wheat NILs upon R\u2019 signature  in response to rust pathogen has also been reported in previous studies [Upon pathogen reception, signalling cascade induces TFs involved in activation of defence responses . Upregulpathogen . Previou studies , 18, 56.Biotic stress induced TFs are involved in activation of defence pathways. Several key genes central to the HR during plant pathogen interaction , heat shock proteins, chitinase, alcohol dehydrogenase, ankyrin repeat profile containing protein) were upregulated in the HW2004, in response to stem rust infection . MoreoveLr34 and Lr10 have showed upregulation of ABC, MATE efflux, pleiotropic drug transporters [2+, K+, H+) have been reported in resistance response to Xanthomonas in rice [HW2004 showed upregulation of multiple transporter proteins  and many proteins with transporter domain . Such chsporters , 47, whi in rice .Defence mechanisms activate ROS generation to restrict the pathogens , 11, andLr34 gene [Secondary metabolites such as flavonoids (derived from phenylpropanoid metabolism) comprise an integral component of plant defence responses against pathogens . Genes ir34 gene . Phenylar34 gene . Lipoxygr34 gene .Xanthomonas [Lr34 response have also shown modulation of TCA cycle and GABA shunt pathway, while, Lr1 response study showed upregulation of glycolysis [Defence response to pathogen also involves modulation of primary metabolic pathways (catering for energy requirement), to restrict pathogen growth. Genes involved in steroid biosynthesis and, linoleic acid metabolism were upregulated in HW2004 . This wathomonas . Overallycolysis , 18.Several uncharacterized genes were substantially upregulated in the resistant wheat NIL HW2004, some of which are likely to be involved in resistance to stem rust, with possible roles in detection of pathogen, or defence responses . FurtherSr24 gene is introgressed in wheat due to a translocated fragment from T. elongatum. NCBI-Blast-based sequence similarity search mapped 77 DEGs with significant hits to the 70 Mbp region harbouring the Sr24-linked marker (Xbarc-71 SSR marker) in T. elongatum Click here for additional data file.S2 Table(XLSX)Click here for additional data file.S3 Table(XLSX)Click here for additional data file.S4 Table(XLSX)Click here for additional data file.S5 Table(XLSX)Click here for additional data file.S1 Fig(TIF)Click here for additional data file.S2 Fig2 fold change versus -log10 FDR corrected p-value. Red dots represent significantly upregulated while green genes significantly downregulated DEGs respectively. * Denotes comparison of expression of DEGs at 72 hpi in HW2004 compared to 10 hpi.Expression data of genes are plotted as log(TIF)Click here for additional data file.S3 FigIn HW2004 (A), C306 (B) based on hierarchical clustering. Global expression profile of differentially expressed genes in HW2004 compared to C306 (C).(TIF)Click here for additional data file.S4 Fig(TIF)Click here for additional data file.S5 FigUpregulated genes (A), downregulated genes (B).(TIF)Click here for additional data file.S6 FigBy upregulated genes (A), downregulated genes (B), in C306 at early stage (C), (D) and at late stage of infection (E), (F).(TIF)Click here for additional data file.S7 FigBy early stage upregulated (A), downregulated (B) and late stage upregulated (C), downregulated (D) genes.(TIF)Click here for additional data file.S8 FigIn HW2004 compared to C306 at early stage (10 hpi) of infection. Error bars indicate SD of three independent biological replicates of RT-qPCR.(TIF)Click here for additional data file."}
+{"text": "Staphylococcus aureus express different proteins that modulate intracellular bacterial survival and increase antimicrobial resistance with higher mortality rate. The EsxA and EsxB, substrates of the ESAT-6 like secretion system (Ess) are important during intracellular S.aureus infection. The genes EsxA and EsxB are present in close proximity with 6 other genes, including EsaA, EssA, EsaB, EssB, EssC, and EsaC.S. aureus was cloned and transformed into expression cell line E.coli BL21(DE3) cells under IPTG induction. The expressed proteins were purified using affinity and size exclusion chromatography. Purity and protein structures were checked by using NMR spectroscopy and circular dichroism. Further, purified proteins were evaluated for it's hemolytic and antibiofilm property against S. Aureus (ATCC 6538).EsxB virulence gene from vancomycin resistant S.aureus (ATCC 6538) when treated exogenously. It also showed non hemolytic activity indicating it's non-cytotoxic nature.he purified EsaB protein showed well spread spectra of 1H- NMR spectrum, however, the 15N, 1H-HSQC spectrum showed overlapped peaks or contours in the region of 6.5-10 ppm indicating the absence of well folded 3D conformation in solution state. Circular dichroism showed the presence of beta sheets in structure of EsxB virulence factor. EsxB protein showed antibiofilm activity against This study explains the evidence that bacterial virulent protein EsxB possess antibiofilm activity against its own sensitive strain.All Authors: No reported disclosures"}
+{"text": "Magnetic resonance imaging (MRI) is the diagnostic study of choice for children with acute hematogenous osteomyelitis (AHO). However, there is limited guidance for whether repeat MRIs are clinically impactful for children with AHO who fail to improve after initial treatment. This study aimed to determine whether repeat MRIs changed clinical management among children with AHO.Children admitted to a quaternary care pediatric hospital with a discharge diagnosis of osteomyelitis were identified during a 9-year period. Patients with chronic symptoms, non-hematogenous infections, or significant contributing comorbidities were excluded. Medical records were retrospectively reviewed for all MRIs performed 3 weeks prior to admission to 24 months after discharge. An MRI was considered clinically impactful if it identified a new infectious process  or if it resulted in surgical intervention within 24 hours. Categorical variables were compared using Fisher\u2019s Exact or chi-square tests and continuous with Wilcoxon Rank-Sum tests.Among 239 included patients, 41 (17%) had more than 1 MRI performed during clinical care for their AHO. Twenty-nine repeat MRIs occurred during initial hospitalization and 27 during outpatient follow up. Children who underwent repeat inpatient MRIs had longer hospitalizations  and higher C-reactive protein levels , and were more likely to be critically ill  or to experience a therapeutic failure . Among repeat inpatient MRIs, 19 (66%) were clinically impactful; 9 (31%) led to repeat surgical procedures and 13 (45%) identified new diagnoses. Repeat outpatient MRIs were more likely to be performed in children with vertebral AHO or multifocal infections (P=0.02). Among repeat outpatient MRIs, 7 (25%) were clinically impactful. Six (22%) led to repeat operative procedures and 3 (11%) identified new diagnoses.When used judiciously among ill children with complicated AHO, repeat MRI can be clinically impactful in both the inpatient and outpatient setting. Prospective studies are needed to better define which children with AHO benefit from repeat MRI.Julia S. Sanders, MD, OrthoPediatrics Corp: Advisor/Consultant"}
+{"text": "The rise of hepatitis C (HCV) infections among reproductive-age women increases the number of infants at risk for perinatal HCV infection, but screening remains low. It is unknown if maternal HCV viral load (VL) during pregnancy influences infant screening practices.Using an existing retrospective cohort of mother-infant pairs with longitudinal well-child care from a single healthcare system, we included infants born from 2015 to 2019 with perinatal HCV exposure based on maternal or infant HCV-specific ICD diagnosis codes and/or laboratory testing and confirmed by reviewing electronic health records. Maternal HCV VL during pregnancy was classified as positive (+), negative (-) or unknown based on HCV RNA testing (or lack-thereof) obtained between 12 months before to 3 months after the infant\u2019s birth date. Adequate infant screening included an HCV RNA test obtained \u2265 2 months of age or an HCV antibody test \u2265 12 months of age. We used univariate logistic regression to compare odds of infant screening based on maternal HCV VL during pregnancy.Of the 501 HCV-exposed infants, 139 (28%) were born to HCV+/VL- women, 100 (20%) to HCV+/VL unknown women, and 262 (52%) to HCV+/VL+ women. The proportion of screening tests ordered ranged from 68-82%, while test completion ranged from 64-70% . Overall, screening for HCV varied by maternal HCV VL (43% (60/139) HCV+/VL-; 50% (50/100) HCV+/VL unknown; 58% (152/262) HCV+/VL+). Perinatal HCV ranged from 1.7-6% depending on maternal HCV VL status . Infants born to HCV+/VL+ women were two times more likely to have a screening order compared to infants of HCV+/VL- women; but there was no difference for infants of HCV+/VL unknown women (Table 1). Among those with tests ordered, there was no difference in completion between groups (Table 1).Although infants born to HCV+/VL+ women are more likely to be screened for HCV, many, regardless of maternal HCV VL during pregnancy, are never adequately screened and pediatric HCV infections are going undetected. Efforts to increase caregiver and clinician awareness of infant HCV screening guidelines, including consideration of earlier RNA or office-based HCV screening, may improve screening rates and detection of HCV infected infants.Catherine Chappell, MD, MSc, Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|Organon: Grant/Research Support"}
+{"text": "Candida auris (CA) is a multidrug-resistant fungal pathogen of increasing concern and has caused infection outbreaks in hospitals as a result of nosocomial transmission. CA has caused both invasive bloodstream and wound infections with significant morbidity and mortality. Recently, a novel polygalacturonic and caprylic acid (PG+CAP) antimicrobial wound ointment was highly effective in healing microbially contaminated chronic wounds in a pilot prospective randomized clinical trial when compared to MediHoney. In order to better combat CA wound infections, here we assessed the effectiveness of PG+CAP and MediHoney wound ointments in eradicating mature CA biofilms in vitro.CA (AR0381 and AR0382) were formed separately on silicone discs and then exposed to PG+CAP or MediHoney wound ointment for two hours. The silicone discs were sonicated in neutralizer, then serially diluted, plated and counted to enumerate viable colonies remaining following exposure to the ointments. Positive controls were discs that had no wound ointment treatment.A well-established biofilm eradication model was used to quantify antimicrobial efficacy. Forty-eight-hour biofilm of two different strains of Figure 1 presents the median number of viable colonies recovered from 6 replicates following two-hour exposures of the mature CA biofilms to the wound ointments and positive control.Both ointments fully eradicated biofilm for CA strain AR0381. PG+CAP fully eradicated AR0382 biofilm (greater than 5-log reduction) but MediHoney achieved less than a 3-log reduction against AR0382. The difference between PG+CAP and MediHoney for AR0382 was significant (p = 0.02). These results suggest PG+CAP might be a promising ointment for use in treating CA wound infections and merits further study.Joel Rosenblatt, PhD, Novel Anti-Infective Technologies, LLC: Licensed Technology Issam I. Raad, Distinguished Professor, Novel Anti-Infective Technologies, LLC: Technology License"}
+{"text": "Standard platinum-based therapy for ovarian cancer is inefficient against ovarian clear cell carcinoma (OCCC). OCCC is a distinct subtype of epithelial ovarian cancer. OCCC constitutes 25% of ovarian cancers in East Asia  and 6\u201310% in Europe and North America. The cancer is characterized by frequent inactivation of ARID1A and 10% of cases of endometriosis progression to OCCC. The aim of this study was to identify drugs that are either FDA-approved or in clinical trials for the treatment of OCCC.High throughput screening of 166 compounds that are either FDA-approved, in clinical trials or are in pre-clinical studies identified several cytotoxic compounds against OCCC. ARID1A knockdown cells were more sensitive to inhibitors of either mTOR (PP242), dual mTOR/PI3K (GDC0941), ATR (AZD6738) or MDM2 (RG7388) compared to control cells. Also, compounds targeting BH3 domain (AZD4320) and SRC (AZD0530) displayed preferential cytotoxicity against ARID1A mutant cell lines. In addition, WEE1 inhibitor (AZD1775) showed broad cytotoxicity toward OCCC cell lines, irrespective of ARID1A status.In a selection of 166 compounds we showed that inhibitors of ATR and WEE1 were cytotoxic against a panel of OCCC cell lines. These two drugs are already in other clinical trials, making them ideal candidates for treatment of OCCC.The online version contains supplementary material available at 10.1186/s13048-023-01160-y. Ovarian clear cell carcinoma (OCCC) patients show low response rates 10\u201325%) to standard ovarian cancer therapy (carboplatin and paclitaxel). This therapy is effective (~\u200980% response rate) in other subtypes  of ovarian cancer 0\u201325% to . MoreoveWe established ARID1A isogenic OCCC cell lines and performed high throughput drug screening using 166 compounds . We identified 7 inhibitors of OCCC targeting WEE1 (AZD1775), mTOR (PP242), dual mTOR/PI3K (GDC0941), ATR (AZD6738), MDM2 (RG7388), BH3 domain (AZD4320) and SRC (AZD0530). We found that the combination of WEE1 (AZD1775) and ATR (AZD6738) inhibitors synergistically killed the OCCC cells. These two drugs are in clinical trials for other cancer-types, making them ideal candidates for treatment of OCCC.OVCA429 OCCC cell line , 19\u201324 wCells were harvested in the presence of lysis buffer  plus protease inhibitor cOmplete cocktail (Sigma). Protein lysates were separated by SDS polyacrylamide gel electrophoresis followed by Western blotting with different antibodies. Expression levels of individual protein were quantified using ImageJ . RepreseRNA extraction from cells were performed by using RNeasy mini kit (Qiagen). After digestion with DNase (ThermoFisher Scientific), cDNA was synthesized using MAXIMA H(-) MASTERMIX (ThermoFisher Scientific). Real-time PCR was performed using POWRUP SYBR MASTER MIX (ThermoFisher Scientific) in CFX96 Real-time system (Bio-Rad).Human OCCC cell lines  were from in-house collection of ovarian cancer cell lines purchased or acquired from various sources described in Supplementary Table\u00a0Lentiviral vector pLKO.1 was used to select stable silencing (shRNA) of ARID1A in 3 ARID1A wild type cell lines  by puromycin. Two shRNA target sequences for ARID1A were Sh1 (GAAAGCGAGGGCCCCGCCGT) and sh5 (GCTTCGGGCAACCCTACGGC) as well as control scrambled shRNA (shC) (GAACCTATTCCCGCAATCTAA). Isogenic silencing of ARID1A in OVCA429, ES2, JHOC5 was verified by real-time PCR and Western blots  were treated with drugs in 96-well plates for 72\u00a0h; and cell viability was measured using MTT -2,5-diphenyltetrazolium bromide). All experiments were performed three times in triplicates. IC50 values were generated using Graphpad Prism software.Data were analyzed by either Student\u2019s t-test or two-way Anova. Generation of hierarchical clustering of heatmap was performed using ClustVis .OCCC  were grown for 14 days in top layer of 0.3% agar with a bottom layer of 0.6% agar in 24-well plates. Drugs were mixed with top layer of soft agar at day 1. Colonies were fixed with formaldehyde and stained with crystal violet. Each assay was performed in triplicates and repeated once. ImageJ2 was used to quantify number of colonies , 31. RepGDSC (The Genomics of Drug Sensitivity of Cancer database) contains drug response data and genomic markers of sensitivity from ~\u20091,000 human cancer cell lines screened with 180 to 400 compounds . This daPropidium iodide-stained cells was used to measure DNA contents after drug treatment. Briefly, after drug treatment, cells were fixed with ethanol, treated with RNaseA, and stained with propidium iodide. APC Annexin V Apoptosis Detection Kit (Biolegend) was used to identify apoptotic cells following manufacturer\u2019s instructions. Data were acquired on LSRII flow cytometer and analyzed with FlowJo software. Representative results are shown from 2 independent experiments. Two-tailed t test was performed. *, p\u2009<\u20090.05, compared to control; #, p\u2009<\u20090.05 combination treatment compared to single agent.p\u2009<\u20090.05) different cytotoxicity between KD and WTC  and ARID1A knockdown (KD). Thirty-eight compounds showed significantly   . After single agent treatment of AZD1775, OCCC cells increased in G1 phase (\u2264\u200923%) Fig.\u00a0\u00a0A. CellsProtein expression levels of molecules involved in cell cycle arrest and apoptosis were measured after drug treatment. Inhibitors of either WEE1 (AZD1775) or ATR AZD6738) alone increased levels of cleaved caspase-3 in OCCC cell lines  and their combination further significantly enhanced expression levels of active caspase-3  targeting both BCL2 and BCL-XL and was selectively more active in Mut compared to WT OCCC cell lines. This inhibitor induced tumor regression and remission in venetoclax-resistant acute myeloid leukemia (AML)  and B-ceActivated SRC is associated with an unfavorable survival in endometriosis-associated OCCC . In our Another frequently activated kinase is PIK3CA (activation mutations found in approximately 50% of OCCC). A prior study identified mTORC1/2 inhibition as treatment for OCCC by analysis of kinase mutations (518 kinases) and copy number alterations . We idenMutations or copy number alterations in DNA repair/cell cycle arrest/apoptosis occur in 82% of OCCC samples . DNA damOCCC has low response rates versus standard ovarian cancer therapy. High throughput drug screening of ARID1A isogenic OCCC cell lines with 166 compounds  identified 7 inhibitors targeting BH3 domain (AZD4320), WEE1 (AZD1775), mTOR (PP242), dual mTOR/PI3K (GDC0941), ATR (AZD6738), MDM2 (RG7388), or SRC (AZD0530). We further revealed combination of AZD6738 and AZD1775 synergistically induced growth inhibition of OCCC cells. These two drugs are already in other clinical trials, making them ideal candidates for treatment of OCCC. These results highlighted drug screening will contribute to discovery of novel therapeutic targets and alternative treatments for the improvement of OCCC patient outcomes.Below is the link to the electronic supplementary material.Supplementary Material 1"}
+{"text": "Introduction\u00a0The progression of medical knowledge competency during surgical residency training is poorly understood. This study measures the acquisition of medical knowledge as orthopedic surgery residents advance during training and the impact of accreditation status on orthopedic in-training examination (OITE) performance.Methods\u00a0Orthopedic surgery residents taking the OITE during 2020 and 2021 were included. Residents were grouped into cohorts by post-graduate year (PGY) and Accreditation Council for Graduate Medical Education (ACGME) accreditation status. Comparisons were made with parametric tests.Results\u00a0Eight thousand eight hundred and seventy-one ACGME-accredited residents (89%) and 1,057 non-ACGME-accredited residents (11%) were evenly distributed by the PGY level . Residents in both ACGME- and non-ACGME-accredited residency programs had a significant increase in OITE performance at each PGY level (P<0.001). At ACGME-accredited programs, OITE performance increased from PGY1 (51%), PGY2 (59%), PGY3 (65%), PGY4 (68%), and PGY5 (70%) (P<0.001). There were progressively smaller percentage increases in OITE performance during accredited residency training , but this increase was linear in non-accredited residency training . At each PGY level, residents at accredited programs outperformed their counterparts at non-accredited programs (P<0.001).ConclusionOITE performance increases during residency training. Among ACGME-accredited residents, performance on the OITE progresses rapidly during junior years and plateaus during senior years. Residents in ACGME-accredited residency programs outperform their counterparts in non-accredited residency programs. More research is needed to understand optimal training environments that promote medical knowledge acquisition during orthopedic surgery residency. The Accreditation Council for Graduate Medical Education (ACGME) outlines core competency training for surgical residency training in the United States (US). Medical knowledge is an ACGME-defined core competency for independent clinical practice -3. The AThe wide breadth of medical knowledge required during orthopedic surgery residency training is tested annually in the orthopedic in-training examination (OITE) . The AmeIn this study, we sought to determine the degree to which OITE performance increases during orthopedic surgery residency training. We hypothesized that OITE performance would increase during each successive PGY level\u00a0but would increase in smaller rates at senior (PGY4-5) relative to junior (PGY1-3) resident levels. Furthermore, we hypothesized that orthopedic surgery residents in ACGME-accredited programs would outperform their international counterparts in non-ACGME-accredited programs.The AAOS\u00a0provided OITE scores from the 2020-2021 and 2021-2022 academic years. OITE performance data included all orthopedic surgery residents at ACGME-accredited residency programs in the United States and select international residents at non-ACGME-accredited residency programs. These international residents were included if their respective residency program voluntarily opted into the OITE administration. Due to the de-identified nature of all data, this study received review exemption status based on the policies of the Institutional Review Board at Howard University.Each year, the OITE is designed to consist of 275 multiple choice questions that cover 10 clinical content domains  covering established treatment principles and modalities in orthopedic surgery. A few practice management questions are occasionally included. The exam is assembled into two sections where residents are allotted 210 minutes for each section for a total of seven hours. The OITE Examination Committee of the AAOS vets questions through a peer-reviewed process, and the final set is ratified by the Board of Directors. All final questions are intended for scoring, but questions are occasionally flagged for poor test performance . In 2020, eight questions were removed from\u00a0final scoring (n=267 scored questions). In 2021, twelve questions were removed from final scoring (n=263 scored questions). The AAOS scores the OITE based on the raw number of questions answered correctly and reports the examinee's raw score along with percentile rank among the national resident class at a specific post-graduate year level.OITE performance was defined in two ways: the number and percentage of OITE questions answered correctly. Parametric and chi square tests were used to compare OITE performance by PGY level within accredited and non-accredited residency programs. This tested the hypothesis that OITE performance increases during residency training. Percentage increases in OITE performance based on annual promotion were compared between junior resident (PGY1-3) and senior resident (PGY4-5) levels. A final separate analysis was conducted to compare the OITE performance between residents at accredited and non-accredited programs. This tested the hypothesis that ACGME accreditation status is associated with greater OITE performance.All statistical tests were performed using GraphPad Prism 9 software . OITE performance data were analyzed with D\u2019Agostino-Pearson Omnibus normality tests and presented as means with standard deviations. Relative proportions of tested content between the 2020 and 2021 OITEs were compared with chi-square tests. Statistical tests were two-tailed and considered significant if P<0.05.OITE performance data from 9,928 unique administrations were included in this study Table . There wThere was a significant increase in mean OITE performance at each PGY level for residents at both ACGME- and non-ACGME accredited residency programs , PGY2 , PGY3 , PGY4 , and PGY5  (Table Graduates of ACGME-accredited orthopedic surgery residency programs must pass the American Board of Orthopaedic Surgeons (ABOS) Part I written examination. Residency programs maintain accreditation, in part, by their ability to successfully graduate residents that pass Part I on the first attempt. To date, OITE performance is the best barometer for future ABOS Part I written examination performance -17. OITEThe ACGME has shifted toward\u00a0competency-based training, which requires objective assessment across six core competencies needed for independent practice -3. MedicThe standardization of global medical training is a strategic priority for the World Health Organization . HistoriThere were several limitations to this study. First, the clinical relevance of additional questions answered correctly on the OITE remains unknown. Future studies should correlate the acquisition of medical knowledge with clinical competency to see if translates into better objective outcomes. Evidence-based recommendations are also needed to inform orthopedic surgery milestones across additional dimensions of medical knowledge . ImportaIn summary, OITE performance increases during orthopedic surgery residency training. Residents in ACGME-accredited programs outperform their international colleagues in non-ACGME-accredited programs. Ultimately, this study provides an objective benchmark that measures how residency promotion affects medical knowledge acquisition during orthopedic surgery residency. More research is needed to understand optimal training environments that promote medical knowledge acquisition during orthopedic surgery residency training, including the potential benefits of ACGME accreditation."}
+{"text": "In recent years, ICU at Tufts Medical Center (TMC) have a higher utilization rate of antifungal agents compared to nationwide ICU data reported to the National Health and Safety Network. The role of empiric antifungal therapy in reducing ICU patient mortality remains controversial. Prudent use of antifungals is needed to mitigate the risk of further antifungal resistance development. Our study aimed to evaluate empiric antifungal use among ICU patients and its association with ICU 30-day all-cause mortality.Candida score, indication for empiric antifungal therapy, use of mechanical ventilation (MV) and broad spectrum antibiotic use. Univariable and multivariable logistic regression analyses were conducted to identify predictors associated with ICU 30-day all-cause mortality among ICU patients who received antifungal therapy.We conducted a retrospective study of all adult ICU patients at TMC who had received fluconazole (F) or micafungin (M) between August 2022 and February 2023. We collected demographics, comorbidities, Candida sp. The median Candida score was 3 [2-4]. Antifungal therapy was initiated for suspected infection in 52 (68%) of patients per prescriber orders indications. The majority of patients were ventilated , of these, 15 (23.8%) were on extracorporeal membrane oxygenation. The 30-day all-cause mortality was 58 (75%). Multivariable logistic regression analysis showed antifungal therapy for \u2265 48 hours was not associated with improved ICU mortality . Chronic heart failure was associated with an increased risk for ICU mortality .A total of 77 ICU patients received antifungal treatment, . The median treatment duration was the same for both therapies, 2 days [1-4]. Only 4 (5%) of patients had positive blood cultures for A high 30-day all-cause mortality among ICU patients who received empiric antifungal treatment was observed. Similar to national trends, the incidence of fungemia was low despite moderate candida scores. Empiric antifungal therapy \u226548 hours was not associated with improved mortality outcome in this population.Maureen Campion, PharmD, BCIDP, Shinoigi: Speaker"}
+{"text": "Tracheostomy is a commonly performed procedure in critically ill patients requiring prolonged mechanical ventilation. However, nationwide practice patterns for the role of a tracheostomy in critically ill burn patients have not been well described.A 25-question Qualtrics online survey was distributed by the American Burn Association (ABA) to their physician members. Questions pertained to practitioner demographics, indications, type of tracheostomy performed, and timing of procedure. The questionnaire further ascertained how presence of inhalation injury and Total Body Surface Area (TBSA) influence timing of tracheostomy; if concurrent percutaneous endoscopic gastrostomy (PEG) tubes were performed, and whether enteral feeds were held prior to tracheostomy.Thirty-seven surgeons responded to the survey and worked primarily at ABA verified academic burn centers. Open tracheostomy was performed more frequently than percutaneous tracheostomy (73% vs 27%). Eighty-three percent of surgeons deferred concomitant PEG despite healthy overlying skin due to the belief that a patient would eventually pass a swallow evaluation (74%). Tube feeds were routinely held by 67% of surgeons, most commonly 6 or 8 hours prior. The most common indication for tracheostomy was prolonged mechanical ventilation. Fifty-four percent of surgeons routinely perform a tracheostomy through open uninfected 2nd degree neck burns. As for 3rd degree neck burns, 35% will perform a tracheostomy only after excision and grafting. For patients requiring prolonged mechanical ventilation 35% of surgeons had no standard time frame for tracheostomy regardless of TBSA. For mechanically ventilated patients with >20% TBSA burns (excluding neck burns), 40% performed early tracheostomy (0-7 days) and 24% performed delayed tracheostomy (8+days). For ventilated patients with inhalational injuries and TBSA < 20%, 35% had no standard time frame, 16% performed early tracheostomy and 49% performed delayed tracheostomy.A national tendency toward open tracheostomy, deferring concomitant PEG, and holding tube feeds 6-8 hours prior to tracheostomy was identified. Patients with TBSA >20% seem to undergo earlier tracheostomy more frequently, whereas those with TBSA < 20% with inhalational injury more frequently undergo delayed tracheostomy. Although TBSA appears to impact timing of tracheostomy, evidence based guidelines are lacking to guide clinical practice and additional studies are needed.Survey results infer practice patterns favoring consideration toward early tracheostomy for patients with >20% TBSA burns requiring prolonged mechanical ventilation."}
+{"text": "This multi-organ analysis of therapy-resistant melanoma presents preliminary insights with potential to improve therapeutic strategies.Metastasis and failure of present-day therapies represent the most common causes of mortality in patients with cutaneous melanoma. To identify the underlying genetic and transcriptomic landscapes, in this study we analyzed multi-organ metastases and tumor-adjacent tissues from 11 rapid autopsies after treatment with MAPK inhibitor (MAPKi) and/or immune checkpoint blockade (ICB) and death due to acquired resistance. Either treatment elicits shared genetic alterations that suggest immune-evasive, cross-therapy resistance mechanisms. Large, non-clustered deletions, inversions and inter-chromosomal translocations dominate rearrangements. Analyzing data from separate melanoma cohorts including 345 therapy-naive patients and 35 patients with patient-matched pre-treatment and post-acquired resistance tumor samples, we performed cross-cohort analyses to identify MAPKi and ICB as respective contributors to gene amplifications and deletions enriched in autopsy versus therapy-naive tumors. In the autopsy cohort, private/late mutations and structural variants display shifted mutational and rearrangement signatures, with MAPKi specifically selecting for signatures of defective homologous-recombination, mismatch and base-excision repair. Transcriptomic signatures and crosstalks with tumor-adjacent macroenvironments nominated organ-specific adaptive pathways. An immune-desert, CD8 Genomic analyses in a rapid autopsy cohort study of patients with melanoma identify the genetic and transcriptomic landscape of melanoma with acquired resistance to MAPK inhibitor and immune checkpoint blockade therapies, providing insights for the potential improvement of therapeutic strategies. Mutually exclusive BRAF and NRAS mutations drive MAPK addiction in ~70% of metastatic CM3. CM genomes also harbor a high burden of structural variants (SVs)4 and chromothripsis5. Current knowledge of this mutational landscape is derived from tumors naive to highly active treatments developed recently and inclusive of earlier-stage disease. How MAPK inhibitor (MAPKi)/immune checkpoint blockade (ICB) therapies alter the mutational landscape and, thereby, cause death remains largely unknown.Cutaneous melanoma (CM) exhibits a UV-related high mutational burden6, and CM is among the most metastatic (>60% of autopsies with brain metastases)8. Despite experimental metastasis studies, the difficulty of accessing patient-derived metastatic tissues has limited understanding of clinical metastatic and organ-specific evolution. Although the concept of an organ-specific pre-metastatic niche has been demonstrated experimentally9, little is known clinically regarding co-adaptations between metastases and their site-specific macroenvironments.Metastases cause most cancer-related deaths18. Metastases to accessible anatomic sites overrepresent current datasets on acquired resistance. Monitoring  and therapeutic strategies to counter resistance require insights into multi-organ mechanisms and heterogeneity. Whole-exome sequencing (WES) and whole-genome sequencing (WGS) can characterize patterns termed \u2018mutational signatures\u2019 that reflect imprints of DNA mutagenic processes and defective DNA damage repair processes20. It is unknown whether rare signatures of a particular malignancy, such as UV-related CM, are common with respect to late mutations, potentially due to the influence of a particular therapy. Such signatures that emerge later during tumor evolution might represent targetable pathway defects or synthetic lethalities.Although MAPKi/ICB have become standard-of-care therapies for patients with metastatic CM in developed countries, clinical relapse occurs commonly, with multi-therapy resistance being highly lethal. Acquired MAPKi resistance in CM has been evaluated at an omics scale in a few cohorts, but knowledge of clinically acquired ICB resistance is limitedBRAFMUT or NRASMUT CM who were treated with and responded initially to MAPKi/ICB therapies but later died because of disease progression. This cohort includes 71 distinct metastatic tumors, 41 tumor-adjacent \u2018normal\u2019 (AN) tissues representing organ-specific tumor macroenvironments and 38 tumor-non-adjacent normal (NAN) tissues. We generated and analyzed WES from tumors and patient-matched NANs as well as WGS from a subset. To dissect the contribution of distinct therapies, we comparatively analyzed WES data from longitudinal pre- and post- tumors from patients with CM who had progressed on either MAPKi-only or ICB-only therapy. Moreover, we developed organ-specific metastatic signatures based on tumorcell-enriched transcriptomes and analyzed ligand\u2013receptor signaling between tumor and AN tissues. Finally, we deconvolved tumor, AN and NAN transcriptomes to decipher organ-specific immune contextures.Hence, we assembled a rapid autopsy melanoma (RAM) cohort from patients with BRAFMUT and four NRASMUT; five of 11 with radiation-treated brain metastasis)  patient-matched pre and post tumors with MAPKi-only or ICB-only treatments  tumor, AN (\u22641\u2009cm from tumor border) and NAN (>1\u2009cm) tissues from deceased patients , ACTA1 (66%) and TERT (42%); deleted regions harbored IFN cluster genes and CDKN2A/B (51%), B2M and SPRED1 (45%), BRCA1 (41%) and JAK2 and CD274 (35%)  was 4,401  and 68.8 mutations per megabase (Mb)   frequencies with Fisher\u2019s exact test, we detected 571 significantly amplified and 132 significantly deleted genes in the RAM cohort     Fig. . In contst) Fig. . Thus, aP\u2009<\u20090.05 cutoff) called 110 SMGs. Among these, we nominated 62 SMGs  tumors  were previously reported as SMGs  Fig. . To circons Fig. . ConsistMGs Fig. .BRAF displayed a mean ratio of variant-to-normal allelic frequency of 1.87  were affected by both deletions and mutations. Among B2M-mutated tumors, 100% harbored bi-allelic loss-of-function alterations (deletion of one and mutation of another copy) , we found enrichment of ID1 and ID7 signatures among B2M-mutated tumors  Fig. . Becauseors Fig. , suggestBRAF, MNX1, EZH2, XRCC2 and ACTA, and truncal deletions involved JAK2 and CDKN2A  preceded B2M IDs , SBS31 (platinum treatment) and SBS87 (thiopurine treatment) among late mutations in most patients. SBS11 (temozolomide) was detected among late somatic mutations in association with ICB treatment  consisting of pre-treatment and acquired-resistant tumors ) (Supplementary Table BRAFMUT or NRASMUT cohort (29 tumors from eight models) consisting of model-matched vehicle-treated and acquired-resistant tumors derived in patient sex-matched NSG mice  a clinical 4. We first classified SV/rearrangements as clustered or non-clustered25 and found 67% as non-clustered translocations, 17% as non-clustered deletions and 13% as non-clustered inversions. Rearrangement signature (RS) 2 (ref. 24), defined by large (>100\u2009kb) non-clustered deletions, inversions and inter-chromosomal translocations, was most frequent, regardless of case, site or treatment  increased among intermediate (versus early) SVs; and (3) the frequencies of RS2 increased among late SVs  from a subset of RAM tumors   repair mechanisms, we analyzed the breakpoint-junctional sequences of early Fig. , intermeCDKN2A (52%), PTEN (38%) and BRCA1 (~29%)  SVs involving SMAD4. Notably, MAPKi-only or MAPKi+ICB tumors harbored recurrent deletions in MMR genes . Finally, we identified BRAF amplification via intrachromosomal complex genomic rearrangements and extrachromosomal DNAs in association with MAPKi treatment  Fig. . Notably9%) Fig. . Second,ent Fig. .P\u2009=\u20090.0082) higher with MAPKi-only and MAPKi+ICB treatments . Finally, we assessed the temporality of HRR and MMR alterations. Early nonsense BRCA2 mutations occurred in RAM19005 (ICB-only), and intermediate SV-associated BRCA1 deletions occurred in RAM14006 (MAPKi+ICB), which may explain RS5 enrichment , potentially contributing to MMR SBS signatures   and tumor-to-AN (GH1 and AVP) axes. Lastly, immunofluorescence studies confirmed IFN\u03ba expression preferentially in the AN of brain metastases, IFNAR2 intratumorally and their overlap intratumorally  Fig. , EPO andlly Fig. .Fig. 5Or29 via unsupervised clustering revealed immune macroenvironments, more than TIMEs, as organ-specific or patient-specific  of the same archetype in TCGA\u2013SKCM tumors29, 30% of which belong to two immune archetypes: T cell-centric macrophage biased and T cell-centric dendritic cell biased29. These and the immune-rich CD8+ or CD4+ archetypes were all but absent in our RAM cohort. Interestingly, ~5% of liver TIMEs comprised the myeloid-centric, cDC2-biased archetype (associated with tumor fibrosis).We next evaluated organ-specific (intra)tumor immune microenvironments (TIMEs) and immune macroenvironments (within AN and NAN tissues). Analysis of 12 pan-cancer immune archetypesfic Fig. . We thenfic Fig. . AN and CCL8  with patient-matched pre-treatment tumors, we resolved further how each therapy distinctly and convergently shapes the high mutational, CNA and SV burdens of acquired-resistant CM. SMGs and genes altered by CNAs and SVs enrich in immune-evasive processes  and by RAM\u2019s relatively small sample size, which may contribute to false-positive SMGs. We mitigated false positives by requiring SMGs to display gene expression and by analyzing validation cohorts. Future RAM studies should expand the current cohort size and increase representation of CM subtypes, ethnic and ancestral diversities and the treatment-naive landscape.31. Melanoma brain metastasis (MBM) displays signatures of IFN signaling, oxidative phosphorylation and PI3K-AKT signaling32. The brain-specific macroenvironment appears to be a predominant source of IFN ligands. Overall, RAM tumors, including MBM, strongly display an immune-desert but CD8+-macrophage-biased archetype with enrichment of T-cell exhaustion. For MBM, loss of antigen presentation and enrichment of type-2 immunity suggest TGF\u03b2 blockade and upregulation of cytotoxic natural killer (NK) cell-mediated or CD4+ T cell-mediated anti-tumor immunity33 as potential therapeutic strategies. The pro-tumorigenic TAM phenotype of MBM also suggests therapeutic co-targets. Thus, we have uncovered a preliminary set of organ-specific metastatic signatures, tumor macroenvironment crosstalks and immune contextures that characterize therapy-resistant CM, justifying expanded RAM-based and functional analyses.Our analysis, by computationally depleting bulk metastatic tumor transcriptomes of patient-matched and organ-matched normal tissue-derived transcriptomes, sheds light on organ-specific metastatic signatures. Liver and spleen metastases display neural differentiation, suggesting therapeutic targetsBRAF or NRAS mutant allele frequencies .We performed warm autopsies with informed consent at the University of North Carolina at Chapel Hill and the University of California, Los Angeles (UCLA). In brief, patients or persons holding the healthcare power of attorney signed the Autopsy Authorization Form and the institution-specific tumor tissue procurement and banking consent form. Research in this study involving autopsy specimens does not meet the regulatory definition of human subject research. The last tissue sample of each case was excised and stored no longer than 6\u2009hours from death. We collected metastatic tumor, AN (\u22641\u2009cm away from tumor border) and NAN (>1\u2009cm) tissues from 11 RAM cases. We collected formalin-fixed, paraffin-embedded (FFPE) tissues from all available sites. If tissue was sufficient, we also collected snap-frozen tissues and stored them at \u221280\u2009\u00b0C. An autopsy pathologist (Leigh B. Thorne) reviewed hematoxylin and eosin tissue sections. Histopathologic analysis selected for high tumor content and against necrosis, AN with \u226410% tumor cell contamination and NAN without tumor cell contamination. We further selected for tumor purity >30% based on Sanger-sequencing-estimated BRAFMUT CM obtained before treatments with and responses to MAPKi and then at the time of disease progression , along with patient-matched normal tissues (Supplementary Table BRAFMUT or NRASMUT CM) treated with vehicle or trametinib (at sufficient in vivo doses to induce tumor regression) in NSG mice /2, and we excluded data from occasional animals that died before final analysis. We assigned tumors with volumes ~500\u2009mm3 randomly into experimental groups. A special mouse chow (Test Diet) incorporated trametinib (LC Laboratories) to achieve daily dosing at 5\u2009mg/kg/day.To develop PDX models, tumor fragments derived from metastatic CM, with approval by UCLA institutional review boards and the UCLA Animal Research Committee, were transplanted subcutaneously in sex-matched NSG mice (4\u20136\u2009weeks old) from the UCLA vivarium or Jackson Laboratory. We conducted all animal experiments in accordance with approved protocol and regulations (ARC 2016-086). We adhered to the maximal tumor size for experimental endpoints, which was ~1,500\u20132,000\u2009mmWe extracted gDNAs from snap-frozen tumors, NANs and ANs using the QIAGEN AllPrep DNA/RNA Mini Kit; from FFPE tumors  using the QIAGEN QIAamp DNA FFPE Tissue Kit; and from frozen blood using the QIAGEN FlexiGene DNA Kit. Quantification of gDNAs was based on NanoDrop (Thermo Fisher Scientific) and/or Qubit fluorometer using the Qubit dsDNA Broad Range (BR) Assay Kit (Life Technologies). Size and quality of gDNAs were based on TapeStation (Agilent Technologies) and/or agarose gel electrophoresis to ensure gDNA library preparation from equal gDNA input and from intact high-molecular-weight gDNA. We prepared whole-exome libraries using the Roche NimbleGen Exon-Seq Kit, the Roche NimbleGen SeqCap Kit or the Roche KAPA HyperPlus Library Preparation Kit with KAPA HyperCap Workflow version 3.0 for exome hybridization (Supplementary Table 200\u2009>\u200970%) and 100\u2009ng of RNA for medium-quality and low-quality RNA (DV200\u2009<\u200970%). After RNA fragmentation and cDNAs synthesis, we purified dscDNAs using AMPure XP beads (Beckman Coulter). After A-tailed enrichment, we quantified cDNA libraries by the Qubit dsDNA HS Assay Kits (Thermo Fisher Scientific); quality was assessed by TapeStation. We used 200\u2009ng of each DNA library for exome enrichment. After amplification and purification, we removed free adapters by using Illumina Free Adapter Blocking Reagent (Illumina). All libraries were pooled at equal molar and sequenced with a 2\u2009\u00d7\u2009150-bp read length on the Illumina NovaSeq 6000 S4 platform.We extracted total RNAs from snap-frozen tissues using the QIAGEN AllPrep DNA/RNA Mini Kit and the Ambion mirVana miRNA Isolation Kit. Total RNA quantification was based on the Qubit RNA High Sensitivity (HS) Assay Kit (Thermo Fisher Scientific) and/or a NanoDrop (Thermo Fisher Scientific). RNA quality was based on TapeStation (Agilent Technologies) and used to calculate the input for RNA library preparation. We prepared RNA libraries using KAPA RNA HyperPrep Kit with RiboErase (Roche) or TruSeq RNA Exome Kit (Illumina), TruSeq RNA Single Indexes Set A Kit (Illumina) and TruSeq RNA Single Indexes Set B Kit (Illumina) following the manufacturers\u2019 protocols  and VarScan2 . SNV/IDs were supported by at least five reads in the tumor samples and none in the patient-matched normal tissues. Somatic SNV/IDs were then annotated by Oncotator36. Finally, we used Sequenza37 to detect tumor purity, ploidy, somatic CNAs and loss-of-heterozygosity regions.We used BWA for mapping and Picard for removal of duplications. We identified somatic SNVs and IDs of tumors38) to identify the significantly deleted and amplified regions using each RAM tumor\u2019s copy number segmentation file as the input. We generated circos plots with both q values and G-scores representing the amplitude of the aberration. Only regions with q values less than 0.05 were defined as significantly altered regions. We performed Fisher\u2019s exact test to identify differentially amplified or deleted genes in the RAM tumor cohort versus the BRAF or NRAS mutated TCGA\u2013SKCM cohort . We downloaded TCGA\u2013SKCM CNA data from cBioPortal and compiled the frequencies of CNA genes (Supplementary Table P\u2009<\u20090.05 and a higher frequency in RAM (versus TCGA\u2013SKCM) cohort.We applied GISTIC2.0  versus pre-treatment melanoma by using Fisher\u2019s exact test. When multiple post tumors were available from a given patient, they were considered as an entirety, and an amplified or deleted gene was counted in this patient if it was identified from at least one of the post tumors. Multiple pre-treatment tumors from one patient were also counted as an entirety. We nominated a post-enriched amplified or deleted gene if its frequency is higher in post (versus pre) tumors and the FDR-adjusted An amplified or deleted gene enriched in acquired ICB resistance was defined by its amplification or deletion frequency in the post tumors being >2\u00d7 that in the pre tumors and by its detection in \u22652 patients\u2019 post tumors.39 and identified by MutSig2CV genes at P\u2009<\u20090.05. To reduce false positives, we nominated SMGs by filtering for RNA expression. Based on the mean values of normalized expression levels (log2 counts per million (CPM)) of RAM tumors, we annotated MutSig2CV SMGs as no expression (mean log2CPM\u2009<\u20090), expressed (0\u2009\u2264\u2009mean log2CPM\u2009<\u20094) or highly expressed (mean log2CPM\u2009>\u20094) and excluded those with no expression. We performed Fisher\u2019s exact test to compare the patient-level frequency of each SMG in the RAM versus TCGA\u2013SKCM cohorts and used the FDR approach to adjust the P values. We then performed GO enrichment analysis with the clusterProfiler package to detect the significant biological processes for expressed SMGs. Moreover, we identified SMGs with MutSig2CV for post tumors from patients with MAPKi-only or ICB-only treatments by using each patient\u2019s mutational profile of post tumor(s) as input and each patient (not each post tumor) as an identifier. For patients with multiple post tumors, a mutation was considered to exist in this patient if it was detected in \u22651 tumor. We defined post/acquired-resistant SMGs as genes identified by MutSig2CV at P\u2009<\u20090.05 in the post tumors and not identified in the patient-matched pre tumor(s).We applied MutSig2CV to identify SMGs using each RAM case\u2019s mutational profile as the input and each RAM case (not each tumor sample) as an identifier. A mutation exists in a given RAM case if it was identified in \u22651 tumor. To circumvent the limitation of a small sample size, we inflated type I error by not performing multiple testing35 and annotated each tree with potential drivers of tumorigenesis and/or resistance. All tumors in each case shared early somatic SNVs; a subset shared intermediate SNVs; and late SNVs were unique to one tumor. The contribution of each mutational type and mutational signature was then determined for early, intermediate and late mutations through the R package deconstructSigs40 with COSMIC SBS signatures version 3.3 as reference. For the pre and post MAPKi-only and ICB-only cohorts, we identified mutations unique to post tumors per patient, which were then subjected to mutational signature analysis. We used the R package MutationalPatterns with COSMIC ID signatures version 3.3 as reference to determine ID signatures underlying all identified B2M IDs.We performed phylogenetic analysis using the PHYLIP program with the parsimony algorithm41 and assessed each mutation\u2019s cancer cell fraction (CCF). Mutations were clonal if the CCF approaches 1; otherwise, mutations were subclonal. The ratio of subclonal mutations to all mutations determined ITH. We determined preferentially mutated genes for each organ as follows: (1) selected for non-synonymous mutations; (2) calculated \u0394CCF  versus tumors of other organs ; (3) identified organ-specific enriched mutations with a \u0394CCF of >0.2 for each RAM case; and (4) defined a gene as \u2018preferentially mutated genes\u2019 of organ A when organ-A-enriched mutations in this gene occurred in \u22653 patients.We conducted a subclonal analysis for each RAM case using PyClone-VI42. SAMtools43 sorted alignments and removed PCR duplicates. CNVkit44 with default parameters called CNVs. SVs were concordant by two or more of three methods: SvABA45, TIDDIT46 and DELLY47. For high-coverage data (>15\u00d7), we used default parameters. The parameter minimum number of points (-l) was set to 5 in TIDDIT for low-coverage data. SVs detected in matched-normal genomes were removed from the tumor samples to infer somatic SVs. We estimated rearrangement signatures based on a previous classification26. For RAM cases with \u22652 tumors, we computed early, intermediate (only feasible with RAM12.01 and RAM14006) and late somatic SVs. For each case, early and late somatic SVs consisted of SVs common to all tumors and unique to each tumor, respectively, and the rest were classified as intermediate. We carried out breakpoint junctional sequence analysis by examining the presence of homologous sequences. Homologous sequences with 0\u20131\u2009bp, 2\u20136\u2009bp and >6\u2009bp were attributed to NHEJ, alternative NHEJ (microhomologous end joining) and HRR, respectively. Genes overlapping with somatic SVs were annotated using AnnotSV48. We performed pathway enrichment analysis using the Molecular Signatures Database (MSigDB)49 with pathway datasets listed in KEGG, Reactome and Pathway Interaction databases.We mapped WGS reads to GRCh38/hg38 human reference genome using BWA-MEM50. In brief, we determined the list of potential intervals for each amplicon, for which copy numbers and SVs were estimated using read depth and discordant read signatures. It then constructed a breakpoint graph. Simple cycles were then decomposed from the breakpoint graphs and amplicons classified into ecDNAs, CGRs and linear amplicons. We used CNVKit to infer the initial set of CNV seed regions. SV view of amplicons was generated using functions available in AmpliconArchitect.Focal amplicon identification and elucidation of circular extrachromosomal DNAs (ecDNAs) and complex genomic rearrangements (CGRs) using WGS data were carried out by AmpliconArchitect51) with default parameters and then subjected to mutational and ID signature analyses using the R package deconstructSigs40 and MutationalPatterns52, respectively, with COSMIC SBS/ID signatures version 3.3 as reference. Classification of early, intermediate and late somatic SNVs was in accordance with that for WES-based mutations.Somatic SNVs and IDs were identified using Strelka2  using the prcomp function in R package stats to visualize the clustering of samples.We analyzed single-end and paired-end RNA-seq data55. For RAM tumors, we performed single-sample gene set enrichment analysis (GSEA) to generate the enrichment scores of the organ-matched normal organ-specific gene signature. CPM values were input into the gene set variation analysis (GSVA) program using the default \u2018kcdf=Gaussian\u2019 option.We first used the DESeq2 package to detect DEGs between NANs from one specific organ versus other organs. We defined organ-specific normal gene signatures as the top five significantly upregulated genes, all of which were confirmed to display organ-specific expression in the human protein atlas2-transformed expression fold change metrics (log2FC). We calculated the enrichment nominal P values by permutation test , with Benjamini\u2013Hochberg FDR correction for multiple testing. We then performed GSEA to identify the DGSs for both tumors and NANs of one organ versus other organs. We defined normal-corrected DGSs (NC-DGSs) in tumors of organ A as those DGSs detected in the tumors of organ A (versus other organs) but not in the NAN compartment of organ A (versus other organs).GSEA via the fgsea package used the human hallmark (H) gene sets (MSigDB). Genes were pre-ordered by the logA versus TB) were corrected for expression of the same genes between the normal tissue pair of the same two organs . We calculated normal-corrected fold change (NC-FC) of each gene between TA versus TB as the FC of this gene between TA versus TB divided by the FC of this gene between NA versus NB. We defined the genes with NC-FC\u2009>\u20092 or NC-FC\u2009<\u20090.5 as the upregulated or downregulated NC-DEGs between these two organs. We then computed the recurrence (\u226530%) of NC-DEGs by collecting NC-DEGs of tumors from one specific organ against all other tumors from other organs of the same RAM case across all RAM cases. GO enrichment analysis via the \u2018clusterProfiler\u2019 package56 identified the top five significant GO biological processes for recurrently upregulated or downregulated NC-DEGs of each organ-specific metastasis.To filter out normal tissue-specific DEGs from bulk tumor transcriptomes, we used RNA-seq derived from each tumor\u2019s organ-matched NANs and public datasets of normal organ/tissue gene expressions from the Illumina Human Body Map and GTEx. DEGs between a tumor pair from two organs  of TCGA\u2013SKCM RNA-seq (inclusive of only BRAF or NRAS mutant tumors) from cBioPortal. CIBERSORTx estimated the absolute abundance of 22 immune cell types with the normalized expression level as an input. We calculated the enrichment scores of two signatures, \u2018T cell exhaustion\u2019 and \u2018type 2 immunity\u201933, by GSVA using the default \u2018kcdf=Gaussian\u2019 option.We performed single-sample GSEA to generate the absolute enrichment scores of the 12 immune archetypes for each tissue, using CPM values of all expressed genes as input for GSVAFFPE RAM tissue sections were heated at 90\u2009\u00b0C for 25\u2009minutes and immersed in xylene and gradient ethanol to achieve deparaffinization and re-hydration. Then, tissue sections were subjected to heat at 95\u2009\u00b0C 10\u2009mM citrate buffer (pH 6.0) for 15\u2009minutes to retrieve antigens. After permeabilization and blocking with 0.1% Triton X-100/10% normal goat serum in PBS for 1\u2009hour, tissue sections were incubated with primary antibodies, including anti-GRIK4 , anti-GRIN1 , anti-GABRG1 , anti-GABRA2 , anti-IFN\u03ba  and anti-IFNAR2 , at 4\u2009\u00b0C overnight. Visualization was achieved with goat anti-mouse IgG highly cross-absorbed secondary antibody, Alexa Fluor Plus 488  or goat anti-rabbit IgG highly cross-absorbed secondary antibody, Alexa Fluor 555 , and nuclei were counterstained by DAPI . We captured images on a Leica confocal SP8-STED/FLIM/FCS microscope.Using Ventana Discovery Ultra (Roche) and Opal fluorophores (Akoya Biosciences), we deparaffinized 5-\u00b5m-thick tissue sections using EZ-Prep reagent (Roche) and retrieved antigens in CC1 buffer . Discovery Inhibitor (Roche) was applied to inhibit enzymatic activities, followed by six sequential rounds of staining. Each round included the addition of a primary antibody followed by secondary antibody detection using either OmniMap anti-Ms HRP  for mouse or OmniMap anti-Rb-HRP  for rabbit following the manufacturer\u2019s specifications. We amplified signals by using Opal fluorophores at 1:400. Between rounds of staining, the tissue sections underwent heat-induced epitope retrieval to remove the primary/secondary-HRP antibody complexes before staining with the subsequent antibody. The primary antibodies and corresponding fluorophores are anti-MRT-1  in Opal 480; anti-iNOS  in Opal 520; anti-CD68  in Opal 570; anti-CD163  in Opal 620; anti-CD206  in Opal 690 and anti-SOX10  in Opal 780. We counterstained nuclei with Spectral DAPI  and mounted the stained tissues with ProLong Diamond Antifade mounting medium (Thermo Fisher Scientific). Subsequently, we imaged stained tissues (\u00d720) using the Vectra Polaris imaging system (Akoya Biosciences). After image capture, unmixing of the spectral libraries was performed with inForm software (Akoya Biosciences). Unmixed images were then imported into HALO (Indica Labs) for stitching, cell segmentation and cell phenotyping. We analyzed whole tumor regions from each slide. Data were exported and graphed with Prism (GraphPad). Representative images were exported from HALO after spectral unmixing.We conducted statistical analyses in R 4.02, Python 3.8.0, Python 2.7.17 and Prism.Further information on research design is available in the Any methods, additional references, Nature Portfolio reporting summaries, source data, extended data, supplementary information, acknowledgements, peer review information; details of author contributions and competing interests; and statements of data and code availability are available at 10.1038/s41591-023-02304-9.Reporting SummarySupplementary TablesBRAFMUT and NRASMUT melanoma from published cutaneous melanoma studies. Table 8. Significantly amplified and deleted regions and genes in the RAM tumor cohort analyzed by GISTIC2.0. Table 9. Significantly amplified and deleted genes in RAM versus TCGA\u2013SKCM (BRAF and NRAS mutated) cohorts: results of two-sided Fisher\u2019s exact test. P values adjusted by FDR. Table 10. SMGs in the RAM cohort identified by MutSig2CV without multiple testing. Table 11. Recurrent somatic translocations. Table 12. Recurrent somatic structure variation-associated genes. Table 13. Mutational status of genes associated with cross-therapy resistance among RAM cases. Table 14. Summary of WES library preparation kits. Table 15. Summary of RNA-seq library preparation kits. Table 16. CNAs of the BRAF and NRAS mutant TCGA\u2013SKCM cohorts .Supplementary Table 1. Clinical information and tissue collection. Table 2. WES data quality, characteristics and availability of sample-matched WGS and/or RNA-seq. Table 3. WGS data quality, characteristics and availability of sample-matched WES and/or RNA-seq. Table 4. RNA-seq data quality and availability of sample-matched WES and/or WGS. Table 5. Clinical information for patient-matched tumors biopsied pre-treatment and at disease progression. Table 6. Clinical information and driver mutations for PDX models. Table 7. TMB of"}
+{"text": "Mycobacterium tuberculosis (MTB) genes, conferring BDQ and CFZ resistance, have been reported that predominantly arose from sporadic mutations that have not been comprehensively characterized. Herein, MTB clinical isolates collected from drug-susceptible (DS)-, multidrug-resistant (MDR)-, and extensively drug-resistant (XDR)-TB patients were cultured in vitro with BDQ or CFZ to generate progeny strains with resistance to these drugs. Progeny strains exposed to CFZ exhibited increased CFZ minimum inhibitory concentrations (MICs) that exceeded MIC increases of BDQ-exposed progeny strains. Notably, mmpR and pepQ mutations accounted for 83% and 17% of BDQ-induced spontaneous gene mutations, respectively, and 86% and 14% of CFZ-induced spontaneous gene mutations, respectively. Analyses of predicted mutation-induced changes in amino acid sequences and structures of MmpR and PepQ mutants revealed several point mutations affected sequence conversation and functionality as an underlying mechanism for observed acquired BDQ/CFZ resistance. Moreover, our results revealed differences in patterns of BDQ- and CFZ-induced acquired spontaneous mutations that may enhance our understanding of MTB BDQ/CFZ-resistance mechanisms.The 2022 World Health Organization guidelines recommend use of two core anti-tuberculosis (TB) drugs, bedaquiline (BDQ) and clofazimine (CFZ), for treatment of drug-resistant (DR)-TB. However, several mutated in vitro with BDQ or CFZ. Results of protein sequence and structural analyses provided insights into potential mechanisms underlying associations between MTB gene mutations and DR phenotypes. Taken together, these results revealed differences in acquired BDQ and CFZ resistance mechanisms as a new perspective that may enhance our understanding of BDQ/CFZ resistance mechanisms and facilitate the development of new methods for detecting MTB drug resistance genes.This study of MTB drug resistance mechanisms revealed patterns of spontaneous MTB mutations associated with acquired BDQ and CFZ resistance that arose after clinical MTB isolates were cultured  Mycobacterium tuberculosis (MTB), remains a major public health issue and one of the leading causes of human deaths worldwide (Tuberculosis (TB), an infectious disease caused by orldwide . Notablyorldwide \u20134. Thein vitro and in vivo (Bedaquiline (BDQ) and clofazimine (CFZ) are core anti-TB drugs recommended by 2022 World Health Organization (WHO) guidelines for the treatment of DR-TB cases, with both drugs predominantly used to treat multidrug-resistant/rifampicin-resistant TB (MDR/RR-TB) . BDQ is  in vivo , 9. In f in vivo \u201313. Fu in vivo , 15. BasatpE (Rv1305), mmpR (Rv0678), and pepQ (Rv2535c) have been associated with phenotypic resistance to BDQ, while mutations of the latter two genes have been implicated in cross-resistance to CFZ and BDQ -, MDR-, and XDR-TB strains according to the pre-2021 WHO definition . UltimatThe resazurin microtiter assay (REMA) was conducted to determine BDQ and CFZ minimal inhibitory concentrations (MICs) for the abovementioned clinical MTB strains . ConcentWe further adapted the method of Ismail et al. to generate spontaneous mutants of clinical strains . BrieflyatpE, mmpR, and pepQ were amplified and sequenced for BDQ-treated progeny strains and corresponding parent strains, while coding regions of mmpR, pepQ, and Rv1979c were amplified and sequenced for CFZ-treated progeny strains and corresponding parent strains. Each PCR was performed in a final volume of 50 \u00b5L containing 5 \u00b5L PCR buffer, 2 mM MgCl2, 200 \u00b5M of each dNTP, 0.2 \u00b5M of each primer set, and 1 U HotStar Taq polymerase (Qiagen). Amplified products were sent to the Tsingke Company  for DNA sequence analysis. DNA sequences were aligned to corresponding sequences of the standard laboratory MTB strain H37Rv using BioEdit Sequence Alignment Editor version 7.1 (https://bioedit.software.informer.com/7.1/).Genomic DNA extraction and sequencing were performed using DNA sequencing and amplification primers as reported previously . Coding Mycobacterium tuberculosis McSpoligotyping Kit  as described in previous studies (http://www.pasteur-guadeloupe.fr:8081/SITVIT2/submit.jsp) and used to assign spoligotype international types and corresponding clades to our MTB isolates.Genotyping of MTB was performed using a MeltPro  studies . Each amhttps://www.uniprot.org/blast/) to find orthologs of MmpR and PepQ. Sequence alignment was performed using ClustalO (https://swissmodel.expasy.org/var3d/).We first performed BLAST against the UniProt database , and templates were obtained from Protein Data Bank (PDB) (https://www.rcsb.org/) and AlphaFold Protein Structure Database . Templates used to model mutant MmpR and PepQ proteins included PDB file 4NB5 and AlphaFold file AF-I6YDN6-F1, respectively, while the PDB file 1Z9C template was used to model the MmpR-DNA complex.Structures of mutant proteins were modeled using SWISS-MODEL  were randomly selected to serve as parent strains, with MIC values of the 30 parent strains shown in After 4 wk of culture, progeny strains treated with BDQ or CFZ were harvested and analyzed; BDQ-treated strains could only be obtained from plates with 0.125 \u00b5g/mL BDQ , not from plates with 0.25 \u00b5g/mL BDQ . Ultimately, progeny strains were obtained from nine parent strains (30%) that included four DS strains , two MDR strains (MDR-7 and MDR-8), and three XDR strains . After CFZ treatment, 21 parent strains (70%) yielded progeny strains that grew on plates containing 0.5 \u00b5g/mL CFZ , while 11 parent strains (37%) yielded progeny strains that grew on plates containing 1 \u00b5g/mL CFZ . The 21 parent strains that yielded progeny strains when cultured on CFZ plates included seven DS strains , seven MDR strains (MDR-1 to MDR-4 and MDR-7 to MDR-9), and seven XDR strains . Notably, six parent strains  yielded progeny strains when cultured on both BDQ plates and CFZ plates .mmpR, pepQ, and atpE genes. Of the remaining 12 progeny strains, 10 strains (83%) possessed mutations within mmpR and 2 strains (17%) possessed mutations within pepQ, while no atpE mutation was detected. Analysis of these mutations  indicated that they would induce nine different types of amino acid sequence alterations  possessed mmpR mutations and 3 strains (14%) possessed pepQ mutations. Analysis of strains with mutations within sequenced regions of atpE, pepQ, and mmpR revealed a total of 21 distinct types of amino acid sequence-altering mutations that included 12 point mutations, 5 frameshift mutations, 1 insertion, and 3 stop codon-generating mutations  was randomly selected for culture by taking one progeny strain colony from each plate. During the culturing of progeny strains, four strains were excluded due to contamination, yielding 42 progeny strains that were subjected to further analyses. Of these, 20 progeny strains lacked utations . For CFZMmpR is a transcriptional repressor of MmpL5 and MmpS5, whereby mutations that inactivate MmpR may lead to increased MmpL5 and MmpS5 levels and elevated CFZ and BDQ MICs . To evalThe function of PepQ is still unclear. However, BLAST results revealed that the PepQ L316 residue was highly conserved. Meanwhile, the PepQ mutation that induced the L316R substitution markedly reduced the PROVEAN score to below \u22122.282 as an indication that this mutation reduced the similarity between the mutant MTB PepQ sequence and sequences of MTB PepQ orthologs. Moreover, predicted free energy changes  suggested that this amino acid substitution would potentially cause structural instability of PepQ, as consistent with results of a detailed structural analysis suggesting that the PepQ L316R substitution led to loss of hydrophobic interaction(s) . Taken tin vitro experiments to generate progeny strains with increased BDQ and/or CFZ resistance that were derived from DS, MDR, and XDR-TB clinical isolates (parent strains). Subsequent sequencing of coding regions of several genes associated with progeny strain phenotypic resistance to these drugs resulted in the identification of novel gene mutations. Results of analyses of predicted amino acid sequence and protein structural changes induced by detected BDQ/CFZ-induced mmpR and pepQ mutations revealed potential impacts of these point mutations on MTB phenotypic expression of BDQ and/or CFZ resistance.In the present study, we performed in vitro-induced BDQ and CFZ resistance and strains with BDQ/CFZ resistance acquired in vivo during MTB infection of mice  exhibited a fold change in CFZ MIC (relative to that of the parent strain) that was greater than that observed for its corresponding BDQ MIC.Results of previous studies have confirmed that phenotypic cross-resistance between BDQ and CFZ can occur in clinical MTB isolates with resistance to these drugs, including MTB strains with  of mice , 24, 40.mmpR, pepQ, and atpE, as consistent with results of previous studies (mmpR mutations accounted for the highest proportion of detected mutations (83%), while the remaining mutations (17%) were detected within pepQ. Importantly, we did not identify any mutations within atpE, as consistent with results of previously reported studies showing that such mutations were infrequently detected in clinical samples  of BDQ-resistant strains and 97% (93/96) of CFZ-resistant strains harbored mmpR mutations (mmpR gene (71\u201380%)  were located within the MmpR DNA-binding domain (residues 32\u201397), thus indicating this domain is a potential hotspot where drug resistance-induced amino acid changes with low fitness costs are frequently found. Similarly, results described in a recent systematic review of mutations associated with BDQ and CFZ resistance revealed that amino acid sequence changes resulting from BDQ/CFZ-induced mmpR mutations occurred most frequently within three MmpR DNA-binding domain regions   and 20 CFZ-treated progeny strains 48%) harbored no gene mutations in sequenced regions of  studies \u201343. Th samples , 44. Meautations , 45. Sim(71\u201380%) , 46, 47.% harborein vitro drug treatments of our clinical isolates may have remained undetected. Nevertheless, parent strains studied herein were derived from clinical isolates and thus were more closely related to clinically relevant organisms than standard laboratory strains. However, previously reported Q76*, G78A, and F93S MmpR mutants (in vitro is a dynamic process, such that mmpR mutation-induced acquisition of low-level BDQ resistance may be an initial transient, but required, step for subsequent acquisition of high-level BDQ resistance through mutation of atpE (The most important limitation of the present study pertains to the fact that some mutations induced by  mutants , 44, 47, of atpE . Nonethe"}
+{"text": "A\u00a065-year-old male was admitted to the hospital to further investigate broad complex tachycardia. Coronary heart disease was excluded previously. Subsequent cardiac magnetic resonance imaging revealed the typical picture of cardiac sarcoidosis and additional lung involvement in computed tomography (CT) scan. Left ventricular ejection fraction was preserved LVEF 52%) and right ventricular ejection function was impaired RVEF 32%). The transbronchial biopsy confirmed numerous granulomas containing giant cells without caseating necrosis in the lung parenchyma. In accordance, fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT)-imaging Fig.\u00a0 showed b% and rig2%. The t"}
+{"text": "Enterococcus faecium (VRE) depends on reliable detection methods. In this study we investigated if metagenomic sequencing enhances our understanding of VRE gut colonization in addition to selective culture.Investigation of the colonization dynamics of vancomycin resistant We performed metagenomic sequence analysis on 48 stool and rectal swab samples from 15 medical intensive care unit (MICU) patients with dynamic VRE colonization patterns by selective culture. After metagenomic sequences were quality-filtered, trimmed and human sequences were removed, the antimicrobial resistance (AMR) genes were identified using AMR++ v3.0 and the AMR database MEGARes v3.0.Microbial sequencing depth varied between samples due to low total DNA and varied percentage of human DNA . We obtained a median of 1.4 million microbial sequence reads/sample (IQR: 0.6 - 6.0 million). Vancomycin resistance gene cluster sequences (Van-type genes) were detected in the metagenomes of 14 samples. There was agreement between VRE-status as by selective culture and detection of Van-type gene sequence in 33/48 samples. 12 samples that were VRE positive by culture did not have Van-type genes detected in the metagenome, possibly due to lower microbial sequencing depth  compared to samples with Van-type genes detected .Three VRE culture-negative samples had Van-type genes detected. 2 of these contained the same Van-type genes found in other samples from the same subject, suggesting that they represent actual VRE colonization. In another patient, 2 VRE culture-positive samples collected 15 days apart had the same 11 VanA-type gene sequences, suggesting the same VRE strain was present in both samples.Metagenomic detection of VRE was influenced by microbial sequencing depth, which is related to total sequencing depth and percentage of host reads. Greater sequencing depth may improve sensitivity of metagenomics to detect resistant organisms. Longitudinal analysis of antimicrobial resistance gene sequences from metagenomes has the potential to provide insight on colonization dynamics.Vincent B. Young, MD, PhD, ASM: Senior Editor for mSphere Journal|Debiopharm: Consultant|mSphere: Senior Editor|Vendanta Biosciences: Consultant"}
+{"text": "Staphylococcus aureus outbreaks in the neonatal intensive care units (NICU) have been reported with the great majority due to methicillin-resistant Staphylococcus aureus. We describe successful control of an outbreak caused by methicillin-susceptible S. aureus (MSSA) in the NICU.spa typing.We report a MSSA bacteremia outbreak which occurred in the NICU at a tertiary level hospital from November 29, 2020 to January 6, 2021. Molecular typing of MSSA isolates were performed including multi-locus sequence typing (ST) and th case. Infection control measures, including isolation of cases, contact precaution and universal 0.5% chlorhexidine bathing of all NICU patients, were implemented. Surveillance cultures of patients (n=36) and health care workers (HCW) (n=60) were performed. Excluding bacteremia patients, 13% (4/31) of neonates and 32% (19/60) of HCW were identified as MSSA nasal carriers and targeted decolonization with intranasal mupirocin was performed. After implementation of control measures and decolonization, there were no new cases. Molecular analysis identified two strains [ST15 spa type t593 (n=3) and ST101 spa type t4171 (n=2)] as the cause of this bacteremia outbreak. Among MSSA nasal carriers, all 4 neonates colonized the ST15 spa t593 strain. ST15 spa t593 strain was also colonized in one HCW, however antibiotic susceptibility pattern differed. The rest of HCWs colonized many different types of MSSA. All MSSA isolates were negative for Panton-Valentine Leucocidin toxin gene.A total of 5 MSSA bacteremia cases occurred in 39 days. Outbreak investigation was initiated after the 5Molecular analysis identified two different MSSA strains in this outbreak. MSSA colonization was prevalent among HCWs, however molecular analysis showed variance in distribution. Although outbreak strains were not found in HCWs, one strain was colonized among other neonates, suggesting horizontal transmission and potential of further cases. The outbreak was successfully controlled with reinforcement of precautions, universal chlorhexidine bathing and surveillance cultures with targeted decolonization. Early recognition and prompt implementation of control measures are important for outbreak control in NICU.All Authors: No reported disclosures"}
+{"text": "The investigational \u03b2-lactam/\u03b2-lactamase inhibitor combination of cefepime (FEP)/enmetazobactam (ENM) met criteria for non-inferiority and superiority compared to piperacillin/tazobactam in a phase 3 clinical trial of adult patients with complicated urinary tract infections (cUTI)/acute pyelonephritis (AP). In this study, a population pharmacokinetic (PK) model is presented that describes FEP and ENM plasma PK in adult cUTI/AP patients.Plasma PK samples were analyzed from participants receiving FEP (n=588) and ENM (n=649) in three phase 1 (n=132), and single phase 2 (n=43) and phase 3 (n=488) clinical trials. Population PK parameters were assessed and the relationship between different covariates and model parameters were investigated. The effect of infection on disposition was assessed by testing disease covariates on fixed and random effects for all PK parameters.A two-compartment model with linear clearance of FEP (5.95 L/h) and ENM (7.68 L/h) from the central compartment best described the PK of both compounds. Common covariates for both compounds were de-indexed estimated glomerular filtration rate (eGFR), age, and body weight while ENM PK covariates also included cUTI infection and sex. Simulations showed that the only covariate requiring dose adjustment was renal function. The final model simultaneously described FEP and ENM plasma PK, which enabled estimates of the correlation of the random effects between PK parameters. Clearances and volumes of distribution (Vd) were strongly correlated within individuals between the two compounds (correlation coefficients >0.9). Variability was higher in cUTI patients although differences in mean ENM or FEP exposures between healthy subjects and cUTI patients were negligible. The total Vd was 16.9 L for FEP and 20.6 L for ENM. Clearance of both agents was found to depend on de-indexed eGFR (covariate coefficients \u22650.83), suggesting that renal filtration is the predominant clearance mechanism. The terminal elimination half-life was 2.2 h for FEP and 2.0 h for ENM.Final population PK model population parameter estimates for cefepime and enmetazobactam determined from the pooled phase 1 to phase 3 clinical studiesThe population PK models for FEP and ENM predict exposures in cUTI patients, including subjects with renal impairment. These models support Monte-Carlo simulations and target attainment estimations in adult cUTI/AP patients.Adam Belley, PhD, Allecra Therapeutics SAS: Advisor/Consultant Patrick Velicitat, MD, Allecra Therapeutics SAS: Salary"}
+{"text": "Life's Simple 7 (LS7) to compare CVH in ART-Naive PLWH and HIV-uninfected adults in Tanzania.People living with HIV (PLWH) have complex cardiovascular health (CVH) profiles due to a combination of traditional, HIV-specific and lifestyle factors. Thorough characterization is necessary to guide primary prevention efforts. Previous studies that evaluated CVH in PLWH were mainly done in those on stable antiretroviral therapy (ART) and data in newly diagnosed PLWH is scarce. Therefore, we applied Life's Simple Seven (LS7) definitions (Table 1) and compared the distribution of LS7 metrics between study groups. Each LS7 was dichotomized as \"ideal\" (1 point) and \"not ideal\" (0 points) to obtain a total LS7 score. Poisson regressions were employed to investigate associations between HIV status and count of ideal total LS7 components (0-7). Logistic regression was employed to investigate individual LS7 metrics. Regressions were adjusted for age, sex, education, income.A cross-sectional analysis was conducted on a cohort of ART-naive PLWH and HIV-uninfected adults recruited from HIV clinics in Mwanza, Tanzania (CICADA cohort). We applied modified Figure 1). This difference remained significant even after adjusting for potential confounding . Distribution of LS7 metrics varied between groups . PLWH were more likely to have ideal BMI , ideal blood pressure  and ideal total cholesterol . By contrast, PLWH were less likely to have ideal smoking , ideal blood glucose .Our study included 1,224 participants . PLWH had higher total LS7 scores  and higher prevalence of ideal overall CVH (40% vs 35%, Life's Simple 7 score. Our findings indicate favorable cardiovascular health in newly diagnosed PLWH, driven by lower rates of metabolic risk factors. However, such patients would still benefit from primary prevention efforts prioritizing smoking cessation, diabetes screening to mitigate remaining CVD risk.Early HIV influences several key determinants of cardiovascular health encompassed in All Authors: No reported disclosures"}
+{"text": "C. difficile colonization among parents caring for an asymptomatically-excreting infant , suggesting infants as a nidus of adult infection. Herein we define the molecular epidemiology of the organisms isolated within these families.We previously reported a high incidence of -month well child visit at a suburban pediatric practice. Soiled diapers were mailed every two weeks for 4 months ) to a research laboratory. Stool was inoculated onto CDBA plates with portions broth- enriched. Simultaneously sent parental diaper wipes were handled identically. C. difficile was identified by colony morphology and GDH assay. Specimens from each family were assessed for relatedness by PCR ribotyping, and Whole Genome Sequencing (WGS) was utilized to determine genetic relatedness of repeatedly excreted organisms over time, both employing methods previously described .Families were enrolled at the baby\u2019s 4> 4 TPs. Prevalence of infant colonization/TP ranged from 50-72%, and cumulatively 90% were positive at least once (median 4 samples positive/subject). Prevalence among mothers was 18-39%/TP  and fathers 20-41%/TP . In 27 families C. difficile was isolated from > 1 member, with all but 1 including the infant. Isolates from 24 families could be ribotyped. In 6 families each member had a non-identical ribotype, in 3 families there was a single identical ribotype, and in 15 families some ribotypes were shared but > 1 member harbored > 1 ribotype. For example, one infant-mother pair shared two different ribotypes, but each harbored 1 additional distinct ribotype. WGS of persistently carried isolates with identical ribotypes from both infants and adults were related, usually exhibiting < 3 SNP differences.30 families (babies and mothers plus 22 fathers) participated, with 25 families submitting specimens at C difficile is prevalent in families caring for infants. Molecular analysis revealed a previously unrecognized complex epidemiology, with most family members sharing at least 1 common strain but frequently accompanied by additional unrelated ribotypes.All Authors: No reported disclosures"}
+{"text": "P = 0.002). Consistently, an elevated ICI response rate was also noticed in the SETBP1-MUT group . The Association of SETBP1 mutations with favorable immunotherapeutic prognosis and response was further supported by an independent NSCLC cohort (both P < 0.05). Additional immunological analyses revealed that favorable immune infiltration, tumor immunogenicity, and immune response circuits were enriched in SETBP1-MUT patients. Overall, our findings suggest that SETBP1 mutations may serve as a new biomarker for stratifying beneficiaries of ICI treatments in melanoma and NSCLC, which provides possible evidence for tailoring clinical immunotherapeutic strategies.SET binding protein 1 (SETBP1) plays crucial roles in various biological processes; however, its involvement in cancer immune checkpoint inhibitor (ICI) treatments has never been studied. In this study, we collected a total of 631 melanoma and 109 non-small cell lung cancer (NSCLC) samples treated with ICI agents . Additionally, we obtained their corresponding somatic mutational profiles. We observed that SETBP1 mutated (SETBP1-MUT) melanoma patients exhibited significantly prolonged ICI survival outcomes compared to wild-type patients (HR: 0.56, 95% CI: 0.38-0.81,  Cancer patients often have a dysfunctional immune system, which can be targeted through the use of distinct immune checkpoint inhibitors (ICI) . ICI trePrevious evidence has demonstrated the critical roles that mutations in a single gene can play in cancer progression, immune regulation, and immune treatment response. For example, Feng et al. curated comprehensive somatic mutational profiles and clinical immunotherapy information from NSCLC patients and found that FAT1 mutations were predictive of favorable tumor immune infiltration and, importantly, better ICI treatment efficacy . ConsistSET binding protein 1 (SETBP1) is an important transcription factor that plays vital roles in multiple biological processes, such as DNA replication. Several previous studies have revealed that SETBP1 drives potential molecular mechanisms in hematologic malignancies. For example, Pacharne et al. reported that the upregulation of SETBP1 promoted FLT3-mutated acute myeloid leukemia . Mutant Cancer immunotherapy is commonly used for two cancer types of melanoma and NSCLC. In this integrated study, we collected genomic mutational data and clinical immune treatment information for both tumor types and performed multi-dimensional immunological analyses. Our findings suggest that SETBP1 mutations could be a promising biomarker in clinical cancer immunotherapies.The detailed work process of this study was shown in P < 0.001; P = 0.002; P = 0.016; P = 0.048; We first explored the ICI prognostic roles of SETBP1 mutations in pooled melanoma patients. Kaplan-Meier results showed that SETBP1 mutated (SETBP1-MUT) melanoma patients exhibited a markedly improved ICI survival benefit than wild-type patients  is recently reported as a hopeful indicator for cancer immunotherapies and its level is linked with tumor immunogenicity. We thus analyzed the connection of SETBP1 mutations with TMB in melanoma. Results showed that SETBP1-MUT patients harbored a significantly increased TMB than other patients  of 109 had SETBP1 mutations. Kaplan-Meier results demonstrated that SETBP1-MUT NSCLC patients presented a markedly improved ICI survival benefit than wild-type patients . Moreover, gene set enrichment analysis showed that pro-inflammatory related T cell receptor signaling pathway  and less infiltration of immune-suppressive cells  in the SETBP1-MUT subgroup .We comprehensively searched previously published studies and cancer-related databases to obtain cancer patients with both genomic mutational data and clinical ICI treatment information. Finally, a total of 631 melanoma \u201339 and 1https://depmap.org/portal/ccle/) to validate the relevant connections.In the cellular level, we obtained a total of 57 cell lines for the melanoma and 98 cell lines for the NSCLC with both somatic mutational data and transcriptomic mRNA expression profiles from the Cancer Cell Line Encyclopedia (CCLE) project . Signaling pathways stored in the KEGG database were regarded as the background reference. In addition, to evaluate the detailed enrichment scores of collected Angelova et al. lymphocytes and immune-related signatures, a single sample GSEA  was useR software (version 4.2.1) was used in this study to achieve related analyses and figures. Tumor mutational signatures were determined according to a procedure reported by Kim et al. . WaterfaAll data used in this study are acquired from publicly available cohorts.Supplementary FiguresSupplementary Table 1Supplementary Table 2Supplementary Table 3Supplementary Table 4Supplementary Table 5Supplementary Table 6"}
+{"text": "Individuals with post-acute COVID syndrome (PAC), also known as long-COVID, have new or continuing symptoms lasting more than 1 month from COVID-19 infection. Patients may present with neuropsychiatric (NP) and non-NP symptoms. Whether prior mental health disorders correlate with NP symptoms is unknown. The study aims were to describe the demographics, clinical factors, comorbid conditions, and presenting symptoms of PAC.We included patients evaluated at Baystate Health PAC clinic from January 2021-April 2022, with prior COVID-19 infection and new or persistent symptoms of at least 6 weeks. We defined the primary presenting symptoms as NP (cognitive dysfunction (brain fog), anxiety, or depression) or non-NP . The clinician\u2019s diagnostic impression was recorded and characterized as NP or non-NP.DemographicsWe randomly selected 150 of 250 clinic patients for chart review. Most were women, 117 (78%); mean age was 52. Most 106 (71%) had mild acute COVID illness; 36 (24%) were hospitalized. 49% (n=73) had a pre-existing mental health disorder: mood disorder (depression/bipolar) 26 (17%), anxiety 18 (12%), both anxiety and mood disorder 27 (18%). The most common presenting symptoms in order of frequency were fatigue, dyspnea, brain fog, anxiety, depression, and palpitations. 106 (71%) had at least 1 NP presenting symptom or combination of NP symptoms; cognitive dysfunction with anxiety in 23 (15%), and cognitive dysfunction with anxiety and mood disorder in 13 (9%). The clinician's final diagnostic impression was fatigue (47%), cognitive dysfunction (36%), anxiety (29%) depression (33%) and PTSD (3%). A NP diagnosis was made in 81 (54%).Primary SymptomsPrimary DiagnosisThe majority of PAC clinic patients were female and had mild COVID illness. We noted a high prevalence of pre-existing mental health disorders. More than two-thirds presented with one or more NP symptom. Further studies should explore the association of pre-COVID mental health disorders with PAC.All Authors: No reported disclosures"}
+{"text": "Scientific Reports 10.1038/s41598-023-31517-8, published online 14 March 2023Correction to: The Acknowledgments section in the original version of this Article was incomplete.\u201cThe authors gratefully acknowledge the financial support provided by Ghent University Global Campus.\u201dnow reads:\u201cThe authors gratefully acknowledge the financial support provided by Ghent University Global Campus and Sari Agricultural Sciences and Natural Resources University (grant number: 02-1400-02).\u201dThe original Article has been corrected."}
+{"text": "Correction to: Clinical and Translational Oncology 10.1007/s12094-022-03016-1In this article the author names Silvia Rodr\u00edguez Villalba, Elena Villafranca Iturre and Ruth Gracia Lucio were incorrectly written as Rodr\u00edguez Rodriguez Villalba, Villafranca Villafranca Iturre and Garcia Gracia Lucio.The original article has been corrected."}
+{"text": "Endoscopic treatment using balloon enteroscopy-assisted endoscopic retrograde cholangiopancreatography (ERCP) is useful for hepaticojejunostomy anastomotic strictures. Although biliary stent placement is conducted to avoid stricture recurrence or realize stricture resolution after balloon dilationAn 11-year-old-boy, who had undergone hepaticojejunostomy for pancreaticobiliary maljunction 1 year earlier, underwent single-balloon endoscope-assisted ERCP to resolve a benign anastomotic stricture . After We used a novel 7-Fr Tanenbaum-type biliary stent integrated with a nasobiliary drainage catheter  to prevent distal stent migration . As theVideo\u20061\u2002Use of a novel outside biliary stent with the outer sheath of a snare designed for the colon to avoid distal stent migration for a benign hepaticojejunostomy anastomotic stricture.To reduce distal stent migration, a unique 7-Fr biliary stent integrated with a nasobiliary drainage catheter using the outer sheath of a snare designed for the colon may be helpful in surgically altered anatomy.Endoscopy_UCTN_Code_TTT_1AR_2AZ"}
+{"text": "The optimal treatment for patients with oligometastatic non-small cell lung cancer (NSCLC) remains unclear. Some patients with oligometastatic disease can experience prolonged remission after locally consolidative radiation therapy (RT), while others harbor micrometastatic disease (below current limits of detection by imaging) that may benefit from further prioritization of systemic therapy. To better risk-stratify this population and identify the patients most likely to benefit from locally consolidative radiation therapy, we performed a multi-institutional cohort study of patients with oligometastatic NSCLC undergoing liquid biopsy analysis of circulating tumor DNA (ctDNA).Among this real-world cohort of 1,487 patients undergoing analysis (using the Tempus xF assay), a total of 1,880 ctDNA liquid biopsies along with paired clinical data were obtained across various timepoints. Approximately 20% (n=309) of patients had ctDNA obtained prior to RT and after their diagnosis of oligometastatic disease. Samples were de-identified and analyzed for mutational burden and variant frequencies of detectable deleterious (or likely deleterious) mutations in plasma.P = 0.0031 for mutational burden, P = 0.0084 for maximum VAF) and overall survival . Patients without detectable ctDNA prior to RT had significantly improved progression-free survival (P = 0.004) and overall survival (P = 0.03) compared to patients with detectable ctDNA prior to RT.Patients with undetectable ctDNA before RT had significantly improved progression-free survival and overall survival compared to patients with detectable ctDNA prior to RT. In patients that received RT, 598 pathogenic (or likely deleterious) variants were identified. ctDNA mutational burden pre-RT and ctDNA maximum variant allele frequency (VAF) pre-RT were both significantly inversely correlated with both progression-free (These data suggest that in patients with oligometastatic NSCLC, pre-radiotherapy ctDNA analysis can potentially identify the patients most likely to benefit from locally consolidative RT and experience prolonged progression-free and overall survival. Similarly, ctDNA may be useful to identify those patients with undiagnosed micrometastatic disease, in whom it may be appropriate to prioritize systemic therapy. Oligometastatic non-small cell lung cancer (NSCLC) offers a unique opportunity for personalized liquid biopsy-guided therapies. While NSCLC patients with widespread metastatic disease are incurable and generally have poor outcomes, patients with a limited metastatic burden of disease can sometimes achieve prolonged remission after definitive management of the primary tumor and metastatic sites through a combination of systemic agents and local consolidative therapies such as RT \u20133.However, identifying patients who have truly oligometastatic disease and are most likely to benefit from locally consolidative radiation therapy is challenging. Many patients with perceived oligometastatic NSCLC on imaging likely harbor undetected widespread metastatic disease (micrometastatic disease) below the limit of detection of current imaging technologies. Establishing a new liquid biopsy biomarker to segregate those patients with truly oligometastatic disease from those with widespread micrometastatic disease could alter treatment approaches. Patients with evidence of micrometastatic disease could be triaged to earlier systemic therapies or enrollment in clinical trials \u2014 in addition to sparing the costs, systemic therapy breaks, and potential side effects associated with local consolidative therapies. Similarly, clinicians could provide more concrete guidance to patients regarding the possibility of prolonged remission, and potentially offer more aggressive locally consolidative treatment in truly oligometastatic patients who do not harbor liquid biopsy evidence of micrometastatic disease.We have previously shown that post-RT plasma circulating tumor DNA (ctDNA) is powerfully prognostic in localized NSCLC ,5. Here,Median follow-up time after initial blood collection for liquid biopsy analysis was 10.3 months. Across all ctDNA assays, 3,503 pathogenic or likely pathogenic variants were identified . Of the sub-cohort of 309 patients who underwent liquid biopsy after the diagnosis of oligometastatic disease and before RT, 48% (n=151) experienced progressive disease and 11% (n=34) died during the study period. ctDNA quantitation was based on the detection of pathogenic or likely pathogenic variants in plasma. ctDNA was detected in 74% of oligometastatic NSCLC patients prior to RT (n=230) while the remaining 26% (n=79) had no detectable ctDNA pre-RT. Among the 230 ctDNA-detectable patients, 76% (n=175) had 1\u20133 variants, while the remainder (n=55) had \u22654 pathogenic or likely pathogenic variants present.Overall survival was significantly worse in oligometastatic NSCLC patients with detectable ctDNA from pre-RT liquid biopsies, as compared to those without detectable ctDNA pre-RT, with a median OS of 16.8 months versus 25 months  . SimilarctDNA levels  demonstrated significant risk correlations, with the maximum pre-RT ctDNA VAF associated with increased risk of both disease progression (p=0.0084)  and deatThe definition of the oligometastatic disease state has remained frustratingly subjective since its original proposal in 1995 by Hellman and Weichselbaum . LocallyIndeed, to our knowledge, this study represents the largest ever real-world analysis of liquid biopsies in oligometastatic NSCLC, leveraging a multi-institutional dataset of 1,487 patients who underwent 1,880 liquid biopsies. Our analysis reveals that ctDNA testing performed pre-RT can risk-stratify those patients with truly oligometastatic NSCLC from those who likely harbor widespread micrometastatic disease (below current imaging limits of detection). Our modeling shows that the risk of disease progression and survival are informed by ctDNA quantitation, whether by mutational burden or the overall amount of ctDNA represented by VAF.This approach should be prospectively evaluated in a clinical trial that redefines oligometastatic NSCLC to include a discrete liquid biopsy metric encompassing a low or undetectable ctDNA level. This technique may also be valuable for those patients who undergo curative-intent treatment for earlier stages of NSCLC, but subsequently develop oligometastatic disease (deemed \u201coligorecurrence\u201d) and are weighing individualized treatment decisions.This was a real-world study, with data collected from multiple clinical sites including both academic and community practices. Clinical data including metastases and RT were provided by the managing clinicians. Given incomplete data regarding the exact timing of oligometastatic disease diagnosis and RT, we explicitly focused on a sub-cohort where a liquid biopsy was definitively performed prior to RT administration in oligometastatic NSCLC patients. Progression status was determined by individual clinician assessments and did not follow a standard criterion. Although this introduces clinical heterogeneity into the dataset, it may also more accurately capture real-world clinical practice patterns and suggests broader extensibility of our clinical-correlative liquid biopsy findings. Moreover, our significant PFS data was corroborated by similarly significant OS data in this real-world cohort.In conclusion, this study suggests that pre-RT ctDNA may be a powerful biomarker to accurately identify micrometastatic disease in patients with oligometastatic NSCLC. Earlier risk stratification using this liquid biopsy biomarker could support future clinical trials to enable personalized decision-making based on per-patient ctDNA risk profiles. Patients with high-risk ctDNA profiles could undergo systemic therapy prioritization and potentially escalation , while patients with undetectable ctDNA or low ctDNA risk profiles could potentially be offered locally consolidative stereotactic radiotherapy.All analyses were performed using de-identified patient data. The study was exempt from institutional review board evaluation and informed consent given the de-identified nature of the data.We leveraged a multi-institutional real-world cohort consisting of 1,487 patients from both academic and community practices who were diagnosed with oligometastatic NSCLC. Peripheral blood samples were collected for liquid biopsy analysis between 2016 and 2022. The cohort mean age (SD) was 64.7 years (10.1), with similar numbers of male and female patients  . ApproxiThe Tempus xF liquid biopsy assay is a laboratory developed test (LDT) designed to detect oncogenic and resistance mutations in cell-free DNA. The assay detects single nucleotide variants (SNVs), insertions/deletions (indels), rearrangements, copy number variations (CNVs), and microsatellite instability (MSI) with high sensitivity and specificity . ctDNA rMedian follow-up time was determined using the reverse Kaplan-Meier method. Outcomes for overall survival (OS) and progression-free survival (PFS) were both calculated from the start of RT . Progression was reported by the managing clinicians. Kaplan-Meier curve p-values represent the log-rank test. Hazard ratios for OS and PFS in Kaplan-Meier analyses reflect the Mantel-Haenszel test. Multivariate Cox regression p-values were calculated using the Wald test. Data were managed using Apache Superset and statistical analyses were performed using GraphPad Prism version 9.5.0 and R version 4.2.2.Supplement 1"}
+{"text": "Cascades of care have been used by health departments to evaluate outcomes and gaps in HIV care and until recently, no standard existed for HCV cascades. The CDC guidance for HCV viral clearance cascades allows standardized use of HCV surveillance data. We adapted this approach for persons with HIV/HCV coinfection for 5 health jurisdictions in the US.Lists of coinfected persons were generated by matching HCV surveillance data to prevalent HIV surveillance (eHARS) as of 12/31/2019. Dispositions based on HCV test results were created for viral clearance cascade steps: ever infected, viral testing, initial infection, cleared, and persistent infection. We collected aggregate data from each jurisdiction\u2019s prevalent HIV, HCV, and coinfected populations. Quarterly updated data were submitted and analyzed from 12/31/2019-12/31/2021.Overall, jurisdictional coinfected populations were White (61%), Male [sex at birth] (75%), over 45 (76%) with IDU as HIV transmission risk factor (44%). As of most recent submission: virally tested was 73%  of ever-infected; initial infection 83% (81-89%) of virally tested; cleared 44% (21-63%) of initial infection. Those more likely to receive viral testing include persons over 45, IDU, and those with more recent HCV and HIV lab tests; less likely were MSM (HIV transmission) along with Asian and Native American persons. Those more likely to achieve HCV clearance include those over 45, those with more recent HCV and HIV lab tests, and persons with undetectable HIV viral loads; less likely were Transgender persons.Diverse health jurisdictions successfully developed data strategies including enhancing HCV surveillance databases to implement the CDC HCV viral clearance cascade adapted for persons with HIV/HCV co-infection. Jurisdictions are now able to not only assess HCV cure rates of their co-infected population but testing and treatment gaps as well. The viral clearance cascades can provide key implementation strategy data for HCV microelimination through the development of innovative engagement strategies focused on the identified gaps.Ralph P. Brooks, MS, Merck: Stocks/Bonds"}
+{"text": "Antimicrobial resistance threatens the ability to successfully prevent and treat infections. While hospital benchmarks regarding antimicrobial use (AMU) have been well documented among adult populations, there is less information from among paediatric inpatients. This study presents benchmark rates of antimicrobial use (AMU) for paediatric inpatients in nine Canadian acute-care hospitals.Acute-care hospitals participating in the Canadian Nosocomial Infection Surveillance Program submitted annual AMU data from paediatric inpatients from 2017 and 2018. All systemic antimicrobials were included. Data were available for neonatal intensive care units (NICUs), pediatric ICUs (PICUs), and non-ICU wards. Data were analyzed using days of therapy (DOT) per 1000 patient days (DOT/1000pd).Nine hospitals provided paediatric AMU data. Data from seven NICU and PICU wards were included. Overall AMU was 481 (95% CI 409\u2013554) DOT/1000pd. There was high variability in AMU between hospitals. AMU was higher on PICU wards (784 DOT/1000pd) than on non-ICU (494 DOT/1000pd) or NICU wards (333 DOT/1000pd). On non-ICU wards, the antimicrobials with the highest use were cefazolin (66 DOT/1000pd), ceftriaxone (59 DOT/1000pd) and piperacillin-tazobactam (48 DOT/1000pd). On PICU wards, the antimicrobials with the highest use were ceftriaxone (115 DOT/1000pd), piperacillin-tazobactam (115 DOT/1000pd), and cefazolin (111 DOT/1000pd). On NICU wards, the antimicrobials with the highest use were ampicillin (102 DOT/1000pd), gentamicin/tobramycin (78 DOT/1000pd), and cefotaxime (38 DOT/1000pd).This study represents the largest collection of antimicrobial use data among hospitalized paediatric inpatients in Canada to date. In 2017/2018, overall AMU was 481 DOT/1000pd. National surveillance of AMU among paediatric inpatients is necessary for establishing benchmarks and informing antimicrobial stewardship efforts. The advent of antibiotics has saved many lives and has created the conditions for much of modern medicine . HoweverAntibiotic use is very common among hospitalized children . In studAmong hospitalized paediatric patients, it is estimated that potentially 9\u201343% of prescriptions are unnecessary or inappropriate \u201318. MisuAntimicrobial stewardship programs aim to find a balance between the \u201cpotent ability of antibiotics for individual patients and their potentially hazardous effects\u201d . PaediatAntimicrobial use (AMU) surveillance can identify opportunities for interventions, enable evaluation of antimicrobial stewardship programs and help garner political will for successful stewardship campaigns .There are published AMU data from a paediatric hospital  and fromCNISP is a collaboration between the Canadian Hospital Epidemiology Committee, a subcommittee of the Association of Medical Microbiologists and Infectious Disease, and the Public Health Agency of Canada. As of January 2022, 89 sentinel hospitals, from across 10 provinces and one territory participate in the CNISP network. Forty hospitals serve paediatric inpatients; nine are standalone paediatric hospitals.CNISP established a working group for antimicrobial use in 2007/08. Paediatric AMU surveillance started as a pilot study among a few hospitals before transitioning to routine surveillance. The results of this current study represent the nine hospitals that participated in CNISP paediatric AMU surveillance in 2017 and/or 2018.Paediatric patients were defined as those\u2009<\u200918\u00a0years of age or those patients on wards where the majority of patients are\u2009<\u200918\u00a0years of age. Surveillance included all acute care inpatient units (including intensive care units) and admissions in emergency departments. Non-admitted patients in emergency departments were excluded. Participating sites provided corresponding paediatric inpatient-day denominators by ward. Estimates of national inpatient days by year and age group were obtained from the Canadian Institute for Health Information .Participating hospitals provided total paediatric inpatient AMU separated by type of antimicrobial and ward category . Hospitals were asked to submit either dispensed or administered antimicrobials and to separate their data by administration route  if possible. All systemic antibacterial use was included in the surveillance using Anatomical Therapeutic Chemical (ATC) codes: J01s, P01AB01  and A07AA09  . QuantitParticipating hospitals submitted annual data files. The WHO ATC/DDD Index  was adapNine CNISP hospitals provided paediatric AMU data. Eight hospitals provided data for both 2017 and 2018 calendar years; one hospital provided data only for 2018. Total inpatient days included in surveillance (507 583 patient days) represented about a quarter of paediatric inpatient days in Canada in 2017/18. Three participating hospitals were in western Canada, four in central Canada (Ontario/Quebec), and two in eastern Canada. Five of the hospitals were paediatric acute care centres with\u2009\u2264\u2009200 beds and four hospitals were mixed adult/paediatric hospitals with 201\u2013500 beds. Seven PICUs and seven NICUs were included in surveillance. PICUs and NICUs represented 9% and 23% of included patient days, respectively. Participating site characteristics are summarized in Table From January 2017 to December 2018, total AMU was 481 (95% CI 409\u2013554) DOT/1000 patient days (/1000pd). AMU varied substantially between hospitals; the interquartile range (IQR) for total AMU spanned 217 DOT/1000pd: 352\u2013569 DOT/1000pd and there was 17-fold variability between hospitals\u2019 rates of overall AMU . Among the seven PICUs included in surveillance, the interquartile range (IQR) for total AMU spanned from 502 to 900 DOT/1000pd. The ten most frequently used antimicrobials among PICUs were ceftriaxone (115 DOT/1000pd), piperacillin-tazobactam (115 DOT/1000pd), cefazolin (111 DOT/1000pd), vancomycin , meropenem (44 DOT/1000pd), ampicillin (42 DOT/1000pd), azithromycin (41 DOT/1000pd), trimethoprim-sulfamethoxazole (35 DOT/1000pd), cefotaxime (32 DOT/1000pd) and gentamicin/tobramycin (25 DOT/1000pd). These ten antimicrobials represented 84% of total AMU among PICUs.Although AMU among PICUs represented only a small proportion of the total AMU , the rate of AMU was more than 50% higher among PICUs (784 DOT/1000pd) than among non-ICU wards  compared to non-ICU wards from nine hospitals (30 DOT/1000pd), among the three hospitals with available data, the rate of oral vancomycin use was higher among non-ICU wards (5 DOT/1000pd) than among PICU wards (3 DOT/1000pd). Only cephalexin, metronidazole, ceftazidime and amoxicillin were used substantively more frequently among non-ICU wards compared with PICU wards; cephalexin use was 65% higher on non-ICU wards, metronidazole use was 40% higher, ceftazidime use was 28% higher and amoxicillin use was 22% higher.The rate of total AMU among the seven NICUs (333 DOT/1000pd) was lower than on non-ICU wards (494 DOT/1000pd). Among the seven NICUs included in surveillance, the interquartile range (IQR) for total AMU spanned from 296 to 437 DOT/1000pd. The five antimicrobials used most often on NICUs were ampicillin (103 DOT/1000pd), gentamicin/tobramycin (78 DOT/1000pd), cefotaxime (38 DOT/1000pd), vancomycin , and meropenem (16 DOT/1000pd). These five antimicrobials represented 78% of AMU among NICUs.To date, these surveillance results represent the largest collection of dispensed or administered antibiotic use data from hospitalized paediatric patients in Canada. From January 2017 to December 2018, among hospitalized paediatric patients, the rate of overall AMU was 481 DOT/1000pd with substantial variation between hospitals and between ward types.AMU data from hospitalized paediatric populations are limited and differences in methods (eg. metrics to express AMU), services, and patient populations make national and international comparisons difficult. However, there are studies that report paediatric AMU rates similar to those in this study (IQR: 352\u2013569 DOT/1000pd). A study of 20 hospitals in the United States reported an overall annual paediatric AMU rate of 540 DOT/1000pd in 2007 . A four-There are also Canadian and international studies that report higher rates of paediatric AMU than those found in our study. Our AMU rate among non-ICU wards (494 DOT/1000pd) is 55% of the median-adjusted AMU rate found among non-ICU wards from 41 hospitals in the United States (893 DOT/1000pd from billing data) . A CanadIn our study, the rate of AMU among PICU wards was about 1.5 times as high as the rate of AMU among non-ICU wards. Higher rates of AMU among PICU wards are expected due to the higher prevalence of infection among critically ill patients. Perioperative antibiotic prophylaxis, suspected ventilator-associated pneumonia and sepsis are drivers of AMU on PICU wards \u201349. In aOur rate of AMU among PICU wards (784 DOT/1000pd) was lower than most rates reported by others possibly due to the state of stewardship programs at these centres. A large study of billing data from 41 PICUs in the United States reported a median-adjusted rate of 1043/1000pd in 2010\u20132014 . StudiesStaphylococcus aureus across jurisdictions [Glycopeptide use among PICUs (98 DOT/1000pd) was more than three-times higher than glycopeptide use among non-ICU wards (30 DOT/1000pd); this is likely due in part to more frequent use of central lines and coverage for coagulase negative staphylococci on PICUs. Glycopeptide use among PICUs in this study was similar to use on a German PICU (90 DOT/1000pd) , but lowdictions . Vancomydictions , 57\u201359.Our rate of overall AMU among NICUs (333 DOT/1000pd) is similar to some reports from Canada and the United States. Among five NICUs in Alberta, Canada, rates of AMU ranged from 155 to 624 DOT/1000pd in 2011\u20132014 . In the We acknowledge the limitations of our work including the risk of selection bias due to hospitals voluntarily opting to participate. The majority of the hospitals included had well-developed antimicrobial stewardship programs, which may not reflect all paediatric hospitals in Canada. Data were collected only from teaching hospitals and were not collected from every province so are not representative of all Canadian hospitals. We did not identify which hospitals or wards had patient groups with higher expected levels of AMU. Our surveillance system does not capture data on indication for use or appropriateness of use. There are also shortcomings to using DOTs to measure aggregate antibiotic use . InterprOur study describes Canadian paediatric AMU data from nine hospitals and represents the largest collection of dispensed/administered antibiotic use data from paediatric inpatients in Canada to date. In 2017/2018, overall AMU was 481 DOT/1000pd. There is need for high-quality, hospital-based AMU surveillance to support antimicrobial stewardship efforts."}
+{"text": "Psychiatric home hospitalisation is a service aiming to support people with mental illnesses in their acute stage at their own home. This care model has been recently implemented in our territory with the main objective of avoiding hospital admissions.Our goal is to describe a cohort of patients followed up over 2-years in the context of a pilot mental health program within a community-based model .We conducted a prospective longitudinal study including 125 patients attended from 01/11/2020 to 09/11/2022 in our reference area of 250,000 inhabitants. The team was formed by 1 psychiatrist and 1 mental health nurse. DSM-5 diagnoses, socio-demographic variables, mean stay and care trajectories were collected.-old. Mean stay: 24 days. The most frequent diagnoses: non-affective psychotic disorders (58%), affective disorders (30%), followed by anxiety and personality disorders. Referrals from Community Mental Health Outpatient Services (CMHS) (72%), Acute Inpatient Unit (25%), and Psychiatric Emergency Service (3%). Referrals after discharge: CMHS (83%), Adult Acute Inpatient Unit (13%), others (4%). Individualized mental health plans were carried out in all cases, in coordination with community mental health services. Follow-up adherence after discharge was about 95%. Patients with first-episode of psychosis showed the highest degree of satisfaction (N=46).One-hundred twenty-five patients were attended (women: 70). Mean age at consultation: 38.3 yearsPatients with emerging psychosis were the profile of users who showed the highest benefit of our service. Women showed higher adherence, and loss to follow-up was lower than we expected.None Declared"}
+{"text": "Scientific Reports 10.1038/s41598-020-66286-1, published online 15 June 2020Correction to: The Data Availability section in the original version of this Article was omitted.It now appears as below:\u201cThe RNA-seq raw reads of six samples have been submitted in BioSample Archive under project number PRJNA578979.\u201dThe original Article has been corrected."}
+{"text": "EPB41L5 (Yurt) as a central podocyte gene to generate a cell type-specific disease model. Loss of Yurt in fly nephrocytes caused protein uptake and slit diaphragm defects. Transcriptomic and proteomic analysis of human EPB41L5 knockout podocytes demonstrated impaired mechanotransduction via the YAP/TAZ signaling pathway. Further analysis of specific inhibition of the YAP/TAZ-TEAD transcription factor complex by TEADi led to the identification of ARGHAP29 as an EPB41L5 and YAP/TAZ-dependently expressed podocyte RhoGAP. Knockdown of ARHGAP29 caused increased RhoA activation, defective lamellipodia formation, and increased maturation of integrin adhesion complexes, explaining similar phenotypes caused by loss of EPB41L5 and TEADi expression in podocytes. Detection of increased levels of ARHGAP29 in early disease stages of human glomerular disease implies a novel negative feedback loop for mechanotransductive RhoA\u2014YAP/TAZ signaling in podocyte physiology and disease.Glomerular disease due to podocyte malfunction is a major factor in the pathogenesis of chronic kidney disease. Identification of podocyte-specific signaling pathways is therefore a prerequisite to characterizing relevant disease pathways and developing novel treatment approaches. Here, we employed loss of function studies for  Glomerular disease and related podocytopathies are central factors in the pathogenesis of chronic kidney disease (CKD) ,2. UncovEpb41l5 results in foot process effacement and podocyte cell detachment. Furthermore, it affects GBM development and presents with the development of nephrotic syndrome . RN. RNEpb41henotype . Given terformed a 17,22],22Epb41landscape . Detaileandscape . These oandscape . Interesmponents . Interes YAP/TAZ . Here, wet gene) . In summTEADi system)  a 34]. T. TTEADi ormation . Moreoveormation e\u2013i. InteDi cells a. Interend RCAN1 . In a nete genes g,h. This pathway i\u2013n.ARHGAP29 , probably reflecting the requirement for balanced RhoA activity levels for coordinated generation of cellular protrusions (ARHGAP29 KD cells (24 h after seeding) showed impaired formation and morphology of lamellipodia   IACs  . Moreoveameters) . Given tby TEADi . This shre) IACs f\u2013j. In sArhgap29 and further YAP target genes   and minimal change disease (MCD). In contrast, destructive glomerular diseases such as diabetic nephropathy (DN), focal segmental glomerulosclerosis (FSGS), and collapsing FSGS (cFSGS) showed reduced levels of ARHGAP29 expression. Interestingly, similar expression patterns were detected for ACTN4 and PDLIM5, two IAC and actin cytoskeleton-associated scaffold proteins involved in the regulation of YAP/TAZ signaling . Pr. PrARHGAent IACs . This phent IACs  43]. La. LaARHGAARHGAP29 expression in early glomerular disease stages (ARHGAP29 in in vivo models of glomerular disease and its potential for targeted therapeutic approaches.Reorganization of the actin cytoskeleton and of cell-matrix adhesions towards a contractile and mechanically enforced RhoA-dependent actomyosin cytoskeleton is a common pattern in podocytopathy and considered a driving factor of glomerular disease ,12,19,62e stages . In line"}
+{"text": "Lenvatinib was expected to enhance the effect of immune checkpoint inhibitors (ICIs) for unresectable HCC; however, their combination therapy failed to show the synergy in the phase III clinical trial.To elucidate lenvatinib-induced molecular modulation, we performed bulk RNA-sequencing and digital spatial profiling of 5 surgically resected human HCC specimens after lenvatinib treatment and 10 matched controls without any preceding therapy.Besides its direct antitumor effects, lenvatinib recruited cytotoxic GZMK+CD8 T cells in intratumor stroma by CXCL9 from tumor-associated macrophages, suggesting that lenvatinib-treated HCC is in the so-called excluded condition that can diminish ICI efficacy.  To reveal lenvatinib-induced molecular modulation, we performed multilayer transcriptome analyses of surgically resected human HCC samples after lenvatinib treatment as neoadjuvant therapy in the phase II clinical trial together with matched control HCCs without any preceding therapy .HCC, representing >80% of primary liver cancer, is the fourth leading cause of cancer-related death worldwide.This study consisted of 5 patients who underwent surgical resection for HCC after neoadjuvant lenvatinib treatment in the phase II clinical trial (LENS-HCC) and 10 matched HCC patients without any preceding treatment between April 2018 and July 2020 at the University of Tokyo Hospital. The matched control patients were selected according to age, sex, tumor size, and etiology.Total RNA extracted from human frozen HCC tissues by ISOGEN (NIPPON GENE) was subjected to RNA-seq library preparation with the TruSeq Stranded mRNA Library Prep (Illumina) and sequenced with NovaSeq. 6000 system (Illumina) according to the manufacturer\u2019s instructions. The dataset is publicly available at the NCBI GEO .The 5 lenvatinib-treated HCCs and 1 metastatic lymph node were subjected to the DSP. In total, 72 regions of interest were included. The formalin-fixed paraffin-embedded slides were deparaffinized and stained with immunofluorescent antibodies to detect tumor cells (KRT8/18), immune cells (CD45), T cells (CD3), and DNA to visualize the morphology for regions of interest. Once the staining was completed, slides were loaded onto a GeoMx DSP instrument and scanned to produce digital immunofluorescence images.Continuous variables were compared by nonparametric Wilcoxon rank-sum test and Spearman correlation. All bioinformatic and biostatistical analyses were performed using R statistical language (www.r-project.org).http://links.lww.com/HC9/A409.The details for patient selection and multilayer transcriptome, histological, and statistical analyses were described in Supplemental Methods, http://links.lww.com/HC9/A409. Median dosing and washout period were 43  and 16  days, respectively, indicating that these samples were appropriate for analyzing the ongoing effects of lenvatinib on HCC. Among 5 lenvatinib-treated HCCs, 3 (60%) achieved partial response . Molecular pathway analyses revealed that the VEGFR pathway, especially the VEGFR2 pathway, was downregulated together with other HCC drivers in lenvatinib-treated HCC, whereas no significant modulation of other potential lenvatinib targets, such as FGF receptor 4 pathway, was observed . VEGF is known to suppress antitumor immunity through various mechanisms,5 among which VEGF-mediated permeability and hypoxia pathways were significantly downregulated in lenvatinib-treated HCC, suggesting that lenvatinib might improve aberrant tumor vascularity and promoted immune cell infiltration that can exert antitumor immunity. Indeed, lenvatinib-treated HCC pathologically exhibited more frequent immune cell infiltration compared with control HCC  . Besides, lenvatinib-treated HCC showed upregulated fibrosis-related pathways, especially among patients who achieved a partial response , suggesting more abundant extracellular matrix (ECM) deposition . Collectively, these findings suggested that lenvatinib increased GZMK+CD8 T-cell infiltration by improving tumor-aberrant vascularity through downregulated VEGFR pathways.The study design and patient demographics are summarized in Supplemental Figure S1A, B, 6 Consistently, higher GZMK expression in HCC was associated with a favorable prognosis in multiple HCC cohorts . To further characterize GZMK+CD8 T-cell\u2013rich microenvironment in lenvatinib-treated HCC, we performed a spatial transcriptome analysis using Digital Spatial Profiling technology (NanoString) .7 GZMK+CD8 T cells coexisted with other immune cells as evidenced by high immune-related gene expressions, irrespective of intratumoral and peritumoral regions. Interestingly, differential expression analysis revealed that C-X-C motif chemokine ligand 9 (CXCL9) (encoding CXCL9) and CD68 (encoding CD68) showed significantly higher expression more specifically in intratumor GZMK+CD8 T-cell\u2013rich regions, suggesting that CXCL9-expressing tumor-associated macrophages (TAMs) and GZMK+CD8 T cells exist in close proximity . CXCL9-expressing TAMs have been well-recognized to promote T-cell infiltration in various tumors.8 Consistently, the expression levels of CXCL9 and GZMK were strongly correlated in HCCs from multiple independent cohorts .A recent large-scale single-cell RNA-sequence study showed that GZMK+CD8 T cells in liver cancer are cytotoxic rather than exhausted.9 Altered-excluded tumors are generally believed to be less responsive to ICI,10 which might lead to failure to show the additive effects of their combination therapy. Various factors can drive tumors toward altered-excluded status.10 Given improved aberrant vascularity and T-cell chemotaxis by CXCL9 after lenvatinib treatment, ECM might be a potential target to tackle the limited efficacy of combination therapy of lenvatinib and ICI. Recently, anti-ECM compounds, such as fresolimumab (collagen synthesis inhibitor) and simtuzumab (collagen cross-linking inhibitor), have been actively explored for cancer treatment in early-stage clinical trials.11 Adding these anti-ECM drugs to the combination therapy of lenvatinib and ICI might enable cytotoxic GZMK+CD8 T cells to more easily penetrate inside the HCC cell area, eventually leading to improved drug efficacy and favorable patient prognosis. Higher resolution spatial transcriptome analyses would enable us to infer the cell-cell interaction between GZMK+CD8 T cells and CXCL9-expressing TAMs/fibroblasts.In this study, multilayer transcriptome analyses revealed that lenvatinib recruited cytotoxic GZMK+CD8 T cells by improving aberrant vascularity and its direct antitumor effect. However, the majority of these cytotoxic CD8 T cells appeared to be trapped in the intratumor stroma, indicating that lenvatinib-treated HCC might be \u201caltered-excluded\u201d due to physical barriers by ECM rather than exhausted."}
+{"text": "Growing evidence supports the contention that immune dysregulation and autoimmunity predispose and contribute to the pathological remodelling that characterise pulmonary arterial hypertension (PAH) . PAH is a common complication of connective tissue diseases (CTDs), especially systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) [3]. In addition, idiopathic PAH (IPAH) patients exhibit immune cell infiltration of remodelled vessels, a shift in Th17/Treg axis and elevated levels of circulating cytokines and autoantibodies [2]. We have explored toll-like receptor 7 and 8 (TLR7/8)-induced autoimmunity in perpetuating vascular endothelial growth factor receptor antagonist Sugen 5416 (SU5416)-induced pulmonary endothelial injury and dysfunction in the initiation and further development of pulmonary vascular disease in rats (R-SU). This study introduced a combination of autoimmune stimuli (TLR-7/8 agonist) and endothelial injury (Sugen) and established a novel rat model representing immune\u2013vascular pathological events mimicking human PAH associated with autoimmune disordershttps://bit.ly/3P3H5V0 To the Editor:Growing evidence supports the contention that immune dysregulation and autoimmunity predispose and contribute to the pathological remodelling that characterise pulmonary arterial hypertension (PAH) , 2. PAH in vivo . Typ. Typ7]. od cells . Repolarod cells . Producte.g. pulmonary fibrosis, viral pneumonia due to COVID-19), and serve as a novel and important experimental tool in the pulmonary vascular research field.This study highlights the complex immune\u2013vascular interactions involved in pulmonary vascular diseases associated with autoimmune/infectious disorders. Compared with existing PH experimental models, such as the Sugen-hypoxia rats, R-SU rats display prominent inflammatory cells accumulation in the perivascular regions of the remodelled vessels in the lungs. R-SU rats manifest the immune\u2013vascular pathological events representative of human PAH and other relevant pulmonary diseases (10.1183/13993003.00204-2023.Shareable1This one-page PDF can be shared freely online.ERJ-00204-2023.ShareableShareable PDF"}
+{"text": "We evaluated inappropriate treatment among patients without urinary tract infection (UTI) symptoms who underwent urine testing, regardless of the significance of growth in culture.Unnecessary treatment of asymptomatic bacteriuria (ASB) is an important target for antimicrobial stewardship efforts. However, patients with urine colony counts <10Patients who underwent urine testing during September 8, 2022 - March 11, 2023, were reviewed across ten critical access hospitals participating in the University of Washington Center for Stewardship in Medicine. Culture growth was categorized as no growth, \u226410,000 CFU/mL, 11,000-50,000 CFU/mL, 51,000-100,000 CFU/mL or >100,000 CFU/mL. Asymptomatic for UTI was defined as the absence of documented signs or symptoms of UTI, per the National Hospital Safety Network definition and Infectious Diseases Society of America Guidelines. We assessed the number of patients with a positive UA  treated with antibiotics and the association of urine colony cutoffs on inappropriate antibiotic prescribing. Variables were compared using Mantel-Haenszel chi square test. A two-sided p-value of < 0.05 was considered statistically significant.5 CFU/mL lacked signs or symptoms of UTI. Among these 117 patients, 72 (62%) were treated with antibiotics. There was a significant trend that treatment in asymptomatic patients increases with colony count in urine culture (p< 0.001).The analysis included 616 patients- 249 were classified as asymptomatic for UTI (40%). Patients with asymptomatic pyuria (n=188) were more likely to receive treatment than those without pyuria (n=42) . One hundred seventeen patients with urine colony counts < 10Treatment of ASB alone inadequately captures the total number of patients receiving unnecessary antibiotics for suspected UTI. A more comprehensive means of quantifying unnecessary UTI treatment may be capturing all patients who undergo urine cultures-including those with asymptomatic pyuria or asymptomatic nitrituria, even with low growth on culture.All Authors: No reported disclosures"}
+{"text": "CMV-transformed Ovarian cells\u201d (CTO). The infection with the two high-risk clinical strains, namely HCMV-DB and BL provoked a distinct cellular and molecular mechanisms in infected OECs. EZH2 upregulation and cellular proliferation were curtailed by using EZH2 inhibitors. The HGSOC biopsies were characterized by an elevated EZH2 expression, possessing a strong positive correlation between the aforementioned marker and HCMV. From HGSOC biopsies, we isolated three HCMV clinical strains that transformed OECs generating CTO cells which displayed proliferative potentials in addition to EZH2 upregulation and PGCCs generation; these features were reduced upon EZH2 inhibition. High-risk HCMV strains transformed OECs confirming an HCMV-induced epithelial ovarian cancer model and highlighting EZH2 tumorigenic properties. Our findings might be highly relevant in the pathophysiology of ovarian tumors thereby nominating new targeted therapeutics.Human cytomegalovirus (HCMV) infection has been implicated in epithelial ovarian cancer (OC). Polyploidy giant cancer cells (PGCCs) have been observed in high-grade serous ovarian carcinoma (HGSOC); they possess cancer stem cell-like characteristics and give rise to progeny cells expressing epithelial-mesenchymal transition (EMT) markers. EZH2 plays a potential oncogenic role, correlating with high proliferative index and tumor grade in OC. Herein, we present the experimental evidence for HCMV as a reprogramming vector that elicited human ovarian epithelial cells (OECs) transformation leading to the generation of \u201c Epithelial ovarian cancer (OC), the most common and life-threatening cancer amongst gynecologic malignancies, has a 5-year age-standardized survival rate of 30\u201340%. Nearly 75% of all OC cases are diagnosed at late stages . Despite+ hematopoietic progenitor cells, with periodic reactivation . Correlation analysis was done using Spearman, Pearson, and Kendall\u2019s Tau correlation tests. Microsoft Excel was used to construct the plots and histogram data.Quantitative results are reported as mean\u2009\u00b1\u2009SD of independent experiments. Statistical analyses were done using Wilcoxon and MannSupplementary data"}
+{"text": "Direct patient discharge from the Emergency Department (ED) presents an ideal time to promote antimicrobial stewardship (AS). On March 1, 2021 we initiated a pilot program where ED pharmacists conduct a review of discharge antibiotic prescriptions (abx Rxs). The aim of this program is to ensure appropriate discharge abxs. Willow Pharmacy Epic Analysts, ED and AS pharmacists collaborated on this program which included Epic integration of Rx Discharge Track Board, ED Discharge InBasket, ED Discharge Rx iVent and AS-led education sessions.Data for 2022 ED patients with discharge abx Rxs and iVents were extracted via Epic Reports. The first encounter per patient was included. We compared discharge abx Rxs and patient outcome data in Pharmacy vs No Pharmacy Review Groups . Pharmacy iVents were used as a process measure.nd generation cephalosporin . The PRG also decreased use of 3rd generation cephalosporin , quinolones  and clindamycin . There was no difference in ED length of stay (LOS 4.8h in each group), C. difficile infection (CDI) within 8 weeks , and 30 days repeat ED visit or inpatient admission with the same diagnosis as index ED encounter . Pharmacists intervened in 10% (272/2638) of ED abx Rxs with 92% (249/272) acceptance rate. The top 3 pharmacy interventions were recommending alternative abx (42%), dose optimization (31%) and abx duration (6%).Among 5747 ED adult patients with discharge abx Rxs, 2638 (46%) were reviewed by pharmacy (PRG). PRG and NPRG had similar prevalence of chronic pulmonary disease (12% vs. 13%), diabetes mellitus (9% vs. 10%), malignancy (8% vs. 9%), peripheral vascular disease (6% vs. 8%), renal disease (4% vs. 5%), and HIV (1% vs. 2%) despite a difference in mean Charlson Comorbidity Index . The primary ED diagnosis was skin and soft tissue, urinary, intra-abdominal infections and pneumonia . In PRG, discharge abxs demonstrated an increase use of penicillin  and 2Engaging pharmacists in ED discharge Rxs review resulted in use of narrower spectrum abx with lower CDI risk without any negative impact on ED LOS and clinical outcomes.All Authors: No reported disclosures"}
+{"text": "Antimicrobial Peptides (AMPs) are immune effectors that are key components of the invertebrate innate immune system providing protection against pathogenic microbes. Parasitic helminths (phylum Nematoda and phylum Platyhelminthes) share complex interactions with their hosts and closely associated microbiota that are likely regulated by a diverse portfolio of antimicrobial immune effectors including AMPs. Knowledge of helminth AMPs has largely been derived from nematodes, whereas the flatworm AMP repertoire has not been described.Ascaris suum biofluid. These data represent a significant advance in our understanding of the putative helminth AMP repertoire and underscore a potential untapped source of antimicrobial diversity which may provide opportunities for the discovery of novel antimicrobials. Further, unravelling the role of endogenous worm-derived antimicrobials and their potential to influence host-worm-microbiome interactions may be exploited for the development of unique helminth control approaches.This study highlights limitations in the homology-based approaches, used to identify putative nematode AMPs, for the characterisation of flatworm AMPs, and reveals that innovative algorithmic AMP prediction approaches provide an alternative strategy for novel helminth AMP discovery. The data presented here: (i) reveal that flatworms do not encode traditional lophotrochozoan AMP groups ; (ii) describe a unique integrated computational pipeline for the discovery of novel helminth AMPs; (iii) reveal >16,000 putative AMP-like peptides across 127 helminth species; (iv) highlight that cysteine-rich peptides dominate helminth AMP-like peptide profiles; (v) uncover eight novel helminth AMP-like peptides with diverse antibacterial activities, and (vi) demonstrate the detection of AMP-like peptides from  Invertebrate antimicrobial peptides (AMPs) form the first line of defence against pathogenic microbes. Helminths are worms  that live in microbe-rich environments throughout their lifecycles, however little is known about how they protect themselves against pathogens or how they interact with microbes. Understanding AMP profiles in helminths, their importance to helminth biology, and how they shape microbial communities could reveal novel approaches for anthelmintic and/or antimicrobial development.Ascaris suum body fluid supporting the need to further characterise these peptides and their function(s) in helminths. These data present novel opportunities to better understand helminth biology, discover new antimicrobials, and develop future control strategies for helminth parasites.In this study we describe a novel integrated homology- and computational-based pipeline for the discovery of helminth AMPs. This approach revealed that, whilst flatworms do not possess traditional AMPs, they have a repertoire of unique AMP-like peptides that are predominantly cysteine-rich. Significantly, eight novel helminth AMP-like peptides, discovered using this pipeline, have antibacterial activities against a range of bacteria highlighting their potential as novel antimicrobials. Further, peptidomics analyses demonstrate the presence of AMP-like peptides in  Minimum inhibitory concentrations (MICs) were determined for gram-positive and gram-negative bacterial isolates , transported to the laboratory in saline (0.9%NaCl), and maintained in Ascaris Ringers Solution  at 37\u00b0C until use.Adult Ascaris suum pseudocoelomic fluid (As-PCF) was collected from ~20 female A. suum (>20cm) within 3 hours of collection as previously described [escribed . A totalAs-PCF was treated with 1ml of ice-cold acidified methanol :Acetic acid) as previously described  with minAs-PCF was filtered using a 10kDa molecular weight cut-off membrane prior to LC-MS/MS as previously described  with minAs-PCF samples were resuspended in 50\u03bcl of 0.1% formic acid via sonication for 3 mins in a benchtop water bath sonicator  and vortexed for 30 secs; this was repeated until the sample was fully resuspended. As-PCF samples were centrifuged at 16,000g for 10 mins to pellet any debris. The supernatant was removed and placed into a fresh 2ml low-binding microcentrifuge tube. Custom STop And Go Extraction (STAGE) tips were produced using established protocols . STAGE t2O with 0.1% formic acid. Mobile phase B consisted of 100% acetonitrile and 0.1% formic acid. Peptides were separated with a 5\u03bcl/min linear gradient of 5\u201325% B for 68 mins, 35\u201345% B for 5 mins, 80% B for 3 mins and 3 mins equilibration at 5% B. Data were collected in positive electrospray ionisation (ESI) data-dependant mode (DDA). The 30 most abundant ions were selected for MS/MS following a 250ms TOF-MS survey scan and 50ms MS/MS scan. Dynamic exclusion time was set to 15s. Selected parent ions had charged states between 2 and 4 and were fragmented by Collision-induced dissociation (CID).Stored peptide samples were dissolved in 9\u03bcl 3% acetonitrile and 0.1% formic acid. Micro-LC-MS/MS analysis was carried out by injection of 8\u03bcl of peptide sample into a Eksigent Expert Nano LC system  coupled to a Sciex Triple-TOF 6600 mass spectrometer . A Kinetex 2.6\u03bcm XB-C18 100 A  column was used for chromatographic separation. Mobile phase A consisted of 100% Hin silico analyses . The error tolerances for parent mass and fragment mass were set as 15ppm and 0.1Da, respectively. An enzyme search with unspecific digestion was used. Post-translational modifications were as follows: C-terminal amidation, Pyro glut\u2013Q, Pyro-glut-E, sulfation and oxidation of methionine. A custom prepropeptide AMP library was used in the peptide search process. The peptide database was compiled via comprehensive hods and ). Uniquehods and  partner S. mansoni . Schistocins are cryptic peptides and have not been biochemically isolated [S. mansoni Dermaseptin like peptide, which has been biochemically isolated [S. mansoni CS\u03b1\u03b2 peptides, previously identified from an expressed sequence tag dataset [S. mansoni genome. However, the lack of conservation of these peptides in any other flatworm genome suggests that they do not represent conserved flatworm AMP groups. As a result, it is difficult to direct flatworm AMP discovery through homology-based searches using known flatworm AMPs. This provides a rationale for expanding the homology-based approach to include AMPs derived from other Lophotrochozoa as seed sequences for BLAST searches.Eight AMPs were previously reported in mansoni . While the absence of Big Defensin-encoding genes in flatworms has been noted previously , the absThe absence of canonical lophotrochozoan-type AMPs in flatworms suggests that flatworms may possess AMP groups that are currently undiscovered and distinct from those found in other lophotrochozoan phyla. This finding drives the development and application of alternative approaches for AMP discovery in flatworms.In addition to the limitations of the homology-based analyses described in this study for flatworms, reduced AMP profiles have been reported in some nematode clades . Indeed,The helminth predicted protein datasets employed in this study  and werInvertebrate AMPs often possess multiple homologs , such thGene Ontology (GO) annotations were retrieved for the remaining helminth AMP-LPs. Any helminth AMP-LPs that were associated with non-AMP related Biological Process and Molecular Function GO terms were removed from the pipeline; all peptides without GO annotations were retained. It is possible that the removed AMP-LPs with non-AMP related GO annotations also possess antimicrobial activities, however this step was included to reduce the likelihood of false positives. This removed 525 nematode and 107 flatworm peptides from the prioritised helminth AMP-LP list, resulting in 5,295 helminth AMP-LPs.S. mansoni Kunitz Inhibitor protein (SmKI-1) [For the helminth AMP-LPs that were removed, the associated non-AMP GO terms were analogous demonstrating that the AMP algorithms were comparably scoring sequences that possess similar functions see . Many of(SmKI-1) . This prIt is also interesting to note that some antimicrobial proteins such as lysozymes were also picked up in the pipeline described here. Although lysozymes were outside of the scope of this study as they are antimicrobial proteins , this piMost AMPs are <60 AAs in length; indeed ~90% of invertebrate AMPs are <50 AAs . As a reCysteine-rich peptides are common across invertebrate AMP cohorts. Indeed, within helminths, three of the five known nematode AMP families are cysteine-rich . SignifiOf the 1,727 prioritised AMP-LPs identified from the computational AMP prediction pipeline, 479 AMP-LPs were predicted to have linear structure. Most of these (92%) originated from nematode species which may reflect the expansion in genome datasets available for nematodes relative to flatworms. Twenty peptides  were selected for peptide synthesis based on: (i) peptide conservation across multiple species; (ii) overall AMP prediction tool scores; and (iii) evidence of expression in key helminth species and life stages. Due to helminth AMP-LP homology, the antimicrobial activity data arising from the 20 peptides screened here see  informs Eight AMP-LPs displayed antibacterial activity (MIC < 100\u03bcg/ml) against at least one bacterial species see . These dMeloidogyne species  nAMP-LPTrichuris suis and Trichuris trichuria  but did not display activity against either S. aureus isolate . nAMP-Lncta see . While mncta see  was the Heligmosomoides polygyrus indicating that these peptides are highly restricted in nematodes  all thrTaenia species (see E. coli and A. baumannii) and gram-positive activity  (see fAMP-LP-5 was identified in three cies see . fAMP-LPcies see . The teslis) see . This peA. suum pseudocoelomic fluid (As-PCF) detected 60 high-confidence peptide spectrum matches (PSMs) above the 1% FDR threshold Click here for additional data file.S2 File(XLSX)Click here for additional data file.S3 File(XLSX)Click here for additional data file.S4 File(XLSX)Click here for additional data file.S5 File(XLSX)Click here for additional data file.S6 File(XLSX)Click here for additional data file.S7 File(XLSX)Click here for additional data file."}
+{"text": "Patients with undetectable ctDNA (pathogenic or likely pathogenic variants in plasma using the Tempus xF assay) before RT had significantly improved progression-free survival (PFS) (P\u2009=\u20090.004) and overall survival (OS) (P\u2009=\u20090.030). ctDNA maximum variant allele frequency (VAF) pre-RT and ctDNA mutational burden pre-RT were both significantly inversely correlated with PFS  and OS . These findings were corroborated by multivariate Cox proportional hazards models that included eight additional clinical and genomic parameters. Overall, these data suggest that in patients with oligometastatic NSCLC, pre-RT ctDNA can potentially identify the patients most likely to benefit from locally consolidative RT and experience prolonged PFS and OS. Similarly, ctDNA may be useful to identify undiagnosed micrometastatic disease where it may be appropriate to prioritize systemic therapies.The optimal treatment paradigm for patients with oligometastatic non-small cell lung cancer (NSCLC) remains unclear. Some patients with oligometastatic disease experience prolonged remission after locally consolidative radiation therapy (RT), while others harbor micrometastatic disease (below limits of detection by imaging) and benefit from systemic therapy. To risk-stratify and identify the patients most likely to benefit from locally consolidative RT, we performed a multi-institutional cohort study of 1487 patients with oligometastatic NSCLC undergoing liquid biopsy analysis of circulating tumor DNA (ctDNA). In total, 1880 liquid biopsies were performed and approximately 20% of patients ( While NSCLC patients with widespread metastatic disease are incurable and generally have poor outcomes, patients with a limited metastatic burden of disease can sometimes achieve prolonged remission after definitive management of the primary tumor and metastatic sites through a combination of systemic agents and local consolidative therapies such as RTHowever, identifying patients who have truly oligometastatic disease and are most likely to benefit from locally consolidative radiation therapy is challenging. Many patients with perceived oligometastatic NSCLC on imaging likely harbor undetected widespread metastatic disease (micrometastatic disease) below the limit of detection of current imaging technologies. Establishing a new liquid biopsy biomarker to segregate those patients with truly oligometastatic disease from those with widespread micrometastatic disease could alter treatment approaches. Patients with evidence of micrometastatic disease could be triaged to earlier systemic therapies or enrollment in clinical trials \u2014 in addition to sparing the costs, systemic therapy breaks, and potential side effects associated with local consolidative therapies. Similarly, clinicians could provide more concrete guidance to patients regarding the possibility of prolonged remission, and potentially offer more aggressive locally consolidative treatment in truly oligometastatic patients who do not harbor liquid biopsy evidence of micrometastatic disease.5. Here, we hypothesized that ctDNA analysis could be applied earlier (pre-RT) to risk-stratify patients with oligometastatic NSCLC and enable patient-personalized determination of local consolidative radiotherapy versus systemic therapy.We have previously shown that post-RT plasma circulating tumor DNA (ctDNA) is powerfully prognostic in localized NSCLCn\u2009=\u2009151) experienced progressive disease and 11% (n\u2009=\u200934) died during the study period. ctDNA quantitation was based on the detection of pathogenic or likely pathogenic variants in plasma. ctDNA was detected in 74% of oligometastatic NSCLC patients prior to RT (n\u2009=\u2009230) while the remaining 26% (n\u2009=\u200979) had no detectable ctDNA pre-RT. Among the 230 ctDNA-detectable patients, 76% (n\u2009=\u2009175) had 1\u20133 variants, while the remainder (n\u2009=\u200955) had \u22654 pathogenic or likely pathogenic variants present.Median follow-up time after initial blood collection for liquid biopsy analysis was 10.3 months. Across all ctDNA assays, 3503 pathogenic or likely pathogenic variants were identified . Of the sub-cohort of 309 patients who underwent liquid biopsy after the diagnosis of oligometastatic disease and before RT, 48%  [Fig. p\u2009=\u20090.030, HR\u2009=\u20091.65, CI\u2009=\u20091.05\u20132.61) [Fig. Both progression-free survival (PFS) and overall survival (OS) were significantly worse in oligometastatic NSCLC patients with detectable ctDNA from pre-RT liquid biopsies, as compared to those without detectable ctDNA pre-RT. Patients with detectable ctDNA pre-RT had a median PFS of 5.4 months versus 8.8 months (13) Fig. . Similar61) Fig. .Fig. 1Sup\u2009=\u20090.008) and death (p\u2009=\u20090.007) [Supplementary Fig. p\u2009=\u20090.025, HR\u2009=\u20093.78, CI\u2009=\u20091.08\u201311.30) [Fig. p\u2009=\u20090.006, HR\u2009=\u20095.42, CI\u2009=\u20091.49\u201317.03) [Fig. p\u2009=\u20090.044), while for PFS, squamous histology and age at diagnosis also demonstrated significance. Other clinical and genomic parameters including gender, smoking status, metastatic burden, initial disease stage, and presence of known common mutations and alterations were not significant with regard to survival outcomes.ctDNA levels  demonstrated significant risk correlations, with the maximum pre-RT ctDNA VAF associated with increased risk of both disease progression (30) Fig.  and OS (03) Fig. . Notablyp\u2009=\u20090.003) and death (p\u2009=\u20090.045) [Supplementary Fig. p\u2009=\u20090.004, HR\u2009=\u20091.14, CI\u2009=\u20091.03\u20131.24) [Supplementary Fig. p\u2009=\u20090.014, HR\u2009=\u20091.13, CI\u2009=\u20091.02\u20131.23) [Supplementary Fig. p\u2009=\u20090.039), while other clinical and genomic parameters were not.Similar findings were observed when stratifying patients by pre-RT ctDNA mutational burden (the number of detectable pathogenic or likely pathogenic variants detected in plasma), with increasing ctDNA mutational burden associated with both progression , a finding hinted at by other recent workThis approach should be prospectively evaluated in a clinical trial that redefines oligometastatic NSCLC to include a discrete liquid biopsy metric encompassing a low or undetectable ctDNA level. This technique may also be valuable for those patients who undergo curative-intent treatment for earlier stages of NSCLC, but subsequently develop oligometastatic disease (deemed \u201coligorecurrence\u201d) and are weighing individualized treatment decisions.This was a real-world study, with data collected from multiple clinical sites including both academic and community practices. Clinical data including metastases and RT were provided by the managing clinicians. Given incomplete data regarding the exact timing of oligometastatic disease diagnosis and RT, we explicitly focused on a sub-cohort where a liquid biopsy was definitively performed prior to RT administration in oligometastatic NSCLC patients [Supplementary Fig. In conclusion, this study suggests that pre-RT ctDNA may be a powerful biomarker to accurately identify micrometastatic disease in patients with oligometastatic NSCLC. Earlier risk stratification using this liquid biopsy biomarker could support future clinical trials to enable personalized decision-making based on per-patient ctDNA risk profiles. Patients with high-risk ctDNA profiles could undergo systemic therapy prioritization and potentially escalation , while patients with undetectable ctDNA or low ctDNA risk profiles could be offered locally consolidative stereotactic radiotherapy with biomarker-driven confidence.All analyses were performed using de-identified patient data. The study was exempt from institutional review board evaluation and informed consent given the de-identified nature of the data.n\u2009=\u2009309 patients) [Supplementary Fig. n\u2009=\u20091178) [Supplementary Fig. We leveraged a multi-institutional real-world cohort consisting of 1487 patients from both academic and community practices who were diagnosed with oligometastatic NSCLC. Peripheral blood samples were collected for liquid biopsy analysis between 2016 and 2022. The cohort mean age (SD) was 64.7 years (10.1), with similar numbers of male and female patients  [Table 11. ctDNA results were analyzed for variants using VarDict12 and characterized as pathogenic or likely pathogenic based on their predicted functional impact as determined by SnpEff13 and clinical evidence, following the ACMG/AMP guidelines for variant classification14. We excluded variants considered benign, likely benign, or having conflicting evidence. Variants were quantified per patient, along with the maximum variant allele frequency (VAF). Fusions and CNVs were identified using SpeedSeq15 and CNVkit16, respectively. Patient-level data of time to outcomes, ctDNA mutational burden, VAF, and other parameters used in this study are provided in Supplementary Table The Tempus xF liquid biopsy assay is a laboratory developed test (LDT) designed to detect oncogenic and resistance mutations in cell-free DNA. The assay detects single nucleotide variants (SNVs), insertions/deletions (indels), rearrangements, copy number variations (CNVs), and microsatellite instability (MSI) with high sensitivity and specificityp-values represent the log-rank test. Hazard ratios for OS and PFS in Kaplan\u2013Meier analyses reflect the Mantel\u2013Haenszel test. Multivariate Cox regression p-values were calculated using the Wald test. Data were managed using Apache Superset 2.1.0, and statistical analyses were performed using GraphPad Prism version 9.5.1 and R version 4.2.2.Median follow-up time was determined using the reverse Kaplan\u2013Meier method. Outcomes for overall survival (OS) and progression-free survival (PFS) were both calculated from the start of RT . Progression was reported by the managing clinicians. Kaplan\u2013Meier curve Further information on research design is available in the Supplementary MaterialReporting SummarySupplementary Table 1"}
+{"text": "E. faecium is a common hospital-acquired bacteria in the United States, with a high prevalence of vancomycin resistance seen within this species. Hospital-adapted vancomycin-resistant E. faecium (VREfm) lineages, such as ST17 and ST117, contribute to the spread and persistence of VREfm within healthcare systems. Although the dynamics of these lineages within healthcare systems have been characterized, little is understood as to what drives strain replacement in VREfm.Comparative genomic analyses were performed on 718 clinical VREfm isolates collected between January 2017 and December 2022 at a large tertiary care center as part of the Enhanced Detection System for Hospital-Associated Transmission (EDS-HAT). Clusters of potential healthcare-associated transmission were determined using split kmer analysis (SKA) with a threshold of 20 single nucleotide polymorphisms (SNPs). Spot killing assays were performed using representative ST17 and ST117 isolates.in vitro .Of 718 clinical isolates, most were collected from urine (42%) followed by blood (23%), wounds (19%), and tissue (10%). Nearly all isolates (92%) belonged to 11 well characterized, hospital-adapted VREfm lineages . In total, 116 potential transmission clusters were identified containing 62% of isolates collected. Prior to 2019, lineage ST17 was dominant, but this lineage was replaced by the emergence of ST117 beginning in 2019 . Comparative genomic analyses revealed minimal differences in accessory genes between these lineages, including antimicrobial resistance genes (ARGs) and virulence factors. Spot killing assays showed that a lineage ST117 isolate inhibited the growth of a lineage ST17 isolate The core genome phylogenetic tree was constructed using RAxML-HPC using a core genome alignment from Roary. The tree is midpoint-rooted. Isolates are colored by multi-locus sequence type (MLST) and year of culture.Datapoints represent the distribution of multi-locus sequence types (MLST) collected within 6-month windows throughout the study period. The number of isolates (n) is indicated for each timeframe.A) Experimental design of spot killing assay. Molten Brain Heart Infusion (BHI) top agar was mixed with 100 \u00b5L of 1:100 overnight culture of a representative ST117 or ST17 isolate and plated onto 25 mL of solidified BHI bottom agar. After the top agar set, 5 \u00b5L of the overnight cultures of ST17 and ST117 were spotted onto the bacterial lawns. Plates were incubated overnight, and inhibition zones were measured in millimeters (mm). Plates show spot killing assay of representative ST117 and ST17 isolates (B-E). B) Lawn of ST17 exposed to ST117 spot. C) Lawn of ST117 exposed to ST117 spot. D) Lawn of ST117 exposed to ST17 spot. E) Lawn of ST17 exposed to ST17 spot.This study provides insight into the temporal population dynamics and healthcare-associated transmission patterns of VREfm within a large tertiary care facility. We demonstrate that the 11 most prominent VREfm lineages share highly similar ARG and virulence factor profiles, which may enable persistence in the nosocomial niche. Additionally, we find evidence that emergence of specific lineages, such as ST117, may be driven by direct growth inhibition of lineages that were previously dominant in our setting.Graham M. Snyder, MD, SM, Infectious Diseases Connect: Advisor/Consultant Alexander Sundermann, DrPH, CIC, FAPIC, OpGen: Honoraria"}
+{"text": "Background: Antimicrobial resistance (AMR) in Neisseria gonorrhoeae (NG) is an emerging public health crisis. Whole-genome sequencing (WGS) is an efficient way of predicting AMR determinants and their spread in the population. In a previous study, genotype\u2013phenotype correlation analyses among NG isolates to determine antimicrobial resistance revealed discordance for azithromycin (AZM) and ceftriaxone (CRO) compared to other antibiotics. We investigated the evolutionary relatedness of NG isolated from patients with sexually transmitted infection (STI) using WGS in southeastern Michigan. Methods: Isolates, corresponding demographic data, and minimum inhibitory concentrations (MIC) via E-test (CRO) and broth microdilution (AZM) were obtained from the Michigan Department of Health and Human Services. Whole-genome libraries were prepared using the QIAseq FX kit followed by sequencing on a NovaSeq6000 (>200X Coverage); samples were aligned to NG reference strain TUM19854 (NZ_AP023069.1) using Snippy before phylogenetic tree generation using Neighbor-joining clustering on the core.aln files. Phylogenetic trees were visualized using ATGC:PRESTO. Results: In total, 38 isolates were analyzed. Demographic data and susceptibility testing results are noted in Table 1. Most isolates were from males (63%), Blacks (44.7%), individuals living in Detroit City proper (47.3%), and those with unknown HIV status (55.2%). More than one-third had prior STI, including NG. All isolates were susceptible to CRO . Within the phylogenetic tree, 8 main branches were identified . Moreover, 1 branch contained a cluster with 12 closely related isolates, which included the 9 isolates with nonsusceptible AZM. Nearly all isolates in that cluster had been collected from Detroit City proper and Wayne County, suggesting epidemiological overlap and potential spread of resistant strains in those counties.Conclusions: Comparative whole-genome and phylogenetic analyses among a subset of NG isolates revealed clustering of AZM resistance strains, suggesting a genomic component to AMR. Further studies are needed to determine the utility of WGS in diagnosis, outbreak investigations, and management of NG infections.Disclosures: None"}
+{"text": "In the US, 90% of dentists work in private practice (PP). We aim to describe how infectious diseases (ID) antibiotic stewardship (AS) experts collaborated with dentists to provide dental AS education.Fifteen PP dentists completed a study conducted in 2021 by an ID-AS pharmacist and physician assessing their antibiotic use to identify AS opportunities. After learning dental AS from ID\u2013AS experts, these dentists optimized and significantly decreased their antibiotic use. An AS \u201ccall to action\u201d was launched in Sept. 2021 on how to expand our education to additional dentists to optimize antibiotic prescribing further. Dentists recommended ID-AS experts provide dental AS education to their long standing established local and national dental study club networks and other dental continuing education (CE) venues. Education focused on 5 areas: decreasing antibiotic use and durations, eliminating clindamycin and quinolones, incorporating shared decision making with patients, reviews of evidence based studies, and penicillin allergic patient management. Attendees were asked 3 questions prior to each lecture; 1. Have you heard of the term dental AS?; 2. Do you use clindamycin for penicillin allergic patients? 3. What is your standard duration of antibiotic therapy? Educational events were recorded through April 2023.ID-AS experts provided AS education to 3742 PP dental providers, students/faculty over 20 months (Table 1). Prior to our lectures, most (90%) dentists were unfamiliar with dental AS; 88% prescribed clindamycin for penicillin allergies and 7 days were the most frequent duration for antibiotics.PP dentists and faculty embraced AS education. Dental study clubs/CE forums provide excellent opportunities for ID-AS experts to engage and educate PP dentists. Dentists who attended AS lectures strongly support a 1-hour AS annual CE, similar to annual dental opioid CE required by many states.All Authors: No reported disclosures"}
+{"text": "Chemo- and optogenetic manipulations of microglia in vivo are powerful in interrogating microglial function in chronic pain. This review summarizes these emerging tools in studying the role of microglia in chronic pain and highlights their potential applications in microglia-related neurological disorders.Chronic pain relief remains an unmet medical need. Current research points to a substantial contribution of glia-neuron interaction in its pathogenesis. Particularly, microglia play a crucial role in the development of chronic pain. To better understand the microglial contribution to chronic pain, specific regional and temporal manipulations of microglia are necessary. Recently, two new approaches have emerged that meet these demands. Chemogenetic tools allow the expression of designer receptors exclusively activated by designer drugs (DREADDs) specifically in microglia. Similarly, optogenetic tools allow for microglial manipulation  Neuropathic pain is a chronic condition that results in pain hypersensitivity and allodynia  after nerve damage that can occur after a host of insults, such as physical injury, diabetes, or autoimmune diseases . When ti2, brain-derived neurotrophic factor, and reactive oxygen species. These signals can lead to chronic pain [Microglia undergo functional changes during chronic pain states. In homeostatic conditions, microglia dynamically respond to changes in the microenvironment with their remarkably motile processes \u201313. Howenic pain , 14. In nic pain . Howevernic pain , 16. Recnic pain .The cellular mechanisms of microglia in chronic pain have been investigated through pharmacological approaches. For example, systemic inhibition of microglia and macrophages by the broad inhibitor minocycline attenuates pain hypersensitivity , 8. HoweThe importance of spinal microglia in the development of chronic pain has also been demonstrated by using genetic approaches to remove key microglial genes such as P2X4 , P2X7 2, CX3CR1 2+ signaling [Chemogenetic approaches refer to the expression and activation of DREADDs , 40. DREignaling , memory ignaling \u201347, neurignaling , and paiignaling , 50. Micignaling . In partignaling  and duriignaling , 53, 54.in vivo is complicated, and it may not achieve robust transfection levels [2+. Thus, Gq DREADD activation induces pro-inflammatory mediator production, while Gi DREADD activation inhibits lipopolysaccharide- (LPS) and chemokine (C-C motif) ligand 2-induced inflammatory signaling in vitro [Several studies have used chemogenetic approaches in microglia Table . The Watn levels . Howevern levels . On the n levels , 59, potin vitro . One potin vitro . Howeverin vitro . NonetheCx3cr1cre/+:R26LSL-hM4Di/+ mice results in Gi DREADD expression in all CX3CR1-expressing cells including microglia and monocytes [Cx3cr1creER/+:R26LSL-hM4Di/+\u00a0mice [+ cells have rapid turnover while microglia are longer-lived, it is possible to achieve greater microglial specificity by waiting for cell turnover after tamoxifen administration [+ microglia in the spinal cord and brain 4 weeks after tamoxifen injection [Other studies have more commonly applied gene knock-in approaches to selectively express Gi/Gq DREADD in microglia \u201363. The onocytes . To exclstration . Indeed,njection \u201363.Fig. Cx3cr1creER/+:R26LSL-hM3Dq/+ mice were used for the functional expression of microglial Gq DREADDs [2+ elevation and the phagocytosis of FluoSpheres in primary microglia. Unexpectedly, chronic Gq DREADD activation attenuated the LPS-induced increase of pro-inflammatory cytokines, including TNF\u03b1, IL-1\u03b2, and IL-6 in the mouse brain. In line with these results, chronic Gq DREADD activation in microglia robustly increased social exploration 2 h after LPS-induced inflammation [Cx3cr1creER/+ mice [Cx3cr1creER/+:R26CGaMP5g\u2013tdTomato/+LSL-hM3Dq- mice were used for the expression of microglial Gq DREADDs. Activation of Gq DREADDs in microglia that interact with arterioles and microvessels in the cortex led to the withdrawal of perivascular microglial processes around arterioles and reduced the cerebral blood flow in response to whisker stimulation. Taken together, these bi-directional chemogenetic approaches have proven to be powerful tools in interrogating microglial function in the brain.In addition to pain research, chemogenetic methods were also recently applied to microglia to investigate their functions in inflammation, vascular interaction, and aversive behaviors. For example, inducible  DREADDs . Gq DREAammation . RecentlR/+ mice . Using tR/+ mice . ChemogeR/+ mice . Cx3cr1c2+ elevation for pro-inflammatory cytokine production or release [The first study applying chemogenetic approaches through the viral expression of DREADDs in microglia studied the contribution of microglia to morphine-induced persistent sensitization in rats . While o release , 71.Using viral expression of both Gq and Gi DREADD specifically in microglia, the group further studied the role of microglia in chronic pain in rats . Gi DREACx3cr1cre/+:R26LSL-hM4Di/+ mice, Kiguchi\u2019s group showed that microglia expressing Gi DREADDs in the spinal cord, upon activation, alleviate pain sensitization after partial sciatic nerve ligation (PSL) [Cx3cr1creER/+:R26LSL-hM4Di/+ mice, we showed that Gi DREADDs are specifically expressed in microglia in adult mice [After Cre-inducible DREADD mice were generated in 2016 , both Kion (PSL) . Using iult mice . Microglult mice .in vivo are reduced upon activation of microglial Gi DREADD. These results complement and expand previous findings that selective microglial activation in the spinal cord promotes synaptic strengthening and synaptic plasticity between primary afferent C-fibers and spinal neurons [Several potential mechanisms underlying microglial Gi DREADD in pain attenuation have been proposed . First,  neurons , 75. TogCx3cr1cre/+:R26LSL-hM3Dq/+ mice [Microglial function in chronic pain was further investigated by using Gq DREADD in constitutive q/+ mice . After G+ cells attenuates mechanical allodynia after PSL only in male mice [Cx3cr1cre/+versus inducible Cx3cr1creER/+ mouse lines impacting different sets of cell classes) or different CNO dose paradigms (one time-point only at 10 mg/kg vs three times at 5 mg/kg/day). Further, no sex differences have been reported in chronic pain attenuation after CX3CR1+ cells are genetically ablated [These findings are part of a larger literature finding an interesting sex-dependent microglial function in chronic pain. Although microglial activation (microgliosis) develops in both sexes in neuropathic pain models, emerging reports suggest that microglial inhibition resolves pain only in male mice. For example, microglia-targeted inhibitors  are effective in attenuating neuropathic pain in male but not female rodents \u201378. One ale mice . While Gale mice . This di ablated . Future Optogenetics fuse genetic and optical procedures to allow the manipulation of specific cell populations, conferring the unique capability to sense and respond to light through light-sensitive proteins in behaving animals . All kno+ or Ca2+ channels in vivo. Microglia mediate ionic fluxes using multiple ion channels including K+ channels [+ channel conductance often precedes the reactive state transition [+ channels are also essential for microglial process surveillance and chemotactic responses to extracellular ATP/tissue injury [Ionotropic signaling is an overlook mechanism underlying microglial interactions with the brain microenvironment . Unlike channels , 91, prochannels , transiechannels , pannexichannels , 95, andchannels . The chaansition , 97. K+ e injury , 99. Howe injury , 100.Iba1-tTA:tetOChR2(CS128S)-EYFP mice [Cx3cr1creER/+:R26LSL-ReaChR/+ mice [Cx3cr1creER/+:R26LSL-ReaChR/+ mice. In the spinal cord, rhodopsin protein is only co-localized with Iba1+ microglia [2+ influx [2+-dependent cytokine release.Only a few studies have used optogenetic approaches in microglia so far Table . In a prYFP mice . Blue liR/+ mice . The advR/+ mice . Selectiicroglia . ReaChR + influx . Thus, oCx3cr1creER/+:R26LSL-ChETA-tdTomato/+ mice [+ channel activation is part of the mechanism for rapid chemotactic reactions to laser injury or basal motility [Cx3cr1creER/+:R26LSL-ArchT-EGFP/+ mice [Similarly, ChETA (a modified form of ChR2) was expressed in microglia using o/+ mice . ChETA ao/+ mice . Microglo/+ mice . Indeed,motility , 98, 99.motility . NeverthP/+ mice . Unlike via Ca2+ signaling [2+ in microglia is strongly correlated with pathophysiological activation such as neuroinflammation [2+-permeable ion channels [2+ influx. As a result, ReaChR activation of microglia leads to Ca2+-independent cytokine release [2+-free extracellular solutions, microglial chemotaxis to damage sites is significantly slowed, similar to the increased ionic influx during ChETA activation [2+ elevation, thus slowing the chemotaxis of microglial processes. The underlying mechanism might be due to the reduction of the driving force for Ca2+ during depolarization in microglia. Interestingly, previous studies found that the removal of extracellular Ca2+ alone induces the convergence of microglial processes, similar to that reported in seizures and stroke [in vivo Ca2+ imaging are needed to directly investigate whether optogenetic activation of microglia increases or decreases microglial Ca2+ signaling.Microglia sense neuronal activity and the brain environment ignaling , 105. Inammation , seizureammation , stroke ammation , and neuammation . Since Cchannels , optogen release . On the tivation . Therefod stroke , 111. FuCx3cr1creER/+:R26LSL-ReaChR/+ mice to exclusively express ReaChR in microglia, spinal microglia can be depolarized in real time to examine their function in pain behaviors  or by promoter-driven conditional expression . Unless activated, these proteins have no biological effects. Upon activation, existing DREADDs and opsins allow for a range of modulatory effects on microglia, including depolarization, hyperpolarization, and GPCR signal transduction. Chemo- and optogenetic manipulations of microglia are able to inhibit nerve injury-induced neuropathic pain or directly trigger chronic \u201cmicrogliogenic\u201d pain. However, it is important to note the limitations of chemo- and optogenetic approaches, as both use artificially-engineered proteins activated by designed stimuli. With chronic DREADD approaches, it has been suggested that repeated administration of CNO may lead to clozapine accumulation, which may have side effects unrelated to DREADDs . The opt2+ levels allows the investigation of the role of Ca2+ signaling in microglia. Interrogation of the downstream Gi and Gq signaling in microglia is also made possible. Thus, the recent advances in microglial chemo- and optogenetic manipulations highlight the importance and novelty of these emerging tools in studying the function of microglia in neurological diseases, particularly in chronic pain.Here, we highlight the future of investigations of microglia by applying chemo- and optogenetic tools. (1) Microglia play a central role in many pathophysiological processes, such as in epilepsy , stroke"}
+{"text": "Background: Carbapenem-resistant Acinetobacter baumannii (CRAB) are bacteria that cause healthcare-associated infections and outbreaks. Most produce carbapenemases like New Delhi metallo-\u03b2-lactamase (NDM), which are more commonly found in carbapenem-resistant Enterobacterales but rarely in CRAB. In 2018, selected laboratories began participating in a public health sentinel surveillance program by routinely submitting CRAB and other antimicrobial-resistant isolates to the AR Laboratory Network for specialized testing. In May 2020, the Antimicrobial Resistance Laboratory Network detected the first NDM-CRAB case in California, triggering an investigation. Initial whole-genome sequencing of subsequent isolates indicated high relatedness. Methods: We defined confirmed cases as patients with NDM detected in CRAB isolates and probable cases as NDM detected in a screening swab from a patient epidemiologically linked to a known case(s) with specimens collected during May 2020\u2013September 2022. We defined outbreak facilities as having (1) 1 or more newly identified cases during a point-prevalence survey in response to a known case or (2) at least 2 cases identified within 4 weeks of each other that were epidemiologically linked. We analyzed demographic and specimen characteristics, as well as healthcare exposure history using R Studio version 1.3.959 software. Results: Of 230 total patients, 176 (77%) were confirmed and 54 (23%) were probable cases; 150 (65%) were identified through colonization screening. Among 176 NDM-CRAB isolates, the most common specimen sources were respiratory (n = 29), wound (n = 28), and urine (n = 24), and 87 (49%) of 176 isolates were nonsusceptible to all antimicrobials tested. Among patients, median age was 65 years , 127 (55%) were male, 37 (15%) were Hispanic or Latino, and 100 (43%) were White. We identified 37 outbreak facilities across 13 counties, including 25 acute-care hospitals (ACHs), 6 skilled nursing facilities (SNFs), 5 ventilator-equipped SNFs (vSNFs), and 1 long-term ACH. We identified 125 cases (54%) in SNFs and vSNFs and 93 cases (40%) in ACHs; among ACH patients, 43 (46%) had been SNF or vSNF residents within the prior year. No patients reported international exposure. Conclusions: The first known case of NDM-CRAB in California was detected by sentinel surveillance. In this extensive regional outbreak, most cases were identified by screening at public health and clinical laboratories. Transmission occurred across healthcare settings connected by patient sharing, underscoring the importance of communication, active surveillance, and implementation of infection prevention and control practices to mitigate spread within and between facilities. Expanding these efforts, with support and resources from public health departments, is key to detecting, characterizing, and containing future outbreaks of antimicrobial-resistant pathogens.Disclosure: None"}
+{"text": "Adults living in long-term care (LTC) facilities are at increased risk of respiratory infectious diseases, including pneumococcal disease. On August 13, 2014, the Advisory Committee on Immunization Practices recommended 13-valent pneumococcal conjugate vaccine (PCV13) in addition to 23-valent pneumococcal polysaccharide vaccine (PPSV23) for adults aged \u226565 years based on data that showed PCV13 vaccination confers protection against all-cause community-acquired pneumonia (CAP) and invasive pneumococcal disease (IPD). We assessed PCV13 vaccination coverage and incidence of CAP and IPD among Medicare beneficiaries with \u22651 LTC stay.We identified Medicare Fee-for-Service beneficiaries aged \u226565 years with no prior PCV13 receipt and \u22651 LTC facility stay during September 1, 2014 through December 31, 2019 through Minimum Data Set assessments and skilled nursing facility claims. PCV13 and PPSV23 vaccination history was determined through Medicare claims using Healthcare Common Procedure Coding System and Current Procedural Terminology codes. Incident IPD and CAP outcomes were identified through inpatient Medicare claims using International Classification of Diseases diagnosis codes (ICD-9-CM/ICD-10-CM). Outcome incidence was calculated based on time during and outside LTC stays. PCV13 coverage was assessed by LTC residency status on December 31, 2019.There were 3,643,248 beneficiaries with \u22651 LTC facility stay during the observation period. Beneficiaries were majority white (89.9%), female (62.1%), aged \u226575 years (67.7%), and had \u22651 chronic medical condition (55.7%); 25.6% had received PPSV23 vaccination at the study start date. By December 31, 2019, PCV13 coverage was 55.3%; coverage among those residing in and outside a LTC facility was 47.5% and 57.3%, respectively. Incidence of CAP and IPD were higher during LTC compared with time outside LTC stay  (Table).Incidence of IPD and CAP were higher during an LTC stay compared with time residing outside of a LTC facility. PCV13 coverage was lower among those in LTC. Improving pneumococcal vaccination coverage may help mitigate the risk of IPD and CAP in this population.All Authors: No reported disclosures"}
+{"text": "Mycobacterium bovis is the primary causative agent of bovine tuberculosis, a zoonotic infectious disease of concern for human health, livestock, and wildlife conservation. We report a complete genome sequence of an endemic Mycobacterium bovis strain affiliated with a wildlife reservoir of bovine tuberculosis found in wood bison in Wood Buffalo National Park, Canada. Mycobacterium bovis is the most common causative agent of bovine tuberculosis (bTb), an important zoonotic disease (Bison bisonathabascae) in and around Wood Buffalo National Park (WBNP) acts as a wildlife bTb reservoir  by Parks Canada Agency wildlife health staff in March 2022 and submitted for bacterial culture to the National Reference Laboratory for Bovine Tuberculosis, Canadian Food Inspection Agency. The samples were collected under Parks Canada research and collection permit number 45863. The tissue samples were processed for inoculation into several types of liquid and solid media and incubated at 37\u00b0C until typical mycobacterial colonies were observed and characterized according to standard microbiological methods (M. bovis strain 2022/0038 (OLF-AH-2022-TB-0122) was isolated from modified Middlebrook with malachite green (MMMG) medium and taxonomically identified using biochemical (rpoB gene sequencing. Genomic DNA (gDNA) was purified from an MMMG subculture using the MasterPure Gram-positive DNA purification kit . An Illumina sequencing library was prepared using the Nextera XT DNA library preparation kit , and 2,643,748 paired-end 250-bp reads were generated on the Illumina MiSeq platform. For Nanopore sequencing, gDNA samples were additionally treated with the short-read eliminator XS kit . The Nanopore library was prepared using the ligation sequencing gDNA kit  without shearing and sequenced on a Flongle FLO-FLG001 flow cell using the MinION Mk1B device (ONT), generating 71,783 reads with an N50 value of 5,978\u2009bp. Base calling of the Nanopore reads was performed using Guppy v6.3.7 in super-accuracy mode. The reads were trimmed using Porechop v0.2.4 and filtered using Filtlong v0.2.1 . Gene prediction and annotation were performed using the NCBI Prokaryotic Genome Annotation Pipeline v6.4 . Whole-genome comparison of the strain 2022/0038 with the M. bovis reference strain AF2122/97  has been deposited at GenBank under accession number CP117298.The Illumina and Nanopore sequencing reads are available in the NCBI Sequence Read Archive under accession numbers"}
+{"text": "Here, we report the genome sequences of 10 Carnation mottle virus variants. Six variants originated from a single proprietary carnation cultivar, and four were derived from four different proprietary cultivars. All variants showed nucleotide differences, but the last four did not show any variation at the amino acid level. Carnation mottle virus  is a single-stranded positive-sense RNA virus with four open reading frames (ORFs) (Dianthus caryophyllus (carnation), can result in mild mottling in young leaves but typically only faint chlorosis in mature leaves. Besides the CarMV genome reference sequence NC_001265.2, just 11 complete variant genome sequences are present in Genbank (s (ORFs) . Infecti Genbank .To gain deeper understanding of the CarMV genetic variation, we conducted small-RNA sequencing (sRNA-seq) on 10 asymptomatic carnation plants from various undisclosed commercial cultivars sourced from an anonymous plant-breeding company in the Netherlands. In carnation experiment 1 (CE1), six out of eight plants belonging to the same confidential cultivar were found positive for CarMV enzyme-linked immunosorbent assay (ELISA). In carnation experiment 2 (CE2), four distinct confidential cultivars that tested positive for CarMV ELISA were used. All samples were collected in February 2020 from a greenhouse complex situated in the southern region of the North-Holland province in the Netherlands. Genomes sequences of possible CarMV variants were determined by examining the siRNA response of the plants .https://shop.wur.nl/primediagnostics/carnation-mottle-virus-carmv.html) following the protocol provided by the manufacturer. Small-RNA was isolated by grinding a flash-frozen \u00b11 cm2 leaf fragment to fine powder using mortar and pestle, dissolving the powder in QIAzol Lysis Reagent (Qiagen) and enriching small-RNA using the miRNeasy Mini Kit (Qiagen). Barcoded small-RNAseq libraries were generated using Ion Total RNA-Seq Kit v2 and Ion Xpress RNA-Seq Bar Coding Kit (Thermo Fisher Scientific). Sequencing (150 bases) with an Ion Proton System using Ion PI-v3 chips and a Ion Chef System using Ion PI-Hi-Q-Chef Kit (Thermo Fisher Scientific) CE1 and CE2 yielded on average 5 (CE1) and 31 (CE2) million reads per sample.The ELISA assay was performed using the Prime Diagnostics  CarMV Kit , mutations were observed, ranging from 108 (2.7 %) to 141 (3.5%) nucleotides  to 23 (2.0%) amino acids. Although there are nucleotide differences between the four CE2 CarMV variants, they are identical at the protein level, whereas the six CE1 CarMV variants are different at the genome and protein level."}
+{"text": "In the original publication , there wThe correct legend of Figure 4 is as follows:Figure 4. Branched and linear nucleation factors are crucial for cell wound repair. (A) Schematic diagram depicting crucial factors for stabilizing and nucleating linear actin filaments. Formins add actin monomers to the barbed end of the actin filament, whereas crosslinkers aid in bundling linear filaments. (B) Schematic diagram depicting branched filament assembly via the Arp2/3 complex and WAS family proteins. (C\u2013F) XY super-resolution view of actin ring organization at 70% percent wound closure in control cell wounds showing a dense actin mesh circumscribing the wound (C), Diaphanous RNAi knockdowns (disrupting linear actin formation) exhibit a diffuse mesh of branched actin at the wound periphery (D), alpha-actinin RNAi knockdowns (an actin crosslinker needed for actin bundling) form a more sparse ring at the wound edge compared to that at control wounds (E), and Arp 2/3 RNAi knockdowns (disrupting branched actin formation) do not form an actin ring at the wound periphery, but rather have unusually long linear actin filaments within the wound (F). Scale bar: 5 \u00b5m. (G) Schematic diagram depicting different types of actin architectures. Reprinted from Ennomani et al., (2016), Curr. Biol. 26(5): 616\u2013626. doi:10.1016/j.cub.2015.12.069 [60], with permission from Elsevier.The authors state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."}
+{"text": "Critically ill patients, particularly those treated with extracorporeal devices or at extremes of weight, experience pharmacokinetic variability which can compromise beta-lactam (BL) antibiotic target attainment and treatment response. Therapeutic drug monitoring (TDM) for BL antibiotics can improve precision pharmacotherapy but has had limited implementation. The objective of this study was to evaluate the frequency of BL target attainment among adult intensive care unit (ICU) patients who underwent TDM.2 or > 40 kg/m2). Percentage of patients with initial serum trough concentrations within the therapeutic range was calculated (Table 1).This observational study evaluated adults treated with cefepime, piperacillin/tazobactam or meropenem in ICUs at the Mayo Clinic in Rochester, Minnesota who underwent TDM from June-September 2022. During the study timeframe, multidisciplinary teams were encouraged to perform BL TDM on patients requiring extracorporeal membrane oxygenation, continuous kidney replacement therapy, or at an extreme of body weight  were initial troughs during the antibiotic course, and 5 (9%) were repeat troughs. Thirty-six (73%) of the initial trough concentrations were within the therapeutic range. Among the trough concentrations outside the therapeutic range, 10 (77%) were too high, and 3 (23%) were too low (Table 2). Dose adjustment occurred in 19 (39%) of initial trough evaluations, including 6 which were adjusted despite a level within the therapeutic range. All of the repeat trough concentrations drawn during the same antibiotic course were within the therapeutic range .One-fourth of initial BL trough concentrations were outside of the therapeutic range. BL levels outside the therapeutic range prompted dose adjustment to improve the potential for effectiveness or limit the potential for toxicity. BL TDM appears to be a promising strategy to enhance precision pharmacotherapy in the critically ill.Sara Ausman, PharmD, Gilead: Honoraria Christina G. Rivera (O'Connor), Pharm.D, Gilead Sciences: Advisor/Consultant|Gilead Sciences: Board Member|Gilead Sciences: Grant/Research Support|Gilead Sciences: Honoraria"}
+{"text": "To evaluate a novel method of semisupervised learning (SSL) guided byautomated sparse information from diagnostic reports to leverageadditional data for deep learning\u2013based malignancy detection inpatients with clinically significant prostate cancer.P values for performance differences were generatedwith a permutation test.This retrospective study included 7756 prostate MRI examinations (6380patients) performed between January 2014 and December 2020 for modeldevelopment. An SSL method, report-guided SSL (RG-SSL), was developedfor detection of clinically significant prostate cancer usingbiparametric MRI. RG-SSL, supervised learning (SL), and state-of-the-artSSL methods were trained using 100, 300, 1000, or 3050 manuallyannotated examinations. Performance on detection of clinicallysignificant prostate cancer by RG-SSL, SL, and SSL was compared on 300unseen examinations from an external center with a histopathologicallyconfirmed reference standard. Performance was evaluated using receiveroperating characteristic (ROC) and free-response ROC analysis.At 100 manually annotated examinations, mean examination-based diagnosticarea under the ROC curve (AUC) values for RG-SSL, SL, and the best SSLwere 0.86 \u00b1 0.01 (SD), 0.78 \u00b1 0.03, and 0.81 \u00b10.02, respectively. Lesion-based detection partial AUCs were 0.62\u00b1 0.02, 0.44 \u00b1 0.04, and 0.48 \u00b1 0.09, respectively.Examination-based performance of SL with 3050 examinations was matchedby RG-SSL with 169 manually annotated examinations, thus requiring 14times fewer annotations. Lesion-based performance was matched with 431manually annotated examinations, requiring six times fewerannotations.RG-SSL outperformed SSL in clinically significant prostate cancerdetection and achieved performance similar to SL even at very lowannotation budgets.Keywords: Annotation Efficiency, Computer-aided Detectionand Diagnosis, MRI, Prostate Cancer, Semisupervised Deep LearningSupplemental material is available for thisarticle.Published under a CC BY 4.0 license.  Malignancy detection models trained using semisupervised learning with pseudolabels guided by clinical reports required up to 14 times fewer manualannotations for training and achieved similar performance compared withsupervised learning methods.\u25a0 A novel semisupervised learning (SSL) method, which leveragesclinical reports to guide voxel-level pseudo labels, was developed forjoint detection and segmentation of malignancy.\u25a0 Report-guided SSL reduced the required number of manualannotations by up to 14 times for detection of clinically significantprostate cancer using biparametric MRI examinations.P< .001) and improved lesion-based sensitivity at onefalse-positive per examination from 48.9% \u00b1 5.0 to 67.1% \u00b12.6 (P < .001).\u25a0 Report-guided SSL with 100 manually annotated prostateexaminations improved area under the receiver operating characteristiccurve for risk stratification for clinically significant prostate cancerfrom 0.78 \u00b1 0.03 to 0.86 \u00b1 0.01  biopsies . MultipaDatasets used for detection and diagnosis of prostate cancer have significantly fewertraining samples than datasets used to train top-performing deep learning systems inother medical applications \u20133. For eA previous study investigated the effect of training set size on performance ofclinically significant prostate cancer detection . The autAccording to our principal annotator, about 4 minutes are needed to annotate oneprostate cancer lesion on three-dimensional images. Difficult examinations arediscussed with radiologists, further increasing the overall duration. Annotatingtens of thousands of examinations would therefore incur huge costs and a large timeinvestment, motivating efforts to reduce this annotation burden.We show that SSL with report-guided pseudo labels can leverage unlabeled examinationsto significantly improve detection performance, without additional manual effort. Inaddition, we show that our method allows development of detection artificialintelligence with similar performance compared with supervised training, whilerequiring substantially fewer manual annotations. To demonstrate efficacy, wetrained semisupervised models for detection of clinically significant prostatecancer with several manual annotation budgets and compared them against supervisedtraining and state-of-the-art semisupervised training methods. Pseudo labels weregenerated offline, allowing easy integration into any existing trainingframework.nsig. The third is topredict the cancer likelihood heatmap for unlabeled examinations with theteacher model and generate pseudo labels by iteratively extracting thensig most likely lesion candidate from theheatmap. The fourth and final step is to train a semisupervised model on thefull dataset with manually and automatically labeled examinations, commonlyreferred to as the student model. Optionally, the student model can be used asthe teacher model in a second iteration. The pipeline is depicted in https://fastmri.eu/research/bosma22a).Our novel SSL method leverages diagnostic reports to guide the generation ofpseudo labels for semisupervised malignancy detection. At a high level, ourreport-guided SSL method consists of the following four steps: The first step isto train a supervised model with manually labeled examinations, commonlyreferred to as the teacher model. The second is to automatically parse thediagnostic reports to assess the number of clinically significant findings inunlabeled examinations, Count clinically significant findings in diagnosticreports.\u2014 Our report-guided pseudo labelsleverage the number of clinically significant findings described in thediagnostic report (nsig). For detection ofclinically significant prostate cancer using MRI, we definednsig as the number of lesions deemed (very)likely to harbor clinically significant prostate cancer by the radiologist(PI-RADS \u2265 4). See AppendixS1 for details on the automatic extractionof nsig from the radiology reports from clinicalroutine.Generate report-guided pseudo labels.\u2014Report-guided pseudo labels were generated in an offline fashion. First, ateacher model was trained on the manually labeled examinations. Then, weperformed inference with the teacher model, which comprises an ensemble ofclinically significant prostate cancer segmentation models.  From the resulting voxel-levelconfidence maps, we created detection maps with distinct lesion candidates, asdescribed in detail in AppendixS1.nsig candidates with highest confidence for alesion. Examinations with fewer lesion candidates than clinically significantreport findings were excluded.Report-guided pseudo labels were then generated by keeping theb-value [\u22651400 sec/mm2]diffusion-weighted imaging, and apparent diffusion coefficient maps) forprostate cancer detection were used.Two retrospective datasets with biparametric MRI scans  was used to train and tune our modelsand included 7756 examinations (6380 patients) from 9275 consecutiveexaminations (7430 patients) performed between January 2014 and December 2020 atRadboud University Medical Center. A total of 1519 examinations were excludedbecause of incomplete examinations, previous treatment, severe misalignmentbetween sequences, severe artifacts, a previous positive biopsy finding (Gleasongrade group [GGG] \u2265 2) .The development dataset (DGG] \u2265 2) , orprepdev,labeled) comprised the3050 examinations from Ddev performed between January 2016 and August2018. All 1315 lesions graded as PI-RADS 4 or greater were manually delineatedby trained investigators , who inturn were supervised by an experienced radiologist .The manually labeled development dataset (Dtest]) of 300examinations (300 patients) performed between March 2015 and January 2017 fromZiekenhuisgroep Twente was used. All patients in the test set underwenttransrectal US-guided biopsy, and patients with suspicious findings at MRI(PI-RADS \u22653) also underwent MRI-guided biopsy. For 61 patients (20.3%),radical prostatectomy was performed . The presence of clinicallysignificant prostate cancer (GGG \u2265 2) was derived from radicalprostatectomy (if available) or MRI-guided biopsy. Systematic biopsies were usedto upgrade MRI-guided biopsy findings but were not used to downgrade findings.All examinations in the test set had histopathologically confirmed ground truthwhile retaining the patient cohort observed in clinical practice.To test our models, an external dataset   .For the SSL setting, we investigated budgets of 100, 300, 1000, and 3050 manuallylabeled examinations, paired with the remaining 7656, 7456, 6756, and 4706unlabeled examinations, respectively. Models were trained with fivefoldcross-validation, with randomly generated cross-validation splits at the patientlevel.For report-guided SSL, the teacher model was used to generate pseudo labels forthe unlabeled portion of the training data by ensembling the predictions of the15 models . The pseudo-labeled datawere combined with the manually labeled data to train a student model. Toinvestigate convergence of our SSL method, a second iteration was performed. Thestudent model from the first iteration then became the teacher model in thesecond iteration.AppendixS1)  .First, we evaluated the quality of our report-guided pseudo labels by comparingthem with the manual labels. Then, we trained semisupervised student models withseveral manual annotation budgets. Finally, we calculated the annotation burdenreduction.Extraction of report findings.\u2014 The accuracyof natural language processing for automatically counting the number of PI-RADSof 4 or greater lesions in a report (nsig) wasdetermined by comparing against the number of PI-RADS 4 or greater lesions inDdev,labeled. To account for multifocal lesions (which can beannotated as two distinct regions or a single larger one) and human error in theground truth annotations, we manually checked the radiology report and verifiedthe number of lesions when there was a mismatch between the manual label andautomatic estimation.Localization of report findings.\u2014Localization performance of the artificial intelligence methods was comparedusing free-response receiver operating characteristic (FROC) analysis. Analysiswas performed with fivefold cross-validation on Ddev,labeled.AppendixS1 for the model selection method).Pseudo labels from uncertainty-aware mean teacher and cross pseudo supervisionwere generated at each training site. For fair comparison, we evaluated thepseudo labels from the best checkpoint . This evaluation was performed with fivefold cross-validationon Ddev,labeled.To enable spatial similarity evaluation of the soft pseudo labels fromuncertainty-aware mean teacher, we binarized the labels with a threshold of 0.5,following the strategy used by cross pseudo supervision.Prostate cancer detection.\u2014 Prostate cancerdetection models were evaluated on 300 external examinations withhistopathologically confirmed ground truth (Dtest). Examinations withat least one clinically significant prostate cancer (GGG \u2265 2) lesion wereconsidered positive.Patient-based diagnostic performance was analyzed using receiver operatingcharacteristic (ROC) analysis and was summarized using the AUC. Lesion-baseddetection performance was analyzed using FROC analysis and was summarized usingthe partial AUC between 0 and 1 false-positive findings per examination.Annotation burden reduction.\u2014 SSL canleverage unlabeled examinations for training, potentially reducing the number ofmanually labeled examinations required to reach expert-level diagnosticperformance. To investigate the extent to which SSL reduces the annotationburden, we assessed how many manually labeled examinations are required in thesemisupervised setting to match the performance achieved in the fully supervisedsetting with 3050 manually labeled examinations. The annotation burden reductionfactor is then defined as follows: supervisedN representing the number ofmanually labeled examinations used for supervised training andsemi supervisedN representing the number ofmanually labeled examinations used for semisupervised training.We used piecewise logarithmic interpolation to obtain a continuous performancecurve as a function of the number of manually labeled examinations.We trained models with fivefold cross-validation and three restarts for ourreport-guided SSL method, two restarts for uncertainty-aware mean teacher, andone restart for cross pseudo supervision, resulting in 15 or 10 AUCs and partialAUCs on the test set for each model configuration. Comparison of performancebetween groups of independent models allows for investigation of the differencein performance due to training configuration rather than variation inperformance inherent to the stochastic nature of deep learning.  To determine the probability of one configurationoutperforming another, we performed a permutation test of the performancemetrics with 1\u2009000\u2009000 iterations. We used a statisticalsignificance threshold of .05.n-of-n patients with replacement andcalculating the target metric. Iterations that sampled only one class wererejected. Statistical analyses were implemented in Python 3.8.We estimated 95% CIs for the performance of radiologists by bootstrapping1\u2009000\u2009000 iterations, with each iteration selectingdev,labeled. Examinations with negative results (PI-RADS\u22643) were identified with 99.7% accuracy.Our natural language processing score extraction algorithm identified the correctnumber of PI-RADS 4 or greater lesions for 3024 of the 3044 (99.3%) radiologyreports in Ddev,labeled and 121 of 4706 examinations (2.6%) from theremaining examinations of Ddev . Manualinspection revealed that 34 of these 121 unlabeled examinations (28%) containedPI-RADS 4 or greater classifications (with nonstandard reporting) or were not aprostate cancer detection examination. Exclusion of these examinations improvedthe quality of the pseudo-labeled examinations because they would have beenincluded as negative otherwise. We excluded reports and their examinations when no PI-RADS scores could beextracted from the report: six of 3050 examinations (0.2%) fromDnsig,greatly reduced the mean number of false-positive lesions per examination from0.39 \u00b1 0.14 (SD) to 0.064 \u00b1 0.008 for our report-guided pseudolabels . This sixfold reduction infalse-positive lesions greatly increased the quality of the pseudo labels.The clinically significant prostate cancer detection models achieved highsensitivity. At this high sensitivity, the models also propose manyfalse-positive lesion candidates .Maskingnsig lesion candidates were excluded. Among theexcluded examinations were those where we are certain to have missed lesions,thus increasing sensitivity. From the first iteration of report-guided pseudolabels, we excluded 119 examinations, resulting in a sensitivity of 83.8%\u00b1 1.1 (192 \u00b1 12 of 229 \u00b1 14 lesions) at 0.063 \u00b10.008 (36 \u00b1 4 of 578 \u00b1 15) false-positive lesions per examinationacross fivefold cross-validation.Examinations for which we could extract fewer thanBinarization of uncertainty-aware mean teacher\u2013generated soft pseudolabels yielded pseudo labels with a sensitivity of 50.1% \u00b1 3.5 (132\u00b1 17 of 263 \u00b1 16) at 0.114 \u00b1 0.031 (70 \u00b1 19 of 610\u00b1 21) false-positive lesions per examination.AppendixS1) performed better than naivebinarization. See Use of cross pseudo supervision generated binarized pseudo labels with asensitivity of 60.3% \u00b1 3.8 (157 \u00b1 6 of 263 \u00b1 16) at 0.115\u00b1 0.035 (62 \u00b1 20 of 610 \u00b1 21) false-positive lesions perexamination. Binarization of the softmax predictions gave lower detectionperformance than the FROC curve because our lesion extraction.Iteration 2 generally performed better than iteration 1, although onlyexamination-based performance for manual annotation budgets of 100 or 300examinations improved significantly , showing quick convergence.Uncertainty-aware mean teacher and cross pseudo supervision failed to improvemodel performance compared with SL . The exception was uncertainty-aware mean teacher with 1000 manual labels,in which uncertainty-aware mean teacher outperformed SL at examination-baseddiagnosis (P = .004) and lesion-based detection(P < .001).Report-guided SSL significantly increased model performance for all investigatedmanual annotation budgets compared with SL with the same number of manuallylabeled examinations (P < .003),except for examination-based performance of uncertainty-aware mean teacher with1000 manual labels.Report-guided SSL (iteration 2) outperformed uncertainty-aware mean teacher andcross pseudo supervision at examination- and lesion-based performance for allmanual annotation budgets  with 300 manual labels exceeded examination-basedAUC performance of SL with 2440 manually labeled examinations. Performance with100 manual labels came close to SL. Interpolation suggests that supervisedperformance is matched with 169 manual labels (14 times annotation burdenreduction).Report-guided SSL (iteration 2) with 1000 manually labeled examinations exceededlesion-based partial AUC performance of SL with 2440 manually labeledexaminations. Performance with 300 manual labels came close to that of SL.Interpolation suggests that supervised performance is matched with 431 manuallabels (six times annotation burden reduction).Large-scale SL can reach expert-level diagnostic performance but requireslabor-intensive manual annotation, which is expensive and infeasible to obtain foreach (cancer) detection use case. Our novel report-guided SSL method significantlyimproved diagnostic performance at all investigated manual annotation budgetscompared with SL and SSL without report guidance except for examination-basedperformance of uncertainty-aware mean teacher with 1000 manual annotations. Thereport-guided pseudo labels are of sufficient quality to improve semisupervisedmalignancy detection, even when only 100 manually labeled examinations areavailable. This improved performance demonstrates the feasibility of report-guidedSSL for malignancy detection.In this study, the training procedure with report-guided pseudo labels is presentedfor detection of clinically significant prostate cancer with MRI using radiologyreports. However, the underlying method is not limited to clinically significantprostate cancer, MRI, or radiology reports and can be applied universally. Anydetection task with countable structures of interest and clinical informationreflecting these findings can use our training method to reduce the annotationburden.Report-guided SSL allowed us to leverage the full dataset of 7756 examinations, whichis a substantial increase in the number of training examinations compared with theprevious largest dataset for detection of clinically significant prostate cancerusing MRI of 1736 examinations. This brings detection of clinically significantprostate cancer much closer to the dataset sizes used to train top-performing deeplearning systems, where up to 29\u2009541 training examinations were used.Negative examinations were identified with 99.7% accuracy, suggesting that negativeexaminations  can be automatically annotated almost perfectly,speeding up the manual annotation process substantially. Furthermore, thesegmentation masks are often of sufficient quality to require only verification ofthe location, saving ample time for positive examinations as well.To our knowledge, we are the first to investigate SSL for malignancy detection usingthree-dimensional images. Our presented method, report-guided SSL, has severallimitations that should be considered. Report-guided SSL has the risk of introducingsystematic pseudo label errors by reinforcing possibly incorrect model predictions.This could drive the subsequent semisupervised detection model to confidentlypredict benign abnormalities as being malignant. Thus, careful evaluation of themodel before is necessary.Direct applicability of the rule-based PI-RADS score extraction from radiologyreports is limited because it needs to be adapted for reports with differentstructures or languages. For unstructured reports, a deep learning\u2013based NLPmodel can be trained on the manually labeled subset to perform the task of countingthe number of clinically significant findings.In addition, PI-RADS 4 or greater lesions reported with PI-RADS version 2 or version2.1 were used to train the clinically significant prostate cancer detection models.Radiologically estimated lesions contain both false-positive and false-negativelesions. Inclusion of PI-RADS 3 lesions as clinically significant prostate cancer totrain the algorithms would decrease the number of false-negative lesions at the costof introducing many false-positive results. Although these training annotations arenot perfect, they have been shown to be suitable for training clinically significantprostate cancer detection models ,14, as aIn conclusion, report-guided SSL allows for substantial reduction in annotationburden by leveraging unlabeled examinations paired with diagnostic reports. Ourproposed method is widely applicable, paving the way for larger datasets with equalor reduced annotation time."}
+{"text": "Besides cutaneous involvement by T cell lymphoma, differential diagnoses included cutaneous sarcoidosis and pityriasis rosea. Biopsy of a subcutaneous nodule revealed no evidence of malignancy but granulomatous inflammation (B3) most consistent with reactive granulomatous dermatitis. After initiation of prednisone therapy, all (sub-)cutaneous lesions quickly resolved, and the patient was eligible for stem cell transplantation. Follow-up [18F]FDG-PET/CT demonstrated only residual tracer uptake of some lesions and a sustained complete lymphoma response (C).A 36-year-old male with anaplastic large T cell lymphoma  who had received six cycles of chemotherapy  presented for restaging prior to autologous stem cell transplantation. A few days earlier, the patient had noticed multiple new tender subcutaneous nodules, and erythemato-squamous, polymorphous, partially atrophic plaques all over his body (B1). [18F]FDG-PET/CT mimicking cutaneous lymphoma manifestations.Reactive granulomatous dermatitis is a very rare skin disease with only several hundred cases reported worldwide so far , most co"}
+{"text": "One in three persons with HIV (PWH) without active hepatitis B virus (HBV) coinfection have a positive hepatitis B core antibody (cAb) suggesting prior HBV exposure. This group is at risk for HBV reactivation (HBVr) when changes to antiretrovirals (ARV) result in cessation of nucleos(t)ide reverse transcriptase inhibitors (NRTIs) with dual activity against HIV and HBV, e.g. tenofovir. Case reports of HBVr in PWH with positive cAb after NRTI cessation have been published, but the frequency of reactivation is unknown. Since FDA approval of dolutegravir-rilpivirine in 2017 and long-acting injectable cabotegravir-rilpivirine in 2021, increasing numbers of PWH are switching to ARV without HBV activity. We describe HBV reactivation in cAb positive PWH following switch to ARV without HBV activity (AHB-) from ARV with HBV activity (AHB+).We used data from 60,290 PWH enrolled in the Veterans Aging Cohort Study to identify 7,860 who switched to AHB- prior to 12/31/2022 with prior positive cAb and negative pre-switch hepatitis B surface Ag (sAg). We excluded 779 due to active HBV (positive sAg or hepatitis B DNA [HBDNA] on nearest result pre-switch), leaving 7,081 eligible for analysis. We included PWH with remote prior positive sAg not meeting active HBV criteria. We defined HBVr as detection of HBDNA or sAg. AHB+ included lamivudine, emtricitabine, and/or tenofovir.HBVr occurred in 1.6% of PWH with positive cAb (n = 115) after switch to AHB-, with demographics summarized in Table 1. Table 2 shows prespecified subgroup analyses by prior sAg and hepatitis B surface antibody (sAb). Reactivation risk was 1.0% in those with no prior positive sAg and 20.2% in those with remote prior positive sAg (p < 0.0001). Among those with no prior positive sAg, HBVr risk in those with positive sAb was 0.4%, compared with 1.1% in those without positive sAb (p = 0.065); among those with remote prior positive sAg, no difference in risk by sAb status was found (p = 0.64).Overall risk of HBVr is low after AHB+ to AHB- switch among cAb positive PWH with no prior positive sAg. Our results will inform provider-patient discussion about risks of HBVr when considering switching to newer NRTI-sparing AHB- and also highlight the importance of pre-switch review of all prior hepatitis serology results.All Authors: No reported disclosures"}
+{"text": "Somatic HER2 mutations are a novel class of therapeutic targets across different cancer types. Treatment with the tyrosine kinase inhibitor (TKI) neratinib as a single agent continues to be evaluated in HER2-mutant metastatic disease. However, responses are heterogeneous, with frequent early progression. Herein, we discuss the under-explored effects of individual HER2 mutant alleles on therapeutic response, a role for HER2 mutation in metastatic propensity, and differences in patient outcomes in ER+ invasive lobular carcinoma (ILC) versus invasive ductal carcinoma (IDC). The preclinical efficacy of additional agents is also discussed, particularly the pan-HER inhibitor poziotinib. The Cancer Genome Atlas (TCGA) consortium first identified HER2 somatic mutations in non-HER2-amplified solid tumors over the last decade. Based on functional analyses and clinical trial data, our group and others have concluded that HER2 somatic mutations are indeed therapeutically targetable in estrogen receptor positive (ER+) non-HER2-amplified advanced breast cancer as well as other common solid tumors \u201312. ImpoWe recently reported distinct prognostic effects of recurrent HER2 mutations in metastatic ER+ ILC versus IDC. HER2 L755 alterations (L755S or L755 insertions/deletions) are the commonest mutations in ILC, while HER2 exon insertions/deletions are more frequent in IDC. The METABRIC primary breast cancer sequencing data demonstrated that ER+ ILC patients harboring HER2 mutations have reduced overall survival in comparison to patients with HER2 mutant ER+ IDC. Of all the HER2 mutations evaluated, HER2 L755 alterations are selectively associated with poor outcome in lobular histology .Based on these HER2 allele selective prognostic effects, the impact of different HER2 alleles on endocrine therapy sensitivity, modulation of signal transduction by neratinib, orthotopic tumor growth, and multi-organ metastasis was investigated. A key finding was that HER2 mutations constitutively activate HER2 oncogenic signaling more generally; mTOR signaling is particularly hyperactivated. Thus, mTOR activation is a likely focus for HER2 mutation-induced neratinib resistance , 18, 19.in vivo models, it was evident that HER2 L755S induces resistance to neratinib and endocrine therapy in an estrogen-independent manner. In contrast, the recurrent HER2 extracellular domain mutation S310F remains highly estrogen-dependent and sensitive to endocrine therapy and neratinib. Additionally, HER2 L755S phenotype correlated with secondary ovary metastasis, an established clinical feature of lobular carcinoma, also in an estrogen-independent manner. Furthermore, these studies recapitulated the neratinib and endocrine resistance in two ER+ recurrent ductal HER2 mutant in vivo models, MCF7 HER2 L755S and HCI-003 PDX model  [By deploying several ER+ lobular 780 dup) . These fin vivo models, our study demonstrated that the pan-HER TKI poziotinib as a single agent inhibits HER2 mutant-driven PI3K-mTOR oncogenic signaling, endocrine resistance, efficacy in neratinib resistance settings, and multi-organ metastasis in breast cancer. Structural modeling studies revealed that poziotinib binds more closely to S755-mutant HER2 than to the HER2 wild type, suggesting that poziotinib has mutant-specific binding activity [Using three independent HER2 mutant activity . These factivity , 21 withactivity . While pactivity . The schThe existing evidence  suggestsIn summary, preclinical findings described above support clinical investigation of poziotinib in a subset of ER + mBC harboring HER2 somatic mutations and suggest further studies to evaluate poziotinib as a therapeutic agent in additional tumor types.The preclinical and clinical actions of poziotinib have already been evaluated in patients with metastatic NSCLC carrying recurrent HER2 exon 20 insertions . Our resIn current preclinical models and clinical trials, we are testing pan-HER TKI\u2019s that are designed to inhibit HER2 WT activation in HER2 mutant cancers, but the pan HER TKI\u2019s clinical responses are short lived with toxicity. Therefore, it is imperative to investigate HER2-mutant specific vulnerabilities and design HER2-mutant-selective treatment strategies for durable clinical responses with low levels of drug related toxicities. Recent data from the DESTINY-Lung phase II clinical trials have revealed the clinical benefit of Trastuzumab-Deruxtecan (T-DxD) in patients with HER2 mutant NSCLC, suggesting new therapeutic options for patients with HER2 mutant NSCLC cancers . The fut"}
+{"text": "Streptococcus (GBS) infection during infancy, and gastrointestinal (GI) colonization is an important precursor. Previously, we described a murine model of postnatal GBS GI colonization that resulted in sustained colonization and progression to invasive disease. Capsular polysaccharide is an important GBS virulence factor. Vaccines based on a subset of capsular serotypes are in clinical trials. However, little is known regarding the role of specific GBS capsular serotypes in GI colonization. We examined the role of GBS capsule in GI colonization using capsule-producing and acapsular strains derived from GBS strain A909 (serotype Ia) in a murine model. Using isogenic GBS strains differing only in capsular serotypes, we explored the role of specific serotypes in GI colonization by determining competitive indices during cocolonization. We found that GBS A909 colonizes the murine GI tract without causing invasive disease. In monocolonization experiments, there was colonization persistence with the capsule-producing strain (100%) compared to the acapsular mutant strain (13%). In cocolonization experiments, the capsule-producing strain outcompeted its isogenic acapsular mutant, with a geometric mean competitive index of 8, 95% confidence interval (CI)  in the colon at 7 days post-colonization. A909 expressing its native serotype Ia capsule outcompeted an isogenic mutant that expresses serotype III capsule, with a geometric mean competitive index of 2.5, 95% CI  in the colon at 7 days post-colonization. Thus, polysaccharide capsule production enhances GBS GI colonization in vivo. In an A909 genetic background, the production of a serotype Ia capsule provides a competitive advantage over an isogenic strain producing type III capsule. The murine model is a valuable tool to understand the role of GBS capsule types in GI colonization.Late-onset disease is the most common clinical presentation of Group B Streptococcus (GBS) acquisition and invasive disease. Using this model, we explored the importance of GBS polysaccharide capsule production on gastrointestinal colonization. We found that the expression of capsule (compared to isogenic acapsular strains) provides an advantage in intestinal colonization and, importantly, that capsule type Ia has an advantage over capsule type III in a GBS A909 strain background. We speculate that specific serotypes may differ in colonization fitness, which may play a role in serotype distribution in neonatal disease.The establishment of GBS intestinal colonization is believed to be a critical precursor to late-onset disease in neonates, which has a significant impact on neurodevelopment outcomes in this population. Our prior work described a murine model of postnatal Group B  Streptococcus agalactiae [Group B Streptococcus (GBS)] is a leading cause of neonatal sepsis .cpsE), capsule switch (CS) (A909 strain expressing type III capsule), and revertant strains (Rev) (A909 strain expressing native Ia capsule) were used (GBS wild-type (WT) strains A909 (serotype Ia), its derivatives, and COH1 were grown to stationary phase at 37\u00b0C in trypticase soy (TS) broth and enumerated by plating on TS agar or CHROMagar StrepB plates. Previously described capsule-deficient  were purchased from Jackson Laboratories , given at least 3 days to acclimate to the local facility, and mated as pairs and trios. Dams were monitored for the birth of litters, and animals aged 12\u201314 days were designated as preweaning mice in this cohort.cpsE) strains, bacterial cultures were grown overnight to the stationary phase. Following overnight growth, the optical densities of the two strains were normalized. Cultures were then centrifuged and resuspended in sterile Dulbecco\u2019s phosphate-buffered saline (DPBS) to a final concentration of 109 CFU/mL. Animals were orally fed using a sterile feeding tube with 108 CFU of GBS resuspended in 50 \u00b5L of DPBS, respectively, and remained with their biologic, non-colonized dam. The animals were monitored daily for signs of illness and mortality. Rectal swabs were collected at predetermined time intervals , and serial dilutions were plated for determination of GBS CFUs on chromogenic agar.For the monocolonization model with WT A909 (Ia) and capsule-deficient , animals were euthanized, and the GI tract was harvested. Each portion  was homogenized using a Next Advance Bullet Blender Storm 24 Place Bead Homogenizer. Serial dilutions were plated on CHROMagar StrepB for the determination of GBS CFUs. In addition to plating serial dilutions, dilutions were spread on CHROMagar plates with glass beads for the determination of serotype by colony immunoblot. In additional cohorts, preweaning mice were similarly inoculated, and rectal swabs were obtained longitudinally.Streptococcus group B type antisera (Statens Serum Institut) and incubated for 30 minutes with gentle shaking. Type Ia antiserum was diluted 1:2,000 in the blocking solution, and type III antiserum was diluted 1:5,000 in the blocking solution. Blots were then washed three times in PBS. Blots were incubated in horseradish peroxidase (HRP)-conjugated goat anti-rabbit secondary antibody (Pierce) diluted 1:1,000 in a blocking solution for 2 hours. Blots were washed three times in PBS and stained using a 3,3\u2032-diaminobenzidine tetrahydrochloride substrate kit (Abcam). Colonies positive for each capsule type were counted. In experiments comparing WT to acapsular mutants, nonreacting GBS colonies representing the acapsular mutants were also counted. Competitive index (CFU strain 1 recovered/CFU strain 1 inoculated)/(CFU strain 2 recovered/CFU strain 2 inoculated) was calculated and log-transformed for calculation of geometric mean and 95% confidence interval (CI) for each condition and time point.Following growth at 37\u00b0C, colonies were counted to identify plates with 20\u2013200 colonies for subsequent immunoblotting. Plates were briefly overlaid with nitrocellulose membranes (Amersham) to allow adherence of GBS material to the membrane. Membranes were blocked in 3% bovine serum albumin (BSA) in PBS (blocking solution) for 1 hour. Blots were then transferred to type Ia or type III Preweaning animals were euthanized at predetermined time points, and the distal small intestine (1 cm segment) and distal colon were removed and fixed in 4% paraformaldehyde. The NYU Langone\u2019s Experimental Pathology/Immunohistochemistry Core Laboratory embedded all fixed tissues in paraffin and then serially sectioned onto slides. NYU Experimental Pathology Immunohistochemistry Core Laboratory performed hematoxylin and eosin (H&E) staining using the Leica ST5020 Multistainer in conjunction with the Leica CV5030 Coverslipper for optimized workflow. Slides were scanned at 40\u00d7 resolution using the Leica SCN400 whole slide scanner. Immunofluorescent labeling of GBS was performed following deparaffinization and rehydration of sectioned tissue. Heat-induced epitope retrieval was performed as per the manufacturer\u2019s recommendations (Abcam). Nonspecific binding sites were blocked with 10% normal goat serum and 1% bovine serum albumin (Sigma). Rabbit anti-GBS polyclonal antibody  was applied. Following serial washes with PBS + 0.025% triton X-100, Alexa Fluor 647 goat anti-rabbit immunoglobulin G  was added for 30 minutes in the dark. Slides were counterstained using Hoechst 33342 (Invitrogen). Coverslips were mounted with Vectashield Hardset mounting medium (Vector Laboratories), and slides were stored at 4\u00b0C. Slides to which no primary antibody or no secondary antibody was added served as negative controls. Slides were scanned at 20\u00d7 resolution using the Hamamatsu NanoZoomer 2.0HT scanner.cpsE KO was compared using the Log-rank (Mantel-Cox) test.Statistics were calculated using GraphPad Prism 9 Software. The persistence of GI tract monocolonization between WT A909 (Ia) and A909 cpsE (capsule deficient) in separate cohorts. Animals were monitored daily for signs of illness. Rectal swabs were performed at 7-day intervals to assess GI colonization. Animals infected with A909 WT had a survival of 88% compared to 100% in the A909\u0394cpsE-infected cohort    with A909WT (capsule producing) and A909\u0394og-rank) . On asseog-rank) .cpsE in a GI cocolonization model. Preweaning mice (12\u201314 days) were orally infected as described in separate experimental groups. In the first group, animals were monitored for survival and colonization status. There was 100% survival in this experimental cohort, with some animals (22%) remaining colonized until 28 days post-infection as determined by rectal sampling .We assessed the fitness of encapsulated A909 WT (serotype Ia) vs A909\u0394sampling . In the sampling . In the sampling . In the sampling . This doWe competed matched capsule switch (CS) (A909 strain expressing type III capsule) and revertant (Rev) (A909 strain expressing native type Ia capsule) strains in the murine GI cocolonization model to further probe the role of these two capsular serotypes. We previously confirmed that these strains produce similar amounts of capsule . PreweanGBS intestinal colonization is important for the pathogenesis of LO disease in infants , 21. WeiPreviously described murine models of GBS GI colonization have evaluated the role of critical bacterial factors, including SrtA sortase and HvgA adhesin, needed for adhesion to and invasion of the GI epithelial surfaces , 24. Thein vivo and ex vivo work. The polysaccharide capsule enhances GBS virulence by facilitating evasion of the innate immune response by different mechanisms . The most frequent GBS serotype-causing disease in infants is serotype III (61.5%), followed by serotypes Ia (19.1%), V (6.7%), and Ib (5.7%) . The impchanisms , 29. Nobchanisms . Expresschanisms . Here weStreptococcus pneumoniae , a phenomenon described in in eumoniae \u201334. Th"}
+{"text": "The binding affinities of Bap to the potential target proteins were further evaluated using molecular docking, while the isothermal titration calorimetry (ITC) interaction measurements indicated nanomolar-level Kd values. Importantly, we found that Bap weakened the antioxidant capacity by destroying the activities of SOD3 and GPX4, which provided a new understanding of the mechanism of hepatotoxicity induced by Bap. Moreover, our provided workflow integrating metabolomics and label-free chemical proteomics, can be regarded as a practical way to identify the targets and inter-mechanisms for the various environmental compounds.Benzo[\u03b1]pyrene (Bap) is recognized as a ubiquitous environmental pollutant among the polycyclic aromatic hydrocarbons (PAHs) class. Previous studies have shown that the hepatotoxicity of Bap is mainly caused by its metabolites, although it remains unclear whether Bap itself induces such damage. This study integrated metabolomics and chemical proteomics approaches to comprehensively identify the potential target proteins affected by Bap in liver cells. The results from the metabolomics showed that the significant changed metabolites were related with cellular redox homeostasis. CEllular Thermal Shift Assay (CETSA) showed that Bap induced protein thermal displacement of superoxide dismutase 3 (SOD3) and glutathione peroxidase 4 (GPX4), which are closely related to oxidative homeostasis. Further validation through  \u2022Benzo[\u03b1]pyrene induced oxidative damage by disrupting the antioxidant system of liver cells.\u2022Benzo[\u03b1]pyrene had a strong affinity with SOD3 and GPX4.\u2022Benzo[\u03b1]pyrene significantly reduced the activities of SOD3 and GPX4.\u2022Propose a method for screening environmental pollutant targets by combining metabolomics with Cellular Thermal Shift Assay. Especially in areas with frequent industrial activities, polycyclic aromatic hydrocarbons emissions are significantly higher ,2. Benzotrans-7,8-dihydroxy-7,8-dihydro-bep can covalently combine with DNA to form BPDE-DNA adduct, leading to DNA mutation ; Chinese Pharmacopoeia Commission [Grant No.: 2022Y12]; and the Fundamental Research Funds from 10.13039/501100010877Shenzhen Science and Technology Innovation Commission [Grant No. RCBS20210609104424065].Funding: This work was supported by the Yanwei Wang: Methodology, Investigation, Writing -Original draft, Data curation. Jiahui Zhao: Investigation, Visualization. Yipeng Xu: Investigation, Writing-Review & Editing. Cimin Tao: Investigation, Data analysis. Jie Tong: Investigation, Writing-Review & Editing. Yingjie Luo: Writing -Review & Editing, Funding acquisition. Yong Chen: Investigation, Writing -Review & Editing. Xuesong Liu: Funding acquisition. Tengfei Xu: Conceptualization, Writing-Review & Editing, Project administration, Funding acquisition.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."}
+{"text": "Here, we report the full nucleotide sequence of the RvA1B/KZ/2021/87 rhinovirus, identified through metagenomic sequencing of nasopharyngeal swabs collected from patients exhibiting respiratory symptoms in Kazakhstan during 2021. Enterovirus genus, HRV encompasses three distinct species: HRV-A, HRV-B, and HRV-C (Human rhinovirus (HRV) is a prevalent respiratory pathogen known to cause mild to moderate respiratory illnesses in humans. Its initial identification in 1956 involved patients with mild upper respiratory tract infections . Subsequently, cDNA synthesis, amplification, and primer removal were performed using the SeqPlex RNA Amplification Kit  to generate cDNA fragments ranging from 150 to 400 nucleotides in length. Quantity and quality of the amplified cDNA products were evaluated through NanoDrop and Qubit assessments. Libraries suitable for downstream analysis were prepared using the Ion Plus Fragment Library Kit (Thermo Fisher Scientific).https://czid.org) (OL133751). The assembled genome of RvA1B/KZ/2021/87 encompasses a length of 7,047 base pairs. Notably, the genome displayed a GC content of 38.21% while achieving full genome coverage at a depth exceeding 1,000\u00d7. Upon employing the BLAST program for sequence comparison, it was revealed that the nucleotide sequences of rhinoviruses isolated in the USA during 2021 bear the closest resemblance. Specifically, the highest degree of nucleotide identity, at 99.69%, was observed with the RvA1B/USA/2021/PSC7PE strain (GenBank ID: OL133751). All tools were run with default parameters unless otherwise specified. The analytical framework for evolutionary assessments was conducted within the MEGA11 software  , facilit"}
+{"text": "Adaptive platform trials (APTs) have become increasingly popular in recent years in infectious diseases research. However, few studies have compared APT design against conventional randomized clinical trial (RCT) design from a cost-effectiveness standpoint. We aimed to evaluate the cost-effectiveness of APT versus conventional RCTs and quantify the trade-offs involved in choosing between these designs.We conducted a model-based economic evaluation using a two-level, hierarchical simulation model comparing two strategies: (1) APT comparing three drugs simultaneously against a single control group, and (2) three sequential 2-arm parallel group conventional RCTs . Cost inputs were obtained from a recently completed conventional RCT studying bloodstream infections (BSI) and a recently launched APT for Gram-negative BSI (Table 1). 1000 Monte Carlo 2nd order iterations were performed to simulate 1000 RCTs to determine empirical Type I and II error rates across several scenario analyses.2crit values of 3.841 and 6.635 respectively) compared to conventional design (fixed at 0.05 by design) .In the base case analysis where a less stringent interim analysis stopping rule was used, and the drugs being tested were effective, APT design was associated with lower cost , shorter duration (135 vs 242 weeks), and lower mean type II error (0.086 vs 0.213) (Table 2). However, results were highly sensitive to different scenario analyses where more stringent stopping rules were applied or if the tested drugs had no true effect. Effect sizes were less precise and on average were over-estimated with APT design . Type I error rates were also consistently higher with the APT strategy .All Authors: No reported disclosures"}
+{"text": "Scientific Reports 10.1038/s41598-022-26617-w, published online 26 January 2023Correction to: The original version of this Article contained an error in the Funding section.\u201cThis work was funded by Ministry of Health and Welfare (Grant no. NIPA 1711120339).\u201dnow reads:\u201cThis work was funded by Ministry of Science and ICT (Grant no. NIPA 1711120339).\u201dThe original Article has been corrected."}
+{"text": "Gender inequities in promotion within academic medicine, including academic infectious diseases (ID), are well-documented. Effective mentorship is a key component of career advancement and data show that same-gender mentorship can be valuable for women junior faculty learning to navigate academia. We compared the gender, bibliometrics, and mentorship opportunity distributions of ID faculty at each academic rank  across several US medical centers.We randomly selected five academic medical centers from the US World News & Reports top 100 medical school rankings that had ID division websites including a faculty listing with ranks and years since graduation. We recorded each physician faculty\u2019s rank and gender based on the written biography, using a validated tool (genderize.io) to determine gender if not given, and collected each faculty\u2019s traditional bibliometric data via Google Scholar.We included 221 faculty (107 women) from five ID divisions (mean 44 faculty). Women accounted for 5/12 (42%) of instructors, 62/109 (57%) of assistant professors, 19/44 (43%) of associate professors, and 21/56 (38%) of full professors. Junior faculty women (instructor or assistant) had a median 0.6 potential same-gender senior mentors per mentee within their divisions versus 1.1 for men; associate professor women had a median 1.0 potential same-gender senior mentor per mentee versus 1.7 for men. Measures of academic productivity, such as annual publications, citations, and h-index growth since graduation from fellowship were similar between men and women.Our findings support published studies demonstrating lower proportions of women in successively senior positions within academic ID divisions despite similar scholarly activity and suggest that fewer within-institution opportunities for senior mentorship might be a contributing factor.Andrea J. Zimmer, MD, Allovir: Grant/Research Support"}
+{"text": "Correction to: Archives of Orthopaedic and Trauma Surgery (2023) 143:4331\u20134337 10.1007/s00402-023-04829-7The original version of this article unfortunately contained a mistake. The corrected details are provided below:Michael C. LiebensteinerAlexander RuzickaMaximilian HinzHermann LeitnerAlois HarrasserDietmar DammererMartin KrismerAll authors\u2019 first names were missing and correct author names should have appeared as below."}
+{"text": "Enterococcus and Enterobacterales species. Experimental models have demonstrated that metabolites produced by the intestinal microbiome, including short chain fatty acids (SCFAs), secondary bile acids and indole compounds, enhance host epithelial and immune defenses against enteric pathogens. Microbiome derived metabolites likely contribute to resistance against infectious diseases in LT patients, however, this remains uninvestigated.Liver transplantation (LT) is associated with postoperative infections caused by antibiotic-resistant bacterial pathogens that reside in the intestine. An intact intestinal microbiome suppresses expansion of enteric pathogens, however patients with severe liver disease often have reduced microbiome diversity and increased density of antibiotic-resistant Graphical AbstractWe prospectively enrolled 158 liver transplant candidates and determined peri-transplant fecal microbiome compositions including relative and absolute fecal metabolite concentrations. We then used microbiome composition characteristics and metabolite profiles to predict postoperative bacterial infection.EnrollmentEnterococcus and/or Enterobacterales species that were associated with postoperative infection. Gas chromatographic (GC-) and liquid chromatographic (LC-) Mass spectrometric analyses revealed decreased concentrations of SCFAs, secondary bile acids, and indole compounds in fecal samples with low microbiome diversity and associated expansion of Enterococcus and Enterobacterales populations. Enterococcus and Enterobacterales expansion at 20% and 2.5% respectively reliably predicted postoperative infection. Reduced short chain fatty acids, secondary bile acids, and indole metabolites predicted postoperative bacterial infection as well as Enterococcus and Enterobacterales expansion.Fecal microbiomes in LT recipients ranged from highly diverse to complete loss of diversity resulting in expansion of Microbiome Compositions of LT recipients vary widely(A) Fecal microbiome composition plots of liver transplant (LT) patients and healthy donors (HD) vertically organized by relative abundance and color coded by taxa. Individual samples were ordered horizontally by Shannon diversity. (B) taxUMAP1 plot of taxonomic composition, HD are denoted as triangles. Samples are color coded by the most abundant taxon and size determined by the relative abundance of that taxon. (C-E) Comparison of Alpha diversity between LT diversity groups and between high diversity and HD using (C) Inverse Simpson, (D) Shannon, and (E) Richness. (F-J) Comparison of relative abundance of select taxa between LT diversity groups and HD. (F) Lachnospiraceae; (G) Enterococcus; (H) Enterobacterales; (I) Bacteroidetes; (J) Oscilospiraceae. Significance tested by Kruskal-Wallis test *p\u2264 0.05 **p\u22640.01 ***p\u22640.001 ****p\u22640.0001Qualitatively measured microbiome derived fecal metabolites vare widely among LT recipientsIndividual metabolite abundances represented on a colorimetric heat map by log2 fold change from the mean between samples. Red indicating increased abundance; blue indicating reduced abundance. Significance was measured between LT groups using the Kurskal-Wallis test and denoted on a colorimetric scale where green represents lower p-values, adjusted for multiple comparisons. HD were included for visual comparison. Add. Compounds include kynurenine pathway and phenolic aromatics. Abbreviations: 1\u00b0-Primary; 2\u00b0-Secondary; Add.-Additional; 3-Oxo-D-Or-3-Oxocheno.-1-Oxo-Deoxycholic or 3-Oxochenodeoxycholic acid, which could not be completely discriminated chromatographically and are included together.Enterococcus and Enterobacterales expansion microbiome predicts postoperative infection(A) Fecal microbiome composition plots color coded by taxon. Plots are categorized by presence of bacterial infection and ordered by descending relative abundance of Enterococcus. Colored tiles indicate an infection caused by the denoted organism associated with that stool sample. For taxonomic color palate refer to Figure 1. (B) Receiver operator curve using Enterococcus abundance to predict Enterococcus infection. Cut point determined by Youden Index to optimize both sensitivity and specificity. 95% Confidence intervals for Accuracy (0.74-0.91), Specificity (59-94%), and Sensitivity (65-100%). (C) Fecal microbiome composition plots organized by relative abundance of Enterobacterales. (D) Receiver operator curve using Enterobacterales abundance to predict Enterobacterales infection. 95% Confidence intervals Accuracy (0.82-0.96), Specificity (72-94%), and Sensitivity (100-100%). Abbreviations: AUC-Area under the curve; ACC-Accuracy; Spec.-Specificity; Sens.-Sensitivity.Enteroccoccus expansion, Enterobacterales expansion, and microbial metabolite abundances accurately predicted LT patients who developed postoperative infection.Microbiome derived fecal metabolites identify alpha diversity and post operative infection(A) sPLS-DA using input matrix of sample metabolites and predicted microbial diversity group. Comparison between predicted groups was visualized on a grid with dividing lines and optimized by maximum distance between groups. Accuracy was: Low Diversity 77%, Medium Diversity 72%, and High Diversity 78%. Sensitivity ranged from 60-84%. Specificity ranged from 62-95%. (B) sPLS-DA using input matrix of sample metabolites and predicted postoperative infection. Comparison between outcomes was visualized on a grid with a dividing line and optimized by maximum distance between groups. Accuracy was 82.2% [73.9-89.1%], sensitivity was 63% [42.4-80.6], specificity was 88.9% [80-94.8%], and odds ratio was 13.6 [4.8-38.6].Eric Pamer, MD, Seres Therapeutics: Inventor on patent application # WPO2015179437A1 and #WO2017091753A1 and receives royalties from Seres Therapeutics, Inc."}
+{"text": "The Infectious Diseases Society of America and The Joint Commission recommend Antimicrobial Stewardship Programs (ASPs) incorporate preauthorization and/or prospective audit and feedback (PAF) as mechanisms for stewardship interventions. However, each institution must customize their ASP workflow. The ASP at West Virginia University Hospitals (WVUH), a rural, comprehensive academic medical center, was recently revamped by leveraging clinical decision support (CDS) tools via a tiered workflow in efforts to prioritize stewardship interventions for preauthorization and PAF.In March 2021 ASP pharmacists created a tiered workflow incorporating CDS tools from Theradoc\u00ae and Epic\u00ae. Review of patients identified on CDS alerts (Table 1), preauthorization, and PAF were conducted Monday through Friday 8:00 am to 5:00 pm by ASP pharmacist(s). Tiered workflow effectiveness was measured by internal and external benchmarking: antimicrobial days of therapy (DOT)/1000 days present, antimicrobial spend, and Standardized Antimicrobial Administration Ratio (SAAR). Interventions were documented within the electronic medical record and tracked via a Quality Assurance and Performance Improvement (QAPI) format. Post implementation data from March 2021 to March 2023 was analyzed and compared to baseline 2019 data.CRE: Carbapenem-resistant Enterobacterales; ESBL: Extended Spectrum Beta-Lactamase; HIV: Human Immunodeficiency VirusThe following outcomes were observed within the post implementation timeframe. Monthly average DOT/1000 days present decreased \u2265 20% for the following antimicrobials: vancomycin (27%), ceftaroline (53%), cefepime (20%), ertapenem (59%), aztreonam (68%), tigecycline (23%), fosfomycin (80%), micafungin (27%), ceftazidime-avibactam (40%). Monthly average total antimicrobial SAAR decreased by 11% from 1.216 to 1.074. Additionally, monthly average antimicrobial spend/patient day decreased by 36% from $26.47 to $16.95. QAPI data demonstrated a 74% intervention acceptance rate including correction of 344 drug-bug matches.Implementation of a tiered ASP workflow effectively identified patients for interventions, decreased antimicrobial utilization, and demonstrated antimicrobial cost containment. Acceptance of stewardship interventions was favorable. This tiered approach may serve as a model for other ASPs.All Authors: No reported disclosures"}
+{"text": "Treatment guidelines recommend prompt ART initiation after HIV diagnosis, but implementation barriers persist. This project aimed to identify gaps and improve clinical practices surrounding rapid ART initiation in the US.Baseline surveys were completed by 130 healthcare professionals (HCPs) in 8 HIV clinics assessing knowledge and practice around ART initiation. Responses informed the development of interactive, live virtual audit-feedback sessions at 8 clinics from 5/2022 \u2013 8/2022. Pre and post-program surveys were administered, team-based action plans developed, and HCPs completed 60- and 120-day follow-up surveys.Top reported challenges impeding rapid ART initiation were medication adherence for patients with unstable housing/substance use disorders (SUD) (63%), incomplete lab results (33%) and co-infections/opportunistic infections (28%). Knowledge was assessed using case vignettes. For a patient with hepatitis C and SUD, 45% of learners correctly chose to promptly start ART, which improved to 94% after the sessions (p< .001). More HCPs were confident initiating ART for patients with unstable housing/SUD (70%) and before confirmatory HIV testing (74%) after the sessions than before .Follow-up surveys noted a 10% increase in proportion prescribing ART within 7 days of a positive screening test (32% to 42%) along with increased ART prescribing the same day as a positive test and before additional test results, Figure 1. Action plans implemented after the sessions included coordination with off-site labs, new intake forms, and staff training. HCPs self-reported improvements including appropriate prompt ART initiation (81% and 88%), integrating new patients to avoid loss to follow-up (85% and 88%), and alignment with guidelines (88% and 91%). HCPs identified care coordination (31%) and identifying candidates for rapid ART initiation (31%) as areas of need to improve rapid ART initiation. Challenges reported included scheduling conflicts, timely lab results and coordination with case management.Tailored implementation discussion with live audit-feedback and action planning led to measurable practice improvements. These outcomes may inform other practice-changing implementation needs.Jonathan Colasanti, MD, MSPH, DKB MED LLC: Honoraria|Prime Education LLC: Advisor/Consultant Aadia I. Rana, MD, Merck: Grant/Research Support JEWEL SAWYER, PA-C, MSHS, AAHIVS, Janssen: Speakers Bureau|Prime Education: Speakers Bureau"}
+{"text": "Enterobacterales (CRE) infections are endemic in Indian hospitals however, studies examining intestinal colonization of CRE on admission to intensive care units (ICUs) are very limited. This study examines the prevalence and risk factors for CRE colonization on admission to two ICUs in a tertiary-care hospital in India.Carbapenem-resistant TMmSuperCARBATM) within 24 hours of collection for CRE isolation. Identification and susceptibility of presumed CRE isolates were confirmed by VITEK2. The modified carbapenem inactivation (mCIM) test and the EDTA carbapenem inactivation method (eCIM) were used to assess carbapenemase production. Information on CRE colonization risk factors  was collected.Peri-rectal swabs were collected from consented patients prospectively enrolled between December 16, 2022 and March 31, 2023 in the medical ICU (MICU) and surgical ICU (SICU). Swabs were plated on selective agar . Peri-rectal swab was obtained within 48 hours of admission for 78 patients , and CRE prevalence in this cohort was 42% [33/78], with significantly higher prevalence noted among patients in the MICU compared to SICU . Hospitalization, or ICU admission within the last 1 year, and long-term dialysis were significantly associated with CRE colonization (Table 1).Klebsiella pneumoniae (59% [20/34 isolates]) followed by Escherichia coli (38% [13/34 isolates]). Among the 34 CRE isolates, 19 were metallo-beta-lactamase producers and 15 were serine carbapenemase producers.Among 33 patients with CRE colonization on admission, the most common CRE isolated was Table 1High prevalence of CRE colonization on admission was observed in the two ICUs, with prior hospitalization significantly associated with CRE colonization. Significantly higher proportion of CRE colonization was seen in the MICU as compared to SICU. Future studies should examine the risk factors associated with CRE acquisition during hospitalization to design interventions.All Authors: No reported disclosures"}
+{"text": "Z\u2032 \u2265 0.5), demonstrating excellent discriminationof photocleaved known membrane-permeable and -impermeable model librarybeads. Droplet-scale permeation screening will enable pharmacokineticmapping of bRo5 libraries to build predictive models.Combinatorial library screening increasingly exploreschemicalspace beyond the Ro5 (bRo5), which is useful for investigating \u201dundruggable\u201dtargets but suffers compromised cellular permeability and thereforebioavailability. Moreover, structure\u2013permeation relationshipsfor bRo5 molecules are unclear partially because high-throughput permeationmeasurement technology for encoded combinatorial libraries is stillnascent. Here, we present a permeation assay that is scalable to combinatoriallibrary screening. A liposomal fluorogenic azide probe transducespermeation of alkyne-labeled molecules into small unilamellar vesiclesvia copper-catalyzed azide\u2013alkyne cycloaddition. Control alkynes benchmarked theassay. Cell-permeable macrocyclic peptides, exemplary bRo5 molecules,were alkyne labeled and shown to retain permeability. The assay wasminiaturized to microfluidic droplets with high assay quality ( These difficult targets, such as protein\u2013proteininterfaces3 and intrinsically disorderedproteins,4 account for the vast majorityof the human proteome and therefore interest in investigating themis accelerating.6 Exploring molecules with higherMW (500\u20131500 Da) and HBD/HBA (>5/>10) can enable chemicalprobediscovery,8 however, chemical matter that is beyondthe Rule of 5 (bRo5) criteria usually exhibits compromised cell permeationand therefore bioavailability.10 In this bRo5 chemical space, a central remaining correlate withbioavailability short of animal studies is membrane permeability.Lipinski\u2019s Rule of 5 (Ro5) describesa set of physicochemicalproperties that collectively correlate small molecule structure withoral bioavailability and has strongly directed drug discovery anddevelopment over the past decades. The Ro511 and the cellular monolayer absorption assay measures permeationthrough a confluent layer of either MDCK (Madin-Darby canine kidney)or Caco-2 (human colon carcinoma) cells.13 In both assays, the permeating molecule is detected via LC-MS orUV absorption. Neither transwell assay is particularly convenientfor ultrahigh-throughput screening, but they have been deployed onthe scale of conventional compound collections because knowledge ofmembrane permeability is critical for further development.2 Recent innovative permeation measurement technologydevelopment has included fluorogenic copper-catalyzed azide alkynecycloaddition (CuAAC),14 liposomal dyedisplacement or LC-MS liposome pulldown,20 droplet-interface bilayer (DIB) permeation assay,22 black lipid membrane (BLM) label-free penetration assay,23 or cellular chloroalkane penetration assay (CAPA).25 Although all of these approaches can measure the permeation of bRo5molecules individually, none are amenable to screening large split-and-poolcombinatorial libraries (>104 members), which are thesourceof most bRo5 chemical matter.Membrane permeability is typically determined using two differenttranswell assays. The parallel artificial membrane permeability assay(PAMPA) measures the membrane permeation property of molecules viapassive diffusion through a synthetic lipid membrane,30 Unlike conventional compound collections, which canbe analyzed for bioavailability by proxy using assays of membranepermeation, the inherent nature of encoded libraries as complex mixturesrenders them incompatible. As a result, almost nothing is known aboutthe pharmacokinetic (PK) properties of these libraries, and very recentdisclosures have detailed how combinatorial split-and-pool librariescan be analyzed in pools via permeation assays to identify structure\u2013permeabilitytrends, highlighting the growing interest and need for technologydevelopment in this area.32 Solid-phase one-bead-one-compound(OBOC) DEL synthesis protocols35 and accompanying microfluidicactivity-based screening instrumentation37 have expanded library analysis beyond binding. We desired to integrateknown droplet-scale permeation measurement approaches39 with innovations in homogeneous fluorescence-based PAMPA to enablecombinatorial library-scale analysis and thereby uncover the moleculardeterminants of permeability in bRo5 chemical space.Combinatorial library synthesisaffords the opportunity to explorenovel bRo5 chemical space cheaply and expansively. In particular,encoded library modalities, such as DNA-encoded library (DEL) technologyand the mRNA display-based random nonstandard peptides integrateddiscovery (RaPID) platform, enable synthesis and affinity selectionof billion-member compound collections.39 A fluorogenic CuAACprobe is encapsulated in the SUVs, which transduce the permeationof an alkyne-labeled molecule of interest into a gain of fluorescencesignal. We benchmark the assay in microtiter plate format using alkyneswith known permeation  and known cell-permeablealkyne-tagged macrocyclic peptides as model bRo5 combinatorial librarymembers. The validated assay was further miniaturized to microfluidicdroplets to demonstrate compatibility with high-throughput OBOC libraryscreening.Here, wedisclose a liposomal permeation assay that is scalableto and compatible with high-throughput combinatorial chemical libraryfunctional screening. We posited that small unilamellar vesicle  liposomes would provide model bilayermembranes for assaying permeation and that SUVs would be advantageousfor droplet-based screening.3)40 and ascorbic acid (AA) during lipid film hydration.Unencapsulated probe was removed by dialysis after extrusion. SUVformation and uniformity were confirmed via dynamic light scattering, Figure S1). Only membrane-permeable alkynes penetrate the SUV bilayer, reactingwith the CF-N3 probe in a CuAAC reaction, resulting ina fluorescent triazole product . Controlswere analyzed in real-time fluorogenic CuAAC reactions in the presenceof CF-N3-loaded DOPC-POPC SUVs or with free CF-N3 was extracted to quantitate permeation  were loaded with membrane-impermeablefluorogenic azide probe .High Z\u2032 values, reflecting excellent assayquality, substantiatedthe assay\u2019s suitability for implementation in microplate- andmicrofluidic droplet-scale HTS.Control alkyne permeation in the liposomal assaytracked with gold-standardPAMPA permeation measurements. All alkynes reacted readily with freeCF-NFigure S2). The fourmacrocycles\u2019 permeation coefficients as determined via PAMPAwere largely independent of alkyne labeling . Alkyne-labeledmacrocycle permeation was measured in the liposomal permeation assayusing DOPC, DOPC-POPC, DOPC-POPC-cholesterol (DOPC-POPC-Ch), and brainpolar lipids and compared with permeation positive and negative controls,PPA and PEG4s, respectively . Molecularweight correlation with permeability was explored next using a modelseries of alkyne-labeled PEG  in either single-concentration(Table S1). As an example of the assay\u2019sability to detect permeation of an alternative alkyne-labeled scaffold,we synthesized and assayed the cell-penetrating peptide \u201dDD5o\u201d24 and two of its diastereomers. DD5o was alsoobserved to be permeable in the liposomal permeation assay, whilestereochemical inversions altered permeation to varying degrees .PAMPA is compatible with differentlipid bilayer compositions andpermeating molecules, thus we sought to determine whether the liposomalCuAAC permeation assay exhibited similar versatility. A series ofmembrane-permeable bRo5 macrocyclic peptides was derivatized by additionof a C-terminal propargylglycine residue to introduce the requisitealkyne label Cyc1\u20134, S2. The fN-methylations. These features are variouslyknown to influence compound stability and permeability, and thesefour compounds were selected from a larger library of macrocyclesbased on their observed and enhanced permeability.42 Lipid formulation was generally important across all alkynes:addition of cholesterol to DOPC-POPC bilayers increased permeationof all species, in agreement with one known behavior of cholesterolin bilayers43 and brain lipid SUVs wereless permeable for all species studied. Permeation positive and negativecontrols  were consistent acrossthe different lipid formulations and Cyc1\u20133 all exhibited robustpermeation, in agreement with their high PAMPA Pe compared to the more modest Pe of Cyc4. Membrane-permeable species were readily detected regardlessof lipid formulation, although some membrane formulations were morepermeable than others. Permeation also trended with expectations basedon the known inverse correlation between molecular weight and permeability:the more massive mPEG17 was largely impermeable, while the Ro5-compliantmPEG4 and mPEG8 readily permeated through multiple SUV formulations.The liposomal permeation measurement of the DD5o cell-penetratingpeptide agrees with Kritzer\u2019s observations using CAPA.24 The unusual dependence of permeation on stereochemicalconfiguration agrees with ours and others\u2019 findings; furthersynthesis and assay data are needed to understand these structure-permeationtrends.44The liposomal permeation assay accommodated structurallydivergentalkyne-tagged molecules and expected permeation trends were preservedusing compositionally diverse SUVs. Several macrocyclic peptides thatmodel those typically found in display-type encoded libraries weresynthesized and evaluated in both PAMPA and liposomal permeation assays.The macrocycles contain a thioether linkage, a variety of naturaland non-natural amino acids, points of stereochemical inversion, anddiverse Pe, we devised the PC50 measurement. The Pe is formally an apparent diffusion coefficient,where passive diffusion through the membrane is assumed to be limitingfor permeation. The PC50 measurement detects whether saturating permeationoccurred. At this concentration, the fluorogenic CuAAC reaction progressis no longer limited by permeation through the membrane. PC50 values,determined for E. coli extract SUVs, correlated withPAMPA Pe values. Thus, PC50 may be a reasonableproxy for the more standard measurement. End point assays are nonethelessmore practical for medium- and high-throughput screening in microplateswithout the need for transwell assemblies, LC-MS sample detection,or engineered cell lines, and the liposomal assay\u2019s performanceis sufficient for these purposes.To quantifypermeation analogous to the permeation coefficient, 3 probe would be loaded into microfluidic water-in-oildroplets together with alkyne-labeled molecule; CuAAC reagents wouldbe present either in the droplet  or with the probein the SUVs (ascorbic acid reducing agent). Membrane-permeable alkyneswould transit the membrane and then react with the probe, generatingfluorescent triazole product and increasing droplet fluorescence whilemembrane-impermeable alkynes would not . The optimal configuration for microfluidic permeationscreening was BTTP ligand, 9% w/v dextran, 25 \u03bcM alkyne, and70 min online incubation.The robust performance of the liposomal permeation assay in microplateformat suggested that it could be useful for DEL screening if miniaturizationto microfluidic droplet scale was feasible. Conceptually, the liposomalCF-Nould not 3A. Assayd mPEG17 3B. Assay39 Second,more hydrophobic CuAAC ligands might have undesirably partitionedinto the oil, compromising reaction kinetics. We used advanced Cu(I)ligands with enhanced water solubility to disfavor oil partitioning.46 However, this was a nuanced optimization, asTHPTA exhibited superior CuAAC performance in free solution, but notin the liposomal assay, presumably due to its low predicted membranepermeability . Third,it was not clear whether density additives required for droplet-scalescreening47 would negatively impact assayperformance; assay performance remained robust even with dextran . In spite of these concerns,optimization yielded a microfluidic assay that was ready for proof-of-conceptbead screening.Flow injection analysis confirmed the compatibilityof the liposomalpermeation assay with microfluidic droplet-scale screening. It wasnot immediately obvious that the assay would be droplet-compatible.First, the lipids used for SUV formation are surfactants and mighthave destabilized the microfluidic emulsion, but we did not observethis behavior in perfluorinated oil.Figure S8). Photocleavage products were characterizedby mass spectrometry and by fluorogenic CuAAC reaction monitoring. Assay quality score Z\u2032= 0.7 was measured between fluorescence gain folds of PC\u2013PPA\u2013Vand PC\u2013PPA\u2013PEG17 in liposomal permeation plate assays. The two different controlbead types  wereseparately loaded into microfluidic liposomal permeation assay dropletsfor subsequent on-chip UV photocleavage and fluorescence detection.48 Hit droplets were identified as high fluorescence signal (\u03bbem = 530 nm), such that droplet fluorescence was 5\u03c3 greaterthan the mean fluorescence; droplet generation rate, bead introductionrate, and hit rate were plotted as a function of run time .We next sought todemonstrate that all steps involved in microfluidic droplet-scalefunctional OBOC screening were also feasible. To label all librarymembers with a minimal N-propargylamide tag, we designed and synthesizedan alkyne-tagging photolinker 4A. SolidN-propargylamidewas permeable,38 and we again observedthat behavior in these droplet assays. Impermeable PEG17 cleaved fromresin yielded marginal permeation signal. Given the 5\u03c3 sortthreshold (P = 3 \u00d7 10\u20137) and40\u202f000 droplets measured over 20 min, 0.01 false discoverieswould be expected, thus the source of signal from the PC\u2013PPA\u2013PEG17beads derives from other systematic sources. Beads traversing thelaser focus generate a \u201dbead spike,\u201d which is usefulfor approximating droplet occupancy.37 Althoughthese spikes are smoothed, larger spikes (from multibead droplets)are not smoothed, resulting in false positive signals. Multibead dropletsalso inherently deliver high [alkyne], and because transport is concentrationdependent, this is another mechanism for generating false positivesignals. We have previously shown that multibead droplets are partof a larger Poisson distribution-derived source of error in OBOC DELscreening; identifying replicate hits in screens of multiple libraryequivalents completely mitigates these sources of error.36Photocleavable control bead signal in the dropletliposomal permeationassay agreed with the previously measured values in microplates andfurther confirmed compatibility of all on-chip OBOC analysis steps.We had previously shown that valine-37The validated fluorogenic CuAAC liposomalpermeation assay developedhere introduces important throughput and generality advantages thatwill be useful for library screening. Known membrane-permeable and-impermeable molecules via gold-standard PAMPA assays behaved similarlyin the liposomal permeation assay, as did cell-permeable macrocyclicpeptides. The assay was compatible with a broad range of lipids, requiringonly a minimal alkyne tag that can be readily introduced during solid-phaselibrary synthesis. Finally, the assay is homogeneous, fluorescence-basedand compatible with droplet-scale assays, suggesting that it couldbe implemented for high-throughput solid-phase DEL screening.19 or implementing liposomal formulations.39 A recent pooled library screening approach demonstratedthe deep structure\u2013permeation insights that can be gained,such as how stereochemistry and N-methylation affectmacrocycle permeability.32 The presenttechnology offers opportunities to build on these capabilities byscreening individual library members and pairing with nucleic acidencoding, a highly parallel and generalized structure deconvolutionstrategy to increase the breadth of structure\u2013permeation measurements.49 Combinatorial synthesis in particular wouldallow ready access to bRo5 space, where permeation trends remain largelyunclear.52The assay\u2019s high-throughput screeningcompatibility withmicroplates or droplets is particularly important. The transwell formatand LC-MS detection of PAMPA and MDCK assays make implementation inhigh-throughput settings difficult, thus limiting the scope of structure\u2013permeationrelationship measurements. Significant technology development effortshave aimed at transforming these assays into homogeneous fluorescence-basedapproachesPe, the PC50 ofthe concentration-dependent permeation curve makes inroads towardestablishing such a metric. The liposomal membrane format does offera potentially important advantage, however, in being a unilamellarmembrane bilayer. A recent study showed that the PAMPA membrane thicknessis dramatically higher than that of a bilayer and may not accuratelyapproximate passive diffusion through a cellular bilayer.23 Further evaluation of this assay in librarycontexts may shed light on the importance of a more accurate cellularmembrane model during permeation screening. Finally, screening librariesof model alkynes, obtained either through site-selective labeling or installed as alinker during combinatorial synthesis as described above, could generatethe requisite correlations. Furthermore, dose\u2013response microfluidicscreening by modulating photocleavage intensity48 could provide such a link at library scale.Future studieswill seek to draw direct correlations between theformal permeation coefficient and the PC50 and establish the generalityof the alkyne labeling strategy. While the liposomal assay does notreadily yield defined quantitative permeation metrics, such as thepermeation coefficient, 53 Library members that induce membrane lysis willalso register as permeation hits but are uninteresting from the perspectiveof transport. Inclusion of an orthogonal liposomal dequenching assayusing a dye with different emission properties could allow us to discriminatelysis from passive diffusion.39 The resultingmultiplexed assays could advantageously offer the possibility of discoveringstructures that disrupt membranes, a common property of antimicrobialpeptides and candidates for drug delivery through endosome escape.54Movingtoward library screening, there are several minor considerations.It may be necessary to identify and minimize false positive signalsgiven a potentially high \u201dpermeation hit\u201d rate. Falsepositive permeation hits are most likely to be synthesis truncatesor membranolytic. Synthesis truncates are potentially false positivesbecause they are likely to be more membrane-permeable on the basisof lower molecular weight and fewer hydrogen bond donors/acceptors.Truncate artifacts are a known and accepted possibility in combinatoriallibrary screening, and emerging machine learning-based synthesis predictionstrategies could identify building blocks or building block pairswith poor coupling efficiency, resulting in truncation.In conclusion, we have developed and validateda fluorogenic CuAAC-basedliposomal permeation assay that is compatible with high-throughputscreening applications. The assay sensitively measures the permeationof known control molecules and structurally novel bRo5 macrocyclicpeptides. These bRo5 molecules hold great promise to ligand difficulttargets, but structure\u2013permeation relationships that couldguide the development of these molecules into clinical assets mustbe established. The liposomal permeation assay of this study pavesthe way to bRo5 DEL design, synthesis, and screening experiments thatwill allow us to generate the needed empirical data and build modelsthat will ultimately reveal such relationships.H-1,2,3-triazol-4-yl)methyl]amine , BTTP , 5(6)-carboxytetramethylrhodamine , CalFluor 488 azide , l-ascorbic acid , 1,2-dioleoyl-sn-glycero-3- phosphocholine , 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine , Brain Polar Lipid Extract , E. coli PolarLipid Extract , 1,2-dioleoyl-sn-glycero-3-phospho-(1\u2032-rac-glycerol) , cholesterol , m-PEG17 acid , m-PEG4-propargyl , m-PEG8-propargyl, m-PEG17-propargyl , propargyl-PEG4-sulfonic acid , Slide-A-Lyzer dialysis cassettes , dextran from Leuconostoc spp. , PAMPA multiscreen Transport (up) , Multiscreen Transport(bottom) , 3 M Novec7500 Engineered Fluid , and Pico-Surf (5% (w/w)in Novec 7500, Sphere Fluidics, Cambridge, UK) were used as provided.All synthesized compounds had purity >95% by LC-MS analysis.All reagents were purchased from MilliporeSigma unless otherwise specified. Tris V0 was divided by the correspondingbroken liposome maximum [alkyne] V0,broken. These normalized data were fit to a sigmoid to determine the [alkyne]at which V0/V0,broken was 50% maximum (PC50).Assays were assembles as described above, combining liposomal probe with stabilizer (4%Pico-Surf) was loaded into a syringe  fitted with blunt-end needle  and connected to the microfluidic device OIL1inlet via Tygon microbore tubing . Aqueous inputs  were loaded into the syringes and connected toAQ inlets of the microfluidic device. Novec 7500 was loaded into syringes(10 mL) and similarly connected to the device via Tygon microboretubing as spacing oil (OIL2) and flow focusing oil (OIL3). The incubationchannel was primed with Novec 7500 by filling from the OIL2 and OIL3inputs before initiating flows from OIL1 and AQ inlets. OIL and AQflows were driven by syringe pumps : AQ1 (400 nL/min) AQ2 (400 nL/min), OIL1 (500 nL/min), OIL2 (16\u03bc L/min), and OIL3 (6 \u03bcL/min). Droplets were equilibrated(15/70 min) prior to beginning data acquisition.Microfluidic droplet-basedscreening was performed in a UV-free room as previously described.E. coli polar lipid SUV suspension , CuSO4 , and BTTP . For flow injection analysis experiments,AQ2 included alkyne  and cTMR (0.2 \u03bcM) with or without dextran  in PBS.For bead analysis experiments, AQ2 included  with cTMR (0.2 \u03bcM) and dextran (9% w/v) in PBS buffer. Afterbeads were encapsulated, they were irradiated in flow using a customoptical fiber patch cable that was coupled to a high-power UV LED .48 All experiments used the maximum LED voltage(5 V).AQ1 was preparedby combining 36 CF-N3 probe fluorescence was detectedin PMT 1. PMT data were digitized using a DAQ board  and processed using custom dataacquisition control software written in LabVIEW .38 Median smoothing (window width = 5) was applied to both channels.Once a droplet was detected, the average PMT 1 signal was calculated.Data analysis for droplet-scale Z\u2032 determination,droplet generation, bead occupancy, and hit rate visualization wasperformed as previously described.37Fluorescence data were acquired using a custom confocallaser-inducedfluorescence detection system. Droplets were detected based on internalstandard (cTMR) signal in PMT 2 as previously described."}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-023-31407-z, published online 13 March 2023Correction to: The original version of this Article contained an error in the Funding section.\u201cThe funding was provided by Princess Nourah Bint Abdulrahman University (PNURSP2022TR140).\u201dnow reads:\u201cThe authors extend their appreciation to the Deputyship for Research & Innovation, Ministry of Education in Saudi Arabia for funding this research work through Project Number RI-44-0422.\u201dThe original Article has been corrected."}
+{"text": "Light is well-establishedfor control of bond breakagebut notfor control of specific bond formation in complex environments. Wepreviously engineered the diffusion-limited reactivity of the SpyTag003peptide with its protein partner SpyCatcher003 through spontaneousisopeptide bond formation. This system enables precise and irreversibleassembly of biological building blocks with applications from biomaterialsto vaccines. Here we establish a system for the rapid control of thisamide bond formation with visible light. We have generated a cagedSpyCatcher003, which allows light triggering of covalent bond formationtoSpyTag003 in mammalian cells. Photocaging is achieved through site-specificincorporation of an unnatural coumarin-lysine at the reactive siteof SpyCatcher003. We showed a uniform specific reaction in cell lysateupon light activation. We then used the spatiotemporal precision ofa 405 nm confocal laser for uncaging in seconds, probing the earliestevents in mechanotransduction by talin, the key force sensor betweenthe cytoskeleton and the extracellular matrix. Reconstituting talininduced rapid biphasic extension of lamellipodia, revealing the kineticsof talin-regulated cell spreading and polarization. Thereafter wedetermined the hierarchy of the recruitment of key components forcell adhesion. Precise control over site-specific protein reactionwith visible light creates diverse opportunities for cell biologyand nanoassembly. Our initial construct contained the N-terminalregion of transferrin receptor (TfR), SpyCatcher003 with an amberstop codon at K31 (K31TAG), and superfolder green fluorescent protein(sfGFP). Based on Western blotting, we optimized the dose of HCK andthe ratio of the SpyCatcher003 construct to HCK RS .To establish our uncaging approach,we cotransfectedthe humancell-line HEK293T with HCK tRNAs and HCK tRNA synthetase (HCK RS)23 Talin changes conformation in response to force, regulating associationand release of multiple proteins involved in the cell\u2019s responseto mechanical cues.24 Talin recruitmenthas been previously controlled by an elegant strategy using rapamycinas a cell-permeable small molecule to reconstitute FRB- and FKBP-splittalin fragments.25 However, this approachlacks subcellular spatial resolution and was only tested to withstandforce of 4 pN,25 which may not resist sustainedcytoskeletal tension acting on talin at 10\u201340 pN.27 Split talin reconstitution using LOV domains would allow spatialcontrol but depends on continuous 488 nm illumination and has limitedinteraction stability.28 Because of thecomplex structure and natural turnover of adhesion structures, estimatingthe impact of such non-covalently reconstituted talin on adhesionfunction is challenging. Rapid light-mediated induction of covalenttalin reconstitution would allow precise control over early phasesof adhesion formation to decipher molecular details of talin-dependentprocesses.We then applied a photocontrolled reactionto gain insight intocell adhesion, focusing on talin protein. Talin bridges the cytoplasmicdomain of \u03b2-integrin to the actin cytoskeleton and functionsas a molecular clutch required for actin-dependent cell spreading.Figure S1B,C). Western blot withantiserum to SpyCatcher003 or anti-EGFP  demonstratedlight-dependent SpyCatcher003(K31HCK) activation and isopeptide bondformation. Without HCK, no SpyCatcher003 expression was detected,indicating that the stop codon led to chain termination . To understand the practicality forselective uncaging, we assessed uncaging by ambient light. Room lightingor U.K. sunlight for 120 min did not lead to substantial uncagingin cell lysate in microcentrifuge tubes . Depending on the used wavelength and required light dose,optogenetic control of cells even with visible light can lead to phototoxicity.29 We confirmed the biocompatibility of 405 nmlight on fibroblast cells using a resazurin-based metabolic activityassay. We observed full viability of cells in Trolox-supplementedmedia even after 3 min of continuous 405 nm exposure .To establish optical control of talin reconstitution,we incorporatedSpyCatcher003(K31TAG) in a split talin construct 1D. We st21 We transfectedwith Talin head-SpyTag003 and SpyCatcher003(K31HCK)-Talin rod-mScarletI,along with HCK tRNAs and HCK RS with LifeAct-mNeonGreen to visualizeactin. Cells were cultured with HCK and imaged by confocal microscopywith lasers at 405 nm (photoactivation), 488 nm , and 561 nm . Unactivated cells could not spread or polarize, consistentwith the lack of functional talin , indicating the rapid reconstitutionof talin in cells. We did not observe spreading of unactivated cellsimaged at 488 nm (Movie S1), so typical microscopyconditions did not cause unintended photoactivation. Similarly, wedid not observe spreading upon 405 nm exposure of cells transfectedas described above but with the equivalent DMSO concentration in placeof HCK  followed by a slower phase(10\u201320 nm/s) 2C,D. ActeonGreen2E. UnacteonGreen2F. TalineonGreen2F. The s23 Given the covalent SpyTag003:SpyCatcher003 interaction, this photoactivationstrategy should allow extended cell polarization experiments coveringtens of minutes. Talin knockout fibroblasts transfected with Talinhead-SpyTag003, SpyCatcher003(K31HCK)-Talin rod-mScarletI, and HCKRS plasmids were cultured with HCK and photoactivated with wide-field405 nm light for 1 min. Cells were fixed at selected time points andanalyzed for cell area and morphology. Activated cells showed fastinitial spreading and reached close to a maximal area \u223c10 minafter photoactivation .5 We observed reduced spreading of unactivated cells expressing SpyTag003mutants compared to SpyTag003 itself , suggesting that SpyCatcher003(K31HCK) may form a transient non-covalentcomplex with SpyTag003 before uncaging. While the SpyTag003 complex was unable to mediate stable talin reconstitution andadhesion formation in the absence of light, cell spreading and polarizationwere equivalent to SpyTag003 after 405 nm activation . SpyTag003(M115G) did allow increasedcell spreading after light activation but showed little cell polarization. Therefore, these peptidevariants provide alternative properties for light-regulated peptide\u2013proteininteraction.We next explored the feasibility of fine-tuningSpyTag003/SpyCatcher003light regulation via single or double amino acid mutations in SpyTag003 is a central adhesion complex tyrosinekinase that is activated by phosphorylation at tyrosine 397 (pY397).33 Paxillin is an adaptor protein interacting withboth structural and signaling components.33 Vinculin is recruited to mechanically activated sites in the talinrod domain and binds F-actin to reinforce mechanically the adhesioncomplex.34 Vasodilator-stimulated phosphoprotein (VASP)is an actin regulator, promoting actin filament elongation throughmultiple mechanisms.30 We observed fastinitial FAK pY397 recruitment to adhesions, reaching half-maximalintensity <1 min after photoactivation (S5B).Paxillin and vinculin reached half-maximal intensity at 3 min, withpaxillin being slightly faster . In contrast, recruitment of VASP reached half-maximal intensityonly after 10 min .Stretching of talin rod regulates recruitment andrelease of manyadhesion components, generating a structure with distinct functionallayers 3D.31 How35 However, local changes in force magnitude, duration, and applicationrate can affect bond stability and lead to inconsistent or unrepresentativeresults. To overcome this limitation, we developed SpyCatcher003(K31HCK)for visible-light photoactivation and demonstrated its applicationin the covalent reconstitution of split talin. Optical control oftalin reconstitution allowed us to probe the time scale of initialadhesion complex formation, revealing biphasic extension of lamellipodiaupon engagement of the adhesion clutch. We also demonstrated the useof SpyCatcher003(K31HCK) coupling over a longer time course, establishinga hierarchy of adhesion protein recruitment after engaging the adhesionclutch. The recruitment rates of adhesion proteins followed the layerstructure of the adhesion complex with HaloTag (33 kDa).Beyondadhesion, SpyCatcher003(K31HCK) may become a broadly applicabletool for the photocontrol of biomolecules. A robust cellular responsewas initiated in seconds here, opening possibilities for spatiotemporalcontrol of highly dynamic intracellular and extracellular processes."}
+{"text": "Streptococcus (iGAS) hospitalizations in Colorado, similar to trends reported in other countries.Since the fall of 2022, we have observed a sharp rise in pediatric invasive group A From October 2022 \u2013 March 2023, iGAS cases were prospectively identified in patients hospitalized at Children\u2019s Hospital Colorado and medical charts were systematically reviewed. iGAS was defined as isolation of GAS from a sterile site (confirmed case) or a non-sterile site with clinically consistent disease (probable). Using laboratory specimen records, we compared the number of patients with sterile site GAS-positive cultures across three time periods: Pre-COVID-19 (Jan 2015 \u2013 Mar 2020), COVID-19 pandemic (Apr 2020 \u2013 Sep 2022), and Outbreak (Oct 2022 \u2013 Mar 2023).(Table 1), median age was 6 years old; 64% of patients were male and 69% were previously healthy. 33% of patients required pediatric intensive care unit (PICU) admission, and two patients died. iGAS was more commonly associated with upper respiratory infection (URI) symptoms (63%) than isolated sore throat (5%) or trauma/skin findings (15%). The most common clinical manifestations were head and neck infections (37%), musculoskeletal infections (32%) and pneumonia (20%). 11% had toxic shock syndrome and 4% had necrotizing fasciitis. Lab findings associated with PICU admission were bandemia, leukopenia and higher CRP values. Disease severity and treatment varied by clinical manifestation (Table 2). There were more iGAS cases during the outbreak (average 10.0/month) compared to pre-pandemic years (3.8/month over the same period) and during the pandemic (1.2/month over the same period) .Among the 81 iGAS cases identified during the outbreak We report an unprecedented outbreak of iGAS in pediatric patients in Colorado, with case numbers close to triple the pre-pandemic baseline at our hospital. The timing and high proportion of cases with associated URI symptoms suggest a link to the recent surges in respiratory viruses, although iGAS cases have continued to persist past the peak of respiratory season. Invasive GAS can be severe and evolve rapidly; there are important clinical and laboratory features that may help in earlier identification of children who are critically ill.Samuel R. Dominguez, MD, PhD, Biofire Diagnostics: Advisor/Consultant|Biofire Diagnostics: Grant/Research Support|Cobio Diagnostics: Board Member|Karius: Advisor/Consultant|Pfizer: Grant/Research Support"}
+{"text": "Serratia infective endocarditis (SIE) in recent years are healthcare-associated. At our urban institution with a high prevalence of people who inject drugs (PWID), we noted an increasing number of Serratia bacteremias (SB) and SIE over the past decade. Our study describes patient factors associated with SB and SIE.The majority of reported We evaluated charts of patients with SB at our institution between 2010 and 2022 to determine risk factors and clinical outcomes.There were 157 episodes of SB in 153 patients. The majority were male (57%), white (57%) with a mean age 53. The most common source of infection was catheter- line-associated infection (CLABSI) (27%), followed by primary bacteremia (19%). Twenty-six % were PWID with younger mean age (41 years). PWID had lower mortality than non-PWID . Sixty-nine (46%) were admitted to the intensive care unit (ICU) with significantly higher mortality associated with ICU admission .Echocardiograms were performed in 59% (93/157) of SB episodes and 14% had SIE (13/93). Most SIE (69%) occurred after 2017 with 89% in PWID (8/9). The most common comorbidity with SIE was injection drug use (IDU) (69%). All non-IDU SIE were CLABSI-related; 75% had hemodialysis catheters. Tricuspid valves were infected in 46%. Sixty-two % of those with SIE had septic emboli. Most SIE (69%) required ICU admission. Overall mortality was 31%.Only 2% (3/153) of patients with SB developed antibiotic resistance on therapy. Clinical worsening or failure occurred in 20% (32/157). Only 5% (7/157) had microbiologic recurrence within 30 days. 32% of discharged patients re-presented to the hospital within 30 days. Almost all deaths (92%) occurred during initial admission.Patients with SB were quite ill with a high rate of in-hospital mortality; over half of the patients had antibiotic exposures prior to developing SB or presented within 90 days of a prior hospitalization. The majority of SB were line-associated, including all episodes of non-IDU SIE. IDU was the second most common comorbidity and PWID with SB had a higher rate of SIE, with most IDU-associated SIE diagnosed after 2017. This aligns with other recent studies documenting the increased prevalence of SB, especially in PWID.Madeline King, PharmD, La Jolla: Advisor/Consultant|Shionogi: Advisor/Consultant"}
+{"text": "Breast implant illness (BII) is a poorly understood heterogeneous disorder treated with implant removal; however, patient-reported symptoms and outcomes following treatment remain unclear.A retrospective review of patients undergoing bilateral breast implant removal related to BII by two surgeons between 2018-2022 was performed. Patients were surveyed with the BREAST-Q augmentation model with the American Society of Plastic Surgeons (ASPS) BII survey extension. Outcomes were analyzed using a multivariable logistic regression adjusting for patient-associated factors.Forty-seven patients were surveyed with a response rate of 51% (n=24). Of the 20 patients completing the survey, the majority were Caucasian (85%), with 45% (n=9) having a documented history of psychiatric illness. Six (30%) had capsular contracture and four (20%) had documented implant rupture. The majority of implant removals  were not covered by insurance. Fourteen (70%) had a net improvement in their symptoms after implant removal\u2014most commonly improving chest discomfort, muscle pain, fever, and headaches. Self-pay was predictive of increased breast satisfaction scores (p=0.009), but had no impact on symptomatic improvement. Reduced time to implant removal was predictive of fewer residual symptoms (p=0.032). Capsular contracture was predictive of reduced psychosocial, sexual, and breast satisfaction scores (p=0.015). Psychiatric illness had no significant impact on outcomes.In the setting of suspected or diagnosed BII, reduced time to implant removal may decrease the risk of residual symptoms and improve overall patient satisfaction. In patients with capsular contracture, preoperative counseling should emphasize the fact that implant removal may improve physical symptoms only."}
+{"text": "Burns that involve the perineum, buttocks and genitals (PBG) have been associated independently with more challenging therapeutic needs and worse clinical outcomes in case series and smaller patient collectives, while large scale epidemiology of this injury is lacking. We studied a cohort of 1024 patients admitted to our burn center to assess clinical outcomes based on the presence of PBG burns.Medical records were screened for patients who did or did not sustain PBG burns and patients stratified accordingly (PBG vs. control (CTR)). Demographic baseline data, burn etiology, presence of inhalation injury (IHT), presence of full thickness burns (FT), number of operations (NOR), mortality, length of ICU treatment (LOS ICU) and hospitalization (LOS) were assessed to compare clinical characteristics and outcomes between the groups. Multivariate regression analyses adjusting for TBSA, sex and age were conducted for key clinical outcomes.Between 2014 and 2022, 1024 patients were included in the analysis . PBG burns were older (median (IQR) 54 (38) vs. 44, (31) years, p< 0.0001), more frequently female  presented with larger TBSA burns overall (27 (37) vs. 10 (13) %, p< 0.0001) and sustained FT burns more frequently (69% vs. 26% p< 0.0001). Scald burns were more frequently the cause of PBG burns , PBG patients needed twice as many surgical procedures (2 (4) vs. 1 (1), p< 0.0001) as CTR. PBG patients remained longer in the ICU per per cent TBSA (0.9 (1.1) vs. 0.5 (0.8) days/%TBSA, p< 0.001). Mortality was higher in patients with PBG burns . Multivariate logistic regression yielded significant effects of PBG burns on LOS ICU, LOS and NOR.Burns to the perineum, buttocks and genitals are associated with more challenging baseline characteristics upon admission and substantially worse clinical outcomes than burns not involving PBG.Expectable therapeutic challenges regarding prolonged intensive care, more frequent surgeries and increased risk for mortality should be taken into account and planned for when admitting patients with PBG burns."}
+{"text": "Outpatient parenteral antimicrobial therapy (OPAT) provides an effective and convenient means to complete extended courses of antimicrobial therapy for the treatment of serious infections. There is scant data addressing OPAT related outcomes such as readmission in solid organ transplant (SOT) recipients.In this observational cohort study, we analyzed all adult SOT recipients discharged from Henry Ford Hospital \u2013 an 877 bed quaternary care center in Detroit, Michigan - on OPAT between January 2015 and December 2020. The primary endpoint was 30-day all-cause readmission. The secondary endpoints included evaluation of risk factors associated with readmission  and all-cause mortality at one year.p=0.04 and p=0.02 respectively) while renal transplants were protective against readmission (p=0.02) (Table 1). Other factors associated with readmission include development of an OPAT related complication including treatment failure (p< 0.001) (Table 2). Patients discharged without Infectious Disease follow up were less likely to be readmitted (p=0.04) (Table 3) as these patients generally had less serious infections not meriting a follow up appointment. There was no difference in mortality at one year between study populations (Table 3).There were 201 patients discharged on OPAT. Demographics between study populations were comparable (Table 1). A total of 83 out of 201 (41.3%) patients were readmitted. There were 38 (18.9%) patients readmitted for OPAT related complications and 45 (22.4%) for non-OPAT related reasons. Intestinal and multi-visceral transplants were associated with readmission (While the overall readmission rate of SOT discharged on OPAT is high, most readmissions were unrelated to OPAT. Patients with readmissions had higher rates of OPAT related complications and treatment failures. Further studies are warranted to optimize OPAT outcomes in the SOT population.All Authors: No reported disclosures"}
+{"text": "National estimates of central line-associated bloodstream infections (CLABSI) focus on acute care hospital settings. Little is known about CLABSI that develop outside of hospitals and are present on admission (CLABSI-POA). We aimed to describe the epidemiology of CLABSI-POA to develop appropriate prevention strategies.We performed a retrospective cohort study of all adult and pediatric patients admitted from 11/01/2020 to 10/31/2021 in two large medical systems in the US, one in Maryland and one in Missouri. Adapting the National Healthcare Safety Network acute care CLABSI definition, we included patients who had a central venous catheter (CVC) present on admission (or had a CVC discontinued within 72 hours prior to admission) and a positive blood culture within 72 hours before and/or after admission. We performed descriptive statistics to characterize the epidemiology of CLABSI-POA.Staphylococcus aureus (21%), Enterococcus spp. (12%), Candida spp. (11%), Escherichia coli and Klebsiella pneumoniae (10% each), and Pseudomonas aeruginosa (7%). Forty-five (11%) cases were due to multidrug resistant organisms. Overall in-hospital mortality was 10%.Of 402 patients with CLABSI-POA, 52% were male, 68% were age \u226545 years, and 45% had Medicare insurance as primary payer. Half of the cases had a hospitalization 30 days prior to the index admission, 22% had at least one prior CLABSI, and 40% received chemotherapy in the last 6 months. The most common indications for catheter placement were chemotherapy (34%), total parenteral nutrition (21%), dialysis (15%), and outpatient parenteral antimicrobial therapy (11%). Attribution of CLABSI-POA based on site where the catheter was routinely accessed included oncology clinics (34%), home infusion therapy (32%), hemodialysis centers (12%), and skilled nursing facilities (9%). The most common causative microorganisms were coagulase-negative staphylococci (23%), CLABSI-POA were common in those attending oncology clinics and receiving home infusion therapy. Lack of routine surveillance of CLABSI-POAs leads to an underestimation of the burden of CLABSIs in the healthcare system. Tailored prevention strategies should be focused in those groups at higher risk.Stephanie Mayoryk, MAS BSN RN CIC, PDI: Honoraria Sara E. Cosgrove, MD, MS, Debiopharm: Advisor/Consultant|Duke Clinical Research Institute: Advisor/Consultant Carlos Mejia-Chew, MD, INSMED: Grant/Research Support|RevImmune: Grant/Research Support Sara C. Keller, MD, MPH, MSPH, Pfizer: Advisor/Consultant"}
+{"text": "Because severe burn patients are at higher risk for catheter-related infections, routine changes of central venous catheters (CVCs) are commonly performed for them. However, there are limited information on pathogen colonization of the CVC tip and associated bloodstream infections (BSI) in burn patients.In this study, medical records of severe burn patients, in whom routine CVC changes were performed every 7 days, were retrospectively reviewed. The results of CVC tip cultures and concurrently performed blood cultures were investigated.p < 0.001), higher total body surface area burn (p < 0.001), renal replacement therapy (p < 0.001), and femoral catheter (p < 0.001) were significantly associated with the development of catheter-related BSI in a multivariate analysis. Most cases of tip colonization (81.3%) and BSI (82.9%) were caused by Gram-negative bacteria: Acinetobacter baumannii and Klebsiella pneumoniae were most frequently identified.A total of 686 CVCs in 214 severe burn patients admitted to the burn intensive care unit were analyzed. A median of 2 CVCs (range: 1\u201315 CVCs) were inserted in each patient, and each CVC was maintained for a median of 8 days (range: 2\u201324 days). The median duration of catheterization was 17 days (range: 4\u2013117 days). Of the 686 CVCs, 138 (20.1%) CVC tips were colonized by 150 pathogens (two pathogens in 12 CVCs), and 82 (59.4%) of them accompanied BSIs caused by the same pathogen. Non-flame burn (Catheter-related BSI was accompanied in 12.0% of the changed CVCs: nine of ten CVCs might not require routine changing. Therefore, selective CVC changing at higher risk for catheter-related BSI seems to be appropriate rather than routine CVC changing in severe burn patients. Also, source control for burn wounds should be emphasized because most common pathogens of burn wound infection caused CVC tip colonization and BSI.All Authors: No reported disclosures"}
+{"text": "Intravenous (IV) and oral (PO) antibiotics (ABX) are standard treatments for pulmonary exacerbations (PEx) in people with cystic fibrosis (pwCF). Frequent ABX use may lead to adverse events and ABX resistance. Cystic fibrosis transmembrane conductance regulator modulator treatments have significantly reduced PEx in qualifying pwCF, but impact on ABX use is unknown. The approval of elexacaftor/tezacaftor/ivacaftor (ETI) in 2019 makes these treatments accessible to the majority of pwCF. The primary objective was to examine utilization of ABX pre-and post-ETI in pwCF managed at Children\u2019s Mercy Kansas City\u2019s (CMKC) CF center.A retrospective analysis of PO and IV ABX for CF PEx was performed at CMKC. The pre-ETI treatment period was defined as 1/1/2017-12/31/2019 and post-ETI treatment period as 1/1/2020-12/31/2022. A paired analysis including pwCF managed by CMKC during both periods was used to compare ABX courses pre- and post-ETI.Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus significantly decreased between periods. The median duration of ABX did not significantly change for IV  or PO  ABX during both periods.A total of 293 pwCF and 110 pwCF received PO and IV ABX during the study period, respectively. Of these, 224 pwCF managed by CMKC during both periods were included. IV ABX were received by 25 pwCF in both periods whereas 138 pwCF did not receive IV ABX in either period. There were 43 pwCF who received IV ABX only in the pre-ETI period compared to 18 pwCF who received IV ABX only in the post-ETI period (p=0.0021) resulting in a discordance of 27.2%. PO ABX were prescribed for 119 pwCF in both periods whereas 35 pwCF did not have PO ABX prescribed in either period. There were 52 pwCF who received PO ABXs in the pre-ETI period only compared to 18 pwCF who received PO ABX in the post-ETI period only (p=0.0001) resulting in a discordance of 31.3%. The number of patients receiving ABX directed against CMKC pwCF experienced a dramatic decline in prescribing both PO and IV ABX following approval of ETI. Future investigations are necessary to determine this trend nationwide and ascertain the overall impact from decreased ABX exposure in pwCF.All Authors: No reported disclosures"}
+{"text": "A third dose of measles-mumps-rubella vaccine (MMR) may be administered for various reasons, but there are limited data on long-term immunogenicity. We assessed persistence of measles and rubella neutralizing antibodies among adults after receipt of three MMR doses.Adults who received two MMR doses in childhood and a third dose as young adults (aged 18-28 years) in 2009-2010 were recalled at around 5 (2014-2016) and 9-11 (2019-2021) years after receipt of the third MMR dose. Measles and rubella antibody levels were assessed by plaque-reduction and soluble immunocolorimetric neutralization assays, respectively. Participants with measles antibody concentrations < 120 mIU/ml or rubella antibody concentrations < 10 U/mL were considered potentially susceptible to infection. Generalized estimating equations models were used to estimate geometric mean concentrations (GMC) and 95% confidence intervals (CI) of antibody levels over time.Approximately 5 and 9-11 years after receipt of the third MMR dose, 408 (aged 22-33 years) and 304 (aged 26-37 years) adults were reassessed, respectively. For measles, GMC was 428 mIU/mL  at 5 years after the third MMR dose, declining to 381 mIU/mL  at 11 years after the third MMR dose . Measles antibody concentrations during both long-term follow-up periods declined to levels lower than before receipt of the third dose . At the last follow-up visit (2019-2021), 10% of participants were potentially susceptible to measles infection compared to 3% before receipt of the third MMR dose up to 11 years earlier. For rubella, GMCs were stable throughout the long-term follow-up period (63 U/mL to 65 U/mL) . Rubella antibody concentrations during the long-term follow-up periods remained higher than levels before receipt of the third MMR dose and were similar to levels at 1 year after receipt of the third MMR dose . None of the participants were susceptible to rubella at the last follow-up visit.The solid black line shows the trend in population GMC estimates from before vaccination (0 year) through 12 years after receipt of the third MMR dose. The gray lines show the measles virus antibody concentrations over time for each individual. The dotted horizontal line shows concentration <120 mIU/mL used as the cutoff for susceptibility.The vertical dotted lines represent the cutoff for susceptibility.The geometric mean concentrations (GMCs) were estimated using generalized estimating equations model. The solid black line shows the trend in population GMC estimates from before vaccination (0 year) through 12 years after receipt of the third MMR dose. The gray lines show the rubella virus antibody concentrations over time for each individual. The dotted horizontal line shows concentration <10 U/mL used as the cutoff for susceptibility.Neutralizing antibody levels to measles and rubella remained high and persisted through 11 years after vaccination among adults who received three MMR doses. However, some adults may become susceptible to measles infection over time despite receipt of three MMR doses.Stephen N. Crooke, PhD, Bionano Genomics: Stocks/Bonds|Caribou Biosciences: Stocks/Bonds|Pfizer: Stocks/Bonds|Vistagen Therapeutics: Stocks/Bonds Huong McLean, PhD, MPH, Seqirus: Grant/Research Support"}
+{"text": "Figure\u00a01A). Repeated thromboaspiration using a 7 Fr Rebirth catheter  eliminated the fresh red thrombus and achieved recanalization . However, intravascular ultrasound (IVUS) confirmed a residual thrombus on the plaque without evident rupture, with persistent coronary flow disturbance . Prolonged balloon inflation using a 3.5/20 mm perfusion balloon  was performed three times for a total of 9\u2005min to compress the thrombus and plaque. In addition, intracoronary sodium nitroprusside infusion  was performed during perfusion balloon angioplasty to restore coronary flow, resulting in an angiographically optimal outcome with sufficient coronary flow improvement . Due to the sufficient luminal gain achieved with perfusion balloon angioplasty following thromboaspiration, the subsequent drug-coated balloon angioplasty using a SeQuent Please 4.0/30 mm  successfully resulted in stentless PCI . Subsequently, the highest CK and CK-MB levels were 4867\u2005U/L and 401\u2005ng/mL, respectively. Transthoracic echocardiography showed focal left ventricular asynergy in the inferior myocardium with a reduced left ventricular ejection fraction of 48%. Thereafter, the patient had an uneventful clinical course.A 51-year-old man who presented with chest pain that had persisted for 19\u2005h was diagnosed with inferior ST-segment elevation myocardial infarction. On admission, the patient\u2019s creatine kinase (CK) and CK-myocardial band (CK-MB) levels were already elevated (3351\u2005U/L and 315\u2005ng/mL). Emergency coronary angiography revealed a mid-right coronary artery occlusion with large thrombi .1 Intracoronary infusion with drugs including adenosine and sodium nitroprusside (available in some regions as strong coronary vasodilators instead of adenosine) provides cardioprotective effects by reducing reperfusion-mediated injury.2\u20135 The presented case demonstrated the utility of combined intracoronary drug infusion during prolonged perfusion balloon inflation, facilitating sufficient luminal gain and coronary flow improvement. This resulted in stentless PCI with drug-coated balloon angioplasty, even in a case of thrombotic ACS. Thus, drug infusion therapy during perfusion balloon angioplasty serves a dual purpose of improving epicardial coronary obstruction and microvascular disorders in the myocardium, increasing the potential for stentless PCI even in challenging ACS cases.In acute coronary syndrome (ACS) cases, massive coronary thrombus poses clinical challenges, leading to slow/no reflow. Distal embolization caused by balloon angioplasty should be prevented in such situations. Perfusion balloon, which features a central lumen and multiple side holes in the shaft, may allow coronary flow during prolonged inflation and effectively compress the thrombus (ytad609_Supplementary_DataClick here for additional data file."}
+{"text": "This cross-sectional study examines whether proposed myelin oligodendrocyte glycoprotein antibody\u2013associated disease (MOGAD) diagnostic criteria can exclude other diseases, such as multiple sclerosis, and rely on results of cell-based assays. We investigated the reliability of the MOGAD diagnostic criteria to address these 2 challenges.With recognition of myelin oligodendrocyte glycoprotein (MOG) antibody\u2013associated disease (MOGAD) as a distinct entity and wider availability of MOG-IgG testing, clinicians are frequently confronted with the challenge of diagnosing MOGAD.3 Institutional review boards of participating centers approved this cross-sectional study. All patients provided written informed consent. We followed the STROBE reporting guideline.We analyzed data from a multicenter study of patients with suspected or confirmed demyelinating diseases.4 with positive MOG-IgG results in a live cell-based assay (CBA) were included and independently rated by 2 neurologists  for final diagnosis (MOGAD2 or MS4). For challenge 2, patients with at least 1 core clinical demyelinating event suggestive of MOGAD2 and 2 independent MOG-IgG results in a live CBA and a fixed CBA were included , interassay, and intercenter diagnosic concordance rates were calculated . Challenge 1 group included 28 patients with positive MOG-IgG results, of whom 21  received MS diagnosis, 2  MOGAD diagnosis, and 5  discordant diagnoses. Twenty-seven patients (96%) presented records of core demyelinating events that were compatible with MOGAD. All 28 patients fulfilled imaging criteria for the MS diagnosis, 21 of whom (75%) also presented at least 1 supporting magnetic resonance imaging (MRI) feature compatible with MOGAD diagnosis. All 5 patients with discordant diagnoses presented positive cerebrospinal fluid (CSF)\u2013specific oligoclonal bands, which were usually associated with myelitis (4 [80%]), and supportive imaging features for MOGAD . The intChallenge 2 group included 134 patients, of whom 108  exhibited concordant MOG-IgG results. Among 26 patients with divergent results, 17 (65%) had low-positive results in either CBA. A 90% (121 of 134) diagnostic agreement rate was observed when applying the proposed criteria to each center\u2019s MOG-IgG results .Findings revealed that the proposed diagnostic criteria in some cases may not accurately distinguish MOGAD from MS, contributing to diagnostic inconsistencies across centers. MOG-IgG testing and consideration of MOGAD diagnosis are recommended only in the absence of better alternative causes, such as MS. While this recommendation prevents unwarranted MOG-IgG testing, with potential false-positive results, the precondition cannot always be met because patients often present with overlapping clinical and imaging features. Consideration of additional laboratory, advanced MRI, or optical coherence tomography features may be needed in establishing accurate diagnoses.2 additional strategies are necessary to mitigate the risk of false-positive or false-negative results. Standardized testing remains unavailable worldwide, but repeated testing of sera with alternative assays or CSF testing in cases of seronegative results may increase diagnostic certainty in patients with high disease suspicion. A study limitation was its retrospective and cross-sectional design.Inconsistent replicability of MOG-IgG detection across assays and decreased reproducibility of low-positive results pose additional challenges. Although the panel aimed to increase comparability by categorizing antibody results as clear-positive or low-positive,The proposed criteria mark a breakthrough toward improved MOGAD diagnosis. However, additional research and validation are needed to establish standardized assays and develop novel biomarkers to refine these criteria."}
+{"text": "Tooth root development involves intricate spatiotemporal cellular dynamics and molecular regulation. The initiation of Hertwig\u2019s epithelial root sheath (HERS) induces odontoblast differentiation and the subsequent radicular dentin deposition. Precisely controlled signaling pathways modulate the behaviors of HERS and the fates of dental mesenchymal stem cells (DMSCs). Disruptions in these pathways lead to defects in root development, such as shortened roots and furcation abnormalities. Advances in dental stem cells, biomaterials, and bioprinting show immense promise for bioengineered tooth root regeneration. However, replicating the developmental intricacies of odontogenesis has not been resolved in clinical treatment and remains a major challenge in this field. Ongoing research focusing on the mechanisms of root development, advanced biomaterials, and manufacturing techniques will enable next-generation biological root regeneration that restores the physiological structure and function of the tooth root. This review summarizes recent discoveries in the underlying mechanisms governing root ontogeny and discusses some recent key findings in developing of new biologically based dental therapies. Consequently, the loss of teeth instigates multifaceted detriments to both oral and systemic health, underscoring the exigency for swift and efficacious remedial interventions.4Dental integrity stands as an essential cornerstone of overall physiological well-being, given that teeth assume pivotal functions in processes such as mastication, digestion, phonation, and self-perception.7 In this context, nascent paradigms rooted in biological tooth regeneration have surfaced, leveraging the tenets of stem cell-based bioengineering.8 These innovative approaches portend outcomes that are more congruent with the innate physiology, durability, and bioresponsive dynamics of natural tooth structure, thereby heralding a promising and forward-looking therapeutic avenue.9Presently, osseointegrated dental implants emerge as the prevailing clinical benchmark for ameliorating tooth absence. However, it is noteworthy that certain limitations are attendant, encompassing elevated prerequisites for bone volume and an absence of sensory biofeedback mechanisms.10 This intricate collaboration of molecular dialogs advances through discrete phases, beginning with the development of the tooth crown and terminating with the formation of the tooth root.A pivotal prerequisite for advancing the therapeutic trajectory is the elucidation of ontogenetic processes that underpin the morphogenesis of tooth roots. This pursuit holds the promise of unveiling novel focal points for inciting intrinsic dental repair mechanisms and the orchestrated construction of tooth organ substitutes. The orchestration of tooth organogenesis ensues through a sequence of orchestrated, reciprocal molecular interplays between distinct specialized cell populations-the dental epithelial cohort and the cranial neural crest (CNC)-derived mesenchymal contingent.11 Following the accomplishment of crown development, the root morphogenesis commences, spearheaded by the inception of Hertwig\u2019s epithelial root sheath (HERS). The orchestration of the signaling cascades in the HERS serves as the conductor directing odontoblast differentiation, ultimately leading to the deposition of radicular dentin. Concurrently, the dental follicle takes on the role of generating cementoblasts, which oversee the deposition of acellular and cellular cementum onto the nascent root surface, subsequent to the dissolution of HERS.A strip of oral epithelium that has thickened marks the beginning of the creation of the crown, giving rise to the dental lamina.12 It is worth acknowledging that deviations from the norm within these signaling pathways choreographies underlie a panoply of root anomalies, spanning from abridged root dimensions to anomalies at the furcation junctures. Thoroughly deciphering the molecular mechanisms underlying the morphogenetic processes of tooth roots promises to unveil innovative perspectives for biotherapeutic interventions that activate intrinsic tooth repair and regeneration cascades.Throughout the trajectory of root ontogeny, the precise orchestration of spatiotemporally regulated signaling pathways assumes a nonpareil significance, serving as the compass directing HERS dynamics and the interplay between epithelial and mesenchymal compartments. Key protagonists in this narrative include signaling pathways entities, including Bone Morphogenetic Protein (BMP), Wnt, Transforming growth factor-\u03b2 (TGF-\u03b2), Ectodysplasin A (EDA), and Sonic hedgehog (SHH), alongside a constellation of Mitogen\u2011activated protein kinase (MAPK) cascades.14 The crown develops first, marked by the thickened oral epithelium proliferates and penetrates into the beneath CNC-derived mesenchyme and then give rise to the dental lamina structure.15 The dental lamina undergoes rapid cell proliferation, morphological expansion, and elongation, eventually developing into the enamel organ.17 Simultaneously, the CNC-derived mesenchyme condenses surrounding the dental lamina, serves as the major source of DMSCs. The dental lamina, together with the condensed mesenchyme around it, forms the tooth germ. The dental lamina develops into the enamel organ, and meanwhile the condensed mesenchyme diverges into the dental papilla and the dental follicle at the cap stage.18 The enamel organ produces enamel, while the dental papilla and the dental follicle subsequently form pulp-dentin complex and periodontal tissues, respectively.21Tooth development involves the lineage development of CNC cells, complex mutual interactions between dental epithelium and dental mesenchymal stem cells (DMSCs), and a precise sequence of morphological stages.Tfap2b+/Lhx6+/Pax9+ in the condensed CNC-derived mesenchyme is identified as the progenitor cell population contributing to tooth formation. During the cap stage, the homogenous CNCCs segregate into dental papilla and dental follicle lineages, marked by specific genes like Crym/Egr3/Fgf3 and Epha3/Foxf1/Fxyd7 respectively.21 The dental papilla and follicle undergo further segregation at the bell stage. The dental papilla divides into distinct coronal and apical domains, marked by expression of Lmo1/Fgf3/Smpd3 and Lhx6/Fst/Gldn respectively. Concurrently, the dental follicle divides into Lepr/Foxf1/Bmp3 marked lateral domain and Aldh1a2/Rasl11a/Sgk1 marked apical domains. For instance, Lepr+ lateral follicle cells mainly form periodontal tissues. At the postnatal stage, dental papilla contains four distinct cell populations, including mature Phex+/Ifitm5+ odontoblasts, Enpp6/Fabp7+ coronal papilla, Nnat+/Rab3b+ middle papilla, and Aox3+/Tac1+ apical papilla cells. The latter was identified as bipotent progenitors for odontoblasts and pulp. In the follicle, Pthrp+/Bmp3+/Tnmd+ lateral and Pthrp+/Smoc2+/Slc1a3+ apical domains resemble those present at the bell stage and Pthrp+ dental follicle progenitors generate periodontal ligament (PDL) and cementum at the root-forming area and the furcation region.22 Particularly, a population of Slc1a3+ cells from the dental follicle\u2019s apical area control cell lineages and aid in the formation of periodontal tissues at the root furcation. In addition, a range of other cells, such as glial cell derivatives, and pericytes can also serve as stem cell resources for dental mesenchyme.25 The perivascular niche contains NG2+, Gli1+, and Acta2+ cells that can differentiate into odontoblasts. The perineural niche is derived from Schwann cell precursors. Throughout the formation and regeneration following tooth damage, dental pulp cells and odontoblasts can be differentiated from PLP1+ and Sox10+ Schwann cells.26The tooth germ experiences three stages in sequence during development: bud, cap, and bell stage. During mouse molar development, CNC-derived DMSCs separate into various cell populations and domains, which is a crucial phase in DMSCs differentiation and functional specialization Fig. . At the 27 As the crown nears completion, the inner and outer enamel epithelium at the edge cervical loop continues to proliferate and elongate towards the future apical foramen from the cervical loop, which is located at the enamel organ\u2019s cervical margin and is the region where the future crown and root of the tooth meet, also known as cementoenamel junction. This elongation gives rise to HERS, which is vital for the root development.28Gli1+ cells, residing in HERS, apical dental papilla, and dental follicle, have been identified as progenitor cells in the root and play a crucial role during root development.29. Moreover, Sox2+ stem cells that resides in dental epithelial contribute to all epithelial cell lineages at the bell stage, while Osx+ progenitor cells that distributes in dental papilla and dental follicle, especially in the area adjacent to HERS, differentiate into odontoblasts, dental pulp cells, cementoblasts, and PDL cells.32Sox2+ cells located at the cervical loop continue to exist in mouse incisors, while they disappear in mouse molars after birth.34 The cells from cervical loop and HERS, respectively, have their own different gene expression patterns. HERS cells have a relative higher level of BMP2 and BMP4, but a lower level the genes involved in enamel formation and mineralization, such as amelogenin (AMGN), ameloblastin (AMBN), osteopontin (OPN), bone sialoprotein (BSP), Osteocalcin (OCN) and dentin sialophosphoprotein (DSPP).35 HERS cells also express both Cytokeratin 14 (Ck14) and Epithelial cadherin (E-cadherin), while detached cells from HERS are only Ck14 positive with reduced E-cadherin expression.37Once the crown has formed during the late bell stage, the root development commences, marked by the formation of HERS.38 If the entire epithelial diaphragm boundary develops equally and ultimately merges, a normal single root will be formed. In the development of multirooted teeth, when the root is going to divide, several tongue-shaped epithelial diaphragms formed from HERS protrude toward each other and subsequently fuse to form continuous bridges, which will be the root furcation. The dental papilla is then divided into equivalent parts, ultimately resulting in the formation of equivalent roots.39At the initial phase of HERS development, the ends of the double-layered enamel epithelium of HERS curve toward the dental papilla, forming an epithelial diaphragm structure, histologically encapsulating the dental papilla and surrounded by the dental follicle. This diaphragm has a determinantal role in root morphology, including shape, number, and length of the root.41 As dentin formation progresses, the dental papilla becomes confined to a smaller space and eventually forms the dental pulp. Once the very first coat of radicular dentin is formed and the tooth root begins to elongate, HERS loses its integrity but remains a network of connections during root development through localized apoptosis or epithelial-to-mesenchymal transition (EMT), and the remaining HERS cells in the PDL are called \u2018epithelial rests of Malassez (ERM)\u2019, which contribute to cementum regeneration.44When the outermost mesenchymal cells of the apical papilla establish connections with the innermost cells of the HERS, they are induced to differentiate into odontoblasts and gradually retreat to the center of the dental papilla, secreting radicular dentin.45 In the region of the cervical root, cementoblasts first deposit cementum on the dentin and withdraw from the progressing mineralization front so that they do not incorporate themselves into the cementum, termed acellular cementum, also known as primary cementum. In more apical and inter-radicular areas, unlike acellular cementum formation, cellular cementum, also known as secondary cementum, is secreted by cementoblasts when the tooth reaches the occlusal plane, mineralizing rapidly and occasionally embedding some cementoblasts as cementocytes.49 The dental follicle also contributes osteoblasts and periodontal ligament cells to form the PDL and alveolar bone.50 In addition to dental follicle resources, some researchers have suggested that cementoblasts and PDL fibroblasts can also be derived from HERS cells through EMT and can be directly engaged in the deposition of cementum and PDL fibers during the development of periodontal tissues.51Following the disintegration of the HERS, the lateral mesenchymal cells of the dental follicle acquire interaction with the radicular dentin and then differentiate into cementoblasts, forming acellular cementum and cellular cementum.42 HERS development seems to be an especially solid procedure at the shift from the crown to the root morphological formation, whereas apical HERS development related to root elongation and the establishment of the root furcation appears to be more vulnerable to a variety of intrinsic as well as extrinsic negative effects.53. Developmental abnormalities in HERS can cause defects in tooth root formation.The HERS serves as a critical regulator in the proper formation of the tooth root. One primary role of it in tooth root formation is to induce odontoblast differentiation and subsequent dentinogenesis.53 Another phenomenon associated with failed HERS disintegration is the formation of enamel pearls. This occurs when HERS cells keep attached to the dentin and differentiate into ameloblasts, enamel pearls are formed.54When the continuity of HERS is compromised, stem cells from apical papilla (SCAPs) failed to differentiate into odontoblasts, leading to radicular dentin defects at that site and the formation of lateral accessory canals. Conversely, if HERS does not disintegrate after the first layer of dentin is formed and remains adhered to the dentin, it will block the engagement between dental follicle stem cells (DFSCs) and radicular dentin, preventing them from differentiating into cementoblasts and forming cementum. In some cases, delayed formation of the epithelial diaphragm in the multirooted teeth can result in taurodontism or single-rooted teeth. Following the completion of the bridges, future interradicular dentinogenesis and cementogenesis can be unaffected.14 Proper spatiotemporal coordination of these cell-cell interactions is mediated by several evolutionarily conserved signaling pathways.Root formation is susceptible to various effects that can influence molecular processes. The underlying molecular mechanisms tightly coordinate morphogenic events, cytodifferentiation, mineralization, and maturation during tooth root development in a precise spatial and temporal way. Any disruptions of the involved regulatory mechanisms could lead to root malformations. The interaction and regulation among the signaling pathways and a range of molecular factors contribute to various processes during tooth root development Fig. . Normal 55 Simultaneous conditional deletion of Bmp2 and Bmp4 in dental epithelium resulted in persistent HERS with reduced apoptosis and downregulation of BMP/SMAD and MAPK  signaling pathways in HERS cells. The impaired BMP/SMAD signaling pathway further caused decreased expression of SHH in HERS and downregulated expression of GLI family zinc finger 1 (GLI1) in root mesenchyme cells, leading to downregulation of the downstream target gene Nuclear Factor I C (NIFC). Reduced NIFC ultimately resulted in defective differentiation and maturation of root odontoblasts, decreased Osterix (OSX) and DSPP expression, and impaired dentin formation, resulting in short root anomaly. Dspp transgenic expression partially alleviated the short root phenotype.56 Therefore, optimal spatiotemporal expression levels of epithelial BMP ligands were required to properly coordinate HERS dissolution and odontogenesis through intricate reciprocal epithelial-mesenchymal molecular interactions over the entire course of root development.56 However, one study suggested BMP4 ligand was secreted by surrounding DPSCs and bound to BMPR-IB and BMPR-II expressed on HERS epithelial cells. Organ culture studies employing developing mouse molars demonstrated that BMP4 derived from mesenchyme bound to BMPR-IB/II dimers on HERS cells, thereby providing negative feedback to inhibit further HERS elongation while simultaneously promoting odontoblast differentiation.57 Mice harboring an epithelial-specific deletion of Smad4, a pivotal intracellular BMP effector, exhibited arrested root developmental owing to failed HERS elongation and stratification, confirming SMAD4\u2019s indispensable role.58 Specifical deletion of Smad4 downregulated SHH expression within HERS and the surrounding inner enamel epithelium. Ectopic SHH expression in mutant mice partially rescued the root defects by restoring NFIC expression and normal dentin formation by newly differentiated odontoblasts.59 Epithelial SMAD4-SHH signaling pathway triggered mesenchymal NFIC expression to enable HERS morphogenesis and subsequent root formation. In contrast, conditional ablation of Smad4 specifically in dental epithelium led to prolonged molar crown morphogenesis associated with maintained cervical loop structures harboring proliferative Sox2+ epithelial stem cells. Additional deletion of Shh in the epithelium in these compound mutant mice partially rescued this aberrant phenotype and eliminated Sox2+ epithelial stem cells. Hence, BMP-SMAD4 signaling pathway in the mesenchyme provided crucial negative feedback to restrict dental epithelial stem cell expansion during the later phase of root formation by suppressing the SHH-GLI1 signaling pathway in the epithelium.33The BMP signaling cascade, particularly BMP2 was crucial in determining root patterning and elongation.\u03b2-catenin severely disrupted root morphogenesis and HERS dissociation. Studies suggested that suppressing \u03b2-catenin in HERS led to earlier disruption and thinner HERS, while stabilizing \u03b2-catenin in HERS prevented HERS dissociation after root dentin formation.60 Conditional deletion of \u03b2-catenin permitted molar tooth eruption accompanied by HERS elongation but completely abrogated root formation.61 Yet, odontoblast-specific deletion of \u03b2-catenin likewise caused premature pathological dissociation of HERS via upregulating BMP7, downregulating Noggin and Follistatin in odontoblasts, and accompanied by increased phosphorylation of SMAD1/5/8 in HERS cells.14 During molar furcation morphogenesis, canonical Wnt signaling pathway induced by epithelial WNT10A ligand critically patterned organized cell division and differentiation behaviors by modulating mesenchymal WNT4 expression and localized Wnt/\u03b2-catenin activity. In the furcation area, epithelial deletion of Wnt10a caused a decrease in epithelial cell proliferation but an increase in dental papilla mesenchymal cell proliferation, resulting in pathological taurodontism phenotype. Wnt10a deletion in dental epithelium causes compensatory upregulation of other Wnt ligands like WNT4, resulting in excessive \u03b2-catenin activation and overgrowth of dental papilla mesenchyme. Silencing of aberrant WNT4 partially rescued this abnormal furcation phenotype, validating that epithelial WNT10A precisely orchestrated dental epithelial and papilla mesenchymal cell proliferation by modulating the activation of mesenchymal WNT4 to guide root furcation morphogenesis.62The canonical Wnt/\u03b2-catenin signaling pathway was also indispensable for proper differentiation of functional odontoblast lineage cells and root dentin formation. During root development, \u03b2-catenin was essential for preserving the proliferation, polarity, and adhesion of HERS cells. HERS-specific deletion or overexpression of 63 During EMT, HERS cells must precisely balance antagonistic Sema-RhoA and TGF-\u03b2 signaling pathways, whereby the Sema-RhoA signaling pathway promoted the maintenance of epithelial polarity and adhesion while TGF-\u03b2 signaling pathway drove the acquisition of mesenchymal attributes and enhanced migratory capacity.36 Furthermore, mesenchymal TGF-\u03b2 signaling pathway indirectly help sustain the residual dental epithelial stem cell population by modulating Wnt signaling pathway activity in cervical loop through the induction of key ligands like WNT5a and FGF3/1064.During the progression of tooth root maturation, HERS cells experienced EMT and relocated into the emerging periodontium. This EMT process could be induced in vitro by exogenous stimulation with either TGF-\u03b21 or FGF2 growth factors, which activated MAPK/ERK intracellular signaling cascades.65 Eda-Edar signaling pathway represents another critical signaling pathway that directly participates in proper root formation and elongation. Both Ectodysplasin A (Eda) and Ectodysplasin A receptor (Edar) knockout mice exhibited substantially increased HERS proliferation and subsequent root developmental defects including shortened root length and taurodontism.66Moreover, DFSCs and cementoblasts could trigger apoptosis of both inner enamel epithelial-derived ameloblasts and HERS cells by upregulating FAS ligand (FASL) expression, which binds to and activates FAS-mediated extrinsic apoptotic signaling cascades.In summary, intricate molecular signaling networks centered upon BMP, canonical Wnt/\u03b2-catenin, TGF-\u03b2, Fas/FasL, and Eda pathways precisely directed HERS behaviors and epithelial-mesenchymal interactions at distinct developmental stage of tooth root morphogenesis. Comprehensive elucidation of these intersecting regulatory mechanisms using advanced genetic models will uncover novel therapeutic targets to enhance endogenous tooth root repair and inform sophisticated bioengineering strategies for whole tooth regeneration.67 SCAPs have a considerably greater proliferation and mineralization capacity than dental pulp stem cells (DPSCs).69 During tooth development, a substantial number of SCAPs reside in the apical papilla. Through complex molecular signaling pathways, the apical papilla provides a niche regulating the organized differentiation of SCAPs. To promote further root elongation and dentin formation, SCAPs can differentiate into odontoblasts.70 The regulation of biological behaviors of SCAPs, such as differentiation, maturation, and mineralization, is tightly controlled by a cascade of signaling pathways, including TGF-\u03b2, WNT, and MAPK pathways  express classic mesenchymal markers and have multi-differentiation potential.ays Fig. .71Fig. 3Alp and Ocn in a SMAD3-dependent manner. The TGF-\u03b21\u2019s inhibitory effect on SCAPs differentiation was enhanced by NFIC knockdown, whereas overexpression of NFIC antagonized these effects.72 Another study yielded the contrary results that TGF-\u03b21 increased SCAPs proliferation and collagen production, which could be inhibited by blocking ALK5/SMAD2 and MEK/ERK pathways. Moreover, TGF-\u03b21 had dual effects on regulation of Alkaline phosphatase (ALP) activity in SCAPs. For instance, low doses of TGF-\u03b21 stimulated ALP activity which could be blocked by inhibiting ALK5/SMAD2 and MEK/ERK pathways, while higher doses inhibited ALP which could be rescued only by ALK5/Smad2 inhibition.73TGF-\u03b21 inhibited SCAPs proliferation and osteogenic differentiation by downregulating osteogenic genes like \u03b2-catenin in odontoblasts, it was observed that odontoblast differentiation was impeded and the expression of DSPP, OCN, and Type I collagen (COL I) in regions anticipated to form the root was significantly diminished. The loss of differentiated odontoblasts prevented root dentin formation, mineralization, and periodontal attachment, though the epithelial root sheath developed normally but failed to induce odontoblast differentiation in the absence of \u03b2-catenin signaling pathway.74 Low-dose Wnt agonist LiCl inhibited Glycogen synthase kinase 3 beta (GSK3\u03b2) and \u03b2-catenin degradation in nuclear, leading to \u03b2-catenin accumulation and stimulating cell cycle genes, thereby enhancing SCAPs proliferation and differentiation.75 WNT3a and BMP9 were reported to synergistically promote the osteogenic/odontogenic differentiation of SCAPs, which required functional \u03b2-catenin.76 Apurinic/Apyrimidinic (AP) endonuclease 1 (APE1) expression decreased during tooth development. APE1 inhibition promoted osteogenic differentiation of DPSCs via stimulating the canonical Wnt signaling pathway.77 Similar results were obtained that Secreted frizzled-related protein 2 (SFRP2) blocked Wnt signaling pathway activation by competing with Frizzled receptor for Wnt, increasing \u03b2-catenin phosphorylation and nuclear exclusion and thus downregulating Wnt target genes. Sfrp2 overexpression enhanced while its knockdown inhibited osteogenic/odontogenic differentiation of SCAPs.79 LIM homeobox 6 (LHX6) coordinated Wnt activity and SCAPs differentiation to ensure correct root patterning and furcation development. LHX6 maintained active canonical Wnt signaling by inhibiting SFRP2 which physically interacted with WNT10A and suppressed WNT10A-induced odontoblast differentiation in the furcation area, resulting in defective dentin bridge formation. Moreover, LHX6 negatively regulated Cyclin-dependent kinase inhibitor 1C (CDKN1C) to maintain SCAPs proliferation.80 One recent study unraveled the tissue-specific role and molecular mechanisms of the non-canonical Wnt receptor, Receptor tyrosine kinase like orphan receptor 2 (ROR2), during molar root development. ROR2 was highly expressed in root-forming apical dental mesenchymal cells. Conditional deletion of Ror2 in Gli+ DMSCs impaired root elongation and furcation formation, inhibited dental mesenchymal cell proliferation, disrupted HERS invagination, and decreased odontoblast differentiation through epithelial-mesenchymal interactions, but without affecting crown morphogenesis. Mechanistically, ROR2 regulated dental mesenchymal cell proliferation and root patterning likely by modulating the activity of Cell division cycle 42 (CDC42).81 However, Wnt inhibition might be required for normal development, as \u03b2-catenin overexpression in dental mesenchyme resulted in upregulated SMAD4 in odontoblasts while downregulation of Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) in cementoblasts, causing hypomineralized dentin and excessive cementum deposition respectively.83 Deletion of Runt-related transcription factor 2 (Runx2) in Gli1+ DMSCs resulted in impaired odontoblast differentiation, downregulation of NOTUM and upregulation of WNT/\u03b2-catenin signaling. RUNX2 directly upregulated the NOTUM expression, which was specifically expressed in pre-odontoblasts and inhibited HERS-secreted WNT ligands, WNT3a as well as WNT4, and thus regulated WNT/\u03b2-catenin signaling in the dental mesenchyme.84The proper development of roots and deposition of dentin and cementum rely heavily on the precisely spatiotemporal management of the Wnt signaling pathway. In the mice with specifically deleted Gli1+ DMSCs during root development. Arid1a deletion in Gli1+ DMSCs resulted in shortened roots and impaired dentin and periodontal tissues. ARID1A interacted with transcription co-Factor Pleomorphic adenoma gene-like 1 (PLAGL1) and directly regulated the transcription of GLI1, thereby controlling the switch from proliferation to differentiation.85 Enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) and ARID1A antagonistically regulated the expression of Cyclin dependent kinase inhibitor 2\u2009A (CDKN2A) to control cell proliferation in the root-forming region, thereby coordinating furcation development and determining molar root number. Loss of EZH2 led to upregulation of CDKN2A, resulting in reduced cell proliferation and defective furcation formation. In contrast, monoallelic deletion of Arid1a rescued the root defects caused by loss of Ezh2.86At-rich interaction domain 1\u2009A (ARID1A) was also expressed in 87 One study showed bFGF enhances stemness in SCAPs and decreases osteogenic/dentinogenic differentiation and related gene expression. Meanwhile, bFGF pretreatment enhanced the subsequent osteogenic differentiation potential of SCAPs.88 Epiregulin (EREG), an epidermal growth factor family member, stimulated the MEK/ERK and JNK signaling cascades, resulting in increased SCAPs proliferation.89Furthermore, growth factors played crucial roles in apical papilla development. SCAPs expressed all four fibroblast growth factor (FGF) receptors. Basic FGF (bFGF) can activate Extracellular signal regulated kinase (ERK) and Transforming growth factor beta-activated kinase 1 (TAK1) phosphorylation in SCAPs. The MEK/ERK inhibitor U0126 and the TAK1 inhibitor 5Z-7-oxozeaenol compromise bFGF-induced upregulation of Plasminogen Activator Inhibitor-1 (PAI-1), Urokinase-type Plasminogen Activator (uPA), Urokinase Plasminogen Activator Receptor (uPAR), and Tissue Inhibitor of MetalloProteinase-1 (TIMP-1) expression. They also partially reversed bFGF-mediated inhibition of OCN expression in SCAPs. This suggests bFGF may regulate SCAPs proliferation, migration, and matrix turnover while suppressing differentiation through MEK/ERK and TAK1 signaling pathways.90 17beta-estradiol (E2) enhanced SCAPs osteogenic/odontogenic differentiation without affecting proliferation, by upregulating ALP, DSPP, Dentin matrix acidic phosphoprotein 1 (DMP1), and matrix mineralization and activating JNK, p38 MAPK pathways and downstream nuclear factors like c-Jun and c-Fos.91 Estrogen receptor \u03b1 (Er\u03b1) also enhanced SCAPs osteogenic/odontogenic differentiation via the same mechanism.92Additionally, lncRNA H19 promoted SCAPs osteogenic/odontogenic differentiation by binding to miR-141 and upregulating Sperm associated antigen 9 (SPAG9), which activated MAPK pathway by regulating the phosphorylation of p38 and JNK.29 Intriguingly, Lysine-specific demethylase 1A (KDM1A) had different regulatory roles at distinct stages during osteogenic/dentinogenesis. Inhibiting KDM1A reduced the activity of early osteogenic/dentinogenic markers and mineralization in SCAPs, but increased the expression of middle and late stage osteogenic/dentinogenic genes like Bsp, Dspp, and Dmp1. KDM1A can bind to Procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (PLOD2) to form a protein complex. Inhibition of PLOD2 had similar effects as inhibition of KDM.93 Additionally, there was a study suggested inhibition of PI3K/Akt/mTOR signaling pathway enhanced osteogenic/dentinogenic differentiation and calcification of SCAPs and SCAPs spheroids.94 Discoidin domain receptor family member 2 (DDR2) expressed in dental papilla, odontoblasts, dental follicle, as well as PDL during tooth development. Mice lacking the Ddr2 gene exhibited short tooth roots, abnormal root/crown ratios, PDL defects, and progressive alveolar bone loss with impaired differentiation of cultured dental pulp and PDL cells.95 Moreover, Epigallocatechin-3-gallate (EGCG) facilitated osteogenic/odontogenic differentiation and mineralization of SCAPs by activating BMP2 expression and SMAD1/5/9 phosphorylation.96 Furthermore, the immune checkpoint molecule Programmed cell death 1 (PD1) that was expressed on SCAPs suppressed osteogenic differentiation by activating Src homology-2-containing protein tyrosine phosphatase 2 (SHP2) which inhibited its downstream NF-\u03baB signaling pathway.97 Protein arginine methyltransferase 6 (PRMT6), a member of type-I enzymes, inhibited osteogenic/odontogenic differentiation of SCAPs by downregulating C-X-C motif chemokine ligand 12 (CXCL12) expression through increasing H3R2 methylation and forming a complex with Lamin A/C (LMNA) inhibiting its nuclear entry.98In addition to the previously delineated signaling pathways orchestrating the regulatory landscape of SCAPs, an array of noteworthy molecular factors also contributes to its behavior. Researchers found HERS cells secrete SHH ligand, and it antagonized NFIC which activated Hedgehog-interacting protein (HHIP) (a Hh inhibitor) to ensure normal Hh signaling pathway activity pattern in apical papilla, promoting proper apical papilla growth and root formation.99Further insights into the regulatory network revealed that immune cells make up 83% of all tooth germ cells, demonstrating their regulatory responsibilities. They could directly modulate multiple processes during tooth development via secreted cytokines and acted on specific receptors, providing evidence for the novel roles of the immune system in tooth development.101 Under specific induction conditions, when DFSCs and DPSCs were transplanted in vivo and simultaneously treated with dentin matrix, both cells could differentiate into odontoblast-like cells, express dentin-related markers and facilitate the dentin-pulp as well as the cementum-periodontium complex regeneration. However, DFSCs possess greater proliferation potential, osteogenic differentiation capacity, and mineralization ability compared to DPSCs. In contrast, DPSCs exhibit stronger angiogenic and dentinogenic potential.102 DFSCs are primarily responsible for the formation of cementum, PDL, and alveolar bone, which is governed by a number of signaling pathways , down-regulates the Wnt/\u03b2-catenin signaling pathway, leading to suppressed osteoblast differentiation of DFSCs. The expression of DKK3 was decreased during osteogenic differentiation of DFSCs. Dkk3 knockdown enhanced the osteogenic potential of DFSCs, as evidenced by increased calcified nodules, and expression of osteogenic markers. Dkk3-deficient DFSCs also formed more osteoid matrix when implanted in vivo. These findings implied that DKK3 knockdown induced \u03b2-catenin accumulation in nuclear and activated canonical Wnt signaling pathway.104 Despite its role as a Wnt antagonist in other cell types, Naked cuticle homolog 2 (NKD2), an inhibitor of Wnt signaling pathway, enhanced the Wnt/\u03b2-catenin signaling pathway, thus promoted osteogenic differentiation of DFSCs.105The precise balance of Wnt and BMP signaling pathways is critical for determining DFSCs fate. Canonical Wnt signaling pathway was required for DFSCs differentiation. Researchers co-cultured HERS cells and DFSCs of rat molars and observed increased mineralized nodule formation by DFSCs. The results suggested that HERS cells triggered the Wnt/\u03b2-catenin pathway in DFSCs through tight junctions with DFSCs, which in turn secreted extracellular matrix containing vesicles that promoted osteogenic differentiation of DFSCs and matrix mineralization.106 An in vivo study showed BMP2 could induce cementoblast/osteoblast differentiation of DFSCs by intricate interaction between BMP and Wnt pathways to balance DFSCs fate. Exogenous WNT3a, a member of canonical Wnt signaling pathway, inhibited BMP2-induced differentiation, suggesting BMP-induced differentiation was suppressed by the Wnt/\u03b2-catenin signaling pathway. This was due to Wnt3a enhancing Lymphoid enhancer-binding factor 1 (LEF1), expression, which could inhibit RUNX2-dependent Ocn promoter activation. However, the \u03b2-catenin knockdown decreased BMP2-induced expression of RUNX2, ALP, and OCN, indicating endogenous Wnt/\u03b2-catenin signaling pathway was essential for BMP2 to induce DFSCs differentiation. BMP2 strongly induced Wnt inhibitor factor 1 (WIF1) expression, suggesting it initiated a negative feedback loop to control DFSCs maturation by inhibiting Wnt signaling pathway.107 Furthermore, the BMP2/PKA/\u03b2-catenin/DLX3 signaling pathway enhanced DFSCs osteogenic differentiation. BMP2 enhanced \u03b2-catenin transcriptional activity by activating PKA, which induced phosphorylation of \u03b2-catenin at Ser675. Activated \u03b2-catenin combined with LEF1 and SMAD4 to form a complex that promoted Distal-less homeobox 3 (DLX3) expression. Overexpression of Dlx3 further activated the Wnt/\u03b2-catenin signaling pathway. In contrast, WNT3a suppressed BMP2-induced osteogenic differentiation of DFSCs by suppressing PKA activity.108 However, WNT3a was reported to initiate osteogenic commitment, promote the early cementoblast/osteoblast differentiation of DFSCs due to it activating the canonical Wnt signaling pathway and inducing the expression of osteogenic regulators. However, it was insufficient to drive terminal differentiation and mineralization which might be due to WNT3a inducing the expression of WNT5a to negatively regulate WNT3a-induced ALP and OSX expression.110 Similarly, a study revealed that WNT3a protein administration caused OSX overexpression, which could be blocked by p38 MAPK inhibitors but not by ERK or JNK inhibitors, indicating p38 MAPK activation was indispensable for WNT3a-mediated OSX induction. P38 MAPK activation was not affected by Dickkopf-1 (DKK1), suggesting WNT3a activated p38 MAPK independently of the Wnt/\u03b2-catenin pathway. Additional studies demonstrated inhibition of p38 MAPK did not impact WNT3a-induced phosphorylation of GSK3\u03b2 or the levels and nuclear localization of \u03b2-catenin. However, p38 MAPK inhibition impaired Wnt3a-stimulated \u03b2-catenin transcriptional activity.111 Expression of Secreted frizzled-related protein 1 (SFRP1), a Wnt signaling pathway inhibitor, was significantly more prevalent in PDL cells than in dental follicle, cementoblasts, and alveolar bone cells. Inhibiting SFRP1 raised the active Trimethylation of histone H3 lysine 4 (H3K4me3) histone marked on the promoters of the Runx2 and Sp7 genes, boosting their expression and stabilizing \u03b2-catenin levels in DFSCs-derived PDL cells, enhancing \u03b2-catenin transcriptional activity.112 A study found that Long non-coding RNA maternally expressed gene 3 (lncRNA MEG3) combined with EZH2 inhibited the osteogenic differentiation of human DFSCs via blocking the Wnt signaling pathway. EZH2 was a histone methyltransferase that mediated Trimethylation at lysine 27 of histone H3 (H3K27me3). During osteogenic differentiation, EZH2 and H3K27me3 levels decreased while Wnt ligands and \u03b2-catenin increased in human DFSCs. Knockdown of lncRNA MEG3 or EZH2 promoted osteogenesis and Wnt pathway gene expression in human DFSCs. Chromatin immunoprecipitation showed EZH2 enrichment on Wnt gene promoters along with H3K27me3 accumulation, indicating epigenetic suppression. Inhibition of EZH2 reduced H3K27me3 occupancy on Wnt gene promoters, thus activating the Wnt/\u03b2-catenin signaling pathway to facilitate osteogenic differentiation.113WNT3a was strongly expressed in HERS and crucial for the formation of dental roots by interacting with the BMP signaling pathway. BMP2 could activate the AKT signaling pathway and induce Early growth response factor 1 (EGR1) expression during osteogenic differentiation of DFSCs. Inhibition of AKT prevented EGR1 expression and osteogenic differentiation of DFSCs.Pthrp+ progenitor cells differentiated into PDL fibroblasts, acellular cementoblasts, as well as alveolar crypt bone osteoblasts.21 Parathyroid hormone receptor-1 (PTH1R) was a receptor for PTHrP and is expressed in Osx+, Pthrp+ and Prx1+ progenitor cells. PTHrP-PTH1R autocrine signaling pathway was required to maintain their physiological cell fates. In Osx+ dental mesenchymal progenitors, PTH1R deletion resulted in defects in cellular survival, proliferation, and aberrant differentiation, which caused shorter dental roots, PDL loss, and ankylosis. The PTH1R signaling pathway likely acts through Histone deacetylase 4 (HDAC4), as the PTH1R-deficient root condition was partially recapitulated by HDAC4 deletion.22 PTH1R also likely suppressed Myocyte enhancer factor 2\u2009C (MEF2C) and bone matrix proteins to prevent precocious differentiation of Pthrp+ progenitors.114Prx1+ cells were craniofacial mesenchymal progenitors expressing the transcription factor PRX1. When PTH1R was conditionally deleted in Prx1+ cells, it resulted in arrested incisor eruption and delayed molar eruption. PTH1R ablation caused decreased expression of osteogenic genes like Runx2 and Osx, resulting in reduced alveolar bone formation. In vitro, PTH1R deletion suppressed osteogenic differentiation of DMSCs. The balance of bone remodeling was disrupted due to decreased bone formation when PTH1R was knocked out in Prx1+ cells. Reduced alveolar bone growth failed to provide sufficient eruptive force for tooth eruption. PTH1R deletion also led to aberrant PDL development with decreased Periostin expression. Therefore, the PTH1R signaling pathway in Prx1+ progenitors was indispensable for osteogenesis, bone remodeling, and PDL function during tooth eruption.115 Chromodomain-helicase-DNA binding protein 7 (CHD7) promoted osteogenic potential of human DFSCs by increasing PTH1R expression and enhancing PTH/PTH1R signaling pathway. PTH1R also was a key mediator of CHD7 regulation of osteogenic differentiation in human DFSCs as it was the direct transcriptional target of CHD7.116During cementogenesis, Parathyroid hormone-related peptide (PTHrP) was mainly produced by cells in the dental follicle. These 117 In DFSCs, BMP9 transfection significantly elevated ALP activity, calcium deposition as well as osteogenic markers expression via activating non-canonical MAPK pathways, including increased p38 MAPK phosphorylation and decreased ERK1/2 phosphorylation.118. Interleukin-1alpha (IL-1\u03b1) bound to Interleukin-1 (IL-1) receptor on DFSCs and activated the downstream JNK and p38 MAPK pathways. Osteoclastogenesis was boosted and osteoblast differentiation was reduced when JNK and p38 MAPK were activated. These altered bone remodeling activities in dental follicle facilitate bone resorption around the erupting tooth and allow tooth eruption to proceed.119Gene expression profiling reveals activation of BMP and TGF-\u03b2 pathways during early osteogenic differentiation.Runx2 mutation in Cleidocranial dysplasia (CCD) patient DFSCs impaired matrix remodeling and osteoclast induction in patient DFSCs, which may cause delayed tooth eruption.121 But cellular senescence in the dental follicles was reduced in CCD patients compared to healthy controls. Isolated DFSCs from the patient showed increased proliferation, accelerated cell cycle, and downregulated senescence-associated genes and proteins. The patient\u2019s DFSCs had decreased ERK phosphorylation, indicating a suppressed MAPK/ERK signaling pathway. Inhibition of ERK reduced senescence in control DFSCs, while ERK activation increased senescence in patient DFSCs. Therefore, the presence of the Runx2 mutation in CCD prevents the cellular senescence process of DFSCs by blocking the ERK signaling pathway.122RUNX2 played important roles in regulating osteogenic differentiation, matrix remodeling, and osteoclast induction in DFSCs. 123 Laminin inhibited early but promoted late osteogenic differentiation in human DFSCs through integrin-\u03b12/\u03b21 and FAK/ERK pathway.14 Laminin also induced mineralization and cementogenic gene expression while suppressing ALP activity in DFSCs.124 Transient receptor potential melastatin 4 (TRPM4) knockdown enhanced osteogenesis but inhibited adipogenesis of DFSCs by modulating calcium signaling pathway and related gene expression, suggesting a regulatory function for TRPM4 played in the differentiation of DFSCs.125Activated Notch1 signaling pathway was required in the osteogenic differentiation of DFSCs. Activation of the NOTCH1 inhibited osteogenic differentiation via BMP2/DLX3 pathway in DFSCs.126Heterogeneity was crucial for maintaining the properties of DFSCs. Subclones showed decreased osteogenic ability compared to heterogenous DFSCs. Selecting subclones disrupted the heterogeneity of DFSCs and altered their gene expression. The TGF-\u03b2 signaling pathway had a significant impact on subclones\u2019 ability to differentiate due to its cross-talk with the Hippo, Wnt, and stemness pathways.127Strategies to modulate key developmental pathways could help stimulate innate dental repair mechanisms. For instance, local delivery of BMP ligands or agonists may promote HERS remodeling and odontoblast differentiation to treat root defects or stimulate reparative dentin formation. Modulating Wnt, Eda, PTH1R and FGF signalings could also direct dental stem cell behaviors. Further research should explore controlled, sustained delivery systems and optimize dosages for clinical translation.128 However, recreating the complex microenvironmental dynamics of the native dental stem cell niche remains challenging.129 Smart biomaterial scaffolds that mimic key cues like signaling pathway molecules and architecture could guide dental stem cell organization into dental tissues.130 Emerging bioprinting techniques allow precise spatial control over the distribution of cells, signals, and materials to mimic native tissue architecture and function.131 Future efforts should uncover developmental mechanisms to inform scaffold and bioink design for precision engineering of the dentin-pulp complex.132 Combined innovations in dental stem cells, biomaterials, and bioprinting have immense potential to transform restorative dentistry through bioinspired tooth regeneration.Tissue engineering approaches leveraging dental stem cells offer an attractive bio-inspired therapeutic avenue.133 Recent studies have developed protocols to acquire iPSCs-derived dental epithelial and DMSCs using precisely orchestrated signaling pathways molecules like FGFs, BMPs, and WNTs.134 For example, Kim et al. generated dental epithelial-like stem cells from human ESCs and iPSCs through a stepwise procedure involving embryoid body formation, induction with retinoic acid, and keratinocyte serum-free medium.135 The iPSC-derived epithelial cells exhibited odontogenic capacity when recombined with mouse dental mesenchyme. Other research groups have guided iPSCs to form cranial neural crest-like cells, the odontogenic precursor tissue, which was further induced into functional odontoblast-like cells secreting dentin matrix upon FGF and BMP stimulation.137 Advanced 3D culture systems like peptide hydrogels have also been harnessed to enable the CNC-like cells to reproduce dental pulp-like tissue with embedded odontoblasts and vascularization in vivo.136 Overall, iPSCs offer an exciting platform for personalized biological tooth restoration, but further optimization of tooth organogenesis and maturation protocols will be critical for clinical translation.Patient-specific induced pluripotent stem cells (iPSCs) is a prospective cell source that can be applied in tooth regeneration and personalized dentistry.141 Recent clinical trials have reinforced the translational promise of this approach in human subjects, promoting the regeneration of compromised dental pulp and periodontal tissues, thus enabling the repair of traumatized or avulsed teeth.142 This achievement in tooth tissue regeneration stands as a pivotal milestone in regenerative dentistry. To realize its full potential, it is imperative to optimize manufacturing processes, enhance regenerative efficacy, and ensure the stability of cell aggregates. In-depth explorations of interactions with host cells and tissues are essential to bolster biocompatibility. Further investigations into their performance in pathological microenvironments and the integration of biomaterials and bioactive molecules hold the potential for increased regenerative success.The application of dental stem cell-derived stem cell aggregates has successfully emulated the intricate developmental processes of odontogenic mesenchymal cell condensation, culminating in the regeneration of damaged dental pulp in murine models and the restoration of pulp-like structures and functions reminiscent of normal dental pulp.In recent decades, enormous advancement has been made in dental tissue engineering, but the clinical translation of whole-tooth regeneration remains unsolved. Several key obstacles need to be addressed, including recapitulating the intricate spatiotemporal signaling pathway dynamics during odontogenesis, optimizing vascularization and innervation of bioengineered teeth, and ensuring proper integration with surrounding hard and soft tissues. Continued interdisciplinary research on innovative biomaterials, dental stem cells, growth factors, and advanced manufacturing techniques like bioprinting will be critical to unlock the full potential of biological tooth regeneration. Seamless integration of these emerging tools and technologies will usher in a new era of next-generation, bioinspired dental treatments that far surpass traditional prosthetic tooth replacements.Elucidating the intricate developmental mechanisms directing tooth root morphogenesis is critical to advance biological tooth restoration. Spatiotemporal orchestration of signaling pathways precisely regulates dental epithelial and mesenchymal stem cell behaviors during root formation. Thoroughly decoding these complex regulatory networks promises to uncover novel therapeutic targets to incite endogenous tooth repair mechanisms. Emerging tissue engineering that based on dental stem cells has enabled the engineering of biological tooth root replacements. However, recreating the native stem cell niche environments with proper biomaterials, growth factors, and architectural cues remains a key challenge for clinical translation. Advances in these areas that accurately recapitulate developmental dynamics will be instrumental to guide organized differentiation and functional integration of dental stem cells into bioengineered root structures. Moving forward, seamless integration of interdisciplinary innovations in developmental biology, stem cells, biomaterials, and advanced manufacturing techniques is imperative to realize the immense promise of transforming regenerative technologies into biologically based tooth root regeneration therapies that restore native physiological structure and function."}
+{"text": "The genome of mammalian sperm is largely packaged by sperm-specific proteins termed protamines. The presence of some residual nucleosomes has, however, emerged as a potential source of paternal epigenetic inheritance between generations. Sperm nucleosomes bear important regulatory histone marks and locate at gene-regulatory regions, functional elements, and intergenic regions. It is unclear whether sperm nucleosomes are retained at specific genomic locations in a deterministic manner or are randomly preserved due to inefficient exchange of histones by protamines. Recent studies indicate heterogeneity in chromatin packaging within sperm populations and an extensive reprogramming of paternal histone marks post fertilization. Obtaining single-sperm nucleosome distributions is fundamental to estimating the potential of sperm-borne nucleosomes in instructing mammalian embryonic development and in the transmission of acquired phenotypes. Current Opinion in Genetics & Development 2023, 79:102034Developmental Mechanisms, Patterning and EvolutionThis review comes from a themed issue on Haruhiko KosekiEdited by Developmental Mechanisms, Patterning and Evolution (2023)\u201dFor complete overview of the section, please refer to the article collection, \u201chttps://doi.org/10.1016/j.gde.2023.1020340959-437X/\u00a9 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Box 1The process of sperm generation, called spermatogenesis, initiates in testes at puberty in humans or few days after birth in mice. Initially, spermatogonial precursor germ cells expand through several mitotic divisions. Germ cells then progress as spermatocytes through a lengthy meiotic prophase during which parental genomes exchange genetic information via meiotic recombination. Following a reductional and an equational cell division, the\u00a0resulting haploid and genetically diversified spermatids remain functionally interconnected due to incomplete cytokinesis. Such round spermatids further develop into mature sperm through a complex cell differentiation process termed spermiogenesis. During spermiogenesis, cellular structures that are required for fertilization develop, such as the flagellum and the acrosome. Further, transcription is globally shut\u00a0down, the nucleus elongates and condenses, and the cytoplasm is shed. Nuclear compaction co-occurs with extensive displacement of histones from the genome and incorporation of protamines following an apical\u2013caudal directionality. Whereas all mammals express PRM1, primates, most rodents, and some other placental mammals also express PRM2 Nucleosomes constitute the first layer of chromatin organization in eukaryotes. Through their presence, their post-translational modifications (PTMs), and the diversity of histone variants, nucleosomes regulate numerous cellular processes. In mammalian sperm, small basic proteins called protamines (PRMs) are the main constituents of chromatin. PRMs bind directly to DNA inducing circularization into toroidal structures  [1]. NonThe replacement of histones by protamines initiates in early elongating spermatids upon translation of transition proteins (TNPs) and PRMs  Figure . While TRoles of histone PTMs: Mounting evidence indicates that histone H4 acetylated at N-terminal lysine (K) residues (H4ac) is targeted for removal. While predominantly located at transcriptionally active promoters in round spermatids In vitro, protamines displace hyperacetylated nucleosomes more efficiently than unmodified ones Defective histone displacement also occurs upon dysfunction of certain DNA damage repair factors and associated PTMs such as poly(ADP-ribosyl)ation (PARylation) and serine (S)- 139 phosphorylation at histone variant H2AX (\u03b3H2AX) Rnf8 deletion co-occurs with reduced H4ac due to diminished chromatin binding of the histone acetyltransferase (HAT) MOF Interestingly, several histone PTM pathways crosstalk during spermatogenesis. For example, decreased histone ubiquitination upon Contrary to histone displacement, little is known about potential molecular machineries safeguarding nucleosomes from protamine exchange. Proteomics data indicate that most H3K27, H4K20, and H3K9 residues are modified in mature mouse sperm Roles of histone variants: PRMs are thought to bind DNA through arginine-mediated electrostatic interactions causing displacement of DNA-binding factors H2al2-deficient sperm contain less variant TH2B, H2AL2\u2019s predominant dimerization partner Roles of TNP/PRM PTMs: PTMs of PRMs and TNPs are emerging as modulators of chromatin remodeling. To modulate their DNA-binding affinity, PRMs become phosphorylated shortly after synthesis and partially dephosphorylated upon loading onto DNA. Dephosphorylation of mouse PRM2 at S56 is required for sperm head morphogenesis and male fertility K49A sperm contain excessive amounts of histones but lower H4ac, arguing for independent removal of H4ac histones and/or a role of PRM PTMs in fine-tuning replacement of nucleosomes with diverse compositions. Importantly, dysfunction of acetylation-controlling factors frequently leads to TNP/PRM mislocalization. For instance, deletion of the Sirt1 histone deacetylase (HDAC) or the testis-specific nuclear protein in testis (Nut) results in decreased H4ac, elevated histone levels, and impaired TNP/PRM nuclear distribution Nut, Sirt1, and H2AL2 deficiencies Box 2In vitro removal of protamines with Nucleoplasmin2  greatly aids in granting homogeneous chromatin accessibility Protamines compact sperm chromatin several-fold, thereby safeguarding sperm DNA against damaging agents. Hence, studying sperm chromatin frequently requires experimental decondensation of sperm nuclei to grant accessibility to enzymes, antibodies, and other reagents. Pretreatments include permeabilization of membranes, reducing protamine disulfide bonds , and removing PRMs  are depleted in complete digestions Finally, given the large differences in chromatin composition and organization between sperm and somatic cells, it is crucial to study pure sperm samples. Contamination of somatic or germ precursor cells, combined with partial solubilization of sperm chromatin, may lead to inconclusive results. Accordingly, a recent study has challenged chromatin accessibility, nucleosome\u00a0and PTM occupancies, and nuclear organization studies published to date arguing that reported results originate from contaminating cell-free DNA present in sperm samples Three decades ago, biochemical studies first suggested that certain regions of the sperm genome are predominantly packaged with histones, protamines, or both Gene promoters: Numerous studies using diverse technical procedures report nucleosomes at certain classes of gene promoters characterized by overlapping DNA hypomethylated CpG islands (CGIs) Genes involved in embryogenesis, morphogenesis, and cell fate commitment, including developmental miRNAs and noncoding RNAs, retain H3K27me3-marked nucleosomes at their DNA hypomethylated promoters and are occasionally comarked with H3K4me3 Distal-regulatory regions, enhancers, CTCF, and TADs: Several groups reported chromatin accessibility at intergenic regions in mouse and human sperm by ATAC-seq Centromeres: Centromeres are chromosomal regions enabling correct chromosome segregation during cell division. They are composed of tandem repetitive DNA  and are epigenetically specified by the H3 variant CENP-A. CENP-A locates to centromeres in spermatozoa of human, mouse, and bull, but also of Xenopus laevis and Drosophila melanogastercis-binding of satellite transcripts, among others Drosophila, depletion of CID, the CENP-A ortholog, results in failure to propagate paternal centromeres and to segregate paternal chromosomes during the first embryonic division Pericentromeric heterochromatin (PCH): centromeres are flanked by pericentromeric heterochromatic domains composed of tandem satellites (i.e. major satellites in mouse), other non-satellite repeats and abundant constitutive heterochromatic PTMs such as H3K9me3 and H4K20me3. Similarly marked nucleosomes are present at PCH in human sperm and are transmitted to the zygote to propagate constitutive heterochromatin during embryogenesis Telomeres and interspersed repetitive elements: mammalian telomeres are composed of (TTAGGG)n tandem repeats which locate at chromosome ends and preserve the genetic material during DNA replication. In human sperm, telomeres partly release nucleosome ladders upon mild MNase digestions Interspersed repetitive elements constitute major parts of mammalian genomes and have the capacity to transpose across the genome. Initial genomic studies reported nucleosome enrichments at certain repeat families in human and bull sperm Disclaimer: despite nucleosomes have been localized at loci described above, their relative abundances in sperm vary between studies. Hence, it remains unclear to what extent and in what locations nucleosomes are preferentially retained within mammalian sperm genomes , and the 10.13039/501100000781European Research Council (ERC) under the European Union\u2019s Horizon 2020 research and innovation programme (grant agreement ERC-AdG 695288 \u2014 Totipotency).This project was supported by the L.G.T. wrote the paper. A.H.F.M.P. supervised L.G.T and edited the paper.Nothing declared."}
+{"text": "Neuropsychiatric diseases (NPD) represent a significant global disease burden necessitating innovative approaches to pathogenic understanding, biomarker identification and therapeutic strategy. Emerging evidence implicates heart/brain axis malfunction in NPD etiology, particularly via the autonomic nervous system (ANS) and brain central autonomic network (CAN) interaction. This heart/brain inter-relationship harbors potentially novel NPD diagnosis and treatment avenues. Nevertheless, the lack of multidisciplinary clinical approaches as well as a limited appreciation of molecular underpinnings has stymied progress. Large-scale preclinical multi-systemic functional data can therefore provide supplementary insight into CAN and ANS interaction. We here present an overview of the heart/brain axis in NPD and establish a unique rationale for utilizing a preclinical cardiovascular disease risk gene set to glean insights into heart/brain axis control in NPD. With a top-down approach focusing on genes influencing electrocardiogram ANS function, we combined hierarchical clustering of corresponding regional CAN expression data and functional enrichment analysis to reveal known and novel molecular insights into CAN and NPD. Through \u2018support vector machine\u2019 inquiries for classification and literature validation, we further pinpointed the top 32 genes highly expressed in CAN brain structures altering both heart rate/heart rate variability (HRV) and behavior. Our observations underscore the potential of HRV/hyperactivity behavior as endophenotypes for multimodal disease biomarker identification to index aberrant executive brain functioning with relevance for NPD. This work heralds the potential of large-scale preclinical functional genetic data for understanding CAN/ANS control and introduces a stepwise design leveraging preclinical data to unearth novel heart/brain axis control genes in NPD.The online version contains supplementary material available at 10.1007/s00335-022-09974-9. Neuropsychiatric diseases (NPD) are clinically heterogeneous and comprise 7% of the global disease burden  and attention deficit hyperactivity disorder (ADHD)  axis, inflammatory signaling and ANS dysfunction  into physiological responses (autonomic efference). The efferent system dichotomizes into sympathetic (SNS) and parasympathetic (PNS) branches Fig.\u00a0 Karemak. SNS preThe CAN encompasses brain cortical and subcortical mood and memory influences on ANS cardiovascular activity, dividing into \u2018feedforward\u2019 (FF-ANS) and \u2018feedback\u2019 (FB-ANS) brain regions Fig.\u00a0 Dampney. The forFeedback control involves brainstem ANS nuclei mediating reflex effects in response to peripheral receptor input Fig.\u00a0. The medThe neuroanatomical organization of the CAN permits psychological states to influence cardiovascular ANS control via or even bypassing the brainstem homeostatic nuclei. Thus, HRV, the HR beat-to-beat variability measured in an electrocardiogram (ECG), is a valuable non-invasive ANS index in humans and animal models  Version 17.0,  was applied to group mouse brain regions (columns) as well as expression energies of genes (rows) for the heat map. The genes with the most similar expression patterns are closest in proximity in the heat map with rows scaled and represented as a z-score. The red color denoted higher expression levels and the blue had lower expression levels. We included the dendrogram for the columns, where we highlighted the subtrees with numbers , Jensen Diseases and Enrichr Submissions TF [transcription factor]-gene co-occurrence  terms associated with FF-ANS genes related to behavioral brain function. These included hyperactivity, abnormal sleep behavior, decreased exploration of a new environment, decreased startle reflex and impaired sensorimotor gating [decreased prepulse inhibition] Fig. B. The toP value [Padj], Fig. Conversely, the FB-ANS gene set did not enrich for behavior but rather ECG-related phenotypes such as shortened RR interval, increased HR and abnormal sinus arrhythmia Fig. B. Pre-weSatb2, Stx1a, Adnp2, Ust and Acap2. Both Satb2 and Stx1a are highly expressed in the adult mouse ACC and insular cortices , expressed during development and associated with ASD and SCZ   protein with no prior NPD annotations. Thus, four of the top five ECG genes within CAN brain structures (FF-ANS) have previous NPD associations.To validate our clustering approach, we used a support vector machine (mSVM-RFE) to pinpoint the top expressed genes defining the clusters  protein), Srprb  protein) and Tcf19 (encoding Transcription Factor 19 protein) while exhibiting relatively higher brain expression in the brainstem nuclei . Figure\u00a0Cdk13 (encodes cyclin-dependent kinase 13 (CDK13) enzyme) and Hunk  protein) express in adult mouse insular/cingulate cortices and hippocampus respectively . Nevertheless, at least one of these genes plays a developmental disorder role . Thus, 1700086L19Rik is a potential novel NPD-risk gene predicted by our clustering algorithm, related to CAN and autonomic dysfunction that is of interest for future detailed investigation.Of the HR-altering CAN genes, two also decreased HRV, rve Fig.\u00a0A and B. rve Fig.\u00a0]. This pPitx3 (Pituitary homeobox 3), Gsg1l (Germ Cell-Specific Gene 1-Like Protein) and Zfp395 (zinc finger protein 395). Pitx3 expresses in midbrain dopaminergic neurons , high amygdala and hippocampal expression  protein] is highly expressed in the heart and the IMPC predicts a role for this gene in the ANS disease Neuropathy, Hereditary Sensory and Autonomic, Type Vi (https://www.mousephenotype.org/data/genes/MGI:1314882). Moreover, loss of the mouse genes Spred3 [Sprouty Related EVH1 Domain Containing 3 (SPRED3) protein] and Fbxl1 (F-box/LRR-repeat protein) increase HRV and alter emotionality requiring further investigation to determine the disease relevance.The picture for increased mouse HRV and altered behavior associated with CAN-expressed gene clustering is less clear Table . NeverthEvidence implicates heart/brain axis and CAN/ANS dysfunction in NPD yet there remain gaps in understanding the genetic underpinnings as well as in delineating potential therapeutic targets. Moreover, HRV, as an index of intact CAN-ANS interaction, is a highly heritable trait and putative non-invasive proxy of higher brain function and NPD endophenotype  in CAN brain regions using, for example, the conditional Cre/LoxP system. In this case, a brain-specific (particularly forebrain) transgenic Cre line, e.g. calcium/calmodulin-dependent protein kinase II alpha subunit (CaMKII\u03b1)-Cre, can be implemented in concert with functional assays to ascertain whether HRV abnormality associated with specific genes is secondary to CAN dysfunction. Alternatively, viral vector approaches such as the AAV vector-based RNA interference systems can be applied to similar effect Supplementary file2 (XLSX 531 KB)Below is the link to the electronic supplementary material."}
+{"text": "Klebsiella pneumoniae (NDMKP) outbreak with genetic and epidemiological evidence of transmission via a non-therapeutic gastroscope.Endoscopic transmission of carbapenem-resistant Enterobacterales (CRE) has mostly involved elevator channel-containing duodenoscopes. We describe a New Delhi metallo-\u03b2-lactamase producing Endoscope sampling and cultures were performed using FDA protocols. Carbapenemase gene testing was performed at the New Jersey Department of Health. CRE rectal colonization screening and whole-genome sequencing (WGS) were performed at the New York State Department of Health\u2019s Wadsworth Center.Four NDMKP cases were identified from clinical cultures between March\u2013April 2022 in patients without travel history. Three of four cases underwent \u2265 1 gastrointestinal endoscopic procedure within two weeks prior to their infection, including four shared devices. Cultures from shared endoscopes were negative. Among 18 patients exposed to shared endoscopes who underwent NDMKP colonization screening, 2/18 (11%) screened positive. All isolates were highly related by WGS, with a maximum of 23 single nucleotide polymorphism (SNP) difference. Audits of endoscope reprocessing and a transition to duodenoscopes with disposable end caps occurred by June 2022.In October 2022 a post-endoscopy NDMKP infection (case 7) was identified with two SNPs shared with case #2 (in March 2022). Two shared gastroscopes were identified with case #2 (GIF-1TH190 and GIF-H190); cultures from both were negative. GIF-H190 is a non-therapeutic gastroscope without an elevator channel. Four repairs to GIF-H190 for fluid intrusion or device buckling occurred from January\u2013August 2022. Of 49 patients exposed to GIF-H190 who underwent NDMKP colonization screening; 1/49 (2%) was positive, with 14 SNPs from case #2. Boroscopic evaluation of endoscopes was initiated and repair work was transitioned from a third party to the device manufacturer. No further NDMKP cases have been identified to date.Each line represents a scope, each color represents a patient. Left axis indicates date, right axis indicates which scope was used. *Patients identified via rectal swab screen, without clinical signs of infection.Non-therapeutic gastroscopes without elevator channels may pose a risk for CRE transmission, particularly in the setting of mechanical damage. Reprocessing programs should focus on measures to promptly identify and repair physical damage to endoscopes.Steven Brant, MD, Bristol Myers Squibb: Research Grant on Education Hispanic population in inflammatory bowel disease Keith S. Kaye, MD, MPH, Abbvie: Advisor/Consultant|Abbvie: Honoraria|Entasis: Advisor/Consultant|Entasis: Honoraria|GSK: Advisor/Consultant|GSK: Honoraria|Merck: Advisor/Consultant|Merck: Honoraria|Shionogi: Advisor/Consultant|Shionogi: Honoraria|VenatoRx: Advisor/Consultant|VenatoRx: Honoraria"}
+{"text": "This cohort study compares the use and outcomes of high-sensitivity cardiac troponin assay vs conventional troponin assay in transgender adults. Medical transitioning includes gender-affirming hormone therapy.5 Exposure to hormone therapy affects levels of cardiac biomarkers.6 There is no established cardiac troponin diagnostic threshold for transgender individuals. This study aimed to determine the role of implementing sex-specific troponin thresholds in the diagnosis and management of suspected acute coronary syndrome (ACS) in transgender patients.Diagnosing acute myocardial infarction (AMI) requires the detection of cardiac troponin above the 99th percentile upper reference limit.STROBE reporting guideline.This population-based cohort study included Kaiser Permanente Southern California (KPSC) members (aged \u226518 years) presenting with suspected ACS between 2007 and 2022. The KPSC Institutional Review Board approved the study and waived the informed consent requirement because the study presented minimal risks. We followed the 2 Patients were followed up for 30 days for outcomes.Transgender patients were identified through review of an internal registry, hormonal treatment history, sex assigned at birth, and medical records. Patients never treated with hormonal therapy were excluded. In 2021, the KPSC health system implemented a high-sensitivity cardiac troponin I (hs-cTnI) assay  with sex-specific diagnostic thresholds. Prior to 2021, a conventional troponin assay with a single threshold was used. Troponin levels on presentation were identified, and cause of troponin elevation was adjudicated by physicians using the universal definition of myocardial infarction (MI).2 test. Two-sided P\u2009<\u2009.05 defined statistical significance. Statistical analyses were conducted with Stata/MP 17.0 (StataCorp LLC).Outcomes before and after the hs-cTnI assay implementation were compared using the \u03c7Among the 1108 patients included, 661 (59.7%) were transgender women and 447 (40.3%) were transgender men, with a median (IQR) age of 33 (25-47) years. Overall, patients self-identified as Asian (77 [6.9%]), Black (108 [9.8%]), Hispanic (360 [32.5%]), or White (524 [47.3%]). Two hundred sixty-two patients (23.6%) were evaluated after implementation of the hs-cTnI assay with sex-specific thresholds; all other patients (846 [76.4%]) were evaluated using a conventional troponin assay with a single threshold. With the conventional troponin assay, 24 individuals (2.8%) had abnormal troponin levels . With thThree patients (1.1%), who would be reclassified if their sex assigned at birth were used for the threshold, had type 2 MI or myocardial injury. No patients with type 1 MI would have been reclassified. No significant differences in clinical outcomes at 30 days were observed before and after implementation of sex-specific troponin diagnostic thresholds.In this cohort study of transgender patients, implementing sex-specific troponin thresholds for diagnosing AMI did not significantly affect outcomes. Use of sex-specific thresholds aligned with affirmed gender identity was not associated with significant reclassification. None of the few reclassified patients had myocardial injury due to type 1 MI. Patients presenting with ST-segment elevation MI and type 1 non\u2013ST-segment elevation MI had troponin levels that were much higher than the diagnostic thresholds and were appropriately identified regardless of the threshold used.Study limitations were short follow-up time, small sample size, and the observational design. The findings suggest that troponin thresholds in accordance with the patient\u2019s affirmed gender identity may be used in transgender individuals. Doing so may reduce confusion and distress for both patients and clinicians and help patients receive truly gender-affirming care."}
+{"text": "BRAF is one of the most frequently mutated oncogenes, with an overall frequency of about 50%. Targeting BRAF and its effector mitogen-activated protein kinase kinase 1/2 (MEK1/2) is now a key therapeutic strategy for BRAF-mutant tumors, and therapies based on dual BRAF/MEK inhibition showed significant efficacy in a broad spectrum of BRAF tumors. Nonetheless, BRAF/MEK inhibition therapy is not always effective for BRAF tumor suppression, and significant challenges remain to improve its clinical outcomes. First, certain BRAF tumors have an intrinsic ability to rapidly adapt to the presence of BRAF and MEK1/2 inhibitors by bypassing drug effects via rewired signaling, metabolic, and regulatory networks. Second, almost all tumors initially responsive to BRAF and MEK1/2 inhibitors eventually acquire therapy resistance via an additional genetic or epigenetic alteration(s). Overcoming these challenges requires identifying the molecular mechanism underlying tumor cell resistance to BRAF and MEK inhibitors and analyzing their specificity in different BRAF tumors. This review aims to update this information. BRAF is one of the most frequently mutated oncogenes, with an overall frequency of about 50%. Commonly occurring BRAF mutations switch the codon usage in the activation segment of the kinase domain, such as Val600 to Glu, Lys, or Asp, and render the kinase constitutively active independently of its upstream activator RAS, thereby causing the hyperactivation of its downstream effector, the MEK-extracellular signal-regulated kinase (ERK) cascade. Among the BRAF mutations identified thus far, BRAFV600E is most common with frequencies ~50% in melanomas, ~40% of papillary thyroid carcinomas, ~10% of colorectal cancers, ~5% of lung adenocarcinomas while also being detected in a subset of brain and hematological malignancies (BRAFV600E tumors [gnancies . As suchE tumors .\u00ae) and the MEKi trametinib (MEKINIST\u00ae) is an effective dual BRAF/MEK inhibition for cancer therapy, and the U.S. Food and Drug Administration (FDA) has approved these drugs for mono- and combination-therapy . Understanding the similarities and differences in therapy resistance in different tumor types is crucial. The goal of this review is to update this information.Combining the BRAFi dabrafenib  signaling in response to the BRAFi, which does not occur as effectively in melanoma cells due to their intrinsically low EGFR expression [BRAFV600E thyroid cancer cells can rapidly relieve the negative feedback-regulation of human epidermal growth factor receptor 3 (HER3/ErbB3) transcription and increase autocrine secretion of the HER2 and HER3 ligand neuregulin 1 in response to vemurafenib, which also does not occur as effectively in melanoma cells [BRAFV600E melanoma cell lines following exposure to BRAFi and/or MEKi, HER3 activation mainly leads to protein kinase B (AKT) hyperphosphorylation. Antibodies directed against different HER3 surface epitopes prevented the establishment of resistance to BRAF/MEK inhibitors [Specific tumor cells can rapidly adapt to the presence of BRAF/MEK inhibitors by turning on a feedback mechanism that can reestablish MEK/ERK signaling, which is often mediated through a receptor tyrosine kinase (RTK) signaling pathway  site in the activation loop of ERK1/2 cannot be replaced by phosphomimetic amino acids to generate a constitutively active mutant [ERK mutation, but not other ERK mutations that affect ERK interaction with MEK1/2, phosphatases, or scaffolds, is probably not a feasible strategy for tumor cells to resist BRAF and MEK1/2 inhibition. Of note, different ERK mutations arise in ERK inhibitor-resistant tumor cells in culture, and it is important to understand by what mechanism these mutations facilitate restoring ERK activity in the tumor cells [e mutant . Autophoe mutant ,85,86. Ne mutant ,88. Consor cells .BRAFV600E colorectal cancer cells, which have relatively high intrinsic resistance to BRAFi/MEKi combination [Interestingly, the combination of trametinib with the BRAFi PLX4720 induced ERK1/2 translocation to endoplasmic reticulum in BRAF mutant melanoma cells, and the protein kinase R-like endoplasmic reticulum kinase (PERK) phosphorylated ERK1/2 upon exiting endoplasmic reticulum . Consistbination , the addbination .In addition to MEK/ERK reactivation, other mechanisms also drive therapy resistance . For exaLoss of phosphatase and tensin homolog (PTEN): The status of PTEN, an important regulator of phosphoinositide 3-kinase (PI3K), is important for determining the propensity of BRAFV600E tumor cells to acquire BRAFi resistance through ERK1/2 reactivation. For example, wild-type PTEN-carrying tumors required hyperactivation of ERK1/2 and AKT to resist BRAFi [PTEN-deficient melanoma cells [st BRAFi , whereasst BRAFi . The PTEma cells . Activation of PI3K/AKT pathway: BRAFi monotherapy or D/T combination therapy frequently led to rebound of AKT phosphorylation at an early stage of treatment in melanomas, suggesting that adaptive resistance involving upregulation of the PI3K/AKT pathway is developed and may affect clinical outcomes of BRAFi therapy [BRAFV600E melanoma cells [BRAFV600E colorectal cancer patients identified molecular subgroups not associated with known clinical characteristics. One subgroup exhibited elevated PI3K/mTOR/AKT/eukaryotic initiation factor 4E-binding protein 1 signaling, whereas the other subgroup dysregulated cell cycle and checkpoint pathways [ therapy . While i therapy . The insma cells . Similarma cells . This supathways . Interespathways .Activation of survival pathway and altered translation via persistent formation of eukaryotic translation initiation factor 4F (eIF4F) complex: Myeloid leukemia 1 (Mcl-1) overexpression was detected in D/T combination-resistant progressive melanoma biopsies [BRAFV600E melanoma, colon, and thyroid cancer cells. The apoptotic activator, BMF, regulated this complex formation by acting on eIF4G cleavage. While vemurafenib induced BMF overexpression, BMF silencing conferred BRAFi resistance and was detected in drug-resistant melanoma cells [biopsies . Indeed,biopsies . Consistbiopsies . As statbiopsies . Persistbiopsies . This stma cells . TherefoActivation of a G-protein-coupled receptors (GPCR)/cyclic AMP-dependent signaling network: At low frequencies, mutation or overexpression of the transcription factors E26 transformation-specific (ETS) and sterile alpha motif domain containing 4B (SAMD4B) were detected in melanoma relapse after D/T combination therapy [V600EBRAF melanoma biopsies revealed that CREB phosphorylation decreases upon BRAF inhibition but is restored in relapsing tumors [ therapy . A \u201cgain therapy . This stg tumors . Given tDevelopment of c-JUN-mediated mesenchymal-like phenotype: Vemurafenib resistance in BRAFV600E melanoma cell lines is associated with a high abundance of c-JUN and characteristics of a mesenchymal-like phenotype [KRAS-mutant lung cancers [henotype , suggest cancers , and it  cancers . Activation of signal transducer and activator of transcription 3 (STAT3) signaling pathway: The EGFR-SRC family kinase (SFK)-STAT3 pathway is involved in vemurafenib resistance of melanoma. For example, increased EGFR and SFK activity was detected in association with increased tumor cell proliferation, invasion, and metastasis in tumor biopsies from patients with intrinsic or acquired vemurafenib resistance, and EGFR inhibitors cooperated with BRAFi to block the growth of the resistant cells in vitro and in vivo [ in vivo . In line in vivo . Given t in vivo . Upregulation of Hippo and yes-associated protein 1 (YAP1) signaling: YAP was identified as a vemurafenib resistance gene by shRNA-mediated loss of function screening in the BRAFV600E NSCLC line HCC364 [BRAFV600E tumor patients [e HCC364 . In thise HCC364 . This stpatients . The sigpatients ,101,102.Reprogramed metabolic processes: Oncogenic BRAF can regulate oxidative metabolism via peroxisome proliferator-activated receptor \u03b3 coactivator 1-\u03b1 (PGC1\u03b1), whose transcription is directly regulated by microphthalmia-associated transcription factor (MITF), a target of BRAF for negative regulation [BRAFV600E melanoma cells enhance aerobic glycolysis while suppressing mitochondrial respiration by downregulating these transcription factors [BRAF-mutated melanoma cells through MITF and PGC1\u03b1 upregulation. Moreover, melanoma cells intrinsically resistant to or adapted to BRAF inhibition exhibit lower basal levels of mitochondrial biogenesis and addiction to oxidative phosphorylation, respectively [KRAS-mutant NSCLC cells exhibit increased mitochondrial respiration [RAS or RAF mutations leading to malignant thyroid epithelium transformation are accompanied by dedifferentiation and a decrease in the sodium-iodide symporter (SLC5A5) expression, which results in resistance to radioactive iodine therapy. Indeed, D/T combination, but not dabrafenib alone, upregulated sodium-iodide symporter expression in patient-derived thyroid tumor cells in culture, suggesting the possibility that D/T combination may increase tumor cell uptake of radioactive 131I [gulation . BRAFV60 factors . Consistectively ,105. Simpiration . Notablypiration ,109,110.piration . Anotherive 131I . Intriguive 131I . An in-dive 131I .BRAF-mutant melanoma patients [BRAF melanoma patients in a phase III trial, but overall survival benefit was not observed [BRAF-mutant colorectal cancer patients, and a single-cell RNA sequencing analysis of this cohort revealed that more effective induction of tumor cell-intrinsic immune programs and MEK/ERK inhibition is associated with better clinical outcomes [Increasing evidence suggests that BRAF and MEK inhibitors have immune-modulating effects and can enhance antitumor immunity . Overcoming these challenges requires identifying the molecular background of a tumor type, other than BRAF mutations, that also determines clinical outcomes. Indeed, many potential gene signatures of MEK/ERK functional outputs have been identified from therapy-resistant tumor cells. For example, a 13-RAS effector gene signature has been identified to predict the existence of compensatory signaling in selumetinib-resistant tumor cells [RAS-mutant tumor responsiveness to PI3K and RAS pathway inhibition [Precision medicine cancer treatment has greatly advanced by accumulating data on the genotype\u2013phenotype relationship of various oncogenic mutations. Targeting BRAF and MEK1/2 in combination is now a key therapeutic strategy for or cells . Severalor cells . A 147-ghibition . Multiplhibition ,40. In vhibition ,61. The hibition . Identifying reliable prognosis markers through active correlative and functional analysis of molecular alterations associated with clinical outcomes will enable the establishment of a reliable guideline for companion diagnostics. Whether similar across tumor types or tumor type-specific, knowledge of these alterations is expected to refine patient selection and improve clinical outcomes, eventually providing the maximal benefit of BRAF/MEK/ERK targeted therapies."}
+{"text": "Helicase-like transcription factor (HLTF) also known as SMARCA3, protects genome integrity. A tumor suppressor, HLTF is expressed in tumor cells but not in the tumor microenvironment (TME) in early-stage colorectal cancer (CRC). With disease progression, there is high concordance between epigenetic silencing of HLTF in CRC cells and negligible HLTF expression in the TME. We developed a cell line-derived xenograft (CDX) model and show for the first time that HLTF-deletion in cancer cells and the TME results in metabolic reprogramming that mitigates oxidative stress in lymphatic intravascular metastatic niches. The two metabolic pathways that derive energy from glucose\u2014glycolysis and oxidative phosphorylation (OXPHOS)\u2014are variously utilized by cancer cells depending upon the TME. HIF-1\u03b1, a master regulator of glycolysis, was eliminated from a role in reprogramming metabolism to satisfy CDX energetic requirements by RNAseq and spatial transcriptomics. Variability in the gut microbiome, with a putative role in altered metabolism, was also eliminated. HLTF-deleted cancer cells recovered from DNA damage at a transcriptomic level induction of DNA repair and OXPHOS genes linked to an amoeboid-associated phenotype at the tumor border . HLTF-deleted cancer and endothelial cells of lymphatic (PDPN) intravascular niches in the TME shared a site-specific protein S-glutathionylation signature  for three glycolytic enzymes  that diverted glycolysis in support of continued glutathione biosynthesis. The collective absence of HLTF/Hltf from tumor and TME achieved redox homeostasis throughout the CDX and promoted metastasis. Colorectal cancer (CRC) is the third most common cause of cancer-related deaths worldwide . The preHLTF emerged as a promising candidate because it is epigenetically silenced in 43% of CRC cells [HLTF DNA in serum samples significantly correlated with tumor size, more aggressive tumors, advanced stage (III or IV) metastatic disease, including micro-metastasis, and shorter survival [HLTF was not detected in any of the fibroblast populations despite measured changes in mRNA levels between normal and tumor cells. HLTF in normal endothelial and lymphatic endothelial cells (Human Protein Atlas), is purported to have a scaffolding function with LINC00607, an endothelial-specific long non-coding RNA, in the regulation of gene transcription [HLTF is not expressed in endothelial cells in CRC [The fact that aberrant DNA methylation in CRC cells increased cell-free serum DNA levels  drove thsurvival , 6. The survival . HLTF wacription . Howevers in CRC .HLTF-deletion from tumor cells and cells of the TME has never been studied in vivo, we developed a HCT116 cell line-derived xenograft model (CDX) of tumorigenesis. In the first study [Hltf-deleted and control male mice received direct orthotopic cell microinjection (OCMI) of HLTF+/+HCT116-Red-Fluc cells in the cecum. RNAseq with species-specific mapping unambiguously differentiated gene expression in tumor cells from cells of the TME and showed Hltf-deletion from the mouse TME reprogramed the HLTF+/+ human tumor transcriptome and initiated a gene deletion-specific program for metastasis.Because the effects of st study , immunodHLTF+/+CDX vs HLTF-/-CDX in ID Hltf-deleted mice. First, we generated an isogenic HLTF-/-HCT116-Red-FLuc cell line that was otherwise identical to the parental line. Next, we established primary HLTF-/-CDX tumors in ID Hltf-deleted male Rag2-/-IL2rg-/- mice by direct OCMI of the cells into the cecum. Combinatorial use of RNAseq with species-specific mapping, spatial transcriptomics, immunohistochemistry and 2D DIGE, MALDI-TOF/TOF mass spectrometry provided a holistic understanding of a major mechanism coordinating escape from oxidative stress in lymphatic intravascular metastatic niches when HLTF expression is silenced in tumor cells and cells of the TME.Whole transcriptomic sequencing provided an exceptional view of the dynamic interaction between cells of the tumor and TME. However, gene information in a spatial context was lost due to tissue homogenization. Spatial transcriptomics on formalin-fixed paraffin embedded (FFPE) tissue captures positional gene patterns within intact tissue. In this second study, we utilized high-throughput RNAseq with species-specific mapping in conjunction with spatial transcriptomics in a direct comparison of early-stage vs late-stage primary tumors, i.e., E. coli , Glutathione reductase , and glutathione . Primary and secondary antibodies used with FFPE tissue sections in immunohistochemistry (IHC-P) and confocal immunocytochemistry (ICC/IF) are listed in doi.org/10.17504/protocols.io.ewov1oe37lr2/v1).Microbiome collection kits were obtained from TransnetYX . McCoy\u2019s 5a Medium (30\u20132007) and fetal bovine serum (30\u20132020) were purchased from American Type Culture Collection . Puromycin (ant-pr) was purchased from InvivoGen . XenoLight D-luciferin potassium salt (122799) was purchased from PerkinElmer . ThermoScientific  was the source of glutathione mouse monoclonal antibody  and the Pierce\u2122 reagent HENS buffer (90106). PerkinElmer  was the source of Bioware\u00ae Brite Cell Line HCT116 Red-FLuc (BW124318). 10X Genomics  was the source of all Visium reagent kits for whole transcriptome profiling of intact formalin fixed paraffin embedded (FFPE) tissue sections including test slide (PN-1000347), slide kit (PN-1000188), reagent kit (PN-1000361), human transcriptome probe kit (PN-1000361), accessory kit (PN-1000194) and dual index kit TS Set A (PN-1000251). KAPA SYBR FAST qPCR master mix (KK4600) was purchased from Roche Diagnostic Corporation . SPRIselect (B23317) was purchased from Beckman Coulter Life Sciences . ProLong Gold antifade reagent with DAPI (P36935) and Streptavidin-FITC (19538\u2013050) were from Invitrogen by ThermoFisher Scientific. 3- biocytin (MPB) was from Santa Cruz Biotechnology (sc-216373). The following were purchased from Millipore Sigma: NADPH, tetrasodium salt (481973), Glutaredoxin-S2, Hltf+/+ (n = 9) and Hltf-/- (n = 5) immune deficient (ID) male mice. Libraries were sequenced using Illumina NovaSeq at a dept of 2 million read pairs (2x150 configuration) sufficient for species and strain level taxonomic resolution. FASTQ files were uploaded onto One Codex analysis software [Individual mice were allowed to defecate normally in autoclaved cages with no bedding. Using a sterile 26Gx1/2 needle (one per mouse), the first two fecal pellets per mouse were submerged in stabilization buffer in a barcoded sample collection tube. Collection tubes were shipped to TransnetYX for DNA extraction (Qiagen DNeasy 96 PowerSoil Pro QIAcube HT kit/protocol), library preparation (KAPA HyperPlus protocol), and sequencing. High molecular weight genomic DNA captured the true microbial diversity of stool samples from two cohorts: six- to eight-week-old software  and analHLTF. Thus, System Biosciences  produced a custom stable cell line with shRNA sequence targeting of HLTF [HLTF shRNA sequence was cloned into pGreenPuro shRNA expression lenti vector (SI505A-1). HCT116-Red-Fluc cells infected with 10 MOI of HLTF-shRNA-SI505 virus (lot#171009\u2013008) yielded puromycin-resistant polyclonal HCT116-Red-FLuc HLTF-/- cells. For each CDX experiment, cell stocks in liquid nitrogen at passage 2 were thawed using T25 flasks, expanded in T150 flasks for 2 days, passaged overnight and harvested at 70\u201375% confluency. We used this protocol as a unified framework for comparative gene expression analysis.Bioware\u00ae Brite Cell Line HCT116-Red-FLuc is a luciferase-expressing derivative of a highly metastatic cell line . PerkinElmer\u2019s recommendation that the Bioware\u00ae Brite Cell Line HCT116-Red-FLuc only be passaged 10 times, precluded the use of CRISPER/Cas9 to generate a stable knockout of  of HLTF . BrieflyHltf knockout (KO) mice were developed in collaboration with genOway  as previously described [Hltf KO C57BL/6J mice [Hltf KO mice >99% C57BL/6 background genome. ID Hltf KO mice were housed in a barrier facility with a 12:12 light/dark cycle, access to food and water ad libitum and bedding changes 2\u20133 times/week. Routine testing of sentinel mice ensured the colony was disease free. All studies and the anticipated mortality were conducted in accord with the NIH Guidelines for the Care and Use of Laboratory Animals, as reviewed and approved by the Institutional Animal Care and Use Committee at Texas Tech University Health Sciences Center  global escribed . Speed c/6J mice  that wer/6J mice  to generHLTF-/-HCT116 xenograft model, six- to eight-week old ID Hltf KO mice (n = 7) received direct OCMI of HLTF-/-HCT116-Red-Fluc cells (2x106 cells/10 \u03bcl) between the mucosa and the muscularis layers of the cecal wall. Each surgery was performed with isoflurane (isothesia) and the SomnoSuite\u00ae Low-Flow anesthesia system (Kent Scientific) with far infrared warming pads during surgery and recovery. Efforts to minimize suffering included an IP injection of Buprenorphine  prior to surgery to manage incisional pain followed by a second dose 4\u20138 hours later, if needed. The cecum was exteriorized via small midline incision on the linea alba between the rectus abdominus muscles to eliminate bleeding. Non-invasive bioluminescence imaging (BLI) with an IVIS Spectrum In Vivo Imaging System was used to validate the quality and accuracy of the injection, and to track and quantify tumor growth and metastasis. Histopathology at necropsy confirmed placement of the inoculum. Mouse behavior and well-being were monitored daily. Tumor growth/metastasis was monitored weekly with BLI.For the orthotopic HLTF-/-CDX (hereafter HLTF-/-CDX) tumors were quickly removed, rinsed in physiological saline and either flash frozen for biochemical evaluation  or formalin fixed paraffin embedded (FFPE) for routine histopathology, IHC-P, laser scanning confocal ICC-IF and spatial transcriptomics.Mice were placed under continuous isothesia for imaging and killed immediately thereafter (<15 seconds) by cervical dislocation at the humane endpoint of 28 days post CDX establishment. Primary HLTF-/-CDX were serially sectioned (3\u20134 \u03bcm) for histopathology, IHC-IP and ICC-IF. Two sections were placed on each slide and deparaffinized prior to staining. Beginning with the first slide, sections on every fifth slide were stained with hematoxylin and eosin (H&E) for evaluation by light microscopy. Sections on alternate slides were processed for IHC-IP with heat-induced epitope retrieval (HIER). Two tissue sections per slide facilitated the use of one section for positive immunostaining, and the companion section for negative (minus primary antibody) control staining. Pairing of primary antibodies with secondary antibodies is shown in 4Cl in PBS), and ProLong Gold DAPI (DNA-specific blue-violet fluorescent dye).FFPE in situ in FFPE HLTF-/-CDX sections (3\u20134 \u03bcm) with a biotin switch assay [Protein S-glutathionylation (Pr-SSG) was detected ch assay . Free thHLTF-/-CDX  were flash frozen and sent to Genewiz, the next generation sequencing (NGS) division of Azenta Life Sciences  RNA-sequencing. Briefly, total RNA was isolated, and evaluated for its integrity and purity with an Agilent Bioanalyzer (>80% of bases >Q30). Sequence reads were trimmed to remove possible adapter sequences and nucleotides with poor quality using Trimmomatic v.0.36. The trimmed reads were mapped to either the Homo sapiens GRCh38 reference genome or the Mus musculus GRCm38 reference genome on ENSEMBL using the STAR aligner (v.2.5.2b) that detects splice junctions and incorporates them to help align the entire read sequences. BAM files were generated as a result of this step.analyzer . RNA wasHLTF-/- and HLTF+/+CDX from ID Hltf KO mice. Log2 fold changes (L2 FC) were calculated. P-values were obtained with the Wald test, and adjusted p-values (padj) were calculated with the Benjamini-Hochberg method. Genes with padj < 0.05 and absolute L2 FC >1 were called as differentially expressed genes for each comparison. New RNAseq data for Hltf-/-CDX in ID Hltf KO are accessible through NCBI\u2019s Gene Expression Omnibus (GEO) SuperSeries accession number GSE234728, SubSeries GSE234725 (RNA-Seq). RNAseq data for Hltf+/+CDX in ID Hltf KO are accessible through GSE161961.Unique gene hit counts were calculated by using featureCounts from the Subread package v.1.5.2. The hit counts were summarized and reported using the gene_id feature in the annotation file. Only unique reads that fell within exon regions were counted. After extraction, gene hit counts were used for downstream differential gene expression analysis (DESeq2) of five basic steps were necessary to implement spatial transcriptomics technology to quantify inter and intra tumor heterogeneity. Step 1, placement of FFPE CDX on capture areas of a Visium gene expression (GEX) slide. Step 2, H&E staining followed by brightfield microscopic imaging with ZEISS Axioscan 7 high-performance slide scanner . Step 3, permeabilize tissue and construct barcoded libraries with a final sample index PCR according to the manufacturer\u2019s instructions. Step 4, short-read sequencing (Illumina NovaSeq) of barcoded libraries by Genewiz. Step 5, data analysis of tissue images and sequencing files in FASTQ format with Space Ranger run on Ubuntu 22.04 LTS\u2013Thelio Mira-b3 by System76, Inc. . The space ranger aggr pipeline aggregated data from replicate samples and from replicate regions. Loupe browser visualization software was accessed in a desktop application via Windows (Dell Optiplex 990).HLTF-/- and HLTF+/+CDX from ID Hltf KO mice were placed within fiducial frames of capture areas A,B and C,D respectively, on Visium GEX slide V11D13-089-A1.CDX sections (5 \u03bcm) were processed with the RNeasy FFPE kit for DV200 analysis. Replicate sections from each of 4 capture areas (6.5 x 6.5 mm each) inside fiducial frames (8 x 8 mm each) contain 5,000 gene expression spots (55 \u03bcm in diameter) with a distance of 100 \u03bcm between the centers of each spot (1\u201310 cells/spot). Visium for FFPE uses RNA-templated ligation (RTL) probes targeting the whole transcriptome. The assay captures probes via a capture sequence, e.g. poly-A for FFPE probes. Each gene expression spot has primers with a unique spatial barcode. Probes are designed against the entire human genome, each with primers that include Illumina TruSeq Read 1 , 16 nt spatial barcode, 12 nt unique molecular identifier (UMI), and 30 nt poly(dT) sequence (captures ligation product). Spatially barcoded, ligated products were released from the slide, and harvested for qPCR with KAPA SYBR Fast qPCR master mix. The threshold for determining the Cq value for each sample was set along the exponential phase of the amplification plot at ~25% of the peak fluorescence value with QuantStudio 12 K Flex real-time PCR system (ThermoFisher Scientific). Sample index sets were selected to distinguish each of the 4 samples in a multiplexed sequencing run. Samples were amplified using Ilumina-compatible indexing primers, cleaned up with SPRIselect reagent, and bi-directionally sequenced.Visium Human Transcriptome Probe Set v1.0 contains 19,144 gene ids targeted by 19,902 probes. Gene ids  targeted by 1,272 probes were excluded by default due to predicted off-target activity to a different gene. As a result, 17,943 gene_ids  were present in the final filtered output. During data analysis, read 2 sequences were mapped against the reference human genome (GRCh38/hg38) and read 1 sequences were used for UMI filtering to obtain spatial information.Illumina NovaSeq NGS was performed at GeneWiz. Unique dual indexing\u2014unique identifiers on both ends of the sample\u2014allowed for an increase in the number of samples sequenced per run. Sequencing depth, a minimum of 50k read pairs per spot covered with tissue, was calculated by estimating the percent of capture area covered by the tissue section based upon the H&E brightfield image. Actual values are provided in HLTF-/- and HLTF+/+CDX tumors in ID Hltf KO mice are accessible through NCBI\u2019s Gene Expression Omnibus (GEO) SuperSeries accession number GSE234728, SubSeries GSE234517 .Visium Spatial Gene Expression Software Suite includes Space Ranger and Loupe Browser. Spaceranger mkfastq demultiplexed the Illumina sequencer\u2019s base call files (BCLs) for each flow cell directory into FASTQ files. Spaceranger count combined a brightfield microscope slide image and FASTQ files from spaceranger mkfastq and performed alignment, tissue detection, fiducial detection, barcode/UMI counting, and prepared a full resolution slide image for visualization in Loupe Browser. The pipeline used the Visium spatial barcodes to generate feature-spot matrices, determine clusters, and perform gene expression analyses. The pipeline used a probe aligner algorithm for FFPE tissues. Spaceranger aggr used the output of multiple runs of spaceranger count from related samples and aggregated their input, normalizing those runs to the same sequencing depth, and then recomputed the feature-barcode matrices and the analysis on the combined data. The aggr pipeline combined data from multiple samples into an experiment-wide feature-barcode matrix and analysis. Loupe Browser was used to interrogate significant genes, characterize and refine gene clusters, and perform differential expression analyses. Spatial transcriptomics data for HLTF-/-HCT116-Red-Fluc cells used for OCMI and resultant HLTF-/-CDX in ID Hltf KO mice was performed by Applied Biomics, Inc . Briefly: cell pellet (control) and CDX (n = 2 mice) were homogenized/sonicated (Polytron) in 4 volumes HENS buffer. Protein concentrations were determined (OD280) with NanoDrop One (ThermoFisher), adjusted to a final concentration of 2 \u03bcg/\u03bcl with HENS buffer and frozen for analysis.Parallel analysis of Pr-SSG in Differential Pr-SSG between cell and tumor proteins was evaluated by large-format two-dimensional gel electrophoresis (Western blot) and two-dimensional difference gel electrophoresis (2D DIGE) in which cell (gel 1) and tumor proteins (gel 2) labeled with Cy2  were interrogated with mouse monoclonal anti-glutathione (0.5 \u03bcg/ml) and Cy5-labeled donkey anti-mouse IgG (1:2000 dilution). These two gels provided information on the difference in glutathionylation between cells and tumor (glutathionylation ratio). Difference in protein levels between the two samples (ratio) was determined by comparing Cy2 labeled cell proteins with Cy3 labeled tumor proteins by 2D DIGE (gel 3). The final glutathionylation ratio for each spot was obtained by adjusting the glutathionylation ratio by the protein ratio. 2D-DIGE guided the excision of 61 spots. Protein identification was based on peptide fingerprint mass mapping (using MS data) and peptide fragmentation mapping (using MS/MS data). MASCOT search engine was used to identify human and mouse proteins from primary sequence databases (SWISSProt). Posttranslational modification (glutathionylation) authentication was based on matrix-assisted laser-desorption ionization time-of-flight (MALDI-TOF/TOF).Hltf+/+ (n = 9) and global Hltf KO (n = 5) ID Rag2-/IL2- males\u2014we were able to eliminate the gut microbiome as a variable in this study , shared the same morphology in culture, and had the same kinetic curve for their bioluminescence signal post-Luciferin injection (peak time 10\u201320 minutes) as parental HLTF+/+HCT116-Red-FLuc cells. Cells were further characterized as controls in the 2D-DIGE MALDI-TOF/TOF mass spectrometry experiments.The goal of the second experiment was to characterize the HCT116-Red-FLuc isogenic cell line. The shRNA-silenced stable isogenic cell line was expanded and monitored for GFP expression . When grHLTF-/-HCT116-Red-FLuc cells in ID Hltf KO mice. When Cespedes et al [+4 days. We implemented the model to confirm the negative correlation between HLTF expression in tumor cells and survival in mice previously identified with a non-metastatic AOM/DSS model [Hltf KO mice are associated with a worse prognosis and are 5-times more likely to die during the treatment protocol compared to ID Hltf+/+ mice [Hltf KO mice inoculated with HLTF-/-HCT116-Red-FLuc cells  genes. There was a total of 1,599 upregulated genes and 3,493 downregulated genes (HLTF-/-CDX vs HLTF+/+CDX in ID Hltf KO mice was tested using Fisher exact test (GeneSCFv1.1-p2).In the fourth experiment, DESeq2 was used for comparison gene expression analysis between ed genes . FollowiHLTF-/-CDX ID Hltf KO mice  of 39 genes involved in the cellular response to a DNA damage stimulus  in heart [HIF-1\u03b1 gene transcription in HLTF+/+CDX ID Hltf KO mice was unaffected by the presence or absence of Hltf in the TME. In the fifth experiment, we show deletion of HLTF from the tumor and the TME had no effect on total HIF-1\u03b1 transcription or on its downstream targets. Neither the hypoxia-responsive genes involved in angiogenesis  nor the glycolytic enzymes  with hypoxia response elements were transcriptionally activated. Cluster experiments from spatial transcriptomics allowed us to visualize HIF-1a throughout the tumors (t-distributed neighbor embedding (t-SNE) projection plots\u2014a statistical method for understanding high-dimensional datasets\u2014identified UMI counts and 16 distinct clusters that strongly recapitulated CDX histology (Excessive production of reactive oxygen/nitrogen species (ROS/RNS) causes oxidative stress that has been implicated in the development and progression of CRC . Mitochoin heart . We previn heart  HIF-1\u03b1 ge tumors . The datistology .HIF-1\u03b1 activation, a total of 23 human genes in mitochondrial electron transport, NADH to ubiquinone (GO:0006120), were transcriptionally activated (padj 3.73E-05) in conjunction with 25 human genes (padj 9.83E-05) in the mitochondrial respiratory chain complex 1 assembly (GO:0032981). Human MT-CYB \u2014a mitochondrially encoded component of the ubiquinol-cytochrome c reductase complex (complex III or cytochrome b-C1 complex), a respiratory chain that generates an electrochemical potential coupled to ATP synthesis\u2014was one of the genes transcriptionally activated . Immunolabeling of MT-CYB protein\u2014a marker for OXPHOS\u2014identified mitochondria in tumor cells in the Hltf-/-CDX and in the host lymphovasculature  in HLTF-/-CDX.Mitochondria are key generators of cellular reactive ROS  and theyGSH gene expression and compensated for the loss of structure that resulted from tissue dissociation for RNAseq experiments. It enabled us to simultaneously document cancer cell location in the CDX histology sections, and view the combinatorial expression of genes in GSH synthesis within that morphological context  [HLTF-/-CDX  . Region-TF-/-CDX .HLTF-/-CDX/TME showed protein S-glutathionylation in human tumor cells and endothelium of mouse lymphovasculature. These data support the conclusion that increased availability of glutathione buffers oxidative stress, and drives tumor/endothelial cell proliferation and migration in the HLTF-/-CDX/TME model.In mouse TME a total of 22 genes in the glutathione metabolic process (GO:0006749) were upregulated (padj 0.025974). GSH plays a critical role in endothelial function especially vasodilation and paracellular permeability . GlutathS-glutathionylation of HIF-1\u03b1 on Cys520 (mouse Cys533) stabilizes the protein [HLTF-/-CDX/TME targeted Hif-1\u03b1 protein in the sixth experiment. A total of 61 differentially expressed proteins were identified by 2D-DIGE comparison of glutathione-labeled proteins from Hltf-/-HCT116-Red-Fluc cells at the time of OCMI and resultant HLTF-/-CDX from ID Hltf KO mice  nor mouse (Cys533) HIF-1\u03b1 is a target of S-glutathionylation in this CDX model. Further use of MALDI-TOF/TOF followed by species-specific data analysis identified highly conserved cysteines in identical peptide fragment ion spectra (S2) from human and mouse, leading us to conclude humans and mice share the same Pr-SSG protein targets in this HLTF-/-CDX/TME model. Protein conservation is shown in Neither human (Cys247 shuttles GAPDH to the nucleus where it transfers the glutathione to Sirtuin-1 (SirT1) during SirT1-p53-mediated apoptosis [Importantly, three of five Pr-SSG protein targets are glycolytic enzymes that control reversible steps 7, 8 and 9 in the 10-step glycolysis pathway . Glycolypoptosis .Phosphoglycerate kinase (PGK1) and phosphoglyceromutase (PGAM1) are redox sensitive and exposure to glutathione stabilizes them (prevents inactivation) presumably via the newly identified S-glutathionylation sites reported here. PGK1 is a highly conserved so-called moonlighting protein because of its involvement in varied cellular processes as a protein kinase . As the HLTF-deleted CDX/TME had the highest (>5.0) final WB ratio indicating Pr-SSG occurred in cells of the CDX rather than the cultured cells from which it was derived. PGAM1 was also transcriptionally activated  in HLTF-/-CDX compared to HLTF+/+CDX from ID Hltf KO mice. Upregulation of PGAM1 is consistent with its upregulation in several human cancers [HLTF-/-CDX/TME \u2014is catalyzed by the rate-limiting enzyme, alpha enolase (ENOA1), another moonlighting enzyme . Becausetivation , 50. Res-CDX/TME .263), was neither transcriptionally activated nor did it have a high final WB ratio  is completely alymphoid, which precludes confusion of cellular identify. Extravascular amoeboid cancer cells displayed aggressive metastatic directional movement consistent with an epithelial-to-mesenchymal transition [Independent of its metabolic activity, PGAM1 interacts with \u03b1-smooth muscle actin (ACTA2), and ANXA1 is linked to the actin cytoskeleton. Importantly, glutathionylated actin (GS-actin) on Cysisoforms , was notmotility . Co-locamotility . Howeveransition .TMSB4X) gene  whose secreted G-actin sequestering protein regulates actin dynamics. Transcriptional Cluster 1 was subepithelial and extended into the tumors resulting from circumferential cellular migration. Extravasculature PGAM1/ANXA1-positive tumor cells corresponded to membership in spatial transcriptional Cluster 14 ((EMP1) gene , a pro-metastatic factor responsible for metastatic recurrence in CRC. Transcriptional Cluster 14 subtends the epithelium independent of the tumor.PGAM1/ANXA1-positive tumor cells in intravascular niches corresponded to membership in spatial transcriptional Cluster 1  concomituster 14  enriched237, Cys442, and Cys447). Previously identified PTMs [237 and S-guanylation at HSP60 Cys440. This is the first report of S-glutathionylation at HSP60 Cys447.HSP60 is evolutionarily conserved. HSP60 typically resides in mitochondria where it maintains protein homeostasis via a protein folding apparatus with its co-chaperone HSP10 . HSP60 mied PTMs  related HLTF-/-CDX/TME model\u2014show for the first time\u2014that tumor cell recovery from DNA damage via robust transcriptional activation of DNA repair and OXPHOS genes coincided with a highly metastatic phenotype. Loss of HLTF function throughout the CDX/TME co-sponsored an amoeboid-associated TME at the tumor border. Cancer and endothelial cells of the TME share site-specific Pr-SSG signatures for 3 glycolytic enzymes that divert glycolysis in support of glutathione biosynthesis that prevents OXPHOS inhibition and promotes redox homeostasis.Results from this Experimental advantages of this CDX model of CRC are validated by results from this study. First, by manipulating the genotype of the mice and HCT116 cells, the CDX model recapitulates the beginning and end of disease progression. Second, when human CRC is propagated in immune-deficient mice, not only does murine stroma and vasculature begin to replace the human equivalents immediately , but theOne potential disadvantage of the CDX model is its development in an immune-deficient mouse. In defense of that approach, ~80\u201385% of CRC patients have so-called \u201ccold tumors\u201d meaning they do not have a strong immune response (do not express T-cells). Consequently, cold tumors are resistant to immunotherapy . We posiHLTF-deletion in cancer cells with resultant metabolic reprogramming\u2014a hallmark of metastasis\u2014is likely a prototypical example of cancer cells modifying their metabolic requirements in response to Hltf-deletion in the TME. The complete absence of HLTF from tumor cells and the TME produced the most aggressive metastatic phenotype with the shortest life expectancy. The next question is whether or not the complete absence of HLTF is a diagnostic marker for chemoresistance mechanisms in CRC because drug resistance is strongly correlated with glutathione synthesis [Collective results from the CDX model strongly support the conclusion that ynthesis .S1 Checklist(PDF)Click here for additional data file.S1 File(ZIP)Click here for additional data file.S1 Raw images(PDF)Click here for additional data file."}
+{"text": "Fomitopsis pinicola isolate FBCC 1181 is a 66.5 kbp circular chromosome. It contains 64 predicted genes, including a set typical for Basidiomycota Agaricomycetes mitogenomes. Introns of cox and cob genes contain several homing endonucleases of both LAGLIDADG and GIY-YIG types.The mitochondrial genome of the brown rot fungus  Fomitopsis species is that of Fomitopsis palustris strain FFPRI 0507_CJ35 (NC_034349.1). Here, we report the complete mitochondrial genome sequence for isolate FBCC 1181 of the Fomitopsis type species, Fomitopsis pinicola (Sv.) P. Karst, a wood-decaying brown rot fungus   was assembled from long reads produced with PacBio Sequel II from total DNA, extracted from mycelium cultured in liquid malt extract medium, using a modified hot cetyltrimethylammonium bromide (CTAB) extraction protocol . A sequeast.cgi) . Predictast.cgi)  to deterrps3) and DNA polymerase (dpo) , apocytochrome b (cob), NADH dehydrogenase subunits (nad1\u20136 and nad4L), and ATP synthase subunits (atp6, atp8, and atp9; rps3 and dpo are present, as well as the ribosomal RNA genes rnl and rns. There are 28 tRNA genes for the 20 common amino acids. Four LAGLIDADG and two putative GIY-YIG endonuclease genes were identified within introns of the cox1 and cob genes.The average size of all currently available Basidiomycota mitochondrial genomes is 78 kbp and typically contains 14 conserved protein-coding genes, two ribosomal RNA genes, and 20\u201331 tRNA genes . In addi"}
+{"text": "Diadema setosum) shells reinforced with polyvinyl alcohol for alveolar bone tissue engineering\u2019 by Muhammad Amir Jamilludin et al., RSC Adv., 2023, 13, 32444\u201332456, https://doi.org/10.1039/D3RA06165E.Correction for \u2018Functionalized cellulose nanofibrils in carbonate-substituted hydroxyapatite nanorod-based scaffold from long-spined sea urchin ( The authors regret that the C-HAp degree of crystallinity is incorrectly presented in The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "Correction to: Archives of Orthopaedic and Trauma Surgery (2022) 142:3927\u20133935 10.1007/s00402-021-04290-4The original version of this article unfortunately contained a mistake. The given name and family names were interchanged.The correct given name and family names should be:Ewa BreborowiczPrzemyslaw LubiatowskiMarta JokielMaciej BreborowiczJakub StefaniakAdam ZygmuntMarcin WojtaszekPiotr KaczmarekLeszek RomanowskiThe original article has been corrected."}
+{"text": "Background:International Classification of Diseases, Tenth Edition (ICD-10) data help track outpatient antibiotic prescribing but lack validation in immunocompromised populations or subspecialty clinics for this purpose. Asymptomatic bacteriuria (ASB) and urinary tract infection (UTI) are important stewardship targets in renal transplant (RT) patients, but they may require alternative metrics to best monitor prescribing patterns. We describe ICD-10 utilization for RT clinic encounters in which antibiotics were prescribed. We developed a metric classifying \u201cacute urinary antibiotics\u201d (AUA) to track antibiotic use for ASB and UTI, and we validated systematic identification of AUA to enable practical implementation. Methods: We examined RT clinic visit and telemedicine encounters from 2018 to 2021 conducted 1 month after transplant. This project was deemed non\u2013human-subjects research by the Stanford Panel on Human Subjects in Medical Research. Results: The analytic cohort included 420 antibacterial prescriptions from 408 encounters . Of 238 patients, 136 (57%) were male and 112 (47%) were Hispanic or Latino. The most common primary ICD-10 code was Z94.0 (kidney transplant status) ; 26 encounters (6%) were coded for UTI ; and 214 encounters (53%) had multiple ICD-10 codes. The R82.71 code (bacteriuria) was never used. However, 215 prescriptions (51%) were classified as AUA . The validation cohort included 130 prescriptions; 59 (45%) were classified as AUA and 51 (39%) had documented intent to treat ASB or UTI  (Table 1). For patients >1 month after transplant, the positive percent agreement was 95% and the negative percent agreement was 98%. Of 51 patients receiving AUA, 32 (63%) were asymptomatic despite frequently having a code for UTI . Conclusions: ICD-10 coding may not be helpful in monitoring antibiotic prescribing in RT patients. The AUA metric offers a practical alternative to track antibiotic prescribing for urinary syndromes and reliably correlates with physician intent. Monitoring AUA prescribing rates could help identify opportunities to optimize antibiotic use in this complex outpatient setting.Disclosures: None"}
+{"text": "Rousettus aegyptiacus) and their argasid tick ectoparasites, Ornithodoros (Reticulinasus) faini. Although tick salivary gland components have been shown to potentiate virus infection in vertebrate non-reservoirs , there is a lack of information on the effect of tick salivary gland components on viral infection and shedding in vertebrate reservoirs.The human-pathogenic Kasokero virus (KASV) circulates in an enzootic transmission cycle between Egyptian rousette bats  faini tick salivary gland extract (SGE).To determine the impact of tick salivary gland components on KASV infection and shedding in ERBs, KASV loads were quantified in blood, oral swab, rectal swab, and urine specimens collected daily through 18\u00a0days post inoculation from groups of ERBs intradermally inoculated with KASV or KASV\u2009+\u2009Bats inoculated with KASV\u2009+\u2009tick SGE had significantly lower peak and cumulative KASV viremias and rectal shedding loads compared to bats inoculated with KASV only.We report for the first time to our knowledge that tick salivary gland components dampen arbovirus infection and shedding in a vertebrate reservoir. This study advances our understanding of biological factors underlying arbovirus maintenance in nature.The online version contains supplementary material available at 10.1186/s13071-023-05853-7. Nairoviridae, genus Orthonairovirus) was first described by scientists at the Uganda Virus Research Institute (UVRI) following the isolation of infectious virus (2.7% [2/74] bats) and detection of virus-specific antibodies (67.6% [50/74] bats) in serum samples collected from Egyptian rousette bats  captured at Kasokero Cave, Uganda, in 1977 ). Anti-KASV IgG responses were measured using a previously described indirect enzyme linked immunosorbent assay ) protect the structural stability and functional activity of proteins in aqueous solutions subjected to high-dose gamma irradiation (5 megarads) [Previous studies investigating the effect of tick salivary gland components on virus infection in small animal models of human disease used SGE prepared from colonized ticks , 6. Due egarads) , 8.In conclusion, we report for the first time\u00a0to our knowledge that tick salivary gland components dampen arbovirus infection and shedding in a vertebrate reservoir. This study advances the understanding of biological factors that influence arbovirus maintenance in nature.Additional file 1: Fig. S1. Anti-Kasokero virus (KASV) IgG responses. Whole blood for serology was collected at 0, 7, and 14 DPI and at the end of the study (18 or 20 DPI) from KASV- and KASV\u2009+\u2009tick salivary gland extract (SGE)-inoculated bats. Bat identification numbers correspond to numeric codes generated by scanning implanted passive integrated transponder tags."}
+{"text": "A 60-year-old man was referred to our Respiratory Department with progressive dyspnea on exertion and productive cough over the past two months. High-resolution computed tomography showed diffuse ground glass opacities with superimposed interlobular and intralobular septal thickening mainly in the middle and lower lobes, compatible with crazy paving pattern. Serology tests revealed positive antibody\u00a0transcriptional intermediary factor-\u03b31 (TIF-1\u03b3) in myositis panel and bronchoalveolar lavage revealed milky appearance and positive periodic acid-Schiff (PAS) stain. Pulmonary function tests showed moderate reduction in diffusing capacity for carbon monoxide. The working diagnosis of autoimmune pulmonary alveolar proteinosis was established by high detectable levels of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies. Despite clinical and radiological improvement following treatment with whole lung lavage and inhaled sargramostim, patient\u2019s follow-up chest computed tomography revealed an enlargement of lower left paratracheal lymph node 4L. Endobronchial ultrasound bronchoscopy (EBUS) biopsy was compatible with small cell lung cancer (SCLC). Chemotherapeutic agents were promptly administrated, with no adverse events up until now. Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by alveolar accumulation of surfactant and progressive hypoxemia ,2. PAP iWe herein report a rare case of autoimmune pulmonary alveolar proteinosis in the setting of small cell lung cancer in a middle-aged man presented with acute onset respiratory failure. Clinical vigilance and thorough diagnostic evaluation led to early diagnosis of the disease and timely therapeutic interventions. The following report presents in detail the patient\u2019s management and clinical course, as well as highlights the cardinal role of close follow-up in management of rare clinical entities.A 60-year-old male patient, current smoker (120 pack years), presented to our department with progressive dyspnea on exertion and productive cough with thick white sputum over the past two months. High resolution computed tomography of the chest (HRCT) revealed diffuse ground glass opacities with superimposed interlobular and intralobular septal thickening mainly in the middle and lower lobes, compatible with crazy paving pattern, with slightly enlarged (1.5 cm) left lower paratracheal lymph node (station 4L) that was firstly considered as reactive lymphadenopathy Figure\u00a0. He deniPhysical examination revealed the following vital signs: blood pressure of 140/80 mm Hg; heart rate, 80 beats/min; temperature, 36.8\u02daC and oxygen saturation, 87% on ambient air. Lung auscultation revealed bilateral inspiratory crackles, while heart and abdomen examination was unremarkable. There were no palpable lymph nodes, rash or clubbing.At the time of referral to the Respiratory Department, arterial blood gases on ambient air : 56 mmHg, partial pressure of carbon dioxide (pCO2): 35 mmHg, pH: 7.41, bicarbonate (HCO3): 23 mmol/L) were indicative of respiratory failure type 1.\u00a0The complete blood and metabolic panel as well as immunologic and serology tests (anti-nuclear antibodies (ANA), cytoplasmic antineutrophil cytoplasmic\u00a0antibodies (c-ANCA), perinuclear antineutrophil cytoplasmic\u00a0antibodies (p-ANCA), rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP)) were normal, except for positive antibody transcriptional intermediary factor-\u03b31 (TIF-1\u03b3) in myositis panel that was considered cross-reactivity and raised the suspicion of autoimmune PAP. Subsequently, the patient underwent conventional bronchoscopy without abnormal structural findings. Culture of washing for common pathogens or Mycobacterium infection and cytological examination of washing for malignancy were negative. Analysis of bronchoalveolar lavage (BAL) revealed milky appearance, mild lymphocytosis, mild neutrophilia  and positive periodic acid-Schiff (PAS) stain. Histopathological examination of the transbronchial biopsy of\u00a0lateral and posterior basilar segmental bronchi (LB9-10) was compatible with inflammation, with no signs of malignancy. Pulmonary function tests (PFTs) showed moderate impairment of diffusing capacity of the lungs : 3.46, 89%, forced expiratory volume in the first second (FEV1): 2.68, 88%, FEV1/FVC: 0.77, diffusing capacity of lung for carbon monoxide (DLCO): 11.85, 50%). Echocardiogram was normal with no signs of pulmonary hypertension.On the basis of compatible clinical (cough and dyspnea on exertion), functional (diffusing capacity impairment) and radiological features (crazy paving), a working diagnosis of alveolar pulmonary proteinosis was set. In this context, serum levels of GM-CSF autoantibodies were measured. Titer of anti-GM-CSF antibodies was positive in high detectable levels (163 pg/mL) and as a consequence a diagnosis of aPAP was established.Following multidisciplinary discussion and taking into account disease severity, whole lung lavage (WLL) -the standard of care- was promptly implemented in a total of four cycles (twice for each lung) Figure . Due to In a follow-up appointment after three weeks, the patient presented with clinical improvement without episodes of dyspnea or desaturation on exertion. Despite radiological improvement of ground glass opacities and intralobular thickening on HRCT, a new-onset enlargement of lower left paratracheal lymph node 4L (4.3cm) was observed Figure . ConsequIn this report we present a rare case of co-existence of aPAP and lung cancer. Currently there are only a few described cases of coexistence of pulmonary alveolar proteinosis with primary lung cancer -11. DespThe main pillars of treatment in patients with PAP are based on pathogenetic causes and on disease severity. The current standard of care in primary PAP and some causes of secondary PAP is WLL . With reBased on the above, despite applied treatment modalities, there is an amenable need for close follow-up in management of PAP. Increasing awareness is a crucial step for early diagnosis and optimal management as these patients may develop -except for fibrotic phenotype and respiratory failure- concomitant lung cancer and benefit from timely interventions."}
+{"text": "A national pharmacy benefits management company implemented a rheumatoid arthritis (RA) disease therapy management (DTM) program as an enhanced offering to patients receiving specialty pharmacy services. The program was designed to improve medication adherence, maximize therapeutic outcomes, and enhance physical functioning and health-related quality of life (HRQOL) by empowering patients and improving their knowledge of RA.To evaluate (a) adherence to injectable RA medications for patients participating in an RA DTM program compared with nonparticipating patients receiving injectable RA medications at specialty or community pharmacies and (b) HRQOL, work productivity, and physical functioning before versus after completing the RA DTM program.Patients who had an RA diagnosis and a pharmacy claim for an injectable RA medication during the identification period (August 2007 through September 2008) and were continuously enrolled with the plan from 4 months before through 8 months after the identification date were stratified into 3 patient cohorts: DTM, specialty pharmacy, and community pharmacy. DTM patients were further categorized into a DTM intent-to-treat (ITT) cohort  and a DTM completer cohort (subset of 266 ITT patients who completed the month 6 consultation). DTM completer, specialty, and community pharmacy cohorts were matched 1:1:1 (n = 244 in each cohort after matching) using a propensity score that represented the likelihood of completing the DTM program. The primary outcome was adherence to injectable RA medications, measured as the proportion of days covered (PDC) over an 8-month post-identification period. Patient-reported outcomes  were evaluated among all 371 DTM patients who completed the month 0 and month 6 consultations regardless of whether they met continuous enrollment requirements (patient-reported sample).Of specialty pharmacy patients, approximately 14% chose DTM participation. During the post-identification period, mean PDC was 0.83 for DTM ITT, 0.89 for DTM completer, 0.81 for specialty pharmacy, and 0.60 for community pharmacy patients. Differences were statistically significant for both DTM cohorts compared with the community pharmacy cohort (P less than 0.001) and for the DTM completer cohort compared with the specialty pharmacy cohort (P less than 0.001), but not for the DTM ITT cohort compared with the specialty pharmacy cohort (P = 0.291). In the patient-reported sample, mean SF-12 physical component scores significantly increased by 1.1 points (P = 0.048); mean SF-12 mental component scores were not significantly changed (P = 0.679); mean WPAI work productivity decreased by 10.8 percentage points (P = 0.045); and mean HAQ-DI scores significantly improved by 0.08 points (P less than 0.001).Patients participating in the RA DTM program had significantly higher injectable RA medication adherence compared with community pharmacy patients. Adherence to injectable RA medications was significantly higher for patients completing the RA DTM program, but not for the DTM ITT group, compared with patients receiving specialty pharmacy services alone. Patients completing the RA DTM program experienced improvements in SF-12 physical component and HAQ-DI scores but did not demonstrate improvements to SF-12 mental scores or work productivity."}
+{"text": "RCA) and NIRS/IVUS-derived plaque measures were compared in patients with PCATRCA attenuation\u2009\u2265\u2009and\u2009<\u2009-78.3 HU (median). Lesions with PCATRCA attenuation\u2009\u2265\u2009-78.3 HU exhibited a greater frequency of maxLCBI4mm\u2009\u2265\u2009400 , plaque burden\u2009\u2265\u200970%  and spotty calcification . Whereas positive remodeling  did not differ between two groups. On multivariable analysis, maxLCBI4mm\u2009\u2265\u2009400 , plaque burden\u2009\u2265\u200970% , and spotty calcification  independently predicted high PCATRCA attenuation. Of note, while the presence of only one plaque feature did not necessarily elevate PCATRCA attenuation (p\u2009=\u20090.22), lesions harboring two or more features were significantly associated with higher PCATRCA attenuation. More vulnerable plaque phenotypes were observed in patients with high PCATRCA attenuation. Our findings suggest PCATRCA attenuation as the presence of profound disease substrate, which potentially benefits from anti-inflammatory agents.Inflammation has been considered to promote atheroma instability. Coronary computed tomography angiography (CCTA) visualizes pericoronary adipose tissue (PCAT) attenuation, which reflects coronary artery inflammation. While PCAT attenuation has been reported to predict future coronary events, plaque phenotypes exhibiting high PCAT attenuation remains to be fully elucidated. The current study aims to characterize coronary atheroma with a greater vascular inflammation. We retrospectively analyzed culprit lesions in 69 CAD patients receiving PCI from the REASSURE-NIRS registry (NCT04864171). Culprit lesions were evaluated by both CCTA and near-infrared spectroscopy/intravascular ultrasound (NIRS/IVUS) imaging prior to PCI. PCAT attenuation at proximal RCA (PCATThe online version contains supplementary material available at 10.1007/s10554-023-02907-w. Inflammation has been considered as an important driver which promotes atherosclerosis . Recentlvivo . Furthermore, the addition of PCATRCA with clinical features  improved its prediction  , the correlation of PCATLesion attenuation with NIRS/IVUS-derived plaque features were weak. Most of published studies have measured PCAT attenuation at the proximal 40\u00a0mm segment of RCA, and they reported that PCATRCA predicted a future cardiovascular event [4mm was associated with PCATRCA but not PCATLesion attenuation. Our observation also supports the measurement of PCAT attenuation at the proximal segment of RCA to more appropriately evaluate coronary artery inflammation.The current study used PCATar event . In addiar event . These aRCA attenuation is not fully established yet. Tzolos et al. reported that PCATRCA attenuation\u2009\u2265\u2009-70.5 HU predicted future outcome[RCA attenuation in the entire subjects (-78.3 HU) as a cut-off value of PCATRCA attenuation. Further studies are required to identify the best cut-off value of PCATRCA attenuation associated with plaque instability and cardiovascular outcomes.To date, clinically adequate cut-off value of PCATe outcome, whereasConsiderable interests have recently focused on inflammation as a therapeutic target because of its biological properties. The CANTOS (Canakinumab Antiinflammatory Thrombosis Outcome Study) study demonstrated the clinical benefit of modulating interleukin-1\u03b2 to reduce future atherosclerotic cardiovascular disease in patients with an elevated level of high-sensitivity c-reactive protein . A signiRCA attenuation with monocyte chemoattractant protein-1\u00a0and interleukin-7 [Several caveats should be noted. Firstly, this study is a single-center retrospective observational study. Secondly, the sample size of the current study is relatively small, which may lead to the wide 95% CI in the multivariable analysis However, our calculation of study sample size shows that 56 lesions provide 90% power at a two-sided alpha level of 0.05 to detect a nominal difference of 10% (standard deviation\u2009=\u200910%). Thirdly, CCTA imaging was used according to each physician\u2019s discretion. These may cause a potential bias to select study population. Fourthly, the use of lipid-lowering therapy and its intensity were decided by each physician. Fifthly, while one recent study showed the association of PCATleukin-7 , the curRCA attenuation more likely exhibited greater atheroma burden containing lipidic materials and spotty calcification. Of note, a higher PCATRCA attenuation was observed in association with an increased number of these phenotypic features. Our findings suggest that CCTA-derived PCATRCA attenuation has a potential to non-invasively identify patients harboring high-risk plaque phenotype who may require preventive medical therapies including anti-inflammation agent.In conclusion, patients with an elevated PCATCAD= coronary artery disease, CCTA= coronary computed tomography angiography, HU= Hounsfield units, IVUS= intravascular ultrasound, NIRS= near infrared spectroscopy, PCAT= pericoronary adipose tissue, PCI= percutaneous coronary intervention, RCA= right coronary arterySupplementary file1 (TIF 767 kb)\u2014Patient\u2019s disposition. Lesion attenuation and PCATRCA attenuation. PCAT= pericoronary adipose tissue. RCA= right coronary arterySupplementary file2 (TIF 1080 kb)\u2014The correlation between PCATLesion attenuation. a MaxLCBI4mm, b Plaque burden, c Remodeling index. IVUS= intravascular ultrasound, NIRS= near infrared spectroscopy, PCAT= pericoronary adipose tissueSupplementary file3 (TIF 1887 kb)\u2014The correlation between plaque features derived from NIRS/IVUS and PCATLesion attenuation with spotty calcification. PCAT= pericoronary adipose tissueSupplementary file4 (TIF 487 kb)\u2014The relationships of PCATBelow is the link to the electronic supplementary material."}
+{"text": "Optimal treatment (rx) of staphylococcal CIED IE requires removing the entire CIED. Difficulty of dx plus cost and potential morbidity of rx make treatment challenging. Complicated staphylococcal bacteremia is associated with prolonged detection of plasma mcfDNA during antibiotic rx. To assess for IE, we studied plasma mcfDNA kinetics in CIED patients (pts) with staphylococcal bacteremia undergoing CIED removal.\u00ae at Karius CLIA certified Laboratory  on batched pt specimens. Clinical data were obtained from the electronic medical record. CIEDs were removed through sterile pockets or surgically except in pt 012. Definite CIED IE was defined by multiple d of bacteremia plus a definite lead / tricuspid vegetation per echocardiogram, direct inspection or lead tip culture; multiple d bacteremia or a definite vegetation defined possible CIED IE.With written consent, CIED pts (no persistent confounding infection) with bacteremia in the prior \u2264 7 days (d) and planned CIED removal had serial plasma specimens collected [Figure]. Quantitative mcfDNA-Seq was done using the Karius TestStaphylococcus aureus (7 pts) or S. epidermidis (2 pts: 012 who due to retained lead fragment relapsed after rx 021) [Table 1]. At consent, after 2-11 d rx (median 6 d) mcfDNA was detected in 8 of 9 pts; in all 9, on CIED extraction mcfDNA increased significantly from consent and pre-extraction levels [Table3]. Five pts with possible S.aureus CIED IE had 1-3 d (median1 d) bacteremia [Table 2]. None had plasma mcfDNA after 5 d rx and 4 of 5 had no mcfDNA detectable on device extraction [Table3]. McfDNA patterns in definite CIED IE (8 of 9 pos on consent / pre-extraction and had an increase on extraction) differed from those in possible CIED IE (4 of 5 neg at 5 d of rx and none detected on extraction) [p=0.023 Fisher Exact].Nine pts with definite CIED IE had bacteremia 3-13 d (median 6 d) with Quantitative mcfDNA patterns can help distinguish definite from possible CIED IE and absence of mcfDNA in plasma of possible CIED IE on device extraction suggests that the CIED may not be infected. After 5 days of rx, plasma mcfDNA-Seq in CIED pts with staphylococcal bacteremia coupled with clinical features may identify patients that can be effectively treated without device removal - a testable hypothesis.Adolf W. Karchmer, MD, DeBiopharma: Advisor/Consultant|DeBiopharma: Honoraria|Karius: Grant to Institution for this study Jason D. Matos, MD, Merck: Wife is an employee Nicholas R. Degner, MD, MPH, MS, Karius: Employer"}
+{"text": "Pseudomonas aeruginosa (CRPA) in a transplant patient with multiple hospitalizations in California, USA. Whole-genome sequencing revealed the isolate was genetically distinctive, despite \u224895% similarity to other global strains. The patient\u2019s lack of international travel suggests this CRPA was acquired domestically.We describe a case of New Delhi metallo-\u03b2-lactamase 1\u2013producing carbapenem-resistant  Pseudomonas aeruginosa (CRPA) is increasing worldwide and has up to 30% prevalence in US P. aeruginosa isolates (https://arpsp.cdc.gov/profile/arln/crpa). New Delhi metallo-\u03b2-lactamase (NDM)\u2013producing CRPA is prevalent in Eurasia and the Middle East. Sporadic NDM CRPA cases linked to international travel have been reported in the United States, the earliest of which was identified in Delaware in 2014  testing detected NDM. We performed whole-genome sequencing by using MiSeq  and assembled reads de novo by using CLC Genomics Workbench . We submitted tentative assemblies to the Comprehensive Antibiotic Resistance Database Resistance Gene Identifier tool  for resistance gene detection and verified results by using ResFinder   . The isoblaNDM-1, including in isolates from Serbia, France, and Italy (aac(6')-Ib9 and chloramphenicol resistance genes cmlA and catB7  235, frequently associated with We used CSIPhylogeny (Center for Genomic Epidemiology) to perform single-nucleotide polymorphism (SNP) analysis against other NDM-1\u2013producing ST235 isolates, then CLC Bioinformatics Workbench (QIAGEN) to generate a phylogenetic tree. The isolate from this study exhibited highest homology (\u224830 SNPs difference) with 2 non\u2013NDM-producing ST235 isolates from Malaysia . Among NThe NDM CRPA isolate we report exhibited susceptibility to cefiderocol, which was used to clear the urinary tract infection. Upon phenotypic carbapenem resistance identification, cefiderocol susceptibility testing indicated sensitivity. The rapid availability of susceptibility testing results and preliminary testing performed within 24 hours after isolation were crucial for appropriate clinical management and antimicrobial drug choice, leading to safe heart transplantation and receipt of immunosuppression. Carbapenemase-producing bacteria should not disqualify a patient from transplantation. blaNDM-1 remains unknown. Infection control measures and expanded surveillance efforts, including routine laboratory screening of all CRPA isolates via carbapenemase tests, could curb the spread of this high-risk genotype.In conclusion, high mortality rates of ST235 NDM CRPA in invasive infection and a potential community spread in southern California warrant concern. The mobilization potential of Pseudomonas aeruginosa, Southern California, USA, 2023.Additional information domestically acquired NDM-1\u2013producing"}
+{"text": "HIV prevention services like pre-exposure prophylaxis (PrEP) remain underutilized. This project aimed to support health care professionals (HCPs) in settings like federally qualified or community health centers and free and charitable clinics in expanding HIV prevention services for underserved populations, including immigrant communities.Baseline surveys were administered to interdisciplinary care teams in 6 clinics across the eastern US from January \u2013 March 2022. Survey data informed 4 live virtual education sessions featuring pre- and post-program surveys and team-based action planning. To promote exchange of clinical strategies, clinics with different levels of HIV prevention experience were paired together. Content was extended nationwide in an on-demand video.Baseline survey respondents (N = 121) noted the greatest challenges in PrEP implementation were limited HCP knowledge/awareness (47%) and lack of training on PrEP workflows (33%). HCPs identified common barriers to patient PrEP uptake as lack of PrEP knowledge/awareness (58%), low perception of self-risk (47%), and low health literacy (38%). HCPs felt training was most needed in patient outreach/engagement (36%) and sexual history taking (32%), and 65% reported their team could most improve on normalizing sexual health conversations. 119 HCPs attended the education sessions (Table 1). HCP knowledge of laboratory monitoring for patients on PrEP rose from 40% to 57% (p = .037), as did the proportion of HCPs reporting high confidence in initiating/monitoring PrEP use . Action plans included improving communication/care coordination (46%), increasing staff training/education (35%), and increasing patient outreach (35%) and education (35%). System champions from each clinic reporting 90-day outcomes (n = 16) agreed their clinics had improved in identifying patients for PrEP (94%) and evidence-based PrEP use (69%). As of March 2023, 1,531 HCPs had accessed the online video.HCPs gained confidence and knowledge in patient engagement and PrEP use and made action plans that helped improve PrEP implementation, emphasizing the potential impact of targeted education on HIV prevention services in underserved communities.Meredith E. Clement, MD, Gilead Sciences: Grant/Research Support|ViiV Healthcare: Advisor/Consultant Claudia T. Martorell, MD MPH, AbbVie: Honoraria|Gilead Sciences: Honoraria|GSK: Grant/Research Support|Theratechnologies: Grant/Research Support|ViiV: Honoraria"}
+{"text": "Neisseria gonorrhoeae (GC). We examined trends in tetracycline resistance (TetR) and tetM plasmid-mediated high-level tetracycline resistance (TetHLR) among GC isolates collected from MSM and transgender women through national sentinel surveillance.Doxycycline, a tetracycline analog, is being considered for use as post-exposure prophylaxis (PEP) to reduce bacterial sexually transmitted infections (STIs) among gay, bisexual, and other men who have sex with men (MSM) and transgender women. Pre-existing tetracycline resistance may contribute to the varied effectiveness of doxycycline in preventing Genital , pharyngeal and rectal GC isolates were collected from MSM and transgender women during 2018\u20132021 at 12 Enhanced Gonococcal Isolate Surveillance Project (eGISP) and 8 Strengthening the U.S. Response to Resistant Gonorrhea (SURRG) sites. We determined overall prevalence of TetR and TetHLR  among MSM and transgender women by anatomic site of infection and described annual trends among MSM.Among 10,853 isolates collected from 8,667 MSM, overall TetR prevalence was 31% , and annual TetR prevalence decreased during 2018\u20132021 (Table 1). Overall TetHLR prevalence among MSM was 13%  and annual TetHLR prevalence for genital and pharyngeal infections increased during 2018\u20132021. Among 108 isolates collected from 89 transgender women, overall TetR prevalence was 23%  and TetHLR prevalence was 9% , though numbers were small.Approximately 1/3 of GC isolates collected from MSM and 1/4 of GC isolates collected from transgender women were tetracycline resistant. Prevalence of tetracycline resistance was similar across anatomic sites. Providers should continue to follow recommended screening and treatment guidelines for gonorrhea among persons using doxycycline as STI PEP. Additionally, given high levels of TetHLR, enhanced tetracycline resistance surveillance is needed with implementation of doxycycline as STI PEP.All Authors: No reported disclosures"}
+{"text": "Steroids is an effective medicine to improve lung lesions and clinical prognosis in COVID-19 pneumonia patients. The outcomes and chest CT images of steroid dose adjustment in CT progressive patients is still unknown. The study is to investigate the effects of increasing steroids dosage to chest CT areas and clinical outcomes in non-severe COVID-19 patients with progressive chest CT lesions.This retrospective study used Zhongshan hospital affiliated to Fudan University clinial data to identify 319 adult hospitalized in infectious diseases department for COVID-19 pneumonia between December 2022 and January 2023. We made a treatment strategy tailoring the steroids dosage according to the CT chest images to optimizing methylprednisolone (MP) dose precisely in these patients. Chest radiology were performed at admission and were follow-up during MP treatment. According to adjustment of MP dosage, we classified patients with radiology progression into MP increment group and MP no-change group. Clinical features, CT severity scores changes within 7 days after steroids adjustment, 96 hours WHO outcome scores, length of stay (LOS) and 28-day mortality rate were recorded and assessed between groups.Among 319 participants, average age were 72(IQR 66-82), male were 207(64.9%), severe illness accounted for 44.2%(n=141). 105 patients with aggressive chest radiology during MP treatment were classified into increment group(n=79) and no-change group(n=26). 6(7.6%) and 1(3.8%) patients had increasing WHO outcome scores 96h after MP adjustment(p=0.678), LOS [15(IQR 10-24) vs 14(IQR 10-25) (p=0.994)] and 28-day mortality  showed no significant differences in increment group and no-change group respectively. 95 patients have available chest CT follow-up with 7 days after CT progressive. Meanwhile, univariate and multivariate logistic regressive analysis revealed that patients receiving increased MP dose was significantly associated with improvement in CT lesion areas compared with those in no-change group.The orange and purple bars present CT score changes in MP increment group and in MP unchanging group respectively. These CT score changes showed no significant differences in groups.The bar with light color presents MP increment group and the bar with dark color presents MP unchanging group. the three sets of bars showed the dynamics of WHO outcome scores components before and after MP dose adjustment.Odd ratios are plotted as squares, with the size of each square proportional to the amount of statistical information that was available; the horizontal lines represent 95% confidence intervals.Increasing MP dosage in CT worsening patients improves CT lesions while fails to decrease serious adverse outcomes.All Authors: No reported disclosures"}
+{"text": "Fecal microbiota transplantation (FMT) can effectively decolonize multidrug-resistant organisms but its efficacy is variable. We evaluated the impact of FMT treatment at eliminating carbapenemase-producing Enterobacterales (CPE) carriage compared to spontaneous decolonization and identified microbial signatures of successful decolonization.Prospective study, with patients colonized with CPE receiving a single dose of FMT via the nasogastric route. CPE-colonized patients who did not meet our inclusion criteria or decided not to participate in the study comprised the control group where spontaneous decolonization was evaluated. Primary endpoint was complete elimination of CPE carriage 2 weeks after FMT. A secondary endpoint for decolonization was set at 3 months post-FMT. Successful decolonization was defined by 2+ consecutive negative rectal swabs as determined by both culture and PCR. Shotgun metagenomic sequencing was performed to assess gut microbiota composition of donors and recipients before and after FMT.Faecalibacterium prausnitzii, Parabacteroides distasonis, Collinsella aerofaciens, Alistipes finegoldii and Blautia_A sp900066335 were associated with response . Furthermore, CPE abundance levels at baseline were significantly higher in non-responders than in responders .Twenty patients colonized with CPE were included, 72.5 \u00b1 18.8 years. Median duration of carriage of CPE before FMT was 62.5 days (IQR 48.75-122.5). At 3 months post-FMT, 40% (n=8/20) of patients were successfully decolonized, while 20% (n=4/20) meeting the 2-week primary endpoint. Kaplan-Meier curves between patients in the FMT cohort and those in the control group (n=82) revealed the same rate of decolonization over time (p=0.9). Microbiota composition analyses post-FMT revealed significantly higher bacterial species richness and alpha diversity in responders versus non-responders , and specific taxa including Box and whisker plots of the percent relative abundance for the indicated species in samples from patients with CRE clearance on day 14 , and patients without CRE clearance on day 14 (orange). The median (\u00b1interquartile range) is plotted for each species in each group. Whiskers extend to the lowest and highest values no greater than 1.5x the interquartile range from the closest hinge. The displayed taxa were significantly altered between patients with and without CRE clearance at day 14 across all samples, with q-values below 0.01 (MaAslin2 log-transformed linear model).Box and whisker plots indicating the cumulative percent relative abundance of CRE species in samples from patients with CRE clearance on day 14  and patients without CRE clearance on day 14 (orange). The median (\u00b1interquartile range) is plotted for each group at the indicated timepoints. Whiskers extend to the lowest and highest values no greater than 1.5x the interquartile range from the closest hinge. Patients with CRE clearance on day 14 have significantly lower CRE relative abundance than patients without CRE clearance on day 14 at baseline and 1 week post-FMT (Wilcoxen Rank-Sum test with FDR adjustment).FMT administration led to complete CPE eradication in a subset of colonized patients but did not achieve statistical significance. Response to FMT was not donor-dependent and correlated with the transfer of specific bacteria taxa and CPE colonization levels.Andrea Watson, PhD, Vedanta Biosciences: Advisor/Consultant|Vedanta Biosciences: Honoraria Gianluca Galazzo, PhD, Vedanta Biosciences: Advisor/Consultant|Vedanta Biosciences: Honoraria Ed J. Kuijper, Prof. Dr., Vedanta Biosciences: Advisor/Consultant Silvia Caballero, PhD, Vedanta Biosciences: Advisor/Consultant|Vedanta Biosciences: Board Member|Vedanta Biosciences: Ownership Interest"}
+{"text": "Herpes zoster (HZ) results from the reactivation of latent varicella-zoster virus and commonly affects older or immunocompromised patients. Clinical manifestations include painful vesicular skin eruptions that normally respect a dermatomal distribution. Prognosis is normaly favorable but a minority of patients develop complications such as generalized infection, ocular involvement, meningoencephalitis or visceral dissemination. Post-herpetic neuralgia and secondary bacterial infections are frequent complications. Preventive strategies like vaccination are important to mitigate the burden of HZ.This retrospective study reviewed the charts of all patients older than 18 years hospitalized in a Portuguese hospital with the diagnosis of herpes zoster infection diagnosis between January 1, 2012 and December 31, 2022.The study included 152 patients with a mean age of 70 years old; 58% were female. In terms of clinical manifestations: 47% suffered from localized herpes zoster (thoracic dermatome in 40%) and only 11% had generalized zoster. Other manifestations included meningitis/encephalitis (7%), keratitis (n=4) and Ramsay-Hunt syndrom (n=3). About half of patients (51%) had an identified cause of imunodepression upon hospital admission: 25% had malignancy on chemotherapy and 6% had a reumatic disead on immunossupressive therapy, only 7 patients were HIV positive. Most patients (78%) were treated with aciclovir (mean duration 9 days). Post-herpetic neuralgia and secondary bacterial infections were common . All-cause in-hospital mortality was 6%.Patients hospitalized for herpes zoster are frequently elderly people with comorbidities, especially cancer. Thoracic envolvement was most frequent in localized infection. Post-herpetic neuralgia and bacterial infections were frequent complications. Its important to implement preventive strategies such as vaccination for herpes zoster to prevent shingles and post-herpetic neuralgia in older adults, especially in those who are immunosupressed. This measure would probably help mitigate the burden of this disease in this population.All Authors: No reported disclosures"}
+{"text": "After performing laparoscopic unilateral adnexectomy in a 53-year-old woman for a rapidly grown unilateral adnexal mass, pathologists reported a primary ovarian leiomyoma with no genuine ovarian tissue. This rare diagnosis is found in less than 100 reports after systematic literature review, a greater number of asymptomatic ovarian leiomyomas can be expected. Thorough preoperative diagnostic measures are essential as rare cases of malignancy have been described. A 53-year-old postmenopausal woman was referred to our tertiary referral university hospital with a rapidly grown unilateral adnexal mass and abnormal sonogram. She experienced no specific symptoms or discomfort, CA-125 level was normal. We carried out IOTA ADNEX model-sonography and estimated a 95% probability for benignity with suspected ovarian fibroma (Fig.\u00a0Discussion: systematic literature review revealed less than 100 reports of primary ovarian leiomyomas, with some cases finding residual ovarian tissue . Up to 8"}
+{"text": "Wastewater (WW)-based surveillance of SARS-CoV-2 is an established tool for COVID-19 pandemic monitoring, providing a leading indicator to cases and hospitalizations. However, its potential for monitoring endemic respiratory viruses has not been elucidated. We assessed the occurrence of Influenza A (IAV), Influenza B (IBV), and Respiratory Syncytial Virus (RSV) RNA in WW treatment plants (WWTP) in Alberta's largest city and its correlation with clinical disease.Twenty-four-hour composite WW samples were collected weekly from three WWTP in Calgary between Mar'22/Apr'23. WW was concentrated and RNA extracted using the 4S-Silica Column. Viral RNA was quantified using a commercial TaqMan assay  and established RT-qPCR assays targeting: the hemagglutinin gene (IBV) and nucleocapsid gene (RSV). Flow rates at each WWTP were used to create a composite city-wide metric for each target. WW values were compared to clinical data reported by Alberta Health Services and reported as total cases and test positivity rates across the Calgary Zone (or entire Province if granular data was unavailable).r= 0.83, p< 0.0001 for signals recorded the same week, and r= 0.85, p< 0.0001 for the prior week). The positive correlation existed regardless of influenza typed as H3N2, H1N1 or untyped. Furthermore, specimen test positivity rates across the entire province correlated with Calgary's WW measured IAV . The IBV WW signal correlated with clinical cases  and test positivity rates  across the entire province. Calgary's RSV WW correlated with clinical cases  and test positivity rates  across Alberta.IAV peaked in Calgary's WW between November-December 2022, IBV between February-April 2023 and RSV between November 2022-February 2023 . The composite-IAV signal positively correlated with weekly confirmed clinical cases within the Calgary Zone (Spearman's There is a peak in the RSV signal from November 2022 to February 2023, with a correlation to Alberta\u2019s weekly confirmed clinical cases.WW surveillance is an emerging technology enabling objective, unbiased and inclusive population-level monitoring of endemic respiratory viral infections.All Authors: No reported disclosures"}
+{"text": "Patients receiving outpatient parenteral antimicrobial therapy (OPAT) are often medically complex and require carefully tailored treatments to address severe and often concomitant infections.We conducted a cohort study of patients enrolled in the University of North Carolina Medical Center OPAT program between March 2015 and December 2022 (2358 OPAT courses among 2072 unique patients). Patients were followed from OPAT regimen initiation (day 0) until observed treatment stop date, based on a grace period of 5 days to confirm discontinuation. Using hierarchical and mutually exclusive categorization schema, we classified patients into 1 of 10 infection diagnosis groups , and classified all observed antibiotic cocktails  into 18 treatments . For each patient, we assessed their planned OPAT duration to classify their observed discontinuation as \u201cplanned,\u201d \u201cunanticipated early stop,\u201d or \u201cunanticipated prolonged treatment.\u201d Stratified by infection diagnosis and treatment classifications, we used stacked bar charts to describe treatment heterogeneity, and Aalen-Johansen-based cumulative incidence curves to estimate occurrence of each type of discontinuation amid competing events.The cohort was 59.7% male with median age 56 years (IQR 45-66); the most common infection diagnosis was osteomyelitis +/- diabetic foot infection . Medication exposures were heterogeneous within and across infection diagnoses . Median planned OPAT duration was 36 days (middle 90% 15-44). Overall cumulative incidence of unanticipated early discontinuation was 11.9%; overall incidence of unanticipated prolonged treatment was 22.9% .Day-level data on medication use in this registry provided evidence of heterogeneity in medication exposure and unplanned discontinuation from OPAT, within and across infection diagnoses. These data highlight the need for multi-layered ascertainment of medication exposure, microorganisms, and infection diagnosis in this medically complex patient population to inform surveillance for adverse effects and comparative effectiveness research for post-discharge antibiotic treatment.Asher J. Schranz, MD, MPH, WoltersKluwer: Honoraria Alan C. Kinlaw, PhD, MSPH, Genentech: Grant/Research Support"}
+{"text": "ARL13B, SMO, and GLI2 expression are more aggressive, but the relationship to cilia is unclear. Previous studies have showed that increasing ARL13B in glioblastoma cells promoted ciliary SMO accumulation, independent of exogenous SHH addition. Here, we show that SMO accumulation is due to increased ciliary, but not extraciliary, ARL13B. Increasing ARL13B expression promotes the accumulation of both activated SMO and GLI2 in glioma cilia. ARL13B-driven increases in ciliary SMO and GLI2 are resistant to SMO inhibitors, GDC-0449, and cyclopamine. Surprisingly, ARL13B-induced changes in ciliary SMO/GLI2 did not correlate with canonical changes in downstream SHH pathway genes. However, glioma cell lines whose cilia overexpress WT but not guanine exchange factor-deficient ARL13B, display reduced INPP5e, a ciliary membrane component whose depletion may favor SMO/GLI2 enrichment. Glioma cells overexpressing ARL13B also display reduced ciliary intraflagellar transport 88 (IFT88), suggesting that altered retrograde transport could further promote SMO/GLI accumulation. Collectively, our data suggest that factors increasing ARL13B expression in glioma cells may promote both changes in ciliary membrane characteristics and IFT proteins, leading to the accumulation of drug-resistant SMO and GLI. The downstream targets and consequences of these ciliary changes require further investigation.ADP-ribosylation factor-like protein 13B (ARL13B), a regulatory GTPase and guanine exchange factor (GEF), enriches in primary cilia and promotes tumorigenesis in part by regulating Smoothened (SMO), GLI, and Sonic Hedgehog (SHH) signaling. Gliomas with increased  Glioblastoma (GBM) is the most lethal form of primary brain tumors in adults, presumably originating from a transformed glial cell lineage . GBMs al+ cilia and displayed prolonged survival .,25.ARL13pression . We showpression , we finds ARL13B ,25,74. G"}
+{"text": "We generated metagenome sequences of the GU0601 sample collected from the Han River and constructed metagenome-assembled genomes (MAGs) to identify their bacterial composition. We identified six MAGs belonging to Alphaproteobacteria, Cyanobacteria, and Flavobacteria. Freshwater environments are important habitats in nutrient cycling and food supply for diverse organisms and are necessary for industrial activities , 2. To sde novo assembly function in Geneious Prime (v2023.1.2). We manually confirmed and accepted each re-assembled MAG that allowed for identical (or one nucleotide mismatched) overlapping between the re-assembled contigs. We predicted and annotated protein-coding sequences (CDSs), 16S rRNA, and tRNA of the MAGs by prokka program (v1.11) with default options (To predict metagenome-assembled genomes (MAGs), we analyzed our metagenome assembly using the MetaBAT2 program with default options . A total options . To vali options . To defi options . As a re options  using Ge"}
+{"text": "A novel, circular DNA molecule was identified in the serum of 4-week-old Holstein calves via Illumina sequencing. Comparisons with the NCBI nucleotide data bank indicate that the sequence is unique. The circle contains one predicted open reading frame (ORF), whose translated protein sequence shows high similarity to bacterial Rep proteins. Bos taurus) breeds , and 930\u2009ng were added to a 40-\u03bcL rolling-circle amplification (RCA) reaction with \u03c629 polymerase and random hexamer primers (Bovine meat and milk factors (BMMFs) are circular DNAs claimed to be involved in the development of cancer and to be present only in European cattle  breeds . Since B6 paired-end reads . The contigs were assembled with Unicycler v0.4.4 (Fragment libraries were prepared using the Illumina DNA prep (M) Tagmentation Kit with Nextera DNA combinatorial dual (CD) indexes and sequenced using a NextSeq midoutput flow cell (300 cycles) on a NextSeq 550 sequencer. The raw data were quality controlled and trimmed using fastp , yieldinStreptococcus dysgalactiae (NCBI protein accession number MSU87956.1) showing 99% sequence coverage and 58% identity. Multiple nucleotide BLAST . However, a three-dimensional structure prediction using RoseTTAFold  of 651 bases, whose translated protein sequence via BLASTP (PRJNA900058.The sequence of Kb273 has been deposited in GenBank under the accession number OP796838 and the associated raw reads under BioProject accession number"}
+{"text": "Figure S1). She reported a history of palpitations, chest pain, hot flashes, and feeling more short-tempered lately. Due to significantly elevated high-sensitivity cardiac troponin T (3614 ng/L) and N-terminal prohormone of brain natriuretic peptide (7208 ng/L), coronary artery disease was ruled out by invasive coronary angiography (see Video S1). Echocardiography showed a severely impaired left ventricular ejection fraction (LVEF 15%) with apical akinesia and hypercontractility of the basal segments (see Video S2). Cardiovascular magnetic resonance imaging confirmed the severely impaired ejection fraction (LVEF 29%) and regional wall motion abnormalities . T2 mapping revealed myocardial oedema in the apical two-thirds of the myocardium with corresponding mildly elevated myocardial extracellular volume (C). There was no myocardial infarction or focal fibrosis on late gadolinium enhancement images (D). Free serum metanephrine, normetanephrine, and chromogranin were significantly elevated. A dedicated abdominal magnetic resonance imaging demonstrated a round, well-demarcated tumour of the right adrenal gland (38 \u00d7 45 \u00d7 46 mm) which corroborated the diagnosis of an adrenal phaeochromocytoma with secondary takotsubo syndrome. Alpha and beta adrenergic blockade were administered prior to laparoscopic right adrenalectomy, and a 50 \u00d7 40 \u00d7 35 mm measuring tumour was removed (F + G). Histopathology confirmed the diagnosis of a phaeochromocytoma with small nests of basophilic neuroendocrine cells expressing chromogranin A (H). In a follow-up echocardiography 2 weeks post-surgery, LVEF and wall motion abnormalities had completely recovered (see Video S4). This case illustrates the rare (reversible) condition of a secondary takotsubo syndrome due to a phaeochromocytoma-induced catecholamine storm.An otherwise healthy 41-year-old female patient presented with an onset of cardiogenic shock . Electrocardiogram revealed sinus tachycardia without evidence of ischaemia (see European Heart Journal - Cardiovascular Imaging online.Consent: The patient consented to the use of her anonymized health care data for publication as a case report.Data availability: The data underlying this article will be shared on reasonable request to the corresponding author.jead053_Supplementary_DataClick here for additional data file."}
+{"text": "Mycobacterium tuberculosis (Mtb) infection defined as persistently negative tuberculin skin test (TST) and interferon gamma release assay (IGRA) reactivity among highly exposed contacts (RSTR phenotype).A mechanistic understanding of uncommon immune outcomes such as resistance to infection has led to the development of novel therapies. Using gene level analytic methods, we previously found distinct monocyte transcriptional responses associated with resistance to Using transcript isoform analyses, we aimed to identify novel RSTR-associated genes hypothesizing that previous gene-level differential expression analysis obscures isoform-specific differences that contribute to phenotype.M. tuberculosis (H37Rv) or left unstimulated (media) prior to RNA isolation and sequencing. RSTR-associated gene expression was then identified using differential transcript isoform analysis.Monocytes from 49 RSTR versus 52 subjects with latent Mtb infection (LTBI) were infected with PDE4A and ZEB2, which each had multiple DETs with higher expression among RSTR subjects, and ACSL4 and GAPDH that each had a single transcript isoform associated with RSTR.We identified 81 differentially expressed transcripts (DETs) in 70 genes (FDR <0.05) comparing RSTR and LTBI phenotypes with the majority (n = 79 DETs) identified under Mtb-stimulated conditions. Seventeen of these genes were previously identified with gene-level bulk RNAseq analyses including genes in the IFN\u03b3 response that had increased expression among LTBI subjects, findings consistent with a clinical phenotype based on IGRA reactivity. Among the subset of 23 genes with positive differential expression among Mtb-infected RSTR monocytes, 13 were not previously identified. These novel DET genes included Transcript isoform-specific analyses identify transcriptional associations, such as those associated with resistance to TST/IGRA conversion, that are obscured when using gene-level approaches. These findings should be validated with additional RSTR cohorts and whether the newly identified candidate resistance genes directly influence the monocyte Mtb response requires functional study. Mycobacterium tuberculosis (Mtb) results in diverse outcomes including tuberculosis disease (TB), asymptomatic infection with risk of progression to TB, and clearance of the pathogen through innate and/or cellular immune responses. The host-pathogen determinants that result in clearance of the bacillus are poorly understood, in part due to the limitations in microbiologically defining these phenotypic outcomes. Clinically, the term latent Mtb infection (LTBI) currently describes asymptomatic and TB immunoreactive subjects as defined by the interferon gamma (IFN\u03b3) release assay (IGRA) or the tuberculin skin test (TST). While TB immunoreactivity is an imperfect surrogate for Mtb infection . AmoR 0.143)  of the 7PDE4A, ZEB2 and TIMP1  and are obscured using gene-level analysis.To further explore transcript expression patterns of these DETs of interest, we contrasted fold-change (RSTR versus LTBI) expression for each DET and other transcripts within that gene and noted two patterns . First, nd TIMP1 . Second,and LST1  had a siPDE4A, ZEB2, TIMP1 and ACSL4 (FDR <0.05). A correlation between the FDR for each DET and its corresponding RSTR DEG incorporating these adjustments identifies IFNG, CIITA, IRF1, HAPLN3, IRF8, TIMP1, ZEB2 and PDE4A among the most significant hits that are robust to both analyses and suggests they have the strongest association with biologic differences in the monocyte Mtb response between LTBI and RSTR donors  and performed kinship-adjusted differential gene expression analysis (RSTR versus LTBI comparison) using lmekin for the media or Mtb condition. The majority (47 of 67) of these genes remained DEGs , and amoR donors . OverallIFNG, CIITA, IRF1, STAT1) among subjects with LTBI. Yet 51 of the 68 genes with at least one DET were not previously identified using gene-level analysis. Several of these newly identified genes with significantly higher transcript expression among RSTR donors (Sleuth FDR <0.05) included PDE4A, ZEB2, ACSL4, LST1 and GAPDH. We conclude that isoform-level analysis identifies genes previously ignored by gene-level analysis but the role that these genes play, if any, during resistance to TST/IGRA conversion must be evaluated experimentally.We explored whether differential transcript isoform expression analysis provides additional biologic insight into mechanisms of TST/IGRA resistance. Compared to a previous gene-level analysis of monocyte bulk RNAseq data, our transcript level analysis yielded highly consistent results including higher transcript-specific expression of genes involved with IFN\u03b3 and inflammatory signaling  signaling [HDAC2 and expression has been linked to tumorigenesis [Our results suggest several mechanisms that may contribute to the monocyte Mtb response and influence TST/IGRA conversion. By regulating intracellular cyclic nucleotide concentrations, phosphodiesterase 4A (PDE4A) expression in immune cells results in increased inflammatory mediator secretion and is the target of various FDA approved immune modulators . In a prectively . DISC1 iectively . Zinc fiignaling . ZEB2 geigenesis  and reguigenesis \u201328. Netwigenesis . Interesigenesis  providinACSL4  and GAPDH  each of which are regulators of carbon metabolism. Mtb-induced metabolic perturbations within the host macrophage are well described [ACSL4, catalyzes the formation of long-chain acyl-CoA from free fatty acids (FFAs) targeting them for subsequent synthetic or degradative pathways whereas glyceraldehyde-3-phosphate dehydrogenase, encoded by GAPDH, plays a central role in glycolysis and gluconeogenesis while coupling its metabolic activity to NADH synthesis that supports mitochondrial oxidative phosphorylation. Taken together, the DETs identified here with increased expression among RSTR monocytes offer plausible targets for inflammatory and immunometabolic studies to delineate the roles these genes and pathways play in mediating resistance to TST/IGRA conversion.Interestingly, among our top DETs with increased RSTR expression were escribed \u201333, but escribed . Acyl-CoPDE4A and ZEB2 each had multiple DETs with increased expression among RSTR donors in the Mtb condition whereas these genes were not identified in the lmekin interaction model. The discordant findings may reflect the effects of other transcripts within each gene that minimize the gene-level fold-change or differences in degrees of freedom and power between the two models. Importantly, our kinship-adjusted secondary gene-level analysis (lmekin) found that ZEB2 and PDE4A were among DEGs with the strongest RSTR associations supporting the utility of the contrast model and filtering gene lists using isoform differential expression. In contrast, we also found transcripts such as ACSL4-213 and GAPDH-201 with expression that strongly associated with the RSTR phenotype while all other transcript isoforms within the same genes had no association. Since these transcripts are among the most expressed isoforms in our analysis and are the reference protein-coding transcripts for their respective genes, these expression differences are likely to translate to biological effects and supports the robustness of DET level findings. These genes were also confirmed in our secondary analysis but missed the original gene-level analysis, potentially due to contributions from the non-protein coding transcripts and genome-wide false discovery correction.The identification of new transcripts, or transcripts with stronger RSTR associations compared to our previous gene-level analysis, could reflect biological or methodological differences. The previous gene-level expression model incorporated the interaction between stimulation (Media\u2013Mtb) and phenotype (RSTR\u2013LTBI) to identify DEGs and adjusted for kinship using lmekin. We identified no DETs (FDR <0.05) when incorporating a similar interaction model without kinship since Sleuth does not support matrix random effects . HoweverOur study has several limitations including its exploratory nature requiring validation either through transcriptional or proteomic profiling of separate RSTR cohorts or through mechanistic studies that confirm these DETs modulate monocyte Mtb responses. We hypothesized that mRNA splice variant analysis would yield novel insight as compared to traditional gene-level differential expression, and while additional DET genes were identified, our overall findings are highly consistent between transcript isoform and gene-level approaches. Whether similar host gene pathways would be identified among RSTR subjects following other Mtb lineages or clinical strains should be considered since our study used only the H37Rv strain lineage 4) as cell availability from participants was limited. Finally, TB immunoreactivity as defined by TST/IGRA is only a surrogate for Mtb exposure and not Mtb infection, which would require a direct microbiologic diagnostic test that is not currently available. The RSTR and LTBI subjects included in this study show immunologic evidence of Mtb exposure  as cell , 8. Our S1 FigSigma plots demonstrate improved fit for ~80% of transcripts when the model is adjusted for sequencing batch, whereas only 28% and 37% of transcripts have improved fit when the model is adjusted for age and sex, respectively. All three adjustments were applied to the final model.(TIF)Click here for additional data file.S2 FigGenes (n = 67) with \u22651 differentially expressed transcript  either from the media (n = 2 DETs) or Mtb-stimulated condition (n = 77 DETs) were analyzed by STRING (string-db.org) using known interactions , co-expression and text mining. One gene (AC055839.2) did not map to STRING. Nodes represent genes. Edges are combined scores >400 (medium confidence) with thickness indicating score value.(TIF)Click here for additional data file.S1 TableDifferentially expressed transcripts (DETs) for the RSTR\u2014LTBI comparison are listed for the media (S1A worksheet) and Mtb stimulated conditions (S1B worksheet) and ranked by false discovery rate (FDR). Direction indicates whether expression is increased within the RSTR group (up) or LTBI group (down). Genes with \u22651 DET (FDR <0.05) are also noted (Y/N) if they were previously identified  as diffe(XLSX)Click here for additional data file.S1 ChecklistEthical considerations, permits and authorship and Human subjects research is available.PLOS checklist regarding (DOCX)Click here for additional data file."}
+{"text": "V/Q) mismatch within the lungs. Several methods have been proposed, some of them neglecting the absolute value of alveolar ventilation (VA) and cardiac output (QC). Whether this omission results in acceptable bias is unknown.Electrical impedance tomography (EIT) can be used to assess ventilation/perfusion (V/Q maps of 25 ARDS patients were computed once considering (absolute V/Q map) and once neglecting (relative V/Q map) the value of QC and VA. Previously published indices of V/Q mismatch were computed using absolute V/Q maps and relative V/Q maps. Indices computed with relative V/Q maps were compared to their counterparts computed using absolute V/Q maps.Pixel-level VA/QC)\u2009>\u20091, relative shunt fraction was significantly higher than absolute shunt fraction , while relative dead space fraction was significantly lower than absolute dead space fraction . Relative wasted ventilation was significantly lower than the absolute wasted ventilation , while relative wasted perfusion was significantly higher than absolute wasted perfusion . The opposite findings were retrieved in the four patients with VA/QC\u2009<\u20091.Among 21 patients with ratio of alveolar ventilation to cardiac output (V/Q mismatch indices using EIT in ARDS patients results in significant bias, whose direction depends on the VA/QC ratio value.Neglecting cardiac output and alveolar ventilation when assessing The online version contains supplementary material available at 10.1186/s13054-023-04467-w. V/Q ratios have been reported   vs 11% (7\u201319), respectively, p\u2009<\u20090.001; Bland\u2013Altman comparison: bias 5%, LAL \u2212\u00a01%, UAL 11%]. Bland\u2013Altman plots are available in the supplement  was intermediate in order not to promote extreme values of alveolar ventilation to cardiac output ratios.Patients were assessed at a single PEEP level. However, the level chosen , this risk seems minimal.Our study has several limitations:V/Q mismatch indices using EIT in ARDS patients results in significant bias, whose direction depends on the ratio of alveolar ventilation to cardiac output.In conclusion, neglecting cardiac output and alveolar ventilation when assessing Additional file 1.\u00a0Supplementary appendix: detailed methods and supplemental results."}
+{"text": "Sporadic clusters of healthcare-associated coronavirus disease 2019 (COVID-19) occurred despite intense rostered routine surveillance and a highly vaccinated healthcare worker (HCW) population, during a community surge of the severe acute respiratory coronavirus virus 2 (SARS-CoV-2) B.1.617.2 \u03b4 (delta) variant. Genomic analysis facilitated timely cluster detection and uncovered additional linkages via HCWs moving between clinical areas and among HCWs sharing a common lunch area, enabling early intervention. However, healthcare-associated outbreaks persist with emergence of more transmissible variants, such as the severe acute respiratory coronavirus virus 2 (SARS-CoV-2) B.1.617.2 \u03b4 (delta) variant. Increased transmissibility and shortened incubation periods of novel SARS-CoV-2 variants further challenge the ability of outbreak investigation in guiding real-time exposure management given its time-consuming nature. Whole-genome sequencing (WGS) can potentially supplement the investigation of COVID-19 outbreaks in a clinically relevant timeframe.Strict infection prevention measures may lower secondary attack rates of coronavirus disease 2019 (COVID-19) in healthcare facilities. Large community outbreaks attributed to the B.1.617.2 variant provided impetus for heightened infection prevention measures, including surveillance via routine rostered testing of healthcare workers (HCWs) and patients. We utilized epidemiological investigations and WGS to provide insights into potential nosocomial COVID-19 clusters.In Singapore, enhanced infection prevention measures initially contained nosocomial spread. The emergence of the B.1.617.2 variant in 2020, however, led to a major healthcare-associated COVID-19 outbreak.Our healthcare campus hosts a 1,785-bed tertiary-care hospital (mostly 5\u20136-bed cohort cubicles), a 545-bed community hospital, the national cardiac center and a large cancer center. Almost 13,000 HCWs work on campus. Vaccination uptake among HCWs was high, with \u226590.0% receiving 2 doses of mRNA vaccines (Pfizer/Moderna) by the end of June 2021. In contrast, 65.0% of inpatients were fully vaccinated by the end of June 2021. The study period spanned 5 months from June 21, 2021, through November 22, 2021. HCWs donned N95 respirators in all clinical areas as a mandatory minimum; HCWs in isolation areas donned N95 respirators and disposable gloves, long-sleeved gowns, and face shields.Suspected COVID-19 cases with epidemiological risk  were admitted to negative-pressure single-bed isolation rooms, whereas patients without epidemiological risk presenting with clinical syndromes compatible with COVID-19 were isolated in reduced-density cohort cubicles in the respiratory surveillance ward until SARS-CoV-2 was excluded.All symptomatic HCWs had access to free polymerase chain reaction (PCR) testing at the staff clinic. Routine rostered testing was conducted for all asymptomatic HCWs beginning in April 2021, initially with fortnightly PCR. Given surging community transmission, HCW surveillance was stepped up to twice-weekly rapid antigen detection beginning September 29, 2021. HCWs working in high-risk inpatient areas were required to obtain confirmatory PCR testing. Inpatient screening was instituted from June 2021 via PCR testing on admission and subsequent weekly testing. HCWs and patients with significant close contact with a PCR-confirmed COVID-19 patient underwent a 14-day enhanced surveillance regimen. Patients were tested via PCR on days 1, 4, 7, and 10 and via daily rapid antigen detection until day 14. HCWs were tested via PCR on days 1 and 14 and via daily rapid antigen detection until day 14.:Community onset: PCR positive \u22642 days after admissionIndeterminate healthcare associated: PCR positive 3\u20137 days after admissionProbable healthcare associated: PCR positive 8\u201314 days after admissionDefinite healthcare associated: PCR positive \u226515 days after admissionAll COVID-19 inpatient cases were classified into community-onset or potentially healthcare-associated infection as follows For HCWs, significant close contact was defined as contact within 2 m of the index for \u226515 minutes. Significant unprotected contact was defined as not having utilized N95 respirators during a significant close contact episode and/or not having donned disposable gowns and gloves during episodes of prolonged physical contact. HCWs with significant unprotected contact were furloughed during the enhanced surveillance period.Incubation periods were defined as 1\u201314 days prior to positive PCR. The infectious period was defined as 2 days prior to symptom onset if symptomatic or 7 days prior to positive PCR if asymptomatic to 10 days after positive PCR. Significant patient close contact was defined as contact within 2 m of the index case for \u226515 minutes during the index case\u2019s infectious period.Epidemiological clusters were defined as \u22652 COVID-19 cases among patients and HCWs in the same setting . These cluster outbreaks ended when no cases were diagnosed for 14 days. Genomic clusters were detected based on whole-genome similarity analysis, when sequences were \u22643 SNPs different and fell in the same branch of the genome similarity tree.Contact tracing was performed for all potentially healthcare-associated COVID-19 inpatient cases and all community-onset COVID-19 inpatient cases initially managed outside isolation areas, as well as all HCWs at work during their infective periods. Cases with a cycle threshold (Ct) value <31 were sent for WGS using the ARTIC protocol on Oxford Nanopore minION sequencers  to enable fortnightly turnaround.Ethics approval for outbreak investigation was not required under our institutional review board guidelines.1 online). Overall, 352 HCWs with COVID-19 were identified during the study period. The odds ratio (OR) of COVID-19 acquisition among exposed inpatients, compared with exposed HCWs, was 14.8 .Over 5 months, 1,523 (6.3%) of 24,361 admissions had COVID-19. Most were diagnosed <48 hours after admission . Only 45 (3.0%) of 1,523 cases were classified as potentially healthcare associated, with 31 (68.9%) of these 45 detected >7 days after admission. Also, 12 (26.7%) of these 45 cases were reclassified as plausible community-onset cases  (Supplementary Table 2 online). Also, 6 clusters were mixed (comprising HCWs and inpatients); 6 comprised inpatients only; and 8 occurred among HCWs. Apart from the general wards, clusters were also detected in oncology and renal wards. Contact tracing did not reveal linkages at the dialysis center . Of 8 HCW clusters, 7 involved staff sharing work areas; a large cluster involved cleaners working in different areas but who mingled at a common lunch area (Supplementary Table 2 online). WGS was utilized to link previously unlinked clusters. Evidence of genomic linkage was identified between the cluster of cleaners sharing a common lunch area and the renal-ward inpatient cluster  of 45 healthcare-associated inpatient cases and 203 (57.7%) of 352 HCW cases. The remaining 247 cases were community-onset cases initially managed outside isolation areas. Epidemiological investigations revealed 20 clusters . For the cluster in the respiratory surveillance ward, 3 patients were exposed to the index patient for 5 hours, and 1 patient tested positive upon readmission at day 9 after exposure. However, these 2 sequences were not linked (Fig. In isolation areas, WGS was also utilized to rule out transmission. Two clusters were reported from isolation areas: 2 inpatients admitted to a respiratory surveillance ward and 2 nurses working in the container-isolation ward that housed COVID-19 patients in negative-pressure\u2013modified containers (Supplementary Table  WGS allowed earlier identification of transmissions based on locations other than ward of diagnosis, which facilitated subsequent intervention. The use of genomic analysis to disprove nosocomial transmission in high-risk isolation areas, despite classical epidemiological methods suggesting linkage, was crucial in maintaining staff confidence in infection prevention protocols.Genomic analysis enabled linkage of sporadic outbreaks, prompting further investigation that uncovered additional linkages via HCWs who moved between multiple wards and clinical areas but shared a common lunch area. Timely recognition of outbreaks spanning multiple areas remains challenging, given resources required to track patients and HCWs over space and time.This study had several limitations. Although comprehensive, sequencing was not available for all healthcare-associated infections, given difficulties with WGS at low viral loads. Additionally, these findings cannot be extrapolated to future variants with different immune escape properties.In conclusion, sporadic healthcare-associated COVID-19 clusters occurred despite intense surveillance and enhanced infection prevention measures. Genomic analysis facilitated early cluster detection and timely intervention."}
+{"text": "Adjunctive clindamycin has survival benefit in invasive Group A streptococcus (GAS) infections. Like clindamycin, linezolid also leads to decreased toxin and virulence factor production. However, rising clindamycin resistance among GAS isolates and inadequate clinical data on linezolid both offer pause on which to choose. We examined the impact of adjunctive clindamycin vs. linezolid on survival among patients with GAS bloodstream infections (BSI) in the presence and absence of clindamycin resistant (clinda-R) isolatesClinical characteristics, antimicrobial susceptibility testing (AST), and antibiotic therapy were examined for unique adult inpatient encounters with GAS BSIs in the PINC-AI Database. Patients treated with a \u03b2-lactam for \u22653 days \u00b13 days of culture who received clindamycin \u00b13 days of culture were overlap weighted on a propensity-score to those who received linezolid using basine patient and hospital factors. The primary outcome was odds ratio (OR) of in-hospital mortality associated with clindamycin (vs linezolid). The secondary outcome was length of stay (LOS) among survivors. Subgroups analyses were conducted excluding clindamycin receipients with clinda-R isolates (subgroup 1) and also missing clindamycin AST.Selection of patients with Group A streptococcal blood stream infections. The database was queried for inpatients (aged \u226518 years) with blood culture displaying growth of Group A streptococcus, filtered on the basis of receiving \u03b2-lactam antibiotics within 3 days either side of culture sampling for a minimum duration of 3 days and received either adjunctive clindamycin or linezolid treatment within 3 days either side of culture sampling.Figure 1). Overlap weighting resulted in well balanced groups . In the overlap weighted cohort, mortality risk was similar between recipients of clindamycin  vs linezolid . Among survivors median[interquartile range] LOS was similar between the two groups . Removing those with clinda-R isolates (N=84) and also missing AST (N=166) yielded similar results .Of 3019 \u03b2-lactam\u2013treated inpatients with GAS BSI, 500 (17%) received clindamycin and 160 (5%) received linezolid. The prevalence of clinda-R isolates was 19%;1 isolate was linezolid resistant and excluded (Standardized mean differences for covariates included in the propensity score generation averaged across exposure categories in the unweighted cohort (blue triangles) and overlap weighted cohort weight (red circles). After overlap weighting, the mean standard difference at each variable assessed was zero . Abbreviations: ICU: intensive care unit, IVIG: intravenous immunoglobulin, NSTI: necrotizing soft tissue infectionThe ORs (95% CIs) of in-hospital mortality (including discharge to hospice) in the primary analysis and subgroup analysis with patients withclindamycin resistant isolates (subgroup 1) and those with clindamycin resistant isolates and missing clindamycin susceptibility results (subgroup 2) removed from clindamycin group. Abbreviations: CI: confidence intervalAmong \u03b2-lactam-treated patients with GAS BSI, linezolid and clindamycin displayed comparable effectiveness as adjunctive antitoxin agents. Similar intrinsic effectiveness  supports linezolid as an alternative even in low clinda-R settings.Ahmed Babiker, MBBS, Roche: Advisor/Consultant Morgan Walker, MD, Cytovale: Advisor/Consultant"}
+{"text": "Correction: BMC Musculoskelet Disord 24, 139 (2023)10.1186/s12891-023-06239-7Following publication of the original article , the autThe incorrect author names are:Muratori FrancescoScanferla RobertoRoselli GiulianaFrenos FilippoCampanacci Domenico AndreaThe correct author names are:Francesco MuratoriRoberto ScanferlaGiuliana RoselliFilippo FrenosDomenico Andrea CampanacciThe author group has been updated above and the original article  has been"}
+{"text": "Myxedema crisis (MC) refers to an unusual state of regulatory dysfunction precipitated by uncontrolled hypothyroidism. The pathogenic consequences of MC are broad and may contribute to significant bodily decompensation across multiple organ systems. However, shock-induced ischemic optic neuropathy (SION) in this setting has not been reported previously. Here, we present the case of a 76-year-old female with presumed bilateral optic neuropathy following abdominal surgery. The patient experienced a prolonged and complicated postoperative course in which she remained off supplemental levothyroxine. Subsequently, her clinical status deteriorated until she met diagnostic criteria for acute decompensated hypothyroidism (MC). Upon awakening from a comatose state, she reported significant vision loss. A neuro-ophthalmologic evaluation later confirmed significant constriction of her visual fields, optic disc pallor, and global retinal nerve fiber layer loss consistent with nonarteritic ischemic optic neuropathy. Acute decompensated hypothyroidism (myxedema crisis (MC)) is a potentially life-threatening but uncommon complication of untreated hypothyroidism. Although multi-system organ failure, hypotension, and shock can occur in MC, optic neuropathy is a previously unreported complication in the English language ophthalmic literature.Shock-induced ischemic optic neuropathy (SION) refers to vision loss in the setting of severe systemic hypotension with subsequent hypoperfusion of the optic nerve. SION represents a subtype of nonarteritic ischemic optic neuropathy and has previously been described after sudden and dramatic blood loss. Postoperative vision loss resulting from general surgical, neurosurgical, spine, and cardiac procedures have all been attributed to SION previously . Here, wA 76-year-old white female presented to the emergency department with a two-day history of progressive abdominal pain. An abdominal computed tomography (CT) scan demonstrated an internal hernia complicated by small bowel obstruction. After failing conservative medical management, the patient underwent an uncomplicated exploratory laparotomy with hernia reduction and minimal blood loss. Her past medical history was significant for autoimmune hypothyroidism (Hashimoto's thyroiditis) treated with levothyroxine. In the weeks prior to admission, the patient\u00a0described only partial adherence to her medication regimen. Immediately postoperatively, the patient had normal mentation without visual complaints.Her postoperative course following abdominal surgery was complicated by a prolonged ileus, nausea, vomiting, and an inability to tolerate her usual oral medications. The patient remained off her usual supplemental levothyroxine for a total of 10 days postoperatively with likely weeks of suboptimal dosing prior to admission.\u00a0Despite restarting oral levothyroxine, the patient began to experience worsening drowsiness by postoperative day 12. Shortly thereafter, she was found to have acute renal failure that required continuous intravenous fluid replacement therapy and later hemodialysis. Serial complete blood counts at this time showed progressive anemia with hemoglobin levels of 6.8\u00a0(12-16 g/dL). The patient's status declined further as she developed a generalized tonic-clonic seizure, transient hypotension (blood pressure = 87/55), and acute hypoxemic respiratory failure  = 86%). She required tracheostomy tube placement and remained significantly obtunded in a state of myxedema coma. Cranial CT was performed and showed no acute intracranial hemorrhage. Magnetic resonance imaging (MRI) of the brain and orbits demonstrated T2-weighted and fluid-attenuated inversion recovery (FLAIR) hyperintensity at the anterior column of the right fornix but was otherwise unremarkable.Thyroid function studies at this time revealed a low free T4 of 0.7 (0.9-1.7 ng/dL) and elevated thyroid-stimulating hormone (TSH) of 40 (0.27-4.20 uIU/mL) consistent with acute decompensated hypothyroidism. The patient had a myxedema score of 75\u00a0and was started on intravenous levothyroxine and hydrocortisone [Upon presenting to neuro-ophthalmology, her best-corrected visual acuity was 20/20 in the right eye (oculus dextrus (OD)) and 20/30 in the left eye (oculus sinister (OS)). Her pupils were isocoric with a left relative afferent pupillary defect. There were no motility deficits. Intraocular pressure measurements were 12 mm Hg OD and 13 mm Hg OS. Humphrey visual field testing demonstrated a mean deviation of -15.33 dB OD and -25.93 dB OS with dense superior and inferior arcuate defects and a constricted visual field oculus uterque (OU)  may precipitate vision loss and secondary optic neuropathy from multiple pathogenic mechanisms including MC-related hypotension, hypoxia, and metabolic derangement. MC can lead to coma (myxedema coma) and can be fatal. The prognosis depends on early recognition and treatment with parenteral levothyroxine."}
+{"text": "CD388 is a novel antiviral drug-Fc conjugate (DFC) designed to deliver universal prevention of seasonal and pandemic influenza. Nonclinical studies have shown CD388 was effective prophylactically against a wide range of seasonal and pandemic influenza A and B strains in lethal and nonlethal mouse models of infection.The design of the ongoing blinded CD388 First in Human study, which is being conducted in healthy subjects is shown in Figure 1. CD388 for injection (100 mg/mL) was administered by intramuscular (IM) or subcutaneous (SQ) routes of administration. Single dose pharmacokinetics were determined for subjects in the 50 and 150 mg cohorts of each dosing route at protocol specified nominal time points; alias subject numbers were used to maintain blind. Plasma CD388 concentrations were determined for subjects randomized to receive CD388 using a validated hybrid immunoassay LC-MS method with lower limit of quantitation (LLOQ) of 0.1 \u00b5g/mL.max) appearing from 2 to 13 days post dose, and quantifiable concentrations ( >LLOQ) lasting for several weeks to months . Mean apparent half-life of elimination was \u223c 50 days. Increases in CD388 exposures were approximately dose proportional for both routes .CD388 appeared to be well absorbed by IM or SQ routes of administration with maximum plasma concentrations (TNo dose limiting local or systemic safety concerns were noted from review of ongoing blinded safety data and the study is proceeding at doses higher than those reported herein.Plasma concentrations of CD388, were similar following intramuscular or subcutaneous routes of administration and were sustained. No safety concerns have been noted in this ongoing study.Shawn Flanagan, PhD, Cidara Therapeutics: Salaried Employee|Cidara Therapeutics: Stocks/Bonds Voon Ong, Executive Director, Cidara Therapeutics: Stocks/Bonds Tristan Baguet, PharmD, Johnson & Johnson: Employee Roxana E. Rojas, M.D., Ph.D., Janssen: Employee|Janssen: Stocks/Bonds Sy-Shi Wang, Ph.D., Janssen Pharmaceutical: Employee Ozlem Equils, MD, Cidara Therapeutics: Employee|Cidara Therapeutics: Stocks/Bonds"}
+{"text": "The discrepancy between true prevalence and reported penicillin (PCN) allergies results in suboptimal antimicrobial use, which is associated with increased adverse drug reactions, antimicrobial resistance, increased hospital length of stay, and poor outcomes. Many patients with mild-moderate reactions tolerate other beta-lactams, but allergy records are often inaccurate or missing information. In 2021, our institution began suppressing prescriber-facing PCN allergy alerts when ordering cephalosporins for patients with mild-moderate PCN reactions. More recently, a pharmacist-driven allergy assessment via chart review +/- patient interview was piloted to clarify PCN allergy documentation. This quasi-experimental study evaluated the effect of PCN allergy interventions on antimicrobial use.Days of broad-spectrum antimicrobials in patients with PCN allergies was compared between groups . Patients were excluded for cephalosporin allergy, MRSA or ESBL history, surgical prophylaxis or UTI indication, or antibiotics within 48 hours of mechanical ventilation. Groups were matched 2:2:1 based on length of stay and antibiotic indication. Additional outcomes included cephalosporin use, allergy clarifications, and time spent per allergy assessment.The most common antibiotic indications were pneumonia (54%) and intra-abdominal infection (28%). No differences were noted in median duration of broad-spectrum therapy  or cephalosporin therapy . However, more patients received cephalosporins as initial therapy post-alert suppression, G1 40 (40%) vs G2 57 (57%), p=0.02 vs G3 26 (52%). A pharmacist completed 50 allergy assessments (50 chart review with 19 interviews) and clarified 43 (86%) records to include previous beta-lactam tolerance. Average time of chart review and interview was 4 minutes each.PCN allergy alert suppression significantly increased initial cephalosporin use and decreased broad-spectrum use. Pharmacist allergy assessment improved allergy documentation accuracy, but future study is required to assess the clinical impact on antimicrobial use.All Authors: No reported disclosures"}
+{"text": "Leopardus pardalis (ocelot) and a partial genome were assembled and annotated through high-throughput sequencing protocols followed by Sanger sequencing validation. The full-length virus obtained comprises 2,003 bp, while the partial genome comprises 1,224 bp. Phylogenetic analysis grouped these two sequences in two distinct clusters related to previously described Felidae anelloviruses. The ORF1 of the partial genome was identified as a new species provisionally called Torque teno ocelot virus, with 53.6% identity with its sister lineage. The complete genome was inferred as a new representative of the Torque teno felid virus 3 species, with 73.28% identity to the closest reference. This study expands known virus diversity and the host span of anelloviruses.A complete genome of the first anellovirus infecting the wild felid  Anelloviridae family represents non-enveloped single-stranded viruses with circular negative-sense DNA, whose genomes range from 1.6 to 3.9 kb. The group is classified in 30 genera and 155 species by the International Committee of Virus Taxonomy (Puma concolor), bobcats (Lynx rufus), Canada lynx (Lynx canadensis) and caracals  . In the present study, we characterize two novel anelloviruses in a Brazilian felid, the ocelot . The Taxonomy . AnellovTaxonomy . They arTaxonomy  and theiTaxonomy . In wildLeopardus pardalis). This project was performed with the authorization number 64515 from the Brazilian Institute for the Environment and Renewable Natural Resources (IBAMA). Plasma was filtered, centrifuged and the supernatant was discarded, leaving the bottom 0.2 mL to digestion with several nucleases. Viral nucleic acid was then extracted using QIAamp Mini Elute Virus Spin Kit (QIAGEN) and subjected to complementary DNA (cDNA) synthesis using Superscript III First-Strand Synthesis Supermix Kit (ThermoFisher). The second strand cDNA synthesis was performed with Klenow Fragment 3\u2019-->5\u2019 exo- (NEB). To get a highly efficient purification with superior quality DNA without salt carryover, the Agencourt AMPure XP Kit (Sinapse Biotecnologia) was used. To quantify double-strand DNA (dsDNA), the QuBit dsDNA High Sensitivity Assay Kit (ThermoFisher) was used, and the library was prepared using the Nextera XT DNA Library Preparation Kit (Illumina). Next-generation sequencing was conducted using the Illumina MiSeq V2 500-cycle kit. FASTq reads were processed with an in-house pipeline that included quality trimming, host genome filtering  and two rounds of BLASTx against RefSeq virus and nr (non-redundant) NCBI databases, as described by  - Brazil, a blood sample was collected from a nine-year-old female ocelot . Annotation was performed by aligning each ORF of the Torque teno felis virus 2 (accession number: NC_038349) against the novel genome, which allowed the inference of homologous genome regions. Three open reading frames (ORF) encoding ORF 1 , ORF 2 (321-bp) and ORF 3 (468-bp) were inferred. One partial genome was also assembled, comprising an incomplete ORF1 sequence with 1,173 nucleotides and was provisionally named WF10 strain 2 (accession number: OL449682). Felidae anelloviruses can be found in two major lineages and phylogenetic analysis of ORF1 gene grouped both new strains within feline anellovirus Group 1, in distinct lineages (Torque teno felis virus (MT538137) (SH-aLRT = 100 / Bootstrap = 100). Sequences shared 73.8% of pairwise identity, confirming they belong to the Torque teno felid virus 3 species in accordance with findings in Torque teno felid virus 3, indicating that more than one viral species might be found in the present lineage upon further sampling  with robust node support (SH-aLRT = 98 / Bootstrap = 100) (Torque teno viverrid virus 3 (LC387548) was recovered with high support (SH-aLRT = 98.3 / Bootstrap = 100), indicating that the present monophyletic lineage likely descends from an ancient virus that co-diverged along the Suborder Feliformia. Based on ICTV species delimitation criteria (identity below 69%) (Torque teno ocelot virus - with 53.72% identity to the closest reference (accession number: EF538878). The ORF1 of the WF10 strain 2 (OL449682) was retrieved as sister to the p = 100) . As an olow 69%) , the parL. pardalis explored by HTS protocols was coinfected by two different species of Anelloviruses, one new strain of Torque teno felid virus 3 (accession number: MK069470) and a putative novel species provisionally named Torque teno ocelot virus (accession number: OL449682). Anelloviridae co-infection by multiple unique lineages is common in healthy humans (Anelloviridae host span and may assist further studies aiming to characterize the complex evolutionary history of anelloviruses (The captive y humans , and thiy humans . The chaoviruses ."}
+{"text": "The pendent cis-diol groups withinthe steric stabilizer chains of these precursor nanoparticles werethen oxidized using sodium periodate to produce the correspondingaldehyde-functional spheres. Similarly, hydrophilic cis-diol-functionalized methacrylic brushes grafted from a planar siliconsurface using activators regenerated by electron transfer atom transferradical polymerization (ARGET ATRP) were selectively oxidized to generatethe corresponding aldehyde-functional brushes. Ellipsometry and X-rayphotoelectron spectroscopy were used to confirm brush oxidation, whilescanning electron microscopy studies demonstrated that the nanoparticlesdid not adsorb onto a cis-diol-functional precursorbrush. Subsequently, the aldehyde-functional brushes were treatedwith excess small-molecule diamine, and the resulting imine linkageswere converted into secondary amine bonds via reductive amination.The resulting primary amine-functionalized brushes formed multipledynamic imine bonds with the aldehyde-functional diblock copolymerspheres, leading to a mean surface coverage of approximately 0.33on the upper brush layer surface, regardless of the nanoparticle size.Friction force microscopy studies of the resulting nanoparticle-decoratedbrushes enabled calculation of friction coefficients, which were comparedto that measured for the bare aldehyde-functional brush. Frictioncoefficients were reasonably consistent across all surfaces exceptwhen particle size was comparable to the size of the probe tip. Inthis case, differences were ascribed to an increase in contact areabetween the tip and the brush-nanoparticle layer. This new model systemenhances our understanding of nanoparticle adsorption onto hydrophilicbrush layers.Dynamic covalent chemistry has been exploited to preparenumerousexamples of adaptable polymeric materials that exhibit unique properties.Herein, the chemical adsorption of aldehyde-functional diblock copolymerspherical nanoparticles onto amine-functionalized surface-graftedpolymer brushes via dynamic Schiff base chemistry is demonstrated.Initially, a series of  Of particular relevance to the present study are imine bonds,which are formed when reacting an aldehyde with a primary amine. SuchSchiff base chemistry has been used to generate covalent adaptablenetworks (CANs)29 and hydrogels5 for potential biomedical applications,30 while it has also been exploited for conjugation of oligonucleotidesto aldehyde-functional polymer brushes, which were prepared via partialoxidation of a poly(2-hydroxyethyl methacrylate) (PHEMA) precursorbrush.31In the context of polymer science, DCChas enabled the developmentof self-healing polymers and mechanically/macroscopically-responsivematerials with adaptable properties.34 This polymer can either be directly synthesized fromthe corresponding methacrylic monomer (AGEO5MA) or it can be generatedvia selective oxidation of a cis-diol-functionalPGEO5MA precursor using sodium periodate (NaIO4).32 PAGEO5MA-based diblock copolymer spheres orvesicles can be reacted with various amino acids  via Schiff base chemistry followed by reductiveamination.35 PAGEO5MA-based diblock copolymerworms form soft, free-standing gels that exhibit strong mucoadhesion,34 while PAGEO5MA brushes grafted from a planarsurface can be reacted with model globular proteins, such as bovineserum albumin (BSA).36 This involves theformation of multiple imine bonds between the aldehyde groups on thebrush chains and the primary amine groups located at the surface ofthe protein. Each individual imine bond is relatively weak and proneto hydrolysis, but a sufficient number of these bonds remain intactat any given time to ensure that the protein remains conjugated tothe polymer brush.Recently, we reported anew hydrophilic aldehyde-functional polymer(PAGEO5MA).39 For example, Huck and co-workers examined the adsorptionof gold nanoparticles within or onto polymer brushes.42 In this case, nanoparticle adsorption occurred via non-covalentelectrostatic interactions, rather than by DCC.The design of well-defined nanoparticle-brushhybrid surfaces enablesthe construction of complex interfacial structures and multicomponentmaterials with tailored properties. This offers potential applicationsranging from energy storage and plasmonics to drug release and frictionmodification.34 precursor was chain-extended with 2-hydroxypropylmethacrylate (HPMA) to generate a series of kinetically-trapped diblockcopolymer spheres via reversible addition\u2013fragmentation chaintransfer (RAFT) aqueous dispersion polymerization (34-PHPMAy (denoted GO34-Hy) diblock copolymer nanoparticles were analyzedby dynamic light scattering (DLS), small-angle X-ray scattering (SAXS),and electron microscopy. Their pendent cis-diol groupswere then selectively oxidized using a stoichiometric amount of NaIO4 under mild conditions with no loss of colloidal stability.The resulting aldehyde-functional PAGEO5MA34-PHPMAy (denoted AGO34-Hy) nanoparticles were then exposed to a series ofhydrophilic PAGEO5MA brushes, which had been previously reacted witha small-molecule diamine. Dynamic imine bond formation between thenanoparticles and the primary amine-functional brushes led to theirchemical adsorption. Subsequently, friction force microscopy was usedto examine the relationship between nanoparticle diameter, surfacetopography, and measured friction coefficient.Herein, we reportthe adsorption of aldehyde-functional diblockcopolymer spherical nanoparticles of varying size onto amine-functionalizedsurface-grafted polymer brushes via DCC to generate a library of nanoparticle-brushplanar surfaces with tunable friction coefficients. More specifically,a PGEO5MArization 1. These 34 (or GO34) precursor was firstsynthesized via RAFT solution polymerization of GEO5MA in ethanolat 70 \u00b0C using a non-ionic trithiocarbonate chain transfer agent,following a similar experimental protocol to that previously reportedby our group (Scheme S2).33 A final GEO5MA conversion of 86% was achieved after 180 min, asdetermined by 1H NMR analysis in CD3OD. End-groupanalysis of the purified PGEO5MA homopolymer using the same techniqueindicated a mean degree of polymerization (DP) of 34 . Size exclusion chromatography (SEC)analysis (DMF eluent containing 10 mM LiBr) for this GO34 precursor revealed a narrow molecular weight distribution with anapparent number-average molecular weight (Mn) of 15.8 kg mol\u20131 and a relatively low dispersity(Mw/Mn) of1.16 . This latter parametersuggested a well-controlled RAFT polymerization.A PGEO5MA33 weanticipated that this relatively massive cis-diol-functionalGO34 precursor should produce kinetically-trapped diblockcopolymer spheres when conducting RAFT aqueous dispersion polymerizationsyntheses at a sufficiently low copolymer concentration . Accordingly, this water-soluble GO34 precursorwas subsequently chain-extended via RAFT aqueous dispersion polymerizationof HPMA (H) at 37 \u00b0C to afford a series of GO34-Hy diblock copolymer spheres at 10% w/w solids(y) was systematically varied from 125 to1500 to produce nanoparticles of increasing size. Near-quantitativeHPMA conversions (>99%) were achieved within 16 h in all cases,asdetermined by 1H NMR studies in CD3OD (Table S1). SEC analysis confirmed that the GO34 precursor was efficiently chain-extended, with Mn values for the resulting GO34-Hy diblock copolymers increasing linearly when targetinghigher PHPMA DPs. Relatively low dispersities (Mw/Mn \u2264 1.34) were calculatedfor the GO34-H125 and GO34-H250 diblock copolymers, but significantly higher values wereobtained when targeting longer PHPMA blocks (Table S1). These observations are broadly consistent with previously reporteddata when targeting high core-forming block DPs using aqueous PISAprotocols.43 A weak high-molecular-weightshoulder was only observed for GO34-H1000: thisfeature can be attributed to chain transfer to polymer or terminationby recombination owing to traces of dimethacrylate impurities withinthe HPMA monomer.45 Unfortunately, the GO34-H1500 diblock copolymer proved to be poorly soluble inDMF and hence was unsuitable for SEC analysis.Based on ourrecent experience,w solids1. The ta34-Hy diblock copolymer nanoparticles wasassessed usinga series of scattering and microscopy techniques. In particular, DLSanalysis confirmed narrow, monomodal particle size distributions.Targeting higher PHPMA DPs resulted in a monotonic increase in themean hydrodynamic diameters (Dh) from30 to 250 nm with relatively low polydispersities (PD \u2264 0.08)(Table S1). Subsequently, SAXS analysis verifiedthese DLS data. Zero gradients were observed in the low-q region (where q is the scattering vector) of I(q) vs q plots, whichsuggested a spherical morphology in each case. Furthermore, a progressiveshift in the local minimum at lower q was evidentwhen targeting higher PHPMA DPs, while a satisfactory fit was obtainedfor each SAXS pattern using a well-documented spherical micelle model for this nanoparticleseries, which were consistent with the corresponding DLS data .Next, the size and morphology of the GOle model2C.46 Thicis-diol-functionalGO34-Hy diblock copolymer nanoparticleswere examined by conventional transmission electron microscopy (TEM).Well-defined, uniform spherical nanoparticles were observed in allcases (DTEM) . As expected for particle size distributions offinite width, DTEM values were moderatelylower than DSAXS, whereas the z-average diameters (Dh) determinedby DLS were always systematically higher . Scanning electronmicroscopy (SEM) and atomic force microscopy (AFM) were also utilizedfor imaging of the dried aqueous dispersions of GO34-Hy diblock copolymer spheres. These complimentarytechniques provided further evidence for well-defined spherical nanoparticlemorphologies when examining significantly larger numbers of particlesthan TEM (S5).Morphologies for the entire series of llcases 2D.Correthan TEM 2E and S5Figure S6 and Table S1).Moreover, aqueous electrophoresisstudies were performed for allcopolymer dispersions in a background salt concentration of 1 mM KClat pH 6.8  withzeta potentials ranging between \u221213 and \u221217 mV, regardlessof the PHPMA DP  and immediately quenchedupon exposure to air, while cooling to 20 \u00b0C. These samples werethen analyzed by 1H NMR spectroscopy in CD3ODfor HPMA conversion calculations, SEC for determination of Mn and Mw/Mn, DLS for measurement of Dh and PD, as well as TEM for assessing the intermediatenanoparticle morphologies.To further evaluate the extentof polymerization control achievedfor such PISA syntheses and to monitor the evolution in particle sizeand polydispersity, kinetic studies were conducted during the synthesisof GOTable S2). Duringthe first 90 min, relatively slow RAFT solution polymerization occurredto produce water-soluble GO34-Hy diblock copolymer chains. After approximately 90 min\u2014whichcorresponds to 10% monomer conversion, or a PHPMA DP of 100\u2014a\u223c3.5-fold increase in the rate of HPMA polymerization was observed,which indicated the onset of micellar nucleation. At this stage, theformed nascent micelles immediately become swollen with unreactedmonomer, which leads to a relatively high local concentration andhence a much faster rate of polymerization.45 Finally, an additional four-fold rate enhancement was observed after\u223c180 min . This phenomenonhas been reported for similar PISA formulations and is tentativelyattributed to the formation of more compact nanoparticles via gradualexpulsion of residual solvent molecules from the nanoparticle cores.48 Importantly, SEC analysis revealed a linear evolution in Mn with increasing monomer conversion, suggestinga controlled RAFT polymerization at each stage (Table S2).On inspection of the constructedconversion vs time curve, almostall of the HPMA monomer (99%) had reacted within 8 h. The correspondingsemi-logarithmic plot revealed a pseudo-first-order kinetic profilefor this aqueous dispersion polymerization that was separated in threedistinct reaction regimes (Table S2). Once micellar nucleation occurredat 90 min (10% HPMA conversion), a linear increase in Dh was observed from 56 nm up to 124 nm over the following120 min (67% HPMA conversion after 210 min), with a correspondingsequential increase in the derived count rate up to 186,700 kcps.As the remaining monomer within the nanoparticle cores is consumed,it is no longer replenished from the continuous phase. Additionally,as the growing nanoparticles become less swollen with the monomer,they also become denser (as low-density monomer is converted to higher-densitypolymer). Thus, only a rather modest increase in Dh and derived count rate was observed between this timepoint and the end of the polymerization. Notably, the Dh of 140 nm measured for the final GO34-H1000 diblock copolymer spheres produced during this kineticstudy is comparable to that obtained for the respective sample withthe same composition synthesized in the absence of any periodic samplingof the reaction mixture (Dh = 128 nm).However, the Dh values measured for theseries of GO34-Hy diblock copolymerspheres isolated during this kinetic study are significantly higherthan those observed when targeting compositionally similar diblockcopolymers  (Tables S1 and S2). Thisdiscrepancy is attributed to the monomer-swollen nature of the spheresin the former case. Importantly, DLS PDs remained below 0.07 for allkinetic samples, while TEM analysis confirmed the formation of near-monodispersespheres of increasing size at higher HPMA conversions (S7).Further insights into the onset of micellar nucleationand sizeevolution were provided by DLS analysis of the same samples withdrawnat intermediate HPMA conversions from the reaction mixture. No particleswere detected within the first 90 min, as judged by the relativelylow scattering intensity (derived count rate <370 kcps), suggestingthe initial formation of molecularly-dissolved copolymer chains  under mild reaction conditionsto form the respective aldehyde-functional PAGEO5MA-based materials.The resulting PAGEO5MA chains can be further functionalized usingvarious primary amines (including amino acids) via reductive amination.36 In the present study, our aim was to extend these reports by investigatingwhether dynamic imine bond formation could be used to promote thechemical adsorption of PAGEO5MA-stabilized diblock copolymer spheresof varying size onto surface-grafted amine-functionalized PDAGEO5MAbrushes to produce a library of model soft hybrid surfaces of tuneabletopography for friction coefficient measurements.Recently, we reported that the pendent 34-Hy diblock copolymer spheres was achievedby addition of NaIO4 to 10% w/w aqueous copolymer dispersionsat 22 \u00b0C in the dark for 20 min to yield a series of aldehyde-functionalPAGEO5MA34-PHPMAy (AGO34-Hy) spheres, where y = 125-1500  confirmed the appearance of a new signalat approximately 3.5 ppm, whose intensity was proportional to the cis-diol content of each copolymer. This new feature isattributed to the formation of aldehyde groups in their hydrated germinaldiol form, indicating the successful oxidation of the steric stabilizerchains .32 In principle, the secondary alcohol groups within the hydrophobicPHPMA block could be oxidized to form ketone groups. However, NaIO4 is highly selective toward cis-diol groups,49 so in practice this side reaction was not observed under the statedconditions.Accordingly,selective oxidation of the precursor GO125-1500 1. A [cis34-Hy diblock copolymers (DMF +10 mM LiBr eluent)indicated a discernible increase in Mn and Mw/Mn compared to the original GO34-Hy copolymers. Moreover, the development of high-molecular-weightshoulders led to significantly broader molecular-weight distributions,with such features being more pronounced for shorter PHPMA DPs  . These observations are attributed to aldol cross-linking reactionsoccurring between the aldehyde and cis-diol groupsof the stabilizer block chains at intermediate conversions duringperiodate oxidation or between the pendent aldehyde groups of PAGEO5MAand the hydroxyl groups of the partially hydrated PHPMA block.33Additionally, SEC analysis of the resulting AGO34-Hy diblock copolymerspheres. These nanoparticles exhibit almost identical Dh and DSAXS diameters to thosedetermined for the precursor GO34-Hy spheres prior to oxidation (S11 and Table S3). These data were furthersupported by TEM, SEM, and AFM images, which indicated that near-monodispersespherical nanoparticles of tuneable size were obtained for the wholediblock copolymer series (Table S3). Furthermore, no significant changes in zeta potentialwere observed by aqueous electrophoresis studies for the periodate-treatedspheres  .Importantly, DLS and SAXS analyses confirmedthat periodate oxidationdid not affect the particle size or colloidal stability of the developedAGO34-Hy spheres of increasing size. As highlighted above, our aim was togenerate suitably modified PDAGEO5MA brushes to enable the chemicaladsorption of such nanoparticles via dynamic imine bond formation.The synthetic route employed for the preparation of nanoparticle-decoratedAGO34-Hy@PDAGEO5MA hybrid surfacesis illustrated in So far we have demonstrated the synthesis of near-monodispersekinetically-trapped AGO50 Surface-initiated activators regenerated byelectron transfer atom transfer radical polymerization (SI-ARGET ATRP)was then used to graft uniform PGEO5MA brushes of \u223c120 nm drythickness, as determined via ellipsometry (Table S4), from these modified substrates, following a procedurerecently reported by our group.36 While,ultimately, aldehyde functionality is required for diamine functionalizationand subsequent nanoparticle adsorption, cis-diol-functionalPGEO5MA brushes were first grown herein as they allow for preparationof more densely grafted surfaces compared to brushes synthesized directlyfrom polymerization of the respective AGEO5MA monomer.36Initially, ATRP initiator groups were introducedonto planar siliconwafers using a previously reported experimental protocol.4 solutionfor 30 min at 22 \u00b0C (36 Selective oxidationof the pendent cis-diol groups was confirmed by bothellipsometry and X-ray photoelectron spectroscopy (XPS) studies. Periodateoxidation should lead to a reduction in the molecular weight of eachrepeat unit owing to the loss of a formaldehyde molecule.32 Thus, given that the dry brush thickness isproportional to the polymer molecular weight,51 complete oxidation of the PGEO5MA repeat units is expected to producean approximate 8.5% reduction in dry thickness.36 Indeed, ellipsometry measurements confirmed such a reductionin dry brush thickness equal to this theoretically expected valueafter exposing each PGEO5MA brush to NaIO4 (mean dry PAGEO5MAbrush thickness = 111 nm) (Table S4). Moreover,comparing the C 1s XPS data obtained for the PGEO5MA and PAGEO5MAbrushes revealed a shift in the ratio of the O\u2013C=O, C=O, C\u2013O\u2013C/C\u2013O\u2013H, and C\u2013H peaks that is consistent with brush oxidation.36To produce the analogous aldehyde-functionalPAGEO5MA brushes,such PGEO5MA brushes were exposed to an aqueous NaIOat 22 \u00b0C 2.36 Sele32 diblock copolymer nano-objects,35 and brushes36 can be further functionalizedwith various amino acids, such as l-histidine, via reductiveamination. For surface-grafted PAGEO5MA brushes, this involves immersioninto an aqueous solution containing the desired amine reagent andsodium cyanoborohydride (NaBH3CN), prior to heating to50 \u00b0C for 24 h. Herein, this protocol was adapted to functionalizePAGEO5MA brushes using a hydrophilic diamine (Jeffamine EDR-148) toprepare the corresponding PDAGEO5MA brushes, as illustrated in 52 Furthermore, this derivatization reaction ofthe PAGEO5MA brushes with the diamine was performed in a binary solventmixture (CH2Cl2/methanol 3:1), that is a poorsolvent for the PAGEO5MA chains. Thus, the brushes were functionalizedin their collapsed (rather than extended) conformation. This shouldlimit diamine reaction with only the near-surface aldehyde groupsof the brushes.54Recently, we have reported that PAGEO5MA-based chains,Table S4). For the latter technique, the measured increase in dry brush thicknessis compared to the maximum increase calculated for complete diamineconjugation (assuming no cross-linking side-reactions). More specifically,the molecular weight of the brush repeat units should increase from351 g mol\u20131 for PAGEO5MA to 483 g mol\u20131 for PDAGEO5MA, which would result in a theoretical 38% increasein dry brush thickness. Hence, the mean degree of diamine functionalizationthroughout the entire PDAGEO5MA brush layer was calculated to be 36\u00b1 4% for the entire brush series (Table S4).55The formation of diamine-functional PDAGEO5MAbrushes was verifiedby XPS 5Aand qu+  and N0  prior to drying for XPS analysis. The pKa of the protonated primary amine of a similar Jeffamine moleculeshifts from 9.7 in solution to 7.1 when grafted to a surface.57 A similar pKa shiftis observed for poly(tertiary amine methacrylate)-based brushes, wherebythe pKa of surface-grafted chains is significantlylower than that of either free chains or the corresponding monomer.61 Peak area analysis revealed a N0/N+ atomicratio of approximately 3.0. Notably, this relatively low degree ofamine protonation (25%) suggests a similar pKa shift for the amine groups within the PDAGEO5MA brushes.XPS analysis was also employed to examine the surfacecompositionof PDAGEO5MA brushes. The high-resolution N1s spectra for PGEO5MA,PAGEO5MA, and PDAGEO5MA brushes are shown in 62 so such data only provide the near-surface compositions, ratherthan throughout the whole brush layer. By comparing the experimentalN/O atomic ratio to its maximum theoretical value , the degree of functionalization was determinedto be 56% for the upper surface of the PDAGEO5MA brush. This is significantlyhigher than the mean degree of functionalization calculated from ellipsometrymeasurements (36 \u00b1 4%). This discrepancy provided evidence forthe  surface confinement of the diamine groups. This is notunexpected given that reductive amination was conducted in a poorsolvent for the PAGEO5MA brush chains.54The degree of diamine functionalization was also examined by calculatingthe corresponding N/O atomic ratio. However, XPS only interrogatesthe upper \u223c10 nm of the dry brush,Figure S15), they appear tobe a drying artifact resulting either from the ultrahigh vacuum environmentor the gold sputter coating required for SEM imaging.SEM images acquiredfor a bare silicon wafer and representativeexamples of the surface-grafted PGEO5MA, PAGEO5MA, and PDAGEO5MA brushesare shown in 36 Herein, we used a complimentaryapproach to adsorb a series of aldehyde-functional AGO34-Hy diblock copolymer spheres of varyingsize onto amine-functionalized PDAGEO5MA brushes via the same DCC.Recently,we demonstrated the chemical adsorption of BSA onto asurface-grafted PAGEO5MA brush through the formation of multiple iminebonds between amines on the protein and the aldehyde groups on thepolymer brush.34-Hy@PDAGEO5MA hybrid surfaces are shown in 34-Hy diblock copolymer nanoparticle formulations  could be distinctly observed via SEM,whereas the surface of the corresponding precursor PDAGEO5MA brushwas essentially featureless (y = 125 and 250) could not be clearlyvisualized by SEM owing to insufficient resolution. However, AFM analysisconfirmed the presence of all six types of nanoparticles at the brushsurface . In addition to visual confirmationof the adsorption of the AGO34-Hy diblock copolymer spheres, AFM height image analysis alsorevealed a significant increase in the roughness of each nanoparticle-decoratedsurface with increasing nanoparticle diameter.Nanoparticle adsorption onto PDAGE5OMA brushes was achieved viaovernight immersion of the modified silicon wafers into 1% w/w aqueousdiblock copolymer dispersions at 22 \u00b0C 2. Represtureless 5B. Unforsurface 6B.Impor34-Hy@PDAGEO5MA surfacescoated with the four largest AGO34-Hy nanoparticles (y = 500\u20131500). Thisapproach led to measurement of mean surface coverages of 31\u201338%. Such data are comparableto that reported in the literature for nanoparticle adsorption ontoother polymer brushes65 or bare substrates67 via electrostatic interactions or covalent bond formation.Curiously, visual analysis of the AFM images acquired for the driednanoparticle-coated surfaces indicated a notably higher degree ofcoverage. This discrepancy likely arises when further dehydrationoccurs on exposure of the samples to the ultrahigh vacuum during SEMimaging. This drying of the hybrid surfaces could result in particlesseparating on the surface, revealing the brush layer underneath. Giventhat XPS (S14) indicated that 56% of the originalaldehyde groups were converted into amines, such surface coveragessuggest complete saturation of the available binding sites. Thus,despite the relatively weak nature of each individual imine bond (plustheir propensity to undergo hydrolysis in aqueous solution), the DCCexploited herein leads to relatively efficient nanoparticle adsorption,presumably via formation of multiple imine bonds per nanoparticle.It is perhaps also worth mentioning that nanoparticle diffusion withina relatively dense brush layer is extremely unlikely, particularlyfor the larger nanoparticles.68 As such,DCC is almost certain surface-confined.The mean brush surface coverage by each nanoparticlesample wasestimated by digital image analysis of the SEM images acquired forAGO34-H1000 spheres (AGO34-H1000@Si). Second, a cis-diol-functionalPGEO5MA brush was exposed to GO34-H1000 spheres(GO34-H1000@PGEO5MA) with SEM image analysisbeing used to quantify the extent of surface coverage in each case. Minimal nanoparticle adsorptiononto the bare silicon wafer was observed (mean surface coverage \u223c1%),whereas no detectable nanoparticle adsorption was observed for thePGEO5MA brush, hence excluding physical adsorption as a means of nanoparticleconjugation.To confirm that dynamicSchiff base chemistry is responsible forthe observed nanoparticle adsorption (rather than merely non-specificbinding), two control experiments were conducted. First, a bare siliconwafer was exposed to AGOcis-diolfunctional PGEO5MA brushes toward both proteins36 and sterically-stabilized nanoparticles (this work) highlightthe importance of Schiff base chemistry in promoting nanoparticleadsorption. During their close approach to well-solvated polymer brushchains, such nanoparticles experience a repulsive force owing to theincrease in osmotic pressure (as well as the concomitant reductionin entropic freedom).72 The formation of DCBs between the spheres and each polymer brushis clearly essential for particles to overcome this repulsive barrier.The anti-fouling capabilities of the 34-Hy@PDAGEO5MA surfaces was examined byAFM . Both the PDAGEO5MA brushchains and the steric stabilizer PAGEO5MA chains expressed at thesurface of the adsorbed nanoparticles should become swollen when exposedto water. Nevertheless, in accordance with the analysis performedin dry conditions, the attachment of the nanoparticles was evidentwhen compared to the bare PAGEO5MA hydrated brush . Moreover, there is a significant apparent increasein nanoparticle surface coverage. The continued presence of the nanoparticleson the brush surface following a drying-hydration cycle further highlightedDCC as the driving force for their adsorption.Importantly, the topography of hydrated nanoparticle-decoratedAGO74 By investigating the correlation between surface topography andlateral force exerted on a probe, we can elucidate apparent disparitiesin surface coverage depicted in AFM and SEM images. Additionally,this will facilitate understanding of the interaction between nanoparticle-brushsurfaces and extrinsic systems.Clearly, DCCcan be exploited for the immobilization of polymernanoparticles to surface-grafted polymer brushes to generate a libraryof composite interfaces. In principle, this approach could be extendedto attach other polymer nano-objects, including worms and vesicles,opening these hybrid interfaces to a range of applications such asnanoreactor capture to surfaces and programmable surface lubrication.For each of these applications, an understanding of the surface topographyand its interaction with other materials is required. In general,further development of this library of model nanoparticle-decoratedbrushes offers an opportunity to examine the role of topography onfriction of soft surfaces, complementing existing alternative approaches.34-Hy@PDAGEO5MA brush was examined in aqueoussolution at 24 \u00b0C. A single AFM tip was used for all experiments, and the friction of each surface wasnormalized relative to a nanoparticle-free PAGEO5MA brush. The topography of each nanoparticle-brushhybrid surface was furtherexamined by nanofriction measurements using friction force microscopy.The presence of the nanoparticles in the polymer film influences thelateral deflection of the AFM cantilever by modifying both the topographyand the mechanical properties of the surface. Differences in specificinteractions and adhesion are considered negligible since the stericstabilizer chains on the surface of the nanoparticles are chemicallyidentical. Friction force microscopy studies were undertaken usingthe same AFM instrument. More specifically, each AGO77 According to these prior studies, the total frictionalforce (FF) can be regarded as the sumof load-dependent (plowing) and area-dependent (shearing) terms.80 The balance of these two components determines the relationshipbetween applied load and friction. In the present work, a linear responseto increasing load was observed for all surfaces. Consequently, eachdata set was analyzed using Amontons\u2019 law, FF = \u03bcFN, where FN is the applied load and \u03bc is the frictioncoefficient.81 Hence, the gradient of thedata fit is equal to the friction coefficient. As a single tip wasused for all surfaces, normalization of these coefficients to thenanoparticle-free PAGEO5MA brush  did not deviate significantly fromthat of the bare brush. However, a four-fold increase in this parameterwas observed for the AGO34-H250@PDAGEO5MA brush.In this case, the nanoparticle radius (22 nm) is just over twice thatof the nominal AFM tip radius (10 nm). However, as the nanoparticleradius increased further, a gradual reduction in the friction coefficientwas observed with the AGO34-H1000/1500@PDAGEO5MAbrushes exhibiting \u223c50% of the bare PAGEO5MA brush frictioncoefficient.For the smallest AGO84 For significantly larger nanoparticles, theirdiameter is much larger than the tip dimensions, and their interfacialcurvature approaches that of the planar surface  particles(at similar surface coverages to those presented herein) exhibiteda monotonic reduction in friction with increasing particle size.88 Similarly, a significantly lower friction coefficientwas observed within the boundary lubrication regime when conductingtribology experiments on epoxy-functionalized diblock copolymer nanoparticlescovalently attached onto a planar stainless-steel substrate relativeto comparable measurements performed using similar nanoparticles bearingno epoxy groups.67 Nevertheless, we positthat friction force studies via AFM are ideally suited for probingsubtle differences in surface roughness for the nanoparticle-decoratedbrush surfaces reported herein. In this context, an interesting findingwas reported by Pe\u00f1a-Par\u00e1s et al., who used wear measurementsto assess friction for a series of particle lubricants.89 This team found that using particles of intermediatesize led to significantly less wear compared to both larger and smallerparticles. This was attributed to the former particles being comparablein size to the surface roughness of the planar substrate. Thus, adsorptionof such particles within the surface interstices reduced the overallsurface roughness.Notably, surface forces apparatus is commonlyemployed to assessmacroscopic surface friction.34-Hy diblock copolymer spheres (y = 125\u20131500)of varying size onto amine-functionalized polymer brushes. First,a series of cis-diol-functional precursor GO34-Hy diblock copolymer nanoparticleswere prepared via RAFT aqueous dispersion polymerization and characterizedby DLS, SAXS, TEM, SEM, and AFM. Well-defined spheres of increasingsize were obtained when targeting higher PHPMA DPs. Kinetic studiesduring the synthesis of GO34-H1000 diblock copolymerspheres revealed a linear increase in Mn with HPMA conversion and a monotonic increase in particle Dh with polymerization time. Subsequently, selectiveoxidation of GO34-Hy nanoparticlesusing sodium periodate produced the corresponding aldehyde-functionalAGO34-Hy nanoparticles withno discernible changes in either particle size or colloidal stability.In parallel studies, PGEO5MA precursor brushes were grafted from planarsilicon wafers using surface-initiated ARGET ATRP. Ellipsometry andXPS analyses were used to confirm NaIO4 oxidation to affordthe corresponding PAGEO5MA brushes and their subsequent chemical modificationusing a hydrophilic diamine in excess to generate amine-functionalizedPDAGEO5MA brushes. This derivatization was deliberately performedin a poor solvent for the PAGEO5MA brush to ensure a surface-confinedreaction. A control experiment confirmed that the precursor PGEO5MAbrush was strongly resistant to nanoparticle adsorption. In contrast,the amine-functionalized PDAGEO5MA brushes readily formed imine bondswith the aldehyde-functional AGO34-Hy spheres. Thus DCC can be used to promote chemical adsorptionof such nanoparticles. SEM analysis of AGO34-Hy@PDAGEO5MA surfaces indicated a mean surface coverageof 33 \u00b1 4% for the whole nanoparticle series. Moreover, frictionforce microscopy studies of such nanoparticle-decorated surfaces enabledcalculation of friction coefficients, which were compared to thatof a bare PAGEO5MA brush. Since the chemical structure of the stericstabilizer chains in the nanoparticles is the same regardless of theirsize, any observed variation in the friction coefficient can be attributedto changes in surface topography associated with nanoparticle adsorption.Reasonably consistent friction data were observed for all surfaces,except when the sphere diameter was comparable to the width of theAFM probe tip. In this case, the tip can penetrate between adjacentnanoparticles, which leads to a significant increase in contact areabetween the tip and the brush-nanoparticle layer and hence a higherfriction coefficient. In principle, such systems provide useful modelsubstrates for conducting friction force studies of soft surfaces.Moreover, the chemical adsorption of aldehyde-functional nanoparticlesonto well-defined brushes via DCC is expected to be a generic approach.In particular, we are currently exploring the adsorption of enzyme-loadeddiblock copolymer vesicles onto such brushes to produce surface-immobilizednanoreactors for enzyme-mediated catalysis applications.DCC has been exploited to promote chemicaladsorption of a seriesof aldehyde-functional AGOSupporting Information.Materials, characterization techniques,and detailed synthesisprotocols are provided in the"}
+{"text": "The duration of humoral response in immunocompromised populations according to the number of doses in the primary vaccine regimen and the number of booster doses is little known.in vitro neutralization assay, original strain) tests were carried out centrally.Participants from the French national multi-center prospective cohort study ANRS0001S COV-POPART were included (11 specific subpopulations and 2 control groups (18-64 years and over 65 years)). We evaluated the immune response to COVID-19 vaccines up to 6 months after the second dose, distinguishing participants having received two or three doses in their initial vaccination scheme and those with or without a booster dose before 6 months. Participants with positive anti-nucleocapsid (NP) antibodies or SARS-CoV-2 infection during follow-up were excluded. Serological (ELISA EuroImmun\u00ae) and seroneutralisation . Fifteen percent of participants in a specific sub-population received 3 doses within their initial vaccine scheme (mostly solid organ transplants (SOT) and Hematopoietic stem cell transplants (HCT)) and 11.2% received a booster dose within 6 months after a median time of 5 months after the last dose. The control groups and all specific sub-populations who received two doses as the primary regimen, except solid SOT and HCT groups, increased their anti-Spike and seroneutralisation titer after a booster dose .The booster dose had little effect on participants who received three doses as a primary vaccination regimen compared to those who did not receive the booster dose .6-month median (IQR) anti-Spike IgG titers (BAU/mL) in specific subpopulations who received two (A) and three doses (B) within their initial vaccine scheme. 6-month seroneutralisation titers in specific subpopulations who received two (C) and three doses (D) within their initial vaccine scheme.Solid organ transplantation (SOT), hematopoietic stem cell transplantation (HCT), chronic renal failure (CKD), systemic autoimmune diseases (SAD), inflammatory rheumatic diseases (IRD), multiple sclerosis (MS) or neuromyelitis optica spectrum disorders (NMOSD).A booster dose in those who received 2 doses as a primary vaccination regimen increased 6-month humoral responses in almost all sub-populations except SOT and HSCT. The effect of booster doses in those receiving three doses as a primary vaccination regimen was low, reflecting the profound immunosuppression of these patients.Paul LOUBET, MD, PhD, Astrazeneca: Advisor/Consultant|Astrazeneca: Board Member|Moderna: Board Member|Pfizer: Advisor/Consultant|Pfizer: Board Member Odile Launay, MD, PhD, Moderna: Advisor/Consultant|Pfizer: Advisor/Consultant|Pfizer: Board Member"}
+{"text": "This sedimentary logging and facies characterized dataset of 28 outcrops exposed along Kuala Tahan \u2013 Kampung Pagi \u2013 Kampung Bantal which is situated in the central part of Peninsular Malaysia (in the state of Pahang). This dataset is recorded in 2017 during the construction of roadway. It consist of Mangking Formation of Tembeling Group with the total length of 410\u00a0m. The outcrops are arranged into 8 continuous sections. This data can be further correlated stratigraphically to produce composite log, facies analysis, depositional processes, and the depositional environment. Specifications Table1\u2022The outcrops and sedimentary logs can inspire researchers to conduct more advanced studies on sedimentology, facies analyses and depositional environment interpretation on Jurassic-Cretaceous rocks of the region.\u2022The dataset can be stratigraphically correlated with the geology of Peninsula Malaysia, Thailand, and Indochina especially on the Jurassic-Cretaceous aged strata (red beds).\u2022The outcrops/exposures are now inaccessible due to dense vegetation and cementing through rock/slope stabilization techniques. Other Jurassic-Cretaceous rocks in this region are difficult to access.2\u24c7 to show the locations of outcrops  Outcrop Details, 2) Compiled Sedimentary Logs, 3) Locality Map, and 4) Digitization Raw Files. Folder 1 (Outcrop Details) contains excel file with coordinates, bedding orientations (strike and dip) and note on structures (fault and folding). Sedimentary logs and outcrop photos are arranged in Folder 2 (Compiled Sedimentary Logs) based on section (Section 1 to 11)  and 3. Toutcrops .Table 1Shttps://data.mendeley.com/datasets/3sz9g6nrc8/1). The eight sedimentary facies identified are 1) Clast-Supported Conglomerate Facies (Gc), 2) Trough Cross-Stratified Conglomerate (Gt), 3) Trough Cross-Stratified Sandstone Facies (St), 4) Massive Sandstone Facies (Thick: Smi & Thin: Smii), 5) Tabular Cross-Stratified Sandstone Facies (Sp), 6) Parallel Laminated Sandstone (Sh), 7) Interbedded Sandstone and Mudstone Stripes (Fl), and 8) Mudstone Facies (M). Below is a summary of the eight facies .3(i)Sedimentary logging\u24c7 into sedimentary logs (refer (ii)Facies characterizationThe sedimentary characteristics recorded during field excursion are lithology, grain size, primary sedimentary structures, bedding, external geometry, fossils, thickness, grain size, and color based on Tucker (2011) gs refer  and 3.(i(iii)Locality MapDetailed facies characterization were done using Miall (1996) \u24c7 , some sedimentary structures may be altered or completely obliterated. These structureless beds are recorded as Structureless Sandstone Facies (Sm).This work did not involve studies with animals or human. The authors declare that they have no known competing financial interests or personal relationships which have or could be perceived to have influenced the work reported in this article.Wei Chung Khor: Conceptualization, Methodology, Writing \u2013 review & editing, Funding acquisition. Kamal Roslam Mohamed: Writing \u2013 review & editing, Funding acquisition, Supervision. Mohamed Shafeea Leman: Funding acquisition, Supervision. Che Aziz Ali: Supervision."}
+{"text": "Kd \u2248 10\u20133\u201310\u20136 M). For applicationsaimed at recruiting anticarbohydrate antibodies to tumor cells, largesynthetic scaffolds are used that contain both a tumor-binding domain(TBD) and a multivalent antibody-binding domain (ABD) comprising multiple l-rhamnose monosaccharides. This allows for stable bridgingbetween tumor cells and antibodies, which activates tumoricidal immunefunction. Problematically, such multivalent macromolecules can facelimitations including synthetic and/or structural complexity and thepotential for off-target immune engagement. We envisioned that smallbifunctional \u201cproximity-inducing\u201d molecules containinga low-affinity monovalent ABD could efficiently engage carbohydrate-bindingreceptors for tumor-immune proximity by coupling weak binding withcovalent engagement. Typical covalent drugs and electrophilic chimerasuse high-affinity ligands to promote the fast covalent engagementof target proteins , driven by a favorably small KI for binding. We hypothesized the much lessfavorable KI associated with carbohydrate\u2013proteinbinding interactions can be offset by a favorably large kinact for the covalent labeling step. In the current study,we test this hypothesis in the context of a model system that usesrhamnose-specific antibodies to induce tumor-immune proximity andtumoricidal function. We discovered that synthetic chimeric moleculescapable of preorganizing an optimal electrophile  for protein engagement can rapidly covalently engage naturalsources of antirhamnose antibody using only a single low-affinityrhamnose monosaccharide ABD. Strikingly, we observe chimeric moleculeslacking an electrophile, which can only noncovalently bind the antibody,completely lack tumoricidal function. This is in stark contrast toprevious work targeting small molecule hapten and peptide-specificantibodies. Our findings underscore the utility of covalency as astrategy to engage low-affinity carbohydrate-specific proteins fortumor-immune proximity induction.Carbohydrate-bindingreceptors are often used by the innate immunesystem to potentiate inflammation, target endocytosis/destruction,and adaptive immunity . To access this class of receptors for cancer immunotherapy,a growing repertoire of bifunctional proximity-inducing therapeuticsuse high-avidity multivalent carbohydrate binding domains to offsetthe intrinsically low affinity associated with monomeric carbohydrate\u2013proteinbinding interactions ( We demonstatethat heterobifunctional electrophilic moleculescan covalently engage carbohydrate-specific proteins for tumor immunotherapy,leveraging only simple low-affinity sugars. For example, the mannose receptor (CD206) on macrophagesrecognizes mannose/fucose on pathogenic targets, leading to phagocytosis,and is a marker for macrophage polarization (CD206 overexpressed onM2-like tumor-associated macrophages).26 therapeutic strategies function through the highly stabilized engagementof carbohydrate binding receptors. One strategy uses lysosome targetingchimeras (LYTACs), which integrate a tumor-targeting antibody witha multivalent array of GalNac and M6Pn sugars.28 The simultaneous engagement of ASGPR or CI-M6PR and the target leadsto endocytosis and lysosome accumulation/degradation of the cell surfaceor soluble target proteins. Notably, analogous nonantibody-based approacheshave also been reported.30Severalbifunctional \u201cproximity-inducing\u201d35 Upon reaching a critical threshold of antibodies localized to thetarget surface (opsonization), subsequent engagement of immune components(i.e. tumor-immune proximity induction) can affect target eliminationvia complement-dependent cytotoxicity (CDC), antibody-dependent cellularcytotoxicity (ADCC), or antibody-dependent cellular phagocytosis (ADCP).In fact, glyco-engineering the mAb glycan at position Asn297 can uniquelyincrease antitumor function by increasing antibody glycan bindingaffinity for Fc receptors.41 For example, defucosylation can stabilize glycan CD16\u03b1 interactions,leading to enhanced ADCC.43A second strategyuses monoclonal antibodies (mAbs) which functionby simultaneously binding both tumor antigens (via their Fab domain)and sugar-specific immune receptors (via their glycosylated Fc domain).45 Alternatively, Sheridan et al., Jakobsche et al., and Goyard etal. demonstrated antirhamnose-induced CDC of target cells throughartificial multivalent rhamnose arrays on target cells .48 Interestingly, Li et al. used rhamnose- and folic acid-functionalizedliposomes to induce targeted CDC in vitro and tumor regression invivo.49A third strategyuses multivalent macromolecular chimeric scaffoldsto engage endogenous serum antirhamnose antibodies for tumor-immuneproximity induction 1. Here aKd \u2248 10\u20133\u201310\u20136 M, typically defined by rapid koff) limits probe and therapeutic pursuits to target sugarbinding receptors.52 The engagement strategies discussed above  used multivalent carbohydrate modalitiesto enhance the apparent binding affinity for sugar-binding receptors.Such modalities leverage rapid microscopic rebinding kon events to offset rapid microscopic dissociation koff events. This reduces the overall dissociationof the bound therapeutic into the bulk solvent (increased Kdapp). Multivalent immune-binding modalities,however, have been shown to cluster and activate immune proteins/receptorsbefore localization to the target.58 In the context of tumor immunotherapy, this phenomenon would complicatetherapeutic pharmacokinetics and potentially limit applications todirect tumor injection. Additionally, due to rapid microscopic dissociationevents, these multivalent modalities may insufficiently stabilizeimmune cell\u2013tumor cell proximity and synapse formation, toenforce anticancer immune function .60 Indeed, the effects of rapid microscopic dissociation and rebindingeffects on the efficiency of immune receptor activation are currentlynot well-defined and may not be as effective as a slow microscopicdissociation event .61 Furthermore, the function of multivalent engagershas shown a subtle dependence on the spatial optimization of bindingligands, complicating design.65 Taken together, while conventional multivalent approachesto engage sugar-binding receptors can enhance Kdapp, they are associated with the potential for off-targetimmune activation and complex design requirements, and may not optimallypromote tumor-immune proximity induction.Intrinsically weak carbohydrate\u2013proteinbinding affinity(Kdapp through theelimination of koff). We previously developedcovalent antibody recruiting molecules (cARMs) which can covalentlyengage endogenous small molecule and peptide-specific antibodies withina ternary complex.66 cARMs complement \u201cchemicallyprogrammed\u201d monoclonal antibodies and \u201creactive immunization\u201dtechnologies by expanding access to endogenous protein receptors.68 Electrophilic chimeras such as cARMs and covalent drugs in generaltypically use high-affinity ligands to promote fast labeling kineticswith the target protein .70 This has traditionally limitedaccess to engaging sugar binding receptors using these therapeuticmodalities due to a weak (large) KI forbinding. We hypothesized that optimal preorganization of a key electrophileproximal to the carbohydrate, however, could offset an intrinsicallyless favorable KI through significantincreases in kinact.72As an alternativeto multivalent engagement, we sought to developa small bifunctional molecule approach that uses a minimal monovalentcarbohydrate affinity ligand to engage sugar binding receptors withhigh apparent affinity. We hypothesized this could be achieved bycoupling reversible carbohydrate binding with irreversible covalentengagement. This would kinetically stabilize monovalent carbohydrate\u2013receptorinteractions and potentially enhance therapeutic function .77 In this work, we observed that cARMs equipped with only a singlemonovalent rhamnose ligand can selectively covalently engage low-affinityrhamnose-specific serum antibodies. We also demonstrate that substitutionsat the anomeric center (\u03b1-O vs \u03b1-S/\u03b2-S) are toleratedby these polyclonal antibodies. Additional kinetic studies with acommercial monoclonal antibody (anti-23F), derived from patients vaccinatedwith PPV23, show a uniquely distinct preference for the \u03b1-glycosidicconfiguration and reveal a potential for novel therapeutic synergybetween antirhamnose recruitment chemical strategies and bacterialvaccinations.24 The discovery that a bacterialvaccine-induced antibody recognizes monovalent \u03b1-O-rhamnose cARMs provided a key model monoclonal antibody to optimizecARM covalent kinetics (kinact). We foundthat the weak KI associated with bindingrhamnose-specific antibodies could be offset by substituting the acylimidazole electrophile on cARM, with an optimally pre-organized arylsulfonyl fluoride electrophile. This substitution enabled dramaticincreases in kinact and subsequently thesecond-order labeling rate constant kinact/KI. Finally, in functional tumor-immuneproximity induction assays, we observed that covalency is criticallyrequired for cARM dependent immune function, with analogous noncovalentARMs completely lacking immunotherapeutic efficacy. This representsthe most striking example of covalent enhancement in tumor-immuneproximity induction in the literature. This work also contributesa rare example of an efficacious electrophilic bifunctional molecule/chimerathat uses a weak affinity (\u03bcM) binding ligand for proximityinduction. This discovery further increases the accessibility of sugar-bindingimmune receptors for synthetic immunotherapy using small chimericmolecules.cARMs wereequipped with a monomeric rhamnose ABD to bind serumantirhamnose antibodies, an acyl imidazole electrophile, and an establishedglutamate urea (GU) TBD to target prostate-specific membrane antigen. This is particularly problematic since the monomeric rhamnosebinding affinity for specific antibodies is substantially weaker thanthe typical range of ligand affinities (\u223cnM) commonly usedfor covalent drug development. For these reasons, we sought to testhow structural perturbations to the glycosidic linkage  impact recognition by anti-rhamnoseserum antibodies. This has yet to be systematically explored in theantibody recruiting literature.The most efficient syntheticroute for incorporating a rhamnose binding ABD into cARM moleculesrequires elaboration from the glycosidic linkage. This allows facileincorporation of both a covalent electrophile and TBD. Functionalizationat the anomeric center, however, can significantly reduce/block theaffinity for anti-rhamnose, which will decrease/inhibit covalent engagementkinetics . This enabled rhamnose immobilizationonto streptavidin surfaces and subsequent antibody binding studies.We used biolayer interferometry (BLI) to estimate and compare theapparent affinity of serum polyclonal antirhamnose antibodies foreach rhamnose affinity probe (1\u20133) was loaded onto streptavidin-coated biosensors and submerged ina solution of human IgG (26.25 \u03bcM) isolated from pooled humanserum, followed by measurement of the association kinetics . In the context of proximity-inducing molecule development,this low monovalent sugar-binding affinity will ultimately limit ternarycomplex formation. A parallel ELISA study demonstrated similar resultsin the context of whole human serum . These results demonstrate that rhamnose-specific serum antibodiestolerate structural permutations about the rhamnose glycosidic linkage.The confirmation of low affinity binding also supports why multivalencyhas been historically required to efficiently engage antirhamnoseantibodies for tumor-immune proximity induction and engage sugar bindingreceptors in general.We began by synthesizing antirhamnoseaffinity probes consisting of \u03b1-O/\u03b1-S and \u03b2-S rhamnoseglycosides functionalized with a propargyl group for CuAAC-mediatedcoupling to a biotin TBD (compounds ty probe 1B. Each 24 We proceeded to study anti-23Fin BLI assays as done in 1 and 2). Notably, the calculatedaffinity of anti-23F antibody is \u223c10\u00d7 stronger than thatfor polyclonal serum antirhamnose, predominantly through increasesin kon (Tables S1 and S2). Collectively, our data supportthe use of anti-23F as a model monoclonal antirhamnose antibody andsuggest a potential novel therapeutic synergy between PPV23 vaccinationand antirhamnose recruitment chemical strategies . Furthermore, given the efficient recognitionof \u03b1-rhamnose by both endogenous human polyclonal and monoclonalantirhamnose sources, it was selected as the ABD for subsequent cARMdevelopment.The advancement of synthetic immunotherapeutic modalities targetinganti-rhamnose antibodies has been complicated by a lack of model monoclonalantibody to enable medicinal chemistry optimization. Previous studiesrelied on polyclonal antirhamnose sources for validation studies. We hypothesized that antibodies induced byvaccination against the 23F serotype of streptococcus pneumonia (whichcontains \u03b1-rhamnose) would serve as a source of novel monoclonalantibodies. FDA-approved vaccines (such as PPV23) can induce anti-23Fantibodies, with patient-derived monoclonal anti-23F antibody sequencescommercially available.Figure S2).An initial set of cARM tool compounds were synthesized to test ifthe cognate low-affinity monovalent rhamnose ABD can direct selectivelabeling of antirhamnose antibodies . If successful,this would represent a rare example of leveraging weak binding sugarligands to affinity label endogenous protein receptors.85 cARM chemical synthesis requires careful considerationof both the glycosidic linkage and acylimidazole activated ester reactivities.Given the lability of these functionalities to both pH and nucleophiles,we developed a convergent synthetic strategy that connects a preassembledelectrophilic building block with an \u03b1-rhamnose glycoside fragment,via late-stage CuAAc coupling (Scheme S1).cARM design was guided by in-silico dockingusing anti-23F. Here a flexible PEG spacer tethered to the ABD wasused to preorganize an appended acyl imidazole (AI) group, with K104on the antibody heavy chain S2.An in4 \u03b1-O rhamnose or 5 \u03b1-S rhamnose)  and noncovalent analog ARMs  were incubated with 2% human serum for 48 h followedby addition to a streptavidin-ELISA plate. Antibody recruitment tothe plate surface was measured via the addition of HRP-conjugatedanti-IgG or anti-IgM secondary antibody, followed by a chromogenicsubstrate. To assess labeling selectivity, the rhamnose competitor(Comp) was added during the incubation of cARM with antibody. Thecompetitor will inhibit only ABD binding-dependent covalent labelingand antibody recruitment to the plate, but not nonspecific labeling.In the absence of a competitor, we observed robust absorbance signalin samples incubated with cARM. In the presence of a competitor, however,the signal was largely attenuated or abolished, consistent with selectivecovalent labeling. To discern covalent versus noncovalent antibodyengagement, this experiment was repeated with rhamnose competitoradded after the 48 h incubation to quench the selective labeling reaction,prior to addition to the ELISA plate. This quench control showed abaseline signal for each ARM compound (1 and 2) as anticipated since covalent engagement is not possible. The quenchcontrol for cARM compounds 4 and 5, however,still exhibited significant antibody binding signal, supporting covalentengagement of anti-rhamnose. Comparing cARM compounds 4 and 5, we observed that the \u03b1-O rhamnose cARMcovalently engages more antibody compared to the \u03b1-S variant.Since the results in Next, we tested if cARM tool compounds can selectively label endogenoushuman polyclonal antirhamnose antibodies via ELISA (hamnose) 2B. cARMs6 fluorescein-\u03b1-O rhamnose, 7 fluorescein-\u03b1-Srhamnose, or 8 A647-\u03b1-O rhamnose). Each compound(4 \u03bcM) was incubated with anti-23F (2 \u03bcM) for 24 h directlyin 10% human serum and analyzed via reducing SDS-PAGE. Covalentlyengaged proteins were visualized via fluorescent gel imaging. cARMcompound 7 demonstrated significantly reduced capacityfor labeling anti-23F as compared to compound 6. Thiswas largely attributed to the hydrolytic instability of the acylimidazoleon 7 . In linewith docking studies, cARM compound 6 exclusively labelsthe heavy chain of anti-23F. Consistent with the results in 6 was significantly reducedin the presence of fluorescein competitor. To further test this hypothesis,we repeated the labeling experiment with cARMs that substitute fluoresceinwith the more hydrophilic A647 fluorophore (compound 8), connected with a longer peg linker. Compound 8 showedsignificantly reduced HSA labeling while retaining the ability toselectively label anti-23F antibody.To investigate cARM covalent engagement of higher-affinity monoclonalanti-23F, fluorescent cARMs were synthesized and evaluated using SDS-PAGE(oleon 7 S4. In li8 (2\u2013100 \u03bcM) was incubated withanti-23F (2 \u03bcM) for up to 4 h. Densitometry analysis of fluorescentlylabeled protein bands was used to quantify antibody labeling . Low product conversion allowed foran initial rates analysis to approximate both kinact and KI, . Labeling selectivitywas demonstrated by incubating cARM with isotype IgG, which led toa significantly lower fluorescence band signal (even at high 50 \u03bcMcARM). Furthermore, labeling selectivity is supported by the observationof a plateau in a plot of kobs vs concentration.This is inconsistent with a nonspecific bimolecular reaction thatoccurs independently of a pre-equilibrium binding step. The extractionof KI from Kd (since koff \u226b kinact) and is comparable to data obtained inBLI studies  cARMs and a comparable rhamnose-ARM . These compoundswere then evaluated for their capacity to activate immune cells againstPSMA cancer targets (Hek-PSMA cells) in an ADCC reporter assay (Supporting Information). Antibody mixtures werethen added directly to Hek-PSMA cells followed by the addition ofCD16\u03b1 expressing jurkat cells and incubation . cARM 9 with a flexible PEG spacerand ARM 11 failed to induce immune activation. Interestingly,cARM 10 with an alkyl spacer successfully mediated specificimmune activation. The inclusion of rhamnose competitor during theantibody labeling reaction (\u201cRhC\u201d) ablated signal, demonstratingthe specificity of anti-rhamnose labeling vs abundant off-target antibodiesin the sample. Use of a specific PSMA inhibitor as well as isogenic PSMA(\u2212) Hek cell line controls  showed no immune activation, demonstrating targetspecificity. Additional studies indicated that the loss of cARM 9 function compared to cARM 10 was due to animpaired ability to covalently label anti-23F . We hypothesize that the incorporation of the GUTBD and rhamnose ABD allows for intramolecular H-bonding between GU\u2212COO\u2013 and rhamnose \u2212OH groups formingan inactive intramolecular complex unable to efficiently bind andlabel antibody. The formation of this complex may be prevented bythe alkyl linker, which could adopt a fixed conformation via hydrophobiccollapse. Taken together, these results show that both covalency andlinker properties are critical to stabilizing ternary complexes withsugar binding receptors for proximity induction.Previous studiesusing high-affinity haptens or peptides to direct covalent antibodyengagement revealed functional enhancements compared to noncovalentanalogs. Given the high binding affinity interaction, however, noncovalentanalogs also demonstrate varying degrees of function.er assay 3. Brieflkinact/KI) is relatively small to function efficiently directlyin vivo. cARMs would thus require high concentrations and long incubationtimes for immune function. To function efficiently in vivo, antibodylabeling kinetics must occur on a time scale of minutes to hours tocompete with fast renal excretion. Strategies to enhance covalentchimera/inhibitor protein labeling kinetics typically include optimizingelectrophile preorganization or enhancing the ligand binding affinity.For targeting sugar binding receptors using cARMs, however, theseapproaches are likely to require extensive medicinal chemistry toyield only modest improvements that are applicable to only a subsetof polyclonal antirhamnose antibodies. Given the significant labelingrate enhancements observed in our laboratory using SuFEx chemistrycombined with its versatile amino acid reactivity,84 we redesigned rhamnose cARMs to substitute the acyl imidazole foran aryl sulfonyl fluoride (SO2F) electrophile.Rationally designed rhamnose-cARMsdemonstrated specific covalent engagement of polyclonal and modelmonoclonal antirhamnose antibodies; however, the second-order labelingrate constant . To evaluate the capacity of rhamnose-SO2F-cARMsto specifically label polyclonal antirhamnose antibodies, a tool cARMwith a biotin TBD was synthesized . As an orthogonal kinetics assay to fluorescentgels, tool compound 12 labeling kinetics was first evaluatedusing an in-house BLI assay and compared to acyl imidazole cARM andARM analogs. Here, each biotin containing cARM 12 or 4, or comparable ARM 1 (10 \u03bcM), was incubatedwith human IgG (230 \u03bcM) for up to 25 h, followed by 8\u00d7dilution with rhamnose competitor .Solutions were immediately loaded onto streptavidin probes . In this assay, rhamnose competition blocks noncovalentantirhamnose recruitment, thus the signal amplitude is directly proportionalto the covalently labeled antibody product. The signal amplitude (labeledantibody) from BLI biosensor data  was plotted as a function of reaction time  for up to 2 h andrun directly on reducing SDS-PAGE. Initial rates kinetic analyseswere performed as in Figure S9). Once again, minimal isotype IgG labelingwas observed, supporting high target antibody labeling selectivity.Consistent with in-silico studies and the capacity of SO2F to label multiple amino acids, compound 13 labeledboth heavy and light chains of anti-23F. Extraction of kinact/KI using initial rates.The significantly improved labeling rate suggests that SO2F cARMs can also function more effectively in targeted immune activationassays and potentially in vivo. This significant increase in kinact for SuFEx versus AI is striking, giventhat both electrophiles are comparably preorganized for reaction withthe antibody, and suggests that features of the antibody binding pocketuniquely enhance SuFEx reactivity compared to that of other electrophilesused for affinity labeling applications such as acylimidazoles. Thisincrease in kinact also serves to uniquelyoffset the weak KI for monovalent carbohydrate\u2013proteinreceptor binding, i.e., antirhamnose, to afford rapid second-orderreaction kinetics.As a reciprocal method to quantitatively compare rhamnose-SOFigures S10 and S11). Rhamnose-SO2F-cARM was foundto specifically label lysine 104 of the heavy chain, in line within-silico studies. No other labeling site was detected on the lightchain; however, the lability of the SO2F-serine/tyrosinelinkage to MS sample preparation protocols likely limited completelabeling site coverage. Based on dual heavy/light chain labeling observedin SDS-PAGE , it is highly likely that rhamnose-SO2F-cARMlabels other binding pocket proximal residues, which is ideal forengaging a structurally heterogenic protein target such as serum antirhamnoseantibodies. Due to the low labeling efficiency of rhamnose-AI-cARM,no labeling site could be identified. Collectively, these resultsdemonstrate the kinetic advantage of using SO2F vs acylimidazoleelectrophiles for covalently stabilizing carbohydrate\u2013proteininteractions using bifunctional molecules. These results also supporthigh selectivity for the covalent engagement of rhamnose specificantibodies versus off-target antibodies and serum proteins. Determiningthe selectivity for antirhamnose antibodies in the presence of off-targetcell surface proteins will be the focus of future in vivo studies.To further confirm selectivity, an MS studywas conducted to determinethe site of labeling .The ability to selectively induce opsonization of model prostate cancercells via monoclonal anti-23F was first evaluated using fluorescencemicroscopy . Compound 14 (8 \u03bcM) was incubated with anti-23F (4 \u03bcM) for 24 h followedby addition to PSMA expressing Hek-PSMA cells. Following a 20 minincubation, fluorescent secondary antibody was added. After an additional20 min incubation, cells were fixed and imaged using an incucyte imager.cARM compound 14 was observed to induce target opsonizationin contrast to antibody alone through specific PSMA-dependent targeting. The addition of rhamnose competitorduring the antibody labeling reaction again inhibited covalent antibodyengagement and opsonization of target cells . Interestingly, comparable ARM 11, whichallows for noncovalent engagement of antirhamnose antibody, failedto opsonize target cells despite high affinity binding to PSMA onHek-PSMA cells and high PSMA expression .54 This is likely due to low affinity binding interactionsbetween rhamnose and antirhamnose antibody (Kd \u2248 15 \u03bcM) which limits ternary complex formation.This result illustrates the power of covalency for the proximity inductionof carbohydrate binding receptors using a low-affinity sugar ligand.To test the antitumor immune function of rhamnoseSOcroscopy S12. Comp10, alkyl-ARM 11, and SO2F-cARM 14 to direct immuneactivation via polyclonal anti-rhamnose antibodies was evaluated usinga modified ADCC reporter assay  during incubation significantly attenuatedimmune activation; however, some antibody labeling and jurkat activationwas observed. Since labeling selectivity is well established in reciprocalassays described above, we hypothesize that this is due to the rapidlabeling kinetics of 14 and weak binding affinity (rapid koff) of the rhamnose competitor (which attenuatesits competitive efficacy). Addition of cARM 14 directlyto antibody and the target without prior incubation  leads to a baseline signal. Thisdemonstrates the necessity of covalent engagement for functional immuneactivation. Repeating the experiment with isogenic PSMA(\u2212)Hek cell lines failed to induce immune activation, demonstrating targetspecificity. A similar experiment using monoclonal anti-23F in lieuof polyclonal antibody directed analogous immune activation .Next, the capacity of alkyl-AI-cARM er assay 5C. ADCC 14 inducedphagocytosis of all PSMA-expressing target cancer cells in a PSMA-dependentmanner ).74 Failure of compound 14 to induce ADCP with isotypeantibody supports high covalent labeling selectivity. Consistent withprevious data, AI-cARM 10 is nonfunctional even againstvery high target expressing Hek-PSMA cells with affinity matured anti-23Fantibody. The failure of ARM 11 as well as 14 at time zero  to induce ADCP demonstratesfunctional dependence on covalent antibody engagement. These resultsalso demonstrate the inability of monovalent ARMs to induce efficaciousADCP/ADCC with low-affinity monovalent carbohydrate ligands. Additionally,we show that optimized SuFEx cARMs can covalently stabilize theselow-affinity antirhamnose antibody\u2013sugar binding interactionsmore efficiently than previous cARMs that used activated ester electrophilesto further enhance tumor-immune proximity induction.Finally, the capacity of Rha-cARMsto induce ADCP of multiple targetcell lines (varying in PSMA expression) was evaluated. ADCP representsa major mode of antitumor monocyte/macrophage immunotherapeutic function,also invoked by several FDA-approved monoclonal antibody therapies.In these assays, each compound was incubated with monoclonal anti-23Ffor 24 h followed by addition to target cells (stained with DiO celldye) and IFN\u03b3 activated U937 monocytes (stained with DiD celldye). These mixtures were incubated , and ADCP wasmeasured via flow cytometry. cARM compound kinact to affordthe first covalent chimera that efficiently engages a sugar-specificprotein and overcomes the obstacle posed by intrinsically weak carbohydratebinding affinity . cARMcovalent chimeras also uniquely stabilize carbohydrate\u2013proteininteractions to rescue the loss of tumoricidal function associatedwith noncovalent ARM analogs. Our covalent glyco-chimeric strategyalso presents a potential alternative to multivalency to engage sugar-specificreceptors for proxmity induction using simple available monovalentcarbohydrate ligands.We report a proof of concept covalent proximity induction strategyfor carbohydrate-specific protein engagement, with applications inglyco-immunotherapeutic development. Structure\u2013activity relationshipanalysis surrounding the rhamnose glycosidic linkage, combined withthe discovery of a model monoclonal anti-rhamnose antibody (anti-23F),contributes new knowledge and toolsets to aid the future developmentof antibody recruitment technology. We also reveal a potential therapeuticsynergy between antirhamnose recruitment and FDA-approved antibacterialvaccines. Substituting activated ester electrophiles with SuFEx enabledstriking increases in"}
+{"text": "Over the past decade, developers have made advances in addressing sexual and reproductive health (SRH) needs through multipurpose prevention technologies (MPTs)\u2014products designed to simultaneously prevent HIV, Sexually transmitted infections (STIs), and/or unintended pregnancy . MultiplThe majority of MPTs under development incorporate HIV prevention  12) con con12) cNon-HIV STIs account for 98% of all prevalent STIs worldwide , 16. In Non-HIV STIs are inextricably linked to HIV and contraception. Infection with some STIs such as HSV, chlamydia and gonorrhea may increase the risk of HIV acquisition , 25. UseWhile not universally available, the global market for HIV prevention includes medications taken pre- or post-exposure with different formulations including daily pill, long-acting injectables and vaginal rings \u201332. PrevTriple protection MPTs with broad pregnancy, non-HIV STIs, and HIV prevention make up about a quarter of all MPTs in development  12). Ad. Ad12). Efforts to counter the STI epidemic through MPTs rely on several key actions listed in BOX 1"}
+{"text": "To the Editor: Blood transcriptional profiling is a powerful tool to evaluate immune responses to infection; however, blood collection via traditional phlebotomy remains a barrier to precise characterization of the immune response in dynamic infections, especially when early and frequent measurements are desired. During acute viral infections, the complex interplay between innate and acquired immunity drives a rapidly evolving immune landscape; a delicate balance between pro- and antiinflammatory molecules can pivot an individual toward effective pathogen elimination or excessive host tissue damage. Thus, tracking the immune kinetics at deep temporal resolution during this period can offer valuable mechanistic insights into pathogenesis of the infection. Our team recently developed a home collection toolkit (homeRNA) that enables self-collection of liquid capillary blood coupled with immediate in-field stabilization of RNA  and uninfected (n = 5) participants self-collected blood using homeRNA every other day, in addition to completing daily nasal swabs and symptom surveys across a 2-week observational window  and 74% of pathways  showing statistically significant temporal dynamicity  with VL for all COVID-19+ participants , the cytidine deaminase (APOBEC3G) involved in host-dependent viral editing, chemokine receptors , DNA/RNA sensor (ZBP1), the transcription factor (XBP1) associated with endoplasmic reticulum stress, and cytolytic granule protein perforin-1 (PRF1)  using temporally aligned blood and swab samples to better understand mechanisms that potentially drive viral clearance. A single ISG, icipants . Moderat1 (PRF1) . Prior sptors CCR, CX3CR1,n status , suggest"}
+{"text": "TRDMT1 gene knockout (KO) on DNA methylome was analyzed.We have previously shown that TRDMT1 methyltransferase is a regulator of chemotherapy-associated responses in glioblastoma cells. Despite the fact that glioblastoma, a\u00a0common and malignant brain tumor, is widely characterized in terms of genetic and epigenetic markers, there are no data on TRDMT1-related changes in 5-methylcytosine pools in the genome. In the present study, the effect of TRDMT1 KO glioblastoma cells. Total 5-methylcytosine levels in DNA, DNMT1 pools and DNMT activity were studied using ELISA. Reduced representation bisulfite sequencing (RRBS) was considered to comprehensively evaluate DNA methylome in glioblastoma cells with TRDMT1 KO.CRISPR-based approach was used to obtain TRDMT1 KO cells were characterized by decreased levels of total 5-methylcytosine in DNA and DNMT1, and DNMT activity. RRBS-based methylome analysis revealed statistically significant differences in methylation-relevant DMS-linked genes in control cells compared to TRDMT1 KO cells. TRDMT1 KO-associated changes in DNA methylome may affect the activity of several processes and pathways such as telomere maintenance, cell cycle and longevity regulating pathway, proteostasis, DNA and RNA biology.TRDMT1 should be considered as a prognostic marker and carefully monitored during glioblastoma progression.TRDMT1 may be suggested as a novel modulator of gene expression by changes in DNA methylome that may affect cancer cell fates during chemotherapy. We postulate that the levels and mutation status of The online version contains supplementary material available at 10.1007/s11060-023-04304-8. IDH1) is a driver of the CpG island methylator phenotype (CIMP) in gliomas [IDH1 gene in primary human astrocytes promoted extensive DNA hypermethylation and reshaped the methylome that mimicked the changes noted in G-CIMP-positive lower-grade gliomas [Glioblastoma is a common and aggressive brain tumor. Although a\u00a0number of anti-glioblastoma therapies are available , prognosis is poor and long-term survival is limited . Gliobla gliomas . The lac gliomas . More stTRDMT1 knockout (KO) increased sensitivity to PARP inhibitors in osteosarcoma cells and TRDMT1 was proposed to be a novel target in DNA damage-based anti-cancer therapies [TRDMT1 KO may modulate chemotherapy-associated responses that affected genetic stability and promoted cellular heterogeneity in stress-induced senescent glioblastoma cells [TRDMT1 KO also affected microRNA pools during doxorubicin-stimulated ER stress in glioblastoma cells [Despite the fact that TRDMT1 methyltransferase was initially classified as DNA methyltransferase (former name: DNMT2), TRDMT1-mediated DNA methylating activity is established to be residual . In contherapies . More rema cells . TRDMT1 ma cells . HoweverTRDMT1 KO on DNA methylation at a\u00a0genome-wide scale at single-nucleotide resolution was analyzed using a cellular model of glioblastoma in vitro, namely U-251 MG cell line. Reduced representation bisulfite sequencing (RRBS) revealed significant differences in methylation-relevant DMS-linked genes in TRDMT1 KO glioblastoma cells. Signaling pathways associated with DMS-linked genes were also identified by the means of gene ontology (GO) analysis.In the present study, the effect of CRISPR-based DNMT2/TRDMT1 gene as previously described [\u2122 3000  according to the manufacturer\u2019s instructions. Plasmid-mediated effects  were also monitored using Control Double Nickase Plasmid (Santa Cruz Biotechnology). Cells with DNMT2/TRDMT1 KO (D-NIC cells) were selected in the presence of puromycin  and DNMT2/TRDMT1 gene knockout was confirmed using anti-DNMT2 antibody  and western blotting [U-251 MG human glioblastoma cell line was used . Cells were routinely cultured as described elsewhere . CRISPR-escribed . Brieflyblotting .DNA was isolated using a GenElute\u2122 Mammalian Genomic DNA Miniprep Kit . The levels of 5-methylcytosine in DNA samples (100\u00a0ng) were evaluated using MethylFlash\u2122 Global DNA Methylation (5-mC) ELISA Easy Kit  and an absorbance microplate reader according to the manufacturer\u2019s instruction. Results were normalized to C-NIC cells.\u2122 DNA Methyltransferase Activity/Inhibition Assay Kit (EpiGentek), respectively, according to the manufacturer\u2019s instruction.The nuclear extracts were obtained as previously described . DNMT1 . RRBS library was created using normalized DNA samples and Premium RRBS kit . 100\u00a0ng of DNA were digested with methyl-insensitive restriction enzyme (MspI) to obtain DNA fragments containing at least one CpG site. Digested DNA samples were ligated to methylated adapters including indexes and were purified using magnetic beads . DNA was then bisulfite converted and enriched using PCR amplification. Obtained RRBS libraries were quantified using QUBIT High Sensitivity dsDNA Assay (Thermo Fisher Scientific) and their quality was assessed using High Sensitivity DNA ScreenTape Analysis of the TapeStation system . Three pools of four indexed equimolar RRBS libraries were subjected to next generation sequencing (NGS) on the Hiseq Illumina system using 150 cycles of pair end mode of NGS.http://www.bioinformatics.babraham.ac.uk/projects/fastqc), followed by trimming procedure that allowed to remove reads that did not fulfill the following criteria:\u2009<\u200920 phred quality, reads shorter than 35\u00a0bp, presence of adapters (Flexbar) [http://www.bioinformatics.com.cn) was used. The RRBS results were presented as peak chromosome distribution and circle plot. Enriched horizontal bars with colors were created using WeiShengxin on the basis of data generated with DIANA tools.The raw reads were checked for quality assessment with the use of FastQC software (Flexbar) . After tFlexbar) , followeFlexbar) . Next, thttps://david.ncifcrf.gov/). The data collected from the Functional Annotation search included gene groups identified in a specific biological process (GOTERM BP DIRECT), molecular function (GOTERM MF DIRECT), cellular compartment (GOTERM CC DIRECT), Uniprot keywords (UP KEYWORDS), and KEGG pathway term (KEGG PATHWAY). Functional Annotation Clustering uses an algorithm to reduce redundant term association and provides an enhanced biological interpretation of specific gene groups being analyzed. For the visualization of DMS results, analytics platform WeiShengxin (http://www.bioinformatics.com.cn) was used. The DMS results were presented as Gene Ontology (GO), chord and enrichment bubble plot.The annotation of variably methylated CpG sites was provided using reference human genome (build HG38) using variant effect predictor tool of the Ensembl database (version 104). In order to retrieve biological context of observed differential methylation, overrepresentation tests were performed for genes linked to differentially methylated CpG sites using functional annotation chart of DAVID web available tools  that promoted cellular heterogeneity during drug-induced senescence [TRDMT1 KO also affected the levels of 5-methylcytosine RNA methyltransferase NSUN family in chemotherapy-stimulated senescent glioblastoma cells [TRDMT1 KO modulated microRNA pools during doxorubicin-induced ER stress in glioblastoma cells [As TRDMT1 may regulate cellular stress responses by 5-methylcytosine modification of RNA , 21, we nescence . TRDMT1 ma cells . Furtherma cells . Thus, TTRDMT1 KO glioblastoma cells was initially evaluated using ELISA-based approach  and TRDMT1 KO cells (D-NIC cells)  was used to provide a\u00a0comprehensive analysis of differentially methylated sites in TRDMT1 KO in glioblastoma cells resulted in the presence of DM loci of genes that products methylate DNA or histone proteins . In addition, aforementioned DMS linked genes may be implicated in the regulation of cell cycle, cellular senescence and cellular responses to DNA damage (Table S2).TRDMT1 KO cells that are relevant to the functioning of nervous system such as neuron differentiation based on the group of hypomethylated and hypermethylated genes in C-NIC versus D-NIC cells (Table S3). 36 DMS linked genes were selected for additional analysis of 15 GO terms crucial for cellular process such as apoptosis, mTOR signaling pathway, cellular senescence, autophagy, cell cycle, mRNA surveillance pathway, longevity regulating pathway, proteasome, protein export, RNA degradation, RNA polymerase, protein processing in endoplasmic reticulum, p53 signaling pathway, ferroptosis and DNA replication. We have found that the most DMS linked genes were involved in mTOR signaling pathway  (Table S4). DAVID overrepresentation test showed that enhancer-related CpG sites variably methylated between C-NIC and D-NIC cells were found in loci of genes encoding transcription factors (mostly homeobox proteins) overrepresented in DNA binding processes (Table S4).Due to irregular distribution of differential methylation values of enhancer-related CpG sites between C-NIC and D-NIC cells, we have also performed overrepresentation testing for their co-occurred genes. As a result, we found a list of 47 genes significantly overrepresented in selected GO terms  in terms of RNA methylome and associated DEGs [As we have already stated, there are no data on ted DEGs . The autted DEGs .TRDMT1 should be analyzed during glioblastoma progression as novel prognostic markers.In conclusion, we have shown that apart from TRDMT1-mediated regulation of gene expression by RNA modification , microRNSupplementary file1 (XLSX 2120 kb)Below is the link to the electronic supplementary material."}
+{"text": "Septic children can develop a severe compensatory anti-inflammatory response, termed \u201cimmunoparalysis (IP)\u201d, which is strongly associated with adverse outcomes. IP can be defined as a reduced ability of innate immune cells to produce TNF\u03b1 when whole blood is stimulated ex vivo with LPS (a TNF\u03b1 response < 200 pg/ml). Adaptive (lymphocyte-based) immune function is poorly understood in IP. We hypothesize that septic children with IP will also have suppressed lymphocyte cytokine production capacity and reduced lymphocyte populations.Single-center, prospective, observational study of children (< 18 yrs) with septic shock. Subjects were enrolled and sampled < 48 hrs from shock onset. Ex vivo whole blood stimulation assays were used to evaluate innate (LPS-induced) and adaptive (PHA-induced) cytokine production capacities . Cell populations were measured by flow cytometry . Identical sampling and processing were done in a cohort of healthy control children. Data represent median (IQR).TNF\u03b1 production after lipopolysacharide (LPS) stimulation (innate immune response) is measured by chemiluminescence . Cytokine production after phytohemagglutinin (PHA) stimulation (adaptive immune response) is measured by multiplex assay (Biorad).Table 1Whole blood was stained within 30 minutes of collection and included the cell populations shown above. Samples were acquired on the cytometer within a week of staining and analyzed using FlowJo 10.8.0 software.30 children with septic shock  and 11 healthy controls  were enrolled. Among septic subjects, length of stay was 5  days in the ICU and 17  days in the hospital. Etiologies and sites of infection are shown in Fig3.Septic subjects had lower ex vivo PHA-induced cytokine production , and relative lymphopenia by flow cytometry vs healthy controls, especially double negative-T cells  and \u03b3\u03b4-T cells .12 septic subjects had IP. Rates of viral detection  and viral-bacterial co-detection  were higher in the IP group vs non-IP septic subjects. Subjects with IP had lower monocyte HLA-DR expression but no differences in lymphocyte populations. PHA-induced production of Th1 cytokines was lower in those with IP, while production of Th2 cytokines was preserved .*Subjects where included in analysis if treated as presumed bacterial infections. Abbreviations: PCR: Polymerase chain reaction; GI: Gastrointestinal; MSSA: Methicillin susceptible S aureus; MRSA: Methicillin resistant S aureus; Rh/E: Rhinovirus/Enterovirus; RSV: Respiratory Syncytial virus; PIV: Parainfluenza Virus.Comparisons done by Mann-Whitney U test. Asterisks represent p-value <0.05.Comparisons done by Mann-Whitney U test. Asterisks represent p-value <0.05.and adaptive immune suppression. Immunoparalysis was associated with skewing to a Th2 profile of cytokine production, and with the presence of viral infections. This approach has the potential to drive enrollment into clinical trials of personalized immunomodulation in this population.Children with septic shock have early innate Mark Hall, MD FCCM, Abbvie: Advisor/Consultant|Kiadis: Honoraria|Partner Therapeutics: complementary study drug Sobi for a clinical trial for which I am the Principal Investigator|Sobi: Complementary study drug for a clinical trial for which I am the Principal Investigator"}
+{"text": "Nearly \u2153 of outpatient antibiotic prescriptions are unnecessary or inappropriate. QuizTime is a web-based application based on Test-Enhanced Learning Theory that delivers daily case-based questions to a learner\u2019s email or cell phone. We performed a prospective cohort study to evaluate the impact of a QuizTime module on appropriateness of pediatric outpatient antibiotic prescriptions.Table 1). Participants were pediatric prescribers  in a primary care, urgent care, retail health, or emergency department setting. Antibiotic prescription data were collected during the \u201cbaseline\u201d period  though 3 months after QuizTime participation (Jul 15 \u2013 Oct 15 2022) defined as the \u201cpost-quiz\u201d period. Pre- and post-intervention data were analyzed in aggregate (not at the provider-level). Significance was determined by calculating a 95% confidence interval (CI) for the difference of proportions. Outcome measures are listed in Table 1.Participants received one question daily for 10 days starting in July 2022. Quiz topics included age-appropriate antibiotic duration for acute otitis media (AOM), empiric antibiotics for uncomplicated urinary tract infections (UTI), and empiric antibiotics and duration for community-acquired pneumonia (CAP) . AOM guideline-concordant antibiotic duration was significantly higher among participants than non-participants (Table 2). There were encouraging trends towards improvement in secondary outcomes .Eighty clinicians participated in QuizTime totaling 13,478 antibiotic prescriptions  compared to 776 non-QuizTime clinicians totaling 43,321 antibiotic prescriptions  (Clinicians who participated in a QuizTime module on pediatric outpatient antibiotic prescribing showed improvement in antibiotic appropriateness suggesting web-based microlearning modules are an effective tool for disseminating antibiotic stewardship education. Creation, dissemination, and evaluation of additional QuizTime modules is ongoing.Ritu Banerjee, MD, Ph.D, bioMerieux: Grant/Research Support|bioMerieux: company is providing partial support for an ongoing trial unrelated to submitted abstract Sophie E. Katz, MD MPH, Dolly Parton Pediatric Infectious Diseases Research Funds: Grant/Research Support|Optum: Advisor/Consultant|Pfizer: Grant/Research Support"}
+{"text": "CEBPB, while gRNAs targeting WSB1, MED28, and p73 were observed multiple times. CEBPB is a transcription factor associated with activation of proinflammatory response genes suggesting that inflammation may be present in DC cells. The inflammatory response was investigated using RNA sequencing to compare DC and control cells. Expression of inflammatory genes was found to be significantly elevated (P < 0.0001) in addition to a key subset of these inflammation-related genes . which are regulated by CEBPB. Exogenous TERT expression led to downregulation of RNA/protein CEBPB expression and the inflammatory response genes suggesting a telomere length-dependent mechanism to regulate CEBPB. Furthermore, unlike exogenous TERT and p53 shRNA, CEBPB shRNA did not significantly decrease ROS suggesting that CEBPB's contribution in DC cells\u2019 senescence is ROS independent. Our findings demonstrate a key role for CEBPB in engaging senescence by mobilizing an inflammatory response within DC cells.Aging is the consequence of intra- and extracellular events that promote cellular senescence. Dyskeratosis congenita (DC) is an example of a premature aging disorder caused by underlying telomere/telomerase-related mutations. Cells from these patients offer an opportunity to study telomere-related aging and senescence. Our previous work has found that telomere shortening stimulates DNA damage responses (DDRs) and increases reactive oxygen species (ROS), thereby promoting entry into senescence. This work also found that telomere elongation via TERT expression, the catalytic component of the telomere-elongating enzyme telomerase, or p53 shRNA could decrease ROS by disrupting this telomere\u2013DDR\u2013ROS pathway. To further characterize this pathway, we performed a CRISPR/Cas9 knockout screen to identify genes that extend life span in DC cells. Of the cellular clones isolated due to increased life span, 34% had a guide RNA (gRNA) targeting  V12). These pathways can alter gene expression and arrest the cell cycle .Senescence is the result of cellular programming to prevent aged, damaged, or abnormal cells from continued proliferation. Cell intrinsic/extrinsic factors include telomere attrition (due to steady-state proliferation), DNA damage , and oncogene-induced senescence  repair pathway . HoweverCDKN1A . SustainINK4A-RB . FurtherTERC , TERT , DKC1 , and TINF2 (telomere-stabilizing protein interacts with telomere-binding proteins TRF1 and TRF2). The clinical DC phenotype is variable and classically consists of leukoplakia, abnormal skin pigmentation, and nail dystrophy in addition to pulmonary fibrosis and bone marrow failure. While hematopoietic stem cell (HSC) transplantation is the only curative therapy for bone marrow failure in DC, it is associated with significant posttransplant complications. Using several different cell types, including HSCs, fibroblasts, and lymphocytes from varying DC genotypes, we have found these cells display premature DNA damage responses (DDRs), resulting in elevated reactive oxygen species (ROS) (Dyskeratosis congenita (DC) is characterized by telomere shortening due to mutations in telomerase- and telomere-related genes. A partial list of these genes includes es (ROS) . The incOne strategy to better understand a pathway like telomere-dependent senescence is to deploy a genome-wide screen. The GeCKO  lentiviral library delivers CRISPR/Cas9 to cut gRNA-targeted genes, knocking them out via insertions/deletions created by nonhomologous end joining (NHEJ) (TINF2 mutation) were transduced with the GeCKO library. We identified a number of candidate genes, including the transcription factor CEBPB, that regulate senescence in telomere-shortened cells. RNA sequencing (RNA-seq) revealed a significant inflammatory gene expression response , CXCL2 (GROb), and CXCL5) in DC cells that could be corrected upon exogenous TERT (exogTERT) expression. Cells expressing exogTERT also had a decrease of both CEBPB (RNA and protein) and CEBPB\u2013SASP-related gene expression. These findings identify new genes and downstream pathways that could promote senescence in a background of shortened telomeres.We designed a forward genetic experiment whereby primary fibroblasts from a DC patient (TINF2 (R282C) and TERT (R631W) as previously reported (DKC1 (A353V). Primary skin fibroblasts were expanded and grown in DMEM supplemented with 10% fetal bovine serum under atmospheric oxygen conditions, as previously described . Skin punch biopsies were collected from DC patients and healthy volunteers after written informed consent. DC mutations included https://www.addgene.org/pooled-library/zhang-human-gecko-v2/). DNA purification adjustments were made to ensure equal amplification of each DNA vector  (https://media.addgene.org/cms/files/GeCKOv2.0_library_amplification_protocol.pdf). For lentiviral virus production {GeCKO, CEBPB/p53/scrambled shRNA [(Dharmacon)], 293 T HEK cells were transfected with the purified DNA library or vector in combination with accessory lentiviral plasmids  using Fugene 6  during log-phase growth and washed 16 h later. Puromycin antibiotic selection (1 \u00b5g/mL) was added to media for 5 days to isolate cells infected with virus. To isolate gRNA clones derived from the GeCKO library transductions, cell colonies were ring-cloned to permit sequencing gRNAs. Retroviral exogenous TERT . Isolated genomic DNA was PCR-amplified  with primers flanking the gRNA common to each GeCKO. PCR-amplified DNA was cloned using the TA cloning system (Invitrogen) and transformed into DH5\u03b1 bacteria. Individual bacterial colonies were isolated, DNA-extracted, and submitted for Sanger sequencing .http://broadinstitute.github.io/picard). The read count tables were generated using HTSeq (v0.6.0)  and control fibroblasts were scraped in the presence of Trizol. RNA was extracted using the Qiagen RNeasy Mini RNA extraction kit. Total RNA was submitted for sequencing using the NextSeq500 (Illumina). Sequencing reads were mapped to the reference genome (hg19) using the STAR aligner (v2.5.0c) ((v0.6.0) , normali(v0.6.0) , and dif(v0.6.0)  and bedGROS analysis was performed as previously reported (\u2212\u0394\u0394CT (Expression of CEBPB was examined in cells expressing 5 different CEBPB shRNAs (Dharmacon). Isolated RNA was converted to cDNA via iScript cDNA synthesis (Bio-Rad). CEBPB and \u03b2-actin (ACTB gene) were amplified from cDNA with Power SYBR Green PCR Master Mix (Life Tech) to assess relative expression between control (scrambled shRNA) and CEBPB shRNA cells. Analysis was performed on the ViiA Real-Time PCR expression analyzer (Life Tech) using equation 2\u2212\u0394\u0394CT .Standard western blotting techniques were used as previously described . TINF2-mutated fibroblasts were transduced with the GeCKO lentiviral CRISPR knockout library at a low multiplicity of infection (MOI) to prevent transduction of cells with multiple viruses/gRNAs. In total, 38 colonies were isolated and submitted for Sanger sequencing of the incorporated gRNAs, uncovering \u223c42 gRNAs with an average 2.0 unique gRNAs per colony. To verify that the gRNAs were indeed cutting the locus of interest, genomic DNA was PCR-amplified flanking the cut site and Sanger-sequenced to verify genomic targeting. A representative figure of typical CRISPR verification is presented in CEBPB and MED28, 2 other genes were also found repeatedly knocked out and deemed high-value. As noted in CEBPB (13 clones), WSB1 (3 clones), MED28 (3 clones), and TP73 (3 clones).We set out to identify human genes that promote senescence due to telomere dysfunction using primary skin fibroblasts from a DC patient with a single p53 shRNA in TINF2-mutated cells. Expression of exogTERT, but not p53 shRNA, caused near complete loss of CEBPB protein expression . Each genotype was transduced with vector control, exogTERT or p53 shRNA, and examined for gene expression changes by pooling genotypes together. DC cells expressing exogTERT showed a 40% decrease in CEBPB expression . Expression of another SASP factor, CSF3 (G-CSF), was the most variable among all genotypes in the targeted analysis of CEBPB-regulated genes. Its expression among the 3 DC genotypes averaged a 37-fold increase (P < 0.001) and decreased an average of \u223c20\u00d7 in exogTERT cells . Using all 3 genotypes, a pairwise comparison of DC cells and those expressing exogTERT found a statistically significant difference (P < 0.0001). However, knocking down p53 in DC cells created a more robust inflammatory response than untreated DC cells (P < 0.0001). Together these data suggest that DC cells mobilize CEBPB to augment the expression of SASP-related genes to promote an inflammatory response. The concomitant decrease in CEBPB gene/protein expression and genes regulated by CEBPB in exogTERT cells suggests the reduced SASP/inflammatory response is likely telomere length-dependent.GSEA was performed on the RNA-seq data sets and provided further evidence that primary DC cells have a significant underlying inflammatory response , there was no significant decrease in ROS within these same cells (P < 0.001), as previously reported. These results provide evidence that primary DC cells may have multiple, redundant, prosenescence pathways that are either DDR/ROS-dependent or CEBPB-dependent.Telomere elongation or me cells . Decreasp53 shRNA) rescued proliferation and decreased ROS , CXCL2 (GROb), CXCL5, CSF3 (G-CSF)] and others  confirming the capacity of the screen to return credible gene candidates. Finally, knockout of WSB1 may have imparted and extended life span via an E3 ubiquitin ligase that targets and destabilizes ATM through ubiquitination in 293T and MEF cells (The GeCKO screen also recovered a gRNAs targeting ignaling . CEBPB dTERT expression or blocked a functional DDR from taking place. It is also possible that gRNAs may have targeted and knocked out unanticipated genes; however, off-target minimization was a consideration designing the library (We cannot rule out that alternative explanations may account for increased life span in colony knockouts. Gene knockouts may have led to the activation of endogenous The recovery of CEBPB and other genes within our CRISPR screen indicates that additional mediators of senescence exist that may have not been previously appreciated. CEBPB and the downstream SASP response appear to be influenced by TERT activity and not DDR according to our p53 shRNA/ROS experiments. Although initiated by dysfunctional telomeres, the CEBPB and DDR/ROS pathways likely belong to independent but redundant pathways each contributing to senescence. A model for the relationship among shortened telomeres, DDR, and CEBPB/inflammation is presented in jkad207_Supplementary_DataClick here for additional data file."}
+{"text": "Zika virus (ZIKV) infection continues to pose a significant public health concern due to limited available preventive measures and treatments. ZIKV is unique among flaviviruses in its vertical transmission capacity  yet the underlying mechanisms remain incompletely understood. Here, we show that both African and Asian lineages of ZIKV induce tunneling nanotubes (TNTs) in placental trophoblasts and multiple other mammalian cell types. Amongst investigated flaviviruses, only ZIKV strains trigger TNTs. We show that ZIKV-induced TNTs facilitate transfer of viral particles, proteins, and RNA to neighboring uninfected cells. ZIKV TNT formation is driven exclusively via its non-structural protein 1 (NS1); specifically, the N-terminal region (50 aa) of membrane-bound NS1 is necessary and sufficient for triggering TNT formation in host cells. Using affinity purification-mass spectrometry of cells infected with wild-type NS1 or non-TNT forming NS1 (pNS1\u0394TNT) proteins, we found mitochondrial proteins are dominant NS1-interacting partners, consistent with the elevated mitochondrial mass we observed in infected trophoblasts. We demonstrate that mitochondria are siphoned via TNTs from healthy to ZIKV-infected cells, both homotypically and heterotypically, and inhibition of mitochondrial respiration reduced viral replication in trophoblast cells. Finally, ZIKV strains lacking TNT capabilities due to mutant NS1 elicited a robust antiviral IFN-\u03bb 1/2/3 response, indicating ZIKV's TNT-mediated trafficking also allows ZIKV cell-cell transmission that is camouflaged from host defenses. Together, our findings identify a new stealth mechanism that ZIKV employs for intercellular spread among placental trophoblasts, evasion of antiviral interferon response, and the hijacking of mitochondria to augment its propagation and survival. Discerning the mechanisms of ZIKV intercellular strategies offers a basis for novel therapeutic developments targeting these interactions to limit its dissemination."}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-023-29521-z, published online 20 February 2023Correction to: The original version of this Article contained an error in the Author Information section.\u201cThese authors contributed equally: Seungju Park, Kyung Hwa Lee, Beomseok Ko and Namkug Kim.\u201dnow reads:\u201cThese authors contributed equally: Seungju Park and Kyung Hwa Lee.\u201dThe original Article has been corrected."}
+{"text": "Atopic eczema is the most common chronic inflammatory skin condition  [We identified 37 patients with atopic eczema between January to October 2022 who attended with novel ocular surface toxicity, related in time-period often <1week) to Epimax initiation ). Most patients reported using Epimax ointment , with seven (18.9%) using Epimax original cream (seven unknown). Most reported subjectively reduced VA, frequently associated with photophobia (89.2%). Clinical findings included bilateral involvement (67.6%), with conjunctival injection (97.3%), corneal staining (97.3%), and corneal oedema (27%). Ocular pH was documented in seven initial cases (range 7\u20138). Four patients (10.8%) had complete/near complete corneal epithelial defects. No patients had limbal ischaemia. [See Fig.\u00a0week to EFollowing diagnosis, most patients received topical lubricants (86.5%), topical antibiotics (73%) and topical steroids (64.9%). Mean visual acuity improvement in affected eyes was 15.8 EDTRS letters with significant symptom resolution by first follow up appointment (average 7.3 days (range 2\u201334)). No geographic clustering was identified on postcode analysis, or association identified with Scottish Index of Multiple Deprivation scores .Like most emollients, the Epimax range contains safety information advising no contact with the eyes. See Fig.\u00a0 Aspire PIn summary, we report the first large case-series of patients with eczema experiencing Epimax-related ocular surface toxicity (EROST). Patients should avoid periocular application of Epimax, and healthcare professionals made aware of this potential association."}
+{"text": "Objective: To present clinical findings and multimodal imaging of three patients who developed bacillary layer detachments (BALADs) shortly after half-fluence, half-dose (HFHD) verteporfin photodynamic therapy (PDT). Methods: Retrospective observational case series. Three patients were treated with HFHD-PDT for (1) macular neovascularisation five years after resolved central serous chorioretinopathy (CSC), (2) persistent serous retinal detachment (SRD) from chronic CSC, and (3) neovascular age-related macular degeneration with persistent SRD despite intravitreal anti-VEGF therapy. Results: Each patient developed a BALAD after HFHD-PDT. Acute fulminant exudation caused subretinal fluid expansion into the inner photoreceptor layer, cleaving myoid from ellipsoid zones in the central macula. Subretinal fluid and the BALADs subsequently resolved over 6\u20138 weeks. Conclusions: The subretinal fluid and BALAD following HFHD-PDT were transient and did not cause photoreceptor damage over a 6-month follow-up period. We speculate that the reduced-impact HFHD protocol decreases direct tissue damage but increases proinflammatory cytokines. The long-term pathophysiological consequences of the resolved BALADs are unknown. PDT went site ,4,5. Curent site ,8. PDT wd laser 60 nm irraent site .Reduced dose and fluence PDT protocols were developed in the mid-2000s in the hope of decreasing adverse PDT effects including choroidal ischemia with transient vision loss, retinal pigment epithelium (RPE) atrophy, and macular neovascularization (MNV) . InitialThe HFHD-PDT protocol aims to preserve the beneficial effects of PDT while minimizing associated chorioretinal damage. Unfortunately, a reduced photosensitizer-effect protocol can cause unexpected and undesired increases in post-operative exudation and even bacillary layer detachments (BALADs) have been described in patients treated for cCSC ,19,20,21A 60-year-old man presented with SRD and MNV 5 years after previously resolved cCSC. Six monthly intravitreal anti-VEGF (aflibercept) injections reduced exudation but the persistence of a SRD prompted a change in treatment and the choice of PDT. Six weeks after the last aflibercept injection, HFHD-PDT was performed with a laser spot size of 2000 \u00b5m. Preoperative visual acuity was 20/100. Fluorescein and OCT-angiography at that time revealed MNV at the superior-nasal border of the fovea and structural OCT imaging documented the associated SRD .Two days after PDT, the patient returned complaining of decreased vision in his right eye. Visual acuity was 20/200. OCT showed increased subretinal fluid (SRF) extending to the central fovea where there was a central BALAD . The BALA 56-year-old man was referred for metamorphopsia and decreased vision in his right eye persisting for several months. His visual acuity was 20/100. Multimodal imaging showed active cCSC. His symptoms persisted for three more months and the patient was treated by performing HFHD-PDT with a spot size of 3000 \u00b5m. The patient returned two days after PDT complaining of markedly decreased vision in his right eye. Visual acuity had decreased there to 20/250. Structural OCT showed a foveal BALAD, a small central RPE detachment, and increased SRF extending from the optic disc to the temporal macula . The patA 74-year-old woman had persistent SRF despite multiple anti-VEGF (aflibercept) injections for MNV due to nAMD in her left eye. HFHD-PDT (spot size 3000 \u00b5m) was performed six weeks after the last aflibercept injection in an effort to stop further SRF accumulation and visual decline. The patient presented three days after the PDT for an additional intravitreal aflibercept injection. She reported significant vision loss in her left eye where structural OCT now showed a prominent increase in SRF and a central BALAD . The BALHere, we report clinical and multimodal imaging findings of three patients treated with HFHD-PDT for (1) MNV from resolved cCSC, (2) persistent serous retinal detachment (SRD) from cCSC, and (3) nAMD with persistent SRD despite intravitreal anti-VEGF therapy.The patient records and images were reviewed retrospectively and data abstracted for this report. All patients underwent multimodal imaging, including color, near-infrared and autofluorescence imaging, fluorescein angiography , and optical coherence tomography (OCT) . The findings in Case 2 were discussed in an earlier report  but we hAll visual acuities listed thereafter are best-corrected visual acuities expressed as Snellen ratios and measured at 5 m.2) over 83 s using a 693 nm wavelength) Vitra PDT, Quantel Medical, Cournon-d\u2019Auvergne, France) adapted on a slitlamp biomicroscope  15 min after the infusion of a half-dose of verteporfin  (3 mg/m2) over 10 min. The PDT laser spot size varied according to the patient\u2019s condition.Each patient received half-fluence PDT  causes endothelial cell and collateral tissue damage ,2. CelluExudation after PDT has been previosuly referred to as \u201ctransient serous retinal detachment\u201d , \u201cacute Manayath et al. identified PDT-induced acute exudative maculopathy only in patients treated with full-dose PDT and spots sizes \u22653500 \u00b5m. Fern\u00e1ndez-Vigo et al.\u2019s protocol limited them to 4000 \u00b5m spot sizes in their full-dose PDT cCSC treatment protocol. Unlike these studies, we used a half-dose, half-fluence protocol in an effort to minimize collateral PDT damage. We found that post-PDT exudative BALADs can occur with smaller 2000\u20133000 \u00b5m treatment spot sizes in half-dose PDT. Additionally, the Fern\u00e1ndez-Vigo et al. study found BALADs after PDT therapy for cCSC patients, but we also identified them after PDT for MNV in nAMD and MNV that occurred without active CSC in an eye previously treated for cCSC (pachychoroid neovasculopathy ). In our three patients, increased exudation and BALAD formation was transient and did not cause photoreceptor damage in the post-operative monitoring period. The long-term effects of resolved BALADs, if any, have yet to be determined. Limitations of our study include its small size and retrospective design. We believe that patients undergoing HFHD-PDT should be informed that an infrequent but prominent decrease in vision can happen post-operatively and recommend that they return for further evaluation should that occur."}
+{"text": "Elderly women have increased aortic stiffness, measured by pulse wave velocity (PWV), and show little increase in PWV with inotropic stress. The aim of this study was to examine gender related differences in aortic stiffness at rest and during physiological exercise stress in young non-athletic subjects.Eighteen healthy subjects without known cardiovascular disease  underwent cardiovascular magnetic resonance (CMR) imaging at rest and supine bicycle exercise for cine and high-resolution flow imaging.At rest both genders demonstrated similar haemodynamic parameters and PWV. To achieve 85% of the age-predicted heart rate (apHR), men required significantly greater workload (p=0.05) and showed higher systolic blood pressure  than women. Imaging at 60% apHR, sustained by hand-grip exercise, revealed an increase in stroke volume and cardiac index in men (p=0.05), whereas women showed no difference from rest (p=0.45). Men showed a strong increase in PWV (p=0.02), whereas women showed only a trend towards a difference (p=0.09).In young healthy non-athletic males there is a greater increase in PWV and systolic BP than women. Our findings concord with previous observations in elderly population during inotropic stress and inform on the gender differences in maximal performance and ageing.NIHR"}
+{"text": "Left ventricular mass (LVM) quantification by cine-CMR is typically performed by planimetry of contiguous LV short axis images. This approach relies on use of anatomic landmarks or quantitative binary cutoffs to define the basal-most aspect of the LV. Methodological discordance concerning criteria for LV basal slice selection has the potential to alter cine-CMR quantified LVM. This study assessed frequency of methodological variability in published LV basal slice definitions, as well as its impact on cine-CMR quantification of LVM.A Pubmed search was performed using the terms \"left ventricular mass\", \"left ventricular hypertrophy\", \"myocardial mass\", or \"hypertrophy\" AND \"cardiac MRI\", \"CMR\" or \"magnetic resonance imaging\" . Manuscripts were reviewed by an AHA/ACC level III CMR trained physician for methodology concerning basal slice criteria; methods were categorized based on quantitative and anatomic criteria as defined in each manuscript. Published methods were then applied to an established registry of CAD patients: Cine-CMR images were planimetered for percent circumferential LV myocardium and basal-most LV short axis slices were assigned using the most common quantitative cutoffs determined by literature review.2) for ED50 and 22.0\u00b110.0gm (11.2\u00b15.0 gm/m2) for EDS50, respectively constituting 3.2% and 13.0% of total LVM as calculated when all CMR-evidenced LV myocardium was included.129 original research publications that measured LVM by cine-CMR were identified by systematic literature review. Basal slice criteria were unspecified in 35%, included all LV myocardium in a small minority (5%), with the remainder evenly divided in use of anatomic landmarks (30%) or quantitative cutoffs (30%) Figure . LVM conMarked variability exists in published CMR literature regarding anatomic and quantitative criteria to define the basal-most LV on short axis cine-CMR. Application of established binary cutoffs frequently excludes LV myocardium from CMR measurements, resulting in 3-13% decrements in calculated LVM.K23 HL 102249-01, Lantheus Medical Imaging (unrestricted research grant)"}
+{"text": "Epstein-Barr virus (EBV)-associated post-transplant smooth muscle tumours (PTSMT), are rare complications following organ/stem cell transplantation. Despite the mainly benign behaviour of PTSMT, alternative therapies are needed for those patients with progressive tumours. In tumours not approachable by surgery or reduction of immunosuppression, the angiogenic microenvironment might be a potential target of therapy, an approach that is well utilised in other soft tissue neoplasms. In a previous study, we evaluated the expression of EBV-related genes and the microRNA profile in PTSMT, but so far the characteristics of angiogenesis in PTSMT are not known. Therefore, the aim of this study was to evaluate the expression pattern of angiogenesis-related genes in PTSMT, in order to identify potential target molecules for anti-angiogenic therapy.PTSMT (n\u2009=\u20095 tumours) were compared with uterine leiomyomas (n\u2009=\u20097). Analyses included real-time PCR of 45 angiogenesis-associated genes, immunohistochemistry  and assessment of tumour vascularisation by conventional histopathology.PTSMT showed similar or fewer vessels than leiomyomas. Of the genes under investigation, 23 were down-deregulated (pro-angiogenic and some anti-angiogenic factors) and five were up-regulated (e.g. PTGS1 which is expressed at very low levels in leiomyomas but moderately higher levels in PTSMT).In summary, no particular target molecule could be identified, because tumour angiogenesis in PTSMT is characterised by low levels of major pro-angiogenic factors and there is no prominent increase in tumour vascularisation. EBV can induce angiogenesis via its viral late membrane protein 1 (LMP1) but PTSMT frequently do not express LMP1, which could be an explanation why, despite EBV infection, PTSMT show no exaggerated tumour angiogenesis. Epstein-Barr virus (EBV)-associated post-transplant smooth muscle tumours (PTSMT) are rare complications following solid graft and stem cell transplantation . The molFrom other tumours, in particular renal cell cancer, we know that hypoxia-inducible factor 1, alpha subunit (HIF1A) signalling mediates expression of VEGF, platelet-derived growth factor (PDGF) and angiopoietin via the PI3K/mTOR pathway ,5. These+ PTSMT samples from four patients, including two tumours from one patient (#4), and seven EBV- benign uterine leiomyomas from solid graft recipients were analysed. These cases had been characterised earlier . Statistical analysis was performed with Prism 5.0  by applying the non-parametric Kruskal-Wallis test followed by the Mann-Whitney test for two-group comparison. P values\u2009<\u20090.05 were considered as statistically significant.Tissue from FFPE blocks with >90% tumour cells were cut and processed for further PCR analysis. In blocks with <90% aberrant neoplastic cells, the PTSMT compartments of the specimens were laser microdissected using a SmartCutPlus-System , as previously described ,10. Cell+ vessels per 10 high power fields (HPF) and then correlating them in serially cut haematoxylin-eosin-stained sections. Statistical analysis was performed with Prism 5.0 as described above.Deparaffinised and rehydrated FFPE tissue sections (1-2 \u03bcm) were stained after autoclave pre-treatment. For staining of platelet/endothelial cell adhesion molecule 1 (VCAM1/CD31), sections were processed in an automated staining system . Prostaglandin endoperoxide synthase 1 (prostaglandin G/H synthase and cyclooxygenase) (PTGS1) was stained manually (positive control: FFPE prostate cancer tissue). Mouse monoclonal antibodies were used. Vascularisation was quantified by counting CD31in situ hybridisation (FISH) [As previously described, PTSMT tumour cells themselves were negative for CD31. In the cerebral PTSMT we could previously demonstrate aneuploidy of the MYC locus 8q24 by fluorescence + vessels/10 HPF, p\u2009=\u20090.0480; Figure\u00a0PTSMT showed similar or fewer vessels than leiomyomas  were up-regulated , kinase insert domain receptor (VEGFR2/KDR) and VEGFA as well as anti-angiogenic serpin peptidase inhibitor, clade E , member 1 (SERPINE1), thrombospondin 1 (THBS1) and TIMP metallopeptidase inhibitor 2 (TIMP2).Except for CD31, significant differences of other up-regulated factors were due to very low expression in leiomyomas rather than strong expression in PTSMT. These factors were angiopoietin 2 (ANGPT2), PDGFRA, PTGS1 and thymidine phosphorylase (TYMP). Because PTGS1 can be inhibited by widely used non-steroidal anti-inflammatory drugs, immunohistochemistry was performed for evaluation if the tumour cells showed a corresponding protein expression. A weak expression of PTGS1 proteins in PTSMT and leiomyomatous smooth muscle spindle cells was detectable . This might principally indicate a limited ability to circumvent therapy and therefore anti-angiogenic drugs might not necessarily be ineffective since this would disrupt the equilibrium of PTSMT vascularisation. Anti-angiogenic drugs could still be administered to PTSMT patients with no other treatment options available but, in these present analyses, we could not identify a specific target molecule.In summary, our analyses of the tumour angiogenesis in PTSMT revealed no particular target molecule, because PTSMT are characterised by low levels of major pro-angiogenic factors and there is no prominent increase in tumour vascularisation.The authors of this manuscript have no conflicts of interests to disclose.Histomorphology , molecular analysis , data collection, analysis of data and manuscript preparation . All authors read and approved the final manuscript.Figure S1.\u2009Fluorescence in situ hybridisation of the MYC gene shows no aneuploidy in endothelial cells (white arrows) while a subfraction of PTSMT cells had an aneuploidy.Patient cohort. Click here for file"}
+{"text": "They harvest light using bacteriochlorophyll (BChl) Rhodobacterales, Sphingomonadales and the NOR5/OM60 clade. Sphingomonadales contained comparatively smaller PGCs with an approximately size of 39 kb whereas the average size of PGCs in Rhodobacterales and NOR5/OM60 clade was about 45 kb. The distribution of four arrangements, based on the permutation and combination of the two conserved regions bchFNBHLM-LhaA-puhABC and crtF-bchCXYZ, does not correspond to the phylogenetic affiliation of individual AAP bacterial species. While PGCs of all analyzed species contained the same set of genes for bacteriochlorophyll synthesis and assembly of photosynthetic centers, they differed largely in the carotenoid biosynthetic genes. Spheroidenone, spirilloxanthin, and zeaxanthin biosynthetic pathways were found in each clade respectively. All of the carotenoid biosynthetic genes were found in the PGCs of Rhodobacterales, however Sphingomonadales and NOR5/OM60 strains contained some of the carotenoid biosynthetic pathway genes outside of the PGC.Aerobic anoxygenic phototrophic (AAP) bacteria represent an important part of marine microbial communities. Their photosynthetic apparatus is encoded by a number of genes organized in a so-called photosynthetic gene cluster (PGC). In this study, the organization of PGCs was analyzed in ten AAP species belonging to the orders Proteobacteria.Our investigations shed light on the evolution and functional implications in PGCs of marine aerobic anoxygenic phototrophs, and support the notion that AAP are a heterogenous physiological group phylogenetically scattered among  These phototrophic microorganisms are thought to be important players in oceanic carbon cycling Alpha- and GammaproteobacteriaAlphaproteobacterial AAPs belong to Roseobacter clade and the order Sphingomonadales, which includes members of the genera Erythrobacter and CitromicrobiumGammaproteobacteria belong to the clade NOR5/OM60 which contains Congregibacter litoralis KT71 Aerobic anoxygenic photototrophic (AAP) bacteria represent an important group of marine microorganisms inhabiting the euphotic zone of the ocean. They harvest light using bacteriochlorophyll (BChl) crt-bchCXYZ-puf (about 10 kb) and bchFNBHLM-IhaA-puh (about 12\u201315 kb) were identified in PGCs of different phototrophic ProteobacteriapufBA and pufLM). Interestingly, the regulatory elements such as the transcriptional regulator ppsR gene were conserved as well, suggesting that the operons in the PGCs are co-expressed. The organization of puf  operon varies among different AAP bacterial species. The presence/absence of pufC and pufQ, as well as various gene orders of puf genes, were observed Compared to the oxygenic phototrophs, the anoxygenic species contain a relatively simple photosynthetic apparatus, which consists of a reaction center surrounded by one to three types of antenna complexes Despite its diversity, complexity and functional importance for AAP bacteria, a detailed investigation of the gene and operon arrangement of PGC has not been performed in their entirety. In this study, we analyzed the structure and arrangement of PGC in the AAP bacterial genomes available to date, with the aim of addressing the frequency of homologous gene recombination as well as the differences in carotenoid gene composition and biosynthetic pathways.pufM genes, the ten strains were classified into three main groups: Roseobacter clade , Erythrobacter-Citromicrobium clade  and NOR5/OM60 clade (Gammaproteobacteria) (Roseobacter clade contained six strains belonging to five genera: Roseobacter (Rsb.) denitrificans OCh 114 Rsb. litoralis Och 149 Loktanella vestfoldensis SKA53, Dinoroseobacter shibae DFL12 Jannaschia sp. CCS1, and Roseovarius sp. 217 Shingomonadales: Erythrobacter sp. NAP1 Citromicrobium sp. JL354 Gammaproteobacteria: Congregibacter (Cb.) litoralis KT71 Gammaproteobacterium HTCC2080 L. vestfoldensis) to 4,763 kb (Roseovarius sp. 217). The PGCs represented roughly 1% of the genomes  whereas the average size of PGCs in Rhodobacterales and NOR5/OM60 clades was about 45 kb  . Roseoba genomes . Sphingout 45 kb . The GC ut 45 kb . This matopology .bch genes encoding enzymes of BChla biosynthetic pathways, puf operons encoding proteins forming the reaction centers, puh operons involved in the RC assembly, crt genes responsible for biosynthesis of carotenoids and various regulatory genes. A core set of 27 genes were identified, which were present in all analyzed PGCs  is almost identical in terms of gene arrangement and composition. When compared to Roseobacters, this group contains less carotenoid genes and no light-harvesting 2 (LH2) genes. The presence of a smaller number of photosynthetic genes in Sphingomonadales is consistent with the smaller size of their PGCs  was usually observed in upstream regions of PGCs of NOR5/OM60 clade bchFNBHLM-LhaA-puhABC and crtF-bchCXYZ (bchFNBHLM-LhaA-puh plus forward crtF-bchCXYZ-puf) includes Rsb. denitrificans OCh 114 and Rsb. litoralis Och 149. Cb. litoralis KT71, Gammaproteobacterium HTCC2080 and Roseovarius sp. 217 belong to type II (forward bchFNBHLM-LhaA-puh plus reverse crtF-bchCXYZ-puf), and the last five organisms form type III (forward crtF-bchCXYZ-puf plus forward bchFNBHLM-LhaA-puh). The last possible arrangement  has not been yet found in AAP (or AAP candidates) bacterial genomes  which are sensitive to light intensity and oxygen concentration crtJ gene was found, which controls aerobic repression of BChl, carotenoid, and LH2 gene expression There are four conserved regions in PGCs for BChl lis KT71 . There apuf gene organization were observed in the ten PGCs: pufQBALMC, pufQBALM, pufBALM and pufLMCBA. Unlike the purple non-sulfur species Rba. sphaeroides and Rba. capsulatus, all the AAP strains studied lack the pufX gene in the PGC. The pufQ gene, is absent in the puf operon of NOR5/OM60 and Sphingomonadales clades. In addition, Sphingomonadales and L. vestfoldensis SKA53 do not have a pufC gene. The gene encoding 1-deoxy-D-xylulose-5-phosphate synthase (DXPS) is always located downstream of puf genes in the Roseobacter clade. DXPS is part of a mevalonate-independent pathway for isopentenylpyrophosphate (iPP) biosynthesis, a precursor for carotenoid and bacteriochlorophyll biosynthesis puf gene cluster is observed in NOR5/OM60 clade (pufLMC-BA) compared to the other two AAP clades (pufBA-LMC).Four structural types of puhABC-hyp-ascF-puhE is conserved in Roseobacter and Sphingomonadales clades. However in NOR5/OM60 clade, puhABC and puhE are located together and ascF is at a site near BLUF. LhaA, encoding a possible LHI assembly protein puh genes. In downstream puh genes, there are hemN (NOR5/OM60 clade) or hemA  The structure of crt genes identified in Rba. capsulatus contains crtAIBKCDEFJ (crtAIBCDEF) was also found in some Roseobacter species  for it are located in the PGCs . Zeaxanthin is obtained by two step hydroxylation of \u03b2-carotene catalyzed by \u03b2-carotene hydroxylase (crtZ gene product). Interestingly, the key genes (crtY and crtZ) for zeaxanthin pathway are not organized in the PGCs, but are spread throughout the chromosome (Citromicrobium) and erythroxanthin (in genus Erythrobacter)  .Cb. litoralis KT71 is spirilloxanthin, the same as in Rhodospirillum rubrum DSM 467TcrtD was found to be out of PGC in Cb. litoralis KT71  Loktanella vestfoldensis SKA53 (NZ_AAMS00000000), Dinoroseobacter shibae DFL 12 (NC_009952) Roseobacter denitrificans OCh 114 (NC_008209) Jannaschia sp. CCS1 (NC_007802), Roseobacter litoralis Och 149 (NZ_ABIG00000000) Roseovarius sp. 217 (NZ_AAMV00000000) Roseobacter sp. CCS2 (NZ_AAYB00000000), Roseobacter sp. AzwK-3b (NZ_ABCR00000000), Erythrobacter sp. NAP1 (NZ_AAMW00000000) Congregibacter litoralis KT71  (NZ_AAOA00000000) gammaproteobacterium HTCC2080 (NZ_AAVV00000000) Ten full-length PGC sequences and gene locations were obtained from the GenBank genome database. The GenBank accession numbers are: Rhodobacter sphaeroides strain 2.4.1 (NC_007493) and Rhodobacter capsulatus SB 1003 (NC_014034) also were included in the analysis. Another three green sulfur bacteria genome information used to outgroup of phylogenetic tree, and their Genbank accession numbers are Chloroflexus aggregans DSM 9485 (NC_011831), Chloroflexus aurantiacus J-10-fl (NC_010175) and Roseiflexus castenholzii DSM 13941 (NC_009767). In some cases the automatic gene annotation was corrected manually.For comparison two anaerobic anoxygenic phototroph pufM (>900 bps) genes and 27 core proteins in PGCs were used to construct phylogenetic trees pufM gene sequences collected from NCBI database were aligned using Clustal X and phylogenetic trees were constructed using the neighbour-joining and maximum-parsimony algorithms of MEGA software 3.0 Nearly complete Rsb. denitrificans OCh 114 (DSM 7001), Rsb. litoralis Och 149 (DSM 6996) and Erb. longus DSM 6997 were purchased from the DSMZ culture collections. D. shibae JL1447, Cmi. bathyomarinum JL354 and Erythrobacter sp. JL475 were isolated and maintained in the laboratory Sphingomonadales species) or 7\u22362 (vol\u2236vol) acetone-methanol (in the case of Roseobacter species). The pigment extract and analysis were done by high performance liquid chromatography (HPLC) as described previously Six strains were used for pigment analyses: Figure S1bch genes; red, puf and regulator genes; pink, puh genes; orange, crt genes; blue, hem and cyc gene; yellow, LhaA gene; blank, uncertain or unrelated genes; grey, hypothetical protein.Photosynthetic gene cluster structure and arrangement in other phototrophs. Green, (PPT)Click here for additional data file.Figure S2bchBCDFGHILMNOPXYZ-crtCF-pufABLM- lhaA-puhABCE-ascF. Bar, 0.1 substitutions per amino acids position.Neighbor joining phylogenetic analysis of 27 core proteins in PGCs from GenBank database. The core proteins are (PPT)Click here for additional data file.Table S1The major carotenoid composition in AAP bacteria.(DOC)Click here for additional data file."}
+{"text": "Purpose. Genetic polymorphisms of MICA and DEPDC5 have been reported to correlate with progression to hepatocellular carcinoma (HCC) in chronic hepatitis C patients. However, correlation of these genetic variants with HCC recurrence following hepatectomy has not yet been clarified. Methods. Ninety-six consecutive HCC patients who underwent hepatectomy, including 64 patients who were hepatitis C virus (HCV) positive, were genotyped for MICA (rs2596542) and DEPDC5 (rs1012068). Recurrence-free survival rates (RFS) were compared for each genotype. Results. Five-year HCC recurrence-free survival (RFS) rates following hepatectomy were 20.7% in MICA GG allele carriers, 38.7% in GA, and 20.8% in AA, respectively (P = 0.72). The five-year RFS rate was 23.8% in DEPDC5 TT allele carriers and 31.8% in TG/GG, respectively (P = 0.47). The survival rates in all (including HCV-negative) patients were also similar among each MICA and DEPDC5 genotype following hepatectomy. Among HCV-positive patients carrying the DEPDC5 TG/GG allele, low fibrosis stage (F0-2) occurred more often compared with TT carriers (P < 0.05). Conclusions. Neither MICA nor DEPDC5 genetic polymorphism correlates with HCC recurrence following hepatectomy. DEPDC5 minor genotype data suggest a high susceptibility for HCC development in livers, even those with low fibrosis stages. Hepatocellular carcinoma (HCC) is among the top five causes of cancer-related death worldwide  and is rMICA [DEPDC5 genes [MICA gene encodes a major histocompatibility complex class I polypeptide-related sequence A, which is a membrane protein that activates the anticancer effect of natural killer cells or CD8 positive T cells [DEPDC5 remains unknown, but is suggested to correlate with several other cancers [MICA and DEPDC5 may also correlate with HCC recurrence after curative therapies among HCV patients, or even among the other patients suffering from various kinds of liver diseases.Recent technical developments in genome sequencing have enabled genome-wide association studies, which clarified that two single nucleotide polymorphisms (SNPs) are associated with progression to HCC among HCV patients. The SNPs are in the MICA  and DEPDC5 genes . The MIC T cells , A allel cancers . G allel cancers . Taken tMICA and DEPDC5 genetic polymorphisms were significant prognostic factors for HCC recurrence following hepatectomy. In this study, we investigated whether From January 2002 to December 2006 at our institute, 146 consecutive patients underwent hepatectomy for primary HCC, of which 97 patients were positive for HCV. Among these 146 and 97 patients, 96 of the total patients and 64 HCV-positive patients gave informed consent and their DNA was available for genotyping. Tumor stage and differentiation, or liver fibrosis stage, were diagnosed by pathological specialists according to the TNM stage definition proposed by the Liver Cancer Study Group of Japan , which aMICA genetic polymorphism (rs2596542) and the DEPDC5 genetic polymorphism (rs1012068) were genotyped using the StepOnePlus real-time PCR system (Applied Biosystems). Genomic DNA was extracted from the patients' nontumor liver tissues obtained at hepatectomy. The All data were analyzed using JMP statistical software . A chi-square test was performed for qualitative variables, and a Wilcoxon test was performed for quantitative variables. A Logrank test was performed for survival rates using the Kaplan-Meier method.MICA GG allele was seen in 30 and GA and AA were seen in 22 and 12 patients, respectively  among HCV-positive patients among those carrying GG (20.7%), GA (31.8%), and AA (20.8%) alleles, respectively  were more often observed than progressive stages (F3-4), compared with TT allele carriers (P < 0.05). There was no difference in RFS between each DEPDC5 genotype among HCV-positive patients  was significantly lower than those whose AFP levels were less than 100\u2009ng/mL (n = 55) , even in a small number of cases. Similarly, the other clinical factors such as tumor stage and liver function (platelet count of over 100 thousands or not) also reflected significantly HCC recurrence after hepatectomy . All the patients whose platelet count <100 thousands among HCV-positive showed HCC recurrence within five years, whereas 5-year RFS rate of those whose platelet count \u2265100 thousands was 32.5% (P = 0.0002). Among these clinical factors, tumor stage, and platelet count were still significant factors associated with HCC recurrence after hepatectomy by multivariate analysis  level, a well-known predictive factor for HCC recurrence . As show Figures . RFS ratanalysis .HCC recurrence among HCV-positive patients is a serious problem. Unlike other malignant tumors, multicentric recurrence can occur among these patients, even after curative resection of the liver. Identification of associated risk factors would permit early diagnosis and an opportunity for tailored therapy. We previously reported the significant association of hepatitis status or functions of the remnant liver with HCC recurrence, especially that caused by multicentric recurrence , 5. NotaMICA and DEPDC5 genes, both of which had been first reported as genetic factors using genome-wide association study (GWAS) associated with HCV-induced HCC occurrence, were genotyped among HCC patients who had undergone hepatectomy. No correlation between these SNPs and HCC recurrence was detected. In this study, two SNPs in the MICA SNPs were suggested to affect antitumor immunity [DEPDC5 SNPs were reported to associate with other cancers, with or without HCV [Although the molecular mechanism by which these two SNPs correlate with HCC progression remains unclear, immunity  and DEPDhout HCV . HoweverMICA and 1.75 for DEPDC5, as described in the previous reports [The problem that we are concerned with is that this study was limited to small sample size. The odds ratios of these SNPs with regard to susceptibility to HCC are as low as 1.39 for  reports , 7. An iDEPDC5 minor genotype was more susceptible to HCC development, even among those patients with low fibrosis stage (DEPDC5 genetic polymorphism at least affects susceptibility to HCC development in livers without pathological progression. In livers progressing to fibrosis or HCC, however, HCC recurrence may not depend on these genetic factors. Interestingly, the is stage . In the MICA nor DEPDC5 genetic polymorphisms might be a risk factor for HCC recurrence following hepatectomy. Patients carrying the DEPDC5 minor allele were more susceptible to HCC development, even those with low fibrosis stages. In conclusion, neither"}
+{"text": "Drosophila genetic manipulations to cause accumulation or depletion of ceramide and sphingosine-1-phosphate (S1P) intermediates. Sphingolipidomic profiles were characterized across mutants for various sphingolipid metabolic genes using liquid chromatography electrospray ionization tandem mass spectroscopy. Biochemical assays and microscopy were used to assess classic hallmarks of obesity including elevated fat stores, increased body weight, resistance to starvation induced death, increased adiposity, and fat cell hypertrophy. Multiple behavioral assays were used to assess appetite, caloric intake, meal size and meal frequency. Additionally, we utilized DNA microarrays to profile differential gene expression between these flies, which mapped to changes in lipid metabolic pathways. Our results show that accumulation of ceramides is sufficient to induce obesity phenotypes by two distinct mechanisms: 1) Dihydroceramide (C14:0) and ceramide diene (C14:2) accumulation lowered fat store mobilization by reducing adipokinetic hormone- producing cell functionality and 2) Modulating the S1P: ceramide (C14:1) ratio suppressed postprandial satiety via the hindgut-specific neuropeptide like receptor dNepYr, resulting in caloric intake-dependent obesity.Obesity is defined by excessive lipid accumulation. However, the active mechanistic roles that lipids play in its progression are not understood. Accumulation of ceramide, the metabolic hub of sphingolipid metabolism, has been associated with metabolic syndrome and obesity in humans and model systems. Here, we use  Drosophila to accumulate and deplete a variety of ceramide species and other related lipids. Our results showed that modulation of ceramide and related lipids is sufficient to induce obesity through two distinct mechanisms: a caloric intake-dependent mechanism works through suppression of neuropeptide Y satiety signaling, while a caloric intake-independent mechanism works through regulation of hormone producing cells that regulate fat storage. These data implicate ceramides in actively promoting obesity by increasing caloric intake and fat storage.Obesity is characterized by excessive weight gain that increases one's risk for pathologies such as Type II diabetes and heart disease. It is well-known that a high calorie diet rich in saturated fats contributes to excessive weight gain. However, the role that saturated fats play in this process goes far beyond simple storage in fat tissue. Saturated fats are essential building blocks for the bioactive lipid ceramide. Accumulation of ceramide has recently been associated with obesity. However, it is not known whether its accumulation plays an active role in the induction of obesity. Here, we utilized genetic manipulation in  Obesity is a condition in which body weight, caused by excessive accumulation of stored body fat, is increased to the point where it becomes a risk factor for certain health conditions and mortality. Overweight and obese individuals are at an increased risk for hypertension, dyslipidemia, Type 2 diabetes, heart disease, stroke and certain forms of cancer. Unfortunately, obesity is a growing worldwide epidemic with over 1 billion of the global population either overweight or clinically obese. Our ability to understand the underlying mechanisms involved in the pathogenesis and progression of obesity are essential to developing new methods and approaches for combating this disease.in vivo is now just becoming understood with the emergence of suitable complex genetic models for analysis.In the present study, we describe a central mechanistic role for sphingolipids (SL) in the progression of obesity. SLs are a versatile class of bioactive lipids, which play roles in a variety of signaling pathways that regulate diverse cellular functions such as programmed cell death, proliferation, migration, membrane stability, host-pathogen interactions and the stress response ob/ob mice, ceramide levels were elevated in the serum de novo ceramide synthesis, using the serine palmitoyl-transferase inhibitor myriocin, induced weight loss and decreased fat storage Ceramide, the metabolic hub of sphingolipid metabolism, has recently been associated with metabolic syndrome and obesity in humans as well as a variety of animal model systems Drosophila as a model organism to determine whether direct perturbation of sphingolipid metabolism is sufficient to induce obese phenotypes. We used genetic manipulation to cause accumulation or depletion of ceramide intermediates, as well as to modulate the sphingosine-1-phosphate to ceramide ratio . We demonstrate that genetic manipulations that cause direct ceramide accumulation induce obesity by two distinct mechanisms: 1) Dihydroceramide (C14:0) and ceramide diene (C14:2) accumulation lowered fat store mobilization by reducing adipokinetic hormone- producing cell functionality and 2) decreasing the S1P: ceramide (C14:1) ratio suppressed postprandial satiety via the hindgut-specific neuropeptide like receptor dNepYr.Here, we use de novo SL synthesis is catalyzed by serine palmitoyl-transferase (SPT)  . In fliet levels , with sit levels .k05305/2lace flies show significant reductions in whole fly triglyceride (TG) levels at 2 days (\u221221%), 8 days (\u221223%) and 15 days (\u221227%) of age relative to wt flies (lace knockdowns showed comparable reductions in both lace transcript (k05305/2lace mutants (0.97 mg/fly vs.1.10 mg/fly in wt)  ,S2C. Mutwt flies . Both mewt flies  and lipiwt flies  were redwt flies . Collectk05305/2lace mutants was dependent on changes in caloric intake. First, flies were subjected to 3 hours of starvation on agar-only media, and then transferred to Bromophenol blue stained food. The relative starvation-induced appetite response of flies was quantified as the percentage of flies which scored positive for feeding (blue abdomens) over time k05305/2lace mutants and wt flies. Furthermore, there were no differences in mean daily caloric intake  subspecies, with C14:0 dihydroceramide (DHC), dihydrosphingosine (DHS) and dihydrosphingosine 1-phosphate (DHS1P) intermediate levels increased +306%, +83%, and +257% respectively. Conversely, levels of monounsaturated C14:1 ceramides (\u221210%), sphingosine (\u221215%) and S1P (\u221231%) SL intermediates were reduced. Notably, these lines also accumulate the polyunsaturated C14:2 ceramide \u201cdiene\u201d (+190%) and sphingosine \u201cdiene\u201d (+206%) Downstream of  schlank , ifc encceramide . Mutant anscript , and sig4ifc flies exhibit increased whole fly TG at 2 days (+58%), 8 days (+50%) and 15 days (+85%)  . Both trockdowns  exhibit ockdowns \u2013B. Hemolockdowns , S2D. Suockdowns . Mean boockdowns , S2C. Thockdowns , increasockdowns , and incockdowns . Collect4ifc mutants, the starvation-induced appetite response was slightly increased relative to wt flies  and total ceramide (+55%) levels. Conversely, S1P levels are undetectable using our method in these flies , 8 days (+72%) and 15 days (+101%) (KG050894Sk2 mutants over their deficiency and Sk2 RNAi mediated knockdowns (KG050894Sk2 mutants exhibit an obese phenotype relative to wt flies.Mutant  (+101%) . Both trockdowns  exhibit ockdowns \u2013B. Increockdowns . Survivaockdowns . Mean boockdowns . These rockdowns , increasockdowns \u2013F, and iockdowns . CollectKG050894Sk2 mutants exhibit a substantial increase in starvation-induced appetite response, where over 50% of these flies consumed food within the first hour post-starvation relative to just 15% of control flies (KG050894Sk2 mutants relative to wt flies (KG050894Sk2 mutants consumed an average of 34.7% more food per day than controls (1.55 ul/day vs.1.15 ul/day)  , exhibit ul/day)  and size ul/day) . Based oSply, which irreversibly degrades S1P  and ceramide diene levels (\u221273%), as observed in k05305/2lace flies , 8 days (\u221240%) and 15 days (\u221247%)  . This cos (\u221247%) , and abds (\u221247%) . Fat bods (\u221247%)  was alsos (\u221247%) \u20132G. Furtl volume . These fl volume .4; Sk2KG050894ifc,  and ceramide dienes (+62%), as observed in 4ifc flies , 8 days (+140%) and 15 days (+184%)  . This co (+184%) , S2C, an (+184%) . Fat bod (+184%) , with el (+184%) \u20132G. Furtl volume . These fl volume .Drosophila transcripts of the Drosophila genome. Heatmap and DAVID analysis revealed differential expression of apoptosis-related genes between k05305/2lace and 4ifc mutants. Analysis showed that specific subsets of proapoptotic genes were downregulated while anti-apoptotic genes were upregulated in k05305/2lace  flies . Hence, we hypothesized that regulation of apoptosis in Akhpcs might be involved in caloric intake-independent phenotypes.Recently, apoptosis-induced cell death of Adipokinetic hormone-producing cells (Akhpc) was shown to increase TG storage Akh mRNA expression, elevated TG levels, live longer under starvation and exhibit five times higher TG levels after starvation-induced death relative to control flies 4ifc flies exhibit reduced Akh mRNA expression  was sufficient to induce a significant reduction in Akh transcript expression; with a concomitant increase in adult fly TG levels , to determine if the loss of GFP expression might be due to inhibition of Akh-g4 expression in these constructs. All Akh-g4/Akh RNAi 3rd instar larvae examined expressed detectable levels of GFP , which inhibits the activity of proapoptotic caspases Dronc and Drice. If ifc knockdown induced Akhpc ablation, we hypothesized that overexpression of dIAP1 should rescue Akhp cell death as well as normalize reduced Akh mRNA and elevated TG levels.These data suggest that the absence/reduction of GFP expression in Akhpc of Akh-g4/ifc RNAi 3dIAP1  increased Akh transcript expression and decrease TG levels relative to control flies   , exhibitAkh mRNA  and wholAkh mRNA . In 3rd jections ,S6A,SF6E larvae. .Sply may play a role in Akhp cell viability and function. First, expression levels of Akh mRNA in Sply05901 are slightly reduced compared to wild-type flies (Sply05901 flies exhibit slightly elevated TG levels at 2 days (+9%). However, these flies show no significant difference in post-starvation TG levels, suggesting that fat mobilization is largely unperturbed (Some data suggest that pe flies . Secondlerturbed .Sply knockdowns (Akh-g4/Sply RNAi) exhibit an increase in TG levels (+40%)   that corpression . These eockdowns , S5D, suKG050894Sk2 flies and lean 05901Sply flies. Heatmap and DAVID analysis showed opposing expression in gene subsets regulating major lipid metabolic pathways, including fatty acid biosynthesis and oxidation, as well as oxidative phosphorylation   of dNepYr in full overlapping orientation , with peak expression seen in late embryos (16 hr\u201324 hr) and throughout adulthood   [13]. A entation  [13]. In hindgut , with lodulthood  [16].dNepYr is upregulated in KG050894Sk2 and downregulated in 05901Sply mutants . KG050894Sk2 mutants were more responsive to a lower concentration of dRYamides then wt flies. At 10 uM dRYamides, Sk2 mutants exhibited a reduction in TG levels relative to 0 uM fed KG050894Sk2 mutants, and were not statistically different to control flies fed either 0 uM or 10 uM dRYamide containing food  than wt flies   . Furtherl levels .dNepYr mRNA levels  between normalized SL intermediate levels and phenotypes .dNepYr mRNA expression levels . Hence, dNepYr mRNA and TG levels were also positively correlated, albeit to a lesser extent . Conversely, Akh mRNA expression showed a negative correlation with TG levels .First, these data show a strong positive correlation between stored TG levels  and caloric intake , as would be expected. Caloric intake also exhibited a strong positive correlation with dNepYr mRNA expression were C14:1/C20:0 and C14:1/C24:0 ceramides . Conversely, a strong negative correlation was observed with C14:1 S1P . The ratio of total S1P: C14:1 ceramide displayed the strongest negative correlation to dNepYr mRNA expression . Importantly, the S1P: C14:1 ceramide ratio also showed a prominent negative correlation with caloric intake  and to a lesser extent, TG levels . Thus, these data establish a relationship between the S1P: ceramide ratio, dNepYr mRNA expression, caloric intake and TG stores, which are primary drivers of caloric intake-dependent phenotypes in Sply, Sk2 and their respective double mutants. No significant correlation was observed between sphingosines, dihydroceramides, or ceramide dienes with dNepYr mRNA expression levels . A negative correlation was also observed with ceramide dienes . Additionally, dihydrosphingosine  and to a lesser extent C14:1/C20:0 ceramides  were also negatively correlated. Interestingly, C14:0 S1P showed a modest correlation  with Akh mRNA expression. Furthermore, the S1P: C14:2 ceramide ratio exhibited a stronger correlation to Akh mRNA expression then C14:2 ceramides alone . Importantly, dihydroceramide species display a significant positive correlation with TG levels . These data establish a strong correlation between specific ceramide subspecies, Akh mRNA levels and TG stores, which are primary drivers of caloric intake\u2013independent phenotypes in lace, ifc and their respective double mutants. Additionally, these results suggest that S1Ps could exhibit a modest opposing role in these processes  may play in obesity. Both Sphk1 and SphK2 knockout mice are viable, with no observable abnormalities compared to wild type mice \u2212/\u2212Sphk1 mice \u2212/\u2212 Sphk2\u2212/\u2212Sphk1 double knockout mice exhibit undetectable levels of S1P, and do not survive past embryonic day 13.5, due largely to neural and vascular developmental defects KG050894Sk2 mutant flies do not exhibit compensatory function from Sk1, as S1P levels are nearly undetectable in these flies. Despite the dramatic reduction of S1P, these mutants are viable into adulthood. Interestingly, KG050894Sk2 mutant flies don't appear to exhibit metabolic adaptation to elevated ceramide levels as was recently observed in early adult 1dcerk (ceramide kinase 1) mutant flies Sk2 but not dcerk1 mutants. However, differential expression of gut lipases was similarly observed, which likely contribute to the observed obesity phenotype in both Sk2 and late adult dcerk1 mutants Sply flies exhibit caloric intake-dependent leanness in which S1P accumulation in the context of increased ceramide levels is associated with a lipolytic/leptogenic gene program. We showed that anorexic feeding behavior in these flies' stems from the gain of dNepY receptor mediated satiety signaling.Mutant SPL knockout mice (sphingosine 1-phosphate lyase) are also lean and exhibit a pronounced lack of adipose tissue. Interestingly, elevated lipid levels, including TG levels, are observed in both plasma and in fatty livers, reminiscent of human lipodistrophies. However, these mice fail to thrive and do not survive beyond weaning. This has been attributed to multiple abnormalities including congenital defects, anemia, pathological lesions, and a presumed reduction in caloric intake.Comparatively, 05901Sply mutants are viable. This allows for the study of the roles of SL metabolites in regulating feeding behavior and lipid metabolism outside of the context of other serious abnormalities throughout development and in adults. It is interesting to speculate that feeding behavior defects in SPL mutant neonates might be attributed in part to suppression of appetite via S1P accumulation.Lipodistrophies are difficult to distinguish in the context of flies as the fat body cells share functional homology with both adipose tissue and the liver. However, the fly model is advantageous in that Our data suggest that sphingolipid metabolism is involved in regulating Akhpc viability and function via the caspase dependent intrinsic apoptotic pathway. Interestingly, these data also suggest that dihydroceramide and ceramide dienes are likely potent inducers of this pathway and may be involved in the regulation of Akhp cell viability and function. In flies, Akh regulates fat mobilization in the fat body 14:1 ceramide ratio in Sk2 mutants. These data correlated with reduction in postprandial satiety via the hindgut-specific neuropeptide like receptor dNepYr, resulting in caloric intake-dependent obesity. Furthermore, these data show that dietary administration of dRYamide 1 and 2 was sufficient to overcome these effects through induction of dNepYr signaling. In addition, dietary administration of the S1P analog FTY720P was also effective at inducing satiety and downregulation of dNepYr mRNA expression.Our results showed a substantial reduction in the S1P: C14:1 ceramide ratio in Sply mutants. These flies exhibit suppressed appetites, which also appear to be dependent upon dNepYr. Sply;dNepYr double knockdowns exhibited increased caloric intake and TG levels comparable to dNepYr knockdowns. These data suggest that S1P acts upstream of dNepYr and induces satiety via dNepYr signaling.Conversely, we showed a substantial increase in the S1P: Cde novo S1P production is dependent upon the availability of both dietary saturated fats and ATP, it is an attractive candidate molecule for regulating satiety via dNepYr, which is expressed almost exclusively in the hindgut of the closed digestive system. In addition, a set of pancreatic TG lipases, which appear to be overlapping cis-NATs of dNepYr, exhibit co-expression patterns and thereby may constitute a coordinated system for dietary fat digestion and satiety.Since yw, 05901Sply (BL-11393), k05305lace (BL 12176), lace2 (BL 3156), k6050894Sk2, ifc4 (BL-1549), UAS-dIAP (BL-6657), Global Actin 5c-Gal4 (BL 4414). All double mutants were generated using classic genetics in-house . UAS-dNepYr-RNAi, UAS-lace-RNAi, UAS akh-RNAi, UAS-ifc-RNAi,UAS-Sk2-RNAi,UAS-Sply-RNAi,and UAS-CG40733-RNAi were acquired through Vienna Drosophila RNAi Stock Center Akh-gal4, UAS-GFP driver lines were graciously provided by the lab of Dr. Ronald Kuhnlein.All fly lines were propagated on synthetic yeast based media as described Nearest human homologues to fly sphingolipid proteins were determined using protein sequences from Flybase Drosophila) were acquired through Avanti Polar Lipids and used as internal standards in positive-mode multiple reaction monitoring (MRM). MRM experiments were adapted from those previously described so that only major sphingolipid species previously identified in Drosophila were monitored, identified, and quantified Measurement of major sphingolipid intermediates was performed using liquid chromatography tandem mass spectroscopy (LC/MS/MS) on a Thermo Finnegan triple quadrupole machine. Fly lipid extracts were prepared as previously described Drosophila TG levels were determined using Infinity TAG Reagent kits as previously described Fly stocks were cleared and newly emerged flies collected at the end of 6 hours. Each fly line was sorted into 10 food vials with 10 flies each, 5 males and 5 females, until 2 days of age. Flies were then transferred to agar-vials which provided only a supply of water. Survival rate was determined by the regular counting of non-responsive flies. The experiment was performed in triplicate, with each time point representing the mean based on 300 flies per line. These experiments were adapted from previous studies Fat cells were extracted from 1 day old (\u00b16 hours) flies, spilled into Ringer's buffer, fixed with 4% paraformaldehyde, stained with Nile red (10 ug/mL) and DAPI (1 ul/mL). Fat cells were then immediately photographed using a Canon 1500 digital camera on a compound light microscope at 400\u00d7magnification. The area of each cell was calculated using ImageJ Imaging Software. Each value represented is the mean of 50 random fat cell measurements taken per fly with the corresponding standard deviation. The experiment was performed in triplicate with the data representing a final mean of 150 cells. Lipid droplet size was assessed in 10 representative fat body cells for each line based on mean fat body cell size. The area of the 10 largest lipid droplets within each cell was measured. A second measure of nile red positive area was performed using a preset color threshold across all FBs and lines. This area was quantified as a % area of the total cell area.At three days of age, flies were transferred to agar-only starvation vials for 2 hours. These flies were then transferred into synthetic yeast-based food vial stained with 0.10% Bromophenol Blue. Flies were scored for blue colored abdomens every 30 minutes for 3 hours. Each value represented is the mean of 100 flies taken per fly line with the corresponding standard deviation. The experiment was performed in triplicate with each data point representing a final mean of 300 flies. This experiment is based on variations of the methods described One week old male flies were raised in a humidity controlled (>70%) incubator at 22\u00b0C on a 12 hour day and night cycles. Daily food consumption was measured in microliters per day based on displacement of liquid food levels in a 5 ul microcapillary tube. The experimental setup, procedures and determination of meal frequency were performed as described Synthetic yeast based food was allowed to cool to near room temperature and mixed with appropriate concentrations of 1\u22361 dRYamide 1: dRYamide 2 peptide before setting. For the CAFE assays, peptide was added to liquid food media described in Total RNAi was isolated from 25 whole flies with a Qiagen RNeasy Isolation kit as per manufacturer's protocol. Total RNA (1 ug) was checked for quality and purity using gel electrophoresis and UV spectrophotometry. RNA was subsequently reverse-transcribed using an iScript cDNA synthesis Kit from Biorad as per manufacturer's protocol. Primers were designed using Perl Primer software and ordered from ValueGene. Standard PCR was used to test primer sets for single amplicon products. Annealing temperature of the primers was optimized and One-Step qPCR was carried out using a BioRad iCycler IQ. Housing keeping gene RPL-32 was used as a control.Drosophila genes. Statistical validation of duplicate experiments results were carried out using Affymetrix software Gene Spring. Heat mapping analysis of metabolic gene subsets was carried out using open source MeV software provided generously to the public by TIGR. The gene subsets selected were based on globally expressed Drosophila metabolic genes found to be homologous to mammalian genes by KEGG Pathways using DAVID (david.abcc.ncifcrf.gov/).RNA was isolated from 25 female flies aged 2 days using a Qiagen RNA isolation Kit. Affymetrix chips were used with oligo targets for 14,131 known Akh mRNA expression, and dNepYr mRNA expression. Coefficients were determined using relevant data points across all fly lines  normalized to wt levels. P-values were calculated using a standard t-test.Pearson correlation coefficients (multiple r) were calculated using the excel correlation data function to measure the degree of correlation between normalized SL metabolites and various metabolic parameters, including 2, 8 and 15 day TG levels, caloric intake, Figure S11118 respectively). Each SL mutant and RNAi KD fly was measured for mRNA expression of their respective target gene. (A\u2013D)P element mutants. (E\u2013H) RNAi-mediated KD. Error bars represent S.E.M. .Verification of SL gene expression in P element and RNAi knockdown flies. Data is represented as relative mRNA expression normalized to wildtype flies (canton-s and w(TIF)Click here for additional data file.Figure S2Hallmarks of obesity. Mean triglyceride (TG) levels in (A) SL mutants over deficiency lines and (B) globally driven SL RNAi knockdown flies. (C) Mean body weight (mg/fly). (D)Mean hemolymph TG. (E) Size distribution of lipid droplet size. Red dots denote the largest lipid droplet from each of fat body cell. Red bar denotes their mean. Black dots represents all droplets and black bar denotes their mean.(F)Mean absolute nile red positive area(red) and unstained area (black), with (G) nile red positive area size also represented as a percentage of total FB cell area.(TIF)Click here for additional data file.Figure S3Sply (C) lace (D) lace/Sply (E) ifc (F) Sk2 (G) ifc;Sk2.SL mutants and abdominal adiposity. Cryostat sections (30 uM) of flies oriented in a dorsal (left) and sagittal (middle and 60\u00d7 right) positions. Red\u200a=\u200alipid positive oil red o. (A)wt (B) (TIF)Click here for additional data file.Figure S4www.flybase.org) and (C) expression throughout development. (D) dNepYr mRNA expression in global dNepYr KDs (E) TG levels (ug/mg fly). (F) Caloric Intake in the cafe (ul food/day). (F) Daily caloric intake. CG40733 encodes for RYamide, a known ligand of dNepYr. In global CG40733 KD flies: (G) CG40733 mRNA (H) Caloric intake (ul food/day) and (I) TG levels (ug/mg fly).Characterization of dNepYr and CG40733. (A)The dNepYr gene location, (B) tissue expression profile ((TIF)Click here for additional data file.Figure S5Role of dNepYr and akh in SL obesity phenotypes. (A) Relative dNepYr mRNA expression and (B) relative Akh mRNA expression in SL mutants and double mutants. (C) Pre and post starvation TG levels (D)Akh mRNA expression levels in Akh-specific Sply KD flies. (E) TG levels in Akh specific Sply KD flies. (F) Akh mRNA levels in global ifc KD flies.(TIF)Click here for additional data file.Figure S6rd instar larvae. Representative 40\u00d7 images of GFP expressing Akhpc in 3rd instar larvae through the cuticle. First Column is overlayed with DIC. Akh specific gal4 drivers were crossed with UAS RNAi lines. Images include (A) Akh-ga4/+ controls (B) Akh-g4/Akh RNAi (C) Akh-g4/ifc-RNAi (D) Akh-g4/+;UAS-dIAP1 (E) Akh-g4/lace-RNAi (F) % of Larvae that were positive for GFP (G) Area and optical density of GFP expression (H) Akh mRNA expression in 3rd instar larvae.Adipokinetic hormone producing cells in 3(TIF)Click here for additional data file."}
+{"text": "Signalling by NO/cGMP is significant for regulation of cardiovascular and renal function.3RI) associated protein cGMP kinase substrate (IRAG). NO/cGMP and ANP/cGMP-dependent relaxation of aortic smooth muscle was strongly affected in IRAG-deficient mice. NO/ANP-dependent inhibition of intracellular calcium release was suppressed in IRAG-deficient vascular smooth muscle cells (VSMC). Furthermore, reduction of store operated calcium entry by cGMP was affected in IRAG-KO VSMC. Basal mean arterial blood pressure, heart rate and activity were not changed in IRAG knockout mice. However, under pathophysiological conditions like sepsis (induced by E. coli lipopolysaccharide application) IRAG knockout mice were resistant to blood pressure reduction.For the functional analysis of cGMP signalling, transgenic murine mutants were used. cGKI signalling pathways include interaction of the cGKI\u03b2-isozyme with the inositol 1,4,5-trisphosphate receptor I (IPThese results suggested that cGKI/IRAG signalling is a predominant signal transduction pathway of NO/ANP/cGMP which may be involved in vascular diseases including pathophysiological modulation of blood pressure. Further results provided evidence that cGMP signalling is essential for prevention of renal diseases suppressing interstitial fibrosis."}
+{"text": "This study used delayed enhancement CMR (DE-CMR) and invasive angiography to evaluate relationships between papillary muscle and left ventricular (LV) chamber wall infarction following ST segment elevation MI (STEMI). Results demonstrate that papillary muscle infarction (PMI) parallels infarct transmurality and contractile dysfunction within the adjacent LV wall.Papillary muscles and myocardium within the adjacent LV wall constitute two components of the mitral valve apparatus. Prior studies have demonstrated variable papillary arterial supply, and the relationship between PMI and overall LV infarct pattern is unknown. DE-CMR enables in-vivo study of infarct pattern within the LV - papillary muscle complex.Patients with initial STEMI were enrolled in a prospective imaging registry. CMR (1.5T) was performed within 6 weeks (27\u00b18 days) post-STEMI. Cine-CMR (SSFP) was used to assess LV wall motion  DE-CMR  was used to assess infarct morphology: PMI was graded for location and extent ; LV infarction was quantified based on global size and regional transmurality . Invasive coronary angiograms were read blinded to CMR.153 patients were studied, among whom 30% had PMI . Overall LV infarct size on DE-CMR was larger among patients with PMI (p=0.01). PMI strongly related to LV infarct distribution ."}
+{"text": "Empiric broad-spectrum antibiotic treatment for orthopaedic implant infections after surgical lavage is common practice while awaiting microbiological results, but lacks evidence.Our objective was to question the indication of broad-spectrum empiric therapy in this clinical setting.Staphylococcus aureus endemicity ranged from 23-32% among clinical S. aureus isolates throughout the study period. Bacteremic cases were excluded.Single-centre cohort study conducted from 1996 to 2011. Methicillin-resistant S. aureus  and coagulase-negative staphylococci . Median duration of empiric antibiotic coverage after surgical drainage was 3 days before switching to targeted therapy. Vancomycin was the most frequently used initial empiric agent (147), followed by intravenous co-amoxiclav (44). Most empiric antibiotic regimens  proved sensitive to the causative pathogen, but were too broad in 111 episodes (32%). Although they would have covered 59% of later identified causative pathogens, cephalosporins and penicillins were used only in 44 and 10 cases, respectively. Empiric anaerobic coverage was given in 130 episodes (38%), although only five co-pathogens were anaerobes. Multivariate Cox regression analysis showed that neither susceptible antibiotic coverage  nor exaggerated broad-spectrum use  changed remission rates.We retrieved 342 implant infections and followed them for a median of 3.5 years . Infected implants were arthroplasties (n=186), different plates, nails, or other osteosyntheses. Main pathogens were Provided that surgical drainage is performed, broad-spectrum antibiotic coverage during the first 3 days does not enhance remission of orthopaedic implant infections. If empiric agents are prescribed from the first day of infection, narrow-spectrum penicillins or cephalosporins can be considered to avoid unnecessary broad-spectrum and anti-anaerobic antibiotic use. Randomized controlled trials are needed to confirm our findings.None declared"}
+{"text": "Natural colloid albumin induces a lesser degree of dilutional coagulopathy than synthetic colloids. Fibrinogen concentrate has emerged as a promising strategy to treat coagulopathy, and factor XIII (FXIII) works synergistically with fibrinogen to correct coagulopathy following haemodilution with crystalloids. Objectives were to examine the ability of fibrinogen and FXIII concentrates to reverse albumin-induced dilutional coagulopathy.in vitro with 5% albumin of blood samples from healthy volunteers, monitored by rotational thromboelastometry (ROTEM).High and low concentrations of both fibrinogen and FXIII were used to reverse coagulopathy induced by 1:1 dilution P <0.001). Following haemodilution, both doses of fibrinogen significantly corrected all ROTEM parameters (P \u22640.02), except the lower dose did not correct AA. Compared with the lower dose, the higher dose of fibrinogen significantly improved FIBTEM MCF and EXTEM MCF, AA and CFT (P <0.001). The lower dose of FXIII did not significantly correct any of the ROTEM parameters, and the high dose only improved EXTEM CT (P = 0.004). All combinations of high/low concentrations of fibrinogen/ FXIII significantly improved all ROTEM parameters examined (P \u22640.001). Fibrinogen concentration generally had a greater effect on each parameter than did FXIII concentration; the best correction of ROTEM parameters was achieved with high-dose fibrinogen concentrate and either low-dose or high-dose FXIII.Haemodilution with albumin significantly attenuated EXTEM maximum clot firmness (MCF), \u03b1 angle (AA), clotting time (CT) and clot formation time (CFT), and FIBTEM MCF (Fibrinogen concentrate successfully corrected initiation, propagation and clot firmness deficits induced by haemodilution with albumin, and FXIII synergistically improved fibrin-based clot strength."}
+{"text": "We demonstrate that adenosine stress CMR using variable density spiral perfusion pulse sequences accurately detects obstructive coronary artery disease. These pulse sequences produce high quality perfusion images with minimal artifacts resulting in high diagnostic accuracy.Adenosine stress perfusion imaging with CMR has been limited by motion-induced dark-rim artifacts, which may be mistaken for true perfusion abnormalities. We have previously demonstrated that spiral pulse sequences can produce high quality first-pass perfusion images. We have 2, nominal resolution 2.0 mm2, 8 spiral interleaves, FA 300, TR/TE 10ms/1ms. Cine and late gadolinium enhanced (LGE) images were also obtained using standard methodology. All subjects underwent cardiac catheterization following the CMR and significant stenosis was defined as >50%. Two blinded reviewers evaluated the spiral perfusion images for the presence of adenosine-induced perfusion abnormalities. Image quality was graded on a 5 point scale (1 - poor to 5- excellent).CMR perfusion imaging was performed during adenosine stress (140\u00b5g/kg-min) and at rest on a Siemens 1.5T Avanto scanner in 23 subjects scheduled to undergo cardiac catheterization for evaluation of chest pain. Subjects with prior coronary artery bypass surgery were excluded. Perfusion images were acquired during injection of 0.1mmol/kg Gd-DTPA at 3 short-axis locations using a saturation recovery (SR) interleaved variable-density spiral pulse sequence with an integrated field-map for off-resonance correction during reconstruction. Sequence parameters included: SR time 80 ms, FOV 320-340mmFigure Spiral adenosine stress CMR results in high diagnostic accuracy for the detection of obstructive coronary artery disease with excellent image quality.This work was funded by AHA 10SDG2650038 Salerno(PI) and Siemens Medical Solutions."}
+{"text": "Patients with newly diagnosed dilated cardiomyopathy and advanced heart failure have a very high morbidity and mortality with an unpredictable clinical course. We investigated the role of CMR via LGE in this cohort of patients.Hypothesis Utilizing cardiovascular MRI (CMR), via the late gadolinium enhancement (LGE), we assessed the prognostic value in primary dilated cardiomyopathy(DCM).Over 39 consecutive months, 51 cardiomyopathy patients were referred for standard 3D CMR to interrogate the LV pattern, distribution and extent of DHE . Inclusion criteria were met in 21 patients. DCM were categorized into: 1) +midwall Stripe 2)-Stripe groups. Major adverse clinical events (MACE), mortality, need for LV assist device (LVAD), and urgent cardiac transplantation (Tx), were evaluated over the ensuing 6 and 12 months.2= 9, p<0.005). Similarly, +Stripe predicted MACE by Cox regression modeling (p<0.05). No patient in the \u2212Stripe group had a MACE at 6 months .All patients were alive at 12 months while 11/21(52%) demonstrated a +Stripe. There were no differences between groups for demographics, baseline LVEF, LV end-diastolic diameter, NYHA class or hemodynamics. The group with +Stripe categorization strongly predicted the need for LVAD and/or urgent Tx surgery over the ensuing 6 (or 12) months (p<0.005). Specifically, 7/11(74%) +Stripe patients required urgent Tx by 6 months, while no patients in the \u2212Stripe group ever experienced the need for LVAD/urgent Tx (Kaplan-Meier: XThe presence of +Stripe on CMR is predictive of LVAD and Tx need over the ensuing 6 months and remains robust out to 12 months in DCM patients. Incorporating CMR imaging into routine clinical practice may help to identify early those high risk DCM patients; conservatively manage low-risk pts while expectantly manage high-risk patients."}
+{"text": "In sub-Saharan Africa, bloodborne pathogens exposure (BPE) is a serious risk to health care workers (HCW). Reporting BPE is necessary for effective post-exposure prophylaxis (PEP), an important element of workplace safety in health facilities. Limited data are available on factors associated with BPE reporting among HCW.We conducted a cross-sectional study assessing experiences of occupational BPE, history of BPE reporting, and use of PEP among health care workers at three public hospitals in Tanzania. From August to November 2012, HCW were interviewed using Audio-Computer Assisted Self-Interview. All HCW at risk for BPE were invited to participate. Factors associated with reporting BPE were identified using logistic regression.Of the 1,102 eligible HCW, 973 (88%) completed the interview. Of these, 690 (71%) were female and 387 (40%) were nurses. Of 357 HCW who had a BPE in the past 6 months, 120 (34%) reported it. Among these 120 reported exposures, 93 (78%) HCW reported within 2 hours of exposure, 98 (82%) received pre- and post-HIV test counseling, and 70 (58%) were offered PEP; 68 (97%) of these 70 HCWs completed PEP. Independent risk factors associated with reporting BPE were being female (adjusted odds ratio (AOR)=2.0 [95% confidence interval (CI) 1.2-3.5), having ever-received BPE training , knowledge that HCW receive PEP at another facility  and HIV testing within the past year .Despite the significant proportion of HCW with a recent BPE, only one in three reported it. Our results highlight the importance of appropriate and continuous training on the prevention and reporting of occupational exposures to increase acceptance of HIV testing after BPE.None declared."}
+{"text": "Treatment options approved for pulmonary arterial hypertension (PAH) failed in secondary forms of pulmonary hypertension (PH) often related due to decrease in oxygenation. Therefore we established an animal model to evaluate different vasodilator mechanisms under experimental conditions of heterogeneous lung ventilation in respect to their \u201cdesaturation-potential\u201d.Single-lung ventilation (right sided) was induced in 7-wk old minipigs (4-5 kg BW). In each animal 5 repetitive cycles of 10 min. left lobe blockade were followed by 30 min. bilateral ventilation. Hemodynamics (e.g. mean pulmonary artery pressure (mPAP), blood pressure (BP)) and arterial hemoglobin saturation (SaO2) were monitored continuously. We compared 5 different groups (n=6 each): vehicle control group, the endothelin antagonist bosentan , the PDE5 inhibitor sildenafil , and the sGC stimulators BAY 41-8543  and riociguat . The vasodilator doses were chosen to achieve equal BP reduction. Cumulative doses of vasoactive compounds were applied before successive unilateral ventilation and effects on desaturation  and maximal hypoxic mPAP were compared to vehicle conditions in each animal.SaO2). The vasodilators were compared in respect to their ability to decrease maximal hypoxic mPAP (positive treatment effect) and AUCSaO2 (unwanted desaturation effect). In contrast to vehicle treated control animals all vasodilators lead to a dose-dependent decrease in hypoxic mPAP  and bosentan. Furthermore, in comparison to bosentan and sildenafil the sGC stimulators were less likely to cause an unwanted decrease in SaO"}
+{"text": "Integration of TCDD-induced genome-wide AhR enrichment, differential gene expression and computational dioxin response element (DRE) analyses further elucidate the hepatic AhR regulatory network.The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor (TF) that mediates responses to 2,3,7,8-tetrachlorodibenzo-Global ChIP-chip and gene expression analyses were performed on hepatic tissue from immature ovariectomized mice orally gavaged with 30 \u03bcg/kg TCDD. ChIP-chip analysis identified 14,446 and 974 AhR enriched regions  at 2 and 24 hrs, respectively. Enrichment density was greatest in the proximal promoter, and more specifically, within \u00b1 1.5 kb of a transcriptional start site (TSS). AhR enrichment also occurred distal to a TSS (e.g. intergenic DNA and 3' UTR), extending the potential gene expression regulatory roles of the AhR. Although TF binding site analyses identified over-represented DRE sequences within enriched regions, approximately 50% of all AhR enriched regions lacked a DRE core (5'-GCGTG-3'). Microarray analysis identified 1,896 number of TCDD-responsive genes  > 0.999). Integrating this gene expression data with our ChIP-chip and DRE analyses only identified 625 differentially expressed genes that involved an AhR interaction at a DRE. Functional annotation analysis of differentially regulated genes associated with AhR enrichment identified overrepresented processes related to fatty acid and lipid metabolism and transport, and xenobiotic metabolism, which are consistent with TCDD-elicited steatosis in the mouse liver.Details of the AhR regulatory network have been expanded to include AhR-DNA interactions within intragenic and intergenic genomic regions. Moreover, the AhR can interact with DNA independent of a DRE core suggesting there are alternative mechanisms of AhR-mediated gene regulation. AhR enriched regions without the DRE core were also verified, further demonstrating that the AhR can interact with DNA independent of a DRE core, but does not eliminate the possibility of AhR interaction through DNA looping or protein tethering. Interestingly, the fold enrichment values for regions without the DRE core were consistently lower than those with a DRE core, suggesting AhR interactions are stronger in regions containing a DRE.Selected regions of AhR enrichment identified by ChIP-chip analysis at 2 hrs were confirmed by ChIP-PCR Figure . Three rTCDD-elicited changes in gene expression are mediated through AhR signaling via binding to the substitution intolerant DRE core sequence (5'-GCGTG-3'). Overlaying TCDD-induced AhR enrichment with DRE core locations throughout the mouse genome  identifibona fide functional DREs [Matrix similarity (MS) scores have been calculated for each 19 bp DRE sequence within the mouse genome using a position weight matrix (PWM) constructed from nal DREs . Of the 6C[T|A]TG-3') has also been reported TG-3') TG-3') ,41 were A]TG-3') , such asIntegration of gene expression, ChIP-chip, and DRE distribution data suggests that ~35% of all differentially expressed hepatic genes are mediated by direct AhR binding to a DRE. Consequently, 65% of the gene expression responses elicited by TCDD do not involve direct AhR binding to a DRE. However, TF binding analyses based on tiling arrays is limited by the extent of probe coverage Figure . GenomicTCDD induces hepatic vacuolization and lipid accumulation with differential gene expression associated with fatty acid metabolism and transport ,53. IndeCyp7a1 and Gck, exhibited AhR enrichment and were repressed by TCDD. Cyp7a1 is the rate-limiting enzyme in the bile acid biosynthetic pathway that converts cholesterol into bile acids. Transgenic mice over-expressing Cyp7a1 are protected from high-fat diet induced obesity, fatty liver and insulin resistance [Gck that reduce kinase activity are associated with insulin resistance and maturity onset diabetes of young 2 (MODY2) in humans [Cyp7a1 and Gck, possibly due to AhR - COUP-TF interactions at HNF4\u03b1 response elements, is consistent TCDD-induced hepatic lipid accumulation in mice. Interestingly, TCDD exposure has been linked to diabetes and metabolic syndrome in humans [Consistent with this proposed mechanism, several HNF4\u03b1 regulated genes, including sistance . Moreovesistance . Gck phon humans -76. Furtn humans . The down humans -84. Studin vivo and incorporates DRE distribution and differential gene expression data to further elucidate the hepatic AhR regulatory network. In addition to identifying interactions in regions associated with genes, AhR enrichment in distal non-coding intergenic regions was characterized. The functional significance of these distal interactions is unknown but intergenic binding has been reported for other TFs, and warrants further investigation. Moreover, only ~50% of all AhR enriched regions involved a DRE, suggesting that indirect AhR binding to DNA plays a significant role in the AhR regulatory network.This study identified the genome-wide locations of TCDD-induced hepatic AhR enrichment Hepatic tissue samples from immature female ovariectomized C57BL/6 mice obtained from a previous study  were use\u00ae mouse 2.0R tiling arrays  as previously described [TCDD to triplicate IgGTCDD using a moving average (MA) approach with default settings in TileMap v2 [ChIP assays were performed as previously described  with theescribed . The hybescribed . EnricheleMap v2 . RegionsThe mouse genomic assembly (mm9) and associated annotation within the refGene and refLink databases were downloaded from the UCSC Genome Browser . Individhttp://www.genomatix.de that contains an extensive database of TF binding motifs. Identified module families and individual matrices with z-scores > 3 were considered significant [De novo motif discovery was performed using the Gibbs motif sampler in CisGenome on AhR regions of enrichment sequences not containing a DRE. Matrices for over-represented motifs were compared to existing TF binding motifs in JASPAR and TRANSFAC [The locations of AhR enrichment were compared against 5'-GCGTG-3' DRE core sequence locations in the mouse genome . Identifnificant . De novoTRANSFAC ,49 usingTRANSFAC .Results from the ChIP-chip and DRE analysis were integrated with whole-genome gene expression profiling data from mice orally gavaged with 30 \u03bcg/kg TCDD using 4 \u00d7 44 k whole-genome oligonucleotide arrays from Agilent Technologies  . The genhttp://www.ingenuity.com/) to identify over-represented molecular and cellular functions based on the Fisher's Exact Test p-value < 0.01.Functional annotation clustering of Gene Ontology (GO) terms for genes associated with significant AhR enrichment was performed using DAVID  . In addiED performed the computational analyses and integration of the ChIP-chip data with the computational DRE and microarray gene expression analyses, and the initial preparation of the manuscript. JM optimized and performed the ChIP experiments, and normalized the ChIP-chip data. TL and RL validated the ChIP-chip results with ChIP-PCR from regions identified by ED. TRZ oversaw the completion of the study. All the authors have given final approval of the version to be published.Genomic location, gene annotation and enrichment values of significant (FDR < 0.01) TCDD-induced AhR enrichment at 2 hrs. Detailed results of the AhR ChIP-chip analysis that include the genomic location and TCDD-induced enrichment values, and the gene annotation of enrichment peaks located within the 10 kb upstream and transcribed region of a gene.Click here for fileGenomic location, gene annotation and enrichment values of significant (FDR < 0.01) TCDD-induced AhR enrichment at 24 hrs. Detailed results of the AhR ChIP-chip analysis that include the genomic location and TCDD-induced enrichment values, and the gene annotation of enrichment peaks located within the 10 kb upstream and transcribed region of a gene.Click here for fileDefinitions of various genomic regions used to map regions of AhR enrichment. A) Genomic locations from the UCSC Genome Browser refGene database were used to obtain sequences for 10 kb region upstream of the TSS, the 5' and 3' UTRs, and the CDS of every known human, mouse and rat RefSeq sequence. A gene region is defined as the sequence spanning the region 10 kb upstream of a TSS through to the end of the 3' UTR. B) Intragenic DNA regions in a genome were determined by combining the non-overlapping gene regions. For example, gene regions of tissue specific isoforms of a gene that have different TSS positions were merged to determine the longest spanning range (genes C & C' and genes E & E'). Additionally, overlapping genes on both strands of the genome were also merged (genes B + E + E'). Non-transcribed DNA segments that span the regions between adjacent intragenic regions are defined as the intergenic DNA regions.Click here for fileTCDD-induced AhR enrichment (FDR < 0.01) density across the mouse genome at 2 hrs. The density of significant AhR enrichment (per Mbp) at 2 hrs were calculated for each of the defined genomic regions across the individual chromosomes.Click here for fileTCDD-induced AhR enrichment (FDR < 0.01) density across the mouse genome at 24 hrs. The density of significant AhR enrichment (per Mbp) at 24 hrs were calculated for each of the defined genomic regions across the individual chromosomes.Click here for fileTranscription factor binding site analysis of significant TCDD-induced AhR enrichment (FDR < 0.01) at 2 hrs. DNA sequences for the regions of significant AhR enrichment at 2 hrs were analyzed for transcription factor (TF) binding site motif over-representation using RegionMiner. The results list the TF matrices and their corresponding over-representation and z-score value.Click here for fileTranscription factor binding site analysis of significant TCDD-induced AhR enrichment (FDR < 0.01) at 24 hrs. DNA sequences for the regions of significant AhR enrichment at 24 hrs were analyzed for transcription factor (TF) binding site motif over-representation using RegionMiner. The results list the TF matrices and their corresponding over-representation and z-score value.Click here for fileOver-representation of transcription factor binding motifs located proximally (10-50 bp) of a DRE in a significantly AhR enriched region (FDR < 0.01). DNA sequences for the regions of significant AhR enrichment at 2 and 24 hrs possessing a DRE core sequence (5'-GCGTG-3') were analyzed for transcription factor (TF) binding site motif over-representation using RegionMiner. The results list the TF matrices and their corresponding over-representation and z-score value.Click here for filede novo motif analysis of significant intragenic and intergenic AhR enriched regions (FDR < 0.01) lacking a DRE coreRepetitive sequence elements identified in the . The repetitive over-represented motifs from each region are shown with their consensus and reverse complement sequence, and the Gibbs motif sampler score.Click here for filePathway analysis of genes associated with DRE-containing regions of AhR enrichment (FDR < 0.01) at 2 hrs. List of the most significant Bio-Functions (p < 0.01) identified using Ingenuity Pathway Analysis for the genes associated with a significant AhR enriched region (FDR < 0.01) containing a DRE core (5'-GCGTG-3') at 2 hrs.Click here for filePathway analysis of genes associated with DRE-containing regions of AhR enrichment (FDR < 0.01) at 24 hrs. List of the most significant Bio-Functions (p < 0.01) identified using Ingenuity Pathway Analysis for the genes associated with a significant AhR enriched region (FDR < 0.01) containing a DRE core (5'-GCGTG-3') at 24 hrs.Click here for fileCircos plots integrating DRE analysis, AhR enrichment  and heatmaps for hepatic differential gene expression responses (|fold change| \u2265 1.5 and P1(t) > 0.999) induced by TCDD across the genome. Circos plots illustrate the ideograms for each individual chromosome and the entire genome and integrate the results of the DRE, ChIP-chip and gene expression analyses.Click here for filePathway analysis of differentially regulated genes (|fold change| \u2265 1.5 and P1(t) > 0.999) associated with regions of AhR enrichment (FDR < 0.01) at 2 hrs. List of the most significant Bio-Functions (p < 0.01) identified using Ingenuity Pathway Analysis for TCDD-elicited gene expression responses (|fold change| \u2265 1.5 and P1(t) > 0.999) associated with a significant AhR enriched region (FDR < 0.01) containing a DRE core (5'-GCGTG-3') at 24 hrs.Click here for filePrimer sequences used to verify 2 hr ChIP-chip responses. QRTPCR primers used to verify AhR enriched regions isolated from the 2 hr ChIP-chip.Click here for file"}
+{"text": "LVAD = Left Ventricular Assist Device; LV = Left Ventricle; LA = Left Atrium; AO = Aorta A 41-year-old male Indian patient was admitted to our hospital due to refractory congestive heart failure. The patient received a left ventricular assist device (LVAD) as destination therapy. The images show the preoperative, intraoperative, and postoperative echocardiography findings Figures .Figure"}
+{"text": "Myocardial perfusion reserve (MPR) acquired using first-pass cardiac MRI is a measure of the severity of microvascular coronary dysfunction (MCD) in subjects with signs and symptoms of ischemia but no obstructive coronary artery disease (CAD) [Shufelt 2011]. Semi-quantitative measures (upslopes) have been used to analyze MPR data in the previous work [Shufelt 2011]. In this work, we propose using a fully quantitative myocardial blood flow (MBF) analysis to evaluate whether MPR is different between subjects with MCD and normal controls.Control (n=9) and MCD subjects (n=10) from the Women's Ischemia Syndrome Evaluation Coronary Vascular Dysfunction (WISE CVD) multi-center National Heart, Lung, and Blood sponsored study underwent cardiac perfusion MRI studies on a Siemens 1.5T Avanto system with IRB approval and written consent. Control subjects were middle aged women with no risk factors and normal exercise ECG. Diseased subjects were middle aged women presenting with signs and symptoms of ischemia but no obstructive CAD (<50% stenosis) on angiography. A standardized first pass adenosine stress and rest first pass perfusion protocol with breath hold was performed. Segmentation (AHA) and upslope analysis were performed using CAAS MRV . Only the midslice segments were analyzed to insure minimize effect of cardiac phase related MBF variations [Radjenovic 2010]. Signal intensity curves used for MBF estimation was found using the same segments and exported using CAAS MRV. MBFs were found using nonparametric deconvolution code written in MATLAB [Jerosh-Herold 2002]. A two sided Student's t-test was performed to compare groups.Mean MPR for diseased and normal populations averaged across all AHA segments in the midslice are summarized in table MPR measured by quantitative MBF analysis provides better detection of MCD than that using semi-quantitative upslopes. This finding could be explained by the observation that upslopes may not be sensitive to high blood flows [Hsu 2006], which potentially reduces the difference between diseased (ischemic) and normal tissues. In conclusion, fully quantitative MBF analysis improves detection of MCD over semi-quantitative measures. Additional work in more subjects, as well as validation with MPR measured by PET is needed.T32 EB51705; RO1 EB002623; AHA 11POST7390063; N01-HV-68161; N01-HV-68162; N01-HV-68163; N01-HV-68164; U0164829; U01 HL649141; U01 HL649241; T32HL69751; 5R01HL090957; 1R03AG032631."}
+{"text": "Penicillium species. The target of MPA is inosine-5'-monophosphate dehydrogenase (IMPDH), which catalyses the rate limiting step in the synthesis of guanine nucleotides. The recent discovery of the MPA biosynthetic gene cluster from Penicillium brevicompactum revealed an extra copy of the IMPDH-encoding gene (mpaF) embedded within the cluster. This finding suggests that the key component of MPA self resistance is likely based on the IMPDH encoded by mpaF.Many secondary metabolites produced by filamentous fungi have potent biological activities, to which the producer organism must be resistant. An example of pharmaceutical interest is mycophenolic acid (MPA), an immunosuppressant molecule produced by several mpaF dramatically increased MPA resistance in a model fungus, Aspergillus nidulans, which does not produce MPA. The growth of an A. nidulans strain expressing mpaF was only marginally affected by MPA at concentrations as high as 200 \u03bcg/ml. To further substantiate the role of mpaF in MPA resistance, we searched for mpaF orthologs in six MPA producer/non-producer strains from Penicillium subgenus Penicillium. All six strains were found to hold two copies of IMPDH. A cladistic analysis based on the corresponding cDNA sequences revealed a novel group constituting mpaF homologs. Interestingly, a conserved tyrosine residue in the original class of IMPDHs is replaced by a phenylalanine residue in the new IMPDH class.In accordance with our hypothesis, heterologous expression of Penicillium subgenus Penicillium. The novel IMPDH variant from MPA producer P. brevicompactum was shown to confer a high degree of MPA resistance when expressed in a non-producer fungus. Our study provides a basis for understanding the molecular mechanism of MPA resistance and has relevance for biotechnological and pharmaceutical applications.We identified a novel variant of the IMPDH-encoding gene in six different strains from  The target of MPA is inosine-5'-monophosphate dehydrogenase (IMPDH) , Aspergillus terreus [GenBank:XM_001218149], Aspergillus niger [GenBank:XM_001391855], P. chrysogenum putative IMPDH-A coding gene, [GenBank:XM_002562313], putative IMPDH-B coding gene [GenBank:XM_002559146], P. marneffei [GenBank:XM_002151867]. \u03b2-tubulin sequences from A. nidulans [GenBank:XM_653694], A. terreus [GenBank:XM_001215409], A. niger [GenBank:XM_001392399], P. chrysogenum [GenBank:XM_002559715] and P. marneffei [GenBank:XM_002151381]. The MPA gene cluster sequence from P. brevicompactum, which contains the IMPDH-B sequence (mpaF) is available from GenBank under accession number [GenBank:HQ731031].BLASTx search was performed with standard settings: 'blastp algorithm', 'expect threshold = 10', 'word size = 3', 'max matches in query range = 0', 'matrix = BLOSUM62', 'gap open cost = 11', 'gap extension cost = 1', and no filters were used. Alignment of DNA coding regions were performed with ClustalW  as impleplicates . The DNAhttp://www.clcbio.com/) by using the following parameters: 'gap open cost = 20.0', 'gap extension cost = 1.0', and 'end gap cost = free'.Amino acid sequences were aligned with ClustalW  as implePenicillium bialowiezense \u03b2-tubulin [GenBank:JF302653], putative IMPDH-A coding gene [GenBank:JF302658], putative IMPDH-B coding gene [GenBank:JF302662], P. brevicompactum \u03b2-tubulin [GenBank:JF302653], imdA [GenBank:JF302657], Penicillium carneum \u03b2-tubulin [GenBank:JF302650], putative IMPDH-A coding gene [GenBank:JF302656], putative IMPDH-B coding gene [GenBank:JF302660], Penicillium paneum \u03b2-tubulin [GenBank:JF302651], putative IMPDH-A coding gene [GenBank:JF302654], putative IMPDH-B coding gene [GenBank:JF302661], Penicillium roqueforti \u03b2-tubulin [GenBank:JF302649], putative IMPDH-A coding gene [GenBank:JF302655], putative IMPDH-B coding gene [GenBank:JF302659].All sequences obtained via degenerate PCR were submitted to GenBank Table . PenicilKRP, UHM, BGH and TBR conceived the study. BGH designed the experiments. BGH, HJG, CSK and JBN carried out the research. JCF contributed to the design of experiments and provided expertise in mycology. BGH and HJG prepared the first draft of the manuscript. UHM and KRP contributed to the experimental design and preparation of the manuscript. All authors were involved in the revision of the draft manuscript and have agreed to the final content."}
+{"text": "Nucleoside Reverse Transcriptase Inhibitors, NRTIs; Non-Nucleoside Reverse Transcriptase Inhibitors, NNRTIs; Nucleotide Reverse Transcriptase Inhibitors, NtRTIs) [Human immunodeficiency virus (HIV) from a family of retroviruses is a causative organism for acquired immuno deficiency syndrome (AIDS), affecting more than 40 million people worldwide . Reverse NtRTIs) . The NNRSix NNRTIs in development were selected for the study viz. Etravirine, Rilpivirine, Calanolide A, IDX899, RDEA806 and Lersivirine). These selected molecules were rigorously analyzed through Lipinski\u2019s Rule of 5 (Ro5) by molinspiration software . In an oAll six molecules successfully passed the Lipinski\u2019s Ro5 filter to be as a probable drug candidate except some minor violations. In terms of molecular docking, they presented excellent scoring and binding affinity towards the receptor due to the close interatomic contacts through strong H-bonds Lys103 , His235, Tyr318 (RDEA806), Lys101  Val179 (Etravirine), pi-pi Tyr181  and pi-cation interactions through Lys101 (RDEA806), Tyr103 (Rilpivirine).As a concluding remark, preliminary screening by Lipinski\u2019s Ro5 acted as filter to obtain potential molecule from large datasets, whereas, pi-pi interaction was coined as a major interatomic interaction for stabilizing receptor-ligand complex and minor with hydrogen bonding and pi-cation interaction. We have anticipated a pivotal facet for designing the next generation of NNRTIs with improved activity based upon molecular docking studies."}
+{"text": "Uribe et al 2008)A single-phase 3d steady-state-free precession whole heart approach with respiratory navigator gating and ECG triggering (3d SSFP) is now frequently used for diagnostic imaging in children with congenital heart disease (CHD). However, certain cardiac structures may be better assessed during the systolic and others in the diastolic rest period. Therefore, a previously described dual phase 3d-SSFP whole heart sequence may offer clinical benefit in these patients. . Twelve patients were referred for RVOT assessment. Dimensions were measured at valvar, supravalvar and pre-bifurcation levels. CNR, image quality and RVOT measurements were compared between systole and diastole.50 consecutive children with CHD underwent 3D SSFP dual-phase imaging. All cardiac chambers and great vessels were analyzed for contrast-to-noise ratio (CNR) and image quality (IQ) .50 children  underwent 3d dual-phase SFFP imaging. The mean HR was 90 bpm (56 to 139). Dual phase yielded diagnostic imaging for all chambers and great vessels in 48 cases. Systolic imaging alone was diagnostic in 45 cases and diastolic imaging in 47 cases. CNR (paired t-test) and IQ (Wilcoxon Signed Ranks test) were significantly (p<0.05) higher in systole for the pulmonary veins (figure Dual phase 3D SSFP imaging improved the success rate of diagnostic quality imaging compared to single-phase imaging. Cardiac chambers and pulmonary veins are better imaged in systole possibly due to improved blood exchange. Less blood flow turbulence may have improved branch pulmonary arteries or arterial stenosis imaging in diastole. Our data confirms that under-sizing of RVOT stent-valve would have occurred if diastolic imaging were used to guide intervention."}
+{"text": "Thoracic aortic aneurysm (TAA) is life-threatening and requires close follow-up to prevent aortic dissection and/or rupture. Aortic wall stiffness and luminal size are considered to be coupled. Regional aortic wall stiffness in patients with TAA is unknown. Evaluation of regional stiffness may supplement monitoring for prediction of progressive aortic dilatation. Aortic Pulse Wave Velocity (PWV), a marker of vascular stiffness, can be assessed regionally using in-plane two-directional velocity-encoded (VE) MRI. The purpose of this study was to evaluate coupling between regional PWV and aortic luminal diameter in patients with TAA.In 40 TAA patients  regional aortic diameters and regional PWV were assessed by 1.5T MRI (Philips). Marfan's disease was excluded. A fast gradient-echo T1-weighted contrast-enhanced MR angiogram of the full aorta was obtained by first pass imaging 25 mL contrast bolus Dotarem (Guerbet) with molarity 0.5 mmol/mL, infused at 2mL/s. Five regional aortic segments were evaluated: ascending aorta (S1), aortic arch (S2), thoracic descending aorta (S3), suprarenal (S4) and infrarenal abdominal aorta (S5). Regional PWV was obtained from multi-slice 2-directional VE MRI, covering the full aorta by 3 double-oblique sagittal slices with in-plane velocity-sensitivity 150cm/s. Regional PWV was determined by wave propagation analysis and calculated as segment length divided by the transit-time of the flow velocity wave propagating through this segment. The incidence of increased diameter  aortic segments . Regional aortic diameter was increased in 28 (14%) segments . In Figure 9% aorticNormal regional PWV assessed in the full aorta with in-plane VE MRI demonstrates absence of increased luminal diameter, with high specificity and negative predictive value in the descending thoracic to abdominal aorta and moderate results in the ascending aorta and aortic arch. Increased regional PWV may be a precursor to aortic luminal dilatation, but normal regional PWV rules out disease.None"}
+{"text": "Primary Sj\u00f6gren\u2019s syndrome (pSS) is an autoimmune rheumatic disease affecting the exocrine glands. Several pSS-associated clinical and laboratory parameters may predispose to thromboembolic risk, however clinical data is conflicting.My primary objective was to test whether whole blood clot formation is abnormal in pSS using several complementary approaches: Thromboelestrography (TEG) and Multiplate platelet mapping (MPP) for pSS patients compared to healthy and disease (lupus-SLE) controls and compare the size/composition of blood clots formed ex-vivo between pSS patients and healthy controls using a clotting chamber, which simulates the clotting process in-vivo.My secondary objectives were to determine if any clinical/laboratory/cytokine parameters were associated with abnormal clotting.TEG and MPP were performed on blood samples from 12 healthy controls, 24 pSS and 11 SLE patients.For TEG: clot formation speed, strength and lysis rate were analysed. For MPP, platelet receptor responses to common agonists were investigated.12 pSS patients completed a clotting chamber procedure.Univariate correlation analysis was used to determine the relationship between clotting and clinical/laboratory/cytokine parameters.All TEG and MPP parameters were similar between groups. Statistically significant correlations were found for (a) ESR and clot lysis parameters (p<0.007); (b) CD40L and clot formation/lysis rate (P<0.01).Analysis of clot specimens from the clotting chamber is on-going. Preliminary data indicate that several cytokines are \u201cconsumed\u201d during the clot formation.There was no difference in clotting and platelet receptors function between pSS patients and lupus patients/healthy controls. Interestingly, several laboratory/clinical parameters significantly correlate with clotting/platelet receptor function."}
+{"text": "Uncomplicated acute rhinosinusitis (ARS) is usually a self-limiting inflammatory condition often treated with antibiotics. This study evaluated an alternative treatment for symptomatic relief of uncomplicated ARS, fluticasone furoate nasal spray (FFNS).This randomized, double-blind, placebo-controlled, parallel-group, multicenter, 2-week treatment study evaluated FFNS 110 mcg once daily, twice daily vs. placebo in adults/adolescents with uncomplicated ARS. Eligibility criteria reflected a clinical diagnosis and eliminated confounding conditions like common cold, symptomatic allergic rhinitis (AR), and other sinonasal conditions. Subjects with daily major symptom score  >4.5 at baseline were randomized.The study demonstrated a statistically significant reduction in daily MSS by both FFNS doses compared to placebo . The differences in median time to symptom improvement between placebo (8 days) and each FFNS dose (7 days) were not statistically significant. There were no treatment differences in antibiotic use due to the development of possible fulminant bacterial rhinosinusitis (3% in each group). The safety profile of FFNS was similar to placebo.FFNS reduced symptoms of uncomplicated ARS compared to placebo and was well tolerated, providing support for withholding antibiotics in selected patients. (FFR113203/ GSK funded)"}
+{"text": "The Belfast Breast Screening Programme serves a population of approximately 25,000 patients. We aimed to analyse radiological and pathological trends between screen-detected and interval breast cancers, and determine our screening lesion miss rate.Using the Quality Assurance Reference Centre (QARC) database patients were identified with screen-detected or interval breast cancers diagnosed via the Belfast Breast Screening Programme over a fixed period. Film packs and operative specimen reports were analysed for radiological and pathological data.Screening identified 75% of breast cancers. Only 30% of screen-detected lesions were palpable by breast clinicians. Sixty-one per cent of lesions were in the upper outer quadrant, with equal left-right distribution. Radiological measurements underestimated lesion size by 22%. There was moderate correlation between lesion size and lymph node status. No other correlations were identified. Twenty-three per cent of interval cancers presented in year 1 following screening, 28% in year 2 and 49% in year 3. They were larger at presentation than screen-detected cancers (29.4 mm vs. 18.2 mm mean size) and of pathologically higher grade (39% vs. 13% grade III). Screen-detected cancers were mostly IDC (63%) or DCIS (18%) subtype. Interval lesions were predominantly IDC subtype (87%). Interval lesions showed more nodes positive per patient. Retrospective review of past screening films of interval-detected cancers showed suspicious features present in 17% of cases.Breast screening identifies three-quarters of breast cancers in the screening population. Interval cancers present with increasing frequency through the screening cycle and are faster growing, pathologically more aggressive lesions."}
+{"text": "Heterogeneity and varying malignancy risk makes B3 lesion management difficult. Can histological features predict malignancy risk?in situ neoplasia (LISN), and so forth. Age-adjusted logistic regression to assess risk of malignancy (Stata11).A retrospective review of B3 lesions (April 2005 to March 2010) following 14G biopsy, followed to final pathology. Key phrases from pathology identified; atypia, radial scar/complex sclerosing lesion (RS/CSL), atypical intraductal proliferation (AIDP), atypical ductal/lobular hypertrophy (ADH/ALH), flat epithelial atypia (FEA), lobular A total of 205 B3 lesions were identified; 112 lesions with subsequent excision biopsy were analysed. Patients had mean age of 56 years (95% CI = 55 to 57 years). Thirty out of 112 lesions were upgraded to B5 diagnosis. Nine out of 112 had final diagnosis of LCIS. Multivariate analysis of odds ratios for malignancy, after age adjusting, is shown in Table P < 0.001; 95% CI = 2.62 to 21.39). Similarly, lesions containing AIDP, FEA and columnar cell change (CCC) have significantly increased odds for malignancy. LISN did not confer an increased risk of malignancy. Stratifying lesions in this way can direct future management.Atypia on core biopsy significantly predicts malignancy, with 7.48 times the odds of malignancy compared with lesions without atypia ("}
+{"text": "The NiII cations are coordinated by two terminal N-bonded thio\u00adcyanate anions (trans) and four pyridazine ligands in a slightly distorted octa\u00adhedral geometry. The discrete complexes are arranged into layers parallel to the ab plane which are separated by additional non-coordinated pyridazine ligands.The reaction of nickel(II) thio\u00adcyanate with an excess of pyridazine leads to single crystals of the title compound, [Ni(NCS) DOI: 10.1107/S1600536812023306/bt5930Isup2.hklStructure factors: contains datablock(s) I. DOI:  crystallographic information; 3D view; checkCIF reportAdditional supplementary materials:"}
+{"text": "Productive thymopoiesis is essential for a robust and healthy immune system.Thymus unfortunately is acutely sensitive to stress resulting in involutionand decreased T cell production. Thymic involution is a complication of manyclinical settings, including infection, malnutrition, starvation, andirradiation or immunosuppressive therapies. Systemic rises inglucocorticoids and inflammatory cytokines are known to contribute to thymicatrophy. Little is known, however, about intrathymic mechanisms that mayactively contribute to thymus atrophy or initiate thymic recovery followingstress events.Phenotypic, histologic and transcriptome/pathway analysis of murine thymictissue during the early stages of endotoxemia-induced thymic involution wasperformed to identify putative mechanisms that drive thymic involutionduring stress. Thymus atrophy in this murine model was confirmed bydown-regulation of genes involved in T cell development, cell activation,and cell cycle progression, correlating with observed phenotypic andhistologic thymus involution. Significant gene changes support thehypothesis that multiple key intrathymic pathways are differentiallyactivated during stress-induced thymic involution. These included directactivation of thymus tissue by LPS through TLR signaling, local expressionof inflammatory cytokines, inhibition of T cell signaling, and induction ofwound healing/tissue remodeling.Taken together, these observations demonstrated that in addition to theclassic systemic response, a direct intrathymic response to endotoxinchallenge concurrently contributes to thymic involution during endotoxemia.These findings are a substantial advancement over current understanding ofthymus response to stress and may lead to the development of noveltherapeutic approaches to ameliorate immune deficiency associated withstress events. Ongoing and productive thymopoiesis is essential for development and maintenance of arobust and healthy immune system. Many factors have a negative effect onthymopoiesis and acute thymic atrophy is a complication among a variety of clinicalsettings, including bacterial infection Endotoxemia-induced acute thymic atrophy is a useful model to study the impact ofacute stress on thymopoiesis These reports support an evolving paradigm of thymus involution, in which intrathymicmechanisms actively contribute to increased local inflammation, decreased thymusoutput, and increased tissue atrophy. It is therefore hypothesized that intrathymicpathways are active during endotoxemia-induced acute thymic atrophy leading tothymopoietic and morphologic dysregulation. A phenotypic, histologic andtranscriptome/pathway analysis of murine thymic tissue during the early stages ofendotoxemia-induced involution was undertaken in this study to define intrathymicmechanisms that drive acute thymic atrophy. Reported findings support the hypothesisthat multiple key intrathymic pathways are differentially activated duringendotoxemia-induced thymic involution. These include direct activation of thymustissue by LPS through TLR signaling, local expression of inflammatory cytokines,inhibition of T cell signaling, and induction of wound healing/tissueremodeling.To demonstrate the effects of endotoxin stress on thymus homeostasis, 8\u201310week old mice were injected intraperitoneally (IP) with either saline or 100\u00b5g lipopolysaccharide (LPS) and thymic atrophy was assessed. Thymus weightwas unchanged by LPS one day post treatment, yet was significantly decreased byLPS three days post challenge (n\u200a=\u200a10) . Total tChanges in thymus architecture were assessed with hematoxylin and eosin stainingof frozen thymus tissue four days post LPS challenge. Distinct areas of thymuscortex and medulla were visible in thymus tissue from saline-treated mice of cytokines measured at 1, 2, 4, or 6 hr post treatment versus saline controls.SpecifiTo investigate if intrathymic production of pro-inflammatory cytokines waspresent during thymic atrophy, gene expression analysis was performed on excisedmouse thymus tissue. Many of the cytokines that were increased significantly inserum after endotoxin challenge also had significantly increased mRNA levelwithin thymus tissue . These iTranscriptome analysis of whole thymus during the early stages of acute thymicatrophy revealed significant gene dysregulation induced by endotoxemia.Significantly modulated intrathymic genes were grouped into gene ontologycategories (GO categories) based on statistical overrepresentation of GO termsas determined by a conditional hypergeometric test. Overall, GO category analysis of thymus tissue transcriptome revealeddown-regulation of important processes in thymocyte development andup-regulation of inflammatory and wound healing responses. Taken together, theseresults suggested that intrathymic gene regulation can directly contribute toinflammation and thymic atrophy induced by systemic endotoxin challenge. Beloware categorized descriptions of the significant intrathymic gene expressionchanges induced by systemic endotoxin challenge.Bcl11b, Rorc, and Runx1.B-cell CLL/lymphoma 11B (Bcl11b) is a transcription factornecessary for DP thymocyte development Rorc) is a transcriptionfactor for Th17 cells Runx1) is a transcription factor necessary for properthymocyte development Dclre1c,Lig4, Rag1, and Rag2 is involved in chromatin remodeling andtranscriptional regulation, and is normally highly expressed in the thymus,functioning to promote differentiation, survival, and/or expansion ofthymocytes at the transition from the DN to the DP developmental stage Lat), signaling lymphocyteactivation molecule family member (Slamf1) andleukocyte-specific protein tyrosine kinase (Lck), are allimportant in T cell activation Ppp3cb) is required for positive selection andcontributes to a developmental period of ERK hypersensitivity, allowing veryweak signals to induce positive selection Stat5 is down-regulated, IL-7R is up-regulated inresponse to endotoxemia. Other up-regulated genes of note include Casitas Bcell lymphoma b (Cblb), which negatively regulates T cellantigen receptor (TCR) signaling and is important for MHC-dependent CD4 andCD8 thymocyte development Pawr), which down-regulate theanti-apoptotic protein Bcl2 Furthermore, many genes involved in lymphocyte activation and thymocytedifferentiation were decreased, including dStat5a . Adam17 Adamts1, an extracellular metalloproteinase thatpromotes inflammation Cebpd), an important transcription factor forpro-inflammatory cytokine production in a TLR/MyD88-dependent pathway inmacrophages F3), and thrombospondin 1 (Thbs1). Ofnote, complement factor B (Ctb) and connective tissuegrowth factor (Ctgf) were up-regulated.Many of the top intrathymic genes identified in the biological regulation GOcategory (GO:0065007) are involved in tissue inflammation .Adamts1Osm). Many chemokines were up-regulated in the thymusafter endotoxin stress and were categorized in gene ontologies of immuneresponse and response to stress. These included monocyte chemotactic protein(MCP)-5 (CCL12), MCP-1 (CCL2), macrophage inflammatory protein (MIP)-1(CCL3), Regulated Upon Activation, Normal T-cell Expressed and Secreted(RANTES/CCL5), MIP-1 delta (CCL9), granulocyte colony stimulating factor3(G-CSF/Csf3), KC (CXCL1), IP-10 (CXCL10), B lymphocyte chemo-attractant(BLC/CXCL13), MIP-2\u03b1 (CXCL2), epithelial-derived neutrophil-activatingpeptide 78 (ENA-78/CXCL5), monokine induced by gamma interferon (MIG/CXCL9).Interestingly, Cd14, a co-receptor for TLR4, and cytotoxicT-lymphocyte-associated protein 4 (Ctla4) were alsoup-regulated in response to endotoxin stress in the thymus , including the pro-inflammatory cytokineIL-6 and the receptor for the IL-6 cytokine family member oncostatin M, which playanti-inflammatory roles in protection against heavy metal toxicity andscavenging of free radicals Timp1) and orosomucoid 1(Orm1). Orosomucoid 1 has been shown to stimulatefibroblast proliferation and contribute to the process of wound healingMoreover, factors associated with anti-inflammatory properties were alsoinduced by endotoxemia. Endotoxin challenge induced metallothionein 1 and 2 and matrix metalloprotein(Mmp13) proteolytic systems are activated in stressedthymus tissue Mmp13 expression was increased27-fold in endotoxin challenged thymus , laminin , and fibronectin (Fn1). Genesfor integrins that bind laminin , fibronectin, and collagen (\u03b21) are also upregulated d thymus . In addiPak1, Vav1, Pik3r3,Pik3ca, Pik3r1,Cdc42, Ptk2/Fak, and Ptencan directly contribute to thymocyte apoptosis through dysregulation of theactin cytoskeleton Actb) and actin regulators Arp2/3 and cofilin also decreasedsignificantly  genes critical for antigen presentation to thymocytes wereup-regulated following endotoxin challenge , and mRNA for T cellsurface molecules CD3 epsilon, CD4, CD28, CD2, and LFA-1 were significantlylower in the atrophic thymus  and NFAT(Nfatc1 and Nfatc3) Itgal,Itgb2) Vav1, Wasl,Was, Cdc42, Rac2)supported an important role for adhesion and cytoskeletal remodeling in TCRsignaling Double positive thymocytes are the most severely affected cell type inthymus, compared to thymic stroma, during endotoxemia, which results incharacteristic acute thymic atrophy seen after LPS challenge . Thymocyhallenge . Interesc thymus . These aWhile an abundance of critical TCR signaling-related genes weredown-regulated in thymus following endotoxic stress, CTLA-4 wassignificantly up-regulated . The regIntrathymic mechanisms driving acute thymus atrophy following endotoxemia wereinvestigated in a mouse model. Within 24 hours endotoxin challenge activated asystemic and intrathymic pro-inflammatory cytokine cascade which resulted in lossesof thymic cellularity, TCR\u03b1 gene rearrangement, and DP thymocyte distribution.These characteristic responses to endotoxic stress culminated in significantremodeling of thymus architecture within three to four days post treatment.A phenotypic, histologic and transcriptome/pathway analysis of murine thymic tissueduring the early stages of endotoxemia-induced involution was undertaken in thisstudy to define intrathymic mechanisms that drive this observed acute thymicatrophy. These studies support the hypothesis that multiple key intrathymic pathwaysare differentially activated during endotoxemia-induced thymic involution anddemonstrate for the first time direct activation of thymus tissue by LPS through TLRsignaling, local thymus expression of inflammatory cytokines, inhibition of T cellsignaling, and induction of wound healing/tissue remodeling.Whole murine thymus transcriptome analysis one day post endotoxin challengeidentified several intrathymic pathways to be modulated during stress-induced acutethymic atrophy, suggesting active involvement of thymic residents in thymopoieticand morphological dysregulation. Findings presented identified up-regulation ofgenes involved in inflammation and wound healing and down-regulation of genesinvolved in cell cycle, immune response, and thymocyte activation/signaling duringearly stages of stress-induced thymic involution. Taken together, these observationssuggested that both systemic and direct intrathymic responses to endotoxin challengeconcurrently contribute to thymic involution during endotoxemia. These findings area substantial advancement over current understanding of thymus response to stressand may lead to the development of novel therapeutic approaches to ameliorate immunedeficiency associated with stress events.Bcl11b) and factors necessary for lymphocyte development  and intracellular signaling molecules  were alldown-regulated , an importantpro-inflammatory cytokine, was up-regulated intrathymically (Osmr) was also up-regulated in response to endotoxemia Vav1, Wasl, Was,Cdc42, Rac2) correlated with the observeddecrease in TCR signaling machinery, confirming the interaction of cytoskeletalremodeling and TCR signaling pathways . All efforts were made to minimizepain and suffering. No human samples were used in this study.Escherichia coli-derived lipopolysaccharide (LPS) waspurchased from Sigma-Aldrich  and reconstituted at 1mg/mL in PBS. LPS (100 ug) or saline were administered by intraperitonealinjection. Replicate groups of animals were bled at various time points todetermine serum cytokine levels prior to euthanasia for tissue harvest (30minutes to 7 days post treatment). Serum was isolated by centrifugation for 10min at 3,000\u00d7g and transferred to a 96-well round-bottom culture plate andstored at \u221220\u00b0C until thawed for analysis. Mice were euthanized byCO2 administration for 10 minutes followed by cervicaldislocation. Thymus tissue was removed and weighed. Organs were divided into twohalves; one half was placed in a 60-mm tissue culture dish containing 3 mL RPMI1640  with 5% fetal calf serum (tissuemedium) and one half was placed into a 1.8 mL cryotube and snap frozen in anethanol/dry ice bath.Female C57BL/6 mice (8\u201310 weeks old) were purchased from Charles River.Thymus tissue was teased to a single-cell suspension through a 70 \u00b5m cellstrainer  in tissue medium. Thymocytes werecentrifuged at 1,500 rpm for 5 minutes and resuspended in 2\u20135 mL tissuemedium for cell counts and immunofluorescent staining. Cell counts wereperformed in triplicate on a Coulter Z1 Dual threshold cell counter  and mean recorded. Total thymus cell counts were extrapolated basedon percentage weight of the teased portion of thymus relative to whole thymusweight. Immunofluorescence staining was performed with anti-mousedirectly-conjugated monoclonal antibodies: anti-CD3 FITC, anti-CD4 PE, anti-CD8PerCP-Cy5.5 (BD Biosciences). Cell suspensions were added to PBS Wash  anddiluted antibody, incubated for 45 minutes at 4\u00b0C, washed and resuspended inPBS Wash containing 0.4% (w/v) paraformaldehyde. Immunophenotype datawere acquired on a BD LSRII or BD FACS Canto and analyzed with FlowJo software.TCRD sjTREC werequantified by real-time PCR using a standard curve of known number of moleculesof mouse (m) TREC, specific primers and fluorescent probe as previouslydescribed (21). Briefly, an excess of forward and reverse DNA primers for themTREC sequence and DNA probe conjugated to a fluorescent dye was added togenomic thymus DNA. Real-time PCR using BioRad iCycler IQ allowed detection andquantification of mTREC numbers per 1 \u00b5g DNA in each sample. Numbers ofmTREC were normalized to reflect levels per mg thymus tissue.Total genomic DNA from thymus tissue was extracted using Trizol Reagent(Invitrogen) per manufacturer's protocol. DNA was quantified byspectrophotometry (260 nm). Molecules of mouse Thymus tissue was removed from mice as described above and embedded in O.C.T.Tissue Tek medium (Sakura). Tissue was frozen in a Histo Bath (Shandon/Lipshaw)and stored at \u221280\u00b0C. Tissue sections (5 \u00b5m) were cut on aCryocut 1800 (Leica Biosystems), placed on Superfrost Plus microslides  and stored at \u221280\u00b0C until staining. Sections were fixedfor 2 minutes in ice cold acetone (\u221220\u00b0C) and then air dried. Slideswere stained with hematoxylin and counterstained with eosin. Analysis wasperformed with a Nikon Eclipse TE2000-E and NIS Elements 2.0 software (NikonInstruments Inc) in the DHVI Light Microscopy Shared Resource Facility, Durham,NC.Serum cytokine levels were determined by multiplex bead-based assays usingBioPlex mouse cytokine/chemokine kits according to the manufacturer'sprotocol . All bead assay samples were quantified on theBioPlex protein array reader (BioRad) in the DHVI Immune Reconstitution andBiomarker Shared Resource Facility .Total RNA from snap frozen thymus tissue was extracted using Trizol Reagent(Invitrogen) per manufacturer's protocol and quantified byspectrophotometry (260 nm). RNA was cleaned using an RNeasy Mini Kit permanufacturer's protocol (Qiagen). RNA microarrays were performed by theDuke Microarray Facility in the Duke Institute for Genome Sciences & PolicyDepartment . Briefly, RNA quality was assessed on an Agilent 2100Bioanalyzer (Agilent Technologies). Hybridization of total RNA to AffymetrixMouse genome 430.2 oligonucleotide arrays was performed according to DukeMicroarray Facility protocols. Control and LPS treatment data representexperimental replicates.http://www.bioconductor.org). Pathway analysis on statisticallysignificant genes was performed using MetaCore software by GeneGo . Figures in the text are adaptations based on those created by the MetaCoresoftware. The original MetaCore figures are included in supporting supplementalfigures. For animal studies, two-tailed Student's t test was employed tocompare the means between data sets.Microarray data analysis was performed using Bioconductor packages under the Rstatistical language environment Figure S1Activated TLR3 and TLR4 signaling during acute thymic atrophy.TLR3/TLR4 pathway was the most differentially affected pathway(p\u200a=\u200a3.40\u00d710\u22123) whencomparing saline-treated to LPS-treated mice. Red data thermometers reflectrelative mRNA transcript levels in thymus tissue for control and LPSchallenge. EC: extracellular; PM: plasma membrane; IC: intracellular; NU:nuclear. A full legend of all GeneGo pathway map symbols is in http://www.genego.com/pdf/MC_legend.pdf.(TIFF)Click here for additional data file.Figure S2Increased cytoskeleton remodeling during acute thymic atrophy.The cytoskeleton remodeling pathway scored highest in Metacore pathwayanalysis based on number of significant genes. Datathermometers reflect relative fold change in mRNA steady-state levels inthymus tissue following LPS challenge. Red thermometers representsignificantly increased mRNA levels and blue thermometers representsignificantly decreased mRNA levels. EC: extracellular; PM: plasma membrane;IC: intracellular; NU: nuclear. A full legend of all GeneGo pathway mapsymbols is in http://www.genego.com/pdf/MC_legend.pdf.(TIFF)Click here for additional data file.Figure S3Down-regulation of G1/S cell cycle transition. The cell cycletransition pathway revealed many genes involved with cell cycle progressionto be significantly down-regulated(p\u200a=\u200a3.09\u00d710\u221210) in thymustissue following endotoxin challenge http://www.genego.com/pdf/MC_legend.pdf.(TIFF)Click here for additional data file.Figure S4Modulation of IL-17 signaling during acute thymic atrophy. TheIL-17 pathway ranked as the third most statistically significant pathway usingMetacore pathway analysis. This pathway includes genes for both secretedpro-inflammatory cytokines and the intracellular response through IL-17R.Data thermometers reflect relative fold change in steady-state mRNA level inthymus tissue following LPS challenge. Red thermometers representsignificantly increased mRNA levels and blue thermometers representsignificantly decreased mRNA levels. EC: extracellular; PM: plasma membrane;IC: intracellular; NU: nuclear. A full legend of all GeneGo pathway mapsymbols is in http://www.genego.com/pdf/MC_legend.pdf.(TIFF)Click here for additional data file.Figure S5Modulation of IL-1 signaling pathway during acute thymicatrophy. Differential gene expression of members of the IL-1receptor signaling pathway(p\u200a=\u200a3.5\u00d710\u22129). Datathermometers reflect relative fold change in gene transcript levels inthymus tissue following LPS challenge. Red thermometers representsignificantly increased mRNA levels and blue thermometers representsignificantly decreased mRNA levels. EC: extracellular; PM: plasma membrane;IC: intracellular; NU: nuclear. A full legend of all GeneGo pathway mapsymbols is in http://www.genego.com/pdf/MC_legend.pdf.(TIFF)Click here for additional data file.Figure S6Dysregulation of immunological synapse formation during acute thymicatrophy. The immune synapse pathway ranked sixth in statisticalsignificance usingMetacore analysis. Positive regulators of immune synapse formation andfunction were decreased following endotoxin stress in thymus. Datathermometers reflect relative fold change in gene transcript levels inthymus tissue following LPS challenge. Red thermometers representsignificantly increased mRNA levels and blue thermometers representsignificantly decreased mRNA levels. EC: extracellular; PM: plasma membrane;IC: intracellular; NU: nuclear. A full legend of all GeneGo pathway mapsymbols is in http://www.genego.com/pdf/MC_legend.pdf.(TIFF)Click here for additional data file.Figure S7Decreased CD28 signaling during acute thymic atrophy. The CD28pathway ranked fifth in significance and fourth by differential expression usingMetacore pathway analysis. Genes involved in TCR signaling and thymocytestimulation via the CD28 pathway are down-regulated in thymus tissue fromendotoxin challenged mice. Data thermometers reflect relative fold change ingene transcript levels in thymus tissue following LPS challenge. Redthermometers represent significantly increased mRNA levels and bluethermometers represent significantly decreased mRNA levels. EC:extracellular; PM: plasma membrane; IC: intracellular; NU: nuclear. A fulllegend of all GeneGo pathway map symbols is in http://www.genego.com/pdf/MC_legend.pdf.(TIFF)Click here for additional data file.Figure S8Activated CTLA-4/CD80/CD86 pathway during acute thymic atrophy.Pathway analysis of significant genes determined the CTLA-4 pathway to bedifferentially affected.CTLA-4, CD86 and CD80 were increased while CD28 and TCR-related mRNA levelswere decreased. Data thermometers reflect relative fold change in genetranscript levels in thymus tissue following LPS challenge. Red thermometersrepresent significantly increased mRNA levels and blue thermometersrepresent significantly decreased mRNA levels. EC: extracellular; PM: plasmamembrane; IC: intracellular; NU: nuclear. A full legend of all GeneGopathway map symbols is in http://www.genego.com/pdf/MC_legend.pdf.(TIFF)Click here for additional data file.Figure S9GeneGo pathway map legend. Available for download at http://www.genego.com/pdf/MC_legend.pdf.(PDF)Click here for additional data file.Table S1Significant gene increases within thymus tissue. Followingnormalization, microarray data was tested using the limmaBioconductor package for linear model fitting and an empirical Bayes methodof determination of statistical significance. After false discovery rate wascorrected using the Benjamin-Hochberg method, significant gene expressionchanges (corrected p<0.05) were sorted. Shown are all genes with a meanexpression level above 5 and fold changes greater than 1.4.(XLS)Click here for additional data file.Table S2Significant gene decreases within thymus tissue. Followingnormalization, microarray data was tested using the limmaBioconductor package for linear model fitting and an empirical Bayes methodof determination of statistical significance. After false discovery rate wascorrected using the Benjamin-Hochberg method, significant gene expressionchanges (corrected p<0.05) were sorted. Shown are all genes thatdecreased more than 1.4 fold. Genes with a mean expression level below 5 arenot shown.(XLS)Click here for additional data file."}
+{"text": "Bovine oviduct epithelial cells have been widely used in co-culture experiments to condition culture media and improve early embryonic development . However surface . The tri2 & 20% O2. The development of primary cultures was assessed daily and the medium was renewed every 48 hours. After 3 weeks of monolayer culture, the ultrastructural features of oviduct cells were examined by scanning electron microscopy while the integrity of monolayer was tested by transepithelial electrical resistance and permeability to radiolabeled 14C-Mannitol. Non-parametric statistical analysis was done using Kurskal-Wallis Test.Oviducts were excised from the genital tracts of cows slaughtered in abattoir. Following mechanical isolation, the oviduct epithelial cells were cultured on three different membrane supports i.e. polyester membrane , polytetrafluoroethylene membrane  and cellulose ester membrane . The culture of oviduct epithelial cells was done in TCM-199 medium  with 10% fetal bovine serum at 39\u00b0C in a humidified atmosphere of 5% CO14C-Mannitol across the monolayer of oviduct epithelial cells showed a tendency for lowest permeability (P=0.6) in polyester (Thincert\u2122) membrane support  and cellulose ester (Millicell\u2122) membrane supports while no such monolayer was seen in polytetrafluoroethylene (Transwell\u2122) membrane support. The test of transepithelial electrical resistance across monolayer of oviduct epithelial cells showed no significant difference (P>0.25) between the three membrane supports Fig. . The tesort Fig. .in vitro culture may serve as a model to study different cellular functions such as transport, absorption and secretory capacity of bovine oviduct epithelial cells as well as embryo-maternal interactions.The potential of polyester membrane supports (Thincert\u2122) to maintain ultrastructural features  and ensure monolayer integrity  during"}
+{"text": "Furthermore, inhibition of paracrine factor hepatocyte growth factor (HGF) signaling in vivo suppressed the BMPC-mediated inhibition of miR-155 expression and the associated protective effect on cardiac fibrosis and function. In vitro studies confirmed that the conditioned media of BMPC inhibited miR-155 expression and profibrotic signaling in mouse cardiac fibroblasts under diabetic conditions. However, neutralizing antibodies directed against HGF blocked these effects. Furthermore, miR-155 over-expression in mouse cardiac fibroblasts inhibited antifibrotic Sloan-Kettering Institute proto-oncogene (Ski) and Ski-related novel gene, non-Alu-containing (SnoN) signaling and abrogated antifibrogenic response of HGF. Together, our data demonstrates that paracrine regulation of cardiac miRNAs by transplanted BMPCs contributes to the antifibrotic effects of BMPC therapy. BMPCs release HGF, which inhibits miR-155-mediated profibrosis signaling, thereby preventing cardiac fibrosis. These data suggest that targeting miR-155 might serve as a potential therapy against cardiac fibrosis in the diabetic heart.Diabetes is associated with a higher incidence of myocardial infarction (MI) and increased risk for adverse vascular and fibrogenic events post-MI. Bone marrow-derived progenitor cell (BMPC) therapy has been shown to promote neovascularization, decrease infarct area and attenuate left ventricular (LV) dysfunction after MI. Unlike vascular effects, the anti-fibrosis mechanisms of BMPC, specifically under diabetic conditions, are poorly understood. We demonstrated that intramyocardial delivery of BMPCs in infarcted diabetic  Experimental and clinical studies have shown the potential benefits of bone marrow-derived progenitor cell (BMPC) therapy for cardiovascular diseases Diabetic patients have a 2- to 5-fold increased risk of developing heart failure and higher incidence of ischemic heart disease db/db) mice after MI regulates cardiac miRNAs. BMPC administration reduced the expression of profibrotic miR-155 and fibrosis response in the diabetic hearts. We further show that neutralizing hepatocyte growth factor (HGF) signaling, both in vitro and in vivo, inhibits miR-155 expression and Ski/SnoN signaling leading to aggravated fibrogenesis response.In this study, we demonstrate that administration of BMPC in diabetic  in accordance with previously published methods Mouse BMPC isolation, 6 cells were cultured for 48 hours in growth factor-free EBM-2 with 1% FBS. The conditioned medium was then collected, filtered with a 0.22 \u00b5m filter  to harvest cell-free solution and concentrated (10X) by centrifugation using Ultrafree filter membranes (Millipore). EBM-2 containing 1% FBS without supplements served as control medium. Release of HGF into the media was measured by quantitative ELISA using HGF immunoassay kit  as per manufacturers instructions. At least three independent measurements were performed in duplicates. HGF secretions from mouse endothelial cell line SVECs cultured under similar conditions were used for comparison. HGF levels are depicted in To produce BMPC conditioned medium (BMPC-CM), 5\u00d7102. Confluent cells were almost exclusively fibroblasts (>98% purity), as previously reported Cardiac fibroblasts (CFs) were isolated from hearts of 12-week-old C57BLKS/J mice, as previously described in vitro, we exposed cardiac fibroblasts to diabetic milieu to activate fibrogenesis signaling and evaluated the effect of conditioned medium derived from cultured BMPC. To replicate the in vivo context (diabetic milieu), cardiac fibroblasts were grown in serum-free normal glucose (control) medium [5.5 mM glucose] for 24 h and exposed to 25 mM glucose +10 ng/ml TGF-\u03b21 (diabetic milieu) with BMPC-CM or control medium. To correct for hyperosmolarity, a separate set of cells were exposed to 5.5 mM glucose +19.5 mM mannitol . For assessing miR-155 expression (24 hr after treatment), total RNA was isolated using miRNeasy kit (Qiagen) and miRNA was analyzed by Taqman MicroRNA assay kits  in accordance with the manufacturer\u2019s protocol. miRNA levels were normalized with RNU6B (U6 control) expression. To evaluate fibrogenic response, expression of collagen type I alpha 1 (Col1A1), collagen type 3 alpha 1 (Col3A1) and alpha-smooth muscle actin (\u03b1-SMA) in cardiac fibroblast after 48 hr of treatment was assessed by qRT-PCR or Western blotting.To determine the effects of BMPC-CM on cardiac fibroblast miR-155 expression and fibrosis signaling To enable detailed study of miR-155 effects on fibrosis-related genes in cardiac fibroblasts, we transfected cardiac fibroblasts with either pre-miR-155 (miR mimics) or negative control mimics. Cardiac fibroblasts were grown in DMEM media without antibiotics and transfected with either miRNA mimics or controls  using Lipofectamine RNAiMAX (Invitrogen) for 72 hrs as per the manufacturer instructions. Transfected cells were \u223c95% viable (data not shown). miRNA was assessed by qRT-PCR. Pre-miR-155 transfection significantly increased miR-155 expression as compared to mimic control transfected cells . Using Lipofectamine RNAiMAX (Invitrogen), the siRNA at a final concentration of 30 nM in Opti-MEM media (Invitrogen) was transfected into BMPCs, according to the manufacturer\u2019s instructions. After 48 hrs of transfection, HGF secretion from these cells was confirmed by ELISA. siRNA directed against HGF significantly suppressed HGF secretion in vitro in comparison with control siRNA transfected cells  against mouse db/db (diabetic) mice and their normal littermate controls (db/+ mice) were purchased from The Jackson Laboratories . Baseline blood glucose levels (blood obtained by tail snip) were measured using One Touch Ultra2 blood glucometer . db/db mice exhibited marked hyperglycaemia compared with relative db/+ controls . Mice were subjected to myocardial infarction (MI) by permanent ligation of left anterior descending coronary artery (LAD) as described previously 6 BMPCs in a total volume of 15 \u00b5L was injected intramyocardially into 3 different sites in the periinfarct area distal to the ligation of the artery. Control animals received a corresponding volume of normal saline.All animal research in this study was conducted in accordance with the protocols approved by the Institutional Animal Care and Use Committee (IACUC) at Northwestern University . Ten-weeks-old male C57BLKS/J To determine if the antifibrosis effect of BMPC treated mice is inhibited by blocking HGF signaling, a subset of mice that underwent MI surgery and BMPC transplantation were injected intraperitoneally with neutralizing goat anti-HGF antibodies  or normal goat IgG for 7 days, post-MI. Antibody dose is based on previous published data Transthoracic two-dimensional M-mode echocardiogram was obtained using Vevo 770  equipped with a 30 MHz transducer. Echocardiographic studies were performed before (baseline) and at 7 and 28 days post-MI on mice anesthetized with a mixture of 1.5% isoflurane and oxygen (1 L/min). M-mode tracings were used to measure end-systolic diameter (LVESD) and end-diastolic diameter (LVEDD) and percent ejection fraction (%EF) was calculated as described previously Histopathology studies were performed as described previously qRT-PCR was performed as described previously Protein isolation and Western blotting for cultured cells were performed as previously described t-test for single comparisons or by ANOVA for multiple comparisons, with Bonferroni post-hoc test. Values of P<0.05 were considered statistically significant.All data are expressed as mean \u00b1 SEM. Differences between groups were assessed by an unpaired Student\u2019s To determine whether BMPCs regulate fibrosis-related miRNAs in infarcted heart, we injected mouse BMPCs in infarcted hearts of C57BLKS/J mice and determined (at 3 days post-MI) the expression of miRNAs . Cardiac fibroblasts were grown in serum-free normal glucose (control) medium [5.5 mM glucose] for 24 h and exposed to 25 mM glucose +10 ng/ml TGF-\u03b21 (diabetic conditions) with control or BMPC-CM. As shown in Cardiac fibrosis significantly contributes to diabetes-induced diastolic dysfunction in vitro.Among several paracrine factors secreted, the release of VEGF, SDF-1, IGF-1, and HGF was profoundly increased in EPC cell culture supernatants in vivo in db/db mice. As compared to saline treated mice, BMPC transplantation reduced miR-155 expression  significantly increased miR-155 expression in the myocardium . Interestingly, miR-155 over-expression abrogated HGF-mediated decrease in fibrosis-related markers like Col1A1, Col3A1 and \u03b1-SMA  and determined the effect on HGF-mediated anti-fibrosis signaling. As shown in nd \u03b1-SMA ; P<0.01,db/db) mice. Furthermore, neutralization of paracrine factor, hepatocyte growth factor (HGF) aggravates fibrogenic response both in vivo and in vitro  administration regulates expression of miRs  and modulates fibrosis in the infarcted heart in diabetic  is a multifunctional molecule that elicits a wide spectrum of biological activities in many patho-physiological processes in vivo abrogates the antifibrosis effect of BMPC therapy, suggesting that BMPC release of paracrine factor (HGF) suppresses profibrogenic signaling in diabetic hearts. In addition, we studied the effect of recombinant HGF protein administration on cardiac fibrotic response to account for any loss or marginalization of effect in BMPC transfected with HGF siRNA. Together, these data correlate with the previous study that demonstrated that in vivo gene transfer of HGF before ischemia showed multiple beneficial actions , therefore contributing to the reduction in the infarct size and the improvement of left ventricular dysfunction after infarction HGF has been shown to inhibit TGF-\u03b2 mediated fibrosis signaling in a variety of disease models including renal and cardiovascular systems Diabetes is an important risk factor for coronary heart disease and contributes to the development of cardiovascular diseases. An increase in TGF-\u03b2 production is commonly thought to contribute to excessive cardiac fibrosis in patients with diabetes db/db mice that received BMPC transfected with siRNA against HGF, as compared to control siRNA BMPC treated hearts. Similarly, mRNA expression of ECM proteins, such as collagen I, collagen III and \u03b1-SMA, was also significantly increased in correlation with fibrotic response Click here for additional data file.Figure S2miR-155 over-expression in adult mouse cardiac fibroblasts. miR-155 expression (determined by qRT-PCR) was increased in cardiac fibroblasts transfected with miR-155 mimics (pre-miR-155) for 72 h as compared to cells transfected with negative control mimics (control). *P<0.01 compared with control-transfected cardiac fibroblasts.(TIF)Click here for additional data file.Figure S3ELISA for HGF levels secreted from BMPCs transfected with HGF siRNA. HGF secretion was reduced in BMPCs 48 hours after transfection with siRNA directed against HGF. P<0.01 versus control siRNA transfected cells.(TIF)Click here for additional data file.Figure S4Expression of cardiac miRNAs after intramyocardial BMPC transplantation following MI in mice. miRNA expression was measured in the border zone of infarcted area at 3 days post-MI by quantitative RT-PCR. BMPC therapy did not affect miR-27 (A) and miR-30a (B) in comparison with saline-treated group. BMPC, bone marrow-derived progenitor cell; MI, myocardial infarction.(TIF)Click here for additional data file.Figure S5Administration of mouse recombinant HGF provided cardiac protection after MI. (A) HGF administration reduced miR-155 expression, enhanced LV function (increased % EF) (B) and inhibited fibrosis (C). *P value versus saline-treated MI mice.(TIF)Click here for additional data file.Figure S6Transplantation of BMPC transfected with siRNA against HGF in mice after MI. (A) miR-155 expression, percent ejection fraction (% EF) (B) and % fibrosis (C) in mice receiving intramyocardial BMPC transfected with siRNA against HGF after MI. *P<0.05 versus control siRNA BMPC-treated MI mice.(TIF)Click here for additional data file."}
+{"text": "Volume resuscitation is essential to restore normovolemia during hemorrhagic shock, burns and sepsis. However, synthetic colloids cause dilutional coagulopathy. The aims were to determine whether the natural colloid albumin induces a lesser degree of coagulopathy compared with synthetic colloids, and the comparative effectiveness of fibrinogen concentrate to reverse coagulopathy following dilution with these solutions.Rotational thromboelastometry-based tests were used to examine coagulation parameters in samples from 10 healthy volunteers, in undiluted blood and samples diluted 1:1 with saline, Ringer's acetate, hydroxyethyl starch (HES) 130/0.4, buffered HES 130/0.4, 3% dextran 60, 6% dextran 70 or 5% albumin. Samples were analyzed before and after addition of 2 mg/ml fibrinogen concentrate.P <0.001), although a significantly greater coagulopathic effect was seen for samples diluted with synthetic colloid solutions versus albumin (P \u22640.001). A significant reduction in the platelet component of clot strength (EXTEM MCF - FIBTEM MCF) was seen for samples diluted with synthetic colloids (P <0.001) but not albumin (P = 0.10). Following addition of fibrinogen, FIBTEM MCF, EXTEM MCF and EXTEM AA were significantly higher, and EXTEM CFT was significantly shorter in samples diluted with albumin versus those treated with HES or dextran (P \u22640.001).EXTEM maximum clot firmness (MCF), clot formation time (CFT) and \u03b1 angle (AA) decreased significantly upon dilution with all colloid solutions (Hemodilution using albumin induced a lesser degree of coagulopathy compared with the synthetic colloids HES and dextran. In addition, albumin-induced coagulopathy was more effectively reversed following addition of fibrinogen concentrate compared with coagulopathy induced by synthetic colloids."}
+{"text": "We aimed to investigate which indexation of EVLW provides the best association of ELWI and pO2/FiO2 in patients without pulmonary impairment or without ventilation.Extravascular lung water (EVLW) has been indexed to actual BW (BW-act), termed the EVLW index (ELWI). Since in obese patients indexation to BW-act might inappropriately diminish the indexed ELWI-act, ELWI indexed to predicted BW (ELWI-pred) has been introduced. Indexation of EVLW to height might be superior to ELWI-pred/-act. Recent data in a selected collective of ARDS patients suggest that indexation to height might improve the predictive capabilities of ELWI regarding pO2/FiO2 <200 mmHg and other critical thresholds provided by unindexed EVLW as well as ELWI indexed to ideal BW, adjusted BW, BMI, body surface area, height and total lung capacity.In 50 consecutive ICU patients with PiCCO monitoring, 843 triplicate measurements of EVLW and simultaneous blood gas analysis were performed. The endpoint was prediction of pO2/FiO2 <200 mmHg were found for ELWI-height  and EVLW , the lowest AUC for ELWI-act . Similarly ELWI-height and unindexed EVLW provided the largest ROC AUCs regarding pO2/FiO2 >300 mmHg (0.659 and 0.657), normal pO2/FiO2  and acute and/or chronic pulmonary impairment (0.622 and 0.625). All these associations were significant with P < 0.001. Among patients with pulmonary impairment, first values of ELWI-height and EVLW provided the largest ROC AUCs regarding mortality  compared to ELWI-act  and APACHE II score .Measurements in patients without pulmonary impairment 463/843 (54.9%); acute 188/843 (22.3%), chronic 106/843 (12.6%), and both acute and chronic pulmonary disease 86/843 (10.2%). Mechanical ventilation in 458/843 (54.3%) measurements. The largest ROC AUCs regarding pOIndexation to BW-act results in reduced predictive capabilities compared to no indexation at all. ELWI-pred performs slightly better than ELWI-act, but our data do not support that ELWI-pred is superior to no indexation at all in adult ICU patients. In this unselected and prospectively evaluated collective, the highest predictive capabilities regarding several predefined thresholds were found for ELWI-height."}
+{"text": "Myocardial fibrosis occurs in aortic stenosis and is associated with long-term clinical outcome. Myocardial fibrosis is detected by delayed contrast-enhanced cardiac magnetic resonance. The aim of this study was to investigate the influence of myocardial fibrosis on left ventricular (LV) global function and morphology in patients with symptomatic severe aortic stenosis (AS).Eighty-nine patients  with pure severe AS (n = 36) or severe AS with mild aortic regurgitation (n = 53) were included in the study. All patients underwent transthoracic echocardiography (TTE), cardiac computed tomography (CCT) and cardiac magnetic resonance (CMR) and subsequent valvuloplasty operation. Patients were analyzed according to the presence and absence of myocardial fibrosis  on CMR. The differences of cardiac function and morphology between two groups are statistically analyzed.3 vs 1631 \u00b1 1106 mm3, p = 0.0001) and calcium grade by CCT (p =0.0002), more severe AS , higher indexed LV mass by CMR , lower LV ejection fraction by CMR , and larger indexed LV end-diastolic volume by CMR  compared with patients without myocardial fibrosis.Myocardial fibrosis was observed in 37 patients. There were no differences in valvular morphology and clinical characteristics between two groups. Patients with myocardial fibrosis had higher aortic valve calcium volume score (2960 \u00b1 1934 mmMyocardial fibrosis is associated with more severe calcific AS, worse LV functional parameters and higher LV mass index in patients with severe AS. From these results, contrast-enhanced CMR may provide new strategies for the earlier diagnosis of severe AS with myocardial fibrosis.None."}
+{"text": "Spontaneous CSF leakage is now recognized as a secondary chronic daily headache (CDH) and its characteristic feature is a postural (orthostatic) headache. Despite occipital headaches being common, only one published case report exists of occipital neuralgia associated with significant cerebral descent from CSF leakage. Our case is the first one, occurring without prominent cerebral descent. Potential pathogenic mechanisms are discussed.To report a spontaneous CSF leak as an unusual cause for occipital neuralgia.Case report.A 51-year-old woman with CDH for 3 years presented with bilateral, pressure-like headache aggravated by valsalva and alleviated by lying down. Neurologic exam, brain MRI/MRV/MRA and cervical MRI were all unremarkable. Considering a New Daily Persistent Headache (NDPH), amitriptyline was started but failed. Her headache changed to bilateral occipital, shock-like pains, lasting seconds to minutes superimposed on a \u201cspongy, numb\u201d occipital sensation but without postural component. Occipital nerve block resulted in a dramatic response. Repeat brain MRI showed dural enhancement with subtle \u201cbrain sagging\u201d. An empiric lumbar epidural blood patch failed. Spinal MRI showed extradural fluid collections in the lower thoracic region. Conventional computed Tomography (CT) myelogram confirmed a mid-thoracic CSF leak. Subsequent dynamic CT myelography confirmed the location of fast CSF leakage at T4-T5 secondary to a disc extrusion. A decompressive laminectomy with repair of the CSF leak completely aborted her headaches.Occipital neuralgia secondary to CSF leakage may be an under-diagnosed phenomenon. Pressure to the C2-C3 nerve roots during prominent cerebral descent may be the underlying headache cause. In cases without significant cerebral descent such as ours, traction of the C2-C3 nerve roots or the occipital nerve may be a better explanation. Other mechanisms, however, are likely role players as occipital neuralgia is a rare happening in the setting of a spontaneous CSF leak."}
+{"text": "The pigment cells of vertebrates serve a variety of functions and generate astunning variety of patterns. These cells are also implicated in humanpathologies including melanoma. Whereas the events of pigment cell developmenthave been studied extensively in the embryo, much less is known aboutmorphogenesis and differentiation of these cells during post-embryonic stages.Previous studies of zebrafish revealed genetically distinct populations ofembryonic and adult melanophores, the ectotherm homologue of amniotemelanocytes. Here, we use molecular markers, vital labeling, time-lapse imaging,mutational analyses, and transgenesis to identify peripheral nerves as a nichefor precursors to adult melanophores that subsequently migrate to the skin toform the adult pigment pattern. We further identify genetic requirements forestablishing, maintaining, and recruiting precursors to the adult melanophorelineage and demonstrate novel compensatory behaviors during pattern regulationin mutant backgrounds. Finally, we show that distinct populations of latentprecursors having differential regenerative capabilities persist into the adult.These findings provide a foundation for future studies of post-embryonic pigmentcell precursors in development, evolution, and neoplasia. Understanding the biology of post-embryonic stem and progenitor cells is of bothbasic and translational importance. To identify mechanisms by which stem andprogenitor cells are established, maintained, and recruited to particular fates,we are using the zebrafish adult pigment pattern. Previous work showed thatembryonic and adult pigment cells have different genetic requirements, butlittle is known about the molecular or proliferative phenotypes of precursors toadult pigment cells or where these precursors reside during post-embryonicdevelopment. We show here that post-embryonic pigment cell precursors areassociated with peripheral nerves and that these cells migrate to the skinduring the larval-to-adult transformation when the adult pigment pattern forms.We also define morphogenetic and differentiative roles for several genes inpromoting these events. Finally, we demonstrate that latent precursor poolspersist into the adult and that different pools have different capacities forsupplying new pigment cells in the context of pattern regeneration. Our studysets the stage for future analyses to identify additional common and essentialfeatures of pigment stem cell biology. A fundamental challenge for modern developmental biology is to determine howpopulations of stem and progenitor cells are established, maintained, and recruitedto differentiate at particular times and places during post-embryonic developmentand in the adult organism. The significance of the problem cannot be overstated. Notonly are these cells essential for normal development and homeostasis, butunderstanding their biology has profound translational importance. If we seek toevoke regenerative responses in a clinical content, then post-embryonic stem andprogenitor populations may well supply the cells for doing so Pigment cells are of great utility for understanding the biology of post-embryonicstem and progenitor cells. Pigment cells are a classic and enduring system forstudying morphogenesis and differentiation, and a century of effort has provided afirm understanding of many aspects of pigment cell development in the embryo Answers to these questions will provide insights into the basic biology of the adultpigment cell lineage, and can inform our understanding of post-embryonic neuralcrest derivatives as well as stem and progenitor cells more generally. These answersare also of enormous biomedical significance, as the skin pigment cell of mammals,the melanocyte, is associated with a variety of human pathologies In recent years, the zebrafish has proven to be a tractable system for elucidatingfeatures of pigment cell development in the embryo and during the larval-to-adulttransformation, a period of post-embryonic development analogous to laterorganogenesis, fetal and neonatal development of mammals The development of zebrafish adult pigmentation involves a \u201cpigment patternmetamorphosis\u201d in which an embryonic/early larval pigment pattern istransformed into that of the adult picasso andpuma mutants have normal embryonic/early larval melanophores,but profound deficiencies in their complements of metamorphic melanophores.picasso encodes the neuregulin receptor erbb3b, which acts bothautonomously and non-autonomously to the metamorphic melanophore lineage.Pharmacological inhibition of ErbB signaling further revealed thaterbb3b activity is required during neural crest migration forthe later development of metamorphic melanophores, suggesting this locus isessential for establishing a pool of precursors that will differentiate only laterduring the larval-to-adult transformation puma encodes tubulin alpha 8-like 3a (tuba8l3a) and actsautonomously to the metamorphic melanophore lineage. The temperature sensitivity ofthis allele allowed the identification of a critical period during pigment patternmetamorphosis, suggesting a role in maintaining or expanding a population of latentprecursors, or recruiting these cells as melanophores Mutants with pigment pattern defects limited to post-embryonic stages have suggesteda model in which embryonic/early larval melanophores develop directly from theneural crest, whereas metamorphic melanophores develop from latent stem cells ofpresumptive neural crest origin. For example, erbb3b, tuba8l3a or other loci promotethe normal morphogenesis and differentiation of these cells and their progeny, orwhether pigment cell precursors have indefinite or more limited re-populationpotential. Here we investigate these issues using molecular marker analyses,transgenesis, vital labeling, and time-lapse imaging in wild-type and mutantbackgrounds. We show that during post-embryonic development, proliferative pigmentcell precursors are associated with peripheral nerves and ganglia, and migrate tothe hypodermis during pigment pattern metamorphosis where they differentiate asmelanophores and iridophores. Nerve-associated pigment cell precursors are missingor reduced in ErbB-deficient and tuba8l3a mutant backgrounds. Bycontrast, these precursors persist in other mutants having less severe metamorphicmelanophore deficiencies, though their subsequent development is marked both bydefects, and partial regulation, of morphogenesis and differentiation. Finally, weshow that latent precursors persist into the adult but that different precursorpools have different regenerative potentials. These findings provide a criticalcontext for understanding the cellular bases of adult melanophore development, themechanistic underpinnings of mutant phenotypes, and the roles for latent precursorsin adult homeostasis, regeneration, and neoplasia.To date it has not been known where latent precursors to metamorphic melanophoresreside, how foxd3 and sox10, which are expressed byearly neural crest cells, subpopulations of neural crest-derived glia, and someother cell types crestin, which is known only to be expressed by neuralcrest cells and their derivatives To identify tissues that might harbor latent precursors to adult melanophores, weexamined post-embryonic zebrafish for transcripts expressed by embryonic neuralcrest cells, reasoning that some of the cells expressing such markers mightcomprise a population of undifferentiated melanophore precursors. We examinedwp.r.t2Tg(hsp70::kitla), to misexpress themelanogenic factor kit ligand-a (kitla) If extra-hypodermal, post-embryonic cells expressing genes typical of earlyneural crest cells contribute to metamorphic melanophores, we hypothesized thatsome of these cells should differentiate if supplied with appropriate trophicsupport. To test this idea, we used a heat-shock inducible transgenic line,erbb3b is essential for establishingprecursors to metamorphic melanophores erbb3b mutants misexpressing kitla. Indeed,erbb3b; Tg(hsp70:kitla) larvae exhibited \u223c30-fold fewerectopic melanophores than wild-type Tg(hsp70::kitla) larvae(erbb3bactivity in establishing metamorphic melanophore precursors erbb3b activity is lost.Previously we showed that ) larvae. A similerbb3b, wefurther predicted that any candidate extra-hypodermal precursors of these cellsshould be missing in larvae deficient for erbb3b activity.Our identification of extra-hypodermal cells expressing genes typical of earlyneural crest and glial cells, as well as kitla-responsive melanogenic cellswithin the myotomes, led us to ask whether any of these cells embark upon amelanophore differentiation program during normal post-embryonic development.Since precursors to metamorphic melanophores require mitfa, encoding a master regulator of melanophore fatespecification , which faithfullyrecapitulates mitfa expression in the melanophore lineage andin bipotent precursors to melanophores and iridophores in the embryo erbb3b mutants and wild-type larvae treated with AG1478during the embryonic erbb3b critical period  larvae were likewise nerve-associated. The frequency ofEdU labeling amongst foxd3+; mitfa::GFP+ cells did not varysignificantly across stages.Finally, in erbb3b mutants sampled at selected stages, we foundlower levels of EdU incorporation than in wild-type, though small numbers ofcells overall resulted in correspondingly low statistical power  larvae and we assessed after \u22654 d whetherDiI-labeled cells were present within the hypodermis distant from the injectionsites. In 10\u201330% of injected larvae we found hypodermal DiI-labeledmelanized cells, mitfa::GFP+ cells, or iridophores  larvae. Moviesrevealed the differentiation of mitfa::GFP+ cells into melanophores as wellas their migration  transgene into erbb3b andtuba8l3a mutants, which exhibit severely reduced numbers ofmetamorphic melanophores Our findings suggested that a normal complement of adult melanophores depends oncontributions from a pool of extra-hypodermal precursors. If this is the case,we predicted that mutants with severe metamorphic melanophore deficienciesshould have correspondingly severe deficiencies of extra-hypodermally derivedmitfa:GFP+ cells. To test the contributions of extra-hypodermal cells tohypodermal mitfa::GFP+ cells and melanophores, we crossed theerbb3b mutants had dramatically fewer extra-hypodermallyderived mitfa::GFP+ cells  and endothelin receptor b1(ednrb1) mutants. By contrast, late metamorphicmelanophores persist in kita mutants, but are ablated incsf1r and ednrb1 mutants Tg(mitfa::GFP) transgene intob5kita, j4e1csf1rand b140ednrb1 mutants and examined the origins ofhypodermal mitfa::GFP+ cells as well as their frequencies ofdifferentiation, death and proliferation.Amongst the erbb3b and tuba8l3a mutants,kita, csf1r, and ednrb1mutants did not exhibit significantly fewer extra-hypodermally derivedmitfa::GFP+ cells than the wild-type, though cells in kitamutants typically failed to differentiate and instead died at high frequency,whereas cells in csf1r and ednrb1 mutants weremore likely both to differentiate and to die (N\u200a=\u200a3822melanophores observed) and in most of the mutants . Inkita mutants, however, the few melanophores thatdifferentiated divided frequently  b5kita single mutants)at permissive temperature, but should lack all melanophores at restrictivetemperature. Repeated exposure to restrictive and permissive temperatures shouldthus allow for repeated cycles of ablation and regeneration of thesekita-independent, csf1r-dependentmelanophores. As predicted, TSkita; csf1r doublemutants that were initially indistinguishable from kita singlemutants lost body melanophores when shifted to restrictive temperature . Because ErbB signaling can repressmelanocyte differentiation Examination of erbb3b mutants, tuba8l3a mutantsexhibit a post-embryonic demyelination of peripheral nerves and a correspondingcritical period for adult melanophore development tuba8l3a mutant larvae were deficient for mbp+glia, nerve-associated foxd3+ cells and foxd3+; mitfa::GFP+cells, and also had reduced rates of division amongst hypodermalmitfa::GFP+ cells. Because tuba8l3a acts autonomously tothe metamorphic melanophore lineage In contrast to kita, csf1r, andednrb1 all promoted the survival of mitfa::GFP+ cellswhereas kita also promoted the differentiation of these cellsas melanophores. Yet, these analyses revealed compensatory responses of pigmentcells and their precursors in mutant backgrounds as well. For example, residualmitfa::GFP+ cells in mutants with extra-hypodermal precursor deficiencies or hypodermal defectsin cell survival  exhibitedconcomitantly greater rates of differentiation, and, in one instance(erbb3b), an increased rate of proliferation. Moreover, thereduced survival and differentiation of mitfa::GFP+ cells inkita mutants was coupled with a 70-fold increase inmelanophore proliferation. These findings highlight the remarkably regulativenature of zebrafish pigment pattern development Time-lapse imaging comparisons of wild-type and mutant backgrounds furtherdefined roles for genes previously known to function in pigment patterndevelopment: kita andTScsf1r in which loss of residualmelanophores at restrictive temperature likely reflects the withdrawal oftrophic support provided by csf1r-dependent xanthophores kita-independent,csf1r-dependent late metamorphic melanophores. Whether thesame is true of kita-dependent early metamorphic melanophoresremains to be determined. Nevertheless, our finding that scale melanophoresregenerated repeatedly-in contrast to late metamorphic, hypodermalmelanophores-suggests a more highly regulative precursor pool associated withthe adult scales, and highlights the possibility of spatially and temporallydistinct pools of precursors having different morphogenetic and differentiativepotentials. That scale melanophores developed de novo in thesefish, despite their absence from kita single mutants, likelyreflects a priority effect; e.g., initially abundant xanthophores may repressmelanophore development in kita mutants basonuclin-2 mutants, which are deficient for hypodermalmelanophores, nevertheless retain both scale and fin melanophores A particularly dramatic example of pattern regulation occurs during regeneration.Zebrafish larval melanophores regenerate following laser ablation or theadministration of melanocytotoxic drugs erbb3b andtuba8l3a mutants, illustrating the critical role of suchcells in supplying metamorphic melanophores overall. By contrast, we found noevidence for reduced numbers of extra-hypodermally derived mitfa::GFP+cells in kita, csf1r, orednrb1 mutants, indicating that different geneticrequirements of early and late metamorphic melanophores do not reflectdifferences in the establishment or maintenance of these cells. These findingssuggest either of two interpretations. Early and late metamorphic melanophorescould arise from a common precursor pool with differences in residualmelanophore complements among mutants reflecting specific requirements forkita, csf1r, and ednrb1in downstream events of morphogenesis and differentiation. For example, our dataindicate that mitfa::GFP+ cells require kita for theirsurival, and presumably, terminal differentiation: the development of latemetamorphic melanophores in kita mutants could thus reflect thelate appearance of factors able to substitute for kita activityin promoting melanophore differentiation. Conversely, we found thatmitfa::GFP+ cells were only marginally dependent on csf1r:the failure of late metamorphic melanophores to develop incsf1r mutants could, in turn, reflect a late-arising,post-differentiation requirement for trophic support fromcsf1r-dependent xanthophores Finally our study provides new insights into the temporally distinct populationsof melanophores in zebrafish. We found severe deficiencies in the numbers ofextra-hypodermally derived mitfa::GFP+ cells in The identification of extra-hypodermal nerve-associated precursors to adultmelanophores in zebrafish (this study) and amniotes w47Tg(mitfa::GFP) andba2Tg(\u22124.9sox10:egfp) fish weregenerously provided by D. Raible and R. Kelsh, respectively.wp.r.t3Tg(TrDct::mCherry) andwp.r.t2Tg(hsp70::kitla) fish were producedusing tol2kit Gateway vectors and Tol2-mediated transgenesiserbb3b mutants usedeither of two presumptive null alleles,ut.r2e1erbb3b orwp.r2e2erbb3bcsf1r mutants used either the presumptive nullallele j4bluecsf1r or the temperature-sensitiveallele utcsf1rr1e174.kita mutant used the presumptive null alleleb5kitaj115e1tuba8l3a encodes a missensesubstitution with temperature-sensitive effects. Experiments with this allelewere performed at standard rearing temperature, intermediate between restrictive(33\u00b0C) and permissive (24\u00b0C) temperatures tuba8l3a mutation.Animal use conformed to University of Washington IACUC guidelines.Fish were reared at 28\u201329\u00b0C, 14L:10D. Post-embryonic stages arereported as standardized standard length (SSL) measurements, which indicatedevelopmental progress of free-feeding larvae more reliably than dayspost-fertilization Fish were viewed with Olympus SZX-12 or Zeiss Discovery epifluorescencestereomicroscopes or with a Zeiss Observer inverted compound epifluorescencemicroscope with Apotome. Images were collected in Axiovision software usingAxiocam HR or MR3 cameras. For thick specimens, stacks of images were collectedand processed using Zeiss Axiovision 6D Acquisition or Extended Focus modulesand some fluorescence images were deconvolved using the Zeiss AxiovisionDeconvolution module. Alternatively, specimens were viewed and images collectedon Zeiss 510 META or Olympus FV1000 laser confocal microscopes.For immunohistochemistry, larvae were fixed in 4% paraformaldehydecontaining 1% DMSO in PBS, rinsed, embedded in agarose, then sectioned byvibratome at 150\u2013200 \u00b5m. Sections were washed in PBS/1%DMSO/0.3% Triton-X pH 7.4 (PDTX), blocked in PDTX containing10\u201320% heat inactivated goat serum then incubated overnight at4\u00b0C with primary antibody. We used polyclonal antisera raised in rabbitagainst zebrafish sox10  was prepared as a stock solution in DMSO thendiluted to 0.025\u20130.05% in 0.3 M sucrose just before use. Larvaewere anesthetized briefly and injected with 1\u20132 nl of DiI using aborosilicate needle, imaged immediately to ascertain the specificity of stainingin target tissues, then reared individually until analyzed.P<0.05;N\u200a=\u200a67 cells examined). Imaging overlonger durations resulted in increased rates of cell death throughout theexplant and thus were not used for analyses.Larvae were rinsed with 10% Hanks medium, anesthetized and then sacrificedby decapitation using a razor blade. After removing the anterior portion of thetrunk and discarding the tails, larval trunks were placed on 0.4 \u00b5mtranswell membranes (Millipore) in glass-bottom dishes containing L-15 medium,3% fetal bovine serum, and penicillin/streptomycin. Trunks wereequilibrated at 28.5\u00b0C for 3 h then imaged for 18\u201324 h  on a Zeiss Observer inverted epifluorescencemicroscope. Comparisons between isolated trunks imaged continuously for 24 h andrepeatedly anesthetized intact larvae did not reveal gross differences in thesurvival of mitfa::GFP+ cells, though average maximal estimated velocitiesof mitfa::GFP+ cells were reduced by \u223c22% in cultured trunks ascompared to intact larvae (A stock solution of AG1478  was diluted in DMSO. Embryos were treated with 3 \u00b5MAG1478 in 10% Hanks for through either 72 or 96 hours post-fertilization.To facilitate penetration, 0.5% DMSO was added to all media and embryoswere dechorionated prior to treatment. Fish were reared in glass Petri dishesand solutions were changed daily.Larvae were incubated with 0.005% 5-ethynyl-2\u2032-deoxyuridine  in 10% Hank's medium containing 1% DMSO\u00a0for36 h. Larvae were then sacrificed, fixed with 4% PFA/1% DMSO, andvibrotome sectioned (150\u2013200 \u00b5m) for immunohistochemistry followedby histochemical detection of EdU according to manufacturer'srecommendations.Quantitative data were analyzed with JMP 8.0.2 .Frequency data were examined using multiple logistic regression or contingencytable analyses, and tested for effects of genotype, stage, and genotype x stageinteractions. Significance of effects were assessed by likelihood ratio testsand non-significant factors were removed from the final models. Analyses ofvariance were used for continuous variables including counts. Residuals wereexamined for normality and homogeneity of variances, conditions that wereachieved for some variables after transformation by square root or naturallogarithm. Further details of statistical analyses are available uponrequest.Figure S1mitfa::GFP+ cells amongst glia of the lateral line nerve. Sagittal viewof a wild-type larva showing mitfa::GFP+ cells aligned with mbp+ glia (red) of the main trunk lateral line nerve, nearthe horizontal myoseptum.(TIF)Click here for additional data file.Figure S2Ectopic kitla-responsive melanogenic cells were nerve-associated. Shown is anectopic sox10+ (red) melanophore (arrow) within the myotome adjacent toa nerve fiber stained for acetylated tubulin (green).(TIF)Click here for additional data file.Figure S3erbb3b embryonic critical period.  Post-embryonicmbp+ glia  were reduced though not eliminated inAG1478-treated larvae. Inset, mitfa::GFP+ cell (green) aligned onmbp+ glia of a peripheral nerve at the level of the horizontalmyoseptum. sc, spinal cord; m, myotome; e, epidermis; ll, lateral linenerve.  foxd3+ cells  within the myotome weremissing from AG1478-treated larvae.Defects in wild-type larvae treated with ErbB inhibitor AG1478 during the(TIF)Click here for additional data file.Figure S4erbb3b mutants.  Views andannotations correspond to those for wild-type larvae in main text Deficiencies in mitfa::GFP+ cells, foxd3+ cells, and EdUincorporation in (TIF)Click here for additional data file.Figure S5erbb3b-dependence of kita-independenthypodermal melanophores. (A) b5kita presumptivenull allele kita-independenthypodermal melanophores. (B) Fish doubly mutant forb5kita and the presumptive null alleleut.r2e1erbb3b showing loss of manykita-independent melanophores as well as gaps in the\u201cinterstripes\u201d  reflecting an iridophoredeficiency. Patches of residual melanophores may be of clonal origin.(TIF)Click here for additional data file.Figure S6mitfa::GFP+ cells in adult fish. Shown are cross-sections through\u223c20 SSL (\u223c80 days post-fertilization) adult wild-type fish. (A) Apersisting nerve-associated mitfa::GFP+ cell . sc, spinalcord; m, myotome. (B) mitfa::GFP+ cells  within thelateral line nerve. e, epidermis (C) mitfa::GFP+ cells and foxd3+ cells  in the ventral myotomes and base ofthe anal fin (f). (D) mitfa::GFP+ cell  and doublylabeled mitfa::GFP+; foxd3+ cell (arrowhead) associated with anadult scale (s).(TIF)Click here for additional data file.Video S1mitfa::GFP+ cells in a living wild-type larva. Images were collected insagittal planes from the skin to the midline of the trunk. Image rotationreveals extra-hypodermal cells within the myotomes, that typically expressedmitfa::GFP at levels lower than in hypodermal cells.(MOV)Click here for additional data file.Video S2dct were detected only inthe hypodermis. Shown here are cells expressing mCherry driven by theTakifugu rubripes dct promoter.mitfa::GFP+ and dct::mCherry+ melanophores in a living wild-typelarva. In contrast to mitfa::GFP+ cells (green), cells expressing thelater melanophore lineage marker (MOV)Click here for additional data file.Video S3erbb3b mutantlarva. Larva imaged as in mitfa::GFP+ cells are missing from a live (MOV)Click here for additional data file.Video S4mitfa::GFP+ cells differentiate as melanophores in the hypodermis.mitfa::GFP+ cells acquiring melanin (arrows) over \u223c18 h.(MOV)Click here for additional data file.Video S5:GFP+ cells. Low magnification view showing highly migratorymitfa::GFP+ cells over \u223c18 h. This movie loops three times.mitfa::GFP+ cells are highly migratory and extend long probingprocesses. These cells can be seen migrating widely over the flank and alsomigrating from the body into the anal fin at the lower edge of the frame. Incontrast to mitfa::GFP+ cells, xanthophores are larger, less motile andautofluoresce weakly in the GFP channel, particularly from accumulations ofpteridine-containing organelles around the nucleus.(MOV)Click here for additional data file.Video S6Migration of mitfa::GFP+ cells between body and fin. Detail at themargin between body and anal fin, showing movements of mitfa::GFP+cells between these regions.(MOV)Click here for additional data file.Video S7mitfa::GFP+ cells emerging from within the myotome. Severalmitfa::GFP+ cells (arrows) enter the hypodermis from within themyotome; also see (MOV)Click here for additional data file.Video S8mitfa::GFP+ cells emerging from within the myotome. High magnificationview showing a single mitfa::GFP+ cell (arrow) emerging from within themyotome. In this movie, only selected planes of focus from a completez-series are shown, illustrating the progressive movement of this cell fromthe interior myotome to the surface. As the cell approaches the moresuperficial planes, additional mitfa::GFP+ cells already in thehypodermis come into focus.(MOV)Click here for additional data file.Video S9mitfa::GFP+ cell emerging from the vicinity of the horizontal myoseptum.The movie loops three times.(MOV)Click here for additional data file.Video S10mitfa::GFP+ cells entering the hypodermis after migrating over thedorsal myotome. One cell already at the dorsal myotome and another extendinga process over the flank at the beginning of the movie (red arrows). A thirdcell extends a long filopodium (yellow arrow) over the flank before enteringinto the hypodermis.(MOV)Click here for additional data file.Video S11kita mutant. Similar behaviors were observed inwild-type larvae.mitfa::GFP+ cells migrating within the caudal nerve plexus. Shown aremitfa::GFP+ cells along a nerve plexus near the base of the caudal finin the medial region of a larva. This particular individual is a(MOV)Click here for additional data file.Video S12mitfa::GFP+ cells migrating along and dispersing from peripheral nerves.Shown is an enhanced detail of (MOV)Click here for additional data file.Video S13erbb3bmutants. Residual mitfa::GFP+ cells were often patchily distributed andtypically expressed GFP at lower levels than in wild-type. Red arrowhead,mitfa::GFP+ cell dividing. Arrow, mitfa::GFP+ cell emerging fromthe vicinity of the horizontal myoseptum. Yellow arrowhead, death ofmitfa::GFP+ cell.Morphogenesis of residual mitfa::GFP+ cells in (MOV)Click here for additional data file.Video S14Proliferation of mitfa::GFP+ cells. A mitfa::GFP+ cell (arrow)divides within the hypodermis over \u223c14 h in a wild-type larva.(MOV)Click here for additional data file.Video S15kita mutant larva over\u223c16 h (see text for details).Death of mitfa::GFP+ cells. Fragmentation and loss of threemitfa::GFP+ cells (arrows) in a (MOV)Click here for additional data file.Video S16Proliferation of differentiated melanophores. Shown is the posterior tail ofa kita mutant larva, illustrating successive melanophore divisions.mitfa::GFP+ cells also can be observed migrating on the body andbetween the body and caudal fin.(MOV)Click here for additional data file."}
+{"text": "Honey bees are essential pollinators of numerous agricultural crops. Since 2006, honey bee populations have suffered considerable annual losses that are partially attributed to Colony Collapse Disorder (CCD). CCD is an unexplained phenomenon that correlates with elevated incidence of pathogens, including RNA viruses. Honey bees are eusocial insects that live in colonies of genetically related individuals that work in concert to gather and store nutrients. Their social organization provides numerous benefits, but also facilitates pathogen transmission between individuals. To investigate honey bee antiviral defense mechanisms, we developed an RNA virus infection model and discovered that administration of dsRNA, regardless of sequence, reduced virus infection. Our results suggest that dsRNA, a viral pathogen associated molecular pattern (PAMP), triggers an antiviral response that controls virus infection in honey bees.  Apis mellifera) pollination is a vital component of global food production . Recent increased annual losses of honey bee colonies, partially attributed to Colony Collapse Disorder (CCD), have motivated correlative analyses of the parasitic  and environmental  threats to honey bee health . To facilitate gene expression comparisons we utilized a reference-design strategy in which each Cy5-labeled cDNA experimental sample was hybridized with a standardized Cy3-labeled reference honey bee cDNA sample. Microarrays were scanned and global analysis of the differentially expressed genes (DEGs) was performed using Bioconductor\u2019s Linear Models for Microarray Analysis (LIMMA) . In addition, the complete microarray expression data is provided in Excel format in Microarrays were scanned using an Axon 4B scanner and GenePix Pro software (Molecular Devices) for gridding and initial analysis. We performed global analysis of the differentially expressed genes (DEGs) using Bioconductor\u2019s Linear Models for Microarray Analysis (LIMMA)  implemenn arrays . DUPCOR n arrays ,19. The Drosophila melanogaster orthologs identified for 8,902 of the 14,400 unique probes (62%) on the microarray   mapped 5,168 (~36% of the microarray features). Since some Entrez Gene IDs corresponded with multiple array features, there were actually 3,282 unique genes involved in characterized pathways. These 3,282 genes served as a background for over-representation analysis (ORA) using a false discovery rate (FDR) threshold of p-value < 0.05. Using these criteria, the number of DEGs analyzed for virus-infected bees was 62, whereas for dsRNA-treated bees it was 162.Gene Ontology annotations were based on croarray . Since ~Figure S1Honey bees are productively infected with a model virus, SINV-GFP. (A) Increased GFP pixel counts in fluorescence microscope images of three bees each day post-infection demonstrated increased SINV-GFP infection over-time. Specifically, ImageJ was used to split the RGB layers into three images and GFP pixels above the threshold (50) were counted over a uniform area of each green image. GFP pixel counts on the injection day (day 0) and each day post-injection are presented. (B) Virus (SINV-GFP) spread from injection site (thorax) to the head  (white arrow) demonstrated in this fluorescence microscope image. (C) RT-PCR detection of virus (SINV-GFP) (140 bp) in the head, thorax (injection site), and abdomen (ab) of bees that were infected with SINV-GFP containing lysates from other infected bees; bee 1 (lanes 1-3), bee 2 (lanes 4-6), uninfected bee (lane 7), and positive control PCR using the SINV-GFP containing plasmid as the template for PCR (lane 8). (D) SINV-GFP fluorescence  in individual lysates (5 bees per condition) from dissected honey bees over time; day post-injection, thorax (injection site), head and abdomen . (TIFF)Click here for additional data file.Figure S2Relative abundance of SINV-GFP in individual, dissected bees (5 per condition) was assessed by RT-qPCR. Viral genome copy number per 500 ng RNA was calculated based on a SINV standard curve. Virus spread from the injection site (thorax 2.7x106+ 4.1x104 average genome copies per 500 ng RNA) to distal sites  demonstrated productive infection of entire bee by day 3 post injection.(TIFF)Click here for additional data file.Figure S3Western blot analysis of individual honey bees illustrates that the majority of bees (80%) demonstrated reduced virus in the presence of dsRNA whereas 20% were non-responsive to treatment. Western blot analysis using \u03b1-GFP (top panel) and \u03b1-actin (bottom panel) antibodies demonstrated reduced SINV-GFP in individual, whole bee protein lysates of bees treated with dsRNA and poly(I:C), but not in bees treated with NTPs or dsDNA, as compared to bees inoculated with virus alone (lanes 2-6). ImageJ was used to quantify the pixels in equal sized GFP and actin regions of each lane in order to calculate the GFP to actin ratio in individual bee lysates. As expected, the mock-infected  bee had no detectable GFP, therefore the ratio the pixel counts within the GFP and actin regions of lane 1 was set to 1(*) to facilitate comparisons between lanes 2-31.(EPS)Click here for additional data file.Table S1Pathogen test results for honey bees utilized for transcriptional analysis. Arthropod Pathogen Microarray (APM) results determined that SINV-GFP was the predominant infection in virus-infected bees, whereas dsRNA-treated and mock-infected (buffer-injected) controls were not appreciably infected with common honey bee pathogens; APM oligonucleotide list (worksheet 1), APM results (worksheet 2). APM evaluation is performed using a computer algorithm called \"Bee-Predict\", described in Runckel* and Flenniken* et al. PLoS ONE 2011, but the raw APM data is provided in order to support our assessment that the predominant infection in virus-infected bees was SINV-GFP, and that all bees were not appreciably infected with other honey bee pathogens. Since there are multiple spots on the array for each pathogen (see oligo list) one positive spot is not sufficient for pathogen detection, often these single postive spots are located adjacent to a highly positive control spot and therefore are not valid detections.(XLSX)Click here for additional data file.Table S2Honey Bee Gene Expression Microarray Annotation.(XLSX)Click here for additional data file.Table S3Complete Honey Bee Gene Expression Microarray Results. Complete microarray results for virus-infected bees compared to mock-infected bees. Differentially expressed genes with adjusted p-value < 0.05 (worksheet 1) and all data (worksheet 2). Gene Ontology terms for biological process, molecular function, and cellular compartment were assigned and biological process assignments were further categorized into seven functional groups: immune response (red); transcription, splicing, rRNA processing and RNAi (blue); signaling (purple); trafficking (green); metabolism (yellow); translation and protein folding (orange); and chromatin regulation . A small fraction of the DEGs (10-15%) belonged to other biological process gene ontologies (black) and a large fraction was not assigned (gray). Each pie chart represents 100% of the DEGs and gene numbers are reported in each section. *Each oligonucleotide pair was analyzed as a single gene and since multiple microarray probes corresponded to apidaecin variants the majority of annotated immune effectors in this Figure 5. (7 of 10 in virus-infected bees and 8 of 12 in dsRNA) correspond with apidaecin 1.(XLSX)Click here for additional data file.Table S4Complete Honey Bee Gene Expression Microarray Results. Complete microarray results for dsRNA-treated bees compared to mock-infected bees. Differentially expressed genes with adjusted p-value < 0.05 (worksheet 1) and all data (worksheet 2). (XLSX)Click here for additional data file.Table S5Comparison of DEGs  in virus-infected and dsRNA-treated honey bees using Venn diagram analysis (worksheet 1); virus only DEGs, RNA Only DEGs, and overlap between those two DEG lists.We further examined overlapping DEG list, by sorting based on virus list fold-change (FC) (worksheet 2), dsRNA-treated list FC (worksheet3), virus list adjusted p-value  (worksheet 4), and dsRNA-treated list adjusted p-value (worksheet 5). (XLSX)Click here for additional data file.Table S6Pathways Over-Representation Analysis. Over-representation analysis was performed on the DEGs involved in canonical pathways; the 3,282 unique genes on the array that are involved in characterized pathways served as a background and a false discovery rate (FDR) threshold of p-value < 0.05 was set. Using these criteria the number of differentially expressed (including both induced and reduced) genes analyzed virus-infected or dsRNA-treated as compared to mock treated controls was 62 and 162, respectively. Over-represented pathways for each experimental condition are listed as well as the p-value associated with each test. (PDF)Click here for additional data file.Table S7Analysis of the expression of characterized insect immune genes in virus-infected and dsRNA-treated honey bees.(XLSX)Click here for additional data file.Table S8PCR and qPCR primer sequences.(XLSX)Click here for additional data file."}
+{"text": "The TTV miRNAs are transcribed by RNA polymerase II, processed by Drosha and Dicer, and are active in RISC. A TTV mutant defective for miRNA production replicates as well as wild type virus genome; demonstrating that the TTV miRNA is dispensable for genome replication in a cell culture model. We demonstrate that a recombinant TTV genome is capable of expressing an exogenous miRNA, indicating the potential utility of TTV as a small RNA vector. Gene expression profiling of host cells identifies N-myc (and STAT) interactor (NMI) as a target of a TTV miRNA. NMI transcripts are directly regulated through a binding site in the 3\u2032UTR. SiRNA knockdown of NMI contributes to a decreased response to interferon signaling. Consistent with this, we show that a TTV miRNA mediates a decreased response to IFN and increased cellular proliferation in the presence of IFN. Thus, we add Annelloviridae to the growing list of virus families that encode miRNAs, and suggest that miRNA-mediated immune evasion can contribute to the pervasiveness associated with some of these viruses.Torque teno viruses (TTVs) are a group of viruses with small, circular DNA genomes. Members of this family are thought to ubiquitously infect humans, although causal disease associations are currently lacking. At present, there is no understanding of how infection with this diverse group of viruses is so prevalent. Using a combined computational and synthetic approach, we predict and identify miRNA-coding regions in diverse human TTVs and provide evidence for TTV miRNA production  The torque teno viruses (TTVs) are a diverse group of viruses that ubiquitously infect humans and establish persistent infections. Despite their prevalence, TTVs lack concrete disease associations and remain among the most poorly characterized human viruses. Here we use computational and synthetic approaches to identify new noncoding miRNA genes in the TTVs. We demonstrate that TTVs utilize the host miRNA biogenesis machinery to produce biologically active miRNAs. To gain a functional understanding of the new TTV genes, we focus on a particular viral isolate and identify N-myc (and STAT) interactor (NMI) as a direct target. NMI is a known modulator of interferon and cytokine signaling. Similar to other viruses encoding miRNAs, the TTVs likely utilize miRNAs to promote persistence and immune evasion. Our study provides new insights into novel TTV gene products and the interactions of this virus with its host. Anelloviridae and have small (\u223c3.8 kb) circular, ssDNA genomes Torque teno viruses (TTVs) belong to the family C. elegansMicroRNAs (miRNAs) are small \u223c22 nt noncoding RNAs that direct posttranscriptional gene regulation. miRNAs were first identified in the nematode The extent to which different virus families utilize miRNAs remains a fundamental question in the field of viral miRNAs. To address this question we have previously developed computational methods to predict miRNA genes from primary sequence information We investigated TTV genomic sequences for miRNA gene candidates using previously described computational methods that predict candidate pre-miRNAs Next, we asked whether TTV derived miRNAs are detectable during viral replication. We chose to utilize a previously described cell culture based replication system using the TTV-tth8 strain in vivo, small RNA libraries deposited in the NCBI Sequence Read Archive (SRA) were examined et al included two small RNA sequencing libraries derived from primary human PBMCs from apparently healthy individuals To determine whether TTV viral miRNAs are expressed The Anellovirus family includes the torque teno viruses (TTVs), torque teno midi viruses (TTMDVs), torque teno mini viruses (TTMVs), as well as related nonhuman animal viruses The majority of known human and viral miRNAs follow a canonical biogenesis pathway that begins with transcription by host RNA polymerase II. The pri-miRNA transcript is cleaved by the enzyme Drosha, which is the nuclease component of the Microprocessor complex, to liberate the short stem loop pre-miRNA in vitro cell culture virus genome replication system Our miRNA biogenesis and functional characterization focused on TTV isolate tth8 (TTV-tth8) due to the availability of an Next, we investigated the role of Drosha, the endonuclease component of the Microprocessor responsible for excising pre-miRNAs from pri-miRNA transcripts. HEK293Tcells were transfected with siRNA directed against Drosha Dicer is the endonuclease responsible for processing pre-miRNAs into mature miRNA duplex RNAs. DLD1-DicerEx5- is a Dicer-activity-hypomorphic cell line which exhibits impaired conversion of pre-miRNAs to mature miRNAs The final step in the canonical miRNA biogenesis pathway is the incorporation of the mature miRNA into active RISC. Luciferase based reporter constructs specific to each arm of TTV-tth8-miR-T1 miRNA were generated to test for RISC activity. The luciferase based reporter constructs were co-transfected with a TTV-tth8-miR-T1 miRNA expression vector, or control vector, and then dual luciferase assays were performed . The relTaken together, we have identified the general pathway through which biologically active miRNAs are generated. The evidence presented is most consistent with direct utilization of the canonical host miRNA biogenesis machinery.A mutant TTV-tth8 with ablated miRNA production (TTV-MUT) was generated by introduction of a specific 4 nt deletion into the miRNA stem region . A recomWhile we have shown that TTV-MUT does not produce TTV-tth8-miR-T1, it was still possible that other miRNAs could be encoded by the virus that our prediction methods missed. To address this concern and better characterize the miRNAs encoded by TTV-tth8, high throughput small RNA sequencing was performed on small RNA fractions harvested from the cell culture replication system for both the wildtype TTV-tth8 and TTV-MUT . As expein vivo.We hypothesized that the disruption of TTV-tth8-miR-T1 would alter viral replication dynamics. To test this hypothesis, timecourse experiments were performed with TTV-tth8 and TTV-MUT in the cell culture replication system. DpnI protection assays were performed to differentiate between replicated and non-replicated viral DNA Programming of RISC with a mature miRNA sequence directs the complex to target mRNAs resulting in translational repression and enhanced turnover of some of the target mRNAs We identified a putative miRNA binding site for the more abundant 5p arm of TTV-tth8-miR-T1 in the 3\u2032UTR of NMI . To testWhile TTV-tth8-miR-T1 can directly regulate reporter constructs bearing the NMI 3\u2032UTR, we next wanted to know if TTV-tth8-miR-T1 can regulate expression of NMI protein from endogenous NMI transcripts. A miRNA mimic of TTV-tth8-miR-T1 was synthesized based on the sequences from our small RNA profiling experiments. HeLa cells were transfected with the viral miRNA mimic or negative control miRNA mimic and NMI protein levels were assayed by immunoblot analysis . A modesNMI has previously been shown to modulate STAT signaling pathways in response to cytokine stimulation. A luciferase based interferon signaling assay was employed to determine whether TTV-tth8-miR-T1 can modulate interferon signaling activity . Dual luTo further investigate the effects of TTV-tth8-miR-T1 and NMI on interferon signaling, interferon reporter assays were performed with synthetic miRNA mimics or siRNA directed against NMI , S3. Relin vivo  were maintained in DMEM supplemented with 10% (vol/vol) FBS and pen-step (Cellgro). HEK293TT cells Cassettes encompassing the predicted miRNA genes were synthesized by Integrated DNA Technologies (IDT) in the context of the pIDT-SMART-KAN vector  were synthesized by Sigma. Negative control si/miRNA mimic with Qiagen All Stars Negative Control sequence  was synthesized by Sigma and has been described previously pCGAGUAGGCUUCGUGACUUdTdT, pAAGUCACGAAGCCUACUCGdTdT) has been previously described TTV-tth8 miRNA mimics (TTV-tth8 miRNA or an irrelevant miRNA (ebv-mir-BART4) was subcloned into the pLB2 CAG P2Gm (Addgene #19752) lentivector using XhoI and XbaI sites. The following plasmids were transfected into a T75 of HEK 293T cells using Lipofectamine 2000 (Invitrogen): 11.7 ug miR expression vector, 3.5 ug pMD2.G (Addgene #12259), 2.9 ug pRSV-Rev (Addgene #12253), and 5.9 ug pMDLg/pRRE (Addgene #12251). Supernatant was collected after 24 hours and the HEK293T cells were given fresh media. The next day, the supernatant was collected and combined with the previous day supernatant and 0.2 micron filtered. The stocks were titered on 10\u22275 HEK293T cells in 24 well plates. Twenty microliters of serial dilutions of lentiparticle stocks were added to the cells in triplicate. After 48 hours, the cells were washed with PBS. Lentiparticle titers were determined by counting the percent of HEK293T cells that were GFP positive. Transducing units (TU) per mL was calculated using the following equation: ((Percent positive GFP\u00d7number of cells)/100\u00d7 volume of viral dilution added to each well)\u00d71/dilution factor.5\u00d710\u22275 GM19240 B-cells (Coriell Institute) were seeded into a 6-well plate. 1 mL of lentiparticles (1\u00d710\u22276 TU/mL) and 5 ul polybrene (Sigma-Aldrisch) (10 ug/mL) were added to each well in duplicate along with a polybrene only control. After 24 hours, the cells were pelleted and resuspended in fresh media along with puromycin (Sigma-Aldrich) (0.5 ug/mL). Cells were passed every 3 days in media that contained puromycin. The control B-cells did not survive past 2 passages with puromycin selection. After 17 days, selection was removed and cells were used for subsequent experiments.TTV-tth8 miRNA mutant virus plasmid (pUC-TTV-MUT) was generated by digestion of pUC-TTV-tth8 with AflII followed by treatment with mung bean nuclease (New England Biolabs) and self-ligation with T4 DNA ligase (New England Biolabs). The introduction of the expected 4 nt deletion was confirmed by sequencing. The pUC-TTV-SV40 miRNA virus plasmid was generated by PCR amplifying the miRNA encoding sequence of SV40-776 with primers PRIMER1, PRIMER2 and cloning into the AflII site of pUC-TTV-tth8. The introduction of the SV40 miRNA sequence in the same orientation as the wildtype miRNA was confirmed by sequencing.https://code.google.com/p/mirna/Python scripts to predict pre-miRNA like structures in viral genomic sequence utilized the RNAfold Small RNA Northern blot analysis was performed as previously described Viral genome containing plasmids (150 ug) were digested with SalI-HF to release a linear viral genome sequence. Digests were heat inactivated and used to prepare dilute 30 mL T4 DNA ligase reactions. Ligations were incubated at 15C for 48 hours and then purified with HiPure Plasmid Maxiprep Kit (Invitrogen).In vitro cell culture replication of TTV-tth8 and derivative viruses was carried out in HEK293TT cells transfected with viral genome preparations as previously described Genomic DNA was harvested by phenol/chloroform extraction Samples were run on 1% agarose TAE gels. Following electrophoresis, gels were soaked in 0.25 M HCL for 15 minutes. Next, gels were soaked in Southern Transfer Buffer (STB) . Transfers to HyBond N+ membranes were performed overnight blot in STB. After transfer, membranes were soaked in neutralization buffer . Membranes were pre-hybridized for 1 hour at 60C in ExpressHyb Buffer (Clontech). Radiolabeled probes were generated using the Rediprime II DNA Labeling System  using SalI linearized TTV-tth8 genomic DNA. Probes were hybridized overnight at 60C. Blots were washed twice for 20 minutes with Wash Buffer 1  at 60C and twice for 20 minutes with Wash Buffer 2  at 50C. Storage phosphor screens  were exposed and then scanned using a Personal Molecular Imager system (Biorad).Pooled, multiplexed small RNA sequencing was performed as previously described HEK293TT cells were transfected with recircularized genome preparations or pUC control vector. Total RNA was harvested with PIG-B SRA data files SRR039190 and SRR039191 were retrieved from NCBI. The SRA formatted files were converted to FASTA format and sequencing adapters were trimmed with custom Python scripts. The pre-processed files were mapped to a collection of TTV genomic sequences  using thmiRNA stemloop secondary structures were generated using the Mfold RNA folding prediction Web server Renilla luciferase based 3\u2032UTR reporter . Total RNA was harvested with PIG-B HEK293T cells were transfected with 20 nM Drosha siRNA or negative controls siRNA using Lipofectamine RNAi-MAX (Invitrogen). Twenty-four hours later, a second transfection of siRNA was performed followed by transfection of miRNA expression vectors using the Turbofect reagent according to the manufacturer's recommendations (Fermentas). Twenty-four or thirty hours later, total RNA was extracted with PIG-B and Northern blot analysis was performed.Dicer wild-type cells (DLD1) and cells hypomorphic for Dicer activity (DLD1 DicerEx5\u2212/\u2212) HEK293TT cells were transfected with recircularized genome preparations or pUC control vector Fifty percent confluent six well plates of HeLa cells were transfected with 100 pmol of the indicated siRNA or miRNA mimic using Lipofectamine 2000 (Invitrogen). Forty-eight hours later, the transfected HeLa cells were split 1\u22364. The next day, a second transfection was performed. Forty-eight hours later, lysates were prepared with RIPA buffer  including Complete, Mini Protease Inhibitor tablets (Roche). Twenty micrograms of the total lysate was separated in 10% SDS-polyacrylamide gels and transferred to PVDF membranes (Millipore). Membranes were blocked with Odyssey blocking buffer (LI-COR). Primary antibodies used were Nmi (N-16): sc-9482 (Santa Cruz Biotechnology) and \u03b2-Actin (C4): sc-47778 (Santa Cruz Biotechnology). Blots were probed with a 1\u22361000 dilution of each primary antibody in Odyssey blocking buffer. Blots were washed four times with Phosphate Buffered Saline including 0.1% Tween 20 (PBST). IRDye 800CW and IRDye 680LT secondary antibodies (LI-COR) were diluted 1\u223610,000 in Odyssey blocking buffer containing 0.1% Tween 20 and 0.05% SDS. Blots were washed four times with PBST. Blots were scanned on an Odyssey CLx infrared imaging system (LI-COR). Band intensities were measured with Image Studio software (LI-COR). Three independent experiments were performed on different days for quantification and Student's t-test was used to assess statistical significance of observed differences.Renilla luciferase expression in order to control for transfection differences. Fold induction of the ISRE ffLuc reporter was calculated by dividing the comparable experimental wells by the control wells. Induction of each condition is relative to the negative control. Experiments with HeLa cells were conducted in a similar fashion except miRNA/siRNA transfections were performed in six well plates prior to seeding 96 well plates as described below. The HeLa cells were transfected with 50 pmol of siRNA or mimic (100 pmol for combined siRNA/miRNA transfection) using Lipofectamine 2000 (Invitrogen). Forty-eight hours later, cells were split 1\u22364. The next day the cells were subject to a second round of transfection. Twenty four hours later, the HeLa cells were plated in 96 well plates. The next day, the interferon signaling assay was conducted as described above for HEK293T cells.HEK 293T cells were seeded in 96-well plates. The next day, 1 ul Luciferase reporter mix (5 ng/ul pcDNA3.1dsRluc HEK 293T cells in T25 plates were transfected with 7.5 ug plx304 plasmid (DNASU). Forty-eight hours later, the cells were replated in media containing 10 ug/mL Blasticidin S (Sigma-Aldrich). Antibiotic treatment was continued for four days and then removed for subsequent experiments. 12-well plates of HEK 293T were co-transfected with 40 ng pcDNA3.1dsRluc 3\u00d710\u22274 cells of the indicated pooled stable cell lines were seeded into a 6 well plate in 2 mL growth media in triplicate. Viable cells as assayed by trypan blue (Cellgro) staining were counted (Day 1) then 750 units universal type I interferon (IFN) (PBL Interferon Source) or 1 ug bovine serum albumin (BSA) (Sigma-Aldrich) control was added to the wells. Viable cell numbers were counted every day and after each cell count 750 units IFN or 1 ug BSA was added to the wells. Three independent experiments were performed on different days in triplicate.Code S1miRNA Prediction Code. Archive containing miRNA prediction code. Most recent version and additional files available at: https://code.google.com/p/mirna/.(GZ)Click here for additional data file.Figure S1TTV miRNAs expressed from synthetic vectors are generated by the canonical host miRNA biogenesis pathway. (A) Northern blot analysis of RNA from HEK293T cells transfected with synthetic miRNA expression vectors with or without treatment with the RNA pol II inhibitor \u03b1-amanitin. Ethidium bromide stained low molecular weight RNA is shown as a load control. (B) Northern blot analysis of RNA from HEK293T cells co-transfected with synthetic miRNA expression vectors and either Drosha siRNA (siDrosha) or negative control siRNA (siNC). Ethidium bromide stained low molecular weight RNA is shown as a load control. (C) RISC reporter assay for synthetic TTV miRNA expression vectors. HEK293T cells were co-transfected with either empty miRNA expression vector (Vector) or indicated synthetic TTV miRNA expression vector and both firefly luciferase control and Renilla luciferase based reporter plasmids with vector UTR (Vector) or two sites perfectly complementary to the indicated miRNA. The average relative Renilla luciferase activity normalized to firefly luciferase activity of three replicates is shown. Error bars indicate SD of three replicates and p-values were calculated using Student's t-test.(TIF)Click here for additional data file.Figure S2Characterization of cell culture genome replication of wildtype and miRNA mutant TTV-tth8. Southern blot analysis of DpnI protection assay conducted on in vitro cell culture replication of wildtype TTV-tth8 (WT) and miRNA mutant TTV-tth8 (MUT). Lane NC is pUC transfected HEK293TT DNA and lane Ctrl is pUC transfected HEK293TT DNA spiked with viral genome prep. Replicated label indicates expected migration for linearized full length genomes. Input label indicates largest DpnI cleavage fragment.(TIF)Click here for additional data file.Figure S3Knockdown of NMI by siRNA. (A) Confirmation of siRNA mediated knockdown of NMI. Western blot analysis was performed on protein lysates from HeLa cells transfected with siRNA specific to NMI (siNMI) or negative control siRNA (siNC). (B) Interferon signaling assay performed in HeLa cells. Assay is performed as in (TIF)Click here for additional data file.Table S1Pre-miRNA stemloop predictions for human TTVs and related animal viruses.(XLS)Click here for additional data file.Table S2Accessions for TTV genomic sequences used in small RNA sequencing analysis.(XLS)Click here for additional data file.Table S3Microarray analysis and list of putative TTV-tth8-miR-T1 targets.(XLSX)Click here for additional data file.Table S4Oligos and synthetic sequences used in this study.(XLS)Click here for additional data file."}
+{"text": "CDKN1A gene expression and the insulin signaling pathway. In addition to gene expression analyses, we completed a series of metabolomics experiments to help identify how WTp53 and \u0394Np53:WTp53 differentially affect cell physiology. These data sets represent the most comprehensive analysis thus far completed for the human \u0394Np53:WTp53 isoform. Collectively, the microarray and metabolomics data yielded clear predictions  about the cellular pathways disrupted by \u0394Np53:WTp53 specifically. Among the most striking were links to mitochondrial function and the mTOR pathway, which influence longevity in organisms as diverse as yeast and mammals [The initial discovery that p53 could cause accelerated aging in mice was made with an artificial truncated form of p53 . The nat mammals . Numerou mammals . Mitocho mammals .mt). The Auwerx group recently established that \u201cmitonuclear protein imbalance\u201d  could induce UPRmt in metazoans; notably, this response appears to promote longevity [mt (longevity-promoting). Some of our findings with \u0394Np53:WTp53 vs. WTp53 converge on these same processes, but in an opposite manner. For example, the mTOR pathway is activated by \u0394Np53:WTp53 expression. Also, the Auwerx group linked reduced expression of mitochondrial translation factors (e.g. Mrps5) specifically, and reduced mitochondrial translation generally, to UPRmt [met synthetase) about 2.5-fold relative to WTp53 (4). The longevity-promoting effects of UPRmt were also linked to mitochondrial proteostasis (via expression of HSP-70 and HSP-60) and mitochondrial biogenesis [Another interesting question involves potential links to mitochondrial unfolded protein response (UPRongevity . Houtkooto UPRmt . By contto WTp53 . The lonogenesis , we anti"}
+{"text": "The mechanisms underlying Burkitt\u2019s Lymphoma (BL) chemoresistance and how it can be circumvented remain undetermined.The histone deacetylase inhibitors (HDACi) represent a novel class of agents which have demonstrated potent antitumor activity in preclinical models and promising clinical efficacy in cancer patients. The aim of this study was to evaluate the cell death enhancement effect of Sodium Butyrate (NaB), a HDACi combined with suboptimal concentration of etoposide (VP-16) and identify genes differentially regulated by this combination to provide rationale for novel drug combination patterns.Raji BL cell line was treated with NaB isolated or combined with VP-16. Growth inhibition and cell cycle were analyzed in response to treatment using trypan blue exclusion assay and flow cytometry. Gene expression profiles were determined using One-Color Microarray-Based Gene Expression (Agilent Technologies) and analyzed on Feature Extraction v 9.5.1 software.NaB/VP-16 combined treatment decreased cell proliferation and survival, and blocked cell cycle progression at G2/M with a concurrent decrease in S phase in Raji cells at 24h. Microarray profile showed upregulation of genes related to apoptosis, cell cycle arrest and response to DNA breaks. We also observed downregulation of genes related to cell cycle progression and angiogenesis.Alterations in critical genes involved in cell survival, angiogenesis, cell cycle and DNA damage response were identified. Pathways identified may represent potential targets for combined therapy protocols which have been emerging to improve treatment strategies to circumvent responseless BL patients.APQ1/FAPERJ E26/111.330/2011; INCT Cancer, CNPq 573806/2008-0; FAPERJ E26/170.026/2008; PPSUS-2010."}
+{"text": "Cow\u2019s milk allergy is one of the most common food allergies in children. Dietary lipid composition may affect the susceptibility to develop allergic diseases. Aim of this study was to assess whether and how dietary supplementation with long chain n-3 polyunsaturated fatty acids (n-3 LCPUFA) prevents the establishment of food allergy.ex vivo depleted of CD25+ cells, or MACS isolated CD4+CD25+ regulatory T-cells (Treg). Recipient mice were sham- or whey-sensitized and fed control diet.Donor mice were fed a control or fish oil diet before and during oral sensitization with whey. Acute allergic skin response, serum immunoglobulins as well as dendritic cell (DC) and T-cell subsets in mesenteric lymph nodes (MLN), spleen and/or small intestine were assessed. Besides serum transfer experiments, adoptive transfer experiments with splenocytes of whey-sensitized donor mice fed a control or fish oil diet were performed. For this purpose na\u00efve recipient mice received splenocytes either or not Ex vivo depletion of Treg prevented this transfer of tolerance. Transfer of CD4+CD25+ Treg (85% was FoxP3+) from fish oil fed whey sensitized donors prevented the acute allergic skin response most pronounced.The acute skin response as well as whey-IgE and -IgG1 levels were reduced in sensitized donor mice fed the fish oil diet as compared to the control diet. Serum transfer confirmed the Th2 type humoral response to be suppressed since sera of fish oil fed sensitized mice had a diminished capacity to induce an allergic response in na\u00efve recipient mice compared to control sera. Furthermore, the acute skin response was diminished upon passive sensitization with hyperimmune serum in fish oil fed na\u00efve recipient mice indicating suppression of the effector response by n-3 LCPUFA. Fish oil fed whey-sensitized donor mice showed an increased % Treg inducing CD11b+CD103+CD8\u03b1- DC in MLN in association with enhanced FoxP3+ Treg in spleen and intestine compared to sham mice. In whey-sensitized recipient mice transferred with splenocytes from whey-sensitized fish oil fed donor mice, the acute allergic skin response was similar to sham-sensitized recipients. Dietary n-3 LCPUFA largely prevent allergic sensitization in a mouse model for cow\u2019s milk allergy by suppressing the humoral response, enhancing local and systemic Treg and reducing acute allergic symptoms. FoxP3+ Treg play an important role in whey allergy prevention by n-3 LCPUFA.L Van Den Elsen: None declared, B van Esch: Employee of Danone Research, G Hofman: None declared, B van de Heijning: Employee of Danone Research, J Garssen: Employee of Danone Research, L Willemsen: None declared."}
+{"text": "We present the discovery of innovative low molecular weight inhibitors against human immunodeficiency virus 1 (HIV-1) protease. Structure-based virtual screening focused on potential allosteric surface cavities revealed these compounds . The mos"}
+{"text": "The purpose of this study was to assess ID physicians\u2019 familiarity and use of various IM modalities.A national survey of 1,000 practicing ID physicians in the United States was conducted in 2010. The IM modalities studied were mind-body based modalities (MBM), biologically based modalities (BBM), manipulative and body-based modalities (MBBM), energy based modalities (EBM) and whole medical systems (WMS). Participants were asked to indicate their familiarity of each modality. If they were familiar with the modality they were then asked to indicate whether they recommended it to patients.A total of 311 (31%) ID physicians responded to the survey. The mean age was 49 years and 64% were male. ID physicians were most familiar with the following modalities (n=311)*: vitamins and mineral supplementation (83%), massage (80%), acupuncture (79%), chiropractic (77%), yoga (74%), and herbal medicine (72%). They were less familiar with meditation (69%), tai chi (61%), homeopathy (55%), hypnosis/Guided Imagery (GI) (52%), and Traditional Chinese Medicine (TCM) (49%). ID physicians were least familiar with qi gong (17%), Ayurveda (26%) and Healing Touch (HT)/Reiki/Therapeutic Touch (TT) (39%). ID physicians most recommended the following IM modalities: vitamins and mineral supplementation , massage , yoga , acupuncture  and yoga . ID physicians less frequently recommended chiropractic , herbal medicine , hypnosis/GI  and tai chi . Finally, they least recommended qi gong , homeopathy , TCM , Ayurveda  and HT/Reiki/TT .ID physicians are familiar with and recommend IM modalities, particularly BBM and MBBM. They are least familiar with and also least likely to recommend EBM and WMS based modalities."}
+{"text": "To evaluate myocardial feature tracking (FT) as a potential novel quantitative analysis tool for the assessment of myocardial viability using LDDSMR.Low dose dobutamine stress magnetic resonance imaging (LDDSMR) is a widely accepted technique for assessment of hibernating myocardium in patients with ischemic cardiomyopathy (ICMP). It is particularly helpful in patients with intermediate transmurality of scar where prediction of functional recovery by late gadolinium enhancement imaging (LGE) alone is difficult. Analysis of LDDSMR is usually based on visual assessment and is therefore considerably operator dependant. Recently myocardial feature tracking (FT) has been introduced. It tracks tissue voxel motion of cine-MR images to assess circumferential and radial myocardial strain independent of additional sequences.15 consecutive patients with ICMP referred for viability assessment were studied at 3 Tesla (Philips Achieva) at rest and during LDDSMR. ICMP was defined as: angiographically established coronary artery disease, LV-EF \u226445% and \u22652 segments with wall motion abnormalities at rest. Myocardial function was studied by steady state free precession (SSFP) cine imaging in 3 short axis slices covering 16 myocardial segments, excluding the apex.The same segments were studied with dedicated FT software  to assess subendocardial and subepicardial circumferential (Ecc) and radial (Err) strain.subendocardial r=0.84, Ecc subepicardial r=0.72 and Err r=0.7.208 of 240 segments (87%) were analysed by two independent observers. 32 segments were excluded because of insufficient image quality or visualization of the outflow tract. Interobser-variability was: Ecc -1\u00b7 min-1) there was improvement in Ecc subendocardial, Ecc subepicardial  and Err  and Ecc subepicardial (p=0.008) while Err remained unchanged with stress. Hypokinetic segments without scar (n=75) improved in all three strain values . Hypokinetic segments with non-transmural scar (n=60) showed improved Ecc subendocardial , Ecc subepicardial and Err up to 75% transmurality while transmurally scarred segments (n=6) remained unchanged with stress.During LDDSMR (5 and 10 \u00b5g \u00b7 kgFT is a novel technique, which reliably detects quantitative wall motion derived from SSFP CINE imaging. It seems useful for quantitative analysis at rest and during low dose dobutamine stress for viability assessment in patients with ischemic cardiomyopathy."}
+{"text": "N-desulfated re-N-acetylated heparin [NAH]). Four hours after surgery, we collected serum and urine for measurement of renal function and systemic inflammation, invasively determined systemic hemodynamics, harvested kidneys for histology/protein/mRNA, and/or measured glomerular filtration by inulin clearance. CLP-treated mice demonstrated early activation of glomerular heparanase with coincident loss of glomerular filtration, as indicated by a >twofold increase in blood urea nitrogen (BUN) and a >50% decrease in inulin clearance (P < 0.05) in comparison to sham mice. Administration of heparanase inhibitors 2 h prior to CLP attenuated sepsis-induced loss of glomerular filtration rate, demonstrating that heparanase activation contributes to early septic renal dysfunction. Glomerular heparanase activation was not associated with renal neutrophil influx or altered vascular permeability, in marked contrast to previously described effects of pulmonary heparanase on neutrophilic lung injury during sepsis. CLP induction of renal inflammatory gene  expression was attenuated by NAH pretreatment. While serum inflammatory indices  were not impacted by NAH pretreatment, heparanase inhibition attenuated the CLP-induced increase in serum IL-10. These findings demonstrate that glomerular heparanase is active during sepsis and contributes to septic renal dysfunction via mechanisms disparate from heparanase-mediated lung injury.Heparanase, a heparan sulfate-specific glucuronidase, mediates the onset of pulmonary neutrophil adhesion and inflammatory lung injury during early sepsis. We hypothesized that glomerular heparanase is similarly activated during sepsis and contributes to septic acute kidney injury (AKI). We induced polymicrobial sepsis in mice using cecal ligation and puncture (CLP) in the presence or absence of competitive heparanase inhibitors (heparin or nonanticoagulant  Since the original descriptions of \u201cputrefaction\u201d by Hippocrates, sepsis has been consistently recognized as a major source of human suffering and mortality Majno . Today, Using mechanistic animal and human studies, we recently demonstrated the importance of the pulmonary endothelial glycocalyx to lung function during sepsis  is common and of great clinical significance, yet remains poorly understood  from Iduron  and heparin from Moore Medical . We purchased Evans blue dye (EBD), bovine serum albumin (BSA), fluorescein isothiocyanate (FITC)-inulin (Cat # F3272-1G), heparinase-III (H8891), and HS (H7640) from Sigma . We purchased Intramedic PE-10 tubing from Beckton-Dickinson . We purchased male C57BL/6 mice (8\u201310 weeks old) from The Jackson Laboratory . Animals were maintained in standard housing at the University of Colorado Anschutz Medical Center with ad lib access to food and water. Animals of identical age and housing  were randomly assigned to experimental or control groups. The Institutional Animal Care and Use Committee of the University of Colorado approved all mouse protocols. The care and handling of animals were in accord with National Institutes of Health guidelines for ethical animal treatment.We purchased We performed mouse cecal ligation and puncture (CLP) as previously described  and xylazine (15 \u03bcg/g body weight). We ventilated mice  with 10 \u03bcL/g body weight tidal volumes at 120 breaths/min via tracheostomy. We performed a sternotomy and measured left ventricular pressure and heart rate by direct ventricular puncture with a Millar catheter .After completion of the experimental protocol, we collected mouse serum via direct cardiac puncture during organ harvest. Blood urea nitrogen (BUN) and serum creatinine were measured by quantitative colorimetric assays . Serum IL-6, KC, TNF-\u03b1, IL-10, and IL-1\u03b2 were measured via a multiplex immunoassay . We measured serum angiotensin II by enzyme-linked immunosorbent assay (ELISA) after phenyl extraction , as per the manufacturer's instructions .3\u2212) and nitrite (NO2\u2212), as per the manufacturer's instructions . We measured urine angiotensin II by ELISA, as per the manufacturer's instructions .After completion of the experimental protocol, urine was collected beginning 2 h prior to organ harvest. Urine protein  and creatinine  were measured via colorimetric assays. We measured urine HS degradation activity  as previously described /[inulinplasma].Glomerular filtration rate (GFR) was measured by inulin clearance, as previously described  or 200 \u03bcL saline. Ten random images/slide were captured at 1 \u03bcm steps , and Z-stack reconstructions was performed using Nikon Elements   as previously described  using spectrophotometry at 620 nm wavelength . Four hours after CLP, mice were anesthetized with intraperitoneal pentobarbital (60 \u03bcg/g body weight) and 20 \u03bcg/g body weight EBD-albumin was injected into the right external jugular vein, as previously described  as previously described  was treated for 1 h in vitro with either heat-inactivated (100\u00b0C \u00d7 5 min)  with Bonferroni's post hoc testing. Non-normal data were logistically transformed prior to analysis. Differences were statistically significant if P < 0.05. We performed all calculations using Prism .Data are represented as means \u00b1 SEM . We used Student's two-tailed Urine HS degradation activity, a marker of renal heparanase activation . No histologic evidence of acute tubular necrosis (ATN) was apparent 4 h after CLP  may function as a proinflammatory damage-associated molecular pattern . While pharmacologic inhibitors may have unanticipated nonspecific effects, we are reassured by the lack of NAH interference with the systemic inflammatory response to infection Fig. A\u2013D as weThe heparanase-related mechanisms specific to septic renal dysfunction remain unclear. While heparanase activity augmented renal inflammatory gene expression Fig. A, this eInterestingly, we found that NAH pretreatment attenuated CLP induction of serum IL-10 Fig. E, an antOur study is limited by our inability to directly measure glomerular glycocalyx thickness in vivo. While we identify glomerular HS degradation during sepsis Fig. , basemenAs we Fig.  and otheOur data demonstrate that glomerular heparanase activity increases in early murine sepsis and mediates the onset of renal dysfunction. The mechanisms underlying heparanase-mediated renal dysfunction are disparate from those underlying heparanase-mediated ARDS, demonstrating pathophysiologic heterogeneity of organ injury during sepsis."}
+{"text": "A 70-year-old man presented with a 6-year history of oedema of both lower extremities. Ultrasonic examination showed bilateral anterior tibial artery occlusion due to thrombosis, moderate bilateral pleural effusions and ascites. He had severe pancytopenia, chronic renal dysfunction (serum creatinine 223\u00b78 \u03bcmol/l and more than 1 g/24 h of urinary protein) and, on ultrasound examination, mildly enlarged kidneys showing diffuse damage. Serum and urine electrophoresis with immunofixation revealed both monoclonal IgG lambda and monoclonal IgG kappa immunoglobulins (top left). Serum calcium and phosphate were normal, as were the results of a radiographic skeletal survey. Wright's staining of a bone marrow film showed that plasma cells accounted for 13% of nucleated marrow cells. Bone marrow mononuclear cells were enriched by density gradient centrifugation and dual immunofluorescence staining then showed that 13%, 7% and 6% of mononuclear cells were positive for lambda alone (red arrows), kappa alone (green arrows) or both lambda and kappa light chains (yellow arrows), respectively . Cells staining for lambda alone, kappa alone or both lambda and kappa were also demonstrated in ascitic fluid. A diagnosis of multiple myeloma with triphenotypic characteristics  was made. After initial treatment with vincristine, doxorubicin and dexamethasone (VAD) regimen, the patient' condition stabilized, and after 1 year's follow-up he continued treatment with thalidomide alone."}
+{"text": "Antiplatelet therapy (APT) is known to substantially reduce mortality and rate of ischaemic complications after coronary artery bypass grafting (CABG). Rate of perioperative APT resistance varies widely and could be influenced by cardiopulmonary bypass (CPB). The purpose of the study was perioperative assessment of platelet function with respect to administered APT and CPB, and determination of patients with APT resistance who could benefit from more aggresive treatment strategy.In prospective study we enrolled 192 patients undergoing elective CABG. Patients were divided into 4 groups with respect to their preoperative APT management. All patients received Aspirin (ASA) 300 mg/ day postoperatively starting on the day of procedure. Platelet function was assessed prior to surgery and at fourth postoperative day (POD 4) using multiple electrode aggregometry (MEA). Adenosine diphosphate (ADP test) and arachidonic acid (ASPI test) induced platelet aggregation tests were used.Group of patients exposed to ASA preoperatively had lower values of ASPI test (P<0.001) comparing to patients not receiving ASA. However, we registered 28.6% ASA resistant patients. Both ASPI (P<0.001) and ADP (P<0.001) test values increased significantly at POD 4, suggesting postoperative platelet hyperactivity. Postoperatively, we registered 33.3% ASA resistant patients despite higher ASA dosing regimen.MEA can recognize patients with ASA resistance during the both the pre- and post- CABG period. Postoperatively, ASA 300mg did not sufficiently inhibit platelet aggregation in 33.3% patients. In this subgroup, dual antiplatelet therapy with ASA and clopidogrel could be useful for maintaining graft patency, and preventing adverse ischemic events."}
+{"text": "The present study addressed whether reduced FGFR3 expression enhanced telomerase activity, mRNA expression of telomerase reverse transcriptase (TERT) and RNA component of telomerase (TR), and chondrocyte proliferation, and whether the stimulation of FGFR3 by T3 evoked the opposite response.Fibroblast growth factor receptor 3 (FGFR3) inhibits growth-plate chondrocyte proliferation and limits bone elongation. Gain-of-function FGFR3 mutations cause dwarfism, reduced telomerase activity and shorter telomeres in growth plate chondroyctes suggesting that FGFR3 reduces proliferative capacity, inhibits telomerase, and enhances senescence. Thyroid hormone (T3 significantly enhanced FGFR3 mRNA and protein expression and reduced telomerase activity (p\u2009<\u20090.05); TERT and TR were not significantly reduced. The action of T3 at the growth plate may be partially mediated through the FGFR3 pathway.Sheep growth-plate proliferative zone chondrocytes were cultured and transfected with siRNA to reduce FGFR3 expression; FGFR3 siRNA reduced chondrocyte FGFR3 mRNA and protein resulting in greater proliferation and increased TERT mRNA expression and telomerase activity (p\u2009<\u20090.05). Chondrocytes treated with TThe results suggest that FGFR3 inhibits chondrocyte proliferation by down-regulating TERT expression and reducing telomerase activity indicating an important role for telomerase in sustaining chondrocyte proliferative capacity during bone elongation. Linear bone growth is a function of the proliferative capacity of the endochondral growth plate and the size of the hypertrophic cells. Regulators of chondrocyte proliferation greatly influence the rate and extent of long bone growth and the resulting mature skeletal size,2. FibroThe inhibitory regulation by FGFR3 and its localized expression within the growth plate proliferative zone are unique among the family of four fibroblast growth factor receptors. The other FGFRs, 1, 2 and 4, promote proliferation and are primarily expressed in the perichondrium,9. Evide3) and skeletal size-propanesulfonic acid; DNA: Deoxyribonucleic acid; DEPC: Diethylpyrocarbonate; DMEM: Dulbecco's modified Eagle's medium; ECL: Enhanced chemiluminescence; FBS: Fetal bovine serum; FGF: Fibroblast growth factor; FGFR: Fibroblast growth factor receptor; GAPDH: Glyceraldehyde 3-phosphate dehydrogenase; mRNA: Messenger RNA; PBS: Phosphate buffered saline; PCR: Polymerase chain reaction; PVDF: Polyvinylidene fluoride; qPCR: Quantitative PCR; RNA: Ribonucleic acid; ScR: Scrambled DNA transfection control; siRNA: Small interfering RNA; TBS: Tris buffered saline; T3: Tri-iodothyronine; TERT: Reverse transcriptase catalytic subunit of telomerase; TR: Template RNA subunit of telomerase; Zmoles: Zepto moles (x10The authors declare that they have no competing interests.LBS participated in study design, carried out the experiment, and drafted the manuscript; JMB provided input in study design, analysis, and drafting the manuscript; AMO participated in study design, analysis, study coordination, and drafting the manuscript. All authors have read and approved the final manuscript."}
+{"text": "Lentivirus infection of wild rhesus macaques (Macaca mulatta) and langurs (Semnopithecus entellus) from forests of Rajasthan was suspected based on testing of simian plasma samples by commercial HIV-1 WB in 1998. Though simians have a religious connotation in India, aggressive monkey bites are frequently reported from urban and rural areas due to habitat fragmentation of wild simians. Blood samples from 34 feral rhesus macaques and 9 langurs were collected recently from forests of Rajasthan. Plasma samples were tested using monoclonal antibody against capsid proteins of SIVmac (p27) and HIV-1 (p24). Mitochondrial gene analyses confirmed the species of origin. Integrated provirus was detected by Alu-LTR amplification. Lentiviral genes, gag, pol, env, nef, vif, vpr and LTR were amplified and sequenced. Viral load assay was performed independently. Virus purified from simian plasma by ultracentrifugation was used to infect human PBMC, H9  and U87  cell lines. Virus replication in vitro was detected by p24 antigen capture ELISA and microscopic syncytia formation. Phylogenetic analyses of viral sequences demonstrated intriguing homology to subtype B HIV-1 rather than any known SIV. Significant sequence divergence from HXB2 existed in different regions of viral genome except for conserved pol (RT) region, ruling out inadvertent laboratory contamination. Serological activity was observed against HIV-1 p24 but not SIVmac p27. Reverse transmission of subtype B HIV-1, which is transmitted in north India from infected humans to feral simians due to bleeding monkey bite followed by horizontal spread of the infection in troops of wild simians is proposed."}
+{"text": "HIV-1 envelope glycoprotein is the primary target for HIV-1-specific antibodies. The native HIV-1 envelope spike on the virion surface is a trimer, but trimeric gp140 and monomeric gp120 are currently believed to induce comparable immune responses. Indeed, most studies on the immunogenicity of HIV-1 envelope oligomers have revealed only marginal improvement over monomers. We report here that stable and homogenous envelope trimers with characteristics expected for the native viral spikes are substantially superior at eliciting neutralizing antibodies in guinea pigs.Stable envelope gp140 trimer derived from clinical isolate sequences were stabilized with the T4-fibritin C-terminal trimerization tag and produced in stablely transfected 293T cells. Characterization of Env trimers was performed by Western blotting, size-exclusion chromatography (SEC), analytical-ultra centrifugation (AUC), multi-angle light scattering (MALS) and surface plasmon resonance (SPR). Guinea pigs were immunized six times with 100 \u00b5g of protein trimer or monomer in CpG/Emulsigen adjuvants. Antibody responses were determined by ELISA and TZM.bl neutralizing antibody assays.Homogeneous trimer and monomer preparations exhibited high purity as measured by SEC and SDS-PAGE. AUC and MALS analyses revealed expected molecular weight for both trimer and monomer. SPR analyses revealed expected binding with CD4 and multiple broadly neutralizing antibodies. These trimers have markedly different antigenic properties than those of monomeric gp120s derived from the same sequences. They induce potent, cross-clade neutralizing antibody responses with titers substantially higher than those elicited by the corresponding gp120 monomers for a diverse set of both tier 1 and tier 2 viruses.We have demonstrated the importance of generating high-quality envelope trimers for antigenic and immunogenic studies; furthermore these results highlight the immunologic differences between monomers and high-quality envelope trimers, illustrating important implications for HIV-1 vaccine development and immunogen selection in large clinical trials."}
+{"text": "During the early stage of HIV-1 replication, integrase (IN) plays important roles at several steps, including reverse transcription, viral DNA nuclear import, targeting viral DNA to host chromatin and integration. Previous studies have demonstrated that HIV-1 IN interacts with a cellular lens epithelium-derived growth factor (LEDGF/p75) and that this viral/cellular interaction plays an important role for tethering HIV-1 preintegration complexes (PICs) to transcriptionally active units of host chromatin. Small molecule inhibitors of HIV IN/LEDGF have emerged as promising new class of antiviral agents for the treatment of HIV/AIDS. Present work is to study the small molecule inhibitor of HIV IN/LEDGF.Isatine-sulphadimidine derivative (SPIII-5H) selected for these studies. HIV IN/LEDGF interaction inhibition assay performed by ALPHA screen technique, HIV integrase assay investigated by oligonucleotide based assay and molecular modeling studies also carried by using computational methods.Lead molecule SPIII-5H inhibits HIV IN/LEDGF interaction (protein-protein interaction) at 10 uM and HIV integrase activity at 6.8 uM. From molecular modeling study indicates that SPIII-5H bind with active site of HIV integrase (DDE), change the conformation and interrupt the binding of HIV integrase with LEDGF.SPIII-5H novel class of inhibitors of HIV IN/LEDGF interaction and this lead molecule is suitable for further molecular modifications."}
+{"text": "We previously demonstrated that vaccine prime with a recombinant replication-competent modified vaccinia Tiantan (rMVTTSIVgpe) was able to enhance the boost effects of a rAd5SIVgpe for eliciting protective immunity against SIV mucosal challenge in rhesus macaques. Whether this heterologous prime and boost regimen is able to elicit potent mucosal immunity specific to SIV remains less understood.Different groups of mice were immunized with the following regiments: rMVTTSIVgpe-rAd5SIVgpe, rAd5SIVgpe-rMVTTSIVgpe and rAd5SIVgpe-rAd5SIVgpe. rMVTTSIVgpe was administrated through intraoral and intranasal routes (ioin) routes whereas rAd5SIVgpe was given through the intramuscular injection (im).Consistent with previous findings in macaques, mice immunized with the rMVTTSIVgpe-rAd5SIVgpe regimen generated significantly stronger systemic cellular immune responses as well as serum antibody responses than any other vaccine regimens. Furthermore, as compared with other groups, this rMVTTSIVgpe-rAd5SIVgpe regimen induced significantly higher frequencies of gut-homing CCR9+ Gag-specific CD8+ T cells as well as CCR6+ Gag-specific CD4+ and CD8+ T cells. This regimen also elicited the highest level of CD8+ T cell ELIspot responses against Gag, Pol and Env antigens in mesenteric lymph nodes (mLN). Besides, SIV-specific IgGs could be detected in the rectal wash of mice received rMVTTSIVgpe-rAd5SIVgpe immunization with detectable neutralizing activity.These findings demonstrated that mucosal priming with rMVTTSIVgpe significantly promoted mucosal immunity against SIV, which may have implications to the effectiveness of the mucosal rMVTTSIVgpe prime-systemic rAd5SIVgpe boost vacciniation strategy in preventing mucosal infection of SIVmac239 in macaques."}
+{"text": "Recombinant factor VIIa (rFVIIa) may produce rapid hemostasis in warfarin-associated intracerebral hemorrhage (WICH) but may carry high thromboembolic risks. We compared baseline thromboembolic risk factors and thromboembolism rates in WICH patients treated with rFVIIa to those treated with FFP and vitamin K alone.We identified 45 consecutive WICH patients treated with rFVIIa and 34 treated with FFP and vitamin K, and compared their incidence of pre-existing thromboembolic risk factors, troponin elevation, EKG changes, ischemic stroke, pulmonary embolism (PE), and deep vein thromboses (DVT).P = 0.0061) and baseline abnormal EKG (P = 0.02) were independently associated with clinically significant MI following WICH. Incidence of DVT/PE (2% vs. 9%) and ischemic stroke (2% vs. 0%) are comparable between rFVIIa-treated and control groups. Recombinant FVIIa-treated patients had lower mean INR at 3 (P = 0.0001) and 6 hours (P < 0.0001) and received fewer units of FFP transfusion .Both rFVIIa-treated and control WICH patients have high prevalence of pre-existing thromboembolic risk factors including atrial fibrillation (73% vs. 68%), DVT/PE (10% vs. 6%), coronary artery disease (CAD) (38% vs. 32%), and abnormal EKG (78% vs. 85%). Troponin elevation is common in WICH and incidence of troponin elevation (47% vs. 41%) and clinically significant myocardial infarction (MI) (13% vs. 6%) are similar between treatment groups. Past history of CAD (Recombinant FVIIa use in WICH is not associated with increased thromboembolic complications compared with FFP and vitamin K alone and may decrease the quantity of FFP use. A prospective randomized study is necessary to determine whether rFVIIa improves outcome of WICH."}
+{"text": "To illustrate the radiological features of noncalcified DCIS (NC-DCIS) on mammography, ultrasound and MRI. To highlight the role of MRI in determining extent of disease.DCIS accounts for 20% screen-detected cancers and 5% of symptomatic cancers. Eighty to 90% present mammographically as microcalcifications, but 10 to 20% are noncalcified and can be mammographically occult. With reported re-excision rates as high as 65% for breast-conserving surgery in DCIS, accurately determining disease extent on preoperative imaging is important.Imaging of 117 patients with pure DCIS from 2007 to 2011 was reviewed retrospectively. Fifteen patients with NC-DCIS were identified. Imaging findings were compared with disease extent on postoperative histology.NC-DCIS appeared as follows. Mammography: occult 33%, diffuse increased breast density 33%, focal architectural distortion 13%, well-circumscribed lesion 13%, tubular ductal density 7%. Ultrasound: occult 7%, intraductal lesion 13%, microcystic lesion 13%, solid lesion 53%, ill-defined echo poor focus 13%. MRI: nonmass-like nodular enhancement in a ductal, segmental or regional distribution 83%, amorphous nonmass-like enhancement 17%. MRI best depicted the true extent of disease.Recognition of these imaging features is important for accurate surgical planning. MRI has an important role in accurately delineating disease extent and should be considered in treatment planning for NC-DCIS."}
+{"text": "Cell transplantation therapy has been proposed as a treatment for intractable muscle degenerative disorders. Several reports have demonstrated the ability of bone-marrow derived cells (BMDC) to contribute to non-haematopoietic tissues including epithelium, heart, liver, skeletal muscle and brain following transplantation by means of fusion and reprogramming. A key issue is the extent to which fusion and reprogramming can occur +) bone marrow cells were transplanted into non-irradiated c-kit receptor \u2013 deficient (W41) mdx mice. This model allows BMDC reconstitution in the absence of irradiation induced myeloablation. We provide the first report of BMDC fusion in a W41/Dmdmdx deficient mouse model.To investigate the therapeutic potential of bone marrow transplantation in monogenetic myopathy, green fluorescent protein-positive (GFP+ cardiomyocytes and muscle fibres were detected 24 weeks post BMT. It was expected that the frequency of fusion in the hearts of W41Dmdmdx mice would be similar to frequencies observed in infarcted mice In the absence of irradiation induced injury, few GFPAlthough, it is clear from this study that individual cardiomyocytes with monogenetic deficiencies can be rescued by fusion, it is as clear that in the absence of irradiation, the formation of stable and reprogrammed fusion hybrids occurs, with the current techniques, at very low levels in non-irradiated recipients. Lack of functional dystrophin leads to degeneration of muscle fibres and infiltration of connective and adipose tissue. Cell transplantation therapy has been proposed as a treatment for intractable muscle degenerative disorders. Several reports have demonstrated the ability of bone-marrow derived cells (BMDC) to contribute to non-haematopoietic tissues including epithelium, heart, liver, skeletal muscle and brain Previously the contribution of donor BMDC has been shown to occur only in muscle regenerating after damage, and predominantly in irradiated host muscle +) bone marrow cells were transplanted into non-irradiated c-kit receptor \u2013 deficient (W41) mdx mice. This model of muscular dystrophy allows BMDC reconstitution in the absence of irradiation induced myeloablation 41/Dmdmdx deficient mouse model. Although reconstitution efficiency was low, bone marrow cells contributed to reprogrammed myocytes with normal expression of dystrophin in skeletal muscle and myocardium.To investigate the therapeutic potential of bone marrow transplantation in DMD, green fluorescent protein-positive (GFP41/W41 (ref 15) were back-crossed 10 generations onto the Dmdmdx strain (Jackson Laboratories). The amplification-resistant mutation assay (ARMS) was used to genotype the Dmdmdx mice \u03b2-actin promoter driven GFP mice 41/Dmdmdx mice or sub-lethally irradiated (650 rad) W41/Dmdmdx controls. Individual mice received 80\u00d7106 cells. Haematopoietic reconstitution was evaluated 8 weeks post transplantation and prior to sacrifice by flow cytometry.Whole un-fractionated bone marrow was transplanted by intravenous (tail-vein) injection into non-irradiated adult W41/Dmdmdx mice were treated with ciprofloxacin (125 mg/l) in drinking water to prevent irradiation induced inflammation, starting from the day of irradiation Irradiated recipient Win situ, post fixed at 4\u00b0C with Stefanini solution and equilibriated in 20% sucrose, frozen and sectioned at 8\u201310 \u00b5m on a cryostat. Sections were stained with primary antibodies to pan-haematopoietic CD45 (Neomarkers or Abcam); cardiac troponin-T (cTNT) (Neomarkers); \u03b1-actinin (Sigma); dystrophin (Abcam); GFP . Secondary antibodies used were FITC donkey anti rabbit (Jackson Immunoresearch); Alexa Fluor 555 goat anti mouse (Molecular Probes); Cy5 donkey anti rat (Jackson Immunoresearch); Alexa Fluor 555 goat anti rabbit (Molecular Probes); Alexa Fluor 488 donkey anti mouse (Molecular Probes) all at pre-determined optimal concentrations. DAPI was used to visualize nuclei. Immunofluorescense images were captured using an Olympus BX51  fluorescence microscope and a DP70 Olympus digital camera (DP manager software Version 1.1.1.71) or a Zeisss Axiovert 200 M microscope  equipped with a Zeiss ApoTome and a XB075 fluorescence lamp and a Zeiss AxioCam MRm (Zeiss Axio Vision software).Chimeric mice were sacrificed by cervical dislocation. Muscle and heart tissue were perfused Blood samples were collected 8 weeks post transplantation and again prior to sacrifice after 24 and 52 weeks respectively. Peripheral blood was collected in heparinized eppendorff tubes and mixed with PBS/1% FCS. Red blood cells were sedimented and removed by Dextran 1\u22361 at 37\u2032C for 20\u201325 min. The cells were washed with PBS/1% FCS and further stained with pre-determined optimal concentrations of monoclonal mouse antibodies on ice for 15 minutes. After washing the cells, samples were resuspended in PBS/1% FCS and analyzed on a BD FACSCalibur. 7-amino actinomyosin (7-AAD) added prior to analysis to exclude dead cells. The following monoclonal antibodies were used for lineage readout: anti CD4-FITC, CD8-FITC, Gr-1-PE, Mac-1-PE and B220-APC .+ donor-derived non-haematopoietic cells in each tissue was determined by screening equal amounts of sections from irradiated and non-irradiated W41/Dmdmdx mice. Approximately 200,000 cardiomyocytes, 10,000 tibialis anterior and soleus muscle fibres per mouse were evaluated + cells by the number of mice and the total number of cells analyzed in each tissue. Data are presented as means \u00b1 SD.The frequency of GFP41Dmdmdx double mutant mice. In addition to muscular dystrophy, these mice are haematopoietic deficient due to a genetically altered c-kit receptor. Dystrophin membrane localization in W41/Dmdmdx mice was ablated in comparison to WT expression in skeletal muscle and myocardium . Virtually all GFP+ mononucleated cells were co-expressing pan-haematopoietic marker CD45.To investigate bone marrow as a source for cell therapy without exposing mice to irradiation, we used Wocardium Figure 1+ \u03b1-actinin+ CD45neg. The distribution of GFP+ myofibers was inherently low in the skeletal muscles of W41Dmdmdx unconditioned mice with 15 and 9 fibres detected in all mice at 24 and 52 weeks respectively , and DAPI (top right panel) GFP and CD45 co-localization (bottom left and bottom right panel.). Scale bars represent 100 \u00b5m.(TIF)Click here for additional data file."}
+{"text": "Pseudomonas syringae, obtained from numerous environmental sources and geographically proximate crop species. Overall, these sequences provide a wealth of information about the differences (or lack thereof) between isolates from disease outbreaks and those from other sources.Here, we report the draft genome sequences for 7 phylogenetically diverse isolates of  Pseudomonas syringae is well known as a facultative phytopathogen of many plant species, including crops, such as tomato, bean, and wheat, as well as the laboratory model Arabidopsis  UB246 (AVEQ00000000), CC1543 (AVEJ00000000), CC94 (AVEA00000000), UB303 (AVDZ00000000), CC1416 (AVEP00000000), CC1458 (AVEN00000000), CC1544 (AVEI00000000), CC1559 (AVEG00000000), CC440 (AVEC00000000), CC457 (AVEB00000000), CC1557 (AVEH00000000), USA007 (AVDY00000000), and CC1583 (AVEF00000000), as well as P.\u00a0viridiflava strains CC1582 (AVDW00000000) and TA043 (AVDV00000000). These assemblies are not included within this announcement due to poor assembly quality.The collection of these isolates has been previously described \u20135. Genom quality . These ahttp://img.jgi.doe.gov/) with the JGI taxon IDs listed in The nucleotide sequence accession numbers for Genbank are found in"}
+{"text": "Excessive aortopulmonary collateral (APC) flow is hypothesized to negatively affect outcome after a Fontan operation. Lack of an accurate and readily applied technique to measure APC flow has hindered research on this issue.We used a recently described cardiac MRI (CMR) method to quantify APC flow in a large cohort of late Fontan survivors, and evaluate its relationship with clinical outcomes.We performed a retrospective review of patients late after Fontan operation who underwent CMR measurement of APC flow at our institution from 2003 through 2009. APC flow was quantified as either aortic flow minus total caval flow or aortic flow minus sum of branch pulmonary artery flow, and was indexed to body surface area (BSA). Patients with a patent fenestration or baffle leak were excluded.2 (interquartile range 0.13-0.79 L/min/m2), accounting for a median of 15% of systemic flow (interquartile range 4-28%). Excluding patients with >mild valve regurgitation (n=10), higher APC flow/BSA was associated with larger ventricular end-diastolic volume (EDV)/BSA . APC flow/BSA was not associated with age at CMR, age at Fontan, history of systemic-pulmonary artery shunt (n=61) or bidirectional Glenn shunt (n=35), history of catheter-based occlusion of APCs (n=10), congestive heart failure (n=21), atrial or ventricular arrhythmias (n=54), >mild atrioventricular valve regurgitation (n=10), ejection fraction, and peak oxygen consumption (VO2) on maximal exercise stress test (n=43) within 1 year of CMR.APC flow was quantified in 78 patients  15.9\u00b17 years after Fontan operation. Median APC flow was 0.43 L/min/mIn this cohort of late survivors of a Fontan operation, APC flow measured by CMR comprised a significant proportion of cardiac output and was associated with larger BSA-adjusted ventricular volume. It did not correlate with surgical history, history of catheter-based occlusion of APCs or clinical outcomes. Continued follow-up is required to further determine the long-term relationship between APC flow and clinical outcomes."}
+{"text": "CEL genes, and encoded proteins using data from several vertebrate genome projects. A proline-rich and O-glycosylated 11-amino acid C-terminal repeat sequence (VNTR) previously reported for human and other higher primate CEL proteins was also observed for other eutherian mammalian CEL sequences examined. In contrast, opossum CEL contained a single C-terminal copy of this sequence whereas CEL proteins from platypus, chicken, lizard, frog and several fish species lacked the VNTR sequence. Vertebrate CEL genes contained 11 coding exons. Evidence is presented for tandem duplicated CEL genes for the zebrafish genome. Vertebrate CEL protein subunits shared 53\u201397% sequence identities; demonstrated sequence alignments and identities for key CEL amino acid residues; and conservation of predicted secondary and tertiary structures with those previously reported for human CEL. Phylogenetic analyses demonstrated the relationships and potential evolutionary origins of the vertebrate CEL family of genes which were related to a nematode carboxylesterase (CES) gene and five mammalian CES gene families.Bile-salt activated carboxylic ester lipase (CEL) is a major triglyceride, cholesterol ester and vitamin ester hydrolytic enzyme contained within pancreatic and lactating mammary gland secretions. Bioinformatic methods were used to predict the amino acid sequences, secondary and tertiary structures and gene locations for  Bile-salt activated carboxylic ester lipase  is a major triglyceride, cholesterol ester and vitamin ester hydrolytic enzyme contained within pancreatic and lactating mammary gland secretions \u201310. CEL CEL genes and cDNA sequences have been determined, including human (Homo sapiens) [Gorilla gorilla) [Mus musculus) [Rattus norvegicus) [Bos taurus) CEL genes [CEL gene comprises 11 exons and is localized on chromosome 9 [CEL gene encodes a variable number of tandem repeat sequences region (VNTR) (17 repeats are most common) which is highly polymorphic in human populations and contributes to plasma cholesterol and lipid composition [CEL gene defects in this region are responsible for a monogenically derived diabetes condition called maturity-onset diabetes of the young type 8 (MODY8), also known as diabetes and pancreatic exocrine dysfunction (DPED), which causes a defect in insulin secretion [Structures for several human and animal sapiens) , 17\u201319, gorilla) , mouse (usculus) \u201323, rat vegicus) \u201326, and EL genes . The hummosome 9 . Severalmosome 9 , 30. Exoposition . Moreoveecretion , 32. CEL is expressed predominantly in the lactating mammary gland and beta cells of the exocrine pancreas, where the enzyme contributes significantly to triglyceride, cholesterol ester and vitamin ester metabolism [CEL expression has also been reported in the human pituitary gland, and a possible role for CEL in the regulation of hormone secretion and ceramide metabolism has been described [\u2212Cel/\u2212Cel knock out mice have shown that other enzymes besides CEL are predominantly responsible for the hydrolysis of dietary cholesteryl esters, retinyl esters, and triglycerides [Cel-null mice however have reported that a lack of CEL activity causes an incomplete digestion of milk fat and lipid accumulation by enterocytes in the ileum of neonatal mice which suggests a major role for this enzyme in triglyceride hydrolysis in breast-fed animals [Human tabolism \u201310. CEL tabolism  which matabolism . CEL expescribed . Studiesycerides . Metabol animals , 34. Mor animals . CEL-like gene (designated as CELL) has also been identified on human and gorilla chromosome 9, about 10 kilobases downstream of CEL, which is transcribed in many tissues of the body but lacks exons 2\u20137 and is unlikely to be translated into protein [CELL pseudogene gene duplication apparently occurred prior to the separation of Hominidae  from Old World monkeys (macaque) with CELL being restricted to genomes of man and the great apes [A  protein , 20, 35.Three-dimensional structural analyses of human CEL have shown that the enzyme belongs to the alpha/beta hydrolase fold family with several key structural and catalytic features, including an active site catalytic triad located within the enzyme structure and partially covered by a surface loop, the carboxyl terminus region of the protein which regulates enzymatic activity by forming hydrogen bonds with the surface loop to partially shield the active site, and a loop domain which binds bile salt and frees the active site to access water-insoluble substrates , 36\u201338. CEL genes and proteins, the predicted secondary and tertiary structures for vertebrate CEL protein subunits, and the structural phylogenetic and evolutionary relationships for these genes and enzymes with mammalian CES (carboxylesterase) gene families [This paper reports the predicted gene structures and amino acid sequences for several vertebrate families , 41. http://blast.ncbi.nlm.nih.gov/Blast.cgi) [Homo sapiens) [Pan troglodytes) [Pongo abelii) (http://genome.wustl.edu/); the cow (Bos Taurus) [Equus caballus) [Mus musculus) [Monodelphis domestica) [Gallus gallus) [Xenopus tropicalis) [Danio rerio) [BLAST  studies were undertaken using web tools from the National Center for Biotechnology Information (NCBI) (ast.cgi) . Proteinsapiens) , chimp (lodytes) , orangut Taurus) , horse  , mouse (usculus) , opossummestica) , platypumestica) , chicken gallus) , clawed picalis) , and zebo rerio) . This pro rerio) . Predicthttp://genome.ucsc.edu/cgi-bin/hgBlat) [CEL genes, including predicted exon boundary locations and gene sizes. Structures for human, mouse, and rat CEL isoforms (splice variants) were obtained using the AceView website (http://www.ncbi.nlm.nih.gov/IEB/Research/Acembly/index.html?human) to examine predicted gene and protein structures [http://www.ebi.ac.uk/Tools/clustalw2/index.html). BLAT (BLAST-Like Alignment Tool) analyses were subsequently undertaken for each of the predicted vertebrate CEL amino acid sequences using the University of California Santa Cruz (UCSC) Genome Browser (/hgBlat)  with theructures . Alignmeructures  (http://http://bioinf.cs.ucl.ac.uk/psipred/) [http://swissmodel.expasy.org/), respectively [http://au.expasy.org/tools/pi_tool.html). SignalP 3.0 web tools were used to predict the presence and location of signal peptide cleavage sites  for each of the predicted vertebrate CEL sequences [http://www.cbs.dtu.dk/services/NetNGlyc/). Predicted secondary and tertiary structures for vertebrate CEL-like subunits were obtained using the PSIPRED v2.5 web site tools (sipred/)  and the ectively , 56. Theectively  served aequences . The Nethttp://genome.ucsc.edu/) [CEL and mouse Cel genes, respectively, (http://biogps.gnf.org/) [The UCSC Genome Browser (sc.edu/)  was usednf.org/) . Gene arAlignments of vertebrate CEL and human, mouse, and nematode CES-like (carboxylesterase) protein sequences were assembled using BioEdit v.5.0.1 and the default settings . AlignmeMonodelphis domestica) and chicken  CEL subunits and for zebrafish (Danio rerio) CEL1 and CEL2 subunits are shown in Homo sapiens) [Mus musculus) [Bos taurus) [Gorilla gorilla) (39 repeats) [Macaca mulatta) (15 repeats) CEL, whereas other mammalian CEL subunits usually contained 3 VNTR repeats, with the exception of the predicted dog (Canis familiaris) CELC-terminus, which contained 13 VNTR-repeat sequences. A comparison of the 11-residue repeat sequences for the mammalian CEL subunits examined showed the following consensus sequence: Pro-Val-Pro-Pro-Thr-Gly-Asp-Ser-Glu-Ala-Ala (The deduced amino acid sequences for opossum (sapiens) , 39, mouusculus) , and bov taurus) , 63 CEL repeats) , human (repeats) , and rhe-Ala-Ala , for whiOrnithorhynchus anatinus) CEL which contained two predicted N-glycosylation sites at Asn381-Val382-Thr383 and Asn548-Leu549-Thr550 (Monodelphis domestica) CEL; Asn270-Thr271-Thr272 and Asn381-Leu382-Thr383 for chicken  CEL; Asn270-Thr271-Thr272 for lizard (Anolis carolensis); Asn550-Val551-Thr552 for fugu (Takifugu rupides) CEL  . These i9-Thr550 . Predictdes) CEL . Given t\u03b1-helix \u03b2-sheet structures were observed for all of the vertebrate CEL subunits examined. Consistent structures were particularly apparent near key residues or functional domains including the \u03b2-sheet and \u03b1-helix structures near the active site Ser194 (\u03b28/\u03b1D) and Asp320 (\u03b210/\u03b18) residues, and the N-glycosylation site at Asn207-Ile208-Thr209 (near \u03b28) [\u03b1N) for the vertebrate CEL subunits was readily apparent, as were the five \u03b2-sheet structures at the N-termini of the CEL subunits (\u03b21\u2013\u03b25). It is apparent from these studies that all of these CEL subunits have highly similar secondary structures.Analyses of predicted secondary structures for vertebrate CEL sequences were compared with the previously reported secondary structure for bovine and human CEL , 68 Fig. Similarnear \u03b28) . The sin\u03b2-sheets interspersed with several \u03b1-helical structures [ructures , 68 whicructures . The actructures , 70, 71.CEL genes based upon BLAT interrogations of several vertebrate genomes using the reported sequences for human, gorilla, mouse, rat, and bovine CEL [CEL genes were located on human chromosome 9 and mouse chromosome 2, which are distinct to the carboxylesterase (CES for human or Ces for mouse) gene family cluster locations in each case: on human chromosome 16 and mouse chromosome 8, respectively (Danio rerio) genome showed evidence of tandem duplicated CEL genes, with predicted CEL1 and CEL2 genes being located about 7.3 kilobases apart on zebrafish chromosome 21 . Consequently, even though CEL and CES genes and proteins are members of the same serine hydrolase superfamily [CEL is not a close relative of the CES gene family, for which at least five genes are clustered on a single chromosomes on human and mouse chromosomes and are more similar in gene structure to each other than they are to the CEL gene . CEL transcripts for the major transcript isoform in each case [CEL mRNA transcripts. The human CEL genome sequence contained a microRNA site (miR485-5p) located in the 3\u2032-untranslated region and a CpG island (CpG51). The occurrence of the CpG island within the CEL gene may reflect a role in regulating gene expression [CEL (\u00d71.5 times higher). Figure\u2009\u20092 of Supplementary Material shows a nucleotide sequence alignment diagram for the CpG51 region of the human CEL gene in comparison with several other mammalian and other vertebrate CEL genes. The Multiz alignment patterns observed demonstrated extensive sequence conservation for the CpG island which contains dinucleotide and trinucleotide repeat sequences in most genomes examined. ach case . The trapression  which maCEL is also potentially of major significance for the regulation of this gene. MicroRNAs are small noncoding RNAs that regulate mRNA and protein expression and have been implicated in regulating gene expression during embryonic development [CEL expression during pancreatic beta cell development. Table\u2009\u20091 of Supplementary Material presents comparative nucleotide sequences for miR485-5p-like CEL gene regions for several vertebrate genomes which shows high levels of sequence identity, particularly among mammalian CEL miRNA target sites and suggests that this site has been predominantly conserved during vertebrate evolution, particularly by eutherian mammalian CEL genes. The prediction of a microRNA  binding site in the 3\u2032untranslated region of human elopment . Moreoveelopment . A similCEL gene, including the 5\u2032-flanking, 5\u2032-untranslated, intronic, exonic, and 3\u2032untranslated regions of this gene, with the corresponding sequences for 10 vertebrate genomes, including 5 eutherian mammals , a marsupial (opossum), a monotreme (platypus), and lower vertebrate genomes. Extensive conservation was observed among these genomic sequences, particularly for the rhesus CEL gene and for other eutherian mammalian genomes. In contrast with the eutherian mammalian genomes examined, other vertebrate genomes retained conserved sequences only within the 11 exonic CEL regions. It would appear that exonic CEL nucleotide sequences have been conserved throughout vertebrate evolution whereas only in eutherian mammalian genomes have other regions of the CEL gene been predominantly conserved. http://genome.ucsc.edu/; http://biogps.gnf.org/) [CEL, particularly for the pancreatic islets, the pituitary gland, and fetal liver, which is consistent with previous reports for these genes  mice (or CELKO mice) have demonstrated that CEL is not an essential enzyme for these metabolic functions [nf.org/) . These dnes (see ). High lneonates . The locneonates , which sneonates . A high neonates . Recent unctions , 83, altunctions , 84, andunctions . The latunctions , 86. CEL gene arose from a gene duplication event of an ancestral CES-like gene, resulting in at least two separate lines of gene evolution for CES-like and CEL-like genes. This is supported by the comparative biochemical and genomic evidence for vertebrate CEL and CES-like genes and encoded proteins, which share several key features of protein and gene structure, including having similar alpha-beta hydrolase secondary and tertiary structures [A phylogenetic tree  was calcructures , 71, 78 CEL genes and encoded CEL enzymes represent a distinct alpha-beta hydrolase gene and enzyme family which share key conserved sequences and structures that have been reported for the human CES gene families. CEL is a major triglyceride, cholesterol ester and vitamin ester hydrolytic enzyme contained within exocrine pancreatic and lactating mammary gland secretions and is also localized in plasma where it contributes to chylomicron assembly and secretion, in the selective uptake of cholesteryl esters in HDL in the liver and in reverse cholesterol transport, including biliary disposal of cholesterol. Bioinformatic methods were used to predict the amino acid sequences, secondary and tertiary structures and gene locations for CEL genes, and encoded proteins using data from several vertebrate genome projects. A proline-rich and O-glycosylated 11-amino acid C-terminal repeat sequence (VNTR) previously reported for human and other higher primate CEL proteins was also observed for other eutherian mammalian CEL sequences examined. Opossum CEL, however, contained a single C-terminal copy of this sequence while CEL proteins from lower vertebrates lacked the VNTR sequence. Evidence is presented for tandem duplicated CEL genes for the zebrafish genome. Vertebrate CEL protein subunits shared 53\u201397% sequence identities and exhibited sequence alignments and identities for key CEL amino acid residues as well as extensive conservation of predicted secondary and tertiary structures with those previously reported for human CEL. Phylogenetic analyses demonstrated the relationships and potential evolutionary origins of the vertebrate CEL family of genes which were related to a nematode carboxylesterase (CES) gene and five mammalian CES gene families. These studies indicated that CEL genes have apparently appeared early in vertebrate evolution prior to the teleost fish common ancestor more than 500 million years ago [In conclusion, the results of the present study indicate that vertebrate ears ago .Supplementary Figure 1 shows that one of the major differences between vertebrate CEL sequences and those of other serine esterases (such as the carboxylesterases CES1-CES6) is an apparent insertion at positions 139\u2013146 which appears to act as a surface loop that partially covers the opening to the catalytic triad and allows access to the active site by water soluble substrates by the truncated CEL. This active site loop is also readily apparent in the predicted structures for mouse CEL and zebrafish CEL1.CEL gene in comparison with several other mammalian and other vertebrate CEL genes; derived from the UCSC Genome Browser using the Comparative Genomics track to examine alignments and evolutionary conservation of CEL gene sequences for the CpG51 region containing dinucleotide and trinucleotide repeats; regions of sequence identity are shaded from black to a lighter color according to the degree of identity. The Multiz alignment patterns observed demonstrated extensive sequence conservation for the CpG island which contains dinucleotide and trinucleotide repeat sequences in most genomes examined.Supplementary Figure 2 shows a comparative nucleotide sequence alignment diagram for the CpG51 region of the human CEL gene regions for several vertebrate genomes which shows high levels of sequence identity, particularly among mammalian CEL miRNA target sites and suggests that this site has been predominantly conserved during vertebrate evolution, particularly by eutherian mammalian CEL genes.Supplementary Table presents comparative nucleotide sequences for miR485-5p like Click here for additional data file.Click here for additional data file.Click here for additional data file."}
+{"text": "Intravenous IgG (ivIg) is a therapeutic alternative for lupus erythematosus. Relative oligoclonality of circulating T-cells in SLE has been reported. Also CD4+Foxp3+ regulatory T-cells (Tregs) have a characteristically reduced activity in SLE, reflected by CD25 surface density. Aiming to study the role of Tregs for ivIg therapy, we characterized Tregs and determined TCR spectratypes of four Vb families with reported oligoclonality, in 15 lupus patients (14 with SLE and one with discoid LE) treated with ivIg in cycles of 2-6 consecutive monthly infusions. Among these 15 patients, 11 responded with clinical improvement. Cell counts, cytometry and TCR spectratypes were obtained from peripheral blood at various time points before, during and after ivIg treatment. T-cell oligoclonality was assessed as Vb-familywise repertoire perturbation, calculated for each patient in respect to an individual reference profile averaged over all available time points. For 11/15 patients, average Vb1/Vb2/Vb11/Vb14 repertoires were less perturbed under ivIg treatment than outside ivIg therapy. The four exceptions with relatively increased average perturbation during ivIg therapy included three patients who failed to respond clinically to an ivIg therapy cycle. Patients' Treg CD25 surface density (cytometric MFI) was, other than Treg/CD4+ frequency, clearly reduced when compared to healthy controls, but not obviously influenced by ivIg. However, patients' average Treg CD25 MFI was found negatively correlated with both Vb11 and Vb14 perturbations measured under ivIg therapy, which indicates a role of active Tregs in the therapeutic effect of ivIg."}
+{"text": "Clostridium botulinum strains are a group of Gram-positive, spore-forming anaerobic bacteria that produce a genetically, biochemically, and biophysically indistinguishable 150 kD protein that causes botulism. The genomes of three type A1 C. botulinum strains have been sequenced and show a high degree of synteny. The purpose of this study was to characterize differences among these genomes and compare these differentiating features with two additional unsequenced strains used in previous studies.Type A1 C. botulinum type A1 strain genomes revealed the presence of four comparable blocks. Strains ATCC 3502 and ATCC 19397 share the same genome organization, while the organization of the blocks in strain Hall were switched. Lastly, PCR was designed to identify UMASS and ATCC 3502* strain genome organizations. The PCR results indicated that UMASS strain belonged to Hall type and ATCC 3502* strain was identical to ATCC 3502 (Sanger Institute) type.Several strategies were deployed in this report. First, University of Massachusetts Dartmouth laboratory Hall strain (UMASS strain) neurotoxin gene was amplified by PCR and sequenced; its sequence was aligned with the published ATCC 3502 Sanger Institute Hall strain and Allergan Hall strain neurotoxin gene regions. Sequence alignment showed that there was a synonymous single nucleotide polymorphism (SNP) in the region encoding the heavy chain between Allergan strain and ATCC 3502 and UMASS strains. Second, comparative genomic hybridization (CGH) demonstrated that the UMASS strain and a strain expected to be derived from ATCC 3502 in the Centers for Disease Control and Prevention (CDC) laboratory (ATCC 3502*) differed in gene content compared to the ATCC 3502 genome sequence published by the Sanger Institute. Third, alignment of the three sequenced C. botulinum type A1 strains including Sanger Institute ATCC 3502, ATCC 3502*, ATCC 19397, Hall, Allergan, and UMASS strains demonstrate differences at the level of the neurotoxin gene sequence, in gene content, and in genome arrangement.Taken together,  Clostridium botulinum is a Gram-positive, spore-forming anaerobic bacterium that causes the severe neuroparalytic illness in humans and animals known as botulism. There are seven serologically distinct types of botulinum neurotoxin -types A, B, C, D, E, F, and G. Comparison of 16 S rRNA sequences , CDC ATCC 3502 (ATCC 3502*), ATCC 19397 [GenBank: CP000726], Hall [GenBank: CP000727], Allergan, and University of Massachusetts Dartmouth laboratory Hall strain (UMASS strain), all belonging to subtype A1. The results indicated that genetic diversity existed among these subtype A1 strains including those designated simply as \"Hall\".In this communication, the genetic diversity of C. botulinum type A1 neurotoxin complex genomic cluster spans 11719 bp in ATCC 3502 . The identical genomic cluster was also found in four other genome sequences, whose GenBank accession numbers are CP000727 , CP000726 (C. botulinum A strain ATCC 19397), DQ409059 , and AF461540 .The ha70, ha17, ha33, botR, ntnh, and bont/A, whose coding regions in aggregate consist of 11215 bp out of 11719 bp botulinum A neurotoxin genomic cluster (Sanger Institute ATCC 3502). Sequence alignment of this cluster with each individual gene sequence [GenBank: AF488745-AF488750] from the Allergan Hall strain  were aligned by using EBI ClustalW2 http://www.ebi.ac.uk/Tools/clustalw2/index.html.PCR primers were designed to amplify the l strain  and ATCCC. botulinum type A1 strain ATCC 3502 comparative genomic hybridization arrays was used as described previously [2 ratios of the fluorescence intensity of the reference strain/test strain. The CGH microarray data were deposited in the NCBI Gene Expression Omnibus (GEO) [Accession: GSE21241]Genomic DNA extraction was performed as described previously . A custoeviously . GenomicC. botulinum type A str. ATCC 3502 complete genome [GenBank: AM412317]; C. botulinum type A str. ATCC 19397 complete genome [GenBank: CP000726]; and C. botulinum type A str. Hall complete genome [GenBank: CP000727].Multiple genome alignments were performed by using Mauve . SpecifiBased on the genome organizational patterns observed by multiple genome alignment, PCR primers were designed in the way that the expected PCR fragment will span the boundaries between the rearranged block 3 (ATCC 3502 block number) and its surrounding blocks 2 and 4 for both patterns. The common upstream primers, which are inside the rearranged block 3, are 5'-GAA GGC CTC CGG TGG CGA TAT C-3'  and 5'-GTG TAG AGA ATC GAA ACA AAA TCA TCC ACA TC-3' . The downstream primers inside the block 4 of ATCC 3502 and ATCC 19397 are 5'-CTT GAA TGG CTT GGC ATA TTA AGT GGG-3'  and 5'-AGT TGG CTT TAT AAT CCC TTG GAT TTC AGG-3' . The downstream primers inside block 2 of Hall are 5'-CAG AAT TAG CAG ACA GAC TAC TTT CTA CC-3'  and 5'-ATA GCC TTA TTT GGA GGC GGT CAG G-3' . Eight PCR reactions containing different upstream and downstream primer combinations were set up using genomic DNA isolated from either ATCC 3502* strain or UMASS strain. The PCR product amplified with primers Puo and P2do from the UMASS strain was cloned into pCR4-TOPO  and sequenced, and the sequencing results were used to search the GenBank database.PKF drafted the manuscript and carried out part of experiments. BHR reviewed the manuscript and carried out part of experiments. BRS, SEM, and SC conceived, supervised, and coordinated the work; and reviewed the manuscript. All the authors read and approved the final manuscript."}
+{"text": "Cardiomyocyte calcium overloading has been implicated in the pathogenesis of Duchenne muscular dystrophy (DMD) heart disease. The cardiac isoform of sarcoplasmic reticulum calcium ATPase (SERCA2a) plays a major role in removing cytosolic calcium during heart muscle relaxation. Here, we tested the hypothesis that SERCA2a over-expression may mitigate electrocardiography (ECG) abnormalities in old female mdx mice, a murine model of DMD cardiomyopathy.12 viral genome particles/mouse of adeno-associated virus serotype-9 (AAV-9) SERCA2a vector was delivered to 12-m-old female mdx mice (N = 5) via a single bolus tail vein injection. AAV transduction and the ECG profile were examined eight months later.1 \u00d7 10The vector genome was detected in the hearts of all AAV-injected mdx mice. Immunofluorescence staining and western blot confirmed SERCA2a over-expression in the mdx heart. Untreated mdx mice showed characteristic tachycardia, PR interval reduction and QT interval prolongation. AAV-9 SERCA2a treatment corrected these ECG abnormalities.Our results suggest that AAV SERCA2a therapy may hold great promise in treating dystrophin-deficient heart disease. The heart is often afflicted in Duchenne muscular dystrophy (DMD), a lethal muscle disease caused by dystrophin deficiency (reviewed in ). DystroThe sarcoplasmic reticulum is the primary calcium storage organelle in muscle cells. In cardiomyocytes, removal of cytosolic calcium is mainly accomplished by the cardiac isoform of sarcoplasmic reticulum calcium ATPase (SERCA2a) via its pump activity (reviewed in ). Basica12 viral genome (vg) particles/mouse of AAV-9 SERCA2a vector to 12-m-old female mdx mice via a single bolus tail vein injection. Electrocardiography (ECG) was performed when mice reached 20 months of age. Compared to that of age- and gender-matched untreated mdx mice, the ECG profile of AAV-9 SERCA2a treated mdx mice was significantly improved.Among various gene transfer vectors, adeno-associated virus serotype-9 (AAV-9) is by far the most robust vector for transducing the mdx heart when administrated intravascularly -13. We hcis plasmid for AAV-9 SERCA2a vector production has been extensively characterized and used in various animal studies and human trials [The n trials -19. In tn trials ,21. Recon trials . Viral tn trials ,23.12 vg particles of AAV-9.All animal experiments were approved by the Animal Care and Use Committee of the University of Missouri and were in accordance with NIH guidelines. Dystrophin-deficient mdx mice and normal control C57Bl/10 (BL10) mice were purchased from The Jackson Laboratory . AAV-9 SERCA2a vector was injected to conscious 12-m-old mdx mice in a single bolus through the tail vein according to a previously described protocol . Each moDNA was extracted from frozen heart tissue sections as we described before . The AAVThe frozen heart was ground to fine powder in liquid nitrogen. Whole heart muscle lysate was prepared according to our published protocol ,25. PrimSERCA2a expression was confirmed by immunofluorescence staining. Briefly, 10 \u03bcm frozen heart sections was blocked with 20% goat serum at room temperature for 30 min. The rabbit polyclonal anti-SERCA2a antibody was then applied at the dilution of 1:3,000 overnight at 4\u00b0C . SERCA2aGeneral heart histology was evaluated by hematoxylin and eosin (HE) staining. Cardiac fibrosis was examined by Masson trichrome staining as we described before . FibrotiMice were anesthetized with isoflurane . A non-invasive 12-lead ECG was performed according to our published protocol . ECG sigpost hoc analysis. Difference was considered significant when P < 0.05.Data are presented as mean \u00b1 standard error of mean. Statistical analysis was performed with the SPSS software  using one-way ANOVA followed by Bonferroni To evaluate SERCA2a gene therapy in a dystrophin-deficient heart, we packaged the CMV.SERCA2a construct into AAV-9 Figure . Since tOn histopathologic examination, the hearts of SERCA2a treated mice were not different from those of untreated mdx mice Figure . SpecifiCardiac complications are a major health issue in DMD. Current treatments are limited to symptomatic medications and heart transplantation . In an eOver the last decade tremendous progress has been made in our understanding of the pathogenesis of DMD cardiomyopathy. An emerging theme is the disruption of calcium homeostasis . FirAAV SERCA2a therapy has successfully reversed cardiac dysfunction in several large animal models ,30. A PhOur results here have opened a new avenue to treat DMD cardiomyopathy using AAV SERCA2a gene delivery. Future studies in aged mdx mice, dystrophin/utrophin double knockout mice and dystrophin-deficient dogs may further validate AAV SERCA2a mediated gene therapy for DMD.AAV: adeno-associated virus; BL10: C57Bl/10; CFTR: cystic fibrosis transmembrane conductance regulator; CMV: cytomegalovirus; DMD: Duchenne muscular dystrophy; ECG: electrocardiography; HE: hematoxylin and eosin; PCR: polymerase chain reaction; SERCA2: cardiac isoform of sarcoplasmic reticulum calcium ATPase; vg: viral genome.Dr. Hajjar has ownership interest (include stock options and rights in patents) in Celladon Corporation, a company involved in SERCA2a clinical trials. The other authors declare that they have no competing interest.BB participated in ECG assay. DD conceived of study and wrote the manuscript. JS performed PCR, western blot, immunostaining, histology and ECG assay. RH provided critical reagents and advice. YY made AAV vector and participated in morphology and ECG studies. All authors read and approved the final manuscript."}
+{"text": "Plasmodium berghei. To allow constitutive and abundant expression of the mCherry protein we profiled expression of all members of the P. berghei heat shock protein 70 (HSP70) family. We identified PbHSP70/1, an invariant ortholog of Plasmodium falciparum HSP70-1, as the protein with the highest expression levels during Plasmodium blood, mosquito, and liver infection. Stable allelic insertion of a mCherry expression cassette into the PbHsp70/1 locus created constitutive red fluorescent P. berghei lines, termed Pbred. We show that these parasites can be used for live imaging of infected host cells and organs, including hepatocytes, erythrocytes, and whole Anopheles mosquitoes. Quantification of the fluorescence intensity of several Pbred parasite stages revealed significantly enhanced signal intensities in comparison to GFP expressed under the control of the constitutive EF1alpha promoter. We propose that systematic transcript profiling permits generation of reporter parasites, such as the Pbred lines described herein.Live cell imaging of recombinant malarial parasites encoding fluorescent probes provides critical insights into parasite-host interactions and life cycle progression. In this study, we generated a red fluorescent line of the murine malarial parasite  Plasmodium, single cell eukaryotes that follow a complex developmental program during life cycle progression. Although many aspects of the parasite life cycle are known since decades, previously unrecognized aspects of the clinically silent and diagnostically inaccessible pre-erythrocytic phase, such as cell traversal prior to productive invasion Plasmodium biology. These observations were possible because generation of a bright green fluorescent sporozoite line, CSP::GFPMalaria is caused by blood infection of the obligate intracellular parasite Plasmodium parasites and is an invaluable tool for in vivo studies on temporal and spatial gene expression. In addition, fluorescent parasites can serve as reference lines for biological studies. The fluorescent proteins of choice include green fluorescent protein (GFP) from the jellyfish Aequorea victoriaPlasmodium line was generated by stable integration of a dihydrofolate reductase/thymidylate synthase (DHFR-TS) \u2013 GFP fusion protein into the P. berghei genome EF1a) promoter, resulting in constitutive, but only moderate, fluorescence throughout the parasite life cycle Stable transgenic expression of fluorescent proteins is an established strategy in P. berghei parasites towards robust live cell imaging throughout the entire Plasmodium life cycle. For this purpose, we focused on members of the heat shock protein 70 (HSP70) family, because they are ubiquitous, typically abundant, and likely to perform important functions in Plasmodium parasites Plasmodium species encode at least four conserved HSP70 members that localize to various compartments in the parasite and likely fulfill distinct chaperone functions  PfHsp70-1 contains a distinct carboxy-terminal tetrapeptide repeat, GGMP, which is a signature of the subfamily of heat shock cognate 70 kDa proteins (Hsc70). Importantly, Hsc70 is constitutively expressed, unlike canonical heat shock proteins P. berghei ortholog  displays an exceptionally high degree of invariant residues PbHSP70/1 also recognize recombinant PfHsp70-1 PfHsp70-1 and PyHSP70/1 expression in early liver stage development PbHSP70/1 is expressed, albeit weak, in sporozoites, lending further support for constitutive expression of this HSP70 member Plasmodium protein have not been addressed experimentally, partial complementation of Escherichia coli DnaKSaccharomyces cerevisiae SSA1PfHsp70-1. PfHsp70-1 is a major immunogen of purified blood stage parasites, and an immuno-epidemiological study in a holoendemic area in West Africa revealed an age-dependent acquisition of anti-PfHsp70-1 antibodies and significant T cell reactivity PfHsp70-1 are apparently recognized in Plasmodium-infected hepatocytes PyHSP70/1 leads to an undesired increase in gametocyte formation and, hence, higher malaria transmission P. vivax and P. falciparum-infected individuals reacted with recombinant P. vivax Hsp70-1 The first Toxoplasma gondii ortholog, TgHSP70.1  was readily identified  is present only in P. falciparum and the related parasite P. reichenowi, where it fulfills a specialized role in remodeling the host erythrocyte A entified . IntriguPfHsp70-2  is translocated to the endoplasmic reticulum (ER) and, hence, resembles binding immunoglobulin protein (BiP)/78 kDa glucose-regulated protein (GRP-78) Plasmodium species and related apicomplexan parasites  and its orthologs (P. berghei ortholog PbHSP70/3 (PBANKA_091440) was initially identified as upregulated in infectious sporozoites protein 24 (UIS24), indicative of developmental regulation of PbHSP70/3/UIS24 expression PfHsp70-y  that contains a predicted apicoplast transit peptide in addition to the cleavable signal sequence and a less conserved Hsp70 domain  showed a cytoplasmic localization and indicated that the protein might associate with PfHSP70-1 PbHOP  and TgHOP  are readily identified based on high sequence conservation (Tab. S1).We finally included the Hsp70/Hsp90 organizing protein (HOP) in our expression analysis. HOP was originally identified as a 60 kDa stress-related protein that forms a complex with HSP70 and HSP90 P. berghei HSP70 family throughout the entire Plasmodium life cycle and, thereby, identified Hsp70/1 as a candidate promoter region for robust, constitutive, and high level expression of a red fluorescent reporter protein for live cell imaging applications.In this study, we performed systematic transcript profiling of the HSP70 and HOP mRNAs in different life cycle stages of the murine malarial parasite P. berghei  cultured ookinetes, (iv) sporozoites liberated from infected Anopheles salivary glands, and cultured sporozoite-infected hepatoma cells, representing (v) early (24 h) and (vi) late (48 h) liver stages. Profiling of steady-state transcript abundance by qRT PCR using gene-specific primer pairs and normalization to GFP expressed under the control of elongation factor 1 alpha (EF1a) revealed robust expression for all transcripts analyzed  profiling of  berghei . To thisanalyzed .PbHSP70/1 was the most abundant transcript compared to all other HSP70 members tested. Expression levels were also typically 2\u201310-fold higher than the GFP reference transcript. This difference was most apparent in ookinetes, schizonts/merozoites, and late liver stages, indicating substantially enhanced signal intensity as compared to EF1a, making PbHSP70/1 the prime candidate to drive reporter gene expression.In all life cycle stages examined, PbHSP70/2/BIP/GRP-78 steady-state levels fluctuated substantially depending on the life cycle phase, ranging from very low (\u223c100 fold reduced) expression in sporozoites to high (\u223c10 fold upregulated) levels in schizonts . Upon linearization in the 5\u2032UTR the targeting plasmid is integrated via a single cross-over event  parasites (strain ANKA) and clone 507 EF1a promoter generating Pbred cloneANKA (Pbred cANKA) and Pbred clone507 (Pbred c507), respectively. Generation of the Pbred c507 parasite line, emitting GFP controlled by the EF1a promoter and mCherry driven under the Hsp70/1 promoter, allowed us to quantify and compare both fluorescent signals in individual parasites.We performed transfections into two in vivo by limiting dilutions, resulting in two clonal Pbred cANKA and Pbred c507 parasite populations.Genotyping by diagnostic PCR revealed the predicted site-specific integration in both recipient parasites . The resin vivo (Pbred clones are indistinguishable from wild-type (WT) parasites during blood stage development.Next, we monitored blood infection in outbred NMRI mice to ascertain that the expression cassette does not interfere with parasite growth in vivo . MonitorPbred parasites by determination of salivary gland sporozoite numbers in infected A. stephensi mosquitoes . This finding indicates normal liver stage development of Pbred c507 parasites. Together, we conclude that Pbred parasites are suitable as a P. berghei reference line, since replication, viability, and infectivity are indistinguishable from WT parasites.We next analyzed mosquito stage development of the squitoes . Sporozoex vivo revealed bright red fluorescence throughout all asexual blood stage parasites and gametocytes  promoter We next analyzed parasite development in the mosquito vector . Mosquite organs . This fiPbred-infected mosquitoes at various time points recovered bright red fluorescent ookinetes, infected midguts, single midgut-associated oocysts, and individual salivary gland sporozoites, respectively  as compared to EGFP (1.0) or dtTomato (1.44) advantages of mCherry include fast protein maturation (15 min) and enhanced photo-stability in vitro and in vivo imaging of Plasmodium parasites Pbred clones can be used as reference strains alone or in combination with constitutive green fluorescent parasites hsp20(-) sporozoites, which revealed a specific role for the small heat shock protein 20 (HSP20) in fast, continuous sporozoite locomotion and natural malaria transmission The Plasmodium life cycle. Robust and continuous monitoring of live parasites during processes such as host cell invasion, tissue transmigration, intracellular growth, proliferation, and host cell egress in the mammalian and invertebrate hosts are expected to expand our insights into fundamental aspects of parasite stage conversion and adaptation to new environments. Similarly, capturing of innate defense responses and targeted inactivation by the adaptive immune system will generate important mechanistic insights into the molecular mechanisms of host susceptibility and refractoriness, of naturally acquired immunity, and of vaccine-induced protection. Since effector cells in Plasmodium hosts are typically labeled by transgenic GFP expression, mCherry-expressing parasites provide the matching partners for capturing pathogen-host cell interactions at single cell resolution.Fluorescent reporter parasites are important tools to study the complex developmental program, parasite/host cross talk, and parasite population dynamics throughout the All animal work was conducted in accordance with the German \u2018Tierschutzgesetz in der Fassung vom 18. Mai 2006 (BGBl. I S. 1207)\u2019, which implements the directive 86/609/EEC from the European Union and the European Convention for the protection of vertebrate animals used for experimental and other scientific purposes. The protocol was approved by the ethics committee of MPI-IB and the Berlin state authorities (LAGeSo Reg# G0469/09).P. berghei ANKA and isogenic parasites expressing GFP under the control of the EF1a promoter Female NMRI and C57Bl/6 mice were from Charles River Laboratories. We used P. berghei wild-type (WT) parasites (strain ANKA) \u2212\u0394\u0394Ct method (Applied Biosystems). Expression data was normalized to the constitutive GFP gene expression of P. berghei ANKA GFP parasites For qRT-PCR analyses, mRNA was isolated from schizont-enriched blood stages (merozoites), gametocytes, ookinetes, sporozoites, and 24- and 48-hour liver stages of GFP-expressing P. berghei life cycle, we chose the promoter sequence of the constitutive highly expressed gene HSP70/1 (PBANKA_071190) protein to drive fluorescent mCherry protein expression. An HSP70/1 5\u2032 region of 2,220 bp was selected as promoter sequence and amplified from gDNA using primers HSP70_for and HSP70_rev. The resulting fragment was cloned via EcoRI and BamHI restriction sites into a P. berghei targeting plasmid, termed pSE61 (kindly provided by Dr. Sabine Engelmann). Subsequently, mCherry was amplified from the plasmid B3D+mCherry BamHI and SpeI downstream of the 5\u2032 promoter sequence. mCherry transcript stability was facilitated by cloning of the 3\u2032 UTR of P. berghei dihydrofolate reductase/thymidylate synthase (DHFR/TS) downstream of mCherry. The final plasmid, pHSP70/1::mCherry, was used for P. berghei transfection BstBI-linearized pHSP70/1::mCherry and gradient-purified schizonts of either green fluorescent ANKA parasites (cl507) In order to obtain strong mCherry expression throughout the complete in vivo in asynchronous infections using NMRI mice. Gametocyte differentiation and exflagellation of microgametes were detected in mice before mosquito feedings. Anopheles stephensi mosquito rearing and maintenance was carried out under a 14 h light/10 h dark cycle, 75% humidity and at 28\u00b0C. Once infected, Anopheles mosquitoes were kept at 80% humidity and 20\u00b0C. Sporozoite populations were separated and analyzed as described previously Pbred and WT infected mosquitoes. Pre patency period was determined by daily microscopic examination of Giemsa-stained blood smears. Asexual blood-stage development was investigated by infection of mice with intravenous injection of 1,000 infected erythrocytes. Parasitemia of recipient mice  was monitored daily by examination of Giemsa-stained blood smears.Blood stage development was analyzed Mixed blood stage parasites were obtained by tail vein puncture of infected NMRI mice and imaged live in 37\u00b0C pre-warmed RPMI media on ConcavalinA coated glass cover slips. Ookinetes were cultured for 18 h and purified as described Pbred c507 parasite stages was performed by wide-field fluorescence microscopy using the Apoptome Imager Z2 Microscope (Zeiss) equipped with an AxioCam (Zeiss). For GFP detection filter sets 38 (Zeiss) with excitation BP 470/40 and emission BP 525/50, and for mCherry detection, filter set 43 (Zeiss) with excitation BP 550/25 were used. Whole ex vivo blood samples were imaged in 37\u00b0C pre-warmed RPMI media. Images were captured with the Plan-Apochromat 63\u00d7/1,40 oil objective (Zeiss), and GFP and mCherry signals were measured using same exposure settings of 20 ms to allow direct comparison. To quantify the fluorescence intensity we determined grey values over the parasite area using the software ImageJ and presented our results as the mean of intensity values per pixel. The distribution of grey values in each channel was measured over the parasite area by drawing a \u201cmask\u201d, encircling the parasite, and the cumulative grey values and corresponding pixel numbers calculated with the histogram function of ImageJ. To compare fluorescence intensities of GFP and mCherry between all parasite stages, the mean of grey values (\u00b1 S.E.M.) was calculated. Statistical tests were computed with GraphPad Prism 5.0. Statistical significance for fluorescence intensities was determined using the two-tailed t-test. A P value of <0.05 was taken as significant.Live cell imaging of Figure S1Normal sporozoite formation of Pbred parasites. Sporozoite numbers from WT ) and Pbred  parasites where determined by dissection of salivary glands from infected mosquitoes. Sporozoite numbers are depicted as mean (\u00b1 SEM) from 8 and 11 independent feeding experiments, respectively.(TIF)Click here for additional data file.Table S1Plasmodium berghei Heat Shock Protein 70 (HSP70) members.Overview of (PDF)Click here for additional data file.Table S2Primer sequences.(PDF)Click here for additional data file.Table S3Image analysis.(PDF)Click here for additional data file."}
+{"text": "The fragmented delivery of healthcare and social services as advanced by WHO 2002.This project of international collaboration assesses integrated home care (IHC) for frail elder somatic patients as compared to usual hospital care.The HTA follows the special application for Tele-medicine (MAST). An introductory literature review identified stroke, heart failure (HF) and COPD as prototypes of IHC. Pre-existing evidence has been complemented by additional trials and surveys.1. Definition/organization of IHC:Is carried out by a multidisciplinary team visiting the homeConsiders effectiveness, quality, access and user satisfaction in an economic way and uses Tele-facilities as far as they serve these goalsHas finance across organizational settings.2. Clinical effectiveness of IHC for moderately disabled patients by 6\u201312 months follow-up:Stroke: In 14 randomized trials (n=2139) intervention patients were by meta-analysis significantly less likely (p=0.001) to be dead or dependent compared with conventional care.HF: 2 RCT (n=386) demonstrate each a significant reduction of all-cause readmissions (p=0.003 and p=0.001).COPD: 5 studies  (n=1249) demonstrate each a significant reduction in readmissions/total admission days (p<0.05).3. Health economic evaluation:For each selected condition the first year benefit surmounts the costs of intervention using the Dutch Standardization by Oostenbrink as a common price catalogue across resources/trials/countries.4. Patient satisfaction:Focus group interviews confirm literature findings of very good satisfaction by IHC both among patients/carers and health professionals.Calculated net savings of 1450\u20ac per patient in IHC are not supposed to materialize in \u2018cool\u2019- cash but enables local negotiation of adapted solutions with a minimum of national legislation/finance (Meso-strategy of dissemination).IHC is an approach to clinical continuity for a majority of frail elder somatic patients."}
+{"text": "A 59 year-old woman presented for abdominal pain, fatigue and decreased urine output. Eight months before she underwent a hysterectomy with bilateral salpingo-oophorectomy for a uterine leiomyosarcoma but was diagnosed 6 months later with local recurrence. She refused radiotherapy and palliative chemotherapy but rather preferred alternative treatment with oral high-dose vitamin C. Acute renal failure (ARF) was diagnosed (creatinine 166 versus 48 \u00b5mol/L 2 months before) and urinalysis revealed abundant calcium oxalate. Abdominal scan did not reveal renal obstruction. Renal biopsy showed extensive tubular calcium oxalate crystal deposition with some degree of acute tubular injury and mild interstitial inflammation with eosinophils  and 2. S"}
+{"text": "Three-dimensional myocardial perfusion MRI offers better myocardial coverage than conventionally used two-dimensional methods. bSSFP three-dimensional myocardial perfusion MRI at 3 Tesla potentially offers further improvement of signal characteristics and may enhance the use of three-dimensional myocardial perfusion MRI for clinical application.Twenty-five healthy volunteers and 2 patients were included upon written informed consent and local ethics committee approval. Dynamic contrast-enhanced 3D bSSFP perfusion imaging was performed on a 3 Tesla MRI scanner equipped with dual-source RF transmission technology .Local RF Shimming with dual source RF transmission significantly improved B1 field homogeneity (P=0.0107). For bSSFP perfusion imaging, it allowed a reduction of TR from 3.4 to 2.2 ms at the same flip angle. Image quality was similar for TFE and bSSFP but there were more artefacts for bSSFP , mean SNR was , but signal homogeneity measured in the myocardium was improved .Three-dimensional bSSFP myocardial perfusion MRI using local RF Shimming with dual-source RF transmission at 3 Tesla is feasible with improved signal characteristics. Image artifacts however remain an important limitation.Prof. Plein is funded by British Heart Foundation fellowship FS/10/62/28409 and receives research grant support from Philips Healthcare.Prof. Kozerke receives funding from the Swiss National Science Foundation (grant number CR3213_132671/1) and research support form Bayer (Switzerland) AG. Prof. Nagel receives grant support from Bayer Healthcare and Philips Healthcare."}
+{"text": "Alstr\u00f6m syndrome (ALMS) is a rare autosomal recessive genetic disorder characterised by progressive endocrine disarray, sensorineural deficit, cardiac, renal, and hepatic abnormalities. Idiopathic infantile dilated cardiomyopathy (CMP) is common, presenting acutely in 45% of individuals and recurs or develops de novo in 65% of adolescents with high rates of morbidity and mortality. Myocardial fibrosis has been demonstrated at post-mortem and on MRI with patchy diffuse late gadolinium enhancement (LE) in an older cohort of ALMS patients. We hypothesise that subclinical diffuse fibrosis in young patients with ALMS precedes any change in conventional parameters of ventricular function or overt scarring on LE.Thirteen patients  from the National Specialist Commissioning Group for Alstr\u00f6m Syndrome, Birmingham, UK and matched age and gender controls were prospectively assessed with 2D echocardiography and cardiac MRI (1.5T). Late gadolinium enhancement images were acquired 5-7 minutes after contrast. Myocardial extracellular volume (ECV) was assessed using T1-mapping pre and 15 minutes post gadolinium (0.1mmol/Kg) using a modified look-locker inversion recovery sequence (MOLLI) . Septal myocardial ECV was increased in ALMS compared to controls . Three male older ALMS patients (mean 43 +/- 5 years vs. 27 +/- 10 years) all without a history of infantile CMP, had patchy diffuse LE in non-coronary artery territories with an increased ECV compared to remote \"normal\" myocardium . There were no differences in mean LV mass, LV ejection fraction or LA volume between ALMS and controls. Increased septal myocardial ECV correlated with a reduction in lateral and septal TDI systolic velocities . NT-BNP was not correlated with septal ECV but was increased in patients with LGE (median 178 pmol/L vs. 44 pmol/L).Patients with ALMS demonstrate a spectrum of myocardial fibrosis, which correlates with reduced longitudinal contractility before changes in conventional markers of LV structure and function. This precedes a clinically significant increase in BNP that appears with overt LE and suggests that increased ECV may be a target for early modification of pharmacological therapy.National Commissioning Group"}
+{"text": "Osteoarthritis (OA) is associated with the metabolic syndrome, however the underlying mechanisms remain unclear. We investigated whether low density lipoprotein (LDL) accumulation leads to increased LDL uptake by synovial macrophages and affects synovial activation, cartilage destruction and enthesophyte/osteophyte formation during experimental OA in mice.\u2212/\u2212) mice and wild type (WT) controls received a cholesterol-rich or control diet for 120\u00a0days. Experimental OA was induced by intra-articular injection of collagenase twelve weeks after start of the diet. OA knee joints and synovial wash-outs were analyzed for OA-related changes. Murine bone marrow derived macrophages were stimulated with oxidized LDL (oxLDL), whereupon growth factor presence and gene expression were analyzed.LDL receptor deficient (LDLr\u2212/\u2212 mice). Synovial wash-outs of LDLr\u2212/\u2212 mice and supernatants of macrophages stimulated with oxLDL led to increased transforming growth factor-beta (TGF-\u03b2) signaling compared to controls.A cholesterol-rich diet increased apolipoprotein B (ApoB) accumulation in synovial macrophages. Although increased LDL levels did not enhance thickening of the synovial lining, S100A8 expression within macrophages was increased in WT mice after receiving a cholesterol-rich diet, reflecting an elevated activation status. Both a cholesterol-rich diet and LDLr deficiency had no effect on cartilage damage; in contrast, ectopic bone formation was increased within joint ligaments . Moreover, increased osteophyte size was found at the margins of the tibial plateau (4.4 fold increase after a cholesterol-rich diet and 5.3 fold increase in LDLrLDL accumulation within synovial lining cells leads to increased activation of synovium and osteophyte formation in experimental OA. OxLDL uptake by macrophages activates growth factors of the TGF-superfamily. Osteoarthritis (OA) is a common disease of unknown etiology. The association of OA with metabolic syndrome has long been established but the exact mechanism remains unclear ,2. The iDecreased levels of high-density lipoprotein (HDL) and increased levels of low-density lipoprotein (LDL) particles are, amongst other features, part of the metabolic syndrome . In a coA substantial population of OA patients develops a thickened lining layer comprising macrophages that exhibit an activated phenotype. Macrophages derived from biopsies with early OA produce elevated amounts of pro-inflammatory mediators . DepletiTransforming growth factor-\u03b2 (TGF-\u03b2) and bone morphogenetic proteins (BMP) are important growth factors involved in the formation of new cartilage or bone in ligaments (enthesophyte formation) or along the bone surface (ectopic bone formation or osteophyte formation) . In prev\u2212/\u2212) mice, which are generally used in atherosclerotic research -4743-47]and MMP9 . These eoduction . Studies\u00a0\u03bcg/mL isoduction . AlthougWe did not find osteophyte or enthesophyte formation in na\u00efve knee joints of mice with an LDLr deficiency receiving a cholesterol-rich diet (data not shown). This would suggest that systemically enhanced LDL levels alone are not sufficient to induce joint pathology. Only when there are pro-inflammatory or damage associated stimuli present , may enhanced LDL levels result in increased osteophyte/enthesophyte formation.This study shows for the first time that increased LDL cholesterol levels in an OA milieu are able to enhance ectopic bone formation. Our experimental data points towards a potential mechanism in which uptake of oxLDL by synovial lining macrophages results in activation of TGF-\u03b2 and to a lesser extent BMP. Further research is needed in order to elucidate what factors in particular are responsible for the enhanced levels of active TGF-\u03b2 and BMP, since direct production does not seem to increase according to mRNA expression levels. Nevertheless, this mechanism provides a firm step forward to unraveling possible factors affecting etiopathology of OA and osteophyte formation in particular.ApoB: Apolipoprotein B; BMP: Bone morphogenetic proteins; BRE-Luc: Bone morphogenetic protein responsive element luciferase reporter plasmid; BSA: Bovine serum albumin; CAGA-Luc: CAGA-box luciferase reporter plasmid; Ct: Threshold cycle; DAB: Diaminobenzidine; (D)MEM: (Dulbecco\u2019s) Modified Eagle\u2019s Medium; FCS: Fetal calf serum; GFP: Green fluorescent protein; HDL: High-density lipoprotein; H & E: hematoxylin and eosin; IL: Interleukin; LDL: Low-density lipoprotein; LDLr\u2212/\u2212: Low-density lipoprotein receptor deficient; LOX-1: Lectin-like oxidized low-density lipoprotein receptor-1; M-CSF: Macrophage colony stimulating factor; MMP: Metalloproteinase; OA: Osteoarthritis; oxLDL: Oxidized low-density lipoprotein; PBS: Phosphate-buffered saline; qPCR: Quantitative real-time polymerase chain reaction; TGF-\u03b2: Transforming growth factor-\u03b2; TNF-\u03b1: Tumor necrosis factor-alpha; WT: Wild type.The authors declare that they have no competing interests.WdM, AB and PvL were involved in conception and design of the study, acquisition and analysis of data, and interpretation of data. MH and BW were involved in performing animal experiments and acquisition of histological data. PvdK, LJ and WvdB were involved in conception and design of the study. All authors have been involved in revising the manuscript. All authors read and approved the final manuscript."}
+{"text": "Animal models have demonstrated a recovery in systolic strain following reperfusion of acutely ischemic myocardium, however this has not been shown in clinical practice.We aimed to determine whether there was long term improvement of regional strain in acutely ischemic myocardium following primary coronary intervention using cardiac magnetic resonance imaging (CMR)We studied 16 patients with acute ST elevation myocardial infarction (STEMI) who had received successful primary coronary intervention (PCI) to the culprit coronary artery. CMR was performed on a 1.5T Philips Achieva system  within 7 days of PCI and again at 1 year. We used segmentation of T2-weighted spectrally-selective inversion recovery (SPIR) imaging to detect the ischemic area-at-risk and delayed enhancement inversion recovery imaging to measure infarct size and transmural thickness. Complementary spatial modulation of magnetization (CSPAMM) tagging with harmonic phase analysis (HARP) was used to measure peak midwall systolic strain at baseline and follow-up. Each section was divided according to the American Heart Association classification providing a total of 96 myocardial segments for analysis at each visit.2=0.01, NS).All patients showed acute myocardial edema within the reperfused territory and a variable transmural extent of enhancing necrosis. Mean myocardial salvage, given as the proportion of viable myocardium within the ischemic area-at-risk, was 62\u00b121% at baseline. The mean infarct area at baseline was 20\u00b110.2% and 14\u00b15.7% at 1 year follow-up. In total 45 segments showed enhancing necrosis and the peak systolic midwall circumferential strain (Ecc) improved between baseline and follow-up . In the remaining non-infarcted 45 segments there was no change in Ecc . The mean radial transmural extent of necrosis showed no correlation with \u0394Ecc (rThese findings demonstrate a long-term improvement in systolic function in acutely ischemic reperfused myocardium."}
+{"text": "Chloroacetaldehyde (CAA) is a chlorination by-product in finished drinking water and a toxic metabolite of a wide variety of industrial chemicals  formation and glutathione depletion suggesting that oxidative stress contributed to the CAA cytotoxic mechanism. CAA-induced oxidative stress cytotoxicity markers were significantly prevented by antioxidants, ROS scavengers, mitochondrial permeability transition (MPT) pore sealing agents, endocytosis inhibitors, ATP generators and xanthine oxidase inhibitor. In our study the hepatocyte mitochondrial membrane potential was rapidly decreased by CAA which was prevented by antioxidants and ROS scavenger indicating that mitochondrial membrane damage was a consequence of ROS formation. CAA cytotoxicity was also associated with lysosomal membrane rupture. 450 and xanthine oxidase, mitochondrial respiratory chain disruption and lysosomal Haber-weiss reaction, were involved in CAA induced ROS formation and other subsequent cytotoxic events. Our other interesting finding was that the lysosomotropic agents prevented CAA induced mitochondrial membrane potential collapse and mitochondrial MPT pore sealing agents inhibited lysosomal membrane damage caused by CAA. It can therefore be suggested that there is probably a toxic interaction  between mitochondrial and lysosomal oxidative stress generating systems, which potentiates each organelle damage and ROS formation in CAA- induced hepatotoxicity. Our findings showed that at least four different intracellular sources including: metabolic enzymes cytochrome P With the advent of synthetic polymers in the industrial world, many chemicals are releasing into the environment in large quantities. Similarly, many chemicals are used as pesticides or as food preservatives have caused a series of environmental problems. Halogenated hydrocarbons are a main group of these environmental contaminants and some of these have been shown to be carcinogenic whereas others are mutagens and several of these compounds bind to DNA -2. Vinyl2H3Cl; CCA), an organic compound, is an alkylating agent and potent mutagen that specifically generates ethenobase DNA lesions . Chloroacetaldehyde  techniques. \u03b1- Tocopherol and butylated hydroxytoluene or BTH), radical scavengers (mannitol and DMSO), MPT pore sealing agents (carnitine and Trifluoperazine), endocytosis inhibitors (chloroquine and methylamine), ATP generators (fructose and L-glutamine), xanthine oxidase inhibitor (oxypurinol) as well as NADPH P450 reductase inhibitor (diphenyliodonium chloride) and reduced CYP2E1 inhibitor (phenylimidazole) for predicting of exact cellular and molecular mechanisms involved in CAA hepatotoxicity .In this investigation, we tested several classes of inhibitors and antagonists (based on our speculations and previous published works) including antioxidants , bovine serum albumin (BSA), N-(2-hydroxyethyl)piperazine-N\u2019-(2-ethanesulfonic acid) (HEPES), O-phthalaldehyde, Acridine orange, 2\u2019,7\u2019-dichlorofluorescin diacetate (DCFH-DA), Trichloroacetic acid, dimethyl sulfoxide (DMSO), 1-Bromoheptane, butylated hydroxytoluene, diphenyliodonium chloride, Trypan blue and heparin were purchased from Sigma-Aldrich Co. . All other chemicals were of the highest commercial grade available.Chloroacetaldehyde (CAA), rhodamine 123, collagenase  and an environmental temperature of 21-23 \u00b0C with a 50-60% relative humidity. The animals were fed with a normal standard chow diet and tap water ad libitum. All experiments were conducted according to the ethical standards and protocols approved by the Committee of Animal Experimentation of Shaheed Beheshti University of Medical Sciences, Tehran, Iran.Isolation and incubation of hepatocytes6 cells/mL in round-bottomed flasks rotating in a water bath maintained at 37\u00b0C in Krebs-Henseleit buffer (pH = 7.4), supplemented with 12.5 mM HEPES under an atmosphere of 10% O2, 85% N2, and 5% CO2 (Hepatocytes were obtained by collagenase perfusion of the liver and viability was assessed by plasma membrane disruption determined by trypan blue (0.2 w/v) exclusion test . Cells wd 5% CO2 . Hepatocd 5% CO2 .Determination of EC50 for CAA50 concentrations for CAA. As described by Galati et al. 2000, the EC50 of a chemical in hepatocyte cytotoxicity assessment technique  is defined as the concentration, which decreases the hepatocyte viability down to 50% following the 2 h of incubation  (data and curves not shown). Finally, the concentration of 300 \u03bcm (EC50) was selected for examination in our study.To avoid either non-toxic or very toxic conditions in this study, we used ECcubation . All tesCell viabilityThe viability of isolated hepatocytes was assessed from the intactness of the plasma membrane as determined by the trypan blue (0.2% w/v) exclusion test , 20. AliDetermination of reactive oxygen species6 cells (To determine the rate of hepatocyte reactive oxygen species (ROS) generation induced by CAA, dichlorofluorescin diacetate (DCFH-DA) was added to the hepatocytes. It penetrates hepatocyte cells and becomes hydrolyzed to non-fluorescent dichlorofluorescin (DCFH). The latter then reacts with ROS to form the highly fluorescent dichlorofluorescein (DCF), which effluxes the cell. The fluorescence intensity of DCF was measured using a Shimadzu RF5000U fluorescence spectrophotometer. Excitation and emission wavelengths were 500 and 520 nm, respectively. The results were expressed as fluorescent intensity per 106 cells .Intracellular GSH and extra cellular GSSG assessment GSH and GSSG were determined according to the spectrofluorometric method . Each saMitochondrial membrane potential assayMitochondrial uptake of the cationic fluorescent dye, rhodamine123, has been used for estimation of mitochondrial membrane potential  followed by Tukey\u2019s HSD as the 502h concentration found for CAA was 300 \u03bcM. As shown in \u03b1-Tocopherol and BHT), radical scavengers (mannitol and DMSO), MPT pore sealing agents (carnitine and Trifluoperazine), endocytosis inhibitors (chloroquine and methylamine), ATP generators (fructose and L-glutamine), xanthine oxidase inhibitor (oxypurinol) as well as by NADPH P450 reductase inhibitor (diphenyliodonium chloride) and reduced CYP2E1 inhibitor (phenylimidazole) (At least 80-90% of the control cells were viable following 3 h of incubation. The ECidazole) , 2. 450 reductase inhibitor, reduced CYP2E1 inhibitor and 1-bromoheptan (used for GSH depleting) did not significantly (p < 0.05) increase hepatocyte membrane lysis and ROS formation at concentrations used while incubated alone in isolated hepatocytes (Data not shown). Our results also showed that depleting hepatocyte glutathione (GSH) beforehand could increase the CAA induce hepatocyte cytotoxicity and ROS formation. All of the reagents used including antioxidants, radical scavengers, MPT pore sealing agents, endocytosis inhibitors, ATP generators, xanthine oxidase inhibitor, NADPH P\u03b1- Tocopherol and BTH), radical scavengers (mannitol and DMSO), MPT pore sealing agents (carnitine and Trifluoperazine), endocytosis inhibitors (chloroquine and methylamine), ATP generators (fructose and L-glutamine), xanthine oxidase inhibitor (oxypurinol), NADPH P450 reductase inhibitor (diphenyliodonium chloride) and reduced CYP2E1 inhibitor (phenylimidazole) significantly (p < 0.05) prevented both CAA induced hepatocyte intracellular GSH decrease and extracellular GSSG increase (As shown in increase . All of \u03b1-Tocopherol and BTH) and radical scavengers (mannitol and DMSO) suggesting that CAA induced mitochondrial membrane potential decrease was subsequent of ROS formation. In addition xanthine oxidase inhibitor (oxypurinol), NADPH P450 reductase inhibitor (diphenyliodonium chloride) and reduced CYP2E1 inhibitor (phenylimidazole) inhibited decline of mitochondrial membrane potential. CAA induced hepatocyte mitochondrial membrane potential collapse was also potentiated when CAA was incubated in GSH depleted hepatocytes. All of these mentioned inhibitors did not show any significant effect (p < 0.05) on hepatocytes mitochondrial membrane potential at concentrations used while incubated alone (Data not shown). As shown in \u03b1-Tocopherol and BTH), radical scavengers (mannitol and DMSO), ATP generators (fructose and L-glutamine), xanthine oxidase inhibitor (oxypurinol), NADPH P450 reductase inhibitor (diphenyliodonium chloride) and reduced CYP2E1 inhibitor (phenylimidazole) (When hepatocyte lysosomes were loaded with acridine orange (a lysosomotropic agent), a significant release of acridine orange into the cytosolic fraction ensued within 120 min of incubation with CAA indicating a severe damage to lysosomal membrane . CAA- inidazole) . Again dThe interesting finding was that CAA induced hepatocyte mitochondrial membrane potential collapse prevented by lysosomotropic agent (chloroquine and methylamine) and on the other hand lysosomal membrane leakiness induced by CAA were also prevented by mitochondrial MPT pore sealing agents (carnitine and Trifluoperazine)  and 5.e.g. vinyl chloride) and chemotherapeutic agents (e.g. cyclophosphamide and ifosfamide)  is a toxic metabolite of a wide variety of industrial chemicals (sfamide) -25.In prsfamide) , 26. Howsfamide) . It was sfamide) . It was tegrity. , 26-27.i.e. glutathione and coenzyme A derivatives that ultimately result in cellular oxidative damage  causes oxidative stress in different cells  against CCA-induced cytotoxicity.It is proven that oxidative stress establish with an imbalance between the production and removal of ROS. Therefore, overproduction of these substances or significant depletion of antioxidant defense molecules , xanthine oxidase inhibitor (oxypurinol), mitochondrial pore sealing agents (carnitine and Trifluoperazine) and lysosomotropic agents (chloroquine and methylamine) suggesting that at least four different intracellular sources: cytochrome P450, xanthine oxidase, metal destructive interaction, mitochondrial electron transfer chain disruption and lysosomal Haber\u2013Weiss reaction are involved in CAA induced ROS formation and its subsequent cytotoxic events. On the other hand, CYP2E1 is one the most powerful inducers of oxidative stress in liver cells . CYP2E1 ubstrate -37. In oOur results showed that hepatocyte mitochondrial membrane potential was rapidly decreased by CAA .CAA induced mitochondrial membrane decrease was prevented by ROS scavengers, antioxidants, mitochondrial ATP generator (glutamine), MPT pore sealing agents (carnitine) and glycolytic substrates (fructose) indicating that mitochondrial membrane damage was a consequence of ROS formation and cellular energy depletion. Furthermore, the ATP generators prevented CAA- induced cytotoxicity and ROS generation suggesting that the collapse may be a consequence of MPT pore opening and ATP depletion. The \u0394\u03a8m is maintained by continuous pumping of protons from the matrix across the inner mitochondrial membrane into the inter-membrane space. Because these protons in turn are used to drive the ATP synthase, a collapse of the \u0394\u03a8m invariably results in compromised ATP synthesis . Any damLysosomes are one of the intracellular sources for ROS generation in toxic conditions . Haber-w450 monooxygenase (CYP2E1) and xanthine oxidase leads to considerable free radical formation. Increased ROS formation could directly damage hepatocyte mitochondria via MPT pore opening, cytochrome c expulsion and disruption of electron transfer chain. Hydrogen peroxide (H2O2) originated either from CAA metabolic activation or damaged mitochondria diffuses into lysosomes (due to lipophilic nature) and a Fenton type reaction (Haber- weiss) catalyzed by intra-lysosomal redox-active Fe2+/Fe3+ occurs. This leads to highly reactive hydroxyl radical (HO.) generation. Hydroxyl radicals could destabilize the lysosomal membrane integrity and release of digestive proteases (i.e. cathepsins). These released proteases and hydroxyl radicals could either open the mitochondrial MPT pore via oxidation of surrounding thiol groups or through activation of Bid or Bax pro-apoptotic proteins and other lytic enzymes including phospholipase A2 (PLA2). Disruption of electron transfer chain potentiates mitochondrial H2O2 generation and continues the cycle of mitochondrial/lysosomal oxidative stress toxic cross-talk that accelerates CAA hepatocyte toxicity (Metabolic activation of CAA through cytochrome Ptoxicity .In our study CYP2E1 inhibitor and xanthine oxidase inhibitor perfectly prevented toxicity markers including: cytotoxicity, ROS formation, GSH depletion, mitochondrial membrane potential decrease and lysosomal membrane rupture. Therefore, it can be suggested that shared metabolism of CAA with CYP2E1 and xanthine oxidase is a primary event in CAA toxicity that leads to ROS formation. Excessive ROS targets mitochondria and lysosomes and causes oxidative stress membrane damages in both sub-organelles. Finally, mitochondrial/ lysosomal toxic cross-talk potentiates oxidative stress that accelerates CAA hepatocyte cytotoxicity."}
+{"text": "The innate immune recruiting property of antibodies are elicited following an Fc/Fc-receptor interaction. We previously demonstrated that HIV-specific antibodies from elite controllers (ECs) robustly recruit NK cells to mediate antibody dependent cellular viral inhibition (ADCVI) compared to antibodies from chronic progressors. To gain further insights into the biophysical properties of EC antibodies that enable them to recruit Fc-effector functions so robustly, we performed at 24 dimensional analysis  of the antibody profiles mounted in ECs and HIV-progressors to define the humoral signature(s) associated with most robust innate immune recruiting activity.A total of thirty donors were included in this study . Anti-gp120, p24, gp41 and gp140 antibody binding titers were quantified by ELISA and a customized-multiplex HIV binding assay against HIV recombinant gp120, p24, gp41 and gp140. Fc-receptor affinity was analyzed by Biacore. ADCVI, ADCC, and ADCP were quantified as previously described.While no differences were observed in the antibody binding titer between ECs and chronic progressors against gp120 or gp41, we showed that ECs exhibited a higher level of p24-specific antibodies, associated with robust ADCVI activity. Moreover, humoral responses in ECs were skewed toward IgG1 and IgG3 responses, compared to chronic progressors, that strongly predicted enhanced ADCVI activity. Similar skewing of antibody responses were observed in RV144 vaccinees, strongly suggesting that specific cues elicited within this vaccine trial may have resulting in the induction of highly potent innate immune recruiting antibodies similar to those found in ECs.Overall, ECs elicit a skewed humoral immune response marked by the preferential selection of HIV specific IgG1 and IgG3 antibody subclasses, that parallels the humoral immune responses observed in RV144 vaccinees. Therefore, characterizing these unique antiviral capacities may provide critical information on humoral responses that could potentiate vaccine-induced responses."}
+{"text": "Dobutamine stress magnetic resonance  has been established as a valuable tool for the detection of inducible wall motion abnormalities. Additional perfusion imaging during DSMR (DSMR-perfusion) was shown to improve sensitivity for the detection of myocardial ischemia. Current experience is based on 1.5T only, mainly due to insufficient image quality of steady state free precession (SSFP) cine imaging at higher field strengths. Recently, image quality and diagnostic accuracy of SSFP sequences was significantly improved by dual-source parallel radiofrequency (RF) transmission for 3.0T. We examined whether the addition of myocardial perfusion imaging during DSMR at 3.0T is feasible and whether it provides incremental benefit for the evaluation of CAD.DSMR-wall motion and -perfusion were combined in 48 consecutive patients on 3.0T clinical systems  applying a standard high dose dobutamine-atropine protocol. Perfusion images were acquired in three short axis views during maximum stress. Wall motion and perfusion images were interpreted sequentially by two blinded readers with invasive coronary angiography serving as the reference standard.Assessment of wall motion and perfusion at rest and during stress were feasible in 98% of patients. One patient (2%) developed atrial fibrillation during dobutamine infusion and the examination had to be terminated. Two patients (4%) developed wall motion abnormalities before reaching target heart rate and DSMR-perfusion was performed at this time. Mean dobutamine dose was 32\u00b18 \u00b5g/kg/min, atropine was given in 28 (58%) patients. Interobserver agreement was very good for DSMR-wall motion (\u03ba 0.88) and -perfusion (\u03ba 0.83). The prevalence of CAD (>70% stenosis) was 64% and involved 45 coronary territories. On a patient basis, diagnostic accuracy of DSMR-wall motion and DSMR-perfusion were similar (Table). DSMR-wall motion correctly identified 28 (62%) territories supplied by a stenotic coronary artery, whereas DSMR-perfusion correctly identified significantly more ischemic territories . The ability to recognize a patient as having multivessel disease by more than one territory demonstrating an ischemic reaction was improved significantly by use of DSMR-perfusion .DSMR-perfusion is feasible with a high procedural success rate at 3.0T applying dual-source RF transmission and has additional diagnostic value compared to DSMR-wall motion regarding the extent of stress inducible ischemia.none"}
+{"text": "Myocardial scar burden, measured by delayed hyperenhancement cardiac magnetic resonance (DHE-CMR), is an independent predictor of mortality in patients with ischemic cardiomyopathy (ICM) and severe left ventricular (LV) systolic dysfunction. It is unknown if myocardial scar burden impacts the protective benefit of implantable cardioverter defibrillators (ICDs).In patients with severe ICM, we sought to assess the impact of LV myocardial scarring and ICD implantation on survival in patients with severe ICM.Patients (n = 337) with \u2265 70% disease in \u22651 epicardial coronary artery  undergoing CMR  between 2003-2007 were studied. CMR evaluation included long and short axis assessment of LV function on steady state free precession cine images along with assessment of myocardial scar (on inversion recovery DHE-CMR sequence ~ 10-20 minutes after injection of 0.2 mmol/kg of Gadolinium dimeglumine). Scar was identified as regions of interest > 2 SD above normal myocardium. LV scar was categorized based on mean scar % and transmural extent . Total scar score was determined from the summed scar score of 17 segments per patient divided by 17. 94 patients underwent subsequent ICD implantation. The composite end-point was cardiac transplantation and all-cause mortality. Results: Over a follow-up of up to 8 years, there were 107 events . Receiver operating characteristic curve analysis was used to select the optimum threshold of mean scar % \u2265 33%, total scar score \u2265 2.3 to predict death/transplantation. On multivariate variate analysis, only age, total scar score, diabetes, gender, and ICD implantation were independent predictors of mortality/transplantation (Table In patients with ICM and severe LV dysfunction, ICD provides mortality benefit, irrespective of myocardial scar burden. Nonetheless, scar burden remains a powerful predictor of mortality/cardiac transplantation even after ICD implantation."}
+{"text": "In pulmonary arterial hypertension (PAH) increased pressure and resistance in the pulmonary vascular bed cause right ventricular (RV) hypertrophy with increased myocardial oxygen demand. Studies in animals with RV hypertrophy demonstrated maintained resting but reduced stress perfusion and coronary perfusion reserve, which may contribute to RV failure.The purpose of our study was to investigate myocardial perfusion by comparing coronary sinus flow reserve (CFR) between PAH patients and healthy controls and to correlate CFR with biventricular function and pulmonary hemodynamics using magnetic resonance imaging (MRI).norm = CSF/RPP). CFR was calculated by dividing stress CSF by resting CSFnorm (CFR = Stress CSF / Rest CSFnorm).Thirty-one patients with known or clinically suspected PAH underwent right heart catheterization (RHC) and 3T cardiac MRI on the same day. Twenty patients were found to have PAH, eleven patients did not have PAH. Seventeen age- and gender-matched healthy volunteers were also studied with MRI. Rest and adenosine-stress coronary sinus flow (CSF) were measured with phase contrast MRI Figure  and adju2 (area under the ROC curve 0.81 (95% CI: 0.55-1.00); sensitivity 83.3%, specificity of 85.7% for a threshold value of 1.67).CFR for PAH patients was significantly lower (2.22 1.40-3.22]) than for controls  (Table .40-3.22)PAH patients have a reduced CFR compared to healthy volunteers, which correlates with pulmonary hemodynamics and RV dysfunction. A decreased CFR is predicted by RV mass and may contribute to RV failure. Further studies are warranted to investigate the predictive value of CFR with regards to patient outcome."}
+{"text": "Dnmt3a hepatic mRNA levels decreased accompanying the high-fat-sucrose consumption. Furthermore, a negative association between Dnmt3a liver mRNA levels and plasma homocysteine concentrations was found. Maternal high-fat-sucrose diet during lactation could program offspring obesity features, while methyl donors supplementation prevented the onset of high hyperhomocysteinemia. Maternal dietary intake also affected hepatic DNA methylation metabolism, which could be linked with the regulation of the methionine-homocysteine cycle.Maternal perinatal nutrition may program offspring metabolic features. Epigenetic regulation is one of the candidate mechanisms that may be affected by maternal dietary methyl donors intake as potential controllers of plasma homocysteine levels. Thirty-two Wistar pregnant rats were randomly assigned into four dietary groups during lactation: control, control supplemented with methyl donors, high-fat-sucrose and high-fat-sucrose supplemented with methyl donors. Physiological outcomes in the offspring were measured, including hepatic mRNA expression and global DNA methylation after weaning. The newborns whose mothers were fed the obesogenic diet were heavier longer and with a higher adiposity and intrahepatic fat content. Interestingly, increased levels of plasma homocysteine induced by the maternal high-fat-sucrose dietary intake were prevented in both sexes by maternal methyl donors supplementation. Total hepatic DNA methylation decreased in females due to maternal methyl donors administration, while  One of 12, which may prevent the transgenerational amplification of obesity by epigenetically silencing the murine agouti transposon  . Twenty-five microlitres from each reaction were applied on Whatman DE-81 ion-exchange filters  and air-dried for 1.5 h. Then, filters were washed three times with Sodium-Phosphate buffer  and radioactivity levels were measured by liquid scintillation counting . Background results were subtracted from enzyme-treated samples and global DNA methylation calculated as previously described [Global DNA methylation was measured using the [3H]dCTP extension assay. Briefly, about 300 ng of genomic DNA  was performed by triplicate using ABI PRISM 7900 HT Fast real-time PCR system  and Taqman primers  for Dnmt1 (Rn00709664_m1*), Dnmt3a (Rn01027162_g1*) and Dnmt3b (Rn01536419_m1). Fold change between groups was calculated using the 2\u2212\u0394\u0394Ct method. cDNA integrity was checked with 18S (Hs99999901_s1) probe and gene expression levels were normalized with respect to beta-actin (Rn00667869_m1*) as internal control.Quantitative real-time PCR (3.7.vs. HFS + HFS supp) plus the effect of Supplementation (C + HFS vs. C supp + HFS supp). This statistical test is also able to define interactions between both factors by DMS post hoc test for multiple comparisons. Male and female offspring were separately analyzed due to sexual dimorphism. Pearson\u2019s rank correlation was also used to analyze Dnmt3a liver mRNA and plasma homocysteine levels potential association. The statistically significant probability was set at p < 0.05. All the statistical analyses were performed with SPSS 15.0 program for Windows .Results are expressed as means \u00b1 standard error (SE). Maternal features during pregnancy and before lactation were assessed using one way ANOVA. Offspring outcomes were assessed using 2 \u00d7 2 factorial ANOVA tests (Diet \u00d7 Supplementation); effect of obesogenic diet intake (C + C supp 4.In conclusion, maternal high-fat sucrose dietary intake during lactation could program offspring obesity-related physiological features in both sexes. Interestingly, maternal supplementation with a micronutrient cocktail based on methylation donor substrates appears to protect against plasma hyperhomocysteinemia, probably affecting key metabolic enzymes involved in the methionine-homocysteine cycle."}
+{"text": "Gait parameters such as excessive pronation have been suggested as contributing to the development of hallux valgus (HV). HV has also been linked to functional disability in older adults. However, the literature investigating gait parameters in HV has not previously been systematically evaluated.A systematic review was conducted, searching electronic databases to October 2011. Cross-sectional studies with clearly defined HV and non-HV groups were included. Two investigators rated papers for methodological quality. Effect sizes ) were calculated as standardized mean differences (SMD) for continuous data and risk ratios (RR) for dichotomous data.Nine papers were included . One study showed that during terminal stance HV participants had reduced ankle dorsiflexion  and less rearfoot supination  compared to controls. In another study HV participants showed early onset of intrinsic muscle activity . Four studies investigating spatio-temporal parameters found no significant differences between groups, although one study found reduced speed (SMD -0.73), step length (SMD -0.66 to -0.59) and less stable gait patterns (SMD -0.86 to -0.78) in older adults with moderate to severe HV. Six studies investigated plantar pressures with inconsistent findings.Altered gait kinematics and muscle activity are apparent in HV, and these parameters warrant further investigation. Although conclusions regarding causality cannot be drawn from cross-sectional studies, interventions targeting these parameters may improve clinical outcomes in HV."}
+{"text": "Dobutamine stress magnetic resonance imaging (DSMR) has consistently high diagnostic and prognostic utility. Its value for clinical decision making still needs to be defined. Hence, the purpose of this study was to assess the role of DSMR regarding clinical management of patients with suspected and known coronary artery disease (CAD) in a routine setting.Standard DSMR was performed in 1532 consecutive patients with suspected and known CAD. Patients were stratified according to the results of DSMR: DSMR-positive patients were recommended to undergo invasive coronary angiography and DSMR-negative patients received optimal medical treatment. Of 609 (40%) DSMR-positive patients coronary angiography was performed in 478 (78%) within 90 days. In 409 of these patients significant coronary stenoses  were present (sensitivity 86%). Of 923 (60%) DSMR-negative patients 833 (90%) received optimal medical therapy. During a median follow-up period of 2.1 years 8 DSMR-negative patients (0.96%) sustained a cardiac event.In 131 DSMR-positive patients who did not undergo invasive angiography, 20 patients (15%) suffered cardiac events. In 90 DSMR-negative patients (10%) invasive angiography was performed within 2 years (range 0.01 to 2.0 years) with 56 patients having coronary stenoses \u226550%. Figure DSMR can be used as an arbiter in a routine setting for clinical decision making and has high utility for clinical management of patients with suspected and known CAD."}
+{"text": "Nosocomial rhino sinusitis causes major problems in all Intensive Care Units (ICUs).To describe incidence, epidemiologic, clinical manifestations, and microbiologic findings in ICUs admitted cases with nosocomial sinusitis.A prospective, cross sectional study done in Pediatric & Adult ICUs in Rasoul Akram Hospital; Tehran Iran (2007-2008). Para-nasal sinus computed tomography (CT) was performed in all adults with fever of unknown origin (FUO) within 48h of admission and repeated thereafter (4-7 days). Infectious sinusitis was diagnosed by microbiological analysis of sinus fluid aspirates.S. aureous, Streptococus spp). The remainders  consisted of mixed aerobic/anaerobic bacteria.Acute bacterial nosocomial sinusitis proved in 82% (51/ 63) of all cases. Head trauma was the most common cause;  of cases. The results of culture were positive for 45 cases (82%). Of 45 culture positives, 19 yielded Gram negative organisms (41%) and 9 (22%) gave Gram positives (S. pneumonia (n = 5), Hemophilus influenza (n = 2). The type of organisms were not related to Glasgow Coma Scale in cases (P = 0.3).Seven cases, were positive in gram staining of sinus drainage and these were positive in culture for Nosocomial organisms isolated were quite different from community acquired rhino sinusitis cases. Investigation of CT scan and drainage of Para-nasal sinuses would be helpful in undiagnosed FUO cases, especially in traumatic patients. Optimal treatment usually consists of removal of the tubes, mobilizing the patient, and administration the broad-spectrum antibiotics. Para nasal sinuses are a common place for infection in children and adults , 2. CommCareful search for nosocomial rhinosinusitis and appropriate treatment is needed to decrease both morbidity, mortality and subsequent other nosocomial infections \u201311. SomeLevin et al., reported nosocomial rhino sinusitis with imipenem-resistant Acinetobacter spp . This study was approved by the Ethical Committee in the Research Center of Pediatric Infectious Diseases in Tehran University of Medical Sciences.Consent letter obtained from patients (or parents). Initially a questionnaire was completed by an authorized physician, followed by complete clinical exams. Para nasal sinus CT was performed only in all adult cases with FUO (but not in children) within 48h of admission in ICU and repeated thereafter ( 4-7 days) if no obvious cause revealed after initial clinical and diagnostic screening .Well-defined nosocomial rhino sinusitis cases selected according to CDC criteria .Phenylephrine drop (0.5%) used by physician in middle meatus of selected cases for antral drainage. Direct smear from the sinus materials were prepared and stained. The specimens were also cultured in both aerobic and anaerobic BACTEC media (Becton Dickenson company) in automated system (BioMerieux). Isolates were identified using the standard techniques .Infectious rhino sinusitis was diagnosed if the specimens were positive in Gram staining (direct smear)/ or positive in rapid antigen detection test (Latex Particle Agglutination). Isolation and identification of organisms from sinus fluid aspirates was also used for diagnosis.Patients admitted at ICUs > 48 hours) who fulfilled criteria of nosocomial rhinosinusitis according to CDC criteria were included in this study (8 hours w1) adults cases diagnosed as community acquired rhino sinusitis revealed with abnormality in the first CT scan. Diagnostic parameters for community acquired rhino sinusitis in children based on clinical history/ or imaging diagnostic parameters for rhino sinusitis criteria before admission; 2) Another site for infection concomitant with rhino sinusitis .63 cases had a full CDC criterion and followed for nosocomial rhino sinusitis. 55.8% males, 42.3% females. Cases were between 1-86 years; mean age = 17 + 25 years 58.8% of studied cases (n = 30) aged less than 10 years .Head trauma was the most common cause for ICUs admission in 45% (n = 22),other medical diseases : 20.4% (n = 10),brain tumour: 16.3% (n= 8),Cerebral palsy: 2%, face abnormality: 2%.Glasgow Coma Scale (GCS) < 7 observed in 74.4% (n = 32), 86.5% (n = 32) had NGT (nasogastric tube), 77.8% (n = 43) cases received anti convulsive drugs.K. pneumoniae, P. aeruginosa and Acinetobacter spp.) in 41% (n = 19) Gram positive organisms  in %22 (n = 9) and mixed aerobic/anaerobic organisms in 37% (n = 17) of cases.Allergic rhino sinusitis diagnosed in 18% (n = 12) of studied cases. Acute bacterial nosocomial rhino sinusitis proved in 82% (51/63). Positive sinus cultures included Gram negative organisms . Mean age of cases for Gram negative organisms was seven years; for S. aureus 14 years; mixed aerobic/anaerobic infection 27 years. We did not observe any correlation between type of organisms and GCS in cases; (P = 0.3).Seven patients (with negative culture) were positive in Gram staining of smear or in rapid antigen detection test (Latex Particle Agglutination) in sinus material included. . Themajority of diagnosed cases (20.4%) had medical diseases . If a careful search for this disease and appropriate treatment are found, decrease in morbidity, mortality and subsequent other nosocomial infections would happen  in %22; Gram negative organisms  in 41% (n = 19), mixed aerobic/anaerobic organisms in 37% (n = 17) of cases. Similarly, Stein et al. described nosocomial sinusitis which frequently isolated Staphylococcus spp., Pseudomonas spp. and other nosocomial organisms , followed by E. coli (13.7%) and Klebsiella spp. (12%). They did not report any vancomycin-resistant strains of S. aureus. Rifampin and ciprofloxacin had good activity against most of Gram-positive and Gram-negative organisms , while 48.7% of Klebsiella spp were ESBL-producing isolates. 15% of S. aureus were oxacillin-resistant. Carbapenems were highly active against Enterobacteriaceae  strains with cephalosporines resistance (Nosocomial rhino sinusitis is a well-recognized but insufficiently understood complication of critical illness in patients admitted by ICU in our center. Barati nfection . Here, wr center . Acinetorganisms . The mossistance In conclusion, nosocomial organisms isolated were quite different from community acquired rhino sinusitis cases. Investigation of CT scan and drainage of para-nasal sinuses would be helpful in undiagnosed FUO cases, especially in traumatic patients. Optimal treatment usually consists of removal of the tubes, mobilizing the patient, and administration the broad-spectrum antibiotics."}
+{"text": "Gene Parity Plots revealed a 28.8 kb region conserved among the alpha- and beta-baculoviruses. Overall comparisons of BusuNPV to other baculoviruses point to a distinct species in group II Alphabaculovirus.The genome of Buzura suppressaria nucleopolyhedrovirus (BusuNPV) was sequenced by 454 pyrosequencing technology. The size of the genome is 120,420 bp with 36.8% G+C content. It contains 127 hypothetical open reading frames (ORFs) covering 90.7% of the genome and includes the 37 conserved baculovirus core genes, 84 genes found in other baculoviruses, and 6 unique ORFs. No typical baculoviral homologous repeats ( Baculovirdae is an insect-specific family of viruses with double stranded circular DNA genomes of 80 kb \u2013180 kb. Among the so far sequenced baculoviruses, Xestia c-nigrum granulovirus (XecnGV) has the largest genome  with the smallest in the Neodiprion lecontei nucleopolyhedrovirus  Gammabaculovirus, two distinct progeny phenotypes are produced, the budded virus (BV) that disseminates systemically and the occlusion derived virus (ODV) required for oral infectivity The Baculoviridae is classified into 4 genera: Alphabaculovirus (NPVs isolated from Lepidoptera); Betabaculovirus (GVs isolated from Lepidoptera); Gammabaculovirus (NPVs isolated from Hymenoptera) and Deltabaculovirus (NPVs isolated from Diptera) Alphabaculovirus are further clustered into groups I and II based on phylogenetic analyses and the presence or absence of the gp64 gene. Only group I contains gp64 gene while group II has a gene encoding fusion protein (F) The family Buzura suppressaria is a pest insect of tea, tung oil, citrus and metasequoia plants. The Buzura suppressaria NPV (BusuNPV) was first isolated from dead larva of B. suppressaria and subsequently used as an insecticide against this pest pep), the conotoxin-like protein gene (ctl), the inhibitor of apoptosis (iap), superoxide dismutase (sod) Alphabaculovirus with a genome distinct from other so far sequenced baculoviruses.The genome of BusuNPV was sequenced using the Roche 454 GS FLX system with shotgun strategy. A total of 97,246 reads were obtained with the average length of 340 bp. The BusuNPV genome was assembled by Roche GS De Novo assembler software and assisted by the published restriction maps polyhedrin gene was defined as the first ORF and the A of its initiation codon as the first nucleotide (nt) of the genome. So far, 78 baculoviral genomes have been completely sequenced including BusuNPV  were supposed to be characteristic for many baculovirus genomes. The hrs are repeat regions with palindrome structure interspersed in the genome. Hrs consist of similar repeat sequence with varying length in a genome, but the hr sequence vary widely in different baculoviruses Hrs were suggested to be origins of DNA replication in baculovirus hr had no effect on the replication of AcMNPV hrs. They appear to bind to ie1 in AcMNPV and promote the transactivation level of IE1 Hrs are absent from the BusuNPV genome.Homologous repeated sequences , lef-2 (Busu104) and lef-3 (Busu56). Other genes related to DNA replication include very late factor-1 , DNA binding proteins-1,2 , lef-11 (Busu28), alkaline exonuclease  and me-53 (Busu22) Although the mechanism of baculovirus genome replication is not totally clear, several viral genes have been identified as important for DNA replication lef-4 (Busu68), lef-8 (Busu50), lef-9 (Busu35) and P47 (Busu25). The lef-5 (Busu75) and vlf-1 (Busu61) are two other core genes involved in transcription. In addition, four non-core transcription related gene: 39k/pp31 (Busu29), lef-6 (Busu10), lef-11 (Busu28), Protein kinase-1  are present in BusuNPV. The early transcription genes found in BusuNPV are Immediate early gene  and ie-0 (Busu21) Like all other baculovirus, BusuNPV encodes all four subunits of RNA polymerase p6.9 (Busu76) encodes a nucleocapsid protein and participates in DNA condensation. VLF-1 (Busu61) is a structural protein in both ODV and BV required for very late genes expression and is essential for nucleocapsid production 38K (Busu74), 49k (Busu20), odv-ec27 (Busu18), odv-e43 (Busu82), odv-e18 (Busu19), vp39 (Busu67), vp91/p95 (Busu66), vp1054 (Busu42), desmoplakin (Busu57), Ac53 (Busu45), p18 (Busu70) and gp41 (Busu63). The p33 (Busu69) encodes a type of a sulfhydryl oxidase in baculoviruses c42 (Busu77) and pp78/83 (Busu2) participate in nuclear actin polymerization BusuNPV contains all structural core genes identified in other baculoviruses. In the alphabaculoviruses, Other non-core structural proteins encompass the F protein (Busu120), which is essential for virus entry and budding and VP80 (Busu80), which is involved in nucleocapsid packaging and trafficking p74 (Busu23), per os infectivity factors-1 , pif-2 (Busu101), pif-3 (Busu90), pif-4 (Busu73), pif-5/odv-e56 (Busu6) and pif-6(Busu55) So far 7 conserved genes were identified to be essential for oral infectivity of baculovirus including Busu34 is a homologue of the gene encoding viral enhancing factor (VEF) that dissolves the peritrophic membrane (PM) of the midgut cathepsin (Busu24) and chitinase (Busu51), both are involved in liquefaction of insect and OB release egt gene which prevents larvae molting and pupation egt gene kill the infected larvae faster than wild type stains sod (Busu92) and three iap genes . Three Baculovirus repeated orf (bro) genes have also been found. The absence or duplication of these genes is common in baculovirus, although between stains with closer affinity bro genes encode a protein with DNA binding activity, especially to single stranded DNA parg, Busu88), which is conserved in group II alphabaculoviruses with a function of poly (ADP-ribose) catabolism Ubiquitin is encoded by most baculoviruses as well as BusuNPV. Like most alphabaculoviruses and some betabaculoviruses, BusuNPV also encodes Six unique ORFs  with no homology to other baculovirus ORFs were identified and potentially encode functional proteins.The Busu100 encodes a 532 aa protein with low homology to tryptophan repeat gene family in entomopoxvirus . Busu109 encodes a 155 aa protein sharing a very low homology to 5-methyltetrahydropteroyltriglutamate\u2013homocysteine methyltransferase in some bacteria .Alphabaculovirus. Phylogenetically, it is most closely related to EcobNPV, EupsNPV, OrleNPV and ApciNPV. It does not contain typical baculovirus hrs, but contain a new repeat structure, the function of which needs to be further characterized. A 28.8 kb conserved region was identified among alpha- and betabaculoviruses.In summary, the genome sequence revealed BusuNPV is a distinct species in group II B. suppressaria larvae and OBs were purified by differential centrifugation BusuNPV was propagated in The genome was sequenced with the Roche 454 GS FLX system by using shotgun strategy. The reads were assembled with Roche GS De Novo assembler software. Contigs assembly was assisted by previously generated restriction maps http://www.softberry.com/berry.phtml) http://blast.ncbi.nlm.nih.gov/Blast.cgi). Repeat structures were detected by BLAST alignment of two sequences (http://blast.ncbi.nlm.nih.gov/Blast.cgi). The identity among homologous genes was done with MegAlign software using clustalW with default parameters. Regulatory regions and promoter motifs were identified as described previously Hypothetical ORFs were predicted by softberry FGENESV program  with default setting of DNA Nucleic Acid Type Secondary structure was drawn by Predict a Secondary Structure online server . NP means no published. Genomes used to build phylogeny tree marked by \u2018 *\u2019.(DOCX)Click here for additional data file.Table S2The ORF positions in the genomeof BusuNPV. E or L means early or late promoter motif and ORF directionrepresented by+ or \u2013.* stands for stain HearNPV G4. a, position of granulin in CpGV genome. b, BJDP stands for DnaJ domain protein. c, PKIP stands forProtein kinase interacting.(DOCX)Click here for additional data file."}
+{"text": "Drosophila, we performed chromatin immunoprecipitation-sequencing analysis with the insulin/IGF regulated transcription factor dFOXO in long-lived insulin/IGF signaling genotypes. Dawdle, an Activin ligand, is bound and repressed by dFOXO when reduced insulin/IGF extends lifespan. Reduced Activin signaling improves performance and protein homeostasis in muscles of aged flies. Activin signaling through the Smad binding element inhibits the transcription of Autophagy-specific gene 8a (Atg8a) within muscle, a factor controlling the rate of autophagy. Expression of Atg8a within muscle is sufficient to increase lifespan. These data reveal how insulin signaling can regulate aging through control of Activin signaling that in turn controls autophagy, representing a potentially conserved molecular basis for longevity assurance. While reduced Activin within muscle autonomously retards functional aging of this tissue, these effects in muscle also reduce secretion of insulin-like peptides at a distance from the brain. Reduced insulin secretion from the brain may subsequently reinforce longevity assurance through decreased systemic insulin/IGF signaling.Reduced insulin/IGF signaling increases lifespan in many animals. To understand how insulin/IGF mediates lifespan in  dawdle, the Activin-like ligand in fruit flies. We show that down-regulation of Activin signaling in muscle, but not in adipose tissue, leads to extended lifespan. In part it does so when it alleviates the negative transcriptional repression of its Smox transcription factor (a Smad transcription factor) upon a keystone autophagy gene, Atg8a. This double signaling cascade autonomously improves muscle performance  and nonautonomously extends lifespan as it reduces the secretion of insulin peptides from the brain. The work develops the emerging model for interacting autonomous-nonautonomous roles of insulin/IGF signaling as a systems integrative mechanism of aging control.It is widely known that reduced insulin/IGF signaling slows aging in many contexts. This process requires the forkhead transcription factor (FOXO). FOXO modulates the expression of many genes, and the list of those associated with slow aging is impressive. But there are few data indicating the mechanisms or genes through which FOXO actually slows aging. Here, we identify a novel FOXO target,  Caenorhabditis elegans, mutants in insulin-like receptor daf-2 live twice as long as wild type InR and insulin receptor substrate (chico) increase adult lifespan in the fruit fly Drosophila melanogasterIgf1r) extend lifespan Reduced insulin/IGF-1 signaling increases the lifespan of nematodes, flies and rodents C. elegans lifespan extension of daf-2 and age-1(PI3 kinase) mutants requires daf-16, a FOXO homolog in worms DrosophilaFoxO3A to associate with exceptional longevity Genetic evidence places the forkhead transcription factor FOXO as the downstream effector of insulin/IGF-1 signaling Drosophila aging. Systemically reducing insulin signaling by mutations of the insulin receptor (InR) and insulin receptor substrate (chico) slows the decline in cardiac performance of aging flies while a similar outcome is produced by overexpressing FOXO and PTEN just within cardiomyocytes Drosophila fat body modulates lifespan by inducing fat body dilp6 transcription, which in turn suppresses neuronal DILP secretion One aspect that is clear is that insulin/FOXO signaling operates both nonautonomously and autonomously to control C. elegans have been used to probe how daf-16 controls lifespan in response to insulin signaling. Microarray analyses have identified many mRNA that are affected directly or indirectly by daf-16, and reducing some of these genes by RNA interference (RNAi) increases longevity daf-16 upon aging daf-16 in the long-lived daf-2(e1370) mutant, and three out of 33 tested target genes were found to increase lifespan when gene expressions were reduced by RNAi: lin-2, egl-10 and sca-1.Genome-wide studies with Drosophila, work to date has identified binding targets of dFOXO primarily from wild type adults. Alic et al identified 1423 dFOXO binding sites in wildtype adult female Drosophila using a ChIP-on-chip approach In Drosophila lifespan by identifying genes transcriptionally regulated by dFOXO in long-lived insulin signaling mutants. We conducted ChIP analysis with a dFOXO antibody followed by Illumina high-throughput sequencing from chico heterozygous mutants, which are long-lived and normal sized, and from adult flies with ablated insulin producing cells (IPCs), which are also long-lived dawdle (daw), an Activin-like ligand in TGF-\u03b2 superfamily. In genetic trials, reducing daw or its downstream transcription factor Smox increases lifespan, preserves muscle function and reduces poly-ubiquitinated protein accumulation. The muscle specific benefits of activated dFOXO are mediated through the control of autophagy by Smox, which we find to bind and transcriptionally repress Atg8a/LC3, a reported longevity assurance gene of DrosophilaAtg8a in muscle was also sufficient to increase lifespan. Furthermore, reducing daw in muscle decreased DILP2 peptide secretion from the brain while peripheral insulin/IGF signaling was correspondingly reduced. Our results suggest that insulin/IGF signaling controls lifespan in part through dFOXO-mediated repression of muscle Activin signaling and its downstream functions including muscle autophagy, muscle proteostasis and subsequent remote control of systemic insulin/IGF signaling.Here we aim to understand how reduced insulin/IGF-1 signaling extends Drosophila lifespan we sequenced promoters derived from chromatin-immunoprecipitation with antibody against dFOXO in two genotypes of long-lived flies with reduced insulin signaling. Heterozygotes of 1chico live 36% longer than co-segregating wildtype sibs chico+/\u2212 adults have normal development time, body size and fecundity. Aging is likewise retarded by partially ablating adult IPCs by inducing apoptosis with a cell specific inducible driver  chico and IPCs ablated flies respectively, corresponding to 2042 and 1012 candidate genes (To understand how dFOXO extends te genes .puckered (puc) in both longevity assurance genotypes (puc is a negative regulator of JUN kinase basket (bsk), and mutation of puc extends Drosophila lifespan We identified 273 genes common to both longevity-assurance genotypes . Biologienotypes . In the To determine how candidate dFOXO targets affect longevity we selected 23 genes for further analyses  based onchico null mutant (chico\u2212/\u2212) and chico; foxo double mutant  , oxo \u2212/\u2212) . Transcrdaw, Glyp and Tsp42Ef) extended lifespan by consistently reducing age-specific mortality -Gal4 driving either UAS-RNAi or UAS-transgene. The effect of RNAi on lifespan was assessed for all 23 candidates. Knockdown of three genes  by consistently reducing mortality rate   and Activin (ligands: Daw and Act-\u03b2). These ligands signal through subfamily-specific Type I receptors  and shared Type II receptors . BMP-like ligands and Activin-like ligands activate distinct downstream signaling cascades leading respectively to phosphorylation of the Smad transcription factors Mad and Smox , the shared Type-II receptor (Punt and Wit) and two other TGF- \u03b2 ligands (Myo and Mav)  .Drosophila are homologous to C. elegans TGF-\u03b2/dauer and Sma/Mab. Recent reports clarify that the TGF-\u03b2/dauer pathway can regulate somatic aging, while the Sma/Mab pathway appears to modulate reproductive aging C. elegans, Drosophila and mouse  and mouse , while the Sma/Mab ligand in C. elegans, DBL-1, is similar to BMP-like ligands in Drosophila and mouse. Together these results suggest that Activin may be a conserved longevity pathway.The TGF-\u03b2 signaling pathways of nd mouse . SimilarDrosophila aging we determined which tissues produced this control. daw mRNA is highly expressed in muscle and fat body, a tissue with both liver and adipose-like activities , and this effect was reversed in chico; foxo double mutants  (babo-Act) reduced the number of autophagosomes  . In contagosomes . Since ADrosophila encode 18 autophagy genes Smox mRNA produces elevated autophagy in aged muscle, we studied the phosphorylation of this transcription factor in old flies. Smox phosphorylation is increased in aging muscle  and measured its interaction with biotin-labeled Atg8a oligonucleotide probes containing Smad box (5\u2032-AGAC AGAC-3\u2032). Smox-MH1 strongly bound to the Atg8a probe, and this interaction was blocked by addition of unlabeled wildtype cold probes  (Atg8a. This Smad binding element contains a direct repeat of two Smad boxes (AGAC). Upon activation, Smox, the Drosophila homologue of Smad2/3, binds to the Smad box located within the promoter of Atg8a. Activin signaling represses autophagy via direct transcriptional regulation on the key autophagy gene Atg8a.An electrophoretic mobility shift assay (EMSA) confirms that Smox binds directly within d probes . To defid probes . FurtherAGAC-3\u2032) . TogetheAtg8a expression within muscle is sufficient to promote lifespan, we over-expressing Atg8a using a muscle-specific driver . Lifespan was modestly but significantly increased, suggesting that Atg8a gene is a specific instance of a longevity assurance genes that that functions through muscle downstream of Activin signaling   .4eBP in longevity mutants with reduced insulin, some but not all insulin/IGF pathway mutants have reduced fecundity. Here we found normal fecundity in females with reduced muscle Activin signaling  mutants) can be suppressed by daf-16 mutants, suggesting that TGF-\u03b2 signaling intersects with the insulin/IGF-1 pathway for longevity in C. elegansInsulin/IGF-1 signaling modulates longevity in many animals. Genetic analysis in C. elegans were resolved only when the matricide or \u2018bagging\u2019 (due to progeny hatching within the mother) was prevented by treating daf-7(e1372) mutants with 5-fluorodeoxyuridine (FUdR) to block progeny development C. elegansDrosophila. These parallels between reproductive and somatic aging among invertebrate models and humans suggest that unopposed Activin signaling is pro-aging while favoring reproduction.Longevity benefits of reduced Activin (TGF-\u03b2/dauer) in Drosophila fly lifespan while decreasing IPC production of systemically secreted DILP2 Reduced insulin/IGF signaling extends lifespan through interacting autonomous and non-autonomous actions. Reducing IIS in some distal tissues has been shown to slow aging because this reduces insulin secretion from a few neurons: reducing IIS by increasing dFOXO in fat body or muscle extends Atg8a in Drosophila CNS is reported to extend lifespan by 56% Drosophila while lysosome activity and macroautophagy decline. Muscle performance with age  was preserved by inactivating Activin within this tissue. This genetic treatment also reduced the accumulation of protein aggregates. These effects are mediated by blocking the transcription factor Smox, which otherwise represses Atg8a. Smox directly regulates Atg8a through its conserved Smad binding motif (AGAC AGAC). These results, however, contrast with an observation where TGF-\u03b21 promotes autophagy in mouse mesangial cells Aging muscle may produce different myokine-like signals in response to their physiological state. Aged muscles degenerate in many ways including changes in composition, mitochondria, regenerative potential and within-cell protein homeostasis Atg8a. If extrapolated to mammals, pharmaceutical manipulations of Activin may reduce age-dependent muscle pathology associated with impaired autophagy, and potentially increase healthy and total lifespan through beneficial signaling derived from such preserved tissue.Insulin/IGF-1 signaling is a widely conserved longevity assurance pathway. Our data indicate that reduced insulin/IGF-1 retards aging at least in part through its FOXO-mediated control of Activin. Furthermore, affecting Activin only in muscle is sufficient to slow its functional decline as well as to extend lifespan. Autophagy within aging muscle controls these outcomes, and we now find that Activin directly regulates autophagy through Smox-mediated repression of Flies were reared and maintained at 25\u00b0C, 40% relative humidity and 12-hour light/dark. Adults were maintained upon agar-based diet with cornmeal (0.8%), sugar (10%), and yeast (8% unless otherwise noted). RU486  used to activate GeneSwitch-Gal4 was dissolved in ethanol to a concentration of 200 \u00b5M and added to the food.MHC-Gal4Tub-GS-Gal4da-GS-Gal4S106-GS-Gal4dilp2-GS-Gal4 (provided by H. Jasper); dilp2-GS-Gal4,UAS-dicer2 (provided by S. Helfand). RNAi lines for dFOXO target genes and TGF-\u03b2 pathway are from Bloomington stock center (TRiP line) and Vienna Drosophila RNAi Center . UAS-lines are: UAS-hairyUAS-pucUAS-RhoGAP18BUAS-vriUAS-witUAS-cv-2UAS-babo-Act  UAS-Atg8-CherryFly stocks included: Chico mutants were made in our lab as describe previously 1; cn1; ry506y (wildtype), 1; cn1 chico1/cn1; ry506y (\u2212/+chico), 1; cn1 chico1/cn1 chico1; ry506y (\u2212/\u2212chico), 1; cn1 chico1/cn1 chico1; foxo21 ry506y . Adult on-set IPC ablation flies were made by crossing Dilp2-GS-Gal4 to UAS-rpr and inducing the cell death in IPC cells by feeding flies with RU486 for 15 days.chico\u2212/+ and IPC ablation. Chromatin immunoprecipitation (ChIP) was performed according to previously published methods with modification Two insulin mutants were used in ChIP-Seq experiments, Drosophila reference genome using Bowtie short read aligner To map the dFOXO binding sites, we pooled the raw reads (about 20 million reads per sample) from two replicates into one data file and aligned it to Act5C) and sry genomic region were used as negative controls.For ChIP-PCR analysis, the binding enrichment was calculated as the fold change of ChIP DNA versus input DNA. The binding to the coding region of Actin gene (http://flybase.org/) and de novo motif analysis was performed using MEME Suite The DAVID functional classification tool was used for pathway and molecular function analysis on the dFOXO target genes RpL32, also known as rp49) by the method of comparative CT. Primer sequences are shown in Total RNA was extracted from 10 whole flies or from tissue of 15 flies in Trizol reagent . DNase-treated total RNA was quantified with a NanoDrop ND-1000. About 50\u2013100 ng of total RNA was used for quantification with SuperScript One-Step RT-PCR reagent  and measured on an ABI prism 7300 Sequence Detection System . Three biological replicates were used for each experimental treatment. mRNA abundance of each gene was normalized relative to ribosomal protein L32 , flies were first tapped down to the bottom of a standard (empty) food vial, and the percentage of flies that climbed up 8 cm within 20 seconds was recorded. A total of 80 females  were scored for each genotype.Antibodies for immunostaining included: anti-polyubiquitin FK2 (1\u2236200) , and anti-rabbit IgG-DyLight 488 (1\u2236300) . F-actin was visualized by Alexa Fluor 488-conjugated Phalloidin . Lysosome was monitored by LysoTracker Red DND-99 at the concentration of 100 nM . DNA was stained with Hoechst 33342 (1 \u00b5g/ml) . Samples were processed as described in Smox polyclonal antibody was generated against the peptide sequence (DSIVDYPLDNHTHQ) corresponding to amino acids 143\u2013156  and affinity purified  . Empty vector was used as a negative control.cDNA for Smox-MH1 DNA binding domain (1\u2013420 nt) was cloned into pFN29K-His6HaloTag protein expression vector . After expression in Biotin-labeled DNA probes were generated using 3\u2032-end biotin labeling . The binding reactions were carried out in a 10 \u00b5l of assay mixture containing 10 mM Tris\u00b7HCl (pH 7.5), 150 mM KCl, 5 mM MgCl2, 10 ng/\u00b5L poly(dI-dC), \u223c50 ng labeled probe and 20 \u00b5g purified recombinant protein. After incubation at room temperature for 20 min, the mixtures were electrophoresed on 0.8% agarose gels in 0.5\u00d7 Tris/borate/EDTA buffer. Biotin-labeled DNAs were transferred to a positive-charged nylon membrane  and detected using GelShift Chemiluminescent EMSA .10-day-old mated female flies were maintained on standard food (2% yeast) for five days at three females per vial and 8\u201310 vials per group. Flies were passed daily to new vials over five days and eggs were counted daily.We followed our recently reported EIA assay to measure hemolymph DILP2 Data are presented as mean \u00b1 SEM from three independent biological replicates, unless otherwise noted. Statistical significances were evaluated by t-test and one-way ANOVA analyses using GraphPad Prism Software.Figure S1\u2212/\u2212chico  mutants. (B). Binding of dFOXO to 4ebp promoter is enhanced in chico mutants, which is rescued by the removal of dFOXO. Primers for the coding region of Actin gene (Act5C) were used as negative control. (C). Pathway analysis of 273 identified dFOXO target genes. (D). Motif analysis on the promoters of dFOXO target genes. (E\u2013F). ChIP-PCR validation of the binding of dFOXO to its target genes in \u2212/+chico  and IPC ablation mutants. Primers for the coding region of Actin gene (Act5C) and sry genomic region Summary and verification of dFOXO ChIP-Seq. (A). The nuclear localization of dFOXO is promoted in (PDF)Click here for additional data file.Figure S2daw RNAi females (RU induced) relative to self-control (no RU) shows strong and consistent reduction. (B) Mortality rate of Glyp RNAi females (RU induced) relative to self-control (no RU) shows generally consistent reduction across ages where mortality rate increases with age. (C) Mortality rate of Tsp42Ef RNAi females (RU induced) relative to self-control (no RU) shows reduced rate across the final 30 of 40 days where mortality increases with age.Mortality rate for survival plots of three dFOXO target genes in (PDF)Click here for additional data file.Figure S3dpp RNAi females (RU induced) relative to self-control (no RU) shows proportionally elevated death across ages where mortality increases with age, suggesting that loss of dpp (BMP) in muscle accelerates aging. (B) Muscle specific daw RNAi (RU induced) relative to self-control (no RU) shows strong and consistent reduction in mortality, except at oldest ages. (C) Mortality rate of Mad RNAi females (RU induced) relative to self-control (no RU) shows elevated death across ages where mortality increases with age, suggesting that loss of Mad (BMP) in muscle accelerates aging. (D) Muscle specific Smox RNAi (RU induced) relative to self-control (no RU) shows consistent reduction in mortality across intervals where mortality increases with age, although the rate fluctuates at oldest ages.Mortality rate for survival plots of TGF-\u03b2 pathway in (PDF)Click here for additional data file.Figure S4daw by RNAi in muscle (A) consistently lowers mortality rate while daw RNAi expressed in fat body (B) increases mortality rate. Reduction of Smox by RNAi in muscle (C) consistently lowers mortality rate while Smox RNAi expressed in fat body (D) increases mortality rate. Reduction of babo by RNAi in muscle (E) consistently lowers mortality rate while babo RNAi expressed in fat body (B) increases mortality rate at the oldest ages but otherwise does not affect mortality.Mortality rate for survival plots of tissue-specific RNAi of Activin pathway in (PDF)Click here for additional data file.Figure S5Drosophila Smox protein. (B). This Smox antibody can also specifically recognize recombinant Smox proteins expressed in E. coli. (C). Fat body-specific knockdown of Smox results in reduced protein level visualized with this Smox antibody.Verification of Smox antibody. (A). Smox antibody generated in this study recognizes a 51KDa band that presents in all four tissues tested, which is close to predicted molecular weight for (PDF)Click here for additional data file.Figure S6daw, Smox and babo RNAi. (D). The comparison of age-dependent climbing activity between control and daw RNAi flies. Asterisk indicates significant difference between treatment and control (p<0.05). (E). dFOXO shows less binding to the promoter of Atg8a. (F). Fat body-specific daw RNAi increased the level of circulating DILP2.(A\u2013C). Knockdown efficiency of (PDF)Click here for additional data file.Figure S7Atg8a in muscle by the constitutive driver MHC-gal4 consistently reduces mortality rate across intervals where the death rate increases with age. There is high variability in mortality rate after age 70 days including an interval where no deaths were observed in the MHC; UAS-Atg8a genotype. (B) Mortality rate for survival plots of the genetic epistasis between daw and Atg8a. Reducing daw by RNAi lowers mortality rate relative to wildtype control after age 40 days. The net survival benefit of daw RNAi in this trial is muted because this cohort shows somewhat high mortality rate across the early intervals when death rate does not yet increase with age in the control cohort. Atg8a RNAi alone shows nearly identical mortality rate as control. Mortality rate of the daw and Atg8a RNAi double is similar to or slightly greater than that of control, indicating that Atg8a RNAi rescues the mortality benefit conferred by daw RNAi. Statistics of Cox proportional hazard for this epistasis are presented in Mortality rate for survival plots of the impact of Atg8a upon aging, text (PDF)Click here for additional data file.Figure S8Proposed model for the autonomous and non-autonomous roles of Activin signaling combine to control aging. Activin signaling targeted by insulin/dFOXO negatively regulates muscle autophagy, protein homeostasis and muscle functions in a cell autonomous manner, while it could also nonautonomously modulate longevity, the secretion of insulin peptides from the brain and peripheral insulin signaling. InR: insulin receptor; IPC: insulin producing cells. Myokine refers to unknown muscle-derived hormonal factor.(PDF)Click here for additional data file.Table S1Summary of lifespan analyses for 23 dFOXO-target genes reduced by RNAi.(DOCX)Click here for additional data file.Table S2Summary of lifespan analyses for seven dFOXO-target genes increased by over-expression.(DOCX)Click here for additional data file.Table S3Summary of lifespan analyses for Drosophila TGF-\u03b2 pathway.(DOCX)Click here for additional data file.Table S4Atg8a over-expression.Summary of lifespan analyses for tissue-specific knockdown of Activin signaling and of (DOCX)Click here for additional data file.Table S5dawdle and Atg8a.Mean lifespan and sample size of muscle-specific knockdown of (PDF)Click here for additional data file.Table S6dawdle and Atg8a.Cox proportional hazard survival analysis for the effects of muscle-specific knockdown of (PDF)Click here for additional data file.Table S7chico and IPC ablation mutants.dFOXO direct target genes in (XLSX)Click here for additional data file.Table S8Primers for mRNA analyses.(XLSX)Click here for additional data file."}
+{"text": "Human T-cell leukemia virus type I (HTLV-1) infection in human causes an aggressive malignancy, adult T-cell leukemia (ATL), as well as inflammatory diseases such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). A transgenic mouse model expressing Tax in mature thymocytes and peripheral T lymphocytes caused mature T cell leukemia resembling ATL. We also found that inflammatory arthropathy develops among Tax-expressing mice without leukemia. The pathological findings of arthropathy in Tax transgenic mice were similar to those seen in human rheumatoid arthritis or mouse models of rheumatoid arthritis, with synovial proliferation and a positive rheumatoid factor. No group differences between control mice and arthropathic mice were found in the proportion of T and B cells in spleens. The arthropathic mice showed a significantly decreased proportion of splenic CD4+ T cells, whereas the proportion of splenic CD8+ T cells was increased. The Th17 cells were not detected in arthropathic mice. Regulatory T cells (CD4+CD25+Foxp3+) were significantly decreased and CD8+ T cells that expressed the chemokine receptor CCR4 (CD8+CCR4+) were significantly increased in arthropathic Tax transgenic mice. The expression of tax mRNA was strong in the spleen and joints of arthropathic mice, with a 40-fold increase compared with healthy-transgenic mice.Tax transgenic mice develop rheumatoid-like arthritis; however, splenic T-cell subsets in these mice was completely different from other commonly used animal models of rheumatoid arthritis. The crucial T-cell subsets in these mice appear to resemble those in HAM/TSP patients rather than those in rheumatoid arthritis patients."}
+{"text": "Calreticulin (CRT) is a chaperone protein which normally resides in the endoplasmic reticulum (ER). However, recent studies have demonstrated that pre-apoptotic cancer cells release internalized CRT to their surface prior to death, and this surface exposure of CRT acts as an \u2018eat-me\u2019 signal to local phagocytes. Some chemotherapeutic agents and gamma-irradiation have been shown to induce ER stress and promote CRT surface translocation in cancer cells, resulting in their recognition and phagocytosis by innate immune cells, such as macrophages and dendritic cells (DC). In turn, innate immune cells which have phagocytized CRT-expressing tumor cells become capable of priming antigen-specific T cell responses directed against malignant cells. Unfortunately, chemotherapy and irradiation which can induce immunogenic cell death (ICD) through CRT, can also result in local and/or systemic immune suppression in the host. To bypass the requirement of exposing the host to chemotherapy to induce translocation of CRT to the cell surface, C1498 AML cells were engineered to constitutively express cell surface CRT (C1498.CRT). Introduction of C1498.CRT cells subcutaneously (SC) into syngeneic C57BL/6 mice resulted in either significantly delayed tumor outgrowth or complete protection from tumor development compared to parental C1498 cells which universally progressed in vivo. A SC challenge with C1498.CRT cells also protected mice from tumor outgrowth following a subsequent re-challenge with parental C1498 tumor cells, suggesting that C1498.CRT cells promote immunologic memory. Differences in tumor outgrowth between mice inoculated with parental C1498 and C1498.CRT leukemia cells were abrogated in immunodeficient RAG-/- and RAG2-/-\u03b3c-/- animals, arguing that the immune-mediated effect of cell-surface CRT expression is dependent upon a functional adaptive immune system. To model a clinically relevant scenario, parental C1498 or C1498.CRT cells were inoculated intravenously (IV) into C57BL/6 mice. Significantly prolonged survival was observed in hosts harboring C1498.CRT versus parental C1498 cells systemically. Systemic inoculation with C1498.CRT cells expressing the model SIYRYYGL (SIY) peptide antigen (C1498.SIY.CRT cells) resulted in enhanced expansion and effector cytokine production by antigen-specific T cells compared to T cells from hosts challenged with control C1498.SIY cells. Our current on-going experiments are focusing on identifying the mechanism(s) through which calreticulin appears to promote anti-tumor immunity."}
+{"text": "Reliable surveillance methods are indispensable for benchmarking of healthcare-associated infection rates. The National Healthcare Safety Network (NHSN) recently introduced surveillance of ventilator-associated events (VAE), including ventilator-associated conditions (VAC) . This neRetrospective analysis of an ICU cohort with prospective assessment of ventilator-associated pneumonia (VAP) in two academic medical centers (January 2011 to June 2012). The algorithm was electronically implemented as specified by the NHSN using minute-to-minute ventilator data. Two minor modifications were developed to improve stability and comparability with manual surveillance (10th percentile and intermittent ventilation). Concordance was assessed between the algorithms and prospective surveillance. Attributable mortality of VAC was estimated by multivariable competing-risk survival analysis.Two thousand and eighty patients contributed 2,296 episodes of mechanical ventilation (MV). VAC incidence was 10.0/1,000 MV days. Prospective surveillance identified 8 VAP cases/1,000 MV days. The original VAC algorithm detected 32% (38/115) of patients affected by VAP; positive predictive value was 25% (38/152). Using the 10th percentile identified the same number of VAC cases, but only 116 were identical. VAC incidence was 24.9/1,000 MV days with the intermittent ventilation modification. Concordance between the original algorithm and the modified versions was suboptimal. Estimates of attributable mortality varied by implementation: original VAC subdistribution hazard ratio (sdHR) = 4.33, 10th percentile sdHR = 6.26 and intermittent ventilation sdHR = 2.40.Concordance between manual VAP surveillance and the VAE algorithm was poor. Although electronic implementation of the VAE algorithm was feasible, small variations considerably altered the events detected and their effect on mortality. Using the current specifications, comparability across institutions using different electronic or manual implementations remains questionable."}
+{"text": "A 58-year-old diabetic female who underwent coronary angioplasty of left anterior descending coronary artery (LAD) using DES 1 year back was admitted with the diagnosis of acute coronary syndrome (NSTEMI). Repeat coronary angiography showed moderate instent restenosis in LAD stent and new onset severe disease in right coronary artery (RCA) and left circumflex coronary artery (LCX). LV angiogram was performed using pigtail catheter with 25 ml of non-ionic contrast injected at a rate of 15 ml/sec. During LV angiography, she developed multiple ventricular premature complexes(VPCs) which culminated into ventricular fibrillation. Immediately, the pigtail catheter was withdrawn and VF was reverted to sinus rhythm by DC cardioversion. Careful examination of recorded LV angiogram with simultaneous electrocardiographic recording revealed R-on-T phenomena (arrow in image) preceding the initiation of VF , Video 1Click here to view as Video 1"}
+{"text": "The following sentence was incorrectly cited: \"Interestingly, Yadav et al have recently shown that VPAC1 KO mice present milder DSS-induced colitis compared to WT mice, suggesting that VIP may exert proinflammatory actions through this receptor [30].\"The correct citation is [49], which is missing from the Reference list. Reference 49 is the following:Yadav M, Huang MC, Goetzl EJ (2011) VPAC1  receptor type 1) G protein-coupled receptor mediation of VIP enhancement of murine experimental colitis. Cell Immunol. 267:124-32"}
+{"text": "Cerebral autoregulation (CA) maintains cerebral blood flow over a range of perfusion pressure. Continuous CA monitoring might define pressure targets minimising secondary brain injury, but application is limited by available monitoring modalities. Near-infrared spectroscopy (NIRS) is a noninvasive optical technique characterising aspects of CA. The NIRS-derived tissue oxygenation index (TOI) is correlated with blood pressure (BP) to produce an index of vascular reactivity (TOx) . The con2), transcranial Doppler and NIRS . ORx and Mx were derived from continuous correlation between BP and neuromonitoring [Thirteen brain-injured patients were studied. Ipsilateral 60-minute recordings included intracranial pressure, brain tissue oxygen , ORx  and Mx. TOx showed no significant correlation (r = 0.18) as individual recordings demonstrated TOI fluctuations paradoxical to other monitoring. The mean lag between BP and HHb (24 seconds) was shorter than PbrO2 (68 seconds).There was correlation between HHBx (HHb may provide a surrogate to inform cerebrovascular reactivity assessment. Complexity in the oxyhaemoglobin component of TOI may be introduced by vasopressor-related skin artefact or arterial volume changes  explaini"}
+{"text": "The effect of Timothy grass AIT treatment on a Canadian subpopulation was assessed post-hoc using data from 2 randomized, double-blind, trials designed to evaluate grass AIT in North American subjects.Phleum pratense, 75,000 SQ-T, ~15\u03bcg Phl p5) or placebo starting approximately 16 weeks before and continuing throughout the 2009 grass pollen season (GPS). Subjects used daily e-diaries to record ARC symptoms and use of symptomatic medications from randomization through study end (approximately 24 weeks). The primary efficacy endpoint comprised the average total combined daily symptom and medication score (TCS) during the entire GPS. Secondary endpoints included average daily symptom score (DSS) and average daily medication score (DMS). Safety was assessed by monitoring adverse events (AEs).Subjects 5 years and older with ARC with/without asthma received once-daily 2800 BAU sublingual grass AIT  for entire and 45% (P=.005) for peak seasons in TCS; of 38% (P=.013) for entire and 40% (P=.008) for peak seasons in DSS; and of 39% for entire (P=.238) and 60% (P=.005) for peak seasons in DMS. Among the overall population, most treatment-related AEs were mild or moderate. No serious or life-threatening treatment-related AEs occurred; no new safety concerns emerged.The Canadian subpopulation included 103 subjects . AIT-treated subjects showed reductions, vs placebo, of 38% (Timothy grass AIT, a novel therapeutic modality, significantly improved ARC caused by Timothy grass pollen and related grasses in Canadian adults and children 5 years and older."}
+{"text": "Malignant tumors escape from host immune surveillance through multiple mechanisms. Of these, abnormal tumor vasculature and hypoxia are critical in establishing an immunosuppressive tumor microenvironment, and consequently, impeding an active cancer immunotherapy. Thus, we hypothesized that vascular normalization can recondition the tumor immune microenvironment and enhance a cancer immunotherapy. Here, we compared the dosage effects of anti-vascular endothelial growth factor receptor 2 antibody DC101) treatments on tumor vasculature, and demonstrated that appropriate low dose DC101 treatment significantly improves functional tumor vessels and reduces tissue hypoxia, compared to control or high dose DC101 treatment in orthotopic preclinical breast tumor models. Consistently, our flow cytometry and gene profile analysis data showed that the lower doses are superior to the high doses at polarizing perivascular tumor-associated macrophages (TAMs) from M2-like to M1-like phenotype, in facilitating CD8+ T cell tumor infiltration, while reducing myeloid-derived suppressor cells (MDSCs) in the tumor parenchyma. Based on this mechanism, synchronizing vascular normalization with T cell activation induced by a whole cancer cell vaccine therapy significantly enhanced anti-cancer efficacy in a CD8+ T cell-dependent manner in both orthotopic and spontaneous breast cancer models. These findings indicate that vascular normalizing lower doses of anti-VEGFR2 antibody treatment can reprogram the tumor microenvironment away from immunosuppression toward potentiation of cancer vaccine therapies (Figure 01 treatm"}
+{"text": "Transcatheter aortic valve implantation (TAVI) removes the valvular impedance associated with aortic stenosis but can be complicated by significant aortic regurgitation. Using cardiovascular magnetic resonance we assessed the change in trans-aortic pressure gradient and regurgitant fraction 6 months post-TAVI and compared this to a surgical aortic valve replacement (SAVR) cohort. TAVI was superior at reducing aortic pressure gradient and equal to SAVR at reducing aortic regurgitation at 6 months.Transcatheter aortic valve implantation (TAVI) is a rapidly developing procedure for the treatment of patients with severe aortic stenosis (AS) at high surgical risk. A reduction in trans-aortic pressure gradient is important to allow the ventricle to reverse remodel, but post-operative aortic regurgitation is a commonly reported complication. The quantification of aortic regurgitation (AR) by echocardiography and fluoroscopic techniques is limited, in part due to the paravalvular nature of regurgitation. We aimed to use cardiovascular magnetic resonance (CMR) imaging to determine the change in trans-aortic pressure gradient and accurately quantify paravalvular and valvular regurgitation post-TAVI compared to surgical aortic valve replacement (SAVR).Fifty high-risk patients (EuroSCORE \u226520) with severe AS (peak velocity >4m/s) underwent TAVI (n=25) or SAVR (n=25). TAVI was performed using the Medtronic CoreValve prosthesis (26mm (20%) and 29mm (80%). Bioprosthetic SAVR of varying sizes 18-26mm) were used in 24 (96%) and mechanical 1 (4%) patients. Baseline and 6 month post-operative scans were performed on 1.5T systems (Phillips Intera or Siemens Avanto) using identical protocols. Through-plane velocity encoded (VENC) phase contrast imaging was performed perpendicular to the aortic valve jet at the aortic sinotubular junction . Post-operatively the trans-aortic pressure gradient was significantly lower in both groups , although when compared to SAVR the TAVI group had a significantly greater reduction in their pressure gradient (P=0.017). Aortic regurgitant fraction at baseline was similar between the TAVI and SAVR groups . Valve replacement/implantation resulted in an 8% reduction of AR in both groups, reaching statistical significance in the TAVI group (P=0.003) but not in the SAVR group (P=0.09). However, comparison of the procedures by 2-way ANOVA showed no difference (P=0.46) in their efficacy to reduce AR.TAVI results in a greater improvement in aortic valve pressure gradient compared to SAVR and reduces aortic regurgitation to a similar degree. This is clinically important as a lower aortic pressure gradient may encourage greater left ventricular (LV) reverse remodeling and post-operative aortic regurgitation may result in pulmonary oedema and impaired ventricular remodeling.None."}
+{"text": "To highlight unusual presentations of Churg Strauss Syndrome (CSS) in children.Raising clinical awareness of atypical presentations.Case note review and literature search.9/l, ESR normal, no proteinuria). On needle biopsy, dilated ducts contained necrotic eosinophilic debris, intense infiltrate of eosinophils and plasma cells without granulomatous infiltration or vasculitis. Despite withdrawing Montelukast the mass persisted but treatment with steroids was successful.A 15 year old girl with worsening asthma and rhinitis presented with a persistent 10x6 cm breast lump 6 months after starting Montelukast. Chest X-rays and CT scan were normal, maxillary sinuses congested, with absolute eosinophilia of 2.4 x 109), anaemia, ESR 114 and positive pANCA (non PR3 / MPO). A good clinical response to treatment with steroids, cyclophosphamide (IV) and immunoglobulin is currently maintained on MMF and low dose steroid with anticoagulation (warfarin). Her cardiac mass has not regressed, but remained static, most likely representing chronic endocardial fibrosis.A 14 year old girl presented with worsening asthma associated with malaise, weight loss, an intermittent vasculitic rash and abdominal pain. She had a large right ventricular mass with pericardial effusion and endocardial impairment, pulmonary infiltrates, microscopic haematuria, vasculitic changes on cerebral MRI, a raised eosinophil count (6.16x10These cases illustrate atypical presentations of CSS in children. Eosinophilic mastitis may be idiopathic, parasitic or part of CSS - reported following treatment with Montelukast but never with eosinophilic mastitis. Cardiac masses in CSS have been reported occasionally in adults, but not previously seen in children."}
+{"text": "Approximately 30% of HIV-infected patients are co-infected with hepatitis C (HCV). The current treatment standard of care for HCV, pegylated interferon and ribavirin (RBV), has demonstrated a sustained virologic response (SVR) in less than 50% of HCV/HIV co-infected patients, and only 17-35% in HCV genotype 1 patients. It has been previously shown that using a weight-based RBV dose results in favorable SVR rates. Prior studies suggest that HCV/HIV co-infected patients receiving a HAART regimen that included tenofovir (TDF) had higher SVR rates than those who received abacavir (ABC) in their nucleos(t)ide analogue (N(t)RTI) backbone.At our specialty clinic for the treatment of HCV/HIV co-infected patients, we re-examined the efficacy of HCV treatment in patients receiving either agent in their regimen with weight-based ribavirin doses.Patients with HIV/HCV co-infection (HCV genotype 1) met with a multidisciplinary team before therapy initiation for education and teaching. HCV treatment consisted of weekly injections of 180 mcg pegylated interferon subcutaneously and weight-based dosing of RBV (13mg/kg/day to maximum of 1200 mg/day). Treatment duration was 48 weeks with longer treatment in slow responders; side effects and adverse events were treated promptly. The HAART regimen consisted of a N(t)RTI backbone with either ABC or TDF and a protease inhibitor or non-NRTI. We retrospectively compared SVR rates in patients being treated with either ABC or TDF.Thirty-four patients met the inclusion criteria. In an ITT analysis, 20 of 34 (59%) patients receiving HAART demonstrated SVR with no significant differences between races (p=.31). Among those twenty HAART patients with SVR, 9 patients were being treated with ABC and 11 were being treated with TDF (p=.13). The length of treatment between ABC and TDF treated groups did not differ significantly . No significant difference in SVR rates was shown between the two groups.The rate of SVR in patients with HIV/HCV genotype 1 dosed with weight-based RBV was significantly higher than generally reported. There was no difference in SVR rates in HIV/HCV co-infected patients receiving ABC or TDF in their HAART regimen with weight-based RBV. These results may give providers flexibility in their selection of N(t)RTI backbone while receiving treatment for HCV."}
+{"text": "Staphylococcus aureus strains of the 8325 lineage, especially 8325-4 and derivatives lacking prophage, have been used extensively for decades of research. We report herein the results of our deep sequence analysis of strain 8325-4. Assignment of sequence variants compared with the reference strain 8325 (NRS77/PS47) required correction of errors in the 8325 reference genome, and reassessment of variation previously attributed to chemical mutagenesis of the restriction-defective RN4220. Using an extensive strain pedigree analysis, we discovered that 8325-4 contains 16 single nucleotide polymorphisms (SNP) arising prior to the construction of RN4220. We identified 5 indels in 8325-4 compared with 8325. Three indels correspond to expected \u03a611, 12, 13 excisions, one indel is explained by a sequence assembly artifact, and the final indel (\u039463bp) in the spa-sarS intergenic region is common to only a sub-lineage of 8325-4 strains including SH1000. This deletion was found to significantly decrease (75%) steady state sarS but not spa transcript levels in post-exponential phase. The sub-lineage 8325-4 was also found to harbor 4 additional SNPs. We also found large sequence variation between 8325, 8325-4 and RN4220 in a cluster of repetitive hypothetical proteins (SA0282 homologs) near the Ess secretion cluster. The overall 8325-4 SNP set results in 17 alterations within coding sequences. Remarkably, we discovered that all tested strains of the 8325-4 lineage lack phenol soluble modulin \u03b13 (PSM\u03b13), a virulence determinant implicated in neutrophil chemotaxis, biofilm architecture and surface spreading. Collectively, our results clarify and define the 8325-4 pedigree and reveal clear evidence that mutations existing throughout all branches of this lineage, including the widely used RN6390 and SH1000 strains, could conceivably impact virulence regulation. Staphylococcus aureus is a leading cause of human disease ranging from minor skin infections to life-threatening endocarditis, pneumonia and septicemia . Despite storage at -80C, strain instability (measured by hemolytic activity) not commonly seen in NCTC8325 [16] was noted in our study in four independent strain examples.(TIF)Click here for additional data file.Table S1Oligonucleotide PCR primers used for SNP analysis and indel analysis.(PDF)Click here for additional data file.Table S2Deletions in 8325-4seq compared to NCTC8325.(PDF)Click here for additional data file.Table S3Oligonucleotide q-RT-PCR primers.(PDF)Click here for additional data file.Sequence S1Sequence file 8325-4 fasta format.(FASTA)Click here for additional data file."}
+{"text": "EF assessed by echocardiography and EF assessed by CMR are only moderately correlated. The exact quantification of EF by CMR provides additional prognostic information and may affect further treatment strategies, such as intensification of medication including aldosterone antagonist use or even device therapy.Left ventricular ejection fraction (EF) is a strong prognostic marker for clinical outcome after ST-elevation myocardial infarction (STEMI). In clinical practice echocardiography is most commonly used to assess EF, although cardiac magnetic resonance imaging (CMR) might have higher accuracy. However, it remains unclear if measuring EF by CMR in comparison to echocardiography provides incremental prognostic information for the assessment of long-term outcome in patients with STEMI.STEMI patients reperfused by primary angioplasty (n=392) within 12 hours after symptom onset underwent transthoracic echocardiography and CMR 3 days after the index event (interquartile range [IQR] 2-4). Assessment of EF by echocardiography (EFecho) was performed in standard apical 4-chamber view. Standard cine steady-state-free-precession sequences in short-axis views were carried out to measure EF by CMR (EFcmr). The corresponding EF was graded as severely decreased (<35%), mildly to moderately decreased (35-55%) and normal (>55). Clinical follow-up was conducted after 19 months (IQR 10-27). The primary endpoint was defined as a composite of death and congestive heart failure.EFecho was 45% (IQR 40-55), whereas EFcmr was 50% (IQR 40-58). EFecho was only moderately correlated to EFcmr . Both EFecho and EFcmr were significantly associated with the occurrence of the primary endpoint . Comparison of a risk prediction model including only EFecho to a model including EFcmr on top of EFecho resulted in a significant increase of the c-statistics from 0.65 to 0.69 (p=0.04) demonstrating therefore an incremental prognostic value of EFcmr. Finally, EFcmr led to re-grading of 144 patients (36.7%): 122 patients were re-classified to a group with less severely impaired EF, whereas only 22 patients displayed a higher grade of decrease in EF.EFecho and EFcmr are only moderately correlated. The exact quantification of EF by CMR provides additional prognostic information and may affect further treatment strategies, such as intensification of medication including aldosterone antagonist use or even device therapy.None."}
+{"text": "Acute human immunodeficiency virus type 1 (HIV-1) infection results in dysregulated immunity which contributes to poor control of viral infection. Dendritic cells (DCs) are key regulators of both adaptive and innate immune responses needed for controlling HIV-1 and we surmised that plasma factors elicited during acute HIV-1 infection (AHI) may impede DC function. Such inhibitory factors present in AHI plasma include apoptotic microparticles (MPs), small membranous blebs derived from dying cells.Plasma samples over sequential time points were obtained from AHI patients or healthy controls. Apoptotic MPs were isolated from supernatant of UV-irradiated PBMCs, AHI patient plasma or control plasma. Human DCs were treated with MPs or 10% plasma (control or AHI) and subsequently stimulated with various TLR agonists. DC activation was then assessed. MP-specific receptors were isolated from the DC surface and sequenced by mass spectrometry.AHI plasma inhibited TLR-stimulated DC cytokine production. The inhibitory capacity of AHI plasma occurs at time of viral ramp-up, whereas plasma at times before plasma viremia is not inhibitory. We determined this inhibition was not mediated by virus. Because apoptotic MPs are elevated in AHI plasma, we treated DCs with experimental and AHI plasma-derived MPs, both of which reduced DC activation. The inhibition of DCs by AHI plasma or MPs blocked DC capacity to prime IFNg-producing T helper 1 CD4+ T cells as well as NK cell activation. Mass spectrometric analysis revealed CD44 a MP receptor, and blocking CD44 on DCs relieves MP-mediated suppression. Direct ligation of CD44 also inhibits DC activation. MP-CD44 interaction activates Rac1, c-Abl, and AKt signaling.Determining the factors in AHI which block DC function will provide potential targets to stimulate HIV-specific immunity. We are currently investigating molecular mechanisms of CD44-mediated DC inhibition and downstream signaling events that can be targeted to alleviate DC inhibition."}
+{"text": "Each manganese(II) cation is coordinated by two terminally N-bonded seleno\u00adcyanate anions and four bpe ligands within a slightly distorted octa\u00adhedron. The manganese(II) cations are linked by the bpe ligands into chains that are further connected by these ligands into layers. These layers are stacked, forming cavities in which additional bpe solvent molecules are embedded.The crystal structure of the title compound, {[Mn(NCSe) DOI: 10.1107/S1600536811016199/bt5535Isup2.hkl            Structure factors: contains datablocks I. DOI:  crystallographic information; 3D view; checkCIF report            Additional supplementary materials:"}
+{"text": "Mature ELP shares approximately 55.4% similarity with the colostrum-specific bovine colostrum trypsin inhibitor (CTI) protein. Although ELP and CTI both have a single bovine pancreatic trypsin inhibitor (BPTI)-Kunitz domain and are secreted only during the early lactation phases, their evolutionary history is yet to be investigated.The marsupial ELP was isolated from a genomic library and the fat-tailed dunnart and Southern koala ELP genes cloned from genomic DNA. The tammar ELP gene was expressed only in the mammary gland during late pregnancy (Phase 1) and early lactation (Phase 2A). The opossum and fat-tailed dunnart ELP and cow CTI transcripts were cloned from RNA isolated from the mammary gland and dog CTI from cells in colostrum. The putative mature ELP and CTI peptides shared 44.6%-62.2% similarity. In silico analyses identified the ELP and CTI genes in the other species examined and provided compelling evidence that they evolved from a common ancestral gene. In addition, whilst the eutherian CTI gene was conserved in the Laurasiatherian orders Carnivora and Cetartiodactyla, it had become a pseudogene in others. These data suggest that bovine CTI may be the ancestral gene of the Artiodactyla-specific, rapidly evolving chromosome 13 pancreatic trypsin inhibitor (PTI), spleen trypsin inhibitor (STI) and the five placenta-specific trophoblast Kunitz domain protein (TKDP1-5) genes.Tammar ELP and eutherian CTI evolved from an ancestral therian mammal gene before the divergence of marsupials and eutherians between 130 and 160 million years ago. The retention of the ELP gene in marsupials suggests that this early lactation-specific milk protein may have an important role in the immunologically na\u00efve young of these species.Marsupial  Smithopsis macroura)  dCTP-labelled probe [DECAprime II Random Priming DNA Labelling Kit (Ambion)] and incubated for ~16\u2009hr at 42\u00b0C. The tammar ELPRsaI digested LGB  and hybridized in 25\u2009mL  with an , Southern koala [GenBank: JN191337] and fat-tailed dunnart [GenBank: JN191336], the ELP transcripts of the tammar [GenBank: JN191338], fat-tailed dunnart [GenBank: JN191339] and South American opossum [GenBank: JN191340] and CTI transcripts of the cow (Holstein-Friesian breed) [GenBank: JN191341] and dog (Labrador breed) [GenBank: JN191342]. Third party annotations of the ELP/CTI gene were also submitted to GenBank for the cat: [GenBank: BK008083], dog: [GenBank: BK008082], dolphin [GenBank: BK008086], opossum [GenBank: BK008085] and panda [GenBank: BK008084].ril 2011  and UCSCril 2011  genome dPIGTELP/CTI and WFDC2 genes in different species were sourced from either the Ensembl or UCSC genome databases for sequence comparisons using mVISTA , fat-tailed dunnart (FT) [GenBank: JN191339], opossum [GenBank: JN191340], cow (Holstein-Friesian breed) [GenBank: JN191341], dog (Labrador breed) [GenBank: JN191342] and brushtail possum, plus the transcripts predicted from the ELP genes of the stripe-face (SF) dunnart [GenBank: AC186006], koala [GenBank: JN191337], cat [GenBank: BK008083], pig [Ensembl: F1SD34_PIG (ENSSSCT00000008098)], Giant panda [GenBank: BK008084], and Common bottlenose dolphin [GenBank: BK008086] were aligned with ClustalW2. Black shading indicate nucleotide residues common to at least 10 of the species and grey, those that differ. Teal shading indicates nucleotides common to marsupials only, whilst those common to eutherians are shaded blue. The putative translation start site (ATG) is shaded green, the predicted stop codons red, and the polyadenylation signal (AATAAA) is indicated by red text. Nucleotides which encode the signal peptide are indicated by a blue arrow and the Kunitz domain motifs  are indicated by red and green lines, respectively. The codons which encode the 6 cysteine residues that form the 3 disulphide bonds of the 51 amino acid Kunitz domain are boxed red. The putative P1-P1' reactive site residues are shaded yellow and purple respectively. Black arrows indicate the location of ELP exons and gaps within the alignment are indicated (\u2212).Click here for fileTable S2 Percentage similarity between and within the marsupial ELP and eutherian CTI transcripts. Pairwise similarities were determined using MatGAT2.01 software , PTI [GenBank: P00974], STI [GenBank: NP_991355], TKDP1 [GenBank: NP_991345], TKDP2 [GenBank: AF241777], TKDP3 [GenBank: DAA23071], TKDP4 [GenBank: AAF61250], TKDP5 [GenBank: XP_614808] and SPINT4 [GenBank: XP_614808] precursor proteins. Amino acid residues are numbered based upon the translation start of the precursor proteins and indicated on the right hand side of the alignment. The signal peptides were predicted by SignalP and boxed (blue). The region encoded by the Kunitz domain exon is also boxed (red). The six conserved cysteine residues , which form the three disulphide bonds that produce a globular protein are shaded red. Notably, C2 and C4 are absent from the TKDP3 and TKDP4 proteins , PTI [GenBank: NM_001001554], STI [GenBank: NM_205786], TKDP1 [GenBank: NM_205776], TKDP2 [GenBank: NM_001012683], TKDP3 [GenBank: XM_584746], TKDP4 [GenBank: NM_205775], TKDP5 [GenBank: XM_614808], SPINT4 [Ensembl: ENSBTAT00000039210] and SLPI [GenBank: NM_001098865].Click here for fileFigure S6 Genomic arrangement and mVISTA plot of pairwise alignments for the bovine CTI, PTI, STI and TKDP1-5 genes. A. Arrangement and orientation of the bovine chromosome 13 CTI, PTI, STI, TKDP1 TKDP2, TKDP3, TKDP4 and TKDP5 genes. B. (i-viii) Homology between the CTI PTI, STI and TKDP1-5 genes as determined by mVISTA pairwise sequence alignment. Grey horizontal arrows indicate genes, coding exons are indicated by blue boxes and UTRs of the gene as light green rectangles. The right axis indicates the percentage identity for each pairwise comparison within a 100\u2009bp window, ranging from 10% to 100%. Regions sharing greater than 25% identity are shaded and the black horizontal line indicates 70% identity. The horizontal axis indicates the size of the reference sequence used for each comparison: (i) Bovine CTI, (ii)PTI, (iii)STI, (iv)TKDP1, (v)TKDP2, (vi)TKDP3, (vii)TKDP4, and (viii)TKDP5. The CTI Kunitz domain was most similar to that of PTI, STI, and TKDP3, whilst PTI and STI homology was greatest within the TKDP gene family.Click here for fileFigure S7 Transposable elements located within the bovine CTIPTISTI and TKDP1-5 genes. Conserved transposable elements within the CTIPTISTITKDP1TKDP2TKDP3TKDP4 and TKDP5 genes  were identified using CENSOR [TKDP N-domain-encoding exons located between exon 1  and the Kunitz domain-encoding exon (light blue rectangle) were most likely to have arisen due to the \u201cexonisation\u201d of an intron [TKDP5 (A) which is adjacent to a MER21 element may be the ancestral exon of the unique 3-exon N-domains. The ancestral TKDP5 gene was probably then duplicated to produce either the ancestral TKDP4TKDP3 or TKDP2 gene. Within this copied gene, the retroelement (and the exonised intron) was most likely duplicated a further two times (B) and (C), producing a tripartite N-domain of 3 exons: C, B and A (yellow bar 1). This gene subsequently underwent 3 rounds of duplication, resulting in four genes with one N-domain, i.e. three exons which encode the N-domain. Three of these genes, TKDP4TKDP3 and TKDP2, retained the original N-domain. However, for the fourth (TKDP1) the tripartite N-domain was replicated twice (yellow bar 2 and yellow bar 3). The horizontal axis indicates the relative sizes of the regions compared, with all genes transcribed from left to right. Exons are indicated by red rectangles, with the exception of the Kunitz domain-encoding exon which is shown as a blue rectangle. Coloured rectangles indicate the different retroelement classes: Transposable elements: DNA transposon (maroon), LTR  retrotransposons (brown), Endogenous retrovirus (orange), Non-LTR retrotransposons (blue), interspersed repeat (black) and simple repeat (green). White space indicates the absence of transposable elements. Coloured lines link elements conserved between genes. Selected retroelements are identified, with the conserved fragment size and orientation shown . Conserved elements are indicated by coloured text and those that differ, by black text. Arrows indicate the relative orientation of each gene on bovine chromosome 13.g CENSOR ,108. Then intron . Their en intron ,51,63. TClick here for fileTable S4 Location, identity and orientation of transposable elements within the bovine CTIPTISTI and TKDP1-5 genes. CENSOR [CTIPTISTITKDP1TKDP2TKDP3TKDP4 and TKDP5 genes.. CENSOR ,108 outpClick here for fileTable S5 Tammar wallaby mammary gland cDNA microarray data presented in Figure ELP, (ii) LGB and (iii) GAPDH - throughout the lactation cycle derived from custom-made tammar mammary gland cDNA microarrays. Stages of the reproductive cycle investigated included the virgin female mammary gland, Phase 1 (pregnancy), Phase 2A (early lactation), Phase 2B (mid-lactation) and Phase 3 (late lactation). The EBI ArrayExpress Accesion number (E-MTAB-1057) and GenBank Accession numbers for each clone (microarray spot) are provided, plus the average expression of ELP, CTI and LGB and the associated standard deviation and standard errors.Click here for file"}
+{"text": "Animal studies suggest matrix metalloproteinase-8 (MMP8) (neutrophil collagenase) impairs neutrophil (PMN) recruitment in inflammation; in humans, MMP8 has been associated with inflammation. We hypothesized that septic patients with single nucleotide polymorphisms (SNPs) in the MMP8 promoter region will have a survival advantage, and this advantage is due to differences in MMP8 enzymatic activity and not MMP8 levels.We examined data from patients with CAP-associated sepsis (GenIMS), analyzed three functional SNPs  in 1,567 Caucasians and tested associations with 60-day and 90-day mortality and severe sepsis incidence. We simulated functional MMP8 SNPs using anisotropic network modeling. Modeling suggested pro-domain structural stability affecting zymogen activation. Based upon the predictions, we then studied zymogen activation using bioluminescent resonance energy transfer (BRET). We generated recombinant pro-MMP8 with a pro-domain tag of luciferase and carboxy terminus tag of green fluorescent protein. BRET signal was generated when luciferase-cleaved substrate produced a photon transferring energy to the GFP acceptor. GFP in turn emitted a green light signal when the donor/acceptor pairs were spatially close. Upon MMP activation, pro-domain is cleaved causing a loss in BRET signal.P = 0.007). Cumulative incidence showed that the A allele was associated with better 90-day survival. Computer simulation of the mutation suggests a delayed activation. BRET assay confirmed that pro-domain mutation of MMP8 (K87E) rendered it less amenable to activation.The rs1940475 genotype causing an amino acid mutation in the pro-domain was significantly associated with 90-day mortality (AA: 8.5%, AG: 11.1%, GG: 14.7%, Our results suggest altering the structural stability of the inhibitory MMP8 pro-domain impacts enzyme activation. Therapeutics targeting pro-domain could be used to modulate MMP function and control downstream inflammatory processes in sepsis."}
+{"text": "Left ventricular (LV) remodeling following myocardial infarction (MI) is the result of complex interactions between various factors, including presence or absence of early revascularization. Cardiovascular Magnetic Resonance (CMR) imaging with contrast-enhancement (CE) permits assessment of myocardial tissue and LV dimensions and function, but the impact of early revascularization on the relationship between infarct tissue characteristics and LV remodeling has not yet been investigated.We assessed the relation between infarct tissue characteristics and LV remodeling in a consecutive series of patients with vs. without successful early revascularization for prior MI who were examined with CE-CMR for clinical reason.CE-CMR data >1 month  after acute MI were obtained in 93 patients with vs. without successful early revascularization. Cine-CMR measurements included parameters of LV remodeling such as end-diastolic and end-systolic volumes, LV ejection fraction, and wall motion score index (WMSI). CE-CMR images were analyzed for infarct tissue characteristics including core, peri and total infarct size (IS), transmural extent, and regional scar scores.2=0.38-0.46). In patients without successful early revascularization (n=47), only a weak correlation between peri IS and WMSI was found . Figure Effect modification by revascularization status was clear; therefore results were demonstrated separately. In early revascularized patients (n=46), infarct tissue characteristics correlated significantly with all parameters of LV remodeling . Multivariate analyses identified peri IS as the best predictor of all parameters indicating LV remodeling (ROnly in successful early revascularized MI patients, a correlation between infarct tissue characteristics and LV remodeling was demonstrated with peri IS being the best determinant of remodeling. Our findings underline the importance of incorporating infarct tissue characteristics and the success of early revascularization when investigating LV remodeling."}
+{"text": "Footwear is intended to prevent lower extremity injuries caused by excessive foot-ground impacts and faulty mechanics. However, no clear relationship between shoe habits and injury risk has been established . Many stFive healthy participants  with low arch structure completed 10 running trials at 4.0 (\u00b110%) m/s in flat sandal and barefoot conditions. Marker clusters placed on the skin or custom-built wands identified six functional articulations: rearfoot complex (RC), calcaneonavicular complex (CNC), calcaneocuboid joint (CC), medial forefoot (MFF), lateral forefoot (LFF), and 1st metatarsophalangeal complex (MTP). Repeated measures MANOVAs (\u03b1 \u2264 0.05) were used to analyze within-subject sagittal, frontal and transverse plane range of motion (ROM) and initial contact position differences between footwear conditions for the RC, CNC, and CC articulations. Dependent t-tests (\u03b1 \u2264 0.05) were performed to assess MTP, MFF and LFF articulation sagittal plane ROM differences between the footwear conditions.ROM between conditions are shown in Table Runners alter their gait from shod to barefoot running. The ROM differences suggest runners adapt by increasing motion during stance phase. Initial contact positions demonstrate differences in strike pattern. Higher sagittal plane values for barefoot trials may indicate more midfoot/forefoot landing. These data may enhance the understanding of shoe-wear and running-related injuries."}
+{"text": "There is legitimate concern that minority drug-resistant mutants may be selected during the initial HIV-1 RNA decay phase following antiretroviral therapy initiation, thus undermining efficacy of treatment. The goal of this study was to characterize viral resistance emergence and address viral population evolution during the first phase of viral decay after treatment containing initiation.454 sequencing was used to characterize viral genetic diversity and polymorphism composition of the HIV-1 integrase gene during the first two weeks following initiation of raltegravir-containing HAART in four ART-experienced subjects. No low-prevalence Raltegravir (RAL) drug resistance mutations (DRM) were found at baseline. All patients undergoing treatment received a fully active ART according to GSS values (GSS\u2009\u2265\u20093.5). No emergence of DRM after treatment initiation was detected. Longitudinal analysis showed no evidence of any other polymorphic mutation emergence or variation in viral diversity indexes.This suggests that fully active salvage antiretroviral therapy including raltegravir achieves a complete blockade of HIV-1 replication in plasma. It is unlikely that raltegravir-resistant HIV-1 may be selected in plasma during the early HIV-1 RNA decay after treatment initiation if the administered therapy is active enough. There is legitimate concern that minority drug-resistant mutants may be selected during the initial HIV-1 RNA decay phase following antiretroviral therapy initiation, when decreasing but still detectable HIV-1 RNA levels transiently coexist with suboptimal drug levels. Studies using allele-specific PCR suggested that drug-resistant HIV-1 might be selected and replicate in the first weeks of suppressive antiretroviral therapy (ART) . If theyIn the past, however, first-line treatment with 4, 5, or more antiretrovirals did not produce better virological outcomes than standard 3-drug ART [Mathematical models of HIV resistance kinetics predict faster selection of resistant viruses with more potent regimens. On the other hand, previous studies correlated higher resistance selection with longer time to achieving undetectable HIV-1 RNA levels . raltegrWe thus sought to explore in a proof-of-concept study whether raltegravir-resistant mutants were selected during the initial HIV-1 RNA decay following initiation of raltegravir-containing ART in 4 treatment-experienced subjects with HIV-1 resistance to at least 2 antiretroviral drug classes using ultrasensitive, quantitative 454 sequencing. We also sought to characterize the diversity and viral population shifts in HIV-1 integrase during this initial HIV-RNA decay phase.R/ape package [The study included 4 ART-experienced HIV-1-infected subjects who initiated salvage ART including raltegravir (RAL) with more than 3 active drugs (Table\u00a0 package .The genotypic susceptibility score (GSS) of the salvage treatment was \u22653.5 in all patients according to population sequencing. Sensitivity scores were further confirmed considering 454 deep sequencing data obtained for integrase and protease/retrotranscriptase, when available . Initiation of treatment with raltegravir was associated with a rapid decline in HIV-1 RNA levels but no changes in integrase diversity or shifts relative to an HXB2R external reference  are used ,7. Also,In conclusion, raltegravir-resistant HIV-1 may not be selected in plasma during the early HIV-1 RNA decay after salvage treatment initiation, provided that subjects are given a fully effective regimen that is able to shut down plasma replication. Further studies are required to assess whether similar findings might also be observed with other drugs or regimens and to clarify what is the minimum GSS  required to block HIV-1 evolution during HIV-1 RNA decay following ART initiation.The authors declared that they have no competing interest.RP, BC and MN designed the study. CR, SP, and MN performed the analysis, MC and CP performed 454 sequencing experiments, JP collected all samples. RP and MN drafted the article, which was reviewed, edited and approved by all authors.Methods for UDS-454 DNA library preparation and primer design.Click here for fileTable S2. The evolution of HIV integrase diversity during the initial HIV-1 RNA decay. VL: Viral Load, GSS: HIVdb Genotypic Susceptibility Score, NA: Not available. Mean pairwise distance calculated vs HXB2R. Shannon Entropy Score calculated for haplotype set multiple alignments. Table S3. Number of sequence readouts obtained for each Sample/timepoint and Amplicon before and after applying the pNL4-3 contamination filter to raw sequence data. Percent values are shown when \u22650.1%. Table S4. Polymorphisms frequencies at baseline as obtained for each amplicon separately. .Drug resistant mutations at baseline for all patients obtained from 454 Data. NRTI: Nucleoside-analogues Reverse Transcriptase Inhibitor; NNRTI non- Nucleoside-analogues Reverse Transcriptase Inhibitor; PI: Protease Inhibitor; INSTI: integrase strand transfer inhibitor. Click here for fileFigure S2. Longitudinal evolution of summed Shannon Entropy values. Each boxplot shows results from Shannon Entropy values calculated and collapsed for the four integrase amplicons in a particular sample/timepoint combination.Longitudinal evolution mean pairwise distance versus an external reference (HXB2R). Each boxplot shows results from HXB2 referenced pairwise distance for the four integrase amplicons. R/ape package, with a Kimura-80 model was used to calculate pairwise distances. Click here for file"}
+{"text": "PreImplantation factor (PIF) secreted by viable embryos exerts essential regulatory role on global systemic immune response. Synthetic PIF (PIF) translates endogenous effects to immune disorder models. Metastatic melanoma displays tumor-immunological behaviour. Static magnetic field (SMF) affects inflammatory reactions. There is increased interest toward SMF\u2019s potential anti-tumor effects. Herein examined a novel anti-melanoma strategy using combined physical and immune-based therapy.Daily whole-body SMF exposure, combined with subcutaneous PIF administration was examined in engrafted HT199 melanoma cells\u2019 progression, transplanted into NSG mice. PIF effect on unique tumor-associated antigen expression relevant for tumor proliferation/ invasion was examined in vitro using specific antibodies. Direct PIF anti-proliferative effects on several cancer cell lines were tested using MTT.PIF potentiates SMF beneficial effect by reducing tumor volume vs. control (Mmax=96%) on day 34. Metastatic spleen mass is reduced by SMF alone (M=59%) or combined with PIF (M=62%). Daily SMF exposure alone inhibits tumor outgrowth =21.16) while in combination with PIF, effect is considerably potentiated (M=80%), F5.32(P<0.0004)=34.84). PIF did not impair tumor antigen expression nor reduced significantly cultured tumor cell lines\u2019 proliferation.Collectively, results indicate that PIF\u2019s potentiating anti-tumoral effect is mainly immune-regulatory, synergizing with SMF\u2019s pro-tumor necrosis properties. The preserved tumor-associated antigen expression is important for the maintained antitumor immune activity. Overall, combined physico / immune regulatory treatment represents a useful, promising novel avenue for anti-cancer strategy."}
+{"text": "Pulsed arterial spin labeling (PASL) is a non-contrast MRI technique capable of quantifying calf muscle perfusion with comparable accuracy to contrast enhanced-MRI perfusion in normal subjects and peripheral arterial disease (PAD) patients. Peak perfusion can be achieved with exercise or during post-occlusion hyperemia. However, exercise stress may underestimate peak perfusion because of submaximal effort and/or heterogeneous flow. We hypothesized that post-occlusion hyperemia would yield higher peak calf muscle flow compared to peak exercise calf muscle flow measured with PASL.Twenty-five normal subjects with no PAD risk factors or exertional symptoms were enrolled. Peak calf muscle perfusion was measured in 15 volunteers at peak exercise (Ex-PASL) and in 10 volunteers during post-cuff occlusion hyperemia (Cuff-PASL). Ex-PASL volunteers performed supine plantar flexion exercise using a pedal ergometer until exhaustion. Cuff-PASL volunteers had a thigh cuff inflated to 200 mmHg for 5 minutes. At end-exercise or immediately after cuff deflation, 15 averaged PASL images were acquired using a single-shot echo-planar pulse sequence . PASL was performed using the proximal inversion with control for off-resonance effects technique and proximal blood labeling. The QUIPSS II with thin-slice TI1 periodic saturation technique minimized errors from variable transit delay of spins from labeling region to imaging slice and contamination of perfusion signal by intravascular blood. Peak perfusion was measured by placing a region of interest in the calf muscle group with the greatest signal intensity.Fifteen of the subjects had ABI testing and all values were normal. Mean age was 54\u00b19 years for Ex-PASL and 54\u00b17 years for Cuff-PASL. Exercise time (mean\u00b1SD) was 631\u00b1388s. Peak calf muscle perfusion (mean\u00b1SD) was higher with Cuff-PASL than with Ex-PASL , mean difference 44 mL/min-100g (95% CI 22-65mL/min-100g). (Figure Post-cuff occlusion hyperemia yields higher and more homogeneous peak calf muscle perfusion compared to peak exercise in normal volunteers. These characteristics make cuff occlusion an attractive form of stress for patients with PAD in whom peak perfusion may be underestimated due to exercise limiting symptoms. However, exercise does allow testing of specific muscle groups used in the exercise and is a more physiologic stress. Further studies are needed to compare the performance and reproducibility of the two techniques in PAD patients.R01 HL075792, 5T32EB003841"}
+{"text": "Technical developments have led to improvements in myocardial perfusion CMR, particularly through accelerated data acquisition methods. These permit the acquisition of data at higher spatial resolution than conventional CMR techniques, though it is unknown whether this improves diagnostic performance.k-t BLAST with eightfold acceleration and 11 training profiles was used, yielding a mean in-plane spatial resolution of 2.0 x 2.0mm and 103ms shot duration (1). The standard pulse sequence used twofold SENSE acceleration, yielding a mean 2.7 x 2.7mm in-plane resolution and 136ms shot duration. Otherwise the 2 pulse sequences were similar . Each patient also underwent conventional SPECT and X-ray coronary angiography studies (2). Investigations were reported by observers blinded to the other test results.Forty-seven patients with chest pain of potentially cardiac origin underwent two adenosine stress and rest myocardial perfusion studies on separate days. For acquisition of high-resolution data, Dark rim artefact diameter was lower using high-resolution than standard CMR imaging  but image quality did not differ . The sensitivity and specificity of high-resolution CMR were 83% and 91%, standard CMR 74% and 88%, and SPECT 67% and 87% but no statistically significant differences were seen. Receiver operator characteristic curve analysis of summed stress perfusion scores revealed similar diagnostic accuracies for high-resolution and standard CMR techniques (areas under curve 0.87 and 0.84 respectively, p=0.58; figure High-resolution and standard CMR myocardial perfusion imaging show similarly high levels of sensitivity and specificity for the detection of X-ray angiography defined coronary artery disease. Both modalities are at least equivalent to SPECT imaging. Larger studies are needed to definitively determine whether diagnostic accuracy is improved with the high-resolution technique."}
+{"text": "Diagnosis of food allergy relies on clinical history, tests for allergen specific IgE and oral food challenges. A recent reaction consistent with IgE-mediated symptoms in conjunction with a positive allergen-specific IgE test (either skin prick test (SPT) or serum allergen specific IgE (sIgE)) is usually sufficient to diagnose food allergy. In the absence of a reaction history, a positive skin prick test or serum allergen-specific IgE test may not necessarily indicate clinical allergy and it is often necessary to perform resource-intensive and potentially dangerous oral food challenges. We aimed to develop diagnostic algorithms in infants, using sIgE testing, that will minimize the requirement for food challenges and resource utilization of over burdened allergy services.HealthNuts is a population-based, longitudinal food allergy study. Infants were recruited from council-run immunization sessions and underwent SPT to four allergens; those with any evidence of sensitisation were invited to undergo oral food challenges and sIgE testing. Diagnostic pathways of food allergy were identified through expert consultation. Predictive modeling was used to develop sIgE thresholds for each pathway that could accurately identify challenge-confirmed allergic and tolerant infants.Three diagnostic pathways were identified: (A) history of immediate reaction consistent with IgE-mediated food allergy, (B) early-onset eczema in the absence of reaction history, and (C) family history of food allergy in the absence of reaction history. Clinical decision points for egg sIgE testing reduced the need for oral food challenges in pathway A by 89% (95% CI 82-95), pathway B by 82% (95% CI 75-87%) and pathway C by 65% (95% CI 52-76%). Clinical decision points for peanut sIgE testing reduced the need for oral food challenges in pathway A by 81% (95% CI 58-95%), pathway B by 47% (95% CI 39-55%) and pathway C by 71% (95% CI 58-92%). Infants who fell into the indeterminate category (sIgE result between the two thresholds), would still require assessment by specialist allergy services.Our new diagnostic algorithms were highly efficient in minimising oral food challenges and were reliable in a population-based setting."}
+{"text": "Peripheral perfusion assessment is increasingly being recognized as a potential surrogate of global perfusion parameters during septic shock resuscitation. Nevertheless, its correlation with other perfusion parameters is not well established. This study explores the relationship between peripheral perfusion parameters and macrohemodynamic, metabolic, hepatosplanchnic, and micro-circulatory-related parameters during hyperdynamic septic shock.2) septic shock patients  during the first 24 hours of resuscitation. Assessment included: echocardiographic and pulmonary artery catheter-derived parameters; indocyanine green plasma disappearance rate  and gastric tonometry; metabolic parameters  CO2); sublingual microcirculatory assessment (SDF); thenar StO2 and vascular occlusion test (VOT) derived parameters (NIRS); peripheral perfusion parameters including capillary refill time and central to toe temperature difference.Thirty-nine sets of parallel assessments of hemodynamic or perfusion-related parameters were performed in 13 hyperdynamic (cardiac index >2.5 l/minute/mP = 0.009), better metabolic parameters , and better StO2 recovery slope after VOT  as compared with an abnormal one. No correlation could be demonstrated with macrohemodynamic parameters, hepatosplanchnic perfusion parameters (gastric tonometry and ICG-PDR), or with sublingual microcirculatory parameters.Peripheral perfusion was normal in 22 sets (56%) and abnormal in 17 (44%). A normal peripheral perfusion was associated with lower APACHE II scores (23.2 \u00b1 3 vs. 28.4 \u00b1 7, A normal peripheral perfusion is associated with normal metabolic perfusion parameters and less impaired micro-vascular reactivity. No relation between peripheral perfusion and hepatosplanchnic or sublingual microcirculatory flow could be established in this study.ClinicalTrials.gov Identifier: NCT01271153"}
+{"text": "Mycobacterium bovis BCG strains used in different countries and vaccination programs show clear variations in the genomes and immune protective properties of BCG strains. The aim of this study was to characterise the genomic and immune proteomic profile of the BCG 1931 strain used in Mexico.Studies of Region of Difference 1 (RD1), RD2 and N-RD18 and one copy of IS6110, indicating that BCG Mexico 1931 belongs to DU2 group IV within the BCG vaccine genealogy. In addition, this strain contains three new RDs, which are 53 (RDMex01), 655 (RDMex02) and 2,847 bp (REDMex03) long, and 55 single-nucleotide polymorphisms representing non-synonymous mutations compared to BCG Pasteur and BCG Tokyo. In a comparative proteomic analysis, the BCG Mexico 1931, Danish, Phipps and Tokyo strains showed 812, 794, 791 and 701 protein spots, respectively. The same analysis showed that BCG Mexico 1931 shares 62% of its protein spots with the BCG Danish strain, 61% with the BCG Phipps strain and only 48% with the BCG Tokyo strain. Thirty-nine reactive spots were detected in BCG Mexico 1931 using sera from subjects with active tuberculosis infections and positive tuberculin skin tests.BCG Mexico 1931 has a circular chromosome of 4,350,386 bp with a G+C content and numbers of genes and pseudogenes similar to those of BCG Tokyo and BCG Pasteur. BCG Mexico 1931 lacks fadD23) is associated with enhanced macrophage binding and RDMex03 contains genes that may be involved in regulatory pathways. We also describe new antigenic proteins for the first time.BCG Mexico 1931 has a smaller genome than the BCG Pasteur and BCG Tokyo strains. Two specific deletions in BCG Mexico 1931 are described (RDMex02 and RDMex03). The loss of RDMex02 ( Mycobacterium tuberculosis strains  and the partial deletion of two genes [(BCG3926 and BCG3889 (fadD23)] in BCG Mexico 1931 , RDMex02 (655 bp) and RDMex03 . These regions were deleted in the BCG Mexico 1931 sequence based on alignment with the BCG Pasteur and BCG Tokyo sequences. The deletions were confirmed by alignment with the BCG0767 (rpsN1) and BCG0768 (rpsH) genes, which encode two subunits of the 30S ribosomal protein. The biological effect of this deletion is unknown.RDMex01 is an intergenic deletion located between the BCG3889 (fadD23), affecting a conserved region of the protein that includes two transmembrane domains. This gene encodes a probable fatty-acyl CoA ligase involved in lipid degradation. Lynett et al. have reported that this protein is involved in sulpholipid production and that disruption of the gene results in increased association between bacteria and macrophages  belonging to the WhiB protein family (1-7). This family has been proposed to form part of a new redox system in M. tuberculosis . On the basis of functional classes, the genes containing nsSNPs encoded hypothetical proteins (19%), proteins involved in intermediary metabolism and respiration (16%), proteins related to lipid metabolism (16%) and PE/PPE family proteins (16%) , leading to amino acid substitutions Tables . Four SNBCG0510c (pcaA), BCG0532 (regX3), BCG0692c (mma3), BCG0484c (sigK) and BCG3734 (Table BCG0692c (mma3) causes an amino acid change with a concomitant loss of methoxymycolates in BCG strains obtained from the Pasteur Institute after 1927 . To close gaps and resolve duplicated regions, the complete sequences of three fosmids (approximately 40 kb) and 110 PCR end reads were obtained. Annotation was performed using the RAST Server  and BCG Mexico sequences were compared using Consed software  and used to rehydrate 11-cm pH 4-7 IPG strips . Isoelectric focusing (IEF) was performed on a Multiphor II system  until reaching 52,000 VH at 17\u00b0C. The strips were equilibrated twice in a solution containing 4% urea, 30% glycerol (v/v), 50 mM Tris-HCl (pH 8.8), 2% SDS (w/v), and 0.002% bromophenol blue supplemented with 90 mM DTT for the first incubation (15 minutes) and 250 mM iodoacetamide (IAA) for the second incubation (15 minutes). Second-dimension electrophoresis was performed on a 12% polyacrylamide gel  for approximately five hours with a voltage gradient of 50-200 V. Once fixed, the proteins were silver-stained, and gel images were captured in a digital format . Gel analysis was performed using the program 2-D PDQuest Advance V.8.0 . Duplicate gels with proteins obtained from independent cultures were included in the analysis. A master image gel was created using three replicates of each experiment and was used for comparison [mparison .To identify antigenic proteins in BCG Mexico 1931, we conducted an immune blot analysis from the 2D-PAGE gels. Proteins were transferred onto Hybond P polyvinylidene difluoride (PVDF) membranes  using a Trans-Blot SD Semi-Dry Transfer system  for 1 h at 10 V. The membranes were blocked with Tris-buffered saline (TBS) containing 0.05% Tween-20 and 5% skim milk at 4\u00b0C overnight. The membranes were then incubated for 1 h at room temperature with sera from subjects with PPD+, PPD-, pulmonary TB or mycobacterioses caused by NTMs. The membranes were incubated with selected sera from each group having the highest IgG2 titres against each of the groups described above (data not shown). Then membranes were subsequently incubated with an alkaline phosphatase-conjugated mouse anti-human IgG2 antibody  for 1 h at room temperature. Immune detection was accomplished using the Inmobilon Western System . Chemiluminescence signals were measured using the Genius Plus system .M. tuberculosis complex subset of the National Centre for Biotechnology Information (NCBI) non-redundant database (NCBI nr20070623).Reactive proteins were sequenced using a 3200 QTRAP hybrid tandem mass spectrometer  equipped with a nano-electrospray ion source (NanoSpray II) and a MicroIonSpray II head. Proteins were identified based on their MS/MS spectra datasets using the MASCOT search algorithm . A BLAST search was conducted using the Mycobacterium bovis BCG Mexico 1931 has been deposited in the NCBI GenBank database under accession number CP002095. The GenBank accession numbers for the identified protein sequences are: JN034599 (pckA), JN034600 (tig), JN034601 (sahH), JN034602 (atpD), JN034603 (icl), JN034604 (fumC), JN034605 (lpd), JN034606 (tuf), JN034607 (kasA), JN034608 (fadA), JN034609 (kasB), JN034610 (BCGMEX_2464c), JN034611 (thrC), JN034612 (groEL2), JN034613 (BCGMEX_2988), JN034614 (BCGMEX_3456c), JN034615 (TB31.7), JN034616 (tsf), JN034617 (nusG), JN034618 (fixB), JN034619 (BCGMEX_0855c), JN034620 (cysA2), JN034621 (sucD), JN034622 (cfp30B), JN034623 (echA8), JN034624 (fbpC), JN034625 (fbpA), JN034626 (nuoC), JN034627 (ahpC), JN034628 (clpP), JN034629 (ssb), JN034630 (rplL), JN034631 (hspX) and JN034632 (ndkA).The complete genome sequence of BCG: Bacille Calmette-Gu\u00e9rin; DU: Tandem Duplications; NTM: Non-Tuberculous Mycobacteria; nsSNPs: Nonsynonymous SNPs; RD: Regions of Difference; SNPs: Single Nucleotide Polymorphisms; WHO: World Health Organization.PO participated in the design and performance of the experiments, and writing of the paper; IGH and AAH performed experiments; GMH performed protein identification by sequencing; MAC, SPL and YLV participated in the study design and writing of the paper. All authors read and approved the final manuscript.TableS1. Detection data for antigenic proteins in BCG Mexico 1931.Click here for file"}
+{"text": "Onset of transcription is followedby cellular and morphological changes involving cell speciation and gastrulation.Previous genome-wide surveys of transcriptional changes only assessed geneexpression levels; however, recent studies have shown the necessity to mapisoform-specific transcriptional changes. Here, we perform isoform discovery andquantification on transcriptome sequences from before and after zebrafish zygoticgenome activation (ZGA).Zebrafish embryos are transcriptionally silent until activation of the zygoticgenome during the 10pou5f1, sall4 and dnmt1. Genes involvedin cell-cell interactions such as f11r and magi1 display isoformswitches with alterations of coding sequences. We also detect over 1000transcripts that acquire a longer 3\u2019 terminal exon when transcribed by thezygote compared to their maternal transcript counterparts. ChIP-sequencing datamapped onto skipped exon events reveal a correlation between histone H3K36trimethylation peaks and skipped exons, suggesting epigenetic marks being part ofalternative splicing regulation.We identify novel isoforms and isoform switches during ZGA for genes related tocell adhesion, pluripotency and DNA methylation. Isoform switching events includealternative splicing and changes in transcriptional start sites and in 3\u2019untranslated regions. New isoforms are identified even for well-characterizedgenes such as The novel isoforms and isoform switches reported here include regulators oftranscriptional, cellular and morphological changes taking place around ZGA. Ourdata display an array of isoform-related functional changes and represent avaluable resource complementary to existing early embryo transcriptomes. At the time of ZGA, development proceeds from a controlby mRNAs synthesized during oogenesis and stored in the egg  tomRNAs produced by the embryo\u2019s own genome. Following ZGA, blastomeres divide lessfrequently and more asynchronously, they start to differentiate and migrate to form thethree germ layers of the gastrulating embryo . OurRNA-seq data are available under [NCBI GEO GSE22830].RNA-seq: RNA-sequencing; ChIP-seq: Chromatin immunoprecipitation sequencing; ZGA:Zygotic genome activation; MBT: Mid-blastula transition; CDS: Coding sequence; UTR:Untranslated region; TSS: Transcription start site; AS: Alternative splicing; TTS:Transcription termination site; FPKM: Fragments per kilobase per million mappedfragments; ORF: Open reading frame; GO: Gene ontology; FDR: False discovery rate; ES:Exon skipping; AD: Alternative donor site; AA: Alternative acceptor site; IR: Intronretention.The authors declare that they have no competing interests.HA designed the study, wrote the manuscript, made the figures and performed allbioinformatics analysis, including writing python scripts. O\u00d8 performed RT-qPCR,cDNA cloning and sequencing, contributed to figures and the manuscript. ISA performedChIP experiments. LFM collected embryos, isolated RNA and made figures. SM designed thestudy, initiated the RNA-seq experiment and generated all the basic data. PC supervisedChIP-seq work, designed the study and wrote parts of the manuscript. PA designed thestudy, wrote the manuscript and supervised the work. All authors approved the finalmanuscript.Supplementary figures 1\u20139.Click here for fileNon-redundant gene annotations file containing a merger of all Ensembl andassembled transcripts.Click here for fileExpression values pre-ZGA and post-ZGA for all isoforms in the\u2018all\u2019 gene annotation.Click here for fileGene annotation for robustly expressed isoform (>3 FPKM pre-ZGA orpost-ZGA).Click here for fileTest results for whether loci with multiple TSSs exhibited a shift in TSSusage between pre-ZGA and post-ZGA.Click here for fileGO term analysis results from DAVID of genes marked with H3K4me3.Click here for fileGO term analysis results from DAVID of genes marked with H3K27me3.Click here for fileAnatomical ontology results from DAVID of genes marked with H3K4me3.Click here for fileAnatomical ontology results from DAVID of genes marked with H3K27me3.Click here for fileResults from a statistical test of whether genes exhibit a significantchange in alternative splicing between pre-ZGA and post-ZGA.Click here for fileResults from sequencing of cloned dnmt1 fragments.Click here for fileResults from sequencing of cloned pou5f1 fragments.Click here for fileAll last exons with evidence for an extended 3\u2019UTR post-ZGA relativeto the pre-ZGA.Click here for fileDifferent scripts used in the analyses.Click here for fileA list with description of the primers.Click here for file"}
+{"text": "Previous studies suggest that HTLV-1 PVL remains constant over time. We compare PVL, at baseline and follow-up, in patients with rapidly progressive HAM/TSP who received empirical treatment.4 PBMC.Rapidly progressive HAM/TSP was defined by patients\u2019 incapacity to walk unaided within two years after symptoms\u2019 onset. These cases are treated at our center with prednisone in combination with Lamivudine and/or Zidovudine at standard doses. PVL were performed by duplicate in PBMC of blood samples drawn before (baseline) and during treatment; values are reported in copies /10We evaluated 11 patients (6 women); their median age was 50 years-old, interquartile range [IQR] 20, with significant differences between men and women . Median HAM/TSP duration at diagnosis was 12 months (IQR 4). The median time  between the symptoms onset and the beginning of therapy was 14 (IQR: 9); between HAM/TSP onset and the baseline PVL, 14 (IQR: 13); between PVL determinations, 7 (IQR: 7). Median PVL values were 1183 (IQR: 1425) at baseline, and 1002 at follow-up (IQR: 1425). In the group of 7/11 patients where PVL decreased, differences between baseline and follow-up determinations were significant (p=0.01), with a median paired reduction of 362 (IQR: 1425). In the four cases where PVL increased, differences were not significant (p=0.06).In most of the cases here reported, PVL decreased significantly during empirical therapy. Clinical correlates and long-term evaluation of these findings demand controlled therapy trials."}
+{"text": "Autistic spectrum disorder (ASD) is characterized by impaired language,communication and social skills, as well as by repetitive and stereotypicpatterns of behavior. Many autistic subjects display a dysregulation of theimmune system which is compatible with an unresolved viral infection withprenatal onset, potentially due to vertical viral transmission. Recently,the xenotropic murine leukemia virus-related virus (XMRV) has beenimplicated in chronic fatigue syndrome (CFS) and in prostate cancer byseveral, though not all studies.gag genomic sequences, we screened DNA samples from:(i) peripheral blood of 102 ASD patients and 97 controls, (ii) post-mortembrain samples of 20 ASD patients and 17 sex- and age-matched controls, (iii)semen samples of 11 fathers of ASD children, 25 infertile individuals and 7fertile controls. No XMRV gag DNA sequences were detected,whereas peripheral blood samples of 3/97 (3.1%) controls werepositive for MLV.We assessed whether XMRV or other murine leukemia virus (MLV)-related virusesare involved in autistic disorder. Using nested PCR targeted toNo MLV-related virus was detected in blood, brain, and semen samples of ASDpatients or fathers. Hence infection with XMRV or other MLV-related virusesis unlikely to contribute to autism pathogenesis. Ourresults do not support the frequent involvement of XMRV or MLV-related viruses inautism pathogenesis.Using nested PCR, XMRV and MLV post-mortem brain tissues dissected from the superiortemporal gyrus (Brodmann Areas 41/42 or 22) were obtained through the AutismTissue Program from the NICHD Brain & Tissue Bank  and theHarvard Brain Tissue Resource Center . These tissue samples largelyoverlap with those employed in our previous studies All subjects, except for post-mortem brain donors, were recruited in Italy andare ethnically Italian. The demographic characteristics of these samples aresummarized in gag nested PCR was performed as previously described DNA was recovered by phenol/chloroform extraction and ethanol precipitation,following cell digestion with proteinase K at 55\u00b0C overnight. XMRVgag sequences were detected in 96 blood samplesand 20 post-mortem brains of ASD patients, as well as in 25 semen fractionsbelonging to 9 fathers of ASD children (gag sequences. Three out of 97 (3.1%) peripheral bloodsamples from unaffected controls were positive . No mousegenomic contamination was detected in these three positive MLV control samples bynested PCR targeting the mouse histone deacetylase 5 (Hdac5) gene.No MLV-related virus children . Similarchildren  were negpositive . The difOur results show that infection with XMRV or other MLV-related viruses, assessed bothin the central nervous system and in blood, is not associated with ASD nor is likelyimplicated in vertical viral transmission through parental gametes. We thusreplicate and largely extend a recent study reporting no association between XMRVinfection and autistic disorder A search for viruses as primary etiological agents in autism is well justified.Congenital infection with rubella or cytomegalovirus (CMV) represents one of thebest-documented environmental factors significantly associated with ASD (for reviewsee XMRV represents an interesting candidate to potentially play a role in autismpathogenesis. It was initially identified by PCR in approximately 10% ofprostate cancer patients Our results, combined with those reported by Sutherfield et al"}
+{"text": "Progesterone receptors (PR) are emerging as important breast cancer drivers. Phosphorylation events common to breast cancer cells impact PR transcriptional activity, in part by direct phosphorylation. PR-B but not PR-A isoforms are phosphorylated on Ser294 by mitogen activated protein kinase (MAPK) and cyclin dependent kinase 2 (CDK2). Phospho-Ser294 PRs are resistant to ligand-dependent Lys388 SUMOylation . Antagonism of PR small ubiquitin-like modifier (SUMO)ylation by mitogenic protein kinases suggests a mechanism for derepression  of target genes. As a broad range of PR protein expression is observed clinically, a PR gene signature would provide a valuable marker of PR contribution to early breast cancer progression.Global gene expression patterns were measured in T47D and MCF-7 breast cancer cells expressing either wild-type (SUMOylation-capable) or K388R (SUMOylation-deficient) PRs and subjected to pathway analysis. Gene sets were validated by RT-qPCR. Recruitment of coregulators and histone methylation levels were determined by chromatin immunoprecipitation. Changes in cell proliferation and survival were determined by 3--2,5-diphenyltetrazolium bromide (MTT) assays and western blotting. Finally, human breast tumor cohort datasets were probed to identify PR-associated gene signatures; metagene analysis was employed to define survival rates in patients whose tumors express a PR gene signature.MSX2, RGS2, MAP1A, and PDK4) with the steroid receptor coactivator, CREB-(cAMP-response element-binding protein)-binding protein (CBP), and mixed lineage leukemia 2 (MLL2), a histone methyltransferase mediator of nucleosome remodeling. PR SUMOylation blocks these events, suggesting that SUMO modification of PR prevents interactions with mediators of early chromatin remodeling at 'closed' enhancer regions. SUMO-deficient (phospho-Ser294) PR gene signatures are significantly associated with human epidermal growth factor 2 (ERBB2)-positive luminal breast tumors and predictive of early metastasis and shortened survival. Treatment with antiprogestin or MEK inhibitor abrogated expression of SUMO-sensitive PR target-genes and inhibited proliferation in BT-474 (estrogen receptor (ER)+/PR+/ERBB2+) breast cancer cells.'SUMO-sensitive' PR target genes primarily include genes required for proliferative and pro-survival signaling. DeSUMOylated K388R receptors are preferentially recruited to enhancer regions of derepressed genes  phospho-PRs may benefit from endocrine (antiestrogen) therapies that contain an antiprogestin. Breast cancer is the most commonly diagnosed cancer in women, and the second leading cause of cancer-related death . The molin vivo . These gene lists were uploaded into the IPA software where a core analysis was completed to determine the association of each gene with various biological functions or network pathways. IPA comparison analyses were used to reveal whether or not cells expressing WT or KR PR upregulated functionally distinct pathways. Analyses were scored based on significance  and the threshold for a gene list to be significantly involved in a particular biological function was P < 0.05  > 1.30).Ingenuity Pathway Analysis (IPA) was used to compare two distinct gene lists: those upregulated by progestin in T47D cells expressing WT PR compared to genes upregulated by progestin in cells expressing SUMO-deficient PR [See Additional file Metagene analysis was conducted using gene expression microarray data from cell lines constitutively expressing empty vector, WT PR, or K388R PR, and treated with either vehicle or R5020. A strategy of identifying metagenes within each sample was employed using non-negative matrix factorization . This stet al. human breast tumor dataset [et al. data are supplied as z-scores, the data were un-logged and used in the fcnnls algorithm . Samples were taken to express a metagene if they showed a non-zero value in the fitted coefficient matrix (scoring matrix).The Loi  dataset  contains dataset  was load dataset  for procP < 0.01) as measured using either platform (Illumina and Affymetrix were combined) and duplicates were removed before Venn diagram comparison to previously known upregulated genes using the bioinformatics tool, VENNY [Ligand-dependent and -independent PR-target gene lists from two previously published studies ,22 were l, VENNY .Gene set enrichment analysis (GSEA) software ,33 was e6 cells per 15 cm culture dish in cMEM for two days, then serum starved in modified IMEM for two days. Cells were treated with R5020 (10-8 M) or vehicle for one or four hours. For T47D cells expressing inducible PR, AP21967 (10-9 M) was added during the starvation step. Chromatin was sheared using a Bioruptor sonicator , for 30 minutes (30 seconds on/off). Immunoprecipitations were prepared with 60 ul of sheared chromatin, 2 ug antibody and immunoprecipitated overnight. Using the purified ChIP and input DNA, relative recruitment was determined by qPCR in triplicate. Assays were performed on a Roche LightCycler II using SYBR green master-mix. Target locus quantification was normalized as a percentage of the input DNA quantification.Chromatin immunoprecipitation (ChIP) assays were performed according to the ChIP-IT Express instruction manual . Cells were plated at 15 \u00d7 106 cells were plated in cMEM, serum starved in modified IMEM and induced with AP21967 (10-9 M) treatment for two days. One day later, cells were treated with R5020 (10-8 M) for four hours and chromatin was harvested and immunoprecipitated as previously described [To assay H3K4me2 levels, nucleosomes were isolated using micrococcal nuclease (MNase). In 15 cm dishes, 12 \u00d7 10escribed .4 cells/well were plated in cMEM (inducible PR expression was induced with AP21967 (10-9 M) for two days), cells were washed and steroid starved in modified IMEM supplemented with 5% dextran-coated charcoal-treated (DCC) FBS for one day before the addition of R5020 (10-8 M). At days 0, 2, 4, and 6, cell proliferation was determined by adding 60 ul MTT (5 mg/ml) to each 0.5 ml cell culture well for three hours, medium was carefully removed and solubilization solution (90% v/v dimethyl sulfoxide (DMSO)/PBS) was added to lyse the cells. Lysate absorbance (650 and 570 nm) was measured using a plate reader. The 650 nm measurements were subtracted from 570 nm measurements and sample means were normalized to day zero.Cell proliferation was measured using MTT assays . In 24-well plates, 1 \u00d7 106 cells/dish) in cMEM and induced with AP21967 (10-9 M). Cells were washed, induced, and serum starved for four days. Cells were then treated with R5020 (10-8 M) for six hours before adding doxorubicin (8 uM) to dishes for 24 hours. Protein was harvested using standard RIPA lysis buffer, subjected to SDS-PAGE and western blotting using cleaved-PARP and PR antibodies. Beta-actin western blotting was performed for sample loading controls.Poly (ADP)-ribose polymerase 1 (PARP) cleavage assays were used to measure the level of apoptosis in cell cultures after treatment with cytotoxic concentrations of doxorubicin. T47D cells expressing inducible PR were plated in 10 cm dishes (2 \u00d7 104 cells/well) containing cMEM. Cells were washed and steroid starved in modified IMEM supplemented with 5% DCC FBS for one day. Cells were treated with R5020 (10-8 M) for six hours before doxorubicin (6 uM) was added to the wells. After four days, cell viability was determined by adding Cell-Titer-Glo substrate and luminescence was measured using a plate reader. Sample means were normalized to day zero ).Cell viability after treatment with cytotoxic doxorubicin was determined by measuring the concentration of ATP, which is directly proportional to viable cell number , using CRGS2) were queried in The Cancer Genome Atlas (TCGA) Breast 2 dataset. Oncomine output data was sorted to isolate 'cancer versus normal' associations and reported , Invasive Ductal and Lobular Carcinoma (RGS2), Intraductal Cribriform Breast Adenocarcinoma (MAP1A), and Mucinous Breast Carcinoma (PDK4).The relative expression of individual PR target genes in human breast tumor samples was determined by searching the Oncomine database . Individ Figure  as the cMultiple breast cancer 'concepts', as described in the Oncomine database, were associated with the ligand dependent (LD) KR > WT gene signature [See Additional file For unknown reasons, there is little overlap between PR-regulated genes in normal, relative to neoplastic, breast tissues . One mec-8 M), for six hours  is over-expressed in the basal/myoepithelial compartment and substantially elevated in a majority of breast tumors [BCL2L11 (BIM) is a pro-apoptotic mediator involved in ERBB/MAPK-dependent luminal cell clearing [We identified genes that were upregulated > 1.5 fold by PR in a LD orLI manner and discovered gene expression overlap between cells expressing either KR or WT receptors, as well as subsets of uniquely regulated genes Figure . Notablyt tumors . In contclearing  whose ex-9 M) and R5020 (10-8 M) and assayed for changes in gene expression using the Affymetrix U133A 2.0 microarray platform. Remarkably, PR-dependent gene expression profiles obtained from T47D cells stably expressing PR (assayed using the Illumina platform) were significantly similar to gene array data obtained from the same parental cells (T47D) inducibly expressing PR  than previous reports [These results essentially repeated in T47D cells engineered to express either WT or KR PR from an inducible vector system [See Additional file  reports ,22; micr reports .MSX2, RGS2, MAP1A and PDK4) from our microarray analysis for further study. These specific genes were dramatically upregulated in cells expressing KR, but not WT receptors  in the absence or presence of the PR antagonist, RU486 (10-7 M) for six hours . Additionally, their R5020-induced mRNA expression was completely abolished by addition of RU486, indicating that regulation of these genes is indeed entirely PR-dependent.To investigate mechanisms of regulation of 'SUMO-sensitive' PR-target genes, we selected four genes , we employed PR-null T47D cells or T47D cells stably expressing WT, KR, or phospho-mutant S294A (SA) PR-B [We showed previously that SUMO-deficient KR receptors closely mimic phospho-Ser294 (WT) PR species . To demoSA) PR-B . MutatioSA) PR-B . Consist-8 M). Both MAP1A and RGS2 were insensitive to EGF alone over a two-day time course  T47Dco cells treated for six hours . Taken together, our data suggest that PR dynamically regulates multiple endogenous genes according to its phosphorylation and SUMOylation status; growth factors favor phospho-PR that act as derepressed transcription factors.Treatment of breast cancer cells with EGF induces robust PR Ser294 phosphorylation and deSUMOylation . We there Figure . Howevere Figure . We obses Figure . PerhapsMSX2. Similar to PR-B, this homeobox transcription factor is essential for mammary gland development and transgenic expression of MSX2 causes ductal hyperplasia in mice [MSX2 induces cyclin D1 and E1 expression [et al. [MSX2 expression is significantly elevated in both luminal B and HER2-enriched molecular subtypes of breast cancer, despite being associated with good prognosis . We identified multiple consensus progesterone response element (PRE) sequences up- and downstream of the MSX2 transcriptional start site using MatInspector software [MSX2 is transcriptionally upregulated in response to progestin treatment of T47D or MCF-7 cells stably or inducibly (T47D) expressing SUMO-deficient PR, but not WT receptors , and performed ChIP assays. Following progestin treatment, both WT and KR PR were readily detected at the PRE enhancer region  activity [MSX2 locus is significantly elevated in cells expressing SUMO-deficient KR PR, but not WT PR  were treated with R5020 (10-8 M) for four hours and nucleosomes were isolated after micrococcal nuclease (MNase) digestion; histone methylation was determined by ChIP, followed by qPCR  to visualize local histone dimethylation patterns  are epigenetic modifications known to significantly impact chromatin dynamics and thereby affect changes in gene expression (reviewed in ). GeneraR Figure  left. H3s Figure  right. PMSX2 enhancer in cells expressing either iWT or iKR PR. Recently, a chromatin remodeling complex, including the subunit mixed lineage leukemia 2 (MLL2) methyltransferase, was implicated in progestin-dependent H3K4 trimethylation [MSX2 enhancer in progestin treated cells expressing SUMO-deficient KR PR, but not WT PR . In contrast, pre-existing 'open' regions may be insensitive to PR SUMO modification . Additionally, preferential association of SUMO-deficient PR with other factors  may contribute to PR promoter selection; KR recruitment to the MSX2 enhancer region is significantly enhanced relative to WT receptor in the presence of progestin  in cells stably expressing either WT or KR receptors. Upon progestin treatment, SUMO-deficient PR, but not WT, significantly upregulated gene sets assigned to multiple proliferative and pro-survival biological functions [See Additional file Ingenuity Pathway Analysis  softwarMTT assays measure viable (surviving) cells over time and PRs have been implicated in breast cancer cell pro-survival ,61. ThusP < 0.01). These genes were predominantly upregulated in cells expressing KR receptors and/or downregulated only in cells expressing WT receptors. This analysis was performed for both ligand-dependent and ligand-independent PR target genes. Using these criteria, unique 151- and 92-gene signatures were created and defined as PR-target genes differentially upregulated (compared to WT) by LD and LI KR receptors, respectively [See Additional file Human breast cancers often contain high levels of MAPK, AKT, and/or CDK protein and/or kinase activities, thus favoring PR derepression ,16. To pP < 0.0001, FDR < 0.01) [See Additional file These gene signatures were then uploaded into the Oncomine Research Premium Edition (Compendia Bioscience ) and thein vitro; similar results were observed with the MEK inhibitor, U0126 (data not shown). We first measured the expression of PR target genes (CHN2 and RGS2) primarily regulated by KR  compared to KR PR (approximately 20-fold) , although phospho-Ser294 PR is readily detected, total PR levels are greatly diminished and appear undetectable (lane two), presumably due to LD (proteasome-mediated) downregulation of activated PR species [CHN2 and RGS2 expression  SR-positive breast cancer cells. Similar to CHN2 and RGS2  might represent independent means utilized by breast cancer cells to drive cell proliferation and survival. Indeed, HER2-enriched breast cancers are frequently SR negative ,66. Altey Figure . Recall ) Figure . ACOT6 e6 Figure . Note th species . Pre-tre2 Figure , we predet al. dataset [P = 0.000785; Figure P < 0.1). To include the contribution of LI (KR) PR target genes, we combined patients whose tumors expressed both KR metagenes (KR -R5020 or KR +R5020). These patients experienced significantly reduced distant metastasis free survival relative to those whose tumors did not express either of the two KR metagenes (P = 0.0261)  Figure . With reIn this study, we performed gene expression profiling to understand better how PR SUMO modification impacts transcriptional activity and promoter selection. Using newly engineered breast cancer cell line models, we identified a (deSUMOylated) PR-driven gene signature that is present in human tumors and associated with decreased patient survival. Previously, we showed that PR phosphorylation at Ser294 antagonizes PR SUMOylation at Lys388 . Our novHBEGF, IRS1, and STC1 [We previously reported that PR SUMOylation is transcriptionally repressive at a limited number of endogenous gene loci, including and STC1 ,16; all and STC1 -74. In tand STC1 ,22 but aNotably, our comparison of genes regulated by WT versus KR PRs revealed considerable overlap suggesting that the majority of PR regulated genes are relatively insensitive to dynamic modification of PR-B by SUMOylation/deSUMOylation  was entirely blocked; transcriptional upregulation was rescued in cells expressing the PR K388R/S294A double mutant , and tends to slow the rate of ligand-dependent PR downregulation via proteasome mediated turnover [MSX2; expression was substantially upregulated by SUMO-deficient KR PR, but not WT PR  alters co-factor interactions that occur at the level of PR DNA binding. Related to this finding, PIAS3, a PR SUMOylation E3 ligase, directly inhibits PR binding to PRE DNA sequences in vitro [Modification of protein substrates by the addition of SUMO molecules can influence protein-protein interactions and/or alter protein stability, localization, or transcriptional activity (reviewed in ). PR SUM1Fturnover , but doeturnover . NumerouR Figure . Additior Figure . The finin vitro . Thus, Pet al. [MSX2 enhancer in cells expressing SUMO-deficient KR PR, compared to WT PR. In this model, deSUMOylated PR may preferentially recruit the histone methyltransferase, MLL2 , resulting in sustained H3K4 dimethylation that allows formation of productive transcriptional complexes at active sites that are normally repressed by SUMOylated receptors.Promoter structure is likely to be an important determinant of promoter selection by SUMOylated transcription factors, including PR. Holmstrom et al.  found thet al. . Relatedet al. ,83. Indeet al. . H3K4me2et al. . We haveFinally, DNA binding specificity for SRs is also highly dependent on sequence composition. Studies investigating GR demonstrate that single base pair changes in consensus GRE/PRE sequences can dramatically affect receptor binding and cofactor interaction . Thus, DTargeting ER function in luminal breast cancers with selective ER modulators  and/or aromatase inhibitors  is very effective for a majority of women ,88. Indede novo progesterone synthesis, a process mediated by growth factor-dependent signaling [Indeed, much research has shown that PR is not only a clinical marker of functional ER expression, but also an important independent driver of tumor progression (reviewed in ). Notablignaling -94. TumoSurprisingly, we found that breast cancer cells expressing deSUMOylated phospho-PR drive the expression of cell proliferation genes [See Additional file The intense study surrounding the molecular subtypes of breast cancer has provided great insights into genetic characteristics of this heterogeneous cancer , but curWe have determined that PR transcriptional action is more complex than originally thought, insofar as PR are sensors for mitogenic stimuli whereby phosphorylation events drive the receptor toward the deSUMOylated state, resulting in a dramatically altered transcriptional program that promotes cell proliferation and pro-survival. We have uncovered a deSUMOylated phospho-PR gene signature of both known and novel PR target genes that is a marker of hyperactive PR signaling in breast cancer cell models; this signature is indeed also present in a subset of patients with recurrent breast cancer Figures.  and 5D. Bp: base pair; BH: Benjamini and Hochberg; BUS: B upstream segment; CBP: CREB-(cAMP-response element-binding protein)-binding protein; CDK: cyclin dependent kinase; ChIP: chromatin immunoprecipitation; cMEM: complete minimal essential medium; DCC: dextran-coated charcoal treated; EGF: epidermal growth factor; ER: estrogen receptor; ERBB2/HER2: human epidermal growth factor receptor 2; FBS: fetal bovine serum; GR: glucocorticoid receptor; GSEA: gene set enrichment analysis; H3K4me2: histone H3 lysine 4 dimethylation; HAT: histone acetyl-transferase; HRT: hormone replacement therapy; IQR: interquartile range; IPA: ingenuity pathway analysis; KR: K388R PR-B mutant; KRSA: K388R and S294A PR-B mutant; LD: ligand dependent; LI: ligand independent; MAPK: mitogen activated protein kinase; MLL2: mixed lineage leukemia 2; MNase: microsomal nuclease; NEAA: non-essential amino acids; PARP: poly (ADP) ribose polymerase 1; PR: progesterone receptor; PRE: progesterone receptor response element; RIPA: radioimmunoprecipitation assay; RTqPCR: reverse transcriptase quantitative polymerase chain reaction; SA: S294A PR-B mutant; SERM: selective estrogen receptor modulator; SR: steroid receptor; SUMO: small ubiquitin-like modifier; WT: wild-type PR-B.The authors declare that they have no competing interests.TPK and CAL conceived of the study, participated in its design and coordination, and drafted the manuscript. TPK performed all experiments and analyses except where noted below. ARD carried out the western blot in Figure Genes differentially regulated by wild-type and SUMO-deficient PR. Gene names and their normalized expression values from each Venn diagram category  and BH adjusted P < 0.01 are presented in the corresponding Excel worksheets. In each worksheet, multiple sample comparisons  and the log2 normalized intensities are displayed for each gene. Data were sorted based on the highest expression (log2 fold change) in the specific sample comparison being presented in each corresponding Excel worksheet (columns highlighted with grey cell background color). If multiple probe sets represented a single gene, the probe set with the highest expression value was used in downstream analyses and other probe sets were removed.y Figure  were orgClick here for fileCreation and validation of isogenic models of inducible PR expression in T47D cells. (A) Clonal inducible cell lines were developed as described in the Materials and methods section and PR protein expression was determined by western blotting after treatment with inducer molecule AP21967 for two days and R5020 for one hour. Progestin-dependent PR phosphorylation was measured using a PR phospho-Ser294 specific antibody. Beta-actin western blotting was performed as a loading control. Short-term treatment with R5020 demonstrated progestin-dependent PR global phosphorylation  and equal levels of ligand-dependent Ser294 phosphorylation. (B) Gene set enrichment analysis (GSEA) comparison of whole genome expression profiling data sets derived from two independent model systems and platforms: (i) T47D cells stably expressing WT and mutant KR PRs (-/+R5020) using the Illumina HT-12v4 platform and (ii) T47D cells expressing inducible WT or mutant KR PR  using the Affymetrix U133A 2.0 platform. Genes most upregulated in the Illumina dataset by WT +R5020 (or KR +R5020) appear on the far left (darkest red) and genes most downregulated by WT +R5020 (or KR +R5020) appear on the far right side (darkest blue). Using the GSEA application, Affymetrix genes  were positioned along the Illumina dataset (from upregulated to downregulated genes) and the statistical enrichment score was determined. All the treatment groups between Affymetrix and Illumina were statistically significant (P < 0.001). (C) Gene expression levels were validated for two PR target genes (MSX2 and MAP1A) in T47D cell lines expressing iWT and iKR PR. Cells were treated with AP21967 to induce PR expression and co-treated with RU486 and/or R5020 before RT-qPCR gene expression analysis. Data are represented as mean of n = 3 +/- SD.Click here for fileOverlapping lists of PR-dependent target genes from previously described gene expression microarrays. Excel workbook comparing previously known PR target genes [P < 0.01. Analyses were performed for genes upregulated in response to progestin treatment or genes upregulated in ligand-independent conditions. Analyses of genes downregulated by PR were omitted (few PR target genes were previously known to be downregulated by PR-B). Notably, very few ligand-independent PR target genes have been reported to date [et genes ,22 to no to date . PerhapsClick here for fileRelative recruitment of WT and SUMO-deficient PR molecules to selected PR target gene enhancers. (A) Recruitment of PR molecules to consensus PRE sequences in upstream promoter/enhancer regions of RGS2, MAP1A, and PDK4 (following one hour R5020) was measured by standard ChIP assay in inducible models of T47D cells expressing WT (iWT) and KR (iKR) receptors. Recruitment of PR to an intronic region of the HBB gene was included as a negative control. (B) ChIP assays were performed as in part A, to demonstrate differential PR recruitment to a RGS2 enhancer in T47D cells stably expressing either WT or SUMO-deficient (KR) PR. Data are represented as mean of n = 3 +/- SD.Click here for fileMSX2 proximal promoter regionRecruitment of phospho-Ser5 and total-RNA polymerase II to the . (A) Recruitment of total RNA polymerase II to the MSX2 proximal promoter region (following one hour R5020) was measured by standard ChIP assay in inducible models of T47D cells expressing WT (iWT) and KR (iKR) receptors. (B) ChIP assay was performed as in part A, using an antibody targeting functionally active RNA polymerase II, as measured by detection of CTD Ser5 phosphorylation. Data are represented as mean of n = 3 +/- SD.Click here for fileSUMO-deficient PR upregulates genes involved in cell proliferation determined by Ingenuity Pathway Analysis. Significant expression (y-axis) of multiple cellular functions (x-axis) containing genes upregulated by progestin  in cells expressing either WT or KR PR. Biological pathways that contain a significant number of upregulated genes display bars above the horizontal line, representing BH adjusted P < 0.05.Click here for fileThe ligand-dependent (LD) and ligand-independent (LI) KR > WT gene signatures. For each gene signature, the gene names, normalized expression values, and the BH adjusted P values are provided for all biological samples and sample comparisons. The LD (151 genes) and LI (92 genes) KR > WT gene signature lists are provided in whole.Click here for fileBreast tumor Oncomine concepts associated with PR dependent gene signatures. This Excel workbook contains detailed data produced from the Oncomine analysis described in Figure Click here for fileDetailed antibody and PCR primer set information. This Excel workbook contains all the antibody information and primers sets used in RT- and ChIP-qPCR assays.Click here for file"}
+{"text": "NF-\u03baB is a master gene regulator involved in plethora of biological processes, including lymphocyte activation and proliferation. Reversible ubiquitinylation of key adaptors is required to convey the optimal activation of NF-\u03baB. However the deubiquitinylases (DUBs), which catalyze the removal of these post-translational modifications and participate to reset the system to basal level following T-Cell receptor (TCR) engagement continue to be elucidated.Here, we performed an unbiased siRNA library screen targeting the DUBs encoded by the human genome to uncover new regulators of TCR-mediated NF-\u03baB activation. We present evidence that knockdown of Ubiquitin-Specific Protease 34 (USP34) selectively enhanced NF-\u03baB activation driven by TCR engagement, similarly to siRNA against the well-characterized DUB cylindromatosis (CYLD). From a molecular standpoint, USP34 silencing spared upstream signaling but led to a more pronounced degradation of the NF-\u03baB inhibitor I\u03baB\u03b1, and culminated with an increased DNA binding activity of the transcription factor.Collectively, our data unveils USP34 as a new player involved in the fine-tuning of NF-\u03baB upon TCR stimulation. Nuclear factor-\u03baB (NF-\u03baB) transcription factors initiate transcription of genes essential for mounting an adequate immune response . UbiquitTo identify additional negative regulators of TCR-mediated NF-\u03baB activation, we conducted a siRNA library screen against 98 DUBs through a gene reporter luciferase assay in Jurkat T cells stimulated with either anti-CD3 and anti-CD28 antibodies or PMA plus ionomycin to mimic TCR engagement Figure\u00a0 and 2. AIn addition to NF-\u03baB, TCR ligation kindles various signaling pathways including Nuclear factor of activated T-cells (NFAT) and the Mitogen-activated protein kinase (MAPK) Extracellular signal-regulated kinases (ERK) . Gene reTo gain insights on the signaling basis for the exacerbated NF-\u03baB activity in USP34-depleted cells, we first examined BCL10 and MALT1 ubiquitinylation status since it governs the strength of TCR-mediated NF-\u03baB activation . BCL10 uAlmost 100 DUBs were identified in the human genome and yet, only a few have been ascribed a function . As for CYLD: Cylindromatosis; DUBs: Deubiquitinylases; ERK: Extracellular signal-regulated kinases; I\u03baBs: Inhibitors of NF-\u03baB; IKK: I\u03baBs kinase; MAPK: Mitogen-activated protein kinase; NFAT: Nuclear factor of activated T-cells; NF-\u03baB: Nuclear factor-\u03baB; PMA: phorbol 12-myristate 13-acetate; TCR: T-Cell receptor.The authors declare that they have no competing interests.KP designed and conducted most experiments, analyzed the data and wrote the manuscript. EMH, NC, SMD, HML, CL, and CA designed and conducted experiments, and analyzed the data. EMH and JG helped drafting the manuscript. JG and AV analyzed the data. NB conceived the project, analyzed the data and wrote the manuscript. All authors read and approved the final version of the manuscript.Methods description.Click here for fileDesign of the siRNA library screen.Click here for fileBCL10 and MALT1 ubiquitinylation, CBM assembly, and IKK phosphorylation in USP34-silenced cells.Click here for fileCYLD and USP34 silencing enhanced etoposide- and TNF\u03b1-mediated NF-\u03baB activation.Click here for file"}
+{"text": "Sodium acetate, at doses comparable to that generated by complete GTA catalysis, but not glycerol also promoted growth arrest, whereas long chain triglycerides promoted cell growth. To begin to elucidate its mechanism of action, the effects of GTA on ASPA and acetyl-CoA synthetase protein levels and differentiation of established human oligodendroglioma cells (HOG and Hs683) and primary tumor-derived oligodendroglioma cells that exhibit some features of cancer stem cells (grade II OG33 and grade III OG35) relative to an oligodendrocyte progenitor line (Oli-Neu) were examined. The nuclear localization of ASPA and acetyl-CoA synthetase-1 in untreated cells was regulated during the cell cycle. GTA-mediated growth arrest was not associated with apoptosis or differentiation, but increased expression of acetylated proteins. Thus, GTA-mediated acetate supplementation may provide a safe, novel epigenetic therapy to reduce the growth of oligodendroglioma cells without affecting normal neural stem or oligodendrocyte progenitor cell proliferation or differentiation. Cancer is associated with globally hypoacetylated chromatin and considerable attention has recently been focused on epigenetic therapies. N-acetyl-L-aspartate (NAA), the primary storage form of acetate in the brain, and aspartoacylase (ASPA), the enzyme responsible for NAA catalysis to generate acetate and ultimately acetyl-Coenzyme A for histone acetylation, are reduced in oligodendroglioma. The short chain triglyceride glyceryl triacetate (GTA), which increases histone acetylation and inhibits histone deacetylase expression, has been safely used for acetate supplementation in Canavan disease, a leukodystrophy due to ASPA mutation. We demonstrate that GTA induces cytostatic G GTA induced cytostasis via reduced proliferation, but not increased apoptosis. Scale bar = 100 \u03bcm.(TIF)Click here for additional data file.Figure S6OG33 cells express wild-type ASPA. PCR amplification and sequencing of genomic DNA corresponding to exon 5 of ASPA was performed to determine whether the novel 26 kDa ASPA immunoreactive species present in OG33 cells (33 cells  could ar(TIF)Click here for additional data file.Figure S7OG cells express markers of immature and young oligodendrocytes, but not myelin basic protein (MBP), a marker or more mature oligodendrocytes. OG33 and OG35 cells were plated in stem cell medium (SCM) adherently on PLL-coated wells or differentiation medium (DM) for 5 days. Both cells abundantly express NG2, PDGFR\u03b1, and CNPase in SCM and retain expression in DM; however, cells failed to express detectable MBP immunoreactivity. Scale bar = 100 \u03bcm.(TIF)Click here for additional data file.Figure S8OG cells do not undergo osteoblastic differentiation. OG33 (A) and OG35 (B) cells were plated in DM (DMEM with 10% FBS) or osteogenic medium for up to 3 weeks. Medium was replenished every 3-4 days. After 5 days in osteogenic medium, reduced cell growth and altered cell morphology was apparent relative to cells in DM. However, in 3 week cultures, no Alizarin Red S positive cells or mineralized foci were detected (not shown). Furthermore, no increased CNPase immunoreactivity was observed and cells did not display immunoreactivity for myelin basic protein (MBP) or glial fibrillary acidic protein (GFAP). Thus, even protracted growth under differentiation conditions failed to induce mature glial or mesenchymal differentiation. Scale bar = 100 \u03bcm.(TIF)Click here for additional data file."}
+{"text": "Status Epilecticus induced by pilocarpine (PILO) exhibit morphological changes including narrower arborizations, greater number of branches and more endings in the inner molecular layer (IML) [Newly born dentate gyrus (DG) granule cells (GCs) after er (IML) . The incer (IML) . Howeverer (IML)  to evaluer (IML)  with morer (IML) . The scher (IML)  taking ier (IML)  with 10%er (IML)  and to oer (IML) , showing"}
+{"text": "The titles for Table 2 and 3 were switched. The title for Table 2 should read, \"Table 2. Resistance status of Cx. quinquefasciatus TPRI strain. Percentage mortality of Cx. quinquefasciatus TPRI strain after exposure in cylinder bioassays lined with treated papers at diagnostic concentrations.\"The title for Table 3 should read, \"Table 3. Summary of Bottle Bioassay Results; KDT-50 and Resistance Ratios for Cx. quinquefasciatus TRI (susceptible) and Muheza strains (resistant). Time taken (minutes) for 50% of mosquitoes to be knocked-down (KDT-50) during exposure in 250 ml glass bottles treated with 10 mg/ml permethrin alone (no synergist) or mixed with synergists PBO, DEF or PBO+DEF (n = 100 for each treatment).\""}
+{"text": "J. Path. 223:88\u201398, 2011). To determine the contribution of iNOS, we generated iNOS deficient mdx4cv mice. Genetic elimination of iNOS did not alter muscle histopathology. Further, the EDL muscle of iNOS/dystrophin DKO mice yielded specific twitch and tetanic forces similar to those of mdx4cv mice. Additional studies suggest iNOS ablation did not augment nNOS expression neither did it result in appreciable change of nitrosative stress markers in muscle. Our results suggest that iNOS may play a minor role in mediating nitrosative stress-associated force reduction in DMD.Nitrosative stress compromises force generation in Duchenne muscular dystrophy (DMD). Both inducible nitric oxide synthase (iNOS) and delocalized neuronal NOS (nNOS) have been implicated. We recently demonstrated that genetic elimination of nNOS significantly enhanced specific muscle forces of the extensor digitorum longus (EDL) muscle of dystrophin-null mdx4cv mice (Li D et al  Duchenne muscular dystrophy (DMD) is an X-linked lethal muscle disease affecting approximately 1\u20133 of every 10,000 newborn boys Recent studies suggest that inducible nitric oxide synthase (iNOS) may represent a common link among several of these proposed mechanisms In normal muscle, the ryanodine receptor (RyR) regulates calcium release from the sarcoplasmic reticulum (SR). When RyR is S-nitrosylated, it becomes leaky. Excessive entry of SR calcium into the cytosol activates calcium-dependent calpain proteases and causes muscle damage and force reduction In accordance with these findings, here we hypothesize that genetic elimination of iNOS may improve EDL muscle contractility in dystrophin-null mice, presumably via reduced RyR S-nitrosylation. To test this hypothesis, we crossed the C57Bl/6 (BL6) background iNOS knockout (KO) mice with the BL6 background mdx4cv mice. Progeny mice were genotyped by PCR. After confirming dystrophin and iNOS expression by western blot, we examined the histopathology and contractile profile of the EDL muscle in age-matched male BL6, mdx4cv, iNOS KO and iNOS/dystrophin double knockout (iNOS/Dys DKO) mice. Much to our surprise, ablating iNOS did not reduce histological signs of muscle damage neither did it alter specific muscle forces. BL6 and iNOS KO yielded similar specific twitch and tetanic forces. In mdx4cv and iNOS/Dys DKO mice, specific forces were significantly lower than those of normal. However, there was no significant difference between mdx4cv and iNOS/Dys DKO mice. Interestingly, iNOS/Dys DKO mice appeared slightly more resistant to eccentric contraction-induced injury. To further probe this intriguing finding, we examined nNOS expression and muscle nitrosative stress markers. We did not find evidence of nNOS up-regulation in iNOS-null normal and dystrophic mice. Nitro-tyrosine, total cellular ryanodine receptor 1 (RyR1) and S-nitrosylated RyR1 levels were not altered by iNOS ablation either. Our results suggest that iNOS may be less important than it has been suggested in modulating force generation in dystrophin-deficient muscle.Dmdmdx-4Cv/J (mdx4cv) mice were purchased from The Jackson Laboratory . Experimental iNOS/Dys DKO mice were generated by crossing iNOS KO and mdx4cv mice (http://jaxmice.jax.org/strain/002609.html). Briefly, two independent PCR reactions were conducted using a common primer (ACATGCAGAATGAGTACCGG) and a wild type allele specific primer (TCAACATCTCCTGGTGGAAC) or a mutant allele specific primer (AATATGCGAAGTGGACCTCG). The wild type allele yielded a 108 bp band and the mutant allele yielded a 275 bp band (GCGCGGCTTGCCTCTGACCTGTCCTAT), a wild type allele specific primer (GATACGCTGCTTTAATGCCTTTAAGAACAGCTGCAGAACAGGAGAC) and an mdx4cv allele specific primer (CGGCCAGAACAGCTGCAGAACAGGAGAT). The wild type allele yielded a 141 bp band and the mdx4cv allele yielded a 123 bp band  and were in accordance with NIH guidelines. BL6, B6.129P2-Nos2tm1Lau/J (iNOS KO) and  was used as loading control for S-nitrosylated RyR1. For all other western blots, membrane was probed with an anti-\u03b1-tubulin antibody as the loading control .Morphological studies were performed in the EDL and tibialis anterior (TA) muscles. Both muscles mainly consist of fast-twitch type II myofibers. Haematoxylin and eosin (HE) staining was used to reveal general histology and centrally nucleated myofibers. Sarcolemmal integrity was assessed with the IgG infiltration assay 3. The specific force (kN/m2) was calculated by normalizing the absolute muscle force with the CSA. After tetanic force measurement, the muscle was rested for 10 min and then subjected to eccentric contraction injury according to our previously published protocol Twitch and tetanic  forces of the EDL muscle was measured in vitro at 30\u00b0C using a 300B dual-mode servomotor transducer . The force data was analyzed using a DMC/DMA software (Aurora Scientific) P<0.05.Data are presented as mean \u00b1 standard error of mean. Statistical analysis was performed with the SPSS software . Statistical significance was determined by one-way ANOVA followed by Bonferroni post hoc analysis. Difference was considered significant when To eliminate potential influence of the genetic background, we crossed iNOS KO with mdx4cv mice . Both stAdult male mice (9.0\u00b10.7 months) were used in the study. No significant difference was observed in body weight among BL6, mdx4cv, iNOS KO and iNOS/Dys DKO mice . The EDLHE staining was performed to evaluate overall histopathology changes . BL6 andTo study sarcolemmal integrity, we performed an in vivo IgG infiltration assay To study the physiological consequences of iNOS ablation on dystrophin-deficient muscle, we measured the specific twitch (1 Hz) force and specific tetanic forces under low (50 Hz), moderate (80 Hz) and high (120 and 150 Hz) stimulation frequencies . No signNext, we examined the force decline profile following repeated cycles of eccentric contraction. iNOS KO and BL6 mice showed similar profiles. In both cases, muscle force was largely preserved over four rounds of eccentric contraction . EccentrTo determine whether iNOS knockout influences nNOS expression, we performed western blot, nNOS activity staining and nNOS immunofluorescence staining . SarcoleWe recently demonstrated that nNOS ablation reduced nitrosative stress in dystrophin-deficient muscle Nitrosative stress-mediated RyR S-nitrosylation contributes to force reduction in DMD In nNOS/dystrophin double null (n-dko) mice, mislocalized cytosolic nNOS is completely removed Recently, Villalta et al generated iNOS/dystrophin-double null mice by crossing BL6 background iNOS KO mice with C57Bl/10 background mdx mice To exclude the confounding factor of the genetic background, we generated iNOS/Dys DKO mice in the same genetic background (BL6) . Since DThe results from our n-dko mice and iNOS/Dys DKO mice suggest that mislocalized nNOS, rather than elevated iNOS, may play a determining role in nitrosative modification of RyR and force decline in dystrophin-deficient muscle  and 5 [1"}
+{"text": "Several studies report abnormal aortic properties in congenital heart disease patients, possibly worsening risk for aneurysm formation. We sought to describe patient characteristics and Cardiovascular Magnetic Resonance (CMR) parameters associated with worsened aortic strain and stiffness in a single center retrospective chart review of tetralogy of Fallot (TOF) patients undergoing CMR.227 TOF patients underwent CMR from 2007-2011 at the University of Michigan Health System. Exclusion criteria were: exposure to sedation, history of aortic stenosis, coarctation or prior aortic root replacement, surgical repair after 20 years of age, limited protocol or inadequate image quality for necessary measurements. Patient anthropomorphic measurements, clinical history, standard CMR measurements, aortic pulse wave velocity (PWV) and aortic strain data were collected, with strain defined as: (Areamin-Areamax)/(Areamin)x100; Areamax and Areamin are the maximal and minimal lumen areas (mm2) of the ascending aorta and PWV (m/s) calculated by the aortic path length between ascending and descending aorta/ transit time of systolic wave front. Correlation between aortic stiffness or strain and multiple parameters was examined via Pearson and Spearman correlation coefficients, two-sided t-test and Wilcoxon rank sum. Candidate variables were evaluated in a multivariate regression model for strength of association.124 patients were included. Mean age at repair was 1.9 years and mean age at CMR was 24.6 years. 55 patients (44%) had a history of shunt placement. 29 patients (23.4%) were on anti-hypertensive or anti-arrhythmic medications. Mean LV ejection fraction was 54 \u00b1 7.5%. Increased aortic stiffness was associated with age at repair , cross-sectional ascending aortic area , aortic regurgitation  and history of shunt placement (p=0.01). In a multivariate model controlling for use of cardiac medications and history of shunt placement, the log transformed age at repair and increasing ascending aortic cross-sectional area were predictive of aortic stiffness . Decreased aortic strain was also associated with age at TOF repair , cross-sectional ascending aortic area , aortic regurgitation  and history of shunt placement (p=0.01). LV ejection fraction did not correlate with aortic parameters.Increasing age at TOF repair and cross-sectional area of the ascending aorta correlated with worsened aortic stiffness and strain and were independently associated with worsened aortic stiffness on multivariate regression models. Early repair may decrease mechanisms of aortic pathology that promote aneurysm formation, a treatable morbidity that may become more important as this population ages.N/A"}
+{"text": "Cobalt chloride (CoCl2) is a widely used hypoxia-mimetic; preconditioning with cobalt has been reported to exert protection against ischemic injury as well as decreasing pro-inflammatory cytokine levels . Exposuto investigate the effects of chronic (CoCl2) administration on nociception and orofacial formalin-induced pain in mice.Sixteen Swiss male mice were divided into 2 groups: control  and chronic (CoCl2) . Tail flick (TF), hot plate (HP), mechanical (electronic von Frey aesthesiometer) and thermal (Hargreaves method) withdrawal thresholds were measured before cobalt/saline administration and thereafter every two days. 24 hours after the last dose, each group was evaluated for the nociceptive tests (TF&HP) and heat/mechanical hyperalgesia. Results were compared with the baseline using paired Student\u2019s t test. After the nociceptive tests, the mice were injected with 20 \u00ecl of 5% formalin into the upper right lip in order to assess the orofacial pain. The results were compared with saline group using unpaired Student\u2019s t test.Chronic (CoCl2) administration, significantly increased nociception in TF (p<0.001) and HP (p<0.001) tests and decreased the mechanical withdrawal threshold (p<0.02). On orofacial formalin pain, (CoCl2) tends to exert a pronociceptive effect on the first phase (p=0.09) and produces a significant antinociceptive effect (p=0.04) on the inflammatory phase.Taken together, our results demonstrate that chronic cobalt exposure increases acute nociception  but has an antinociceptive effect on the inflammatory pain induced by orofacial formalin injection."}
+{"text": "In BLT (bone marrow-liver-thymus) humanized mice, human thymocytes are educated by autologous human thymic tissue, resulting in functional human T cells capable of rapidly selecting for CTL escape mutations in HIV. In contrast, limitations to B cell maturation have been noted. But despite this, we show for the first time that HIV infected BLT mice can produce class-switched anti-HIV antibodies with neutralizing activities.JRCSF and bled at various time-points. HIV neutralizing activity was measured using Tat-induced luciferase reporter TZM-bl cells.Humanized BLT mice were generated by transplanting irradiated NOD-scid/IL2rgnull (NSG) mice with fetal thymus and liver fragments and then injecting them with autologous human CD34+ stem cells. BLT mice were then infected with HIVHuman transitional B cells were present in greater frequencies in BLT mice than adult humans. Most of these cells had a T1 phenotype in the blood and spleen. But despite this B cell maturation defect, class-switched IgG Abs against various HIV proteins were detected by Western Blot in HIV-infected BLT mice. Using ELISA to determine anti-p24 IgG Ab titers, Abs were present as early as 8 weeks post infection (p.i.), with peak Ab titers seen after 15 weeks. One infected mouse demonstrated a peak titer similar to that seen in a chronically infected human. Finally, plasma samples from infected BLT mice after 22 weeks p.i. demonstrated neutralizing activities against the challenge virus. Average IC50 neutralizing titers in these mice were similar to those from infected human samples.The ability of humanized BLT mice to generate functional humoral immune responses may be further improved by strategies to improve their B cell maturation, which will further improve the potential of these mice to become a model system to study candidate HIV vaccines and therapies."}
+{"text": "Measurement of the Inferior Vena Cava (IVC) diameters and collapsibility index (CI) for the detection of early volume depletion in healthy donors was recently investigated by Resnick et al. who showed no significant changes using different approaches after blood loss.To investigate the usefulness of IVC diameters and CI measurement to detect early volume depletion after blood loss of 400-450 ml using different sonographic windows.54 consecutive healthy donors were enrolled. 7 were excluded .Ultrasound measurements were obtained using M Mode, immediately before and as soon as possible after blood donation. Time from end of donation was recorded. Antero-posterior mid hepatic IVC diameter (long-axis and short-axis) were taken under the hepatic veins while distal IVC diameter was measured at the left renal vein junction. All data were fully recorded for a post processing study with an open source software (Image J).47 donors  had satisfactory IVC visualization in 92.1%, 88.2%, 58.8% of cases for hepatic long-axis, hepatic short-axis and renal vein approach respectively.No statistical difference between real time and post processing hepatic short-axis measurements was found. All mean IVC diameters decreased  and mean CI increased  for each window after blood letting (p<0.00). Mid hepatic IVC long-axis revealed a correlation between the time after donation and CI ( 20% CI decrease within 5 minutes until 0% after 20 minutes).Both IVC diameters and CI changes identified volume depletion in a healthy donor model. The mid hepatic long-axis window showed the best correlation between the IVC-CI and early volume variations following blood loss and post-donation volume repletion."}
+{"text": "In our previous work, this sepsis determined splanchnic tissue hypoxia, gut bacterial overgrowth, and bacterial translocation (BT) and these events were inflammatory amplification causal factors.Herein we examined the hypothesis that preserving splanchnic microcirculation with lasting visceral parasympathetic vasodilatation plus a rapid hyperfluid therapy, during the early phase of severe sepsis (DLn = 86) were anesthetized and submitted to: sepsis (S) (2 ml Escherichia coli 108 CFU/ml i.v.) and/or thoracic epidural analgesia (E) (0.2 ml of 0.05% bupivacaine) and/or hyperfluid therapy (H) (30 ml/kg/20 minutes of Ringer lactate) according to the group (G) design: SG; SEG; SHG; SEHG; EG and; NG (naive). Epidural analgesia and fluid therapy were initiated 30 minutes after sepsis. At the 24-hour period, animals were monitored to: microcirculatory hemodynamics  with sidestream darkfield imaging (SDF), gut Gram-negative bacterial count  and BT event in mesenteric lymph node (MLN), liver and spleen. Mortality was followed for 30 days.Adult Wistar-EPM rats (SDF findings showed that both EG and EHG preserved the microvascular and perivascular tissue architecture following sepsis induction in all organs. However, the SEH combination group showed larger microvessel diameter as compared with SEG, suggesting a better withholding of the intravascular blood volume subsequently improved tissue perfusion Figure . A signiThe splanchnic sympathetic blockage by epidural analgesia attenuated abdominal organs' microcirculatory dysfunction by augmentation of the parasympathetic vasodilatation effect, which might have preserved gut microcirculation, minimizing bacterial overgrowth, BT and subsequent gut immune activation. In addition, vigorous fluid therapy in the early phase of sepsis might have modulated the host systemic inflammatory response by ensuing better tissue perfusion. The combined therapy, by acting differently via an inflammation trigger, might have promoted a synergistic effect. Studies are in progress to verify the combined therapy potentials in the later phase of sepsis."}
+{"text": "Previous investigators have reported a prognosis value of StO2 measurements realized during severe sepsis. Hyperbaric oxygen (HBO) is recommended as an associated treatment during soft-tissue severe infection. Interestingly, a microcirculation improvement has been reportedly identified in septic animals treated by HBO. The aim of this study is to evaluate the microcirculatory effect of HBO therapy in septic patients assessing dynamics changes in StO2.Reduced microvascular perfusion has been implicated in organ dysfunction and multiple organ failure associated with severe sepsis. Near-infrared spectroscopy (NIRS) can provide a non-invasive estimation of local tissue oxygenation (StO2), macro-circulation and metabolic assessment was performed before and after each HBO session (for the first three). Thenar eminence StO2 was measured continuously by NIRS during a vascular occlusion test: a 3-minute transient ischemia inflating an arm cuff 50 mmHg above the systolic arterial pressure . HBO increases cardiac output (P = 0.003) and reduces arterial blood lactate (P = 0.001). HBO improves post-ischemic microcirculatory parameters: hyperemic area (P = 0.01), \u0394StO2 (P = 0.02), maximum StO2 (P = 0.04) and tends to improve reperfusion slope (P = 0.1). A significant negative correlation between reperfusion slope and blood lactate was observed. No correlation between macrohemodynamic and microcirculatory parameters, including baseline StO2 with ScvO2, was observed.The reperfusion slopes on day 1 were lower in nonsurvivors compared with survivors (2 reperfusion slope at admission. Originally, we demonstrated a post-ischemic NIRS parameter improvement by HBO therapy. This microcirculatory effect, independent of the HBO action on systemic hemodynamic parameters, was associated with a significant reduction of arterial lactate, a major prognostic factor in septic patients. These variations are probably due to capillaries recruitment induced by microvascular reactivity modifications.If microvascular dysfunction is the key to the development of multiple organ failure in sepsis, the microcirculation should be a key therapeutic target. Our data confirm a good predictive value for outcome of the StO"}
+{"text": "The aim of this study was to evaluate the relationship between late gadolinium enhancement (LGE) of the right ventricular (RV) insertion point (RVIP) and clinical outcomes in patients with pulmonary hypertension (PH).Previous studies suggest a significant inverse correlation between extent of LGE and RV function. However, the potential role of LGE as a non-invasive predictor of survival remains unknown.We evaluated 83 consecutive patients with suspected PH referred for CMR between January 2009 and July 2010. Imaging was performed on a Philips 1.5T MRI scanner. Retrospectively gated cines of a short axis stack were obtained using SSFP . LGE images of the same views were obtained 10 minutes after infusion of Gd-DTPA (0.2 mmol/kg) using phase sensitive inversion recovery . The cines were used to determine RV volume, ejection fraction (RVEF) and mass. Two readers blinded to hemodynamic, functional, and laboratory data jointly determined the presence of RVIP-LGE. A subgroup of these patients underwent right heart catheterization (n=40) and exercise testing (n=54). Medical records and social security death index were reviewed on a monthly basis for occurrence of primary endpoint  in patients with cath-defined PH (mean pulmonary artery pressure [mPAP] > 25 mmHg).Overall, 45/78 (58%) of patients had RVIP-LGE. LGE was indeterminate in 5 patients. Patients with RVIP-LGE had a significantly larger RV volume and mass index, lower RVEF, higher PA pressure, lower cardiac index and lower metabolic equivalents (METs) achieved during treadmill test (Table In patients with PH, RVIP-LGE is associated with reduced RV function, poorer functional capacity, and worse hemodynamics. The presence of RVIP-LGE is a predictor of death and hospitalizations and may help identify patients who require earlier or more intensive medical management."}
+{"text": "To measure Cold Pressor Test (CPT)-induced changes in MBF and compare them to adenosine induced  changes in MBF.The CPT induces endothelial-dependent vasodilation with increased myocardial blood flow (MBF) in normal coronary arteries. It has been used to demonstrate abnormal coronary vasomotion by invasive (angiography) and non-invasive techniques (SPECT and PET). Cardiovascular Magnetic Resonance (CMR) allows the assessment of MBF in separate myocardial layers due to its high spatial resolution, but has not previously been used to measure physiological responses to CPT.Eleven healthy volunteers  attended for a CMR perfusion scan , performed at rest, during CPT (120s of foot immersion in 0-4\u00b0C water) and adenosine hyperaemia (140mcg/kg/min for 4 minutes). Each perfusion scan was separated by 15 minutes. Heart rate (HR) and blood pressure (BP) were simultaneously recorded .This information was then used to calculate mean arterial pressure (MAP= 2*Diastolic BP (DBP)+ Systolic BP (SBP)/3), rate-pressure product (RPP= HR x SBP) and coronary vascular resistance (CVR= MAP/ MBF). MBF (ml/g/min) was estimated for a mid-ventricular slice by Fermi-constrained deconvolution.MBF increased significantly from rest to CPT  and from CPT to stress   and endothelial-independent (adenosine) MBF in a single examination. Furthermore, CMR demonstrates differences in the physiological response to CPT and maximal hyperaemia between the endocardium and epicardium. Future studies should establish the role of this new method in at risk groups such as those with diabetes or smokers."}
+{"text": "Mycobacterium (NTM) that turned brilliant yellow upon light exposure (BstE II and Hae III confirmed the diagnosis of Mycobacterium marinum infection. The lesion regressed completely with 3 months of doxycycline treatment.An immunocompetent 28-year-old male aquarium store employee presented with 1 month of intermittent epistaxis. A bleeding granulomatous lesion was identified over the right nasal septum . Histopaexposure . PolymerMycobacterium marinum, an opportunistic NTM, commonly found in aquatic environments.Mycobacterium marinum infection. Superficial lesion sometimes resolves spontaneously, but several months of antimicrobial drug are usually necessary. Various monotherapies, including doxycycline, are effective.2Fish tank granuloma is a rare granulomatous skin infection caused by"}
+{"text": "Escherichia coli leads to hypersensitivity to the mutagenic and toxic effects of N-hydroxylated base analogs, such as 6-N-hydroxylaminopurine (HAP). This phenotype is due to the loss of two Moco-dependent activities, YcbX and YiiM, that are capable of reducing HAP to adenine. Here, we describe two novel HAP-sensitive mutants containing a defect in iscS or tusA (yhhP) gene. IscS is a major L-cysteine desulfurase involved in iron\u2013sulfur cluster synthesis, thiamine synthesis, and tRNA thiomodification. TusA is a small sulfur-carrier protein that interacts with IscS. We show that both IscS and TusA operate within the Moco-dependent pathway. Like other Moco-deficient strains, tusA and iscS mutants are HAP sensitive and resistant to chlorate under anaerobic conditions. The base-analog sensitivity of iscS or tusA strains could be suppressed by supplying exogenous L-cysteine or sulfide or by an increase in endogenous sulfur donors (cysB constitutive mutant). The data suggest that iscS and tusA mutants have a defect in the mobilization of sulfur required for active YcbX/YiiM proteins as well as nitrate reductase, presumably due to lack of functional Moco. Overall, our data imply a novel and indispensable role of the IscS/TusA complex in the activity of several molybdoenzymes.Lack of molybdenum cofactor (Moco) in  N-hydroxylated derivatives of purines and pyrimidines, such as 6-N-hydroxylaminopurine (HAP) . These agents have been shown to be strong mutagens in bacteria, yeast, and mammalian cells  Fig. A, 2-aminan cells . HAP canEscherichia coli strains lacking molybdenum cofactor (Moco) are hypersensitive to the toxic and mutagenic action of HAP   -reductase family, which utilize a molybdopterin (MPT)-guanine-dinucleotide (MGD) form as cofactor  broth Miller  or minimE. coli strains used in this study are listed in Table tusA::kan mutant was obtained from a genome-wide search for HAP-sensitive mutants using the EZ-Tn5\u2122 <R6K\u03b3ori/KAN-2>Tnp Transposome\u2122 Kit from Epicentre, Madison, WI. The \u0394iscS, \u0394iscU, \u0394iscA, \u0394iscUA, \u0394sufS, \u0394sufA, \u0394csdA(b2810), \u0394nfuA, \u0394tusBCD, and \u0394tusE deletions were generated in strain BW25113/pKD46 by the polymerase chain reaction (PCR)-based gene replacement method of (Datsenko and Wanner r module of plasmid pKD13 (Datsenko and Wanner tetA tetR tetracycline-resistant (Tetr) module of transposon Tn10 as a template. Primers for the PCR reactions were (upper case letters indicate the sequences of Tn10 or pKD13) iscS-p1 (5\u2019-gta agc cat tat aaa ttc tcc tga ttc cga tac cga tta atg atg agc ccG TGT AGG CTG GAG CTG CTT CG-3\u2019) and iscS-p4 (5\u2019-ggt agc ctg att cct tgc att gag tga tgt acg gag ttt ata gag caa tgA TTC CGG GGA TCC GTC GAC C-3\u2019) for generating \u0394iscS::kan; iscU-p1 (5\u2019-caa ctc tta ttt tgc ttc acg ttt gct ttt ata gtc cgc aat ggc ggc ttG TGT AGG CTG GAG CTG CTT CG-3\u2019) and iscU-p4 (5\u2019-cgg aat cag gag aat tta taa tgg ctt aca gcg aaa aag tta tcg acc atA TTC CGG GGA TCC GTC GAC C-3\u2019) for \u0394iscU::kan; iscA-p1 (5\u2019-aaa ccc cac gcg cag gcg acc acg gtg ggg tta tcg gta tgc gca tca aaG TGT AGG CTG GAG CTG CTT CG-3\u2019) and iscA-p4 (5\u2019-gga cta taa aag caa acg tga agc aaa ata aga gtt gag gtt tgg tta tgA TTC CGG GGA TCC GTC GAC C-3\u2019) for \u0394iscA::kan; iscU-p1 and iscA-p4 for \u0394iscUA::kan; sufS-p1 (5\u2019-gac aca tcg cag gga cgt tgt aat agg cca tca atg gca ttg cgc agt gaG TGT AGG CTG GAG CTG CTT CG-3\u2019) and sufS-p4 (5\u2019-gca aga tga ttt ttt ccg tcg aca aag tgc ggg ccg act ttc cgg tgc ttA TTC CGG GGA TCC GTC GAC C-3\u2019) for \u0394sufS::kan; sufA-p1 (5\u2019-ttt tga cat cgt cag ttg ctt cag tat tac gag aca tag tac cgc cta taG TGT AGG CTG GAG CTG CTT CG-3\u2019) and sufA-p4 (5\u2019-cac taa cat gct gtt ata cgc tga aag cga tga agt gag gta aat cga tgA TTC CGG GGA TCC GTC GAC C-3\u2019) for \u0394sufA::kan; csdA-p1 (5\u2019-aag ccg agg agt acc atg aac gtt ttt aat ccc gcg cag ttt cgc gcc caG TGT AGG CTG GAG CTG CTT CG-3\u2019) and csdA-p4 (5\u2019-taa tcc acc aat aat tcc agc gcg cgg tca acg gca ttc acc agc gca tcA TTC CGG GGA TCC GTC GAC C-3\u2019) for \u0394csdA::kan; nfuA-p1T (5\u2019-ggc gta tta taa cca act aaa ata gtc aac tat tag gcc att act atg atA AGA GGG TCA TTA TAT TTC G-3\u2019) and nfuA-p4T (5\u2019-tta gcg tcg cat cgg gca atc tac aaa aga ggg gat aac tta gta gta ggA CTC GAC ATC TTG GTT ACC G-3\u2019) for \u0394nfuA::tet; tusBCD-p1T (5\u2019-ttt agg gcg atg ccg aaa agg tgt caa gaa ata tac aac gat ccc gcc ata AGA GGG TCA TTA TAT TTC G-3\u2019) and tusBCD-p4T (5\u2019-ctc tac atc cgc cag ttc aag agc ggt gat ttc cag ggg caa gat aag taA CTC GAC ATC TTG GTT ACC G-3\u2019) for \u0394tusBCD::tet; and tusE-p1 (5\u2019-cct cgg ggg aat taa ccg att ttc gta tcc gtt aaa tac att tta ccg gtG TGT AGG CTG GAG CTG CTT CG-3\u2019) and tusE-p4 (5\u2019-tgt tac act gcc gcc agt ctg att aag gta gta ata att atg ctg atc ttA TTC CGG GGA TCC GTC GAC C-3\u2019) for \u0394tusE::kan. The resulting deletion\u2013insertions were then transferred into strain NR10836 by P1 transduction using P1virA, and the Kanr modules, if necessary, were eliminated using pCP20 plasmid, as described by Datsenko and Wanner . After the spots had dried, a few microliters of a 1-mg/mL solution of HAP in DMSO was spotted onto the center of the plate. The plates were incubated overnight at 37\u00b0C and inspected the next day for zones of inhibition.Stationary 3 cells were plated on LB plates containing 0.2% KClO3 (Miller Approximately 103 Miller . The pla5 cells. The cultures were grown with shaking for 48 h at 37\u00b0C. Mutant frequencies were determined by plating of 10\u2013200 \u03bcL (depending on strain and presence of the mutagen in the growth media) on an LB-rifampicin plate (to obtain the number of rifampicin-resistant cells per culture) and of 50 \u03bcL of a 10\u22126 dilution on LB plates .For each strain, six independent 1-mL VB cultures supplemented (or not) with 0.75 ng/mL of HAP were started from \u223c10tusA (formerly yhhP) open reading frame. This mutant was hypersensitive to HAP , as previously established for Moco-deficient strains like the moaE strain in Figure tusA strain appeared slightly more sensitive than the moaE strain, based on the diameter of the zone of inhibition (46 mm vs. 41 mm)  Fig. A. Part oiscS is the second gene in an operon containing up to eight genes . We found that the iscS mutant, like tusA, conferred HAP hypersensitivity .To investigate the possible role of IscS in base-analog detoxification, we also deleted this gene. As ity Fig. A as welltusA or iscS defects alone or in combination with the moaE defect. The tusA moaE double mutant showed essentially equal sensitivity to the single tusA mutant (47 mm vs. 46 mm). Likewise, the iscS moaE double mutant displayed similar activity as the single iscS mutant (53 mm vs. 51 mm). These results suggest that the tusA and iscS defects are likely epistatic to the moaE defect. This is further confirmed by the identical sensitivity of the triple tusA iscS moaE mutant relative to the double tusA iscS mutant  mutant, and that the iscS moaE double mutant, as well as the iscS tusA moaE triple mutant, was equally susceptible as the single iscS or the double iscS tusA mutant  strain, likely reflecting some indirect sensitization due to the pleiotropic characteristics of iscS  allele  at the wobble position of certain tRNAs  the involvement of Moco as cofactor  sulfur donor for the synthesis of iron\u2013sulfur clusters in E. coli  did not produce any sensitivity to HAP  does cause detectable HAP sensitivity. It appears that sufficient Fe\u2013S centers must be present in the YcbX protein and MoaA protein  are members of the DMSO Reductase family of molybdoenzymes and carry the Mo-bisMGD form of Moco, which does not contain the extra sulfur ligand  has been identified as a main activity . Likewise, an increase in the intracellular cysteine or sulfide concentration in the absence of any additions to the media was also achieved (data not shown) by constitutive expression of the CysB regulon, which normally controls the cysteine biosynthesis pathway  revealed normal HAP resistance (aerobic condition) as well as normal chlorate resistance (anaerobic condition), suggesting that the role of YnjE protein as alternative sulfur carrier may be limited.The recent study by Dahl et al.  has alsoant Fig.  must indN-hydroxylated base analogs have provided a sensitive window into several important biological phenomena. Detoxification of hazardous agents, either produced endogenously or encountered in the environment, is an important cellular activity. The severe sensitivity of Moco-deficient strains has enabled the discovery of the YcbX and YiiM enzymes that represent a novel class of activities. The question of the physiological substrate of these enzymes is still an open question, and deserves further investigation, especially in light of the discoveries of corresponding mammalian enzymes (mARC) that have a mitochondrial membrane localization (Wahl et al. Our genetic studies with the"}
+{"text": "A single injection of regadenoson can be used instead of an adenosine infusion to produce coronary vasodilatation and demonstrate myocardial ischemia during first-pass perfusion cardiac MRI.Cardiac stress MR perfusion imaging requires an MRI compatible infusion pump for the administration of adenosine or a non-MRI compatible pump housed in the control room or beyond the 10-Gauss line. Regadenoson is a recently FDA-approved A2A receptor agonist that can be given intravenously in a single bolus. It has been shown to provide diagnostic information regarding myocardial ischemia on SPECT-MPI.42 patients  with a reversible myocardial perfusion defect on SPECT-MPI underwent a cardiac perfusion MRI within 7 days of the SPECT-MPI. MR exams consisted of short and long axis cine steady state free precession (SSFP) imaging, matched gradient-recalled echo (GRE) GRAPPA temporal parallel acquisition (TPAT) first-pass stress perfusion , and delayed contrast-enhanced (DCE) T1 GRE imaging. First-pass perfusion images were obtained 30 seconds after regadenoson 400 micrograms administered in a single IV bolus and during power injection of 0.075 mmol/Kg of gadobenate dimeglumine at 5 mL/sec IV followed by normal saline flush. DCE imaging was obtained 10 minutes after injection of an additional 0.025 mmol/Kg of contrast agent.All but one patient tolerated the regadenoson MR examination. One patient had chest pain shortly after imaging, and received aminophylline, with resolution of symptoms. MR showed ischemia in 33/42 subjects. In 8 subjects the MR perfusion exam was normal. Five of these 8 patients underwent clinically-ordered invasive cardiac catheterization (ICA) within 3-18 days of the MRI examination. ICA showed no stenoses, suggesting SPECT attenuation artifact. The other 3/8 patients had no MACE within 30-180 days. In one patient, SPECT demonstrated ischemia only, while MRI showed infarct only in the same segment.Regadenoson can be used in cardiac MR perfusion imaging to demonstrate ischemia. MRI perfusion imaging may be useful in differentiating attenuation artifact from true disease.Funding for this project was provided by Astellas. Additional research support provided by Siemens Medical Systems."}
+{"text": "TM) [The concept of instability footwear is to reduce stability, increase muscle activation and \u201ctone\u201d. Recently numerous brands have developed instability footwear for significant sales. Despite extensive marketing claims there are few empirical studies quantifying effects of instability footwear on muscle activity or motion in healthy individuals aside from Masai Barefoot Technology (MBTTM) ,2. The aTM). The instability footwear conditions were FitFlopTM, MBTTM, Reebok Easy-ToneTM and Skechers Tone-UpsTM. IEMG is presented normalised to control.Fifteen female subjects participated . The protocol quantified Centre of Pressure (CoP) excursion (Kistler) and lower extremity integrated muscle activity (IEMG) (Noraxon) for three thirty second single-leg standing trials in four experimental conditions and one control (Earth Footwearp=0.012), FitFlop (p=0.033) and Skechers (p=0.014) (Table p=0.042).Repeated measures ANOVA revealed significant differences in CoP with MBT having significantly greater anterior-posterior range than Control p=0.02, FitFloIncreased anterior-posterior CoP range in MBT is expected due to the rocker profile . Other c"}
+{"text": "Biomarkers such as the neuron-specific enolase (NSE) have been proposed as potential prognostic markers following traumatic brain injury (TBI) ,2. Howev2 tests. Sensitivity analyses were planned to explain statistical heterogeneity .We systematically searched MEDLINE, Embase, Cochrane, Biosis, Scopus, Trip, references of eligible studies, reviews and conference proceedings. Eligible studies were cohort studies including \u22654 patients with moderate or severe TBI having measured the association between NSE levels (first 24 hours) and mortality or the Glasgow Outcome Scale (GOS). Independently, two reviewers selected studies and extracted data using a standardized form. Pooled results using random-effect models were used using weighted mean differences (WMD); heterogeneity was assessed using In = 757). Seventeen studies used the GOS as an outcome measure while 10 studies reported mortality. Most studies evaluated outcomes at 6 months or beyond (range: 1 to 12 months). Ten studies could not be included in the pooled analyses: three reported mean levels of serial samplings, two presented peak levels, two reported medians, one did not report any measure of dispersion and data could not be extracted from two studies. We observed a significant association between serum NSE levels and mortality (five studies: WMD 25.90 (95% CI 15.97 to 35.83), I2 = 60%) and GOS \u22643 (10 studies: WMD 17.69 (95% CI 12.14 to 23.24), I2 = 64%). Similar results were found with or without extracerebral injuries. The number of studies included in pooled analyses precluded performing relevant sensitivity analyses.We retrieved 4,711 citations and included 22 studies  not influenced by extracerebral injuries. Further studies need to evaluate the usefulness of serum NSE levels for prognosis assessment in TBI and its potential impact on clinical decision-making."}
+{"text": "Axillary ultrasound staging with core biopsy (CB) or fine needle aspiration (FNA) in primary breast cancer is well established. Negative patients will have a sentinel lymph node biopsy (SLNB). This study compares the initial ultrasound finding versus final axillary histology in patients undergoing SLNB.A total of 249 breast carcinoma patients, who underwent SLNB between August 2007 and January 2011, were included. Axillary ultrasound and histology results were reviewed. Ultrasound findings and any subsequent biopsies were recorded in positive and negative SLNB groups. The axillary lymph node biopsy histology slides were reviewed in the false negative axillary ultrasound biopsy/FNA group.P = 0.2). See Figure Of 249 patients, 191 (76.7%) were SLNB-negative and 58 (23.3%) were SLNB-positive. Thirty out of 191 (16%) patients without axillary metastases had ultrasound-guided sampling. Two out of 191 did not have ultrasound-guided sampling as the procedure was deemed unsafe. Twelve out of 58 (21%) SLNB-positive patients had abnormal ultrasound appearances; 8/12(67%) had CB and 4/12 (33%) had FNA, not significantly different to the CB/FNA rates in SLNB-negative patients (24/32 (75%) and 6/32 (25%), respectively; There are no significant differences in the rate of axillary ultrasound abnormality between SLNB-positive and SLNB-negative patients. This suggests that ultrasound nodal abnormalities due to malignancy are probably being diagnosed by ultrasound-guided sampling and do not progress to SLNB. It also supports SLNB for sonographically abnormal lymph nodes as opposed to axillary nodal dissection, as many of these patients will not have metastases, if USS sampling is negative. Our small study has not shown significant benefit of CB over FNA in axillary staging. We found a low upgrade rate on reviewing original ultrasound-guided histology slides, supporting current pathology techniques."}
+{"text": "Relapses following nonoperative treatment for clubfoot occur in 29-37% of feet following initial correction . In patiThirty children (37 feet) were evaluated pre- and 2.0\u00b10.6 yrs (range: 0.8 to 2.9) post-op following ATT transfer. Foot progression angle (FPA) and sagittal ankle kinematics were assessed using a VICON system. Plantar pressures were collected using the Emed ST Platform. Representative trials were chosen for each subject for gait and plantar pressures. Plantar pressures were divided into medial and lateral hindfoot, midfoot and forefoot. Variables included: contact time (CT%), contact area , peak pressure (PP), hindfoot-forefoot angle [Changes in plantar measures in the hindfoot show normalization of the CA% and CT% post-op Table . The forChanges seen in plantar pressures would suggest that during stance, the foot is better aligned, more evenly distributing pressures throughout the foot rather than focused to the lateral midfoot and forefoot regions. Based on gait results, pre-operative foot progression angle may be an indicator for successful outcomes of ATT transfer in patients with residual deformity."}
+{"text": "Recently, temporally constrained k-t BLAST reconstruction using principal component analysis (k-t PCA) has been proposed to further improve temporal resolution of k-t undersampled data. In addition, multi-transmit technology has become available, which aims to improve image uniformity and SAR limitations at higher field strength. We have developed a pulse sequence for 3D perfusion-CMR that utilises both k-t PCA and multi-transmit technology at 3 Tesla.k-t PCA accelerated perfusion CMR was performed on a 3T Philips Achieva Multi-transmit system . FFR was measured in all vessels with visually significant stenosis using a pressure sensor-tipped wire (Volcano\u00ae). FFR < 0.75 was considered haemodynamically significant. Two experienced observers blinded to the results of the angiogram visually interpreted ischemia on CMR data as relative underperfusion of a sector within a slice or relative endocardial vs epicardial underperfusion within a coronary teritory. The performance of visual analysis of CMR to detect flow-limiting coronary stenosis on angiography was determined.8 patients with suspected coronary artery disease underwent 3D perfusion MR imaging at rest and adenosine stress prior to angiography and fractional flow reserve assessment. Acquisition was feasible in all patients. Signal intensity (SI) profiles showed improved temporal fidelity of k-t PCA Figure  compared3D myocardial perfusion imaging using Multi-transmit technology and k-t PCA reconstruction is technically feasible. Improved temporal fidelity was observed using multi-transmit technology. Perfusion deficits in patients with suspected CAD correlate well with invasive FFR measurements in this small pilot study."}
+{"text": "Inactivation of all utrophin isoforms in dystrophin-deficient mdx mice results in a strain of utrophin knockout mdx (uko/mdx) mice. Uko/mdx mice display severe clinical symptoms and die prematurely as in Duchenne muscular dystrophy (DMD) patients. Here we tested the hypothesis that marginal level dystrophin expression may improve the clinical outcome of uko/mdx mice. It is well established that mdx3cv (3cv) mice express a near-full length dystrophin protein at \u223c5% of the normal level. We crossed utrophin-null mutation to the 3cv background. The resulting uko/3cv mice expressed the same level of dystrophin as 3cv mice but utrophin expression was completely eliminated. Surprisingly, uko/3cv mice showed a much milder phenotype. Compared to uko/mdx mice, uko/3cv mice had significantly higher body weight and stronger specific muscle force. Most importantly, uko/3cv outlived uko/mdx mice by several folds. Our results suggest that a threshold level dystrophin expression may provide vital clinical support in a severely affected DMD mouse model. This finding may hold clinical implications in developing novel DMD therapies. Duchenne muscular dystrophy (DMD) is a prevalent lethal muscle disease caused by dystrophin gene mutation In sharp contrast to human patients, dystrophin-deficient mdx mice display very mild symptoms. Despite clear histological evidence of muscle damage, young adult mdx mice do not show muscle wasting and they maintain a close-to-normal daily activity. Further, the lifespan of mdx mice is only moderately reduced Mdx3cv (3cv) mice carry a point mutation that abolishes all wild type dystrophin transcripts  [7]. IntDmdmdx/J (mdx), and B6Ros.Cg-mdx-3CvDmd/J (3cv) mice were purchased from The Jackson Laboratory . The original utrophin heterozygous mdx (utrn+/\u2212/mdx) breeders were gifts of Dr. Mark Grady at Washington University All animal experiments were approved by the Animal Care and Use Committee of the University of Missouri and were in accordance with NIH guidelines. C57Bl/10Snj (BL10), C57BL/10ScSn-Experimental mice were genotyped for utrophin knockout, 3cv mutation, and mdx mutation using strain-specific three-primer PCR protocols as we reported Western blot was performed according to a previously published protocol 2 fragment of goat anti-mouse IgG (H+L) .Dystrophin immunofluorescence staining was performed according to a published protocol 3. The specific force (kN/m2) was calculated by normalizing the absolute muscle force with the CSA. After tetanic force measurement, the muscle was rested for 10 min and then subjected to five rounds of eccentric contraction injury according to our previously published protocol The absolute twitch and tetanic  forces of the EDL muscle were measured in vitro at 30\u00b0C using a 300B dual-mode servomotor transducer and a DMC/DMA software  as we published before P<0.05.Data are presented as mean \u00b1 standard error of mean. Statistical analysis for body weight and EDL muscle contractility was performed with the SPSS software . Statistical significance was determined by t test. Statistical analysis for survival was performed with the Prism 4 software . Statistical significance was determined by the Mantel-Cox log-rank test. The Bonferroni corrected threshold was used to set the significance level. Difference was considered significant when Experimental uko/mdx mice were generated by crossing utrophin heterozygous mdx mice  [5]. ExpDystrophin and utrophin expression was confirmed by western blot . In uko/At 8 months of age, mdx, 3cv and uko/3cv were essentially indistinguishable on visual examination . There wAll uko/mdx mice die within four months after birth To study the influence of marginal level dystrophin expression on muscle contractility, we measured the anatomic property, twitch/tetanic force and eccentric contraction profile of the EDL muscle in 2.5-m-old male mice. Compared to that of uko/mdx mice, muscle weight, optimal length and cross-sectional area were significantly increased in uko/3cv mice . Uko/3cvTremendous progress has been achieved over the last few years in developing novel pharmacological and genetic therapies for treating DMD. Many approaches (such as stop codon read-through and exon skipping) aim at expressing a functional dystrophin molecule Uko/mdx mice are well-established clinical DMD models A crucial issue in developing DMD therapy is to determine the minimal levels of dystrophin needed to mitigate the clinical manifestation. Previous transgenic studies suggest that dystrophin expression at 20% of the normal level is sufficient to ameliorate histological lesions and correct functional deficits in mdx skeletal muscle While the finding is encouraging, we would also like to point out several important limitations. First, the sample size is relatively small, especially for the life span study .(TIF)Click here for additional data file.Video S18-m-old mdx, mdx3cv and uko/3cv male mice show similar activity. The strain is marked by color tape on the tail. Gray, mdx; green, mdx3cv; red, uko/3cv.(MPG)Click here for additional data file."}
+{"text": "To describe acupuncture and chiropractic (acu/chiro) use among 11,960 chronic musculoskeletal pain patients enrolled in a Pacific Northwest Health Maintenance Organization (HMO).We identified 119,732 HMO members with chronic musculoskeletal pain from electronic medical records data. Patients were contacted by mail and invited to complete an online survey. Those not responding were either contacted by email or mailed a paper copy of the survey. Survey questions included items related to diagnosis, acu/chiro utilization and payment, and communication about acu/chiro use with HMO clinicians.Of 119,732 patients invited to participate, 11,960 completed the survey. Self reported pain diagnoses included back pain (65%), joint pain (56%), arthritis (53%), extremity pain (53%), neck pain (37%), muscle pain (30%), headaches (21%), fibromyalgia (13%), and abdominal or pelvic pain (10%). Participants were predominantly caucasian (90%) and female (58%), with mean age of 59 years. Roughly a quarter of participants  reported acupuncture use, while slightly more participants  reported chiropractic use. Of those using acupuncture, 39% did not discuss acupuncture use with their HMO clinician, and 82% paid out-of pocket for at least a portion of the care. Of those using chiropractic services, 38% did not discuss chiropractic use with their HMO clinician, and 91% paid out-of-pocket for at least a portion of the care. The most common reason given for out-of-pocket payment to acu/chiro providers was that insurance coverage didn\u2019t cover such care or required a co-payment. Patients with a self referral acu/chiro benefit were more likely to use acu/chiro than those without such coverage (p<.0001), but were not more likely to communicate acu/chiro use to HMO clinicians (p=.13).Acu/chiro use is prevalent among HMO patients with chronic musculoskeletal pain. However, such use frequently is not reported to HMO clinicians, even by patients having a self referral acu/chiro benefit."}
+{"text": "In mammals, IFIT (Interferon [IFN]-induced proteins with Tetratricopeptide Repeat [TPR] motifs) family genes are involved in many cellular and viral processes, which are tightly related to mammalian IFN response. However, little is known about non-mammalian IFIT genes. In the present study, IFIT genes are identified in the genome databases from the jawed vertebrates including the cartilaginous elephant shark but not from non-vertebrates such as lancelet, sea squirt and acorn worm, suggesting that IFIT gene family originates from a vertebrate ancestor about 450 million years ago. IFIT family genes show conserved gene structure and gene arrangements. Phylogenetic analyses reveal that this gene family has expanded through lineage-specific and species-specific gene duplication. Interestingly, IFN gene family seem to share a common ancestor and a similar evolutionary mechanism; the function link of IFIT genes to IFN response is present early since the origin of both gene families, as evidenced by the finding that zebrafish IFIT genes are upregulated by fish IFNs, poly(I:C) and two transcription factors IRF3/IRF7, likely via the IFN-stimulated response elements (ISRE) within the promoters of vertebrate IFIT family genes. These coevolution features creates functional association of both family genes to fulfill a common biological process, which is likely selected by viral infection during evolution of vertebrates. Our results are helpful for understanding of evolution of vertebrate IFN system. The innate immune response to viral infection is largely dependent on host production of interferons (IFNs) that are a family of cytokines with antiviral, antiproliferative and immunomodulatory properties IFI56  is the first ISG to be discovered and cloned Genomic structure analyses of mammalian IFIT family genes reveal a common evolutionary origin possibly by gene duplication. The first evidence is that four human IFIT members, including IFI56/IFIT1, IFI54/IFIT2, IFI60/IFIT3 and IFI58/IFIT5, are tandem located in a locus on chromosome 10 and consistently, three mouse homologues of IFIT members are also clustered together although loss of IFI58 homologue Carassius auratus), showing a low level of identity and similarity to their mammalian homologues Fish IFIT-like genes have recently been identified from crucian carp  IFIT genes and three mouse (Mus musculus) IFIT genes have been well-characterized D. rerio) genes, which have been annotated in genome databases, were easily identified as IFIT genes (P. troglodytes) and rhesus monkey (M. mulatta) were identified, 49 of which were identified by GENSCAN  and mouse lacking IFIT5, and horse  lacking IFIT1 (P. troglodytes), dog (C. familiaris), mouse and rat. These genes are tandem located in a common chromosome except for the pseudogenes IFIT1Ps of three primate species and dog IFIT5L, which reside in separate chromosomes (O. anatinus), a monotreme mammalian species exhibiting a fascinating combination of reptilian and mammalian characters All mammalian species available contain four members of IFIT family, including IFIT1, IFIT2, IFIT3, and IFIT5, with the exception of both rat (ng IFIT1 . In addiomosomes . Three IT. guttata) but only one in chicken  . Fish genomes also contain varied IFIT-like genes, with one in torafugu (T. rubripes) but ten in zebrafish, three-spinned stickleback (G. aculeatus) and medaka (O. latipes) (C. milii), a cartilaginous fish that is the phylogenetically oldest species of living jawed vertebrates and is not believed to experience the whole-genome duplication event In contrast to a relatively constant number of IFIT family genes in mammals, there are varied gene copies in birds, reptiles, amphibians, and fish . For exa gallus) ; a totallatipes) . Since zlatipes) . ElephanS. kowalevskii) and Cephalochordata species lancelet (B. floridae) were selected since they showed the closest BLAST hit with E-value<10\u22126. According to the same criteria, three genes are identified in sea lamprey (P. marinus) and one in hagfish (E. burger) by BLAST search of EST and protein databases  were further analyzed. Due to lack of mRNA or EST information, the genomic structures of IFIT genes in green anole, western clawed frog and the remaining five fish species were unavailable. As shown in M. mulatta), a gene duplication event occurred within IFIT loci of human and chimpanzee, which gave a birth of IFIT1B paralogous to IFIT1 genes. The same is true for IFIT loci of dog, mouse and rat , an effective IFN stimulus Human and mouse IFIT genes respond to IFN or IFN stimuli through the ISRE motifs present in their promoters To determine the role of ISRE motif in responsiveness of fish IFIT genes to IFN, 6 zebrafish IFIT gene promoters are cloned to make promoter-driven luciferase constructs . We hypoIn mammals, IRF3 directly induced the expression of human IFI56 through binding to ISRE motifs without the need of IFNs \u22126 occurred around 450 Myr ago Interestingly, there is a similar evolutionary history for vertebrate IFN gene family and IFIT gene family. First, IFN genes and IFIT genes are found in the genomes from the jawed vertebrates including elephant shark but not from invertebrates. Second, similar to IFIT gene family, IFN family genes have undergone extensive lineage-specific expansion trans retinoic acid (ATRA) can induce IFIT gene expression and subsequently, ATAR is identified as an effective IFN stimulus Subsequent expression analyses of zebrafish IFIT family genes reveal functional association of both IFIT and IFN gene families since generation of jawed vertebrates. In mammals, the biological function of IFIT gene family is tightly related to IFN response, as these genes are directly regulated by IFN signaling, which is triggered by IFN as well as IFN stimuli, such as viral infection, dsRNA and LPS  and Ensembl (http://www.ensembl.org/info/about/species.html), including ten mammalian species: human , chimpanzee , rhesus monkey , mouse , rat , cattle , horse , pig , dog  and platypus , two avian species: chicken  and Zebra Finch , one reptilian species: green anole , one amphibian species: western clawed frog , and six fish species: zebrafish , torafugu , spotted green pufferfish , three-spinned stickleback , medaka  and elephant shark , three invertebrates: Sea urchins (Strongylocentrotus purpuratus), acorn worm  and lancelet (Branchiostoma floridae) (Petromyzon marinus) and hagfish (Eptatretus burger) was retrieved from EST databases by a strict BLAST search .Using human, mouse and crucian carp IFIT protein sequences as baits, TBLASTN search was performed against the genome database from NCBI (loridae) . The IFIhttp://www.ncbi.nlm.nih.gov/Structure/cdd/cddsrv.cgi?ascbin=8&maxaln=10&seltype=2&uid=29151), a putative TPR motif was identified when more than 4 out of the 8 key sites were conserved. The conservation in the other sites was also considered. The exon/intron structure information was retrieved from NCBI genome databases (http://www.ncbi.nlm.nih.gov/mapview), except that Zebra Finch IFITA, chimpanzee IFIT1P and rhesus monkey IFIT1P1 were analyzed by GENSCAN. For gene synteny analyses, approximate 10-million-base-pare sequences flanking IFIT locus were collected, and then compared by local blast software from NCBI (http://blast.ncbi.nlm.nih.gov/Blast.cgi?CMD=Web&PAGE_TYPE=BlastDocs&DOC_TYPE=Download). 5\u2032-flanking sequences of IFIT gene loci were retrieved from NCBI genome databases and ISRE motifs were identified by software TFSEARCH and Geneious combined with manual inspections based on the consensus sequence (G/A/T)GAAAN(1-2)GAAA(G/C)(A/T/C) Multiple alignments and phylogenetic tree were performed by Geneious Pro 5.4.6 program. Based on the consensus sequence of TPR motifs [WLF]-X(2)-[LIM]-[GAS]-X(2)-[YLF]-X(8)-[ASE]-X(3)-[FYL]-X(2)-[ASL]-X(4)-[PKE] (Carassius auratus blastulae embryonic cells (CAB) Kpn I/Xho I sites of pGL3-Basic luciferase reporter vector (Promega). Wild type zebrafish IRF3 and IRF7 plasmids were generated by insertion of their whole ORF into the Xho I/Kpn I sites of pcDNA3.1/myc-His(\u2212) A vector (Invitrogen). Wild type zebrafish IFN1 was cloned into pcDNA3.1/myc-His(\u2212) A vector. The primers are listed in Zebrafish IFIT gene promoter-driven luciferase constructs were generated by insertion of 5\u2032-flanking sequences upstream of the translation start sites of DrIFIT5A (\u2013865/+17), DrIFIT12A (\u2013922/+75), DrIFIT13A (\u2013529/+38), DrIFIT17A (\u2013925/+59), DrIFIT17B (\u2013996/+202), DrIFIT17C (\u20131091/+94) into 5 cells/well. Cells were transfected with various concentrations of plasmids using Lipofectamine 2000 kit (Invitrogen). For luciferase assays, cells seeded in 24-well plates overnight were cotransfected with various plasmids at a ratio of 1\u223610  or 1\u223610\u223610  using Lipofectamine 2000 (Invitrogen) according to previous reports Transfection assays were performed according to our previous reports Figure S1Phylogenetic tree of 107 IFIT family proteins by Geneious Pro 5.4.6 program with maximum likelihood method.(PDF)Click here for additional data file.Figure S2Phylogenetic analyses of 102 vertebrate IFN family proteins by neighbor joining method.(PDF)Click here for additional data file.Figure S3Analysis of promoters of IFIT genes identified in this study.(DOC)Click here for additional data file.Table S1Definition of IFIT genes identified in this study.(XLS)Click here for additional data file.Table S2Identities among IFIT proteins and TPR-containing proteins that were identified in this study.(XLSX)Click here for additional data file.Table S3Primers for expression analysis and luciferase assays of zebrafish IFIT genes.(DOC)Click here for additional data file."}
+{"text": "To assess the safety and immunogenicity of the bivalent HPV vaccine (Cervarix) in patients with Juvenile Idiopathic Arthritis (JIA), Systemic Lupus Erythematosus (SLE) and Juvenile Dermatomyositis (JDM).A prospective controlled observational trial was initiated in female patients and healthy controls aged 12-18 years. Patients and controls were vaccinated  and followed for 12 months. HPV16 and 18-specific antibody concentrations were measured using a fluorescent microspheres-based multiplex immuno-assay after 12 months. Adverse events (AE\u2019s) 2 weeks after each vaccination were systematically documented in diaries. In patients, medication use was monitored and disease activity was measured by the Juvenile Arthritis Disease Activity Score of 27 joints (JADAS-27), SLE Disease Activity Index, or the Childhood Myositis Assessment Scale.58 patients  and 51 healthy controls are currently included, patients are still being enrolled. The percentage of patients responding to vaccination (response rate) was similar in patients and controls. However, HPV16 antibodies were lower in JIA , SLE  and JDM patients  compared with healthy controls (8799 LU/ml). HPV18 antibodies were similar in JIA patients and controls ; SLE  and JDM patients  showed markedly lower antibody levels. MTX-use did not lower vaccine responses.The median JADAS-27 did change considerably between visits (1.9-2.5), but JADAS-27 was significantly elevated at 7 months (p=0.001) due to one outlier. SLE and JDM disease activity remained similar. AE\u2019s were similar in patients and controls.Cervarix was safe in girls with rheumatic diseases. The response rates were similar in patients and healthy controls, whereas antibody concentrations were markedly lower in SLE and JDM patients."}
+{"text": "The growth regulation of mammary tumor cells controlled by VAPB appears to be mediated, at least in part, by modulation of AKT activity. Overexpression of VAPB in MCF10A-HER2 cells enhances phosphorylation of AKT. In contrast, knockdown of VAPB in MMTV-Neu tumor cells inhibited pAKT levels. Pharmacological inhibition of AKT significantly reduced three-dimensional spheroid growth induced by VAPB. Collectively, the genetic, functional and mechanistic analyses suggest a role of VAPB in tumor promotion in human breast cancer.VAPB (VAMP- associated protein B) is an ER protein that regulates multiple biological functions. Although aberrant expression of VAPB is associated with breast cancer, its function in tumor cells is poorly understood. In this report, we provide evidence that VAPB regulates breast tumor cell proliferation and AKT activation. VAPB protein expression is elevated in primary and metastatic tumor specimens, and VAPB mRNA expression levels correlated negatively with patient survival in two large breast tumor datasets. Overexpression of VAPB in mammary epithelial cells increased cell growth, whereas VAPB knockdown in tumor cells inhibited cell proliferation  Vesicle associated membrane protein associated protein B (VAPB) is a highly conserved type II integral membrane protein that belongs to the VAP protein family In addition to familial ALS, VAPB expression has been observed with cancer. A genome-wide microarray analysis of 50 human breast cancer cell lines and 145 clinical specimens revealed that VAPB is often amplified or overexpressed in breast cancer In this report, we studied the role of VAPB in breast cancer. We analyzed the expression of VAPB in both a breast cancer tissue microarray and two published large mRNA expression datasets and correlated VAPB expression with clinical outcomes. To determine the causal role of VAPB in cancer, we overexpressed VAPB in mammary epithelial cells or stably knocked down VAPB in tumor cells. Cell proliferation, apoptosis, spherical growth in 3D culture, and tumor growth in vivo were analyzed. Finally, we identified molecular mechanisms by which VAPB regulates tumor cell proliferation.5\u2032-GCACACACAAATATAGCATAA-3\u2032) and KD# 2 (5\u2032-CGGAAGACCTTATGGATTCAA-3\u2032) and VAPB cDNA were obtained from OpenBiosystems. Growth factor-reduced Matrigel and TO-PRO3 was purchased from BD Biosciences and Invitrogen, respectively. The AKT 1/2 inhibitor 5J8/0360263-1 was produced by the Vanderbilt University Department of Chemistry as described previously Antibodies against the following proteins were used: anti-VAPB (K-16), anti-VAPA (K-14), anti-actin (I-19), anti-\u03b2-tubulin (Santa Cruz Biotechnologies), and anti-PCNA (NeoMarkers), anti-Myc, anti-cleaved casepase 3, anti-pThr308AKT, anti-pSer473AKT, anti-pERK, anti-AKT, anti-ERK . Lentiviral control and VAPB shRNA plasmids KD# 1  overnight at 4\u00b0C, followed by a biotinylated goat anti-rabbit secondary antibody , an avidin-peroxidase reagent , and stained with liquid 3,3\u2032-diaminobenzidine tetrahydrochloride (DAB) substrate kit (Life Technologies/Zymed Laboratories). Relative expression in TMAs was scored using a continuous scale as Breast tumor spectrum Tissue Microarrays  were purchased from US Biomax, Inc. . Immunohistochemical staining for VAPB was performed as described previously MMTV-Neu tumor cells were isolated as previously described MCF10A cells were obtained from American Type Culture Collection (ATCC) and cultured as previously described MMTV-Neu tumor cells or MCF10A-HER2 cells were plated on a solidified layer of Matrigel (2 mm thick) using an 8-well, glass chamber slide (Thermo Scientific) as previously described 2 \u00d7 0.52). Harvested tumors were further processed for H&E staining and immunohistochemistry analysis of proliferation (Ki67) or apoptosis (cleaved caspase-3). Proliferating tumor cells were quantified by enumerating Ki67 positive nuclei in 4 random fields per tumor and presented as a percentage of Ki67+nuclei/total nuclei. A total of 8\u201310 tumors were quantified in two independent experiments. Statistical significance was assessed by single factor ANOVA.All animals were housed under pathogen-free conditions, and experiments were performed in accordance with AAALAC guidelines and with Vanderbilt University Institutional Animal Care and Use Committee approval. FVB female recipient animals were cleared of endogenous epithelium as described previously For immunoblot analysis of VAPB knockdown or overexpression, cells were washed with PBS and lysed in Radioimmunoprecipitation Assay (RIPA) buffer  supplemented with protease and phosphatase inhibitor tablets (Roche). Approximately 30\u201350 ug of total cell lysate was separated by SDS-PAGE and probed with anti-VAPB (1\u22361000) overnight in 5% nonfat dry milk/TBS-Tween (0.05%) and detected with anti-goat HRP (1\u22361000). For analysis of pAKT levels in VAPB expressing cells, cells were serum starved overnight and stimulated with DMEM/F-12 with 20 ng/mL of EGF for 20 minutes. For some experiments, an AKT inhibitor was added under normal growth conditions for 3 hours prior to cell lysis. Data are a representation of three independent experiments.P-values are given in the figure legends, and values of P<0.05 were considered to be statistically significant. Statistical analyses were performed by single factor ANOVA and unpaired, two-tailed Student t-test using PRISM software . For TMAs, statistical significance of VAPB expression between patient samples was determined by Chi-Square analysis.Results are presented as mean values\u00b1standard error. VAPB mRNA were significantly associated with poorer recurrence free survival    [20]. ToBecause the VAPB allele is often amplified in human breast cancer As an independent approach to determine whether VAPB is necessary for tumor cell growth, we knocked down VAPB in MMTV-Neu cells. These cells are derived from spontaneously arising mammary tumors from the MMTV-Neu mouse model in vivo in a mammary tumor orthotopic transplantation model in vivo.Next, we investigated the role of VAPB in tumor growth To understand the mechanisms through which VAPB enhances proliferation, we investigated potential links between VAPB and signaling molecules relevant to tumor growth. Because ERK and AKT signaling pathways are two major players in regulating cell proliferation in mammary tumor cells, we assessed their activities by western blot analysis. MCF-10A.HER2 cells carrying wild-type VAPB expression construct or the control vector were serum-starved overnight and stimulated with EGF at the indicated time points. In response to EGF stimulation, there is a rapid increase in phosphorylation of AKT at Thr308 and Ser473, indicating activation of its kinase activity. The phospho-AKT levels were more pronounced in cells overexpressing VAPB than those carrying the control vector . In contin vitro and suppressed tumor growth in orthotopic mammary tumor allografts. The growth regulation of mammary tumor cells controlled by VAPB appears to be mediated, at least in part, by modulation of AKT activities. Collectively, the genetic, functional and mechanistic analyses suggest a role of VAPB in tumor promotion in human breast cancer.VAPB was originally identified as one of the vesicle-associated membrane protein (VAMP) associated proteins. Although VAPB was implicated in a wide range of cellular processes, its function in cancer has not been characterized. In this report, we provide evidence that VAPB regulates mammary tumor growth and proliferation via activation of AKT activity. VAPB protein expression is elevated in primary and metastatic tumor specimens, and VAPB mRNA expression levels correlated negatively with patient survival in two large breast tumor datasets. Overexpression of VAPB increased spheroid size and proliferation in MCF10A-HER2 cells. Conversely, knockdown of VAPB in MMTV-Neu mammary tumor cells inhibited tumor cell proliferation in 3-D culture In breast cancer, approximately 30% of tumors have mutations in one or more components of the PI3K/AKT pathway Major subcellular compartments where VAPB is localized are the ER and Golgi, where secretory and membrane proteins are synthesized and transported to cell surface scs2, the yeast homolog of VAPs, was reported to reduce phosphoinosotide levels Aside from interacting with Arf1/Rab1, we and others also found VAPB in complex with other proteins including lipid transfer binding proteins such as Nir2  [22], [3C. elegans and DrosophilaOur results suggest that VAPB enhances breast tumor cell proliferation is mediated through the AKT pathway. However we cannot rule out other functions of VAPB that also may contribute to the phenotypes observed in this study, such as lipid sensing and transport In summary, we identified a functional role of VAPB in promoting tumor cell proliferation in breast cancer. This discovery opens up a number of exciting avenues for future studies of both full length VAPB and the secreted MSP domain in cancer. As VAPB overexpression is associated with poor patient survival, targeting VAPB-associated protein secretory pathway may provide novel targets for future pharmacological strategies in cancer therapy.Figure S1Knockdown of VAPB does not affect VAPA expression. VAPB expression was silenced in MMTV-Neu tumor cells by two independent lentiviral-mediated shRNAs (d shRNAs . VAPA prd shRNAs .(EPS)Click here for additional data file.Figure S2VAPB expression does not affect apoptosis. (A) MCF10A-HER2 or (B) MMTV-Neu knockdown cells were stained for cleaved caspase-3 at day 8 in 3-dimensional culture. Cleaved caspase-3 positive spheroids (green) were quantified by confocal microscopy analysis. No significant changes were observed in both cell lines. (C) in vivo analysis of apoptosis was measured by cleaved caspase-3 staining of tumor sections. Cleaved caspase-3 positive nuclei were quantified. VAPB deficiency does not significantly affect apoptosis in vivo. Arrows: cleaved caspase-3 positive cells. (e cells. .(EPS)Click here for additional data file.Figure S3PCNA analysis of tumor allografts. Proliferating tumor cells were quantified by enumeration of PCNA- positive nuclei and presented as a percentage of PCNA+ nuclei/total nuclei. VAPB knockdown tumors showed a significant decrease in proliferation . Arrows: PCNA positive cells. (e cells. .(EPS)Click here for additional data file.Figure S4Analysis of AKT and ERK activities in VAPB expressing cells. MCF10A-HER2 (A) and MMTV-Neu knockdown cells (B) expressing VAPB or carrying control vector were serum starved and stimulated with 20 ng/mL EGF at the indicated time points. Phospho-ERK levels were measured by western blot analysis and quantified. (C) VAPB was knocked down in MMTV-Neu cells (KD#1) and re-expressed via retroviral transduction (KD#1_VAPB). Phospho-AKT and phospho-ERK levels were measured by western blot analysis. Representative blots from 3 independent experiments are shown. (e shown. .(EPS)Click here for additional data file.Figure S5PI3K inhibition attenuates VAPB dependent spheroid growth. (A) Cells were cultured in 3D Matrigel for 2 days and then treated with LY294002 (20 \u00b5M) or vehicle control every 2 days. Tumor cell spheroids were quantified at day 8. (B) Inhibition of AKT activity was confirmed by western blot analysis for phospho-AKT levels. Shown were representative blots from two independent experiments. (riments. .(EPS)Click here for additional data file.Figure S6VAPB facilitates the transport of secretory proteins to cell surface. (A) MCF10A-HER2-VAPB expressing cells were transfected with the ts045 temperature sensitive vesicular stomatitis viral glycoprotein (VSVG) GFP and incubated at 40\u00b0C for 16 hours to accumulate misfolded VSVG protein in the ER. Following a 30-minute incubation with cyclohexamide, the cells were shifted to a permissive temperature (32\u00b0C) to allow transport along the secretory pathway. Total VSVG was visualized by GFP fluorescence (green) and cell surface VSVG was detected using an antibody against VSVG ectodomain (red) under non-permeable condition. (B) The kinetics of appearance of VSVG-GFP at the cell surface was measured by cell-surface biotinylation and subsequent quantification of immnoblots with anti-VSVG in two independent experiments . (t test). .(EPS)Click here for additional data file.Figure S7VAPB interacts with Arf1 and Rab1 small GTPases. HEK 293T cells were co-transfected with VAPB-Myc and Arf1-HA or FLAG-Rab1 expression constructs. VAPB and Arf1 or Rab1 was immunoprecipitated from cell lysates by anti-Myc, anti- HA, or anti-FLAG, and the resulting protein complexes were analyzed by western blot for Arf1 (A) and Rab1b (B) or VAPB, respectively. (ctively. .(EPS)Click here for additional data file.Table S1Representative Candidates of VAPB binding proteins. MMTV-Neu control or VAPB knockdown cells were treated with chemical crosslinkers prior to lysis. Cell lysates were immunoprecipitated with anti-VAPB and resulting protein complexes were subjected to mass spectrometry analysis. The following criteria were used for selection of candidate proteins: (1) spectral counts \u22655 and (2) the ratio of vector/knockdown \u22654. 170 candidate proteins were classified based on biological processes as annotated in PANTHER (EPS)Click here for additional data file.Materials and Methods S1.(DOC)Click here for additional data file."}
+{"text": "Sheep and goats sampled in Kuwait during February 2010 were seropositive for bluetongue virus (BTV). BTV isolate KUW2010/02, from 1 of only 2 sheep that also tested positive for BTV by real-time reverse transcription\u2013PCR, caused mild clinical signs in sheep. Nucleotide sequencing identified KUW2010/02 as a novel BTV serotype. Bluetongue virus (BTV) infects ruminants, camelids, and occasionally large carnivores. Clinical signs of bluetongue disease (BT) are usually more severe in sheep or white-tailed deer, particularly in populations previously unexposed to the virus; cattle and goats are often asymptomatic  in order of decreasing size   since 1951  at the Veterinary Diagnostic Laboratory and Animal Research Center in Kuwait, or by double antigen-recognition ELISA  at the Institute for Animal Health in the United Kingdom.t) values of 35 and 28, respectively. Previous attempts to isolate BTV from blood samples with Ct values >32 were usually unsuccessful, and no further work was done with animal 364. Washed blood from animal 374 (reference collection sample KUW2010/01)  all gave negative results by real-time reverse transcription\u2013PCR (rRT-PCR) targeting either BTV Seg-1 .KUW2010/02 RNA analyzed by agarose gel electrophoresis generated a genome segment migration pattern (electropherotype) typical of BTV . Althougwww.ncbi.nlm.nih.gov/BLAST) analysis of KUW2010/02 Seg-2 and Seg-3 sequences (GenBank accession nos. HM590642 and HM590643) showed highest identity with equivalent genome segments of other BTVs, although for Seg-2 the search algorithm was changed from megablast (highly similar sequences) to blastn (somewhat similar sequences).RNA from KUW2010/01 and KUW2010/02, extracted by using TRIzol  , conducted by using neighbor-joining methods and p-distance matrices  alignments and neighbor-joining trees also confirmed the identity of KUW2010/02 as a BTV. Virus neutralization tests of KUW2010/02 , suggesting that the clinical signs were not caused by ongoing BTV infection. All samples were also tested for peste des petits ruminants virus by rRT-PCR  indicates a low viremia, suggesting that the severe clinical signs observed were not caused by BTV. Experimental infection of previously unexposed sheep with KUW2010/02 also caused only mild clinical signs (data not shown).At peak viremia, a previously unexposed sheep infected with a virulent BTV strain could be expected to show CDifferent isolates of a single BTV serotype show >68.4%/72.6% nt/aa identity in Seg-2/VP2, with 40.5%/22.1% to 71.5%/77.8% identity between different serotypes ("}
+{"text": "Neuroimaging studies of implicit emotional processing are important for understanding the neural mechanisms and its social and evolutionary significance. Two major experimental tasks are used to explore the mechanisms of implicit emotional processing: masking tasks and inattention tasks, both using emotional faces as stimuli. However, it is unclear whether they have identical or distinct neural substrates since few studies have compared the two tasks. The purpose of the present study was to explore the mechanisms of implicit processing of emotional faces, and compare the activation patterns between different tasks. Through a literature search, 41 studies exploring implicit processing of emotional faces were collected. A total of 830 healthy subjects and 513 foci were obtained. Separate activation likelihood estimation (ALE) meta-analyses were conducted for the entire group of studies and for different tasks for comparison purposes. The results showed that there were differences, as well as overlap, in activation patterns between masking and inattention tasks. Bilateral amygdala, middle occipital gyrus and fusiform gyrus were activated across both tasks. While masking tasks were more associated with inferior temporal gyrus, parahippocampal gyrus and amygdala, inattention tasks were more associated with right fusiform gyrus. The differences in activation patterns between masking and inattention tasks may be indicative of separate mechanisms underlying early and late stages of implicit emotional face processing. Human facial expressions are powerful non-verbal emotional cues which elicit direct and automatic responses. Many studies therefore, have focused on the neural substrate of emotional face processing. Activation of the occipital regions, middle and superior temporal gyrus, limbic regions, as well as ventral and medial prefrontal regions has been reported during facial expression processing  are identical while emotional faces are presented at the same time  meta-analysis of fMRI studies  fMRI studies published in peer reviewed journals with healthy subjects; (2) used emotional faces as experimental stimuli; (3) used experimental paradigms implied implicit emotional processing ; (4) used image subtraction methodology, results reported in emotional vs. neutral contrasts; (5) results reported as normalized spatial coordinates, either in Montreal Neurological Institute (MNI) or Talairach space. Literature were excluded for one or more reasons below: (1) used non-fMRI techniques, such as positron emission tomography (PET) or event-related potential (ERP) studies; (2) used other types of emotional stimuli , or used faces in a non-emotional way (such as familiar faces); (3) experimental paradigms focused on psychological processes which implied only explicit processing, such as emotional faces recognition or recollection; (4) no specific emotional vs. neutral contrasts available, such as emotional vs. baseline contrasts, correlational studies or functional connectivity studies; (5) no data available in standard spatial coordinates; (6) results from case studies or reviews. Although studies with psychiatric patients were not excluded, only the results from healthy controls were included in the meta-analyses. Both negative and positive emotional stimuli were included in the meta-analyses, but separate sub-analyses were carried out to examine possible influence of emotional valence. Similarly, separate sub-analyses were carried out for event-related and block design studies, as well as sub-analyses for studies with high and low perceptual load tasks.Two reviewers independently screened the literature using the above criteria. Reference lists of the selected literature were also checked for potential inclusion. A total of 41 studies with 830 subjects, 513 foci were included in the ALE meta-analysis. Table http://brainmap.org/ale/). A subject-based full-width half-maximum (FWHM) , as well as sub-analyses for studies without using ROI analysis. The comparison between the ALE maps generated by different tasks was obtained by subtraction of ALE values in each voxel using GingerALE too  and overlaid onto the \u201ccolinbrain\u201d anatomical template normalized to MNI space . As suggested in Figure Forty-one studies with 830 subjects and 513 foci were identified for inclusion in the ALE meta-analysis . See Figure The ALE map for masking paradigms (showing 20 studies with 498 subjects and 312 foci) indicated activation in three clusters including bilateral amygdala and right middle occipital gyrus (BA 19) . See Figure The ALE map for inattention paradigms (showing 21 studies with 332 subjects and 201 foci) indicated activation in 5 clusters, including bilateral amygdala, right fusiform gyrus (BA 37), right medial frontal gyrus (BA 10) and left insula (BA 13) . High perceptual load tasks (showing 5 studies with 19 foci) revealed significant activation in right fusiform gyrus (BA 37), right medial frontal gyrus (BA 9), and left parahippocampal gyrus (BA 34) .Low perceptual load tasks (showing 16 studies with 182 foci) revealed significant activation in bilateral amygdala, right fusiform gyrus (BA 37), right medial frontal gyrus (BA 10) and left insula (BA 13) . Inattention tasks (showing 12 studies with 135 foci) revealed significant activation in right fusiform gyrus (BA 37), left middle occipital gyrus (BA 18), right thalamus, left inferior frontal gyrus (BA 47) and right precuneus gyrus (BA 19) .For those studies without using ROI analysis, masking tasks (showing 8 studies with 131 foci) revealed significant activation in bilateral middle occipital gyrus (BA 19) and right lingual gyrus . Inattention tasks (showing 16 studies with 138 foci) revealed significant activation in bilateral amygdala, right fusiform gyrus, right medial frontal gyrus and left insula .For negative emotional faces, masking tasks (showing 18 studies with 208 foci) revealed significant activation in bilateral amygdala . Inattention tasks (showing 5 studies with 15 foci) revealed no significant activation.For positive emotional faces, masking tasks (showing 9 studies with 88 foci) revealed significant activation in left amygdala . Inattention tasks (showing 6 studies with 38 foci) revealed significant activation in right fusiform gyrus (BA 37), right thalamus, left parahippocampal gyrus (BA 34) and right medial frontal gyrus (BA 9) .For event-related studies, masking tasks (showing 8 studies with 87 foci) revealed significant activation in bilateral amygdala, bilateral thalamus, left fusiform gyrus, left inferior frontal gyrus (BA 47), right postcentral gyrus (BA 3), right precuneus gyrus (BA 7), and left middle temporal gyrus (BA 21) . Inattention tasks (showing 15 studies with 163 foci) revealed significant activation in bilateral amygdala, right fusiform gyrus (BA 37), right medial frontal gyrus (BA 10), and left insula (BA 13) .For block studies, masking tasks (showing 12 studies with 225 foci) revealed significant activation in bilateral amygdala and right middle occipital gyrus . Meanwhile, left parahippocampal gyrus, right inferior temporal gyrus and bilateral amygdala were found to be more active in masking tasks than in inattention tasks . See Figure Z-values of the subtracted image were displayed in Table The comparison between two tasks obtained by subtraction revealed significantly higher right fusiform gyrus BA37) activation for inattention tasks than masking tasks  for inattention tasks to reveal significant results. Different emotional valence was indicated to have different activation patterns (Fusar-Poli et al., The present study used the ALE meta-analysis method which is more reliable than a single study. The expanded sample size increased statistical power. In addition, the entire scope of activation was provided. However, there were some limitations to this method of study. First, meta-analysis inherently lacks data homogeneity, thus making conclusions open to further study. Second, The ALE meta-analysis method does not account for strength of activation. It is therefore possible that important brain regions with lower activation levels may be overlooked. Third, the conversion between different coordinate systems and heterogeneous definitions of anatomical labels may also affect results.Although masking tasks are widely accepted and used to explore implicit processing, there is no good evidence to suggest that masked faces are processed completely subliminally. Pessoa  reportedNeuroimaging studies of the implicit emotional face processing were analyzed and compared using the ALE meta-analysis method. There were distinct and overlapping results between masking tasks and inattention tasks. Masking tasks implied early stages of implicit emotional processing while inattention tasks suggested later stages of implicit emotional processing. This meta-analysis provides a new point of view to evaluate the effects of different tasks and emphasizes the importance of experimental task selection in the exploration of different domains.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "KLF1\u2013KLF17) and nine SP genes (SP1\u2013SP9) with diverse functions. We used sequence similarity searches and gene synteny analysis to identify a new putative KLF gene/pseudogene named KLF18 that is present in most of the placental mammals with sequenced genomes. KLF18 is a chromosomal neighbor of the KLF17 gene and is likely a product of its duplication. Phylogenetic analyses revealed that mammalian predicted KLF18 proteins and KLF17 proteins experienced elevated rates of evolution and are grouped with KLF1/KLF2/KLF4 and non-mammalian KLF17. Predicted KLF18 proteins maintain conserved features in the zinc fingers of the SP/KLF family, while possessing repeats of a unique sequence motif in their N-terminal regions. No expression data have been reported for KLF18, suggesting that it either has highly restricted expression patterns and specialized functions, or could have become a pseudogene in extant placental mammals. Besides KLF18 genes/pseudogenes, we identified several KLF18-like genes such as Zfp352, Zfp352-like, and Zfp353 in the genomes of mouse and rat. These KLF18-like genes do not possess introns inside their coding regions, and gene expression data indicate that some of them may function in early embryonic development. They represent further expansions of KLF members in the murine lineage, most likely resulted from several events of retrotransposition and local gene duplication starting from an ancient spliced mRNA of KLF18. Kr\u00fcppel-like factors (KLF) and specificity proteins (SP) constitute a family of zinc-finger-containing transcription factors that play important roles in a wide range of processes including differentiation and development of various tissues. The human genome possesses 17 KLF genes ( The separations between the first, second, and third cysteine pairs are four residues, four residues, and two residues, respectively. Such a pattern together with the number of C2H2 domains (three) appears to be a unique feature of SP/KLF members in mammalian genomes compared to the patterns of other known C2H2-domain-containing proteins  and specificity proteins (SP) are an important family of transcription factors (SP/KLF family) under extensive research \u20133. They database  revealeddatabase . These rKLF1-KLF17) and nine SP genes (SP1\u2013SP9) are currently annotated in the human genome. Compared to KLF proteins, SPs are characterized by a unique cysteine-rich motif  in the region N-terminal to the zinc fingers. Several phylogenetic analyses of the SP/KLF family proteins x[sE][QH]) found very few proteins with a high density of this motif (motif density is defined as the number of motifs divided by protein length). Although the cysteine-rich keratins have high concentrations of this motif, their motifs have cysteines in the first position as opposed to mostly tyrosine in predicted KLF18 proteins. Another protein with a high density of this motif is RNA-binding protein 14 (GenBank: NP_006319.1). This protein possesses the \u201c[GS]Y[GS]\u201d repeats often found in proteins from RNA granules . The YC and HHprKLF18 in species from all four major groups (superorders) x[GASTDNPE][QH]\u201d (x: a single letter) are highlighted in cyan. Zinc finger regions are highlighted in magenta.(PDF)Click here for additional data file.Figure S3A phylogenetic tree of representative SP/KLF proteins with the human Wilms\u2019 tumor protein (human_WT1) as an out-group. This tree was generated by MrBayes. Each protein node is denoted by its species name followed by the protein name.(PDF)Click here for additional data file.Figure S4A phylogenetic tree of SP/KLF proteins generated by MOLPHY. Each protein is denoted by its species name abbreviation followed by the protein name. Species name abbreviations are: bt, Bos taurus (cow); cf, Canis familaiaris (domestic dog); ch, Choloepus hoffmanni (two-toed sloth); cj, Callithrix jacchus (common marmoset); cp, Cavia porcellus (guinea pig); dn, Dasypus novemicinctus (nine-banded armadillo); do, Dipodomys ordii (kangaroo rat); dr, Danio rerio (zebrafish); ec, Equus caballus (horse); hs, Homo sapiens (human); la, Loxodonta Africana (African Savannah elephant); mm, Mus musculus (mouse); oc, Oryctolagus cuniculus (rabbit); rn, Rattus norvegicus (rat); sa, Sorex araneus (common shrew); tb, Tupaia belangeri (tree shrew); xt, Xenopus tropicalis (Western clawed frog).(PDF)Click here for additional data file."}
+{"text": "Recent findings suggest that the Surgical Care Improvement Project (SCIP) a US-Based \u201cprocess initiative\u201d fails to reduce the risk of SSIs. The following evidence-based discussion proposes a SCIP-PLUS perspective for reducing risk of SSIs through enhanced antimicrobial prophylaxis and embracing innovative antimicrobial risk reduction technology.Four risk reduction initiatives were studied, A: Impact of BMI on antimicrobial prophylactic dosing in general, OB and CT surgical patients; B: Development of standardized regimen of CHG preadmission cleansing to improve outcome in surgical patients; C: Efficacy of antimicrobial sutures to reduce the risk of suture contamination at wound closure and D: The impact of an innovative antimicrobial surgical glove to reduce the risk of microbial contamination following glove microperforation.p<0.05); B: Standardization of skin cleansing using a 2% CHG polyester cloths was effective at providing skin concentrations sufficient to inhibit/kill wound pathogens compared to non-standardized regimen (p<0.001); C: Laboratory/clinical studies demonstrate that antimicrobial suture technology is effective (p<0.05) at reducing the risk of suture contamination and SSI; D: Innovative antimicrobial surgical glove was effective (p<0.001) at reducing bacterial passage following microperforation which can lead to wound contamination.A: 2-gm dosing in surgical patients failed to provide adequate tissue concentrations at BMI >30 (An effective SCIP-PLUS strategy requires multi-faceted evidence-based approach including antimicrobial dosing to compensate for BMI, thoughtful preadmission skin cleansing, use of antimicrobial suture technology at wound closure and embracing innovative antimicrobial surgical glove technology reducing the risk of bacterial passage into the surgical wound.None declared."}
+{"text": "Cocaine abuse is associated with an increased risk for coronary artery disease and myocardial infarction. However, there is a paucity of data on myocardial injury in asymptomatic cocaine abusers. T1 mapping cardiovascular magnetic resonance (CMR) has the ability to quantify diffuse alterations in myocardial tissue composition by assessing the extracellular volume fraction (ECV). This study aimed at detecting silent myocardial injury in cocaine abusers using CMR.myocardium/\u0394R1blood pool).CMR was performed in eleven cocaine abusers and eleven matched controls without a history of cardiovascular disease. CMR protocol consisted of standard cine-, T2-STIR- and late gadolinium enhancement (LGE) CMR sequences to assess cardiac volumes and function, myocardial edema and focal myocardial fibrosis, respectively. Myocardial extracellular volume fraction (ECV) was assessed using a T1 mapping sequence (MOLLI) before and after administration of 0.075 mmol/kg gadolinium BOPTA: T1 maps were calculated with a dedicated plug-in written for the OsiriX software. Relaxation rates (1/T1 = R1) were calculated for myocardium and blood pool. The difference in R1 between pre- and post contrast media was calculated as \u0394R1. Myocardial ECV was then estimated using the formula: ECV = 1-hematocrit * . Neither cocaine abusers nor controls had myocardial edema on T2-STIR images. Discrete LGE with non-ischemic pattern was found in three cocaine abusers (27%) but not in controls p=0.21). Global ECV was significantly larger in cocaine abusers compared to controls . Figure . Global Our findings indicate an increased myocardial extracellular space in asymptomatic cocaine abusers. These subtle myocardial alterations could represent early diffuse myocardial fibrosis and herald future cardiovascular events.None."}
+{"text": "Only a fraction of patients with metastatic colorectal cancer (mCRC) receive clinical benefit from therapy with anti-epidermal growth factor receptor (EGFR) antibodies. Gene mutations along the Ras pathway  correlate with poor response to anti-EGFR antibodies.By implantation and serial propagation in NOD/SCID mice, we produced large xenograft cohorts from 85 patient-derived mCRC samples (\"xenopatients\").Xenopatients retained the histological and genomic features of the original counterparts, responded to the anti-EGFR antibody cetuximab similarly to clinical observations, and could be prospectively stratified as responders or nonresponders based on predictive biomarkers. Genotype-response correlations indicated HER2 amplification specifically in a subset of cetuximab-resistant, KRAS/NRAS/BRAF/PIK3CA wild-type cases. In this subset, combined HER2/EGFR inhibition induced long-lasting tumor regression. We also assessed the effects of MEK and PI3K/mTor inhibitors (AZD6244 and BEZ235 respectively) in 40 specimens harboring KRAS/ NRAS/BRAF/PIK3CA mutations. Cotreatment of xenografts with AZD6244+BEZ235 induced disease stabilization in the majority of cases (70%) but did not lead to tumor regression. Monotherapy was less effective, with BEZ235 displaying higher activity than AZD6244. Triple therapy with cetuximab provided further advantage. The extent of disease control declined upon prolonged treatment.Our preclinical platform prospectively recapitulated biomarker-based case stratification and was instrumental in identifying HER2 as a predictor of resistance to cetuximab and of response to combination therapies against HER2 and EGFR. The prevalent growth-suppressive effects produced by MEK and PI3K/mTOR inhibition suggest that this strategy may retard disease progression in KRAS-mutant mCRC patients.AIRC, Associazione Italiana per la Ricerca sul Cancro; FPRC, Fondazione Piemontese per la Ricerca sul Cancro."}
+{"text": "The search for asymptomatic bacterial urinary tract colonization (UTC) and its eradication before elective hip and knee arthroplasty surgery is controversial, but reflects widespread practice. The influence of perioperative antibiotic prophylaxis on the dynamics of UTC is unknown.We investigate the role of preoperative urinary tract colonization in patients undergoing elective joint arthroplasty.Prospective observational cohort study (November 2011-October 2012) with urine analyses before and 3 days after surgery. Patients with symptomatic infections or long-term urinary catheter carriage were excluded. Post-discharge surveillance included questionnaires to patients and general practitioners at 3 months.E. coli. Urine analysis revealed also 169 episodes of leukocyturia. Almost all (95%) received a single-dose perioperative prophylaxis of cefuroxime 1.5 g IV. Median duration of postoperative urinary catheter carriage was 0 days .480 asymptomatic patients  were enrolled. On admission, 171 patients (35%) had bacterial UTC, mostly due to On postoperative day 3, urinary analysis was abnormal in 90 episodes of leukocyturia and 198 episodes of UTC, respectively. Day 3 -bacterial UTC was different from preoperative sampling among 50% of patients and microbiological results revealed a higher proportion of Gram-positive organisms.Only 30 patients (6%) developed a symptomatic urinary tract infection during a follow-up of 3 months; one-third of pathogens were unrelated to those found during hospitalization. All symptomatic infections were treated with oral antibiotics. There was no seeding of joint prostheses. Estimated minimal laboratory costs for preoperative urinary analyses were \u20ac 27,300.Pre- or postoperative routine urine evaluation of asymptomatic arthroplasty patients is costly and only moderately predicts the pathogen of a potential urinary tract infection. If symptomatic infection occurs, a targeted individualized antibiotic therapy prevents urosepsis and hematogenous spread to joint prosthesis.None declared"}
+{"text": "To evaluate the value of different MRI derived parameters to differentiate left ventricular noncompaction of the myocardium (LVNC) in patients with known familial LVNC from other cardiomyopathies.LVNC is a rare disease characterized by numerous, excessively prominent ventricular trabeculations and deep intertrabecular recesses communicating with the ventricular cavity. Cardiac MRI (cMRI) has been reported as an ideal imaging modality to characterize patients with LVNC. Nevertheless, qualitative parameters to differentiate normal compaction of the myocardium in healthy subjects from LVNC or from other cardiomyopathies like dilated cardiomyopathy (DCM) or hypertrophic cardiomyopathy (HCM) may fail due to highly variable left ventricular trabeculations. Therefore, absolute quantification should be performed.comp), MM-Index=MMI [g/m2], MMnon-comp, percental MMnon-comp, ventricular volumes and function were calculated using the CAAS MRV  with known familial LVNC carrying a gene mutation, 11 DCM (32.6 years\u00b117) and 10 HCM patients compared with 24 healthy volunteers (20.2 years\u00b16.3) using a 1.5 T scanner and a standard steady state free precession sequence in standard orientations. Total left ventricular muscle mass (MM), the compacted muscle mass , but only a poor specificity (27%). None of the LVNC patients demonstrated with intramyocardial late gadolinium enhancement (LGE), but HCM and DCM patients did. Furthermore, increased trabeculations in the basal and septal segments, especially in the segments 4-6, are additional strong indicators for LVNC.The mean EF was significantly reduced (p<0.05) in LVNC patients compared to all cardiomyopathies and healthy subjects, total MM was increased, but not significantly different from HCM patients. The total MMInon-comp or the percental MMnon-comp together with an absence of LGE and increased trabeculations in basal segments allows to reliably diagnose familial LVNC.Absolute cMRI quantification of the MMI"}
+{"text": "Tracheal epithelial remodelling, excess mucus production, and submucosal gland hyperplasia are features of numerous lung diseases, yet their origins remain poorly understood. Previous studies have suggested that NF-\u03baB signalling may regulate airway epithelial homeostasis. The purpose of this study was to determine whether deletion of the NF-\u03baB signalling pathway protein myeloid differentiation factor 88 (Myd88) influenced tracheal epithelial cell phenotype. We compared wild-type and Myd88-deficient or pharmacologically inhibited adult mouse tracheas and determined that in vivo Myd88 deletion resulted in increased submucosal gland number, secretory cell metaplasia, and excess mucus cell abundance. We also found that Myd88 was required for normal resolution after acute tracheal epithelial injury. Microarray analysis revealed that uninjured Myd88-deficient tracheas contained 103 transcripts that were differentially expressed relative to wild-type and all injured whole tracheal samples. These clustered into several ontologies and networks that are known to functionally influence epithelial cell phenotype. Comparing these transcripts to those expressed in airway progenitor cells revealed only five common genes, suggesting that Myd88 influences tracheal epithelial homeostasis through an extrinsic mechanism. Overall, this study represents the first identification of Myd88 as a regulator of adult tracheal epithelial cell phenotype. Copyright \u00a9 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Airway mucus production is central to lung immunity and pathogen clearance. In humans, mucus is produced within specialized proximal airway secretory cells and appendages termed submucosal glands (SMGs) . In contEDAR mutations are known to inhibit airway mucus cell development and are associated with increased respiratory infection [Several groups have investigated mechanisms of submucosal gland development and mucus cell differentiation using murine transgenic and knockout models. These studies have determined that deletion of the transcription factor Lef1 inhibits tracheal submucosal gland formation  and thatnfection , 10. Sepnfection . These sIn addition to studies in murine models, it has been observed that human respiratory diseases with mucus cell metaplasia often exhibit NF-\u03baB signalling pathway activation , 12. NF-Myd88 deletion within bone marrow-derived cells (BMDCs) also exhibited increased airway epithelial hyperreactivity after challenge [Genetically modified mouse models designed to elucidate how NF-\u03baB signalling regulates airway mucus cell metaplasia have produced conflicting results. Epithelial-specific I\u03baB super-repressor (I\u03baB-SR) (NF-\u03baB inhibited) transgenic mice display increased mucus metaplasia following chrysotile asbestos fibre exposure  but reduhallenge \u201319. Convhallenge .Myd88 deletion increased adult tracheal SMG abundance as well as mucus cell metaplasia and that Myd88 was required for normal resolution after acute tracheal epithelial injury. We also describe a unique tracheal gene expression profile associated with Myd88 deficiency that suggests potential regulatory mechanisms for mucus cell and submucosal gland metaplasia.In this study, we determined that Myd88 knockout (KO) mice were housed in individually ventilated cages on a 12 h light/dark cycle and allowed access to food and water ad libitum. Mice were kept in specific pathogen-free conditions and no infections were detected via sentinel screening during these studies. KO mice were generated as previously described [Adult, 4- to 6-month-old male and female C57/Bl6 wild-type and escribed , followen = 3 animals were used for each recovery time point. Mice were sacrificed by sodium pentobarbital overdose and all experiments were performed with approval of the UK Home Office (licence number 70/6077).In order to study tracheal repair, mice were anaesthetized with isofluorane and tracheas were damaged by oropharyngeal instillation of 10 \u00b5l of 2% polidocanol . This established protocol results in rapid desquamation of tracheal epithelial cells within 24 h, followed by robust proliferation 3 days after injury, keratin 14 hyperplasia and transdifferentiation within 7\u201310 days , and comTissues were fixed overnight in 4% paraformaldehyde, processed, and sectioned longitudinally. Haematoxylin and eosin (H&E), periodic acid Schiff (PAS), Alcian blue, and Gram  histochemical staining was performed using standard protocols on an automated staining system .Immunohistochemical and immunofluorescent staining of sections and air\u2013liquid interface cell wholemounts followed standard conditions . Primary5 cells per well in MTEC/plus [Tracheal epithelial cells from five knockout and six wild-type mice were harvested using aseptic techniques, pooled, cleaned, digested in pronase, and cultured as previously described . Enzyme TEC/plus . Upon vim guanidine isothiocyanate as previously described [Total RNA was prepared from whole tracheal homoge-nates suspended in 4 escribed . We prepp < 0.01 by one-way, parametric ANOVA, followed by Benjamini and Hochberg multiple test correction. All microarray data are MIAME compliant (GSE17268).Labelled input RNA (2 \u00b5g) was prepared using an Agilent RNA amplification system according to the manufacturer's instructions . We analX-axis and the average stem or progenitor cell expression (K5/lectin double or single positive) relative to lectin plus keratin 5 negative (\u2018double negative\u2019) cells along the Y-axis. We considered those genes exhibiting at least a two-fold increase in either the stem or the progenitor cells relative to double negatives as being significantly enriched. All genes identified in our comparison exhibited a p value less than or equal to 0.05 in the previously published study [We compared the expression profiles of genes that we identified as differentially expressed in Myd88-deficient, uninjured tracheal samples with a publicly available tracheal epithelial stem and progenitor cell profiles (GSE 15 724) . Gene exed study .n = 3 was used for all morphometric sample analyses. Statistical significance of epithelial cell differentiation and abundance was determined using an unpaired Student's t-test for pairwise comparisons or ANOVA followed by Tukey's post-test pairwise comparison for multivariate sample comparisons.Epithelial cell densities were determined as previously described by measuring the incidence of specific cell types as a function of basement membrane length , 28. A mMyd88 influenced epithelial cell phenotypes, we compared adult (4- to 6-month-old) C57/Bl6 wild type and Myd88 knockout (Myd88KO) tracheas. We used haematoxylin and eosin (H&E) staining to identify any histological differences between mice . This technique causes rapid undifferentiated epithelial cell growth, followed by basal, ciliated, and secretory cell differentiation . ALI culithelium . There withelium . DespiteWe next investigated whether Myd88 deficiency influenced resolution or repair following acute tracheal injury. To test this, adult mice were administered 2% polidocanol by oropharyngeal instillation to damage their epithelium and were allowed to recover for 3, 10, or 30 days. This method results in the rapid desquamation of tracheal epithelial cells within 24 h, followed by robust proliferation after 48\u201372 h and restoration of a phenotypically normal tracheal epithelium within 7\u201310 days . AlthougThese differences in epithelial hyperplasia were not due to altered cell proliferation or apoptosis. Control, 3-, 10-, and 30-day-recovered wild-type and Myd88KO mice were injected with 10 mg/kg BrdU 1 h prior to sacrifice and tissue sections stained using a BrdU-specific antibody . We obseTo determine whether KO-specific tracheal epithelial hyperplasia was due to abnormal metaplasia or ongoing epithelial-to-mesenchymal transition (EMT) processes, we examined mucus, Clara, basal, and smooth muscle actin (SMA)-expressing cell abundance 3, 10, and 30 days after injury . Consistp < 0.01 were considered to be differentially expressed. Using these criteria, 2908 transcripts exhibited differential expression between wild-type uninjured controls and injury samples; 168 between KO uninjured controls and KO injury; and 139 between WT controls and KO controls  using Agilent gene expression microarrays (GEO series GSE17268). Genespring X7.3 software was used to screen 41,267 total transcripts, and samples exhibiting a minimum statistical significance of controls A. BecausHal), monoacylglycerol O-acyltransferase 2 (Mogat2), and netrin 4 (Ntn4) relative to uninjured wild-type samples (Trim12), oncomodulin (Ocm), and pituitary tumour transforming gene 1 (Pttg1) expression versus uninjured wild-type controls  software . IPA software collates findings presented in peer-reviewed publications into networks of physical, transcriptional, or enzymatic interactions to reveal functional and mechanistic pathway associations. The most significant of these was associated with NF-\u03baB activation and included genes encoding the cell surface ectodysplasin A receptor (Edar) and lipopolysaccharide binding protein (Lbp). Interestingly, both of these genes have previously been functionally associated with epithelial mucus production and submucosal gland differentiation , 36 FigE.X-axis based on its expression in knockout tissue relative to uninjured wild-type samples. Along the Y-axis, we plotted expression of these same genes based on their expression in either tracheal lectin plus keratin 5-expressing (stem) or lectin-only (progenitor) cell populations  and were also not present during embryogenesis. The observed adult tracheal mucous cell metaplasia phenotype was recapitulated following systemic administration of the commercially available Myd88 inhibitory peptideIMG-2005. This finding strongly implicates the Myd88/NF-\u03baB pathway as a central mediator of airway homeostasis and mucus production. Myd88 was also required for normal resolution from epithelial injury. Interestingly, however, Myd88-deficient cells exhibited normal We observed increased submucosal gland formation, mucus cell abundance, and epithelial hyperplasia only within tracheas, despite global Myd88 deletion. This result was consistent with the observation that murine mucus hypersecretion and mucus cell transdifferentiation are limited to proximal airways, despite the use of injury models that target the whole lung . Additioin vitro air\u2013liquid interface. This result suggests that extrinsic, rather than epithelial cell autonomous or cell-intrinsic, factors influence adult tracheal secretory cell phenotypes.Our data are consistent with previous reports linking Myd88, NF-\u03baB activity, and initial lung epithelial differentiation , 38, 39.Edar and Lbp, each of which are known regulators of lung epithelial cell phenotype. Ectodysplasin A (Eda) and Edar-deficient mouse strains  lack submucosal gland development, despite normal basal keratinocyte progenitor cell abundance [Lbp knockout mice fail to exhibit reduced airway hyperreactivity and mucus cell metaplasia after endotoxin exposure [Lbp has also been shown to directly regulate airway hyperreactivity by facilitating lipopolysaccharide binding to myeloid cells [Ingenuity Pathway Analysis performed as part of this study identified several gene-interaction networks that are differentially regulated in KO tracheas and may mechanistically explain our observed phenotypes. These networks included the genes bundance . Separatexposure . Lbp hasid cells .Mogat2, Hal, and Ntn4) exhibited significant up-regulation. It has previously been shown that Mogat2-deficient mice exhibit numerous epithelial defects including overabundant intestinal epithelial mucus production [Hal gene expression has been associated with altered skin epithelial cell differentiation [Trim12, Ocm, and Pttg1. Interestingly, these genes are also known regulators of epithelial homeostasis and differentiation [Trim family members are required for maintenance of skin epithelial cells in an undifferentiated state [Ocm and Pttg1 are both modulators of epithelial growth and regeneration [Microarray analysis revealed differential expression of 103 transcripts in Myd88KO versus WT tracheas. Differentially expressed genes included both uncharacterized and previously identified regulators of epithelial cell phenotypes. We assessed the expression of six of these genes in adult tracheas using quantitative RT-PCR (QPCR). Three of these genes (oduction . Separatntiation . Netrin ntiation . Down-rentiation \u201347. Speced state , whereasneration , 34, 48.This report is the first to identify a role for Myd88 in adult tracheal submucosal gland abundance. Overall, the results of this study, alongside those of previous publications, suggest a complex mechanism of signalling network interactions that regulates postnatal tracheal submucosal gland development, mucus cell homeostasis, and metaplasia."}
+{"text": "The mid-wall intramyocardial 'stripe' is now shown to be robust in its prediction of subsequent need for LVAD and/or transplantion and death out to 12 months following index CMR exam.Patients with newly diagnosed dilated cardiomyopathy (DCM) and advanced heart failure have a very high morbidity and mortality with an unpredictable clinical course. We investigated the role of CMR via LGE (late gadolinium enhancement) in this cohort of high-risk patients.Hypothesis Utilizing cardiovascular MRI (CMR), we assessed the prognostic value of LGE in primary dilated DCM patients referred for possible transplantation/LVAD consideration.Over 49 consecutive months, 61 consecutive DCM pts were referred for standard 3D CMR  to interrogate the LV pattern, distribution and extent of LGE . Inclusion criteria for a primary non-ischemic dilated DCM and EF <45% were met in 31 pts. DCM were categorized into: 1) +midwall LV Stripe 2) \u2212midwall LV Stripe groups. MACE defined by the composite of death, need for LV assist device (LVAD), and urgent cardiac transplantation (Tx) were evaluated over the ensuing 12 months.There were no differences between groups for demographics, baseline LVEF, NYHA class or invasive hemodynamics. There were 18/31 (58%) pts with + mid-wall Stripe. Nine events occured: 7 pts required urgent Tx \u00b1 LVAD and 2 pts died among the 31 pts. The group with +Stripe categorization strongly predicted the need for LVAD, urgent Tx surgery and death over the ensuing 12 months . Specifically, all the events occured in the +Stripe pts: 7/18 (39%) +Stripe pts required urgent Tx or LVAD by 6 months and 2/18 (11%) +Stripe pts died by 12 months. The \u2212Stripe group never experienced the need for Tx, LVAD or death, indeed revealing signs of improvement in NYHA and LVEF (p<0.05). Neither LVEF, LVEDV, RVEF, RV size, PCWP, PAP, NYHA or age predicted MACE via univariate analysis. LVEDD was statistically different between +Stripe and \u2212Stripe group but by Multivariate analysis did not predict MACE.The presence of +Stripe on CMR is strongly predictive of LVAD, transplant need and death over the ensuing 12 months in DCM patients. All \u2212Stripe pts possess a 100% favorable sign through one year. Incorporating CMR imaging into routine clinical practice may help to identify DCM risk; conservatively manage low-risk patients while expectantly manage high-risk patients.Internal."}
+{"text": "Recent studies suggest a role for Th17 responses in the increased airway neutrophilia associated with severe asthma. House dust mite (HDM) is a natural allergen to which asthmatics are often sensitized. Mice repeatedly challenged with HDM extract developed robust airway neutrophilia rapidly evolving into asthma-like disease with increased numbers of eosinophils and lymphocytes in bronchoalveolar lavages (BAL) as well as inflammatory infiltrates, vascular/muscular hypertrophy, interstitial fibrosis, epithelial hyperplasia and mucus accumulation in lung tissues. RNA and protein screening revealed a robust Th17 component post-HDM exposure. We thus evaluated whether IL-17A deficiency could modulate HDM-induced allergic airway disease. Airway neutrophilia was indeed abrogated in IL-17A deficient mice weekly challenged with HDM (acute model), however total BAL cellularity and lung mechanics remained comparable to those of HDM-challenged WT mice. In contrast, IL-17A deficient mice daily exposed to HDM (chronic model) had decreased BAL cellularity associated with reduced numbers of BAL macrophages, neutrophils, eosinophils and lymphocytes. Interestingly antibody neutralization of TL1A, a member of the TNF superfamily known to promote Th2 and Th17 responses, reduced BAL cellularity to baseline levels in HDM-challenged WT mice. Our results thus indicate that targeting Th17 responses can alleviate HDM-induced airway neutrophilia, and can also broadly modulate allergic airway disease."}
+{"text": "Accurate dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) protocol evaluation is necessary to ensure reliable classification of contrast-agent (CA) uptake curves. This work presents a novel retrospective method to assess the dynamic range that constructs CA uptake curves using enhancement of the internal mammary artery.n = 45). CA uptake curves were constructed from a standardised axial slice through the right mammary artery, and maximum relative enhancement (maxE) and time-to-peak enhancement (maxT) were measured for each examination [max Eand max Twere compared between protocols . For each protocol, calculated values of maximum relative enhancement  were derived from the Bloch equations and compared with max Eto validate the results.Routine clinical breast examinations were performed using 3D fat-suppressed spoiled gradient-echo sequences 1.5T). Retrospective analysis was approved by the Clinical Audit Committee. Five different protocols were evaluated , radial or linear k-space sampling), with seven to 10 patients in each group . Radial protocols exhibited greater max Tthan linear protocols at FAs of both 14\u00b0 (P = 0.025) and 18\u00b0 (P < 0.0001). calc Ewas found to increase with FA as expected, with good agreement between calc Eand maxE.A lower FA and radial k-space sampling resulted in a statistically significant decrease in Significant differences were found between patient groups with only small alterations in protocol. Observations agreed with expected results, validating this method of retrospective analysis. The dynamic range is optimised at higher flip angles and with linear k-space sampling."}
+{"text": "Pancreatic ductal adenocarcinoma (PDA) has a prominent stroma which includes collagen, lymphoid, myeloid, and stellate cells. Adequate preclinical models are needed to advance immunotherapy for PDA. Indeed many xenograft models poorly mimic the morphology, stroma, and phenotype of the human PDA microenvironment. Thus, further development and use of relevant spontaneously arising genetically engineered murine models (GEMM) of PDA is important for accurate preclinical assessment of immune therapies. We have demonstrated that PDA-associated stellate cells promote the differentiation of myeloid-derived suppressor cells (MDSC) in a STAT3-dependent manner. Thus it is important that tumor and stroma in murine PDA models recapitulate a human patient\u2019s immune phenotype. To date, the contribution of various cytokines or soluble factors in these models has not been well characterized. We hypothesized that various pancreatic cancer GEMM would accurately replicate alterations in STAT3 signaling and immune suppressive phenotypic properties both systemically and within the tumor microenvironment. We examined the role of IL-6/STAT3 signaling within the microenvironment from four separate spontaneously arising GEMM of PDA  which recapitulate human tumors. KPC, BRCA-KPC, and Mist1(KRasG12D/+) mice develop spontaneously arising KRAS mutant  pancreatic tumors. Similar to human PDA, fibrosis was evident in all tumors, with cystic regions found in BRCA1-KPC tumors. Murine pancreatic stellate cells from Mist1(KRasG12D/+) were alpha-SMA+ and produced IL-6 similar to human stellate cells. STAT3 was constitutively phosphorylated at Tyr705 in both malignant and stromal cells of the tumor microenvironment in each GEMM. Similar to patients with advanced PDA, high-throughput bioplex analysis revealed plasma from tumor-bearing mice contained high levels of IL-6 (mean 4729 pg/ml) and other important inflammatory factors. Time course data from the Mist1(KRasG12D/+) GEMM revealed elevated levels of MDSC at early stages of 3 months (4.6%\u00b11.7), with higher levels (8.9%\u00b1 0.3) by 8 months as compared to healthy, age matched littermates (2.3%). Similarly, MDSC were significantly higher in BRCA1-KPC mice  versus healthy, age-matched littermates . These data demonstrate that multiple spontaneously arising GEMM for PDA display a phenotype comparable to the microenvironment of human patients. Future studies will take advantage of these properties and use these models for therapeutic evaluation of agents targeting the IL-6/JAK/STAT pathway within the tumor microenvironment."}
+{"text": "Prevention of secondary neurologic injuries is paramount for improved neurologic outcomes after traumatic brain injury (TBI). Evidence suggests that although therapeutic hypothermia (TH) lowers intracranial pressure and attenuates secondary cerebral insults after TBI , it alsoSix domestic cross-bred pigs were subjected to epinephrine infusion after general anesthesia, standardized TBI and transpulmonary hypothermia (32\u00b0C for 48 hours). All animals received the same care, aiming for a mean arterial pressure >60 mmHg. At hour 24, animals received additional vasopressin infusion at 0.04 units/minute. We measured the cumulative epinephrine dose for each animal pre and post vasopressin infusion Figure  and perfP = 0.003), based on the Wilcoxon rank-sum test.The median cumulative epinephrine dose in the animals that received the vasopressin infusion was 715 mg with a 25th to 75th interquartile range (IQR) of 320 to 930 mg. The median cumulative epinephrine dose in the control group was 2,044 mg . This was statistically significant (A low-dose infusion of vasopressin can significantly reduce vasopressor requirements and improves hemodynamics in hypothermic, brain-injured swine. This hemodynamic stability may improve neurological outcomes."}
+{"text": "We sought to determine the feasibility and reproducibility of cardiac magnetic resonance (CMR) myocardial feature tracking (FT) for quantitative wall motion assessment during intermediate dose dobutamine stress magnetic resonance (DSMR) imaging.DSMR imaging is an established tool to assess hibernating myocardium and ischemia. Analysis is typically based on visual assessment with considerable operator dependency. CMR-FT is a recently introduced technique for tissue voxel motion tracking on standard steady-state free precession (SSFP) images to derive circumferential and radial myocardial mechanics.10 healthy subjects were studied at 1.5 Tesla. Myocardial strain parameters were derived from SSFP cine images using dedicated CMR-FT software . Right ventricular (RV) and left ventricular (LV) longitudinal strain (EllRV and EllLV) and LV long-axis radial strain (ErrLAX) were derived from a 4-chamber view at rest. LV short-axis circumferential strain (EccSAX) and ErrSAX, LV ejection fraction (EF) and volumes were analyzed at rest and during dobutamine stress (10 and 20 \u03bcg * kg-1* min-1).In all volunteers strain parameters could be derived from the SSFP images at rest and stress. EccSAX values showed significantly increased contraction with DSMR . ErrSAX increased significantly with dobutamine . In parallel with these changes, EF increased significantly with dobutamine . Observer variability was best for LV circumferential strain (EccSAX ) and worst for RV longitudinal strain (EllRV) as determined by 95% confidence intervals of the difference.CMR-FT reliably detects quantitative wall motion and strain derived from SSFP cine imaging that corresponds to inotropic stimulation. The current implementation may need improvement to reduce observer-induced variance. Within a given CMR lab, this novel technique holds promise of easy and fast quantification of wall mechanics and strain.AS receives grant support from the British Heart Foundation (BHF) (RE/08/003 and FS/10/029/28253) and the Biomedical Research Centre (BRC-CTF 196). SK receives grant support from the American College of Cardiology Foundation, the Edna Ittner Pediatric Foundation, and the Children\u2019s Hospital and Medical Center Foundation."}
+{"text": "Although low back pain (LBP) is a common reason older adults seek treatment from either medical doctors (MD/DO) or doctors of chiropractic (DC), collaborative care between these providers is rarely reported. The purpose of our study is to develop a model for such collaborative care in LBP patients, based upon an existing integrative medicine model , focusing on four facets of interprofessional collaboration: attitudes, knowledge, referral, and integrative practice.An interdisciplinary committee composed of DCs, MDs, a pharmacist, biostatistician and health services researchers developed a collaborative care model for implementation within the context of a clinical trial. Family medicine physicians (n = 18) and chiropractic clinicians (n = 29) completed a survey, including the Integrative Medicine Questionnaire (IM-30). A pre-selected group of MD/DO residents and DC clinicians then completed five interprofessional education sessions (IPE) on the model and clinical trial, and participated in job shadowing experiences.Median IM-30 scores measured pre-IPE indicated DC and MD/DO providers had comparable overall (61.1 vs 59.3) and subscale scores for openness to working with alternate paradigm practitioners (60.8 vs 55.0); readiness to refer patients to alternate paradigm practitioners (66.7 vs 66.7); and provision of patient-centered care (66.7 vs 75.0). DCs scored higher than MDs/DOs on subscales measuring willingness to learn from alternate paradigms (55.0 vs 30.0) and integrative medicine safety (80.0 vs 60.0). These data will be compared to Year 1 follow-up surveys currently underway. IPE fieldnotes documented collegial debate on the evidence-base supporting chiropractic and medical LBP treatments, clinical examination and imaging interpretation, and safety concerns.Early evaluation of our collaborative care model revealed similarities in DC and MD/DO attitudes towards working with alternate paradigm health practitioners on LBP care for older adults. Provider safety concerns and willingness to learn from alternate disciplines may require additional IPE training to overcome."}
+{"text": "Respiratory complexity (RC) as assessed by sample entropy (SampEn) is lower in patients failing spontaneous breathing trials. We evaluated the role of RC in monitoring subjects with severe acute respiratory distress syndrome (ARDS) treated with the Cardiohelp  extracorporeal life-support system (ECLS). We hypothesized that RC is reduced during apnea.2 was 0.5. Sheep were on CPAP of 8 cmH2O with FiO2 of 1 via tracheostomy. After ~6 hours of ECLS, ARDS was induced by injection of 0.1 ml/kg oleic acid. Apneas (defined as >60% reduction in minute ventilation) developed both before (Preinjury) and after ARDS (Postinjury). Heart rate (HR), mean arterial pressure (MAP), respiratory rate (RR) and tidal volume (TV) were recorded, and the PaO2:FiO2 ratio (PFR) calculated corresponding to sections of respiratory pressure waveforms containing 200 breaths during Baseline, during Preinjury and Postinjury apnea periods. Similar periods were selected before and after apneas. Inter-breath interval (IBI) and its deviation, SampEn, percentage of forbidden words (FW), bit per-word entropy (BPWEn), symbol distribution entropy (DisNEn), and stationarity (StatAv) were calculated using software. Statistics by one-way ANOVA with adjustment for multiple comparisons.Six sheep sedated with midazolam were connected to the Cardiohelp via a 23F Avalon catheter. Blood flow was ~2 l/minute and FiOr2 = 0.31, P <0.001).See Table Respiratory complexity during apnea and ECLS remains unchanged in a healthy state but decreases after ARDS. It has a significant association with PFR and may serve as an index of injury severity."}
+{"text": "Listeria monocytogenes has an established predilection for disseminated infection during pregnancy that often results in spontaneous abortion or stillbirth, the specific host-pathogen interaction that dictates these disastrous complications remain incompletely defined. Herein, we demonstrate systemic maternal Listeria infection during pregnancy fractures fetal tolerance and triggers fetal wastage in a dose-dependent fashion. Listeria was recovered from the majority of concepti after high-dose infection illustrating the potential for in utero invasion. Interestingly with reduced inocula, fetal wastage occurred without direct placental or fetal invasion, and instead paralleled reductions in maternal Foxp3+ regulatory T cell suppressive potency with reciprocal expansion and activation of maternal fetal-specific effector T cells. Using mutants lacking virulence determinants required for in utero invasion, we establish Listeria cytoplasmic entry is essential for disrupting fetal tolerance that triggers maternal T cell-mediated fetal resorption. Thus, infection-induced reductions in maternal Foxp3+ regulatory T cell suppression with ensuing disruptions in fetal tolerance play critical roles in pathogenesis of immune-mediated fetal wastage.Although the intracellular bacterium  Listeria monocytogenes that preferentially lives inside infected cells. Since infection during pregnancy often triggers prematurity, abortion, or stillbirth, we propose that understanding how these complications occur represent important prerequisites for improving the health of mothers and the developing fetus. Here we investigate the specific interaction between Listeria and a subset of immune-suppressive cells in the mother that expand to create and maintain a hospitable environment for the fetus. We find although Listeria, especially with highdosage infection, can invade the fetus, damage can also occur by infection-induced changes in maternal immune cells that make it markedly less hospitable for the fetus. Under these circumstances, maternal immune-mediated rejection causes fetal injury without direct pathogen invasion. We show this occurs using both reduced-dosages of virulent or weakened Listeria for infection. By comparing pregnancy outcomes and infection-induced changes in the mother that make it more or less hospitable for the fetus, we further demonstrate Listeria gaining entry inside infected cells is the critical factor for immune-mediated fetal injury. These results illustrating infection-induced changes in the mother that lead to fetal injury have important implications for designing new ways to improve the outcomes of pregnancy.Pregnant women are uniquely susceptible to the bacterium  Listeria monocytogenes (Lm) is a ubiquitous human pathogen with a unique predisposition for invasive disseminated infection during pregnancy that represents a significant etiology of spontaneous abortion, stillbirth, and neonatal infection + regulatory CD4 T cells (Tregs) during gestation was shown to compromise host defense against Lm and other pathogens that cause prenatal infection in utero pathogen invasion could explain the only modest fraction of concepti with recoverable Lm born to mothers with invasive infection In addition to these quantitative changes, fluctuations in Treg suppressive potency also occur. These shifts fine-tune the delicate fluid balance between immune stimulation and suppression. In particular within the first few days after infection in non-pregnant mice with Lm or other pathogens that primarily cause acute infection, progressive reductions in either Treg number or their suppressive potency have each been described GFP reporter mice were used so that maternal Tregs could be purified based on their lineage-defining marker in utero invasion. Together, these studies demonstrate Lm entry into the cell cytoplasm disrupts fetal tolerance sustained by maternal Foxp3+ Tregs that triggers immune-mediated fetal wastage.To address these questions, we investigated maternal Tregs and the maintenance of fetal tolerance using escalating dosages of virulent Lm for infection during pregnancy. Foxp3in utero invasion during syngeneic pregnancy d males with C57Bl/6 H-2b females) for mating. We found Lm infection midgestation (E10.5) caused dose-dependent reductions in the number of live pups born at term \u223c10 days thereafter (4 CFUs); 3.7\u00b10.9 (103 CFUs)] for mice infected with each respective Lm dosage  was also enumerated. Consistent with dose-dependent reductions in the number of live pups born at term, progressively increased rates of fetal wastage were found with escalating dosages of Lm used for infection (4 CFUs), the recovery of bacteria among resorbed fetuses declined sharply with reduced inocula   at these earlier time points (data not shown). Furthermore, the absence of direct Lm placental-fetal invasion for the majority of resorbed concepti using this intermediate 103 Lm dosage was reinforced by the absence non-viable bacteria using PCR-based detection with primers specific for Lm hly and lmo0056 among culture negative concepti (data not shown). Together, these results demonstrate although Lm has the potential for in utero invasion, especially after high-dose infection, infection-induced fetal injury can also occur without direct pathogen invasion of the placenta or fetal tissue.To more comprehensively evaluate infection-induced fetal injury, the frequency of nfection . Interes02 CFUs) . Given t+ Tregs in maintaining pregnancy + among CD4 cells, suggesting quantitative reductions in maternal Tregs do not occur in this context  compared with 3.68\u00b10.60 live pups in T cell-sufficient pregnancies (n\u200a=\u200a19), P\u200a=\u200a0.027]. Taken together, these results demonstrate Lm cytoplasmic entry is essential for disrupting fetal tolerance that triggers maternal T cell-mediated fetal wastage.To further establish how these reductions in maternal Treg suppression induced by attenuated Lm impact fetal tolerance, the expansion and activation of maternal T cells with specificity to the surrogate fetal-OVA antigen were also enumerated after infection in pregnant C57Bl/6 mice mated with OVA-expressing Balb/c males. Similar to WT Lm, Lm\u0394actA inoculated midgestation primed the robust expansion and IFN-\u03b3 production by fetal-OVA specific T cells . Compara+ Tregs. Our results demonstrate infection-induced dampening of Treg suppression that unleashes immune activation required for optimal host defense in vitro or after in vivo stimulation in non-pregnant mice Ureaplasma and Chlamydia sp.) are also sufficient to stimulate fetal injury.The intracellular bacterium Lm represents a significant infectious cause of pregnancy loss and stillbirth in utero fetal invasion, immune-mediated fetal injury alone does not fully address the pathogenesis of these infections. In this regard, an important clue from our studies is that although virulent Lm-induced fetal resorption and invasion are each dose-dependent, these processes can be readily dissociated based on the inocula of Lm used for infection. Accordingly, we propose a model whereby low-dose maternal infection dampens Treg suppression enough to stimulate the activation of immune effectors that rapidly eliminate the pathogen so that fetal injury occurs almost exclusively via immune-mediated pathways .b), Balb/c (H-2d), and B6.PL-Thy1 (CD90.1) mice were purchased from The National Cancer Institute or The Jackson Laboratory. Foxp3GFP mice backcrossed to C57Bl/6 mice, OVA-expressing backcrossed to Balb/c mice, and OT-I TCR transgenic mice maintained on a CD90.1 background have been described C57Bl/6 (H-2600 0.1) in brain heart infusion media at 37\u00b0C, washed and diluted with saline to 200 \u00b5l, and injected intravenously via the lateral tail vein hly and lmo0056  Lm strains 10403 s (WT), 1942 (\u0394actA), and 2319 (\u0394LLO\u0394PLC) were each grown to early log phase (OD257\u2013264 peptide in media containing GolgiPlug (BD Biosciences) was enumerated using previously described procedures + cells (105) isolated from OT-I TCR transgenic (CD90.1) mice were injected intravenously into recipient (CD90.2) mice one day prior to Lm infection at midgestation. For T cell depletion, purified anti-mouse CD4 (GK1.5) and anti-mouse CD8 (2.43) antibodies (BioXcell) were administered intraperitoneally (500 \u00b5g each antibody per mouse) one day prior to Lm\u0394actA infection at midgestation.Fluorophore-conjugated antibodies and other reagents for cell surface, intracellular cytokine, and intranuclear Foxp3 staining were purchased from eBioscience or BD Biosciences. The expansion of fetal-OVA-specific CD8 cells among splenocytes, and cytokine production after stimulating splenocytes with OVAGFP reporter mice, followed by sorting for the GFP+ CD4 subset + Tregs were verified to be >98% pure by staining for Foxp3 expression. Responder CD8+ T cells isolated from na\u00efve CD90.1 mice were labeled with CFSE (5 \u00b5M for 10 minutes at room temperature), and co-cultured in triplicate in 96-well round bottom plates (1\u00d7104 responder cells per well) with purified GFP+ Tregs at the indicated ratios. The relative suppressive potency of Tregs in each experiment was calculated by comparing responder cell proliferation (CFSE dilution) after co-culture with GFP+ Tregs from uninfected control mice as described For enumerating Treg suppressive potency, CD4 cells were first enriched by negative selection (Miltenyi Biotec) from Foxp3P<0.05 taken as statistical significance.The number of live pups, resorbed concepti, cell numbers, and percent cytokine producing cells were first analyzed and found to be normally distributed. Thereafter, differences between groups were analyzed using an unpaired Student's t test  with Text S1 Representative plots demonstrating proliferation (CFSE dilution) among responder CD90.1+ CD8 cells (Tresp) after co-culture with each ratio of GFP+ Tregs isolated from virgin or pregnant C57Bl/6 mice midgestation after mating with Balb/c males, and stimulation with anti-CD3 antibody (black line), compared with no Treg (gray filled) or no stimulation (black filled) controls (top). Relative suppression of responder cell proliferation (CFSE dilution) after co-culture with GFP+ Tregs for the mice described above normalized to suppression by GFP+ cells from non-pregnant controls at a 1\u22361 Treg\u2236Tresp ratio (bottom). Comparable in vivo bacterial burden after Lm\u0394actA and Lm\u0394LLO\u0394PLC infection . Number of recoverable CFUs in the liver one day after infection with 107 Lm\u0394actA compared with 108 Lm\u0394LLO\u0394PLC. Each data point represents results from an individual mouse from two independent experiments each with similar results.(DOC)Click here for additional data file."}
+{"text": "Raphanus sativus) in India.Emerging whitefly transmitted begomoviruses are major pathogens of vegetable and fibre crops throughout the world, particularly in tropical and sub-tropical regions. Mutation, pseudorecombination and recombination are driving forces for the emergence and evolution of new crop-infecting begomoviruses. Leaf curl disease of field grown radish plants was noticed in Varanasi and Pataudi region of northern India. We have identified and characterized two distinct monopartite begomoviruses and associated beta satellite DNA causing leaf curl disease of radish (Radish leaf curl virus (RaLCV) sharing maximum nucleotide identity of 87.7% with Tomato leaf curl Bangladesh virus-[Bangladesh:2] (Accession number AF188481) while the virus causing radish leaf curl disease-Pataudi is an isolate of Croton yellow vein mosaic virus-[India] (CYVMV-IN) (Accession number AJ507777) sharing 95.8% nucleotide identity. Further, RDP analysis revealed that the RaLCV has a hybrid genome, a putative recombinant between Euphorbia leaf curl virus and Papaya leaf curl virus. Cloned DNA of either RaLCV or CYVMV induced mild leaf curl symptoms in radish plants. However, when these clones (RaLCV or CYVMV) were individually co-inoculated with their associated cloned DNA betasatellite, symptom severity and viral DNA levels were increased in radish plants and induced typical RaLCD symptoms. To further extend these studies, we carried out an investigation of the interaction of these radish-infecting begomoviruses and their associated satellite, with two tomato infecting begomoviruses (Tomato leaf curl Gujarat virus and Tomato leaf curl New Delhi virus). Both of the tomato-infecting begomoviruses showed a contrasting and differential interaction with DNA satellites, not only in the capacity to interact with these molecules but also in the modulation of symptom phenotypes by the satellites.We demonstrate that RaLCD is caused by a complex of two Old World begomoviruses and their associated betasatellites. Radish leaf curl virus-Varanasi is identified as a new recombinant species, This is the first report and experimental demonstration of Koch's postulate for begomoviruses associated with radish leaf curl disease. Further observations also provide direct evidence of lateral movement of weed infecting begomovirus in the cultivated crops and the present study also suggests that the exchange of betasatellites with other begomoviruses would create a new disease complex posing a serious threat to crop production. Geminiviridae) have circular single stranded DNA genomes that are encapsidated in twinned quasi-isometric particles and are classified into four genera: Begomovirus, Mastrevirus, Curtovirus and Topocuvirus . Intergenic region (IR) sequences (~290 nt) contained conserved nonanucleotide sequence, putative Rep (C1) protein binding sites and the TATA box. The nucleotide identity of full-length genome and IR sequences between RaLCD-associated-Varanasi and RaLCD-associated-Pataudi were 79.6 and 71.6%, respectively, indicating involvement of two distinct species  (~87.7%) Table . PhylogeHowever, RaLCD-associated-Pataudi virus sequence was 95.8% identical to Croton yellow vein mosaic virus-[India] (CYVMV-[IN]) isolates Table  and therThe predicted amino acid sequences of the ORFs of RaLCV-[IN:Var:05] were compared to those of other begomoviruses. TrAP, REn, CP and AV2 of RaLCV-[IN:Var:05] showed maximum amino acid identity  whereas CYVMV-[IN:Rad:Pat:08] and CYVMV-IN iterons sequences were identical (GGGGA-CTC-GGGGGA) (data not shown). The major difference between the RaLCV-[IN:Var:05] and ToLCBDV-[BD:2] was found in spacer sequence of two iterons, as RaLCV-[IN:Var:05] contains AC while ToLCBDV-[BD:2] contains AT. A third iteron was present in 5' end of the intergenic common region (ICR) of RaLCV. Noticeably, besides GC rich region, stem loop region and the TATA Box were conserved for all geminiviruses and all the viruses tested here shared two short sequences, AATGGCA and TAAT, located at the 5'end of the region between TATA box and stem-loop.EF175734) and 1367 nt (GenBank Accession no. FJ593630), respectively. These two betasatellites had structural features similar to those of other betasatellites i.e. a single ORF \u03b2C1, satellite conserved region (SCR) and A rich region. The complete nucleotide sequence identity between RaLCV-[IN:Var:05] and CYVMV-[IN:Pat:Rad:08] was 63.2%, indicating that these are distinct betasatellite species. The complete sequence of DNA betasatellite associated with RaLCV-[IN:Var:05] and CYVMV-[IN:Pat:Rad:08] shared maximum nucleotide identity with Tobacco leaf curl betasatellite [Pakistan:Rahim Yar Khan:1998] (TbLCB-[PK:RYK:98]) (83%) and Croton yellow vein mosaic betasatellite [Pakistan:Punjab:2006] (CroYVMB-[PK:Pun:06]) (91.1%), respectively  of betasatellites was cloned from both (Varanasi and Pataudi) RaLCD samples using universal primers . The comORF \u03b2C1 of RaLCB-[IN:Var:05] and CYVMB-[IN:Pat:Rad:08] showed maximum nucleotide identity with TbLCB-Pak-NIB 12-1] (89.1%) and CroYVMB-[PK:Pun:06] (93.8%), respectively (Table -1 (89.1%Rep coding region (from nt 2154 to 2519). Bootscan and Simplot analysis also supported these observations  and CYVMV-[IN:Pat:Rad:08] (CRA) genomes were analyzed using two independent methods  and the results indicated definite evidence of recombination within RaLCV-[IN:Var:05] genome Figure . In RaLCs Figure a, b. To To detect possible evidence of recombination in the CYVMV-[IN:Pat:Rad:08] genome, Simplot and RDP analysis were performed with begomoviruse bearing the closest identity viz., CYVMV-[IN], and with two tomato-infecting begomoviruses viz., Tomato leaf curl Gujarat virus-[India:Varanasi:2001] (ToLCGV-[IN:Var:01]) and Tomato leaf curl New Delhi virus-India [India:New Delhi:Severe:1992] (ToLCNDV- [IN:ND:Svr:92]). Simplot and RDP analyses revealed that this is not a recombinant virus; rather it is a derivative of CYVMV-[IN]. Similarly, simplot and RDP analysis carried out for betasatellite molecules DNAs (RaLCB-[IN:Var:05] and CroYVMB-[IN:Pat:Rad:08]) could not reveal any evidence of recombination.N. benthamiana plants by agroinoculation. Radish plants co-inoculated with RLA + RL\u03b2 developed systemic symptoms including downward leaf curling within 20 days post inoculation (dpi)  onto radish, tomato and ) Figure , however) Figure . Similar) Figure , while C) Figure ; Table 3) Figure b and 4c N. benthamiana resulted in leaf curling, enations and mild stunting of test plants  or ToLCGV (VB) did not influence symptom severity nor the time required for symptom appearance Figure ; Table 4N. benthamiana plants inoculated with NA + RL\u03b2 showed distinguishable symptoms like typical downward leaf curling, interveinal chlorosis and twisting of petiole  can replicate autonomously and move systemically in their natural host (radish), and induce mild leaf curl symptoms. However, in the presence of DNA betasatellite, RLA or CRA induces these symptoms, which appear similar to those observed in the fields in Varanasi and Pataudi, India. Therefore, the RaLCD disease complex is caused by cognate association of DNA-A and DNA betasatellite. Prerequisite association of a begomovirus and satellite DNA-\u03b2 has also been found to be necessary for typical disease development ,15,34. Heviously ,39. Increviously ,41. Tranthamiana -45. Our thamiana .Croton yellow vein mosaic virus and betasatellite DNA, isolated from RaLCD infected plant could infect tomato, we further extended study to test interaction of CRA and CR\u03b2 with predominant tomato-infecting begomoviruses species (ToLCNDV and ToLCGV) from India. Plants (N. benthamiana and tomato) inoculated with mixtures of either combinations of CRA + VA + CR\u03b2, CRA + NA + CR\u03b2, CRA + VA + VB, CRA + NA + NB, CRA + VA + VB + CR\u03b2 and CRA + NA + NB + CR\u03b2, produced severe symptoms compared with plants infected with isolates of only one begomovirus species. Viral DNA accumulation (CRA) was also slightly enhanced in plants inoculated with CRA + VA + VB + CR\u03b2 or CRA + NA + NB + CR\u03b2 inoculated plants compared to plants inoculated with CRA + CR\u03b2. Interestingly, beta satellite accumulation was decreased (upto 60%) in the presence of DNA-B component (either NB or VB) in the above combinations tested. This is in concurrent with earlier observation  and Tomato leaf curl Gujarat virus [ToLCGV]) [Agrobacterium cultures containing respective constructs (Table Trans-complementation with genomic components of tomato-infecting begomoviruses (ToLCGV])  was alsots Table  were mixet al. dCTP by random oligonucleotide-primed synthesis [For southern hybridization analysis, total genomic DNA (8 \u03bcg) was separated on agarose gel (1%) and transferred to Hybond-N+ membrane , following standard procedures . Viral Dgment nt 9-506 wasynthesis . Viral DThe authors declare that they have no competing interests.AKS performed the experiments. AKS, BC and SC were involved in data analysis experimental design and writing the manuscript. All the authors read and approved the final manuscript."}
+{"text": "The oxalate anion is located on an inversion centre and bridges two metal ions, resulting in a polymeric structure with infinite zigzag chains extending parallel to [010].In the crystal structure of the title compound, [Zn(C DOI: 10.1107/S1600536811030479/wm2511Isup2.hkl            Structure factors: contains datablock(s) I. DOI:  crystallographic information; 3D view; checkCIF report            Additional supplementary materials:"}
+{"text": "Barlow disease represents a surgical challenge for mitral valve repair (MR) in the presence of mitral insufficiency (MI) with multiple regurgitant jets. We hereby present our mid-term experience using a midified edge-to-edge technique to address this peculiar MI.From March 2003 till December 2012, 28 patients  affected by severe Barlow disease with multiple jets were submitted to MR. Preoperative transesophageal echo (TEE) in all the cases showed at least 2 regurgitant jets, involving one or both leaflets in more than one segment. In all the patients, a triple-orifice valve (TOV) repair with annuloplasty was performed. Intraoperative TEE and postoperative transthoracic echocardiography (TT) were carried out to evaluate results of the TOV repair.There was no in-hospital death and one late death (non-cardia related). At intraoperative TEE, the three orifices showed a mean total valve area of 2.98+/-0.3 cm2 (range: 2.5-3-3) with no residual regurgitation  and no sign of valve stenosis . At follow-up (mean: 68.9+/-12 months), TEE showed favourable MR and no recurrence of significant MI . Stress TEE was performed in 5 cases showing persistent effective velve function . All the patients showed significant NYHA functional class improvement.This report indicates that the TOV technique is effective in correcting complex Barlow mitral valves with multiple jets. Further studies are required to confirm long-term applicability and durability in more numerous cases."}
+{"text": "IGHV) mutation status are linked to the B-cell receptor (BCR) complex, supporting a role for triggering the BCR in vivo in the pathogenesis. The miRNA profile upon stimulation and correlation with IGHV mutation status is however unknown. To evaluate the transcriptional response of peripheral blood CLL cells upon BCR stimulation in vitro, miRNA and mRNA expression was measured using hybridization arrays and qPCR. We found both IGHV mutated and unmutated CLL cells to respond with increased expression of MYC and other genes associated with BCR activation, and a phenotype of cell cycle progression. Genome-wide expression studies showed hsa-miR-132-3p/hsa-miR-212 miRNA cluster induction associated with a set of downregulated genes, enriched for genes modulated by BCR activation and amplified by Myc. We conclude that BCR triggering of CLL cells induces a transcriptional response of genes associated with BCR activation, enhanced cell cycle entry and progression and suggest that part of the transcriptional profiles linked to IGHV mutation status observed in isolated peripheral blood are not cell intrinsic but rather secondary to in vivo BCR stimulation.Chronic lymphocytic leukemia (CLL) is a disease with variable clinical outcome. Several prognostic factors such as the immunoglobulin heavy chain variable genes ( IGHV) and the expression of CD38, lipoprotein lipase (LPL) and zeta-chain associated protein kinase 70 kDa, ZAP-70 in vivo triggering of the BCR is believed to contribute to pathogenesis and clinical evolution of the disease in vitro results in a heterogeneous response among CLL cases, as assessed by tyrosine phosphorylation, Ca2+ mobilization or even by measuring survival after Ig cross-linking IGHV mutation status Chronic lymphocytic leukemia (CLL) patients show a highly variable clinical course: some patients have an almost normal life expectancy without need for treatment, while other patients die of drug-resistant disease within 2 years after initial diagnosis IGHV mutated and unmutated CLL cells respond to BCR ligation in vitro with prominent MYC expression and changes in the miRNA profile, typically showing an induction of the hsa-miR-132-3p/hsa-miR-212 miRNA cluster. Transcriptome analysis further shows induction of FOS, NFAT5, DUSP2, EGR1 and ELK1. All these are part of a larger induced profile of genes associated with cell cycle initiation and progression, further confirmed phenotypically. This transcriptional response upon BCR triggering cluster probably supports a MYC amplified proliferative response that allows CLL cells to multiply in suitable niches in vivo.We report here that both The study protocol was approved by the Ghent University Hospital Ethical Committee. Patient samples were obtained after informed consent.+CD5+ CLL cells  were isolated on a Lymphoprep  layer, and contained as expected for the majority CD19Detection of copy number aberrations was done either by fluorescence in situ hybridization (FISH)  or by array comparative genomic hybridization (array-CGH) . FISH was performed as previously described http://medgen.ugent.be/arrayCGHbase) Array-CGH was performed using a 60K SurePrint G3 unselected oligonucleotide array . For the hybridization of the arrays 200 ng of tumor DNA and reference DNA were labelled with Cy3 and Cy5, respectively . Further processing was done according to the manufacturers' instructions. Features were extracted using the feature extraction v10.1.0.0.0 software program and processed with an in-house developed visualization software arrayCGHbase (Cells were cultured as described before + cells was assessed by flow cytometry and was at least 98.2% (data not shown).CLL cell purification was performed after stimulation by negative depletion using EasySep technology . The percentage of viable CD19To measure cell cycle progression, stimulated CLL cells were labelled with CD-19-PE, CD3-FITC and DRAQ5  after 48 hours of stimulation and analyzed by flow cytometry.Total cellular RNA was extracted using the miRNeasy kit , cDNA was synthesized and LPL measured with qPCR as published before 750 ng of total RNA from freshly isolated CLL cells was used for Illumina microarray analysis in an external facility . Quality and integrity of the RNA samples was analyzed with the Agilent Bioanalyzer (Agilent Technologies). The Illumina TotalPrep RNA Amplification Kit  was used to synthesize biotine labeled cRNA. Biotinylated cRNA (750 ng) was hybridized onto the HumanHT-12 v3 Expression BeadChip. Illumina's GenomeStudio v1 software with the default settings was used for Gene Expression analysis.www.bioconductor.org). Bead summary data were log2-transformed and normalized by quantile normalization using the bead array package The Illumina mRNA expression data were normalized using quantile normalization from the \u2018affy\u2019 package using Rgui statistical language .To identify putative functions associated with the miRNAs of interest, we performed an integrative mRNA \u2013 miRNA expression analysis according to Mestdagh et al. http://www.ingenuity.com/products/pathways_analysis.html).Ingenuity Pathways Analysis software version 9.0 application 2011-07-23, content 2011-05-18  was used to identify and visualize modulated pathways .For comparing stimulated versus unstimulated samples, the Wilcoxon matched pairs test and for comparing unmutated versus mutated samples the Mann-Whitney U test was applied using the GraphPad Prism 5 statistical software .IGHV mutated and IGHV unmutated CLL cells transcriptionally respond to BCR ligation in vitro, other studies reported that IGHV mutated CLL cells poorly respond to IgM stimulation, in contrast to IGHV unmutated CLL cells which do respond IGHV mutated and IGHV unmutated CLL cells induced MYC expression to the same level . This illustrates that our samples are inherently different according to mutational status, since previous reports Previous studies showed that expression profiles of CLL cells freshly isolated from peripheral blood show considerable overlap between unmutated and mutated samples me level . Similarmulation . CollectIGHV mutated and IGHV unmutated CLL samples. Interestingly, expression of DUSP2, a negative regulator of ERK that drives expression of these transcription factors, was induced simultaneously in these samples, suggesting a negative feedback. In addition, expression of NFAT5 was induced in both IGHV mutated and IGHV unmutated CLL samples reaching a peak after 3 hours , but expression remained high up to 24 hours of stimulation . To furt 3 hours , indicatIGHV mutated and unmutated CLL cells, in 6 of the 8 samples tested.Since especially MYC is an amplifier associated with cell cycle entry in B cells Genome-wide transcriptome analysis was performed on samples stimulated for 3 and 24 hours, two time points that are fit to discriminate the kinetic profiles we observed with the selected genes observed above in an independent series of samples , a significant association with the KEGG BCR signaling pathway was found, containing upstream components like CD19, CD79A en CD79B. Possibly, early downregulation of these genes we observed is in part mediated by hsa-miR-132-3p and hsa-miR-212.The miRNAs hsa-miR-132-3p and hsa-miR-212 belong to the same cluster www.mirnabodymap.org) To evaluate the function of the genes correlating with induced miRNA after BCR stimulation, we used our in-house developed web-based algorithm  and stained with CD3-FITC, CD19-PE, and for stoichiometric staining of DNA, DRAQ5 was used. Plots show lymphocyte scatter gated (plots A), CD19+/weak CD3\u2212 gate cells (plots B), DRAQ5 wideness versus amplitude, allowing to gate on single cells (plots C), and DRAQ5 intensity histogram (histograms D). Figures indicate percentage of CLL cells in S/G2, present in the gated cells. This example shows results of patient CLL17 (IGHV mutated).(TIFF)Click here for additional data file.Figure S2BCR stimulation of CLL cells induces CCL3 and CCL4 chemokine secretion. Chemokine CCL3 and CCL4 secretion measured by ELISA in cultures of IgM stimulated CLL cells. Concentration measured (pg/mL) in function of time (hours of stimulation) is shown.(TIFF)Click here for additional data file.Figure S3BCR stimulation of CLL cells induces reduced CXCR4 gene expression. Kinetics of expression of CXCR4. Scatter plots show normalized mRNA expression for IGHV mutated  and IGHV unmutated cases , horizontal lines represent average values. Significant differences are indicated (* p<0.05).(TIFF)Click here for additional data file.Figure S4CXCR4 and CD19 cell surface expression is reduced after BCR stimulation of CLL cells. (A) Bivariate dotplots of flow cytometric analysis of CXCR4 versus CD19 expression on PBMC incubated for 24 hours with anti-IgA (left panel) or anti-IgM beads. Events were gated on live cells, a representative sample is shown. (B) Expression of surface membrane CXCR4 in CLL cells stimulated with anti-IgA or anti-IgM beads for 24 hours. Scatter plots show normalized expression (ratio's of mean fluorescence intensity) for IGHV mutated  and IGHV unmutated cases , horizontal line represent average value. Significant decrease of CXCR4 expression (p<0.05), however not significantly different between IGHV mutated and IGHV unmutated cases.(TIFF)Click here for additional data file.Figure S5Unsupervised clustering of samples according to miR expression. Heat-map shows unsupervised clustering of samples according to expression of all miRNAs detected, highlighted either for mutational status  or stimulation . From blue over white to red indicates increased miR expression.(TIF)Click here for additional data file.Figure S6Modulation of gene expression of selected genes upon BCR triggering in CLL cells. Expression of indicated genes in CLL cells, after 3 hours (A) or 24 hours (B) of stimulation with anti-IgM beads. Fold change to the expression level in CLL cells incubated with anti-IgA beads is shown, grey scale indicate magnitude of fold change for representation purposes. Arrows represent \u201cacts on\u201d, hooks represents \u201cinhibits\u201d. Image constructed using Ingenuity IPA\u00ae software.(TIF)Click here for additional data file.Figure S7Cell cycle control genes are modulated upon BCR stimulation in CLL cells. Expression of indicated genes in CLL cells, after 24 hours of stimulation with anti-IgM beads. Fold change to the expression level in CLL cells incubated with anti-IgA beads is shown, grey scale indicate magnitude of fold change for representation purposes. Arrows represent \u201cacts on\u201d, hooks represents \u201cinhibits\u201d, P: phosphorylated protein. miR-132/212: hsa-miR-132-3p and hsa-miR-212 miRNA. Hypothetical model, constructed using Ingenuity IPA\u00ae software.(TIFF)Click here for additional data file.Table S1Overview of patient samples used.(PDF)Click here for additional data file.Table S2Patient characteristics.(PDF)Click here for additional data file.Table S3Rank-product analysis for significantly  up- or downregulated genes (fold change FC at least 2) in samples stimulated for 3 and 24 hours, ranked according to increasing percentage false positive.(PDF)Click here for additional data file.Table S4Gene Set Enrichment Analysis of unstimulated versus stimulated sample categories. Table shows gene sets found significantly enriched in either sample category from gene set collections KEGG (shown in black characters), Gene Ontology Biological Process (shown in blue characters), and Transcription Factor Targets (shown in red characters), ranked according normalized enrichment score (NES). False discovery rate (FDR) q value, based on 1,000 permutations of category labels, was below 0.05. Category indicates sample type gene set is enriched in (negative scores of NES for stimulated samples).(PDF)Click here for additional data file.Table S5miRNAs detected in BCR stimulated CLL cells.(PDF)Click here for additional data file.Table S6Rank-product analysis of detected miRNA, showing fold change FC in samples stimulated for 3 and 24 hours, ranked according to increasing percentage false positive.(PDF)Click here for additional data file.Table S7Canonical pathways associated with modulated genes after 3 hours or 24 hours of BCR stimulation.(PDF)Click here for additional data file.Table S8Correlation coefficient between gene and hsa-miR-132-3p or hsa-miR-212 miRNA expression.(PDF)Click here for additional data file.Table S9Gene sets enriched for genes negatively correlating with hsa-miR-132-3p or hsa-miR-212 miRNA expression.(PDF)Click here for additional data file."}
+{"text": "The emergence of multi-drug resistant Gram-negatives (MDRGNs) coupled with an alarming scarcity of new antibiotics has forced the optimization of the therapeutic potential of available antibiotics. To exploit the time above the minimum inhibitory concentration mechanism of \u03b2-lactams, prolonging their infusion may improve outcomes. The primary objective of this meta-analysis was to determine if prolonged \u03b2-lactam infusion resulted in decreased mortality and improved clinical cure compared to intermittent \u03b2-lactam infusion.2 and Chi-square statistics. Pooled relative risks (RR) and 95% confidence intervals (CI) were calculated using Mantel-Haenszel random-effects models.Relevant studies were identified from searches of MEDLINE, EMBASE, and CENTRAL. Heterogeneity was assessed qualitatively, in addition to IFourteen randomized controlled trials (RCTs) were included. Prolonged infusion \u03b2-lactams were not associated with decreased mortality  or clinical cure  compared to intermittent infusions. Subgroup analysis for \u03b2-lactam subclasses and equivalent total daily \u03b2-lactam doses yielded similar results. Most studies had notable methodological flaws.No clinical advantage was observed for prolonged infusion \u03b2-lactams. The limited number of studies with MDRGNs precluded evaluation of prolonged infusion of \u03b2-lactams for this subgroup. A large, multicenter RCT with critically ill patients infected with MDRGNs is needed. In the last several years, a progressive increase in resistance among Gram-negative pathogens has continued unabated. The emergence of multi-drug resistant Gram-negative organisms (MDRGNs) coupled with an alarming scarcity of new antibiotic classes in the pipelines of the pharmaceutical industry has forced the healthcare community to optimize the therapeutic potential of currently available antibiotics .The primary determinant of \u03b2-lactam efficacy is the duration of time in which the non-protein bound drugconcentration (fT) exceeds the minimum inhibitory concentration (MIC) of the organism (fT>MIC) . \u03b2-lactaSeveral trials comparing clinical outcomes of prolonged infusion \u03b2-lactams with standard dosing have been completed, with conflicting results . MoreoveProlonged infusion of \u03b2-lactam antibiotics consisted of either extended infusion or continuous infusion of the antibiotic. Extended infusions were defined as intermittent infusions lasting \u2265 3 hours, whereas continuous infusion involved administration over a 24-hour period at a fixed rate . IntermiThe primary outcomes of the analysis were mortality and clinical cure. Mortality was assumed to be in-hospital mortality, a biologically relevant period in which death can be considered a consequence of treatment failure. Clinical cure was defined by the discretion of the authors because of the heterogeneous nature of the study population, pathogens involved, and the sites of infections. The secondary outcome of the analysis was adverse effects during \u03b2-lactam treatment.nd, 2011) and a review of the citations for each article were conducted to search for further potentially relevant articles to include. First authors of studies needing further clarification were contacted . Pro. Pro4]. sion arm . Of impoa priori. The definition of adverse effects varied substantially between studies preventing calculation of a meaningful pooled RR ratio .Another noteworthy limitation is that participants in the available studies were frequently receiving additional antibiotics, generally aminoglycosides, limiting conclusions about the sole contribution of the \u03b2-lactam antibiotics. In reality, however, when prolonged \u03b2-lactams are administered, it is generally a final attempt to rid the body of a particular pathogen and is administered in conjunction with aminoglycoside therapy, making the design of several of these studies similar to actual clinical practice . Only siPerhaps the biggest limitation to our study is that the bacterial isolates identified in the included RCTs generally had MICs in the susceptible range. Little difference exists between intermittent and prolonged administration of \u03b2-lactams in achieving fT>MIC in this range of susceptibility . HoweverDespite these limitations, this systematic review and meta-analysis add useful information to the literature. The 14 included studies span 4 continents and are not restricted to the English language, thus increasing generalizability. As only RCTs were included, baseline characteristics including age, severity of illness, body site of infection, responsible pathogens, and underlying medical conditions were similar between the treatment groups. Confounding by indication can be extremely problematic in observational studies, as prognostic factors may influence treatment decisions. However, this was unlikely in the included trials because of the process of randomization.Optimizing the pharmacokinetics-pharmacodynamics of currently available antibiotics is necessary in the era of MDRGN infections. Known \u03b2-lactam pharmacodynamics support the concept of prolonged infusion to maximize fT>MIC, but limited clinical data exist regarding the comparative efficacy of prolonged \u03b2-lactam infusion. The results of this meta-analysis do not support an advantage to the use of prolonged infusion \u03b2-lactam antibiotics as standard practice for hospitalized patients. These findings remained consistent in the multiple sensitivity and subgroup analyses that were evaluated.Prolonged infusion \u03b2-lactam antibiotics may have value in a specific subsets of patients, such as those with highly-resistant Gram-negative infections because of exploitation of their property of fT>MIC. Unfortunately, the very limited number of patients in the included RCTs with MDRGNs precluded evaluation of this subgroup in the present meta-analysis. Methodologically rigorous studies analyzing prolonged infusion \u03b2-lactams for critically ill patients with MDRGN infections are necessary to substantiate this potential benefit.MDRGNs: multidrug-resistant Gram-negatives; MIC: minimum inhibitory concentration; RCT: randomized controlled trial; CENTRAL: Cochrane Central Register of Controlled Trials; RR: relative risk; CI: confidence interval; VAP: ventilator-associated pneumonia;The authors declare that they have no competing interests.PDT formulated the research question and was involved in manuscript preparation. All authors were involved in determining the search strategy, data collection for the review, and quantitative and qualitative analysis. All authors read and approved the final manuscript.((\"beta-lactams\"[MeSH] OR \"beta-lactams\"[tiab] OR \"beta lactam\"[tiab]) AND  OR \"anti-bacterial agents\"[tiab] OR \"antibiotics\"[tiab] OR \"antibiotic\"[tiab]) OR \"beta-lactam antibiotics\"[tiab] OR \"beta-lactam antibiotic\"[tiab] OR doripenem[Title/Abstract] OR cefepime[Title/Abstract] OR ceftazidime[Title/Abstract] OR piperacillin[Title/Abstract] OR piperacillin/tazobactam[tiab] OR piperacillin-tazobactam[tiab] OR cefamandole[tiab] OR cefazolin[tiab] OR cefotaxime[tiab] OR ceftriaxone[tiab] OR imipenem[tiab] OR meropenem[tiab] OR ertapenem[tiab] OR cefoperazone[tiab] OR penicillin[tiab] OR penicillins[tiab] OR imipenem-cilastatin[tiab] OR ampicillin[tiab] OR ampicillin-sulbactam[tiab] OR sulbactam-ampicillin[tiab] OR tazocin[tiab] OR carbenicillin[tiab] OR carbapenem[tiab] OR cephalosporin[tiab] OR cephalosporins[tiab] OR ticarcillin-clavulanate[tiab] OR cefpirome[tiab] OR flucloxacillin[tiab] OR mezlocillin[tiab] OR aztreonam[tiab] OR cefuroxime[tiab] OR ceftizoxime[tiab])AND AND (administration[tiab] OR infusion[tiab] OR dosing[tiab])))AND AND (\"care\"[tiab] OR \"unit\"[tiab] OR \"illness\"[tiab])))AND) AND  OR \"anti-bacterial agents\"[all fields] OR \"antibiotics\"[all fields] OR \"antibiotic\"[all fields]) OR \"beta-lactam antibiotics\"[tiab] OR \"beta-lactam antibiotic\"[tiab] OR doripenem[Title/Abstract] OR cefepime[Title/Abstract] OR ceftazidime[Title/Abstract] OR piperacillin[Title/Abstract] OR piperacillin/tazobactam[tiab] OR piperacillin-tazobactam[tiab] OR cefamandole[tiab] OR cefazolin[tiab] OR cefotaxime[tiab] OR ceftriaxone[tiab] OR imipenem[tiab] OR meropenem[tiab] OR ertapenem[tiab] OR cefoperazone[tiab] OR penicillin[tiab] OR penicillins[tiab] OR imipenem-cilastatin[tiab] OR ampicillin[tiab] OR ampicillin-sulbactam[tiab] OR sulbactam-ampicillin[tiab] OR tazocin[tiab] OR carbenicillin[tiab] OR carbapenem[tiab] OR cephalosporin[tiab] OR cephalosporins[tiab] OR ticarcillin-clavulanate[tiab] OR cefpirome[tiab] OR flucloxacillin[tiab] OR mezlocillin[tiab] OR aztreonam[tiab] OR cefuroxime[tiab] OR ceftizoxime[tiab])AND AND (administration[tiab] OR infusion[tiab] OR dosing[tiab])))AND AND (\"care\"[tiab] OR \"unit\"[tiab] OR \"illness\"[tiab]))) OR  OR  OR  OR  OR  OR  OR )AND(('beta lactams'/exp) OR 'doripenem':ab,ti OR 'cefepime':ab,ti OR 'ceftazidime':ab,ti OR 'piperacillin':ab,ti OR 'piperacillin tazobactam':ab,ti OR 'piperacillin':ab,ti OR 'piperacillin tazobactam combination product':ab,ti OR 'tazobactam':ab,ti OR 'cefamandole':ab,ti OR 'cefazolin':ab,ti OR 'cefotaxime':ab,ti OR 'ceftriaxone':ab,ti OR 'imipenem':ab,ti OR 'meropenem':ab,ti OR 'ertapenem':ab,ti OR 'cefoperazone':ab,ti OR 'penicillin':ab,ti OR 'penicillins':ab,ti OR 'imipenem-cilastatin':ab,ti OR 'ampicillin':ab,ti OR 'ampicillin-sulbactam':ab,ti OR 'sulbactam-ampicillin':ab,ti OR 'tazocin':ab,ti OR 'carbenicillin':ab,ti OR 'carbapenem':ab,ti OR 'cephalosporin':ab,ti OR 'cephalosporins':ab,ti OR 'ticarcillin-clavulanate':ab,ti OR 'cefpirome':ab,ti OR 'flucloxacillin':ab,ti OR 'mezlocillin':ab,ti OR 'aztreonam':ab,ti OR 'cefuroxime':ab,ti OR 'ceftizoxime':ab,ti)AND OR  OR 'intermittent therapy':ab,ti OR  AND ))AND OR ('randomization'/exp)))AND[humans]/limANDNOT ('review'/exp OR review)The authors would like to thank Swaroop Vedula, Dolly Chang, Tianjing Li, and Kay Dickersin for all of their guidance and thoughtful suggestions. We would also like to thank our translators - Haruhi and Tsuyoshi Inokuchi (Japanese) and Lila Bouadma and Patrice Savard (French). We appreciate the assistance of the Welch medical librarians in finalizing our search strategy. P.D.T, A.L.R, and K.J.V. are funded by a National Institute of Health 5KL2RR025006 award. None of the authors report any relevant conflicts of interest.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2334/11/181/prepub"}
+{"text": "The PLZF/RARA fusion protein generated by the t translocation in acute promyelocytic leukaemia (APL) is believed to act as an oncogenic transcriptional regulator recruiting epigenetic factors to genes important for its transforming potential. However, molecular mechanisms associated with PLZF/RARA-dependent leukaemogenesis still remain unclear.We searched for specific PLZF/RARA target genes by ChIP-on-chip in the haematopoietic cell line U937 conditionally expressing PLZF/RARA. By comparing bound regions found in U937 cells expressing endogenous PLZF with PLZF/RARA-induced U937 cells, we isolated specific PLZF/RARA target gene promoters. We next analysed gene expression profiles of our identified target genes in PLZF/RARA APL patients and analysed DNA sequences and epigenetic modification at PLZF/RARA binding sites. We identify 413 specific PLZF/RARA target genes including a number encoding transcription factors involved in the regulation of haematopoiesis. Among these genes, 22 were significantly down regulated in primary PLZF/RARA APL cells. In addition, repressed PLZF/RARA target genes were associated with increased levels of H3K27me3 and decreased levels of H3K9K14ac. Finally, sequence analysis of PLZF/RARA bound sequences reveals the presence of both consensus and degenerated RAREs as well as enrichment for tissue-specific transcription factor motifs, highlighting the complexity of targeting fusion protein to chromatin. Our study suggests that PLZF/RARA directly targets genes important for haematopoietic development and supports the notion that PLZF/RARA acts mainly as an epigenetic regulator of its direct target genes. RARA) gene on chromosome 17, finds itself involved in chromosomal recombination with one of several different potential partner genes (designated \u201cX\u201d), i.e. PML, PLZF, NuMA, NPM1, FIP1L1, PRKAR1A, STAT5b or BCOR, generating X/RARA fusion proteins Retinoic acid receptors (RARs) belong to a family of nuclear receptors that can activate or repress transcription of target genes by recruiting co-activator or co-repressor complexes. It is the binding of its natural ligand, retinoic acid (RA), which transforms the activity of RAR from a repressor to an activator of transcription by inducing a conformational change in the ligand binding domain structure all-trans RA (ATRA) and arsenic trioxide (ATO) de novo target genes due to the sequence-specific DNA binding activity of PLZF. In addition, the situation is made more complicated by expression of the reciprocal RARA/PLZF that can potentially bind to PLZF binding sites where it may function as a transcriptional activator The nature of the fusion partner X has a decisive impact on the disease state and sensitivity to the therapeutic effects of Here, we report a genome-wide ChIP-on-chip study of PLZF/RARA gene targets using an inducible cell system. We identify 413 high-confidence specific target genes that provide clues as to how PLZF/RARA contributes to APL pathogenesis.HOXD cluster HOXD4 and HOXD9 genes in both U937-PLZF/RARA and control cell lines. These data were corroborated by quantitative PCR analyses of independent PLZF ChIP samples (ChIP-qPCR) (RARB2 (the RARA fusion model target gene) as well as C/EBPE, ASB2, PRAM1 and IL8, that have all previously been reported to be regulated by X/RARA fusion proteins To identify gene targets directly regulated by PLZF/RARA, we took advantage of a zinc-inducible U937 cell system either expressing the PLZF/RARA fusion protein or harbouring an empty vector IP-qPCR) . To idenIP-qPCR) . Among tbona-fide binding regions. Functional classification of specific PLZF/RARA target genes according to gene ontology (GO) analyses showed that PLZF/RARA binds to genes implicated in either basic cellular processes or developmental related processes . A highly significant 20% of the genes targeted by PLZF/RARA have altered expression patterns  with 11% becoming down regulated and 9% being up regulated upon PLZF/RARA binding  IDH2, PAX5 and DAZAP1. IDH2 is frequently mutated in acute myeloid leukaemia and its mutations confer adverse prognosis in cytogenetically normal AML PAX5 and DAZAP1 are both involved in translocations associated with acute lymphoblastic leukaemia To determine the transcriptional effect of PLZF/RARA on its identified target genes, gene expression profiling was performed in U937-MT (control) and U937-B412 (PLZF/RARA) cell lines. Expression profiling following PLZF/RARA induction was evaluated by microarray analysis and 4321 genes were identified with altered expression levels  and RARB2 repression  PLZF/RARA has conserved the DNA binding domain of RARA that binds to RA response elements (RAREs) defined by a direct repeat of the core motif By comparing PLZF bound regions between U937 and PLZF/RARA-induced U937 cells we identified 413 specific PLZF/RARA target genes. This selection of bona-fide PLZF/RARA targets was significantly enriched in genes important for hematopoietic development and included genes effectively downregulated in primary PLZF/RARA+ APL cells. Moreover, PLZF/RARA binding was preferentially associated with gene repression at sites enriched for the repressive H3K27me3 histone modification mark. Analysis of PLZF/RARA bound sequences suggests PLZF/RARA binds canonical and degenerate RARE motifs, and recruitment of PLZF/RARA may also occur via other hematopoietic specific TFs. This study helps to clarify the role of the PLZF/RARA fusion protein as an oncogenic transcriptional regulator during leukaemogenesis and provides further insights into the pathogenesis of the disease.4 for at least 24 h.Human myelomonoblastic cell lines U937-MT and U937-B412 Total RNA was extracted using the RNeasy Mini kit according to the manufacturer's protocol (Qiagen), For cDNA synthesis, reverse transcription was performed with 2 \u00b5g of the total RNA, oligo dT, dNTPs, DTT, buffer and Superscript Retrotranscriptase II (Invitrogen). cDNA was analyzed by qPCR using Brilliant SYBR Green Master Mix (Stratagene) according to the manufacturer's instructions with the 7500 Fast Real Time PCR system (Applied Biosystems). Primers used for real-time PCR are given in Supporting Information.7 cells per condition was used. For ChIP using H3K27me3 , H3K4me3  or H3K9K14Ac , chromatin from 5\u00d7106 cells per condition was used. Chromatin was diluted 5\u00d7 in 150 mM NaCl, 10 mM Tris-HCl pH 8.0, 1% TritonX-100, 0.1% sodium deoxycholate (NaDOC), 1 mM EDTA, 0.5 mM EGTA. Chromatin, precleared 1 h with protein G-coupled magnetic beads, was incubated overnight at 4\u00b0C using the different antibodies followed by an incubation for 2 h with blocked protein G-coupled magnetic beads . Real-time PCR was performed using Brilliant SYBR Green Master Mix (Stratagene) according to the manufacturer's instructions with the 7500 Fast Real Time PCR system (Applied Biosystems). Primers used are given in Chromatin Immunoprecipitation (ChIP) was essentially performed as described before by Boukarabila et al. Total DNA and ChIP DNA were amplified using the whole genome amplification kit  and fluorescently labelled using BioPrime Array CGH Genomic labelling kit (Invitrogen). Labeled samples were hybridized following the manufacturer's instructions to a custom promoter array  containing 236.992 probes spanning the promoter regions  of 18.000 refseq genes (UCSC assembly HG17). Experiments were performed in duplicate and showed high correlation (R\u22650.769). All data is MIAME compliant. Median-normalized log2 enrichment ratios (ChIP/Input) of merged replicates were calculated using CoCAS software Target genes were classified using DAVID http://www.perl.org) on ChIP-on-chip peak sequences. The expression code was built according to the known repeat pattern (A/G)G(G/T)TCA. We allowed a gap ranging from 0 to 100 bases and performed the calculation for finding DR, IR and ER on both strands. Analyses of transcription factor binding site enrichments were performed using MatInspector tool from GENOMATIX software (http://www.genomatix.de).We looked for the consensus RARE motif using Perl regular expressions (P<0.05). For patient samples, microarray raw data was taken from Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/projects/geo/), under the data set GSE8510 for primary PLZF/RARA+ APL patient cases and under the data set GSE15061 for normal bone marrow samples (NBM). Details of the patient samples analysed have been reported previously MT and B412 cells were cultured in duplicate in the presence of zinc for 48 hours. RNA was extracted using QIAGEN RNeasy and quality was tested using an Agilent Bioanalyzer. 1 \u00b5g of RNA was hybridized to U133 Plus 2.0 arrays (Affymetrix). Affymetrix U133A.CEL data files from B412 cells and MT cells were imported into R and probe intensities were normalized using GC-RMA. A total of 4321 genes were found to be differentially expressed  and U937-B412 (2) treated with zinc and were immunobloted for PLZF/RARA and PLZF (\u03b1-PLZF) or RARA (\u03b1-RARA).(TIF)Click here for additional data file.Figure S2Transcription factor binding sites over-represented in PLZF/RARA target promoters. MatInspector tool from GENOMATIX was used to identified transcription binding sites in PLZF/RARA bound promoters.(TIF)Click here for additional data file.Table S1List of PLZF/RARA target genes. Indicated in the table are symbols and full names of PLZF/RARA target genes, the presence, number and type of RAREh in PLZF/RARA enriched peak and micro array data of PLZF/RARA target genes. Diff mean corresponds to the difference of the mean between MT and B412 cell lines.(XLSB)Click here for additional data file.Text S1Supplemental experimental procedures.(DOCX)Click here for additional data file."}
+{"text": "To determine the effectiveness and impact of a newly developed functional medicine program in diabetes patients using widely used quality of life measures, instruments frequently/increasingly used in functional medicine, in addition to traditional clinical outcomes.Adult clinic patients with diabetes were eligible to participate in a longitudinal comprehensive mindfulness-based therapeutic lifestyle change program involving weekly educational classes dedicated to teaching wellness and lifestyle changes. Patient outcome assessments were administered at baseline, 3- and 6- months, and included traditional clinical parameters and self-completed patient reported outcome measures: Five Facet Mindfulnesss Questionnaire (FFMQ) and Medical Symptom Questionnaire (MSQ); two generic quality of life measures, EuroQol\u2019s EQ5D and Short Form 12 (SF-12); and the Summary Diabetes Self-Care Activities Questionnaire (SDSCA), a diabetes specific instrument.Twenty-six patients with diabetes (96% type 2) participated in the study [mean age of 64.1 years (SEM=2.05), 70% Female). Patients\u2019 weight, waist circumference and BMI decreased over 6 months (p<.05). FFMQ\u2019s nonjudging on inner experience dimension improved over 6 months (p=.004). MSQ\u2019s joint, weight, energy and emotion dimensions improved over 6 months (p<.05). EuroQol\u2019s EQ5D-VAS showed patients\u2019 overall quality of life improved (p<.05). SF-12\u2019s role functioning and emotional health dimensions improved . SDSCA showed significant improvements in diet, exercise, and glucose control (p<.05). By self-report at 6 months all diabetes patients participating reported improved quality of life.A functional medicine program piloted in a small group of patients with diabetes was effective. Patients showed significant improvements in traditional clinical parameters in addition to functional medicine metrics and widely used quality of life scales. This clinical trial is ongoing and expanded to include other conditions with the aim of integrating mindfulness based approaches to chronic disease into medical education at the Tallahassee Memorial HealthCare Family Medicine Residency Program."}
+{"text": "Although sudden death is a leading cause of mortality in patients with sarcoidosis, cardiac involvement is often unrecognized clinically. Delayed enhancement cardiovascular magnetic resonance (DE-CMR) has been shown to detect cardiac involvement in patients with sarcoidosis. We sought to evaluate the prognostic value of myocardial sarcoid involvement by DE-CMR.Consecutive patients with biopsy proven extracardiac sarcoidosis or suspected isolated cardiac sarcoidosis were prospectively recruited. Patients with history of cardiac surgery, heart transplant, documented coronary artery disease, congenital heart disease were excluded. Of the 251 meeting criteria, 231 participants were enrolled  underwent CMR, and followed for 2.7\u00b12.2 years for major adverse cardiac events . CMR images were analyzed by a consensus of two experienced readers who where blinded to all other data.Patients were predominantly middle-aged 48\u00b111 years), female (63%), and African-American (72%). More than half (53%) were on corticosteroid therapy at the time of CMR. Lung (87%) and lymph nodes (45%) were the most common organs of sarcoid involvement. On chest radiography, most were pulmonary stage I /II (66%). Overall, left ventricular ejection fraction (EF) was preserved (58 \u00b113%). Right ventricular EF was also preserved (49% \u00b111%). Myocardial involvement (hyperenhancement) on DE-CMR was found in 60 patients (26%). Most  had involvement of the interventricular septum. On follow-up, 16 patients had 19 cardiac adverse events, including 6 cardiac deaths, 2 heart transplants, 7 appropriate shocks, and 4 pacemaker implantations for high grade AV block. Patients with myocardial involvement by DE-CMR had a significantly higher rate of adverse cardiac events than patients without (Figure 1 years, In patients with sarcoidosis, myocardial involvement by DE-CMR is the strongest independent predictor of adverse cardiac prognosis.None."}
+{"text": "Myocardial fibrosis (MF) that occurs in aortic stenosis (AS) has been shown to be associated with a poor prognostic outcome post surgical aortic valve replacement (SAVR) but not in the high risk patients suitable for Transcatheter aortic valve implantation (TAVI). Using the technique of late-gadolinium enhancement we have shown that MF regresses post-TAVI but not post-SAVR, and that ejection fraction rather than MF is the independent predictor of reverse remodeling.Myocardial Fibrosis (MF) occurs as part of the remodelling process in left ventricular hypertrophy associated with severe aortic stenosis (AS). MF has been shown to be associated with reduced left ventricle (LV) ejection fraction and poor prognosis following surgical aortic valve replacement (SAVR). Transcatheter aortic valve implantation (TAVI) has become a standard procedure for the treatment of severe aortic stenosis in high risk or inoperable patients. The significance of MF in this high-risk patient population has to date not been assessed. We aimed to assess the baseline burden of MF, its change following TAVI and SAVR, and its influence on LV reverse remodeling.Fifty high-risk patients (EuroSCORE \u226520) with severe AS (peak velocity >4m/s) underwent TAVI (n=25) or SAVR (n=25). Steady-state free procession short axis (SA) cine imaging was performed to determine LV mass and volumes. MF was assessed by late-gadolinium enhancement (LGE) in 47 patients. A look-locker sequence was performed 10 minutes following the administration of 0.2mmol/kg of Gadoteric acid . The inversion time was individually adjusted and 10-12 short axis slices  were acquired.MF was detected in 25 (53%) patients (TAVI 13(59%) vs. SAVR 12(48%), P=0.38). Fibrosis was predominantly found in the basal region and septal segments for both groups. MF burden was greater in the TAVI group (10% (35/352) of segments) compared to the SAVR group (5% (19/400) segments), (P=0.01), Figure MF burden is associated with poor baseline LV volumes and function. Baseline EF rather than MF independently predicts reverse remodeling post TAVI and SAVR. Significant regression of fibrosis occurred only post-TAVI. This reduction of fibrosis may be important in improving prognosis following aortic valve replacement.None."}
+{"text": "A pediatric HIV-1 vaccine is required to protect infants against HIV-1 transmission from breastfeeding. Such a vaccine would need to induce protective immunity at mucosal surfaces in neonates as soon as possible after birth. Recombinant adenovirus (rAd) vectors have been shown to elicit potent systemic and mucosal virus-specific immune responses in adult non-human primates and humans but have not previously been studied in detail in infants.Newborn rhesus monkeys were injected intramuscular (i.m.) with 10^11 viral particles of rAd serotype 26 or 35 vectors expressing SIVmac239 Gag. Peripheral blood was collected to determine systemic Gag-specific cellular and humoral immune responses. At week 52, peripheral lymph nodes, bronchoalveolar lavage (BAL) and pinch biopsies of colorectal, duodenal and oral cavity mucosa were collected to evaluate mucosal Gag-specific T lymphocyte responses.A single injection of rAd26 encoding SIVmac239 Gag in rhesus monkeys on the day of birth elicited detectable SIV-specific cellular immune responses, but these responses were transient and waned quickly. In contrast, an accelerated heterologous prime-boost regimen involving administration of rAd35 at birth and rAd26 at 4 weeks of life elicited potent and durable Gag-specific cellular and humoral immune responses in neonatal rhesus monkeys, including mucosal responses that remained detectable at one year of age.These results suggest the potential of an accelerated heterologous rAd prime-boost regimen as a candidate neonatal HIV-1 vaccine in newborns."}
+{"text": "Many lung carcinogens activate mitogen activated protein kinase (MAPK) pathways and DNA methyltransferases (DNMTs) are under investigation as therapeutic targets for lung cancer. Our goal is to determine whether C10 type II alveolar epithelial cells are a sensitive model to investigate ERK-dependent transformation and DNMT expression patterns in experimental lung cancer.Ectopic expression of an extracellular signal regulated kinase (ERK)-green fluorescent protein (ERK1-GFP) induces acquisition of growth in soft agar that is selectively associated with latent effects on the expression of DNA methyl transferases (DNMT1 and 3b), xeroderma pigmentosum complementation group A (XPA), DNA-dependent protein kinase catalytic subunit (DNA-PKcs), increased phosphatase activity and enhanced sensitivity to 5-azacytidine (5-azaC)-mediated toxicity, relative to controls.Ectopic expression of ERK alone is sufficient to promote phenotypic conversion of C10 cells associated with altered DNMT expression patterns and sensitivity to DNMT inhibitor. This model may have applications for predicting sensitivity to DNMT inhibitors. ERK1-GFP protein expression was confirmed by Western blot   and in sysiology -11. C10 ysiology ,13. Typeysiology . Here weysiology  and askein vitro [ERK1-GFP transduced cells exhibit a morphological change upon prolonged passaging  as a loading control for nuclear extracts because the expression of this protein generally showed little change under a variety of experimental conditions. However, we observed a marked increase in the expression of XPA in late passage ERK1-GFP cells, relative to early passage cells and vector controls Figure A. We subDNMTs possess HDAC binding domains  and DNMTTo determine if increased DNMT expression was linked to cell fate regulation, we asked whether vector control, early and late passage ERK1-GFP cells were differentially sensitive to a DNMT inhibitor 5-azaC). Cells were treated with 0.5\u201350\u2009\u03bcM 5-azaC for 7\u2009days and cell viability was determined using a neutral red assay as previously described . Cell vi-azaC. Ce3VO4) to determine whether a broad spectrum phosphatase inhibitor could restore P-ERK levels. P-ERK levels were restored within minutes of Na3VO4 treatment  levels, but not total ERK protein levels, relative to vector controls and early passage ERK1-GFP cells Figure A. Treatmt Figure B, suggesEctopic expression of ERK alone is sufficient to induce phenotypic conversion of C10 cells and this model may provide insight into the underlying molecular determinants of this response. The window between early and late passage ERK-transduced variants that encompasses phenotypic conversion (approximately 15 passages) is a reasonable time frame to enable interrogative studies to define molecular determinants. Our expectation is that causal molecular processes will precede the appearance of the transformed phenotype and will be observed in early passage cells. At present, we have characterized changes in DNMT, DNA damage recognition and repair proteins and phosphatase activities that are selectively altered in late, but not early passage cells, suggesting they are secondary to transformation. Additional studies, perhaps with a more global screening approach, may provide insight into those molecular processes perturbed by ERK overexpression in early passage cells. Alternatively, because DNMTs are under investigation as therapeutic targets for lung cancer, the C10 model may provide insight into the molecular processes that confer sensitivity to DNMT inhibitors and regulate their aberrant expression.5-azaC = 5-azacytidine; CRM1 = chromosome region maintenance protein 1; DNA-PKcs = DNA-dependent protein kinase catalytic subunit; DNMT = DNA methyl transferase; EMT = epithelial-mesenchymal transition; ERK = extracellular signal regulated kinase; ERK1-GFP = ERK1-green fluorescent protein; HDAC = histone deacetylase; LB = leptomycin B; MAPK = mitogen activated protein kinase; Na3VO4 = sodium orthovanadate; P-ERK = phospho-ERK; XPA = xeroderma pigmentosum complementation group A.The authors declare that they have no competing interests.RS completed all experiments described under supervision by TW. All authors read and approved the final manuscript."}
+{"text": "A 55-year-old male presented to the outpatient services of the Ophthalmology department with complaints of gradual, painless progressive diminution of vision both eyes (OU) for the last two years. Ocular examination showed best corrected visual acuity to be counting fingers at a distance of two metres OU. Anterior segment findings were unremarkable OU. Examination of the fundus revealed bilateral severe proliferative diabetic retinopathy with active fibrovascular membranes extending from the optic disc along both superior and inferior temporal arcades and also nasal to the optic disc Figures  and 2. TOn systemic examination by an internist the patient had multiple clinical features of acromegaly including enlarged hands and feet, mandibular enlargement, prognathism, coarse facial features, large fleshy nose, deep and hollow sounding voice, arthropathy, skin tags, acanthosis nigricans and weakness of proximal muscles. X-ray sella (cone down view) showed widening of the sella with destruction of the floor. A magnetic resonance scan revealed the presense of an intrasellar pituitary macroadenoma (1.4 \u00d7 1.1 cm) involving the anterior lobe of the pituitary with no parasellar or suprasellar extension .Blood pressure was recorded to be 150/100mm Hg. Biochemical investigations revealed fasting blood sugar level varying between260-320mg/ml, glycosylated Hb (Hb A1c) > 8%., serum GH 42 ng/ml, free T3 2.9 pg/ml, free T4 1.1 ng/ml, TSH 3.7 microIU/ml. The patient was diagnosed to have intrasellar pituitary macroadenoma with acromegaly  associated with secondary hypertension and diabetes mellitus and severe proliferative diabetic retinopathy. Trans sphenoidal resection of the pitutary adenoma was advised to be followed by vitrectomy for management of ocular complications.Acromegaly leads to development of secondary diabetes mellitus in 25-55.9% of cases. The hypein vivo via vascular endothelial growth factor (VEGF).[Elevated levels of IGF-I in the vitreous cavity 5-8 ng/ml) and serum (80-220 ng/ml) have been demonstrated in patients having proliferative diabetic retinopathy associated with primary diabetes. Inokuchi-8 ng/ml r (VEGF). Thus groIn our case there was severe proliferative diabetic retinopathy associated with acromegaly. Patients with acromegaly should therefore be kept under close observation to detect the occurrence of diabetic retinopathy which though uncommon may be of the proliferative type."}
+{"text": "Membrane bound receptor for advanced glycation end products (RAGE) is over-expressed in response to increasing concentrations of its ligand (eg S100A12) and triggers an inflammatory immune response. Its truncated form sRAGE acts as decoy receptor and competes for ligands thus down-modulating inflammation. Decreased sRAGE levels are associated with rheumatoid arthritis, Sjogren syndrome and Kawasaki disease, however limited data is available in JIA thus we studied its levels in JIA-ERA patients.sRAGE levels were estimated in serum of patients with ERA (n=101), SoJIA and polyJIA (n=10 each) and healthy controls (n=45). Synovial fluid (SF) sRAGE was measured in ERA, RA, ReA and OA patients (n=10). S100A12 levels were also measured. 24 ERA patients were followed up for 4 months. Disease activity was assessed by swollen joint count (SJC), tender joint count (TJC) and ESR.Serum sRAGE (pg/ml) level was significantly lower in patients compared to healthy controls . In paired samples, SF had lower levels compared to corresponding plasma level .S100A12 (ng/ml) was higher in SF  than sera . Serum sRAGE negatively correlated with S100A12 levels , ESR , SJC but not with TJC . The levels of sRAGE remained stable over time in patients with stable disease.sRAGE levels are reduced in patients with ERA and negatively correlate with disease activity and S100A12 levels. sRAGE may be a modulator of inflammation in these patients."}
+{"text": "The objective of this study was to analyze the prevalence, risk factors and impact on outcome of electrographic seizures (ESz), nonconvulsive status epilepticus (NCSE), and periodic epileptiform discharges (PEDs) in critically ill patients admitted to two mixed medico-surgical ICUs.This was a retrospective study of 58 consecutive ICU patients  who underwent continuous electroencephalography (cEEG) monitoring for altered mental status. Outcome was assessed as hospital mortality.n = 10) had ESz, 10% (n = 6) had NCSE, 19% (n = 11) had periodic lateralized epileptiform discharges and 26% (n = 15) had epileptiform discharges.Sixteen patients (28%) were admitted with a primary neurological diagnosis. Mean duration of cEEG was 12 \u00b1 17 hours. Thirty-four patients (59%) were comatose and 32 patients were mechanically ventilated (55%) during cEEG monitoring. Seventeen percent (In a mixed population of medical and surgical patients, ESz and NCSE are frequent and associated with increased hospital mortality."}
+{"text": "To describe a case series of children treated with a naturopathic protocol for acute otitis media (AOM). Acute otitis media places a large burden on pediatric populations. Antibiotics provide modest benefits; however, these benefits must be weighed against the risk of adverse events and antibiotic resistance. Current American Academy of Pediatrics guidelines includes \u201cwatchful waiting\u201d: withholding antibiotics and providing analgesics and supportive care in selected patients.A retrospective case series was compiled by searching the electronic records from 2010-2011 from pediatrics teaching rotations at two naturopathic teaching clinics. Thirty cases were identified. Stringent criteria were applied to increase diagnostic accuracy, as viral respiratory infections are often misclassified as AOM. Inclusion criteria were: (1) acute onset of otalgia (2) tympanic membrane (TM) cloudiness or redness (3) Impaired TM mobility (4) TM bulging or fullness. Twenty-four children between 2 and 7 years-of-age met the inclusion criteria . Cases were treated with a whole practice naturopathic treatment, including a botanical formula, nutritional supplementation, low-antigenic diet and hydrotherapy. Seventy-five percent received an acute homeopathic prescription and 54% received botanical analgesic eardrops. Primary outcomes: pain duration, assessed at 24 hours and days 2-7. Secondary outcomes: treatment failure, complications of AOM, and adverse events. Tympanometry was performed in 9 children at approximately 1 month to assess for residual effusion and hearing impairment.The number of children with pain at 24 hours was 7 of the 24 (31%). No children had pain by days 2-7. Adverse events: One patient discontinued the eardrops due to the garlic odor. There were no perforations or suppurative complications. Among the group that returned for tympanometric assessment, 6 of 7 (86%) had normal (Type A) tympanograms.Naturopathic protocols may be a valuable adjunct in patients selected for watchful waiting for management of AOM."}
+{"text": "Impaired extinction of fear is a hallmark of a variety of disabling anxiety disorders including panic disorder, post-traumatic stress disorder, social anxiety disorder and specific phobias. Therapeutic interventions that reverse deficits in fear extinction represent a tractable approach to treating these disorders. We recently revealed that 129S1/SvImJ (129S1) mice are unable to extinguish learned fear responses following \u2018normal\u2019 fear conditioning, establishing these mice as a clinically relevant model to identify extinction-facilitating targets.129S1 mice were subjected to multi-trial \u2018normal\u2019 and \u2018weak\u2019 cued fear conditioning/extinction paradigms and novel treatment strategies to rescue deficient extinction were tested.N-methly-D-aspartate partial agonist) or MS-275 (histone deacetylase (HDAC) inhibitor), applied after extinction training. We next examined the ability of different drugs and non-pharmacological manipulations to rescue the extreme fear extinction deficit in 129S1 following \u2018normal\u2019 fear conditioning with the ultimate aim to produce low fear levels in extinction retrieval tests. Results showed that rescue of both impaired extinction acquisition and deficient extinction consolidation/retrieval was achieved with prior extinction training administration of valproic acid (a GABAergic enhancer and HDAC inhibitor) or AMN082 [metabotropic glutamate receptor 7 (mGlu7) agonist], while MS-275 or PEPA (AMPA receptor potentiator) failed to affect extinction acquisition in 129S1 mice. Lastly, deep brain stimulation (DBS) by applying high frequency stimulation to the nucleus accumbens  during extinction training, indeed significantly reduced fear during extinction retrieval compared to sham stimulation controls.Results revealed that \u2018weak\u2019 fear conditioning permitted fear reduction during massed extinction training in 129S1 mice, but also revealed a specific deficiency in extinction memory consolidation/retrieval. Rescue of this impaired extinction consolidation/retrieval was achieved with D-cycloserine (Collectively, these data identify potential beneficial effects of various drug treatments and DBS, including those with HDAC inhibiting or mGlu7 agonism properties, as adjuncts to facilitate the outcome of exposure-based therapies for anxiety disorders."}
+{"text": "Achieving a sustained improvement in hand hygiene compliance is WHO\u2019s first global patient safety challenge. There is no RCT evidence showing how to do this. Systematic reviews require long term well designed RCT be done, testing effectiveness of a behavioural intervention designed using behavioural theory.Three year stepped wedge cluster RCT of a feedback intervention in 16 English/Welsh Hospitals , testing null hypothesis that intervention no more effective than routine practice.Intervention-based on Goal & Control theories. Repeating 4 week cycle of 20 mins observation, feedback & personalised action planning, recorded on forms. Computer generated stepwise randomisation.Primary outcome: direct blinded observation of hand hygiene compliance (%).All 60 wards randomised, 33 implemented intervention (11 ITU 22 ACE). Mixed effects regression analysis  accounting for confounders, temporal trends, ward type & fidelity to intervention (forms/month used).Intention to treat (ITT) analysis: estimated odds ratio (OR) for hand hygiene compliance rose post-randomisation  in ITUs but not ACE wards, equivalent to 7-9% absolute increase in compliance.Per protocol analysis for implementing wards: OR for compliance rose for both ACE  & ITUs  equating to absolute increases of 10-13% & 13-18% respectively. OR fell or unchanged on non-implementing ACE & ITU wards. Fidelity to intervention closely related to compliance on ITUs .Despite difficulties in implementation, ITT, per protocol & fidelity to intervention analyses showed an intervention coupling feedback to personalised action planning significantly improved hand hygiene compliance, in wards implementing a national handhygiene intervention. Further implementation studies are needed to maximise the intervention\u2019s effect in different settings.S. Stone Grant/Research support from GOJO."}
+{"text": "Approximately, 5% of carrier will develop ATL after a long latent period. A characteristic of this virus is that HTLV-1 can transmit only by cell-to-cell contact. Therefore, HTLV-1 increases infected cells HTLV-1 bZIP factor (HBZ) gene is transcribed from minus strand of provirus using 3\u2019 long terminal repeat (LTR) as the promoter/ enhancer. Among ATL cases, only the HBZ gene is expressed in all ATL cases, suggesting an importance of the HBZ gene in ATL cells. Indeed, transgenic expression of the HBZ gene induced T-cell lymphoma and inflammatory diseases. Furthermore, regulatory T (Treg) cells increased in HBZ-transgenic (HBZ-Tg) mice. As a mechanism, HBZ induces transcription of the Foxp3 gene through enhanced Smad/ TGF-\u03b2 pathway and converts infected cells to Treg cells. Concurrently, HBZ impairs function of Treg via interaction of HBZ with Foxp3 and associated factors. Thus, HBZ increases functionally impaired Treg cells in vivo, which resembles to phenotype of HTLV-1 infected cells and ATL cells. It is speculated that HTLV-1 infected Treg cells escape the host immune surveillance by acquired phenotype of Treg cells. Treg cells derived from HBZ-Tg mice progressively lost Foxp3 expression in vitro and produced IFN-\u03b3, indicating that HBZ induces inflammation through unstable Foxp3 expression. Thus, HBZ is responsible for both T-cell lymphoma and inflammatory diseases.Previous studies suggest that Tax plays central roles in leukemogenesis by HTLV-1. However, Tax expression is frequently impaired in ATL cells. The HBZ has pleiotropic functions as well as Tax. HBZ enhances TGF-\u03b2/Smad pathway while Tax inhibits it. Likewise, HBZ suppresses canonical NF-\u03baB whereas Tax activates canonical and noncanonical NF-\u03baB pathways. Thus, HBZ has opposite effects to Tax in many pathways. Interplay between HBZ and Tax likely coordinates to promote viral replication and proliferation of infected cells, leading to important roles in the pathogenesis."}
+{"text": "Maternal fish oil supplementation during pregnancy has been associated with altered infant immune responses and a reduced risk of clinical allergy. The objective of this study was to examine the effect of early postnatal fish oil supplementation on infant cellular immune function at six months of age and infant allergic diseases.In a double-blind randomized controlled trial (ACTRN12606000281594), 420 infants of high atopic risk received fish oil (containing 280mg docosahexaenoic acid (DHA) and 110mg eicosapentanoic acid (EPA)) or control oil daily from birth to six months. Fatty acid levels, induced cytokine responses, were assessed at 6 months of age in 150 infants. Eczema, food allergy, asthma and sensitization were assessed in 323 infants who completed clinical follow up at 12 months of age.DHA and EPA levels were significantly higher in the fish oil group and erythrocyte arachidonic acid (AA) levels were lower . Infants in the fish oil group had significantly lower IL-13 responses (p=0.036) to house dust mite and higher IFNg (p=0.035) and TNF (p=0.017) responses to phytohaemaglutinin. Infants with relatively high DHA levels had lower Th2 responses to allergens including lower IL-13 (p=0.020) and IL-5 (p=0.045) to b-lactoglobulin. Although n-3 PUFA levels at 6 months were associated with lower risk of eczema (p=0.033) and recurrent wheeze (p=0.027), the association with eczema was not significant after multiple comparisons. Between group comparisons revealed no differences in the occurrence of allergic outcomes.Postnatal fish oil supplementation increased infant n-3 polyunsaturated fatty acid (PUFA) levels and associated with lowered allergen-specific Th2 responses and elevated polyclonal Th1 responses. However, postnatal fish oil supplementation did not prevent childhood allergic disease."}
+{"text": "Burkholderia pseudomallei (Bp), the causative agent of the often-deadly infectious disease melioidosis, contains one of the largest prokaryotic genomes sequenced to date, at 7.2 Mb with two large circular chromosomes (1 and 2). To comprehensively delineate the Bp transcriptome, we integrated whole-genome tiling array expression data of Bp exposed to >80 diverse physical, chemical, and biological conditions. Our results provide direct experimental support for the strand-specific expression of 5,467 Sanger protein-coding genes, 1,041 operons, and 766 non-coding RNAs. A large proportion of these transcripts displayed condition-dependent expression, consistent with them playing functional roles. The two Bp chromosomes exhibited dramatically different transcriptional landscapes \u2014 Chr 1 genes were highly and constitutively expressed, while Chr 2 genes exhibited mosaic expression where distinct subsets were expressed in a strongly condition-dependent manner. We identified dozens of cis-regulatory motifs associated with specific condition-dependent expression programs, and used the condition compendium to elucidate key biological processes associated with two complex pathogen phenotypes \u2014 quorum sensing and in vivo infection. Our results demonstrate the utility of a Bp condition-compendium as a community resource for biological discovery. Moreover, the observation that significant portions of the Bp virulence machinery can be activated by specific in vitro cues provides insights into Bp's capacity as an \u201caccidental pathogen\u201d, where genetic pathways used by the bacterium to survive in environmental niches may have also facilitated its ability to colonize human hosts. Burkholderia pseudomallei, causes melioidosis, an often fatal infectious disease of humans and animals. Possessing a large multi-chromosomal genome, B. pseudomallei is able to persist and survive in a multitude of environments. To obtain a comprehensive overview of B. pseudomallei expressed transcripts, we initiated whole-genome transcriptome profiling covering a broad spectrum of conditions and exposures \u2014 a so-called \u201ccondition compendium\u201d. Using the compendium, we confirmed many previously-annotated genes and operons, and also identified hundreds of novel transcripts including anti-sense transcripts and non-coding RNAs. By systematically examining genes exhibiting highly similar expression patterns, we ascribed putative functions to previously uncharacterized genes, and identified novel regulatory elements controlling these expression patterns. We also used the compendium to elucidate candidate virulence pathways associated with quorum-sensing and infection in mice. Our study showcases the power of a B. pseudomallei condition compendium as a valuable resource for understanding microbial physiology and the pathogenesis of melioidosis.Bacterial transcriptomes are dynamic, context-specific and condition-dependent. Infection by the soil bacterium,  Analysis of >7,000 prokaryotic genomes in the PAThosystems Resource Integration Center  has revealed striking diversity in microbial genome sizes Mycoplasma pneumoniae, Bacillus subtilis) have been reported A central goal of pathogen genomics involves identifying the complete repertoire of functional genetic elements within pathogen genomes, including protein-coding genes, Burkholderia pseudomallei (Bp) is the causative agent of melioidosis, a tropical infectious disease of humans and animals. Among sequenced microbial genomes, the Bp genome is large (7.2 Mb), composed of two chromosomes (Chr 1 and 2) The Gram-negative bacterium cis-regulatory motifs associated with condition-dependent expression programs, and applied the compendium to elucidate candidate virulence pathways associated with quorum-sensing and in vivo infection. Taken collectively, the condition-dependent expression compendium represents a valuable resource for understanding Bp physiology and the pathogenesis of melioidosis. Moreover, our findings may also prove applicable to other bacterial pathogens with multiple chromosomes.In this study, we sought to obtain a global overview of how the environment might influence the Bp transcriptional landscape, by integrating expression data from whole-genome tiling microarrays covering >80 diverse environmental and genetic conditions. Our aims in this study were threefold: First, we generated a comprehensive strand-specific catalog of condition-dependent transcripts in Bp, including genes, operons, and non-coding RNAs. Second, we explored if the two Bp chromosomes might be associated with distinct patterns of transcription, related to their overall functions. Third, we defined www.patricbrc.org).Whole-genome tiling microarrays containing strand-specific probes overlapping at 35-base resolution were used to profile Bp transcriptional responses under 82 different conditions \u2013C. CondiWe confirmed detectible expression of 5,467 out of 5,935 Sanger genes (92.1%) . InteresBPSL0061.1, encoding a short 31 aa predicted protein, was only detectably expressed in anaerobic conditions, during macrophage infection, and in quorum sensing mutants , protein-folding (BPSL2697-BPSL2698) and global transcriptional regulation  , two component sensing  and flagella motility   , S5. In xposure) .Prokaryotic antisense transcription is emerging as an important mechanism regulating many processes including stress response and virulence BPSS0665, a tauD gene homolog involved in taurine metabolism Genomic Islands (GIs) are regions in a bacterial genome representing horizontal transfer events pendence . For exaB. mallei (Bm) and B. thailandensis (Bt) respectively, at both the levels of sequence identity and chromosomal synteny (Non-coding RNAs (ncRNAs) are emerging as an important class of regulatory molecules in several prokaryotes  synteny ,B.BPNC10070F was up-regulated 12-fold in nutrient-limiting conditions, and BPNC10061R exhibited high expression in high osmolarity and nutrient deprivation  but not P. aeruginosa. Interestingly, the predicted secondary structure of BPNC10061R is similar between Bp and Bm but distinct to Bt . First, we used ARACNe, an information theoretic algorithm for biological network construction, to identify significantly co-expressed pairs of Bp genes We sought to define groups of genes (\u201cclusters\u201d) commonly co-expressed under different conditions, as co-expressed genes often share similar cellular functions unctions .in vitro conditions (arcDABC operon), C247 (narKGH operon), and C126 (paaABCDE operon) were commonly overexpressed under conditions of temperature, ultra-violet exposure, and oxidative stress. Almost half (43/98) of the MRCNs comprised a mixture of functionally annotated and non-annotated clusters. For example, one MRCN highly expressed upon heat exposure comprised two clusters - C131, containing genes related to heat-stress   . InteresSynechocystis sp.Unsupervised clustering associating the different conditions to one another defined 12 robust condition groups encompassing 54 of the 66 condition-specific profiles  P. aeruginosa LasR binding sequence for a cluster related to secondary metabolism (C024); and the R. solanacearum HrpB binding sequence for clusters related to T3SS2  To identify  genes ) . Supportcis-regulatory motif in C030 (BPSS1512 \u2013 BPSS1533), which is associated with T3SS3, a known mammalian virulence factor. Comparisons of homologs of BPSS1512 \u2013 BPSS1533 in Bm and Bt revealed that this motif is conserved in all three species, suggesting that it is functionally important. Other cis-regulatory motifs significantly conserved in Bt or Bm were found in clusters related to capsular biosynthesis   respectively, which are regulated by Fur Our analysis also identified previously unknown regulatory motifs. For example, we discovered a candidate in vitro experimental conditions, could be exploited as \u201cmolecular fingerprints\u201d to deconvolute independent and high-complexity Bp transcriptomes of biological interest. As a proof-of-concept, preliminary analysis of two independent T3SS3 mutants  revealed that genes differentially expressed in T3SS3 mutants, were mapped onto the condition-dependent network, were associated with i) significantly closer network distances to the mutated gene compared to randomized gene sets  . To applBPSL1505 (rpoS)), other quorum sensing pathways (BPSS1180 (bpsI2), BPSS1176 (bpsR2)) and oxidative stress (BPSL2863 (dpsA)) wzt2, which encodes a component of the ABC transporter required for the delivery of capsular polysaccharides to the outer membrane In Bp, genetic disruption of the PmlI-PmlR QS system has been shown to attenuate virulence in mouse infection models We sought to validate these results at the phenotypic level. In motility assays, consistent with the network results we observed significant differences in mobility between wild type and mutant strain when cultured on soft agar, with the mutant being less motile . To inveBPSS1498 (tssD-5), BPSL3319 (fliC), BPSS1525 (bopE), BPSS1529 (bipD) and BPSS1532 (bipB). These effectors were identified using the program PSORTb 3.0 BPSL1775 (C446), an iron uptake receptor, and the pyochelin genes (pch) and fptA in cluster C087. The murine lung infection profile was also significantly similar to in vitro profiles related to nutrient starvation  Bacillus subtilis (46 a.a.) Escherichia coli (<50 a.a.) In this study, we integrated strand-specific whole-genome transcriptional data over 80 environmental, chemical and genetic perturbations to generate a transcriptional condition compendium of Bp. Previous molecular studies on Bp have largely focused on protein-coding genes defined by the original genome annotation study bona-fide ncRNA signals from background noise. ncRNAs are emerging as a major new class of regulatory molecules governing many aspects of prokaryote biology, including protein synthesis (e.g. tRNAs), cellular regulation (riboswitches) and cellular catalysis (ribozymes). ncRNAs associated with virulence and host-pathogen interactions have also been found in Yersinia spp and E. coliBPNC10134F, BPNC20132R, BPNC10175R expressed in normal human serum and BPNC10090R, BPNC20136F, BPNC20142R expressed upon insulin exposure. Besides ncRNAs, we also discovered genome-wide expression of antisense RNAs in Bp. In other prokaryotes, antisense RNAs have been shown to modulate gene transcription by promoting RNA degradation or transcriptional interference H. pylori and L. monocytogenes, antisense RNAs are involved in regulating metabolic enzymes and virulence factors Besides potential coding genes, we also identified in this work >700 Bp condition-dependent ncRNAs. This is a conservative estimate, since in our study potential ncRNAs shorter than 100 bp were excluded from analysis due to challenges in resolving E. coli, L. monocytogenes and B. subtilis1 in B. anthracis and pSymB in S. meliloti, respectively Vibrio cholerae).Our data demonstrates that the two Bp chromosomes exhibit very different transcriptional landscapes. Specifically, Chr 1 genes were often constitutively and highly expressed, while Chr 2 genes exhibited \u201cmosaic\u201d expression, where distinct subsets of Chr 2 genes were expressed in a strongly condition-dependent manner. Previous genome analysis has also suggested that the two Bp chromosomes are distinct in composition and function, and Chr 1 has been proposed as a \u201chousekeeping\u201d chromosome. Interestingly, when compared against other prokaryotic transcriptome studies, the transcriptional landscape of Bp Chr 1 bears high resemblance to other single chromosomal microbes cis-regulatory motifs. For functional discovery, genes encoding proteins participating in the same pathway, or forming part of the same protein complex, often display patterns of co-regulation when surveyed across a large number of diverse conditions www.genome.jp/kegg/pathway.html). Linking these genes to other co-expressed genes of known function may thus prove useful in inferring potential functions. For example, we highlighted a set of \u201chypothetical\u201d protein-coding genes  which strongly co-expressed with genes associated with heat-shock and protein unfolding. Once identified, these genes can then be further tested through targeted experimentation. Indeed, ongoing in silico analyses by the PATRIC team have revealed that BPSL2829 is a heatshock protein GrpE. Besides protein-coding genes, we also discovered numerous associations between ncRNAs and the co-expressed genes. For example, the ncRNAs BPNC20122R and BPNC20135F were positively correlated with the T3SS3-related expression clusters C030 and C035  similar motifs in other species have not been studied, (ii) regulation of the same cellular process in Bp has been changed due to evolutionary pressures or (iii) the DNA-binding protein and the motif it recognizes have mutated in a parallel manner For PmlI, a master regulator of quorum sensing. We also used this approach to highlight T3SS3 and iron acquisition as two of the most highly regulated pathways during murine in vivo infection. A recent Bp study showed that the disruption of ferric-pyochelins and other iron acquisition mechanisms significantly reduced bacterial loads in murine lungs, though a mba pch hmu hem quadruple mutant was still capable of iron acquisition and inducing lethality in an acute murine melioidosis model B. cepacia strains, exogenously supplied pyochelin increased bacterial virulence Finally, our study presents a general approach to integrate condition-dependent transcriptome data with genetic data, for the purpose of dissecting transcriptional profiles of biological interest but formidable complexity. Applying this concept to the process of quorum sensing, we were able to highlight two processes, cell motility and capsule formation, as likely contributors to the attenuation of virulence previously observed in a mutant genetically disrupted in In conclusion, similar to recent tiling microarray studies of other bacterial species Bp strains used are listed in High-density tiling arrays were fabricated by Roche NimbleGen  based on the BpK96243 reference genome de novo TAR identification A moving window binomial approach was performed for e cutoff .th percentile and above of expressed probes, and vi) the minimum length of an ncRNA is 100 bp. Secondary structure predictions were performed using RNAfold We applied the following criteria to identify new candidate ncRNAs: i) the ncRNAs should be a subset of the identified TARs, ii) ncRNAs should be distinct from other genic features (e.g. protein-coding genes) by a minimum of 3 consecutive probes (105 bp), iii) ncRNAs are strictly located in intergenic regions, iv) ncRNAs should not be antisense to any genic feature, v) expression levels of probes corresponding to the ncRNA must be the top 90Co-expression associations between genes were defined by the ARACNe algorithm c incoming from other clusters or genes; m is the total number of highly weighted links bridging different clusters. Clusters connected by To define co-expression clusters, we identified groups of highly co-expressed genes using Markov Clustering (MCL) Burkholderia species were measured using TOMTOM Candidate regulatory motifs were identified using the MEME algorithm For mouse infections, female BALB/c mice  were maintained under Animal Biohazard Containment Level 3 conditions. All animal experiments were performed in accordance with the guidelines of the Animals (Scientific Procedures) Act of 1986 and were approved by the local ethical review committee at the London School of Hygiene and Tropical Medicine. Prior to intranasal (i.n.) infection, mice were anesthetized intraperitoneally with ketamine  and xylazine  diluted in PFS. Challenge was performed by administering a total volume of 50 \u00b5l i.n. containing 2500 colony forming units (CFU) BpK96243. At day 3 post-infection (p.i.), mice were killed and lungs aseptically removed into 3 ml of cold Trizol Reagent . Organs were homogenized using a Polytron homogenizer and samples stored at \u221280\u00b0C until further processing.Figure S1BPSS1434 and BPSS1439 are membrane anchored cell surface proteins found on Chr 2 with probe counts of 2 to 10. Each shares significant similarity with streptococal hemagglutinin. There are 16 adhesin genes encoding for proteins with conserved domains associated with the Hep-Hag family hemagglutinin-like proteins in the BpK96243 genome, out of which, 9 of them correspond to high probe redundancy in our array design. (D) Quantitation of array reproducibility and robustness. (i) Technical replicates. Scatter plot comparing signal intensities of all probes from 2 technical replicates of LBS were plotted and the Pearson coefficient of determination computed and shown at the bottom right. The dynamic range of signal intensities is limited by the scanner. (ii) Biological replicates. Scatter plot comparing the probe expression ratios of all probes from 2 biological replicates of LBS. The corresponding Pearson correlation coefficient is shown at the bottom right. For ii), note that expression ratios are being compared rather than absolute intensities. Thus, two replicate profiles are deemed reproducible if their probe ratios cluster around 0. More than 98% of probes lie within the acceptable range (grey dots). Blue dots (\u223c2%) represent outliers that are random.BpK96243 tiling microarray design and quantification. (A) Probes were tiled across both forward (+) and reverse (\u2212) strands of the 2 Bp chromosomes. Red bars show the locations of annotated Sanger genes in the genome on the respective strands of the chromosomes. Blue bars represent the probes. (B) Schematic representative example of probes on the tiling array. Precise 50 mer reverse complement probes were designed for both top (forward) and bottom (reverse) strands of both chromosomes of BpK96243. Sense probes are located within predicted genes and on the coding chromosomal strand. Reverse complements of sense probes constitute the antisense probes. (C) Genes with high probe redundancy (probe counts). Two representative examples are shown. (TIF)Click here for additional data file.Figure S2BPSL0074 (dnaN) and BPSL0075 (dnaA) from K9LBS; ii. Motility gene \u2013 BPSL3319 (fliC) from K942C16hrs; iii. Virulence genes (T3SS3) \u2013BPSS1546 (bsaN), BPSS1525 (bopE), from K9UV1hr; iv. Capsule gene \u2013 BPSL2800 (wcbH) from K930NHS. (B) FGENESB novel genes. PCR products using primers from Left to Right, 1. BPSL0393.1-F&R, 2. BPSL0706.1-F&R, 3. BPSL1304.1-F&R, 4. BPSL2880.1-F&R, 5. BPSL2882.1-F&R, 6. BPSS0035.1-F&R, 7. BPSS0279.1-F&R, 8. BPSS0818.1-F&R, 9. BPSS1773.1-F&R, 10. BPSS1927.1-F&R and Lane M: 100 bp molecular ladder. (C) Operons. Bp operon BpOpr0007 (BPSL0026 \u2013 BPSL0032). Operon expression from condition K9TaurineES was validated by RT-PCR. Regions between the gene members were amplified by primers as shown by black arrows above. (D) Antisense transcription. Experimental validation of antisense transcription of Sanger genes using strand-specific real-time PCR. Fourteen Sanger genes were experimentally validated; 7 of them exhibited normal gene expression  and 7 of them with associated antisense transcripts on the microarray . The figure shows concordance of results for most of the genes (except BPSL0502 and BPSL2540) using strand-specific real-time PCR. (E) Non-coding RNA (ncRNAs). (i) Experimental validation of five novel ncRNA transcripts using RT-PCR; (ii) Experimental validation of ncRNA BPNC10061R transcripts under different conditions.Experimental RT-PCR validation of detected transcripts and novel genomic features. (A) Sanger gene expression. SignalMap snapshots of expressed Sanger genes belonging to different functional classifications and their respective RT-PCR validations (100 bp molecular ladder): i. DNA replication genes \u2013 (TIF)Click here for additional data file.Figure S3in vivo infection , two operons belonging to T3SS3 exhibited antisense transcription: BpOpr1082 (BPSS1529 and BPSS1530) and BpOpr1083 (BPSS1531 \u2013 BPSS1533).Antisense transcription of Bp operons. During (TIFF)Click here for additional data file.Figure S4Expression heat-map of 16 genomic islands. Gene expression of 16 genomic islands (GIs) in the BpK96243 genome were normalized to mean zero across non-genetic perturbations. The over- and underexpression of genes are indicated in red and green, respectively. Overexpression of GIs in specific perturbations are marked by yellow boxes and the involved conditions are indicated on the right.(TIF)Click here for additional data file.Figure S5B.pseudomallei K96243 being conserved in B.cenocepacia AU1054, HI2424, B.mallei ATCC23344 and B.thailandensis E264. The number of conserved ncRNAs in one species is indicated in brackets. (B) Shared synteny statistics. Conserved ncRNAs are flanked by (i) two homologs with conserved genes' order; (ii) two homologs with reversed genes' order; (iii) one homolog, the gene's order is either conserved or reversed. We determined the order of genes/homologs by using K96243 as reference. (C\u2013D) The distributions of up-regulated and down-regulated ncRNAs across the conditions are shown respectively.Sequence, chromosomal synteny conservation and differential expression of ncRNAs. (A) Total number of ncRNAs in (TIF)Click here for additional data file.Figure S6Common down-regulated genes in Bp during exposure to antibiotic treatment, osmotic stress and prolonged heat stress. 158 genes were commonly down-regulated by at least 2-fold in the presence of chloramphenicol (K9Chlamp), ceftazidime (K9Ceft), 2M of sorbitol (K9Sorb) or under 42\u00b0C for 16 hours (K942C16hrs). Genes that are significantly enriched ((TIF)Click here for additional data file.Figure S7bprC, bsaN and weighted clustering coefficient properties of the pmlI network. (A) bprC transcriptional network. The distances between bprC and other differentially expressed genes are significantly shorter  and the distribution of WCC obtained from a set of randomized networks (red line).Visualization of condition-dependent networks of (TIF)Click here for additional data file.Figure S8rpoE mutants compared to wild type Comparison between transcript levels from our study to protein levels from published literature. (A) The scatter plot shows the ratio of 28 transcripts to corresponding proteins in (TIF)Click here for additional data file.Table S1Burkholderia pseudomallei transcriptome.Details of conditions used for (XLS)Click here for additional data file.Table S2Burkholderia pseudomallei.Overview of transcriptional landscape in (XLS)Click here for additional data file.Table S3Primers for RT-PCR validation of transcripts and novel genomic features.(DOC)Click here for additional data file.Table S4Details of genes without detectible expression.(XLS)Click here for additional data file.Table S5The total number of expressed genomic features in each condition.(XLS)Click here for additional data file.Table S6Predicted secondary structures of novel Bp ncRNAs using RNAFold.(DOC)Click here for additional data file.Table S7Details of transcriptional landscape comparison between chromosome 1 (Chr1) and chromosome 2 (Chr2) in each condition.(XLS)Click here for additional data file.Table S8Coexpression network analysis revealed a collection of gene clusters, functional enrichments in the clusters and associations between clusters - maximum relatedness cluster network (MRCN).(XLS)Click here for additional data file.Table S9Correlation between ncRNAs and clusters.(DOC)Click here for additional data file.Table S10Condition subgroups identified by condition clustering.(DOC)Click here for additional data file.Table S11cis-regulatory motifs detected using genic upstream sequences from clusters and MRCNs.(DOC)Click here for additional data file.Table S12cis-regulatory motifs.ncRNAs with identified (DOC)Click here for additional data file.Table S13Differential expression of quorum sensing signature genes.(DOC)Click here for additional data file.Table S14Quorum-sensing (QS) associated genes found in literature.(DOC)Click here for additional data file.Table S15Bacterial strains and sources used in this study.(DOC)Click here for additional data file.Text S1Supplemental methods and supplemental references.(DOC)Click here for additional data file."}
+{"text": "Salmonella and non-pathogenic E. coli. Both microbes entered intestinal Peyer\u2019s patches and, surprisingly, induced qualitatively and quantitatively similar initial inflammatory responses revealing a striking discrimination failure. Diverging inflammatory responses only occurred when Salmonella subsequently proliferated and induced escalating neutrophil infiltration, while harmless E. coli was rapidly cleared from the tissue and inflammation resolved. Transient intestinal inflammation induced by harmless E. coli tolerized against subsequent exposure thereby preventing chronic inflammation during repeated exposure. These data revealed a striking failure of the intestinal immune system to discriminate pathogens from harmless microbes based on distinct molecular signatures. Instead, appropriate intestinal responses to gut microbiota might be ensured by immediate inflammatory responses to any rise in microbial tissue loads, and desensitization after bacterial clearance.The intestinal immune system mounts inflammatory responses to pathogens but tolerates harmless commensal microbiota. Various mechanisms for pathogen/non-pathogen discrimination have been proposed but their general relevance for inflammation control is unclear. Here, we compared intestinal responses to pathogenic  The intestinal mucosa is a major site of pathogen entry. To fight infection, the intestinal innate immune system detects pathogens and tries to control them with immediate inflammatory responses. Important receptors for pathogen detection include toll-like receptors (TLRs) and NOD-like receptors that recognize bacterial components such as lipopolysaccharide, peptidoglycan, and flagella Various molecular mechanisms have been proposed to discriminate pathogens from harmless gut bacteria including (i) poorly stimulatory microbial-associated molecular patterns (MAMP) in commensals but potent MAMPs in pathogens, (ii) \u201csymbiont-associated molecular patterns\u201d (SAMPs) that suppress inflammation Salmonella and non-pathogenic E. coli in murine intestinal Peyer\u2019s patches, and characterized underlying mechanisms using mouse mutants and various Salmonella strains. The results suggested surprising similar initial inflammatory responses to both pathogenic/avirulent Salmonella and harmless E. coli indicating a striking discrimination failure. However, appropriate responses were still possible since inflammation depended on bacterial tissue load. Salmonella, which survived and proliferated in Peyer\u2019s patches, thus induced escalating inflammation, while harmless E. coli was rapidly cleared and inflammation resolved.In this study, we compared intestinal inflammatory responses to pathogenic Salmonella enterica serovar Typhimurium. We initially used high doses of 1011 CFU that have previously been used to study intestinal immune responses to SalmonellaSalmonella, Salmonella were detected in dome areas of intestinal Peyer\u2019s patches (gut-associated lymphoid tissues) (me Ly-6Ghi CD11bhi) and some mobile monocyte precursors (Ly-6Chi Ly-6Glo CD11bhi) had already infiltrated infected dome areas   as obserme areas ; Fig. S1Salmonella triggered initial neutrophil infiltration through activation of MyD88 with some involvement of TLR4 but not IL-1\u03b2 or IL-18 . EcN is a probiotic bacterium that can prevent or ameliorate chronic intestinal inflammation in animal models and human patients Salmonella , there was little initial neutrophil accumulation. However, Salmonella slowly proliferated to high tissue loads and this was associated with a parallel neutrophil accumulation as observed for wildtype Salmonella at a faster time scale  hly\u2212, mcm+ was obtained from a local pharmacy (Mutaflor\u2122) and grown in Lennox LB medium. A spontaneous streptomycin mutant was selected and used for mouse experiments. In addition, an avirulent E. coli strain that we had isolated from mouse feces Salmonella or E. coli late log phase cultures were resuspended in PBS. Some bacterial suspensions were fixed with 2% formalin in PBS on ice for 1 h followed by two washes with PBS.10E. coli Nissle 1917, or 5\u00d71010Salmonella using a round-tip stainless steel needle. At various time intervals after infection Peyer\u2019s patches were prepared. After mucus was removed using Kim-Wipes, Peyer\u2019s patches were thoroughly washed in PBS, homogenized between the sanded ends of microscopy slides, mixed with Triton X-100 , and plated on LB media containing 90 \u00b5g ml\u22121 streptomycin that effectively suppressed endogenous flora.All animals were handled in strict accordance with good animal practice and all animal work was approved by local animal care and use committee (license 04/862 Nieders\u00e4chsisches Landesamt f\u00fcr Verbraucherschutz und Lebensmittelsicherheit). Eight to 12 weeks old female C57BL/6 mice, congenic gene-deficient mice female mice, or female BALB/c mice were intragastrically infected with about 5\u00d710Salmonella, Sifin; rabbit polyclonal anti LPS-O6 kindly provided by A. Fruth; anti-Ly-6G-FITC, BD Biosciences) followed by secondary antibodies . Sections were examined with a confocal microscopy (Leica SP5).Peyer\u2019s patches were embedded in Tissue-Tek (Sakura) and frozen on dry ice. Cryotome sections (8 \u00b5m) were blocked for 30 min (Molecular Probes blocking solution), and incubated with primary antibodies . Stained cells were analyzed using flow cytometry . PMN were identified as CD11bFigure S1lo Ly-6Chi) in Peyer\u2019s patches after administration of virulent Salmonella (filled circles) or probiotic E. coli Nissle . Means and standard deviations are shown for groups of three to four mice Click here for additional data file.Figure S2Salmonella loads in wildtype (B6) and mutant mice with various defects in innate immunity. Infection kinetics differed between the various mouse strains. We therefore compared highly infected mice .Neutrophil infiltration of Peyer\u2019s patches at high (TIF)Click here for additional data file.Figure S3Salmonella aroA (filled circles) or E. coli Nissle 1917 (open circles). Means and standard errors for groups of three to five individuals from two independent experiments are shown.Immediate neutrophil infiltration 3 h after oral administration of different doses of (TIF)Click here for additional data file.Figure S4E. coli strain. A) Colonization levels of E. coli E2 (open triangles) and PMN infiltration (filled circles) in Peyer\u2019s patches at various time intervals post infection . The data might overestimate actual bacterial tissue loads due to potential contamination with residual luminal EcN especially at early time points after oral administration. Means and standard deviations are shown for groups of three mice. B) Neutrophil accumulation in Peyer\u2019s patches two days after oral infection with pathogenic Salmonella in BALB/c mice. One day before Salmonella infection, mice received PBS (open circles), or a single dose of murine E. coli E2 (filled circles). Significance of differences between groups was determined using t-test .Neutrophil infiltration and colonization of Peyer\u2019s patches after administration of a murine (TIF)Click here for additional data file."}
+{"text": "Mast cell tumors (MCTs) are the most common cutaneous tumor in the dog. MCTs exhibit wide variation in biological behavior. KIT mutations and aberrant KIT expression have been identified in canine MCTs. Unlike human mastocytosis patients, in which point mutations primarily occur in the kinase domain of KIT, internal tandem duplications (ITD) have been identified in the juxtamembrane domain of KIT in canine MCTs. Among several KIT mutations identified, an ITD in exon 11 has been analyzed most consistently and is significantly associated with malignant behaviour of affected tumors. The goal of this pilot study was to describe ITD KIT mutation in six high grade MTCs and four low grade MCTs.The KIT was performed using a primer pair for C-KIT exon 11, forward primer 5\u2019-CCATGTATGAAGTACAGTGGAAG-3\u2019 and reverse primer 5\u2019-GTTCCCTAAAGTCATTGTTACACG-3\u2019. PCR products were analyzed by 1.5% agarose gel electrophoresis and visualized with SYBR\u00ae Safe DNA Gel Stain. Two of six high grade MCTs (2/6) had ITD KIT mutations. All of these tumors had aberrant diffuse cytoplasmic c-KIT (CD117) localization by immunohistochemistry.PCR amplification mutational analysis of KIT mutations, and of these tumors only one (1/4) had aberrant c-KIT immunostaining. Internal tandem duplication of KIT exon 11 mutation was associated with high grade tumors and aberrant C-KIT localization by immunohistochemistry in canine MCTs.None of low grade tumors 4/4 had ITD FAPESP."}
+{"text": "Prosthesis-related alterations of blood flow in the ascending aorta after aortic valve replacement (AVR) may influence aortic remodeling. The study aimed at analyzing ascending aortic flow characteristics after various types of AVR.peak) in the ascending aorta.Flow-sensitive four-dimensional magnetic resonance imaging (4D-flow) was acquired in 38 AVR patients  and 9 healthy controls. Analysis included grading of vortex and helix flow , assessment of systolic flow eccentricity , and quantification of the segmental distribution of peak systolic wall shear stress  and stentless (1.3\u00b10.7N/m2) compared to autografts  and controls . Autografts exhibited lower absolute WSSpeak than controls .Compared to controls, mechanical prostheses showed the most distinct vorticity , while stented bioprostheses exhibited most distinct helicity  . AJB is funded by the Whitaker Postdoctoral and Fulbright Grants . MM is supported by the NMH Excellence in Academic Medicine (EAM) Program 'Advanced Cardiovascular MRI Research Center' ."}
+{"text": "Foot ulcers are a common reason for diabetes-related hospitalisation. Foot ulcer simulation training (FUST) programs have increased podiatry participants self-confidence to manage foot ulcers. However, supervisors\u2019 perspectives on their participants attending these simulation programs have not been investigated. This mixed method  study aimed to investigate home clinical supervisors\u2019 perspectives on any changes to their participants\u2019 competence and practice following FUST.Clinical supervisors of fifteen podiatrists, who participated in a two-day Foot Ulcer Simulation Training (FUST) course, were recruited. Supervisors completed quantitative surveys evaluating their participants\u2019 foot ulcer competence pre-FUST and 6-months post-FUST, via a purposed designed 21-item survey using a five-point Likert scale . Supervisors also attended a semi-structured qualitative group interview to investigate supervisors\u2019 perspectives on FUST.p < 0.05). Five supervisors attended the group interview. Five sub-themes emerged: i) FUST provided a good foundation for future learning, ii) FUST modelled good clinical behaviour, iii) clinical practice improvement was evident in most participants, iv) clinical improvements were dependent on participant\u2019s willingness to change and existing workplace culture, v) FUST needs to be reinforced back in the home clinic.Supervisors surveys returned were pre-FUST (n=10) and post-FUST (n=12). Significant competence improvements were observed at the 6-month survey (mean scores 2.84 cf. 3.72, Overall, supervisors of FUST participants indicated that the course improved their participants\u2019 competence and clinical practice. However, the degree of improvement appears dependant on the participants\u2019 home workplace culture and willingness to embrace change."}
+{"text": "Concerns exist regarding the central nervous system (CNS) penetration and cognitive sequelae when utilising novel, nucleoside-sparing treatment strategies such as protease-inhibitor monotherapy.The aim of this study was to assess changes to cerebral function parameters in HIV-1 infected subjects, stable on antiretroviral therapy with a plasma HIV RNA<50 copies/mL, randomised to commence on a one to one basis, either darunavir/ritonavir (800/100 mg one daily) alone (DRVmono) or with nucleoside analogues (DRVnrti), within the MONET study. Cerebral function was assessed via a detailed, validated, computerised neurocognitive function assessment (CogState\u2122) and cerebral metabolites measured via cerebral proton spectroscopy in three anatomical locations ), at baseline and after 48 weeks. Associations between cerebral function parameters and study treatment arms were evaluated using linear regression.6 subjects were enrolled (3 assigned to each treatment arm) with a mean age of 44 years (SD 4.5) and 83% male. Mean baseline plasma CD4+ cell count was 503 cells/uL (SD 173). Over 48 weeks, mean score improvements were observed in 6 of 8 neurocognitive tasks assessed including speed domains (2.5% increase identification speed), accuracy domains  and executive function (30% reduction in errors). Reductions in cerebral metabolite markers of cerebral inflammation (choline:creatine (Cr) and myo-inositol:Cr ratios) were also observed in all cerebral locations assessed . No associations between study treatment arm and these improvements in cerebral function parameters were observed .On detailed assessment of cerebral function, overall improvements were observed over 48 weeks in subjects allocated to either DRVmono or DRVnrti. Despite very small numbers, our study highlights future tools which can practically be utilised to assess cerebral function in HIV-treatment programmes."}
+{"text": "Septic shock is a common cause of mortality and morbidity in the ICU. Endotoxin hemoadsorption using a Polymyxin B fiber column can improve patient outcome . This stn = 8) or standard therapy plus two 2 hourly sessions of Alteco endotoxin hemoperfusion . Standard therapy included infective source control, appropriate early antibiotic, low-dose steroid, early continuous renal replacement therapy in the presence of acute kidney injury (RIFLE Injury class or more), hemodynamic optimization and lung-protected ventilatory support. Primary outcome was change in organ dysfunction at 48 hours measured by Sequential Organ Failure Assessment (SOFA) scores. Secondary outcomes were change in vasopressor requirement (measured by vasopressor score), PaO2/FiO2 (fraction of inspired oxygen) ratio, total urine output at 72 hours and 28-day mortality.An open, controlled, prospective, randomized, single-centre trial conducted between February 2010 and June 2012. Patients with septic shock due to intra-abdominal sepsis were recruited and randomized to either standard therapy , vasopressor score , PaO2/FiO2 P ratio , total urine output from 0 to 72 hours  and 28-day mortality . No significant side effect was noted when using this new hemoadsorption device.This study was terminated early as interim analysis identified no significant clinical benefit. Baseline characteristics (age/APACHE IV score) were similar between two groups of patients. No significant difference was noted between two groups with respect to change in total SOFA score (+1 vs. -5.5 for AT vs. ST, This small study cannot identify any extra clinical benefit on addition of Alteco endotoxin hemoadsorption to standard therapy in patients suffering from intra-abdominal sepsis with shock due to Gram-negative bacterial infection."}
+{"text": "Activation of focal adhesion kinase (FAK) is hypothesized to play an important role in the pathogenesis of human breast cancer.To directly evaluate the role of FAK in mammary tumour progression, we have used a conditional FAK mouse model and mouse mammary tumour virus (MMTV)-driven Cre recombinase strain to inactivate FAK in the mammary epithelium of a transgenic mouse model of ErbB2 breast cancer.Although mammary epithelial disruption of FAK in this model resulted in both a delay in onset and a decrease in the number of neoplastic lesions, mammary tumours occurred in 100% of virgin female mice. All of the tumours and derived metastases that developed were proficient for FAK due to the absence of Cre recombinase expression. The hyperplastic epithelia where Cre-mediated recombination of FAK could be detected exhibited a profound proliferative defect. Consistent with these observations, disruption of FAK in established tumour cells resulted in reduced tumour growth that was associated with impaired proliferation. To avoid the selection for FAK-proficient ErbB2 tumour epithelia through escape of Cre-mediated recombination, we next intercrossed the FAK conditional mice with a separate MMTV-driven ErbB2 strain that co-expressed ErbB2 and Cre recombinase on the same transcriptional unit.While a delay in tumour induction was noted, FAK-deficient tumours arose in 100% of female animals indicating that FAK is dispensable for ErbB2 tumour initiation. In addition, the FAK-null ErbB2 tumours retained their metastatic potential. We further demonstrated that the FAK-related Pyk2 kinase is still expressed in these tumours and is associated with its downstream regulator p130Cas. These observations indicate that Pyk2 can functionally substitute for FAK in ErbB2 mammary tumour progression. Elevated expression of FAK has been associated with highly invasive human breast cancers ,2. In pain vivo importance of FAK in tumourigenesis derives from several recent studies in which components of the integrin signaling pathway were selectively ablated in the germline of mice. For example, mice heterozygous for a FAK null allele exhibit a dramatic delay in tumour induction in a chemically-induced skin carcinogenesis model [Direct evidence for the is model . Becauseis model ,11, it iis model . More reis model .in vivo. In the polyomavirus middle T (PyVmT) model of mammary tumour progression, mammary epithelial disruption of FAK prevented the transition of mammary hyperplastic growths into mammary adenocarcinomas [Although these studies have largely focused on tissues such as skin, there is compelling evidence suggesting that activation of FAK is directly involved in the induction of mammary tumours rcinomas . This rercinomas -17. By crcinomas . Taken tGiven the dramatic impact of FAK deletion on PyVmT tumour induction, we evaluated whether deletion of FAK in an activated ErbB2 mouse model resulted in a comparable phenotype. To accomplish this, we first intercrossed the mouse mammary tumour virus (MMTV)-activated ErbB2 strain (NDL2-5) to separate strains of mice bearing the MMTV-Cre and conditional FAK alleles and monitored virgin female cohorts for the development of mammary tumours. Although a delay in mammary tumour onset was observed, all animals developed mammary tumours that were highly metastatic. Genetic and biochemical analyses revealed that the majority of these tumours had escaped Cre-mediated recombination of the conditional FAK alleles and were proficient for FAK expression, indicating a strong selection for retention of FAK signaling. Cre-mediated deletion of FAK in established ErbB2 mammary tumour cells resulted in a profound delay in tumour growth that was further associated with a proliferative defect. Finally, using a transgenic mouse model that co-expressed ErbB2 and Cre recombinase, we demonstrated that while mammary epithelial ablation of FAK delayed tumour onset and reduced the number of neoplastic lesions, animals developed mammary tumours with 100% penetrance. Collectively these observations argue that while FAK contributes to ErbB2 tumour cell proliferation, it is ultimately dispensable for ErbB2 mammary tumour initiation and progression.flox mice were generated and characterized as described [flox mice were interbred with MMTV-NDL2-5, MMTV-Cre and MMTV-NIC mice and routine genotyping was performed by PCR as described [MMTV-Cre and GTRosa26 mice were described previously ,19. MMTVescribed ,20,21. Fescribed . Experimin situ \u03b2-galactosidase assays, lungs were processed as described previously [The No. 4 inguinal mammary glands were used for wholemount analyses and the No. 3 thoracic glands for histological analyses. Mammary gland wholemounts were prepared as previously described . For in eviously . For hisFor immunohistochemistry (IHC) and immunohistofluorescence (IHF), tissue sections were deparaffinized in xylene, endogenous peroxidase activity was blocked with 3% hydrogen peroxide in methanol, and antigen retrieval was done in 10 mmol/L sodium citrate (pH 6) using a pressure cooker . Sections were then blocked with Power Block Universal Blocking Agent , incubated in primary antibody as described previously , then inLysates were prepared from mammary tumour tissues flash frozen in nitrogen, and immunoblots were performed as described previously . AntibodTumours at 8 weeks post-palpation were processed using a McIlwain tissue chopper , dissociated in collagenase B/dispase II  for 2 hours at 37\u00b0C, washed with PBS + 1mM EDTA and plated in DMEM supplemented with 2% FBS and Mammary Epithelial Growth Supplement (MEGS - Invitrogen). pMSCV retroviral vector containing Cre recombinase or empty pMSCV vector were used for virus production in 293VSV cells and subsequent transductions were carried out as previously described . TransduCellTiter Aqueous MTS  proliferation assays were performed according to the manufacturer's protocols using 2,500 cells per well in 96-well optical bottom plates . For migration and invasion assays, cells were seeded in serum-free medium in transwell chambers  with complete medium as a chemoattractant, and for the invasion assay chambers were coated with 5% matrigel (BD Biosciences). Cells were incubated for 24 hours, formalin-fixed, and stained with crystal violet. Cells that passed through the membrane were visualized by microscopy and pixel counts were determined using ImageJ software.4 cells per well and allowed to adhere for either 15 or 120 minutes at 37\u00b0C in 24-well plates coated with fibronectin . At various time points, wells were washed twice with PBS and adherent cells were fixed with 10% neutral buffered formalin and then stained with crystal violet (0.1%). After extensive washing to remove the free dye, the stained cells were visualized by microscopy and cell spreading was determined by counting at least 200 cells.Cells of approximately 80% confluence were trypsinized, washed in serum-free DMEM/0.5% BSA + MEGS containing 100ug/ml soybean trypsin inhibitor (STI), and re-suspended with serum-free DMEM/0.5% BSA + MEGS. Suspension cells were seeded at 5 \u00d7 105 cells in PBS) were injected into the fourth inguinal mammary fat pad of athymic nude mice . Mice were monitored twice weekly for tumour formation by palpation. Tumour growth was assessed by weekly caliper measurements.Stable cell lines  and infected them with empty vector controls or retroviral vectors expressing Cre recombinase   with sepe Figure . One potin vitro and in vivo settings -negative mammary epithelial neoplastic cells do not exhibit an increase in apoptosis. (a) Paraffin sections of hyperplastic mammary glands from 6-month-old FAKwt/wt and FAKflox/flox/mouse mammary tumour virus (MMTV)-Cre/-NDL2-5 mice were submitted to immunofluorescence analyses with Cre- and FAK-specific antibodies. Note that Cre-positive cells in lesions from FAKflox/flox/MMTV-Cre/-NDL2-5 mice are FAK-negative. (b) Paraffin sections of hyperplastic mammary glands from 6-month-old FAKwt/wt and FAKflox/flox/MMTV-Cre/-NDL2-5 mice were submitted to immunofluorescence analyses of Cre and cleaved caspase-3 expression. Scale bars: 20 \u03bcm. (c) Graphical representation of the immunostaining shown in (b). Percentages (\u00b1 standard error of the mean) were calculated after counting multiple fields from at least five animals from each genotype.Click here for fileFigure showing that focal adhesion kinase (FAK)-deficient tumour cells exhibit proliferative, migratory and invasive defects. (a) FAK ablation in NDL2-5 tumour cells decreases proliferation. MTS proliferation assays (n = 3) were performed on NDL2-5/FAKwt/wt and NDL2-5/FAKflx/flx cell lines expressing empty vector (vector) or Cre vector (Cre). Data are normalized to values at 24 hours for the control cells. Error bars represent standard error of the mean (SEM). P < 0.01, vs. empty vector control (unpaired Student's t-test). (b) Migration and invasion through matrigel was assayed in NDL2-5/FAKwt/wt and NDL2-5/FAKflx/flx cell lines expressing empty vector (vector) or Cre vector (Cre). Pixel count analyses of crystal violet-stained membranes were performed on five different fields for each cell line (n = 3). Error bars represent SEM. (c) Tumour lysates from FAK-deficient and -proficient NDL2-5 cell lines injected into the cleared fat pads of immunodeficient mice were immunoblotted with the indicated antibodies. \u03b2-actin was used as loading control.Click here for fileFigure showing that focal adhesion kinase (FAK)-deficient tumour cells exhibit a cell spreading defect. (a) Quantification of cell spreading shown in (b) by counting the number of spread cells (marked by arrows in b) among at least 200 cells in NDL2-5/FAKwt/wt and NDL2-5/FAKflx/flx cell lines expressing empty vector (vector) or Cre vector (Cre). The percentage of spread cells  in five microscopic fields was determined. Cells were fixed for either 15 or 120 minutes after plating on fibronectin-coated slides and then stained with crystal violet. Error bars represent SEM. (b) Representative image of cell spreading after 120 minutes. Scale bars: 5 mm.Click here for fileFigure showing that focal adhesion kinase (FAK)-ablated tumours show reduced levels of tyrosine phosphorylated p130Cas and Paxillin. (a) Lysates from FAKwt/wt and FAKflx/flx/MMTV-NIC end-stage mammary tumours were immunoblotted for the indicated proteins. Data are from 10 animals of each genotype. \u03b2-actin was used as loading control. (b) Quantification using ImageJ software of the immunoblots shown in (a) for total p130Cas and Paxillin, normalized to cytokeratin 8 (CK8) . P < 0.05 vs. FAKwt/wt mice, Student's t-test. (c) Quantification using ImageJ software of phosphorylation levels for the indicated proteins relative to total protein from the immunoblots shown in (a), normalized to CK8 . P < 0.05 vs. FAKwt/wt mice, Student's t-test.Click here for fileFigure showing that S5 Pyk2 is still overexpressed and associated with p130Cas in focal adhesion kinase (FAK)-deleted tumours. (a) Pyk2 expression was determined by immunoblotting tumour lysates from FAKwt/wt and FAKflx/flx mouse mammary tumour virus (MMTV)-NIC tumours. \u03b2-actin was used as a loading control. Data are representative of at least 10 animals of each genotype. (b) Quantification using ImageJ software of the immunoblots shown in (a) for total Pyk2 expression, normalized to \u03b2-actin. (c) Pyk2 and ErbB2 expression in both adjacent and tumour epithelia was evaluated by immunoblot analyses with Pyk2- and ErbB2-specific antisera. \u03b2-actin was used as a loading control. (d) Upper: lysates from FAKwt/wt and FAKflx/flx/MMTV-NIC end-stage mammary tumours were immunoprecipitated with anti-Pyk2 (left) and anti-p130Cas (right) antibodies (n = 3). Immunoprecipitates were immunobloted with phosphotyrosine, Pyk2 and p130Cas antibodies. Lower: the bar graphs show Pyk2 phosphorylation relative to levels in FAKwt/wt from the immunoprecipitation with anti-Pyk2 (left) and Pyk2 interaction with p130Cas relative to levels in FAKwt/wt from the immunoprecipitation with anti-p130Cas (right). No significant differences were observed (unpaired Student t-test).Click here for file"}
+{"text": "Dickeya (formerly Erwinia chrysanthemi) species cause diseases on a wide range of crops and ornamental plants worldwide. Here we present the draft sequences of 17 Dickeya isolates spanning four Dickeya species, including five isolates that are currently unassigned to a species. Dickeya genus (previously Erwinia chrysanthemi) of phytopathogenic bacteria cause disease in a wide range of plant species, including crops, worldwide , D.\u00a0zeae strain Ech586 (accession no. NC_013592), D.\u00a0chrysanthemi strain Ech1591 (accession no. NC_012912), and D.\u00a0dadantii strain Ech3937 (accession no. NC_014500), along with a draft D.\u00a0zeae strain sequence, have been deposited in GenBank.Species of the orldwide . The Dicadisiaca , 3 and t.\u00a0solani . Draft gescribed , and fouDickeya, including isolates of D.\u00a0dadantii, D.\u00a0chrysanthemi, D.\u00a0zeae, and D. paradisiaca and five isolates currently unassigned to a species ; former D.\u00a0dadantii subspecies dieffenbachiae type strain NCPPB 2976, isolated from dieffenbachia (United States); D. dadantii NCPPB 3537, isolated from potato (Peru); D.\u00a0chrysanthemi type strain NCPPB 402, isolated from chrysanthemum (United States); D.\u00a0chrysanthemi biovar parthenii NCPPB 516, from Parthenium argentatum (Denmark); D. chrysanthemi NCPPB 3533, isolated from potato (United States); D.\u00a0zeae CSL RW192, isolated from river water (England); D. zeae MK19, isolated from river water (Scotland); the D.\u00a0zeae phylotype II type strain NCPPB 2538, isolated from maize (United States); D. zeae NCPPB 3531 and NCPPB 3532, both isolated from potato ; and D.\u00a0paradisiaca type strain NCPPB 2511, isolated from plantain (Colombia). The five isolates with unassigned species are CSL RW240/1 from river water (England), DW0440 from river water (Finland), MK7 from river water (Scotland), NCPPB 569 from sugarcane , and NCPPB 3274 from Aglaonema (St. Lucia).We announce draft genome sequences of 17 isolates of species . The 12 T and NCPPB 2511T were sequenced using paired-end libraries, and the remaining isolates were sequenced using single-end libraries. Sequences of nine strains  were assembled de novo using 454 Life Sciences NEWBLER v2.5.3; meta-assemblies of NEWBLER de novo and reference-guided assemblies to the above-named sequences from GenBank were used for NCPPB 516 and NCPPB 3533 (to accession no. NC_012912); NCPPB 2511T (to accession no. NC_012880); NCPPB 569, NCPPB 898T, NCPPB 3274, and NCPPB 3537 (to accession no. NC_014500); and NCPPB 3532 (to accession no. NC_013592).All strains were sequenced using 454 pyrosequencing . Isolates NCPPB 402Dickeya sequences , AONW00000000 (NCPPB 3532), AONY00000000 (CSL RW192), AONZ00000000 (CSL RW240), AOOA00000000 (NCPPB 402T), AOOC00000000 (NCPPB 516), AOOD00000000 (NCPPB 569), AOOE00000000 (NCPPB 898T), AOOF00000000 (NCPPB 2538T), AOOG00000000 (NCPPB 2976T), AOOH00000000 (NCPPB 3274), AOOI00000000 (NCPPB 3531), AOOJ00000000 (NCPPB 3533), AOOL00000000 (NCPPB 3537), AOON00000000 (DW0440), AOOO00000000 (MK7), and AOOR00000000 (MK19).The draft sequences of these"}
+{"text": "Drosophila antennal lobe reveals the complexity of lineage development and Notch signaling in cell fate specification.A high-resolution neuronal lineage analysis in the  Drosophila lateral antennal lobe (lAL) neuronal lineage. Single-cell mapping of the lAL lineage by twin-spot mosaic analysis with repressible cell markers (ts-MARCM) revealed that projection neurons (PNs) and local interneurons (LNs) are made in pairs through binary fate decisions. Forty-five types of PNs innervating distinct brain regions arise in a stereotyped sequence; however, the PNs with similar morphologies are not necessarily born in a contiguous window. The LNs are morphologically less diverse than the PNs, and the sequential morphogenetic changes in the two pairs occur independently. Sanpodo-dependent Notch activity promotes and patterns the LN fates. By contrast, Notch diversifies PN temporal fates in a Sanpodo-dispensable manner. These pleiotropic Notch actions underlie the differential temporal fate specification of twin neurons produced by common precursors within a lineage, possibly by modulating postmitotic neurons' responses to Notch-independent transcriptional cascades.Binary cell fate decisions allow the production of distinct sister neurons from an intermediate precursor. Neurons are further diversified based on the birth order of intermediate precursors. Here we examined the interplay between binary cell fate and birth-order-dependent temporal fate in the  Drosophila brain develops from a limited number of neural stem cells that produce a series of ganglion mother cells (GMCs) that divide once to produce a pair of neurons in a defined order, termed a neuronal lineage. Here, we provide a detailed lineage map for the neurons derived from the Drosophila lateral antennal lobe (lAL) neuroblast. The lAL lineage consists of two distinct hemilineages, generated through differential Notch signaling in the two GMC daughters, to produce one projection neuron (PN) paired with a local interneuron (LN). Both hemilineages yield distinct cell types in the same sequence, although the temporal identity (birth-order-dependent fate) changes are regulated independently between projection neurons and local interneurons, such that a series of analogous local interneurons may co-derive with different projection neurons and vice versa. We also find that Notch signaling can transform a class of nonantennal lobe projection neurons into antennal lobe projection neurons. These findings suggest that Notch signaling not only modulates temporal fate but itself plays a role in the distinction of antennal lobe versus nonantennal lobe neurons.The  Drosophila melanogaster has a relatively tractable neural development, study of which has revealed multiple mechanisms that act in sequence to diversify neuron fates The computing power of a brain is rooted in its complex neural network, composed of numerous types of neurons. Understanding how diverse neurons are specified is fundamental for elucidating how such an intricate organ develops and evolves from simple to higher organisms. Drosophila central nervous system (CNS) arise from a stereotyped set of neural progenitors called neuroblasts (NBs) Neurons in the Drosophila embryonic NB lineage 5\u20136 have demonstrated that lineage determinants and temporal fating factors do not simply work additively to specify a final neuron fate. Instead, lineage identity genes may refine neuronal temporal fates by subdividing the temporal window defined by a single temporal identity factor into multiple subdomains with distinct transcriptional outputs Although much has been learned about each of the neuronal diversification processes, scientists have just begun to elucidate how these serial fating mechanisms are integrated to determine a neuron's terminal fate. A combinatorial expression of various transcription factors may confer lineage identity based on where the NBs originate in early embryos Drosophila neuronal lineages. However, many CNS lineages exist as a lone hemilineage because one entire hemilineage has undergone premature cell death Notch/Numb has been shown to specify A/B binary cell fates of twin neurons derived from a GMC spdo-independent role of Notch in specifying a set of temporal fates in the PN hemilineage. Despite the complex binary and temporal fate transformations, Notch mutant clones maintained the normal dynamic expressions of Chronologically inappropriate morphogenesis (Chinmo) chinmo expression, loss of Chinmo affected PN and LN temporal fates in hemilineage-dependent manners, arguing that Notch acts downstream of temporal fating factors to modulate neuronal temporal fates. Taken together, we established the Drosophila lAL lineage as a model system for studying the origin-dependent neuron fate specification and demonstrated that Notch not only underlies binary cell fate decision but also determines temporal fates in both Notch-high and Notch-low sister neurons.Here we determined the twin neurons made by each GMC of the larval lAL lineage, using twin-spot mosaic analysis with repressible cell markers (ts-MARCM) that permits labeling of sister clones  derived from a common precursor  in distinct colors nSyb-GAL4 revealed neuronal cell bodies packed along the lateral border of the AL. They elaborate densely in the antennal lobe (AL) and the neighboring antennal mechanosensory and motor center (AMMC)  lineage yields about 200 neurons during larval neurogenesis r (AMMC)  and furtr (AMMC) . It is nnSyb-GAL4. We determined ganglion mother cell (GMC) progeny born in 2-h windows throughout larval development . We identified lAL GMC clones based on cell body positions and neurite trajectory patterns that match the lAL NB clones generated at various time points (unpublished data). Except near the lineage end (see below), both daughter neurons derived from each lAL GMC survived into the adult stage. Notably, one projection neuron (PN) consistently paired with one local interneuron (LN). They exist as twin clones when differentially labeled by ts-MARCM , unilateral PN (unPN), bilateral PN (biPN), AMMC PN, and suboesophageal ganglion (SOG) PN . mPNs coIn addition to the AL PNs, we obtained 16 types of AMMC neurons and three types of SOG neurons that may account for the AMMC and SOG elaborations seen in the lAL NB clones . Most ofIn sum, the lAL NB yields not only AL PNs but also AMMC and SOG neurons, which may contribute to distinct neural circuits (see Discussion). Does the GMC birth order guide the derivation of these multiclass neurons one group by another along the Notch-off hemilineage of the complex lAL pedigree The twin single-cell clones collected for this study were induced in discrete 2-h windows to sample neurons born at different times from larval hatching to puparium formation. Notably, distinct lAL PNs were preferentially hit at different developmental times. To deduce their possible birth order, we attempted to arrange the identified lAL PN types chronologically based on when their precursors are susceptible to mitotic recombination. We first determined the primary window(s) of susceptibility for each lAL PN type (shaded boxes in GAL4-GH146-labeled NB clones (GAL4-GH146 (unpublished data). Ignoring those gaps, we derived the following birth sequence for the 12 types of lAL mPNs: VA4-VC2-VC1-DM1-DM2-VA5-VA7m-DA1-DL3-DA1-VM1-DA2-DM4. The same birth order was obtained from the analysis of nSyb-GAL4-labeled single-cell clones  whose distinction depends on the LN diversity, we refined the PN grouping and determined the subgroups' windows of production. We found that DA1/lavish, DA1/patchy, and DL3/patchy are born earlier in a contiguous sequence and that DL3/sparse and DA1/sparse are born later in separate windows . When thThe pan-AL LNs paired with distinct PNs are morphologically indistinguishable from one another. They show analogous electrophysiological profiles Using the glomerular innervation frequencies to represent the LNs associated with a particular PN type and arranging them chronologically based on the deduced PN birth order revealed that the PN and LN hemilineages alter temporal identity independently. The PN hemilineage is longer and yields many more morphologically distinct neurons than the LN hemilineage. In addition, contrasting with PNs that arise in a rather complex sequence, the four LN classes are produced roughly in the order of pan-AL\u2192lavish\u2192patchy\u2192sparse  and 5E. The independent PN/LN temporal fate specification is further evidenced by two unilateral PN fate duplications. The DA1 and DL3 mPNs were initially made at 46 to 58 h after larval hatching (ALH) paired with lavish or patch LNs. After that, the lAL NB switched to produce AMMC PNs paired with various LNs. Notably, around 70 to 84 h ALH, the lAL lineage yielded additional DL3 and DA1 mPNs in reverse birth-order and associated with sparse LNs ,AF,AI. TIt is hard to image how the temporal fates of twin neurons can be differentially patterned, given that neuronal temporal identities are presumably conferred in the precursors by a set of sequentially and transiently expressed transcription factors spdo mutant lAL NB clones. We selectively marked the 12 types of mPNs, born in multiple clusters from 18 to 96 h ALH, with GAL4-GH146. We further checked distinct populations of AMMC neurons using GAL4-GR20C03 and GAL4-GR72G12. We found that the spdo mutant lAL NB clones, labeled with any of the three GAL4 drivers, show wild-type morphologies but carry two times more cell bodies  exhibited abnormal PN compositions. Labeling entire clones with nSyb-GAL4 revealed missing of the AMMC neurite tracks specifically in the notch or Su(H) mutant NB clones (Su(H) clones were comparable. Moreover, they carried analogous numbers of mitotic cells (notch and Su(H) mutant clones have made GMCs that yield viable neurons in correct numbers and at right timings, making us wonder if the prospective AMMC neurons have adopted other PN fates and acquired non-AMMC neurite trajectories. Given the prominence of AL neuronal elaborations in those clones lacking AMMC trajectories, we examined if the notch and Su(H) mutant NB clones carry many more AL PNs at the expense of AMMC neurons. We found that notch mutant lAL NB clones contain about five times more GH146-positive AL neurons than wild-type controls  mutant clones (Su(H) mutant clones (notch or Su(H). These observations suggest that the prospective AMMC neurons of notch/Su(H) mutant clones might have aberrantly adopted the AL PN fates characteristic of siblings born at different times, reminiscent of some temporal cell fate transformation.In contrast with the faithful duplication of diverse PNs in the B clones . There wic cells  as reveacontrols . A threet clones . Note tht clones , indicatnotch mutant lAL NB. We fed the larvae harboring GAL4-GH146-labeled wild-type or notch clones with EdU, a thymidine analog that labels proliferating cells, for 1 d at 0\u201324, 24\u201348, or 48\u201372 h ALH   . We concGAL4-GH146 to monitor the orderly production of the 12 types of mPNs with ts-MARCM, we demonstrated the requirement of Chinmo for proper specification of the VC2, VC1, DM1, and DM2 temporal fates (chinmo mutant LN of the VC2 mPNs (LN2) has adopted the fate of LN3 (the twin LN of the VC1 mPN) rather than the fate of LN6 (the twin LN of the VA5 mPN)  . CompareVA5 mPN) , the proborn LN3 . The traborn LN3 , althougmPN fate . We did chinmo as a temporal fating factor in the lAL lineage. Notably, the Notch-independent dynamic expression of Chinmo governs LN and PN temporal fates in hemilineage-specific  manners, arguing that Notch acts in parallel with or downstream of temporal fating factors to determine terminal temporal fates  neurons as well as neurons that innervate other brain regions, and exemplifies how diverse neurons of different classes can derive from a common progenitor. The lAL neuroblast (NB) gives rise to a rather heterogeneous population of neurons, which is achieved through the derivation of two distinct hemilineages that yield projection neurons (PNs) and local interneurons (LNs), respectively. The LN hemilineage produces LNs exclusively for the AL, while the PN hemilineage generates not only AL PNs but also PNs of the antennal mechanosensory and motor center (AMMC) and suboesophageal ganglion (SOG). Furthermore, the paired hemilineages yield diverse PNs and LNs concurrently but in distinct temporal patterns. Various neurons of different LN classes are made one class after another. By contrast, distinct PNs arise in a complex intercalated sequence. Given that most Drosophila neuronal lineages  consist of two distinct hemilineages or exist as a lone hemilineage Drosophila brain development.Detailed analysis of the lateral antennal lobe (lAL) lineage attests to the stereotypy of clonal development in the sanpodo (spdo) mutant clones, we confirm that the lAL lineage is made up of a Notch-high LN hemilineage and a Notch-low PN hemilineage. Despite their derivation from common GMCs, PNs and LNs undergo temporal fate changes independently. The lAL PNs exhibit higher cellular diversity and thus alter their temporal fates more frequently than their LN sibs do. However, there are also developmental periods when one LN interclass fate switch consistently occurs during the continuous production of a particular PN type. Notably, knocking down spdo through the lAL lineage development has resulted in duplication of the entire PN hemilineage. This indicates that the prospective LNs have been transformed into PNs with correct PN temporal fates. It argues that twin neurons are born with identical temporal fating factors and that the Spdo-dependent Notch activity has not only promoted the LN fate but also governed the birth time/order-dependent neuronal diversification in the LN hemilineage.Interestingly, Notch governs hemilineage identity and further patterns the hemilineage-characteristic temporal fate changes. By lineage mapping using ts-MARCM and through analysis of Notch or Su(H), but not spdo, mutant lAL NB clones, the prospective AMMC neurons aberrantly adopted various AL PN fates. Diverse AMMC neurons and distinct AL PNs normally arise in alternative blocks. Regardless of the AMMC-to-AL fate transformation, the overall temporal patterning appeared intact in the AMMC-lacking PN hemilineages as evidenced by comparable increases in the AL PNs of various types  that connect a single glomerulus of the AL to mushroom body (MB) calyx and lateral horn (LH) In sum, the lAL NB makes multiple classes of diverse neurons in a complex yet stereotyped pattern, manifested as a series of LN/PN pairs and orchestrated through distinct Notch activities. The Spdo-dependent Notch action that occurs in the Numb-negative offspring has not only conferred the LN fate but also patterned the LN temporal identities. A novel Spdo-independent Notch action is further utilized to increase the PN temporal fates by promoting AMMC neuronal fates in otherwise AL PNs. Both Notch-mediated temporal fate regulations are apparently executed after proper deployment of temporal fating factors. Taken together, Notch plays integral roles in the derivation of final neuronal temporal cell fates.GAL4-GH146asense-GAL4; (3) FRT19A,notch[55e11],UAS-mCD8::GFP; (4) FRT40A,UAS-mCD8::GFP,UAS-rCD2i,Chinmo[1],GAL4-GH146/CyO; (5) hs-FLP[1];FRT40A,UAS-rCD2::RFP,UAS-GFPi; (6) FRT40A,UAS-mCD8::GFP,UAS-rCD2i;nSyb-GAL4(2-1); (7) FRT82B,spdo[27]/TM6B; (8) 40A,Su(H)[delta 47]/CyOFRT19A,hs-FLP[122],tubp-GAL80;GAL4-GH146; (10) FRT19A,hs-FLP[1];nSyb-GAL4; (11) hs-FLP[1];GAL4-GH146;FRT82B,tubp-GAL80; (12) hs-FLP[1];FRT82B,UAS-rCD2::RFP-UAS-GFPi; and (13) FRT82B,spdo[27],UAS-mCD8::GFP-UAS-rCD2i.The fly strains used in this study include (1) nSyb-GAL4. In such cases, confocal images of the brains containing clones of the same neuron type were carefully compared stack by stack to determine the background clones. The brain with the least background was chosen and the background clones were manually masked to reveal the clone of interest.Larvae 0\u20132 h old with proper genotype were collected and put into vials  containing standard fly food. The larvae were raised at 25\u00b0C until desired stages. To induce clones, the larvae were heat-shocked at 37\u00b0C for 15\u201340 min. After heat shock, the larvae were put back to 25\u00b0C until dissection at desired stages. Only male flies were dissected for the detailed lineage analysis of the lAL neurons. Because background olfactory receptor neuron (ORN) clones often interfered with the lAL clones in the antennal lobe, we removed antennae 1 d after adult eclosion and waited for 3 d for the ORN axons to degenerate before brain dissection. For the ts-MARCM clones in FRT19A,notch[1],UAS-mCD8::GFP/hs-FLP[122],FRT19A,tubp-GAL80;GAL4-GH146,UAS-mCD8::GFP/CyO or FRT19A,UAS-mCD8::GFP/hs-FLP[122],FRT19A,tubp-GAL80;GAL4-GH146,UAS-mCD8::GFP/CyO were heat-shocked at 37\u00b0C for 1 h to induce MARCM clones. To feed the larvae EdU at 0\u201324 h ALH, the larvae were transferred into vials  containing standard fly food with 100 \u00b5g/ml EdU (Invitrogen) for 24 h at 25\u00b0C, and then transferred into vials  with standard fly food only until adult eclosion. To feed the larvae EdU at 24\u201348 h or 48\u201372 h ALH, the larvae, after heat-shock, were transferred into vials  containing standard fly food for 24 h or 48 h at 25\u00b0C. The larvae were then transferred into vials  containing standard fly food with 100 \u00b5g/ml EdU for 24 h at 25\u00b0C. After the EdU feeding, the larvae were transferred back to the vials with standard fly food and raised at 25\u00b0C until adult eclosion. The adult brains were dissected in 1\u00d7 Phosphate buffered saline (PBS) and stained for EdU using Click-iT EdU Alexa Fluor 555 Imaging Kit (Invitrogen). After the EdU staining, the brains were washed three times by 1\u00d7 PBS with 0.75% Triton X-100  for 15 min each. The brains were then incubated with rabbit anti-GFP Ab  and mouse nc82 mAb  at 4\u00b0C overnight. Next day, the brains were washed with 0.75% PBT three times for 15 min each and incubated with Alexa 488-conjugated goat anti-rabbit  and Cy5-conjugated goat anti-mouse secondary antibodies  at 4\u00b0C overnight. Next day, the brains were washed with 0.75% PBT three times for 15 min each before mounted using SlowFade gold anti-fade reagent (Invitrogen).Larvae 0\u20132 h old with the genotype of Fly brains were dissected in 1\u00d7 PBS, fixed in 1\u00d7 PBS with 4% formaldehyde (Fisher Scientific) at room temperature for 20 min, washed by 1\u00d7 PBS with 0.75% Triton X-100  three times for 15 min each, and incubated in 1\u00d7 PBS with 0.5% goat normal serum (Jackson ImmunoResearch) for 30 min before incubation with primary antibodies at 4\u00b0C overnight. Next day, the brains were washed in 0.75% PBT three times for 15 min each before incubated with secondary antibodies at 4\u00b0C overnight. Next day, the brains were washed with 0.75% PBT for 15 min for three times and mounted using SlowFade gold anti-fade reagent (Invitrogen). The immunofluorescent signals were collected by Zeiss LSM confocal microscope and processed using Fiji and Adobe Photoshop. Primary antibodies used in this study include rat anti-mCD8 mAb , mouse nc82 mAb , rabbit anti-Dsred , mouse anti-Br-C (core) , rabbit anti-Chinmo  Figure S1The projectome of lAL PNs. Schematic illustration of lAL PNs (arrows) and their projections among various brain regions. The directions of arrows indicate putative information flow from dendrites to axonal terminals. The mPNs, unPNs, and biPNs (labeled in green) have dendritic arborization in the AL, probably involved in olfactory circuit (green). The AMMC PNs (labeled in blue) possibly contribute to the auditory/gravity-sensing neural network (blue). The SOG PNs (labeled in gray) are likely involved in the gustatory neural circuit (gray). The PLP receives many inputs from the AL and thus might be another odor information-processing center besides the MB calyx (Ca) and lateral horn (LH). In addition, the IVLP receives inputs from AL as well as AMMC and potentially integrates olfactory and auditory/gravity information. AL, antennal lobe; cAL, contralateral AL; PLP, posteriorlateral protocerebrum; PVLP, posterior ventrolateral protocerebrum; cPVLP, contralateral posterior ventrolateral protocerebrum; SOG, suboesophageal ganglion; IB, inferior bridge; Ca, mushroom body calyx; LH, lateral horn; AMMC, antennal mechanosensory and motor center; cAMMC, contralateral antennal mechanosensory and motor center; IVLP, inferior ventrolateral protocerebrum; cIVLP, contralateral inferior ventrolateral protocerebrum; SMP, superior medial protocerebrum; CRE, crepine.(TIF)Click here for additional data file.Table S1The description of the lateral antennal lobe neurons. The different zones in AMMC and their corresponding sensory inputs were identified based on Kamikouchi et al. (TIF)Click here for additional data file.Table S2spdo, and Su(H) lAL clones at 30 h and 70 h ALH.The average number of PH3-positive cells and percentage of PH3-positive neuroblasts (NBs) in wild-type (WT), (TIF)Click here for additional data file."}
+{"text": "The s908 mutation leads to a leucine to arginine substitution in the ectodomain of the hepatocyte growth factor (HGF) tyrosine kinase receptor, Met. This missense mutation impedes the proteolytic maturation of the receptor, its trafficking to the plasma membrane, and diminishes the phospho-activation of its kinase domain. Interestingly, during pancreatogenesis, met and its hgf ligands are expressed in pancreatic epithelia and mesenchyme, respectively. Although Met signaling elicits mitogenic and migratory responses in varied contexts, normal proliferation rates in donut mutant pancreata together with dysmorphic, mislocalized ductal cells suggest that met primarily functions motogenically in pancreatic tail formation. Treatment with PI3K and STAT3 inhibitors, but not with MAPK inhibitors, phenocopies the donut pancreatic defect, further indicating that Met signals through migratory pathways during pancreas development. Chimera analyses showed that Met-deficient cells were excluded from the duct, but not acinar, compartment in the pancreatic tail. Conversely, wild-type intrapancreatic duct and \u201ctip cells\u201d at the leading edge of the growing pancreas rescued the donut phenotype. Altogether, these results reveal a novel and essential role for HGF signaling in the intrapancreatic ducts during exocrine morphogenesis.In a forward genetic screen for regulators of pancreas development in zebrafish, we identified  donut because the body of the pancreas fails to elongate and thus remains rounded. The mutation leading to this phenotype affects the extracellular domain of Met, the hepatocyte growth factor (HGF) receptor, impairing its maturation, plasma membrane localization and phospho-activation. Although HGF/Met signaling may elicit many context-dependant cellular responses, our data indicate that HGF/Met signaling triggers the migration, but not the proliferation, of the pancreatic ductal cells to drive the extension of the pancreatic tail.The pancreas functions as an endocrine and exocrine gland that secretes hormones regulating blood glucose homeostasis, and pancreatic juice that aids the digestion and absorption of nutrients, respectively. Contrary to endocrine tissue development, that of the exocrine pancreas has received less attention. We conducted a forward genetic screen in zebrafish and identified HGF/Met signaling as a key regulator of exocrine development. We called the mutant  The vertebrate pancreas is an endodermal organ that is part endocrine, releasing hormones that regulate glucose metabolism, and part exocrine, releasing pancreatic juices that aid in digestion. Pancreatic endocrine and exocrine developmental dysmorphogenesis and dysregulation, including diabetes mellitus and pancreatic adenocarcinoma, can result in human diseases with high morbidity and mortality. Thus, a more sophisticated understanding of molecular mechanisms mediating pancreatic development and homeostasis will certainly refine the treatment of these diseases.In zebrafish as in mammals, all pancreatic endocrine and exocrine tissues derive from the fusion of a dorsal and ventral bud arising at the level of somites 2\u20139 Hepatocyte Growth Factor (HGF) is a stromally-produced ligand which binds Met, a receptor tyrosine kinase that is predominantly expressed in epithelia. Upon receptor dimerization and autophosphorylation, Met activates a bevy of cellular processes including motogenesis, tubulogenesis, mitosis, chemotaxis, and cell survival 2-color liver, insulin, exocrine pancreas) zebrafish with EGFP-expressing pancreatic acinar cells and DsRed-expressing pancreatic beta-cells and hepatocytes s908donut mutants, which show shortened (type 1) or absent (type 2) exocrine pancreatic (xp) tails. jh1Tg(ptf1a:GFP)s908donut background to reveal the short exocrine pancreas phenotype at 3 days post fertilization  domain in the Met ectodomain, which together with IPT4 comprises a high affinity HGF binding site . We found that even low doses of metMO (2 ng) could reproduce the shortened pancreatic tail phenotype observed in donut mutants with high penetrance (s908+/\u2212donut embryos were injected with a near-threshold (1 ng) dose of MO, 53.4% displayed a short pancreas phenotype, as compared to 29.1% of injected wild-type embryos  also developed shortened pancreata , during (52 hpf), and after its caudal extension  between 52 and 80 hpf :GFP) line (hereafter duct:GFP) which highlights the intrapancreatic ducts (IPDs) met was expressed in both IPD and acinar cells at 60 hpf, a time of active pancreatic tail extension . Alternately, residual Met protein, which is expressed in endoderm prior to the onset of Pdx1 expression, or a parallel/redundant mechanism could drive exocrine outgrowth in mammals. Additional targeted studies are needed in mice to determine whether the role of Met in exocrine pancreas growth is conserved.To clarify how HGF signaling is implemented in pancreatogenesis, we examined the expression of  anlagen . Additio 80 hpf; . We found 80 hpf . Importat 75 hpf , indicatxtension . A role donut mutation affects Met function, we generated an I776R point mutation in murine Met, an analogous lesion to the s908donut mutation, and then transfected either WTMet or I776RMet into TOV112D cells. This cell line lacks endogenous Met activity, but expresses the intracellular components of the Met signaling pathway WT, most of the nascent polypeptide was cleaved to the mature form (150 kDa+30 kDa), while a small proportion of the receptor remained unprocessed (190 kDa). Since the I776R lesion lies far from the furin cleavage site (residues 302\u2013307) I776R precursor polypeptide failed to be cleaved (R306A) can signal normally WT and MetI776R using specific anti-phosphorylated Met antibodies directed against several key tyrosine residues. Upon HGF binding, Met dimerizes and its cytoplasmic catalytic region is activated by trans-phosphorylation of tyrosines Y1234 and Y1235. Subsequently, residues Y1349 and Y1356 are phosphorylated in the Met multifunctional docking site, which connects Met to multiple downstream branches, including Ras/MAPK and PI3K, through several adapter proteins. In addition, phosphorylation of tyrosine Y1003 negatively regulates Met signaling by promoting receptor turnover. Compared to MetWT, phosphorylation of Y1234-5, Y1349, and Y1003 were significantly diminished in MetI776R . Antibody staining was evident at the membrane of unfixed, unpermeabilized HEK293T cells expressing MetWT or cleavage incompetent MetR306A, but not MetI776R . Together, these data support the hypothesis that deficient signaling through MetL775R causes the hypomorphic effect observed in s908donut mutants. Likely, reduced Met signaling is due to (1) localization of MetL775R away from the plasma membrane, (2) impaired binding of HGF to the high-affinity binding site in IPT3-4, and/or (3) impaired assembly of Met co-receptor moieties, that would then lead to defective phospho-activation of Met.To model how the MetI776R . FinallyMetI776R . HoweverMetI776R . Thus, ta stages . As obsedonut mutants, we first assayed cell proliferation using 30 min incorporation of the thymidine analog EdU at two time points during pancreatic tail growth: 56 and 75 hpf  and metMO-injected  (see Methods) embryos were directed toward an endodermal fate by cas mRNA coinjection ptf1a:GFP+ acinar or ptf1a:GFP\u2212 ductal cell compartments in the distal or proximal portion of the exocrine pancreas  hosts (data not shown). Next, we assessed the rescue of exocrine pancreatic tail outgrowth by transplanting varying numbers of WT Tg(hs:mCherry) cells into the endoderm of metMO-injected hosts s892Tg(ins:CFP-NTR)m1018Tg(ins:dsRed)ia3Tg(nkx2.2a(-3.5 kb):GFP) (a.k.a. \u201cduct:GFP\u201d) jh1Tg(ptf1a:eGFP)Tg line (a.k.a. Tg(hs:mCherry)), H2B-GFP was replaced in the plasmid hsp70l:loxP-mCherry-loxP-H2B-GFP-cryaa:CeruleanFish were raised and maintained under standard conditions donut mutant embryos. donut mutants were subsequently genotyped using a dCAPS strategy: a PCR product amplified by the primer set: 5\u2032-TCCAG CCCAA ACATT CTTTC and 5\u2032- CGTTT GTGTG GGTTG TATAG ACTCA CCACT TGGAA GAGTT TGCCC TCAGT GGCGG CAGcG was digested with HhaI.An ENU mutagenesis screen was executed as described Pymol software (Schr\u00f6dinger) was used to manipulate the PDB model of human IPT1-4 in situ hybridization, and proliferation analysis with EdU were performed as described in situ hybridizations were performed as described met: CGGAG AGAGA GGGAG GAAG and TAATA CGACT CACTA TAGGG AGACA TTGAT GTCCG TGATG GAG; hgfa: TGTGT GCTTG AGAAA GAGAG AGA and TAATA CGACT CACTA TAGGG AGATC GACAA ATTGC CACGA TAA; hgfb: AGCCA CTGCA GGGAG ACTAC and TAATA CGACT CACTA TAGGG AGAGG GGTAC CTTTT AGGGT GGA; furina: GTGTC GGAGT GGCCT ACAAT and TAATA CGACT CACTA TAGGG AGGGT CTTCA TCCCA GGAGT; furinb: TGACC TGGAG AGACA TGCAG and TAATA CGACT CACTA TAGGG AATGC TGGGG GATTT TCTCT. For cytoimmunofluorescence, human embryonic kidney cells (HEK293T) were maintained in DMEM supplemented with 10% FBS. HEK293T cells were plated on polylysine-coated coverslips and transfected with lipofectamine with either murine pBabe-puro-MetWT (Addgene) or site directed mutagenesis-generated pBabe-puro-MetI776R. Cells were transfected 48 h before immunostaining: unfixed cells, as well as 4% paraformaldehyde-fixed and 0.1% Triton-permeabilized cells were incubated with indicated antibodies for 2 hours prior to incubation with appropriate fluorescent secondary antibodies.Whole mount antibody staining, WT and MetI776R were transfected into TOV112D cells with lipofectamine. Coimmunoprecipitations and protein blot analyses were performed as previously described TOV112D human ovarian carcinoma cells were obtained from ATCC  and cultured using a 1\u22361 mixture of MCDB 105 medium and medium 199 supplemented with 15% FBS. Metia3; Tg(ptf1a:dsRed)jh1Tg(nkx2.2a(-3.5 kb):GFP) embryos, distributed in 12-well plates (20 embryos per well), were incubated with different chemicals from 60 to 76 hpf, during the growth of the pancreatic tail. Chemicals were specific inhibitors of MEK , p38MAPK , PI3K , Src kinase  and furin .in vitro, by kit (Ambion), and 150 pg of mRNA was injected. Live imaging of embryos was performed 5 hours post-injection. For transplantation, capped cas/sox32in vitro, and donor Tg embryos, which exhibit strong, ubiquitous RFP expression in the absence of Cre recombinase, were injected with 200 pg of cas mRNA alone or with 4 ng of met morpholino. Cell transplantations were performed as described cas-injected putative met mutant cells were transplanted, donors were genotyped after transplantation.The morpholinos (Gene Tools) used for gene knockdown were described in Figure S1donut mutants variably lack muscle tone in pectoral fins. (A\u2013C) 9 dpf Tg(ptf1a:GFP) larvae imaged from the dorsal aspect to show fin morphology (arrows). In WT larvae, fins are folded closely against the body (A), while in type 1 (B) and type 2 (C) donut mutant larvae, the pectoral fins lack tone, and display an open wing configuration. Bar\u200a=\u200a0.5 mm.(TIF)Click here for additional data file.Figure S2s908donut sensitizes embryos injected with met morpholino. Clutches resulting from donut heterozygote to WT crosses were injected with 1 ng of metMO and scored for pancreatic morphology. Embryos presenting type 1 and 2 phenotypes were pooled separately from WT clutchmates, and were retrospectively genotyped. Penetrance of short pancreas was increased from 29.1% in WT embryos to 53.4% in heterozygotes. Significance determined using 2-sided Chi squared test, p\u200a=\u200a0.0002.Heterozygosity for (TIF)Click here for additional data file.Figure S3furina and furinb expression during pancreatogenesis by whole-mount in situ hybridization. Both furina and furinb are expressed in endoderm (brackets); furina is expressed in liver (Li) and pancreas (Pa) at 75 hpf. Dorsal views, anterior to the top.(TIF)Click here for additional data file.Figure S4hgfMO-injected larvae. (A\u2013B) 84 hpf hgfMO-injected host larvae with a high contribution of transplanted WT endodermal cells (red). Extensive contribution of WT cells to both duct and acinar compartments did not rescue type 1 (A) or type 2 (B) exocrine pancreas tail outgrowth.WT endoderm cannot rescue exocrine tail formation in (TIF)Click here for additional data file."}
+{"text": "Hypocrea/Trichoderma.Mycoparasitism, a lifestyle where one fungus is parasitic on another fungus, has special relevance when the prey is a plant pathogen, providing a strategy for biological control of pests for plant protection. Probably, the most studied biocontrol agents are species of the genus Trichoderma atroviride (teleomorph Hypocrea atroviridis) and Trichoderma virens , and a comparison with Trichoderma reesei (teleomorph Hypocrea jecorina). These three Trichoderma species display a remarkable conservation of gene order (78 to 96%), and a lack of active mobile elements probably due to repeat-induced point mutation. Several gene families are expanded in the two mycoparasitic species relative to T. reesei or other ascomycetes, and are overrepresented in non-syntenic genome regions. A phylogenetic analysis shows that T. reesei and T. virens are derived relative to T. atroviride. The mycoparasitism-specific genes thus arose in a common Trichoderma ancestor but were subsequently lost in T. reesei.Here we report an analysis of the genome sequences of the two biocontrol species The data offer a better understanding of mycoparasitism, and thus enforce the development of improved biocontrol strains for efficient and environmentally friendly protection of plants. Hypocrea/Trichoderma, Trichoderma atroviride (Ta) and Trichoderma virens (Tv) - teleomorphs Hypocrea atroviridis and Hypocrea virens, respectively - being among the best mycoparasitic biocontrol agents used in agriculture ; 3 [DQ08724]; 4 [HM182969]; 5 [HM182984]; 6 [HM182965]; 7 [AF545565]; 8 [AF545517]; 16 [FJ442769]; 17 [AY391900]; 18 [FJ179608]; 19 [FJ442715]; 20 [FJ442771]; 21 [AY391945]; 22 [EU498358]; 23 [DQ834463]; 24 [FJ442725]; 25 [AF545508]; 26 [AY391919]; 27 [AF545557]; 28 [AF545542]; 29 [FJ442738]; 30 [AF545550]; 31 [AY391909]; 32 [AF545516]; 33 [AF545518]; 34 [AF545512]; 35 [AF545510]; 36 [AF545514]; 37 [AY391921]; 38 [AF545513]; 39 [AY391954]; 40 [AY391944]; 41 [AF545534]; 42 [AY391899]; 43 [AY391907]; 44 [AF545511]; 45 [AY391929]; 46 [AF545540]; 47 [AY391958]; 48 [AY391924]; 49 [AF545515]; 50 [AY391957]; 51 [AF545551]; 52 [AF545522]; 53 [FJ442714]; 54 [AF545509]; 55 [AY391959]; 56 [DQ087239]; 57 [AF545553]; 58 [AF545545]; 59 [DQ835518]; 60 [DQ835521]; 61 [DQ835462]; 62 [DQ835465]; 63 [DQ835522]; 64 [AF545560]; 65 [DQ835517]; 66 [DQ345348]; 67 [AF545520]; 68 [DQ835455]; 69 [AF545562]; 70 [AF545563]; 71 [DQ835453]; 72 [FJ179617]; 73 [DQ859031]; 74 [EU341809]; 75 [FJ179614]; 76 [DQ087238]; 77 [AF545564]; 78 [FJ179601]; 79 [FJ179606]; 80 [FJ179612]; 81 [FJ179616]; 82 [EU264004]; 83 [FJ150783]; 84 [FJ150767]; 85 [FJ150786]; 86 [EU883559]; 87 [FJ150785]; 88 [EU248602]; 89 [EU241505]; 90 [FJ442762]; 91 [FJ442741]; 92 [FJ442783]; 93 [EU341805]; 94 [FJ442723]; 95 [FJ442772]; 96 [EU2415023]; 97 [EU341801]; 98 [EU248600]; 99 [EU341808]; 100 [EU3418033]; 101 [EU2485942]; 102 [AF545519]; 103 [EU248603]; 104 [EU248607]; 105 [EU341806]; 106 [DQ086150]; 107 [DQ834460]; 108 [EU711362]; 109 [EU883557]; 110 [FJ150790].The species phylogram of Ta: Trichoderma atroviride; TE: transposable element; Tr: Trichoderma reesei; Tv: Trichoderma virens.CAZy: Carbohydrate-Active enZYmes; CBM: carbohydrate binding module; EST: expressed sequence tag; GH: glycosyl hydrolase; HET: heteroincompatibility; KEGG: Kyoto Encyclopedia of Genes and Genomes; KOG: clusters of eukaryotic orthologous groups; NRPS: non-ribosomal peptide synthase; PKS: polyketide synthase; RIP: repeat-induced point mutation; SSCP: small secreted cysteine-rich protein; CPK, IVG, BH, EM, SEB, CMK, and AHE contributed equally to this work as senior authors. AA, JC, MM, AS, and IVG performed global annotation and analysis, MZ and HS did the assembly, OC and CH finished the assembly, and EL and SL performed the genome and EST sequencing. SEB, AH-E, CMK and CPK designed the study, and coordinated and supervised the analysis; CPK drafted and submitted the paper. All other authors contributed research . All authors read and approved the final manuscript.T. reesei, T. virens and T. atrovirideComparative properties and gene inventory of . This file contains additional information on genomic properties and selected gene families from the three Trichoderma species comprising 19 tables. Table S1 summarizes the satellite sequences identified in the Trichoderma genomes and four other fungal genomes. Table S2 summarizes manually curated sequence alignments of transposable element families from the Trichoderma genomes. Table S3 lists the total number of CAZy families in Trichoderma and other fungi. Table S4 lists the glycoside hydrolase (GH) families in Trichoderma and other fungi. Table S5 lists the glycosyltransferase (GT) families in Trichoderma and other fungi. Table S6 lists the polysaccharide lyase (PL) families in Trichoderma and other fungi. Table S7 lists the carbohydrate esterase (CE) families in Trichoderma and other fungi. Table S8 lists the carbohydrate-binding module (CBM) families in Trichoderma and other fungi. Table S9 lists the NRPS, PKS and NRPS-PKS proteins in T. atroviride. Table S10 lists NRPS, PKS and NRPS-PKS proteins in T. virens. Table S11 lists the putative insecticidal toxins in Trichoderma. Table S12 lists the cytochrome P450 CYP4/CYP19/CYP26 class E proteins in Trichoderma. Table S13 lists the small-cysteine rich secreted protein from Trichoderma spp. Table S14 lists the most abundant PFAM domains in those genes that are unique to T. atroviride and T. virens and not present in T. reesei. Table S15 surveys the assembly statistics. Table S16 provides gene model support. Table S17 summarizes gene model statistics. Table S18 provides numbers of genes with functional annotation according to KOG, Gene Ontology, and KEGG classifications. Table S19 lists the largest KOG families responsible for metabolism.Click here for fileTrichoderma, methods used for genome sequencing, and legends for the figures in Additional file Additional information on selected gene groups of Click here for fileFigures that illustrate selected aspects of the main text. Figure S1 provides a phylogeny of Trichoderma NPRSs. Figure S2 compares the numbers of epoxide hydrolase genes in Trichoderma with that in other fungi. Figure S3 compares the codon usage in genes from syntenic and nonsyntenic regions of the genomes of Trichoderma reesei, T. atroviride and T. virens.Click here for file"}
+{"text": "Neutrophil gelatinase-associated lipocalin (NGAL), measured early after cardiac surgery, has been demonstrated to predict postoperative acute kidney injury (AKI). Fluid overload potentially masks a subsequent acute renal function loss through dilution of serum creatinine and maintenance of urine output just above AKI-defining criteria.We investigated the early postoperative value of NGAL versus that of simultaneously measured serum creatinine to predict subsequent fluid overload. We studied 100 adult cardiac surgery patients in the control arm of a RCT (NCT00672334). Severe postoperative fluid overload was defined as positive fluid balance >10% of preoperative body weight within 48 hours after surgery.Severe postoperative fluid overload was present in 5% of patients with a mean positive fluid balance of 15.8 \u00b1 9.5 l. At ICU admission, urine NGAL predicted severe fluid overload (AUC-ROC 0.82 (95% CI = 0.70 to 0.94)) (Figure Early NGAL-guided adjustments to fluid management may reduce organ edema after cardiac surgery. Findings should be validated in larger cohorts."}
+{"text": "Receptor tyrosine kinases (RTKs) drive breast cancer progression, particularly in human epidermal growth factor receptor 2 and basal tumors, the two worst prognosis subtypes. Tumor cells recruit host stromal components, including immune cells, which strongly influence disease progression. This has been studied in human breast cancer and translated to murine models of breast cancer. Stromal immune components including cytotoxic T lymphocytes (CTLs) and natural killer cells, destroy cancer cells through a process termed immune surveillance. Unfortunately, clinically detectable tumors escape these immune protective effects through their ability to limit the infiltration, activation, and/or survival of CTLs in breast tumors. The immunosuppressed state of established tumors limits the success rate of immune-based therapies, and possibly other therapeutic modalities that depend on host immunity. Published studies demonstrate that RTKs facilitate breast cancer progression, in part, by establishing immune suppression. This raises the intriguing possibility that pharmacological RTK inhibitors may be exploited to sensitize breast cancer patients to immune-based therapies. This includes normal, luminal A/B, HER2, and basal/triple negative  are in clinical trials in triple negative breast cancer patients, chemotherapy remains the standard of care for this subtype. This highlights the need to better understand factors that influence responsiveness to targeted therapies. Herein, we discuss whether RTK therapies can locally re-activate anti-tumor immunity and sensitize poor outcome breast cancers to immunotherapy.Amplification, overexpression or activation of RTK promotes disease progression in HER2 and basal breast cancers. HER2 [also known as v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ErbB2)] amplification is a defining feature of the HER2 subtype, correlating with poor outcome . Overexpin situ (DCIS), transition to invasive ductal carcinoma (IDC) and development of metastatic disease. Dynamic interactions between cancer and immune cells influence each of these processes  class I molecules on the surface of tumor cells. This activates CTLs to kill tumor cells by perforin-mediated permeabilization of the plasma membrane and delivery of granzyme-containing granules into the cytoplasm. Granzymes are serine proteases that promote cell death through multiple mechanisms. Granzyme A increases oxidative stress by decreasing the mitochondrial membrane potential. In contrast, Granzyme B activates the apoptotic machinery by cleaving numerous cellular targets. These include: (1) direct cleavage and activation of effector caspases  and (2) cleavage of Bid, a pro-apoptotic Bcl2 family member, which translocates to and oligomerizes in the outer mitochondrial membrane, which stimulates cytochrome c release to promote apoptosome-mediated Caspase-9 activation. Emerging evidence also suggests a novel pro-inflammatory role for extracellular granzymes released from target cells (Cytotoxic T lymphocytes (CTLs) are CD8et cells . Along wet cells . Retrospet cells .While M1-polarized macrophages possess anti-tumorigenic properties, M2-type tumor-associated macrophages (TAMs) facilitate tumorigenesis through their ability to secrete cytokines, growth factors, and proteases that induce immunosuppression, angiogenesis, and re-modeling of the extracellular matrix . Increas+ helper T (Th) cells differentiate into numerous sub lineages that perform distinct biological functions (Th1 cells elicit an anti-tumor immune response by secreting high levels of interferon (IFN)\u03b3 and interleukin (IL)-2, which induce M1 macrophage polarization and promote CTL proliferation/survival, respectively (Tregs) establish immune suppression by inhibiting CTL/NK cell function via diverse mechanisms. These include: (1) competitive binding of IL-2 to the high affinity IL-2 receptor (CD25); this deprives effector T cells of IL-2, leading to apoptosis; (2) secretion of immunosuppressive cytokines [IL-10 and transforming growth factor beta (TGF\u03b2)], which impairs antigen-activated CTL clonal expansion; and (3) upregulation of cell surface inhibitory molecules cytotoxic T lymphocyte associated protein 4 (CTLA-4) that inhibit dendritic cell maturation  inhibiting Th1 differentiation, and (2) secreting immunosuppressive cytokines such as IL-10 and TGF\u03b2  machinery are ubiquitously expressed in adult tissues. MHC class I-restricted Ag presentation on the surface of breast cancer cells contributes to immune surveillance through the activation of CTLs, leading to tumor cell lysis. APP is a complex process. Ubiquitinated proteins are cleaved by a multi-subunit complex called the proteasome. Peptides are transported into the endoplasmic reticulum via the transporter associated with antigen processing  heterodimer where they are processed by ER aminopeptidase-associated with antigen processing  proteins. Also in the ER, the MHC class I heavy human leukocyte antigen (HLA) and light chains (\u03b22-microglobulin) assemble into a functional MHC class I complex. Finally, the peptides are loaded onto MHC class I complexes and translocate to the cell surface for presentation to CTLs . SeveralThe CD28 family of co-receptors are expressed on the surface of T cells and transduce co-stimulatory or inhibitory signals following antigen activation. Programmed cell death 1 (PD1) is an inhibitory member that is expressed on the surface of antigen-activated CTLs. Upon binding to its cognate ligand programmed cell death ligand 1 (PD-L1) on the surface of antigen presenting cells, PD1 transduces a signal that reduces CTL proliferation and cytolytic activity, eventually leading to CTL apoptosis . PD-L1 iAn increasing body of evidence is emerging that Th1/CTL-driven anti-tumor immunity plays a critical role in contributing to enhanced patient outcome and therapeutic responsiveness in breast cancer patients, particularly within the poor outcome HER2 and basal subtypes.-/PR-, and/or basal breast tumors and strongly correlates with favorable prognosis in this subset  for breast cancer patients . Subsetss subset . Paradoxpatients . Taken t+ breast cancer patients. The therapeutic efficacy of trastuzumab relies both on its ability to elicit anti-tumor immunity by engaging FcR-mediated cytotoxicity and by blocking ErbB2-driven signal transduction , which is indicative of high macrophage density and low CTL infiltration that predicts poor recurrence free survival in node-positive breast cancer patients. Moreover, macrophage infiltration is significantly increased in breast tumors from patients who underwent adjuvant chemotherapy compared to women without any pre-operative intervention  relative to luminal tumors. Despite this fact, a large percentage of patients within the HER2 and basal subtypes experience relapse . Recent rvention . Macrophrvention . Take toin vivo.In addition to these clinical correlations, functional studies in murine breast cancer models have demonstrated an important role for RTK signaling in blocking anti-tumor immunity and promoting disease progression. The laboratory of Dr. Brad Nelson has engineered the first immunological mouse model for ErbB2-driven breast cancer. MMTV/ErbB2 transgenic mice were generated using a modified version of ErbB2 that was tagged with T cell epitopes from the model antigen ovalbumin (OVA). A large panel of tumor cell lines [referred to as neu ovalbumin peptide (NOP) lines] from spontaneous ErbB2/OVA-expressing mammary tumors were established. When implanted in host mice and challenged by adoptive transfer of OVA-specific CTLs, NOP tumors show highly reproducible responses. Some tumor lines demonstrate a CR, whereas others demonstrate a partial response (PR) or progressive disease PD; . This pa+) and basal (ER-/PR-/ErbB2-) subtypes and associate with poor outcome in breast cancer patients (fl/fl), we defined a causal role for ShcA in establishing immune suppression. ShcA loss in the mammary epithelium severely delays mammary tumor onset  element neu-ires-cre NIC; . MMTV/NIpatients . Using bor onset . ShcA-deor onset . Thus, RThe immune response is an attractive target for therapeutic intervention in treating breast cancer. Several immune-based therapies have been tested in clinical trials. These include: (1) DNA, peptide and protein vaccines to tumor antigens such as HER2 and MUC1, (2) autologous dendritic cell-based vaccines, (3) cytokine therapies, including granulocyte macrophage-colony stimulating factor (GM-CSF), as immune adjuvants, and (4) compounds that block Treg function. Unfortunately, such trials have met with limited success in treating breast cancer patients. It is likely that local immunosuppression contributes to this poor success rate . One appThe author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Psychological stress in the workplace is an independent risk factor for cardiometabolic diseases and related mortality. This exploratory study compared the effect of acute (15 min) yoga postures and guided meditation practice, performed while seated in the office workspace, on psychological and physiological markers of stress.A within-subjects crossover design was utilized. Each participant completed three conditions, including yoga postures, meditation, and control , separated by >24hrs. Perceived stress and blood pressure were evaluated before, immediately after, and at 3x 5-min intervals post intervention. Heart rate, respiratory rate and parameters of heart rate variability (HRV) were collected continuously, before, during and post intervention. Twenty adults (39.6\u00b19.5yr) completed the study.The yoga and meditation interventions significantly reduced perceived stress versus control. This effect was maintained throughout the 15-min post-intervention period. Yoga postures increased heart rate while meditation reduced heart rate versus control (both p<0.05). Respiratory rate was reduced during both yoga and meditation versus control (p<0.05). Time and frequency domains of HRV  were significantly improved during yoga versus control. Additional HRV outcomes (LF and LF:HF) indicated increased parasympathetic modulation during yoga versus control. Meditation improved HRV outcomes versus control only during the initial 5-minutes of the 15-min intervention period. All physiological parameters generally regressed to baseline during the post intervention period. Blood pressure indicated normotension during the baseline recording in all conditions and did not improve in yoga versus control. Meditation induced a reduction in both systolic and diastolic blood pressure at 5-min post intervention versus control (p<0.05).Yoga postures or meditation performed in the office environment can acutely improve several psychological and physiological parameters associated with the stress response. Use of such practical interventions to mitigate stress in the workplace may reduce the risk of cardiometabolic diseases and enhance job satisfaction and productivity."}
+{"text": "HTLV-1 oncoprotein, Tax, is a potent activator of classical and alternative NF-\u03baB signaling pathways and is thought to promote cell proliferation and transformation via NF-\u03baB activation. We have shown recently that hyper-activation of NF-\u03baB by Tax immediately triggers the cellular senescence checkpoint. Down-regulation of NF-\u03baB activation, by contrast, rescues cells from Tax-induced rapid senescence (Tax-IRS). Here, we demonstrate that the IKKalpha and NEMO subunit of the IKK complex are absolutely essential to Tax-IRS. Repression of IKKalpha or NEMO expression by small hairpin RNAs abrogated Tax-mediated activation of both classical and alternative NF-\u03baB pathways and rendered the knockdown cells resistant to Tax-IRS. IKKalpha deficiency moderately affected Tax-induced I-\u03baB-alpha degradation and NF-\u03baB nuclear localization, but drastically repressed NF-\u03baB transcriptional activation. While IKKbeta and TAK1 knockdown significantly attenuated Tax-induced NF-\u03baB transcriptional activation respectively, they only partially prevented Tax-IRS and did not display significant effect on the alternative pathway. Importantly, NIK knockdown yielded similar effects as IKKalpha and NEMO knockdown. These data suggest that Tax, through its interaction with NEMO, help recruit NIK and TAK1 for IKKalpha and IKKbeta activation respectively. Tax-mediated senescence as driven by the NEMO/NIK/IKKalpha complex involves both classical and alternative NF-\u03baB pathways. Thus, the quality rather than the quantity of NF-\u03baB activity is more important for promoting senescence."}
+{"text": "It has long been observed that many neuronal types position their nuclei within restricted cytoplasmic boundaries. A striking example is the apical localization of cone photoreceptors nuclei at the outer edge of the outer nuclear layer of mammalian retinas. Yet, little is known about how such nuclear spatial confinement is achieved and further maintained. Linkers of the Nucleoskeleton to the Cytoskeleton (LINC complexes) consist of evolutionary-conserved macromolecular assemblies that span the nuclear envelope to connect the nucleus with the peripheral cytoskeleton. Here, we applied a new transgenic strategy to disrupt LINC complexes either in cones or rods. In adult cones, we observed a drastic nuclear mislocalization on the basal side of the ONL that affected cone terminals overall architecture. We further provide evidence that this phenotype may stem from the inability of cone precursor nuclei to migrate towards the apical side of the outer nuclear layer during early postnatal retinal development. By contrast, disruption of LINC complexes within rod photoreceptors, whose nuclei are scattered across the outer nuclear layer, had no effect on the positioning of their nuclei thereby emphasizing differential requirements for LINC complexes by different neuronal types. We further show that Sun1, a component of LINC complexes, but not A-type lamins, which interact with LINC complexes at the nuclear envelope, participate in cone nuclei positioning. This study provides key mechanistic aspects underlying the well-known spatial confinement of cone nuclei as well as a new mouse model to evaluate the pathological relevance of nuclear mispositioning. Many CNS tissues display a laminar organization that consists in various number of nuclear layers separated by synaptic zones. A good example is the mammalian retina \u2013 an accessible and well-defined part of the CNS \u2013 that is composed of three distinct nuclear layers separated by two zones of synaptic contacts, the inner and outer plexiform layers . Six neuronal types populate the retina: cone and rod photoreceptors whose nuclei form the outer nuclear layer (ONL), horizontal, bipolar and amacrine cells whose nuclei form the inner nuclear layer (INL), and retinal ganglion cells (RGC) whose nuclei delineate the ganglion cell layer (GCL). M\u00fcller cells, that form the retinal glia, position their nuclei within the INL. Cone photoreceptors provide spectacular examples of polarized nuclear positioning. Indeed, their nuclei invariably localize on the apical side of the ONL while their axons extend across the thickness of the ONL to establish synaptic contact with second order neurons within the OPL Recently, major progress has been achieved in the identification of nuclear envelope (NE) proteins that mediate nuclear migration and/or anchorage . The NE C.elegans and D.melanogaster have established the central role that SUN/KASH interactions play in nuclear positioning during development Genetic alterations of either SUN or KASH domain-containing orthologs in Animal protocols used in this study strictly adhered to the ethical and sensitive care and use of animals in research and were approved by the Washington University School of Medicine Animal Studies Committee .+/\u2212 (B6.129S1(Cg)-tm1StwLMNA/BkknJ, #009125) and Sun1+/\u2212  were purchased from The Jackson Laboratory The KASH domain of mouse Nesprin2 (amino acids 6810 to 6874 from NP_001005510.2) was amplified by RT-PCR from C2C12 mouse myoblasts and cloned into BglII/BamH1 sites of pEGFP-C1. The EGFP-KASH2 open reading frame was subcloned in HindIII and ApaI sites of the pCMV-flox polylinker 2 inhalation and ocular globes were immediately isolated and rinsed in PBS. Several incisions were performed in the cornea before incubating the whole eye in 4% paraformaldehyde (PFA)/PBS for 1 h at 4\u00b0C. To analyze vertical retina slices, whole eyes were rinsed in PBS, incubated overnight in a 30% sucrose/PBS solution and embedded in OCT compound (Tissue-TEK). For immunofluorescence microscopy, cryosections (10 \u03bcm) on Superfrost Plus slides (VWR) were fixed for 10 min in 4% PFA in PBS, rinsed three times in PBS, permeabilized in 0.5% Triton-X100/PBS and incubated with primary antibodies diluted in 10% donkey serum/0.5% Triton X-100 in PBS. Secondary antibodies conjugated to Alexa594 or 488 (Invitrogen) were incubated in the same conditions. Following DAPI staining, slices were mounted in fluorescent mounting medium (DAKO). For retinal flat mounts, cornea, lens and vitreous were removed after PFA fixation. The retina was then separated from the sclera, washed three times for 30 min in TBST and permeabilized in 3% Triton X-100 in PBS overnight at 4C and incubated with primary antibodies diluted in 3% bovine serum albumin/TBST overnight. After three washes in TBST, secondary antibodies were applied overnight. Retinas were then washed and counterstained with DAPI before being mounted between two coverslips. For X-gal staining, fixed retinas were washed twice in PBS and incubated in three changes of wash solution . X-gal staining was performed overnight in wash solution containing 6 mM K3Fe(CN)6, 3 mM K4Fe(CN)6 and 1 mg/ml Xgal. All images were acquired on an Eclipse Ti (Nikon) inverted fluorescence microscope using either dry 20X  or oil 40X  objectives.Mice were sacrificed via COAnti-V5 and anti-Lamin B2 (Invitrogen), anti-Lamin A/C , anti-Lamin B1, anti-G\u03b1t1 and anti-BOP (Santa Cruz Biotechnology), anti-cone arrestin (Millipore) and anti-Ribeye (BD Transduction Laboratories) were used in this study. Rabbit anti-mouse Sun1 was raised against a luminal epitope located downstream from the transmembrane domain. Rabbit anti-Nesprin1 and anti-Nesprin2 sera were raised against fusion proteins corresponding to epitopes located just upstream from their respective KASH domains and the Nesprin3 antiserum was raised against a fusion protein corresponding to the whole cytoplasmic region of mouse Nesprin3 (Primm Biotech). Sun1, Nesprin2 and Nesprin3 antisera were immunoaffinity purified prior to use. An anti mouse Sun2 serum was kindly provided by Dr. Min Han + rod and cone nuclei from the outer edge of the ONL, distances between their respective centroids and the outer edge of the ONL (drawn in the DAPI channel using NIS-Elements quantification tools (Nikon)) were measured. For EGFP-KASH2+ rod nuclei, the distribution of measured distances among four equal subdivisions of the ONL (Q1 to Q4) was then compared to a random distribution using a Chi Square test. For cone nuclei, distances measured in LMNA+/+, Sun1+/\u2212 and Tg(CMV-LacZ/EGFP-KASH2) retinas were used to determine their respective inclusion zones defined as the average distance from the ONL \u00b1 2SD. Distances measured in LMNA\u2212/\u2212, Sun1\u2212/\u2212 and Tg(floxHRGPCMV/EGFP-KASH2) littermates retinas were then used to determine whether a given cone centroid localized either within or outside the inclusion zone. To compare the intensity of apical vs. basal EGFP-KASH2+ cone nuclei within Tg(floxHRGPCMV/EGFP-KASH2) retinas, sum intensities of EGFP-KASH2+ nuclei was quantified, and normalized to the total area of the nucleus. Background signal, averaged from five cone nuclei-free areas per retina field, was substracted from average normalized intensities. Mean background-corrected values were then calculated for ectopic nuclei and nuclei residing within the inclusion zone. Maximum Feret diameters of apical vs. basal EGFP-KASH2+ cone nuclei were measured in Tg(floxHRGPCMV/EGFP-KASH2) retinas by applying the appropriate macros of NIS-elements on nuclei whose perimeters were drawn over EGFP-KASH2+ nuclear rims. To compare the size of cone populations between Tg(floxHRGPCMV/EGFP-KASH2) and Tg(CMV-LacZ/EGFP-KASH2) littermates, the number of cone outer segments stained with anti-cone arrestin was counted in two retinas from each genotype. Sections lengths were measured by tracing the apical edge of DAPI stained ONL. Average cone numbers per 100 \u03bcm of retinal sections were then estimated. To quantify PNA signal intensities underneath EGFP-KASH2+ nuclei, maximum intensity projections of Z-stacks were acquired from Tg(floxHRGPCMV/EGFP-KASH2) retinas stained with PNA. To compare PNA signals intensities associated either to EGFP-KASH2+ cone nuclei mislocalizing within the OPL or to cone pedicles from regions devoid of EGFP-KASH2+ nuclei, background-corrected mean intensities were measured using appropriate macros . 3D renditions of corresponding Z-stacks were used to unequivocally associate a PNA signal underneath a given EGFP-KASH2+ cone nucleus. 3D rendering of CAR and PNA signals within Tg(floxHRGPCMV/EGFP-KASH2) retinas  hereafter) displayed EGFP-KASH2+ rim-like patterns reminiscent of perinuclear EGFP-KASH2+ rims observed in transfected mammalian cells + rod nuclei among 4 equal ONL bins  retinas  retinas with rod outer segments , which separates inner and outer segments from photoreceptor somas, was structurally intact  mice were initially bred to Tg(Rx-Cre) mice that initiates the expression of Cre recombinase at \u223cE9.5 in most cells of the optic field  [30]. As retinas . The fra+ nuclei were observed in the INL of Tg(floxRxCMV-EGFP-KASH2) retinas (floxRxCMV-EGFP-KASH2) embryonic retinas . Consistent with that notion, alteration of LINC complexes within Zebrafish retinal progenitor cells modifies cell fate decision While transgenic expression of LacZ/V5 was restricted to the ONL of Tg(CMV-floxLacZ-EGFP/KASH2) mice , a signi retinas  or origifloxRxCMV-EGFP-KASH2) retinas, we observed a few EGFP-KASH2+ nuclei that were positive for cone arrestin (CAR), a cone-specific marker. By contrast to non-transgenic cone nuclei, these nuclei mislocalized on the basal side of the ONL (floxHRGPCMV/EGFP-KASH2) littermates displayed EGFP-KASH2+ nuclear rims within the ONL (+ nuclei in the ONL of Tg(floxHRGPCMV/EGFP-KASH2) retinas was much larger than the small population of transgenic cones we detected in Tg(CMV-LacZ/EGFP-KASH2) retinas using either Xgal staining or V5 immunostaining  retinas. One population, which expressed low levels of EGFP-KASH2 localized normally on the apical side of the ONL while the other, which expressed higher levels of EGFP-KASH2, localized ectopically on the basal side of the ONL  retinas  retinas (+ cone nuclei fell outside the inclusion zone in Tg(floxHRGPCMV/EGFP-KASH2) retinas  retinal flat mounts with CAR further confirmed that the structural integrity of cone OS expressing EGFP-KASH2 was preserved (floxHRGPCMV/EGFP-KASH2) by comparison to Tg(CMV-LacZ/EGFP-KASH2) littermates retinas indicating that cone degeneration is not at play  retinas. Within P8 Tg(CMV-LacZ/EGFP-KASH2) retinas, cone precursors were indeed scattered across the apical two third of the developing ONL (floxHRGPCMV/EGFP-KASH2) retinas, cone precursor expressing high levels of EGFP-KASH2 already mislocalized at basalmost locations of the developing ONL  retinas. While cone arrestin (CAR) strongly labeled thick pedicles in cones devoid of basal most nuclei, we observed a much weaker CAR signal that \u201cwrapped\u201d EGFP-KASH2+ cone nuclei mislocalizing within the OPL . Taken together, these results indicate that mislocalization of EGFP-KASH2+ cone nuclei within the OPL interferes with the overall architecture of cone pedicles.In P8 retinas, opsin antibodies clearly labeled pyramid-shaped cone pedicles arrows,  beneath  the OPL . Alexa59The expression pattern of lamins and LINC complex components was examined within the ONL of wild-type adult retinas   4. In add retinas .\u2212/\u2212 retinas did not display any cone nuclei mispositioning phenotype  retinas  retinas. Importantly, this is the first time that this phenotype is observed in a cell autonomous manner. While we did not observe any nuclear mislocalization phenotype in cones expressing EGFP (data not shown), non-specific effects of EGFP-KASH2 transgenic expression on nuclear positioning cannot formally be excluded. However, our observations parallel the failure of photoreceptor precursor nuclei that either lack Klar, a KASH protein, or Klaroid, a SUN protein, to migrate towards the apical surface of developing Drosophila ommatidia. As a result, these nuclei mislocalize in the optic stalk We show that transgenic expression of EGFP-KASH2 severely impairs cone photoreceptors nuclei positioning on the apical side of the ONL in adult Tg(\u2212/\u2212 retinas by comparison to Tg(HRGPfloxCMV-EGFP-KASH2) retinas. Furthermore, relatively few Sun1\u2212/\u2212 cone nuclei mislocalized within the OPL. These results strongly suggest that, similarly to the mediation of nuclear positioning during CNS and skeletal muscle development Our data are also in line with the ectopic localization of cone nuclei recently reported in Sun1 and Nesprin2 KO retina \u2212/\u2212 and Nesprin2\u2212/\u2212 retinas RxfloxCMV-EGFP-KASH2) adult retinas (HRGPfloxCMV-EGFP-KASH2)  . Our obs\u2212/\u2212 mice that die within \u223c4\u20135 weeks of age from cardiomyopathy and/or muscular dystrophy We found that A-type lamins are dispensable for cone nuclei positioning even though A-type lamins interact with the nucleoplasmic domain of Sun proteins in vitro and in immunoprecipitation experiments HRGPfloxCMV-EGFP-KASH2) retinas as well as nuclear shape abnormalities we observed in basal EGFP-KASH2+ nuclei directly originate from the uncoupling of dynein with the nuclear envelope , an essential component of cone phototransduction, and significantly delayed in cone photoreceptor function loss 1 (cpfl1) mice that carry a spontaneously arising mutation in the cone phosphodiesterase gene and display acute cone degeneration floxHRGPCMV/EGFP-KASH2) by comparison to Tg(CMV-LacZ/EGFP-KASH2) retinas indicating that cone degeneration is most likely not at play upon EGFP-KASH2+ expression. This result contrasts with the reported degeneration of photoreceptors in Zebrafish retinas following the forced expression of a dominant negative KASH construct floxHRGPCMV/EGFP-KASH2) retinas. In mice, whereas Sun1\u2212/\u2212 cones appear structurally intact, Nesprin2\u2212/\u2212 retina display acute cone OS degeneration Mislocalized EGFP-KASH2+ nuclei were significantly less elongated and occasionally misoriented. A similar loss of nuclear elongation was observed in basally displaced Zebrafish photoreceptors nuclei + cones appeared normal as long as their displaced nuclei remained within the limits of the ONL. However, EGFP-KASH2+ cone nuclei that mislocalized within the OPL appeared to \u201cflatten\u201d pedicles. This suggests that cone terminals architecture is affected not as much as a consequence of EGFP-KASH2 expression but rather as a consequence of acute nuclear mispositioning within the OPL. Whether this observation illustrates a mechanism through which nuclear mispositioning may progressively affect neuronal communication and/or circuitry organization remains to be examined. To that regard, the mispositioning of cone photoreceptor nuclei appears to be a natural phenomenon associated with aging Pedicles of EGFP-KASH2Figure S1A) V5 immunostaining of Tg(CMV-LacZ/EGFP-KASH2) retinal flat mount showing the enrichment of transgenic expression on the dorsal side of transgenic retinas. B) Maximum intensity projection of Z-stacks from the apical region of Tg(CMV-LacZ/EGFP-KASH2) retinal flat mounts immunostained with V5 (red) and cone opsin (green). The majority of transgenic photoreceptors correspond to rods whereas only a few cones (labeled with cone opsin) express V5 (arrowheads).(TIF)Click here for additional data file.Figure S2RxfloxCMV-EGFP-KASH2) embryos were processed for DAPI staining. Note the paucity of EGFP-KASH2 expressing cells at that development time. Scale bar: 50 \u03bcm.E14 retinas display only a few EGFP-KASH2 + nuclei. E14 retina from Tg((TIF)Click here for additional data file.Figure S3HRGPfloxCMV-EGFP-KASH2) retina was processed for CAR immunostaining. Shown is a Z-stacks reconstruction of the photoreceptor side showing intact OS atop EGFP-KASH2 + IS of cone photoreceptors (yellow arrow).EGFP-KASH2 expression in cones does not affect outer segment architecture. Flat mount of a P36 Tg((TIF)Click here for additional data file.Figure S4\u2212/\u2212 genotype. Vertical error bars represent the standard deviation of the mean ONL thickness across contiguous viewing fields. Note that, as reported by Yu et al \u2212/\u2212 retinas was significantly thinner by comparison to their heterozygous counterparts (p<0.05).Graphical presentation of cone nuclei centroid positions relative the apical side of the ONL for the indicated genotypes. Measurements were obtained from 5 contiguous viewing fields within the central retina from two different mice for all but the LMNA(TIF)Click here for additional data file.Movie S1HRGPfloxCMV-EGFP-KASH2) retina section stained with CAR. Note the paucity and the presentation of CAR signals underneath EGFP-KASH2+ nuclei by comparison to pedicles from regions devoid of EGFP-KASH2+ nuclei.3D rendering of Z-stacks acquired from a 15 \u03bcm-thick Tg((AVI)Click here for additional data file.Movie S2HRGPfloxCMV-EGFP-KASH2) retina section stained with PNA. Note the paucity or lack of PNA signals underneath EGFP-KASH2+ nuclei by comparison to regions devoid of EGFP-KASH2+ nuclei. See 3D rendering of Z-stacks acquired from a 15 \u03bcm-thick Tg((AVI)Click here for additional data file."}
+{"text": "We aimed to investigate the early characteristics of critical illness polyneuropathy in surgical patients in a 5-day follow-up setting.Twenty critically ill patients were enrolled showing signs of systemic inflammatory response, sepsis or multiorgan failure featuring APACHE II score \u226512 on admittance aged 26 to 86 years. Routine noninvasive nerve conduction study of bilateral median and ulnar nerves was performed on a two-channel portable Keypoint Medtronic apparatus. Nerve conduction studies were performed on five consecutive days starting within at most 2 days after admittance, then weekly follow-up was carried out. Electrophysiological findings were compared to age-matched control group parameters.P < 0.001). During the 5-day study period four patients showed improvement. Sensory nerve fibres were less severely affected than motor fibers. The consecutive measurements revealed negative correlation with the severity of peripheral interstitial oedema determined by circumference of the elbow. Changes in CMAP and SNAP amplitudes also showed a negative correlation with daily rated APACHE II and SAPS II severity scores, and thus with patients' general condition.On first examination, within 2 days following admission 17 of 20 (85%) patients showed signs of axonal type sensory-motor polyneuropathy. Medians of compound muscle action potential (CMAP) and sensory nerve action potential (SNAP) amplitudes of all nerves showed a significant decrease compared to control values (Electrophysiological alterations appear early after the development of critical illness -4. Early"}
+{"text": "We aimed to determine the prognostic value of wall motion assessment during high-dose dobutamine stress cardiac magnetic resonance imaging (DCMR) for the prediction of hard cardiac events in a large patient cohort and within a long follow-up duration. DCMR can accurately identify between patients with inducible ischemia who are at increased risk for future hard cardiac events and revascularization procedures. Within the \u2018primary warranty time\u2019 of 3 years after DCMR excellent outcomes  are recorded in patients with normal findings.We aimed to determine the prognostic value of wall motion assessment during high-dose dobutamine stress cardiac magnetic resonance imaging (DCMR) for the prediction of hard cardiac events in a large patient cohort and within a long follow-up duration.Consecutive patients with suspected or known coronary artery disease underwent DCMR at two experienced cardiac-MRI centers , using a standard protocol with a 1.5T Philips MR-scanner. Wall motion was assessed at rest and during maximum stress, and outcome data including cardiac death and non-fatal myocardial infarction (defined as hard cardiac events) and \u2018late\u2019 revascularization (percutaneous coronary intervention or coronary artery bypass grafting) performed >90 days after the MR-scans were prospectively collected at least 6 months after DCMR.Follow-up data were available in 3138 consecutive patients . Hard cardiac events occurred in 183 (5.8%) patients during the follow-up period. Patients with an inducible wall motion abnormality (WMA) experienced hard cardiac events and late revascularization at significantly higher rates (hazard ratio (HR): 6.9; 95%; confidence interval (CI): 4.9-9.7, and HR=3.8; 95%CI=2.9-5.0, respectively, p<0.001 for both) .Interestingly, patients without inducible ischemia who underwent early revascularization yielded similar hard cardiac event rates, compared to those who were continued on medical treatment. Conversely, patients with inducible ischemia and early revascularization yielded significantly improved prognosis compared to patients with inducible ischemia who were continued on medical treatment Figure .DCMR can accurately identify between patients with inducible ischemia who are at increased risk for future hard cardiac events and revascularization procedures. Within the \u2018primary warranty time\u2019 of 3 years after DCMR excellent outcomes  are recorded in patients with normal findings.None."}
+{"text": "The ability to measure intra-voxel phase dispersion, however, comes at the expense of clinically infeasible scan times. We have recently extended  the auto-calibrating parallel imaging technique SPIRiT  to exploit temporal correlations in dynamic k-t signal space and successfully applied it to radially undersampled FVE data. Prior assumption of Gaussian velocity spectra additionally allows undersampling along the velocity encoding dimensions . In this work, a scheme is proposed to non-uniformly undersample the kv-axes in addition to undersampling k-t space for reconstructing mean and standard deviation (SD) of the velocity spectra for each voxel in aortic flow measurements.Fourier velocity encoding (FVE)  assesses the distribution of velocities within a voxel by acquiring a range of velocity encodes (kv=0). Undersampled radial data sets were obtained by separately re-gridding these 4-point measurements onto Golden-angle profiles  fully sampled cine FVE data of the aortic arch for 3 orthogonal velocity components was obtained from 5 healthy volunteers on a 3T Philips Achieva scanner  using a 6 element receive array. Three different first gradient moments corresponding to encoding velocities of 25cm/s, 50cm/s and 200cm/s were applied along with a reference point . A 7x7x3 neighborhood in kx-ky-t space was chosen for the k-t space interpolation kernel. The weights were calculated from a 30x30x(nr cardiac phases) calibration area (Fig.The interpolation operator ames Fig.. Data coig.D Fig.. Then, xarea Fig.. Mean anFig.A novel auto-calibrating reconstruction technique for dynamic radial imaging was successfully applied to undersampled 4-point FVE data from five healthy volunteers. Results show that up to 12-fold radial undersampling provides accurate quantification of mean velocities and turbulence intensities derived from velocity spectra."}
+{"text": "Natural humoral immune response and autoimmune mechanisms have great importance in keeping the balance of tumorimmunity, although it has not yet been fully understood. We aimed to reveal potential anti-tumor immune response by immunoglobulin (Ig) profile analysis of patients with metastatic melanomas.A complex panel assay has been performed at expressed DNA and protein levels on antibodies originating from patients' peripheral blood (n = 92) or cancerous tissue biopsies (n= 87) (ETT TUKEB 16462- 02/2010). Heavy and light chain immunoglobulin variable gene regions were sequenced and analysed with Vector NTI Advance 11, Bioedit 7.0, ClustalX2.0.11, TreeView 1.6.6 programs using available databases . Patients' sera, purified human Ig preparations and antibody fragments from tumor infiltrating B cells were tested by ELISA, immunofluorescence FACS and confocal laser microscopy.Cluster analysis revealed specific antibody variable region gene subgroups in the VH3 family, amongst which there are the ones with cancer associated antigen binding capacity. The purified immunoglobulin's strong SK-Mel28 melanoma binding potential paralleled with the clinical outcome. Some selected expressed antibody fragments showed tumor associated antigen labelling on melanoma tissues Fig. . A compeWe could prove the extensive presence of highly tumor associated unique GD3 sialilated glycosphingolipid specific antibody variable regions in patients with melanoma. Our novel panel assay confirmed the potentials of antibody profile analysis in characterizing anti tumor humoral immune response and its worth for diagnostics."}
+{"text": "Otopetrin 1 gene (Otop1) in mice and fish produce an unusual bilateral vestibular pathology that involves the absence of otoconia without hearing impairment. The encoded protein, Otop1, is the only functionally characterized member of the Otopetrin Domain Protein (ODP) family; the extended sequence and structural preservation of ODP proteins in metazoans suggest a conserved functional role. Here, we use the tools of sequence- and cytogenetic-based comparative genomics to study the Otop1 and the Otop2-Otop3 genes and to establish their genomic context in 25 vertebrates. We extend our evolutionary study to include the gene mutated in Usher syndrome (USH) subtype 1G (Ush1g), both because of the head-to-tail clustering of Ush1g with Otop2 and because Otop1 and Ush1g mutations result in inner ear phenotypes.Mutations in the OTOP1 is the boundary gene of an inversion polymorphism on human chromosome 4p16 that originated in the common human-chimpanzee lineage more than 6 million years ago. Other lineage-specific evolutionary events included a three-fold expansion of the Otop genes in Xenopus tropicalis and of Ush1g in teleostei fish. The tight physical linkage between Otop2 and Ush1g is conserved in all vertebrates. To further understand the functional organization of the Ushg1-Otop2 locus, we deduced a putative map of binding sites for CCCTC-binding factor (CTCF), a mammalian insulator transcription factor, from genome-wide chromatin immunoprecipitation-sequencing (ChIP-seq) data in mouse and human embryonic stem (ES) cells combined with detection of CTCF-binding motifs.We established that Otop and Ush1g families, and establish a framework for studying the possible interaction(s) of Ush1g and Otop in developmental pathways.The results presented here clarify the evolutionary history of the vertebrate  Although bilateral vestibular pathology is an important cause of imbalance in humans, it is underdiagnosed and poorly understood. Approximately 50% of dizziness is attributed to benign paroxysmal positional vertigo (BBPV), a major risk factor for falls, bone fractures, and accidental death, particularly in the elderly . The etiOtop1) is one of a handful of known genes that, when mutated, cause an imbalance phenotype with selective otoconial involvement in animal models . A multi-species protein sequence alignment was created that included all known amphibian, mouse, human, and dog Otop sequences. Otop proteins contain 12 trans-membrane domains [http://tree.bio.ed.ac.uk/software/figtree/).A comprehensive phylogeny of the ODP family in vertebrates and invertebrates has been described elsewhere . Here, wDNA, Nlo ; also thUSH1G; also SANS): USH subtype 1G gene; (SAM): Sterile alpha motif domain; (Otop): otopetrin; (ODP): Otopetrin Domain Protein; (Nlo): neural crest-lateral otic vesicle localization gene; (Zfp509): zinc finger protein 509; (Lyar): Ly1 antibody reactive clone; (Tmem128): transmembrane protein 128; (Drd5): dopamine receptor 5; (Slc2a9): facilitated glucose transporter member 9; (OR): olfactory receptor; (SD): segmental duplication; (TBSD): tumor break-prone segmental duplication; (USP17): deubiquitinating enzyme gene; (Fads6): fatty acid desaturase domain family member 6; (C17orf2): hypothetical protein; (Cdr21): cerebellar degeneration-related protein 2-like; (BAC): Bacterial Artificial-Chromosome clone; (FISH): Fluorescence in situ hybridization; (CTCF): CCCTC-binding factor, zinc finger protein; (ChIP-seq): chromatin immunoprecipitation-sequencing; (ES): embryonic stem cells; (MCSs): Multi-species Conserved Sequences; (HRE): human renal epithelial cells; (BJ): skin fibroblasts; (HUVEC): human umbilical vein endothelial cells; (SAEC): small airway epithelial cells; (NHEK): normal human epidermal keratinocytes; (EST): expressed sequence tag; (Oc-22): otoconin-22; (MYO7A): myosin VIIa; (CDH23): cadherin 23; (PCDH15): protocadherin 15; (js): Jackson shaker; (tlt): tilted; (mlh): mergulhador; (ied): inner ear defect; (bsk): backstroke; (WGAC): genome assembly comparison; (WSSD): genome shotgun sequence detection; (ML): Maximum Likelihood; (MP): maximum parsimony; (array CGH): Array Comparative Genome Hybridization.(USH): Usher syndrome; (BH and EDG designed the overall study. BH, TMB, FA, and JFR performed all analyses and drafted the manuscript. NISC Comparative Sequencing Program provided sequence data. IH, EEE, DMO, and EDG edited the manuscript. All authors read and approved the final manuscript.Xenopus tropicalis Otop1b; Xenopus tropicalis Otop1aUCSC custom track bed file: .Click here for fileTable S1. Pair-wise alignment between the proximal and distal segmental duplications flanking human cytogenetic band 4p16.1-p16.3Click here for fileFigure S1. Comparative genomic architecture of the chromosome 4p16.3 regionClick here for fileSegmental duplication content of the Otop1-proximal and distal regions in the h17 and h19 human genome sequence assemblies; orthologous conservation of the TBSD family in the primate genomesClick here for fileFigure S2. Segmental duplication content of the Otop1-proximal and Otop1-distal regions in the hg17 and hg19 genome assembliesClick here for fileFigure S3. Distribution of the TBSD segmental duplication family across the human genomeClick here for fileGasterosteus aculeatus Sansa; Gasterosteus aculeatus Sansb; Gasterosteus aculeatus SanscUCSC custom track bed file: Click here for fileTetraodon nigroviridis Sansa; Tetraodon nigroviridis Sansb; Tetraodon nigroviridis SanscUCSC custom track bed file: Click here for fileOryzias latipes Sansa; Oryzias latipes Sansab; Oryzias latipes Sansac;UCSC custom track bed file: Click here for fileTakifugu rubripes Sansa; Takifugu rubripes Sansb: Takifugu rubripes SanscUCSC custom track bed file: Click here for fileDanio rerio Sansb; Danio rerio SanscUCSC custom track bed file: Click here for fileFigure S4. Comparative analysis of the Ush1g proteins in five fish speciesClick here for fileUCSC custom track bed file: ExactPlus 7-5-4 MCSs; ExactPlus 7-5-4 overlaps phastConsElement30way MCSsClick here for file"}
+{"text": "Endovascular treatment of ruptured abdominal aortic aneurysms (r-EVAR) has the potential to offer improved outcomes. A frequent cause of post-operative mortality following ruptured aortic aneurysm repair is multi-organ failure (MOF) as a consequence of abdominal compartment syndrome (ACS). We reviewed our experience to identify predisposing factors for ACS Fig.  and a waFrom January 2005 to December 2009, 53 patients underwent emergent endovascular repair of r-AAA. We mainly used bifurcated prostheses (44 patients), apart from 5 cases of aorto-uni-iliac device and 4 cases of straight endografts. Nine patients developed ACS and were submitted to abdominal decompression by retroperitoneal surgical drainage . Early mortality was recorded in unstable patients only. Stable patients (24) had no mortality in the first 30 days. Among patients who underwent retro-peritoneal drainage, the 30-day mortality rate was 33.3% (3/9). At a median follow up of 34 months (33.8 + 17.0) 3 patients died of aneurysm or procedure related causes.One of the priorities in the management of r-EVAR is to prevent and eventually treat the ACS. A surgical evacuation of the retroperitoneal hematoma through extraperitoneal access has considerable advantages, mainly in high risk and older patients. In r-EVAR the particular factor is the retroperitoneal hematoma. Therefore we perform abdominal decompression via retroperitoneal access."}
+{"text": "H. pylori, the gastric cancer associated carcinogen, leads to the ubiquitination and reduction of Drosha protein levels. H. pylori infection of AGS cells has no significant effects on Drosha mRNA levels. Our findings establish a central mechanism of protein homeostasis as playing a critical role in miRNA biogenesis.The RNase III enzyme Drosha initiates microRNA (miRNA) biogenesis in the nucleus by cleaving primary miRNA transcripts into shorter precursor molecules that are subsequently exported into the cytoplasm for further processing. While numerous disease states appear to be associated with aberrant expression of Drosha, the molecular mechanisms that regulate its protein levels are largely unknown. Here, we report that ubiquitination and acetylation regulate Drosha protein levels oppositely. Deacetylase inhibitors trichostatin A (TSA) and nicotinamide (NIA) increase Drosha protein level as measured by western blot but have no effects on its mRNA level in HEK293T cells. TSA increases miRNA-143 production in a miRNA sensor assay and in a qPCR analysis in HEK293T cells. Treatment of AGS and HEK293T cells with proteasome inhibitors MG132 or Omuralide increases Drosha protein levels. Furthermore, the N-terminal, but not the C-terminal Drosha can be acetylated by multiple acetyl transferases including p300, CBP and GCN5. Acetylation of Drosha competes with its ubquitination, inhibiting the degradation induced by the ubiquitin-proteasome pathway, thereby increasing Drosha protein levels. Infection of the gastric mucosa AGS cells by  MicroRNAs (miRNAs) are a class of short non-protein coding RNAs with length of \u223c22 nt which impact protein expression by targeting complementary mRNA for degradation or translational inhibition. MiRNAs play important regulatory roles in myriad cellular functions such as stem cell self-renewal and cancer development While a great deal of knowledge has accumulated on the roles of individual miRNA in human health and disease, little is known regarding cellular mechanisms, if any, that globally regulate miRNA synthesis. Such insight is critical given that certain disease states such as cancer appear to be associated with widespread decrease in miRNA expression We report here our unanticipated finding that Drosha protein levels are increased in various cells including HEK293T, AGS and HeLa treated with deacetylase inhibitors such as trichostatin A (TSA) or nicotinamide (NIA). Using a series of Drosha expression constructs, we show that N-terminal lysines act as molecular targets that regulate Drosha protein levels by serving as substrates for the opposing forces of ubiquitination and acetylation. Multiple acetyl transferases are involved and acetylation appears to preserve Drosha protein levels by preventing ubiquitination.pfu DNA polymerase (Stratagene) as previously described AGS cells (ATCC) were cultured in Ham\u2019s F-12 medium (ATCC) plus 10% fetal bovine serum (FBS) (Invitrogen). HEK293T and Huh-7 cells (ATCC) were cultured in Dulbecco\u2019s Modified Eagle\u2019s medium (Invitrogen) with 10% FBS and 2 mM L-glutamine (Lonza). HeLa cells (ATCC) were grown in Eagle\u2019s Minimum Essential Medium (Lonza) supplemented with 10% FBS, 2 mM L-glutamine and non-essential amino acids (Lonza). MCF-7 cells (ATCC) were grown in Eagle's MEM, supplemented with 10% FBS, non essential amino acids (0.1 mM), 10 ug/mL Insulin (Cell Applications) and 1 mM sodium pyruvate (Mediatech). Cells were trypsinized with typsin-EDTA (Mediatech) and reseeded in culture plates 1 day before transfection. HEK293T transfection was performed with Lipofectamine (Invitrogen) when cell confluency was \u223c60%. AGS cells were transfected with GenJet Plus DNA Transfection Reagent (SignaGen Laboratories) when cell confluency was \u223c70%. GFP-Drosha construct has been described previously Drosha (D28B1) rabbit mAb (anti-Drosha), Dicer rabbit Ab, aceylated-lysine mouse mAb (ace-K) and lysine 48 linkage specific polyubiquitin antibody (K48 linked polyubiquitin) were purchased from Cell Signaling Technology; GAPDH (0411) mouse monoclonal antibody, GAPDH (FL-335) rabbit polyclonal antibody, c-Myc (9E10) mouse monoclonal antibody, c-Myc (A-14) rabbit polyclonal antibody, GFP (FL) rabbit polyclonal antibody, GFP (B-2) mouse monoclonal antibody, Exportin-5 (A-11) mouse monoclonal antibody, \u03b2-actin (R-22) rabbit polyclonal antibody, FNDC3B rabbit polyclonal antibody and protein G plus-agarose beads were purchased from Santa Cruz Biotechnology; DGCR8 rabbit polyclonal antibody was purchased from Proteintech Group.Cell lysates were separated by 10% SDS\u2013PAGE electrophoresis and electroblotted to nitrocellulose membrane (Bio-Rad). Blotted membranes were probed with their respective primary antibodies, rotating at 4\u00b0C overnight. Membranes were washed three times in TBST buffer and probed with secondary antibody  at room temperature for 1 h. Membranes were then washed three times in TBST buffer and direct infrared fluorescence detection was performed with a Licor Odyssey\u00ae Infrared Imaging System HEK293T cells transfected with GFP-Drosha1\u2013390 or GFP-Drosha391-1374. Forty-eight hours post-transfection, cell lysates were prepared with IP Lysis Buffer (Pierce). GFP antibody conjugated sepharose beads (Abcam) were used to immunoprecipitate GFP-Drosha fusion proteins. After 3 cycles of centrifugation and washing, immunoprecipitates were co-incubated with p300 (Millipore) and acetyl CoA (Sigma) at 37\u00b0C for I hr. Twenty microliters of reaction product was used for western blot.GFP-Drosha was cotransfected with CBP into HEK293T cells and incubated for 48 h. Six hours before harvesting the cells, 1 \u00b5M trichostatin A (TSA) (Sigma) was added to cell culture. Immunoprecipitated GFP-Drosha protein was resolved by 10% SDS-PAGE and visualized using Coomassie blue stain. Bands of the above protein were excised and subjected to mass spectrometry analysis as described previously We used the psi-CHECK2 system (Promega) to create sensor assays for quantifying mature miRNA-143 function by placing the anti-sense sequence of miRNA-143 in the 3\u2032UTR of the gene encoding Renilla luciferase. In the presence of mature miRNA-143, the luciferase activity of Renilla decreases through the classical RNAi pathway H. pylori at a 100\u22361 ratio (bacterium: cell) for 0,1,3,6,12 and 24 h respectively. Total mRNA was extracted with TRIZOL reagent (Invitrogen) and 1 \u00b5g of total mRNA was used for cDNA synthesis using MMLV reverse transcriptase (New England Biolabs) as described in the manufacturer\u2019s manual. 1.5 \u00b5l of cDNA was used for PCR reaction to check Drosha gene expression . To measure the mRNA levels of transfected GFP-Drosha wt and mutants, total RNA was extracted from HEK293T cells transfected with respective plasmid. 1 \u00b5l of cDNA was used for PCR reaction to check mRNA levels of Drosha wt or mutants . GAPDH was used as control for normalization. All PCR reactions were run for 28 cycles in triplicate and products were visualized on 1% agarose gel. As for measuring miR-143 levels in HEK293T cells treated with vehicle control or TSA overnight, TaqMan real time RT-PCR microRNA detection kits (Applied Biosystems) that include RT primers and TaqMan probes were used to quantify the levels of mature miR-143 and 18S RNA was used for normalization. All PCR reactions were run in triplicate.AGS cells were treated with t test.Quantitative data were analyzed by unpaired Student\u2019s Lysine residues serve as substrates for acetylation leading to overall stabilization of proteins To identify which part of Drosha is the target for acetylation, we created both a Drosha N-terminal construct (GFP-Drosha1-390) and a Drosha C-terminal construct (GFP-Drosha 391-1374). We transfected these two constructs into HEK293T cells separately and immunoprecipitated the N-terminal and C-terminal Drosha proteins. Using these immunoprecipitated Drosha proteins as substrates to incubate with purified p300 and acetyl CoA, we found that the N-terminal Drosha1-390, but not the C-terminal Drosha 391-1374 construct, harbored the likely lysine substrates for acetylation . To idenPrevious studies have shown that acetylation inhibits ubiquitination of some proteins by competing for the same lysines As mentioned, the basis of proteasomal degradation is the linkage of ubiquitin moieties to target lysine. To better define the molecular anatomy of Drosha and identify lysine motifs responsible for its stability, we created a series of GFP-tagged truncated expression constructs in which we deleted either the N-terminal 390 amino acids or C-terminal 524 amino acids . We founTreatment of HEK293T cells with deacetylase inhibitor not only increased Drosha acetylation and protein levels, but also simultaneously decreased Drosha ubiquitination , suggestH. pylori infection accelerated p27 degradation via a proteasome-dependent pathway H. pylori strain 60190 (ATCC49503) at a 100\u22361 ratio (bacterium: cell) significantly increased K48 linked polyubiquitin, indicating that the ubiquitin-proteasome pathway was activated by H. pylori  and found that Drosha protein levels were preserved despite H. pylori infection and approached levels found in uninfected cells (H. pylori infection had no appreciable effect on Drosha acetylation (Our earlier work had demonstrated that . pylori . We meas 6 hours . Drosha tionally . H. pyloexamined . To furted cells . Omuralied cells . H. pylotylation .In silico screening suggested that several lysines on the N-terminus of Drosha could be the targets for ubiquitination or acetylation. Using a series of truncated and mutated Drosha constructs, we confirmed that N-terminus of Drosha habors a major region containing lysines which can be ubiquitinated or acetylated. These mutually exclusive post-translational modifications have opposing effects of degradation and stabilization, respectively, and suggest that N-terminal centered lysines serve as molecular targets mediating Drosha protein expression. This regulation of protein stability is reminiscent of that observed for other proteins: acetylation of p53 inhibits its ubiquitination MiRNA biogenesis is a step-wise process involving multiple proteins and precedence exists for post-translational modifications impacting the expression and function of miRNA related proteins Our previous study showed that increase of Drosha expression level dramatically facilitates miRNA-143 expression H. pylori-infected gastric epithelial cells, the proteasome-mediated degradation of the cyclin-dependent kinase inhibitor p27kip1 is enhanced H. pylori infected patients H. pylori infection enhances the ubiquitin-proteasome pathway which is constitutively active in gastric epithelial cells. Of the miRNA regulatory proteins, Drosha appears far more sensitive to ubiquitin-proteasome pathway induced degradation than Dicer, DGCR8 or exportin-5. Activated ubiquitin molecules are ligated to the N-terminal lysines of Drosha leading to its degradation. Those lysine residues are also the acetylation sites of multiple acetyl transferases such as p300, CBP. Acetylation of Drosha on those N-terminal lysine sites prevents Drosha ubiquitination, thereby preventing its degradation. In conclusion, our findings clarify cellular mechanisms impacting Drosha protein levels and provide a mechanism by which H. pylori alters miRNA expression and downstream global gene regulation. Our discoveries also indicate a mechanistic link between chronic H. pylori infection and malignant transformation of gastric cells. These findings implicate a potential therapeutic insight for mitigating the influence of long-term H. pylori infection on its adverse clinical sequelae, including gastric malignancies In some human diseases, the ubiquitin-proteasome pathway may be disrupted. For example, in colon and renal cell cancers, the ubiquitin ligases are coded by oncogenes"}
+{"text": "Given the burden of disability arising from severe traumatic brain injury (TBI) , plain at test, Mann-Whitney test, logistic regression, ROC curve and chi-squared analyses were used for statistical purposes.A prospective study enrolling 133 patients  with TBI (associated or not with multiple trauma) and GCS \u22648 admitted to our ICU. Demographics, acute care preadmission factors (hypotension and hypoxemia), injury severity  and acute physiological disturbance  were evaluated. According to functional outcome (GOS) upon ICU discharge, two subgroups of patients were identified: GOS 4 to 5 (favorable outcome), and GOS 1 to 3 (poor outcome). Independent n = 43). Logistic regression analysis identified APACHE II (P = 0.004), CT scan grade (P = 0.002) and pupil reactivity upon ICU admission (P = 0.01) as the strongest predictors of functional outcome. Area under the ROC curve for APACHE II score was 0.841 .Data are presented in Table Acute physiological disturbance, poor preadmission clinical data and neurological signs, presence of severe intracerebral injuries combined with additional extracerebral injuries and advanced age, seem to be powerful determinants that adversely influence the early course of recovery and functional survival of patients with sustained severe TBI. Among them APACHE II, CT scan grade and pupil reactivity upon ICU admission were identified as the strongest early prognostic indicators."}
+{"text": "Inborn error of metabolisms (IEM) have been detected worldwide using gas chromatography mass spectrometry since 1980s, but few related date presently exit in Southern China. This study aimed to evaluate the prevalence, spectrum and clinical presentation of IEM in Southern China.From January 2009 to March 2012, 16075 urine samples were collected from patients with developmental delay, seizures, vomiting and metabolic acidosis in Guangzhou Women and Children\u2019s Medical Center.We diagnosed 148 cases of IEM by urine GC-MS analysis, including 97 cases of organic acid disorders, 41 cases of amion acid disorders and 10 cases of fatty acid oxidative disorders. Methylmalonic aciduria (MMA) was most common(48 cases), followed by urea cycle disorder (21 cases), phenylketonuria (20 cases),propionic aciduria(11 cases), multiple carboxylase deficiency(8 cases), glutaric aciduria type I (7 cases), oxoproliemia(7 cases), isovaleric aciduria(6 cases),glutaric aciduris type II and Short chain acyl-CoA dehydrogenase deficiency(4 cases),3-hydroxy-3-methylglutaric aciduria(3 cases), amionadipic aciduria(2 cases),maple syrup urine disease(2 cases), very long-china acyl-CoA dehydrogenase deficiency(2 cases), Malonic aciduria(1 case), Canavan disease(1 case) and mevalonic aciduria(1 case). Average age at diagnosis was 18 months. Prompt therapy was taken, including dietary and medicine treatment. Clinical improvements were observed in more than half of the patients.In Southern China, the majority of IEM were organic acid disorders and amino acid disorders. Fatty acid oxidation disorders were relatively rare. The age at diagnosis was early and incidence of IEM gradually decreased with the age. Urine GC-MS was an important technique to diagnose IEM, which helped to improve patients\u2019 prognoses."}
+{"text": "To determine whether contractile activity regulates nitric oxide synthase (NOS) expression, spontaneously contracting, neonatal rat ventricular myocytes (NRVM) were treat with L-type calcium channel blockers (nifedipine and verapamil) or myosin II ATPase inhibitors (butanedione monoxime (BDM) and blebbistatin) to produce contractile arrest. Both types of inhibitors significantly reduced iNOS but not eNOS expression, and also reduced NOi production. Inhibiting contractile activity also reduced focal adhesion kinase (FAK) and AKT phosphorylation. Contraction-induced iNOS expression required FAK and phosphatidylinositol 3-kinase (PI(3)K), as both PF573228 and LY294002  eliminated contraction-induced iNOS expression. Similarly, shRNAs specific for FAK (shFAK) caused FAK knockdown, reduced AKT phosphorylation at T308 and S473, and reduced iNOS expression. In contrast, shRNA-mediated knockdown of PYK2, the other member of the FAK-family of protein tyrosine kinases, had much less of an effect. Conversely, overexpression of a constitutively active form of FAK (CD2-FAK) or AKT (Myr-AKT) reversed the inhibitory effect of BDM on iNOS expression and NOi production. Thus, contraction-induced iNOS expression and NOi production in NRVM are mediated via a FAK-PI(3)K-AKT signaling pathway.Intracellular nitric oxide (NO All three isoforms are expressed in cardiomyocytes. eNOS and nNOS are constitutively expressed, whereas iNOS is up-regulated under pathological conditions such as sepsis, hypertension, hypertrophy and heart failure i transients and contractile activity) or the myosin II ATPase inhibitors butanedione monoxime (BDM) and blebbistatin (which block contractile activity but have relatively little effects on spontaneous [Ca2+]i transients) i and mechanical activity contributed to enhanced NOi production. The partial [Ca2+]i dependence of NOi production is consistent with the known role of Ca2+-CaM in regulating eNOS activity [Spontaneously contracting NRVMs were treated with the L-type calcium channel blockers nifedipine and verapamil (which inhibit both spontaneous [Cansients) , 28\u201330. activity .To investigate the role of FAK and PI(3)K in regulating contraction-dependent iNOS expression, NRVMs were first treated with PF573228 or LY294002, which are potent and highly selective inhibitors of FAK  activiti2+ channel blockers or inhibitors of myosin ATPase demonstrated reduced FAK and AKT phosphorylation. shRNA-induced FAK knockdown also reduced AKT phosphorylation at both sites (Previous studies have demonstrated that FAK autophosphorylation at Y397 provides a docking site for the binding and tyrosine phosphorylation of the p85 subunit of PI(3)K, which is required for its activation in NRVM , 35 and th sites . In contth sites .i production using DAF-2-DA. Both WT-AKT and Myr-AKT were sufficient to restore NOi production under BDM inhibition (Myr-AKT > WT-AKT) K, and AKT in regulating contraction-dependent iNOS expression, we attempted to \u201crescue\u201d BDM inhibition of iNOS expression by overexpressing wildtype (WT) FAK, \u201cconstitutively active\u201d FAK , WT-AKT, or a constitutively active form of AKT (Myr-AKT) . As seen WT-AKT) . These ri production via Ca2+-dependent and Ca2+-independent signaling pathways. As demonstrated in i production to a greater extent than either BDM or blebbistatin. Previous studies have also shown that acute mechanical stimulation, such as, by sheer stress [i production in endothelial cells. A similar effect of acute mechanical loading on NOi production was observed in cardiomyocytes [2+-CaM signaling in different cell types [2+ influx and contractile arrest led to a further reduction in NOi production as compared to the inhibition of mechanical activity alone. These results are consistent with other observations that Ca2+-dependent and Ca2+-independent NOSs are both involved in mechanical stimulation-induced NOi production. In our previous study, we showed that either decreased (BDM or blebbistatin) or increased (EMD 57033 or CGP 48506) contractile strength affected changes in field stimulation-induced NOi production without changing Ca2+ influx (12). Here we demonstrate that contractile activity can also induce iNOS gene expression and NOi production through a FAK-PI(3)K-AKT signaling pathway without interfering with Ca2+ handling. A schematic diagram outlining this signaling pathway is depicted in As demonstrated in this report and our previous study , cardiomr stress , 44 and r stress  stimulatmyocytes , 46, 47.ll types , 44, 48.2+ channel blockers or myosin II ATPase inhibitors. These results suggest that load-induced eNOS upregulation may be mediated by a different signaling mechanism. Liao et al. [2+ signal was very likely the trigger for subsequent NOi signaling in cardiomyocytes, and the NOi signal further amplified itself by increasing iNOS expression. However, both types of inhibitors could not completely eliminate iNOS expression or NOi production, suggesting that contraction-induced iNOS expression may also be subjected to NOi autoregulation. Previous studies have shown that mechanical stretch can induce both iNOS and eNOS expression in NRVM , 49. Howo et al.  also ind5\u2009cells/cm2) in order to enhance spontaneous contractile activity and increase iNOS expression. Under these conditions, FAK and AKT were also highly phosphorylated, but their phosphorylation could be reduced by inhibitors of contractile activity. Hines et al. [Our experiments utilized NRVM plated at high density K and AKT, as the highly specific PI(3)K inhibitor LY294002, or overexpression of a dominant-negative mutant of AKT, partially blocked contraction-dependent NOi production [Although FAK appears both necessary and sufficient to induce AKT activation in NRVM, the intermediary steps linking contractile activity to FAK and AKT activation remain unclear. As indicated in our previous paper, contraction-induced NOoduction . Similaroduction , who shooduction . In thisoduction \u201341. Wei oduction  showed toduction  also dem2O2, leading to downstream phosphorylation of AKT at both T308 and S473. Although we demonstrate that PYK2 is not necessary for contraction-induced AKT activation, it is conceivable that FAK, or the FAK/Src complex may function in a similar manner, thereby causing the tyrosine phosphorylation of PDK1 and subsequent AKT activation. Thus, the requirement for PI(3)K to mediate contraction-induced AKT activation would be conferred through the generation of phosphoinositides necessary for PDK1 and AKT recruitment to the cell membrane and not directly via formation of a FAK/PI(3)K complex. Of note, Xia et al. [\u03b21 integrins (accomplished with an anti-\u03b21 integrin antibody) activated both FAK and AKT in a Src- and PI(3)K-dependent manner, although FAK-p85 complexation could not be demonstrated. Alternatively, Taniyama et al.  have shoa et al.  demonstrSeveral studies have used genetically modified animal models to address the function of iNOS in the heart. Three different research groups have shown that iNOS deletion improved ventricular function, reduced myocardial nitrotyrosine content, decreased apoptosis, and improved survival after experimental myocardial infarction \u201358. Zhan"}
+{"text": "To compare ischaemia assessment by Fractional flow reserve (FFR) with non-invasive testing in patients with intermediate coronary artery stenosis.FFR was initially validated against SPECT, Dobutamine Stress Echo and Exercise Testing . It is nPatients due for investigation of presumed cardiac chest pain were recruited and underwent SPECT , perfusion-CMR  and coronary angiography. Any vessel that was angiographically determined as intermediate severity (40-70%) was assessed by QCA and pressure wire-derived FFR .In 23 study patients , 33 FFR measurements were performed . FFR was classified negative (>0.80) in n=20. Perfusion-CMR detected ischaemia in 3 vessels (2 with positive FFR and one with 'grey' FFR). SPECT also detected ischaemia in 3 vessels (2 negative FFR and one positive FFR), (Table Non-invasive imaging does not correlate well with FFR measurements in intermediate coronary lesions. Perfusion-CMR whilst not significantly discriminating between the groups had no false negatives and may thus be the more useful additional test to determine the significance of \u2018grey\u2019 lesions on FFR."}
+{"text": "Mannheimia haemolytica is a respiratory pathogen affecting cattle and related ruminants worldwide. M.\u00a0haemolytica is commonly associated with bovine respiratory disease complex (BRDC), a polymicrobial multifactorial disease. We present the first two complete closed genome sequences of this species, determined using an automated assembly pipeline requiring no manual finishing. Mannheimia\u00a0haemolytica is a Gram-negative rod bacterium commonly associated with severe acute hemorrhagic fibrinonecrotic bronchopneumonia  were among many M.\u00a0haemolytica BRDC clinical case isolates that were chosen for sequencing. Genomic DNA was extracted using a Qiagen blood and cell culture DNA kit and Genomic-tip 100/G columns according to the directions of each manufacturer. Closed genomes were generated using a hybrid assembly pipeline in two steps. In step one, 50-fold coverage of Roche GS-FLX Titanium reads was used to error-correct continuous long Pacific BioScience RS sequencer reads (clPBr) (C2 chemistry) using the pacBioToCA pipeline (http://genskew.csb.univie.ac.at) was used to localize the approximate origin of replication of the chromosome so that the base pair numbering could be reindexed to reflect the origin of replication at base pair position 1. A local instance of Do-It-Yourself Annotator (DIYA) (pipeline . Both geM. haemolytica USDA-ARS-USMARC 183 and USDA-ARS-USMARC 185 were deposited in GenBank under accession no. CP004752 and CP004753, respectively.The completed genome sequences of"}
+{"text": "Vogt-Koyanagi-Harada disease is an uncommon autoimmune disorder. Its pathophysiology is related to T-cell-mediated autoimmune processes directed against one or more antigenic components of melanocytes. The diagnosis of this condition is primarily based on clinical features including: ocular findings  neurological  and integumentary manifestations . We report the case of a 25 years old woman presented with 1 month history of painful vision loss with tinnitus and headache. She didn't report any previous ocular trauma or surgery. At examination there was a bilateral mild anterior chamber inflammation. Dilated funduscopy (Panel A) revealed mild vitritis with multiple yellowish deep retinal lesions at the level of the retinal pigment epithelium (white arrowheads) and optic disc hyperemia (arrows). At general examination we noted a temperature of 38 \u00b0 with a painful stiff neck. There were also some areas of cutaneous depigmentation (Panel B) on the forehead and nose bridge. Cranial computed tomography was unremarkable. A lumbar puncture revealed a sterile liquid with pleocytosis (25 mononuclear cells/dL). A work-up was performed including: ANCA C and P, Compete -Blood- Count, erythrocyte sedimentation rate, Rheumatoid factor, angiotensin conversing enzyme, lysozyme, Lyme titers, Interferon-gamma release assays, Rapid Plasma Reagin, all of which were unrevealing. Fluorescein angiography (Panel C) revealed multiple punctate hyperfluorescent dots (white arrowheads) with dye leakage and disc hyperfluorescence indicating severe papillitis (black arrowheads). Findings on audiometry were within normal limits. The patient was diagnosed with VKH disease. High dose methylprednisolone pulse was started (10mg/kg/day), followed by 60 mg prednisolone and 75 mg of cyclosporine per day with progressive tapering of oral steroids. Visual acuity improved to 20/25 after 1month with complete resolution of the intraocular inflammation."}
+{"text": "Odocoileus virginianus) represents one of the most successful and widely distributed large mammal species within North America, yet very little nucleotide sequence information is available. We utilized massively parallel pyrosequencing of a reduced representation library (RRL) and a random shotgun library (RSL) to generate a complete mitochondrial genome sequence and identify a large number of putative single nucleotide polymorphisms (SNPs) distributed throughout the white-tailed deer nuclear and mitochondrial genomes. A SNP validation study designed to test specific classes of putative SNPs provides evidence for as many as 10,476 genome-wide SNPs in the current dataset. Based on cytogenetic evidence for homology between cow (Bos taurus) and white-tailed deer chromosomes, we demonstrate that a divergent genome may be used for estimating the relative distribution and density of de novo sequence contigs as well as putative SNPs for species without draft genome assemblies. Our approach demonstrates that bioinformatic tools developed for model or agriculturally important species may be leveraged to support next-generation research programs for species of biological, ecological and evolutionary importance. We also provide a functional annotation analysis for the de novo sequence contigs assembled from white-tailed deer pyrosequencing reads, a mitochondrial phylogeny involving 13,722 nucleotide positions for 10 unique species of Cervidae, and a median joining haplotype network as a putative representation of mitochondrial evolution in O. virginianus. The results of this study are expected to provide a detailed template enabling genome-wide sequence-based studies of threatened, endangered or conservationally important non-model organisms.The white-tailed deer ( Odocoileus virginianus), a highly successful and widely distributed ruminant mammal species of the order Artiodactyla and family Cervidae Odocoileus, the primary species are the white-tailed deer (O. virginianus) and mule deer , and Columbian white-tailed deer (O. virginianus leucurus) Based primarily on geographic variation in body size, differences in antler growth, and other relatively minor morphological characteristics, as many as 38 subspecies of de novo approaches which will rapidly enable sophisticated research programs for biologically important species for which research funds are limited.Unlike most traditional model organisms, and many free ranging wildlife species, white-tailed deer are distributed across a large range that includes both free ranging and captive populations, with a recent trend in North America toward establishing captively-propagated livestock lines from founders originating from a variety of wild populations. The farming of deer, and particularly white-tailed deer, has become a significant alternative livestock industry within the U.S. and Canada de novo approach, and contig alignments were used to identify a large number of putative single nucleotide polymorphisms (SNPs) distributed throughout the nuclear and mitochondrial genomes. Herein we also produced a complete mitochondrial genome sequence assembly for the white-tailed deer, with annotations supported by comparative sequence analysis, and a Bayesian mitochondrial phylogeny involving 10 unique species of Cervidae. Validated mitochondrial SNP variation and a median joining haplotype network analysis were utilized to investigate mitochondrial evolution in O. virginianus. Based upon established homology between domestic cow (Bos taurus) and white-tailed deer chromosomes B. taurus genome assembly to estimate the genomic distribution and relative density of white-tailed deer contigs and putative SNPs. Finally, we conducted a functional annotation analysis to characterize and classify the genomic information content of contigs produced from the de novo assembly of the pyrosequencing data. Our results clearly demonstrate that species-specific de novo assemblies in conjunction with comparative contig overlay can be used to enable whole-genome analyses for species with little or no genome sequence data. Moreover, we also utilize novel genome-wide sequence data and reagents to produce the first large-scale genome-wide polymorphism and comparative analyses for O. virginianus. The results of this study will enable genomics research for all species of Odocoileus, including the endangered Florida key deer, and will facilitate efforts to identify genetic variation associated with health-related trait information, genome-wide signatures of selection, and genomic variation underlying mechanisms of adaptation.We generated a reduced representation library (RRL) AluI restriction enzyme digestion of a pooled DNA sample followed by a manual reduction in genome complexity via gel excision and purification of size-selected (\u2248350\u2013400 bp) DNA fragments de novo assembly of RRL sequence reads, repeat masking of the resulting contigs, and utilization of the masked contig sequences to perform a reference assembly using the RRL sequencing reads (CLC Genomics Workbench 3.7.1). The resulting assembly contained 55,526 contigs comprising 19,207,189 bp of nucleotide sequence, with an average contig length of 346 bp. The minimum estimated repetitive DNA content for the 55,526 contigs was approximately 17%, as predicted by RepeatMasker (Human and/or Bovine Repeat Libraries). This relatively low estimate reflects our inability to mask all white-tailed deer repeats given the absence of a complete species-specific repeat library. Utilization of the masked contigs to perform a RRL reference assembly produced 44,385 final contigs averaging 338 bp, with approximately 6.2 sequence reads/contig, and a mean depth of 4.2X  via blastn resulted in 18,301 contigs producing 19,667 E-value informative hits  to either a single chromosome  or a single chromosome plus one unknown chromosome . These alignment criteria were chosen to maximize the likelihood of achieving unambiguous alignments while also allowing for potential gene family members, duplications, and limitations of the bovine genome assembly . Overall, the average percent identity was approximately 92%, with an average alignment length of 306 bp, and 17,084 contigs (93%) produced one unique alignment to a bovine chromosome .B. taurus and white-tailed deer.Collectively, 6,877 putative SNPs  were detected within 18,301 blastn-aligned contigs using a 3X minimum depth of coverage for all potential variable sites , with 5,CHRM3 and ZNF33B ; and 2) Within a putative intronic region of LOC532077 . Both bovine regions are near a small break in the cattle-human comparative map Odocoileus species, with both white-tailed and mule deer possessing five more autosomes than cattle Interestingly, we observed a disproportionately large number of SNPs for deer contigs that aligned with BTA28. Further investigation revealed two clusters comprising 14 total contigs that aligned to BTA28 as follows: 1) Between To functionally characterize the sequence content of 18,301 blastn-aligned contigs, we performed functional annotation, pathway mapping, and putative ortholog matching by mapping the assembled sequences onto relevant classification schemes such as Gene Ontology (GO) terms de novo assembly process, which resulted in 126,980 contigs (average contig length of 433 bp) representing 55,020,760 bp of sequence. The minimum estimated repetitive content predicted by RepeatMasker was approximately 21% (Human and/or Bovine Repeat Libraries). After masking the de novo contigs and performing a reference assembly, 94,070 final contigs averaging 400 bp, with approximately 5.0 reads/contig, and a mean depth of 3.4X remained  from a single male deer included in the RRL and produced 778,792 sequence reads comprising 286,843,168 bp on a Roche GS FLX instrument. The pooled RRL and RSL reads  were assembled via CLC Genomics Workbench 3.7.1 using the previously described three stage remained . Neverthremained . Final cremained .From the pooled analysis we detected 17,813 putative SNPs  within 56,084 blastn-aligned contigs using a 3X minimum depth of coverage requirement for potential variable sites , S8. NotB. taurus and caribou (Rangifer tarandus) mitochondrial genome refseqs  in conjunction with BLAST , we successfully annotated 13 white-tailed deer mitochondrial protein coding genes  and two ribosomal RNA genes . Using tRNAscan-SE (http://lowelab.ucsc.edu/tRNAscan-SE/) http://blast.ncbi.nlm.nih.gov/Blast.cgi; blastn) produced a top hit  to the complete mitochondrial genome of R. tarandus (GenBank Accession NC_007703).In the RRL analysis, only six contigs provided evidence for a putative mitochondrial origin . HoweverTo functionally characterize the sequence content of the 56,084 blastn-aligned contigs, the assembled sequences were again mapped onto the relevant classification schemes, with 5,057 contigs (9%) producing putative functional hits and detailed annotation data, including 606 identified functional ontology terms, categories, and keywords . Pooling12S rRNA, 16S rRNA, ND1, ND2, COX1, COX2, ATP8, ATP6, COX3, ND3, ND4L, ND4, ND5, ND6, and CYTB genes were used to produce the phylogeny. Distance, maximum composite likelihood, and maximum parsimony approaches (transitions+transversions) employing bootstrap resampling produced similar overall tree topologies, with the exception that Elaphodus cephalophus and Hydropotes inermis could not be unambiguously placed within the tree due to inadequate bootstrap support . Our Bayesian mitochondrial phylogeny (H. inermis) is more closely related to Odocoileinae (new world deer) than any other subfamily represented in our analysis. These findings are generally consistent with recent phylogenies produced from either partial mitochondrial genome sequences O. virginianus within our tree is consistent with a nuclear phylogenomics study involving 39,695 parsimony informative characters derived from 40,843 nuclear SNPs Using a DNA panel of 96 white-tailed deer that included the 16 deer used to create the RRL and RSL, we estimated the proportion of total putative SNPs that were likely to be valid by fluorescent allele-specific PCR hylogeny  providesCYTB gene for the white-tailed deer ; Bos, including B. taurus, B. indicus, B. frontalis, and B. javanicus . Importantly, amino acid 211 of the CYTB gene falls within a domain of unknown function according to the Simple Modular Architecture Research Tool online (http://smart.embl-heidelberg.de/). The unusual nature of this shared synonymous polymorphism provides some potential evidence for either selective and/or functional constraint at amino acid 211 across several highly divergent taxa and should be further investigated.In addition to our phylogenetic analyses, we also aligned the annotated white-tailed deer mitochondrial sequence with known bovine mitochondrial polymorphism data using blastn. The results of our alignments revealed one validated SNP that was conserved among highly divergent taxa. Specifically, nucleotide 633 of the predicted Generation of a white-tailed deer genome sequence assembly would provide a valuable resource for population geneticists and physiologists studying the basis of adaptation and fecundity B. taurus, 2.87 Gb genome; de novo white-tailed deer assembly at a modest cost, with single molecule sequencing de novo genome assemblies. However, every genome sequence needs a good map At a cost of $10,000 per GS FLX instrument run, with each fully optimized run producing approximately 400 Mb of sequence data, a theoretical 1X coverage of the white-tailed deer genome would cost approximately $70,000, assuming a genome size similar to that of the domestic cow  RRL AluI; HaeIII; New England Biolabs) which recognize four base sequences  and produce blunt-ended fragments were tested via overnight digestion of 2.8 \u00b5g of white-tailed deer DNA . AluI was selected for RRL preparation based on modest repetitive content observed within size-selected swine digestion fragments In the absence of a genome sequence against which to perform an AluI, as suggested by the manufacturer (New England Biolabs). The resulting fragments were separated via 2.5% ULTRA-SIEVE high resolution agarose (IBI Scientific) gel electrophoresis according to instructions for enhanced separation (IBI Scientific), with ethidium bromide staining for visualization. Three regions of the gel were excised for purification: A) Fragments \u2248350\u2013400 bp, with efforts to avoid a faint band at \u2248340 bp; B) Fragments \u2248220\u2013280 bp; and C) Fragments \u2248160\u2013180 bp. Restriction fragments were purified using the Qiaquick Gel Extraction Kit (Qiagen), with an extended elution incubation period (10\u201312 min) and reduced elution volume (20 \u00b5l). Following gel purification, the smaller fragments were archived and the largest fragment population (\u2248350\u2013400 bp) was utilized for pyrosequencing  unrelated white-tailed deer representing a sampling of northern and southern U.S. nuclear germplasm derived from both captive and free ranging populations. Ethical clearance is not applicable to samples obtained from lawfully harvested white-tailed deer. A total of 14 \u00b5g of DNA was digested overnight  with quencing . A sequeO. virginianus) utilized in the preparation of the RRL was selected and a GS FLX Titanium Rapid Library was prepared via nebulization, fragment end repair, random ligation of sequencing adaptors, fragment size selection, and quantitation as directed by the manufacturer (Roche Applied Science). All subsequent procedures also followed manufacturer protocols (Roche Applied Science).To construct a white-tailed deer RSL, one male white-tailed deer (http://www.repeatmasker.org/). Unmasked sequence reads were imported into CLC Genomics Workbench 3.7.1 and a strict de novo assembly was performed with user defined parameters: add conflict annotations\u200a=\u200ayes, conflict resolution\u200a=\u200avote , create report\u200a=\u200ayes, create sequence list\u200a=\u200ayes, non-specific matches\u200a=\u200aignore, minimum contig length\u200a=\u200a200 bp, mismatch cost\u200a=\u200a2, insertion cost\u200a=\u200a3, deletion cost\u200a=\u200a3, minimum read length fraction\u200a=\u200a0.90, minimum fraction of identity (similarity)\u200a=\u200a0.90. Contigs produced were processed with RepeatMasker , and the masked contigs became the reference sequences used for SNP discovery; an approach similar to that used for the rainbow trout Two assemblies, each with SNP detection and BLAST annotation analyses were performed using identical workflows. For the first assembly, only sequence reads generated from the RRL were utilized (RRL only), whereas the second assembly included sequence reads from both the RRL and the RSL (Pooled RRL+RSL). In both cases, a three step assembly procedure was utilized in conjunction with CLC Genomics Workbench 3.7.1 (CLC Bio) and RepeatMaster  which is a high throughput distributed BLAST engine based upon WND-BLAST White-tailed deer consensus contig sequences were mapped to functional classification schemes such as Gene Ontology (GO) terms Nuclear SNPs were selected from white-tailed deer contigs that produced a single blastn hit  to one discrete bovine chromosomal coordinate . All SNPhttp://www.ebi.ac.uk/Tools/clustalw2/index.html), with manual adjustment . A Bayesian approach implemented within the program MrBayes 3.1.2 6 generations, GTR model with gamma-distributed rate variation, and four simultaneous Markov chains B. taurus outgroup was constructed and visualized within TreeView 1.6.6. For comparison, we also constructed phylogenetic trees using distance (Kimura 2 parameter), maximum composite likelihood, and maximum parsimony (transitions+transversions) with bootstrap resampling , as referenced and implemented within the program MEGA4 All mitochondrial sequences were aligned using the ClustalW2 webserver  of 19,667 blastn hits (E\u22641e-50) for 18,301 white-tailed deer (WTD) sequence contigs and 6,877 putative SNPs (\u22653X coverage) derived from sequencing a WTD reduced representation library (RRL).(TIF)Click here for additional data file.Figure S2Comparative Contig Overlay with Putative SNPs. Histogram displaying the bovine chromosome locations (Btau4.0) of 17,084 uniquely aligned (E\u22641e-50) white-tailed deer (WTD) sequence contigs and 5,710 putative SNPs (\u22653X coverage) derived from sequencing a WTD reduced representation library (RRL).(TIF)Click here for additional data file.Figure S3Comparative Contig Overlay with Putative SNPs. Histogram displaying the bovine chromosome locations (Btau4.0) of 61,553 blastn hits (E\u22641e-50) for 56,084 white-tailed deer (WTD) sequence contigs and 17,813 putative SNPs (\u22653X coverage) derived from sequencing a WTD reduced representation library (RRL) and random shotgun library (RSL).(TIF)Click here for additional data file.Figure S4AluI, a 2.5% Ultra Sieve Gel (IBI Scientific) with ethidium bromide staining, and the New England Biolabs 100 bp ladder.Reduced representation library (RRL). White-tailed deer (WTD) genomic DNA used in the preparation of a RRL via overnight digestion of genomic DNA using (TIF)Click here for additional data file.Table S1White-tailed Deer RRL Contig Table.(XLSX)Click here for additional data file.Table S2White-tailed Deer RRL Informative blastn Hits (E#1e-50).(XLSX)Click here for additional data file.Table S3White-tailed Deer RRL Putative SNPs ($3X coverage).(XLSX)Click here for additional data file.Table S4White-tailed Deer RRL Functional Annotation.(XLSX)Click here for additional data file.Table S5White-tailed Deer RRL plus RSL (Pooled) Contig Table.(XLSX)Click here for additional data file.Table S6White-tailed Deer RRL plus RSL (Pooled) Informative blastn Hits (E#1e-50).(XLSX)Click here for additional data file.Table S7White-tailed Deer RRL plus RSL (Pooled) Putative and Validated SNPs ($3X coverage).(XLSX)Click here for additional data file.Table S8White-tailed Deer RRL plus RSL (Pooled) Mitochondrial SNP Table ($3X coverage).(XLSX)Click here for additional data file.Table S9White-tailed Deer RRL plus RSL (Pooled) Functional Annotation.(XLSX)Click here for additional data file."}
+{"text": "In the longer term, correction of iPSC from human patients with CGD has therapeutic potential not only through generation of transplantable haematopoietic stem cells, but also through production of large numbers of autologous functional neutrophils.Murine models of human genetic disorders provide a valuable tool for investigating the scope for application of induced pluripotent stem cells (iPSC). Here we present a proof-of-concept study to demonstrate generation of iPSC from a mouse model of X-linked chronic granulomatous disease (X-CGD), and their successful differentiation into haematopoietic progenitors of the myeloid lineage. We further demonstrate that additive gene transfer using lentiviral vectors encoding  CYBB gene on chromosome Xp21.1 encoding membrane bound phoxgp91 (where phox stands for phagocyte oxidase). X-CGD in human patients can be cured by haematopoietic stem cell transplantation from HLA genotypically-matched donors with high rate of success. Gene therapy using gammaretroviral vectors has also proved to be useful for short term treatment of life-threatening infection, although complicated by insertional mutagenesis. Treatment of those patients without HLA-matched donors remains problematic. In addition to haematopoietic stem cell (HSC) based therapy, refractory infections in CGD patients can be successfully treated using repeated infusions of functional allogeneic neutrophils, although this strategy often results in exaggerated inflammation and allo-immunisationThe successful application of induced pluripotent stem cell (iPSC) technology in murine models of human diseases, and in generating disease-free autologous cells from patient samples offers considerable potential for development of personalized cell based therapies of monogenic disorders th and 5th week and subsequent histological analysis of tumour sections revealed the presence of ectodermal , mesodermal (cartilage) and endodermal (gut epithelium) structures as shown in Induced pluripotent stem cells (iPSCs) generated from adult fibroblasts of X-CGD mice were adapted to feeder-free condition for five passages and subsequently characterized for stem cell morphology , alkaline phosphatase activity, and expression of pluripotency markers Sox2, Oct4, Klf4, Nanog, SSEA-1, and c-Myc . Based oin-vitro haematopoietic differentiation of mouse embryonic stem cells and iPSC with minor modificationsIn-situ immunostaining further confirmed the presence of cellular derivatives from all three germinal layers  to their cognate receptors in a stage and lineage specific manner resulting in the derivation of mature granulocytes or monocytes/macrophages. The scheme for differentiation is outlined in lineage negative, Sca-1 positive, c-kit positive (LSK) population of nascent haematopoietic stem cells (7.38%) as shown in It has been previously shown that reprogrammed murine fibroblasts can be induced to differentiate into cells of the mesodermal lineages when cultured on collagen type IV (ColIV)LSK cells were assayed for their clonogenic haematopoietic potential by culturing in semi-solid medium containing suitable cytokines promoting myeloid differentiation. It has been shown previously that lineage negative, Sca-1 positive bone marrow cells consist of a virtually pure population of multilineage haematopoietic stem cellsphoxgp91 transgene expressed from an internal spleen focus forming virus (SFFV) derived promoter (LentiSFFVgp91) at different multiplicities of infection (m.o.i). CFU derived from transduced EBs were analysed for functional activity of the NADPH-oxidase by Nitroblue Tetrazolium (NBT) assay. CFUs derived from lentivirus transduced EBs showed positive staining in the NBT assay  were transduced with a self-inactivating (SIN) lentiviral vector encoding a codon optimized BT assay  comparedBT assay . We alsoBT assay . This isBT assay , we obsein-vitro restoration of NADPH-oxidase activity in derived X-CGD granulocytes by transduction of the iPSCs  with lentivectors expressing the phoxgp91, and therefore have provided a proof-of-principle that iPSC technology can be combined with gene therapeutic approaches for modelling a rare primary immunodeficiency such as CGD. Vector design is an important consideration for effective genetic correction of cells prior to reprogramming as epigenetic modifications during this process may lead to irreversible silencing. Utilisation of iPSC for screening alternative vector configurations may therefore prove to be particularly useful. Further investigation is needed to determine if haematopoietic stem cells (HSCs) generated from the gene corrected iPS cells can be employed for long-term multi-lineage reconstitution of murine models and functional correction of the disease phenotype (i.e. susceptibility to invading microorganisms). Derivation of HSCs from human embryonic stem (hES) cell lines and iPSC remains a significant hurdle to translation of this technology, but has obvious clinical application for transplantation. Several groups have recently reported the successful derivation of mature and functional neutrophils from hES cell linesIn this study we have demonstrated successful generation of iPSCs from X-CGD mice and their induced differentiation into haematopoietic myeloid progenitors and functional neutrophils. We observed no significant difference between iPSCs generated from wild-type mice and those generated from X-CGD mice regarding their ability to differentiate. We have also demonstrated All animals were handled in strict accordance with good animal practice as defined by UK Home Office Animal Welfare Legislation, and all animal work was approved by the Institutional Research Ethics Committee  and performed under project license number 70/7024.phox or pCCLSFFVcogp91phoxphox and LentiSFFVgp91phox respectively).Generation and titration of retroviral vectors used for reprogramming adult fibroblasts isolated from X-CGD mice, and the self-inactivating (SIN) lentiviral vectors used for the purpose of correcting the X-CGD genetic defect have been previously described tm1Din/J deficient on phoxgp91X-CGD mice B6.129S6-Cybb4 fibroblasts were seeded on each well of a six-well plate. Next day, the cells were infected with a cocktail of retroviral reprogramming vectors together with protamine sulphate. After three days, transduced cells were split into gelatine-coated six-well plates and maintained in ESGRO Complete Plus Clonal medium [Millipore] with regular medium changes until colonies appear and are ready for clonal isolation and expansion. The iPSC were cultured feeder-free on gelatine-coated flasks in ESGRO Complete Plus Clonal medium at 37\u00b0C, 5% CO2. Cells were passaged using Accutase [Millipore].Adult mouse fibroblasts isolated from X-CGD mice using standard protocol were cultured in Dulbecco's modified Eagle's medium (DMEM)  supplemented with 10% fetal calf serum (FCS) and 1% penicillin-streptomycin for two to three passages under standard conditions and then frozen into aliquots. The day before transduction, 5\u00d7106 iPS cells in matrigel (per site per injection) were injected subcutaneously into immunodeficient mice . Mice were sacrificed within 4-6 weeks after injection and teratoma was dissected and processed for haematoxylin/eosin staining and immunostaining with suitable antibodies. Following primary antibodies along with suitable secondary conjugated antibodies were used in this study: anti-tubulin beta III isoform (Tuj1) , anti-alpha-actinin , anti-alpha fetoprotein  . As control for non-specific staining, fluorophore-conjugated secondary antibodies were employed in absence of primary antibodies. Teratoma images were processed with ImageJ software.1\u00d7104 cells per well in 1 ml of \u03b1\u2013minimum essential medium [Invitrogen] supplemented with 20% FBS, 1% penicillin/streptomycin, interleukin (IL)-3 (5 ng/ml), and granulocyte colony-stimulating factor  for up to 7 days. Half of the medium with cytokines was replaced every 2 days. OP9 cells were obtained from American Type Cell culture (ATCC).For Embryoid Body (EB) formation, iPSC were dissociated using enzyme free cell dissociation buffer, resuspended in LIF free medium and cultured at low attachment condition. For the collagen IV cultures, iPSC derived EBs were triturated and transferred to collagen IV-coated flasks [BD Biosciences]. For OP9 co-culture, Flk1-positive iPSC derived from collagen IV cultures were enriched by fluorescence activated cell sorting (FACS) and plated on OP9 stromal cells in 24 well plates at a concentration of 2 \u00d7 10Cells were pelleted by centrifugation, washed in PBS, and stained with fluorescein isothiocyanate (FITC)-, phycoerythrin (PE)-, or allophycocyanin (APC)-conjugated monoclonal rat anti-mouse antibodies against Flk1, Sca1, c-Kit, Gr-1, and CD11b. Nonspecific fluorochrome and isotype matched Ig's served as controls. Dead cells were excluded from analysis and all analysis was performed using a BD LSRII flow cytometer. FACS data were analyzed using FlowJo software.+, lineage negative c-kit+, Sca-1+ cells were plated in methylcellulose medium containing cytokines for myeloid differentiation . Colonies were scored between 1-2 weeks.To determine the myeloid potential, iPSC derived Flk-1Methylcellulose plate containing the CFUs was overlaid with one-fifth volume of NBT-saturated RPMI-1640 medium (Invitrogen) containing 100 ng/ml PMA (Sigma) and 5% human serum albumin  and incubated at 37\u00b0C. After 30 minutes of incubation, the dishes were examined on an inverted microscope, and the colonies with blue formazan precipitates were scored as NBT-positive.CFU colonies were extracted from methylcellulose cultures and washed rigorously to get rid of any methylcelluose. The cells were incubated with 30 \u00b5M DHR at 37\u00b0C for 5 min and stimulated with 5 \u00b5g/ml PMA at 37\u00b0C for 30 min. ATG AAA GAT TTT ATT TG 3\u2032; Reverse, 5\u2032 TCT AAA AAC CAT CTA CTC TTA ACC T 3\u2032. PCR products were cloned into TOPO-TA vector (Invitrogen) and sequenced.Genomic DNA was isolated from cells using the DNeasy kit (Qiagen) and sodium bisulfite treatment of genomic DNA was performed using the EpiTect bisulfite kit (Qiagen). PCR primers were designed based on converted sequences. Primers were chosen to cover partial length of the SFFV covering the enhancer region (containing 11 CpG sites). PCR conditions were as follows: first round, annealing temperature 58\u00b0C, 33 cycles; second round, annealing temperature 56\u00b0C, 32 cycles. The PCR primer sequences used were as follows: (i) SFFV promoter: Forward, 5\u2032GGG GGA"}
+{"text": "Patients with acute pulmonary embolism (PE) who has normal systemic arterial pressure and right ventricular (RV) dysfunction are considered to have sub-massive pulmonary embolism (SPE), with 3-month mortality risk of 21% . A studyTwo patients were evaluated at the Dammam Medical Complex, Dammam, Saudi Arabia between June and December 2012. The diagnosis of PE was established by helical computed tomography (CT) angiogram that showed a thrombus at both pulmonary arteries at presentation. They had normal systemic blood pressure, PH documented by echocardiography demonstrated an estimated systolic pulmonary artery pressure >45 mm Hg and findings of RV dysfunction suggestive of acute changes. Both patients received therapeutic anticoagulation with low-molecular-weight heparin and targeted warfarin dose to international normalized ratio of 2\u20133. They were still symptomatic and required more oxygen, for which they were offered TT. They declined TT, but agreed to receive inhaled iloprost through a nebulized device of 2.5\u20135.0 \u00b5g per inhalation for 15 min, 8\u00d7 daily for 3 months.The main efficacy index was defined as the changes in WHO-FC, 6MWD, oxygen saturation, and echocardiography parameters during 3-month inhalation therapy. These parameters were assessed at baseline, 3-month post-inhalation, and 3-month post-cessation of iloprost. Both patients tolerated the treatment well. They showed significant improvement in their clinical symptoms and echocardiographic parameters .In conclusion, iloprost might have favorable acute effects on symptoms, exercise tolerance, and pulmonary hypertension in sub-massive pulmonary embolism.Abdullah Hassan Alsaghir Department of Medicine Dammam Medical Complex Dammam, Saudi ArabiaEmail: asaghir4000@yahoo.comSoror Abdullah Alaithan Department of Medicine Dammam Medical Complex Dammam, Saudi ArabiaBasima Alsihati Department of Medicine Dammam Medical Complex Dammam, Saudi ArabiaDhia Naji Alhajjaj Department of Medicine Dammam Medical Complex Dammam, Saudi Arabia"}
+{"text": "Positive end-expiratory pressure (PEEP) improves oxygenation in acute lung injury (ALI) patients by increasing end-expiratory lung volume (EELV). Electrical impedance tomography (EIT) is a relatively new non-invasive bedside method to monitor regional distribution of tidal ventilation and EELV changes, validated in preclinical studies. We tested EIT as a monitor of PEEP-induced tidal redistribution and EELV changes in ALI patients, and the relationship between EIT parameters and oxygenation.\u00ae; Dr\u00e4ger Medical GmbH, L\u00fcbeck, Germany) dividing the lung imaging field into four contiguous same-size regions of interest (ROIs): ventral right (ROI 1) and left (ROI 2) and dorsal right (ROI 3) and left (ROI 4). EIT allowed us to measure changes in EELV at different PEEP levels by measuring differences in end-expiratory total lung electrical impedance. We randomly performed the following two steps for 15 minutes, leaving tidal volume and FiO2 unchanged: PEEPlow  and PEEPhigh (PEEPlow +5 cmH2O). At the end of each step, we recorded: ventilation parameters, arterial blood gas analysis, percentage of tidal ventilation distribution in the four ROIs and EELV change. Analyses were performed by paired t test and linear regression.We enrolled 14 consecutive ALI patients admitted to our ICU, intubated and undergoing mechanical ventilation. We monitored the regional tidal ventilation distribution by means of a new EIT system , the proportional distribution of tidal ventilation changed in all four ROIs , moving from ventral to dorsal, and EELV increased by 349 \u00b1 121 ml. Changes in PaO2/FiO2 correlated better with ventral-to-dorsal shifts of tidal ventilation than with EELV changes .Patients were 55 \u00b1 12 years old and seven were women. ALI etiology was: trauma (14%), septic shock (21%), pneumonia (37%) and postoperative respiratory failure (28%). PEEPEIT allowed us to detect ventral-to-dorsal tidal ventilation redistribution at higher PEEP levels. This mechanism may be a key determinant of PEEP-induced oxygenation improvement."}
+{"text": "Rapid and dynamic changes in the expression of small RNAs are seen during ovule and fiber development in allotetraploid cotton. Cotton fiber development undergoes rapid and dynamic changes in a single cell type, from fiber initiation, elongation, primary and secondary wall biosynthesis, to fiber maturation. Previous studies showed that cotton genes encoding putative MYB transcription factors and phytohormone responsive factors were induced during early stages of ovule and fiber development. Many of these factors are targets of microRNAs (miRNAs) that mediate target gene regulation by mRNA degradation or translational repression.Here we sequenced and analyzed over 4 million small RNAs derived from fiber and non-fiber tissues in cotton. The 24-nucleotide small interfering RNAs (siRNAs) were more abundant and highly enriched in ovules and fiber-bearing ovules relative to leaves. A total of 31 miRNA families, including 27 conserved, 4 novel miRNA families and a candidate-novel miRNA, were identified in at least one of the cotton tissues examined. Among 32 miRNA precursors representing 19 unique miRNA families identified, 7 were previously reported, and 25 new miRNA precursors were found in this study. Sequencing, miRNA microarray, and small RNA blot analyses showed a trend of repression of miRNAs, including novel miRNAs, during ovule and fiber development, which correlated with upregulation of several target genes tested. Moreover, 223 targets of cotton miRNAs were predicted from the expressed sequence tags derived from cotton tissues, including ovules and fibers. The cotton miRNAs examined triggered cleavage in the predicted sites of the putative cotton targets in ovules and fibers.Enrichment of siRNAs in ovules and fibers suggests active small RNA metabolism and chromatin modifications during fiber development, whereas general repression of miRNAs in fibers correlates with upregulation of a dozen validated miRNA targets encoding transcription and phytohormone response factors, including the genes found to be highly expressed in cotton fibers. Rapid and dynamic changes in siRNAs and miRNAs may contribute to ovule and fiber development in allotetraploid cotton. Auxin Response Factors (ARFs) and gibberellin signaling  for Gh-MIR164 and [Genbank:GU190713] for Gh-MIR167.All predicted miRNAs were deposited in miRBase. Small RNA sequencing data and miRNA microarray expression data reported in this paper were deposited in the NCBI Gene Expression Omnibus database under the series record numbers [GEO:GSE16632] ([GEO:GSM409656-GSM409659]) and [GEO:GSE16986], respectively. GenBank accession numbers of cotton genomic sequences for two miRNA precursors are [Genbank:N1N1 mutant were enriched from total RNA using a mirVana isolation kit . Each custom-designed chip contained four identical arrays spotted with anti-sense DNA oligonucleotides corresponding to miRNAs (version 9.1) [Arabidopsis Small RNA Project [2PO4, 6 mM EDTA, pH 7.4) and 3\u00d7 SSPE and twice with 0.5\u00d7 SSPE (each solution containing 0.05% Triton X-100). Finally, hybridized chips were scanned using a Genepix 4000B , and data were extracted using software provided by CombiMatrix. A total of 12 hybridization intensities in three biological replicates per miRNA were obtained, and log values of hybridization intensities were used for normalization and statistical analysis. If the hybridization intensities of a miRNA were not significantly higher than the background signals , the miRNA was considered to be not expressed.miRNA microarrays were performed using the arrays manufactured by CombiMatrix  . Small Rion 9.1) , tasiRNA Project . After pi in replicate (R)j and stages (S)k is as follows:The statistical analysis was performed as previously described . Brieflywhere i = 1... 117; j = 1, 2, 3; k = 1, 2, 3, 4; and G, R, and S are main sources of variation from gene (G), replicate (R), and stages or conditions (S).o): Sk + (GS)ik = Sk' + (GS)i'k', was used to test the miRNA difference between two stages . Differential accumulation of miRNAs among TM-1 fiber (+7 DPA), N1N1 mutant ovules (+3 DPA), TM-1 fiber-bearing ovules (+3 DPA), and TM-1 leaves was tested using F-test in the linear model for distinct mature miRNAs:The null hypothesis  of Benjamini and Hotchberg .32P-ATP using T4 Polynucleotide kinase . The blot was prehybridized in Church buffer [Total RNA (25 \u03bcg) per sample was resolved in a 15% denaturing polyacrylamide gel  and was transferred to Amersham Hybond\u2122-N+ nylon membranes . DNA oligonucleotide probes  were labeled with \u03b3h buffer  for 2 hoTo map the cleavage sites of target transcripts, we used RNA ligation-mediated (RLM) rapid amplification of 5' complementary DNA ends (5' RACE) using a GeneRacer kit  that was modified from a published protocol . In brieHISTONE H3 (AF024716) was used to normalize the amount of gene-specific RT-PCR products [Gene-specific primers were designed using Primer Express version 2.0 software . The qRT-PCR reaction was carried out in a final volume of 20 \u03bcl containing 10 \u03bcl SYBR Green PCR master mix, 1 \u03bcM forward and reverse primers, and 0.1 \u03bcM cDNA probe in a ABI7500 Real-Time PCR system (Applied Biosystems). Cotton products . All reaArabidopsis thaliana; ARF: auxin response factor; Aux: auxin; CGI: Cotton Gene Index; DCL: Dicer-like; DPA: days pre-/post-anthesis; EST: expressed sequence tag; Gh: Gossypium hirsutum; Gm: Glycine max; IAA: indole acetic acid; miRNA: microRNA; Mt: Medicago truncatula; NAM: no apical meristem; Os: Oryza sativa; Pol: polymerase; Pp: Physcomitrella patens; Pt: Populus trichocarpa; qRT-PCR, quantitative RT-PCR; RACE: rapid amplification of complementary DNA ends; rasiRNA: repeat associated siRNA; Sb: Sorghum bicolor; So: Saccharum officinarum; siRNA: small interfering RNA; tasiRNA: trans-acting siRNA; TIR1: transport inhibitor response 1; TM-1: Texas Marker-1; TPQ: transcripts per quarter million; WGS: whole-genome shotgun; Zm: Zea mays.AGO: Argonaute; At: ZJC designed experiments, PM performed miRNA expression assays and validated miRNA targets, AWW made small RNA libraries and performed initial sequence analysis, VA analyzed small RNA sequence data and predicted miRNA targets, VR performed miRNA microarray experiments, MH analyzed mRNA microarray data, XG performed miRNA target gene expression assays, XC analyzed miRNA data, BAT and DMS contributed plant materials, and PM, VA, AWW and ZJC analyzed data and wrote the paper.The following additional data are available with the online version of this paper: a table listing normalized small RNA reads (transcripts per quarter million) per megabase of available repetitive sequences  per megabase of available repetitive sequences.Click here for fileCotton miRNAs and their predicted precursors.Click here for fileCotton miRNAs and their targets predicted from ESTs.Click here for fileDifferentially expressed miRNAs in cotton.Click here for filePrimers for target cleavage assays and oligonucleotide probes for small RNA blot analysis.Click here for file"}
+{"text": "Severe right ventricular dysfunction (RVD) is an important prognostic parameter in dilated cardiomyopathy (DCM). The relationship between myocardial fibrosis of the left ventricle (LV) and particularly the septum and right ventricular (RV) function remains poorly understood. We sought to investigate this relationship in a large cohort of DCM patients using cardiovascular magnetic resonance (CMR).We studied 257 patients  with known DCM using a clinical 1.5 T CMR scanner (Philips Achieva). Short axis slices covering entirely both ventricles were acquired using standard SSFP-sequences for measurement of LV and RV volumes and ejection fraction (EF). Focal myocardial fibrosis was assessed in late gadolinium enhancement (LGE) CMR images acquired 10 minutes after i.v. injection of 0.2mmol/kg Gd-DTPA (Magnevist). SSFP and LGE CMR images were assessed by different observers who were blinded to measurement results and clinical data. Severe RVD was defined as RVEF<35%. In a subgroup of patients (n=96) invasive measurement of pulmonary artery pressure was performed.Mean LVEF was 35\u00b114% while mean RVEF was 42\u00b113%. Focal myocardial fibrosis was present in 92 (36%) patients and was located a) intra-murally within the inter-ventricular septum in 29 patients (LGE -septum) or b) sub-epicardially/diffuse in 63 patients (any-LGE). None of the patients had sub-endocardial LGE. LGE-septum patients exhibited a significantly higher RVEF , a higher RV EDV index  and a higher RV ESV index  compared to the patient group with `any-LGE`. LVEF was not significantly different  between the two LGE-groups. Fifty-five (21%) patients had severe RVD (<35%RVEF) with a mean RVEF of 24\u00b18%. The presence of myocardial fibrosis  was not significantly associated with severe RVD (p= 0.23). Also, there was no age and gender dependency in RVD. Invasively, RVD patients had significantly higher pulmonary artery pressure . RV EDV index correlated significantly with pulmonary artery pressure .The presence of LGE indicating focal fibrosis is not related to severe RV dysfunction in DCM. Interestingly, patients with ventricular septal fibrosis, i.e. mid wall sign, exhibited superior RV function. This may be explained by the pronounced mechanical shear stress exerted by the well-functioning RV on the inter-ventricular septum, potentially inducing focal myocardial fibrosis in DCM patients.none"}
+{"text": "This study sought to compare dual IR prepulse and conventional IR sequences with histopathological findings in an animal model of reperfused acute myocardial infarction.Cardiovascular magnetic resonance (CMR) deploying late gadolinium-enhanced inversion-recovery (IR) sequence is today's standard reference for myocardial infarction evaluation. However, the conventional IR sequence can yield poor image contrast between infarct and intracavity blood pool which complicates precise endocardial border delineation. This compromises accurate infarct size determination and small subendocardial infarct detection. PeelUnder general anaesthesia, ischaemia-reperfusion injury was induced in nine pigs (40 kg) by 40-minute balloon occlusion in LAD followed by reperfusion. One day post-injury, CMR was performed using conventional IR and dual IR sequences at 1.5T. After this, the pigs were euthanized. Their hearts were then explanted, axially cut and incubated in a 2,3,5-triphenyltetrazolium chloride (TTC) solution (10%). CMR images were matched to the corresponding histopathology and the infarct sizes were compared.Nine pigs underwent the ischaemia-reperfusion procedure. Two were excluded due to ECG-triggering problems. Five out of the remaining seven pigs showed myocardial infarction after TTC staining. Both dual IR and conventional IR confirmed infarctions in all five pigs. Short-axis dual IR images show improved blood suppression compared with IR images and show good correlation with TTC images Figure . In BlanIn this preliminary, experimental study, the dual IR prepulse resulted in more accurate myocardial infarct size determination compared with conventional IR sequence owing to better blood suppression.King's College London."}
+{"text": "P301L)4510, with those expressing comparable levels of wild type human tau, rTg(tauwt)21221. rTg(tauP301L)4510 mice express the human tauP301L variant in their forebrains and display cellular, histological, biochemical and behavioral abnormalities similar to those in human FTD, including age-dependent differences in tau phosphorylation that distinguish them from rTg(tauwt)21221 mice. We compared FTD-hallmark tau phosphorylation in neurospheres from rTg(tauP301L)4510 mice and from rTg(tauwt)21221 mice. The tau genotype-specific phosphorylation patterns in neurospheres mimicked those seen in mice, validating use of neurosphere cultures as models for studying tau phosphorylation. Genotype-specific tau phosphorylation was observed in 35 independent cell lines from individual fetuses; tau in rTg(tauP301L)4510 cultures was hypophosphorylated in comparison with rTg(tauwt)21221 as was seen in young adult mice. In addition, there were fewer human tau-expressing cells in rTg(tauP301L)4510 than in rTg(tauwt)21221 cultures. Following differentiation, neuronal filopodia-spine density was slightly greater in rTg(tauP301L)4510 than rTg(tauwt)21221 and control cultures. Together with the recapitulation of genotype-specific phosphorylation patterns, the observation that neurosphere lines maintained their cell line-specific-differences and retained SC characteristics over several passages supports the utility of SC cultures as surrogates for analysis of cellular disease mechanisms.Stem cell (SC) lines that capture the genetics of disease susceptibility provide new research tools. To assess the utility of mouse central nervous system (CNS) SC-containing neurosphere cultures for studying heritable neurodegenerative disease, we compared neurosphere cultures from transgenic mice that express human tau with the P301L familial frontotemporal dementia (FTD) mutation, rTg(tau The ability to generate human embryonic stem cell lines by somatic cell nuclear transfer While our goals are to develop and validate approaches that can be applied to patient-specific cell lines, mouse models offer important advantages for experimental analysis. Each human patient is unique, but members of inbred mouse strains are genetically homogeneous, allowing discrimination of variation that may be inherent to SC isolation from genetic effects. Mouse models also allow tracking of the subtle biochemical, histological, and behavioral changes that occur long before clinical signs appear. By exploiting SC lines from well-characterized mouse models, we hope to relate cell culture phenotypes to pre-clinical pathogenic events.P301L)4510  is used to indicate rTg(tauP301L)4510) in which MAPT transgene expression is largely restricted to forebrain cells to avoid early spinal cord pathology that develops in mice with prion protein promoter driven mutant tau Frontotemporal dementia (FTD) is a neurodegenerative disorder in which aggregates comprised of microtubule associated protein tau (MAPT) form in neurons. FTD, like other tauopathies, including Alzheimer\u2019s disease, is characterized by tau phosphorylation and aggregation events associated with neuronal death and dementia. Transgenic mouse lines expressing human MAPT with a proline to leucine mutation at amino acid 301 (P301L) recapitulate aspects of familial FTD P301L) mice and from recently created transgenic mice that express comparable levels of human tauwt, rTg(tauwt)21221, hereafter referred to as rTg(tauwt) Here we report the isolation and characterization of neurosphere lines from rTg(tauP301L) and rTg(tauwt) mice, along with similar lines described in Results, were generated using a bigenic system of responder and activator transgenes. Tg(tauP301L) and Tg(tauwt) mice (designated TRE-tauP301L\u00ad and TRE-tauwt) carry their corresponding tetO-tau responsive element transgenes and were produced and maintained on the FVB/NCr background wt construct was identical to that used to construct Tg(tauP301L)4510 mice except for the presence of a wild type proline codon at position 301. The rTg(tauwt)21221 line expressed human tau at levels comparable to rTg(tauP301L)4510 rTg(tautm1(GFP)Klt Tg(MAPT)8cPdav/J mice, referred to as 8c 0/0Mapt, have a targeted disruption of mouse Mapt exon one and express a complete human MAPT transgene. They have been described previously 0/0Mapt mice were mated with Tg(tauwt), Tg(tauP301L), or Tg(CK-tTA) mice. Mice hemizygous for activator or responder transgenes and heterozygous for endogenous Mapt were backcrossed to the 0/0Mapt line to produce Tg(tauwt) 0/0Mapt, Tg(tauP301L) 0/0Mapt, and Tg(CK-tTA) 0/0Mapt mouse lines on mixed genetic backgrounds that were used to produce 0/0Mapt rTg mice with both the responder and transactivator transgenes.MaptThe studies at McLaughlin Research Institute (MRI), which is fully accredited by AAALAC International, were carried out in accordance with the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health, U.S. Public Health Service. MRI\u2019s Animal Assurance number from the Office of Laboratory Welfare of the National Institutes of Health is A3901\u201301. All procedures involving animals were reviewed and approved by MRI\u2019s Institutional Animal Care and Use committee under protocol GAC-05. Fetuses were harvested from timed pregnant females euthanized by cervical dislocation performed by trained personnel.wt or TRE-tauP301L females were mated with Tg(CK-tTA) males. Neurospheres were isolated from whole brains from individual E14 fetuses using established protocols described previously Smcx and Smcy5 cells/mL in 15 mLs \u201cComplete\u201d NeuroCult NSC medium (Stem Cell Technologies) and maintained in a humidified incubator at 37\u00b0C in 6% O2 and 6.8% CO2 . Neurosphere lines were passaged every 5\u20137 days. Time of passage was determined by neurosphere density and media color change. Colorimetric cell proliferation assays (MTT) to assess neurosphere growth rates were conducted according to the manufacturer\u2019s recommendations .TRE-tau4 cells/well, were plated on fibronectin (Invitrogen) coated 24-well glass bottom plates (Greiner) and placed in a humidified incubator at 37\u00b0C at 6% CO2 6% O2 overnight.For immunofluorescent analysis (IFA) or immunohistochemistry, undifferentiated single cells, 8\u00d7104 cells/well in complete NeuroCult medium (SCT). After overnight culture the growth factor-containing medium was removed and 0.3 \u00b5mol retinoic acid was added every other day for seven days. Between days 8\u201325, cells were fed with B27-containing medium (Gibco) on alternate days. IFA was performed on day 21 or day 25.To induce differentiation, dissociated cells were plated on laminin/poly-L-ornithine (15 \u00b5g/mL poly-L-ornithine and 5 \u00b5g/mL laminin) 24-well coated glass plates at a density of 12\u00d7106 cells from neurosphere lysates, or 10 \u00b5L from a 10% embryonic brain homogenate were electrophoresed on 12% Bis-Tris gels (Invitrogen) and electro-blotted onto PVDF membranes (Millipore). In some cases, neurosphere samples were treated with phosphatase prior to running; protein lysates were suspended in 0.5 \u00b5g/10 \u00b5L of NEBuffer 3 (New England Biolabs) and incubated with 10U/\u00b5L of calf intestinal phosphatase (CIP) (New England Biolabs) for 60 minutes at 37\u00b0C. We used the following anti-tau antibodies: Tau13 at 1\u22365000 (Covance); Tau1 at 1\u2236200 (Chemicon); CP13, AT8, PHF-1, and DA9 (provided courtesy of Dr. Peter Davies) at 1\u2236200. The specificity of these antibodies is summarized in Adult mouse hemibrains for Western blot analysis were prepared as described previously For whole neurosphere IFA, neurospheres were fixed in 4% phosphate buffered paraformaldehyde followed by 30% sucrose and equilibrated at 4\u00b0C overnight. Fixed neurospheres were placed in embedding medium (Sakura Tissue-Tek O.C.T.) and snap frozen in liquid nitrogen. Neurospheres were sectioned at \u221215\u00b0C; 8 \u00b5m sections were adhered to SuperFrost Plus microscope slides (Fisher) and stored at \u221220\u00b0C for later IFA. Cryosectioned neurospheres were stained with the following primary antibodies: rabbit anti-Nestin at 1\u2236200 (Covance); mouse anti-human Tau13 at 1\u22365000 (Covance); mouse anti-Tau46 at 1\u2236600 . The secondary antibodies Alexa488-goat anti-mouse and Alexa546-goat anti-rabbit were used at 1\u22361500 dilution (Molecular Probes).4 and 3% PFA). Cells were permeabilized in 0.3% Triton X-100, placed in blocking buffer , then incubated in primary antibody. Primary antibodies Tau13, Tau46, Tau1, CP13, AT8, PHF-1, and DA9 were used at dilutions described above. Rabbit anti-\u03b2 tubulin III at 1\u22362000 (Covance); chicken anti-MAP2 at 1\u223610,000 (Covance); and rabbit anti-GFAP at 1\u22361000 (Chemicon) also were used. The following secondary antibodies from Molecular Probes were diluted 1\u22361500: goat anti-mouse Alexa Fluor 546; goat anti-mouse Alexa Fluor 488; goat anti-rabbit Alexa Fluor 546; goat anti-rabbit Alexa Fluor 488; goat anti-rabbit Alexa Fluor 647. The goat anti-chicken Alexa Fluor 488 antibody was from Jackson ImmunoResearch, Inc and used at 1\u2236200. Cells were coverslipped with ProLong Gold antifade reagent containing DAPI (Invitrogen). Images were acquired with a Nikon Eclipse TE2000 microscope and analyzed with MetaMorph software. The proportion of total cells expressing human tau (Tau13 positive) was determined for each cell line. Fluorescence intensity and area stained, the threshold parameters, were based on Tg(CK-tTA) control cell fluorescence and fluorescence of cells incubated only with secondary antibody. All image acquisition and cell counts were conducted by an experimenter blind to genotype.For analysis of individual undifferentiated cells plated on fibronectin substrate and differentiated cells plated on LPO substrate, cells were fixed at 37\u00b0C in PIPES fixative  per manufacturers instructions. Neurospheres were probed with Tau13 at a dilution of 1\u22365000.To determine filopodia-spines densities, total Map2 positive neurite lengths were measured 21 or 25 days post-differentiation; an individual not involved in this experiment assigned a code to each slide so the experimenter was blind to genotype. All Map2-positive projections were measured using MetaMorph software and counted along the Map2 positive neurites; projections >12 \u00b5m were called neurites and <12 \u00b5m were called filopodia-spines. The number of filopodia-spines/100 \u00b5m was calculated. Between 75\u2013100 total Map2 and TUJ-1 double positive cells were counted from each cell line. The average filopodia-spine density/cell was calculated for each cell line.wt) and rTg(tauP301L) neurosphere lines. For paired analysis, individual rTg(tauwt) and rTg(tauP301L) were paired within each experiment according to order of harvest (line number); in two experiments the numbers of mutant and wild type lines were not equal, reducing the number of samples from 22 to 20. For the ANOVA, experiment and tau genotype were independent variables with fraction human tau positive, the dependent variable. For ANOVA of the effects of differentiation on the fractions tau positive cells in rTg(tauP301L) and rTg(tauwt) neurosphere lines, differentiation state and tau genotype were the independent variables. Independent variables for analysis of spine density were time post-differentiation and genotype. Post-hoc Bonferroni/Dunn analysis was performed on ANOVA results. Correlation coefficients for the relationship between spine density and fluorescence intensity were calculated using StatPlus.Both ANOVA and paired t tests were performed using StatView 5 for Macintosh  for the determining significance levels for differences in tau expression levels between rTg(tauwt) transgenic line that harbors human wild type 4R0N tau transgenes driven by the same TRE as Tg(tauP301L). When crossed to Tg(CK-tTA) mice, the resulting rTg(tauwt) mice express human wild type tau at levels comparable to those in rTg(tauP301L) mice P301L and TRE-tauwt controls. Activator and responder mouse lines were maintained hemizygous for their respective transgenes; therefore one-fourth of all pups were expected to contain both the activator and responder transgenes and express the protein of interest.We previously generated a Tg (Expression of 12 (E12) . This vewt and Tg(CK-tTA) \u00d7 TRE-tauP301L matings, and were genotyped. All cultures grew as non-adherent free-floating aggregates characteristic of neurospheres (P301L) and rTg(tauwt) cultures contained cells that also expressed human tau (P301L) and rTg(tauwt) neurospheres, and showed that, as in mice, transgenic human tau was expressed at comparable levels in neurospheres derived from each genotype  \u00d7 TRE-tauospheres . Neurospospheres  as previuman tau , but Tg varied in transgene expression. Cryosectioned neurospheres stained with Tau13 indicated that transgene-expressing cells were not preferentially located at the periphery nor deep within most spheres , but neuWe analyzed individual cells for human tau protein levels by measuring Tau13 fluorescence intensity. At passages 3 and 6 we dissociated, fixed, and immunostained neurospheres . Total cwt) fetuses contained a higher proportion of cells expressing human tau than cultures harvested from rTg(tauP301L) fetuses (wt and Tg(CK-tTA) \u00d7 TRE-tauP301L matings. The percentages of cells expressing tauP301L was less in each experiment than the percentages of cells expressing tauwt, though comparison of lines derived from fetuses harvested at different times showed some overlap between mutant and wild type lines. The fraction of positive cells within each culture persisted over passage.Cell lines generated from rTg(tau fetuses . This waP301L)4510 and rTg(tauwt)21221, but at lower levels as assessed by immunoblotting. In a single experiment, we determined the percent of human tau expressing cells present in neurosphere cultures produced from the additional mouse lines. rTg(tauwt)14238 and rTg(tauP301L)14718 mice both express human tau at \u223c50% the level of rTg(tauP301L)4510 and rTg(tauwt)21221. The single neurosphere culture derived from a rTg(tauwt)14238 fetus expressed human tau in 42.5% of its cells, while the three neurosphere cultures derived from rTg(tauP301L)14718 fetuses had 46%, 45%, and 71% expressing cells. The third transgenic mouse line, rTg(tauP301L)14319, expressed human tau at approximately 75% the level of rTg(tauP301L)4510 and expressed human tau in \u223c60% of its cells. In general, the proportions of cells expressing human tau in the additional lines were within the range seen in the larger series of experiments and reinforce the observation that the proportion of cells expressing tau in an individual line is not necessarily predictive of human tau genotype.To further assess effects of mutant and wild type human tau on the fraction of tau positive cells, we generated neurospheres from three additional transgenic mouse lines that express the same human tau variants as rTg(tauwt) cultures (P301L) cultures (P301L) cultures had a lower proportion of total cells expressing human tau (wt) cells (P301L) cells and 19% of Tg(tauwt) cells that expressed human tau at very low levels consistent with the leaky expression reported previously To determine the profile of Tau13 fluorescence intensity of transgene expression, transgene-positive cells were binned (1 to >10) based on fluorescence intensity . The \u201cdicultures  and for cultures  taken frcultures . While tuman tau , they couman tau  than rTgt) cells . The TREP301L)4510 FTD mouse model is tau misprocessing, primarily phosphorylation. To determine if mutant tau-specific phosphorylation occurred in neurospheres, we used a battery of phospho-tau specific antibodies. Due to the numerous sites for phosphorylation and other posttranslational modifications of the tau protein, immunoblotted tau most often does not resolve as distinct bands but instead as a heterogeneous protein smear. To discriminate distinct tau species within the total tau population, we used antibodies specific to total tau (DA9), human tau (Tau13), and phospho-tau epitopes , rTg samples had additional DA9 signals that appeared as a dense series of diffuse bands up to \u223c60 kDa in rTg(tauwt) samples and \u223c58 kDa in rTg(tauP301L) samples. Strikingly, the diffuse band in tauwt-expressing samples had a slower migrating component than tauP301L-expressing neurospheres. The slower migration of tauwt also was revealed by DA9, Tau13, CP13, AT8, and PHF-1 antibodies  expression and visualize the electrophoretic migration pattern of tau from both species . Densitotibodies , possiblwt band, we used human-specific Tau13, phospho-tau specific antibodies, and alkaline phosphatase treatment. The diffuse series of bands in rTg samples and the slower migrating tauwt species were observed with the Tau13 antibody confirming that they contained transgene-encoded human tau. All tau transgene-negative control samples lacked Tau13 signal confirming its specificity for human tau. We analyzed the neurosphere lysates for phosphorylated tau epitopes using CP13, AT8, and PHF-1 antibodies. The phospho-tau immunoreactivity in Tg(CK-tTA) and TRE-tauP301L control samples indicated endogenous mouse tau and appeared as distinct 52 and 53 kDa bands (wt) samples and to \u223c58 kDa in rTg(tauP301L) samples indicative of phosphorylated human tau. Strikingly, the more slowly migrating tauwt band became more apparent with the phospho-tau antibodies providing evidence that it was a phosphorylated tau species. Densitometric normalization to GAPDH, showed that rTg samples had greater immunoreactivity to CP13 (2.9x), AT8 (1.9x), and PHF1 (2.4x) than controls without human tau transgenes.To better characterize the tau species within the diffuse bands and the nature of the slower migrating tauDa bands . Human twt and tauP301L was due to phosphorylation. The Tau1 antibody recognizes tau species that are not phosphorylated at or near Ser198/202, and has decreased immunoreactivity when tau is phosphorylated at these epitopes. Both tauwt and tauP301L-expressing cultures contained Tau1-immunoreactive non-phosphorylated tau with identical banding patterns migrating at \u223c53 and 52 kDa (wt and tauP301L expressing cultures on the 0/0Mapt background lacking endogenous mouse tau expression. Phosphatase treatment abolished the higher molecular weight bands (>52 kDa) providing evidence that they were phosphorylated human tau. Only a single tau band migrating at \u223c52kDa, the known molecular weight of recombinant human tau 4R0N Tau1 immunoreactivity and alkaline phosphatase treatment confirmed that the migration difference between taud 52 kDa . TRE and0/0Mapt cultures have not been fully characterized. Here we used them to help distinguish between mouse and human tau bands. The wt3 rTg(tauwt) 0/0Mapt culture with low total tau (DA9) and human tau (Tau13) immunoreactivity may be due to the low proportion of human tau expressing cells (42%) compared to the other rTg(tauwt) 0/0Mapt culture, wt4 with 62% tau-expressing cells.wt) brain homogenates displayed a distinctly slower migrating tau species than rTg(tauP301L)  wt) mice contained a higher molecular weight Tau1-immunoreactive tau species than adult rTg(tauP301L), suggesting that young adult rTg(tauwt) mice express a tau species not phosphorylated at Ser198/202 that is either more heavily phosphorylated at other epitope(s), or has other post-translational modifications distinct from tauP301L. Results from these analyses are summarized in Brain homogenates from E14, the developmental stage at which neurospheres were harvested, and young adult 2.5 month-old mice were analyzed for tau phosphorylation. As seen in neurospheres, rTg(tauauP301L)  demonstr0/0Mapt cells and likely represents binding of 3R pSer202/Thr205 mouse tau to nucleolar organizing regions in dividing cells as reported previously 202, nor in non-dividing cells after differentiation. The presence of appropriately phosphorylated nucleolar mouse tau in dividing, but not differentiated cells, indicates that overexpression of human tau did not compromise physiological tau modification and function.We assessed tau phosphorylation in dispersed cells from dissociated neurospheres. For each cell culture we determined the proportion of nestin stained cells that also were immunoreactive with phospho-tau antibodies. rTg cultures contained a greater proportion of cells immunoreactive to phospho-tau antibodies than Tg(CK-tTA) controls. The AT8 antibody revealed focal staining in nuclei of all genotypes expressing mouse tau . The staP301L-expressing cultures had a shorter, though non-significant, doubling time of 23.3\u00b14 hours (n\u200a=\u200a3), than controls and rTg(tauwt) with 29.4\u00b18.8 hours (n\u200a=\u200a5) and 29.3\u00b15.5 hours (n\u200a=\u200a3) doubling times. Sex of the mice of neurosphere origin did not influence transgene expression or growth rates.We examined the variability of self-renewal and differentiation among independent cell lines. Although there was an effect of the P301L mutation on tau phosphorylation, expression of mutant or wild type human tau did not obviously interfere with their SC properties. Human tau expression did not alter the proliferation rate of neurosphere lines; regardless of genotype, all cell lines required passaging every 5\u20137 days. We conducted quantitative cell proliferation assays between passages 2\u20133 and between passages 6\u20137 on cell lines of all genotypes. Independent cultures of all genotypes had similar doubling times ranging from 20 to 32 hours as previously reported for neural SC lines P301L), rTg(tauwt), and Tg(CK-tTA) control neurospheres all contained cells positive for neuronal proteins microtubule associated protein 2 (recognized by Map2 antibody) and \u03b2-tubulin III (recognized by TUJ-1 antibody) or the astrocytic protein, glial fibrillary acidic protein (GFAP)  . Though n (GFAP) .wt-expressing cultures, tauP301L cultures contained fewer neuronal protein expressing cells that also expressed human tau; the proportions mirrored that of undifferentiated cells co-expressing nestin and human tau  and rTg(tauwt) differentiated cells at 25 days after exposure to differentiation stimuli. Mature dendritic spines develop from elongated filopodial projections P301L cultures; conversely, the filopodia-spine density in the tauwt and control cultures slightly decreased during this interval. At 25 days post-differentiation, cells derived from tauP301L-expressing neurospheres had a 23\u00b13% higher filopodia-spine density than neurons derived from tauwt-expressing cultures, and 20+/\u22124% higher filopodia-spine density than non-Tg expressing controls (p<0.0001); rTg(tauP301L) 0/0Mapt and rTg(tauwt) 0/0Mapt cultures showed similar results (data not shown). Interestingly, we saw an association with cell culture genotype, but not with the level of transgene expression in individual cells, with spine density. Within a single culture, cells expressing high levels of human tau had filopodia-spine densities similar to those in cells expressing low levels of human tau and cells in which transgene-encoded protein was not detectable 4510 mice coincides with memory and behavioral abnormalities P301L seen in young mice may have pre-clinical significance and deserves attention. Transgenic mice that express pseudohyperphosphorylated tau, an engineered tau variant that mimics constitutively phosphorylated tau by replacing Ser/Thr residues with glutamate R406W, a variant that remains hypophosphorylated compared to tauwt even in aged mice, developed age-dependent tau aggregates The impetus for these studies was to use a well-characterized mouse model for frontotemporal dementia to assess whether CNS-SC cultures reproduced genetic differences seen in the mice from which they were derived and whether independent isolates from genetically identical hosts produced consistent phenotypes. Neurospheres derived from tauP301L species in neurospheres and young mice may represent free tau not associated with microtubules (MT). Tau bound to MTs acquires more phosphorylation than free tau as demonstrated by in vitro phosphorylation of tau in the presence or absence of MTs wt displaces mutant tau from MTs P301L aggregates or neurofibrillary tangles (NFTs) in neurospheres and in young mice, despite phosphorylation at many of the sites most frequently phosphorylated in AD and FTD  The hypophosphorylated tauPhosphorylation of mouse tau also reflects appropriate phosphorylation corresponding to the differentiation state. Heavily phosphorylated 3R mouse tau is know to bind to nucleolar organizing regions in dividing cells wt and tauP301L differentiated cells. Developmentally, dendritic spine morphology evolves from long thin filopodia-spines to mature spines of various morphologies; during this transformation, filopodia-spine density decreases P301L cultures than those derived from tauwt or cultures that did not express MAPT. While the level of transgene expression within individual cells did not affect filopodia-spine density, we have not ruled out an effect of the transgene insertion site. Interestingly, in a separate P301L mouse line that that harbors the mutation in the longest mouse tau isoform, 4R2N, driven by the Thy1 promoter, young mice with \u201chypophosphorylated\u201d tau have enhanced learning and memory and increased Long Term Potentiation (LTP) in the dentate gyrus compared to controls P301L)4510 mice decreases and coincides with increased neuronal excitability P301L cultures relates to enhanced LTP in young mice or neuronal vulnerability later in life in unknown, but warrants further exploration.We observed differences in filopodia-spine densities between tauP301L to dendritic spines, as reported in aging mice We did not observe mislocalization of tauwt) expressing fetal brains expressed human tau in a higher proportion of cells than those derived from rTg(tauP301L) expressing fetal brains.Overall, phenotypes of neurosphere cultures isolated from individual fetuses at different times reflected the genotype of the mice from which they were derived and proved highly similar in transgene expression, proliferation, and differentiation. Unlike clonal cultures, these neurospheres were formed by aggregation, which results in culture heterogeneity wt) mice express comparable levels of transgenic tau as rTg(tauP301L) P301L) cultures had a lower proportion of total cells expressing human tau, they contained a greater proportion of cells that expressed higher levels of tau (brighter fluorescence intensity). This feature of some transgenes is caused by position-effect variegation wt-expressing neurospheres expressed human tau in a higher proportion of cells than those derived from tauP301L-expressing neurospheres. Likely, non-transgene expressing progenitor cells gave rise to non-transgene expressing differentiated cells and transgene expressing progenitor cells differentiated into transgene expressing mature cells. Alternatively, tauP301L transgene expression may have decreased neural precursor survival. Since neurospheres proliferated and differentiated over several passages in both genotypes, and differentiated transgene expressing cell proportions mirrored that of the undifferentiated condition, evidence favors the former explanation.Total brain homogenates indicate that rTg4510 and rTg(tauwt)21221, overlapped in the percentages of cells expressing human tau, but within the same range as our more extensively studies lines. It is likely that there are effects of transgene insertion site as well as the tau mutation.Some of the differences we saw between tauin vitro system will fully recapitulate a complex disease process involving complex cell interactions, biologically relevant models that provide reproducible results are invaluable resources. This SC model shares the genetics of mice that model human FTD, and has shown the capacity to model pre-disease, genotype-specific phenotypes. By using mice expressing either of two distinct transgenes as the source of SCs, we have established that neurosphere cultures maintain genotype-specific characteristics.With the emergence of methodologies to culture neurospheres from human patients P301L and tauwt mice and neurosphere cultures. Preliminary results are encouraging and show consistency in genotype-specific gene expression patterns among independently derived neurosphere lines. This will direct hypotheses about potential pathways targeted in cells that carry the tauP301L gene. By extending this research to patient-specific SCs, high-throughput cell based genetic screening (cDNA or siRNA) assays could uncover small molecules and potential pathways involved in pathogenesis and, ideally, the genetic specificity of the system may lead to treatment therapies tailored to unique patient needs.Our results lend credence to the growing body of data supporting the development and use of patient specific-stem cell lines to study disease. We have already shown that these cells reproducibly mimic biological events of the mice from which they were derived, and that they express the appropriate molecules involved in tau modification genetically validating the utility of SC as a model system. We are now in a position to interrogate the system. We are focusing on microarray analysis experiments to uncover differentially regulated genes between tauFigure S1Entire, unrearranged immunoblots used to generate .wt control. (C) Lane arrangement was identical for CP13 and AT8 membranes. (D) Lane arrangement for PHF-1. In 1, P301L1, wt2, P301L2, etc.) correspond to those shown in (TIF)Click here for additional data file.Figure S2Original immunoblots used to generateshowing results from embryonic day 14 mice. For simplicity, only one representative mouse for each genotype was shown in (TIF)Click here for additional data file.Figure S3Original 2.5-month-old mouse immunoblots used to generate . For simplicity, only one representative mouse for each genotype was shown in (TIF)Click here for additional data file.Figure S4wt) neurospheres were more heavily phosphorylated at Ser235 than rTg(tauP301L) neurospheres.rTg(tau rTg(tauwt) and rTg(tauP301L) neurospheres, with or without endogenous mouse tau, were immunoreactive with the MC6 (anti-pSer235) antibody. As seen with the other phospho-tau antibodies, rTg(tauwt) neurospheres displayed a slower migrating band than rTg(tauP301L) neurospheres. The membrane was subsequently probed with Tau13; the characteristic migration difference between tauwt and tauP301L\u2013expressing samples was apparent.(TIF)Click here for additional data file."}
+{"text": "Therefore, we hypothesised that \u03b11AMPK preserves tight junction organisation and vascular permeability during sepsis in the coronary microcirculation.A compromising endothelial cell (EC) monolayer affects vascular permeability and leads to fluid extravasation. Tight junctions and more particularly Zonula occludens 1 (ZO-1) play a major role in maintaining vascular barrier integrity and are regulated by cytoskeletal proteins. During sepsis, endothelial barrier disruption occurs in most organs and contributes to organ dysfunction. We and others have demonstrated that the \u03b1In vitro, tight junction organisation (ZO-1 staining), cytoskeleton organisation  and vascular permeability were measured in endothelial cells in culture (HCAECs). Endothelial cells were pretreated with 1 mM AICA riboside (AICAr) before LPS challenge (50 \u03bcg/ml O55:B5). In vivo, wild-type (\u03b11AMPK+/+) mice were treated with LPS  and compared with \u03b11AMPK knockout animals (\u03b11AMPK-/-). ZO-1 localisation was determined on frozen heart sections. Vascular permeability was evaluated using Evans Blue dye leakage. In addition, myocardial wall oedema was assessed by magnetic resonance imaging (MRI).In vitro, LPS-challenged cells displayed a significant disruption of the ZO-1 linear configuration after 24 hours and exhibited a decrease in peripheral actin filaments. Gap areas appeared in the cellular monolayer exposed to LPS, unlike untreated cells for which the monolayer remained unaltered. Consequently, LPS treatment gradually increased endothelial cells monolayer permeability in a time-dependent manner. AMPK activation by AICAr preserved the linear pattern of ZO-1 and prevented gap areas in the monolayer. More interestingly, AMPK activation reduced LPS-induced hyperpermeability. In vivo, according to the in vitro experiments, a dramatic decrease in ZO-1 staining was observed in \u03b11AMPK-/- hearts compared with \u03b11AMPK+/+, after LPS challenge. This resulted in an increased Evans Blue extravasation and, more importantly, in an exaggerated myocardial wall oedema observed by MRI. Finally, treating C57Bl6 mice with AICAr reduced cardiac vascular hyperpermeability in our model of sepsis.The AMPK signalling pathway protects the endothelial barrier during sepsis by preserving tight junction organisation. Since AMPK counteracts the molecular events involved in the LPS-induced barrier disruption in coronary microcirculation, it could consequently represent a new therapeutic molecule during sepsis."}
+{"text": "Dermatophagoides pteronyssinus (Dpt) and Dermatophagoides farinae (Df), are one of the commonest aeroallergens worldwide eliciting allergic manifestations [Dpt allergens belong of lipid-binding proteins, including Der p 2 (protein with myeloid differentiation protein 2 (MD-2) related lipid recognition domain), Der p 7  and Der p 13 (lipid transporter molecule) [Dermatophagoites pteronyssinus mites extract.House dust mites (HDM), including stations . Allerge-specific IgE and IgG1 antibodies [Liposomes were prepared by ethanolic injection using dipalmitoyl phosphatidylcholine/cholesterol or dipalmitoyl phosphatidylethanolamine/ cholesterol diluted in ethanol. To Poll-down assays, Dpt allergens were incubate with liposome preparations and than washed three times with PBS solution. The adsorbed proteins on liposome surface were removed by SDS treatment and then analyzed by SDS-PAGE. Additionally, the lipid-binding proteins were analyzed by ELISA to evaluate the immunoreativity of Dpttibodies .Dermatophagoides pteronyssinus for further studies in allergic diseases.Several proteins ranging from 21 to 205 kDa were enriched in poll-down assays, including a polypeptide with high molecular weight (>205 kDa). In addition, Dpt-adsorbed on liposomes were reactive to IgE and IgG1 antibodies from allergic patients analyzed by ELISA. Further analysis using mass spectrometry will be conducted to identify the proteins adsorbed on liposome surface. Liposomes might be used to produce enriched fractions of lipid-binding proteins from"}
+{"text": "Little is known about the efficacy of \"RT\"  for increasing receipt of substance use disorder (SUD) treatment by patients with unhealthy drug use identified by screening. We compared receipt of SUD treatment between baseline and 6 months across three randomized groups: no intervention and two different types of brief interventions.Adults presenting to a hospital-based primary care clinic with recent drug use  were enrolled in a randomized clinical trial comparing: (1) a 10-15 minute structured interview conducted by health educators (BNI), (2) a 30-45 minute intervention based on motivational interviewing by Masters-level counselors (MOTIV), or 3) no brief intervention. All received information on treatment resources. We assessed receipt of any SUD treatment in a statewide database. Logistic regression analyses adjusted for main drug (self-identified), drug dependence, and past SUD treatment.Among 528 participants the main drug was marijuana (63%), cocaine (19%), and opioids (17%); 46% met 12-month drug dependence criteria ; 18% had ASSIST scores (\u00bf27) consistent with dependence (past 3-months). At 6 months, 14% (73/528) received any SUD treatment. There were no significant differences in SUD treatment receipt: BNI vs control ; MOTIV vs control . There were no significant interactions between intervention and main drug, severity (ASSIST), or prior SUD treatment.Brief intervention did not increase receipt of SUD treatment in primary care patients. Future research should address how to make referral to treatment successful among screen-identified patients who could benefit from it."}
+{"text": "Three main imaging techniques are commonly used to identify cardiac transthyretin (ATTR) amyloidosis: echocardiography, MRI and DPD scintigraphy. Each one provides specific diagnostic and prognostic informations but also has its specific limitations. We sought to evaluate a multimodality imaging strategy to diagnose cardiac amyloidosis in ATTR.Seventy seven consecutive patients with multimodality imaging evaluation  to diagnose cardiac amyloidosis were identified from the database of the French National Reference Center for Amyloidosis. Patients with pacemaker or severe renal failure did not undergo cardiac MRI and were analyzed on the basis of the echocardiography and scintigraphy (n=17). Three groups were compared: patients with positive agreement to diagnose cardiac ATTR (PA-ATTR group), patients with positive agreement to exclude cardiac ATTR  and patients with negative agreement (NA).The mean age was 52 years [44-70]; 59% were male. Transthyretin mutations were Val30Met in 67%, other in 21%, and 12% had acquired ATTR from previous domino liver transplantation; 30 patients had a positive echocardiography, 37 positive MRI and 36 positive DPD scintigraphy. Positive imaging agreement was encountered in 50/77 patients . Negative agreement was observed in 27/77 patients (35%). Compared with PA-ATTR patients, NA patients were younger  and thinner interventricular septum (17 [14-20] mm vs. 12 [10-14]), all p values <0.0001). The two main causes for negative agreement between techniques was the sole positivity of the MRI (n=10) and the sole negativity of the DPD scintigraphy(n=6). Compared with PA-ATTR patients, patients with a sole MRI positivity were younger (41 [39-44] years vs. 68 [64-72] p<0.001), more frequently women , had thinner interventricular septum , had lower BNP levels (26 [24-36] vs 149 [92-249] p<0.0001) and had less diffuse late gadolinium enhancement pattern . As compared with PA-ATTR patients, patients with a sole negativity of the DPD scintigraphy had acquired ATTR from domino liver transplantation in all but one case .In transthyretin amyloidosis, the agreement between echocardiography, cardiac MRI and DPD scintigraphy to diagnose cardiac amyloidosis was observed in 65% of patients. Patients without agreement between these three techniques had distinct patterns of cardiac involvement: sole positivity of the MRI was encountered in patients in the early stages of ATTR; patients with acquired ATTR due to domino liver transplantation often had negative DPD scintigraphy."}
+{"text": "BOC and TPV are potent NS3/4A protease inhibitors for the treatment of chronic hepatitis C (HCV) genotype 1 infection. BOC and TPV are both substrates and strong inhibitors of the CYP3A, therefore presenting a wide interindividual pharmacokinetic variability and multiple drug interactions especially with ARV such as lopinavir/r, darunavir/r or efavirenz, thus restricting options for concomitant ARV therapy. We evaluated plasma concentrations of coinfected and monoinfected patients treated with BOC and TPV and the PK data of patients treated with non recommended ARV.Data from patients whose BOC and TPV trough concentration had been assessed during treatment were retrospectively analyzed. Plasma concentrations were determined using a LC-MS/MS method. Mann-Whitney U test was used for statistics (PASW Statistics 17).Overall, 58 patients were included ), treated with BOC (25) or TPV (33). Thirty-two (55%) patients are coinfected  and 26 (45%) are monoinfected . Median  TPV and BOC trough concentrations were respectively, 1928 ng/mL  and 111 ng/mL  in coinfected patients versus 2787 ng/mL  and 153 ng/mL  in monoinfected patients, which is statistically different only for TPV (p<0.05). Six patients received non recommended ARV: 4 were treated with darunavir/r , 1 with efavirenz and BOC and 1 with lopinavir/r and TPV. Median (range) TPV and BOC concentrations were respectively, 1967 ng/mL (580-3204) and 103 ng/ml (33-903) with recommended ARV versus 1304 ng/mL (92-2565) and 146 ng/ml (65-304) with non recommended ARV.This study highlights a strong interindividual variability in BOC and TPV trough concentrations. Lower concentrations were observed in coinfected patients but remaining within the expected range, which may be explained by drug interactions with some ARV. Hence, therapeutic drug monitoring is useful to manage these interactions and evaluate the risk-benefit balance of using non recommended ARV in coinfected patients with advanced hepatic disease."}
+{"text": "Nmf9, based on a forward genetic screen for neurological function. ENU-induced and genome-edited null mutations in mice produce deficits in vestibular function, fear learning and circadian behavior, which correlated with Nmf9 expression in inner ear, amygdala, and suprachiasmatic nuclei. Homologous genes from unicellular organisms and invertebrate animals predict interactions with small GTPases, but the corresponding domains are absent in mammalian Nmf9. Intriguingly, homozygotes for null mutations in the Drosophila homolog, CG45058, show profound locomotor defects and premature death, while heterozygotes show striking effects on sleep and activity phenotypes. These results link a novel gene orthology group to discrete neurological functions, and show conserved requirement across wide phylogenetic distance and domain level structural changes.Many protein-coding genes identified by genome sequencing remain without functional annotation or biological context. Here we define a novel protein-coding gene,  Drosophila melanogaster. Each of these species has a single homolog of this gene family, but differ by inclusion of a ras-association (RA) domain present in most invertebrate species but missing in mammals. Null mutations in both mice and flies produce neurological phenotypes, but while the mouse phenotypes are comparatively mild , null flies rarely survive to adulthood and surviving flies have severe locomotor deficits. Interestingly, heterozygous flies have significant sleep-related phenotypes. Together, our results provide a detailed first look at comparative function for a gene lineage with an unusual evolutionary history.Genome sequencing projects have identified large numbers of genes that encode proteins of unknown function. Many of these genes show strong evolutionary conservation, predicting important and well-conserved functions. A fraction of these show strong conservation of core domains but dynamic changes in other domains, predicting both conserved and lineage-dependent functions. Here we identify neurological functions associated with one such gene identified by a forward genetic screen in mice. We use recently developed genome editing tools both to confirm the mouse studies and to test comparative functions in a model insect, the fruit fly  The biological functions of many protein-coding genes remain unknown, often despite conservation across considerable evolutionary distance. Such \u201corphan\u201d molecules may include genes whose functions affect fitness but not overt phenotypes in experimental settings, genes that affect overt but under-studied phenotypes, and/or genes that have been difficult to study due to unusual molecular properties, such as low level expression or poor physical annotation in genomes of well-studied organisms. Forward genetics offers one entry point into functional studies by highlighting those genes whose alterations produce measurable effects , 2. A keNmf9 and its homologs were essentially unknown prior to our studies. The nmf9 mutation was recovered in a N-ethyl-N-nitrosourea (ENU) screen at the Neuroscience Mutagenesis Facility (NMF) of the Jackson laboratory , wakeKG02188 [14082], wakeKG08407 [15129], wakeMI02905 [37162], Df(3R)Exel6273 [7740], Df(3R)ED6085 [150049], Df(3R)ED6091 [9092], Df(3R)BSC527 [25055], Df(3R)Exel6192 [7671], Df(3R)BSC618 [25693], and Df(3R)ED6090 [150614].Mutations were verified by Sanger sequencing of PCR products encompassing targeted genomic loci. Transposon mutant and deficiency lines for CG45058 were obtained from the Bloomington Stock Center according to the following stock numbers: Drosophila Activity Monitoring System . Sleep was defined as 5 minutes of inactivity and, along with waking activity, was measured at 25\u00b0C using custom software as previously described [Flies were raised at room temperature (~21\u00b0C) on standard cornmeal/molasses. Within 1\u20132 days of eclosion, flies were assayed for wing orientation and the ability to maintain a standing position. For sleep assays, 1\u20135 day old flies were loaded into 65x5 mm glass tubes containing 5% sucrose and 2% agarose and entrained to a 12hr:12hr light:dark (LD) cycle for 2 days before recording sleep/wake patterns using the escribed .Mice were euthanized by CO2 inhalation or by perfusion or organ removal under deep anesthesia with tribromoethanol (avertin). Fish embryos were euthanized by fixation or snap-frozen in E3 media. All vertebrate animal procedures were approved by the University of California San Diego Institutional Animal Care and Use Committee (IACUC). The University of California San Diego is AAALAC accredited, AAALAC institutional number 000503.S1 TableDinucleotide repeat sequences were identified from an early draft public mouse reference sequence (MGSCv2) and tested for length polymorphism in mapping strains.(XLSX)Click here for additional data file.S2 Table(XLSX)Click here for additional data file.S3 TableAnimals were housed in 12:12 LD cycles for a minimum of 7 days prior to transition to DD. Tau, power, and onset were calculated as average over ~14 days. N = 14 +/+ females, 12 mutant females, 9 +/+ males, 10 mutant males. Data was analyzed using two-way ANOVA.(XLSX)Click here for additional data file.S4 TableNmf9 were identified in various databases and hand curated. Due to quality of genomes available, sequences that contain more than 50% gaps were removed and not included in this list. Due to poor assembly, all homolog sequences, with the exception of H. sapiens, was manually assembled utilizing the BLAST, BLAST, TBLASTN tools available in many of the databases, the ID of the seed sequence was listed when available. Species highlighted in yellow indicate the sequences used on whole-protein conservation analysis. 52 species containing ancestral versions of the homolog and 61 species containing derived version of the homolog were used for the region specific analysis of conservation.Homologs of (XLSX)Click here for additional data file.S5 Table(XLSX)Click here for additional data file.S6 Table(XLSX)Click here for additional data file.S1 Fignmf9 animals. (B) Acoustic brainstem responses were within normal range (waveform threshold \u226425 dB) for 5 of 6 mutant mice between 2\u20134 months age. (C) Acoustic startle responses were also normal in a separate cohort animals between 2\u20136 months age. Two-factor MANOVA p = 0.30 for genotype, p = 0.28 for sex. N = 12 +/+ females, 12 +/+ males, 13 mutant females, 7 mutant males. Error bars, s.e.m.(A) Ampulla, saccule, Scarpa's ganglion, utricle, and semi-circular canals were grossly normal in (TIF)Click here for additional data file.S2 FigAnkfn1 and 5\u2019 exons of E22 compared to BLAT alignment of empirically determined Nmf9 mRNA sequence. Positions of primers used for RT-PCR are indicated. (B) Relative quantities for real-time fluorescence measurements (SYBR) of RT-PCR products from the indicated assays from either brain cDNA or cloned plasmid. (C) Publicly deposited cDNA sequences for insect , echinoderm (S. purpuratus), nematode (C. elegans) and cnidarian (N. vectensis) also support a single transcript across segments homologous to Ankfn1 and E22. (D) In situ hybridization patterns were indistinguishable for Ankfn1 and E22 probes in ventromedial hypothalamus (VMH), amygdala (AMY), lateral septum (LS), piriform cortex (PC), suprachiasmatic nuclei (SCN) and spinal cord (SpC). This mirrors data for both annotations in the Allen Brain Atlas ((A) UCSC Genome Browser shows minus-strand transcripts for the 3\u2019 exons of in Atlas .(TIF)Click here for additional data file.S3 FigNmf9 RNA was detected by in situ hybridization as early as E14.5 in ventricular zones, inner ear, and nasal epithelium.(TIF)Click here for additional data file.S4 FigNmf9 homology group are shown in blue. An aminoterminal CRIB domain was found only in the two choanoflagellae species, while inclusion or loss of a ras-association domain (RA) appears not to be monophyletic. Vertebrate species basal to mammals had paralogous copies, one with and one without the RA domain in each species. All mammals examined had only one copy, which never had an identifiable RA domain. Conservation of the first ANK repeat, and consensus match to the motif definition were poor or absent in some invertebrate and choanozoa species.Known motifs are indicated in green. Highly consereved domains novel to the (TIF)Click here for additional data file.S5 FigHigh-resolution sliding window analysis of domains, with inclusion of species that lacked full-length sequence. Separate analyses were performed for ancestral homologs and vertebrate-derived homologs. Y-axis shows dN/dS values calculated using HyPhy . The 10 (TIF)Click here for additional data file.S6 FigNmf9 homologues were expressed during development in (A) fruit fly and (B) zebrafish. Samples included 3 biological replicates for fruit fly, but only technical replicates of single samples for each zebrafish stage and paralogous gene. (C) In situ hybridization to Drosophila embryos showed broad CG45058 expression, including CNS, agreeing with stage-specific expression in the BDGP in situ database (http://insitu.fruitfly.org/). (D) Expression in sea anemone N. vectensis planulae (left) includes endoderm (arrow) and some apical tuft cells. In polyps, expression appears uniform throughout the endoderm (arrow) and mesenteries. (E) In zebrafish embryos, ancestral paralog retained a broad but weak expression pattern that includes expression in the developing inner ear (box and inset). The derived paralog showed a cleaner, more restricted pattern.(TIF)Click here for additional data file.S7 FigCG45058 locus shows exon position of encoded protein domains (blue) across transcripts (navy) from the UCSC browser. Chromatin accesibility to DNase I at stage 5 (green), 9 (orange), 10 (red), 11(blue) and 14 (purple) embryos suggests dynamic regulation of alternative transcripts. (B) UCSC transcripts (navy) in the interval around CG45058 (red) on Drosophila chromosome 3R are shown relative to deficiencies that complement (green bars) or fail to complement (red bars) frameshift mutation at conserved domain 2 (GLYLGYLK). The inferred interval (yellow box) defined by the shared breakpoint of Df(3R)Exel6273 and Df(3R)Exel6192 and the right breakpoint of Df(3R)ED6090 contains parts of 6 transcription units.(A) Schematic of the (TIF)Click here for additional data file.S1 VideoBehavior in the home cage shows circling by a strongly affected mutant female compared to non-circling littermate control.(MOV)Click here for additional data file.S2 VideoBirth date and identifier is indicated for each animal.(MP4)Click here for additional data file."}
+{"text": "True node-negative small sized non-small cell lung cancers are optimal candidates for sublobar resection without systematic lymph node dissection.The purpose of this study is to identify the predictive factors of true node-negative clinical stage IA non-small cell lung cancer.A multicenter database of patients with completely resected clinical stage IA lung adenocarcinoma (n = 502) or squamous cell carcinoma (n = 100) was retrospectively analyzed. The relationship between lymph node status and preoperative factors such as tumor size on HRCT and maximum standardized uptake value (SUVmax) on FDG-PET/CT were examined.Multivariate analyses revealed that solid tumor size on HRCT (Odds ratio (OR), 1.42; p < 0.001) or SUVmax on FDG-PET/CT  was identified as an independent predictor of lymph node metastasis in patients with lung adenocarcinoma. The predictive criteria of node-negative lung adenocarcinoma were solid tumor size <0.8 cm or SUVmax <1.5. Among patients who met the node-negative criteria, recurrence-free survival at 5 years was not significantly different between those who underwent lobectomy (96.0%) and those who underwent sublobar resection (97.2%). In patients with squamous cell carcinoma of the lung, no independent predictive factors for lymph node metastasis were identified in univariate or multivariate analysis.Either solid tumor size on HRCT or SUVmax on FDG-PET/CT was a significant independent predictor of nodal status in clinical stage IA lung adenocarcinoma. The node-negative criteria of solid tumor size <0.8 cm or SUVmax <1.5 are helpful for choosing candidates for sublobar resection without systematic lymphadenectomy. In patients with clinical stage IA lung squamous cell carcinoma, systematic lymphadenectomy is advisable."}
+{"text": "This prompted a genome-wide study to ascertain whether NME2 exerts its anti-metastatic action through transcriptional regulation. Chromatin-immunoprecipitation followed by massively parallel sequencing (ChIPseq) along with transcriptome profiling uncovered a network of genes involved in intercellular contact, focal adhesion and actin assembly under direct transcriptional control of NME2. In line with this, NME2-depleted cells displayed increased focal adhesion points and altered actin stress fiber organization. Our findings demonstrate that NME2 regulates transcription of a key focal adhesion factor vinculin and its localization within adhesion foci. NME2-depleted A549 lung cancer cells showed higher invasiveness in vitro and seeded more metastases in vivo. Consistent with these findings, expression of several NME2-transcriptional target genes related closely to advanced tumor stages with metastatic proclivity, and NME2 levels predicted patient survival.The mechanism of action of NME2, a widely accepted metastasis-suppressor gene, is poorly understood. Recently we found that NME2 directly regulates transcription of the"}
+{"text": "Initial baseline fetal heart rate of 140 beats per minute (bpm) with normal variability and accelerations.Intermittent variable and prolonged decelerations.Beginning three hours prior to delivery, increasing frequency and severity of variable decelerations associated with every instance of maternal pushing.Fifty minutes prior to delivery, a prolonged deceleration of eight minutes followed by a fetal heart rate of 160\u2013190\u2009bpm.Fetal heart rate tracing ends 27 minutes prior to delivery at 190\u2009bpm.Apgar scores were 01/05/010/020.I read with interest \u201cIntrapartum Intrauterine Fetal Demise with Normal Umbilical Cord Blood Gas Values at Birth,\u201d by Michael D. Benson . I am mo2/PO2/BE);vein: 7.27/48/<25/\u221210 Cord occlusion with terminal fetal bradycardia and near-normal cord gases may occur in the absence of a widened venoarterial pH difference, although this finding is quite rare . In ordeCord gases only reflect uteroplacental status (vein) and uteroplacental-fetal status (arteries) while blood flow continues."}
+{"text": "Is to establish the relationship between Cardiac Stress MR Perfusion findings with occurrence of major adverse cardiac events in patients with moderate coronary artery stenosis.Performed stress CMR for 80 patients referred for ischemia assessment after Invasive Coronary angiogram. CMR examination included are Cine Cardiac function , Adenosine stress Perfusion, Rest Perfusion and late Gadolinium enhancement with appropriate sequences.Follow up done for these Patients for a period of one year after CMR study for occurrence of Major adverse cardiac events , Unstable angina, Arrhythmias & Death).June 2010 to Sep 2013 . MR equipment - 1.5 Tesla ( Avanto-Siemens).Adenosine used as Stress agent & Contrast is Gadolinium based.Stress MR - Dark / Hypo intense defect in the Myocardial wall of the arterial territory.Major adverse Cardiac Events - Follow up Patients done for a period of one year after CMR study, for occurrence of Myocardial Infarction (MI), Unstable angina, Arrhythmias & Death.80 patients with moderate CAD.Stress CMR > Perfusion defects in 54 patients & No defects in 26 patients.54 Patients > 32 had Transmural & 22 had Subendocardial perfusion defects in corresponding territories.Follow up for MACE:29 of 80 Patients with moderate CAD (29%) had adverse events & 28 of 54 patients with CMR -Perfusion defects had adverse events ( 51 %).19 of 32 Transmural Perfusion defects had adverse events - 7 had MI , 6 had unstable angina, 4 arrthymia & 2 deaths (59% MACE).9 of 22 Subendocardial Perfusion defects had adverse events - 2 had MI , 4 Unstable angina,& 3 arrthymia (40% MACE).1 of 26 patients without CMR- Perfusion defect had unstable angina in follow period.Stress perfusion CMR study will assess the Significance of moderate Coronary artery stenosis for Inducible Ischemia by detecting the perfusion defects.Development of Adverse cardiac events is more likely in patients with moderate CAD demonstrating Perfusion defects on stress CMR.No funding."}
+{"text": "Physical restraint (PR) is common in Canadian intensive care units (ICUs); used in up to 76% of mechanically ventilated patients. PsychotrTo characterize alterations to psychotropic drug regimens 1 hour prior and 6 hours after PR application for critically ill, mechanically ventilated adults.Prospective single centre observational study (Feb 2014 to Jan 2015). Eligible patients were physically restrained while receiving mechanical ventilation. Psychotropic drug data were collected 1 hour before PR and for 6 hours after PR. We recorded PR indications, psychotropic drug interventions including new drug initiation, dose increase, dose decrease, and drug cessation. We documented total duration of PR, Sedation Agitation Scale (SAS) scores and presence of delirium (Intensive Care Delirium Screening Checklist score \u22654). We used McNemar's tests to compare across time points.We enrolled 93 patients meeting our inclusion criteria. Mean age 59 years, 53% male, and 65% medical admissions. Median (IQR) mechanical ventilation duration was 5 2, 9) days. 111 indications for PR included prevention of treatment interference , agitation , physical violence towards staff , and self-harm . Median (IQR) duration of restraint application was 21  hours. of the 69 patients with delirium screening documented, 23 (33%) were delirious. More patients received a psychotropic drug intervention after PR  and more patients received an opioid after PR . Use of other drugs did not differ (Table , 9 days.Psychotropic drug interventions were more common after PR application with opioids used most frequently suggesting priority of analgesia over sedation. Most patients had a SAS score indicating appropriate or oversedation in the hour prior suggesting PR was used more often as a preemptive approach."}
+{"text": "ZNF389 as highly associated with small ruminant lentivirus (SRLV) proviral concentration among infected sheep.ZNF389 was associated with control of SRLV proviral concentration in multiple sheep flocks.4Genome-wide association identified a gene region including We sampled 764 Idaho Rambouillet, Polypay and Columbia ewes as described.sas v9.2 (SAS Institute) as described.The deletion variant was g.29500068_29500069delAT relative to NC_019477.1 (rs397514112). Genotyping was performed as describedZNF389 deletion variant was not consistently associated with any tested production traits between lifetime and partial-lifetime SRLV-negative groups (Tables S1 and S4). Insertion homozygotes previously associated with reduced SRLV proviral concentration were associated with lower birth weight in the partial-lifetime group (Bonferroni P = 0.033; P = 0.41; ZNF389 deletion variant with ewe lifetime production. Other breeds and additional traits, such as wool diameter and infectious disease traits besides control of SRLV, should be examined to more fully assess this locus.The"}
+{"text": "Exosomes are microvesicles (30-100nm) released from living cells that shuttle and transfer selected cellular biomolecules, including cytokines, cell surface molecules, growth factors, mRNA, and miRNA. Tumor-derived exosomes (TEX) allow for a sophisticated means of communication with a variety of cells, including immune cells, within the tumor microenvironment. Ionizing radiotherapy (RT) promotes anti-tumor immune responses by promoting uptake of tumor antigens by dendritic cells and by enhancing antigen presentation to activate effector T cells. We hypothesized that TEX released from irradiated tumors may play a role in altering the susceptibility of tumor cells to immune-mediated rejection.in vitro with sham RT, 1 dose of 20Gy, or 3 fractions of 8Gy (8Gyx3). Cells were transferred to exosome-depleted media following RT and supernatant was collected 48hr later. TEX were isolated using differential ultracentrifugation and purified by sucrose gradient. Electron microscopy confirmed TEX expected size and morphology. TEX were lysed for protein identification using label-free quantitation mass spectrometry (LFQ-MS) followed by MS/MS analyses. To characterize miRNA signatures of TEX and their parent cells, RNA was isolated for nanoString nCounter Mouse miRNA expression assay kit using a panel of 578 mouse miRNAs. Normalized results were analyzed with MultiExperiment Viewer.Mouse mammary carcinoma cells TSA were treated LFQ-MS revealed significant changes in TEX proteomic profiles when their parent cells were treated with RT. Significant differences in TEX protein composition was observed based on the RT regimen used (20Gy vs 8Gyx3). In two separate experiments, TEX from 8Gyx3-but not 20Gy-treated TSA cells showed significant increase in proteins involved in the Antigen Processing and Presentation pathway (p= 0.012). Additionally, 17 unique proteins were present in TEX from 8Gyx3-treated TSA cells. Among them were proteins involved in T cell development, MHC class I peptide processing, and proinflammatory lipid signaling, which were not present in TEX from 20Gy-treated cells. Fractionated radiation induced downregulation of 73% of miRNAs expressed in untreated TSA cells. Unique miRNA expression patterns emerged in TEX, which were RT regimen-dependent.Data indicate that cancer cell irradiation alters the molecular composition of released TEX, with some changes being RT regimen-dependent. Changes in immune-related pathways were induced by 8Gyx3 but not 20Gy RT, suggesting that TEX could be biomarkers for more pro-immunogenic RT regimens . We are currently investigating the contribution of TEX to RT-induced T cell priming. TEX-mediated communication networks may provide new therapeutic targets to improve responses to cancer immunotherapy."}
+{"text": "Myocardial infarction results in myocardial scarring which can have an impact on left ventricular (LV) stiffness and contractile function, ultimately leading to reduced LV systolic function and LV remodelling, However controversy remains about the relation between scar extension and segmental wall motion contractility global systolic function, and LV remodelling.To elucidate the relationship between scar extension, wall motion score index (WMSI), LV dimensions and systolic function in a group of patients with previous myocardial infarction by cardiac magnetic resonance (CMR).133 patients with previous (>6 month) myocardial infarction were retrospectively enrolled in the study. Indexed end-systolic volume (ESVi), indexed end-diastolic volume (EDVi), LV ejection fraction (EF), stroke volume (SV), left ventricular mass, WMSI and sum scar score (SSS) were measured using cardiac magnetic resonance.A total of 2261 segments were studied: regional wall motion abnormalities were present in 1032 segments (45 %) and 724 (32 %) showed presence of myocardial infarction  and segments. WMSI correlated significantly with EF (r=-0.87 p<0.0001) in all patients; both in patients with EF \u226540% (r=-0.77 p<0.0001) than in patients with EF<40% (r=-0.68 p<0.0001). WMSI also correlated significantly with SSS . However, correlation between WMSI and SSS was more significant in patients with transmural myocardial infarction  than non transmural myocardial infarction . Significant correlation was found between EF and SSS (r=-0.55 and p<0.0001) and between SSS and LV indexed volumes .Patients with transmural MI demonstrated a more impaired global and regional systolic function together with increased LV dimension. Beyond transmurality, scar extension evidenced even more relation with both segmental and global wall motion abnormalities as well as systolic dysfunction. This emphasised the importance of CMR to evaluate all at once scar dimensions, segmental wall motion and subsequent LV remodelling.This research was supported by NIHR Bristol Cardiovascular Biomedical Research Unit."}
+{"text": "The use of veno-venous Extra-corporeal Membrane Oxygenation (vv-ECMO) in adults with severe respiratory failure is increasing. Nutrition whilst on vv-ECMO is challenging as inadequate feeding, mainly due to gastric intolerance is common \u20134. Our uTo improve our understanding of the nutritional support preferences and practices by conducting an international survey of adult ECMO centres.Details for International ECMO centres were obtained from our database used in previous surveys. Survey questions were developed through an iterative process and assessed for content and face validity. None of the survey domains were mandatory. This resulting 38-question online survey was emailed to 161 eligible ECMO centres using Smart Survey\u00ae . Sole paediatric centres were excluded. The need for informed consent was waived by the local research and ethics committee.Sixty-seven (42%) eligible centres responded to the survey. One third of centres managed less than 10 vv-ECMO patients over the previous year.The most common equation to determine energy requirements is 20-25kcal/kg/day  and 1.5g/kg/day for protein .Out of 37 responses, 29 (78%) use naso-gastic feeding as the initial route of feeding. Five commence parenteral nutrition first (14%) and 3 (8%) post-pyloric feeding.Twenty two out of thirty six respondents (61%) report feeding within 24 hours of commencing vv-ECMO. Twelve centres (33%) feed within 48 hours and one (3%) within 72 hours. One centre (3%) reports never feeding their vv-ECMO patients.Gastro-intestinal intolerance is perceived as common in these patients with 16 out of 26 respondents (69%) reporting that 50% or more of their patients require prokinetics drugs during their vv-ECMO run.The survey identifies significant heterogeneity in assessment and provision of nutritional requirement in these patients. Lack of evidence coupled with lack of guidelines relating to nutritional support explains this heterogeneity. Our survey highlights an urgent need for focused research in this area."}
+{"text": "G12D. Myoblast cell lines were characterized and subjected to proliferation, anchorage-independent growth and differentiation assays to assess the effects of transgenic KrasG12D expression. KrasG12D overexpression transformed p53\u2212/\u2212 myoblasts as demonstrated by an increased anchorage-independent growth. Induction of differentiation in parental myoblasts resulted in activation of key myogenic regulators. In contrast, Kras-transduced myoblasts had impaired terminal differentiation. p53\u2212/\u2212 myoblasts transformed by KrasG12D overexpression resulted in rapid, reproducible tumor formation following orthotopic injection into syngeneic host hindlimbs. Pathological analysis revealed high-grade sarcomas with myogenic differentiation based on the expression of muscle-specific markers, such as Myod1 and Myog. Gene expression patterns of murine sarcomas shared biological pathways with RMS gene sets as determined by gene set enrichment analysis (GSEA) and were 61% similar to human RMS as determined by metagene analysis. Thus, our novel model system is an effective means to model high-grade sarcomas along the RMS spectrum.While genomic studies have improved our ability to classify sarcomas, the molecular mechanisms involved in the formation and progression of many sarcoma subtypes are unknown. To better understand developmental origins and genetic drivers involved in rhabdomyosarcomagenesis, we describe a novel sarcoma model system employing primary murine p53-deficient myoblasts that were isolated and lentivirally transduced with Kras Soft tissue sarcomas (STS) are the most common extracranial solid tumors in childhood and rhabdomyosarcoma (RMS) is the most frequent STS in this population . RMS likRMS is categorized into distinct subtypes based on histopathology, including: embryonal (ERMS), alveolar (ARMS), pleomorphic (PRMS) and sclerosing/spindle cell (SRMS) RMS . GeneticEnhancing biologic models to validate candidate sarcoma genes will provide insight into genomic data and provide a platform for discovering new therapies. The majority of RMS animal models to date employ genetically engineered mice or transgenic zebrafish \u201315. An e\u2212/\u2212 myoblasts into syngeneic hosts. Oncogene delivery into myoblasts was performed using a lentiviral construct encoding Kras (KrasG12D) with a GFP reporter. Myoblasts were selected using fluorescence activated cell sorting (FACS) and injected into syngeneic mice, resulting in rapid formation of high-grade sarcomas with myogenic differentiation.In a recent study investigating the origins of RMS using developmentally restricted murine models, ERMS arose from Myf6-expressing, differentiating myoblasts with inactivated tumor suppressor genes, Trp53 or Ptch1 . To dete\u2212/\u2212 pups  expressed muscle-specific RNA and protein and engrafted host muscle fibers following injection into neonatal p53+/\u2212 pups  in our mosaic model. Lentiviral particles encoding bicistronic constructs of KrasG12D and GFP were successfully delivered into the myoblast genome , Control-H , Kras-L  and Control-L . Proviral integration was quantified with real-time PCR using primers specific to the viral promoter and Kras transgene  whereas empty vector myoblasts did not display significant proviral integration in the host genome. Increased proviral integration resulted in increased Kras protein levels in myoblasts as demonstrated by immunoblot .Since anchorage-independent growth is a hallmark of cellular transformation, myoblast cell lines were assayed Figure  and incr\u2212/\u2212 myoblasts with activated Kras, translated into tumor-forming capacity in vivo, myoblast cell lines were injected orthotopically into syngeneic hosts . Enlarged cells with rhabdoid morphology were occasionally observed within some tumors. Morphologically tumors were compatible with high-grade sarcomas.Tumors were assessed using WHO Classification . GrosslyA standard immunohistochemical panel was employed to classify the sarcomas. All tumors were negative for S100 and only one tumor was found to have rare immunoreactivity for pan-cytokeratin, thereby largely excluding neural crest and epithelial derivations, respectively. Five of 21 tumors had limited expression of one or more muscle specific transcription factors (Myog and/or Myod1), suggesting rhabdomyoblastic differentiation Figure . Expressp < 0.01, Figure p < 0.001, Figure p < 0.01, Figure To investigate if our mosaic mouse tumors were consistent with human sarcoma gene expression patterns, mRNA from myoblasts and tumor tissue was examined with gene expression microarrays. Metagene analysis was performed to determine the correlation between mosaic mouse sarcomas and human pediatric tumors . The mos\u2212/\u2212 cell line Myo25 terminally differentiated as seen by the presence of a large number of multinuclear, MyHC+ muscle fibers  or decreased (Myf6) after 5 days in DM, demonstrating impaired differentiation with KrasG12D overexpression. Finally, myoblast protein lysates were subjected to immunoblot analysis to examine expression of the mature muscle fiber marker MyHC  has yet to be determined. Real-time PCR profiling substantiated the histopathology, as the levels of myogenic markers were lower in tumors compared to normal skeletal muscle controls  and Hrasnografts . When hos of p53 . In contd in UPS , illustrl muscle  which all muscle . The deb\u2212/\u2212 KrasG12D overexpressing myoblasts was enriched for human UPS and ARMS gene signatures, illustrating some degree of skeletal muscle differentiation with our murine sarcomas. Importantly, mosaic mouse tumors generated were most similar to human RMS, as determined by metagene analysis. Therefore, murine tumors generated by overexpressing KrasG12D in p53-deficient differentiating myoblasts, recapitulate human malignancies and are an effective means to model high-grade sarcomas along the RMS spectrum. As additional mosaic mouse models are generated using different oncogenic mutations, it will be essential to investigate how the transcriptome is altered and correlate this profile with what is observed in tumor phenotype.In addition to providing biologic data on the process of cellular transformation, mouse models are the gold standard to model human disease. Gene expression analysis performed compared our murine tumors to the genetic signatures of different human sarcomas. Using GSEA, the gene expression signature of tumors that arose following engraftment of p53In conclusion, the creation of mosaic mouse models effectively recapitulates human sarcoma formation and future work using this approach will help uncover the developmental context and the genetic alterations that are required for sarcomagenesis. To translate this critical knowledge into improved patient care, mosaic models are also powerful tools for testing novel therapeutic agents.p53tm1/Tyj mutant mice [\u2212/\u2212 mouse myoblast cell lines  were generated and propagated using Myoblast Growth Media . Myoblasts expressed muscle-specific genes and proteins upon differentiation into functional muscle fibers in vitro . Second generation packaging (pCMV-dR8.74psPAX2) and envelope (pMD2.G) plasmids and lentiviral expression vectors described below were transfected into 293T cells with Effectene\u00ae Transfection Reagent . Murine KrasG12D (GenBank: 16653) was subcloned between BamHI/XhoI restriction enzyme sites preceding IRES-Emerald (GFP) in the pHR-SIN-SFFV vector . Lentiviral particles in conditioned media from 293T cells at 24 and 48 h following cotransfection with either pHR-SIN-SFFV-KrasG12D-IRES-Emerald or pHR-SIN-SFFV-IRES-Emerald (empty vector) were pooled and centrifuged , filtered (20 \u03bcm pore size) and stored at \u221280\u00b0C. Lentiviral titer was determined using a Lenti-X\u2122 p24 Rapid Titer ELISA . MOI was calculated based on lentiviral titer. High (250) or low (2) MOIs were used and myoblasts were incubated with MGM containing lentiviral particles for 16 h, washed and cultured for 6 days. GFP+-expressing cells were isolated using FACS and expanded. Myoblast KrasG12D transgene expression was confirmed using PCR and protein overexpression was confirmed with immunoblots . Cells were passaged every 2 days and counted . The ability of myoblasts to grow on soft agar was assessed using standard protocols [Proliferation was examined by plating 2 \u00d7 10rotocols .G12D were injected into the right hindlimb, empty vector controls into the contralateral limb and monitored for tumor formation.Myoblast engraftment of syngeneic host skeletal muscle was performed as previously described . Intra-m3 or other experimental end points were reached, including: respiratory compromise or evidence of malnourishment. Necropsy was performed, tumor and contralateral control limb skeletal muscle were harvested and underwent standard fixation. Formalin-fixed, paraffin-embedded tissue was cut into 4 \u03bcm sections for H&E staining and immunohistochemical analysis. Antibodies are described in Mice were sacrificed when tumors measured 1.5 cmProteins were harvested following incubation in RIPA Lysis Buffer including c0mplete Mini, EDTA-free protease (Roche) and phosphatase (Sigma) inhibitors, followed by centrifugation  and quantification of protein concentration using the DC\u2122 Assay . Protein samples were separated and transferred to PVDF membranes using standard western blot conditions. Membranes were blocked and incubated in primary/secondary antibody solutions  for 1 h,in vitro transcribed, hybridized and applied to Affymetrix Mouse 430A arrays . For gene set enrichment analysis (GSEA), gene expression data were normalized to empty vector controls by standard methods and log2-transformed . Genes were ranked according to the absolute fold-change in expression (http://www.broadinstitute.org/gsea/index.jsp) was performed using default parameter settings on two ranked lists. Published gene sets of rhabdomyosarcomas and other pediatric malignancies were used in this analysis [q-value < 0.25 and FWER p-value of < 0.05. The metagene projection method [http://www.ncbi.nlm.nih.gov/gds/) which was performed as previously described [To evaluate global gene expression, RNA was harvested from cell or tumor lysates, was nsformed . The medpression \u20138 using analysis , 32. Sign method  was usedMyoblast differentiation into muscle fibers was examined using standard conditions . MyoblasTo evaluate proviral integration into the myoblast genome and transgene representation in tumor tissue, PCR was performed on genomic DNA using primers and conditions detailed in"}
+{"text": "Nuclear FoxO1 (nFoxO1) mediates retrograde communication by inducing the expression of mitochondrial oxidative and stress defensive genes. Collectively, our findings describe an unusual white/beige fat cell response to nutrient availability highlighting another health-promoting mechanism of fasting.Fasting promotes longevity by reprogramming metabolic and stress resistance pathways. However, although the impact on adipose tissue physiology through hormonal inputs is well established, the direct role of fasting on adipose cells is poorly understood. Herein we show that white and beige adipocytes, as well as mouse epididymal and subcutaneous adipose depots, respond to nutrient scarcity by acquiring a brown-like phenotype. Indeed, they improve oxidative metabolism through modulating the expression of mitochondrial-and nuclear-encoded oxidative phosphorylation genes as well as mitochondrial stress defensive proteins . Such adaptation is placed in a canonical mitohormetic response that proceeds via mitochondrial reactive oxygen species ( FastingmtROS) production promoting a retrograde signaling that triggers the induction of nuclear-encoded mitochondrial stress defensive proteins and ultimately leads to a long-term improved redox state [mitohormesis, and may be relevant to the health-promoting effects of nutrient shortage in model organisms [mtROS by antioxidants impairs the life-extending program and health-promoting capabilities of nutrient restriction thus highlighting mtROS as essential signaling molecules [Several studies demonstrated that in various model organisms the life extending effects of nutrient restriction are consequence of improved oxidative metabolism . In confox state -12. Thisrganisms . Coherenolecules .The nutrient sensing FoxO1 is a crucial metabolic regulator in several tissues and commonly placed into longevity pathways , 14-15. In this report, we propose that the health benefits of fasting may also rely on its capability to favour brown-like changes in WAT via the improvement of cellular metabolism and antioxidant equipment. Further, we demonstrate that WAT adipocytes exploit nutrient-sensitive mtROS/nFoxO1 retrograde signaling as alternative pathway to boost their mitochondrial functionality independently of adrenergic cascade.White (WAT) and brown (BAT) adipose tissue display a diverse mitochondrial OxPHOS equipment, which specifically reflects the cellular and tissue functionality.mtDNA- and nuclear nDNA-encoded OxPHOS genes in white and brown adipose depots, we performed an OxPHOS gene expression array. As showed in Fig. mtDNA- than mtDNA-encoded OxPHOS mRNA. However, the transcriptional efficiency of BAT  Fig. . In ordeBAT Fig.  and T37iBAT Fig.  was mainirements -19, we aX4b Fig. . The anaX4b Fig. . The resX4b Fig. . Conversins Fig.  as well ins Fig. . Further NR Fig. . The disase ClpP , 20. As enes Fig  as well enes Fig . Primaryenes Fig . FinallySOD2 Fig  and ClpPSOD2 Fig  was disceWAT Fig  with res2 consumption along with a drop of ATP level in 3T3-L1 white adipocytes . Differently from isoproterenol stimulation, NR did not induce changes in phospho-active levels of HSL on ser660 (HSLpS660)  prior to fasting. Notably, although SR59230A was effective in limiting fat mass loss during fasting  Fig , suggest fasting , it did  fasting .mtROS) production appears to be a tightly regulated process that is essential for tuning the magnitude or effectiveness of the mitochondrial adaptive response [mtROS that are key mediators of the signal transduction pathway culminating in the metabolic adaptation of 3T3-L1 adipocytes [mtROS production also in X9 cells, while T37i adipocytes were unresponsive  could be linked to basal higher mitochondria antioxidant defensive proteins (SOD2 and UCP1) in BAT with respect to WAT  prior to NR. As expected, NAC was able to prevent mtROS production both in 3T3-L1 and X9 adipocytes  or with a constitutively active form of FoxO1 (Myc-tagged) that is specifically localized within nuclei (nuc-FoxO1) . Westerngeroprotection to improved mitochondrial metabolism and fat mass remodeling [Defective mitochondrial functionality and visceral adipose tissue expansion are crucial footprints of age-related metabolic disorders -27. Dietmodeling -7. The fmodeling .mtDNA/nDNA-encoded OxPHOS complexes ratio, which represents an early response that ultimately leads to OxPHOS machinery reorganization and enhanced mitochondrial functionality. Similarly, Mouchiroud and coworkers revealed that mitonuclear protein imbalance occurs during nutrient-restriction mimicking conditions (i.e. by increasing NAD+ levels) and they have identified this response as a conserved longevity pathway [Herein we have demonstrated that upon nutrient deprivation (i.e. fasting), concomitantly to the previously observed induction of lipid oxidative genes , 17, whi pathway .tuning-up white adipose cells in a high oxidative mode making them more efficient in buffering postprandial nutrient excess. In line with this idea, 6 months randomized clinical trial showed that fasting for two non-consecutive days per week results in reduced body weight and fat mass as well as improved metabolic profile [In our work we reported increased mitochondrial fragmentation in starved white/beige fat cells. Such mitochondrial fragmentation may be an adaptive strategy to more efficiently attain neo-synthesized mitochondrial proteins such as UCP1. In accordance with this assumption, Wikstrom and co-workers, discussed that mitochondrial fragmentation is a helpful mitochondrial response to store neo-synthesized UCP1 in hormonally stimulated brown adipocytes . Interes profile .browning program in a stress defensive response of white fat cells, whereas the higher level of antioxidant proteins harbored by BAT could partially clarify the absence of mitochondrial responses to nutrient deprivation. Mitochondrial UCP1 and SOD2 induction could restrain excessive ROS production deriving from the boosted oxidative metabolism of white fat cells exposed to nutrient shortage. Furthermore, the chemical or genetic strategy enhancing antioxidant defenses (NAC supplementation and SOD2 overexpression) limits the mitochondrial rearrangement of white/beige adipocytes after NR. It is plausible that dietary antioxidants supplementation may affect ROS-dependent physiological processes that are important for metabolic homeostasis. Accordingly, many human clinical studies failed to show benefits of dietary antioxidants in treating age- or obesity-associated diseases [mtROS are key mediators of these responses [mtROS are up-stream inducers of mitochondrial oxidative genes in white adipose cells during NR preventing cell death [mtROS in triggering adaptive responses in adipocytes as they activate a unique pattern of stress defensive genes leading to the acquirement of a brown-like phenotype. As reviewed by Blagosklonny, a weak stress such as calorie restriction prolongs lifespan and delays the occurrence of age-related metabolic disorders. Such hormetic response occurs when the target of rapamycin (TOR) is deactivated [mtROS-mediated signaling in a mitochondrial hormesis (mitohormesis) program that ultimately improves adipocyte metabolism.Emerging is the induction of UCP1 as adaptive response to suppress ROS production in adipose cells. Remarkably, exacerbation of mitochondrial damage by the inhibition of UCP1 supports this idea -33. In ldiseases -38. Seveesponses , 28. In ll death . Here, wctivated . Accordictivated . Based omtROS/nFoxO1 axis, a peculiar signaling that is commonly placed in longevity pathways [Notably, we demonstrated that white/beige adipocytes directly sense nutrient scarcity and WAT mass is consequently reduced in a way that is independent of hormone-mediated cAMP/PKA signaling. Our findings also reveal that the different redox state between white and brown fat could elucidate the diverse response to fasting and emphasize that this dietary approach is healthful for WAT shifting mitochondrial activity toward a brown-like metabolism. The metabolic adaptability of white/beige adipocytes to nutrient deprivation could be allowed through activation of pathways .Overall our data could provide a molecular mechanism that links the beneficial effects of dietary restriction (i.e. fasting or intermittent fasting) to WAT reprogramming and lifespan.We conducted all mouse experimentations in accordance with accepted standard of humane animal care and with the approval by relevant national  and local  committees. CD1 and C57BL/6 adult male mice were purchased from Harlan Laboratories S.r.l. .in vivo experiment, twelve CD1 mice were randomly divided into two age-matched (4 months old) groups: ad libitum fed (Ctr) by standard diet and 20 h fasted (NR). Two C57BL/6 male mice per group were sacrificed to compare mitochondrial OxPHOS proteins in mitochondrial-derived eWAT and BAT at different ages . Adult C57BL/6 mice were randomly divided into three age-matched (4 months old) groups: ad libitum fed (Ctr) by standard diet; 20 h fasted and SR59230A  treated mice. In this period each NR mouse had free access to water and was kept on a 12:12 h light:dark cycle. For treatment with the selective \u03b23-adrenoreceptor antagonist, mice were intraperitoneally (ip) injected with 10 mg/kg of SR59230A dissolved in a physiological saline solution. Both ad libitum and NR group was ip injected with saline solution. SR59230A was injected 6 h prior and at the beginning of fasting experiment. Mice were sacrificed by cervical dislocation, and tissue samples were adequately collected. For total protein and mRNA extraction, epididymal (eWAT), inguinal (iWAT) and brown (BAT) adipose tissue were explanted and immediately processed.For 3T3-L1 cell lines were purchased from ATCC . T37i cell line was gently provided by Prof. Marc Lombes  and X9 cells were gently provided by Prof. Bruce Spiegelman . NR experiments were carried out as previously described , 17. 3T3For isolation of primary adipocytes, the stromal-vascular fraction of the epididymal (eWAT), inguinal (iWAT) and brown (BAT) fat pads of 5 weeks old male C57BL/6 mice were prepared and differentiated for 8 days, as reported by Fisher at al., 2012 .Fully differentiated 3T3-L1-white or X9-beige adipocytes were transfected with FoxO1 (Santa Cruz Biotechnology) or scramble siRNAs (Santa Cruz Biotechnology) by using DeliverX Plus kit . Alternatively, they were transfected with SOD2 cDNA pcDNA3.1 plasmid or pCMV-DsRed plasmid  by using Turbofect Transfection Reagent . Adipocytes were subjected to NR 48 h after transfection. Plasmid nuc-FoxO1 pCMV5 (Addgene #12143) and cyt-FoxO1  were used to transfect 3T3-L1 cells.Nutrient refill (re-feed) was performed by culturing starved adipocytes in complete culture medium (CM) for 1 h. Isoproterenol (Sigma-Aldrich) and N-acetyl cysteine (NAC) (Sigma-Aldrich) were dissolved in PBS and added in culture medium at final concentration of 10 \u03bcM and 2 mM, respectively. NAC was added 1 h prior to NR and maintained throughout the experiment. Rotenone (Sigma-Aldrich) was solubilized in DMSO and added in culture medium at final concentration of 0.1 \u03bcM.Western blotting analysis was performed as previously described . OxPHOS \u0394\u0394Ct method and were normalized to \u03b2-actin. \u0394Ct values were used to generate Heat Map by Excel software.RT-qPCR analysis was carried out as previously described . To calcNuclear and cytosolic fractions were obtained from cells and mice tissues using a commercially available NE-PER\u00ae extraction kit (Thermo Scientific). Mitochondria from differentiated adipocytes and eWAT were obtained as described by Wieckowski et al. .Olympus Fluoview 1000 confocal laser scanning system was used for colocalization experiments. The 488 nm laser was used to excite MTG and AlexaFluor 488-conjugated secondary antibody (Life Technologies). The 543 nm laser was used for detection of MTR and AlexaFluor 568 conjugated secondary antibody (Life Technologies). A 63X objective was used for all images. Nuclei were stained with Hoechst 33342 (10 \u03bcg/ml). Mitochondrial morphology analysis was performed by using Mitophagy Macro Plugin (ImageJ Software), and mitochondria area, perimeter and circularity were reported.Oxygen consumption rate was determined in intact 3T3-L1-white and X9-beige adipocytes. Briefly, at the end of differentiation, cells were either starved for 4 h or cultured in complete culture medium. Real-time oxygen consumption measurement was determined at 30 \u00b0C, for 6 min by Oxygraph Plus oxygen electrode system . Nutrient refill was performed by resuspending starved adipocytes in complete culture medium. Oxygen consumption was normalized for cell number. After cell respiration analysis, ATP level was detected by using ATP Bioluminescence assay kit (Roche Diagnostics) and values were normalized for cell number. To evaluate cellular uncoupling, we conventionally normalized oxygen consumption for ATP content.Mitochondrial ROS, transmembrane potential and number were detected by incubating cells with the fluorescent probe MitoSOX RED (5 \u03bcM), MitoTracker Red CMX ROS (250 nM), Tetramethylrhodamine Ethyl Ester Perchlorate , MitoTracker Green (250 nM) or Nonyl Acridine Orange  (Life Technologies) for 30 min at 37 \u00b0C. Subsequently, cells were collected and used for cytofluorimetric analyses by FACScalibur instrument . Changes in mitochondrial membrane potential were expressed as Red-to-Green ratio .The results are presented as means \u00b1 S.D. Statistical evaluation was conducted by ANOVA, followed by the post Student-Newman-Keuls, by using GraphPad Prism 5 Software (GraphPad Software)."}
+{"text": "Bacillus subtilis strain B-1, a strain known to form biofilms. The biofilm matrix mainly consists of the biopolymer \u03b3-polyglutamate (\u03b3-PGA). The sequence of the genome of this strain allows the study of specific genes involved in biofilm formation.We report here the draft genome sequence of the  Bacillus subtilis are known to form biofilms, but they differ in the compositions of the biofilm matrix . An Illumina standard shotgun library was constructed and sequenced with the Illumina MiSeq platform , which produced 120,000 paired-end reads totaling 85\u00a0Mbp. The reads were then further processed by de novo assembly using the programs Velvet , which resulted in an overall sequence homology of approximately 50%. A direct sequence comparison of several genes important for biofilm formation, namely, ywsC (\u03b3-polyglutamate synthesis) (bslA (surface layer protein) (tasA (amyloid fiber forming protein)  (epsA-O operon (exopolysaccharide synthesis)  , tasA (aprotein) , pel (stnthesis)  was perfCP009684.This draft sequence has been deposited at GenBank/DDBJ/EMBL under the accession no."}
+{"text": "Familial hemiplegic migraine (FHM) is a rare disorder characterized by migraine attacks with motor weakness during aura phase. Mutations in CACNA1A, ATP1A2, SCN1A and PRRT2 genes have been described.To describe a novel mutation in ATP1A2 gene in a FHM case with especially severe and prolonged symptoms.22-year-old woman admitted due to migrainous headache and sudden onset right-side weakness and aphasia. Previous episodes during childhood. Her mother was diagnosed as hemiplegic migraine without genetic confirmation. Ten days before admission mild head trauma. On clinical exam, body temperature of 38\u00baC, diminished consciousness, left gaze preference, mixed aphasia, right facial palsy, right hemiplegia and left crural paresis. Urgent perfusion computed tomography showed hypoperfusion throughout all left cerebral hemisphere. No abnormalities in brain Magnetic Resonance and cerebrospinal fluid. In electroencephalogram diffuse slowing. Impaired consciousness and dysphasia began to improve three days after admission and mild dysphasia and right hemiparesis remained during 10 days. No recurrence during a six months follow-up.Genomic DNA was extracted from peripheral blood and exons were amplified using PCR primers. Capture and massive sequencing of exons of candidate genes obtained using SureSelect Human All Exon 51 Mb kit (Agilent) and Hiseq2000 (Illumina) 30x tests. We identified an undescribed missense variant in heterozygous state in ATP1A2 gene (p.Thr364Met), pathogenic according to different prediction algorithms .Genotype-phenotype correlation in FHM caused by ATP1A2 mutations is not well defined. This new mutation might be linked to especially severe and long lasting attacks.No conflict of interest."}
+{"text": "Mycobacterium tuberculosis among HIV patients.Mannose binding Lectin (MBL) mediates protection against infections by activating the complement system, but certain microorganisms may increase infectivity by exploiting this host defence system. Hence, the purpose of this study is to evaluate MBL genetic variants with the development of TB infection caused by -ART+ (n=30) were collected. Genomic DNA was extracted from Peripheral Blood Mononuclear Cells (PBMC) using salting out procedure. MBL promoter haplotypes of -550 H/L and -221Y/X associated with high, medium and low  secretion was assessed by PCR-SSP.Blood samples from TB+ART+ and TB2X) =4.00; p<0.05).The Promoter haplotype (LY/LX) associated with deficient MBL levels conferred a protective role to TB in our study population with a significant difference (Chi-square (In this study, we could observe MBL2 promoter haplotypes with low MBL secretion may play a protective role to intracellular mycobacterium infections like TB in HIV seropositive individuals."}
+{"text": "Recently, high temporal resolution short-axis cine images have been used to create left ventricular (LV) regional mechanical delay (RMD) maps in patients undergoing cardiac resynchronization therapy (CRT). Generating the endocardial segmentation required for RMD analysis is both time-consuming and subjective. A semi-automated segmentation method for time-continuous contour detection that uses multi-dimensional dynamic programming to enforce user-defined shape constraints without the need for extensive training sets has been previously developed (\u00dcz\u00fcmc\u00fc 2006). Our goal was to compare RMD maps generated from semi-automated and manual segmentation in patients enrolled for CRT.Manual LV endocardial segmentations were compared to contours generated by the semi-automated segmentation method using every 4th, 8th, or 12th contour  in 11 patients scheduled for CRT. Contour agreement was assessed using a signed Euclidean distance-based shape similarity metric (Pluempitiwiriyawaj 2005) where 100% represents perfect agreement. RMD maps generated from each segmentation method were compared by computing the average delay difference between maps and identification the latest contracting AHA segment.Shape similarity between the reference contour set and auto-generated contour sets was high (90.4% - 87.8%), table We identified small differences between semi-automated and manual segmentation of high temporal resolution images of the LV. However, these differences do not significantly affect the identification of the region of latest contraction. Integration of semi-automated segmentation with RMD analysis warrants examination as a workflow enhancement in patients undergoing MRI before CRT.Grants from American Heart Association (AHA) and National Institutes of Health (NIH) to John Oshinski. Jonathan Suever was supported by a National Science Foundation (NSF) Fellowship."}
+{"text": "Allergen inhalation challenge causes significant changes in the blood transcriptomes of mild atopic asthmatic individuals . Systems\u00ae Human Gene 1.0 ST Arrays. The correlation networks (modules) were identified using weighted gene correlation network analysis (WGCNA) [14 participants  with mild, atopic asthma underwent a cat allergen inhalation challenge as part of the AllerGen Clinical Investigator Collaborative. The subjects\u2019 whole blood samples were collected immediately prior to allergen challenge  and 2 hours after the challenge . Whole blood transcriptional profiling was performed using Affymetrix GeneChip 21,727 mRNA transcripts were profiled across 28 samples (14 pre and 14 post). Highly expressed mRNA transcripts  6) were retained for WGCNA. WGCNA identified nine modules many of which were associated with various immune cell-types. A gene module consisting of 384 genes was significantly (p=0.0008) associated with the late phase asthmatic response and also significantly (p=1e-07) correlated with the compositional abundance of T cells. Pathways analysis of these genes indicated T cell receptor signaling pathway, TCR and CD28 co-stimulation in activation of NF-k\u03b2 and ICOS pathway in T-helper cells as the top significant pathways (FDR=10%).Transcriptional networks can be identified using whole blood expression data. Many transcriptional networks were associated with various cell-types frequencies, which may indicate the role of cell-specific gene expression in the development of asthmatic responses. Validation of these transcriptional networks will be performed using a larger asthma blood expression dataset."}
+{"text": "Arthrospira platensis (Paraca), a cultivated and edible haloalkaliphilic cyanobacterium of great scientific, technical, and economic potential.Here we report the whole-genome shotgun sequence of a Peruvian strain of  Arthrospira platensis, a filamentous cyanobacterium, forms massive populations in tropical water bodies characterized by high levels of carbonate and bicarbonate and pH up to 11 . We realized axenic cultures cultivated in a modified Zarrouk medium at 25\u00b0C  with an average G+C content of 44.31%. Annotation through the Prokaryotic Genomes Automatic Annotation Pipeline Group (PGAAPG) predicted 5,824 genes including 5,439 protein coding sequences (CDs). It also identified 6 clustered regularly interspaced short palindromic repeat (CRISPR) arrays, 388 pseudogenes, and 47 RNA genes while RAST analysis .This whole-genome shotgun project has been deposited at DDBJ/EMBL/GenBank under the accession no."}
+{"text": "Mycobacterium abscessus exhibiting a high degree of antibiotic resistance characteristic of this organism  was notified of two persons with rapidly growing nontuberculous mycobacterial (RG-NTM) surgical-site infections. Both patients had undergone surgical procedures as medical tourists at the same private surgical clinic (clinic A) in the Dominican Republic the previous month. Within 7 days of returning to the United States, both sought care for symptoms that included surgical wound abscesses, clear fluid drainage, pain, and fever. Initial antibiotic therapy was ineffective. Material collected from both patients\u2019 wounds grew Attempting to identify additional cases, MDHMH posted Epi-XMycobacterium abscessus infections; two (12%) were M. fortuitum infections; and one (6%) is pending final speciation. Of the 18 patients who were interviewed, 13 (72%) were born in the Dominican Republic.As of February 21, 2014, a total of 19 cases were identified from five states . Sixteen (84%) cases were confirmed, and three (16%) were probable. All patients are female (aged 18\u201359 years). Twelve (63%) reported undergoing surgery at clinic A, and seven (37%) reported surgery at seven other Dominican Republic surgical clinics. The most common cosmetic surgical procedures were liposuction (74%), abdominoplasty (58%), and breast implantation (32%); all procedures occurred during March\u2013November 2013 , and illCDC notified Dominican public health authorities of the outbreak investigation and recommended patient follow-up and onsite assessment of infection control practices at the implicated clinics. Clinic A has been closed temporarily by Dominican authorities. This and other outbreaks underscore the risk for infection, including RG-NTM infection, resulting from medical tourism ,3. CDC a"}
+{"text": "Akap1 gene have been shown to modulate mitochondrial function and reactive oxygen species (ROS) production in the heart. Under conditions of hypoxia, mitochondrial AKAP121 undergoes proteolytic degradation mediated, at least in part, by the E3 ubiquitin ligase Seven In-Absentia Homolog 2 (Siah2). In the present study we hypothesized that Akap1 might be crucial to preserve mitochondrial function and structure, and cardiac responses to myocardial ischemia. To test this, eight-week-old Akap1 knockout mice (Akap1-/-), Siah2 knockout mice (Siah2-/-) or their wild-type (wt) littermates underwent myocardial infarction (MI) by permanent left coronary artery ligation. Age and gender matched mice of either genotype underwent a left thoracotomy without coronary ligation and were used as controls (sham). Twenty-four hours after coronary ligation, Akap1-/- mice displayed larger infarct size compared to Siah2-/- or wt mice. One week after MI, cardiac function and survival were also significantly reduced in Akap1-/- mice, while cardiac fibrosis was significantly increased. Akap1 deletion was associated with remarkable mitochondrial structural abnormalities at electron microscopy, increased ROS production and reduced mitochondrial function after MI. These alterations were associated with enhanced cardiac mitophagy and apoptosis. Autophagy inhibition by 3-methyladenine significantly reduced apoptosis and ameliorated cardiac dysfunction following MI in Akap1-/- mice. These results demonstrate that Akap1 deficiency promotes cardiac mitochondrial aberrations and mitophagy, enhancing infarct size, pathological cardiac remodeling and mortality under ischemic conditions. Thus, mitochondrial AKAPs might represent important players in the development of post-ischemic cardiac remodeling and novel therapeutic targets.A-kinase anchoring proteins (AKAPs) transmit signals cues from seven-transmembrane receptors to specific sub-cellular locations. Mitochondrial AKAPs encoded by the  Mitochondria are central to several cellular processes, as they are both the main source of energy and reactive oxygen species (ROS), and critical regulators of cell death or survival pathways . MitochoAkap1), and are generated by alternative RNA splicing. All splice variants share the first 30 NH2-terminal residues mediating the targeting to the outer mitochondrial membrane and other functions, but diverge significantly at the C-terminus. Mitochondrial AKAP121 is transcriptionally regulated by cyclic adenosine monophosphate (cAMP) in vitro and in vivo  in hearts from (TIF)Click here for additional data file.S2 Fig(A) Representative microphotographs of cardiac cross-sections from wt and Akap1-/- mice undergoing the sham procedure (sham) or 1-week myocardial infarction (MI 1 wk) stained with wheat germ agglutinin (WGA) and counterstained with DAPI. Scale bar = 100 \u03bcm. (B) Quantification of cardiomyocytes area .(TIF)Click here for additional data file."}
+{"text": "Mycobacterium tuberculosis (Mtb) isolates, leading to more effective epidemiological studies involving single nucleotide variations (SNVs) in core genomic sequences based on molecular evolution. We developed an all-in-one web-based tool for genotyping Mtb, referred to as the Total Genotyping Solution for TB (TGS-TB), to facilitate multiple genotyping platforms using NGS for spoligotyping and the detection of phylogenies with core genomic SNVs, IS6110 insertion sites, and 43 customized loci for variable number tandem repeat (VNTR) through a user-friendly, simple click interface. This methodology is implemented with a KvarQ script to predict MTBC lineages/sublineages and potential antimicrobial resistance. Seven Mtb isolates (JP01 to JP07) in this study showing the same VNTR profile were accurately discriminated through median-joining network analysis using SNVs unique to those isolates. An additional IS6110 insertion was detected in one of those isolates as supportive genetic information in addition to core genomic SNVs. The results of in silico analyses using TGS-TB are consistent with those obtained using conventional molecular genotyping methods, suggesting that NGS short reads could provide multiple genotypes to discriminate multiple strains of Mtb, although longer NGS reads (\u2265300-mer) will be required for full genotyping on the TGS-TB web site. Most available short reads (~100-mer) can be utilized to discriminate the isolates based on the core genome phylogeny. TGS-TB provides a more accurate and discriminative strain typing for clinical and epidemiological investigations; NGS strain typing offers a total genotyping solution for Mtb outbreak and surveillance. TGS-TB web site: https://gph.niid.go.jp/tgs-tb/.Whole-genome sequencing (WGS) with next-generation DNA sequencing (NGS) is an increasingly accessible and affordable method for genotyping hundreds of  Mycobacterium tuberculosis (Mtb) resistant to at least isoniazid and rifampicin worldwide [6110 restriction fragment length polymorphism (RFLP), spoligotyping (spacer oligonucleotide typing), and variable-number tandem repeat (VNTR) analysis, are currently used for fingerprinting Mtb strains to detect recent transmission.An estimated 8.6 million people developed tuberculosis (TB) in 2012, and 1.3 million individuals died from this disease. WHO reported 450,000 new cases of multidrug resistant (MDR) 6110-RFLP typing is a standard genotyping approach [6110 genotyping [ISapproach , but reqapproach . Howevernotyping . The Mtbnotyping . Howevernotyping .M. tuberculosis strains. However, the clustered strains defined using these methods might be distantly related, both genetically and historically, reflecting the low reliability of these tests to distinguish recent from past transmissions [Genetic elements for molecular epidemiological genotyping techniques do provide adequate discriminatory power for distinguishing missions . Thus, e6110 fingerprints and 23 out of 24 MIRU-VNTR loci [Whole-genome sequencing (WGS) using next-generation DNA sequencing (NGS) has emerged as an increasingly accessible and affordable method for genotyping hundreds of Mtb isolates, leading to more effective epidemiological studies involving single nucleotide polymorphisms (SNPs) in the core genomic sequence based on the molecular evolutionary clock \u201314. GenoNTR loci . Such heNTR loci . It has NTR loci , 17, 18.NTR loci .http://www.miru-vntrplus.org) are available for analyzing MLVA data (MtbC15-9 type) in combination with other complementary typing data, including spoligotypes, regions of difference (RDs), SNPs in antimicrobial target genes and susceptibility information [In silico spoligotyping is available using SpolPred to more accurately and rapidly determine a spoligotype [http://pathogenseq.lshtm.ac.uk/polytb) to visualize the resulting MTBC genetic variations  and important meta-data  at a genome and global scale [M. tuberculosis genomic variation within epidemiological, geographical and phylogenic settings from 1,601 M. tuberculosis isolates, facilitating the assessment of genotype-phenotype associations [Freely accessible web services facilitate the genotyping of isolated strains alone or in comparison with reference strains from major MTBC lineages. Currently, MIRU-VNTRplus web tools  , SpolPreTotal Genotyping Solution for TB (TGS-TB) web-based tool to facilitate multiple genotyping formats using NGS for the analysis of phylogenies with core genomic single nucleotide variations (SNVs), linkage network analysis of outbreak strains, spoligotyping, the analysis of IS6110 insertion sites and VNTRs (our customized short TR on 43 loci) through a user-friendly, simple click interface  x 250-mer (read2) paired-end sequencing resulted in 70% of 300-mer nucleotide sequences with Phred quality scores above 30 , 6 querP05 Figs  and 5, s6110 insertion . We originally assigned the 43 loci of short tandem repeats (TR), including 10 loci  of the 24-loci MIRU-VNTR . The selin silico analysis through TGS-TB are consistent with conventional molecular genotyping methods  as a reference genome sequence. The performance and accuracy of TGS-TB were examined using seven Japanese Mtb isolates associated with local outbreaks  , and the following nd JP07) .Genomic DNA from Mtb isolates was purified through the benzyl chloride method using the ISOPLANT kit . A genomic DNA library for NGS was prepared using the Nextera XT DNA Sample Prep Kit , followed by insert size selection using 1% TAE agarose electrophoresis to obtain an insert of approximately 600 bp. Sequencing was performed on MiSeq  using the MiSeq Reagent Kit v3 (600 cycle) with 350-mer x 250-mer paired-end short reads and 96-sample multiplexing .embA, gyrA, katG, pncA, rpoB, rpsL, rrs and inhA genes from TBDReaMDB [MTBC lineages/sublineages and potential AMRs were determined using the KvarQ script according to the manufacturer\u2019s instructions . The AMRBDReaMDB  .To investigate the epidemiological linkage between patients, the information from queries for isolate-specific genes or the above mentioned reference genomes can be downloaded as a nexus format file to visualize linkage networks, such as the median-joining network method using PopART  was performed according to an adapter trimming procedure  [Instead of MIRU-VNTR , 19, we r/GPMS/)  using th6110-RFLP were performed on the seven Japanese clinical strains (JP01 to JP07). Spoligotyping was performed according to the standardized protocol using an in-house membrane [6110-RFLP was performed according to a standardized protocol [Three molecular genotyping methods based on spoligotyping, VNTR and ISmembrane . An optimembrane , and IS6protocol .S1 FigNGS was performed on a MiSeq NGS sequencer  using the MiSeq Reagent Kit v3 (600 cycle) with 350-mer x 250-mer paired-end short reads.(PDF)Click here for additional data file.S2 Fig(PDF)Click here for additional data file.S3 Fig6110 insertions, respectively.The red and sky-blue vertical bars on the H37Rv reference genome indicate the forward and reverse IS(PDF)Click here for additional data file.S4 FigThe filled circles indicate positive homology to each oligonucleotide sequence.(PDF)Click here for additional data file.S5 FigThe detected number of TRs is shown on each locus and visualized using a color variation scale. Black and gray boxes indicate no detection of TRs and lower depths, respectively.(PDF)Click here for additional data file.S6 Fig(PDF)Click here for additional data file.S1 Table(PDF)Click here for additional data file.S2 Table(PDF)Click here for additional data file.S3 Table(PDF)Click here for additional data file.S1 TextembA, gyrA, katG, pncA, rpoB, rpsL, rrs and inhA genes from TBDReaMDB [The AMR target list for KvarQ prediction has been improved to detect more reliable genetic alterations for the BDReaMDB .(TXT)Click here for additional data file."}
+{"text": "Examination revealed oral painful erosive lesions with genital erythematous purpuric patch mimiking atypical target-like lesions. No others cutaneous lesions were observed. Skin biopsy showed apoptotic individual keratinocytes, degeneration of basal keratinocytes and intercellular oedema, it concluded to diagnosis of erythema multiforme. The patient was treated by Aciclovir 5mg/kg/day for 1 week with oral antihistamines, analgesics and local skin care. A complete resolution was noted after 2 weeks."}
+{"text": "The exponential increment of various co-morbid disorders among HIV positive individuals includes various medical subspecialties and mental health is one of them. HIV/AIDS affects mental health by its complex interactions which may be the result of the psychological response to the diagnosis or complex neurobiological interactions. Therefore the current study aims at systematic evaluation of psychiatric morbidity in HIV/AIDS patients.Patients attending ART centre during the period of 1 year were selected for the study by random sampling method. After obtaining written consent MINI-PLUS intentional scale was applied to evaluate the psychiatric co-morbidity.P = 0.0426).Of 75 patients MINI-Plus interview revealed co-morbidities of major depressive disorder (10.66%), generalized anxiety disorder (25.33%), panic disorder (1.33%), alcohol dependence (29.33%) and abuse (5.33%), nicotine dependence (32%), opioid & marijuana (1.33%) and schizophrenia (2.66%) and cognitive impairment (5.33%). Both the sex were almost equally affected by the psychiatric morbidities except substance abuse were more prevalent in male participants but patients with primary and secondary education suffered more from anxiety disorder. Interestingly, patients with co-morbid alcohol abuse and dependence had lower CD4 count than non alcoholic counterpart (HIV/AIDS with psychiatric morbidity, out of which generalized anxiety disorder and major- depressive- disorder are common but alcohol and nicotine dependence and abuse, is the highest of co-morbidity. Co-morbid alcohol use problem is associated with low CD4 probably mediated through immune-modulator effect of alcohol. Treatments of co morbidity will definitely ensure a better quality of life and treatment outcome."}
+{"text": "Hepatitis A virus (HAV) epidemiology in Tunisia has changed from high to intermediate endemicity in the last decades. However, several outbreaks continue to occur. The last reported sequences from Tunisian HAV strains date back to 2006. In order to provide an updated overview of the strains currently circulating in Tunisia, a large-scale molecular analysis of samples from hepatitis A cases was performed, the first in Tunisia.Biological samples were collected from patients with laboratory confirmed hepatitis A: 145 sera samples in Tunis, Monastir, Sousse and Kairouan from 2008 to 2013 and 45 stool samples in Mahdia in 2009. HAV isolates were characterised by nested RT-PCR (VP1/2A region) and sequencing. The sequences finally obtained from 81 samples showed 78 genotype IA and 3 genotype IB isolates.A Tunisian genotype IA sequence dataset, including both the 78 newly obtained IA sequences and 51 sequences retrieved from GenBank, was used for phylogenetic investigation, including analysis of migration pattern among six towns. Virus gene flow from Sfax and Monastir was directed to all other towns; in contrast, the gene flows from Sousse, Tunis, Mahdia and Kairouan were directed to three, two, one and no towns, respectively.Several different HAV strains co-circulate in Tunisia, but the predominant genotype still continues to be IA . A complex gene flow (migration) of HAV genotype IA was observed, with Sfax and Monastir showing gene flows to all other investigated towns. This approach coupled to a wider sampling can prove useful to investigate the factors underlying the spread of HAV in Tunisia and, thus, to implement appropriate preventing measures. Hepatitis A virus (HAV), a member of the family Picornaviridae, genus Hepatovirus, is the major cause of acute hepatitis throughout the world and causes substantial morbidity in both developed and developing countries . Their sequence names, reported in Figures\u00a0Two sequence datasets were built. The first one was built to determine the genotype of each isolate and included all the 81 newly obtained sequences plus 27 reference sequences from several countries representative of genotypes I, II, III (human strains) and V (a simian strain), downloaded from the GenBank database via the National Center for Biotechnology Information (NCBI) site . The lisThe second dataset was built to perform phylogenetic analysis and viral gene flow exclusively on genotype IA Tunisian sequences. This dataset included 78 new sequences from the present study (identified as genotype IA among the above 81 new sequences) and 51 Tunisian sequences downloaded from GenBank. These latter sequences were selected according to the following inclusion criteria, based on information available from sequence annotations or from published studies: (1) known sampling town; (2) known sampling year. Their names were coded exactly as the newly obtained sequences (see above): a number  followed by \u201cTu\u201d, then a capital letter  indicating the sampling town and, finally, the sampling year preceded by \u201c_\u201d. The list of the 51 downloaded Tunisian sequences collected in Sfax, Sousse, Mahdia and Monastir from 2001 to 2006 with matched Accession Number (in parentheses) follows: 82TuB_03 (AY875650); 83TuB_03 (AY875651); 84TuB_02 (AY875652); 85TuB_03 (AY875653); 86TuA_03 (AY875654); 87TuC_03 (AY875655); 88TuB_02 (AY875656); 89TuB_01 (AY875657); 90TuB_03 (AY875659); 91TuB_03 (AY875660); 92TuB_02 (AY875661); 93TuB_03 (AY875662); 94TuD_01 (AY875663); 95TuB_01 (AY875664); 96TuA_03 (AY875665); 97TuA_03 (AY875666); 98TuA_03 (AY875667); 99TuA_04 (AY875668); 100TuA_04 (AY875669); 101TuA_04 (AY875670); 102TuB_04 (AY875671); 103TuB_01 (AY875672); 104TuA_03 (DQ380510); 105TuA_03 (DQ380511); 106TuA_03 (DQ380512); 107TuA_03 (DQ380513); 108TuA_03 (DQ380514); 109TuA_03 (DQ380515); 110TuA_03 (DQ380516); 111TuA_03 (DQ380517); 112TuA_03 (DQ380518); 113TuA_03 (DQ380519); 114TuA_03 (DQ380520); 115TuA_03 (DQ380521); 116TuA_03 (DQ380522); 117TuA_03 (DQ380523); 118TuA_03 (DQ380524); 119TuA_06 (HM011106); 120TuA_06 (HM011107); 121TuA_06 (HM011108); 122TuA_06 (HM011109); 123TuA_06 (HM011110); 124TuA_06 (HM011111); 125TuA_06 (HM011112); 126TuA_06 (HM011113); 127TuA_06 (HM011114); 128TuA_06 (HM011115); 129TuA_06 (HM011116); 130TuA_06 (HM011117); 131TuA_06 (HM011118); 132TuA_06 (HM011119).Sequences were aligned with the Clustal algorithm , then edThe best fitting nucleotide substitution model was tested with a hierarchical likelihood ratio test following the strategy described by Swofford and Sullivan , using aThe MacClade version 4 program  was used to test viral gene in/out flow among distinct HAV subpopulations within different geographic regions and towns in Tunisia , using a modified version of the Slatkin and Maddison test as described below .A one-character data matrix is obtained from the original data set by assigning to each taxon in the tree a one-letter code indicating its city of origin. Then, the putative origin of each ancestral sequence  in the tree is inferred by finding the most parsimonious reconstruction (MPR) of the ancestral character. The final tree-length, i.e. the number of observed migrations in the genealogy, can easily be computed and compared to the tree-length distribution of 10,000 trees obtained by random joining-splitting.Observed genealogies significantly shorter than random trees indicate the presence of subdivided populations with restricted gene flow . SpecifiWritten informed consent was obtained from the patients, or their parents in the case of minors, for participation in the study."}
+{"text": "Gossypium spp.) were used to discover putative gene sequences involved in resistance to common soil-borne pathogens. Chromosome (Chr) 11 and its homoeologous Chr 21 of Upland cotton (G. hirsutum) are foci for discovery of resistance (R) or pathogen-induced R (PR) genes underlying QTLs involved in response to root-knot nematode (Meloidogyne incognita), reniform nematode (Rotylenchulus reniformis), Fusarium wilt (Fusarium oxysporum f.sp. vasinfectum), Verticillium wilt (Verticillium dahliae), and black root rot (Thielaviopsis basicola). Simple sequence repeat (SSR) markers and bacterial artificial chromosome (BAC) clones from a BAC library developed from the Upland cotton Acala Maxxa were mapped on Chr 11 and Chr 21. DNA sequence through Gene Ontology (GO) of 99 of 256 Chr 11 and 109 of 239 Chr 21 previously mapped SSRs revealed response elements to internal and external stimulus, stress, signaling process, and cell death. The reconciliation between genetic and physical mapping of gene annotations from new DNA sequences of 20 BAC clones revealed 467 (Chr 11) and 285 (Chr 21) G. hirsutum putative coding sequences, plus 146 (Chr 11) and 98 (Chr 21) predicted genes. GO functional profiling of Unigenes uncovered genes involved in different metabolic functions and stress response elements (SRE). Our results revealed that Chrs 11 and 21 harbor resistance gene rich genomic regions. Sequence comparisons with the ancestral diploid D5 (G. raimondii), A2 (G. arboreum) and domesticated tetraploid TM-1 AD1 (G. hirsutum) genomes revealed abundance of transposable elements and confirmed the richness of resistance gene motifs in these chromosomes. The sequence information of SSR markers and BAC clones and the genetic mapping of BAC clones provide enhanced genetic and physical frameworks of resistance gene-rich regions of the cotton genome, thereby aiding discovery of R and PR genes and breeding for resistance to cotton diseases.Genetic and physical framework mapping in cotton ( Cultivated plant species are under continuous attack by pathogens, which imposes a major challenge for growers by causing significant crop yield loss  whether they are used in defense or not , root-knot nematode [RKN (Meloidogyne incognita)], reniform nematode [REN (Rotylenchulus reniformis)], Fusarium wilt [FOV) (Fusarium oxysporum f.sp. vasinfectum)], Verticillium wilt [VW (Verticillium dahliae)], and black root rot [BRR (Thielaviopsis basicola)] represent expanding threats to crop production . Additional studies using genomic and proteomic technologies have facilitated global comparisons of R and PR expression profiles  for which MUSB-derived single sequence repeat (SSR) markers were previously mapped to chromosomes (Chr) 11 and 21  genome which are now publicly available . Other MUSB markers were selected because they were mapped in the vicinity of an underlying QTL involved in pathogen resistance  to select BAC clones previously sequenced from the Acala Maxxa library by sequence-comparison. These BAC clones were originally sequenced erroneously as part of the maize sequencing project by the Genome Sequencing Center, Washington University School of Medicine. The DNA sequence information of these BACs was deposited into GenBank under the accession numbers: AC193383, AC187848, AC187214, AC187470, AC202821, AC190836, AC202830, and AC187810. Sequences of each BAC clone (Table The second strategy was to use SSR marker-sequences previously mapped on Chr 11 and Chr 21 (CMD: E. coli DH10B host cells. Transformants were selected on Lysogeny broth (LB) plates containing carbenicillan, X-Gal and IPTG. White recombinant colonies were picked robotically using the Genetix Q-bot  and stored as individual clones in Genetix 96-well microtiter plates as glycerol stocks at \u221280\u00b0C. Sequencing was performed using the Dye-terminator cycle sequencing kit v3.1 . Sequence data from the forward and reverse universal priming sites of the shotgun clones were accumulated on an ABI 3730xl DNA analyzer . The BAC clones were sequenced to approximately 8X clone coverage (assuming 120 kb average insert size) and assembled with PHRAP software , KM396695 (28O10), KM396696 (26K03), KM396697 (24E04), KM396698 (40I16), KM396699 (34K01), KM396700 (29O06) KM396701 (33K23), KM396702 (18O18), KM396703 (31K15), KM396704 (30E04), and KM396705 (32H19). The numbers and letters identify the BAC clone.A small-insert (3\u20135 kb) library was constructed from each of the 12 BAC clones, which harbored the selected MUSB markers on Chr 11 and Chr 21  was downloaded from PlantGDB (www.plantgdb.org). Unigene sequences were BLASTN aligned to each BAC sequence individually with an e \u2264 1e-5 and identity \u226590%. Gene Ontology (GO) annotation was conducted using the Blast2GO program with default parameters  matches as additional support for gene identification. All predicted genes and unigenes were subjected to a similar analysis using BLASTX through the National Center for Biotechnology Information (NCBI) (http://www.ncbi.nlm.nih.gov/) nr protein database with a value of 1e-5 to identify previously established protein motifs. Stress response elements (SRE) were identified based on the description of bioprocess of GO annotation. Genes involved in stress response elements were identified according to associated protein molecular function (MF), bioprocess (BP), and cell component (CC).DNA sequence-local alignments were made with the comprehensive G. raimondii diploid D5 whole genome (phytozome.net)   from two independent groups . Comparisons were also made between these BACs and other plant taxa: Arabidopsis thaliana, Vitis vinifera, Populus trichocarpa, and Theobroma cacao.BAC sequences were aligned to the http://www.cottonmarker.org/), especially those underlying QTLs determining resistance to RKN  were used with wide coverage to construct the linkage groups of Chr 11 and Chr 21 on the recombinant inbred line (RIL) population of Upland TM- 1 \u00d7 Pima 3-79  were used to investigate DNA sequence composition. Sequences were then BLASTed through the NCBI (http://www.ncbi.nlm.nih.gov/). Sequences were compared against three databases: (a) Nucleotide collection (nr/nt); (b) Expressed Sequence Tags (EST); and (c) Non-Redundant protein sequences (nr). The top sequence hits found for each sequence in all three databases were then BLASTed through GO (http://www.geneontology.org/). The top functional hits given by GO were collected along with their categorized gene products . SSR markers involved in defense response or stress response were categorized according to top blasted protein function  and GO annotation.SSR markers previously mapped on Chr 11 and Chr 21 reported in the Cotton Marker Database  revealed 467 (Chr 11) and 285 (Chr 21) putative Unigenes (e \u2264 1e-5). Functional signature annotations of BAC-mapped Unigene sequences were aligned to the non-redundant protein database and assigned GO terms. A total of 238 out of 467 of Chr 11 and 233 out of 285 of Chr 21 putative Unigenes were found to be similar to known protein sequences with e \u2264 1e-5  on Chr 21 contained R genes harboring NBS-LRR proteins, including CC-NBS-LRR class disease resistance, tmv resistance protein and other disease resistance proteins . The BAC 31K15 associated with marker MUSB1076 linked to R gene ns Table .More specifically, a percent identity plot of duplication harboring NBS-LRR resistance motifs for BAC clones AC187810 vs. AC202830 on Chr 21 is given in Figure G. arboreum (A2) and G. raimondii (D5)  Tables \u2013S13. Thes Tables , S13 whid Tables . Howevere Tables . The BACG. hirsutum Maxxa to G. hirsutum TM-1 genome showed slight differences between the two sequencing groups BGI and NBI, possibly due to different assembly methods (Tables p < 0.05 (range from 8.12E-33 to 0.041). The 115 GOs included stress response elements, such as oxidoreductase activity, cell-cell signaling, defense response to virus, syncytium formation, response to abiotic stimulus, MAP kinase kinase kinase activity, and transmembrane receptor protein tyrosine kinase signaling pathway.Alignment of Chr 11 and Chr 21 BAC sequences from s Tables , S15. Ins Tables , S15. Frs Tables , S15. Pas Tables , 15. MosArabidopsis thaliana, Vitis vinifera, Populus trichocarpa, and Theobroma cacao, revealed conserved regions of short sequences with each plant species. Alignments with T. cacao and V. vinifera were especially strong for certain cotton BAC clones, but less so with A. thaliana and P. trichocarpa. Results from these comparisons and subsequent GO analyses did not provide additional information.Comparison of Chr 11 and Chr 21 BAC sequences with four other plant taxa\u2014www.cottonmarker.org) were used to develop Upland cotton Chr 11 and Chr 21 linkage groups. Matrix genotypic data of these SSR markers were used to develop the most recent genetic linkage map of the TM-1 x 3-79 RIL population . Categorization of the gene function revealed that markers of Chrs 11 and 21 mapped to genes associated with all three GO: BP, CC, and MF  and predicted gene databases (A/D: 56/16) (Table G. hirsutum) in the diploid G. arboreum A genome and only 1542 TEs on Chr 7  in the diploid G. raimondii D5 genome even though there were similar numbers of loci identified on Chr 7 in both diploid genomes. At least 64.8% TEs were identified in the TM-1 genome by Zhang et al. (G. hirsutum was derived from reuniting of diploid A and D genomes about 1\u20132 million years ago (mya) through independent and differential accumulation of TEs 5 mya  than on Chr 21 (Dt subgenome) according to both 6) Table  reportedg et al.  and 66% g et al. . More TEg et al. . TEs areg et al. . In cottG. hirsutum AD1 whole genome with A2 and D5 were thoroughly conducted by Li et al.   and G. barbadense (AD2) were found to share the same SSR marker MUCS088 alleles as G. arboreum (A2), suggesting nematode resistance introduction was from the diploid cotton (A2) genome  have been utilized successfully to identify genetic variation in plants . Continuing genetic and physical framework alignment of sequence information in cotton will help to expedite the discovery of R and PR genes and the assembly of a whole Upland cotton tetraploid genome, eventually supporting breeding for disease resistance in cotton production.In conclusion, the sequence information and physical mapping of BAC clones provide an additional genomic resource of these resistance gene-rich regions of the Upland cotton genome on Chr 11 and Chr 21. BAC clone sequences are deposited in GenBank (NCBI: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Listeria monocytogenes N2306, a serotype 4b clinical strain isolated during the 2013-2014 nationwide listeriosis outbreak in Switzerland.We present the complete genome sequence of  Listeria monocytogenes causes listeriosis, which is a rare but serious foodborne disease associated with severe life-threatening illnesses and high mortality among those with weakened immune systems .Genomic DNA isolated from N2306 was subjected to single-molecule real-time sequencing on a Pacific Biosciences RS2 device  at the Functional Genomics Centre Zurich (FGCZ). A total of 131,245 sequence reads (126-fold genome coverage) with an average length of 3,261\u00a0kb were generated. The N2306 genome was assembled http://www.pasteur.fr/recherche/genopole/PF8/mlst/index.html).The N2306 genome comprises 2,885 open reading frames, including 2,781 coding sequences (CDS), 18 pseudogenes, 67 tRNA genes, and 6 rRNA operons. An incomplete prophage at position 235,349 to 258,324  of the genome was detected using the Phage search tool (PHAST [The availability of the N2306 genome will enable its comparison with other genomes of listeriosis outbreak strains, providing more insights into virulence factors and stress resistance genetic features associated with this important foodborne pathogen.CP011004.The complete N2306 genome sequence has been deposited in GenBank under the accession number"}
+{"text": "R) genes that encode NBS-LRR domain proteins. Therefore, we sought to test whether NBS-LRR genes would overlap with meiotic crossover hotspots using experimental genetics in Arabidopsis thaliana. NBS-LRR genes tend to physically cluster in plant genomes; for example, in Arabidopsis most are located in large clusters on the south arms of chromosomes 1 and 5. We experimentally mapped 1,439 crossovers within these clusters and observed NBS-LRR gene associated hotspots, which were also detected as historical hotspots via analysis of linkage disequilibrium. However, we also observed NBS-LRR gene coldspots, which in some cases correlate with structural heterozygosity. To study recombination at the fine-scale we used high-throughput sequencing to analyze ~1,000 crossovers within the RESISTANCE TO ALBUGO CANDIDA1 (RAC1) R gene hotspot. This revealed elevated intragenic crossovers, overlapping nucleosome-occupied exons that encode the TIR, NBS and LRR domains. The highest RAC1 recombination frequency was promoter-proximal and overlapped CTT-repeat DNA sequence motifs, which have previously been associated with plant crossover hotspots. Additionally, we show a significant influence of natural genetic variation on NBS-LRR cluster recombination rates, using crosses between Arabidopsis ecotypes. In conclusion, we show that a subset of NBS-LRR genes are strong hotspots, whereas others are coldspots. This reveals a complex recombination landscape in Arabidopsis NBS-LRR genes, which we propose results from varying coevolutionary pressures exerted by host-pathogen relationships, and is influenced by structural heterozygosity.Meiotic crossover frequency varies extensively along chromosomes and is typically concentrated in hotspots. As recombination increases genetic diversity, hotspots are predicted to occur at immunity genes, where variation may be beneficial. A major component of plant immunity is recognition of pathogen Avirulence (Avr) effectors by resistance . Using Arabidopsis ecotypes we also show that natural genetic variation has a strong modifying effect on resistance gene cluster recombination rates. Together our work shows complex variation in resistance gene crossover patterns, which may relate to heterogeneity in coevolutionary pressures experienced at different loci, in addition to the effects of structural genetic diversity.The majority of plants, animals and fungi reproduce sexually, which has a profound effect on patterns of genetic diversity. For sexual reproduction to occur a specialized cell division called meiosis generates gametes (sex cells) with recombined DNA. During meiosis homologous chromosomes undergo reciprocal exchange of genetic material called crossover, which mixes parental sequences. Crossover frequency is highly variable along chromosomes and is typically concentrated in narrow regions called hotspots. Sexual reproduction is proposed to provide a major advantage during host-pathogen coevolution. This theory predicts that crossover hotspots will be associated with genes that play important roles in the immune system, where diversity may be beneficial. To investigate this idea we mapped patterns of crossover frequency in relation to genes that plants use to recognize pathogens. We observe that a subset of  During meiosis, homologous chromosomes recombine via reciprocal exchanges of DNA, called crossovers ,2. CrossAvirulence genes, Avr) by matching plant disease resistance genes (R genes) .,35.R genR genes) . NBS-LRRr parent .R genes. We therefore sought to use experimental genetics to measure meiotic crossovers associated with the Arabidopsis NBS-LRR gene family. We observe strong crossover hotspots in a subset of NBS-LRR genes. However, we also observe significant NBS-LRR gene coldspots, which in some cases associate with structural heterozygosity. We mapped fine-scale crossover patterns within the RESISTANCE TO ALBUGO CANDIDA1 (RAC1) R gene hotspot, which confers resistance against oomycete pathogens .,69.A.thasis Figs . KAN-BAR regions  Tables.MRC KAN-BAR insertions were crossed to generate double kanamycin-glufosinate resistant F1trans-hemizygotes, which were then backcrossed as males to wild type Col females )  markers was used to confirm that they had experienced a crossover within the selected MRC region  (MRC regions a subset of the double-selected MRC1 (n = 725) and MRC5 (n = 714) recombinant individuals were chosen for further analysis by internal genotyping , including intervals containing R genes ) , where NC region  Tables. 8 cM/Mb)  Tables . We. WeMRC1 87 cM/Mb , compare3 (HRG3) . HRG2 anectively . Fine-massovers) . We fineRR genes . We obsend HRG9)  Tables. LRR loci  Tables.MRC intervals with significantly different crossover rates, we constructed 2\u00d72 contingency tables and performed X2 tests using the observed crossover and non-recombinant counts, and those expected at random based on the physical size of each interval. Finally, we applied a false discovery correction, due to multiple testing .\u201374.HRG1,requency  Tables. e to Col , and themorphism . In summR gene we used pollen-typing . Hi. HiRAC1 t1g31550 . TogetheHRG1, HRG2-HRG3 and RAC1 NBS-LRR hotspots show historical and experimental recombination rates above the genome average  to 18 Arabidopsis accessions representing global diversity and measured genetic distance in replicate F1 plants, scoring ~30,000 pollen grains per individual   T-DNA insertions ,97. InheRR genes . We crosdividual . We obse0\u00d710\u221216) . This den plants . TherefoR gene hotspots. For example, RAC1 shows high historical and contemporary crossover frequency, comparable to known plant hotspots  patterns of sequence diversity and evolutionary history .,35.16,35truction . To searTEL1 interval (BAR), and Ds insertions conferring kanamycin resistance in the Ler accession (hereafter named KAN), were chosen with insertion sites flanking the NBS-LRR gene clusters on the south arms of chromosomes 1 and 5 -dCTP using a random priming labelling kit . Blots were washed with 0.5% SSC, 0.1% SDS solution at 65\u00b0C and imaged with a PhosphoImager . We compared Southern blot data with the TAIR10 Col assembly and a Ler assembly generated by Pacific Biosystems (http://blog.pacificbiosciences.com/2013/08/new-data-release-arabidopsis-assembly.html) [1.5 \u03bcg of genomic DNA was digested using 100 units of restriction enzyme (NEB) in a final volume of 200 \u03bcl for 15 hours at 37\u00b0C. Digested DNA samples were isopropanol precipitated, resuspended in TE and electrophoresed in 0.8% agarose-TBE gels. Gels were blotted onto a positively charged nylon membrane , which was hybridized in 0.5 M phosphate buffer, 7% w/v SDS, 1 mM EDTA (pH 8) and 1% BSA at 65\u00b0C. DNA probes to the ly.html) .I5a FTL T-DNAs was performed as described previously [Yi represents the recombinant counts, ni are the total counts, and we wish to model the proportions Yi/ni. Then:Analysis of fluorescent pollen and segregation of eviously . Genetic\u03b5i ~ N. Both replicates and genotypes are treated as independent variables (X) in our model. We considered P values less than 0.05 as significant.Thus, our variance function is:S1 Fig(A) Representative Southern blots used to identify single copy SAIL and SGT lines. Replicate samples indicate DNA isolated from siblings. Single copy lines were identified for further experiments. (B) Self-fertilization of homozygous KAN or BAR lines should yield ~100% resistance progeny on selective plates. (C) Self-fertilization of hemizygous KAN or BAR lines should yield 75% resistant progeny on selective plates. (D) Backcrossing hemizygous KAN or BAR lines should yield 50% resistant progeny on selective plates.(TIFF)Click here for additional data file.S2 Fig(A) The distribution of distances between start coordinates for NBS-LRR genes (black) and sampled data (blue). (B) As for (A), but showing the distribution of gene widths. (C) Boxplot showing the distribution of the number of crossovers per gene from the sampled data. The red point shows the observed value for NBS-LRR genes and the blue point shows that for the non-NBS-LRR genes. (D) As for (C), but showing the number of crossovers overlapping the sampled genes, normalized by the total length of all genes in the sample. (E) Boxplot showing the distribution of the proportion of genes overlapping crossovers in the sampled data. The red point shows the observed value for NBS-LRR genes and the blue point shows that for the non-NBS-LRR genes. (F) As for (E), but showing the number of genes overlapping crossovers normalized by the total length of all genes in the sample.(TIFF)Click here for additional data file.S3 FigRepresentative ethidium bromide stained agarose gels are shown with PCR amplification products generated using either Col or Ler genomic DNA as a template. Reactions were repeated using the gradient of annealing temperatures indicated at the top of the gel. Primers were either template non-specific  or universal reverse (UR)) or allele-specific . Primer sequences are provided in (TIFF)Click here for additional data file.S4 FigEcoRV. DNA was separated using gel electrophoresis, blotting and probing using radio-labelled HRG1 DNA.Genomic DNA was isolated from the indicated accessions and digested with (TIFF)Click here for additional data file.S5 FigAseI. DNA was separated using gel electrophoresis, blotting and probing using radio-labelled RPP4 DNA.Genomic DNA was isolated from the indicated accessions and digested with (TIFF)Click here for additional data file.S6 FigHaeII and PstI. DNA was separated using gel electrophoresis, blotting and probing using radio-labelled RPP1 DNA.Genomic DNA was isolated from the indicated accessions and digested with (TIFF)Click here for additional data file.S1 TableR genes with known biological functions their given name is listed. In addition 3 columns have been added with TRUE/FALSE statements depending if the gene product has a match to the listed Pfam domain . Information is given on R gene locus structure, classified as either singleton, tandem, inverted or complex. The number of members within a repeated locus is listed.For each gene, chromosome, transcriptional start site (TSS) and termination site (TTS) are listed according to TAIR10 representative gene models. Historical recombination (cM/Mb) and diversity parameters (\u03b8 and \u03c0) were calculated for intragenic regions between TSS and TTS, using Eurasian and Swedish SNP datasets \u201374,82. F(XLSX)Click here for additional data file.S2 TableMRC1 crossover individuals, together with Col and Ler genotypes and interval lengths (bp). The number of crossovers identified in each interval is shown, together with cM/Mb. Eurasian and Swedish historical recombination rates estimated by LDhat are shown for the same intervals and NBS-LRR genes present in each interval are listed. A chi-square test was performed between the observed MRC crossover counts per interval and those expected at random using a 2\u00d72 contingency table. P<0.05 values are listed in the P column, or listed as not significantly different (ns). The P adj. column shows the significance level after correction for multiple testing [The table lists marker coordinates used to genotype double-selected  testing .(DOCX)Click here for additional data file.S3 TableMRC5 crossover individuals, together with Col and Ler genotypes and interval length (bp). The number of crossovers identified in each interval is shown, together with cM/Mb. Eurasian and Swedish historical recombination rates estimated by LDhat are shown for the same intervals and R genes present in each interval are listed. A chi-square test was performed between the observed crossover counts per interval and those expected at random using a 2\u00d72 contingency table. P<0.05 values are listed in the P column, or listed as not significantly different (ns). The P adj. column shows the significance level after correction for multiple testing [The table lists marker coordinates used to genotype double-selected  testing .(DOCX)Click here for additional data file.S4 TableThe \u2018Genotyping Assay\u2019 column indicates whether a given marker coordinate was genotyped by KBiosciences (SNP), or via dCAPs assays.(DOCX)Click here for additional data file.S5 TableThe \u2018Genotyping Assay\u2019 column indicates whether a given marker coordinate was genotyped by KBiosciences (SNP), or via dCAPs assays.(DOCX)Click here for additional data file.S6 TableThe \u2018Genotyping Assay\u2019 column indicates whether a given marker coordinate was genotyped by KBiosciences (SNP), or via dCAPs assays.(DOCX)Click here for additional data file.S7 TableThe \u2018Genotyping Assay\u2019 column indicates whether a given marker coordinate was genotyped by KBiosciences (SNP), or via dCAPs assays.(DOCX)Click here for additional data file.S8 TableThe \u2018Genotyping Assay\u2019 column indicates whether a given marker coordinate was genotyped by KBiosciences (SNP), or via dCAPs assays.(DOCX)Click here for additional data file.S9 TableThe \u2018Genotyping Assay\u2019 column indicates whether a given marker coordinate was genotyped by KBiosciences (SNP), or via dCAPs assays.(DOCX)Click here for additional data file.S10 TableThe \u2018Genotyping Assay\u2019 column indicates whether a given marker coordinate was genotyped by KBiosciences (SNP), or via dCAPs assays.(DOCX)Click here for additional data file.S11 TableThe \u2018Genotyping Assay\u2019 column indicates whether a given marker coordinate was genotyped by KBiosciences (SNP), or via dCAPs assays.(DOCX)Click here for additional data file.S12 TableThe mean and maximum crossover frequency (cM/Mb) measured at known plant hotspots is listed, together with the species studied, hotspot name, width of measured region, genetic distance (cM) and crossover frequency (cM/Mb), together with chromosome average recombination rates.(DOCX)Click here for additional data file.S13 Table2 individuals were analysed by genotyping-by-sequencing. The number of crossovers (CO) per F2 and in total are listed, for the whole genome and for each chromosome separately.192 Col\u00d7Ler F(DOCX)Click here for additional data file.S14 TableRAC1 gene was amplified using allele-specific oligonucleotides to estimate the number of parental (non-recombinant) and crossover molecules per \u03bcl of Col/Ler F1 pollen genomic DNA. Genetic distance was calculated as described [A 9.419 kb amplicon  containing the escribed .(DOCX)Click here for additional data file.S15 TableRAC1 crossover molecules were Sanger sequenced to identify recombination sites to the resolution of single polymorphisms. Col and Ler genotypes and number of crossovers per interval are listed, together with cM/Mb.181 single (DOCX)Click here for additional data file.S16 TableRAC1 crossover read pairs. Paired end reads (1 and 2) were separated and aligned to the Col or Ler RAC1 parental template sequences, allowing only exact matches (Mapped). Read pair ends that mapped to both Col and Ler were then excluded (Unique). Read pair ends (1 and 2) that mapped to Col and Ler were identified (Matched), where the Ler mapping read had a lower coordinate than the Col mapping read (Orientate), and that were on opposite strands (Strand). These filters yielded 182,909 crossover read pairs.The number of read pairs surviving sequential analysis filters are listed in order to identify (DOCX)Click here for additional data file.S17 TableMRC genetic maps were divided into two groups according to whether their interval had higher or lower crossover frequency (cM/Mb) compared with the male Col\u00d7Ler genome average (4.82 cM/Mb) [NBS-LRR genes located within the 2 cM/Mb) . We then2 cM/Mb)  to +1 kb(DOCX)Click here for additional data file.S18 TableI5a reporter (Col-0) was crossed to. In the case of Col-0 this represents data from Col-0/Col-0 homozygotes. The total number of pollen counted is listed, in addition to the number with red fluorescence alone (Red), yellow alone (yellow), both colors (Red+Yellow), or neither fluorescence (None). Genetic distance is calculated as cM = 100 \u00d7 (Y/(Y+RY)). Where Y is the number of yellow alone pollen grains and RG is the number of both yellow and red fluorescent pollen grains. To test whether recombinant and non-recombinant counts were significantly different between replicate groups we used a generalized linear model (GLM), assuming that the count data is binomially distributed. Tests were performed between F1 genotypes and Col/Col homozygotes.The first column lists the accession the (DOCX)Click here for additional data file.S19 TablePositions annealing to Col/Ler polymorphic bases in the allele-specific primers are indicated in red. The accession each primer anneals to is listed (Col or Ler), together with a code indicating whether the primer is forward or reverse (F or R) and used in the first or second round of allele-specific amplification (1 or 2).(DOCX)Click here for additional data file."}
+{"text": "We conducted a review of cardiovascular magnetic resonance studies performed in patients with Anderson-Fabry disease (AFD) at our institution aiming to describe the spectrum of imaging findings in this rare disease.All patients with confirmed AFD who had cardiac MRI at our center were included. Short-axis steady state free precession cines and segmented inversion recovery late gadolinium enhancement (LGE) images were acquired using standard parameters. Offline analysis was performed for LV volumes and maximum end-diastolic wall thickness (EDWTmax). Patients were categorized into 4 groups: 1) no wall thickening (EDWT\u226412mm); 2) concentric hypertrophy ; 3) asymmetric hypertrophy ; and 4) apical hypertrophy. LGE was quantified using a semi-automated technique with thresholds of 2SD, 4SD and 6SD. Charts were reviewed for clinical information.k=0.62). 6-SD and 2-SD demonstrated lower agreement with manual threshold quantification k=0.55 and k=0.05 respectively.Forty-one patients were included , median age 45.3 years (range 22.3-68.1). Morphological MR findings are summarized in Table Just over two thirds of patients had late gadolinium enhancement (LGE), but only half of these had typical lateral wall mid-myocardial scar. Only a quarter of patients had both concentric wall thickening and typical lateral wall scar. Only 11 of 25 patients with wall thickening had elevated LVMI. There was significantly more myocardial scar  in patients with elevated LVMI  than in patients with normal LVMI , and significantly more scar in patients with wall thickening  than those without wall thickening. Patients with elevated LVMI had higher incidence of arrhythmia  than those without elevated LVMI . Patients with elevated LVMI had higher incidence of VT than those without elevated LVMI .Concentric thickening and lateral wall mid-myocardial scar are the most common manifestations of AFD, but the spectrum includes cases identical to apical and asymmetric septal hypertrophy subtypes of hypertrophic cardiomyopathy.None."}
+{"text": "Aortic Stenosis (AS) is characterized by pressure overload hypertrophy (LVH) with associated diastolic dysfunction. The presence of LVH, diastolic dysfunction and microvascular dysfunction appear to be important determinants of exercise capacity in AS. There are no medical therapies in AS of proven value. Ranolazine is licenced for the treatment of angina and inhibits late sodium channel activation. Ranolazine has been shown to improve diastolic dysfunction in isolated myocytes.In this prospective, open label study with blinded endpoint analysis, patients with asymptomatic moderate/severe AS and diastolic dysfunction or LVH were recruited. Patients, underwent trans-thoracic echocardiography, exercise testing and adenosine stress cardiac magnetic resonance imaging at baseline, 6 weeks after commencing Ranolazine (maximum dose 750mg BD) and again at 10 weeks (4 weeks after discontinuation). Tagged images were acquired at three short-axis slices on a 3T platform (Siemens Skyra). Myocardial perfusion reserve was calculated from stress and resting blood flow. The primary hypothesis was that Ranolazine would improve peak early diastolic strain rate (PEDSR) on tagged MRI.2, LV mass index 66.72\u00b115.35 g/m2) completed the week-6 visit and 13 completed the final visit. Results are shown in table Fifteen patients . GPM is funded by an NIHR research fellowship and AS by the NIHR Leicester CVBRU."}
+{"text": "Brucella species remains unknown.Recently the genome sequences of two brucellaphages, isolated in Georgia (Tb) and Mexico (Pr) were reported revealing pronounced sequence homogeneity and the presence of two major indels discriminating the two phages. Subsequent genome sequencing of six diagnostic brucellaphages: Tbilisi (Tb), Firenze (Fz), Weybridge (Wb), S708, Berkeley (Bk) and R/C phages identified three major genetic groups. However, the propensity for fine-scale genetic variability of diverse brucellaphages grown on multiple hosts within a single B. abortus strain 141 and after subsequent propagation on B. abortus strain S19. All brucellaphages were isolated and propagated at the Eliava Institute including the original Tb phage. Genomic libraries were quantified using the Qbit and sheared on the Covaris M220. QC for fragmentation was performed on the BioAnalyzer 2100. DNA libraries were prepared using an Illumina Paired-End protocol and sequenced on the Illumina MiSeq. Sequence analysis was performed using Geneious and MEGA software.We sequenced the complete genomes of ten brucellaphages following initial propagation on Staphylothermus marinus F1-like CRISPR spacer and sequences orthologous to both prophage antirepressors of Brucella spp. and intergenic sequences encoded by Ochrobactrum anthropi.Comparative whole genome sequence analysis revealed genetic homogeneity consistent with previously published data as well as multiple nucleotide variations. Genomic changes as a result of passages were observed in similar genes and predominantly occurred at identical sites in separate phages. Multiple instances of within-sample genetic heterogeneity were observed often at shared genomics positions across phages. Positive selection was detected in the tail collar protein gene. We also identified a B. abortus as they are propagated on alternate vaccine strains within the species. Our data extend previous results indicating select variable hotspots and broad genomic homogeneity as well as multiple common polymorphisms and within-sample variation. These data also provide additional genomes for future reference in comparative studies involving the molecular evolution and host specificity of brucellaphages.We surveyed whole genome level diversity in phage lytic for  Brucella genus [B. melitensis, B. suis, B. abortus, B. ovis, B. canis, B. neotomae, B. ceti, B. microti, B. pinnipedialis, and B. inopinata, (http://www.bacterio.net/brucella.html). Typing of Brucella is confirmed by serum agglutination, colony morphology, CO2 requirement, H2S production, growth on thionine or basic fuchsine plates on serum dextrose agar (SDA), and diagnostic brucellaphage lysis [Brucella is an established diagnostic and is used routinely in many diagnostic applications [Brucellosis is an important global zoonotic disease caused by members of the la genus . Membersge lysis . Phage tications -6.M) and a brucellaphage isolated in Mexico (Pr) were reported that revealed pronounced sequence homogeneity (98.7%) and the presence of two major indels discriminating the two strains [Chelativorans and based on amino acid similarity and gene synteny the authors suggest common ancestry between these phages that share evolutionarily related host species (Brucella and Chelativorans). Subsequent comparative whole genome analysis of six diagnostic brucellaphages including Tbilisi (Tb), Firenze (Fz), Weybridge (Wb), S708, Berkeley (Bk) and R/C phages revealed high sequence similarity and identified three major genetic groups consistent with their defined host range phenotypes [B. abortus and B. neotomae while Group II included Bk, R/C, and Pr phages lytic mainly for B. abortus, B. melitensis and B. suis. Phages Wb and S708 lytic for B. suis, B. abortus, and B. neotomae comprised Group III. The Tb phage sequenced by Flores et al was obtained from the Gamaleya Institute of Epidemiology and Microbiology, Moscow, Russia. This genome displayed comparatively greater genetic distance from all other within-group brucellaphages including an alternate Tb phage (designated TbW) [M and the Pr phage genomes [M genome sequence was suggested to have resulted from diversifying selection and/or genetic drift in the laboratory. The study also showed the putative phage collar protein is a hotspot for genetic variation across the major evolutionary groups and is currently undergoing positive Darwinian selection [Brucella spp. remains unknown. Such data may elucidate further the fine-scale genetic structure of this phage population and may facilitate discovery of biological determinants mediating within-species variations in host range.Recently, whole genome sequences of the Tbilisi phage , 281 (B. ovis), 02 (B. ovis), 177 (B. melitensis), 110 (B. melitensis), V (B. abortus), 11sa (B. suis), 544 (B. abortus), 141 (B. abortus 141) , 1066  using kmer size N\u2009=\u200951, minimum contig size\u2009=\u20091000. SNP analysis, genome alignments, and Neighbor-Joining [M phage reference sequence genome for DNA sequencing on the ABI 3130\u00d7L sequencer (GenBank: NC_019446.1). Cycle Sequencing PCR was carried out using the BigDye Terminator v3.1 Cycle Sequencing Kit. For the cycle sequencing reaction, each primer was diluted to the 3.2pmol working concentration and 5-20\u00a0ng of template DNAs was used. Sequencing PCRs for each DNA sample (with single primer) was prepared in triplicate. Purification of the sequencing PCR products was performed by BigDyeX Terminator purification kit or by ETOH purification. Purified DNA products were analyzed on the ABI 3130\u00d7L sequencer (Applied Biosystems). Analysis of the sequencing data was determined using the DNASTAR- Lasergene 9.1 software .Phage DNAs were isolated by standard procedure by phenol/chloroform extraction. Genomic libraries were quantified using the Qbit , sheared using the Covaris M220 focused ultrasonicator , and fragmented QC was performed on the BioAnalyzer 2100 . Libraries were subsequently modified using the Illumina Paired End Sample Prep Kit and sequenced on the Illumina MiSeq platform  per manufacturer\u2019s instructions. Raw fastq files for each phage sample were exported and subjected to Whole genome sequences for all newly phage genomes in this study were deposited in GenBank: 02_19 (KJ133688), 02_141 (KJ133689), 11sa_19 (KJ133690), 11sa_141 (KJ133691), 110_19 (KJ133692), 110_141 (KJ133693), 141_19 (KJ133694), 141_141 (KJ133695), 177_19 (KJ133696), 177_141 (KJ133697), 281_19 (KJ133698), 281_141 (KJ133699), 544_19 (KJ133700), 544_141 (KJ133701), 1066_19 (KJ133702), 1066_141 (KJ133703), Tb_19 (KJ133704), Tb_141 (KJ133705), V_19 (KJ133706), V_141 (KJ133707).In addition, arbitrary designations were used to distinguish the multiple Tb brucellaphage genomes sequenced by other institutes in addition to the Tb phage sequenced here. These include TbE, TbW, and TbM for the Tb phages grown on the S19 host strain here KJ133704) and that by Farlow et al   strain originally isolated in Russia in 1950, then subsequently grown on B. abortus vaccine strain S19. The phenotypic characteristics of all phages are listed in Table\u00a0B. abortus S19 (180\u00a0minutes), average burst size increased on this strain as well (50-53 PFU/cell). Other phages propagated only on the B. abortus 141 host strain also differed in adsorption times , 11613 - TAT to ATA (TbM), 12384 - ATATG to TATAC (TbM), 13145 - ATCCGCTACA to CGAATAGCAC (TbM), 13438 - GCGCGCGTAATTT to ATATATGTAATCC (TbM), and at 17184 an insertion of residues GTAGCG. We also noted a variation unique to the Pr strain at position 34533 that displays the sequence ACCGG compared to CAATT in all other brucellaphages. We also observed partial correspondence in the content of select genes encoding mutations when compared to previously published whole genome data [E across propagation from host strain 141 to S19 included SNPs predominantly in ORF 21 and the phage tail collar gene at positions 15576/15578 (ORF 21) and positions 2185/22178 , Firenze (Fz), Weybridge (Wb), S708, Berkeley (Bk) and R/C brucellaphages as reported previously [We noted a total of 24 polymorphic loci within 13 genes including two SNPs within the 3\u2032 non-coding terminal region . The variable site R63L is located within this domain flanked by multiple potential zinc binding sites within the ZR domain. Furthermore, in contrast to the flanking position of genes encoding terminase subunits and HNH endonucleases (within 5 ORFs) previously observed in tailed Kala et al [We also observed common mutations within the gene encoding the putative brucellaphage HNH endonuclease  Table\u00a0. HNH endla et al , we notela et al . The obsM) spanning two hypothetical proteins that showed significant similarity to a region directly upstream of a phage integrase motif in the genome of Ochrobactrum anthropi. This orthologous sequence shared between brucellaphage and O. anthropi, is interesting as O. anthropi is the closest known relative to the Brucellaceae [Ochrobactrum-like relatives free living in soil and plant-associated rhizosphera. The phage-related Ochrobactrum-like motif observed in the genome of brucellaphages may reflect common ancestry between phages infecting these distantly related bacterial hosts though with low evolutionary signal due to the likely divergent selective pressures separating their current niches. In addition, a 36\u00a0bp residue sequence at the 3\u2032 end of this region (27218-27253) displayed significant similarity to a prophage antirepressor encoded by B. canis strain HSK A52141. This sequence is also shared broadly across other Brucella host species. Further BLAST analysis also revealed a motif comprising 27 nucleotide residues at the 3\u2032 terminus of all phages showed significant similarity to a single CRISPR spacer sequence in the CRISPR database (http://crispr.u-psud.fr/crispr/) encoded by Staphylothermus marinus F1. This orthologous sequence shared between brucellaphage genomes and the S. marinus CRISPR spacer showed no significant similarity to other available sequences in GenBank. Interestingly, phage resistance systems such as CRISPRs are notably absent in Brucella genomes with the exception of questionable CRISPR-like genetic structures in select B. melitensis and B. pinnipedialis strains (http://crispr.u-psud.fr/crispr/).Comparative sequence analysis also revealed a sequence comprising 299\u00a0bp residues (26701-27600; Tbellaceae ,26. It iB. abortus and revealed fine-scale patterns in the genetic structure of these phages as they are propagated on vaccine strains within this species. Previous studies showed the relatively homogenous genomes of brucellaphages derived from diverse Brucella species express frequent polymorphisms in the phage collar protein that may reflect host selection. Our data extend these results confirming such diversity on a finer scale during propagation within the B. abortus species and illustrate multiple common sequence variations across similar genes that frequently display within-sample genetic heterogeneity. These data also provide a comparison of candidate loci for potential genotype-phenotype associations that can be explored in the Tb phage model while also yielding additional genomes for future reference in comparative studies involving the molecular evolution of brucellaphages.We surveyed whole genome level diversity in phage lytic for"}
+{"text": "Juvenile Dermatomyositis (JDM) is a rare serious disease (affecting 2-3 million children/year) presenting with rash and proximal muscle weakness. Serious complications can include calcinosis, GI ulceration, interstitial lung disease (ILD) and even death. It is becoming clear that JDM is a heterogeneous condition. Dividing JDM into sub-phenotypes would allow better prediction of disease severity and more targeted treatments. We have identified novel auto-antibodies in subtypes of JDM that may correlate with specific phenotypes.To define clinical & pathological phenotypes of patients with JDM who have antibodies to Melanoma Differentiation-Associated protein 5 (MDA-5).Patients were included from the Juvenile Dermatomyositis Cohort and Biomarker Study, a multi-centre study including 13 centres from across the UK. The study collects longitudinal clinical and serological data from patients with idiopathic inflammatory myopathies (IIM) of which 85% are diagnosed with JDM or JDM overlap features (currently n=446 patients). Clinical data collected included presence of clinical features, treatment, physicians global assessment and muscle strength assessments including the Childhood Muscle Assessment Score (CMAS).Plasma or serum, available for 285 patients, were screened for the presence of autoantibodies by immunoprecipitation and confirmed by ELISA using recombinant MDA-5 protein.Muscle biopsies were stained and scored using the JDM Muscle biopsy score tool as described  .The validated muscle biopsy score tool measures severity of muscle pathology across 4 domains and with a separate visual assessment score (0-10).Autoantibody screening identified the presence of MDA-5 antibodies in 7.4% of patients (21/285 cases). MDA-5 positive patients had significantly increased incidence of ulceration (p=0.03), arthritis (p<0.01) and lung disease, yet had less severe muscle involvement, measured by CMAS score (p=0.03), than MDA-5 negative patients. In addition, median muscle biopsy scores for the MDA-5+ve patients were significantly lower than the MDA-5-ve patients (p<0.005) suggesting a less severe muscle pathology.JDM is a heterogeneous condition with sub-phenotypes defined by autoantibody status, clinical features and muscle pathology. Identification and classification of sub-phenotypes could be used to predict disease course and severity. In the future, JDM specific autoantibodies could be used as biomarkers allowing for stratified approaches to treatment.None declared."}
+{"text": "The PI3K/Akt/mTOR pathway is overactivated and heat shock protein (HSP) 90 is overexpressed in common cancers. We hypothesized that targeting both pathways can kill intrahepatic cholangiocarcinoma (CCA) cells. HSP90 and PTEN protein expression was evaluated by immunohistochemical staining of samples from 78 patients with intrahepatic CCA. CCA cell lines and a thioacetamide (TAA)-induced CCA animal model were treated with NVP-AUY922 (an HSP90 inhibitor) and NVP-BEZ235 (a PI3K/mTOR inhibitor) alone or in combination.Both HSP90 overexpression and loss of PTEN were poor prognostic factors in patients with intrahepatic CCA. The combination of the HSP90 inhibitor NVP-AUY922 and the PI3K/mTOR inhibitor NVP-BEZ235 was synergistic in inducing cell death in CCA cells. A combination of NVP-AUY922 and NVP-BEZ235 caused tumor regression in CCA rat animal model. This combination not only inhibited the PI3K/Akt/mTOR pathway but also induced ROS, which may exacerbate the vicious cycle of ER stress. Our data suggest simultaneous targeting of the PI3K/mTOR and HSP pathways for CCA treatment. Intrahepatic cholangiocarcinoma (CCA) is a relatively rare, but increasing more common, hepatobiliary cancer \u20133. CCA, The ABC-02 trial showed improved overall survival of CCA patients treated with gemcitabine plus cisplatin compared to those treated with gemcitabine alone (11.7 versus 8 months), and defined gemcitabine plus platinum as a standard treatment for advanced biliary tract cancer . SeveralThe molecular chaperone heat shock protein 90 (HSP90) plays an important role in post-translational maturation and activation of many oncogenic client proteins that increase the survival, growth, and invasive potential of cancer cells , 9. HSP9PIK3CA  activating mutations are rarely found in CCA  fluoro-ur group . Brieflymean) of the normal liver and tumor tissue was determined, and the tumor-to-liver radioactivity ratio was calculated for comparison.These values were calculated according to the recommendations of the European Organization for Research and Treatment of Cancer . The tumU test or the Kruskal-Wallis test. Overall survival was calculated using the Kaplan-Meier method. Eighteen clinicopathological variables were selected for difference analysis using the log-rank test (univariate). The Cox proportional hazards model was employed for multivariate regression analysis. SPSS statistical software for Windows was used for statistical analysis . P values \u2264 0.05 were considered statistically significant.All data are presented as mean \u00b1 standard deviation (SD). Differences between experimental animals and controls were calculated using the Mann-Whitney"}
+{"text": "GATA1 mutations, transient myeloproliferative disorder (DS-TMD) and acute megakaryocytic leukemia (DS-AMKL). Trisomy of the Erg gene is required for myeloproliferation in the Ts(1716)65Dn DS mouse model. We demonstrate here that genetic changes specifically attributable to trisomy of Erg lead to lineage priming of primitive and early multipotential progenitor cells in Ts(1716)65Dn mice, excess megakaryocyte-erythroid progenitors, and malignant myeloproliferation. Gene expression changes dependent on trisomy of Erg in Ts(1716)65Dn multilineage progenitor cells were correlated with those associated with trisomy of HSA21 in human DS hematopoietic stem and primitive progenitor cells. These data suggest a role for ERG as a regulator of hematopoietic lineage potential, and that trisomy of ERG in the context of DS foetal liver hemopoiesis drives the pre-leukemic changes that predispose to subsequent DS-TMD and DS-AMKL.Down syndrome (DS), with trisomy of chromosome 21 (HSA21), is the commonest human aneuploidy. Pre-leukemic myeloproliferative changes in DS foetal livers precede the acquisition of  ERG, an ETS family transcription factor, has been implicated in abnormal blood system development in Down syndrome. In this study we show how trisomy of Erg in a murine Down syndrome model perturbs hematopoietic progenitor cells in a manner similar to that observed in human Down syndrome by inducing gene expression changes and lineage priming in early multi-potential progenitors. We show that the gene expression signature specifically attributable to trisomy of Erg in the murine model is strongly correlated with gene expression changes in human Down syndrome hematopoietic cells. The data suggest that Erg is an important regulator of megakaryocyte-erythroid lineage specification in multipotential hematopoietic cells and that trisomy of Erg in the context of DS prediposes to a transient myeloproliferative disorder and acute megakaryocyte leukaemia in a multi-step model of leukemogenesis.An excess number of genes in trisomy on human chromosome 21 leads to the development of specific diseases in human Down syndrome. An excess copy of the gene,  GATA1 in virtually all cases [JAK1, JAK2, JAK3, FLT3, TP53, TRIB1, MPL, EZH2, APC, PARK-2, PACRG, EXT1, DLEC1 and SMC3, and further suggested that GATA-1 mutations alone in the context of HSA21 trisomy were sufficient for development of DS-TMD [Down syndrome (DS) is the commonest human aneuploidy . DS infall cases . Howeverf DS-TMD \u201312.GATA1 mutations, human DS foetal livers exhibit perturbed hematopoiesis. Increased numbers and clonogenicity of hematopoietic stem (HSC) and progenitor cells, increased frequency of bi-potential megakaryocyte-erythroid progenitors, and reduced numbers of granulocyte-macrophage-committed progenitor cells have been described [16)65Dn mouse, which is trisomic for orthologs of ~104 human chromosome 21 genes [16)65Dn mice display progressive myeloproliferation chracterised by thrombocytosis, megakaryocyte hyperplasia, dysplastic megakaryocytic morphology and myelofibrosis. Similarly, blasts with erythro-megakaryocytic features and myelofibrosis are commonly observed in organs affected by DS-TMD/AMKL, while DS foetal livers show increased numbers of bipotential megakaryocyte-erythroid progenitors with increased clonogenicity and megakaryocyte/erythroid potential as well as megakaryocytosis [Preceding acquisition of escribed \u201315. Thisescribed \u201319. A we21 genes . Ts65Dn mice [Erg has previously been shown to be essential for normal hematopoietic stem cell function [Erg deregulation can cause erythro-megakaryocytic leukemia in mice [ERG/TLS-FUS fusion, complex karyotype AML with amplification of 21q, normal karyotype adult AML, MLL-rearranged paediatric AML and in T-ALL, high levels of ERG expression correlate with poor prognosis [We previously implicated the ETS family transcription factor 5Dn mice . Erg hasfunction . Moreove in mice ,25, and rognosis \u201329.Erg contributes in trisomy to myeloproliferation in Ts(1716)65Dn mice, and whether molecular changes specifically driven by three copies of Erg in this model reflect those associated with human DS, remained to be elucidated. To address these questions, we detailed hematopoietic progenitor perturbations associated with malignant myeloproliferation in 4 month-old Ts(1716)65Dn mice, the youngest age at which myeloid progenitor abnormalities have been observed [16)65Dn mice to define the relevant biological and genetic changes by which trisomy predisposes to development of myeloproliferation in this DS model [Erg in the Ts(1716)65Dn mouse were then compared to expression changes due to trisomy of chromosome 21 (HSA21) in human DS CD34+CD38- hematopoietic cells [ERG gene dosage in human disease.The detailed mechanisms by which observed . We thenDS model . Transcric cells  to explo+Sca1+ (LSK) population has been previously shown to be expanded in trisomic Ts(1716)65Dn DS mice [16)65Dn mice when Erg was specifically reduced from trisomy to functional disomy [16)65Dn DS model. Ts(1716)65Dn trisomic mice were crossed to mice carrying the non-functional ErgMld2 allele as previously described [Erg (Ts65Dn/Erg+/+/+), mice disomic for functional Erg and trisomic for the remaining ~103 genes in the trisomic segment (Ts65Dn/Erg+/+/Mld2), euploid mice (Erg+/+) and disomic mice with one functional Erg allele (Erg+/Mld2), were analysed at 4 months of age for abnormalities in common myeloid progenitors (CMP), granulo-monocytic progenitors (GMP), and megakaryocyte-erythroid progenitors (MEP) as previously defined [Ts65Dn/Erg+/+/+ mice 65Dn DS model.The stem-cell enriched lineage-negative cKit DS mice ,30. This DS mice , was corl disomy . Moreovel disomy . We therescribed . The fou defined . Consist+/+ mice . These ald2 mice , suggestTs65Dn/Erg+/+/+ mice were then examined in greater detail, with particular emphasis on the recently described series of progressively maturing BEMP, CD150+CD9hi and CD150+Fc\u03b3R+ bipotential erythroid-megakaryocyte progenitors [Ts65Dn/Erg+/+/+ mice contained increased numbers of GMP and CD150+CD9hi bipotential progenitor cells, and these were normalised in number when Erg was reduced to functional disomy in Ts65Dn/Erg+/+/Mld2 mice. Conversely, the numbers of GMPs and bipotential megakaryocyte-erythroid progenitor populations  were reduced in Erg+/Mld2 mice haploinsufficient for functional Erg. Trisomic Ts65Dn/Erg+/+/+ mice were noted to have significantly fewer CFU-E, an anomaly that was not evident in Ts65Dn/Erg+/+/Mld2 mice and Erg+/Mld2 mice had an expanded population of these late erythroid progenitors, supporting previous data that suggested Erg normally restrains terminal erythroid differentiation [Ts65Dn/Erg+/+/+ bone marrow demonstrated stimuli-specific increases in the numbers of granulocyte, macrophage and megakaryocyte colony-forming units (CFU). This myeloproliferation was moderated in Ts65Dn/Erg+/+/Mld2 mice 65Dn mice resembles progenitor abnormalities observed in pre-leukemic human DS foetal livers prior to acquisition of GATA1 mutations, although human DS foetal livers exhibit reduced numbers of GMP, in contrast to the mouse model [Myeloid progenitors in genitors ,34, as wgenitors ,35, defintiation ,24,25. Cld2 mice . TogetheTs65Dn/Erg+/+/+, Ts65Dn/Erg+/+/Mld2, Erg+/+ and Erg+/Mld2 mice. Gene expression changes within each cell population that were attributable to changes in functional Erg gene dosage were determined by specific pair-wise comparisons using linear modeling and empirical Bayes moderated t-statistics [Ts65Dn/Erg+/+/+ versus Erg+/+ mice, trisomy-induced changes specifically attributable to trisomy of Erg were evident from comparison of Ts65Dn/Erg+/+/+ versus Ts65Dn/Erg+/+/Mld2 (effects specific to Erg trisomy), changes due to trisomy with two copies of functional Erg (effects due to non-Erg gene trisomy) emerged from comparison of Ts65Dn/Erg+/+/Mld2 versus Erg+/+, and changes due to Erg haplo-insufficiency from comparison of Erg+/Mld2 versus Erg+/+.We undertook gene expression profiling of prospectively isolated LSK, CMP, GMP and MEP populations from atistics . ChangesTs65Dn/Erg+/+/+ mice compared with their expression in Erg+/+ cells. Increased expression of these genes in trisomc cells varied and was also dependent on the specific hematopoietic cell type examined 65Dn mice  or specifically to Erg trisomy (Ts65Dn/Erg+/+/+ versus Ts65Dn/Erg+/+/Mld2) occurred in the LSK compartment, while gene expression changes attributable to trisomy of non-Erg genes in the interval (Ts65Dn/Erg+/+/Mld2 versus Erg+/+) were fewer and occurred principally in MEP and GMP populations  was undertaken. GENAS is a relatively new statistical technique that estimates the biological correlation between two differential expression profiles, correcting for any technical correlation and for the statistical uncertainty with which the fold changes are estimated [Erg. The strongest correlation between expression changes resulting from full trisomy and those due to trisomy of non-Erg genes occurred within MEP cells 65Dn trisomic segment.Given the correlation of gene expression changes induced by full trisomy with those associated specifically with trisomy of stimated ,38. UnliEP cells . NotablyErg is the dominant influence within the Ts(1716)65Dn trisomic interval, three copies of which specifically drives gene expression changes that are evident primarily within multipotential hematopoietic progenitor populations rather than more lineage-restricted progenitors.Together, these findings establish that in hematopoietic progenitor cells, Erg could lead to perturbations of hematopoietic progenitors and the myeloproliferative phenotype observed in Ts(1716)65Dn mice. To do this, we undertook an expression signature analysis of the expression changes in the Ts65Dn/Erg+/+/+ versus Ts65Dn/Erg+/+/Mld2 cells using curated gene sets from the Molecular Signatures database (MSigDB version 2.5) and pathway gene sets defined by the BioCarta, KEGG and Reactome databases. A ROAST test was conducted for each signature gene set. ROAST is a gene set test suitable for small samples and linear models that accounts for inter-gene correlation [Ts65Dn/Erg+/+/+ cells 65Dn mice could be interpreted in terms of cell lineage priming. We generated gene expression signatures that define specific cell populations: LSK, GMP and their precursors , megakaryocytes and their progenitors , and CFU-E and pre-CFU-E. An expression signature was defined for each cell population by compiling the significantly up-regulated genes in that cell type compared to the average of all the other populations, together with the magnitude of the up-regulation for each gene as measured by the moderated t-statistic (Ts65Dn/Erg+/+/+ versus Erg+/+), the specific effects of Erg trisomy (Ts65Dn/Erg+/+/+ versus Ts65Dn/Erg+/+/Mld2), the effects of trisomy of non-Erg genes (Ts65Dn/Erg+/+/Mld2 versus Erg+/+) and Erg haploinsufficiency (Ts65Dn/Erg+/+ versus Erg+/Mld2) in LSK, CMP, GMP and MEP populations.Given these findings, and as we had observed perturbations in specific hematopoietic progenitor populations in e marrow , we examtatistic . ROAST t- cells, granulo-monocytic progenitors (PreGM Flt3+ and GMP), bipotential megakaryocyte-erythroid progenitors (CD150+CD9hi and CD150+Fc\u03b3R+) and megakaryocytes, were enriched in the gene expression changes due to trisomy of Erg in LSK cells, and this was also evident in CMPs by this comparison (Erg in LSK and CMP cells (Erg in Ts(1716)65Dn LSKs and CMPs were concordant with the increased numbers of GMP and megakaryocyte-committed cells and fewer erythroid progenitors that were evident in Ts65Dn/Erg+/+/+ but not Ts65Dn/Erg+/Mld2+ mice, as well as the relative enrichment of erythroid progenitors in mice with Erg haploinsufficiency 65Dn mice occur primarily in multipotential hematopoietic cells with priming for specific hematopoietic progenitor lineages leading to myeloid progenitor perturbation, myeloproliferative changes and megakaryocytosis.Thus, the data support a model in which gene expression changes attributable specifically to trisomy of -CD45+CD34+CD38- bone marrow cells enriched for HSCs and multipoential hematopoietic progenitors that had been previously combined with transcriptomes of DS neurospheres derived from foetal cortical precursors, demonstrated differences in gene expression when compared to diploid controls [-CD45+CD34+CD38- bone marrow cells specifically demonstrated gene expression changes associated with trisomy of HSA21 when compared to diploid controls, and if these were related to differential gene expression due to Erg trisomy in LSKs in the Ts(1716)65Dn DS model. From the published data [16)65Dn LSK cells, as well as those specific to trisomy of Erg and those due to trisomy of non-Erg genes (Erg trisomy in Ts(1716)65Dn LSK cells, but not with those attributable to trisomy of non-Erg genes (Erg in Ts(1716)65Dn LSK cells significantly correlated with gene expression changes due to trisomy of HSA21 in human DS Lin-CD34+CD38- cells 65Dn DS model. Unlike transgenic and retroviral models of induced Erg expression, the use of the non-functional ErgMld2 allele in this model allows accurate characterisation of effects of functional Erg gene dosage while expression is endogenously regulated. The hematopoietic changes in Ts(1716)65Dn mice reflected the pre-leukemic changes observed in human DS foetal livers prior to acquisition of GATA-1 or other somatic mutations. While these analyses do not exclude contribution from other genes within the trisomic interval, they clearly establish that three copies of Erg is specifically required to drive transcriptome changes in HSCs and early multipotential progenitors in Ts(1716)65Dn mice. Moreover, the data provide a mechanism by which deregulation of Erg leads to perturbation of myeloid progenitor populations, myeloproliferation and megakaryocytosis in trisomy. Our findings show that perturbation of functional Erg gene dose by trisomy or by haploinsufficiency, is associated with lineage specific gene expression changes and \"lineage priming\" of multipotential hematopoietic progenitor cells. Notably, the effects specific to trisomy of Erg on gene expression and progenitor cell alterations in Ts(1716)65Dn mice were strongly reflected in Erg+/Mld2 mice, but in the opposite direction. Finally, we demonstrate that the gene signature specifically associated with trisomy of Erg in Ts(1716)65Dn LSK cells is directly related to gene expression changes in human DS Lin-CD34+CD38- cells enriched for HSCs and early multipotential progenitors. These data support a key role for ERG as a critical gene in trisomy of HSA21 that drives hematopoietic changes in human DS.We show here, in comparisons between Erg is an important regulator of HSC self-renewal after establishment of definitive hematopoiesis in the embryo [Erg for lineage priming in early multipotential hematopoietic cells which affects subsequent myeloid lineage development 65Dn model led to expansion of bipotential megakaryocyte-erythroid progenitors, fewer committed erythroid progenitors and megakaryocytosis [Erg overexpression [Erg in predisposing to acute bipotential megakaryocytic-erythroid leukemia [+CD9hi cells within bipotential megakaryocyte-erythroid progenitor compartment in Ts(1716)65Dn mice is similar to that observed in murine models of thrombopoietin driven myeloproliferation [16)65Dn mice exhibited increased numbers of GMP, while human DS foetal livers exhibit reduced numbers of these progenitors [Erg expression in murine models relative to human hematopoietic cells [ERG overexpression, reduction in GMP number was observed in murine foetal livers [Previous analyses established that e embryo  and in ee embryo ,22. The elopment . This inocytosis . This fiocytosis  and othepression ,40. Indeleukemia . The selferation ,34, provgenitors . This diTs65Dn/Erg+/+/+ mice, which is specifically dependent on trisomy of Erg [Erg favors progenitor specification at the expense of HSC maintenance. This finding is in keeping with the increased multi-potential pre-progenitor cell frequency in Ts65Dn/Erg+/+/+ bone marrow [Erg gene dose inducing a program of self-renewal as a leukemogenic mechanism in the development of DS-AMKL and DS-TMD. Indeed, competitive transplantation assays using the Ts1Rhr trisomic murine model of DS, which carries a trisomic segment that includes the Erg gene, demonstrated fewer competitive repopulating units compared to disomic controls [- progenitor signature was also upregulated in Ts65Dn/Erg+/+/+ CMPs relative to Ts65Dn/Erg+/+/Mld2 suggests that in trisomy, Erg allows maintenance of multipotential progenitor potential while promoting specific lineage commitment toward megakaryocyte and granulocyte-monocyte differentiation. This would be in keeping with the increase in numbers of total colonies, particularly megakaryocyte-containing colonies, observed by in vitro culture experiments.It is notable that the expansion of the LSK compartment in y of Erg , reflecty of Erg , and wase marrow  and the e marrow . These ocontrols . NeverthERG trisomy in the context of DS as our data may suggest, could be amenable to therapeutic targeting in the prevention or treatment of DS-TMD or DS-AMKL in addition to currently available strategies.It remains to be determined whether the consequences of genetic perturbations due to trisomy and effects specific to ErgMld2 mutant allele has been described [16)65Dn mice (The Jackson Laboratory) were maintained as previously described [Erg+/Mld2 and Ts(1716)65Dn mice and genotyped as previously described [Derivation and genotyping of the escribed . Ts. Clonal analysis of bone marrow cells (2.5x104) was performed in 1 mL semisolid agar cultures of 0.3% agar in Dulbecco/s modified Eagles medium containing 20% newborn calf serum and stem cell factor; SCF (100 ng/mL), erythropoietin; EPO (2 U/mL), and interleukin-3; IL-3 (10 ng/mL), granulocyte colony stimulating factor; G-CSF (103 U/mL), granulocyte-macrophage colony stimulating factor; GM-CSF (103 U/mL) and/or macrophage colony stimulating factor; M-CSF (103 U/mL). Cultures were incubated at 37\u00b0C for 7 days in a fully humidified atmosphere of 10% CO2 in air, then fixed, dried onto glass slides, and stained for acetylcholinesterase, Luxol fast blue, and hematoxylin, and the number and type of colonies were determined.Single-cell suspensions from bone marrow were prepared in balanced salt solution , Gr1 (Ly6G and Ly6C), Mac1 (CD11b), B220 (CD45R), CD4, CD8, CD41, CD34, CD16/32, Sca1 (Ly6A/E), cKit (CD117) and CD150 (Biolegend) and IL-7 receptor \u03b1 (IL7R\u03b1), CD48, CD105, and CD9 (eBioscience). Secondary staining used streptavidin PE-Texas-Red (BD Pharmingen). Cells were analyzed using a LSR Fortessa flow cytometer (Becton Dickinson), or cells were sorted using a FACSAria II (Becton Dickinson) flow cytometer after antibody staining with lineage depletion.Student's unpaired two-tailed t-tests were used using GraphPad Prism v. 5.0a for Mac Os X (GraphPad Software), unless otherwise specified.Ts65Dn/Erg+/+/+, Ts65Dn/Erg+/+/Mld2, Erg+/+ and Erg+/Mld2) at ~ 4 months of age. Total RNA was isolated from 100,000\u2013500,000 cells pooled from genotype and cell population matched samples using the RNeasy Micro kit (Qiagen). RNA quality was assessed with the Agilent Bioanalyzer 2100 (Agilent Technologies) by using the Agilent RNA 6000 Nanokit (Agilent Technologies) according to the manufacturer's protocol. Up to 200ng of RNA was labelled with the Total Prep RNA amplification kit (Ambion), and complementary RNA (1.5 \u03bcg) was hybridized to 48 arrays using six Illumina Mouse WG-6 V2.0 Expression BeadChips  according to Illumina standard protocols. The resultant microarray probe level data were analyzed by using the limma software package Version 3.21.1 [P value < 0.05). Pairwise comparisons were made by using linear modeling and empirical Bayes moderated t statistics [http://www.ebi.ac.uk/arrayexpress) with accession number E-MTAB-2574.Bone marrow LSK, CMP, GMP and MEP populations were isolated by FACS from 2\u20134 mice including males and females from each genotype  and Erg+/+ controls  at ~ 4 months of age. Sequencing was performed on an Illumina Hi-Seq 2500, producing at least 15.9 million 100bp paired-end reads per sample. Reads were mapped to the mm10 mouse genome (Genome Reference Consortium GRCm38) using the Subread aligner [featureCounts [edgeR [limma software packages. Genes were filtered as not expressed if they failed to achieve at least 0.5 counts per million reads in at least 2 of the 6 samples. All Entrez gene IDs without an official symbol were removed from further analysis, as were Y chromosome genes, Xist, and immunoglobulin genes, leaving 14,551 genes for downstream analysis. Library sizes were normalised using the TMM method [2 counts per million with associated precision weights [Ts65Dn/Erg+/+/+ versus Erg+/+ LSK cells  and of the differentially expressed genes identified from the microarray comparison, over fifty genes were also identified as differentially expressed using non-pooled independent samples by RNA-Seq with a P value of less than 0.05.Validation of the microarray data was undertaken via RNA-seq. Total RNA was extracted using the RNeasy Plus minikit (Qiagen) from LSK cells sorted independently from three trisomic  aligner . Read coreCounts  using NCs [edgeR  and limmM method . The voo weights . There w+CD38- HSCs and multipotential progenitors [Affymetrix microarray CEL files containing gene expression profiles of human DS CD34genitors  were obthttp://bioinf.wehi.edu.au/software/MSigDB/). Genuine Association analysis [Gene sets from the Molecular Signatures Database  were mapped from human to mouse orthologs Click here for additional data file.S2 TableTs65Dn/Erg+/+/+ versus Erg+/+), trisomy of Erg (Ts65Dn/Erg+/+/+ versus Ts65Dn/Erg+/+/Mld2) and non-Erg gene trisomy (Ts65Dn/Erg+/+/Mld2 versus Erg+/+) in LSK, CMP, GMP and MEP hematopoietic cells  of 0.05 as a consequence of full trisomy Ts65Dn/Er(XLSX)Click here for additional data file.S3 TableP-values.Upregulated genes sets are shown with ROAST (XLSX)Click here for additional data file.S4 TableAn expression signature was defined for each cell population by compiling the significantly up-regulated genes in that cell type compared to the average of all the other populations using a false discovery rate (FDR) of 0.05. See also (XLSX)Click here for additional data file.S5 TableSee also (XLSX)Click here for additional data file.S1 Fig2 fold changes of genes expressed in microarray data.Heatmap diagram of log(TIF)Click here for additional data file."}
+{"text": "TERT-CLPTM1L region has been identified by genome-wide association studies as a susceptibility locus of multiple malignancies. However, the involvement of this locus in esophageal squamous cell carcinoma (ESCC) development is still largely unclear. We fine-mapped the TERT-CLPTM1L region through genotyping 15 haplotype-tagging single nucleotide polymorphisms (htSNPs) using a two stage case-control strategy. After analyzing 2098 ESCC patients and frequency-matched 2150 unaffected controls, we found that rs2853691, rs2736100 and rs451360 genetic polymorphisms are significantly associated with ESCC risk in Chinese . Reporter gene assays indicated that the ESCC susceptibility SNP rs2736100 locating in a potential TERT intronic promoter has a genotype-specific effect on TERT expression. Similarly, the CLPTM1L rs451360 SNP also showed allelic impacts on gene expression. After measuring TERT and CLPTM1L expression in sixty-six pairs of esophageal cancer and normal tissues, we observed that the rs2736100 G risk allele carriers showed elevated oncogene TERT expression. Also, subjects with the rs451360 protective T allele had much lower oncogene CLPTM1L expression than those with G allele in tissue specimens. Results of these analyses underline the complexity of genetic regulation of telomere biology and further support the important role of telomerase in carcinogenesis. Our data also support the involvement of CLPTM1L in ESCC susceptibility.The chromosome 5p15.33  TERT-CLPTM1L region has been repeatedly proved to be a susceptibility locus of multiple malignancies according to genome-wide association studies (GWAS). Independent susceptibility single nucleotide polymorphisms (SNPs) in this region were identified in lung cancer  including the rs2736100 flanking region) from human genomic DNA carrying TERT rs2736100 TT genotype or GG genotype. Similarly, the intron 16 segment of CLPTM1L (chr.5: 1285954\u223c1286844 bp [GRCh38.p2] including the rs451360 flanking region) was amplified with human genomic DNA carrying CLPTM1L rs451360 GG genotype or TT genotype. The PCR products were then digested with KpnI and XhoI (New England Biolabs) and ligated into an appropriately digested pGL3-Basic vector (TERT) or pGL3-Promoter vector (CLPTM1L). The resultant TERT reporter gene plasmids were designated pTERT-T or pTERT-G, which were only different at rs2736100 polymorphic site. The resultant CLPTM1L reporter gene plasmids were named as pCL-T or pCL-G, which were identical except for the different allele at rs451360 polymorphic site. Restriction analysis and complete DNA sequencing confirmed the orientation and integrity of these constructs.Specific primer pairs  with theKYSE30 and KYSE150 ESCC cells were transfected with both reporter constructs  and pRL-SV40 . Dual luciferase activities were determined at 48h after transfection as previously described ,47. For TERT and CLPTM1L mRNA expression in cancerous and normal esophagus tissues was examined using the TaqMan real-time quantity PCR method. Relative gene expression quantization for TERT  and CLPTM1L  was calculated using \u03b2-actin  as an internal reference gene was carried out using the ABI 7500 real-time PCR system in triplicates.Total cellular RNA was isolated from sixty-six pairs of ESCC specimens and esophagus normal tissues adjacent to the tumors with TRIzol Reagent (Invitrogen) and converted to cDNA using the PrimeScript RT Master Mix (TAKARA). 2 test was used to examine the differences in demographic variables, smoking status, drinking status, and genotype distributions of rs2853691, rs2736100 or rs451360 SNP between ESCC cases and healthy controls. The associations between rs2853691, rs2736100 or rs451360 genotypes and ESCC risk were estimated by odds ratios and their 95% confidence intervals computed by logistic regression models. All ORs were adjusted for age, sex, smoking or drinking status, where it was appropriate. A P value of less than 0.05 was used as the criterion of statistical significance, and all statistical tests were two-sided. All analyses were performed using SPSS 16.0 (SPSS Inc.).Pearson's \u03c7"}
+{"text": "Pulmonary vascular endothelial activation has been implicated in acute respiratory distress syndrome (ARDS), yet little is known about the presence and role of endothelial activation markers in the alveolar space in ARDS. We hypothesized that endothelial activation biomarkers would be differentially expressed in bronchoalveolar lavage fluid from patients with ARDS compared with healthy volunteers, and that biomarker concentrations would be associated with ARDS severity.We performed a cross-sectional analysis of data from 26 intubated patients with ARDS undergoing evaluation for clinically suspected ventilator-associated pneumonia and five healthy volunteers. Patients underwent bronchoalveolar lavage a median of five days after intubation. Healthy volunteers also underwent bronchoalveolar lavage. Endothelial activation biomarkers  were measured in bronchoalveolar lavage fluid. Clinically suspected ventilator-associated pneumonia was confirmed with microbiologic culture data.Patients with ARDS had significantly higher median sVCAM-1 concentrations in the bronchoalveolar lavage fluid compared with healthy volunteers . Additionally, there was a trend toward greater bronchoalveolar lavage fluid sVCAM-1 concentrations among patients with moderate/severe compared to mild ARDS . We did not detect significant differences in bronchoalveolar lavage fluid levels of sESEL, Ang-1 or Ang-2 between patients with ARDS and healthy volunteers. Median bronchoalveolar lavage fluid biomarker levels did not differ between patients with and without microbiologically-confirmed ventilator-associated pneumonia.sVCAM-1 concentrations were significantly higher in the bronchoalveolar lavage fluid of patients with ARDS compared to healthy controls, and tended to be higher in moderate/severe ARDS compared to mild ARDS. Our findings add to the growing evidence supporting the concept that endothelial activation plays an important mechanistic role in the pathogenesis of ARDS. Further studies are necessary to characterize the role and/or clinical significance of sVCAM-1 and other endothelial activation markers present in the alveolar space in ARDS. As expected, patients with mild ARDS had higher median PaO2:FiO2 ratios compared to patients with moderate/severe ARDS . BALF was collected on day 7 (IQR 2\u201313) of mechanical ventilation among patients with mild ARDS and day 5 (IQR 3\u20138) in those with moderate/severe ARDS. There was no significant difference between the proportion of microbiologically-confirmed VAP among patients with mild compared to moderate/severe ARDS . The most common organism isolated was Haemophilus influenzae followed by methicillin-sensitive Staphylococcus aureus. In-hospital mortality was 14% among patients with mild ARDS and 42% among those with moderate/severe ARDS (p = 0.4).Baseline characteristics were compared between 26 patients with mild and moderate/severe ARDS . Most paIQR 134\u20132000, vs 119 pg/mL, IQR 86\u2013124, p = 0.03; IQR 418\u20137232 vs 209 pg/mL, IQR 42\u20131276, p = 0.06). Median BALF Ang-1, Ang-2 and sESEL concentrations did not differ significantly between ARDS patients and controls or by ARDS severity ; we detected no other associations between BALF biomarker levels and PaO2:FiO2 ratios .Compared to five healthy controls, ARDS patients had significantly higher median BALF sVCAM-1 levels  or in-hospital deaths in our cohort Click here for additional data file."}
+{"text": "Mitral annular plane systolic excursion (MAPSE) reflects longitudinal left ventricular function, predicts survival in heart failure patients and provides a sensitive marker of early systolic dysfunction in hypertensive patients with normal ejection fraction (EF). Doppler mitral annulus velocity (e') in early diastole predicts cardiac mortality, differentiates diseases and estimates filling pressures. We present a practical technique that facilitates measuring atrioventricular junction (AVJ) motion throughout the cardiac cycle from cine cardiac magnetic resonance (CMR) and correlate these measurements with EF and echocardiography-determined e'.Twenty-seven patients underwent CMR and transthoracic echocardiography (TTE) within 24 hours, between June 2010 and September 2013. Using custom-written MATLAB software we tracked AVJ motion throughout the cardiac cycle, using 4-chamber cine images  underwent CMR and TTE. Mean values for CMR-derived EF and TDE e' were found to be 53% (range 28-71% and 11 cm/s (range 3-18 cm/s), respectively. Moderate correlations were found between MVED and e'  as well as EF and MD . A moderate correlation was also found for MD and left ventricular stroke volume . Atrioventricular junction analysis was performed offline and took approximately 10 minutes per patient.Atrioventricular junction analysis is a practical CMR technique that yields CMR measurements of diastolic and systolic function. A moderately strong correlation was found between CMR-derived MVED and e', as well as EF and MD.Supported by the National Heart, Lung and Blood Institute, National Institutes of Health by the Division of Intramural Research, NHLBI, NIH, DHHS."}
+{"text": "Clock\u039419/+ heterozygous (Clk/+) mice, known to display lengthened periodicity and dampened amplitude, as a model of partially perturbed clocks. Interestingly, Clk/+ mice exhibited improved glycemic control and resistance to circadian period lengthening under high-fat diet (HFD). Furthermore, BMAL1 protein levels in Clk/+ mouse liver were upregulated compared with wild-type (WT) mice under HFD. Pharmacological and molecular studies showed that BMAL1 turnover entailed proteasomal and autophagic activities, and CLOCK\u039419 attenuated both processes. Consistent with an important role of BMAL1 in glycemic control, enhanced activation of insulin signaling was observed in Clk/+ mice relative to WT in HFD. Finally, transcriptome analysis revealed reprogramming of clock-controlled metabolic genes in Clk/+ mice. Our results demonstrate a novel role of autophagy in circadian regulation and reveal an unforeseen plasticity of circadian and metabolic networks.Circadian clocks orchestrate essential physiology in response to various cues, yet their mechanistic and functional plasticity remains unclear. Here, we investigated  In mammals, the basic component of the clock system is the cell-autonomous molecular oscillator containing interlocked negative feedback loopsAccumulating evidence has unveiled a critical role of the clock as a master regulator of metabolic and physiological fitness566810125515Clock- and Bmal1-deficient mice6Clock\u039419/\u039419 mutant mice, harboring a dominant negative Clock mutant allele, have been shown to develop a myriad of metabolic disorders, including obesity, hyperlipidemia, hepatic steatosis, hyperglycemia, hypoinsulinemia, and respiratory uncoupling, especially with age or high-fat dietary challenge18Bmal1 has been found to dysregulate energy homeostasis, although the specific effects are highly complex, depending on factors such as tissue type, age, and strain background20Bmal1 knockout were shown to display impaired AKT phosphorylation and circadian insulin response, concomitantly becoming susceptible to obesity when fed with high-fat diet starting at a young ageCLOCK/BMAL1 plays a central role in circadian metabolic regulation. Recent ChIP-seq studies have revealed a largely coincident CLOCK and BMAL1 binding throughout mouse liver genomeClock\u039419/+ heterozygous cells where a weaker  circadian clock persists, yet failed to show any effects in clock-disrupted cells, either Clock\u039419/\u039419 or Bmal1\u2212/\u221223Clock revealed dose-dependent changes in expression of its output genes Period2 as well as compensatory enrichment of both paralogous and non-paralogous clock components 27Clock\u039419 mutant form, lacking the transactivation domain and thus missing two key phosphorylation sites, was more stable than the wild-type CLOCKComplete loss of circadian rhythms in human is rare; rather, our clocks mainly suffer from misaligned phase  or dampened amplitude (aging or chronic diseases)1Clock\u039419/+ heterozygous mice (Clk/+) previously shown to display a 1-h lengthening of the free-running period and partial dampening of circadian amplitudeClock\u039419/\u039419 homozygous mutant mice (Clk/Clk) suffer from various metabolic disorders under high-fat diet (HFD) conditionsTo shed more light on partially disrupted clocks and delineate mechanistic and functional characteristics, we employed the ad libitum conditions. With RC, the WT and Clk/+ mice were essentially indistinguishable in body weight, food intake, fasting glucose levels and glucose tolerance and insulin tolerance (Clock\u039419/\u039419 homozygous mutant mice (denoted as Clk/Clk) exhibit propensity for metabolic dysfunctions such as obesity and hyperglycemia18To determine metabolic adjustments in Clk/+ mice with a partially perturbed clock, we investigated wild-type (WT) and Clk/+ mice fed with regular chow (RC) or high-fat diet (HFD) under olerance , indicatolerance , signifiolerance . On the Clock\u039419 heterozygosity to HFD-induced circadian period lengthening. Next, we measured systemic energy metabolism using CLAMS metabolic chambers , an established mouse genetic model for obesity and diabetes that lacks functional leptin receptors. Interestingly, consistent with the above results from HFD.Clk/+, improved glycemic control was observed in db/db mice with heterozygous Clock\u039419/+ alleles (denoted as db:Clk/+) relative to db/db littermates wild-type for Clock (db:WT). Both fasting glucose and insulin levels were reduced in db:Clk/+ mice, concordant with greater glucose and insulin tolerance relative to the db:WT mice  or even enhanced  in Clk/+ relative to WT. On the other hand, expression of Cry2 and Dbp was significantly dampened in RC.Clk/+. Consistent with previous resultsCry1, Per1 and Rorc). Such HFD-mediated suppression was retained in Clk/+ for Per1, Npas2, Nr1d1 and Nr1d2. Interestingly, expression of several clock genes including Bmal1, Npas2, Rorc and Cry2 was elevated in HFD.Clk/+ compared with HFD.WT mice.We further examined clock gene expression in the livers of WT and Clk/+ mice by real-time qPCR analysis . Under RClock\u039419 allele on BMAL1 in HFD at a cellular level, we treated WT, Clk/+ and Clk/Clk MEF cells with Dexamethasone (DEX) with or without the C16:0 fatty acid palmitate and monitored BMAL1 protein oscillation. In WT MEF cells, palmitate markedly reduced BMAL1 protein levels during the circadian cycle , Flag-tagged CLOCK (Flag-Clock) or CLOCK\u039419 (Flag-Clock\u039419) to 293T cells. Whereas ectopic expression of Flag-CLOCK reduced the steady-state abundance of Flag-BMAL1 in a dose-dependent manner, Flag-CLOCK\u039419 expression did not destabilize Flag-BMAL1 , Flag-Bmal1 with Flag-Clock or Flag-Clock\u039419. Whereas robust BMAL1 polyubiquitination was observed with expression of Flag-CLOCK  MEF cells. In p62\u2212/\u2212 MEF cells, we observed elevated levels of endogenous BMAL1, including both higher molecular weight and truncated forms, compared with WT (p62+/+) and p62\u2212/\u2212 MEF cells with Flag-Bmal1 and Flag-Clock. As shown in p62\u2212/\u2212 cells. We next performed siRNA knockdown experiment to further ascertain a requisite role of p62 in CLOCK-induced BMAL1 degradation. In 293T cells treated with control siRNA, Flag-BMAL1 showed significant decreases in levels with Flag-CLOCK expression, and the decreases were much attenuated with Flag-CLOCK\u039419 (p62/SQSTM1 binds to ubiquitin chains via the ubiquitin-associated (UBA) domain , top res with WT . Next toCLOCK\u039419 , left. pCLOCK\u039419 , right. Growing evidence indicates an important role of the circadian clock, particularly BMAL1, in insulin signaling and energy homeostasis20Finally, to obtain a global view of the circadian transcriptome toward understanding the improved glucose homeostasis in Clk/+ mice compared with WT under HFD, we conducted circadian microarray transcriptome profiling (Affymetrix). Clock gene expression patterns  were larIn the current study, we observed an unexpected improvement in glycemic control in Clk/+ mice relative to WT under HFD feeding. Interestingly, molecular mechanistic studies revealed stabilization of BMAL1 by CLOCK\u039419 via a novel dual mechanism attenuating both proteasomal and autophagic degradation of BMAL1, providing the first evidence of autophagic regulation of a core clock component. Furthermore, we also found enhanced activation of insulin signaling components, as well as specific changes in metabolic gene expression, in HFD-fed ClK/+ mice relative to WT. Our findings reveal a novel mode of clock regulation by autophagy, and extend previous behavioral and cellular studies of Clk/+ circadian rhythms. Under normal RC conditions Clk/+ mice display persistent circadian wheel-running behavior characterized by both period lengthening and amplitude dampening4125Our molecular analysis unveiled a novel mechanism for the enhanced accumulation of BMAL1 in Clk/+ mice involving bifurcated attenuation of both proteasomal and autophagic turnover. Consistent with previous findings36In particular, our studies of BMAL1 K259R and the autophagy cargo protein p62 revealed molecular insight into the dual mechanism of proteasomal and autophagic degradation of poly-ubiquitinated BMAL12744273246ob/ob genetic background181918db/db mutant background, as evidenced by enhancement in both glucose tolerance and insulin tolerance under the conditions tested. It will be interesting to further determine these metabolic parameters as a function of circadian and fasting time. Given the important role of skeletal muscle and adipose tissues in systemic glucose metabolismBmal1\u2212/\u2212 mice were deficient in AKT activation in both liver and muscle and concomitantly suffered from impaired insulin sensitivityin vitro and in vivoBmal1 in lipogenesis regulation by the mTORC2-AKT signalingClk/Clk mice have previously been shown to exhibit normal or enhanced insulin sensitivity at mid-age, under HFD or in the de novo oscillation of circadian transcripts downstream from the core clock when compared with RC feedingWe also observed that HFD feeding, while lengthening the free-running period in WT, did not show a similar effect in Clk/+ mice. This behavioral resistance to HFD-induced period lengthening in Clk/+ mice parallels the observed effects of HFD and CLOCK\u039419 on BMAL1 levels. Acute HFD intake has been reported to alter liver circadian clocks and temporal partitioning of food intake2732In conclusion, our study reveals unexpected behavioral and molecular remodeling in HFD-fed Clk/+ mutant mice as a model for a partially impaired clock. We provide evidence for a novel role of autophagy in CLOCK-dependent BMAL1 turnover, and illustrate activated insulin signaling concordant with improved glycemic control. Studies of partially impaired, yet still rescuable, clocks will yield rich insight into clock plasticity and interventional strategies.Clock\u039419/+ (Clk/+), Clock\u039419/\u039419 (Clk/Clk), db/db (db:WT) and db/db Clock\u039419/+ (db:Clk/+) mice, all on the C57BL/6J genetic background, were obtained as littermates from heterozygous breeding using Clock\u039419/+db/+ breeders (Jackson Laboratory) respectively. Mice were group-housed (2\u20134/cage) in a standard animal facility under a 12\u2009h:12\u2009h light:dark cycle. For circadian locomotor and metabolic chamber studies, mice were single-housed in an approved satellite facility.Husbandry and experimental methods for all the animal experiments were in accordance with IACUC guidelines at the University of Texas Health Science Center at Houston (UTHSC-H), and the study was approved by UTHSC-H. Male wild-type (WT), Flag-Bmal1, HA-Bmal1, Flag-Clock and Flag-Clock\u039419 were subcloned into the pCMV10 3xFlag DNA vector (Sigma) for protein expression. Myc-p62 and Myc-p62\u0394UBA mutant constructs were previously describedBmal1 K259R-F: TGCAACAGGCCTTCAGTACGGGTGGAAGATAAGGACTTC;Bmal1 K259R-R: GAAGTCCTTATCTTCCACCCGTACTGAAGGCCTGTTGCA. All constructs were verified by sequencing. The primary antibodies used in the study are: Flag-tag (Sigma-Aldrich), Myc-tag, AKT, pAKT (Ser473), S6K, pS6K (Thr389) and FOXO1, pFOXO1 (Thr24) , BMAL1 , CLOCK (Santa Cruz), LC3B (Novus), p62/SQSTM1 (Boster), REV-ERB\u03b1 , PER2WT and Clk/+ mice at 6 weeks of age were fed with regular chow diet (Purina 5001) or HFD  until the end of the experimental protocol. Weekly body weight was monitored in WT and Clk/+ mice for 12\u201314 weeks. For db:WT and db:Clk/+ mice, mice at 6\u20138 weeks of age were group-housed (2\u20133/cage) and maintained on RC.2 consumption and CO2 production was continuously recorded over a 24\u2009h period. Average O2 consumption was calculated and compared between different treatments. Food and water were provided ad libitum. To measure food intake, food pellets were weighted every three hours over a 24\u2009h period in WT and Clk/+ mice fed with RC or HFD. The daily food intake was calculated from averaged food intake of three independent experiments.Energy expenditure was examined by measuring oxygen consumption with indirect calorimetry as describedSerum samples were obtained at ZT2 from treated WT and Clk/+ mice as mentioned above. Serum triglyceride, cholesterol and free fatty acid levels were assessed by Serum Triglyceride Determination Kit (Sigma), Cholesterol Assay Kit (Cayman), and Free Fatty Acid Quantitation kit (BioVision) respectively. Serum insulin levels were detected with the Rat/Mouse Insulin ELISA kit (Millipore) according to the manufacturer\u2019s instructions. The assay plates were read by a TECAN M200 instrument (Tecan).Glucose tolerance test (GTT) and insulin tolerance test (ITT) in all groups were performed largely as describedFor insulin challenge, mice were given vehicle (PBS) or insulin (5 U/kg) via i.p following overnight fasting (15\u201318\u2009h). Five minutes after injection, mice were deeply anesthetized by isoflurane inhalation. Isolated liver samples were immediately frozen in liquid nitrogen and stored in \u221280\u2009\u00b0C freezer until later use.ad libitum feeding for another 2 weeks. Wheel-running data was downloaded as VitalView data files and analyzed with the ActiView programAfter 12 weeks feeding of RC or HFD, WT and Clk/+ mice were used for circadian locomoter activity experiments. Briefly, mice were first maintained for 2 weeks in a 12\u2009h:12\u2009h light:dark (LD) cycle, then released into the constant darkness, free-running condition with PureXtract RNAsol reagent (GenDEPOT) following the manufacturer\u2019s protocol. cDNA was synthesized from 2\u2009\u03bcg of total RNA using amfiRivert Platinum cDNA synthesis kit (GenDEPOT). Specific qRT-PCR primers are listed in sTable 3. qRT-PCR was performed using a MaxPro3000 Thermocycler (Agilent) with amfiSure qGreen qPCR Master Mix (GenDEPOT). Expression of the target gene was analyzed by a relative amount quantification method (ddCt) and normalized using Gapdh levels.Total RNA was extracted from cells using the The Western blotting, or immunoblotting, procedures have been previously described5 cells and incubated for 2\u20134 days (100\u2009nM Dex) followed by 50\u2009\u03bcM sodium palmitate treatment for 24\u201336\u2009h before synchronization.Adult mouse ear fibroblast and mouse embryonic fibroblast (MEF) cells were previously describedNuclear and cytoplasmic fractionation was performed as previously described293T cells were transiently transfected with indicated plasmids and treated with 10\u2009\u03bcM MG132 for 1\u2009h before harvesting. Cells were lysed with lysis buffer containing protease and deubiquitinase inhibitors and immunoprecipitated with anti-Flag antibody. The samples were subjected to SDS-PAGE followed by Western blotting. Ubiquitinated BMAL1 was detected by BMAL1 antibody.http://www.webgestalt.org) was used for KEGG pathway analyses. ChIP-seq data8Total RNAs prepared from liver tissues from HFD-fed WT and Clk/+ mice was reverse transcribed into cDNAs, which were then biotin-UTP labeled and hybridized to the Illumina mouse WG-8v2.0 Expression BeadChip. Background was subtracted and arrays were normalized using quantile. To determine differentially expressed genes, genes with lowest detection p\u2009>\u20090.05 were filtered out. The mean expression level across the time course was compared between WT and Clk/+, and genes with statistically significant  and at least 1.2 fold change were determined. Heat maps were generated by MultiExperiment Viewer. The WebGestalt program ."}
+{"text": "Increased numbers of OX40+ T cells within the primary tumor of colorectal cancer (CRC) patients has been associated with improved survival. Similarly, OX40 expression in sentinel lymph nodes is inversely associated with tumor grade and clinical stage in melanoma patients. However, the prevalence of OX40+ tumor-associated lymphocytes remains underreported in many human solid tumor types. In this study, we report prevalence of OX40 by chromogenic immunohistochemistry in melanoma, colorectal, bladder, renal cell (RCC), triple-negative breast (TNBC), non-small cell lung (NCSCLC) and ovarian cancers and its association with available clinical parameters.2 and % OX40+ cell area) were compared with patient age, clinical parameters, and outcome, where available, to determine potential associations.Tumor-associated OX40+ cells in melanoma (n=40), bladder (n=51), CRC (n=40), NSCLC (n=40), TNBC (n=45), ovarian (n=40) and RCC (n=42) patient samples including primary site and a subset of matched metastases have been stained for OX40 using a DAB-based chromogenic immunohistochemistry assay. Stained sections have been independently scored for OX40+ lymphocyte area percentage by two pathologists and a subset will be digitally imaged and analyzed. Image analysis includes OX40+ lymphocyte enumeration and area calculation within pathologist-defined regions of interest (ROI) to include the tumor and surrounding stroma. OX40 prevalence (OX40-positive cells/mmResults to be reported include a.) pathologist scoring of OX40+ cell prevalence b.) image analysis of OX40+ cell number and area percentage in a subset of indications c.) concordance between image analysis and pathologists' scores d.) OX40 prevalence by tumor type e.) OX40 prevalence and association with clinical features, where available, and statistical significance.Prevalence of OX40 expression and association with clinical features are first reported in some solid tumor types."}
+{"text": "Listeria monocytogenes is a significant foodborne pathogen causing severe systemic infections in humans with high mortality rates. The objectives of this work were to establish a phylogenetic framework of L. monocytogenes from China and to investigate sequence diversity among different serotypes. We selected 17 L. monocytogenes strains recovered from patients and foods in China representing serotypes 1/2a, 1/2b, and 1/2c. Draft genome sequences were determined using Illumina MiSeq technique and associated protocols. Open reading frames were assigned using prokaryotic genome annotation pipeline by NCBI. Twenty-four published genomes were included for comparative genomic and phylogenetic analysis. More than 154,000 single nucleotide polymorphisms (SNPs) were identified from multiple genome alignment and used to reconstruct maximum likelihood phylogenetic tree. The 41 genomes were differentiated into lineages I and II, which consisted of 4 and 11 subgroups, respectively. A clinical strain from China (SHL009) contained significant SNP differences compared to the rest genomes, whereas clinical strain SHL001 shared most recent common ancestor with strain SHL017 from food. Moreover, clinical strains SHL004 and SHL015 clustered together with two strains (08-5578 and 08-5923) recovered from an outbreak in Canada. Partial sequences of a plasmid found in the Canadian strain were also present in SHL004. We investigated the presence of various genes and gene clusters associated with virulence and subgroup-specific genes, including internalins, L. monocytogenes pathogenicity islands (LIPIs), L. monocytogenes genomic islands (LGIs), stress survival islet 1 (SSI-1), and clustered regularly interspaced short palindromic repeats (CRISPR)/cas system. A novel genomic island, denoted as LGI-2 was identified. Comparative sequence analysis revealed differences among the L. monocytogenes strains related to virulence, survival abilities, and attributes against foreign genetic elements. L. monocytogenes from China were genetically diverse. Strains from clinical specimens and food related closely suggesting foodborne transmission of human listeriosis. Listeria monocytogenes causes severe systemic infections with high mortality rates  and B (InlB) played essential roles in invasion activities , Tat (twin-arginine translocation), FPE (fimbriae protein exporter), FEA (flagella export apparatus), holins, and Wss (WXG100 secretion system)   , which is composed of five genes contributing to the survival of cells in suboptimal conditions of food environments such as low pH and high salt concentrations /cas system is considered a bacterial immune system against invading genetic fragments by targeting specific sequence including phages and plasmids  (unpublished data) , 1/2b (n = 5), and 1/2c (n = 4).To determine the genetic diversity and to identify the genetic characteristics of de novo and were annotated by NCBI using Prokaryotic Genomes Annotation Pipeline , SHL002 (APIB00000000), SHL004 (APIB00000000), SHL005 (APIB00000000), SHL006 (APIB00000000), SHL007 (APIB00000000), SHL008 (APIB00000000), SHL009 (APIB00000000), SHL010 (APIB00000000), SHL011 (APIB00000000), SHL012 (APIB00000000), SHL013 (APIB00000000), SHL014 (AWWQ00000000), SHL015 (AWWR00000000), SHL016 (AWWS00000000), SHL017 (AWWT00000000), and SHL018 (AWWU00000000).Whole genome sequencing was performed on the 17 strains using Illumina MiSeq technique and associated protocols  with MiSeq Reagent Kit v2 (500 cycle), Nextera XT DNA Sample Preparation kit, and Nextera XT Index Kit. Draft genome data were assembled using CLC Genomic Workbench L. monocytogenes genomes were selected to determine the evolutionary relationship among L. monocytogenes  whereas SHL002 had the highest number of genes (n = 3113). The average genome size in lineages I and II was 2.93 Mb and 2.98 Mb, respectively.Our findings revealed the phylogeny of 41 na Table . SHL013 L. monocytogenes genomes were divided into two lineages based on phylogenetic data. Serotype 1/2b strains belonged to lineage I, whereas serotypes 1/2a and 1/2c strains belonged to lineage II. These two lineages were further split into 4 (Ia to Id) and 11 (IIa to IIk) subgroups, respectively  phylogenetic tree was constructed using more than 154,000 SNPs, which were identified from core genome alignments . Contig number 9 of SHL004  showed 100% identities compared to pLMR479a. Both plasmid sequences from SHL004 and SHL015 were also highly conserved compared to plasmid pLM5578  from strain 08-5578.SHL004 and SHL015 were closely clustered with 08-5578 and 08-5923 in subgroup IIk Figure . Their ginlF, inlI, and inlJ, which were absent in the other three strains. An evolutionary model for subgroup IIk strains was proposed  except SHL015. SHL015 carried genes d Figure .lmo0150  was present in subgroups IIa, IIi, IIj, and IIk; lmo0471  was found in subgroups IIi and IIj. Additionally, we identified strain specific genes within subgroups via comparing the genomes in the same subgroup , inlD, and inlE (5\u2032 to 3\u2032). InlH and inlE were present in all genomes whereas inlG and inlD were found in different subgroups  to 10 , SHL015 (beef), and two outbreak isolates 08-5578 and 08-5923 in Canada  showed close genetic relatedness, suggesting these clones remain and circulate locally. SHL002 and SHL008 shared most recent common ancestor. SHL007 and SHL012 also originated from the same ancestor. Additionally, clinical strains of serotype 1/2a were grouped together with those from foods (SHL015 from beef and SHL017 from bean). Such an association indicated a possible foodborne transmission of listeriosis to humans.The distribution of virulence factors indicated variations in virulence potentials and evolutionary histories in different subgroups. The mean numbers of virulence factors examined in subgroups Ic and IIg Figure  were higL. monocytogenes , contributed to survival under low pH and high salt concentration  and 1/2c strains (IIj), all of which related to intracellular up-regulation in macrophage, although rliC was reported down-regulated in lineage III strains , China-U.S. Collaborative Program on Emerging and Re-emerging Infectious Diseases (1U2GGH000961-01&5U2GGH000961-02) and the Joint Institute for Food Safety & Applied Nutrition, University of Maryland.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In addition, in vitro assays determined and compared the extent of any cell-free virion redistribution that CVC or maraviroc (MVC) may cause.Cenicriviroc (CVC), a once-daily, dual CCR5/CCR2 co-receptor antagonist, has completed Phase 2b development. CVC demonstrated favourable safety and similar efficacy compared with efavirenz (EFV) in Study 202 (NCT01338883); an Ex vivo: intracellular DNA (frozen PBMCs) from 30 subjects with virologic success at Week 24 . Early (strong-stop) and late (full-length) reverse transcript levels were measured by qPCR. In vitro: PM-1 cells were infected with CCR5-tropic HIV-1 BaL in the presence or absence of inhibitory concentrations of CVC (20 nM), MVC (50 nM) or controls. P24 and viral load levels were measured by ELISA and qRT-PCR after 4 hours.Ex vivo analysis showed full-length HIV DNA declines were similar across all groups  at Week 24. Strong-stop HIV DNA declines (a marker of HIV entry) at Week 24 were pronounced for both CVC arms  compared to no decline for the EFV arm. In vitro experiments revealed that CVC-treated cells had lower levels of supernatant P24 at 4 hours versus baseline , but P24 levels remained constant for MVC-treated cells after 4 hours . Viral load levels for CVC-treated cells remained stable after 4 hours . MVC-treated cells exhibited a slight increase in viral load after 4 hours .Ex vivo analysis confirmed that CVC treatment blocks HIV entry (strong-stop HIV DNA declines), while in vitro analysis showed that CVC-treated cells do not repel virus back into the extracellular space, as seen with MVC. Experiments are underway to determine whether or not interactions between CVC and HIV at the binding site may explain these unanticipated findings."}
+{"text": "Physiological and biochemical analyses showed that EG1 encodes a predominantly mitochondria-localized functional lipase and functions in a high temperature-dependent manner. Furthermore, we found that numerous environmentally responsive genes including many floral identity genes are transcriptionally repressed in eg1 mutants and OsMADS1, OsMADS6 and OsG1 genetically act downstream of EG1 to maintain floral robustness. Collectively, our results demonstrate that EG1 promotes floral robustness against temperature fluctuation by safeguarding the expression of floral identify genes through a high temperature-dependent mitochondrial lipid pathway and uncovers a novel mechanistic insight into floral developmental control.The sessile plants have evolved diverse intrinsic mechanisms to control their proper development under variable environments. In contrast to plastic vegetative development, reproductive traits like floral identity often show phenotypic robustness against environmental variations. However, it remains obscure about the molecular basis of this phenotypic robustness. In this study, we found that  EG1 (EXTRA GLUME1) can enhance the floral robustness against temperature fluctuation in rice. EG1 encodes a predominantly mitochondria-localized functional lipase and its loss of function disrupts floral development in a high temperature-dependent manner. In consistent, both EG1 and its lipase activity are positively induced by high temperature. Transcriptomic and genetic analyses revealed that EG1 functions upstream of several floral identity genes, eg, OsMADS1, OsMADS6 and OsG1. Taken together, our results uncover a novel mitochondria-mediated lipid metabolic pathway to promote floral developmental robustness. Our findings may help to genetically improve floral traits of rice to maintain a stable yield when planted in different locations and/or under heat stress conditions.Various mechanisms have evolved to ensure proper organ formation under variable environments in order to complete one organism\u2019s life cycle. In angiosperms, vegetative and reproductive organs show a differential plastic development between varied environments, with a low plasticity or high robustness for flower formation, but little is known about its intrinsic mechanism. Here we report that gene  The sessile plants have evolved various exquisite adaptive strategies to cope with environmental changes ,2. AmongHSP90 (HEAT SHOCK PROTEIN 90) family, as central hubs of numerous biological pathways, are required for maintenance of phenotypic robustness in both animals and plants  of two genotypes respectively. Dotted lines indicate y = x lines and solid lines are the best fit lines by linear regression. (b) Comparisons of environmentally responsive genes between two (TIF)Click here for additional data file.S12 Figeg1 and wild-type. Different colors indicate different samples of Beijing (BJ) and Lingshui (LS). Y axis indicates expression level of genes. Labelled values are log2 [ratios of gene mean expressions in BJ to that in LS] in the corresponding genotypes. \u201c*\u201d labels |log2|>1.Genes with boldface letters indicate genes with significant variations of expression pattern between (TIF)Click here for additional data file.S13 FigColumn diagrams are described as in (TIF)Click here for additional data file.S14 FigArabidopsis thaliana , Glycine max , Ricinus communis (28424.t000001(Rc)) and Medicago truncatula (Medtr7g006400); from monocots: Oryza sativa , Brachypodium distachyon , Zea mays , Sorghum bicolor ; and moss Physcomitrella patens (Phpat.022G001500). Gene IDs come from JGI website. chlo, chloroplast; mito, mitochondria; other, without a chlo/mito targeting peptide.Proteins from dicots: (TIF)Click here for additional data file.S1 Table(XLSX)Click here for additional data file.S2 Table(XLSX)Click here for additional data file.S3 Table(XLSX)Click here for additional data file.S4 Table(XLSX)Click here for additional data file.S5 Table(XLSX)Click here for additional data file.S6 Table(XLSX)Click here for additional data file.S7 Table(XLSX)Click here for additional data file.S8 Table(XLSX)Click here for additional data file.S9 Table(XLSX)Click here for additional data file."}
+{"text": "Prevalence of graft occlusion is high after coronary artery bypass grafting (CABG). Routine use of aspirin after CABG reduces graft failure and ischemic complications. The benefit of concomitant clopidogrel administration remains a controversial issue.We sought to evaluate the impact of use aspirin plus clopidogrel versus aspirin alone on graft patency and adverse cardiovascular events 18 months after CABG.In this single-centre prospective randomized study, 200 consecutive patients undergoing elective CABG were randomly assigned to two groups: 97 patients received aspirin 300 mg (A) and 103 patients received aspirin 100 mg plus clopidogrel 75 mg (AC). Antiplatelet protocol was initiated immediately after surgery and continued daily for one year. Graft patency was evaluated by multislice computed tomography angiography (MSCT) 18 months after surgery. The occurrence of major cardiac or cerebrovascular adverse events (MACCE) and bleeding complications during follow-up were assessed.Preoperative patient characteristics were similar in both groups. MSCT graft patency was assessed in 194 patients (97%). A total of 542 grafts and 680 distal anastomoses were analyzed. Overall graft patency was 83.1% in group A and 89.4% in the AC group (p = 0.04). Patency rates in the A group versus AC group were similar: Left internal mammary artery , right internal mammary artery , radial artery , saphenous vein graft . Clinical follow-up was complete in 200 patients. The incidence of MACCEs was similar in both groups . The need for percutaneous coronary re-intervention showed no statistically significant differences .Compared with aspirin monotherapy, the combination of aspirin plus clopidogrel following CABG did not significantly increase graft patency or reduce the incidence of adverse cardiac events."}
+{"text": "Gout is a painful arthritis associated with high serum urate levels (hyperuricaemia) and subsequent crystal deposition in joints. Although not all people with Asymptomatic Hyperuricaemia (AH) develop gout, crystal deposition and sub-clinical joint damage have been observed in this population. Gout most commonly affects the first metatarsophalangeal joint (1MTP). Existing theories suggest this may be related to the structure and functional role of the joint during gait, yet such characteristics of the 1MTP have not been investigated in people with gout or with AH. The objective of this study was to identify 1MTP characteristics in these people by comparing them with normouricaemic controls.Eighty-eight males  participated in this cross-sectional study. Primary outcome measures were 1MTP pain and passive 1MTP dorsiflexion. Secondary outcome measures were foot-related pain and disability and gait velocity. Exploratory outcome measures included additional patient-reported outcomes , 1MTP plantarflexion and dorsiflexion muscle strength, hallux valgus severity, Foot Posture Index, 1MTP temperature, vibration perception threshold, plantar protective sensation and dynamic plantar pressure distribution .Compared to controls, people with gout had significantly reduced 1MTP dorsiflexion (p<0.0001), greater foot-related pain and disability (p<0.0001), reduced gait velocity (p=0.024), greater activity limitation (p=0.008), reduced lower limb function during activities of daily living (p=0.010) and recreational activities (p<0.0001), higher 1MTP plantar and dorsal temperature  and greater midfoot peak pressure and pressure time integrals (p<0.0001). Compared to controls, people with AH had significantly reduced lower limb function during recreational activities (p=0.033), higher Foot Posture Index (p=0.035), greater midfoot peak pressure and pressure time integral , greater first metatarsal peak pressure (p=0.029) and greater heel pressure time integrals (p=0.042).Gout negatively impacts foot-related patient-reported outcomes and is associated with impaired 1MTP function. The presence of hyperuricaemia in the absence of symptomatic gout is also associated with reduced lower limb function and may influence foot function during gait."}
+{"text": "To verify whether porcine deltacoronavirus infection induces disease, we inoculated gnotobiotic pigs with 2 virus strains (OH-FD22 and OH-FD100) identified by 2 specific reverse transcription PCRs. At 21\u2013120 h postinoculation, pigs exhibited severe diarrhea, vomiting, fecal shedding of virus, and severe atrophic enteritis. These findings confirm that these 2 strains are enteropathogenic in pigs. Coronaviridae, genus Alphacoronavirus) was discovered in the United States in May 2013. The virus has now spread nationwide and caused a high number of deaths among suckling pigs (Deltacoronavirus), has been simultaneously and frequently detected in diarrheic fecal samples from pigs (Porcine epidemic diarrhea virus (PEDV)  specific for the membrane gene (nt 23395\u201323466) as reported  of PDCoV strain OH-FD22 and 11.0 log10 GEs of OH-FD100, respectively. Clinical signs were monitored hourly. Pig 2 was monitored for long-term clinical signs and virus shedding until day postinoculation (dpi) 23. Pigs were euthanized for pathologic examination at 24\u201348 h or >48 h after onset of clinical signs. All animal-related experimental protocols were approved by the Ohio State University Institutional Animal Care and Use Committee.Near-term gnotobiotic pigs were delivered aseptically by hysterectomy from 2 specific pathogen\u2013free sows  were examined. Mean jejunal ratios of villous height to crypt depth were measured as reported  in gnotobiotic pigs  21\u201324, regardless of the inoculum strain or dose . At hpi tic pigs . For pigtic pigs  in pigs Macroscopic examination showed that all infected pigs had PEDV-like lesions characterized by thin and transparent intestinal walls  and accumulation of large amounts of yellow fluid in the intestinal lumen , panel AIn situ hybridization\u2013positive or immunofluorescence-stained cells were observed mainly in the villous epithelium of small (duodenum to ileum) and large intestines , panel J10 GEs/mL) in serum. However, viremia was detected frequently in symptomatic PEDV-infected pigs (Under the experimental conditions used, no PDCoV-inoculated pigs at hpi 72\u2013168 had detectable virus RNA (<3.6 logSince 2013\u20132014, newly emerged PEDV and PDCoV have spread throughout the United States and caused a high number of pig deaths ("}
+{"text": "Seasonal influenza viruses are typically restricted to the human upper respiratory tract whereas influenza viruses with greater pathogenic potential often also target extra-pulmonary organs. Infants, pregnant women, and breastfeeding mothers are highly susceptible to severe respiratory disease following influenza virus infection but the mechanisms of disease severity in the mother-infant dyad are poorly understood. Here we investigated 2009 H1N1 influenza virus infection and transmission in breastfeeding mothers and infants utilizing our developed infant-mother ferret influenza model. Infants acquired severe disease and mortality following infection. Transmission of the virus from infants to mother ferrets led to infection in the lungs and mother mortality. Live virus was also found in mammary gland tissue and expressed milk of the mothers which eventually led to milk cessation. Histopathology showed destruction of acini glandular architecture with the absence of milk. The virus was localized in mammary epithelial cells of positive glands. To understand the molecular mechanisms of mammary gland infection, we performed global transcript analysis which showed downregulation of milk production genes such as Prolactin and increased breast involution pathways indicated by a STAT5 to STAT3 signaling shift. Genes associated with cancer development were also significantly increased including JUN, FOS and M2 macrophage markers. Immune responses within the mammary gland were characterized by decreased lymphocyte-associated genes CD3e, IL2Ra, CD4 with IL1\u03b2 upregulation. Direct inoculation of H1N1 into the mammary gland led to infant respiratory infection and infant mortality suggesting the influenza virus was able to replicate in mammary tissue and transmission is possible through breastfeeding. In vitro infection studies with human breast cells showed susceptibility to H1N1 virus infection. Together, we have shown that the host-pathogen interactions of influenza virus infection in the mother-infant dyad initiate immunological and oncogenic signaling cascades within the mammary gland. These findings suggest the mammary gland may have a greater role in infection and immunity than previously thought. JUN, FOS and BRCA2. We found human breast cells were able to be infected with the influenza virus suggesting the importance of our results to human health. Our data suggests influenza transmission can occur through the mammary glands initiating immunological and pathological events contributing to influenza disease severity impacting infant and maternal health.Influenza is known as a respiratory infectious disease. Breastfeeding allows for frequent microbial exchange between infant and mother. Although infants, pregnant women and breastfeeding mothers are more susceptible to severe respiratory disease following influenza virus infection, the mechanisms of disease severity in infants and mothers is poorly understood. We were interested in understanding the immune responses, pathogenicity, and transmission dynamics in the infant-mother system. With this aim we developed an infant-mother ferret influenza model. Influenza infection in infants led to virus transmission to mothers causing severe disease and mortality. Unexpectedly, influenza-infected infant ferrets transmitted the virus to mother mammary glands leading to live influenza virus in expressed breast milk. Gene regulation analysis in the mammary gland showed reduction of milk production genes such as Prolactin and increased genes involved with breast shutdown. Genes associated with cancer development were significantly increased including  The influenza A RNA virus (Orthomyxoviridae) is a significant threat to human health and the global economy by causing morbidity and mortality through frequent epidemics and sporadic pandemics . SeasonaThe mother-infant dyad represents a unique relationship where the infant and mother are often considered to function as a single unit. Through breastfeeding, mothers provide nutrients, beneficial bacteria, and immune protection to the infant by transfer of cells, antibodies, proteins, and sugars through breast milk ,12. The Breast disease is a significant problem worldwide. The postpartum and lactation phase in breast metamorphosis has been associated with increased breast cancer incidence. While breastfeeding has been shown to protect against long-term breast cancer development, postpregnancy breast cancer is hypothesized to be a consequence of breast remodeling and involution associated with lactation ,18. InfeAlthough infants and mothers are highly susceptible to the influenza virus \u201327, litt5 EID50. Infants were housed with nursing-mothers before and after inoculation. Nasal washes (NW), temperature, weight, clinical assessment, and survival were collected daily as shown in the design schematic . Necropsies were performed at Day 3, 4, 7, and 14 post-inoculation or if an animal was removed from the study (reached weight cut-off or had succumbed to illness). Inoculated infant ferrets developed illness leading to mortality starting with a high fever at 104% of baseline temperature (p<0.05) Day 2 post-infant-inoculation. Infants then developed hypothermia (Day 6) . All infants reached weight cut-off  or died by Day 8 post-infant-inoculation . Four days post-infant-inoculation, nursing-mother ferrets also developed influenza-like symptoms including increased body temperature (103% of baseline). Mother weights significantly decreased by 13% Day 4 post-infant-inoculation . Weight did not recover by study end and one mother reached cut-off . The weight and temperature of the mothers of mock inoculated control infants are presented in S1 Table which showed mothers did not develop symptoms post-mock-inoculation of infant ferrets.To investigate influenza infection in the mother-infant dyad, we intranasally inoculated 4-week-old infant ferrets with the 2009 H1N1 virus, A/California/07/2009 , at 10Fig 2A). The NW of nursing-mothers were positive for influenza virus Day 3 post-infant-inoculation. Viral titers remained high in mother NW Day 6\u20137  at more than 6 TCID50/ml (Log10). Residual virus persisted in the mothers\u2019 NW by Day 10 . Virus transmission between adult ferrets pair-housed  were used as a comparison of transmission dynamics between infants and mother ferrets. For this control, one adult was intranasally inoculated under similar circumstances as the infant-mother inoculations and NW were collected for viral load assessment. Na\u00efve cage mates of inoculated adult ferrets began shedding virus in NW Day 3 post-inoculation. These results showed that the influenza virus was able to be transmitted from direct intranasally inoculated infant ferrets to the upper respiratory tracts of their nursing-mothers on a similar time scale as that of adult ferrets.As the mothers of inoculated infants began to display clinical signs of influenza including temperature increases, weight loss, and mortality, we went on to analyze the upper and lower respiratory tracts of the infants and their mothers to determine virus transmission and pathogenesis. Viral burden in infant NW was first detected Day 1 post-infant-inoculation (50/ml (Log10) in both the trachea and lungs post-infant-inoculation in 2 out of 3 mothers investigated (Day 4 and 7 post-infant-inoculation) . H&E (hematoxylin & eosin) staining of mother lungs revealed delayed, airway-localized inflammation . Day 3/4 post-infant-inoculation, mother lungs showed areas of minimal infiltrating leukocytes  . Increased leukocyte infiltration was observed Day 7 post-infant-inoculation where sites of inflammation were dense in mononuclear cells with lymphocyte-like morphology. Infected mother lungs were compared to the lungs of adult male ferrets directly inoculated with Cal/07 through the intranasal route . The lungs collected from mothers of mock inoculated infants were similar in architecture to that of mock inoculated adult male ferrets. The adult lungs collected Day 3/4 post-direct-inoculation had markedly more leukocyte infiltrates compared to the mother lungs at Day 3/4 post-infant-inoculation . Taken together with the above data, these findings indicated that 2009 H1N1 transmission from infant to mother led to severe respiratory disease with upper and lower respiratory tract infection and accompanying lung pathology but on a delayed time course compared to direct adult infections.We next determined if transmission of the virus from infants to mother led to lower respiratory tract infection. Examination of viral titers in the lower respiratory tract of the mothers found virus levels above 6 TCIDFig 3A). We intranasally inoculated nursing-mothers with Cal/07 at 105 EID50 and observed clinical symptoms as well as determined respiratory viral load and pathogenesis. Following inoculation, nursing-mother ferrets developed a biphasic fever which spiked at 104% (baseline temperature)  Day 3 post-mother-inoculation. Weight loss was observed in the inoculated mothers which reached nadir on Day 7 post-mother-inoculation at 89% of original weight (p<0.05) . Although mother mortality did not occur, the infants of inoculated mothers lost weight, had increased temperature, and all died or reached cut-off by Day 11 post-mother-inoculation . The weight of infants of inoculated nursing-mothers began to decline on Day 3 . Although infants did not have a significant increase in temperature they did become hypothermic as they reached mortality . Virus was detected in mother NW Day 1 post-mother-inoculation (peak Day 2 at 6 TCID50/ml (Log10)) and infant viral shedding began Day 3 . Live influenza virus was detected in the lungs of infants reaching weight cut-off or succumbing to illness between Day 5 and Day 8 post-mother-inoculation (3\u20138 TCID50 (Log10)) . Significant pathology was also detected in lungs of infants feeding from 2009 H1N1 inoculated nursing-mothers Day 7 post-mother-inoculation. The lungs were characterized by areas of dense leukocyte infiltration and alveoli destruction . In summary, these data indicate that influenza transmission was also possible from mother to feeding-infants causing upper and lower respiratory tract infection and respiratory tract disease.To determine if influenza infected nursing-mother ferrets could transmit the virus to their feeding-infants, we reversed the inoculation/infection design as shown in the schematic . All mammary glands were collected from mothers of directly influenza inoculated infants on Day 4 and Day 7 post-infant-inoculation (3 per time point). Live viral load was quantified from each mammary tissue. MDCK titration assay revealed live virus in 7 of the glands  where some viral loads reached 6 TCID50/g (Log10) or higher. All mothers assessed had at least one gland positive for live influenza virus. Nipples of positive mammary glands also had significant amounts of live influenza virus on Day 4 post-infant-inoculation (3\u20137 TCID50/g (Log10)) .Mammary glands are a significant point of contact and possible pathogenic transmission within the mother-infant dyad . To inve50 (Log10) . vRNA analysis from milk collected on separate occasions showed vRNA was present in some milk samples as high as ~10,000 copies/5 ng totRNA. Most samples collected had between 10 and 1000 copies . vRNA and live virus were not detected in milk collected at baseline . High levels as well as moderate and low levels of vRNA were detected in infant ferret feces . Negligible or no amounts of vRNA were found in the peripheral blood of intranasally inoculated infants or their mothers to account for viremia contributing to severe disease or virus shedding from milk . Control directly inoculated adults were also negative for blood vRNA. This data suggested that mammary glands are able to be harbor live influenza virus and viral shedding can occur through milk expression.To determine if influenza virus positive mammary glands were able to shed virus in the milk expressed from the infected mammary gland, we measured both live virus and vRNA in expressed milk from mothers of infected infants. Live virus assessment in milk collected between Day 3 and Day 7 post-infant-inoculation revealed virus presence where some samples contained high virus levels between 6\u20137 TCIDFig 6). The acini of control glands had either thick epithelial cell layers indicative of active milk production (green arrows) or acini filled with pink proteinaceous fluid (milk) (blue arrows) . Virus staining was not detected in Control mammaries (top right panel). At Day 4 post-infant-inoculation, the glands of nursing-mothers had retained tissue architecture although leukocyte infiltration (yellow arrows) was identified. Foci of virus staining (light brown in color) was also observed (Day 4 post-infant-inoculation). By Day 7, marked increases in leukocyte infiltration (yellow arrows) in and surrounding the lobules was noted in some mammary glands  where the lobules of these glands had lost typical mammary acini architecture (bottom left panel). Increased viral staining was seen by Day 7 post-infant-inoculation with loss of significant tissue structure (bottom right panel). Viral staining was more pronounced in epithelial cells (black arrows) . These data provide evidence that the influenza virus is capable of infecting cells of the mammary gland.We next visualized the virus in 2009 H1N1 influenza positive mammary glands (H1N1+ MG) to determine virus localization and gland pathology following infection. Histopathology and virus localization in H1N1+ MG revealed destruction of mammary architecture .To uncover the molecular mechanisms of influenza infection within the mammary glands we performed gene expression analysis on RNA isolated from H1N1+ MGs. Global gene expression analysis by hierarchical clustering using Pearson correlation revealed increased expression of innate immune and cell remodeling genes, as well as downregulation of metabolism and lymphocyte activation genes . Jak-STAT  signaling was prominently affected, highlighted by increased STAT3 and involution signaling . Corresponding decreases were seen in STAT5A/B milk production and STAT associated gene networks PRL (Prolactin), STAT5A/B, SOCS1 , JAK3, EPO (Erythropoietin), and EPOR (Erythropoietin Receptor))  to Influenza A Virus Nucleoprotein  at 1:100 for 60 min. This was followed by staining with Alexa Fluor 647 Donkey Anti-Mouse secondary (Jackson ImmunoResearch). Prior to staining cells were permeablized using Triton X-100 in PBS. Slides were imaged by confocal microscopy using a Zeiss LSM 710 NLO, using objective C-Apo 63x/1.4 NA (oil). For RNA and viral load, cell lysates and supernatants were collected at 3, 24, 48, and 72 h post-inoculation for RNA extraction and live viral load quantification, respectively. The baseline control was determined by incubating the inoculum in assay wells without cells for 72 h. to assess virus decay and viral attachment to the wells. qRT-PCR and viral load were performed as described in above methods section.In vitro studies were performed similarly as reported previously . MCF-10At-test or one-way ANOVAs were conducted. The Log-rank (Mantel-Cox) Test was used to determine significant differences in animal survival. A p value of \u2264 0.05 was considered statistically significant.Unpaired, unequal variance, two-tail Student\u2019s S1 Table(PDF)Click here for additional data file.S2 Table(PDF)Click here for additional data file.S3 Table(PDF)Click here for additional data file.S4 Table(PDF)Click here for additional data file.S5 Table(PDF)Click here for additional data file.S1 FigA) or post-mother inoculation (B) with 2009 H1N1 A/Cal (105 EID50). Live viral loads were assessed by titration on MDCK cells for active viral shedding throughout the time course. Adult ferrets were pair-housed and one ferret was intranasally inoculated with 2009 H1N1 A/Cal (105 EID50) (C). Viral loads were determined for collected NW from both inoculated and na\u00efve cage mate ferrets.Nasal washes from infant ferrets and their feeding mothers were collected on Day 3, 7 and 10 post-infant inoculation ((PDF)Click here for additional data file.S2 FigA) Clustergram of differentially regulated genes involved in Jak-STAT signaling. One-way hierarchical clustering analysis (Pearson\u2019s correlation) was performed on all probes of significantly differentially regulated genes  classified as members of Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway database cfa04630 (left panels). Downregulated genes are in blue, upregulated genes in red. Visualization of Jak-STAT signaling pathway by Ingenuity Pathway Analysis (IPA) (right panels). Gene expression values from D6/7 mammary glands (average of n = 3) were overlaid on IPA pathway entry Jak/STAT Signaling . (B) Clustergram of differentially regulated genes involved in TGF-\u03b2 signaling. One-way hierarchical clustering analysis (Pearson\u2019s correlation) was performed on all probes of significantly differentially regulated genes  classified as members of Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway database (left panels) cfa04350. Downregulated genes are in blue, upregulated genes in red. Visualization of TGF-\u03b2 signaling pathway by Ingenuity Pathway Analysis (IPA) (right panels). Gene expression values from D6/7 mammary glands (average of n = 3) were overlaid on IPA pathway entry TGF-\u03b2 Signaling . (C) Clustergram of differentially regulated genes involved in Wnt-\u03b2-Catenin signaling. One-way hierarchical clustering analysis (Pearson\u2019s correlation) was performed on all probes of significantly differentially regulated genes  classified as members of Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway database (left panels) cfa04310. Downregulated genes are in blue, upregulated genes in red. Visualization of Wnt signaling pathway by Ingenuity Pathway Analysis (IPA) (right panels). Gene expression values from D6/7 mammary glands (average of n = 3) were overlaid on IPA pathway entry Wnt Signaling . (D) Clustergram of differentially regulated genes involved in p53 signaling. One-way hierarchical clustering analysis (Pearson\u2019s correlation) was performed on all probes of significantly differentially regulated genes  classified as members of Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway database (left panels) cfa04115. Downregulated genes are in blue, upregulated genes in red. Visualization of p53 signaling pathway by Ingenuity Pathway Analysis (IPA) (right panels). Gene expression values from D6/7 mammary glands (average of n = 3) were overlaid on IPA pathway entry p53 Signaling . (E) Clustergram of differentially regulated genes involved in Neutrophin/RTK signaling. One-way hierarchical clustering analysis (Pearson\u2019s correlation) was performed on all probes of significantly differentially regulated genes  classified as members of Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway database (left panels) cfa04722. Downregulated genes are in blue, upregulated genes in red. Visualization of Neutrophin/RTK signaling pathway by Ingenuity Pathway Analysis (IPA) (right panels). Gene expression values from D6/7 mammary glands (average of n = 3) were overlaid on IPA pathway entry Neutrophin/RTK Signaling . (F) Clustergram of differentially regulated genes involved in PPAR signaling. One-way hierarchical clustering analysis (Pearson\u2019s correlation) was performed on all probes of significantly differentially regulated genes  classified as members of Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway database (left panels) cfa03320. Downregulated genes are in blue, upregulated genes in red. Visualization of PPAR signaling pathway by Ingenuity Pathway Analysis (IPA) (right panels). Gene expression values from D6/7 mammary glands (average of n = 3) were overlaid on IPA pathway entry PPAR Signaling . (G) Clustergram of differentially regulated genes involved in Toll-Like Receptor signaling. One-way hierarchical clustering analysis (Pearson\u2019s correlation) was performed on all probes of significantly differentially regulated genes  classified as members of Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway database (left panels) cfa04620. Downregulated genes are in blue, upregulated genes in red. Visualization of Toll-Like Receptor Signaling Pathways by Ingenuity Pathway Analysis (IPA) (right panels). Gene expression values from D6/7 mammary glands (average of n = 3) were overlaid on IPA pathway entry Toll-Like Receptor Signaling . (H) Clustergram of differentially regulated gene signaling in Cancer related pathways. One-way hierarchical clustering analysis (Pearson\u2019s correlation) was performed on all probes of significantly differentially regulated genes  classified as members of Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway database (left panels) cfa05200. Downregulated genes are in blue, upregulated genes in red. Visualization of Molecular Mechanisms of Cancer signaling pathway by Ingenuity Pathway Analysis (IPA) (right panels). Gene expression values from D6/7 mammary glands (average of n = 3) were overlaid on IPA pathway entry Molecular Mechanisms of Cancer Signaling . (I) Clustergram of differentially regulated genes involved in Cell Cycle signaling. One-way hierarchical clustering analysis (Pearson\u2019s correlation) was performed on all probes of significantly differentially regulated genes  classified as members of Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway database (left panels) cfa04110. Downregulated genes are in blue, upregulated genes in red. Visualization of Cyclins and Cell Cycle signaling pathway regulation by Ingenuity Pathway Analysis (IPA) (right panels). Gene expression values from D6/7 mammary glands (average of n = 3) were overlaid on IPA pathway entry Cyclins and Cell Cycle Signaling . (J) Clustergram of differentially regulated genes involved in Cell Attachment signaling. One-way hierarchical clustering analysis (Pearson\u2019s correlation) was performed on all probes of significantly differentially regulated genes  classified as members of Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway database (left panels) cfa04510  and cfa04520 . Downregulated genes are in blue, upregulated genes in red. Visualization of Epithelial Adherens Junction Signaling pathway by Ingenuity Pathway Analysis (IPA) (right panels). Gene expression values from D6/7 mammary glands (average of n = 3) were overlaid on IPA pathway entry Epithelial Adherens Junction Signaling . (K) IPA Symbol Key taken from the IPA user manual.((PDF)Click here for additional data file.S3 FigReal-Time PCR was conducted on RNA extracted from 2009 H1N1 ferret mother mammary gland for genes representing Milk Production, Cancer-Associated, and Immune Response pathways. Mammary glands were collected from nursing mothers on Day 3/4 or Day 6/7 post-infant infection and RNA was extracted.(PDF)Click here for additional data file.S4 FigAi). Gene enrichment score profiles for all KEGG-defined signaling pathways which had exhibited significant enrichment among either upregulated or downregulated gene subsets at Days 3/4 or Day 7 (see S4 Table for more detail) (Aii). Clustergrams of significantly differentially regulated genes associated with immune processes (Aiii). Comparative transcriptomic analysis of H1N1+ and bystander mammary glands. The number of significantly differentially regulated genes in H1N1+ glands only, bystander glands only, or both are indicated by Venn diagram and the most prominent functional groups for each gene subset are described (see S5 Table for more detail) (B). Upregulated genes are labeled red and downregulated genes are labeled blue throughout. Samples were collected and analyzed from six independent litter experiments (n = 3/time-point).Global clustering analysis of all significantly differentially regulated genes  at Day 3/4 and/or Day 7 in bystander mammary glands; total number of genes: 6821. Hallmark functional groups of each cluster are indicated ((PDF)Click here for additional data file.S5 Fig5 EID50. Expressed milk was electrophoresed by SDS-PAGE and analyzed by western blot with a beta-casein antibody.Lactating ferret mothers were inoculated intramammary gland with Cal/07 at 10(PDF)Click here for additional data file."}
+{"text": "The precise nature of how cell type specific chromatin structures at enhancer sites affect gene expression is largely unknown. Here we identified cell type specific enhancers coupled with gene expression in two different types of breast epithelial cells, HMEC  and MDAMB231 (triple negative breast cancer cell line).Enhancers were defined by modified neighboring histones [using chromatin immunoprecipitation followed by sequencing (ChIP-seq)] and nucleosome depletion [using formaldehyde-assisted isolation of regulatory elements followed by sequencing (FAIRE-seq)]. Histone modifications at enhancers were related to the expression levels of nearby genes up to 750\u00a0kb away. These expression levels were correlated with enhancer status (poised or active), defined by surrounding histone marks. Furthermore, about fifty percent of poised and active enhancers contained nucleosome-depleted regions. We also identified response element motifs enriched at these enhancer sites that revealed key transcription factors (e.g. TP63) likely involved in regulating breast epithelial enhancer-mediated gene expression. By utilizing expression data, potential target genes of more than 600 active enhancers were identified. These genes were involved in proteolysis, epidermis development, cell adhesion, mitosis, cell cycle, and DNA replication.These findings facilitate the understanding of epigenetic regulation specifically, such as the relationships between regulatory elements and gene expression and generally, how breast epithelial cellular phenotypes are determined by cell type specific enhancers.The online version of this article (doi:10.1186/1471-2164-15-331) contains supplementary material, which is available to authorized users. The human genome has 22 chromosome pairs and 2 sex chromosomes. This single genome gives rise to several hundred distinct cell types including epithelial, neuronal, lymphocytic, germ, etc. In 2003, the human genome was completely sequenced, and it ushered in a new understanding of the breadth and diversity of primary coding sequences . HoweverGenomic DNA is organized into chromatin; 147 base pairs of DNA are wrapped around two copies of each of the core histone proteins, namely H2A, H2B, H3, and H4, forming a single octameric nucleosome core particle. Chromatin is found in two forms: hetero- and euchromatin. Heterochromatin is highly condensed, forming tightly packaged chromatin. In this compact state, a high density of repetitive DNA elements such as satellite DNA and transposable elements are found, and the dense packing of DNA makes it less likely for transcription factors to bind  through the NCBI Gene Expression Omnibus portal. ChIP assays were performed in MDAMB231 as previously described . AntibodLibrary was constructed and sequenced as previously described above in the FAIRE-seq section. Two independent assays per condition were analyzed separately   . AdjusteGAPDH mRNA expression in each cell type.Total RNA from HMEC and MDAMB231 cells were isolated using Aurum Total RNA Mini Kit . Isolated RNAs were reverse transcribed to cDNA by using the qScript cDNA Synthesis Kit . Two primer sets for each selected gene were designed . Equal amounts of protein from whole cell extracts were separated by running on gradient polyacrylamide gels , and transferred to Amersham Hybond polyvinylidene difluoride (PVDF) membranes . These blots were first incubated with either a 1:2000 of anti-P63 (39739)  or anti-beta-tubulin (MAB3408)  for overnight, and followed by incubation with their corresponding secondary antibodies, anti rabbit-HRP-conjugated antibody (diluted 1:2500) (sc-2030) and anti mouse-HRP-conjugated antibody (diluted 1:4000) (sc-2031) . Proteins were visualized using SuperSignal West Pico Chemiluminescent Substrate  and ChemiDoc XRS\u2009+\u2009Imaging System with Image Lab .Gene ontology analysis was performed by using GEO2R . Same nuBy using Oncomine database, released in March 2014, the dataset from the cancer genome atlas (TCGA) breast cancer studies was obtained , 78. TheFigure S1. ChIP-seq data overlap between HMEC and MDAMB231; Figure S2. Genomic distribution of HMEC specific enhancer loci (HSEL); Figure S3. Genomic distribution of MDAMB231 specific enhancer loci (MSEL); Figure S4. The expression value of nearby genes of HSEL and MSEL; Figure S5. Gene expression level for genes with cell type specific enhancers; Figure S6. Nearby gene expression barplot of cell type specific enhancers; Figure S7. The expression values of all genes in HMEC and MDAMB231; Figure S8. The expression levels of genes, which were not within windows of cell type specific enhancer loci; Figure S9. Shared enhancer loci identification in breast epithelial cells (HMEC and MDAMB231); Figure S10. The expression levels of genes nearby shared enhancers; Figure S11. Nearby gene expression boxplot of cell type specific enhancers; Figure S12. The expression levels of genes at each distance interval from enhancer loci; Figure S13. Poised and active cell type specific enhancers with FAIRE signals; Figure S14. Nearby gene expression boxplot for poised and active cell type specific enhancers and FAIRE signal; Figure S15. Workflow diagram of transcription factor motif search between enhancer groups; Figure S16. TP63 binding in breast epithelial cell type specific enhancers; Figure S17. Validation of TP63 binding in breast epithelial cell type specific enhancers in HMEC; Figure S18. Expression level of TP63 gene in breast epithelial cells; Figure S19. Western blot analysis of TP63; Figure S20. A comparison chart for differentially enriched gene ontology (GO) biological processes. (PDF 2 MB)Additional file 1: Table S1. ChIP-seq and FAIRE-seq peak statistics; Table S2. ChIP-seq and FAIRE-seq peak statistics for replicates; Table S3. Overlapped ChIP-seq peak statistics for replicates; Table S4. HMEC Specific Enhancer Loci coordinates and status; Table S5. MDAMB231 Specific Enhancer Loci coordinates and status; Table S6. Expression analyses on nearby genes of cell type specific enhancer and shared enhancer; Table S7. Shared Enhancer Loci coordinates; Table S8. Expression analyses on genes at each distance interval of cell type specific enhancer and shared enhancer; Table S9. Motif enrichment in poised HSEL and active HSEL; Table S10. Motif enrichment in poised MSEL and active MSEL; Table S11. Number of nearby genes (100\u00a0kb) for unique HSEL and MSEL in each expression level category; Table S12. Active HSEL and their putative target genes; Table S13. Active MSEL and their putative target genes; Table S14. Gene Ontology in process comparison between HMEC selected genes and randomly selected overexpressed genes in HMEC (n\u2009=\u2009316); Table S15. Gene Ontology in process comparison between MDAMB231 selected genes and randomly selected overexpressed genes in MDAMB231 (n\u2009=\u2009342); Table S16. Gene Ontology in process comparison between HMEC selected genes and randomly selected overexpressed genes in MDAMB231 (n\u2009=\u2009342); Table S17. Gene Ontology in Process comparison between MDAMB231 selected genes and randomly selected overexpressed genes in HMEC (n\u2009=\u2009316); Table S18. List of the selected MDAMB231 genes found in top 10 percent overexpressed genes in breast tumors; Table S19. List of the selected HMEC genes found in top 10 percent underexpressed genes in breast tumors; Table S20. Oligonucleotide sequences used for ChIP-qPCR and RT-qPCR. (XLS 657 KB)Additional file 2:"}
+{"text": "We showed that absence of flow originates symmetric charon expression [In most vertebrates organ asymmetries arise in early development through the left-right organizer (LRO). LRO ciliated cells induce a leftward fluid flow responsible for the asymmetric expression of Nodal pathway genes in tissues that will originate internal organs. We have recently published that pression . Pkd2 hapression . In agrepression ,5.charon/dand5 phenotype as absent flow.Determine if impaired mechanosensing renders the same charon/dand5 expression patterns by in situ hybridization and qRT-PCR.We injected two morpholinos in zebrafish embryos: a dnah7-MO to stop cilia movement  and a pkcharon/dand5 expression when flow is low and homogeneous or when Pkd2 is absent from LRO ciliary membrane. We will show if charon/dand5 quantification by qRT-PCR is also similar. When both flow and Pkd2 are impaired, 80% of embryos showed symmetric charon/dand5, which indicates a synergistic effect.50-60% of injected embryos have symmetric Although no flow and no Pkd2 have virtually the same phenotype, there seems to be a positive epistasis when both are affected.Supported by FCT-ANR/BEX-BID/0153/2012 grant and PD/BD/52420/2013 PhD scholarship."}
+{"text": "Q61NRAS mutant lung cancer and neuroblastoma cell lines. Signaling changes after incubation with inhibitors were studied and compared to those found in NRAS mutant melanoma.Oncogenic mutations in the Neuroblastoma Rat Sarcoma oncogene (NRAS) are frequent in melanoma, but are also found in several other cancer types, such as lung cancer, neuroblastoma and colon cancer. We designed our study to analyze changes in NRAS mutant tumor cells derived from malignancies other than melanoma. A variety of small molecule inhibitors as well as their combinations was tested in order to find beneficial inhibitory modalities in in vitro. However, we observed strong synergism combining MEK and PI3K/mTOR inhibitors in all cell lines. Our study provides evidence that NRAS mutant cancers share signaling similarities across different malignancies. We demonstrate that dual pathway inhibition of the MAPK and PI3K/AKT/mTOR pathway synergistically reduces cell viability in NRAS mutant cancers regardless of their tissue origin. Our results suggest that such inhibitor combinations may be a potential treatment option for non-melanoma tumors harboring activating NRAS mutations.All cell lines were most sensitive to inhibition in the MAPK pathway with the MEK inhibitor trametinib. MEK/AKT and MEK/CDK4,6 inhibitor combinations did not show any beneficial effects  Rat sarcoma (RAS) genes encode a family of small guanosine triphosphate(GTP)ases: Harvey rat sarcoma viral oncogene homolog (HRAS), Kirsten rat sarcoma viral oncogene homolog (KRAS) and neuroblastoma viral oncogene homolog (NRAS). Under physiological conditions, these proteins are activated by extracellular stimuli and regulate cellular proliferation, differentiation and survival -3. MutatMutations in v-Raf murine sarcoma viral oncogene homolog B1 (BRAF), NRAS and Kit are among the most prevalent driving aberrations in cutaneous melanoma with 15-20% affecting the NRAS oncogene . While tNRAS mutations are frequent in melanoma, however many other cancer types also harbor mutant, constitutively active NRAS. Table in vitro and in vivo studies testing a variety of small molecule inhibitors and their combinations in NRAS mutant melanoma cell lines  in 50mM Tris HCl (pH8.0) supplemented with protease and phosphatase inhibitors  as described previously (36)]. Protein concentrations were determined using the BCA Protein Assay kit  according to the manufacturer's protocol. Proteins were separated by SDS-PAGE with 4-20% gradient gels , transferred to an Immobilon-P PVDF membrane , and blocked in 5% dry milk in Tris Buffered Saline, with Tween 20 (TBST) (Sigma-Aldrich). The membrane was incubated with primary and secondary antibodies, and target proteins were detected with ECL detection reagent . \u03b2-Actin served as a loading control and was obtained from Sigma-Aldrich. Phosphor-ERK (4370), phosphor-AKT (4060), phosphor-S6 (4857), N-Myc (9405S) antibodies were obtained from Cell Signaling Technology . N-Ras antibody (F155) was obtained from Santa Cruz Biotechnology . The NRAS protein knockdown efficiencies were analysed using the software ImageJ (version 1.49d)."}
+{"text": "Nevertheless, titanium alloy implants produce corrosionparticles and fail by mechanisms generally related to surface interaction onbone to promote an inflammation with fibrous aseptic loosening or infection thatcan require implant removal. Further, lowered oxygen concentrations from poorvasculature at a foreign metal surface interface promote a build-up ofhost-cell-related electrons as free radicals and proton acid that can encourageinfection and inflammation to greatly influence implant failure. To provideimproved osseointegration many different coating processes and alternate polymermatrix composite (PMC) solutions have been considered that supply new designingpotential to possibly overcome problems with titanium bone implants. Now forimportant consideration, PMCs have decisive biofunctional fabricationpossibilities while maintaining mechanical properties from addition ofhigh-strengthening varied fiber-reinforcement and complex fillers/additives toinclude hydroxyapatite or antimicrobial incorporation through thermoset polymersthat cure at low temperatures. Topics/issues reviewed in this manuscript includetitanium corrosion, implant infection, coatings and the new epoxy/carbon-fiberimplant results discussing osseointegration with biocompatibility related tononpolar molecular attractions with secondary bonding, carbon fiber invivo properties, electrical semiconductors, stress transfer,additives with low thermal PMC processing and new coating possibilities.The aim of the article is to present recent developments in materialresearch with bisphenyl-polymer/carbon-fiber-reinforced composite that haveproduced highly influential results toward improving upon current titanium boneimplant clinical osseointegration success. Titanium is now the standardintra-oral tooth root/bone implant material with biocompatible interfacerelationships that confer potential osseointegration. Titanium produces aTiO Since Wnditions and formnditions,5.Subsenditions.Ti-6Al-nditions. Also, tnditions.in vivo animaltesting with extreme loads produced defects lateral to osseointegration between boneand metal implant [Recent technology moreover supported through aerospace/aeronauticaldevelopment with epoxy/carbon-fiber-reinforced composites has demonstratedfar-reaching osseointegration increases when compared to Ti-6Al-4V alloy in animalresearch . The bis implant ,18. Conv implant  PMCs wit implant ,5 than t implant  forimpr implant ,5,17 and implant  to suppo2 that preventsfurther oxidation [2 surface layer protects titanium undernormal biologic conditions to regenerate if removed by reactive corrosionequilibrium products as passivation barrier formation and confers high corrosionresistance [2 biomaterials generally corrode less than 20 \u03bcm/year[2 asTi4+ and O2\u2212 with even numbers as the mostcommon oxidation states [3(PO4)2, from divalentCa2+ and O2\u2212 [Corrosion is a diffusion interfacial electron-transfer process that occurs onthe surface of metals. Titanium reacts with oxygen electrochemically rapidly in thepresence of water to form a fine oxide layer of TiOxidation ,20, Equasistance ,21.Titasistance ,22. In tn states are cons and O2\u2212 . (1)Ti+O+) and electrons(e\u2212), Still, all metal implants are not perfectly passive in a hostile corrosivebiological environment to have some solubility and are subject to metal dissolutionwith the formation of metal cations 6(OH)2 produces a roughenedsurface texture that increases surface area to improve osseointegration boneattachment [3(PO4)2 to 97% crystalline[2 surface with a thicker layer [2 surfacethickness increases with increasing process temperatures that increases surfaceroughness, surface energy [Titanium oxide surface layer forms instantly to a depth of 5\u201310 nm,22 in abtachment ,49. The tachment . Commercer layer .Defectser layer .Accordier layer ,50 that e energy  while reOsseointegration and antimicrobial properties are repeatedly hard torealize with titanium/titanium alloy implants , probablinvivo using an animal model, p< 10\u22128. At 0.8 mm distance PBA increased from 10.5\u00b1 5.3 with the metal alloy to 41.6 \u00b1 13.9 with the PMC,p < 10\u22124 [In comparison to a new bisphenol-epoxy/carbon fiber-reinforced compositeimplant material, titanium alloy Ti-6Al-4V produces significantly less boneforming near the implant with much lower levels of osseointegration contact in abone-marrow animal implant model . After tTypical histology ground sections for the epoxy carbon fiber PMC andtitanium-6Al-4V alloy as average Histomorphometry PBA measurements are presentedin Osseointegration for the experimental epoxy carbon fiber PMC was broadalong the length of the implant with structural pore-bearing organization foroxygen and nutrient accessibility. Conversely, titanium-6Al-4V alloyosseointegration was rare and nonstructured, The extent of bone formation for the epoxy/carbon fiber PMC is presentedwith a horizontal section to better appreciate the exuberant extent of boneformation inside the bone marrow that is normally not seen physiologically,Normal difficult-to-see X-rays show how bone grows through the bonemarrow space alongside the epoxy/carbon fiber PMC implant where bone does notusually grow, A photograph provides evidence of the strong osteogenic response for theepoxy/carbon fiber implant with bone growing above the outer cortical bone ontothe PMC surfaces, 2+ andHPO42\u2212 mineralization due to organic bonematrix formation [Bisphenol-epoxy/carbon-fiber PMC provides biocompatibility with biologicfunction through both the polymer matrix and fiber reinforcement . Epoxy iormation .Also, eormation ,54. Bispormation  and decrormation . In termormation  and indormation ,56.For a biologic comparison, the cell membrane that comes in contact witha foreign implant material is composed of lipids, proteins and carbohydrates all of win vivo bone marrow implant testing through separatedifferent mechanisms [Carbon fibers also appear to stimulate strong cell recruitment duringthe extensive bone formation with the bisphenol epoxy implant PMC. Carbon fibersdemonstrated extensive biocompatibility with bone as evidenced from thechanisms .Carbon chanisms  that shochanisms . Carbon chanisms ,53. As aCarbon fibers not only stimulate osteoid bone matrix formation, Because normal low oxygen concentrations in bone marrow further produceacids during mitochondrial energy synthesis, epoxy polymer is softened andpulled away from the implant by bone attached with carbon fibers, 2 surface oxide layer.By measure of bisphenol epoxy polymer degradation with depth of boneosseointegration into the carbon-fiber PMC, a defect in the implant surface canapparently reduce oxygen concentrations more than elsewhere to lower the pH. Theosteocyte bone-forming cell involved tunnels into small spaces to extendcytoplasmic processes that secrete degrading enzymes and bone matrix proteins asosteoid . PotentiCarbon fibers are electrically conductive ,14and wElectrical properties of cells have been studied most extensively at theplasma cell membrane level with a voltage potential of approximate \u221280mV but can range from about \u221250 mV to \u221290 mV where theintracellular fluid is more negative with respect to the more positiveextracellular biologic fluid . The plaIn terms of potential problems arising without proper electrondistribution, higher-than-normal electron concentrations can enter intofree-radical crosslinking reactions to produce structured molecules. The mol2 surface provides the special property for implantosseointegration with bone even at an extremely small thickness down in a rangefrom 5\u201310 nm to 100\u2013200 nm [A safer semiconducting biomaterial surface will provide a morephysiologic interface for better biocompatible faster electron transferinteraction with vulnerable nanocircuits of susceptible cell membranes. As a we0\u2013200 nm . Resisti0\u2013200 nm . CorrespPMCs with carbon fiber reinforcement can supply densities/modulus muchcloser than titanium ,14 to boThermal processing of epoxy PMC thermosets can range from roomtemperature cure up to less than 200 \u00b0C ,53compaResorbable coatings are another feature to consider after the bulkmaterial implant shape is set where thermal process can be controlled carefullyfor temperature sensitive proteins. Highly soluble calcium phosphate is analternative to HA for rapid release during the stabilization phase withbone-to-implant osseointegration during healing. Tissue engineering designprinciples for bone implant osseointegration developed for long-termbulk-material application can then be applied for quick release in an outerresorbable coating to enhance quick implant stabilization with surrounding bone.As examples, low crystalline HA dissolves faster than highly stable crystallineHA to help speed initial bone growth, estrogen can enhance nonpolar lipidmembrane and other organic attraction forces for improved cell recruitment,conductive particles or carbon nanotubes can draw in inflammatory free-radicalswith other excess electrons and antimicrobial/antibiotics can be added tocontrol bacteria introduced during surgical implant insertion.2 osseointegration produces ionicbonds by even oxidation states that act in coordination with the mineralizationphase of bone. PMC osseointegration appears to produce covalent bonds byfree-radical crosslinking with exposed unpaired electrons of the polymer followingacid degradation while organic portions of the bone matrix or bone-cell plasmamembrane condense by covalent bonding onto acid or hydroxyl groups of the oxidizedcarbon fibers. Further mechanical interlocking is achieved with rougher surfaces andwith the PMC by acid degradation polymer removal can occur even with possible bonegrowth surrounding individual 7 \u03bcm diameter carbon fibers. Low pH polymersoftening by acid is considered now to aid in adsorbing excessive stresses by aprotective damping mechanism. Low temperature thermoset polymer cure allows fillersand organic additives to be incorporated by planned design with new tissueengineering for bone implants toward biosuccess. Fillers and additives can beincluded either in the bulk implant material that is polished to reduce microbialattachment colonization or in extremely mild resorbable coatings for rapid releaseto stabilize the initial implant surgical placement. Future research directionsshould examine implications clinically for the robust benefits and also surgicalproblems particularly during possible revision taking into account such strongosseointegration for the bisphenol-epoxy/carbon-fiber implant.Osseointegration bonding occurs by different covalent electron sharing andionic mineralization mechanisms. TiO"}
+{"text": "Multiple studies using various approaches have associated reduced fetal movements (RFM) with stillbirth and small for gestational age infants ,2. More A prospective control study found that 67 out of 303 women (22%) presenting with RFM to St Mary\u2019s Hospital, Manchester, UK had adverse perinatal outcome. Significant predictors of adverse outcome were diastolic blood pressure, estimated weight centile, liquor volume and log[human placental lactogen (hPL)] . Four caCurrent data, based on a large quality improvement study, suggest that mothers should be educated about reporting changes in fetal movements and units should provide standardised care including cardiotocography/non-stress test and ultrasound scan . However"}
+{"text": "Animal research suggests that acute kidney injury (AKI) is an inflammatory condition . Our aimWe enrolled patients with: AKI grade II/III (defined by KDIGO criteria) and systemic inflammatory response syndrome (SIRS) without sepsis; SIRS without AKI; and AKI II/III without SIRS. A healthy control population was used for baseline comparison. Serial blood samples were taken on days 0, 2 and 7. Cells were separated using Percoll gradients and phenotyped using flow cytometry.+++ regulatory T cells, and CD45CD25++ cytokine secreting non-T-regulatory cells (Table The results from 24 day 0 samples identified statistically significant differences between SIRS, AKI, AKI + SIRS and healthy controls amongst: CD8+ cytotoxic T cells, CD45CD25ls Table . The perHuman AKI is associated with a proinflammatory phenotype."}
+{"text": "Salinispora strains provided insight into the diversity and distribution of CRISPR-Cas systems in a cosmopolitan marine actinomycete genus.Prokaryotic CRISPR-Cas systems confer resistance to viral infection and thus mediate bacteria-phage interactions. However, the distribution and functional diversity of CRISPRs among environmental bacteria remains largely unknown. Here, comparative genomics of 75 Salinispora strains, with the majority containing multiple loci and different Cas array subtypes. Of the six subtypes identified, three have not been previously described. A lower prophage frequency in S. arenicola was associated with a higher fraction of spacers matching Salinispora prophages compared to S. tropica, suggesting differing defensive capacities between Salinispora species. The occurrence of related prophages in strains from distant locations, as well as spacers matching those prophages inserted throughout spacer arrays, indicate recurring encounters with widely distributed phages over time. Linkages of CRISPR features with Salinispora microdiversity pointed to subclade-specific contacts with mobile genetic elements (MGEs). This included lineage-specific spacer deletions or insertions, which may reflect weak selective pressures to maintain immunity or distinct temporal interactions with MGEs, respectively. Biogeographic patterns in spacer and prophage distributions support the concept that Salinispora spp. encounter localized MGEs. Moreover, the presence of spacers matching housekeeping genes suggests that CRISPRs may have functions outside of viral defense.CRISPRs were found in all Salinispora suggests that CRISPR-mediated interactions with MGEs represent a major force in the ecology and evolution of this cosmopolitan marine actinomycete genus.This study provides a comprehensive examination of CRISPR-Cas systems in a broadly distributed group of environmental bacteria. The ubiquity and diversity of CRISPRs in The online version of this article (doi:10.1186/1471-2164-15-936) contains supplementary material, which is available to authorized users. CRISPRs  have been detected in approximately 85% of archaeal and 50% of bacterial genomes . They arActinobacteria and cas3 [KJ677987-KJ678124] have been deposited at GenBank  with MAFFT [e 0.123)  and manung MEGA5 . Maximumng MEGA5 , always Streptomyces SV1 phage were compared with the sequenced SV1 type phage (GenBank accession number NC_018848) using the CGView Comparison Tool [Prophages were predicted using PHAST  on both son Tool . Nucleotson Tool  and the son Tool . The alison Tool . A maximhttp://geneious.com). In addition, short-query BLAST was used to determine spacers matching Salinispora prophages as well as self-targeting spacers matching non-CRISPR regions. Furthermore, short-query BLAST against Salinispora prophages was done with spacers from five representative strains from each species that were sorted by Cas-associated, Cas-devoid, associated with known Cas array subtypes , and associated with herein designated Cas array subtypes (I-U). Only perfect matches with 100% identity over the entire spacer length were considered. A separate BLAST search against Aclame was performed which also considered incomplete hits (100% sequence identity over at least 18\u00a0nt), as this may still be indicative of the targeted MGE type. The 18\u00a0nt threshold corresponds to 2/3 of the average Salinispora repeat length, which has been suggested as the minimum for a functioning spacer [Spacers were extracted from genome sequences and sorted by unique  and shared (found in \u22652 genomes). Spacers were searched against different databases  with the standard BLAST parameters for short query sequences  using Geneious Pro v5.5 (available from p\u2009<\u20090.05) the Wilcoxon rank-sum test implemented in R [p\u2009<\u20090.05). The fraction of spacers matching Salinispora prophages in strains with and without prophages was compared using Student\u2019s t-test. Correlations between the number of CRISPRs/spacers/Cas arrays and prophages were calculated using least squares regression.The number of CRISPR loci, prophages and MGE genes per strain were normalized by genome size and gene count, respectively. Values were compared by species, location, and biome (both between and within species) as well as phylotype (only within species) using the Kruskal-Wallis one-way analysis of variance implemented in R  to test ted in R  was usedAll supporting data are included within the article and its additional files.Overview of genome and CRISPR features of 75Salinisporastrains. Origin  and general genome characteristics , CRISPR content , number of prophages, and MGE content of 75 Salinispora strains analyzed in the present study. (XLSX 32 KB)Additional file 1:Phylogeny ofcasgenes and Cas proteins. Maximum likelihood phylogenies of aligned cas1/cas3 nucleotide as well as Cas1/Cas3 amino acid sequences (1000 bootstrap replicates with only those >50 shown). Species names abbreviated  followed by strain number, Cas array subtype, and internal CRISPR locus ID. (PNG 5 MB)Additional file 2:Detected prophages. Prophages detected in the 75 Salinispora genomes, classified based on sequence similarities with known prophages [Additional file 3:rophages , length Salinisporaspecies phylogeny. Maximum likelihood phylogeny (1000 bootstrap replicates) of ten single-copy, concatenated housekeeping genes from 75 Salinispora genomes labeled with origin and phylotype . A detailed description can be found in the original publication [Additional file 4:lication .  compared to subclade 2 (strains CNH-964 and CNP-105). Blue: CRISPRs, yellow: cas genes, green: integrases; pink: tRNAs. (PNG 138 KB)Additional file 5:Salinispora casgene accession numbers. GenBank accession numbers of Salinispora cas1 and cas3 sequences used for phylogenetic analyses. (XLSX 16 KB)Additional file 6:SV1 prophage phylogeny. Maximum likelihood phylogeny (1000 bootstrap replicates) of conserved regions within SV1-related prophages in Salinispora genomes. (PNG 274 KB)Additional file 7:"}
+{"text": "While overall toxicity seems to be moderate, liver toxicities have been reported and are not completely understood. Based on the observation that CD11b-/- CD40and -/-gp91. Mouse and human tumor-induced myeloid suppressive cells were cultured with CD40 agonists to address changes in their immune function.100 mg agonistic CD40 antibody (FGK-45) or isotype control IgG was injected into na\u00efve and tumor-bearing mice. Liver enzymes, histologies and immune infiltrates were analyzed 24 hours after antibody administration. The effect of CD40 agonist was evaluated using bone marrow chimeras and genetically modified mouse strains + immune cells. Anti-CD40 ligation-dependent liver damage was induced by the generation of reactive oxygen species. Furthermore, agonistic CD40 antibody resulted in increased CD80 and CD40 positive liver CD11b+ Gr-1+ immature myeloid cells. CD40 ligation on tumor-induced hepatic myeloid cells or CD14+ HLA-DRlow/neg PBMC from cancer patients reduced their immune suppressor function.Agonistic CD40 antibody caused liver damage into tumor-bearing mice in two unrelated tumor models and mice strains. Using bone marrow chimeras we could demonstrate that anti-CD40 induced hepatitis in tumor-bearing mice was dependent on the presence of CD40Collectively, agonistic CD40 antibody activates the tumor-induced liver myeloid suppressive compartment, enhancing acute inflammation and thus liver damage. Our data in murine and human myeloid suppressive cells point towards a pivotal role for CD40 as a key molecule in modulating myeloid suppressive cell plasticity."}
+{"text": "Homing of iv-infused stem cells to diseased tissues may be critical for cell therapies and is frequently an obstacle to successful cell therapy. We have previously shown that molecular responses from the mechanotransduction effects of pulsed focused ultrasound (pFUS) in normal murine skeletal muscle generate a \u201cmolecular zip-code\u201d consisting of local increases in chemoattractants  that induced MSC homing, potentially improving cellular therapies for regenerative medicine. This study investigated whether pFUS could also enhance MSC homing to dystrophic skeletal muscle in a muscular dystrophy (MD) mouse model. Stem cell therapies for MD are promising, but have been hampered by poor cell homing and the need for direct injections that are invasive and ultimately, impractical clinically. Since molecular signals drive cell homing following iv injection, drugs used to treat MD could potentially interfere with pFUS-enhanced homing and undermine cell therapies for MD.MDX mice (9 weeks) received unilateral pFUS  to hamstrings. Some mice were pretreated with ibuprofen  or saline 15min pre-pFUS. Mice were iv injected with 106 human MSC 3hr post-pFUS. Hamstrings were harvested 24hr post-injection, MSC were detected by immunofluorescence and compared to untreated contralateral hamstrings Fig .Minimal MSC homing was observed to skeletal muscle in MDX mice, but pFUS treatment enhanced MSC homing by ~15 fold (p<0.001) Fig . Numerou"}
+{"text": "Initial data from a Phase I/II study in patients with recently diagnosed metastatic RCC (NCT01525017) demonstrated that intratumoral administration of a cell based allogeneic vaccine adjuvant before nephrectomy was associated with a prominent intratumoral infiltration of CD8+ T cells in a majority of patients and a trend towards prolonged survival was noted Long-term survival as well as data on tumor response after subsequent TKI treatment has been studied.Median overall survival (mOS) for MSKCC intermediate risk patients (n = 5) or high risk patients (n = 6) is still not reached but is currently (08JUL2015) 29.0 and 26.0 months, respectively. Three out of 6 patients who to date have received subsequent treatment with TKIs have experienced an objective tumor response. One sunitinib-responding patient (high risk), exhibited an extensive sarcomatoid transformation of the resected primary tumor. Another patient (high risk) who developed 4 brain metastases 4 months after vaccination responded with a complete disappearance of all 4 brain lesions and is still free from CNS-lesions 21 months after initiation of sunitinib. Both patients exhibited a strong/massive intratumoral infiltration of CD8+ T cells in their removed kidney tumor.The current mOS (26.0 months) in high-risk patients has by far surpassed reported mOS of 9.0 months in comparable high-risk patients with recently diagnosed mRCC receiving upfront mono-therapy with sunitinib before nephrectomy. The objective tumor responses seen in two high risk patients after addition of sunitinib is surprising since historical data indicate that brain metastases as well as extensive sarcomatoid transformation are higly resistant to sunitinib treatment. Our findings indicate that intratumoral administration of an off-the-shelf vaccine adjuvant consisting of activated allogeneic DCs induces a CTL-mediated anti-tumor response that may prolong survival in mRCC-patients. Data on patients who have received additional treatment with sunitinib (known to deplete myeloid-derived suppressor cells) indicate a synergistic anti-tumoral effect. A multi-centre Phase II study (NCT02432846) has recently been initiated."}
+{"text": "EuroSIDA has previously reported a poorer clinical prognosis for HIV-positive individuals in Eastern Europe (EE) as compared with patients from other parts of Europe, not solely explained by differences in patient characteristics. We explored regional variability in self-reported HIV management at individual EuroSIDA clinics, with a goal of identifying opportunities to reduce the apparent inequalities in health.www.chip.dk/eurosida/csurvey) on HIV management was conducted in early 2014 in all currently active EuroSIDA clinics. Responders in EE were compared with clinics in all other EuroSIDA regions combined (non-EE). Characteristics were compared between regions using Fishers exact test.A survey . Significantly fewer EE clinics performed resistance tests before ART as well as upon treatment failure (p<0.0001), whereas most non-EE clinics followed EACS guidelines . The majority of EE clinics and \u00bc non-EE clinics indicated deferral of ART initiation in asymptomatic individuals until CD4 \u2264350 cells/mm3 . Participating clinics reported seeing a total of 133,532 patients [a median of 1300 per clinic (IQR 700\u20132399)]. The majority of clinics requested viral load and CD4 measurements at least every six months for patients on as well as off ART (EE 66.7%, non-EE 75%,  failure . Half ofells/mm3 . There wells/mm3 . Screeniells/mm3 .We found significant regional variability in self-reported HIV management across Europe, with less resistance testing, screening for CVD and substance use in EE. EE clinics indicated deferral of ART initiation for longer than non-EE clinics. Adherence to international guidelines for cervical cancer screening was poor in both regions. Whether differences in HIV management are reflected in clinical outcomes deserves further investigation."}
+{"text": "Currently, no investigations reliably identify placental dysfunction in late pregnancy. To facilitate the development of such investigations we aimed to identify placental features that differ between normal and adverse outcome in late pregnancy in a group of pregnancies with reduced fetal movement.ex vivo was measured. Placental function was then assessed in terms of (i) chorionic plate artery agonist responses and length-tension characteristics using wire myography and (ii) production and release of placentally derived hormones (by quantitative polymerase chain reaction and enzyme linked immunosorbant assay of villous tissue and explant conditioned culture medium).Following third trimester presentation with reduced fetal movement (N = 100), placental structure 2 vs. normal outcome 13 (12\u201315), p = 0.002). Adverse outcome pregnancy placental arteries were relatively insensitive to nitric oxide donated by sodium nitroprusside compared to normal outcome pregnancy placental arteries (50% Effective Concentration 30 (19\u201350) nM vs. 12 (6\u201324), p = 0.02). Adverse outcome pregnancy placental tissue contained less human chorionic gonadotrophin (20 (11\u201350) vs. 55 (24\u2013102) mIU/mg, p = 0.007) and human placental lactogen (11 (6\u201314) vs. 27 (9\u201350) mg/mg, p = 0.006) and released more soluble fms-like tyrosine kinase-1 (21 (13\u201329) vs. 5 (2\u201315) ng/mg, p = 0.01) compared with normal outcome pregnancy placental tissue.Placentas from pregnancies ending in adverse outcome (N = 23) were ~25% smaller in weight, volume, length, width and disc area  compared with those from normal outcome pregnancies. Villous and trophoblast areas were unchanged, but villous vascularity was reduced (median (interquartile range): adverse outcome 10 (10\u201312) vessels/mmThese data provide a description of the placental phenotype of adverse outcome in late pregnancy. Antenatal tests that accurately reflect elements of this phenotype may improve its prediction. Resting vessel diameters were measured at 0.9 of L5.1kPa according to the method previously described by Mills et al. , adapted2 mimetic U46619  and the nitric oxide donor sodium nitroprusside (SNP: 10-10M \u2013 10-4M). Constriction responses were expressed as the maximal pressure generated , the concentration of U46619 at which vessel segments achieved 50% of their maximal response  and the area under the concentration-response curve . Relaxation responses were similarly expressed as Vmax , EC50 and AUC. Arterial length-tension characteristics were determined according to the protocol described by Wareing et al.  under conditions of 6% Oven days .mirVana miRNA isolation kit followed by removal of genomic DNA using a TURBO DNA-free kit . Nucleic acid concentration and contamination were assessed by spectroscopy using the NanoDrop 2000C . Reverse transcription (RT) was performed in triplicate using an AffinityScript Multi-temperature RT kit  in an MX3000 thermocycler . Real time quantitative polymerase chain reaction (qPCR) was then performed on RT triplicates using primers specific to TATA-box binding protein (-\u0394Ct). Triplicates with a coefficient of variance (CoV) <25% were pooled for further qPCR analysis. Subsequently qPCR was performed according to the same protocol, on pooled triplicates using primers for genes encoding TATA-box binding protein, YWHAZ, RPL13A, human chorionic gonadotrophin (hCG), human placental lactogen (hPL), placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) along with CYP11A1  according to the recommendations of Vandesompele et al. [RNA was extracted from fresh villous tissue using a  protein  and Brilynthesis )  (discarded after the first 24h of culture then collected daily) were quantified in duplicate using commercially available colorimetric enzyme-linked immunosorbant assay (ELISA) kits . The optBased on previous observations of placental arterial function, trophoblast area and villous vascularity in FGR , 44, 45 Participants (N = 100) were recruited between January 2012 and May 2014. Twenty-three pregnancies were classified as adverse outcome with the most frequent adverse outcome category being SGA , consequently the median IBC is lower in the adverse versus normal outcome pregnancies. No stillbirths or neonatal deaths occurred amongst the study population. Demographic and pregnancy outcome data are shown in th and 3rd centiles respectively, compared with 36/77 (46.8%) and 17/77 (22.1%) of normal pregnancy outcome placentas (p\u22640.0002). Villous area and trophoblast areas were not significantly different between adverse (N = 11) and normal pregnancy outcome (N = 23) placentas (Placentas from RFM adverse outcome pregnancies (N = 23) were significantly smaller in terms of length, width, volume, weight and area compared with their normal outcome counterparts\u2019 placentas (N = 77) . There wlacentas . A reduclacentas .ex vivo placental arterial function were SGA, of whom four had an IBC<5. CPA resting diameters were well matched between adverse and normal pregnancy outcome placentas (Adverse pregnancy outcome 365 (240\u2013436) vs. normal pregnancy outcome 288 (190\u2013411) \u03bcm). Constriction to U46619 by CPAs from adverse pregnancy outcome placentas was not significantly different from those from normal pregnancy outcome placentas (max (7 (5\u20139) vs. 10 (7\u201313), p = 0.063), and EC50 (49 (33\u201390) vs. 46 (32\u201366)). However, CPAs from adverse pregnancy outcome placentas demonstrated impaired relaxation to nitric oxide donation by SNP in terms of AUC (adverse pregnancy outcome 543 (457\u2013595) vs. normal pregnancy outcome 441 (310\u2013530), p = 0.024), Vmax (87 (57\u201398) vs. 54 (37\u201376) %, p = 0.047) and EC50 (30 (19\u201350) vs. 12 (6\u201324) nM, p = 0.02) compared with those from normal pregnancy outcome placentas  vs. normal pregnancy outcome 1/20 (5.0%), p = 0.002). Eight (88.9%) adverse outcome pregnancies examined for lacentas : AUC . No differences were observed in the relative rates of mRNA transcription for the five genes of interest between adverse (N = 14) and normal pregnancy outcome (N = 21) placentas . HoweverThe data reported here support our hypothesis that there is an altered placental phenotype in pregnancies reporting RFM when there is an adverse pregnancy outcome versus those with RFM and a normal pregnancy outcome. In pregnancies complicated by RFM after 28 weeks gestation, placentas from pregnancies ending in adverse outcome are lighter, smaller and less vascularised and also display aberrant vascular and endocrine function compared to normal outcome RFM pregnancies. These structural and functional changes might reduce transplacental transfer of nutrients and oxygen to the fetus, impairing the ability of the placenta to support the optimal growth and development of the fetus, thereby putting the infant at increased risk of perinatal mortality and morbidity. Alternatively, they may confound the relationship between an alternative causal pathology and adverse pregnancy outcome. In any case, such changes merit exploration as they could form the basis of future tests of placental health to assist the identification of the \u201cat-risk\u201d fetus, for example by measurement of placental size and vascularity by placental ultrasound, or examination of placental endocrine function by assessment of placental hormone concentrations in the maternal circulation.The principal reason for pregnancies in this study to be classified as adverse pregnancy outcome was being SGA at birth ; this is in excess of the rate in unselected populations (~11% ) and in 2; these women are a subpopulation with an increased risk of stillbirth [Conversely, the vascular function profile observed in adverse pregnancy outcome placentas contrasts with that described in studies of FGR (commonly defined for research purposes as IBC <5) which demonstrated an increased sensitivity to U46619  and alteillbirth . Interesillbirth . Separatillbirth . With reillbirth , 28. Thiillbirth . Criticaillbirth . Thus, tDisruption of placental endocrine function was evident by altered production and release of several placental hormones in adverse pregnancy outcome placentas. Reduced hPL protein content per unit of placental tissue described in this study mirrors the reduction in maternal serum hPL concentrations in adverse outcome pregnancies , 55\u201360 ain utero assessment . Technologies under development, such as magnetic resonance imaging may in the future allow assessment of placental oxygen and nutrient transfer or metabolism [The major strengths of our study are the detailed, matched structural and functional characterisation of placental samples with short delivery to collection interval to reduce storage artefact . Additiotabolism \u201375 whichtabolism , but theth centile even amongst \u201cnormal\u201d outcome RFM pregnancies in the cohort (46.8%). Secondly, PlGF and sFlt-1 were measured separately using commercially available ELISA kits, and not by bedside measurement techniques  that might more readily be employed in clinical practice. Although there is a good correlation between PlGF measurements by these techniques [in vivo vascular phenotype; whole placental cotyledon perfusion studies may assist this in the future. Finally, the external validity of these placental findings, outside the context of RFM, may be questioned. However, when compared to The current study has a number of limitations. Outcomes were defined on the basis of a composite primarily influenced by birth weight (the end result of intrauterine growth) and not growth itself, although each component of the adverse pregnancy outcome definition is related to increased perinatal mortality \u201378 and ichniques , it cannin utero during late pregnancy with enough accuracy to detect subtle changes in placental physiology and anatomy. This remains outwith the remit of the current study. Only once reliable, sensitive tests of placental structure and function are developed can we hope to significantly reduce placentally related stillbirth rates.A previous Cochrane review found insufficient evidence to recommend or refute routine measurement of either biochemical  or vascuS1 Tablee = Eurofins Genomics, Ebersberg, Germany. I = Invitrogen, Paisley, UK. TBP = TATA-box binding protein , hCG = human chorionic Gonadotrophin, hPL = human placental lactogen, CYP11A1 = gene encoding CYP450scc (key synthetic enzyme of progesterone), PlGF = placental growth factor, sFlt-1 = soluble fms-like tyrosine kinase-1.Key: (DOCX)Click here for additional data file.S2 TableKey: hCG = human chorionic gonadotrophin, hPL = human placental lactogen, PlGF = placental growth factor, sFlt-1 = soluble fms-like tyrosine kinase-1, DRG = DRG International, Springfield, USA, R&D = R&D Systems, Abingdon, UK, CoV = coefficient of variance.(DOCX)Click here for additional data file."}
+{"text": "Quantitative assessment of myocardial blood flow (MBF) from cardiovascular magnetic resonance (CMR) perfusion images appears to offer advantages over qualitative assessment. Currently however, clinical translation is lacking, at least in part due to considerable disparity in quantification methodology. The aim of this study was to evaluate the effect of common methodological differences in CMR voxel-wise measurement of MBF, using position emission tomography (PET) as external validation.Eighteen subjects, including 9 with significant coronary artery disease (CAD) and 9 healthy volunteers prospectively underwent perfusion CMR imaging using a saturation recovery gradient echo sequence acquired at basal, mid and apical left ventricular short-axis levels during adenosine vasodilator stress and at rest, using 0.05 mmol/kg gadolinium-DTPA. Comparison was made between MBF quantified using: 1. Calculated contrast agent concentration curves  versus raw signal intensity curves; 2. Mid-ventricular versus basal-ventricular short-axis arterial input function (AIF) extraction; 3. Three different deconvolution approaches; Fermi function parameterization, truncated singular value decomposition (TSVD) and first-order Tikhonov regularization with a b-spline representation of the impulse response function. CAD patients also prospectively underwent rubidium-82 positron emission tomography  and MBF measurements made using PET and CMR were compared.MBF was significantly higher when calculated using signal intensity curves compared to contrast agent concentration curves, and when the AIF was extracted from mid-ventricular compared to basal-ventricular images. MBF did not differ significantly between Fermi and Tikhonov, or between Fermi and TVSD deconvolution methods although there was a small difference between TSVD and Tikhonov (0.0 6 mL/min/g). Agreement between all deconvolution methods was high. MBF derived using each CMR deconvolution method showed a significant linear relationship (p < 0.001) with PET-derived MBF however each method underestimated MBF compared to PET (by 0.19 to 0.35 mL/min/g).Variations in more complex methodological factors such as method of deconvolution have no greater effect on estimated MBF than simple factors such as AIF location and observer variability. Standardization of the quantification process will aid comparison between studies and may help CMR MBF quantification enter clinical use.CAM is supported by a Fellowship from the National Institute for Health Research, UK (NIHR-DRF-2010-03-98)."}
+{"text": "We hypothesized that cardiac MRI (CMR) is accurate in measuring transvalvular flow volume and anatomic orifice area (AOA) in normal and obstructed BMVs in an in vitro heart chamber under 3 flow conditions  at rate of 70 beats/min. All constructs were evaluated by phase-contrast (PC) CMR; the reference standards for comparison were continuous wave Doppler imaging, and standard flowmetry.Four sizes of normal BMVs  and 4 stenotic BMVs  were evaluated in a pulsatile 2) and obstructed valves (mean EOA=0.96 cm2). Anatomic orifice area (AOA) correlated well with Doppler effective orifice area (EOA) ; AOA was larger than EOA as expected (mean difference was 0.68 cm2). Furthermore, peak velocity by phase contrast CMR correlated strongly with Doppler peak velocity . Bland-Altman analysis revealed a 95% confidence interval of -44.4 to 19.36 cm/sec.CMR methods accurately measured transvalvular flow and correlated strongly with flow transducer measurements . Bland-Altman analysis demonstrated a 95% confidence interval from -9.5 to 8.6 ml/beat across the range of both normal (mean EOA=1.82 cmPC-CMR methods accurately assess bioprosthetic transvalvular flow, peak velocity and orifice area. The CMR methods described hold promise in evaluating bioprosthetic mitral valve function in cardiac MRI studies, particularly when Doppler methods are unobtainable or discordant.American Heart Association grant #11BGIA5840008."}
+{"text": "For the ninth year running, NAR and Oxford Journals have provided sponsorship and awarded travel bursaries and prizes to students in recognition of their outstanding achievements. This year, sponsorship and prizes were given at 13 different meetings. A list of the awards is presented below. Our warm congratulations go to the prize winners.Travel SponsorshipIS3NA XXI: International Round Table on Nucleosides, Nucleotides and Nucleic Acids (IRT2014)Poznan, Poland24\u201328 August 2014Poster PrizesCRISPR 2014Berlin, Germany14\u201316 May 2014Alexander Hynes Adaptation in CRISPR-Cas immunity is driven by defective phage16th Symposium on Chemistry of Nucleic Acid ComponentsCesky Krumlov, Czech Republic08\u201313 June 2014Dieter Buyst Towards DNA based esterases: uncovering Hoogsteen face regulation of the pKaH of a tethered imidazole functionality by NMR and molecular dynamicsNon-coding RNA \u2013 From Basic Mechanisms to CancerHeidelberg, Germany22\u201325 June 2014Debojyoti Chakraborty Systematic dissection of long non-coding RNAs involved in the regulation of embryonic stem cell pluripotency2014 FASEB \u201cMachines on Genes\u201d meetingSnowmass, CO, USA22\u201327 June 2014Erich Chapman Xrn1-resistant RNA structures: Wrenches in a machine.James Nunez Cas1-Cas2 complex formation mediates spacer acquisition during CRISPR-Cas adaptive immunity.Aline Simon The yeast Ctf4 trimer acts as a protein hub at the replication fork: characterization of its interaction with the helicase/nuclease Dna2.th Nucleic Acids Research Forum10London, UK4 July 2014Anne Plochowietz Characterization of single-molecule FRET in living bacteria using protected DNA FRET standardsFASEB Science Research Conference - Post-transcriptional control of gene expression: Mechanisms of mRNA decayBig Sky, MT, USA6\u201311 July 2014Florian Ebner Myeloid tristetraprolin deteriorates host defense upon invasive infection by compromising neutrophil functionAnne-Laure L\u00e9crivain Mechanistic and evolutionary aspects of tracrRNA:crRNA maturation in the type II CRISPR-Cas systemISMB 2014Boston, MA, USA13\u201315 July 2014Alex Salazar Mycobacterium tuberculosisInvestigating large sequence variants in drug resistant Sarah Keasey The road to linking genomics and proteomics of pathogenic bacteria: from binary protein complexes to interaction pathwaysFEBS/EMBOParis, France30 August\u20134 September 2014Isabel Cruz Gallardo The binding of TIA-1 to RNA C-rich sequences is driven by its pH dependent C-terinal RRM domainSumith Kumar H. pylori strain 26695Characterization of a novel phase variable type IIS restriction endonuclease from 1st biennial Latin America Student Council Symposium (LA-SCS)Belo Horizonte, Brazil7 October 27 2014Raony Guimar\u00e3es Corr\u00eaa Do Carmo Lisboa Cardenas Mendel,MD: a user-friendly online program for clinical exome analysisRicardo Z. N. V\u00eancio Sifter-T: a scalable framework for phylogenomic probabilistic protein domain functional annotationJavier C\u00e1ceres Rational discovery of new capsaicin analogues as TRPV1 activatorsRNA Biochemistry Meeting & Workshop: RNA ModificationBonn, Germany9\u201312 October 2014Juliane SchwartzAnalysis of the translational landscape in stem cells and derived neuronsMarco Preu\u00dfner Circadian alternative splicing of U2af26OTS Annual MeetingSan Diego, CA12\u201315 October 2014Roya Kalantari Building an interaction network of nuclear Argonaute 2Takanori Shimo Evaluation of exon skipping activity by locked nucleic acid-based splice-switching oligonucleotides in vitroJanne Turunen Splice-switching oligonucleotides for inhibiting proinflammatory interleukin-6 signalingDaniel Lazar Aptamer-siRNA conjugates target HIV-1 infected T cells for transcriptional gene silencingPost-Genome Kazan, Russia29 October\u20131 November 2014Nickolay Alexandrovich Kulemin Methods of medical human genomes annotationEvgenia Temlyakova"}
+{"text": "Every year, 500.000 mothers die from pregnancy-related complications, and 99% of these deaths occur in low- and middle-income countries . These mTo identify risk factors affecting maternal outcome among women with Hemolysis, Elevated Liver Enzymes, and Low Platelets (HELLP) syndrome who required transfer for critical care.All 77 women with HELLP syndrome who sought care for delivery and postpartum assessment at the emergency department, and who were treated in our intensive care unit between January 2007 and July 2012 were identified, retrospectively. Findings were analyzed according to surviving and non-surviving patients.p < 0.0001), levels of serum aspartate aminotransferase (p < 0.0001), serum alanine aminotransferase (p < 0.0001), lactate dehydrogenase (p < 0.0001), and bilirubin (p = 0.040) and lower platelet count (p = 0.005).Maternal mortality rate was 14% and perinatal death occurred in 24 of 81 fetuses and newborn (30%). The most common cause of maternal complications was disseminated intravascular coagulation in 22 patients (29%), acute renal failure in 19 patients (25%), and postpartum hemorrhage in 16 patients (21%). Compared with surviving women, non-surviving women had higher mean values for international normalized ratio (The patients with HELLP syndrome should be treated in intensive care unit, especially after cesarean delivery. Disseminated intravascular coagulation is major risk factor affecting maternal outcome."}
+{"text": "The identified six major genomic regions harboring six robust QTLs (11.5\u201321.3 PVE), associated with plant height, were mapped within <0.5\u2009cM average marker intervals on six chromosomes. Five SNPs-containing genes tightly linked to the five plant height QTLs, were validated based upon their high potential for target trait association (12.9\u201320.8 PVE) in 65 desi and kabuli chickpea accessions. The vegetative tissue-specific expression, including higher differential up-regulation (>5-fold) of five genes especially in shoot, young leaf, shoot apical meristem of tall mapping parental accession (ICC8261) as compared to that of dwarf/semi-dwarf parent (ICC12299) was apparent. Overall, combining high-resolution QTL mapping with genetic association analysis and differential expression profiling, delineated natural allelic variants in five candidate genes  regulating plant height in chickpea. These molecular tags have potential to dissect complex plant height trait and accelerate marker-assisted genetic enhancement for developing cultivars with desirable plant height ideotypes in chickpea.In the present study, molecular mapping of high-resolution plant height QTLs was performed by integrating 3625  Plant height is a vital yield-component trait. It affects crop\u2019s performance, particularly lodging and subsequently grain yield and grain quality113Cicer arietinum L.) belonging to family Fabaceae, is a self-pollinated and diploid legume crop species with a genome size of ~740\u2009Mb5desi and kabuli have been sequenced78desi and kabuli) and wild accessions as well as NGS-/array-based large-scale discovery and high-throughput genotyping of informative microsatellite and SNP (single nucleotide polymorphism) markers in natural and mapping populations of chickpea1011121314151617121920212223242526272829303132333426343637Chickpea  in chickpea.ApeKI libraries constructed from 275 RIL mapping individuals and parents (ICC 12299 x ICC 8261) using the reference desi genome-based GBS assay discovered 26785 high-quality SNPs differentiating the two parental accessions ] in parental accessions and 275 RIL mapping individuals was observed across two years based on ANOVA. The coefficient of variation (CV) of PH trait was measured as 9.8%. A bi-directional transgressive segregation, including normal frequency distribution of PH trait in the generated RIL mapping population was evident  QTLs  governing PH, which were mapped on six LGs (except LG5 and LG6) of chickpea (bZIP) transcription factor] and one intergenic SNP tightly linked to the QTLs controlling PH trait in chickpea (A significant difference (p\u2009\u2264\u20090.001) of PH trait [ranging 30.6\u201361.3\u2009cm with mean\u2009\u00b1\u2009standard deviation (SD) of 48.8\u2009\u00b1\u20094.8 and 82% H evident . For molchickpea . The prochickpea , Fig. 2Bchickpea , Fig. 2Bdesi and kabuli chickpea accessions (2) of 65 accessions (\u22125 to 2.1\u2009\u00d7\u200910\u22126 P with 12.9 to 20.8% R2) with PH trait in chickpea (bZIP transcription factor) validated both by high-resolution QTL and association mapping, were considered as candidates for plant height regulation in chickpea. Interestingly, two upstream regulatory (URR) and intronic SNPs (A/G and A/C)-containing cytochrome c biosynthesis protein-coding gene and bZIP transcription factor gene, respectively, tightly linked to the PH QTLs (qPH1.1 and qPH7.1) exhibited strong association (average 20% PVE) with plant height based on QTL mapping and trait association analysis in chickpea.For genetic association mapping, the SNPs (flanking/linked to PH QTLs) mapped at the six major PH QTL regions of an ultra-high density intra-specific genetic linkage map were genotyped in 65 cessions . The SNPcessions . The asschickpea . These Pchickpea . HencefobZIP transcription factor tightly linked to the PH QTLs (qPH1.1 and qPH7.1) exhibited pronounced up-regulation (>6\u20137 folds) in shoots, young leaves and shoot apical meristems of tall parental accession (ICC 8261) as compared to that of dwarf/semi-dwarf parent (ICC 12299)  were utilized in expression analysis. The differential expression profiles of these genes in diverse vegetative and reproductive tissues  of tall (ICC 8261) and dwarf/semi-dwarf (ICC 12299) parental accessions of an intra-specific mapping population (ICC 12299 x ICC 8261) were determined . This reC 12299) . TherefoC 12299) .The implication of GBS-assay in simultaneous genome-wide mining and high-throughput genotyping of high-quality and non-erroneous SNPs in diverse advanced generation intra- and inter-specific mapping populations for construction of ultra-high resolution genetic linkage maps have been demonstrated in chickpea2636142226293536375960The use of ultra-high density intra-specific genetic linkage map generated in our study as a reference identified and mapped six major genomic regions underlying six robust QTLs (11.5\u201321.3% PVE with 35.8% combined PVE) governing PH traits in chickpea. To ascertain the robustness and novelty of the identified PH QTLs, the major genomic regions underlying six robust PH QTLs were compared/correlated with that of previous QTL mapping studies based on correspondence of physical positions of SNPs covering (flanked/linked) the target QTL intervals3726282935363737bZIP transcription factor gene regulates plant morphology by modulating the endogenous contents of gibberellins (GAs) and GA homeostasis. Interestingly, the reduction of GAs by down-regulation of genes  encoding GA biosynthetic enzymes severely inhibit the process of cell elongation/expansion and growth of stem internodes resulting in dwarf phenotype in multiple monocot and dicot plant species. Such GA response modulators, including green revolution genes- Rht (reduced height), d8 (dwarf 8), GAI (gibberellin insensitive) and Sd1 (semi-dwarf) governing GA signaling as well as plant height (dwarfism) have been identified and functionally characterized in wheat, maize, Arabidopsis and rice, respectively3470bZIP transcription factors basing upon their similar expression characteristics in diverse tissues/developmental stages of crop plants is well deciphered. This indicates the involvement of these genes in an analogous functional regulatory pathway underlying both GA biosynthesis and mitochondrial respiration for maintaining growth and development of organs, including plant height72Interestingly, the integration of high-resolution QTL and association mapping validated informative SNPs-carrying five candidate genes harboring five major PH QTLs reflecting the robustness and reliability of identified molecular tags for their immense deployment in marker-assisted genetic improvement of chickpea. The efficacy of these genes in regulating PH trait was further ascertained by their vegetative tissue-specific expression and pronounced up-regulation in tall than that of dwarf/semi-dwarf mapping parental accessions. The added-advantage of such integrated genomics-assisted breeding strategy for delineation of potential candidate genes regulating important yield-contributing traits have been demonstrated in chickpea2324252631323335626364656664667 RIL mapping population (ICC 12299 x ICC 8261) consisting of 275 individuals was generated using a single seed descent method. The mapping parents ICC 12299 and ICC 8261 are dwarf/semi-dwarf and tall desi and kabuli chickpea (C. arietinum) accessions with plant height of 43 and 60\u2009cm, respectively. These RIL mapping individuals along with parental accessions were grown in the field  for two consecutive years (2012\u20132013) at two diverse geographical locations of India. Subsequently, the RILs and parents were phenotyped individually for plant height (PH). The PH was documented by measuring the mean canopy height (cm) of 10 representative plants (selected from each RILs) from soil surface at the time of their flower ending/pod setting initiation stage. The diverse statistical parameters, including broad-sense heritability (H2%), mean, standard deviation, coefficient of variation (CV%), frequency distribution and analysis of variance (ANOVA) of PH trait in a RIL mapping population were determined using SPSS v17.0 and following Saxena et al.et al.An intra-specific Fet al.et al.25http://www.ncbi.nlm.nih.gov/sra) with accession number under BioProject PRJNA320682. The raw FASTA 100-bp single end sequence reads were processed for quality assessment, and subsequently high-quality sequences were filtered and mapped onto the reference genome using TASSEL 5.0 GBS Pipeline v2. The sequence reads with \u226510 phred Q-score across first 72-bp nucleotide sequence were considered high-quality, which were further ascertained through FASTQC v0.10.1. The retained good-quality sequences were de-multiplexed using unique barcodes tagged with each mapping parents and RIL individuals. The high-quality de-multiplexed reads of each mapping parents and RIL individuals were mapped against desi chickpea genomeet al.25The genomic DNA isolated from 275 RIL mapping individuals and two parental accessions  was used to construct the 288-plex (3\u2009\u00d7\u200996-plex) GBS libraries as per Elshire desi genome-based high-quality GBS-SNPs revealing polymorphism between parental accessions (ICC 12299 and ICC 8261) and 275 RIL mapping individuals were analyzed using JoinMap 4.1 . The identified QTLs that validated across multiple environments (locations)/years were considered as \u2018robust QTLs\u2019 governing PH traitdesi and kabuli chickpea accessions  with PH trait at a significant cut-off P\u2009\u2264\u200910\u22125 were selected. This was performed by eliminating the confounding effect of population structure and implementing the Bonferroni correction of P-value (based on multiple comparisons) for each PH-associated SNPs at the false discovery rate (FDR) of 5% significance.The SNPs (flanking/linked to PH QTLs) exhibiting differentiation between dwarf (ICC 12299) and tall (ICC 8261)-PH types parental accessions, mapped at the major QTL intervals, were genotyped in 65 et al.The high PH-associated genes with SNPs delineated at the major genomic regions harboring robust PH QTLs  were selected to determine their regulation by differential expression profiling. The RNA isolated from diverse vegetative and reproductive tissues  of tall (ICC 8261) and dwarf/semi-dwarf (ICC 12299) parental accessions was amplified using the gene-specific primers through quantitative RT-PCR assay ."}
+{"text": "Pseudomonas sp. LFM046 is a medium-chain-length polyhydroxyalkanoate (PHAMCL) producer capable of using various carbon sources  and was first isolated from sugarcane cultivation soil in Brazil. The genome sequence was found to be 5.97\u00a0Mb long with a G+C content of 66%. Pseudomonas sp. LFM046 was isolated from sugarcane soil in Brazil as a polyhydroxyalkanoate (PHAMCL) producer  and quantified using Qubit 2.0 fluorometer . We obtained 550-bp DNA fragments using Covaris S2 , subsequently visualized on agarose gel electrophoresis, and quantified using a Qubit 2.0 fluorometer. A paired-end sequencing library was constructed using a True Seq DNA PCR Free LT sample preparation kit . Library insert size was verified using a 2100 Bioanalyzer  and quantified by real-time PCR (qPCR) using a library quantification kit for the Illumina genome analyzer . The sequencing library was prepared according to the manufacturer\u2019s protocols and sequenced on an Illumina MiSeq sequencer .https://usegalaxy.org/). De novo genome assembly was performed using Velvet Assembly ; methylglyoxal metabolism (43 genes); pyruvate metabolism II: acetyl-CoA, acetogenesis from pyruvate (37 genes); pyruvate-alanine-serine interconversions (16 genes); glyoxylate bypass (8 genes); glycolysis and gluconeogenesis (13 genes); Entner-Doudoroff pathway (16 genes); dehydrogenase complexes (15 genes); TCA cycle (18 genes); pyruvate metabolism I: anaplerotic reactions, PEP (12 genes); pentose phosphate pathway (10 genes); and glycolate-glyoxylate interconversions (8 genes).A total of 3,700,436 reads (forward and reverse) were generated, decreasing to 3,032,982 reads after quality control using Galaxy software (MCL biosynthesis from plant oils and carbohydrates, respectively. Thirty-six genes from \u03b2-oxidation and 46 from fatty acids biosynthesis were identified. The fine prediction and annotation of genes involved in PHAMCL biosynthesis, carbohydrates, and fatty acid catabolism are in progress to build up a genomic scale metabolic network. To improve PHAMCL production and evaluate the potential of the strain to generate new biotechnological compounds, in silico experiments considering the resulting network are being conducted.The presence of genes from \u03b2-oxidation and biosynthesis of fatty acids were also investigated since they contribute precursors to PHAPseudomonas sp. LFM046 were deposited in the DDBJ/EMBL/GenBank database under the accession number JYKO00000000. The version described in this paper is the first version, JYKO01000000.The contig sequences generated from the whole-genome sequence of"}
+{"text": "Nanobodies: site-specific labeling for super-resolution imaging, rapid epitope-mapping and native protein complex isolation. Published December 3, 2015An error was identified in Figure 6d (bottom right panel). The image of XL177 cells stained with the Alexa Fluor 647 maleimide-labeled anti-Nup93 nanobody mistakenly duplicated the neighbouring Nup98 image. The error occurred during figure assembly in Adobe Illustrator.The corrected Figure 6 is shown here:The originally published Figure 6 is also shown for reference:The article has been corrected accordingly."}
+{"text": "Despite recent advances in resuscitation medicine, survival rates to discharge following out-of-hospital cardiac arrest (OHCA) remain poor. Recent data support the implementation of early critical care interventions including therapeutic hypothermia (TH) and immediate percutaneous coronary intervention (PCI). We describe a pre-hospital service where early delivery of critical care interventions and the capacity to transfer these unstable patients directly to a cardiac intervention centre is available through the deployment of a specialist physician response unit (PRU).Prospective data were gathered on all cases of OHCA attended by the PRU, transferred to a single interventional cardiology centre. Data included patient demographics, clinical characteristics, clinical interventions at the scene and at hospital, and clinical outcome.th July 2013 and 19th August 2013, data were obtained on 28 patients, with a mean age of 59 (range 29-85). Twenty-three were male (82%). Presenting rhythms were ventricular fibrillation (VF) 68%, asystole 14%, pulseless electrical activity 11% and ventricular tachycardia (VT) 7%. There were return of spontaneous circulation (ROSC) at scene in 89%. PRU interventions included advanced airway management 90%, rapid sequence induction 71%, early TH 89%, mechanical load distributing band CPR device was used in 82% and mechanical resuscitation during transfer 14%.Between 14Survival data were as follows: Overall survival to cardiac intensive care (CICU) was 56%, with overall survival to discharge 48%. Of those patients (17) who underwent emergency angiography, 76% survived to CICU, with 64% surviving to discharge. Of patients presenting in VF, 62% survived to discharge. Interestingly, 72% of patients who received TH survived to discharge. All patients who underwent successful PCI survived to discharge with good neurological outcomes.In selected cases, outcomes following OHCA can be optimized by integrating a physician-led cardiac arrest service enabling urgent delivery of patients to a cardiac arrest centre, with the early application of neuro-protective strategies, circulatory support and interventional cardiology techniques."}
+{"text": "There is an ongoing debate on the merit of whole-heart 3D CMR perfusion imaging in terms of improving the overall diagnostic accuracy of myocardial perfusion CMR . Whole-hA total of n = 995 patients n = 504 males) with suspected CAD underwent Tc-99-Sestamibi rest/stress MPS, n = 650 of which had correlative angiography within 60 days and the remainder n = 345 patients where considered low likelihood (< 5% based on Diamond and Forrester criteria) [ males wiFigure The diagnostic performance of whole-heart TPD is significantly superior to the 3-slice model of TPD with moderate correlation between the TPD scores. Despite technical differences between the CMR and MPS modalities, these results show added value of whole heart perfusion imaging and provide motivation for pursuing 3D whole-heart perfusion CMR techniques.Grant sponsors: National Institutes of Health grants nos. NHLBI R01HL089765, R01HL38698. American Heart Association Postdoctoral Fellowship Award 11POST7390063."}
+{"text": "Escherichia coli (STEC) O26:H11 is one of the most frequent pathogens associated with diarrhea and hemolytic-uremic syndrome (HUS). In this report, we present the draft genome sequences of seven strains of STEC O26:H11 carrying the stx2aor stx2d gene only and isolated in France from HUS patients.Shiga toxin-producing  Escherichia coli (STEC) isolates, serotype O26:H11 is the second most frequently associated with severe human diseases worldwide, after O157:H7  patients. Although most of the strains appeared to correspond to this new clone, 12 of them exhibited significantly different characteristics.In a previous study , we analstx gene subtype, and virulence gene profile.In order to investigate more thoroughly the genetic relationship between the different clones, we sequenced seven of these strains covering the different combination observed between sequence types (ST), de novo assembly , producing 192 to 223 contigs (N50 between 65 kbp and 114 kbp (http://www.ncbi.nlm.nih.gov/genomes/static/Pipeline.html.Genomic DNA was extracted from an overnight culture in tryptic soy broth (TSB) medium using the DNeasy blood and tissue kit (Qiagen), with an additional RNase A (Roche) treatment. Libraries were prepared using the Nextera XT kit (Illumina). Whole-genome sequencing was performed using an Illumina MiSeq platform (Illumina), according to the manufacturer\u2019s instructions. Two MiSeq runs were carried out, one with paired-end 150-nucleotide (nt) reads on MiSeq V2 microchemistry and another with paired-end 300-nt reads on V3 chemistry. The raw reads were trimmed  and assembled in CLC Genomics Workbench 7.5.1 by  contigs . The med 114 kbp . The seqstx genes confirmed the previously identified subtypes (The average size of the genomes in this study is 5.47\u00a0Mb, with 5.23 Mb being the smallest genome size (isolate 36084, subtypes .A detailed report on further analyses of the draft genome sequences will be released in a future publication.LDXB00000000 to LDXG00000000 and LDXI00000000 (The annotated draft whole-genome sequences of these O26:H11 strains were deposited in DDBJ/ENA/GenBank under the accession numbers 00000000 . The ver"}
+{"text": "Changes in myocardial strain have been shown to precede onset of systolic dysfunction in patients with cardiomyopathy. Traditionally performed with echocardiography, acoustic windows can limit strain evaluation. Preliminary work has shown good agreement between myocardial strain derived from deformation field analysis at balanced steady-state free-precession (bSSFP) cine MRI and speckle tracking echocardiography. The application of a novel prototype iterative SENSE reconstruction with L1 regularization (IR-SENSE) to highly accelerated segmented bSSFP cine acquisitions can maintain or improve the effective temporal resolution with a shorter breath-hold. The purpose of this study is to evaluate left- and right-ventricular stain analysis from bSSFP cine acquisitions using conventional GRAPPA and highly accelerated T-PAT with IR-SENSE. We hypothesize that myocardial strain parameters derived from accelerated T-PAT cine acquisitions with IR-SENSE are similar to those obtained using conventional segmented bSSFP with comparable effective temporal resolutions.9 healthy volunteers  underwent imaging at 1.5 T . The following 5 pulse sequences were acquired in the short axis and 4-chamber orientations: GRAPPA factor 2 standard bSSFP cine with 5 and 14 views per segment (Seg NIR), and T-PAT factor 4 bSSFP cine with 2, 8, and 14 views per segment reconstructed using a prototype IR-SENSE algorithm (Seg IR) (Table All T-PAT 4 cine bSSFP acquisitions were successfully reconstructed using the IR-SENSE algorithm. Average and peak systolic strains by region and sequence are shown in Table This preliminary study demonstrates that myocardial strains derived from deformation field analysis on highly accelerated bSSFP cine acquisitions with IR-SENSE are similar to strains derived from conventionally reconstructed segmented bSSFP cine sequences with similar effective temporal resolutions.None."}
+{"text": "Of these, 22,542 SNPs were structurally annotated in different coding and non-coding sequence components of genes. Genes with 3296 non-synonymous and 269 regulatory SNPs could functionally differentiate accessions based on their contrasting agronomic traits. A high experimental validation success rate (92%) and reproducibility (100%) along with strong sensitivity (93\u201396%) and specificity (99%) of GBS-based SNPs was observed. This infers the robustness of GBS as a high-throughput assay for rapid large-scale mining and genotyping of genome-wide SNPs in chickpea with sub-optimal use of resources. With 23,798 genome-wide SNPs, a relatively high intra-specific polymorphic potential (49.5%) and broader molecular diversity (13\u201389%)/functional allelic diversity (18\u201377%) was apparent among 93 chickpea accessions, suggesting their tremendous applicability in rapid selection of desirable diverse accessions/inter-specific hybrids in chickpea crossbred varietal improvement program. The genome-wide SNPs revealed complex admixed domestication pattern, extensive LD estimates (0.54\u20130.68) and extended LD decay (400\u2013500 kb) in a structured population inclusive of 93 accessions. These findings reflect the utility of our identified SNPs for subsequent genome-wide association study (GWAS) and selective sweep-based domestication trait dissection analysis to identify potential genomic loci (gene-associated targets) specifically regulating important complex quantitative agronomic traits in chickpea. The numerous informative genome-wide SNPs, natural allelic diversity-led domestication pattern, and LD-based information generated in our study have got multidimensional applicability with respect to chickpea genomics-assisted breeding.The genome-wide discovery and high-throughput genotyping of SNPs in chickpea natural germplasm lines is indispensable to extrapolate their natural allelic diversity, domestication, and linkage disequilibrium (LD) patterns leading to the genetic enhancement of this vital legume crop. We discovered 44,844 high-quality SNPs by sequencing of 93 diverse cultivated  Cicer arietinum L.) is a self-pollinated and diploid (2n = 2x = 16) crop species belonging to Fabaceae  near about 10,000 years ago  and desi  representing diverse gene pools have been successfully sequenced , transcripts, genes and genome sequences of diverse desi, kabuli, and wild accessions using traditional Sanger and high-throughput next-generation sequencing (NGS) approaches  are highly preferred in plant genetic and genome analyses because of their excellent genetic attributes, such as wide genomic distribution, co-dominant inheritance, high reproducibility, and chromosome-specific location Brookes, . For a lWith advent of barcoded multiplexing and restriction enzyme (RE)-based NGS approaches, the simultaneous integration of large-scale discovery, validation and genotyping of SNPs is now possible in numerous diverse crop accessions. These NGS-based methods have evolved plenty of high-throughput and cost-effective SNP genotyping assays and applications for many small diploid and larger polyploid crop genomes. Some of these assays include reduced representation libraries (RRLs)  and also complexity reduction (targeting lower copy number of genome) ability, especially in larger complex plant genomes -based improved NGS method that has gained considerable attention of crop researchers for large-scale discovery and genotyping of SNPs simultaneously in diverse crop germplasm accessions and mapping populations at a genome-wide scale  and wild chickpea accessions at a genome-wide scale. The genotyping information of validated SNPs was further utilized to understand their functional significance and determine the molecular diversity pattern, population genetic structure and LD patterns among chickpea accessions.Keeping that in view, the present study has utilized GBS approach for the first time to discover, validate and genotype SNPs in 93 diverse [with significant seed yield (g) per plant variability] cultivated (C. arietinum desi (39 accessions) and kabuli (53), and one C. reticulatum wild accession (ICC 17160) were utilized /plant] and genotypic diversity  were selected from available chickpea germplasm collections   following the manufacturer's instructions.Ninty-three accessions belonging to 92 cultivated ApeKI and ligated to adapters containing one of 96 unique barcodes to construct 96-plex GBS libraries. These libraries were pooled together  as biological replicates (Supplementary Table http://creskolab.uoregon.edu/stacks) was utilized to examine the quality distribution of each sequence read. The reads with an average quality below 90% confidence  was digested with desi and kabuli genome were processed using reference-based GBS pipeline of STACKS to identify accurate SNPs in 96 accessions. The SNP identification process in pstacks is efficient enough for handling gapped alignments properly to accommodate InDels and soft-masked alignment fragments. This prevents the SNP model from wrongly calling polymorphisms due to InDel frameshifts. Stacks algorithm also filters paralog and high-copy loci by read coverage, assuming random coverage across loci. We removed the putative loci with more than twice the standard diversion of coverage depth to filter out repetitive elements and stacks of paralogs loci. A maximum likelihood statistical model was used in STACKS to identify valid and high-quality SNPs , supported by at least 10 sequence reads. A catalog was built to record all SNP loci identified in 96 accessions by matching each accession to that catalog and detecting accurate alleles (minimum sequence read depth: 10) that are present at every SNP locus in each accession.The sequence alignment map (SAM) files generated from each de novo genotyping approach of STACKS, the sampled SNP loci from each accession were reassembled from the sequenced reads  for creating stacks. A de novo method was employed to group all exactly matching sequences into stacks, forming putative loci from high-confidence unique stacks. To detect polymorphism and infer SNP alleles, each putative locus of one-nucleotide position at a time was examined using a maximum likelihood framework  were used to deduce accurate genomic distribution, including the structural and functional annotation of SNPs (synonymous and non-synonymous SNPs). To determine the genomic distribution of identified SNPs across chickpea chromosomes, the SNPs with synonymous and non-synonymous substitutions were plotted individually based on their unique physical positions (bp) on eight chromosomes (pseudomolecules) of desi and kabuli genomes and visualized using Circos visualization tool  of SNPs identified by reference-based GBS approaches were correlated with the GFF file containing the genome annotation of desi and kabuli genome annotations . The SNP-carrying genes were BLAST searched  against the KOGnitor NCBI database (ftp://ftp.ncbi.nih.gov/pub/COG/KOG) for detailed functional classification. Gene Ontology (GO) enrichment analysis of SNPs-containing genes was performed using BiNGO plugin of Cytoscape V2.6 , the Benjamini and Hochberg false discovery rate correction was employed.The putative functions, including conserved domains in the proteins encoded by SNP-carrying genes were predicted based on available desi and kabuli genomes were compared among accessions and analyzed following the methods of Li et al. .For estimation of Ka (number of non-synonymous substitutions per non-synonymous site)/Ks (number of synonymous substitutions per synonymous site) substitution ratio, the SNP-carrying coding sequences of genes annotated from the reference i et al.  and Devii et al. . To furtin silico SNP database of same accessions according to their nature/types and bp on the desi (ICC 4958) genome  on desi and kabuli genomes, were included in our validation study. For these analyses, the primers designed from 300-bp sequences flanking either side of 214 selected SNPs were PCR amplified using the genomic DNA of 93 chickpea accessions. The amplified PCR products were purified and sequenced. The aligned high-quality sequences were used to detect SNPs among accessions following Kujur et al. (http://www.sequenom.com) following Saxena et al.  was compared/correlated with an available r et al.  and Saxer et al. ,b. Addita et al. ,b. The Shttp://www.maizegenetics.net) to estimate the PIC (polymorphism information content) and for constructing an unrooted neighbor-joining (NJ)-based phylogenetic tree , including LD decay  in each desi and kabuli genomes, the genotyping data of SNPs that were physically mapped on eight chromosomes were analyzed using a command (\u2013r2 \u2212ld-window 99999 \u2212ld-window-r2 0) line interface of PLINK  and following Saxena et al.  with accession number SRX845396 (Release date: 31st March 2015). Using both reference and de novo-based GBS approaches in 96 accessions, 44,844, including 20,439 and 24,405 high-quality SNPs  were identified from desi and kabuli genomes, respectively  used as biological replicates was observed. The transitions were more frequent than the transversions that composed slightly more than a-half  of the identified SNPs  and kabuli (29.7%) chickpea compared to A/C (11.8% in desi) and G/T (12.1% in kabuli) transversions   and minimum (29.8 kb) average marker density, respectively , with SNP submission (SS) accession numbers 974751673\u2013974768048, which will be publicly available in the next NCBI db SNP Build (B142), year 2015 (http://www.ncbi.nlm.nih.gov/SNP/snp_viewTable.cgi?handle=NIPGR).A total of 24,405 SNPs discovered from the y Figure . The refkb Table . A genom Figures , 2B. Thedesi reference genome-based SNPs showed the presence of 9567 SNPs in 4010 genes and 4026 SNPs in the intergenic regions  specifically from desi genome  and ICC 17160 (C. reticulatum) and minimum (0.47) between ICC 7346 (kabuli) and ICC 15512 (kabuli). The Tajima's D estimate further inferred that a higher proportion (95%) of SNP-carrying genes under purifying selection with reduced D = \u22122.48 (D < \u22122) and remaining 5% genes had elevated D > 2.The structural annotation of 13,593 \u221231), followed by biological process  and cellular component   gene was found to be polymorphic between drought tolerant (ICC 4958 and ICCV 93954) and sensitive (ICCV 93954) chickpea accessions  and susceptible (ICC 4951) chickpea accessions  and susceptible (ICC 4951) chickpea accessions. In addition, this non-synonymous SNP revealed polymorphism between salinity tolerant (ICC 4951) and sensitive (ICC 12968) chickpea accessions  compared to that estimated in other genic SNPs (Ka/Ks: 0.84 and Tajima's D: \u22122.48).The functional annotation of 5588 genes with SNPs revealed their maximum correspondence to growth, development and metabolism-related proteins , followed by TFs  and signal transduction proteins , with a minimal correspondence to genes encoding hypothetical proteins   controlling drought tolerance-component root traits in chickpea (Supplementary Tables Ascochyta blight (ar2aQTL) and Fusarium wilt (FW_Q_APR_6_1) resistance QTLs mapped on kabuli chromosomes 2 (2.39 Mb: 31.58\u201333.97 Mb) and 6 (0.1 Mb: 29.47\u201329.57 Mb), respectively were discovered  reference genome-based SNPs (with MAF \u2265 0.05) discovered in 93 accessions were compared and correlated with the available resequencing-based SNP database  of four chickpea accessions . On the basis of congruent physical positions (bp), the correspondence of 8.8% (777 SNPs) of the SNPs present in our GBS data (8776 SNPs) was observed with that of SNPs mined by genome resequencing of the four accessions (Supplementary Table desi) and ICC 17160 (wild) and minimum between ICC 4958 (desi) and ICC 4951 (kabuli)  were found to be common between past genome sequencing and our present GBS data (6244 SNPs)  and MALDI-TOF mass array SNP genotyping (240 SNPs) of 454 selected non-synonymous and regulatory SNP loci discovered by reference genome- and de novo-based GBS approaches  showing polymorphism among 93 diverse desi, kabuli, and wild chickpea accessions had higher PIC , MAF (mean: 0.37), and nucleotide diversity (mean \u03b8\u03c0: 1.30 and mean \u03b8\u03c9: 1.51)  of SNPs revealed polymorphism between cultivated C. arietinum and wild C. reticulatum species. The SNPs detected a higher intra-specific polymorphic potential within 39 desi accessions  compared with that of 53 kabuli accessions   was almost comparable to that of kabuli chromosomes  (Table desi (mean \u03b8\u03c0: 1.33 and \u03b8\u03c9: 1.69) and kabuli chromosomes 4 (1.31 and 1.72).In total, 23,798 SNPs  revealed a wider range of genetic distances, from 0.13 (ICC 7346 and ICC 15512) to 0.89 (ICC 15264 and ICC 17160), with an average of 0.56 (Supplementary Table desi and kabuli accessions within the cultivated (C. arietinum) species varied from 0.12 to 0.76, with a mean of 0.45. A relatively less genetic diversity in 53 cultivated kabuli accessions (mean genetic distance: 0.38) as compared to the 39 desi accessions (0.43) was evident (Supplementary Table kabuli and desi) in accordance with their pedigree relationships and parentage , POP II , and POP III (40 accessions)  (log-likelihood) value (showing the greatest apparent inflection)  was observed between POP I and POP III (0.62), followed between POP II and POP III (0.43) and minimum between POP I and POP II (0.30). The FST-based population differentiation was highest within POP II (0.21), followed within POP III (0.16), whereas it was least within POP I (0.10). All 93 accessions clearly belonged to a structured population with 78% inferred ancestry derived from one of the model-based population and the remaining 22% had admixed ancestry. Admixed ancestry was maximum in POP II (16%), followed by POP III (11%) and minimum in POP I (5%). Highest admixed ancestry was obtained between POP III and POP II (19%) compared to that between POP III and POP I (13%). The admixture was not detected in 9.7% (nine accessions) of chickpea accessions, whereas 37.6% (35) and 47.3% (44) of accessions showed up to 20 and 10% admixed ancestry, respectively.The population genetic structure determination among 93 accessions with genotyping data of genome-wide  96 SSR  and extent of LD decay using all possible pair-combination of genome-wide 3321 and 8592 desi and kabuli SNPs  were calculated among 93 chickpea accessions constituting three populations  and a diversity panel. In the whole population, 64.3% global marker-pairs exhibited significant LD (P < 0.0001), indicating the existence of an extreme LD level in a panel of 93 accessions (Table P < 0.0001) was observed for 65 and 54.8% of the linked and unlinked marker-pairs, respectively (Table desi chromosome 3 (67.3%) and kabuli chromosome 4 (58.4%)  and kabuli  chromosomes are comparable to each other, whereas these parameters for unlinked markers were higher in the chromosomes of desi  than kabuli   was observed in any population up to a 1000 kb physical distance for the desi and kabuli chromosomes  showed a shorter LD decay (~400 kb in desi chromosomes and ~600 kb in kabuli chromosomes) than that of the less diverse populations of POP I (~700 kb in both desi and kabuli chromosomes) and POP II (~750 kb)  and integrating both reference genome- and de novo-based GBS pipelines for genome-wide discovery and genotyping of SNPs in chickpea. By implementing these novel approaches, many  non-erroneous and high-quality SNPs with wider genome coverage were identified in chickpea. In contrast to the conventional TASSEL GBS pipeline (maximum SNP detection limited to 64-bp sequence reads), the use of integrated reference genome (desi and kabuli)\u2013and de novo-based GBS approaches would be of heightened interest for SNP discovery and genotyping. Consequently, our study for the first time identified SNPs in high-quality longer sequence reads  by involving a broader range of filtration tools , thereby enriching the chickpea genome with reduced computational time. The advantages of this integrated GBS approach for discovery and genotyping of SNPs at a genome-wide scale is well-documented in many crop plants, including soybean and rice  through amplicon resequencing and MALDI-TOF mass array SNP genotyping assay based on strong sensitivity (93\u201396%) and specificity (99%) were also apparent. These findings reflect the major strength and reliability of GBS assay in rapid discovery and high-throughput genotyping of accurate SNPs in chickpea genome with sub-optimal use of resources. Henceforth, this highly versatile integrated GBS approach developed in our study could find multidimensional applicability for genome-wide discovery and genotyping of SNPs in small as well as large genome plant species. The identification of a relatively higher frequency of SNPs showing transition substitutions (57%) than transversions is consistent with previous genome-wide SNP discovery studies in crop plants, including chickpea  compared with kabuli chromosomes  could be attributed to the greater (~2.8 times) differences in pseudomolecule assemblies/lengths between desi (124.37 Mb) and kabuli (347.24 Mb) genomes  resulting in sequencing of different regions of genomes between desi and kabuli chickpea  identified from desi and kabuli genomes could prove useful for various marker-based applications of chickpea genetics, genomics, and breeding.The physical mapping of a lesser number of SNPs on eight desi (9567 SNPs in 4010 genes) and kabuli  genomes. Furthermore, the structural and functional annotation of 12,773 SNPs (submitted to NCBI dbSNP) detected in 5588 non-redundant chickpea genes and 3296 non-synonymous and 269 regulatory SNPs in 2225 genes provided a faster mode of selection of functional gene-based SNPs to establish marker-trait linkages and identify a number of genes/QTLs governing qualitative and quantitative agronomic traits in chickpea. The estimated mean ratio of non-synonymous to synonymous SNPs (Ka/Ks: 0.84) in chickpea genes is comparable with that obtained (Ka/Ks < 1) from orthologous chickpea genes/transcripts . The identification of non-synonymous and regulatory SNPs in protein-coding genes,  showing polymorphism between abiotic /biotic (Fusarium wilt) stress tolerant/resistant and sensitive/susceptible accessions, have documented the evolutionary/adaptive advantages of these non-synonymous SNP loci  sequence components of protein-coding genes individually predicted from desi (mean \u03b8\u03c0: 1.20 and \u03b8w: 1.33) and 53 kabuli (\u03b8\u03c0: 0.96 and \u03b8w: 1.07) accessions was comparable to that obtained using genome-wide SNP markers \u2013and inter-specific polymorphic potential and wider genetic diversity /functional molecular diversity  among 93 accessions were identified. They could assist us in selecting desirable diverse accessions/inter-specific hybrids in cross-breeding program (introgression breeding) for chickpea varietal improvement.The intra (49.5% and PIC: 0.38)- and inter (50.5% and 0.40)-specific polymorphic potential detected by 23,798 SNPs among 93 cultivated and wild chickpea accessions was much higher than that estimated previously with SNP markers  was consistent with their expected pedigree relationships and parentage. A significant deviation from accurate population assignment based on pedigree relations was more pronounced in cultivated desi and kabuli accessions belonging to POP II. The geographical origin and adaptive environment, rather than parentage, of these accessions had a greater effect on their assignment to a specific population group. Higher (22%) admixed ancestry among accessions reflected their multiple domestication at archeological sites of south eastern Turkey ~10,000 years ago, followed by a complex breeding history involving inter-crossing/introgression coupled with strong adaptive selection pressure. The inclusion of diverse non-recurrent desi and kabuli germplasm lines as common parental lines in crop improvement breeding program to develop/breed most of the selected chickpea accessions in our study for valuable agronomic traits and higher yield might have influenced their population group assignment and domestication pattern, resulting in numerous admixtures among these accessions  in three populations of 93 accessions and furthermore, across eight desi (0.56) and kabuli (0.52) chromosomes using linked SNP-pairs compared with unlinked SNPs, reflected the direct correlation of LD patterning with the physical linkage of SNPs on chromosomes and the density required to cover genomic regions. The extensive LD estimates and extended chromosomal LD decay (~1000 kb) calculated in three populations of self-pollinated chickpea, were much higher than the cross-pollinated  regulating important agronomic traits in chickpea. Moreover, our studies regarding the molecular diversity, population genetic structure and LD mapping among chickpea accessions (three population groups) using genome-wide SNPs could essentially identify trait-influencing target genomic regions (candidate genes) across chromosomes/genomes that possibly got influenced by strong selection pressure during domestication.A greater LD estimate (mean de novo-based GBS assays. The structurally and functionally annotated SNPs in diverse coding and non-coding sequence components of genes could have potential to be utilized for various large-scale marker-based genotyping applications in chickpea (Supplementary Figure We identified 44,844 non-erroneous SNPs in chickpea at a genome-wide scale using reference genome- and The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The GWAS in a structured population of 93 sequenced accessions detected 15 major genomic loci exhibiting significant association with seed coat color. Five seed color-associated major genomic loci underlying robust QTLs mapped on a high-density intra-specific genetic linkage map were validated by QTL mapping. The integration of association and QTL mapping with gene haplotype-specific LD mapping and transcript profiling identified novel allelic variants (non-synonymous SNPs) and haplotypes in a MATE secondary transporter gene regulating light/yellow brown and beige seed coat color differentiation in chickpea. The down-regulation and decreased transcript expression of beige seed coat color-associated MATE gene haplotype was correlated with reduced proanthocyanidins accumulation in the mature seed coats of beige than light/yellow brown seed colored desi and kabuli accessions for their coloration/pigmentation. This seed color-regulating MATE gene revealed strong purifying selection pressure primarily in LB/YB seed colored desi and wild Cicer reticulatum accessions compared with the BE seed colored kabuli accessions. The functionally relevant molecular tags identified have potential to decipher the complex transcriptional regulatory gene function of seed coat coloration and for understanding the selective sweep-based seed color trait evolutionary pattern in cultivated and wild accessions during chickpea domestication. The genome-wide integrated approach employed will expedite marker-assisted genetic enhancement for developing cultivars with desirable seed coat color types in chickpea.The study identified 9045 high-quality SNPs employing both genome-wide GBS- and candidate gene-based SNP genotyping assays in 172, including 93 cultivated ( Cicer arietinum L.) is the third largest produced food legume crop globally that serves as a vital human dietary source of protein enriched with essential amino acids   underlying the QTLs regulating seed coat color during domestication have established seed color as a common target trait for both domestication and artificial breeding in crop plants  and SSR (simple sequence repeat) marker-based genome-wide association study (GWAS), candidate gene-based association analysis and traditional bi-parental QTL mapping in conjunction with differential gene expression profiling and gene-based molecular haplotyping/LD (linkage disequilibrium) mapping is a widely recognized strategy for dissecting the complex yield and quality component quantitative traits in different crop plants, including chickpea  quantitation assay to identify novel potential genomic loci (genes/gene-associated targets) and alleles/haplotypes regulating seed coat color and understand their haplotype-based evolutionary/domestication patterns in cultivated and wild chickpea.desi (39 accessions) and kabuli (54) chickpea accessions  were selected , C. echinospermum (8), C. judaicum (22), C. bijugum (19), and C. pinnatifidum (15) and one perennial species C. microphyllum were chosen for haplotype-based evolutionary study  individually using Illumina two-lane flow cell of HiSeq2000 NGS (next-generation sequencing) platform following Elshire et al.  for identifying the high-quality SNPs  from 172 accessions  and 1000-bp upstream regulatory regions (URRs) of identified true kabuli chickpea gene orthologs  were targeted to design  the forward and reverse primers with expected amplification product size of 500\u2013700 bp. For mining the gene-based SNPs, primarily 24 desi, kabuli, and wild chickpea accessions were selected randomly from 172 accessions (utilized for genome-wide GBS-based SNP genotyping) (Table http://www.sequenom.com) as per Saxena et al.  Table . The geng) Table . The gena et al. . Accordihttp://www.maizegenetics.net). A 100-kb non-overlapping sliding window approach of TASSEL v5.0 was implemented to estimate the various nucleotide diversity measures  following Xu et al. (To measure the PIC (polymorphism information content) and genetic diversity coefficient  and LD decay  in chromosomes and population of chickpea.A model-based program STRUCTURE v2.3.4 was utilized to determine the population genetic structure among chickpea accessions adopting the methods of Kujur et al. , 2014 an2) of seed coat color were measured using SPSSv17.0 (http://www.spss.com/statistics) as per Kujur et al. (One hundred seventy-two chickpea accessions were grown in the field [following randomized complete block design (RCBD)] during crop growing season for two consecutive years 2011 and 2012) at two diverse geographical locations  of India. The seeds of all accessions were phenotyped and classified/characterized into different seed color types by visual estimation of seed coat/pericarp color of mature seeds (stored no longer than 5 months) representing each accession with at least three replications  and relative kinship matrix (K) data using GLM (Q model)- and MLM (Q+K model)-based approaches of TASSELv5.0 -value for each SNP marker-trait association were compared individually utilizing quantile-quantile plot of GAPIT. According to false discovery rate (FDR cut-off \u2264 0.05)  regions revealing significant association with seed coat color trait variation at highest R2 (degree of SNP marker-trait association) and lowest FDR adjusted P-values (threshold P <1 \u00d7 10\u22126) were identified.The genome-wide and candidate gene-based SNP genotyping information of 93 cultivated 7 RIL mapping population (ICC 12299 \u00d7 ICC 8261) was developed. The chickpea accessions ICC 12299  and ICC 8261 (originated from Turkey) are LB/YB and BE seed coat colored desi and kabuli landraces, respectively. A selected set of 384 SNPs showing polymorphism between mapping parental accessions (ICC 12299 and ICC 8261) and 96 previously reported SSR markers  was measured at significant LOD (logarithm of odds threshold >5.0) to identify and map the major genomic loci underlying robust seed color QTLs in chickpea.For validation of seed color-associated genomic loci through QTL mapping, an intra-specific 190 Fdesi: ICCX810800, desi: ICC 12299, desi: ICCV 10, desi: ICC 4958, desi: ICC 15061, kabuli: ICC 6204, and kabuli: Annigeri) and BE  were selected (Table EF1\u03b1) was utilized as internal control in RT-PCR assay for normalization of expression values across various tissues and developmental stages of accessions and mapping parents/individuals. The significant difference of gene expression in immature and mature seed coats as compared to vegetative leaf tissues and seeds without seed coats (considered as control) of each accessions and mapping parents/individuals was determined and compared among each other to construct a heat map using TIGR MultiExperiment Viewer .To infer differential gene regulatory function, the expression profiling of seed color-associated genes validated by both GWAS/candidate gene-based association analysis and QTL mapping was performed. For expression analysis, 11 contrasting chickpea accessions as well as parental accessions and two homozygous individuals of a RIL mapping population (ICC 12299 \u00d7 ICC 8261) representing two predominant seed coat color types, LB/YB  to screen blue/white colonies. The plasmids isolated from 20 random positive white clones carrying the desired inserts were sequenced in both forward and reverse directions twice on a capillary-based Automated DNA Sequencer  using the BigDye Terminator v3.1 sequencing kit and M13 forward and reverse primers. The trace files were base called separately for all the 10 clones of individual accessions and/primers, checked for quality using phred and then assembled into contigs using phrap. The high-quality sequences generated for the gene were aligned and compared among 172 chickpea accessions using the CLUSTALW multiple sequence alignment tool in MEGA 6.0  of one strong seed color-associated gene  amplified from 172, including 93 cultivated and 79 wild chickpea accessions Table  were cloThe seed coats (~50 mg)  from matured seeds of aforementioned six contrasting chickpea accessions, mapping parents and two homozygous RIL individuals representing LB/YB and BE seed coat color haplotypes were scraped. These seed coat tissues were used for soluble (with 0.2% DMACA) and insoluble (with butanol-HCl) PA extraction and quantification following the methods of Pang et al.  and Liu ApeKI GBS libraries generated on an average of 200.7 million high-quality sequence reads that are evenly distributed (mean: 2.1 million reads per accession) across 172, including 93 cultivated and 79 wild chickpea accessions (Table kabuli reference genome. The sequencing data generated from 93 cultivated (desi and kabuli) and 79 wild chickpea accessions in this study have been submitted to a freely accessible NCBI-short read archive (SRA) database (www.ncbi.nlm.nih.gov/sra) with accession numbers SRX845396 (http://www.ncbi.nlm.nih.gov/gquery/?term=SRX845396) and SRX971856, respectively. In total, 8673 high-quality SNPs  differentiating 172 accessions were discovered using kabuli reference genome-based GBS assay  and Arabidopsis were targeted in our study for genetic association mapping of seed color traits in chickpea. To access the potential of aforesaid known/candidate genes for seed color trait association in chickpea, genetic association mapping was performed by high-throughput genotyping of novel SNP allelic variants mined from diverse sequence components of these genes in 93 cultivated and 79 wild accessions. The PCR amplicon-based sequencing of 28 seed color-related known/candidate kabuli gene (CDS and 1 kb-URRs) orthologs in 24 selected chickpea accessions and further comparison of their high-quality gene amplicon sequences detected numerous coding and non-coding SNP allelic variants. The subsequent large-scale validation and high-throughput genotyping of these mined SNP alleles in 172 cultivated and wild accessions by MALDI-TOF mass array successfully identified 372 genic SNPs (233 coding non-synonymous/synonymous and 139 URR SNPs) with an average frequency of 2.82 SNPs/kb (varied from 1.58 to 3.65 SNPs/kb)  in the seed coat for its coloration/pigmentation have been identified and characterized in kabuli genome, respectively  were mapped on chromosome 8. The structural annotation of 9045 SNPs identified 5903 (65.3%) and 3142 (34.7%) SNPs in the 1859 genes and intergenic regions of kabuli genome  and 79 wild accessions are depicted individually in a Circos circular ideogram  chickpea species was lower as compared to that of inter-specific polymorphism and nucleotide diversity among species  and nucleotide diversity  potential Table . The intes Table .desi, kabuli and wild chickpea accessions exhibited a broader range of genetic distances varying from 0.15 to 0.83 with a mean of 0.52. A lower genetic diversity level (mean genetic distance: 0.32) was observed among 93 desi and kabuli chickpea accessions than that of 79 wild chickpea accessions (0.47). The unrooted neighbor-joining phylogenetic tree construction using 9045 genome-wide and candidate gene-based SNPs depicted a distinct differentiation among 172 cultivated and wild chickpea accessions and further clustered these accessions into two major groups (cultivated and wild) as expected  and wild chickpea accessions is much higher compared to that of earlier similar documentation  demonstrated a higher LD estimate (r2: 0.68) and extended LD decay  approximately at 350\u2013400 kb physical distance in kabuli chromosomes  among 93 accessions belonging to a population was evident. The accessions exclusively exhibiting consistent phenotypic expression of seed coat color across two geographical locations/years (supported by high H2) were utilized for subsequent SNP marker-trait association. The integration of outcomes from four model-based approaches [TASSEL (GLM and MLM) and GAPIT (EMMA and CMLM)] with a quantile-quantile plot of the expected and observed -log10P-values at FDR cut-off \u22640.05 in GWAS and candidate gene-based association analysis identified 15 genomic loci showing significant association with seed coat color at a P \u2264 10\u22126  as well as non-coding intronic (two SNPs) and URR (five) sequence components of 13 kabuli genes  an average of 28% (ranging 20\u201343%) seed coat color phenotypic variation in a population of 93 chickpea accessions. The total phenotypic variation for seed coat color explained by the 15 SNPs was 61%. The significant association of 15 multiple SNP loci in more than one genomic region (genes) with seed coat color gave clues for complex genetic inheritance pattern/regulation of this target quantitative trait in chickpea. This association was evident from high chromosomal and population-specific LD estimates with preferable LD decay of trait-associated linked/unlinked multiple SNP loci and further by the observed genetic heterogeneity of seed color traits across two populations. We observed no significant differences concerning the association potential of SNP loci with seed color in different populations despite diverse genetic architecture of seed coat color traits in two populations and along entire population. Therefore, seed coat color-associated genomic loci (genes) identified by us employing both GWAS and candidate gene-based association mapping could have potential for establishing rapid marker-trait linkages and identifying genes/QTLs regulating seed color in chickpea. Seven (three non-synonymous coding and four URR SNPs) SNP loci in the six different known cloned and candidate seed color genes  had significant association (P: 1.3 \u00d7 10\u22126 to 1.5 \u00d7 10\u22128 with R2: 20\u201335%) with seed coat color trait in chickpea (Table kabuli chromosome 2) exhibiting strong association (P: 1.7 \u00d7 10\u22129 with R2: 43%) with seed color than that of other 14 seed color-associated SNPs was selected as a potential candidate for further analysis. The discovery of non-synonymous and regulatory SNP loci particularly in coding and URRs of known/candidate genes associated with seed color traits signifies their functional relevance in rapid seed color trait-regulatory gene identification and characterization in chickpea. The non-synonymous (amino acid substitutions) and regulatory SNPs in the genes have known to alter their transcriptional regulatory mechanism for controlling diverse traits of agronomic importance, including seed/grain size and weight in rice  and strong purifying selection along with reduced Tajima's D (\u22122.89 to \u22122.63) specifically in LB/YB seed colored cultivated desi chickpea accessions compared with BE seed colored kabuli accessions  was evident  reported earlier at the selective sweep region of ly Table . Interesnt Table . These f2 in this developed mapping population (ICC 12299 \u00d7 ICC 8261) was observed. Two principal seed coat color (BE and LB/YB) groupings; primary (PC1) and secondary (PC2) components accounted for 52 and 48% of the total seed coat color variance, respectively in 190 RIL mapping individuals and parental accessions were evident  by integrating 415, including 382 SNP and 33 previously reported parental polymorphic SSR markers across eight chickpea LGs (LG1 to LG8). This genetic map covered a total map length of 1065.7 cM, with a mean inter-marker distance of 2.57 cM Table . The most Figure . This cokabuli chromosomes (Table 2) varied from 20.1 to 38.7%. The PVE estimated for all five major QTLs was 39.4%. All these QTLs revealed additive gene effects (ranging \u22123.9 to \u22122.5), inferring the effective contribution of ICC 8261 alleles at these loci for BE seed coat color trait. The five SNPs in the genes showing tight linkage with all five major seed color-associated robust QTLs  had high seed color trait association potential based on our GWAS and candidate gene-based association analysis (Table 2: 35.6\u201338.7%) and genetic association analysis (R2: 43%)  genomic regions harboring robust QTLs  controlling seed coat color traits, which were mapped on five es Table . The pheis Table  Table S6es Table  varied fdesi and kabuli chickpea accessions and mapping population under study. These comparative analyses revealed correspondence of one known QTL (CaqSC2.1) regulating seed coat color between past  and our present studies based on congruent flanking [CWSNP 1273 (25.2 cM)-CWSNP1277 (30.2 cM)]/linked marker (CWSNP 1275) physical/genetic positions on chromosome (LG) 2. Henceforth, 14 genomic loci and 4 QTLs regulating seed color identified by us employing high-resolution GWAS/candidate gene-based association and QTL mapping are novel and exhibited population-specific genetic inheritance pattern for seed color trait regulation in chickpea. Further validation of these functionally relevant molecular tags is required in diverse genetic backgrounds and/or through fine mapping/map-based positional cloning prior to their utilization in marker-assisted genetic improvement of chickpea for desirable seed color.To determine the potential and novelty of seed coat color-regulating 15 genomic loci and five major QTLs detected by association and QTL mapping, respectively, the markers linked/flanking the seed color-associated known QTLs/genes  and BE  was amplified with these gene-specific primers using semi-quantitative and quantitative RT-PCR assays  showed seed coat-specific differential  expression [compared with leaves and seeds (without seed coats)] specifically in two seed developmental stages of LB/YB and BE seed colored desi and kabuli accessions  in the mature/immature seed coats of BE seed colored chickpea accessions  as compared to that of mature/immature seed coats of LB/YB seed colored accessions   of this seed coat-specific gene in the mature seed coats of all four BE seed colored chickpea accessions in contrast to immature seed coats of all seven LB/YB seed colored accessions was observed. However, differential down-regulation  of MATE gene in the mature seed coats than the immature seed coats of the accessions within an individual LB/YB and BE seed coat colored group was evident  showing strong association with seed coat color trait exhibited its higher differential down-regulation  Figure . A pronot Figure . The redkabuli gene (Ca18123) were sequenced and compared among 93 cultivated and 79 wild chickpea accessions. These analyses identified four SNPs, including one URR and two coding SNPs as well as one coding SSR in the MATE gene  of the gene with seed coat color trait. Moreover, we observed a significant higher degree of LD (r2 > 0.85 with P < 1.1 \u00d7 10\u22126) resolution across the entire 6843 bp sequenced region of this strong seed color-associated gene 3-G-T-A] affected by one functional non-synonymous coding SNPs (T/G) in the MATE gene had strong association potential for BE and YB/LB seed coat color differentiation, respectively  and kabuli (68.5%) accessions, respectively. A higher down-regulated expression (~5-fold) of BE seed color-specific gene haplotype I was observed in mature seed developmental stages of BE seed colored three contrasting chickpea accessions  as well as mapping parents and homozygous RIL individuals compared with three YB/LB seed colored accessions , mapping parents and homozygous mapping individuals 3-G-T-A] in a MATE gene regulating BE and YB/LB seed coat color differentiation, respectively in kabuli and desi chickpea accessions. The implication of such combinatorial approach for rapid delineation of functionally relevant genes/QTLs controlling diverse agronomic traits, including starch biosynthesis, seed pericarp coloration/pigmentation, seed shattering and seed setting rate in rice as well as seed size/weight and pod number in chickpea have been well understood , the 6843 bp cloned amplicon covering the entire 2 kb URR, 7 exons, 1 kb DRR and 6 intronic regions of MATE secondary transporter e Figure . This ine Figure . The hape Figure . Remarkay Figure . The haps Figure . To corrs Figure , we estis Figure . Collectdesi and kabuli as well as 79 wild accessions representing primary, secondary and tertiary gene pools   seed color-associated haplotype II. A maximum haplotypes sharing of BE seed color-associated haplotype I in cultivated kabuli accessions with YB/LB seed color-associated haplotype II in desi accessions following YB/LB seed color-associated haolotype II between desi and wild C. reticulatum accessions was evident  and Tajima's D estimation  Figure . The wilt Figure . The B/Gon Table  further MATE gene is a homologs of Arabidopsis TT12 (transparent testa 12) and Medicago MATE1 genes encodes a membrane protein of multidrug and toxic compound extrusion (MATE) secondary transporter  biosynthesis into the vacuoles of seed coat endothelial cells in developing immature seeds for their coloration/pigmentation 3-G-T-A]. These results are in agreement with earlier observations on lower accumulation of PAs (soluble/insoluble) in the vacuole endothelial cells of mature seed coat during later stages of seed development and their involvement in differential seed coat/pericarp coloration in crop plants (Abrahams et al., MATE secondary transporter gene is required to decipher its underlying regulatory mechanism, evolutionary cues and biochemical interactions governing diverse seed coat coloration in desi, kabuli and wild accessions during chickpea domestication. Therefore, the strong seed color-regulatory MATE gene once functionally well characterized, can be utilized in marker-assisted seed color breeding for developing varieties with improved seed coat color of consumer preference and trade value in chickpea.The chickpea The reviewer Bharadwaj Chellapilla declares that, despite being affiliated with the same institute and having previously collaborated with the author Shailesh Tripathi, the review process was handled objectively. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The Allergic Rhinitis Clinical Investigator Collaborative (AR-CIC) is a Canadian multi-center initiative with the primary goal of performing standardized nasal allergen challenge (NAC) to study the anti-allergic effects of novel therapeutic agents for allergic rhinitis (AR). The model further allows identification of potential mechanisms of allergic disease and biomarkers. In this study we examined differential counts, more specifically eosinophil numbers, in nasal lavage samples before, 1 hour (1H) and 6 hours (6H) after direct nasal allergen challenge.Thirty-three atopic and five non-atopic participants were enrolled at four study centers. All atopic participants had AR symptoms following exposure to environmental allergens and a supportive skin test response. Using the Pfeiffer Bidose Nasal Delivery Device 100\u03bcl allergen solution was delivered to each nostril. Atopic pilot study participants were challenged with a threshold dose of allergen determined via titration 1 week prior to NAC, non-atopic participants were challenged with a 1:2 allergen dose. The allergens used included either ragweed, grass, D. farina, D. pteronyssinus and cat hair. Nasal lavage samples were collected at baseline, 1H and 6H post NAC. Total cell counts (TCC) were determined on unstained samples prior to cytospin. Cytospin slides were prepared and differentially stained (i.e. DiffQuick).Atopic individuals exhibited eosinophilia at 1H and 6H post NAC when compared to baseline samples. Non-atopic participants did not display a significant increase in eosinophils at any time point. Furthermore, TCCs were increased at 1H post NAC in atopic participants. This trend was not observed in non-atopic samples.Differences were noted in eosinophil numbers (elevated) between baseline, 1H and 6H post direct NAC only in participants with AR. Nasal lavage collection for differential count analysis is a robust assay that can be integrated into clinical trials conducted using the AR-CIC."}
+{"text": "Presenting vaccine antigens in particulate form can improve their immunogenicity by enhancing B cell activation.We describe ferritin-based protein nanoparticles that display multiple copies of native-like HIV-1 envelope glycoprotein trimers (BG505 SOSIP.664). Trimer-bearing nanoparticles were significantly more immunogenic than trimers in both mice and rabbits. Furthermore, rabbits immunized with the trimer-bearing nanoparticles induced significantly higher neutralizing antibody responses against most tier 1A viruses, and higher responses (but not significantly), to several tier 1B viruses and the autologous tier 2 virus than when the same trimers were delivered as soluble proteins.This or other nanoparticle designs may be practical ways to improve the immunogenicity of envelope glycoprotein trimers. Helicobacter pylori ferritin greatly improved NAb responses against influenza in animals [An HIV-1 subunit vaccine should induce a broad and potent neutralizing antibody (NAb) response against the envelope glycoprotein spike (Env) \u20135. These animals , 13.H. Pylori ferritin (GenBank accession no. NP_223316) could potentially present eight BG505 SOSIP.664 trimers. Therefore we fused the ferritin N-terminus, starting from Asp5, to the SOSIP.664 C-terminus, separated by a Gly-Ser-Gly (GSG) linker . More than 70\u00a0% of the particles on the EM grid resembled ferritin cages with protruding spikes that were 30\u201340\u00a0nm in diameter Fig.\u00a0d. When sWe first immunized mice  to compare the antibody response of SOSIP.664-ferritin nanoparticles with soluble  SOSIP.664 trimers. The anti-trimer binding responses were eightfold higher in mice vaccinated with nanoparticle-displayed trimers compared to soluble trimers   by improving the design of native-like trimers such as BG505 SOSIP.664 and/or how they are used as immunogens. If and when this goal is achieved, the superior immunogenicity of a particulate antigen presentation should be valuable."}
+{"text": "Contrast-enhanced abdominal multidetector CT (MDCT) is an important and accurate diagnostic approach for acute abdominal symptoms or searching for an infection focus such as sepsis. But contrast dye can cause renal damage especially in critically ill patients. Noncontrast CT can be alternative options but few studies have shown the effectiveness of noncontrast MDCT. We want to evaluate the effectiveness of noncontrast abdominal MDCT in the emergency department.This is a retrospective chart review study conducted in a single tertiary academic hospital from January 2011 to April 2012. Patients were enrolled if they visited the emergency department with acute abdominal symptoms or infection signs, had elevated serum creatinine level, and received noncontrast 16-channel MDCT.During study period, 78 patients with renal insufficiency received noncontrast abdominal CT. Causes of CT were infection focus , abdominal pain , GI bleeding , abnormal labs , ureter stone  and abdominal distension evaluation . Any abnormal CT findings were detected in 61 (78.2%) patients. For 42 (53.8%) patients, noncontrast CT findings showed diagnostic abnormal findings. For excluding abdominal pathology, 35 (44.9%) were helpful. In one (1.6%) case with hematochezia, noncontrast CT showed no benefit for patient diagnosis. Additional contrast-enhanced CTs were performed in 32 (41%) and additional findings were found in five cases (6.4%). There were 40 patients with severe sepsis or septic shock. Abnormal CT findings were found in 30 (75%) cases. Additional contrast enhanced CT was done for 13 (32.5%) patients but no additional information was detected.Performing noncontrast abdominal MDCT to the patient with renal insufficiency for evaluating acute abdominal symptoms, severe sepsis or septic shock in the emergency department was feasible and effective."}
+{"text": "Both delayed and premature liberation from mechanical ventilation (MV) are associated with increased morbimortality. Positive pressure ventilation exerts beneficial effects in individuals with cardiogenic pulmonary edema; inspiratory fall in intra-thoracic pressure during spontaneous breathing trial (SBT), in its turn, may precipitate cardiac dysfunction through abrupt increase in venous return and in left ventricular afterload.Determine the impact of radiological signs of pulmonary congestion prior to submission to SBT on weaning outcomes in a mixed ICU population.A prospective, observational study in an adult medical-surgical ICU. All enrolled patients met eligibility criteria for weaning from MV. Traqueostomized subjects were excluded. The primary end point was SBT failure, defined as inability to tolerate a T-piece trial during 30 to 120 minutes, in which case patient was not extubated. An attending radiologist applied a radiological score (RS)There was a total of 170 SBTs procedures; SBT failure eventuated in 28 (16.4%). Nineteen patients (11.2%) had systolic heart failure (ejection fraction < 35%), 4 (2.4%) had chronic obstructive pulmonary disease (COPD) and 31 (18.2%) had been intubated due to respiratory sepsis. One hundred thirty-three patients (78.3%) were extubated at first attempt. RS was similar between SBT failure and success subjects , which means only intersticial lung congestion for both groups. Receiver operating characteristic (ROC) curves analysis demonstrated fail accuracy (area under curve [AUC] = 0.58) of CXRs prior to T-piece trial for discrimination between SBT failure and success individuals. There was no correlation between fluid balance in the 48 hours preceding SBT and RS (\u03c1 = -0.13).Radiological findings of pulmonary congestion should not delay SBT indication since they did not predict greater probability of SBT failure in medical-surgical critically ill population."}
+{"text": "Ralstonia solanacearum displays variability in its virulence to solanaceous crops. We report here the draft genome sequences of eight phylotype I strains and one phylotype III strain differing in virulence to the resistant eggplant genotype AG91-25. These data will allow the identification of virulence- and avirulence-related genes. Ralstonia solanacearum, the causal agent of bacterial wilt, is one of the most harmful plant-pathogenic bacteria worldwide (Solanaceae and Musaceae (R. solanacearum species complex (RSSC) is composed of four phylotypes . Among these, the pandemic phylotype I displays population structure (demographic expansion) and genomic features (recombination traces) probably at the origin of its high evolutionary potential   . The strains were sequenced to a depth of ~100\u00d7 using the Illumina HiSeq 2500 technology (150-base paired-end reads with an average insert size of 450\u00a0bp). The reads were quality trimmed using HTQC  before bRalstonia T3E website (https://iant.toulouse.inra.fr/bacteria/annotation/site/prj/T3Ev2/)   for T3E  GMI1000 . Convers GMI1000 . We did The nine genome sequences have been deposited in the European Nucleotide Archive (ENA) under the study accession number PRJEB11298. The genome accession numbers are summarized in"}
+{"text": "OS results from chronically high reactive oxidative species (ROS) formation and reduced antioxidant status. OS plays a key role in CVD development by initiating atherosclerosis ; therefore obese individuals are at increased risk of atherosclerosis development. Increased monocyte ROS generation instigates atherosclerotic plaque formation by increasing the recruitment, binding and transmigration of monocytes across arterial endothelial cells and into the arterial wall. An increased dietary antioxidant intake or up-regulation of endogenous antioxidant enzymes may counteract this OS state and therefore lower CVD risk. Selenium is an essential dietary micronutrient incorporated within the catalytic site of endogenous antioxidant Glutathione Peroxidase (GPx) enzymes, which protect cells from OS and consequent cell damage. There is, however, a lack of knowledge concerning the effect of selenium supplementation in an OS state representative of sedentary overweight/obese individuals. The aim of this work was to investigate the ability of selenium supplementation to modify monocyte cell viability/ROS production under OS.Two thirds of the UK population are either overweight or obese (body mass index (BMI) 25-29.9 and >30 kg/m2SeO3; 100nM or 200nM) or not and cultured for 48 hours at 37\u00b0C. Paraquat (100mM) and S-Nitroso-N-acetyl-DL-penicillamine (10mM) (PQ/SNAP) were added to the cells to induce OS. Cell viability was assessed via MTS -5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay while ROS production was determined by Flow Cytometry using the reagent CM-H2DC-FDA.U937 monocyte cells were supplemented with sodium selenite  and significantly attenuated ROS generation by 32% (p<0.001) when compared to un-supplemented PQ/SNAP treated cells. Additionally, 100nM Na2SeO3 supplementation resulted in a significantly greater increase in cell viability compared to 200nM Na2SeO3 supplementation of PQ/SNAP treated cells (p<0.01).PQ/SNAP treatment significantly reduced U937 cell viability and significantly increased ROS generation compared to untreated control U937 cells (p<0.001); confirming the induction of OS. U937 cells cultured in medium containing either 100nM or 200nM NaThis study indicates that selenium supplementation may be effective in reducing the detrimental effects of OS by significantly improving cell viability and ROS quenching ability; thus providing preliminary data to support the potential role for selenium supplementation with regards to CVD prevention of overweight/obese individuals."}
+{"text": "Haptolina (formerly Chrysochromulina) ericina. CeV-01B and its closest relative Phaeocystis globosa virus define an emerging subclade of the Megaviridae family with smaller genomes and particles than the originally described giant Mimiviridae infecting Acanthamoeba.We report the complete genome sequence of CeV-01B, a large double-stranded DNA virus infecting the unicellular marine phytoplankton  Haptolina (formerly Chrysochromulina) ericina is a phytoplankton species with a worldwide distribution. It most commonly occurs in low numbers but has occasionally been observed to form blooms (Chlorella spp. (\u2013Emiliania huxleyi (Coccolithophyceae) (Phaeocystis globosa (Prymnesiophyceae) (Aureococcus anophagefferens (Pelagophyceae)  , Phaeocyphyceae) , and Aurphyceae) .Haptolina ericina virus CeV-01B was isolated from Norwegian coastal waters in 1998 (k\u00a0=\u00a097). Two scaffolds, with sizes of 67\u00a0kb and 410\u00a0kb were initially obtained. The scaffolder SSPACE , of which 163 (59.5%) were most similar to their PgV homolog and an additional 40 had their closest homologue in other Megaviridae. These best matches in PgV include usual phylogenetic markers such as the DNA polymerase B , the major capsid protein , as well as two enzymes characteristic of Megaviridae: the mismatch DNA repair enzyme MutS7 , using GeneMark , and 12 me MutS7    , progresbfamily) , 13, 21.bfamily)  with PgVHaptolina ericina virus CeV-01B is available in Genbank under accession number KT820662.The completely annotated genomic sequence of"}
+{"text": "Therapeutic vaccination against prostate cancer (CaP) remains marginally effective. A reason for failure may stem from the fact that vaccine cells are usually cultured in ordinary air. Solid tumours including CaP contain regions with oxygen deficiency (hypoxia) secondary to the lack of blood supply to the growing tumour nodules, which may lead to changes in expression of cancer-associated antigens in tumour cells. To test this hypothesis we determined whether oxygen-sensitive CaP-associated antigens in cultured CaP cell lines and human tumour tissues exist.2) and hypoxic (2% O2) environment. At first, we measured release of vascular endothelial growth factor (VEGF) by ELISA and the expression of VEGF-\u03b1 mRNA by RT-PCR. To identify potential CaP-associated antigens, we prepared CaP cell lysates, resolved them by 2D electrophoresis and immunoblotting using spontaneous antibodies from plasma derived from CaP patients and control subjects. Antibody-labelled spots were analysed by MALDI-TOF mass spectrometry. Furthermore, we evaluated the expression of selected candidates in native CaP tissue.LNCaP and VCaP prostate cancer cells were propagated in culture media conditioned by the cells at normoxic (20% O2-sensitive. Level of the two proteins were two times higher in CaP tissue than in control benign prostate tissue (p<0.05).Hypoxic CaP cells released more VEGF (P<0.05) and expressed more mRNA for VEGF-\u03b1 (p<0.001) than normoxic cells. After two days of culture, hypoxic cells expressed some forty fold higher amount of VEGF transcripts compared to normoxic cells. CaP-associated spots identified in this study included heat shock protein 70 (HSP70), HSP60 and heterogeneous nuclear ribonucleoprotein L (hnRNP L). Among them, HSP70 and hnRNP L were O2-sensitive CaP-associated antigens exist in CaP tumour tissues and spontaneous antibodies are detected in plasma derived from CaP patients. Therefore, CaP cells grown at hypoxic condition may provide a better antigen match to tumours in situ and may be more effective vaccines. (Supported by UMMC Incentive (to TMA), DOD PC094680 and PCF Creativity Award (to CRG).A unique set of O"}
+{"text": "MYO5B gene and sequenom iPLEX genotpying of 29 candidate SNPs were performed on a larger set of 33 members of this NSCL/P family (10 affected + 4 obligate carriers + 19 unaffected relatives) to find SNPs significantly associated with NSCL/P trait. SNP vs. NSCL/P association analysis showed the MYO5B SNP rs183559995 GA genotype had an odds ratio of 18.09  compared to the reference GG genotype. Additionally, the following SNPs were also found significantly associated with NSCL/P risk: rs1450425 (LOXHD1), rs6507992 (SKA1), rs78950893 (SMAD7), rs8097060, rs17713847 (SCARNA17), rs6507872 (CTIF), rs8091995 (CTIF), and rs17715416 (MYO5B). We could thus identify mutations in several genes as key candidate SNPs associated with the risk of NSCL/P in this large multi-generation family.Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common congenital birth defects. NSCL/P is a complex multifactorial disease caused by interactions between multiple environmental and genetic factors. However, the causal single nucleotide polymorphism (SNP) signature profile underlying the risk of familial NSCL/P still remains unknown. We previously reported a 5.7-Mb genomic region on chromosome 18q21.1 locus that potentially contributes to autosomal dominant, low-penetrance inheritance of NSCL/P. In the current study, we performed exome sequencing on 12 familial genomes  of a six-generation family to identify candidate SNPs associated with NSCL/P risk. Subsequently, targeted bidirectional DNA re-sequencing of polymerase chain reaction (PCR)-amplified high-risk regions of  IRF6 gene (chromosome 1q32.2)  is one of the most common congenital craniofacial birth defects that accounts for 93\u201395% cases of Cleft Lip with or without Cleft Palate (CL/P) and represents almost half of facial dysmorphology  significantly associated with the risk of NSCL/P. Exome sequencing was done on six affected individuals, two obligate carriers, and four unaffected individuals from the NSCL/P family that identified candidate SNPs including multiple highly significant SNPs within the gene Our results identified SNPs within several genes in the 18q21.1 region as potentially pathogenic variants associated with high risk of NSCL/P in this family.**) beside the pedigree symbols. Red (#) indicates individuals who were exome sequenced. The study was approved by the Institutional Review Board at the University of Minnesota.Familial NSCL/P subjects included in the study are shown in the pedigree provided in Figure n = 33: 10 affected + 4 obligate carriers + 19 unaffected relatives) using DNA-extraction kits, described previously  from the NSCL/P family using Illumina HiSeq with TruSeq Exome Enrichment .High-quality, binary alignment mapping (.bam) files were generated by processing raw reads as described in the PALEOMIX mapping pipeline  genomes from the 1000 Genomes Project were utilized as unaffected controls  and chr18:47365313\u201347365672 (360 bp). Primer designing was done using the PrimerSelect module of DNASTAR Lasergene 11 Core Suite software  and oligos were synthesized at the University of Minnesota Genomics Center (UMGC). Prior to oligo synthesis, the primer sequences were verified using DNA BLAT and In-Silico PCR tools available at the UCSC Genome Browser website (https://genome.ucsc.edu/index.html) to avoid any nonspecific DNA binding. PCR was performed in a 1X PCR buffer using 100 ng of genomic DNA, 10 pmol each of forward and reverse primers, and GoTaq\u00ae Colorless Master Mix . Unincorporated nucleotides and primers were removed prior to sequencing through incubation with shrimp alkaline phosphatase and exonuclease I  for 30 min at 37\u00b0C and inactivation at 80\u00b0C for 15 min. Bi-directional DNA Sequencing was performed with an ABI Prism 3700 automated sequencer  at the UMGC using the PCR primers (forward and reverse) or internal primers (sequence available on request). Sequences were assembled using SeqMan, the Multiple Sequence Alignment module of DNASTAR Lasergene 11 Core Suite software .Primers were designed for PCR amplification of two separate regions within the Table p < 0.05 was used as level of significance.Genotype and allele frequencies were calculated and SNP data was analyzed for association with NSCL/P risk using a combination of the softwares Haploview 4.2 and snpStats using gender as a covariate. SNPStats is a software application that performs genotype-phenotype association analysis based on linear or logistic regression according to the response variable and calculates raw and adjusted odds ratios along with corresponding 95% confidence intervals  as well as GATK  in order to assess consensus between the two callers and to account for possible differences due to arbitrary program parameters. A total of 788,916 high-quality variants were in the intersection between GATK and SAMtools which were prioritized and kept for subsequent analysis. Seven hundred and forty seven variants were within chr18q21.1 region, called by both Broad's GATK (864 variants) and SAMtools (1643 variants). Among these variants, 200 SNPs remained after genotype quality control . This set of variants were computationally annotated by using the human database GRCh37.75 with snpEff/SnpSif  and chr18:47365313+47365672 (contains rs183559995) on the larger subset of all 33 family members from the six-generation family. A total of 71 genetic variants were identified including 9 indels (insertion-deletions) and 15 SNPs already reported in dbSNP database (Table GG vs. GA) of 18.09 . Furthermore, analysis of SNP-SNP interactions showed statistically significant (Wilcoxon p < 0.05) NSCL/P risk due to the combined effects of the mutant genotype of rs183559995 (GA) and mutant genotype of any of the following MYO5B SNPs rs201748833, rs368561623, rs369480218, rs373003146, rs375226833, rs375530149, or rs75335611 (data not shown).To further characterize the MYO5B SNP rs183559995 to the exon/intron junction, we used the web-based splice site prediction software Exonic splicing enhancer (ESE) finder to predict whether the mutant allele disrupts the binding of splice site proteins. ESE finder screens for the potential splice sites and binding affinities for the four main serine/arginine (SR)-rich splicing factors (SRSFs): SF2/ASF, SC35, SRp40, and SRp55, -based measure of significance for multiple hypothesis tests, was performed using Bioconductor's q-value package in R version 3.2.3 (https://cran.r-project.org/)  showed significant risks associated with the mutant genotypes of rs1450425 (LOXHD1), rs6507992 (SKA1), rs78950893 (SMAD7), rs8097060, rs17713847 (SCARNA17), rs6507872 (CTIF), rs8091995 (CTIF), rs183559995 (MYO5B), rs17715416 (MYO5B). The SNP rs78950893 within SMAD7 gene showed the highest association with NSCL/P phenotype. Compared to the reference genotype rs78950893 CC, the mutant genotypes combined (CT+TT) presented an OR of 22.69 . The SKA1 rs6507992 GG genotype displayed a very high OR of 15.41  when compared to the genotypes rs6507992 AA+GA combined. The SNP rs8097060, located within a gene desert in chromosome 18q21.1 and flanked by the genes SKA1 and MAPK4, also showed high risk association. When combined, the genotypes rs8097060 AG and AA had an OR of 11.27  compared to the reference genotype (GG). On the other hand, the LOXHD1 SNP rs1450425 showed an inverse association. Presence of the heterozygous rs1450425 CT genotype had reduced NSCL/P risk compared to the reference rs1450425 CC genotype . Additionally the SNPs rs17713847 (SCARNA17), rs17715416 (MYO5B) and the CTIF SNPs rs6507872 and rs8091995 showed significant association (p < 0.05) with NSCL/P when log-additive models were considered.Table  Storey, . The det Storey,  and resu Storey, , were obIRF6, MSX1, TBX22), growth factors , xenobiotic metabolism genes , and genes involved in immune response (PVRL1), although the results have been conflicting  consisted of 10,555 SNPs equally distributed in the genome, with mean intermarker distances of 250 kb and an average heterozygosity of 0.38. Our genome wide genotyping study identified a 5.7-Mb genomic region on chromosome 18q21.1 spanned by proximal marker rs1824683  and distal marker rs768206  that potentially contains a pathogenic, high-risk variant signature associated with NSCL/P in this family , a myosin family member which is involved in protein trafficking, neuronal morphogenesis, cell signaling, vesicular trafficking, plasma membrane recycling and epithelial polarization. Mutations in the MYO5B gene have been previously implicated in human diseases including microvillus inclusion disease (MVID) in newborns  in MYO5B is a strong candidate genetic risk variant for NSCL/P in this family. Although, rs183559995 is an intronic variant whose function has not been described, predictions using ESEFinder indicate that presence of the mutant allele (A) has the potential to disrupt binding of splicing factors. Further, SNP-SNP interaction analysis showed statistically significant increase in NSCL/P risk due to the combined effects of the presence of rs183559995 (A) along with mutant alleles of these MYO5B SNPs rs201748833, rs368561623, rs369480218, rs373003146, rs375226833, rs375530149, or rs75335611. In addition, we also found another MYO5B SNP, rs17715416 that showed significant association with NSCL/P (gender-adjusted Plog\u2212additive model = 0.0065).Subsequently, targeted re-sequencing of these high-risk MYO5B gene, we used GIANT , a webserver-based system that integrates human genomic data to build functional networks with edges supported by various types of interaction or co-expression evidence  in patients with MVID resulted in global changes in polarity at the villus tips that could lead to a number of complications including aberrant junctions, and losses in transcellular ion transport pathways , which plays a key role in adherens junctions, have previously been associated with cleft lip/palate , rs1450425 (LOXHD1), rs6507992 (SKA1), rs8097060, rs17713847 (SCARNA17), rs6507872 (CTIF), rs8091995 (CTIF), and rs17715416 (MYO5B). Inhibition of SMAD pathway by all-trans retinoic acid (atRA) have previously been implicated in cleft palate. It was shown that atRA-induced inhibition of SMAD pathway played important role in the degradation of the basal laminin within the midline epithelial seam (MES) which might contribute to failure of palatal fusion . In contrast, the heterozygous LOXHD1 rs1450425 CT genotype was found positively associated with NSCL/P risk. LOXHD1 codes for a highly conserved conserved stereociliary protein involved in targeting proteins to the plasma membrane. LOXHD1 mutations have been previously implicated in the genetic etiology of autosomal recessive nonsyndromic hearing loss (ARNSHL)  is a microtubule-binding protein that localizes to spindle microtubule and the outer kinetochore interface during mitosis and is therefore essential for proper chromosome segregation . CBP80/20-dependent translation initiation factor (CTIF) is a component of the CBP80 translation initiation complex that binds cotranscriptionally to the cap end of nascent mRNA, recognizes premature termination codons (PTCs) in mRNAs and directs nonsense-mediated decay (NMD) in PTC-containing mRNAs. SNPs in CTIF have been shown to be associated with hearing function in children  with statistically significant association with NSCL/P risk .Furthermore, we performed genotyping of 29 SNPs included from the 18q21.1 region to identify additional genetic variants associated with NSCL/P risk. The Exome sequencing of this family showed several loci with co-segregating variants associated with NSCP/P. This relatively small cohort of 12 individuals, even when cross referencing variants observed within the 1000 genomes, poses several difficulties. First, the low penetrance of the disease confounds case/control status for several of the individuals within the family (Figure AM designed experimental procedures and conducted experiments, performed data analysis and wrote most of the manuscript. HS contributed to experiment design, sample processing, and manuscript writing. RS, WW, and CM provided technical computation support in Exome sequencing data analysis and manuscript writing. BV and SB supervised all project design.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Volume-controlled ventilation has been suggested during nebulization to optimize lung deposition although promoting spontaneous ventilation is targeted for ventilated patient management. Comparing topographic lung aerosol deposition during volume-controlled and spontaneous ventilation in pressure support has never been performed.The aim of this study was to compare lung deposition of a radiolabeled aerosol generated with a vibrating-mesh nebulizer during invasive mechanical ventilation, using two ventilation modes: pressure support ventilation (PS) and volume-controlled ventilation (VC).\u00ae, Aerogen Ltd., Galway, Ireland) connected to the endotracheal tube. Pulmonary and extrapulmonary particles deposition was analyzed by planar scintigraphy.Seventeen postoperative neurosurgical patients without pulmonary disease volunteered to participate in the study and were randomly ventilated in PS (n = 8) or VC (n = 9) with constant inspiratory flow. Diethylenetriaminepentaacetic acid labelled with technetium-99 m (2 mCi/3 mL) was administered using a vibrating-mesh nebulizer . Higher endotracheal tube and tracheal deposition was observed during PS . a similar aerosol penetration from the inner to the outer region of the right lung (p = 0.347) and the left lung (p = 0.239) was observed.Volume-controlled ventilation improved lung deposition of aerosolized particles as compared to pressure support ventilation. The clinical benefit of this effect warrants further studies."}
+{"text": "Typically, neural oscillations appear in networks presenting some degree of recurrent connections and feedback. Recurrent connections between neurons may promote synchronization. In particular, networks of interconnected inhibitory neurons synchronize and constitute a potent substrate for gamma ~ 40 Hz) oscillations . Also, d0 Hz osci"}
+{"text": "ICC 7184 \u00d7 desi cv. ICC 15061). The QTL-seq-derived major SW QTL (CaqSW1.1) was further validated by single-nucleotide polymorphism (SNP) and simple sequence repeat (SSR) marker-based traditional QTL mapping (47.6% R2 at higher LOD >19). This reflects the reliability and efficacy of QTL-seq as a strategy for rapid genome-wide scanning and fine mapping of major trait regulatory QTLs in chickpea. The use of QTL-seq and classical QTL mapping in combination narrowed down the 1.37 Mb (comprising 177 genes) major SW QTL (CaqSW1.1) region into a 35 kb genomic interval on desi chickpea chromosome 1 containing six genes. One coding SNP (G/A)-carrying constitutive photomorphogenic9 (COP9) signalosome complex subunit 8 (CSN8) gene of these exhibited seed-specific expression, including pronounced differential up-/down-regulation in low and high seed weight mapping parents and homozygous individuals during seed development. The coding SNP mined in this potential seed weight-governing candidate CSN8 gene was found to be present exclusively in all cultivated species/genotypes, but not in any wild species/genotypes of primary, secondary and tertiary gene pools. This indicates the effect of strong artificial and/or natural selection pressure on target SW locus during chickpea domestication. The proposed QTL-seq-driven integrated genome-wide strategy has potential to delineate major candidate gene(s) harbouring a robust trait regulatory QTL rapidly with optimal use of resources. This will further assist us to extrapolate the molecular mechanism underlying complex quantitative traits at a genome-wide scale leading to fast-paced marker-assisted genetic improvement in diverse crop plants, including chickpea.A rapid high-resolution genome-wide strategy for molecular mapping of major QTL(s)/gene(s) regulating important agronomic traits is vital for in-depth dissection of complex quantitative traits and genetic enhancement in chickpea. The present study for the first time employed a NGS-based whole-genome QTL-seq strategy to identify one major genomic region harbouring a robust 100-seed weight QTL using an intra-specific 221 chickpea mapping population ( Most of these yield-contributing (seed size/weight) and stress tolerance traits targeted for chickpea genetic enhancement are complex and quantitative in nature and governed by multiple major and/or minor genes/QTLs (quantitative trait loci). Identification and fine mapping/map-based cloning of genes underlying QTLs controlling important agronomic traits have been established as the most effective approach for quantitative dissection of these complex traits in crop plants, including chickpea. Significant efforts have been made towards identifying the QTLs associated with diverse yield component and abiotic/biotic stress tolerance traits  in chickpea.27 However, only limited number of these QTLs alongside the QTLs regulating seed weight, nodulation, drought tolerance, and Fusarium wilt and Ascochyta blight resistance traits have been fine mapped till date and subsequently utilized for marker-assisted genetic improvement of chickpea.29 To drive the fine mapping of trait-regulating QTLs, the large-scale genotyping of simple sequence repeat (SSR) and prior discovered single-nucleotide polymorphism (SNP) markers in individuals of inter-/intra-specific mapping populations employing multiple high-throughput genotyping assays are found to be fairly suitable in chickpea.24 This includes SSR markers-based genotyping assay like fluorescent dye-labelled automated fragment analyzer and array-based genotyping platforms, including Illumina GoldenGate/Infinium and Competitive Allele Specific PCR (KASPar) assays and MALDI-TOF (matrix-assisted laser desorption ionization-time of flight) mass array for large-scale genotyping of SNP markers. However, in chickpea with low marker genetic polymorphism, these approaches demand huge cost, labour, time and resources for detecting polymorphic markers between the parents of mapping populations and also sample-by-sample low-throughput genotyping of limited number of markers in a larger set of mapping individuals. Interestingly, the fine mapping of trait-associated QTLs has now become simpler and easy to accomplish with advent of a next-generation sequencing (NGS)-based genotyping-by-sequencing (GBS) assay that demonstrated its efficacy by simultaneous discovery and genotyping of SNPs in mapping individuals at a genome-wide scale.41 The need of extensive bioinformatics analysis and suitable computational genomics tools in SNP imputation and scanning of high-quality and non-erroneous SNP genotyping information, particularly from individuals of advanced generation mapping populations could restrain the use of GBS assay for molecular mapping of QTLs in preliminary populations of chickpea. Henceforth, efforts should be made to develop an alternative genome-wide strategy that involves less cost, time and labour for high-resolution QTL identification in chickpea.Chickpea is among the most important food legumes of the world. To meet the dietary protein demand of the fast increasing global population, it is vital to raise the world-wide chickpea production and seed/pod yield potential. The seed size/100-seed weight, one of the most crucial seed and pod yield-contributing trait, has always been a trait of consumer preference and trade, besides an important component of domestication and adaptation in chickpea.42 Quite recently, this strategy when employed in preliminary F2 and advanced generation recombinant inbred line (RIL) mapping populations successfully identified major genes underlying QTLs associated with seedling vigour and blast resistance in rice and flowering time in cucumber.43 The wider applicability and added advantages of QTL-seq over other traditional QTL mapping strategies available in diverse plant species have been truly realized.43 Henceforth, its usage in rapid genome-wide scanning and fine mapping of major genes underlying robust QTLs in a large chickpea genome with narrow genetic base assumes relevance. This could eventually accelerate the genomics-assisted breeding as well as genetic improvement of chickpea with optimal use of resources.In this perspective, a high-throughput genome-wide QTL-seq strategy that employs NGS technology for whole-genome resequencing of two DNA bulks of progeny from a segregating mapping population with extremely contrasting phenotypic trait values seems quite pertinent. Since its inception, this has become the most popular approach for quick identification of high-resolution robust and major QTLs controlling qualitative and quantitative traits in crop plants.desi) F4 mapping population (ICC 7184 \u00d7 ICC 15061) for identifying a major genomic region harbouring the robust QTL associated with 100-seed weight in chickpea. The QTL-seq-derived major seed weight QTL was further validated by SNP and SSR marker-based classical QTL mapping. The integration of QTL-seq and traditional QTL mapping with differential expression profiling delineated a potential candidate gene at the major QTL interval regulating seed weight in chickpea. Mining of novel allelic variants and analysis of natural allelic diversity in this seed weight-associated potential gene across diverse cultivated and wild genotypes gave deeper insight into the complex seed weight trait evolution during chickpea domestication.As a proof of concept, the present study for the first time made an effort to implement a genome-wide NGS-based high-throughput QTL-seq approach in an intra-specific (2.2.1.4 mapping population (ICC 7184 \u00d7 ICC 15061) derived from low (desi cv. ICC 7184 with 100-seed weight 8.9 g) and high (desi cv. ICC 15061 with 30.1 g) seed weight landraces was developed by single seed descent method. The mapping individuals and parental genotypes were grown (following \u03b1-design field plot method) for three consecutive years (2010\u201313) with at least two replications during the crop growing season at two diverse geographical locations of India. The mapping individuals along with parental genotypes were phenotyped individually for 100-seed weight (SW). The SW (g) was estimated by considering the average weight (g) of 100-matured seeds at 10% moisture content by selecting 10\u201312 representative plants from each mapping individuals. The diverse statistical attributes, including coefficient of variation (CV), broad-sense heritability (H2), frequency distribution, correlation coefficient and analysis of variance (ANOVA) of SW in mapping population, were analysed using SPSS v17.0 (http://www.spss.com/statistics) and following the methods of Kujur et al.21An intra-specific 221 F2.2..21 The high-quality genomic DNA isolated from fresh leaves of these homozygous mapping individuals was quantified  to equal concentration. The isolated genomic DNA from 10 of each low and high seed weight homozygous mapping individuals were pooled together with an equal ratio (amount) to constitute LSB (low seed weight bulk) and HSB (high seed weight bulk), respectively. About 5\u201310 \u00b5g of DNA isolated from two bulked samples and two parental genotypes were used to construct pair-end sequencing libraries (100-bp read length). These libraries were sequenced individually using HiSeq2000  NGS platform. The FASTQ raw sequence reads with a minimum phred Q-score of 30 across >95% of nucleotide sequences were considered as high quality. These sequences were further rechecked for their quality using FASTQC v0.10.1. The filtered high-quality sequences obtained from two bulks and parental genotypes were aligned and mapped on to the reference desi (ICC 495844) chickpea genome using Burrows-Wheeler alignment tool (BWA) with default parameters.45 The high-quality SNPs  were discovered using SAM tools46 and following the detail procedures of Lu et al.43 and Takagi et al.42For QTL-seq study, 10 of each low and high seed weight homozygous mapping individuals representing two extreme ends of SW normal frequency distribution curve were screened based on the preliminary clues obtained from our conventional QTL mapping study. The homozygous genetic constitution of these individuals for either of the low and high seed weight trait was assured in QTL mapping through their multi-location/years replicated field phenotyping as well as genotyping of genome-wide well-distributed 96 SSR markerset al.47; Takagi et al.42; Lu et al.43) were used to identify candidate genomic region(s) harbouring the major QTL(s) associated with seed weight in chickpea. In our study, \u0394 (SNP-index) was measured based on subtraction of SNP-index  between LSW and HSW bulks. The SNP-index was measured as \u20180\u2019 and \u20181\u2019, when entire short sequence reads contained genomic fragments derived from ICC 7184 and ICC 15061, respectively. An average distribution of \u0394 (SNP-index) of SNPs physically mapped across eight desi chromosomes was estimated in a given genomic interval by using sliding window approach with 5 Mb window size and 10 kb increment. The \u0394 (SNP-index) of LSB and HSB and their corresponding SNP-index within the specified window size were plotted in a graph to generate SNP-index plots. To improve the accuracy of QTL identification through QTL-seq, we estimated the statistical confidence intervals of \u0394 (SNP-index) with a given read depth under the null hypothesis of no QTLs, following the detail procedures of Takagi et al.42 and Lu et al.43A well-documented QTL-seq approach relying on the estimation of SNP-index and \u0394 (SNP-index) (following the recommended parameters of Abe 2.3.desi chromosome 1 in which major QTL was identified through QTL-seq) showing polymorphism between parental genotypes (ICC 7184 and ICC 15061) was performed. A selected 192 SNPs  differentiating ICC 7184 and ICC 15061 were used for their validation and high-throughput genotyping in 192 representative mapping individuals and parental genotypes using Illumina GoldenGate assay. The custom oligo pool assay (OPA) designing, custom Sentrix Array Matrix (SAM) synthesis and GoldenGate SNP genotyping assays  were performed using the genomic DNA of mapping individuals and parental genotypes .48 The hybridization of fluorescent dye-labelled PCR products onto a decoded SAM was performed using Illumina BeadArray Express Reader. The Illumina GenomeStudio Genotyping software V2011.1 was used for normalization of intensity data and assigning cluster positions of each SNP. To assign valid genotypes at each SNP locus and for measuring the reliability of SNP detection based on distribution of genotypic classes, minimum GenCall and GenTrain cut-off scores of 0.3 were used. The cluster separation score provided by GenCall software module for 192 mapping individuals and parental genotypes was optimized manually based on degree of separation between homozygous and heterozygous clusters as normalized \u03b8 value [(2/\u03c0) Tan\u22121 (Cy5/Cy3)] in each SNP locus.To validate the major SW QTL identified by QTL-seq, the traditional QTL mapping by selecting the SNP and SSR markers  showing polymorphism between parents of mapping population were selected. The synthesized SSR markers  were PCR amplified in the genomic DNA of 192 selected mapping individuals and parental genotypes using touchdown thermal cycling profiling and standard PCR constituents52 and resolved on 3.5% metaphor agarose gel and automated fragment analyzer. For automated fragment analysis, the amplified FAM-labelled PCR products along with ABI GeneScan-600 LIZ size standard  were resolved in automated 96 capillary ABI 3730xl DNA Analyzer. The electropherogram containing trace files were analysed  using GeneMapper V4.0.Moreover, 48 previously reported genomic SSR markers2.4.http://www.kyazma.nl/index.php/mc.JoinMap) at higher LOD (logarithm of odds) threshold (>5.0) with Kosambi mapping function. The markers integrated into linkage group (LG) based on their centiMorgan (cM) genetic distance were designated corresponding to genetic/physical positions of markers (anchor SSR markers) mapped on the chromosome as reported by previous studies.56 The QTL mapping was performed by integrating the genotyping data of markers mapped on LG of intra-specific genetic map with multi-location/years replicated SW field phenotyping data of 192 mapping individuals. The composite interval mapping function of QTL Cartographer v2.557 and multiple QTL model (MQM mapping) of MapQTL v6.158 at significant (P \u2264 0.05) LOD threshold score of \u22654.0  were used to estimate the phenotypic variation explained  by the QTLs and their additive effect on SW trait.The SNP and SSR marker genotyping data showing goodness of fit to the expected Mendelian 1:1 segregation ratio were used for linkage analysis using JoinMap 4.1  and parental genotypes was amplified using the gene-specific primers via semi-quantitative and quantitative RT\u2013PCR assays .To infer the gene regulation patterns during seed development, differential expression profiling using the genes annotated at the major genomic interval underlying a robust SW QTL  was performed. The RNA isolated from different vegetative (leaf) and reproductive (seed) tissues and two seed developmental stages2.6.59) along with mapping parents and individuals constituting the LSB and HSB. The amplicons were cloned and sequenced, and SNPs were mined within the gene following Kujur et al.21 To estimate the average pair-wise nucleotide diversity (\u03b8\u03c0) and Watterson's estimator of segregating sites (\u03b8\u03c9), the SNP genotyping data were analysed with MEGA v5.060 and TASSEL v3.0 (http://www.maizegenetics.net).For mining the novel alleles and determining the natural allelic diversity, one SW-associated candidate gene validated by QTL-seq, traditional QTL mapping and differential expression profiling was targeted. The fragments covering the entire coding and non-coding sequence components (including 2 kb upstream and 1 kb downstream regulatory region) of this gene were amplified using the genomic DNA of 94 cultivated and wild chickpea genotypes  in 221 F4 individuals and parental genotypes of an intra-specific mapping population (ICC 7184 \u00d7 ICC 15061) across 3 yrs (2010\u201313) . The SNP-index of individual SNP differentiating the ICC 7184 and LSB from ICC 15061 and HSB was estimated. The average SNP-index across a 5 Mb genomic interval was measured individually in LSB and HSB using a 10-kb sliding window approach and plotted against all eight chromosomes of desi reference genome  on chromosome 1 displaying an average SNP-index of higher than 0.9 in HSB and lower than 0.1 in LSB was identified  regulating SW at the 35 kb  genomic interval on chromosome 1 of chickpea  interval (identified by QTL-seq) with expected allelic discrimination were further validated through resequencing of PCR amplicons amplified from the mapping individuals constituting the LSB and HSB, including parental genotypes.The NGS-based high-throughput whole-genome resequencing of two parental genotypes as well as LSB and HSB of an intra-specific mapping population generated \u223c61\u201365 millions of 100-bp high-quality short sequence reads covering 91\u201393% of reference 3.3.4 mapping individuals  (covered by seven SNP and SSR markers) on chickpea chromosome 1  interval with 1,366,372 bp [CaSNP7  to CaSNP12 ] genomic region on chromosome 1. The proportion of phenotypic variance explained (R2) by CaqSW1.1 QTL was 47.6%. The identified CaqSW1.1 QTL exhibiting consistent phenotypic expression, including major effect on SW trait variation across three geographical locations as well as years/seasons in field, was considered as \u2018robust QTL\u2019 as per Saxena et al.24 The positive additive gene effect of this QTL for increasing seed weight with effective allelic contribution from high seed weight genotype ICC 15061 was evident. In addition, one genomic region [CaSNP50 (52.6 cM) to CaSNP55 (60.2 cM)] underlying a robust SW QTL (CaqSW1.2) (8.7% R2 at LOD 5.4) covered with four SSR and SNP markers was identified and mapped on chromosome 1. This 7.6 cM target QTL interval showing positive additive effect corresponded to 139,393 bp [CaSNP50  to CaSNP55 ] genomic region on chromosome 1.To check the accuracy of a major SW QTL identified by QTL-seq, the traditional QTL mapping was performed. For this, the genotyping data of 95 markers (including 87 SNPs and 8 genomic SSR anchor markers mapped on a high-density intra-specific genetic map of LG/chromosome 1) showing polymorphism between parental genotypes as well as LSB and HSB was integrated with multi-location/years replicated field phenotyping data of 192 Fe 1 Fig.\u00a0C. The in3.4.CaqSW1.1) interval harbouring a 35 kb major genomic region  on chromosome 1 was associated with 100-seed weight in chickpea  gene showing tight linkage with a major SW robust QTL (CaqSW1.1)  was considered as one of the potential candidate regulating seed weight in chickpea.The correspondence of QTL-seq outcomes with classical QTL mapping inferred that one narrow 0.6 cM [3.9 (CaSNP8) to 4.5 (CaSNP10) cM] robust QTL  as well as pronounced up-regulation (>7-folds) in high seed weight parental genotype (ICC 15061) and homozygous mapping individuals during seed development  could be a potential candidate regulating seed weight in chickpea.To delineate the potential candidate gene regulating seed weight in chickpea, differential expression profiling of six genes annotated at the 35 kb major genomic region underlying a ays Fig.\u00a0A. One SNent Fig.\u00a0B. Howeve3.5.CSN8 gene validated by QTL-seq, classical QTL mapping and expression profiling was selected. The cloned fragments amplified from entire coding and non-coding regions (including 2 kb upstream and 1 kb downstream regulatory regions) of this 6,741 bp gene were sequenced among 94 cultivated and wild chickpea genotypes  along with mapping parents and individuals constituting the LSB and HSB  compared with cultivated species/accessions (0.12 and 0.10) was evident.To infer the natural allelic diversity , one SW-governing HSB Fig.\u00a0A. This a4.CaqSW1.1) on chromosome 1 using an intra-specific desi chickpea mapping population via whole-genome NGS-based high-throughput QTL-seq approach. This QTL-seq (based on SNP-index)-derived SW QTL (CaqSW1.1) was further validated by SNP and SSR marker-based traditional QTL mapping (at higher LOD >19). This suggests the validity and robustness of QTL-seq as a strategy for quick and efficient scanning of major QTL at a genome-wide scale in chickpea. The advantages of QTL-seq vis-a-vis other available traditional QTL mapping approaches  to identify major QTLs governing seedling vigour, blast resistance and flowering time in crop plants (including rice and cucumber) for instance, have been recently reported.41 Moreover, our study ascertained the wider applicability of QTL-seq approach both in preliminary as well as much advanced generation mapping populations (RILs) by identifying a major seed weight-regulatory QTL in an intra-specific F4 mapping population of chickpea. The narrowing down of 1.8 cM CaqSW1.1 major QTL interval [CaSNP7 (3.7 cM) to CaSNP12 (5.5 cM)] identified by classical QTL mapping into 0.6 cM seed weight-associated QTL region [CaSNP8 (3.9 cM) to -CaSNP10 (4.5 cM)] through QTL-seq was evident. This reflects the potential of QTL-seq over traditional QTL analysis for high-resolution genome mapping and subsequent fine mapping of target candidate genomic region harbouring a major trait-associated QTL. The underlying reason could be the NGS-based high-throughput genome-wide SNP scan between parental genotypes and individuals selected under study with contrasting phenotypes (low and high seed weight) of an intra-specific mapping population. A much closer examination of SNP-index and \u0394 (SNP-index) among parental genotypes as well as individuals constituting the HSB and LSB at major CaqSW1.1 QTL indicated minor contribution of \u223c20% low seed weight alleles in high seed weight parental genotypes and mapping individuals. This is in line with transgressive segregation and quantitative genetic inheritance pattern of 100-seed weight observed in the intra-specific mapping population under study. The detection of another minor (<10% R2 at LOD 5.4) SW QTL (CaqSW1.2) in chromosome 1 through traditional QTL mapping infers the possible shortcoming of QTL-seq approach to identify minor QTLs explaining low phenotypic variation specifically for quantitative agronomic traits. Further large-scale validation of these identified major (CaqSW1.1) and minor (CaqSW1.2) SW QTLs in diverse genetic background and/or through fine mapping/positional cloning is essential prior to their implementation in genomics-assisted breeding of chickpea for higher seed weight and yield.The present study identified and mapped one major genomic region harbouring a robust 100-seed weight QTL (CaqSW1.1) into a 35 kb physical interval [CaSNP8  to CaSNP10  carrying six genes] on chromosome 1, which explained \u223c47.6% of the phenotypic variation of 100-seed weight. The differential expression profiling of six protein-coding genes annotated at this target genomic region further delimited the 35 kb physical interval into a coding SNP (G/A)-carrying potential CSN8 gene. The seed-specific expression as well as pronounced differential up-/down-regulation of this candidate gene in high and low seed weight parental genotypes and homozygous mapping individuals during seed development was apparent. However, we could not find any SNPs in the 2 kb upstream and 1 kb downstream regulatory regions of a SW-associated CSN gene that showed differentiation among the cultivated desi and kabuli genotypes, including mapping parents and individuals of LSB and HSB. Therefore, speculating any possible correlation between regulatory sequence polymorphism and molecular mechanism underlying differential transcript accumulation of CSN gene during seed development especially in cultivated chickpea requires further experimentation. The sequence variant analysis targeting beyond the 2 kb upstream and 1 kb downstream regulatory regions of CSN gene may provide additional clues regarding its differential regulation during seed development in chickpea. The functional relevance of coding gene-derived SNPs for regulating diverse agronomic traits, including seed (grain) size/weight, have been well demonstrated in rice and chickpea.21 These findings collectively inferred that a combinatorial approach of QTL-seq, traditional QTL mapping and differential gene expression profiling have the potential to delineate one coding SNP (G/A)-carrying CSN8 candidate gene at a major QTL interval regulating seed weight in chickpea. The implication of integrated genomic approach (combining genetic and association mapping with transcript profiling) to delineate potential candidate genes harbouring major trait-associated QTLs has been well documented in chickpea.68 The non-congruence of two SW QTLs (CaqSW1.1 and CaSW1.2) identified in our study with that of previously reported known SW QTLs71  was observed. This suggests the population-specific genetic inheritance pattern of our identified novel QTLs regulating seed weight in chickpea. Henceforth, our proposed integrated strategy can be employed for rapid identification of major potential genes, QTLs and alleles associated with qualitative as well as quantitative traits in diverse crop plants. The novel allelic variants mined from the diverse coding and non-coding sequence components of one seed weight-associated CSN8 gene revealed a dramatic reduction of natural allelic diversity in cultivated species/genotypes in contrast to wild species/genotypes encompassing primary, secondary and tertiary gene pools. In spite of higher allelic diversity in wild species/genotypes, one seed weight-associated locus (G/A) in CSN8 gene was completely absent from all the wild genotypes. However, this potential seed weight-regulating gene locus was present in all the desi and kabuli genotypes of cultivated species. This clearly reflects the possible effect of strong artificial and/or natural selection pressure on this seed weight gene locus during chickpea domestication. Further analysis involving all the natural allelic variants mined and potential locus targeted by natural and/or artificial selection in a SW-governing gene is required to gain a deeper insight into the complex seed weight trait evolution in chickpea. This will further assist us to decipher the molecular mechanisms underlying fixation of such complex quantitative trait in domesticated chickpea that are adapted to diverse agro-climatic conditions.The integration of QTL-seq with traditional QTL mapping  narrowed down the 1.37 Mb [CaSNP7  to CaSNP12  containing 177 genes] major seed weight QTL region (CSN8) chickpea gene homolog having 83% amino acid sequence conservation with Arabidopsis thaliana gene (At4g14110)  Fig.\u00a0B is knowSupplementary data are available at www.dnaresearch.oxfordjournals.org.Department of Biotechnology (DBT), Government of India (102/IFD/SAN/2161/2013-14). S.D. and A.K. acknowledge the CSIR  and DBT for Junior/Senior Research Fellowship awards. Funding to pay the Open Access publication charges for this article was provided by the National Institute of Plant Genome Research (NIPGR).The authors acknowledge the financial support for this research study provided by a research grant from the"}
+{"text": "Mesenchymal stem cells (MSCs) are multipotent stromal cells originated from bone marrow and other adult tissues. MSCs are capable of differentiating into adipogenic, osteogenic, and chondrogenic lineages. Transplantation of bone marrow-derived MSCs has displayed some promise in the management against ischemic injuries such as myocardial infarction. Aging exhibited increased vulnerability of MSCs to hypoxic injury, higher inositol pyrophosphate 7 (IP7) levels, and decreased Akt phosphorylation. Inhibition of inositol hexakis phosphate kinases (IP6Ks) activates Akt signaling, decreases apoptosis, and modulates paracrine profiles in aged MSCs, and this greatly enhances the therapeutic efficacy of aged MSCs in the face of hypoxic injury. Stem Cell Research & Therapy, Zhang and colleagues report that the advanced aging process drastically increases the vulnerability of mesenchymal stem cells (MSCs) to hypoxic injury [In this issue of c injury . These fc injury ,3. Nonetc injury . How to c injury . NonetheStem Cell Research & Therapy, Zhang and colleagues report that aged MSCs exhibited higher apoptotic index, decreased Akt phosphorylation (Thr308), enhanced Bad activation, and decreased Bax/Bcl-2 ratio. Interestingly, inhibition of inositol hexakis phosphate kinases (IP6Ks) using the kinase inhibitor TNP overtly decreased inositol pyrophosphate 7 (IP7) production and relieved the MSC apoptotic index as evidenced by Akt phosphorylation (Thr308) and Bax/Bcl-2 ratio [A previous study has demonstrated that the aging process may unfavorably affect the functional activity of stem cells and the tissue environment that surrounds them, thus limiting the therapeutic potential of MSCs . Nonethe-2 ratio . IP7, fo-2 ratio . The ben-2 ratio ,11. HoweIt is noteworthy that the overall efficacy of stem cell transplantation relies on the activity of donor cells and tissue environment. Novel approaches aiming at reversing dysfunction of transplanted cells or refreshing target tissues should provide a useful avenue for improvement of cell therapy efficacy in patients with AMI. The findings reported in this work  that inhAMI: Acute myocardial infarction; IP6K: Inositol hexakis phosphate kinase; IP7: Inositol pyrophosphate 7; MSC: Mesenchymal stem cell; Thr308: Threonine 308.The authors declare that they have no competing interests."}
+{"text": "Previous research has demonstrated that habitual dietary macronutrient distribution affects energy substrate utilization at rest and during exercise. The primary purpose of the current study was to examine the relationships between habitual baseline macronutrient intakes, expressed relative to bodyweight and percentage of total energy intake, and metabolism at rest and after exercise in women.Twenty recreationally active women  volunteered for the current study. Prior to metabolic testing, participants completed strength testing to determine their 1RM for six resistance exercises and completed a 3-day dietary log. Participants were provided with detailed instructions for accurately logging food intake and portion sizes, and instructed to record their regular food intake on two week days and one weekend day. Logs were analyzed using The Food Processor software . Body composition was determined using dual-energy X-ray absorptiometry (DXA). Exercise was prescribed using baseline strength data and heart rate reserve calculations. Respiratory exchange ratio (RER) and resting energy expenditure (REE) were analyzed via indirect calorimetry (Parvomedics TrueOne 2400) before exercise (PRE), and during minutes 0-10 (IP), 25-35 (30min), and 50-60 (60min) post-exercise. Bivariate correlations and independent samples t-tests were completed using SPSS software . Participants were stratified based on fat intake as a percentage of total caloric intake  and relative to bodyweight . Consent to publish the results was obtained from all participants.A significant inverse relationship between carbohydrate (CHO) intake (g/kg) and REE was observed at IP , 30min , and 60min , with a trend toward significance at PRE . Participants consuming > 35% of kilocalories from fat had a significantly higher bench press 1RM (p=0.048) and lower RER at 30min (p=0.033) and 60 min (p=0.033). Participants consuming > 1.3 g/kg of fat per day trended toward lower fat mass (p=0.09) and BF% (p=0.07).Results indicate that baseline macronutrient distribution impacts post-exercise energy metabolism in women. Higher fat and lower CHO intake was associated with greater post-exercise REE and lower post-exercise RER, indicating greater fat utilization. Higher fat intakes may also influence resistance exercise performance and body composition; participants with higher fat intake had a greater bench press 1RM and trended towards lower indices of adiposity. These results suggest that the relative contributions of CHO and fat to total caloric intake may have significant implications for metabolism and body composition in women. Future research should evaluate the effects of modulating habitual macronutrient distribution to impart favorable effects on energy metabolism, body composition, and resistance exercise performance in women."}
+{"text": "Bacillus strain X1 is the source strain for the restriction enzyme BstXI. Its complete sequence and full methylome was determined using single-molecule real-time (SMRT) sequencing. Bacillus strain X1  was originally provided by Dr. Neil Welker, while he was at Northwestern University, and is now housed in the New England Biolabs culture collection (NEB278). It is the original source of the type II restriction enzyme (REase) BstXI, first isolated in 1981 and sold commercially in 1983  RSII instrument . The genes responsible for these modifications were identified by amino acid sequence comparisons with previously characterized DNA methyltransferases (MTases) as described previously  (6mANNNNNNNNNTGG. Also present in the genome is a more complicated R-M system comprising one REase gene (HW35_01470) and three MTase genes (REBASE: http://rebase.neb.com/cgi-bin/seqget?BstXII). All four encode proteins with strong similarity to well-characterized enzymes recognizing GATC  (ction NEB78. It ist?BstXI) . M.BstXICP008855 (BioProject PRJNA253895).This complete genome sequence has been deposited in DDBJ/ENA/GenBank under the accession no."}
+{"text": "We hypothesised that pharyngeal oxygen concentrations would be maintained higher and for longer with transnasal humidified rapid insufflation ventilatory exchange (THRIVE) than conventional bag-mask pre-oxygenation (CPO). CPO requires the mask to be removed during laryngoscopy; this means that air may enter the mouth so subsequent apnoeic oxygenation will be less effective. Oral suctioning could exacerbate this process. However, if high pharyngeal oxygen concentrations and an open airway are maintained, apnoeic oxygenation could be substantially improved. Methods used have included NO-DESAT  and rece2 = 1, FEO2 >0.8) or THRIVE , EAM was simulated by voluntary apnoea and pharyngoscopy with the laryngoscope blade tip placed 2 cm from the posterior pharyngeal wall. Capnography at the laryngoscope tip confirmed apnoea. Pharyngeal gas samples (20 ml) were collected during apnoea, and after 5 seconds of oropharyngeal suctioning. Pre-oxygenation was repeated between sampling. Samples (n = 100) were analysed using calibrated fuel cells.A volunteer with a nasopharyngeal sampling catheter underwent simulated emergency airway management (EAM), using both CPO and THRIVE, with and without suction. Following 3 minutes of pre-oxygenation with CPO (FiOP < 0.05).Pharyngeal oxygen concentrations (mean and SEM) are shown in Figure Pharyngeal oxygen concentration rapidly falls following CPO. This may be detrimental for apnoeic oxygenation during conventional laryngoscopy. Conversely, THRIVE maintains high pharyngeal oxygen concentrations over time. Suction has an immediate negative effect on pharyngeal oxygen concentration that is attenuated by THRIVE. Assessment of NO-DESAT (15 l/minute) was abandoned due to discomfort."}
+{"text": "Staphylococcus aureus is a common cause of hospital, community and livestock-associated infections and is increasingly resistant to multiple antimicrobials. A significant proportion of antimicrobial-resistance genes are plasmid-borne, but only a minority of S. aureus plasmids encode proteins required for conjugative transfer or Mob relaxase proteins required for mobilisation. The pWBG749 family of S. aureus conjugative plasmids can facilitate the horizontal transfer of diverse antimicrobial-resistance plasmids that lack Mob genes. Here we reveal that these mobilisable plasmids carry copies of the pWBG749 origin-of-transfer (oriT) sequence and that these oriT sequences facilitate mobilisation by pWBG749. Sequences resembling the pWBG749 oriT were identified on half of all sequenced S. aureus plasmids, including the most prevalent large antimicrobial-resistance/virulence-gene plasmids, pIB485, pMW2 and pUSA300HOUMR. oriT sequences formed five subfamilies with distinct inverted-repeat-2 (IR2) sequences. pWBG749-family plasmids encoding each IR2 were identified and pWBG749 mobilisation was found to be specific for plasmids carrying matching IR2 sequences. Specificity of mobilisation was conferred by a putative ribbon-helix-helix-protein gene smpO. Several plasmids carried 2\u20133 oriT variants and pWBG749-mediated recombination occurred between distinct oriT sites during mobilisation. These observations suggest this relaxase-in trans mechanism of mobilisation by pWBG749-family plasmids is a common mechanism of plasmid dissemination in S. aureus. Staphylococcus aureus is a common cause of serious skin infections, pneumonia, sepsis and endocarditis and is carried asymptomatically by roughly a third of the human population  lineages, including MW2, USA300, JKD6177 and JKD6159. The sequence divergence between these CA-MRSA suggests pMW2 arrived in each strain independently, despite pMW2 not carrying conjugation genes  sequence and becomes covalently attached to it  capable of transferring a protein-tethered DNA substrate to a recipient cell in an energy-dependent process . In gramed to it ,17. The s sparse ,19 and bproteins ,11. Thesene loci ,21. Mathene loci \u201324. TherS. aureus isolated from carriers of CA-MRSA in remote Western Australian communities   . In thisE. coli and S. aureus strains were cultured on solid or liquid LB medium, supplemented with appropriate antibiotics to maintain plasmids. Primers listed in Supplementary Table S2 were used to amplify oriT regions that were subsequently cloned into pLI50 as EcoRI-HindIII or EcoRI-BamHI fragments. All pLI50 constructs were sequenced using primers 21 and 22. S. aureus plasmid DNA was extracted as previously described (Strains and plasmids are listed in Supplementary Table S1. escribed . For conescribed  and pWBGescribed . BrieflyS. aureus plasmid sequences (http://hcv.lanl.gov/content/sequence/ELIMDUPES/elimdupes.html). Duplicate sequences and sequences >60 kb were discarded. This produced a collection of 360 unique plasmid sequences as of January 10th 2013 (Supporting Dataset S1). The sequences were used to create custom BLASTN databases using standalone BLAST version 2.2.20 , CadD (GI: 695199049), MobA (GI:212383462) and Pre (GI:60392927) as query sequences. TBLASTN searches for antimicrobial-resistance loci on pWBG749-like contigs in the Orange County MRSA dataset were carried out using BlaZ (SAP030A_004), AacA-AphD (GI:618846397), VanA (YP_003864126), VanB (GI:618846277), MphBM (GI:3892644), CAT (GI:1015408) and TetM (GI:302750286) as queries. All BLAST hits were manually inspected for false positives.For analysis of staphylococcal plasmid sequences, the NCBI RefSeq database was queried with the term \u2018Staphylococcus[Organism] AND plasmid[Title]\u2019. Retrieved sequences were added to an existing collection of equences . DuplicaoriT sequences were carried out using T-Coffee in rcoffee mode with default settings (Single-stranded DNA (ssDNA) structure predictions were carried out using Mfold  and predsettings ,40 or Clsettings  and redrsettings . Circulasettings  in \u2018ungasettings . Tree cosettings  producedstaphylococcal mobilisation plasmid proteins SmpA-SmpX. PSI-BLASTP queries using SmpP (SAP031A_037) revealed it showed similarity to relaxases on conjugative plasmids of Bacillus thuringiensis MC28 (pMC189) and Lactococcus gavieae (pGL5) and the vancomycin-resistance plasmids pMG2200 of Enterococcus faecalis and pHT\u03b2 of E. faecium (MG family of relaxases (P family of relaxases (E = 4 \u00d7 10\u221247).Sequence comparisons of pWBG745, pWBG748, pWBG749 and pBRZ01 revealed that all these plasmids carried a conserved \u223c24 kb cluster  carrying 24 open-reading-frames (ORFs), encoding proteins with likely roles in conjugation (Supplementary Table S3) . Proteinelaxases ,48, incloriT DNA sequences are commonly located upstream of their cognate Mob gene and usually comprise at least one hairpin-forming inverted-repeat (IR) sequence located 5\u2032 to a \u2018core\u2019 region containing the DNA cleavage site nic. Core sequences are often conserved between divergent oriT\u00a0sequences (oriT core). A structurally comparable configuration of IR sequences was identified adjacent to the core site on each plasmid . Mfold secondary-structure prediction  from the same donor  was int9e 2.8 \u00d7 0\u22125 from oriT . To investigate if the identified putative oriT\u00a0sequences  enabled mobilisation by pWBG749, the oriT sequence from each plasmid was cloned into pLI50 and the resulting constructs pLI744, pLI747, pLI762\u201349, pLI761a and pLI756b were used in mobilisation experiments. Each construct was capable of being mobilised by pWBG749e at a rate similar to that of pLI749a  were used as queries in BLASTN searches against a database of 360 non-identical staphylococcal-plasmid sequences collected from GenBank (Supporting dataset S1). Of 280 S. aureus plasmids, 147 (53%) carried sequences resembling the pWBG749 oriT. These included the three most prevalent large (>20 kb) plasmid families: pMW2, pUSA300HOUMR and pIB485 (pWBG744) . oriT sequences were found on RCR plasmids (22 plasmids ranging from 2.8 to 4.4 kb) and larger theta-replicating plasmids (132 plasmids ranging from 14.6 to 57.9 kb). TBLASTN searches failed to identify ORFs with similarity to Mob . This general absence of Mob/Pre genes on\u00a0oriT-carrying plasmids is consistent with the proposed relaxase-in trans mechanism of pWBG749-mediated mobilisation. Of the larger oriT-carrying plasmids, 42 plasmids harboured two copies of the oriT sequence and 15 harboured three copies. Inspection of the BLASTN output of oriT-sequence queries revealed that plasmids encoding two oriT sequences invariably carried them on opposite DNA strands, while all plasmids encoding three oriT never carried all three on the same strand. In total, 229 sequences closely resembling the pWBG749 oriT were identified on 154 staphylococcal-plasmid sequences in the dataset.Identified ) Figure . In a laids, 147 3% carriey to Mob  or Pre  or CadD (100/154), compared to only 9% for plasmids not encoding an oriT (18/206). These observations strongly suggest that acquisition of oriT sequences by large S. aureus plasmids has occurred through integration of RCR plasmids carrying cadmium-resistance loci . rep psould 305   into laS. aureus isolates was recently released by the MRSA Orange County initiative of the Broad Institute (broadinstitute.org) (not included in plasmid database in Supporting dataset S1). BLASTN of this dataset using the pWBG749 sequence as a query identified 24 contigs with contiguous nucleotide similarity across the entire pWBG749 conjugation cluster . These putative pWBG749-family plasmids were carried by strains isolated from blood, wounds and sputum. Astonishingly, 736 copies of the oriT sequence were identified across all contigs for the 397 genomes. Thus pWBG749-like plasmids are present in a minority of clinical S. aureus isolates, but pWBG749-like oriT sequences appear to be abundant.Whole-genome sequencing data for 397 clinical oriT sequences suggested that each oriT might be functionally distinct. Closer inspection revealed that when multiple oriT sequences were carried on a single plasmid they often contained different IR2 sequences. Sequence alignment of the region encompassing AR3, IR1, IR2, IR3 and the core was carried out for all oriT\u00a0sequences identified in our plasmid database using T-coffee in rcoffee (RNA) mode, to account for ssDNA structural motifs . Tree construction using PhyML . Subclades with lower bootstrap support were supported by a maximum credibility tree constructed using Markov Chain Monte Carlo software BEAST and TreeAnnotator using the same DNA alignment (not shown). Further inspection of the DNA sequence alignments within each clade revealed that there were at least five distinct IR2 sequence variants, while the repeat sequences of IR1, IR3 and the core were near-identical between all the sequences. Two of the distinct oriT IR2 variants (named OT49 and OT45) corresponded with IR2 motifs within oriT sequences on conjugative plasmids pWBG748/pWBG749 and pWBG745/pBRZ01, respectively, while a further three IR2 motifs matched oriT sequences located upstream of SmpO-gene homologues on pWBG749-like conjugation clusters found in the genome sequences of S. aureus M0408 (named OT408), S. epidermidis (named OTSep) and S. aureus W24216 (named OTUNa) ). OT45, OT49 and OTUNa all carried AR sites resembling those of pWBG749, while OTSep and OT408 oriT sites contained a different set of AR repeats in the same positions  Figure . Of the s Figure . InteresoriT sequences revealed that most did not carry copies from the same oriT subfamilies [58/67]. The most common configuration for plasmids carrying three oriT\u00a0sequences was OT49/OT45/OTUNa [13/15], while for those carrying two oriT\u00a0sequences it was OT49/OT45 [27/42]. Plasmids carrying the combinations OT45/OTUNa [7], OT49/OT49 [7] OTSep/OTUNa/OTUNa [1], OT45/OT49/OT49 [1], OTSep/OTUNa [1] and OTSep/OT408 [1] were also observed. Therefore, assuming oriT acquisition is a random process, most plasmids appear to have preferentially maintained or acquired oriT sequences of different subfamilies, further indicating that the oriT sites are not functionally equivalent.Inspection of plasmids carrying multiple oriT\u00a0sequences from different subfamilies   and a plasmid carrying the pWBG762 OT49 oriT (pLI762\u201349) was mobilised by pWBG749. The OTUNa and OT45 sites from pWBG762 and the oriT of pWBG745 were cloned into pLI50 and used in mobilisation experiments. Neither of the resultant clones were able to be mobilised by pWBG749e  were responsible for the discrimination of OT49 and OT45 oriT sites by pWBG749, the oriT-smpO-smpP regions of both plasmids were cloned into pLI50, producing pKY9TOP and pKY5TOP. pWBG749 mobilised both these clones at rates similar to those of pLI749a, indicating that the presence of pWBG745-encoded smpO or smpP enabled pWBG749-mediated mobilisation of OT45 sites  on pKY5TO9P that enabled mobilisation of the OT45 site by pWBG749. To test this hypothesis, a clone carrying only the oriT-smpO region of pWBG745 was constructed, producing pKY5TO. This clone was mobilised by pWBG749 at levels similar to pLI749a, confirming that the presence of pWBG745-encoded smpO enabled the mobilisation of the OT45 oriT sequence by pWBG749. Thus the SmpO proteins of pWBG749-family plasmids likely act as specificity factors for the oriT, possibly through direct recognition of the IR2 sequence. A comparison of the SmpO sequences encoded on pWBG749 and pWBG745 revealed that they shared 86% amino-acid identity and have diverged mostly in their N-terminal regions (predicted \u03b2-sheet region) . To investigate if the SmpP genes of pWBG749 and pWBG745  Figure .oriT sequences has been documented for plasmids and integrative and conjugative elements (ICEs)  . The nucleotide polymorphisms between the OT45 and OT49 oriT sequences  and mobilisation experiments with truncated oriT sequence clones  containing the 11-bp sequence conserved on divergent plasmids carrying MOBMG-family Mob proteins  ,56\u201361. RpWBG749e . RestricoriT  and carry distinct oriT . The MoboriT ,63. In t BR-VRSA , as welloriT sequence was initially identified through the comparison of MOBMG conjugative plasmids pMC189, pGL5, pMG2200 and pHT\u03b2 . This might suggest that the oriT-smpO region of pWBG745 (or conversely pWBG749) may have been recently acquired, enabling the evolved plasmid to recognise OT45 sites or avoid exploitation by non-conjugative plasmids carrying OT49 sites. In contrast, the S. aureus W24216 SmpO sequence shows only 49% and 46% amino-acid identity to SmpO genes of pWBG749 and pWBG745 (respectively), despite being encoded downstream of an OTUNa oriT sequence that closely resembles OT45  facilitates mobilisation at only 2.5% of the rate of pWBG749 (Figure cis-acting preference of a conjugative plasmid's relaxase for its oriT has been observed for some rhizobial plasmids (in trans mechanism may be less efficient than the relaxase-in cis mechanism, the higher rate of conjugative transfer observed for pWBG749 may raise the relative mobilisation rate to within evolutionarily significant levels. Alternatively, the relaxase-in trans mechanism may be more widespread than is currently appreciated, but due to mechanistic preconceptions of mobilisation (in trans mechanism of mobilisation has been documented for the mobilisation of non-conjugative genomic islands and cryptic chromosomal oriT sites by ICEs (oriT sequence and presumably encodes a Mob protein compatible with pS7a and pS7b (Bacillus subtilis plasmids, which likely involves interactions between plasmid RCR-Rep proteins and the ICEBs1-encoded T4SS (It is clear from the abundance of pWBG749-like  plasmid ,77. In c(\u22124\u201310\u22125 , the mob9 Figure . A stronplasmids ,79, so tlisation , investi by ICEs  and plas by ICEs ,32. Mobiand pS7b . Additioded T4SS . Thus ouin trans mechanism of mobilisation will undoubtedly progress our understanding of the molecular biology, evolution and epidemiology of plasmid transfer in S. aureus and other bacteria. The wide prevalence and sequence diversity of pWBG749-like oriT sequences and the intramolecular recombination of non-identical oriT\u00a0sequences presents itself as a natural and genetically tractable platform from which to tease apart the roles of oriT sequence moieties required for DNA recognition, binding, cleavage, replication and termination of plasmid transfer. From the perspective of molecular evolution and epidemiology, the ability to identify which specific pWBG749-family plasmid mobilises each plasmid based on oriT-subfamily type may enable reconstruction of the evolutionary events leading to the emergence of pathogenic strains. In summary, further characterisation of both the mobilisation mechanisms and the epidemiology of pWBG749-family plasmids will undoubtedly expand our understanding of horizontal gene transfer in S. aureus and in bacteria in general.Further investigation into the pWBG749 relaxase-"}
+{"text": "Enterobacter cloacae strain S611, an endophytic bacterium isolated from surface-sterilized germinating wheat seeds. We present the assembly and annotation of its genome, which may provide insights into the metabolic pathways involved in adaptation.We report draft genomes of  Enterobacter cloacae comprise a heterogeneous species that include many agriculturally beneficial strains. Strains of E.\u00a0cloacae are rapid colonizers of the plant spermosphere and are often used to control fungal pathogens of crops and vegetables  with those from Enterobacter sp. strain SP1, an endophytic nitrogen-fixing bacterium isolated from sugarcane in China (Pantoea sp. SL1_M5 (Filtered genomic sequences were assembled g SPAdes , whereing SPAdes . Strain in China . InteresE.\u00a0cloacae strain S611 whole-genome shotgun project was deposited at DDBJ/EMBL/GenBank under the accession number AXOM00000000.The"}
+{"text": "Acinonyx jubatus) population in zoological institutions has never been self-sustaining because of challenges in natural reproduction. A retrospective analysis of North American zoo-breeding records has revealed that >90% of litters produced since 2003 occurred in facilities \u2018off-display\u2019 from the public. We examined seminal, endocrine, and behavioral traits of 29 adult male cheetahs that were: 1) managed in public exhibit or off-display facilities; 2) maintained by different numbers of cheetah-specific care-givers; and 3) living adjacent to varying numbers of adult conspecifics. Cheetahs housed off-display produced more total motile sperm/ejaculate (P = 0.04) than on-exhibit males. This finding was mirrored in our laboratory\u2019s historical records where two-fold more total motile sperm (P < 0.01) were measured in ejaculates from individuals with no public exposure (n = 43) compared to on-exhibit (n = 116) counterparts. Males at institutions with \u22643 care-givers also produced more total motile sperm/ejaculate (P < 0.03) and spent more time behaviorally active (P < 0.01) than at facilities using >3 care-givers. Exposure to high numbers of conspecifics within the same institution did not impact (P > 0.05) seminal traits, and presence of the public, care-giver number, or animals/facility had no influence (P > 0.05) on androgen or glucocorticoid excretion or other behavioral metrics. Findings indicate that male cheetahs are sensitive to general public exposure and too many care-givers, resulting in compromised motile sperm output/ejaculate with mechanism of action unrelated to altered androgen or glucocorticoid excretion.The collective cheetah ( Acinonyx jubatus) population is in decline with only ~10,000 individuals remaining in nature today   \u201311 , a small-size felid known to be highly sensitive to its captive surroundings  [Otocolobus manul]   and Palls manul] ), where s manul]  and artis manul] , 84) ands manul] .ex situ environment exposed to significant numbers of people (both visitors and care-givers) has practical implications. The finding that >90% of cheetah offspring have been produced in off-display facilities already has begun to influence the structure of the breeding program for this species in North America. For example, since 2012, cheetah adults identified as the most genetically valuable have been moved from traditional urban zoos into spacious centers, most of which have no  visitor exposure. Based on our findings here, this strategy also should help maintain higher sperm outputs especially if these off-exhibit facilities additionally rely on a smaller, dedicated keeper staff to promote familiarity with daily routines. Such expansive environments that can maintain far more cheetahs than in a typical city zoo also allow opportunities to conduct more hypothesis-based research, such as contemporary priorities associated with mate choice, onset of puberty, and how to diagnose pregnancy noninvasively during the first trimester of gestation. Meanwhile, present findings demonstrate that, at least for the cheetah, environmental/management conditions influence physiological function as well as behaviors. Application of findings to improve best-practice management protocols will advance the field of conservation breeding for achieving a self-sustaining ex situ cheetah population.Our conclusion that sperm output and behavioral activity are compromised in cheetahs living in an S1 FigSolid horizontal lines indicate mean androgen concentration before and after implant insertion.(TIF)Click here for additional data file.S2 FigP < 0.05) in cortisol concentrations among injection times.Different superscripts represent differences ((TIF)Click here for additional data file.S3 FigP > 0.05) in any trait between groups.There were no differences ((TIF)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S5 Table(DOCX)Click here for additional data file.S1 Text(DOCX)Click here for additional data file.S2 Text(DOCX)Click here for additional data file."}
+{"text": "Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease that can involve any organ system, and may lead to significant morbidity and even mortality. Childhood-onset SLE (cSLE) is a rare disease with an incidence of 0.3-0.9 per 100.000 children-years and a prevalence of 3.3-8.8 per 100.000 children.SLE is called the great mimicker, as the disease shares characteristics with many other (autoimmune) diseases. Especially when the classic malar rash is absent, diagnosing SLE can be a challenge. Most patients who are diagnosed with juvenil SLE fulfill 4 or more of the American College of Rheumatology (ACR) classification criteria for SLE. The Systemic Lupus International Collaborating Clinics (SLICC) have recently suggested a new set of criteria for the classification of SLE. In recently study, SLICC criteria performed better, was more sensitive (p <0.001), and less specific (p = 0.016) than ACR criteria in childhood.JSLE patients (n = 83) from 2 different centers whose diagnosis fulfilled four or more of the ACR criteria were divided into two groups: those with at least one ACR mucocutaneous criterion (ACR skin feature positive) and those without (ACR skin feature negative) at diagnosis. The relative frequency of skin involvement was described by the paediatric adaptation of SLICC.We studied 83 patients  with SLE from two regions of Turkey. The mean age at diagnosis was 13\u00b12,95 years. The common criteria besides ANA in ACR all patients were, respectively, haematological [n = 55 (66%)], musculoskeletal [n = 45 (54%)], and renal [n = 40 (48%)]. Fourty-five patients (54%) had ACR-defined skin involvement with no significant demographic differences compared with those without. ACR skin feature positive patients showed greater major organ involvement , renal (51% vs 45%). At the time of diagnosis, median SLICC score was 8 in ACR skin feature positive group while 6 in others. Fifty-eight per cent of ACR skin feature negative patients had skin involvement using SLICC (n=13), which included maculopapular rash (76%), toxic epidermal necrosis (0.8%), bullous rash (19%), fotosensitive rash (92%). The thirteen patients showed greater musculoscaletal, haematological and renal involvement at diagnosis (P>0.05).There are a number of other important mucocutaneous manifestations commonly found in JSLE patients apart from the four listed in the ACR criteria. These additional lesions are also associated with major organ involvement.None declared"}
+{"text": "Vaccinia virus Lister-Butantan, which was used in Brazil during the WHO smallpox eradication campaign. Its genome showed an average similarity of 98.18% with the original Lister isolate, highlighting the low divergence among related Vaccinia virus vaccine strains, even after several passages in animals and cell culture.Here, we report the 187.8-kb genome sequence of  Vaccinia virus strain Lister-Butantan (LBT), a strain largely used during the national smallpox eradication campaign in Brazil.Among strains used in the Smallpox Eradication Programme, Lister-derived strains were by far the most widely distributed around the world . Due to http://www.softberry.com/). The functional annotations were performed using the Blast2GO platform . The DNA was used as a template for producing 20 overlapping PCR amplicons. The templates were sequenced by primer walking on both strands using Applied Biosystems BigDye 3.1 chemistry and ABI 3730XL automated DNA . The resulting reads covered the genome in a 9-fold average redundancy at each base position. Chromatogram data were assembled using SeqMerge , Phred/Phrap was used for base-calling and assembly software, and Consed was used for sequence editing. The FgenesV tool was used for gene prediction (platform . The genThe LBT genome is a linear double-stranded DNA (dsDNA) molecule of 187,893\u00a0bp long, with a G+C content of 33.66%. This molecule was predicted to contain 222 ORFs, with size ranging from 40 to 1,286\u00a0amino acids (aa) . The LBT and LO strains showed a mean amino acid identity of 99.47%. Moreover, we identified a total of 535 nucleotide substitutions, of which 206 (38.5%) were nonsynonymous.Vaccinia virus (VV) strain Lister, commonly used in Europe during the smallpox eradication program  revealed that LBT is related to  program .Regarding main differences between the LBT and LO strains, we highlight the single nucleotide polymorphisms (SNPs) and/or other kinds of polymorphisms in genes involved in: (i) evasion of host defense mechanisms or virulence: ORF 013 (serine protease inhibitor [SPI-1]), ORF 019 (interleukin 18 [IL-18] binding protein), M2L and K1L genes (NF-kB inhibitor protein), and B2R and B3R genes (\u201cSchaflen genes\u201d family); (ii) structural and enzyme proteins: ORF 103 (thymidine kinase), ORF 164 (ATPase/DNA packaging protein), ORF 182 (thymidylate kinase), ORF 189 (hemagglutinin protein), and ORF 033 (complement control protein\u2014B5R in VACV-Cop); and (iii) proteins recognized by the immune system: ORF 099  and ORF 192 (serine-threonine kinase). Despite these polymorphisms, we conclude that these findings corroborate previous studies that showed a close relationship between the Lister-derived strains in terms of DNA and protein sequences, regardless of numerous historical passages and maintenance of vaccine stocks.KX061501.The genome sequence of VV strain Lister-Butantan was submitted to GenBank with the accession no."}
+{"text": "Current diabetes care is considered as insufficient regarding early diagnostics, targeted prevention and treatments tailored to the person. Further, gender specific diagnostics and treatment are not the issue of currently applied medical services in diabetes care. This is to understand status quo in diabetes complications and co-morbidities more typical for the female sub-populations.Pubmed literature search within the years 1980-2013 [Cardiovascular disease (CVD) is the best acknowledged complication in patients with Diabetes mellitus type 1 and type 2. It has been well documented that female diabetics demonstrate poorer outcomes of CVD. A combination of the female gender and diabetes is the best recognised risk factor for high operation mortality by and low efficacy of the replacement of calcified valves ,4:\u2756 endomentrium carcinoma versus general female subpopulation)\u2756 ovarian carcinoma \u2756 lymphoma (1.9-times higher risk)\u2756 uterus carcinoma (1.7-times higher risk)\u2756 rectum cancer (1.7-times higher risk)\u2756 stomach cancer (1.6-times higher risk)\u2756 leukaemia (1.4-times higher risk)\u2756 kidney cancer (1.4-times higher risk)\u2756 pancreatic cancer (1.3-times higher risk)\u2756 breast cancer (1.2-times higher risk)\u2756 lung cancer (1.1-times higher risk).versus \u201catypical\u201d co-morbidity profiles in diabetic females.Common risk factors moderating the outcomes in the most frequent female pathologies, namely DM type 2, CVD and breast cancer are progressing age, overweight, poor diet, physical inactivity and depression. Modifiable risk factors persist from childhood and adolescence into adulthood and tend to cluster with synergistic negative effects for consequent manifestation of co-morbid pathologies . Howeverversus rare complication profiles in cardiovascular diseased patient cohorts should be created for advanced treatment regiments.Although the coincidence is common in women, consistent data do not exist to recognise complications and co-morbid pathologies by patient profiling. Complications and complex clinical situations in elderly populations should be considered as the persistent challenge that requires new strategies in healthcare. Integrative medical approaches are strongly desirable to analyse common risk factors as well as their individual and synergistic effects. Frequent"}
+{"text": "There has been only one report analyzing whole blood transcriptome (WBT) in menstrual migraine.To investigate interictal WBT in patients suffering from migraine with aura (MWA).We performed 52 RNA-seq experiments with 26 controls  and 26 interictally-drawn samples  from sex- and age-adjusted patients suffering from MWA using Illumina Hi-seq high-throughput sequencing machine. To detect differentially expressed (DE) genes between affected and unaffected samples we used the edgeR (robust dispersion estimation) software correcting by sex.We obtained more than 100 million short reads per sample. We identified 93 up-regulated genes in unffecteds, and 7 up-regulated genes in affecteds (FDR< 5%). Interestingly, among those DE genes we found some related to endothelial function , and other related to solute carriers, energetic mechanisms, and apoptosis were also found up-regulared in controls; overexpression of genes involved in inflamation were found in affecteds. We also performed a gene ontology enrichment for the differentially expressed genes (DAVID database) and found eritrocyte and myeloid differentiation processes to be significant (Bonferroni <0.1). Other gene ontologies, like apoptosis or positive regulation of synaptic transmission, showed uncorrected significant P values (<0.05).Our preliminary results after analyzing WBT found 100 differentially expressed genes in MWA. The most significantly DE genes are involved in endothelial homeostasis. These results open new targets for understanding migraine pathophysiology.Funded by grants from ISCIII FISS PI11/1232 and IFIMAV.No conflict of interest."}
+{"text": "Porcine stool-associated circular virus 5 (PoSCV5) was detected in the feces of a pig with diarrhea. The complete 3,062-nucleotide genome contains two bidirectionally transcribed open reading frames (ORFs). Phylogenetic analysis of the deduced replication initiator protein (Rep) places PoSCV5 alone on a deep branch among the small circular Rep-encoding single-stranded DNA viruses. Circoviridae, Geminiviridae, or other known viral families with small circular replication initiator protein (Rep)-encoding ssDNA (CRESS-DNA) genomes , an uncultured marine virus , and several unclassified viruses from rodent feces   circular DNA viruses . This re genomes \u20134. The oIn PoSCV5, the putative ORFs are separated by a small intergenic region (SIR) of 173\u00a0nt and a larger intergenic region (LIR) of 201\u00a0nt. Transcription initiates at the SIR and terminates at the LIR. The LIR contains a stem-loop with a 14-nt loop sequence, GGGTGGGCTCTGGT, which is substantially different from the conserved nonanucleotide (TAGTATTAC) of circoviruses and geminiviruses (KJ433989.The complete genome sequence of PoSCV5 (isolate CP3) has been deposited at GenBank under the accession no."}
+{"text": "Vibrio toranzoniae (CECT 7225T) was isolated from healthy reared carpet shell clams in Galicia (Northwest Spain). In addition, this species has been recently identified as a potential pathogen of red conger eel in Chile. The draft genome sequence has 4.5 Mbp, a G+C content of 43.9%, and >3,800 protein-coding genes. Vibrio toranzoniae, isolated from reared carpet shell clams (Ruditapes decussatus) in Northwest Spain, forms part of the Splendidus clade  (us clade . The Splio genus . Recentlg system . Studiesnd Bolch  found thV.\u00a0toranzoniae CECT 7225T was extracted using the QIAamp DNA minikit (Qiagen), according to the manufacturer\u2019s protocol. The purified DNA was used to prepare a library, according to the Illumina TruSeq DNA sample prep protocol . A 100-bp paired-end sequencing run of the library was performed using a HiSeq 2500 instrument (Illumina). The reads were trimmed using Trimmomatic 0.32  . AdditioThis genome sequence will be valuable for comparative genomic studies and searches of virulence factors, thus expanding the understanding of this potential pathogen for fish.LMXU00000000. The version described in this paper is version LMXU01000000.This whole-genome shotgun project has been deposited at DDBJ/EMBL/GenBank under the accession no."}
+{"text": "Changes in myocardial strain have been shown to precede onset of systolic dysfunction in patients with cardiomyopathy. Traditionally performed with echocardiography, acoustic windows can limit strain evaluation. Preliminary work has shown good agreement between myocardial strain derived from deformation field analysis at balanced steady-state free-precession (bSSFP) cine MRI and speckle tracking echocardiography. The application of a novel prototype iterative SENSE reconstruction with L1 regularization (IR-SENSE) to highly accelerated segmented bSSFP cine acquisitions can maintain or improve the effective temporal resolution with a shorter breath-hold. The purpose of this study is to evaluate left- and right-ventricular stain analysis from bSSFP cine acquisitions using conventional GRAPPA and highly accelerated T-PAT with IR-SENSE. We hypothesize that myocardial strain parameters derived from accelerated T-PAT cine acquisitions with IR-SENSE are similar to those obtained using conventional segmented bSSFP with comparable effective temporal resolutions.9 healthy volunteers  underwent imaging at 1.5 T . The following 5 pulse sequences were acquired in the short axis and 4-chamber orientations: GRAPPA factor 2 standard bSSFP cine with 5 and 14 views per segment (Seg NIR), and T-PAT factor 4 bSSFP cine with 2, 8, and 14 views per segment reconstructed using a prototype IR-SENSE algorithm (Seg IR) (Table All T-PAT 4 cine bSSFP acquisitions were successfully reconstructed using the IR-SENSE algorithm. Average and peak systolic strains by region and sequence are shown in Table This preliminary study demonstrates that myocardial strains derived from deformation field analysis on highly accelerated bSSFP cine acquisitions with IR-SENSE are similar to strains derived from conventionally reconstructed segmented bSSFP cine sequences with similar effective temporal resolutions.None."}
+{"text": "In animals, K+-dependent and K+-indendent Na+/Ca2+ exchangers (NCKX and NCX) are important CaCA members. Recently it was proposed that all rice and Arabidopsis CaCA proteins should be classified as NCX proteins. Here we performed phylogenetic analysis of CaCA genes and protein structure homology modelling to further characterise members of this transporter superfamily.The Ca+/Cation exchanger (CAX) and cation/Ca2+ exchanger (CCX) families dominant in higher plants but the NCKX and NCX families absent. NCX-related Mg2+/H+ exchanger (MHX) and CAX-related Na+/Ca2+ exchanger-like (NCL) proteins are instead present. Analysis of genomes of ten closely-related rice species and four Arabidopsis-related species found that CaCA gene family structures are highly conserved within related plants, apart from minor variation. Protein structures were modelled for OsCAX1a and OsMHX1. Despite exhibiting broad structural conservation, there are clear structural differences observed between the different CaCA types.Phylogenetic analysis of rice and Arabidopsis CaCAs in comparison with selected CaCA members from non-plant species demonstrated that these genes form clearly distinct families, with the HMembers of the CaCA superfamily form clearly distinct families with different phylogenetic, structural and functional characteristics, and therefore should not be simply classified as NCX proteins, which should remain as a separate gene family.The online version of this article (doi:10.1186/s12284-016-0075-8) contains supplementary material, which is available to authorized users. Gene faima Fig.\u00a0. All rich et al.  suggesteCAX2, CAX, CAX6 , H+/Mn2+ (AtCAX2), H+/Mg2+ (AtMHX), H+/K+ (AtCCX3), and Na+/Ca2+ (AtNCL) (Hirschi et al. +/Ca2+ exchangers.NCX/MHX, NCKX, YRBG, CCX and CAX/NCL proteins are a unique family of ion exchangers that share conserved structural features but also clear distinctions. While phylogenetic distinctions between NCX and MHX genes or CAX and NCL genes could be argued, there is clear phylogenetic separation between the CAX/NCL, NCX/MHX, NCKX, YRBG and CCX families Fig.\u00a0. Thus it"}
+{"text": "Ricinus communis) has been in the limelight for bioenergy research due to the availability of its genome which raises the bar for genome-wide studies claiming advances that impact the \u201cgenome-phenome challenge\u201d. Here we report the application of phytohormone ABA as an exogenous factor for the improvement of storage reserve accumulation with a focus on the complex interaction of pathways associated with seed filling.The potential biodiesel plant castor bean  in treated seeds. Exogenous ABA (10 \u03bcM) enhanced the accumulation of soluble sugar content (6.3%) followed by deposition of total lipid content (4.9 %). To elucidate the possible ABA signal transduction pathways towards overall seed filling, we studied the differential gene expression analysis using Illumina RNA-Sequencing technology, resulting in 2568 (1507-up/1061-down regulated) differentially expressed genes were identified. These genes were involved in sugar metabolism , lipid biosynthesis , storage proteins synthesis , and ABA biosynthesis . Further, we confirmed the validation of RNA-Sequencing data by Semi-quantitative RT-PCR analysis.After the application of exogenous ABA treatments, we measured an increased ABA levels in the developing seeds cultured Taken together, metabolite measurements supported by genes and pathway expression results indicated in this study provide new insights to understand the ABA signaling mechanism towards seed storage filling and also contribute useful information for facilitating oilseed crop functional genomics on an aim for utilizing castor bean agricultural and bioenergy use. Picea glauca and rapeseed cultures , 3-phopshoglycerate dehydrogenase [3-PGA] [29801.m003106], NADP malic enzyme 29794.m003406], NADH dehyrogenase [29726.m003961], UDP-glucosyltransferase [29970.m000993], cellulose synthase [29863.m001055], UDP glucose 6-dehydrogenase [30174.m009132] and PEP carboxynase (ATP) [28179.m000470]. As a result of the mediation of crucial sucrose metabolic enzymes; rate limiting enzymes participating in lipid biosynthesis as well as metabolic pathway  for the synthesis of ricinoleic acid in castor bean seeds showed high expression comparing to control levels . In relation to this, several seed specific transcription factors analyzed showed differential response for exogenous ABA. Among such MYB factor , r2r3 MYB factor , TINY [29938.m000611], F-box and wd 40 domain protein factor [29851.m002476], CCAAT binding factor (NF-YB6) , WRKY factor , binding factors related to ABI3/VP1 (RAV1) [29738.m001050], long chain fatty acid cofactor [27446.m000490], NAC domain factor , bZIP  and Bhlh factor [29827.m002528] showed up-regulated expression , Acyl coA binding protein (RcACBP), ER glycerol-3-phophate acyltransferase (RcGPAT2 and RcGPAT3), type 1 Diacylglycerol acyltransferase (RcDGAT1), Omega-6 desaturase (RcFAD2) and the two ABA biosynthesis genes (RcNCED1 and RcNCED3) showed positive response to ABA treatment with a negative response being observed for biotin carboxylase subunit of Het-Accase (RcBACC) gene  followed by a significant storage lipid enhancement (4.9% increases) in castor developing seeds. Triacylglycerols (TAGs) are the major storage lipids in diverse oilseeds  and at different developmental stages [right].Click here for file(A) Fresh weight/ Dry weight of developing seeds (7-63 DAP) (B) Lipid, protein and sugar metabolite levels at different seed developmental stages (7-63 DAP).Click here for file(A) Measured ABA levels in cultured seeds and (B) time course study of ABA levels in culture medium.Click here for fileOverall differentially expressed genes identified with ABA treatment (2568 DEGs).Click here for filePrimers used in this study.Click here for file"}
+{"text": "BRAF mutated melanoma). Given hypothesized risk of triggering exacerbations of autoimmune diseases and/or chronic viral infections, clinical trials (including regulatory studies) evaluating checkpoint blocking antibodies PD-1 and CTLA-4 have excluded patients with autoimmune diseases, chronic hepatitis B/C virus (HBV/HCV), and/or human immunodeficiency virus (HIV) infections. Herein, we describe two patients with advanced melanoma and concomitant HCV/HIV infections treated with PD-1 inhibitor pembrolizumab. Patient 2 with HIV/HCV coinfection progressed after 2 doses of pembrolizumab. Patient 1 who had HCV alone was treated with pembrolizumab with initial partial response. HCV viral load remained stable after 9 cycles of pembrolizumab following which 12-week course of HCV-directed therapy was commenced, resulting in prompt reduction of HCV viral load below detectable levels. Response is ongoing and HCV viral load remains undetectable. In both patients, no significant toxicities were observed when pembrolizumab was initiated. We argue for the further investigation of checkpoint inhibition in cancer patients with underlying chronic viral infections in the context of carefully designed clinical trials.On the basis of remarkable antitumor activity, programmed death receptor-1 (PD-1) inhibitors pembrolizumab and nivolumab were approved for the treatment of advanced melanoma in the second-line setting following progression on either CTLA-4 inhibitor ipilimumab or BRAF/MEK inhibitors (for  Pembrolizumab is a programmed death receptor-1 (PD-1) blocking antibody approved for the treatment of metastatic melanoma that has progressed past cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor Ipilimumab and BRAF inhibitors such as vemurafenib or dabrafenib (if BRAF mutated). Pembrolizumab was granted accelerated approval by the Food and Drug Administration (FDA) on the basis of a phase I trial that evaluated two cohorts that received either 2\u2009mg/kg or 10\u2009mg/kg of pembrolizumab every 3 weeks in which investigators reported high response rates (38%\u201352%) with most of the responders (82%) remaining on treatment [PD-1/PD-L1 and CTLA-4 play important roles in regulating the immune system; hence, patients with autoimmune diseases requiring systemic immunosuppression and/or patients with hepatitis B/C (HBV/HCV) or human immunodeficiency virus (HIV) infection have been excluded from studies evaluating these agents over concerns about inadvertent augmentation of infectious and/or inflammatory activity. Although anti-CTLA-4 treatment has been shown to trigger or worsen severity of autoimmune diseases in experimental models, a similar effect has not been shown for PD-1/PD-L1 abrogation \u20134.We report on two patients with advanced melanoma and concomitant HCV/HIV infections  treated with PD-1 inhibition. In both cases, pembrolizumab was well tolerated with no exacerbation of underlying HCV/HIV infection or observed toxicity. BRAF V600 or NRAS codon 61 mutations. Staging positron emission tomography (PET) and magnetic resonance imaging (MRI) scans confirmed two metabolically active nodules in right lower lung with no evidence of metastases in other visceral structures, brain, or skeletal system.A 59-year-old Caucasian female presented with a subcutaneous right breast lesion on screening mammography in August 2014. Ultrasound-guided biopsy revealed malignant cells with an immunophenotype consistent with metastatic melanoma. Physical examination was negative for a possible primary lesion. Molecular testing was negative for eitherPrior history was notable for HCV infection documented in March 2014 following mildly elevated blood alanine transaminase (ALT) and aspartate aminotransferase (AST) levels. HCV-specific characteristics included high viral load  and 1A genotype. Clinically relevant parameters included IL28B polymorphism CC genotype, mild-moderate active chronic hepatitis (Ishak index 6/18) with moderate portal/peri-portal hepatic fibrosis (fibrosis stages 2-3/6). Her social history was notable for history of intranasal cocaine and intravenous drug abuse between ages of 20 and 30. She was in a long-term monogamous relationship with her husband of 30 years without prior high-risk sexual partners.Given the minimal disease burden, we encouraged her to pursue initial HCV therapy followed by therapy for advanced melanoma given the recent approval of antiviral agents with unprecedented levels of antiviral activity in HCV. However, she elected against this. In the setting of mild-moderate hepatitis with moderate fibrosis and mildly elevated ALT/AST, we were concerned about a heightened risk of ipilimumab-related hepatitis. Following an extensive discussion of the available options and carefully considering the respective risks of treatment, she commenced therapy with PD-1 inhibitor pembrolizumab at 2\u2009mg/kg every three weeks. Restaging scans following 3 cycles showed a mixed response, slight increase in size of right breast lesion and new hilar and right axillary lymphadenopathy although pulmonary lesions were significantly decreased in size with an overall reduction in total tumor burden. Restaging scans following further 3 cycles of therapy showed significant reduction in size of both hilar/axillary lymphadenopathy and pulmonary nodules consistent with partial response see . After 9A 47-year-old Caucasian male was diagnosed with a left axillary 0.8\u2009mm nonulcerated melanoma in September 2001. Following negative wide excision and negative sentinel lymph node mapping, no adjuvant therapy was offered. He was followed closely with period examinations and presented with palpable left axillary lymphadenopathy in September 2012. CT imaging confirmed a 2.1 \u00d7 1.0\u2009cm left axillary lymph node with no other evidence of metastases. Excisional biopsy of left axillary lymph node confirmed malignant melanoma and subsequently underwent completion lymph node dissection which revealed multiple foci of metastatic melanoma in 2 of 36 lymph nodes removed with no extracapsular extension. Molecular testing confirmed BRAF V600E mutation though NRAS codon 61 mutation was not identified.Past medical history was significant for remote diagnosis HIV-1 and chronic HCV diagnosed in June 2011. He was treated with an antiretroviral therapy (ART) regimen that consisted of 2 nucleoside reverse transcriptase inhibitors and 1 nonnucleoside reverse transcriptase inhibitor. HIV-1 viral load was consistently undetectable. HCV-specific characteristics included low viral load  and 1C genotype. Clinically relevant parameters included IL28B polymorphism CT genotype and chronic hepatitis associated with mild activity (Ishak index 5/18) and mild-moderate portal/peri-portal fibrosis (fibrosis stage 2/6). His social history was notable for homosexual orientation with multiple prior high-risk partners though recently monogamous and there was no prior history of intravenous drug abuse.He received adjuvant high-dose interferon (IFN) between December 2012 and May 2013, during which time HIV and HCV viral loads were unchanged. IFN was stopped given development of subcutaneous melanoma metastases. Given well-controlled HIV and HCV, he was offered CTLA-4 inhibitor ipilimumab and received 3 doses (3\u2009mg/kg every 3 weeks) between October and December 2013, discontinued for progression. Subsequent treatments included 2 cycles of high-dose IL-2  from January to March 2014 and dabrafenib/trametinib from March to August 2014, discontinued for progressive cutaneous and pulmonary disease with new hepatic lesions. Given excellent performance status despite widely metastatic disease, PD-1 inhibitor pembrolizumab (2\u2009mg/kg every three weeks) was initiated after careful consideration of risks and benefits of treatment and he received 2 doses. Throughout treatment, despite progressive disease, he experienced no immune-related adverse events (ir-AEs), substantial increases in HIV/hepatitis C viral loads, and/or any abnormalities in hepatic function studies. Throughout treatment, he was maintained on ART.Unfortunately, following 2 doses of pembrolizumab, he developed brain metastases requiring stereotactic radiosurgery and declined in performance status. Pembrolizumab was stopped and he transitioned to hospice care. He passed away shortly thereafter.NCT02028403) and HCC associated with HBV/HCV related hepatitis (NCT01658878) with anti-PD L1 BMS-936559 and anti-PD-1 BMS-936558, respectively. However, HIV/HCV patients have hitherto been systematically excluded from clinical trials of pembrolizumab in advanced melanoma and whether pembrolizumab truly exacerbates HCV/HIV infection remains unknown. Prior phase I studies of PD-1 inhibitor BMS-936558 and PD-L1 inhibitor BMS-936559 had similarly excluded patients with HCV/HIV infection [We describe two patients with active HCV/HIV infections and advanced melanoma treated with pembrolizumab in the setting of limited alternative treatments. To our knowledge, this is the first report of advanced melanoma patients with active HCV or HIV infection to be treated with pembrolizumab. The PD-1/PD-L1 pathway is known to be upregulated in chronic viral  infections where it may attenuate T-cell or NK-cell mediated antiviral host immune responses, thereby sustaining chronic infection . Abrogattis NCT0158878 witAlthough patient 2 did not demonstrate antitumor benefit from pembrolizumab (or any other prior treatment including the combination of dabrafenib/trametinib), HIV viral load remained undetectable likely secondary to continued compliance with ART therapy while on therapy. Previously received treatments including HD IL-2, CTLA-4 inhibitor ipilimumab, and PD-1 inhibitor pembrolizumab were discontinued secondary to clinical and/or radiologic progression rather than development of ir-AEs. Throughout treatment, HCV viral loads were variable though HIV viral load was undetectable. ALT/AST elevations were of no more than Common Terminology Criteria for Adverse Events (CTCAE) grade 1 severity.Remarkably, patient 1 has demonstrated an ongoing sustained response to therapy following a mixed response at first staging evaluation. The clinical development of ipilimumab was notable for the heterogeneity of responses observed which led several authors to propose \u201cimmune-related response criteria\u201d (irRC) to specifically evaluate responses to immunotherapeutic agents . Using tGiven the incidence of chronic viral hepatitis  and HIV infection (0.4%) separately and HIV/HCV coinfection (up to 80% in intravenous drug abusers) and the rising incidence of melanoma, evaluating the safety of immunotherapies for the treatment of melanoma in these cohorts is of pressing importance. Additionally, viral hepatitis and HIV are global health scourges which have an outsized impact on patients in developing countries. Demographic and lifestyle changes in developing countries will likely result in cancer incidences that approach those of developed countries such as the United States, Australia, and the European Union. These trends coupled with the availability of highly active treatments that turn HCV and HIV into chronic illnesses make these diseases important considerations as we develop and evaluate effective antitumor immunotherapy.Anecdotal reports are not substitutes for well-conducted clinical trials to evaluate the safety and efficacy of agents in specific settings. Moreover, our experience with these two patients is in no way generalizable to other patients. However, this experience argues for the systematic evaluation of PD-1/PD-L1 immunotherapy in patients with chronic HBV/HCV and/or HIV infection and potentially other entities including autoimmune illnesses requiring systemic immunosuppression, either as extensions of existing studies or within the confines of an organ dysfunction trial."}
+{"text": "Arterial stiffness is an independent predictor of cardiovascular outcomes in hypertensive patients including myocardial infarction, fatal stroke, cerebral micro-bleeds which predicts cerebral hemorrhage in hypertensive patients, as well as progression to hypertension in non-hypertensive subjects. The association between arterial stiffness and various cardiovascular outcomes  remains after adjusting for age, sex, blood pressure, body mass index and other known predictors of cardiovascular disease, suggesting that arterial stiffness, measured via carotid-femoral pulse wave velocity, has a better predictive value than each of these factors. Recent evidence shows that arterial stiffening precedes the onset of high blood pressure; however their molecular genetic relationship (s) and sex-specific determinants remain uncertain. We investigated whether distinct or shared genetic determinants might underlie susceptibility to arterial stiffening in male and female Dahl salt-sensitive rats. Thus, we performed a genome-wide scan for quantitative trait loci (QTLs) affecting arterial stiffness in six-week old F2 (Dahl S x R)-intercross male and female rats characterized for abdominal aortic pulse wave velocity and aortic strain by high-resolution ultrasonography.AS-m1 on chromosome 4 and AS-m2 on chromosome16, LOD 8.8) in males and two distinct interacting QTLs  in females affecting pulse wave velocity. One QTL  was found to influence aortic strain in a sex-independent manner. None of these arterial stiffness QTLs co-localized with previously reported blood pressure QTLs detected in equivalent genetic intercrosses.We detected five highly significant QTLs affecting aortic stiffness: two interacting QTLs -intercrosses. CYP11B2 and NOS3 have been confirmed by genome-wide linkage studies , the Activin A receptor, Type 1 (ACVR1) at position 44.6 Mbp could underlie the AS-1 effect on aortic strain in our (Dahl S x R) intercross. ACVR1 is a receptor for TGF-\u03b21, a multifunctional cytokine that influences the vascular wall via actions on endothelial cells and modulation of the extracellular matrix  and untransformed aortic Strain as quantitative traits. Data analysis was not controlled for BP since at six weeks of age Dahl S and Dahl R rats have equivalent BP , therefon\u2009=\u200998) and SSLP markers (n\u2009=\u200912) were identified as informative markers between our parental strains by using SNPlotyper from the Rat Genome Database. SNP assays (TaqMan assays) were procured from Applied Biosystems and were validated in our laboratory.DNA purification from spleen tissue samples was done by using the DNeasy Blood & Tissue Kit (QIAGEN) following manufacturer\u2019s instructions. SNP genotyping was carried out on an Applied Biosystems 7900 Real-Time PCR System. SNPs (We performed one-way ANOVA followed by all pairwise multiple comparisons using the Holm-Sidak Test for PWV and Strain measurements as indicated per experimental comparison."}
+{"text": "To evaluate the efficacy of non-invasive high intensity MR guided focused Ultrasound Surgery (MRgFUS) for pain palliation of bone metastasis in patients who had exhausted EBRT or refused other therapeutic options.This is a prospective, single arm, multicentre study performed after IRB approval. 72 patients  with painful bone metastases were enrolled. 87 non-spinal lesions underwent MRgFUS treatment using ExAblate 2100 system (InSightec). European Organization for Research and Treatment of Cancer QLQ-BM22 was used for clinical assessment additionally to Visual Analog Scale (VAS), at baseline and 1,3 and 6 months after treatment. All patients underwent CT and MRI before treatment and 3-6 months afterward.Results: No treatment-related adverse events were recorded. 34/72 (47.2%) patients reported complete response to treatment and discontinued medications. 29/72 (40.3%) experienced a pain score reduction >2 points, consistent with partial response. Remaining 9 (12.5%) patients had recurrence after treatment. Statistically significant differences between baseline  and follow-up  VAS values and medication intake were observed (p<0.05). Similarly a significant difference was found for QLQ-BM22 between baseline and follow-up (p<0.05).Conclusion: MRgFUS can be safely and effectively used as totally noninvasive treatment for pain palliation of bone metastasis in patients who had exhausted EBRT and also in patients not previously treated with EBRT."}
+{"text": "For the tenth year running, NAR and Oxford Journals have provided sponsorship and awarded travel bursaries and prizes to students and junior scientists in recognition of their outstanding achievements. This year, sponsorship and prizes were given at 13 different meetings. A list of the awards is presented below. Our warm congratulations go to the prize winners.Student Travel Bursary2015 Mammalian DNA Repair Gordon Research ConferenceVentura, CA, USAFebruary 8\u201313, 2015Poster PrizesDNA Repair in Chromatin SymposiumPullman, WA, USAMay 21\u201323, 2015Amelia J. Hodges John W. Smerdon International Meeting on Quadruplex DNABordeaux, FranceMay 26\u201328, 2015Louis K. M. Chan Small Molecule Destabilisation of Intermolecular G-QuadruplexesDaniela Verga G-quadruplex DNAzyme-modified Nucleotides for Diagnostic ApplicationsRNA Stability 2015 ConferenceEstes Park, CO, USAJune 1\u20134, 2015Eva Kowalinski th Nucleic Acids Research Forum11London, UKJuly 10, 2015Jonathan Burns International Conference on Intelligent Systems for Molecular Biology/ European Conference on Computational BiologyDublin, IrelandJuly 10\u201314, 2014Robin van der Lee Jonas Ibn-Salem 7th New England Biolabs Meeting on DNA Restriction and ModificationGdansk, PolandAugust 24\u201329, 2015Jasmina Dikic Ewa Wons 42nd International Symposium on Nucleic Acids Chemistry (ISNAC 2015)Hyogo, JapanSeptember 23\u201329, 2015Ken Yamada Effects of Sugar Conformational Preferences during Nucleotide Excision by HIV-1 Reverse TranscriptaseMasayuki Tera Development of Barbering Dimmer as a Turn-on Fluorescent G-quadruplex LigandEnvironmental Mutagenesis and Genomics Society MeetingNew Orleans, LA, USASeptember 26\u201330, 2015Student New Investigator Poster Session supportGenome Engineering (European Lab Automation)Hanover, GermanyOctober 7\u20138, 2015Jamal Alzubi Annual Meeting of the Oligonucleotide Therapeutics SocietyLeiden, the NetherlandsOctober 11\u201314, 2015Umar Burki In vivo Pharmacokinetic and Biodistribution Profile of Peptide-Conjugated Phosphorodiamidate Morpholino OligonucleotidesAlexandre Debacker Optimized DNA-PNA Chimeras for Silencing Structured RNAsAnna Dysko Synthesis of Modified Oligonucleotides Containing Triazole BackbonesEllen Gyssels Covalently Locking Nucleic Acid Structures by the Inducible Furan Cross-link Strategy: New ApplicationsMarcel Hollenstein General Compatibility of Nucleoside Triphosphates with Rolling CircleamplificationSatish Jadhav Synthesis of Carbohydrates/Bisphosphonate-Oligonucleotide Conjugates and their PET ImagingSilvana Jirka Evaluation of 2\u2032- deoxy-2\u2032-fluoro Antisense Oligonucleotides for Exon Skipping in Duchenne Muscular DystrophyYifat Oren Restoration of cftr Function by Antisense Oligonucleotide Splicing ModulationMaire Osborn Polyunsaturated Fatty Acid-siRNA Conjugate Targeting Huntingtin (Htt) mRNA Shows Prolonged Efficacy, Minimal Toxicity, and Broad Distribution in Mouse BrainDina Polyak Hindering Tumor Growth by Polymer-based Targeted Delivery of OligonucleotidesJurri\u00ebn Prins Post-Transcriptional Guidance of Monocyte to Macrophage Differentiation by the RNA-Binding Protein QuakingLodewijk Toonen Ataxin-3 Exon Skipping as a Treatment Strategy for Spinocerebellar Ataxia Type 3Tirsa Van Westering Cmah-/-mdx Mouse Early Onset Cardiac Phenotype and Correction of Dystrophin by Peptide-PMO for Duchenne Muscular DystrophyAnn Fiegen Durbin Signal Interrupted: How RNAs Containing Modified Nucleotides Suppress RIG-I Activation6th Argentine Conference on Computational Biology and Bioinformatics (CAB2C)Bah\u00eda Blanca, ArgentinaOctober 14\u201316, 2015Diego Javier Zea and Cristina Marino Buslje Estefan\u00eda Mancini, Sabrina Sanchez, Rub\u00e9n Gustavo Schlaen, Andr\u00e9s Romanowski, Esteban Hernando and Marcelo Yanovsky Alexander Monzon, Diego Zea, Mar\u00eda Silvina Fornasari, Silvio Tosatto and Gustavo Parisi th International Symposium on Aminoacyl-tRNA Synthetases10Barcelona, SpainOctober 18\u201322, 2015Ita Gruic-Sovulj Renaud Geslain"}
+{"text": "Brevibacillus laterosporus is a spore-forming bacterium that causes a secondary infection in beehives following European Foulbrood disease. To better understand the contributions of Brevibacillus bacteriophages to the evolution of their hosts, five novel phages  were isolated and characterized. When compared with the five Brevibacillus phages currently in NCBI, these phages were assigned to clusters based on whole genome and proteome synteny. Powder and Osiris, both myoviruses, were assigned to the previously described Jimmer-like cluster. SecTim467 and Jenst, both siphoviruses, formed a novel phage cluster. Sundance, a siphovirus, was assigned as a singleton phage along with the previously isolated singleton, Emery. In addition to characterizing the basic relationships between these phages, several genomic features were observed. A motif repeated throughout phages Jenst and SecTim467 was frequently upstream of genes predicted to function in DNA replication, nucleotide metabolism, and transcription, suggesting transcriptional co-regulation. In addition, paralogous gene pairs that encode a putative transcriptional regulator were identified in four Brevibacillus phages. These paralogs likely evolved to bind different DNA sequences due to variation at amino acid residues predicted to bind specific nucleotides. Finally, a putative transposable element was identified in SecTim467 and Sundance that carries genes homologous to those found in Brevibacillus chromosomes. Remnants of this transposable element were also identified in phage Jenst. These discoveries provide a greater understanding of the diversity of phages, their behavior, and their evolutionary relationships to one another and to their host. In addition, they provide a foundation with which further Brevibacillus phages can be compared. Brevibacillus laterosporus.Due to their ability to transfer genetic material or to lyse and kill their hosts, the study of bacteriophages is critical to understanding the evolution of their host bacteria . This evBrevibacillus laterosporus (BL) is one of several secondary invaders often associated with Melissococcus plutonius infection, the causative agent of European foulbrood in honeybees , Davies (B. laterosporus) [NC_022980], Emery (B. laterosporus) [KC595516], Jenst (B. laterosporus) [KT151955], Jimmer1 (B. laterosporus) [KC595515], Jimmer2 (B. laterosporus) [KC595514], Osiris (B. laterosporus) [KT151956], Powder (B. laterosporus) [KT151958], SecTim467 (B. laterosporus) [KT151957], Sundance (B. laterosporus) [KT151959].Kalign \u201335 was uBrevibacillus phage terminase large subunit or terminase large subunit-like protein. Sequences for phylogenetic analysis were first aligned using MUSCLE [Sequences of closest phage relatives for phylogenetic comparisons were found from BLASTP \u201341 searcg MUSCLE . Neighbog MUSCLE  with boog MUSCLE . The accBacillus phage SPP1 (B. subtilis) [NP_690654]; Brevibacillus phages Abouo (B. laterosporus) [AGR47449], Davies (B. laterosporus) [YP_008858637], Emery (B. laterosporus) [AGR47349], Jenst (B. laterosporus) [ALA07151], Jimmer1 (B. laterosporus) [AGR47249], Jimmer2 (B. laterosporus) [AGR47149], Osiris (B. laterosporus) [ALA07344], Powder (B. laterosporus) [ALA48012], SecTim467 (B. laterosporus) [ALA07521], Sundance (B. laterosporus) [ALA47835]; Clostridium phages c-st (C. botulinum) [YP_398598], D-1873 (C. botulinum) [EES90358]; Lactococcus phages phiL47 (L. lactis subsp. cremoris DPC6860) [YP_009007060], 949 (L. lactis strain ML8) [YP_004306307]; Microcystis phages Ma-LMM01 (M. aeruginosa) [YP_851132], MaMV-DC (M. aeruginosa) [AGR48682]; Pseudomonas phage PaBG (P. aeruginosa PAO1) [YP_008433440]; Staphylococcus phages PH15 (S. epidermidis) [YP_950664]; Streptomyces phage Jay2Jay (S. lividans JI1326) [AIW02598]; Synechoccus phage S-CBS4 (Synechococcus sp. CB0101) [YP_005098309]; Thermus phages phiOH2 (T. thermophilus) [YP_008240332], phiYS40 (T. thermophilus) [YP_874075], TMA (T. thermophilus HB27) [YP_004782268]; Treponema bacterial strain Treponema phagedenis F0421 [EFW38857].MEME  was usedBrevibacillus phages were found using the NCBI Conserved Domain Database  [Phamerator was used to group similar proteins into protein families called \u201cphams\u201d  using pa 3JXB_C] . HHPred  3JXB_C]  and Rapt 3JXB_C] \u201357 were  3JXB_C]  and comp 3JXB_C] .Brevibacillus laterosporus LMG 15441 [NZ_CP007806] to the putative transposon region in SecTim467 was prepared using Gepard  call was based on a match to an integrase encoded in a P. elgii chromosome with 75% similarity, E-value 3e-123. However, no stable lysogens were formed from a lysate containing Emery , Jimmer2 gp65 [AGR47199.1]), which aids host attachment to its target cell [YP_009199067.1], SecTim467 gp6 [ALA07508.1]) and the plasmid partition protein ParA (Sundance gp7 [YP_009194057.1]), which allow for proper allocation of plasmid in dividing bacteria [YP_009194090.1]), which may aid in secretion and killing of target cells [AGR47420.1]) and T (Emery gp72 [AGR47438.2]), which allow for normal sporulation of the host to occur [In order to assess putative functions for the amerator  and the amerator \u201350 . Abouo and Davies contained only one copy of the gene coding for this protein. These proteins formed two groups based on 60% or greater amino acid similarity. Group 1 consisted of Jimmer1 gp53 [YP_009226363.1], Jimmer2 gp53 [AGR47190.2], Abouo gp49 [YP_009220106.1], Osiris gp55 [YP_009215069.1], and Powder gp55 [ALA48065.1], while Group 2 consisted of Jimmer1 gp57 [YP_009226367.1], Jimmer2 gp57 [AGR47193.1], Davies gp51 [YP_008858686.1], Osiris gp59 [YP_009215073.1], and Powder gp59 [ALA48069.1]. Based on RaptorX  with a It is difficult to determine whether Jenst or SecTim467 was the progenitor as the GC content of these two phages flanked by the inverted repeats is very similar , with thBrevibacillus phages and their comparison to the five previously reported Brevibacillus phages. The detailed analysis of these ten phages lays the foundation for future work concerning the Brevibacillus phages, as well as related phages, and aids in understanding and affirming the dynamics of phage-host co-evolution. The genomic comparison and clustering of these phages, along with the identification of putative transcriptional units and proteins, may aid in understanding these phages\u2019 lifecycles. In addition, the identification of host-related proteins and a putative transposon region found in both the phage and host underscore intricate relationships between phages and the evolution of their host.Herein we have reported the isolation and characterization of five novel Brevibacillus phages identified two phage clusters and two singleton phages\u2014a proportional one cluster, one singleton increase from the previously reported one cluster and one singleton [Brevibacillus phage from another cluster. This trend has been previously reported for the Enterobacteriaceae phages and may be due to a small sampling size compared to the large reservoir of phages and their hosts, or due to the ability of phages to acquire new hosts [Brevibacillus phages have been isolated from samples gathered in Utah (and only ten have been fully sequenced thus far), this will remain unclear until more phages are isolated from more locations. However, it is likely that distinct evolutionary lines will still be seen between many clusters even as a large phage reservoir is sequenced, since different clusters may contain phages of very different lifestyles . The addition of these five Brevibacillus phages, representing two new phage \u2018cluster types\u2019, thus provides greater opportunity for use in phage therapy as therapies are more likely effective when they contain phages from different clusters, providing diversity in the different strains they are able to infect. Such therapies may prove to be useful in the treatment of European Foulbrood or other infections where BL is a documented secondary invader [Whole genome nucleotide dotplot and ANI analysis of all ten ingleton . Powder ew hosts . For exa invader .Bacillus phage. Further studies are necessary to characterize this motif, including analyzing the expression of the genes downstream of this motif to see if they are coordinated and measuring the infection time to expression of these genes [Genomic analysis of these phages revealed a shared promoter-like motif in the Jenst-like cluster, which was located upstream of ORFs whose encoded proteins may predominately function in DNA metabolism see . Thus, tse genes ,94.Brevibacillus phages revealed that, in addition to structural proteins, several proteins that may be important for host virulence or the evolution of transcriptional regulation were present. Putative virulence factors identified in the analysis of Brevibacillus phage genomes . This helix-turn-helix transcriptional regulator has homology to the classic P22 c2 repressor and may thus be involved in the regulation of the lysogenic state ,84. ThesBrevibacillus bacterial chromosome that is homologous to this transposable region, the phages\u2019 ability to access the bacterial gene pool is underscored. Future investigation of the functions of the hypothetical proteins in the putative transposable region could prove fortuitous in understanding whether or not this region contributes to host pathogenicity and function.Finally, the presence of a putative transposon in both SecTim467 and Sundance, but which was either removed from SecTim467 to create Jenst or added to Jenst to create SecTim467, provides a novel mechanism of driving gene exchange and evolution between these phages and their host, expanding the base of understanding of how these entities have evolved over time see . While tS1 FigPallindrome  was used(TIF)Click here for additional data file.S1 Table(XLSX)Click here for additional data file."}
+{"text": "Bacteroidetes bacterium Zunongwangia profunda SM-A87 can produce high quantities of EPS, and its EPS production is enhanced significantly by lactose. Here, we studied the reasons behind the significant advantage that lactose has over other carbon sources in EPS production in SM-A87. RNA-seq technologies were used to study lactose-regulated genes in SM-A87. The expression level of genes within the EPS gene cluster was up-regulated when lactose was added. Supplement of lactose also influenced the expression of genes located outside the EPS gene cluster that are also involved in EPS biosynthesis. The major glycosyl components of SM-A87 EPS are mannose, glucose and galactose. Genomic metabolic pathway analyses showed that the EPS precursor GDP-mannose can be synthesized from glucose, while the precursor UDP-glucose must be synthesized from galactose. Lactose can provide glucose and galactose simultaneously and prevent glucose inhibition. Lactose can also greatly stimulate the growth of SM-A87. Taken together, lactose acts not only as an inducer but also as a carbohydrate source for EPS production. This research broadens our knowledge of the regulation of EPS production in marine bacteria.Many marine bacteria secrete exopolysaccharides (EPSs) that have important ecological and physiological functions. Numerous nutritional and environmental factors influence bacterial EPS production. However, the regulatory mechanisms of EPS production are poorly understood. The deep-sea  Many marine bacteria secrete high molecular weight exopolysaccharides (EPSs). EPS surrounds bacterial cells and enhances their survival ,2,3,4,5.Zunongwangia profunda SM-A87 , a bacterium isolated from deep-sea sediment in the southern Okinawa Trough, yields high quantities of EPS with interesting rheological properties, such as high viscosity and tolerance to high temperatures and salinities  and translation, ribosomal structure and biogenesis [J] .. By dayEscherichia coli ; Amino acid transport and metabolism [E]; Nucleotide transport and metabolism [F]; Carbohydrate transport and metabolism [G]; Coenzyme transport and metabolism [H]; Lipid transport and metabolism [I]; Translation, ribosomal structure and biogenesis [J]; Transcription [K]; Replication, recombination and repair [L]; Cell wall/membrane/envelope biogenesis [M]; Posttranslational modification, protein turnover, chaperones [O]; Inorganic ion transport and metabolism [P]; Secondary metabolite biosynthesis, transport and catabolism [Q]; General function prediction only [R]; Function unknown [S]; Signal transduction mechanisms [T]; Intracellular trafficking, secretion, and vesicular transport [U]; Defense mechanisms [V].(DOC)Click here for additional data file.S4 FigThe control is basal medium. (A) Basal medium supplied with lactose; (B) basal medium supplied with combination of glucose and galactose. The ORF ZPR_2833 is galactokinase; ORFs ZPR_0544, ZPR_0546, ZPR_0558 and ZPR_0566 are EPS biosynthesis genes within the EPS gene cluster; ORF ZPR_1094 is LPS related gene; ORF ZPR_2582 is carbohydrate kinase.(DOC)Click here for additional data file.S5 FigStrains were grown in the basal medium supplemented with sucrose and galactose. After 5 and 42 hours of supplement of IPTG, the cells were collected and RT-qPCR experiments were performed.(DOC)Click here for additional data file.S1 Table(DOC)Click here for additional data file."}
+{"text": "Malaria symptoms are unspecific in acute undifferentiated fever. Seropositivity against various previous infections might be high in exposed populations. Serological results in a cohort of malaria patients in India are presented.et al., Malaria Journal 2013). At the monitoring site Dengue IgM capture ELISA (MAC-ELISA), Scrub typhus immunofluorescence (IFA) on Scrub ELISA positive samples and Leptospira Microscopic Agglutination Test (MAT) on Leptospira ELISA positive samples were also performed. Convalescence samples for test of rise in titer were not collected due to logistical challenges. Malaria PCR was considered gold standard for the diagnosis of malaria.Serological tests from patients with malaria in an observational fever study were analyzed. During April 2011-November 2012, 1564 patients aged \u22655 years with fever for 2-14 days were consecutively included at seven secondary community hospitals in Tezpur (Assam), Raxaul (Bihar), Mungeli (Chhattisgarh), Ratnagiri (Maharashtra), Anantapur (Andhra Pradesh), Oddanchatram and Ambur (Tamil Nadu). Scrub typhus IgM ELISA , Leptospira IgM ELISA , Chikungunya IgM ELISA , Dengue rapid NS1 antigen and IgM Combo test  were performed at the hospital sites. At the monitoring site , malaria genus mitochondrial PCR was performed on all samples and 18S species-specific PCR or sequencing performed on genus positive samples with methods as described previously , 15% (173/268) had positive Dengue MAC-ELISA, 14% (37/268) positive Leptospira MAT, 8% (29/233) positive Chikungunya IgM ELISA and 35% (25/71) positive Scrub typhus IFA. Both Chikungunya ELISA and Dengue MAC were positive in 6/268, both Leptospira MAT and Dengue MAC in 4/268, both Scrub typhus IFA and Leptospira MAT in 6/268, both Scrub typhus IFA and Chikungunya ELISA in one and both Scrub typhus IFA, Dengue MAC and Chikungunya ELISA also positive in one patient.Serological tests generally considered gold standard for the diagnoses of scrub typhus, leptospirosis, Dengue fever and chikungunya were positive in a high number of malaria patients. Multiple etiologies of fever in addition to malaria to such an extent are not likely, while persistent antibodies after previous infections or cross reactivity more likely explain the findings. Results of a single serological test should be interpreted with caution when treating patients with acute undifferentiated fever in India and malaria should be considered a differential diagnoses also when IgM antibodies against other pathogens are detected."}
+{"text": "Managing patients with scoliosis with curve > 90 degrees remains challenging. Bruchowski et al reported temporary internal distraction rods (TIDRs) can be used instead of halo traction for severe spinal defmormity. We report 5 cases of severe scoliosis managed with a 2-stage operation using a TIDR.Since 2009, 5 patients were treated with spinal instrumentation with TIDRs. These were 4 female and 1 male patients with a mean age of 28 years (13-55 years) at surgery. Mean preoperative Cobb angle was 116 degrees. All patients had restricted pulmonary dysfunction. For all patients, 2-stage operation using temporary internal distraction was performed. In one case, anterior release followed by 2-stage operation with a temporary distraction rod was performed.Mean postoperative Cobb angle was 39 degrees (22-67 degrees), corresponding to a mean correction rate of 69% (55-75 %). Mean estimated blood loss was 4024ml, but only one patient required homologous blood transfusion. After first stage operation, CT revealed screw malposition in one patient, but it was removed in 2nd stage operation. We encountered no preoperative complications.TIDR is an alternative approach in patients undergoing spinal fusion for severe scoliosis. Gradual correction of the spine in 2-stage operation may prevent neurological complications. It decreased the need of homologous blood transfusion."}
+{"text": "To assess the technical and clinical results of MRgFUS treatment and factors affecting clinical treatment success.252 women  with uterine fibroids underwent MRgFUS treatment using an ExAblate 2100 system . All patients underwent MRI screening before treatment. Results were evaluated with respect to post-treatment non-perfused volume (NPV), symptom severity score (SSS), reintervention rate, pregnancy and safety data.NPV ratio was significantly higher in fibroids characterized by low signal intensity in contrast-enhanced T1-weighted fat saturated MRI images and in fibroids that are distant from spine (>3cm). NPV ratio was lower in fibroids with septations, with subserosal component and in skin-distant fibroids (p< 0.001). NPV ratio was in high correlation with clinical success: NPV of more than 80% resulted clinical success in more than 80% of patients. Reintervention rate was 12.7% . Expulsion of fibroids (22%) significantly correlated with a high clinical success rate. No severe adverse events were reported."}
+{"text": "Cicer accessions through integrated reference genome- and de novo-based GBS assays. High intra- and inter-specific polymorphic potential (66\u201385%) and broader natural allelic diversity (6\u201364%) detected by genome-wide SNPs among accessions signify their efficacy for monitoring introgression and transferring target trait-regulating genomic (gene) regions/allelic variants from wild to cultivated Cicer gene pools for genetic improvement. The population-specific assignment of wild Cicer accessions pertaining to the primary gene pool are more influenced by geographical origin/phenotypic characteristics than species/gene-pools of origination. The functional significance of allelic variants (non-synonymous and regulatory SNPs) scanned from transcription factors and stress-responsive genes in differentiating wild accessions  from cultivated desi and kabuli accessions, fine-mapping/map-based cloning of QTLs and determination of LD patterns across wild and cultivated gene-pools are suitably elucidated. The correlation between phenotypic  and molecular diversity-based admixed domestication patterns within six structured populations of wild and cultivated accessions via genome-wide SNPs was apparent. This suggests utility of whole genome SNPs as a potential resource for identifying naturally selected trait-regulating genomic targets/functional allelic variants adaptive to diverse agroclimatic regions for genetic enhancement of cultivated gene-pools.We identified 82489 high-quality genome-wide SNPs from 93 wild and cultivated  Furthermore, this process can be complemented with marker-based introgression of trait-associated novel genes, QTLs (quantitative trait loci) and natural allelic variants scanned from diverse wild gene pools into cultivated accessions.Chickpea  governing drought tolerance traits, particularly the root traits (58.2% PVE) mapped on an intra-specific genetic map (ICC 4958 \u00d7 ICC 1882) of linkage group (LG) 4, was selected to evaluate the potential of our identified genome-wide GBS-based SNPs for fine mapping. A major genomic region (9102618\u201316180940\u2009bp spanning 7.08\u2009Mb on chromosome 4) harboring this robust QTL was defined by integrating that region with inter-specific genetic linkage (ICC 4958 \u00d7 PI 489777) and physical map of the kabuli genome. The comprehensive GBS-based SNP analysis at this 7.08\u2009Mb target QTL interval among 93 wild and cultivated Cicer accessions detected 375 SNPs. The structural annotation of these SNPs on the kabuli genome revealed the presence of 161 SNPs in the intergenic regions with 214, including 36 (29 genes) non-synonymous and 58 (31) regulatory, SNPs in the 60 genes. The functional annotation of 60 non-synonymous and regulatory SNP-carrying genes exhibited maximum correspondence to transcription factors (25%) and stress-responsive genes (33%). The differential expression analysis of 60 non-synonymous and regulatory SNP-containing genes based on in silico digital expression profiling showed pronounced differential up-/down-regulation (2 to 18.5-fold) of 51 genes in at least one of the tissues of ICC 4958 compared to others. The preferential and tissue-specific expression (\u22654-fold) in the roots compared to the leaves of ICC 4958 was evident. The LD estimates and LD decay using 439 SNPs (with significant LD at MAF \u22650.05) identified and annotated on a 7.08 Mb drought responsive QTL region of kabuli chromosome 4 were determined. The LD estimates in the QTL region varied from 0.09 to 0.52 with a mean of 0.21, which is much lower than the LD estimates measured on all of kabuli chromosome 4 (mean LD: 0.39) using 2418 SNPs. The LD decay  determined at a 200\u2009kb physical distance from the target QTL is much faster compared to all eight kabuli chromosomes, including kabuli chromosome 4 (500\u2013550\u2009kb).The structural and functional annotation as well as Cicer species depicted that a larger fraction (>90%) of such genes had Ka/Ks\u2009<\u20091.0, indicating negative/purifying selection pressure (62289C. arietinum [desi (0.37)/kabuli (0.40)] and C. judaicum, and lowest between C. arietinum [desi (0.14)/kabuli (0.18)] and C. microphyllum. The time of divergence estimation based on synonymous substitution rates (Ks) among conserved SNP-carrying genes between each of the wild and cultivated Cicer species revealed the highest Ks between C. arietinum (desi/kabuli) and C. judaicum, giving their approximate divergence time at 0.61 and 0.65 Mya, respectively (C. arietinum [desi (0.58 Mya)/kabuli (0.62 Mya)] and C. bijugum and by the minimum between C. arietinum [desi (0.35 Mya)/kabuli (0.38 Mya)] and C. microphyllum  is consistent with a number of previous studies62289The estimation of the proportionate distribution of Ka to Ks substitution rates across SNP-carrying genes conserved between each of the wild and cultivated pressure  and 5I. raction >% of suchectively  and 5I. ophyllum  and 5I. raction >% of suchCicer species from diverse geographical origins selected for genome-wide discovery and high-throughput SNP genotyping using GBS assay had considerable phenotypic diversity with regard to multiple agromorphological and disease resistance traits based on their multi-location replicated phenotyping at two diverse agro-climatic zones of North Western India by Singh et al.C. reticulatum accession ILWC 36 originating from Turkey (52 days), C. judaicum accessions (ILWC 4 and ILWC 273) from Lebanon (41 days) and C. pinnatifidum accessions (ILWC 226 and ILWC 251) also from Turkey (41 days) displayed multiple resistance against Ascochyta blight and root knot nematodes. One accession of C. judaicum (ILWC 256) originally from Jordan containing a higher number of pods/plant (284) vis-a-vis cultivated desi and kabuli Cicer species showed resistance to both Ascochyta blight and Botrytis gray mold. Therefore, large-scale non-synonymous and regulatory SNPs in the stress-responsive known/candidate genes and transcription factors differentiating the wild Cicer accessions  from sensitive cultivated desi and kabuli accessions scanned by us could potentially be utilized as functional markers for various large-scale genetic analyses in chickpea. The practical significance of these functional alleles (SNPs) mined at a genome-wide scale was apparent for fine-mapping/map-based cloning of genes underlying QTLs as well as for understanding natural allelic diversity and domestication pattern among diverse wild and cultivated Cicer species/accessions across gene pools based on their population genetic structure and LD patterning. These findings could help us to identify potential natural targets for adaptive trait genetic enhancement in cultivated gene pools that are domesticated in diverse agro-climatic regions. This would eventually accelerate genomics-assisted breeding, including hybridization breeding programs by introgressing diverse traits of agronomic importance from the wild Cicer gene pools into cultivated Cicer species for genetic improvement.The wild accessions constituting six annual and perennial Cicer accessions representing one annual cultivated C. arietinum (12 accessions), five annual wild species, namely C. reticulatum (16), C. echinospermum (8), C. judaicum (22), C. bijugum (19) and C. pinnatifidum (15) and one perennial species C. microphyllum were selected (C. reticulatum and C. judaicum) were used as biological replicates to evaluate the reproducibility of GBS-based SNPs. To constitute 96-plex GBS libraries, the genomic DNA of 95 accessions was digested with ApeKI and ligated to adapters carrying unique barcodes, while one sample (without genomic DNA) was considered as control. These libraries were pooled together and sequenced (100-bp single end) using Illumina HiSeq2000 adopting the methods of Elshire et al.et al.desi  to identify the high-quality and non-erroneous SNPs from 93 accessions.For genome-wide discovery and genotyping of SNPs, 93 diverse selected . The genospermum , C. judajudaicum , C. bijuculatum 1, C. echidesi and kabuli genomes and visualised using Circos visualisation tool. For structural and functional annotation of SNPs in diverse coding and non-coding sequence components of genes and genomes (chromosomes/pseudomolecules and scaffolds), the physical positions (bp) of reference-based SNPs were correlated with the GFF of desikabulihttp://snpeff.sourceforge.net), PFAM database v27.0 (http://pfam.sanger.ac.uk) and KOGnitor NCBI database (ftp://ftp.ncbi.nih.gov/pub/COG/KOG).To deduce the genomic distribution of GBS-based SNPs across chickpea chromosomes, the total SNPs, including non-synonymous SNPs were plotted individually based on their unique physical positions (bp) on eight chromosomes (pseudomolecules) of Cicer accessions was correlated with an available in silico SNP database of four chickpea accessions  based on their nature/types and congruent physical positions on the desi (ICC 4958) genomeCicer accessions. The PCR amplicons were sequenced and aligned to detect SNPs among accessions as per Kujur et al.80The SNP genotyping data obtained from 93 wild and cultivated Cicer accessions was analysed with PowerMarker v3.51, MEGA v5.0 and TASSEL v3.0 (http://www.maizegenetics.net). Based on these outcomes, the PIC (polymorphism information content), average pair-wise nucleotide diversity (\u03b8\u03c0) and Watterson\u2019s estimator of segregating sites (\u03b8\u03c9) were measured and an unrooted neighbour-joining (NJ)-based phylogenetic tree (with 1000 bootstrap replicates) among accessions was constructed. To determine optimal value of population number (K) and population structure among 93 accessions, the SNP genotyping information was analyzed in STRUCTURE v2.3.4 following Kujur et al.et al.The SNP genotyping information  generated from 93 wild and cultivated Cicer accessions for diverse yield contributing qualitative and quantitative traits  were obtained from Singh et al.et al.Cicer accessions were executed using NTSYS-pc V2.1 and POPGENE V1.32, and the methods of Zhang et al.The replicated multilocation  field phenotyping information of 93 wild and cultivated 2; average correlation coefficient among pairs of alleles across a pair of SNP loci) individually in desi and kabuli chickpea, the genotyping information of SNPs physically mapped on eight chromosomes were analysed using PLINK and the full-matrix approach of TASSEL, following Zhao et al.et al.2 against 50\u2009kb uniform physical intervals across eight desi and kabuli chromosomes using aforementioned methods.To access the genome-wide and population-specific LD patterns (rCicer species from accessions of cultivated (desi and kabuli) species were functionally annotated. To determine the differential expression pattern of these SNPs-carrying genes, in silico digital expression profiling was employed. For this, the global transcript profiling data (whole genome transcriptome sequencing) available for selected informative non-synonymous and regulatory SNPs-carrying genes in different vegetative  and reproductive (flower bud and young pod) tissues of chickpea  were obtained. The differential expression profiling data assayed by SNPs-carrying genes in diverse vegetative and reproductive tissues of ICC 4958 was compared and a heat map was constructed using the TIGR MultiExperiment Viewer .To determine the functional significance of SNPs, the gene-derived SNPs (including non-synonymous coding and regulatory SNPs) differentiating accessions belonging to each of the wild kabuli genomein silico digital expression profiling and heat map construction were performed following aforesaid methods.The potential of GBS-based SNPs identified in our study for fine mapping/map-based cloning of QTLs was further assessed. For this, the genetic positions of markers linked/flanking the known QTLs regulating various yield component and stress tolerant traits mapped on eight LGs/chromosomes of diverse chickpea intra- and inter-specific genetic linkage maps were correlated and integrated with that of available high-resolution reference genetic linkage map (ICC 4958 \u00d7 PI 489777)Cicer species were analyzed using the CODEML program in PAML interface tool of PAL2NAL . The time  of divergence among Cicer species was measured using a synonymous mutation rate of \u03bb substitutions per synonymous site per year as T\u2009=\u2009Ks/2\u03bb (\u03bb\u2009=\u20096.5\u2009\u00d7\u200910\u22129)For estimation of divergence time, the synonymous (Ks) and non-synonymous (Ka) substitution rates of the aligned amino acid sequences and their corresponding cDNA sequences of SNPs-carrying genes conserved across each of seven wild and cultivated How to cite this article: Bajaj, D. et al. Genome-wide high-throughput SNP discovery and genotyping for understanding natural  allelic diversity and domestication patterns in wild chickpea. Sci. Rep.5, 12468; doi: 10.1038/srep12468 (2015)."}
+{"text": "An early diagnosis of ICU-acquired weakness (ICU-AW) is difficult because disorders of consciousness preclude strength assessment . ElectroNewly admitted unconscious ICU patients RASS <-3), ventilated for \u22652 days, were included in this single-center prospective cohort study. EMG testing included ulnar (motor/sensory), peroneal (motor) and sural (sensory) studies. Myography was performed when coagulation was normal . Reliability of results was checked by an experienced neurophysiologist, blinded for strength. Motor/sensory studies were abnormal if amplitudes were below the 2.5th percentile reference values , ventila), blindeWe included 35 patients ICU-AW: 17). EMG testing was done on day 4 (IQR: 3 to 6). Feasibility was 94%, 89%, 77%, 34% and 31% for ulnar motor, peroneal motor, ulnar sensory, sural sensory and myography studies, respectively. Figure 7. EMG teFeasibility of ulnar and peroneal studies was acceptable; feasibility of sural and myography studies was low. Diagnostic accuracy was low for all studies. This may be improved with new reference values."}
+{"text": "A 66-year-old female was transferred from an outside hospital for possible ST segment elevation myocardial infarction (STEMI). The patient reported feeling poorly for the last day, with epigastric pain, nausea, and multiple episodes of vomiting. Patient\u2019s medical history was significant for diabetes mellitus, hypertension, atrial fibrillation, and multiple sclerosis. Electrocardiogram (EKG) was as noted . InitialDigoxin concentration subsequently returned at 8.8ng/mL (reference range 0.5\u20131ng/mL). The ST segment changes gradually improved as the digoxin concentration declined. An echocardiogram demonstrated moderate concentric left-ventricular hypertrophy with estimated ejection fraction of 80%, rheumatic heart disease, and possible hypertrophic obstructive cardiomyopathy physiology. Troponin peaked at 0.29ng/mL and then returned to baseline. Creatine kinase remained within normal limits.Digoxin may cause a multitude of EKG changes including ST depression and numerous cardiac dysrhythmias."}
+{"text": "Atopic allergic asthmatic individuals experience acute bronchoconstriction (early response) upon allergen exposure. Several hours after the initial exposure, some individuals exhibit a chronic late phase  whereas others do not . The purpose of this study is to determine changes in Th17 and regulatory T (Treg) cell numbers and their associated gene expression profiles in whole blood between allergen-induced ERs and DRs.14 participants with mild, atopic asthma (8 ERs and 6 DRs) underwent a cat allergen inhalation challenge as part of the AllerGen Clinical Investigator Collaborative. Whole blood was collected immediately prior to challenge (pre) and 2 hours post-challenge. DNA methylation analysis was used to measure the frequency of Th17, Treg, B and T cells . Whole blood transcriptome profiling was performed using Affymetrix GeneChip\u00ae Human Gene 1.0 ST Arrays. Statistical analysis was performed using R.Sum of the T cell and B cell frequencies obtained using the methylation assays strongly correlated (r = 0.95) with the lymphocyte frequency obtained using a hematolyzer. Allergen inhalation did not significantly (p>0.05) change Th17, Treg, B and T cell counts between ERs and DRs. However, the Th17/Treg ratio was significantly (p=0.03) different between ERs and DRs post challenge. 199 genes positively correlated with Th17 cells at an FDR of 5%. 463 genes positively correlated with Treg cells at an FDR of 5%. Th17 genes were inversely correlated with Treg genes.Th17/Treg ratio derived using DNA methylation analysis discriminates allergen-induced early from dual asthmatic responses. The inverse correlation between Th17 genes and Treg genes may be indicative of the inflammatory or suppressive phenotypes of these cells."}
+{"text": "The prevalence of risky alcohol consumption, associated factors and its impact on the brain is not well established in clinically stable HIV patients.Within the PIVOT neurocognitive sub-study, effectively suppressed HIV-infected adults on either standard cART or ritonavir-boosted PI monotherapy completed the Alcohol Use Disorders Identification Test (AUDIT) designed to detect risky alcohol consumption. They also completed a brief neuropsychological assessment (NPZ 5) composed by five measures. For this cross-sectional analysis, we calculated rates of hazardous (AUDIT=8\u201315) or harmful (AUDIT=16\u201319) consumption and likely dependence (AUDIT>20). We explored the association between risky alcohol intakes (AUDIT>8) and clinical/demographical variables, conducting logistic regressions when significant association was found (p<.05). Also, the association between cognitive performance and alcohol consumption was calculated and adjusted by potential confounders.Of the 146 included participants, the majority were male (86.3%), white (81.5%) and educated . Average age was 47.6 years (SD=8.7), and 36.3% had risky consumption . White ethnicity and male sex were positively associated with risky consumption . After aDespite the substantially high prevalence of risky alcohol consumption, it was not associated with worse adherence, immunological or quality of life measures in this cohort of effectively suppressed patients but prevalence of likely alcohol dependency was extremely low. White patients were more vulnerable to risky consumption. Moreover, positive association between cognitive performance and risky alcohol consumption remained after adjustment. In our study, the association we found between cognitive function and alcohol consumption does not reflect the effect of alcohol dependency on cognition."}
+{"text": "Lactobacillus casei Lbs2. The bacterium shows probiotic and immunomodulatory activities. The genome assembly and annotation will help to identify molecules and pathways responsible for interaction between the host immune system and the microbe.We report here a 3.2-Mb draft assembled genome of  Lactobacillus and Bifidobacterium species) that promote health  and L.\u00a0casei Immunitas (Actimel). Although complete L.\u00a0casei genome sequences  are available and genome analysis has elucidated its symbiotic mechanisms  and available at the probiotic repository established at the Molecular Biology Unit, NDRI, Karnal (India). The strain possesses probiotic attributes, such as acid and bile tolerance, hydrophobicity, and auto- and coaggregation properties. Intragastric administration of Lbs2 to mice induced a strong regulatory response with the generation of CD103+ dendritic cells (DCs) and FoxP3+ T-regulatory (Treg) cells in the mesenteric lymph nodes and intestinal lamina propria. High titers of regulatory cytokines (interleukin 10 [IL-10] and transforming growth factor-\u03b2 [TGF-\u03b2]) were observed in the serum and colonic tissue lysates. As extracellular proteins of bacteria interact directly with mucosal cells  application on the NCBI server (http://www.ncbi.nlm.nih.gov/genomes/static/Pipeline.html), and both annotations concurred. The final annotated assembly has about 2,894 structural genes, 2,453 coding sequences (CDSs), 402 pseudogenes, 8 rRNAs, 29 tRNAs, and 2 ncRNAs.Whole-genome sequencing of ing IDBA . IDBA asing IDBA  was usedThis genome sequence and annotation hold great promise for the discovery of novel probiotic effector molecules.JPKN00000000.The genome sequences are now available at NCBI under the accession number"}
+{"text": "Consistent with AID, comparable somatic hypermutation frequencies and class-switching indicated affinity-matured antibodies in normal and malignant skin. A melanoma-associated antibody subset featured shorter complementarity-determining (CDR3) regions relative to those from circulating B cells. Clonal amplification in melanoma-associated antibodies and homology modeling indicated differential potential antigen recognition profiles between normal skin and melanoma sequences, suggesting distinct antibody repertoires. Evidence for IgG-expressing B cells, class switching and antibody maturation in normal and malignant skin and clonally-expanded antibodies in melanoma, support the involvement of mature B cells in cutaneous immunity.B cells participate in immune surveillance in human circulation and tissues, including tumors such as melanoma. By contrast, the role of humoral responses in cutaneous immunity is underappreciated. We report circulating skin-homing CD22+CLA+B cells in healthy volunteers and melanoma patients (n\u2009=\u200973) and CD22+ cells in melanoma and normal skin samples (n\u2009=\u2009189). Normal and malignant skin featured mature IgG and CD22 mRNA, alongside mRNA for the transiently-expressed enzyme Activation-induced cytidine Deaminase (AID). Gene expression analyses of publically-available data  confirmed heightened humoral responses  in melanoma. Analyses of 51 melanoma-associated and 29 normal skin-derived IgG sequence repertoires revealed lower IgG1/IgG Despite being important immune sentinels in inflammation, antigen presentation, and adaptive immunity through antibody production, the recruitment and roles of B cells and the humoral immune compartment in cancer immune surveillance and in normal tissue homeostasis are insufficiently understood.B cells that are exposed to antigens in peripheral tissues can undergo clonal expansion and class switching to mature antibody classes . Antigen challenge triggers daughter cells to undergo somatic hypermutation (SHM) and to express antibodies with increasing affinity for the specific antigen. Class switch recombination (CSR) and SHM, involving the enzyme Activation-induced cytidine Deaminase (AID) can occur both in lymph node germinal centers and also in tissues  in response to antigenic challenge. This provides an enriched antibody repertoire with reactivity and affinity against encountered antigens and of different isotypes, conferring the potential to generate antibodies with a variety of Fc-mediated immune effector functions12The presence and nature of skin-resident B cells are ill-defined due to low cutaneous B cell infiltrate numbers. Preliminary findings describe a subset of B cells distinct from those in lymph nodes, circulating through sheep skin568We provide the first report of the human mature skin-resident B cell compartment and its IgG-expressing profiles in cutaneous melanoma and in normal skin. We describe evidence for the presence of cutaneous mature B cells, distinct IgG subclass distribution profiles, clonal expansion, somatic hypermutation in the IgG heavy chain variable regions, and predicted antigen binding site characteristics of the mature humoral response repertoire in cutaneous malignant melanoma lesions and in normal skin.We aimed to investigate B cell surveillance in cutaneous sites. We found that a small proportion of circulating CD45+CD3-CD14-CD19+CD22+B cells in healthy volunteers (n\u2009=\u200924) and patients with melanoma (n\u2009=\u200949) express the skin-homing Cutaneous Leucocyte-associated Antigen (CLA) . ImmunohAnalysis of publicly-available gene expression data extracted from human melanoma samples derived from Gene Expression Omnibus (GEO)11121415Thus, B cells may be recruited to normal skin and cutaneous melanoma sites, based on expression of the humoral immune cell markers CD20, CD22 and AID.To determine the subclass distribution and heavy chain variable region profiles of antibodies expressed at cutaneous sites in our sample collection, we identified n\u2009=\u200951 unique mature IgG sequences from 9 cutaneous melanoma samples  and proportionally-higher levels of IgG4/IgGtotal (~20%) than those in human adult circulation at the protein level 817total sequences (24%) (We previously reported that B cells in melanoma feature distribution of IgG subclasses with lower representation of IgG1/IgGes (24%) . These pIn the same sample cohort , the sequences derived from cutaneous melanoma lesion B cells featured representation of immunoglobulin variable heavy chain region (IgVH) families (VH1-5), with highest representation from VH3 (36%) and VH5 (431) . IgG seqWe then explored the lengths of the complementarity-determining CDR3 regions (IMGT/V-quest), the hypervariable areas largely responsible for determining antibody binding specificity and affinity to cognate antigensThis may suggest the rise of a specific group of B cell clones in malignant skin when compared to healthy volunteer skin and circulating B cells from melanoma patientsTo assess the maturation state of the IgG antibodies expressed at cutaneous sites, we measured the silent and non-silent mutations which result in divergence from respective germline sequences.in situWe found comparable mutagenic rates in melanoma and normal skin antibodies, suggesting similar levels of affinity maturation in situ, 63% of Together, these suggest that the rates of mutation, and by extension, the maturation of the antibody variable region sequences, in normal skins and melanoma lesions appear comparable.We examined the amino acid residue positions at which cumulative divergence from the germline occurred Furthermore, we examined individual residues predicted to be involved in antigen recognition (i-Tasser)We then constructed homology models of the VH immunoglobulin fold, to highlight the residues predicted to likely be involved in antigen binding in >25% of the sequences from each cohort  mediated binding.in situ cutaneous class-switch recombination. Additionally, clonally-related sequences of separate IgG subclasses determined by identical V(D)J germline \u2018parent\u2019 clones were detected only in melanoma samples (three of nine samples)  . B cell samples) ; furtherTogether, these indicate active class switch recombination (CSR) to different IgG subclasses in normal and malignant cutaneous sites, alongside B cell clonal expansion in melanoma lesions only, pointing to humoral responses against local immune and inflammatory signals or antigenic challenge.We present evidence supporting the presence of mature, skin-resident IgG antibody-expressing B cells. Our findings add to previous reports of IgG-expressing B cells in melanoma lesions, B cells from patients that express antibodies reactive to tumor cells, and dysregulated levels of IgG subclasses in melanoma lesions and patient sera14Despite previously-reported positive associations between tumor-associated B cells and better clinical prognosis in melanoma152526Subsets of circulating (CD22+) B cells in patients with melanoma and healthy volunteers harbor skin homing potential, based on expression of CLAtotal). Surprisingly, we detected a lower than expected proportional IgG1/IgGtotal expression profile in normal skin samples. Dysregulated levels of IgG4 were also expressed by patient blood B cells, consistent with previous reported findings17Humoral immunity can mount antibody responses through recognition of upregulated cancer-associated antigens, but conversely, cross-talk with tumors may educate these responses to adopt regulatory functions3031The presence of a skin-resident IgG-expressing cutaneous humoral compartment is not entirely unexpected. B cells are reported in autoimmune conditions with cutaneous pathogenic manifestations such as Pemphigus vulgaris, where B cells and auto-reactive antibodies are detected in skin and systemically, contributing to disease pathology353637383941We observed an active B cell compartment in melanoma lesions, supported by different findings and these, along with gene expression analyses of published data, implicate tissue-resident B cells and AID expression in primary and in metastatic melanomas. A subset of melanoma-resident and perhaps skin-resident B cell clones displayed different CDR3 lengths when compared with those from the circulation, indicating humoral immune responses focused towards a specific antigenic stimulus. Consistent with antigen-focused clonal expansion, homology modeling of melanoma-derived antibodies suggested structural clustering of amino acid residues highly predicted to be involved in binding. This may indicate antibody maturation under clonal selection pressure in melanoma. Furthermore, we found active class switching in identical B cells in normal and in malignant cutaneous sites. Importantly, we found class switching in clonally-related B cells and clonal family trees in melanomas but not in normal skin samples, possibly associated with responses to tumor antigens and tumor evolution43In summary, we report basal levels of a mature humoral immune response in normal skins and an enhanced B cell clonal presence in cutaneous melanomas. Skin tumor-associated B cell receptor repertoires and IgG subclass profiles point to an active tumor-infiltrating B cell compartment with features distinct to those of circulating B cells. Our findings of local B cell clonal expansion, antibody affinity maturation and predicted antigenic binding patterns on antibody variable regions also raise the possibility that a heightened mature IgG antibody response in melanoma may be edited towards specific antigen stimuli. Melanoma may activate but also pervert skin-resident humoral immune response homeostasis to control activated, mature B cell responses. This may be through maintaining skin-resident antibody subclass distribution featuring immune regulatory subclass antibodies such as IgG4, as a mechanism of evading immune surveillance.Our data thus report a humoral response in skin immune surveillance and homeostasis and support expanded tumor-associated humoral immunity in cutaneous melanoma. These findings mandate a closer study of the cutaneous humoral immune cell compartments to elucidate the involvement of B cells and locally-expressed antibodies in skin immune surveillance and their roles in melanoma tumor pathology.Patients with malignant melanoma were staged and classified according to the American Joint Committee on Cancer Melanoma Staging and Classification criteriaFor evaluations of CLA+B cells, peripheral blood mononuclear cells (PBMC) were isolated by Ficoll-Paque Plus density centrifugation GE Healthcare). Cells were resuspended in RPMI 1640 medium (Life Technologies) 11.25% human serum albumin , 10% DMSO (Sigma) and stored in liquid nitrogen. For analyses, cells were thawed, selected based on SSC-A/FSC-A properties, dead cells excluded using LIVE/DEAD\u00ae Fixable Dead Cell Stains in Qdot585 (Life Technologies) and single cells selected by FSC-A/FCS-H. Cells were incubated with antibodies for the following surface markers (BD Biosciences): CD45(V500), CD22 (APC), CD19 (BV605), CD3 (APC-Cy7), CD14 (Alexa Fluor 700) and CLA (FITC). Samples were subsequently acquired on a 5-laser SORP Fortessa (BD Bioscience) and data analyzed using FlowJo software (Treestar).2. Tissues were filtered through a 100\u2009\u03bcm strainer. B lymphocytes were also identified from matched peripheral blood samples after Ficoll-Paque  gradient centrifugation. Cells were treated with FcR Blocking Reagent (Miltenyi Biotec), selected based on SSC-A/FSC-A properties, DAPI to exclude dead cells and labeled with anti-human antibodies to the following markers: CD19 (FITC), CD22 (FITC), CD45 (PE) or with CD19 (FITC) and CD45 (PerCP) (BD Biosciences) to detect B cells by flow cytometry . Data were analyzed using FlowJo software (Treestar).Single cell suspensions from normal skin and cutaneous melanoma samples were obtained by mild physical dissociation . Cells were allowed to crawl out from tissues overnight in RPMI 1640 medium, 10% FCS, at 37\u2009\u00b0C, 5% COTo detect CD22 expression, 6\u20138\u2009\u03bcM-thick melanoma tissue microarray  samples were de-paraffinized in xylene before rehydration. Heat antigen retrieval and staining with mouse anti-human CD22 (Abcam) were followed by biotinylated goat/rabbit anti-mouse IgG (DAKO) and detection using Vector red alkaline phosphatase substrate with levamisole (Vector labs). Images were acquired using ZeissAxioScan microscope with 40x objective and Olympus Provis stereology microscope with 40x planapo objective, and analyzed using the Zen Blue software (Leica).ssues stored in RNAlater were thawed at room temperature, homogenized in RLT buffer  using a Kinematica Polytron homogenizer (Fischer Scientific). RNA was extracted using the RNeasy kit (QIAgen) and quantified using a Nanodrop spectrophotometer (Thermo Scientific). 500\u2009ng RNA was used to synthesize cDNA using SuperScript \u00ae II reverse transcriptase (Life Technologies). RNA extracted from 27 normal skin and 21 melanoma samples yielded n\u2009=\u200929 IgG sequences from 13 normal skins and n\u2009=\u200951 IgG sequences from 9 melanoma samples; RNA from n\u2009=\u200936 single B cell IgG sequences was obtained from PBMC samples of 12 patients with melanoma using a single cell lysis kit  following manufacturer recommendations. cDNA synthesis was conducted using the SuperScript VILO cDNA Synthesis kit .Ti\u0394Ct). AID expression was normalized against CD22 mRNA (VIC) (2\u0394Ct).cDNA was synthesized and used in conjunction with a FAM-labelled Taqman gene expression kit for human CD22 (Hs00998488) and AID (Hs00757808), with VIC-labeled \u03b22-microglobulin as endogenous control (Life Technologies); 384-well plates were used with the 7900HT system (Applied Biosystems) to amplify CD22 and AID. Endogenous control and mRNA abundance were normalized against human \u03b22-microglobulin mRNA (VIC) (21L-VH6L), along with an IgGPr reverse primer at 0.5\u2009\u03bcM in a PCR reaction with high fidelity polymerase master mix Phusion Flash (Thermo Scientific) (nd reaction proceeded with Phusion Flash mix using 2\u2009\u03bcL of the first reaction with class-specific PCR forward primers (VH1F-VH6F) and the same IgGPr reverse primer as in 1st reaction (at 0.5\u2009\u03bcM). VH-C\u03b3 transcripts were identified by (1%) agarose gel electrophoresis (650\u2009bp). Fragments were isolated by band excision and DNA extraction . DNA was cloned by blunt-ended ligation into pCR-Blunt from the Zero Blunt\u00ae cloning kit (Life Technologies). Ligation reactions were transformed into chemically-competent E. coli OneShot\u2122 TOP10 cells (Life Technologies). Colonies were selected and treated for pCR-Blunt plasmid extraction (QIAgen plasmid miniprep kit). Plasmids were sequenced using the M13 forward and reverse sequencing primers (Source Bioscience) (Amplification of VH-C\u03b3 transcripts consisted of 2 rounds of semi-nested PCR: 1st reaction used 2\u2009\u03bcL of the cDNA and 6 leader sequence PCR forward primers (VHentific) ; 2nd reascience) .http://selection.med.yale.edu/baseline/).The Baseline server compares expected versus observed rates of mutation to quantify selective pressure; a binomial test is used to quantify statistical significance. IgG subclass was determined by comparing the reverse IgG variable region sequence in the NCBI database using human BLASTCloned IgG V-region sequences were obtained from sequence reactions using the FinchTV software (PerkinElmer). Forward and reverse IgG sequences were analyzed using IMGT/V-Quest to determine IgG heavy chain family, V-D-J germline, and hypermutation sitesPublicly-available data from n\u2009=\u2009234 human skin and melanoma samples were extracted from the Gene Expression Omnibus (GEO) database http://cancergenome.nih.gov/) were also used to analyze CD20, CD22 and AID mRNA expression in melanoma progression. We only considered samples from patients who had not received neo-adjuvant treatment prior to tumor resection for the sample submitted for TCGA. Normalized mRNA expression data were downloaded from cBioPortalGene expression data of n\u2009=\u2009384 human melanoma samples from The Cancer Genome Atlas (TCGA) database (www.graphpad.com) was used for statistical analyses . For survival analyses, mRNA expression data from TCGA samples were categorized as low expression and high expression using the median expression as cut-off. Kaplan Meier survival curves were compared among patient subsets using the log-rank test. The Hazard Ratio (HR) was calculated using the Cox proportional hazard model. Survival analyses were performed using the SPSS software . Differences with P-values\u2009<\u20090.05 were considered statistically significant and all tests were two-sided .GraphPad Prism software ."}
+{"text": "Cancer anorexia-cachexia is a frequent, debilitating and life-threatening condition in which altered metabolism and reduced food intake contribute to weight loss (mainly due to lean body mass [LBM] loss), which cannot be reverted by conventional nutritional support. Safe/effective treatments for cancer cachexia remain an unmet need. The hunger hormone ghrelin has been shown to activate key pathways in the regulation of body composition. Anamorelin (ANAM) is a novel, selective, oral ghrelin receptor agonist with appetite-enhancing and anabolic activity. Anamorelin is currently being investigated in phase III studies for the treatment of anorexia-cachexia in advanced non-small cell lung cancer .Eighty-two patients with advanced cancer, ECOG performance score \u2264 2 and weight loss 5% within prior 6 months were treated with placebo (n=36) or 50mg anamorelin (n=38) once daily for 12 weeks. Body composition by DXA, handgrip strength (HGS) and Quality of Life  were assessed at baseline, 4, 8 and 12 weeks. Solid tumors represented prevalent malignancy (>93%) with no difference in cancer types between treatment groups.2=0.7249, p< 0.0001). Anamorelin treatment improvements in HGS and QoL were previously presented [Treatment with anamorelin for 12 weeks significantly increased total body mass (TBM) and LBM. Increases in LBM and TBM in anamorelin-treated patients were strongly correlated (rDecreased body weight and LBM are poor prognostic factors in cancer cachexia patients. This study demonstrates that 50mg anamorelin treatment for 12 weeks significantly increased LBM, which largely contributed to the increases in total body mass. Together with its appetite-enhancing activity, these results support the further development of anamorelin in treating cancer anorexia-cachexia."}
+{"text": "Chronic diarrhea, vomiting, reflux, bloating, flatulence, and chronic stomach pain accompanied by cranky behavior are common symptoms related to delayed food sensitivity reactions in preschool children ranging from one to five years of age. It is not known whether immune intolerance and/or inflammatory reactions are playing any role in these children due to over-reactivity to food specific immunoglobulin load.At Alletess Medical Laboratory, we analyzed 966 preschool children. Our 96 food ELISA assay was used to assess food specific IgG antibody loads at three different levels low (10 \u2013 25 ug/ml), moderate (25 \u2013 50 ug/ml), and high (>50 ug/ml). The 96 foods were categorized into dairy products, animal proteins, grains, nuts, fish, shell fish, herbs, spices, vegetables, and fruits groups.Our results revealed the following percentages of this subpopulation with high IgG antibody loads: dairy products (18 - 21%), grain/seeds (19 - 32%), eggs (29%), tree nuts (6 - 20%), peanuts (29%), animal proteins (< 2%), vegetables and fruits (< 5%), and yeasts (3 - 13%).Overload of food specific IgG antibodies could be the cause of intolerance and/or symptoms related to inflammatory reactions of the bowels. The burden related to this IgG overload could be lowered by replacing offending foods with well-balanced food alternatives in preschool children in order to improve their overall wellness.Further clinical studies are recommended to confirm these findings including observing IgA and IgE immunoglobulin levels as well as IL-10 level studies for those with bowel related symptoms."}
+{"text": "Presenting symptoms in patients with Glu89Gln transthyretin (TTR) gene mutation are related to peripheral and autonomic nervous system damage; nevertheless, Glu89Gln TTR gene mutation is responsible for early and severe cardiac involvement (which significantly worsens the prognosis). Early diagnosis of cardiac involvement in subjects with TTR gene mutation can significantly affect patient therapy.We compared 99mTc-3, 3-diphosphono-1, 2-propanodicarboxylic acid (DPD) imaging with electrocardiography (ECG), echocardiography, biomarkers dosage  and troponin-I) and magnetic resonance (MR) imaging with late gadolinium enhancement (LGE) in order to determine the most sensitive technique in early detection of cardiac amyloid deposition in subjects with Glu89Gln TTR gene mutation.Seven asymptomatic subjects  with Glu89Gln TTR gene mutation and normal interventricular septum (IVS) thickness and NT-proBNP level underwent three 99mTc-DPD scans (at baseline and two and four years later) and were followed-up for 5-8 years by clinical examination, ECG, echocardiography and cardiac biomarkers dosage. Baseline MR imaging with LGE was also available.Scintigraphic images were analyzed visually  and semiquantitatively.Three patients showed no myocardial accumulation in all 99mTc-DPD scans; increased IVS thickness occurring four years after the last 99mTc-DPD scan was the only abnormal finding in these patients. In two patients, 99mTc-DPD scan revealed grade 2 radiotracer uptake; baseline MR imaging showed focal LGE in both patients. In these patients, mean left ventricle (LV) wall thickness >12 mm occurred within 3 years; NT-proBNP reached the current diagnostic level for cardiac amyloidosis in only one patient, six years after the positive scan. Two patients had negative baseline 99mTc-DPD scan and cardiac uptake in the following scans. Increased mean LV wall thickness was found three years after positive scintigraphy; NT-proBNP increased later in one patient. ECG abnormalities appeared some years after a positive 99mTc-DPD scan had occurred.Cardiac uptake of 99mTc-DPD precede clinical, instrumental and laboratory signs of amyloidosis; it may represent the earliest sign of cardiac amyloidosis development in subjects with Glu89Gln TTR gene mutation preceding of some years fulfillment of current diagnostic criteria for cardiac amyloidosis."}
+{"text": "Immunoglobulin replacement therapy is standard of care for patients with primary humoral immunodeficiency . CompareAdult patients with common variable immunodeficiency or X-linked agammaglobulinemia transitioning from IVIG to SCIG were invited to participate in this prospective, open-label, pilot study. At least one set of Short-Form 36 Health Survey (SF-36), Profile of Mood States (POMS), Epworth Sleepiness Scale (ESS) and nighttime sleep questionnaires was administered prior to the final IVIG infusion. These were repeated monthly for 3 months following the transition. Magnitude of change was estimated between IVIG trough and final SCIG steady-state data. Statistical significance was determined using linear mixed models for repeated measures with Kenward-Rogers correction.Twenty-seven patients were included in the analysis. Two of eight SF-36 quality of life domains showed significant improvement: role limitations due to physical health (p = 0.01) and emotional problems (p = 0.04). Two of six POMS mood subscales significantly improved: depression (p = 0.03) and anger (p = 0.04). One of six POMS mood subscales  and POMS total mood disturbance scores (p = 0.09) trended towards improvement. No significant changes were noted in ESS or nighttime sleepiness scores.Patients transitioning from IVIG to SCIG for treatment of primary antibody immunodeficiency showed significant improvement in several quality of life and mood subscales. A larger study verifying these findings could encourage patients to switch to SCIG self-administration, producing quality of life benefits while decreasing health care costs."}
+{"text": "We hypothesized that dysferlin functions may contribute to muscle cell viability in the knock-in mice; however, pathological interactions between glycosylation abnormalities and dysferlin defects remain unexplored. To investigate contributions of dysferlin deficiency to the pathology of dystroglycanopathy, we have crossed dysferlin-deficient dysferlinsjl/sjl mice to the fukutin-knock-in fukutinHp/\u2212 and Large-deficient Largemyd/myd mice, which are phenotypically distinct models of dystroglycanopathy. The fukutinHp/\u2212 mice do not show a dystrophic phenotype; however, (dysferlinsjl/sjl: fukutinHp/\u2212) mice showed a deteriorated phenotype compared with (dysferlinsjl/sjl: fukutinHp/+) mice. These data indicate that the absence of functional dysferlin in the asymptomatic fukutinHp/\u2212 mice triggers disease manifestation and aggravates the dystrophic phenotype. A series of pathological analyses using double mutant mice for Large and dysferlin indicate that the protective effects of dysferlin appear diminished when the dystrophic pathology is severe and also may depend on the amount of dysferlin proteins. Together, our results show that dysferlin exerts protective effects on the fukutinHp/\u2212 FCMD mouse model, and the (dysferlinsjl/sjl: fukutinHp/\u2212) mice will be useful as a novel model for a recently proposed antisense oligonucleotide therapy for FCMD.Defects in dystroglycan glycosylation are associated with a group of muscular dystrophies, termed dystroglycanopathies, that include Fukuyama congenital muscular dystrophy (FCMD). It is widely believed that abnormal glycosylation of dystroglycan leads to disease-causing membrane fragility. We previously generated knock-in mice carrying a founder retrotransposal insertion in  O-mannosyl glycosylation and a novel phosphodiester-linked modification of O-mannose, termed post-phosphoryl modification, are necessary for \u03b1-DG to serve as a functional laminin receptor Muscular dystrophies are a heterogeneous group of genetic disorders characterized by the progressive loss of muscle strength and integrity. Several lines of evidence have established that the structural linkage between the muscle extracellular matrix and the cytoskeleton is essential in preventing the progression of muscular dystrophy fukutin, the gene responsible for FCMD, and a 3-kb SINE-VNTR-Alu (SVA) retrotransposon insertion into the 3\u2032 UTR of fukutin as the founder mutation in FCMD fukutin have been reported in patients both inside and outside Japan, and recent studies have revealed a broad clinical spectrum for fukutin-deficient muscular dystrophies O-mannosyl sugar chains on \u03b1-DG O-mannosyl chain synthesis and post-phosphoryl modification; mutations in these pathways commonly result in abnormal glycosylation of \u03b1-DG and reduced ligand-binding activity, disrupting the DG-mediated linkage between the extracellular matrix and the cytoskeleton Fukuyama congenital muscular dystrophy (FCMD: MIM 253800) is an autosomal recessive disorder characterized by severe muscular dystrophy, abnormal neuronal migration associated with mental retardation and, frequently, eye abnormalities 2+ concentration, eventually leading to necrosis and myofiber degeneration. Myofibers possess an intrinsic mechanism for repair of damaged membranes, and dysferlin plays a pivotal role in the skeletal muscle membrane repair pathway. In humans, dysferlin deficiency leads to LGMD2B, Miyoshi myopathy or a distal myopathy with anterior tibial onset Defects in DGC components or \u03b1-DG glycosylation disrupt the linkage between the extracellular matrix and the cytoskeleton, thus rendering the sarcolemma more susceptible to contraction-induced damage. This is thought to trigger an increase in intracellular Cafukutin ortholog We previously described a new FCMD mouse model that carries the retrotransposal insertion in the mouse Dysf gene fukutin allele (fukutin+/\u2212) fukutin ortholog (fukutinHp/Hp) have been described previously Dysf mutant allele and the fukutin mutant allele was performed as described previously ad libitum at the animal facility of Kobe University Graduate School of Medicine. Well-trained and skilled researchers and experimental technicians, who have knowledge of methods to prevent unnecessary excessive pain, handled the animals and carried out the experiments. Euthanization was done by cervical dislocation. At sacrifice, the muscles were harvested and snap-frozen in liquid nitrogen (for biochemistry) or in liquid-nitrogen-cooled isopentane (for immunofluorescence and histology). The number and ages of animals used in each experiment is indicated in Figure legends and graphs.Dysferlin-deficient SJL/J mice, a strain with a large deletion in the dysferlinsjl/sjl; SJL background) with two different lines of fukutin mutant mice. One is a transgenic mouse carrying a neo cassette disruption for a single fukutin allele  fukutin ortholog fukutinHp/Hp; 129-C57BL/6 background) (dysferlinsjl/sjl: fukutin+/\u2212); (dysferlinsjl/+: fukutin+/\u2212); (dysferlinsjl/+: fukutinHp/Hp); and (dysferlinsjl/sjl: fukutinHp/Hp). We further crossed (dysferlinsjl/sjl: fukutin+/\u2212) with (dysferlinsjl/+: fukutinHp/Hp) mice or (dysferlinsjl/+: fukutin+/\u2212) with (dysferlinsjl/sjl: fukutinHp/Hp) mice (dysferlinsjl/+: fukutinHp/+); (dysferlinsjl/+: fukutinHp/\u2212); (dysferlinsjl/sjl: fukutinHp/+); and (dysferlinsjl/sjl: fukutinHp/\u2212). To generate double mutant mice for dysferlin and Large deficiency, we crossed dysferlin-deficient SJL/J mice (C57BL/6 backcross 7) with Large-deficient Largemyd mice  dysferlinsjl/+: Largemyd/+); (dysferlinsjl/sjl: Largemyd/+); (dysferlinsjl/+: Largemyd/myd); and (dysferlinsjl/sjl: Largemyd/myd). For more effective breeding, we crossed (dysferlinsjl/+: Largemyd/+) mice with (dysferlinsjl/sjl: Largemyd/+) mice (Dysferlin+/+: Largemyd/myd) mice were obtained from the dysferlin/Large double mutant line and Largemyd mouse colonies.To generate double mutant mice for dysferlin and fukutin deficiency, we crossed dysferlin-deficient SJL/J mice kground) , line B./+) mice . ; mouse monoclonal antibody IIH6 against \u03b1-DG (Millipore); affinity-purified goat polyclonal antibody against the \u03b1-DG core protein (AP-074G-C) fukutinHp/\u2212 mice and litter control fukutinHp/+ mice that were backcrossed to C57BL/6 mice more than 10 times. Protein concentration of the solubilized fractions was measured by Lowry methods, using BSA as a standard. Proteins were separated using 3\u201315% linear gradient SDS-gels. Gels were transferred to polyvinylidene fluoride (PVDF) membrane (Millipore). Blots were probed with antibodies and then developed with horseradish peroxidase (HRP)-enhanced chemiluminescence . Protein bands were detected using the LAS-4000 system (Fujifilm), and band intensities were quantified using Multi Gauge V3.2 software (Fujifilm). Statistical analysis was performed with a two-tailed unpaired t test. A p value of <0.05 was considered to be significant.DG was enriched from solubilized skeletal muscle as described previously For H&E staining, cryosections (7 \u00b5m) were stained for 2 min in hematoxylin, 1 min in eosin, and then dehydrated with ethanol and xylenes. For Masson trichrome staining, sections were fixed with Bouin's solution (Sigma) for 1 hour at 60\u00b0C. The slides were incubated in solution A  for 30 min, and then stained with Weigert's iron hematoxylin  for 15 min. After a rinse with 0.5% HCl in 70% ethanol and a subsequent rinse with warm water, the slides were incubated in solution B  for 1 min, and then stained with FUCHSIN-PONCEAU solution. The slides were washed with 1% acetic acid, incubated in 2.5% phosphomolybdic acid for 5 min, washed with 1% acetic acid, stained with aniline blue, washed with 1% acetic acid, dehydrated, and mounted.For immunofluorescence analysis, sections were treated with cold ethanol/acetone (1\u22361) for 1 min, blocked with 5% goat serum in MOM Mouse Ig Blocking Reagent (Vector Laboratories) at room temperature for 1 h, and then incubated with primary antibodies diluted in MOM Diluent (Vector Laboratories) overnight at 4\u00b0C. The slides were washed with PBS and incubated with Alexa Fluor 488-conjugated or Alexa Fluor 555-conjugated secondary antibodies (Molecular Probes) at room temperature for 30 min. Permount (Fisher Scientific) and TISSU MOUNT (Shiraimatsu Kikai) were used for H&E staining and immunofluorescence, respectively. Sections were observed under fluorescence microscopy .p values <0.05 were considered significant (Student's t-test and Mann\u2013Whitney U test).For quantitative evaluation of muscle pathology, the percentages of myofiber with centrally located nuclei were counted for at least 1,000 fibers for each genotype (n>4). For evaluation of the F4/80-positive and the collagen I-positive area, the immunofluorescence signal was quantitatively measured using Image J software. Statistical analysis was performed using values represent means with standard deviations, and dysferlinsjl/sjl) fukutin ortholog (fukutinHp/Hp) fukutin disruption (fukutinHp/\u2212) showed more abnormal glycosylation of \u03b1-DG than did mice homozygous for the insertion (fukutinHp/Hp mice), although fukutinHp/\u2212 mice did show a detectable amount of residual \u03b1-DG glycosylation dysferlinsjl/sjl: fukutinHp/\u2212) genotype (Largemyd mouse (Largemyd/myd) Largemyd/myd mice is greatly reduced compared with that in fukutinHp/\u2212 mice To generate double mutant mice, we crossed dysferlin-deficient SJL/L mice (genotype . The othdysferlinsjl/sjl: fukutinHp/+), (dysferlinsjl/sjl: fukutinHp/\u2212), (dysferlinsjl/sjl: Largemyd/+), and (dysferlinsjl/sjl: Largemyd/myd) mice (dysferlinsjl/+: fukutinHp/\u2212), (dysferlinsjl/sjl: fukutinHp/\u2212), (dysferlinsjl/+: Largemyd/myd), and (dysferlinsjl/sjl: Largemyd/myd) -agarose beads. Western blot analysis showed a dramatic reduction of dysferlin protein in skeletal muscle from (yd) mice . We alsomyd/myd) . Overalldysferlinsjl/sjl: fukutinHp/\u2212) mice by hematoxylin and eosin (H&E) staining. The (dysferlinsjl/+: fukutinHp/\u2212) mice showed no obvious pathological features of muscular dystrophy (dysferlinsjl/sjl: fukutinHp/+) mice showed mild dystrophic changes such as the presence of necrotic fibers and centrally located nuclei (dysferlinsjl/+: fukutinHp/\u2212) and (dysferlinsjl/sjl: fukutinHp/+) mice are similar to those described previously for retrotransposon knock-in fukutin mutant mice and dysferlin-deficient SJL/J mice, respectively dysferlin or one fukutin allele does not affect the phenotype of fukutinHp/\u2212 or dysferlinsjl/sjl single mutant mice, respectively. H&E staining showed that the (dysferlinsjl/sjl: fukutinHp/\u2212) mice showed further progressed and more severe dystrophic features than did the (dysferlinsjl/sjl: fukutinHp/+) mice in quadriceps (Quad), gastrocnemius (Gast), and tibialis anterior (TA) muscles (dysferlinsjl/sjl: fukutinHp/\u2212) mice than that in the (dysferlinsjl/sjl: fukutinHp/+) mice (We examined the histopathology of (ystrophy . The (dyd nuclei . The phe muscles . Compari/+) mice .dysferlinsjl/sjl: fukutinHp/\u2212) and (dysferlinsjl/sjl: fukutinHp/+) skeletal muscle more precisely, we counted the percentage of muscle fibers (TA) with centrally located nuclei at different ages (dysferlinsjl/sjl: fukutinHp/+) and the (dysferlinsjl/sjl: fukutinHp/\u2212) mice, but no significant differences were seen between the two (data not shown). At 15 weeks and 30 weeks of age, the (dysferlinsjl/sjl: fukutinHp/\u2212) mice show significantly more fibers with centrally located nuclei than do the (dysferlinsjl/sjl: fukutinHp/+) mice (dysferlinsjl/sjl: fukutinHp/\u2212) mice increased with age. These results indicate more frequent cycles of muscle cell degeneration and regeneration in the (dysferlinsjl/sjl: fukutinHp/\u2212) mice. We next compared infiltration of macrophage and connective tissue as indicators of disease severity. Immunofluorescence analysis using the monoclonal F4/80 antibody, a marker for macrophages, indicated that macrophage infiltration was increased in (dysferlinsjl/sjl: fukutinHp/\u2212) skeletal muscle compared with (dysferlinsjl/sjl: fukutinHp/+) skeletal muscle (dysferlinsjl/sjl: fukutinHp/\u2212) skeletal muscle (dysferlinsjl/sjl: fukutinHp/\u2212) skeletal muscle (dysferlinsjl/sjl: fukutinHp/\u2212) skeletal muscles (dysferlinsjl/sjl: fukutinHp/\u2212) skeletal muscle. Importantly, although the (dysferlinsjl/+: fukutinHp/\u2212) mice do not show muscle pathology, the (dysferlinsjl/sjl: fukutinHp/\u2212) mice show a more severe phenotype than do the (dysferlinsjl/sjl: fukutinHp/+) mice, suggesting that dysferlin plays a protective role in preventing disease manifestation in the (dysferlinsjl/+: fukutinHp/\u2212) mice.To compare the pathological severity in (ent ages . In 8-we/+) mice . The prol muscle . Quantifl muscle . Masson l muscle . Quantif muscles . These dfukutinHp/\u2212 skeletal muscle dysferlinsjl/sjl: fukutinHp/\u2212) mice, we analyzed the population of albumin-positive muscle fibers. Intracellular albumin staining often is used as an indicator of muscle fiber damage or increased membrane permeability dysferlinsjl/+: fukutinHp/+) and (dysferlinsjl/+: fukutinHp/\u2212) and only sparsely observed in (dysferlinsjl/sjl: fukutinHp/+) skeletal muscles, whereas they appeared increased in (dysferlinsjl/sjl: fukutinHp/\u2212) skeletal muscle (dysferlinsjl/sjl: fukutinHp/\u2212) mice (dysferlinsjl/+: fukutinHp/\u2212) mice have latent membrane fragility, which is protected partially by dysferlin functions, and membrane fragility caused by synergy of reduced \u03b1-DG glycosylation and dysferlin-deficiency underlies the deteriorated phenotype of the (dysferlinsjl/sjl: fukutinHp/\u2212) mice.Our previous data and those of others suggest that muscle cell membrane fragility due to loss of DG or its functional glycosylation triggers disease manifestation l muscle . Quantif/\u2212) mice . These dfukutinHp/\u2212 mice. Western blot analysis showed that levels of dysferlin, caveolin-3, and MG53 were not significantly different between fukutinHp/\u2212 and fukutinHp/+ skeletal muscle  mice. Largemyd/myd mice show severe muscular dystrophic phenotypes such as infiltration of connective and fat tissues and marked variation in fiber size Largemyd/myd mice dysferlinsjl/+: Largemyd/myd) mice was more severe than that in (dysferlinsjl/sjl: Largemyd/+) mice  and (dysferlinsjl/sjl: Largemyd/myd) mice. The (dysferlinsjl/+: Largemyd/myd) mice showed necrotic and centrally nucleated fibers, indicating frequent cycles of muscle degeneration and regeneration (dysferlinsjl/sjl: Largemyd/myd) mice exhibited severe pathology, including marked variation in fiber size and large areas with infiltration (dysferlinsjl/sjl: Largemyd/myd) than in (dysferlinsjl/+: Largemyd/myd); however, we did not observe statistically significant differences between the two groups. Furthermore, quantification of collagen I immunofluorescence showed no significant difference in connective tissue infiltration between (dysferlinsjl/sjl: Largemyd/myd) and (dysferlinsjl/+: Largemyd/myd) skeletal muscles. These results suggest that dysferlin function produces limited protective effects against the progression of severe muscular dystrophy in Largemyd/myd mice. Interestingly, however, when compared with the (dysferlin+/+: Largemyd/myd) mice, the (dysferlinsjl/sjl: Largemyd/myd) mice showed significant increases in F4/80, collagen I and intracellular albumin staining (dysferlinsjl/sjl: Largemyd/myd) and (dysferlinsjl/+: Largemyd/myd) skeletal muscles was estimated to be \u223c20% and \u223c60% of that from (dysferlin+/+: Largemyd/myd) muscle, respectively (dysferlinsjl/sjl: Largemyd/myd) mice. Overall, our results suggest that the protective effects of dysferlin on dystroglycanopathy phenotype appear to be diminished when the dystrophic pathology is severe and progressive and also may depend on the amount of dysferlin proteins.We subsequently analyzed the histopathology of (/+) mice . To examneration . In addineration . The  mice did not exhibit a muscular dystrophy phenotype, (dysferlinsjl/sjl: fukutinHp/\u2212) mice developed a more exacerbated phenotype than did the dysferlin single-mutant (dysferlinsjl/sjl: fukutinHp/+) mice. It has been widely accepted that \u03b1-DG glycosylation plays an important role in preventing disease-causing membrane fragility by maintaining a tight association between the basement membrane and the muscle cell membrane, and its defects produce muscle membrane that is susceptible to damage dysferlinsjl/sjl: fukutinHp/\u2212) mice suggests latent membrane fragility in fukutin-deficient fukutinHp/\u2212 skeletal muscle. Indeed, the increased number of intracellular albumin-positive fibers in the (dysferlinsjl/sjl: fukutinHp/\u2212) mice also supports this hypothesis. It is assumed in the fukutinHp/\u2212 myofiber that interaction between the basement membrane and the cell membrane may be weakened, and therefore disease-causative membrane damage could occur during muscle contractions. However, such presumable membrane fragility may be protected in part by the dysferlin functions.Here we have characterized the contribution of dysferlin-deficiency to the pathology of dystroglycanopathy using double mutant mice for dysferlin and \u03b1-DG glycosylation. To date, several dystroglycanopathy model mice have been established. fukutinHp/\u2212 mice, suggesting that dysferlin functions other than membrane repair may play protective roles in the fukutinHp/\u2212 mice. Recently, accumulating evidence has suggested new dysferlin roles other than membrane repair, such as T-tubule formation, maintenance, and stabilizing stress-induced Ca2+ signaling It is known that dysferlin plays a role in membrane repair pathway and several proteins are known to interact with dysferlin, suggesting that dysferlin forms a protein complex during the membrane repair process. MG53 has been shown to interact with dysferlin and participate in membrane repair, and genetic disruption of MG53 in mice results in muscular dystrophy dysferlinsjl/sjl: Largemyd/myd) mice did not exhibit significant deterioration of muscle pathology compared with the single-mutant (dysferlinsjl/+: Largemyd/myd) mice. These data suggest that the protective effects of dysferlin in Largemyd/myd mice were slightly or much reduced compared with those in fukutinHp/\u2212 mice. Since Largemyd/myd mice showed severe and rapid progressive pathology while fukutinHp/\u2212 mice were asymptomatic, our data suggest that the protective effect of dysferlin may be less when disease pathology is advanced and/or severe. It has been reported that a double mutant of dysferlin and dystrophin produced a more exacerbated phenotype than did either single mutant Largemyd/myd mice show much more severe and rapid progressive pathology than do dystrophin-deficient mdx mice, supporting our hypothesis of a limited protective effect of dysferlin in dystrophic pathology. Interestingly, the (dysferlinsjl/sjl: Largemyd/myd) mice, however, showed a significantly worse phenotype that did the (+dysferlin/+: Largemyd/myd) mice. In addition, there is a tendency toward a worse phenotype in the order of dysferlin amount, i.e. (+dysferlin/+: Largemyd/myd), (dysferlinsjl/+: Largemyd/myd), and (dysferlinsjl/sjl: Largemyd/myd). These data support the possibility that the protective effect of dysferlin is present even in the severe dystrophic Largemyd/myd mice. We conclude that dysferlin has the potential to protect muscular dystrophy progression; however, its effect may depend on disease severity and the amount/activity of dysferlin proteins.Our results showed, rather unexpectedly, that the double-mutant  fukutinHp/\u2212 mice do not exhibit any signs of muscular dystrophy dysferlinsjl/sjl: fukutinHp/\u2212) mice compared with (dysferlinsjl/sjl: fukutinHp/+) mice. Since the (dysferlinsjl/sjl: fukutinHp/\u2212) mice possess the retrotransposal insertion and show dystrophic phenotype, they will be used as the first model for evaluation of the antisense oligonucleotide therapy for FCMD. There is a possibility that the absence of dysferlin could add hurdles on how to interpret the results of the antisense oligonucleotide treatments; however, our quantitative assessments established in this study could overcome this issue. For example, macrophage infiltration (dysferlinsjl/sjl: fukutinHp/\u2212) mice. These parameters in the (dysferlinsjl/sjl: fukutinHp/+) mice were not changed compared with those in the (dysferlinsjl/+: fukutinHp/+) and the (dysferlinsjl/+: fukutinHp/\u2212) mice, and therefore can be used for quantitative evaluation for therapeutic effects of the antisense oligonucleotide treatments. We hope that generation of this novel FCMD model and establishment of the quantitative evaluation for disease severity will accelerate the future translational researches to overcome FCMD.Recently, we showed that the retrotransposal insertion in the 3\u2032-UTR region of ltration , connectltration , and memltration  were sigFigure S1Expression of dysferlin and dysferlin-interacting proteins in fukutinHp/\u2212 mice. (A) Western blot analysis of dysferlin, caveolin-3, and MG53 in skeletal muscle extracts from fukutin-deficient fukutinHp/\u2212 (Hp/\u2212), and control fukutinHp/+ (Hp/+) mice. A representative two individual samples for each mouse line are shown in the blots. (B) Quantification of protein expression (panel A) was shown in graphs. Data shown are the average with standard deviations . (C) Immunofluorescence analysis of dysferlin in fukutinHp/\u2212 (Hp/\u2212) and fukutinHp/+ (Hp/+) mice. Bar, 50 \u00b5m.(DOCX)Click here for additional data file."}
+{"text": "Clostridium species are gram-positive, anaerobic, spore-forming bacteria and some species have pathogenic nature. There is limited data regarding Clostridium non-difficile infection in critically ill patients available. Symptoms of infection are often non-specific, which leads to delayed diagnosis and therapy initiation in these patients.Aim of this study was to evaluate patients with positive microbiological cultures of Clostridium non-difficile infection with the need of critical care medicine.Patients with microbiological result of Clostridium non- difficile infection admitted to the intensive care unit (ICU) were included in this study. Patient\u00b4s characteristics including admission diagnosis, severity of illness (SOFA- score), therapeutic procedures and outcome were recorded.A total of 47 critically ill patients  with Clostridium non-difficile infection were included in this study. The most common pathogens were Clostridium innocum (n = 23), Clostridium perfringens (n = 11), Clostridium tertium (n = 6) and others (n = 7). Pathogens were detected in 62% intra-abdominal, in 29% in blood cultures and 8% of patients had soft tissue infection. Intra-abdominal infections (71%) were the most common source of infection.Admission diagnoses were septic shock (54%), surgical treatment (44%) and others (2%). Highest incidence of septic shock was seen in patients with Clostridium innocum infection, (p < 0.05). Preexisting, mostly abdominal (90%) malignancy was seen in 46% of these patients. Invasive ventilation was needed in 50%, vasopressor therapy in 71% and renal replacement therapy in 38%. The overall ICU mortality was 45%. Highest ICU mortality rate was found in patients with Clostridium innocum infection (45%), followed by Clostridium perfringens (23%) and Clostridium tertium (17%). Patients with septic shock showed significantly higher mortality rates (p < 0.05). By means of source of infection highest mortality rate was found in abdominal infection (65%) followed by bacteremia (43%).Clostridium non-difficile infection in critically ill patients is associated with high mortality and organ failure. Worst outcome was observed in patients with septic shock."}
+{"text": "Adoptive T cell therapy can mediate durable regression of cancer . While pin vitro culture and after adoptive transfer in vivo. Streamlining the generation of large numbers of high-frequency tumor-specific T cells in a cost effective, reproducible fashion through Enrichment+Expansion could be a powerful addition to autologous tumor immunotherapy protocols.To quickly generate large numbers of functional tumor-specific T cells from na\u00efve T cell precursors, we developed a T cell Enrichment+Expansion strategy using paramagnetic, nanoscale artificial Antigen Presenting Cells (nano-aAPC), which are capable of enriching rare tumor-specific T cells in a magnetic column and activating them. We generated up to 150,000 total Trp2-specific cells in only one week from 10 million polyclonal CD8 lymphocytes containing approximately 10 precursor cells ["}
+{"text": "Headaches recur in up to 87% of migraine patients visiting the emergency department (ED), making ED recidivism a management challenge.We aimed herein to determine the role of corticosteroids in the acute management of migraine in the ED and outpatient care.A PubMed search was employed for Clinical Studies and Systematic Reviews on the PubMed Clinical Queries tool combining the terms \u2018migraine\u2019 and \u2018corticosteroids\u2019 from 1980 until May 1, 2014.Twenty-two studies  and four systematic reviews were included. International Classification of Headache Disorders criteria were applied in 68%. Twenty-one studies indicated observed outcome differences favoring benefits of corticosteroid administration. Median absolute risk reduction was 30% (range 6 - 48.2%) and 11% (6 - 48.6%) for 24- and 72-hour headache recurrence, respectively. Parenteral dexamethasone was the most commonly (65%) administered steroid, at an average single dose of 12.8 mg (range 4 - 24 mg). All meta-analyses revealed efficacy of adjuvant corticosteroids to various abortive medications \u2013 indicating generalizability. Adverse effects were tolerable. Higher disability, status migrainosus, incomplete pain relief, and previous history of headache recurrence predicted outcome favourability.Our literature review suggests that with corticosteroid treatment, recurrent headaches become milder than pretreated headaches and later respond to nonsteroidal therapy. Single-dose intravenous dexamethasone provides reasonable option for managing resistant, severe, or prolonged migraine attacks; recommendations include 6-8 administrations per year with follow up of adverse effects.No conflict of interest."}
+{"text": "Zaire ebolavirus) originating from Guinea that are now being widely used in laboratories in North America for research regarding West African Ebola viruses.Here, we report the complete genome sequences, including the genome termini, of three Ebola virus isolates (species  CurrentH.\u00a0sapiens-tc/GIN/2014/Makona-WPGC05, Ebola virus/H.\u00a0sapiens-tc/GIN/2014/Makona-WPGC07, and Ebola virus/H.\u00a0sapiens-tc/GIN/2014/Makona-WPGC15). These viruses were grown in Vero E6 cells (sequences were derived from p1 stocks) and are now used by a number of high-containment laboratories in North America, making their sequences of interest to these facilities. RNA was extracted from cell supernatant using a viral RNA extraction kit (Qiagen) using protocols approved by the Institutional Biosafety Committee and reverse transcribed using Superscript III (Invitrogen). PCR products of approximately 700 bp in length were amplified using IProof polymerase (Bio-rad) and subjected to conventional Sanger sequencing. Terminal sequences were determined by 5\u2032 and 3\u2032 rapid amplification of cDNA ends (RACE) based on ligation-anchored PCR, as previously described (5We have determined the complete genome sequences, including the genome termini, of three virus isolates originating from Guinea (Ebola virus/scribed 57. SequenAll three full-length genome sequences showed very high similarities to nearly complete genome sequences of West African EBOVs previously published, although there were between 2 and 4 nucleotide differences to published EBOV sequences from Guinea . SurprisKP096420, KP096421, and KP096422.The complete genome sequences of the EBOV isolates WPGC05, WPGC07, and WPGC15 have been submitted to GenBank under the accession numbers"}
+{"text": "Because the brain integrates peripheral physiology and white adipose tissue (WAT) is the primary energy source during hibernation, we hypothesized that both of these organs play a crucial role in hibernation, and thus, their activity would be relatively increased during hibernation. We carried out the first genomic analysis of small RNAs, specifically miRNAs, in the brain and WAT of a hibernating bat (Myotis ricketti) by comparing deeply torpid with euthermic individual bats using high-throughput sequencing (Solexa) and qPCR validation of expression levels. A total of 196 miRNAs (including 77 novel bat-specific miRNAs) were identified, and of these, 49 miRNAs showed significant differences in expression during hibernation, including 33 in the brain and 25 in WAT (P\u22640.01 &\u2502logFC\u2502\u22651). Stem-loop qPCR confirmed the miRNA expression patterns identified by Solexa sequencing. Moreover, 31 miRNAs showed tissue- or state-specific expression, and six miRNAs with counts >100 were specifically expressed in the brain. Putative target gene prediction combined with KEGG pathway and GO annotation showed that many essential processes of both organs are significantly correlated with differentially expressed miRNAs during bat hibernation. This is especially evident with down-regulated miRNAs, indicating that many physiological pathways are altered during hibernation. Thus, our novel findings of miRNAs and Interspersed Elements in a hibernating bat suggest that brain and WAT are active with respect to the miRNA expression activity during hibernation.MicroRNAs (miRNAs) regulate many physiological processes through post-transcriptional control of gene expression and are a major part of the small noncoding RNAs (snRNA). As hibernators can survive at low body temperatures (T Torpor is often expressed when animals are exposed to low ambient temperature (Ta), and the decrease in energy use is crucial for survival during adverse conditions and food shortages  hibernation, many detailed studies have analyzed miRNAs during torpor  and the sea cucumber (Apostichopus japonicus) during hypometabolism, but these species\u2019 genomic backgrounds and miRNA data are not available in miRbase [Myotis lucifugus, as the animal model to explore miRNA expression in two vital organs (brain and WAT) during hibernation.Our findings were possible with the ultrahigh-throughput sequencing technique (RNA-seq) Illumina/Solexa sequencing, which provides a great platform to discover and analyze small RNAs. It has been previously used in non-model species, such as the Arctic ground squirrel [ miRbase , 21. The miRbase . However miRbase . In the M. lucifugus genome database and removing the reads that matched genome \u226520, the small RNA annotation indicated that miRNAs  are the most abundant fraction of small RNAs   , includiogFC\u2502\u22651)  [18, 20,ogFC\u2502\u22651) . We concP<0.05), and all of them were affected by differentially expressed miRNAs, particularly by down-regulated miRNAs  identified here may help further explore the phylogenetic evolution of heterothermy in bats. With the progress of the M. lucifugus genome sequencing project and the increased accuracy of gene annotation, more detailed information on miRNAs involved in hibernation will likely be uncovered from bat transcriptome libraries. These can be used to better understand heterothermy the physiology and evolution of heterothermy.We identified 196 miRNAs (77 novel miRNAs) in bats by in-depth analysis of the small RNAs in the hibernating species S1 FigHomo sapiens reference sequences were downloaded from the NCBI Reference Sequence database (http://www.ncbi.nlm.nih.gov/RefSeq/).(JPG)Click here for additional data file.S2 Fig(PNG)Click here for additional data file.S3 FigGallus gallus; has: Homo sapiens; cel: Caenorhabditis elegans; dme: Drosophila melanogaster; sme: Schmidtea mediterranea.gga: (JPG)Click here for additional data file.S1 Table(DOC)Click here for additional data file.S2 TableThe table summarizes the total number of small RNA reads by Solexa sequencing. After removing adapter contaminants, reads less than 18 nt and containing Ns, the clean reads from each library were used for the small RNA screen. HB: hibernating state brain; AB: active state brain; HA: hibernating state adipose tissue; AA: active state adipose tissue.(DOC)Click here for additional data file.S3 TableRedundancy among libraries was calculated to estimate the quality of the Solexa small RNA libraries. Moreover, the numbers of state/tissue-specific expressed reads were identified. HB: hibernating state brain; AB: active state brain; HA: hibernating state adipose tissue; AA: active state adipose tissue.(DOC)Click here for additional data file.S4 Table(DOC)Click here for additional data file.S5 Table(DOC)Click here for additional data file.S6 Table(A) 90 conserved miRNA hairpins. (B) 101 novel miRNA hairpins.(XLSX)Click here for additional data file.S7 TableP\u22640.01 & \u2502logFC \u22651). (C) List of 25 miRNAs differentially expressed in adipose tissue (P\u22640.01 & \u2502logFC\u2502\u22651). (D) List of 9 miRNAs differentially expressed in both brain and adipose tissue (P\u22640.01 & \u2502logFC\u2502\u22651). (E) List of 31 tissue/state-specifically expressed miRNAs in brain (23) and adipose tissue (8).(A) Expression details of 196 miRNAs (119 conserved miRNAs and 77 novel miRNAs). (B) List of 33 miRNAs differentially expressed in the brain ((XLSX)Click here for additional data file.S8 Table(XLSX)Click here for additional data file.S9 TableKEGG pathway analysis (A) and GO annotation (B) of target genes regulated by 196 miRNAs, 119 conserved miRNAs, 8 conserved miRNAs differentially expressed in the brain, 13 conserved miRNAs differentially expressed in adipose tissue, 77 novel miRNAs, 25 novel miRNAs differentially expressed in the brain, and 12 novel miRNAs differentially expressed in adipose tissue. T-tests were performed to analyze the bio-activity of each physiological process in both tissues by comparing hibernation vs. active state.(XLS)Click here for additional data file.S10 TableGenes, only identified by DGE sequencing and not the targets of differentially expressed miRNAs which obtained in this study, are in green.(XLS)Click here for additional data file."}
+{"text": "The re-emerging invalidating chikungunya (CHIK) disease has recently extended to temperate areas. Following the acute febrile polyarthritis, miscellaneous long-lasting rheumatic musculoskeletal disorders (RMSKD) are reported, consistent with chronic inflammatory rheumatisms (CIR) notably rheumatoid arthritis (RA). The post CHIK-infection stage remains a challenge to treat, while the early use of disease-modifying antirheumatic drugs (DMARDs) is recommended in RA. After the 2005-2006 CHIK outbreak in Reunion Island, we retrospectively categorized CHIK-related RSMKD and analyzed the empirical use of DMARDs starting with methotrexate (MTX) to treat the CIR forms.We reviewed medical files of patients referred to rheumatologists in Saint Denis between 12/2005-05/2012 for persisting rheumatic disorders (>4 months) after a proven CHIK infection. We distinguished de novo post-CHIK RMSKD from exacerbation of pre-existing disorders. CIR included: 1) RA defined according 2010 ACR/EULAR criteria, 2) spondylarthropathy (SA) defined according ESSG classification, and 3) undifferentiated polyarthritis (UP) defined as at least three swelling joints. Response to MTX was efficacy versus failure . Determinants for efficacy were identified using Fisher exact test.Among 159 patients included, 122 suffered from de novo RSMKD with 28 presenting chronic pains and 94 fulfilling CIR criteria. RA accounted for 40/92 (12 positive for anti-CCP antibodies); SA for 33/94 (15 with psoriasis); and distal UP for 21/94. 72 of them (including the 31 CIR with joint damages) were treated with MTX , reaching efficacy in 54 cases  versus failure in 18 cases . No severe side event was observed. The group efficacy did not differ with age, sex or type of CIR, but was significantly associated with the early introduction of MTX within the first year of CIR progression .Among the wide spectrum of post CHIK RMSKD, CIR should benefit from the early use of MTX. DMARD\u2019s efficacy could bring some clues to investigate the underlying post CHIK-infection disorders."}
+{"text": "Ophthalmic evaluations finalized the clinical diagnosis of CD for the two patients in this family, both of whom presented macular atrophy with no remarkable changes in the peripheral retina. Comprehensive genetic screening approach revealed biallelic missense mutations in the Leber congenital amaurosis 5 (LCA5) gene, p.[Ala212Pro];[Tyr441Cys], as disease causative for this family. Both mutations were novel. The first substitution was predicted to eliminate a hydrogen bond and alter the tertiary structure of lebercilin, protein encoded by LCA5. We for the first time report novel biallelic LCA5 mutations in causing CD. Our study extends the phenotypic and genotypic spectrums for LCA5-associated retinopathies and better illustrates its genotype-phenotype correlations, which would help with better genetic diagnosis, prognosis, and personalized treatment for CD patients.We aim to characterize the clinical features and genetic causes for two affected siblings from a Chinese family with cone dystrophy (CD). Two patients and four unaffected family members were recruited and received complete ophthalmic examinations. Genomic DNA was isolated from the peripheral blood samples from all patients. Targeted next-generation sequencing (NGS) approach followed by intrafamilal cosegregation and  LCA5) gene (MIM 611408) are reported to cause one to two percent of patients with Leber congenital amaurosis (LCA). LCA is the most severe form of inherited retinal dystrophies (IRDs). Its typical features include blindness or severe visual impairments within the first year of life, congenital nystagmus, sluggish or absent pupillary responses, photophobia, and high hyperopiaLCA5 mutations have been widely reported as LCA causative in multiple ethnic groups34567891012LCA5 mutations in two Asian families with early-onset retinal dystrophy (EORD) and a Spanish family with retinitis pigmentosa (RP)12Mutations in the Leber congenital amaurosis 5  in two affected siblings from a Chinese family with autosomal recessive inheritance pattern.Two patients, two unaffected siblings and their asymptomatic parents were included in the present study with their family pedigree presented in LCA5 c.[634G>C];[1322A>G], were potential disease causing mutations for the two patients  machinery, and functions as an integral element for the transport of certain proteins through photoreceptor cilia313LCA5 mutations have previously been reported, of which 30 mutations are implicated in the etiology of LCA, 3 in EORD, and one in RP , VEP, ERG and OCT examinations. FAF imaging and FFA was selectively conducted on the proband, patient YZ-II:4. Additionally, 150 unrelated healthy controls free of retinal or other major ocular diseases were also included. Peripheral venous blood samples (5\u2009mL) were collected from all included participants for genomic DNA isolation with a QIAmp DNA Mini Blood Kit .http://hgdownload.cse.ucsc.edu/goldenPath/hg19/database/snp137.txt.gz.), HapMap Project (ftp://ftp.ncbi.nlm.nih.gov/hapmap), 1000 Genome Project (ftp://ftp.1000genomes.ebi.ac.uk/vol1/ftp), YH database (http://yh.genomics.org.cn/), Exome Variant Server (http://evs.gs.washington.edu/EVS/), and Exome Aggregation Consortium (http://exac.broadinstitute.org/), were subsequently used for the filtration process. Variants found homozygous or with a minor allele frequency (MAF) of over 0.01 in these SNP databases were then discarded. Intrafamilial cosegregation analysis and prevalence test in 150 additional controls were further conducted using Sanger sequencing with the primer information detailed in Targeted NGS approach was selectively employed on patient YZ-II:1 for mutation identification using a previously described microarray targeting 180 IRDs causative and 9 candidate genes171819Homo sapiens (ENSP00000376686), Pan troglodytes (ENSPTRP00000031394), Canis lupus familiars (ENSCAFP00000004169), Bos taurus (ENSBTAP00000053829), Sus scrofa (ENSSSCP00000004819), and Mus musculus (ENSMUSP00000034791).Vector NTI Advance 11 software  was applied to assess the evolutionary conservation of mutated residue by aligning the orthologous sequences of lebercilin in the following species, including How to cite this article: Chen, X. et al. Next-generation Sequencing Extends the Phenotypic Spectrum for LCA5 Mutations: Novel LCA5 Mutations in Cone Dystrophy. Sci. Rep.6, 24357; doi: 10.1038/srep24357 (2016)."}
+{"text": "Two mediastinal masses were incidentally detected at high resolution computed tomography (HRCT) of a 72 year-old male patient, former smoker, affected by chronic obstructive pulmonary disease with worsening dyspnea and 2-year medical history of polycythemia secondary to hypoxia. Integration with a multidetector computed tomography (MDCT) scan after administration of intravenous injection contrast medium showed slightly inhomogeneous increase of enhancement of masses, suggesting in the first case potential malignancy. Diagnosis of extramedullary hematopoiesis was achieved by fine needle aspiration citology (FNAC). Extramedullary hematopoiesis must be considered in differential diagnosis in patients with medical history of polycythemia and severe hypoxia. He presented a 2-years medical history of polycythemia secondary to hypoxia, and for these reasons underwent periodic phlebotomies. He was smoker (30 cigarettes / day for 45 years) with a history of pulmonary heart disease with moderate pulmonary hypertension, diabetes mellitus, hypertension and respiratory failure, treated with oral hypoglycemic agents, diuretics, acetylsalicylic acid, and OBody temperature was normal. Physical examination showed dyspnea at rest, acral cyanosis and peripheral edema and splenomegaly. Physical examination of the chest revealed bronchostenosis and rales on both lower field of lungs.12/l; hemoglobin (Hb) 15 g/dl; mean corpuscular volume (MCV) 86.3 fl; hematocrit (HCT) 55.3 %; mean corpuscular hemoglobin (MCH) 23.4 pg; mean corpuscular hemoglobin concentration (MCHC) 27.1 g/dl; red blood cell distribution width - coefficient variation (RDW-CV), 19.1%; red blood cell distribution width - standard deviation (RDW-SD) 56.1 fl; WBC 8.18\u00d7109/l; PLT 127\u00d7109/lLaboratory analysis showed the following: red blood cell (RBC) 6.41\u00d7102 69.7 mmHg; pO2 42.0 mmHg; cHCO\u22123 29.8 mmol/L; cBase: 9.6 mmol/L; flow-volume spirometry test showed a restrictive pattern with obstructive component : forced vital capacity (FVC) 35% ; forced expiratory volume 1 second (FEV1) 31%  ; Tiffeneau Index FEV1/FVC 74.3%; peak expiratory flow (PEF) 32%  ; forced expiratory flows FEF25% 19% ; FEF50% 15% ; FEF75% 27% . Coagulation profile, amylase and lipase levels were normal. Hepatitis screen was negative.Arterial blood gas analysis showed an hypoxaemic hypercapnic respiratory failure, with respiratory acidosis : pH 7.329; pCOChest X-Ray during his workup in the hospital showed diffuse thickening of peribronchial interstitium; spine did not show any X-Ray abnormality .Chest high resolution computed tomography (HRCT) showed the peribronchial thickening, typical of COPD and peripheral areas of parenchymal consolidation in the medial segment of the middle lobe and lingula; interstitium was not tickened. .HRCT scan of the chest showed two masses occupying left and right paravertebral mediastinal regions, that required a volumetric multidetector computed tomography (MDCT) scan before and after intravenous administration of contrast medium .MDCT scan confirmed the presence of two lobulated masses with dense soft parts; borders were smooth and there was not calcification inside. Masses were located into the posterior mediastinum showing a paravertebral distribution at the level of the tenth thoracic vertebra . After iMultiplanar reconstructions (MPR) at the anatomic levels of symmetric lesions were performed. Maximum extension was 33 mm on coronal view. Tenth thoracic vertebra, showed demineralization signs compatible with angiomatous lesion without bone erosion. Other finding was splenomegaly  . LymphadCT guided percutaneous fine needle aspiration cytology (FNAC) was performed on left paravertebral mass and confirmed the diagnosis of extramedullary hematopoiesis (EMH) .12/lit, hemoglobin (Hb) was 13.7 g/lit, while the CT scan confirmed the approximately same dimensions of masses. The patient underwent to a single phlebotomy during follow up.The patient started a closer follow up for respiratory failure and hematological changes; with a more adequate therapy with maximum dose of bronchodilator drugs (beta2 agonists with corticosteroids 50/500 mcg twice a day and anticholinergic drugs once a day) and an increase of O2 to 2 lit. per minute at rest and during night, and 2.5 lit. per minute under exercise during 24 hours, with bi-level positive airway pressure (BPAP), the last hematocrit (HTC) was 50.6 %, the red blood cells count (RBC) was 5.85\u00d710IV.EMH is considered a physiological compensatory mechanism, characterized by proliferation of hematopoietic cells outside the bone marrow, occurring when the bone marrow is unable to satisfy the physical demand .EMH is often associated with congenital hemoglobinopathies  or with acquired bone marrow replacement disorders  \u20135.Extramedullary hematopoiesis tissue usually develops in sites related to hematopoiesis during fetal development \u20138; experEMH causes usually no symptoms and findings are incidental. Diagnosis of intra-thoracic EMH can be suspected on a chest X-Ray, CT or magnetic resonance imaging (MRI) .Chest X-Ray is often normal, but if intra-thoracic EMH is large, it may show paravertebral lobulated masses with well-defined borders, usually bilateral, without calcifications or bone erosion. Bone lesions, if present, are related to underlying disease \u201316.On CT scan, intra-thoracic EMH is characterized by presence of lobulated masses with dense soft parts, usually homogeneous with smooth borders, without calcification inside and may be present adipose tissue within the mass. Usually those masses are bilateral and located below the level of the sixth thoracic vertebra \u201318. AfteMRI may be useful to identify adipose tissue within the mass and demonstrate thoracic rib expansion without evidence of cortical bone erosion. EMH masses usually present low signal on both T1w and T2w images; after intravenous administration of contrast medium, is evidence of low enhancement, although EMH tissue is highly vascular .99mTc sulfur colloid or 111In has a role not yet been clarified, but it can be used to demonstrate areas of focal uptake of the tracer localizing to paravertebral masses (hematopoietic activity) [Radionuclide bone scintigraphy using ctivity) .The diagnosis can be obtained with FNAC, open biopsy, or thoracoscopic biopsy in uncertain cases .Other causes of posterior mediastinal masses include neurogenic tumors , benign bone tumors of the spine , mesenchymal tumor, hemangioma, lymphangioma, malignant neoplasms , infective etiologies  . Calcifi"}
+{"text": "Included were consecutive patients at all ages with pre-hospital cardiac arrest treated by eight anaesthesiologist-staffed pre-hospital critical care teams in the Central Denmark Region.We prospectively registered data  accordinWe registered data from 595 cardiac arrest patients; in 58.9 % (n=350) of these cases the pre-hospital critical care teams performed pre-hospital endotracheal intubation.2 measurement following pre-hospital endotracheal intubation were available in 270 cases.An initial end-tidal CO2 below 1.33 kPa.We identified 22 patients, who had an initial ETCOFour of these patients achieved return of spontaneous circulation. All four patients were admitted to hospital, three with stable circulation and one with ongoing automated CPR due to recurrent cardiac arrest.2 below 1.33 kPa during pre-hospital cardiac arrest should not be used as a cut-off value for the achievability of return of spontaneous circulation.Our results indicates that an initial ETCO"}
+{"text": "Southern tomato virus (STV) isolate on tomato plants in a seed production field in Bangladesh was obtained for the first time using next-generation sequencing. The identified isolate, STV_BD-13, shares a high degree of sequence identity (99%) with several known STV isolates worldwide.The complete genome sequence of a  Southern tomato virus (STV) is a double-stranded RNA (dsRNA) virus with a small genome of approximately 3.5\u00a0kb containing two overlapping open reading frames (ORFs). Based on its dsRNA genome and the pattern of genome structure, STV was classified in the genus Amalgavirus of the family Amalgaviridae (Tobacco mosaic virus (TMV) and Potato virus Y (PVY) (Pepino mosaic virus (PepMV), Tomato spotted wilt virus (TSWV), and Tomato yellow leaf curl virus (TYLCV) (Cucumber mosaic virus (CMV), and Tomato chlorosis virus  . In Spaiis virus . In summis virus  and sequis virus . From this virus . BLASTn is virus . Such brSouthern tomato virus isolate STV_BD-13 has been deposited in GenBank under the accession number KT634055.The genome sequence of"}
+{"text": "Drosophila bithorax locus in which a multitude of regulatory elements control segment specific gene activity. Centrosomal protein 190 (CP190) is targeted to insulators by CTCF or other insulator DNA-binding factors. Chromatin analyses revealed that insulators are characterized by open and nucleosome depleted regions. Here, we wanted to identify chromatin modification and remodelling factors required for an enhancer blocking function. We used the well-studied Fab-8 insulator of the bithorax locus to apply a genome-wide RNAi screen for factors that contribute to the enhancer blocking function of CTCF and CP190. Among 78 genes required for optimal Fab-8 mediated enhancer blocking, all four components of the NURF complex as well as several subunits of the dREAM complex were most evident. Mass spectrometric analyses of CTCF or CP190 bound proteins as well as immune precipitation confirmed NURF and dREAM binding. Both co-localise with most CP190 binding sites in the genome and chromatin immune precipitation showed that CP190 recruits NURF and dREAM. Nucleosome occupancy and histone H3 binding analyses revealed that CP190 mediated NURF binding results in nucleosomal depletion at CP190 binding sites. Thus, we conclude that CP190 binding to CTCF or to other DNA binding insulator factors mediates recruitment of NURF and dREAM. Furthermore, the enhancer blocking function of insulators is associated with nucleosomal depletion and requires NURF and dREAM.Chromatin insulators of higher eukaryotes functionally divide the genome into active and inactive domains. Furthermore, insulators regulate enhancer/promoter communication, which is evident from the  Drosophila genome also codes for the additional insulator factors zeste white5 (Zw5) and boundary element associated factor 32 (BEAF-32) Drosophila genome with 80% of them being bound by at least one of the five DNA-binding insulator factors. This suggests that CP190 may confer an important role in insulator function Chromatin insulators mediate boundary or barrier functions as well as an enhancer blocking activity Fab-8 and compared the identified set of factors with those detected by either purifying CTCF or CP190. With these three strategies we identified the nucleosome remodelling factor NURF and components of the multi-subunit transcription repressor complex dREAM. Chromatin \u201copening\u201d and efficient insulator mediated enhancer-blocking are facilitated by these complexes.We used an unbiased functional screen involving the CTCF/CP190-dependent insulator Fab-8 insulator that separates the regulatory elements of the bithorax complex, which specifies the third thoracic segment and all eight abdominal segments of the fly Fab-8 was shown to depend on CTCF and on CP190 Fab-8 element placed between the enhancer and the reporter, a second Fab-8 sequence upstream of the enhancer (F8OF8L) , was used. This library contains approximately 21,000 dsRNAs targeting 13,900 genes and is provided in a 384-well-plate format . The NURF complex is composed of the chromatin remodelling ATPase ISWI and the components NURF-38, NURF-301 and CAF-1/p55 Drosophila RBF, dE2F2, dMYB and the dMYB-interacting proteins MIP40, MIP120 and MIP130 In order to identify cofactors involved in CP190 mediated chromatin insulation we utilized a genomic region that has been well characterized for insulator function as well as for the functional dependency on CTCF and CP190. Such a region is the (F8OF8L)  allows fe format . After ae format . The z-se format . These 7e format . Six of Fab-8 element at the enhancer blocking position , 1% penicillin/streptomycin and glutamine). Synthesis of dsRNA and RNAi treatment was done as described on www.flyrnai.org (see supplements for primer sequences).www.flyrnai.org). The library comprises 66\u00d7384-well plates and covers the entire genome. A detailed description of the RNAi screening, RNAi hit validation and RNAi on other insulation sites can be found in the supplementary methods (The genome-wide dsRNA library (DRSC 2.0) was produced by the Drosophila RNAi Screening Center (DRSC) at Harvard Medical School ( methods . A basicS2 cells were cultured and processed for chromatin immunprecipitation as described previously 4 for 24 h. For endogenous Co-immunoprecipitation wildtype S2 cells were used. Nuclear extract preparation was performed as described S2 cells were stably transfected with pRm-HA/FLAG-dCTCF or -CP190 and the expression of cell clones induced with 500 mM CuSORabbit anti-dCTCF http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE51600.Data has been deposited in NCBI's Gene Expression Omnibus (GEO) database under accession number GSE51600: Figure S1F8OL and F8OF8L clone pools show the expected CTCF dependent enhancer blocking. S2 cell clone pools with the integrated F8OF8L insulator reporter or the control F8OL reporter construct were incubated with dsRNA against GFP (control) or against CTCF (CTCF). Reporter gene activity is expressed as relative light units. Error bars indicate the standard deviation of three individual replicates.(TIF)Click here for additional data file.Figure S2CP190 binding profiles are very similar to DREAM and ISWI/Nurf301 profiles. Publicly available ChIP-chip data for DREAM components   as well as CP190, CTCF, ISWI, Nurf301 and several other profiles (ModEncode) serving as controls were binned into 100 bp bins by calculating the average enrichment of ChIP over input within each bin. Pair wise correlation coefficients were calculated. Hierarchical clustering of coefficients is shown as color coded heat map. The numbers behind ModEncode derived profile names refer to ModEncode IDs.(TIF)Click here for additional data file.Figure S3DREAM and NURF associate with CP190 and CTCF/CP190 but not with stand-alone CTCF binding sites. Cumulative binding profiles for indicated factors across the 3 classes of CTCF/CP190 binding sites . Stand-alone CP190 as well as common CTCF/CP190 sites are bound by DREAM and NURF components to a similar extent whereas stand-alone CTCF sites are devoid of both complexes. All binding data are from ModENCODE.(TIF)Click here for additional data file.Figure S4CTCF as well as CP190 sites bound simultaneously by NURF are enriched for promotor associated annotations. Distribution of genomic elements  upstream region (\u22121 kb to \u221210 kb upstream of TSS), green for TSS (+/\u22121 kb around TSS), light blue for exon and dark blue for intron and purple for transcriptional end sites (TES)) across CTCF and CP190 binding sites with respect to overlap with NURF301 binding (data from ModENCODE). Enrichment for TSS-associated binding of CTCF and CP190 is associated with simultaneous NURF301 binding.(TIF)Click here for additional data file.Figure S5Western blot after knockdown of CTCF and CP190 demonstrates CP190 and CTCF depletion. S2 cells were transfected with dsRNA corresponding to dCTCF and CP190 (dsCTCF/CP190) or firefly luciferase (dsLuci) as control. Cell extracts of three independent experiments were analyzed by Western blot with antibodies directed against dCTCF, CP190 or tubulin as loading control.(TIF)Click here for additional data file.Figure S6Depletion of ISWI or MIP130 does not affect CTCF or CP190 binding. (A) Western blot after knockdown of ISWI  and Mip130  demonstrates ISWI and Mip130 depletion, but no influence on CTCF/CP190 protein level. knockdown control, dsLuci; protein loading control, Tubulin. (B) ChIP in S2 cells treated with dsRNA against ISWI (dsISWI) and Mip130 (dsMip130) or against luciferase as control (dsLuci). Antibodies were used specific for dCTCF (top) and CP190 (bottom). The genomic regions tested are strong binding sites for dCTCF and CP190: Sbr, cg31472, Adar, cg12772, wgn, CG1354; a weak binding site for dCTCF: cg17681 and two negative control sites: Fab-8 ctrl and cg8745 ctrl. Values are expressed as % input. Error bars indicate the standard deviation of three independent experiments.(TIF)Click here for additional data file.Figure S7Genome browser view of insulators Fab-8, bcd, CG31472 and Fab-6. Publicly available ChIP-chip data for CP190, CTCF and other insulator binding proteins , Modmdg4 and GAF) (ModEncode) show the binding profiles at the tested insulator elements (bottom black box in each case). Known transcripts are shown at the top in each case. (A) Fab-8 sequence (B) bicoid sequence (C) CG31472 sequence (D) Fab-6 sequence (E) control site to compare general peaks of the insulator binding proteins .(TIF)Click here for additional data file.Figure S8Western blot after knockdown of CTCF plus CP190 and of ISWI demonstrates depletion of these factors. S2 cells were transfected with dsRNA corresponding to dCTCF and CP190 (dsCTCF/CP190), ISWI (dsISWI) or firefly luciferase (dsLuci) as control. Cell extracts of two independent experiments were analyzed by Western blot with antibodies directed against dCTCF, CP190, ISWI or tubulin as loading control.(TIF)Click here for additional data file.Figure S9Depletion of CTCF/CP190 and ISWI interferes with nucleosome depletion at CP190 positive DNase I hypersensitive sites. Cumulative representation of changes in H3- binding and MNase-protection as detected by H3 ChIP-seq and MNase-seq after depletion of CTCF/CP190  or ISWI (orange). Data is shown as coverage for specific knock-down normalized to luciferase control knock-down (luci) after log2-transformation. Average effects are shown across DNase I hypersensitive sites ) positive for CP190 binding (colored) or control DHSs devoid of significant CP190 binding (grey).(TIF)Click here for additional data file.Figure S10Depletion of CTCF/CP190 and ISWI interferes with nucleosome depletion as determined by MNase digestion or by H3 ChIP. Representation of changes in H3-binding (top) and MNase-protection (bottom) after MNase treatment and H3 ChIP in S2 cells treated with dsRNA against dCTCF and CP190 , ISWI  or against luciferase as control . All sites with increased MNase-protection and H3 binding after CTCF/CP190 depletion (positive sites) show a similar MNase-protection and H3 increase upon ISWI depletion. Non-responding sites after CTCF/CP190 depletion do not respond to ISWI depletion. Error bars indicate the standard deviation error of the mean of two independent experiments .(TIF)Click here for additional data file.Figure S11Depletion of CTCF/CP190 and ISWI interferes with nucleosome depletion at CP190 binding site clusters 2 to 5 marked by NURF an DREAM binding. Cumulative representation of changes in histone H3-binding after depletion of CTCF/CP190 (A: green/DKD) or ISWI (B: orange). Data was analyzed separately for CP190 binding sites clusters 1\u20136 identified in (TIF)Click here for additional data file.Table S1Z-score list of all dsRNA sequences with a z- score \u22652. NURF- and dREAM components are highlighted in pink and blue.(XLSX)Click here for additional data file.Table S2Sequences, localisation, size and other characteristics of tested sites in the reporter assays (top) and ChIP assays (bottom). bp, base pairs; chr, chromosome; fwd., forward; re, restriction enzyme; rev., reverse; TES, transcriptional end site; TSS, transcriptional start site.(XLSX)Click here for additional data file.Text S1Supplementary information on methods and references.(DOCX)Click here for additional data file."}
+{"text": "BCR-ABL translocation resulting from rearrangement of the minor breakpoint cluster region (m-bcr) in BCR gene. Subsequent evaluation of the disease showed calreticulin (CALR) 52-bp deletion as well as the absence of JAK2V617F heterozygous mutation in granulocyte population of peripheral blood using allele-specific PCR and bi-directional DNA sequencing. To our knowledge, this is the first case of a patient initially diagnosed as p190 BCR-ABL transcript positive CML in blast crisis characterized by a 52-bp deletion in CALR gene.We introduce a 78-year-old woman presented with thrombocytosis and high blast count who had a history of splenectomy. Her cytogenetic analysis revealed aberrant chromosomal rearrangements in different clonal populations harboring 46XX karyotype with t . RT-PCR assay detected the e1a2  This rare fusion transcript, also known as minor breakpoint cluster region (m-bcr), codes for a smaller (190kDa) oncoprotein with a unique clinical presentation between CML and chronic myelomonocytic leukemia (CMML).4Chronic myeloid leukemia (CML) is the most important myeloproliferative neoplasm (MPN) developed due to the known t9;22)q34;q11) chromosomal translocation in pluripotential hematopoietic progenitor cells. This genetic alteration results in the formation of Philadelphia chromosome (Ph\u2032), comprising portions of Abelson JAK2) and thrombopoietin receptor (MPL) genes BCR/ABL negative MPNs, calreticulin (CALR) gene mutations have also been used in classification and determination of diagnostic criteria for MPNs and myelodysplastic/myeloproliferative neoplasms (MDS/MPN), including essential thrombocythemia (ET), primary myelofibrosis (PMF) and refractory anemia with ring sideroblasts associated with marked thrombocytosis (RARS-T), respectively.CALR does not occur in CML, but some authors have recently reported the existence of these somatic changes in remaining portions of nonmutated JAK2 and MPL MPN cases.6Besides the identification of mutations in Janus kinase 2 , white blood cell (WBC) count of 68200/\u03bcL with 16% neutrophils, 1% eosinophils, 1% monocytes, 48% lymphocytes, 16% atypical lymphocytes and 18% blasts. Morphologic review of the PB smear revealed basket cells and nucleated red blood cells. BM aspirate smears showed hypercellular marrow with increased blasts  revealed anemia with a hemoglobin concentration of 8.6 g/dL, thrombocytosis  , der(17) and der18) chromosome abnormalities in different clonal populations harboring 46XX karyotype with t9;22)   in additn (FISH) . In the  chromoso;22 .CALR mutation in p190 BCR-ABL CML and its likely impact on the clinical course and prognosis of our patient. So far, CALR mutation status has been associated with thrombocytosis in MPNs, including ET and PMF.CALR 52-bp deletion in our CML case imparts the high platelet count and ultimately mimics its progression toward cases other than CML in MPNs. Since platelet count acts as a prognostic factor in the evaluation of response to TKIs, we suggest the detection of CALR mutation in all p190 BCR-ABL CML patients initially presenting with thrombocytosis given the prognosis and treatment strategies in such cases.CALR 52-bp deletion may act as a distinctive feature in the diagnosis of p190 BCR-ABLCML patients. Questions remain regarding the exact contribution of CALR deletion to MPNs.CMML-like phenotype with monocytosis seems to be a useful diagnostic picture for most cases of p190 BCR-ABL CML especially in chronic phase,"}
+{"text": "Trigemino-spinal sensitization and impaired descending inhibitory control (DNIC) has been reported in chronic migraine.1 Further mechanism behind occipital nerve stimulation (ONS) remains speculative.This observational study characterises peripheral and central sensitization in patients undergoing ONS for intractable chronic migraineQuantitative Sensory testing (QST) measurements were carried out in patients before and after ONS (n=6).1. Measurement of pressure pain thresholds (PPT): Computer-controlled pressure algometer  measured PPTs at standardized three points .2. DNIC: DNIC response was measured using PPT on cheekbone with an inflated cuff insitu on one arm.Patients with chronic migraine demonstrated loss of DNIC, (PPTs 56.0 KPa vs 46.2kPA cuff inflated). A \u201cnormal\u2019 DNIC response was observed two weeks following ONS (58.4 kPA vs 100.4kPA cuff inflated) continuing positively over next three months. In contrast the PPTs remained same before and after the ONS.This case series reports sustained reversal of the loss of DNIC response in patients undergoing ONS for intractable headache whilst having no effect on peripheral pain thresholds.No conflict of interest."}
+{"text": "Cardiac function was similar between groups after TAC although +dP/dT and -dP/dT trended towards improvement in MycKO-TAC versus Cont-TAC. In sham hearts, Myc knockout did not affect cardiac function or substrate preferences for the citric acid cycle. However, Myc knockout altered fractional contributions during TAC. The unlabeled fractional contribution increased in MycKO-TAC versus Cont-TAC, whereas ketone and free fatty acid fractional contributions decreased. Additionally, protein posttranslational modifications by O-GlcNAc were significantly greater in Cont-TAC versus both Cont-Sham and MycKO-TAC. In conclusion, Myc alters substrate preferences for the citric acid cycle during early pressure overload hypertrophy without negatively affecting cardiac function. Myc also affects protein posttranslational modifications by O-GlcNAc during hypertrophy, which may regulate Myc-induced metabolic changes.Hypertrophic stimuli cause transcription of the proto-oncogene c-Myc (Myc). Prior work showed that myocardial knockout of c-Myc (Myc) attenuated hypertrophy and decreased expression of metabolic genes after aortic constriction. Accordingly, we assessed the interplay between Myc, substrate oxidation and cardiac function during early pressure overload hypertrophy. Mice with cardiac specific, inducible Myc knockout (MycKO-TAC) and non-transgenic littermates (Cont-TAC) were subjected to transverse aortic constriction . Additional groups underwent sham surgery . After two weeks, function was measured in isolated working hearts along with substrate fractional contributions to the citric acid cycle by using perfusate with  The proto-oncogene c-Myc (Myc) is an important regulator of cardiac hypertrophy \u20139. AlthoN-acetylglucosamine (O-GlcNAc)  in a parasternal short axis mode for at least three heart beats. The pulsed Doppler velocity was measured across the aortic constriction site. This velocity serves as a non-invasive estimate of the peak instantaneous pressure gradient across the constriction site and is calculated by the modified Bernoulli equation (\u0394 pressure gradient = 4*velocity2). Clinically, the calculated mean pressure gradient is often a better estimate of the pressure gradient measured invasively from cardiac catheterization. The mean pressure gradient was estimated by dividing the modified Bernoulli equation in half.Serial echocardiograms were performed prior to and after two weeks of TAC. Mice were initially sedated with 3% isoflurane in OIn vivo afterload increases with aortic constriction. To simulate in vivo conditions, the MycKO-TAC and Cont-TAC hearts were perfused at a higher afterload than the Sham hearts. We felt that this strategy would more accurately reflect in vivo substrate utilization patterns than perfusing sham and TAC hearts at the same afterload. Additionally, studies in Langendorff (retrograde aortic) mouse heart perfusions have shown that different perfusion pressures are needed to achieve similar coronary flows between aortic constricted and sham hearts acetoacetic acid , L-lactic-3-[13C]acid , and U-[13C]-long-chain mixed free fatty acids  bound to 0.75% (wt/vol) delipidated bovine serum albumin reconstituted with deionized water. Insulin (50 microunits/ml) was included in the perfusion solutions. To establish the origin of the unlabeled fraction in the aortic constricted mice, 2 hearts each from Cont-TAC and MycKO-TAC were perfused with unlabeled lactate (1.2 mmol/l), 1-[13C]glucose (5.5 mmol/l), 1,3-[13C]ACAC (0.17 mmol/l), U-[13C]free fatty acids (0.35 mmol/l). The hearts subjected to TAC  were initially stabilized at 50 mmHg afterload and 15 mmHg preload for 10 minutes before acutely increasing afterload to 80 mmHg. Sham mice were perfused with standard loading conditions of our laboratory consisting of a 12 mmHg preload and a 50 mmHg afterload. An SPR-PV-Catheter  was inserted into the left ventricle through the apex for continuous measurement of left ventricular pressure (LVP). Only aortic outflow that bypasses the coronary arteries is recirculated. Left atrial inflow was measured with a flow probe  and aortic (not including coronary flow) flow was measured via 30 second timed collections. Coronary flow was calculated as the difference between left atrial inflow and aortic flow although this measurement is affected by perfusate leak from the left atrium. Every 10 minutes, left atrial influent and coronary effluent was collected for determination of PO2, PCO2, and pH with an ABL800 blood gas analyzer . The coronary effluent is collected as it drips from the heart. Although we attempt to limit effluent exposure time to the atmosphere, some atmospheric gas exchange likely occurs which would affect the oxygen tension levels and calculations based upon this measurement . Continuously recorded parameters are left ventricular (LV) pressure (mmHg), HR (beats/min), and rate of LV contraction and relaxation . Myocardial oxygen consumption (MVO2) was calculated as MVO2 = CF x [(PaO2\u2014PvO2) x (c/760)] x heart weight, where CF is coronary flow (ml\u00b7min\u22121g wet weight\u22121), (PaO2\u2014PvO2) is the difference in the partial pressure of oxygen  between perfusate and coronary effluent, and c is the Bunsen solubility coefficient of O2 in perfusate at 37\u00b0C (22.7 \u03bcl O2\u00b7atm-1\u00b7ml-1). Cardiac work was calculated as the cardiac output times the developed pressure. Cardiac efficiency was defined as cardiac work/MVO2.Experiments were performed as previously described with changes noted below ,18. The m hearts ,20. Beca13C-labeled substrates in combination with NMR spectroscopy. Glutamate isotopomer analyses provide fractional contribution of acetyl-CoA to the citric acid cycle from up to three differentially labeled substrates as well as the unlabeled components.Myocardial tissue was extracted as previously described ,18. Subs13C NMR spectral acquisition. NMR free-induction decays (FIDs) were acquired on a Varian Direct Drive (VNMRS) 600 MHz spectrometer  equipped with a Dell Precision 390 Linux workstation running VNMRJ 2.2C. The spectrometer system was outfitted with a Varian triple resonance salt-tolerant cold probe with a cold carbon preamplifier. A Varian standard one dimensional carbon direct observe sequence with proton decoupling was used to collect data on each sample. Final spectra were accumulations of 4800 individual FIDs. Each FID was induced using a nonselective, 45-degree excitation pulse (7.05 us @ 58 dB), with an acquisition time of 1.3 seconds, a recycle delay of 3 seconds, and a spectral width of 224.1 ppm.Lyophilized heart extracts were dissolved in 99.8% D2O for decoupled 2 and the stoichiometric relationships between oxygen consumption and citrate formation from the various substrates as previously described [FIDs were baseline corrected, zero-filled, and Fourier transformed. Labeled carbon resonances of glutamate were integrated with the Lorentzian peak fitting subroutine in the acquisition program . The individual integral values were used as starting parameters for the citric acid cycle analysis fitting algorithm tcaCALC, kindly provided by Drs. Malloy and Jeffrey . This alescribed ,22.Western blots were performed as previously described on freshly isolated hearts (i.e. separate from the perfused hearts) ,18. BrieReported values are means \u00b1 standard error (SE) in figures and text. Data were analyzed with two-way unpaired t-test or a single factor ANOVA (multiple comparisons). If significance was identified between the groups by ANOVA ; then a two-way unpaired t-test was performed. Criterion for significance was p < 0.05 for all comparisons.in vivo systolic function measured during TAC [in vivo systolic functional differences between MycKO-TAC and Cont-TAC hearts after TAC. Compared to baseline (pre-TAC), ejection and shortening fractions were unchanged by TAC in both groups. Left ventricular end diastolic diameter decreased in both groups after TAC whereas end systolic diameter declined in Cont-TAC only. The diameter changes are likely due to the development of hypertrophy.Prior echocardiogram studies demonstrated that Myc knockout did not affect ring TAC . We simiIn prior studies, Myc knockout during aortic constriction attenuated the ratio of heart weight to tibial length, reduced cardiomyocyte size, and decreased ANP levels ,10. To cEx vivo functional assessments were made during the working heart perfusions. All reported values are after 20 minutes of stable left atrial infusion.in vivo conditions, Cont-TAC and MycKO-TAC hearts were perfused at high afterload (80 mmHg) whereas Cont-Sham and MycKO-Sham hearts were subjected to standard afterload (50 mmHg). The different afterloads affect functional parameters; therefore we did not compare sham heart function to TAC. Ex vivo cardiac function was similar between Cont-Sham and Cont-MycKO (max (p = 0.08) and-dP/dTmin (p = 0.05) in MycKO-TAC hearts compared to Cont-TAC although other functional parameters were similar  gave an average calculated glucose fractional contribution of 0.135\u00b10.005 in Cont-TAC and 0.22\u00b10.02 in MycKO-TAC, which indicates that the majority of the unlabeled fraction was from exogenous glucose in the TAC groups.Next, we determined the fractional contribution of acetyl-CoA to the citric acid cycle for each studied substrate. In sham hearts, fractional contributions were unaffected by Myc knockout  . As partMyc knockout reduced global O-GlcNAc levels during pressure overload hypertrophy. Laczy et al. found that acute O-GlcNAcylation promoted fatty acid oxidation . They peMyc knockout did not affect protein levels of the key O-GlcNAc regulatory enzymes GFAT, OGT or OGA. Although Myc commonly acts as a transcription factor, our results suggest that Myc alters O-GlcNAc levels through non-transcriptional mechanisms. These mechanisms potentially include changes in GFAT, OGT and/or OGA activity by post-translational modifications. Additionally, generation of the O-GlcNAc moiety depends on shuttling glucose into the hexosamine biosynthesis pathway; an accessary pathway from glycolysis. Although O-GlcNAc may influence substrate preferences; paradoxically, metabolic changes could also influence O-GlcNAc levels by affecting hexosamine biosynthesis flux . The intAlthough we tried to limit atmospheric exposure, the oxygen tension in the coronary effluent is potentially altered by atmospheric gas exchange. This limitation would affect the oxygen consumption values used to calculate estimated flux for overall citric acid cycle and individual substrates. Accordingly, the flux values should be considered calculated estimated values. However, individual substrate fractional contributions to the citric acid cycle are not affected by this limitation.Hypertrophy often affects non-oxidative glycolysis; however, the MRS based method used in this study does not measure glycolytic flux. Thus, we cannot make conclusions on Myc\u2019s affect for overall glucose utilization during hypertrophy.The current study demonstrates that Myc affects myocardial substrate utilization preferences for the citric acid cycle during early pressure overload hypertrophy, but not during normal physiology. However, Myc\u2019s regulation of metabolic changes was not necessary to maintain cardiac function. Myc knockout altered global O-GlcNAc levels during aortic constriction, which may mechanistically regulate the changes in substrate preferences.S1 TableFlux units are \u03bcmol/g/min. Acetoacetate was used for ketones. Note: Sample 042213A was excluded for flux value calculations because of a perfusate leak from the left atrium, which would render the MVO2 value inaccurate. However, the leak does not affect the fractional contribution values.(XLSX)Click here for additional data file.S2 TableThe O-GlcNAc western blot and total protein quantification pictures are shown in manuscript (XLSX)Click here for additional data file."}
+{"text": "The correct name is: Reeta Subramaniam Mani. The correct citation is Mani RS (2016) Human Rabies Survivors in India: An Emerging Paradox? PLoS Negl Trop Dis 10(7): e0004774. doi:"}
+{"text": "Tobamovirus (Virgaviridae) comprises 33 accepted species with the recent addition of eight new viruses and is divided in to three subgroups based on the origin of assembly of the virion and host range. Within the subgroup 1 tobamoviruses the orchid-associated tobamovirus was hypothesized to be a chimeric derivative of recombinations between genome fragments from subgroup 3 and 1. Recombination events involving RdRp, movement and coat protein genes are recorded within subgroup 1 and 2. However natural recombinations have not previously been reported between subgroup 3 tobamoviruses.The genus Ribgrass mosaic virus clade of subgroup 3 tobamoviruses. Recombination detection analyses indicated that the isolate was a chimeric genome with fragments of high similarity to Ribgrass mosaic virus (RMV) strains NZ-439 (HQ667978) and Actinidia-AC (GQ401365.1) infecting herbaceous Plantago sp. and woody Actinidia spp., respectively. The recombinant differed across the whole genome by 3-8\u00a0% from other published RMV genomes.The organization and phylogenetic analyses of the complete genome and the different ORFs placed the new isolate within the -AC (GQ401365.1), in the replicase component between viral-methyltransferase and viral-helicase regions, resulting in a novel RMV strain FSHS (JQ319720.1) that represents the first described natural recombinant within the RMV cluster of subgroup 3 tobamoviruses.In this investigation we report an intra-specific recombination between RMV strains NZ-439 (HQ667978) and ActinidiaThe online version of this article (doi:10.1186/s12985-016-0487-5) contains supplementary material, which is available to authorized users. Tobamovirus (http://ictvonline.org/virusTaxonomy.asp) that exhibit co-divergence and host-switching have a widespread geographical distribution, an extensive host range and prevail even in abiotic natural ecosystems [Odontoglossum ringspot virus (ORSV). The subgroup 2 viruses are highly diverse infecting members of Cactaceae, Cucurbitaceae, Fabaceae, Malvaceae and Passifloraceae, showing host range specificity and serological relatedness that may prelude an increased number of subgroups [Ribgrass mosaic virus (RMV), Turnip vein clearing virus (TVCV) and Youcai mosaic virus (YoMV) clusters, based on coat protein phylogeny and host range [The viruses of the genus osystems , 21, 24.ubgroups . Subgrouubgroups , 15. Thest range . Althougst range .Plantago lanceolata L. (Plantaginaceae) and has been described with various acronyms and synonyms over the years [Plantago sp., followed by isolation of two strains of RMV viz. Kons. 1105-V2 (HQ667980) and NZ-439 (HQ667978) from the same genus [-AC (GQ401365.1) and Actinidia-AD (GQ401366.1) were isolated from infected leaves of Actinidia chinensis and A. deliciosa respectively (Actinidiaceae) [sensu stricto), confirming three distinct clusters within subgroup 3 tobamoviruses [RMV was first reported by Holmes from he years , with ishe years , 5. The oviruses  and placVirgaviridae, recombinants have been recorded in Furovirus [Hordeivirus [Tobamovirus [Tobravirus [Tobacco mosaic virus (TMV) and Tobacco mild green mosaic virus (TMGMV) appeared to have resulted in a novel TMGMV isolate H7 [Tomato mosaic virus (ToMV), including RdRp, movement and coat protein genes [Cactus mild mottle virus (CMMoV) and Frangipani mosaic virus (FrMV) were shown to be related to viruses infecting diverse host groups, indicating possible recombinations [In the family urovirus , Hordeivdeivirus , Tobamovamovirus , 15 and bravirus  groups. bravirus , 15. Witin genes . In subginations , 20. HowP. major L., showing mild interveinal mottling, from the Waitakere ranges, Auckland region, New Zealand. The presence of tobamoviruses in symptomatic leaves was confirmed using a TMV immunostrip (Agdia #ISK 37800/0024) and also by indirect ELISA using both TMV and RMV specific antisera [The RMV isolate FSHS was collected from leaf tissues of antisera . RNA exthttp://blast.ncbi.nlm.nih.gov/Blast.cgi), all other complete RMV genome sequences [The complete genome, nucleotide (nt) and amino acid (aa) sequences of all the ORFs and the 5\u2032 and 3\u2032UTR sequences of the new strain (JQ319720.1) were compared with GenBank (equences  and reprequences . Phylogeequences .-AC (GQ401365.1), representing the RMV cluster, were analysed using seven different recombination detection algorithms viz. RDP, GeneConv, Bootscan, MaxChi, Chimaera, SiScan and 3Seq (http://web.cbio.uct.ac.za/~darren/rdp) for the possible recombination events with RDP4 [P values obtained for the various algorithms used. Additionally, phylogenetic trees were constructed exclusively for RMV sequences ignoring recombinations, using NJ, UPGMA, FastNJ, ML and Bayesian tree programs built in RDP 4; also ML (GTRCAT) tree incorporating the recombinations [The whole genome and nucleotide sequence of all the ORFs of the strains FSHS JQ319720.1), Kons. 1105 (HQ667979), NZ-439 (HQ667978) and Actinidia720.1, Ko-AC GQ4065.1, repThe genome of RMV strain FSHS (JQ319720.1), comprising 6311nts, showed the typical organisation of a subgroup 3 tobamovirus with four open reading frames (ORFs), with untranslated regions at 5\u2032 and 3\u2032 ends Fig.\u00a0. ORF1 anThe complete FSHS genome differs from the reference sequence RMV strain Kons. 1105 isolate R14 HQ667979) and the Actinidia strains (GQ401365.1 and GQ401366.1) by 8\u00a0%, from RMV NZ-439 (HQ667978) by 3\u00a0%, and from representative members of TVCV and YoMV clusters by 13\u00a0% and 19\u00a0%, respectively. The 5\u2032UTR sequence of FSHS was identical to all other sequences in the RMV cluster and differed by 1-9\u00a0% from TVCV and YoMV respectively. The 3\u2032UTR differed by <3\u00a0% to other sequences in the RMV cluster and 6-8\u00a0% from representative members of TVCV and YoMV clusters respectively. Comparisons between the nucleotide (nt) and amino acid (aa) sequences of the four ORFs of strain FSHS (JQ319720.1) and representative species from three clades within subgroup 3 are summarised in Table\u00a079 and thThe phylogenetic analyses of the whole genome of the RMV strain FSHS JQ319720.1) with 33 different tobamoviruses Fig.\u00a0 placed F720.1 witRecombination detection analyses indicated the occurrence of recombination events within the RMV cluster, as summarised in Table\u00a0The fact that RMV is readily mechanically transmissible provides an opportunity for cross-species transmission, possibly resulting in mixed infections and subsequent recombination. Such recombination events might prelude the ability of the new strain to infect both herbaceous and woody asterids expanding the host range, enabling the recombinant to adapt to new micro-replicative niches producing a new range of symptoms, as has been observed in artificially derived tobamovirus recombinants , 23, 24."}
+{"text": "A 75-year-old man underwent elective biological aortic valve replacement. Two weeks aftersurgery, transthoracic echocardiography (TTE) showed a small pericardial effusion. On thefollowing day, the patient suffered from syncope. A repeated TTE revealed a \"giant\"echo-dense mass (90x80\u00a0mm) occupying the entire right atrium and severely limitingtricuspid valve inflow. Although the initial differential diagnosis included thedevelopment of an intracavitary process, the rapidly-growing mass with a characteristicecho\u2011lucent layer at its atrial aspect  (arrows) led to the final diagnosis of a pericardial hematoma mimicking a hugeatrial mass. Emergency surgical exploration confirmed the diagnosis."}
+{"text": "Escherichia coli does not routinely import manganese, but it will do so when iron is unavailable, so that manganese can substitute for iron as an enzyme cofactor. When intracellular manganese levels are low, the cell induces the MntH manganese importer plus MntS, a small protein of unknown function; when manganese levels are high, the cell induces the MntP manganese exporter and reduces expression of MntH and MntS. The role of MntS has not been clear. Previous work showed that forced MntS synthesis under manganese-rich conditions caused bacteriostasis. Here we find that when manganese is scarce, MntS helps manganese to activate a variety of enzymes. Its overproduction under manganese-rich conditions caused manganese to accumulate to very high levels inside the cell; simultaneously, iron levels dropped precipitously, apparently because manganese-bound Fur blocked the production of iron importers. Under these conditions, heme synthesis stopped, ultimately depleting cytochrome oxidase activity and causing the failure of aerobic metabolism. Protoporphyrin IX accumulated, indicating that the combination of excess manganese and iron deficiency had stalled ferrochelatase. The same chain of events occurred when mutants lacking MntP, the manganese exporter, were exposed to manganese. Genetic analysis suggested the possibility that MntS exerts this effect by inhibiting MntP. We discuss a model wherein during transitions between low- and high-manganese environments E. coli uses MntP to compensate for MntH overactivity, and MntS to compensate for MntP overactivity. Escherichia coli can employ manganese to activate a variety of enzymes, but it does so only when iron is unavailable or the cell is assaulted by oxidants. Under those stress conditions, E. coli activates the synthesis of its MntH manganese importer. However, manganese can also be toxic, and over-accumulation of the metal must be avoided. We investigated additional mechanisms by which the cell ensures that its intracellular manganese pool is sufficient but not excessive. MntS was identified as a small protein that is synthesized when manganese levels decline; it helps to enlarge the manganese pool. In contrast, MntP is a manganese exporter that is synthesized when intracellular manganese levels rise; it keeps manganese levels from becoming too high. In manganese-rich medium either the forced expression of MntS or the absence of MntP led to manganese toxicity, suggesting the possibility that MntS operates as an inhibitor of MntP. This toxicity occurs because excess manganese inhibits the synthesis of heme, a cofactor that is essential for aerobic growth. Thus E. coli controls manganese levels by balancing the actions of MntH, MntP, and MntS against one another. This arrangement allows cells to adapt to shifts in manganese availability and demand.The model organism  Escherichia coli appears not to use manganese as an enzyme cofactor. In this aspect the bacterium probably resembles ancient microbes, which evolved in an anoxic world whose metabolism was configured around the catalytic capabilities of iron. However, after the advent of photosystem II, molecular oxygen gradually accumulated in the atmosphere and caused the oxidation and precipitation of most environmental iron ethanesulfonic acid (MES), o-dianisidine dihydrochloride, o-nitrophenyl-\u00df-D-galactopyranoside (ONPG), potassium ferricyanide, potassium cyanide, tricine, protoporphyrin IX, and xanthine were purchased from Sigma. Ethylenediamine tetraacetic acid (EDTA), guanidine hydrochloride, hydrochloric acid, and 3-(N-morpholino) propane-sulfonic acid (MOPS) were purchased from Fisher Scientific; Coomassie protein assay reagent and albumin standard, from Thermo Scientific; sodium dithionite, from Fluka; and glacial acetic acid, from J.T.Baker.Antibiotics, 5-aminolevulinic acid hydrochloride (5-ALA), \u00df-mercaptoethanol, \u00df-NADH, bovine xanthine oxidase, casein acid hydrolysate, cytochrome mntS-null deletion removes the entire gene sequence, including the non-coding region.The strains and plasmids that were used in this study are listed in lacZ transcriptional fusions, the promoter regions of given genes were amplified by PCR using primers designed with restriction sites. The product was digested and inserted into pSJ501, a plasmid derivative of pAH125 that was modified to express the chloramphenicol acetyl transferase gene (cat) flanked by FLP sites, thereby enabling selection under anoxic conditions. The resulting plasmid constructs were confirmed by restriction analysis and sequencing. Plasmids were then integrated into the \u03bb attachment site, while the wild-type genes remained at their native positions  carrying an empty vector (pACYC184) or pMntS2 . B. MntH functions in the absence of mntS. Strains were JEM1177 (Hpx- \u0394mntS) and JEM1227 (Hpx- \u0394mntS \u0394mntH). C. MntS functions in the absence of mntH. OD600 of strains AA30 (Hpx- \u0394mntH) and JEM1227 (Hpx- \u0394mntH \u0394mntS) grown in the presence of increasing concentrations of MnCl2 for 6 hr.Cells were pre-cultured in anaerobic M9 glucose/casamino acids medium and then diluted at time zero into the same aerobic medium with or without 15 \u03bcM H(TIF)Click here for additional data file.S3 Fig2+. EPR peak heights varied with point of harvest and do not provide a precise comparison of Mn content. Temperature = 30 K, modulation = 5 g, power = 2 mW.Cultures were grown with 500 \u03bcM manganese in LB medium. Peaks represent Mn(TIF)Click here for additional data file.S4 Fig2. Strains were JEM1542/JEM1536 (\u0394ryhB) harboring empty vector (pBAD24) or pMntS  and JEM1538/JEM1540 (\u0394fur \u0394ryhB) harboring empty vector or pMntS. The data are representative of at least three independent experiments.Cells were pre-cultured in aerobic LB medium and then diluted at time zero into fresh LB/arabinose medium with 0.5 mM MnCl(TIF)Click here for additional data file.S5 Fig2 and aerated for 2.5 hr before harvesting. Data represent the mean of three independent cultures. A, B. Levels of NADH dehydrogenase 1 (an iron-sulfur enzyme) and NADH dehydrogenase 2 (an iron-free enzyme) are not diminished during manganese intoxication. Strains were OD502 (\u0394suf) harboring empty vector (pBAD24) or pMntS . C. Transcription of the iscR and sufA genes was not induced during manganese intoxication, indicating that IscR remained in its cluster-containing form. Strains bearing iscR\u2019-lacZ were JEM1474 (WT/pBAD24) and JEM1475 (WT/pLW112). Strains bearing sufA\u2019-lacZ were JEM1476 (WT/pBAD24) and JEM1477 (WT/pLW112).Cells were grown in anaerobic LB/arabinose medium with or without 0.5 mM MnCl(TIF)Click here for additional data file.S6 FigkatG\u2019-lacZ transcriptional fusion were pre-cultured in aerobic LB and then diluted into LB/arabinose medium with or without 0.5 mM MnCl2. Cells were harvested after 2.5 hr treatment. Strains were AL441 harboring empty vector (pBAD24) or pMntS (pLW112).Cells bearing the (TIF)Click here for additional data file.S7 FighemA were pre-cultured in anaerobic LB medium and then diluted at time zero into fresh aerobic LB/arabinose medium with or without 5-ALA. Strains were SMA1091 (\u0394hemA) harboring empty vector (pBAD24) or pMntS . The data are representative of at least three independent experiments.A. The heme biosynthentic pathway. B. Cells lacking (TIF)Click here for additional data file.S8 FighemA-null mutants were grown in aerobic LB/arabinose medium supplemented with 1 mM 5-ALA. Cells were harvested and intracellular porphyrins were quantified after 2.5 hr treatment with or without 0.5 mM MnCl2 or 100 \u03bcM DIP. Data represent the mean of three independent cultures. Strains were JEM1579 (\u0394hemA/pBAD24), JEM1580 (\u0394hemA/pLW112), JEM1683 (\u0394mntP/pBAD24).(TIF)Click here for additional data file.S9 Fig600, and data are presented as the amount of residual growth after removal of the vitamins. (B) A \u0394hemA derivative of MG1655 (SMA1139) was cultured > 4 generations in aerobic minimal A medium containing 1% casamino acids as the sole carbon source plus 1 mM 5-aminolevulinic acid (ALA) to enable heme synthesis. The medium was chosen to mimic the effects of LB medium while avoiding the presence of peptides, since ALA is imported through the dipeptide transporter. At time zero the exponentially growing cells were centrifuged, washed three times, and suspended in the same medium +/- ALA, and growth was monitored.(A) The wild-type strain MG1655 and mutant strains defective in synthesis of thiamine (AB1157), lipoic acid (KER176), and biotin (NRD25) were cultured for 4 generations in minimal A medium supplemented with 0.5 mM of the 20 standard amino acids, plus 5 \u03bcg/ml of the required vitamin. At time zero the cells were then centrifuged, washed three times, and suspended in the same media lacking vitamins. Growth was monitored by absorbance. Cells were repeatedly subcultured to maintain densities < 0.3 OD(TIF)Click here for additional data file.S10 Fig2 (open symbols), and subsequent growth was monitored. The analogous experiment under aerobic conditions causes complete growth arrest for the Mn-supplemented pMntS strain  or containing pMntS  were grown exponentially in anoxic LB medium. At time zero cells were diluted into the same medium with no additions (filled symbols) or with 0.5 mM MnCl; squaresain Figs .(TIF)Click here for additional data file.S11 FigiucC\u2019-lacZ and fhuA\u2019-lacZ in WT strains  harboring the indicated plasmids. B. KatG activity determined from WT (GS45) strains harboring the indicated plasmids.Data represent the mean of three independent cultures. A. Transcription levels of the Fur-regulated genes (TIF)Click here for additional data file.S12 FigsodB \u0394mntS strain JEM1234 containing pDT1\u201316, which overexpresses sodA. Extract were treated to remove Mn from the MnSOD protein. Remetallation was performed in 37o C pH 7.8 Tris/EDTA buffer through the addition of 200 \u03bcM MnCl2, with or without the addition of 0.36 \u03bcM purified MntS. The graph has been scaled to emphasize the early time; two- and three-hour time points revealed the same activity as the one-hour time point.Cell extracts were prepared from the \u0394(TIF)Click here for additional data file.S13 Fig2 and harvested after 2.5 hr of aerobic growth, followed by ICP-MS analysis (A and B) or porphyrin accumulation (C). Data represent the mean of three independent cultures. Strains were MS025 (\u0394mntP) harboring empty vector (pBAD24) or pMntS . Note that data represented by empty vector has been reprinted from Cells pre-cultured in aerobic LB medium were diluted into fresh LB/arabinose medium with or without 0.5 mM MnCl(TIF)Click here for additional data file.S14 Fig600. Cells were washed and resuspended in arabinose medium for 10 min to induce MntS. They were then washed again and suspended in the original glucose medium supplemented with 10 \u03bcM manganese to induce MntP from its native promoter and to reproduce the growth phenotype. At intervals cells were harvested and MntP-SPA content was evaluated by western blot with anti-SPA antibodies. The higher MntP levels in the mntS-overexpressing strains likely results from the increased manganese levels under these conditions Click here for additional data file.S15 FigryhB-\u2018lacZ transcriptional fusion strain JEM1500 (with vector), JEM1501 (pMntS), JEM1503 (fur with pBAD vector) and JEM1504 (fur with pMntS) were grown exponentially in aerobic LB/arabinose medium, and \u00df-galactosidase activity was assayed as a representation of ryhB expression. Where indicated dipyridyl (0.1 mM) was added to moderately restrict iron availability, or an inhibitory dose of manganese (0.5 mM) was added to toxify the pMntS strain. Error bars indicate the standard deviation from 3\u20134 replicates.The (TIF)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table562 (CybC) and ferrous iron transporter (EfeUOB), both of which are cryptic in K-12 strains. E. coli K-12 synthesizes two proteins with siroheme cofactors: sulfite reductase and soluble nitrite reductase (NirB). Ferrochelatase is not involved in siroheme synthesis.Non-K-12 strains additionally express heme-containing soluble cytochrome b(DOCX)Click here for additional data file."}
+{"text": "C. elegans. Suppression and management of protein damage is essential for optimal survival under hypertonic conditions. ASH chemosensory neurons allow C. elegans to detect and avoid strongly hypertonic environments. We demonstrate that mutations in osm-9 and osm-12 that disrupt ASH mediated hypertonic avoidance behavior or genetic ablation of ASH neurons are associated with enhanced survival during hypertonic stress. Improved survival is not due to altered systemic volume homeostasis or organic osmolyte accumulation. Instead, we find that osm-9(ok1677) mutant and osm-9(RNAi) worms exhibit reductions in hypertonicity induced protein damage in non-neuronal cells suggesting that enhanced proteostasis capacity may account for improved hypertonic stress resistance in worms with defects in osmotic avoidance behavior. RNA-seq analysis revealed that genes that play roles in managing protein damage are upregulated in osm-9(ok1677) worms. Our findings are consistent with a growing body of work demonstrating that intercellular communication between neuronal and non-neuronal cells plays a critical role in integrating cellular stress resistance with other organismal physiological demands and associated energy costs.Protein function is controlled by the cellular proteostasis network. Proteostasis is energetically costly and those costs must be balanced with the energy needs of other physiological functions. Hypertonic stress causes widespread protein damage in  Cellular life requires precise control of protein structure and function, which are determined by protein conformation, concentration, assembly and localization. The homeostatic mechanisms that maintain protein function are collectively termed proteostasis. The proteostasis network is evolutionarily conserved and comprises the tightly integrated and regulated activities of gene transcription, RNA metabolism and protein synthesis, folding, assembly, trafficking, disassembly, repair and degradation \u20133.Proteostasis is under constant challenge. Protein structure is inherently unstable ,5 and reC. elegans have pointed to a critical role for the nervous system and communication between different tissue types in coordinating organismal proteostasis needs. For example, Morimoto and co-workers have demonstrated that the heat shock response of non-neuronal cells is modulated by inhibitory inputs from AFD thermosensory neurons as well as neural circuits that respond to metabolic status and nutrient availability , SD551[let-60(ga89)], NL790 gpa-4(pk381), PY7505 oyIs84[gpa-4p::TU#813 + gcy-27p::TU#814 + gcy-27p::GFP + unc-122p::dsRed], TU3311 uIs60[Punc-119::YFP + Punc-119::sid-1], and Is[sra-6p::mCasp]. VC1262 and AM140 strains and TU3311 and SD551 strains were crossed to generate osm-9(ok1677); rmIs132[Punc-54::Q35::YFP] and let-60(ga89);uIs60[Punc-119::YFP + Punc-119::sid-1] worms, respectively. F2 progeny were selected for YFP expression and the presence of the osm-9(ok1677) or let-60(ga89) alleles were verified by PCR. Is[sra-6p::mCasp] [The following strains were obtained from the ::mCasp]  worms we::mCasp] . HypertoThe number of body wall muscle cell Q35::YFP aggregates were quantified manually in blinded experiments using a Zeiss Stemi SV11 microscope . Single aggregate volume measurements and fluorescence recovery after photobleaching (FRAP) analysis were carried using confocal microscopy as described previously .RNA interference. RNA interference (RNAi) was performed by feeding worms from the L1 larval stage with bacteria expressing a nonspecific scrambled dsRNA or dsRNA specific to osm-9. Late stage L4 RNAi worms were transferred to control or high NaCl growth plates seeded with dsRNA expressing bacteria.let-60(ga89) mutant worms were maintained at the permissive temperature of 16\u00b0C. Defective egg hatching or larval arrest phenotypes were quantified by transferring 1-day old gravid adults to 300 mM NaCl feeding plates and then removing them after 24 h. Eggs were scored for failure to hatch or develop past the L1 larval stage.Temperature sensitive Synchronized late L4 worms were exposed to various stressors and survival was determined by prodding animals with a platinum wire. Worms were considered to be dead if they did not respond to repeated prodding. All survival studies were done blinded.Synchronized L4 larvae were transferred to 51mM NaCl agar plates containing 50 \u03bcg/ml 5-fluorodeoxyuracil . Animals were transferred onto fresh plates containing FUDR every 2 days for the first week, then every 4\u20135 days thereafter. Survival was scored daily for touch provoked movement.35S-methionine into total protein was used to assess rates of protein synthesis and degradation. Radiolabeling was carried out using methods similar to those described by others  transgenic has defects in avoidance of noxious chemicals  transgenic strain. The transgenic strain showed significantly (P<0.02) increased survival when exposed to 500 or 600 mM NaCl for 24 h  loss-of-function mutants and the PY7505 transgenic strain in 500 and 600 mM NaCl. gpa-4 encodes a G-protein alpha subunit and has been reported to be expressed selectively in ASI neurons , which exhibits increased sensitivity of neurons to RNAi  worms were fed bacteria expressing scrambled (control) or osm-9 dsRNA. As expected, exposure of worms fed scrambled dsRNA at 16\u00b0C to 300 mM NaCl caused a striking and significant (P<0.006) increase in egg hatching defects and larval arrest. Silencing of osm-9 function by RNAi reduced the expression of the mutant phenotype by ~70% (P<0.005)  .osm-9(ok1677) mutant worms, we therefore also characterized the lifespan of this strain and its resistance to heat, heavy metal and oxidative stress. Median and maximum lifespan were not significantly (P>0.3) different in wild type and osm-9(ok1677) mutants (osm-9(ok1677) mutant exhibited sensitivity to heat shock similar to that of wild type animals (osm-9(ok1677) worms  worms . Quinoneosm-9(ok1677) mutants could result from a number of different physiological changes. When exposed to hypertonic stress, protein synthesis is rapidly reduced in C. elegans and this reduction in translation functions in part to minimize protein damage [osm-9(ok1677) mutants. However, reductions in rates of translation were not significantly different (P>0.7) in wild type and osm-9(ok1677) worms exposed for 2 h to 200 mM NaCl  different in the two groups of animals  worm strain could be due to altered expression of genes encoding components of the proteostasis network. To begin testing this possibility, we performed RNA-sequencing gene expression analyses on wild type and osm-9(ok1677) worms under control and hypertonic stress conditions. In unstressed osm-9(ok1677) worms we found significant (P<0.05) upregulation of genes that have well defined or likely roles in protein degradation, synthesis and folding as well as genes with RNAi phenotypes of increased protein aggregation, altered sensitivity to protein aggregation and/or decreased hypertonic stress resistance. For example, in control osm-9(ok1677) worms we identified 23 upregulated (1.4- to 3.2-fold) genes that play known or presumptive roles in protein degradation including proteases, proteins associated with lysosome function, E3 ubiquitin ligases and E2 ubiquitin-conjugating enzymes  worms (Twenty-two genes with diverse functions that are not associated with proteostasis in obvious ways were upregulated 1.5- to 9.9-fold in control 7) worms . RNAi knosm-9(ok1677) worms placed under hypertonic stress also exhibited significant (P<0.05) differential upregulation of genes associated with proteostasis (eostasis . Eight ohttp://modencode.org). As shown in Tables osm-9(ok1677) worms have binding sites for these two transcription factors. DAF-16 and SKN-1 targets were enriched significantly (P<0.01) in the upregulated genes identified in osm-9(ok1677) worms under control conditions (osm-9(ok1677) worms.The transcription factors DAF-16 and SKN-1 play important roles in regulating stress resistance, longevity and proteostasis \u201357. Targnditions . Twenty-osm-9, osm-12 and sra-6, which drives ASH ablation [ASH chemosensory neurons mediate avoidance behavior to hypertonic solutions as well as other noxious chemical and mechanical stimuli . Animalsablation , are expablation . The onlablation . ASI neuablation . Howeverosm-9(ok1677) mutant and osm-9(RNAi) worms exhibit reduced protein damage during hypertonic stress  mutant worms may be due in part to the upregulation of genes that play known or likely roles in protein synthesis, folding and degradation  worms also have no known proteostasis function, but protein aggregation is increased by RNAi knockdown of their activity. Two of these genes showed particularly striking upregulation. Expression of col-176 and let-4 was increased compared to wild type animals 9.9- and 3.6-fold and 9.9- and 5.4-fold under control and hypertonic stress conditions, respectively  worms may improve epithelial barrier function under hypertonic conditions. While speculative, it is also possible that leucine-rich repeat proteins like collagens may preferentially bind with denatured proteins and slow aggregate formation.In ntegrity . Disruptosm-9(ok1677) mutant worms may be unique to this strain and not to loss of osm-9 function per se. Therefore, it will also be important to determine if other worm strains with defective ASH neuron function show similar differences in gene expression and proteostasis capacity. If our findings are confirmed, it will be necessary to determine the cellular locations of altered gene expression and the mechanisms by which differentially expressed genes confer increased hypertonic stress resistance.It should be stressed here that while RNAseq has been shown to be an accurate tool for assessing differential gene expression \u201373, addiC. elegans has begun to provide insights into the underlying molecular mechanisms. For example, Prahlad and Morimoto [C. elegans thermosensory neurons normally suppresses heat shock transcription factor 1 (HSF-1) dependent chaperone expression in muscle and intestinal cells. Signaling from ASH as well as ASI sensory neurons negatively regulates the innate immune response by MAP kinase dependent inhibition of the expression of genes that are part of the noncanonical unfolded protein response pathway [An animal\u2019s nervous system plays a critical role in detecting its complex and constantly changing external environment and integrating those environmental cues to coordinately regulate multiple physiological processes. Because of its relatively simple nervous system and genetic and molecular tractability, Morimoto  have sho pathway . In a siIn summary, we have demonstrated that defects in ASH mediated hypertonic avoidance behavior are associated with enhanced hypertonic stress resistance and improved proteostasis. Our findings are consistent with a growing body of work demonstrating that intercellular communication between neuronal and non-neuronal cells plays a critical role in integrating cellular stress responses with other organismal physiological demands and associated energy costs.S1 Appendix(XLSX)Click here for additional data file."}
+{"text": "Development of a simple, widely applicable risk score for chronic kidney disease (CKD) allows comparisons of risks or benefits of starting potentially nephrotoxic antiretrovirals (ARVs) as part of a treatment regimen.2 after 1/1/2004) were excluded. CKD was defined as confirmed (>3 months apart) eGFR <60. Poisson regression was used to develop a score predicting low (<0 points), medium (1\u20134 points) and high (>5 points) risk of developing CKD. Increased incidence of CKD associated with starting ARVs was modelled by including ARVs as time-updated variables. The risk score was externally validated on two independent cohorts.A total of 18,055 HIV-positive persons from the Data on Adverse Drugs (D:A:D) study with >3 estimated glomerular filtration rates (eGFRs) >1/1/2004 were included. Persons with use of tenofovir (TDF), atazanavir (ritonavir boosted (ATV/r) and unboosted (ATV)), lopinavir (LPV/r) and other boosted protease inhibitors (bPIs) before baseline . Older age, intravenous drug use, HCV+ antibody status, lower baseline eGFR, female gender, lower CD4 nadir, hypertension, diabetes and cardiovascular disease predicted CKD and were included in the risk score . The incTraditional and HIV-related risk factors were predictive of CKD; all are routinely available, making the risk score easy to incorporate into clinical practise and of direct relevance for clinical decision making. NNTH in persons starting potentially nephrotoxic ARVs at high risk of CKD were low, and alternative ARVs may be more appropriate."}
+{"text": "On August 23, 2013, the Georgia Poison Center was notified of eight persons examined in an emergency department in Brunswick, Georgia, after smoking or inhaling fumes from synthetic cannabinoids. The Georgia Poison Center notified the Georgia Drug and Narcotics Agency, which informed the Georgia Department of Public Health (DPH). The Brunswick emergency department was asked to report any additional patients who reported use of synthetic cannabinoid to the Coastal District Health Department. DPH investigators reviewed recent medical records of patients who had gone to the emergency department and found that 22 patients had been examined after using synthetic cannabinoids during August 22\u2013September 9, 2013.The 22 patients were aged 16\u201357 years (median: 25 years); 18 (82%) were male. Patients experienced hyperglycemia (13 [59%]), hypokalemia (nine [41%]), acidosis (seven [32%]), tachycardia (13 [59%]), nausea/vomiting (eight [36%]), confusion/disorientation (seven [32%]), aggression (seven [32%]), somnolence/unresponsiveness (seven [32%]), and seizures (three [14%]). Complications included pneumonia (two patients), rhabdomyolysis (one), and myocardial infarction (one). Six (27%) patients were admitted to the intensive care unit; five (23%) required assisted ventilation; none died. Serum from seven of the initial eight patients was tested for synthetic cannabinoid by the Clinical and Environmental Toxicology Laboratory at the University of California, San Francisco. Five tested positive for ADB-PINACA -1-pentyl-1H-indazole-3-carboxamide), a previously unrecognized synthetic cannabinoid related to indole compounds recently identified in Europe and Japan (Law enforcement authorities removed the synthetic cannabinoid from the implicated Brunswick smoke shop,Synthetic cannabinoids are designer drugs often smoked as a marijuana alternative. Despite laws prohibiting synthetic cannabinoid sales, they are still widely available, and recent increases in reports of synthetic cannabinoid use and adverse health effects have occurred ,3. Commo"}
+{"text": "Tool, recruitment process, multi-centric clinical trials.This tool supports administering and monitoring the recruitment process for multi-centric trials within a single clinical centre. It works together with the EHR4CR central workbench and allows receiving, accepting or rejecting invitations to participate in clinical trials Figure . Local uUnder evaluation by the EHR4CR pilot sites (November 2014).Clinical sites  investigators, study nurses, treating physicians).http://www.ehr4cr.eu"}
+{"text": "Emotional processing is basic for social behaviour. We examine for the first time the facial emotion processing in long-term HIV-suppressed patients.Cross-sectional study comparing (ANOVA) six facial emotional processing tasks  between HIV-suppressed patients (HIV+) on effective antiretroviral therapy (>2 years) and matched  healthy controls (HCs). Accuracy in the recognition of basic emotions  in each recognition task was also compared (Mann\u2013Whitney U test) between HIV+ and HCs. In the subset of HIV+, we evaluate which factors were associated with impaired recognition of basic emotions (accuracy below 50%) by multiple logistic regression analysis. Overall performance in all six emotional tasks were separately compared between neurocognitive impaired and non-impaired HIV+.We included 107 HIV+, mainly Caucasian (89%) male (72%) with a mean age of 47.4 years, neurocognitively non-impaired (75.5%), and 40 HCs. Overall discrimination (p=0.38), memory (p=0.65) and recognition tasks (p=0.29) were similar in both groups. However, HIV+ had lower sadness recognition in both recognition tasks and lower sadness, anger and fear recognition in the facial affect selection task . Only esWe did not find difference in the overall emotion processing between HIV+ and HIV- individuals. However, we found particular recognition deficits in the entire HIV+ sample. Estimated pre-morbid functioning was associated with sadness and anger recognition deficits in the facial affect selection task. Neurocognitive impaired HIV+ had additional memory deficits. These recognition deficits might conduct to social difficulties."}
+{"text": "To date, immune-modulatory treatments in sepsis have proved unsuccessful. Better understanding of inflammatory processes might help tailor such therapies more effectively and improve their efficacy. It is now recognised that some patients may require immune stimulating therapies.1. TNF converting enzyme (TACE), activated via p38-mitogen activated protein kinase (MAPK) mediated pathway2, is essential for the shedding of TNF and TNF receptors (TNFRs)-1&2. Altered TACE behaviour may be mechanistically important in deactivation.Monocytes display altered behaviour in response to systemic inflammation; this has been called \u201cdeactivation\u201d and is characterised by reduced HLA-DR expression and attenuated tumour necrosis factor-\u03b1 (TNF) release in response to lipopolysaccharide (LPS) stimulusTo determine whether monocyte TACE activity is affected by sepsis and is reflective of illness severity.3.Sixteen patients with sepsis, 15 healthy volunteers and 8 patients with non-infectious systemic inflammatory response syndrome (NI-SIRS) were recruited and data collected at baseline (D0), day 2 (D2) and day 4 (D4). Peripheral blood mononuclear cells were separated by density gradient centrifugation with HLA-DR, TACE and TNFR expression  determined by flow cytometry. LPS-induced TNF release was measured using ELISA. Monocytes were isolated using magnetic bead selection and TACE catalytic activity  was measured using fluorescence resonance energy transfer assayHLA-DR expression and LPS-induced monocyte TNF release were attenuated in sepsis and NI-SIRS (p< 0.01), consistent with deactivation. Sepsis, but not NI-SIRS, produced elevated basal monocyte TACE activity (p< 0.01) while LPS-induced increases in TACE activity were attenuated. Elevated D0 basal TACE activity positively correlated with APACHE II score in sepsis (p< 0.01), but not NI-SIRS.TACE expression was unaltered across all groups, but LPS-induced TNFR shedding appeared reduced by sepsis. Sepsis patients displayed an attenuated p38-MAPK response to LPS.Our data indicate that sepsis induces specific changes in monocyte TACE catalytic activity profiles that may reflect illness severity, whilst such changes were not seen in NI-SIRS. These changes in TACE activity attenuated LPS-induced release of TNFR and TNF from monocytes, and appear to be mediated through altered upstream p38-MAPK signalling."}
+{"text": "We investigated the effects chronic hypobaric hypoxia exposure would have on alpinists' physiological adaptations, including: aerobic fitness, body composition, haematological variables and digit perfusion responses to cold stress, performed before and immediately after a 35 day high altitude climbing expedition.Seven elite Slovenian alpinists completed a battery of physiological tests, including a cold stress test protocol previously used to determine changes in digit temperatures -3. Brief5/7 alpinists successfully summited Broadpeak (8051 m elevation). Of those alpinists, 4/5 demonstrated higher cold-induced vasodilation (CIVD) wave amplitudes in mean finger temperatures, or higher recovery temperatures, (or both), post-expedition. In the feet, 1/5 had higher wave amplitudes, 1/5 had higher passive recovery temperatures, whereas 2/5 had lower mean toe temperatures during cold exposure, and one had no discernible alterations post-expedition. One alpinist declined participation in the cold stress testing in this expedition because he had previously completed an identical protocol and reported extreme discomfort in his digits during the cold water immersion phase of testing. Area under the curve calculations for the hands found 5/5 alpinists had higher values post-expedition, whilst in the toes, 3/5 had higher values compared to pre-expedition.per se occurs in both hands and feet following combined exposure to high altitude and cold in this particular population.Previous results have demonstrated a significant enhancement of the CIVD response in both fingers and toes of alpinists returning from high altitude expeditions Alpinists presented vastly different digit responses to cold stress after exposure to hypobaric hypoxia."}
+{"text": "That most epithelium remains AR positive, but ligand independent, suggests the presence of oncogenic AR variants. To address this hypothesis, we have used a panel of recently described -/-Pten tumor cell lines derived from both from hormone intact  and castrated Pten mutants  followed by RACE PCR to identify and characterize three novel truncated, amino terminus containing AR variants . Variants appear not only conserved throughout progression but are correlated with nearly complete loss of full length AR (AR-FL) at castrate androgen levels. The overexpression of variants leads to enhanced transcriptional activity of AR while knock down studies show reduced transcriptional output. Collectively, the identification of truncated AR variants in the conditional PTEN deletion model supports a role for maintaining the CRPC phenotype and provides further therapeutic applications of this preclinical model.Androgen receptor (AR) variants are associated with resistance to anti androgen therapy both in human prostate cancer cell lines and clinical samples. These observations support the hypothesis that AR isoform accumulation is a consequence of selective therapeutic pressure on the full length AR. The Pten deficient prostate cancer model proceeds with well-defined kinetics including progression to castration resistant prostate cancer (CRPC). While surgical castration and enzalutamide treatments yield an initial therapeutic response,  These AR variants all contain the AR-NTD with only one containing a partial sequence overlap with the AR-LBD. The relative expression of these variants not only increases in response to castration but in response to AR targeted therapy including casodex and enzalutamide. Remarkably, after progression at long term of castrate androgen levels, we observed a significant reduction in full length AR but maintenance of the identified isoforms. Functional studies revealed that overexpression or knock down of AR-Va and AR-Vc could regulate AR transcriptional output.Collectively, our data support the presence of new AR variants that may serve as important contributors during progression to CRPC. Variant identification also significantly enhances the utility of the PTEN null prostate cancer model both in terms of understanding the function of AR and as a system for assessing therapies targeting resistant forms of the androgen receptor.Pten null mutant mice. Cell lines were characterized as being Pten-/-, having activated PI3K/Akt signaling and features of the primary tumor model . To. ToPten or model  and humal  [18 [1817] . One of  therapy  35]  and and26] aTotal cellular RNAs were isolated from E8 and cE1 by RNAqueous-4PCR Kit (Life technologies) used as the source. The detection of mouse AR splice variants from them was achieved by GeneRacer Kit with SuperScript III RT and TOPO TA Cloning Kit for Sequencing (life technologies) as per manufacture\u2019s protocols. Briefly, extracted RNAs were first reverse transcribed using the GeneRacer oligo (dT) primer and SuperScript III RT module from the kit. RACE-ready cDNAs were subjected to the 3\u2019 rapid amplification of cDNA end PCR (3\u2019 RACE-PCR) using a forward gene-specific primer (GSP) and reverse GeneRacer 3\u2019 primer from the GeneRacer Module. Another round of nested PCR was conducted for further amplification using a forward GSP nested primer and reverse GeneRacer 3\u2019 Nested primer provided in the kit. SuperTaq Plus Polymerase (Life technologies) was used for both 3\u2019RACE and nested PCR. Forward GSP and nested primers anchored within exon1  for predPlasmid constructs used in this study included: Rat AR full-length , human AR full-length , and PSA-luciferase reporter and PCDNA3.1-myc . pCR4-TOPO was purchased in the TOPO TA Cloning Kit for Sequencing (life technologies).CDS (coding sequences) for mARVa, Vb and Vc were amplified by PCR from cDNAs of E8 and cE1 using the primer sets enclosing the entire open reading frame (ORF), and sub cloned into pcDNA3.1-myc-HisC. To generate the ARVa-myc and ARVc-myc constructs, reverse primers were re-designed to be anchored upstream of their own stop codons and in-framed with the ORF of expression vector. Hifi AccuStart Taq DNA Polymerase (Quanta Biosciences) and HotStar Taq DNA Polymerase (Qiagen) were applied in PCR cloning. Sequences of primer used to clone Va, Vb, Vc, Va-myc and Vc-myc were provided in Total cellular RNAs were extracted from all parental and other derivative cell lines and then reverse transcribed using oligo (dT) primer and SuperScript III First-Strand Synthesis (Life technologies). RNA samples used for various assays were isolated from cells with different batches. Conventional PCR was performed on cDNAs using the same forward primer anchored within exon1 paired with reverse primer specific for mAR-Va, b, c and AR-FL, respectively . Quantit1\u20132 days prior to transfection, cells were placed in media containing charcoal-stripped serum (CSS). For all transfections, pools of cells were transfected using Lipofectamine Plus (Invitrogen) with empty vector control plasmid, full-length AR plasmid, or AR splice variant plasmids along with the androgen-responsive constructs MMTV-firefly luciferase or PSA-firefly luciferase  and the COS cells were transfected with mARVa-myc or mARVc-myc together with Rat AR-FL using Lipofectamine 2000 (Life technologies) as per the manufacture\u2019s protocol. About 48 hrs. post-transfection cells were lysed with 1% CHAPS lysis buffer . Then 500 \u03bcl cleared cell lysate were immunoprecipitated by incubation with 5 \u03bcg anti-myc mAb (Roche) and Protein G PLUS-Agarose (EMD Millipore) overnight at 4\u00b0C. The isotype matched control mAbs were included in all immunoprecipitation experiments as negative control. Immunoprecipitates were washed twice in 0.1% lysis buffer followed by elution separation on 4\u201320% Criterion Tris-HCl Gel (Bio-Rad) under reduced conditions.Whole-cell lysates from cell lines and primary tissues were prepared as described previously . Proteinad libitum. Breeding and experimental procedures were performed according to mouse protocols approved by the Institutional Animal Use and Care Committee (IACUC) at the University of Southern California and Icahn School of Medicine, Mount Sinai. The current study is specifically approved under the protocol: \u201cThe Function of the PTEN tumor suppressor gene in tumorgenesis and animal development\u201d with Lab Animal Protocol Reference #LA13-00060. Conditional Pten-null mutant mice  and Pten-null;Ar-null mutant mice were carried on a pure C67/BL6 background Only male mice were used for experimental procedures.All mice were maintained in a temperature and humidity controlled, pathogen free housing units, with light-dark cycles  allowing food and water distribution Surgical castration recovery surgery was carried out in Pten mutant mice while under full anesthetic using Ketamine (50 mg/ml) and Xylazine (20 mg/ml) according to an approved animal protocol (Reference #LA13-00060).S1 FigSequences were obtained through 3\u2019 RACE PCR on cDNA generated from murine prostate cancer cell lines . RACE PCR was followed by nested PCR to identify new AR variants.(PDF)Click here for additional data file.S2 Fig(PDF)Click here for additional data file.S3 FigC+;PtenL/L, n = 5) were treated for >20 wks with enzalutamide and then assessed for AR expression using antibodies against the animo terminus  or carboxyl terminus . Significant nuclear expression is observed with the N-20 antibody but only low expression with the C-19.Pten mutants ((PDF)Click here for additional data file.S4 FigbVariant dependent PSA-luc transactivation   .Presence of AR-FL is required for transactivation of the PSA-luc reporter  . (PDF)Click here for additional data file.S5 FigC+;PtenL/L, 6 wks) and assessed at 30 wks for AR  and FRKBP5 expression . Hormone intact Pten-null;Ar-null  mutants assessed at 30 wks for AR  and FRKBP5 expression . CRPC Pten-null cell lines derived from the Pten-null mouse model assessed for Fkbp5 gene expression in hormone intact (FBS), castrate (CSS) or with exogenous androgen (1 nM R1881) over 20 hours treatment .a) Pten null mutants were castrated ((PDF)Click here for additional data file.S1 Table(PDF)Click here for additional data file.S2 Table(PDF)Click here for additional data file.S3 Table(PDF)Click here for additional data file.S4 Table(PDF)Click here for additional data file.S5 Table(PDF)Click here for additional data file.S6 Table(PDF)Click here for additional data file."}
+{"text": "Several studies suggest that circulating bone marrow derived stem cells promote the regeneration of ischemic tissues. For hematopoietic stem cell transplantation combinatorial granulocyte-colony stimulating factor (G-CSF)/Plerixafor (AMD3100) administration was shown to enhance mobilization of bone marrow derived stem cells compared to G-CSF monotherapy. Here we tested the hypothesis whether combinatorial G-CSF/AMD3100 therapy has beneficial effects in cardiac recovery in a mouse model of myocardial infarction.We analyzed the effect of single G-CSF (250 \u00b5g/kg/day) and combinatorial G-CSF/AMD3100 (100 \u00b5g/kg/day) treatment on cardiac morphology, vascularization, and hemodynamics 28 days after permanent ligation of the left anterior descending artery (LAD). G-CSF treatment started directly after induction of myocardial infarction (MI) for 3 consecutive days followed by a single AMD3100 application on day three after MI in the G-CSF/AMD3100 group. Cell mobilization was assessed by flow cytometry of blood samples drawn from tail vein on day 0, 7, and 14.Peripheral blood analysis 7 days after MI showed enhanced mobilization of white blood cells (WBC) and endothelial progenitor cells (EPC) upon G-CSF and combinatorial G-CSF/AMD3100 treatment. However, single or combinatorial treatment showed no improvement in survival, left ventricular function, and infarction size compared to the saline treated control group 28 days after MI. Furthermore, no differences in histology and vascularization of infarcted hearts could be observed.Although the implemented treatment regimen caused no adverse effects, our data show that combinatorial G-CSF/AMD therapy does not promote myocardial regeneration after permanent LAD occlusion. Cytokine mediated mobilization of peripheral blood stem cells for autologous stem cell transplantation is a generally accepted therapeutic option for the hematopoietic reconstitution after myoablative chemotherapy. The clinically used cytokine granulocyte-colony stimulating factor (G-CSF) is known to mobilize various subsets of hematopoietic stem and progenitor cells (HSPC) into blood circulation that may contribute to tissue repair. Additionally G-CSF was shown to have anti-apoptotic, anti-inflammatory and antioxidant effects Especially in the field of ischemic heart disease numerous studies investigated the efficacy of G-CSF induced stem cell mobilization in myocardial regeneration. While early animal studies and small clinical trials indicated beneficial effects on cardiac regeneration, these results were later challenged by studies that could not confirm these positive effects or even reported deleterious effects of G-CSF therapy on cardiac recovery  was shown to rapidly mobilize stem cells by reversibly disrupting the interaction between CXCR4 and SDF-1\u03b1 that tethers stem cells to the bone marrow (BM) environment On the basis of these results we explored possible beneficial effects of combinatorial G-CSF/AMD therapy in myocardial regeneration in a mouse model of MI. We applied a treatment regimen were G-CSF administration started directly after induction of MI for 3 consecutive days followed by a single dose of AMD in order to attain positive effects on stem cell mobilization while avoiding negative effects on stem cell homing.Eight to ten weeks old male FVB/NJ mice (Charles River) were anaesthetized with an intraperitoneal injection of midazolam (5.0 mg/kg), fentanyl (0.05 mg/kg), and medetomidin (0.5 mg/kg). The animals were intubated and ventilated using a rodent ventilator  with a stroke volume of 0.2 ml and respiration rate of 200 strokes/min. Inhalation anesthesia was maintained with 1.5% isoflurane through a vaporizer with 100% oxygen. After left lateral thoracotomy at the left third intercostal space, the left anterior descending coronary (LAD) was ligated with 7\u20130 prolene sutures (Ethicon) 1 mm below the tip of the left atrial auricle. The chest and skin were closed with 6\u20130 vicryl (Ethicon) sutures. The sham group underwent the same procedure except for the ligation of the LAD. After induction of MI animals were randomly divided into 3 groups and stem cell mobilization was induced by the following dosing regimen:1) G-CSF  subcutaneously (s.c.) starting 1 h post-MI and then daily on days 1 and 2; 2) Combination of G-CSF s.c. starting 1 h post-MI and then daily on days 1 and 2+ AMD3100  s.c. as single dose on day 3 post-MI; 3) the control MI group received at the same time points equal volumes of saline (0.9% NaCl). Data acquired from control MI and sham groups contributed in parallel to another study but were pooled with new animals 3) and incubated with Alexa Fluor 647-labeled anti-Flk-1/VEGFR2 (clone 89B3A5), Phycoerythrin (PE)-conjugated anti-Ly-6A/E (Sca-1) (clone D7), and allophycocyanin(APC)-labeled anti-CD117 (c-kit) (clone 2B8) . Appropriate isotype controls were always included. Cells were analyzed on FACSCanto II flow cytometer using FACSDiva software (BD Biosciences) and analyzed with FlowJo software (TreeStar).Whole blood samples were drawn from the tail vein 0, 7 and 14 days after MI and circulating white blood cells (WBC) were counted with an animal blood counter (Scil Vet abc). For fluorescence activated cell sorting (FACS) analysis, blood mononuclear cells were separated via gradient-density centrifugation using Histopaque-1083 (Sigma-Aldrich). Cells were blocked with normal rat serum and anti-CD16/32 monoclonal antibody (mAb) (clone 93) in FACS buffer  was inserted through the right carotid artery into the left ventricle to record baseline pressure-volume loops in the closed chest. Conversion of raw conductance data to calibrated volumes was performed by determination of parallel conductance (Vp) using hypertonic saline dilution method 2) in 10 sections per heart (n\u200a=\u200a5\u20138 for each group) within the border zone, infarcted and remote area. Alpha-smooth muscle actin positive vascular structures were counted per area assessed with ImageJ software. Both parameters are expressed as positive stained vascular structures per mm2.At day 28, hearts were excised, fixed overnight with 4% formalin/PBS-buffered and embedded in paraffin. Transversal sections of a thickness of 3 \u00b5m were cut from apex to base and mounted on glass slides for histological and immunhistochemical staining. Masson trichrome (MT) staining was done according to standard protocols. Infarction size was determined using midline length measurement on MT stained sections from the surgical LAD occlusion to the base Data are reported as mean value \u00b1 standard error of the mean (SEM), and were analyzed by two-tailed unpaired Student's t-test. A p-value of less than 0.1 was considered as a trend a p-value less than 0.05 was considered significant. Group comparisons were performed using One-way ANOVA followed by the Tukey's test. Survival analysis was assessed by Kaplan-Meier method.Circulating white blood cells (WBC) and progenitor cells were determined before (0 days) and after MI in drug treated mice and untreated controls. Treatment with G-CSF (*p<0.05 vs. day 0) and G-CSF/AMD (p\u200a=\u200a0.075 vs. day 0) enhanced the MI induced mobilization of circulating WBC, without reaching statistical significance compared to the untreated group 7 days after MI . AlthougA total of 106 mice  were included into cumulative Kaplan-Meier survival analysis. There were no statistical differences in overall mortality between saline and drug treated groups . In ordeSurgical induction of MI severely impaired cardiac function compared to sham-operated animals as assessed by hemodynamic measurements 28 days after surgery. In sham-operated mice the left ventricular ejection fraction (EF) was 66.2%\u00b15.2 and declined to 23.8%\u00b12.9 (p<0.001) in control MI mice. G-CSF and G-CSF/AMD treatment did not improve EF 28 days after MI . DetaileDetermination of infarction size 28 days post MI either by TTC staining or midline infarct length method on Masson trichrome stained sections revealed no significant difference between drug treated animals and control MI mice . QuantifTwenty-eight days after LAD ligation characteristic signs of late phase postinfarction remodelling of the heart were visible. Infarcted left ventricles showed typical loss of myocardium, left ventricular wall thinning and fibrous scar formation. Masson trichrome staining of infarcted regions revealed a viable subendocardial layer followed by collagen rich fibrous tissue reaching into border zone myocardium . No obviEPC as well as certain subsets of WBC are known to exert angiogenic properties in ischemic tissues. Using antibodies against endothelial (CD31/PECAM-1) and smooth muscle cells (\u03b1-smooth muscle actin), the abundance of capillaries and arterioles in remote area (RA), border zone (BZ) and infarct zone (IF) was analyzed . TreatmeIn the present study, the potential regenerative properties of a combinatorial G-CSF/AMD therapy were tested in a model of permanent LAD occlusion. During the last decade numerous studies investigated the hypothesis that cytokine mediated mobilization of stem cells contribute to cardiac regeneration after MI. Implementing different cytokines and mobilization protocols these studies yielded controversial results ranging from beneficial effects to even deleterious effects on cardiac regeneration G-CSF as well as the CXCR4 inhibitor AMD3100 has been shown to mobilize HSPC and potential angiogenic cells from BM + cells, but with huge animal-to-animal variations was also seen in a rat model of MI after G-CSF treatment by Werneck-de-Castro et al. In the present study we found that G-CSF and G-CSF/AMD treatment promoted mobilization of WBC and EPC into peripheral blood. Mobilization tended to be higher in treatment groups compared to control mice without reaching statistical significance. This was due to large variations within treatment groups suggesting that not all animals responded to the treatment in the same way. Inter-individual variations in G-CSF induced HSPC mobilization are also evident in humans + or CD133+ HSPC.Combination of G-CSF with AMD did not synergistically increase WBC counts, HPC or EPC numbers at day 7 after MI (4 days after AMD treatment). The rapid AMD mediated mobilization might be an explanation for this, however, significantly increased EPC mobilization could be detected even 7 days after single AMD injection in a mouse MI model Survival analysis showed no significant differences in mortality between saline and drug treated groups. On the basis of the applied drug regimen, beneficial effects on cardiac recovery resulting from either direct or paracrine actions of mobilized stem cells would not be conceivable until day 4 after MI. However, exclusion of animals that died in the first 4 days after MI did not uncover a reduced mortality of drug treated animals. Furthermore, pressure volume relationships of control and drug treated animals were recorded to evaluate heart function 28 days after MI. Drastically reduced heart function was evident in control MI mice compared to sham operated mice. Although G-CSF and G-CSF/AMD treatment led to a slight improvement of some hemodynamic parameters, no significant changes compared to the control MI group were observable. Moreover, there was no reduction in infarction size visible in drug-treated versus control MI animals. Since these basic parameters indicated no improvement of heart regeneration with respect to the applied therapy, histology and vascularization of infarcted hearts was evaluated. Histological analysis showed drastically reduced myocardium at the ischemic site of the left ventricle that was replaced by a thin collagen rich, fibrous tissue layer. In control MI as well as treatment groups similar histological pattern were visible showing no obvious signs of cardiac regeneration.Besides postulated direct actions of cytokines or stem cells on myocyte regeneration, numerous studies linked HSPC mobilization to favorable angiogenic effects promoting neovascularization of ischemic tissues In conclusion, although the applied drug regimen enhanced the mobilization of potentially regenerative cells, the combination of G-CSF and AMD did not significantly improve cardiac recovery after MI compared to control MI mice. On the other hand, no adverse effects of the applied drug treatment on cardiac function and remodeling could be observed. Further studies are needed to elucidate the complex mechanisms after cardiac injury to figure out treatment regimens that more specifically promote cardiac healing.Beneficial effects of stem cells or cytokines were already observed after permanent LAD occlusion Figure S1FACS analysis of peripheral white blood cells of na\u00efve (day 0) mice and 7 days post MI. (A) Mononuclear cells were gated on forward scatter (FSC) and side scatter (SSC) plot to exclude blood cells, debris and dead cells. Percentages of (B) c-Kit/Sca-1 double positive and (C) Flk1/Sca-1 double positive sub-populations were recorded. Representative dots plots are shown.(TIF)Click here for additional data file."}
+{"text": "Utilizing these techniques, novel treatment strategies that could be explored were identified, including potential benefit with anti-EGFR therapies, immune checkpoint inhibitors, topoisomerase inhibitors, and taxanes. The frequency of overexpression of proteins that mark resistance to chemotherapeutic drugs, such as MRP1 (chemotherapy efflux pump), ERCC1 (resistance to platinum-based chemotherapy), and thymidylate synthase (resistance to fluoropyrimidines) were also identified, suggesting a lack of benefit. This multiplatform strategy could be explored for its potential to generate a personalized treatment selection for patients with advanced ASCC, provide a guide for future therapeutic development for this cancer, and be extended to other rare cancer types as well.Anal squamous cell carcinoma (ASCC) is a rare, HPV-associated malignancy typically diagnosed in early stages and definitively treated with chemoradiation. In situations where patients exhibit metastatic or recurrent disease, treatment options are severely limited. In this study, molecular alterations were identified that could be used to aid in therapeutic decisions for patients with metastatic or recurrent anal squamous cell carcinoma. Specimens from patients with this cancer were tested via a multiplatform profiling service  consisting of gene sequencing, protein expression by immunohistochemistry, and gene amplification with  Anal squamous cell carcinoma (ASCC) is a rare, HPV-associated malignancy accounting for 2.5% of digestive system malignancies. In 2015, there are expected to be about 7270 new cases of anal carcinoma with 1010 deaths from the disease in the United States . The fivIn local and locally advanced anal squamous cell carcinoma, the standard of care for most patients is concurrent chemoradiation therapy, with a complete response rate of 80% . Albeit As metastatic ASCC is rare, there is limited experience to guide management. Treatment of systemic disease consists of chemotherapy administered with palliative intent, where the most accepted regimen used is cisplatin and 5FU. This use of a doublet of cisplatin and 5FU has demonstrated overall survival rates of 62.2% and 32.2% at 1 and 5 years, respectively . AlthougKRAS status, as is known to occur with its treatment of colorectal adenocarcinomas  or fluorescent in situ hybridization [FISH]. Gene sequencing was performed using Sanger or next generation sequencing [NGS].Specimens were submitted in the form of formalin fixed paraffin embedded (FFPE) samples. A multiplatform profiling service was conducted on these samples to assess protein expression and gene aberrations. Protein expression was performed using immunohistochemistry [IHC]. Gene amplification was assessed using chromogenic Immunohistochemistry analysis was performed on formalin-fixed, paraffin-embedded (FFPE) tumor samples using commercially available detection kits and automated staining techniques . Antibodies for the following were utilized: androgen receptor (AR), multiple resistance protein 1 (MRP1), topoisomerases 1 and 2A  ; estrogen receptor (ER), progesterone receptor (PR), MET proto-oncogene receptor tyrosine kinase (cMet), human epidermal growth factor receptor 2 (HER2), programmed death - one (PD-1), and programmed death ligand (PD-L1) ; tyrosine protein c-Kit receptor kinase (c-Kit), phosphatase and tensin homolog (PTEN) [Dako], epidermal growth factor receptor (EGFR) ; O(6)-methylguanine-methyltransferase (MGMT), P-glycoprotein (PGP), thymidylate synthase (TS) ; DNA excision repair cross-complementing one protein (ERCC1) ; breast cancer resistance protein (BCRP), transducin-like enhancer of split 3 (TLE3) ; platelet-derived growth factor alpha (PDGFRA) ; ribonucleotide reductase M1 (RRM1) ; and tubulin beta-3 chain (TUBB3) . Scoring system and cutoffs for all antibodies are provided in in situ hybridization (FISH) evaluated for amplification of the ([chromosome 17 centromere] probe), (probe), , and (probe) genes. The ratio > 2.2 was considered amplified . amplification was defined as > = 2, or > = 15 EGFR copies per cell in > = 10% of analyzed cells. was considered amplified if > = 5 copies were detected, while amplification was defined as TOP2A/CEP17 ratio > = 2.0. ALK was also assessed using FISH in a few patients for gene rearrangement .Fluorescent HER2 and MET status were also evaluated using chromogenic in situ hybridization . The same scoring system was applied as for FISH.Next-Generation Sequencing. Direct sequence analysis was performed on genomic DNA isolated from formalin-fixed paraffin-embedded tumor samples using the Illumina MiSeq platform . Specific regions of 47 genes of the genome were amplified using the Illumina TruSeq Amplicon Cancer Hotspot panel. Sequencing depth average was 1500X.KIT and PIK3CA and was performed using M13-linked polymerase chain reaction (PCR) primers designed to amplify targeted sequences. PCR products were bi-directionally sequenced using the BigDye Terminator v1.1 chemistry , and analyzed using the 3730 DNA Analyzer (Applied Biosystems). Sequence traces were analyzed using Mutation Surveyor software v3.25 .Sanger Sequencing. Mutational analysis using Sanger sequencing involved selected regions of The frequency of the various protein expression, and gene sequence and amplification data was compared across the tumor samples that were analyzed, to assess for frequency and trends, in order to assess for possible therapeutic targets. These results were also compared to the available demographic patient data. Data analysis was performed using SPSS 20  Statistical software and JMPv10.0 ."}
+{"text": "To reduce deleterious effects of C-CPB novel concepts have been developed based on miniaturized cardiopulmonary bypass (Mini-CPB) with closed circuits, low priming volumes and optimized perfusion system. In CABG surgery, it has previously shown that the use of Mini-CPB can reduce systemic inflammation compared to C-CPB [25] and so attenuate the pathologic effects of C-CPB.The aim of this study was to compare miniaturized cardiopulmonary bypass (Mini-CPB) versus conventional cardiopulmonary bypass (C-CPB) in patients undergoing coronary artery bypass grafting (CABG) in term of sternal wound healing and lymphocyte depletion.A total of 847 patients undergoing isolated coronary artery bypass grafting (CABG) surgery were studied. Exclusion criteria were: redos, emergencies, CPB time longer than 180 min, antibiotic therapy within two weeks prior to surgery. Finally, 697 consecutive patients who underwent CABG, between January 2012 and September 2014, were studied prospectively. C-CPB was used in 397 (56.9%) patients (Group A) and Mini-CPB was used in 300 (43.1%) (Group B). Patients in the two groups were similar with respect to demographic and preoperative status. To detect lymphocyte depletion, blood was sampled for lymphocyte measurements at three time points: preoperatively (T1), 24 (T2) and 72 h postoperatively (T3) The presence of infections was evaluated according to the ASEPSIS wound scoring system. Antibiotic prophylaxis with cefazolin was performed preoperatively, according to the routine of the institution.The study groups had similar EuroSCOREs. A total of 26/697 (3.7 %) patients had sternal wound infection (SWI). Patients from Group A showed a higher incidence of SWI compared to Group B . In Group A 14/26 (54 %) patients developed deep SWI, and 12/26 (46 %) developed superficial SWI. The Group A but not the Group B showed significant lymphocyte depletion from preoperative during the 1st postoperative day . Also in 3rd postoperative day, lymphocyte depletion was lesser in Group B . The most frequently cultured isolated were Staphylococcus epidermidis (37%), Staphylococcus aureus (22.2%). 22 (85%) patients were treated by debridement and vacuum therapy and 4 (15%) patients underwent surgical sternal reconstruction.This study shows that Mini-CPB for patients undergoing isolated CABG is associated with a reduced risk of SWI occurrence. This may be related to the lesser inflammatory response of Mini-CPB compared to C-CPB and to the lesser lymphocyte depletion. Further studies are needed to confirm these findings."}
+{"text": "Eighteen isolates belonging to a genomic cluster grouped most closely with recently identified isolates in New Mexico. The continued transmission of emm59 in the southwestern United States poses a public health concern.The hyper-virulent  Streptococcus (GAS) disease were detected in January 2015 in a northern Arizona hospital. A substantive percentage of the cases were associated with a homeless shelter and a local jail; outbreak case-patients were predominantly male and Native American. Other studies have shown an increase in infection risk for invasive GAS in Native American/First Nations populations  following manufacturer\u2019s protocol. Genomic DNA libraries were prepared by using the Nextera XT library prep kit  and sequenced with paired-end reads (250 bp) on an Illumina MiSeq instrument, as previously described (emm59 Canadian clone MGAS15252 (GenBank accession no. CP003116) and high-quality publicly available sequence-read data from 44 US isolates, from NCBI short read archive (BioProject #PRJNA194066), were included in the subsequent phylogenetic analyses. The final core genome  for single-nucleotide polymorphism (SNP) detection was 1,636,024 bp (98.6% of reference).We identified isolates for sequencing from 29 invasive GAS cases diagnosed in patients in a northern Arizona hospital during January\u2013July 2015 and randomly selected an additional 99 GAS isolates from a repository of >2,000 Arizona GAS isolates collected during 2002\u20132006 (no isolates from patients in Arizona were available for 2007\u20132014). Four additional isolates from central Arizona identified in 2015 were included in the analysis  Table. Ahttp://tgennorth.github.io/NASP/) for whole-genome SNP typing as previously described . GAS emm subtypes were assigned by using BLAST (http://blast.ncbi.nlm.nih.gov/Blast.cgi), querying the study genome assemblies against the Centers for Disease Control and Prevention\u2019s (CDC) emm type-specific sequence database (http://www.cdc.gov/streplab/m-proteingene-typing.html). We resolved dual emm-type hits using CDC\u2019s emm typing Sanger sequencing primers (http://www.cdc.gov/streplab/protocol-emm-type.html) as a BLAST query and noting hit locations.We used NASP SNP analysis pipeline , emm5 (n = 2), emm58 (n = 1), emm81 (n = 2), emm83 (n = 1), emm89 (n = 2), and emm94 (n = 1). The 99 historical and 4 contemporary background Arizona isolates included 25 distinct emm types . The additional emm59 isolates make up additional lineages separated from one other by 8\u201328 SNPs. No recombination was identified among the Arizona isolates. A relatively large number of SNPs and indels were seen within an approximate 23-kilobase region  system (http://www.cdc.gov/abcs/reports-findings/survreports.pdf) identified 40 US emm59 isolates during 2000\u20132009  appeared to be closely related to the Canadian clone (defined by the authors as being separated by <16 SNPs)  were from Native Americans; of 5 isolates from New Mexico in that study, 3 were from Native Americans. The emm59 studies in the United States (Given the apparent distal nature of the Arizona/New Mexico isolates to the Minnesota population in our study, it is reasonable to propose an unidentified epidemiologic relationship between these case populations. However, caution must be used in drawing conclusions regarding the relationships of isolates from disparate geographic regions because only limited comparable sequence data from previous List of Arizona Group A Streptococcus strains."}
+{"text": "MR tissue phase mapping (TPM) enables assessment of regional myocardial velocities. The purpose of this study was to compare regional myocardial velocities obtained by both TPM and speckle tracking echocardiography (STE) to assess agreement and potential systematic differences between modalities.N=19 patients with congenital heart abnormalities and biventricular physiology who had undergone cardiac MRI including TPM and transthoracic echocardiography within 6 months of MRI were identified (mean age=14 (7-20) years). Average time between MR and echo studies was 2.3\u00b11.4 months. MRI was performed on a 1.5T MR-system . TPM were acquired data in short axis orientation using a black-blood prepared cine phase-contrast sequence with tri-directional phase encoding . Analysis included manual segmentation of the left ventricular contours and transformation of the acquired tri-directional velocities into radial, circumferential, and long-axis velocities.Echocardiograms were reviewed retrospectively. Mid-chamber short axis images with adequate endocardial visualization were selected. 2-dimensional STE assessment was performed offline using TomTec Image Arena (version 4.3) with determination of peak radial velocities and time-to-peak (TTP) analysis for both systole and diastole. Assessments were performed during a single cardiac cycle with imaging frame rate of 30 frames per second.To directly compare regional velocities, data from both modalities were mapped onto the mid-ventricular section of the AHA 16-segment model and systolic and diastolic radial peak velocities as well as TTP were calculated for each segment. Inter-modality differences for peak velocities and TTP were assessed using paired t-tests; p<0.05 was considered significant.2=0.82)   Figure . Compari) Figure . Mean ra) Figure .Regional myocardial velocities in pediatric patients can be measured by TPM and results correlate well with STE. Comparisons of regional velocities are similar, but systematically underestimated by STE. Diastolic TTP showed no significant difference. Further studies are needed to identify factors that may contribute to these differences.None."}
+{"text": "Fetal alcohol spectrum disorder (FASD), birth defects associated with ethanol exposure in utero, includes a wide spectrum of congenital heart defects (CHDs), the most prevalent of which are septal and conotruncal defects. Zebrafish FASD model was used to dissect the mechanisms underlying FASD-associated CHDs. Embryonic ethanol exposure (3\u201324 hours post fertilization) led to defects in atrio-ventricular (AV) valvulogenesis beginning around 37 hpf, a morphogenetic event that arises long after ethanol withdrawal. Valve leaflets of the control embryos comprised two layers of cells confined at the compact atrio-ventricular canal (AVC). Ethanol treated embryos had extended AVC and valve forming cells were found either as rows of cells spanning the AVC or as unorganized clusters near the AV boundary. Ethanol exposure reduced valve precursors at the AVC, but some ventricular cells in ethanol treated embryos exhibited few characteristics of valve precursors. Late staged larvae and juvenile fish exposed to ethanol during embryonic development had faulty AV valves. Examination of AVC morphogenesis regulatory networks revealed that early ethanol exposure disrupted the Bmp signaling gradient in the heart during valve formation. Bmp signaling was prominent at the AVC in controls, but ethanol-exposed embryos displayed active Bmp signaling throughout the ventricle. Ethanol exposure also led to mislocalization of Notch signaling cells in endocardium during AV valve formation. Normally, highly active Notch signaling cells were organized at the AVC. In ethanol-exposed embryos, highly active Notch signaling cells were dispersed throughout the ventricle. At later stages, ethanol-exposed embryos exhibited reduced Wnt/\u03b2-catenin activity at the AVC. We conclude that early embryonic ethanol exposure alters Bmp, Notch and other signaling activities during AVC differentiation leading to faulty valve morphogenesis and valve defects persist in juvenile fish. Fetal alcohol spectrum disorder (FASD) is an inclusive term describing preventable birth defects and disabilities caused by prenatal alcohol exposure. FASD prevalence is as high as 2 to 5 per 100 children, while the more severe fetal alcohol syndrome (FAS) occurs 1 to 2 per 1,000 children . In addiCardiogenesis is a complex series of events, involving precise specification and differentiation of cardiac cell lineages, which coordinate cellular morphogenesis events , 6. Cardbmp4, which was present in the entire heart tube during early cardiogenesis, becomes restricted to the AVC cardiomyocytes during AVC differentiation  embryos contains KikGR fluorophore that fluoresces brightly with a green signal. A brief exposure to UV light permanently photoconverts KikGR from green fluorophore to a red fluorophore. Tg[myl7:nlsKikGR] embryos were exposed to UV light through DAPI filter to convert to red fluorophore.Zebrafish [lsKikGR) , Tg(bre:re:EGFP) , Tg(kdrlmCherry) , Tg(Tcf/iP:dGFP)  transgeniP:dGFP) . IndianaEmbryos were maintained in embryo medium until 3 hpf. At this time, embryos were transferred to one of the following conditions: embryo medium (control); embryo medium containing 100 mM ethanol (E100) or 150 mM ethanol (E150). At 24 hpf, respective solutions were replaced with fresh embryo medium. Control and ethanol exposed embryos  were put into the fish system at 5 dpf and raised maintaining same conditions.Histology was performed at Indiana University Histology Core. Embryos were fixed in 4% paraformaldehyde (PFA) in phosphate buffered saline (PBS), dehydrated to 95% ethanol, embedded in JB-4 resin (Polysciences), sectioned at 5 \u03bcm thickness using a Leica RM2265 microtome and stained with hematoxylin and eosin or Masson\u2019s trichrome dye.Brightfield images on a Leica MZ12 dissecting stereomicroscope were digitally acquired with a color Leica DFC290 camera .Confocal images were acquired using a Zeiss LSM 700 confocal microscope on an Observer Z1 using 40X 1.1 NA W objective; or 20X 0.8 NA objective. For live imaging, embryos were embedded in 1% low melting agarose containing 0.017% tricane on a coverslip glass bottom microwell dish. Phospho-smad 1,5,9 stained embryos were mounted in low melting agarose and pericardium was manually removed before imaging. 3D renderings were produced from image volumes using Volocity software (PerkinElmer/Invitrogen).For Selective Plane Illumination Microscopy (SPIM), embryos were embedded in 1% low melting agarose in plastic syringe, and hearts in living embryos were imaged at 100 frames per second (fps) using ImageJ software . Movies were made using QuickTime player.Scanning electron microscopy was performed at Indiana University Electron Microscopy Center. Fish were fixed in 4% PFA, hearts were dissected, post fixed in 2% osmium tetroxide and then followed the procedure as described in Hu et. al. . Atrium Whole-mount immunostaining was performed as previously described with slight modification . For Phobmp4 (generously provided by Dr. Ela W. Knapik), her2 (generously provided by Dr. Pamela Raymond) and axin2 (Addgene) were synthesized using DIG RNA Labeling Kit .Whole-mount in situ hybridization of zebrafish embryos was performed as described . Digoxigenin-labeled riboprobes for Stock solution was made following manufacture\u2019s protocol by dissolving BODIPY-ceramide  in DMSO. BODIPY-ceramide staining solution was made by diluting the stock solution to 0.1 mM by adding embryo medium containing 1% DMSO. Embryos were dechorionated manually and incubated in staining solution from 30 to 48 hpf (15 embryos / 1 ml solution). Embryos were washed in embryo medium before imaging.Statistical analyses comparing control and ethanol treated groups were performed using unpaired two-tailed Student\u2019s t-test .To understand the effects of early ethanol exposure on valve morphogenesis, zebrafish embryos were exposed to ethanol (E100 or E150) from 3 to 24 hpf, and then embryos were returned to normal embryo medium. Hearts and AV valves were analyzed at later stages. All ethanol treated embryos developed pericardial edema, showed reduced cardiac looping at 2 dpf (data not shown), as shown in our previous studies , 32. HigTg(fli1:EGFP) embryos, labeling endothelium and endocardium, were examined using high-speed SPIM. SPIM images showed completely filled chambers and the AVC at the open and closed states  embryos at 52 hpf. In control embryos, the endocardial cells at the AVC showed strong phalloidin staining (F-actin). Moreover, a row consisting 5\u20137 cells at the superior aspect and another consisting 3\u20134 cells (based on the cell count in 8 embryos) at the inferior aspect of AVC became cuboidal in shape . Ethanol-exposed larvae reaching 18 dpf stage showed significant defects in the AV valve morphology. Masson's trichrome stained serial coronal heart sections of 18 dpf larvae showed that the developing valve leaflets were curved and short in control larvae, but were longer and often straight in ethanol exposed larvae .Tg(kdrl:EGFP) larvae and imaged using confocal microscopy. Optical sagittal sections through the heart showed two short and narrow AV valve leaflets in 18 dpf control larvae. However, ethanol exposed larvae showed long and thickened valve leaflets (Tg(kdrl:EGFP) larvae were stained with WGA (the lectin binds to n-acetyl glycosamino glycan). Atrium was removed manually before confocal imaging and AV valves were imaged. Comparison of 3D rendering of confocal sections of control and ethanol treated larvae showed that the AV valves of ethanol treated larvae were severely malformed and AV junctions were much wider than the control  fish at 35 dpf. Since the maturation of valves depends on the larval size [Juvenile fish AV valves were then analyzed using phalloidin staining in val size , we examTg(kdrl:EGFP) fish exposed to ethanol during embryonic development. WGA stained fish showed a similar result that observed in one-month old fish. Valve leaflets in ethanol exposed fish were small and the shape of the adjacent leaflets do not closely correspond to allow complete closure of the AV junction . Analysis of bmp4 at 24 hpf showed its expression in the linear heart tube in the control embryos. Ethanol exposed embryos showed relatively uniform bmp4 expression in the forming heart tube at this stage (data not shown). At 48 hpf, bmp4 expression was restricted at the AV boundary and near the outflow tract (OFT) in control embryos , which express GFP in response to a Bmp response element that reports Bmp/Smad signaling [Tg(bre:EGFP) embryos from 48 hpf to 52 hpf showed that GFP signal was progressively lost from chamber cardiomyocytes but the GFP positive cells were seen in AV canal, in the inner curvature of the ventricle and at the base of the atrium in the control embryos  and MF20  double label immunostaining was performed at 48 hpf. Three-dimensional reconstruction of confocal z-sections showed more phospho-Smad-1/5/9-labeled cardiomyocytes at the base of the atrium, at the AVC and inner curvature of the ventricle in the control embryos . Opticalignaling . Time co embryos . However embryos .bmp4 expression from the chambers during AVC differentiation caused increased expression of has2  that subsequently led to the expansion of cardiac jelly between myocardium and endocardium [A previous study showed that failure to repress ocardium . To analocardium , 42. EthSince Bmp plays crucial roles throughout cardiogenesis including AV cushion development, ethanol effects on Bmp signaling were examined from 17 hpf until 75 hpf, a period encompassing the formation of heart cone until two-chambered heart. Reduced Bmp signaling was observed in the heart cone and heart tube of ethanol exposed embryos at 17\u201330 hpf compared to control . Around Tg(TP1:mCherry);Tg(kdrl:EGFP) and Tg(TP1:mCherry);Tg(myl7:GFP) double transgenic embryos. Tg(TP1:mCherry) transgene labels Notch active cells and Tg(myl7:GFP) labels cardiomyocytes. Live imaging of Tg(TP1:mCherry);Tg(kdrl:EGFP) control embryos at 50 hpf showed that mCherry labeled Notch active cells present in the ventricular endocardium can be grouped into two categories: (i) compact clusters of strongly labeled mCherry positive cells (high Notch activity) present at the AVC, and (ii) weakly labeled mCherry positive cells (low Notch activity) present in the ventricular endocardial lining (Tg(TP1:mCherry);Tg(myl7:GFP) embryos showed more prominent clustering of high Notch-active cells at the AVC and OFT. In contrast, ethanol exposed embryos showed persistent defects in Notch-active cell distribution at later stages  embryos. Confocal sectioning of the stained embryos showed high Notch active cells in the endocardium at the AVC express high level of F-actin. Inside the AVC of control embryos, strongly labelled mCherry positive cells lined up in a row, and those highly Notch active cells along with a few neighboring cells expressed high level of F-actin and were cuboidal in shape ;Tg(myl7:nlsKikGR) double transgenic zebrafish were used. Tg(Tcf/Lef-miniP:dGFP) reporter reveals transcriptional activities of four Tcf/Lef members, Lef1, Tcf7, Tcf7l1a, and Tcf7l2, controlled by Wnt/\u03b2-catenin signaling [Tg(myl7:nlsKikGR) transgene labels cardiomyocytes. At 52 hpf, control embryos showed GFP expression in two rows of AVC cardiomyocytes  expression and the expression of TGF-\u00df pathway components at the AVC [Bmp2 reduces the expression of Notch1 and Snail expression in the AVC endocardium, suggesting that Bmp signaling maintains Notch signaling during cardiac cushion formation [Hey1 and Hey2 suppress Bmp2 and Tbx2 expression from the chambers and restricts their expression at the AVC [Valve development mechanisms are extremely well conserved from zebrafish to human, sharing many genes and pathways that control cardiac valve development , 6. As t and OFT . Notch2 d at AVC . Notch tocardium . In zebrocardium , 16. Myoocardium . Bmp sig the AVC . Deletioormation . Notch s the AVC , 52, 54.has2 [Our experiments showed that embryonic ethanol exposure prevents regionalization of Bmp activity at the AVC during valvulogenesis. Experiments detecting Bmp ligand and measuring Bmp activity in the heart during endocardial cushion formation showed similar results, validating our findings. Ethanol causes chamber myocardial and endocardial cells to achieve some characteristics of valvular cells. It was shown that Bmp regulates the production of cushion extracellular matrix by activating has2 , 57. HigTg(TP1:mCherry) Notch reporter line showed similar results. Highly active Notch cells arranged in a row at the AVC in control embryos expressed high level of F-actin and were cuboidal in shape, suggesting those cells were valve forming differentiated endocardial cushion cells. But ethanol exposure reduced the number of highly active Notch cells at the AVC and subsequently reduced F-actin positive cuboidal cells at the AVC. On the other hand, chamber cells with high Notch activity exhibited F-actin staining, suggesting those cells acquired subset of valvular characteristics.Similar to Bmp, we found that Notch activity is not restricted at AVC in endocardial cells. Embryonic ethanol exposure changes the distribution of high and low Notch active cells in the endocardium. Instead of forming clusters at the AVC, high Notch active cells were dispersed throughout the ventricle. Frequently, these ectopic Notch active cells were in the posterior region of the ventricle. Previous murine study showed that constitutive Notch1 activation in endocardium promotes ectopic noninvasive EMT and confer valvular features to otherwise non-vavlular ventricular endocardium . Our expIn addition to their roles in AV valvulogenesis, Bmp and Notch signaling play crucial roles throughout cardiogenesis. Bmp signaling is required for cardiac specification, differentiation, endocardial differentiation, cardiac looping, chamber morphogenesis, and OFT septation during embryogenesis , 58\u201362. Hex1 and Islet1 were suppressed in ethanol-exposed quail embryos during cardiac cell specification [Recent study by Borsoda et al. showed that Wnt/\u03b2-catenin signaling is not required for EMT at AVC in mice, but it promotes AVC cushion expansion following EMT . A zebrafication .Our results show that embryonic ethanol exposure alters Bmp, Notch and Wnt/\u03b2-catenin signaling networks during heart valve development. The genesis of these altered regulatory networks by embryonic ethanol exposure is still unknown. We speculate that ethanol exposure alters the incorporation of second heart field and neural crest derived cells, which alters the cellular environment in the heart. Altered cardiomyocyte populations might change signaling in the remaining cardiomyocytes. Those cardiomyocytes fail to suppress Bmp activity within the ventricular chamber, expanding valvular territory. These altered cardiomyocytes influence underlying endocardial cells leading to defective valvulogenesis. Alternatively, ethanol exposure could directly affect the endocardial cells, producing an altered phenotype during valvulogenesis. Additional studies are needed to understand the primary causes for all these defects. Nevertheless, our study systematically followed the consequences of embryonic ethanol exposure on AV valve development, linking those defects to faulty valvulogenesis regulatory pathways.S1 Fig(A-I) 3D reconstruction of confocal sections of phospho-Smad-1/5/9  and MF20  double immunostained embryos showed Bmp responsive phospho-Smad-1/5/9 positive cardiomyocytes at the base of the atrium and in the inner curvature of the ventricle in control embryos (A); regionalization of phospho-Smad-1/5/9 positive cardiomyocytes were not evident in ethanol exposed embryos ; A\u2019, D\u2019, G\u2019: magnified images of boxed areas of A, D, G.(TIF)Click here for additional data file.S2 Figher2 expression in the control heart (A); her2 expression in ethanol treated embryo hearts . Arrow: heart.(A-C) (TIF)Click here for additional data file.S3 Figaxin 2 showed expression of the gene in the heart near AVC in control embryos (A); weak expression in E100 ethanol treated embryo (B) and no expression in E150 ethanol treated embryo. Arrows: pointing axin 2 expression in the heart.(A-C) In situ hybridization detecting (TIF)Click here for additional data file.S1 MovieTg(fli1:EGFP) embryo taken at 100 fps and shown at 16 fps. Orientation of the embryo: Ventricle is facing upward.SPIM movie of the beating heart of a control (MOV)Click here for additional data file.S2 MovieTg(fli1:EGFP) embryo taken at 100 fps and shown at 16 fps. Orientation of the embryo: Ventricle is facing upward.SPIM movie of the beating heart of an ethanol treated (E100) (MOV)Click here for additional data file.S3 MovieTg(fli1:EGFP) embryo taken at 100 fps and shown at 16 fps. Orientation of the embryo: Ventricle is facing upward.SPIM movie of the beating heart of an ethanol treated (E150) (MOV)Click here for additional data file."}
+{"text": "Atrioventricular nodal reentry tachycardia (AVNRT).Last conducted V after block of the previous during AVNRT Fig.\u00a0.Fig. 1IA fusion complex Fig.\u00a0.P-wave morphology  rules out sinus tachycardia and atrial fibrillation, and makes an atrial flutter unlikely  in patients without structural heart disease. The differential diagnosis of this tachycardia comprises a junctional ectopic tachycardia (JET), an atrial tachycardia (AT), an atrioventricular reentry tachycardia (AVRT), or an atypical AVNRT .In adults, JET has been linked to both triggered activity and enhanced automaticity, but is rarely seen without prior cardiac surgery . AbnormaThe short PR interval without preexcitation makes fast antegrade conduction, either through an accessory pathway or through the AV node, unlikely .CSM resulting in an isolated P\u2019 wave and subsequently an isolated QRS complex simply excludes AVRT. AVNRT, not needing either the ventricle or the atrium to sustain itself, however, explains the eighth QRS complex Fig.\u00a0. Interbe"}
+{"text": "Current concepts for tricuspid valve surgery recommend concomitant tricuspid valve reconstruction (TVR) utilizing annuloplasty devices over simple suture annuloplasty.It is unclear if flexible bands offer the same long-term results like rigid or semi-rigid rings. We aimed to evaluate possible outcome differences between the flexible SJM Tailor Band (FB group) and the Carpentier-Edwards rigid MC3-Ring (RR group).We retrospectively evaluated 141 patients undergoing tricuspid valve reconstruction (TVR) with the MC3-ring or the Tailor Band or suture annuloplasty between 01/11 and 12/13. Demographic variables, intraoperative parameters, pre- and postoperative echocardiographic studies were analyzed. A total of 108 pts undergoing TVR formed the RR group and 20 the FB group. Patients treated with suture annuloplasty or other devices were excluded.Age, gender, preop. Euroscore II and severity of tricuspid regurgitation (TR) did not differ among groups. Intraoperative parameters  were also similar. Long-term mortality with a median follow-up of 1361d (range: 854-1900d) was similar, too. Postoperative echocardiographic follow-up revealed a trend for more severe TR after reconstruction with the band than with the rigid ring . Subgroup analysis of patients undergoing mitral valve plus concomitant tricuspid valve reconstruction demonstrated more moderate TR in the FB group (Table Tricuspid valve reconstruction with the rigid MC3 ring yields a higher rate of just trace tricuspid regurgitation than with a flexible band in patients undergoing concomitant mitral valve surgery. A trend towards more trace tricuspid regurgitation was observed in the overall study cohort. Longer follow-up or even more desirable a multi-center study is warranted to determine if usage of flexible bands will lead to more reoperations or more overt right-sided heart failure than rigid rings."}
+{"text": "Chronic progressive external ophtalmoplegia (CPEO) and Kearns-Sayre syndrome (KSS) belong to the broad heterogeneous group of mitochondrial myopathies (MM) - a group of neuromuscular disorders resulting from primary dysfunction of the mitochondrial chain with impaired cellular energy metabolism. Recently, a potentially characteristic myocardial fibrosis pattern with intramural late gadolinium enhancement (LGE) in the left ventricular (LV) inferolateral wall was documented by cardiovascular magnetic resonance imaging (CMR) in these patients.mitochondrial encephalopathy with lactic acidosis and stroke-like episodes - MELAS) this aspect was also evaluated.The present study aimed at characterizing the presence and pattern of cardiac abnormalities in a larger CPEO/KSS patient population by means of CMR. Based on the fact that patients with other MM syndromes may show a concentric LV remodelling/hypertrophy  underwent neurological and cardiac evaluations including CMR studies comprising cine- and LGE-CMR (1.5-Tesla). Additionally, CMR scans were performed in 25 age-, gender- and cardiac risk factor-matched asymptomatic CONTROLS  without known heart disease.In the CPEO/KSS group, 18 (55%) patients had at least one pathological finding based on the CMR results: 8 (24%) patients demonstrated an impaired LV-EF (<60%), 3 (9%) patients showed presence of LV hypertrophy and 10 (30%) patients showed non-ischemic LGE with a predominantly intramural pattern, mostly confined to the basal LV inferolateral wall.There were no significant differences in LV volumes, mass or ejection fraction between CPEO/KSS and CONTROLS. However, CPEO/KSS patients demonstrated significantly higher LV mass/ end-diastolic volume ratios as surrogate for LV concentric remodelling when compared to CONTROLS .CPEO/KSS patients frequently show myocardial fibrosis with a predominantly intramural pattern located in the LV inferolateral wall as depicted by LGE-CMR. Moreover, although overt LV hypertrophy is relatively rare, when compared to matched controls, CPEO/KSS seem to show a concentric LV remodelling already described in other MM syndromes.None."}
+{"text": "Severe chronic peripheral arterial disease (PAD) manifests as critical limb ischemia (CLI) with a 5-year mortality rate >70%. Mesenchymal stem cells (MSC) show promise to minimize CLI progression and restore perfusion in experimental models, but approaches suffer from minimal homing to ischemic tissue and require clinically impractical direct injections of cells. We show that pulsed focused ultrasound (pFUS) noninvasively establishes a \u201cmolecular zip-code\u201d of locally upregulated chemoattractants  that lead to enhanced homing permeability and retention of IV-infused MSC to pFUS-treated muscle. This study investigated if pFUS could enhance MSC homing in a CLI model in aged mice and whether they could ultimately improve limb perfusion.CLI was induced by ligating the external iliac artery in C3H mice (9-12 months old). At 14 days post-CLI, mice were grouped as followed: saline controls (n=8); pFUS alone (n=7), MSC alone (n=8), or MSC+pFUS (n=17). Mice were treated, according to their group, daily for 3 days . pFUS was applied to ischemic hamstrings at 40W . For mice receiving MSC, 106 MSC were IV injected via the lateral tail vein. Mice receiving pFUS+MSC had MSC injected ~1hr pre-pFUS. To assess MSC homing, mice were euthanized at 15 days post-CLI (24 hr after last treatment). Fe-labeled MSC were counted by microscopy after Prussian Blue staining. Laser Doppler perfusion imaging (LDPI) was performed weekly for 7-8 weeks post-treatment.Results: Significantly more MSC homed to pFUS-treated ischemic hamstrings than ischemic hamstrings without pFUS p<0.01) or normal hamstrings (Fig  or norma"}
+{"text": "Cardiac magnetic resonance (CMR) imaging at 3.0T results in improved signal-to-noise ratio (SNR), however additional challenges arise that affect image quality. Here, we describe frequently encountered artefacts at 3.0T and how to optimise scanning techniques to provide good quality cardiac images.Glenfield Hospital  performs ~ 2500 CMR scans annually, 700 at 3.0T. These include complex congenital and stress perfusion scans as well as a diverse portfolio of research studies. Image optimisation methods (described below) can prevent or limit general and specific artefacts seen at 3T, improving image quality and patient through-put.Retrospective as defaultArrhythmia detection for occasional ectopicsProspective for frequent ectopics or atrial fibrillation, using short acquisition windowFinger-pulse oximiter when ECG failsReal-time for poor ECG and poor breath-holdingIncreasing parallel-imaging factors (up to x 4 routinely) will reduce breath-hold with minimal impact on SSFP qualityReduce spatial resolution - small reductions in phase resolution will significantly reduce breath-holdIncreasing the echo train/segments shorten breath-hold, with slight decrease in temporal resolutionIncrease the number of averages(3-5) for free-breathing cine images in sedated/deaf subjectsUtilise increased SNR to acquire 2 slices per breath-hold in good breath holders to shorten exam timeCMR at 3.0T requires careful, targeted shimming to significantly improve image quality for SSFP cine, T1-mapping and myocardial nulling on late gadolinium enhanced images.Frequently occur at 3.0T on SSFP images; adjusting the radiofrequency pulse frequency offset can shift artefacts away from the area of interest. Figure Switching to gradient echo with no flow compensation together with tight shimming reduces the appearance of flow artefacts within vessels. Figure Increased SNR results in improved spatial resolution for single shot acquisition. Reduce phase resolution to decrease TR and maintain single beat acquisition for high heart rates (>115bpm)Ensure proper adjustment of shim and center frequency to minimize off resonance Routinely isocenter. Use large field-of-view (~400mm) and consider motion-corrected or shortened T1-mapping sequence (ShMOLLI) if available, to minimize breathing artefactsGood quality CMR images at 3.0T are achievable with adapted scanning techniques and meticulous image optimisation. This improves the diagnostic value of acquired images, minimises scanning time and therefore improves subject experience and throughput in the clinical setting.N/A."}
+{"text": "The CRISPR/Cas9 system has been adapted as an efficient genome editing tool in laboratory animals such as mice, rats, zebrafish and pigs. Here, we report that CRISPR/Cas9 mediated approach can efficiently induce monoallelic and biallelic gene knockout in goat primary fibroblasts. Four genes were disrupted simultaneously in goat fibroblasts by CRISPR/Cas9-mediated genome editing. The single-gene knockout fibroblasts were successfully used for somatic cell nuclear transfer (SCNT) and resulted in live-born goats harboring biallelic mutations. The CRISPR/Cas9 system represents a highly effective and facile platform for targeted editing of large animal genomes, which can be broadly applied to both biomedical and agricultural applications. Targeted genome editing technologies are crucial for basic biology research, development of animal models and improvement of animal traits for agriculture. Zinc finger nucleases The CRISPR system, as an adaptive immune system in bacteria and archaea, uses small RNAs and CRISPR-associated (Cas) proteins to defend against invading viruses and plasmids Genetically modified goats are an important tool for producing valuable therapeutic protein In the present study, we show that Cas9/gRNAs can induce precise mutations with efficiency of 9%\u201370% in goat primary fibroblasts. A single co-transfection of pooled Cas9/gRNAs enabled isolation of cell colonies carrying simultaneous disruption of four genes with high efficiency. The Cas9/gRNA-modified fibroblasts were subjected to nuclear reprogramming by somatic cell nuclear transfer, resulting in live-born goats carrying single-gene mutation.All experiments involving animals were conducted under the protocol approved by the Animal Care and Use Committee of Shihezi University and Utah State University.Bicistronic expression vector (pX330) expressing both Cas9 and gRNA was generously provided by Dr. Feng Zhang of Broad Institute of MIT and Harvard Goat fetal fibroblasts were isolated as described previously Genomic DNA was isolated from treated and wild-type cell colonies, or ear biopsies of cloned and wild-type goats. PCR was performed on 500 ng of genomic DNA using specific primers against MSTN, BLG, PrP and NUP . 10 \u00b5L oGoat somatic cell nuclear transfer was performed as we described previously Protein extracts were taken from biceps brachii muscles of cloned and wild type goats. To raise antibodies against goat MSTN, the C-terminal region of goat MSTN (amino acids 266\u2013375) was expressed in bacteria, purified with a nickel column and then used as antigen to immunize rabbits. Anti-goat MSTN monoclonal antibody (1\u22362000 dilution) and 1\u22361000 dilution of a mouse anti-actin antibody  were used for the western blot analysis. Western blotting was performed as previously reported http://www.ncbi.nlm.nih.gov/genome/10731) against 13 bp of MSTN-1 gRNA seed sequence. Eight potential off targets were found in goat genome for MSTN-1 gRNA. These potential off-target sites were amplified from all cloned goats and subjected to TA cloning. Fifteen transformed colonies (E. coli strain) for each potential off-targets were randomly picked up and sequenced.The potential off-target sites were selected based on the following rules: (1) the protospacer-adjacent motif (PAM) sequence is NGG; (2) the homology with the 12 base \u201cseed sequence\u201d at the 3\u2032 end of the gRNA To test Cas9/gRNA activity in goat primary fibroblasts, we designed six gRNAs targeting myostatin (MSTN), nucleoporin 155 (NUP), prion protein (PrP), and beta-lactoglobulin (BLG), respectively . Each biIsolation of single cell-derived colonies is required for developing methods of Cas9/gRNA-mediated targeting in livestock by animal cloning. We first tried to isolate indel-mutant colonies from MSTN gRNA transfected fibroblasts. Of 22 colonies by the RFLP assay, seven carried mutations in the MSTN gene and three of them had biallelic mutations of MSTN . DNA seqThe high efficiencies of Cas9/gRNAs inspired us to attempt targeting two genes simultaneously in goat primary fibroblasts. MSTN Cas9/gRNA and PrP Cas9/gRNA were co-transfected into goat fibroblasts and 9 out of 45 colonies were identified to carry mutations in both genes by the RFLP assay . Among cWe next tested the efficiency of Cas9/gRNAs disrupting four genes simultaneously by co-transfecting pooled Cas9/gRNAs targeting MSTN, BLG, PrP and NUP genes. The RFLP assay showed that 3 out of 107 colonies had biallelic mutations in all four genes . DNA seqCell colonies with MSTN biallelic mutations (MSTN-KO) were used for nuclear transfer. MSTN-KO colonies (MSTN-KO4 and MSTN-KO16) yielded seven pregnancies from 21 transfers. Three pregnancies were maintained to term, resulting in three live-born goats (Goat1 to goat3) . The RFLTo assess potential off-targets of Cas9/gRNA in goats, we searched for other genomic sequences that could potentially be targeted by MSTN Cas9/gRNA. Eight potential off targets were found in goat genome for MSTN gRNA1. These potential off-target sites were analyzed by DNA sequencing, but no unwanted mutation occurred at these genomic sites in all cloned goats . These rIn this study, we demonstrate for the first time that Cas9/gRNA-mediated gene knockout approach is highly efficient in goats resulting in successful generation of cloned goats with biallelic mutations. Recently, Hai et al. reported generation of single-gene knockout pigs by zygote injection of CRISPR/Cas system We also demonstrate the feasibility of Cas9/gRNA-mediated multiple gene modifications in primary cells. A single co-transfection using two and four Cas9/gRNAs enabled isolation of cell colonies harboring double and quadruple disruptions in 20% and 2% of colonies, respectively, which may not be easily achieved with ZFNs and TALENs technologies. The one-step generation of multiplex mutations in large animals marks a significant improvement over traditional sequential targeting, a process necessitating multiple rounds of animal cloning to target different genes. For example, Kuroiwa et al. reported that it took upwards of 21.5 months or longer for producing double-gene knockout cattle In conclusion, we show for the first time that the CRISPR/Cas9 mediated genome editing can be efficiently accomplished in goats. Cas9/gRNA can be easily engineered against almost all endogenous genes within a 3-day period of time, and goats carrying multiplex mutations can be generated within 5 months (gestation length 150\u2013155 days). Cas9/gRNA-mediated gene targeting demonstrated in this study can be used for other livestock species, which will contribute to advancing transgenic applications of large animal in biomedical and agricultural sciences.Figure S1RFLP assay for detecting Cas9/gRNA-mediated mutations. PCR products from MSTN, NUP, BLG and PrP Cas9/gRNA-treated cells were digested with Van91I, BSTZ171, HindIII, FatI, NlaIII, Bsu36I, respectively; WT: PCR products from wild-type cells were digested with Van91I, BSTZ171, HindIII, FatI, NlaIII, Bsu36I, respectively.(PDF)Click here for additional data file.Figure S2Genotyping of double-mutant colonies by DNA sequencing. Of nine colonies with MSTN/PrP double mutations, five colonies had biallelic mutations of both genes. The PAM sequence is labeled in red.(PDF)Click here for additional data file.Table S1Oligonucleotides used in this study.(PDF)Click here for additional data file.Table S2Potential off targets of MSTN gRNA1.(PDF)Click here for additional data file."}
+{"text": "There is controversy of which parameters better associate with early mortality, and thus should be implemented as the microcirculation end point resuscitation [In severe sepsis and septic shock patients, lactate clearance >10% and central venous oxygen saturation  hospitalized in the ICU, Cipto Mangunkusumo Hospital, Indonesia. Patients' early outcomes were observed during first 120 hours of hospitalization. Cox's regression analysis was used to analyse risk of early mortality in subject groups achieving lactate clearance target only, ScvO2 target only, 138 achieved both targets, 60 did not achieve any target. Subjects who achieved both targets had a significant lowest early mortality risk (P = 0.104 compared with subjects achieved lactate clearance target only and P = 0.000 compared with remaining subject groups) .Subjects consisted of 268 patients. Early mortality developed in 70 subjects. Fifty-four subjects achieved lactate clearance target only, 16 achieved ScvO2 targets in 6 hours after onset of resuscitation associates with lowest early mortality risk in severe sepsis and septic shock patients. Patients who achieve lactate clearance target only have a significant lower early mortality risk compared with those who achieve ScvO2 target only.Achieving both lactate clearance and ScvO"}
+{"text": "S4 Figx [12] and anti-mNax antibodies. Immunohistochemical staining was performed as described in S5 File. Neither rat nor mouse MnPO was negative for Nax (A). On the other hand, the median eminence was clearly stained with both antibodies (B). AC, anterior commissure. Scale bars, 200 \u03bcm.Immunohistochemical staining of the coronal sections of rat and mouse brains, containing the median preoptic nucleus (MnPO) (A) and median eminence (B) with anti-rat Na(TIF)Click here for additional data file."}
+{"text": "Our previous study suggested that PMID induces the activation of Nrf2/ARE pathway, then protecting against oxidative stress-mediated cell death. However, little is known regarding the anti-inflammatory properties of PMID in severe inflammatory phenotypes. In the present study we determined if PMID treatment protects mice from dextran sodium sulphate- (DSS-) induced colitis. The result suggests that treatment with PMID prior to colitis induction significantly reduced body weight loss, shortened colon length, and decreased disease activity index compared to control mice. Histopathological analysis of the colon revealed attenuated inflammation in PMID pretreated animals. The levels of inflammatory markers in colon tissue and serum were reduced associated with inhibition of NF-\u03baB activation. The expression levels of Nrf2-dependent genes such as HO-1, NQO1, and Nrf2 were increased in PMID pretreated mice. However, PMID pretreatment did not prevent DSS-induced colitis in Nrf2 knockout mice. These data indicate that PMID pretreatment in mice confers protection against DSS-induced colitis in Nrf2-dependent manner, suggesting a potential role of PMID in anti-inflammatory response.Nrf2 is the key transcription factor regulating the antioxidant response which is crucial for cytoprotection against extracellular stresses. Numerous  Chronic inflammation has been identified as a potential risk factor for colorectal and other cancers. Inflammatory bowel diseases (IBD) are forms of chronic, recurrent colitis, most commonly Crohn's disease and ulcerative colitis, and many epidemiologic and clinical studies have shown that IBD increases the risk of colorectal cancer . Reactiv in vivo studies indicate that Nrf2 may play a role in the regulation of inflammation. Nrf2 protects against chemical-induced pulmonary injury and inflammation \u03baB signalnjury [\u03b1 , and resnjury [\u03b1  was obseing Nrf2 . Docosahpathways . The pro pathway . Schisanof NF-\u03baB . Cyclo (pression . Our pre in vivo.In summary, the present study provides evidence that PMID confers protection against DSS-induced colitis in Nrf2-dependent mannerFigure S1. PMID pre-treatment did not affect the AP1 activity in DSS-induced colon.Table S1. Disease activity index.Table S2. Real-time quantitative PCR primers."}
+{"text": "AbstractAgrodiaetus H\u00fcbner, 1822 blue butterflies. Using this approach we provide first evidence for presence of Polyommatus (Agrodiaetus) poseidon  in Georgia.We show how combination of chromosomal and molecular markers can be applied for proper species identification in  PageBreakAgrodiaetus H\u00fcbner, 1822 belongs to the genus Polyommatus Latreille, 1804   . In oppodiaetus) , many Ag n = 134 . TherefoAgrodiaetus. Using this approach we provide first evidence for presence of Polyommatus (Agrodiaetus) poseidon  in Georgia.Here we show how combination of chromosomal and molecular markers can be applied for proper species identification in 41.60N, 43.06E, 1000 m alt., 18 July 2014, V. Lukhtanov et V. Tikhonov leg., samples 2014VL56, 2014VL57, 2014VL58, 2014VL62, 2014VL63, 2014VL64, 2014VL65, 2014VL68, 2014VL69, 2014VL70). The methods of DNA sequencing, chromosomal analysis and phylogenetic inference were described previously (Polyommatus belonging to Polyommatus (Agrodiaetus) poseidon species complex  poseidon  is known to be an endemic of the Middle East sporadically distributed from K\u00fctahya in West Turkey to Artvin in North-East Turkey (Polyommatus (Agrodiaetus) putnami  was described from East Turkey (provinces Erzurum and A\u011fri) (Polyommatus (Agrodiaetus) poseidon and differs from Polyommatusposeidon by chromosome number and karyotype structure (Polyommatus (Agrodiaetus) poseidon has relatively low haploid chromosome number , all the chromosomes form a gradient size row with no especially large or small chromosomes (Polyommatus (Agrodiaetus) putnami has higher chromosome numbers . Its karyotype is asymmetrical and includes chromosomes of two distinct classes: class of large chromosomes and class of small chromosomes (Polyommatus (Agrodiaetus) putnami is treated as a distinct species (Polyommatus (Agrodiaetus) poseidon (The species t Turkey . Phenotynd A\u011fri) . The lastructure . Polyommomosomes . Chromosomosomes . Polyommomosomes . Current species  or a subposeidon .Polyommatus (Agrodiaetus) deebi  discovered in Lebanon and Syria is often considered as a subspecies of Polyommatus (Agrodiaetus) poseidon (e.g. Polyommatus (Agrodiaetus) damocleskrymaeus  was also considered as subspecies of Polyommatus (Agrodiaetus) poseidon (COI and COII it is very distant from Polyommatus (Agrodiaetus) poseidon and was shown to be a subspecies of Polyommatus (Agrodiaetus) damocles   .PageBreakPolyommatus (Agrodiaetus) poseidon have plesiomorphic (Polyommatus (Agrodiaetus) caeruleus , Polyommatus (Agrodiaetus) damocles and Polyommatus (Agrodiaetus) damonides  is difficult. With respect to COI barcodes, Polyommatus (Agrodiaetus) poseidon is indistinguishable from Polyommatus (Agrodiaetus) hopfferi  and Polyommatus (Agrodiaetus) putnami . As it was stated above, the chromosome number varies within Polyommatus (Agrodiaetus) poseidon (Polyommatus (Agrodiaetus) elbursicus , Polyommatus (Agrodiaetus) cyaneus , Polyommatus (Agrodiaetus) ectabanensis , Polyommatus (Agrodiaetus) hamadanensis , Polyommatus (Agrodiaetus) alcestis , Polyommatus (Agrodiaetus) altivagans , Polyommatus (Agrodiaetus) mithridates , Polyommatus (Agrodiaetus) shirkuhensis ten Hagen et Eckweiler, 2001 and Polyommatus (Agrodiaetus) pierceae   .PageBreakPolyommatus (Agrodiaetus) poseidon  in population from Akhaltsikhe and other populations of Polyommatus (Agrodiaetus) poseidon and Polyommatus (Agrodiaetus) putnami  poseidon from Amasya (Polyommatus (Agrodiaetus) putnami (n=26)  Fig. . All chrm Amasya  and Artvm Amasya , but difi (n=26) .Polyommatus (Agrodiaetus) poseidon. This is the first evidence of Polyommatus (Agrodiaetus) poseidon for Georgia and for Caucasus region at whole.Thus, although in the studied case neither the DNA barcodes nor chromosomal numbers are species-specific characters, their combination clearly indicates that the population from Akhaltsikhe should be identified as"}
+{"text": "P = 1.8 x 10-7; OR = 1.9). Recurrent microdeletions at seven known genomic hotspots accounted for 36.9% of all microdeletions identified in the GGE cohort and showed a 7.5-fold increased burden (P = 2.6 x 10-17) relative to controls. Microdeletions affecting either a gene previously implicated in neurodevelopmental disorders  or an evolutionarily conserved brain-expressed gene related to autism spectrum disorder  were significantly enriched in the GGE patients. Microdeletions found only in GGE patients harboured a high proportion of genes previously associated with epilepsy and neuropsychiatric disorders . Our results demonstrate that the significantly increased burden of large and rare microdeletions in GGE patients is largely confined to recurrent hotspot microdeletions and microdeletions affecting neurodevelopmental genes, suggesting a strong impact of fundamental neurodevelopmental processes in the pathogenesis of common GGE syndromes.Genetic generalised epilepsy (GGE) is the most common form of genetic epilepsy, accounting for 20% of all epilepsies. Genomic copy number variations (CNVs) constitute important genetic risk factors of common GGE syndromes. In our present genome-wide burden analysis, large (\u2265 400 kb) and rare (< 1%) autosomal microdeletions with high calling confidence (\u2265 200 markers) were assessed by the Affymetrix SNP 6.0 array in European case-control cohorts of 1,366 GGE patients and 5,234 ancestry-matched controls. We aimed to: 1) assess the microdeletion burden in common GGE syndromes, 2) estimate the relative contribution of recurrent microdeletions at genomic rearrangement hotspots and non-recurrent microdeletions, and 3) identify potential candidate genes for GGE. We found a significant excess of microdeletions in 7.3% of GGE patients compared to 4.0% in controls  represent the most common group of epilepsies with predominant genetic aetiology, accounting for 20% of all epilepsies. Despite their strong heritability, the genetic basis of the majority of patients with GGE remains elusive. Genomic microdeletions constitute a significant source of genetic risk factors for epilepsies. The present genome-wide burden analysis in 1,366 European patients with GGE and 5,234 ancestry-matched controls explored the role of large and rare microdeletions  in the complex genetic architecture of common GGE syndromes. Our results revealed a 2-fold excess of microdeletions in GGE patients relative to the population controls, 2) a 7-fold increased burden for known hotspot microdeletions  previously associated with a wide range of neurodevelopmental disorders, and 3) a more than 4-fold enrichment of microdeletions carrying a gene implicated in neurodevelopmental disorders. Our findings reinforce emerging evidence that genes affected by microdeletions in GGE patients have a strong impact in fundamental neurodevelopmental processes and dissect novel candidate genes involved in epileptogenesis. The epilepsies comprise a clinically heterogeneous group of neurological disorders defined by recurrent spontaneous seizures due to paroxysmal excessive and synchronous neuronal activity in the brain . EpilepsGPHN) 26], *** (XLS)Click here for additional data file.S1 FigMicrodeletions identified in patients with genetic generalised epilepsies (GGEs) and ethnically-matched European population controls differentiated by microdeletion type. Top left: Proportion of recurrent hotspot vs. non-recurrent microdeletions in population controls. Top right: Proportion of recurrent vs. non-recurrent deletions in GGE patients. Below: Relative distribution of recurrent microdeletions at seven genomic rearrangement hotspots in GGE patients.(PDF)Click here for additional data file.S2 Fighttp://www.genome.ucsc.edu).Genomic organisation of recurrent microdeletions at the genomic rearrangement hotspots 1q21.1, 15q11.2, 15q13.3, 16p11.2, 16p12.2, 16p13.11 and 22q11.2. Tracks in red = patients with genetic generalised epilepsies (GGEs); tracks in beige = population controls. The annotations of genes (GRCh37/hg19) shown below are generated by the University of California, Santa Cruz Genome Browser ((PDF)Click here for additional data file.S3 Fighttp://www.genome.ucsc.edu). Genomic organisation of the microdeletion region: Red bars represent microdeletion size and genomic location in reference to genes affected by the microdeletion .Chr: chromosome, start/end: genomic start and end position of the deleted segment, hg19; GGE, genetic generalised epilepsy; GGE syndromes: CAE: childhood absence epilepsy, JAE: juvenile absence epilepsy, JME: juvenile myoclonic epilepsy, EGMA: epilepsy with generalised tonic-clonic seizures alone predominantly on awakening, EGTCS: epilepsy with generalised tonic-clonic seizures alone, gsw: generalised spike and wave discharges on the electroencephalogram, number/: age-at-onset of afebrile generalised seizures. Bold gene symbols indicate genes previously implicated in epileptogenesis. Signal intensity plots of microdeletions were visualized using the Affymetrix Chromosomal Analyze Suite software. Top track: Red bars represent the computed area of the observed microdeletions. Second track: Signal intensities (Log2 ratios) of a SNP or CN probe are represented by dots, one dot per probe. A segmental decline of consecutive probe signal intensities indicates a genomic deletion. Third track: Allele difference plot, a dot shift to zero indicates loss of heterozygosity which augments high-confidence deletion calling. Bottom track: Survey of the genomic organisation of the microdeletion generated with the University of California, Santa Cruz (UCSC) Genome Browser ((PDF)Click here for additional data file.S4 FigDAPPLE direct networks derived from genes deleted in GGE patients. Depicted are the most connected networks in GGE. Connectivity is coloured from yellow to red describing low to high connection evidence respectively. Significant interactors are marked bold.(PDF)Click here for additional data file."}
+{"text": "Pseudomonas amygdali, which is newly reclassified from Pseudomonas syringae by DNA-DNA hybridization and ribotyping, cause many serious diseases of major crop plants. Herein, we present draft genome sequences of P.\u00a0amygdali pv. tabaci strain ATCC 11528 and P.\u00a0amygdali pv. lachrymans strain 98A-744.Certain pathovars of  Pseudomonas syringae are plant pathogens that grow epiphytically on plant hosts. Earlier studies gave rise to the idea of the \u201cPseudomonas syringae complex,\u201d a single species with many populations capable of infecting specific hosts  and lachrymans (strain 98A-744) were chosen for genome sequencing.Most bacterial strains classified under the species ic hosts . Howeversyringae . Specifiamygdali . Moreoveo exists . To undeP.\u00a0amygdali pv. tabaci ATCC 11528 was purchased from the American Type Culture Collection . P.\u00a0amygdali pv. lachrymans 98A-744, originally obtained from the Department of Horticulture, University of Wisconsin, Madison, USA  for ATCC 11528, and 193 scaffolds  for 98A-744. To improve the latter assembly, a 3-kb jumping library was constructed with the 5500 SOLiD mate pair library kit and Ion Torrent PGM sequencing was performed, which was carried out by GenoTech Corporation . Reads generated from one PGM 314 chip were split into 470,694 paired reads  using the CLC Genomics Workbench 8.0 (CLC bio). A5-miseq assemblies and mate pair reads  were scaffolded with the SSPACE Premium v2.3 (BaseClear), followed by automatic gap filling using the GapFiller , our assemblies are much closer to the complete level. Automatic genome annotation was carried out using the NCBI Prokaryotic Genome Annotation Pipeline (PGAP) service.pipeline . The iniP.\u00a0amygdali as well as P.\u00a0syringae use the system to suppress pathogen-associated molecular pattern-elicited immunity (PTI) and effector-triggered immunity (ETI). Both pathovars include the biosynthesis gene cluster of coronatine that acts as a plant immune inhibitory toxin and stomata closure determinant (The two pathovars possess 146 genes for type III secretion system and effectors indicating that erminant , 9.LCWS00000000 and LCWT00000000, respectively. The versions described in this paper are versions LCWS01000000 and LCWT01000000.These whole-genome shotgun projects of ATCC 11528 and 98A-744 have been deposited at DDBJ/EMBL/GenBank under the accession numbers"}
+{"text": "In the UK, ethnic minority groups have reported lower awareness of breast screening and have presented with breast cancer symptoms later than Caucasian women. Our study compared prognostic indices in symptomatic and screen-detected breast cancer between Asian and Caucasian patients.Of the 310 Asian women diagnosed with breast cancer between 1999 and 2014 in the Asian Breast Cancer Database, 217 with invasive cancer were selected (57 screen-detected and 160 symptomatic). Data on invasive tumour size, grade, lymph node status and NPI were compared with age and mode-matched Caucasian breast cancer patients.p <0.001); higher proportions of grade 3 tumours (64.4 %) (p = 0.007) and with more than one lymph node involved (46.2 %) (p = 0.004), compared with Caucasian patients (48.8 % and 30.0 % respectively); worse NPI scores , compared with Caucasian patients  (p <0.001); and higher proportions with poor prognosis (33.8 %), compared with Caucasian patients (11.9 %) (p <0.001). Multivariable analysis showed invasive grade and tumour size were statistically significant independent discriminators with lymph node status as borderline significant. However, there was no statistically significant difference between the ethnic groups for screen-detected invasive tumours.Asian symptomatic women had larger invasive tumours , compared with Caucasian patients  (Prognostic indices in Asian women were worse in symptomatic breast cancer, but similar in screen-detected invasive cancer, compared with age-matched Caucasian women. Greater initiatives need to be implemented to promote breast cancer awareness, education and screening among the Asian ethnic minorities."}
+{"text": "PRRT2) gene was identified to be related to paroxysmal kinesigenic dyskinesia (PKD), infantile convulsions with PKD, PKD with migraine and benign familial infantile epilepsy (BFIE). The present study explores whether the PRRT2 mutation is a potential cause of febrile seizures, including febrile seizures plus (FS+), generalized epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome (DS); thus, it may provide a new drug target for personalized medicine for febrile seizure patients. We screened PRRT2 exons in a cohort of 136 epileptic patients with febrile seizures, including FS+, GEFS+ and DS. PRRT2 genetic mutations were identified in 25 out of 136 (18.4%) febrile seizures in epileptic patients. Five loss-of-function and coding missense mutations were identified: c.649delC (p.R217Efs*12), c.649_650insC (p.R217Pfs*8), c.412C>G (p.Pro138Ala), c.439G>C (p.Asp147His) and c.623C>A (p.Ser208Tyr). PRRT2 variants were probably involved in the etiology of febrile seizures in epileptic patients.Previous studies reported that the proline-rich transmembrane protein 2 ( PRRT2) as the causative gene in some nervous system diseases, including paroxysmal kinesigenic dyskinesia (PKD), infantile convulsions with PKD, benign familial infantile epilepsy (BFIE), hemiplegic migraine and episodic ataxia alone ..PRRT2 gePRRT2 might underlie a broader range of seizure subtypes than what was previously suspected. Overall, PRRT2 mutations were probably involved in the etiology of febrile seizure-related epilepsy. As a new susceptibility gene, the PRRT2 gene may provide a new drug target for personalized medicine for febrile seizure patients.Nowadays, although more and more research has been focused on the susceptibility and drug efficacy of epilepsy, there are still some patients who cannot benefit from the anti-epileptic drug efficacy. The susceptibility genes as drug targets play a key role in the optimization of treatment. As a new susceptibility gene of epileptic patients with febrile seizures, mutations of"}
+{"text": "Among comorbidities associated to irritable bowel syndrome (IBS) there are headaches including migraine attacks, frequently reported in female gender.Assessment of vascular involvement of migraine without aura in female patients with IBS.30 female patients, mean age= 47,47\u00b18,38 years, previously diagnosed with IBS (Rome II criteria), 15 predominant constipation(IBS-C) and 15 predominant diarrhea(IBS-D), complaining of mild to moderate migraine without aura , with no records of cigarettes smoking, hypertension, diabetes mellitus, obesity or treatment requiring dyslipidemia, undertook Duplex carotidian examination with a linear 12 MHz transductor, GE Loqic 5 Expert high resolution ultrasound device. We assessed intima-media thickness (IMT) at 1cm before right and left common carotid artery(CCA) bifurcation at the posterior wall and presence and severity of atherosclerotic plaques.12 patients(40%) exhibited no vasular issues, IMT normal (6: IBS-D and 6: IBS-C); 18 patients (60%) showed various aspects of endotelial dysfunction: abnormal IMT in 15 patients  and small nonstenotic, stable plaques in 3 patients  with fibrolipidic features. There was no statistically difference between the two groups neither having vs not having vascular issues , nor between abnormal IMT vs presence of atherosclerotic plaques .More than half of IBS female patients complaining of migraine without aura presented features of endotelial dysfunction: either increasesd IMT or patent signs of early atherosclerotic plaques. No statistically significant differences concerning vascular issues were set between the two groups: IBS-C vs IBS-D patients.No conflict of interest."}
+{"text": "Setaria italica L.) is a model crop for investigating systems biology of millets and bioenergy grasses. Further, the crop is also known for its potential abiotic stress-tolerance. In this context, a comprehensive genome-wide survey was conducted and 209 MYB protein-encoding genes were identified in foxtail millet. All 209 S. italica MYB (SiMYB) genes were physically mapped onto nine chromosomes of foxtail millet. Gene duplication study showed that segmental- and tandem-duplication have occurred in genome resulting in expansion of this gene family. The protein domain investigation classified SiMYB proteins into three classes according to number of MYB repeats present. The phylogenetic analysis categorized SiMYBs into ten groups (I - X). SiMYB-based comparative mapping revealed a maximum orthology between foxtail millet and sorghum, followed by maize, rice and Brachypodium. Heat map analysis showed tissue-specific expression pattern of predominant SiMYB genes. Expression profiling of candidate MYB genes against abiotic stresses and hormone treatments using qRT-PCR revealed specific and/or overlapping expression patterns of SiMYBs. Taken together, the present study provides a foundation for evolutionary and functional characterization of MYB TFs in foxtail millet to dissect their functions in response to environmental stimuli.MYB proteins represent one of the largest transcription factor families in plants, playing important roles in diverse developmental and stress-responsive processes. Considering its significance, several genome-wide analyses have been conducted in almost all land plants except foxtail millet. Foxtail millet ( Zea mays involving the regulation of anthocyanin biosynthesis In plants, transcription factors (TFs) play crucial role in regulating the gene expression and thereby guiding various biological processes including growth, development, cell division and response to stresses. Deciphering the molecular and physiological roles of these TFs has become hottest topic of research since understanding the control of gene expression would enable researchers to develop elite varieties of crop plants with desired agronomic traits which will ensure global food security in the scenario of climate change. Hence research on TFs had gained momentum and numerous TFs regulating vital biological processes in plants have been identified. MYB (myeloblastosis) TFs are omnipresent in eukaryotic systems and in plants was first identified in MYB proteins possess a highly conserved MYB DNA-binding domain throughout the eukaryotes at N-terminus and 1\u20134 imperfect repeats  Setaria italica L.).There are numerous reports available demonstrating the role of MYB TFs in various plant processes such as secondary metabolism http://faostat.fao.org/). Being a C4 panicoid crop, it is efficient in photosynthesis and better water use efficiency (WUE). Photosynthesis in C4 crops is more efficient than C3 plants even under high light intensity and high temperatures since phosphoenolpyruvate carboxylase (PEPC) helps in immediate uptake of carbon di oxide and delivering it to RuBisCO. The immediate quenching of carbon di oxide and delivery by PEPC does not require keeping stomata open for a long period and hence less water is lost by transpiration resulting in better WUE Panicum virgatum), napier grass (Pennisetum purpureum) and pearl millet (Pennisetum glaucum) in silico expression profiling using RNA-Seq data, (v) ortholog identification in related grass genomes, (vi) evolutionary analysis of orthologs and paralogs, and (vii) expression analysis of candidate MYB genes using qRT-PCR.Foxtail millet is a member of Poaceae family and it is the second most-widely cultivated millets, next to pearl millet  www.phytozome.net) of Setaria italica. All hits with expected values less than 1.0 were retrieved and compared with MYB protein dataset available in Foxtail millet Transcription Factor Database (http://59.163.192.91/FmTFDb/) S. italica MYB (SiMYB) proteins were examined using CDD search (http://www.ncbi.nlm.nih.gov/Structure/cdd/wrpsb.cgi) for presence of one or more MYB DNA-binding domains. The chromosomal location and identification of alternate transcripts of SiMYBs were performed by executing BLASTP search against the foxtail millet protein sequences in Phytozome and redundant sequences with different identification numbers and same chromosome locus were discarded. Based on ascending order of chromosomal position from short arm telomere to long arm telomere, SiMYBs were annotated as SiMYB001 to SiMYB209 and physical map was constructed using MapChart v2.2 The Hidden Markov Model (HMM) profile of MYB DNA-binding domain (PF00249) downloaded from Pfam v27.0 (http://hmmer.janelia.org/search/hmmscan). BioEdit tool (http://www.mbio.ncsu.edu/bioedit/bioedit.html) was used to perform multiple sequence alignment (MSA) of SiMYB amino acid sequences. The physicochemical properties of SiMYB proteins were then investigated using ExPASy ProtParam tool (http://web.expasy.org/protparam/). Gene Structure Display Server was used to identify the position of introns and exons in respective SiMYB genes (http://gsds.cbi.pku.edu.cn/) The presence of conserved domains in SiMYB proteins were analysed by employing hmmscan tool  Setaria italica miRNAs (Sit-miRs) targeting SiMYBs were predicted by aligning Sit-miRs SiMYB transcript sequences using psRNATarget The amino acid sequences of SiMYB are loaded in Blast2GO suite Setaria italica Illumina RNA-HiSeq reads for 4 tissues namely spica, stem, leaf and root were retrieved from European Nucleotide Archive  http://59.163.192.90:8080/ngsqctoolkit/) S. italica using Bowtie2 Brachypodium  to predict the MYB orthologs in these grass species. A reciprocal BLAST (BLASTP) was also performed to ensure unique relationship between the orthologous genes and all hits with E-value\u22641e-5 and at least 80% homology were considered significant. The orthologous relationships between foxtail millet and these grass species were then visualized using Circos v0.55 (http://circos.ca/). The synonymous (Ks) and non-synonymous (Ka) substitution rates were estimated for paralog and ortholog MYB gene pairs through CODEML program in PAML interface tool of PAL2NAL  \u22129SiMYB protein sequences were BLASTP searched against the peptide sequences of sorghum, maize, rice and SiMYBs. The seedlings were grown in a plant growth chamber  for 21 d after germination at 28\u00b11\u00b0C day/23\u00b11\u00b0C night/70\u00b15% relative humidity with a photoperiod of 14 h and a photosynthetic photon flux density of 500 \u00b5mol m\u22122 s\u22121. The plants were watered daily with one-third strength Hoagland's solution A salt and dehydration tolerant foxtail millet cultivar \u2018Prasad\u2019 260: OD280 nm absorption ratio (1.8\u20132.0)] and integrity of RNA was checked by resolving on 1.2% agarose gel containing 18% formaldehyde. An amount of \u223c1 \u00b5g total RNA was reverse transcribed to first strand cDNA using random primers by Thermo Scientific Verso cDNA kit  following manufacturer's instructions. The qRT-PCR primers were designed using GenScript Real-time PCR Primer Design tool (https://www.genscript.com/ssl-bin/app/primer) \u22121 by the default software (Applied Biosystems).Total RNA was isolated by following the method described by Longeman et al. /primer) . qRT-PCRhttp://www.rcsb.org/pdb/) for predicting the best template with homologous amino acid sequence and known structure. The result was then imported in Phyre2 server  for predicting three-dimensional structures of proteins by homology modeling under \u2018normal\u2019 mode http://zhanglab.ccmb.med.umich.edu/COACH/) and highlighted using UCSF Chimera 1.8.SiMYB protein sequences were searched against Protein Data Bank (PDB) (http://59.163.192.91/FmTFDb/) SiMYBs were primary transcripts and 20 were alternate transcripts. SiMYB017 had a maximum of three alternate transcripts, whereas SiMYB080, SiMYB137, SiMYB143 and SiMYB185 have two splice variants. Thirteen SiMYBs were evidenced to have one splice variant each.The availability of foxtail millet whole genome sequence Brachypodium has 132, 155 and 98 MYB genes, respectively  SiMYBs on individual chromosomes also revealed certain physical regions with a relatively higher accumulation of gene clusters. For instance, SiMYBs located on chromosomes 1, 3, 4, 5, 6 and 9 appear to be clustered at both upper end and lower end of the arms. Moreover, examination of gene duplication showed that SiMYB genes underwent both tandem and segmental duplications . The longest protein sequence was SiMYB053 (1741 amino acids) and the least was SiMYB194 (98 amino acids)  . The enoThe phylogenetic tree constructed using neighbour-joining (NJ) method for all 209 SiMYB proteins conformed to the phylogenetic classification enlisted in FmTFDb . The intOryza sativa protein database and its biological processes, molecular functions and cellular components were identified (Gene Ontology (GO) annotation for all 209 SiMYB proteins was performed using Blast2GO. The SiMYB protein sequences were BLAST searched against entified . The resentified . Noteworentified . The bioentified . The molentified . In addicis-acting elements upstream of SiMYB genes (SiMYB genes. ARR1AT (NGATT) is a cytokinin response regulator binding motif 4 plants cis-elements cis-elements were present unique to specific SiMYBs such as AAGACGTAGATACL12 in SiMYB167, ABADESI1 in SiMYB025, ABADESI2 in SiMYB110, ABRE3HVA22 in SiMYB158 and ABREDISTBBNNAPA in SiMYB122. Further, Setaria italica miRNAs (Sit-miRs) targeting the SiMYB transcripts for post-transcriptional gene regulation were also identified. Three Sit-miRs namely Sit-miR5568.58, Sit-miR2118d and Sit-miR159a were evidenced to target SiMYB026, SiMYB028, SiMYB029, SiMYB130 and SiMYB190  were evidenced to possess DNA markers (SiMYBs were found predominant (\u223c90%) followed by ILP markers (\u223c10%). Among the SSRs (63), tri-nucleotide repeats were maximum (41) followed by di-nucleotide repeats (20). Only two eSSRs namely SieSSR302 and SieSSR70 were found to be present in SiMYB030 and SiMYB094, respectively, and both the markers were of tri-nucleotide repeat type. SSRs SiGMS12780 and SiGMS8287 were a tetra- and hexa-nucleotide repeats, evidenced to be present in SiMYB179 and SiMYB125, respectively . Except the presence of conserved nucleotide and amino acid sequences of MYB domain between foxtail millet-rice and foxtail millet-Brachypodium, the regions other than the MYB domain were highly diverse. The degree of decrease in orthologous relationships among foxtail millet-sorghum, -maize, -rice and Brachypodium is due to genetic relatedness of these genomes. Foxtail millet along with sorghum and maize belong to Panicoideae, whereas rice and Brachypodium belong to Ehrhartoideae and Pooideae, respectively. This pattern of decreasing synteny was also observed in the comparative mapping of NAC TFs 2H2-type zinc finger TFs Of the 209 SiMYB genes, 72 (\u223c34%) showed significant orthologous relationships with sorghum, 55 (\u223c26%) with maize, 23 (\u223c11%) with rice and 13 (\u223c6%) with hypodium \u2013S10. FoxSiMYB. The ratios of Ka/Ks for segmentally and tandemly duplicated gene-pairs ranged from 0.02 to 0.1 and 0.07 to 0.1, respectively (2H2-type zinc finger TFs by Muthamilarasan Setaria since divergence of sorghum and maize had occurred \u223c13 Mya The ratios of non-synonymous (Ka) versus synonymous (Ks) substitution rate (Ka/Ks) were estimated for duplicated and orthologous gene-pairs of ectively \u2013S12. TheSiMYB, average Ka/Ks value was maximum between foxtail millet and Brachypodium followed by foxtail millet and rice  and late (24 h) duration of abiotic stresses , and hormone treatments  were studied using qRT-PCR . The data of foxtail millet  excludes alternate transcripts.(PDF)Click here for additional data file.Figure S2Conserved domains in SiMYB proteins, identified using CDD database.(PDF)Click here for additional data file.Figure S3The multiple sequence alignment of \u2018MYB-related\u2019 proteins.(PDF)Click here for additional data file.Figure S4The multiple sequence alignment of \u2018MYB-R2R3\u2019 proteins.(PDF)Click here for additional data file.Figure S5The multiple sequence alignment of \u2018MYB-R1R2R3\u2019 proteins.(PDF)Click here for additional data file.Figure S6Gene structures of SiMYB proteins. Exons and introns are represented by green boxes and black lines, respectively.(PDF)Click here for additional data file.Figure S7Predicated three dimensional structures of all the 209 SiMYB proteins.(PDF)Click here for additional data file.Table S1Details of primers used for quantitative real-time PCR.(DOC)Click here for additional data file.Table S2Characteristic features of 209 MYB Transcription factor gene family members identified in Setaria italica.(XLS)Click here for additional data file.Table S3Summary of functional domains present in the 209 SiMYB proteins.(XLS)Click here for additional data file.Table S4Blast2GO annotation details of SiMYB protein sequences.(XLS)Click here for additional data file.Table S5Characteristics of the promoter region of SiMYB genes.(XLS)Click here for additional data file.Table S6Details of DNA markers present in SiMYB genes.(XLS)Click here for additional data file.Table S7The Ka/Ks ratio, estimated divergence time and percentage identity for orthologous SiMYB proteins between foxtail millet and sorghum.(XLS)Click here for additional data file.Table S8The Ka/Ks ratio, estimated divergence time and percentage identity for orthologous SiMYB proteins between foxtail millet and maize.(XLS)Click here for additional data file.Table S9The Ka/Ks ratio, estimated divergence time and percentage identity for orthologous SiMYB proteins between foxtail millet and rice.(XLS)Click here for additional data file.Table S10The Ka/Ks ratio, estimated divergence time and percentage identity for orthologous SiMYB proteins between foxtail millet and Brachypodium.(XLS)Click here for additional data file.Table S11The Ka/Ks ratios and estimated divergence time for segmentally duplicated SiMYB genes.(DOC)Click here for additional data file.Table S12The Ka/Ks ratios and estimated divergence time for tandemly duplicated SiMYB genes.(DOC)Click here for additional data file.Table S13List of templates used in homology modelling of 209 SiMYB proteins.(XLS)Click here for additional data file."}
+{"text": "Cardiovascular Magnetic Resonance myocardial feature tracking (CMR-FT) is a quantitative technique tracking tissue voxel motion on standard steady-state free precession (SSFP) cine images to assess ventricular myocardial deformation. The importance of left atrial (LA) deformation assessment is increasingly recognized and can be assessed with echocardiographic speckle tracking. However atrial deformation quantification has never previously been demonstrated with CMR. We sought to determine the feasibility and reproducibility of CMR-FT for quantitative LA strain and strain rate (SR) analysis.s], peak positive SR [SRs]), LA conduit function  and LA booster pump function .10 healthy volunteers, 10 patients with hypertrophic cardiomyopathy (HCM) and 10 patients with heart failure and preserved ejection fraction (HFpEF) were studied at 1.5 Tesla. LA longitudinal strain and SR parameters were derived from SSFP cine images using dedicated CMR-FT software . LA performance was analyzed using 4- and 2-chamber views including LA reservoir function  and impaired LA conduit function as compared to healthy controls . LA booster pump function was increased in HCM while decreased in HFpEF . Observer variability was excellent for all strain and SR parameters on an intra- and inter-observer level as determined by Bland-Altman, coefficient of variation and intraclass correlation coefficients.In all subjects LA strain and SR parameters could be derived from SSFP images. There was impaired LA reservoir function in HCM and HFpEF (eCMR-FT reliably quantifies LA longitudinal strain and SR from standard SSFP cine images. CMR-FT based atrial performance analysis discriminated between patients with impaired left ventricular relaxation and healthy controls. CMR-FT derived atrial deformation analysis seems a promising novel approach for the study of atrial performance and physiology in health and disease states.N/A."}
+{"text": "The transmural extent of myocardial infarction (MI) as assessed by late gadolinium enhancement (LGE) CMR predicts functional recovery. In acute MI (AMI), myocardial edema and effects of reperfusion therapy reduce the predictive accuracy of LGE. LGE assesses tissue dichotomously as \"viable\" or \"non-viable\", but does not consider the severity of tissue damage within the hyperenhanced infarct zone. Extracellular volume (ECV) estimation, using native and post-contrast T1 mapping CMR, allows for quantitative assessment of severity of myocardial damage. We aimed to assess if CMR-derived measurement of infarct ECV offers additional predictive value over LGE extent for contractile recovery in reperfused AMI.35 patients presenting with first ST-segment elevation AMI treated by primary percutaneous coronary intervention underwent acute (day 2) and convalescent (3 months) CMR at 3.0 Tesla. Cine imaging, tissue tagging, modified Look-Locker inversion T1 mapping  natively and 15 minutes post gadolinium-contrast administration and LGE imaging at 20 minutes were performed. The ability of acute infarct ECV and acute transmural extent of LGE to predict convalescent wall motion, ejection fraction (EF) and strain were compared. A per-patient analysis was performed using a region of interest corresponding to the core of the infarct, excluding any microvascular obstruction (MO). Segmental analysis was also performed and evaluated using a multilevel linear mixed-effects model to account for non-independence of segmental data.Per-patient, ECV and transmural extent of LGE correlated with convalescent wall motion score  and convalescent EF . Per-segment, acute ECV and LGE transmural extent were associated with convalescent wall motion score ."}
+{"text": "Solitary papillary muscle (PM) hypertrophy is an unique type of hypertrophic cardiomyopathy (HCM), which is characterized by predominant papillary muscle hypertrophy sparing the rest of other left ventricular segments. It has recently drawn our attention about the mechanism of left ventricular mid-cavity obstruction and the influence of pressure gradient in the left ventricular outflow tract (LVOT), thus carries clinical importance.We reported a symptomatic, 83-year-old woman who presented with dynamic, high resting left ventricle (LV) mid-wall gradient without obvious septal hypertrophy or systolic anterior motion (SAM). Subsequent real-time (RT) three-dimensional echocardiography (3DE) and cardiac magnetic resonance imaging (MRI) demonstrated large, hypertrophic accessory papillary muscles squeezing mid-cavity of left ventricle producing dynamic pressure gradient during systole in the absence of left ventricular wall anomalies.We proposed that combined use of echocardiography particularly RT-3DE and cardiac magnetic resonance imaging (MRI) can accurately identify this specific type of hypertrophic cardiomyopathy without remarkable traditional features. Hypertrophic obstructive cardiomyopathy (HOCM) refers to those subjects with significant dynamic left ventricular outflow tract (LVOT) obstruction due to mechanical causes, with most presents with asymmetrical septal hypertrophy resulting in dynamic systolic anterior motion (SAM) of mitral leaflets .Solitary papillary muscle (PM) hypertrophy, a peculiar form of HCM manifested as predominant PM hypertrophy sparing the rest of other LV segments, has recently gained much attention owing to its mechanical consequences on left ventricular outflow tract (LVOT) pressure gradient formation ,3.A 83-year-old woman with history of hypertension and hyperlipidemia. The blood pressure and hyperlipidemia were well-controlled with medication. She was admitted to our hospital with chest pain on effort and exertional shortness of breath. Her vital sign was stable with blood pressure 131/70 mmHg and heart rate 67 beats per minute at initial presentation. A mid-systolic ejection murmur was heard along the left sternal border with chest X-ray showed minor pulmonary congestion. Incidental high resting LV mid-wall pressure gradient  though significantly hypertrophied PMs . Beta-blockade was then prescribed and the symptoms improved drastically during the subsequent follow up.Repeated 2D transthoracic echocardiogram during hospitalization revealed no more pressure gradient (plummeted to 5 mmHg) after holding diuretics Figure\u00a0B. MeanwhSo far, left ventricular hypertrophy remained the predominant and major phenotypic component of hypertrophied cardiomyopathy . Few casWhile HCM subjects with concomitant morphological papillary muscle anomalies may present with higher degree of resting LVOT gradient , it is nCurrent guidelines for LV mass calculation do not take papillary muscle mass into account, while our relevant findings may suggest include papillary muscles in LV mass assessment, especially for these morphologically abnormal papillary muscle subjects.Solitary papillary muscle hypertrophy as an uncommon variant form of HCM with coexisted additional, accessory papillary muscle may develop abnormally high resting LV mid-wall pressure gradient without SAM or significant regional LV wall hypertrophy. Cardiac MRI and RT-3DE may have their peculiar roles in uncovering these cardiac morphological/structural anomalies aiming for a more comprehensive analysis on their spatial relationships.In conclusion, we recommended that for subjects with unusually high LV mid-wall or LVOT pressure gradient with unrevealing regional LV segment anomalies, RT-3DE and MRI should be considered as a screening tool to disclose these under-diagnosed, specific HCM subjects in daily routine.Written informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.LV: Left ventricle; RT: Real time; 3DE: three-dimensional echocardiography; MRI: magnetic resonance imaging; PM: Papillary muscle; HCM: Hypertrophic cardiomyopathy; HOCM: Hypertrophic obstructive cardiomyopathy; LVOT: Left ventricular outflow tract; SAM: Systolic anterior motion; DHE: Delayed hyperenhancement.The authors declare that they have no competing interests.KTS was the primary author of the text. CHY assisted in image acquisition and retouching. CLH conceived of the report, provided the images, and modified the manuscript. JYH provided additional supervision. All authors have read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2261/14/34/prepubReal time 3D Echocardiography, four chamber view.Click here for fileReal time 3D Echocardiography, short axis view.Click here for fileReal time 3D echocardiography sequences in short axis view, divided the left ventricle into 9 slices during end-diastolic phase.Click here for file"}
+{"text": "The influence of skin substitutes upon angiogenesis during wound healing is unclear.To compare the angiogenic response in acute cutaneous human wounds treated with autogenic, allogenic and xenogenic skin substitutes to those left to heal by secondary intention.On day 0, four 5mm full-thickness punch biopsies were harvested from fifty healthy volunteers (sites 1-4). In all cases, site 1 healed by secondary intention (control), site 2 was treated with collagen-GAG scaffold (CG), cadaveric decellularised dermis (DCD) was applied to site 3, whilst excised tissue was re-inserted into site 4 (autograft). Depending on study group allocation, healing tissue from sites 1-4 was excised on day 7, 14, 21 or 28. All specimens were bisected, with half used in histological and immunohistochemical evaluation whilst extracted RNA from the remainder enabled whole genome microarrays and qRT-PCR of highlighted angiogenesis-related genes. All wounds were serially imaged over 6 weeks using laser-doppler imaging and spectrophotometric intracutaneous analysis.Inherent structural differences between skin substitutes influenced the distribution and organisation of capillary networks within regenerating dermis. Haemoglobin flux (p = 0.0035), oxyhaemoglobin concentration (p = 0.0005), and vessel number derived from CD31-based immunohistochemistry (p = 0.046) were significantly greater in DCD wounds at later time points. This correlated with time-matched increases in mRNA expression of membrane-type 6 matrix metalloproteinase (MT6-MMP) (p = 0.021) and prokineticin 2 (PROK2) (p = 0.004).Corroborating evidence from invasive and non-invasive modalities demonstrated that treatment with DCD resulted in increased angiogenesis after wounding. Significantly elevated mRNA expression of pro-angiogenic PROK2 and extracellular matrix protease MT6-MMP seen only in the DCD group may contribute to observed responses. Angiogenesis is a crucial mechanism during wound healing involving the dynamic co-ordinated interaction of structural, cellular and molecular components . DefinedAfter injury, an abundant blood supply is required to fuel the increased local metabolic demands of the healing process, whilst endothelial cells themselves are pivotal co-ordinators of fibroplasia and ECM remodelling . UnbalanTreatment options within the chronic wound field have expanded significantly with the introduction of dermal skin substitutes (dSS). These bioengineered materials have variable design depending on their source  and cellular content (acellular versus cellular) . FundameIn this unique human clinical study, we quantitatively compared the angiogenic response to wounding in 50 healthy volunteers, treated with different dSS  and autograft) and compared them to secondary intention wound healing (Control). Using correlating invasive and non-invasive assessment tools, we successfully investigated whether the angiogenic influence of dSS seen in chronic wounds was translated to the acute wound setting, established whether this behaviour was dependent upon dSS characteristics and provided supporting experimental data for observed behaviour.National Research Ethics Service (NRES reference number 12/NW/0078) and local research and development department  approval was granted. Fifty healthy volunteers meeting study inclusion/exclusion criteria  gave infOn day 0, anatomical sites on each arm (sites 1\u20134), located 2cm proximal and 2cm distal to the mid-point of a line connecting the axillary hairline with the medial epicondyle were assigned . Skin atFive millimetre full-thickness punch biopsies were taken from allocated sites under local anaesthetic  . Full thPatients attended follow-up on day 7, 14, 21, 28 and 42 where wounds were assessed using non-invasive tools . FLPI anHistology (n = 10 patients/group). Formalin-fixed paraffin-embedded tissue sections at a thickness of 3\u00b5m were prepared on glass slides. Haemotoxylin and eosin staining (H&E) was performed using Tissue-Tek Prisma automated stainer . Slides were dewaxed with xylene  and rehydrated before being stained with Harris haematoxylin  for 7 minutes. Excess haematoxylin was removed by washing in a 0.05% solution of acid alcohol for 10 seconds. Nuclei were then blued using Scott\u2019s tap water substitute for 1 minute and 15 seconds. Tissue sections were stained with alcoholic eosin (CellPath) for 2 mins. Following staining, slides were dehydrated in 99% industrial methylated spirit and rinsed in xylene before being mounted using KP coverslipping tape .Immunohistochemical staining (n = 10 patients/group). Formalin-fixed, paraffin-embedded tissue sections at a thickness of 3\u00b5m were mounted onto positively-charged glass slides . All immunohistochemical steps were performed using Ventana Benckmark Ultra automated stainers  and UltraView Universal DAB Detection Kits . Washing steps were performed between each step of the protocol using Reaction Buffer . Tissue sections were dewaxed by heating slides to 60\u00b0C and incubating in EZ Prep solution  for 4 minutes followed by 3 rinses with EZ Prep solution. Antigen retrieval was performed as per the protocol in RNA extraction (n = 5 patients/group). Tissue from day 0 and extraction biopsies were homogenised in 300\u03bcL of RLT buffer  mixed with \u03b2-mercaptoethanol  (10\u03bcl \u03b2-mercaptoethanol/ml RLT buffer) using 5-mm stainless steel beads and a Qiagen TissueLyser II (Qiagen GmbH) at 30 oscillations/second for 10 minutes. RNA was extracted using RNeasy Fibrous Tissue Mini Kits (Qiagen GmbH) and Qiagen Qiacube (Qiagen GmbH). Eluted RNA quantity and purity was assessed using NanoDrop ND-100 v3.0.1 spectrophotometer  and RNA integrity measured via Agilent 2100 Bioanalyser .Whole genome microarray (n = 3 patients/group). Agilent Whole Human Genome (8\u00d760K) Oligo Microarrays (Agilent Technologies) containing 50,599 features and the manufacturer\u2019s protocol titled One-Colour Microarray-Based Gene Expression Analysis (Low Input Quick Amp Labelling\u2014Version 6.5 May 2010) were employed. 50ng RNA templates were used to create labelled complimentary-RNA using Quick Amp Labelling Kits (One-Colour) (Agilent Technologies). Gene Expression Hybridisation Kits (Agilent Technologies) were utilised for 17-hour array hybridisation, following which arrays were washed with Gene Expression Wash Buffer Kit stabilisation and drying solution (Agilent Technologies). Arrays were scanned at 5\u03bcM scan resolution using Axon GenePix 4400A  and images extracted using GenePix Pro 7 (Molecular Device Ltd). Normalised data was analysed using Qlucore Omics Explorer 2.3 . Comparisons between patient-matched d0 biopsies (n = 15) and subsequent time points for each treatment group (n = 3) were performed. For each comparison, the top 500 genes with p and q-values of <0.05 were selected.qRT-PCR (n = 5 patients/group). To validate microarray results, expression of selected candidate genes and a reference gene was studied using qRT-PCR. 1\u03bcg RNA was used as template to synthesise complementary DNA (cDNA) using qScript cDNA Synthesis Kit . Ribosomal protein L32 (RPL32) was used as a reference gene for normalisation. PCR reactions were carried out in triplicate using the Roche LightCycler 480 system (Roche Diagnostics GmBh) as explained previously [eviously . NegativNational Health Service Blood & Transplant derived Decellularised Dermis (DCD). DCD is a tissue allograft licensed for human application/transplantation and approved by the UK Human Tissue Authority. DCD is prepared from donated cadaveric split thickness skin grafts. Sequential treatments are applied to remove the epidermis and cellular components of the dermis as described by Hogg et al before it is terminally sterilised [erilised .Collagen-Glycosaminoglycan Wound Matrix Scaffold (CG). Integra Matrix Wound Dressing is a single layered acellular dermal replacement comprising a porous matrix of cross-linked type I bovine tendon collagen and shark chondroitin-6-sulphate. Integra is licensed for multiple indications including venous and diabetic ulcers and gained US Food and Drug Administration approval in 2002.Initial analysis was performed that tested for an \u201carm effect\u201d (left arm versus right arm) in order to rule out site-specific variations. For each variable, testing showed there was no significant difference between the mean response on the left arm and the mean response on the right arm. On the basis that the arm effect was not statistically significant, a second analysis (listed below) was performed for each investigational modality that looked for differences between treatment groups.SIAscopy, FLPI and Immunohistochemistry. Differences between treatments at each time point were compared using ANOVA with Greenhouse-Geisser method. Time points with significant treatment differences underwent additional pair-wise comparisons and Bonferroni adjustments for multiple testing were applied. Conventional two-sided 5% significance level was used.qRT-PCR. Non-parametric Friedman tests compared fold changes between treatments at days 7, 14, 21 and 28 separately. If significant differences were found, paired Wilcoxon rank sum tests were utilised to analyse differences between specific types. Significant changes within treatment groups over time were assessed using one-sample Wilcoxon signed-rank tests. Conventional two-sided 5% significance levels were used.FLPI and SIAscopy were used to non-invasively assess wound sites before, and at weekly intervals after punch biopsies with associated skin substitute treatments. Seven days (d) post-wounding, mean haemoglobin flux derived from FLPI in DCD and autograft groups was significantly lower than controls (p = 0.0008 and p = 0.0001 respectively). However, this reversed by d21 and d28, with the DCD group showing significantly increased haemoglobin flux compared to controls (p = 0.0035 and p<0.0001 respectively) . SIAscopPunch biopsies of healing tissue from all 4 wound sites in each patient were excised at time points determined by study group allocation. Harvested tissue was stained with haemotoxylin and eosin facilitating time-matched histological comparison of controls and treatment groups. In control wounds, there was progressive formation of granulation tissue in the wound bed after injury . After 1Whole genome analysis identified 1689 genes with significantly altered expression after injury . After rThere was significantly increased expression of HIF2A, PROK2 and MT6-MMP after injury in all treatment groups . Significantly reduced HIF3A expression was observed at d7 in DCD and control groups (both p = 0.028) as well as d21 in CG samples (p = 0.043). However, HIF3A down-regulation in autografts did not reach statistical significance (p = 0.08\u20130.14). Furthermore, there was a statistically significant difference in PROK2 expression between treatment groups on d21 and d28 (p = 0.021 & p = 0.004) with DCD values significantly greater than other treatments. On d28 PROK2 expression was also significantly greater in CG and autografts compared to controls (p = 0.043) . There wCD31 levels changed significantly after injury in all treatment groups . Statistically significant differences in vessel number between treatment groups were found on d14 when CG was greater than autografts (p = 0.016), and at d28 when DCD was significantly raised in comparison to controls .New blood vessel formation contributing to development of granulation tissue is a critical component of wound healing, requiring tightly regulated dynamic reciprocity between endothelial cells, bioactive molecules and ECM components . The strDCD, which is derived from human cadaveric split-thickness skin grafts, exerted the strongest pro-angiogenic influence, particularly 3\u20134 weeks post injury. The same effect was noted previously utilising DCD in treatment-resistant leg ulcers . CollageBy the same logic, autografts should have exerted an equally strong pro-angiogenic effect but we found reduced markers of angiogenesis in this group. This may be because autografts are markedly different to DCD with a full cellular complement, intact dermal vascular architecture and a reservoir of growth factors. Previous studies in mice showed autograft revascularisation is a two stage process. Inosculation between existing graft and wound bed vessels is predominant early on, helping to restore tissue viability. This is associated with a later, limited neovascularisation response producing new vessels between wound bed and autograft \u201331. Our Development of vascular architecture after treatment with autografts and DCD was similar, with both predominantly re-establishing pre-existing vascular channels via defined entry points at the graft-host interface. However, autografts contained functionally intact vessels whilst DCD required complete reconstitution of the vascular network through endothelial cell migration and proliferation. Subsequent differences in angiogenic behaviour may consequently have been due to earlier restoration of blood flow, altered cellular recruitment and secretion profiles as well as reduced neovasculogenesis in autograft samples. By contrast, the looser matrix structure of CG resulted in uniform infiltration of host granulation tissue without any of the prescribed pathways seen in DCD and autografts. Consequently, numerous disorganised granulation tissue vessels developed de-novo, which were rapidly replaced by fibrotic tissue.The relationship between angiogenesis and fibrosis during wound healing is complex. Evidence is growing that application of angiogenic inhibitors to acute wounds such as VEGF-R2 blockers result in reduced scar formation, whilst pro-angiogenic molecules including IL-8 and TGF-\u03b2 are found at lower concentrations during scarless foetal healing \u201334. AutoWhilst histology demonstrated structural characteristics of dSS influenced subsequent vascular architecture, microarray studies revealed variations in gene expression that may underlie differential angiogenic behaviour. Many pro-angiogenic effects of hypoxia are mediated through hypoxia-inducible transcription factors (HIFs) which control expression of important genes including VEGF, endothelial nitric oxide synthase and heme oxygenase-1 . HIFs arPROK2 expression in DCD samples was uniquely up-regulated for a second time 21 days after injury, coinciding with maximal CD31 expression, haemoglobin flux and mean oxyhaemoglobin levels. The 2 forms of prokineticin (PROK1 and 2) are potent angiogenic factors and mitogenic stimulants for endothelial cells that act independently of VEGF \u201343. TheyIn conclusion, this study compared angiogenesis in control wounds with those treated using CG, DCD and autograft in healthy individuals. Angiogenic responses and neovascular architecture post-wounding were variable between treatment groups suggesting behaviour is strongly influenced by composition and biomechanical characteristics of matrix materials. There is clear evidence from invasive and non-invasive modalities that treatment with DCD resulted in increased angiogenesis. Significantly elevated mRNA expression of pro-angiogenic PROK2 and ECM protease MT6-MMP seen only in the DCD group may contribute to the observed response.S1 Table(XLS)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S1 FigAll images in this figure are derived from the same patient. CG\u2014collagen-GAG scaffold, DCD\u2014decellularised dermis. Scale bar is identical in each image.(TIF)Click here for additional data file."}
+{"text": "Lif, Il27ra, Tle4, Ptk7, Nfatc2, and Runx3) are differentially expressed between HDM-treated CS mice and HDM-treated FA mice. Our findings confirm that prenatal exposure to cigarette smoke is sufficient to modify allergic airway disease; however, it is unlikely that specific methylation changes account for the exposure-response relationship. These findings highlight the important role in utero cigarette smoke exposure plays in the development of allergic airway disease.Prenatal and postnatal cigarette smoke exposure enhances the risk of developing asthma. Despite this as well as other smoking related risks, 11% of women still smoke during pregnancy. We hypothesized that cigarette smoke exposure during prenatal development generates long lasting differential methylation altering transcriptional activity that correlates with disease. In a house dust mite (HDM) model of allergic airway disease, we measured airway hyperresponsiveness (AHR) and airway inflammation between mice exposed prenatally to cigarette smoke (CS) or filtered air (FA). DNA methylation and gene expression were then measured in lung tissue. We demonstrate that HDM-treated CS mice develop a more severe allergic airway disease compared to HDM-treated FA mice including increased AHR and airway inflammation. While DNA methylation changes between the two HDM-treated groups failed to reach genome-wide significance, 99 DMRs had an uncorrected p-value < 0.001. 6 of these 99 DMRs were selected for validation, based on the immune function of adjacent genes, and only 2 of the 6 DMRs confirmed the bisulfite sequencing data. Additionally, genes near these 6 DMRs ( Smoking during pregnancy has long been identified as an independent risk factor for short term maternal and fetal outcomes, such as intrauterine growth restriction, ectopic pregnancy, premature birth, and developmental deficiencies. Furthermore, this exposure can lead to long-lasting changes in disease susceptibility, including asthma, behavioral disorders, obesity, and respiratory illness . In factDespite the well know risks of smoking during pregnancy, an estimated 23% of women reported they smoked 3 months prior to pregnancy while 11% of pregnant women continue to smoke throughout pregnancy in the United States . In the Cigarette smoke is known to influence epigenetic mechanisms, including epigenetic machinery , 6, postBased on these observations, we hypothesized that cigarette smoke exposure during prenatal development generates long lasting differential methylation altering transcriptional activity that corresponds with altered disease.C57BL/6J mice were purchased from Jackson Laboratories. Animals were housed under standard conditions and protocols were approved by the Institutional Animal Care and Use Committee of the University of Colorado Denver.3 TSP  or filtered air for 5 hours/day, 5 days/week for 4 weeks (1 week acclimation included) prior to mating with C57BL/6J males. Cigarette smoke was generated by the TE-10 smoking machine (Teague Enterprises) from 2R4F research cigarettes (University of Kentucky). Cigarette smoke contained a mixture of both side and mainstream smoke. Exposure was continued until birth of pups at which time all exposures were stopped and mothers and pups were placed under normal housing conditions.12 week old C57BL/6J females were exposed to cigarette smoke at ~50 mg/mAllergic airway disease was induced using an adapted house dust mite model . BrieflyTo measure DNA methylation in whole lung tissue, bisulfite sequencing was performed utilizing Agilent\u2019s SureSelect Methyl-Seq Target Enrichment System for Illumina Multiplexed Sequencing. Experimental procedures followed SureSelect Human Methyl-Seq Protocol Version B using SureSelect Methyl-Seq Reagent Kit and Mouse Methyl-Seq Capture Library. Additional information is provided in the supplemental methods .Bisulfite-sequencing reads were handled using bwa-meth  which alDMRs identified through bisulfite sequencing were confirmed through pyrosequencing PCR on Qiagen\u2019s Pyromark MD. Additional information is provided in the supplemental methods .Differential expression was tested through qRT-PCR on the Viia7 Real-Time PCR system (Applied Biosystems) using Taqman assays (Applied Biosystems). Additional information is provided in the supplemental methods .in utero cigarette smoke caused increased allergic airway inflammation. Significant differences between groups were identified by analysis of variance. For validation, pyrosequencing data was analyzed using a 1 tailed Mann-Whitney U test for HDM-treated CS mice versus HDM-treated FA mice. A 2 tailed Mann-Whitney U test was applied to qRT-PCR data to compare HDM-treated CS mice versus HDM-treated FA mice. GraphPad Prism version 5.04  was used to perform statistical calculations. Pathway analysis was performed using Ingenuity Pathway Analysis (IPA) software.Data were expressed as mean \u00b1SEM. Individual comparisons between groups were confirmed by a 1-tailed Mann-Whitney U test because we were testing only 1 outcome, that These results support previously published data that mice exposed during gestation to cigarette smoke (CS) develop a more severe allergic airway disease phenotype \u201324. HMD-We observed no differences in IL-4 and IL-5 concentrations in WLL between HDM-treated CS and FA mice . HDM-treAgilent\u2019s SureSelect targeted methyl-sequencing was performed in whole lung tissue to determine methylation patterns at specific sites throughout the genome. On average, each sample approximated 64 million reads with 88% of the reads falling within the targeted regions with greater than 50% of the regions with 20x coverage . CompariDMRs are annotated based on nearest gene, and these genes were uploaded into IPA. Despite the small number of genes entered, 65 canonical pathways are enriched of which many involved immune function . IngenuiDMRs selected for validation from the 99 DMRs  were chosen based on known immune function of genes within 25kb of the DMR . SpecifiRunx3, Tle4, Nfatc2, Lif, Ptk7, and Il27ra were measured Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S5 Table(DOCX)Click here for additional data file."}
+{"text": "Our studies contribute to proteomic profiling and improve our understanding of TNBC heterogeneity to provide therapeutic opportunities for this disease.Our understanding of breast cancer heterogeneity at the protein level is limited despite proteins being the ultimate effectors of cellular functions. We investigated the heterogeneity of breast cancer (41 primary tumors and 15 breast cancer cell lines) at the protein and phosphoprotein levels to identify activated oncogenic pathways and developing targeted therapeutic strategies. Heterogeneity was observed not only across histological subtypes, but also within subtypes. Tumors of the Triple negative breast cancer (TNBC) subtype distributed across four different clusters where one cluster (cluster ii) showed high deregulation of many proteins and phosphoproteins. The majority of TNBC cell lines, particularly mesenchymal lines, resembled the cluster ii TNBC tumors. Indeed, TNBC cell lines were more sensitive than non-TNBC cell lines when treated with targeted inhibitors selected based on upregulated pathways in cluster ii. In line with the enrichment of the upregulated pathways with onco-clients of Hsp90, we found synergy in combining Hsp90 inhibitors with several kinase inhibitors, particularly Erk5 inhibitors. The combination of Erk5 and Hsp90 inhibitors was effective  Gene expression profiling has contributed significantly to our understanding of breast cancer heterogeneity, biology and prognosis. Patterns of gene expression dissect the heterogeneity of breast cancer into five subtypes  that relate to histopathological parameters and immunophenotyping , 2. Moreet al  and progesterone [PR] receptors and HER2 were obtained from pathology reports . The cutFresh frozen primary breast tumors and fresh frozen cell lines were lysed using the Kinex\u2122 lysis buffer as per the manufacturer instructions . Dye-labeling of protein lysates, hybridization to the Kinex\u2122 antibody array (KAM-1.3 Antibody Microarray) and signal intensity extraction were performed by Kinexus Corporation. Signal intensities for the 812 probes , which included pan-specific antibodies for total proteins and phospho-specific antibodies against specific phosphorylations, were analyzed using BRB-ArrayTools . Signal Pathway analysis was performed using the Ingenuity Pathway Analysis\u00ae (IPA) software  and we limited the analysis to direct protein-protein interactions only to identify signaling networks and canonical signaling pathways. The Oncomine\u2122 database   were prepared using D-chip Analyzer software [Small molecule inhibitors were purchased from Tocris Biosciences (R&D Systems): PF-4708671, U 73122, GSK2334470, IPA3, SL0101-1 and XMD 8-92 or from Selleck Chemicals LLC : PF-562271, Enzastaurin (LY317615), AUY922 (NVP-AUY922), 17-AAG (Geldanamycin), PF-04929113 (SNX-5422), AZD6244 (Selumetinib), AT7867, CHIR-98014, LY2228820, BIX 02188, AS703026, PH-797804, SP600125, NU7441. All inhibitors were prepaed in DMSO at 100 mM. Cells were treated with inhibitors prepared in culture media where the final concentration of DMSO was 2% v/v. Vehicle control treatments consisted of culture media containing 2% v/v DMSO. Six days after treatment, cell survival was measured in comparison to vehicle controls using the CellTiter 96\u00ae Assay as per manufacturer instructions . Data were analyzed in GraphPad Prism\u00ae version 5.00 for Windows  to measure the log6 per fat pad) in 50 \u00b5L of 50:50 PBS:Matrigel\u2122 . Treatments started when tumors were 50 \u00b1 1 mm3 as calculated from caliper measurement of tumor's longest (a) and shortest (b) diameters: tumor volume (mm3) = a/2 \u00d7 b2. Docetaxel, doxorubicin and the Hsp90 inhibitor AUY922 were purchased from Selleck Chemicals and the Erk5 inhibitor XMD 8-92 from Tocris Biosciences. All drugs were diluted in 5% solution of D-glucose in PBS for intraperitoneal injection. Doses and schedule of treatments are detailed in Figure legends. Mice were monitored for change in weight and other toxicity indications and none were observed. Tumor growth was monitored by caliper measurements to calculate the change in tumor volume compared to day 0. Six tumors were excised on day 13 to perform ex vivo studies as below.The local animal ethics committee gave approval for use of the mice. Female balb/c nude mice at 5 weeks of age  were inoculated in the mammary fat-pads with exponentially growing MDA-MB-231 TNBC cells  was calculated for each combination according to Chou [ex vivo studies, tumors excised from mice on day 13 (after treatment completion) were bisected where one half was fixed in 10% saline-buffered formalin solution and the second half was used to prepare protein lysates.For the combination index studies  to Chou . For immStandard immunoblots were performed on lysates from cells grown in vitro and from tumors excised after treatments. The rabbit polyclonal antibodies against Erk5, phospho-Erk5 (Thr218/Tyr220), Hsp70, Hsp90, Erk1/2 and phosphor-Erk1/2 (Thr202/Tyr204) were purchased from Cell Signaling . The rabbit monoclonal antibodies against Bak and Bim were from Epitomics . The mouse monoclonal antibodies against Bcl-xL and \u03b2-actin were from BD Biosciences . The rabbit monoclonal antibody against COXIV was purchased from LI-COR Biosciences . Secondary antibodies against mouse and rabbit IgG conjugated to HRP were from Cell Signaling and blots were developed using developed using the chemiluminescence reagent plus .Formalin fixed, paraffin embedded tumors were used for standard H&E or Masson's trichrome staining. Immunohistochemical staining (IHC) was performed to detect double strand DNA breaks (DSBs) using the anti-phospho-histone H2AX  mAb  or apoptosis using ApopTag\u00ae Peroxidase In Situ Apoptosis Detection Kit (Merk Millipore) as per manufacturer instructions. For IHC quantification, images of ten random regions from each tumor section were analyzed using ImageJ  (V1.46d)Statistical analysis of the Kinex\u2122 antibody arrays was performed in ArrayTools as described above. Other statistical analyses were performed in GraphPad Prism\u00ae."}
+{"text": "Salmonella enterica is principally a foodborne pathogen that shows considerable serovar diversity. In this report, we present two draft genome sequences of Salmonella enterica subsp. enterica serovar Lubbock, a novel serovar. Salmonella enterica is a foodborne pathogen, showing considerable antigenic diversity with more than 2,500 serovars characterized to date  and 2012K-0273 (GenBank accession no. ARYT00000000.1). Further hqSNP-based comparison of the two isolates with 128 S. Mbandaka isolates publicly available from the NCBI Sequence Read Archive (SRA) (February 2015) showed that 10TTU468 and 11TTU1590 differ by 187 shared hqSNPs from the most closely related S. enterica serovar\u00a0Mbandaka strain . Fifty-two hqSNPs mapped to a 4.5-kbp region containing the fliC gene. The high SNP density suggests homologous recombination within this region, and a BLASTn  and 4,709 11TTU1590) protein-coding sequences were annotated in each genome. No plasmid-associated sequences were found, and both genome sequences contain seven intact prophages and five incomplete prophage regions. A kSNP-based (TTU1590 pa BLASTn  search oJXYU00000000 (10TTU468) and JXYV00000000 (11TTU1590). The versions described in this paper are JXYU01000000 and JXYV01000000.These whole-genome shotgun projects have been deposited in DDBJ/EMBL/GenBank under the accession numbers"}
+{"text": "Despite initial recovery, many onco-hematological patients require ICU readmission, which is a burdensome condition with implications both for mortality and quality of life. Nevertheless, little has been published regarding identification of risk factors for ICU readmission in the onco-hematological population of critically ill patients.To determine the admission factors associated with ICU readmission among onco-hematological patients.Retrospective cohort study using an ICU database (Sistema Epimed\u2122) from a tertiary oncological center. From January 2012 to December 2012, 2629 patients were admitted to our ICU. Forty-nine percent (1155 patients) had onco-hematological conditions and were the subject of this retrospective study. We used univariate and multivariate analysis to identify at admission risk factors associated with later ICU readmission in the same hospitalization period.p <0.001), had a nonsurgical reason for hospitalization , more frequently came from the ward , had longer hospital length of stay (LOS) before ICU admission (15 days (8.5-29) vs. 1 day (0-2) respectively, p <0.001), more frequently came to the ICU due to respiratory failure  or neurological disturbances , more frequently required mechanical ventilation  and vasoactive drugs , and had higher hospital mortality . On multivariate analysis, longer hospital LOS before ICU transfer, neurological disturbances and nonsurgical reason for admission were independent risk factors for ICU readmission.One hundred and five patients (9.1%) were readmitted after ICU discharge. Patients readmitted were sicker compared with the nonreadmitted group (SAPS III of 49 (IQR 33-53) vs. 37 (28-49) respectively, We identified some risk factors associated with ICU readmission in onco-hematological patients, but unfortunately all are not amenable to interventions. Identification of risk factors at ICU discharge might be more promising."}
+{"text": "One important barrier to cancer immunotherapy. We used cyclic dinucleotides (CDNs) and Listeria vaccine and LPS treated HA-specific CD8 tolerance B10. D2 mice. Our results demonstrated T cells IFN-gamma increased in CDNs and Listeria vaccine plus CDNs treatment groups. But CDNs didn't significantly increase Treg cells. The data showed CDNs can reverse established T cell tolerance that improved cancer immunotherapy in the future. We will further explore T cells tolerance in cancer bearing T cell tolerance mice model in vivo."}
+{"text": "The temporal pattern of coronary artery flow velocity through the cardiac cycle provides important information about coronary haemodynamics. The \u2018gold standard' for coronary artery velocity assessment is the Doppler flow wire which is inserted directly into the coronary artery under X-ray fluoroscopic guidance, which is invasive, uses ionising radiation and has a small but significant risk of serious complication. In this study, we perform an in vivo comparison of coronary blood flow velocities measured with breath-hold high temporal resolution spiral phase velocity mapping and Doppler flow wire measurements.Breath-hold proximal coronary artery velocity maps were acquired in 5 left anterior descending (LAD) and 3 right coronary arteries (RCAs) in patients who had undergone invasive Doppler flow wire assessment as part of a clinical assessment. Acquisition parameters were: pixel size 1.4 x1.4 mm (reconstructed to 0.7 x 0.7 mm) x 8 mm, true temporal resolution 19 ms, 1-1 water excitation (WE), 17 cardiac cycle breath-hold, velocity sensitivity 30-50cm/s, retrospective ECG gating (reconstructed 50 phases). Extraction of MR coronary artery blood flow velocity-time curves was performed using a custom MATLAB program which tracked the motion of the vessel over the cardiac cycle and corrected for the through-plane motion of the vessel using a region of adjacent tracked myocardium (LAD) or a region of surrounding epicardial fat (RCA) from a separately acquired fat-excitation acquisition. For each vessel, the mean through-plane motion-corrected MR velocities at all timepoints were plotted against the equivalent flow wire velocities. If necessary, the profiles were first time-shifted to take into account small differences in data triggering between the two techniques. The correlation between the two profiles was assessed using simple linear regression analysis.2 values ranging from 0.6 - 0.95 in the 8 vessels studied (mean R2 = .80).Figures As expected, absolute measures of velocity obtained with the Doppler flow wire are higher than MR measurements as Doppler determines the peak velocity in a small sample volume, rather than the mean velocity over the cross-sectional area of the vessel. However, temporal flow profiles measured in the proximal coronary arteries using breath-hold interleaved spiral phase velocity mapping are highly similar to those measured with Doppler flow wire. We conclude that spiral phase velocity mapping of coronary artery blood flow has the potential to assess temporal flow patterns in the proximal coronary arteries.British Heart Foundation clinical research training fellowship;Wellcome Institutional Startegic Support Fund: Networks of Excellence Scheme."}
+{"text": "Nematostella vectensis, Hydra magnipapillata and Acropora digitifera) were added to the analysis for a total of eleven species representing two classes, three subclasses and eight orders within the phylum Cnidaria.Microsatellite loci have high mutation rates and thus are indicative of mutational processes within the genome. By concentrating on the symbiotic and aposymbiotic cnidarians, we investigated if microsatellite abundances follow a phylogenetic or ecological pattern. Individuals from eight species were shotgun sequenced using 454 GS-FLX Titanium technology. Sequences from the three available cnidarian genomes  contains supplementary material, which is available to authorized users. As ancestral metazoans  Figure\u00a0, CnidariMicrosatellites or Simple Sequence Repeats (SSRs) are sequences of no more than 6 basepairs (bp), repeated tandemly . Point mMicrosatellite loci are genomic features well suited for the study of mutational processes. Apart from high mutation rates, they influence a variety of phenotypic traits from skeletal morphology to host-pathogen interactions , 14. RecDrosophila species , Tanacetipathes sp [Genbank: SRX327567], Plumarella sp [Genbank: SRX326898], Eunicea flexuosa [Genbank: SRX326897], Corynactis californica [Genbank: SRX326758], Amplexidiscus fenestrafer [Genbank: SRX326761], Metridium senile [Genbank: SRX327565], Millepora alcicornis [Genbank: SRX323169].Sequences were trimmed with PipeMeta  and asseNematostella vectensis[Acropora digitifera[Hydra magnipapillata strain 105 [N. vectensis and sperm for A. digitifera) [Hydra for which contaminant sequences were removed manually after assembly [In addition, the whole genome sequence scaffolds from ectensis, Acroporgitifera and Hydrrain 105  were obtitifera) , 37 exceassembly , 20, 37.E. flexuosa, A. fenestrafer and M. alcicornis). When available, DNA was extracted from Symbiodinium-free larvae (E. flexuosa). Amplexidiscus DNA was extracted from the base of the anemone\u2019s foot, which contains lower concentrations of symbionts [Millepora DNA was extracted from bleached colonies which also feature a significantly reduced symbiont density [Symbiodinium species: 454 sequences of clade C  and assembled EST sequences of clades A and B [Symbiodinium sequences. Sequences with more than 75 percent identity, alignment lengths larger than 50\u00a0bp and e-values lower than 1e-05 were filtered out of the cnidarian sequences because they represented putative Symbiodinium DNA and aligned against the NCBI database  database  and procN. vectensis and H. magnipapillata: Sanger, A. digitifera: Roche 454GS-FLX and Illumina Genome Analyser IIx) and those that were sequenced in this study likely resulting in different sequencing biases between these two data sets [Microsatellite coverage and GC content were calculated for each species based on the full data set, using SciRoKo . BecauseFor the phylogenetic analysis, COI sequences for each species were downloaded from Genbank  used to construct the Cytochrome Oxidase I genealogy. Table S5: Average microsatellite length (average nucleotide length/microsatellite type) found in Cnidaria. Table S6: Mann\u2013Whitney Rank Sum Test between microsatellite cover (A) and microsatellite length (B) of symbiotic and non-symbiotic Cnidarians. Table S7: Mann\u2013Whitney Rank Sum Test between microsatellite cover (A) and microsatellite length (B) for species with fast or slow mitochondrial evolution. (DOCX 225 KB)Additional file 1:Summary statistics.(DOCX 121 KB)Additional file 2:"}
+{"text": "Post-cardiotomy cardiogenic shock (PCCS) occurs in 2-6% of patients undergoing surgical revascularization or valvular surgery. Approximately 0.5-1.5% of patients are refractory to maximal inotropic and intra-aortic balloon counter pulsation (IABP) support. Refractory PCCS leads to rapid multi-organ dysfunction syndrome and is an almost universally fatal clinical state without advanced mechanical circulatory support (AMCS) i.e. extra-corporeal membrane oxygenation (ECMO) or ventricular assist devices (VAD). However, the associated major complications and cost related to such complex devices has led to centralization of such valuable services to only a few UK centers.We assessed the outcome of salvage AMCS for PCCS in a non-transplant cardiothoracic surgery unit over an eleven-year period.The data was gained through the Royal Infirmary of Edinburgh cardiac surgery database. Our inclusion criteria included any patient from April 2004-April 2015 who had received salvage Veno-Arterial ECMO or VAD for PCCS (Cardiac Index < 2.2 L/min per square meter OR Systolic BP < 90 mmHg) refractory to IABP and maximal inotropic support following adult cardiac surgery.We identified 16 patients who met the inclusion criteria in the aforementioned period. Age range was 34-83 years (Median 71). There was a large male predominance of 12 (75%). Overall 15 patients (94%) had received ECMO of which number, 12 (80%) had received central ECMO and 3 (20%) had received peripheral ECMO. 1 patient (6%) had VAD. Most common procedural related complication was haemorrhage. Massive stroke, Femoral artery pseudo-aneurysm, septic shock, and renal failure also occurred in this group. Overall survival was 31.2%. All survivors had NYHA class I-II on 24 months follow-up.Our survival rate is identical to the reported data from previous studies. AMCS for refractory PCCS remains a controversial approach his is perhaps due to the high cost and serious complication rates. However the survivors appear to continue living with an acceptable quality of life."}
+{"text": "AML pathogenesis is attributed to several recurrent chromosomal abnormalities in nearly half of the AML cases while the rest of the AML cases show at least one or more molecular abnormalities. Activating mutations and/or high expression of receptor tyrosine kinase (RTK) family members  have been well documented in AML. Specific RTK inhibitors (TKI) have been developed for targeted therapy of AML and many are currently under study . Sunitin+ ALDH+ cells were stained using Aldefluor Kit (Stem Cell Technologies) and CD34-VioBlue antibodies (Miltenyi Biotech).Human primary AML patient bone marrow or peripheral blood mononuclear cells (AML-MNC) were isolated by density gradient centrifugation. Human normal hematopoietic stem/progenitors cells (HSPC) were isolated from umbilical cord blood using anti-CD34 antibodies on a magnetic separator (Miltenyi Biotech). AML-MNCs and HSPC were incubated in SFEM (Stem Cell Technologies) with varying concentrations of Sunitinib malate (Sigma) and DMSO as vehicle control for 24 hours. Clonogenic assays were performed by plating the drug treated cells in Methycellulose and the colonies were evaluated after 10-14 days. CD34+ALDH+cells and CD34- ALDH- cells were sorted and incubated with or without Sunitinib. AML colonies were detected only in CD34+ALDH+ population that showed total inhibition by 7 \u00b5M Sunitinib.With 7\u00b5M Sunitinib, there was a 75% reduction  of AML-CFC as compared to untreated, while 70\u00b5M Sunitinib treatment showed total eradication of AML-CFC. Treatment of normal HSPC with 7\u00b5M Sunitinib showed only 29% reduction  Figure  of normaSunitinib is effective in reduction of clonogenic AML cells. Sunitinib also inhibits normal HSPC derived CFCs albeit less effectively than AML-CFC. This study highlights the relevance of TKI inhibitors in targeting AML. Further studies are aimed at confirming the molecular mechanisms involved in the inhibition as well as taking this study further for targeting patient derived leukemic stem cells using immuno-deficient mouse models.Authors would like to thank KACST for funding this project (grant number 09BIO-693-03)."}
+{"text": "Necdin (Ndn) as a germline modifier of metastasis. Differential expression of Ndn induces a gene-expression signature that predicts prognosis in human breast cancer. Additionally, a non-synonymous germline single nucleotide polymorphism  in Ndn distinguishes mouse strains with differing metastatic capacities. To better understand how hereditary factors influence metastasis in breast cancer, we characterized NDN-mediated transcription. Haplotype analysis in a well-characterized breast cancer cohort revealed that NDN germline variation is associated with both NDN expression levels and patient outcome. To examine the role of NDN in mammary tumor metastasis and transcriptional regulation, mouse mammary tumor cell lines stably over-expressing either the wildtype 50T or variant 50C Ndn allele were generated. Cells over-expressing Ndn 50T, but not Ndn 50C, exhibited significant decrease in cell invasiveness and pulmonary metastases compared to control cells. Transcriptome analyses identified a 71-gene expression signature that distinguishes cells over-expressing the two Ndn allelic variants. Furthermore, ChIP assays revealed c-Myc, a target gene of NDN, to be differentially regulated by the allelic variants. These data demonstrate that NDN and the T50C allele regulate gene expression and metastasis efficiency.Metastasis is the primary cause of death in breast cancer. Earlier studies using a mammary tumorigenesis mouse model identified  Necdin (Ndn) was identified as a driver of extracellular matrix (ECM) gene expression ; q value cutoff = 0.05; range for calculating regional lambda: 1000 bps and 10000 bps.ChIP-seq was performed on the Illumina HiSeq2500 platform as previously described . Sequenc"}
+{"text": "These eQTLs provide insights into regulatory mechanisms underlying disease risk. However, few studies systematically characterized eQTL results across cell and tissues types. We synthesized eQTL results from >50 datasets, including new primary data from human brain, peripheral plaque and kidney samples, in order to discover features of human eQTLs.Gene expression genetic studies in human tissues and cells identify cis-eQTLs and far fewer trans-eQTLs consistent across tissues. Analysis of 45 full human GWAS scans indicates eQTLs are enriched overall, and above nSNPs, among positive statistical signals in genetic mapping studies, and account for a significant fraction of the strongest human trait effects. Expression QTLs are enriched for gene centricity, higher population allele frequencies, in housekeeping genes, and for coincidence with regulatory features, though there is little evidence of 5\u2032 or 3\u2032 positional bias. Several regulatory categories are not enriched including microRNAs and their predicted binding sites and long, intergenic non-coding RNAs. Among the most tissue-ubiquitous cis-eQTLs, there is enrichment for genes involved in xenobiotic metabolism and mitochondrial function, suggesting these eQTLs may have adaptive origins. Several strong eQTLs  coincide with regions of reported human lineage selection. The intersection of new kidney and plaque eQTLs with related GWAS suggest possible gene prioritization. For example, butyrophilins are now linked to arterial pathogenesis via multiple genetic and expression studies. Expression QTL and GWAS results are made available as a community resource through the NHLBI GRASP database [http://apps.nhlbi.nih.gov/grasp/].We find a substantial number of robust cis-eQTLs that may have important biologic roles and could serve as positive controls in future studies. Our results indicate some strong tissue-ubiquitous eQTLs may have adaptive origins in humans. Efforts to expand the genetic, splicing and tissue coverage of known eQTLs will provide further insights into human gene regulation.Expression QTLs inform the interpretation of human trait variability, and may account for a greater fraction of phenotypic variability than protein-coding variants. The synthesis of available tissue eQTL data highlights many strong The online version of this article (doi:10.1186/1471-2164-15-532) contains supplementary material, which is available to authorized users. Discovery of eQTLs may help elucidate the genetic mechanisms underlying natural variation in gene expression   .eQTL dataset origins and descriptions. eQTL dataset sources and information about sample sizes, total cis and trans eQTLs and eSNPs, SNP and expression platforms. (XLSX 14 KB)Additional file 1:Summary of all eQTLs and eGenes and their mapping and filtering. Description of filtering steps and number of eQTLs, eSNPs and eGenes. (XLSX 10 KB)Additional file 2:Hierarchical clustering analysis of 248 eGenes found in\u2009\u2265\u200925/53 datasets used in pathway and ontology analyses. Clustering diagram of eGenes found in\u2009\u2265\u200925 datasets. (DOC 128 KB)Additional file 3:Pathway and ontology analysis results for 248 most ubiquitous eGenes. Significantly enriched gene categories among highly repeated eGenes across tissues. (XLSX 13 KB)Additional file 4:Full gene names and descriptions for 33 eGene significant in \u226535 datasets. Full gene names and descriptions for 33 eGene significant in \u226535 datasets. (XLSX 13 KB)Additional file 5:Overlap of master-cis and trans-eQTLs with ENCODE regulatory features. Intersection of master-cis and trans-eQTLs with ENCODE regulatory features  as determined with RegulomeDB queries. (XLSX 17 KB)Additional file 6:Trans-eQTL and cis-eQTL associations in chr12q13.2 region. Trans-eQTL and cis-eQTL associations in chr12q13.2 region. (XLSX 12 KB)Additional file 7:Trans-eQTL loci results (for loci summarized in Table\u00a0). Individual trans-eQTL loci results for those loci summarized in Table\u00a0Additional file 8:Putative novel trans-eQTL and results at chr 11p15.5. Putative novel trans-eQTL and results at chr 11p15.5. All cis and trans results for 11p15.5 are displayed. (XLSX 11 KB)Additional file 9:Long range cis eQTLs (P\u2009<\u20095E-8) and their short and long cis-eQTL associations. Short- and long-range cis-eQTL associations for chromosome 16 and 20 regions with associations overlapping ENCODE 5C (chromatin conformation) interactions in lymphoblastoid cell lines. (XLSX 13 KB)Additional file 10:Significance of eSNPs relative to distance from their associated eGenes for different tissue types. Significance of eSNPs relative to distance from their associated eGenes for different tissue types, respectively. PanelA: blood tissues and cell types (n\u2009=\u200914 datasets), PanelB: brain tissues (n\u2009=\u200924 datasets), PanelC: liver (n\u2009=\u20095 datasets), PanelD: fat-related (n\u2009=\u20093 datasets), PanelE: other tissues (n\u2009=\u20097 datasets). Y-axis is scaled to a cutoff at P\u2009<\u20091E-150 obscuring a small proportion of results. (DOC 1 MB)Additional file 11:cis-eQTL representation by chromosome . Proportion of unique best cis- and trans-eQTLs by autosomal and sex chromosome. Proportions after adjustment for chromosome length, number of CCDS genes, total HuRef human RNA lengths, and number of HuRef variants are displayed, along with overall mean ranks for most to least cis-eQTLs per chromosomes across all adjustments. (XLSX 12 KB)Additional file 12:Comparison of eQTL results to NHGRI GWAS catalog SNPs. Comparison of eQTL results  to NHGRI GWAS catalog SNPs. (XLSX 9 KB)Additional file 13:Correlation between eQTL and GWAS p-values in the NHGRI GWAS catalog. The correlation in strength of signal  between reported eQTL studies and trait GWAS associations represented in the NHGRI GWAS catalog. (DOC 54 KB)Additional file 14:Enrichment or depletion of nSNPs  and eQTLs  among 45 full trait GWAS scans. Pubmed identifiers and GWAS traits are given for 45 full GWAS scans whose results were compared to nSNPs  and eQTLs . Genomic inflation factors (\u03bb) are given for each trait and nSNPs and eQTLs for the full scans and at a threshold of P\u2009<\u20091E-2 in the GWAS. Komogorov-Smirnoff (K-S) test p-values for differences in distributions are given. Enrichments are highlighted in blue and depletions in grey, with significant K-S tests in red and non-significant ones in green. (XLSX 17 KB)Additional file 15:Kidney eQTLs reported in this study and association with GWAS traits (P\u2009<\u20095e-8). Kidney eQTLs reported in this study were queries against the NHLBI GRASP GWAS database for overlaps. All GWAS intersections are given and GWAS results with particular relevance to renal function  are highlighted. (XLSX 13 KB)Additional file 16:Peripheral plaque eQTLs reported in this study and association with GWAS traits (P\u2009<\u20095e-8). Plaque eQTLs reported in this study were queries against the NHLBI GRASP GWAS database for overlaps. All GWAS intersections are given and several associations with coronary artery disease and myocardial infarction are highlighted. (XLSX 38 KB)Additional file 17:Supplemental methods description of eQTL analysis for novel data . Detailed methods and demographics for new eQTL analyses in included in this study. (DOCX 40 KB)Additional file 18:Flow chart of overall study, data collection and annotation and analysis. Flow chart of overall study, data collection and annotation and analysis. (DOC 280 KB)Additional file 19:"}
+{"text": "Multiple brain magnetic resonance imaging (MRI) studies showed enlarged ventricles but no masses. Immediately before surgery, a discrete cystic structure was visible on imaging (A 33-year-old male presented for resection of an intracranial mass after 1 year of recurrent headaches and dizziness. Cerebrospinal fluid testing had shown a lymphocytic pleocytosis (163 cells/mm"}
+{"text": "Biodegradable polymer carriers offer attractive features for therapeutic cancer vaccines including delivery of multiple vaccine components, efficient internalization, and sustained release of adjuvants and tumor-associated antigens (TAAs). We previously demonstrated that local delivery of depots containing nucleic acid-based toll-liked receptor agonists (TLRas) to lymph nodes (LNs) potently enhances antigen-specific T cell immunity. Building on this work, we hypothesized that local LN delivery of microparticles loaded with TAA-encoding plasmid DNA (pDNA) and TLRas might drive strong local expression and presentation of antigen by LN-resident antigen presenting cells. These effects could help drive more potent and effective CD8+ T cell functions that slow or stop tumor growth.co-glycolide) microparticles synthesized by water-oil-water emulsion, stabilized with polyvinyl alcohol. The inner aqueous phase was loaded with a TLR9 agonist (CpG oligodeoxynucleotide) and pDNA. Size and loading were characterized by laser diffraction and UV-vis spectroscopy. Murine splenocytes expressing CD11c were harvested, isolated, and treated overnight in triplicate with empty particles or particles encapsulating CpG only, pDNA only, or both CpG+pDNA. Cells were analyzed by flow cytometry using markers for viability (DAPI-) and dendritic cell activation .Plasmids were designed and synthesized to encode model reporter genes or a conserved T cell peptide epitope, TRP2 (SVYDFFVWL) for human and murine melanoma. Screening studies with primary dendritic cells utilized poly flanking repeating units of the antigenic epitope. This vector was synthesized with and without a sequence encoding ubiquitin to provide efficient proteasomal peptide processing and antigen expression. Particles exhibited mean diameters 2.5-4.4\u00b5m depending on cargo and synthesis energy. Cargo loading was measured for CpG particles at 3.8\u00b5g CpG/mg particles and for pDNA particles at 11.1\u00b5g pDNA/mg particles. During Initial studies demonstrate microparticles loaded with TLRa and pDNA effectively stimulate primary immune cells, supporting a platform for loading and driving local TAA expression alongside vaccine components like TLRas. Ongoing studies will assess gene expression levels in primary cells and secondary lymph organs using a mouse melanoma model and will correlate local TAA expression with antigen-specific T cell expansion and efficacy during tumor challenge."}
+{"text": "FMR1). The full mutation, defined as >200 cytosine-guanine-guanine (CGG) triplet repeats, causes FXS. Individuals with 55\u2013199 CGG repeats, classified as premutation carriers, are affected by two distinct disorders depending on their premutation status. Disorders associated with premutation carriers include: Fragile X-associated Tremor Ataxia Syndrome (FXTAS) and Fragile X-associated Primary Ovarian Insufficiency (FXPOI). The molecular similarities of FXTAS and FXPOI (e.g. overabundance of FMR1 transcript and intranuclear inclusions) suggest that similar molecular mechanisms underlie both FXTAS and FXPOI. The current hypothesis describes the underlying mechanism for FXTAS as an mRNA gain-of-function mutation, however the underlying mechanism for FXPOI remains unresolved. New data suggests that repeat associated non-AUG (RAN) translation could underlie FXPOI.Fragile X syndrome (FXS) and its associated disorders are caused by the expansion of the CGG repeat in the 5\u2032 untranslated region of the fragile X mental retardation 1 gene ( FMR1); this mutation affects\u2009>\u200998% of individuals with FXS[FMR1[FMR1 results in the loss of Fragile X Mental Retardation Protein (FMRP), which is necessary for neuronal development and cognition. FMR1 premutation carriers also have disorders associated with ovarian function including loss of fertility and hypoestrogenism  and neurodegeneration with associated memory loss and general Parkinsonism .Fragile X Syndrome  is caused by hypermethylation of the expanded CGG repeats adjacent to exon 1 of the Fragile X Mental Retardation 1 gene ; FXTAS: Fragile X-associated tremor ataxia syndrome (FXTAS); FXPOI: Fragile X-associated primary ovarian insufficiency (FXPOI); RAN: Repeat associated non-AUG (RAN) translation; SNP: Single nucleotide polymorphisms; TNR: Trinucleotide repeat expansion disorders.CNV: Copy number variation; FMR1: Fragile X mental retardation 1 gene (The author declares he has no other competing interests."}
+{"text": "The left ventricular global function index (LVGFI) is a novel indicator of cardiac performance. Recently, the LVGFI was linked to left ventricular ejection fraction and infarct characteristics in patients presenting with acute ST-segment elevation myocardial infarction (STEMI). In this study we sought to investigate the association of serially measured high-sensitivity cardiac troponin T (hs-TnT) concentrations and LVGFI assessed early after acute STEMI.122 patients with first STEMI (mean age 58 \u00b1 11 years) reperfused by primary percutaneous coronary intervention (p-PCI) were enrolled in this observational study. All patients underwent cardiac magnetic resonance (CMR) imaging within the first week after STEMI. Left ventricular dimensions and function were measured by cine true-FISP sequences. hs-TnT concentrations were assessed serially for up to 48 hours after p-PCI by a commercially available immunoassay. Fisher's r to z transformation was applied for comparison of correlation coefficients.The median delay to reperfusion was 205 min (IQR 144 to 391 min). The mean LVGFI was 35 \u00b1 8 %. The median value of maximum hs-TnT concentrations was 5043 ng/l (IQR 2322 to 8104 ng/l). The LVGFI was significantly associated with maximum creatine kinase activity  and with maximum hs-TnT concentration . Statistically significant correlations were also detected between LVGFI and single time-point hs-TnT concentrations . Receiver operator characteristics analysis  revealed hs-TnT concentrations measured 6 hours after p-PCI to most accurately predict a LVGFI below the median value of 34 %.This study demonstrates that hs-TnT concentrations assessed serially after acute STEMI are associated with LVGFI. hs-TnT levels measured 6 hours after p-PCI best predicted a LVGFI below the median value.Austrian Society of Cardiology."}
+{"text": "Aberrant DNA methylation is a hallmark of many cancers. Classically there are two types of endometrial cancer, endometrioid adenocarcinoma (EAC), or Type I, and uterine papillary serous carcinoma (UPSC), or Type II. However, the whole genome DNA methylation changes in these two classical types of endometrial cancer is still unknown.XIST expression. Importantly, we discovered that the majority of the DMRs harbored promoter or enhancer functions and are specifically associated with genes related to uterine development and disease. Among these, abnormal methylation of transposable elements (TEs) may provide a novel mechanism to deregulate normal endometrium-specific enhancers derived from specific TEs.Here we described complete genome-wide DNA methylome maps of EAC, UPSC, and normal endometrium by applying a combined strategy of methylated DNA immunoprecipitation sequencing (MeDIP-seq) and methylation-sensitive restriction enzyme digestion sequencing (MRE-seq). We discovered distinct genome-wide DNA methylation patterns in EAC and UPSC: 27,009 and 15,676 recurrent differentially methylated regions (DMRs) were identified respectively, compared with normal endometrium. Over 80% of DMRs were in intergenic and intronic regions. The majority of these DMRs were not interrogated on the commonly used Infinium 450K array platform. Large-scale demethylation of chromosome X was detected in UPSC, accompanied by decreased DNA methylation changes are an important signature of endometrial cancer and regulate gene expression by affecting not only proximal promoters but also distal enhancers.The online version of this article (doi:10.1186/1471-2164-15-868) contains supplementary material, which is available to authorized users. PTEN, KRAS, and CTNNB1 (\u03b2-catenin) genes. UPSC is characterized by frequent TP53 mutation, Her-2/neu overexpression, and an aneuploid karyotype -vector  using T4-ligase (NEB) and transformed into chemically competent DH5\u03b1-cells. The positive clones were verified by enzyme digestion and sequencing. 800\u00a0ng of reporter plasmid (or empty pGL4.23[luc2/minP]-vector control) was cotransfected into HEK-293T cell line with the CMV promoter driven http://epigenome.wustl.edu/Cancer_Epigenome/). Sequencing data has been deposited in the NCBI\u2019s Gene Expression Omnibus repository under the accession number GSE51565.The data set supporting the results of this article are available at the accompanying website (Supplementary tables and figures legend.(DOCX 161 KB)Additional file 1:Supplementary figures.(PDF 6 MB)Additional file 2:"}
+{"text": "Also, SpO advised . The objWe prospectively collected data  from eigAmong 1081 consecutive pre-hospital advanced airway management patients, we identified 54 with a traumatic brain injury and an initial Glasgow Coma Scale score <9. Guideline adherence regarding airway management was 92.6%. Reasons for non-adherence were patient\u2019s condition, anticipated difficult airway management and short distance to the emergency department. Following rapid sequence intubation, 11.4% suffered an oxygen saturation <90%, 9.1% had a first post-rapid sequence intubation systolic blood pressure <90 mmHg and 48.9% had a first post-rapid sequence intubation systolic blood pressure <120 mmHg. The incidence of hypertension following pre-hospital rapid sequence intubation was 4.5%. The incidence of post-endotracheal intubation hyperventilation was 71.1%.The adherence to airway management guidelines was high. The incidences of post-rapid sequence intubation hypoxia and systolic blood pressure <90 compare to results reported from other physician-staffed pre-hospital services. The incidence of systolic blood pressure <120 as well as that of hyperventilation following pre-hospital endotracheal intubation in traumatic brain injury patients call for a change in our current practice."}
+{"text": "The complete genome sequence  of a papaya ringspot virus isolate infecting genetically modified papaya in Hainan Island of China was determined through reverse transcription (RT)-PCR. The virus shares 92% nucleotide sequence identity with the isolate that is unable to infect PRSV-resistant transgenic papaya. Potyvirus in the family Potyviridae (Papaya ringspot virus (PRSV), a filamentous flexuous rod virus (760 to 800 \u00d7 12\u00a0nm) with a single-stranded positive-sense RNA as its genome . The first-strand cDNA was synthesized using the TaKaRa RNA PCR kit (AMV) version 3.0 kit  with oligo-dT as primers. Four primer pairs were designed to produce overlapping amplicons spanning the PRSV genome sequence according to the formerly cloned complete sequences of PRSV HN1 isolate (HQ424465). These four overlapping DNA fragments, ranging in size from 2,015 to 3,177 nucleotides (nt), were PCR amplified and cloned into pMD 18-T vector . The independent clones of each fragment were picked up to be sequenced by Invitrogen . The complete genome sequence  was assembled using the four overlapping sequences, and this isolate infecting GM papaya in Hainan, China, was named PRSV-HN2. A BLAST search using the full genome sequence indicated that the PRSV-HN2 isolate showed 81% to 92% nucleotide sequence identities to known PRSV sequences. The isolate had the highest homology (92%) to the other three Hainan PRSV isolates (EF183499 , HQ42446KF791028.The full genomic sequence of PRSV Hainan isolate infecting GM papaya was deposited in GenBank under the accession number"}
+{"text": "DTG is a once-daily integrase inhibitor that in combination with ABC/3TC, demonstrated superior efficacy with favorable tolerability over TDF/FTC/EFV (SINGLE study) at 48 weeks. EFV is associated with reduced Vitamin D levels through CYP450 enzyme induction; TDF has been associated with decreased bone mineral density (BMD). Antiretroviral treatment (ART) initiation is characterized by initial rapid decline in bone mineral density (BMD) that subsequently stabilizes. Bone turnover markers are increased during these BMD changes.In the double-blind SINGLE study table  we measu833 subjects were analyzed: 84% males; 68% whites. Mean BL VL: 4.7 log10 c/mL; 32% VL>100,000 c/mL and mean BL CD4 cell count = 350 cells/mm3. Bone markers increased in both groups but the increases were significantly greater in subjects treated with TDF/FTC/EFV. Vitamin D levels decreased in both treatment groups; the differences were not significant between groups.After 48 weeks, significantly greater changes from baseline were observed for all bone markers in subjects receiving TDF/FTC/EFV, indicating more active bone turnover when compared to changes seen in subjects receiving DTG + ABC/3TC. These differences may correlate with known TDF-associated changes in BMD over time and further study of the potential advantages of a DTG+ABC/3TC regimen appear warranted."}
+{"text": "Repeated blood culture sampling is common in critically ill neonates though precise indications are unknown.To describe clinical characteristics driving repeated blood culture sampling: clinical indications, time interval between cultures, and rates of blood culture-positivity.Prospective multicenter study of characteristics for repeated blood culture sampling in neonates admitted to three tertiary-referral intensive care units (period 7/2013-12/2014). Repeated blood culture samples were included when obtained within 14 days after the previous sample. Clinical sepsis is defined as the presence of 2 clinical signs and the duration of antibiotic therapy for \u22655 days. Blood cultures positive for skin commensals are considered contaminated if no 2 clinical signs and no CRP of > 2mg/dL are identified.P =. 016); also shorter interval between cultures  and higher CRP values  were noticed. No significant difference in lab-confirmed sepsis was observed between the prior ABT vs no prior ABT cohort.Of the 413 initial blood culture samples in 286 neonates, 132 (32%) were repeated blood cultures sampled in 97 neonates, 42 of which had a birth-weight \u22641500 g. Repeated cultures resulted in: (1) no sepsis, i.e. no growth  and contamination , (2) clinical sepsis , and (3) lab-confirmed sepsis . Clinical characteristics of repeated cultures for the total and those three cohorts are in Figure CRP rise seems not a good indicator for repeated blood culturing, though mostly identified as an indicator in particular in the prior-ABT-cohort. Prior ABT influences indications and interval for repeated cultures but has no effect on blood culture-positivity. Repeated blood culture samples seems indicated when \u22652 clinical signs occur.Grant by Belgian Research Fund (BOF)"}
+{"text": "Circulating tumor cells (CTCs) are cancer cells that can be isolated via liquid biopsy from blood and can be phenotypically and genetically characterized to provide critical information for guiding cancer treatment. Current analysis of CTCs is hindered by the throughput, selectivity and specificity of devices or assays used in CTC detection and isolation.Here, we enriched and characterized putative CTCs from blood samples of patients with both advanced stage metastatic breast and lung cancers using a novel multiplexed spiral microfluidic chip. This system detected putative CTCs under high sensitivity   rapidly from clinically relevant blood volumes (7.5 ml under 5 min). Blood samples were completely separated into plasma, CTCs and PBMCs components and each fraction were characterized with immunophenotyping , fluorescence in-situ hybridization (FISH) (EML4-ALK) or targeted somatic mutation analysis. We used an ultra-sensitive mass spectrometry based system to highlight the presence of an EGFR-activating mutation in both isolated CTCs and plasma cell-free DNA (cf-DNA), and demonstrate concordance with the original tumor-biopsy samples.We have clinically validated our multiplexed microfluidic chip for the ultra high-throughput, low-cost and label-free enrichment of CTCs. Retrieved cells were unlabeled and viable, enabling potential propagation and real-time downstream analysis using next generation sequencing (NGS) or proteomic analysis. Circulating tumor cells (CTCs) is a collective term to describe cancer cells of solid tumor origin found in the blood of cancer patients. The heterogeneous nature of CTCs provides a comprehensive yet non-invasive means for characterizing tumor molecular subtypes, which can be utilized for stratifying patients to appropriate cancer therapy We previously developed a novel integrated spiral microfluidic device for CTC enrichment from whole blood g, 10 min). Blood samples were then lysed using red blood cell (RBC) lysis buffer  according to manufacturer's recommendations. The nucleated cell fraction was resuspended with phosphate buffered saline (PBS) to desired concentration  and local ethics committee ) . Informed and written consent was obtained from all patients. IRB and ethics committee approval was also granted for NSCLC samples where retrospective archival specimens were retrieved . Ten blood samples from healthy donors and 58 (56+2) blood samples from patients with metastatic lung or breast cancer were acquired. Blood samples were stored in EDTA-coated vacutainer tubes . Plasma was fractionated from whole blood for the lung samples by centrifugation (1500\u00d7ntration .The microfluidic chips were fabricated using standard soft-lithography techniques in polydimethylsiloxane (PDMS) described elsewhere Blood samples at 2X concentration  was placed into a 10 ml BD Luer-Lok syringe  and pumped into the multiplexed chip using a syringe pump . Sheath consisted of 0.5% BSA in PBS supplemented with 2 mM EDTA and was similarly introduced into the biochip via a separate syringe pump . Sample and sheath were introduced into the device at a fixed flow ratio of 1\u22369 for optimal separation. Device was connected to syringes and collection tubes  by Tygon tubings . The enrichment process was visualised with an inverted microscope (Olympus IX71) linked to a high-speed CCD camera  and operated using the Phantom Camera Control software.2 to allow adherence of viable cells. Non-adherent cells were washed and removed gently with 1X PBS after 72 hr. Adherent cells were then stained with FITC conjugated pan-cytokeratin antibodies and APC conjugated CD45 antibodies. Some samples were also stained for 15 min on ice with potassium iodide (PI) after microfluidic processing to determine viable proportion of enriched cells.Enriched cell fractions were fixed with 4% paraformaldehyde  for 10 min at room temperature, permeabilized with 0.1% Triton X-100 , mixed and incubated with fluorescein isothiocyanate (FITC) conjugated pan-cytokeratin antibodies, allophycocyanin (APC) conjugated CD45 antibodies  and Hoechst 33342 dye  in PBS buffer supplemented with 0.5% BSA on ice for 30 min. Other antibodies used included EpCAM (APC), CD44 (FITC) and CD24 (APC) . Stained cells were concentrated and imaged with an Olympus inverted microscope   equipped with an automated stage. Enriched cells were placed within the well of a 96-well plate  and the well was automatically scanned in a 1 mm\u00d71 mm grid format using a programmable stage and Metamorph software . Corresponding image sets (at 40X magnification) were compared to determine presence of putative CTCs. Hoechst-positive/pan-cytokeratin-positive (CK+)/CD45-negative (CD45-) enriched cells generally (but not exclusively) with round nucleus and high nuclear to cytoplasmic ratio were considered putative CTCs. Enriched cells of some samples were also seeded onto 2D Geltrex (Invitrogen) coated substrates and incubated at 37\u00b0C and 5% CODNA extraction was carried out on pooled cells ), plasma DNA ) and formalin-fixed paraffin embedded tumour specimens ). Absolute number of intact copies of extracted genomic DNA was determined by Sequenom Sample ID panel . Targeted somatic mutation analysis was performed by PCR amplification followed by Single Allele Base Extension Reaction (SABER) Cell spots were prepared with Cytospin centrifuge  , fixed (acetic acid/methanol) and dehydrated via ethanol series . Slides were treated with RNase (4 mg/ml)  , washed ), denatured  and quench dehydrated via ice-cold ethanol series. EML4-ALK probe  hybridization was carried out under dark and humid conditions . Hybridized slides were washed with 50% formamide/2X SSC and 2X SSC at 45\u00b0C, counterstained with 4', 6-diamidino-2-phenylindole (DAPI) and sealed.As CTC levels in patients were not normally distributed, results were presented as counts and medians with the corresponding percentages and ranges.The microfluidic device consisted of three stacked spiral microfluidic chips with two inlets and two outlets . SuspendBlood samples (7.5 ml) from 10 healthy donors (Table S1 in File S1) and 58 patients (Table S2 in File S1) with metastatic breast or non-small cell lung cancer (NSCLC) were processed using the multiplexed spiral microfluidic chip. Two samples included in the table were not enumerated for CTCs and their enriched samples were directly processed for SABER molecular analysis (see section below). Hoechst positive/pan-cytokeratin-positive (CK+)/CD45-negative (CD45-) enriched cells were considered putative CTCs . These cFDA approved CellSearch assay and our multiplexed spiral biochip were conducted with 10 blood samples from patients with breast or lung cancer. CTCs were detected in 80% (8/10) samples using CellSearch, and 100% of the samples (10/10) by the multiplexed spiral microfluidic chip. A significantly lower range of CTC count was obtained from CellSearch as compared to the multiplexed spiral device  and further identified therapeutically tractable genomic alterations (EML4-ALK translocation) in CTCs, using gold standard FISH assays as well as a mass spectrometry based method for mutational profiling. In a patient with paired CTCs and plasma, we demonstrated concordance in EGFR mutation in both cf-DNA and CTCs. Despite the low WBC count through the use of the spiral microfluidic biochips, somatic mutations were found in pooled CTCs at very low frequencies (1.5% and 0.05%). Possible reasons include the presence of heterogeneous cell populations in circulation whose molecular profiles are discordant from the primary. Given the amount of DNA required for this high sensitivity assay, multiplexed mutational analysis may be feasible to reliably obtain genetic patterns of CTCs. The fast processing time and label-free nature of the spiral microfluidic biochip lends itself to a broad range of potential genomic and transcriptomic applications. There are currently ongoing studies to apply RNA-based single-cell molecular analysis and next generation sequencing (NGS) on captured CTCs. The improvisation of such upcoming techniques for CTC enrichment and characterisation will hopefully shed new light on the CTC biology  and utilisation for therapeutics and treatment.File S1Table S1: List of healthy samples as controls. Table S2: List of patient samples for clinical validation. Clinico-pathological characteristics are provided for patients with metastatic lung or breast cancer who provided samples for CTC enumeration. Samples may be serially obtained from a single patient and these are indicated by the patient number. C: Cycle, D: Day. Post sutent pre AC samples are stated to be <3 weeks post-treatment. Figure S1: EpCAM staining of enriched cell populations. (A) Immunostaining with EpCAM-FITC and CD45-APC antibodies. (B) Flow cytometry analysis of EpCAM/CD45 cell populations. Scale bar: 20 \u00b5m. Figure S2: CTC images displaying variation in EMT biomarker expression. (A) CK+ cells can either be E-cadherin+ or E-cadherin- on breast CTCs. (B) CK+ cells can either be Vimentin+ or Vimentin- on breast CTCs. Scale bar: 20 \u00b5m. Figure S3: Scattered plot obtained with flow cytometry analysis. Potassium iodide staining of enriched samples to determine viability. Figure S4: Flow cytometry analysis of CD44-FITC/CD24-APC cell populations.Contains the following Supporting Information files: (DOC)Click here for additional data file."}
+{"text": "Contaminated environment is a risk factor of hospital-acquired infection. Inappropriate cleaning/disinfection of environment may enhance vancomycin-resistant enterococci (VRE) transmission from environments to patients.The investigation was made after 3 patients with VRE infection/colonization noted in November 2014 in an adult intensive care unit of a medical center in Taiwan.Samples were taken from frequently contacted surfaces including bed rails, bed control, monitor control panel, EKG touch panel, work table and drawer handles in rooms previously occupied by VRE infected/colonized patient. The ATP (Adenosine Tri-Phosphate) bioluminescence ) and swab culture was performed before and after cleaning and disinfection of environment on 6 checkpoints each room. Totally, 36 samples were taken to evaluate the effectiveness of cleaning and disinfection. The swab cultures were also performed on hands of healthcare workers.Totally 70 samples were taken including 56 samples from environments and 14 samples from hands of healthcare workers. Before cleaning and disinfection, all 18 samples from environments were more than 250 RLU by ATP bioluminescence. The non-qualified rate was 100%. After cleaning and disinfection, 8 out of 18 (44%) check points were detected abnormal by ATP bioluminescence. These 8 check points included 3 samples from bed rails (544~4869RLU), 2 samples from bed controls (1800~3231RLU) and each one sample from drawer handle, EKG touch panel and IV pump control panel (375~1607RLU).VRE can survive for months on environments and patients. Hands of healthcare worker may transmit VRE and cross-infection between patients may occur. Through emphasizing the importance of environmental cleaning/disinfection and taking appropriate infection control measures, hospital-acquired infection can be prevented. Hand hygiene and environmental cleaning/disinfection are essential to ensure patient safety.None declared."}
+{"text": "Mechanisms underlying sepsis-induced acute kidney injury remain uncertain. Mitochondrial dysfunction is a hallmark of established sepsis, and may contribute to renal dysfunction.To determine the effect of septic serum on renal tubular epithelial cell mitochondrial physiology.Multiphoton confocal microscopy images were recorded over 45 minutes in intact renal sections  incubated in either physiologic saline solution (PSS) (n=6), sham serum (n=3), septic serum (n=3), and septic serum co-incubated with 10nM of the anti-oxidant 4-OH-Tempo (n=4). Pooled septic serum was obtained from (n=5) rats 24 hrs after induction of faecal peritonitis. Sham serum was obtained from 3 healthy controls. The percentage change in NADH redox state (using NADH autofluorescence), reactive oxygen species (ROS) production  and mitochondrial membrane potential (using dihydroethidium) are expressed as ratios compared to baseline values. Wilcoxon Rank Sum test was used to compare groups with p< 0.05 taken as significant.Mitochondrial dysfunction was seen in both proximal and distal tubular epithelial cells incubated in septic serum. NADH became more reduced, reactive oxygen species increased and mitochondrial membrane potential fell compared to either sham serum or PSS. The increases in NADH reduction and ROS production  on exposure to septic serum could be prevented by co-incubation with 4-OH-Tempo Figure .Figure 1Circulating mediators within septic serum can induce mitochondrial dysfunction in healthy renal tubular cells. Co-incubation with an anti-oxidant offered protection, suggesting these mediators are likely to be oxygen or nitrogen reactive species."}
+{"text": "The cells of the prostate gland are dependent on cell signaling pathways to regulate their growth, maintenance and function. However, perturbations in key signaling pathways, resulting in neoplastic transformation of cells in the prostate epithelium, are likely to generate subtypes of prostate cancer which may subsequently require different treatment regimes. Accumulating evidence supports multiple sources of stem cells in the prostate epithelium with distinct cellular origins for prostate tumorigenesis documented in animal models, while human prostate cancer stem-like cells (PCSCs) are typically enriched by cell culture, surface marker expression and functional activity assays. As future therapies will require a deeper understanding of its cellular origins as well as the pathways that drive PCSC maintenance and tumorigenesis, we review the molecular and functional evidence supporting dysregulation of PI3K/AKT, RAS/MAPK and STAT3 signaling in PCSCs, the development of castration resistance, and as a novel treatment approach for individual men with prostate cancer. Prostate cancer (PCa) is the most common non-cutaneous male malignancy and the second leading cause of cancer-related deaths in males, with an estimated 233,000 new cases  expected to occur in the United States in 2014 [Histological studies of PCa tissues have identified a specific lesion of prostatic intraductal dysplasia , now comIn this review, we define prostate stem cells (PSCs) as the cells capable of differentiating into single (unipotent) or multiple cell types (multipotent) that form the prostate epithelium. The PCa cell-of-origin refers to the cancer-initiating cell(s) within the prostate epithelium, whether it is a stem/progenitor cell itself or its differentiated progeny which acquire mutations that re-instigate self-renewal ability and prevent post-mitotic differentiation, resulting in the emergence of cancer stem cells . ProstatThe prostate contains epithelial cells of various lineage hierarchy that compose this glandular tissue. In adult males, the prostate gland contributes to the production of secretory proteins which are present within the seminal fluid . Within Tissue-specific stem cells are defined by their capacity for long-term self-renewal and to produce mature progeny, which include non-renewing progenitors and terminally-differentiated cells that constitute distinct cell types within the tissue of interest . Self-re+ cells with embryonic urogenital sinus mesenchyme (UGSM) cells under the renal capsule of mice [+) Sca-1+ cells from luminal (CD24+CD49f\u2212), stromal (CD34+), haematopoietic , and endothelial (CD31+) cell lineages (Lin), purified Sca-1+CD49f+Lin\u2212 cells demonstrated self-renewal ability in vitro and formed in vivo prostatic ducts containing basal and luminal cells [+CD133+CD44+CD117+Lin\u2212 marker profile, generated a secretion-producing prostate when transplanted with UGSM cells under the kidney capsule [In the mouse prostate, there is evidence for distinct PSCs with either a basal or luminal phenotype. Prostate cells expressing stem cell antigen-1 (Sca-1) reconstitute secretory-producing prostatic ducts lined with basal and luminal cells, which form upon combining Sca-1 of mice . Using sal cells . Further capsule .in situ following castration-driven prostate regression and androgen-mediated prostate regeneration studies. Expression of a tamoxifen (TAM)-inducible Cre-recombinase (Cre) driven by the CK5 promoter labelled rare basal cells within the prostate epithelium that produced both basal and luminal cell progeny in situ following androgen-mediated regeneration [in situ [Although the functional prostate regeneration assay has demonstrated that murine prostate basal cells are capable of being bipotent, generating both basal and luminal cell lineages, such tissue reconstitution assays involve co-culturing basal cells with UGSM cells -29 whichneration . Similarneration , 31, whineration . These f[in situ , 32, wit[in situ .p63-null prostate lacks basal cells, however, prostatic ducts containing luminal cells formed upon grafting p63-null prostate epithelial cells along with UGSM cells and supplementing with testosterone [PSA promoter labelled prostate luminal cells that were capable of surviving castration and reconstituting the luminal cell compartment in situ following androgen treatment [Additional evidence supports the existence of PSCs that are of luminal cell origin. The osterone . Furtherreatment . A populreatment . Thereforeatment , 34, 35.in vitro [+) and luminal  cell populations contain bipotent cells which retain the ability to differentiate towards prostate basal and luminal cell lineages in vitro, as well as in tissue reconstitution assays involving UGSM cells [in situ histology in an in vitro setting.In the human prostate, initial evidence supported PSCs confined to the basal cell compartment. Human prostate cells with a basal phenotype undergo self-renewal in vitro , with thin vitro , 37. TheSM cells . HoweverSM cells , 39, sugSM cells , 39, and2\u03b21 (\u03b12\u03b21hi), another prospective PSC marker. Primary prostate \u03b12\u03b21hi-expressing cells formed slow-proliferating colonies in culture displaying a basal phenotype (PSA\u2212CK5/14+) and produced epithelia consisting of basal and secretory luminal (PSA+AR+) cells when combined with stromal cells and implanted in recipient mice [+ human prostate epithelial cells, which are restricted to the integrin \u03b12\u03b21-expressing basal cell subpopulation and account for less than 1% of prostate basal cells, generated prostate acini in vivo that resemble prostate epithelia consisting of basal and luminal cells [A number of cell surface markers have been used to identify prospective human PSCs. CD44, which binds the extracellular matrix component hyaluronate , enricheent mice , which went mice , is anotent mice , 44. CD1al cells   progeny may subsequently undergo oncogenic transformation and correspond to the PCa cell-of-origin. Similarly, genetic lineage-tracing in a glioma mouse model has shown that neural stem cells acquire oncogenic mutations, however, it is their descendent oligodendrocyte progenitor cells that act as tumor-initiating cells during gliomagenesis [The PCa cell-of-origin refers to the cell(s) within the prostate epithelium, whether it be a PSC or its lineage-restricted progeny, which acquires tumor-promoting mutations and subsequently initiates tumorigenesis . At presitiation . CD133/At tumors . While tagenesis . TherefoElucidation of the cell lineage relationships within the prostate epithelium is relevant for understanding the origins of PCa. Given that prostate adenocarcinoma has a luminal phenotype, the cell-of-origin for PCa should correspond to a luminal cell that has undergone oncogenic transformation, or a basal cell that differentiates and proliferates as luminal progeny following tumorigenesis . A basalPten (Phosphatase and tensin homolog deleted on chromosome 10) tumor suppressor gene in luminal CARN cells resulted in carcinoma formation following androgen treatment [Pten deletion in prostate basal or luminal cells are histologically similar [in situ [Genetically-engineered animal models have been utilized to address the cell-of-origin in PCa. Murine prostate basal cells have been reported to undergo neoplastic transformation , 32, 49.reatment . While p similar , 32, bas[in situ . This lo[in situ .Nkx3.1 tumor suppressor gene, whose expression is restricted to luminal cells in human prostate glands [Pten [PTEN loss following PSA promoter-driven TAM-inducible Cre expression (CreERT2Ptenlox/loxPSA) resulted in PIN formation (2-3 months) followed by invasive adenocarcinoma development (8-10 months) [+/\u2212Pten, +/\u2212Pten+/\u2212Nkx3.1, TRAMP, and transgenic 2/probasinARR-driven Myc) in situ [Animal models also support a luminal cell origin for PCa. Loss of the e glands , inducede glands -52, withds [Pten , 54 or ods [Pten  promotin months) . More re in situ . Further in situ .NKX3.1 haploinsufficiency, PTEN loss and/or allelic gain of the c-MYC gene in human PCa are associated with increased biochemical relapse (recurrence of PSA serum levels) following radiotherapy [In addition to influencing the tumor cell's malignant potential, recent evidence suggests that the nature of the cellular target within the prostate tumor may also influence tumor histopathology. Basal tumor cells can generate tumor lesions exhibiting a mixture of squamous and adenocarcinoma regions in tissue reconstitution assays, while luminal-like tumor cells generate tumors with solely an adenocarcinoma phenotype . Therefootherapy , 59. Thiin situ, the ability of an isolated, phenotypically distinct population of cancer cells to initiate tumor formation in immunocompromised mice is currently the standard assay available to define human CSCs in vivo [PCa is characterized by the excessive and uncontrolled growth of abnormal cells that invade the basement membrane, metastasizing primarily to the lymph nodes or bone. Like many other carcinomas, PCa exhibits a functional hierarchy of cells with tumor-propagating cells positioned at the apex and having the ability to differentiate into a spectrum of less tumorigenic progeny , 61. The in vivo .+CD44+\u03b12\u03b21hi were suggested to be prospective candidates of PCSCs [2\u03b21 [+ cells isolated from PCa cell lines display increased tumorigenicity in vivo compared to CD44\u2212 cells [+\u03b12\u03b21+ cell population being enriched in PCSCs [in vivo compared to an equal number of CD133/AC141\u2212CD44\u2212 cells [+CD44+\u03b12\u03b21hi cells as prospective PCSCs, it still remains to be demonstrated whether CD133+CD44+\u03b12\u03b21hi cells isolated from primary PCa tissues are capable of tumor initiation in vivo.Accumulating evidence supports the existence of human PCSCs. A small population of primary PCa cells expressing the cell surface antigenic profile CD133/AC133of PCSCs , as CSCsof PCSCs . ConsistSCs [2\u03b21 -68, and SCs [2\u03b21 . These o4\u2212 cells , with thin PCSCs . Further4\u2212 cells . Despite2\u03b21, but not CD133/AC133, formed xenografts with malignant characteristics [\u2212 cells [+ stem-like cells [2\u03b21 and CD24, both basal and luminal cytokeratins, and display increased tumorigenicity in vivo [+ or CD24+ PCa cells, isolated from tumor growths and serially diluted, initiate secondary tumor xenograft formation at comparable frequencies [+CD166+CD151+ cells initiating tumor formation in vivo at increased efficiency following serial dilution of cells compared to TRA-1-60+ cells [in vivo source of human PCa cells, which can be propagated following serial transplantation in a number of grafting sites and subsequently used to isolate prospective human PCSCs. However, the recent generation of patient-derived PCa organoid cultures that recapitulate the diverse mutational landscape and histology observed in their original PCa tissue samples [Due to the constraints in obtaining a sufficient amount of human PCa material to isolate and characterize prospective PCSCs, established PCa cell lines and/or xenograft models have become useful surrogate sources for investigating human PCSCs. Immortalized human prostate cells expressing integrin \u03b1eristics , implica[\u2212 cells  as beingke cells . Human P in vivo . Using hquencies . Moreove0+ cells . Tumor x0+ cells . Therefo samples  will likin vitro approach towards propagating and evaluating the stem-like properties of putative CSCs derived from solid tumors [in vivo [Different culture methods have been utilized to propagate PCSCs derived from human PCa cell lines including suspension or low adherence culture , 68, andd tumors , includid tumors , 70, 72.d tumors , the sphd tumors . The seld tumors , which d[in vivo .in vivo tumor formation unlike the non-SP cell population [+ and ABCG2\u2212 PCa cells displayed similar tumorigenic potential in vivo [While purification of human PCa cells based on the expression of surface markers isolates stem-like cells with tumor-initiating ability Table , flow cypulation . The SP pulation , which apulation . However in vivo , implicahi) were isolated and displayed increased tumorigenicity in vivo [1 ALDHhiCD44+\u03b12\u03b21+ cells isolated from LAPC9  tumor xenografts generated secondary tumors in castrated mice whereas 104 ALDHlowCD44\u2212\u03b12\u03b21\u2212 cells were required for tumor formation, indicating that the ALDHhiCD44+\u03b12\u03b21+ phenotype in a PSAlow cell population is enriched for castration-resistant PCSCs [in vivo. As no individual method isolates bona-fide human PCSCs exclusively, a combination of methods  can be used to enrich for and characterize human PCSCs, with subsequent implantation in immunocompromised mice to evaluate their tumor-propagating activity and serial transplantation to assess their long-term self-renewal capability in vivo [An alternative strategy towards purifying PCSCs involves measuring their aldehyde dehydrogenase (ALDH) activity. Elevated ALDH activity has been associated with CSCs in various solid tumors  and is r in vivo . In addint PCSCs . While 1nt PCSCs , other A in vivo .A number of cell signaling pathways have been implicated in PCa progression towards an androgen-resistant state including receptor tyrosine kinases, like epidermal growth factor receptor (EGFR) -94, and PTEN loss and AKT activation, as measured by Ser 473 phosphorylation, are associated with biochemical relapse following radical prostatectomy [PTEN deletion  is associated with biochemical relapse following local therapy [PTEN loss is associated with PCa progression and predicts a shorter time for metastasis-free survival in patients [Dysregulation of PI3K/AKT signaling has been implicated in PCa given the discovery that its negative regulator, PTEN, is mutated and frequently lost in PCa. Loss of PTEN function, as a result of mutation, deletion or reduced expression, occurs at a frequency of ~40% in PCa , 106. Inatectomy , 108, wh therapy . Intense therapy  and tumo therapy , while Ppatients .Pten+/\u2212 mice were first reported to display hyperplastic lesions in the prostate, with benign PIN lesions being observed in some mice at a young age (\u226414 weeks) [Pten deletion in prostate basal or luminal cells has also been carried out to promote PI3K/AKT signal activation in order to determine the prostate cell lineage responsible for subsequent tumor initiation [probasin (PB) promoter-driven Pten deletion was conducted, resulting in PI3K/AKT signal activation specifically in both prostate basal and luminal cells [Pten require mammalian target of rapamycin (mTOR) complex 2 (mTORC2) for neoplastic transformation [PB promoter [ [Pten loss, with the propensity to undergo AKT-driven tumorigenesis.The role of PI3K/AKT signaling in PCa has also been examined in animal models. 4 weeks) , 113. Ptitiation , 32, 35,al cells . By 6 weal cells . Moreoveormation , therebypromoter , or afteomoter [ . Therefo+CD44+ stem-like cells [+CD44+ cell population in vivo and subsequently delayed tumor formation [in vitro [in vivo [The role of PI3K/AKT signaling in the proliferation and maintenance of PCSCs has been examined in human PCa. PTEN knockdown in DU145 PCa cells resulted in an increased ability to enrich for CD133/AC141ke cells . Treatmeke cells  while thormation . Howeverin vitro . While P[in vivo .RAS isoforms  have been detected in human PCa specimens (3 \u2013 30%), particularly among Japanese men [B-RAF(V600E) has been observed in ~10% of Korean PCa patients [Mitogen-activated protein kinases (MAPKs) are cytoplasmic Ser/threonine kinases that transduce signals by activating extracellular signal-regulated kinases (ERKs) through the RAS-RAF-MEK-ERK (RAS/MAPK) signal transduction cascade . Similarnese men -124, whipatients . These cin vivo tumorigenicity compared to parental cells. More than two-thirds of these HRAS-expressing PCa xenografts were resistant to castration and displayed robust activation of MAPK signaling post-castration [Further evidence in support of a relationship between RAS/MAPK signaling and PCa progression towards an androgen-independent state has been demonstrated in the preclinical setting. Ectopic expression of HRAS(T35S) in androgen-sensitive LNCaP cells maintained MAPK signal activation under serum-free conditions and increased their stration . Conversstration . Furtherstration , supportin vitro, as treatment with MEK inhibitor U0126, ectopic expression of dominant-negative MEK1(K97M), or knockdown of either ERK1 or ERK2 reduced their sphere-forming ability [CreKrasG12D/+PB) or deleting Pten (CrePtenlox/loxPB) in prostate epithelial cells initiated orthotopic tumor formation, while neither PCSC population was capable of generating detectable macrometastases by 10 weeks post-transplantation. However, PCSCs demonstrating concurrent activation of both PI3K/AKT and RAS/MAPK signaling (CrePtenlox/loxKrasG12D/+PB) promoted metastasis to the lymph nodes, lung and liver, with MEK inhibitor (PD325901) treatment reducing orthotopically-engrafted tumors and inhibiting their ability to metastasize [PTEN loss and B-Raf(V600E) expression following Nkx3.1-driven TAM-inducible Cre expression (CreERT2Ptenlox/loxB-RafV600E/+Nkx3.1) resulted in murine prostate tumors that were inherently castration-resistant and which metastasized to the lung, lymph nodes and bone marrow [+) cell proliferation and the development of invasive prostate adenocarcinoma independently of PI3K/AKT signal activation [As studies suggest that RAS-driven MAPK activation plays a substantial role in PCa progression towards CRPC development and metastasis, the role of MAPK signaling in prostate tumor formation is less defined. DU145 PCSCs require MAPK signaling for their propagation  ability . Murine astasize . Similare marrow . While ttivation , supportSignal transducer and activator of transcription (STAT) proteins have been implicated in prostate tumorigenesis, particularly STAT3 protein , 131. AcPB promoter-driven Stat3C expression promoting the development of PIN lesions while invasive adenocarcinoma developed when combined with Pten heterozygosity [In preclinical studies, STAT3 signaling promotes PCa development. Treating mice bearing subcutaneously-engrafted TRAMP-C1 PCa cells (TC1) with flutamide, an AR antagonist, immediately following engraftment resulted in elevated STAT3 activation compared to vehicle-treated mice. Moreover, knockdown of STAT3 in TC1 cells reduced tumor growth . Substitzygosity . In humazygosity , with inzygosity , 142. Cozygosity .+\u03b12\u03b21hi) with increasing concentrations of STAT3 inhibitor LLL12 abrogated their tumor-propagating ability in vivo [in vivo [While STAT3 activation has been implicated in PCa development, its role in PCSCs has only recently been investigated. Pre-treating human PCSCs  PCa . Howeverin vivo compared to their parental, docetaxel-sensitive cells [The standard treatment for non-metastatic, localized (intermediate and high risk) PCa remains to be external beam radiotherapy or radical prostatectomy, with strong evidence indicating that the efficacy of these therapies is related to the extent of killing local, proliferating tumor clones with PCSC properties -153. Incve cells . Therefove cells , 162, deThe progression towards an androgen-resistant state is associated with elevated PI3K/AKT, RAS/MAPK and STAT3 signaling, signaling pathways that promote PCSC self-renewal and tumorigenesis, as previously described. Indeed, a reciprocal feedback loop exists between PI3K/AKT and AR signaling which regulates castration-resistant PCa growth , 164. NeNkx3.1+/\u2212Pten+/\u2212 mice, particularly following castration [Pten loss and oncogenic Kras(G12D) expression showed reduced primary tumor burden compared to PD325901 treatment alone, and ablated their ability for macrometastatic colonization [Pten loss combined with oncogenic B-Raf(V600E) expression [in vivo [A combinatorial approach towards blocking multiple signaling pathways that are coordinately dysregulated in PCa has shown to be an effective strategy towards inhibiting PCa growth in the preclinical setting. Targeting PI3K/AKT/mTOR and MAPK pathways by combined PD325901 (MEK inhibitor) and rapamycin (mTOR inhibitor) treatment reduced prostate tumor burden of stration . Furthernization . This copression . Finally[in vivo . Taken tDespite PCa being a prevalent malignancy in men, our understanding of prostate tumorigenesis remains limited, including knowledge of its origin, as well as the factors and signaling pathways that regulate its initiation. Based on the reported tumor-propagating abilities demonstrated for CSCs in various solid tumors, PCSCs are believed to sustain prostate tumorigenesis and efforts have been made using cell-based and animal models to address their existence. Evidence in support of the existence of PSCs has been demonstrated in prostate regeneration experiments following castration and re-administration of androgen, with candidate PSCs displaying either basal or luminal cell characteristics in prostate glands that survive androgen depletion. Although aberrant cytokine-driven and receptor tyrosine kinase-driven signaling in prostate cells promotes PCa development, there is insufficient evidence demonstrating that PSCs acquire tumor-promoting mutations and serve as the PCa cell-of-origin, or whether it is their differentiated progeny that initiate prostate tumorigenesis. While PCa is generally accepted to be heterogeneous in nature, distinct subtypes formed due to the activation of different oncogenic pathways remain undefined, and whether human prostate basal and luminal epithelial cells are equally vulnerable to oncogenic transformation and subsequently account for the multifocality of neoplastic lesions within a given section of PCa tissue remains unclear. In addition, PCSCs are believed to be dynamic entities that co-exist in equilibrium with non-PCSC populations, which are likely to display variable phenotypes depending on their cell-of-origin and produce different PCa subtypes. A deeper understanding of PCa heterogeneity and multifocality, patient tumor profiling to determine the most effective combinatorial treatment, and subsequent monitoring of their tumors during treatment will be critical in achieving an efficacious response in personalized therapy."}
+{"text": "We have recently demonstrated, using MRI measurements, that normotensive hypovolaemia (NTH) is associated with correlated decreases in cerebral blood volume flow (CBVF) and cardiac output (CO). This is in disagreement with previous studies using trans-cranial Doppler measurements.1. Control and labelled images were subtracted and a two-parameter fit for bolus arrival time (BAT) and perfusion was performed on a voxel by voxel basis, producing perfusion and BAT maps. Perfusion was calculated with units ml/100ml/min. Automated tissue segmentation masks were created from aligned T1 images applied to co-registered perfusion and BAT maps for both cortical and sub-cortical grey matter structures.Eleven healthy volunteers  underwent MRI studies with a lower body negative pressure (LBNP) chamber. Imaging included quantitative phase contrast angiographic (PCA) measurements of blood volume flow in the carotid and vertebral arteries and ASL of the whole brain. An ASL sequence followed by PCA acquisition was performed at rest (control) and under -20mmHg LBNP. ASL imaging used STAR labeling collected at 4 inversion times: 800ms, 1200ms, 1600ms and 2000ms. PCA acquisition was collected using 2D cine phase-contrast images. Throughout scanning the subjects pulse and blood pressure were monitored. ASL images were analysed using in-house code assuming a single blood compartment modelDuring -20mmHg LBNP, CBVF was reduced by 0.5 l/min, blood pressure remained constant and pulse was raised by 7 bpm. There was no difference between ASL grey matter perfusion values (mean 39.2ml/100ml/min and 42.3ml/100ml/min respectively) or sub-cortical grey matter perfusion values (31.3ml/100ml/min and 33.1ml/100ml/min) between control and -20mmHg Fig . BAT wasIn the presence of constant perfusion this indicates regional vasodilatation. Comparing the sub-cortical structures, the hippocampus (19.5%) caudate (21%) and putamen (28%) showed the greatest % increase in BAT during -20mmHg LBNP.In young healthy individuals NTH induces reductions in CBVF which are compensated by vasodilatation of small vessels in normal grey matter, preserving grey matter perfusion despite reductions in total cerebral blood flow. This presumably occurs at the expense of white matter blood flow although that could not be measured with the current methodology. These results suggest a local, intra-cerebral autoregulation mechanism, independent of perfusion pressure, capable of preserving grey matter blood flow in the face of decreasing minute volume cerebral blood flow."}
+{"text": "Critically ill patients cared for in ICUs often require radiological investigation using iodinated contrast agents. Contrast- induced nephropathy (CIN) - a form of acute kidney injury (AKI) - is a complication following the use of such contrast. Although CIN has been thoroughly studied in some populations , it has not been investigated in large numbers of ICU patients .We conducted a single-centre retrospective review of the electronic patient records of general adult ICU patients who received iodinated contrast over a 3-year period (2009 to 2011). Our review identified evidence of CIN or AKI post scan (assessed using CIN and KDIGO criteria); and clinical outcomes post scan , ICU length of stay, mortality). Patients were excluded if: they had received pre-scan RRT; they did not have pre/post-scan creatinine measurements. Univariate analyses investigated the relationship between CIN or AKI and ICU outcomes , using chi-squared tests for categorical outcomes and nonparametric tests for continuous outcomes.2. Scans occurred a median of 2.9 (0.8 to 8.8) days from admission. A total of 266 (56%) scans were associated with CIN . Clinical outcomes were significantly worse in patients developing higher grades of CIN . Ninety-five (20%) scans were associated with AKI . Clinical outcomes were again significantly worse in patients developing AKI .A total of 479 scans involving 331 patients were included. In total, 303 (63%) scans involved males, median age 61 (IQR 46 to 71) years, 119 (25%) diabetic, with median pre-scan eGFR of 85 (38 to 113) ml/minute/1.73 mRenal impairment/injury is common in adult ICU patients undergoing investigations using iodinated contrast and the incidence varies depending upon the classification used. Whichever classification is used, patients developing CIN/AKI following contrast administration have poorer clinical outcomes than patients who do not."}
+{"text": "Feature tracking strain (FTS) is a new technique to assess cardiac function from cardiac magnetic resonance (CMR) images. We compared FTS with conventional function parameters in single ventricle subjects with Fontan physiology undergoing exercise CMR.28 Fontan subjects  underwent a resting and exercise CMR. Standard high resolution, segmented balanced steady state free precession (SSFP) images were acquired with breath holds at rest. Cartesian real time (RT) cine images were acquired at rest then repeated at exercise, targeting the HR at anaerobic threshold on a recent metabolic exercise stress test (EST). Ventricular volumes and cardiac output were calculated offline. Off-line strain analysis was performed  on the \"4-chamber\" and short-axis views at basal, mid, and apical levels.At rest there was moderate correlation between global circumferential strain (GCS) and stroke volume (SV), Pearson r = 0.48 (p = 0.009) and cardiac index (CI), r = 0.39 (p = 0.04), Figure In single ventricle Fontan patients there is moderate correlation between strain and measures of ventricular output (SV and CI) at rest and exercise, but not directly to ventricular size or ejection. Further studies are required to determine the role of feature-tracking strain in the assessment of ventricular function. Analysis of regional strain may helpful in understanding myocardial mechanics in the single ventricle.Dr Kevin K. Whitehead: NIH K23 Grant HL089647 from the National Heart, Lung and Blood Institute. Dr. Mark Fogel: NIH R01HL098252-01, \"Understanding mechanisms of Fontan failure and key predictors for patient outcome.\""}
+{"text": "Coronary artery reimplantation is crucial step during the arterial switch (ASO) and Ross operation. Mortality and long-term outcome after the operation mainly depend on the patency and function of the reimplanted coronary arteries due to risk of stenosis, stretching, or occlusion.Cardiovascular magnetic resonance (CMR) imaging has emerged as a promising diagnostic tool for the evaluation of children heart. We utilized advanced CMR methods to perform a noninvasive assessment of myocardial blood flow, viability, function and diffuse fibrosis in patients after ASO and Ross operation to guide further therapy and for a better understanding of the microcirculation.MRI first-pass perfusion imaging  was performed in 36 patients  and in 10 age matched healthy controls. Myocardial blood flow (ml/g/min) was calculated in 6 LV segments per slice (2-3 slices/pt). Quantitative blood flow at rest and stress (Adenosin 140 \u00b5g/kg/min) was derived from signal intensity curves by model independent deconvolution. Late enhancement studies (Gd 0.1 mmol/kg) using T1 weighted inversion recovery sequences were performed to detect myocardial scar. A Look-Locker technique  for measurements of T1 was used for detecting of LV diffuse fibrosis. Furthermore, cine MRI and 3 D coronary artery imaging were performed to assess ventricular function and coronary anatomy.Of the entire cohort 15 pts (41.7 %) had known or suspected coronary problems such as occlusion, stenosis or hypoplasia. In 7/15 pts (46.7%) we found regional ischemia, scar tissue (28.6%) and regional or global impairment of LV function (30%). As a consequence of our findings one patient received MIDCAB surgery and 4 patients (26.7%) were treated medically.In pts with patent epicardial coronaries (58.3%) myocardial perfusion reserve (MPR) was significantly reduced as compared to the healthy controls  and only in one patient scar tissue was detected. No regional or global wall motion abnormalities were detected. Furthermore, T1 mapping showed increased extracellular matrix expansion suggestive of diffuse fibrosis .CMR imaging can provide a comprehensive assessment of myocardial perfusion, viability and function in patients after coronary reimplantation to guide further therapy such as surgical revascularisation. Of note, in patients with patent epicardial coronaries, we measured an impaired myocardial perfusion reserve and increased interstitial fibrosis.Kinderherzen-Wollen-Leben e. V, Neum\u00fcnster, Germany."}
+{"text": "Epidemiological data point to the involvement of a cow milk factor in the etiology of multiple sclerosis (MS). Eleven circular DNA molecules closely related to transmissible spongiform encephalopathy (TSE)-associated isolate Sphinx 1.76 were isolated from healthy cattle serum, cow milk, and serum and brain tissue from MS patients. The etiology of multiple sclerosis (MS) has not been resolved. Epidemiological data point to the involvement of a cow milk factor . We analyzed 120 serum samples from healthy cattle, 4 samples from commercially available milk, as well as serum and brain tissue samples from MS patients, for the presence of yet unknown factors that might play a role in MS etiology.DNA was extracted by the phenol-chloroform method from milk and the postmortem brain tissue of MS patients. DNA was extracted from all serum samples using the High Pure viral nucleic acid kit (Roche). Pools of 5 bovine serum samples were subjected to density gradient ultracentrifugation, rolling circle amplification (RCA) with random primers on DNA from protein-associated fractions, restriction digestion, cloning, and sequencing of the resulting fragments . Three cLK931487 (CMI1.252), LK931488 (CMI2.214), LK931489 (CMI3.168), LK931490 (CMI4.158), LK931491 (MSBI1.176), LK931492 (MSBI2.176), LK931495 (HCBI3.108), LK931496 (HCBI4.296), LK931497 (HCBI5.173), LK931493 (HCBI6.252), and LK931494 (HCBI6.159).The complete sequences of 11 isolates have been deposited in the EMBL Databank under accession numbers"}
+{"text": "Given recent advances in pulse molecular biology, genomics-driven breeding has emerged as a promising approach to address the issues of limited genetic gain and low productivity in various pulse crops.The global population is continuously increasing and is expected to reach nine billion by 2050. This huge population pressure will lead to severe shortage of food, natural resources and arable land. Such an alarming situation is most likely to arise in developing countries due to increase in the proportion of people suffering from protein and micronutrient malnutrition. Pulses being a primary and affordable source of proteins and minerals play a key role in alleviating the protein calorie malnutrition, micronutrient deficiencies and other undernourishment-related issues. Additionally, pulses are a vital source of livelihood generation for millions of resource-poor farmers practising agriculture in the semi-arid and sub-tropical regions. Limited success achieved through conventional breeding so far in most of the pulse crops will not be enough to feed the ever increasing population. In this context, genomics-assisted breeding (GAB) holds promise in enhancing the genetic gains. Though pulses have long been considered as orphan crops, recent advances in the area of pulse genomics are noteworthy, e.g. discovery of genome-wide genetic markers, high-throughput genotyping and sequencing platforms, high-density genetic linkage/QTL maps and, more importantly, the availability of whole-genome sequence. With genome sequence in hand, there is a great scope to apply genome-wide methods for trait mapping using association studies and to choose desirable genotypes via genomic selection. It is anticipated that GAB will speed up the progress of genetic improvement of pulses, leading to the rapid development of cultivars with higher yield, enhanced stress tolerance and wider adaptability. The Fabaceae/Leguminosae or legume family with ~20,000 species is the third largest family in the plant kingdom and second most important after Gramineae or Poaceae as mainstays for human food/protein security  Walp.), pea (Pisum sativum L.), lentil (Lens culinaris Medik.) and faba bean (Vicia faba L.).Owing to their immense agricultural value, exhaustive research has been done for pulse improvement through conventional breeding, resulting in the development and release of several high-yielding varieties  Walp.), also referred to as black-eyed pea, crowder pea or lobia, is a self-pollinating diploid (2n\u00a0=\u00a02x\u00a0=\u00a022) species with an estimated genome size of 620\u00a0Mb  of cowpea that reflects remarkable morphological variations from African cowpea (cv.-gr. unguiculata) in plant architecture, growth habit and various pod-/seed-related characters  Dye), rust (Uromyces phaseoli var. vignae Barclay), Sphaceloma scab (Elsinoe phaseoli Jenkins) and leaf spot (Septoria vignicola Rao), and insects/pests such as legume flower thrips , pod borer (Maruca vitrata Fabricius) and storage weevil  (Singh Striga gesnerioides (Willd.) Vatke and Alectra vogelii (L.) Benth) resulting in 85\u2013100\u00a0% loss have also been observed in cowpea  Singh . Apart fPisum sativum L.) is a self-pollinating crop with 4,063\u00a0Mb genome organized into seven pairs of homologous chromosomes (2n\u00a0=\u00a02x\u00a0=\u00a014)  Snyd. and Hans.), Ascochyta blight, a complex fungal disease caused by Mycosphaerella pinodes (Berk. and Blox.) Vestergr., Phoma medicaginis Malbr. and Roum. var. pinodella and Ascochyta pisi Lib.), root rot (Aphanomyces euteiches Drech.) and powdery mildew (Erysiphe pisi DC) are the most devastating diseases causing significant losses (Dixon Acyrthosiphon pisum (Harris), causing complete crop failure under conditions of severe infestations  is a self-pollinated diploid (2n\u00a0=\u00a02x\u00a0=\u00a014) crop with a large genome size  (Arumuganathan and Earle Lentil (Ascochyta blight (A. lentis Vassilievsky), Fusarium wilt (F. oxysporum f.sp. lentis Vasd. and Srin.), anthracnose (C. truncatum (Schwein.) Andrus and Moore), blight , rust (Uromyces viciae-fabae Pers.), collar rot (Sclerotiunrolfsii Sacc.), root rot (Rhizoctoniasolani K\u00fchn), dry root rot\u00a0(R. bataticola Taub.) and white mould (Sclerotinia sclerotiorum (Lib.) de Bary) , also known as broad bean or horse bean, has six pairs of chromosomes and 13,000\u00a0Mb genome representing one of the largest genomes among legumes that is almost three times greater than pea and lentil  J. Schr\u00f6t.), chocolate spot (Botrytis fabae Stard.), Ascochyta blight (A. fabae Sperg.) and downy mildew (Peronospora viciae (Berk.) Caspary) are of considerable economic importance , roo rot (F. solani Mart.) and blister disease (Olpidium viciae Kusano) also cause significant yield loss, particularly in China , medic aphid (Aphis medicaginis Koch and Myzus persicae) and root nodule weevil (Sitonaamurensis Faust and S. lineatus L.) are the other damaging agents (Bardner Orobanche crenata Forks) often presents a great menace to faba bean cultivation in the Mediterranean region, North Africa and the Middle East , the global area under faba bean cultivation has declined over the last five decades FAOSTAT . Faba be Bardner . MoreoveBesides biotic constraints, faba bean also suffers from drought and cold stresses, frost injury and presence of ANFs in seeds  different kinds of bacterial artificial chromosome (BAC)-derived resources like BAC libraries, BAC-end sequences (BESs), BAC-associated simple sequence repeat (SSR) markers (BES-SSRs) and physical maps; (2) genome-wide distributed molecular markers and automated genotyping platforms; and (3) the transcriptome and whole-genome assemblies.http://phymap.ucdavis.edu/cowpea/).BAC libraries are valuable tools for facilitating various genetic applications such as DNA marker development, gene/QTL cloning, construction of physical map and BAC-to-BAC genome sequencing , consistent improvements have been made in the area of DNA marker development and genotyping  and Infinium assays, which are able to accommodate up to 3,000 and 4 million SNPs, respectively  have been introduced to incorporate small to moderate number of SNPs for specific applications , especially EST-SSR, SNP, intron-targeted primer (ITP) or intron spanning region (ISR) markers , NGS methods were initially considered suitable for re-sequencing of genotypes where a high-quality reference genome sequence was available , whole/draft genome sequence has become available for soybean  and restriction site-associated DNA (RAD) sequencing of germplasm lines for exploring genetic diversity and population dynamics /GAB. Among various genomic resources, molecular markers are of direct application in crop breeding, as these are heavily deployed in trait mapping studies using either family-based linkage (FBL) mapping approaches or germplasm-based association mapping (AM) (Mackay and Powell 2 or backcross (BC) harbours considerable heterozygosity, thus limiting opportunities for replicated measurements  suitable for coarse mapping only . Besides fine mapping of QTL(s), the stable MAGIC lines have direct or indirect applications in germplasm enhancement and cultivar development . Similarly, notable consensus maps were developed for pea and faba bean comprising 619 loci  and 729 loci , respectively  and GA 3-oxidase (GA3ox) with regard to yield was revealed  showed markedly different patterns of LD decay between the two cultivar groups, viz. unguiculata and sesquipedalis. From the trait mapping perspective, this study offered a concrete framework for initiating genome-wide association (GWA)-based dissection of complex traits in cowpea. More recently, Muchero et al. (Css 1-10), which were initially detected in eight different RI populations by family-based QTL analysis. Further, most of the underlying QTLs exhibited syntenic relationship with genomic regions controlling seed weight in soybean. Notably, one of the candidate QTLs (Css-3) colocalized with another QTL known to impart resistance to foliar thrips (Thr-1) in cowpea, whereas two other QTLs (Css-4 and Css-9) overlapped with loci governing charcoal rot resistance (Mac-6 and Mac-8) , have been used in these pulse crops  and targeting-induced local lesion in genomes (TILLING). To establish a transgenic system the prerequisites are: (1) an efficient and reliable genetic transformation procedure, (2) a reproducible, economically viable and easy-to-use regeneration protocol and (3) an appropriate selectable marker with corresponding selective agent to recover transformants  with enhanced transformation efficiency (~7\u00a0%). Though constant refinements are being made in the transformation systems and regeneration protocols, stable transmission of a foreign gene to subsequent progenies and its predictable expression still remains challenging  has been preferred over somatic embryogenesis  detection of cleaved products using instruments such as LI-COR . Further, the efficacy of Arabidopsis thaliana mismatch-specific endonucleases (ENDO1) to detect mutation in gibberellin 3 beta-hydrolase gene of P. sativum was successfully demonstrated in the \u2018Terese\u2019 population  and tendril-less (tl) genes in controlling seed size and tendril formation, respectively . Gr\u00f8nlund et al.  successfWith a deluge of omics information being generated worldwide, easy access to data remains one of the foremost challenges to large-scale integration of omics information into crop improvement /marker(s) rather than relying entirely on phenotypic expression. Outstanding success stories on the deployment of the marker(s)/QTL(s) in routine breeding programme are available in several crops including rice, maize, wheat, pearl millet and mustard /RB18680 (SCAR) and OPO61250 (RAPD) associated with Ascochyta blight and Anthracnose resistance, respectively, allowed identification of genotypes carrying resistance genes to both Ascochyta blight and Anthracnose   were successful (accuracy up to 95\u00a0%) in discriminating high tannin-containing genotypes from genotypes with zero tannin content  is the simplest way to introgress QTLs, particularly a finite number of QTL(s)/gene(s) experiencing strong and durable effects on the phenotype  and primitive landrace (P. sativum ssp. abyssinicum), and the investigation revealed important genes/QTLs for domestication-related traits that collectively represent a \u2018domestication syndrome\u2019   is used for genotyping only and eventually for selecting the superior individuals  phenotyping. In addition, the recently developed NGS-based methods like WGRS/GBS/RADseq would efficiently extract valuable information from complex mapping resources such as MAGIC or NAM. Besides high-resolution QTL mapping, nearly homozygous MAGIC lines have direct implications in variety development (see Bandillo et al."}
+{"text": "Hepatitis C virus (HCV) infection is the leading cause of chronic liver disease thatcurrently affects at least 170 million people worldwide. Although significantefforts have been focused on discovering inhibitors of a viral polymerase (NS5B) orprotease (NS3), strategies to cure HCV infection have been hampered by the limitedtherapeutic target proteins. Thus, discovery of a novel target remains a majorchallenge. Here, we report a method that combines transcriptome expression analysiswith unbiased proteome reactivity profiling to identify novel host cell responsefactors in HCV infection. A chemical probe for non-directed proteomic profiling wasselected based on genome-wide transcriptome expression analysis after HCV infection,which revealed noticeable alterations related to disulfide bond metabolism. On thebasis of this result, we screened the proteome reactivity using chemical probescontaining thiol-reactive functional groups and discovered a unique labeling profilein HCV-infected cells. A subsequent quantitative chemical proteomic mapping studyled to the identification of a target protein, T-plastin (PLST), and its regulationof HCV replication. Our approach demonstrates both a straightforward strategy forselecting chemical probes to discriminate disease states using a model system andits application for proteome reactivity profiling for novel biomarker discovery. Flaviviridae family that contains 9.6 kb of RNA.11Hepatitis C virus (HCV) infection is the leading cause of liver transplantation in theUnited States, and almost 80% of patients suffer a persistent chronic infection thatresults in fibrosis, cirrhosis, and hepatocellular carcinoma.3467To examine host cell responses to HCV infection, biologists have utilized conventionalhigh throughput (HTS) techniques, such as gene or proteomic expression profiling.1314151618202224transcriptomeexpression assisted non-directedproteomic profiling (TEAnDPP) to identify host cell response factorsin genotype 2a HCV infection  expressing the HCV2asubgenomic replicon . The repliconsystem was developed for stable expression of HCV2a proteins in host cells,32Unlike other diseases that cause dramatic pathological changes, HCV infection tends toinduce subtle and chronic interference in the host cell. In our cell line model, the HCVreplicon expression did not produce noticeable changes in the cell morphology or thetotal proteome band pattern, which was measured using coomassie staining . To visu13C6,15N4) and lysine (13C6), and APC140 cells were grown in \u201clight\u201dmedia. As illustrated in To investigate the host cell factors that are selectively up-regulated upon HCVreplication, we employed competition-based quantitative chemical proteomic profilinggeared to determine the identity of labeled proteins .InspireFrom the SILAC-based quantitation results, proteins exhibiting competition in both caseswere considered to be non-directed target proteins of Flu-IA. In all, 71 proteins wereidentified from the competition experiment in \u201clight\u201d APC140 cellshaving a SILAC ratio (Heavy/Light) greater than two folds , and 46 212+-binding domains and actin-binding domains (ABD).42The plastin family comprises actin-bundling proteins that are critical to actinregulation in eukaryotes.39Renilla luciferase activity encodedin the HCV2a replicon . All protein lists and quantitative analysis resultsare also available in the SI.Supplementary InfoSupplementary Dataset ISupplementary Dataset II"}
+{"text": "CD19+ DCs were more susceptible to MuLV infection than B cells or conventional (CD19neg) DCs, proliferated faster than B cells from early stages of MuLV infection and exhibited mature antigen presenting cell (APC) phenotypes, unlike conventional (CD19neg) DCs. Moreover, interactions with CD4 T cells were necessary to sustain functional IDO expression by CD19+ DCs in vitro and in vivo. Splenocytes from MuLV-infected IDO1-sufficient mice induced pain hypersensitivity in uninfected IDO1-deficient recipient mice, while selective in vivo depletion of DCs alleviated pain hypersensitivity in MuLV-infected IDO1-sufficient mice and led to rapid reduction in splenomegaly, a hallmark of MuLV immune pathogenesis. These findings reveal critical roles for CD19+ DCs expressing IDO in host responses to MuLV infection that enhance pain hypersensitivity and cause immune pathology. Collectively, our findings support the hypothesis elevated IDO activity in non-CNS due to virus infections causes pain hypersensitivity mediated by Kyn. Previously unappreciated links between host immune responses to virus infections and pain sensitivity suggest that IDO inhibitors may alleviate heightened pain sensitivity during infections.Increased pain sensitivity is a comorbidity associated with many clinical diseases, though the underlying causes are poorly understood. Recently, chronic pain hypersensitivity in rodents treated to induce chronic inflammation in peripheral tissues was linked to enhanced tryptophan catabolism in brain mediated by indoleamine 2,3 dioxygenase (IDO). Here we show that acute influenza A virus (IAV) and chronic murine leukemia retrovirus (MuLV) infections, which stimulate robust IDO expression in lungs and lymphoid tissues, induced acute or chronic pain hypersensitivity, respectively. In contrast, virus-induced pain hypersensitivity did not manifest in mice lacking intact IDO1 genes. Spleen IDO activity increased markedly as MuLV infections progressed, while IDO1 expression was not elevated significantly in brain or spinal cord (CNS) tissues. Moreover, kynurenine (Kyn), a tryptophan catabolite made by cells expressing IDO, incited pain hypersensitivity in uninfected IDO1-deficient mice and Kyn potentiated pain hypersensitivity due to MuLV infection. MuLV infection stimulated selective IDO expression by a discreet population of spleen cells expressing both B cell (CD19) and dendritic cell (CD11c) markers  increased pain sensitivity. Influenza infection caused transient increase in pain sensitivity, which returned to normal levels after infections were cleared. However persistent MuLV infections caused sustained increase in pain sensitivity. Virus-induced pain sensitivity was reduced substantially in mice lacking the enzyme indoleamine 2,3 dioxygenase (IDO), which degrades the amino acid tryptophan. Moreover a natural compound produced by cells expressing IDO enhanced pain sensitivity when administered to mice lacking IDO genes. Thus cells expressing IDO caused increased pain sensitivity in infected mice. A distinctive cell type expressed IDO selectively and accumulated in spleens of MuLV-infected mice. Transfer of spleen cells from MuLV-infected mice caused increased pain sensitivity in uninfected mice while eliminating specific cells in MuLV-infected mice abolished enhanced pain sensitivity. Our findings show that host immune responses to virus infections cause increased pain sensitivity and suggest novel ways to alleviate pain during infections. Enhanced pain sensitivity is a hallmark of inflammation and is a debilitating feature of many clinical diseases, including chronic Human Immunodeficiency Virus-1 (HIV-1) infections . HoweverWe tested the hypothesis that virus infections enhance pain sensitivity by stimulating IDO using murine models of acute or chronic virus infection in which IDO enzyme activity is elevated. Acute influenza A virus (IAV) infection stimulates robust increase in lung IDO activity which wanes after virus clearance . Murine Methods. As soon as one day post infection (dpi) paw withdrawal thresholds (PWT) were reduced significantly, relative to baseline thresholds in the same mice before infection  lymph nodes . To testnfection . Increasnfection . Thus IDMuLV (LP-BM5 strain) causes persistent infections and progressive pathologies, including polyneuropathy and pain hypersensitivity \u201311. SomeTo test if pharmacologic IDO inhibition alleviated pain hypersensitivity the IDO inhibitor 1-methyl-[D]-tryptophan  was administered continuously in drinking water to B6 mice with established MuLV infections (60dpi). Oral D-1MT treatment for 20 days led to significant reduction in pain sensitivity, relative to controls given vehicle only . It is u+ DCs). Increased IDO1 transcription was not detected in any other spleen cells, including sorted B cells and conventional (CD19neg) DCs. At early times in MuLV infection (28dpi), ecotropic helper (GAGEco) and pathogenic (GAGDef) MuLV retrovirus genes were transcribed at high levels in sorted cells expressing neither CD19 or CD11c (CD11cnegCD19neg) and to lesser extents in CD19+ DCs, relative to sorted conventional DCs and B cells  at later stages of MuLV. Given previous reports of B cell-specific LP-BM5 expression -tryptophan  was kindly provided by NewLink Genetics Inc. D-1MT was administered in sweetened drinking water (2mg/ml) as described . IDO enzEco and GAGDef were evaluated as described [Ct(\u03b2-actin) \u2212 Ct(target gene).RNA was purified using HP total RNA kits , reverse-transcribed using a random hexamer cDNA RT kit , and quantitative RT-PCR was performed using an iQ5 or CFX system with SsoFast EvaGreen supermix . Primers for murine \u03b2-actin were (forward) 5\u2032-TACGGATGTCAACGTCACAC-3\u2032 and (reverse) 5-AAGAGCTATGAGCTGCCTGA-3\u2032. Validated primers for murine IDO1 were purchased . Relative expression of GAGescribed . Threshot tests were used to analyze data generated in all other experiments. Two-tailed p values <0.05 were considered significant. GraphPad Prism was used to perform all data analyses.Time courses of mechanical nociception (PWT) were analyzed by two-way ANOVA with multiple comparisons. Unpaired Student This study was carried out in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All protocols were reviewed and approved by the Animal Care and Use Committee at the Georgia Regents University (AUP#2011\u20130330).Gene ID: 15930; Ensembl: ENSMUSG00000031551; Vega: OTTMUSG00000020648S1 FigA, B. Pain thresholds (PWT) were measured at 56dpi and 70dpi in MuLV-infected mice bred in the local facility (A) or purchased from Taconic (B). Slight decreases in pain thresholds in IDO1-KO mice were not statistically significant, relative to pain thresholds in na\u00efve mice. Statistical analyses were performed using Student\u2019s t test (A) or 2-way ANOVA (B); *** p<0.001, **** p<0.0001. Data were pooled from 2 or more experiments, except data in panel B was from one experiment. C-F. Inflammatory cytokine levels in serum and spleen were measured by multiplex analyses (Luminex) in na\u00efve and MuLV-infected (42dpi) B6 and IDO1-KO mice; IFN\u03b3 (C), IL6 (D), TNF\u03b1 (E) and IP10 (F). Statistical analyses revealed no significant differences in cytokine levels in samples from MuLV-infected mice WT and IDO1-KO mice (Student\u2019s t test).(TIF)Click here for additional data file.S2 Figt test; ** p<0.01. Experiments were performed once.Tissues from na\u00efve or MuLV-infected WT mice were analyzed to detect IDO enzyme activity in spleen  or IDO1 gene transcripts (qPCR) in spinal cord . Statistical analyses were performed using Student\u2019s (TIF)Click here for additional data file.S3 FigMuLV-infected WT mice (28dpi) were treated with anti-CD4 mAbs on two successive days  and were injected with the dye EdU  3 days after the second mAb treatment. After 16 hours, spleen samples were stained with CD11c and CD19 mAbs and analyzed by flow cytometry to detect proliferating DCs marked with EdU. Statistical analyses were performed using Student\u2019s t test; **** p<0.0001. Data were pooled from 2 experiments.(TIF)Click here for additional data file."}
+{"text": "Regular measurement of systemic and post-filter ionized calcium (iCa) concentrations is imperative to correctly handle regional citrate anticoagulation dose during continuous renal replacement therapy (CRRT). Keeping post-filter iCa within a tight range guarantees optimal circuit function and enhances filter life span , 2, wherCritical Care) of Schwarzer et al. expose an alarming inaccuracy for measuring post-filter iCa with currently available blood gas analyzers [The new findings (published recently in nalyzers . This prnalyzers . Howevernalyzers , 2. Direnalyzers . Prelimi"}
+{"text": "We hypothesised that; 1) obesity would impair myocardial carbohydrate oxidation, in turn reducing energetic reserve and predisposing to functional impairment and 2) normalisation of carbohydrate metabolism either pharmacologically or with calorie restriction would reverse these changes. Unlike traditional methods, hyperpolarized [in vivo hyperpolarized [1-13C] and [2-13C]pyruvate MRS  to assess carbohydrate metabolism, echocardiography to assess diastolic function and perfused heart 31P-MRS (11.7T) to assess myocardial energetics. Two groups of obese rats were subsequently treated with either calorie restriction  or a GLP-1 analogue  to increase carbohydrate metabolism and restudied.Long Evans rats with high fat diet induced obesity (n=36) and normal weight controls (n=12) were diet standardised. We used 13C-MRS demonstrated that obesity not only dramatically reduced myocardial PDH flux  but also increased the normalised rate of 13C label incorporation into citrate  and glutamate  without change in 13C label incorporation into lactate or acetylcarnitine (P=ns). Obesity impaired the myocardial energetic state: both the free energy change of ATP hydrolysis and PCr/ATP ratio were significantly impaired . Obesity significantly increased tissue PDK4 levels (P<0.05), the major regulator of cardiac PDH. Liraglutide treatment  and calorie restriction  normalised PDH flux, TCA cycle metabolism, myocardial energetics and function .Obese animals demonstrated left ventricular hypertrophy and diastolic, but not systolic, dysfunction . Hyperpolarized 13C-MRS identified abnormal cardiac metabolic substrate selection which was associated with abnormal TCA cycle metabolism, impaired high energy phosphorous metabolism and functional deficit. Normalisation of PDH flux with either Liraglutide or calorie restriction reversed this energetic deficit and normalized function, suggesting PDH may be a novel therapeutic target.In a rodent model of obesity, hyperpolarized The Academy of Medical Sciences, British Heart Foundation."}
+{"text": "Investigating transcriptomics in whole blood is a promising avenue of research for helping to understand the allergic response . However14 individuals with allergic rhinitis were simultaneously exposed to ragweed pollen in the Environmental Exposure Unit. Peripheral blood samples were collected using PAXgene Blood RNA tubes before and after the 3 hours of pollen exposure. Gene expression profiling was performed using Affymetrix GeneChip\u00ae Human Gene 1.0 ST Arrays. Publicly available expression data (E-GEOD-48558) was used to estimate the cellular composition from whole blood expression profiles. The estimated proportions were compared against those measured by an automated hematology analyzer.2=0.70, RMSE=0.036) and granulocytes , but relatively poor in monocytes . No significant changes in cellular proportions between pre-challenge and post-challenge samples were identified. 261 (110 up-regulated and 151 down-regulated) differentially expressed probe sets were identified comparing pre and post-challenge samples at a false discovery rate (FDR) of 10%.The estimated proportions of lymphocytes, granulocytes and monocytes were compared against the observed proportions. The prediction was good in lymphocytes , to assess differential expression in T cells. The CD4"}
+{"text": "The role of adjuvant chemotherapy for stage I lung cancer is unknown. Some Japanese trials demonstrated that tegaful-uracil chemotherapy improved the prognosis of stage I lung cancer over 2 cm.The purpose of this study is to determine the significance of the maximum standardized uptake value (SUVmax) on F-18-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) images to postoperative adjuvant chemotherapy for early lung adenocarcinoma.We reviewed 174 consecutive patients with completely resected pathological T1b-2aN0M0 lung adenocarcinoma between January 2006 and March 2011, and assessed recurrence-free interval and overall survival based on SUVmax values derived from preoperative FDG-PET/CT images. All patients were assessed by FDG-PET/CT before surgeryNinety patients received adjuvant chemotherapy and 84 did not. Patients given adjuvant chemotherapy were older, but had the lower T status tumor than patients who were not . Adjuvant chemotherapy conferred benefits upon recurrence-free interval and overall survival compared with observation . Multivariate Cox proportional hazard analyses revealed SUVmax as an independent prognostic factor for recurrence-free interval . Recurrence-free interval and overall survival were significantly longer for patients who received adjuvant chemotherapy compared with those who did not in the group with SUVmax \u2264 2.6 . However, recurrence-free interval and overall survival did not significantly differ between such patients in the group with SUVmax < 2.6 .Preoperative SUVmax on FDG-PET/CT images reflected the efficacy of postoperative adjuvant chemotherapy in patients with pathological T1b-2aN0M0 lung adenocarcinoma. Indications of adjuvant chemotherapy for eraly lung adenocarcinoma might be more precisely determined using SUVmax on FDG-PET/CT images together with tumor size."}
+{"text": "As a result of vendor errors being introduced during processing, the original version of this article  was publDd432-LpKC875348 Dd432-LpKC875349 Dd432-LpFR821799 Dd432Dd636Dd432Dd636 Dd636LpKC875348Dd636LpKC875348 Dd636LpKC875348Dd636LpKC875348 Dd636LpFR821799Dd636LpFR821799Should be:Dd432-LpKC875348 Dd432-LpKC875349 Dd432-LpFR821799 Dd432-Dd636 Dd636-LpKC875348 Dd636-LpKC875349 Dd636-LpFR821799In addition, the alignment of Table 1 attribute listed as \u201cAA\u201d is incorrect and should correspond as shown in the below updated version.Lastly Page 10, third paragraph included an incorrect citation. This should read as \u201c\u201d instead of \u201c\u201d.The original version of this manuscript has been updated to reflect the above changes.We apologise for any inconvenience this has caused."}
+{"text": "Ralstonia solanacearum species complex into three species. This pathogen group consists of diverse and widespread strains that cause bacterial wilt disease on many different plants.The increased availability of genome sequences has advanced the development of genomic distance methods to describe bacterial diversity. Results of these fast-evolving methods are highly correlated with those of the historically standard DNA-DNA hybridization technique. However, these genomic-based methods can be done more rapidly and less expensively and are less prone to technical and human error. They are thus a technically accessible replacement for species delineation. Here, we use several genomic comparison methods, supported by our own proteomic analyses and metabolic characterization as well as previously published DNA-DNA hybridization analyses, to differentiate members of the R. solanacearum species complex. In parallel we profiled the proteomes of 73 strains using Matrix-Assisted Laser Desorption/Ionization-Time of Flight Mass Spectrometry (MALDI-TOF-MS). Proteomic profiles together with genomic sequence comparisons consistently and comprehensively described the diversity of the R. solanacearum species complex. In addition, genome-driven functional phenotypic assays excitingly supported an old hypothesis ), that closely related members of the R. solanacearum could be identified through a simple assay of anaerobic nitrate metabolism. This assay allowed us to clearly and easily differentiate phylotype II and IV strains from phylotype I and III strains. Further, genomic dissection of the pathway distinguished between proposed subspecies within the current phylotype IV. The assay revealed large scale differences in energy production within the R. solanacearum species complex, indicating coarse evolutionary distance and further supporting a repartitioning of this group into separate species.We used three different methods to compare the complete genomes of 29 strains from the R. solanacearum species complex into three species, consistent with recent literature, and demonstrate the utility of proteomic and genomic approaches to delineate bacterial species.Together, the results of these studies support the proposed division of the The online version of this article (doi:10.1186/s12864-016-2413-z) contains supplementary material, which is available to authorized users. Ralstonia solanacearum species complex (RSSC) cause bacterial wilt diseases in plants. These bacteria colonize the xylem tissue of host plant vascular systems causing stunting, wilting, yield reduction, and death. This pathogen group has major economic and social impact worldwide .Genomes used in this study are available at the following repositories and accession numbers: GMI1000 , FQY_4 , Y45 [GenBank: AFWL00000000], IPO1609 , UW551 [GenBank: AAKL00000000], UW349 [GenBank: JQOI00000000.1], UW365 [GenBank: JQSI00000000.1], UW491 [GenBank: JQSH00000000.1], RS2 [EMBL: PRJEB8309], CFBP3858 [EMBL: PRJEB8309], MolK2 [GenBank: CAHW01000040], CFBP1416 [EMBL: PRJEB7434], CIP417 [EMBL: PRJEB7427], UW179 [EMBL: PRJEB7426], UW163 [EMBL: PRJEB7430], CFBP6783 [EMBL: PRJEB7432], Po82 [GenBank: CP002819 CP002820], IBSBF1503 [EMBL: PRJEB7433], CFBP7014 [EMBL: PRJEB8309], CFBP2957 , K60 [EMBL: CAGT01000001], Grenada 9-1 [EMBL: PRJEB7428], UW181 [EMBL: PRJEB8309], B50 [EMBL: PRJEB7421], IBSBF1900 [EMBL: PRJEB8309], CMR15 , PSI07 , BDB R229 [EMBL: FR854059 to FR854085],"}
+{"text": "As our world becomes warmer, agriculture is increasingly impacted by rising soil salinity and understanding plant adaptation to salt stress can help enable effective crop breeding. Salt tolerance is a complex plant phenotype and we know little about the pathways utilized by naturally tolerant plants. Legumes are important species in agricultural and natural ecosystems, since they engage in symbiotic nitrogen-fixation, but are especially vulnerable to salinity stress.Medicago truncatula in field and greenhouse settings demonstrate that Tunisian populations are locally adapted to saline soils at the metapopulation level and that saline origin genotypes are less impacted by salt than non-saline origin genotypes; these populations thus likely contain adaptively diverged alleles. Whole genome resequencing of 39 wild accessions reveals ongoing migration and candidate genomic regions that assort non-randomly with soil salinity. Consistent with natural selection acting at these sites, saline alleles are typically rare in the range-wide species' gene pool and are also typically derived relative to the sister species M. littoralis. Candidate regions for adaptation contain genes that regulate physiological acclimation to salt stress, such as abscisic acid and jasmonic acid signaling, including a novel salt-tolerance candidate orthologous to the uncharacterized gene AtCIPK21. Unexpectedly, these regions also contain biotic stress genes and flowering time pathway genes. We show that flowering time is differentiated between saline and non-saline populations and may allow salt stress escape.Our studies of the model legume This work nominates multiple potential pathways of adaptation to naturally stressful environments in a model legume. These candidates point to the importance of both tolerance and avoidance in natural legume populations. We have uncovered several promising targets that could be used to breed for enhanced salt tolerance in crop legumes to enhance food security in an era of increasing soil salinization.The online version of this article (doi:10.1186/1471-2164-15-1160) contains supplementary material, which is available to authorized users. Adaptation of populations to their local environments plays a fundamental role in the maintenance of genetic diversity  and is aThere are multiple metrics that are widely used to detect local adaptation in performance data from reciprocal transplant experiments. The \"local versus foreign\" comparison requires that genotypes from a given habitat type outperform genotypes from a different habitat type in their source habitat, but are outperformed in the alternative habitat. The \"home versus away\" comparison requires that genotypes perform better in their source habitat type than they do in the alternative habitat type. The local versus foreign metric has been preferred over the home versus away metric because in order for subpopulations (demes) to resist invasion by foreign genotypes they must outperform these non-adapted genotypes . In addiMedicago contains 83 species whose native distributions surround the Mediterranean basin , NS: nonsaline, S: saline. Tables to the right of each main table contain the results of post-hoc tests between each of the origin soil type by destination soil type groups. (XLS 40 KB)Additional file 2:Means, standard errors, and sample sizes for three phenotyping experiments.(XLS 31 KB)Additional file 3:Fitness predictors in the field. Multiple regression and single-trait linear regression to assess the relationship between aboveground biomass and pod production in naturally occurring (spontaneous) plants within our field garden exclosures. (XLS 37 KB)Additional file 4:Analysis of reciprocal field soil experiment. Only plants harvested prior to greenhouse failure were included in the analysis; same patterns found when all plants included. Analyzed using mixed models with genotype and all interactions with genotype treated as random effects and significance assessed with AIC. Num df: numerator degrees of freedom, Den df: denominator degrees of freedom, SO: soil origin, Pop: population, GST: garden soil type [saline/nonsaline], LL: log-likelihood, AIC: Akaike's an information criterion. (XLS 38 KB)Additional file 5:Additional file 6: Analysis of 0 vs 100mM NaCl greenhouse experiment. Analyzed using mixed models with genotype and all interactions with genotype treated as random effects. Num df: numerator degrees of freedom, Den df: denominator degrees of freedom, SO: soil origin, Pop: population, GST: garden soil type [saline/nonsaline], LL: log-likelihood. Significance of random effects are \u03c7 2 tests comparing the difference in -2 log likelihood of the full model and the model excluding that factor with 1 degree of freedom. (XLS 30 KB)Genome-wide LD decay. Linkage disequilibrium (r2 between SNPs) decay across each M. truncatula chromosome. Light gray denotes the 5% and 95% quantiles; dark gray denotes the 10% and 90% quantiles. (PDF 38 KB)Additional file 7:Genome-wide hierarchical F-statistics. Distribution of hierarchical F-statistics computed for each SNP identified in the collection of 39 Tunisian M. truncatula. Note that the x-axes differ. (PDF 75 KB)Additional file 8:Results from 5 replicate STRUCTURE runs on biallelic SNPs in 39 TunisianM. truncatula. A) Evanno's delta K statistic, B) Likelihood scores of each run, C) representative distruct plots for K\u2009=\u20092 to 7. Note that delta K peaks strongly at K\u2009=\u20092. (PDF 92 KB)Additional file 9:Migrate-n parameter estimates. Means, standard deviation, and ranges of 10 replicate runs with 96 10Kbp intervals each. Saline: S1, S2; non-saline: NS1, NS2. Two individual run results below with saline and non-saline populations with the most similar estimates of theta and with the most dissimilar estimates of theta; note the wide and overlapping confidence intervals. (XLS 41 KB)Additional file 10:Soil-assorting SNPs. SNPs that associate with soil type using a chi-squared test with Bonferroni correction at 0.05 family wide error rate. Red: saline origin genotypes. Blue: non-saline origin genotypes. (XLS 66 KB)Additional file 11:Genes in soil-assorting LD blocks. 198 genes contained within the 16 soil-assorting LD blocks. (XLS 44 KB)Additional file 12:Candidate genes. Genes in soil-assorting LD blocks with soil-assorting amino-acid mutations. (XLS 40 KB)Additional file 13:Candidate amino acid substitutions. Amino acid changes in soil-assorting genes. * indicates conserved a.a. (XLS 32 KB)Additional file 14:Gene trees of CPK and CIPK gene candidates. Phylogenetic analysis of (A) CPK and (B) CIPK proteins in M. truncatula (red circles) and Arabidopsis (green circles). Maximum Likelihood trees with bootstrap support shown (1000 replications). Trees are unrooted, as these gene families have expanded as far back as mosses. Focal genes discussed in main text are depicted by filled circles. (PDF 64 KB)Additional File 15:False discovery rate 0.01 genes. Genes intersected by SNPs that assort with soil type at a FDR\u2009<\u20090.01 threshold. (XLS 164 KB)Additional file 16:Using Sanger sequence data to set empirical thresholds for SNP-calling in Illumina data. AlleleBalance (AB): For bi-allelic sites, the genotype-quality-weighted ratio of ref bases/. The annotated value is the average over each sample with a heterozygous genotype of the  x .; BaseQualityRankSumTest (BaseQRankSum): The phred-scaled p-value from the Wilcoxon Rank Sum Test of het vs. ref base qualities.; DepthOfCoverage (DP): The depth of coverage at the given position (including spanning deletions if present).; HomopolymerRun (HRun): The length of the largest contiguous homopolymer run of the variant allele in either direction.; MappingQualityRankSumTest (MQRankSum): The phred-scaled p-value from the Wilcoxon Rank Sum Test of het vs. ref read mapping qualities.; MappingQualityZero (MQ0): The number of mapping-quality zero reads at the position.; QualByDepth (QD): The QUAL (confidence) value of the VCF record divided by the sum of depths of all samples with non-reference genotypes.; RMSMappingQuality (MQ): The root mean square mapping quality of the reads in the pileup.; SpanningDeletions (Dels): The percentage\\ of reads with deletions spanning this position.; HaplotypeScore (HaplotypeScore): Estimate of the probability that the reads at this locus are coming from no more than 2  haplotypes. RED: Not a Sanger SNP . CYAN: A Sanger SNP (True Positive). Size of point: allele frequency in the 39 TN lines. (PDF 326 KB)Additional File 17:Empirical threshold for SNP-calling in TunisianM. truncatulaIllumina data. Four loci were sequenced in all forty TN lines in both directions (see Methods). RED: Not a Sanger SNP . CYAN: A Sanger SNP (True Positive). Size of point: allele frequency in 40 TN lines. QD: GATK quality scaled by depth, line at QD\u2009=\u200930 is the selected threshold for SNP calling and the number of false positives/true positives is given for each of the four loci. (PDF 92 KB)Additional file 18:"}
+{"text": "Recently we showed increased expression of atrophy genes MuRF-1 and Atrogin-1 during early course of critical illness resulting in MyHC loss and finally the clinical presentation of ICU-acquired weakness. Appropriate studies of systematic electron microscope investigations from this early time in critical illness do not exist yet.To investigate muscle ultrastructure with electron microscopy within the time course of critical illness.M. vastus lateralis) were obtained at median day 5 and 16. Electron microscope studies were performed and counting of myosin filaments in cross section was done using Image J Software. Reference values were taken from Riley et al.. Muscle strength was assessed using Medical Research Council (MRC)-Scale when patients were alert later in ICU course. Non-parametric tests were performed. Ethic vote (Charit\u00e9 EA2/061/06).Controlled, prospective, monocentric observational study. We included 30 mechanically ventilated, critically ill patients (SOFA score \u2265 8 at 3 within 5 days after ICU admission). Two open muscle biopsies (2(mean/SD): 577/193 vs.1054/71. There is no significant ongoing decrease of myosin filament later according to second biopsy - n/\u00b5m2(mean/SD):416/172. We found a significant correlation of myosin filament density and MRC-Scale for the first biopsy, yet not for the second biopsy.We see a significant reduction of myosin filament to almost half the normal density already in the first biopsy: n/\u00b5mElectron microscopy reveals a serious reduction of myosin filament density very rapidly after onset of critical illness. However, during course of critical illness the further reduction of myosin filament density is of minor degree. The early myosin filament loss determines development of ICU-acquired weakness later during ICU stay, when patients emerge from sedation.Funded by DFG, KFO 192, WE 4386/1-2."}
+{"text": "We present a case of renal infiltration of grade 3A follicular lymphoma (FL) mimicking renal cell carcinoma (RCC).Chronic renal failure (CRF) was diagnosed in a 63-year-old male during routine health controls. Ultrasonography results emphasized a left renal mass. Multislice computed tomography (MSCT) confirmed the prior findings of a solid multilobular mass (48x46x79 mm), reduced kidney parenchyma, and intact surrounding lymph nodes (LNs) mimicking RCC. Without previous oncological evaluation, urologists performed nephrectomy. Histopathology revealed FL of grade 3A, with perirenal infiltration. Immunohistochemistry was typical: CD79\u03b1+, CD20+, CD10+, MUM1-, Bcl-2+, Bcl-6+, cyclin D1-, CD23-, CD3, CD5-, CK AE1/AE3-, and EMA-, with a Ki-67 index of 20% . After sPrimary renal lymphoma (PRL) is defined as lymphoma arising in the renal parenchyma and not invasion from an adjacent lymphomatous mass . Since tPRL is a systemic disease manifesting initially in the kidneys, with poor outcome even if localized. It disseminates rapidly and mean survival is less than 1 year after diagnosis . Renal iStandardized PRL treatment is undefined. R-CHOP could be the elective treatment according to experience and some recently published studies ,6. ImproLong-term survivors occasionally have been reported after combined complete resection surgery/chemotherapy treatment, with longer disease-free survival and OS, but only one with kidney involvement ,7. The aIn conclusion, solid renal lesions mimicking RCC may suggest underlying renal lymphoma infiltration. Although exceptionally uncommon, renal FL may be the pathological subtype. No standardized therapy exists in this specific situation. Rituximab with its documented survival benefit in FL is recommended to be included in the treatment regimen. The accompanying chemotherapy may depend on many variables, including ECOG performance status, patient age, FL grade, FLIPI index, and single-center decision.The authors of this paper have no conflicts of interest, including specific financial interests, relationships, and/ or affiliations relevant to the subject matter or materials included."}
+{"text": "Left atrial (LA) structural and functional changes are determinant steps on the pathway toward heart failure with preserved ejection fraction in hypertensive (HT) patients. Most LA studies are based on LA volumes evaluation in CMR and echocardiography or on echocardiographic speckle tracking estimation. Since LA functional evaluation by CMR is now emerging we aimed at 1) evaluating LA function by CMR in controls and hypertensive patients (moderate and severe HT) using feature tracking technique on conventional cine data; 2) evaluating the relationship between the components of LA function  and left ventricular (LV) remodeling.We studied 22 patients with HT  matched with 20 healthy individuals for age and gender. Steady state free precession (SSFP) CMR cine loops were acquired in three long axis views and a custom automated feature tracking tool was used to estimate: global longitudinal strain (Sl) and strain rate (SRl), radial motion fraction (MrR) and relative velocities (Vr) as well as LA volumes using a multi plane area-length method. LA functional parameters were defined for reservoir (R), conduit (E) and LA contraction (A) phases. The LV mass index, LV wall thickness and LV ejection fraction were measured from short-axis images using the Qmass software.vs. 44.5\u00b113.1mL/m2). Alteration of LA function in hypertension was highlighted by a significant reduction in longitudinal strain and motion fraction (p<0.03) between moderate and severe HT patients . LA reservoir and LA contraction longitudinal strains were lower in resistant HT patients as compared to moderate HT (p<0.04) and controls . Moreover, longitudinal strain rates and relative velocities were significantly reduced for reservoir and contraction phases in severe HT vs. controls  and severe vs. moderate HT . However, there was no significant difference in LA conduit phase strains and strain-rates between groups.Maximal indexed LA volumes were in the normal range in HT patients and comparable to controls , indexed LV mass  and LV mass/end-diastolic volume .CMR-measured functional LA parameters were altered in severe hypertensions even with normal LA volumes. This suggests that functional LA alterations may precede significant LA dilation. Moreover, LA functional alterations were strongly associated with LV remodeling and might be accordingly useful for therapeutic management in the setting of hypertension.N/A."}
+{"text": "Despite the high incidence of acute kidney injury (AKI) in critically ill patients, studies evaluating histopathological renal findings in these patients yielded inconsistent results. No studied specifically evaluated renal histology in intensive care unit (ICU) patients treated by continuos renal replacement therapy for severe AKI.To describe histopathological findings in patients treated with CRRT for severe AKI.post-mortem (PM) examination. Predefined exclusion criteria were: history of end-stage kidney disease requiring dialysis before admission, CRRT required for any reason other than kidney failure and death in the first 24 hours of admission. Kidney histology examination was by light microscopy only.We retrospectively identified all patients admitted to our department of Intensive Care during a two-year period (2012-2013) who required CRRT at any time during ICU stay, who died and had Post-mortem autolysis precluded analysis in 4 patients and these were excluded from further analysis. Acute tubular necrosis (ATN) was the clinical diagnosis in 21/28 (75%) patients. However, histological features of ATN were only seen in 5 of these. There was significant discordance between the clinical and histological renal diagnosis in 6 patients; 3 had unexpected chronic pyelonephritis, 1 had bilateral renal infarction, 1 had septic emboli and 1 had acute interstitial nephritis. Background atherosclerotic reno-vascular disease was common (32%). Nine patients had normal kidneys at PM examination (32%).Thirty-two post-mortem examinations were performed within 24 hours of death. Mean age was 63 [53-67] years; 12/32 patients (37%) had arterial hypertension and 9/32 patients (28%) had past medical history of chronic kidney disease. The most common ICU diagnosis was severe sepsis/septic shock , cardiogenic shock  or liver failure . ATN is a rare pathological finding in renal PM analysis of ICU patients treated with CRRT for severe AKI. One fifth of patients had an unanticipated renal pathology. Normal renal parenchyma was found in one third of all patients."}
+{"text": "Picornaviridae and Flaviviridae including hepatitis C virus (HCV) evade this process using internal ribosomal entry sequences (IRESs). Although HCV IRES translation is a prerequisite for HCV replication, only few host factors critical for IRES activity are known and the global regulator network remains largely unknown. Since signal transduction is an import regulator of viral infections and the host antiviral response we combined a functional RNAi screen targeting the human signaling network with a HCV IRES-specific reporter mRNA assay. We demonstrate that the HCV host cell cofactors PI4K and MKNK1 are positive regulators of HCV IRES translation representing a novel pathway with a functional relevance for the HCV life cycle and IRES-mediated translation of viral RNA.Cellular translation is down-regulated by host antiviral responses.  Hepatitis C virus (HCV) is a positive stranded RNA virus replicating in intracellular phospholipid-enriched membrane domains. Several unbiased RNAi screens identified a panel of host factors required for HCV entry, replication and assembly12367111516175192022) in gene silenced hepatoma cells 48\u2009h post siRNA transfection as described previously26Renilla luciferase mRNA initiated by a m7G cap structure and firefly luciferase mRNA containing a non-physiological adenosine cap structure (\u2018A-cap\u2019) and the HCV IRES element. The A-cap maintains stability of the mRNA, but is not recognized by the cap binding complex. Luciferase expression was assessed by a Mithras LB 940 (Berthold Technologies) using Dual-Luciferase Reporter Assay or Bright-Glo (Promega). Toxicity of gene silencing was assessed using MTT (Sigma) and Presto Blue (Sigma) for the tertiary screen. In the primary screen targeting 893 genes we identified 46 candidates that predominant impact HCV IRES-dependent over cap-dependent translation  as described previously22 reporter mRNA was transfected 48\u2009h post siRNA transfection using TransMessager reagent (Qiagen) as described previouslyIn vitro transcription of mRNAs were described previouslyfirefly: cap-renilla) of 1:4 in the primary screen. In the secondary screen reporter mRNAs  were transfected side-by-side. Luciferase expression was assessed by a Mithras LB 940 (Berthold Technologies) using Dual-Luciferase Reporter Assay System System or Bright-Glo (Promega). Toxicity was assessed using MTT assay (Sigma) and Presto Blue assay (Sigma) for the tertiary screen and the MKNK1 inhibitor experiments. RNA was extracted using RNeasy kit (Qiagen) and cDNA were generated using Maxima Reverse Transcriptase (Life Technologies). qPCR was performed using RT2 SYBR Green qPCR Mastermix (Qiagen) and a C1000 Touch Thermo Cycler (Bio-Rad).All transfections were performed at the High Throughput Screening platform of the Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire (IGBMC) in Illkirch, France. Gene silencing by RNAi for all screens was performed on 5000 cells/3.5\u2009pmol siRNA/0.3\u2009cmfirefly luciferase pT3FireflyLuc(pA), the renilla luciferase control plasmid pT3RenillaLuc(pA) and pHCV-IRES-luc has been described previously27352 qPCR assays). MKNK1 inhibitor was obtained from Calbiochem (Merck Millipore) and solved in DMSO.Cell growth conditions of hepatoma cell lines Huh7.5 and Huh7.5.1 were described33firefly luciferase and capped renilla luciferase reporter mRNAs were formed and values normalized by the plate median of the relative light signals. Measurements were scored calculating z-scores using CellHTS2 software. Hits were assigned from the primary screen if z\u2009=\u2009<\u22121.29. Secondary screening results were normalized to % luciferase activity of control cells transfected with scrambled siRNAs. Hits were assigned if target silencing decreased IRES-dependent firefly luciferase activity and if the ratio of IRES- to cap-dependent firefly luciferase activities is <0.8. An impact of target-specific siRNA (four siRNA per target) on infection with HCVcc was identified in a tertiary screen using the method of strictly standardized mean differences (SSMD)37To evaluate the impact of gene silencing on IRES and cap-dependent translation, ratios of relative light units emitted by cells transfected with IRES How to cite this article: Lupberger, J. et al. PI4K-beta and MKNK1 are regulators of hepatitis C virus IRES-dependent translation. Sci. Rep.5, 13344; doi: 10.1038/srep13344 (2015)."}
+{"text": "Patients that require aortic valve replacement, having previously undergone cardiac surgery, have a higher morbidity and mortality with increased risks of mediastinal injury during re-operation.In the era of TAVI for high risk surgical candidates, we analysed our experience with redo conventional surgical aortic valve replacement (SAVR) and compared these results with those from patients who had undergone TAVI as a second heart operation.A retrospective, observational, comparative study was performed in the national centre offering TAVI. 149 consecutive patients underwent redo operation with SAVR (n = 59) or TAVI (n = 90) between October 2012 and February 2015. In the SAVR group patients with concomitant procedures (n = 8) or endocarditis (n = 8) were excluded from the analysis.Mean logistic Euroscore was 29.6 for redo-TAVI compared to 18.6 for redo-SAVR (p < 0.05). Type of previous cardiac surgery performed in each redo group is summarised in Table TAVI access was transfemoral (65.5%), transapical (6.7%), or trans-aortic (27.8%).Despite a higher incidence of MACE (major adverse cardiac events) in SAVR patients, results indicated no significant differences between two groups in terms of all-cause and cardiovascular related mortality, stroke, myocardial infarction.In details, hospital mortality was higher in SAVR group (5.1%) compared to TAVI group (2.2%), although it did not reach statistical significance.There was a higher incidence of CVA in the SAVR versus TAVI group .Patients were found to require permanent pacemaker insertion more often after TAVI .Finally, average length of post-operative hospital stay was significantly shorter in TAVI than SAVR group .This retrospective analysis suggests that TAVI is preferable to SAVR in this high risk group of patients. Redo-SAVR remains a valid option for younger patients in whom long-term durability of the prosthetic valve is a concern."}
+{"text": "Pneumonia is the most frequent type of infection in cancer patients and a frequent cause of ICU admission. The primary aims of this study were to describe the clinical and microbiological characteristics and outcomes in critically ill cancer patients with severe pneumonia.Prospective cohort study in 325 adult cancer patients admitted to three ICUs with severe pneumonia not acquired in the hospital setting. Demographic, clinical and microbiological data were collected.S. aureus [42 (24.9%)], P. aeruginosa [41(24.3%)] and S. pneumonia [21 (12.4%)]. A relatively low incidence of MR [23 (13.6%)] was observed. Adequate antibiotics were prescribed for most patients [136 (80.5%)]. In multivariate analysis, septic shock at ICU admission [OR 5.52 (1.92\u201315.84)], the use of invasive MV [OR 12.74 (3.60\u201345.07)] and poor Performance Status [OR 3.00 (1.07\u20138.42)] were associated with increased hospital mortality.There were 229 (71%) patients with solid tumors and 96 (29%) patients with hematological malignancies. 75% of all patients were in septic shock and 81% needed invasive mechanical ventilation. ICU and hospital mortality rates were 45.8% and 64.9%. Microbiological confirmation was present in 169 (52%) with a predominance of Gram negative bacteria [99 (58.6%)]. The most frequent pathogens were methicillin-sensitive Severe pneumonia is associated with high mortality rates in cancer patients. A relatively low rate of MR pathogens is observed and severity of illness and organ dysfunction seems to be the best predictors of outcome in this population. Adequatedelines. . ATS/IDSand HCAP , 17,27]performan HCAP . Univariate and multivariate logistic regression analyses were used to identify factors associated with hospital mortality. The area under the receiver-operating characteristic curve (AROC) was used to assess the models\u2019 discrimination ,30. VariDuring the study period, a total of 325 patients fulfilled the eligibility criteria and were evaluated. There were 229 (71%) patients with solid tumors and 96 (29%) patients with hematological malignancies. The main primary sites of solid tumors were head and neck 72 (22%), lung 38 (12%) and urogenital 27 (8%); 96 patients had hematological malignancies and were classified in high-grade 48 (15%) and low-grade 48 (15%).Neutropenia was present in 35 (11%) patients at ICU admission. No patient presented prolonged neutropenia. Regarding supportive care, 75% of patients were in septic shock, 91% of patients needed ventilatory support, mainly (81%) invasive mechanical ventilation (MV). Renal replacement therapy (RRT) was employed in 27% patients. The patients\u2019 main characteristics are depicted in n = 99 (59%)]. There were 40 (24%) positive blood cultures and 150 (89%) bacterial isolation in tracheal aspiration sample or bronchoalveolar lavage. Simultaneous bacterial identification was present in blood culture and tracheal aspiration sample or bronchoalveolar lavage in 21 (12%) patients. The most frequently identified pathogens were methicillin-sensitive S. aureus (MSSA) [n = 42 (25%)], followed by P. aeruginosa [n = 41 (24%)] and S. pneumoniae [n = 21 (12%)]. MR pathogens represented 13.6% (n = 23) of patients. Detailed microbiological data is described in Microbiological confirmation was present in 169 (52%) of study population with a predominance of Gram negative bacteria [in vitro susceptibility testing) demonstrated that adequate antibiotic therapy was prescribed in the majority of patients [136 (81%)]. However, adherence to CAP and HCAP ATS/IDSA guidelines [guidelines were the absence of double therapy (addition of amikacin or quinolones) [n = 174 (54%)] and lack of coverage for methicillin-resistant S. aureus (MRSA) [n = 134 (41%)] or Pseudomonas sp [n = 32 (10%)].The evaluation of antibiotic therapy based on microbiological identification  and those without MR pathogens (n = 146). Demographic characteristics, type of cancer, need for life-sustaining therapies and clinical outcomes were comparable between the two groups. There were no significant differences regarding ATS/IDSA guidelines adherence in these two groups . Detailed comparisons between MR patients and no MR patients are provided in Tables We performed a comparison between patients where MR pathogens were identified n = 2 and thosens n = 16. DemogrP = 0.007]. Factors associated with hospital mortality in a univariate analysis were described in The ICU and hospital mortality rates were 46% and 65%, respectively. Higher severity of illness and need for life-sustaining therapies as vasopressors use, invasive MV and need of RRT were observed in the group of nonsurvivors. Adequate antibiotic therapy was comparable in both groups. Atypical pathogen coverage was more frequently prescribed in survivors than in non-survivors  in the group of survivors [Surv 33 (62%) vs 50 (43%) p = 0.031]. However higher severity of illness and need for life-sustaining therapies as vasopressors use, invasive MV and need of RRT were more frequent in nonsurvivors. Detailed comparison of patients with microbiological confirmation was described in In multivariate analysis, septic shock at ICU admission, the use of invasive MV and poor PS were associated with increased hospital mortality. A multivariate analysis of predictors of hospital mortality was described in n = 132 (41%)] and HCAP [n = 193 (59%)]. The most frequent criteria for HCAP classification were: previous chemotherapy [n = 109 (57%)], prior hospitalization [n = 106 (55%)], attended a hospital, nursing home or hemodialysis clinic [n = 49 (25%)] and previous radiation therapy [n = 35 (18%)]. Patients with HCAP had a higher frequency of neutropenia at ICU admission and previous corticosteroids use as compared to those with CAP.The study population was classified as CAP  between CAP and HCAP. Detailed characteristics of CAP and HCAP patients separately are provided  with pneumonia, with low hospital mortality rates (< 15%). , 33], [33]The present study has some limitations. First, this was a strictly observational study and although the centers have a high case volume of cancer patients, specific protocols for the investigation and care of patients with pneumonia were not designed and implemented in our study. Therefore, we did not employ systematically other microbiological investigation methods  to establish the etiologic diagnosis of pneumonia, which limited our ability to identify pathogens such as viruses and atypical pathogens. Additionally, we did not collect data on process of care measures, other than adherence to antimicrobial guidelines, although we acknowledge that these may be important contributors to clinical outcomes . AdditioIn conclusion, we believe that cancer patients are a distinct group of patients with pneumonia and that a classification of HCAP or CAP according to ATS criteria does not add to risk assessment or to guidance of antimicrobial therapy. In these patients, a relatively low rate of MR pathogens is observed and severity of illness and organ dysfunction seems to be the best predictors of outcome in this population.S1 TableDefinition of abbreviations: CAP = community-acquired pneumonia; HCAP = healthcare-associated pneumonia; LOS = length of stay; ICU = intensive care unit; NIV = noninvasive ventilation; SOFA score D1 = sequential organ failure assessment score in first day at ICU; SAPS II score = simplified acute physiology score; RRT = renal replacement therapy.(DOCX)Click here for additional data file.S2 Table1- Adequate empiric antibiotic treatment was based in the sensitivity test of the identified bacteria. 2- The MR pathogens were defined as non-susceptibility to at least one agent in three or more antimicrobial categories. {Magiorakos:2012be} 3- ATS/IDSA guidelines adherence was based in definitions of empiric antimicrobial treatment for CAP and HCAP. {AmericanThoracicSociety:2005kw}, {Mandell:2007ik}. Definition of abbreviations: ATS = American Thoracic Society; CAP = Community Acquired Pneumonia; HCAP = Healthcare-associated Pneumonia; MR = Multiresistant; MRSA = Methicilin-resistant Staphylococcus aureus.(DOCX)Click here for additional data file.S3 TableDefinition of abbreviations: CAP = community-acquired pneumonia; LOS = length of stay; ICU = intensive care unit; NIV = noninvasive ventilation; SOFA score D1 = sequential organ failure assessment score in first day at ICU; SAPS II score = simplified acute physiology score; RRT = renal replacement therapy.(DOCX)Click here for additional data file.S4 TableDefinition of abbreviations: HCAP = healthcare-associated pneumonia; LOS = length of stay; ICU = intensive care unit; NIV = noninvasive ventilation; SOFA score D1 = sequential organ failure assessment score in first day at ICU; SAPS II score = simplified acute physiology score; RRT = renal replacement therapy.(DOCX)Click here for additional data file.S5 TableDefinition of abbreviations: LOS = length of stay; ICU = intensive care unit; NIV = noninvasive ventilation; SOFA score D1 = sequential organ failure assessment score in first day at ICU; SAPS II score = simplified acute physiology score; RRT = renal replacement therapy.(DOCX)Click here for additional data file.S6 Table1- Adequate empiric antibiotic treatment was based in the sensitivity test of the identified bacteria. 2- The MR pathogens were defined as non-susceptibility to at least one agent in three or more antimicrobial categories. {Magiorakos:2012be}. 3- ATS/IDSA guidelines adherence was based in definitions of empiric antimicrobial treatment for CAP and HCAP. {AmericanThoracicSociety:2005kw}, {Mandell:2007ik}. Definition of abbreviations: ATS = American Thoracic Society; MR = Multiresistant; MRSA = Methicilin-resistant Staphylococcus aureus.(DOCX)Click here for additional data file.S7 Table1- Adequate empiric antibiotic treatment was based in the sensitivity test of the identified bacteria. 2- The MR pathogens were defined as non-susceptibility to at least one agent in three or more antimicrobial categories. 223- ATS/IDSA guidelines adherence was based in definitions of empiric antimicrobial treatment for CAP and HCAP. 5, 20 Definition of abbreviations: ATS = American Thoracic Society; MR = Multiresistant; MRSA = Methicilin-resistant Staphylococcus aureus.(DOCX)Click here for additional data file.S8 Table1- Previous hospitalization is defined when a patient was hospitalized in an acute care hospital for two or more days within 90 days of the infection. 2- Previous chemotherapy is defined as chemotherapy within the past 30 days of the current infection. 3- Previous radiation therapy is defined as radiation therapy within the past 30 days of the current infection. Definition of abbreviations: LOS = length of stay; ICU = intensive care unit; NIV = noninvasive ventilation; SOFA score = sequential organ failure assessment score; SAPS score = simplified acute physiology score; RRT = renal replacement therapy(DOCX)Click here for additional data file.S9 TableDefinition of abbreviations: LOS = length of stay; ICU = intensive care unit; NIV = noninvasive ventilation; SOFA score D1 = sequential organ failure assessment score in first day at ICU; SAPS II score = simplified acute physiology score; RRT = renal replacement therapy.(DOCX)Click here for additional data file.S10 Table1- Adequate empiric antibiotic treatment was based in the sensitivity test of the identified bacteria. 2- The MR pathogens were defined as non-susceptibility to at least one agent in three or more antimicrobial categories. {Magiorakos:2012be}. 3- ATS/IDSA guidelines adherence was based in definitions of empiric antimicrobial treatment for CAP and HCAP. {AmericanThoracicSociety:2005kw}, {Mandell:2007ik}. Definition of abbreviations: ATS = American Thoracic Society; MR = Multiresistant; MRSA = Methicilin-resistant Staphylococcus aureus.(DOCX)Click here for additional data file."}
+{"text": "Myocardial architectural abnormalities, have been identified in hypertrophic cardiomyopathy(HCM) gene mutation carriers without hypertrophy(G+LVH-). Some of these changes may be related to the underlying mutation, but whether they can predict gene carriage in relatives of HCM probands is unknown. Cardiac trabeculae may be prominent in overt HCM, suggesting they could form part of this constellation of abnormalities but previous techniques have not permitted more detailed study. We developed a fractal method for quantitation of trabeculae, tracked their development in embryonic mice and applied it to humans imaged by CMR. We hypothesize that fractal analysis may detect abnormal trabeculae in HCM mutation carriers before development of LVH and that a combination of cardiac architectural abnormalities could be used to predict gene carriage in HCM.TRABECULAE IN MOUSE EMBRYONIC DEVELOPMENT-63 Murine hearts were examined from the time of ventricular septation(E14.5) till just before birth(E18.5). Trabeculae ware charted by fractal analysis of high-resolution episcopic microscopy images using a box-counting method. HUMAN MORPHOLOGY-74 G+LVH- sarcomere mutation carriers(29 \u00b1 13 yr[SD]|51%M) were identified in 12 US-centers(HCMNet|n = 35) and UCL(n = 39). Subjects underwent CMR and fractal analysis. Results were compared with 111 overt HCM patients and 136 matched controls(36 \u00b1 16 yr|63%M). We analyzed a single-center(UCL) G+LVH- case-control cohort to identify factors associated with gene carriage, evaluating anterior mitral valve leaflets(AMVL), wall thickness, clefts, trabeculae and other variables. We validated identified associations in the multi-center HCMNet cohort, and combined significant parameters into a model for predicting genetic carriage.In mice a fractal atlas of trabecular development showed decreasing complexity across the basal LV while complexity in the mid/apical LV rose again just before birth and by the European Union (Science and Technology Research Grant). Her work on HCMNet in Bethesda (NIH) and Boston (BWH) was funded by the UCL Charlotte and Yule Bogue Research Fellowship. Murine HREM Experiments are funded by the The Wellcome Trust ."}
+{"text": "High-flow nasal cannula (HFNC) is increasingly proposed as respiratory support for hypoxemic non-intubated acute respiratory failure patients. Clinically, HFNC therapy decreases dyspnea, improves patient's comfort, improves oxygenation and enhances clearance of upper airway secretions . We pres2/FiO2 \u2264300 mmHg) admitted to the ICU of the San Gerardo Hospital and prescribed to receive oxygen by facial mask. We delivered the same air/oxygen mix by HFNC  and facial mask (20 minutes per step). Continuous recordings of regional lung volumes by EIT  and of inspiratory effort by esophageal pressure (Pes) were obtained and analyzed offline by dedicated software.We performed a prospective randomized cross-over study on hypoxemic non-intubated patients  and end-expiratory lung impedance (corresponding to aeration) . Moreover, HFNC decreased the respiratory rate , as well as negative Pes swings  and corrected minute ventilation  . Finally, central venous pressure increased , possibly indicating positive end-expiratory pressure effect.We enrolled 15 patients , age 57 \u00b1 16 years. Compared with standard facial mask, HFNC significantly improved PaO2 tension.In non-intubated hypoxemic critically ill patients, HFNC improves oxygenation and end-expiratory aeration; moreover, HFNC reduces the inspiratory effort and the minute ventilation needed to maintain normal arterial CO"}
+{"text": "A developmentally delayed 28-month-old male toddler was referred to us for brain MRI. Imaging revealed corpus callosum dysgenesis, forniceal hypoplasia, vermian hypoplasia, and hypothalamic dysmorphism characterized by tuber cinereum diverticula. Subsequent chromosomal microarray showed an Xq21 deletion. We present a case of Xq21 deletion syndrome with midline brain anomalies and a novel hypothalamic malformation. Xq21 deletion syndrome comprises intellectual disability, choroideremia, and deafness. By strict definition, defects affecting both CHM and POU3F4 genes must be present [A 28-month-old male toddler underwent workup for global developmental delay and mild hypotonia. He was the product of an uncomplicated pregnancy, born at term via C-section due to concern for possible cephalopelvic insufficiency. The parents were nonconsanguineous and had no significant past medical history. The patient was of normal height and weight for age; body mass index was at the 68th percentile. Ophthalmic examination performed for evaluation of intermittent exotropia was otherwise normal. A neonatal otoacoustic emissions hearing exam was also normal. Ultimately, chromosomal microarray revealed a pathogenic Xq21.1q21.2 chromosome deletion involving the following genes: POU3F4, CHM, POF1B, RPS6KA6, HDX, UBE2DNL, APOOL, SATL1, ZNF711, and DACH2. During the course of the workup, the patient was referred to our imaging service to exclude congenital intracranial abnormalities.Brain imaging was performed on a 1.5T MR . Prescribed pulse sequences included Sagittal T1WI SPGR (Spoiled Gradient Echo), axial T2WI, axial fat saturated T2 FLAIR (Fluid Attenuation Inversion Recovery), axial diffusion weighted images, axial SWAN (Susceptibility-Weighted Angiography), and coronal fat saturated T2WI.Midline sagittal images demonstrate corpus callosum dysgenesis, hypoplastic fornices, and vermian hypoplasia . ParasagXq21 deletion is a rare genetic syndrome with phenotypic manifestations including intellectual disability, hearing loss, and vision loss. Intellectual disability is a common consequence of X chromosome aberrations; genetic defects in Xq12-Xq21 are often responsible . Visual The hypothalamus marginates most of the anteroinferior 3rd ventricle. The hypothalamic component of the 3rd ventricular floor extends from the pituitary infundibulum (anterior) to the mammillary bodies (posterior), with the tuber cinereum located in between  Figure . The tubBrain MR revealed midline anomalies including dysgenesis of the corpus callosum, forniceal hypoplasia, vermian hypoplasia, and broadening of the 3rd ventricular floor. Additionally, a novel hypothalamic dysmorphology was discovered. Small diverticula were present extending from the ventrolateral margins of the tuber cinereum Figures . NeitherWe discovered an unprecedented hypothalamic malformation characterized by ventrolateral tuber cinereum diverticula in a male toddler with Xq21 deletion. Additional midline brain anomalies including corpus callosum dysgenesis, forniceal hypoplasia, and vermian hypoplasia were coexistent."}
+{"text": "Brachypodium distachyon is an emerging model system for cereals, temperate grasses and biofuel crops. In this study, a comprehensive investigation of the molecular characterizations, phylogenetics and expression profiles under various abiotic stresses of the NAC gene family in Brachypodium distachyon was performed. In total, 118 BNAC genes in B. distachyon were identified, of which 22 (18.64%) were tandemly duplicated and segmentally duplicated, respectively. The Bayesian phylogenetic inference using Markov Chain Monte Carlo (MCMC) algorithms showed that they were divided into two clades and fourteen subfamilies, supported by similar motif compositions within one subfamily. Some critical amino acids detected using DIVERGE v3.0 might contribute to functional divergence among subfamilies. The different exon-intron organizations among subfamilies revealed structural differentiation. Promoter sequence predictions showed that the BNAC genes were involved in various developmental processes and diverse stress responses. Three NAC domain-encoding genes , orthologous of NAC1, were targeted by five miRNA164 , suggesting that they might function in lateral organ enlargement, floral development and the responses to abiotic stress. Eleven (~9.32%) BNAC proteins containing \u03b1-helical transmembrane motifs were identified. 23 representative BNAC genes were analyzed by quantitative real-time PCR, showing different expression patterns under various abiotic stresses, of which 18, 17 and 11 genes were up-regulated significantly under drought, H2O2 and salt stresses, respectively. Only four and two genes were up-regulated under cold and cadmium stresses, respectively. Dynamic transcriptional expression analysis revealed that six genes showed constitutive expression and period-specific expression. The current results provide novel insights into the structure and function of the plant NAC gene family.NAC  transcription factors are involved in regulating plant developmental processes and response to environmental stresses.  Un. Un78]. pression . Furtherpression ,80. Saltmination ,81. It iice NTLs  contribuBrachypodium NAC gene family. Motif compositions and exon-intron organizations analyses of BNACs and ANACs revealed their similar NAC architecture. Type-I and Type-II functional divergence might be relevant to functional classification of NAC gene family. The predicted functions of some BNAC genes were consistent with the phylogeny-based functional prediction. qRT-PCR revealed that BNAC genes were regulated under various abiotic stresses, which may manifest their involvement in general stresses response rather than stress-specific responses. These results not only provide a better understanding of the structures and functions of BNAC genes but will also facilitate genome-wide studies of NAC transcription factors in several important related species.The current analyses demonstrated that segmental and tandem duplications may be responsible for the expansion of the S1 FigThe schematic diagram of motifs was derived from MEME program. Each motif is represented by a colored box, whose order was automatically generated according to scores shown at the bottom. A detailed motif introduction is shown in (PDF)Click here for additional data file.S2 FigThe schematic diagram was derived from MEME. The order of motifs in the diagram was automatically generated by MEME according to scores.(PDF)Click here for additional data file.S3 FigBNAC and 115 ANAC genes were aligned using MUSCLE program and the trees were generated based on Bayesian inference using Markov Chain Monte Carlo (MCMC) methods.The amino acid sequences of 118 (PDF)Click here for additional data file.S4 FigThe methods generating the diagram were based on those used in BNAC genes. A detailed motif introduction is shown in (PDF)Click here for additional data file.S5 FigThe schematic diagram was derived from MEME. The order of motifs in the diagram was automatically generated by MEME according to scores.(PDF)Click here for additional data file.S6 FigThe green boxes represent exons, the black solid lines connecting two neighboring exons represent introns and the blue boxes represent 5\u2019-UTR and 3\u2019-UTR. The grid scales show the gene sizes (kb).(PDF)Click here for additional data file.S1 FileBNAC genes under different abiotic stresses . Of 6 representative BNAC genes during drought and salt stresses . Of 6 representative BNAC genes during cold, gibberellin and H2O2 stresses . The red standard curve represents reference genes and other blue curve represents BNAC genes.Of 23 (PDF)Click here for additional data file.S2 File. The predicted structure of the Bdi-miR164 synthetic precursors . Mapping of BNAC mRNA cleavage sites. The red box represents target sequences of mature miR164. The cleavage sites are indicated by arrows .Sequence LOGO view from 113 mature miRNA164 sequences. The height of the letter at each position represents the degree of conservation (PDF)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(XLSX)Click here for additional data file.S3 Table(XLSX)Click here for additional data file.S4 Table(XLSX)Click here for additional data file.S5 Table(DOCX)Click here for additional data file.S6 Table(XLSX)Click here for additional data file.S7 Table(TXT)Click here for additional data file.S8 Table(XLSX)Click here for additional data file.S9 Table(PDF)Click here for additional data file."}
+{"text": "Ultrasound examination detected the early onset of a rapidly growing, homogeneous and spherical tumor in about 60% of OPN\u2212/\u2212 TRAMP mice. Such neoplasms seldom occurred in parental TRAMP mice otherwise prone to adenocarcinomas and were characterized for being androgen receptor negative, highly proliferative and endowed with neuroendocrine (NE) features. Gene expression profiling showed up-regulation of genes involved in tumor progression, cell cycle and neuronal differentiation in OPN-deficient versus wild type TRAMP tumors. Down-regulated genes included key genes of TGFa pathway, including SMAD3 and Filamin, which were confirmed at the protein level. Furthermore, NE genes and particularly those characterizing early prostatic lesions of OPN-deficient mice were found to correlate with those of human prostate NE tumours. These data underscore a novel role of OPN in the early stages of prostate cancer growth, protecting against the development of aggressive NE tumors.Osteopontin (OPN) is a secreted glycoprotein, that belongs to the non-structural extracellular matrix (ECM), and its over expression in human prostate cancer has been associated with disease progression, androgen independence and metastatic ability. Nevertheless, the pathophysiology of OPN in prostate tumorigenesis has never been studied. We crossed TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice with OPN deficient (OPN Prostate carcinoma (PCa) is one of the most common tumors in developed countries and the second leading cause of cancer-related death in the USA . PCa is Stromal microenvironment modifications occurring at the stage of precancerous PIN lesions are no longer considered bystanders. In this context, SIBLINGs , a family of non-structural extracellular matrix (ECM) proteins, seem to favor tumor progression by hijacking their physiological functions in wound healing and tissue remodeling .\u2212/\u2212) mice with the TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice, which carry the SV40 large T antigen (Tag) under the control of the rat probasin regulatory element, selectively activated by androgens in the prostate epithelia. TRAMP mice invariantly develop PIN (8-16 weeks) that progresses to focal invasive adenocarcinoma (16-20 weeks) and then to moderately differentiated (24 weeks) and poorly differentiated (24-30 weeks) adenocarcinoma [Osteopontin (OPN) is a secreted protein, belonging to SIBLINGs, present in body fluids and almost ubiquitous in tissues. OPN contributes to tissue homeostasis through the regulation of stem cell pools within specific niches . OPN ovep PIN 8-1 weeks tharcinoma .\u2212/\u2212TRAMP mice, we unexpectedly observed the early onset of highly proliferative, anaplastic androgen-independent tumors, characterized by a neuroendocrine (NE) phenotype. The corresponding human NE carcinoma characterized by aggressive behaviour, poor response to standard treatments and dismal prognosis [Although the reported over-expression of OPN in advanced disease let envisage tumor reduction in OPNrognosis , 9 accourognosis , 11. Fivrognosis .\u2212/\u2212TRAMP (n = 14) and TRAMP (n = 16) mice between 12 and 30 weeks (wks) of age by ultrasound (US) echographic examination. US allows evaluating prostate morphology and dimensions, and the elastomeric response to the echographic probe pressure, highlighting density alterations. The scan performed in 3D mode allows inspection of every prostatic lobe for the presence of tumor before it becomes palpable. US and histologic analyses of the prostate revealed no differences between the two strains until mice were 15 wks old. Between 18 and 22 wks of age a large, well-defined spheroid tumor appeared in OPN\u2212/\u2212TRAMP . Anaplastic lesions Figure , right wge Table , left wege Table .\u2212/\u2212TRAMP mice were characterized by marked anaplasia and higher expression of Ki67, N-cadherin and laminin . Unfortunately these patients frequently develop androgen resistance and ineffective treatment options remain. This setting can be modeled in TRAMP mice by castration [\u2212/\u2212TRAMP mice (both n = 11) were castrated before sexual maturation (6 wks) and tumor growth was monitored by US examination. Among castrated TRAMP mice, 9 showed prostate involution, 1 developed adenocarcinoma and the remaining one developed an anaplastic spheroid tumor with incidence similar to that of non-castrated TRAMP mice . Prostate involution occurred in the remaining 3 (27%) castrated mice  transplantation was performed to obtain chimeras lacking or not OPN in the prostatic epithelium or in the radio-resistant stroma cell components. In detail, BM from OPN-competent wild-type (WT) mice was transplanted into 6 wks old OPNchimeras . These rWhether prostatic NE cancers have a distinct cellular origin from adenocarcinomas or rather they originate from the peculiar differentiation of common precursors is still debated. As far as the TRAMP model is concerned, it is believed that NE tumors can arise from a subset of stem/progenitor cells populating the basal cell layer of glandular ducts , 17, 18.\u2212/\u2212TRAMP mice luminal CK8 cells mostly lacked Ki-67  with those from 30 wks old TRAMP mice (T30) representative of adenocarcinomas (ADC). A detailed description of samples used from microarray comparison is reported in Suppl. Figure 3To obtain a broad view of the transcriptional features distinctive of NE and adenocarcinoma lesions, we compared gene expression profiles of prostate samples collected from 18 weeks old OPN\u2212/\u2212TRAMP mice with NE tumor  were visualized as interaction networks using the Enrichment map plugin in Cytoscape  and synaptophisin , confirming the NE phenotype of anaplastic tumors arising in OPN\u2212/\u2212TRAMP mice. Upregulation at protein level of DDC and SYP in NE tumors was validated by western blot . Indeed 157 targets of Tgfb1 were listed as differentially expressed genes and 84 of them had an expression consistent with Tgfb1 pathway inhibition. This finding was supported by the significant down-regulation of Tgfb1 in OPT-tm (FDR=0.005), although this gene was excluded from the list of differentially expressed genes because of a fold-change of \u22121.53. Moreover, Filamin A (FLNA), a key TGF\u03b2 activator [IPA predicted ctivator , was amoTgfbr2 and Tgfbr3 transcripts were significantly down-regulated in OPT-tm, whereas Tgfbr1, which is responsible for SMADs phosphorylation and activation, was up-regulated. As protein levels of TGFbRI and TGFbRII were comparable between OPN\u2212/\u2212TRAMP NE tumors and TRAMP adenocarcinoma (not shown), we focused on proteins downstream the TGF\u03b2 pathway, particularly Smad2 and Smad3, which are crucial mediators of TGF\u03b2 activity in PCa [Smad3 was down-regulated in GEP and in western blot in NE tumors from OPN\u2212/\u2212TRAMP mice  and from OPN\u2212/\u2212 TRAMP mice of 15 (n = 5) or 18 (n = 9) wks of age  all devoid of US-detectable lesions , indicating that at the time of sacrifice they were likely bearing a developing NE tumor, well before any possible diagnosis. The second cluster contained 17 samples, hereafter called Early-ADC, whose gene expression profile was similar to that of TRAMP adenocarcinomas. All early samples from TRAMP (T18) and from OPN\u2212/\u2212 TRAMP mice, without NE features, fell into this cluster. To identify early markers specific for NE tumor a comparison between Early-NE and Early-ADC GEPs was performed. We found that all the 184 differentially expressed genes (absolute fold change \u2265 2 and FDR < 5%), were upregulated in the Early-NE group  and Early-ADC samples , a cytoskeletal SMAD-binding protein, binds SMAD2 for effective TFG\u03b2 receptor signaling; accordingly, FLNA-deficient melanoma cells have impaired TGF\u03b2 signaling . In OPN\u2212 pathway  and its  pathway . Accordi pathway . OverallEarly-NE vs Early-ADC tissues identified 184 genes that were all up-regulated in prostates from OPN\u2212/\u2212TRAMP at the onset of the still undetectable NE tumors, and that might contain possible biomarkers for early diagnosis.Nested class comparison between \u2212/\u2212TRAMP as a reliable model for human NE prostate cancer came from the GSEA analysis on Beltran dataset of PCa patients [\u2212/\u2212TRAMP mice. Common were the genes belonging to canonical pathway related to cancer, neuronal development, cell growth and cell cycle progression.The validation of OPNpatients . Indeed,Modification of the genetic background has been found to change the frequency of NE tumors in TRAMP mice , suggest+/\u2212) and screened according to [tm1BlhSpp1/J (OPN\u2212/\u2212) mice were purchased from Jackson Laboratories and intercrossed to TRAMP mice, in order to obtain congenic B6.tgN (TRAMP)8247 Ng Spp1<tm1Blh>/J (OPN\u2212/\u2212TRAMP). Female mice heterozygous for Tag (TRAMP+/\u2212) and OPN\u2212/\u2212 were bred with male OPN\u2212/\u2212 mice to obtain experimental OPN\u2212/\u2212TRAMP+/\u2212 mice, which were genotyped for Tag expression [TRAMP mice (C57BL/6-tgN (TRAMP)8247 Ng) were kindly provided by Dr. Vincenzo Bronte , under agreement with Dr. Norman Michael Greenberg . TRAMP mice were maintained heterozygous . Alternatively, after re-hydratation and antigen retrieval, immunohistochemistry was performed using the streptavidin-biotin-peroxidase complex method, and 3,3\u2032-Diaminobenzidine tetrahydrochloride as chromogenic substrate. Primary antibodies were: Ki67 , N-cadherin , Laminin , Androgen Receptor  Synaptophysin , SV40 Tag , OPN (AbCam). Slides were analyzed under a Leica DM2000 optical microscope equipped with a Leica DFC320 digital camera .Sections were incubated with primary antibody anti Ki67 o/n at 4\u00b0C, then washed in PBS and incubated for 1h with an Alexa-488 anti-rabbit antibody. Slides were then incubated with anti CK8 or anti p63 antibodies (Abcam) for 1h, washed and further incubated with Alexa-568 anti-mouse antibody. Sections were counter stained with DAPI and analyzed with a Microradiance 2000  confocal microscope equipped with Ar (488 nm), HeNe (543 nm) and red laser diode (638 nm) lasers. Confocal images (512 \u00d7 512 pixels) were obtained using a x200, 0.5 NA Plan Fluor DIC or x600 1.4 NA oil immersion lens and analyzed using ImagePro 7.0.1 software.Prostates were lysed with TRIzol  and RNA was purified by phenol/chloroform extraction followed by loading onto RNeasy MINI kit . On-column DNAse treatment was performed. RNA purity and yield was assessed using NanoDrop ND-100 Spectrophotometer .Gapdh (Mm99999915_g1), Ccne2 (Mm00438077_m1), Ccnd1 (Mm00432359_m1), E2f2 (Mm00624964_m1), Ddc (Mm00516688_m1), Syp (Mm00436850_m1). Expression values were normalized to internal control (Gapdh) and to control sample (TRAMP prostate) calculating the \u0394\u0394CT.RNA was Reverse Transcribed using High Capacity cDNA Reverse Transcription Kit (Applied Biosystems). RT-qPCR reaction was prepared using TaqMan (R) Fast Universal PCR Master Mix and run on a 7900 HT Fast Real-time PCR System  as described previously . The fol\u2212/\u2212TRAMP tumors were lysed, run on a 4-12% Bis-Tris Gel (Invitrogen) and transferred on a NC membrane . Primary antibodies against Smad3, Smad2, phospho Smad2, phospho Smad3, Filamin, DDC and Syp were from Cell Signaling Technology, against \u03b2-actin from SIGMA Aldrich. Secondary HRP antibodies were goat anti-rabbit and rabbit anti-goat (Invitrogen). Densitometric analysis was performed using the ImageJ 1.48v software (http://imagej.nih.gov/ij).Ten sections of 10 mm from frozen samples of TRAMP or OPNn = 4), with null or minimal disease, from 30 wks old TRAMP mice  in which adenocarcinoma was palpable and detectable by US, from OPN\u2212/\u2212TRAMP mice of 15 or 18 wks of age  without any detectable lesion and from 18 wks old OPN\u2212/\u2212TRAMP mice with detectable NE tumor mass . A detailed description of samples used for microarray comparison is in Suppl. Figure 3We collected prostates from 18 wks old TRAMP mice . Significantly enriched gene sets (p < 0.001 and FDR< 0.05) were visualized using Cytoscape v2.8.3 and the Enrichment Map plugin [www.qiagen.com/ingenuity).Differentially expressed genes between classes were identified using the  package . P-valueis (GSEA ) was appp plugin . Functiot-test was used for comparison of quantitative variables. Association between categorical variables was carried out using Fisher's exact test. Log-Rank test was applied for survival curves. All statistical tests were two-sided and a p-value <0.05 was considered significant.We used GraphPad Prism software . Student's"}
+{"text": "Relatively little attention has been paid to asthma in elderly (AIE) subjects. Our goal is to describe the comorbidities in an Argentinean old population with asthma.An observational descriptive study was performed at five different health care facilities in Buenos Aires. Clinical records during three months of 2014 were searched. Allergists reviewed all clinical histories and elderly was defined as older than 60 years. We evaluated the presence of comorbidities in old patients diagnosed with asthma.Total 152 patients were included and their average age (SD) were 66.83 years (6.52), 73% women, 78% Caucasian and 22% Hispanic. Arterial hypertension was the most frequent comorbidity (27%), followed by chronic rhino sinusitis (14%), RGE (10%), diabetes (5%) and obesity (5%). Other comorbidities were also searched, but they were only found in a few patients, such as eosinophilia esophagitis, nasal polyps, dyslipemia, coronary heart disease and pulmonary hypertension. Specifically with respect to allergic comorbidities, patients presented mainly chronic rhino sinusitis , and seasonal ( 16%) and perennial rhinitis (16%), or both chronic rhino sinusitis and perennial rhinitis simultaneously (18%). Only a few patients exhibited chronic rhino sinusitis and seasonal rhinitis . Considering the well-known association between allergic rhinitis and early-onset asthma (EOA), we observed that most of the patients with EOA exhibited allergic rhinitis , but we also observed that half of the patients with long-onset asthma (48%) presented chronic rhino sinusitis or allergic rhinitis.Understanding comorbidities associated with AIE may identify at-risk patient populations, improve disease management, and guide treatment advances."}
+{"text": "To the Editor:Emmonsia spp., dimorphic fungi found worldwide, cause disease mainly among lower-order mammals   and Histoplasma capsulatum (patient 2). Co-infection with Mycobacterium avium (patients 1 and 2) and M. tuberculosis (patient 2) was observed  (The fungal isolates were not identified molecularly before patients 1 and 2 died. Sequencing of the ribosomal DNA internal transcribed spacer region of isolates from all 3 patients showed 97%\u201399% homology with the previously described novel Emmonsia spp. to Histoplasma spp., the antifungal minimum inhibitory concentrations of emmonsia reported thus far (The patients in our study received an initial misdiagnosis. Kenyon et al. (Emmonsia sp. probably extends throughout southern Africa. Of the 13 previously reported patients (Although HIV-associated emmonsiosis was suggested to be geographically isolated to the Western Cape Province, South Africa (Laboratory results, culture results, treatment summaries, and images for patients with disseminated HIV-associated emmonsiosis in Johannesburg, South Africa."}
+{"text": "New functional and metabolic imaging techniques may provide the ability to assess biological changes that act as indicators of therapy response ,2. Partib factors (0\u2013800 s/mm2) and ADC were obtained. The average ADC values for each lesion were analyzed in comparison between pre- and post-treatment.This prospective, double arm, randomized study with EBRT serving as control arm, received IRB approval. 36 consecutive patients  with painful bone metastases were enrolled. 18 patients underwent MRgFUS treatment, using ExAblate 2100 system (InSightec), and 18 patients underwent EBRT. Pain palliation was evaluated by visual analog scale (VAS), pain questionnaires and changes in the patients\u2019 medication. All patients underwent 3T ce-MRI  before treatment and at 1, 2, and 3 months afterward. MRI protocol included DWI sequences with five No treatment-related adverse events were recorded for both arms. Statistically significant difference between baseline and follow-up VAS values and medication intake for both MRgFUS and EBRT patients (p<0.05) was noted. DWI showed substantial increase in mean ADC values after treatment for both MRgFUS  and EBRT ; there were no significant statistical differences in ADC shift following between MRgFUS and ERBT (p>0.5). Progressive decrease in VAS values positively correlated to an increase in mean ADC values (p>0.01) for both treatment modalities (Tables DW-MRI with ADC is a viable option for assessing tumor response to MRgFUS therapy for bone metastases. The increase in mean ADC values of ablated bone metastases could reflect pathophysiologic alterations that occur after ablative therapy . It is t"}
+{"text": "Chest physiotherapy is frequently provided to ICU patients but its role remains questionable. Intrapulmonary percussive ventilation physiotherapy with assisted autogenic drainage (IPV-AAD) is an emerging form of chest physiotherapy designed to enhance clearance of endobronchial secretions whilst enhancing alveolar recruitment.To evaluate the effect of IPV-AAD on the occurrence of Gram-negative (GN) ventilator-associated tracheobronchitis (VAT) or pneumonia (VAP).6 CFU/mL of a true GN pathogen from an endotracheal specimen or at least 104 CFU/mL from bronchoalveolar lavage fluid. Statistical analysis used non-parametric tests for independent samples and Fisher exact test to compare treatment groups.Consecutive patients admitted to a mixed medicosurgical ICU were eligible for study enrolment if they required oral intubation and mechanical ventilation for at least 48h. Patients who at outset presented any pulmonary infiltrate(s) were excluded. Patients were randomly assigned to receive either IPV-AAD, conventional physiotherapy (CPT) or no physiotherapy (NPT). CPT consisted of expiratory chest wall vibrations, positioning, rib-springing, aerosol therapy, and airway suctioning. The NPT group underwent mobilization, aerosol therapy and tracheobronchial aspiration. Standard institutional VAP precautions were guaranteed in all patients. IPV-AAD and CPT were performed by 2 dedicated and skilled respiratory therapists. Sessions were delivered twice daily for 20 min on a 24/7 basis. VAT and VAP were diagnosed according to established criteria (1). Study endpoint was clinically documented VAT or VAP plus a quantitative bacterial culture of at least 10Forty-five patients  were enrolled with 15 subjects included in each study arm. IPV-AAD patients were younger (46 \u00b1 17 years) than CPT (62 \u00b1 18 years) and NPT (64 \u00b1 16 years) subjects  but APACHE II scores were comparable between groups . GN VAT or VAP was diagnosed in 2 patients (13%) in the IPV-AAD group, 7 patients (47%) in the CPT group and 7 patients (47%) in the NPT group . Time from start of the study till VAT/VAP diagnosis ranged from 3 to 11 days. Survival was not different between groups.In this small patient cohort, adjunctive IPV-AAD tended to decrease the incidence of ventilator-associated GN infection as compared with conventional or no chest physiotherapy."}
+{"text": "Drosophila NURF (Nurf301/Enhancer of Bithorax (E(bx)) has defined NURF as a critical regulator of homeotic, heat-shock and steroid-responsive gene transcription. It has been speculated that NURF controls pathway specific transcription by co-operating with sequence-specific transcription factors to remodel chromatin at dedicated enhancers. However, conclusive in vivo demonstration of this is lacking and precise regulatory elements targeted by NURF are poorly defined. To address this, we have generated a comprehensive map of in vivo NURF activity, using MNase-sequencing to determine at base pair resolution NURF target nucleosomes, and ChIP-sequencing to define sites of NURF recruitment. Our data show that, besides anticipated roles at enhancers, NURF interacts physically and functionally with the TRF2/DREF basal transcription factor to organize nucleosomes downstream of active promoters. Moreover, we detect NURF remodeling and recruitment at distal insulator sites, where NURF functionally interacts with and co-localizes with DREF and insulator proteins including CP190 to establish nucleosome-depleted domains. This insulator function of NURF is most apparent at subclasses of insulators that mark the boundaries of chromatin domains, where multiple insulator proteins co-associate. By visualizing the complete repertoire of in vivo NURF chromatin targets, our data provide new insights into how chromatin remodeling can control genome organization and regulatory interactions.NURF is a conserved higher eukaryotic ISWI-containing chromatin remodeling complex that catalyzes ATP-dependent nucleosome sliding. By sliding nucleosomes, NURF is able to alter chromatin dynamics to control transcription and genome organization. Previous biochemical and genetic analysis of the specificity-subunit of  In eukaryotes DNA is folded and compacted into manageable units by wrapping around a protein spool of histone proteins to form nucleosomes. By varying the position and dynamics of nucleosomes using energy-dependent chromatin remodeling enzymes, genes can be selectively turned off or on in cells, controlling development and cellular function. Distinct sub-families of ATP-dependent chromatin remodeling enzymes have been characterised. However, their specific nucleosome targets in the genome and how they are recruited to these are not completely defined. Here we have identified nucleosome targets of the conserved higher eukaryotic chromatin remodeling enzyme NURF. Our data indicate three distinct functions for NURF during transcription. NURF organizes nucleosome positions at gene enhancer elements to regulate transcription initiation, but is also required to maintain nucleosome position downstream of the transcription start site of active genes. In addition, we detect NURF remodeling and recruitment at distal insulator sites that are required for functional organisation of the genome. We postulate that NURF function at insulators as well as promoters reflects functional interaction between distant insulators and active promoters, with functional clustering of regulatory elements providing a solution to how chromatin remodeling enzymes engage multiple targets in the genome. The organization of DNA in nucleosomes has a major function in controlling accessibility of DNA to the protein complexes that process genetic information. By altering nucleosome dynamics, targets for the transcription, replication and repair machineries can be rendered inaccessible or made available. A number of mechanisms exist by which chromatin states can be altered. Post-translational modification of the histone tails (HPTMs) can change associations between histones and DNA, altering chromatin flexibility and conformation (reviewed in Tessarz and Kouzarides ). Howevenucleosome remodeling factor (NURF) is one of the founding members of this family. Although chromatin remodeling complexes based on ISWI type catalytic subunits are present in all metazoa, NURF is an innovation of the bilateria. NURF complexes are built around a large, bilaterian-conserved, NURF-specific subunit, in Drosophila Nurf301/Enhancer of bithorax (E(bx)), in humans BPTF (Bromodomain and PHD finger Transcription Factor) [Nurf301/E(bx) were initially identified as regulators of the bithorax-complex [The imitation switch (ISWI) family of ATP-dependent chromatin remodeling factors mediate energy-dependent nucleosome sliding , 4. The  Factor) , 6. Like Factor) , 6, allo-complex , and sub-complex \u20139.Current models for NURF function propose activity at defined enhancers leading to regulation of a restricted set of gene targets. We and others have shown that Nurf301/E(bx) can directly interact with sequence-specific TFs that include the GAGA factor (Trithorax-like (Trl)), ecdysone receptor (EcR), and the repressor Ken , 8, 9, sNurf301E(bx) mutants [The core promoter regulates transcription initiation by serving as the recognition site for the basal transcription apparatus and determines specificity for upstream enhancers. In bilateria marked diversification of core promoter architecture occurs, with complexes including the canonical TATA-binding protein (TBP) containing complex TFIID, as well as complexes containing TBP-related factors (TRFs) such as the DREF/TRF2 complex, binding distinct core sequences \u201312. Prev mutants , suggestDrosophila based on enhancer blocking function which can be mediated by combinations of three DNA-binding proteins\u2014Boundary Element Associated Factor (BEAF), CCCTC-Binding Factor (CTCF) and Suppressor of Hairy wing (Su(Hw))\u2013and two associated proteins, Centrosomal Protein 190 (CP190) and Modifier of mdg4 (Mod(mdg4)) [In turn, intra- and inter-chromosomal communication between the core promoter and enhancer regions can be controlled by insulator elements. These were first defined in d(mdg4)) .in vivo nucleosome targets of a metazoan chromatin remodeling enzyme. Our data indicate NURF action at three distinct transcription regulatory elements. In addition to upstream enhancer elements, we identify a novel function of NURF in orchestrating nucleosome spacing downstream of the +1 nucleosome on active genes regulated by DREF/TRF2. Moreover, we also detect NURF remodeling and recruitment at distal insulator sites, where NURF interacts with DREF and known insulator proteins including CP190 to establish nucleosome-depleted domains.To provide an unbiased assessment of regulatory elements at which NURF acts, we have used whole genome MNase-sequencing to map at base pair resolution nucleosomes that require NURF for positioning. In parallel, we have used chromatin immunoprecipitation sequencing (ChIP-Seq) of the Nurf301/E(bx) specificity subunit to identify sites of stable recruitment of NURF. To our knowledge this is the first comprehensive base pair resolution map of Drosophila WT and NURF deficient primary macrophages (hemocytes). As a first step normalized tag densities of uniquely-mapped reads were determined in a sliding 50 bp window across the genome and log2 fold changes between mutant and wild-type (WT) were used to define regions of altered read densities, we term shifts. Using this approach, we identified 47,000 shifted nucleosomes in Nurf301/E(bx) deficient larval hemocytes. Assuming an averaged female Drosophila genome size of 175 Mb [To identify sites of NURF activity in the genome we profiled nucleosome distribution in f 175 Mb , this coThe distribution of NURF nucleosome shifts relative to known gene features was then determined. Consistent with the hypothesis that NURF regulates transcription by remodelling enhancer nucleosomes, we observed significant enrichment of nucleosome shifts on 5\u2019 regulatory elements and under-representation on coding exons and gene bodies , S2 Fig.Nurf301/E(bx) mutant backgrounds, nucleosomes that require NURF to maintain position could be discriminated. The validity of this mapping procedure was confirmed by analysing nucleosome positions on heat-shock loci, the targets originally used to identify NURF [Nurf301/E(bx) mutants this nucleosome position was not maintained and new nucleosome positions were detected  mutants corresponded to sites of NURF localisation determined by ChIP-seq. Nurf301/E(bx) ChIP peaks were ordered according to strength of associated signal, and sub-divided into quintiles from highest (1st) to lowest (5th) Nurf301/E(bx) signal. Analysis of nucleosome position flanking these sites demonstrated consistent changes in nucleosome position in Nurf301/E(bx) mutants (Nurf301/E(bx) mutant hemocytes. Analysis of expression of 667 genes that have assigned GO (gene ontology) molecular functions related to chromatin and transcription  mutants these positions were lost and chromatin flanking the site was more accessible, suggesting these TFs potentially could tether NURF to mediate directional nucleosome sliding. In contrast, class IV predicted TF-binding sites, exemplified by Trl (Nurf301/E(bx) mutants. The final mode was observed flanking consensi for DNA-binding proteins including Su(Hw) (Nurf301/E(bx) mutants.Predicted binding sites for class I TFs were independent of NURF and located within nucleosomes, . Bindingd by Trl , were log Su(Hw) . BindingNurf301/E(bx) mutants  mutant backgrounds. This showed the expected nucleosome distribution in WT samples with a nucleosome-depleted region flanking the TSS, a well-positioned +1 nucleosome and a regular downstream array of nucleosomes (Nurf301/E(bx) mutants, a superficially similar distribution was observed, with a regular array of nucleosomes downstream of the TSS. However absolute nucleosome position was shifted towards the TSS for the first six nucleosomes following the TSS (+1 to +6 nucleosome positions).However, NURF function was not restricted to remodelling nucleosomes at enhancers. Our initial comparative analysis of nucleosome tag densities detected potential nucleosome shifts not only upstream but also downstream of the TSS . To elucleosomes . In NurfNurf301/E(bx) mutants (Nurf301/E(bx) mutants were propagated over the next five nucleosomes after which the nucleosome array reset and limited differences between mutant and WT arrays were observed.This analysis included both active and inactive TSSs. To discriminate if NURF differentially affected transcriptionally active versus inactive promoters, we categorized active and inactive TSSs in hemocytes by profiling the hemocyte distribution of the H3K4me3 HPTM, which decorates the +1 nucleosome of active genes . ProfiliCG10699 gene showed a 10 bp change in position of the +1 nucleosome in Nurf301/E(bx) mutants  mutants. In contrast, on inactive genes, the extrapolated WT average nucleosome repeat length of 185 bp was unchanged in Nurf301/E(bx) mutants. Similar analysis of nucleosome positions at other genomic regions, for example flanking exon-intron boundaries, also showed no change in nucleosome spacing in Nurf301/E(bx) mutants. Taken together we conclude that NURF has a specific nucleosome positioning and spacing function downstream of active TSSs.Calculating average nucleosome repeat length downstream of the TSS on active and inactive genes in both genetic backgrounds showed that nucleosome repeat length on active genes decreased from 175 bp in WT samples to 170 bp in Nurf301/E(bx) mutant hemocyte gene expression levels were determined by Affymetrix microarray profiling. TSSs were binned into quintiles based on normalized WT transcript level from high (1st) to low (5th), and averaged nucleosome position flanking TSSs of each quintile determined in both backgrounds. We observed that, while the WT +1 nucleosome dyad location was shifted downstream as expression level increased (from +125 bp in the lowest expression quintile to +136 bp in the highest quintile), for all quintiles +1 nucleosome positions were relocated towards the TSS in Nurf301/E(bx) mutants  mutants. Surprisingly, real-time RT-PCR (Nurf301/E(bx) mutant hemocytes. Furthermore, using whole genome expression profiles to categorize TSSs with increased or decreased expression in Nurf301/E(bx) mutants, and profiling averaged nucleosome densities flanking the corresponding TSSs, indicated that only TSSs up-regulated in Nurf301/E(bx) mutants demonstrated signature NURF-dependent +1 nucleosome shifts  mutants. This showed clear NURF activity on promoters containing DREs and Ohler motifs 1, 5, and 7 (Nurf301/E(bx) mutants. NURF activity on DREF-dependent promoters was confirmed by comparison of Nurf301/E(bx) and published DREF ChIP-Seq profiles [We demonstrated a specific NURF nucleosome spacing function downstream of active TSSs. To discriminate if NURF promoter targeting was mediated by core promoter components we classified TSSs based on associated core promoter elements. Nucleosome organisation flanking these distinct categories of TSSs was then determined in WT and 5, and 7 , S7 Fig,profiles . HeatmapNurf301/E(bx) mutants  mutants  ChIP-Seq profiles revealed NURF localisation to isolated elements that corresponded to previously defined insulator elements, including the Fab8 and Mcp boundaries in the bithorax complex . This coNurf301/E(bx) mutants, nucleosome-depleted domains at CP190-containing insulator sites were reduced in size and nucleosomes repositioned. Consistent with the discriminating role of CP190, reciprocal co-immunoprecipitation revealed that NURF and CP190 were physically associated in S2 cell extracts  and BEAF  showed textracts .Nurf301/E(bx) mutants, nucleosome-depleted domains at DREF-containing insulator sites were reduced in size. Consistent with DREF action at insulators, co-immunoprecipitation showed that the DREF/TRF2 subunit Wash and CP190 were physically associated in S2 cell extracts  and CP190 at insulator elements in the bithorax complex  and predextracts . In addiextracts , a hallmin vivo was confirmed using the known enhancer blocking function of gypsy retrotransposons. These contain binding sites for Su(Hw), which can recruit insulator components to establish a functional insulator. When integrated between the wing enhancer and promoter of the cut gene in the ct6 mutation, gypsy elements suppress ct wing expression and disrupt the adult wing margin. This normally is decorated with approximately 90 mechanosensory bristles. Loss of bristles in ct6 mutants can be used as a sensitive assay for gypsy insulator function. In the absence of other mutations ct6 alleles reduce mechanosensory bristle number to 14  , 25, sug domains . Consist domains , and inv domains .Finally, as Nurf301/E(bx), DREF and CP190 colocalize at insulators, and Nurf301/E(bx) and DREF also overlap at active promoters, we tested whether insulator components may also be similarly localized to active promoters. Comparison of CP190 and Nurf301/E(bx) ChIP-Seq profiles in S2 cells reveals that CP190 was present at TSSs. However, CP190 was only detected on active genes .CP190 binding to both active promoters and distant insulator elements resembles the reported association of TAF3 with CTCF that mediates looping between distal enhancer elements and the proximal promoter , raisingin vivo targets and mechanisms by which ATP-dependent chromatin remodelling activity is deployed. Here we have used mononucleosome mapping of WT and Nurf301/E(bx) mutant cells to discriminate nucleosomes remodelled by NURF in vivo. We detect interactions with transcription factors and insulator components that direct NURF activity to both gene promoters and distant regulatory elements. To our knowledge this is the first comprehensive base pair resolution map of in vivo nucleosome targets of a metazoan chromatin remodeling enzyme. Our data indicate NURF remodelling occurs at discrete sites in the genome, but we speculate that by mediating local chromatin reorganization NURF can profoundly impact genome organization and long-range regulatory interactions.Modulation of nucleosome dynamics by ATP-dependent chromatin remodelling enzymes has the potential to regulate all chromatin templated reactions. Key to understanding functions in diverse processes ranging from transcription to repair and replication is to elucidate Drosophila ISWI abundance [Nurf301/E(bx) mutants [Nurf301/E(bx) mutants suggest more localized effects on nucleosome positioning [A central question in the ATP-dependent chromatin remodelling field is whether remodelers are highly abundant, affecting all nucleosomes and genome function generally, or more restricted factors that are recruited to discrete sites to regulate specific nuclear processes. Early estimates of bundance , and dis mutants , 27, weritioning . Data geitioning .Nurf301/E(bx) mutants. Nevertheless, these results are broadly consistent with in vitro experiments demonstrating for example how GAL4 provides a \u201cbarrier\u201d that competes with nucleosomes for occupancy at DNA targets [NURF targets defined here include upstream enhancers, consistent with the original isolation of NURF as a TF cofactor and initial transcriptome analysis \u20139, 17. O targets , 30 or,  targets .Nurf301/E(bx) mutants.However, our data reveal an additional nucleosome spacing function for NURF downstream of active TSSs including house-keeping targets of TRF2/DREF. The consequences of this are distinct from remodelling at enhancers, which mediates high-level changes in transcription of specific developmental/signal transduction pathways, instead exerting a general dampening effect on active gene transcription. Our data indicate that NURF shifts nucleosomes in the 3\u2019direction away from the TSS, similar to yeast ISW1b and CHD1 remodelers  and alsoNURF localisation and activity has parallels with yeast ISWI remodelling complexes, which show recruitment to TSSs but action on gene bodies , 36. We in vitro [Promoter localization of NURF is likely further stabilized by NURF binding HPTMs that decorate the +1 nucleosome , 39 but,in vitro . A precein vitro . It has in vitro . In our in vitro , 39.Nurf301/E(bx) mutants are not the consequence of loss of NURF ATP-dependent nucleosome-sliding activity, but rather that NURF acts stoichiometrically and non-catalytically at some sites, binding and physically occupying linker DNA in a manner incompatible with nucleosome formation. Changes in nucleosome position could thus potentially be due to the lack of NURF physical presence at some sites. The ability of remodelers to engage in either \u201ctraditional\u201d catalytic ATP-dependent nucleosome sliding versus and non-catalytic modes would allow diversification of remodeler function, and offer the potential that allosteric modulation (by for example histone modifications) could switch complexes between different modes of remodeling to program distinct local chromatin architectures. The use of strains containing catalytically inactive NURF induced by expressing mutant forms ISWI, in which ATPase activity is eliminated but complex assembly unaffected, could offer one approach to experimentally investigate this.It is formally possible that some changes in nucleosome positioning observed in Nurf301/E(bx) mutants. Indeed initial analysis of yeast remodeling enzymes required depletion of three remodeling enzymes  to observe substantial effects on nucleosome organisation [It is also important to consider that these experiments were performed in cells in which function of other remodeling complexes was unaffected. Systematic profiling of yeast chromatin remodeler distributions indicates overlapping domains of function. As such it is possible that NURF is functionally redundant with other chromatin remodeling enzymes . Thus, tnisation Nurf301/E(bx) mutants modify bithorax mutations and that Nurf301 corresponds to Enhancer of bithorax E(bx) [bithorax mutations are caused by gypsy transposons that bind Su(Hw) and act as ectopic insulators to disrupt expression. NURF remodeling at insulator elements is also consistent with results showing that NURF is required for Drosophila cell-based insulator/enhancer blocking assays [Finally, our data reveal that NURF interacts with the insulator elements and interacts with components including CP190 and DREF. Activity of NURF at insulators is consistent with our initial studies showing that ax E(bx) . The bitg assays . This apg assays  and integ assays .Interestingly, colocalization between Nurf301/E(bx) and insulator proteins is not only detected at distal insulator regions but also at active promoters. We postulate that overlap of insulator components and NURF at insulators as well as promoters reflects functional interaction between distant insulators and active promoters as has been speculated for CTCF at mammalian promoters , 47. It Nurf3012, Cp1901 and Cp1902 alleles were as described [Nurf3012 allele is an EMS-induced mutation that encodes a glutamine to stop codon substitution (aa 545) that truncates Nurf301 after the first PHD finger and which behaves genetically as a null allele. Unless stated flies were raised at 25\u00b0C.escribed , 48. TheNurf3012 mutant female third instar larvae as described previously [g for five minutes. Cells were washed three times with ice cold 1XPBS containing protease inhibitors and stored as pellets at -80\u00b0C until required.Third instar larvae were sexed and primary hemocytes collected from wild-type and eviously . BrieflyS2-DRSC cells were cultured at 25\u00b0C in Insect-XPRESS medium (Lonza) containing 10% FCS. S2 cells for standard ChIP were fixed with 1% formaldehyde and washed as described above.2 was added to a final concentration of 1 mM, 800U MNase (Worthington) added, and the sample incubated for 12 minutes at 16\u00b0C to liberate mononucleosomes. Digestion was stopped by adding an equal volume of Stop buffer (0.1 M Tris (pH 8.5), 0.1 M NaCl, 50 mM EDTA, 1% SDS) and samples centrifuged at 17,400g for 10 minutes to purify soluble chromatin. Formaldehyde cross-links were removed by addition of NaCl to 150 mM, one-tenth volume Proteinase K (Roche) and incubation at 65\u00b0C overnight. DNA was purified by phenol/chloroform extraction and ethanol precipitation, treated with RNase (Promega) at 37\u00b0C for 1 hour and then run on 2.2% recovery FlashGels (Lonza). Mononucleosomal DNA was pipetted from recovery wells in FlashGel Recovery Buffer and DNA subjected to further round of phenol/chloroform extraction and ethanol precipitation. Libraries were generated from two biological replicates for each genotype, sequenced, and reads pooled for nucleosome mapping.Hemocyte preparations from 1000 larvae were thawed, pooled and resuspended in buffer A (15 mM Tris (pH 7.4), 15 mM NaCl, 60 mM KCl, 0.34 M sucrose, 1 mM DTT, 25 mM sodium metabisulfite, 0.5 mM spermidine, 0.15 mM spermine). Cells were homogenized with a pellet pestle. CaClFor MNase-ChIP experiments, hemocytes from 1000 larvae were processed as above but soluble chromatin after Stop buffer addition was diluted in ChIP dilution buffer (16.7 mM Tris (pH 8.1), 167 mM NaCl, 1.2 mM EDTA, 0.1% SDS, 1.1% Triton X-100), and processed for ChIP as described below.3) for 15 minutes at room temperature. Cross-links were reversed as described above and ChIP DNA purified using 1.8 volumes Agencourt AMPure XP beads (Beckman Coulter). The following antibodies were used: rabbit anti-NURF301, rabbit anti-H3K4me3 , rabbit anti-CP190 [ChIP was performed as described in  with theti-CP190 . DNA forDrosophila genome (BDGP R5/dm3 Assembly) in color space using Bowtie [Drosophila genome (BDGP R5/dm3 Assembly) using the bioscope mapping tool (Life Technologies). Reads were then filtered for high quality reads where read quality was greater than 15 using Samtools [SOLiD reads for nucleosome mapping were mapped to the g Bowtie  and filtg Bowtie . To deteSamtools . ChIP peSamtools  and MACSSamtools . PublicaSamtools  were usew1118 and Nurf3012 wandering third instar larvae were staged using the blue-gut method and hemocytes isolated in batches of 50 larvae as described previously [http://www.R-project.org) and the gcrma and limma libraries of Bioconductor version 3.0 (http://www.bioconductor.org). Expression values were computed using gcrma [eviously , 38. mRNeviously , 38 and ng gcrma . Array dDrosophila S2 cells using a modification of the protocol of Wysocka and colleagues [2, 5% Glycerol, 0.5 mM DTT, 1 mM Sodium Metabisulphite, 1x Protease inhibitors ) for 1 hour on ice with gentle swirling. Extracts were clarified by centrifugation at 100,000 g for 1 hour at 4\u00b0C. SNF was dialysed against extraction buffer adjusted to 100mM KCl. Protein G-conjugated Dynabeads (Invitrogen) were blocked by incubation in blocking buffer ) and antibodies bound by incubation overnight at 4\u00b0C. SNF was diluted into bind buffer  incubated with antibody-coated Protein G-conjugated Dynabeads for 2.5 hrs with rotation at 4\u00b0C. Beads were washed four times, 10 minutes each, using wash buffer . Bound proteins were eluted by boiling in 1XSDS-PAGE sample buffer. 5% input run as a loading control for all IPs.Soluble nuclear fraction (SNF) was prepared from lleagues  to prepa2, 0.5mM CaCl2 0.1% Tween-20) containing the respective enzymes at 37\u00b0C for 10 minutes, followed by three further washes in wash buffer. Bound proteins were eluted as described above.Additional IPs were performed using soluble chromatin prepared according to the protocol of Wysocka and colleagues . Nuclei Antibodies used were rabbit anti-NURF301, rabbit anti-CP190 , mouse aFor confirmation of microarray expression data, mRNA was isolated from wild-type and mutant hemocytes using \u03bcMacs columns according to manufacturer\u2019s instructions  and reverse transcribed by Superscript II (Invitrogen) at 42\u00b0C. Primer sets used are listed in S1 Fig(A) Schematic illustrating a Hilbert plot. These are continuous space-filling curves in which one-dimensional data  is mapped in two dimensions allowing visualization of all data simultaneously. In this procedure a unit square is progressively divided into smaller quadrants and the one-dimensional line corresponding to each chromosome arm folded such that it passes through the center of each quadrant. The iterative folding has the advantage of allowing all data to points to be observed simultaneously and preserves locality, points that co-localize on the line typically co-map on the curve. In the example two features are plotted\u2014in red (closely juxtaposed arrays of peaks), and in green peaks that are well separated from their neighbours. When the entire chromosome arm is viewed as in a genome browser window, it is impossible to discriminate between these two features due to the low resolution of the whole chromosome arm view. However, if these features are plotted as a Hilbert plot, as the linear arm is folded through smaller and smaller quadrants resolution increases and it becomes possible to discriminate closely juxtaposed and well separated features. In this context, extended domains of nucleosome re-organization would result in clusters of shifts being detected as extended clusters/domains on the Hilbert plot. (B) Hilbert plots of NURF-dependent nucleosome shifts on all chromosome arms.(TIF)Click here for additional data file.S2 Fig(A) Distribution of nucleosome shifts relative to chromosome arms compared with genome average of features. (B) Promoter distribution of nucleosome shifts compared with genome average of features. (C) Gene body distribution of nucleosome shifts compared with genome average of features. (D) Distribution of nucleosome shifts downstream of terminators compared with genome average of features.(TIF)Click here for additional data file.S3 FigNurf301 mutation affects expression of transcription factors or chromatin regulators that could indirectly affect nucleosome organisation in Nurf301 mutant hemocytes GO Molecular Function assignments (Flybase) were used to identify 667 targets of interest. Venn diagram indicates respective sub-categories of molecular function. (B) Expression of this set of 667 genes was analysed in Nurf301 mutant hemocytes relative to control wild-type hemocytes. Eight genes display elevated expression in Nurf301 mutant hemocytes, twelve show reduced expression. Of these, nine are male-expressed genes and, as nucleosome profiles were analysed in female hemocytes, these could be excluded from the analysis. None of the remaining eleven genes have known functions in control of global chromatin organisation or nucleosome positioning suggesting that the effects of Nurf301 mutants on nucleosome organisation are unlikely to be mediated through indirect effects on expression of other factors. (C) No change in expression of transcription factors previously analysed for effects on nucleosome organisation was observed. Expression of selected genes previously identified to be up-regulated (up-regulated controls) or down-regulated (down-regulated controls) in Nurf301 mutant hemocytes are displayed as controls. Change in expression is listed as log fold change in Nurf301 mutant hemocytes relative to wild-type hemocytes.(A) To distinguish whether (TIF)Click here for additional data file.S4 FigDrosophila TFs Asense, BEAF, Biniou, Broad, Brinker, Caudal, Crocodile, Deformed, Engrailed, Ets were determined using MEME and averaged nucleosome probability plots flanking predicted TF sites generated for both wild type (WT) and Nurf301 mutant populations. Five categories of nucleosome organization around TF sites could be distinguished. Dyad position of the +1 nucleosome is labeled. (B) Averaged profile plots of predicted TF-binding sites relative to the TSS.(A) Predicted binding sites for (TIF)Click here for additional data file.S5 FigDrosophila TFs Ftz, Hr46, Mef2, Repo, Runt, Scute and Zerknult were determined using MEME and averaged nucleosome probability plots flanking predicted TF sites generated for both wild type (WT) and Nurf301 mutant populations. Five categories of nucleosome organization around TF sites could be distinguished. Dyad position of the +1 nucleosome is labeled. (B) Averaged profile plots of predicted TF-binding sites relative to the TSS.(A) Predicted binding sites for (TIF)Click here for additional data file.S6 FigNurf301/E(bx) mutants.To discriminate whether nucleosome profiles were affected by clustering of TF binding sites, sites for (A) Snail, (B) Antp, (C) Stat and (D) Su(Hw) were divided into those with at least 2 sites within 50 bp (clustered sites) or those that did not possess neighbouring sites (isolated). Averaged nucleosome probability plots flanking these sites generated for both wild type (WT) and (TIF)Click here for additional data file.S7 FigNurf301 mutants. (B) TSSs were categorized based on core promoter motifs associated with DREF/TRF2 targets, the DRE and Ohler Boxes 1,5,6,7,8. Averaged nucleosome probability plots flanking the TSS of each category generated for both wild type (WT) and Nurf301 mutants. Dyad position of the +1 nucleosome is labeled.(A) TSSs were categorized based on core promoter motifs associated with developmentally regulated transcripts, TATA-box, initiator (INR) element, TCT motif, Motif Ten Element (MTE) and the downstream core promoter element (DPE). Averaged nucleosome probability plots flanking the TSS of each category generated for both wild type (WT) and (TIF)Click here for additional data file.S8 FigNurf301 mutants at (A) all TSSs, and TSSs with (B) paused polymerase or (C) active not stalled polymerase. Dyad position of the +1 nucleosome is labeled.TSSs were categorized as stalled or active . Averaged nucleosome probability plots flanking the TSS were generated for both wild type (WT) and (TIF)Click here for additional data file.S9 FigNurf301 mutant hemocytes at all CTCF sites ordered according to CTCF signal. CP190 signal is shown for comparison. (B) Heatmap of nucleosomes in wild-type and Nurf301 mutant hemocytes at CTCF sites that contain CP190 ordered according to CP190 signal. CP190 and CTCF signal is shown for comparison. (C) Heatmap of nucleosomes in wild-type and Nurf301 mutant hemocytes at CTCF sites that lack CP190 ordered according to CTCF signal. CTCF signal is shown for comparison. Graph shows averaged nucleosome probability at CTCF sites that either contain (+CP190) or lack (-CP190) in wild-type and Nurf301 mutant backgrounds.(A) Heatmap of nucleosomes in wild-type and (TIF)Click here for additional data file.S10 FigNurf301 mutant hemocytes at all Su(Hw) sites ordered according to Su(Hw) signal. CP190 signal is shown for comparison. (B) Heatmap of nucleosomes in wild-type and Nurf301 mutant hemocytes at Su(Hw) sites that contain CP190 ordered according to CP190 signal. CP190 and Su(Hw) signal is shown for comparison. (C) Heatmap of nucleosomes in wild-type and Nurf301 mutant hemocytes at Su(Hw) sites that lack CP190 ordered according to Su(Hw) signal. Su(Hw) signal is shown for comparison. Graph shows averaged nucleosome probability at Su(Hw) sites that either contain (+CP190) or lack (-CP190) in wild-type and Nurf301 mutant backgrounds.(A) Heatmap of nucleosomes in wild-type and (TIF)Click here for additional data file.S11 FigNurf301 mutant hemocytes at all BEAF sites ordered according to BEAF signal. CP190 signal is shown for comparison. (B) Heatmap of nucleosomes in wild-type and Nurf301 mutant hemocytes at BEAF sites that contain CP190 ordered according to CP190 signal. CP190 and BEAF signals are shown for comparison. (C) Heatmap of nucleosomes in wild-type and Nurf301 mutant hemocytes at BEAF sites that lack CP190 ordered according to BEAF signal. BEAF signal is shown for comparison. Graph shows averaged nucleosome probability at BEAF sites that either contain (+CP190) or lack (-CP190) in wild-type and Nurf301 mutant backgrounds.(A) Heatmap of nucleosomes in wild-type and (TIF)Click here for additional data file.S12 FigNurf301 mutant hemocytes at Mod(mdg4)2.2 sites that contain CP190 ordered according to Mod(mdg4)2.2 signal. Mod(mdg4)2.2 and CP190 signals are shown for comparison. (B) Heatmap of nucleosomes in wild-type and Nurf301 mutant hemocytes at Mod(mdg4) sites that contain CP190 ordered according to Mod(mdg4) signal. CP190 and Mod(mdg4) signal is shown for comparison. (C) Heatmap of nucleosomes in wild-type and Nurf301 mutant hemocytes at Mod(mdg4) sites that lack CP190 ordered according to Mod(mdg4) signal. Graphs show averaged nucleosome probability at Mod(mdg4)2.2 and Mod(mdg4) sites that either contain (+CP190) or lack (-CP190) in wild-type and Nurf301 mutant backgrounds.(A) Heatmap of nucleosomes in wild-type and (TIF)Click here for additional data file.S13 FigNurf301 mutant hemocytes at CP190 sites ordered according to CP190 signal. (B) CTCF, Su(Hw), Mod(mdg4) signals are shown for comparison. (C) BEAF and Mod(mdg4)2.2 signal is shown for comparison. Graph shows averaged nucleosome probability at CP190 sites in wild-type and Nurf301 mutant backgrounds.(A) Heatmap of nucleosomes in wild-type and (TIF)Click here for additional data file.S1 TableList of primers used in RT-PCR analysis of gene expression levels.(DOCX)Click here for additional data file."}
+{"text": "GFP), we observed binding and internalization of MV-derived CD147 with HMCLs. Cells with greater CD147GFP internalization proliferated at a higher rate than did cells with less CD147GFP association. Lastly, MVs obtained from CD147 downregulated HMCLs were attenuated in their ability to stimulate HMCL proliferation. In summary, this study demonstrates the significance of MV shedding and MV-mediated intercellular communication on malignant plasma cell proliferation, and identifies the role of MV-enriched CD147 in this process.Multiple myeloma (MM) is characterized by the clonal expansion of malignant plasma cells within the bone marrow. There is a growing literature that tumor cells release biologically active microvesicles (MVs) that modify both local and distant microenvironments. In this study, our goals were to determine if MM cells release MVs, and if so, begin to characterize their biologic activity. Herein we present clear evidence that not only do both patient MM cells and human MM cell lines (HMCLs) release MVs, but that these MVs stimulate MM cell growth. Of interest, MM-derived MVs were enriched with the biologically active form of CD147, a transmembrane molecule previously shown by us to be crucial for MM cell proliferation. Using MVs isolated from HMCLs stably transfected with a CD147-GFP fusion construct (CD147 Multiple myeloma (MM) remains a largely incurable neoplasm defined by the presence of a clonal expansion of malignant plasma cells (PC) in the bone marrow (BM), \u22653 g/dL of monoclonal immunoglobulin , and the presence of end organ damage which may include lytic bone lesions . Monoclo2+) concentrations -thymidine (TdR) incorporation  were performed as previously described [DNA synthesis assays measuring [escribed .hi and GFPlo cell populations using the FACStar (BD Biosciences). Data were analyzed using FlowJo software .HMCLs were incubated in complete IMDM media containing 10 \u03bcM bromodeoxyuridine (BrdU) overnight prior to staining the next day using a BrdU-APC flow kit (BD Biosciences) as previously described . MV incoCD147 was assayed by a conventional sandwich based ELISA following the manufacturer's protocol . Captured CD147 was visualized and absorbance readings were made at 450 nm, using a 96-well EPOCH microplate spectrophotometer . CD147 levels in samples were determined by interpolation from a standard curve.Cells lysates were subjected to 10% SDS-PAGE and CD147 probing was performed as previously described . Blots wMVs were labeled with a PKH26 red fluorescent labeling kit  per manufacturer's instructions. ALMC-2 cells were stained for cytoplasmic Ig using FITC-conjugated polyclonal anti-human Ig (H+L) antibody (BD Biosciences) after fixing with 95% ethanol for 5 minutes. Slides were washed in PBS for 5 minutes prior to mounting with Vectashield containing DAPI  and viewed by confocal microscopy . Images were acquired using an Olympus DP71 microscope digital camera equipped with Olympus DP manager software .XhoI site while the reverse primer (5'-GTCCGCCAGAGGAACTCTT CCCGGGATCCATCA-3') was engineered to include a BamHI site to facilitate in-frame cloning into the pEGFP-N1 vector . The construct was validated by Sanger sequencing. To establish stable cell lines that permanently express the CD147-GFP fusion protein, the construct was linearized using the ApaLI restriction enzyme and then transfected into ALMC-2, RM43, and KP-6 cells by electroporation. Five days after transfection, GFP-expressing cells were sorted on an ARIA II FACS sorter (BD Biosciences). The expression of the fusion protein was validated by FACS analysis and Western blotting (data not shown).To generate the CD147-GFP fusion construct, the full-length CD147 isoform 1  cDNA , includiCD147/BSG siGenome siRNA duplexes were purchased from Dharmacon Research, Inc. . Transfection of the siRNA duplexes was achieved via electroporation as previously described , 55. Folp less than 0.05 were considered significant.Statistical analysis was performed using a Wilcoxon rank test. Values of"}
+{"text": "Liver transplantation (LT) in acetaminophen-induced acute liver failure (APAP-ALF) patients often presents significant challenges. The King's College Criteria (KCC) have been validated on admission but not in later phases of illness. The aim was to improve determinations of prognosis on and after admission in APAP- ALF patients using the classification and regression tree (CART) methodology to construct optimal binary splits on independent variables to predict outcome.n = 803) APAP-ALF patients enrolled between January 1998 and September 2013 with complete outcome data. Training data were used to build CART trees and test data were used to evaluate prediction accuracy (AC), sensitivity (Sn) and specificity (Sp).CART models were applied to US ALFSG registry data for prediction of 21-day spontaneous survival on admission and late stage (days 3 to 7). Analyses were carried out using R software (package rpart) for all (n = 679), KCC  yielded an AC of 69%  at admission. For late-stage data (n = 341), KCC provided similar AC (70%) and Sn (97%), but suffered poor Sp (15%). CART analysis using the KCC variables on admission offered predictive AC (66%) and Sn (65%), with increased Sp (67%). Using day 3 to 7 data, the KCC-CART model had increased AC (82%) and Sn (86%), with improved Sp (46%) compared with logistic KCC. New CART models were developed with 18 variables based on previous literature. A new CART model on admission  performed better than KCC-CART. For days 3 to 7, a CART model  offered superior prediction  compared with days 3 to 7 KCC-CART.Of the 803 APAP-ALF patients, the median age was 37 (29 to 47) years and 76% were female. A total of 238 (30%) patients were listed for and 87 (11%) received LT. A total of 531 (66%) patients recovered without LT at 21 days. Using standard logistic regression methods for all patients with complete data (CART analysis increased predictive performance compared with traditional KCC. KCC-CART trees have higher Sp and similar predictive AC compared with traditional KCC, with newer CART trees providing marginal improvement over KCC-CART models."}
+{"text": "Talaromyces marneffei in Non-AIDS Patients Given Monoclonal Antibodies against CD20 and Kinase Inhibitors . An addendum and reference have been added to the article online (http://wwwnc.cdc.gov/eid/article/21/7/15-0138_article).An additional case report publication was found after publication of Disseminated Infections with"}
+{"text": "Soilborne wheat mosaic virus (SBWMV) 19K protein is a cysteine-rich protein (CRP) and shares sequence homology with CRPs derived from furo-, hordei-, peclu- and tobraviruses. Since the hordei- and pecluvirus CRPs were shown to be pathogenesis factors and/or suppressors of RNA silencing, experiments were conducted to determine if the SBWMV 19K CRP has similar activities. The SBWMV 19K CRP was introduced into the Potato virus X (PVX) viral vector and inoculated to tobacco plants. The SBWMV 19K CRP aggravated PVX-induced symptoms and restored green fluorescent protein (GFP) expression to GFP silenced tissues. These observations indicate that the SBWMV 19K CRP is a pathogenicity determinant and a suppressor of RNA silencing.Amino acid sequence analyses indicate that the  Cucumber mosaic virus (CMV) 2b, the Tobacco etch virus (TEV) HC-Pro, and the Tomato bushy stunt virus (TBSV) P19 . The p26SBE-2 plasmid was digested with The author(s) declare that they have no competing interests.Jeannie Te did all cloning, plant inoculation experiments, gene silencing experiments. Ulrich Melcher did the amino acid sequence alignments and phylogenetic comparisons. Amanda Howard did some gene silencing experiments, photography. Jeanmarie Verchot-Lubicz conceived the study, did some molecular analysis, and wrote the paper. Special thanks to Wenpiny Qiu at Southwest Missouri State University for assistance with studies using TBSV to express the SBWMV 19k."}
+{"text": "Background: NDM/OXA-23 carbapenemase-producing Acinetobacter baumannii isolates have been reported worldwide, but rarely in the United States. A California acute-care hospital (ACH) A identified 3 patients with pan-nonsusceptible A. baumannii during May\u2013June 2020, prompting a public health investigation to prevent further transmission among the regional healthcare network. Methods: A clinical isolate was defined as NDM/OXA-23\u2013producing A. baumannii from a patient at ACH A or B, or an epidemiologically linked patient identified through colonization screening during May 2020\u2013January 2021. ACHs A and B are sentinel sites for carbapenem-resistant A. baumannii surveillance through the Antibiotic Resistance Laboratory Network (AR Lab Network), where isolates are tested for carbapenemase genes. The California Department of Public Health with 3 local health departments conducted an epidemiological investigation, contact tracing, colonization screening, and whole-genome sequencing (WGS). Results: In total, 11 cases were identified during May 2020\u2013January 2021, including 3 cases at ACH A during May\u2013June 2020, and 8 additional cases during November 2020\u2013January 2021: 5 at ACH A, 1 at ACH B, and 2 at skilled nursing facility (SNF) A. Isolates from ACHs A and B were identified through testing at the AR Lab Network. Of the 11 patients (including the index patient), 4 had exposure at SNF A, where 2 cases were identified through colonization screening. Screening conducted at ACH A and 5 other long-term care facilities (LTCFs) identified no additional cases. WGS results for the first 8 cases identified showed 2\u201313 single-nucleotide polymorphism differences. Antibiotic resistance genes for all isolates sequenced included NDM-1 and OXA-23. On-site assessments related to a COVID-19 outbreak conducted at ACH A identified infection control gaps. Conclusions: Hospital participation in public health laboratory surveillance allows early detection of novel multidrug-resistant organisms (MDROs), which enabled outbreak identification and public health response. A high COVID-19 burden and related changes in infection control practices have been associated with MDRO transmission elsewhere in California. This factor might have contributed to spread at ACH A and hampered earlier screening efforts at SNF A, likely leading to undetected transmission. Extensive movement of positive patients among a regional healthcare network including at least 6 ACHs and 7 LTCFs likely contributed to the prolonged duration of this outbreak. This investigation highlights the importance of enhanced novel MDRO surveillance strategies coupled with strong infection prevention and control practices as important factors in identifying outbreaks and preventing further transmission in regional networks.Funding: NoDisclosures: None"}
+{"text": "Weizmannia (Bacillus) coagulans (ProBC Plus) strain isolated from fermented rice is reported here. The complete genome analysis of the strain will be helpful in the future to combat multitudinous problems and will be helpful in providing insights regarding potential probiotic properties.The whole-genome sequence of a  Weizmannia coagulans LMG S-31876 (GenBank accession number MZ687045) (The strain was isolated from fermented rice samples and cultured in de Man-Rogosa-Sharpe (MRS) medium for 24 to 48 h at 37\u00b0C. The 16S rRNA gene region was amplified using the forward primer 27F 5\u2032 (AGA GTT TGA TCM TGG CTC AG) 3\u2032 and the reverse primer 1492R 5\u2032 (TAC GGY TAC CTT GTT ACG ACT T) 3\u2032. The gene was sequenced by the Sanger dideoxy sequencing method at Macrogen . The strain exhibited 100% similarity to Genomic DNA from a culture pellet was fragmented with the phenol-chloroform method  and sonide novo genome assembler SPAdes v3.15.5  quality control (QC) Toolkit, with a Phred quality score cutoff value of 20 for high-quality filtering . The highblA, hblB, hblC, and hblD), nonhemolytic enterotoxin (NHE) , and cytotoxin K (hemolysin IV) were not found. BLASTx comparisons were performed between the Weizmannia coagulans LMG S-31876 draft genome and biogenic-amine-producing protein sequences, and genes such as those for histidine decarboxylase (hdc), tyrosine decarboxylase (tdc), ornithine decarboxylase, agmatine dihydrolase (deiminase), and putrescine were absent (Weizmannia coagulans LMG S-31876 contained one confirmed CRISPR sequence (Weizmannia coagulans LMG S-31876 indicates that it meets probiotic safety criteria on the genome level.The genome was screened to determine putative virulence factors (with the Virulence Factor Database [VFDB] ), plasmie absent . CRISPRFsequence . AnalysiWeizmannia coagulans LMG S-31876 has been deposited in DDBJ/EMBL/GenBank under the accession number JANKOH000000000. The version described in this paper is the first version, JANKOH010000000. The raw sequence reads have been submitted to the NCBI SRA with accession number SRR21429472.The whole-genome shotgun sequence of"}
+{"text": "In 2020, the United States Preventive Services Taskforce recommended one-time Hepatitis C virus (HCV) screening for all adults aged 18-79. As the largest provider of HCV treatment in the US the Veterans Health Administration (VA) is committed to implementing these recommendations; thus, understanding perspectives of primary care teams towards this is critical.We disseminated a 24-item online survey to PCPs at the VA Greater Los Angeles Healthcare System (VAGLAHCS), serving 1.5 million Veterans within an area that spans five counties. Our sample included physicians, pharmacists, nurse practitioners, and physician assistants on primary care teams. Our survey contained questions on demographics, provider knowledge of HCV testing, practice patterns and beliefs, and preferences for new screening tools. Descriptive statistics were completed and we compared item responses across demographics. Hypothesis testing was performed using Wilcoxon rank sum test for continuous variables and Fisher\u2019s exact or Chi-square tests for categorical variables.In total, 107 PCPs responded to the survey (107/385=28% response rate), with 100 complete responses. Most respondents were women (63%) with median age of 42 years, physicians (53%), Internal Medicine-trained (47%), and of Asian descent (45%). A majority (59%) were aware of new screening recommendations. Most PCPs reported confidence (71%), intent (77%), and commitment towards (82%) HCV screening. Only 38% reported remembering to screen Veterans regularly. Physicians were most aware of new recommendations (73%), compared to pharmacists (55%) and nurse practitioners (42%). The most strongly preferred strategies to enhance screening included automatic test orders during physician visits (71%), automatic electronic-consults (68%), clinician reminders for HCV screening (57%), and opt-out phlebotomy (48%).In a sample of providers within a large and diverse VA, 3 in 5 PCPs were aware of new universal HCV screening recommendations. There is high motivation among PCPs to perform screening, but forgetting to screen is still common. Several strategies to augment universal HCV screening were acceptable towards PCPs.Debika Bhattacharya, MD, MSc, Gilead: Grant/Research Support|Regeneron: Grant/Research Support."}
+{"text": "On September 1, 2022, bivalent COVID-19 mRNA vaccines, composed of components from the SARS-CoV-2 ancestral and Omicron BA.4/BA.5 strains, were recommended by the Advisory Committee on Immunization Practices (ACIP) to address reduced effectiveness of COVID-19 monovalent vaccines during SARS-CoV-2 Omicron variant predominance  persons received positive test results . Among taVE of a bivalent booster dose received after \u22652 monovalent doses (compared with being unvaccinated) was similar among persons aged 50\u201364 years (28%) and \u226565 years (22%) but varied somewhat by number of previous monovalent vaccine doses . Among aAmong persons who received \u22652 monovalent vaccine doses, rVE increased with time since the most recent monovalent vaccine dose in all age groups . At 2\u20133 Among symptomatic adults who received testing for SARS-CoV-2 infection at pharmacies nationwide during September 14\u2013November 11, 2022, bivalent mRNA vaccines provided additional protection against infection compared with previous vaccination with 2, 3, or 4 monovalent vaccines alone. These are the first published estimates of VE for newly authorized bivalent mRNA booster vaccines. In this study, relative benefits of a bivalent booster compared with monovalent vaccine doses alone increased with time since receipt of last monovalent dose.Postauthorization immunogenicity studies have shown similar neutralizing antibody titers to BA.4/BA.5 after receipt of either a monovalent or BA.4/BA.5\u2013containing bivalent vaccine as a fourth dose (Waning VE with time since monovalent vaccine receipt has been observed during the Omicron-predominant period, with more rapid waning during the period when Omicron BA.4/BA.5 lineages predominated.This study evaluated aVE and rVE by number of previous monovalent doses received and generally found similar additional benefit of the bivalent vaccine regardless of the number of previous monovalent vaccine doses received, when controlling for time since receipt of the last monovalent dose. These findings support the current COVID-19 vaccination policy recommending a bivalent booster dose for adults who have completed at least a primary mRNA vaccination series, irrespective of the number of monovalent doses previously received.In the United States, >90% of adults have received \u22651 COVID-19 vaccine dose.The findings in this study are subject to at least six limitations. First, vaccination status, previous infection history, and underlying medical conditions were self-reported and might be subject to recall bias. In particular, if previous infection provides protection against repeat infection, then VE estimates in this study would likely be biased toward the null, because self-reported previous infection differed by vaccination status, and statistical power was not sufficient to stratify VE estimates by presence of previous infection. In addition, previous infection might have been underreported (In this study of immunocompetent persons tested at ICATT locations, bivalent booster doses provided significant additional protection against symptomatic SARS-CoV-2 infection during a period when Omicron variant BA.4/BA.5 lineages and their sublineages predominated. All persons should stay up to date with recommended COVID-19 vaccines, including bivalent booster doses, if it has been \u22652 months since their last monovalent vaccine dose (Monovalent mRNA COVID-19 vaccines were less effective against symptomatic infection during the period of SARS-CoV-2 Omicron variant predominance. In this study of vaccine effectiveness of the U.S.-authorized bivalent mRNA booster formulations, bivalent boosters provided significant additional protection against symptomatic SARS-CoV-2 infection in persons who had previously received 2, 3, or 4 monovalent vaccine doses. Due to waning immunity of monovalent doses, the benefit of the bivalent booster increased with time since receipt of the most recent monovalent vaccine dose. All persons should stay up to date with recommended COVID-19 vaccinations, including bivalent booster doses for eligible persons."}
+{"text": "Fig.\u00a01). By early June, COVID-19 hospital bed and intensivecare unit (ICU) bed occupancy in the capital of Ulaanbaatar exceeded total capacity. This impacted both health-care delivery for COVID-19and other essential health services. At its peak, 2746 new cases (18 June 2021) and 17deaths (3 July 2021) were reported in a single day, totalling 166 145 cases and 812deaths as of 1 August 2021. (At the beginning of the coronavirus disease 2019 (COVID-19) pandemic, Mongolia took earlyand stringent response measures that were considered successful until early 2021.  clinical management guidelines recommend that COVID-19care pathways be established at the national, subnational and local levels to treatpatients in the right settings according to disease severity and risk.  such as restrictionson business operation and interprovincial movement were introduced from mid-June 2021.To increase care capacity, 1947 additional beds were mobilized by mid-June includingapproximately 100 additional ICU beds and newly established intermediate facilities andtreatment centres in Ulaanbaatar. Intermediate facilities with oxygen supplies andtemporary ICU beds accommodated primarily non-severe patients with risk factors forsevere disease and severe patients who needed oxygen, while treatment centres providedcare for severe and critical patients. Severe patients in intermediate facilities werereferred to treatment centres as bed availability and their condition allowed. Despitethese measures, bed occupancy was rapidly overwhelmed. By 14 June, 33 deaths werereported among patients with severe disease monitored at home who rapidlydeteriorated.Fig.\u00a03). , including health-care capacity to inform proactive policydecisions and adaptations to health-care pathways. ("}
+{"text": "Scientific Reports 10.1038/s41598-022-23037-8, published online 11 November 2022Correction to: The original version of this Article contained an error in the Acknowledgements section. The name of the university was incorrect.\u201cAif University Researchers Supporting Project number (TURSP\u20142020 /19), Taif University, Saudi Arabia.\u201dnow reads:\u201cTaif University Researchers Supporting Project number (TURSP\u20142020 /19), Taif University, Saudi Arabia.\u201dThe original Article has been corrected."}
+{"text": "We also performed in vitro studies to verify the effects of GSP on neuronal protection and microglial polarisation and their potential mechanisms. We found that GSP regulated microglial polarisation and inhibited apoptosis in PC12 cells induced by M1-BV2 cells through the Toll-like receptor 4- (TLR4-) mediated nuclear factor kappa B (NF-\u03baB) and phosphatidylinositol 3-kinase/serine threonine kinase (PI3K/AKT) signaling pathways. This suggests that GSP regulates microglial polarisation and prevents neuronal apoptosis, possibly by the TLR4-mediated NF-\u03baB and PI3K/AKT signaling pathways.Spinal cord injury (SCI) is a highly disabling disorder for which few effective treatments are available. Grape seed proanthocyanidins (GSPs) are polyphenolic compounds with various biological activities. In our preliminary experiment, GSP promoted functional recovery in rats with SCI, but the mechanism remains unclear. Therefore, we explored the protective effects of GSP on SCI and its possible underlying mechanisms. We found that GSP promoted locomotor recovery, reduced neuronal apoptosis, increased neuronal preservation, and regulated microglial polarisation  Spinal cord injury (SCI) is a serious neurological disorder worldwide, with devastating effects . The patMicroglial activation is the key to the pathogenesis of secondary inflammatory injuries , 8. Acti\u03baB and inhibit the PI3K/AKT pathway via MyD88 recruitment . Ou. Ou\u03baB [\u03bain vivo suggested that the NF-\u03baB pathway was strongly activated following SCI, whereas PI3K/AKT pathway activity was inhibited. This trend was reversed by GSP treatment. To further explore the effects of GSP on these two pathways, we detected changes in related protein levels in vitro. Compared to the LPS group, the NF-\u03baB pathway was inhibited, and the PI3K/AKT pathway was activated after GSP treatment. One strategy for inhibiting LPS-mediated signaling pathways is to block their receptors. Therefore, we blocked TLR4 with TAK242. We found that both TAK242 and GSP effectively reduced the high activity of NF-\u03baB induced by LPS and upregulated PI3K/AKT signaling-related protein expression. Compared to TAK242, the regulation of GSP is limited or milder but sufficient to reduce LPS-induced neuroinflammation. We demonstrated that GSP regulates microglial polarisation by inhibiting the TLR4-mediated NF-\u03baB and PI3K/AKT signaling pathways. Nevertheless, further experiments should be performed to explain the precise underlying mechanism of crosstalk between TLR4/NF\u03baB and PI3K/AKT signaling pathways.The results \u03baB/PI3K/AKT signaling cascade is a suitable target for treating SCI. However, this study did not explore the long-term side effects of GSP, and the exact mechanism needs to be further explored.In summary, GSP can regulate microglial polarisation, thereby reducing neuronal apoptosis and improving functional recovery after SCI by inhibiting TLR4. Therefore, the TLR4/MyD88/NF-\u03baB signaling pathway and activating the PI3K/AKT signaling pathway mediated by TLR4. This study demonstrated the potential of GSP as a therapeutic SCI drug.GSP inhibited neuroinflammation and neuronal apoptosis by regulating microglial polarisation. Thus, GSP plays a neuroprotective role, which may be achieved by inhibiting the NF-"}
+{"text": "Also, Nramp horizontal gene transfer (HGT) toward bacteria led to mntH polyphyly. Prior demonstration that evolutionary rate-shifts distinguishing Slc11 from outgroup carriers dictate catalytic specificity suggested that resolving Slc11 family tree may provide a function-aware phylogenetic framework. Hence, MntH C (MC) subgroups resulted from HGTs of prototype Nramp (pNs) parologs while archetype Nramp (aNs) correlated with phagocytosis. PHI-Blast based taxonomic profiling confirmed MntH B phylogroup is confined to anaerobic bacteria vs. MntH A (MA)\u2019s broad distribution; suggested niche-related spread of MC subgroups; established that MA-variant MH, which carries \u2018eukaryotic signature\u2019 marks, predominates in archaea. Slc11 phylogeny shows MH is sister to Nramp. Site-specific analysis of Slc11 charge network known to interact with the protonmotive force demonstrates sequential rate-shifts that recapitulate Slc11 evolution. 3D mapping of similarly coevolved sites across Slc11 hydrophobic core revealed successive targeting of discrete areas. The data imply that pN HGT could advantage recipient bacteria for H+-dependent Mn2+ acquisition and Alphafold 3D models suggest conformational divergence among MC subgroups. It is proposed that Slc11 originated as a bacterial stress resistance function allowing Mn2+-dependent persistence in conditions adverse for growth, and that archaeal MH could contribute to eukaryogenesis as a Mn2+ sequestering defense perhaps favoring intracellular growth-competent bacteria.Solute carriers 11 (Slc11) evolved from bacterial permease (MntH) to eukaryotic antibacterial defense (Nramp) while continuously mediating proton (H In contrast, the corresponding NRMT-specific residues facilitate instead H+-independent uptake of Mg(II), thereby indicating type II coevolutionary rate-shifted sites that defined Slc11 specificity  and Divalent metal transporter (DMT1). Slc11 3D architecture fits the \u201cLeuT-fold,\u201d a structural paradigm for the Amino acid-Polyamine-organoCation (APC) superfamily of chemiosmotic transporters or carriers (Pfam Clan CL0062). This Pfam Clan includes the family PF01566, which comprises both the Slc11 family and its phylogenetic outgroup that shows less than 30% sequence identity as well as distinct catalytic specificities  . Slc11-scificity .2+) displacement of the H+ initially bound to outward open Slc11 carrier triggers rocking of a helical bundle (TMS1/2/6/7) over a relatively inert \u201chash\u201d module (TMS3/4/8/9) that anchors more mobile elements acting as coordinated gates . While Me2+ is transported between TMS1, 3, 6 and 8, (symported) protons could travel along a network of ionizable charges distributed across TMS3, 4, 6 and 9 (The APC conserved architecture includes a 10 transmembrane segments (TMS) hydrophobic core formed by juxtaposed copies of a constitutive protomer, the inverted topology repeat LeuT-like, which display little sequence similarity and fold intertwined. It is thought that metal-ion  are polyphyletic (before aerobiosis) and MntH A , as well as a group of seemingly eukaryotic descent designated MntH C   . Of 2 tynd MCaU) .+ translocation, altered geometry of the Me2+ binding site  toward eukaryotic nutritional immunity function (Nramp) thus has the potential to reveal the molecular logic of H+-dependent Me2+ import catalyzed by Slc11 carriers and to indicate functional innovations serving host cell defense  exhibits pseudo-symmetric \u201ceukaryotic signature\u201d marks in TMS4&9 . By analpN donor.Eukaryotic HGT towards bacteria are rare but several examples have previously been reported . As molecular databases expanded, so did diversity of MntH C subgroups and notably that of an initially minor subset closely related to eukaryotic pN , herein Nramp genes from widely diverse eukaryotic supergroups .To examine this possibility, ergroups  were color LECA, . A robusogenesis . Notably2+ binding site. In contrast, MA corresponding structures (Deinococcus radiodurans (Dra) Nramp 6D91 and 6D9W) (+ uniport activity (Increased branch length leading to aNs and aN-IIs shows asymmetric evolution  relativend 6D9W)  display activity  . All predicted type II (8/8), the majority of type I (4/6) and half of type I/II rate shifts locate to the inner core of the carrier structure and demonstrate possible interactions with residues from neighbor TMS, in either one or both conformations studied. Several candidate divergent sites map to the thick gate area of the inward facing carrier, while another group clusters around the internal gate. Thus, aN divergence, which correlates with phagotrophic way of life in simple eukaryotes (Supplementary Appendix S2)  , may refndix S2) .To relate eukaryotic pN isotypes and bacterial MC subgroups non-overlapping sets of sequences (seqs) representing MCa, MCb, MCg and MCaU subgroups were assembled, filtered at given pairwise identity levels, and combined with pN seqs for phylogenetic analyses using MA as prokaryotic outgroup. Sequence patterns iteratively deduced for each MC subgroup  generated PHI-Blast hits with distinct taxonomic profiles that indicated subgroup specificity (Supplementary Table S2). Yet, because these patterns were assembled using logos that included all substitutions observed at any site selected for analysis, PHI-Blast outputs were not exempt of cross-contamination, especially for MCa that is the most diverse and prevalent MC subgroup.Curation of PHI-Blast results using MMseqs2 classification and IQ-Tree phylogenetics (plus the number of TMS (11 vs. 12) to segregate MCa from MCaU, respectively) yielded group-specific, non-overlapping sets of non-redundant seqs  that establish MCa as the most prevalent subgroup (2368 seqs), followed by MCaU (1161 seqs), MCb (821 seqs) and MCg (398 seqs). Variations in subgroup prevalence may owe to database sequence sampling bias; it could as well indicate distinct ecological niches, more or less conducive for secondary bacterial HGT, or reflect on specific origins.pN-I and pN-II types, and leading to evolutionary novel phylogroups of bacterial MntH with MCa, MCb and MCg on one hand and MCaU on the other hand.Reduced sets representative of subgroup diversity (filtered at 60% identity (60% id): MCa, 34 seqs and MCaU, 56 seqs or filtered at 70% id: MCb, 37 seqs, and MCg, 33 seqs) were selected to establish their relationships with pN-I and pN-II while limiting the effect of microbe sampling bias. Phylogenetic trees show MCa seqs are closer to green plant pN-I than MCb seqs , and MCg is even more distantly related , suggesting that MCa, MCb and MCg could all derive from pN-I isoform(s). In contrast, MCaU appears sister to pN IIs . These results indicate a minimum of two inter-kingdom HGT events involving both pN transgenes. MCa is markedly present in Alphaproteobacteria , Rhodospirillales, Rhodobacterales, Supplementary Table S3) as well as Cyanobacteria, including lineages associated with protistan plankton (endo) symbiosis  and now filtered at 80% id) showed them as \u201ccrown species\u201d of sister clusters that segregate all cyanobacterial MCa on the one hand from a divergent (second) Synechococcal clade on the other hand . Seqs diverging basally from each cluster appear diverse and belong to various bacterial phyla . Accordingly, HGT of pN-I in Cyanobacteria, from a protist source for instance, could lead to MCa lateral spreading across diverse bacteria, including APB  maintained solely MCb copy, similarly to few Orbales and Moraxellales spp. also found in the gut of insects  (Supplementary Appendix S3). Besides, \u223c20% of Bifidobacteria (Actinomycetia), mostly species associated with pollinating insects  Burkholderiales from several families found in the rhizosphere   is induced during macrophage infection and likely influences bacterial virulence . Its distance from pN-I cluster suggests that MCg, like MCb, could derive from secondary zosphere   , implyinnadales) , legume nadales)  and opponadales) . One of irulence , which duisition . The datpN-II HGT from eukaryote to prokaryote. Phylogenetic analysis shows MCaUs from Bacteroidetes classes forming a \u201ccrown cluster\u201d while seqs from other taxa lie between Bacteroidetes and pN-II, in a succession of separate branches  that suggests their position may owe to long branch attraction (LBA) artefact  chromosome (not shown), provides a reminder that horizontally acquired genes require suitable conditions to remain functional. The data presented suggest some Bacteroidetes ancestor as recipient of pN-II HGT and MCaU propagation among diverse taxa sharing the same environmental niche.MCaU subgroup, uniquely derived from pN-II, is found principally in Bacteroidetes  and it is abundantly represented in environmental metagenome samples affiliated to this order . Known example of Flavobacteria endosymbiont of amoeba  suggestsartefact . Also, sMC HGT come from human pathogens. Replacement of MA by MCb was noted in Bifidobacteria and other obligate anaerobes , some facultative anaerobes  and obligate aerobe . In contrast, in Listeriaceae  were in fact derived from pNs, and given the distance separating pNs and MA , an evolutionary intermediate linking MA to Nramp ancestor is theoretically plausible. This \u201cmissing link\u201d could inform on Slc11 carrier evolution in the context of eukaryogenesis and host cell resistance to infection. Candidate seqs, which resemble MA but display some \u201ceukaryotic-signature\u201d functional marks, were identified in hyper-thermophilic archaea and designated MntH H (MH) .Dictyoglomus and Caldisericum spp. previously proposed to have originated before onset of earth aerobiosis  and compare their taxonomic profiles (Supplementary Table S2). Both MB and MA display relatively broad distribution, similar to MCa and MCaU while MAV is principally found in MCg bearing spp., e.g., Burkholderiales (Supplementary Table S2). Notably, MB is confined to anaerobic bacteria, including robiosis  as well  of Mn2+  . Only aNs form a monophyletic cluster (vs. pNs), as expected from pNs diversity  and bacteria (BH). Since AH and BH segregated as sister species in Slc11 phylogeny, specific patterns were derived from each subgroup for additional PHI-Blast analyses. AH is present in at least 70 microorganisms, all from TACK (53), DPANN (7), Asgard (1) and unclassified archaea (6), except 2 candidate CPR bacteria: At least 42 microorganisms encode bacterial MH (BH), mainly (D-T) Thermales (16), (GPB) Thiotrichales (10), (APB) Rhizobiales (7), (CFB) Ignavibacteria (3), 1 Planctomycetes and 1 Chloroflexi bacteria. Filtering PHI-Blast outputs at 95% identity gave 100 AH seqs and 31 BH seqs, indicating higher prevalence in archaea. Filtering at 70% identity yielded 32 (AH) and 10 (BH) curated seqs, demonstrating diversity in both subgroups. Higher prevalence of AH and evidence of recent HGT toward bacteria both suggest AH predated BH.Thorarchaeota AH sampled on 3 continents form a clade suggesting vertical inheritance of MH in Asgard . Considering AH dominance over BH together with evidence of recent HGT of BH genes among Thermales  and Thiotrichales, which may both share with hyperthermophilic TACK archaea such ecological niche as hydrothermal vents (AH HGT toward bacteria.MH seqs (filtered at 70% id) were used to detail AH and BH relationship to pNs . MH is sister to pN group, implying MH predated MC subgroups. BH conserved haplotype suggests a common origin for BH seqs  although contrarily to AH, they do not appear monophyletic . This may result from LBA artefact caused by the most divergent sequences. In contrast, al vents , the dat+ transport  and/or variations in the electrochemical potential of the membrane (delta-psi), which together generate the protonmotive force. It was established that S. cerevisiae pN-I (Smf1p), rat aN-II (DCT1/DMT1) and D. radiodurans MA (Dra Nramp) all exhibit variable stoichiometry in H+/Me2+ symport resulting from uncoupled co-substrate uptake. Uncoupled uptake of Na+ (Smf1p) or H+ (DMT1) was proposed to regulate toxic accumulation of metal-ions in certain conditions, such as respectively, alkaline pH or acidic pH and negative membrane potential , which assumes distinct orientations in NRMT and MntH  and rearranges upon Mn2+ binding by MntH  while altering the inner and outer gate topology . Lastly, 2 polar sites were introduced in TMS8 of Nramp ancestor, which line the extended outer cavity  and regulate DMT1 voltage-dependence and H+ influx , then modified in archaeal pre-eukaryotic cells and completed in FECA. This suggests that stepwise evolution of Slc11 phylogroups reflects functional adaptations to environmental changes . Other isolated sites shift spatially upon opening of Slc11 internal gate. Slc11-specific sites thus likely contribute to couple co-substrate binding and carrier gating.Slc11-specific sites that remained conserved since MB emergence define (v) a novel, large area sitting in the middle of the membrane in the plane that accommodates the co-substrate binding sites. This broad network connects areas (ii) and (iv) through specific binding of Mn+ translocation pathway toward the cytoplasm, and another local network (vii) that is rearranged during carrier cycling. Additional sites fixed in MA extend previous networks (i), (iii) and (iv). Accordingly, coevolutionary rate-shifts dating back to MA ancestor allowed reengineering of Slc11 carrier by opening a divergent intracytoplasmic H+ release pathway and fine-tuning of local rearrangements that accompany carrier cycling.Slc11-conserved sites that fixed before MA divergence populate various locations surrounding the co-substrate binding cavity (v). These include a second large area (vi), situated within the \u201chash\u201d module below the plane accommodating the co-substrate binding sites, which opens a H+ translocation pathway toward the cytoplasm on one hand and toward TMS1 Me2+ binding site one the other hand (Nramp residues inherited from MA transition to MH appear to consolidate pre-existing networks (i) and (vii), with sites located in mid-TMS1b/TMS7 carboxy-end and mid-TMS7, respectively, and (vi) with 3 potential charges added. These evolutionary changes could tweak structural rearrangements within the helical bundle and extend the Hher hand  thus lik+ translocation and membrane potential sensing  had consequently amended network (vi), now extending upward along TMS3&8 and vis a vis TMS4&9 by adding polar residues presumably adjusting paths for H sensing . Rearran sensing  suggests2+ and they sustain growth of organisms from different eukaryotic supergroups that graze on bacteria  models predicted for seqs of bacterial descent  or eukaryotic origin (MCs) were compared. The Alphafold (AF) database provides the opportunity to appreciate the conformational space of virtually any protein family . RegardiAF2 models for Slc11 outgroup resemble more NRMT inward open structure than MntH templates and suggest candidate conformational intermediates toward a hypothetical NRMT outward open state. MB predicted structures appear more distant from NRMT and closer to MntH A templates, in agreement with Slc11 family tree. MA conformers roughly sit along the path from 6D91 to 6D9W with a large majority near to outward open state. Both MAV and MH conformers behave likewise. A pooled selection of MA-MAV-MH models distributes along the 6D91 to 6D9W path, placing MH models on the margin. These 3D data support close relationship of MA and MAV with MH that is consistent with Slc11 phylogeny.In contrast, AF2 models for MCg, MCa and MCaU seqs appear as similar clusters of remote outliers while MCb conformers populate a hypothetical path linking 5M87 to 5M94 rather evenly. Plant pN-Is  behave smntH polyphyly - which are consistent with olyphyly  and Slc1olyphyly  and sugg+-driven Mn2+ uptake before onset of earth aerobiosis remains however obscure. In an anaerobic world, Mn requirements seem negligible for metabolic purposes as well as the need for antioxidant defenses. Yet transient Mn accumulation at the expense of Mg entry may be beneficial to resist adverse conditions for growth.The reason why bacteria would select HRecovery from severe stress  involves the functional switch of the Mg/Mn-dependent AMPylator (YdiU), which regulates redox homeostasis in normal conditions, into a Mn-dependent UMPylator. As recovery from stressful conditions depletes ATP stores YdiU-dependent UMPylation turns off chaperone activity to conserve cellular energy and favor cell persistence . MagnesiSelective Mn import may also favor host cell survival upon viral infection. Several examples of bacterial antiphage systems demonstrate signaling or effector activities that are specifically Mn-dependent  and someAs increased intracellular Mn/Mg ratio allows functioning of Mn-dependent activities that sustain bacterial resistance to severe stress even in anaerobiosis , it is speculated that (Slc11) MB emerged to meet the need for a selective Mn import pathway enabling rapid , transie+-dependent Mn2+ import catalyzed by MB could serve some \u201celemental chaperone\u201d purpose in anaerobiosis, because Mn can substitute for both Mg2+ and ATP cofactors to prolong cell stress resistance when cellular energy is depleted. Mn accumulation might as well help anaerobes coping with episodic exposure to O2, which prohibits photoautotrophic growth  bacteria remain carried chronically in the reticuloendothelial system (RES) for as long as 1\u00a0year after infection  , which cMining sites of interaction/flexibility  that canMaximum Likehood (ML)  phylogenetic analyses were performed using IQ-Tree , an apprPhylogenetic mixture models combine several a.a. replacement matrices in attempt to better model the complex process of site evolution, which depends on factors such as genetic code, solvent exposure, secondary and tertiary structure as well as protein function. These include both unsupervised mixture models  that learn site categories empirically and knowledge-based mixture models, such as EX2 (exposed/buried) and EX3 (exposed/intermediate/buried), EHO (extended/helix/other) and EX-EHO. For each analysis the number of sequences used was adjusted to ensure that the number of free parameters (tree branches and model parameters) was inferior to the number of distinct site patterns analysed. Also, 1000 replica of each of two types of branch support calculations (ultrafast bootstrap and SH-aLRT single branch test) were routinely performed to estimate confidence in the tree clades obtained. A scale bar representing the number of substitutions per site is provided with each tree presented.Site-specific evolutionary conservation was calculated between Nramp types using Consurf  and a BaTo predict sites of potential functional divergence between Slc11 parologs, complementary approaches were tested: Diverge 3.0  and a li\u221260 as e-value cutoff  and archetype Nramp (aN-I and aN-II) were searched using PSI-BlastP  and TBlaThe outgroup used in this study comprises the sequences most closely related to Slc11 carriers but lacking the specific features required for Mn and proton transport. This outgroup is related to but distinct from NRMT group. The 3 clades  form the PF01566 family. Both Slc11 phylogeny and Slc11-specific collection of evolutionary rate-shifts were resilient to outgroup diversification using NRMT sequences , implying the proposed phylogenetic framework reflects functional properties intrinsic to the Slc11 family. Stochastic errors, inherent to sequence length, were observed in Slc11 family tree  despite"}
+{"text": "Sequencing studies have deciphered the genetic landscape of primary central nervous system lymphoma (PCNSL) paving novel therapeutic avenues in recent years.2 Frequent 9p24.1 copy number gains, the genetic locus of programmed cell death protein 1 (PD-1) ligands PD-L1 and PD-L2, were detected and suggestive of immune evasion via activation of PD-1 signaling. Systemic nivolumab, a monoclonal PD-1 antibody, was hence evaluated in a small retrospective PCNSL cohort yielding promising long-term responses. Intracranial efficacy of systemically administered monoclonal antibodies may however be impeded by an intact blood-brain barrier (BBB) resulting in lower cerebrospinal fluid (CSF) penetration. To bypass the BBB and reduce systemic toxicities, intraventricular/intrathecal immunochemotherapy is being investigated. Intrathecal nivolumab combined with its systemic administration was recently found safe and effective in melanoma with leptomeningeal dissemination,4 prompting us to evaluate intraventricular nivolumab for recurrent primary CNS lymphoma (PCNSL) in an elderly patient unable to tolerate aggressive systemic polychemotherapy. Intraventricular nivolumab achieved a lasting (>12 months) complete remission including parenchymal lesions distant from cerebrospinal fluid spaces. No toxicities or adverse events related to the mode of administration were noted. Our case suggests intraventricular nivolumab is active in recurrent parenchymal PCNSL. Together with detected 9p24.1 gains this argues for further prospective evaluation, for which our treatment protocol provides a framework.4 Glucocorticoids were avoided before and during therapy. Staging magnetic resonance imaging (MRI) was performed after the first, fourth, and eighth dose during induction and every 3 months during maintenance therapy. International Primary CNS Lymphoma Collaborative Group criteria were used for radiological response assessment.5 Treatment-related toxicities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.We describe a patient with unequivocal recurrence of a PCNSL who was subsequently treated with intraventricular nivolumab. Informed consent for placement of a Rickham reservoir, off-label use of nivolumab on a compassionate care basis, and for publication was obtained. Nivolumab (20 mg) was diluted in 3 ml of perseverative-free saline and administered following removal of equivalent CSF volumes. For induction, eight doses of nivolumab were injected at biweekly dosing intervals. For maintenance, it was administered every 4 weeks. The dose and intervals were selected based on clinical trial experiences in metastatic melanoma.6 Therapy achieved complete radiographic response (CRR) but also caused grade III toxicities including leukopenia, infection, and diarrhea. The patient was then followed expectantly with scans every 3 months.Treatment protocol, pathological, and radiological findings are summarized in 7 Intraventricular nivolumab treatment was continued, and parenchymal lesions have remained in CRR for more than 12 months at the time of publication. Repeated CSF analyses revealed normalization of CSF/serum albumin ratio indicative of BBB recovery under intraventricular nivolumab treatment and stable cell counts without evidence for malignancy. No treatment-related toxicities or application-associated adverse events were noted.Multifocal parenchymal PCNSL relapse was diagnosed 24 months after initial diagnosis when clinically silent, homogeneously enhancing lesions with restricted water diffusion were detected on MRI. CSF analysis revealed a normal cell count (3/mcf) and mildly elevated CSF/serum albumin ratio  without evidence for malignancy on cytology and flow cytometry. Pathological re-evaluation of the specimen obtained at initial diagnosis revealed robust PD-L1 expression of lymphoma cells . After R8 This may suggest the involvement of the controversial glymphatic system in parenchymal drug delivery after intraventricular administration. As a result of arterial wall pulsatility, the glymphatic system is thought to transport CSF along with periarterial Virchow-Robin spaces deep into the parenchymal interstitium with drainage via perivenous spaces and meningeal lymphatic vessels to mediate CNS waste clearance.10 In a primate Alzheimer\u2019s disease model, intraventricular \u03b2-secretase 1 (BACE1) antibody therapy achieved uniform intraparenchymal distribution, which was linked to the glymphatic system.11 Although its role in drug delivery particularly in disease states, which may affect CSF transport rates, warrants further investigation, it could similarly have allowed intraventricular nivolumab to sufficiently reach deep parenchymal lesions.We report successful intraventricular nivolumab therapy for recurrent multifocal PCNSL achieving long-term intracranial disease control without treatment- or application-related toxicities and adverse events. It is noteworthy that CRR included intraparenchymal lesions distant (2-3 cm) from CSF spaces. In line with previous studies assessing different agents, this observation continues to challenge the notion that intraventricular therapy is only active within their proximity and hence ineffective for intraparenchymal masses.3 At a fraction of the overall dose, bypassing the BBB may allow higher CSF and lower systemic drug concentrations likely minimizing dose-dependent side effects outside the CNS. Reported CSF penetration following intravenous nivolumab ranged between 1:52 and 1:299.12 In comparison, a total of 360 mg nivolumab\u2014less than a single intravenous infusion\u2014were administered intraventricularly over the course of 12 months and 18 cycles of ongoing nivolumab treatment. Durable parenchymal response with isolated intraocular relapse, which responded well to local methotrexate treatment, could point to insufficient nivolumab delivery to the vitreoretinal compartment and/or development of resistance.Like its systemic application, sole intraventricular administration appears effective in PCNSL.4 Notably, systemic polychemotherapy\u2014particularly in the elderly\u2014is often associated with severe hematological toxicities. The PRIMAIN study registered grade \u22653 toxicity in 81.3% and treatment-related death in 8.4% of participants.6 Similarly, three grade III toxicities were noted in our patient. Systemic nivolumab is associated with lower toxicity rates. However, in a trial evaluating intravenous PD-1 blockade for relapsed DLBCL (diffuse large B-cell lymphoma), treatment-related adverse events were nonetheless recorded in 62% with 24% experiencing grade \u22653 toxicities.13 Intraventricular immunochemotherapy could constitute a less hematotoxic alternative\u2014particularly in the elderly and other cohorts who cannot tolerate aggressive systemic polychemotherapy.In agreement with this report, intrathecal nivolumab was found feasible and safe in 23 patients with metastatic melanoma. No application- and limited treatment-related toxicities (grade 3: 22%) without relevant neurological events were recorded.Our study and recently detected 9p24.1 gains argue for further prospective evaluation in PCNSL, for which our treatment protocol may provide a framework. The efficacy for intraparenchymal lesions also makes it a candidate for other CNS malignancies with active PD-1 signaling."}
+{"text": "Lymphedema is a chronic inflammatory disorder characterized by edema, fat deposition, and fibrotic tissue remodeling. Despite significant advances in lymphatic biology research, our knowledge of lymphedema pathology is incomplete. Currently, there is no approved pharmacological therapy for this debilitating disease. Hypoxia is a recognized feature of inflammation, obesity, and fibrosis. Understanding hypoxia-regulated pathways in lymphedema may provide new insights into the pathobiology of this chronic disorder and help develop new medicinal treatments. Lymphedema manifests as an initial accumulation of extracellular fluid and heightened inflammation with progressive chronic tissue remodeling characterized by fat deposition and fibrosis . In the Prior research demonstrated that hypoxia regulates tumor lymphangiogenesis by promoting lymphatic endothelial expression of Prox-1 and pro-growth molecules such as VEGFC/VEGFR3 and CXCL12/CXCR4 . Emergin+ T cells, including Th1, Th2, Th17, and regulatory T cells (Tregs) (4 (LTB4) promotes lymphedema and blocking LTB4 production reverses the disease  . Th2 cel (Tregs) , whereas (Tregs) . Tregs a (Tregs) . Innate  (Tregs) . For ins (Tregs) ; macroph (Tregs) ; and the disease . Prolong disease .Anti-inflammatory therapies, including ketoprofen (NSAID) and Th2 cell inhibition, improve skin pathology but are ineffective in reducing limb volume and fat deposition . Finding2+) and \u03b1-ketoglutarate  components such as collagen and fibronectin, is a dysregulated tissue repair response following various types of tissue injury with chronic inflammation . FibroblFibrosis in lymphedema affects the dermis and subcutaneous tissue, representing a crucial factor promoting tissue hardening and non-pitting edema . AdditioChronic lymphedema poses a significant health burden on afflicted patients and requires effective pharmacological treatments. Hypoxia and HIF-mediated responses appear to regulate lymphedema pathogenesis . Availab"}
+{"text": "Multiple sclerosis (MS) is a multifocal and progressive inflammatory disease of the central nervous system (CNS). However, the compartmentalized pathology of the disease affecting various anatomical regions including gray and white matter and lack of appropriate disease models impede understanding of the disease. Utilizing single-nucleus RNA-sequencing and multiplex spatial RNA mapping, we generated an integrated transcriptomic map comprising leukocortical, cerebellar and spinal cord areas in normal and MS tissues that captures regional subtype diversity of various cell types with an emphasis on astrocytes and oligodendrocytes. While we found strong cross-regional diversity among glial subtypes in control tissue, regional signatures become more obscure in MS. This suggests that patterns of transcriptomic changes in MS are shared across regions and converge on specific pathways, especially those regulating cellular stress and immune activation. In addition, we found evidence that a subtype of white matter oligodendrocytes appearing across all three CNS regions adopt pro-remyelinating gene signatures in MS. In summary, our data suggest that cross-regional transcriptomic glial signatures overlap in MS, with different reactive glial cell types capable of either exacerbating or ameliorating pathology.The online version contains supplementary material available at 10.1007/s00401-022-02497-2. Multiple sclerosis (MS) is a multifocal progressive inflammatory disease of the central nervous system (CNS) characterized by demyelination, astrogliosis and varying levels of cell type vulnerability and reactivity during lesion development , 43, 46.To assess cell type diversity and reactivity in MS across different CNS regions, we performed droplet-based single-nucleus RNA-sequencing (snRNA-seq) from well-characterized tissue samples comprising cerebellar, spinal cord and leukocortical samples  obtainedPostmortem human tissue samples from a total of 41 donors  were provided by the UK Multiple Sclerosis Tissue Bank at Imperial College, London via prospective donor scheme following ethical approval by the National Research Ethics Committee in the UK (08/MRE09/31). Samples were obtained from 21 donors without evidence for pathological abnormalities within the examined tissue areas and from 20 donors who were diagnosed with multiple sclerosis (MS). Additional clinical and pathological details about control and MS donors as well as quality control of the samples are provided .Integrity of mRNA was used as a sample selection criterion, and only samples with a high quality of tissue RNA were included. We prepared 100-\u00b5m thick sections on a CM3050S cryostat (Leica) to obtain 10\u00a0mg tissue to isolate RNA, which was done using TRIzol (Thermo Fisher) and Qiagen RNAeasy Kit following manufacturer\u2019s recommendations. RNA integrity was measured on an Agilent 2100 Bioanalyzer using the RNA 6000 Pico Kit (Agilent) according to the manufacturer\u2019s instructions. Samples with RNA integrity number (RIN)\u2009\u2265\u20096.5 were selected for further snRNA-seq analysis.+/CD45+/CD68high) in lesion center areas  and perivascular cuffing of T cells (CD45+/CD3+) and macrophages (CD45+/IBA1low/CD68high) . Chronic active lesions were classified by a demarcated demyelinated lesion center and a hypercellular lesion rim with increased presence of macrophages and activated microglia (CD45+/IBA1high/CD68low) . Inactive lesions demonstrated fully demyelinated lesion centers with absence of macrophages; in normal-appearing and periplaque lesion areas we observed an abundance of ramified microglia (CD45+/IBA1high)  . h Violin plots showing expression of OL subtype markers of J\u00e4kel et al. [22] in all four OL subtypes. Suppl. Fig. 9 Transcription factor activity and trajectory analysis of white matter oligodendrocytes in MS. a, b Heatmap showing the altered TF activity in SLC5A11 oligodendrocytes between control and MS cells for cerebrum (a) and spinal cord (b). c Venn diagram showing the overlap of altered TFs identified in . Notably, almost one fourth of identified TFs overlap between the regions in MS, whereas only five overlaps in control. d Upper panel: UMAP representation of SLC5A11-expressing (SLC5A11+) leukocortical oligodendrocytes. CTRL, control, ACA, acute/chronic-active, CI, chronic-inactive. Lower panel: Trajectory inference of leukocortical SLC5A11+ oligodendrocytes identifies two transcriptomic branches according to inflammatory stage. Note coloring indicates pseudotime score; gray cells do not have a value for one lineage. e Heatmap representation of differentially expressed genes based on pseudotime analysis. Note genes classified as differentially expressed (adjusted p < 0.05) between the endpoints of the two branches (d) are plotted for all SLC5A11+ OLs from both leukocortical and spinal cord MS samples. (PDF 26043 KB)Suppl. Table 1 Clinical and pathological metadata of control and MS samples (XLSX 15 KB)Suppl. Table 2 Cluster-specific marker genes for integrated and regional data sets (XLSX 2317 KB)Suppl. Table 3 Differential gene expression analysis of neuroglial subtypes (XLSX 31 KB)Suppl. Table 4 Differential expression of region-specific genes in control astrocytes (XLSX 222 KB)Suppl. Table 5 Enrichment of region-specific GO terms in control astrocytes (XLSX 596 KB)Suppl. Table 6 Ligand\u2013receptor analysis of Bergmann glia and Purkinje cells (XLSX 64 KB)Suppl. Table 7 Differential expression of region-specific genes in MS astrocytes (XLSX 66 KB)Suppl. Table 8 Enrichment of region-specific GO terms in MS astrocytes (XLSX 103 KB)Suppl. Table 9 Cluster-specific marker genes for integrated astrocytes (XLSX 271 KB)Suppl. Table 10 Differential gene expression analysis for white matter astrocyte subtypes (XLSX 243 KB)Suppl. Table 11 Differential expression of region-specific genes in control oligodendrocytes (XLSX 12 KB)Suppl. Table 12 Differential expression of region-specific genes in control microglia (XLSX 27 KB)Suppl. Table 13 Differential expression of region-specific genes in control OPCs (XLSX 14 KB)Suppl. Table 14 Cluster-specific marker genes for integrated oligodendrocytes (XLSX 420 KB)Suppl. Table 15 Differential gene expression and GO term semantic similarity analysis of SLC5A11-expressing white matter oligodendrocytes from cerebrum and spinal cord (XLSX 49 KB)Suppl. Table 16 Differential gene expression analysis between trajectory endpoints for subcortical white matter oligodendrocytes (XLSX 40 KB)Below is the link to the electronic supplementary material."}
+{"text": "Immunohistochemical staining demonstrated PSMA expression in the endothelial cells of tumor tissue. This interesting image should remind colleagues to consider malignant thyroid neoplasia in PSMA-positive thyroid lesions.We present an interesting image of an intense PSMA-positive follicular thyroid carcinoma incidentally detected by [ The man received his diagnosis of prostate cancer 11 years ago . The patient had undergone prior local therapies, such as robotic prostatectomy, salvage local lymphadenectomy, and salvage external beam radiation of prostate bed . For localization of recurrence, we performed a prostate-specific membrane antigen (PSMA)-targeted positron emission tomography\u2013computed tomography (PET/CT) using [ thyroid . 68Ga]Ga-PSMA-11 PET/CT appears to be very difficult; thus, histologic or cytologic examination should be sought. In clinical examination, a palpable formation was identified on the left side of the neck. Subsequently, we performed a sonography of thyroid and neck showing an approximately 5 cm large echo-complex nodule in the left thyroid. Blood examination revealed normal TSH, fT3, fT4, and antibody values. Fine needle aspiration was waived and thyroidectomy was performed. Histopathological preparation revealed a minimally invasive follicular thyroid carcinoma with limited capsular penetration A. PSMA-pThis interesting image should remind colleagues to consider malignant thyroid neoplasia in PSMA-positive thyroid lesions."}
+{"text": "Incidence of myocarditis following messenger RNA coronavirus disease 2019 vaccination has been widely described, but this clinical scenario after adenoviral vector coronavirus disease 2019 vaccination has only been rarely reported. In addition, a few case reports of thyroiditis after adenoviral vector coronavirus disease 2019 vaccination have been published.A 55-year-old Thai woman presented with palpitation without neck pain 14 days after receiving AstraZeneca coronavirus disease 2019 vaccination. Electrocardiography revealed sinus tachycardia. Her blood tests showed elevation of cardiac troponin and free triiodothyronine with suppressed serum thyroid stimulating hormone, reflecting a hyperthyroid status. Evidence of myocardial inflammation and necrosis from cardiac magnetic resonance imaging supported the diagnosis of recent myocarditis. Laboratory results and imaging findings were consistent with thyroiditis. After 3 weeks of symptomatic treatment, her symptom and blood tests had returned to normal.This case demonstrates that the adenoviral vector coronavirus disease 2019 vaccine could possibly cause myocarditis and painless thyroiditis. Clinicians should have a high index of suspicion and promptly evaluate these conditions, despite minimal symptoms.The online version contains supplementary material available at 10.1186/s13256-022-03438-z. Since the emergence of the coronavirus disease 2019 (COVID-19)/severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, effective vaccines against COVID-19 have been developed . This vaWe report the case of a patient who developed concomitant myocarditis and painless thyroiditis after receiving the AstraZeneca COVID-19 vaccine.A 55-year-old Thai woman presented with palpitation 14 days after receiving the second dose of the AstraZeneca COVID-19 vaccination. She had no history of fever, dyspnea, chest pain, neck pain, or weight loss. Her past medical histories were essential hypertension and hypercholesterolemia. She had no history of thyroid disease. On admission, she had tachycardia with a heart rate of 120/min. Other examinations including respiratory rate, body temperature, and thyroid gland were unremarkable. Twelve-lead electrocardiography (ECG) revealed sinus tachycardia without evidence of ST\u2013T segment change. Plain chest radiography showed a normal cardiothoracic ratio and pulmonary vasculature. High-sensitivity cardiac troponin I was 2007.5 ng/L . Thyroid function tests showed elevated serum free triiodothyronine of 7.37 pg/mL , normal serum free thyroxine of 1.08 ng/dL  with suppressed serum thyroid stimulating hormone (TSH) of 0.113 uIU/mL . Thyroid peroxidase, thyroglobulin, and TSH receptor antibodies were negative , has been reported after various types of vaccine, including all COVID-19 vaccine platforms. This condition predominantly affects women in an age range from 26 to 75 years \u201314. SympAstraZeneca COVID-19 vaccine contains recombinant replication-deficient chimpanzee adenovirus vector encoding the SARS CoV-2 spike protein. Possible mechanisms for post-vaccination myocarditis and thyroiditis are molecular mimicry between SARS CoV-2 spike protein and self-antigens (myocyte protein and thyroid peroxidase) as well as triggering of preexisting dysregulated immune pathways , 17. HowTo our knowledge, this is the first case report of concomitant myocarditis and painless thyroiditis following AstraZeneca COVID-19 vaccine administration. The true association cannot be established, although we demonstrate the temporal relationships between vaccine and these conditions.This case demonstrates that the adenoviral vector COVID-19 vaccine could possibly cause myocarditis and painless thyroiditis. Clinicians should have a high index of suspicion and promptly evaluate these conditions. Given a low incidence and minimal symptoms in most cases, the COVID-19 vaccine is recommended in the pandemic situation because the benefit from the vaccine greatly outweighs the risks.Additional file 1. SSFP cine image in basal short-axis (SAX) view demonstrating regional wall motion abnormality."}
+{"text": "Scientific Reports 10.1038/s41598-022-13526-1, published online 16 June 2022Correction to: The original version of this Article contained an error in the Author Information section.\u201cThese authors contributed equally: Hyeon-Kyoung Koo, Jinsoo Min, Ju Sang Kim and Jae Seuk Park.\u201dnow reads:\u201cThese authors contributed equally: Hyeon-Kyoung Koo and Jinsoo Min. These authors jointly supervised this work:\u00a0Ju Sang Kim and Jae Seuk Park\u201d.The original Article has been corrected."}
+{"text": "The COVID-19 pandemic significantly impacted people working and living in nursing homes. A virtual five-week curriculum was developed to support recovery and foster growth in direct care workers (DCWs). We hypothesized DCWs would be interested, acquire knowledge and self-care skills, and utilize a post traumatic growth (PTG) self-assessment tool for reflection. The 5 week voluntary program was offered twice. Sessions consisted of a didactic presentation, Q&A, skill practice and action commitment. Each 30 minute session was offered twice weekly, a.m. and p.m., to accommodate shift schedules. Polls were conducted within sessions. Participants who attended all sessions received a certificate of attendance and completed a 4 question, 5-point Likert scale survey and the PTG tool. 53 DCWs participated in at least one session; 30 completed the program and ranked weeks 2 (95%), 3 (65%), and 4 (60%) as most useful. Most used skills were breathing (95%), gratitude practice (91%), catch-check-change (61%), self-massage (61%), and reducing exposure to toxic news (61%). DCWs endorsed self-improvement (96%), curiosity (91%), and \u201chaving a hard time\u201d (61%) as most common reasons for enrolling. 100% reported the course completely or almost completely met their goals. In-session polling indicated attendees \u201cfelt better or more confident\u201d at the conclusion of each session. 100% successfully utilized the PTG tool. The curriculum was responsive to DCWs needs and interests. DCWs acquired and utilized resilience skills. Some components of the curriculum were more effective than others. Shorter staff training sessions are more attractive to staff and employers. Further study is warranted."}
+{"text": "In the United States, 75% of preterm infants receive ampicillin after birth for evaluation of early onset sepsis. Excess antibiotic exposure in preterm infants is associated with morbidity and mortality. Pharmacokinetic (PK) simulations suggest that very low birthweight (< 1500g) infants receiving ampicillin may experience excess and prolonged therapeutic exposures to ampicillin after drug discontinuation, called post-discontinuation antibiotic exposures (PDAE). It is unknown if low birthweight ( > 1500g to < 2500g) infants that receive ampicillin experience prolonged PDAE.We conducted a pilot prospective PK clinical trial at a single tertiary care center. We enrolled infants with gestational age (GA) < 36 weeks and birthweight (BW) > 1500g and < 2500g who received ampicillin 200 mg/kg/day per standard of care. All infants received 6 ampicillin 66mg/kg doses administered Q8H within 24 hours following birth. Post-discontinuation PK samples were collected between 8-120 hours after the last dose of ampicillin. We performed descriptive statistics on patient characteristics, and graphically displayed ampicillin plasma concentrations following discontinuation. We defined therapeutic exposures as concentrations above the minimum inhibitory concentration (MIC) for Group B Streptococcus (0.25mcg/mL).We analyzed 20 PK samples from 12 infants with median (IQR) GA of 32 weeks  and BW of 1838g . See Table\u00a01 for clinical characteristics. All infants (N=8) with post-discontinuation samples collected within 48 hours of last dose had continued therapeutic ampicillin exposures, only 25% of infants had continued therapeutic exposures between 48 and 72 hours post last dose (N=4), and none had therapeutic ampicillin exposures beyond 72 hours post-dose . Samples (n=5) within 24 hours of last dose had median (IQR) ampicillin concentration of 13.2mcg/mL ; those within 25-48 hours (n=3) had median concentration of 0.9 mcg/mL .In this small cohort of premature infants, exposures of ampicillin remained therapeutic for at least 24 hours post drug discontinuation and suggests that shorter duration of empirical ampicillin treatments may be warranted in this population.Daniel Benjamin, Jr., MD PhD MPH, Allergan: Advisor/Consultant|Melinta Therapuetics: Advisor/Consultant|Syneos Health: Advisor/Consultant Rachel Greenberg, MD, MB, MHS, Provepharm Inc: Advisor/Consultant|Tellus Therapeutics: Advisor/Consultant."}
+{"text": "Gene expression patterns among cancer types in the TMA (EdgeSeq) and TCGA (RNA-seq) were similar. EdgeSeq gene signature analyses aligned with the majority of pathological cancer types/subtypes and identified cancer-specific gene expression patterns. TMA IHC H-scores for HER3 varied across cancer types/subtypes. In a few cancer types, HER3 mRNA and protein expression did not align, including lower liver hepatocellular carcinoma IHC H-score, compared with mRNA. Although all TNBC and ovarian cancer subtypes expressed mRNA, some had lower protein expression. This was seen in TMA and TCGA data sets, but not in CCLE. The EdgeSeq TMA data set can expand upon current biomarker data by including cancers not currently in TCGA. The primary analysis of EdgeSeq and IHC comparison suggested a unique protein-level regulation of HER3 in some tumor subtypes and highlights the importance of investigating protein levels of ADC targets in both tumor and normal tissues.Molecular and protein biomarker profiling are key to oncology drug development. Antibody-drug conjugates (ADCs) directly deliver chemotherapeutic agents into tumor cells based on unique cancer cell biomarkers. A pan-cancer tissue microarray (TMA) data set and gene panel were validated and gene signature analyses were conducted on normal and cancer tissues to refine selection of ADC targets. Correlation of mRNA and protein levels, and human epidermal growth factor receptor (HER) expression patterns were assessed. An EdgeSeq biomarker panel (2862 genes) was used across 8531 samples  with an established TMA data set, and immune cell and cell cycle gene signatures were analyzed. Discriminating gene expression signatures were defined based on pathological classification of cancer subtypes. Correlative analyses of HER2 and HER3 mRNA (EdgeSeq) and protein expression (immunohistochemistry  EGFR, HER2, HER3) ) were calculated and used for the analyses. An empirical parameter was set to reduce data of low-quality samples from the final data set using house-keeping gene expression levels. Correlations (R) between each sample data and an average of universal RNA (uRNA) gene expression levels were calculated from 89 samples that passed the sequencing filter. Samples with low correlations (R < 0.4) were considered low quality and a sample quality filter was applied by empirically setting an exclusion parameter based on average of expression values of nine housekeeping genes (Supporting Information). Through these processes, we obtained 2479 data samples  for 2867 probes. For the described analyses, five probes/genes among 2867 were not used for comparison of the EdgeSeq data with the Human Genome build 38 (hg38) data set used by TCGA and in-house RNA-seq (Supporting Information).Quality filters were applied to exclude the following samples with <1.5 million total read count or <0.1 of relative standard deviation of all probes (Supporting Information). Background signal from negative controls  was subtracted from all gene probes as well as undergoing upper-quartile (UQ) normalization to reduce tissue-specific bias of the expression data (Supporting Information). Log transformed values (loghttps://xenabrowser.net/). Some probes were not used in the comparison of EdgeSeq with TCGA or with in-house RNA-seq data because of circumstances described in Supporting Information. Comparisons were based on gene symbol with Ensemble Gene-ID. Gene annotations for cell type gene signature analysis were provided by HTG and public data  (RNA-seq data for TCGA were downloaded from UCSC-Xena (9198524)  Files. Z9198524) \u2013S7 FilesCancer cell lines  were har2 [TPM-UQ + 1]) and EdgeSeq data (log2 [adjCPM-UQ + 1]) were calculated.For RNA-seq analysis, mRNA was purified from 1 \u03bcg of total RNA using NEBNext Poly(A) mRNA Magnetic Isolation Module . Complementary DNA (cDNA) was generated using NEBNext Ultra RNA Library Prep Kit for Illumina (New England Biolabs) (Supporting Information). EdgeSeq raw data (94 cell line samples) were processed in the same manner as TMA data  and correlations, slopes and intercepts between RNA-seq data (logR > 0.4 and approaching 1.0) for most genes, including HER2, HER3 and PD-L1 , progesterone receptor-positive (PR+), HER2\u2212 breast cancer (ER+/PR+/HER2\u2212), while generally lower in normal tissues , endometrioid (n = 34), mucinous (n = 14) and serous (n = 110); the first three are not a component of TCGA. Genes selectively over- or under-expressed in each subtype among the ovarian cancer samples were assessed (CEACAM6 (mucinous), DKK1 (endometrioid), HNF1B (clear cell and mucinous), PGR (endometrioid), TFF3 (mucinous) and WT1 (serous) , adenoid cystic carcinoma [Ad], basal cell adenoma [Ba] and mucoepidermoid carcinoma [Mu]), benign epithelial tumor subtypes (pleomorphic adenoma [Pl] and warthin tumor [Wa]) and normal salivary gland tissue (n = 10). Marker genes for each subtype were selected based on higher and lower expression over other subtypes and normal salivary gland tissues. Analysis suggested overall correspondence between pathological and gene signature subtypes for salivary gland cancer  and cell cycle-related genes . These patterns (complementary profiles in Ad and Bl and a unique Mu profile) were reflected in principal component analysis , housekeeping genes, cell cycle genes and CAFs were determined for TNBC and salivary gland cancer subtypes . For TNBHER gene family member expression in salivary gland cancer showed that Mu and Wa subtypes had higher EGFR expression among the salivary gland cancer subtypes  and CCLE (R = 0.834 and R = 0.844)  .HER3 mRNA (HER3 EdgeSeq mRNA level (Comparison of HER2 mRNA (EdgeSeq) and protein levels by H-score  were highest in the serous subtype  and in vivo (TMA) data, as well as those between mRNA and protein expression. In TMA and TCGA data sets, expression levels of HER3 mRNA/protein in TNBC were higher in LAR and M than BL1 and BL2, with similar levels as ER+/PR+/HER2\u2212 and HER2+ breast cancer subtypes. However, the same expression patterns in TNBC were not observed in the CCLE data set  Click here for additional data file.S2 File(XLSX)Click here for additional data file.S3 File(XLSX)Click here for additional data file.S4 File(XLSX)Click here for additional data file.S5 File(XLSX)Click here for additional data file.S6 File(XLSX)Click here for additional data file.S7 File(XLSX)Click here for additional data file.S8 File(DOCX)Click here for additional data file."}
+{"text": "Despite higher physiological vulnerability to stress, older adults may accumulate resources through prior experiences that can promote resilience . During the COVID-19 pandemic, older adults drew on prior experiences and resources to cope , although these events were typically not specified. Some found vulnerability due to prior trauma . We examined whether older adults drew upon specific experiences or more general resilience resources in coping with this novel stressor. Data were collected using an online survey from April 28-May 4, 2020 from 235 older adults in Oregon . We examined open-ended responses from a question that asked whether prior experiences influenced how they were dealing with the COVID-19 situation. Nearly 2/3 provided valid responses (n=144). After inductive open coding, preliminary consolidation resulted in three broad categories: past experiences (74%), resources (19%), and both (8%). The most common prior experiences were illness (n = 20) and work (n = 19). Some (n=10) reported specific coping strategies learned during prior stressful experiences. Resources include personal characteristics , financial  and social resources (\u201cloving spouse\u201d). Five reported experiences that made COVID-19 more difficult (\u201cPTSD/anxiety prior to COVID-19 makes this even worse\u201d). Although 1/3 of the sample could not draw upon a prior experience in coping with this novel stressor, many older participants could utilize their lived experience when coping with problems during the COVID-19 pandemic."}
+{"text": "Schizophrenia is a heterogeneous disorder and it is unknown what causes individual variability in symptoms and cognitive ability.To examine the association between nine clinical predictors measurable at the onset of schizophrenia and five phenotype dimensions: positive, negative (diminished expressivity), negative (motivation and pleasure), disorganised symptoms and cognitive ability.-3) for multiple testing.852 participants (mean age 49 years old) with a diagnosis of schizophrenia or schizoaffective depression were included from the CardiffCOGS cross-sectional sample. Phenotype dimensions were created using confirmatory factor analysis and a 5-factor model. Associations were tested using linear regression, adjusting for age and sex. A Bonferroni correction was applied for (p<1.1x10-6). Lower premorbid IQ was associated with diminished expressivity , reduced motivation and pleasure , disorganised symptoms  and reduced cognition . Poor premorbid social adjustment held associations with all except positive. Developmental delay was associated with reduced cognition . Cannabis use (year before onset), psychosocial stressors (within 6 months), childhood abuse and family history of schizophrenia held no associations.Age of onset of psychosis was significantly associated with positive symptoms (\u03b2=-0.18, p=4.0 x10Clinical indicators measurable at schizophrenia onset are associated with lifetime symptom variability. A younger psychosis onset is associated with more severe positive symptoms, suggesting possible age-targeted management. Pre-established links of lower premorbid IQ with poor premorbid social adjustment and negative symptom severity with cognition are strengthened. Further investigation could potentially improve diagnosis and guide treatment choice for aspects of schizophrenia with poor outcomes.No significant relationships."}
+{"text": "Based on the RECOVERY trial, the NIH strongly recommends systemic corticosteroids for COVID-19 pneumonia with hypoxia. The study demonstrated reduced 28-day mortality after dexamethasone 6mg daily for up to 10 days compared to SOC alone. In practice, physicians may continue therapy for longer periods if potential benefit outweighs potential risk. Little is known about adverse events associated with prolonged corticosteroid use in patients with COVID-19; however, in general, this can increase risk for bacterial or fungal infections. This study aimed to explore the incidence of secondary infections during extended corticosteroid use for COVID-19.A retrospective study was performed in adults at two community hospitals between September 2020 and May 2021 with a diagnosis of respiratory failure secondary to COVID-19 infection. Those with at least one new, laboratory-confirmed secondary infection during hospitalization after at least 10 cumulative days of corticosteroids were included. Demographic characteristics, clinical data and outcomes were extracted from the medical records. Quantitative analyses was performed using SPSS v27.0 and R.Table\u00a01). No patient received immunomodulators for COVID-19 treatment. Patients had a median of 18 days on corticosteroids (range 10-65 days) prior to first positive culture. There were 130 positive cultures identified in blood, urine, and sputum samples , including polymicrobical cultures, yielding 34 clinically relevant organisms (Table\u00a02). Hospital course was complicated by septic shock (68.5%), worsening of lung function (76.7%), and acute organ damage (57.5%); 55 (75%) patients expired during index admission.Of over 1,500 COVID-19 admissions within the timeframe, 73 patients met inclusion criteria (Patients with COVID-19 on extended courses of corticosteroids have relatively higher rates of clinically significant invasive secondary infections and associated poor outcomes. Given there is limited information suggesting improved outcomes with these prolonged courses, risk to benefit analysis must be considered when deciding whether to extend corticosteroid treatment for more than 10 days for COVID-19.All Authors: No reported disclosures."}
+{"text": "The goal of this study was to test whether interpersonal dysfunction, characterized by loneliness and/or dissatisfaction with relationships, is an imminent predictor of financial exploitation vulnerability (FEV) among older adults within a 6-month observation period. This study also tests whether FEV prospectively predicts interpersonal dysfunction. Twenty-six adults aged 50 or older completed a study involving baseline data collection and 13 follow-ups over 6 months. Linear mixed models were used for primary analyses. After adjustment for demographic, psychological, and cognitive covariates, there were between-person effects of FEV and interpersonal dysfunction across follow-ups, suggesting that those with generally higher interpersonal dysfunction compared to other participants also reported greater FEV (B(SE)=1.09(.33), p=.003). There was a within-person effect (B(SE)=.08(.03), p=.007) of elevated interpersonal dysfunction predicting greater FEV two weeks later across all follow-ups. Within-person effect of FEV was not predictive of interpersonal dysfunction (B(SE)=.25(.15), p=.10). Among older adults, individuals with higher interpersonal dysfunction relative to others in the study reported greater FEV throughout the 6-month observation period. Increased loneliness and social dissatisfaction, relative to one\u2019s average level, predicts subsequent increases in FEV, and may be an imminent risk factor for exploitation."}
+{"text": "Mammaliicoccus sciuri (previously Staphylococcus sciuri) is a frequent colonizer of mammals. We report the draft genomes of a methicillin-resistant strain (2254A) isolated from an armadillo and a methicillin-susceptible strain (6942A) from a cow. Genomes were sequenced using long-read Nanopore sequencing. Staphylococcus species belonging to the Staphylococcus sciuri group  were recently reassigned to the novel genus Mammaliicoccus  strain 2254A and methicillin-susceptible M. sciuri (MSMS) strain 6942A were sampled from animals with confirmed clinical infections  containing diluted bacteria and 550 \u03bcL of Bashing Bead Buffer in the initial step. We quantified DNA concentration using Qubit fluorometer (Invitrogen) and DNA quality using NanoDrop spectrophotometer (Thermo Scientific).Sequencing libraries were prepared using the Genomic DNA by Ligation (SQK-LSK110) kit from Oxford Nanopore Technologies (ONT), including the DNA repair step prior to adapter ligation. Long-read sequencing was performed using the MinION platform with R9 flow cells. Sequencing quality was monitored using the MinKNOW v4.5.4 GUI interface. Sequences were base called and demultiplexed using Guppy v5.1.12 (https://github.com/tseemann/abricate), AMRfinderPlus  and SRR19790864 (6942A). Genome assemblies are available at NCBI under accession numbers CP100353 (2254A) and CP099816/CP099817 (6942A).Raw sequence reads have been deposited in the NCBI Sequence Read Archive (SRA) under the BioProject"}
+{"text": "Several restrictive measures have been implemented to reduced COVID- 19 impact with unknown consequences on people daily life.The primary objective is to asses the psychosocial impact and employment status changes since lockdown COVID-19 measures in Chile.Cross-sectional study was implemented using an anonymous and self-administered online questionnaire. Adult people were invited to participate through social networks between May to June 2020. The questionnaire included sociodemographic information, coping strategies, changes in income and working conditions and psychological distress .3102 participants over 18 years answered the questionnaire. 69.9% reported psychological distress mainly women (82.2%), members of the public health system (59%), dependent workers (39.8%), people who suffered income reduction (36.8%)., and those who changed their employment status (26.4%). Participants who presented income reduction were 1.83 times more likely to present psychological distress than those without changes (p <0.001)Pandemic crisis had impacted population health, especially in some specifics groups that could be targeted for future interventions."}
+{"text": "Figure 1A), low grade fever and arthralgias. ENT examination revealed nasal septum perforation , and sensorineural hearing loss. He complained about dry cough and CT thorax  revealed multiple granulomas bilaterally. Nasal mucosa biopsy revealed signs of acute and subacute inflammatory changes with infiltration of neutrophils and histiocytes. From urine microscopy there was microscopic haematuria with glomerular red blood cells. Patient had high c-ANCA (1/160) and PR3 titre. After setting the diagnosis of polyarteritis with granulomatosis (PGA), symptoms regressed with methylprednisolone pulses and cyclophosphamide. Despite immunosuppression, nasal septum deformity requires surgical repair.Nasal and lung features in a patient with Granulomatosis with Polyangiitis . A 39-year-old man presented with a 6-month history of recurrent sinusitis, nose deformity ("}
+{"text": "Background: COVID-19 in hospitalized patients may be the result of community acquisition or in-hospital transmission. Molecular epidemiology can help confirm hospital COVID-19 transmission and outbreaks. We describe large COVID-19 clusters identified in our hospital and apply molecular epidemiology to confirm outbreaks. Methods: The University of Iowa Hospitals and Clinics is an 811-bed academic medical center. We identified large clusters involving patients with hospital onset COVID-19 detected during March\u2013October 2020. Large clusters included \u226510 individuals  with a laboratory confirmed COVID-19 diagnosis (RT-PCR) and an epidemiologic link. Epidemiologic links were defined as hospitalization, work, or visiting in the same unit during the incubation or infectious period for the index case. Hospital onset was defined as a COVID-19 diagnosis \u226514 days from admission date. Admission screening has been conducted since May 2020 and serial testing (every 5 days) since July 2020. Nasopharyngeal swab specimens were retrieved for viral whole-genome sequencing (WGS). Cluster patients with a pairwise difference in \u22645 mutations were considered part of an outbreak. WGS was performed using Oxford Nanopore Technology and protocols from the ARTIC network. Results: We identified 2 large clusters involving patients with hospital-onset COVID-19. Cluster 1: 2 hospital-onset cases were identified in a medical-surgical unit in June 2020. Source and contact tracing revealed 4 additional patients, 1 visitor, and 13 employees with COVID-19. Median age for patients was 62 , and all were male. In total, 17 samples  were available for WGS. Cluster 2: A hospital-onset case was identified via serial testing in a non\u2013COVID-19 intensive care unit in September 2020. Source investigation, contact tracing, and serial testing revealed 3 additional patients, and 8 HCWs. One HCW also had a community exposure. Patient median age was 60 years  and all were male. In total, 11 samples (4 patients and 7 HCWs) were sequenced. Using WGS, cluster 1 was confirmed to be an outbreak: WGS showed 0\u20135 mutations in between samples. Cluster 2 was also an outbreak: WGS showed less diversity (0\u20133 mutations) and ruled out the HCW with a community exposure (20 mutations of difference). Conclusion: Whole-genome sequencing confirmed the outbreaks identified using classic epidemiologic methods. Serial testing allowed for early outbreak detection. Early outbreak detection and implementation of control measures may decrease outbreak size and genetic diversity.Funding: NoDisclosures: None"}
+{"text": "Pediatric chronic osteomyelitis (COM) is an uncommon, poorly defined, debilitating disorder often requiring multiple surgeries and prolonged antibiotic courses. Serious long-term sequelae may occur. As accepted diagnostic criteria do not exist, assessments of disease incidence, medical/surgical approach to management and outcomes are lacking.We created a 14-question web-based survey sent to 390 pediatric infectious disease (PID) physician members of the Emerging Infections Network of the Infectious Diseases Society of America. With no standard definition of COM, respondents were asked to conceptualize this disease as they would during routine clinical practice. Of the 148 (38%) survey respondents so far (Table\u00a01), 126 (85%) reported caring for children with COM. We assessed provider characteristics, diagnostic approach, and site-standard surgical and antibiotic management . We performed descriptive statistics on survey results.Of the 126 respondents, most were >5 years post-fellowship training and nearly half reported managing 3-6 cases of COM per year (Table\u00a02). Prolonged duration of symptoms (79%), normal inflammatory markers (45%), and abnormal plain films (44%) were the most common findings used for diagnosis; however, diagnostic criteria varied. The most common risk factor was orthopedic implants (44%). Management choices and duration are in Figure\u00a01. Most treated with IV antibiotics for < 2 weeks (34%), continuing oral antibiotics for at least 3-6 months (55%). In COM with retained orthopedic implant, most physicians (48%) use oral therapy until implant removal. Considerations for transition from IV to oral antibiotics included improved physical examination (60%), inflammatory markers (52%), extent of disease (55%), causative organism (41%) and location of infection (38%). Though 85% reported being comfortable diagnosing and managing COM, practices varied widely.Reported approaches to surgical management (a), duration of IV antibiotics (b), and duration of oral antibiotics (c) in children with COM, and management of COM in patients with implanted hardware (d)Responses from 126 pediatric infectious diseases physician participating in an Emerging Infections Network survey regarding diagnosis and management of chronic osteomyelitis (COM). Figure\u00a01a) missing data for 2 respondents; figure 1b) missing data for 5 respondents; figure 1c) missing data for 2 respondents; figure 1d) missing data for 9 respondents. COM: Chronic osteomyelitis; IV: intravenous; abx: antibiotics.Pediatric COM is a complex infection. Formal diagnostic criteria and future prospective studies for medical/surgical management by pathogen/site of infection and presence of foreign material are needed to optimize care and outcomes.Daniel Benjamin, Jr., MD PhD MPH, Allergan: Advisor/Consultant|Melinta Therapuetics: Advisor/Consultant|Syneos Health: Advisor/Consultant."}
+{"text": "People living with HIV (PLHIV) with viral hepatitis C (HCV) co-infection have higher risk of liver failure and mortality. Globally, >2 million people globally have HIV/HCV co-infections. Central Asia is one of the regions most affected by HCV. Since 2018, Kyrgystan has provided HCV treatment free of charge to 427 PLHIV. We analyzed factors associated with HCV treatment success among PLHIV in Kyrgystan.We conducted retrospective cohort survey among PLHIV > 18 years old on HIV antiretroviral treatment that completed viral hepatitis C treatment before September 2021. We defined treatment success as having RNA PCR < 15 IU/mL post-treatment and negative DNA PCR 12 and 24 weeks post-treatment. We abstracted demographic, clinical, and laboratory data from the national registry and interviewed consenting participants using structured questionnaires. We used logistic regression to identify factors associated with treatment success.Of 302 participants, 81% were \u2265 40 years old, 79% were male, 72% had ever injected drugs, 53% had ever been incarcerated, and 15% were on methadone. Treatment outcomes were classified as success among 86%. Reluctance to seek healthcare services due to fear of HIV status disclosure was reported by 39% of participants and was associated with reduced odds of treatment success . Participants receiving SMS counseling (64%) had increased odds of treatment success  as did those who followed an HCV diet . Participants with an opportunistic infection (32%) and or HIV stage 3 or 4 (49%) also had decreased odds of treatment success . Initiation of care in 2020 (COVID-19 pandemic beginning) was also associated with reduced odds .Our study found high HCV treatment success in a difficult-to-treat population including during the COVID-19 pandemic. Programs that reduce stigma towards people living with HIV, promote early engagement in care, and provide SMS-based counseling could help increase treatment success for PLHIV in groups at higher risk for non-retention in care.All Authors: No reported disclosures."}
+{"text": "Pregnant women in sub-Saharan Africa represent a high-risk group for HIV infection, but most endemic countries including Uganda do not engage specific HIV prevention measures in pregnancy. This longitudinal study aimed to assess outcomes of a comprehensive, ANC-embedded strategy to prevent seroconversions during pregnancy in Western Uganda.HIV-negative ANC clients were administered an HIV risk assessment tool, followed by individual risk counselling. They received a fixed appointment for repeat HIV testing after three months. Those attending ANC without partners obtained formal partner invitation letters. At follow-up after three months, women not attending repeat testing were reminded via text message. Post-intervention risk behavior engagement was captured. We analyzed uptake of the intervention, HIV incidence rate, and associations with risk behavior.Of 1081 participants, 116 (10.7%) reported risk behavior engagement at first ANC visit, 148/1081 (13.7%) were accompanied by partners. The repeat test visit was attended by 848/1081 (78.5%) women, 42  reported post-intervention risk behavior engagement, and 248  were accompanied by partners. Seroconversion occurred in two women. In multivariable logistic regression, rural facility clients compared to urban ones , and women with positive or unknown partner HIV-status  and partner alcohol abuse  had increased odds for engagement in risk behavior despite the intervention.After our intervention, risk behavior in pregnancy was reduced by half, and partner attendance had doubled compared to baseline. Our cohort showed a 0.76/100 women-years HIV incidence rate compared to 2.85 in pre-intervention data from the same setting. Clients from rural settings and women experiencing precarious partner situations require special attention to reduce risk behavior engagement during pregnancy.\u2022\u2002HIV incidence in pregnancy in Western Uganda can be significantly reduced through a comprehensive, ANC-based counselling intervention.\u2022\u2002Pregnant women from rural settings and those experiencing precarious partner situations require special attention regarding sexual risk behavior."}
+{"text": "Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer. Low numbers of HCC patients being suitable for liver resection or transplantation and multidrug resistance development during pharmacotherapy leads to high death rates for HCC patients. Understanding the molecular mechanisms of HCC etiology may contribute to the development of novel therapeutic strategies for prevention and treatment of HCC. UDP-glucose ceramide glycosyltransferase (UGCG), a key enzyme in glycosphingolipid metabolism, generates glucosylceramide (GlcCer), which is the precursor for all glycosphingolipids (GSLs). Since UGCG gene expression is altered in 0.8% of HCC tumors, GSLs may play a role in cellular processes in liver cancer cells. Here, we discuss the current literature about GSLs and their abundance in normal liver cells, Gaucher disease and HCC. Furthermore, we review the involvement of UGCG/GlcCer in multidrug resistance development, globosides as a potential prognostic marker for HCC, gangliosides as a potential liver cancer stem cell marker, and the role of sulfatides in tumor metastasis. Only a limited number of molecular mechanisms executed by GSLs in HCC are known, which we summarize here briefly. Overall, the role GSLs play in HCC progression and their ability to serve as biomarkers or prognostic indicators for HCC, requires further investigation. Liver cancer is the third leading cause of cancer-related deaths worldwide . In 2020Uridine diphosphate (UDP)-glucose ceramide glucosyltransferase (UGCG) catalyzes the first glycosylation step in the synthesis of GSLs. By transferring UDP-glucose to ceramide, glucosylceramide  is produced, which is the precursor for all complex GSLs. Therefore, UGCG, which resides in the Golgi apparatus, is the key enzyme of GSL metabolism. For more detailed insight into GSL production, we refer to our review from 2020 [Glycosphingolipids (GSLs) contain lipid and sugar moieties. They are important components of the cellular membrane and act as signaling molecules in cellular processes such as apoptosis . Uridinerom 2020 . By addirom 2020 ). The prPrevious studies have demonstrated that UGCG gene expression is altered in 0.8% of HCC tumors  ,11, and glucocerebrosidase (GBA). Furthermore, we summarize how GSL species levels are altered in HCC. We will not cover chronic liver diseases such as NASH, which is an important driver of HCC, since this is already covered in depth here [In this review, we discuss UGCG in normal liver cells and mention briefly how UGCG and GSLs influence cells affected by Gaucher disease, an inherited genetic disorder caused by the deficiency of the enzyme pth here .AMP-activated protein kinase (AMPK) \u03b1 (P-Thr172). This leads to inhibition of energy producing pathways such as glycolysis [rapidly accelerated fibrosarcoma 1 (Raf-1)/extracellular signal-regulated kinase activation, and apoptosis induction [glycosphingolipid-enriched microdomains (GEMs)  markers  cells (NMuLi/UGCG OE) . Overexpycolysis . In neurnduction . Since Aished in ) of UGCGiewed in ) EPCAM, iewed in . Interesiewed in . A conneiewed in . AMPK-iniewed in . Howeveriewed in . In summglucocerebrosidase (GBA) gene results in GlcCer accumulation and is described as the lysosomal storage disease Morbus Gaucher [GBA1 have been identified. Gaucher disease patients exhibit heterogeneous phenotypes. The age of onset and the absence/presence or extent of neurological complications defines the clinical Gaucher disease type. Type 1 is defined as non-neurological, Type 2 as acute neuronopathic, and type 3 as chronic neuronopathic (reviewed in [Mutation of the  Gaucher . More thiewed in ). Morbusiewed in  (revieweiewed in ) and an iewed in . Therefoiewed in ,32). In iewed in ). Futureiewed in . An alteiewed in ). We sugiewed in ).sphingosine-1-phosphate (S1P) levels increase [diethylnitrosamine (DEN)-induced liver tumors in mice, which exhibit a liver specific UGCG knockout (KO) [mechanistic target of rapamycin (mTOR)-activated HCC tumors, and UGCG inhibition reduced proliferation of hepatocytes, tumor burden, and markers of liver damage [Previous studies have shown that UGCG expression is altered in 0.8% of HCC tumors  ,11. UGCGincrease . This deincrease ). Besideout (KO) . The effout (KO) . Since ar damage . These dphosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and RAF)/mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase signaling were detected in liver cancer cells [ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3) in the human liver cancer cell line HepG2 led to increased levels of GlcCer  and downregulation of ORMDL1 also led to an increase in GlcCer levels  to an even greater extent [glucosylceramidase beta 3 (GBA3) is significantly decreased in HCC tissues [The role of UGCG in liver tumorigenesis is likely mTOR-dependent and mTORC2 might be a potential target to treat HCC. Another study showed sorafenib induced UGCG expression leading to sorafenib resistance in liver cancer cells . Howeverer cells . These, r extent . Furtherr extent . Ying et tissues , leading tissues ). GBA3 m tissues . FurtherThere is a limited number of published studies about lactosylceramide and how they impact HCC . One stuDisialosyl galactosyl globoside (DSGG), Gb3, and Gb2 are increased in the serum of HCC patients compared to the serum of healthy individuals [ividuals ; therefoividuals . DSSG haividuals . Contradividuals . Howeverividuals . Furtherividuals , while Aividuals . Thus, gVery early studies showed that GM2 levels are increased in two HCC samples compared to normal liver tissue ,45 and tepithelial cellular adhesion molecule (EpCAM) positive cancer stem cell (CSC)-like HCC cell line JHH7 (D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), an inhibitor of UGCG, decreased ganglioside synthesis and suppressed cell proliferation and spheroid growth of JHH7cells; whereas apoptotic and necrotic cell death were not impacted [Su et al. showed that ganglioside synthesis is increased in the livers of mice in an animal model featuring activation and expansion of liver progenitor-like cells and liver cancer (stem) cells . Togetheine JHH7 B. D-threimpacted . PDMP efimpacted . The autimpacted . Howevercysteine-rich secretory protein (CRISP) family) exhibits anticancer activity in HCC by inhibiting cell proliferation and inducing apoptosis. Lu et al. identified gangliosides as potential biomarkers for natrin-induced apoptosis [Interestingly (and contrary to other studies), natrin (purified from snake venom and a member of the poptosis . FollowiKyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, the authors showed that the immunity groups differ in gene expression of ganglio series GSL producing proteins [Another important parameter to consider is the immune response in HCC development. Zhu et al. investigated immune responses based on the HCC cohort of The Cancer Genome Atlas (TCGA) database . By assiproteins   and iso-CD75s-gangliosides  are increased in HCC tissue, but independent of ST6GAL1 and ST3GAL6 expression . NeuGcGM3HexNAc-Cer , Fuc\u03b13GlcNAc\u03b23Gal\u03b24Glc\u03b21Cer, Fuc\u03b14GlcNAc\u03b23Gal\u03b24Glc\u03b21Cer), Fuc2(Hex)3HexNAc-Cer GlcNAc\u03b23Gal\u03b24Glc\u03b21Cer (Leb-6), Fuc\u03b12Gal\u03b24(Fuc\u03b13)GlcNAc\u03b23Gal\u03b24Glc\u03b21Cer (Ley-6)), and Fuc(Hex)4HexNAc-Cer  are expressed in HCC samples [Zhu et al. showed that fucosylated GSLs are overexpressed in HCC samples compared to the adjacent tissue . In deta samples . More repaired amphipathic helix protein (SIN3B) leading to reduced binding affinity of SIN3B to histone deacetylase 2 (HDAC2). Subsequently, HDAC2 recruitment to the integrin \u03b1V gene promoter is reduced and the promoter thereby activated. This leads to enhanced tumor metastasis [Sulfatides are highly expressed in HCC  and regutastasis  (Table 1enzyme replacement therapy (ERT) or substrate reduction therapy (SRT). SRT encompasses treatment with the UGCG inhibitors eliglustat (first-line therapy) [UGCG/GlcCer is potentially involved in the development of sorafenib resistance in HCC . The comtherapy)  or miglutherapy) . HoweverA4GALT), the reason is the unknown crystal structure of the protein . A moreMany cancer types overexpress certain GSL species such as GD2 and Gb3. GD2 is almost not expressed in normal tissue (reviewed in ). Being"}
+{"text": "Correction to: Scientific Reports, 10.1038/s41598-022-26636-7, published on 13 January 2023In the original version of this Article author Yeajina Lee was omitted as an equally contributing author.\u201cThese authors contributed equally: Jeyul Yang and Seung Ah Choi\u201dnow reads:\u201cThese authors contributed equally: Yeajina Lee, Jeyul Yang and Seung Ah Choi\u201dThe original Article has been corrected."}
+{"text": "Severe spinal cord injury in adults leads to irreversible paralysis below the lesion. However, adult rodents that received a complete thoracic lesion just after birth demonstrate proficient hindlimb locomotion without input from the brain. How the spinal cord achieves such striking plasticity remains unknown. In this study, we found that adult spinal cord injury prompts neurotransmitter switching of spatially defined excitatory interneurons to an inhibitory phenotype, promoting inhibition at synapses contacting motor neurons. In contrast, neonatal spinal cord injury maintains the excitatory phenotype of glutamatergic interneurons and causes synaptic sprouting to facilitate excitation. Furthermore, genetic manipulation to mimic the inhibitory phenotype observed in excitatory interneurons after adult spinal cord injury abrogates autonomous locomotor functionality in neonatally injured mice. In comparison, attenuating this inhibitory phenotype improves locomotor capacity after adult injury. Together, these data demonstrate that neurotransmitter phenotype of defined excitatory interneurons steers locomotor recovery after spinal cord injury. Bertels et al. identify that spinal neurons switch neurotransmitter phenotype from excitation to inhibition after spinal cord injury. Manipulation of neurotransmitter phenotype reveals that maintaining excitatory phenotype is essential for locomotor recovery. However, these are only temporary aids to enable movement generation and do not overcome the obstacle of regaining long-term mobility after injury.Severe spinal cord injury disrupts connections between the brain and the spinal cord, which leads to the inability of body movements controlled by the spinal cord below the lesion. Consequently, spinal circuits require pharmacological agents, electrical stimulation or perineal/tail pinching to generate movements in adult rodents9. This ability to \u2018walk without the brain\u2019 involves spinal-cord-autonomous functions associated with increased excitability of spinal circuits below the lesion11, but the underlying mechanisms remain elusive. In addition, how the same insults imposed at different ages lead to divergent locomotor recovery is unknown, even though insights on these processes likely play a pivotal role in developing interventions that enhance locomotor recovery after spinal cord injury in the adult.Intriguingly, although complete spinal cord lesion leads to paralysis in adult rodents, the same injury given to neonatal rodents results in a strikingly proficient hindlimb locomotor ability in adulthood, without any descending axon regeneration across the lesion or any form of external stimulation14. Along with an injury-induced change in intrinsic motor neuron (MN) properties16, the balance of synaptic input to MNs is one of the determinants of MN excitability. Although severe injury increases inhibitory synaptic input to MNs innervating limb muscles below the lesion, long-term locomotor training reverses the increased inhibitory drive on MNs derived from the local interneurons19. This activity-dependent reorganization of EI input ratio from spinal interneurons to MNs likely contributes to locomotor improvement after long-term training. Furthermore, neuronal activity can trigger long-lasting modification of gene expression profiles that alter neurocircuit functions in a cell-type-specific manner, including neurotransmitter (NT) phenotype switches23. However, little has been explored on whether such activity-dependent mechanisms steer functionality of the spinal cord after injury and how age of injury shapes circuit reorganization.Studies with pharmacological perturbation suggest that regulation of excitation\u2013inhibition (EI) balance of circuits below the lesion is a critical mechanism that defines the motor capacity of spinal-cord-injured cats and rodents, regardless of the age of injury27. PA activity is essential for spinal circuit assembly and function during development29 and locomotor recovery after an incomplete spinal cord injury30. Given the role of proprioception in circuit development, motor control and recovery, PAs are in a prime position to direct locomotor circuits to a functional network after spinal cord injury in the absence of the brain.After a complete spinal cord injury, somatosensory feedback is the only external input to the spinal circuits below the lesion. Among somatosensory populations, proprioceptive afferents (PAs) directly contact MNs and multiple classes of spinal interneurons to transmit movement-matched information necessary for motor controlIn this study, we found that subsets of excitatory, but not inhibitory, spinal interneurons mediate the age of injury-dependent synaptic connectivity profiles to MNs. NT phenotype specification regulates spatially defined subsets of excitatory interneurons to maintain glutamatergic identity after neonatal injury and to gain inhibitory phenotype after adult injury. Furthermore, disrupting their NT identity from excitatory to inhibitory after neonatal injury abolishes the ability to walk without the brain, demonstrating that preserving the glutamatergic phenotype is essential. Using an intersectional genetic model, we found that removal of PAs disrupts glutamatergic phenotype of the subsets of excitatory interneurons after neonatal injury, indicating that continued glutamatergic phenotype expression is dependent on PA activity. Lastly, genetically attenuating inhibitory phenotype after an adult injury significantly improved defined locomotor parameters, especially when combined with locomotor training. Together, our study reveals age of injury-dependent flexible NT phenotype expression of specific classes of excitatory interneurons as critical neuronal substrates that steer locomotor capacity after severe spinal cord injury.To determine the age of injury-dependent locomotor capacity, we subjected wild-type mice to a complete spinal cord transection (cSTX) at low thoracic level ~T10) either at postnatal day 5 (P5) or as an adult (~P60). We used ten high-speed cameras to quantitatively characterize hindlimb kinematics of each group together with intact controls during bipedal treadmill locomotion, all at 3\u20134\u2009months of age Fig. . Althoug0 either 30. We computed 102 parameters  with TauLSL-nlsLacZ-SynGFP reporter mice to conditionally express synaptophysin tagged with green fluorescent protein (GFP) (SynGFPON) in either excitatory or inhibitory spinal interneurons. This approach indelibly labeled synaptic terminals derived from either genetically glutamatergic vGlut2ON or inhibitory vGATON interneuron populations  at the junction of choline acetyltransferaseON (ChATON) MNs in intact spinal cords  output that controls muscle contractions. As inhibitory synaptic input to MNs is known to increase after injury, we asked whether the EI synaptic input ratio from spinal interneurons to MNs that innervate hindlimb muscles depends on injury age. To visualize excitatory and inhibitory synaptic terminals, we crossed major excitatory or inhibitory NT Cre-driver lines  in vGlut2cre::Tau-SynGFPLSL spinal cords where almost half of the synaptic terminals derived from vGlut2ON neurons became vGAT+  and vGAT (Slc32a1) mRNA. In an intact spinal cord, we detected neurons with a singular expression of vGlut2 or vGAT transcripts in equal abundance with only a minor proportion of neurons co-expressing vGlut2 and vGAT transcripts, distributed sparsely along the dorsoventral axis -specific transcription factor  and Shox2ON (V2a), but not Sim1ON (V3), interneurons exhibited increased SynGFPON/vGAT+ and decreased SynGFPON/vGlut2+ terminals to MNs cre and AdvilliniDTR mouse lines, to express human diphtheria toxin (DTX) receptor (DTR) in PVON/AdvillinON somatosensory afferents30. This approach enabled ablation of PAs with DTX at the time of injury at P5 (P5 cSTX+PADTX), which led to a substantial reduction of central PAs marked by vGlut1ON terminals while leaving the minor non-proprioceptive somatosensory vGlut1ON terminals unaffected put Fig. . Given tted Fig. . In contvGlut2 and vGAT mRNA in P5 cSTX, P5 cSTX+PADTX and intact+PA ablation alone at P5 (intact+PADTX) groups. Although P5 cSTX alone does not alter the transcript ratio, P5 cSTX combined with PA ablation showed a marked increase in neurons with vGAT/vGlut2 co-expression in the dorsal and intermediate lamina, like the adult cSTX group  by excitatory neurons  against vGAT gene expression in the lumbar segments , AdvilliniDTR (ref. 64), vGlut2cre (JAX stock no. 028863), vGATcre (JAX stock no. 016962), Tlx3cre (041158-UCD), Shox2cre (ref. 55), Sim1cre (ref. 65), Rosa26LSL-tdTomato (JAX stock no. 007908) and TauLSL-nlsLacZ-SynGFP-INLA (ref. 29) mouse strains were maintained on a mixed genetic background (129/C57Bl6). Adult mice of both sexes, aged 2\u20136\u2009months, were used for all experiments. Mice were group housed, and all mice were kept on a 12-hour light/dark cycle in a facility where temperature was kept at 22\u2009\u00b1\u20092\u2009\u00b0C and ~50% humidity. All animal procedures were conducted in accordance with Belgian regulations and were approved by the institutional ethical committee of KU Leuven.Wild-type (C57Bl6), \u22121) was provided after surgery, and antibiotics  were provided for 3\u2009days after surgery. Mice were housed on a 12-hour light/dark cycle with ad libitum access to food and water and cared for twice daily with manual bladder voiding. Complete transections were confirmed postmortem by visual inspection of the spinal cord.For neonatal complete spinal cord transection, 5-day-old pups were anesthetized with ice, and muscles were separated along the midline to expose the vertebral column. Laminectomy was performed using forceps at spinal segment \u223cT10, and the spinal cord was completely transected using micro-scissors. After surgery, mice were placed in a heat chamber until fully awake. All other surgical procedures were performed under aseptic conditions and full general anesthesia with isoflurane in oxygen-enriched air (1\u20132%). Adult mice underwent a mid-dorsal skin incision to access the spinal cord, and a laminectomy was made over the spinal segment T10. A complete spinal cord transection was performed using micro-scissors. Analgesia  at 5\u201315\u2009cm\u2009s\u22121, after intraperitoneal injection of monoaminergic agonists, consisting of 5-HT1A/7 agonist 8-Hydroxy-DPAT hydrobromide  and 5-HT2A/C agonist Quipazine . Neonatally injured or adult injured mice with muscle atrophy, incomplete spinal cord injury or occasional spinal cord degeneration were excluded from the study.Bipedal locomotor kinematic recordings were performed using the high-speed motion capture system Vicon (Vicon Motion Systems). Ten infrared cameras (200\u2009Hz) were used to detect 3-mm reflective markers attached bilaterally on the mice overlying the iliac crest, the greater trochanter (hip), the lateral condyle (knee), the malleolus (ankle) and the base of the metatarsal phalangeal joint. Positions of the markers were reconstructed offline in three dimensions (3D) using Vicon Nexus software (version 2.12). The hindlimb was modeled as interconnected segments, and joint angles were calculated accordingly. Parameters  are extracted, color-coded based on their correlation value and regrouped into functional clusters.Locomotor analysis after shRNA injection. For the shRNA+training group, mice underwent daily locomotor training starting from 2\u2009weeks after lesion for 4\u2009weeks. Kinematic recordings were performed at week 5 and week 6 for all four groups . The number of consecutive steps, dorsal and plantar steps combined and bouts were quantified over one recording session (30\u2009seconds) from either week 5 or week 6. Dragging is defined as a contact of the dorsal surface of the foot to the ground during the swing phase. After kinematic reconstruction, each step cycle is manually inspected by an experimenter with 100-Hz digital camera recordings to confirm foot ON/OFF segments.\u22121) and subcutaneously for P5 mice (100\u2009\u00b5g\u2009kg\u22121) following an established protocol30. To verify ablation efficiency, we determined vGlut1ON afferent density postmortem. Inclusion criteria were set at >50% ablation after normalization compared to intact conditions.DTX  was injected intraperitoneally for adult mice  for adult mice or hypothermia for P5 mice, a mid-dorsal skin incision and laminectomy were performed to expose the spinal cord. The intraspinal injection was made using a pulled calibrated glass pipette (World Precision Instruments) by multiple short pulses  using a picospritzer (Parker Hannifin).vGlut2cre::TauLSL-lacZ-SynGFP-INLA mice was performed concomitantly with a T10 complete transection of the spinal cord on neonatal mice at P5. We aimed to deposit the virus in the dorsal/intermediate lamina, where the NT phenotype switch occurs. Mice underwent kinematic recordings around P60. Virus infection efficiency was determined postmortem, with inclusion criteria set at >95% survival of genetically marked vGlut2ON interneurons, compared to a cohort of mice without intraspinal injection, and >90% of virus-tagged neurons are in the dorsal or intermediate lamina where the double-positive neurons reside after adult injury or P5 cSTX+PADTX. In addition, we only included mice that showed the vGAT gradient ranges from the highest vGATON/SynGFPON terminal value of P5 cSTX+vGAT to the lowest of P5 cSTX+control , within \u00b12 standard deviations of the % SynGFPON/vGAT+ computed from individual MNs in the adult cSTX group  at week 5 or week 6. For the shRNA+training group, mice underwent daily locomotor training for 4\u2009weeks, and kinematic recordings were obtained. Virus infection efficiency was determined postmortem, with inclusion criteria set at <30% mean expression of vGAT+ at SynGFPON terminals. A subset of mice underwent a mock injection before the injury as a control.A bilateral intraspinal virus injection of AAV-floxed-\u22121) subcutaneously for analgesia. Mice were perfused for analysis 4\u2009days after injections.Using isoflurane anesthesia, mice underwent laminectomy to expose the surface of the spinal cord. A pulled calibrated glass pipette (Drummond Scientific) was used for local application of 100\u2009nl of virus by multiple short pulses  using a picospritzer (Parker Hannifin). After surgery, mice were administered Metacam  does not differ from P5 cSTX at ~P35.We used spinal cord tissue >1 month after injury for both P5 and adult cSTX groups. To make sure that age of tissue per se is not the driving factor for In situ detection was performed on 16-\u00b5m-thin cryosections of fresh frozen spinal cord sections using RNAscope Fluorescent Multiplex Assay (Advanced Cell Diagnostics) with custom-designed probes (RNAscope Probe-Mm-Slc17a6 (vGlut2) 319171, RNAscope Probe-Mm-Slc32a1-C2 (vGAT) 319191-C2 and RNAscope Probe-Mm-TdTomato-C3 317041-C3). Tissue sections were labeled with DAPI .\u22121, intraperitoneally) and xylazine  and perfused with 4% paraformaldehyde. All collected tissue was cryoprotected in 30% sucrose/PBS and cut on a cryostat . Floating tissue sections were incubated with antibodies in individual wells and slide-mounted for imaging. Antibodies used in this study were as follows: chicken anti-\u03b2-galactosidase ; chicken anti-GFP ; goat anti-ChAT ; guinea pig anti-gephyrin ; guinea pig anti-vGlut1 ; mouse anti-glycine receptor alpha 1 (GlyR\u03b11) ; mouse anti-NeuN ; mouse anti-vesicular GABA transporter (vGAT) ; mouse anti-vesicular glutamate transporter 2 (vGlut2) ; rabbit anti-GABA ; rabbit anti-GFP ; rabbit anti-vesicular GABA transporter (vGAT) ; and rabbit anti-vesicular glutamate transporter 2 (vGlut2) . Fluorophore-coupled secondary antibodies were obtained from Jackson Laboratory and used at 1:1,000: Alexa Fluor 488 donkey anti-chicken (703-545-155); Alexa Fluor 488 donkey anti-guinea pig (706-545-148); Alexa Fluor 488 donkey anti-mouse (715-545-150); Cy3 donkey anti-goat (705-165-147); Cy3 donkey anti-guinea pig (706-165-148); Cy3 donkey anti-mouse (715-165-150); Cy3 donkey anti-rabbit (711-165-152); Alexa Fluor 647 donkey anti-goat (705-605-147); Alexa Fluor 647 donkey anti-mouse (715-605-150); and Alexa Fluor 647 donkey anti-rabbit (711-605-152).All mice were deeply anesthetized with ketamine  spot detection and color-coded according to their location based on Paxinos and Franklin\u02bcs mouse brain atlas. Coordinates of rabies-marked neurons were assigned manually.All brain and spinal cord images were acquired using a slide scanner  or a confocal  microscope and aligned using ImageJ TrakEM. Surfaces were automatically detected using the Imaris Surface Detection module. RabiesvGlut2 or vGAT only when the cell contained >8 transcripts of vGlut2 or vGAT. Neurons were considered double-positive when the cell contained >8 transcripts of one NT and >4 transcripts of the other NT. The number of neurons per category was normalized to the volume of the gray matter. Alignments were normalized using central canal coordinates. Poorly prepared samples were excluded from the study .Spinal cord pictures were acquired using a slide scanner microscope . Neurons were categorized into three different categories using Imaris. Neurons were considered ON MNs. Synaptic density was computed by the number of synaptic terminals normalized to the surface area of ChATON MNs. The ROUT method was used for the identification and removal of outliers.High-resolution analysis of synaptic input to interneurons and MNs was acquired using a confocal microscope . Imaris was used for the quantification of interneuronal input to ChATImages were acquired using a confocal microscope . Alignment, quantification and extraction of coordinates were performed with ImageJ.t-tests  were randomly assigned to experimental groups. Data collection and analysis were not performed blinded to the conditions of the experiments. Animals from different experimental groups were age-matched. A subset of animals was excluded from experiments post hoc (see above subsections for exclusion criteria).All statistical analyses were performed and plotted using R (version 3.5), MATLAB (version 2014a or version 2018a) or GraphPad Prism (version 8.0). The means of different data distributions were compared using two-sided unpaired ts Figs.  and 5e, ts Figs.  and 8b,dts Figs. . SignifiFurther information on research design is available in the Any methods, additional references, Nature Research reporting summaries, source data, extended data, supplementary information, acknowledgements, peer review information; details of author contributions and competing interests; and statements of data and code availability are available at 10.1038/s41593-022-01067-9.Supplementary InformationSupplementary Table 1Reporting SummarySupplementary Video 1\u22121) compared to dragging adult cSTX miceIntact and P5 cSTX mice show proficient weight-supported bipedal locomotion (15\u2009cm\u2009sSupplementary Video 2A complete spinal cord retransection of P5 cSTX mice does not alter locomotor proficiencySupplementary Video 3ON neurons after neonatal injury deteriorates the ability to walk without the brainVirus-mediated vGAT expression by vGlut2Supplementary Video 4ON neurons after adult injury facilitates stepping abilityVirus-mediated vGAT suppression by vGlut2"}
+{"text": "Drosophila have provided a powerful platform to study the basic principles of tumour growth and progression via cell-cell communications. This led to the identification of oncogenic cell-cell interactions triggered by endocytic dysregulation, mitochondrial dysfunction, cell polarity defects, or Src activation in Drosophila imaginal epithelia. Such oncogenic cooperations can be caused by interactions among epithelial cells, mesenchymal cells, and immune cells. Moreover, microenvironmental factors such as nutrients, local tissue structures, and endogenous growth signalling activities critically affect tumorigenesis. Dissecting various types of oncogenic cell-cell interactions at the single-cell level in Drosophila will greatly increase our understanding of how tumours progress in living animals.Cell-cell interactions within tumour microenvironment play crucial roles in tumorigenesis. Genetic mosaic techniques available in  For instance, colorectal cancer is developed by the sequential acquisition of genetic mutations in the 53 genes . This in53 genes .Drosophila have identified crucial tumour-suppressor genes including components of the Hippo pathway and dissected the underlying mechanisms [Drosophila enables to visualize and genetically manipulate cell clones in vivo [Drosophila imaginal epithelium, clones of cells expressing a constitutively activated form of Ras (RasV12) form benign tumours, which develop into malignant tumours when additional mutations in the apico-basal polarity gene such as scribble (scrib) or discs large (dlg) are introduced [V12 clones with loss of cell polarity cause unlimited growth, invasion, metastasis, and the animal lethality [Drosophila is a useful model organism to investigate clonal behaviour of cells with oncogenic alterations in vivo. Another achievement of the fly works using the genetic mosaic technique is that it has unveiled the existence of oncogenic alterations that promote non-autonomous tumour progression in surrounding cells via cell-cell interactions [Drosophila have shown that oncogenic cell clones drive tumour progression via cell-cell communications with normal epithelial cells, tumour cells with distinct oncogenic alterations, and other type of cells. In this review, we summarize the mechanisms of tumour progression driven by cell-cell communications found in Drosophila and discuss the roles of such oncogenic cell-cell interactions in other biological contexts, as well as the similarity between Drosophila and mammalian cancer progressions.Genetic studies in chanisms . Particu in vivo ,10, whic in vivo . In Drostroduced ,12. RasVethality ,12. Thusractions . Recent Drosophila imaginal discs have discovered that oncogenic mutations can drive tumour progression via cell-cell communications  in the imaginal disc cause overproliferation of surrounding cells [Rab5 (an early endosome component) drive non-autonomous overgrowth of surrounding tissue via Upd, but the underlying mechanism is different from that caused by vps25 or ept mutants. Clones of Rab5 mutant cells activate EGFR-Ras and Eiger (a TNF homolog)-JNK signalling, which cooperate to activate the transcriptional coactivator Yorkie  via inactivation of the Hippo pathway, leading to the induction of its target Upd [vps25 and Rab5 mutants, both mutant cells exhibit the same cell cycle status. Rab5 mutant cells enter the endocycle by downregulating Cyclin B via cooperation between JNK and Yki-DIAP1 (Drosophila inhibitor of apoptosis protein 1) signalling, thereby becoming polyploid giant cells [vps25 or avalanche  show polyploidization phenotype, which is caused by Eiger/TNF-JNK signalling [Genetic screens in ng cells . These mng cells   overproduce reactive oxygen species (ROS), which activates JNK signalling. JNK and Ras signalling cooperatively activate Yki via inactivation of the Hippo pathway, leading to overproliferation of surrounding cells via induction of Upd and Wingless  [\u2212/\u2212/RasV12mito cells cause tumour malignancy in their neighbouring RasV12 benign tumours [\u2212/\u2212/RasV12mito cells undergo cellular senescence via enhanced activation of JNK signalling through cooperation between ROS production and p53-mediated cell cycle arrest and thus exhibit SASP (senescence-associated secretory phenotype) [V12 clones, RasV12 cells with higher p53 expression support survival of neighbouring RasV12 cells with lower p53 expression by inducing Upd [\u2212/\u2212/RasV12Drosophila mito cells, IR irradiation in human lung cancer cells causes production of mitochondrial ROS and G2/M phase arrest [+/NADH ratio and AMPK-induced p53 activation are required for the induction of MiDAS [Mutational activation of  cancers ,24. A geg tissue . Mechanihomolog)   , suggest tumours   . SASP isenotype) ,29. Thesenotype) ,29. Relacing Upd . Similare arrest . Notablyof MiDAS . The facof MiDAS  suggestsscrib or dlg massively overgrows and develops into invasive tumours [scrib clones drives tumour progression when Ras signalling is activated in their neighbouring cells [scrib clones propagates to neighbouring RasV12 cells, thereby causing metastatic overgrowth of Ras-activated clones via activation of JAK-STAT signalling triggered by JNK-dependent Upd induction [scrib-induced cell competition, it has been shown that JNK-induced upd expression in neighbouring wild-type cells promotes cell proliferation and thus compensates for the lost space after scrib cell elimination [V12 overexpression and scrib knockdown (scrib-KD) overproduce mitochondrial ROS, which elevates TOR signalling in these cells and causes engulfment of neighbouring scrib-KD cells [Drosophila, scrib-KD MDCK cells are excluded from epithelial cell sheet, although it is not caused by JNK but by p38 MAPK signalling [scrib-KD/V12Ras MDCK cells outcompete neighbouring scrib-KD MDCK cells by entosis, suggesting that oncogenic mutant cells can clonally expand their territory by cell competition in the early stage of carcinogenesis.Apico-basal polarity is essential for maintaining epithelial integrity and its disruption is often a critical event for cancer progression . Epithel tumours . Interes tumours ,12, a ph tumours . Eiger-J tumours ,41 and c tumours , and is  tumours . While E tumours ,45. JNK  tumours . Interesng cells   are eliminated by cell competition when surrounded by wild-type cells [Drosophila imaginal disc [V12 and Src clones increase the cell surface ligand Delta and its receptor Notch, respectively, and thus Delta-Notch interaction occurs at the boundary between these clones. Activated Notch signalling in Src clones induces the transcriptional repressor Zfh1 (a ZEB1 homolog), which transforms Src cells into malignant tumours by downregulating shotgun  and a pro-apoptotic gene hid [V12 cells. STAT activation in RasV12 cells causes Chinmo-mediated repression of shg and thus induces tumour malignancy [V12 clones show limited tumour growth. Notably, loss of cell polarity in RasV12 clones causes Yki-mediated induction of microRNA bantam, which cancels Ras-induced cellular senescence by downregulating Pnt [V12 cells evade Pnt-mediated cellular senescence. One possibility is that Src cells induce non-autonomous activation of Yki in neighbouring RasV12 cells. Indeed, while Src clones surrounded by wild-type cells are eliminated by JNK-dependent cell death, Src cells simultaneously propagate Yki activity to neighbouring cells in a JNK-dependent manner [The tyrosine kinase Src is a classical oncoprotein and its expression and activity have been shown to be correlated with cancer development . In Drospe cells ,56. Elimpe cells ,58. Givepe cells , Src-actnal disc  , scrib clones evade cell competition and develop into tumours by elevated insulin signalling [chico levels overproduce Drosophila Insulin-like peptide 2 (Dilp2), which causes hyperinsulinemia and remotely activates insulin-TOR signalling in scrib mutant clones, thereby evading cell competition by increasing intracellular protein synthesis [Recent transcriptomics and metabolomics analyses have revealed that human cancer cells utilize nutrients for cell proliferation, survival, invasion, and metastasis . Interesulinemia . Brieflygnalling  , which activates TOR-S6 signalling by uptaking leucine to promote tumour growth [Rab5 mutation with overexpression of microRNA bantam (\u2212/\u2212Rab5/ban) [\u2212/\u2212/RasV12scrib and \u2212/\u2212Rab5/ban clones in Drosophila.It has also been shown that amino acid metabolism plays pivotal roles in tumorigenesis in ergrowth . Intrigur growth ,64. Thesr growth   . Thus, s\u2212/\u2212/ban) , leucineV12 clones with mutations in C-terminal Src kinase  (\u2212/\u2212/RasV12csk) induce Branchless  that causes systemic muscle wasting, leading to increased circulating amino acids (\u2212/\u2212/RasV12csk clones then uptake proline via the SLC36 transporter Pathetic (Path) that is upregulated by Yki activation, thereby promoting tumorigenesis via TOR-S6 signalling activation [\u2212/\u2212/RasV12csk clones [Src-activating cells require other amino acids for tumorigenesis. In flies fed with high dietary sucrose (HDS), Rasno acids . csk\u2212/\u2212/tivation  , a transcription factor involved in epigenetic control, massively overgrow [EGFR+psq-RNAi cells produce Decapentaplegic , which activates Mad (a Smad homolog) in myoblasts (progenitor cells for flight muscles) that exist at the basal side in the notum region of the wing disc  marker \u03b1-smooth muscle actin (\u03b1-SMA) [ZEB1 deletion suppresses mammary tumour formation in a mouse model of breast cancer [Drosophila could contribute to understand human cancer development.In the wing imaginal disc, EGFR-activated cells with loss of overgrow . In thising disc . The MadAi cells   . Jagged  (\u03b1-SMA) . In addit cancer . Notablyt cancer . Thus, sDrosophila macrophage-like cells plasmatocytes (hereafter macrophages) are recruited to malignant tumours in the imaginal epithelium. \u2212/\u2212/RasscribV12 clones generate damaged basement membrane and reactive oxygen species (ROS), which are required for macrophage recruitment [\u2212/\u2212/RasscribV12 clones via JNK activation [scrib [dlg mutant tumours, which causes tumour cell death by inducing Eiger [dlg mutant tumours [V12scrib-RNAi+Ras cells is unaffected by loss of macrophage [Macrophages penetrate tumour tissues and support tumour progression by regulating tumour growth, invasion, metastasis, angiogenesis, and immunosuppression . It has ruitment . It has tivation ,86 , which is secreted from macrophages by exosome-like vesicles for systemic immunity [Thus, the role of fly macrophages in tumorigenesis is still obscure. A possible explanation for this is that different macrophage subsets infiltrate into different tumours. In mammals, there are two subtypes of macrophages, M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophages, and their roles and functions are plastically changed in response to tissue environmental cues . Intriguulations  and its ulations , bacteriulations . Anothernfection . In adulnfection . This vDimmunity . Thus, fimmunity . If fly Drosophila have elegantly dissected the origin of tumorigenesis and regeneration in the wing imaginal disc. In the pouch region of the wing disc, clones of scrib cells are basally eliminated from the tissue, whereas those cells induced in the hinge region delaminate from the apical side and initiate tumorigenesis in the lumen [Drosophila, apically delaminated polarity-deficient cells originate tumorigenesis, while oncogenic cells that are basally delaminated can cause non-autonomous tumour growth. In the wing disc, the basally delaminated cells with chromosomal instability (CIN) (e.g. bub3- or rod-depleted cells expressing a caspase inhibitor p35) cause epithelial tumorigenesis via JNK-mediated Wg expression [\u2212/\u2212/RasV12mito, CIN also causes cellular senescence through mitochondrial dysfunction and triggers non-autonomous growth. Thus, downregulation of mitochondrial function may be an etiology of cancer development through oncogenic cell-cell interactions.Epithelial tissue structures differ even within the same tissue, and its patterning is thought to be a crucial factor for tumour initiation and development. For instance, colon cancers frequently develop at the rectum and sigmoid colon regions . Similarhe lumen . Genetiche lumen . Such tihe lumen ,105. IR-he lumen . These ohe lumen . In addihe lumen . Notablypression . Delaminpression . AlongsiDrosophila have provided a brilliant platform to understand the basic principle of tumour progression via cell-cell communications. In this review, we summarized the studies on tumour progression driven by local and systemic cell-cell interactions in Drosophila (scrib mutations during tumour development [Drosophila ovary [Drosophila. Given that recent multi-omics techniques allow us to analyse cells in human cancer tissues at the single-cell level and that single-cell techniques and applications using Drosophila tissues/organs are rapidly developing [Drosophila tumours at the single-cell level will greatly increase our understanding of the mechanisms of tumour initiation and progression.Genetic studies in osophila . Recent elopment ,112. A sla ovary . Thus, dveloping , dissect"}
+{"text": "Substantial progress in the treatment of multiple myeloma (MM) has led to improved patient outcomes and prolonged survival of patients. These therapeutic advances have resulted in increased cumulative immunosuppression leading to increased susceptibility to opportunistic infections including CMV infection. The significance of CMV infection in MM patients is not well understood. We sought to describe the clinical characteristics and outcomes of patients with MM who develop CMV infection.Retrospective chart review of MM patients at Mount Sinai Hospital in NY who had CMV DNA PCR sent. The Mount Sinai Multiple Myeloma Database was utilized to identify patients who developed CMV viremia. Demographic, clinical and laboratory data were abstracted from electronic medical records. IRB approval was obtained.Statistical AnalysisFactors associated with 30-day mortality by univariate analysis were evaluated using Fischer\u2019s exact and Wilcoxon rank-sum test.Demographics414 MM patients had CMV PCR sent at least once. Forty-six cases of CMV infection were identified.CMV Infection CharacteristicsForty-six patients were found to have CMV viremia, defined as PCR >500 IU/mL. Twenty-two (47%) had symptomatic infection. One patient had CMV pneumonitis and in 7/46 (15%) patients, CMV end-organ disease was suspected. Twenty (43%) patients had progressive disease status, 73% had prior history of autologous stem cell transplant and 85% had received steroids within 30 days of CMV infection. Twenty-nine (63%) patients had concurrent infections within 30 days of CMV infection, including bloodstream infection (n=16), bacterial pneumonia (n=9), respiratory viral infection (n=6), infectious colitis (n=5), and fungal infection (n=3).Outcomes9/46 (19%) patients died within 30 days of CMV infection and 12/46 (26%) required ICU admission during that hospitalization. In univariate analysis of risk factors associated with mortality, higher weekly steroid dose approached statistical significance (p=0.06) and peak CMV PCR >1000 IU/mL (p.008) was associated with lower mortality.CMV infection is associated with morbidity and mortality in MM patients. Prospective studies are needed to better assess the clinical significance of CMV reactivation in this population.Emily Baneman, MD, Merck: Grant/Research Support."}
+{"text": "Background: Although many infectious conditions can be safely treated with oral antimicrobials, select circumstances require parenteral antimicrobial therapy. Benefits of OPAT include prevention of hospital-associated conditions and significant cost savings. However, risks of OPAT include adverse drug events (ADEs) and vascular access device (VAD) complications. We analyzed the safety of OPAT regimens as part of implementing a collaborative OPAT program. Methods: We reviewed adult patients discharged home from an academic hospital between January 2019 and June 2021. Patients with cystic fibrosis were excluded. Data on OPAT agents, ADEs, and VAD complications were collected from electronic medical records by 2 reviewers using a standardized REDCap instrument. The institutional review board approved this study. Results: The cohort comprised 265 unique patients; 212 (80%) received single-drug therapy and 53 (20%) received multidrug therapy. In total, 81 patients (31%), who received a total of 110 antimicrobials, experienced an ADE. In total, 55 patients (21%), who received a total of 72 antimicrobials, experienced a VAD complication. Patients who received >1 antimicrobial were more likely to experience an ADE  or a VAD complication . Cephalosporins were the most frequently prescribed antimicrobial class  the selection of OPAT therapy and (2) the standardized monitoring of patients who receive OPAT going forward in the implementation of this collaborative OPAT program.Funding: NoneDisclosures: None"}
+{"text": "Neurofilament light chain (NfL) is a biomarker indexing axonal integrity where small NfL variations may be associated with cognitive performance in early adulthood and high values associated with neurodegenerative disorders such as Alzheimer\u2019s disease. In the Colorado Adoption/Twin Study of Lifespan behavioral development and cognitive aging (CATSLife1) individuals were tested at 28\u201349 years . Quanterix Simoa assays of plasma NfL (pNfL) were measured in duplicate, and we included values for 1159 individuals where 1098 had available general cognitive ability scores and sociodemographic covariates. Unadjusted NfL values were consistent with other studies of early-mid adulthood  and 6% showed values outside expected normal reference limits (>10 pg/mL). After adjusting for technical covariates and skew, higher natural log-transformed pNfL was associated with age (r = 0.27) and female sex (r = 0.07). Moreover, adjusting for sociodemographic covariates, higher pNfL was associated with lower general cognitive ability (GCA) (r = -.06), where associations were more pronounced above the mean pNfL value (r = -.08). Multi-level regression analyses suggested that GCA-NfL associations were modified by age, whereby the worse performance was observed at higher ages and pNfL values (p <= 0.03), accounting for sibling relatedness and sociodemographic covariates. We observed small negative associations of higher plasma NfL and lower cognitive performance, where associations may become magnified with increasing age in early- to mid-adulthood."}
+{"text": "The benefits of routine engagement in physical activity (PA) on vascular health are well established; lesser known is whether vascular health associates with accelerometry-based daily patterns of PA in mid-to-late life. Using linear regression models adjusted for demographics and comorbidities, we modeled the cross-sectional associations between ankle brachial index (ABI) and PA patterns  in 7,848 HCHS/SOL participants . Compared to those with normal ABI (1.0-1.4), those with low ABI (\u22640.9) had more fragmented daily activity ; primarily between 12 and 8 PM . Similarly, those with low ABI had lower daily activity throughout the day  also mainly between 12 and 8 PM . Results suggest a diminished, less favorable PA profile patterns in those with low ABI. Future longitudinal studies should consider whether patterns of PA assist in determining PAD risk."}
+{"text": "Endoscopic resection techniques have become the primary treatment strategy for the vast majority of large (\u2265 20mm) non-pedunculated colonic polyps (LNPCPs). Despite this, surgery is still commonly performed with evidence suggesting an increasing trend over time. There is limited Canadian data confirming the effectiveness and safety of an endoscopic management strategy for LNPCPs.To investigate clinical outcomes of patients referred for endoscopic management of a LNPCP.Retrospective single-centre analysis of patients referred to a single endoscopist for the management of LNPCPs within a tertiary referral practice. LNPCPs were further subdivided into non-complicated (NC-LNPCP) or complicated (C-LNPCP) defined as those involving the ileocecal valve, appendiceal orifice, circumferential or previously attempted. Performance outcomes were evaluated by the frequencies of technical success  and need for colorectal surgery. Safety was evaluated by the frequencies of clinically significant intraprocedural bleeding (CSIPB), clinically significant post-endoscopic resection bleeding (CSPEB), intra-procedural perforation and delayed perforation. Recurrence (either endoscopic or histologic) was evaluated at first surveillance colonoscopy (SC1). Continuous variables were summarized using median (IQR). Categorical variables were summarized as frequencies (%). To test for association between categorical variables, the Pearson \u03c72 or the Fisher exact test were used, where appropriate. For continuous variables, the Mann-Whitney U test was used. A probability (p) value of <0.05 was considered statistically significant.Between January 2021 to March 2022, 263 LNPCP were referred for endoscopic resection and 41 LNPCP were excluded . 222 LNPCP  underwent endoscopic resection. Median size was 25mm (IQR 20-30mm) with the majority undergoing cold snare resection . Polyposis (Adenomatous or serrated) was present in 23 (12.6%) cases respectively. Technical success was 97.3%. Cancer was present in 5 (2%). Clinically significant bleeding (CSPEB) occurred in 2.7%, DMI IV in 1.8% and there were no delayed perforations. Recurrence occurred in 4 (3.5%) at SC1 and 11 (5%) required surgery due to technical failure, submucosal invasion on pathology and clinically significant bleeding.Endoscopic resection as the primary treatment strategy for LNPCPs offers a safe and effective alternative to surgery in British Columbia.NoneNone Declared"}
+{"text": "Prospective studies of interferon-gamma release assays (IGRA) on healthy subjects in tuberculosis-endemic regions have not examined the long-term variability of serial assays. This issue is relevant to the interpretation of tuberculosis (TB) vaccine trials based on prevention of infection.T-SPOT.TB assays were performed manually on healthy adolescents during a tuberculosis vaccine trial in Tanzania at 5 intervals over 3 years. Assay results were defined as negative, positive, borderline or invalid. Subsequently, microtiter plates were analyzed by an automated reader to obtain quantitative counts of spot forming cells (SFCs) for the present analysis.p < 0\u00b7007); 44 vs 34 for ESAT-6 (p = 0\u00b712).3387 T-SPOT.TB samples were analyzed from 928 adolescents; manual and automated assay results were 97% concordant. Based on the quantitative results 143 (15%) participants were prevalent IGRA-positives at baseline, were ineligible for further study. Among the remaining IGRA-negative participants, the annual rate of IGRA conversion was 2\u00b79%. Among 43 IGRA converters with repeat assays 12 (28%) were persistent converters, 16 (37%) were transient converters, and 15 (35%) comprised a new category defined as irregular converters (\u22652 different subsequent results). ESAT-6 and CFP-10 responses were higher in prevalent than incident positives: 53 vs 36 for CFP-10 (M. tuberculosis disease.Definitions of IGRA conversion, reversion, and persistence depend critically on the frequency of testing. Multiple shifts in categories among adolescents in a TB-endemic country may represent multiple infections, variable host responses in subclinical infection, or assay variation. These findings should to be considered in the design and interpretation of TB vaccine trials based on prevention of infection. Household contact studies could determine whether even transient IGRA conversion might represent exposure to an active case of  The World Health Organization (WHO) has recently targeted identification and treatment of persons with latent tuberculosis infection (LTBI) as a critical component of TB control in countries with both low and high TB incidence . LTBI isIn a recently completed trial of the investigational TB vaccine DAR-901, we performed \u2265 5 serial T-SPOT.TB assays over three years on a cohort of adolescents in Tanzania, and used manual counts of Spot-Forming Cells  to define study endpoints . Subjects with first positive IGRA at an unscheduled visit ((DOCX)Click here for additional data file."}
+{"text": "Background: Inappropriate antibiotic use for SARS-CoV-2 infection has the potential to increase the burden of antibiotic resistance. Brazil experienced spread of a new SARS-CoV-2 variant in the fourth quarter (Q4) of 2020, resulting in the highest case counts in Latin America, raising concerns of antibiotic overuse. To better understand antibiotic use during the COVID-19 pandemic, we evaluated prescribing changes in antibiotics commonly used for outpatient respiratory infections  among adults aged \u226520 years in Brazil in 2020 versus 2019. Methods: We analyzed the IQVIA MIDAS medical data set for AALM prescribing by age group , comparing Q4 2020 rates to those in Q4 2019. We estimated crude rate ratios and 95% CIs using prescription number as the numerator (assuming Poisson counts) and age-adjusted population as the denominator. We also determined the most common prescribing specialties for each antibiotic across both time points. Results: Compared to Q4 2019, Q4 2020 azithromycin prescribing increased among all ages, ranging from 90.7%  in those aged 20\u201339 years to 927.2%  in those aged 65\u201374 years (Fig. Conclusions: Despite decreases in prescribing of amoxicillin-clavulanate and respiratory fluoroquinolones for most adults, azithromycin prescribing increased dramatically across all adults during the COVID-19 pandemic. Targeting inappropriate outpatient antibiotic use in Brazil, particularly azithromycin prescribing among general practitioners, gynecologists, and surgeons, may be high-yield targets for antibiotic stewardship.Funding: NoneDisclosures: None"}
+{"text": "Scientific Reports 10.1038/s41598-022-24016-9, published online 13 December 2022Correction to: The original version of this Article contained a typo in the Abstract.\u201cProduction of phosphorus efficient genotypes in groundnut can improve and also reduces environmental pollution.\u201dnow reads:\u201cProduction of phosphorus efficient genotypes can reduce environmental pollution\u201d.The original Article has been corrected."}
+{"text": "Several preservation technologies can be used with fresh produce, such as chemical treatments, physical applications, and other approaches. This Special Issue aimed to collect the latest trends in diverse mechanisms of fresh product preservation and covered six chemical treatments: 1-Methylcyclopropene (1-MCP) [2) , hydroge2) [2S) , essenti2) [2S) , lactic 2) [2S) , in a br2) [2S) , and chl2) [2S) , were ut\u22121 concentration of 1-MCP treatment effectively induced antioxidant capacity in Chives (Allium schoenosprasum L.). The application of 1-MCP in this medicinal leafy vegetable considerably improved organosulfur profiles such as isoalliin and total-S-alk(en)ylcysteine sulfoxides (ACSOs) content [2 in loquat (Eriobotrya japonica) fruit postharvest storage maintenance [2+ is an essential trigger in the stress tolerance physiology of plants. The study showed that CaCl2 mitigated chilling injury and improved quality by modulating reactive oxygen species (ROS) homeostasis via higher antioxidant activities and scavenging capacity. Similarly, CaCl2 improves the ascorbate-glutathione (AsA-GSH) cycle and a higher expression level of corresponding genes, namely ascorbate peroxidase (EjAPX), glutathione reductase (EjGR), monodehydroascorbate reductase (EjMDHR), and dehydroascorbate reductase (EjDHAR) [2 treatment in loquat fruit.1-MCP plays a crucial role in postharvest products, suppressing respiration and limiting ethylene peak. The study reported by Dai et al. showed that 100 \u03bcL L\u22121) remarkably improved quality in postharvest guava (Psidium guajava L.) fruit [2S is utilized in horticultural products with low concentrations. The study proves that H2S effectively improved antioxidant activity and increased the activities of enzymes involved in energy metabolisms, including cytochrome C oxidase (CCO), succinate dehydrogenase (SDH), H+-ATPase, and Ca2+-ATPase [2S regulated proline metabolisms by enhancing key synthesizing enzymes, ornithine aminotransferase (OAT) and \u03941-pyrroline-5-carboxylate syntheses (P5CS) activities. Therefore, H2S could potentially alleviate chilling injury and maintain the quality of cucumber fruits [Hylocereus undatus). In addition, hydrogen peroxide and superoxide anion production were limited by the essential oil treatment. Thus, the maintenance of fruit quality was attributed to the activated antioxidant enzymes namely superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), and higher expressions of several corresponding genes encoding antioxidants enzymes  [Escherichia coli O157:H7 contamination in fresh products [E.coli-susceptible fruit and vegetables [As an organic preservative, melatonin is a vital stress regulator in plants physiology, with a possible role in the postharvest life of fruit and vegetables. The application of melatonin (600 \u03bcmol L.) fruit . The mec.) fruit . In anot+-ATPase . Furtherr fruits . In anotLactobacillus paracasei WX322, which was induced by 10 days of fermentation of tomato juice. This bacteriocin is an antibacterial (precursor) polypeptide. The Lactobacillus paracasei WX322 causes severe damage to soft rot pathogen, namely Pectobacterium cartovorum (Pcb BZA12). Eventually, antimicrobial activity reduced soft rot and decay in cucumber, tomato, and green beans [Penicillium digitatum, Penicillium italicum and Geotrichum citri-aurantii) [Food waste postharvest poses a significant bottleneck, and an innovative reused approach is crucial in these areas. The antimicrobial properties of the 12 discarded vegetables were studied for distractive soft rot disease . In testen beans . TherefoCucumis sativus L.) [Brassica rapa subsp. chinensis) [\u20135 mol L\u22121 and 405 nm light (22.27 J cm\u22122 per day)) treatment improved quality indicators, including vitamin C, total soluble solids and color preservation. Furthermore, it eliminated ROS accumulation by enhancing SOD and POD enzymes activities. The chlorophyllin treatment possibly attacked bacterial extracellular polysaccharides and extracellular proteins in vegetables. Hence, ChI-PDI is effectively used for fresh-cut preservation and displays good antimicrobial properties [In physical treatment approaches, the study showed that the combined effect of cold shock and passive atmosphere packaging (CS-PAP) significantly improved the quality and sensory attributes, as well as the nutritional value in postharvest cucumber fruit (ivus L.) . Thus, aivus L.) . Concerninensis) . The repoperties .This editorial summarizes the selected latest chemical preservatives applications on fruits and vegetables for the regulation of antioxidant attributes, defense response, cold stress regulation, and subsequent shelf-life extension. Similarly, physical treatment can be applied to storage for preservation of fruits and to reduce distractive disease infestation."}
+{"text": "The case of antibiotic resistance has become a major global concern and Extended Spectrum \u03b2-lactamase (ESBL) producing organisms have so far remained the biggest culprit. The consequences of urinary tract infection (UTI) and antibiotic resistance among pregnant women cannot be underestimated. We investigated UTI and ESBL production among urinary pathogens isolated from pregnant women.TEM, BlaSHV, and BlaCTX-M using polymerase chain reaction (PCR). Data were analyzed using SPSS v24 and p-values < 0.05 were considered statistically significant.We obtained non-repeat, clean catch midstream urine samples from 1345 pregnant women suspected of having UTI for bacterial identification at the Ho Teaching Hospital Laboratory between June 2013 and March 2015. The isolates were taken through relevant biochemical testing for identification and then subjected to antimicrobial agents for susceptibility testing using the disc diffusion method. We tested for ESBL production by the combined disc method and ESBL positive (+ESBL) phenotype isolates were genotyped for BlaStaphylococcus aureus (29.6%) followed closely by Escherichia coli (28.7%) both of which were highest during the second trimester of gestation. We isolated 152 gram-negative isolates with 41.4% (63/230) being + ESBL. Of the 63 + ESBL, 45 (71.4%) possessed blaTEM, 42 (66.7%) had blaCTX-M and 2 (3.2%) possessed blaSHV genes; 38 possessed multiple ESBL genes comprising 2 with both SHV and TEM genes and 36 with both CTX-M and TEM genes.Of the 1345 urine samples tested, 230  yielded significant bacteriuria. The most common bacterium isolated was High prevalence of UTI and persistent transmission of ESBLs among pregnant women in the Ho Municipality is worrying and a course for public health concern. We recommend urine culture during pregnancy as a routine laboratory investigation to avoid birth-related complications. Extended spectrum \u03b2-lactamase; Antimicrobial; Urinary bacteria; Pregnancy; Antenatal clinic."}
+{"text": "Case Presentation. We report a case of a patient with idiopathic primary pulmonary hypertension who presented with massive pericardial effusion complicated with rapid hemodynamic and respiratory deterioration. Gradual therapeutic pericardiocentesis was done but progressive circulatory collapse occurred. Emergent veno-arterial extracorporeal membrane oxygenation (VA-ECMO) was applied. Echocardiography revealed severe right ventricle failure. Unfortunately, the patient developed acute progressive thrombocytopenia and bilaterally diffuse subarachnoid hemorrhage after 4 days of ECMO support.  Pericardiocentesis is a therapeutic lifesaving intervention for patients presenting with cardiogenic shock due to pericardial effusion with signs of tamponade. Pericardial decompression syndrome (PDS) is a rare fatal complication that may occur after pericardiocentesis.  Therapeutic pericardiocentesis can be occasionally fatal in cases of significant pulmonary hypertension with massive pericardial effusion when complicated by pericardial decompression syndrome. Acute significant thrombocytopenia may occur with VA-ECMO support resulting in fatal bleeding. Idiopathic pulmonary artery hypertension (IPAH) is a rare rapidly progressive disease affecting the pulmonary precapillary vasculature and results in right-sided heart failure and death. The World Health Organization (WHO) classified IPAH as a part of group I pulmonary hypertension , 2. The Pericardiocentesis is a therapeutic lifesaving intervention for patients presenting with cardiogenic shock due to pericardial effusion with signs of tamponade , 6. Peri2). She was diagnosed to have idiopathic pulmonary artery hypertension (IPAH) for 3 years and was maintained on maximized pulmonary vasodilators including oral riociguat and macitentan and intravenous continuous infusion of treprostinil. She started to develop progressive right-sided heart failure including bilateral lower limb edema, dyspnea on minimal effort, and pleural and pericardial effusions. She was listed for lung transplantation. She was admitted to our institution with 1 week of exaggerated dyspnea and palpitations. On admission, she presented with sinus tachycardia of 130 beats/min, blood pressure of 90/45\u2009mmHg with presence of jugular venous distention, and pulse oximetry saturation (SPO2%) of 80% on room air. After central venous catheterization, CVP range was 25-30\u2009cm H2O , platelet count of 189 (109/L), hemoglobin 114 (g/L), serum Na 132\u2009mmol/L, NT-proBNP 3693\u2009pg/mL, normal kidney, and liver chemistries. Septic and virology screening was done including COVID-19 PCR. Echocardiography was done and revealed a large circumferential pericardial effusion without signs of tamponade. Also it showed a severe dilatation of right ventricle with severe systolic dysfunction and flattened interventricular septum. There was a severe right atrium dilatation with left sided shift of interatrial septum. The estimated pulmonary artery systolic pressure (PASP) was more than 115\u2009mmHg while the left ventricle was underfilled but with a good systolic function . Emergency echocardiography revealed normal left ventricle while severely dilated right ventricle with systolic dysfunction and increased PASP more than 150\u2009mmHg and minimal pericardial effusion .2, but gradual recovery happened without renal replacement therapy. Neurological assessment was frequently done during sedation withdrawal and pupils' size and reactivity to light every 2 hours according to our hospital protocol. Near-infrared spectroscopy (NIRS) was used continuously for monitoring of cerebral and lower limb oxygen saturations. The patient developed a rapid decline of platelet count, and heparin-induced thrombocytopenia (HIT) was unlikely. Despite the HIT 4T score was 6, the heparin\u2013PF4 antibody test was 0.11 (reference \u2264 0.39). Exclusion of significant hemolysis was done by laboratory work-up: blood schistocyte was <0.5%, Coombs test was negative, haptoglobin level was 0.7 (reference: 0.3-2\u2009g/L), peak bilirubin was 42.4 (reference: 0-21\u2009\u03bcmol/L), and LDH 585 (reference: 135-214 units/L). The patient developed a thrombus at the tip of ECMO drainage cannula which made the decision to stop anticoagulation exceedingly difficult. So frequent platelet transfusions were done to keep platelet count more than 50 (109/L). Daily sedation withdrawal and neurological assessment was done, and continuous monitoring of brain oxygen saturation by near-infrared spectroscopy (NIRS) was maintained.Emergent peripheral veno-arterial extracorporeal membrane oxygenation (VA-ECMO) via femoral approach with reperfusion cannula was applied and cardiopulmonary resuscitation was done. Anticoagulation started with unfractionated heparin infusion guided by activated clotting time (ACT) target of 180-220 seconds, heparin level (target 0.3-0.7\u2009units/mL), and antithrombin III activity (target > 50%).The patient had acute kidney injury with decrease of glomerular filtration rate (GFR) from more than 60 to 40\u2009mL/min/1.73\u2009m9/L). After 4 days of the cerebral bleeding, the patient developed brain death and brain CT imaging revealed diffuse brain ischemia. Withdrawal of support was done, and the patient was declared dead  imaging revealed left occipital hemorrhagic stroke and bilateral diffuse subarachnoid hemorrhage with intraventricular extension complicated with hydrocephalus. Cerebral angiography excluded aneurysmal dilatation or arteriovenous cerebral malformation. Relief of intracranial hypertension was done using external ventricular draining, head positioning, keeping normocapnia, and osmotic diuresis. Anticoagulation was discontinued immediately when the consciousness was impaired, and platelet count was kept more than 100  and occurrence of platelet dysfunction during VA-ECMO support without association with ECMO duration . JiritanThe occurrence of intracerebral bleeding was sudden and significant that necessitated neurosurgical intervention to insert external ventricular drain and decrease the intracranial pressure. Female gender, thrombocytopenia, and low body mass index were linked to early intracerebral bleeding in ECMO patients , 27, 40.Finally, our case highlights the importance of gradual judicious decompression during therapeutic pericardiocentesis especially in presence of significant pulmonary hypertension to avoid acute right ventricle failure or pericardial decompression syndrome. Also, careful hemodynamic monitoring after pericardiocentesis should be done for early detection of impaired tissue perfusion and need for cardiopulmonary support. Moreover, acute significant thrombocytopenia may happen shortly after ECMO support and may be complicated with fatal bleeding.Therapeutic pericardiocentesis can be occasionally fatal in cases of significant pulmonary hypertension with massive pericardial effusion when complicated by pericardial decompression syndrome. Acute significant thrombocytopenia may occur with VA-ECMO support resulting in fatal bleeding."}
+{"text": "Adults aged 85 years and older (\u201coldest-old\u201d) are perceived as survivors resilient to age-related risk factors. Although considerable heterogeneity has been often observed in this population, less is known about the unmet needs in health and healthcare service utilization for diverse patients in healthcare systems. We examined racial-ethnic variation in patterns of multimorbidity associated with emergency department (ED) and clinic visits among oldest-old patients with multiple chronic conditions (MCCs). Administrative and clinical data from an integrated healthcare system for five years included 25,801 oldest-old patients with MCCs. Hierarchical cluster analysis identified patterns of MCCs by four racial-ethnic groups . Clusters associated with ED and clinic visits were analyzed using generalized estimation equations. The average of 5.79 (\u00b12.79) MCCs ranging from 5.36 (\u00b12.61) for Other to 5.82 (\u00b12.79) for Hispanic patients at baseline decreased over time. Hypothyroidism, Alzheimer\u2019s Disease and related dementia, bone-and-joint, metabolism syndrome, and pulmonary-vascular clusters were commonly observed across the groups. Unique cluster patterns were identified among Black patients . While almost all clusters were significantly associated with ED and clinic visits among White patients, distinctive clusters were significantly related to ED and clinic visits among Hispanic patients . Patterns of multimorbidity and its significant association with healthcare service utilization varied by race-ethnicity. Findings suggest a need for culturally tailored care management within integrated healthcare systems."}
+{"text": "The emergence of treatment resistance significantly reduces the clinical utility of many effective targeted therapies. Although both genetic and epigenetic mechanisms of drug resistance have been reported, whether these mechanisms are stochastically selected in individual tumors or governed by a predictable underlying principle is unknown. Here, we report that the dependence of cancer stem cells (CSC), not bulk tumor cells, on the targeted pathway determines the molecular mechanism of resistance in individual tumors. Using both spontaneous and transplantable mouse models of sonic hedgehog (SHH) medulloblastoma treated with a SHH/Smoothened inhibitor (SMOi), sonidegib/LDE225, we show that genetic-based resistance occurs only in tumors that contain SHH-dependent CSCs. In contrast, SHH medulloblastomas containing SHH-dependent bulk tumor cells but SHH-independent CSCs (SI-CSC) acquire resistance through epigenetic reprogramming. Mechanistically, elevated proteasome activity in SMOi-resistant SI-CSC medulloblastomas alters the tumor cell maturation trajectory through enhanced degradation of specific epigenetic regulators, including histone acetylation machinery components, resulting in global reductions in H3K9Ac, H3K14Ac, H3K56Ac, H4K5Ac, and H4K8Ac marks and gene expression changes. These results provide new insights into how selective pressure on distinct tumor cell populations contributes to different mechanisms of resistance to targeted therapies. This insight provides a new conceptual framework to understand responses and resistance to SMOis and other targeted therapies.The mechanism by which individual tumors become resistant to targeted therapies is thought to be unpredictable. This study provides novel insights into how selective pressure on cancer stem versus bulk tumor cells drives distinct and predictable mechanisms of resistance to targeted therapies. This finding paves a way for future treatment strategies that incorporate anticipated resistance mechanisms in devising second-line therapies in a personalized manner. The sonic hedgehog (SHH) pathway is a highly conserved developmental signaling pathway that is activated in many human cancers, including basal cell carcinoma (BCC), acute myeloid leukemia (AML), and medulloblastoma . CurrentSmoothened (Smo-M2) expression are indistinguishable. However, cancer stem cells (CSC) from different cells of origin have distinct cellular characteristics, including their dependence on SHH signaling  occur only in tumors in which CSCs depend on the targeted pathway. We hypothesized that in tumors where CSCs and bulk tumor cells depend on different mitogenic pathways, targeted therapy selected on the basis of bulk tumor analysis results in only a transient response (debulking) followed by resistant tumor growth due to the presence of inherently resistant CSCs. Specifically, we tested whether SMOi-resistant tumors containing SHH-dependent CSCs (SD-CSC) acquire new mutations in the SHH pathway, while SHH medulloblastomas containing SHH-independent CSCs (SI-CSC), that is, SI-CSC medulloblastomas, do not . The resPtch , FSmoM2 , hGFAP-cre , p53 , NSG (NOD. Cg-scidPrkdc) tm1WjlIl2rg/SzJ , and B6  mice were obtained from the JAX repository. Medulloblastoma subtype determination was performed as described previously (23). To eliminate potential spatial heterogeneity within the parental tumor, each Ptch;p53 spontaneous medulloblastoma was first minced into a slurry, and equivalent pools of tumor cells were injected into male or female 6 to 8 weeks old NSG mice. When the tumor volume reached 100\u2013200 mm3, mice were treated with 40 mg/kg LDE225 or vehicle control  until harvest. FSmoM2;hGFAP-cre pups were treated with LDE225 using the same dose and schedule as Ptch;p53 MBs, starting at p2 or p3. Mice were randomly assigned to each group and were age and sex matched at the time of the experiment. Mice were housed and handled in accordance with the protocols and procedures approved by The Jackson Laboratory and the HMRI Institutional Animal Care and Usage Committees.The SD-CSC and SI-CSC tumor subtype designation methods were reported previously . BrieflyPtch;p53 or FsmoM2;hGFAP-Cre mouse medulloblastomas and cultured in serum-free, NSC medium with or without exogenous growth factors, bFGF and EGF. For SD-CSC tumor cells, we used NSC medium. SI-CSC tumorspheres were cultured in the TSC medium. Cells were treated with the indicated concentrations of inhibitors: LDE225 , GANT61 , and trichostatin A . Histone acetyltransferase inhibitor IV , histone acetyltransferase inhibitor VIII , MG132 , and JQ1 .Primary tumorsphere cells were isolated from Mycoplasma infection by a PCR assay to ensure that all cultured cells are Mycoplasma free. Cryo-preserved primary cells used in the study were tested negative for Mycoplasma upon recovery.No established cell lines were used in this study. Cells used in this study were freshly dissociated spontaneous mouse tumors that developed in our animal facility. Mice that develop spontaneous tumors are genotyped in our lab using PCR assays before tumor harvests. In addition, our lab routinely tests for potential http://broadinstitute.github.io/picard/). The resulting BAM files were further realigned around indels and recalibrated for base quality using GATK, RRID:SCR_001876 . Next, the recalibrated BAM files were used as tumor-normal pairs to detect somatic mutations using MuTect, RRID:SCR_000559. Finally, SnpEff, RRID:SCR_005191  and Bamtools, RRID:SCR_015987 to obtain general alignment statistics from the bam file. Analyses of aligned reads were performed using the R package edgeR, RRID:SCR_012802. Gene set enrichment pathway analysis was performed using edgeR preranked gene lists with the fgsea  and GAGE (RRID:SCR_017067) R packages or log2-normalized CPM (counts per million) values with the gene set variation analysis (GSVA) R package. Plots were generated using ggplot2 and RRID:SCR_014601, and heatmaps were generated using ComplexHeatmap and RRID:SCR_017270.RNA sequencing (RNA-seq) analysis was carried out using the in-house pipeline at The Jackson Laboratory. Trimmomatic, RRID:SCR_011848 (version 0.33) was used to remove adapters and leading and trailing low-quality bases. Reads fewer than 36 bases long were discarded. Reads with more than 50% low-quality bases overall were filtered out, and the remaining high-quality reads were then used for expression estimation. Alignment estimation of gene expression levels using the EM algorithm for paired end read data was performed using RSEM, RRID:SCR_013027 (package version 1.2.12). RSEM uses Bowtie 2 and RRID:SCR_016368 as aligners to align the mapped reads against the mm10 reference genome. Data quality control was performed using Picard, RRID:SCR_006525  at 37\u00b0C overnight. The tryptic peptides were desalted prefractionated into five fractions using C18 beads. LC/MS-MS analysis was carried out using a nanoLC1200 system coupled to an Orbitrap Fusion Tribrid mass spectrometer (Thermo Fisher Scientific). One microgram of peptide was loaded onto a C18  trap column and switched in line with a 50 mm \u00d7 150 \u03bcm analytic column packed with the same C18 beads. The peptides were eluted using a 75-minute linear gradient of 4% to 26% acetonitrile, ionized, and measured in data-dependent mode acquiring fragmentation spectra of the top 30 strongest ions and under the direct control of Xcalibur software ver. 4.0 . The MASCOT search engine  was used to match the spectrum to the corresponding peptide sequence searched against NCBI's mouse RefSeq protein. The Mascot results were validated with the Percolator-based q value in the Proteome Discoverer software . Dynamic modification was allowed for oxidation (methionine), protein N-terminal acetylation, and deamidation (asparagine and glutamine). The maximum tolerance for precursor ions was set to 20 ppm; the fragment mass tolerance was set to 0.5 daltons; and a maximum of two missed cleavages was allowed. The calculated AUC of peptides was used to calculate iBAQ and iFOT for protein abundance based on a previous publication , and heatmaps were generated using ComplexHeatmap (RRID:SCR_017270).Gene set enrichment analysis (GSEA) was performed using msmsTests::msms.edgeR preranked gene lists with fgsea , GAGE (RRID:SCR_017067) R packages or logCell-based Proteasome-Glo Assay for Chymotrypsin-like protease activities (Promega) was performed following the manufacturer's instructions. Equal numbers of cells were plated, and the reporter assay levels were normalized to viability in each sample. All assays were repeated at least three times in triplicate, and error bars represent the SEM.https://github.com/therneau/survival) and plotted using the \u2018\u2018survminer\u2019\u2019 R package (https://github.com/kassambara/survminer).To assess the correlation between BRD2 or BRD4 expression and survival in the publicly available human medulloblastoma dataset . Subsequent Western analyses were performed using standard procedures. Antibodies against CBP , GCN5 , PCAF , HDAC1 , HDAC2 , HDAC3 , histone H3 , H3K9ac , H3K14ac , H3K18ac , H3K27ac , H3K56ac , histone H4 , H4K5ac , H4 Antibodies against Gli1 , actin , and tubulin  were purchased from Santa Cruz Biotechnology. Antibodies against HAT1  were purchased from Proteintech. For IHC was performed following standard protocols using paraffin sections with the indicated primary antibodies: NEUN .n) values are indicated in figures or in figure legends. P values were determined by an appropriate statistical test, such as Student t tests or ANOVA, with multiple comparison corrections, as indicated in the figure legend. Fisher exact test was used to test the difference in the rate of acquired mutations in the different subtypes.Statistical comparisons were performed using GraphPad Prism (RRID:SCR_002798) or R Project for Statistical Computing (RRID:SCR_001905). Values and error bars represent the mean\u2009\u00b1\u2009SEM. The respective number of replicates (https://www.ncbi.nlm.nih.gov/bioproject/PRJNA793810). RNA-seq data are available through the SRA portal (https://www.ncbi.nlm.nih.gov/bioproject/PRJNA834841).Exome-seq and methyl-seq data are available through the SRA portal (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE85217) was downloaded from Gene Expression Omnibus and used to analyze BRD2 and BRD4 expression levels in different medulloblastoma subtypes and survival  in which the activated SMO (SMO-M2) allele is conditionally expressed upon Cre recombinase expression , and they are insensitive to SHH inhibition NOD-SCID;Il2gr host mice to generate three allograft cohorts with isogenic tumors , we resumed treatment. In all SI-CSC medulloblastomas, resistant tumors grew immediately after the initial debulking phase  from both ges >20%  and S5. n humans ; Gli2 amfication ; and Mycfication . These Sfication . In contsubtypes .FSmoM2;hGFAP-cre medulloblastomas. Remarkably, none of the seven LDE225-treated FSmoM2;hGFAP-cre medulloblastomas had acquired mutations in the SHH pathway (P = 0.008) SHH medulloblastomas in the SD-CSC versus SI-CSC subtypes, respectively. These results in two different SHH medulloblastoma models strongly support our hypothesis that treatment-induced mutations in the SHH pathway occur only when the CSCs depend on the SHH pathway.To validate this finding in an independent model, we performed additional WES from seven  pathway . TogethePtch;p53 medulloblastomas, we performed RT-PCR on tumors subjected to both acute and long-term treatment. Acute treatment (3 days in vivo) in both subtypes resulted in significant reductions in the levels of SHH pathway genes >2; Fsmo;hGFAP-Cre medulloblastomas showed significant downregulation of histone acetyltransferases (HAT: Hat1 and Kat2a/GCN5), the histone deacetylase (HDAC) Hdac1, and the histone acetylation reader Brd2 between vehicle- and LDE-treated samples ; however, HDAC1 and BRD4 levels were significantly downregulated at the protein level  and HDACs  in an independent cohort of samples by Western blot analysis of both medulloblastoma models. We observed a dramatic reduction in the protein levels of specific HATs  in SMOi-resistant FSmoM2;hGFAP-cre and Ptch;p53 SI-CSC tumors compared with vehicle-treated tumors.  LDE225 treatment did not reduce the protein levels of HATs or HDACs  in the targeted pathway is dictated by the dependency of its CSCs and not its bulk tumor cells on the selected pathway. Second, we show that it is possible to predict prior to treatment whether a tumor will acquire resistance via a genetic or epigenetic mechanism based on the phenotype of its CSCs. Although the translation of this approach is currently challenging, it has significant clinical implications in terms of guiding second-line therapy selection or designing combination therapies in a timely manner. Third, we reveal a new mechanism of therapeutic resistance: epigenetic reprogramming of bulk tumor cells through changes in histone acetylation via enhanced degradation of specific HATs resulting in an altered histone code. A previous study reported that transformed Smo/Smo medulloblastoma tissues have increased HDAC1, HDAC2, and HDAC3 and decreased HDAC11 expression compared with wild-type or untransformed Smo/Smo cerebellum tissues , suggestFSmoM2;hGFAPCre) resulted in infantile medulloblastomas that contain SI-CSCs  resulted in adult SHH medulloblastomas that contain SD-CSCs  plays a broader role in therapeutic resistance in other cancer types, particularly in pediatric cancers, where epigenetic mechanisms play critical roles in tumorigenesis .Supplementary Figures and Tables 1-2Supplementary figures and Tables 1 & 2Click here for additional data file.Supplementary Table 3Supplementary Table 3: Mutational profiles for Ptch;p53 SD-CSC tumorsClick here for additional data file.Supplementary Table 4Supplementary Table 4: mutational profiles for Ptch;p53 SI-CSC tumorsClick here for additional data file.Supplementary Table 5Supplementary Table 5: mutational profiles for Fsmo;GFAP-cre SD-CSC tumorsClick here for additional data file.Supplementary Table 6Supplementary Table 6: DEG in LDE vs control treated fSMO;GFAP-cre tumorsClick here for additional data file.Supplementary Table 7Supplementary Table 7: DEG in LDE vs. control treated SI-CSC Ptch;p53 tumorsClick here for additional data file.Supplementary Table 8Supplementary Table 8: DEG in LDE vs control in SD-CSC Ptch;p53 tumorsClick here for additional data file.Supplementary Table 9Supplementary Table 9: Differentially expressed proteins in LDE vs. control treated Ptch;p53 SI-CSC and SD-CSC tumorsClick here for additional data file."}
+{"text": "Lentivirus) are complex retroviruses that infect a broad range of mammals, including humans. Unlike many other retrovirus genera, lentiviruses have only rarely been incorporated into the mammalian germline. However, a small number of endogenous retrovirus (ERV) lineages have been identified, and these rare genomic \u201cfossils\u201d can provide crucial insights into the long-term history of lentivirus evolution. Here, we describe a previously unreported endogenous lentivirus lineage in the genome of the South African springhare (Pedetes capensis), demonstrating that the host range of lentiviruses has historically extended to rodents (order Rodentia). Furthermore, through comparative and phylogenetic analysis of lentivirus and ERV genomes, considering the biogeographic and ecological characteristics of host species, we reveal broader insights into the long-term evolutionary history of the genus.Lentiviruses (genus The online version contains supplementary material available at 10.1186/s12977-022-00615-2. Lentivirus) are an unusual group of retroviruses (family Retroviridae) that infect mammals and are associated with a range of slow, progressive diseases in their respective host species groups [The lentiviruses  and hare (Lepus europaeus) genomes, demonstrating that genome invasion occurred prior to divergence of these species\u2009~\u200912 million years ago (Mya) [Lentiviruses have only rarely been incorporated into the germline of host species. However, a handful of Lentivirus-derived ERV lineages have now been identified Table , and thego (Mya) . Endogengo (Mya) , 21; musgo (Mya) , 23; andgo (Mya) \u201326. Togego (Mya) , 22, 25.go (Mya) , 26.Pedetes capensis), demonstrating that lentivirus host range extends to rodents. Furthermore, through comparative and phylogenetic analysis, incorporating all available data, we provide broader insight into the origins and long-term evolutionary history of lentiviruses.In this study we perform comprehensive screening of published mammalian genomes and identify a previously unreported endogenous lentivirus lineage in the genome of the South African springhare  were classified via comparison to published retrovirus genome sequences (again using BLAST). Consensus genome sequences for endogenous lentivirus lineages were extracted from the supplementary material of associated publications, as follows: RELIK [We used database-integrated genome screening (DIGS)  to derivs: RELIK ; PSIV1 [s: RELIK ; PSIV2 [s: RELIK ; MELV [2s: RELIK ; DELV [2s: RELIK .We compiled a set of endogenous lentivirus loci  as implemented in RAxML (version 8.2.12) . Protein. . We used. .We systematically screened WGS data representing 431 mammalian species , and the reverse transcriptase (RT) coding region encoded by one of these ERVs groups with previously described lentivirus species  as a query in BLASTn-based searches of the P. capensis genome assembly. This revealed the presence of a repetitive sequence showing the characteristic features of a retroviral LTR  in the expected position upstream of the Gag ORF. Using this LTR sequence as input for screening enabled us to identify another 10 SpELV loci represented by solo LTR sequences (Table env) gene associated with any SpELV insertions, nor did we identify any contigs containing complete proviruses with paired LTR sequences. Furthermore, because the longest provirus sequence we identified was truncated in pol we could not determine whether any accessory genes might have been encoded downstream of this gene. Nonetheless, the partial genome obtained in our analysis exhibits the characteristic features of lentivirus genomes, including (a) a primer-binding site specific for tRNA Lysine  element  known lentivirus distribution and (b) biogeographic range onto a time-calibrated phylogeny of boreoeutherian mammals provides some thought-provoking insights into lentivirus ecology and evolution Fig.\u00a0. FirstlyRegarding the ultimate origins of lentiviruses in mammals, molecular clock-based analyses of DELV insertions supports the presence of archaeolentiviruses in Asia (the only region where colugos occur) up to 60 Mya  \u2013 i.e., We describe a novel endogenous lineage in the genome of the South African springhare. The identification of SpELV demonstrates that lentivirus host range has historically extended to rodents.Additional file 1.Table S1. Whole genome sequence assemblies screened in this study.Additional file 2.Table S2.\u00a0Details of all endogenous lentivirus loci identified in this study.Additional file 3.Figure S1. Phylogenetic and genomic characteristics of springhare endogenous lentivirus. (a) Maximum likelihood (ML) phylogeny based on an alignment of reverse transcriptase (RT) protein sequences and showing the reconstructed evolutionary relationships between lentiviruses and other retroviruses. Asterisks indicate nodes with bootstrap support\u2009>\u200970% (1000 replicates). The scale bar shows evolutionary distance in substitutions per site. (b) ML phylogeny showing reconstructed evolutionary relationships between SpELV long terminal repeat (LTR) sequences. Numbers next to nodes indicate bootstrap support values (1000 replicates). The scale bar shows evolutionary distance in substitutions per site. (c) Consensus genome structures of ancient lentiviral paleoviruses. DELV\u2009=\u2009Dermopteran endogenous lentivirus; RELIK\u2009=\u2009Rabbit endogenous lentivirus type K; Mustelidae endogenous lentivirus (MELV); BIV\u2009=\u2009Bovine immunodeficiency virus; SIV\u2009=\u2009Simian immunodeficiency virus; FIV\u2009=\u2009Feline immunodeficiency virus; Human immunodeficiency virus\u2009=\u2009HIV; Prosimian immunodeficiency virus\u2009=\u2009PSIV; RV\u2009=\u2009Retrovirus; LV\u2009=\u2009Leukemia virus.Additional file 4.Figure S2. The SpELV consensus sequence. Inverted repeats present at the ends of the 5\u2032 long terminal repeat (LTR) sequence are highlighted in light grey. Regions of nucleic acid secondary structure, the transactivation responsive (TAR) element and primer binding site (PBS) are highlighted in dark grey. The locations of the proteins encoded by the gag and pol  genes were determined by homology to the DELV consensus sequence [sequence \u201326.Additional file 5.Figure S3. The putative SpELV TAR (transactivation responsive region) element. Secondary structures were predicted using the MFOLD thermodynamic folding algorithm [lgorithm  and asseAdditional file 6.Figure S4. Nucleotide compositional bias in lentivirus genomes. Nucleotide composition of whole genomes of Lentiviruses were normalised to length and plotted as percentages using R in R Studio (version 4.2.1). Reference genome sequences for each virus correspond to those given in Table"}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-022-18252-2, published online 29 August 2022Correction to: The original version of this Article contained an error in the Abstract.\u201cAmong the five soldiers biopsied, all had constrictive bronchiolitis.\u201dnow reads:\u201cAmong the five soldiers biopsied, all had constrictive bronchiolitis or bronchiolitis or severe pulmonary fibrosis.\u201dThe original Article has been corrected."}
+{"text": "Background: Emerging evidence supports the use of billing data to identify stewardship targets in primary care. Standardizing an approach to antibiotic prescribing rate (APR) calculations could facilitate external benchmarking. Methods: Using methodology and an ICD-10 dictionary validated in urgent care clinics,1 we created an expanded ICD-10 dictionary to incorporate additional ICD-10 codes from primary care associated with antibiotic prescriptions  (Fig. Conclusions: The expanded ICD-10 dictionary allowed for classification of more encounters in primary care; however, it did not meaningfully change antibiotic prescribing rates. Antibiotic prescribing rates were likely diluted by classifying more encounters without identifying an associated increase in antibiotic prescribing. A more sophisticated classification system may help to accommodate the diversity and volume of ICD-10 codes used in primary care.Clin Infect Dis 2020;70:1781\u20131787.1. Stenehjem E, et al. Funding: NoneDisclosures: None"}
+{"text": "To assess accuracy of telephone triage in identifying need for emergency care amongst those with suspected COVID-19 infection and identify factors which affect triage accuracy.An observational cohort study of adults who contacted the NHS 111 telephone triage service provided by Yorkshire Ambulance Service between March and June 2020 with symptoms indicating possible COVID-19 infection. Patient-level data encompassing triage call, primary care, hospital care and death registration records relating to 40,261 adults were linked.The accuracy of triage outcome (self-care/non-urgent assessment versus ambulance/urgent assessment) was assessed for death or organ support 30 days from first contact. Multivariable logistic regression was used to identify factors associated with risk of false negative or false positive triage.Callers had a 3%  risk of serious adverse outcomes. Telephone triage recommended self-care or non-urgent assessment for 60% , with a 1.3%  risk of adverse outcomes 30 days from first contact. Telephone triage had 74.2% sensitivity (95% CI: 71.6 to 76.6%) and 61.5% specificity (61% to 62%) for the primary outcome. Analysis suggested respiratory comorbidities may be over-appreciated and diabetes under-appreciated as predictors of deterioration. Repeat contact with triage service appears to be an important under-recognised predictor of deterioration.Patients advised to self-care or receive non-urgent clinical assessment had a small but non-negligible risk of serious clinical deterioration. Repeat contact with telephone services needs recognition as an important predictor of subsequent adverse outcomes."}
+{"text": "Proteins are capable of highly specific interactions and are responsible for a wide range of functions, making them attractive in the pursuit of new therapeutic options. Previous studies focusing on overall geometry of protein\u2013protein interfaces, however, concluded that PPI interfaces were generally flat. More recently, this idea has been challenged by their structural and thermodynamic characterisation, suggesting the existence of concave binding sites that are closer in character to traditional small-molecule binding sites, rather than exhibiting complete flatness. Here, we present a large-scale analysis of binding geometry and physicochemical properties of all protein\u2013protein interfaces available in the Protein Data Bank. In this review, we provide a comprehensive overview of the protein\u2013protein interface landscape, including evidence that even for overall larger, more flat interfaces that utilize discontinuous interacting regions, small and potentially druggable pockets are utilized at binding sites. Proteins are involved in most fundamental biological processes, including cell proliferation , signallOriginally, interacting interface regions were considered to be large, hydrophobic, flat and featureless , leadingWhile large compilations of PPI networks are important to elucidate which proteins interact with each other, they lack in-depth information of how those interactions occur. Despite a relatively small proportion of the interactome being covered by structural data, advances in experimental structure resolution and application of structural bioinformatics  add promHere we report the results of a large-scale analysis for the structural landscapes of PPI interfaces based on 3D structures available in the Protein Data Bank (PDB) . We invehttps://academic.oup.com/bib), with interactions involving peptides being predominantly single segmented. This allowed us to categorize the interfaces as either single (continuous) or multi-segmented (discontinuous). https://academic.oup.com/bib) shows the distribution of planarity for interfaces of different segmentations and types. Single segmented interfaces were significantly more planar than multi-segmented ones (https://academic.oup.com/bib) and, while there was no significant difference in segmentation between peptide-type interfaces. Non-identical pairs were significantly more planar than identical pairs with symmetric and non-symmetric interfaces. The former was the most planar among all interface types (https://academic.oup.com/bib).Analysis of the interface segmentation distribution of PPI interfaces within the PDB revealed that having up to five interface segments were the most prevalent, accounting for 70% of interfaces (<table-wrap position=\"float\" id=\"TB1\"><label>Table S1</label></table-wrap><table-wrap position=\"float\" id=\"TB2\"><label>Table S2</label></table-wrap><table-wrap position=\"float\" id=\"TB3\"><label>Table S3</label></table-wrap>https://academic.oup.com/bib). Loop residues dominated on average at smaller sides of single segmented interfaces, and on both sides of multi-segmented interfaces, while \u03b2-sheet residues were significantly less prevalent in all interfaces. However, \u03b1-helix dominated in the interface cores of multi-segmented interfaces and the larger sides of single segmented interfaces, but not in the smaller sides of single segmented interfaces. Loops were significantly more present in the interface peripheries of all segmentations of interfaces than \u03b1-helix, which in turn were significantly more present than \u03b2-sheet residues. With respect to secondary structure use by interface types, loops were more prevalent at identical non-symmetrical interfaces than \u03b1-helix, whereas there were no significant differences in \u03b1-helix and loop usage in identical symmetric interfaces. Peptides had significantly more loops than other interfaces; however, while the enzyme\u2019s interface regions of Enzyme-Peptide interfaces tended to be formed of loops, the protein interface regions of Protein-peptide interfaces were significantly more helical than unstructured. In the interface core, however, for peptides of Protein-peptide interfaces, \u03b1-helix made up a greater proportion of interface cores than all other types of interfaces, and helices were significantly more present in identical symmetric core residues than loops. Loops were significantly more present in the interface peripheries of all interface types, followed by \u03b1-helix and \u03b2-sheets.Single and multi-segmented interfaces were also largely composed of residues in loops and \u03b1-helices in their core and periphery regions (<table-wrap position=\"float\" id=\"TB4\"><label>Table S4</label></table-wrap><table-wrap position=\"float\" id=\"TB5\"><label>Table S5</label></table-wrap>https://academic.oup.com/bib). Peptidic interfaces were the most well packed, followed by identical pairs with non-symmetric interfaces and non-identical pairs, which did not differ significantly in packing, and identical pairs with symmetric interfaces (https://academic.oup.com/bib). Similar to NIP, Normalized Shape correlation (NSc) was significantly higher in single segmented interfaces than in multi-segmented interfaces (https://academic.oup.com/bib). Peptidic interfaces were the most complementary; however, enzyme-peptide interfaces had significantly higher NSc values than protein-peptide ones. Identical pairs with symmetric interfaces were the least complementary and non-identical pairs and identical pairs with non-symmetric interfaces were not significantly different from each other (https://academic.oup.com/bib).With respect to Normalized Interface Packing (NIP), single segmented interfaces were significantly more well-packed than multi-segmented interfaces (<table-wrap position=\"float\" id=\"TB6\"><label>Table S6</label></table-wrap><table-wrap position=\"float\" id=\"TB7\"><label>Table S7</label></table-wrap><table-wrap position=\"float\" id=\"TB8\"><label>Table S8</label></table-wrap><table-wrap position=\"float\" id=\"TB9\"><label>Table S9</label></table-wrap>https://academic.oup.com/bib). Single segmented interfaces used significantly greater proportions of interface core residues on their larger sides than either side of multi-segmented interfaces (https://academic.oup.com/bib). However, they utilized a significantly smaller proportion of interface core residues per interface on the smaller side of the interface than multi-segmented interfaces, which differ significantly between smaller and larger side (https://academic.oup.com/bib).The average buried surface area (BSA) was significantly higher for multi-segmented interfaces than single segmented interfaces, by over 1000\u00a0\u00c5   show distributions of use of non-covalent contacts for PPI interfaces in the dataset, by interface segmentation and interface type, respectively. Single segmented interfaces were significantly enriched in VdW, hydrogen/polar, atom\u2013ring interactions compared with interfaces with multiple segments, which showed to have significantly more ionic, hydrophobic, carbonyl, amide-ring and amide\u2013amide interactions. With respect to types of interfaces, individual interaction types showed different variations. For some interface types, numbers of interactions per 100\u00a0\u00c5 [Looking at the intermolecular interactions per 100\u00a0\u00c5  BSA reveer 100\u00a0\u00c5  BSA matc<table-wrap position=\"float\" id=\"TB14\"><label>Table S14</label></table-wrap><table-wrap position=\"float\" id=\"TB15\"><label>Table S15</label></table-wrap><table-wrap position=\"float\" id=\"TB16\"><label>Table S16</label></table-wrap>https://academic.oup.com/bib). By comparison, small-molecule natural product ligands occupy concavities of less than 5\u00a0\u00c5 with 60\u201395% of their atoms [Concave geometry of protein surfaces is implicated in the formation of surface regions suitable for the binding of small, potentially drug-like, molecules. The majority of observations indicated that both single and multi-segmented interfaces made use of concavities over the whole interface surface; however, single segmented interfaces were bound significantly deeper on average, binding at a \u2018groove\u2019 magnitude of concavity (ir atoms  (measure<table-wrap position=\"float\" id=\"TB17\"><label>Table S17</label></table-wrap><table-wrap position=\"float\" id=\"TB18\"><label>Table S18</label></table-wrap><table-wrap position=\"float\" id=\"TB19\"><label>Table S19</label></table-wrap><table-wrap position=\"float\" id=\"TB20\"><label>Table S20</label></table-wrap><table-wrap position=\"float\" id=\"TB21\"><label>Table S21</label></table-wrap>https://academic.oup.com/bib) . Both single and multi-segmented interfaces exhibited outliers with very large chain lengths. Single segmented interfaces also utilized significantly fewer interacting residues than multi-segmented interfaces (https://academic.oup.com/bib), while each globular interface type was significantly different in number of interacting residues from one another (https://academic.oup.com/bib). No significant difference in the chain length for the two types of peptidic interfaces was observed, neither between identical pairs with symmetric and non-symmetric interfaces (https://academic.oup.com/bib). Notably, identical pairs with symmetric interfaces used significantly more residues than all the other types of interfaces.The importance of concavity on average and at the deepest level varied as the protein molecule size and interface size of the protomer increased (<table-wrap position=\"float\" id=\"TB22\"><label>Table S22</label></table-wrap><table-wrap position=\"float\" id=\"TB23\"><label>Table S23</label></table-wrap><table-wrap position=\"float\" id=\"TB24\"><label>Table S24</label></table-wrap><table-wrap position=\"float\" id=\"TB25\"><label>Table S25</label></table-wrap><table-wrap position=\"float\" id=\"TB26\"><label>Table S26</label></table-wrap><table-wrap position=\"float\" id=\"TB27\"><label>Table S27</label></table-wrap><table-wrap position=\"float\" id=\"TB28\"><label>Table S28</label></table-wrap>https://academic.oup.com/bib). As protomer length increased, interfaces became overall flatter regardless of the number of interacting residues. With respect to deepest concavity utilized at interfaces, deep concavities (<4\u00a0\u00c5) were utilized by at least part of the interface for a majority of observations. However, interface deepest concavity tended to take less concave values for longer protomers with fewer interacting residues. Some exceptions to this trend were represented by longer protomers using deep concavities at their deepest, although the interacting region of these two large chains resembles more a peptidic interface.Inspecting averaged concavity values showed that smaller protomers with smaller interfaces were more likely to utilize concavity on average (<table-wrap position=\"float\" id=\"TB29\"><label>Table S29</label></table-wrap><table-wrap position=\"float\" id=\"TB30\"><label>Table S30</label></table-wrap><table-wrap position=\"float\" id=\"TB31\"><label>Table S31</label></table-wrap>https://academic.oup.com/bib). Here, single and multi-segmented interfaces made use of concavity in both the core and periphery. For multi-segment/globular interface categories, residues in the interface core were observed in bimodal distributions; a mode where the residue is bound deeply and using local concavity, and a mode where the residue is bound with varying degrees of local concavity on the partner chain. Multi-segment interfaces utilising discontinuous binding regions were not only larger than single segmented interfaces, but also less well packed and less complementary in shape compared with single segment interfaces. These observations suggest that single interacting segments make tight, selective interactions with their globular partner proteins, compared with looser interfaces in larger multi-segmented complexes. Interface core residues showed deepest average use of concavity for peptidic interfaces, and peptide interface periphery residues occupied deeper concavities than identical pairs with symmetric and non-symmetric interface core residues, which did not differ significantly.Looking more closely, we analyzed how concavity at interfaces was used by individual residues. Residue utilization of concavity, how well the residues of one side of each interface make use of the (sub-)pockets available to them on the partner protein, varied with the nearby formation of concavity on the binding partner protein (<table-wrap position=\"float\" id=\"TB32\"><label>Table S32</label></table-wrap><table-wrap position=\"float\" id=\"TB33\"><label>Table S33</label></table-wrap>https://academic.oup.com/bib) raised the hypothesis that both surfaces of PPI interfaces provide \u2018anchoring\u2019 points for one another. Analysis of interfaces revealed that an \u2018interlocking\u2019 phenomenon, where deep concavity utilized in the 0.5\u00a0\u00c5\u20132\u00a0\u00c5 range was complemented by reciprocal concavity use on the other side of the interface, existed in a greater proportion for multi-segmented/globular interfaces, than for single segmented/peptidic interfaces (https://academic.oup.com/bib). Helix residues bound significantly deeper than loop and sheet residues in single segmented interfaces given the same solvent accessibility, for multi-segmented interfaces helices and sheets bound significantly deeper than loops; however, they were not significantly different from each other (https://academic.oup.com/bib).The large proportion of interfaces that at their deepest occupied deep concavities (<table-wrap position=\"float\" id=\"TB34\"><label>Table S34</label></table-wrap><table-wrap position=\"float\" id=\"TB35\"><label>Table S35</label></table-wrap><table-wrap position=\"float\" id=\"TB36\"><label>Table S36</label></table-wrap><table-wrap position=\"float\" id=\"TB37\"><label>Table S37</label></table-wrap><table-wrap position=\"float\" id=\"TB38\"><label>Table S38</label></table-wrap><table-wrap position=\"float\" id=\"TB39\"><label>Table S39</label></table-wrap><table-wrap position=\"float\" id=\"TB40\"><label>Table S40</label></table-wrap><table-wrap position=\"float\" id=\"TB41\"><label>Table S41</label></table-wrap>https://academic.oup.com/bib). Single segment interfaces used significantly more hotspots per 100\u00a0\u00c5 [https://academic.oup.com/bib). For interactions involving globular proteins, identical pairs with symmetric interactions used significantly more hotspots per 100\u00a0\u00c5 [https://academic.oup.com/bib) illustrate the relationship between residue use of concavity, solvent accessibility and energetic importance for each type of interface in the dataset. Overall, for residues originating from the more deeply bound sides of interfaces, there was no significant correlation between residue occupation of concavity and energetic importance (Pearson correlation coefficient R\u2009=\u2009\u22120.05). When separated by solvent accessibility, the correlations were R\u2009=\u20090.23 for interface core residues and R\u2009=\u20090.02 for peripheral residues. Correlations of hotspots with use of concavity ranged from \u22120.04 to 0.25 for all interface types and environments (https://academic.oup.com/bib).Hotspot density in different interface segmentations and types was calculated using mCSM-PPI to identify the number of hotspots per 100\u00a0\u00c5  BSA  showed that around 80% of PPI interfaces had at least one enclosed residue. Enzyme-peptide interfaces exhibited the largest proportion of interfaces with at least one enclosed residue (93%), followed by Protein-Peptides (90%), identical pairs with symmetric interface (88%), identical pairs with non-symmetric interface (76%) and non-identical pairs (75%).The anchor hypothesis of interaction proposes that initial, fast recognition between protomers is mediated by residues, usually from the smaller interacting partner, that bury a large portion (>100\u00a0\u00c5 ) of surfTo explore how residues utilising concavity may be exploited for drug discovery, enclosed residues at PPI interfaces were clustered in 3D. These enclosed residue clusters represent pockets, or adjacent sub-pockets, that are demonstrably utilized by proteins at interfaces and thus have potential for orthosteric challenge with small-molecules. This revealed that 9253 interfaces possessed enclosed residue clusters (16% of the dataset) . ProteinThe existence of small, buried protein-occupied pockets in larger, multi-segment interfaces, consisting of clusters of multiple small-volume pockets may present opportunities for single residue sites to be competed for with fragments, which could be elaborated into interface competitive small molecules for transient interfaces where interface on/off kinetics could allow competitive inhibition. Geometric clustering of deeply bound and solvent inaccessible residues at interfaces revealed cases in the dataset that presented these dense clusters of enclosed residues, which were potentially occupying druggable pockets. However, the presence of such clusters is not an essential requisite for druggability, as evidenced by only one drugged PPI from the 2P2I dataset  possessiIn this study we explored the nature of PPI binding interfaces with respect to binding-mode geometry, interatomic interactions and structural and energetic importance of interface residues. While often considered flat and featureless, we showed that while the majority of interfaces extracted from the PDB were indeed flat on average, many interfaces did utilize concavity at their deepest point, suggesting that an element of concavity is important for many PPIs. Peptidic interfaces and those utilising continuous binding regions at the interface made greater use of concavity on average, suggesting that these binding sites may be better defined with respect to potential exploitation in drug discovery. Depth may provide a way of improving encapsulation of a residue in smaller interfaces, as evidenced by the greater proportion of peptide interface core residues in protein\u2013peptide interfaces using deeper binding modes, and making proportionally higher use of the local binding site space (complemented pockets) available in comparison to other residue environments. Our findings support the anchor hypothesis of many interfaces having deeply bound and solvent inaccessible residues, which can be an important venue in drug discovery. We show that many interfaces provide concavity on both sides of the interface to support interactions.Surprisingly, no significant correlation was observed between deeply bound or solvent inaccessible residues and their energetic contribution to the interaction, despite hotspot residues being significantly more present at the interface core. On the other hand, significantly larger and multi-segmented interfaces have shown fewer number of hotspots per 100\u00a0\u00c5 , suggestWe hypothesize that differences in interatomic contact usage by smaller, continuous interfaces compared with larger multi-segmented interfaces may reflect differences in the nature of their recognition. As single segments tended to bind using more grooves than multi-segmented PPIs, the significantly greater use of more specifically directional interactions, such as hydrogen bonding, by single segment interfaces may indicate an evolved imperative for the use of directional interactions to lock a segment into a deep binding site without requiring rearrangement of the globular binding partner. Conversely, for larger and multi-segment interfaces, ionic interactions that may be involved in longer range electrostatic steering may contribute more to recognition where overall concavity is not present, and residues occupying concavities are less prevalent.By analyzing a large-scale dataset of structurally characterized PPIs from the PDB, we found that interfaces forming a continuous binding segment make greater overall use of protrusion into partner protein concavities on average than do globular discontinuous interactions. Deeply bound residues existed in a large proportion of all interactions and there was a relationship between depth and solvent accessibility depending on the continuity of the interface. Over 80% of interfaces utilized at least one deeply bound, solvent inaccessible residue, and over 16% of interfaces made use of multiple, small-volume sub-pockets of the kind bound by previously developed orthosteric PPI inhibitors.We propose that while continuous binding sites that make use of concave binding modes overall may be more immediately tractable from a druggability perspective, there may be benefit in targeting globular protein interfaces with discrete, complemented sub-pockets, into which residue-sized small-molecule fragments could protrude. Through analyzing the chemistry of interfaces as an aggregate property, summarizing pairwise atomic interactions, we uncovered different chemical preferences between continuous and discontinuous binding sites, suggesting that single continuous segments require more specific directional interactions, whereas discontinuous interfaces burying larger surface areas rely more on aromatic sealing of the interface, and on electrostatic interactions. These discontinuous interfaces may be more amenable to target by allosteric or interface approaches. Our results move towards a better understanding of the features used at therapeutically relevant PPI interfaces, which can then be used on a more rational approach to drug design.Homo sapiens with reportedly 98% structural coverage of the proteome currently available in the AlphaFold database [Finally, recent advances in protein structure prediction by AlphaFold  and Rosedatabase . More redatabase , allowinPairwise structures of interacting proteins were extracted from the PDB (accessed on 14 April 2021). Interactions with missing atoms at the interface, interfaces that overlapped with other interfaces , interfaces where the product of the number of residues contributed by each protein partner was less than 25 and interfaces where less than 100\u00a0\u00c5 . To simpdifflib Python package, to compare short peptide sequences, with a similarity cutoff of 75%. Representative interface pairs for each cluster were chosen based on a structure quality score [A non-redundant set of PPI interfaces was generated by clustering interfaces first on whether the interacting pair of proteins was identical using CD-HIT at 95% identity cutoff  and substy score .https://academic.oup.com/bib). Interactions between peptides and enzymes were separated from interactions with non-enzymatic proteins by identifying enzyme chains using the SIFTS cross-database mappings of the PDB to EC enzyme classification database [The final dataset of interfaces was partitioned by categorizing interactions between globular proteins and protein\u2013peptide interactions. The dataset consisted of 55\u00a0189 interfaces, of which 15\u00a0920 were identical pairs with symmetric interface, 8580 were identical pairs with non-symmetric interface, 28\u00a0165 were non-identical pairs, 1702 were protein\u2013peptide interfaces and 822 were enzyme\u2013peptide interfaces , unless otherwise stated. Properties analyzed included shape complementary, interface packing and planarity for whole interfaces. The shape correlation (Sc) measure uses interface region surface normal vectors to determine how well fit is the interface between two proteins . HoweverIn this work, segmentation refers to the continuity of an interface with respect to primary structure. Segments can optionally have a gap threshold of how far apart two interface residue can be (in the primary sequence) so they are still considered in a single segment . Segment<fig id=\"f7\"><label>Figure S1</label><graphic mimetype=\"image\" xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"bbac165f7.tif\"/></fig><fig id=\"f8\"><label>Figure S2</label><graphic mimetype=\"image\" xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"bbac165f8.tif\"/></fig><fig id=\"f9\"><label>Figure S3</label><graphic mimetype=\"image\" xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"bbac165f9.tif\"/></fig><fig id=\"f10\"><label>Figure S4</label><graphic mimetype=\"image\" xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"bbac165f10.tif\"/></fig><fig id=\"f11\"><label>Figure S5</label><graphic mimetype=\"image\" xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"bbac165f11.tif\"/></fig><fig id=\"f12\"><label>Figure S6</label><graphic mimetype=\"image\" xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"bbac165f12.tif\"/></fig><fig id=\"f13\"><label>Figure S7</label><graphic mimetype=\"image\" xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"bbac165f13.tif\"/></fig><fig id=\"f14\"><label>Figure S8</label><graphic mimetype=\"image\" xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"bbac165f14.tif\"/></fig><fig id=\"f15\"><label>Figure S9</label><graphic mimetype=\"image\" xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"bbac165f15.tif\"/></fig><fig id=\"f16\"><label>Figure S10</label><graphic mimetype=\"image\" xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"bbac165f16.tif\"/></fig><fig id=\"f17\"><label>Figure S11</label><graphic mimetype=\"image\" xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"bbac165f17.tif\"/></fig><fig id=\"f18\"><label>Figure S12</label><graphic mimetype=\"image\" xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"bbac165f18.tif\"/></fig><fig id=\"f19\"><label>Figure S13</label><graphic mimetype=\"image\" xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"bbac165f19.tif\"/></fig><fig id=\"f20\"><label>Figure S14</label><graphic mimetype=\"image\" xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"bbac165f20.tif\"/></fig><fig id=\"f21\"><label>Figure S15</label><graphic mimetype=\"image\" xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"bbac165f21.tif\"/></fig><fig id=\"f22\"><label>Figure S16</label><graphic mimetype=\"image\" xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"bbac165f22.tif\"/></fig><fig id=\"f23\"><label>Figure S17</label><graphic mimetype=\"image\" xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"bbac165f23.tif\"/></fig><fig id=\"f24\"><label>Figure S18</label><graphic mimetype=\"image\" xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"bbac165f24.tif\"/></fig><fig id=\"f25\"><label>Figure S19</label><graphic mimetype=\"image\" xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"bbac165f25.tif\"/></fig><fig id=\"f26\"><label>Figure S20</label><graphic mimetype=\"image\" xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"bbac165f26.tif\"/></fig><fig id=\"f27\"><label>Figure S21</label><graphic mimetype=\"image\" xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"bbac165f27.tif\"/></fig><fig id=\"f28\"><label>Figure S22</label><graphic mimetype=\"image\" xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"bbac165f28.tif\"/></fig><fig id=\"f29\"><label>Figure S23</label><graphic mimetype=\"image\" xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"bbac165f29.tif\"/></fig>Rinaccess) value, in angstroms, calculated using Ghecom [As for properties of protein residues, here we calculated the proportion of secondary structure types using DSSP via Biopython . Secondag Ghecom . Concavihttps://academic.oup.com/bib).Residues within 5\u00a0\u00c5 of any of the binding partner\u2019s protein atoms were considered to be part of the interface, and were further categorized as being core or periphery based on their solvent accessibility , 26. RelThe Ghecom measurement of concavity together with solvent accessibility was used to elucidate potential anchor residues from interface structure. Any residue that was solvent inaccessible with a residue minimum concavity threshold of 4\u00a0\u00c5 or less was classified as enclosed residues. The DBSCAN density-based clustering algorithm  was usedBinding values from mCSM-PPI [Binding|\u2009>\u20091\u00a0kcal/mol was then used to determine whether a residue was a hotspot or non-hotspot [Finally, \u0394\u0394GmCSM-PPI  were use-hotspot .The one-way analysis of variance (ANOVA), as implemented in the stats module of SciPy , was useThis review presents a detailed analysis of the landscape of therapeutically relevant PPI interfaces.We show that while interfaces forming continuous segments make greater use of concavity, discontinuous interfaces are also amenable to modulation through allosteric or competitive inhibitors.We discuss how a better understanding of features used at therapeutically relevant PPI interfaces can then be used on a more rational approach to drug design.ppi_landscapes_BiB_supps_bbac165Click here for additional data file."}
+{"text": "Prior COVID-19 mRNA vaccine trials included healthy older adults, but mRNA vaccine responses were not studied in frail older adults. We postulated that frailty was associated with immune responses of reduced quality and quantity following mRNA vaccination. A cohort of 15 older adults in a retirement facility were followed from the first Moderna mRNA-1273 vaccine dose in February 2021 with blood collections at baseline and weeks 4 (boost), 6, 18 and 28. Outcomes were IgG titers to SARS-CoV-2 Spike protein with secondary outcomes of T cell responses. Statistical analysis used log transformed geometric mean antibody titers in multivariable regression models with clinical predictors including, age, sex, prior infection status, and clinical frailty scale (CFS) score. Cellular immune response analysis used multivariable regression for function and phenotyping of T cell subsets. All participants with median (IQR) age: 90 years  and CFS score: moderately frail 6  generated robust antibody responses with mean peak titer levels 10-fold higher than baseline. In the adjusted model, individuals with severely frail scores CFS=7 had lower antibody levels compared to mildly frail CFS=5, OR: 0.55  p=0.017. Both chronological age and sex had non-significant relationships with antibody titers. Spike peptide specific CD4 cells and T follicular helper cells were significantly decreased in more frail individuals (p=0.011 and p=0.008 respectively), though the relationship with antibody titers was non-significant. Frailty scores were a better predictor than age for serologic and cellular immune responses to COVID-19 mRNA vaccination in very old adults."}
+{"text": "Scientific Reports 10.1038/s41598-022-15613-9, published online 06 July 2022Correction to: The Acknowledgements section in the original version of this Article was incomplete.\u201cWe thank Katerina Petkanopoulou for her valuable comments.\u201dnow reads:\u201cWe thank Katerina Petkanopoulou for her valuable comments. Financial support was provided by the EU Horizon 2020 Marie Curie Individual Fellowship  to G.L.\"The original Article has been corrected."}
+{"text": "The prebiotic inulin has previously shown both protective and tumor-promoting effects in colorectal cancer. These discrepancies may be due to polyketide synthase-positive (pks+) Escherichia coli promoting carcinogenesis through the production of colibactin, a genotoxin that induces double-strand DNA breaks (DSBs).In this study we investigated the impact of inulin on the genotoxicity of colibactin-producing bacteria.E. coli strains Nissle (EcN), and NC101 (EcNC101) were grown in medium supplemented with inulin. Colibactin expression was assessed by luciferase reporter gene expression and Caco2 cells were used to assess colibactin-induced genotoxicity by \u03b3-H2AX immunofluorescence analysis. ApcMin/+ mice received 2% dextran sodium sulfate (DSS) followed by oral gavage with EcNC101 and were fed a diet supplemented with 10% cellulose (control diet) or 10% inulin for four weeks.Inulin enhanced EcNC101-induced expression of colibactin and DSB levels in Caco2 cells. Inulin supplementation in ApcMin/+ mice led to enhanced EcNC101 colonization and tumor progression.The presence of colibactin producing E. coli in the gut influences the outcome of inulin supplementation in CRC progression. Further studies are needed to investigate the interaction between dietary supplements and cancer-promoting bacteria.CIHR, OtherNSERC, Institut du cancer de montr\u00e9alNone Declared"}
+{"text": "Outpatient peripherally inserted central catheters (PICC) use has grown without standardized protocols for their management. We assessed the impact of a mobile app strategy for outpatient CLABSI prevention using photo-monitoring, assessment, and response to lines with local inflammation/infection in a cohort of cancer clinic patients.This prospective cohort study evaluated adults with PICCs at an academic cancer clinic at baseline (7/2015\u201312/2016) and after implementing the SAFER (Standardizing Assessment For Effective Response) Lines program (intervention 5/2017\u201311/2018). This included a mobile app enabling (1) clinic assessment of localized inflammation or infection defined as Central Line Insertion Site Assessment (CLISA) score 2 or 3, respectively (Table\u00a01), (2) photo-documentation, and (3) score-based automated physician alerts for remote response. We assessed demographics, malignancy type, and line characteristics. Generalized linear mixed effects model assessed program impact on frequency of CLISA 2 or 3 lines, clustered by patient. Cox proportional hazards and Kaplan Meier models assessed days to line removal after CLISA 2 or 3 were identified.Among 4,894 assessments of 528 PICCs in 380 outpatients, there were 272 lines (199 patients) at baseline and 256 lines (181 patients) after SAFER program implementation. Mean age, gender, PICC dwell time, and history of prior PICC were similar at baseline and intervention. The proportion of inflamed (CLISA 2) and infected (CLISA 3) lines decreased 40%  during intervention compared to baseline. Lines with peeling dressings decreased 80% (from 46% to 9%). Mean days to removal of inflamed lines decreased 59% (from 19 to 8 days); removal of infected lines decreased 85% (from 11 to < 2 days). Intervention was associated with 46% lower risk of local inflammation/infection  and faster line removal when such lines were identified .The SAFER Lines mobile app and program decreased the frequency of locally inflamed or infected PICC insertion sites and increased the speed of removal when local inflammation/infection was found in cancer clinic patients.Raheeb Saavedra, AS, Medline: Conducted studies in which hospitals and nursing homes received contributed antiseptic and/or environmental cleaning products|Stryker: Conducted clinical studies in which hospitals and nursing homes received contributed antiseptic products|Xttrium Laboratories: Conducted clinical studies in which hospitals and nursing homes received contributed antiseptic products Raveena D. Singh, MA, Medline: Conducted studies in which hospitals and nursing homes received contributed antiseptic and/or environmental cleaning products|Stryker: Conducted clinical studies in which hospitals and nursing homes received contributed antiseptic products|Xttrium Laboratories: Conducted clinical studies in which hospitals and nursing homes received contributed antiseptic products Susan S. Huang, MD, MPH, Medline: Conducted studies in which hospitals and nursing homes received contributed antiseptic and/or environmental cleaning products|Molnlyke: Conducted clinical studies in which hospitals received contributed antiseptic product|Stryker: Conducted clinical studies in which hospitals and nursing homes received contributed antiseptic products|Xttrium Laboratories: Conducted clinical studies in which hospitals and nursing homes received contributed antiseptic product."}
+{"text": "Pseudomonas fluorescens isolate SBW25. The updated genome assembly, which was derived from the original isolate, is based on PacBio long-read sequence data. It shows three minor differences, compared with the previously published genome sequence. Original annotations were merged with recent automated annotations to preserve information.We report a genome update for  Pseudomonas fluorescens is a Gram-negative bacterium that is commonly found in soil, in water, and on plant surfaces (NCBItxid216595) is a model organism in evolution, population biology, microbe-plant interactions, and genetics. The Pseudomonas fluorescens SBW25 genome was originally sequenced at the Wellcome Sanger Institute (surfaces . Strain  NCBItxid16595 is  NCBItxid16595 is Pseudomonas fluorescens SBW25 genome is a de novo hybrid assembly of Pacific Biosciences (PacBio) Sequel single-molecule real-time (SMRT) long reads and Illumina NextSeq 500 short reads for our stock sample, MPB13884. MPB13884 was obtained by passaging the original strain PBR340, which was held at \u221280\u00b0C, through three consecutive single-colony-derived overnight 6-mL cultures grown at 28\u00b0C, representing approximately 100 to 150 generations.Our updated High-density genomic DNA was extracted using the Nanobind CBB Big DNA kit (Circulomics). The library was prepared with the PacBio template preparation kit v1.0 . InitialThe raw PacBio reads were filtered using Filtlong  options options, 11 bot option:, 13 (optIllumina short-read sequencing was performed at the Max Planck Institute for Evolutionary Biology on the NextSeq 500 platform. DNA was extracted with the Wizard genomic DNA purification kit A1120 (Promega). Library preparation with the Nextera XT kit (Illumina) followed the protocol described previously . The shoWe aligned the old and new assemblies with MAFFT v1.4.0  (defaultPseudomonas fluorescens SBW25 were transferred from RefSeq (GenBank assembly accession number GCF_000009225.2), GenBank (accession number GCA_000009225.1), ENA (accession number GCA_000009225), and Sanger Institute (accession number AM181176) databases to the new assembly using Geneious Prime v2020.2.4 (https://www.geneious.com), applying the protocol described in reference To annotate the new assembly, we applied the following procedure. Public annotations for https://gitlab.gwdg.de/mpievolbio-scicomp/sbw25_newgenome/-/tree/assembly_scripts."}
+{"text": "During July\u2013December 2021, after COVID-19 restrictions were removed in England, invasive pneumococcal disease incidence in children <15 years of age was higher  than during the same period in 2020  and in prepandemic years 2017\u20132019 . Childhood vaccine coverage should be maintained to protect the population. The COVID-19 pandemic and its associated lockdowns, social isolation, and other interventions led to large declines in respiratory infections, including invasive pneumococcal disease (IPD) (We compared IPD cases during July\u2013December 2021 to July\u2013December 2020 and July\u2013December in 3 prepandemic years (2017\u20132019) by using national enhanced surveillance data for England : 32% of cases were among <1-year-olds, 42.5% among 1\u20134-year-olds, 18% among 5\u20139-year-olds, and 7.5% among 10\u201314-year-olds. Of 172 (86%) pneumococcal isolates serotyped, we noted no difference in serotype distribution between years nor within age groups. Nonvaccine types (43%) and serotypes in the 23-valent pneumococcal polysaccharide vaccine  but not in the 13-valent pneumococcal conjugate vaccine (PCV13) predominated compared with PCV7 (5%) and additional PCV13 (16%) serotypes , panel AThe most frequent serotypes among childhood cases remained similar in 2021 to those in prepandemic years , panel AMore IPD cases in 2021 involved bacteremia  compared with the prepandemic period  (p = 0.003). The proportion of cases with meningitis (22%), pneumonia (31%), and other clinical manifestations (7%) were not substantially different. The prepandemic and postpandemic 30-day case-fatality rates also were similar .After lifting COVID-19 social restrictions, England experienced an increase in childhood IPD cases that exceeded prepandemic levels. England\u2019s pandemic social restrictions led to large declines in many infectious diseases, including IPD (Haemophilus influenzae serotype b after mass vaccination in England (https://doi.org/10.2139/ssrn.3998164), who are the main nasopharyngeal carriers of Neisseria meningitidis. Our observed IPD case increase among children is counter to modeling studies that predicted IPD incidence would continue to decline after COVID-19 restrictions were lifted, even accounting for decreased vaccine coverage  that had been in place since 2010 to a reduced 1+1 schedule (12 weeks and 1 year). This change was made on the basis that most protection is through indirect herd or population protection offered by preventing carriage among toddlers, thus interrupting transmission to others (In our cohort, serotype distribution of childhood IPD cases did not change, consistent with the childhood carriage study in Israel and reports from Germany (In conclusion, although total IPD cases remained lower in 2021 than the 3 pre\u2013COVID-19 pandemic years, increases in childhood cases exceeding prepandemic levels could portend increases across all age groups. Maintaining high childhood PCV13 uptake will be critical for ongoing population protection."}
+{"text": "Correction: Biomark Res 10, 89 (2022)https://doi.org/10.1186/s40364-022-00436-7The original article  contains\u2018When combining IMQ, photodynamic therapy (PDT) had a better effect on cutaneous squamous cell carcinoma (cSCC) than either IMQ or PDT alone.\u2019The mention of IMQ is erroneous and should instead be IMA (imatinib mesylate)."}
+{"text": "Keloids are pathologic wound healing conditions caused by fibroblast hyperproliferation and excess collagen deposition following skin injury or irritation, which significantly impact patients by causing psychosocial and functional distress. Extracellular matrix (ECM) deposition and human fibroblast proliferation represents the main pathophysiology of keloid. Long non-coding RNAs (LncRNAs) play important roles in many biological and pathological processes, including development, differentiation and carcinogenesis. Recently, accumulating evidences have demonstrated that deregulated lncRNAs contribute to keloids formation. The present review summarizes the researches of deregulated lncRNAs in keloid. Exploring lncRNA-based methods hold promise as new effective therapies against keloid. Keloids are pathological scars characterized by firm, raised, erythematous plaques or nodules following cutaneous injury, which under normal conditions results in wound healing with a flat scar . KeloidsRecent advances have proved that most human genome is transcribed to RNAs that lack the capacity to encode proteins (non-coding RNAs). Long non-coding RNAs (LncRNAs), are defined as transcripts longer than 200 nucleotides in length without protein-coding capacity . IncreasLiang et al. found that more than 2,500 lncRNAs were differentially expressed between keloid tissue and the normal human skin by microarray analysis and qRT-PCR. Among them, 1,731 lncRNAs was upregulated and 782 lncRNAs was downregulated . FurtherAnother study identified a total of 319 keloid-specific lncRNAs using RNA-seq and miRNA-seq . The stuTo identify lncRNAs differentially expressed during keloid formation, secondary analysis of keloid-related sequencing and microarray data were downloaded from the open-source Gene Expression Omnibus (GEO) database. A total of 2356 lncRNAs was changed before and after injury in keloid-prone groups . Among tA recent study identified 11 differentially expressed 11 EMT-related lncRNAs and 16 mRNA in keloid tissues versus normal tissues . These 1The development of keloid was significantly related with HKFs proliferation, migration, invasion, and apoptosis. LncRNAs and miRNAs can communicate with and co-regulate each other . These lLncRNA-H19 was one of the first reported lncRNAs and associated with proliferation in many tumors . H19 canLncRNA homeobox (HOX) A11 antisense, HOXA11-AS, was recently proved to promote keloid formation through inducing type I collagen (ColI) synthesis. HOXA11-AS and ColI expression levels were increased in human keloid tissues and HKFs . FurtherLncRNA Calcium voltage-gated channel subunit alpha1 G antisense RNA 1  is the antisense RNA of CACNA1G, mRNA of the T-type channel protein Cav3.1 . CAS1 exin vivo. TGF-\u03b21 was proved to be a direct and functional target of miR-3141.Accumulating reports demonstrated that long non-coding RNA LINC01116 was associated with the development of various malignancies . A recenLncRNA-activated by TGF-\u03b2 (lncRNA-ATB) has been proved to promote tumor cell invasion and metastasis, exhibiting oncogenic functions in several cancers . LncRNA-The lncRNA AC073257.2 and its upstream target gene Gli2 were both upregulated in keloid. LncRNA AC073257.2 and HNF1A-AS1 might regulate keloid cell growth and proliferation by its target gene GLI2 and HNF1A respectively. The differentially expressed Hh signaling pathway-related lncRNAs and mRNAs may help to uncover the pathogenesis of keloid .LINC00937 suppresses HKFs proliferation and ECM deposition by targeting the miR-28-5p/MC1R axis . LINC009Wingless type (Wnt) signaling pathway was demonstrated to play a role in the pathogenesis of wound healing . Using aHedgehog (Hh) signaling pathway plays important roles in several biological and pathological processes, especially in malignant tumors . Huang eIn this review, we summarized the published research data about the role of lncRNAs in the pathogenesis of pathological scars, including keloid and HS. In particular, we discussed the regulatory relationships between lncRNAs and miRNAs in the progression of keloid. These researches strongly support the potential role of lncRNAs keloid and HS. Some lncRNAs were upregulated and they promoted skin fibrosis while other lncRNAs were downregulated and suppressed skin fibrosis. LncRNAs regulate key processes involved in keloid and HS, including fibroblast proliferation, ECM deposition, Wnt signaling, Hh signaling and TGF-\u03b2signaling. However, the knowledge about lncRNA-miRNA crosstalk remains largely unexplored in keloid. Investigating the expression and function of lncRNAs will help to increase our understanding about the molecular mechanisms of pathological scars. Recent studies have identified circular RNAs (circRNAs) as important regulators in human keloid . LncRNAs"}
+{"text": "Molecular diagnostics appear promising for early, non-invasive detection of invasive fungal disease (IFD) in immunocompromised patients. Our clinical lab developed and validated cell free DNA (cfDNA) fungal polymerase chain reaction (PCR) assays (Table\u00a01), which have been in clinical use since November 2020 and were recently included in an institutional pediatric clinical care pathway for prolonged febrile neutropenia. We aimed to evaluate the performance of these plasma cfDNA fungal PCR assays in pediatric oncology and hematopoietic stem cell transplant (HSCT) patients with clinical concern for IFD.Candida panel) cfDNA fungal PCR obtained as part of an IFD evaluation at our freestanding quaternary care children\u2019s hospital. The primary outcome was IFD clinical diagnosis  as per EORTC/MSG\u2020 definitions within one month of the cfDNA fungal PCR, which was assigned independently by two physicians, with a third physician utilized in cases of discrepancy. Patient demographics, hospital course, imaging results, and clinical laboratory data were abstracted and maintained in an encrypted REDCap\u00a9 database.We initiated an observational study of inpatient oncology and HSCT patients who had plasma mold panel . Most oncology evaluations were for prolonged febrile neutropenia, while many HSCT were non-neutropenic, but on enhanced immunosuppression with new clinical concerns . Plasma cfDNA detected a mold or yeast consistent with the clinical presentation in 100% of the five proven/probable cases . All 14 possible IFD cases had a negative cfDNA fungal PCR.Proven cases are designated with blue icon, while the probable case is orange. All five cases were in oncology patients who did not have history of hematopoietic stem cell transplant. Cell free DNA (cfDNA) fungal polymerase chain reaction (PCR) results include the organism identified, followed by the cycle threshold (Ct) in parenthesis. Maximum Ct for the assay is 45.Abbreviations: AG: Aspergillus galactomannan index (Ref <0.5); ALL: acute lymphoblastic leukemia.BAL: bronchoalveolar lavage; 1,3-BDG: 1,3-beta-D-glucan (Ref <60 pg/ml); cfDNA: cell free deoxyribonucleic acid; CNS: central nervous system; EORTC/MSG: European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group & the National Institute of Allergy & Infectious Diseases Mycoses Study Group; L-AmB: liposomal amphotericin B; SARS-CoV-2: severe acute respiratory syndrome associated with coronavirus 2.Upfront plasma cfDNA fungal PCR successfully detected a relevant mold or yeast with short turnaround time in 100% of cases that were later classified as proven/probable. This appears promising for early, noninvasive diagnosis that enables prompt optimization of antifungal and surgical management, particularly for mucormycosis cases. Additional data may permit consideration of Mucorales agents PCR as a new EORTC/MSG mycologic criteria.Lauren E. Kushner, MD, Roman: Client of my husband's business.."}
+{"text": "Streptococcus pneumoniae is the leading cause of meningitis in children and is associated with significant morbidity and mortality. Despite conjugate pneumococcal vaccines that have otherwise been successful in reducing invasive disease caused by vaccine serotypes, the incidence of pneumococcal meningitis remains relatively unchanged. Using genome-wide association, we identified sequence elements associated with pneumococcal central nervous system (CNS) infection.in silico serotyping. Fifty-four clinical isolates were from children with CNS infection. Sequence element enrichment analysis was performed using elastic net and linear mixed modeling statistical methods to find genetic variants associated with CNS infection. We identified associated genes by mapping statistically associated variants to a serotype 19F reference S. pneumoniae genome.From 1996 to 2018, 366 clinical pneumococcal isolates were collected from pediatric patients and paired with clinical metadata. All isolates underwent whole-genome sequencing and -7). The top intragenic candidate in our analysis was located within cpsC, a gene involved in regulation of capsule synthesis. The CNS infection-associated cpsC variant was found in serotypes 22F (n = 1), 18C (n = 4), and 14 (n = 2).CNS isolates spanned 22 unique serotypes; the most common were 22F (n = 6), 7F (n = 5), 18C (n = 4), and 35B (n = 4). We identified two intergenic sequence variants and one intragenic sequence variant significantly associated with CNS infection (p < 1.48 \u00d7 10The diversity of pneumococcal isolates associated with CNS infection suggests the importance of genetic determinants beyond capsular serotype. We identified a number of novel microbial genetic variants significantly associated with pneumococcal CNS infection across serotypes, including a coding mutation in cpsC. Functional characterization of cpsC variants is needed to inform mechanisms contributing to pneumococcal CNS virulence.Anne J. Blaschke, MD, PhD, BioFire Diagnostics/Biomerieux: Advisor/Consultant|BioFire Diagnostics/Biomerieux: Grant/Research Support|BioFire Diagnostics/Biomerieux: IP licensed to BioFire Diagnostics through the University of Utah and royalties received through the University of Utah related to the FilmArray|Merck: Advisor/Consultant."}
+{"text": "The experience of being bilingual may accrue cognitive reserve against age-related declines in older adults. Early bilingualism, e.g., second language age-of-acquisition (L2AoA), has been shown to be associated with better theory-of-mind (ToM) performance in older adults . Here, we aim to understand the brain structural correlates associated with bilingualism and ToM performance in normal aging. Forty-six young  and 51 older adult bilinguals  completed 1) ToM assessments, where they viewed vignettes and answered questions about the protagonists\u2019 mental states, 2) an anatomical MRI scan, 3) a demographic questionnaire including L2AoA and years of education, and 4) a general cognitive ability assessment by the Montreal Cognitive Assessment (MoCA) test. As expected, ANCOVA on ToM composite scores revealed a significant main effect of age \u2013 YA showed better ToM performance than OA, F=9.48, p=.003, controlling for education and MoCA scores. Importantly, MRI data were preprocessed to obtain gray matter volume (GMV), proxy of neuronal density, of 430 brain regions. Partial least square correlation analysis identified one significant multivariate pattern linking individual differences in GMV with ToM score and L2AoA . Regardless of age, larger GMV in several regions including prefrontal, frontal, medial temporal, and superior temporal cortices were associated with earlier L2AoA (p=.003) and higher ToM score (p=.004), indicating shared variance between ToM and L2AoA in brain morphology. Findings suggest that earlier bilingual acquisition might promote brain maturation that would preserve ToM ability well into later stages of life."}
+{"text": "Dear Editor,1 Although CaOx nephrocalcinosis is usually asymptomatic, it can also induce severe inflammation and necrosis of renal tubular epithelial cells (TECs). Necrotic TECs release various damage-associated molecular patterns (DAMPs), which induce renal necroinflammation by activating Toll-like receptor 4 (TLR4) and secreting IL-1\u03b2, which triggers proinflammatory M1 macrophages (M1M\u03d5s) and then amplifies CaOx-induced renal injury,2 which can induce further crystal deposition and eventually lead to end-stage renal disease.3 However, information on the pharmacotherapeutics of kidney crystal formation remains limited. In addition, numerous studies have shown that CaOx crystal-induced oxidative stress and inflammatory injury to TECs are vital factors in the progression of crystalline nephropathy.4 Therefore, putting renal inflammation under control is expected to alleviate CaOx-induced inflammatory responses and inflammation-related tubular cell injury.Kidney stones are one of the most common clinical diseases in urology. Approximately 80% of renal calculi are composed of calcium oxalate (CaOx) crystals, which are gradually deposited in the medullary collecting duct or in the renal interstitium, causing nephrocalcinosis.5 Sirtuin1 (Sirt1), an NAD+-dependent protein deacetylase, is significantly activated by Met-mediated promotion of NAD+ and the NAD+/NADH ratio and participates in various cellular processes, such as suppressing inflammation, enhancing M2M\u03d5 polarization, reducing oxidative stress and maintaining mitochondrial function. Determination of whether Met can systemically tune down exaggerated immune responses via inflammatory signaling cascades and can be applied as a therapeutic agent to treat CaOx-induced kidney injury is urgently needed.In principle, the inflammatory responses induced by CaOx crystals involve diverse downstream effectors. Therefore, targeting particular cytokines or even signaling pathways may not be sufficient to alleviate kidney injury. Metformin (Met) is a pleiotropic drug that functions mainly by targeting oxidative stress and inflammation. It has been reported to protect renal tubular cells from inflammation, apoptosis, reactive oxygen stress, and endoplasmic reticulum stress in acute or chronic kidney diseases.In this study, we sought to understand the underlying pathways regulated by Sirt1 and explored the mechanism by which Met regulates CaOx nephrocalcinosis. We pretreated mice with increasing doses of Met  for 3 days, after which a model of CaOx nephrocalcinosis was established for 7 days . Reduced CaOx crystal deposition was observed when the Met concentration increased on day 10. Importantly, Met attenuated kidney injury in TECs caused by CaOx nephrocalcinosis in a dose-dependent manner Fig. . Moreove2FC\u2009|\u2265\u20091.5; P value < 0.05). Gene Ontology enrichment and differential gene expression confirmed that the presence of CaOx crystals increased a spectrum of proinflammatory responses , macrophages recruitment and polarization  . The matrix dot plot enrichment of eight immune cell types showed a significant increase in renal macrophages infiltration in the Gly group  on glyoxalate (Gly)- or saline-treated mouse kidneys (GSE192703). Gly-induced CaOx nephrocalcinosis caused the upregulation of 2596 genes and the downregulation of 2161 genes (|logR4) Fig. . To furtoup Fig. , indicatGiven the anti-inflammatory effect of Met and its known regulatory effects on macrophages, we next performed RNA-seq on calcium oxalate monohydrate (COM)-stimulated bone marrow-derived macrophages (BMDMs) (GSE192593) pretreated with Met or PBS in TECs or COM-TECs . Analysis of differential gene expression confirmed that COM-TECs led to upregulation of a spectrum of proinflammatory transcripts in BMDMs Fig. . KEGG pafl/fl:Lysm-Cre mice and COM-TECs from WT mice. As expected, Sirt1 knockout (KO) significantly promoted M1M\u03d5s polarization and increased TLR4 signaling (Fig. We hypothesized that Met exerts its anti-inflammatory effects partly by interfering with TLR4 and IL-1\u03b2 through Sirt1 in macrophages and modulating macrophages polarization. To evaluate this hypothesis, we cocultured COM-stimulated TECs with Met-treated BMDMs. Fig. ing Fig.  Moreovering Fig. . The resfl/fl:Lysm-Cre mice with Met for 3 days and developed a CaOx nephrocalcinosis mouse model by the intraperitoneal injection of glyoxylic acid. We determined that Met significantly reduced kidney CaOx crystal deposition in the WT mice, while Sirt1cKO reversed this effect (Fig. 18F-FDG uptake by micro-PET-CT to determine the local renal inflammatory response. Micro-PET-CT imaging revealed that Met decreased 18F-FDG uptake in the WT mouse kidneys, while these parameters were enhanced in the Sirt1fl/fl:Lysm-Cre mice (Fig. We further explored whether the effects of Met on CaOx-induced renal inflammation and crystal deposition are Sirt1dependent. We pretreated the WT and Sirt1ect Fig. . We analice Fig. . Furtherice Fig. . PAS, TUice Fig. . In addiice Fig. . In summIn conclusion, the results demonstrated that Met can attenuate crystal deposition and kidney injury in a CaOx nephrocalcinosis mouse model by promoting Sirt1 activation and M2M\u03d5s polarization. A combination of Met with certain anti-oxalate drugs may provide a more effective treatment and prevent recurrence in CaOx nephrocalcinosis. Our study provides strong evidence supporting the therapeutic and preventative potential of using Met in clinical settings.Supplemental Material"}
+{"text": "In recent years, non-alcoholic steatohepatitis (NASH) has become the main cause of hepatocellular carcinoma (HCC). As a means of improving the treatment of NASH-related HCCs based on early detection, this study investigated the feasibility of carcinogenic risk estimation in patients with NASH.ZC3H3 gene, NAFL-W and NASH-W samples from which HCCs had already arisen were confirmed to show carcinogenic risk with 95% sensitivity in the validation cohort.Normal liver tissue (NLT), non-cancerous liver tissue showing histological findings compatible with non-alcoholic fatty liver from patients without HCC (NAFL-O), non-cancerous liver tissue showing NASH from patients without HCC (NASH-O), non-cancerous liver tissue showing non-alcoholic fatty liver from patients with HCC (NAFL-W), non-cancerous liver tissue showing NASH from patients with HCC (NASH-W) and NASH-related HCC were analyzed. An initial cohort of 171 tissue samples and a validation cohort of 55 tissue samples were used. Genome-wide DNA methylation screening using the Infinium HumanMethylation450 BeadChip and DNA methylation quantification using high-performance liquid chromatography (HPLC) with a newly developed anion-exchange column were performed. Based on the Infinium assay, 4050 CpG sites showed alterations of DNA methylation in NASH-W samples relative to NLT samples. Such alterations at the precancerous NASH stage were inherited by or strengthened in HCC samples. Receiver operating characteristic curve analysis identified 415 CpG sites discriminating NASH-W from NLT samples with area under the curve values of more than 0.95. Among them, we focused on 21 CpG sites showing more than 85% specificity, even for discrimination of NASH-W from NASH-O samples. The DNA methylation status of these 21 CpG sites was able to predict the coincidence of HCC independently from histopathological findings such as ballooning and fibrosis stage. The methylation status of 5 candidate marker CpG sites was assessed using a HPLC-based system, and for 3 of them sufficient sensitivity and specificity were successfully validated in the validation cohort. By combining these 3 CpG sites including the After a further prospective validation study using a larger cohort, carcinogenic risk estimation in liver biopsy specimens of patients with NASH may become clinically applicable using this HPLC-based system for quantification of DNA methylation.The online version contains supplementary material available at 10.1186/s13148-022-01379-4. WHSC1  and a \u0394\u03b2NASH-W-NLT value of more than 0.1 or less than\u2009\u2212\u20090.1), indicating that DNA methylation alterations had occurred in the NASH-W samples, which showed histological features compatible with NASH and from which HCC had arisen, in comparison with NLT samples. A Venn diagram showing the number of common and individual differentially methylated probes among the NLT, NASH-O, NASH-W and T samples is shown in Additional file Four thousand and fifty CpG sites showed significant differences in DNA methylation levels between the 22 NASH-W samples and the 36 NLT samples in the initial cohort (Welch\u2019s \u03b2NASH-W\u2009>\u2009\u03b2NLT) and hypo-(\u03b2NASH-W\u2009<\u2009\u03b2NLT) methylation in NASH-W samples relative to NLT samples, respectively. The Youden index was used as a cutoff value for each of the 415 CpG sites to discriminate NASH-W samples from NLT samples. The sensitivity and specificity using each of the 415 CpG sites for such discrimination are shown in Additional file Among the 3234 CpG sites, 415 showed AUC values larger than 0.95; 209 and 206 CpG sites showed DNA hyper-(https://reactome.org). Seventy pathway maps in which such probes were significantly (P\u2009<\u20090.05) accumulated are summarized in Additional file P\u2009=\u20090.000904), R-HSA-1632852 (P\u2009=\u20090.001041), R-HSA-68886 (P\u2009=\u20090.001629) and R-HSA-5693565 (P\u2009=\u20090.006073), respectively) , was examined using 384 cancerous and non-cancerous liver tissues deposited in the TCGA database , indicating that even DNA methylation alterations at CpG sites not involved in the regulation of expression would be potentially excellent surrogate markers.The correlation between DNA methylation levels of the 13 genes, which are included in Table https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE107038) and our own data for NASH-W samples. Even when compared to data for normal healthy liver tissue in the database, significant differences were successfully validated . The DNA methylation levels at all 21 CpG sites discriminated NASH-W samples from NASH-O samples independently from histopathological findings, such as ballooning and fibrosis stage (Brunt classification), which are reportedly correlated with pathological progression , 37   and specificity (73.0\u201393.3%) for such discrimination were obtained in the initial cohort Table .Table 4DP\u2009=\u20091.94\u2009\u00d7\u200910\u22129, P\u2009=\u20091.78\u2009\u00d7\u200910\u22128 and P\u2009=\u20097.78\u2009\u00d7\u200910\u22124, respectively).In order to validate the estimation ability for NASH samples from which NASH-related HCCs had arisen, 22 NLT samples and 11 NASH-W samples in the validation cohort were subjected to anion-exchange HPLC analysis. Using the cutoff values set in the initial cohort and indicated in Table Moreover, the DNA methylation status of both NAFL-W samples and NASH-W samples differed significantly from that of NAFL-O samples and NASH-O samples on the basis of the three analyses, again indicating that tissue samples from which HCC has already arisen can be discriminated from tissue samples that have not yet generated HCC, regardless of their histological features Fig.\u00a0A. In addFinally, a histogram showing the numbers of tissue samples  subjected to HPLC analysis in the validation cohort and the numbers of marker CpG sites satisfying the criteria on cg18210511, cg09580859 and cg13719443 described in Table Our intention in the present study was to devise a protocol for carcinogenic risk estimation in liver biopsy specimens of patients with NASH based on quantification of DNA methylation, in order to facilitate early treatment of NASH-related HCCs through intensive surveillance and early detection. Identification of liver tissue specimens exhibiting histological features compatible with NASH and with the potential to give rise to HCCs, i.e., NASH-W samples, is considered to be the first step of carcinogenic risk estimation. In fact, the DNA methylation status of the 4050 CpG sites examined by Infinium assay clearly differed between NASH-W and NLT and allowed the two to be discriminated on the basis on this status Fig.\u00a0: Fig. S2In a clinical setting, diagnostic criteria that completely discriminate NASH-W from NASH-O may not be adequate, since some patients without HCCs at the time of NASH-O biopsy will ultimately develop HCCs if adequate intervention is not provided. Therefore, we focused on 21 candidate CpG sites Table B, regardThe DNA methylation status of not only the exact Infinium probe CpG site but also neighboring multiple CpG sites\u2014underlined in Additional file ZC3H3 gene   in the initial and validation cohorts for whom HPLC data were obtained . Such rates for cg18210511and cg13719443 were not significantly correlated with age , although the rates for cg09580859 showed marginal significance (P\u2009=\u20090.035). These data indicated that the DNA methylation status of our markers was, in general, not correlated with differences in age and sex, and that such markers would likely be useful irrespective of the age and sex of patients  based on the Infinium assay among samples of normal liver tissue (NLT), non-cancerous liver tissue showing non-alcoholic steatohepatitis (NASH) from partial hepatectomy specimens from patients without hepatocellular carcinoma (HCC) (NASH-O), non-cancerous liver tissue showing NASH from partial hepatectomy specimens from patients with HCC (NASH-W) and cancerous tissue (T). Supplementary Table S3. The 415 CpG sites for which receiver operating characteristic curve analysis showed area under the curve (AUC) values larger than 0.95 for discrimination of non-cancerous liver tissue showing non-alcoholic steatohepatitis (NASH) derived from partial hepatectomy specimens from patients with hepatocellular carcinoma (NASH-W) from normal liver tissue (NLT) samples. Supplementary Table S4. Seventy statistically significant pathway maps in which the 415 probes showing area under the curve (AUC) values more than 0.95 for discrimination of non-cancerous liver tissue samples showing non-alcoholic steatohepatitis from patients with hepatocellular carcinoma (NASH-W) from normal liver tissue (NLT) samples, and were designed for the 339 genes, were significantly (P<0.05) accumulated, as revealed by Reactome pathway analysis (https://reactome.org). Supplementary Table S4. Seventy statistically significant pathway maps in which the 415 probes showing area under the curve (AUC) values more than 0.95 for discrimination of non-cancerous liver tissue samples showing non-alcoholic steatohepatitis from patients with hepatocellular carcinoma (NASH-W) from normal liver tissue (NLT) samples, and were designed for the 339 genes, were significantly (P<0.05) accumulated, as revealed by Reactome pathway analysis (https://reactome.org). Supplementary Table S5. Correlation between levels of DNA methylation and expression for the 13 genes included in Table 2 and for which expression data are available in the The Cancer Genome Atlas database . Supplementary Table S6. Comparison of DNA methylation levels based on the Infinium assay between samples of normal healthy liver tissue (GSE107038) deposited in the GEO database (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE107038) and non-cancerous liver tissue samples showing non-alcoholic steatohepatitis from our cohort of patients with hepatocellular carcinoma (NASH-W). Supplementary Table S7. Multivariate analysis using the 91 samples of non-cancerous liver tissue showing non-alcoholic steatohepatitis (NASH) derived from biopsy specimens of patients with morbid obesity but without hepatocellular carcinoma (HCC) (NASH-O samples) and the 22 samples of non-cancerous liver tissue showing NASH derived from partial hepatectomy specimens of patients with HCC (NASH-W samples) in the initial cohorts. Supplementary Figure S2. Correlation between DNA methylation levels based on the Infinium assay and such levels based on pyrosequencing using samples of normal liver tissue (n=34), non-cancerous liver tissue showing non-alcoholic steatohepatitis from partial hepatectomy specimens from patients with hepatocellular carcinoma (n=22), and cancerous tissue samples (n = 22) in the initial cohort. Infinium data were successfully verified by pyrosequencing. (P<7.36\u00d710-23 and Pearson correlation coefficient [r]>0.864). Supplementary Table S8. Correlation between DNA methylation levels based on the Infinium assay of the 21 marker CpG sites included in Table 2 and obesity in patients with nonalcoholic steatohepatitis (NASH) with and without hepatoceullar carcinoma in the initial and validation cohorts. Supplementary Figure S3. Representative chromatograms obtained by high-performance liquid chromatography analysis using a newly developed anion-exchange column for marker CpG sites in specimens of normal liver tissue (NLT), non-cancerous liver tissue (N) showing non-alcoholic steatohepatitis (NASH) derived from partial hepatectomy specimens frompatients without hepatocellular carcinoma (HCC) (NASH-O), N samples showing NASH from patients with HCC (NASH-W), and cancerous tissue (T) samples. The chromatogram patterns  for most of the NASH-O samples are similar to those for NLT samples, whereas those for T samples (single peak) are similar to those for NASH-W samples. Supplementary Table S9. Correlation between relative methylation rates based on high-performance liquid chromatography (HPLC) and the sex and age of nonalcoholic steatohepatitis (NASH) patients with and without hepatoceullar carcinoma in the initial and validation cohorts from whom HLPC data had been obtained (n=34)."}
+{"text": "IDH-wildtype glioblastomas which meet the histopathological or molecular diagnosis criteria, it remains unclear whether the presence of TERT promotor mutations provides additional prognostic information. Based on a multicenter cohort of 466 IDH-wildtype glioblastomas (including 396 with and 70 patients without TERT promotor mutations), we found that TERT promotor mutations were neither associated with progression-free survival nor overall survival. This held true in various treatment-based or molecular subgroups. This argues against standardized analysis for TERT promotor mutation status for the purpose of prognostic or therapeutic relevance in newly diagnosed IDH-wildtype glioblastoma that otherwise meets the histopathological and molecular diagnosis criteria.In IDH-wildtype astrocytic gliomas either with (1) classical histopathological hallmarks or (2) qualifying molecular features.1 The latter include EGFR amplification, +7/\u221210 genotype, and TERT promotor mutation which are all associated with less favorable outcome when observed in combination with IDH-wildtype status.3 The presence of one of these three markers allows the diagnosis of \u201cmolecular\u201d glioblastoma even when tumors appear histologically lower grade, and 80% of glioblastomas exhibit TERT promotor mutations.4 Whether TERT promotor mutations are of prognostic value in IDH-wildtype glioblastomas which otherwise yet fulfill the diagnostic  criteria for glioblastoma is unclear. Here, we explored such an association based upon a well-annotated glioblastoma cohort from 7 international neuro-oncological centers participating in the RANO resect group.The WHO 2021 classification restricts the diagnosis of \u201cglioblastoma WHO grade 4\u201d to resect group compiled a retrospective database of newly diagnosed IDH-wildtype glioblastomas treated between 2003 and 2022 with a follow-up of \u22653 months.5 For the current study, individuals were selected when information on TERT promotor mutation status was available for review. Demographics, molecular information, clinical data, and outcome were extracted; and date of progression was determined per RANO criteria.With approval of the ethics committee of the Ludwig-Maximilians-University , the RANO IDH-wildtype glioblastomas WHO grade 4, TERT promotor status was available in 466 patients including 396 individuals with (IDHwt/TERTmut) and 70 patients without TERT promotor mutations (IDHwt/TERTwt). Diagnosis rested upon IDH-wildtype combined with histopathological findings in 372 IDHwt/TERTmut (93.9%) and 65 IDHwt/TERTwt patients (92.9%); and was established based on the molecular signature  in the absence of classical histological findings in the remaining patients. Three hundred and fifty-eight IDHwt/TERTmut (90.4%) and 63 IDHwt/TERTwt patients (90%) underwent microsurgical resection, whereas the remaining had biopsy for tissue-based diagnosis. There were no differences in MGMT promotor methylation status, first-line therapy, or pre- and postoperative tumor volumes (both for contrast-enhancing and noncontrast-enhancing tumor) between IDHwt/TERTmut and IDHwt/TERTwt patients . When patients were stratified according to TERT promotor mutation status, no outcome differences were detected for progression-free survival  or overall survival  , unmethylated MGMT promotor status , first-line radiochemotherapy per EORTC 26981/22981 , or classical histopathological findings of glioblastoma .Among 1008 patients  and B. M0.7\u20131.3) . Also, nTERT promotor status adds prognostic information in IDH-wildtype glioblastomas exhibiting classical histopathological hallmarks (or other mutations) sufficient for glioblastoma diagnosis. This is in line with previous reports on IDH-wildtype glioblastomas,7 although these studies have either not controlled for clinical and molecular confounders6 or were substantially limited in sample size.7 Notably, IDHwt/TERTwt glioblastomas may identify a subset with a distinct (epi-)genetic and molecular profile compared to IDHwt/TERTmut tumors and may benefit from different, personalized treatment strategies.6 These biological findings, however, to date do not result in different clinical outcomes. Thus, up to now our retrospective data argue against standardized analysis for TERT promotor mutation status for the purpose of prognostic or therapeutic relevance in newly diagnosed IDH-wildtype glioblastoma that otherwise meets the histopathological and molecular diagnosis criteria. This might change in the future whenever TERT-directed therapies emerge.We did therefore not find evidence that"}
+{"text": "Correction: BMC Nutr 9, 21 (2023)https://doi.org/10.1186/s40795-022-00648-yFollowing publication of the original article , the aut(family name) Zaleha (Given Name)Md Isa (family name) Noor Hassim (Given Name)Ismail (family name) Azmi (Given Name)Mohd Tamil (family name) Mohd Hasni (Given Name)Jaafar (family name) Rosnah (Given Name)Ismail (family name) Nor Ashikin (Given Name)Mohamed Noor Khan (family name) Nafiza (Given Name)Mat Nasir (family name) Nurul Hafiza (Given Name)Ab Razak (family name) Najihah (Given Name)Zainol Abidin (family name) Khairul Hazdi (Given Name)Yusof The author group has been updated above and the original article  has been"}
+{"text": "Vaccination is the primary pharmacological measure to reduce SARS-CoV-2 transmission and its complications. Timely information on vaccines effectiveness in a context of novel variants of concern (VOC) emergence is essential for public health policies. This study aimed to provide a measure of comparative vaccine effectiveness between Omicron (BA.1) and Delta (B.1.627.2) VOC according to vaccination exposure (complete primary regimen or booster dose) for Portuguese population aged 12 or more years old using routinely collected data from electronic health records.We used a case-case study design linking national electronic vaccination registry and surveillance data on 13,134 SARS-CoV-2 RT-PCR laboratory-confirmed cases notified in Portugal during weeks 49-51 of 2021. Notified cases were classified as Omicron or Delta based on whole-genome sequencing or S-gene Target Failure (SGTF) status using the RT-PCR TaqPath\u2122 Covid 19 CE IVD Kit (Thermo Scientific\u2122) assay. The odds of vaccination was compared between Omicron cases and Delta cases using logistic regression adjusted for age group, sex, region and week of diagnosis and laboratory of origin.The odds of vaccination were higher in laboratory-confirmed cases infected by Omicron (BA.1) VOC compared to Delta (B.1.627.2) VOC for both complete primary vaccination (Odds ratio (OR)=2.1; 95% Confidence Interval (95%CI): 1.8 - 2.4) and booster dose , indicating vaccine effectiveness reduction against Omicron.We found significantly higher odds of vaccination in Omicron cases compared to Delta, suggesting lower effectiveness of the primary vaccination and the booster dose in preventing infections by Omicron. Case-case study design has proven to be feasible approach to rapidly compare vaccine effectiveness between VOC in context of novel VOC emergence to timely inform public health stakeholders.\u2022\u2002Reduction of vaccine-induced protection against SARS-COV-2 infection with the Omicron compared to Delta after primary and booster vaccination.\u2022\u2002Continuous monitoring of COVID-19 vaccine effectiveness is essential to support public health policies in context of novel VOC emergence."}
+{"text": "UBQLN4) is a proteasomal shuttle factor that directly binds to ubiquitylated proteins and delivers its cargo to the 26S proteasome for degradation. We previously showed that upregulated UBQLN4 determines the DNA damage response (DDR) through the degradation of MRE11A. However, the regulatory mechanism at DNA level, transcriptionally and post-transcriptional levels that control UBQLN4 mRNA levels remains unknown. In this study, we screened 32 solid tumor types and validated our findings by immunohistochemistry analysis. UBQLN4 is upregulated at both mRNA and protein levels and the most significant values were observed in liver, breast, ovarian, lung, and esophageal cancers. Patients with high UBQLN4 mRNA levels had significantly poor prognoses in 20 of 32 cancer types. DNA amplification was identified as the main mechanism promoting UBQLN4 upregulation in multiple cancers, even in the early phases of tumor development. Using CRISPR screen datasets, UBQLN4 was identified as a common essential gene for tumor cell viability in 81.1%  of the solid tumor derived cell lines. Ovarian cancer cell lines with high UBQLN4 mRNA levels were platinum-based chemotherapy resistant, while they were more sensitive to poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi). Our findings highlight the utilities of UBQLN4 as a significant pan-cancer theranostic factor and a precision oncology biomarker for DDR-related drug resistance.Ubiquilin-4 ( Cancer cells have various repairing mechanisms to maintain genomic integrity after DNA lesions caused by exogenous and endogenous factors . DNA douUbiquilins (UBQLNs) family, which includes UBQLN1-4 and UBQLN-L, are key factors in the regulation of protein degradation in cells . All theUBQLN4 mRNA levels are associated with the efficacy of neoadjuvant chemotherapy (NAC) including platinum-based chemotherapeutic agents in ESCC [UBQLN4 overexpression and its utility as a predictive biomarker in various types of solid tumor cancers remains uncharacterized. Therefore, understanding the mechanism at DNA level, transcriptionally and post-transcriptional levels that control UBQLN4 mRNA levels may provide broad insights and decision-making for precision oncology therapeutic strategies and predictive value for chemotherapy responses inducing DNA damage in specific types of solid cancers.As part of the Ubiquitin\u2013proteasome system (UPS), specific proteasome subunits recognize ubiquitylated proteins for degradation . In addi in ESCC . We have in ESCC ,9. HowevUBQLN4 using large cohorts of cancer patient datasets. The UBQLN4 data analysis described in this study has been obtained from 9,962 tumor tissue samples of 32 different solid tumor types and 719 adjacent normal tissues of ten organ types using The Cancer Genome Atlas (TCGA) and 4.918 normal tissues of sixteen organ types using Genotype-Tissue Expression (GTEx) [UBQLN4 and treatment resistance was analyzed from 1,060 cell lines of the CCLE database. Our results demonstrated that UBQLN4 upregulation derived from frequent DNA amplification was observed in various solid tumors. Confirmatory immunohistochemistry (IHC) analyses for UBQLN4 were performed in paired tissue samples from 48 patients. UBQLN4 was associated with poor prognosis across multiple cancer types. UBQLN4 was detected as a common essential gene across various types of cancer cell lines. High UBQLN4 mRNA levels have been significantly associated with the DNA repair pathway gene set. Consequently, increased UBQLN4 levels were associated with cisplatin resistance and Olaparib sensitivity in pan-cancer cell lines.The aim of this study is to perform a comprehensive pan-cancer analysis of n (GTEx) . The relhttp://depmap.org, accessed on 28 April 2022).Datasets from The Cancer Genome Atlas (TCGA)  and GenoA tissue microarray TMA, BCN962a) for multiple solid tumor types  and respective adjacent normal tissues were obtained from US Biomax . The TMA slide was stained with UBQLN4 monoclonal Ab  at the dilution of 1:100 as previously described [62a for mUBQLN4 copy number values larger than 0.3 were defined as UBQLN4 gene amplified patients.For TCGA analysis, focal-level copy number variation values were generated by using GISTIC2 . For CCLThe CNA analysis in adjacent normal tissues was performed using the TCGA datasets. The data of somatic copy number alterations for 1708 adjacent normal tissues from 27 cancer types in TCGA was obtained from a previous study .p-values for the recurrence of amplification. To calculate p-values in the Poisson binomial tests, the Poisson binomial cumulative probability function in the R package poibin was used . Log scaled p-values were converted to q-values for multiple testing corrections using the Benjamini-Hochberg procedure [The recurrence of CNA for each gene was performed using the PART method as previously described ,27. In bhttp://depmap.org, accessed on 28 April 2022) [CRISPR screen datasets were obtained from the Cancer Dependency Map portal  . In brieil 2022) . Gene Efil 2022) .Common essential genes were identified as previously described . A gene UBQLN4 mRNA levels from the CCLE dataset [http://software.broadinstitute.org/gsea/msigdb/index.jsp, accessed on 28 April 2022). Research manuscripts reporting large datasets that are deposited in a publicly available database should specify where the data have been deposited and provide the relevant accession numbers. If the accession numbers have not yet been obtained at the time of submission, please state that they will be provided during review. They must be provided prior to publication.The association between  dataset  and prevThe area under the dose\u2013response curve (AUC) was downloaded from the DepMap Portal website. AUC values were scaled between 0 and 1 for curves with lower asymptotes less than 1, where lower AUC values indicate increased sensitivity to the treatment.http://www.targetscan.org/, accessed on 28 February 2022), DIANA TOOL , miRcode , and miRDB  were utilized to determine the miRNAs that bind to the 3\u2032-UTR of UBQLN4 mRNA.Four publicly available databases, TargetScan  in a two-tailed way. The distribution and variation within each group of data were assessed before statistical analysis. Two groups were compared using the Mann\u2013Whitney U test. The correlation was determined using Pearson\u2019s correlation test. In survival analysis using TCGA datasets, patients were divided into high UBQLN4 mRNA expression and low UBQLN4 mRNA expression groups using the minimum p-value approach [p-values were calculated using the log-rank test. A p-value < 0.05 was considered statistically significant. All figures were unified using Adobe Illustrator CC .Statistical analyses were performed using R version 4.1.2 , Breast Invasive Carcinoma (BRCA), Lung Adenocarcinoma (LUAD), Ovarian Serous Cystadenocarcinoma (OV), Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (CESC), Uterine Corpus Endometrial Carcinoma (UCEC), Lung Squamous Cell Carcinoma (LUSC), Bladder Urothelial Carcinoma (BLCA), Skin Cutaneous Melanoma (SKCM), Esophageal Carcinoma (ESCA), Testicular Germ Cell Cancer (TGCT), Stomach Adenocarcinoma (STAD), Rectal Adenocarcinoma (READ), Colon Adenocarcinoma (COAD), Low Grade Glioma (LGG), Thyroid Carcinoma (THCA), Kidney Renal Papillary Cell Carcinoma (KIRP), and Prostate Adenocarcinoma (PRAD)  . Moreovedatasets . These rdatasets C. The modatasets C. To sumUBQLN4 mRNA levels across different tumor types. Previous studies from our and other groups showed that high UBQLN4 mRNA levels are associated with poor overall survival (OS) in specific solid tumors [UBQLN4 mRNA levels. TCGA data analysis demonstrated that patients with high UBQLN4 mRNA levels had significantly lower OS than patients with low UBQLN4 mRNA levels in Adrenocortical Carcinoma (ACC), BRCA, COAD, CESC, Kidney Renal Clear Cell Carcinoma (KIRC), KIRP, LIHC, LUAD, Mesothelioma (MESO), Pancreatic Adenocarcinoma (PAAD), Pheochromocytoma and Paraganglioma (PCPG), Sarcoma (SARC), SKCM, and UCEC.  and 86 functional SNVs of UBQLN4 in 10,953 patients (0.79%) in 32 cancer types were detected using the Catalogue of Somatic Mutations In Cancer (COSMIC) and TCGA datasets, respectively . Focusing on individual cancers, PAAD and READ showed a downregulation in miR-370 and a negative correlation between miR-370 and UBQLN4 levels, but the correlation values were not significant or statistically significant but small . In silico analysis also identified miR-7-5p as the only common miRNA targeting UBQLN4  showed that miR-370 decreases UBQLN4 mRNA/protein levels . AdditioUBQLN4 . Expressg UBQLN4 . MiR-7-5UBQLN4 is localized on chromosome 1q22, a region commonly amplified in solid tumors [UBQLN4 copy number variation (CNV). A high proportion of samples in various types of cancers had CNA for UBQLN4 . In contrast, the CNVs in adjacent normal tissues were observed in 4.6%  of patients  datasets D. Data il stages E. CollecUBQLN4 mRNA levels did not change across different histopathology subtypes, such as 1) among the different subtypes of BRCA, and 2) between adenocarcinoma and mucinous carcinoma in COAD/READ and, 3) between esophageal adenocarcinoma (ESAD) and ESCC  [UBQLN4 as a predictive marker for drug sensitivity in pan-cancer, we examined the association between UBQLN4 mRNA expression and drug sensitivity using the combined datasets of CCLE and Profiling Relative Inhibition Simultaneously in Mixtures (PRISM) Repurposing Secondary Screen datasets [UBQLN4 mRNA levels had significantly altered DNA repair pathways . Ovarian cancer cell lines with high UBQLN4 mRNA levels had the lowest sensitivity to cisplatin treatment (p = 0.0041).Our results have demonstrated that radation ,8. Thus,datasets . Cell lipathways A. Then, er types B. In ovaUBQLN4 upregulation improves the sensitivity to PARPi by repressing HR activity through the degradation of MRE11A [UBQLN4 mRNA levels were associated with a better Olaparib response . The Genomics of Drug Sensitivity in Cancer 2 (GDSC2) datasets also showed a negative correlation between UBQLN4 mRNA levels and Olaparib AUC values (p = 0.011). Similar analyses were performed only in BRCA1/2 wild-type ovarian cancer cell lines. No significant differences in UBQLN4 mRNA levels were observed in BRCA1/2 mutants versus wild-type ovarian cancer cell lines . UBQLN4 has been reported to have an impact on the degradation of a wide range of ubiquitylated proteins [UBQLN4 targets STING in triple-negative breast cancer [We demonstrated that cell lines with high proteins ,38,39,40t cancer . Notablyt cancer ,42 and rUBQLN4 mRNA levels are associated with current chemotherapies resistance in cancer cells such as cisplatin resistance and Olaparib sensitivity in many different cancer cell lines. Interestingly, ovarian cancer cell lines which have high mRNA levels of UBQLN4 showed cisplatin resistance and Olaparib sensitivity at the same time. Both drugs are used in treating advanced stages of ovarian cancer [BRCA1/2 wild-type ovarian cancer cell lines. Our findings suggest that UBQLN4 mRNA levels allowed for triaging ovarian cancer patients that will receive platinum drugs or PARPi therapies. Additional studies are required to (1) validate our findings and determine whether UBQLN4 mRNA levels can improve clinical decisions in precision medicine therapeutic strategies; and (2) to determine whether the effect of HRD induced by the UBQLN4 upregulation is synergistic to HRD induced by BRCA1/2 mutations.Our analysis showed that n cancer ,44. The UBQLN4 mRNA and protein levels are regulated by CNA. UBQLN4 has clinical translational implications as a diagnostic, prognostic, and treatment resistance biomarker for adjuvant platinum-based drugs or PARPi therapies.In conclusion, this study provides new evidence that"}
+{"text": "Vascular-disrupting agents promise significant therapeutic efficacy against solid tumors by selectively damaging tumor-associated vasculature. Following administration of the phosphate prodrug OXi6197, dynamic bioluminescence imaging revealed dose-responsive vascular shutdown in MDA-MB-231 human breast tumor xenografts and for the first time murine RENCA kidney tumors. Rapid vascular disruption was observed, which continued over 24 h. Histology showed vascular congestion, hemorrhage and necrosis. Twice-weekly doses of OXi6197 caused a significant growth delay in MDA-MB-231 breast tumors and many RENCA kidney tumors growing orthotopically in mice.\u00ae. When prodrug OXi6197 was administered to mice bearing orthotopic MDA-MB-231-luc tumors, dynamic bioluminescence imaging (BLI) revealed dose-dependent vascular shutdown with >80% signal loss within 2 h at doses \u226530 mg/kg and >90% shutdown after 6 h for doses \u226535 mg/kg, which remained depressed by at least 70% after 24 h. Twice weekly treatment with prodrug OXi6197 (20 mg/kg) caused a significant tumor growth delay, but no overall survival benefit. Similar efficacy was observed for the first time in orthotopic RENCA-luc tumors, which showed massive hemorrhage and necrosis after 24 h. Twice weekly dosing with prodrug OXi6197 (35 mg/kg) caused tumor growth delay in most orthotopic RENCA tumors. Immunohistochemistry revealed extensive necrosis, though with surviving peripheral tissues. These results demonstrate effective vascular disruption at doses comparable to the most effective vascular-disrupting agents (VDAs) suggesting opportunities for further development.The vascular disrupting activity of a promising tubulin-binding agent (OXi6196) was demonstrated in mice in MDA-MB-231 human breast tumor xenografts growing orthotopically in mammary fat pad and syngeneic RENCA kidney tumors growing orthotopically in the kidney. To enhance water solubility, OXi6196, was derivatized as its corresponding phosphate prodrug salt OXi6197, facilitating effective delivery. OXi6197 is stable in water, but rapidly releases OXi6196 in the presence of alkaline phosphatase. At low nanomolar concentrations OXi6196 caused G2/M cell cycle arrest and apoptosis in MDA-MB-231 breast cancer cells and monolayers of rapidly growing HUVECs underwent concentration-dependent changes in their morphology. Loss of the microtubule structure and increased bundling of filamentous actin into stress fibers followed by cell collapse, rounding and blebbing was observed. OXi6196 (100 nM) disrupted capillary-like endothelial networks pre-established with HUVECs on Matrigel Tumor vasculature offers an attractive target since it is directly accessible to systemic therapy. The endothelium of normal blood vessels is largely quiescent, but the invasive proliferating neovasculature of tumors is less differentiated, distinct in morphology, lacks pericyte support, exhibits increased permeability, and is more responsive to angiogenic cell signaling , therebyThe original concept of vascular targeting was proposed some 30 years ago  and seveCombretastatin recently came off patent protection and we note a dramatic increase in interest in developing analogs, particularly next generation agents and effective delivery mechanisms ,21,22,23A diverse range of molecules based on the combretastatin structural motif featuring a trimethoxy aryl ring linked to a second aromatic ring via an unsaturated bond, additional ring, or related molecular component has been reported ,19,20,2150 ~500 nM was determined for inhibition of tubulin polymerization utilizing a cell-free assay  \u00d7 \u03c0/6), and investigations were performed when the tumors reached a size of 5\u20138 mm. Orthotopic RENCA tumors were examined biweekly by BLI and treatment started when the peak emitted light intensity exceeded 10\u00ae small animal imaging system , as described previously [http://www.perkinelmer.com (accessed on 23 August 2022)). OXi6197 was dissolved in saline (5 mg/mL) and doses in the range 5 to 65 mg/kg were administered intraperitoneally (IP) for breast cancer studies and at 15 and 35 mg/kg for kidney cancer. To assess the changes in tumor perfusion, the BLI was subsequently determined as maximum signal during time course following administration of fresh luciferin at 2, 4, (or 6) and 24 h after drug administration, and in some cases additionally at 48 and 72 h.Anesthetized mice (1 to 2% isoflurane) were imaged using an IVIS Spectrumeviously . For BLI6) were implanted in the frontal mammary fat pad of NOD SCID mice and allowed to grow until they reached 6 mm diameter (volume about 200 mm3). Treatment was initiated with twice weekly injections IP of 20 mg/kg OXi6197 (n = 5 mice) or saline (n = 6 mice). Tumor volume was measured using calipers each weekday as well as mouse weight. RENCA-luc tumors were implanted orthotopically in the kidney and allowed to grow until they exhibited a light emission of 106 photons/s at which time they were treated twice-weekly IP with OXi6197  (n = 5)) or as saline controls (n = 7). BLI was performed weekly at least 48 h after a dose of OXi6197 and treatment continued until mice required sacrifice (based on excessive weight loss or tumor burden) or died. MDA-MB-231-luc cells (1 \u00d7 10Growth was compared using Fisher\u2019s Protected Least Significant Difference (PLSD) ANOVA based on tumor volume or BLI signal (as surrogate for tumor volume). For each tumor type non-parametric Kaplan Meir survival was examined based on Mantel-Cox log rank test. The tissues were fixed in 4% paraformaldehyde overnight and then processed and embedded in paraffin. The sections were cut at 5 \u00b5m, and routine H&E staining was performed. Immunohistochemical analysis was performed on representative 3\u20135 \u00b5m formalin-fixed paraffin-embedded (FFPE) whole tumor tissue sections. Staining for routinely used markers including Ki-67 , CD31 , PDL1  was performed using a Dako automated system (Agilent). Slides were imaged using Roche Ventana iScanHT. Immunoreactivity was interpreted as \u201cnegative\u201d if no or <5% tumor cells stained positive. Antigen expression was determined based on product of percentage of tumor cells staining positive and the intensity of expression. Rapidly dividing MDA-MB-231 human breast cancer cells showed a distribution between G1 and G2/M phases of the cell cycle using flow cytometry . Time deHUVECs, cultured on Matrigel-coated 24-well plates, formed a capillary-like network , but extFollowing subcutaneous administration of luciferin to MDA-MB-231-luc tumor bearing mice bioluminescent signal was observed reaching a maximum after about 15 to 20 min followed by gradual decline . Followip < 0.0001, p = 0.0116), day 11 (p = 0.0003), day 18 (p = 0.005). Growth curves are presented for individual tumors (MDA-MB-231-luc tumors dosed twice weekly with OXi6197 (20 mg/kg) showed significant tumor growth delay compared with saline control tumors over the first 18 days   .OXi6196 caused cell cycle arrest in MDA-MB-231 breast cancer cells at 5 nM and microtubule disaggregation in activated HUVECs at 10 nM. Capillary-like vascular tubes formed by cultured HUVECs were disrupted by 100 nM OXi6196. OXi6196 is hydrophobic, but delivery in vivo was achieved using the phosphate prodrug OXi6197, which offered improved water solubility and caused acute vascular shutdown within hours of administration in two distinct tumor types, as revealed by dynamic BLI. A significant tumor growth delay was observed in orthotopic MDA-MB-231 breast tumors treated twice weekly with OXi6197 (20 mg/kg) compared with saline controls. For orthotopic RENCA tumors histology confirmed major acute vascular congestion, hemorrhage and necrosis 24 h after receiving OXi6197 (15\u201335 mg/kg). Many RENCA tumors also showed a significant tumor growth delay with twice weekly dosing at 35 mg/kg. Both OXi6196 and the phosphate prodrug OXi6197 had previously been shown to exhibit cell cycle arrest and cytotoxicity in diverse cultured cells including breast , lung , leukemia (K562), liver (HCT116), colon (KM20L2), ovarian (SKOV3) and prostate (DU-145) ,40,41. TThe triple negative MDA-MB-231 human breast cancer is a particularly popular model for testing novel agents and has been widely reported with respect to diverse vascular disrupting agents ,46,47,48Here, we chose to investigate the RENCA kidney tumor as a syngeneic model in BALB/c mice. Kidney tumors are often well vascularized and one might expect VDAs to be particularly effective. The RENCA tumor arose spontaneously in a male BALB/c mouse and is becoming increasingly popular for evaluating novel therapies ,55,56,57DMXAA was reported to cause massive hemorrhage and necrosis in RENCA tumors. Although no tumor growth delay was seen as a monotherapy in RENCA tumors, combination with the mTor inhibitor everolimus did yield a tumor growth delay . LikewisAs for the combretastatins CA4 and CA1, and previous structurally inspired analogs KGP18, OXi8006 and BNC105, phosphorylation enhanced water solubility of these hydrophobic molecules allowing effective delivery in saline IP ,36,44,67Many diverse modalities are available for pre-clinical imaging and have been successfully applied to observe acute vascular shutdown . Indeed,Histology revealed high density of closely packed cells in the control RENCA tumor with focal regions of necrosis . Tumor cSeveral aspects of the current study are new, noteworthy, and significant. Twice weekly dosing of MDA-MB-231 breast tumor bearing mice with 20 mg/kg OXi6197 was found to be similarly effective to the daily dosing with 25 or 50 mg/kg OXi6197 reported previously . ObviousWe have for the first time demonstrated dose dependent vascular shutdown caused by OXi6197 in RENCA kidney tumors growing orthotopically in mice. Doses as low as 15 mg/kg caused extensive vascular congestion, hemorrhage and necrosis and biweekly dosing led to a tumor growth delay in many individual tumors. We also confirmed acute vascular disrupting effects of OXi6197 in MDA-MB-231 breast tumors in mice and found tumor growth delay based on twice weekly dosing. As with other VDAs, OXi6197 failed to fully control tumor growth, but the promising preliminary therapeutic results suggest opportunities for future investigations to develop effective combination treatment."}
+{"text": "Correction: Trials 23, 809 (2022)https://doi.org/10.1186/s13063-022-06736-5Error 1 (Title) [The sentence currently reads:\u201cProphylactic abdominal drainage or no drainage after distal pancreatectomy (PANDORINA): a binational multicenter randomized controlled trial\u201dThe sentence needs to read:\u201cProphylactic abdominal drainage or no drainage after distal pancreatectomy (PANDORINA): a study protocol of a binational multicenter randomized controlled trial\u201dError 2 (Abstract)The sentence currently reads:\u201cRoutine drainage after DP could potentially be omitted and this could even be beneficial because of the hypothetical prevention of drain-induced infections .\u201dThe sentence needs to read:\u201cRoutine drainage after DP could potentially be omitted and this could even be beneficial because of the hypothetical prevention of drain-induced infections .\u201d"}
+{"text": "Introduction: Residual depressive symptoms are common after a successful acute treatment of late-life depression (LLD), and their presence predicts increased risk of relapse. While electroconvulsive therapy (ECT) is the most effective treatment for LLD, little is known about which particular symptoms remain and impact long-term outcome after a successful acute ECT course.Objectives: We aimed to assess the association between specific residual depressive symptoms after an effective acute ECT course for LLD and relapse at six-month follow-up.Methods: In this prospective cohort study, including 110 patients aged 55 years and older with LLD, information about relapse was collected six months after the acute ECT course. Relapse was defined as a Montgomery-\u00c5sberg Depression Rating Scale (MADRS) score >15, hospital admission or restart of ECT. We used multivariable stepwise logistic regression models including the scores on the 10 individual MADRS items at the end of the acute ECT course to predict relapse.Results: Of the 80 responders with available six-month follow-up data, 29 patients (36.25%) had suffered relapse. Higher scores on the MADRS items \u2018reduced sleep\u2019 (odds ratio (OR)=2.03, 95% confidence interval (CI)=1.11-3.69, p=0.0214) and \u2018lassitude\u2019  at the end of the acute ECT course were significantly associated with increased risk of relapse at six-month follow-up.Conclusions: Some residual depressive symptoms, including sleep disturbance and fatigue, may help better identify patients vulnerable to relapse following a successful acute ECT course for LLD. Future studies assessing interventions that target specific residual symptoms may further reduce post-ECT depressive relapse.No significant relationships."}
+{"text": "This quality improvement study describes use of estimation analytics to augment existing suicide prevention practices during routine mental health specialty encounters at a large US health care system. The most well-known efforts have focused on outreach, such as ReachVet which successfully implemented suicide risk estimation analytics to identify at-risk veterans and address care needs.3 Encounter-based implementation efforts have not been described. Therefore, this mixed-methods quality improvement study describes use of estimation analytics to augment existing suicide prevention practices during routine mental health specialty encounters at Kaiser Permanente Washington.Suicide risk estimation analytics combine use of sociodemographic and clinical characteristics to quantify risk for defined populations. Development and testing have been promising,SQUIRE quality improvement reporting guideline. Preexisting clinical workflows included administration of the Patient Health Questionnaire-9 (PHQ-9) prior to all encounters with patients (aged at least 13 years), and an electronic health record (EHR) prompt to complete the Columbia-Suicide Severity Rating Scale (C-SSRS) among patients reporting frequent thoughts about self-harm (score 2 to 3 on PHQ-9 question 9). A previously developed and validated prediction model2 was implemented via a schedule-based flag to prompt additional C-SSRS administration among patients identified at high risk of suicide attempt (at least 3% in the following 90 days), regardless of their PHQ-9 ninth question responses .EHR data was obtained for a postimplementation observation period  to assess how often the C-SSRS was completed among flagged encounters. In parallel, a sample of flagged 30 adult patients  and all 16 clinicians  were invited to participate in semistructured audio-recorded virtual interviews ,There were 4789 patient encounters  by 1939 patients in the 3.5-month observation period, including 161 (3.5%) encounters newly flagged via suicide risk estimation analytics .The encounter-based risk flag did not consistently prompt additional suicide risk assessment as intended. During newly flagged encounters: 57 patients reported frequent suicidal ideation (PHQ-9 question 9 [Q9]\u2009\u2265\u20092) and, as per preexisting workflow, 54 (95%) completed a C-SSRS; 75 patients reported no or infrequent suicidal ideation (Q9\u2009=\u20090 to 1), but only 10 (13%) completed a C-SSRS, per new workflow; 29 patients did not answer the PHQ-9, and only 1 patient (3%) completed a C-SSRS, per new workflow.Interviewed clinicians (n\u2009=\u20098) identified important implementation concerns, including (1) lack of follow-up, (2) EHR-related inefficiencies, and (3) reliability and accuracy of the flag. Interviewed patients (n\u2009=\u200920) reiterated concerns about reliability and accuracy of estimation analytics. Additionally, clinicians described concerns about access to care and potential liability associated with known suicide risk. Patients echoed concerns about access and expressed fears about identification of suicide risk resulting in coercive care .5 Therefore, use of estimation analytics and other suicide prevention tools and practices should not reinforce a \u201cculture of blame,\u201d6 but rather support therapeutic alliance.This novel quality improvement study highlights important implications for health care organizations considering implementation of estimation analytics to support encounter-based identification of suicide risk. First, while the schedule-based flag was simple and inexpensive to implement, it was not effective\u2014a user-centered approach to clinical decision support design is key for prompting intended actions. Second, bidirectional leadership/clinician communication is critical for addressing implementation outcomes and concerns. For example, opportunities to underscore that suicide risk estimation analytics are designed to augment rather than replace clinical judgement and screening or assessment practices may mitigate concerns about reliability and accuracy. Limitations of this study included timing\u2013redesign efforts will support virtual mental health care delivery (commonplace post-COVID). Finally, findings underscore tensions between clinician concerns about responsibility for patient safety and patient concerns about coercive care."}
+{"text": "Cancer-related cognitive dysfunction (CRCD) is a side-effect of chemotherapy, particularly among young and adult populations. Results indicate CRCD is also prevalent in older adult populations. While various non-pharmacological interventions for cognitive impairments have been studied in young cancer and older adult populations, limited information is available regarding non-pharmacologic interventions for older adults with cancer. The purpose of this systematic review is to describe the current non-pharmacologic interventions for CRCD in the older adult cancer population. Databases searched included PubMed, MEDLINE, CINAHL, and EMBASE. Articles meeting inclusion criteria were appraised by 2 reviewers independently. The Cochrane Risk of Bias Assessment was used to assess study quality. The search located 3441 articles; 4 met inclusion criteria. Cognitive domains assessed by included studies comprised executive function (n=2), attention (n=1), learning/memory (n=2), perceptual-motor (n=1), and a general measure of global cognitive function (n=3). Two studies used exercise interventions and 2 employed cognitive training interventions. One exercise intervention improved executive function, while attention and learning/memory improved following cognitive training. However, a limited number of studies utilizing non-pharmacological approaches for treating cognitive impairment in this population showed high methodological heterogeneity. Non-pharmacologic interventions demonstrated positive outcomes for CRCD, however, methodological concerns in the included studies prevented definitive recommendations from being made. Findings may guide additional studies needed in this field in order to make more robust conclusions."}
+{"text": "Correction: BMC Public Health 22,882 (2022)https://doi.org/10.1186/s12889-022-13101-3The original publication of this article  containeIncorrect:However, a psychological autopsy study conducted on suicide deaths between July 2019 to July 2020 in Dhaka, Bangladesh showed that pesticide poisoning was still the most prevalent suicide method [47].CorrectA psychological autopsy study conducted on suicide deaths between July 2019 to July 2020 in Dhaka, Bangladesh showed that pesticide poisoning was now the second most prevalent suicide method [47]."}
+{"text": "Purple acid phosphatases belong to metallo-phosphatase family. Intracellular phosphatases are crucial for phosphorus (P) distribution in the cell and are highly induced in phosphorus-deprived conditions in the soil. Disparate PAP isoforms exist within discretesubcellular compartments in Setaria italica and their expression in P deprived conditions fosters phosphorus amelioration. We isolated the SiPAP18 gene and developed the homology SiPAP18 protein model based on the crystal structure of the Kidney bean PvPAP(PDB ID: 2QFP) as template (sequence similarity 42.7%) using Modeller 9.12 with adequate validation. Structure model analysis shows the significance of five conserved signatures with seven metal-paired amino acid residues during P-deprivation induced phosphorusamelioration. Phosphorus (P) is a vital macronutrient, basic component of nucleic acid and phopholipids. It is crucial for numerous enzymatic and biochemical pathways in plants, such as photosynthesis, nucleotide synthesis, membrane remodelling, and protein modification .Large aPurple Acid Phosphatases (PAPs) are prerequisite for sustainable Pi mobilization and P utilization from soil is needed for the sustenance of plants . PAPs arSiPAP18 gene was downloaded from National Center for Biotechnology Information (NCBI). PgPAP19 with phytase and PAP activity resembled the sequence of PAP18 (XP_004982542.1) from Setaria italica. Protein modelling was completed using standard homologymodelling . OrtholoThe structure model of SiPAP18 from Setaria italica was created using the Modeller 9.12 software. The MODELLER software implements relative protein structure prediction using structural restraints with known data.The predicted protein model was validated for geometrical and stereo-chemical constraints using tools such as PROCHECK and ProSA-Web .Phylogenetic analysis of the sequences was developed using the UPGMA method available in the Molecular Evolutionary Genetic Analysis (MEGA) software (version 4.0.02) . Each noThe foxtail millet protein sequence comprised of 472 amino acid residues. The homology search using PDB blast picked a target with 42 % sequence identity to SiPAP18 from kidney bean (PDB ID: 2QFP) with an e-value of 6e-153. The ScanProsite server identifiedthe metal ligating string of seven amino acid residues RHGXRXP as the consensus pattern of signature motif for purple acid phosphates in both foxtail millet and kidney bean PAPs. Sequence alignment showed another signature motif that comprised of five metalbinding domains conserved in both target and template PAP sequences . We alsoData showed that the PAP18 protein shared similarity to the known Pennisetum glaucum PAP18 (95%) assigned as SiPAP18. The full-length gene encoded 472 amino acid residues including an extracellular signal peptide. Data showed the structural similarities ofSiPAP18 with PgPAP18 with 95% homology. Sequence analysis showed binuclear metal (Fe+3 -Zn+2) center indicating that SiPAP18 belonged to the family of metallo-phosphatases family. The plant metallo-purple acid phosphatase super-family has been characterized bythe presence of two aspartic acid residues (Asp-180-207), one tyrosine (Tyr-210), one asparagine (Asn-240) and three histidines (H-323- 360-362) with five highly conserved motifs (GDLG-xnGDLSY-xn-GNHE/Dxn-VLLH-xn-GHVH) as in PgPAP18 .PAP actA multigene family that are highly conserved across all cereals encodes the PAP18 proteins. Duplication of genes and their subsequent divergence were central to multiplicity of the PAP gene family. The evolutionary relationship of SiPAP18 with other plantorthologues for PAP18 from closely related 10 species is shown using a phylogenetic tree. The full-length amino acid sequences analysis of SiPAP18 (Acc no. XP_004982542.1) showed 80-95% similarity to other PAP18-like family members .The phyWe document the phylogenetic and modeling analysis data for the purple acid phosphatase 18 (SiPAP18) from Setaria italica."}
+{"text": "Reproducibility and correlation with clinical biomarkers and outcomes were assessed in validation cohort of 17,415 patients and testing cohort of 16,845 patients. Training, validation, and testing cohorts had similar age (54\u201355 years) and sex , distributions. There were four distinct clusters. Physiotype A had physiologic signals consistent with early vasoplegia, hypothermia, and low-grade inflammation and favorable short-and long-term clinical outcomes despite early, severe illness. Physiotype B exhibited early tachycardia, tachypnea, and hypoxemia followed by the highest incidence of prolonged respiratory insufficiency, sepsis, acute kidney injury, and short- and long-term mortality. Physiotype C had minimal early physiological derangement and favorable clinical outcomes. Physiotype D had the greatest prevalence of chronic cardiovascular and kidney disease, presented with severely elevated blood pressure, and had good short-term outcomes but suffered increased 3-year mortality. Comparing sequential organ failure assessment (SOFA) scores across physiotypes demonstrated that clustering did not simply recapitulate previously established acuity assessments. In a heterogeneous cohort of hospitalized patients, unsupervised machine learning techniques applied to routine, early vital sign data identified physiotypes with unique disease categories and distinct clinical outcomes. This approach has the potential to augment understanding of pathophysiology by distilling thousands of disease states into a few physiological signatures.During the early stages of hospital admission, clinicians use limited information to make decisions as patient acuity evolves. We hypothesized that clustering analysis of vital signs measured within six hours of hospital admission would reveal distinct patient phenotypes with unique pathophysiological signatures and clinical outcomes. We created a longitudinal electronic health record dataset for 75,762 adult patient admissions to a tertiary care center in 2014\u20132016 lasting six hours or longer. Physiotypes were derived via unsupervised machine learning in a training cohort of 41,502 patients applying consensus  In this paper, we present a machine learning approach, consensus clustering, to group hospitalized patients based on six routinely collected vital signs measured within six hours of hospital admission into previously undescribed subsets or acute illness phenotypes that may have different risks for a poor outcome or different treatment responses. We identified four acute illness phenotypes associated with distinct clinical characteristics, biomarker patterns, and clinical outcomes. We validated the reproducibility of phenotypes using different dataset and clustering approach. The early identified phenotypes, that have unique disease states and mortality risk, have the potential to augment understanding of pathophysiology by distilling thousands of disease states into a few physiological signatures and clinical decision-support systems under time constraints. Each year in the United States alone there are more than 36 million hospital admissions and seven thousand in-hospital mortalities, nearly one quarter of which may be preventable \u20134. Earlyphysiotypes) that are associated with distinct disease categories and clinical outcomes.Using electronic health record data spanning 75,762 adult hospital admissions, we test the hypothesis that unsupervised ML analysis of vital signs recorded within six hours of hospital admission reveals discrete and reproducible physiologic signatures of acute illness phenotypes  for 75,762 hospital admissions of 43,598 patients representing all adults (age \u226518 years) admitted to the University of Florida Health 1000-bed academic hospital between June 1, 2014 and April 1, 2016 with length of stay greater than or equal to six hours including emergency department admission if applicable. Patients completely missing at least two of the six vital sign measurements  within six hours of admission were excluded . A detaiphysiotypes) using early physiologic signatures, we applied unsupervised ML clustering to temporal measurements of six vital signs recorded within six hours of hospital admission in the training cohort. We assessed physiotype reproducibility by applying alternative clustering methods in the training dataset, assessing physiotype frequency distributions and clinical outcomes in the validation cohort, and predicting physiotypes in the testing cohort  recommendations under the Type 2b analysis category  to chrong cohort .physiotypes with reproducible early physiologic signatures, we applied consensus k-means clustering  of probability. Gray shading corresponds to region with a 45\u201355%  probability of assignment. Inset proportion is the % of 41,502 in the marginal region.(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S5 Table(DOCX)Click here for additional data file.S6 Table(DOCX)Click here for additional data file.S7 Table(DOCX)Click here for additional data file.S8 Table(DOCX)Click here for additional data file.S9 Table(DOCX)Click here for additional data file.S10 Table(DOCX)Click here for additional data file.S11 Table(DOCX)Click here for additional data file.S12 Table(DOCX)Click here for additional data file.S13 Table(DOCX)Click here for additional data file.S14 Table(DOCX)Click here for additional data file.S15 Table(DOCX)Click here for additional data file.S16 Table(DOCX)Click here for additional data file.S17 Table(DOCX)Click here for additional data file.S18 Table(DOCX)Click here for additional data file.S19 Table(DOCX)Click here for additional data file.S20 Table(DOCX)Click here for additional data file."}
+{"text": "Genome-wide association studies (GWAS) have successfully revealed genetic risk variants for schizophrenia (SCZ). However, the vast majority of GWAS largely comprise European samples. As a result, the derived polygenic risk scores (PRS) show decreased predictive power when applied to non-European populations.A long-term scientific cooperation between the Charit\u00e9 Universit\u00e4tsmedizin Berlin and the Hanoi Medical University aims to address this limitation by recruiting a large genetic cohort of comprehensively phenotyped schizophrenia patients and controls in Vietnam.A pilot study was conducted at the Department of Psychiatry of the Medical University Hanoi in 2017. Data collection encompassed i) genome-wide SNP genotyping of 200 schizophrenia patients and 200 control subjects ii) structured interviews to assess symptom severity (PANSS), iii) clinical parameters  and demography.2liability=0.053, p=3.11*10-8, Pd <0.5), followed by PRS based on the East-Asian summary statistics  and the European sample .SCZ-PRS of the pilot sample (N=400) were generated using different training data sets: i) European, ii) East-Asian and iii) mixed GWAS summary statistics from the Psychiatric Genomics Consortium\u2019s latest discovery sample. Most variance explained was observed using a mixed discovery sample (RWith this pilot project we established an efficient recruitment, genotyping and data analysis pipeline. Our results corroborate previous findings indicating that transferability of PRS across populations depends on the ancestral composition of the initial discovery dataset. We therefore aim to expand data collection efforts in the future in order to improve risk prediction across diverse populations.No significant relationships."}
+{"text": "The correct name is: Malik Zia Ullah Bashir. The correct citation is: Zia Ullah Bashir M, Ali R (2018) Cryptanalysis and improvement of an elliptic curve based signcryption scheme for firewalls. PLoS ONE 13(12): e0208857."}
+{"text": "Despite limited efficacy of immunotherapy for advanced non-small-cell lung cancer (NSCLC) with driver mutations, whether neoadjuvant immunotherapy could be clinically valuable in those patients warrants further investigation. We utilized 40 oncogene-mutant NSCLC treated with induction immunotherapy from a large consecutive multicenter cohort. Overall response rate was 62.5% while 2 patients had disease progression. Of 39 patients that received surgery, R0 resection rate was 97.4%. The major pathological response (MPR) rate was 37.5% and the pathological complete response (pCR) rate was 12.5%. Pre-treatment PD-L1 expression was not a predictive biomarker in these patients. Median disease-free survival for all oncogenic mutation and EGFR mutation was 28.5 months. Indirect comparison through integrating CTONG1103 cohort showed neoadjuvant immunotherapy plus chemotherapy yielded the most superior efficacy among erlotinib and chemotherapy for resectable EGFR-mutant NSCLC. No MPR patients were identified with neoadjuvant immunotherapy plus chemotherapy for uncommon EGFR insertion or point mutations. Our results indicated the potential clinical feasibility of neoadjuvant immunotherapy for resectable localized oncogene-mutant NSCLC especially for EGFR-mutant NSCLC. Such novel treatment could enhance antitumor immunity by restoring T lymphocytes\u2019 function leading to long-term benefits3. However, for advanced non-small cell lung cancers (NSCLCs) harboring driver mutations such as EGFR or ALK mutations, immunotherapy exhibited impaired response compared to corresponding targeted therapies6. Even for those rare driver mutations, the efficacy of immunotherapy varied among different mutation types and clinicopathological status such as smoking and tumor mutation burden (TMB), showing significantly inferior response rate to targeted therapies7. The mechanism that caused impaired efficacy in these populations included limited infiltration of CD8+ T lymphocytes, lower PD-L1 expression and strong oncogenic pathway activation9. Unlike immunotherapy alone, IMpower 150 is the first trial that has demonstrated comparable efficacy as an immunotherapy-based combination strategy in pretreated EGFR/ALK mutant NSCLCs10. However, the response mechanism of immunotherapy in mutant NSCLC remained controversial.Anti-PD-1/PD-L1 antibodies, as immune checkpoint blockade therapy (ICB), have been widely applied in advanced lung cancer as a single agent, combined with other checkpoint blockade or platinum-based chemotherapy13. In recent years, multiple phase 2 trials of neoadjuvant immunotherapy have shown dramatic pathological response and elevated surgical resection rate16. However, data on oncogene-mutant NSCLC using novel neoadjuvant modalities are limited. CTONG1103 (EMERGING) (NCT01407822) study compared neoadjuvant targeted therapy and chemotherapy head-to-head and failed to show neither significantly improved major pathological response (MPR) nor overall survival (OS)17. This might be attributed to the highly selective therapeutic mechanism of targeted therapy, intratumor heterogeneity and concomitant mutations which leads to incomplete antitumor response19. In a previous study, neoadjuvant atezolizumab and chemotherapy showed dramatic pathological response even in subjects with sensitive EGFR mutations, providing the clinical potentials of immunotherapy-based combination strategy for oncogene-mutant NSCLC16.For resectable NSCLCs, chemotherapy has remained as the standard neoadjuvant treatment for decadesDespite the limited efficacy of immunotherapy in advanced mutant NSCLC, little is known about whether neoadjuvant immunotherapy could be clinically valuable for NSCLC positive of driver mutations. Herein, we describe the clinical outcome and safety profile of neoadjuvant immunotherapy followed by surgery in a multi-center cohort of patients with oncogene-mutant localized NSCLC. We also conducted dynamic multi-omics sequencing to provide insight of the potential mechanisms that led to differential response of neoadjuvant immunotherapy.EGFR mutation including exon 19del, exon 21L858R, exon 17\u201325 and exon 20 insertion. Other oncogene mutation included KRAS, RET fusion, ALK fusion, ROS1 fusion, BRAF and HER2 insertion. Percentage of residual tumor cells were evaluated in 87.5% (35/40) patients while the other patients did not undergo surgery or comprehensive pathological assessments to determine the specific values of their residual tumors. Clinical information was summarized in Table In total, patients treated with neoadjuvant immunotherapy were preliminarily screened from 26 centers around China, and 40 NSCLC patients that were treated with neoadjuvant immunotherapy and harboring EGFR mutations were collected from 8 thoracic and cancer centers. 60.0% (24/40) were men and 57.5% (23/40) were non-smokers. 32.5% 13/40) patients were pathologically or radiologically confirmed as N2 disease. Only one patient was suspected to have oligometastatic disease of left adrenal gland before neoadjuvant treatment which disappear after neoadjuvant immunotherapy. Among all, there were 47.5% (19/40) patients harboring 3/40 patiAll patients have completed neoadjuvant immunotherapy without treatment discontinuation owing to severe toxicity. No new safety signals were identified regarding previous studies. Only two patients had grade 3 anemia, while others exhibited grade 1-2 adverse events (AEs) such as rash and diarrhea. Detailed AEs profile are shown in Supplementary Table p-value\u2009<\u20090.001) probably due to most patients (91.2%) receiving neoadjuvant immunotherapy and chemotherapy    study to compare the efficacy of different neoadjuvant treatment modalities. Patients were stratified into 3 groups for subsequent analysis: chemotherapy (GC regimen), targeted therapy (erlotinib) and immunotherapy plus chemotherapy (IO\u2009+\u2009CT). The baseline characteristics were relatively well balanced among groups in terms of smoking status, histology and EGFR mutation subtypes. EGFR exon 21 L858R was the most common subtype among groups (Table 2 study t20 to estimate the abundance of infiltrating immune cells and performed unsupervised-clustering. We found distinct immune microenvironment (IME) between PL and normal lymph nodes while metastatic lymph nodes showed similar IME with PLs. Interestingly, we found a pretreatment metastatic N2 lymph node from patient 2 which exhibited no residual cancer after neoadjuvant treatment showed similar IME with PL instead of other normal lymph nodes. We also applied ImmuCellAI to predict the efficacy of immunotherapy where MPR patient showed infiltrating immune features of both PL and DLNs favored immunotherapy and remarkably less tissues showed response to immunotherapy for non-responders  and draining lymph nodes (DLNs). We used ImmuCellAIers Fig. . Relativers Fig. . For paters Fig. , we estaLNs Fig. . Additioden Fig. .Fig. 3Ov24 and suppressor cell (SC)25 score in PLs and DLNs, respectively. We identified elevated T-cell inflamed GEP in DLNs along with lower SC score in PL for responders while the opposite in non-responders  abundance, T/NK cells abundance, IFN activity and T cell exhaustion among primary lung cancer and draining lymph nodes. Notably high expression of these gene sets was found in both PL and DLNs from responder while relatively lower expression in non-responder. Interestingly, despite low expression of these gene sets was observed in PL of PT2, relatively high expression of APC abundance and IFN activity were enriched in corresponding DLNs, and this patient only had 16% residual tumor left in the PL, which might indicate an underlying role of inflamed phenotype in DLNs for promoting the efficacy of immunotherapy Fig. . Throughers Fig. . Gene seers Fig. .Fig. 4ImDespite being a retrospective study with a heterogeneous population, our study described the clinical efficacy of neoadjuvant immunotherapy in the largest cohort of patients with resectable NSCLC harboring oncogene mutations. We observed both encouraging MPR and pCR rate for oncogene-mutant NSCLC treated with neoadjuvant immunotherapy especially for EGFR-mutant NSCLC as well as well-tolerated safety profile.26 showed superior pathological response of neoadjuvant immunotherapy plus chemotherapy compared to chemotherapy alone27. However, most of the neoadjuvant immunotherapy trials precluded EGFR/ALK mutant patients due to the inferior efficacy of immunotherapy in advanced NSCLC harboring EGFR/ALK mutation28. In addition, rare oncogenic mutations were reported to be either insensitive or undetermined efficacy to immunotherapy. Subgroup analysis of NEOSTAR study suggested less efficacy of either neoadjuvant nivolumab or nivolumab plus ipilimumab in canonical oncodriver patients29. However, phase 2 trials evaluating neoadjuvant immunotherapy plus chemotherapy30 showed astonishing pathological response in EGFR-mutant NSCLC, although both contained quite a small sample. In our study, we found that the short-term use of neoadjuvant immunotherapy plus chemotherapy in oncogene-mutant NSCLC could still achieve 37.5% MPR generally which were similar to Checkmate-816 suggesting clinical potentials for neoadjuvant immunotherapy used for oncogene mutant NSCLC. Previous study of neoadjuvant EGFR-TKIs in EGFR mutant patients exhibited relatively lower response rate compared to first-line setting in advanced disease, and MPR was unexpectedly lower which might be due to highly selective TKIs and recurrent co-occurring insensitive mutation clones31. Interestingly, unlike advanced disease, we found comparable efficacy of neoadjuvant immunotherapy for EGFR-mutant patients with MPR of 42.1%. Despite a lower pCR than in Checkmate-816, 10.5% EGFR-mutant patients could still achieve pCR through neoadjuvant immunotherapy while no pCR was found in the EMERGING study17. To be noticed, patients with EGFR rare point mutation or exon20 insertion did not show satisfactory efficacy rates in response to neoadjuvant immunotherapy plus chemotherapy, suggesting other treatment modalities are required for these patients.Recently released data from Checkmate-816Although LCMC4, an umbrella trial evaluating corresponding TKIs for different driver mutations as neoadjuvant treatment, was about to initiated, there remains an open question as to whether neoadjuvant immunotherapy might be feasible for these rare oncogene-mutant patients in consideration of one third of these patients achieved MPR in our cohort and no available neoadjuvant targeted therapy data for these patients. Indeed, limited sample size of these patients might be underpowered to draw solid conclusions.34, did not show correlation with MPR/pCR in some trials35. In the present study, we did not observe a significant correlation between pretreatment PD-L1 status and MPR either. For CA209-159 trial, although TMB was found to be relevant to the efficacy of neoadjuvant CPI15, TMB measures were not available for present study since few patients were performed WES or large panel NGS.A number of prior studies had evaluated potential biomarkers for MPR, but no agreement was made upon predictive biomarkers currently. PD-L1 status, the most well-known predictive biomarkers of CPIs in advanced NSCLCOwing to its retrospective nature, this study had two primary limitations of this study. First of all, the sample size is relatively small with diverse oncogene mutations and PD-1 blockades involved. Nevertheless, this is so far the largest cohort of localized oncogene-mutant NSCLC treated with neoadjuvant PD-1 blockades with median follow-up over 1 year. Besides, 19 patients harboring EGFR mutations, the most common driver mutation of lung cancer, were involved which could shed light on neoadjuvant treatment for EGFR-mutant NSCLC in a way. Last but not least, the lack of central evaluation of pathological response might lead to disparity of MPR which would potentially cause overestimation of MPR. However, evaluation of pCR would be barely affected due to its definition of no residual tumor cell at all. Moreover, pCR of EGFR-mutant NSCLC treated with neoadjuvant immunotherapy plus chemotherapy was notably higher than first-generation EGFR-TKI (CTONG1103)  and third-generation EGFR-TKI  .EGFR-mutant patients and potentially be extended to other rare driver mutations. Considering the underlying influence of tumor heterogeneity to targeted therapy, relatively low pathological response of targeted therapy in neoadjuvant setting and long-term benefit of immunotherapy, we assume front-line use of neoadjuvant immunotherapy plus chemotherapy may provide higher cured potentials and long-term survival benefit. Therefore, we proposed an underlying mode of neoadjuvant immunotherapy in optimizing whole-course treatment for localized oncogene-mutant NSCLC  which evaluated either neoadjuvant gemcitabine plus cisplatin or erlotinib in EGFR-mutant stage III NSCLC. Informed consent was written and received from each patient before treatment as well as informed consents for experimentation with human subjects. This study was approved by the ethical committee of Guangdong Provincial People\u2019s Hospital (KY-Z-2021-567-03).We initiated a national questionnaire of real-world neoadjuvant immunotherapy in resectable NSCLC across 26 cancer research centers and 8 of them reported patients with oncogenic mutations who were treated with neoadjuvant immunotherapy under the real-world circumstances including inadequate biopsy specimen for genetic testing, negative findings of driver mutation from ctDNA, or no available TKI treatment. In case of any potential selection bias, all patients were screened and collected consecutively. Oncogenic mutations included 36 to evaluate residual viable tumor (RVT) except for multiple slides. MPR and pathological complete response (pCR) was defined as less than 10% viable tumor cells in primary lesions and no viable tumor cells in both primary and lympho nodes, respectively.Patients\u2019 demographic and clinical data were retrospectively reviewed, including clinical information, tumor histology, molecular profile, treatment modality, radiological and pathological response assessment. Genotyping assessments were performed through various approaches, including PCR, immunohistochemistry (IHC) (for ALK fusion) and large panel next-generation sequencing (NGS). Radiological response was assessed following formal Response Evaluation Criteria in Solid Tumors (RECIST) measurements. Due to the retrospective nature, pathological assessment was performed independently in the Department of Pathology of each center following recommended assessment processExpression of PD-L1 was independently scored through Dako PD-L1 22C3 (pharmDx) assay. PD-L1 expression was quantified as the proportion of PD-L1-positive tumor cells. Positive PD-L1 expression in a given specimen was defined as \u22651% for tumor cell and \u226550% for high expression. Cases with <100 total tumor cells for scoring were defined as not applicable (NA).We collected serial blood samples, post-treatment primary tumor samples, and draining lymph nodes specimens from four patients. Genomic DNA was extracted from frozen tumor and normal tissue sections using the QIAamp DNA FFPE Tissue Kit (Qiagen) following the manufacturer\u2019s instructions. A minimum of 1ug of DNA was used for WES profiling experiment. The DNA quality was assessed by Nanodrop2000 (Thermo Fisher Scientific), and the quantity was measured by the dsDNA HS Assay Kit using Qubit 2.0 (Life Technologies). WES was only performed when the tumor proportion was above 20%. WES library was sequenced using an Illumina Novaseq 4000 platform according to the manufacturer\u2019s instructions.Total RNA from frozen section samples was extracted using RNeasy FFPE kit (QIAGEN). Ribosomal RNA was depleted using RNase H followed by library preparation using KAPA Stranded RNA -seq Kit with RiboErase (HMR) (KAPA Biosystems), and library quality was accessed by Agilent High Sensitivity DNA kit on Bioanalyzer 2100 (Agilent Technologies), which was then sequenced on Illumina Novaseq NGS platforms.20 to comprehensively decode distribution of different infiltrating immune cells.Base calling was performed on bcl2fastq v2.16.0.10  to generate sequence reads in FASTQ format (Illumina 1.8+ encoding). Quality control (QC) was performed with Trimmomatic (version 0.33). STAR (version 2.5.3a) is used for transcriptome mapping followed by isoform and gene level quantification performed by RSEM (version 1.3.0). Corresponding heatmaps were generated by in-house R scripts. To evaluate the immune construction of primary lung cancer and draining lymph nodes, we applied ImmuCellAI37 mpileup with parameter \u201c-p\u201d:20; \u201c-P\u201d: 20 was used to get mutation supporting reads counts across all tumor regions where a variant (SSNV or InDel) was detected in one or more regions in one patient. For those somatic variants that were not called ubiquitously across tumor regions, the missing variants were picked back up if the mutant read count was \u22653, as well as the read depth, was >10. Sites with sequencing depth \u226410 were marked as \u201cNA\u201d. The neighbor joining phylogenetic trees were constructed using R package named \u201cMesKit\u201d38. The recalled mutation file (.maf format) was set as input and method\u2009=\u2009\u201cNJ\u201d with bootstrap 100 times were set in the function \u201cgetPhyloTree\u201d.SAMtools v1.3.1t-test was used for comparison between groups. Correlations among different variables were examined by Pearson and presented through Pearson r and p-values. Odds ratios were used to compare pathological response between different treatment modalities and Fisher exact test was used to calculate the significance. A two-sided p\u2009<\u20090.05 was determined to be statistically significance.Clinical and genomic data were analyzed using R Package (Version 3.3.0) or Prism 5.0  software. Kruskal-Wallis test was applied to compare the significance among groups and Student\u2019s Further information on research design is available in the REPORTING SUMMARYSupplementary file"}
+{"text": "Control and prevention of HIV infection require sustained adherence to antiretroviral therapy (ART) for patients with HIV (PWH) or those on pre-exposure prophylaxis (PrEP). ART is increasingly designated by payers as a specialty medication and often mandates specialty mail-order pharmacy for refills. Little is known about patient perspectives of pharmacy choice preferences for ART.A 20-question survey was distributed to patients (PWH and PrEP) of the Specialty Care Center in Omaha, NE. Participants >19 years, retained in care for >6 months, and experience with ART/PrEP refills at both local and mail-order pharmacies were considered for study participation. The survey was designed in 3 parts: perspectives on both pharmacy settings, ranking of pharmacy attributes, and pharmacy preference. Descriptive analyses were performed for all survey questions.Surveys were completed by 61 participants . Median age was 52 years, 85% White, 13% Black, 5% Latinx, and 80% commercially insured. Forty-eight participants (79%) reported insurance mandates to use a specialty mail-order pharmacy with 28 (58%) believing the mandate impacted their medical care. Forty-one participants (67%) preferred refilling prescriptions through a local pharmacy. Participants ranked \u201cease of refilling\u201d as the most important attribute  and favored local pharmacies vs mail-order pharmacies for all pharmacy attributes .Scoring scale, 1=strongly disagree to 5=strongly agree.Midwest PWH and PrEP patients generally preferred local pharmacies to refill their antiretroviral therapies versus mail-order pharmacies for nearly all pharmacy attributes. Further, many participants felt specialty pharmacy mandates negatively impacted their medical care. Insurance payers should consider removing restrictive specialty pharmacy mandates for ART/PrEP prescriptions.All Authors: No reported disclosures."}
+{"text": "Bivalent COVID-19 booster vaccines, developed to protect against both ancestral and Omicron BA.4/BA.5 variants, are recommended to increase protection against SARS-CoV-2 infection and severe diseaseParticipants were recruited via Prolific, an online survey platform.Participants reported dates of all previous COVID-19 infections (as determined by positive rapid test results or reverse transcription-polymerase chain reaction test results) and COVID-19 vaccine doses. Participants who reported receiving a bivalent booster dose viewed a randomly ordered set of 10 suggested reasons for getting the booster dose,The initial survey included 1,200 participants, with approximately one third in each age group . Nearly The 396 participants who had received the bivalent booster dose selected a median of five reasons for getting it.https://stacks.cdc.gov/view/cdc/123508). Among adults aged 18\u201339 years, the most commonly reported reasons for not receiving the bivalent booster dose were being unaware that they were eligible (29.8%), being unaware that updated booster doses were available (23.5%), or believing they still had strong protection against infection (18.4%). The most commonly reported reasons among adults aged 40\u201359 years were being unaware that they were eligible (22.1%) or believing they still had strong protection against severe disease (21.3%) or infection (18.5%). Among adults aged \u226560 years, the most commonly reported reasons were believing they still had strong protection against infection (20.2%), concern about side effects (17.5%), or being unsure whether the bivalent booster dose was effective (16.1%).The 714 participants who had not received the bivalent booster dose selected a median of one reason for not receiving it .\u2020\u2020\u2020 ReasAdults aged 40\u201359 and \u226560 years commonly reported not receiving a booster dose because they believed they were already sufficiently protected against infection or severe disease. However, among 223 participants who cited one or both of these reasons, 160 (71.7%) had not experienced a SARS-CoV-2 infection or received a COVID-19 vaccine dose within the preceding 6 months, and 114 (51.1%) had never been infected.Reasons for nonvaccination were descriptively grouped into the following three categories: 1) lack of awareness (related to eligibility and availability), 2) perceived immunity , and 3) concern and uncertainty . Reasons within each descriptive category were more often reported together (co-occurrence frequency >15%)After participants who had not received the booster dose (714) selected their reasons, they read a message about vaccine eligibility and availability and then reported their intention to get the booster dose. Overall, more than two thirds (67.8% [484 of 714]) indicated that they planned to get the booster dose (similar across age groups). Among those who had reported being unaware about eligibility or availability, 88.0% (227 of 258) indicated that they planned to get the booster dose.After 1 month, the 714 participants who had not received the booster dose at the initial evaluation were recontacted; 624 (87.4%) completed the follow-up survey . Among 4****In this online survey aimed at understanding reasons for low bivalent COVID-19 booster vaccination coverage, the most common reasons for not receiving a bivalent booster dose were lack of awareness of eligibility (23.2%) or availability (19.3%) and perceived existing protection against infection (18.9%), although top reasons differed across age groups. Bivalent booster dose coverage in the U.S. was low when the survey was conducted (12.1% of adults), and currently remains low (18.2% of adults) , and convenient access  might motivate persons to act on their intentions , making it impossible to weight the sample by race or ethnicity to represent the general U.S. population. Second, the survey used a nonprobability sample, and the cumulative response rate cannot be reported because Prolific does not report the number of users who viewed a survey but did not opt-in. Third, inferences are limited to persons who received \u22652 previous COVID-19 vaccine doses. These three limitations constrain the generalizability of the findings as well as inferences about demographic or geographic differences. Previous studies have demonstrated racial and ethnic disparities in COVID-19 booster vaccination (This study identified lack of awareness, perceived immunity, and concern and uncertainty as important reasons underlying low adult bivalent booster vaccination coverage. All eligible adults should receive a bivalent booster dose to protect themselves against SARS-CoV-2 infection and severe disease. To help increase bivalent booster coverage, health care professionals and public health practitioners should use evidence-based strategies to convey information about booster vaccination recommendations and waning immunity, in addition to increasing convenient access to vaccination.Bivalent COVID-19 booster vaccines increase protection against infection and severe disease. However, few eligible U.S. residents have received a bivalent booster dose, and factors underlying low coverage are unclear.An online opt-in survey of 1,200 previously vaccinated U.S. residents found that the most common reasons for not getting a bivalent booster dose were lack of awareness about eligibility or availability and overconfidence in immunity; reasons varied by age group.All eligible adults should receive a bivalent COVID-19 booster vaccine. To help increase bivalent booster dose coverage, health care and public health professionals should use evidence-based strategies to inform persons about booster vaccine recommendations and waning immunity."}
+{"text": "MUC16/CA125 is one of the few oldest cancer biomarkers still used in current clinical practice. As mesothelium is an abundant source of MUC16 and a major contributor to stromal heterogeneity in PDAC, we investigated the regulation of MUC16 in tumor and stromal compartments individually. The trajectories constructed using the single-cell transcriptomes of stromal cells from KPC tumors demonstrated continuity in the trajectory path between MUC16-expressing mesothelial cells and other CAF subsets. Further, the tumor tissues of MUC16 whole-body knockout (KPCM) showed dysregulation in the markers of actomyosin assembly and fibroblast differentiation (iCAF and myCAF), indicating that MUC16 has an extra-tumoral role in controlling CAF differentiation. Although we found mesothelium-derivative stromal cells to be bystanders in normal pancreas, the proportion of these cells was higher in invasive PDAC, particularly in TP53 deficient tumors. Moreover, we also detail the regulation of MUC16, KRAS, and SOX9 by TP53 family members (TP53 and TP63) using multi-omics data from knockout models, PDAC cell lines, and human PDAC tissues. The advent of mucin 16 MUC16/CA125) as an Ovarian Cancer biomarker in the 1980s is a major milestone in the biomarker research arena 5 as an O, 4. WhilThe C-terminal portion of the MUC16 protein undergoes protease-mediated cleavage by Type 1 matrix-metalloproteinases. Its circulation levels often correlate with the magnitude of connective tissue involvement during cancer progression and surgical recoveries , 9. The Histologically, most pancreatic tumors show a spectrum of ductal hyperplasia-carcinoma to squamous metaplasia, giving rise to speculation that squamous carcinomas are likely a result of a metaplastic change of adenocarcinoma . Due to In PDAC, the infiltrating tumor cells show high expression of MUC16 relative to matched PanIN\u20103 cells, correlating with tumor size, serosal invasion, and lymph node metastasis . The scRNA data (GSE155698) of 42692 cells from 16 PDAC tissues were considered for the analysis. The samples belonging to tissue 11 (PDAC_TISSUE_11A & 11_B) were not included in the analysis as they were processed at two different core facilities. Out of 42692 cells, 16635 cells met the quality control thresholds (MT reads < 5% & nFeature_RNA > 200) and were subsequently processed using standard (logarithmic) normalization with scale factor of 10000. The top 2000 highly variable features identified using Variance Stabilizing Transformation (VST) were used for principal component analysis (PCA). The first 35 principal components (capturing 83.6% of the variability) were used to perform cell type-based cluster groupings. The top 30 cluster markers for each cluster were used to annotate the clusters with their cell type using Enrichr database (The scRNA data of 16 human PDAC tissues and PBMCs (accession no: GSE155698) and stromal cells (DAPI-_CD45-_CD31-_EPCAM-) from 4 KPC  C57BL6/J mice were individually obtained from NCBI-GEO data repository and subsequently processed using Seurat R package as provided below , 22. Thedatabase . We furtThe RNA-seq processed data of tumor-stromal subtypes  was retrieved from NCBI GEO repository (accession no: GSE71729). Only primary PDAC samples (n = 145) were used for downstream analysis. The prior normalized scRNA data of stromal cells  (GSE129455) from 4 KPC  C57BL6/J mice were used to perform clustering and lineage trajectory analysis. We constructed principal components using the top 2000 variable features. The nearest neighbor graph was computed using the top 50 principal components and was subsequently clustered. A subset of stromal cells expressing either Mesothelin (Msln) or Muc1 or Muc16 (3565 cells) were used to create three cell groups: a) Muc1-expressing (928 cells); b) Muc16-expressing (148 cells); and c) Msln-expressing (2491 cells) for lineage trajectory analysis  and KPCM  mice. The sequence reads were aligned to the mouse genome using HISAT2. The gene counts were estimated using feature Counts and were subsequently normalized using DESeq2 R package.https://bioconductor.org/packages/release/bioc/html/DESeq2.html) prior to differential expression analysis.The bulk RNA-seq data of parental mesothelial cells and FACS sorted eGFP+ mesothelial cells from tumors (CT1BA5 & BMFA3) were obtained from NCBI GEO (accession no: GSE196740). The pre-processing and normalization were performed using DESeq2 R package . The data were log-transformed with a scale factor of 10000 before the downstream analysis. The stromal cells were identified based on PDPN expression. The epithelioid-like cells were identified based on the markers borrowed from pseudotime trajectory findings . The mesothelial cells were identified using markers .www.proteinatlas.org) (51 cell types of 13 tissues) were downloaded from their respective websites (The cell type-specific gene expression data of Descartes (descartes.brotmanbaty.org) developmental database (657 cell types from 15 organs) and Human Protein Atlas . The molecular subtype information according to Bailey\u2019s classification scheme was obtained from previously published sources (https://www.ncbi.nlm.nih.gov/refseq/), and Ensembl-UCSC ID conversion was accomplished using the biomart Ensembl resource. Only samples classified as Pancreatic Adenocarcinoma in \u201ccancer type detailed\u201d clinical information (n = 176) were considered for the analysis, and among them, the samples with MUC16 Z-score expression > 1 were designated as \u201cMUC16-overexpressing\u201d.The processed TCGA-PAAD RNA-seq  and clinical data was obtained from UCSC Xena data portal  and the corresponding sample-wise clinical information regarding histological subtypes was acquired from cBioPortal  web server.https://maayanlab.cloud/Enrichr/) for validation.The Signaling Pathways Project (SPP) database and Ensembl websites were used for the identification of transcriptional factor binding sites in MUC16 and TP63 , 29. We sh/\u00b5shR)) in the expression of genes between p53 R172H/null murine PDAC cells treated with doxycycline-inducible control (shR) or anti-p53 shRNA (sh1 & sh2) were estimated using the data deposited in NCBI GEO (GSE114502). The RNA-sequence data of genotypes KRAS Trp53fl/+ and KRAS Trp53fl/+ TAp63fl/fl were obtained from ArrayExpress (accession code: E-MTAB-4415) and were preprocessed and normalized using Kallisto/sleuth and DESeq2 FPKM function. We then computed log-2-fold differences (log2(\u00b5KPTAp63fl/fl/\u00b5KPC)) in the expression of genes and nominal p-values (t-test).We used the author-deposited differential gene expression data available on NCBI GEO (GSE140484) on pancreatic tumors grown using orthotopically implanted TP63-expressing SUIT2 cells in NOD-scid gamma (NSG) mice. Similarly, the log-2-fold differences  were accessed from cBioPortal  and DepMap (depmap.org) web portals. The normalized gene and protein abundance data was used to perform differential expression analysis between cell line groupings created using MUC16 protein expression (MUC16-high & MUC16-low).The gene signatures of individual cell types of Human Protein Atlas data were estimated using a one-sided Student t-test (p < 0.05). We only considered a gene as a gene signature for a particular cell type if the gene was not overexpressed in more than three cell types .GSEA analysis was performed using in-house generated HPA cell type gene signatures (see HPA cell signatures methods section) on MUC16-high and TP63-high cohorts of TCGA-PAAD with 1000 phenotype permutations.https://descartes.brotmanbaty.org/) of differentially expressed genes of MUC16-high and TP63-high groups were accessed using Enrichr web server  at the invasive front is correlated with poor outcomes in GI cancers , 32, 33.From here on, we will use the term \u201cepithelioid-like\u201d to refer to these CAFs due to their co-expression of both epithelial and myeloid markers. Therefore, to examine if shared Msln expression indicates their co-evolution or shared lineage, we constructed cell trajectories with only mesothelial (Muc16-expressing), Msln-expressing and Muc1-expressing cells (3565 cells). The clustering and trajectory analyses yielded three distinct cell clusters with a continuous trajectory path (LSL\u2212G12D/+TrKPC (Krasp53LSL\u2212R172H/+Cre/+), KIC (KrasLSL\u2212G12D/+Ink4afl/flPtf1aCre/+) and KPfC (KrasLSL\u2212G12D/+Trp53fl/flPdx1Cre/+)Ptf1a) to quantify the fraction of infiltrating mesothelial cells. We saw Pdpn-expressing stromal cells were substantially higher in KPfC late tissues (21%) compared to normal and PDAC tissues from other mice models (4-9%). Although Muc16-expressing mesothelial cell fractions were low in all mice tissues, their presence was noted in late KPfC (~4%) and normal tissues (~7%) but not in KPC (late) tissues. In contrast, the infiltration of epithelioid-like cells was more evident in all late PDAC tissues, with higher prominence in late KPfC tissues. The stromal cells of KPC and KIC tissues were found to be in an \u201cactivated\u201d state relative to KPfC PDAC tissues due to their overexpression of markers lysyl-oxidase (Lox), Col3a1, Sparc, and Il6  influences MUC16 expression and mesothelial cell identity. The FACS sorted eGFP mesothelial cells from mice PDAC tumors (BMFA3 and CT1BA5) showed decreased cell-cell adhesion  and ERM protein Ezrin (Ezr) with concomitant overexpression of mesenchymal , proteases  and cell cycle  genes compared to parental mesothelial cells , and cell-cell adhesion integrity . In paraThe cytoplasmic tail of MUC16 maintains cell-cell adhesion integrity due to its potential interaction with ezrin/radixin/moesin (ERM) proteins that crosslink the actin cytoskeleton . SeveralThe scRNA-seq analysis also revealed a distinct transcriptional profile of MUC16-expressing cells relative to all other epithelial (E-cadherin expressing) cells due to their higher reliance on glycolytic  and unfolded protein response  pathways , 35. Unlde novo adenocarcinomas (n = 70) and adenosquamous (n = 7) cancers compared to PDAC-originated from Intraductal Papillary Mucinous Neoplasms (IPMNs) (n = 12)  pointed to significant overexpression of MUC16 in To further examine the associations between MUC16 and TP63, we profiled the pancreatic tumors grown using orthotopically implanted TP63-expressing SUIT2 cells in NOD-scid gamma (NSG) mice and saw significant overexpression of MUC16 and other basal subtype markers  and cell-cell adhesion proteins   in MUC16-high  than in MUC16-low   and lymph angiogenesis/perineural invasion  in fl/+ TAp63fl/flKRAS Trp53 cell lines (p > 0.05). Interestingly, as we also noted higher expression of TP53 expression in fl/+ TAp63fl/flTrp53 cell lines, we suppose that the lack of TAp63 alpha isoform may revert to oxidative stress-induced apoptotic signaling by TP53  (p < 0.05)  and progenitor (44%) (MHCPan and MHCFlurry and estimated sample-wise putative immunogenic loads. The samples with at least 1 identified immunogenic peptide (n = 70) showed poorer survival probability (p = n.s), a higher proportion of TP53 mutations (one-sided fisher-exact p < 0.05), and overexpression of MUC16 (p < 0.05) (MUC16 showed significant co-expression with antigens (tumor-antigens & autoantigens) and acute phase reactants such as transglutaminases (TGM2), CEACAMs, C-Reactive Protein (CRP), and alkaline phosphatase (ALPP) , MSLN, MUC1, and MUC16 in samples with marked stromal cell infiltration (activated stroma). Also, the immunophenotype of these samples exhibited significant correlations between MUC16 mRNA expression and putative fractions of immune cell subsets, particularly macrophages  and T-regulatory cells . Conversely, MUC16 expression negatively correlated with cell fractions of CD8 T cells  and NK cells  .PDAC progression is triggered by a cascade of events involving stromal cell mediation, autoantigenicity, and desmoplasia . RecentlThe MUC16-expressing epithelial cells displayed a distinct transcriptional profile relative to other mucin-expressing cells due to their overexpression of cancer antigens , cornification/squamous , and cell-cell adhesion . Due to the co-expression of squamous markers in MUC16-expressing tumors, we dissected the associations between TP63, TP53, and MUC16, where we identified that TAp63 also mediates SOX9 and KRAS signaling like TP53-gain-in-function mutants Figure\u00a06Further, the high infiltration of stromal cells, particularly myofibroblasts expressing TIMP3 and PDGFR, may create fibers and extracellular matrix in MUC16-expressing tumors. We assume that these stromal cells are mesothelial-derived due to the retention of their mesothelial-specific markers, WT1 and PDPN. The gene expression profile of KPCM tissues relative to KPC showed considerable downregulation of actinomyosin intermediate filaments required for myofibroblast differentiation and intercellular junction integrity, supporting its more comprehensive  role in PDAC. On the other hand, the increased influx of macrophages in MUC16-high tumors is possibly due to TP53 dysfunction like demonstrated elsewhere rather than MUC16 over-expression by itself .The MUC16-expressing PDAC tumors showed high antigenic loads, differential polarization of mesothelium-derived CAFs, and increased predisposition to TP53 loss. These characteristics likely cumulate and reflect the prognostic burden associated with MUC16 expression in PDAC. Moreover, the genomic and transcriptional dysregulation of TP53 family members (TP53 and TP63) may exhibit a broader impact on mucinous signaling due to their modulation of KRAS and SOX9 activity. This signaling modulation was also accompanied by shifts in the stromal cell proportions and is likely a consequence of altered biological behaviors and the growth of cancer cells. On the other hand, the tumor tissues of the whole-body knockout model of MUC16 showed downregulation of cytoskeletal, smooth muscle contraction, myofibril organization, and focal adhesion pathways besides profound transcriptional changes to fibroblast subtype markers. We expect future studies to address if the decreased myofibroblast polarization in MUC16 deficient tumors results from reshaped tumor-stromal dialogue and impaired MMT process.https://www.ncbi.nlm.nih.gov/, GSE212777.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: The mouse studies conducted followed the US Public Health \u2018Service\u2019 Guidelines for the Care and Use of Laboratory \u2018Animals\u2019 under an approved protocol by the Institutional Animal Care and Use Committee, University of Nebraska Medical Center.RC-V performed data acquisition, research, and manuscript preparation. VD performed data analysis and developed immunogenicity in-silico pipelines. RN performed research and figure modifications. ZA independently reanalyzed the data, validated pipelines, and developed final reports. All authors contributed to the article and approved the submitted version."}
+{"text": "Dear EditorDisheveled\u2010associated activator of morphogenesis 1 (DAAM1) is a member of Formin protein family, which binds to the growing barbed ends and mediates microfilament polymerization during the formation of cell pseudopodia.Firstly, we explored the levels of DAAM1 mRNA expression in multiple tumor types using the RNA\u2010sequencing data from The Cancer Genome Atlas (TCGA) dataset. The results showed that DAAM1 was upregulated in glioblastoma multiforme (GBM), lower grade glioma (LGG), prostate adenocarcinoma (PRAD), stomach adenocarcinoma (STAD), pancreatic adenocarcinoma (PAAD), and cholangio carcinoma (CHOL), and downregulated in uterine corpus endometrial carcinoma (UCEC), lung adenocarcinoma (LUAD), esophageal carcinoma (ESCA), kidney renal papillary cell carcinoma (KIRP), colon adenocarcinoma (COAD), KIRC, lung squamous cell carcinoma (LUSC), skin cutaneous melanoma (SKCM), bladder urothelial carcinoma (BLCA), rectum adenocarcinoma (READ), ovarian serous cystadenocarcinoma (OV), testicular germ cell tumor (TGCT), uterine carcinosarcoma (UCS), adrenocortical carcinoma (ACC), and kidney chromophobe carcinoma (KICH) Figure . With reNext, we deeply investigated the expression and prognostic value of DAAM1 in KIRC. We found that DAAM1 protein expression detected by immunohistochemistry staining was significantly downregulated in three independently validated cohorts Figures\u00a0. In addiGiven the abnormal prognostic value, we next investigated the biological role of DAAM1 in KIRC. Based on the Linked Omics database, we screened the correlated genes and then performed enrichment analysis Figure . The res+ T cell, CD4+ T cell, macrophage, neutrophil, and dendritic cell .Supp InformationClick here for additional data file."}
+{"text": "Urinary tract infections (UTIs) are the most common indication for antibiotic prescriptions in nursing homes (NHs) and frequently result in fluoroquinolone (FQ) prescriptions. We performed a vignette-based survey of NH providers to better understand empiric UTI treatment decision-making.Study participants were recruited nationally through professional organizations and snowball sampling from December 2021 to February 2022. Clinical vignettes depicting four UTI presentations in NH residents  were developed and distributed via electronic survey. Respondents provided free-text antibiotic choice, which two physicians independently reviewed and implicitly determined if a preferred or not-preferred antibiotic was selected. A panel of three physicians adjudicated discrepancies between the primary reviewers. Analysis was performed in R.Of 86 respondents, 74% were physicians and 26% were advanced practitioners. Half of respondents (50%) had >10 years NH experience, 41% were geriatrics trained, and none were infectious disease trained. Figure\u00a01 details antibiotic choices and preferred agents for each case. Overall, 70% of antibiotic choices were deemed preferred antibiotics, with the least number of preferred choices observed for case 3 depicting catheter-associated UTI (53%). FQs (43%) and nitrofurantoin (14%) were the most frequent non-preferred choices. Case 2 received the greatest proportion of FQ prescriptions (38%), but this was a preferred agent. In cases where FQs were not a preferred choice, they comprised 17% of antibiotic choices. There was no difference in FQ or preferred prescribing choices by role. Providers with >10 years NH experience, however, prescribed fewer FQs over the four cases than those with less NH experience .Antibiotic Choice and Preferred Agents per CaseAntibiotic choices are ordered from highest to lowest cumulative frequency.This sample of NH providers made mostly preferred empiric antibiotic choices, however, FQ use remained high, particularly in providers with less NH practice experience. Further exploration of decision-support tools for empiric antibiotic prescribing in this setting may improve antibiotic stewardship.Robin L. Jump, MD, PhD, Merck: Grant/Research Support|Pfizer: Advisor/Consultant."}
+{"text": "Limited studies have quantified older adults\u2019 profiles of social participation and relationship quality. How such profiles were associated with their spouse/partner\u2019s cognitive function also remains unknown. Using the Health and Retirement Study (2014/2016), we identified 3,722 community-dwelling, cognitively intact, married/partnered respondents living with their spouse/partner. Spouse/partner\u2019s cognitive function was ascertained by the Langa-Weier Classification [Intact/Cognitively Impaired but not Demented (CIND)/Demented]. Social participation was measured by the frequency of volunteer, charity, education, sport/social clubs, and non-religious organization activities. Relationship quality was measured by the perceived positive and negative support from spouse, children, relatives, and friends. Latent profile analysis identified profiles of social participation and relationship quality. Multinomial logistic regression estimated the association between spouse/partner\u2019s cognitive function and the respective profiles. Three social participation profiles were identified: (1) Limited social participation ; (2) Frequent volunteer participation (10%); (3) Frequent non-volunteer participation (21%). Three relationship quality profiles were identified: (1) Positive overall support ; (2) Positive spousal support (18%); (3) Negative spousal support with positive non-spousal support (14%). Those with a spouse/partner that were CIND or demented were significantly less likely to frequently participate in volunteer or non-volunteer activities, while more likely to perceive negative spousal support and positive non-spousal support. Given these findings and the essential role of social participation and relationship quality in older adults\u2019 well-being, programs focusing on older adults living with a spouse/partner with impaired cognition are needed to help them maintain social connectedness."}
+{"text": "Massospora cicadina strain MCPNR19 (ARSEF 14555), an obligate entomopathogenic fungus of periodical cicadas. The MAGs include representatives of Pantoea, Pseudomonas, Lactococcus, and one potential new Chryseobacterium species. Future research is needed to resolve the ecology of these MAGs and determine whether they represent symbionts or contaminants.We report six metagenome-assembled genomes (MAGs) associated with  Massospora cicadina (Zoopagomycota) is an understudied obligate entomopathogenic fungus that infects periodical cicadas (M. cicadina strain MCPNR19 (ARSEF 14555)   using Bl species , we sougM. cicadina MCPNR19 (ARSEF 14555) were collected from fungal plugs of infected brood XIII Pharaoh cicadas (Magicicada septendecim) in June 2019. Genomic DNA from spores was sequenced using both Illumina and Nanopore technologies. The Nanopore data were assembled using wtdbg2 v. 2.5  representing six genera, including a high-quality MAG for a potentially new  species ; Table\u00a01SRR17553520 to SRR17553526 and BioProject accession number PRJNA795459. The four medium- and high-quality MAG assemblies have been deposited at DDBJ/ENA/GenBank under accession numbers JALIHL000000000, JALIHM000000000, JALIHN000000000, and JALIHO000000000. The versions described in this paper are JALIHL010000000, JALIHM010000000, JALIHN010000000, and JALIHO010000000. The two low-quality MAG assemblies are archived at Zenodo (The sequence reads have been deposited under SRA accession numbers t Zenodo . Related"}
+{"text": "Are systemic reactions more common after simultaneous administration of COVID-19 mRNA booster and seasonal influenza vaccines than after COVID-19 mRNA booster alone?In this cohort study of self-reported data from 981\u2009099 persons aged 12 years or older, simultaneous administration of a COVID-19 mRNA booster dose and an influenza vaccine was associated with 8% to 11% increases, respectively, in systemic reaction compared with COVID-19 mRNA booster alone. These differences were statistically significant.Findings from this study suggest that simultaneous administration of COVID-19 mRNA booster and influenza vaccines may be associated with increased likelihood of systemic reactions. COVID-19 and seasonal influenza vaccines are essential in preventing respiratory infections and their potentially severe complications. Simultaneous administration of vaccines is efficient and may improve coverage with each vaccine. However, the safety of simultaneous administration of COVID-19 and influenza vaccines has not been well described.To evaluate adverse events and health impacts associated with simultaneously administered COVID-19 mRNA booster and seasonal influenza vaccines in the US population.In this retrospective cohort study, self-reported vaccine data were collected on days 0 to 7 after vaccination from September 22, 2021, through May 1, 2022, through v-safe, a voluntary smartphone-based monitoring system established by the Centers for Disease Control and Prevention. Participants were persons who voluntarily registered in v-safe following COVID-19 vaccination.Receipt of simultaneously administered COVID-19 mRNA booster and seasonal influenza vaccines or COVID-19 mRNA booster alone.Local injection site and systemic reactions  and health impacts reported by v-safe respondents in the week following COVID-19 mRNA booster vaccination. Adjusted odds ratios (aORs) were estimated for simultaneous administration compared with booster dose alone, controlling for sex, age, and week of vaccination.Of a total of 981\u2009099 persons aged 12 years or older registered with v-safe, simultaneous administration of COVID-19 mRNA booster and seasonal influenza vaccines was reported by 92\u2009023 (9.4%) v-safe respondents; of these respondents, 54\u2009926 (59.7%) were female, 36\u2009234 (39.4%) were male, and sex was unknown for 863 (0.9%). In the week following vaccination, any systemic reactions were reported by 36\u2009144 (58.9%) of 61\u2009390 respondents who simultaneously received Pfizer-BioNTech booster and influenza vaccines and 21\u2009027 (68.6%) of 30633 respondents who simultaneously received Moderna booster and influenza vaccines. Respondents who simultaneously received influenza and Pfizer-BioNTech booster vaccines  or influenza and Moderna booster vaccines  were slightly more likely to report any systemic reaction in the week following simultaneous vaccination than respondents who received only a COVID-19 mRNA vaccine booster.In this study, compared with administration of COVID-19 mRNA booster vaccines alone, simultaneous administration of COVID-19 mRNA booster and seasonal influenza vaccines was associated with significant increases in reports of systemic reactions during days 0 to 7 following vaccination. These results may help better characterize the outcomes associated with simultaneously administered COVID-19 booster and influenza vaccines in the US population. This cohort study evaluates adverse events and health impacts reported to a smartphone-based safety surveillance system during days 0 to 7 after simultaneous COVID-19 mRNA booster and seasonal influenza vaccination in US adults. This cohort study was reviewed by the CDC consistent with applicable federal law and CDC policy and was deemed not to be human participant research as defined in 45 CFR 46.102(l)(2); institutional review board review was not required. This report follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for observational studies.The v-safe platform is a smartphone-based active safety surveillance systemThe v-safe platform is a voluntary surveillance system, and registered participants opt in to receive health surveys; no further consent was required. Following COVID-19 vaccination, persons may register with v-safe, indicate COVID-19 vaccine dose and any simultaneously administered vaccines (received during the same visit), and receive regularly scheduled text message reminders about completing online health surveys. During registration, persons indicate their age, race, and ethnicity; demographic variables were collected to evaluate how well the surveillance population represents the general US population. Health surveys sent in the first week postvaccination include questions about local injection site  and systemic reactions  self-identified as mild, moderate, or severe and health impacts   reported simultaneous administration of COVID-19 mRNA booster dose, influenza vaccine, and additional vaccine(s) (n\u2009=\u20092647); (2) reported a booster dose prior to its authorization (n\u2009=\u200926\u2009960); or (3) reported a Moderna COVID-19 vaccine and were aged less than 18 years or Pfizer-BioNTech COVID-19 vaccine and were aged less than 12 years (n\u2009=\u200918). The odds of reporting any injection site or systemic reactions or health impacts following simultaneous administration of COVID-19 mRNA booster dose and influenza vaccines were compared with those following administration of the COVID-19 mRNA booster alone using a logistic regression model, adjusting for sex, age at vaccination, and week of vaccination. Statistical significance was set at \u03b1\u2009=\u2009.05 and 95% CIs were estimated. SAS software, version 9.4 (SAS Institute Inc) was used to conduct all analyses.From September 22, 2021, to May 1, 2022, a total of 92\u2009023 v-safe respondents reported simultaneous receipt of COVID-19 mRNA booster and seasonal influenza vaccines; 889\u2009076 v-safe respondents reported receipt of a COVID-19 mRNA booster alone. Of respondents who simultaneously received COVID-19 mRNA booster and seasonal influenza vaccines, 54\u2009926 (59.7%) were female, 36\u2009234 (39.4%) were male, and sex was unknown for 863 (0.9%); 37\u2009359 (40.6%) were aged 12 to 49 years, 23\u2009760 (25.8%) were aged 50 to 64 years, 24\u2009855 (27.0%) were aged 65 to 74 years, and 6049 (6.6%) were aged 75 years or older .In the week after vaccination, systemic reactions were reported by 36\u2009144 respondents (58.9%) who simultaneously received Pfizer-BioNTech COVID-19 booster and influenza vaccines and 21\u2009027 respondents (68.6%) who simultaneously received Moderna COVID-19 booster and influenza vaccines . Most reHealth impacts in the week after vaccination were reported by 11\u2009658 respondents (19.0%) who simultaneously received Pfizer-BioNTech COVID-19 booster and influenza vaccines and 8210 respondents (26.8%) who simultaneously received Moderna COVID-19 booster and influenza vaccines. Inability to perform normal daily activities in the week following vaccination was reported by 9519 respondents (15.5%) who simultaneously received Pfizer-BioNTech COVID-19 booster and influenza vaccines and 6811 respondents (22.2%) who simultaneously received Moderna COVID-19 booster and influenza vaccines; fewer than 1% of respondents simultaneously administered vaccines required medical care, including 22 respondents (0.02%) who reportedly received care at a hospital. Information regarding reported hospitalizations  was available for 19 (86.4%) of the 22 respondents, including 10 (45.5%) who indicated hospitalization was unrelated or reported in error. Among the remaining respondents, reasons for hospitalization included excessive vomiting, supraventricular tachycardia, cardiac arrhythmia, chest discomfort, autoinflammatory disease flare, kidney infection, hypoxia, and stroke. Respondents who simultaneously received influenza and Pfizer-BioNTech COVID-19 booster vaccines were not more likely to report a health impact in the week following vaccination  than respondents who received a COVID-19 Pfizer-BioNTech COVID-19 booster alone; respondents who simultaneously received influenza and Moderna COVID-19 booster vaccines were slightly more likely to report any health impact in the week following vaccination  than respondents who received a Moderna COVID-19 booster alone.8 that included persons who simultaneously received dose 2 Pfizer-BioNTech COVID-19 and influenza vaccines did not identify any serious safety concerns. Hospitalization following either of these vaccine combinations was uncommonly reported to v-safe. Given the limited data collected by v-safe, it is not possible to determine whether hospitalization was related to vaccination unless specifically noted by the respondent.The v-safe respondents who simultaneously received Pfizer-BioNTech or Moderna COVID-19 booster and seasonal influenza vaccines reported systemic reactions in the week after vaccination 8% to 11%, respectively, more frequently than did respondents who received a COVID-19 mRNA booster vaccine alone. Reactions after simultaneous vaccination or COVID-19 mRNA booster vaccination alone were usually mild. The phase 4 trial9 of simultaneous administration of an adjuvanted recombinant subunit vaccine for prevention of herpes zoster with substantial reactogenicity and quadrivalent inactivated influenza vaccine. Participants aged 50 years or older who received simultaneous vaccination reported systemic reactions more frequently (60.9%) than participants who received adjuvanted recombinant subunit herpes zoster vaccine (52.1%) or influenza vaccine (33.6%) alone; however, this difference was not considered clinically meaningful by Schwarz et al.9 Although we did not collect information on reactions after influenza vaccine alone, influenza vaccines in general are not particularly reactogenic. However, as reported by Falsey et al,10 some influenza vaccines appear to be more reactogenic for others; for example, among adults aged 65 years or older, local reactions were more frequently reported following high-dose influenza vaccine than standard-dose vaccine.Our findings are generally consistent with results from the phase 3 trialThis analysis has limitations. The v-safe platform is a voluntary program, and, as a result, data might not be generalizable to the entire population receiving COVID-19 vaccines. The v-safe program relies on self-report of COVID-19 vaccine received; therefore, some misclassification of exposure is possible. The v-safe app collects information of solicited adverse events following COVID-19 vaccination and is not designed to detect rare unsolicited adverse events. Given the short interval between vaccination and submission of v-safe responses, recall bias should be minimal. To minimize the complexity of data collection for respondents, v-safe does not include information regarding influenza vaccine type. Some influenza vaccines are more reactogenic than others, especially those approved for older adults; however, our model controlled for age, and this adjustment may address the differential reactogenicity of influenza vaccines administered to older adults. In addition, it is possible that the small increases in reactogenicity found with simultaneous administration were due to residual confounding between those who received only a COVID-19 booster vs both COVID-19 and influenza vaccines.In this cohort analysis, initial safety findings from v-safe for simultaneously administered COVID-19 mRNA booster dose and seasonal influenza vaccines indicate that respondents who received simultaneous administration were slightly more likely to report systemic reactions in the week following vaccination than respondents who received COVID-19 mRNA booster alone. In both groups, most reactions reported in the week following vaccination were generally mild. These results may help better characterize the outcomes associated with simultaneously administered COVID-19 mRNA booster and influenza vaccines in the US population."}
+{"text": "Neoplasms contain tumor-initiating stem-like cells (TICs) that are characterized by increased drug resistance. The incidence of many cancer types have trended downward except for few cancer types, including hepatocellular carcinoma (HCC). Therefore mechanism of HCC development and therapy resistance needs to be understood. These multiple hits by hepatitis C virus (HCV) eventually promotes transformation and TIC genesis, leading to HCC development. This review article describes links between HCV-associated HCC and TICs. This review discusses 1) how HCV promotes genesis of TICs and HCC development; 2) how this process avails itself as a novel therapeutic target for HCC treatment; and 3) ten hall marks of TIC oncogenesis and HCC development as targets for novel therapeutic modalities. Hepatitis B and C virus (HBV/HCV) infection, alcoholism and obesity are major risk factors for hepatocellular carcinoma (HCC) . Among aTreatment options for HCC are limited and not encouraging. The 3-years survival rate of HCC is 13%\u201321% without any curative treatment . The 5-yChronic liver damage caused by viral infection and environmental factors  can result in increased risk for HCC. The cirrhotic liver is a permissive factor for HCC due to the large regenerative activity repetitive damage-regeneration cycles or formation of dysplastic nodules . Thus, tHCV-associated cirrhosis can result in HCC by ultimately promoting tumor-initiating stem-like cells (TIC) formation since deposition of extracellular matrix (ECM), including collagen and laminin, promotes tumor-prone microenvironment. These TICs can develop into several different types of liver cancer, e.g., HCC and cholangiocarcinoma (CC). TICs are resistant to conventional chemotherapy and immunotherapy and persist as recurrent tumors or circulating tumor cells. TICs share key features with embryonic stem cells (ESCs) present in preimplantation blastocyst stage embryos, including the expression of a core pluripotency-associated transcription factor (TF) network . Liver pTen hallmarks of cancer  are trigThe following text enumerates HCV connections to a series of cellular \u201cCancer Hallmarsks.\u201d This is important since multiple hits transforms hepatocytes to TIC and HCC. Understanding links between cancer hallmarks and TIC genesis makes conceptual advances to help advance cancer research and therapy by clarifying novel targeting therapy and innovative strategy to suppress theHCC recurrence problems and metastatic spread of HCC cells.Defects in DNA repair genes cause genetic instability, gross chromosomal rearrangements and accumulation of mutations, leading ultimately to neoplastic transformation. Both homologous recombination and nonhomologous end joining (NHEJ) play a role in the repair of double-strand DNA breaks (DSBs) in mammalian cells . The intAPC, and tandem duplications  of chromosomes include translocation, deletion, or inversion of chromosomes of gene ications . HCCs coications , suggestThe take-away message is that HCV-associated HCCs have frequent chromosomal aberrations. These frequent chromosomal aberrations can be targeted and translated into therapies. The status of current related therapeutic strategies is under development. HCV-associated HCCs have frequent MYC loci amplification. These constitutive MYC activation can be targeted and translated into therapies.TP53, CTNNB1, and chromatin modulators, including ARID1A and ARID2, are the most frequently mutated coding genes in HCC  (8%\u201338%), \u03b2-Catenin/Wnt (activating mutations in exon 3 of CTNNB1), and TP53 (30%\u201365%). CTNNB1 point mutations occurred in serine residues  and through the destruction complex (GSK3\u03b2 and CSNK1A1). The more frequent mutations in non-coding regions are found in the TERT promoter and TFPI2. Long intergenic noncoding RNAs, including NEAT1 and MALAT1, are also frequently mutated   induce oxidative stress. ROS-associated oxidative DNA damage (such as 8-oxo-dG) promotes DNA mutagenesis, leading to oncogenic transformation in chronic hepatitis C . For exain vitro  and in v . Individf STAT3) . Activatf STAT3) , leadingf STAT3) . The expf STAT3) .The take-away message is that HCV-associated ROS production promotes DNA damages and inhibits DNA repair, leading to mutator phenotypes. These HCV-associated mutaor phenotype can be targeted by vitamin treatment. However current clinical reports are not optimistic for HCC patients.An HCV-induced oxidative environment may overwhelm cellular antioxidant and DNA-repair mchanisms, leading to accumulation of DSBs and chromosomal abnormalities in HCV-infected cells. As discussed above, HCV infection induces a mutator phenotype by causing DSBs  through DNA repair proteins prevent DNA mutations caused by oxidative damage, but are vulnerable to nitric oxide (NO)-induced oxidative damage. This is because of sulfhydryl, tyrosyl, and/or phenolic side chains in their active sites  is used in HCC patients to inhibit angiogenesis-inducing cytokine VEGF and the MAP Kinase, Raf/Mek/Erk pathways. Rapamycin is also used to inhibit the PI3K/Akt/mTOR pathway . ConstitThe take-away message is that angiogenesis is one of the most effective targets for HCC treatment since multi-kinase inhibitors Sorafenib and Rigorafenib are two FDA-approved chemotherapeutic drugs for HCC treatment after multinational, randomized, placebo-controlled, phase III Sorafenib HCC Assessment Randomized Protocol (SHARP) trial . In HCC + cytotoxic T lymphocytes (CTL)   clears Hes (CTL) , leading+ T, dendritic cells, macrophages and B cells (Although mixed lymphocyte infiltration (T lymphocytes and NK cells) occurs in HCC tissues of patients , these i B cells , indicatNonetheless infected hepatocytes do activate innate immunity by sensing HCV RNA motifs through RIG-I and TLR3. This leads to activation of the NF-\u03baB pathway and generation of interferons and other pro-inflammatory cytokines. Furthermore the viral polymerase NS5B directly activates the inflammatory cascade through NF-\u03baB in a MAVS and TBK-1 dependent manner, resulting in secretion of IL-6 and type I IFN .ex vivo activate donor immune cells against the patient\u2019s TICs , which in turn activate toll-like receptors (TLRs) . TLR actvia activation of fatty acid oxidation and inhibition of oxidative phosphorylation (OXPHOS) (The TLR4-NANOG axis promotes metabolic reprogramming in hepatocytes (OXPHOS) . Liver TTherefore, metabolic inhibitors and/or stemness inhibitors may prevent HCC self-renewal ability to kill HCC cells. Specific metabolic pathways may be novel therapeutic targets in order to selectively kill HCC cancer cells.Chronic immune-mediated inflammation leads to repeated hepatocyte destruction and regeneration. As a consequence, these events lead to fibrogenic wound-healing responses which drive HCC or CC in chronic hepatitis C cases , 2. The Host pathogen-associated molecular pattern (PAMP) receptors sense double-stranded viral RNA replication intermediates to activate IFN Regulatory Factors IRF3/7 and NF-\u03baB, leading to the induction of IFNs and related IFN-stimulated genes (ISGs). Persistent HCV infection induces ISG  althoughDirect-acting antiviral agents might promote tumour occurrence in patients with cirrhosis, or recurrence in patients with presumed cure of hepatocellular carcinoma while DAA significantly reduces viral load. In view of the potential clinical implications, this controversy calls for a thorough and expeditious consideration of the hypothetical oncogenic activity of novel HCV drugs .Due to the \u201cnew\u201d antiviral drugs available for HCV treatment, the incidence of HCC has changed. However, some patients who achieved sustained viral response develop HCC.Mouse hepatocytes that express HCV-NS5A in liver upregulate the expression of Toll-like receptor 4 (TLR4) and develop liver tumors containing NANOG positive, tumor-initiating stem-like cells (TICs). The TLR signaling pathway is often upregulated in chronic liver diseases, especially since many different liver cell types express TLRs . HepatocNanog is one of the core transcription factors found in pluripotent embryonic stem cells (ESCs) . It is eNanog expression alone is not as effective as TLR4 activation in liver tumorigenesis, as shown by our cell transplantation experiments . TLR4 acThe take-away message is that TLR4-NANOG pathway is novel therapeutic targets.The status of current related therapeutic strategies is under development.Epithelial-mesenchymal transition promotes cell migration and invasion, ultimately leading to metastasis. This transition also occurs in development of HCC. As discussed earlier, the combined effect of TLR4-NANOG signaling promotes the development of TICs and tumorigenesis in transgenic mice expressing NS5A. These mice, when placed on a Western diet high in cholesterol and saturated fat (HCFD) activate the TLR4-NANOG axis in combination with the leptin receptor (OB-R)-pSTAT3 signaling pathways. The net resul is the occurrence of liver tumorigenesis through an exaggerated mesenchymal phenotype with prominent Twist1-expressing TICs .Therefore, TWIST1 targetting therapy may prevent HCC cell spread into distal organs. Preventing metastasis spread would be effective strategy to keep HCC in primary organ site.Epigenetics is stable alterations in gene expression without genetic modifications in the sequence . Epigenevia regulation of gene expression. LncRNAs expression  are increased in HCV-related HCCs compared to non-cancerous tissues (dysplasia) while lncRNA AF070632 is decreased in advanced HCC samples compared with early HCC. These lncRNAs are associated with Child-Pugh score. LINC01419 and AK021443 were mostly involved in cell cycle progression, whereas AF070632 regulates cofactor binding, oxidation-reduction and carboxylic acid catabolic process (Non-coding RNAs [LncRNA and microRNA (miRNA)] are dysregulated in HCV-induced liver carcinogenesis  process . Two lnc process . Some of process .LncRNA and miRNAs have been associated with HCC . Due to miRNA targets hundred mRNAs, miRs are diagnostic markers and therapeutic target for personalized therapy. miRNAs are differentially expressed in liver cancer and are related to different stages of liver carcinogenesis, supporting the diagnosis and prognosis tools of miRNAs in HCC patient. miRNAs promote or inhibits carcinogenesis via activation of oncogenes and/or suppression of tumor suppressors . HCV reqmiR-21, miR-17, miR-222, miR-224, and miR-221 are increased in liver cancer  Ladeiro while miDown-regulation of miR-199a/b is associated with poor prognosis and low survival rate . IncreasInduction of HCV proteins or the infection of HCC cells with HCV cell culture (HCVcc) suppresses histone H4 methylation/acetylation and histone H2AX phosphorylation for HCC development, indicating that HCV-induced overexpression of PP2Ac are associated with HCC via deregulation of epigenetic histone modifications . HCV infHCV caused epigenetic alteration mainly occurred on DNA repair-related genes. Induction of HCV proteins or the infection of HCC cells with HCVcc inhibits histone H4 methylation/acetylation and histone H2AX phosphorylation and inhibited DNA damage repair, indicating that HCV-induced overexpression of PP2Ac promotes hepatocarcinogenesis via dysregulation of epigenetic histone modifications .HCV infection accelerates or inhibits the methylation process. DNA methyltransferases (DNMTs) methylates DNA. HCV upregulates DNA methyl transferases, which further block tumor suppressor genes leading to HCC . HCV cor\u2022 DNA hypermethylation\u25cb CDH1: Cell adhesion and metastasis\u25cb RASSF1A: Cell cycle dysregulation\u25cb P21WAF1/CIP1: Cell cycle dysregulation\u25cb Gadd45: Response to genotoxic stress\u25cb MGMT: Dysfunction of DNA repair\u25cb APC: Cell cycle dysregulation/Dysfunction of DNA repair\u2022 DNA hypomethylation (demethylation)\u25cb STAT1: Upregulation of JAK/STAT pro-tumorigenic signaling\u25cb COX-2: Inflammation\u2022 Histone modification\u25cb PP2Ac: InflammationEpigenetic event Contribution in HCC development.The adenomatous polyposis coli (APC) tumor suppressor gene encodes a large protein with multiple cellular functions and interactions, including signal transduction in the WNT-signaling pathway . The APCThe take-away message is that epigenetic regulation promotes envation, migration and metastatic characteristics thorugh aberrant expression of non-coding RNA, histone modification and DNA methylation. These aberrant epigenetic regulation can be targeted and translated into therapies. Indeed, miR-122 restoration strategy is being tested in clinical trials. The status of current related therapeutic strategies includes new miR and/or ncRNA targeted therapies.in vitro  1 (negative regulator of the JAK/STAT pathway). Expression of SOCS1 leads to reduced JAK /STAT phosphorylation, reduced STAT dimerization and imports to the nucleus and reduced transcription of target genes . JAK/STA+, Thy-1+  cells, not CD133(\u2212)cells, had the ability to self-renew, create differentiated progenies, and form tumors , and plasticity. Hepatic small oval progenitor cells around the peripheral branches of the bile ducts, the canals of Hering, differentiates into biliary epithelial cells and hepatocytes . These o, Thy-1+ . A CD117, Thy-1+  while a , Thy-1+ . The CD9m tumors .Forty percent of HCC have clonality, and thus are considered to originate from progenitor/stem cells . TICs exDysregulated signaling and gene expression promotes the plasticity of TICs to resist current FDA-approved therapies, such as sorafenib or regorafenib or anti-PD1 immune checkpoint inhibitor treatment. TICs of HCC are observed to have several elevated oncogenic and anti-apoptotic signaling pathways such as PI3K/AKT , signal ABCB1, and the half-transporter ABCG2 identified in mitoxantrone-resistant cells  transporters, such as nt cells . Cancer nt cells . The drunt cells . The takChronic liver inflammation causes liver injury with compensatory hepatocellular proliferation which indirectly promotes HCC. Regenerative pathways promote dedifferentiation and proliferation to replace damaged tissue in inflammatory liver disease and hepatocellular necrosis associated with chronic hepatitis C infection.For example, the Wnt/\u03b2-catenin pathway is directly altered by HCV. Initially, NS5A promotes \u03b2-catenin stabilization through inactivation of GSK3-\u03b2, which normally promotes \u03b2-catenin degradation . AddiotiCells within such a precancerous field contain mutations that predispose progression to a cancerous phenotype. What is the impact of chronic hepatocyte turnover on tumorigenesis? Perhaps apoptosis of infected hepatocytes,either by immune- or virus-mediated mechanisms with compensatory hepatocellular proliferation, promotes carcinogenesis during decades of chronic HCV infection.\u03baB cell signaling pathways and causes p53 and pRb inactivation to initiate genomic instability and uncontrollable cellular proliferations  have limitationsbecause eventual treatment failures leads to cancer metastasis. Future investigative projects need to address the specific treatment needs of patients with HCC. Current FDA-approved immunotherapy, such as anti-PD-1 or anti-CTLA4 therapy has a limited efficacy for a small fraction of HCC patients (10%\u201325% range undergoing monotherapy). The remaining HCC patients did not respond to this monotherapy, indicating that an immune-checkpoint inhibitor approach has a limited efficacy and other immune mechanisms may be needed to have synergism with tumor-killing cells, such as antigen presenting cells, including dendritic cells and B cells. However inclusion of immune checkpoint inhibitors with combination therapy may break immune tolerance and improve the therapeutic efficacy of this approach.Simply extending patient life spans by several months is not suffiecient. The goal should be to expand the completely cured patient population. This is the biggest challenge of researchers to transform a \u201cpreviously \u201cincurable\u201d malignancy into a curable illness. Discovery of new immune checkpoint inhibitors and incorporation into combination therapies may be a new therapeutic avenue to drastically improve HCC treatment. HCC should not be a death sentence and may become a curable malignancy providing foundational research findings can be translated into game-changing innovative treatments (Refer to the outstanding questions box).Finally, personalized medicine approaches will stratify the HCC patient population into distinct subpopulations that may be responsive to HCC-type specific treatments. As presented in this review, there are several avenues of liver morbidities leading to HCC. Thus, treatment options may likely reflect the original triggering event leading to HCC."}
+{"text": "Examine if the gut microbiota composition changes across repeated samples inpaediatric-onset multiple sclerosis (MS) or monophasic-acquireddemyelinating syndromes (monoADS).A total of 36 individuals (18 MS/18 monoADS) with \u2a7e2 stool samples wereincluded. Stool sample-derived DNA was sequenced. Alpha/beta diversities andgenus-level taxa were analysed.p\u2009>\u20090.09), while one genus \u2013Solobacterium did (p\u2009=\u20090.001).Mean ages at first sample procurement (MS/monoADS)\u2009=\u200918.0/13.8\u2009years. Mediantime (months) between first/second samples\u2009=\u200911.2 and second/third\u2009=\u200910.3.Alpha/beta diversities did not differ between stool samples(The gut microbiota composition in paediatric-onset MS and monoADS exhibitedstability, suggesting that single stool sample procurement is a reasonablefirst approach. Little is known about whether this is sufficient.Many gut microbiota-related studies in multiple sclerosis (MS) have typically reliedon procuring a single sample from participants. We assessed if the gut microbiota composition remained stable across repeatedstool samples (\u2a7e2) procured over the short-term in individuals with paediatric-onsetMS and monophasic-acquired demyelinating-syndromes (monoADS).Individuals with paediatric-onset MS and related diseases represent uniqueopportunities to explore the gut microbiota early on in the disease process, such asthe recently demonstrated relationship between the gut microbiome (usingmetagenomics) and disease activity.Supplementary Data (Methods) for details. Included individuals wereenrolled from six sites across Canada and one in the United States(November/2015-March/2018).Individuals with symptom onset <18\u2009years and no antibiotic use \u2a7d30\u2009days prior,diagnosed with MS  or monoADS who provided \u2a7e2 stool sampleswere eligible. See Cohort characteristics were captured by trained coordinators using standardized formsand questionnaires were completed at home by parents/participants.oC, then DNA wasextracted, amplified and sequenced , and clustered into amplicon sequence variants (ASVs) usingDeblur via QIIME2 . The gut microbiota\u2019s composition was assessed using alpha (Shannon) and beta(unweighted UniFrac) diversity metrics.Stool samples were shipped on ice, stored at \u221280 The top five genera were analysed for variability between stool samples usinglinear mixed effects models with sample number  as theresponse variable, including a participant-specific random intercept, adjusted forage at stool sample, sex and diagnosis (MS/monoADS). Longitudinal similarity of all samples was compared between MS/monoADSparticipants using the non-parametric microbial interdependence test (NMIT). Complementary analyses (MS cases only) explored whether any change indisease-modifying therapy (DMT) use associated with microbiome changes . QIIME2 v2020.11, R v4.0.1 and SPSS v23.0 were used foranalyses.6 Informedconsent/assent and ethics were obtained (Supplementary file).Characteristics of the MS and monoADS participants were described. Alpha diversitywas compared between the first and second stool samples using the pairwise Wilcoxonsigned-rank test and between all three samples using the Friedman test. UnweightedUniFrac was displayed using the first two components from principal coordinates (PC)analysis and confidence ellipsoids. Permutational multivariate analysis of variance(PERMANOVA) was used to compare between stool samples. Phylum-level relativeabundances were summarized. The most important genus-level taxa were identifiedusing feature volatility analysis.p\u2009>\u20090.05; second/third sample-relatedcharacteristics not shown). Alpha and beta-diversity did not differ significantlybetween samples for the entire cohort or MS cases alone . The most abundant phyla were the Firmicutesand Bacteroidetes, followed by Actinobacteria,Proteobacteria, Verrucomicrobia and Lentisphaerae. From the feature volatility analyses andlinear mixed models, the only genus that changed (increased) significantly over timewas Solobacterium (adjusted p\u2009=\u20090.001).Genus-level NMIT results indicated that longitudinally, the MS and monoADSparticipants\u2019 gut microbial composition did not differ statistically from each other. Alpha diversity did not differsignificantly among the four MS participants who stopped/started/switched DMTbetween their first/second stool samples .A total of 36 individuals provided 77 stool samples  over a 26-month period. The median time (months) between thefirst/second sample\u2009=\u200911.2 (range\u2009=\u20092.0\u201325.0) and second/third\u2009=\u200910.3(range\u2009=\u20091.8\u201313.6). Participant characteristics, including the Bristol stool scale,body mass index (BMI) and diet, did not differ significantly between timepoints did not differ between theindividuals with MS compared with those with monoADS. We can infer that, at least inthe short-term, the gut microbiota composition in paediatric-onset MS and monoADSparticipants was relatively stable.Solobacterium. This genus belongs to theClostridium cluster XVI, which has been associated withMS.7Solobacterium moorei, the only species identified in theSolobacterium genus, in concert with other microbes, has beenimplicated as a potential driver of a proinflammatory gut microenvironment.We also examined the five most important genera, as selected by feature analysis, andfound that the only genus that changed (increased) significantly over time wasWe were unable to find another published study that examined whether the gutmicrobiota is stable or fluctuates over time in a paediatric-onset MS or monoADSpopulation. One study did report (primarily descriptively) stability in the gutmicrobiota in 102 adult participants with/without various immune-mediated diseases(19 had MS), at least across 2 samples procured over 2\u2009months. A second study spanned 68\u2009months, with 2\u201313 stool samples procured from 37participants; authors reported overall stability with >70% strain similaritybetween samples.Others have also reported relative stability of the gut microbiota over time inhealthy adults. The first study procured up to 4 stool samples from 9 participantsover 3\u2009months; authors reported minimal within-person variability in gut microbiota composition.To the best of our knowledge, our study is the first to explore the stability of thegut microbiota in paediatric MS and related demyelinating diseases. Paediatric-onsetMS remains relatively rare such that our sample size was modest, and we had accessto a limited number of samples per participant. It would be of value for futurestudies to assess larger cohorts of individuals, with more samples collected atdifferent time intervals and over longer periods of time. Trends observed in ourstudy could potentially become significant in larger studies.Nonetheless, our study findings are reassuring and help inform the design andanalyses of future gut microbiota studies in MS and monoADS. Particularly whenresources are finite and participant burden is prohibitive, our findings providepreliminary evidence to suggest that analysis of single samples from participants isa reasonable approach.Click here for additional data file.Supplemental material, sj-docx-1-msj-10.1177_13524585221079533 for Stability ofthe gut microbiota in persons with paediatric-onset multiple sclerosis andrelated demyelinating diseases by Geoffrey Liang, Feng Zhu, Ali I Mirza, AmitBar-Or, Charles N Bernstein, Christine Bonner, Jessica D Forbes, Morag Graham,Janace Hart, Natalie C Knox, Ruth Ann Marrie, Julia O\u2019Mahony, Gary VanDomselaar, E Ann Yeh, Yinshan Zhao, Brenda Banwell, Emmanuelle Waubant and HelenTremlett in Multiple Sclerosis Journal"}
+{"text": "In the version of this article initially published, there were errors resulting from merged authors\u2019 names. The following sentences highlight the errors and the corrected details:1, ABOH Mercy Itohan2 SALAWU Oluwakayinsola Adeola, KOLA-MUSTAPHA Adeola4 , OLATUNJI Lawrence Aderemi5KATIBI Oludolapo Sherifat."}
+{"text": "Trichoderma harzianum MF780864 into Trichoderma harzianum MZ 066609.Please correct the accession number of 1.In Title of article:This corrigendum presents in text at the following parts:From:Trichoderma harzianum MF780864 as water lead adsorbent for immune status of Nile tilapia (Oreochromis niloticus)Assessment the using of silica nanoparticles (SiO2NPs) biosynthesized from rice husks by Into:Trichoderma harzianum MZ066609 as water lead adsorbent for immune status of Nile tilapia (Oreochromis niloticus)2.Abstract, Line 2:Assessment the using of silica nanoparticles (SiO2NPs) biosynthesized from rice husks by From:Trichoderma harzianum MF780864 (T. harzianum) was isolated and identified based on the Internal Transcribed Spacers (ITS) sequences;An isolate of Into:Trichoderma harzianum MZ066609 (T. harzianum) was isolated and identified based on the Internal Transcribed Spacers (ITS) sequences;3.In the title of Figure no (1):An isolate of From:Trichoderma harzianum. MF780864).Fig. 1. Phylogenetic tree based on ITS sequences of 18S-28S rRNA of the fungal strain (sample _1 Into:Trichoderma harzianum. MZ066609).4.Result section, subsection (3.1) Line (24) Page (5122)Fig. 1. Phylogenetic tree based on ITS sequences of 18S-28S rRNA of the fungal strain (sample _1 From:Trichoderma harzianum was designed as FM-Trichoderma harzianum MF780864.Hence, the isolate of Into:Trichoderma harzianum was designed as FM-Trichoderma harzianum MZ066609.Hence, the isolate of The author would like to apologize for any inconvenience caused."}
+{"text": "Animal models of DYT-TOR1A dystonia consistently demonstrate abnormalities of striatal cholinergic function, but the molecular pathways underlying this pathophysiology are unclear. To probe these molecular pathways in a genetic model of DYT-TOR1A, we performed laser microdissection in juvenile mice to isolate striatal cholinergic interneurons and non-cholinergic striatal tissue largely comprising spiny projection neurons during maturation. Both cholinergic and GABAergic enriched samples demonstrated a defined set of gene expression changes consistent with a role of torsinA in the secretory pathway. GABAergic enriched striatum samples also showed alteration to genes regulating synaptic transmission and an upregulation of activity dependent immediate early genes. Reconstruction of Golgi-Cox stained striatal spiny projection neurons from adult mice demonstrated significantly increased spiny density, suggesting that torsinA null striatal neurons have increased excitability during striatal maturation and long lasting increases in afferent input. These findings are consistent with a developmental role for torsinA in the secretory pathway and link torsinA loss of function with functional and structural changes of striatal cholinergic and GABAergic neurons. These transcriptomic datasets are freely available as a resource for future studies of torsinA loss of function-mediated striatal dysfunction. Tor1a encoded protein torsinA are essential during a developmental critical period but dispensable in adult animals (Tor1a deletion or Tor1a\u0394E knock-in disrupts nuclear envelope structure (DYT-TOR1A (DYT1) is a dominantly inherited dystonia characterized by early onset involuntary abnormal movements and postures . TorsinA animals . Severaltructure , 16 and tructure , 18 duritructure . TorsinAtructure -26 and atructure -30, all tructure -34. The Tor1a\u0394E/+ disease mutation exhibit premature long term potentiation, impaired long term depression, and increased AMPA receptor abundance in corticostriatal synapses during early striatal development  isolated using laser microdissection. Striatal cholinergic and non-cholinergic enriched samples from control vs. Dlx-CKO identified a core set of genes enriched in secretory pathway and synaptic function. We further demonstrate abnormal synaptic structure in Dlx-CKO striatum with Golgi-Cox staining of spiny projection neurons. This study identifies a role for torsinA within the secretory pathway and implicates abnormal synaptic structure in the torsinA deficient striatum.Flx/+) and Dlx-CKO  mice expressing ChAT(BAC)-eGFP (JAX strain 007902) were generated as previously described  was laser microdissected and lysed in buffer RLT with 1% \u03b2-mercaptoethanol (Qiagen). Total RNA was isolated using a RNeasy-micro kit (Qiagen) and eluted in RNase-free water. RNA quantity and integrity was assessed using an Agilent Bioanalyzer and samples with RIN between 7.6\u20139.3 were used for RNA sequencing. Samples were derived from the following number of animals: Chi soma n = 6 control and n = 6 Dlx-CKO; Striatum: n = 4 control and n = 5 Dlx-CKO.Brains were harvested at postnatal day 14 (P14) and snap frozen in dry ice-chilled isopentane. 16 \u03bcm fresh frozen brain sections were generated with a cryostat, mounted on PET membrane slides, and dehydrated in ethanol and xylenes. Laser microdissection was performed using the \u00d720 objective of a Leica LMD7 microscope. ChAT-eGFP+ cell bodies (341\u2013524 GFP+ somas per brain) or GFP-negative striatal tissue (1\u20131.5 million \u03bcmRNA-seq was performed using the HiSeq2500 (Illumina) platform in the University of Michigan Sequencing Core. RNA-seq libraries were generated using SmartSeq4 (Clontech). Libraries were quantified and normalized using an Agilent Bioanalyzer and sequenced using the HiSeq2500 High-Output SBS V4 single-end 50 cycle kit. The quality of the raw reads data was checked using FastQC (version 0.11.3). Low quality bases from individual reads were trimmed using CutAdapt. Tuxedo Suite software package was used for alignment, differential expression analysis, and post-analysis diagnostics -46. We ahttp://geneontology.org/docs/go-enrichment-analysis/ and DAVID https://david.ncifcrf.gov/home.jsp.Differentially expressed genes identified from RNAseq were further analyzed for the identification of biologically enriched pathways by gene ontology (GO) enrichment analyses using the following web based applications: GENEONTLOGY Flx/+) and Dlx-CKO  mice were harvested fresh and immediately processed using the FD Rapid Golgi stain kit (FD Neurotechnologies) as per manufacturer\u2019s instructions and as described previously  were performed using Graphpad Prism (Version 9.3.1).Tor1aFlx/+) and Dlx-CKO  ChI soma (n = 6 control and n = 6 Dlx-CKO) and non-cholinergic striatum (n = 4 control and n = 5 Dlx-CKO) samples and performed RNA-seq analyses  and non-cholinergic cells during development, we performed laser microdissection of dorsolateral striatal Chi somas or surrounding non-cholinergic striatum containing spiny projection neuron cell bodies, interneurons, glia, and neural processes . We purianalyses . ChI somanalyses . Within es  analysis of ng DAVID  identifing DAVID . An annong DAVID , B. Mostng DAVID . Striatung DAVID , E, and ng DAVID .geneontology.org)  , 52 idenogy.org) . An annoogy.org) . Of the egulated . This cl53 = 0.6718, p = 0.5046; rd order dendritic branches was significantly increased in Dlx-CKO brains compared to control , Arc (2 fold), Egr4 (1.8 fold), Nr4a1 (1.8 fold), Npas4 (2.5 fold), Npas2 (2.2 fold), and Ctgf (1.85 fold). In ChI samples, Fos was significantly upregulated (1.6 fold), suggesting that ChI activity may also be increased in Dlx-CKO mice.Increased spine density reflects increased excitatory input to spiny projection neurons. Consistent with the potential for increased excitability, activity-dependent immediate early genes were significantly upregulated in Dlx-CKO non-cholinergic striatum samples. At least 7 immediate early genes were upregulated in striatum, including These studies identify a core set of differentially expressed genes in the striatum of torsinA conditional knockout mice during postnatal CNS maturation. Despite the previously reported divergent phenotype between cell types , both CGABAergic striatal neurons  is enriched in spiny projection neurons (Npas4 (upregulated 2.51 fold) is a transcription factor that regulates GABAergic synaptic function  is a member of the DOC2 family of proteins that modulates spontaneous synaptic transmission (Cnih3 (downregulated 1.84 fold in Dlx-CKO) is an AMPA receptor auxiliary subunit that functions in the endoplasmic reticulum and remains associated with the AMPA receptor complex at the synapse  astrocytes, as increased neuronal activity increases expression of glial Gfap . Fate mapping studies demonstrate that Gfap-expressing progenitors give rise to some neurons, including in the striatum  was upregulated in both ChI soma and non-cholinergic striatum samples of Dlx-CKO mice. ChI soma sample ial Gfap . Howeverial Gfap . Neuronsial Gfap , but we e brain  may reflect microtubule disruption or active degeneration of ChI, while its increase in non-cholinergic striatum (6.98 fold increased) could reflect compensatory neurite outgrowth or axon elongation in surviving cells .Table S2SUPPLEMENTARY TABLE S2 Filtered genes removed from analysis.Table S3SUPPLEMENTARY TABLE S3 Cross reference with the COMPARTMENTS database.Table S4SUPPLEMENTARY TABLE S4 Cross reference with the Human Secretome.Table S5SUPPLEMENTARY TABLE S5 Gene ontology analysis using DAVID: over-representation of genes encoding secreted proteins.Table S6SUPPLEMENTARY TABLE S6 Gene ontology analysis using geneontology.org: over-representation of genes encoding proteins regulating synaptic structure and function.Table S7SUPPLEMENTARY TABLE S7 ChI soma raw count data matrix.Table S8SUPPLEMENTARY TABLE S8 Striatum raw count data matrix.Table S9SUPPLEMENTARY TABLE S9 Aligned reads for each sample."}
+{"text": "SAMD9L mutations). Each patient with SAMD9L mutation also carried an AA-related rare BCORL1 variant or CTLA4 p.T17A GG genotype, respectively, and both presented short telomere lengths. Six of the ten patients analyzed harbored AA-risky HLA polymorphisms. All patients recovered upon non-HSCT (n = 4) or HSCT (n = 8) treatments. Six of the eight HSCT-treated patients were subjected to a modified PTCy-based regimen involving freshly prepared peripheral blood stem cells (PBSC) as graft and exclusion of ATG. All patients were engrafted between post-transplantation days +13 and +18 and quickly reverted to normal life, displaying a sustained complete hematologic response and an absence of graft-versus-host disease. These outcomes indicate most AA cases, including of the SAMD9L-inherited subtype, are immune-mediated and the modified PTCy-based regimen we present is efficient and safe for salvage.Most cases of acquired aplastic anemia (AA) arise from autoimmune destruction of hematopoietic stem and progenitor cells. Human leukocyte antigen (HLA)-haploidentical nonmyeloablative hematopoietic stem cell transplantation (HSCT) plus post-transplantation cyclophosphamide (PTCy) is increasingly applied to salvage AA using bone marrow as graft and anti-thymocyte globulin (ATG) in conditioning. Herein, we characterize a cohort of twelve AA patients clinically and molecularly, six who possessed other immunological disorders (including two also carrying germline  Acquired aplastic anemia (AA), defined by persistent peripheral cytopenia accompanied by reduced bone marrow cellularity, can arise from diverse pathophysiological mechanisms, but it is mostly attributable to autoimmune-mediated destruction resulting in a profound deficit of hematopoietic stem and progenitor cells (HSPC) ,2. Most SAMD9L mutation-associated AA subtypes.In this study, we adopt and modify the previously published protocol of haploidentical HSCT that deploys nonmyeloablative conditioning , intensive GVHD prophylaxis ), and that almost exclusively uses bone marrow as a graft source ,16. ThatBetween 2013 and 2021, twelve pediatric patients  with AA diagnosed at 2.5 to 19.5 years of age were transferred to our institute for salvage of various adverse events. Briefly, Cases 1\u20134 had minor symptoms but Cases 5\u201312 continuously experienced life-threatening bleedings and infections with or without iron-overload at transfer. Their clinical characteristics, treatments given before and after transfer, adverse events at transfer after treatments at previous hospitals, and AA outcomes after salvage are summarized in SAMD9L mutation -labeled telomeric probe. Mean TRF values were determined using TeloTool software [Leukocyte telomere length was analyzed by means of terminal restriction fragment assay, as described previously . In briesoftware .The conditioning treatments consisted of intravenous (i.v.) fludarabine (dose determination using a validated pharmacokinetic model ,62 accor"}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-022-20653-2, published online 11 October 2022Correction to: The original version of this Article contained an error in the Author Information section.\u201cThese authors contributed equally: Yuyeon Jung, Taewan Kim, Seungchul Lee and Youn Jin Choi.\u201dnow reads:\u201cThese authors contributed equally: Yuyeon Jung and Taewan Kim. These authors jointly supervised this work: Seungchul Lee and Youn Jin Choi.\u201dThe original Article has been corrected."}
+{"text": "She reported a worsening condition for 5 days with headache, confusion, and dyspnea. Neurological examination showed dysarthria and mild hemihypoesthesia. A polymerase chain reaction test from the nasopharyngeal swab confirmed the diagnosis of coronavirus disease (COVID-19). Chest computed tomography (CT) scan was also highly suggestive of COVID-19. The unenhanced axial and coronal reformatted thorax CT image demonstrates peribronchovascular and subpleural ground-glass opacities and vascular dilatation (arrows) in the bilateral lung . Magneti"}
+{"text": "In trials, hospital walking programs improved functional ability after discharge, but little evidence exists on their effectiveness under routine practice conditions or their implementation across health systems. We conducted a Type III hybrid implementation-effectiveness, stepped-wedge cluster randomized trial (SW-CRT) in 8 Veterans Affairs hospitals examining a hospital-based walking program known as STRIDE. Based on the SW-CRT design, hospitals were randomized to a sequence (timeline) for STRIDE, and additionally randomized 1:1 to receive implementation support according to the Replicating Effective Programs (REP) framework only or REP plus additional team-based communication training known as CONNECT. The study was powered to examine impact of STRIDE on discharge destination to home vs other (primary outcome); hospital length of stay (LOS) was a secondary outcome. Patient-hospitalizations in pre-STRIDE time periods (n=8167) were similar to post-STRIDE time periods (n=9070) . In adjusted models, odds of discharge to home were higher among eligible patients hospitalized in post-STRIDE time periods  compared to pre-STRIDE. Findings were robust to 3 sets of sensitivity analyses. There was no difference in LOS . Hospitals randomized to CONNECT had higher program reach (mean 13% vs 3%) but lower daily fidelity (mean 25.7% vs 37.5%). Despite limited direct program reach, implementation of a hospital walking program was associated with higher odds of discharge to home. Implementation strategies like CONNECT that enhance teamwork and communication may improve patient access to clinical programs being implemented in new settings."}
+{"text": "More effective influenza vaccines are needed to prevent influenza and its complications. Recombinant influenza vaccines may offer better protection than traditional egg-based vaccines. Using a cluster randomized design to estimate the relative vaccine effectiveness (rVE) of Flublok Quadrivalent recombinant influenza vaccine (RIV4) vs. standard dose inactivated influenza vaccine (SD-IIV4), we separately reported that RIV4 provided significantly better protection against primary outcome of confirmed influenza in adults 50\u201364 yrs in the 2018\u201320 moderately severe influenza seasons. Here we report the rVE against the secondary and exploratory outcomes of hospitalized influenza-related outcomes.We randomized 66 facilities within Kaiser Permanente Northern California (KPNC) to routinely administer RIV4 or SD-IIV4 to adults, alternating vaccine formulations weekly by facility during the influenza season . Hospitalized cases of PCR-confirmed influenza, community-acquired pneumonia, and cardio-respiratory events were prespecified as secondary in 50\u201364 yrs and exploratory in 18\u201349 yrs. We estimated the relative hazard ratio (rHR) using Cox regression on a calendar timeline, adjusting for age, sex, and race, using facility-specific stabilized propensity scores. We calculated rVE as (1\u2013rHR) x 100%.During the 2018\u201319 and 2019\u201320 seasons, the study consisted of 1,630,328 vaccinees 18\u201364 yrs , and included 95 hospitalized influenza cases after RIV4 and 153 after SD-IIV4 among 50\u201364 yrs (Table\u00a01). RIV4 vs. SD-IIV4 was not significantly more protective against hospitalized influenza-related outcomes in adults 50\u201364 yrs or 18\u201349 yrs.While this large cluster randomized study found that RIV4 vs. SD-IIV4 reduced the risk of lab-confirmed influenza in adults 50\u201364 yrs across 2 influenza seasons, RIV4 and SD-IIV4 performed similarly against hospitalized influenza-related outcomes. Evaluating influenza-related hospitalizations during influenza seasons when more hospital outcomes occur may help to better understand the relative effectiveness of recombinant versus standard inactivated influenza vaccines against severe disease.All Authors: No reported disclosures."}
+{"text": "Oral vancomycin causes profound changes to the gut microbiome due to high intra-colonic vancomycin concentrations. However, pharmacokinetics of oral vancomycin causing pharmacodynamic changes have not been explored, especially during the early dosing period. The purpose of this study was to investigate fecal vancomycin concentrations in healthy individuals in relation to gut microbiome diversity changes.Healthy subjects 18-45 years with no antibiotic use for at least 28 days were given oral vancomycin 125 mg was given every 6 hours for 10 days. Stool samples were collected at baseline and during antibiotic therapy. Vancomycin concentrations were obtained through high-performance liquid chromatography (HPLC) assay. For this early pharmacokinetics analysis, stool samples from day 0 (baseline) to day 4 were included. Shotgun metagenomics sequencing was used for microbiome analysis. Descriptive analysis was performed to identify gut-microbiome phyla changes in correlation with detectable oral vancomycin fecal concentrations.2) were included. In the early dosing period (day 0-4), the mean fecal vancomycin concentrations increased daily with the highest concentration of 1,586 \u03bcg/g of stool occurring on day 4. Three of 9 subjects (50%) had undetectable oral vancomycin levels one days 1 and 2 of dosing. Within 24-48 hour of detectable vancomycin levels, subject-specific changes of gut microbiome phylum-level proportions were observable. Overall, an increase in Actinobacteria and Proteobacteria phyla and decrease in Firmicute phylum was observed within 24 hours that vancomycin was detected in the feces.A total of 6 healthy volunteers aged 32\u00b15 years (Male: 100%; Caucasian: 50%; mean BMI: 26.8\u00b14.5 kg/mHigh concentrations of vancomycin are achieved in the stool by day four of dosing for all subjects; however, low concentrations are observed early in the dosing period for some subjects. Proportional, subject specific differences in gut microbiome phyla were observed within 24 hours of detectable vancomycin levels in the feces.Kevin W. Garey, PharmD, MS, Acurx Pharmaceuticals: Grant/Research Support|Paratek Pharmaceuticals: Grant/Research Support|Seres Therapeutics: Grant/Research Support|Summit Pharmaceuticals: Grant/Research Support."}
+{"text": "Valganciclovir (VGCV) prophylaxis is commonly utilized to prevent cytomegalovirus (CMV) infection among high (D+/R-) and intermediate (R+) risk kidney transplant recipients (KTRs). Due to the myelosuppressive effects of VGCV, KTRs may be at an increased risk of opportunistic infections (OIs) resulting in interruptions to VGCV therapy. Therefore, we aimed to quantify the clinical burden of neutropenia among adult KTRs receiving VGCV prophylaxis.A retrospective cohort design was utilized to identify adult KTRs who received VGCV prophylaxis using the IBM MarketScan Commercial and Medicare Supplemental claims databases. First-time KTRs between 1/1/2012 - 12/31/2018 with 1 year of continuous pharmacy and medical coverage before (baseline period) and after (follow-up period) were included. KTRs with a History of other solid organ transplantation were excluded. Fills of \u2265 1 prescription of VGCV (either 450 mg or 900 mg/day) within 30 days of the kidney transplant (KT). Neutropenia events were identified as either \u2265 1 inpatient, or \u2265 2 outpatient ICD-9/ICD-10 diagnoses codes within 14 days.>15 days) were more common in KTRs with neutropenia (P< 0.001).Of the 4,965 adults KTRs with baseline and follow-up enrollment, 3,258 (66%) used VGCV prophylaxis. 311/3256 (9.5%) developed neutropenia within 1-year post KT. Baseline characteristics were similar between those with and without neutropenia (table 1). The majority received the following pre-transplant immunosuppression: tacrolimus (78.9%), mycophenolate mofetil (62.8%) and steroids . KTRs with neutropenia had a nearly two-fold increase in the development of CMV infection compared to those without neutropenia. In addition, KTRs with neutropenia had significantly higher rate of bacterial or fungal infections compared to those without neutropenia (Table\u00a02). Interruptions in VGCV prophylaxis (gap Our findings showed that neutropenia was associated viral, bacterial, and fungal OIs among adults KT receiving VGCV prophylaxis. The findings highlight the needs for interventions to reduce neutropenia and its associated OIs. These results suggest that clinical management steps to reduce rates of neutropenia among KT recipients may warrant further study.Vladimir Turzhitsky, PhD, Merck & Co., Inc.,: Employee|Merck & Co., Inc.,: Stocks/Bonds Amit D. Raval, PhD, Merck and Co., Inc.: Employee of Merck|Merck and Co., Inc.: Stocks/Bonds Pamela Moise, PharmD, Merck & Co., Inc: Employee & Shareholder Sanjay Merchant, PhD, Merck & Co., Inc.: Stocks/Bonds."}
+{"text": "Combined basilar subsegmentectomy via uniportal video-assisted thoracoscopic surgery is an extremely complex surgery. Moreover, no the existing reports describe the procedure and technique. Here, we present the technique of combined basilar subsegmentectomy that was successfully performed via uniportal video-assisted thoracoscopic surgery to treat intralobar pulmonary sequestration in an adult patient.A 57-year-old man underwent surgery for oropharyngeal carcinoma. Preoperative computed tomography showed several cystic lesions in the right lower lobe. Subsequent enhanced computed tomography revealed an anomalous artery branching from the abdominal aorta and a normal pulmonary vein. The patient with diagnosed with Pryce type III intralobar pulmonary sequestration and underwent right S7 posterior\u2009+\u200910bc combined basilar segmentectomy via uniportal video-assisted thoracoscopic surgery. The postoperative course was uneventful, and the patient was discharged 4\u00a0days after surgery. At the 8-month follow-up, computed tomography showed no abnormalities.We successfully performed combined basilar subsegmentectomy via uniportal video-assisted thoracoscopic surgery. This surgical approach is useful for the treatment of intralobar pulmonary sequestration occurring at the basal segment of the lung.The online version contains supplementary material available at 10.1186/s40792-023-01600-3. Intralobar pulmonary sequestration (ILPS) is characterized by a nonfunctional lung segment within the normal pulmonary parenchyma, which is supplied by an anomalous systemic artery . The defA 57-year-old man underwent surgery for oropharyngeal carcinoma. Preoperative computed tomography (CT) revealed several cystic lesions in the right lower lung lobe Fig.\u00a0A with coWe made 4-cm utility incision along the midaxillary line in the sixth intercostal space. After adhesiolysis, an anomalous artery from the abdominal aorta in the lung ligament was ligated and divided. We dissected the lung parenchyma to expose V7. Subsequently, the plane between S7 anterior and S7 posterior was opened using a stapler along the V7 . The B7 posterior was identified beside the inferior basal pulmonary vein and was clipped and divided. Subsequently, the A7 posterior was identified and divided using a vessel-sealing system without proximal ligation. We meticulously dissected the pulmonary parenchyma along the inferior basal pulmonary vein, with the B10bc identified distally and divided using a stapler. After dividing these hilum structures, the pulmonary parenchyma was divided using the stapler. Thereafter, S7 posterior\u2009+\u200910bc combined basilar subsegmentectomy was performed  for intralobar sequestration via uniportal video-assisted thoracoscopic surgery."}
+{"text": "Background: Identification of hospitalized patients with enteric multidrug-resistant organism (MDRO) carriage, combined with implementation of targeted infection control interventions, may help reduce MDRO transmission. However, the optimal surveillance approach has not been defined. We sought to determine whether daily serial rectal surveillance for MDROs detects more incident cases (acquisition) of MDRO colonization in medical intensive care unit (MICU) patients than admission and discharge surveillance alone. Methods: Prospective longitudinal observational single-center study from January 11, 2017, to January 11, 2018. Inclusion criteria were \u22653 consecutive MICU days and \u22652 rectal or stool swabs per MICU admission. Daily rectal or stool swabs were collected from patients and cultured for MDROs, including vancomycin-resistant Enterococcus (VRE), carbapenem-resistant Enterobacterales (CRE), third-generation cephalosporin-resistant Enterobacterales (3GCR), and extended-spectrum \u03b2-lactamase\u2013producing Enterobacterales (ESBL-E) (as a subset of 3GCR). MDRO detection at any time during the MICU stay was used to calculate prevalent colonization. Incident colonization (acquisition) was defined as new detection of an MDRO after at least 1 prior negative swab. We then determined the proportion of prevalent and incident cases detected by daily testing that were also detected when only first swabs (admission) and last swabs (discharge) were tested. Data were analyzed using SAS version 9.4 software. Results: In total, 939 MICU stays of 842 patients were analyzed. Patient characteristics were median age 64 years , median MICU length of stay 5 days , median number of samples per admission 3 , and median Charlson index 4 . Prevalent colonization with any MDRO was detected by daily swabbing in 401 stays (42.7%). Compared to daily serial swabbing, an admission- and discharge-only approach detected \u226586% of MDRO cases . Detection of incident MDRO colonization by an admission- or discharge-only approach would have detected fewer cases than daily swabbing (Figure Conclusions: Testing patients upon admission and discharge to an MICU may fail to detect MDRO acquisition in more than one-third of patients, thereby reducing the effectiveness of MDRO control programs that are targeted against known MDRO carriers. The poor performance of a single discharge swab may be due to intermittent or low-level MDRO shedding, inadequate sampling, or transient MDRO colonization. Additional research is needed to determine the optimal surveillance approach of enteric MDRO carriage.Funding: NoDisclosures: None"}
+{"text": "Enterobacterales are a significant cause of bloodstream infections (BSI) in hospitalized patients. Prior evidence suggests that treatment with piperacillin/tazobactam may not be ideal for BSI. Piperacillin/tazobactam clinical breakpoints were recently updated by the Clinical and Laboratory Standards Institute (CLSI).We retrospectively evaluated Enterobacterales blood isolates identified by MALDI-TOF  between January 1, 2017 through December 31, 2021 at Rush University Medical Center in Chicago, Illinois. Antimicrobial susceptibility testing was performed using NM43 or NM56 panels on the MicroScan WalkAway 96 (Beckman Coulter). The range of dilutions of piperacillin/tazobactam included on both panels was 8/4 to 64/4 \u03bcg/mL. Minimal inhibitory concentrations (MIC) were interpreted using current CLSI breakpoints.Escherichia coli [n=806 (50%)] and Klebsiella pneumoniae [n=358 (22%)]. The majority of isolates (90.4%) were susceptible; 28 (1.8%) isolates were susceptible-dose dependent and 125 (7.8%) were resistant to piperacillin/tazobactam using the new CLSI breakpoints (Table). 236 isolates had a multidrug-resistant phenotype, of which 216 (92%) were confirmed as an ESBL. Among ESBL-producing isolates, the majority (81%) were susceptible [MIC \u2264 8 \u00b5g/mL) to piperacillin/tazobactam. Isolates with confirmed carbapenemase production had off-scale MICs ( > 64 \u00b5g/mL) .We evaluated 1597 Enterobacterales isolates. Most isolates identified were Piperacillin/Tazobactam Breakpoint Revision TableOverall changes in piperacillin/tazobactam interpretations using revised breakpoints.MDR-Enterobacterales piperacillin/tazobactam MIC distributionsPiperacillin/tazobactam minimal inhibitory concentration distributions among multidrug-resistant Enterobacterales isolates.While there was an increase in resistance, our results indicate that most Enterobacterales isolates tested susceptible to piperacillin/tazobactam using the revised CLSI breakpoints.Nicholas M. Moore, PhD, D(ABMM), Abbott Molecular: Grant/Research Support|Cepheid: Grant/Research Support."}
+{"text": "Scientific Reports 10.1038/s41598-022-16441-7, published online 20 July 2022Correction to: The original version of this Article contained an error in the Author information section.\u201cThese authors contributed equally: Hyung Woo Kim, Sohee Park, Helen R. Stagg and Ju Sang Kim.\u201dnow reads:\u201cThese authors contributed equally: Hyung Woo Kim and Sohee Park.These authors jointly supervised this work: Helen R. Stagg and Ju Sang Kim.\u201dThe original Article has been corrected."}
+{"text": "People with migration history (PMH) are underrepresented within health monitoring at Robert Koch Institute (RKI). To better describe the health status of PHM, the RKI is currently conducting the health interview survey GEDA Fokus with different migrant groups. Aim of this contribution is to present which sub-groups in this sequential mixed-mode survey design are reached by which mode.People aged 18-70 years with Croatian (hr), Italian (it), Polish (pl), Syrian (sy) or Turkish (tr) nationality were drawn out of 99 residents\u2019 registration offices all over Germany . Study persons were invited sequentially to participate online (saq-web), paper-based(saq-paper) and in person (CAPI) or by telephone (CATI) in Arabic, Croatian, German, Italian, Polish or Turkish. Saq-web was available in German only or bilingual. Data collection took place from November 2021 to April 2022. Per nationality, 1,200 participants were recruited.As of 25th of April, 6,197 people took part, most often per saq-web (49%), which was less often used among participants aged \u2265 50 years (35% vs. 56%). Pl participants used saq-web most often in German only (55%), sy participants most often used the bilingual version (77%). Saq-paper was more often used by participants aged \u2265 50 years (41% vs. 22%) and less often by tr (21%) and sy (24%) participants. Participants with it nationality most often took part on their own initiative (saq) (92%), while tr (33%) and pl (28%) participants were recruited via personal contact (CAPI/ CATI) more often.Preliminary results show that offering multiple modes of administration helps to reach different sub-groups. Personal contact contributes to reach those not directly taking part on their own initiative. The opportunity to utilize the bilingual version of the questionnaire was well accepted, especially among those with presumably shorter duration of residence in Germany.Offering different modes of survey administration, including personal contact increases survey participation.In order to reach people with migration history in their heterogeneity the utilization of multilingual questionnaires is crucial."}
+{"text": "Saccharomyces cerevisiae populations adapting to glutamine-limited conditions over hundreds of generations. Here, we present the whole-genome sequencing (WGS) assemblies of 7 LTEE strains and their ancestor.Large-scale genomic changes, including copy number variations (CNVs), are frequently observed in long-term evolution experiments (LTEEs). We have previously reported the detection of recurrent CNVs in  Saccharomyces cerevisiae to nutrient-limited growth medium over hundreds of generations  and a drug resistance gene (TEFpr::KanMX::TEFterm) integrated into the upstream intergenic region of GAP1 . We inoculated DGY1657 into 20-mL chemostat vessels . Steady-state populations of 3\u2009\u00d7\u2009108 cells were maintained and sampled at generations 150  and 250  (The ancestor strain DGY1657) is derived from the S288C haploid strain FY4 (7 is deriDGY1751) . Clones 8 cells/mL , with the following exceptions for DGY1657, DGY1728, and DGY1744: (i) incubation times for the enzymatic repair step were increased to 15\u2009min, (ii) Agencourt AMPure XP beads were incubated for 30\u2009min at 37\u00b0C before elution, and (iii) the adapter ligation time was increased to 10\u2009min. All libraries were loaded onto FLO-MIN106D (R9.4) flow cells and sequenced using a MinION instrument (MIN-101B). Default parameters were used for all software unless otherwise specified. Demultiplexing of DGY1657, DGY1728, and DGY1744 was performed using Epi2Me (epi2me.nanoporetech.com). Base-calling was performed using Guppy v4.5.2, gpu , JAMQBF000000000 (DGY1728), JAMQBE000000000 (DGY1734), JAMQBD000000000 (DGY1736), JAMQBC000000000 (DGY1740), JAMQBB000000000 (DGY1744), JAMQBA000000000 (DGY1747), and JAMQAZ000000000 (DGY1751). The versions described in this paper are the first versions, JAMQBG010000000 (DGY1657), JAMQBF010000000 (DGY1728), JAMQBE010000000 (DGY1734), JAMQBD010000000 (DGY1736), JAMQBC010000000 (DGY1740), JAMQBB010000000 (DGY1744), JAMQBA010000000 (DGY1747), and JAMQAZ010000000 (DGY1751). The raw Illumina reads are available under the SRA accession numbers SRR7057840 (DGY1657), SRR7057779 (DGY1728), SRR7057829 (DGY1734), SRR7057832 (DGY1736), SRR7057777 (DGY1740), SRR7057833 (DGY1744), SRR7057780 (DGY1747), and SRR7057828 (DGY1751). The ONT reads can be found under the SRA accession numbers SRR10525523 (DGY1657), SRR19440503 (DGY1728), SRR19440502 (DGY1734), SRR19440501 (DGY1736), SRR19440500 (DGY1740), SRR10525517 (DGY1744), SRR19440499 (DGY1747), and SRR19440498 (DGY1751).The sequencing data and accession numbers are provided in https://github.com/pspealman/WGS_assemble_pipeline [This whole-genome shotgun project has been deposited at GenBank under the accession numbers 00000 DGY57, JAMQB"}
+{"text": "Hepatocellular carcinoma (HCC) remains one of the more incurable diseases. Thus, finding an HCC treatment is urgent for this unmet medical need. Immunotherapy is a break-through treatment that may help 15\u201320% of HCC patients. In this review, pharmacological and immune-therapeutical targeting of druggable cancer drivers, immune checkpoints, and long non-coding RNAs for HCC and cholangiocarcinoma are discussed.Cancer contains tumor-initiating stem-like cells (TICs) that are resistant to therapies. Hepatocellular carcinoma (HCC) incidence has increased twice over the past few decades, while the incidence of other cancer types has trended downward globally. Therefore, an understanding of HCC development and therapy resistance mechanisms is needed for this incurable malignancy. This review article describes links between immunotherapies and microbiota in tumor-initiating stem-like cells (TICs), which have stem cell characteristics with self-renewal ability and express pluripotency transcription factors such as NANOG, SOX2, and OCT4. This review discusses (1) how immunotherapies fail and (2) how gut dysbiosis inhibits immunotherapy efficacy. Gut dysbiosis promotes resistance to immunotherapies by breaking gut immune tolerance and activating suppressor immune cells. Unfortunately, this leads to incurable recurrence/metastasis development. Personalized medicine approaches targeting these mechanisms of TIC/metastasis-initiating cells are emerging targets for HCC immunotherapy and microbiota modulation therapy. Treatment options for HCC are limited. The 3- or 5-year survival rate of HCC is 13\u201321% and 5%, respectively, without any curative treatment in advanced countries such as the U.S. ,5. The iTICs are resistant to conventional chemotherapy and immunotherapy and persist as recurrent tumors or circulating tumor cells (CTC) . TICs exThere are no current targeted therapy options for the most prevalent mutations (most are not \u201cactionable\u201d). HCC has 2.5% of actionable mutations that can be clinically targeted by FDA-approved drugs, while biliary cancer has 45% actionable mutations based on Oncokb.org  and HCC tumor genetics in a TCGA cohort . These iThe molecular tumor board (MTB) review can guide choices of therapy for actionable mutations, clarify diagnosis, and identify patients who require germline testing. Prospective clinical sequencing of 10,000 patients revealed the mutational landscape of metastatic cancer  ClinicalThe frontline drug ; Bevacizumab (anti-VEGF) is an anti-angiogenic agent with additional immuno-modulatory effects that decrease the activity of immune-suppressive cells (MDSCs and Tregs) ,70. BevaTremelumimab and ipilimumab have been clinically tested ,73. The + to NADPH and the reverse reaction, i.e., reductive carboxylation of 2KG to ICT that oxidizes NADPH to NADP+ [Tumor next-generation sequencing (NGS) should be performed in all advanced Intrahepatic cholangiocarcinoma (iCCA), patients since 45% of driver mutations are actionable in iCCA while only 3.5% of driver mutations are actionable for HCCs from the MSK-IMPACT database . There ato NADP+ ,41. Gainto NADP+ ,41.Pemigatinib targets FGFR fusions and works for CCA . FisogatSeveral bacterial species are associated with improved responses against immune checkpoint inhibitors. The modulation of gut microbiota improves the efficacy of PD-L1 blockage therapy . BacteriFecalibacterium prausnitzii, Bacteroides thetaiotamicron, Holdemania filiformis, Dorea formicogenerans, Clostridiales  had an abundance of bacteria from the Ruminococcaceae family and Dorea formicogenerans when compared to patients who did not respond to this therapy , B. lon therapy . This su therapy . Cancer g method , which a therapy A. Germ-f species . Bifidobpatients A. Thus, Bifidobacterium breve [Bifidobacterium longum, and Bifidobacterium adolescentis [Bifidobacterium species enhance protective immunity against tumors, including um breve , Bifidobescentis   cell differentiation mediated by PSA-activated DC [Dietary fibers such as inulin stimulate the human-specific species  promote responses to CTLA-4 blockade immunotherapy [B. fragilis with anticancer properties in cancer patients  Toll-Like Receptor 9 (TLR9) recognizes the CpG PAMP [Unmethylated CpG motifs stimulate the immune system through pathogen-associated molecular patterns (PAMPs)  consisteCpG PAMP  and is eCpG PAMP .13\u20131014), the fungal mycobiome (1012\u20131013), helminths (multicellular eukaryotes: 0\u2013104), and members of the virome (1014\u20131015) [The bacteria of the bacteriome (1014\u20131015)  together14\u20131015) . Example14\u20131015) ,90.Fecal enzyme-linked immunosorbent assay shows that \u03b1-1-antitrypsin levels can distinguish cholangiocarcinoma patients from normal individuals. Therefore, \u03b1-1-antitrypsin level is a potential marker for early diagnosis of cholangiocarcinoma .The Mediterranean diet contains beneficial nutrients which may counter nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) and can contribute to longevity by inclusion of \u03c9-3-fatty acids, polyunsaturated fatty acids antioxidants, and choline . IndividFaecalibacterium prausnitzii of the human gut microbiota [Nutritional interventions (dietary fibers) with prebiotic inulin intake stimulates crobiota ,92. The crobiota , cellulocrobiota ,93.N-acetylglucosamine) stimulate the beneficial gut bacteria F. prausnitzii in healthy human volunteers [Firmicutes growth in rats [F. prausnitzii growth [F. prausnitzii encodes pectinolytic enzymes [F. prausnitzii strains can utilize the glycoprotein N-acetylglucosamine [N-acetylglucosamine heals inflamed and damaged soft tissues of the gut [F. prausnitzii [F. prausnitzii isolates cannot utilize mucin or mucopolysaccharides [F. prausnitzii switches between substrates derived from the diet or the host and benefits from mucin metabolism  100 mg) compared to placebo\u2013control group C (Lactobacillus acidophilus NCFM facilitates mouse myeloid dendritic cells (DCs) to express antiviral genes, such as myxovirus resistance 1, IFN-\u03b2, and IFN stimulated via the TLR2 pathway [Dietary synbiotics reduce cancer risk factors in polypectomized and colon cancer patients . This wa group C B. TreatmTargeting IL-17 signaling is a novel therapeutic strategy for ALD. Alcoholic hepatitis (AH) patients have dysbiotic gut microbiota with the marked loss of butyrate producers, but with the increased serum and hepatic IL17 . IL-17 sMicrobial involvement in AH could be demonstrated by bi-weekly human AH-FMT to C57Bl/6 mice, which led to loss of butyrate-producing bacterial families with decreased butyrate levels in cecal samples . AH-FMT The AH-FMT model recapitulates hepatic pro-inflammatory T cell responses observed in AH patients , includiMprF) protein which counteracts the effects of defensins expressed in the gut (Therapeutic IL-17 targeting showed improvements in three different ALD mouse models: (1) an intragastric ethanol feeding model that recapitulated alcoholic steatohepatitis and fibrosis; (2) a chemical carcinogen diethylnitrosamine (DEN) + alcohol model that mimicked liver cancer associated with alcohol misuse; and (3) a chronic feeding with weekly binge drinking model that mimicked alcoholic hepatitis and steatohepatitis . It is t the gut . MprF coBacteroides vulgatus [Patients post-fecal microbiota transplant (FMT) had lower abundance of vancomycin (VanH), \u03b2-lactamase (ACT), and the rifamycin antibiotic-resistance gene (ARG); this was associated with cognitive improvement . Pre-FMTvulgatus . These Avulgatus .Fecal microbiota transplant from a rational stool donor improved hepatic encephalopathy in a randomized clinical trial . Post-anEpigenetic regulators turn on endogenous retroviruses that activate cGAS-cGAMP-STING-mediated cytosolic DNA sensing and IFN signaling . To actiMetabolites from gut microbiota pass through the gut epithelial layer and reach the liver through the portal vein and affect bile production ,90. AlcoApical sodium-dependent bile acid transporter  and SLC10A2) inhibition for 16 weeks improved multiple features of NASH in a high unsaturated fat diet (HFD) mouse model . InhibitTransplantation of fecal microbiota from alcoholic hepatitis patients induces hepatic recruitment of IL-17-producing inflammatory T cells promoting inflammation and injury . AlcoholConversion of starches to short-chain fatty acid (SCFA) maintains gut integrity . DietaryShort-chain fatty acids (SCFAs), the main metabolites produced by bacterial fermentation of dietary fiber in the gastrointestinal tract, are speculated to have a key role in microbiota\u2013gut\u2013brain crosstalk. Short-chain fatty acids (SCFAs) can mediate microbiota\u2013gut\u2013brain axis crosstalk  through The microbiome is a therapeutic target for numerous cardiometabolic disorders by drugging the microbiome . BacteriGut microbial produced metabolites can be recognized by host pathogen recognition sensors to promote HCC progression. Metabolism of dietary components by the gut microbiota produces short-chain fatty acids, including other metabolites. When combined with microorganism fragments, these can stimulate the meta-organismal endocrine axis to promote HCC onset and growth. For example, trimethylamine (TMA) produced in the gut promotes ALD . Thus, pListeria monocytogenes infection [Targeting of the gut microbiota has great potential as a therapeutic modality for many diseases. However, relatively little is known regarding the contribution of commensal bacteria to normal host physiological functions . For exanfection . Thus, tnfection .Lactobacillus acidophilus stimulates the TLR2 pathway of murine myeloid dendritic cells (mDC) to induce interferon-\u03b2 (IFN-\u03b2), while IL-10 secretion in plasmacytoid DC (pDC) is TLR9 dependent  induce transforming growth factor \u03b2 (TGF-\u03b2) production to inhibit Th2 cell development [Bacteroides fragilis promotes Treg cell secretion and suppresses Th17 activity [Treg cells secrete the anti-inflammatory cytokine IL-10 to attenuate inflammation. IL-6, IL-21, and IL-2 dynamically regulate the balance between Th17 and Treg cell differentiation ,112. Intelopment . Clostrielopment ,116. In elopment . Polysacactivity . The groactivity .+ DC to mobilize lamina propria CD11b+ DC. This in turn stimulates Treg differentiation to promote anergy against immunity induced by CTLA-4 blockade [Alloprevotella or Prevotella driving cluster A and distinct Bacteroides spp. driving clusters B and C. During anti-CTLA4 (ipilimumab) therapy, the proportions of MM patients falling into cluster C increased at the expense of those belonging to cluster B through the colonization of the immunogenic bacteria Bf and Bt [Zwitterionic polysaccharides bind the TLR2 complex on CD11bblockade  via inteblockade  independblockade ,122. A cblockade ,124 distf and Bt ,126,127.Klebsiella pneumoniae causes fatty liver disease [Picovirinae group) were isolated from sewage water. Feeding of four podophages of the virulent Picovirinae group lyse the cytolytic E. faecalis strain [E. faecalis attenuates alcoholic liver disease that promotes E. faecalis expansion (2700-fold increase) by reducing steatosis, inflammation, and liver injury of mice chronically fed ethanol [High-alcohol-producing  disease . Intesti disease ,130. To s strain . Gavage  ethanol . Therefo ethanol , since i ethanol . OvergroA live microbiome was co-cultured with micro-engineered human intestinal villi in a gut-on-a-chip microfluidic device . The intSynbiotic treatment normalizes gut microbiota and concomitantly reduces toxic gut microbiota to repair leaky guts . These bBacteroides caccae [Fecalibacterium prausnitzii, Bacteroides thetaiotamicron, and Holdemania filiformis, whereas patients who responded to pembrolizumab (another PD-1 antibody) showed that their gut microbiota was enriched with Dorea formicogenerans. This treatment increased bacterial diversity and abundance of bacteria from Akkermansia muciniphila [Bifidobacterium spp.  [Enterococcus faecium, and the Ruminococcaceae family, induces Treg accumulation by cooperating with DC in the colon (Patients who responded to nivolumab (PD-1 antibody) were enriched with s caccae  and Fecainiphila , Bifidobfaciens) , Enteroche colon .Bifidobacterium infantis 35624 treatment increases IL-10 secretion through the TLR2/TLR6 pathway in human myeloid dendritic cell (mDC) and monocyte-derived DC (MDDC), while IL-10 secretion in plasmacytoid DC (pDC) is TLR9 dependent. Tregs secrete the anti-inflammatory cytokine IL-10 to attenuate inflammation  transports the SCFA anion [Fermentation of dietary fiber in the colon generates short-chain (ranging from one to six carbon atoms) saturated fatty acids (SCFAs) . ProductFA anion .C. difficile (+) cirrhosis is a deleterious combination with greater mortality via brain dysfunction due to SCFA downregulation. GF mice have altered microbial infection inflammatory markers . Post-FMT GF mice recipients show improved neuro-inflammation [Ruminococcaceae) is currently under investigational new drug application (IND) guidance [Because of microbiota changes or intestinal microbiota transplantation in liver diseases and cirrhosis, use of pharmacotherapeutics must be cognizant of these issues when considering treatment options . Transfeammation . Use of ammation . Oral caguidance . A randoExercise reduces the incidence and progression of hepatocellular carcinoma in mouse models . PersonaC. difficile is important since it is responsible for the chronic liver diseases cirrhosis and alcoholic hepatitis. FMT trials for chronic liver diseases are currently in progress.FMT with multi-drug-resistant organisms (MDRO) can cause problems in donor recipient patients. Avoidance of Future investigative projects need to address specific treatments and FMT short-term changes in patients with HCC. Another consideration is whether allogeneic or autologous FMT should be employed, especially since current FDA-approved immunotherapies, such as anti-PD-1 or anti-CTLA4, have limited efficacy only for a small fraction of HCC patients (10\u201325% range undergoing monotherapy). The remaining HCC patients do not respond to this monotherapy, thus other immune mechanisms may be needed to allow synergism with tumor-killing cells, such as antigen-presenting cells, including dendritic cells and B cells. Inclusion of immune checkpoint inhibitors with combination therapy may break immune tolerance and improve the therapeutic efficacy of this approach."}
+{"text": "Background: Healthcare facilities have experienced many challenges during the COVID-19 pandemic, including limited personal protective equipment (PPE) supplies. Healthcare personnel (HCP) rely on PPE, vaccines, and other infection control measures to prevent SARS-CoV-2 infections. We describe PPE concerns reported by HCP who had close contact with COVID-19 patients in the workplace and tested positive for SARS-CoV-2. Method: The CDC collaborated with Emerging Infections Program (EIP) sites in 10 states to conduct surveillance for SARS-CoV-2 infections in HCP. EIP staff interviewed HCP with positive SARS-CoV-2 viral tests  to collect data on demographics, healthcare roles, exposures, PPE use, and concerns about their PPE use during COVID-19 patient care in the 14 days before the HCP\u2019s SARS-CoV-2 positive test. PPE concerns were qualitatively coded as being related to supply ; use ; or facility policy . We calculated and compared the percentages of cases reporting each concern type during the initial phase of the pandemic (April\u2013May 2020), during the first US peak of daily COVID-19 cases (June\u2013August 2020), and during the second US peak (September 2020\u2013January 2021). We compared percentages using mid-P or Fisher exact tests (\u03b1 = 0.05). Results: Among 1,998 HCP cases occurring during April 2020\u2013January 2021 who had close contact with COVID-19 patients, 613 (30.7%) reported \u22651 PPE concern (Table Conclusions: Although lower percentages of HCP cases overall reported PPE concerns after the first US peak, our results highlight the importance of developing capacity to produce and distribute PPE during times of increased demand. The difference we observed among selected groups of cases may indicate that PPE access and use were more challenging for some, such as nonphysicians and nursing home HCP. These findings underscore the need to ensure that PPE is accessible and used correctly by HCP for whom use is recommended.Funding: NoneDisclosures: None"}
+{"text": "Enterobacter hormaechei that developed FDC resistance following antibiotic exposure.Cefiderocol (FDC) is a novel antimicrobial agent used for multi-drug resistant Gram-negative pathogens. To date, reports of mutations in \u03b2-lactamase and siderophore complex genes have been described and may contribute to FDC resistance. This case describes a New Dehli metallo-\u03b2-lactamase (NDM)-producing strain of Serial respiratory and blood cultures were collected from a lung transplant recipient throughout 72 days of hospitalization. Confirmatory susceptibility and combination minimal inhibitory concentration (MIC) testing were performed using broth dilution and E-test assays. Short-read sequencing libraries were prepared using a seqWell plexWell 96 kit, and whole-genome sequencing was performed using the Illumina NovaSeq platform. Reads from the sample genomes were aligned to the chromosome and three plasmid sequences of reference genome ENCL48880.E. hormaechei isolates and one blood isolate were evaluated. Although initial isolates were susceptible to FDC (MICs 1-2 \u00b5g/mL), two respiratory isolates cultured after 41 days of FDC therapy had MICs of 128 \u00b5g/mL. The blood isolate remained FDC susceptible despite respiratory resistance. The combination of ceftazidime/avibactam and aztreonam was determined to be active via synergy MIC testing in all isolates, and aztreonam therapeutic drug monitoring confirmed an adequate dosing strategy. Whole-genome sequencing revealed no nonsynonymous single nucleotide variants (SNVs) within the chromosomes but identified a deletion of a large urease island in the resistant isolates. In four of the five isolates, a plasmid (p48880_mcr) was identified and analyzed for possible contributions to FDC resistance.Four serial respiratory Enterobacter Isolate AssembliesThis figure demonstrates genomic assemblies from the five Enterobacter clinical isolates, noting an absence of sequence from ECResp2.E. hormaechei isolates during a 41 day course of FDC therapy. Possible causes of resistance include a large chromosomal deletion and plasmid alleles, demonstrating a potential novel mechanism for FDC resistance. Partnering molecular testing and enhanced antimicrobial stewardship should be encouraged to optimize selection of regimens and durations to prevent resistance to FDC.This case demonstrates development of FDC resistance in Michael G. Ison, MD MS, GlaxoSmithKlein: Grant/Research Support|Pulmocide: Grant/Research Support|Viracor Eurfins: Advisor/Consultant Nathaniel J. Rhodes, PharmD, MSc, American Academy of Colleges of Pharmacy: Grant/Research Support|Paratek: Grant/Research Support|Third Pole Therapeutics: Advisor/Consultant."}
+{"text": "A 52-year-old HIV-positive man (CD4\u2009=\u200974 cells) presented with amaurosis and headache. The cerebrospinal fluid (CSF) had increased opening pressure and the magnetic resonance imaging (MRI) findings included irregular leptomeningeal thickening on the right frontoparietal transition and parietal sulci, with restricted diffusion, and irregular nodular gadolinium enhancement 23. Th"}
+{"text": "Stress has been associated with the onset and progression of neuropsychiatric conditions. The neuroendocrine response to psychosocial stressors is mediated via the hypothalamus-pituitary-adrenal axis, resulting in systemic glucocorticoid secretion. FKBP5 is a co-chaperone of the cortisol-bound glucocorticoid receptor. FKBP5 Single Nucleotide Polymorphisms (SNPs) may indicate stress-response alterations, thus affecting vulnerability or resilience to neuropsychiatric phenotypes.To investigate the FKBP5 polymorphism rs1360780 and FKBP5 mRNA levels in a well-characterized, drug-na\u00efve sample of First-Episode Psychosis (FEP) individuals and matched controls.For genotyping rs1360780, whole blood DNA was extracted from FEP individuals and matched controls. The presence of the C (protective)\u2192T (risk) alleles was assessed using TaqMan SNP genotyping assay. Peripheral Blood Mononuclear Cells (PBMCs) were isolated and whole RNA was extracted. FKBP5 mRNA levels were detected with RT-qPCR, using SYBRgreen. Results were normalized against the 18s rRNA reference gene. Statistical analysis was performed in GraphPad Prism 8.The distribution of C\u2192T alleles of rs1360780 genotyped in FEP (N=44) and controls (N=39) indicate a statistically significant prevalence of the C/C alleles in FEP individuals (*p=0.0432). mRNA FKBP5 data revealed increased levels of FKBP5 in FEP individuals (N=25) compared to controls (N=18), (***p=0.0007).Our data show increased FKBP5 mRNA levels in FEP individuals compared to matched controls, as well as the presence of the rs1360780 protective (C) allele. Follow up studies include investigation of the translational profile of stress-mediators, in order to pave an individualized approach towards deciphering psychosis onset pathobiology.No significant relationships."}
+{"text": "Scientific Reports 10.1038/s41598-022-17896-4, published online 17 August 2022Correction to: In the original version of this Article Dongmin Jang was omitted from the equally contributing authors statement.\u201cThese authors contributed equally: Hyojin Heo and Byungsun Cha\u201d.now reads:\u201cThese authors contributed equally: Hyojin Heo, Byungsun Cha and Dongmin Jang\u201d.The original Article has been corrected."}
+{"text": "P<0.05 was considered statistically significant. This activity was reviewed by CDC and conducted consistent with applicable federal law and CDC policy.The rate of nonfatal opioid-involved overdose EMS encounters increased, on average, 4.0% per quarter during January 2018\u2013March 2022, increasing from 98.1 per 10,000 EMS encounters during Quarter 1 (Q1)Nonfatal opioid-involved overdose rates were highest among adults aged 25\u201334 years and lowest among children and adolescents aged 0\u201314 years . AQPCs fNonfatal opioid-involved overdose rates were higher in counties with higher unemployment ; rates iThis report highlights several findings: 1) rates of nonfatal opioid-involved overdose EMS encounters per 10,000 total EMS encounters increased steadily from 2018 through the onset of the COVID-19 pandemic; 2) nonfatal opioid-involved overdose rates increased for both sexes, all age groups except persons aged 15\u201324 years, and all racial and ethnic groups except NH/OPI; 3) nonfatal opioid-involved overdose rates increased among all quartiles of county-level characteristics, except for counties with the lowest percentage of uninsured persons; and 4) higher nonfatal opioid-involved overdose rates and rate increases were observed in urban counties and in counties with higher unemployment rates.Increases in nonfatal opioid-involved overdose EMS encounters through Q3 2020 are consistent with increases in nonfatal opioid-involved overdoses treated in EDs  are increasing, yet ED surveillance does not capture all overdoses because persons who had a nonfatal opioid-involved overdose often refuse transport by emergency medical services (EMS).The rate of nonfatal opioid-involved overdose EMS encounters increased, on average, 4.0% quarterly during January 2018\u2013March 2022, from 98.1 to 179.1 per 10,000 EMS encounters. Rates increased across most sociodemographic and county characteristics.Monitoring nonfatal opioid-involved overdose trends in EMS data in near real time can help identify communities disproportionately affected by overdose and can guide equitable response and prevention efforts, including increased access to harm reduction services and linkage to care and treatment."}
+{"text": "Direct gaze is the most important mediator of social interaction and communication. Existing studies have evaluated eye movements of patients with schizophrenia by presenting stimuli using photographs or pre-recorded videos, but few directly investigated gaze avoidance in real-world situations.To investigate the correlation between gaze avoidance and psychopathology in patients with schizophrenia through eye movement measurements in real-life interpersonal situations.We enrolled 52 clinically stable patients with schizophrenia. Psychopathology was evaluated using the Positive and Negative Syndrome Scale (PANSS), Hamilton Depression Rating Scale, and Hamilton Anxiety Rating Scale. After presenting a visual stimulus, eye movements were measured with Tobii Pro Wearable Glasses 2, and deep learning-based emotional recognition using the residual masking network was used for neutral stimulus verification. Statistical analyses were performed using Pearson\u2019s correlation and regression analyses.Data of 45 participants with verified stimulus neutrality by deep learning image recognition were used for analysis. The first dwelling time was negatively correlated with the PANSS positive syndrome subscale (p=0.028), general psychopathology subscale (p=0.008), total score (p=0.008), 5-factor positive symptoms (p=0.035), and 5-factor depression/anxiety symptoms (p=0.008). The baseline-area of interest (AOI) pupil diameter change was positively correlated with PANSS 5-factor positive symptom scores (p=0.039). After adjusting for additional variables, the same items had a significant effect on the first dwelling time and baseline-AOI pupil diameter change.Psychopathology, particularly positive symptoms, was associated with gaze avoidance and pupil diameter in patients with schizophrenia. Evaluating the characteristics of eye movements in patients with schizophrenia will enable better understanding of their symptoms.No significant relationships."}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-022-25953-1, published online 28 December 2022Correction to: The original version of this Article contained an error in the spelling of the author Kyunghoon Kim\u00a0which was incorrectly given as Kyung Hoon Kim.Additionally, the Article contained an error in the Author Information section.\u201cThese authors contributed equally: Beom Joon Kim, Baek Seung Kim, Chang Won Lim and Kyung Hoon\u00a0Kim.\u201dnow reads:\u201cThese authors contributed equally: Beom Joon Kim and Baek Seung Kim.These authors jointly supervised this work: Chang Won Lim and Kyunghoon Kim.\u201dThe original Article has been corrected."}
+{"text": "Our main objective was to identify abundantly expressed tyrosine kinases in multiple myeloma (MM) as potential therapeutic targets. We first compared the transcriptomes of malignant plasma cells from newly diagnosed MM patients who were risk-categorized based on the patient-specific EMC-92/SKY-92 gene expression signature values vs. normal plasma cells from healthy volunteers using archived datasets from the HOVON65/GMMG-HD4 randomized Phase 3 study evaluating the clinical efficacy of bortezomib induction/maintenance versus classic cytotoxic drugs and thalidomide maintenance. In particular, ERBB1/EGFR was significantly overexpressed in MM cells in comparison to normal control plasma cells, and it was differentially overexpressed in MM cells from high-risk patients. Amplified expression of EGFR/ERBB1 mRNA in MM cells was positively correlated with increased expression levels of mRNAs for several DNA binding proteins and transcription factors with known upregulating activity on EGFR/ERBB1 gene expression. MM patients with the highest ERBB1/EGFR expression level had significantly shorter PFS and OS times than patients with the lowest ERBB1/EGFR expression level. High expression levels of EGFR/ERBB1 were associated with significantly increased hazard ratios for unfavorable PFS and OS outcomes in both univariate and multivariate Cox proportional hazards models. The impact of high EGFR/ERBB1 expression on the PFS and OS outcomes remained significant even after accounting for the prognostic effects of other covariates. These results regarding the prognostic effect of EGFR/ERBB1 expression were validated using the MMRF-CoMMpass RNAseq dataset generated in patients treated with more recently applied drug combinations included in contemporary induction regimens. Our findings provide new insights regarding the molecular mechanism and potential clinical significance of upregulated EGFR/ERBB1 expression in MM. Several tyrosine kinase inhibitors have gone through a meticulous drug development process and have been approved for specific oncologic indications. These precision medicines could be re-purposed as new drugs for diseases beyond their approved target indications if the expression of their specific targets is not limited to the cancer types they are approved for. In the current study, we examined the expression of a broad panel of tyrosine kinase genes in malignant cells from multiple myeloma patients. We identified some tyrosine kinases that are expressed at significantly higher levels in malignant plasma cells from multiple myeloma patients than normal plasma cells. One of these tyrosine kinases is EGFR/ERBB1. Interestingly, multiple myeloma patients with the highest EGFR/ERBB1 expression had worse survival outcomes. Therefore, EGFR/ERBB1 inhibitors may be particularly meaningful as adjuncts of available standard treatment options for these patients. The new insights provided by our study warrant further investigation of the clinical potential of tyrosine kinase inhibitors of EGFR/ERBB1 in treatment of multiple myeloma. RecenSeveral putative driver mutations in MM cells are considered druggable and some have been targeted with serine/threonine kinase inhibitors developed as precision medicines . ExampleProtein tyrosine kinases (PTK) play critical roles in normal lymphohematopoiesis, and they have also been implicated as oncoproteins in the development of B-lineage lymphoid malignancies, including leukemias, lymphomas, and MM -17. The 2.2.1.https://www.ncbi.nlm.nih.gov/geo/ (accessed on 24 September 2022)) to create a working database. We performed a probeset level normalization procedure to enable comparisons of the expression levels of specific genes in CD138+ purified malignant plasma cells from high-risk MM patients versus normal CD138+ purified normal plasma cells, as well as CD138+, purified malignant plasma cells from standard-risk MM patients. The risk categories were based on the patients\u2019 EMC-92/ SKY-92 gene signature profiles ,-92,\u00ae) isonco-1871691-supplementary 2Figure S1: Absolute ERBB1 Gene Expression Levels in Malignant Plasma Cells from SKY-92 Risk-assessed MM Patients and Normal CD138+ Plasma Cells from Healthy SubjectsFigure S2: Absolute ERBB1 Gene Expression Levels in Malignant Plasma Cells from SKY-92 Risk-assessed MM Patients Categorized According to Prognostic ISS Staging CriteriaFigure S3: Correlation matrix of EGFR/ERBB1 probesets and transcription factors in MM patientsFigure S4: Higher ERBB1/EGFR Expression Level is Associated with Shorter PFS and OS in Newly Diagnosed MM patientsFigure S5: The unfavorable impact of higher EGFR/ERBB1 expression level on PFS and OS outcomes of MM patients in univariate and multivariate Cox proportional hazards modelsFigure S6: Expression levels for EGFR/ERBB1 in malignant plasma cells from 766 newly diagnosed MM patients according to prognostic ISS stageFigure S7: Higher ERBB1/EGFR Expression Level is Associated with Shorter PFS and OS in Newly Diagnosed MM patients from the MMRF-COMPASS studyTable S1: Gene expression levels for tyrosine kinases in malignant plasma cells from MM patients vs. normal plasma cells from healthy subjectsTable S2: Descriptive statistics for raw ERBB1 gene expression levels in malignant plasma cells from SKY-92 risk-assessed MM patients and normal CD138+ plasma cells from healthy subjectsTable S3: Descriptive statistics for ERBB1 probesets in malignant plasma cells from newly diagnosed MM patients risk assessed using ISS staging criteriaTable S4: Gene expression levels for tyrosine kinases in malignant plasma cells from high-risk MM patients vs. normal plasma cells from healthy subjectsTable S5: Gene expression levels for tyrosine kinases in malignant plasma cells from high-risk vs. standard-risk MM patientsTable S6: Correlated expression of transcription factor genes with EGFR/ERBB1 gene expression (Probeset: EGFR_1565484_x_at) in MM patientsTable S7: Correlated expression of transcription factor genes with EGFR/ERBB1 gene expression (Probeset: EGFR_1565483_at) in MM patients."}
+{"text": "We offer these reviewers our heartfelt thanks for a task that usually goes unrewarded in the academic environment. This year, we are especially grateful for those people listed below. They have assisted us in reaching the start of our 4th year, by guiding our decisions with your knowledge and capabilities. Journal of Appalachian Health could not be the credible online journal it is without the help of the competent content experts we choose to review each of our research, review, and special articles.As with all peer-reviewed medical journals, the And each year, we offer them our heartfelt thanks for a task that usually goes unrewarded in the academic environment. This year, we are especially grateful for those people listed below. They have assisted us in reaching the start of our 4th year, by guiding our decisions with your knowledge and capabilities.A. Brianna SheppardAaron Kruse-DiehrAdam HegeAl DeliaAlan M DucatmanAlisha FarrisAllison LastingerAllison RossAltaf SaadiAmy A. EylerAna ContardoAndrew C. RucksAnita ChandraAnna G. HooverAnne JulianArthur L FrankAsher SchranzAustin BrownBetsy AumillerBonnie J. HackbarthBradford W. HesseBrandy McCannBrenna KirkBrent EmersonBria GreshamBud NicolaCameron LanierCarol L. SteltenkampCarolann CurryCecily FasslerChris PrenerChristina RosenChristine SchalkoffJanice VickJannine BaileyChristopher SeitzCooper JohnsonCraig G GundersenDanelle Stevens-WatkinsDaniel BrookDaniel YoderDanielle NunneryDannell BoatmanDavid LoganDeborah AzraelDennis McCartyElisa RodriguezElizabeth ShayEman TadrosEmily B ZimmermanEmily GusemanErin BouldinErin N HaynesEverett MagannGary CuddebackGrace GorenfloGretchen ElyGulzar H. ShahHeather M BushHelena VonvilleHilary L. SurrattHollie PellosmaaIngrid E LuffmanJ K IbrahimJade ZimpferJanet BronsteinJanet MullinsJanice Dixon KeyLinda AlexanderLinda G. KeanJenine K HarrisJennie L YoostJennifer A MallowJennifer B ShinnJennifer PoolerJennifer TysonJerod StapletonJill CrainshawJill D. MooreJill KruegerJill NolanJoanne PattersonJoe BohnJoel SegelJonathan C. YoungJudith BeverlyJulie MarshallJulie SakowskiJulie TownsendKandace McGuireKaren CaldwellKate E BeattyKate LegerKatherine A JonesKatherine RossKathi HarpKathleen C BrownKathleen WinterKelly BlakeKelly BrunstKenneth Daniel WardKetrell McWhorterKevin A. PearceKimberly KellyKostas SkordasKyle ThompsonLaura DowneyLaura McArthurLaura R. LanderLauren AndersenLaurie L MeschkeLaurie TheekeRich SutphinRichard N. GreenbergRichard W. ChristianaRick SlavenRobert HeimerMakenzie BarrMarc KiviniemiMark DignanMartha L BuchananMary Beth BabosMary DavisMatthew F HudsonMatthew L BushMatthew MillerMaureen ByrnesMaureen P BezoldMelissa D GutschallMelissa SloneMeredith S. DuncanMichael E ThomasMichael FisherMichael MeitMichael RozierMichael TopmillerMichele MorroneMildred MaisonetMira KatzNadya BelenkyNafisa JadavjiNancy CarlsonNicholas NewmanOlga KhavjouPatricia B WrightPaul ErwinPaul JoudreyPeg AllenPhilip M. WestgateRachel R WaldenRachel R WaldenRachel Vickers-SmithRaeven ChandlerRaj BalkrishnanRandolph F. WykoffRaynor MullinsRebecca Adkins FletcherRebecca ReeceReda WilsonStephanie BooneStephanie Ettinger De CubaStephanie Jilcott-PittsStephanie MooreSteve BrowningRobert M. Shapiro IIRobin VanderpoolRobyn GoodmanRoger L Blackwell JrSamantha M HardenSamuel MathenySarah BrothersSarah E. NelsonSarah RaskinSarah SofkaScott LangevinScott P. HaysScottie B. DaySeth HimelhochSnow Xue FengStephanie BonnesSteve M. DavisTauna GulleyTed RaybouldTerry L. BunnThomas BodenheimerThomas RickettsTimothy A JoynerTina Antill KeenerUmedjon IbragimovVa Nee Van VleckVirginia ValentinW. Jay ChristianWayne CoombsWendy BraundWilliam CopelandYilin Yoshida"}
+{"text": "Brain tumors cause morbidity and mortality in part through peritumoral brain edema. The current main treatment for peritumoral brain edema are corticosteroids. Due to the increased recognition of their side-effect profile, there is growing interest in finding alternatives to steroids but there is little formal study of animal models of peritumoral brain edema. This study aims to summarize the available literature.A systematic search was undertaken of 5 literature databases . The generic strategy was to search for various terms associated with \u201cbrain tumors\u201d, \u201cbrain edema\u201d and \u201canimal models\u201d.We identified 603 reports, of which 112 were identified as relevant for full text analysis that studied 114 peritumoral brain edema animal models. We found significant heterogeneity in the species and strain of tumor-bearing animals, tumor implantation method and edema assessment. Most models did not produce appreciable brain edema and did not test for observable manifestations thereof.No animal model currently exists that enable the investigation of novel candidates for the treatment of peritumoral brain edema. With current interest in alternative treatments for peritumoral brain edema, there is an unmet need for clinically relevant animal models. Peritumoral brain edema is a key contributor to morbidity and mortality in brain tumors resulting in mass effect and raised intracranial pressure , 2.Brain edema is broadly divided into fluid accumulation within cells (cytotoxic edema) or in the interstitial space (vasogenic edema) , althougDexamethasone, a synthetic corticosteroid, has been used to control peritumoral brain edema since the 1950s , 7 and uSince their first use in the late 1940s, numerous categories of animal model have arisen, each with their own strengths and weaknesses . These aWhen testing new agents for the treatment of peritumoral brain edema, pre-clinical models should be carefully assessed regarding their suitability for this task. We here present a systematic scoping review of different pre-clinical brain tumor models claiming to study peritumoral brain edema. As steroids are most commonly necessary for long periods of time in the treatment of primary and secondary tumours within the brain parenchyma, where radiotherapy is a frequent adjunct and surgery not always possible, we limit the review to studies modelling such tumours. This deliberately excludes meningiomata, where peritumoral edema does occur, but is a more variable phenomenon.A systematic search was undertaken of 5 literature databases . No limits were set for date of publication or language. The generic strategy was to search for various terms associated with \u201cintracranial tumors\u201d, \u201cbrain edema\u201d and \u201canimal models\u201d. The detailed search strategy for each database can be found in Appendix A.Reports were screened in two passes. First, two reviewers (MWJS and SPS) screened report titles and clearly unrelated reports were eliminated. Subsequently, two reviewers (MWJS and M-T L) screened the abstract of the remaining reports and eliminated any remaining reports that did not meet the inclusion criteria and those in non-English languages. The inclusion criteria were any form of animal model and any form of intracranial tumor induction method  was deemed sufficiently relevant to proceed to data extraction. Disagreements at both stages were resolved by discussion. The remaining reports underwent full text review and data were extracted by a single author (MWJS). Data were extracted for each animal model \u2013 some reports studied more than one \u2013 and included: host animal characteristics , tumor characteristics , and reported measures of edema  etc.).The subset of selected reports which showed MRI sequences of peritumoral brain edema were reviewed separately. Of twenty-eight reviewed articles, four were excluded as they were devoid of MR imaging. Of the remaining 24 research papers 16 were rat models, 4 were mouse, 3 were cat, and 1 was dog. MR images were reviewed by a consultant neuroradiologist (SC) and assigned the presence or absence of peritumoral edema. Cases with peritumoral edema were classified in to one of two patterns, either \u2018halo\u2019, i.e. a rim of edema around the tumor or \u2018infiltrative\u2019 i.e. edema extending along white matter tracts and also classified by extent depending on whether the volume of edema was volume less, or greater than the volume of the tumor volume, see Fig. Our search identified 603 reports which were narrowed down to 112 for full text review; 14 reports could not be accessed , followed by xenogeneic graft models (n\u2009=\u200931), chemically-induced (n\u2009=\u20094), virally induced (n\u2009=\u20091) and genetically engineered mouse (n\u2009=\u20091); no patient-derived xenograft models or carotid-/cardiac-injection metastasis models were identified. These can be further divided by species , 4 showed a pattern of peritumoral halo all with edema volume less than tumor volume , 6 revealed infiltrative edema with volume less than tumor volume  and the remaining 3  showed infiltrative edema with greater volume than the tumor Table . Eleven We here report the findings from a systematic search and review of the literature on animal brain tumor models in which brain edema was reported. Most of the studies reviewed used indirect measures of cerebral edema  and these may not equate to the edema seen in patients with high grade tumors. Even in those studies where radiology was used, few of the animal models showed peritumoral brain edema in keeping with that seen in patients\u2014and in the models which did show impressive edema, most notably in an immunocompetent feline model with an implanted xenograft tumor, there would be concern that the mechanism of edema formation is different to that seen in glioma. Overall, we found no evidence for a definitive animal model to use when assessing changes in peritumoral brain edema following treatment. The reports that have been published show considerable heterogeneity in design; this likely reflects peritumoral edema having been of secondary concern in designing brain tumor animal models.Our results demonstrate that there is considerable heterogeneity in the combinations of tumor-bearing animal and tumor-induction method combinations and the measures used to assess the extent of edema. Edema measures in the literature presented here can be characterized as measuring BWC, measuring blood vessel leakiness, measuring symptoms or detecting radiological signs of edema Table . There wThe radiological appearances of edema in the animal models were also very different compared to that seen in humans. On review of the imaging shown in the reports selected in this review, none of the animal tumor models showed a clear resemblance to those of humans with high grade brain tumors. The majority showed no peritumoral edema although some did show a halo pattern of edema. The halo gives the impression of a capsule or boundary within which the edema is confined. In contrast, in patients with GBM and metastases there is often widespread edema which migrates along the white matter tracts. In human clinical trials there are no standardized criteria for measuring/recording this cerebral edema\u2014although there are standardized methods for recording radiological response to treatment (e.g. RANO ). CarlsoIn the animal models reviewed here, the extent of peritumoral edema appeared to be model dependent, with immunocompromised animals, perhaps not surprisingly, showing essentially no T2 signal attributable to peritumoral brain edema , 28. GenWe have found only one group of animal model that appears to show peritumoral edema similar to that seen in humans, namely cats injected with one of several rat glioma cell lines, e.g. F98 , RG2, 9LIt is not clear what drives these differences in peritumoral brain edema between the different animal models and between pre-clinical and clinical appearances. We can propose several possible explanations. Firstly, small rodents have a comparatively limited amount of white matter in the brain compared to larger animals. As radiologically demonstrable edema in humans has a predilection for white matter tracts, this may affect the limited amount of edema visible in rodent models. This may be supported by reports of spontaneously occurring canine gliomas which show considerable white matter tract edema  and by tSecondly, there are considerable differences in immune status between the different models. Given the importance of inflammatory mediators in generating vasogenic edema, this may account for at least some of the variability in peritumoral brain edema. In the model where a rat or mouse-derived xenograft is implanted into immunocompetent cats, considerable edema is seen. Interestingly, while there is good evidence that the rat brain is an immune privileged site \u201349 and dWe note that the studies included in this systematic search do not encompass all of the animal model literature: we present a disproportionate number of studies that model gliomata compared with models of metastases, and a notable paucity or absence of certain models. For instance, we present only one genetically-engineered mouse model, and our search did not return any porcine models, despite their existence and the presence of edema on scans . Given oIn summary, differences in the edema generated appear to be partly driven by factors relating to immunogenicity of the tumor/tumor-bearing animal combination, but also the macrostructure of the brain of the tumor-bearing animal. Further, the implanted tumors behave somewhat unpredictably, with considerable between-subjects differences reported in the growth rate of the tumor and the degree of associated brain edema .To conclude, we have shown that there are considerable limitations to the use of the brain tumor animal models presented herein to study tumor-induced brain edema and hence to study potential alternatives to steroids treatment.(i)The tumor must produce an immune response that credibly mimics that of human brain to human tumor, i.e. it must not be driven by a xenogeneic immune reaction.(ii)It must produce a relevant volume of radiologically detectable edema, with manifestations that temporarily improve or resolve with steroid treatment with corresponding changes in other measures of edema such as BWC, symptomatology, extravasation studies and so forth.(iii)The model should be affordable and compatible with the highest standards of animal welfare.We postulate that for an animal model of peritumoral edema to be considered valid, it should fulfill the following criteria:Regrettably, none of the existing models of peritumoral brain edema reviewed here satisfy these fundamental requirements. However, there is opportunity here: there are tumor animal models have not been formally assessed as models of brain tumor edema yet, but could prove to be useful. We have highlighted two key areas of interest: immunocompetent models, and large animal models. Meanwhile, unless a relevant peritumoral brain edema animal model can be characterised, it is likely that potential alternatives to steroids will need to be trialed directly on patients. We would also argue that the neuro-oncology community should agree on standard outcome measures for recording peritumoral brain edema in both animal models and in patients on clinical trials.1 Medline (\"brain edema\").ti,ab 58802 Medline \"BRAIN EDEMA\"/ 13,6653 Medline (\"brain hematoma\").ti,ab 354 Medline \"HEMATOMA, EPIDURAL, CRANIAL\"/ 33315 Medline (\"brain edema\").ti,ab 8576 Medline (\"brain swelling\").ti,ab 14697 Medline .ti,ab 46748 Medline .ti,ab 11609 Medline .ti,ab 25810 Medline (\"cytotoxic brain edema\").ti,ab 11311 Medline .ti,ab 1412 Medline (\"vasogenic brain edema\").ti,ab 25213 Medline .ti,ab 5314 Medline (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8 OR 9 OR 10 OR 11 OR 12 OR 13) 23,49215 Medline (astrocytoma).ti,ab 10,35516 Medline ASTROCYTOMA/ 13,98317 Medline (astroglioma).ti,ab 19518 Medline (\"brain cancer\").ti,ab 241919 Medline \"BRAIN NEOPLASMS\"/ 100,15420 Medline (brain AND (tumor* OR tumor*)).ti,ab 71,92321 Medline ((brain AND (tumor* OR tumor*)) AND metastasis).ti,ab 498922 Medline (\"brain neoplasm*\").ti,ab 76423 Medline (\"brain neoplasm*\" AND benign).ti,ab 3824 Medline (\"brain stem\" AND (tumor* OR tumor*)).ti,ab 184225 Medline \"BRAIN STEM NEOPLASMS\"/ 145326 Medline ((brain AND (tumor* OR tumor*)) AND malignan*).ti,ab 14,98827 Medline ((brain AND (tumor* OR tumor*)) AND primary).ti,ab 14,14328 Medline ((brain AND (tumor* OR tumor*)) AND recurrent).ti,ab 293629 Medline (\"cerebellar neoplasm*\").ti,ab 4630 Medline \"CEREBELLAR NEOPLASMS\"/ 858931 Medline (cerebellar AND (tumor* OR tumor*)).ti,ab 431332 Medline (cerebellum AND (tumor* OR tumor*)).ti,ab 244933 Medline .ti,ab 11434 Medline ).ti,ab 5435 Medline \"CEREBRAL VENTRICLE NEOPLASMS\"/ 339036 Medline .ti,ab 237 Medline (cerebroventricular AND neoplasm*).ti,ab 039 Medline (\"cerebellopontine\" AND (tumor* OR tumor*)).ti,ab 204540 Medline (\"choroid plexus neoplasm*\").ti,ab 3741 Medline \"CHOROID PLEXUS NEOPLASMS\"/ 59742 Medline (\"choroid plexus\" AND (tumor* OR tumor*)).ti,ab 1396.43 Medline (ependymoma).ti,ab 331644 Medline EPENDYMOMA/ 471545 Medline (ependymoblastoma).ti,ab 24646 Medline \"NEOPLASMS, NEUROEPITHELIAL\"/ 80747 Medline (\"fibrillary astrocytoma\").ti,ab 16748 Medline (ganglioglioma).ti,ab 94749 Medline GANGLIOGLIOMA/ 82850 Medline (\"gemistocytic astrocytoma\").ti,ab 6851 Medline (glioma).ti,ab 36,64252 Medline GLIOMA/ 34,56453 Medline (glioma AND astrocytic).ti,ab 78554 Medline (glioma AND mixed).ti,ab 60255 Medline .ti,ab 5856 Medline (glioblastoma).ti,ab 26,72057 Medline GLIOBLASTOMA/ 20,94258 Medline ).ti,ab 69959 Medline .ti,ab 060 Medline .ti,ab 661 Medline .ti,ab 062 Medline \"HYPOTHALAMIC NEOPLASMS\"/ 71263 Medline ).ti,ab 165064 Medline (hypophysis AND (tumor* OR tumor*)).ti,ab 31065 Medline .ti,ab 066 Medline \"INFRATENTORIAL NEOPLASMS\"/ 78167 Medline .ti,ab 468 Medline ).ti,ab 100169 Medline .ti,ab 1270 Medline .ti,ab 105371 Medline .ti,ab 995572 Medline (\"medullary neoplasm*\").ti,ab 1973 Medline (medullary AND (tumor* OR tumor*)).ti,ab 621674 Medline \"NEOPLASMS, DUCTAL, LOBULAR, AND MEDULLARY\"/ 7075 Medline (medulloepithelioma).ti,ab 31676 Medline MEDULLOBLASTOMA/ 63977 Medline .ti,ab 078 Medline (midbrain AND (tumor* OR tumor*)).ti,ab 53879 Medline (midbrain AND neoplasm*).ti,ab 4980 Medline (\"myxopapillary ependymoma\").ti,ab 30981 Medline \"GLIOMA, SUBEPENDYMAL\"/ 16682 Medline (neurocytoma).ti,ab 59683 Medline NEUROCYTOMA/ 56084 Medline ).ti,ab 515785 Medline exp \"NEUROECTODERMAL TUMORS\"/ 265,94986 Medline .ti,ab 487 Medline (oligoastrocytoma).ti,ab 47888 Medline (oligoastrocytic AND (tumor* OR tumor*)).ti,ab 3789 Medline (oligodendroglioma).ti,ab 231890 Medline OLIGODENDROGLIOMA/ 340991 Medline (oligodendrocytosis).ti,ab 592 Medline ).ti,ab 383793 Medline PINEALOMA/ 178294 Medline (\"pilocytic astrocytoma\").ti,ab 121195 Medline ).ti,ab 58096 Medline (pineoblastoma).ti,ab 29597 Medline .ti,ab 25198 Medline (pineocytoma).ti,ab 18799 Medline (PNET).ti,ab 2115100 Medline ).ti,ab 3212101 Medline (\"pons angle\" AND (tumor* OR tumor*)).ti,ab 2102 Medline (\"pontine neoplasm\").ti,ab 2103 Medline (pontine AND (tumor* OR tumor*)).ti,ab 970104 Medline (pontine AND glioma).ti,ab 505105 Medline (\"posterior fossa\" AND neoplasm).ti,ab 110106 Medline (\"posterior fossa\" AND (tumor* OR tumor*)).ti,ab 2887107 Medline (spongioblastoma).ti,ab 109108 Medline \"NEUROECTODERMAL TUMORS, PRIMITIVE\"/ 1661109 Medline (subependymoma).ti,ab 265110 Medline  AND tumor*).ti,ab 2111 Medline .ti,ab 28112 Medline \"SUPRATENTORIAL NEOPLASMS\"/ 2001113 Medline .ti,ab 176114 Medline (cerebri AND (tumor* OR tumor*)).ti,ab 484115 Medline ).ti,ab 8116 Medline (ventricular AND (tumor* OR tumor*)).ti,ab 5805117 Medline (15 OR 16 OR 17 OR 18 OR 19 OR 20 OR 21 OR 22 OR 23 OR 24 OR 25 OR 26 OR 27 OR 28 OR 29 OR 30) 128,452118 Medline (31 OR 32 OR 33 OR 34 OR 35 OR 36 OR 39 OR 40 OR 41 OR 42 OR 43 OR 44 OR 45 OR 46 OR 47 OR 48 OR 49 OR 50 OR 51 OR 52 OR 53 OR 54 OR 55 OR 56 OR 57 OR 58 OR 60 OR 62 OR 63 OR 64) 90,403119 Medline (66 OR 67 OR 68 OR 69 OR 70 OR 71 OR 72 OR 73 OR 74 OR 75 OR 76 OR 78 OR 79 OR 80 OR 81 OR 82 OR 83 OR 84 OR 85 OR 86 OR 87 OR 88 OR 89 OR 90) 276,190120 Medline (91 OR 92 OR 93 OR 94 OR 95 OR 96 OR 97 OR 98 OR 99 OR 100 OR 101 OR 102 OR 103 OR 104 OR 105 OR 106 OR 107 OR 108 OR 109 OR 110 OR 111 OR 112 OR 113 OR 114 OR 115 OR 116) 23,358121 Medline (14 AND 117) 1867122 Medline (14 AND 118) 864123 Medline (14 AND 119) 944124 Medline (14 AND 120) 195125 Medline .ti,ab 1,865,196126 Medline ANIMALS/ OR \"ANIMAL POPULATION GROUPS\"/ 6,167,987127 Medline \"MODELS, ANIMAL\"/ OR \"ANIMAL EXPERIMENTATION\"/ 41,734128 Medline (125 OR 126 OR 127) 6,410,366129 Medline (121 AND 128) 300130 Medline (122 AND 128) 195131 Medline (123 AND 128) 203132 Medline (124 AND 128) 12133 Medline 129 [Animals] 284134 Medline 130 [Animals] 185135 Medline 131 [Animals] 193136 Medline 132 [Animals] 111 PubMed (\"brain edema\").ti,ab 16,3192 PubMed (\"brain hematoma\").ti,ab 553 PubMed (\"brain edema\").ti,ab 8644 PubMed (\"brain swelling\").ti,ab 14845 PubMed .ti,ab 47736 PubMed .ti,ab 11727 PubMed .ti,ab 2608 PubMed (\"cytotoxic brain edema\").ti,ab 1149 PubMed .ti,ab 1510 PubMed (\"vasogenic brain edema\").ti,ab 25311 PubMed .ti,ab 5412 PubMed (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8 OR 9 OR 10 OR 11) 20,55413 PubMed (astrocytoma).ti,ab 35,93714 PubMed (astroglioma).ti,ab 36,03715 PubMed (\"brain cancer\").ti,ab 264416 PubMed (brain AND (tumor* OR tumor*)).ti,ab 765517 PubMed ((brain AND (tumor* OR tumor*)) AND metastasis).ti,ab 882718 PubMed (\"brain neoplasm*\").ti,ab 28919 PubMed (\"brain neoplasm*\" AND benign).ti,ab 720 PubMed (\"brain stem\" AND (tumor* OR tumor*)).ti,ab 41121 PubMed ((brain AND (tumor* OR tumor*)) AND malignan*).ti,ab 20,58722 PubMed ((brain AND (tumor* OR tumor*)) AND primary).ti,ab 20,65123 PubMed ((brain AND (tumor* OR tumor*)) AND recurrent).ti,ab 495524 PubMed (\"cerebellar neoplasm*\").ti,ab 2325 PubMed (cerebellar AND (tumor* OR tumor*)).ti,ab 94826 PubMed (cerebellum AND (tumor* OR tumor*)).ti,ab 46427 PubMed .ti,ab 12128 PubMed ).ti,ab 23429 PubMed .ti,ab 342030 PubMed (cerebroventricular AND neoplasm*).ti,ab 231 PubMed (\"choroid plexus neoplasm*\").ti,ab 532 PubMed (\"choroid plexus\" AND (tumor* OR tumor*)).ti,ab 11933 PubMed (ependymoma).ti,ab 610334 PubMed (ependymoblastoma).ti,ab 37,35535 PubMed (\"fibrillary astrocytoma\").ti,ab 16636 PubMed (ganglioglioma).ti,ab 129637 PubMed (\"gemistocytic astrocytoma\").ti,ab 7038 PubMed (glioma).ti,ab 84,05539 PubMed (glioma AND astrocytic).ti,ab 249440 PubMed (glioma AND mixed).ti,ab 147441 PubMed .ti,ab 62242 PubMed (glioblastoma).ti,ab 33,20643 PubMed ).ti,ab 4044 PubMed .ti,ab 045 PubMed .ti,ab 246 PubMed .ti,ab 047 PubMed ).ti,ab 51748 PubMed (hypophysis AND (tumor* OR tumor*)).ti,ab 59849 PubMed .ti,ab 050 PubMed .ti,ab 251 PubMed ).ti,ab 10152 PubMed .ti,ab 1253 PubMed .ti,ab 29554 PubMed .ti,ab 18,71755 PubMed (\"medullary neoplasm*\").ti,ab 656 PubMed (medullary AND (tumor* OR tumor*)).ti,ab 83557 PubMed .ti,ab 058 PubMed (midbrain AND (tumor* OR tumor*)).ti,ab 8959 PubMed (midbrain AND neoplasm*).ti,ab 132560 PubMed (\"myxopapillary ependymoma\").ti,ab 31461 PubMed (neurocytoma).ti,ab 74562 PubMed ).ti,ab 41963 PubMed .ti,ab 3164 PubMed (oligoastrocytoma).ti,ab 471165 PubMed (oligoastrocytic AND (tumor* OR tumor*)).ti,ab 266 PubMed (oligodendrocytosis).ti,ab 667 PubMed ).ti,ab 26468 PubMed (\"pilocytic astrocytoma\").ti,ab 126569 PubMed ).ti,ab 13270 PubMed (pineoblastoma).ti,ab 194371 PubMed .ti,ab 183372 PubMed (pineocytoma).ti,ab 187973 PubMed (PNET).ti,ab 38,07274 PubMed ).ti,ab 15275 PubMed (\"pons angle\" AND (tumor* OR tumor*)).ti,ab 1476 PubMed (\"pontine neoplasm\").ti,ab 277 PubMed (pontine AND (tumor* OR tumor*)).ti,ab 22378 PubMed (pontine AND glioma).ti,ab 1058.79 PubMed (\"posterior fossa\" AND neoplasm).ti,ab 3846.80 PubMed (\"posterior fossa\" AND (tumor* OR tumor*)).ti,ab 24481 PubMed (spongioblastoma).ti,ab 37,26182 PubMed (subependymoma).ti,ab 48383 PubMed  AND tumor*).ti,ab 184 PubMed .ti,ab 785 PubMed .ti,ab 26086 PubMed (cerebri AND (tumor* OR tumor*)).ti,ab 9987 PubMed ).ti,ab 388 PubMed (ventricular AND (tumor* OR tumor*)).ti,ab 76289 PubMed (69 OR 70 OR 71 OR 72 OR 73 OR 74 OR 75 OR 76 OR 77 OR 78 OR 79 OR 80 OR 81 OR 82 OR 83 OR 84 OR 85 OR 86 OR 87 OR 88) 45,65890 PubMed (49 OR 50 OR 51 OR 52 OR 53 OR 54 OR 55 OR 56 OR 57 OR 58 OR 59 OR 60 OR 61 OR 62 OR 63 OR 64 OR 65 OR 66 OR 67 OR 68) 27,60191 PubMed (29 OR 30 OR 31 OR 32 OR 33 OR 34 OR 35 OR 36 OR 37 OR 38 OR 39 OR 40 OR 41 OR 42 OR 43 OR 44 OR 45 OR 46 OR 47 OR 48) 122,45592 PubMed (13 OR 14 OR 15 OR 16 OR 17 OR 18 OR 19 OR 20 OR 21 OR 22 OR 23 OR 24 OR 25 OR 26 OR 27 OR 28) 75,21993 PubMed .ti,ab 21,587,74194 PubMed (12 AND 92 AND 93) 86795 PubMed (12 AND 91 AND 93) 83296 PubMed (12 AND 90 AND 93) 27297 PubMed (12 AND 89 AND 93) 10298 PubMed (human).ti,ab 17,558,98699 PubMed 94 not 98 76100 PubMed 95 not 98 121101 PubMed 96 not 98 18102 PubMed 97 not 98 81 CINAHL (\"brain edema\").ti,ab 3322 CINAHL \"CEREBRAL EDEMA\"/ 9203 CINAHL (\"brain hematoma\").ti,ab 14 CINAHL (\"brain swelling\").ti,ab 945 CINAHL .ti,ab 4066 CINAHL .ti,ab 847 CINAHL .ti,ab 148 CINAHL (\"cytotoxic brain edema\").ti,ab 49 CINAHL .ti,ab 110 CINAHL (\"vasogenic brain edema\").ti,ab 411 CINAHL .ti,ab 412 CINAHL (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8 OR 9 OR 10 OR 11) 136713 CINAHL (astrocytoma).ti,ab 33314 CINAHL (astroglioma).ti,ab 115 CINAHL (\"brain cancer\").ti,ab 263CINAHL \"BRAIN NEOPLASMS\"/ 475717 CINAHL (brain AND (tumor* OR tumor*)).ti,ab 325118 CINAHL ((brain AND (tumor* OR tumor*)) AND metastasis).ti,ab 39319 CINAHL (\"brain neoplasm*\").ti,ab 3920 CINAHL (\"brain neoplasm*\" AND benign).ti,ab 121 CINAHL (\"brain stem\" AND (tumor* OR tumor*)).ti,ab 2922 CINAHL ((brain AND (tumor* OR tumor*)) AND malignan*).ti,ab 53423 CINAHL ((brain AND (tumor* OR tumor*)) AND primary).ti,ab 72324 CINAHL ((brain AND (tumor* OR tumor*)) AND recurrent).ti,ab 13925 CINAHL (\"cerebellar neoplasm*\").ti,ab 126 CINAHL (cerebellar AND (tumor* OR tumor*)).ti,ab 12227 CINAHL (cerebellum AND (tumor* OR tumor*)).ti,ab 6128 CINAHL .ti,ab 129 CINAHL ).ti,ab 130 CINAHL .ti,ab 031 CINAHL (cerebroventricular AND neoplasm*).ti,ab 032 CINAHL (cerebellopontine AND (tumor* OR tumor*)).ti,ab 6833 CINAHL (\"choroid plexus neoplasm*\").ti,ab 034 CINAHL (\"choroid plexus\" AND (tumor* OR tumor*)).ti,ab 1835 CINAHL (ependymoma).ti,ab 18236 CINAHL (ependymoblastoma).ti,ab 037 CINAHL (\"fibrillary astrocytoma\").ti,ab 238 CINAHL (ganglioglioma).ti,ab 2139 CINAHL (glioma).ti,ab 132640 CINAHL GLIOMA/ 260741 CINAHL (glioma AND astrocytic).ti,ab 2042 CINAHL (glioma AND mixed).ti,ab 2843 CINAHL .ti,ab 144 CINAHL (glioblastoma).ti,ab 109745 CINAHL ).ti,ab 2246 CINAHL .ti,ab 047 CINAHL .ti,ab 048 CINAHL .ti,ab 049 CINAHL (hypophysis AND (tumor* OR tumor)).ti,ab 150 CINAHL .ti,ab 051 CINAHL \"INFRATENTORIAL NEOPLASMS\"/ 7352 CINAHL \"HYPOTHALAMIC NEOPLASMS\"/ 953 CINAHL .ti,ab 154 CINAHL ).ti,ab 1755 CINAHL .ti,ab 156 CINAHL .ti,ab 3757 CINAHL .ti,ab 35858 CINAHL (\"medullary neoplasm*\").ti,ab 059 CINAHL (medullary AND (tumor* OR tumor*)).ti,ab 13460 CINAHL \"NEOPLASMS, DUCTAL, LOBULAR, AND MEDULLARY\"/ 32461 CINAHL (medulloepithelioma).ti,ab 362 CINAHL \"NEUROECTODERMAL TUMORS, PRIMITIVE\"/ 8063 CINAHL (medulloblastoma).ti,ab 28464 CINAHL .ti,ab 065 CINAHL (midbrain AND (tumor* OR tumor*)).ti,ab 1666 CINAHL (midbrain AND neoplasm*).ti,ab 267 CINAHL (\"myxopapillary ependymoma\").ti,ab 1668 CINAHL (neurocytoma).ti,ab 2969 CINAHL ).ti,ab 17170 CINAHL .ti,ab 071 CINAHL (oligoastrocytoma).ti,ab 4572 CINAHL (oligoastrocytic AND (tumor* OR tumor*)).ti,ab 173 CINAHL (oligodendroglioma).ti,ab 11274 CINAHL (oligodendrocytosis).ti,ab 075 CINAHL ).ti,ab 10276 CINAHL (\"pilocytic astrocytoma\").ti,ab 2677 CINAHL ).ti,ab 1578 CINAHL (pineoblastoma).ti,ab 579 CINAHL PINEALOMA/ 2980 CINAHL \"INFRATENTORIAL NEOPLASMS\"/ 7381 CINAHL .ti,ab 282 CINAHL (pineocytoma).ti,ab 383 CINAHL (PNET).ti,ab 10084 CINAHL ).ti,ab 13585 CINAHL (\"pons angle\" AND (tumor* OR tumor*)).ti,ab 186 CINAHL (\"pontine neoplasm\").ti,ab 087 CINAHL (pontine AND (tumor* OR tumor)).ti,ab 3488 CINAHL (pontine AND glioma).ti,ab 2589 CINAHL (\"posterior fossa\" AND neoplasm*).ti,ab 1090 CINAHL (\"posterior fossa\" AND (tumor* OR tumor*)).ti,ab 10891 CINAHL (spongioblastoma).ti,ab 192 CINAHL \"NEOPLASMS, NEUROEPITHELIAL\"/ 8193 CINAHL  AND tumor*).ti,ab 094 CINAHL .ti,ab 295 CINAHL .ti,ab 196 CINAHL MENINGIOMA/ 49397 CINAHL (cerebri AND (tumor* OR tumor*)).ti,ab 2098 CINAHL ).ti,ab 099 CINAHL (ventricular AND (tumor* OR tumor*)).ti,ab 294100 CINAHL (13 OR 14 OR 15 OR 16 OR 17 OR 18 OR 19 OR 20 OR 21 OR 22 OR 23 OR 24 OR 25 OR 26 OR 27 OR 28 OR 29 OR 30 OR 31 OR 32 OR 33 OR 34 OR 35 OR 36 OR 37 OR 38 OR 39 OR 40 OR 41 OR 42 OR 43 OR 44 OR 45 OR 46 OR 47 OR 48 OR 49 OR 50 OR 51 OR 52 OR 53 OR 54 OR 55 OR 56 OR 57 OR 58 OR 59 OR 60 OR 61 OR 62 OR 63 OR 64 OR 65 OR 66 OR 67 OR 68 OR 69 OR 70 OR 71 OR 72 OR 73 OR 74 OR 75 OR 76 OR 77 OR 78 OR 79 OR 80 OR 81 OR 82 OR 83 OR 84 OR 85 OR 86 OR 87 OR 88 OR 89 OR 90 OR 91 OR 92 OR 93 OR 94 OR 95 OR 96 OR 97 OR 98 OR 99) 9685.101 CINAHL .ti,ab 44,880.102 CINAHL \"ANIMALS, LABORATORY\"/ OR \"ANIMAL POPULATION GROUPS\"/ OR ANIMALS/35299103 CINAHL \"ANIMAL STUDIES\"/ 43,675104 CINAHL (101 OR 102 OR 103) 90,301105 CINAHL (12 AND 100) 78106 CINAHL (103 AND 105) 11107 CINAHL (102 AND 105) 12Brain edemaBrain hematomaBrain edemaBrain swellingCerebral edemaCerebral edemaCerebral swellingCytotoxic brain edemaCytotoxic cerebral edemaIntracranial edemaVasogenic brain edemaVasogenic cerebral edemaBrain Disease, Edema (<\u20091992)AstrocytomaAstrogliomaBrain cancerBrain tumor(s)Brain tumor(s)Brain Tumor MetastasisBrain neoplasm(s)Brain neoplasm(s), benignBrain stem tumor(s)Brain stem tumor(s)Brain tumor, malignantBrain tumor, malignantBrain tumor, primaryBrain tumor, primaryBrain tumor, recurrentBrain tumor, recurrentCerebellar Neoplasm(s)Cerebellar Tumor(s)Cerebellar Tumor(s)Cerebellum tumorCerebral AstrocytomaCerebral Ventricle Tumor(s)Cerebral Ventricle Tumor(s)Cerebral Ventricle Neoplasm(s)Cerebroventricular Neoplasm(s)Cerebello Pontine Angle TumorChoroid Plexus NeoplasmsChoroid Plexus TumorsEpendymomaEpendymoblastomaFibrillary AstrocytomaGangliogliomaGemistocytic AstrocytomaGliomaGlioma, AstrocyticGlioma, MixedGlioma, SubependymalGlioblastoma, Giant CellGliosarcomaGlial Cell Tumor(s)Glial Cell Tumor(s)Hypothalamic CancerHypothalamic Neoplasm(s)Hypothalamic TeratomasHypothalamic Tumor(s)Hypothalamic Tumor(s)hypothalamus tumorHypophysis tumorInfratentorial CancerInfratentorial Neoplasm(s)Infratentorial Tumor(s)Infratentorial Tumor(s)Intracranial AstrocytomaIntracranial Neoplasm(s)Malignant GliomaMedullary Neoplasm(s)Medullary Tumor(s)Medullary Tumor(s)MedulloepitheliomaMesencephalic Neoplasm(s)Midbrain Tumor(s)Midbrain Tumor(s)Myxopapillary EpendymomaNeoplasm MetastasesNeoplasm MicrometastasesNeurocytomaNeuroectodermal Tumors, PrimitiveNeurohypophysial Region NeoplasmsOligoastrocytoma.Oligoastrocytic tumorsOligodendrogliomaOligodendrocytosisParenchymal TumorPilocytic AstrocytomaPineal Gland TumorPineal Gland TumorPineal Tumor(s)Pineal Tumor(s)PineoblastomaPinealomaPineocytomaPineocytoma-PineoblastomaPNETPons angle tumorPontine Neoplasm(s)Pontine Tumor(s)Pontine Tumor(s)Pontine GliomaPosterior Fossa Neoplasm(s)Posterior Fossa TumorPosterior Fossa TumorPrimitive Neuroepithelial NeoplasmsSpongioblastomaSubependymomaSubtentorial TumorSupratentorial Neoplasm(s)Tentorial MeningiomaTentorium MeningiomaTumor, CerebriVentricle Tumor, BrainVentricular Tumors, BrainAnimal(s)Animal healthAnimal populationAnimal researchAnimal studiesLaboratory animalsNon-human dataPrimatesRabbitsRatsRodentsAnimal v Human comparative study"}
+{"text": "Individuals with autism spectrum condition (ASC) frequently report difficulties in social communications, combined with restricted inflexible behaviors. However, it is unclear whether this rigidity is pervasive across cognitive flexibility (CF) and affective flexibility (AF) in situations which resolve different social conflicts.To study CF and AF levels and associated brain activity in individuals with ASC.Individuals with ASC and with typical development (TD) performed a moral dilemma task during functional magnetic resonance imaging. For CF, participants made decisions on (1) whether to enforce result-oriented actions to prioritize social/public benefits; and (2) judged whether these actions are right or wrong. For AF, participants made decisions on (1) whether to permit social norm/rule violations in sympathy-evoking situations; and (2) permit these identical violations in no sympathy-evoking situations. We calculated participants\u2019 CF/AF levels by computing the switching-rate of decisions in CF/AF sessions .For CF, ASC participants showed a marked decrease in CF switching-rates compared to TD participants (p < 0.05), and in corresponding brain activity for executive functioning. For AF, although the AF switching rate difference was non-significant, we observed unique brain activities in each group .Our results suggest ASC inflexibility may be further characterized by both CF and AF.No significant relationships."}
+{"text": "Standard urine culture collection techniques have a high risk of false positive results in catheterized patients. IDSA guidelines recommend replacing long-term catheters before specimen collection for cultures. Our goal was to evaluate the impact of clinical decision support (CDS) during the urine culture computerized provider order entry (CPOE) on test use and patient-level outcomes.In March 2021, CDS was added to the urine culture CPOE in the electronic health record (EHR). The order panel includes education regarding appropriate clinical indications for urine culturing, and protocolizes urine collection to determine (A) if a urinalysis was ordered, (B) if special patient population , (C) the presence and duration of an indwelling urinary catheter, and (D) whether the catheter had difficulty with placement. Depending on the criteria identified in A, B, C, and D, the panel recommends catheter removal prior to urine culture . We retrospectively evaluated the impact of panel implementation in our pre- (7/2020- 3/2021) and post-intervention periods (4/2021- 3/2022) using an interrupted time series analysis with Poisson regression. Outcomes included urine cultures/1000 patient days (pd), number of catheter removal orders, catheter-associated urinary tract infection (CAUTI)/1000 catheter days, and days of antibiotic therapy with urinary tract infection (UTI) indication/1000pdOrder Panel FrameworkClinicians selected catheter removal in 183 of 2133 (8.5%) instances of ordering a urine culture when a catheter was detected by the panel . Analysis revealed a significant decrease in urine culture orders , a decreasing trend of antibiotic use with UTI indications , but no significant change in CAUTI rates . Evaluation of the safety reporting system revealed no identifiable increase in safety events related to catheter removal or reinsertion.Catheter Associated Urinary Tract InfectionsBlack boxes indicate Poisson regression model estimatesBlack boxes indicate Poisson regression model estimatesCDS can aid in improving urine culture practice habits, including removal of long-standing catheters before urine culture. The decreasing trend in total urine culture orders  may reflect a \u201dculture change\u201d over time to avoid urine cultures in inappropriate instances.Total Urine Cultures OrderedBlack boxes indicate Poisson regression model estimates. Red circles indicate predicted outcome without \u2018intervention\u2019.Sonali D. Advani, MBBS, MPH, FIDSA, Locus Biosciences: Advisor/Consultant|Locus Biosciences: Honoraria|Sysmex America: Advisor/Consultant."}
+{"text": "Scientific reports 10.1038/s41598-022-08192-2, published online 11 March 2022Correction to: The original version of this Article omitted the Funding section. The Funding section now reads:\u201cThis work was supported by Brazilian Coordination for the Improvement of Higher Education Personnel (CAPES) and Federal University of Pernambuco (UFPE) through the PROPG 02/2021 announcement.\u201dThe original Article has been corrected."}
+{"text": "A 65-year-old woman presented to the Pulmonary Clinic for evaluation after Positron Emission Tomography/Computed Tomography (PET/CT), which was obtained for assessment of a 12 mm right middle lobe solitary pulmonary nodule. She denied shortness of breath, fever, arm swelling, or breast masses. The PET/CT showed intensely FluoroDeoxyGlucose (FDG) avid right axillary lymph nodes (The largest of which measured 30 mm) and the right deltoid muscle . There w"}
+{"text": "Central line-associated bloodstream infection (CLABSI) and catheter-associated urinary tract infection (CAUTI) continue to be the focus of external reporting of healthcare associated infections based on CDC-NHSN criteria. As facilities decrease CLABSI and CAUTI, we sought to understand our non-central line bloodstream infections (NCLABSI) and non-catheter urinary tract infections (NCAUTI).We retrospectively reviewed total healthcare associated bloodstream infections (HABSI) (NCLABSI + CLABSI) and healthcare associated urinary tract infections (HAUTI) (NCAUTI + CAUTI) from July 1, 2016 to June 30, 2021 at our 334-bed quaternary care Children\u2019s Hospital. CLABSI and CAUTI were both defined using CDC-NHSN criteria. Epidemiologic and microbiologic data, total antibiotic days related to infection, and mortality were analyzed for each subgroup.Staphylococcus aureus was the predominant pathogen in all HABSIs . Pseudomonas aeruginosa was seen in 15% of CLABSIs but in no NCLABSIs. P. aeruginosa was seen in both CAUTI (32%) and NCAUTI (11%). Escherichia coli was the predominant pathogen in NCAUTI (39%) . There were 2 NCLABSI (5%), 16 CLABSI (13%), 2 NCAUTI (3%) and 2 CAUTI (11%) patient deaths during hospitalization.In a 5-year period, 255 patients were identified with HABSI and HAUTI; 164 were HABSI  and 91 were HAUTI . While our NCLABSI, CLABSI, and CAUTI infections per fiscal year (FY) have remained relatively stable, our NCAUTIs have increased since FY17 . Total antibiotic days for NCLABSI versus CLABSI and for NCAUTI versus CAUTI were similar . P. aeruginosa, typically an important pathogen in device-associated infections, also contributes to non-device associated infections. We feel that total HABSI and HAUTI may provide more objective measures to report. Infection prevention measures to decrease NCLABSI and NCAUTI also need attention.Our data shows that non-device related healthcare associated infections are a significant proportion of our total healthcare associated infections, comprising one quarter of HABSIs and three quarters of HAUTIs. In addition, All Authors: No reported disclosures."}
+{"text": "Methanobacterium sp. metagenome-assembled genome (MAG) was recovered from high-CO2 enrichments inoculated with drill core material from the tectonic Eger Rift terrestrial subsurface. Annotation of the recovered MAG highlighted putative methanogenesis genes, providing valuable information on archaeal activity in the deep biosphere.A circular, single-contig  High-molecular-weight DNA was prepared using the rapid barcoding sequencing kit  and cleaned up using AMPure XP beads , removing small DNA fragments. The resulting library was sequenced using the MinION platform (ONT) and the Flo-MIN106 flow cell for 72 h. Sequencing raw data was basecalled and demultiplexed using high accuracy with guppy v4.4.2\u2009+\u20099623c1626 (ONT) resulting in 398,466 raw reads with an N50 of 3852bp. Default parameters were used for all software unless otherwise specified. Assembly and polishing were performed with Flye v2.8.2-b1689  allowed the enrichment of native microbial communities. Drill core materials (~5 g each) from eight different depths (46 m to 230 m) were separately enriched in slurries using OMV5 mineral medium under COMethanobacterium. The draft genome was compared to other Methanobacterium genomes by calculating the average nucleotide identity (ANI) using the JSpeciesWS tool (accessed March 2022) (Methanobacterium sp. strain ERen5 shares the most nucleotide-level genomic similarity with Methanobacterium lacus strain AL-21 (ANIb = 91.45% and ANIm = 92.56%). Full-length 16S rRNA sequence comparison  using NCBI BLAST  . MethanoBI BLAST  revealedtic lake .mcrA  and N5-methyltetrahydromethanopterin:coenzyme M methyltransferase subunit mtrA . Phylogenetic assessment of mcrA suggested the recovered genome to be closely related to Methanobacterium lacus and Methanobacterium paludis strains isolated from northern peatlands (Annotation using PGAP  allowed eatlands .Methanobacterium sp. strain ERen5 was deposited at NCBI with the accession number CP099988 under BioProject PRJNA832091. Raw reads are accessible via the accession number SRR19049537. The 16S rRNA sequence is available at NCBI under the accession number ON341022.1.The draft genome of"}
+{"text": "A major outbreak of COVID19-associated mucormycosis (CAM) in India in spring 2021 aggravated the death toll of COVID19. As the causes of that CAM outbreak remain unclear, we performed a multifaceted study of host, pathogen, environmental, and heath care-related factors in adult CAM patients (pts) in the metropolitan New Delhi area.We reviewed the records of all pts diagnosed with culture- or biopsy-proven CAM at 7 hospitals in the New Delhi area . We used a multivariate logistic regression model to compare clinical characteristics of either all CAM cases  or only pts with CAM after moderate or severe COVID19 . As controls for both analyses, we used 69 COVID19-hospitalized contemporary pts. Selected hospital fomites were cultured for Mucorales. Additionally, we compared meteorological data and fungal spore concentrations in outdoor air before the CAM outbreak (January-March 2021) and during the outbreak (April-June 2021). Mucorales isolates from CAM pts were identified by MALDI-TOF-MS and ITS sequencing. A subset of 15 isolates underwent whole genome sequencing (WGS).Figure\u00a01). Supplemental oxygen for COVID19 was associated with a lower CAM risk in both analyses (OR 0.13/0.17). Another significant CAM risk predictor identified only in analysis 1 was severe COVID19 , while remdesivir therapy (OR 0.40) and ICU admission for COVID19 were protective (OR 0.41) . No Mucorales were cultured from hospital fomites. The CAM incidence peak coincided with a significant uptick in environmental spore concentrations but was not linked to specific meteorological factors. Rhizopus was the predominant Mucorales genus (64%) identified by MALDI-TOF-MS and ITS sequencing; WGS found no clonal population of isolates but detected 2 cases of the rare pathogen Lichtheimia ornata.Risk factors for CAM in both analyses were newly diagnosed diabetes mellitus (odds ratio [OR] 8.26/5.67) and active cancer (OR 5.98/5.68) , AbbVie: Advisor/Consultant|Astellas Pharma: Advisor/Consultant|Astellas Pharma: Grant/Research Support|Astellas Pharma: Honoraria|Cidara Therapeutics: Advisor/Consultant|Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|Gilead Sciences: Honoraria|Merck: Advisor/Consultant."}
+{"text": "Moreover, mutant KRAS induces an intrinsic IFN-stimulated gene (ISG) signature that is often seen across many different cancers. Our results indicate that mutant KRAS remodels the repetitive noncoding transcriptome, demonstrating the broad scope of intracellular and extracellular RNAs regulated by this oncogenic signaling pathway.RAS genes are the most frequently mutated oncogenes in cancer, yet the effects of oncogenic RAS signaling on the noncoding transcriptome remain unclear. We analyzed the transcriptomes of human airway and bronchial epithelial cells transformed with mutant KRAS to define the landscape of KRAS-regulated noncoding RNAs. We find that oncogenic KRAS signaling upregulates noncoding transcripts throughout the genome, many of which arise from transposable elements (TEs). These TE RNAs exhibit differential expression, are preferentially released in extracellular vesicles, and are regulated by KRAB zinc-finger (KZNF) genes, which are broadly downregulated in mutant KRAS cells and lung adenocarcinomas   Many human cancers are driven by mutant KRAS, but its effects on noncoding RNA are unclear. Reggiardo et al. show that mutant KRAS regulates this RNA landscape by silencing KRAB zinc-finger genes that normally repress transposable element noncoding RNAs, which are preferentially released from mutant KRAS cells in extracellular vesicles. Most of the human genome is noncoding and transcribed into RNA . Moreovein vitro and in mutant KRAS lung adenocarcinomas in vivo. Moreover, our findings indicate that significant upregulation and extracellular secretion of TE RNAs and ISGs are transcriptomic signatures of mutant KRAS signaling.To investigate the role of mutant KRAS in reprogramming the transcriptome during early stages of cellular transformation, we characterized the composition of both intracellular and extracellular RNA, including protein-coding RNA, lncRNA, and TE RNA, using human airway epithelial cells  and humaTo determine the transcriptomic landscape of protein-coding and noncoding RNAs regulated by oncogenic RAS signaling, we performed RNA sequencing (RNA-seq) on human airway epithelial cells (AALE) that undergo malignant transformation upon the introduction of mutant KRAS . We comp\u03b1 and -\u03b3 responses, as well as the hallmark inflammatory response   using geresponse , along wresponse .in vivo relevance of our findings in both mutant KRAS AALE and HBEC cells, we examined ISG expression in mutant KRAS(G12D) lung adenocarcinomas (LUAD) from The Cancer Genome Atlas (TCGA), which revealed a subset of ISGs that were upregulated in KRAS(G12D) tumors when compared to lung cancer samples with wild-type (WT) KRAS  and in vivo (TCGA LUAD).To further validate the connection observed between mutant KRAS and ISG expression, we compared mutant KRAS-induced ISGs in AALE cells to those that were induced in human bronchial epithelial cells (HBECs) in response to mutant KRAS(G12V) . We obseWT) KRAS . These rTo elucidate potential mechanisms involved in inducing ISG signatures in mutant KRAS AALE cells, we performed the assay for transposase-accessible chromatin using sequencing (ATAC-seq) . In mutaThe genome-wide effects of mutant KRAS-mediated epigenomic reprogramming were further assessed with the Genome Regions Enrichment of Annotations Tool (GREAT) . GREAT aTo test whether extracellular RNAs secreted from mutant KRAS cells also exhibit differential expression relevant to intracellular reprogramming events, we isolated extracellular vesicles from the culture media of control and mutant KRAS AALEs . Extrace\u03b1 and -\u03b3 signatures were enriched in both intracellular and extracellular RNA  and lncRNA   and S2A.ular RNA , indicatTo determine the effects of oncogenic KRAS on noncoding RNA secretion, we also characterized the TE RNAs that were preferentially packaged and released in extracellular vesicles. We found significant upregulation of predominantly long terminal repeat (LTR) RNAs such as LTR12, MER11C, and LTR27C, along with LINE, DNA, and Satellite repeat RNAs in mutant KRAS AALE extracellular vesicles . MoreoveGiven the prevalence of secreted TE RNAs, we investigated intracellular TE RNA dynamics in response to mutant KRAS signaling in AALE cells. Analogous to extracellular RNAs, LTR RNAs were among the most significantly upregulated TE RNAs in response to oncogenic KRAS signaling, including LTR12C RNAs . In addiBased on the functions of KZNF genes in silencing TE RNAs in other contexts , we examTo explore the mechanistic relationship between KZNFs and TE RNA expression, we examined mutant KRAS A549 lung cancer cells that overexpress ZNF257 or ZNF682 , both ofTo determine the extent to which mutant KRAS signaling epigenetically silences KZNF expression, we examined ATAC-seq data for all significantly downregulated KZNF loci. We found that mutant KRAS signaling substantially reduces chromatin accessibility at TSS regions . When weFinally, we explored the clinical significance of the mutant KRAS-induced KZNF silencing we identified in AALE and HBEC cells. Evaluation of KZNF expression in TCGA LUAD RNA-seq data revealed their significant downregulation in mutant KRAS(G12D) samples when compared to WT KRAS lung cancer or matched normal samples, respectively  and 5B. in vivo. Our conclusions are based on deeply sequencing and analyzing the intracellular and extracellular transcriptomes and epigenomes of mutant KRAS-transformed lung cells, building on previous work in which we discovered the coordinate regulation of noncoding RNAs and RAS signaling in the context of epigenomic reprogramming  that correct mutations in KRAS would reveal whether oncogenic RAS signaling is necessary for high ISG expression in tumor cells. Lastly, the biomarker potential of extracellular RNAs that are preferentially secreted from cancer cells with oncogenic RAS signaling would require validation using blood samples from patients with lung and other cancers having activating driver mutations in RAS pathway genes.daniel.kim@ucsc.edu).Further information and requests for resources and reagents should be directed to and will be fulfilled by the lead contact, Daniel H. Kim (This study did not generate new unique reagents.Bulk RNA-seq and ATAC-seq data have been deposited at GEO (GSE120566) and are publicly available as of the date of publication. Accession numbers are also listed in the All original code has been deposited at Zenodo and is publicly available as of the date of publication. DOIs are listed in the Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.2 in SABM Basal Medium  with supplements and growth factors .Immortalized lung epithelial cells , derived at Dana-Farber and immortalized by SV40 large-T antigen  were obt2 in Keratinocyte Serum-Free Media (KSFM) with supplements .HBEC3kt cell lines  were obtained as a gift from the laboratory of Harold Varmus . The HBEC stable cell lines pLenti6/V5-GW/lacZ (control)  and pLenFor AALE cell lines, bulk RNA was isolated from cells using Quick-RNA MiniPrep kit (Zymogen) and RNA was quantified via NanoDrop-8000 Spectrophotometer. 1ug of total RNA was used as input for the TruSeq Stranded mRNA Sample Prep Kit (Illumina) according to manufacturer protocol. Library quality was determined through the High Sensitivity DNA Kit on a Bioanalyzer 2100 (Agilent Technologies). 6 multiplexed libraries, 3 biological replicates of each condition, were sequenced as HiSeq400 100PE runs.For HBEC cell lines, cells grown in 10 cm plates (n = 3 per cell line) were washed twice in cold DPBS then collected in Tri-reagent for storage at \u201380\u00b0C until the bulk RNA was extracted using Direct-Zol RNA Miniprep Kit (Zymo Research). Concentrations of purified RNA in nuclease-free water were determined by Nanodrop-2000 Spectrophotometer and by Qubit RNA BR Assay (ThermoFisher Scientific). Quality RIN numbers ranging from 9.4\u201310 were determined by TapeStation 4150 RNA ScreenTape Analysis (Agilent Technologies) before sending RNA to UC Davis DNA Technologies and Expression Analysis Core Laboratory for poly-A strand specific library preparation to obtain 60 million paired end reads by NovaSeq S4 (PE150) sequencing.100,000 AALE cells were collected and centrifuged at 500xg for 5 min at 4C. Pellets were washed with ice-cold PBS and centrifuged. Pellets were resuspended in ice-cold lysis buffer. Tagmentation reaction and purification were conducted according to manufacturer\u2019s protocol (Active Motif). 2 Libraries, one from each condition, were sequenced on a NextSeq500 as 2 \u00d7 75 paired end reads.The exoRNeasy serum/plasma maxi kit (Qiagen) was used to isolate extracellular vesicles, which were quantified using Nanoparticle Tracking Analysis . 30 mL of AALE cell culture supernatant was filtered to remove particles larger than 0.8 um. The filtrate was precipitated with kit buffer and filtered through a column to collect extracellular vesicles. These vesicles were then lysed with QIAzol\u00ae lysis reagent. Total RNA was isolated using the indicated phase separation method and used to make 6 libraries, 3 biological replicates for each condition, for RNA-seq using the Smart Seq HT low input mRNA library prep kit (Takara). Libraries were sequenced on an Illumina NextSeq500.fastq files were trimmed with Trimmomatic 2 (0.38) (FastQC (All 2 (0.38)  using th . Input gene abundance data was first variance stabilized using DESeq2 and then filtered for genes with 0 standard deviation across the samples.PCA was performed in R using packages memes (1.1.4), universalmotif (1.10.2), BSgenome.Hsapiens.UCSC.hg38 (1.4.3), MotifDBGenomicRanges (1.44.0) and MotifDB (1.34.0)    and filtR package fgsea (1.18.0) (The (1.18.0)  was used(1.18.0)  estimateR package rGREAT (1.24.0) (Bioconductor) was used to process ATAC-seq identified peaks with GREAT and identify enriched GO terms. ATAC-seq peaks unique to either CTRL or KRAS contexts were used as input with the background set to the entire peak library comprised from both contexts.The R using the package ComplexHeatmap (2.8.0)   . Survivage (3.3) .R package bamsignals (1.24.0) (Bioconductor) using the sorted bam files produced by the nf-core pipeline.The nf-core ATAC-seq pipeline was used to process ATAC-seq reads to alignments with BWA, narrow peak calls with MACS2, and ultimately annotated peaks. Read count analysis was performed with the R \u2013 wilcox.test) unless otherwise noted and p values <0.05 were considered significant. All statistical analyses were performed with R (version 4.1.1) running from the Rocker \u2018Tidyverse\u2019 Docker container (rocker/tidyverse:4.1.1). Linear regression was carried out with the lm function.All quantitative data for functional assays have been reported as means \u00b1 standard deviation. Statistical significance for these were calculated using a Wilcox-test (https://genome.ucsc.edu/s/rreggiar/aale%2DKRAS%2DG12%2Dtransformation.UCSC Genome Browser tracks generated from ATAC-seq data: 1"}
+{"text": "The incidence of dementia is rapidly increasing. Identifying risk factors for dementia may help improve risk assessment, increase awareness for risk reduction, and identify potential targets for interventions. We use a life-course multi-disciplinary modeling framework to examine leading predictors of incident dementia (ID). We use the Health and Retirement Study (HRS) to measure 57 exposures across 7 different domains: (1) demographic, (2) adverse childhood socioeconomic and psychosocial, (3) adverse adulthood experiences, (4) adult socioeconomic status, (5) health behaviors, (6) social connections, and (7) adult psychological conditions. Our outcome is ID (over 8-years) operationalized using Langa-Weir classification for adults aged 65+ years who meet criteria for cognitively normal at the baseline when all exposures are measured . We compare standard methods (Logistic regression) with machine learning (ML) approaches  in identifying highly predictive exposures across the risk domains of interest. Standard methods identified lower education, childhood financial duress, and pessimism as among the leading factors associated with ID. Psychological factors explained the highest variance for ID, followed by adult socioeconomic and adverse childhood factors. However, ML techniques differed in their identification of (1) predictors and (2) factors predictive importance. The findings emphasize the importance of upstream risk factors and the long-reach of childhood experiences on cognitive health. The ML approaches highlight the importance of life-course multi-disciplinary frameworks for improving dementia risk assessment. Further investigations are needed to identify how complex interactions of life-course risk factors can be addressed through interventions."}
+{"text": "Acinetobacter baumannii (CRAb) is increasing due to widespread use of antibiotics. Multidrug resistant (MDR) CRAb is a major threat to public health as treatment options are limited. The objective of this study is to elucidate the molecular epidemiology of circulating antibiotic resistance genes causing MDR CRAb infections by using a combination of whole-genome Multi-Locus Sequence Typing (wgMLST) and antibiotic susceptibility phenotyping.Carbapenem-resistant Bacterial isolates were derived from cultures taken from subjects 48 hours following admission as part of routine clinical care for patients between 2017-2020. Isolates were obtained from 16 hospital units (both ICU and non-ICU) across two hospitals in the Detroit area. Whole Genome Sequencing (WGS) was performed using Illumina MiniSeq or Nextseq. WgMLST analysis was performed using BioNumerics software v7.6. ResFinder software was used for analysis of antibiotic resistance genes. Isolates underwent antibiotic susceptibility testing using a broth microdilution method (VITEK2) and Clinical & Laboratory Standards Institute (CLSI) minimum inhibitory concentration (MIC) cut offs.CRAb isolates and of the CRAb isolates, 21(41%) were MDR CRAb. WgMLST identified that majority of the circulating MDR CRAb isolates belonged to ST2Pas (ST195Ox and ST208Ox) based on CDC definitions (Table\u00a01). MDR CRAb isolates were resistant to 3 different classes of antibiotics including aminoglycosides, fluroquinolones and \u03b2-lactams. \u03b2-lactamase genes present include  for both ST195Ox and ST208Ox and  for ST406Pas (ST310Ox). Among the patients with MDR CRAb infections, most were males with respiratory infections in a non-ICU setting.Out of the 95 total isolates, 51(54%) were Pas carrying multiple beta-lactamase genes including blaOXA-23 gene. ST406Pas might be an emerging lineage carrying the blaOXA-23 gene. In addition to stringent infection control measures, continuous surveillance is recommended in limiting the spread of MDR CRAb isolates in the healthcare settings.The study demonstrated a high proportion of isolates belonged to ST2 Chetan Jinadatha, MD, MPH, AHRQ R01 Grant-5R01HS025598: Grant/Research Support|EOS Surfaces: Copper Coupons and materials for testing Keith S. Kaye, MD, MPH, Allecra: Advisor/Consultant|GlaxoSmithKline plc.: Receiving symposia honoraria|GlaxoSmithKline plc.: GlaxoSmithKline plc.-sponsored study 212502|Merck: Advisor/Consultant|qpex: Advisor/Consultant|Shionogi: Grant/Research Support|Spero: Advisor/Consultant Piyali Chatterjee, PhD, AHRQ Grant # 1R03HS027667-01: Grant/Research Support|AHRQ Grant # 1R03HS027667-01: Central Texas Veterans Health Care System."}
+{"text": "The Advisory Committee on Immunization Practices (ACIP) and CDC recommend that all health care personnel (HCP) receive annual influenza vaccination to reduce influenza-related morbidity and mortality among these personnel and their patients  proportions and corresponding 95% CIs for three vaccination measures .\u201322 season; 87.3% completed primary COVID-19 vaccination, 67.1% of whom received a COVID-19 booster dose. Influenza, primary COVID-19, and COVID-19 booster coverage was higher among HCP who reported employer vaccination requirements for those vaccines; coverage was lowest among HCP working in long-term care settings.HCP influenza vaccination coverage was 79.9% during the 2021Enhanced efforts are needed to improve HCP vaccination coverage, especially with COVID-19 booster doses and annually for influenza vaccines. Staying up to date with COVID-19 and influenza vaccines can protect HCP and their patients."}
+{"text": "TP53 variants. The condition represents one of the most relevant genetic causes of cancer in children and adults due to its frequency and high cancer risk. The term Li-Fraumeni spectrum reflects the evolving phenotypic variability of the condition. Within this spectrum, patients who meet specific LFS criteria are diagnosed with LFS, while patients who do not meet these criteria are diagnosed with attenuated LFS. To explore genotype\u2013phenotype correlations we analyzed 141 individuals from 94 families with pathogenic TP53 variants registered in the German Cancer Predisposition Syndrome Registry. Twenty-one (22%) families had attenuated LFS and 73 (78%) families met the criteria of LFS. NULL variants occurred in 32 (44%) families with LFS and in two (9.5%) families with attenuated LFS . Kato partially functional variants were present in 10 out of 53 (19%) families without childhood cancer except adrenocortical carcinoma (ACC) versus 0 out of 41 families with childhood cancer other than ACC alone . Our study suggests genotype\u2013phenotype correlations encouraging further analyses.Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome caused by pathogenic The online version contains supplementary material available at 10.1186/s13045-022-01332-1. TP53 tumor suppressor gene and represents one of the best characterized genetic causes of cancer in children and adults [TP53 germline PVs in individuals who do not meet established clinical LFS criteria, leading to a Li-Fraumeni spectrum classification [Li-Fraumeni syndrome LFS; OMIM151623) is a cancer predisposition syndrome caused by pathogenic variants (PVs) in the 51623 is d adults . The useTP53 PV (pathogenic or likely pathogenic) or with a somatic mosaic TP53 PV were included. All variants were curated according to TP53 specific guidelines [TP53 PV subgroups. A P value of\u2009<\u20090.01 was considered statistically significant. Ethics review and informed consent were obtained.Founded in 2017, the German Cancer Predisposition Syndrome Registry collects information on genotypes, personal medical details, family histories, and surveillance, as well as a range of biospecimens. The cutoff date for study inclusion for the present analysis was July 31, 2021. Patients with a germline idelines . Classicidelines  as well idelines , Kotler idelines  as well idelines  and Dearidelines . We tabuTP53 PVs as well as statistically significant genotype\u2013phenotype correlations are depicted in Fig.\u00a0An overview of all variants, functional data categories, and associated phenotypes including personal and family histories are provided in Additional file LFS, 33 LFS carriers as well as 14 individuals with attenuated LFS and 15 attenuated LFS carriers. No consistent signs of anticipation were observed. In the entire cohort, 33 families (35.1%) did not meet any of the established LFS testing criteria. Thirty-four LFS patients (30.4%) had multiple (between two and five) malignancies, whereas six patients with attenuated LFS (20.7%) had a history of multiple (between two and four) malignancies. Overall, 134 neoplasms occurred in 79 LFS patients, whereas 26 malignancies occurred in 14 individuals with attenuated LFS . Typical LFS childhood cancers \u2014excluding ACC\u2014occurred exclusively in individuals with NULL variants or non-functional missense variants. In general, childhood cancer occurred in more than half of the families with NULL (58.8%) or non-functional missense (52%) variants, whereas in families with partially functional variants ACC was observed as the only childhood cancer, affecting 30% of these families. We observed a statistically significant association between NULL variants and LFS, while this variant type was rare among patients with attenuated LFS: 32 out of 73 families with LFS carried NULL variants, whereas NULL variants were present in two out of 21 families with attenuated LFS . We did not observe additional statistically significant associations when analyzing the other functional variant subgroups. Case ascertainment, differences in overall survival, family size, and/or family clustering may have introduced a potential bias and represent a limitation of our study.Kato partially functional variants were statistically significantly associated with a cancer-free childhood, apart from childhood ACC  and personalized cancer surveillance. Large, international collaboration is required to reach the statistical power to make such risk predictions. Our findings are in agreement with previously published results assessing the correlation between s in LFS , 13. TheAdditional file 1. TP53 (NM_000546.5) variants, functional data categories, and associated phenotypes. Abbreviations: Acute lymphatic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma (ACC), bilateral (bilat), breast cancer (BC), carcinoma (CA), choroid plexus carcinoma (CPC), chronic lymphatic leukemia (CLL), chronic myeloid leukemia (CML), colorectal carcinoma (CRC), ductal carcinoma in situ (DCIS), estrogen receptor (ER), female (f), human epidermal growth factor receptor 2 positive (Her2+), Li-Fraumeni syndrome (LFS), lobular intraepithelial neoplasia (LIN), male (m), medulloblastoma (MB), myelodysplastic syndrome (MDS), neuroblastoma (NBL), non-small-cell lung carcinoma (NSCLC), not available (NA), osteosarcoma (OS), Primitive Neuro-Ectodermal Tumor (PNET), progesterone receptor (PR), rhabdomyosarcoma (RMS), soft tissue sarcoma (STS), triple-negative breast cancer (TNBC). Variants marked * were classified as NULL variants; to reduce complexity, smaller (less than whole exon) deletions were rated as NULL variants as well. The DNE IARC estimation, based largely on studies by Monti and Dearth, was accessed via the TP53 Database (https://tp53.isb-cgc.org)."}
+{"text": "We recently reported the COVID-19-induced circulating leukocytes DNA methylation profile. Here, we hypothesized that some of these genes would persist differentially methylated after disease resolution. Fifteen participants previously hospitalized for SARS-CoV-2 infection were epityped one year after discharge. Of the 1505 acute illness-induced differentially methylated regions (DMRs) previously identified, we found 71 regions with persisted differentially methylated, with an average of 7 serial CpG positions per DMR. Sixty-four DMRs persisted hypermethylated, and 7 DMR persisted hypomethylated. These data are the first reported evidence that DNA methylation changes in circulating leukocytes endure long after recovery from acute illness.The online version contains supplementary material available at 10.1186/s13148-022-01313-8. The COVID-19 pandemic has caused 6 million deaths worldwide. Many COVID-19 survivors fail to recover their pre-infection status, with lasting physical impairments and increased risk of cardiovascular events . DNA met\u00ae platform. Genome-wide leukocyte DNA methylation status was compared to samples from 39 healthy volunteers which were analyzed with the same platform as previously reported [To investigate this hypothesis, all the participants from our original cohort who survived COVID-19 hospitalization between March and April 2020 were recontacted 1 year after discharge . Over 90 % of the lasting DMRs were located near or within gene promoter regions (Fig. Of the 1505 acute illness induced DMRs we previously identified , 71 DMRsMore than 6 million deaths have been attributed to COVID-19, primarily arising from acute respiratory failure . Recent Additional file 1. List of genes persisting dysregulated one year after hospital discharge."}
+{"text": "JCI, Casado and colleagues challenge this dichotomous conception by demonstrating that NK cell\u2013dependent, immune-mediated hematopoietic suppression and HSPC clearance drive BMF in Fanconi anemia (FA). They show that genotoxic stress upregulates natural killer group 2 member D ligands (NKG2D-L) on FA HSPCs leading to NK cell cytotoxicity through NKG2D receptor activation. Inhibition of NKG2D\u2013NKG2D-L interactions enhanced FA HSPC clonogenic potential and improved cytopenias in vivo. These results provide alternative targets for the development of immunosuppressive therapies to reduce HSPC loss and mitigate the risk of hematologic malignancies in FA.Current paradigms of bone marrow failure (BMF) pathophysiology suggest that immune-mediated destruction of hematopoietic stem and progenitor cells (HSPCs) drives acquired aplastic anemia. In contrast, loss of HSPCs due to senescence and/or apoptosis causes BMF in inherited BMF syndromes. In this issue of the  Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome (IBMFS). FA is associated with congenital anomalies, predisposition to hematologic and nonhematologic malignancy, and aplastic bone marrow failure (BMF) developing in most cases by the second decade of life . DefectiJCI, Casado et al. provide this missing downstream link by identifying an immune-mediated mechanism by which activation of DNA damage pathways causes BMF (FA genes encode proteins in the FA/breast cancer gene (BRCA) pathway that are required to correct DNA interstrand crosslinks (ICLs). DNA ICLs can be caused by ionizing radiation, alkylating chemotherapy, or endogenous aldehydes. ICL formation triggers the FA core complex to localize at DNA lesions, which then recruits other FA protein\u2013containing complexes and ICL repair enzymes . Inactivuses BMF   expressed on target cells, inducing direct cytotoxicity and the production of hematopoiesis-suppressing IFN-/IL-2  is a C-type lectin-like receptor expressed by immune effector cells including NK cells and CD8FN-/IL-2 . NKG2D\u2013NFN-/IL-2 , 11. NKGFN-/IL-2 .FANCA) in HSPCs from healthy controls (HCs)  . Treatme-/- mice .These results suggest that NKG2D/NKG2D-L\u2013mediated immune clearance by NK cells may be the downstream cause of BMF in FA. Despite long-described roles of cellular stress in FA and many other IBMFS, including Diamond Blackfan anemia (DBA), Schwachman Diamond syndrome, and telomere biology disorders , no stud+ T cell diversity, HSPC loss through CD8+ cell cytotoxicity, responsiveness of BMF to T cell\u2013directed immune suppression therapy, inactivating HLA class I mutations, and somatic mutations within expanded T cell clonotypes (+ clones downstream of autoantigen recognition as the primary drivers of HSPC loss in aAA (T cell\u2013mediated destruction of HSPCs drives BMF in acquired aplastic anemia (aAA). Patients with aAA display reduced CD8onotypes \u201318. Thess in aAA .+ T cell and HLA class I responses as drivers of BMF in IBMFS. Indeed, most forms of T cell immunosuppression fail to induce remission in these diseases. Although glucocorticoids ameliorate some cytopenias in IBMFS, most notably the anemia in DBA, this response appears to occur independently of immune modulation . AlloSCT outcomes are limited by suitable donor availability and morbidity due to graft-versus-host disease and conditioning-related toxicity . Uncondi+ T cells also play roles in HSPC clearance, providing alternative immunosuppression targets. Finally, NKG2D\u2013NKG2DL interactions may promote HSPC loss in other IBMFS, since HSPC stress represents a shared upstream pathophysiology. Thus, these findings should promote research and therapeutics across the BMF field.The Casado et al. study signals a conceptual paradigm shift in BMF pathophysiology related to FA . The stu"}
+{"text": "High resolution manometry (HRM) is the gold standard for diagnosis of esophageal motility disorders. This is traditionally conducted without sedation, using intranasal intubation with a manometry probe. Inserting the HRM probe immediately after endoscopic examination allows for endoscopic visualization and sedation for probe placement. This method is used commonly used for our patients who are post-peroral endoscopic myotomy (POEM). However, it is unclear whether short acting sedative drugs administered during endoscopy can affect contractility measurements during HRM.The purpose of this study was to determine if conscious sedation with short-acting anaesthetic agents (Midazolam and Fentanyl) influenced HRM readings in patients undergoing evaluation post-perioral endoscopic myotomy (POEM).We conducted a retrospective cohort study, comparing patients post-POEM who had endoscopy under conscious sedation with placement of the manometry probe versus those without preceeding endoscopy/sedation. Post-POEM patients who had undergone HRM over a 3-year period (2019-2022) were identified from motility lab records. Electronic charts were reviewed for data abstraction, and HRM parameters  were determined for both groups and compared using t-tests, and error listed as standard error of the mean.From 2019-2022, 15 patients underwent manometry using a non-endoscopic approach with no sedation and 25 underwent manometry following endoscopy with conscious sedation and placement of the probe during the procedure. In the latter group, HRM occurred within 2 hours of probe placement. The mean doses of fentanyl and midazolam were 115mcg (+/-29.7) and 3.3mg (+/-1.3) respectively. The mean end-expiratory lower esophageal sphincter pressure was 9.8 mmHg (+/- 2.9) in the non-endoscopic group and 26.24mmHg (+/- 5) in the endoscopy group (p <0.02). The median integrated relaxation pressure was 11.2 mmHg (+/-1.2) in the non-endoscopic group and 14.52mmHg (+/- 0.9) in those in the endoscopy group (p <0.04).In conclusion, this small, retrospective cohort study shows that manometry probe placement after endoscopy with conscious sedation may affect esophgeal HRM measurement parameters in the post-POEM patient population. Physicians should consider delaying HRM measurements for >4 hours to maximize clearance of the sedative medications.NoneNone Declared"}
+{"text": "Infectious diarrhea is a common cause of emergency department (ED) visits and hospital admissions. Polymerase chain reaction (PCR) testing allows for quick and expansive pathogen identification and facilitates earlier targeted treatment. We implemented a multiplex gastrointestinal (GI) PCR panel in 2014. In collaboration with the Antimicrobial and Diagnostic Advisement Program (ADAP), post-launch optimization strategies have changed test use. We evaluate the impact of diagnostic stewardship initiatives.GI PCR testing was initially unrestricted for ED or inpatients within 72 hours of admission. After fielding many questions regarding interpretation, the ADAP developed a guidance document in June 2019 regarding treatment considerations for all potential organisms detected. In January 2020, organism-specific treatment considerations were embedded in the test results real-time treatment guidance (figure 1). A pre-post quality improvement assessment of the changes was performed. In August 2021, individual GI PCR panel orders were replaced with an order set containing a decision tree to provide passive guidance evaluating acute vs chronic diarrhea, assessing recent antibiotic use (to consider C. difficile testing), no testing scenarios, and avoiding repeat testing (figure 2).GI PCR panel use peaked in 2019 with 3,142 tests processed. The guidance document was less helpful, requiring an external site link. Embedding organism-specific GI PCR guidance significantly improved appropriate antibiotic prescribing . A precipitous drop off in GI PCR test orders occurred after the COVID-19 pandemic began , partly attributed to supply chain issues. When comparing intra-pandemic years (2020 vs 2021), implementation of a smart order set was associated with a 51.3% reduction in orders  and $131,000 in savings despite significant patient volume increases in 2021. Low use rates have persisted into the first quarter of 2022 (n=229).Diagnostic stewardship changes should be proactive and contextually relevant at the time of result interpretation. Antimicrobial stewardship programs are uniquely positioned to lead optimization initiatives and drive clinical and cost-effective solutions.All Authors: No reported disclosures."}
+{"text": "Pet ownership (PO) or human-animal interaction (HAI) has been associated with better physical and mental health in individuals with existing disease or disability. In experimental studies, HAI improves some aspects of cognitive function. No research addresses HAI and longitudinal changes in cognitive function in older adults. We examined the relationship of PO to maintaining executive function (EF) within generally healthy community-dwelling older adults in the Baltimore Longitudinal Study of Aging (BLSA). We hypothesized less EF deterioration among pet owners than non-owners; and less deterioration among dog-walkers than owners who don\u2019t walk their dogs. 637 women (55.9%) and men aged 50\u2013100 years  completed a PO questionnaire which ascertained ownership history and comprehensive examination every 1\u20134 years over 1\u201313 years . Linear mixed models with time varying PO examined changes in EF according to PO. Pet owners (n=185) were younger (p < 0.001) and healthier (p=0.030) than non-owners; thus, age and comorbidities were included as covariates in the longitudinal analyses. EF, assessed using the Trail-Making Test (TMT), deteriorated with age (p\u2019s < 0.001). Deterioration was less severe among pet owners than non-owners  and dog owners than non-owners , but not among cat owners than non-owners. Among dog owners (n=73), dog walkers experienced less deterioration than non-walkers . This study provides the first longitudinal evidence that PO may contribute to maintaining EF among community-dwelling generally healthy older adults as they age."}
+{"text": "Isatis tinctoria L. leaf extract (ITE) inhibited senescence biomarkers p53, CDKN1Ap21, and INK4Ap16 gene expression, and SASP secretions by inhibiting cellular senescence in the replicative senescent human dermal fibroblast (RS-HDF). ITE has been demonstrated to inhibit the secretion of SASP factors in several senomorphic types by regulating the MAPK/NF-\u03baB pathway via its inhibitory effect on mTOR. ITE suppressed the inflammatory response by inhibiting mTOR, MAPK, and I\u03baB\u03b1 phosphorylation, and blocking the nuclear translocation of NF-\u03baB. In addition, we observed that autophagy pathway was related to inhibitory effect of ITE on cellular senescence. From these results, we concluded that ITE can prevent and restore senescence by blocking the activation and secretion of senescence-related factors generated from RS-HDFs through mTOR-NF-\u03baB regulation.Senescent fibroblasts progressively deteriorate the functional properties of skin tissue. Senescent cells secrete senescence-associated secretory phenotype (SASP) factor, which causes the aging of surrounding non-senescent cells and accelerates aging in the individuals. Recent findings suggested the senomorphic targeting of the SASP regulation as a new generation of effective therapeutics. We investigated whether  INK4Ap16 expression, reduced lamin B1 expression, high mobility group box 1 (HMGB1) translocated into the cytoplasm and released extracellularly, and the secretion of senescence-associated secretory phenotype (SASP) factors such as inflammatory cytokines and metalloproteinases . P. PIsatiscretions A. It hasAltogether, these results showed the potential for the senotherapeutic agent ITE via the SIRT1/mTOR/MAPK/NF-\u03baB signaling pathway. As shown in"}
+{"text": "Comprehensive characterisation of genome engineering technologies is relevant for their development and safe use in human gene therapy. Short-read based methods can overlook insertion events in repetitive regions. We develop INSERT-seq, a method that combines targeted amplification of integrated DNA, UMI-based correction of PCR bias and Oxford Nanopore long-read sequencing for robust analysis of DNA integration. The experimental pipeline improves the number of mappable insertions at repetitive regions by 4.8\u20137.3% and larger repeats are processed with a computational peak calling pipeline. INSERT-seq is a simple, cheap and robust method to quantitatively characterise DNA integration in diverse ex vivo and in vivo samples.The online version contains supplementary material available at 10.1186/s13059-022-02778-9. Development of novel methods for genome editing has enabled an expansion of human gene therapy (HGT) applications , 2. ManyThe discovery and implementation of precise delivery strategies using tools such as ZFN, TALENs and CRISPR-Cas9 , 13 can To determine the resolution gain that increased read length junction capture could provide, we generated a simulated dataset with increasing read length of the insertion-genome junction Fig. a. We samTo implement a long-read based library prep procedure in the optimal range predicted by the model  is ligated. Genome-junctions are amplified with two nested STAT-PCRs . UMIs arTo evaluate INSERT-seq performance in an in-vivo model, liver tissue from mice administered with rAAV serotype 8 was studied to determine the genome-wide integration profile of rAAV. rAAV vectors are being widely tested in gene therapy trials  and theiTo assess potential of INSERT-seq for analysing emerging precise gene delivery vectors, we determined integration sites in a Cas9-PiggyBac chimeric fusion previously reported . We deteRepetitive regions vary in abundance and are usually between 100 bp and 5000 bp  (Additiohttp://synbio.upf.edu/insertseq/).INSERT-seq incorporates amplification based enrichment and UMI amplification correction with a computational pipeline to process integration sites. It can resolve DNA integration sites with increased resolution compared to traditional short read sequencing methods providing higher accuracy in determining integrations in repetitive regions, which compose an important subset of many eukaryotic genomes. We have successfully used INSERT-seq method to analyse lentiviral, transposon and rAAV DNA payloads in the genome of both in vitro and in vivo samples. Reduced hardware requirement in Oxford Nanopore Technologies (ONT) platform and sample processing time should make the method practical across different research environments, as for example in clinical settings, and INSERT-seq should be applicable to other long read sequencing platforms such as PacBio. The protocol is available in the additional material and the code for analysis at Bibucket and as a web application  , 10% FBS, 2 mM glutamine, 0.1 mg/mLpenicillin and streptomycin, was used. K-562 cells [ATCC\u00ae ACS-CCL-243\u2122] were grown in RPMI 1640  supplemented with 10% FBS. To generate MC-2 cell line with isogenic insertional signature, HEK293T cells were transduced with pSICO LV vector at MOI 1, and GFP fluorescent single cells were isolated in to 96 well plates using BD FACSAria (Biosciences) cell sorter and further expanded and validated for GFP expression with BD LSR Fortessa cytometer (BD Biosciences). Mono-clonal poli-insertional cell line (MOPO) was generated following the above described procedure transducing cells at MOI ~40  at Universitat Autonoma of Barcelona. 5*10E+11rAAV8 GFP particles were retro-orbitally injected in Rosa26-Cas9 knockin on B6J (JAX stock #028555) 8 weeks old mice. Nine days after rAAV8 administration, mice were sacrificed and liver tissue was extracted and homogenised. Animals were purchased from Jackson Laboratories; male and female were used without distinction.For SHORT-seq implementation, DNA was extracted using DNeasy Blood and tissue kit (Qiagen) and fragmented to ~ 300bp fragments on a Q800R3 Sonicator using following parameters: 40% Amplitude, 15/15 Pulse, and 1.25 min total sonication time. End repair, A-tailing, and ligation of Y-adapter [KAPA Hyper Prep Kit (KR0961 \u2013 v5.16)] were performed with 5\u03bcg of fragmented DNA, followed by SPRI bead purification using x1 bead ratio. Two nested single-tail adapter/tag (STAT)-PCR  were perhttps://community.nanoporetech.com); read quality was assessed with NanoStats NanoQC and NanoPlot from NanoPack [Nanopore raw reads were basecalled using Guppy 4.0.11 (made available by ONT via their webpage NanoPack . Reads whttps://github.com/nanoporetech/pipeline-umi-amplicon and longread_umi [https://github.com/nanoporetech/medaka).Reads were clustered by UMI using a combination and adaptation of two previously published pipelines (pipeline-umi-amplicon distributed by ONT read_umi ). Brieflread_umi , and theread_umi  and two For the analysis of insertions Fig. c, reads A set of 42 manually selected true insertions and 3393 negative insertions was used to assess the RSS threshold of 1 for peak shape filtering.   subsamplAll the reads that do not map against the reference genome have secondary alignments or map with a quality lower than 30 are labelled as unanchored reads. Those potentially belong to an insertion happening in a repetitive region in the genome  hits obtained from Dfam database . The reaFor short reads, the same algorithm was applied with modified mapping parameters to \u201csr\u201d.Additional file 1: Supplementary figures 1-11 and INSERT-seq protocol.Additional file 2: Supplementary tables S1-S4.Additional file 3. Review history."}
+{"text": "Cancer and its treatments increase risk for age-related disease, and biological aging may be a key mechanism; however, no research to date has examined epigenetic markers of aging in long-term breast cancer survivors. We used data from a national, prospective cohort to test whether older breast cancer survivors had accelerated epigenetic aging compared to non-cancer controls. Non-metastatic breast cancer survivors ages 62\u201384 years who received chemotherapy with or without hormonal treatment (n=29) or hormonal treatment alone (n=51), and controls frequency-matched on age, race, education, and time between blood draws (n=101), provided two blood samples between 24- and 60-months post-diagnosis (time between samples average=1.8 years). DNA methylation profiling (Illumina Infinium EPIC array) derived epigenetic aging measures: extrinsic, intrinsic, phenotypic, Grim, and Dunedin Pace of Aging (PoAm). Mixed-effects models tested effects of treatment group and change over time on epigenetic aging, adjusting for chronologic age and comorbidities. Survivors who received chemotherapy +/- hormonal treatment had a biological age 1.9\u20132.6 years older than controls based on extrinsic, intrinsic, and Grim estimates . Survivors who received hormonal treatment alone had an extrinsic biological age 1.6 years older than controls (p=.032) and a faster Dunedin PoAm (p=.040). Survivors who received chemotherapy +/- hormonal treatment had a trend for accelerated extrinsic aging over time compared to controls (p=.087). Older breast cancer survivors, especially those receiving chemotherapy, showed an accelerated epigenetic aging profile compared to matched women without cancer. Future research is needed to examine associations with age-related survivorship outcomes."}
+{"text": "Osteoarticular infections are commonly treated with intravenous antibiotics even though oral antibiotics may be as effective. In this multicenter study, we evaluated how often patients with osteoarticular infections qualified for oral antibiotic therapy and how often oral antibiotics were prescribed.We randomly selected 2 high-complexity Veterans Affairs (VA) hospitals from each of the 4 US Census regions. Next, we randomly selected patients admitted to these 8 facilities during 2018-2020 who had a discharge diagnosis of an osteoarticular infection, received \u22655 days of inpatient antibiotics, and had an Infectious Disease consult. Manual chart reviews were performed to confirm the diagnosis and to exclude patients who received < 4 weeks of total antibiotics or had infection of the skull, sacrum or pelvis. Eligibility for oral therapy was defined by the inclusion criteria used in a recent randomized controlled non-inferiority trial. Oral antibiotic stepdown was defined as starting an exclusively oral regimen within 2 weeks of antibiotic initiation. The chi-square test was used to compare categorical variables.Staphylococcus aureus (53%). Surgical debridement was performed in 104 (72%) patients, and the median antibiotic duration was 47 days (IQR 43-72). One hundred eight (74%) patients were eligible for oral step-down, but only 18 (17%) of these patients received it . Fourteen (78%) patients treated with oral step-down were from the same hospital. Among patients eligible for oral stepdown therapy, peripheral osteomyelitis was present in 15 (83%) of those who received oral therapy versus 58 (64%) of those who were eligible but did not receive it (p=0.12).After excluding 76 cases, the final cohort included 145 patients . The most common types of osteo-articular infections were peripheral osteomyelitis (66%) and septic arthritis (14%). The most common isolated pathogen was In this retrospective study across 8 geographically-diverse VA hospitals, three-quarters of patients with osteoarticular infections qualified for oral antibiotics but only 1 of 6 eligible patients actually received them. Oral antibiotics may be under-utilized for treating osteoarticular infections in routine practice.Daniel J. Livorsi, MD, Merck & Co.: Grant/Research Support."}
+{"text": "Pseudomonas sp. strain MWU13-3659 was isolated from cultivated cranberry bog soil in Massachusetts, USA. Its closest known relative is Pseudomonas entomophila , and its genome contains putative gene clusters for the production of polyketides, siderophores, and cyclic lipopeptides that have insecticidal activity in other proteobacteria. Pseudomonas spp. constitute a major proportion of bacterial isolates in a multiyear culture-dependent survey of wild and cultivated cranberry bogs . Kits used in this work were used as instructed by their manufacturers. Illumina-compatible genomic DNA libraries were generated using a HyperPlus library preparation kit . DNA was enzymatically sheared to ~500 bp, end repaired, A-tailed, ligated to Illumina-compatible adapters , cleaned using KAPA pure beads (Kapa Biosystems product number KK8002), and amplified with KAPA HiFi enzyme (Kapa Biosystems product number KK2502). Library fragments were sized on an Agilent TapeStation system, quantified by quantitative PCR (KAPA library quantification kit [Kapa Biosystems product number KK4835]) on a QuantStudio 5 system , multiplex pooled, and sequenced in a 2 \u00d7 250 bp flow cell using the Illumina MiSeq platform. All software was used with default settings except as indicated. Raw reads were assembled with Unicycler v0.4.8 within the PATRIC (https://www.bv-brc.org/) Comprehensive Genome Analysis pipeline v3.6.12, with the trim setting set to true (Pseudomonas by Type Strain Genome Server (TYGS) analysis  under accession number SRR18741572. RASTtk annotations are available under open license at Zenodo (https://zenodo.org/record/6458518#.YwQD90fMKUk).This whole-genome sequence project has been deposited in DDBJ/EMBL/GenBank under BioProject accession number"}
+{"text": "Hearing loss is a risk factor for dementia; whether this association differs by race is unknown. Although hearing loss is less prevalent in Blacks than Whites, we hypothesized the hearing loss-dementia relationship is stronger in Blacks. All-cause dementia and mild cognitive impairment (MCI) were adjudicated using longitudinal cognitive data. Hearing was measured using pure tone better-ear thresholds (0.5-4 kHz). Cox proportional hazards models adjusted for demographic and clinical covariates and included an interaction term between hearing and race. In 3,605 participants from a population-based cohort , estimates for 7-year dementia risk per 10 decibels increase in hearing loss were stronger in Blacks :1.07,1.43) than Whites . Hearing loss is a risk factor for dementia in Black Americans. These findings emphasize the need to address existing racial disparities in hearing healthcare."}
+{"text": "Anandamide (AEA) and 2-Arachidonoylglycerol (2-AG) play a pivotal role in food intake and reward aspects of feeding. Aberrant functioning in the endocannabinoid system has been observed in patients with eating disorders (EDs). This dysfunction may influence the incentive processes stimulating behaviors towards food acquisition or the hedonic evaluation of ingested food.The aims of this study are to compare fasting peripheral levels of AEA and 2-AG in ED patients, obese subjects (OB) and healthy controls (HCs), and to explore their association with clinical and anthropometric variables.The sample included a total of 63 adult women. Peripheral blood samples were collected to investigate fasting levels of AEA and 2-AG in 31 ED patients: 22 Anorexia Nervosa (AN) and 9 Binge Eating Disorder (BED), compared to 21 OB and 11 HCs. Several clinical and anthropometric variables were also assessed.Comparing groups, significant differences in AEA levels were found (p=0.001). Specifically, individuals with AN exhibited lower AEA than OB (p<0.001) and BED (p=0.007), while OB showed higher AEA than HCs (p=0.015). 2-AG was positively correlated with hostility dimension in EDs and negatively associated with impulsive traits in OB. AEA showed a direct association with body dissatisfaction in AN, contrary to OB. Finally, in AN, AEA negatively correlated with the body mass index, while 2-AG was positively associated with the fat mass.These results suggest an interaction between biological and clinical factors defining a vulnerability pathway that could help fitting personalized therapeutic approaches in each condition.No significant relationships."}
+{"text": "Fusarium langsethiae is a suspected plant-pathogenic fungus causing cereal contamination with trichothecene mycotoxins. Here, we report the genome sequences of two F. langsethiae strains, MFG217701 (a prototroph) and MFG217702 (a biotin auxotroph), isolated from a grain of oat harvested in Russia. Fusarium langsethiae (F. langsethiae because this species produces mycotoxins (T-2 and HT-2) which are type A trichothecenes  and MFG217702 (biotin auxotrophic), isolated from a sample of a single grain of oat harvested in northwestern Russia (Leningrad Oblast) in 2014. The Fusarium strains were single-spored and stored in the All-Russian Plant Protection Institute collection . Strain MFG217702 grows poorly on synthetic Czapek (CZ) medium; however, it exhibits colony phenotypes comparable with the prototrophic strain MFG217701 on CZ medium supplemented with biotin . Whole-genome sequencing libraries were prepared using the MGIEasy FS DNA library prep set and sequenced on a DNBSEQ-G400RS instrument  using a whole-genome shotgun strategy. After quality filtering and trimming using fastp v0.20.0 with the options for removing adaptors and low-quality reads  with the data set hypocreales_odb10 (F. langsethiae strain Fl201059 (F. langsethiae genomes (MFG217701_contig0169 and MFG217702_contig0164).A summary of the genome assemblies and annotations is shown in es_odb10 . The genFl201059  containiFl201059 . The genF. langsethiae genome sequences were deposited at DDBJ/EMBL/GenBank under accession no. BQKT01000001 to BQKT01003556 (MFG217701) and BQKU01000001 to BQKU01003809 (MFG217702). The raw sequencing reads have been submitted to the DDBJ Sequence Read Archive (DRA) under accession no. DRR333357 (MFG217701) and DRR333358 (MFG217702).The"}
+{"text": "Betaarterivirus suid 1, formerly known as porcine reproductive and respiratory syndrome virus 1. All share a potential recombinant pattern, with a highly pathogenic Italian strain as the putative major parental sequence and three other possible parents.This report describes 28 genome sequences from a new clade within subtype 1 of  Betaarterivirus suid 1, within the Variarterivirinae subfamily  designates porcine respiratory and reproductive syndrome virus 1 (PRRSV1) as ubfamily . Within ubfamily , while subfamily . Within ubfamily .NC_043487), using the Burrows-Wheeler Aligner . The SAMtools view (https://www.hiv.lanl.gov/content/sequence/CONSENSUS/consensus.html). All tools were run with default parameters. The whole-genome sequences obtained , owned by different companies. All farms were suffering severe PRRS outbreaks characterized by high abortion rates and mortality in the sows and increased mortality in the weaners and growers (>20%). Briefly, PRRSV1 was isolated from individual serum samples after a single passage in porcine alveolar macrophages (PAMs). The PAMs were inoculated into Eagle\u2019s minimal essential medium (EMEM), supplemented with penicillin-streptomycin and 7.5% bovine calf serum, and maintained. If a cytopathic effect was observed, supernatant was collected, and total RNA was extracted using TRIzol. Libraries were prepared using the NEBNext RNA library prep kit, without an initial amplification step, and sequenced on the Illumina MiSeq platform (paired-end 251-bp reads). Next-generation sequencing (NGS) reads were trimmed using Trimmomatic v0.36 NC_04347, using ols view  was usedobtained  were comMF346695; 80% of the genome comprised in 5 segments, with 86 to 89% nucleotide identity) and the following three putative minor parental strains: ESP-1991-Olot91 , D40 , and an unknown strain .Local similarity analyses conducted using RDP and GARD revealed a common pattern among all isolates . A localA maximum likelihood (ML) phylogenetic tree placed all the genomes in a monophyletic branch within PRRSV1 subtype 1 .The strains isolated in these outbreaks, characterized by high virulence, potentially originated from the recombination of multiple subtype 1 strains. Its apparent greater pathogenicity should be evaluated in future studies. Furthermore, the regular detection of recombinant PRRSV strains  illustraOM893828 to OM893855; the corresponding fastq files have been deposited in the Sequence Read Archive under the BioSample accession numbers SAMN27285123 to SAMN27285150.The 28 whole-genome sequences described in this report have been deposited at GenBank under the accession numbers"}
+{"text": "Adequate pain control in inflammatory bowel disease (IBD) can require opioids due to their high analgesic potency. The long-term use of opioids, however, is limited by the development of tolerance. This leads to reduced analgesic efficacy over time, resulting in escalating opioid dosing and thus increased risk of serious side effects. We previously demonstrated the safety and effectiveness of a novel pH-sensitive \u00b5-opioid receptor (MOR) agonist, NFEPP, in a murine colitis pain model, but its tolerance potential with chronic administration is unknown.To assess the tolerance potential of NFEPP compared to its parent compound fentanyl during acute colitis in a preclinical mouse model.Acute colitis in C57BL/6 mice was induced using 2.5% dextran sulphate sodium for 5 days. NFEPP or fentanyl were then administered s.c. every 4 hours between 7am and 11pm over 5 days in daily increasing concentrations (0.4-1.5 mg/kg/d). Analgesic tolerance to opioids was assessed in conscious mice by measuring visceromotor responses (VMRs) to noxious colorectal distensions. Tolerance to the MOR agonist DAMGO in NFEPP or fentanyl treated mice was evaluated using patch-clamp recordings from dorsal root ganglion (DRG) neurons and extracellular recordings from lumbar splanchnic nerves that innervate the colon. Inflammation was assessed by macroscopic analyses, histological scoring and tissue-pH measurements of the inflamed colon. Group differences were analyzed using two-way ANOVA with Bonferroni\u2032s or Tukey\u2032s post-test .NFEPP significantly reduced VMRs before and after chronic NFEPP treatment . No differences of NFEPP induced antinociceptive actions were observed comparing VMR measurements before and after chronic administration (p=0.44). However, the analgesic activity of fentanyl decreased over time with less VMR inhibition observed after chronic treatment compared to fentanyl na\u00efve mice (p<0.05). Cross tolerance testing between these two opioids revealed a loss of NFEPP- induced VMR inhibition in fentanyl treated mice, but fentanyl effects in the NFEPP treatment group remained unchanged. In patch-clamp recordings, DAMGO (100nM) evoked antinociceptive actions in DRG neurons from NFEPP treated mice  whereas no change in rheobase with DAMGO was observed in DRG neurons from fentanyl treated mice. Afferent nerve activity from lumbar splanchnic nerves in response to von Frey filament probing decreased after DAMGO (100nM) application in NFEPP treated mice , but showed no change in fentanyl treated mice. Colonic length, diameter, histological damage and tissue-pH did not differ between the two opioid treatment groups.Chronic administration of NFEPP during acute murine colitis does not lead to analgesic tolerance within the visceral nociceptive system, in contrast to its parent compound fentanyl.CCCNone Declared"}
+{"text": "The patients with dual oesophageal squamous cell carcinoma (ESCC) and hypopharyngeal cancer (HPC) have poor prognosis; their underlying genetic pathogenesis is unclear. We hypothesise that development of synchronous ESCC/HPC depends on multicentricity or independent origin, rather than multifocality due to local or lateral spreading.Multiple region whole-exome sequencing (M-WES) and clonality analysis were used to assess clonal relationship and spatial inter- or intra-tumour heterogeneity (ITH) in 62 tumour regions from eight dual ESCC/HPC and ten ESCC patients.p\u2009=\u20090.013) and public data set . This alcohol consumption-related mutation signature 16, commonly involved in multiple alcohol-related cancers, was significantly associated with drinking and alcohol metabolism-related ADH1B rs1229984. The mutational landscape and copy number profiles were completely distinct between the two primary tumours; clonality analysis further suggested the two primary tumours shared no or only one clone accompanying independent subclone evolution. M-WES strategy demonstrated higher sensitivity and accuracy for detection of mutational prevalence and the late branch mutations among different regions in the ESCC tumours, compared to traditional sequencing analysis based on single biopsy strategy. Patients with high ITH assessed by cancer cell fraction analysis after M-WES were significantly associated with both relapse and survival.All synchronous ESCC/HPC patients had COSMIC 16 mutation signatures, compared to only 40% ESCC in the current study (Our hypothesis-generating M-WES ITH assessment data have implications for prognostication. Collectively, our findings support multicentric independent clonal evolution, the field cancerisation theory, and suggest novel insights implicating an aetiologic role of alcohol metabolism in dual ESCC/HPC carcinogenesis. Oesophageal cancer (EC) is a deadly cancer worldwide . OesophaDuring 2018\u20132019, ten ESCC and five synchronous ESCC/HPC patients were recruited from Queen Mary Hospital (QMH), University of Hong Kong. Another three synchronous ESCC/HPC patients were recruited from 2020 at Shanghai Chest Hospital (SCH). Diagnosis of synchronous ESCC/HPC was based on the criteria of clear separation of tumours by histological examination and normal mucosa and the exclusion of the second tumour due to metastasis of the primary tumour . A totalWES libraries were prepared with KAPA HTP Library Preparation and SeqCap EZ Exome+UTR Kits (Roche). WES and bioinformatics analysis were performed, as previously described, and detailed in the supplementary methods , 14. Thehttp://cancer.sanger.ac.uk/signatures/) for mutation signature calling. Reports of somatic mutation prevalence, mutational profiles, COSMIC signature contributions, comparison with cancer signatures, reconstructed mutational profiles, and principal component analysis were downloaded. Mutational signature calling was performed for 165 ESCC patients from previous publications with two data sets from Sequence Read Archive (accession number SRP033394) and European Genome\u2013phenome Archive (accession number EGAS00001000932). Another in-house WES data set included our previous study [Lists of exonic mutations were uploaded to the web-based tool, Mutational Signatures V3.2 (us study .p\u2009<\u20090.05 (2-sided) was considered statistically significant. Analyses were performed with SPSS v26 .The differences between mutation signature occurrence and association of survival and relapse with ITH were examined with Fisher\u2019s exact test. Pearson correlation coefficient was calculated for the correlation between mutation signature 16 and drinking, males, smoking, and dual primary cases. A Detailed clinical information of 18 synchronous ESCC/HPC and ESCC patients for unbiased M-WES analysis is summarised in Table\u00a0TP53 remained the most frequently mutated gene in dual cancer  and ESCC  patients. Surprisingly, both the mutational landscape   Table\u00a0. These iosome 22 , 10. Thep\u2009=\u20090.013) and in the publicly available data set  . By Fisher\u2019s exact test, mutation signature 16 associated significantly with drinking (p\u2009=\u20090.008), smoking (p\u2009=\u20090.047), male gender (p\u2009=\u20090.012) and a trend with relapse (p\u2009=\u20090.101) and overall survival (p\u2009=\u20090.114) (Table\u00a0ADH1B rs1229984 (T>C) in the public ESCC cohort and further confirmed that this signature was associated with the patients carrying the C allele of rs1229984, especially those patients with homozygous CC . Consistently, dual synchronous ESCC/HPC patients were more likely to carry genotype CC compared to other ESCC patients with marginal significance . East Asian individuals carrying the TT/TC genotypes of the alcohol metabolism-related functional SNP ADH1B rs1229984 were more likely to experience drinking discomfort, as the T allele causes rapid accumulation of acetaldehyde after alcohol intake. Our association findings of rs1229984 with COSMIC signature 16 were in line with earlier observation of individual carriers with the CC genotype of ADH1B rs1229984 having a significantly higher risk of multiple alcohol-related cancers of the larynx, pharynx, oesophagus, and pancreas [p53 mutations  patients. RBMXL encodes an RNA-binding protein complex with heterogeneous nuclear RNA (hnRNA) involved in pre-mRNA processing and regulating splicing with unknown functions [TRIP12 (thyroid hormone receptor interactor 12) encodes an E3 ubiquitin-protein ligase regulating degradation of the critical ESCC tumour suppressors including FBXW7 and the p19ARF/ARF/TP53 axis [M-WES analysis of 12 patients in multiple ESCC regions identified 1981 non-silent mutations in 1749 genes in 44 regions Table\u00a0. The medted Fig.\u00a0. The witted Fig.\u00a0. The str targets . this stunctions . TRIP12 P53 axis , 44. Futp\u2009=\u20090.045) and disease relapse (p\u2009=\u20090.005) (Table\u00a0Various degrees of heterogeneity observed in 12 patients are summarised by numbers and distribution frequencies of non-silent trunk and branch mutations Fig.\u00a0. The hetESCC patients are at high risk to develop multiple primary cancers in the upper aerodigestive tract, especially at the hypopharynx and larynx , 47. OurSupplementary materialsSupplementary Table S3Supplementory Table 6Supplementory Table 7Journal checklist summary"}
+{"text": "Scientific Reports 10.1038/s41598-022-26486-3, published online 19 December 2022Correction to: The original version of this Article contained an error in the spelling of the author Jin Hyuk Kim which was incorrectly given as Kim Jin Hyuk.Consequently, the equal contribution statement was incorrect.\u201cThese authors contributed equally: Dong Keon Lee, Kim Jin Hyuk, Jaehoon Oh and Tae Hyun Kim.\u201dnow reads:\u201cThese authors contributed equally: Dong Keon Lee, Jin Hyuk Kim, Jaehoon Oh and Tae Hyun Kim.\u201dThe original Article has been corrected."}
+{"text": "There is an error in affiliation 4 for author Claudio Cerchione. The correct affiliation 4 is: Hematology Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \"Dino Amadori\", Meldola, Italy.There is also an error in affiliation 5 for author Giovanni Martinelli. The correct affiliation 5 is: Scientific Directorate, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \"Dino Amadori\", Meldola, Italy."}
+{"text": "The COVID-19 pandemic has led to a shift in healthcare towards telehealth delivery, which presents challenges for exercise physiology services. We aimed to examine the impact of the COVID-19 pandemic on the reach, efficacy, adoption and implementation of telehealth delivery for exercise physiology services by comparing Australian practises before (prior to 25 January 2020) and during the COVID-19 pandemic (after 25 January 2020).This retrospective audit included 80 accredited exercise physiology clinicians. We examined relevant dimensions of the RE-AIM framework  from the clinician perspective.n\u2009=\u200973/80) of surveyed clinicians offered telehealth delivery service, compared to 25% (n\u2009=\u200920/80) prior. Mean (SD) telehealth delivery per week doubled from 5 (7) to 10 (8) hours. In-person delivery decreased from 23 (11) to 15 (11) hours per week. Typical reasons for not offering telehealth delivery were client physical/cognitive incapacity  and safety . Clinician-reported reasons for typical clients not adopting telehealth delivery were personal preference , physical capacity  and access to reliable delivery platforms . Zoom  and telephone  were the most commonly used platforms. Of the reasons contributing to incomplete treatment, lack of confidence in delivery mode was sevenfold higher for telehealth compared to in-person delivery. No serious treatment-related adverse events were reported.During the COVID-19 pandemic, 91% (During the COVID-19 pandemic, telehealth delivery of exercise physiology services increased and in-person delivery decreased, which suggests the profession was adaptable and agile. However, further research determining comparative efficacy and cost-effectiveness is warranted.The online version contains supplementary material available at 10.1186/s40798-022-00483-2. During the COVID-19 pandemic, telehealth delivery of exercise physiology services increased and in-person delivery decreased.Clinician reasons for not offering telehealth delivery included client physical/cognitive incapacity and safety.Client reasons for not accepted telehealth delivery when offered included personal preference, physical capacity and access to reliable delivery platforms.The coronavirus disease 2019 (COVID-19) pandemic continues to provide unprecedented challenges for healthcare systems worldwide. The imposition of infection control measures, such as physical distancing, has been essential for controlling transmission of COVID-19 [The interest and demand for telehealth delivery of healthcare in general has markedly increased worldwide due to the COVID-19 pandemic . For exaExercise physiology is one of the many allied health professions impacted by the changing healthcare landscape during the COVID-19 pandemic, and the adoption of telehealth delivery   has poteA retrospective audit of exercise physiology services in Australia before (prior to 25 January 2020) and during the COVID-19 pandemic (after 25 January 2020) was conducted. The data collection period spanned 22 July 2020 to 10 November 2020 and included 80 accredited exercise physiology clinicians. The study was conducted in line with the National Statement on Ethical Conduct in Human Research (2007) and approved by Deakin University Human Ethics Advisory Group\u2013Health (90\u20132020-200512). All participants provided written informed consent prior to involvement in the study.Participants were accredited exercise physiology clinicians currently practising within Australia during the COVID-19 pandemic (after 25 January 2020). Exercise physiologists are tertiary qualified allied health professionals who specialise in the prescription of exercise for a range of chronic conditions and are accredited by the peak exercise body within Australia  . PotentiData were collected via an anonymous online survey , Cliniko (www.cliniko.com), Coviu (www.coviu.com), Doxy.me (www.doxy.me), Facebook Messenger (www.messenger.com), FaceTime (www.apps.apple.com/us/app/facetime/id1110145091), HealthBank , HealthConnect , Healthdirect Video Call , Microsoft Teams (www.microsoft.com/en-au/microsoft-teams), MyPhysioRehab (www.myphysiorehab.com), Pexip (www.pexip.com), Physitrack (www.physitrack.com), PracMan (www.pracman.com.au), Skype (www.skype.com), Trainerize (www.trainerize.com), Vidyo (www.vidyo.com), WhatsApp (www.whatsapp.com), Zoom (www.zoom.us), telephone.The following telehealth delivery platforms were considered: Attend Anywhere . Differences between in-person and telehealth delivery were assessed by chi-square test. Odds ratios (OR) and corresponding 95%CI for clinicians offering telehealth delivery (yes/no) based on explanatory variables  were determined via penalised maximum likelihood logistic regression , 15. Unin\u2009=\u200980/6, 315) of the active workforce.The total number of clinicians offered this survey was not measured given the breadth of dissemination. However, when considering recent industry estimates  of 6315 n\u2009=\u200939/80, 49%) of clinician practices were located in the state of Victoria. No clinicians from Tasmania, Northern Territory or Australian Capital Territory provided data. Approximately half  of clinicians were employed by private practices in salary roles. Mean (SD) duration of an exercise physiology session, irrespective of the COVID-19 pandemic, was 51 (21) min  and incurred an hourly fee of A$111.57 .Clinician employment demographics are shown in Table 2. The majority of clinicians reported receiving referral for musculoskeletal complaints , type 2 diabetes  and/or cardiovascular disease . Clinicians also reported typically receiving the following referrals: paediatric healthcare (n\u2009=\u20092), pain management (n\u2009=\u20091), falls prevention (n\u2009=\u20091), general health and fitness (n\u2009=\u20091) and aged care (n\u2009=\u20091). Clinicians most commonly received Medicare  and private referrals , followed by those from the National Disability Insurance Scheme . Other forms of typical client referral pathways included: Australian health practitioner/general practitioner (n\u2009=\u20091), student-led paid services (n\u2009=\u20091), home care packages (n\u2009=\u20091), self-funded (n\u2009=\u20091), residential (n\u2009=\u20091) and university-funded (n\u2009=\u20091).Demographics of the clients commonly treated by clinicians, irrespective of the COVID-19 pandemic, are presented in Additional file me  of surveyed clinicians offered telehealth delivery to a mean (SD) of 49 (64) clients . On average, clinicians offered telehealth delivery to 85% of clients. Clinician reasons for not offering telehealth delivery are shown in Table n\u2009=\u200933/80, 41%) and client safety . Clinicians that had clients referred via any insurance scheme were less likely to offer telehealth delivery . Clinicians that reported typically having clients with a body mass index of 35\u201339\u00a0kg/m2  or obesity/metabolic condition  were more likely to offer telehealth delivery.During the COVID-19 pandemic, 91% n\u2009=\u20097/80 of sun\u2009=\u20092), death from a pre-existing heart condition (n\u2009=\u20091). One treatment-related adverse event occurred during telehealth delivery involving a non-serious pacemaker issues. Two treatment-related non-serious adverse events occurred during in-person delivery: brief loss of consciousness (n\u2009=\u20091), fall (n\u2009=\u20091). One non-serious non-treatment-related fall occurred in a client receiving telehealth delivery. Five non-serious non-treatment-related adverse events occurred in clients receiving in-person delivery: dizziness (n\u2009=\u20093), seizure (n\u2009=\u20091), chest pain (n\u2009=\u20091).No treatment-related serious adverse events occurred in clients receiving telehealth or in-person delivery. No non-treatment-related serious adverse events occurred in clients receiving telehealth delivery. Three non-treatment-related serious adverse events occurred in clients receiving in-person delivery: COVID-19 diagnosis (n\u2009=\u200971/80) of clinicians implemented telehealth delivery, compared to 25% (n\u2009=\u200920/80) pre-COVID-19 pandemic. In-person practice decreased from 99% (n\u2009=\u200979/80) pre-COVID-19 pandemic to 86% (n\u2009=\u200969/80) during the COVID-19 pandemic. Mean (SD) telehealth delivery hours per week per clinician more than doubled from 4.6 (7.1) hours pre-COVID-19 pandemic to 10.3 (7.8) hours during the COVID-19 pandemic. In contrast, in-person delivery hours per week per clinician decreased from 23.0 (10.6) hours pre-COVID-19 pandemic to 14.5 (11.1) hours during the COVID-19 pandemic.During the COVID-19 pandemic, 89%  rather than asynchronous methods . Education  and counselling  were also commonly implemented as part of telehealth delivery. Zoom , telephone  and Physitrack  were the most commonly used delivery platforms by clinicians  of clinicians that utilised telehealth delivery , mobile phones  and tablets  for telehealth delivery  of clinicians that implemented telehealth delivery undertook additional professional development. Mean (SD) professional development duration was 3.4 (2.4) hours .Additional resources utilised by clinicians to facilitate telehealth delivery are shown in Table n\u2009=\u200957/71, 80%), physical capacity  and access to a reliable platform . Clients aged 36\u201345\u00a0years  and those who were referred via Medicare  were more likely to accept telehealth delivery. Among clients who accepted telehealth delivery, 75% completed treatment. When compared to in-person delivery, clients receiving care via telehealth delivery were 6.7 times more likely (P\u2009<\u20090.001) to not complete treatment due to a lack of confidence in the delivery mode, 3.9 times more likely (P\u2009=\u20090.005) to not complete the treatment course due to a lack of understanding of telehealth delivery and 3.1 times more likely (P\u2009<\u20090.001) to not complete the treatment course due to a lack of interest or lack of perceived importance of telehealth delivery. Conversely, clients receiving in-person delivery were 6.2 times more likely (P\u2009<\u20090.001) to not complete treatment due to safety concerns borne from COVID-19 when compared to those using telehealth delivery. Following sensitivity analyses applying the false discovery rate adjustment, statistical significance remained . The study demonstrated that most clinicians implemented synchronous telehealth delivery (implementation) to a range of client demographics from varying referral pathways (reach). The primary reasons for not offering telehealth delivery were client physical/cognitive incapacity and safety concerns (reach). Approximately half the clients accepted an offer of telehealth delivery, with personal preference, physical/cognitive incapacity and access to reliable telehealth platforms cited by clinicians as the most common client reasons for non-acceptance (implementation). Clinicians reported that client non-compliance primarily stemmed from a lack of confidence, understanding and perceived importance of telehealth delivery (implementation). Finally, telehealth delivery appeared safe for the provision of exercise physiology services (effectiveness).n\u2009=\u200911), all trials were published and thus conducted in 2014 or earlier. Given myriad recent advancements in telehealth hardware, software and practise [Clinicians in our study reported a marked shift from in-person to telehealth delivery of exercise physiology services due to the COVID-19 pandemic. This aligns with previous observations regarding telehealth delivery uptake due to COVID-19 among several allied health professions, including exercise physiology , as wellThe current study identified several barriers regarding the implementation and delivery of telehealth exercise physiology services. Concerns about client physical/cognitive incapacity and safety were the most common reason for not offering telehealth delivery. Exercise physiologists were previously reported to have safety concerns when providing video consultations owing to falls risk and an inability to monitor environment and physiological responses during the provision of exercise training . This waIn the current study, almost half the clinicians reported clients who were federally funded by the NDIS to receive individualised financial packages of support for people with a permanent and significant disability under the age of 65\u00a0years. This is surprising based on the relatively recent expansion of claimable items for exercise physiology via NDIS. Overall, 2557 exercise physiology and physical wellbeing-approved service providers are registered to provide services via the NDIS . TeleheaThe current study was strengthened by the broad ranging demographics of clients treated by the participating clinicians. This reflects the wide range of age, body mass index, geographical location, referral pathways and health conditions commonly encountered within the exercise physiology profession in Australia .The study has several limitations that should be considered when interpreting results. First, participants only represented five of the eight Australian states and territories, with nearly half the sample from Victoria. Comparably, the governing body for exercise physiology in Australia reported 20% of members reside in Victoria . This liDuring the COVID-19 pandemic, telehealth delivery services increased, and in-person services decreased among Australian accredited exercise physiology clinicians (adoption). Most clinicians implemented synchronous telehealth delivery (implementation) to a range of client demographics from varying referral pathways (reach). Common reasons for not offering telehealth delivery were physical/cognitive incapacity and safety concerns (reach), whereas client reasons for not accepting telehealth delivery were personal preference, physical/cognitive incapacity and access to reliable platforms (implementation). Client non-compliance appeared to stem from a lack of confidence and understanding of the perceived importance of telehealth delivery (implementation). Finally, telehealth delivery appeared safe (effectiveness). These data suggest that exercise physiology services in Australia can be adaptable and agile. However, further research is warranted to determine the comparative efficacy and cost-effectiveness between delivery modes.Additional file1: Data S1. Survey provided to the 80 accredited exercise physiology clinicians currently practising within Australia during the COVID-19 pandemic (after 25 January 2020). Table S1. Typical client demographics reported by the 80 accredited exercise physiology clinicians currently practising within Australia during the COVID-19 pandemic (after 25 January 2020). Table S2. Sensitivity analysis applying the false discovery rate adjustment to P-values from Table 5."}
+{"text": "Identifying the individual characteristics that predict which adults will develop obesity and diabetes is crucial. This study included national data from 902 participants (aged 25-75) in the Midlife Development in the U.S. (MIDUS) study. Participants completed the Big-5 personality trait measure in 1995-1996, and behavior/health variables between 2004-2009. We tested whether levels of certain personality traits would predict an elevated risk of diabetes via hemoglobin A1c (HbA1c) levels through eating behaviors. A structural equation modeling framework demonstrated good fit when testing indirect effects . Indirect effects revealed that higher levels of neuroticism predicted greater waist circumference and higher HbA1c levels due to an increased use of food to cope with problems . Moreover, indirect effects were found for conscientiousness, albeit in a protective direction. Our findings suggest that personality traits may be an early predictor of behavior and thus long-term adverse health outcomes."}
+{"text": "Dear Editor,2 Previous studies suggested that artesunate (ART), an important derivative of artemisinin and a first-line antimalarial agent, modulated Th17 and regulatory T (Treg) cells balance in rats with collagen-induced arthritis.3Primary Sj\u00f6gren\u2019s syndrome (pSS) is an autoimmune disease characterized by dry eyes and dry mouth caused by glandular inflammation in salivary glands (SG) and lacrimal glands. Currently, pSS patients are suffering from a lack of effective therapies. Many studies have revealed dysregulated immune responses during pSS development, in which Th17 cells are considered as the key driver in disease initiation and perpetuation.2 administration of ART markedly improved salvia secretion and significantly reduced serum levels of autoantibodies including anti-SSA IgG during ESS disease progression  induced saliva secretion dysfunction, whereas ART treatment significantly improved saliva flow rates in these mice  mice, we transferred peripheral blood mononuclear cells (PBMC) from pSS patients into NSG mice and found that PBMCs from pSS patients but not healthy donors decreased saliva secretion and caused intensive SG inflammation in recipient NSG mice  data of PBMC from healthy control and pSS patients,try Fig. . Gene setry Fig. . Th17 cetry Fig. . NotablySIS Fig. .During Th17 cell differentiation, Glut1 expression was significantly elevated whereas ART markedly reduced Glut1 expression in both human and murine Th17 cells in culture Fig. . ConsistSlc2a1, Aldoa and Pgam1  and oxygen consumption rate (OCR) values that reflect metabolic status. Although Th17 cells derived from pSS patients showed increased glycolysis levels compared to healthy donors, ART treatment inhibited glycolysis in Th17 cells from both healthy controls and pSS patients Fig. . ART treSlc2a1 in CD4 T cells (Supplementary Fig. IRF4 is a key regulator of T cell differentiation and function. We observed that IRF4-deficient CD4 T cells failed to differentiate into Th17 cells in culture (Supplementary Fig. Irf4 (Supplementary Fig. + Th17 cells (Supplementary Fig. We next examined the effects of ART on IRF4 expression in Th17 cells. ART-treated humanized SS mice exhibited significantly reduced expression levels of IRF4 (Supplementary Fig. In sum, our findings show that ART effectively suppresses disease development in ESS and humanized SS mice via inhibiting Th17 responses. Moreover, we have identified a novel metabolic modulatory function of ART in suppressing Th17 glycolysis through promoting proteasomal degradation of IRF4. Taken together, these findings suggest that ART may serve as a promising therapeutic candidate for treating pSS patients.supplementary material"}
+{"text": "CHKA and CHKB. Variants in the CHKA gene that decrease enzymatic activity have been shown to cause an inherited neurodevelopmental disorder with epilepsy, while recessive inheritance of nonfunctional CHKB alleles causes an inherited rostrocaudal muscular dystrophy  and evidence of damaged ER (gray arrow) that is engulfed by autophagosomes and fused with lysosomes (red arrow). These findings are highly suggestive of ER-phagy; the scale bar represents 500\u00a0nm. Panel B: Human bone osteosarcoma epithelial cells (U2OS) were treated with the choline kinase inhibitor EB3D (15\u00a0\u03bcM for 48\u00a0h) and ER-phagy monitored using the ER autophagy tandem reporter (EATR) (The major membrane phospholipid phosphatidylcholine is predominantly synthesized through the CDP-choline (Kennedy) pathway at the endoplasmic reticulum (ER). The first step in this pathway is the phosphorylation of choline by choline kinase. Humans contain two choline kinase isoforms, ystrophy , 2. In aactivity . Panel AEQUIPMENT: Transmission electron microscope  with Hamamatsu ORCA-HR digital camera (Hamamatsu) and Zeiss Axio Observer Z.1 Spinning Disk Confocal Microscope (Zeiss).REAGENTS: TetOn-mCherry-enhanced GFP-RAMP4 (EATR) was a gift from Jacob Corn , Lipofectamine 3000 (Thermo Fisher Scientific), EB3D , doxycycline , and Earle's balanced salt solution .The authors declare that they have no conflicts of interest with the contents of this article."}
+{"text": "Chest radiograph revealed multiple lung opacities. Serology was negative for syphilis, cryptococcus, toxoplasmosis, and positive for cytomegalovirus (CMV) but CMV PCR was negative. Sputum and bronchoalveolar lavage (BAL) were negative for tuberculosis and pneumocystis. [18F]-FDG PET/CT was performed for the detection of a clinically occult AIDS-related disease. Maximal intensity projection images (A) and fused axial images  revealed multiple hypermetabolic cutaneous lesions on the scalp, face, and limbs with corresponding skin thickening on CT; a large hypermetabolic pubic lesion extending in the subcutaneous tissues and scrotum; and numerous lung nodules with mild [18F]-FDG uptake. Mildly hypermetabolic peripheral lymph nodes were also observed. Lung nodules were compatible with viral lung disease occurring in immunocompromised patients [A 30-year-old man presented painful disseminated skin and genital lesions with pyrexia. The lesions appeared 1\u00a0month prior to the admission as vesicles, progressively evolving into confluent and crusted lesions. Polymerase chain reaction (PCR) assay of the lesions swab was positive for monkeypox and negative for herpes simplex virus. Laboratory investigations showed elevated C-reactive protein and lymphopenia. Human immunodeficiency virus 1/2 antibody/antigen test was reactive. CD4 count was 23.9 cells/mm"}
+{"text": "Scientific Reports 10.1038/s41598-022-10750-7, published online 04 May 2022Correction to: The original version of this Article contained an error in the Abstract.\u201cIf confirmed in larger series, this finding could constitute a valuable tool for improving the interpretation of radiological.\u201dnow reads:\u201cIf confirmed in larger series, this finding could constitute a valuable tool for improving the interpretation of radiological patterns.\u201dThe original Article has been corrected."}
+{"text": "Individuals with Medicaid as their health care payer source may be either \u201cMedicaid-only,\u201d or \u201cdually eligible,\u201d i.e., qualifying for both Medicaid and Medicare. Medicare included hospice as a full Medicare benefit in 1982; Hospice is an optional Medicaid benefit for states; Connecticut added the Medicaid hospice benefit in 2010. This study explores hospice use in Connecticut\u2019s Medicaid program by comparing hospice use and length of hospice enrollment by Medicaid-only vs. dually eligible and by diagnosis for decedents who died between 2017 and 2020 and had a hospice-appropriate diagnosis. This analysis of 2,990 Medicaid-only and 24,881 dually eligible decedents finds that dually eligible decedents had a significantly (p<.001) higher rate of hospice use (48.1%) compared to Medicaid-only decedents (29.9%). Medicaid-only decedents received hospice for a median of 12 days vs. 13 days for the dually eligible (p=.12). Dually eligible decedents consistently received hospice more often than Medicaid-only decedents across all diagnoses (cancer (p<.05) circulatory (p<.001), dementia (p<.001), respiratory (p<.001) and stroke (p<.001)). Dually eligible decedents had significantly more days of hospice than Medicaid-only decedents for subgroups with a circulatory (p<.05) or stroke (p<.05) diagnosis, but Medicaid-only decedents with a dementia diagnosis had more days of hospice than their dually-eligible counterparts. Additional multi-variate analysis will demonstrate how other factors, like age, may account for differences. Recommendations include encouraging physician use of hospice screening tools and developing education interventions with physicians and patients to increase understanding of the availability and benefits of hospice with particular focus on Medicaid-only patients."}
+{"text": "Scientific Reports, 10.1038/s41598-023-29440-z, published online 10 February 2023Correction to: The Funding section in the original version of this Article was omitted. The Funding section now reads:\u201cThis research was funded by the NATIONAL NATURAL SCIENCE FOUNDATION OF CHINA, Grant Number U20A20271; NATURAL SCIENCE FOUNDATION OF HEBEI PROVINCE, Grant Number E2020209184; SCIENCE AND TECHNOLOGY PROJECT OF TANG-SHAN CITY, Grant Number 20150217C; SCIENCE AND TECHNOLOGY PROJECT OF HEBEI EDUCATION DEPARTMENT, Grant Number ZD2021084.\u201dThe original Article has been corrected."}
+{"text": "Measles remains a global health challenge despite the availability of a safe and effective vaccine. Sporadic outbreaks of measles virus infections continue in Uganda. We report eight near-complete genome sequences of measles virus strains from Uganda cases from 2011 to 2020, providing useful data for assessing vaccine escape and local/regional transmission. Measles morbillivirus species  and is encoded by a negative-sense single-stranded RNA linear genome of about 16,000 nucleotides (nt). Measles is a very transmissible viral infection and, despite an effective vaccine, MV continues to infect and sicken individuals throughout the world. Disruptions of routine vaccination by the\u00a0coronavirus disease 2019 (COVID-19) epidemic are resulting in further increases in global measles cases (Measles virus (MV) is classified in the https://github.com/mlcotten13/Measles_primers). Briefly, total viral RNA was extracted from cell culture material using QIAamp viral RNA minikits following the manufacturer\u2019s instructions. MV RNA was reverse transcribed using amplicon-specific primers and SuperScript III reverse transcriptase (Invitrogen), followed by PCR amplification using Phusion high-fidelity DNA polymerase (Thermo Fisher Scientific). PCR amplicon products were subjected to MinION sequencing library preparation using the SQK-LSK109 barcoding kit (Oxford Nanopore Technologies) according to the manufacturer\u2019s instructions, followed by sequencing on MinION SpotON R9.4.1 flow cells. The resulting fast5 files were base called and demultiplexed using Oxford Nanopore Technologies Guppy software v.5.0.11+2b6dbff (MT789820) as the reference sequence. Consensus genome sequences and final sequence checks were determined using Geneious Prime v.2022.1.1 (MV IgM enzyme-linked immunosorbent assay (ELISA)-positive cases  were ide+2b6dbff  with MVs6dbff MT79820 as tThe eight near-complete MV genome sequences reported here were obtained from Uganda measles cases identified in 2011 to 2020 from locations across the country. Despite small numbers, these eight sequences help address the lack of MV genome sequences from Uganda and from East Africa, where outbreaks of measles occur regularly. The sequences were all classified as genotype B3, the genotype most frequently reported from Africa , 10. TheThe study was approved by the Uganda Ministry of Health (reference number 105/197/01), the Uganda Virus Research Institute Research and Ethics Committee (reference number GC/127/19/12/740), and the Uganda National Council for Science and Technology (reference number HS2741).ON642794 to ON642801. The unassembled read data are available in the SRA with the accession numbers SRX15483626 to SRX15483633 under BioProject accession number PRJNA843031 (https://github.com/mlcotten13/Measles_primers.The genome sequences described here have been deposited in GenBank with the accession numbers NA843031 . Primer"}
+{"text": "Acute lymphoblastic leukemia (ALL) is the most incident pediatric cancer. Although considerable progress has been made on treatment efficacy and survival rates, 15%-30% of patients relapse and/or die. We aimed to identify molecular profiles and microenvironment makeup in leukemic bone marrow samples that could help to better predict disease outcome.We performed RNA-seq on bone marrow samples from pediatric ALL patients at diagnosis (n = 37). Patients were recruited under a multi-center clinical protocol in Argentina (median follow-up: 31 months). We analyzed differential gene expression, gene set variations, mutations in candidate genes, and fusion genes among clinico-pathological features. The abundance of immune-cell populations was inferred by digital cytometry (MIXTURE) and a \u201ccytolytic score\u201d based on the expression of five genes specific to cytotoxic cells.P.adj < .05). We observed that 15%-30% of the DEG corresponded to lncRNAs. We found six differentially expressed pathways relevant to cancer and leukocyte biology among risk groups (P < .01). We identified 17 mutations and three fusion genes in 44% of patients; the presence of these mutations shortened the relapse-free survival . High cytolytic score was associated with activated CD8+T cells, immune cell trafficking, and bone marrow niche signaling genesets, suggesting potential candidates for immunotherapies. Higher CD8+T-cell/NK at diagnosis was marginally associated with worse event-free survival .We detected: (1) 37 differentially expressed genes (DEG) between poor vs good responders to prednisone; (2) 71 DEG between high vs standard-risk groups; (3) 13 DEG between patients who died/relapsed vs those who did not; and (4) 35 DEG between patients that developed severe therapy-related acute toxicity vs those who did not (|log2FC|> 1; Transcriptomic sequencing allowed the analysis and integration of multiple molecular features that might improve pediatric ALL outcome prediction."}
+{"text": "Symptoms started 9 years prior with occurrence during strong exercise but were progressive for the last years to the extent of restricting everyday exercise capabilities such as grocery shopping. Previous medical work-up revealed no pulmonary cause, while cardiac evaluation documented an intermittent LBBB with normal echocardiographic evaluation. Previous empirical therapy with a calcium channel blocker for suspected vasospastic angina or microcirculatory ischemia and with bronchodilator inhalation for suspected bronchial asthma was unsuccessful. Also, cardiac rehabilitation with daily exercise sessions had not yielded beneficial results. During normal sinus rhythm (heart rate below 75 beats per minute [bpm]), no bundle branch block or repolarization abnormalities were noted. Holter monitoring, however, revealed rate-dependent LBBB coinciding with the patient\u2019s symptoms starting at a heart rate of 75 bpm . Exercis2 within 1 year owing to increased capacity during cardiovascular exercise. Device interrogation demonstrated a stable pacing percentage of around 25% and a stable unipolar threshold of 2 V / 1 ms for selective His capture with LBBB correction.Repeat exercise test demonstrated improved exercise capacity (95 W = 79% vs previously 76 W = 60% of age-\u00a0and sex-adjusted average) and improved peak oxygen uptake (VO2 max 20.4 mL/min/kg vs previously 14.4 mL/min/kg). During echocardiographic evaluation offline strain analysis with 3-dimensional rendering of left ventricular deformation was performed using TomTec ImageArena Cardiac Performance Analysis module (v.4.6). Global and segmental strain values were described based on a 16-segment left ventricular model from tracking the left ventricular endocardial border in the apical 2-, 3-, and 4-chamber views according to current recommendations.,,The \u201cPainful LBBB syndrome\u201d consists of anginal symptoms and rate-dependent LBBB during exertion, first published more than 70 years ago.,,,,While no specific treatment protocols for symptomatic LBBB exist, therapeutic options include a physical exercise regimen to increase the rate threshold of LBBB onset, beta blockers to limit heart rate, or pacemaker implantation.However, the effect of His bundle pacing on objective parameters including exercise capacity and echocardiographic parameters of ventricular electrical synchrony in this type of patients has, to the best of our knowledge, not yet been reported. A higher exercise capacity (110 W = 89% vs previously 76 W = 60% of age- and sex-adjusted mean) and peak oxygen uptake (VO2 max 18.4 mL/min/kg vs previously 14.4 mL/min/kg) after HBP implantation was documented in our patient, corresponding well to her significantly improved symptoms. Echocardiographic evaluation demonstrated improved global left ventricular strain, improved electrical dispersion, and improved homogeneity of cardiac contraction ,2,3,4, uPainful LBBB syndrome is a potentially underestimated and underreported disease with potentially debilitating symptoms. In patients with anginal symptoms, LBBB, and absence of other causative diseases, painful LBBB should be considered. His bundle pacing may ameliorate symptoms, increase exercise capacity, and improve homogeneity of cardiac deformation."}
+{"text": "First responders to disasters are at risk of developing post-traumatic stress disorder (PTSD). The trajectories of post-traumatic stress symptom severity differ among individuals, even if they are exposed to similar events. These trajectories have not yet been reported in non-Western first responders.We aimed to explore post-traumatic stress symptom severity trajectories and their risk factors in first responders to the 2011 Great East Japan Earthquake (GEJE)\u2014 a historically large earthquake that resulted in a tsunami and a nuclear disaster.56 388 Japan Ground Self-Defense Force (JGSDF) personnel dispatched to the GEJE were enrolled in this seven-year longitudinal cohort study. PTSD symptom severity was measured using the Impact of Event Scale-Revised (IES-R). Trajectories were identified using latent growth mixture models (LGMM). Nine potential risk factors for the symptom severity trajectories were analyzed using multinomial logistic regression.Five symptom severity trajectories were identified: \u201cresilient\u201d (54.7%), \u201crecovery\u201d (24.5%), \u201cincomplete recovery\u201d (10.7%), \u201clate-onset\u201d (5.7%), and \u201cchronic\u201d (4.3%). The main risk factors for the four non-resilient trajectories were older age, personal disaster experiences, and working conditions. These working conditions included duties involving body recovery or radiation exposure risk, longer deployment length, later or no post-deployment leave, and longer post-deployment overtime.The majority of first responders to GEJE were resilient and developed few or no PTSD symptoms. A substantial minority experienced late-onset and chronic symptom severity trajectories. The identified risk factors can inform policies for prevention, early detection, and intervention in individuals at risk of developing symptomatic trajectories.No significant relationships."}
+{"text": "Prof. Alexander will present a study linking national nursing home (NH) health information technology (HIT) to quality. This research explores relationships between NH HIT maturity and UTIs examined during a repeated cross-sectional study over 4 consecutive years (2013-2017). HIT maturity represents the diversity of technology use in NHs. Researchers conducted bivariate and multivariate regressions using MDS 3.0 resident assessments and post stratified survey weights controlling for NH characteristics. Our sample included 816 NHs. These NHs had 219,730 regular NH resident assessments within 90 days of a survey, representing 80,322 unique NH residents. Of these assessments, 4.1% recorded a UTI. In the multivariate analyses, administrative HIT capabilities was associated with lower odds of UTI , controlling for covariates. Integration of administrative HIT systems may relieve the burden of tracing UTIs, data documentation and record retrieval affording NH staff time to focus their efforts on clinical care."}
+{"text": "Correction to: Mol Cancer 18, 131 (2019)https://doi.org/10.1186/s12943-019-1056-5Following publication of the original article , errors Fig. 3C Representative images showing plate colony formations from different cell lines were incorrectly selected during figure assembly; this affects circ-AKT3 IRES mut U373 (bottom left in left-hand colony formations), and circ-AKT3 shRNA control SW1783 and HS683 (top and bottom left in right-hand colony formations). The correct representative images are now usedFig. 4G Representative images of the control group for Empty Vector U373 (bottom left cell line) was incorrectly used. The correct representative image is now usedThe corrected figures are provided here. The correction does not have any effect on the results or conclusions of the paper. The original article has been corrected."}
+{"text": "Enterobacteriales hosts are presented. Brookers is a P22-like Proteus phage, OddieOddie is a 9g-like Escherichia coli phage, Diencephelon is a Kp3-like Klebsiella phage, and Rgz1 and Lilpapawes are classic T4-like and T7-like virulent Proteus phages, respectively.Full genome sequences of five bacteriophages that were isolated from raw sewage samples and infect  Enterobacteriales species harbor both harmless and disease-causing strains, making understanding their evolutionary differences of key importance  using the phage DNA isolation kit , prepared for Illumina HiSeq 2500 paired-end 250-bp sequencing using the Illumina TruSeq DNA Nano kit, and assembled de novo using Geneious v.R11  (\u223c73% identity over >18% of the genome). In addition, very similar sequences (>94% identity over >50% of the Brooker\u2019s genome) are found in numerous Proteus genomes, indicating that very similar prophages reside in these strains. We conclude that Brookers is a temperate phage.All five phages display similarity in genome size and sequence to previously defined clusters  as deterclusters . The genMorganella morganii subsp. morganii Fulton ATCC 25829 as the host. Rgz1 is a T4-like phage whose closest relatives are Providencia phages PSTRCR 127 (GenBank accession number MW358927) and 121 (GenBank accession number MP358300) and Morganella phage MP1 (GenBank accession number KX078569) (Morganella phage whose closest relative is Morganella phage MP2 (GenBank accession number KX078568)  Trevisan ATCC 10031, respectively. OddieOddie has strong similarity to phages in the 9g-like cluster of Enterobacteriales phages (E. coli phage Seurat (GenBank accession number KM236243) (Seuratvirus. The Diencephelon genome has 91% identity to that of Enterobacter phage ATCEA22 (GenBank accession number MW419910). This places Diencephelon in a previously undescribed Kp3-like Enterobacteriales phage cluster  that contains phages that infect Klebsiella and Enterobacter.The remaining two lytic phages, OddieOddie and Diencephelon, were isolated using BW 25113  and Klebs phages ; in partEnterobacteriales phages are found in The accession numbers for all five"}
+{"text": "The frog sign is a classic physical examination finding of typical atrioventricular nodal re-entrant tachycardia. We present the case of a 78-year-old man with recurrent, symptomatic supraventricular tachycardia referred for ablation in whom the frog sign was observed during physical examination. Upon presentation, he was in tachycardia, and the frog sign was observed on physical examination. An electrophysiologic study with RAP recordings was performed. Frequent non-sustained atrial tachycardia repeatedly induced an \u201cA-on-V\u201d tachycardia that was terminated by late-coupled His-refractory atrial premature depolarizations (*), excluding junctional tachycardia .2 Characteristic low-pressure sinus waveforms transitioned to higher-pressure  fused ventriculoatrial \u201ccannon waves\u201d (VA = 0 ms) during tachycardia. During onset of entrainment from the ventricle, atrial waveforms (\u2193) were dissociated from the ventricle within the transition zone, causing a drop in RAP, but then became fixed with the ventricle (VA = 112 ms) following acceleration of the atrial rate to the pacing cycle length (410 ms) after the third fully paced ventricular complex (hemodynamic \u2206VA [VA(V entrainment) \u2013 VA(SVT)] = 112 ms [>85 ms]) .4 Termination of entrainment revealed an \u201cAV\u201d response with a long hemodynamic post-pacing interval (549 ms) that exceeded the tachycardia cycle length by 131 ms (>115 ms), followed by resumption of cannon waves.6 Slow pathway ablation rendered the AVNRT non-inducible.A 78-year-old man with recurrent, symptomatic supraventricular tachycardia (SVT) was referred for SVT ablation Besides cannon waves, hemodynamic post-pacing interval and \u2206VA intervals derived from RAP waveforms can be useful for the diagnosis of typical AVNRT."}
+{"text": "Neisseria gonorrhoeae (NG) is a public health crisis. Diagnosis of infection is primarily established using nucleic acid amplification technologies (NAATs) without susceptibility testing; thus rapid identification of resistance determinants is crucial. Whole-genome sequencing (WGS) is a promising alternative to current susceptibility methods. The purpose of this study was to describe AMR genes in a subset of isolates using WGS from Southeast Michigan.Antimicrobial resistance (AMR) in Isolates, demographic data, and minimum inhibitory concentrations (MIC) via E-test (ceftriaxone/CRO) and broth microdilution (azithromycin/AZM) were obtained from the Michigan Department of Health and Human Services. Libraries from isolates were generated using QIAseq FX DNA library kit before sequencing on NovaSeq 6000. Reads were trimmed [Trimmomatic] and aligned to the NG genome [Burroughs-Wheeler Aligner] before processing with Samtools suite for variant detection and consensus WGS determination. AMRFinderPlus was used to categorize AMR genes and resistance-associated point mutations.< 0.25). The mtrR gene associated with macrolide resistance was noted in 86.8% isolates. Among 33 isolates where AZM susceptibility was available, resistance was noted in 9 (27%) (CLSI resistance breakpoint MIC > 1).Total of 38 isolates were analyzed. The majority were from males (63%) and Blacks (44.7%) living in Detroit City proper (47.3%) with median age 25 (range 13-56), unknown HIV status (55.2%) and sexual orientation (47.3%) (Table\u00a01). Urine (47.3%) was the most common specimen source, followed by cervix/vagina (28.9%). More than a third had prior NG and other sexually transmitted infections. Eight resistance genes were found among the 38 isolates . The penA gene associated with cephalosporin resistance was found in all isolates; however, all isolates were susceptible to CRO (CLSI susceptible breakpoint MIC We describe a potential utility for WGS to identify AMR genes in NG. Although numerous \u03b2-lactam resistance genes were detected in all isolates, all remained susceptible to CRO. Further research is needed to determine the extent to which genetic diversity affects phenotypic susceptibilities in NG.All Authors: No reported disclosures."}
+{"text": "FLT3) that results in a constitutively active tyrosine kinase and is generally associated with poor prognosis involving shorter overall survival and higher rates of relapse. Advancements in targeted therapies have greatly influenced available treatment options in a landscape that has remained largely unchanged for the past five decades. Tyrosine kinase inhibitors (TKI), specifically FLT3-targeted therapies, are now integral treatment options for patients with this targetable mutation. As allogeneic hematopoietic cell transplant  remains the primary curative therapy for most adult AML patients, the goal is for eligible patients to proceed to transplant. However, post-alloHCT relapse remains exceedingly high even in patients achieving deep responses to therapy. Limited evaluation of FLT3-targeted TKIs as post-alloHCT maintenance therapy in FLT3-positive patients suggest improved outcomes and tolerable safety profiles, with ongoing studies further investigating second-generation agents. Thus, this commentary aims to review the role of post-alloHCT FLT3-targeted maintenance therapy and considerations for clinical practice.Acute myeloid leukemia (AML) is characterized by multiple molecular and cytogenetic abnormalities, with increasing data to support clinical and prognostic implications to guide clinical decision making. One of the most well described mutations involves fms-like tyrosine kinase 3 ( Acute myeloid leukemia (AML) is estimated to account for about one-third of new leukemia cases in 2022 ,2. AML iFLT3), occurring in 30% of adult AML patients [FLT3 AML has been associated with poor prognosis involving shorter overall survival and higher rates of relapse, due in part to its role as a driver mutation and contribution to possible clonal evolution [FLT3+ AML are generally considered for alloHCT. Given the associated risk with FLT3-positivity, development of second-generation FLT3-targeted therapies, and understanding of the critical nature of MRD status, there is growing interest in continuation of FLT3-targeted therapies following alloHCT in an effort to deepen remission and prevent relapse.Allogeneic hematopoietic cell transplant  remains the primary curative therapy for most adult AML patients, particularly in those individuals who achieve complete remission (CR), due in part to the immunologic benefit of the associated graft versus leukemia (GVL) effect. However, relapse remains exceedingly high in certain patient populations, such as in individuals with treatment-related AML, monosomal karyotype or complex cytogenetics on presentation, or those with detectable minimal residual disease (MRD) after induction/consolidation therapy. Currently, high relapse risk populations are also increasingly being identified upfront with next generation sequencing, targeting known myeloid gene panels. One well-defined mutation in AML involves the fms-like tyrosine kinase 3  in-frame internal tandem duplication (ITD) or (2) point mutations within the tyrosine kinase domain (TKD) [FLT3-TKD (5\u201310% of cases) [FLT3-ITD allelic ratio confers increased risk with concomitant expression of other mutations, namely NPM1 [Whole genome sequencing of multiple AML patient samples has revealed increasing numbers of genetic mutations. However, the ed genes \u201310. FLT3in (TKD) . Either ely NPM1 ,5.FLT3-ITD mutations may likely confer a selective survival advantage within the tumor microenvironment. One study reported persistent FLT3 -ITD clones in 75% of patients at the time of relapse [FLT3-targeted therapy with high specificity and binding affinity (discussed below).Comparative studies evaluating clonal evolution of patients with relapsed AML suggest that  relapse . These cFLT3-targeted therapies available. Initial studies evaluated use of first generation multi-targeted kinases including sunitinib and sorafenib [FLT3-ITD positive and not candidates for transplant nor able to receive high-intensity therapy [There are now several orafenib . Both agorafenib . However therapy .FLT3-targeted therapy was the phase 3 RATIFY/CALGB 10603 trial of midostaurin, another tyrosine kinase inhibitor (TKI) that targets FLT3, in combination with conventional induction (7+3) chemotherapy for the treatment of newly diagnosed FLT3-mutated AML. Improved event-free survival  0.78; P = 0.002) and overall survival  was shown compared to conventional chemotherapy alone [FLT3+ AML and appear to remain effective as single-agent therapy [The major breakthrough involving py alone ,13. Many therapy .FLT3+ AML, there has been significant interest in ongoing FLT-directed maintenance therapy after alloHCT while waiting to establish the donor GVL effect. Sorafenib was first evaluated in a phase I dose-escalation study by the Mass General Hospital group, in which patients received sorafenib 45\u2013120 days post-alloHCT for up to 12 28-day cycles [Given the significant findings related to peri-transplant MRD positive or negative status and significant rates of relapse with y cycles . Overally cycles . A folloy cycles . Of notey cycles \u201318.FLT3-ITD in remission [FLT3-ITD with complete hematologic remission (bone marrow blasts <5%) [Based on these initial observations, two randomized, controlled trials of maintenance sorafenib have been performed. The positive results have led to NCCN and EBMT endorsement of sorafenib use post-alloHCT in AML patients with history of emission ,19,20. Ssts <5%) . Patientsts <5%) . PatientFLT3-targeted maintenance therapy describes sorafenib, there are emerging data that support use of midostaurin. The phase II AMLSG 16\u201310 trial evaluated use of midostaurin in combination with intensive chemotherapy similar to the RATIFY trial, but permitted continuation of single-agent midostaurin as maintenance therapy starting as soon as 30 days post-alloHCT [FLT3 phosphorylation to <70% of baseline. The inability to achieve adequate inhibition through the entire patient cohort may have been impacted from adverse effects related to midostaurin, with 63% of patients requiring dose adjustments and 8 patients requiring discontinuation of therapy. Also, it was noted that the control group (76% OS) had better outcomes than otherwise seen historically or in other FLT3 post-alloHCT studies, potentially influencing the outcomes seen.Although the majority of post-alloHCT -alloHCT . Of the -alloHCT . RADIUS FLT3-targeted therapies supported improved outcomes with generally well-tolerated adverse effects and no overt safety concerns related to post-transplant complications [FLT3 maintenance therapy compared to placebo (pooled risk ratio (RR) = 0.35 (95% CI 0.23 to 0.51), P<0.001). Pooled RR for RFS (RR=0.48 (95% CI 0.37 to 0.61), P<0.001) and OS (RR=0.48 (95% CI 0.36 to 0.64), P<0.001) were also significantly improved. There was no difference in NRM or GvHD. Similarly, a large-scale retrospective review across 8 countries involving 1208 patients identified 219 patients who received FLT3-targeted maintenance therapy [A recent systematic review and meta-analysis assessing post-alloHCT ications . The ana therapy . MaintenFLT3 inhibitors with greater specificity may be ideal for post-alloHCT maintenance therapy. Currently, only gilteritinib is approved in the United States for use in relapsed/refractory disease and is currently under investigation for use as maintenance therapy in the phase III BMT CTN 1506 trial (NCT02997202), with analysis pending [FLT3-ITD+ AML patients, most subjects will have already been exposed to a TKI. This specific post-alloHCT trial randomizes patients, after engraftment, to placebo versus gilteritinib. Maintenance continues for 2 years after alloHCT. The primary objective is to compare RFS between the gilteritinib and the placebo arms with secondary objectives of tolerability, OS, aGVHD and exploratory objectives of quality of life analysis, healthcare resource utilization, study drug pharmacokinetics, and determination of FLT3 status at relapse.Second generation  pending . There aFLT3 inhibitors are smaller in scope. A phase I dose escalation study of quizartinib included 13 post-alloHCT patients with planned maintenance therapy of up to 24 months [NCT02400255, NCT03258931).Other studies examining second generation 4 months . One pat4 months . PatientFLT3-targeted therapy as post-alloHCT maintenance therapy. Encouraging results thus far suggest improved survival and lower incidence of relapse with targeted maintenance therapy after alloHCT. The data obtained consistently demonstrate that patients with CR prior to alloHCT with MRD\u2212 status appear to have better outcomes. Early use of alloHCT maintenance therapy is supported, recognizing that relapse often occurs early (<100 days) [FLT3-ITD patients, some ethical concerns may exist related to continued investigation involving placebo, as carefully outlined by Levis et al [There remain several ongoing clinical trials seeking to further investigate use of 00 days) . With this et al . Yet, wiFinally, we must recognize that there are cost considerations which justify the needs for ongoing clinical trials. AlloHCT is an expensive procedure. One recent analysis of a payor claims data base revealed a median of ~$417,000 adjudicated claims payments for the first year of coverage . The MilHealth resource utilization analysis re: the cost of care is needed to best understand what are the true optimal outcomes, analyses often extending beyond RFS to quality-adjusted life years (QALY) gained by an intervention  and the increasingly recognized, critical need for patient reported outcome (PRO) measures.FLT3-targeted post-alloHCT maintenance therapy continues to be an area of interest and ongoing investigations. Guideline recommendations support use of sorafenib as maintenance therapy in patients with a history of FLT3+ disease. Encouraging results suggest similar application of midostaurin, with analysis of second-generation therapies expected to mature in the near future. Patients in CR prior to alloHCT may be ideal candidates to start early maintenance therapy in an effort to maintain MRD negativity, but it is important to note that use of maintenance therapy is not benign given potentially significant adverse effects and costs to the health care system.Routine use of"}
+{"text": "Infectious Disease (ID) clinicians increasingly collaborate via social media and have adopted Twitter and the hashtag #IDTwitter for community-wide conversation. We investigated clinicians\u2019 use of #IDTwitter for peer consultation, examining both the utility of responses and how frequently discussions risked compromising patient privacy.st, 2021. We collected posts that we deemed examples of peer consultation, recording the post\u2019s author, topic, engagement produced, and patient information disclosed. Finally, we recorded whether (by consensus) we judged a question meaningfully answered.We reviewed English-language posts on www.twitter.com with the hashtag #IDTwitter over a 6-week period ending August 31We identified 108 instances of peer consultation; 91 posts (84%) were consultations about a clinical scenario, 17 (16%) included a specific request for medical literature, and seven (6%) included a request for literature interpretation. Twenty-four posts (22%) contained polls, which received a mean 107 (SD 104) votes. We judged 71% of questions meaningfully answered; of these, 68% received responses including explicit justification or reasoning and 35% included citations of supporting literature. Questions were more likely to be meaningfully answered if they included polls . Receipt of a meaningful answer was not predicted by the questioner\u2019s professional role and follower count, the question topic, or the post\u2019s number of likes and shares.A total 28/108 posts (26%) referenced the care of a specific patient, with details shared including gender (74%), age (26%), radiographic or clinical images (7%), and other potentially identifying data (7%). Patients were stated or implied to be currently under the clinician\u2019s care in 70% of cases, and 61 clinicians (92.4%) had their employer listed in their profile or immediately available via internet search.ID clinicians\u2019 peer consultations via #IDTwitter appeared frequently useful, particularly when questions were accompanied by polls. However, most participants sharing patient data were readily identifiable, and best practices to limit sharing of nonessential data and safeguard patient privacy are needed.Jasmine R. Marcelin, MD, Pfizer (Grant reviewer): Honoraria."}
+{"text": "Mitochondrial energy production decreases while fatigability increases with age. Genes associated with energy metabolism may contribute to fatigability. Using Long Life Family Study (LLFS), we initially assessed variants (SNPs) in 272 candidate autosomal genes involved in energy metabolism  with perceived physical fatigability. Two generations of LLFS enrollees  completed the Pittsburgh Fatigability Scale  at Visit 2 (2014-2017). Physical fatigability prevalence was 42.1% (PFS\u226515). Generalized linear mixed models assessed the association of each SNP with continuous PFS (GENESIS R package) adjusted for age, sex, field center, and family relatedness. We found no associations with perceived physical fatigability, all p>2.5E-7 . Next steps will examine variants in the mitochondrial genome and BTBD3, another promising candidate gene recently discovered. Genetic biomarker(s) may identify individuals susceptible to greater fatigability to target for early intervention."}
+{"text": "Cognitive impairment (CI) is a significant age-related risk exacerbated by HIV. However, AIDS Service Organizations (ASO) have not implemented effective screening tools for detection of CI in older adults living w/HIV (OALH). This study examined feasibility for use of those tools by medical case managers (MCM) serving OALH. MCMs from nine Colorado ASOs self-administered a questionnaire measuring baseline knowledge of warning signs and risk factors (WS/RF) of CI in OALH, evaluating familiarity with screening of/response to WS/RF of CI within this population. Data from 24 MCMs showed OALH comprised 47% of all clients, and 68% of respondents reported no related training. Similarly, 67% reported not feeling confident identifying WS/RF. 100% of respondents reported not screening for CI, and many endorsed limited awareness/availability of screening tools (87%), referral resources (87%), and training (83%). This identified a need and desire for use/implementation of cognitive screening tools to improve ASO care for OALH."}
+{"text": "Background: Natural (bovine-/equine-/porcine-derived) or synthetic hydroxyapatite (HA) biomaterials appear to be the preferred technologies among clinicians for bone augmentation procedures in preparation for implant dentistry. The aim of this study was to screen candidate HA biomaterials intended for alveolar ridge augmentation relative to their potential to support local bone formation/maturation and to assess biomaterial resorption using a routine critical-size rat calvaria defect model. Methods: Eighty adult male Sprague Dawley outbred rats obtained from a approved-breeder, randomized into groups of ten, were used. The calvaria defects (\u00f88 mm) either received sham surgery (empty control), Bio-Oss (bovine HA/reference control), or candidate biomaterials including bovine HA , and bovine (403Z014) or synthetic HA/\u00df-TCP  constructs. An 8 wk healing interval was used to capture the biomaterials\u2019 resolution. Results: All biomaterials displayed biocompatibility. Strict HA biomaterials showed limited, if any, signs of biodegradation/resorption, with the biomaterial area fraction ranging from 22% to 42%. Synthetic HA/\u00df-TCP constructs showed limited evidence of biodegradation/erosion . Mean linear defect closure in the sham-surgery control approximated 40%. Mean linear defect closure for the Bio-Oss reference control approximated 18% compared with 15\u201335% for the candidate biomaterials without significant differences between the controls and candidate biomaterials. Conclusions: None of the candidate HA biomaterials supported local bone formation/maturation beyond the native regenerative potential of this rodent model, pointing to their limitations for regenerative procedures. Biocompatibility and biomaterial dimensional stability could suggest their potential utility as long-term defect fillers. Implant dentistry increasingly has become a favored approach to replace missing or severely compromised teeth. However, rehabilitation using a bone-anchored dental implant prosthesis may become a challenge in cases lacking in bone volume and geometry, thus demanding bone augmentation. Although autologous bone grafts represent a benchmark or gold standard for bone augmentation procedures, implant dentistry to a great extent relies on a perceived efficacy of surrogates including cadaver-sourced allogeneic or xenogeneic bone biomaterials, polymeric or ceramic synthetic biomaterials, or combinations thereof, also including devices for guided bone regeneration and, lately, biologic amplifiers ,2,3,4. Natural (bovine-/equine-/porcine-derived) or synthetic hydroxyapatite (HA) biomaterials or varietals combined with \u00df-tricalcium phosphate (\u00df-TCP) appear to be the preferred technologies among clinicians for bone augmentation procedures in preparation for implant dentistry ,6,7. TheMale Sprague Dawley outbred rats, age 11\u201312 weeks, weight 325\u2013375 g, obtained from an approved USDA licensed vendor, were used. The animals were maintained in an Association for Assessment and Accreditation of Laboratory Animal Care International-accredited facility. Housing, husbandry, and experimental manipulations were performed in accordance with the National Research Council\u2019s Guide for the Care and Use of Laboratory Animals following a protocol approved for this study by the Institutional Animal Care and Use Committee, Augusta University. The animals were acclimatized for at least 7 days. They were single housed in plastic cages labeled with cage cards and fitted with ear tags for identification. The cages were housed in purpose-designed rooms air-conditioned with 10\u201315 air changes/h, and temperature (18\u201322 \u00b0C) and relative humidity (30\u201370%) monitored daily. A 12/12 h light/dark cycle was used. The animals had ad libitum access to water and a standard laboratory diet. This report was prepared following the ARRIVE guidelines for reporting animal research .\u00ae, Geistlich, Wolhusen, Switzerland) and sham-surgery  for their potential to enhance local bone formation/maturation and to assess biomaterial resolution using an 8 weeks healing interval  and meloxicam (2 mg/kg SC). Anesthesia was induced using ketamine hydrochloride (65 mg/kg IP) and isoflurane (5%) in an induction chamber. After induction, the skull of the animal was shaved and disinfected using a 2% chlorhexidine solution. Animals were then entered into the surgical theater, stabilized using a stereotaxic device , fitted with an anesthesia nose cone, and draped. Isoflurane (1.0\u20133.0%/O2) was administered to maintain a surgical plane of anesthesia. Experienced surgeons  performed all surgeries using a routine critical-size rat calvaria defect model ,18,19,20The animals received yohimbine hydrochloride (1.5 mg/kg SC) to reverse anesthesia, were placed in cages, warmed on a heating pad, and observed for distress until they were able to move about. Meloxicam  was administered for pain control. Animals still exhibiting signs of pain received additional dose(s) determined by an attending veterinarian. Surgical staples were removed under anesthesia (isoflurane (5%) using an induction chamber) at 7\u201310 days. The animals were euthanized at 8 weeks post-surgery using a pentobarbital sodium/phenytoin sodium anesthetic overdose  followed by bilateral thoracotomy as a secondary method. Calvaria biopsies were harvested carefully removing overlying soft tissues, and then immersed in a 10% buffered formalin solution.The calvaria biopsies were prepared for light microscopy using the \u201csawing and grinding\u201d technique . Briefly\u00ae Dimension 1.11 Digital Imaging Software, Olympus America, Melville, NY, USA). The following parameters were recorded for each defect: Defect width: distance between the defect margins;Defect closure: fraction (%) of accumulated length of new bone formation between the defect margins;Defect area: area of regeneration including newly formed bone, residual biomaterial and other tissue limited by the defect margins, and the titanium mesh;Defect fill: total area of newly formed bone between the defect margins;Bone area fraction: fraction (%) of newly formed bone within the defect area;Residual biomaterial: total area of residual biomaterial between the defect margins;Biomaterial area fraction: fraction (%) of residual biomaterial within the defect area.One experienced examiner (UW) conducted the histopathologic evaluation including observations of woven/lamellar bone formation, cortex formation, and evidence of biodegradation  or bioresorption  of any implanted biomaterial, fibrovascular red or fatty marrow, and eventual biomaterial displacement using polarized and incandescent light microscopy . Two experienced examiners  identified the landmarks and extent of bone formation using polarized and incandescent light microscopy . One calibrated examiner (AFS) performed the histometric analysis using incandescent and polarized light microscopy , a microscope digital camera system  and a PC-based image analysis software . This coefficient ranges between 0 and 1 and values close to 1 mean high reliability. The ICC was >0.95 for all parameters measured.Statistical analysis was performed using statistical software . Measures of central tendency (means and medians) and variability  were calculated and presented. The primary outcome of the study was linear defect closure, and the secondary outcomes bone area fraction and biomaterial area fraction. A one-way analysis of variance followed by pairwise comparisons using the Bonferroni correction was used to estimate Surgeries followed established routines. Healing events were generally unremarkable. Three animals succumbed in the immediate post-surgery sequel, eight animals showed slow recovery and were euthanized on veterinary indications . The defect sites in three additional animals became exposed, however, without need for veterinary intervention .The 8 weeks specimens showed limited lamellar bone formation variably extending from the defect margins for all candidate and control variations . HematomDefect sites receiving sham-surgery showed variable lamellar bone formation egressing from the calvaria periosteum at the defect margins a. The reDefect sites randomized to receive Bio-Oss , the bovine bone-sourced particulate HA reference control, showed lamellar bone formation limited to the defect margins occasionally engaging adjoining biomaterial particles b. The biDefect sites receiving Cerabone , a bovine bone-sourced particulate HA, showed noteworthy lamellar bone formation including cortex formation in three sites, whereas the remainder of the defect sites showed limited bone formation c. The biDirectOss , a bovine bone-sourced particulate HA biomaterial, was associated with occasional and limited bone formation d. The biDefect sites implanted with 03Z013 , a particulate bovine bone-derived HA biomaterial, showed lamellar bone formation circumscribing the particulate HA biomaterial suggestive of osteoconduction (three sites), and one site showing cortex formation in part of the defect d. The HADefect sites receiving 3Z014 , a particulate bovine bone-derived HA \u00df-tricalcium phosphate (\u00df-TCP)-coated biomaterial, showed lamellar bone formation including cortex formation encompassing up to 2/3 of the defect width (three sites) e. The 3ZCeraball , an HA (50%)/\u00df-TCP (50%) micro ball construct, was associated with limited variable bone formation, the micro ball structures immersed in fibrovascular tissue g. LamellDefect sites receiving Reprobone , a synthetic particulate HA (60%)/\u00df-TCP (40%) biomaterial, displayed lamellar bone/cortex formation emerging from the defect margins engaging larger parts of the biomaterial (three sites) as well as solitary islands of bone dispersed amongst the overall intact (geometry/presence) biomaterial suggestive of osteoconduction f. Scant p < 0.001). Limited bone formation was observed for all other groups; no significant differences among experimental groups and the Bio-Oss reference control were observed, with the mean bone area fraction ranging from 3.2% (DirectOss) to 7.2% (Reprobone). p < 0.01). Intermediately, Reprobone (34.3%), Ceraball (28.7%), and DirectOss (25.9%) exhibited a mean biomaterial area fraction ranging from 25% to 35%. The lowest biomaterial area fraction was observed for 403Z013 (21.8%), Bio-Oss (21.3%), and 403Z014 (17.7%). The objective of the present study was to screen candidate HA biomaterials considered for alveolar ridge augmentation relative to their potential to support local bone formation/maturation and to assess biomaterial resolution using a routine critical-size rat calvaria defect model and an 8 weeks healing interval. Six particulate HA species\u2014bovine HA  and bovine (403Z014) or synthetic HA/\u00df-TCP  constructs\u2014were benchmarked to sham surgery and a market-leader bovine HA reference control (Bio-Oss). None of the candidate biomaterials supported bone formation beyond the innate regenerative potential of this model. The present study used one of our laboratory routine critical-size rat calvaria defect models and an 8 weeks healing interval ,18,19,20Mean linear defect closure in the sham-surgery control approximated 40% in the present study consistent with previous studies, with mean linear defect closure in the sham-surgery control ranging from 32% to 58% following an 8 weeks healing interval ,18. MeanUneventful biodegradation/bioresorption are important qualities of bone biomaterials whether considered a stand-alone technology or married to biologic amplifiers ,30. The In summary, none of the candidate HA biomaterials supported local bone formation/maturation beyond the native regenerative potential of this rodent model pointing to their limitations for regenerative procedures. Biocompatibility and biomaterial dimensional stability could suggest their potential utility as long-term defect fillers."}
+{"text": "Many older adults with functional impairment rely on paid caregivers  to remain living at home. Continuity in the provider of healthcare services is known to impact care-recipient outcomes in settings like primary care; however, limited quantitative research has explored variability in provider continuity among home-based long-term care services. We conducted a retrospective pooled cross-sectional study using a secondary analysis of managed long-term care and home care agency records in order to: 1) describe home health aide continuity among a population of older adults receiving Medicaid-funded home-based long-term care using the Bice-Boxerman index, and 2) identify factors associated with greater home health aide continuity using multivariate regression. Among 3,864 older adults who received claim-paid home health aides services between January 1, 2018 and March 10, 2020, average home health aide continuity scores were lower  as care hours increased: 0.71 among those receiving < 3 service hours/day (n=1221), 0.62 among those receiving 3-7 service hours/day (n=1622), and 0.41 among those receiving >7 service hours /day. Among those with the highest care hours (>7 hours /day), increases in the level of ADL impairment and cognitive impairment were significantly associated with decreases in continuity scores. While clients with the highest care needs are the most dependent on their home health aides and may benefit most from stable paid caregivers, home health aide continuity scores are the lowest among this group. Future work will explore the impact of home health aide continuity on long-term care-recipient health outcomes."}
+{"text": "N = 58 patients , only the clinical diagnosis of proliferative leukoplakia was associated with significantly decreased CFS . CD8+ T cells and T regulatory (Treg) were more abundant among proliferative leukoplakia samples (P < 0.01) regardless of degree of epithelial dysplasia, and often colocalized to the dysplasia\u2013stromal interface. Gene set analysis identified granzyme M as the most differentially expressed gene favoring the proliferative leukoplakia subgroup . Programmed death ligand 1 (PD-L1) was comparatively overexpressed among proliferative leukoplakia samples, with higher (>5) PD-L1 scores predicting worse CFS (Padj < 0.01). Proliferative leukoplakia predicts a high rate of malignant transformation within 5 years of diagnosis. A prominent CD8+ T-cell and Treg signature along with relative PD-L1 overexpression compared with localized leukoplakia provides strong rationale for PD-1/PD-L1 axis blockade using preventative immunotherapy.Oral leukoplakia is common and may, in some cases, progress to carcinoma. Proliferative leukoplakia is a progressive, often multifocal subtype with a high rate of malignant transformation compared with the more common localized leukoplakia. We hypothesized that the immune microenvironment and gene expression patterns would be distinct for proliferative leukoplakia compared with localized leukoplakia. We summarize key clinicopathologic features among proliferative leukoplakia and localized leukoplakia and compare cancer-free survival (CFS) between subgroups. We analyze immunologic gene expression profiling in proliferative leukoplakia and localized leukoplakia tissue samples (NanoString PanCancer Immune Oncology Profiling). We integrate immune cell activation and spatial distribution patterns in tissue samples using multiplexed immunofluorescence and digital image capture to further define proliferative leukoplakia and localized leukoplakia. Among This is the first in-depth profiling effort to immunologically characterize high-risk proliferative leukoplakia as compared with the more common localized leukoplakia. We observed a notable cytotoxic T-cell and Treg signature with relative overexpression of PD-L1 in high-risk proliferative leukoplakia providing a strong preclinical rationale for investigating PD-1/PD-L1 axis blockade in this disease as preventative immunotherapy. Oral leukoplakia is defined as a \u201cwhite plaque of questionable risk having excluded other (known) diseases or disorders that carry no increased risk for cancer\u201d . The preTP53 and KMT2C , to characterize the complex oral immune microenvironment of each of these entities and to further nominate therapeutic targets aimed at oral cancer immunoprevention.Patients were retrospectively identified from an existing fully clinically annotated dataset of 149 patients with oral leukoplakia managed jointly at Dana-Farber Cancer Institute  and the Brigham & Women's Hospital  Division of Oral Medicine and Dentistry. Following Institutional Review Board (IRB) approval (DF/HCC protocol# 19-765), patient demographics, clinical characteristics, and survival outcomes were recorded. Patient oral leukoplakia tissue samples were retrieved from archives and their pathologic diagnosis  and clinical phenotype  verified by an expert oral pathologist (S.-B. Woo); previously having been interpreted by one of two head and neck pathology faculty members . Date of first diagnosis of oral leukoplakia, number of oral biopsies obtained in follow-up over time, and time to a first head and neck cancer diagnosis  were summarized. Inclusion in this study required sufficient mRNA isolated from oral leukoplakia tissue for immunologic GEP analysis. Research was conducted in accordance with the U.S. Common Rule and informed consent waived by the IRB due to limited risk to study participants.RNA from each oral leukoplakia specimen was isolated from cores punched from areas of epithelial dysplasia  marked on formalin-fixed paraffin-embedded (FFPE) tissue slides and quantified . Isolated RNA was run on Bioanalyzer to obtain DV200 values (fragment above 200 bp) using Agilent RNA 6000 Pico Kit (Agilent Technologies). A minimum of 100 ng of isolated RNA with greater than DV200 per sample was loaded and run on the HuV1_CancerImmu_v1_1 NanoString platform for analysis of the NanoString PanCancer Immune Profiling Panel (PCI), as described previously . The nCo+, dysplastic, or other immune cells) or all PD-L1\u2013positive dysplastic epithelial cells each divided by any dysplastic epithelial cells (stained using cytokeratin), respectively, across processed digital slide images. Four known head and neck squamous cell carcinoma cases served as internal controls.Multiplexed immunofluorescence (MIF) was performed on 4-\u03bcm\u2013thick, FFPE whole tissue sections from oral leukoplakia specimens using a BOND RX Automated Stainer (Leica Biosystems) as described previously . Brieflyt tests (Mann\u2013Whitney test), ANOVA , and Pearson correlation coefficients, as appropriate. Clinicopathologic features, immunophenotypes, and gene signatures were correlated with survival outcomes and risk of recurrence . Statistical analyses utilized STATA version 14.2. A nominal P < 0.05 was used to denote statistical significance. For each GEP, the Benjamini\u2013Yekutieli procedure was used to control the false discovery rate under arbitrary dependence assumptions.Descriptive statistics were used to summarize patient demographics. Fisher exact test  and a Mann\u2013Whitney test (continuous variables) was used to characterize similarity between localized leukoplakia and proliferative leukoplakia subgroups with respect to clinical features. Overall survival (OS) was determined from the date of first oral leukoplakia diagnosis to death from any cause, while cancer-free survival (CFS) was determined from the date of first oral leukoplakia diagnosis to the diagnosis of first invasive squamous cell carcinoma of the oral cavity or death, whichever occurred first, or censored at last known follow-up . Oral leukoplakia tissue utilized on study was that obtained at or near initial diagnosis, not subsequent oral leukoplakia biopsies, and prior to any topical mucosal therapy application. Associations between immune cell infiltration and GEPs with clinical characteristics was made under a general linear model (nonparametric) with Student The data generated in this study are available upon request from the corresponding author. Multiplexed GEP profiling data generated from RNA (NanoString) was deposited in the public repository Gene Expression Omnibus .n = 29) and proliferative leukoplakia (n = 29) were balanced in terms of baseline characteristics such as age, gender, smoking history, oral cavity subsite, and pathologic diagnosis , with a 2-year CFS of 96.5% versus 82.1% and 5-year CFS of 83.6% versus 46.8% in the localized leukoplakia versus proliferative leukoplakia group. CFS did not appear to differ when considering patient age at diagnosis , gender , or smoking history  in the multivariable model. Similarly, primary site of oral leukoplakia  and degree of epithelial dysplasia  did not predict CFS. Only a clinical diagnosis of proliferative leukoplakia was associated with significantly decreased CFS  tissue samples the two prespecified groups of localized leukoplakia . When comparing immune cell type expression profiles among all samples based on their histologic characterization  irrespective of their localized leukoplakia or proliferative leukoplakia phenotype, DME composition was similar. In addition, when considering clinical parameters such as younger age at diagnosis (<45 years old), gender, and smoking history among the cohort, DME composition was similar . However, only an increased abundance of Tregs predicted first oral cancer progression  . Binary logistic regression modeling suggested greater log2 expression among CYLD (OR = 9.01) and TCF7 (OR = 6.29) predicted risk of progression to cancer regardless of localized leukoplakia or PL phenotype .We first compared immune cell type RNA expression profiles for all localized leukoplakia and proliferative leukoplakia samples . While d< 0.001) . In addi+ T cells was significantly increased at the DSI  when comparing proliferative leukoplakia and localized leukoplakia subgroups, but overall median density (cells/mm2) was high among all cohort samples (range: 9\u20133659). We observed significantly increased mean density (cells/mm2) of all PD-1+ T cells and PD-1+ CD8+ T cells  within the dysplastic epithelium, the stroma, and at the DSI  among proliferative leukoplakia tissues compared with localized leukoplakia. In addition, a significantly greater abundance (cells/mm2) of FOXP3+ Tregs were observed among proliferative leukoplakia tissue samples at the dysplastic epithelium, the DSI, and in the stroma . + T-cell localization to the DSI among proliferative leukoplakia and localized leukoplakia tissues, highlighting the significant increase in T-cell abundance among high-risk proliferative leukoplakia cases when utilizing MIF digital overlay. When considering localization of PD-1+ T cells and Tregs among tissues in the cohort based on histology patterns, findings were similar across tissue regions  regardless of degree of dysplasia; although the mean density (cells/mm2) of CD8+ T cells tended to be higher among moderate-to-severely dysplastic tissues .To complement our immunologic mRNA expression profiling across localized leukoplakia and proliferative leukoplakia subgroups, we next sought to understand spatial or geographic localization patterns of immune cells within the dysplastic or premalignant epithelium (D), the stroma (S), and at the dysplasia\u2013stromal interface (DSI) measured within 40 \u03bcm of the actual dysplasia\u2013stromal border. Fifty-five of 58 samples passed quality control metrics for MIF analysis. The mean abundance of CD8P < 0.0001), but notably values for both were frequently measured at 1 or less (78.1%). When accounting for PD-L1 CPS expression across the dysplastic and stromal tissue area, PD-L1 expression was significantly higher at all subsites  among proliferative leukoplakia samples . However, when evaluating PD-L1 CPS across all samples by degree of dysplasia assessed histologically, regardless of leukoplakia phenotype, expression levels were similar (P = 0.94).Having characterized the geospatial distribution of key immune cells within proliferative leukoplakia and localized leukoplakia samples at the DSI, we next aimed to quantitate and characterize PD-L1 expression patterns throughout these tissues. Broadly, both PD-L1 expression as defined by CPS (dysplastic epithelium and other immune cells) or TPS  was significantly increased among proliferative leukoplakia samples compared with localized leukoplakia ; recognizing that 26 of 27 (93%) of all localized leukoplakia tissue samples demonstrated such low PD-L1 CPS expression levels compared with 6 of 28 (21%) of proliferative leukoplakia tissue samples. + immune cells localized to the stroma and DSI among proliferative leukoplakia and localized leukoplakia tissues, highlighting the significant increase in PD-L1+ immune cell abundance among high-risk proliferative leukoplakia cases when compared with localized leukoplakia utilizing MIF digital overlay.Using previously reported PD-L1 CPS cutoffs of 0\u20131, 1\u20135, and greater than 5, we observed a significantly improved CFS at low PD-L1 expression levels  from the high-risk entity of proliferative leukoplakia (proliferative leukoplakia) has important implications with regards to surveillance and management. Proliferative leukoplakia is typically characterized clinically by a verrucous appearance, either at more than two noncontiguous oral cavity subsites or extensively at one or contiguous sites, and histologically demonstrates epithelial hyperkeratosis or verrucous hyperplasia . ProlifeKMT2C and TP53 .Several recent studies have aimed to broadly characterize the immunologic landscape of oral leukoplakia. Among a cohort of 80 oral leukoplakias evaluated by IHC for immunomodulatory mediators, increased expression of HLA-G/E, IL10, TGF\u03b22/3 was noted when compared with oral carcinoma samples . Subsequltration  suggestiltration . This st+ T cells, and cytotoxic T cells are increased among proliferative leukoplakia samples when compared with localized leukoplakia, while quantitative and spatial techniques clarify this occurs across all regions of the stroma and dysplastic tissue with the highest mean density of PD-1+ CD8+ T cells and Tregs homing to the DSI. This fits with the hypothesis that PD-1\u2013overexpressing cytotoxic T cells migrate to the epithelial tissue border where interactions with dysplastic tissue expressing PD-L1 occurs, permitting immune checkpoint interaction and immune evasion to promote carcinogenesis. Similarly, an abundance of Tregs at the DSI among proliferative leukoplakia samples may promote tumor progression by limiting antidysplasia immunity . Another gene of interest with overexpression among proliferative leukoplakia samples was inducible T-cell costimulator (ICOS), which codes for a T-cell costimulatory receptor that promotes T-cell proliferation, chemokines, and facilitates B-cell antibody secretion . TCF7+ CD8+ T-cell frequency has been linked with tumor regression or checkpoint inhibitor response in melanoma  were not delineated from the MIF panel due to multiplex limitations. Finally, we immunologically profiled dysplastic epithelial tissues at a single timepoint among each case, and thus dynamic changes in the DME or sample heterogeneity must be considered when interpreting our results.We acknowledge some limitations in this study. First, we randomly selected 58 cases (39%) with available tissue samples for immune profiling among a preexisting dataset of 149 patients; although we aimed to minimize selection bias and subgroups were well balanced. We acknowledge that pathologic characterization of high-risk precancerous lesions can be variable. In addition, NanoString reflects gene rather than protein expression levels. Although MIF assessment of immune subsets were consistent with our GEP data, specific immune cell phenotypes (e.g., activated CD8+ cytotoxic T-cell infiltrate with granzyme overexpression that localizes throughout the DSI. A predominant portion of PD-L1+ immune cells appear enriched throughout the tissue stroma and DSI. While PD-L1 CPS scores are low among most oral leukoplakias, proliferative leukoplakia demonstrates higher relative PD-L1 scores which may predict benefit from PD-1/PD-L1 axis blockade alone or in combination with other novel immunotherapies. Actively enrolling trials are already investigating oral preventative immunotherapy among this critical population.Our findings add to an important and evolving literature that suggest high-risk oral precancerous dysplasia may progress to malignancy in part due to local intra-oral immune dysregulation . While pSupplementary Table 1Target antigens, antibody clones, dilution of markers, and antigen retrieval conditions used for multiplex immunofluorescence stainingClick here for additional data file.Supplementary Table 2Clinicopathologic predictors of cancer-free survival among patients with oral leukoplakiaClick here for additional data file.Supplementary Table 3Immunologic and molecular predictors of progression to cancer among oral leukoplakiasClick here for additional data file."}
+{"text": "Clostridioides difficile infection (CDI) is one of the leading causes of hospital\u2013onset infections. Clinically distinguishing true CDI versus colonization with C. difficile is challenging and often requires reliable and rapid molecular testing methods. At our academic center, we implemented a 2-step testing algorithm to help identify true CDI cases. The University of Mississippi Medical Center is a 700+ bed academic facility located in Jackson, Mississippi. Hospital-onset (HO) CDI was defined based on NHSN Laboratory Identified (LabID) event as the last positive C. difficile test result performed on a specimen using a multistep testing algorithm collected >3 calendar days after admission to the facility. HO-CDI data were collected from all inpatient units except the NICU and newborn nursery. HO-CDI outcomes were assessed based on standardized infection ratio (SIR) data. In May 2020, we implemented a 2-step testing algorithm  glutamate dehydrogenase antigen (Ag) testing and toxin A and B testing. The final results were reported as colonization (C. difficile PCR+/EIA Ag+/Toxin A/B\u2212) or true CDI case (C. difficile PCR+/EIA +/Toxin A/B +) or negative (C. difficile PCR\u2212). All patients with colonization or true infection were placed under contact isolation precautions until diarrhea resolution for 48 hours. During the preintervention period (October 2019\u2013April 2020), 25 HO-CDI cases were reported compared to 8 cases in the postintervention period (June 2020\u2013December 2020). A reduction in CDI SIR occurred in the postintervention period  compared to preintervention period  (Figure C. difficile spores.m Figure . All patFunding: NoDisclosures: None"}
+{"text": "Here, we report the recovery of 89 metagenome-assembled genomes (MAGs) derived from a human fecal sample subjected to Pacific Biosciences (PacBio) high-fidelity (HiFi) sequencing. A total of 9 MAGs consisted of complete circular contigs, and 45 MAGs were high-quality draft genomes according to the minimum information about a metagenome-assembled genome (MIMAG) standards. Recent studies have shown that long-read sequencing technologies improve the contiguity of metagenomic assemblies and enable the recovery of repeated regions compared with short-read alternatives , 2. To aA fecal sample was self-collected by a 30-year-old healthy French volunteer for whom written consent was obtained. The sample was stored immediately in a stabilizing solution (RNAlater) following the International Human Microbiome Standards (IHMS) SOP_05_V2 . DNA wasGCA_009914755.3) with minimap v2.24 . We compared our prokaryotic MAGs with the representative genomes of the UHGG catalogue v2 (completeness \u2013 (5 \u00d7 contamination) + log(N50).Below, default parameters were used for all software unless otherwise specified. Reads shorter than 1,000\u2009bp or aligned to the human genome  and primary metagenome assembly (accession ERZ4963561) were deposited in the European Nucleotide Archive (ENA) under BioProject accession number PRJEB50473. Prokka annotation reports, MAG sequences, and related metadata were deposited in the INRAE data portal (data set S63W9S).Sequencing data (accession"}
+{"text": "Medicaid waivers allow states\u2019 provision of home and community-based services (HCBS), leading to variations in design and delivery. States monitor expenditures, but cannot easily anticipate growth. Understanding the needs of this population can aid in early identification and improve service delivery. We conducted a Partitioning Around Medioids cluster analysis of first-time enrollees in Minnesota\u2019s Elderly Waiver HCBS program during 2019 to identify trajectories of entry and characterize activities of daily living (ADL) and instrumental activities of daily living (IADL) needs at enrollment. Administrative data collected via long term care consultation assessments provided enrollment, ADL/IADL needs, living arrangements, and other clinically relevant information that was linked to other sources including Minnesota health care program enrollment and utilization, Minimum Data Set skilled nursing facility (SNF) assessments, and calls to the Senior LinkAge Line (SLL)\u2014a free long-term care counseling service. Of 5,284 first-time enrollees, most had prior engagement with state programs\u2014nearly two-thirds had called the SLL, 36% had a SNF stay, and 56% had prior Medicaid enrollment. We identified six clusters representing three levels of living arrangements and two levels of need: 1) lived alone, low needs (32%), 2) lived with others, moderate needs (20%), 3) congregate living, moderate needs (14%), 4) congregate living, high needs (14%), 5) lived with others, high needs (11%), and 6) lived alone, high needs (9%). Lacking caregivers and prior Medicaid were possible exacerbating reasons for HCBS enrollment. The magnitude of the differences between clusters highlights the constellation of factors leading to enrollment in HCBS."}
+{"text": "Dermatopathology was able to uphold its high standards for published papers due to the outstanding efforts of our reviewers. Thanks to the efforts of our reviewers in 2022, the median time to first decision was 40 days and the median time to publication was 63 days. Regardless of whether the articles they examined were ultimately published, the editors would like to express their appreciation and thank the following reviewers for the time and dedication that they have shown Dermatopathology:Adam I. RubinMa Teresa Fern\u00e1ndez FiguerasAndrzej SlominskiMaged DaruishAngelo RuggieroMar Llamas-VelascoAshley N. ElsensohnMarie-Charlotte Br\u00fcggenCandice BremMaxwell A. FungCarlo CotaMeenakshi BatraniDeepika YadavMichelangelo La PlacaDennis NiebelMichelle Weiting LiangDieter MetzeMuhammad N. MahmoodEiji KiyoharaNadia ShiraziFrancisco BravoPanitta SithinamsuwanG. NandakumarPaola SavoiaGianluca NazzaroPhilip E. LeboitGiorgio FilosaPhyu P. AungGiovanni PaolinoPierre A. De ViraghGiusto TrevisanRahul MannanHans-Joachim SchulzeRajalakshmi TirumalaeHeinz KutznerRenee HowardHelmut BeltraminelliRino CerioHui Yi ChiaSadia AfrinJean KanitakisSanaullah SajibJeffrey P. NorthShang-Ian TeeJivko A. KamarashevShin-Ichi OsadaJoel Hua Liang LimSuat Hoon TanJos\u00e9 Carlos CardosoTakemichi FukasawaJose Manuel MascaroTatsiana PukhalskayaJosef SmolleTeresa GriecoKara E. YoungTeresa LettiniKlaus EisendleThuylinh PhungLeonardo RestaUwe WolinaLeonie BeyerVenkatesh RameshLionel FontaoWayne GraysonLiuyan JiangWei-Ti ChenHigh-quality academic publishing is built on rigorous peer review."}
+{"text": "Methanoperedens genomes. Flanking partial repeats and A-enriched character constrain the TR formation mechanism. TRs can be in intergenic regions, where they might serve as regulatory RNAs, or in open reading frames (ORFs). TRs in ORFs are under very strong selective pressure, leading to perfect amino acid TRs (aaTRs) that are commonly intrinsically disordered regions. Proteins with aaTRs are often extracellular or membrane proteins, and functionally similar or homologous proteins often have aaTRs composed of the same amino acids. We propose that Borg aaTR-proteins functionally diversify Methanoperedens and all TRs are crucial for specific Borg\u2013host associations and possibly cospeciation.Borgs are huge, linear extrachromosomal elements associated with anaerobic methane-oxidizing archaea. Striking features of Borg genomes are pervasive tandem direct repeat (TR) regions. Here, we present six new Borg genomes and investigate the characteristics of TRs in all ten complete Borg genomes. We find that TR regions are rapidly evolving, recently formed, arise independently, and are virtually absent in host  This study shows that extrachromosomal elements associated with methane-consuming Methanoperedens archaea (known as Borgs) are scattered with nucleotide tandem repeats that evolve rapidly. When occurring within genes, the resulting amino acid repeats create largely intrinsically disordered regions. Methanoperedens genus . Nucleotide frequency vectors for each 50 bp substring were then grouped into repeat and non-repeat categories and used as input to the Kruskal\u2013Wallis test, which was implemented in SciPy (v. 1.9.0). The values were then further corrected by performing an FDR correction according to Benjamini\u2013Yekutieli [To assess the significance of the observed compositional bias between the nucleotide TRs and non-TR sequences, we performed a Kruskal\u2013Wallis test . This inekutieli .The secondary structure of TRs was predicted with RNAfold WebServer .A dataset of 11,995 Borg proteins was constructed using all proteins from the ten curated Borg genomes and 37 additional aaTR-proteins from curated contigs of Pink, Blue, Steel, Olive, Grey, and Apricot Borg. All proteins were clustered using the fast and sensitive protein sequence searching software MMseqs2 in an all-versus-all search using sensitivity 7.5, cover 0.5, e-value 0.001  (v7e2840http://elm.eu.org/). The single aaTR unit was queried (cell compartment: not specified), and the functional site covering most of the aaTR was usually selected (S7 Table). Functions of aaTR regions in proteins were also predicted with flDPnn [aaTR-proteins were profiled using InterProScan  The Borg DNA polymerase sequences were aligned with a reference dataset from , alignedStructural modeling of aaTR-bearing Sm proteins was initially performed using SWISS-MODEL  and the S1 FigShown is the GC skew (grey) and cumulative GC skew (green lines). Borg DNA is replicated from the terminal inverted repeats  until the terminus .(TIF)Click here for additional data file.S2 FigThere are two types of repeat units shown as magenta or green segments. They are identical, except for a SNP highlighted in red.(TIF)Click here for additional data file.S3 FigAmino acid sequences of DNA polymerases cluster together in the B9 clade. Additional DNA polymerases present in some Borgs cluster together in the B2 clade. Reference sequences originate from Kazlauskas and colleagues . The tre(TIF)Click here for additional data file.S4 FigS14 Table.The data underlying this Figure can be found in (TIF)Click here for additional data file.S5 Fig(A) The positional frequency of the four nucleotides was calculated for each codon within aaTRs and all other codons. The codons were then divided into six categories (on the x-axis) based on the position of the individual nucleotides in the tripletts. One codon can fall into multiple categories. (B) The codon frequency in aaTR regions was divided by the codon frequency in non-aaTR regions. The same codon use would result in the value 1, codons enriched in aaTR regions have values >1, codons depleted in aaTR regions are <1, and codons absent in aaTRs are at value 0 (7 instances). The data underlying this Figure can be found in S5 Table.(TIF)Click here for additional data file.S6 FigS8 Table and has been sorted in terms of the propensity to introduce intrinsic disorder [The aa abundance reflects the frequency of amino acids in aaTRs divided by the frequency in all proteins. The data underlying this Figure can be found in disorder .(EPS)Click here for additional data file.S7 FigS9 Table.IDRs were predicted with MobiDBLite  (thresho(TIF)Click here for additional data file.S8 FigFig 6B.The sequences shown correspond to the data shown in (EPS)Click here for additional data file.S9 FigA) Multiple sequence alignment of Borg Sm ribonucleoproteins with and without aaTRs, Sm from Methanoperedens bins co-occurring with Borgs, and reference sequences from M. jannaschii (PDB: 4X9D), M. nitroreducens (WP_096203417), and E. coli (PDB: 1HK9). (B) aaTR units of Sm ribonucleoproteins. (C) Predicted structures of aaTR-Sm ribonucleoproteins.((TIF)Click here for additional data file.S1 TableTable accompanies Figs (XLSX)Click here for additional data file.S2 TableAnalysis was performed using inStrain  [(XLSX)Click here for additional data file.S3 TableTable accompanies (XLSX)Click here for additional data file.S4 TableThe nucleotide composition was calculated for the coding strand of each replichore. Subsequently, a sum of both values was formed and divided by the genome length and multiplied by 100%.(XLSX)Click here for additional data file.S5 TableTable accompanying (XLSX)Click here for additional data file.S6 Tablehttps://github.com/rohansachdeva/tandem_repeats).aaTR-proteins were identified using custom code available on GitHub ((XLSX)Click here for additional data file.S7 Tablehttp://elm.eu.org/).This Table accompanies (XLSX)Click here for additional data file.S8 TableThis Table accompanies (XLSX)Click here for additional data file.S9 TableThis Table accompanies (XLSX)Click here for additional data file.S10 Table(XLSX)Click here for additional data file.S11 Table(XLSX)Click here for additional data file.S12 Tablehttp://elm.eu.org/).Features of aaTRs were predicted using the eukaryotic linear motif (ELM) resource for functional sites in proteins ((XLSX)Click here for additional data file.S13 Tablehttp://elm.eu.org/).Features of aaTRs were predicted using the eukaryotic linear motif (ELM) resource for functional sites in proteins ((XLSX)Click here for additional data file.S14 Tablehttps://github.com/rohansachdeva/tandem_repeats).TR regions were identified using custom code available on GitHub ((XLSX)Click here for additional data file.S15 Tablehttps://github.com/rohansachdeva/tandem_repeats).TR regions were identified using custom code available on GitHub ((XLSX)Click here for additional data file."}
+{"text": "Admission procalcitonin measurements and microbiology results were available for 1040 hospitalized adults with coronavirus disease 2019 . Although procalcitonin was higher in bacterial coinfection, this was neither clinically significant  nor diagnostically useful . Antimicrobial therapy is not recommended in coronavirus disease 2019 (COVID-19) in the absence of suspected bacterial infection .Procalcitonin production occurs in response to lipopolysaccharide, bacterial infection, and cytokines including interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-\u03b1) . ElevateDysregulated innate immune responses occur in COVID-19 involving a central role for IL-6 . We hypoThe International Severe Acute Respiratory and Emerging Infections Consortium (ISARIC) World Health Organization (WHO) Clinical Characterisation Protocol United Kingdom (CCP-UK) study is an ongoing prospective cohort study recruiting inpatients in 260 hospitals in England, Scotland, and Wales  performed by the ISARIC Coronavirus Clinical Characterisation Consortium (ISARIC4C). The study protocol is available online (isaric4c.net/protocols). Patients with confirmed or clinician-defined high likelihood of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were eligible for inclusion. Ethical approval was given by the South Central\u2013Oxford C Research Ethics Committee in England (13/SC/0149), the Scotland A Research Ethics Committee (20/SS/0028), and the WHO Ethics Review Committee (RPC571 and RPC572).Streptococcus lugdunensis, Corynebacterium species, or Cutibacterium species in blood cultures or Candida species in sputum). Samples positive for fungi alone were considered negative for this analysis.We have reported microbiological findings from 48 902 patients included in the CCP-UK study, hospitalized between 6 February and 8 June 2020, with reverse-transcription polymerase chain reaction (PCR)\u2013confirmed SARS-CoV-2 infection and an outcome recorded 28 days after admission [corrplot R package) or simple linear regression with correlation assessed using a Spearman test.Planned comparisons of procalcitonin values between groups were done using Mann-Whitney tests . Statistical analyses were performed using GraphPad Prism (version 9.1.2). Relationships between procalcitonin and inflammatory markers  were assessed by correlation matrix analysis . As previously reported, Staphylococcus aureus and gram-negative bacilli were the most prevalent pathogens  patients, respiratory culture results alone for 58 (5.6%), and both for 36 (3.5%). Overall, 170 (17.3%) blood and 60 (63.8%) of respiratory cultures were positive. Blood and respiratory cultures from 6 patients were both positive but with different pathogens in 5 of 6 cases . For patients with positive respiratory cultures (n\u2005=\u200560), median procalcitonin was 0.90  ng/mL compared to 0.71  ng/mL for negative respiratory cultures . Receiver operator characteristic analysis demonstrated that procalcitonin performed poorly as a diagnostic test (considering any culture result): the area under the curve for classifying absence of coinfection was 0.56  was 0.33  ng/mL compared to 0.24  ng/mL for negative cultures , but the sensitivity and specificity of this threshold were low . Similar results were obtained using a threshold of 0.5 ng/mL . Since the prevalence of coinfection in this highly selected cohort might not be representative of all hospitalized people with COVID-19, we have deliberately not reported a negative predictive value as it could be misleading.A procalcitonin threshold of 0.25 ng/mL is commonly used in trials of procalcitonin-guided antimicrobial usage . Observr\u2005=\u20050.54, P\u2005<\u2005.0001), TNF-\u03b1 , and IL-6 , admission procalcitonin did not reliably identify people with positive microbiological findings. Low concentrations were observed in some people with coinfection, and high concentrations in some people without. Positive correlations were identified between procalcitonin and inflammatory markers including IL-6.Procalcitonin is elevated in COVID-19 proportional to disease severity and we propose that IL-6 mediates this independent of bacterial coinfection. In support of this, administration of recombinant IL-6 to humans and stimulation of ex vivo liver slices with IL-6 induces procalcitonin production . In critOur retrospective analysis has important limitations. This is a highly selected cohort derived by necessity to address our specific research question: 1040 of 48 902 (2%) patients in the cohort met inclusion criteria. Selection bias will be present, in particular (1) the degree of clinical suspicion for bacterial coinfection leading to procalcitonin and cultures being performed, (2) ability to obtain microbiological samples, and (3) intersite variability in procalcitonin usage. Rates of recorded microbiological investigation were low and culture positivity was high. There may be a bias for preferential recording of positive microbiology results in the database. Administration of antimicrobials prior to microbiological sampling in community-acquired pneumonia results in false-negative culture results when compared to bacterial PCR . ClinicaIn conclusion, our study of procalcitonin level at admission to hospital in people with COVID-19 being investigated for suspected bacterial coinfection showed that procalcitonin was not a reliable marker for positive microbiological investigations. Overall, procalcitonin may not be a reliable indicator of bacterial infection in severe viral diseases with raised IL-6 levels. Microbiological investigation remains critical to identify coinfections and inform antimicrobial decision-making.ofac179_suppl_Supplementary_MaterialClick here for additional data file."}
+{"text": "Staphylococcus aureus (MRSA) and vancomycin-resistant Enteroccocus (VRE). In a Phase 3 (Ph3) complicated skin and soft tissue infections (cSSTI) clinical trial (MRX-I-06), 719 subjects were randomized to either CZD 800 mg PO q12h or linezolid (LZD) 600 mg PO q12h with a treatment duration of 7-14 days in both groups. CZD was demonstrated to be noninferior to LZD for the primary efficacy outcome, and overall safety assessments were comparable to LZD. The most common treatment emergent adverse events (TEAEs) in both the CZD and LZD groups were gastrointestinal; however, hematologic laboratory abnormalities and TEAEs were less common with CZD. In June 2021, CZD was approved in China for cSSTI. Sequential therapy with intravenous contezolid acefosamil  followed by CZD PO is being evaluated in global Ph3 diabetic foot infection (DFI) and acute bacterial skin and skin structure infection (ABSSSI) clinical trials. Because patients with diabetes commonly have diminished kidney function, pharmacokinetics (PK) in renally impaired subjects were evaluated in MRX-I-06.Contezolid  is a novel oral (PO) oxazolidinone with potent activity against Gram-positive pathogens, including methicillin-resistant In MRX-I-06, subjects enrolled included those with estimated creatinine clearance (CLcr) of 60 to < 90 mL/min (mild impairment) and 30 to < 60 mL/min (moderate impairment); no dose adjustments were made for renal status. In a subset of the CZD group, PK was evaluated for subjects with no (CLcr \u226590 mL/min), mild, and moderate renal impairment.max were comparable between subjects with renal impairment and those with normal renal function.The CZD PK subset had 63 subjects, of which 19 had renal impairment . CZD subjects with CLcr above and below 90 mL/min had similar PK values, and CLcr was not a significant covariate (below are means \u00b1 SD). There was no indication that the variability in CL/F or in AUC was larger due to renal impairment, and the average AUC and CIn a Ph3 cSSTI clinical trial, PK in renally impaired subjects who received CZD appeared similar to those without dysfunction, supporting current Ph3 global DFI and ABSSSI studies with CZD and CZA which will enroll subjects with reduced kidney function.Edward Fang, MD, MicuRx Pharmaceuticals Inc: Employee Huahui Yang, MS, MicuRx Pharmaceuticals Inc: Employee."}
+{"text": "Venous leg ulcers (VLU) are recurring, disabling wounds that develop primarily in older adults with comorbidities. In an ongoing clinical trial testing a nutritional intervention researchers use advanced technology (Swift Skin and Wound) to measure VLU healing over time. This noncontact wound measurement system uses artificial intelligence to automatically calculate wound measurements and track healing progress. However, a subjective component of the Swift system involves delineating wound perimeters on photographs captured with a tablet or smartphone. To evaluate interrater reliability of the system in the current study, measurements of 11 wounds by two independent raters were assessed using an intraclass correlation coefficient (ICC). ICC estimates and their 95% confidence intervals were calculated using SPSS statistical package version 27 based on a mean-rating (k = 2), consistency, 2-way mixed-effects model. For area measures, ICC = 0.99 with 95% confidence interval = 0.998-1.0, indicating the Swift measurement system has excellent interrater reliability."}
+{"text": "Scientific Reports 10.1038/s41598-022-10225-9, published online 12 April 2022Correction to: The Acknowledgements section in the original version of this Article was incomplete.\u201cAuthors gratefully thank MUR  ; Proff. Nicola S. Iacobellis and Giuseppe Surico for provided Psav (PvBa206) bacterial strain; Prof. Davide Cervia, Dr. Elisabetta Catalani, Dr. Elena Paccosi for the help given in preparing and observing samples by confocal microscope.\u201dnow reads:\u201cAuthors gratefully thank MUR   and PON Ricerca e Innovazione 2014-2020. Nanotecnologie chimiche green per la protezione sostenibile delle piante (NEMESI) ARS01_01002 CUP: F36C1800018000X); Proff. Nicola S. Iacobellis and Giuseppe Surico for provided Psav (PvBa206) bacterial strain; Prof. Davide Cervia, Dr. Elisabetta Catalani, Dr. Elena Paccosi for the help given in preparing and observing samples by confocal microscope.\u201dThe original Article has been corrected."}
+{"text": "This cross-sectional study assesses whether health literacy and area deprivation index are associated with completion rates of telehealth video visits among adult patients in a large health care system. However, understanding of how social determinants of health affect health technology use is limited. This study assessed whether health literacy and area deprivation index (ADI) are associated with completion rates of telehealth video visits.4As telehealth continues to evolve, the interface type becomes more important. Audio-only visits are associated with lower patient satisfaction and health understanding, whereas telehealth insurance coverage increasingly requires video interface.5 Self-reported patient address mapped to neighborhood socioeconomic data generated the ADI.6 Race and ethnicity data were obtained from self-reported electronic medical record data and are relevant because prior studies3 have shown that race and ethnicity are possible risk factors for worse telehealth outcomes. This study was approved by the Vanderbilt University Medical Center Institutional Review Board, which waived informed consent for retrospective use of data. This study followed the STROBE reporting guideline.This single-center cross-sectional study of scheduled telehealth visits included all adult medicine outpatient clinics across a large health care system during the COVID-19 pandemic ; visits during this period were telehealth only, eliminating preference bias. Billing codes captured a scheduled telehealth visit with an absentee patient (no-show), a video-conferencing, or an audio-only visit. Visits were first attempted with video but could be converted to audio only if video failed. Patients who completed health literacy questionnaires using the validated 3-item Brief Health Literacy Screen (BHLS) were included.2  testing. Multivariable logistic regression models evaluated the likelihood of a no-show and video vs audio-only visit, adjusting for patient age, sex, race and ethnicity, insurance status, low health literacy (BHLS score \u22649),5 and ADI. Statistical analysis was completed using Stata, version 16.1 (StataCorp LLC). Two-sided P < .05 indicated statistical significance.Statistical analysis included Wilcoxon rank sum (continuous variables) and Pearson \u03c7P < .001 for both)  were no-shows. Patient characteristics included a median age of 60  years, with 10 454 women (58%) and 7676 men (42%). In terms of race and ethnicity, 440 patients (2%) were Asian, 2672 (15%) were Black, 181 (1%) were Hispanic, and 14 882 (82%) were White. Among all patients, 8733 (48%) had noncommercial health insurance. Of 17 455 completed visits, 1375 (8%) were audio only. Patients with audio-only visits exhibited a significantly lower BHLS score  and higher ADI  than patients who completed a video visit (or both) .In multivariable analysis, low health literacy was not associated with overall telehealth no-shows . Higher ADI was associated with higher no-show likelihood  .3 Low health literacy  and higher ADI  were also independently associated with audio-only visits  remained significant,3 Future directions include electronic medical record triggers that identify patients at risk for telehealth failure, study of ADI components, and association of health literacy and patient portal use.This study further defines risk factors that are associated with telehealth access. Although barriers such as wireless internet access, technology cost, and privacy will require societal changes, health care systems should consider ways to improve telehealth access. Previous work has shown that interventions  can improve video telehealth completion."}
+{"text": "Here, we report that AAV_Cre microinjection in the ventral tegmental area (VTA) of ErbB4 Cyt-1-floxed (ErbB4 Cyt-1fl/fl) mice at titers commonly used in the literature (~1012\u20131013 GC/mL) can have neurotoxic effects on dopaminergic neurons and elicit behavioral abnormalities. However, these effects of AAV_Cre microinjection are independent of ErbB4 Cyt-1 recombination because they are also observed in microinjected wild-type (WT) controls. Mice microinjected with AAV_Cre (1012\u20131013 GC/mL) exhibit reductions of tyrosine hydroxylase (TH) and dopamine transporter (DAT) expression, loss of dopaminergic neurons, and they behaviorally become hyperactive, fail to habituate in the open field and exhibit sensorimotor gating deficits compared to controls microinjected with AAV_GFP. Importantly, these AAV_Cre non-specific effects are: (1) independent of serotype, (2) occur with vectors expressing either Cre or Cre-GFP fusion protein and (3) preventable by reducing viral titers by 1000-fold (1010 GC/mL), which retains sufficient recombination activity to target floxed genes. Our studies emphasize the importance of including AAV_Cre-injected WT controls in experiments because recombination-independent effects on gene expression, neurotoxicity and behaviors could be erroneously attributed to consequences of gene ablation.A popular approach to spatiotemporally target genes using the  Brieflyp < 0.05. Outliers  were excluded from data analyses. Experimental sample size was set to 5\u201311 mice/group based on previous behavioral experiments in our laboratory [t test . If data points were missing (due to outlier exclusion), a mixed-effect analysis was performed. For data with different variances, Geisser\u2013Greenhouse or Welch\u2019s correction was applied.Statistical analyses were performed using Graph Pad Prism 8 (RRID: SCR_002798) and JASP . All data represent the mean \u00b1 SEM and statistical significance was set at"}
+{"text": "Lyme disease is the most common pediatric tickborne infection. Due to largely disproven concerns of doxycycline-related dental staining among patients < 8 years old, no prospective data exist on efficacy and adverse effects in young children with Lyme disease. Based on emerging data, our institution has used doxycycline during the past decade when alternatives cannot be given. Our study aims to describe short-term adverse effects and treatment failures among young children receiving oral doxycycline for Lyme disease.Retrospective chart review of patients < 8 years old within the Stony Brook Medicine system from 2010-2020. Patients were identified by ICD-9/-10 codes for Lyme disease prescribed doxycycline at the same visit. We excluded those lacking an objective finding of Lyme disease, including single or multiple erythema migrans (EM), facial nerve palsy, carditis, meningitis (headache with pleocytosis >5 WBC/\u03bcL), and/or arthritis, those with an alternative diagnosis, and those receiving post-tick exposure prophylactic doxycycline. Data collected included demographics, symptoms, laboratory results, treatments, and outcomes. Descriptive statistics were calculated.32 charts were included. Average age was 5.1 years. 66% were male. The majority of the patients presented with a single EM (Table\u00a0for presenting symptoms). Initial antibiotics were doxycycline (63%) or a beta-lactam (37%). Rationale for doxycycline included beta-lactam allergy or intolerance (47%), required for treatment of clinical syndrome (such as CNS disease) (28%), concern for alternative tickborne infection (3%), and no reason given (22%). There were no severe adverse reaction to doxycycline; 2 patients stopped due to nausea/vomiting and 1 due to refusal of oral medications. Among the 29 patients who completed doxycycline, there were no known Lyme disease treatment failures.Presenting symptoms of children <8 years old treated with doxycycline for Lyme diseaseTotal percent exceeds 100% due to patients presenting with multiple symptoms. Percent calculation based on all included patients (n = 32).In this small cohort of young children with Lyme disease, doxycycline was generally well-tolerated, without severe short-term adverse effects, and resulted in no treatment failures. As there is no prospective data evaluating doxycycline in this population and future randomized trials are unlikely, the data presented provides reassurance that doxycycline is effective and safe for this indication.All Authors: No reported disclosures."}
+{"text": "Patients with remitted Cushing\u2019s Disease (CD) often present persisting impairments in executive and cognitive functioning domains. Little research has been conducted regarding the functional neural correlates of an important executive functioning skill, namely the ability to plan, in these patients.To examine visuospatial planning related brain activity in remitted CD patients and matched controls using functional magnetic resonance imaging (fMRI).fMRI scans were made using a 3-Telsa scanner while remitted CD patients (n=21) and age-, gender-, and education matched healthy controls  completed a parametric Tower of London (ToL) task. Psychological and cognitive functioning were assessed using validated questionnaires. Clinical severity was assessed retrospectively using the Cushing\u2019s syndrome Severity Index (CSI).CD Patients were on average 45.1 (SD=7.1) years old, 81% female, and in remission for mean 10.68 (SD=7.69) years. No differences were found in number of correct trials, response times per ToL trial, or in the region of interest analyses. Exploratory wholebrain analyses found that CD patients showed more activation in several brain regions associated with higher cognitive processes on 2-, 3-, and 5-step trials compared to HCs. Over-recruitment of the right parietal operculum cortex in the patients was significantly negatively associated with the prior active disease state on the CSI .The increased brain activation during the ToL in remitted CD patients versus controls signals over-recruitment of certain brain areas involved in higher cognitive processes. CD may thus result in long-lasting, subtle scarring effects during demanding executive functioning tasks, despite remission.No significant relationships."}
+{"text": "Psychosis onset typically occurs during adolescence or early adulthood, coinciding with the latest stage of brain maturation. Alterations in brain functional connectivity (FC) accompany the emergence of psychiatric symptoms and cognitive impairments. Thus, age-related FC changes may be informative regarding psychosis onset.We defined neurotypical age-related FC trajectories and hypothesized that FC of individuals at familial and clinical high risk (HR) for psychosis deviates from FC of neurotypical controls (NC).We analyzed two independent cohorts, of (a) 356 early adult NC , and 127 mature adult NC , and (b) 92 yNC , 33 aNC , 38 early HR adults . We acquired fMRI data from multiple scans . FC was obtained by computing Pearson\u2019s correlations between time-courses of every independent component (IC) defined by an Independent Component Analysis approach (NeuroMark). Age-varying components of interest (yNC/aNC differences on FC based on linear mixed effect regressions) were tested for differences between HR and yNC through the Wilcoxon rank-sumtest.FDR<0.05). HR showed increased FC within a network including dorsolateral and medial prefrontal cortices, and sensorimotor cortex, while decreased FC between cerebellum and the parietal and visual cortices, compared with yNC (pFDR<0.05). HR showed no significant difference compared with aNC (pFDR>0.05).showed age-related FC differences (yNC/aNC) in a set of 17 IC pairs (pThis study tested FC alterations associated with the risk for psychosis and highlighted the relationship between psychosis and potentially altered brain functional processes.No significant relationships."}
+{"text": "REST splicing by SRRM4 ASO administration.Antisense oligonucleotide (ASO) medicine for clinical applications has been becoming a reality. We previously developed a gapmer ASO targeting Ser/Arg repetitive matrix 4 (SRRM4) that is abnormally expressed in small cell lung cancer (SCLC). However the detailed mechanism of ASO through repressing SRRM4 has not been completely elucidated. Further, effectiveness of SRRM4 ASO to prostate cancer (PCa) cells expressing SRRM4 similar to SCLC remains to be elucidated. RE1-silencing transcription factor (REST) is a tumor suppressor, and its splicing isoform (sREST) is abnormally expressed by SRRM4 and causes carcinogenesis with neuroendocrine phenotype in SCLC. The present study aimed to understand the contribution of SRRM4 expression and REST splicing were analyzed by RT-qPCR and conventional RT-PCR after treating SRRM4 ASO, and cell viability was analyzed in vitro. Exogenous reconstitution of Flag-tagged REST plasmid in SCLC cells and the splice-switching oligonucleotide (SSO) specific for REST was analyzed for cell viability. Furthermore, we expanded the application of SRRM4 ASO in PCa cells abnormally expressing SRRM4 mRNA in vitro.REST, resulting reduced cell viability. REST SSO specifically modified REST splicing increased REST expression, resulting in reduced cell viability.SRRM4 ASO successfully downregulated SRRM4 expression, followed by repressed cell viability of SCLC and PCa cells in a dose-dependent manner. Administration of SRRM4 ASO then modified the alternative splicing of REST, followed by affecting REST-controlled genes in recalcitrant tumors SCLC and PCa cells.Our data demonstrate that a gapmer ASO targeting SRRM4 (SRRM4 ASO) reduces cell viability through splicing changes of The online version contains supplementary material available at 10.1186/s12935-022-02842-1. Antisense oligonucleotide (ASO) medicine is currently an effective treatment for intractable diseases . AlthougLung cancer has a high mortality rate and is classified into the two following types: SCLC and non-SCLC (NSCLC). SCLC is a high-grade neuroendocrine carcinoma that is associated with air pollution and tobacco smoking. SCLC has spread quickly and widely, resulting in an extremely high mortality rate. More than 250,000 people die of SCLC annually worldwide . SCLC isREST resulting in suppression of RE1-controlled genes causes neuroendocrine phenotypes to appear. Therefore, the dysregulation of alternative splicing induces the progression of tumors to an aggressive phenotype in SCLC and PCa ) was selected. REST SSO blocks the binding of splicing factor such as SRRM4 as a concept, resulting the inhibition of exon N inclusion  is an extremely aggressive type of PCa. NEPC (t-NEPC) may develop de novo or in patients treated with hormonal therapeutic medicine as a mechanism of resistance . In t-NEc target , 42\u201344. c target . Using Vls Figs.  and 4. TIn summary, our developed SRRM4 ASO successfully reduced SRRM4 mRNA in SCLC and PCa cells and reduced cell viability. Repression of SRRM4 mRNA induced modified alternative splicing producing REST, followed by anti-tumor effects. The degree of anti-tumor effects depending on the subtypes of SCLC cells suggested that studies with appropriate biomarkers categorizing each subtype are important. Several clinical trials with various therapeutic targets appear to differ in subtype specificity. We are currently studying several subtypes of cells for the evaluation of SRRM4 ASO as well as companion diagnostics for future clinical trials.REST through SRRM4 mRNA repression. Alternative splicing of REST from sREST to REST might be a potential cause of anti-tumor effects by SRRM4 ASO in neuroendocrine tumors SCLC as well as PCa.Our study demonstrated that administration of SRRM4 ASO causes the changes in the alternative splicing of Additional file 1: Figure S1. Structure of Amido-bridged nucleic acid (AmNA) and LNA. Figure S2. SRRM4 expression in SCLC and PCa cells. Figure S3. Alternative splicing of REST by SRRM4. Figure S4. Cell viability analysis of H146 and H209 cells transfected with SRRM4 ASO. Figure S5. Cell viability analysis of A549 cells by transfecting SRRM4 ASO. Figure S6. Original image of western blot. Figure S7. Expression of SRRM4 mRNA in prostate cancer (PCa) cell lines. Figure S8. SRRM4 expression in SCLC lines (H146 and N417 cells). Table S1. REST-regulated genes decreased after transfecting SRRM4 ASO by microarray analysis"}
+{"text": "Serious illness communication (SIC) in cancer care describes conversations between clinicians, patients, and families about prognosis and treatment decisions. Cultural context influences SIC. Researchers have studied SIC across diverse settings in Africa. We aimed to describe and synthesize the heterogeneous body of research on SIC practices, preferences, and needs in Africa to identify research and training priorities.Our search strategy identified studies that focused on SIC within cancer or palliative care in Africa. Following PRISMA guidelines, a systematic literature search was performed using PubMed, Embase, Web of Science, CINAHL, African Index Medicus, and PsycINFO, yielding 1811 unique titles. After sequential review of abstracts, full text, and cited references, 42 articles met inclusion criteria. Quantitative and qualitative data describing study characteristics, aims, methods, and findings were abstracted and analyzed using descriptive statistics and thematic analysis. Critical appraisal was performed using the Mixed Methods Appraisal Tool.The 42 included articles were published from 1997-2021, half since 2017, representing 16 countries and all African Union regions: West (33%), East (29%), South (21%), North (12%), and Central (5%). Most study designs were qualitative (45%) or quantitative surveys (50%). Study participants included patients (35%), family caregivers (18%), doctors (18%), nurses (12%), and/or other (11%). Study aims focused on disclosure of diagnosis (27%) or prognosis (20%), breaking bad news (15%), general patient-clinician communication (12%), truth-telling (8%), shared decision-making (7%), information needs/preferences (5%), and/or advance care planning (5%). Despite diverse contexts, common themes emerged. Study authors frequently recommended communication skills training. Critical appraisal demonstrated high quality of studies overall.Research on SIC in Africa has increased in recent years. Most studies have focused on information delivery by clinicians; fewer on eliciting information from patients . Significant opportunities exist for further study and for communication skills training."}
+{"text": "LAMA2-related congenital muscular dystrophy had two pathogenic variants (NM_000426): c.1255delA and c.2461A>C. Magnetic resonance imaging (MRI) of the brain showed signal abnormalities in supratentorial white matter (WM), which are conspicuous findings in this diseaseA 4-year-old boy withLAMA2-related radiological phenotype to include not only WM abnormalities, but also predominantly posterior cerebral cortex changes.This report expands"}
+{"text": "Background: Antibiotics targeted against Clostridioides difficile bacteria are necessary, but insufficient, to achieve a durable clinical response because they have no effect on C. difficile spores that germinate within a disrupted microbiome. ECOSPOR-III evaluated SER-109, an investigational, biologically derived microbiome therapeutic of purified Firmicute spores for treatment of rCDI. Herein, we present the interim analysis in the ITT population at 8 and 12 weeks. Methods: Adults \u226518 years with rCDI (\u22653 episodes in 12 months) were screened at 75 US and CAN sites. CDI was defined as \u22653 unformed stools per day for <48 hours with a positive C. difficile assay. After completion of 10\u201321 days of vancomycin or fidaxomicin, adults with symptom resolution were randomized 1:1 to SER-109 (4 capsules \u00d7 3 days) or matching placebo and stratified by age (\u2265 or <65 years) and antibiotic received. Primary objectives were safety and efficacy at 8 weeks. Primary efficacy endpoint was rCDI (recurrent toxin+ diarrhea requiring treatment); secondary endpoints included efficacy at 12 weeks after dosing. Results: Overall, 287 participants were screened and 182 were randomized . The most common reason for screen failure was a negative C. difficile toxin assay. A significantly lower proportion of SER-109 participants had rCDI after dosing compared to placebo at week 8 . Efficacy rates were significantly higher with SER-109 vs placebo in both stratified age groups (Figure Conclusions: SER-109, an oral live microbiome therapeutic, achieved high rates of sustained clinical response with a favorable safety profile. By enriching for Firmicute spores, SER-109 achieves high efficacy while mitigating risk of transmitting infectious agents, beyond donor screening alone. SER-109 represents a major paradigm shift in the clinical management of patients with recurrent CDI. Clinicaltrials.gov Identifier NCT03183128. These data were previously presented as a late breaker at American College of Gastroenterology 2020.Funding: Seres TherapeuticsDisclosures: None"}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-022-09096-x, Published online 25 March 2022Correction to: The original version of this Article contained an error in the Funding section.\u201cThis research was funded by Progetti di Ricerca Corrente, Istituto Auxologico Italiano IRCCS, Milan, Italy .\u201dnow reads:\u201cResearch funded by the Italian Ministry of Health.\u201dThe original Article has been corrected."}
+{"text": "Myxococcus xanthus strain DZ2 (GenBank accession number CP080538), created using a combination of short reads generated using DNBSEQ technology (BGI Genomics) and long high-fidelity (HiFi) reads generated using Pacific Biosciences (PacBio) technology.We report the assembly and annotation of a high-quality genome sequence for  Myxococcus xanthus isolate (GenBank accession number CP080538) reported here was originally acquired by David Zusman from the Roger Stanier collection at UC Berkeley and named DZ2 (Myxococcus xanthus DZ2 isolate of similar origin (CP070500). While the assembly submitted under GenBank accession number CP070500 represents a big improvement over the previously reported draft DZ2 assembly (CP080538) is both larger in size and different in gene content , 8\u2009mM MgSO4, and 10\u2009mM 3-(N-morpholino)propanesulfonic acid (MOPS), pH 7.6, at 32\u00b0C, harvested by centrifugation, and frozen in liquid nitrogen. The pellet was ground into a fine powder, and DNA was extracted by lysing the cells with cetyltrimethylammonium bromide (CTAB) at 65\u00b0C. The DNA was purified using phenol/chloroform/isoamyl alcohol, followed by ethanol precipitation. DNA sequencing was performed by BGI Genomics using two different technologies: DNBSEQ and high-fidelity (HiFi) PacBio sequencing. Construction of the DNA libraries, DNA sequencing, and quality control (QC) of the long HiFi reads and the short reads derived from PCR-free rolling circle replication of the DNA nanoballs were all performed by BGI Genomics using their standard operating procedures (SOP) . Both assemblies have the same number of rRNAs, tRNAs, ncRNAs, and CRISPR arrays , and \u223c10.2 million 100-bp paired-end DNBSEQ reads, totaling 2,042.54\u2009Mbp (representing 218-fold coverage). Small reads that passed our standard quality control (QC) protocol \u201314 to ve\u2013R arrays .PRJNA748417 and SRA accession numbers SRX11508707 (PacBio reads) and SRX11508706 (Illumina reads). The complete genome sequence has been deposited in GenBank under accession number CP080538.1. The different genome assembly commands and resulting assembly files generated throughout this work have all been deposited at Zenodo (The raw data associated with this publication have been deposited at NCBI under BioProject accession number t Zenodo ."}
+{"text": "BRAFV600E mutation is a driver mutation in the serrated pathway to colorectal cancers. BRAFV600E drives tumorigenesis through constitutive downstream extracellular signal-regulated kinase (ERK) activation, but high-intensity ERK activation can also trigger tumor suppression. Whether and how oncogenic ERK signaling can be intrinsically adjusted to a \u201cjust-right\u201d level optimal for tumorigenesis remains undetermined. In this study, we found that FAK  expression was reduced in BRAFV600E-mutant adenomas/polyps in mice and patients. In Vill-Cre;BRAFV600E/+;Fakfl/fl mice, Fak deletion maximized BRAFV600E\u2019s oncogenic activity and increased cecal tumor incidence to 100%. Mechanistically, our results showed that Fak loss, without jeopardizing BRAFV600E-induced ERK pathway transcriptional output, reduced EGFR -dependent ERK phosphorylation. Reduction in ERK phosphorylation resulted in increased mRNA expression and stability of Lgr4, promoting intestinal stemness and cecal tumor formation. Together, our findings show that a \u201cjust-right\u201d ERK signaling optimal for BRAFV600E-induced cecal tumor formation can be achieved via Fak loss-mediated downregulation of ERK phosphorylation. The license terms selected by the author(s) for this preprint version do not permit archiving in PMC. The full text is available from the preprint server."}
+{"text": "Mycobacterium tuberculosis clinical isolates CN118, CN272, CB131, IP004, and IP016 were isolated from three hospitals in South Korea. Here, we report the whole-genome sequences of the five M. tuberculosis clinical isolates to aid the understanding of their genetic diversity. Mycobacterium tuberculosis. The Global Tuberculosis Report 2021 estimated that 2 billion people were infected with M. tuberculosis, and 1.4 million people died from tuberculosis in 2019  were collected from the sputum of tuberculosis patients at Chungnam National University Hospital (CN118 and CN272), Chungbuk National University Hospital (CB131), and Inje University Ilsan Paik Hospital (IP004 and IP016) in South Korea. Both L\u00f6wenstein-Jensen (L-J) medium and the mycobacterial growth indicator tube (MGIT) culture system were used to isolate the clinical isolates from the sputum samples. Positive culture isolates were confirmed by acid-fast bacillus (AFB) staining with Ziehl-Neelsen stain and MPT64 antigen detection using the Bioline TB Ag MPT64 assay . AFB staining- or MPT64 detection-negative samples were assessed by PCR using the PowerChek MTB/NTM real-time PCR kit . Spoligotyping was carried out by using a spoligotyping kit  according to the protocol described previously . All clinical Quick-DNA fungal/bacterial miniprep kit  following the manufacturer\u2019s instructions. Paired-end (2-\u2009by\u2009150-bp) DNA libraries were generated using a TruSeq Nano DNA kit  and sequenced on an Illumina NovaSeq 6000 platform. Reads generated through sequencing were quality validated and trimmed using Prinseq (v0.20.4) (de novo using SPAdes (v3.15.2) . Thed 2-\u2009by\u200910-bp DNA  to 148\u00d7 . AnnotatJAOUSP000000000 (GenBank), SAMN31178391 (BioSample), and SRR21820123 (SRA); CN272, JAOUSO000000000 (GenBank), SAMN31178392 (BioSample), and SRR21820122 (SRA); CB131, JAOUSN000000000 (GenBank), SAMN31178393 (BioSample), and SRR21820121 (SRA); IP004, JAOUSM000000000 (GenBank), SAMN31178394 (BioSample), and SRR21820120 (SRA); and IP016, JAOUSL000000000 (GenBank), SAMN31178395 (BioSample), and SRR21820119 (SRA).Accession numbers for the isolates are as follows: CN118,"}
+{"text": "We report 24 bovine coronavirus (BCoV) genome sequences from Ireland. BCoV was sequenced directly from nasal swabs that had been collected during a bovine respiratory disease (BRD) outbreak among recently purchased beef suckler and pre-weaned dairy calves. Betacoronavirus and family Coronaviridae) has a single-stranded positive-sense RNA genome of approximately 31\u2009kb (Bovine coronavirus (BCoV) is responsible for neonatal calf diarrhea, winter dysentery in adult cattle, and respiratory disease complex in cattle farms worldwide \u20133. BCoV \u2013ly 31\u2009kb . We assely 31\u2009kb  and Marcly 31\u2009kb , respectThe study was approved by the Teagasc Animal Ethics Committee (TAEC-221-2019). Prior to nucleic acid extraction, 1\u00d7 phosphate-buffered saline (PBS) was added to each nasal swab, which was then vortexed, and 300 \u03bcL of the eluate was removed and subjected to bead beating and then nuclease (RNase and DNase) treatment. A negative (blank swab with PBS) and a positive control  was included alongside each batch of 10 sample extractions. Nucleic acids were extracted using the QIAamp MinElute virus spin kit  with carrier RNA substituted with 5\u2009mg/mL linear acrylamide (Thermo Fisher). Double-stranded cDNA was synthesized using the Maxima H Minus ds-cDNA kit (Thermo Fisher) with random hexamers and purified using the GeneJet PCR purification kit (Thermo Fisher). Illumina libraries were generated using the VAHTS Universal Plus DNA library prep kit, and 150-bp paired-end sequencing was conducted on an Illumina NovaSeq.Sequences were assembled with SPAdes (version 3.15)  and annoAAA66393) from the BCoV reference strain Mebus was aligned by MUSCLE in MEGA 11 (The 1a, rep, 2a, HE, S, E, M, and N genes were identified from the Prokka analysis . The ami MEGA 11 , 11 to tON792941 to ON792964.The complete genome sequences of the BCoV/IRE/GR/2022 variants have been deposited in GenBank under the accession numbers"}
+{"text": "COVID-19 changed access to healthcare, including vaccinations, in the United Kingdom (UK). This study explored UK women\u2019s experiences of accessing pertussis vaccination during pregnancy and infant vaccinations during COVID-19.An online cross-sectional survey was completed, between 3rd August-11th October 2020, by 1404 women aged 16+ years who were pregnant at some point after the first UK lockdown from March 23rd 2020. Ten follow-up semi-structured interviews were conducted.Most women surveyed were pregnant (65.7%) and a third postnatal (34.3%). Almost all women (95.6%) were aware that pertussis vaccination is recommended in pregnancy. Most pregnant (72.1%) and postnatal women (84.0%) had received pertussis vaccination however, access issues were reported. Over a third (39.6%) of women had a pregnancy vaccination appointment changed. COVID-19 made it physically difficult to access pregnancy vaccinations for one fifth (21.5%) of women and physically difficult to access infant vaccinations for almost half of women (45.8%). Nearly half of women (45.2%) reported feeling less safe attending pregnancy vaccinations and over three quarters (76.3%) less safe attending infant vaccinations due to COVID-19. The majority (94.2%) felt it was important to get their baby vaccinated during COVID-19. Pregnant women from ethnic-minorities and lower-income households were less likely to have been vaccinated. Minority-ethnicity women were more likely to report access problems and feeling less safe attending vaccinations for both themselves and their babies. Qualitative analysis found women experienced difficulties accessing antenatal care and relied on knowledge from previous pregnancies to access vaccine appointments.COVID-19 disrupted access to vaccinations in the UK. Vaccine services must ensure equitable access to vaccine appointments during ongoing and future pandemics including tailoring services for lower income and ethnic minority families.\u2022\u2002Pregnancy and infant vaccines was disrupted by COVID-19 with women feeling less safe and having difficulties accessing vaccinations with ethnic minority women more likely to report access issues.\u2022\u2002Equitable access to routine pregnancy and infant vaccine appointments must be prioritised during future pandemics, including considering tailoring services for different population groups."}
+{"text": "Metastatic Breast Cancer has a poor 25% survival rate and currently there are no clinical therapeutics which target metastasis. \u2018Migrastatics\u2019 are a new drug class which target migration pathway effector proteins in order to inhibit cancer cell invasion and metastasis. The p21-activated kinases (PAKs) are essential drivers of breast cancer cell migration and invasion through their regulation of actin cytoskeletal dynamics. Therefore, the PAKs present as attractive migrastatic candidates. Here we review how PAKs regulate distinct aspects of breast cancer actin dynamics focussing on cytoskeletal reorganisation, cell:matrix adhesion, actomyosin contractility and degradative invasion. Lastly, we discuss the introduction of PAK migrastatics into the well-honed breast cancer clinical pipeline. \u2022The p21-activated kinases (PAKs) reside at a nexus of cell signalling pathways which promote breast cancer metastasis.\u2022PAK isoforms employ distinct functional roles specifically regulating actin dynamics to drive breast cancer cell invasion.\u2022Administration of PAK migrastatics with current anti-proliferative treatment could suppress breast cancer metastasis. Stage 1 BCa has a remarkable 98% 5-year survival rate, however this drops to 25% for metastatic Stage 4 BCa, partly explained by a gap in clinical strategy to treat metastasis . Migrast2The regulation of actin dynamics orchestrates cancer cell migration and invasion. Firstly, actin fibre polymerisation and stability drive initial membrane extension at the leading edge. Secondly, adhesion of the extended actin cytoskeleton to the ECM, followed by generation of contractile forces, pull the cell body forward . Next, a2.1The cell periphery maintains high actin monomer density, primed for actin polymerisation and generation of protrusive structures, like lamellipodia and filopodia. Both PAK1 and PAK4 can induce actin polymerisation through LIM-kinase (LIMK) activity which phosphorylates cofilin to inactivate and inhibit its actin severing ability, allowing actin filament stabilisation and growth . PAK1 cade novo actin filaments at a 70\u00b0 angle from the original, exerting a pushing force and initiating cell membrane extension. p41-Arc, a subunit protein of Arp2/3 was found to be regulated by PAK1 in BCa cells (484/Ser485 and promote Arp2/3-dependent actin branching (Stabilisation of polymerised actin occurs through generation of a branched actin network. The seven-subunit actin related protein-2/3 complex (Arp2/3) provides nucleation sites for Ca cells . MCF-7 cCa cells . A proteranching . Despite2.2Metastasising BCa cells must balance actomyosin contractility and formation of cellular adhesions to drive propulsive cell migration. Stress fibres (SF) are contractile actomyosin bundles, composed of 10\u201330 actin filaments held together by actin cross-linking protein, \u03b1-actinin . Located2.3Actomyosin contractility depends upon actin interaction with myosin in the myosin light chain (MLC) pathway. MLC-kinase (MLCK) phosphorylates myosin-II which binds to actin filaments and generates contractile forces countered by SF and FA . Differe2.4113 regulated invadopodia disassembly via a Trio-Rac1-PAK1 signalling axis in metastatic BCa cells, and not in epithelial breast cells. It was proposed that p27 acts by promoting the cortactin/PAK1 interaction and phosphorylation; however this work was not performed in BCa cells (Invadopodia are actin-rich cell protrusions reliant upon actin dynamics for their turnover. They mediate invasion by secreting MMPs to enzymatically degrade ECM and it is thought that BCa cells utilise invadopodia for successful metastatic dissemination . InvadopCa cells . CorroboCa cells . FurtherCa cells .113 phosphorylation site as Moshfegh and colleagues reported, sparking debate over whether PAK1-regulation of invadopodia actin dynamics is cancer-type specific. Further studies in melanoma also supported a role for PAK1-dependent invadopodia formation, whereby PAK1-depleted melanoma cells could not initiate actin puncta (Interestingly, a study in melanoma cells suggested that PAK1 regulated invadopodia formation , intrigun puncta . Evidentn puncta , yet howThere are increasing reports of PAK5 implicated in BCa progression, yet still minimal data exploring its role in invadopodia. In BCa, MMP2 is trafficked to invadopodia leading edges by cortactin to degrade ECM; a study found that in comparison to controls, PAK5-depleted MDA-MB-231 and BT459 BCa cells exhibited reduced in vitro migration and invasion as well as downregulated expression of MMP2 in cell lysates . To the 3Major improvements in cancer patient survival over the past few decades are in part due to advances made in selective/targeted therapy, immunotherapy and cancer screening programmes . UnfortuPfizer compound PF-3758309, initially designed to be a PAK4-specific ATP-competitive inhibitor, disrupted PAK4-dependent cell adhesion and anchorage-independent growth in MDA-MB-231 xenograft tumour models, corresponding to an 89% reduction in BCa tumour growth . HoweverThe clinical pipeline in BCa is well-honed, making the introduction of PAK migrastatics especially challenging. BCa cells may become invasive early in cancer development and can metastasise to liver, lung, brain and bone, although preference is distinct between BCa subtypes . Therefo"}
+{"text": "Mycobacterium smegmatis mc2155. DuncansLeg has a 75,593-bp circular genome that contains 126 predicted protein-coding genes and 10 tRNA genes. DuncansLeg is assigned to actinobacteriophage cluster L3.Bacteriophage DuncansLeg is a siphovirius isolated in 2021 from soil on the Coastal Carolina University campus in Conway, South Carolina, using the host  Actinobacteria within the genus Mycobacterium are of biomedical interest as potential therapeutics for treating patients infected with mycobacterial pathogens, such as Mycobacterium abscessus . Using standard protocols  as measured using ImageJ software (https://imagej.nih.gov/ij).Bacteriophages that target bscessus . Here, wncansLeg  displaye9 PFU/mL) of DuncansLeg using the Promega Wizard DNA cleanup kit and prepared for sequencing on an Illumina MiSeq platform (v3 reagents) using the New England BioLabs (NEB) Ultra II library kit. This sequencing protocol resulted in 361,011 single-end 150-bp reads across the DuncansLeg genome, providing 677-fold coverage. Untrimmed reads were assembled using Newbler v2.9 and then were checked for completeness with Consed v29 following the methods outlined in Russell (TCGATCAGCC-3\u2032). Based upon a gene content similarity of 35% or higher to phages in the Actinobacteriophage database (http://phagesDB.org) and using previously described criteria, DuncansLeg is assigned to subcluster L3  and then manually refined using PECAAN (http://discover.kbrinsgd.org) and Starterator v1.0.1 (https://seaphages.org/software/#Starterator). In total, 136 protein-coding genes were predicted for DuncansLeg, of which functions could be assigned to 50 predicted genes using Phamerator v472  no. SRX14443497.DuncansLeg is available at GenBank with accession no."}
+{"text": "Paraclostridium bifermentans was obtained by assembly of Illumina and Oxford Nanopore (ONT) reads. The sequence will enable study into the organism\u2019s ability to biohydrogenate unsaturated acyl chains in the transformation of C20 polyunsaturated fatty acids (PUFAs) into the corresponding bioactive non-methylene-interrupted fatty acids (NMIFAs).The complete genome sequence of  Paraclostridium bifermentans is a rod shaped, endospore forming, Gram-positive, obligately anaerobic, non-pathogenic bacterium  was purchased from DSMZ. Spores were plated anaerobically at 37\u00b0C onto a Gifu anaerobic medium (GAM) agar plate. A single colony was grown anaerobically overnight in 10\u2009mL GAM media, and genomic DNA was obtained by phenol-chloroform-isoamyl alcohol extraction  flow cell in a GridION system . Guppy 3.0.6 , with meClostridium bifermentans strain cbm  were added as long read scaffolds. All scaffold sequences were updated during the assembly by short-read Illumina data from DSM 14991. The assembly produced 5 complete circular contigs (The genome sequence was assembled using Unicycler 0.4.8  with par contigs . The ass contigs . AnnotatParaclostridium bifermentans DSM 14991 chromosome and plasmids have been deposited in NCBI GenBank under accession numbers CP079737 to CP079741. Sequencing reads have been deposited in the NCBI Sequence Read Archive (SRA) under accession numbers SRX11627627 and SRX11627626.The nucleotide sequences of the"}
+{"text": "The study shows that a pragmatic approach to hormonal assessment (no chronic therapy modification) may reveal patients with AAS. Screening for this subclinical PA presentation is probably more effective with a permissive ADRR than UAldE in such a setting.In recent years, research has emphasized the significance of mild clinical and biochemical presentations of primary aldosteronism (PA) that do not meet current diagnostic criteria of the syndrome. In this study, we assessed the prevalence of autonomous aldosterone (Ald) secretion (AAS), defined as a positive (>1.2 ng/dL/mIU/L) Ald-to-renin ratio (ADRR) combined with unsuppressed Ald (>4 ng/dL), and its associations with blood pressure (BP), cardiac function, and common carotid artery (CCA) intima-media thickness (IMT) in patients with incidentally discovered adrenal adenomas (AI), who were either normo- or hypertensive but had no other cardiovascular disease. Among 332 AI patients hospitalized between November 2018 and December 2019, 63 study participants were recruited (26 normo- and 37 hypertensive), who underwent hormonal examinations, 24 h ambulatory BP measurement, transthoracic echocardiography, and CCA IMT assessment without altering chronic medications. AAS was found in approximately 25% of subjects (seven normo- and nine hypertensive); urinary aldosterone excretion (UAldE) exceeded 10 ug/day in none of the subjects. The left ventricular mass index correlated positively with UAldE in non-diabetic patients ( The recommended method of screening for primary aldosteronism (PA) is determining the aldosterone-to-renin ratio . It is anT) and normokalemia but biochemically proven Ald excess, and (2) patients with HT and normokalemia who meet PA screening but not confirmatory test criteria, provided Ald is not suppressed (in both cases).In fact, accumulating evidence indicates the current approach toward PA does not encompass the whole spectrum of renin-independent excess aldosteronism ,4. RecenWhile a fully objective assessment of Ald secretion requires therapy modification to limit the influence on the renin\u2013angiotensin\u2013aldosterone system (RAAS), this requirement frequently dissuades clinicians from ordering screening \u2014 research shows less than 10% of eligible patients undergo it both in primary care and specialist settings ,7. FurthIn this cross-sectional study, we examined the prevalence of AAS and its associations with blood pressure (BP), cardiac function assessed by transthoracic echocardiography (TTE), and intima-media thickness (IMT) among patients with incidentally discovered adrenal tumors (AI) with radiological features of adrenocortical adenomas and/or hyperplasia, who were either normo- or hypertensive but had no other cardiovascular disease (CVD). Subjects were recruited from November 2018 through December 2019 among patients with adrenal incidentalomas (AI), as defined in the European Society of Endocrinology guidelines }. LVM was indexed to body surface area (BSA) calculated with the Du Bois formula: BSA = 0.007184 \u00d7 W0.425 \u00d7 H0.725 : LVMI = LVM/BSA. Left atrium volume (LAV) was calculated by the disk summation technique (modified biplane) from the apical four and two chamber views. LAV was indexed to BSA: LAVI = LAV/BSA.TTE recordings were performed with a Vivid E9 GE device with an M5Sc transducer in accordance with the European Association of Cardiovascular Imaging and the American Society of Echocardiography recommendations . Study p2, (2) tricuspid regurgitation (TR) velocity > 2.8 m/s, (3) E/e\u2019 > 14, and (4) septal e\u2019 < 7 or lateral e\u2019 < 10 cm/s . FuThe effect of hypotensive drugs, including beta blockers, might also partly underlie surprising negative correlations between Ald and BP in 24 h monitoring. Their action may have triggered Ald release dependent on ACTH in the morning hours, during which blood was collected.A correlation between Ald and LVMI implicates the mineralocorticoid in LV hypertrophy in patients without overt PA. More refined measures of abnormal cardiac function  might provide better insight into the adverse effects of AAS.While the deleterious effects of overt PA are widely appreciated, AAS is currently not an established disorder; mild PA forms remain largely unrecognized . Our stuSuch research has been accumulating in the case of MACS . In our"}
+{"text": "Background: The novel coronavirus (COVID-19) pandemic has caused significant morbidity and mortality in California: 2,218,000 cases and 24,598 deaths had occurred by December 31, 2020. Deaths at skilled nursing facilities (SNFs) and assisted living facilities (ALFs) comprise 26.2% of deaths in California; the fatality rate  in such facilities is nearly 50 times the statewide COVID-19 mortality rate . For healthcare facility  and correctional facility outbreak management, the California Department of Public Health (CDPH) Healthcare-Associated Infections (HAI) Program deployed trained infection preventionists (IPs) to perform on-site infection prevention and control (IPC) assessments and to provide recommendations to staff and local health departments (LHDs). We describe the number and distribution of visits across the state and common IPC challenges identified. Methods: From February 1, 2020, to December 31, 2020, CDPH IP visits were requested directly by facilities, coordinated through LHDs and other state agencies, or prompted by a facility\u2019s increasing case count on twice weekly review of the daily California healthcare facility data survey (Survey 123). Deployed IPs evaluated facility COVID-19 IPC protocols, assessed facility staff adherence using a standardized assessment tool, and provided verbal feedback followed by written summary reports and recommendations. We categorized visits geographically into 5 California Health Officer Association regions and by month, and we reviewed visit reports for common findings. Results: In total, 623 visits were performed for 489 outbreaks at 465 distinct facilities across 46 LHDs; 71 facilities received \u22652 visits. Southern California facilities received 292 visits (46.9%), San Joaquin region facilities received 138 visits (22.2%), Bay Area facilities received 131 visits (21%), Greater Sacramento facilities received 54 visits (8.7%), and Rural North facilities received 8 visits (1.3%) (Figure Conclusions: On-site visits by CDPH IPs during the COVID-19 pandemic in California, though resource-intensive, provided substantial technical support for healthcare facilities during outbreaks and identified key areas for IPC improvement. Ongoing CDPH HAI guidance and training materials for facility-based IP staff are now being informed by these IPC challenges.us COVID-9 pandemiFunding: NoDisclosures: None"}
+{"text": "During hypoxia or inflammation, extracellular adenosine levels are elevated. Studies using pharmacologic approaches or genetic animal models pertinent to extracellular adenosine signaling implicate this pathway in attenuating hypoxia-associated inflammation. There are four distinct adenosine receptors. Of these, it is not surprising that the Adora2b adenosine receptor functions as an endogenous feedback loop to control hypoxia-associated inflammation. First, Adora2b activation requires higher adenosine concentrations compared to other adenosine receptors, similar to those achieved during hypoxic inflammation. Second, Adora2b is transcriptionally induced during hypoxia or inflammation by hypoxia-inducible transcription factor HIF1A. Studies seeking an alternative adenosine receptor activation mechanism have linked netrin-1 with Adora2b. Netrin-1 was originally discovered as a neuronal guidance molecule but also functions as an immune-modulatory signaling molecule. Similar to Adora2b, netrin-1 is induced by HIF1A, and has been shown to enhance Adora2b signaling. Studies of acute respiratory distress syndrome (ARDS), intestinal inflammation, myocardial or hepatic ischemia and reperfusion implicate the netrin-Adora2b link in tissue protection. In this review, we will discuss the potential molecular linkage between netrin-1 and Adora2b, and explore studies demonstrating interactions between netrin-1 and Adora2b in attenuating tissue inflammation. Hypoxia and inflammation are highly interdependent . InflammAdenosine is part of a group of biomolecules termed purines, defined as heterocyclic aromatic molecules . These mIn contrast to the other three adenosine receptors, the Adora2b is somewhat unique in its role for hypoxia adaptation  and has Interestingly, several studies have suggested an alternative adenosine independent mechanism of Adora2b activation, particularly during hypoxia or inflammation. This process involves the neuronal guidance molecule netrin-1. Netrin-1 is one of neuronal guidance molecules that are critical for neuronal development by either attracting or repelling developing neurons . SeveralThat hypoxia is associated with increased extracellular adenosine levels has been known for many years. For example, studies from the early 1990s showed that plasma adenosine levels in rats rose from approximately 80\u00a0nM at baseline to approximately 190\u00a0nM following exposure to ambient hypoxia (8% oxygen) . HypoxiaCd39 or Cd73 suggested that these animals have more severe vascular leakage and inflammatory responses during hypoxia exposure  revealed impaired spinal commissural axon projections, implicating functional roles of netrin-1 in axon guidance  experienced exaggerated mortality and lung inflammation. More detailed examination of the Ntn1loxp/loxp LysMCre + mice demonstrated a functional role of netrin-1 in repelling natural killer cells, a response which could potentially implicate Adora2b signaling   . Moreove\u2212 mice) . These f\u2212 mice) . Indeed,\u2212 mice) . In summ\u2212 mice) .Ntn1+/\u2212) experience more profound weigh-loss and intestinal inflammation when exposed to dextran sulfate sodium (DSS) (Inflammatory bowel disease (IBD) includes Crohn\u2019s disease and ulcerative colitis, and is marked by persistent infiltration of the intestinal tissues with inflammatory cells. Due to its role orchestrating leukocyte trafficking, several studies have investigated the function of netrin-1 in IBD . Mice wium (DSS) . Since pum (DSS)  or intesum (DSS) , subsequum (DSS) . These sum (DSS) . Importaum (DSS) . Togethevia DCC signaling  experienced larger myocardial infarct sizes, and showed attenuated netrin-1 blood levels (Ntrn1loxp/loxp Myosin Cre + mice) had no phenotype with regard to myocardial injury. Subsequent studies using antibody mediated depletion (Lys6G) of PMNs  experienced lower efficacy in reducing neutrophil infiltration, had lower levels of pro-inflammatory cytokines, and exhibited attenuated liver injury during hepatic ischemia/reperfusion injury compared to wildtype control animals , or by using PMNs from Adora2b\u2212/\u2212 mice, implicating a direct functional role of Adora2b signaling in netrin-1-mediated inhibition of inflammatory responses (The original report that identified the netrin-Adora2b link used a two-hybrid screen with the intracellular DCC domain as a bait, and identified binding of DCC and Adora2b intracellular domains . Subsequesponses .via ENTs or intracellular adenosine metabolism by inhibiting adenosine kinase or adenosine deaminase (In addition to conflicting findings regarding the potential activity of netrin-1 on the Adora2b, it also remains unclear how these signaling mechanisms occur from a molecular perspective. While the original description of the netrin-Adora2b link postulates a direct effect of netrin-1 as an endogenous Adora2b agonist , there aeaminase . A receneaminase . Howevereaminase . An addieaminase . This coeaminase . FurtherMany studies support the notion that extracellular adenosine signaling is enhanced during limited oxygen availability, such as occur during ischemia or inflammatory diseases . Signali"}
+{"text": "Dolutegravir (DTG) is the cornerstone of the WHO's recommended first-line antiretroviral treatment (ART) regimen, tenofovir disoproxil fumarate + lamivudine + DTG, known as TLD . ExpandeIn phase 3 clinical trials, long-acting injectable cabotegravir (CAB-LA), an integrase strand-transfer inhibitor (INSTI) and analogue of DTG, was shown to be highly efficacious at reducing risk of HIV infection when used for HIV preexposure prophylaxis (PrEP) compared with the oral-PrEP regimen tenofovir-emtricitabine (TDF/FTC) . With apWe conducted a systematic review of available English language literature on PubMed, according to the following search strategy: \u2018HIV\u2019 and (resistance) and (\u2019GSK1265744\u2019 or \u2018Cabotegravir\u2019). We also searched peer-reviewed abstracts from major HIV conferences between 2019 and 2022. Searches were conducted in March 2022. Bibliographies of relevant articles were screened for additional references. The main analysis included studies reporting resistance emerging from CAB-LA PrEP and excluded pharmacokinetic/pharmacodynamic studies and preclinical trials.https://hivdb.stanford.edu; accessed on 08 April 2022). DTG and CAB resistance were predicted if mutations or mutation profiles had penalty scores at least 15. A pooled prevalence was estimated using a fixed effects model, while heterogeneity was assessed using the I2 statistic.Sixty-nine potentially relevant citations were identified but only two clinical trials met the inclusion criteria and were included in the systematic review. Drug resistance mutations were abstracted and re-analyzed using the Stanford HIV Drug Resistance Database V9.2 (I2 85.4 (P\u200a=\u200a0.009).The two studies included a total of 4097 participants receiving CAB-LA, 20 (0.49%) of whom were diagnosed with HIV infection \u20136. SevenFindings indicate that, while the overall number of people testing positive for HIV following CAB-LA PrEP is extremely low, approximately one in four persons diagnosed with HIV carried a virus resistant to DTG. The prevalence of drug resistance observed in this analysis is consistent with estimates reported in CAB treatment trials 32.5% (95% CI\u200a=\u200a13.7\u201351.4)   from the Infectious Diseases Society of America (IDSA).There are no conflicts of interest."}
+{"text": "Phytolacca americana L.) isolate of mirabilis crinkle mosaic virus (MiCMV) in Japan was determined.The complete genome sequence of a pokeweed ( Potyvirus (family Potyviridae)  plants with mosaic and malformation symptoms on the leaves in China, and three complete genome sequences  isolated from four o\u2019clocks have previously been reported (1Phytolacca americana L.) plants in Japan.Mirabilis crinkle mosaic virus (MiCMV) is a single-stranded positive-sense RNA virus recently proposed as a new member of the genus viridae) . MiCMV weported 13. Here, Chenopodium quinoa. Then, a single local lesion isolate was maintained in Nicotiana benthamiana for further assays. Total RNA was extracted from N. benthamiana leaves using an ISOSPIN plant RNA kit (Nippon Gene). cDNA was synthesized from the extracted RNA using AMV reverse transcriptase with GeneRacer oligo(dT) primer (Invitrogen). Then, the entire genome excluding the 5\u2032 end was amplified as three partially overlapping fragments using MiCMV-specific primers designed from the cloned partial sequence and the reported genome sequences  revealed that the genome contained a large ORF (nt 175 to 9417) encoding a putative 350.3-kDa polyprotein. An alignment of the polyprotein amino acid sequence of MiCMV isolates showed that MiCMV-PA had nine polyprotein cleavage motifs conserved in the family Potyviridae (VHHY/S). PIPO (nt 2934 to 3167), a conserved small ORF induced by transcriptional slippage at highly conserved GA6 motif among Potyvirus species (6 motif (nt 2929 to 2935). The sequence identities of the large ORF calculated between MiCMV-PA and the three MiCMV isolates using the MUSCLE algorithm  was 9,662 nucleotides (nt) long with 43.1% GC content, excluding the poly(A) tail at its 3\u2032 end. Open reading frame (ORF) prediction using NCBI ORFfinder (yviridae  at the p species , was prelgorithm  in the plgorithm  were 90.ectively , MiCMV-PLC603132.The MiCMV-PA genome sequence has been deposited in the DNA Data Bank of Japan/GenBank under accession number"}
+{"text": "BRIGHTE is an ongoing global study evaluating the gp120 attachment inhibitor fostemsavir (FTR) in heavily treatment-experienced (HTE) adults with multidrug resistant (MDR) HIV-1 unable to form a viable antiretroviral (ARV) regimen. An estimated 2 million people living with HIV-1 have been infected with SARS-CoV-2. Those with HIV viremia and/or low CD4+ counts are at increased risk of serious adverse outcome. We describe the reported COVID cases in a clinical trial population of people living with MDR HIV and immune suppression. At the start of the COVID pandemic, all ongoing BRIGHTE subjects had achieved \u2265 192 weeks on FTR and optimized background ARVs; results through Week 96 were presented previously. Investigators used WHO guidelines for COVID diagnosis and reported exposure, testing results and symptom presence.Figure 1. BRIGHTE Study Design3 (IQR 11\u2013202); 30% with \u2264 20 cells/mm3. 250 subjects remained in BRIGHTE at pandemic start. By April 2021, 17 subjects  had confirmed COVID infection (positive PCR test). Severity was Grade 1-3, all cases resolved with no deaths. Six subjects were hospitalized (Table 1); most recent CD4+ count prior to COVID were 293-1641 cells/mm3 and 5/6 subjects were virologically suppressed. Treatments often included prophylactic anticoagulants and supplemental oxygen; no cART changes were made. The remaining 11/17 confirmed cases were managed outpatient. Five more subjects had suspect COVID not confirmed by PCR and 2 subjects had negative PCR tests.371 subjects  were enrolled; 44% were \u2265 50 years of age and 86% had an AIDS history. Median CD4+ count at study start of was 80 cells/mmTable 1. Characterization of Participants with Serious AEs of Confirmed COVID-19 Infections \u2013 All HospitalizationsA total of 22/250 COVID-19 cases  have been reported in BRIGHTE. Outcomes were reassuring with no deaths or known persistent sequelae, despite having advanced HIV and comorbid diseases at baseline associated with poorer COVID outcomes. Outcomes may have benefitted from immunologic improvement during the trial. Shiven Chabria, MD, Viiv Healthcare (Employee) Stephane De Wit, MD, Gilead (Grant/Research Support)Janssen (Grant/Research Support)Merck Sharpe & Dohme (Grant/Research Support)ViiV Healthcare (Grant/Research Support) Amy Pierce, BS, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Bronagh M. Shepherd, PhD, GlaxoSmithKline  Michael Warwick-Sanders, BM BSc DPM MFPM, GSK (Employee) Marcia Wang, PhD, GlaxoSmithKline  Andrew Clark, MD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Peter Ackerman, MD, GSK/ViiV Healthcare"}
+{"text": "Seventy-six percent of pediatric patients with Loeys-Dietz syndrome (LDS), a connective tissue disorder driven by a transforming growth factor-beta (TGF-B) pathway mutation, manifest cervical spine malformations. A prior series showed that 16% required surgical stabilization. Spine surgery in LDS is associated with an 88% complication rate due to poor bone quality and cerebrovascular ectasia.Of 77 patients with LDS, one patient who required spine surgery was identified in an institutional database from 2010 to 2020. A 15-year-old with LDS presented with symptomatic cervical myelopathy from a rapidly progressive and unstable cervical deformity. We performed a C5-6 corpectomy and an O-T2 posterior spinal fusion with recombinant human bone morphogenetic protein-2 (rhBMP-2). We achieved correction of her kyphosis and normalization of her neurologic status. She is neurologically well one year postoperatively with bony fusion.The management of a pediatric patient with LDS, orthotopic heart transplantation (OHT), and craniocervical deformity with instability is a novel challenge. Long-segment constructs are beneficial, rather than sparing the occiput or cervicothoracic junction. Off-label BMP may aid an LDS patient with TGF-B mutation and sternotomy. Surgeons should continue immunomodulatory and antiplatelet medications when required for OHT. Loeys-Dietz syndrome (LDS) is a rare connective tissue disorder associated with transforming growth factor-beta receptor 1 (TGFBR-1) and transforming growth factor-beta receptor 2 (TGFBR-2) mutations . BecauseThis 15-year-old female came to care at six years of age with a 6 cm aortic root aneurysm. She had multiple tortuous vessels and a TGFBR-1 mutation in exon 4 (c.797A>G) [One year after her heart transplant, she was observed to have scoliosis on standing and underwent spine imaging. She had mild thoracic levoscoliosis without cervical kyphosis Figure . She hadWe performed an anterior-posterior reconstruction. The first stage was a C5-6 anterior cervical corpectomy using an expandable cage with adjustable endcaps and C4-7 plating. We then performed an occiput-T2 posterior spinal fusion. Hypoplastic lateral masses, ectatic vertebral arteries, and poor bone density led us to design a longer pedicle-screw-based construct. We placed recombinant human bone morphogenetic protein-2 (rhBMP-2) posterior-laterally for augmentation. She was placed in a cervical collar and continued her aspirin and antirejection medications  with meticulous surveillance of her levels.Her immediate postoperative films showed decompression and good alignment Figure . After sWe report the results of a surgical strategy for addressing complex cervical deformity in a pediatric patient with LDS and an orthotopic heart transplant on antirejection medicine. Spinal deformity caused by skeletal dysplasias may become more common as medical care for previously fatal diseases improves.Patients with LDS have a mercurial phenotype. Although sternotomy during infancy  or childAlthough spine surgery in LDS is treacherous , we achiWe use BMP sparingly to reduce the likelihood of spinal canal compromise or neurovascular compression , placingConnective tissue disorders can cause heart failure requiring transplantation due to vascular abnormalities . AlthougWe continue immunomodulatory medications and aspirin through surgery. Stopping immunomodulatory medications for spine surgery can cause organ rejection , but thePediatric patients with morbid connective tissue disorders may benefit from comprehensive surgical approaches to spinal deformity. We present the first report of a patient with LDS status post-OHT requiring cervical deformity correction. Although prior series implicated a catastrophic failure rate in LDS patients, we achieved neurologic recovery and bony fusion after anterior-posterior reconstruction with corpectomy and plating, followed by long-segment fixation from the occiput to multilevel cervicothoracic pedicle screws with off-label use of BMP supplementation."}
+{"text": "Myasthenia gravis (MG) is an autoimmune neuromuscular junction disorder and rarely coexists with aortic aneurysms requiring open repair. A 66-year-old patient with MG underwent extended thoraco-abdominal aortic aneurysm (TAAA) repair 16\u2009years after onset of type-B acute aortic dissection. At 62\u2009years, the patient was diagnosed with MG (MGFA class IIIa) from positive anti-acetylcholine receptor antibody without thymoma. Preoperatively, MG was well-controlled by prednisolone, cyclosporin and pyridostigmine. Extent II TAAA repair was performed under general anaesthesia maintained by total intravenous anaesthesia. Transcranial motor-evoked potential and somatosensory-evoked potential were applied to monitor intraoperative spinal cord ischaemia and muscle weakness. Amplitudes of motor-evoked potential and somatosensory-evoked potential attenuated intraoperatively but normalized after reperfusion from the reconstructed tube graft. Perioperative steroid coverage was given against surgical stress. The patient was weaned from mechanical ventilatory support on postoperative day 7. No signs of spinal cord ischaemia or muscle weakness were seen. A 66-year-old patient with myasthenia gravis (MG) underwent extended thoraco-abdominal aortic aneurysm (TAAA) repair 16\u2009years after onset of type-B acute aortic dissection. A 66-year-old patient with myasthenia gravis (MG) underwent extended thoraco-abdominal aortic aneurysm (TAAA) repair 16\u2009years after onset of type-B acute aortic dissection. A pacemaker had been implanted due to sick sinus syndrome after catheter ablation for atrial fibrillation at 58\u2009years. At 62\u2009years, the patient was first diagnosed with MG (MGFA class IIIa) from a positive result for anti-acetylcholine receptor antibody. Thymoma was not detected on computed tomography. Immunosuppression therapy including prednisolone, pyridostigmine and cyclosporin following combination therapy with plasma exchanges and intravenous immunoglobulin resolved weakness of the ocular and skeletal muscles. The dissecting aneurysm gradually enlarged to >60\u2009mm in size, so open extent II TAAA repair was planned. Preoperative computed tomography showed a partially thrombosed TAAA and the right renal artery arises from the false lumen  with target-controlled infusion propofol and remifentanil. Transcranial motor-evoked potential (MEP) and somatosensory-evoked potential (SEP) were applied to intraoperatively monitor spinal cord ischaemia and muscle weakness.Mild permissive hypothermia (32\u00b0C) was administered, and then, the aorta was sequentially clamped and opened. A four-branched TAAA graft  was anastomosed. The targeted intercostal arteries were reattached and immediately reperfused. During reconstruction, the amplitudes of both MEP and SEP attenuated but normalized after reperfusion from the reconstructed tube graft. The visceral arteries were also reconstructed separately.After the patient was transferred to the intensive care unit, 50\u2009mg of hydrocortisone was infused every 8\u2009h, with the dose halved every day before starting tube feeding. The patient regained consciousness and spontaneous ventilation was established the next day. Blood testing on postoperative day 4 showed an anti-AChR antibody level of 1.2\u2009nmol/l. The patient was weaned from mechanical ventilatory support on postoperative day 7. No signs of spinal cord ischaemia or muscle weakness were evident. Postoperative computed tomography showed intact reconstructed intercostal arteries and visceral arteries  for their contribution to the peer review process of this article."}
+{"text": "In vivo studies demonstrated that knockdown of NIBAN1 disrupted FAK signaling and sensitized GEM-resistant bladder cancer cells to GEM treatment. Our findings suggest that NIBAN1 might regulate FAK signaling activation to promote GEM resistance in bladder cancer. Targeting NIBAN1/FAK signaling may help sensitize bladder cancer cells to GEM treatment.Although intravesical gemcitabine (GEM) chemotherapy (IGC) can effectively reduce the recurrence risk of non-muscle invasive bladder cancer (NMIBC), the development of GEM resistance may occur and result in cancer recurrence and disease progression. Herein, a label-free proteomics approach was used to characterize the proteomic profiles of primary/post-IGC recurrent NMIBC. A total of 218 proteins were found to be differentially expressed in paired primary and post-IGC recurrent NMIBC. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that multiple signaling pathways including \u201cfocal adhesion\u201d were highly enriched in recurrent NMIBC. Niban apoptosis regulator 1 (NIBAN1) was identified as the top upregulated protein in recurrent NMIBC. Highly increased NIBAN1 expression was observed in a number of GEM-resistant cancer cell lines and in post-IGC recurrent NMIBC specimens. Manipulation of NIBAN1 expression affected the chemosensitivity to GEM in bladder cancer cell models. Moreover, NIBAN1 also regulated focal adhesion/focal adhesion kinase (FAK) signaling activation in bladder cancer cell lines. Highly elevated FAK (pY397) expression was observed in post-IGC recurrent NMIBC specimens, which was positively correlated with NIBAN1 expression. Knockdown of FAK markedly attenuated GEM resistance in GEM-resistant bladder cancer cells.  Niban apoptosis regulator 1 (NIBAN1) was identified as the top upregulated protein in post-IGC recurrent NMIBC. Although NIBAN1 is involved in the carcinogenesis of renal and thyroid cancer This retrospective study was approved by the research ethics committee of Xiangya Hospital, Central South University . Archival FFPE bladder cancer specimens were obtained from patients with following criteria: inclusion criteria: patients were initially diagnosed with NMIBC (Ta-T1) at Xiangya Hospital, Central South University (2017-2020); these patients had no prior history of treatment before receiving TURBT. Exclusion criteria: Patients with any prior nonurothelial or muscle-invasive bladder cancer; patients with previous or concurrent upper urinary tract or prostatic urethral urothelial cancer, previous pelvic radiotherapy for any malignancy, or prior treatment for any malignancy within 5 years.Table S1.All eligible patients had undergone initial TURBT and confirmed cancer free with subsequent second cystoscopy and biopsy before commencing intravesical gemcitabine chemotherapy (IGC). These patients received IGC consisting of eight weekly intravesical instillations (induction course). Gemcitabine was instilled at a dose of 2,000 mg per treatment with 1 h of retention time. Patients received monthly maintenance treatment (8-10 courses) depending on their recurrence risk profile, provided there was no evidence of recurrence on subsequent cystoscopies. The clinical follow-up was prescribed, consisting of urine cytology and cystoscopy per 3 months, and upper tract computed tomography urography during the first year, every 6 months for the next 2 years, and then yearly thereafter Supplementary methods'.Primary antibodies were provided by the following sources: NIBAN1 and \u03b2-Actin ; p-FAK (Y397) and FAK (Affinity Biosciences); p-SRC (Y416), SRC, p-AKT (S473), and AKT . Gemcitabine (GEM) was obtained from Selleckchem . Human bladder cancer cell lines T24 and 5637 were purchased from the Type Culture Collection of the Chinese Academy of Sciences, Shanghai, China. GEM-resistant T24 subline T24GR was cultured as described by Xie et al Fig. . FFPE samples were deparaffinized, lysed and de-crosslinked, followed by centrifugation at 12,000 g for 10 min. After trypsin digestion, the tryptic peptides were desalted with SPE column and dried by vacuum centrifuging. The tryptic peptides were dissolved in 0.1% formic acid, and then loaded onto a nanoElute UHPLC system, followed by the timsTOF Pro mass spectrometry in parallel accumulation serial fragmentation (PASEF) mode. The resulting MS/MS data were processed using MaxQuant search engine (v.1.6.15.0). Tandem mass spectra were searched against the human database . More experimental details regarding protein extraction, trypsin digestion, and LC-MS/MS Analysis could be found in 'Supplementary methods'.The experimental procedure was shown in 3 cells/well). Cell viability was evaluated with a CCK-8 assay kit at 48 hours after GEM treatment. Phosphate buffered saline (PBS) was used as a treatment control. The CCK-8 absorbance was measured by a Multiskan MK3 microplate reader (OD450). The 50% inhibiting concentration (IC50) values were calculated in GraphPad prism 8 software.Bladder cancer cells were plated in 96-well culture plates in triplicate  of enzyme reactions was measured by a Multiskan MK3 microplate reader.Apoptosis of cells was measured using an Abcam caspase-3 colorimetric assay kit as described previously Chemo-na\u00efve primary (n=30) and post-IGC recurrent (n=25) NMIBC specimens were used for IHC analysis. IHC procedure was conducted as described previously The mRNA was extracted from T24GR cells with or without NIBAN1 knockdown. The mRNA libraries were then constructed and RNA sequencing was performed on an Illumina NovaSeq6000 platform . The expression level of protein-coding genes was calculated as Fragments Per Kilobase of exon model per Million mapped fragments (FPKM) value.https://www.ncbi.nlm.nih.gov/). TCGA bladder cancer dataset was downloaded from TCGA official website .GEO expression datasets  were downloaded from National Center for Biotechnology Information (NCBI) website (Metascape (http://metascape.org/gp/index.html) with module sources including GO process and KEGG pathway String 11.0 (https://string-db.org/).Pathway and process enrichment analysis was carried out in GSEA analysis was conducted on TCGA bladder cancer dataset as described previously 6) with or without NIBAN1 knockdown were subcutaneously injected into the left flank of each nude mice (n=5). Inoculated tumors were allowed to establish for 1 week before initiating gemcitabine treatments. PBS was used as a treatment control. Gemcitabine was intraperitoneally administered (10 mg/kg) once every 2 days 3= [length (mm)] \u00d7 [width (mm)]2/2. Mice were sacrificed 4 weeks after tumor inoculation, and the subcutaneous tumors were removed, washed by PBS, and weighted. The expression of NIBAN1, p-FAK, Ki-67, and cleaved caspase-3 in xenograft tissues was evaluated by immunohistochemistry. The immunopositivity of cleaved caspase-3 and Ki-67 in each group was calculated in six random, high-power fields.T24GR cells (2 \u00d7 10 test was used to compare the proteomic data of paired primary/recurrent bladder cancer specimens. The Student's t test (two tailed unpaired) was used to compare means of two groups. One-way ANOVA followed by Tukey's multiple comparisons test was used to compare means of three or more groups. Mann-Whitney test was used to compare the expression of NIBAN1 and p-FAK (Y397) in primary and post-IGC recurrent bladder cancer. The correlation between NIBAN1 and p-FAK (Y397) expression was evaluated by Spearman rank correlation analysis. P < 0.05 was considered significant in all of the tests.SPSS 16.0  was used for statistical analysis. Error bars throughout the figures indicate standard deviation. Wilcoxon rank sumFig. ). Paired primary/post-IGC recurrent NMIBC specimens from a total of eight patients were used for label-free quantitative proteomics analysis; the workflow is illustrated in Figure . Collectively, we detected 51082 unique peptides and 6075 proteins, among which 4983 proteins were successfully quantified . Our label-free quantitative proteomics analysis showed good protein mass distribution and protein sequence coverage . In addition, label-free proteomics detection was reproducible, with a mean relative standard deviation less than 0.4% for primary/recurrent NMIBC specimens (Supplementary ). The heatmap of Pearson correlation coefficients between primary and recurrent NMIBCs is shown in Supplementary . A volcano plot [-log10  vs. log2 (fold change [FC])] was plotted to graphically represent the proteomic changes between primary and recurrent NMIBC specimens . Among the 4983 quantifiable proteins, criteria were set to identify significantly differentially expressed proteins . The number of upregulated or downregulated proteins in recurrent versus primary comparison was 105 and 113, respectively . Several upregulated genes  identified in our study are involved in GEM resistance in human cancer Before proteomics analyses, FFPE sections of paired primary/post-IGC recurrent tumors were stained with hematoxylin and eosin and examined by a pathologist to localize the cancerous lesions . For the downregulated proteins (n = 113), the GO terms in biological process , molecular function , and cellular components  were highly enriched .Differentially expressed proteins were subjected to bioinformatics analysis using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway databases. For upregulated proteins (n = 105), the GO terms in biological process , molecular function , and cellular components  were highly enriched . The downregulated proteins was shown to enrich KEGG pathways including DNA replication , cell cycle , and spliceosome  . The graphical network map of the focal adhesion pathway is shown in Figure S2.KEGG pathways including focal adhesion , complement and coagulation cascades , and vascular smooth muscle contraction  were highly enriched for the upregulated proteins . We also searched for hub genes among upregulated proteins using the cytoHubba plugin of Cytoscape (bottleneck method). The top 10 hub genes in upregulated proteins were ACTN1, FLNA, FBN1, AHSG, SERPINA1, A2M, APOA1, ACTA2, TLN1, and MYLK, with scores ranging from 23 to 14.Protein-protein interaction (PPI) analysis with String 11.0 revealed that recurrence-related proteins could interact with each other to constitute a large PPI networks, which was composed of 98 nodes and 282 edges for upregulated proteins and 110 nodes and 299 edges for downregulated proteins . For the downregulated proteins, MCODE1 was mainly involved in RNA processing, whereas MCODE2 and MCODE 3 were associated with mRNA splicing and DNA packaging, respectively .The PPI network was further analyzed by the Molecular Complex Detection (MCODE) plugin. The top three most significant modules were identified using GO, KEGG, and REACTOME annotations. For the upregulated proteins, MCODE1 was mainly involved in platelet degranulation, whereas MCODE2 and MCODE 3 were associated with focal adhesion and vascular smooth muscle contraction, respectively  is shown in Supplementary Figure S3. Next, we examined the expression of NIBAN1 in chemonaive primary (n = 30) and post-IGC recurrent (n = 25) NMIBCs. The protein expression of NIBAN was greatly increased in post-IGC recurrent NMIBCs compared to chemonaive primary NMIBCs . To confirm the involvement of NIBAN1 in GEM resistance, we analyzed the expression of NIBAN1 in several GEM resistance-related Gene Expression Ominbus (GEO) datasets. Analysis of GEO datasets  revealed increased NIBAN1 expression in GEM-resistant Panc1, HPAFII, BxPC-3, and CFPAC-1 sublines compared to their parental cell lines . Therefore, NIBAN1 might be involved in the regulation of GEM resistance, which needs to be functionally validated in bladder cancer cell models. Cell Counting Kit-8 cytotoxicity analysis showed that GEM-resistant T24GR exhibited a considerably higher GEM IC50 value than GEM-sensitive T24 and 5637 cells . Consistently, NIBAN1 expression was markedly higher in T24GR than in T24 and 5637 . Therefore, NIBAN1 might be a novel regulator of GEM resistance in bladder cancer.The top 10 upregulated proteins in recurrent NMIBC are shown in  Fig. A. The effect of NIBAN1 knockdown on the chemosensitivity of T24GR cells was examined. NIBAN1 knockdown greatly attenuated the chemoresistance to GEM in T24GR cells . Soft agar clonogenesis of NIBAN1-depleted GTN cells was markedly decreased compared to the scrambled (Scr) control . NIBAN1 knockdown further reduced soft agar clonogenesis compared to the Scr control after GEM treatment . Furthermore, knockdown of NIBAN1 markedly reduced BrdU incorporation and increased caspase-3 activity in T24GR cells . Compared with the Scr group, reduced BrdU incorporation and increased caspase-3 activities were also observed in the shNIBAN1 group after GEM treatment .The protein expression of NIBAN1 was markedly reduced by NIBAN1-specific short hairpin RNAs (shRNAs) in T24GR cellsFig. ). The cytotoxic effect of GEM on NIBAN1-expressing T24 and 5637 cells was evaluated. NIBAN1 group exhibited a markedly higher IC50 than the empty vector (EV) group after GEM treatment of T24 and 5637 cells . In addition, overexpression of NIBAN1 also significantly promoted soft agar clonogenesis compared with EV after GEM treatment of T24 and 5637 cells . Furthermore, the NIBAN1 group exhibited higher BrdU incorporation and lower caspase-3 activities after GEM treatment than the EV group . These results suggest that overexpression of NIBAN1 can promote chemoresistance to GEM in GEM-sensitive bladder cancer cells.We also overexpressed NIBAN1 in GEM-sensitive T24 and 5637 cells. The level of NIBAN1 was greatly increased after transfection of the NIBAN1 plasmid in these two cell lines . Focal adhesion kinase (FAK) is a pivotal kinase that regulates focal adhesion process in response to environmental signals initiated by growth factors, extracellular matrix, and surrounding mechanical forces, thus promoting cancer cell growth, migration, and survival Fig. ), we observed highly activated FAK (FAK pY397) and its downstream SRC/AKT signaling in GEM-resistant T24GR cells compared to GEM-sensitive T24 and 5637 cells . Next, we compared the transcriptomic profiles of T24GR cells with or without NIBAN1 knockdown. The number of upregulated  or downregulated  genes in shNIBAN1 versus the Scr group was 323 and 173, respectively . Pathway enrichment analysis of downregulated genes (n = 173) using GO, KEGG, and Reactome Gene Sets annotations showed that knockdown of NIBAN1 attenuated the activity of several signaling pathways including focal adhesion, response to oxygen levels, and blood vessel morphogenesis . These findings might connect the possible function of NIBAN1 with focal adhesion/FAK signaling activation in bladder cancer.We conducted Gene Set Enrichment Analysis on The Cancer Genome Atlas bladder cancer dataset to identify the downstream signaling pathways regulated by NIBAN1. Our analysis revealed that the focal adhesion signaling pathway is the most enriched signaling pathway in NIBAN1-high bladder cancer . By contrast, overexpression of NIBAN1 activated FAK and its downstream SRC/AKT signaling in T24 and 5637 cells Fig. B. In addition, immunofluorescence staining was conducted to evaluate the effect of NIBAN1 knockdown on focal adhesions. As shown in Figure , knockdown of NIBAN1 considerably reduced the formation of long F-actin stress fibers and protrusions/lamellipodia edges. Consistently, knockdown of NIBAN1 also reduced p-FAK expression and p-FAK localization in the edge and protrusions . These results suggest that NIBAN1 might regulate the formation of focal adhesions by activating the FAK signaling pathway. The expression of p-FAK was examined in chemonaive primary (n = 30) and post-IGC recurrent (n = 25) NMIBCs. Increased p-FAK expression was observed in post-IGC recurrent NMIBCs compared to chemonaive primary NMIBCs . Correlated expression of NIBAN1 and p-FAK was seen in these NMIBC specimens .We investigated the effect of NIBAN1 on FAK signaling activity in bladder cancer cell models. Knockdown of NIBAN1 greatly reduced the level of phosphorylated FAK (p-FAK) and its downstream p-SRC and p-AKT in T24GR cells . In addition, knockdown of FAK reduced the GEM IC50 value in T24GR cells . Furthermore, depletion of FAK also markedly reduced soft agar clonogenesis/BrdU incorporation and increased caspase-3 activity after GEM treatment in T24GR cells . Therefore, NIBAN1 might regulate FAK signaling activation to promote GEM resistance in bladder cancer cells.We depleted FAK expression in T24GR cells to confirm the involvement of FAK signaling in the development of GEM resistance. FAK depletion abolished its downstream SRC/AKT signaling activity in T24GR cells  in T24GR Scr tumors. However, NIBAN1 knockdown effectively suppressed the tumor growth after GEM treatment compared with Scr (PBS), Scr (GEM), or shNIBAN (PBS) group . Similarly, the tumor weights in the shNIBAN1 group were maximally reduced after GEM treatment compared with the other three groups . Immunohistochemistry staining showed that knockdown of NIBAN1 markedly attenuated p-FAK expression in xenograft tissues with or without GEM treatment . In addition, GEM treatment maximally reduced Ki-67 positivity and increased cleaved caspase-3 labeling in the shNIBAN1 group compared to the other three groups . Taken together, these findings confirm the role of NIBAN1 as a potential regulator of GEM resistance in bladder cancer in vivo.The Although postoperative IGC is a promising adjuvant therapy to reduce the risk of recurrence of NMIBC, a considerable fraction of patients still experience cancer recurrence within 2 years. One of the possible factors contributing to cancer recurrence is the development of chemoresistance after IGC et al.et al. in vitro cell line models showed that manipulation of NIBAN1 expression affected the chemosensitivity to GEM in bladder cancer cell models, suggesting that NIBAN1 might serve as a potential regulator of GEM resistance in bladder cancer. Understanding the molecular pathways modulated by NIBAN1 may contribute to improvements in the current therapeutic regimens for NMIBC.Recent findings have implicated NIBAN1 in the cellular response to stress. Sun et al. in vivo studies demonstrated that knockdown of NIBAN1 disrupted FAK signaling and sensitized GEM-resistant bladder cancer cells to GEM treatment. Therefore, NIBAN1 might regulate FAK signaling activation to promote GEM resistance in bladder cancer, and targeting NIBAN1/FAK signaling could potentially sensitize bladder cancer cells to GEM chemotherapy.Focal adhesion signaling pathways integrate multiple signaling molecules including integrins, growth factor receptors, and protein kinases/phosphates that regulate cancer cell survival, proliferation, and motility In summary, our study characterized the proteomics profiles associated with cancer recurrence after IGC in NMIBC. We showed that NIBAN1 might modulate activation of the FAK signaling pathway to promote GEM resistance in bladder cancer cells. Our findings highlight the potential role of NIBAN1/FAK signaling in the regulation of GEM resistance in NMIBC, which might have potential translational value in designing experimental therapeutics to treat NMIBC.Supplementary methods, figures and tables.Click here for additional data file."}
+{"text": "OBJECTIVES/GOALS: To evaluate the FAITH!  App mHealth lifestyle intervention by using post-intervention feedback obtained from participants in our intervention pilot study. METHODS/STUDY POPULATION: We used qualitative methods (focus groups) to elicit post-intervention feedback. Participants who completed the pilot study were recruited to one of two focus groups. Semi-structured focus groups were conducted to explore participants\u2019 views on the app functionality, utility and satisfaction as well as its impact on healthy lifestyle change. Sessions were audio-recorded, transcribed verbatim and qualitative data were analyzed by systematic text condensation thematic analysis. RESULTS/ANTICIPATED RESULTS: Nine individuals participated (N = 4 and N = 5) in each of the two focus groups. Their mean age was 47.9 years (SD 12.1), 67% were women, and all had at least an education level of some college. Six overarching themes emerged from the data: (1) overall impression, (2) content usefulness (3) formatting, (4) implementation, (5) impact and (6) suggestions for improvement. Underpinning the themes was a high level of agreement that the intervention facilitated healthy behavioral change through cultural tailoring, multimedia education modules and social networking. Among the suggestions for improvement were streamlining of app self-monitoring features, personalization based on individual\u2019s cardiovascular risk and attentiveness to nuanced cultural perspectives. DISCUSSION/SIGNIFICANCE OF IMPACT: This formative evaluation found the FAITH! App mHealth lifestyle intervention had high reported satisfaction and impact on the health-promoting behaviors of African-Americans, thereby improving their overall cardiovascular health. The findings provide further support for the acceptability of mHealth interventions among African-Americans. CONFLICT OF INTEREST DESCRIPTION: None."}
+{"text": "TM also induced serum but not mucosal antibodies and did not protect against BPZE1 challenge. We have evaluated the induction of serum bactericidal activity (SBA) for Bordetella pertussis by BPZE1 or Boostrix vaccination. A previous study showed that Boostrix induction of SBA is dependent on Prn whereas B. pertussis infection induces SBA targeting Prn and other antigens.In a Phase 2b, multi-center, placebo-controlled, randomized study, intranasal BPZE1 induced mucosal and serum antibodies to pertussis antigens and protected against subsequent colonization following attenuated challenge with BPZE1 3 months later. BoostrixB. pertussis strain B1917. Three timepoints  were analyzed and interpolated 50% killing titers determined. The relationship to Prn IgG concentration was assessed.A convenience set of subjects who had a broad range of Prn and PT IgG serum concentrations from treatment groups who received BPZE1+BPZE1 or Boostrix+Placebo (Day 1 and 85 vaccination) were randomly selected to assess SBA using BPZE1 and Boostrix elicited similar and significant increases in SBA following vaccination. BPZE1 and Boostrix elicit anti-Prn IgG, with Boostrix eliciting higher concentrations. A greater SBA response relative to PRN IgG was observed for BPZE1 compared to Boostrix. SBA-Prn correlations were high post-Boostrix (0.74) as previously reported; correlation was lower (0.35) following BPZE1, suggesting the involvement of broader antigenic protection beyond Prn alone.Table of GMT and GMFR in SBA and Prn IgGB. pertussis strain representative of current disease isolates. SBA-Prn correlations were high post-Boostrix, consistent with prior reports showing Prn is the acellular vaccine antigen that mediates SBA. In contrast, BPZE1 bactericidal antibodies appear broader than Prn which may be important given the global rise of Prn-deficient B. pertussis strains.In this exploratory investigation, the novel intranasal live-attenuated pertussis vaccine BPZE1 induced SBA titers that were similar to Boostrix using a All Authors: No reported disclosures"}
+{"text": "Correction to: BMC Public Health 22, 58 (2022)https://doi.org/10.1186/s12889-021-12433-wIn the original publication , there wIncorrect fundingThe present work has been financed by: Carlos III Health Institute [PI071218 National Plan for Scientific Research 2004\u201307  - EMER 07/046 Grants for emerging research groups  - INT 07/289 Grants for intensification of personal care research (Funded a researcher for 6\u2009months)], Fundesalud [Integral Plan Grant for Cardiovascular Diseases in Extremadura (Funded a lab technician during patient enrolment)] and Junta de Extremadura and European Union (ERDF) [GR18076 Aid to Research Groups 2018 (Funded a research support technician)].Correct fundingThe present work has been financed by: Carlos III Health Institute [PI071218 National Plan for Scientific Research 2004\u201307  - EMER 07/046 Grants for emerging research groups  - INT 07/289 Grants for intensification of personal care research (Funded a researcher for 6\u2009months)], Fundesalud [Integral Plan Grant for Cardiovascular Diseases in Extremadura (Funded a lab technician during patient enrolment)] and Junta de Extremadura and European Union (ERDF) [GR18076 Aid to Research Groups 2018 (Funded a research support technician)\u00a0and\u00a0GR21015 Aid to Research Groups 2021]. We also thank Spain\u2019s Ministry of Science, Innovation and Universities (MICINN) and the ERDF for financial support: PID2020-114231RB-I00 and RTI2018\u2013095256-BI00."}
+{"text": "Escherichia coli and Pseudomonas aeruginosa. This study highlights a potential clinical application of the presented polymeric platform.Biofilm infections are a global public health threat, necessitating new treatment strategies. Biofilm formation also contributes to the development and spread of multidrug-resistant (MDR) bacterial strains. Biofilm-associated chronic infections typically involve colonization by more than one bacterial species. The co-existence of multiple species of bacteria in biofilms exacerbates therapeutic challenges and can render traditional antibiotics ineffective. Polymeric nanoparticles offer alternative antimicrobial approaches to antibiotics, owing to their tunable physico-chemical properties. Here, we report the efficacy of poly(oxanorborneneimide) (PONI)-based antimicrobial polymeric nanoparticles (PNPs) against multi-species bacterial biofilms. PNPs showed good dual-species biofilm penetration profiles as confirmed by confocal laser scanning microscopy. Broad-spectrum antimicrobial activity was observed, with reduction in both bacterial viability and overall biofilm mass. Further, PNPs displayed minimal fibroblast toxicity and high antimicrobial activity in an in vitro co-culture model comprising fibroblast cells and dual-species biofilms of  Biofilm infections are a serious health concern due to their high antibiotic tolerance . In the Biofilms in most clinically relevant biofilm infections, such as diabetic foot ulcers, implant-associated infections and pneumonia in cystic fibrosis patients, are composed of multiple bacterial species ,7,8. Int11 alkyl chain (PONI-C11-TMA) formed polymeric nanoparticles (PNPs)  and dual-species combinations. Species were chosen based on their clinical relevance . A total of 10k NIH 3T3 (ATCC CRL-1658) cells were cultured in Dulbecco\u2019s modified Eagle medium  with 10% bovine calf serum and 1% penicillin\u2013streptomycin at 37 \u00b0C in a humidified atmosphere of 5% COp-value < 0.05 is considered as statistically significant. GraphPad Prism 5 was used to perform statistical analyses.The data in biofilm penetration profiles using CLSM imaging are representative of at least two biological replicates. For MBBC experiments, crystal violet assays, Alamar Blue assays, fibroblast viability and quantitative colony counting, data are presented as the mean of at least three replicates, with error bars representing standard deviation. Statistical analysis was carried out using one-way analysis of variance (ANOVA) followed by Tukey\u2019s post hoc test. A"}
+{"text": "TaMPT) and a methyltransferase (TaSAM). Wheat has three sub-genomes  and gene expression studies demonstrated that TaMPT and TaSAM homoeologs were differentially expressed in response to FHB infection and the mycotoxigenic Fusarium virulence factor deoxynivalenol (DON) in FHB resistant wheat cv. CM82036 and susceptible cv. Remus. Virus-induced gene silencing (VIGS) of either TaMPT or TaSAM enhanced the susceptibility of cv. CM82036 to FHB disease, reducing disease spread (Type II disease resistance). VIGS of TaMPT and TaSAM significantly reduced grain number and grain weight. This indicates TaSAM and TaMPT genes also contribute to grain development in wheat and adds to the increasing body of evidence linking FHB resistance genes to grain development. Hence, Fusarium responsive genes TaSAM and TaMPT warrant further study to determine their potential to enhance both disease resistance and grain development in wheat.Fusarium head blight (FHB) is an economically important disease of wheat that results in yield loss and grain contaminated with fungal mycotoxins that are harmful to human and animal health. Herein we characterised two wheat genes involved in the FHB response in wheat: a wheat mitochondrial phosphate transporter ( Fusarium fungi. It reduces yield and contaminates grain with mycotoxins harmful to human and animal health, most commonly deoxynivalenol (DON)  and [2PP2AA3)^-(CT target- CT ] [P > 0.05).Flag leaves of wheat cv. CM82036 were rub-inoculated at growth stage 47 [PP2AA3)] . Gene ex(TIF)Click here for additional data file.S5 Figin vitro transcribed RNAs BSMV:00 (empty vector) or BSMV: MPT1 or BSMV:MPT2 (construct targeting TaMPT). At mid-anthesis (growth stage 65) [F. graminearum strain GZ3639 or 0.02% Tween-20 (mock treatment), as previously described [Fusarium treatment at silenced plants compared to mock (virus) treated samples. B) Quantification of the number of diseased spikelets per head in cv. CM82036 at 21 days post-treatment. Disease results represents mean data obtained from 60 heads . Bars in graphs indicate standard error of the mean (SEM). Treatments with the same letter are not significantly different (P > 0.05).Flag leaves of wheat cv. CM82036 were rub-inoculated at growth stage 47 [(TIF)Click here for additional data file.S6 Figin vitro transcribed RNAs BSMV:00 (empty vector) or BSMV: SAM1 or BSMV:SAM2 (construct targeting TaSAM). At mid-anthesis (growth stage 65) [F. graminearum strain GZ3639 or 0.02% Tween-20 (mock treatment), as previously described [Fusarium treatment at silenced plants compared to mock (virus) treated samples. (B) Quantification of the number of diseased spikelets per head in cv. CM82036 at 21 days post-treatment. Disease results represents mean data obtained from 60 heads . Bars in graphs indicate standard error of the mean (SEM). Treatments with the same letter are not significantly different (P > 0.05).Flag leaves of wheat cv. CM82036 were rub-inoculated at growth stage 47 [(TIF)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S5 Table(DOCX)Click here for additional data file.S6 Table(DOCX)Click here for additional data file.S7 Table(DOCX)Click here for additional data file.S8 Table(DOCX)Click here for additional data file.S9 Table(DOCX)Click here for additional data file."}
+{"text": "Mammals face environmental stressors throughout their lifespan, which may jeopardize cellular homeostasis. Hence, these organisms have acquired mechanisms to cope with stressors by sensing, repairing the damage, and reallocating resources to increase the odds of long-term survival. Autophagy is a pro-survival lysosome-mediated cytoplasm degradation pathway for organelle and macromolecule recycling. Furthermore, autophagy efflux increases, and this pathway becomes idiosyncratic depending upon developmental and environmental contexts. Mammalian germ cells and preimplantation embryos are attractive models for dissecting autophagy due to their metastable phenotypes during differentiation and exposure to varying environmental cues. The aim of this review is to explore autophagy during mammalian gametogenesis, fertilization and preimplantation embryonic development by contemplating its physiological role during development, under key stressors, and within the scope of assisted reproduction technologies. Mammalian development begins with a plethora of events: fertilization, pro-nuclei formation and syngamy, and the first mitotic division ,2. ThereThe developing embryo subsequently initiates the cavitation period evidenced by the blastocele formation ,9. At thMammalian post-implantation development holds exponential embryonic growth by largely positive balance between cell proliferation against cellular demise. This intense proliferation accompanies irreversible events such as differentiation, migration or cell death . The rapmTORC1) dissociates from the ULK1/2 complex releasing it to activate autophagy [ULK1/2 complex alongside the phosphatidylinositol 3-kinase (PI3K) complex form an isolation membrane known as phagophore. This occurs by sequestering part of a cellular membrane enclosing a fraction of the cytosol containing cargo such as organelles and/or macromolecules [Autophagy (see glossary) is an increasingly appreciated route that cells undergo to maintain viability while facing challenging conditions . Autophautophagy . Free ULolecules . The phaolecules . This auolecules .There is an understanding that autophagy holds a basal activation at any given time . This phAutophagy data are emerging at a fast pace in numerous experimental contexts and organisms ,36,37. TAtg) in Saccharomyces cereviseae and eighteen of them are required for autophagosome formation [ATG orthologs have been systematically interrogated in different cellular or developmental contexts [Beclin1 and autophagy-related protein 5\u2014Atg5) are viable and fertile [Atg5 and autophagy-related protein 7 (Atg7)\u2014have been investigated using both oocyte and zygotic deletions [Most components of the autophagy pathway were first identified in yeast genetic screens. There are over forty annotated canonical autophagy-related genes  as inhibitors of autophagy activation by type III PI3K inhibition in an mTORC1 complex-independent fashion [The application of genome-wide tools accelerated the identification of autophagy-associated genes in mammalian cells. For instance, a proteomic approach searching for proteins interacting with 65 candidate autophagy genes found 409 associated proteins and 751 protein interactions under basal autophagy levels in human HEK293 cells, thus revealing an extensive autophagy regulatory network . Upon in factors . Alterna readout . Follow- fashion . Genome- fashion .ULK1, ULK2, ATG4, ATG7, and others) but the exact gene set and magnitude of gene expression modulation was affected by species (mouse embryonic fibroblasts vs. human fibroblasts) and cell type (fibroblast vs. HCT116 human colon cell line). Nonetheless, autophagy activation occurs in a p53-independent fashion [p53 and autophagy genes highlights the potential of network-based analysis to link autophagy to diverse biological processes, exemplified by the DNA damage response pathway. In turn, these genome-wide approaches remain challenging for germ cells and preimplantation embryos, although embryonic stem cells are an alternative model [Despite the growing number of autophagy-associated genes  in both yeast and mammals ,51,52, t fashion . This cove model . A comprGametogenesis is the process of formation of mature haploid gametes by cell divisions and stepwise differentiation during meiosis. It begins during fetal development in mammals, when PGCs migrate to the genital ridges before gonad formation . PGCs prAtg7 deletion resulted in ovarian insufficiency and subfertility [Atg7 null females displayed diminished follicle counts after birth due to apoptosis. Curiously, the litter size of Atg7 null females after the first gestation was initially indistinguishable from controls (~8 pups/litter), albeit later litters became smaller (~4 pup/litter) or females became infertile [Atg7 null females resembles the primary ovarian insufficiency in women aged <40 years and therefore could become an interesting animal model for this age-dependent human syndrome.The requirement for autophagy during oogenesis depends on the species . In the ertility . The Atgnfertile . This coLC3-II protein [BECLIN1, in pig germinal vesicle oocytes compromised nuclear maturation, mitochondrial function, DNA integrity, and developmental competence [BECLIN1 protein accumulated throughout oocyte maturation but Beclin1 mRNA knockdown disrupted oocyte cytokinesis, independently of autophagy [(ATG14) gene did not affect oocyte nuclear maturation reinforcing that autophagy is not required for this stage of mouse oogenesis [Further research demonstrated that autophagy contributes to oocyte maturation. Pig oocytes subject to in vitro maturation (IVM) accumulate and later degrade  protein , thus sumpetence . In miceutophagy . Knockdoogenesis .PI3K inhibitor 3-methyladenine (3MA) displayed lower cumulus cell expansion and oocyte arrest at the germinal vesicle stage [Pharmacological modulation also indicated the role of autophagy during oocyte maturation. Porcine cumulus\u2013oocyte complexes (COCs) subject to IVM with the type III le stage . Recentlle stage . Alternale stage . Similarle stage .BECLIN1 protein was detected in human theca cells in situ but not in granulosa and oocytes [BECLIN1 protein also correlated with corpus luteum viability, thus marking theca-lutein and granulosa-lutein cells [ATG8, also known as light-chain 3\u2014LC3) was detected at the protein level in cumulus/granulosa cells of several species [LC3 protein accumulation in granulosa cells both in vitro and in vivo [LC3-I/LC3-II conversion compared to oocytes [Atg deletions to determine the magnitude of oogenesis abrogation. For instance, granulosa-specific Beclin1 ablation affected progesterone production in pregnant mice [ATG5 and LC3 levels in theca and granulosa [The completion of oogenesis requires the interplay between oocytes and the follicle microenvironment . Theca,  oocytes . Nonethein cells . In turn species ,98, irre species . Exposur in vivo . Under b oocytes . It woulant mice , albeit ranulosa .LC3 conversion in oocytes, while autophagy inhibition with 3MA enhanced the heat stress-mediated detrimental effects on oocyte developmental competence [Autophagy pathway also plays a role on oocyte survival after exposure to stress, such as post-ovulatory aging and heat stress. For porcine in vitro aged oocytes (an in vitro model of post-ovulatory oocyte aging), treatment with rapamycin for 24 h or 48 h of aging did not contribute to oocyte maturation (percentage of oocytes at metaphase II). However, treatment of 24 h-aged oocytes with rapamycin, increased the percentage of aligned chromosomes, normal spindles, and decreased ROS activity . Consequmpetence .LC3 staining [Atg7-deficiency in mice demonstrated that autophagy is not required for survival of mouse vitrified/warmed oocytes [Oocyte cryopreservation is challenging due to the oocyte relative large size and abundant protein storage for sustaining early development. These traits complicate cell dehydration and increase the potential impact of protein damage diminishing oocyte viability and developmental competence. Cold stress during vitrification of mouse oocytes induced autophagy which was visualized by staining ,66. Addistaining . The use oocytes . Autopha oocytes . These f oocytes  and leadAtg7 in mouse male germ cells led to subfertility and non-viable sperm with cytoskeleton damage and abnormal acrosome [Atg5 or Atg7 knockout in mouse Sertoli cells led to low motility and non-viable sperm [Atg5 or Atg7 in rodent Leydig cells ultimately unbalanced testicular endocrinology, most notably in testosterone biosynthesis [mTORC1 impaired cellular metabolism and protein secretion of epidydimal cells leading to mouse infertility [Autophagy contribution to spermatogenesis has also been explored . Specifiacrosome ,70,71. Ile sperm . Depletiynthesis ,73. Autoertility . These fLC3-I/II conversion [Selective autophagy is emerging as an important process for sustaining sperm physiology. Lipophagy (see glossary) has been demonstrated during spermatogenesis for energy supply to male germ cells and supporting testosterone biosynthesis ,73. In anversion ,79,80. ANumerous stressors have been documented to affect spermatogenesis and testis function ,79,111. In vitro culture of rat spermatocytes under different energy substrates  induced autophagy in contrast to their non-cultured counterparts . This reCaenorhabditis elegans and mammals showed that sperm-borne mitochondria are prone to selective autophagy called mitophagy [The sperm cell embarks on an intense remodeling event after gamete fusion in order to regain transcription and replication competence by active epigenetic reprogramming, removal of protamine, and acquisition of oocyte-derived nucleosomes . Since mitophagy  or combiitophagy ,84,85,86itophagy . Furtheritophagy . Despiteitophagy . Finallyitophagy .Atg5-null mouse embryos between the four-cell and eight-cell stages showed that these stages require autophagy [Atg5-null embryos [Atg5-null eggs with wild-type sperm cells [Atg5 protein became available in these embryos from the two-cell stage onward. After this seminal report, much progress has been made in deciphering autophagy in early embryos  sharply and steadily decreases from the zygote to the blastocyst stage  activation and LC3 in a rather stochastic fashion [Autophagy dependency has been extensively carried out in mammalian early embryos by pharmacological means. As expected, blockage of autophagy by 3MA from zygote-stage onward or from zygote to the two-cell stage, respectively, did not fully arrest embryogenesis  albeit blastocyst yields dropped substantially ,90,91. O fashion . Both 3M fashion . Dose-de2O2) concentrations induced microtubule associated protein 1 light chain 3 beta (MAP1LC3B) and lysosomal associated membrane protein-2 (LAMP2) gene expression and LC3 accumulation [PINK1)\u2014Parkin coupled mechanism is also required for mitochondrial homeostasis in pig embryos, since PINK1 depletion by mRNA knockdown increased abnormal mitochondrial content and induced autophagy and mitophagy [PARP) is tied to selective autophagy of ubiquitinated proteins in pig blastocysts [PARP-1 inhibited mTORC1 by decreasing p-p70S6K-thr389 phosphorylation and sustaining ATG5, BECLIN1, and LC3 gene expression [Sirtuin-class histone deacetylases (HDACs) also lowered pig blastocyst development and cell numbers while accompanied by autophagy activation [Sirtuin deficiency induced LC3 and may have affected the acetylation status of other Atg genes and FoxO-class transcription factors [p62-LD domain fusion protein partially depleted mice embryos from lipid droplets revealing that such structures are necessary for embryogenesis and for fine-tuning overall lipid content [A link between mitochondrial stress and autophagy was made in the pig ,119. Expmulation . The phostocysts . PARP-1 pression . Inhibittivation . This Si factors ,122. Ano factors . An engi content ,123. A rGAPDH activity lowered intracellular glucose content in exposed blastocysts but could not compensate for most of the damage [Preimplantation embryos are highly susceptible to metabolic perturbations . Mouse ee damage . It woule damage , alterede damage  or overle damage . Howevere damage ,126. Of e damage ,89. TherGABARAPLs) gene transcripts are negatively enriched in human ICSI-derived blastocysts under the influence of the paternal age [There is accumulating evidence that ARTs leads to autophagy modulation in early embryos. A single report from an unbiased gene expression analysis has found that gamma-aminobutyric acid receptor-associated proteins  allows cellular reprogramming of a differentiated nucleus by an enucleated oocyte . HoweverLC3 knockdown with short interfering RNAs in pig SCNT embryos showed that autophagy selectively modulates mRNA abundance\u2014and most likely the protein content\u2014of components of the DNA methylation machinery , pluripotency-associated transcription factors , kinases (c-MOS), TGF-\u03b2 pathway (BMP15 and GDF9) but not the core pluripotency TFs OCT4 and SOX2 [Pig SCNT showed different autophagy activation kinetics in comparison to control parthenotes ,96. Autoand SOX2 ,96. In tand SOX2 . Vitaminand SOX2 . The incand SOX2 . These rand SOX2 . These fThe integration of the autophagy data from gametogenesis and preimplantation development gave a broader picture of its contextual roles during development. It becomes clear that the importance of autophagy is dictated by developmental states as well as interactions with stressors and ARTs. More studies with side-by-side comparisons between physiological and stress/ARTs conditions will determine the magnitude of autophagy induction and its potential contribution to sustain cellular viability and function.LC3 reporter assays, which act as an autophagosome marker [The literature review described here points out unaddressed questions for future research . The dose marker . This ste marker ,136. Seve marker . Single-The endeavor of understanding autophagy during mammalian gametogenesis, fertilization, and preimplantation development has rapidly being fulfilled by accumulating information in numerous cell types and organisms. The downside is that progress has been made almost exclusively for macrophagy using low resolution tools. Further mechanistic insight and network-based approaches are thus needed to promote a shift from a relatively fixed dichotomy of \u201call or none autophagy\u201d phenomenon to more contextual autophagy investigations. Novel experimental designs  and novel experimental tools should also contribute to a more detailed understanding of contextual autophagy in mammalian preimplantation embryos and the germline."}
+{"text": "ABSTRACT IMPACT: This study helps translate investigational bedside optical coherence tomography into improved diagnosis and care of preterm infants at risk for retinopathy of prematurity. OBJECTIVES/GOALS: In retinopathy of prematurity screening, fundus photography may be of limited quality in eyes with dark fundus pigmentation (FP). The goal of this study was to evaluate the impact of FP on overall scan quality and retinal layer visibility on investigational bedside optical coherence tomography (OCT) in preterm infants. METHODS/STUDY POPULATION: We analyzed 846 OCT scans captured prospectively from 188 eyes of 94 preterm infants enrolled in the BabySTEPS study (NCT02887157). Trained ophthalmologists, masked to OCT findings, determined FP . Expert graders, masked to FP, evaluated OCT images for: 1) overall OCT quality ; and 2) all age-appropriate retinal layers visible (yes or no). To assess the association of FP with OCT quality (excellent/acceptable or poor/unusable) and retinal layer visibility, we performed multivariable logistic regression modeling, adjusting for biologic and demographic confounders and correlations from repeated OCT scans and paired eyes. RESULTS/ANTICIPATED RESULTS: Mean birthweight was 964 (SD=283) grams, mean gestational age was 27.8 (SD=2.6) weeks, 48 (51%) infants were male, and 51 (54%) were non-white. On exam, 72 (38%) eyes had blond FP, 92 (49%) had medium, and 24 (13%) had dark. OCT quality was excellent or acceptable in 725 scans (86%) and all age-appropriate retinal layers were visible in 781 scans (92%). Compared to eyes with blond FP, eyes with medium and dark FP did not have higher odds of poor/unusable OCT scan quality  or not all age-appropriate retinal layers visible on OCT . DISCUSSION/SIGNIFICANCE OF FINDINGS: Medium and dark FP did not impact overall scan quality or age-appropriate retinal layer visibility on investigational bedside OCT in preterm infants. This study supports the feasibility of using OCT to analyze retinal microanatomy in diverse populations of preterm infants with a range of FP."}
+{"text": "COVID-19 infection is usually mild in children. Progression to severe disease with multiple organ systems compromise described as Multi Inflammatory Syndrome in Children (MIS-C) is a rare occurrence believed to be immunologically mediated. Previous reports describe a possible link between children of Latino origin and high incidence of MIS-C in the US. 40% of the total population in Western Massachusetts is of Latino origin. Retrospective chart review of 30 children admitted to Baystate Medical Center in Springfield, Massachusetts from April 2020-June 2021 meeting Centers for Disease Control and Prevention (CDC) criteria for MIS-C. Demographics, laboratory data, and clinical outcomes including progression to Macrophage Activation Syndrome (MAS) were analyzed.60% of children were Hispanic. Mean age (9.1 yrs). Range (3m-20 yrs). COVID PCR positive (78%) and COVID Antibody positive (68%). The most common symptom was fever (96.8%) followed by gastrointestinal symptoms (84%). Respiratory symptoms (29%), dermatological manifestations (39%). Most common comorbidity, asthma (19%) followed by obesity (17%). Leukocytosis (47%), lymphopenia (45%), Anemia (55%), thrombocytopenia (20%), high CRP (90%), ferritinemia (57%), acute kidney injury (20%), elevated liver enzymes (53%), 52% children had electrocardiogram (EKG) abnormalities, 34% had abnormal echocardiograms, none displayed coronary artery dilation. Progression to MAS (20%). All patients were treated with intravenous immunoglobulin G, steroids, aspirin, and anakinra (IL1 receptor antagonist) if progression to MAS. All patients survived.In our population, gastrointestinal symptoms were predominant despite a high prevalence of asthma and obesity, previous reports of children with MIS-C describe predominance of respiratory manifestations. We did not encounter any coronary aneurysms during admission. Most children had positive PCR or Antibodies for COVID 19 and showed important abnormalities in multiple cell lines and inflammatory markers. More research is needed to fully understand ethnical risk factors associated with disease severity especially the risk of progression to MAS from MIS-C in children of Latino origin diagnosed with COVID 19 infection.All Authors: No reported disclosures"}
+{"text": "Communication is fundamental for dementia care and identifying communication behaviors is key to identifying strategies that facilitate or impede communication. To measure caregiver verbal communication, we adapted the Verbal and Nonverbal Interaction Scale for Caregivers (VNVIS-CG) for second-by-second behavioral coding of video observations. The VNVIS-CG was adapted for computer-assisted Noldus Observer coding of video interactions captured at home by family caregivers from the FamTechCare clinical trial. Operational definitions for verbal communication behaviors were developed and inter-rater reliability was excellent (Kappa = .86) using two independent coders. Videos (N=232) were coded featuring 51 dyads; caregivers were primarily female (80%) spouses (69%) of men (55%) diagnosed with moderate to severe dementia (64.7%). Mean caregiver age was 65 years. Silence occurred most frequently (44.9% of the time), followed by caregiver direction or instruction (22.6%), and the person with dementia (PWD) verbalizing (22.8%). Caregiver communication also included asking questions (14.2%), verbalizing understanding (7.9%), repeating information (2.1%), affirmations (1.0%), acknowledging emotions (0.3%), and ignoring (0.0%). Questions most commonly requested clarification, showed interest, or repetitive quizzing; few questions sought to engage PWD input . Tone was overwhelmingly neutral rather than humorous, aggressive, or patronizing. The adapted behavioral coding scheme provides a reliable measure that characterizes dementia caregiver verbal communication behaviors for analysis of video observations. Ongoing research will identify strategies that facilitate communication as well as determine how strategies vary by dementia stage, diagnosis, and dyad characteristics."}
+{"text": "ABSTRACT IMPACT: Effective robotic pedaling therapy would allow stroke survivors a precision, customized, and adaptable therapy to help recover lower extremity function. OBJECTIVES/GOALS: It has been observed that people post-stroke can pedal each limb individually but not simultaneously when the bicycle is split-crank. This implies that lower extremity movement difficulties are affected more by interlimb rather than unilateral coordination deficits. This work seeks to further develop a robotic split-crank pedaling therapy device. METHODS/STUDY POPULATION: This work uses a robotic split-crank pedaling device to facilitate rehabilitation of interlimb coordination, measured by continuous relative phase (CRP) and paretic neuromuscular output. The effects of three control schemes were tested: assist, resist, and assist+resist. Each limb was strapped to a pedal which was connected to a motor. The participants were asked to pedal forward while keeping the pedals antiphase. The robot aided or resisted according to the activated control scheme. Control schemes were tested on two stroke participants. The control schemes respond proportionally to phasing deviation from 180 degrees. The assist scheme assisted the lagging limb while the resist scheme resisted the leading limb. The assist+resist did both control actions. RESULTS/ANTICIPATED RESULTS: For the assist scheme, CRP improved for participant 1 (P1) and declined for participant 2 (P2). P1 increased paretic velocity while P2 decreased. Rectus Femoris (RF) and Biceps Femoris (BF) activity of both limbs lowered for P1. RF and BF activity of both limbs remained about the same but shifted for P2. For the resist scheme, CRP improved for P1 and declined for P2. P1 increased paretic velocity while P2 decreased. P1 increased BF activity of both limbs while RF activity remained constant. P2 increased paretic BF activity and non-paretic RF activity. For the assist+resist scheme, CRP improved for both participants. Both participants increased paretic velocity. P1 increased paretic BF activity and decreased RF activity. P2 better modulated paretic BF and RF. DISCUSSION/SIGNIFICANCE OF FINDINGS: All control schemes augmented performance, however the assist+resist scheme showed the most promise in terms of CRP and muscle activity. More participants are needed to determine true effects of each control scheme. The control scheme selected will be the foundation for further improvements such as adaptive control and extrinsic feedback."}
+{"text": "Frailty predicts readmissions and mortality after acute hospitalizations. Understanding whether frailty predicts functional recovery after acute hospitalizations may help guide post-acute care and rehabilitation. This feasibility study enrolled 24 adults aged \u226565 years from a skilled nursing facility (SNF) after acute hospitalization. We calculated a deficit-accumulation frailty index  via in-person assessment on SNF admission. We measured weekly functional improvement with modified Barthel Index, as well as quality of life. Modified Barthel Index and quality of life were measured weekly by Patient-Reported Outcome Measurement Information System (PROMIS) . The mean age was 83.3 years [SD 8.0], and 17 (71.8%) were female. Length of stay for those with severe frailty (FI>0.45) was 26.8 days [10.7] compared to those who were not frail, mildly frail, or moderately frail . Those with severe frailty also had delayed functional improvement , compared to those with moderate frailty  or mild frailty . Self-reported mental and physical health-related quality of life was relatively unchanged across SNF episode for all frailty categories. These findings suggest that older adults with moderate or severe frailty may experience a typical course of delayed functional recovery and that further monitoring may be necessary for prognostication."}
+{"text": "S. aureus and streptococci, especially anginosus group), whereas gram-negative pathogens were identified very infrequently . This suggests routine empiric therapy against gram-negative bacteria, though commonly administered, is not required. High rates of clinical cure (88.6%) were observed despite the complex nature of infections and independently of the highly variable intravenous and total antimicrobial durations received. There exists a rationale to devise pragmatic approaches to implement novel individualised treatment plans utilising oral antimicrobial therapy for i-DVT. Despite frequent healthcare interactions, opportunities to address HCV treatment and opioid substitution therapy were frequently missed during these acute admissions.Infected deep vein thrombophlebitis (i-DVT) in people who inject drugs (PWID) is a clinically challenging but poorly characterised disease. We undertook a retrospective observational study of 70 PWID presenting acutely with i-DVT to improve the clinical and microbiological characterisation of this disease. i-DVT was frequently associated with bacteraemia (59.1% patients with blood cultures obtained), groin abscesses , and septic pulmonary emboli (38.6%) requiring anticoagulation. Network analysis identified a cluster of patients presenting with respiratory symptoms but lacking typical DVT symptoms, more likely to have septic pulmonary emboli. A microbiologic diagnosis was frequently achieved (70%). Causative pathogens were predominantly gram-positive (The online version contains supplementary material available at 10.1007/s15010-021-01725-3. People who inject drugs (PWID) are at increased risk of bacterial disease complicating injections, including cellulitis, abscesses and infective endocarditis (IE). Infected deep vein thrombophlebitis (i-DVT) is estimated to account for up to 11% of infectious complications amongst hospitalised PWID, based on a single-centre Swiss retrospective observational study . In geneCases were defined as (1) adults currently injecting drugs intravenously, presenting with (2) radiologically confirmed upper or lower limb DVT  with (3) evidence of infection, either (i) radiological or intra-operative  or (ii) microbiological (bacteraemia or culture-positive intra-operative thrombus sample). Electronic patient records and Infectious Disease consultation records were searched for the terms \u201cDVT\u201d, \u201cPWID\u201d and \u201cIVDU\u201d for patients admitted to infectious disease, vascular surgery or critical care wards from January 2017\u2013December 2018 inclusive, identifying 2957 acute admissions, 70 of which met the case definition and had available records. This work was approved by the NHS Lothian Infection Service Quality Improvement Team.Microbiological cure was defined as a negative blood culture (BC) following a positive BC. Clinical cure was defined as no re-admission due to the same infection within one year of discharge. Symptom clusters were identified by network analysis using the Markov Clustering Algorithm . Groupsn\u2009=\u200928) and/or deep vein thrombosis/pulmonary embolism .Patients were predominantly male  with a median age of 37\u00a0years (Table 9/L [6.9\u201313.9]) but overt sepsis (qSOFA \u22652) was uncommon  (Table n\u2009=\u200929), external iliac (n\u2009=\u200917) or common iliac (n\u2009=\u200914) veins. Abnormalities were present in 21/61 (34.4%) chest x-rays (cavitating pneumonia in four). Thoracic CT  identified definite emboli in 6/37 (16.2%) and cavitation in 23/37 (62.2%) patients who underwent imaging; more often in the respiratory symptom cluster.Network analysis identified distinct symptom clusters. Combinations of leg pain with/without swelling and fever were the most common presenting symptoms, but one cluster of patients presented predominantly with fever and respiratory symptoms . Laboratory evidence of systemic inflammation was common  patients where obtained. Considering BC and intra-operative samples together, a microbiological diagnosis was made in 49/70 (70%) patients; monomicrobial in 32/49 (65.3%). Most monomicrobial infections were due to S. aureus . S. aureus, streptococci  and anaerobes were the most commonly identified pathogens overall (Table S2). Gram-negative organisms were infrequently identified (3 patients).Bacteraemia was identified in 39/66 (59.1%) patients with BC obtained at presentation . Bacteraemic patients had a median of 1 positive BC per organism (range 1\u20133). Seven patients had\u2009>\u20091 positive BC; in all cases n\u2009=\u200968 data available) were initially treated with intravenous antimicrobials continuing for a median of 18\u00a0days (IQR 7\u201329), with oral follow-on therapy in 54/68 (79.4%) patients, prescribed for a median of 14\u00a0days (IQR 14\u201327), resulting in a median total duration of 29\u00a0days (IQR 28\u201343) but with substantial variation  patients receiving agents with activity against gram-positive pathogens including S. aureus  or pseudoaneurysm ligation (n\u2009=\u20094). Therapeutic anticoagulation was initiated with subcutaneous low molecular weight heparin (LMWH) for most patients  or LMWH followed by a direct-acting oral anticoagulant  or DOAC alone (n\u2009=\u20091). Four patients were not anticoagulated and one was already taking therapeutic anticoagulation. The majority of patients received long-term opioid substitution therapy, however, 14/70 (20%) patients were discharged without a treatment plan , were required for intravenous access in 32/70 (45.7%) patients. Surgical intervention was required in 22/70 31.4%) patients, most commonly for abscess drainage  and groin abscesses  were the most common complications. Adjacent arterial involvement  and pseudoaneurysms  were less common. Other metastatic complications included: splenic emboli , IE , vertebral osteomyelitis , septic arthritis , pulmonary artery pseudoaneurysm requiring surgical intervention , right ventricle thrombus containing an embolised needle tip  and necrotising fasciitis of the groin and abdominal wall .Septic pulmonary emboli  cases. Clinical cure was achieved in 62/70 (88.6%) cases and there were no deaths during the index admission. Clinical failure leading to re-admission occurred an average of 17\u00a0days after discharge . 32 (45.7%) patients had a further admission within one year due to other complications of injection drug use. Bacteraemia, S. aureus, streptococci and anaerobes were the most commonly identified pathogens whereas gram-negative pathogens were identified very infrequently . Considering the rarity of identifying gram-negative pathogens, we propose that routine use of broad spectrum/gram-negative therapy empirically is not required.i-DVT in PWID was frequently associated with bacteraemia, groin abscesses and septic pulmonary emboli. Patients often received lengthy antimicrobial courses associated with extended hospitalisations. Despite the complex nature of infections, outcomes were surprisingly good, with clinical cure in 88.6% of patients. Moreover, cure occurred independent of highly variable durations of antimicrobial therapy. Patient characteristics and outcomes reported here are similar to other smaller studies (Table S6) , 5, 6. IAlthough treatment failure of the index infection was uncommon, readmissions within one year with other complications of injection drug use occurred in almost half the cohort (45.7%), justifying intensification of efforts to address causation. Fourteen patients (20%) were discharged without addressing opioid substitution therapy. Active HCV was common (31.4%) but only a minority were successfully engaged in treatment. There was minimal documentation regarding harm reduction measures. In Scotland, drug-related acute admissions are increasing steadily with 10,509 admissions in 2017\u201318 , representing 7,986 distinct patients of which 54% had not been admitted before[The generalisability of these results is limited by the single-centre design. Our ability to identify predictors of treatment failure was limited by the low event rate. Patients re-admitted to hospitals outwith the geographic area of the study would not have been identified so the figures presented for clinical cure represent an upper bound ; however local experience suggests this is unlikely to have been a frequent event.This report addresses a deficit in the clinical and microbiological characterisation of i-DVT in PWID, providing a basis for reformed antimicrobial approaches. Despite frequent interactions and prolonged hospital stays, we also identify missed opportunities to address causal factors and more specifically to target the reservoir of active HCV in PWID. PWID presenting acutely with i-DVT represent a high-risk group in need of an integrated, holistic approach to management and efforts to facilitate healthcare engagement.Supplementary file 1 (PDF 2622 KB)Below is the link to the electronic supplementary material."}
+{"text": "Neutralizing antibody therapies targeting SARS-CoV-2 have been released for emergency use authorization by the FDA. Little is published on their real-world experience. In this retrospective study we share the results of our early experience on patient outcomes from use of these neutralizing antibodies within a large healthcare system.We retrospectively analyzed results of a healthcare system wide program to pro-actively identify and treat COVID-19 patients with neutralizing antibody therapy.The 449 patients identified for SARS-CoV-2 neutralizing antibody therapy during the study period were retrospectively classified as falling in one of the three groups: untreated (199), bamlanivimab (87) and casirivimab/indevimab (125) treated patients (Table 1). Reasons identified patients were not treated most commonly were patient declined (n=74), unable to be contacted (n=36), out of treatment window (n=23), asymptomatic and feeling better (n=21) or did not have transportation (n=9). Bamlanivimab infusion did not reduce emergency room (ER) visits or hospitalization compared to untreated patient within 30-days of follow up (Table 2), and among all patients treated with antibody therapy only treatment with bamlanivimab and non-white race were predictors of need for hospitalization (Table 3). Casirivimab/indevimab did reduce subsequent ER visits or hospitalization within 30 days post-infusion when compared to the untreated group. However, patients treated with either antibody therapy had lower acuity of COVID-19 disease as reflected in need for intensive care unit (ICU) stay, mechanical ventilation or death (Table 2).Table 1. Characteristics of infused vs uninfused patientsTable 2. Outcomes in treated vs untreated patientsTable 3. Risk factors for ED visits or hospitalization in infused patientsEither neutralizing antibody therapy appears to markedly reduce acuity of COVID-19 disease even if patients do progress to requiring hospitalization. However, casirivimab/indevimab therapy also decreased ER visits and hospitalization suggesting better efficacy in our experience. Christopher Polk, MD, Atea (Research Grant or Support)Gilead Humanigen (Research Grant or Support)Regeneron (Research Grant or Support) Mindy Sampson, MD, Regeneron (Grant/Research Support)"}
+{"text": "This paper examined predictors of COVID-19 stressors among 316 custodial grandmothers raising school-aged grandchildren using regression. Grandmothers, who were participants in two nationwide behavioral RCTs, completed an online questionnaire in Spring 2020. Predictors included grandmother demographics, depressive symptoms, perceived caregiving stress and reward, stress management strategies, and grandchild factors. Outcomes included grandmothers\u2019 stress related to using bad coping habits (r2=.24), grandchildren\u2019s remote learning(r2=.39), household conflict (r2=.29), COVID-19 fear and uncertainty (r2=.28), and finances(r2=.24). Regression results indicated that grandmothers\u2019 pre-existing depressive symptoms predicted all outcomes except remote learning stress. Higher caregiving stress was associated with all outcomes, except concerns about using bad coping habits. Grandmothers with less perceived access to care reported greater concern about bad coping habits and remote learning stress, while minority grandmothers reported more financial stress and COVID-19 fear and uncertainty. Findings suggest that the COVID-19 pandemic has compounded the stress experienced by already burdened custodial grandmothers."}
+{"text": "OBJECTIVES/GOALS: Older patients with HL have worse outcomes than younger patients, which may reflect treatment selection, including fewer chemotherapy cycles. Immortal time bias exists when patients must survival to initiation, and even completion, of treatment. We described treatment length and death to evaluate the extent of immortal time bias. METHODS/STUDY POPULATION: This retrospective cohort study utilized SEER-Medicare data from 1999-2014. Patients diagnosed with incident advanced stage HL at age \u226565 years and enrolled in Medicare Part A and B fee for service were included. Chemotherapy or radiotherapy treatment initiated within 4 months of diagnosis was determined from inpatient, outpatient, and physician/supplier claims. No treatment was defined by lack of treatment claims. Dates from claims were used to define length of treatment; \u22654 months of treatment indicated complete chemotherapy cycles. Date of death was obtained from Medicare data. Analyses were limited to 1 year post-diagnosis. Summary statistics were used to describe treatment length and subsequent death. RESULTS/ANTICIPATED RESULTS: We included 1492 advanced stage HL patients with a mean age of 76 years (SD = 7). 428 (29%) patients had no documented treatment; 397 (27%) were treated <4 months indicating fewer chemotherapy cycles; and 667 (45%) were treated for \u22654 months indicating complete chemotherapy cycles. Among those with no documented treatment, 15% died within 1 month of diagnosis with 78% dying by 1 year post-diagnosis. Among those treated <4 months, 36% died within 1 month of their last treatment claim with 64% dying by 1 year post-diagnosis. Among those treated \u22654 months, 7% died within 1 month of their last treatment claim with 14% dying by 1 year post-diagnosis. DISCUSSION/SIGNIFICANCE OF IMPACT: Few untreated patients died within 1 month of diagnosis. One-third of patients treated <4 months died soon after completion of treatment, while patients treated longer survived longer, suggesting some patients did not survive to complete treatment. To account for this immortal time bias, landmark analysis will be used to assess the relationship between treatment and survival."}
+{"text": "Ulcerative colitis (UC) is thought to arise from dysregulated immune responses due to intestinal dysbiosis and altered epithelial barrier function. Dietary components may affect the gut microbiome and contribute to either inflammation or its resolution. The relationship between diet and disease activity in UC warrants further investigation.This prospective cohort study explored the relationship between dietary components, and markers of disease activity: fecal calprotectin (FCP) and partial Mayo score (PMS) in patients with UC.40 participants were recruited from University of Calgary IBD clinics. Study staff obtained two 24-hour diet recalls using the validated automated self administered (ASA)-24 and captured PMS at baseline (T1) and follow-up at week 12 (T2). FCP samples were collected at T1 and T2. Diet variables included adjusted macro/micronutrients (n=44), food groups (n=36) and the validated Canadian healthy eating index-2009 (CHEI) where higher scores reflect healthier intake. CHEI captures intake of dark green and orange foods (DGO) and moderation scoring (MOD) of saturated fats (SF), sodium and added sugars. Higher CHEI scores result from increased intake of DGO and lower intake of SF, sodium and added sugars (higher MOD score). Associations with outcome variables were examined at T1 and T2 individually and across both timepoints (BT). Mixed effect logistic regression models identified relationships between dietary variables, FCP and PMS. Models were adjusted for age, sex, BMI, medications, probiotics, and for repeated measures in both timepoint analyses.A positive association was identified between FCP as a continuous variable and SF  and a negative association identified between FCP with citrus/melon/berries , total sugars  and HEI . FCP increased as SF , DGO , and MOD  scores decreased. The presence of inflammation  was negatively associated with higher fiber intake (BT: Odds Ratio (OR)= 0.016, CI p_adj=0.08). For PMS as a continuous variable, HEI had a negative association with PMS . With PMS as a discrete score (remission=PMS<2) there was no significant association with any diet components.This study suggests that a healthier diet, both in overall pattern and specific dietary components, was associated with lower FCP and PMS. Our findings related to SF, citrus/melons/berries, and DGO parallel the IOIBD dietary guidelines. Future research should explore through controlled intervention studies whether modifying dietary patterns and components independently reduces disease activity.Crohn\u2019s and Colitis Foundation"}
+{"text": "Our Trust increased Balint group provision, relocating virtually for psychiatry doctors to explore the emotional impact of clinical practice and doctor-patient relationships, during unfamiliar challenges of the pandemic. This unique context allowed comparison of multiple virtual and face-to-face (F2F) Balint-type group experiences for participants and facilitators.In March 2020, existing core trainee (CT) year 1 and 2, higher trainee (ST) and consultant Balint groups became virtual, with new CT3 and Speciality Doctor and Associate Specialist (SAS) virtual Balint groups established.All 57 participants and 5 facilitators were sent an anonymous electronic survey to retrospectively rate virtual Balint (March-August 2020) and their preceding F2F Balint group (suggesting September 2019-February 2020) experience.The response rate was 89% for participants (51 respondents) and 100% for facilitators (5 respondents).For group participants, 90%  and 78% (F2F) agreed or strongly agreed that Balint group provided an opportunity to explore challenging aspects of clinical work. 76%  and 71% (F2F) agreed or strongly agreed that it made them feel more supported. Almost 50% agreed or strongly agreed that virtual and F2F Balint group helped work feel less stressful. Both ratings and free-text feedback emphasised virtual Balint attendance being easier.Facilitators rated virtual and F2F formats similarly highly with regards to exploring difficult doctor-patient interactions, richness of discussions and their enjoyment. Facilitators felt virtual attendance was easier but more draining, with more difficult adherence to Balint group etiquette and boundaries.82% of participants and 75% of facilitators agreed or strongly agreed that virtual format made them more likely to attend future Balint groups. The rich pool of free-text comments received were predominantly positive, whilst noting challenges during virtual Balint in remaining present, with more distractions (for participants) and additional difficulty accessing group dynamics (for facilitators).Participant and facilitator responses indicate Balint-type groups being professionally and clinically beneficial across different psychiatrist grades, and promoting clinician wellbeing when both F2F and virtual during pandemic-related restrictions. Facilitator ratings (unlike participants) suggested specific virtual process challenges such as feeling more drained, perhaps in part due to technical application issues around this emerging format.Both participants and facilitators reported attendance being easier when virtual. Although some suggested returning to F2F post-COVID, more preferred to continue virtually or utilise a blended format. This was particularly for non-CT groups where geographical challenges  or competing clinical demands  made regular commitment and attendance more difficult."}
+{"text": "While establishing worldwide collective immunity with anti SARS-CoV-2 vaccines, COVID-19 remains a major health issue with dramatic ensuing economic consequences. In the transition, repurposing existing drugs remains the fastest cost-effective approach to alleviate the burden on health services, most particularly by reducing the incidence of the acute respiratory distress syndrome associated with severe COVID-19. We undertook a computational repurposing approach to identify candidate therapeutic drugs to control progression towards severe airways inflammation during COVID-19. Molecular profiling data were obtained from public sources regarding SARS-CoV-2 infected epithelial or endothelial cells, immune dysregulations associated with severe COVID-19 and lung inflammation induced by other respiratory viruses. From these data, we generated a protein-protein interactome modeling the evolution of lung inflammation during COVID-19 from inception to an established cytokine release syndrome. This predictive model assembling severe COVID-19-related proteins supports a role for known contributors to the cytokine storm such as IL1\u03b2, IL6, TNF\u03b1, JAK2, but also less prominent actors such as IL17, IL23 and C5a. Importantly our analysis points out to alarmins such as TSLP, IL33, members of the S100 family and their receptors  as targets of major therapeutic interest. By evaluating the network-based distances between severe COVID-19-related proteins and known drug targets, network computing identified drugs which could be repurposed to prevent or slow down progression towards severe airways inflammation. This analysis confirmed the interest of dexamethasone, JAK2 inhibitors, estrogens and further identified various drugs either available or in development interacting with the aforementioned targets. We most particularly recommend considering various inhibitors of alarmins or their receptors, currently receiving little attention in this indication, as candidate treatments for severe COVID-19. The pandemic is still progressing actively despite lockdown measures throughout the world, with the recent emergence of highly transmissible viral strains .\u201370.68\u201370emokines . Furtheremokines \u201376 Click here for additional data file.S2 Table(PDF)Click here for additional data file.S3 Table(XLSX)Click here for additional data file."}
+{"text": "Exercise training, including high-intensity interval training (HIIT), improves rheumatoid arthritis (RA) inflammatory disease activity via unclear mechanisms. Because exercise requires skeletal muscle, skeletal muscle molecular pathways may contribute. The purpose of this study was to identify connections between skeletal muscle molecular pathways, RA disease activity, and RA disease activity improvements following HIIT.RA disease activity assessments and vastus lateralis skeletal muscle biopsies were performed in two separate cohorts of persons with established, seropositive, and/or erosive RA. Body composition and objective physical activity assessments were also performed in both the cross-sectional cohort and the longitudinal group before and after 10 weeks of HIIT. Baseline clinical assessments and muscle RNA gene expression were correlated with RA disease activity score in 28 joints (DAS-28) and DAS-28 improvements following HIIT. Skeletal muscle gene expression changes with HIIT were evaluated using analysis of covariance and biological pathway analysis.p < 0.05). HIIT-induced disease activity improvements were greatest in those with an older age, elevated erythrocyte sedimentation rate, low cardiorespiratory fitness, and a skeletal muscle molecular profile indicative of altered metabolic pathways . Specifically, disease activity improvements were linked to baseline expression of RA skeletal muscle genes with cellular functions to (1) increase amino acid catabolism and interconversion , (2) increase glycolytic lactate production , and (3) reduce oxidative metabolism via altered beta-oxidation , TCA cycle flux , and electron transport chain complex I function (NDUFV3). The muscle mitochondrial glycine cleavage system (GCS) was identified as critically involved in RA disease activity improvements given upregulation of multiple GCS genes at baseline, while GLDC was significantly downregulated following HIIT.RA inflammatory disease activity was associated with greater amounts of intramuscular adiposity and less vigorous aerobic exercise (both In the absence of physical activity, RA inflammatory disease activity is associated with transcriptional remodeling of skeletal muscle metabolism. Following exercise training, the greatest improvements in disease activity occur in older, more inflamed, and less fit persons with RA. These exercise training-induced immunomodulatory changes may occur via reprogramming muscle bioenergetic and amino acid/protein homeostatic pathways.ClinicalTrials.gov, NCT02528344. Registered on 19 August 2015.The online version contains supplementary material available at 10.1186/s13075-021-02570-3. Exercise training improves disease activity and systemic inflammation in rheumatoid arthritis (RA) \u20134. In adOne underexplored mediator of exercise-induced improvements in RA inflammation is skeletal muscle. Skeletal muscle is the predominant locomotive organ and is largely responsible for the beneficial health effects of exercise. Skeletal muscle, during acute exercise, communicates widely with other organ systems, including immune cells, via the secretion of proteins termed \u201cmyokines\u201d . MyokineIn RA, chronic inflammation is strongly linked to impaired muscle function and \u201crheumatoid cachexia\u201d or sarcopenic obesity  . Furthern = 47) completed clinical assessments and underwent skeletal muscle biopsies in a cross-sectional design [For the cross-sectional RA cohort #1, persons with RA (l design . All RA l design . Particin = 12) completed clinical assessments and underwent skeletal muscle biopsies before and after a 10-week treadmill walking HIIT program [For HIIT RA cohort #2, persons with RA  [For RA cohorts #1 and #2, health history questionnaires were obtained and inflammatory disease activity was assessed by DAS-28 determined from patient-completed pain and overall health visual analog scales, physician assessed tender and swollen joint counts, and ESR . For the2 peak) , 16; bod2 peak) .Vastus lateralis needle biopsies were obtained from participants after an overnight fast by standard Bergstrom technique and stored at \u221280\u00b0C in the cross-sectional RA cohort #1 and before and after 10 weeks of HIIT in RA cohort #2 at between 24 and 48 h after the last exercise training bout [n = 20) and the HIIT RA cohort #2 (n = 12), respectively. For each frozen sample, 20\u201330 mg of the muscle was homogenized; biotinylated total RNA was prepared using the Illumina TotalPrep RNA amplification kit  and hybridized to the Human HT-12 BeadChips ; and RNA profiling performed as previously described [ing bout . Illuminescribed .p < 0.05) were uploaded for Ingenuity Pathway Analyses ; positive and negative coefficients represented positive and inverse associations, respectively, between gene expression and DAS-28  or \u0394DAS-28 (HIIT RA cohort #2). IPA-defined canonical pathways\u2014created based on right-handed Tukey\u2019s T tests to analyze overrepresentation of genes and pathways based on molecular pathways in the current literature\u2014were identified as pathways with the greatest proportional representation  . Of importance to the interpretation of our analyses, we purposely chose a less stringent significance cutoff  when creating initial gene sets to minimize random false positive and highly related results with downstream pathway analyses. Top differentially associated gene lists (p < 0.001) from both RA cohorts were analyzed for functional classification using the PANTHER Gene List Analysis tool and for overrepresentation against a homo sapiens gene reference database using the PANTHER Overrepresentation Test (http://pantherdb.org) with Reactome pathways (https://reactome.org) annotation [Differential Spearman correlations were performed using Partek Genomics Suite  to assess associations of baseline muscle gene expression with (a) baseline DAS-28 in the cross-sectional RA cohort #1 and (b) HIIT-mediated change  in RA disease activity (\u0394DAS-28) in the HIIT RA cohort #2. For the HIIT RA cohort #2, \u0394DAS-28 was computed as pre-HIIT DAS-28 minus post-HIIT DAS-28 so that larger numbers and positive associations represent improved disease activity. To validate baseline DAS-28 correlations from the cross-sectional RA cohort #1, Spearman correlations were also performed between baseline muscle gene expression and baseline DAS-28 in the HIIT RA cohort #2. Genes with expression correlated with DAS-28 or \u0394DAS28 (Spearman rho notation \u201325. Chanp < 0.001), low thigh muscle density  [p = 0.032), and fewer total daily minutes of high  and very high intensity physical activity    (rho=\u22120.p < 0.001) with RA disease activity scores (DAS-28) in the cross-sectional RA cohort #1. The top highly correlated skeletal muscle gene was IL1RL2  (Supplementary Table p < 0.05): (1) Basigin interactions, (2) cell junction organization, (3) cell\u2013cell communication, (4) interleukin-1 family signaling, and (5) ion channel transport. However, accounting for false discovery, no Reactome pathway was significantly overrepresented.Of 29,042 total mapped gene transcripts analyzed, expression of 25 genes was highly correlated . These data included a total of 1417 molecules . The top canonical pathway was \u201cDNA Methylation and Transcriptional Repression Signaling\u201d  , higher baseline ESR , and lower baseline cardiorespiratory fitness/VO2 peak  . The strongest correlation was for KIF25  (Supplementary Table p < 0.05) involved cellular substrate energy metabolism: (1) glycine degradation, (2) metabolism of amino acids and derivatives, (3) pyruvate metabolism, and (4) tricarboxylic acid (TCA) cycle and respiratory electron transport. The glycine degradation pathway (R-HSA-389661) was the only pathway significantly overrepresented at the false discovery rate   were uploaded. IPA identified 39 canonical pathways (p < 0.05). The top canonical pathway was \u201cProline Biosynthesis II\u201d , we identified a phenotype for an exercise training-induced anti-inflammatory response as being older, more inflamed, less aerobically fit, and with multiple alterations in skeletal muscle metabolic pathways. Based on our transcriptomic analyses of top highly associated genes and IPA canonical pathways, we have identified the apparent skeletal muscle cellular metabolic pathways that (1) are connected to RA inflammation and 2) are associated with exercise training modulation of systemic immune responses  associated with HIIT-related improvements in disease activity, while GLDC (glycine dehydrogenase) was significantly downregulated following HIIT. Glycine is a proteogenic amino acid and critical for multiple metabolic pathways in humans . Catabolleotides , 35, keyleotides , 37. ThuAltered skeletal muscle metabolism of other amino acids also link to RA inflammation. Skeletal muscle branched-chain amino acid (BCAA) catabolism\u2014via increased mitochondrial branched-chain \u03b1-ketoacid (BCKA) dehydrogenase (BCKDH) complex activity\u2014was associated with both baseline RA disease activity and with exercise-mediated disease activity improvements. We theorize that increased RA muscle BCKDH activity might lead to glutamate/glutamine formation via multiple pathways. First, BCAA are metabolized to both BCKA and glutamate directly. Second, BCKA are converted to acetyl-CoA; subsequent \u03b1-ketoglutarate flux from the TCA cycle leads to further glutamate production via ornithine aminotransferase/OAT , 34. GluInterestingly, opposing protein homeostatic pathways involved in both protein synthesis and muscle atrophy associated with subsequent improvement in RA inflammatory disease activity following HIIT. These pathways were highlighted by greater gene expression of RPL15   and the In addition to amino acids, dysregulation of RA skeletal muscle glycolysis and lactate production appears to support chronic immune signaling. We previously showed that, as compared to healthy matched controls, RA skeletal muscle is characterized by increased glycolysis as evidenced by transcriptional downregulation of oxidative metabolism components and accumulation of pyruvate . Here, i2), typically generated through acetyl CoA and TCA cycle metabolism. Our findings suggest that RA muscle amino acid sources contribute more and glucose and fatty acids less than expected to acetyl CoA generation . Interestingly, muscle IL-15 has important roles in regulating fat mass and systemic metabolism, as well as modulating lymphocyte development and acute inflammation [In addition to metabolic alterations, we hypothesized that upregulated RA skeletal muscle immune/inflammatory cytokine pathways would be associated with disease activity and improvements in disease activity following exercise training; however, our data did not consistently support this theory. In the cross-sectional RA cohort #1, IL1RL2 and TAB1 were the only skeletal muscle genes specifically involved in immune function or inflammation to correlate highly with RA disease activity  which somewhat limits the interpretation of exercise training-specific effects on RA muscle and immune function. Thus, further detailed study of cross-talk between RA skeletal muscle and immune cells is necessary to dissect the intricacies of these pathways so they can eventually be exploited to improve patient care.High-intensity interval training yielded the greatest improvements in inflammatory disease activity for persons with RA who were older, less aerobically fit, and with greater systemic inflammation. We identified alterations in multiple RA skeletal muscle metabolic pathways that associate strongly with disease activity as well as exercise training-related improvements in disease activity. Our data suggest that transcriptional remodeling of RA muscle amino acid, glucose, and fat metabolism is intricately linked to chronic inflammation. Exercise training may reprogram these muscle metabolic pathways to help maintain muscle-immune bioenergetic balance and modulate systemic immune responses. Ultimately, our findings provide further evidence for connections between impaired skeletal muscle and immune function in chronic inflammatory diseases such as RA and the ability of exercise training to rectify these underappreciated interorgan maladaptations.Additional file 1: Supplementary Table 1. Cross-sectional rheumatoid arthritis cohort #1 top skeletal muscle genes. Supplementary Table 2. Cross-sectional rheumatoid arthritis cohort #1: Skeletal muscle canonical pathways associated with disease activity. Supplementary Table 3. High-intensity interval training rheumatoid arthritis cohort #2 top skeletal muscle genes associated with improvements in disease activity. Supplementary Table 4. High-intensity interval training rheumatoid arthritis cohort #2: Skeletal muscle canonical pathways associated with improvements in disease activity."}
+{"text": "PredictProtein (https://predictprotein.org) is a one-stop online resource for protein sequence analysis with its main site hosted at the Luxembourg Centre for Systems Biomedicine (LCSB) and queried monthly by over 3,000 users in 2020. PredictProtein was the first Internet server for protein predictions. It pioneered combining evolutionary information and machine learning. Given a protein sequence as input, the server outputs multiple sequence alignments, predictions of protein structure in 1D and 2D  and predictions of protein function  terms, subcellular localization, and protein-, RNA-, and DNA binding). PredictProtein's infrastructure has moved to the LCSB increasing throughput; the use of MMseqs2 sequence search reduced runtime five-fold (apparently without lowering performance of prediction methods); user interface elements improved usability, and new prediction methods were added. PredictProtein recently included predictions from deep learning embeddings (GO and secondary structure) and a method for the prediction of proteins and residues binding DNA, RNA, or other proteins. PredictProtein.org aspires to provide reliable predictions to computational and experimental biologists alike. All scripts and methods are freely available for offline execution in high-throughput settings.Since 1992   PredictProtein (PP)PredictProtein ( at the European Molecular Biology Laboratory (EMBL) in 1992  and position-specific scoring matrices (PSSMs) computed by a combination of pairwise BLAST , PSI-BLAFmax values of 37\u00a0\u00b1 2%, 52 \u00b1 2% and 58 \u00b1 2% for BPO , MFO (molecular function), and CCO (cellular component), respectively  using ProtBert  embeddinproteins ,46. On aproteins . Althougproteins  at 82%),in-house implementation of ProtVec (ProNA2020  predicts ProtVec . Per-res ProtVec . ProNA20Most time-consuming for PP was the search for related proteins in ever growing databases. MMseqs2  finds rePredictProtein.org by submitting a protein sequence. Results are available in seconds for sequences that had been submitted recently (cf. PPcache next section), or within up to 30 min if predictions are recomputed. Per-residue predictions are displayed online via ProtVista .All results displayed on and downloadable from PP are available through Docker  and as sRNA-binding; GO:0003723; ECO:0000213) and CCO  matching annotations found in UniProt , goPredSim predicted protein folding (GO:0006457) and protein ubiquitination (GO:0016567) suggesting the nucleoprotein to be involved in biological processes requiring protein binding. ProNA2020 (We demonstrate PredictProtein.org tools through predictions of the novel coronavirus SARS-CoV-2 (NCBI:txid2697049) nucleoprotein  supportroNA2020  predictsroNA2020  both preroNA2020 ; 6WJI (6roNA2020 ). Both sPredictProtein (PP) has been offering predictions for proteins. PP is the oldest prediction Internet server, online for 6-times as long as most other servers   servers . It pion servers . For theFreely accessible webserverPredictProtein.org; Source and docker images: github.com/rostlab.gkab354_Supplemental_FilesClick here for additional data file."}
+{"text": "Mobility limitations in older adults are associated with negative outcomes including fear of falls (FOF) and poorer quality of life. However, self-reported symptoms contributing to mobility difficulty have not been fully explored as an area for intervention. The study aimed to identify the prevalence of self-reported symptom causes of difficulty walking and stair-climbing. In addition, we examined associations between symptoms and FOF in a population-based cohort of community-dwelling older adults in the MOBILIZE Boston Study. Of the 243 older adults who reported difficulty with walking one quarter of a mile or climbing stairs, 67% were women, 72% were white, average age=79.4y (SD=5.7). FOF was measured with the Tinetti Falls Efficacy Scale. Pain was most commonly reported as the primary symptom responsible for mobility difficulty (38.4%) followed by endurance (21.1%), multiple symptoms (15.6%), weakness (13.2%), balance (8.7%), other symptoms (2.9%). Factorial ANCOVA determined gender differences in associations between symptoms and FOF, adjusting for age. In pairwise comparisons, women who identified balance as their primary symptom had higher FOF than women identifying endurance (p=.017), pain (p=.015), other (p=.017), or multiple (p=.050) symptoms. There were no FOF differences for women identifying balance compared to weakness as the primary issue (p=.395). Men who identified balance as their primary symptom had higher FOF than those who identified pain (p=.036); no other FOF differences were noted in men identifying balance compared to other symptoms. Understanding common symptoms experienced by older adults, and symptoms associated with greatest FOF, will assist in developing tailored interventions for mobility improvement."}
+{"text": "Para-aortic lymph metastases were more common in patients with earliest distant recurrence . Median initial tumor volume in the earliest (n=24), early (n =29) and late (n=9) groups was 57, 28 and 40 mL, respectively (p=0.08); 57 (earliest) vs 30mL (early+late groups), p=0.04. Average mid treatment (fraction 4) and end of treatment (fraction 6) percent shrinkage was 80 (earliest) vs 73 (early+late), p=0.84 and 94 vs 92, p=0.95, respectively. Neither absolute nor percent tumor shrinkage differed between early vs. late groups. DISCUSSION/SIGNIFICANCE OF FINDINGS: Tumor volumetric changes during definitive chemoradiation were not associated with the timing of developing distant metastasis, which is linked to presence of lymph node metastasis and tumor volume at diagnosis.ABSTRACT IMPACT: This study assesses patient and volumetric risk factors for distant recurrence within 6 months of completion of curative chemoradiation with brachytherapy in locally advanced cervical cancer. OBJECTIVES/GOALS: Initial tumor volume and tumor shrinkage velocity are prognostic of cure and survival after curative chemoradiation (CRT) for cervical cancer. We explored whether local tumor volumetric changes influence time to distant recurrences outside the radiation field. METHODS/STUDY POPULATION: We performed a retrospective cohort study of patients with FIGO Stage IB-IVA cervical cancer treated with curative CRT and brachytherapy at a tertiary academic center with minimum 3 months follow up and standard post-treatment FDG-PET. Patients received 6 weekly fractions of brachytherapy interdigitated with external beam radiation and cisplatin. Tumor volumes were assessed by MRI at brachytherapy planning. Patients who developed distant metastasis were classified as earliest (3-6 months), early (6-24 months) or late (>24 months) following completion of CRT. Absolute and percent decrease in tumor volume for each fraction were calculated with respect to first brachytherapy volume. Fisher\u2019s exact and Mann Whitney-U tests were used for comparison of categorical and continuous variables. RESULTS/ANTICIPATED RESULTS: 143 of 574 (25%) patients developed distant metastasis. Distribution of age, histology, FIGO 2018 stage, primary tumor SUV"}
+{"text": "Cytomegalovirus (CMV) infection continues to cause morbidity in kidney transplant recipients, despite prophylaxis and pre-emptive therapy. Predictors of poor outcomes remain incompletely characterized. We questioned whether markers of CMV replication  are associated with adverse outcomes in the current era.We studied 605 people who underwent kidney transplant at Johns Hopkins University (2010 \u2013 2018). Mean follow-up was 45.5 months. The average age was 51.85 years and 39.7% were female. Donor-seropositive, recipient seronegative (D+/R-) patients received valganciclovir 900 mg/day for 6 months, while R+ patients received valganciclovir 450 mg/day for 3 months. CMV recurrence was defined as CMV DNAemia after two undetectable CMV PCR\u2019s. Outcomes of acute rejection, graft failure, and death were evaluated in univariate analysis; p values were calculated by Fisher\u2019s exact test. Peak CMV viral load was not associated with any outcomes (Table 1). There was a trend of increased graft failure in people who had long duration ( >6 month) DNAemia (Table 2). More than two episodes of CMV reactivation was associated with graft failure and rejection (Table 3). CMV reactivation is associated with kidney rejection and failure in univariate models. Multivariate analyses and longitudinal modeling will provide increased data upon which to better instruct preventative strategies. Funding for the research study was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA Robin K. Avery, MD, Aicuris (Grant/Research Support)Astellas (Grant/Research Support)Chimerix (Research Grant or Support)Merck (Grant/Research Support)Oxford Immunotec (Grant/Research Support)Qiagen (Grant/Research Support)Takeda/Shire (Grant/Research Support) Yuexin Tang, PhD, JnJ Merck & Co., Inc.  Kieren Marr, MD, Merck"}
+{"text": "Recent immigrant and undocumented Hispanic/Latino adults in the United States (U.S.) are an underserved segment of the aging population. In this cross-sectional pilot study, we examined associations between self-reported stressors metabolic syndrome, emotional reactivity, and cognitive functioning in a heterogenous sample (N=80) of Hispanic/Latino adults . Participants  underwent blood draw, anthropometrics and NIH-toolbox cognitive and behavioral measures. Linear regressions indicated that, elevated glucose was inversely associated with working memory (r=-.30), whereas higher HDL and controlled glucose were associated with better episodic memory (r=.27) and executive functioning (r=.32). Results further revealed associations between immigration-related trauma and elevated posttraumatic stress symptomatology. Implications for mental health and early detection of modifiable risk factors to promote healthy aging in vulnerable Hispanic/Latino immigrant populations are discussed."}
+{"text": "Here, we report the genomic sequences of five severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains obtained from nasopharyngeal samples from five tested COVID-19-infected patients from the Lambayeque region in Peru during early April 2020. Here, we report the genomic sequences of five severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains obtained from nasopharyngeal samples from five tested coronavirus disease 2019 (COVID-19)-infected patients from the Lambayeque region in Peru during early April 2020. Coronaviridae; genus Betacoronavirus; subgenus Sarbecovirus) variants sequenced from five patients from whom samples were taken in different districts in the Lambayeque region of Peru , during early April 2020.Here, we present the genomes of five severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) . This study has been registered in Proyectos de Investigaci\u00f3n en Salud, del Instituto de Salud del Per\u00fa , with code 37EBF149-F123-447F-8970-680BF549DE1D.TC] values obtained by qPCR,\u2009<25) were sampled, and total RNA was isolated using the GenUP total RNA kit . rRNA depletion was carried out using the Ribozero rRNA removal kit (Illumina). The cDNA libraries were generated using the TruSeq stranded total RNA LT kit (Illumina), using a single index and a fragment size range of 388 to 523 bp. Sequencing for every sample was performed in an Illumina NextSeq 500 model (midoutput 300 cycles), generating paired-end reads (150 bases long). Illumina sequencing was performed at Genoma Mayor .Nasopharyngeal swabs from SARS-CoV-2-positive patients (cycle threshold [MN908947) as a reference. Read mapping was done using SAMtools version 1.10  , all fivMW185823, MW185824, MW185825, MW185826, and MW185827. Illumina raw reads for this sequencing project (PRJNA673055) can be accessed under accession numbers SRR12927887, SRR12927888, SRR12927889, SRR12927890, and SRR12927891.The sequences were deposited in GISAID with the codes EPI_ISL_593772, EPI_ISL_593773, EPI_ISL_593774, EPI_ISL_593775, and EPI_ISL_593776. Assembled genomic sequences were deposited in GenBank under accession numbers"}
+{"text": "Primary: Change in Systolic BP at Month 1; change in percent with controlled blood pressure. Secondary: change in validated measures of cognitive , behavioral (Home BP monitoring), nutritional (food frequency) variables, satisfaction, costs. RESULTS/ANTICIPATED RESULTS: Menu alignment required multiple iterations. Plate Waste and Menu Satisfaction tools were developed. Site 1 enrollment began June 2019; educational sessions and home BP monitors and training were provided. Baseline mean blood pressure (Site 1) was 138/79 +20.5; . DASH-aligned meals began October 2019; Meal satisfaction declined briefly, chefs adjusted menus, and meal satisfaction rose to pre-intervention levels. Site 2 enrollment is ongoing; dietary intervention will start in 2020. Primary outcome data (change in BP) will be complete in March 2020. Secondary outcome data on social and behavioral impact of the interventions will also be presented. DISCUSSION/SIGNIFICANCE OF IMPACT: We leveraged our community-academic research partnership to conduct research addressing uncontrolled hypertension, an urgent unmet health need among seniors. The DASH Implementation Study can inform the broader aging services and healthcare community of the potential for congregate nutrition programs to improve cardiovascular health outcomes.OBJECTIVES/GOALS: The Rockefeller University CCTS, Clinical Directors Network (CDN), and Carter Burden Network (CBN) received a DHHS-Administration for Community Living Nutrition Innovation grant to test whether implementation of DASH-concordant meals and a program to enhance self-efficacy, could lower blood pressure among seniors aging in place. METHODS/STUDY POPULATION: CEnR-Nav model to engage stakeholders, enroll seniors age >60 yr., eating 4 meals a week at 2 CBN congregate meal sites; Advisory Committee to facilitate dissemination; menus aligned with Dietary Approaches to Stop Hypertension (DASH) and New York City Department for the Aging (DFTA) nutritional guidelines; interactive sessions for education ; Omron 10 home BP devices for daily home monitoring. Plate Waste and Meal Satisfaction  to assess taste preference and cost impact. Outcomes:"}
+{"text": "COVID-19 disproportionately impacted older adults in terms of fatalities, but also increased stress, isolation, and loneliness . We examined older adults\u2019 anxiety, depression, and barriers to mental healthcare during the COVID-19 pandemic and their perceptions of these variables prior to the pandemic. Further, we explored whether any perceived changes differed based on geographical location . Data were collected online between mid-June and mid-July of 2020 from 244 individuals aged 65-82 years . The sample was primarily White (91%) and female (60%); most (n=119) lived in suburban settings, with 63 in urban and 60 in rural settings. Repeated-measures ANOVAs at alpha=.01 showed that depressive symptoms, measured by the CESD-10 (p<.001), and anxiety symptoms, measured by the GAD-7 (p<.001), increased during the pandemic as did mental healthcare barriers related to transportation (p=.004) and beliefs that depression is a normal part of aging (p<.001). Only transportation concerns differed based on where older adults lived; those in rural (p<.001) and urban (p=.004) settings reported greater transportation barriers than those in suburban settings. No differences over time were found for barriers related to help-seeking (p=.403), stigma (p=.156), knowledge/fear (p=.180), finding a therapist (p=.030), ageism (p=.302), psychotherapist qualifications (p=.265), physician referrals (p=.207), or finances (p=.818). These findings highlight the impact of COVID-19 on older adults\u2019 perceptions of changes in their psychological well-being as well as their experience navigating mental health services."}
+{"text": "Non-alcoholic fatty liver disease (NAFLD) and depression are common disorders and have bidirectional contributing relationships to metabolic syndrome. We aimed to determine whether a fasting serum signature of recent, self-reported depressive symptoms could be identified in a heterogeneous NAFLD cohort using nuclear magnetic resonance (NMR)-based metabolomics integrated with clinical chemistry. Serum nuclear magnetic resonance (NMR) metabolite profiles and corresponding clinical chemistry were compared between patients with depressive symptoms in the last 12-months (n = 81) and patients without recent depressive symptoms (n = 137 controls) using multivariate statistics. Orthogonal partial least squares discriminant analysis (OPLS-DA) of the biochemical and metabolomic data identified NAFLD patients with recent depression with a cross-validated accuracy of 61.5%, independent of age, sex, medication, and other comorbidities. This led to the development of a diagnostic algorithm with AUC 0.83 for future testing in larger clinical cohorts. Serum triglycerides, VLDL cholesterol, and the inflammatory biomarker GlycA were key metabolites increased in patients with recent depressive symptoms, while serum glutamine level was reduced. Here, serum NMR metabolite analysis provides a link between disturbed lipid metabolism, inflammation, and active mental health issues in NAFLD, irrespective of disease severity. With an estimated worldwide prevalence of one in four individuals, non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder  and has In this study, we performed serum nuclear magnetic resonance (NMR)-based metabolomics on 218 NAFLD patients. NMR allows for the measurement of lipoprotein particle concentration, as opposed to lipoprotein cholesterol content. Many other low-molecular-weight metabolites are also measured simultaneously that are beyond the resolution of standard serological lipid and biomarker panels, including factors involved in immunological and neurological pathways. We aimed to determine whether people with NAFLD and recent (<12 months) depressive symptoms could be distinguished from those without recent depressive symptoms based on clinical or metabolic biomarkers, with a view to gaining further insight into the links between depression and chronic metabolic dysfunction. Here, we report that NAFLD patients with or without recent depressive symptoms can be stratified based on differences in serum metabolite levels, irrespective of disease severity. This suggests that the depression associated with NAFLD is not simply a downstream consequence of NAFLD-induced alterations to the metabolite pool, but a discrete condition with additive metabolic sequelae.The study cohort comprised patients with NAFLD recruited from type 2 diabetes (T2DM) clinics and at-risk populations in primary care between October 2015 and August 2017, who had a fasting serum sample without freeze-thaw available for analysis n = 218). The clinical characteristics of the source population have been previously described  TCI cryoprobe  under parameters described previously , Kolmogorov-Smirnov test p<0.0001. C) OPLS-DA scores plot comparing lifetime/recent depression (N = 111) against NAFLD patients with no history of depression (N = 107). D) Corresponding mean accuracy of OPLS-DA models compared to null distribution, 50.3% [95%CI 49.8\u201350.7], Kolmogorov-Smirnov test p = 0.20.(TIF)Click here for additional data file.S3 FigA) Mean accuracy of OPLS-DA models (61.5% [CI 60.9\u201362.1]). 10-fold cross validation and permutation testing with 100 repetitions verified that the model was significantly better than random chance . N = 81 NAFLD patients with recent depression, N = 137 patients with no/lifetime depression. B) OPLS-DA scores plot coloured by recent (N = 81), lifetime (N = 30), and no history of depression (N = 107) illustrates that the serum metabolic and clinical profile of lifetime depression in non-alcoholic fatty liver disease is most similar to those with no history of depression, rather than those with recent depressive symptoms in the last 12 months. Ellipses show the 70% confidence interval for each patient group according to the key. RD, recent depression (<12 months); ND, no history of depression; LD, lifetime history of depression (>12 months ago).(TIF)Click here for additional data file.S4 FigA) scores plot and B) mean accuracy of serum metabolic and clinical chemistry data, showing modest discrimination between those with any history of depression  compared to those without (N = 107). Kolmogorov-Smirnov test, p<0.0001, accuracy 55.9% [95%CI 55.4\u201356.4].(TIF)Click here for additional data file.S5 FigA) The original orthogonal partial least squares discriminant analysis (OPLS-DA) scores plot coloured by age. N = 81 NAFLD patients with recent depression, N = 137 patients with no/lifetime depression. B) The OPLS-DA scores plot of a randomly selected, age-matched subset taken from the original NAFLD cohort showing similar accuracy, specificity, and slightly reduced sensitivity after age-matching recent depression (N = 70) with non-recent depression (N = 70). C) Receiver operating characteristic (ROC) curve showing AUC \u00b1 95% confidence intervals, based on the scores shown in B).(TIF)Click here for additional data file.S6 FigN = 81 NAFLD patients with recent depression, N = 137 patients with no/lifetime depression. Ellipses show the 70% confidence interval for females and males in the scores plot.(TIF)Click here for additional data file.S7 FigN = 81 NAFLD patients with recent depression, N = 137 patients with no/lifetime depression. Ellipses show the 70% confidence interval for patients on and off antidepressants in the scores plot.(TIF)Click here for additional data file.S1 Data(ZIP)Click here for additional data file."}
+{"text": "In 2017, the multiplex respiratory viral panel (RVP) test was the only test available for patients (pts) with respiratory symptoms in our emergency department (ED). In 2018, the more rapid influenza/respiratory syncytial virus (Flu/RSV) test was incorporated in a stratified testing algorithm (STA) \u2013 depending on clinical features and physician discretion, pts underwent either Flu/RSV or RVP. We analyzed the STA impact by comparing data between winters of 2017 and 2018.\u226518 years diagnosed with viral infections (by either test) were included. We excluded pts diagnosed at another hospital, admitted to intensive care or observation (< 24 hours) units and pts with missing data. Data was collected through electronic medical chart review.In a retrospective, single-center cohort study in suburban NY, admitted pts Primary outcomes were clinical evaluation time [time between triage and test order]; laboratory-turnaround (lta) time (between order and result); ED length of stay [EDLOS] (between admit order and bed assignment). Secondary outcomes included isolation time (between result to start of isolation precautions), treatment time (between result to influenza treatment). Outcome differences were assessed using Chi-Square and Mann-Whitney rank sum tests for categorical and continuous variables, respectively.[Table 1], with no significant differences in other parameters. Lta times were slightly higher after implementation [25 minutes (2017) v/s 29 minutes (2018)].734 pts were included in the study . Median age was 75 years and 55.9% were female. After implementing the STA, EDLOS was significantly lower Table 1. Differences in clinical and laboratory turnaround times among patients admitted with viral infections in winters of 2017 and 2018A stratified diagnostic algorithm may have reduced EDLOS, but without significant differences in other outcomes. A higher lta time might have been due to testing constraints, heterogeneous pt populations or other confounders. Prospective studies will help assess the real-world impact of such algorithms.Prashant Malhotra, MBBS, MD,FACP, FIDSA, Gilead Sciences"}
+{"text": "COVID-19 has inordinately affected assisted living (AL), such that the proportion of fatalities to cases has been 21% in AL versus 2.5% for the general population. Understanding how AL administrators and medical and mental health providers have responded to COVID-19 can inform health care going forward. Using a seven-state stratified random sample of 250 communities, administrators were interviewed and providers completed questionnaires regarding COVID-19 practices. Preliminary data indicate that 79%, 44%, and 62% of administrators reported serving meals in rooms to segregate residents, using telemedicine, and providing extra pay for staff, respectively. Perceived use/effectiveness of practices differed based on dementia case-mix . Providers reported less access to patients (82%), more telehealth (63%), and less ability to provide care (43%). However, they uniformly reported high confidence in AL staff ability to prevent (94%) and respond to outbreaks (96%). Discussion will summarize points important for future care."}
+{"text": "Pneumocystis jirovecii pneumonia and nocardiosis in immunocompromised patients but sometimes is avoided because of purported allergies or side effects. Of 25 immunocompromised patients receiving alternative prophylaxis in whom nocardiosis developed, 16 subsequently tolerated TMP/SMX treatment. Clinicians should consider TMP/SMX allergy evaluation and rechallenging to assess patient tolerance.Prophylactic trimethoprim/sulfamethoxazole (TMP/SMX) prevents  Pneumocystis jirovecii pneumonia (PJP) prophylaxis in immunocompromised patients  is the drug of choice for We conducted a retrospective chart review at Stanford Hospital  for patients with nocardiosis diagnosed during January 1, 1998\u2013January 28, 2020. We included patients avoiding TMP/SMX for PJP prophylaxis in whom nocardiosis was identified on culture or by molecular techniques, such as 16S rRNA PCR-based assay. We used Stanford Hospital\u2019s protocols for defining immunocompromised status requiring PJP prophylaxis. We collected baseline demographic, clinical, microbiological, and outcome information, including immunocompromising condition, PJP prophylaxis indication and agent, reason for TMP/SMX avoidance, and TMP/SMX rechallenge outcome, if performed. This study was approved by Stanford University\u2019s Institutional Review Board .During the study period, nocardiosis developed among 25 immunocompromised patients deliberately avoiding TMP/SMX. Most (68%) patients were female; median age of patients was 55 years. Among the 25 patients, 7 (28%) were lung transplant recipients, 6 (24%) had undergone allogeneic hematopoietic cell transplantation (HCT), 5 (20%) were heart transplant recipients, and 7 (28%) had other immunocompromising conditions (Appendix Table). At diagnosis, 15 (60%) patients were taking atovaquone, 4 (16%) inhaled pentamidine, 3 (12%) dapsone, and 3 (12%) no antimicrobial drug prophylaxis.Thirteen (52%) patients were not taking TMP/SMX because of a reported history of allergy, 6 because of concern for cytopenia (24%), and 3 because of elevated creatinine (12%). TMP/SMX was avoided in 1 patient for elevated transaminases, 1 for gastrointestinal intolerance, and 1 for unstated reasons. Among 10 patients with a TMP/SMX allergy label who attempted challenge or desensitization, 7 (70%) tolerated the drug; nonsevere rash developed in the other 3 patients. Among 10 patients avoiding TMP/SMX prophylaxis for nonallergy reasons, 9 (90%) tolerated TMP/SMX when rechallenged. Overall, TMP/SMX introduction was attempted in 20/25 patients; 80% successfully tolerated the drug, and 20% had mild, reversible adverse effects .In this retrospective case series, 16/25 (64%) patients who had nocardiosis while deliberately avoiding TMP/SMX prophylaxis ultimately were treated with TMP/SMX. Immunocompromised patients often are prescribed alternative drugs to TMP/SMX prophylaxis because of concerns over side effects or allergic reactions  cases occurred in patients receiving alternate PJP prophylaxis (Taken together, these findings suggest that rates of this highly pathological infection might be reduced by systematically reevaluating TMP/SMX avoidance and reconsidering prophylactic TMP/SMX. Consulting with an allergist can detect contraindications, such as severe cutaneous adverse reactions, and opportunities for challenge or desensitization. Patients with a history of maculopapular rash, cytopenia, or increased creatinine with TMP/SMX might tolerate reintroduction. Electronic medical records can be designed to prompt revisiting whether TMP/SMX avoidance is appropriate (The first limitation of our study is that we only included immunocompromised patients from a single healthcare system; our findings might not be generalizable to other settings. Second, some immunocompromised patients with nocardiosis possibly were not included in our cohort; although defining the incidence of nocardiosis would be informative, the intent of our study was to describe consequences of unnecessary TMP/SMX avoidance. Third, specifics of desensitization or graded challenge protocols were not consistently documented and thus might not be uniform.Despite these limitations, our study shows that most patients in whom nocardiosis developed while avoiding TMP/SMX prophylaxis later tolerated TMP/SMX treatment. Future research should prospectively evaluate the risks and benefits of TMP/SMX reintroduction in immunocompromised patients who have had a prior adverse reaction. In conclusion, our findings suggest that revisiting TMP/SMX avoidance could prevent nocardiosis cases. Pneumocystis prophylaxis.Additional information on nocardiosis in immunocompromised patients on alternative"}
+{"text": "TIFYs have been studied in many plants yet reports describing their molecular structure and function in wheat are lacking. In the present study, we have identified 23 novel TIFY genes in wheat genome using in silico approaches. The identified proteins were characterized based on their conserved domains and phylogenetically classified into nine subfamilies. Chromosomal localization of the identified TIFY genes showed arbitrary distribution. Forty cis-acting elements including phytohormone, stress and light receptive elements were detected in the upstream regions of TIFY genes. Seventeen wheat microRNAs targeted the identified wheat TIFY genes. Gene ontological studies revealed their major contribution in defense response and phytohormone signaling. Secondary structure of TIFY proteins displayed the characteristic alpha\u2013alpha\u2013beta fold. Synteny analyses indicated all wheat TIFY genes had orthologous sequences in sorghum, rice, maize, barley and Brachypodium indicating presence of similar TIFY domains in monocot plants. Six TIFY genes had been cloned from wheat genomic and cDNA. Sequence characterization revealed similar characteristics as the in silico identified novel TIFY genes. Tertiary structures predicted the active sites in these proteins to play critical roles in DNA binding. Expression profiling of TIFY genes showed their contribution during incompatible and compatible leaf rust infestation. TIFY genes were also highly expressed during the initial hours of phytohormone induced stress. This study furnishes fundamental information on characterization and putative functions of TIFY genes in wheat.The plant specific TIFY (previously known as ZIM) transcription factor (TF) family plays crucial roles in cross talk between Jasmonic Acid and other phytohormones like gibberellins, salicylic acid, abscisic acid, auxin, and ethylene signaling pathways. Wheat yield is severely affected by rust diseases and many abiotic stresses, where different phytohormone signaling pathways are involved.  TIFY TF gene family, previously known as ZIM (Zinc finger protein expressed in Inflorescence Meristem), constitute of four phylogenetic clusters: (i) TIFY ; (ii) JAZ (Jasmonate TIFY-domain); (iii) PPD (PEAPOD) and (iv) ZML  proteins2. The highly conserved TIFY domain consisting of 36 amino acids is the characteristics the TIFY subfamily1. The TIFY domain comprises of conserved motif variants like TII[F/Y]XG, TLV[F/Y]XG, TLF[F/Y]XG, TIS[F/Y]XG, TLS[F/Y]XG, TMF[F/Y]XG, TLL [F/Y]XG and VIF[F/Y]XG. Glycine in the core motif TIF[F/Y]XG is highly conserved while the other hydrophobic amino acids are variable. Secondary structures of the TIFY domain follows alpha-alpha\u2013beta fold arrangement. The JAZ subfamily orchestrates cross talks between Jasmonic Acid (JA) and other hormone signaling pathways, including auxins, gibberellins (GAs), abscisic acid (ABA), salicylic acid (SA), and ethylene (ET)4. This subfamily consists of a C-terminal conserved characteristic domain Jas (SLX2FX2KRX2RX5PY), which has sequence similarity to N-terminal of CCT domain6. The PPD subfamily consists of a unique PPD domain of about 50 amino acids at the N terminal. Additionally, a diverged Jas motif lacking the conserved amino acids PY is also present at the C-terminus6. Members of the ZML subfamily contain CCT domain, C2C2-GATA zinc finger domain, and the TIFY domain7.The plant-specific 9. JAs and their bioactive derivatives also control plant responses to abiotic stresses and exposure to ozone10. Over-expression of the AtTIFY1 gene in Arabidopsis helped in elongation of petioles and hypocotyls11, whereas AtTIFY4a (PPD1) and AtTIFY4b (PPD2) enhanced leaf growth by controlling lamina size and leaf curvature12. In Arabidopsis, TIFY genes negatively regulate the key transcriptional activator of JA responses13. Additionally, JA signals integrate with other plant hormone signals such as those produced by auxins, ABA, ETs, GAs and SA, thereby modify diverse plant defense responses14. Coronatine, a bacterial phytotoxin is a structural and functional analogue to (+)-7-iso-Jasmonoyl-L-isoleucine (JA-Ile), the biologically active form of Jas; the Jas domain perceives JA-Ile and represses JA signaling pathway15.Jasmonates are fatty acid-derived hormone molecules that regulate many plant physiological and stress-related processes like senescence, root growth, fruit maturing, wounding and pathogenesisBrassica oleracea were activated in response to Methyl Jasmonate (MeJa) but downregulated after SA/ET treatment or differentially modulated after Fusarium oxysporum infection16. Most TIFY genes belonging to the JAZ subfamily were activated in response to JA, salt and drought stress in watermelon17. Different JAZ subfamily genes displayed different levels of expression in the three cultivated cotton species Gossypium hirsutum, G. barbadense and G. arboretum in retort to Verticillium wilt due to Verticillium dahliae infection18. The JAZ genes also exhibited distinct expression patterns in the cotton seedlings treated with JA, MeJA, GA and ABA indicating their specific response to phytohormone signals in cultivated cotton species. The JAZ genes in tomato differentially responded to salinity and osmotic stress as well as were strongly induced in leaves and roots by JA and ABA19. So far, 18 TIFY genes had been identified in Arabidopsis1, 20 in rice20, 21 in Brachypodium distachyon21, 50 in Gossypium hirsutum, 54 in G. barbadense, 28 in G. arboretum18, 24 in Populus tricocarpa21, 20 in tomato19, 15 in watermelon17 and 36 in Brassica oleracea16 through bioinformatics-based approaches. Most of these identified TIFY genes, excepting Arabidopsis and rice, are not annotated. However, the discovery and functional annotation of this gene family in wheat is still limited.Many TIFY proteins belonging to JAZ subfamily in Triticum aestivum L.) is one of the most important cereal crops in terms of both cultivated area (~\u2009215 mha) and grain acreage (~\u2009765 million mt) in the crop year 2019\u20132020 worldwide (www.fao.org). In nature, most crop plants are exposed to multiple stress conditions either simultaneously or sequentially rather than by a single biotic or abiotic stress. Numerous biotic as well as abiotic stresses cause significant losses in wheat yield and reduce grain quality. Of the biotic stresses, the rust diseases, particularly the leaf rust, caused by the obligate biotrophic basidiomycetous fungi Puccinia triticina Eriks., is most prominent and occurs widely23. The disease is difficult to control as the pathogen continually develops new virulence profiles with high adaptability to wide agroclimatic conditions24. Among the abiotic stresses, drought, salinity, heat and waterlogging severely affect wheat production. The allohexaploid wheat genome  originated from three closely related progenitor species, inflicted major challenges for molecular and functional genomics-based improvements25. A low (5\u2009\u00d7) coverage26 and of late a chromosome arm based high-quality reference genome sequence of wheat27 became available that provides the opportunity to study gene structures and regulatory functional networks in wheat. Availability of the genome sequences of two progenitors of hexaploid wheat, Triticum urartu and Aegilops tauschii, also unlocked sub-genome level exploration of wheat genes29.Wheat , Sorghum bicolor (06) and Arabidopsis thaliana (18), were retrieved from Plant TFDB  followed by alpha numeric credential from TaTIFY1 to TaTIFY23 . Four genes belonged to TIFY11A  and three genes belonged to each TIFY11E  and TIFY3 . All these proteins had been characterized as salt and dehydration stress responsive genes in rice. Two genes belonged each to TIFY10C , TIFY6A , TIFY5A  and TIFY11C , while one gene TaTIFY4 belonged to TIFY11C. Details of TaTIFY subclass distribution is provided in Table MSA of the 23 identified TaTIFY sequences  had also been identified. Box W1, a fungal inducer receptive element along with other stress receptive elements  had also been identified that might have important roles in biotic stress. Several light responsive elements  and anaerobic induction motifs  were recognized. Cis-acting elements related with endosperm expression, seed germination and meristem were also detected.PlantCARE database revealed 40 TIFY genes  were found to target the identified wheat The physico-chemical characterization of 23 TIFY proteins are provided in Supplementary Table Analysis of catalytic domains revealed 17 different motifs  had been identified: monopartite (single stretch of basic amino acids) and bipartite (two stretches of basic amino acids)  to be localized outside nucleus in organelles and the remaining 11 proteins were localized within nucleus as well as in cytoplasmic organelles , TM-score , RMSD (Root Mean Square Deviation), cluster density and was subjected to internal evaluation of self-consistency tests. Tertiary structure of TaTIFY1 is provided in Fig.\u00a0The stereo-chemical quality and reliability of predicted TaTIFY models were validated by subjecting the PDB files to PROCHECK and PDBsum server  located on chromosome 2DS in wheat were found to be located on chromosome 1 of Brachypodium, 7 of rice, 2 of barley, chromosomes 1 and 2 of sorghum, and chromosome 1, 2 and 7 of maize respectively. The crucial point is that all four TIFY genes are located on a single chromosome of rice, barley and Brachypodium while on more than one chromosome of sorghum and maize. Thus, it can be inferred that these four TaTIFY genes are highly conserved in rice, barley and Brachypodium in comparison to the other two species. TaTIFY genes  located on chromosome 2BL in wheat were distributed on chromosome 2 of barley and different chromosomes of the other monocot species  displayed orthologous relationships , a gibberellin receptor. Functional partners for binding included B3 DNA binding domain, bZIP TF, helix loop helix DNA binding domain which were mainly involved in inactivation of GID2. Gene occurrence studies revealed the organisms in which these proteins were highly conserved since functional partners often have similar occurrence pattern. These proteins were highly conserved in Streptophyta which included green plants comprising charophyceae  and embryophyta (land plants) . During incompatible interaction, expression was highly induced from 6 hpi onwards. The period of maximum expression at 12, 24 and 48 hpi related to the phase of propagation and spread of secondary hyphae to adjacent cells. At 72 hpi surface mature appressoria collapses and intercellular ramification of secondary infection hyphae starts. To check the movement of infection to adjoining cells, high level expression persists till 168 hpi to prevent the expansion of SSVs in neighboring cells. While susceptible plants displayed much reduced expression. Negligible changes in expression profiles in mock inoculated susceptible and resistant plants were found due to absence of pathogen pressure.Reduced expression of most TIFY genes were evaluated using \u2206Ct values at p\u2009\u2265\u20090.01  and JA (189-fold) for TIFY9 followed by JA (176-fold) and MJ (129-fold) for TIFY20. Their expression decreased after 12\u00a0h. It can be inferred that different TIFY genes respond differently to different phytohormones and the response was mediated through JA pathway since maximum expression was observed during JA and MJ treatment followed by SA.QRT-PCR was also performed for ses Fig.\u00a0. Most TITIFY genes expression during different phytohormone treatments and was assessed using \u2206Ct values  measures the strength of association between two ranked variables accepting values from +\u20091 to \u2212\u20091. A rs of +\u20091 indicates a perfect association of ranks, a rs of zero indicates no association between ranks and a rs of \u2212\u20091 indicates a perfect negative association of ranks. Highest correlation was found in TIFY5 ; TIFY3 also showed high correlation  domain characterizes JAZ proteins. This domain interacts with MYC2, a bHLH transcription factor, to inhibit JA response together with TIFY domain6. TaTIFY genes were classified into nine different sub-families which were involved in stress responses in rice and Arabidopsis. As genes with sequence similarities generally have similar functions across different species, so the identified TIFY genes could be predicted to have similar functions in wheat also. Thus, construction of the phylogenetic tree of TIFY genes among different species provided plausible functions of the newly identified TIFY TF proteins in wheat.In this study, a total of 92 TIFY genes had been initially identified, of which 23 genes had complete ORF containing the TIFY domain. Since limited resources of 35. Although it cannot be proclaimed with high accuracy, certainly gene duplications had played important roles leading to series of genomic rearrangements and expansion of this gene family among the different monocot species as manifested by synteny analysis. Shared synteny denotes the genomic fragments in different species had originated from identical ancestor36. With well-defined synteny relationships between well studied genomes  and newly sequenced genomes like T. aestivum provide knowledge on differentiation of the less-studied gene family like TIFY after species divergence. More importantly, it helps improve the gene annotation of newly sequenced genomes.Chromosomal synteny is important in genome comparison to reveal genomic evolution of related speciesTIFY TFs in wheat built on P. triticina induced biotic stress response analysis  were downloaded from Plant Transcription Factor Database . The wheat genomic sequences (https://www.wheatgenome.org/Tools-and-Resources/IWGSC-RefSeq-v2.0) were obtained from Ensembl Plants (https://plants.ensembl.org/Triticum_aestivum/) and translated into six reading frames using EMBOSS version 6.6.0.0. (ftp://emboss.open-bio.org/pub/EMBOSS/). The retrieved TIFY protein sequences were used for similarity search with the translated wheat genomic sequences using TBLASTN with an e-value cutoff of 10 to predict the TIFY sequences in wheat43. The redundant sequences were removed using CD-HIT (http://weizhongli-lab.org/cd-hit/) and the remaining sequences displaying complete ORF were further examined for TIFY domain using the Hidden Markov Model (HMM) of Simple Modular Architecture Research Tool  and Pfam (http://pfam.sanger.ac.uk/). A pipeline designed is shown in Supplementary Figure To identify sequences belonging to Arabidopsis, we performed sequence based phylogenetic analysis using Clustal X 2.044 and CLC Genomics Workbench 11.0 (https://www.qiagenbioinformatics.com/) at default settings. Another phylogenetic tree based on representative TIFY domains was constructed using MEGA 7.0 and Neighbor Joining method45. Bootstrap values were calculated from 1000 iterations.To elucidate the phylogenetic relationships of TIFY family of wheat with those of rice and TIFY genes were carried out using ProtParam tool (http://web.expasy.org/protparam/). The gene structure of the identified TFs was studied using two HMM-based most accurate gene prediction tools: FGENESH (http://linux1.softberry.com/) and GenSCan (http://genes.mit.edu/GenSCan.html). N- and O-glycosylation potential sites were predicted by NetNGlyc 1.0 and NetOGlyc 1.0 Server (http://www.cbs.dtu.dk) respectively. Different catalytic domains and Nuclear localization signals (NLS) were determined using Motif Scan (https://www.ncbi.nlm.nih.gov/Structure/cdd/cdd.shtml) and NLStradamus software (http://www.moseslab.csb.utoronto.ca/NLStradamus/) respectively.The physico-chemical characterization of the identified novel http://meme-suite.org/). The parameters used were minimum width 3, maximum width 50 and the maximum number of motifs to identify any number of repetitions. The subcellular localization and secondary structures of these sequences were predicted by WoLF PSORT (http://wolfpsort.org/) and PSIPRED Protein Analysis Workbench (http://bioinf.cs.ucl.ac.uk/) respectively. Transmembrane domains and pore lining helices were identified using MEMSAT-SVM tool at PSIPRED that utilizes support vector machine algorithm.To identify presence of additional conserved motifs, Multiple Expectation Maximization for Motif Elicitation (MEME) version 5.1.1 was used . Further, all identified TIFY genes were searched as target genes for conserved and novel wheat microRNAs available at miRBase, release 21 with psRNATarget tool (http://plantgm.noble.org/psRNATarget/) using an E-value cut off 3 for filtering microRNAs because low E-value specifies high resemblance between small RNAs and target genes.46 server based on ab initio methods for structure prediction. Five different models for each TaTIFY protein were generated and the model showing overall best stereo-chemical quality was selected for further assessment. The SAVES (http://services.mbi.ucla.edu/SAVES/) server was used to examine stereo-chemical properties of protein structure and ProSA-web server (http://prosa.services.came.sbg.ac.at/prosa.php) to calculate overall quality score to select the most reliable model. The 3D models were subjected to PyMOL Molecular Graphics System (http://pymol.org/ep) to obtain the final structures. The PDB files of the modeled TaTIFY proteins were subjected to PDBsum server (http://www.ebi.ac.uk/thorntonsrv/databases/pdbsum/Generate.html) for structural motif analysis and to ProSA-web server for obtaining the reliable values for the model generated. The final models were subjected to DoGSiteScorer  to identify the probable binding sites.Tertiary structures were predicted at I-TASSERTaTIFY genes, Blast2GO47 program was used to BLAST against annot8r databases that stores UniProt entries with their associated Gene Ontologies (GO), Enzyme Commission (EC) and Kyoto Encyclopedia of Genes and Genomes (KEGG) annotations (http://www.nematodes.org/bioinformatics/annot8r/). The Web Gene Ontology Annotation Plot  online tool was used to perform GO enrichment analysis of identified TaTIFY genes.To assign putative functions to the identified TaTIFY gene was mapped on wheat chromosomes using BLAST tool at UR INRA \"G\u00e9nomique Info\" , database selecting all wheat chromosomes with an e-value cutoff of 0.001 and identity\u2009>\u200980%. The identified TaTIFY genes were also mapped to rice, sorghum, maize, barley and Brachypodium genomes using Ensembl Plant Database by selecting e-value 0.001 as cutoff criteria48. Multiple genome comparison between the selected pairs of chromosomal regions containing TaTIFY genes was performed for synteny analysis using identified orthologous and paralogous genes of the selected species. The syntenic relationships were visualized using the online Circos tool49.Each identified Lr28 was isolated using DNeasy Plant Mini Kit (Qiagen). DNA amplifications were conducted in 20 \u00b5L volumes containing 100\u00a0ng of genomic DNA and 10\u00a0pM of each primer  were used. The Lr28 gene, effective against all pathotypes of the pathogen in India, was derived from Aegilops speltoides (Teusch) and introgressed on the long arm of chromosome 4AL52. Puccinia triticina pathotype 77\u20135, the most predominant and devastating pathotype in all parts of the Indian subcontinent, was selected as experimental pathogen. Experiments were conducted at the National Phytotron Facility, IARI, New Delhi and seedlings of the isogenic lines were inoculated with either urediniospores of race 77\u20135 mixed with talc (1:1) or mock inoculated with talc. Leaf samples were collected at different time points for RNA isolation: 0\u00a0h (i.e. just before inoculation) and at 6, 12, 24, 48, 72- and 168-h post inoculation (hpi) from five independently treated susceptible and resistant NILs. The collected samples (three leaves from each plant) were immediately frozen in liquid Nitrogen and used for RNA isolation. Susceptible mock inoculated was named S-M, Susceptible Pathogen inoculated as S-PI, Resistant mock inoculated R-M and Resistant Pathogen inoculated as R-PI.Wheat near-isogenic lines (NILs) HD2329  and HD2329\u2009+\u2009\u22122\u00a0s\u22121 and 10\u00a0h of darkness). The pots were watered well regularly. The test seedlings were sprayed with respective phytohormones, while control plants were sprayed with only milli-Q water having no phytohormone. Leaf samples for RNA isolation were collected at 0, 1, 2, 4, 8, 12 and 24\u00a0h post phytohormone application. The collected samples (five leaves from each set) were immediately used for RNA isolation.The wheat cultivar Chinese Spring was used for the abiotic stress study. Four different phytohormones  at concentration of 5\u00a0mM were used for abiotic stress treatments. The samples were divided in two groups: control: 4 plants and treated: 7 plants for each treatment. Treatments were performed in duplicates. Seeds were germinated on autoclaved composite soil containing peat, sand and soil (2:1:1 ratio), grown to three leaf stage (~\u200914\u00a0days after germination) at the Green House facility, BIT, Mesra, Ranchi under ideal conditions (temperature 20\u00a0\u00b0C, relative humidity 80%, 14\u00a0h light at 100\u00a0\u00b5mol\u00a0m53 and gene expression levels were computed using the 2\u2212\u2206\u2206Ct method54.Primers used for qRT-PCR are mentioned in Supplementary Table The qRT-PCR data were statistically analyzed using Wilcoxon signed rank sum test to compare expression data from infected and mock-inoculated materials while, Spearman's correlation was used to compare expression data from phytohormone treated and control plants.Supplementary Information"}
+{"text": "There is a lack of data specifically addressing the effects of triple therapy consisting of baricitinib plus remdesivir plus dexamethasone compared to dual therapy with remdesivir plus dexamethasone among patients with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pneumonia. This retrospective study enrolled hospitalized adults with SARS-CoV-2 receiving supplemental oxygen without invasive mechanical ventilation (IMV) being treated baricitinib (\u226410 days) plus remdesivir (\u226410 days) plus dexamethasone (\u226410 days) or remdesivir (\u226410 days) plus dexamethasone (\u226410 days). The primary endpoint was 28-day mortality. Secondary objectives of this study were to measure progression to IMV, pulse oximetry (SpO2)/fraction of inspired oxygen (FiO2) from hospitalization to discharge, hospital length of stay (LOS), 14-day mortality, 14-day hospital readmissions, inflammatory markers, and safety outcomes.Among patients receiving supplemental oxygen without IMV, 28-day mortality for triple therapy vs. dual therapy was 20% and 24%, respectively (P=1.000). The effect of triple therapy compared to dual therapy on lung function was demonstrated by a 76% vs. 25% increase in SpO2/FiO2. This benefit must be contextualized by an increased progression to IMV among patients receiving triple therapy compared to dual therapy . The increased incidence of IMV translated to a significantly longer hospital LOS among patients receiving triple therapy compared to dual therapy .In patients receiving supplemental oxygen without IMV for SARS-CoV-2, triple therapy was not associated with a clinically meaningful reduction in 28-day mortality when compared to dual therapy. All Authors: No reported disclosures"}
+{"text": "Geminiviridae includes viruses with mono- or bipartite single-stranded, circular DNA genomes of 2.5\u20135.2 kb. They cause economically important diseases in most tropical and subtropical regions of the world. Geminiviruses infect dicot and monocot plants and are transmitted by insect vectors. DNA satellites are associated with some geminiviruses. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family Geminiviridae which is available at ictv.global/report/geminiviridae.The family  Mastrevirus), virions are 22\u00d738 nm, consisting of two incomplete icosahedra (T=1) containing 110 capsid protein (CP) subunits organized as 22 pentameric capsomers (Begomovirus) at 3.3 \u00c5 resolution shows that the N-terminus of CP adopts three different conformations essential for building the interface between geminate halves (Geminiviruses have a unique particle morphology of twinned (geminate) icosahedra. For maize streak virus . DNA satellites are associated with many begomoviruses and some mastreviruses [Viruses in most genera of the family have monopartite genomes, whereas those in the genus oviruses  consist oviruses  resembleeviruses .Complementary-sense DNA synthesis to produce dsDNA depends solely on host factors. Virus ssDNA synthesis is initiated by cleavage of the virion-sense strand by Rep in the 5\u2032-TAATATTAC-3\u2032 sequence conserved in most geminiviruses within the intergenic region (IR)/ long intergenic region (LIR). Geminiviruses do not encode a DNA polymerase, relying on host factors recruited during the early stages of replication. Coding regions in both strands diverge from the IR/LIR, and transcription is bi-directional. Geminiviruses use multiple overlapping transcripts for gene expression . The begictv.global/taxonomy. The family includes multiple genera collectively including >500 species, the most diverse genera being Begomovirus (>440 species) and Mastrevirus (>40 species). Host are dicots except for maldoviruses and mastreviruses (dicots and monocots) and eragroviruses (monocots). Vectors are whiteflies (begomoviruses), aphids (capulaviruses), treehoppers , leafhoppers , or unknown .Current taxonomy: Geminiviridae: ictv.global/report/geminiviridae.Full ICTV Report on the family"}
+{"text": "Norovirus (NV) gastroenteritis has been identified as a cause of significant morbidity among hematopoietic stem cell transplant (HSCT) recipients, often with associated complications. Current guidelines recommend symptomatic relief with antimotility agents, rehydration, and reduction in immune suppression. Nitazoxanide (NTZ) is an anti-parasitic agent but some literature suggests a benefit of nitazoxanide therapy for NV. We conducted a single center, retrospective chart review study and evaluated adult patients (age >18 years) who had NV infection and either: 1) underwent stem cell transplantation; or 2) received myeloablative chemotherapy within 4 weeks of NV diagnosis by positive test on gastrointestinal pathogen panel during the time period from January 2015 through March 2020. 26 patients were reviewed. 14 patients (54%) had a history of HCST prior to infection. Three patients (12%) received both myeloablative chemotherapy and HSCT within four weeks of NV infection. Six patients (46%) had autologous, six (46%) had matched unrelated donor, and one (8%) had haploidentical allogeneic transplants. Nine (69%), three (23%), and one (8%) underwent myeloablative, reduced intensity and non-myeloablative conditioning, respectively. Median duration of diarrhea was 4.5 days (IQR = 2.25-7 days). Three (12%) patients received NTZ or intravenous immune globulin. The 6 month mortality was 42% (11/26), however, none of the deaths were directly attributable to NV infection.NV infection led to severe diarrheal disease in our cohort. Overall mortality was high, and a trend toward increased mortality was seen among patients receiving NV-directed therapy; these patients likely received NV-directed therapy due to the severity of their illness. Clinicians must have a high suspicion for this illness and obtain PCR testing for timely diagnosis and management.Table 1. Characteristics of patients with hematologic malignancies and norovirus infectionAll Authors: No reported disclosures"}
+{"text": "Anxiety disorders among pediatric burn survivors have been shown to be common in both the acute care and outpatient settings. However, there is a paucity of research regarding parental awareness of psychological issues affecting burn-injured Dallas & adolescents. This study examined the relationship between burn-injured youths\u2019 self-reported anxiety levels, as compared to their parent\u2019s perceptions.Parents of burn injured Dallas were invited to complete the Parent Version of the 41-item survey, Screen for Child Anxiety Related Disorders (SCARED) which consists of five anxiety sub-scales as well as a Total Anxiety Score. Their Dallas also voluntarily complete the Child Version. A higher score indicates greater anxiety.s =.20, p >0.25), indicating virtually no association between the two.Forty-five parent-child dyads, with girls (51%) and boys (49%), completed surveys Ethnicity was reported as Caucasian (36%) Hispanic (42%) African Am (18%). Mothers (78%) fathers (18%) grandmothers (2%) & guardian (2%) participated. Mean parent age was 39. Child mean age was 13. Burn scars were visible in 64% of Dallas. Matched-pairs t-tests were used to compare parent and child scores. Parents reported lower SCARED Total Anxiety scores (mean=10.52) than youth (21.06), p< 0.001. Parents also reported significantly lower scores on the Panic Disorder/ Somatic Symptoms (p< 0.001), Generalized Anxiety Disorder (p=.004), Separation Anxiety (p< 0.001), and School Avoidance subscale (p< 0.001). For the Separation Anxiety scale, 23 youth\u2019s self-report exceeded the threshold for suspected disorder, while parent report classified only 3 with separation anxiety. Spearman correlations between parent and youth scale scores yielded no significant results (all less than rResults reveal a lack of parental awareness of their child\u2019s anxiety disorder symptomology. This lack of recognition is of concern because Dallas are dependent on their parents/caregivers to identify psychopathologies and to help them seek services for mental health challenges."}
+{"text": "Our analysis supports a critical role for the metalloprotease Adamdec1 at the interface between tissue remodeling and healing during colitis, demonstrating its requirement for colon epithelial integrity. These findings provide mechanistic insight into how inflammation perturbs stromal cell behaviors to drive fibroblastic responses controlling mucosal matrix remodeling and healing.Chronic inflammation is often associated with the development of tissue fibrosis, but how mesenchymal cell responses dictate pathological fibrosis versus resolution and healing remains unclear. Defining stromal heterogeneity and identifying molecular circuits driving extracellular matrix deposition and remodeling stands to illuminate the relationship between inflammation, fibrosis, and healing. We performed single-cell RNA-sequencing of colon-derived stromal cells and identified distinct classes of fibroblasts with gene signatures that are differentially regulated by chronic inflammation, including IL-11\u2013producing inflammatory fibroblasts. We further identify a transcriptional program associated with  Fibroblasts are essential components of parenchymal tissues, providing the framework that is necessary for tissue structure. However, emerging evidence has revealed critical functions for fibroblast cells that extend beyond their traditional roles as structural scaffolds, including roles in regulating cell survival, differentiation, and migration \u20133.This concept is exemplified in the gut, where fibroblasts have been shown to support mucosal crypt architecture, extracellular matrix (ECM) remodeling, and immune fitness \u20136. By seThe gastrointestinal tract represents a potential vantage point to study fibroblast-imposed immunoregulation, as it constitutes the largest reservoir of immune cells within the human body, ensuring protection from pathogenic infections while promoting mucosal tolerance against commensal microbes. Recent studies have provided foundational insights into how fibroblasts mediate immune activation and inflammation, thus expanding their roles in tissue homeostasis ,11. InteThe coexistence of distinct subsets of fibroblasts is thought to account for their pleiotropic properties in supporting gut homeostasis and disease pathogenesis. Uncovering the heterogeneity of fibroblasts, however, has been hindered by a dearth of molecular tools available for experimental assessment, including molecular markers and transgenic mouse models. Recent advances in technologies such as single-cell RNA-sequencing (scRNA-seq) now permit the survey of stromal cell heterogeneity across organs \u201321.Here, we employed orthogonal technologies, including next generation sequencing of mucosa-associated stroma to survey cellular heterogeneity in the colon. We identified phenotypic and functionally divergent fibroblast populations in mucosal tissues of the gastrointestinal tract and uncovered molecular circuitries governing inflammation and ECM remodeling during colitis, identifying a key role for Adamdec1 in mucosal matrix remodeling and healing.Fig 1A, S1A and S1B Fig). Strikingly, ECM deposition was also documented using high-resolution tissue scanning confocal microscopy , showing alterations in the structural network of reticular fibers, as stained with ER-TR7. ECM protein deposition was similarly increased in mucosal and submucosal tissues of DSS-treated mice, together with muscularis thickening, therefore supporting the notion that chronic DSS treatment can be used to model fibroblast-mediated tissue remodeling in mice.To better understand the cellular and molecular circuitries operating during inflammation, ECM remodeling, and wound healing in the intestine, we implemented a murine model of colonic inflammation based on oral administration of multiple cycles of low-dose dextran sulfate sodium (DSS) to induce epithelial injury and ECM deposition ,23. MiceFig 1C). We collected colons from water- and DSS-treated mice, prepared single-cell suspensions from the lamina propria by adapting a protocol that we have previously optimized to extract stromal cells from various organs  16]. Cell(TIF)Click here for additional data file.S5 FigMethods). DEG, differentially expressed gene; DSS, dextran sulfate sodium; FDR, false discovery rate; IstF, interstitial fibroblast; MAF, mucosa-associated fibroblast; MyoF, myofibroblast.Heatmaps of select DEGs between water- and DSS-treated samples for all fibroblast clusters. Color represents normalized gene expression. Significant DEGs had FDR <0.05 using MAST (see (TIF)Click here for additional data file.S6 FigHeatmap of estimated interaction scores based on L\u2013R pair expression between sender cell type MAF3 (IAFs) and receiver cell types: endothelial cell subsets (A) and fibroblast subsets (B). Interaction scores were computed separately for water-treated and DSS-treated mice. Heatmap displays L\u2013R pairs that are differentially expressed between water-treated and DSS-treated mice; for example, ligands that are up-regulated in DSS in MAF3 and receptors that are up-regulated in receiving endothelial subsets (A) or other fibroblast subsets (B). DSS, dextran sulfate sodium; IAF, inflammation-associated fibroblast; L\u2013R, ligand\u2013receptor; MAF, mucosa-associated fibroblast; MyoF, myofibroblast.(TIF)Click here for additional data file.S7 Fig(A) Average expression levels of top 10 genes enriched for expression in the gastrointestinal tissues and also differentially expressed in water- and DSS-treated conditions. Color represents average expression of marker genes across all stromal cell subsets; diameter represents percentage expression of marker genes. (B) Average expression of top 10 genes enriched for expression in the gastrointestinal tract and also differentially expressed in water- and DSS-treated conditions stratified by annotated stromal cell subsets. Color represents average expression of marker gene in each cluster; diameter represents percentage expression of marker gene within cluster. (C) Column scaled average transcript levels of GI tract\u2013enriched genes in several human tissues profiled in the Human Protein Atlas study by Uhlen and colleagues. DEG, differentially expressed gene; DSS, dextran sulfate sodium; GI, gastrointestinal.(TIF)Click here for additional data file.S8 Fig(A) UMAP projections of dimensionality reduction analysis on the subset of MAF and MyoF cells used for the construction of differentiation trajectory overlaid by their lineage subset labels. (B) Visualization of top 2 diffusion components (DC1) from diffusion map analysis of the subset of MAF and MyoF cells overlaid by their lineage subset labels. (C) Diffusion pseudotime reconstruction of the differentiation trajectory from MAFs to MyoFs. MAF, mucosa-associated fibroblast; MyoF, myofibroblast; UMAP, uniform manifold approximation and projection.(TIF)Click here for additional data file.S9 Fig2O subsequently, and killed on day 11, 13, or 24. HE staining (A) of representative images of colon following DSS in WT and Adamdec1 KO mice. Scale bar, 600 \u03bcm. Immunohistochemistry was performed for CD3 (B) and F4/80 (C) on day 11 or 13 after administration of DSS. Scale bars, 600 \u03bcm and 200 \u03bcm. Representative images, n = 2 per mice per genotype and time point. DSS, dextran sulfate sodium; HE, hematoxylin\u2013eosin; KO, knockout; WT, wild-type.Mice were administered 2% DSS for 7 days, H(TIF)Click here for additional data file.S10 FigAdamdec1 KO and WT mice with the indicated markers. Mice were administered 2% DSS for 7 days and killed on day 7. (A) Indicated ECM component (white). Scale bar, 200 \u03bcm. n = 3 per cohort, raw images representative of 2 experiments. (B) Quantification of indicated ECM components by % area. n = 3 mice per cohort. See IF imaging was performed on colons from (TIF)Click here for additional data file.S1 TableDEG, differentially expressed gene; DSS, dextran sulfate sodium.(XLSX)Click here for additional data file.S2 TableDEG, differentially expressed gene; DSS, dextran sulfate sodium.(XLSX)Click here for additional data file.S3 TableDEG, differentially expressed gene; DSS, dextran sulfate sodium.(XLSX)Click here for additional data file.S4 Table(XLSX)Click here for additional data file.S1 Data(XLSX)Click here for additional data file."}
+{"text": "OBJECTIVES/GOALS: Our overall objective is to develop a directly observable and reproducible method of enhanced blood flow through tumor vessels (i.e. dynamic control) at the time of systemic treatment delivery. Our central hypothesis is that the dynamic control of tumor vessels will improve (1) systemic drug delivery and (2) effector cell trafficking to target tumor. METHODS/STUDY POPULATION: B16 melanoma cells were inoculated into C57BL/6 (B6) mice  in both regional (hind leg) and systemic (flank) models. Dynamic control consisted of an IV saline bolus (500 ul) and phenylephrine (10 ug). Tumor vessel response was observed in real-time through window chambers using intravital microscopy (IVM). Dynamic control was combined with melphalan (20 mg/ml) either regionally (isolated limb perfusion) or systemically. Outcomes included tumor growth, survival, IHC, and toxicity. Dynamic control will be combined with adoptive transfer of effector T cells. B6 mice will be inoculated with B16/OVA (flank with window chamber) and treated with fluorescently labeled , OVA-specific CD8+ T cells from OT-1 transgenic mice. IVM, IHC, and flow cytometry will be used to measure T cell trafficking. RESULTS/ANTICIPATED RESULTS: Dynamic control (1) restored blood flow in non-functional tumor vessels and (2) increased and then transiently reversed blood flow in functional vessels. Vessel diameters did not change, suggesting that shunting of systemic blood to the tumor vasculature accounted for the observed changes. Dynamic control augmented tumor responses in our regional therapy model of melanoma. Increases in DNA adduct formation  detected by IHC, decreased tumor growth, and increased survival were observed with dynamic control. There was no increased limb toxicity. Similarly, dynamic control augmented responses in our systemic therapy model . We anticipate that dynamic control will improve trafficking of effector T cells in the next set of experiments. DISCUSSION/SIGNIFICANCE OF IMPACT: Heterogeneous responses to systemic therapies represent a major gap in current cancer treatment. An essential requirement for any effective therapy is its ability to reach tumor via the tumor-associated vasculature. We have therefore developed an approach to enhance drug delivery (dynamic control), which we also plan to test in clinical trials."}
+{"text": "Chronic calorie restriction (CR) without malnutrition delays the onset of aging, extends lifespan, and improves metabolic function in many species. These CR-induced benefits have largely concentrated on the role of insulin signaling, while ignoring its counter-regulatory hormone, glucagon. Like insulin, hyperglucagonemia and decreased glucagon sensitivity are associated with impaired glucose homeostasis and decreased longevity. Conversely, activation of target molecules downstream of glucagon signaling such as AMPK and FGF21 are known to ameliorate these age-related impairments in metabolic function. To investigate the potential role of glucagon receptor signaling in CR-induced improvements in aging, we have implemented a moderate 15% CR in the mouse. Our studies show that a 15% calorie restriction initiated at 4 months of age enhances hypoglycemia-stimulated glucagon secretion (P<.01) and decreases basal serum glucagon (P<.01), while having no effect on glucagon receptor expression at the liver in 26-month-old mice. Consistent with enhanced hepatic glucagon sensitivity, CR increases glucagon-stimulated hepatic cyclic AMP production (P<.05). Glucagon is a primary regulator of AMPK activation and FGF21 release, both of which have been proposed as key molecules to account for CR-induced benefits to aging. CR increases both hepatic AMPK activation (P<.05) and FGF21 mRNA expression (P<.05). Additionally, CR reduces hepatic lipid accumulation (P<.05), and decreases fasting respiratory quotient (P<.001), indicating an increase in lipid oxidation. Our studies demonstrate that a moderate (15%) CR regimen enhances glucagon sensitivity and decreases hepatic lipid accumulation in aged mice. Thus, we propose glucagon signaling as a mediator of CR-induced improvements in aging."}
+{"text": "The ABC risk score identifies patients at high-risk of mortality in acute lower and upper gastro-intestinal bleeding (UGIB).We aimed to externally validate the ABC score, while comparing it to other prognostication scales when assessing UGIB patients at high-risk of negative outcomes prior to endoscopy.UGIB patients from a national Canadian registry (REASON) were studied, with mortality prediction as primary outcome. Secondary endpoints included prognostication of rebleeding, intensive care unit (ICU) admission, ICU and hospitalization lengths of stay (LOS), and a previously proposed composite outcome measure. Univariable and areas under the Receiver Operating Characteristic Curve (AUROC) analyses compared discriminatory abilities of the ABC score to the AIMS65, Glasgow Blatchford (GBS) and clinical Rockall Scores.The REASON registry included 2020 patients . Overall mortality, rebleeding, ICU admission, transfusion and composite score rates were 9.9%, 11.4%, 21.1%, 69.0%, and 67.3% respectively. ICU and hospitalization LOS were 5.4 \u00b1 9.3 days and 9.1 \u00b1 11.5 days, respectively. The ABC score displayed superior 30-day mortality prediction ) compared to GBS  or clinical Rockall  but not AIMS65 ). Although most scales significantly prognosticated secondary outcomes in univariable analysis except for ICU LOS, discriminatory abilities on AUROC analyses were poor.ABC and AIMS65 display similar good prediction of mortality. Clinical usefulness in prognosticating secondary outcomes was modest for all scales, limiting their adoptions when informing early management of high-risk UGIB patients.International Scientific Partnership Program ISPP at King Saud University for funding this research work through ISPP-21\u2013156"}
+{"text": "Xanthomonas citri pv. citri pathotype A strains mostly originating from the Southwest Indian Ocean region, a subset of which was also sequenced using MinION technology. Some strains hosted chromosomally encoded transcription activator-like effector (TALE) genes, an atypical feature for this bacterium.High-quality Illumina assemblies were produced from 284  Xanthomonas citri pv. citri pathotype A strains mostly originating from the Southwest Indian Ocean region, a subset of which was also sequenced using MinION technology. Some strains hosted chromosomally encoded transcription activator-like effector (TALE) genes, an atypical feature for this bacterium.High-quality Illumina assemblies were produced from 284  Xanthomonas citri pv. citri pathotype A (XccA), from its native area (Asia)  area (210 strains out of 284). The SWIO region comprises several geographically distant and administratively distinct islands, representing a good setting to apprehend XccA genetic structure and accessory gene content. In this region, Asiatic citrus canker management is attempted through integrated strategies, including using copper-based pesticides. Copper resistance involving a conjugative plasmid hosting the copLAB system recently emerged in R\u00e9union, an outermost EU territory in the SWIO region  was extracted from bacterial colonies grown on yeast extract-peptone-glucose agar (YPGA) medium using the Promega Wizard kit. Illumina sequencing was performed by GATC Biotech on a HiSeq 4000 instrument (2\u2009\u00d7\u2009150-bp format) using the genomic Nextera XT protocol. Long-read Oxford Nanopore MinION sequencing was additionally performed on 13 selected strains from gDNA purified using the SQK-RBK004 library preparation kit on a single R9.4.1 flow cell using the manufacturer\u2019s instructions. Default parameters were used for all software unless otherwise specified. The Illumina reads were trimmed based on the quality score using Trimmomatic v. 0.36 with the options LEADING:15, TRAILING:15, SLIDINGWINDOW:4:20, and MINLEN:100  . This paa)  suggested as being circular by Canu. BLASTN searches identified the previously described copper resistance plasmid only in strains from R\u00e9union but not in those collected from other SWIO islands.All the strains sequenced herein contained contigs similar to plasmids previously described in XccA, transcription activator-like effector (TALE) genes, including pthA4, which is necessary for disease development, and other so-called minor TALE genes are primarily plasmid borne  from Texas  (The raw data are available under SRA accession numbers"}
+{"text": "A 40-year-old female, presented with complaints of severe headache since past five days. She is a known case of controlled hypertension. Multislice computed tomography (CT) angiography-brain arteries was done which revealed abnormal high attenuation lesions of blood Hounsfield units (HU), seen in the basal cisterns, suprasellar cisterns, right sylvian fissure and few cortical sulci of right cerebral hemisphere were suggestive of subarachnoid haemorrhage. It also revealed right Middle cerebral artery aneurysm measuring 1.13 x 1.02cm. Surgical management through aneurysm coiling and embolization was done."}
+{"text": "Remitting seronegative symmetrical synovitis with pitting edema syndrome (RS3PE) is a rare elderly onset rheumatic syndrome characterized by acute-onset symmetrical distal extremity edema. Here, we report a case of RS3PE accompanying bilateral pleural effusion.A 71-year-old woman presented to our hospital with a 2-week history of sudden bilateral chest pain onset. Physical examination revealed pitting edema in the dorsum of both hands  and tend"}
+{"text": "The accompanying prolonged antibiotic (AB) exposure likely contributes to chronic gut dysfunction and our ability to induce gut dysfunction in germ free (GF) mice colonized with microbiota from a patient with severe slow transit post CDI (PCDI) supports this notion (10.1093/jcag/gwz047.117). Furthermore, we were able to restore gut function following fecal microbial transfer from healthy murine donors. Our studies have implicated a role for macrophages in the destruction of the Interstitial Cell of Cajal (ICC) network underlying slow colonic transit in the humanized mouse model. These findings prompted us to evaluate microbiota-directed therapy in normalising gut function in this model.Recent evidence suggests an increasing prevalence of gut dysfunction following C. 1)To investigate whether dietary psyllium rescues the development of slow colonic transit (SCT) through modulating host function via microbiota mediated immune mechanisms; and 2)To evaluate the mechanisms underlying the beneficial effects of psylliumGF mice were colonized with either microbiota from the PCDI patient or healthy control (HC) for 3 weeks following which PCDI mice were treated with either a control diet or a 15% psyllium diet (PSY). Colonic motility was assessed before and after the diet intervention using the bead expulsion test. Stool samples were collected for microbial profiling, and short and branched-chain fatty acids (SCFA/BCFA) analysis. Colonic muscle layers encompassing myenteric plexus (MP) were collected for gene expression analysis and to evaluate activated macrophages and ICC degeneration using immunohistochemistry.Microbiota from a PCDI patient induced a SCT phenotype in GF mice (n=13) as compared to mice colonized with HC microbiota (p=0.0002). Psyllium rescued this SCT phenotype in mice (PCDI(n=7) vs.PSY(n=6):p=0.0014). The psyllium-induced rescue was accompanied by normalization of the ICC network and morphological alterations in infiltrating macrophages. This was supported by changes in immune-related gene expression in the MP including CD11b, NOS, Myd88, Mapk1 and NF-\u03baB. Additionally, bacterial composition was different between PCDI and PSY group (p=0.003). SCFAs like acetic and propionic acid were increased, while BCFA like isobutyric and isovaleric acid were decreased following PSY treatment. These alterations in SCFA/BCFA were supported by fluctuations in specific bacteria like Butyricimonas, Phascolarctobacterium and Allistipes.Our results provide evidence that chronic gut dysfunction following CDI and AB exposure is microbiota-driven. Furthermore, microbiota-directed therapy using psyllium could serve as a novel therapeutic strategy to normalize gut function via microbiota-mediated restoration of immune homeostasis in these patients.W. Garfield Weston Foundation"}
+{"text": "Staphylococcus aureus bacteremia (SAB). The clinical characteristics and outcome determinants of SAB in this population are poorly understood. We undertook a prospective cohort study compared the bacterial genotype and clinical outcomes of SAB among SOT and non-solid organ transplant (non-SOT) recipients. Solid organ transplant (SOT) recipients are characterized by extensive healthcare exposure and have high rates of S. aureus bloodstream isolate was genotyped using spa typing and assigned to clonal complexes using Ridom StaphType software. Consecutive patients presenting to our institution with SAB between January 1, 2016 and December 31, 2019 were eligible for study inclusion. Each subject\u2019s initial A total of 32 SOT and 634 non-SOT recipients with SAB were included. Bacterial genotype did not differ significantly between SOT and non-SOT recipients (p=0.4855), including the proportion of SAB caused by USA300 . Ninety-day mortality and incidence of metastatic complications did not significantly differ between SOT and non-SOT recipients . Transplant status was significantly associated with septic shock . Infection with USA300 was not associated with 90-day mortality or septic shock among SOT recipients (p=1.0000 for both). Staphylococcus aureus Genotype by Transplant StatusIn conclusion, SOT recipients with SAB do not experience greater mortality than non-SOT recipients. Differences in genotype of the infecting bacteria do not appear to be a significant determinant of outcome in SOT recipients with SAB. Vance G. Fowler, Jr., MD, MHS, Achaogen (Consultant)Advanced Liquid Logics (Grant/Research Support)Affinergy Affinium (Consultant)Akagera (Consultant)Allergan (Grant/Research Support)Amphliphi Biosciences (Consultant)Aridis (Consultant)Armata (Consultant)Basilea Bayer (Consultant)C3J (Consultant)Cerexa Contrafect Debiopharm Destiny (Consultant)Durata Genentech Green Cross Integrated Biotherapeutics (Consultant)Janssen Karius (Grant/Research Support)Locus (Grant/Research Support)Medical Biosurfaces (Grant/Research Support)Medicines Co. (Consultant)MedImmune Merck (Grant/Research Support)NIH (Grant/Research Support)Novadigm (Consultant)Novartis Pfizer (Grant/Research Support)Regeneron sepsis diagnostics Tetraphase (Consultant)Theravance Trius (Consultant)UpToDate Valanbio xBiotech (Consultant)"}
+{"text": "Scientific Reports 10.1038/s41598-021-81781-9, published online 19 February 2021Correction to: This Article contains errors.In the Results section under the subheading \u2018Differentially expressed genes may determine sexuality in castor flowers\u2019,\u201cDivergence of eight ACSs 1-aminocyclopropane1- carboxylate synthases) of castor genome are shown \u201dshould read:\u201cDivergence of nine ACSs (1-aminocyclopropane1- carboxylate synthases) of castor genome are shown \u201dAdditionally, this Article contains errors in the Acknowledgements section.Ricinus communis L.)\u201d\u201cWe are grateful to the Indian Council of Agricultural Research (ICAR), New Delhi, India for providing fnancial support to the institute project DOR-103-11 (PIMS No: IXX09329) \u2019Elucidating the olecular mechanisms governing sex expression in castor (should read:Ricinus communis L.)\u201d.\u201cWe are grateful to the Indian Council of Agricultural Research (ICAR), New Delhi, India for providing financial support to the institute project DOR 103-11 (PIMS No: IXX09329) 'Elucidating the molecular mechanisms governing sex expression in castor ("}
+{"text": "Here, we present PET images from an ACC patient with pulmonal, pleural metastases, and malignant pleural effusion, with comparable tracer uptake on 68Ga-PSMA-11 PET and 18F-FDG PET.Adenoid cystic carcinoma (ACC) is a rare cancer that arises from salivary glands and other secretory glands. Pulmonary metastases are frequently observed in ACC patients with metastatic disease. Previous research showed that ACC often shows high PSMA uptake on"}
+{"text": "Recurrent vulvovaginal candidiasis (RVVC) affects nearly 138 million women globally each year. Currently there are no FDA approved treatments. The study was conducted to evaluate the efficacy of oral oteseconazole (VT-1161) in the prevention of culture-verified acute VVC episodes through Week 50 and compare the efficacy of oteseconazole and fluconazole in treatment of an acute VVC episode in RVVC subjects.219 subjects with history of RVVC (\u2265 3 acute episodes within prior 12 months) were enrolled at 51 US sites. The study consisted of two phases.Candida were randomized to either:Induction Phase: Subjects who presented with a vulvovaginal signs and symptoms score of \u2265 3 and positive KOH test identifying \u2022 600 mg oteseconazole on Day 1, 450 mg oteseconazole on Day 2 and matching placebo capsules; OR\u2022 3 sequential 150 mg doses (every 72 hours) of over-encapsulated fluconazole together with matching placebo capsulesMaintenance Phase: 185 subjects with resolved acute VVC infections  on Day 14 received:\u2022 150 mg oteseconazole or placebo weekly for 11 weeks \u2022 then 37-week Follow-up periodStudy achieved primary and secondary efficacy endpoints. Oteseconazole was superior to fluconazole/placebo in the proportion of subjects with \u2265 1 culture-verified acute VVC episode through Week 50 in the intent-to-treat (P < 0.001).The average percentage of subjects with \u2265 1 culture-verified acute VVC episode through Week 50 was lower in the oteseconazole group (5.1%) compared to the fluconazole/placebo group (42.2%). Oteseconazole was noninferior to fluconazole in the proportion of subjects with resolved acute VVC infections at Day 14; 93.2% oteseconazole group, 95.8% fluconazole/placebo group.The percentage of subjects who had \u2265 1 treatment-emergent adverse event (TEAE) was similar; oteseconazole (54%), fluconazole/placebo (64%). Most TEAEs experienced were mild or moderate severity in both groups and no drug-related SAEs or adverse effects on liver function or QT intervals.Oteseconazole was shown to be safe and effective in treatment of acute VVC, treatment of RVVC and prevention of recurrence of acute VVC episodes in RVVC subjects. Oteseconazole was non-inferior to fluconazole for treatment of acute VVC in subjects with RVVC.Bassem Maximos, MD, Evofem Biosciences Mycovia Pharmaceutical (Scientific Research Study Investigator)Sage Therapeutics  Thorsten Degenhardt, Ph.D, Mycovia Pharmaceuticals  Karen Person, M.S., Mycovia Pharmaceuticals, Inc. (Employee)Mycovia Pharmaceuticals, Inc. (Employee) Mahmoud Ghannoum, PhD, Mycovia Pharmaceuticals  Stephen Brand, Ph.D, Mycovia Pharmaceuticals (Employee)"}
+{"text": "Genomic sequences from a complete SARS-CoV-2 open reading frame (ORF) were obtained from 24 patients diagnosed in May 2020 in Dhaka, Bangladesh. All sequences belonged to clade 20A or 20B, and none were variants of concern. Interestingly, one sequence showed a 161-nucleotide deletion in ORF7a. We sequenced a complete SARS-CoV-2 open reading frame (ORF) from 24 samples obtained in May 2020 in Dhaka. The study was approved by the Evercare Hospital Dhaka and Hokkaido University ethical committees .TC) values after reverse transcription-quantitative PCR (qRT-PCR)  were used for the sequencing. RNA was purified using the MagMAX viral/pathogen nucleic isolation kit (Thermo Fisher Scientific). The ProtoScript II first-strand cDNA synthesis kit  was used to synthesize cDNAs with oligo(dT) primers. Multiplex PCRs were conducted, using cDNAs and the ARTIC v1 primer set according to the published protocol, with 5\u2032-CATTATGATCTTGCAGTTCAAGTGAG-3\u2032 as the primer instead of the nCoV-2019_91_RIGHT primer. MinION sequencing was performed using flow cells (FLO-MIN106). Libraries were constructed using ligation sequencing (LSK-109) and native barcoding expansion  kits following the manual\u2019s instructions. Another multiplex PCR was conducted for MiSeq sequencing using TaKaRa Ex Taq hot-start (HS) DNA polymerase (RR006A) with three combinations of the same primers  frameshift deletion, from nt 27525 to 27685, was confirmed. The obtained genomes belonged to clades 20A (n = 8) and 20B (n = 16).The sequences were analyzed and assigned to clades using the Nextclade Web service . The phyLC647128 to LC647151, respectively. The raw sequence reads used in this study are available from the INSDC database under GenBank SRA accession numbers DRX308106 to DRX308153.The genome sequences are available from the GISAID and International Nucleotide Sequence Database Collaboration (INSDC) databases under accession numbers EPI_ISL_2350793 to EPI_ISL_2350816 and GenBank accession numbers"}
+{"text": "Many older adults manage multiple chronic conditions requiring adherence to multidrug regimens, yet half are non-adherent, increasing their risk of hospitalization for poorly controlled chronic conditions. Few studies have investigated whether caregivers support medication-related behaviors of community-dwelling older adults. We interviewed 97 patient-caregiver dyads participating in a cognitive aging cohort study to identify factors associated with caregiver assistance in managing multidrug regimens. Patients completed a neuropsychological battery covering five cognitive domains. Health literacy and patient activation were measured using the Newest Vital Sign and Consumer Health Activation Index, respectively. Caregivers reported their medication-related involvement. Predictors of involvement in medication-related tasks were examined using logistic regression models. Patients were on average 71 years old, managing 4 comorbidities and prescribed 5 medications. The majority were female (73%) and identified as Black (46%) or White (47%). Caregivers\u2019 mean age was 65 years; half were female (53%), were predominantly spouses (57%) or children (26%), and lived with the patient (61%). 31% of caregivers ordered patients\u2019 prescribed medications, 40% helped manage their medications, and 50% spoke with the patient\u2019s clinician about their clinical care. Cognitive impairment , limited health literacy , and \u22653 comorbidities  were associated with medication management assistance. Patient activation, gender, cohabitation, or relationship were not associated. These findings suggest that caregivers are assisting with older adults\u2019 medication management and should be included in clinical discussions about medication management, especially among patients with cognitive impairment, low health literacy or multimorbidities."}
+{"text": "GENETICS 2021, 1-1410.1093/genetics/iyab090 due to production error. The definitive uncorrected manuscript version of the above stated article has now been reinstated.An incorrect manuscript was inadvertently published under DOI"}
+{"text": "Best-practice burns first aid is well defined as 20 minutes of cool running water (CRW) within three hours of injury and an expectation of burn care in Australia. This study aims to identify barriers to applying this intervention and assess burn first aid knowledge amongst Australian paramedics.Using multiple methods we assessed; 1) burn first aid adequacy in a cross-sectional study of health care professionals, utilizing a prospectively collected registry of patients managed at an Australian tertiary children\u2019s hospital. Logistic regression models were used to evaluate the relationship between first aid adequacy between health services (eg. Paramedics and emergency departments). Then 2) paramedics completed a questionnaire containing demographic and clinical expertise and environment as well as recording immediate first aid management across five multiple choice burn case scenariosP = 0.045), low socioeconomic status ( P = 0.030) amongst others. Paramedics and general practitioners provided adequate cooling to 184/735 (25.0%) and 52/215 (24.2%) of their patients, respectively. Local general hospitals provided adequate CRW to 1019/1809 (56.3%) patients. Paramedic questionnaire responses (n=326) identified 56% of paramedics answered all burn case scenarios correctly. Respondents who treated a burn within six months scored higher on burn first aid scenarios compared to paramedics who had not recently treated a burn (p=0.004).Overall, 31.3% of children received adequate CRW from caregivers. Factors associated with caregiver inadequacy of CRW were very young age and early adolescence (p< 0.001) rural location ( : deficiencies remain in the cooling of paediatric burns patients at all levels of initial management. First aid delivery was significantly worse in children aged 0\u20102, adolescents aged 15\u201016, those living rurally, and the socioeconomically disadvantaged."}
+{"text": "S. maltophilia should enable early optimization of antimicrobial therapy.The GenMark Dx ePlex BCID Gram-Negative (GN) panel utilizes electrowetting technology to detect the most common causes of GN bacteremia (21 targets) and 6 antimicrobial resistance (AMR) genes from positive blood culture (BC) bottles. Rapid detection of extended spectrum \u03b2-lactamases , and highly resistant bacteria such as In this prospective study, aliquots of positive BC bottles with GN bacteria detected on Gram stain (GS) (n=108) received standard of care (SOC) culture and antimicrobial susceptibility testing (AST). Additionally, samples were evaluated with the BCID-GN panel but only SOC results were reported in the EMR and available to inform clinical decisions. Chart reviews were performed to evaluate the impact of the BCID-GN panel on the time to organism identification, AST results, and optimization of antimicrobial therapy. Escherichia coli was the most common bacteria identified followed by Klebsiella pneumoniae, Pseudomonas aeruginosa, and Enterobacter species (Table 2). There were 11 (10.2%) polymicrobial bacteremias. Repeat BCs were obtained in 68 (63%) patients of which 13 (19%) were persistently positive. Eight (7%) patients had evidence of additional gram-positive (GP) pathogens. Organism identification occurred 26.7 hours faster than culture. In conjunction with GS, negative pan-GP marker data could have helped providers make the decision to remove GP antibiotic coverage in 63 (58%) patients. Narrowing from empiric meropenem could have occurred in 5 patients. Of 10 individuals infected with resistant isolates  empiric therapy was ineffective in 4 (40%) cases. Optimization of antimicrobial therapy for 9 (8.3%) patients could have occurred an average of 52.4 hours earlier than standard methods. A total of 108 patients are included in the analysis (Table 1). Table 1. Patient demographics and co-morbidities.Table 2. Gram-negative bacteria frequency.The BCID-GN panel enabled earlier time to optimal treatment of highly resistant bacteria as well as multiple opportunities for narrowing gram negative spectrum and a higher degree of certainty in cessation of broad-spectrum gram-positive antibioticsTodd P. McCarty, MD, Cidara (Grant/Research Support)GenMark T2 Biosystems (Consultant) Sixto M. Leal, Jr., MD, PhD, Abnova (Grant/Research Support)AltImmune (Grant/Research Support)Amplyx Pharmaceuticals (Grant/Research Support)Astellas Pharmaceuticals (Grant/Research Support)CNINE Dx (Grant/Research Support)GenMark Diagnostics IHMA (Grant/Research Support)IMMY Dx (Grant/Research Support)JMI/Sentry (Grant/Research Support)mFluiDx Dx (Grant/Research Support)SpeeDx Dx (Grant/Research Support)Tetraphase Pharmaceuticals (Grant/Research Support)"}
+{"text": "Frontiers requested research on how a systems approach can explore the mechanisms of cardiovascular complications in Covid-19. The focus of this paper will thus be on these detailed mechanisms. It will elucidate the integrated pathogenic pathways based on an extensive review of literature. Many severe Covid-19 cases and deaths occur in patients with chronic cardiovascular comorbidities. To help understand all the mechanisms of this interaction, Covid-19 complications were integrated into a pre-existing systems-based coronary heart disease (CHD) model. Such a complete model could not be found in literature. A fully integrative view could be valuable in identifying new pharmaceutical interventions, help understand how health factors influence Covid-19 severity and give a fully integrated explanation for the Covid-19 death spiral phenomenon seen in some patients. Covid-19 data showed that CHD hallmarks namely, Hypercoagulability, Hypercholesterolemia, Hyperglycemia/Hyperinsulinemia, Inflammation and Hypertension have an important effect on disease severity. The pathogenic pathways that Covid-19 activate in CHD were integrated into the CHD model. This fully integrated model presents a visual explanation of the mechanism of interaction between CHD and Covid-19 complications. This includes a detailed integrated explanation of the death spiral as a result of interactions between Inflammation, endothelial cell injury, Hypercoagulability and hypoxia. Additionally, the model presents the aggravation of this death spiral through the other CHD hallmarks namely, Hyperglycemia/Hyperinsulinemia, Hypercholesterolemia, and/or Hypertension. The resulting model further suggests systematically how the pathogenesis of nine health factors  and seven pharmaceutical interventions  may either aggravate or suppress Covid-19 severity. A strong association between CHD and Covid-19 for all the investigated health factors and pharmaceutical interventions, except for \u03b2-blockers, was found. It is further discussed how the proposed model can be extended in future to do computational analysis to help assess the risk of Covid-19 in cardiovascular disease. With insight gained from this study, recommendations are made for future research in potential new pharmacotherapeutics. These recommendations could also be beneficial for cardiovascular disease, which killed five times more people in the past year than Covid-19. The coronavirus disease of 2019 (Covid-19) is caused by the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which first emerged in December 2019 in Wuhan, China .Hypertension, Hyperglycemia/Hyperinsulinemia, obesity and/or chronic cardiac disease  result in cardiovascular complications , 6\u20139 and(A) Hypercoagulability, (B) Hypercholesterolemia, (C) Hyperglycemia/Hyperinsulinemia, (D) Inflammatory state and (E) Hypertension.To fully investigate this, the pathogenesis of cardiovascular disease and Covid-19 needs to be integrated. Fortunately, most of the above mentioned vascular Covid-19 effects are included in an existing model of coronary heart disease (CHD)  23, 24), 2423, 2Hypercholesterolemia is a common CHD risk factor, known to aggravate vascular cell dysfunction, aggravate coagulation and upregulate inflammation (Hypercholesterolemia (B), depicted in ammation \u201331. HypeHypercholesterolemia, through vascular complications that arise from high cholesterol levels. Since both Hypercoagulability and Inflammation are known risk factors for Covid-19 and Hypercholesterolemia influences both these hallmarks .We envisage another association between increased Covid-19 severity and allmarks , we alsoAll of the CHD Hallmarks identified in the CHD model  play a sFrontiers:Why do some patients with severe Covid-19 experience sudden death? death spiral? (Section Covid-19 Aggravation in Patients With Pre-existing CHD Comorbidities)How do CHD comorbidities influence this Health Factors on Covid-19 Severity and Effects of Different CHD Pharmaceutical Interventions on Covid-19 Severity)How can an individual reduce the risk of developing severe Covid-19 from a cardiovascular point of view? Are there other opportunities in cardiovascular disease that can be derived from this paper and the Covid-19 crisis? (Section Are There Other Opportunities in Cardiovascular Disease That Can Be Derived From This Paper and the Covid-19 Crisis?).In this paper we will attempt to integrate the CHD pathogenic pathways with those of severe Covid-19 complications, using a systems-based approach. This CHD/Covid-19 integration should provide insight into the following questions, some of which were requested by integrated CHD/Covid-19 model may help answer some of these questions, thereby potentially enhancing the future management of both Covid-19 and CHD.We envisage that the proposed integrated CHD/Covid-19 model is divided into three parts namely the following:The methodology to develop the pathogenic pathways for the Section Description of Existing CHD Model discribes the existing CHD model .8\u201310. Its implications are discussed in the Results sections Integrated Covid-19/CHD Model and Covid-19 Aggravation in Patients With Pre-existing CHD Comorbidities.Section Systems-Based Integration of Covid-19 Factors Into the CHD Model discusses the systems-based method for integration  of CovidHealth Factors and Pharmaceutical Interventions describes the method to evaluate the effects on Covid-19 severity of health factors  and pharmaceutical interventions (blue boxes) as depicted in Health Factors on Covid-19 Severity and Effects of Different CHD Pharmaceutical Interventions on Covid-19 Severity.Section Evaluation of The existing CHD model  was deveintegrated CHD/Covid-19 model is therefore based primarily on CHD attributes, with focus on vascular complications induced by the SARS-CoV-2 virus. We acknowledge that other pathogenic pathways may exist such as the cerebrovascular ones  on body tissues (pink boxes) and investigating the respective pathogenesis (gray lines with numbers), traits (orange boxes) and activated biomarkers (white boxes) related to an increased risk of CHD  to the relevant tissues (pink boxes) and subsequently to the hallmarks of CHD (yellow boxes)  \u201328.. The pharmaceutical interventions, acting on the respective pathways are indicated as blue boxes, where blunted blue arrows  denote antagonize or inhibit and pointed blue arrows  denote up-regulate or facilitate : Firstly, the relevant tissue (denoted as pink boxes in the right-hand corner of Step (2): The activated CHD related biomarkers, traits or hallmarks, reported in severe Covid-19 patients were then identified from literature. These are, respectively, denoted as white, orange and yellow boxes in Step (3): In this step we evaluated the identified CHD biomarkers, traits or hallmarks found in literature, in order to determine whether the activation of these occurs directly or indirectly as a result of the SARS-CoV-2 virus. Steps (4) and (5) describe the two possible outcomes of the identification process.Step (4): If the activation occurs directly, as determined in step (3), then a new (green) pathway that led from the virus to the respective CHD biomarker, trait or hallmark was added to the integrated model as shown in Step (5): If the activation occurs indirectly, as determined in step (3), then a new biomarker or trait was added to the model e.g., the inflammatory cytokines in the top, right-hand white box between pathways 107, 108, and 115 in For the iteration process in Phase 2, the following steps were conducted:Step (6): The activated component  from step (4) to which the green pathway from step (4) leads was further evaluated based on literature. If this component is a biomarker or trait then step (7) was followed. If this component is rather a CHD hallmark, then step (12) was followed.Step (7): In this step it was determined whether the CHD biomarker or trait has any outgoing (gray) CHD pathways. Most biomarkers and traits have outgoing CHD pathways. These gray CHD pathways were further assessed in Step (8). For the biomarkers and traits with no outgoing gray pathways : In this step it was determined whether the gray CHD pathway leads directly or indirectly to a CHD hallmark (yellow boxes in Step (9): The CHD hallmark was further investigated to ensure its activation due to SARS-CoV-2 was relevant to severe Covid-19 patients. If it was reported in literature to be aggravated in severe Covid-19 patients then step (12) was followed (changing the gray pathway to a green pathway) otherwise step (11) was followed (keeping the pathway gray). These steps are explained in more detail in phase 3.Step (10): As determined in step (8), the relevance to Covid-19 severity of the subsequent CHD biomarker or trait to which the gray CHD pathway led to was investigated. If relevance was found, then this CHD biomarker or trait was re-evaluated by following the same approach as in step : This step was followed if the activated CHD biomarkers or traits had, (i) no other outgoing CHD pathway or (ii) the outgoing pathway led to another biomarker or trait that had no relevance to severe Covid-19 patients. If one of these two conditions were met then the biomarker, trait and the subsequent pathway was not evaluated further.These biomarkers, traits and respective pathways e.g., oxidized low-density lipoprotein (oxLDL), nitric oxide (NO) depletion and cortisol were made transparent, as shown in Step (12): Step (12) was followed if the investigated biomarker, trait, CHD hallmark and respective pathways were relevant in most Covid-19 patients with severe disease and these are therefore prominently shown as green lines in integrated CHD/Covid-19 model is given in The Covid-19 pathways were described in this section and shown as green lines in health factors (before infection with SARS-CoV-2) and pharmaceutical interventions (after infection). Only the health factors and pharmaceutical interventions investigated in  in The moderate alcohol consumption  per day for men and half of that for women).Alcohol use: Indicates Food: High glycemic diets (HGD) (glycemic load > 142).moderate exercise .Exercise: Regular Smoking: Current smoker.Oral Health: oor oral health in the form of periodontal disease.Stress: Chronic-level stress at work or home.Depression: Self-diagnosed, physician diagnosed or use of antidepressant medication.Insomnia: Inability to fall asleep or to maintain sleep or the perception of disturbed sleep.Apnoea: Obstructive sleep apnoea or hypopnoea (apnoea-hypopnea index>5/h).Health Factors on Covid-19 Severity to what extent a healthy vascular \u201cbaseline,\u201d as a result of a healthy lifestyle, will influence Covid-19 severity.We will discuss in Results section Effects of Different pharmaceutical interventions that were investigated were limited to those investigated in the original CHD model , whereas others are cohort studies or clinical trials that report on relative risks (RR) or hazard ratios (HR).Although larger studies of how the health factors and pharmaceutical interventions have on CHD risk and Covid-19 severity. This also applies to the data used to compare the risk between coagulation and Covid-19 severity in section The Death Spiral: Inflammation, EC Injury, Coagulation, Vascular Leakage and Hypoxia.Unfortunately, RR, HR and OR are not the same and should only be compared in cases where the event being assessed is rare in the control group. In other words, the baseline risk of the control group should approximately be zero. However, at present it is the best information we have. Until better data becomes available, these studies were used as an initial indicative comparison between the effect what In this paper the comparison of the data between CHD risk and Covid-19 severity was graphically reported using a non-traditional method \u201328. The This method presents a better visual illustration when comparing an increase and decreased risk. For example, a conventional RR = 3 constitutes to a 3-fold increase in risk while a RR = 0.33 constitutes to a 3-fold decrease in risk (1/0.33 = 3). The method has also been used in previous papers \u201328.death spiral seen in some Covid-19 patients.Section Integrated Covid-19/CHD Model discusses death spiral. Five figures are provided (8\u201310). These figures illustrate how patients with pre-existing Hypercholesterolemia , Hyperglycemia/Hyperinsulinemia  or Hypertension  could aggravate this death spiral. Note that 8\u201310 are simplified versions of integrated CHD/Covid-19 model). Only the prominent pathways, which are needed to explain a specific phenomenon, are shown in these Figures.Section Covid-19 Aggravation in Patients With Pre-existing CHD Comorbidities discusses how each pre-existing CHD comorbidity/hallmark could further aggravate this provided , 6, 8\u201310Health Factors on Covid-19 Severity and Effects of Different CHD Pharmaceutical Interventions on Covid-19 Severity the effects that health factors and pharmaceutical interventions have on developing severe Covid-19 are discussed with reference to the model in In sections Effects of Different via ACE2  the mucous membranes  or (ii) the respiratory tract  . This invia ACE2 , which presponse , 36, incresponse  and statpatients , 6\u20139.These effects are illustrated in a) Evidence from literature describing the pathogenesis with the respective (references).8, 9 are then given to illustrate the pathogenesis. Each pathway starts with the relevant tissue, biomarker or trait.b) These relevant pathways in c) The relevant pathway (pw) numbers (#) are denoted as (pw#) e.g., pathway 112 (pw112) links EC injury with vascular leakage.d) The upwards arrow (\u2191) represents an upregulation of the respective biomarker/trait/hallmark while the downwards arrow (\u2193) represents a downregulation.via the following process:via (pw0), which through (pw114) upregulates angiotensin II. This follows a downregulation of biomarker PI3K via (pw54) that increases insulin resistance through (pw69). This leads to a pro-inflammatory state via (pw71), which, through (pw110), results in EC injury. The notation for this pathway and the rest of the paper will be as follows: SARS-CoV-2-(pw0)-Lungs-(pw114)-\u2191angiotensin II-(pw54)-\u2193PI3K-(pw69)-\u2191insulin resistance-(pw71)-\u2191inflammatory state-(pw110)-\u2191EC injury.Angiotensin II can downregulate phosphoinositide 3-kinase (PI3K) pathway, which increases insulin resistance that directly effects inflammatory state . The relSARS-CoV-2-(pw0)-Lungs-(pw114)-\u2191angiotensin II-(pw98)-\u2191ROS-(pw85)-\u2191inflammatory state-(pw110)-\u2191EC injury.Angiotensin II can also upregulate various reactive oxygen species (ROS) at the site of infection, which causes a heightened inflammatory response . See FigSARS-CoV-2-(pw0)-Lungs-(pw114)-\u2191angiotensin II-(pw89)-\u2191platelet factors-(pw73)-\u2191Hypercoagulability-(pw73)-(pw74)-\u2191inflammatory state-(pw110)-\u2191EC injury.An upregulation of angiotensin II may increase platelet factors, which increases the risk for coagulability , 39. SinSARS-CoV-2-(pw0)-Lungs-(pw114)-\u2191angiotensin II-(pw89)-\u2191platelet factors-(pw75)-\u2191platelet aggregation-(pw91)-serotonin-(pw93)-\u2191NFk\u03b2-(pw55)-\u2191inflammatory state-(pw110)-\u2191EC injury.Furthermore, an increase in platelet factors can also upregulate platelet aggregation . This coSARS-CoV-2-(pw0)-Lungs-(pw115)-infect other organs via blood-(pw116)-\u2191EC injury.In addition to this pro-inflammatory state that causes EC injury, the virus can also directly cause EC injury in other organs. This could happen if the virus enters the bloodstream and binds to ACE2 receptors located in other organs . ConsideInfection from SARS-CoV-2 causes damage-associated molecular patterns to occur, which can trigger a hyperimmune response. Most severe cases of patients with Covid-19 display a defective hyperinflammatory state with significantly increased serum levels of pro-inflammatory cytokines and chemokines \u201344.SARS-CoV-2-(pw0)-Lungs-(pw107)-\u2191pro-inflammatory cytokines & chemokines-(pw108)-\u2191inflammatory state-(pw110)-\u2191EC injury.This overproduction of pro-inflammatory cytokines and chemokines can damage lung infrastructure and further induce EC injury of pulmonary blood vessels , 20, 45,SARS-CoV-2-(pw0)-Lungs-(pw107)-\u2191pro-inflammatory cytokines-(pw108)-\u2191TNF-\u03b1, IL-6-(pw41)-\u2191inflammatory state-(pw110)-\u2191EC injury.Most critical cases show increased levels of, among others, the pro-inflammatory cytokines interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor-\u03b1 (TNF-\u03b1) \u201343. ThesSARS-CoV-2-(pw0)-Lungs-(pw107)-\u2191pro-inflammatory cytokines-(pw108)-\u2191IL-6, IL-8-(pw76)-\u2191platelet factors-(pw74)-\u2191inflammatory state-(pw110)-\u2191EC injury.These cytokines can also indirectly upregulate inflammation through dysregulation of platelet factors . See FigSARS-CoV-2-(pw0)-Lungs-(pw109)-\u2191ROS-(pw85)-\u2191inflammatory state-(pw110)-\u2191EC injury.Furthermore, a hyperinflammatory state induced by an unmodulated immune response can also cause EC injury. This happens when neutrophils activate pathways that elevate reactive oxygen species (ROS) , 47. SeeSARS-CoV-2-(pw0)-Lungs-(pw107)-pro-inflammatory cytokines & chemokines-(pw115)-other organs-(pw116)-\u2191EC injury.A hyperinflammatory response of cytokines can circulate to other organs. This could lead to acute inflammation such as septic shock and/or multiple organ damage, which may further cause EC injury . See Fighypoxia shown in hypercoagulation or vascular leakage, both stemming from EC injury -\u2191vascular leakage-(pw113)-\u2191hypoxia.Vascular leakage from EC injury leads to an increase in leucocytes and platelets as well as vascular permeability . This reOn the other hand, coagulation stemming from EC injury articulates glycoproteins that are involved in hemostasis, to which platelets bind. This consequently upregulates the expression of platelet tissue factors, which are the prime activators of a coagulation cascade , 51. Thivia ventilation/perfusion mismatch and low level of mixed venous blood oxygen (EC injury-(pw111)-\u2191Hypercoagulability-(pw73)-\u2191platelet factors-(pw42)-\u2191hypoxia. Hypoxia also results in further upregulation of inflammation by activating IL-6 & TNF-\u03b1 (Hypoxia-(pw60)-\u2191TNF-\u03b1, IL-6-(pw41)-\u2191inflammatory state or Hypoxia-(pw61)-\u2191ROS-(pw85)-\u2191inflammatory state-(pw110)- EC injury.Congestion or clogging of pulmonary blood vessels could increase hypoxemia d oxygen . This bud oxygen , 21, 52. & TNF-\u03b1  or incre & TNF-\u03b1 . See Figdeath spiral are given. Note that inflammation has two different outgoing pathways (loops) that can lead to increased hypoxia. Both pathways are denoted in With the aforementioned knowledge a summary of the main pathogeneses describing the Hypercoagulability (positive feedback loop 1): Inflammation from Covid-19 results in EC injury which may activate the coagulation cascade, forming microthrombi in the blood vessels near the alveoli (inflammatory state \u2013(pw110)-EC injury-(pw111)-\u2191Hypercoagulability-(pw73)-\u2191platelet factors-(pw42)-\u2191hypoxia-(pw60)-\u2191TNF-\u03b1, IL-6-(pw41) AND/OR (pw61)-\u2191ROS-(pw85)-\u2191inflammatory state-(pw110)-Loop repeated-(pw120)-Severe Covid-19. alveoli , 6\u20139. ThVascular leakage (positive feedback loop 2): Inflammation from Covid-19 results in EC injury. EC injury in blood vessels near the alveoli can lead to vascular leakage (inflammatory state \u2013(pw110)-EC injury-(pw112)-\u2191vascular leakage-(pw113)-\u2191hypoxia-(pw60)-\u2191TNF-\u03b1, IL-6-(pw41) AND/OR (pw61)-\u2191ROS-(pw85)-\u2191inflammatory state-(pw110)-Loop repeated-(pw120)-Severe Covid-19. leakage . This ca leakage , subsequdeath spiral is illustrated in A simplified schematic of the To reduce the risk of developing hypoxia one should focus on reducing inflammation that leads to the downstream effects namely EC injury, coagulation and vascular leakage. This is also seen in practice where various pharmaceutical interventions that treat inflammation have shown promising results e.g., corticosteroid dexamethasone in later stage of illness  and antiIf we focus on loop 1 it is expected that people who have a higher risk of developing blood clots (coagulation) should have a higher risk of developing severe Covid-19. There are several uncontrollable factors that are known to increase a person's risk of developing blood clots namely, gender, age, ethnicity, blood type and pregnancy.Although this does not help the patient, it is of interest to help understand Covid-19 severity in these individuals. The data for the risk of coagulation (blood clots) and Covid-19 severity for these individuals are given in Age is an independent risk factor of coagulation, with thrombotic incidences increasing rapidly in people older than 70 years . The oddIf we investigate Covid-19 mortality data, a similar trend is seen with age. Risk of mortality due to Covid-19 is much higher in older patients with a RR of 3.61 in patients older than 70 years , see FigA 25-year population-based study showed that males have a higher risk to coagulate than females . At younCovid-19 data also indicate that males have a higher risk of Covid-19 mortality than females, with a RR of 1.50 , see FigEthnicity has also shown to be an independent risk factor for coagulation. The highest risk of thrombosis being in African Americans, with a RR of 1.5 compared to Europeans . This isAnother risk factor that seems to influence the odds of developing a thromboembolic event is a person's blood type. A single cohort study showed that blood types A&B vs. O have higher risk of developing a thromboembolic event, with the following HRs: A vs. O of 1.44, and B vs. O of 1.45 , see FigA similar trend is seen in the effect of different blood types on Covid-19 severity, with the following ORs: A of 1.06, B of 1.27, O of 0.75 . If thesNone of the blood group values for Covid-19 severity were statistically significant . It is hPregnancy is not necessarily an uncontrollable factor, but for the duration of being pregnant it is. During pregnancy the risk of venous thrombosis is much higher than for non-pregnant women, with an OR of 4.6 , see FigPregnant women are also at a higher risk of developing more severe Covid-19 complications than non-pregnant women, with an OR of 2.35 . Fortunadeath spiral. This could help explain why some patients experience accelerated disease severity. However, better studies for Covid-19 in especially different blood groups are needed.The above mentioned uncontrollable factors may contribute to the coagulation loop 1 of the The high mortality statistics in patients with pre-existing CHD comorbidities \u201312, 70 aHypercholesterolemia. Chronic Hypercholesterolemia may fuel the Covid-19 death spiral by increasing the risk of EC injury via an inflammatory state or plaque buildup. For EC injury induced by an inflammatory state see oxLDL-(pw51)-Hypercholesterolemia-(pw51)-\u2191foam cell-(pw81)-\u2191NFk\u03b2-(pw82)-\u2191IL-6, IL-8-(pw76)-\u2191platelet factors-(pw74)-\u2191inflammatory state-(pw110)-\u2191EC injury. For EC injury induced by plaque buildup see oxLDL-(pw51)-Hypercholesterolemia-(pw119)-\u2191EC injury.One of the risk factors for CHD is Hypercholesterolemia could also have an impact on the severity of Covid-19 by increasing coagulation. This could happen by increased foam cell production and increased thrombin generation (oxLDL-(pw51)-Hypercholesterolemia-(pw51)-\u2191foam cell-(pw81)-\u2191NFk\u03b2-(pw82)-\u2191IL-6, IL-8-(pw76)-\u2191platelet factors-(pw73)-\u2191Hypercoagulability.neration . In turnneration . See FigThe increased coagulation could aggravate thrombi within the lungs and lead to possible hypoxemia , potentiHypercholesterolemia -(pw55)-Hyperglycemia-(pw117)-\u2191EC injury. This further leaves behind eroded arteries which activate processes that lead to atherosclerosis, such as smooth cell proliferation , causing the ECs to detach and enter the bloodstream . See Figferation .Elevated blood glucose (HbA1c)-(pw54)-PI3K:MAPK-(pw69)-\u2191Insulin resistance-(pw72)-\u2191ROS-(pw85)-\u2191inflammatory state-(pw110)-\u2191EC injury. EC turnover is possibly impaired due to accelerated aging or reduced renewal of cells -(pw55)-Hyperglycemia-(pw55)-\u2191inflammatory state-(pw110)-EC injury.A similar pathway also leads to increased inflammation due to a dysregulation of NO, which plays an important role in controlling the vascular tone and arterial pressure. A decrease in NO prevents ECs from responding to increased glucose stress, which may further accelerate cellular deterioration . See FigHyperglycemia is a significant co-morbidity and risk factor for severe Covid-19 patients -\u2191ROS-(pw85)-\u2191Inflammatory state-(pw110)-\u2191EC injury.The indirect impact occurs through hypertension that increases the amount of ROS, especially from the oxidation of endothelial NO synthesis . ROS canHypertension-(pw118)-EC injury. This creates additional areas that require attention and would probably also increase the inflammatory response.Chronic hypertension can also directly cause damage to the microvascular ECs . High blExisting chronic hypertension can therefore possibly cause injury to the ECs through either the indirect or direct pathways. This injury could potentially contribute to the rapid worsening of health in Covid-19 patients with chronic hypertension .health factors with reference to health factor was given in section Evaluation of Health Factors and Pharmaceutical Interventions.We discuss the comparison between CHD and severe Covid-19 for different health factors  and the respective references. Data not statistically significant are indicated with an (*) in health factors, alcohol use and food intake (high glycemic diets). These health factors have not yet been fully investigated in Covid-19 patients. Despite no risk values being available for these health factors, their probable effects on Covid-19 severity are discussed in this section.Where data were unavailable a hash (#) was inserted in health factors that increase/decrease a person's risk for CHD similarly increase/decrease a person's risk (RR/HR/OR) for developing severe Covid-19 . n = 645 087, N = 33)  , 28 as in = 260) (n = 48 440) substantiates the benefit of regular moderate exercise  . The autn = 260) , see Tabexercise .This larger study's results are not presented in Hyperglycemia/Hyperinsulinemia and a heightened Inflammatory state  levels thus decreasing the risk for erolemia , 28. A dlability , 28.The potential decrease of these CHD hallmarks could partially explain the benefit of moderate exercise on the reduced risk of Covid-19 severity. The respective CHD hallmark downregulated by exercise and the activated pathways are denoted in Hyperglycemia/Hyperinsulinemia:Moderate exercise-(pw3a)-muscles-(pw53)-\u2193blood glucose-(pw54)-\u2193PI3K:MAPK-(pw69)-\u2193insulin resistance-(pw72)-Hyperglycemia/ Hyperinsulinemia.Inflammatory state:Moderate exercise-(pw3b)-central nervous system-(pw27)-\u2193cortisol-(pw47)-\u2193insulin resistance-(pw70)-\u2193angiotensin II-(pw89)-\u2193hypertension-(pw100)-\u2193ROS-(pw85)-\u2193COX1/2-(pw85)-\u2193Inflammatory state.Hypercholesterolemia:Moderate exercise-(pw3c)-visceral adiposity-(pw18)-\u2193FFA-(pw37)-\u2193plasma lipids-(pw34)-liver-(pw12)-\u2193LDL-(pw33)-\u2193oxLDL-(pw51)-\u2193Hypercholesterolemia.Hypercoagulability: Moderate exercise-(pw3a)-muscles-(pw53)-\u2193blood glucose-(pw54)-\u2193PI3K:MAPK-(pw69)-\u2193insulin resistance-(pw72)-\u2193platelet factors-(pw73)-\u2193Hypercoagulability.The potential decrease in four of the five CHD hallmarks due to moderate exercise before onset of Covid-19  could partially explain the decreased risk of Covid-19 severity. These beneficial effects of exercise are based on moderate exertion and not heavy exertion. Heavy exertion exercise has the following detrimental effects: transient immune dysfunction, elevated inflammatory biomarkers, and increased risk of upper respiratory tract infections . TherefoSmoking is a risk factor for CHD with a RR of 1.72 . A recenHyperglycemia/Hyperinsulinemia.Most smokers develop insulin resistance and/or Hyperinsulinemia as compared to non-smokers , 121. ThHypercholesterolemia.Moreover, most smokers also have higher plasma triglyceride and lower High-Density Lipoprotein (HDL) cholesterol concentrations than non-smokers , 124. ThInflammatory state. This is due to an upregulation of several inflammatory markers and cytokines such as TNF-\u03b1, granulocyte-macrophage colony-stimulating factor (GM-CSF) and monocyte chemoattractant protein (MCP-1)  .Hypercoagulability -visceral adiposity-(pw19)-\u2193adiponectin-(pw39)-\u2191insulin resistance-(pw72)- \u2191Hyperglycemia/Hyperinsulinemia. Smoking-(pw4b)-central nervous system-(pw27)-\u2191cortisol-(pw47)-\u2191insulin resistance-(pw72)- \u2191Hyperglycemia/Hyperinsulinemia.Hypercholesterolemia:Smoking-(pw4a)-visceral adiposity-(pw30)-\u2193HDL-(pw31)-\u2191 Hypercholesterolemia.Inflammatory state:Smoking-(pw4b)-central nervous system-(pw41)-\u2191TNF-\u03b1-(pw41)-\u2191Inflammatory state.Hypercoagulability:Smoking-(pw4a)-visceral adiposity-(pw49)-\u2191Fibrinogen-(pw73)-\u2191Hypercoagulability.The activation of these pathways and respective CHD hallmarks may explain some of the increased risk of smokers developing severe Covid-19 compared to non-smokers .Using n = 568), the data is widely spread (95% CI of 1.00\u201377.7) and the data is not statistically significant [this statistical insignificance is illustrated on *)] ] .Inflammatory state, Hypercoagulability and Hypercholesterolemia   . This bagivalis) .Inflammation can also be increased via reactive oxygen species (ROS) which is associated with periodontal disease -periodontium-(pw23)-\u2191P. gingivalis-(pw43)-\u2191periodontitis-(pw64)-\u2191platelet factors-(pw73)-\u2191Hypercoagulability.Inflammatory state: Oral health-(pw5)-periodontium-(pw23)-\u2191P. gingivalis-(pw43)-\u2191periodontitis-(pw41)-\u2191TNF\u03b1/IL6-(pw41)-\u2191inflammatory state. Oral health-(pw5)-periodontium-(pw23)-\u2191P. gingivalis-(pw43)-\u2191periodontitis-(pw62)-\u2191ROS-(pw85)-\u2191inflammatory state.Hypercholesterolemia:Oral health-(pw5)-periodontium-(pw23)-\u2191P. gingivalis-(pw43)-\u2191periodontitis-(pw65)-\u2191oxLDL-(pw51)-\u2191Hypercholesterolemia.The potential increase of these CHD hallmarks due to periodontitis could partially explain the increased risk of Covid-19 severity.Health Factors and Pharmaceutical Interventions) is also a common factor linked to an increased risk for CHD, with an OR of 2.17 -central nervous system-(pw27)-\u2191cortisol-(pw48)-liver-(pw14)-\u2191blood glucose-(pw54)-PI3K:MAPK-(pw69)-\u2191insulin resistance-(pw72)-\u2191platelet factors-(pw73)-\u2191Hypercoagulability.Hypercholesterolemia:Chronic stress-(pw6)-central nervous system-(pw27)-\u2191cortisol-(pw48)-liver-(pw12)-\u2191LDL-(pw33)-\u2191oxLDL-(pw51)-\u2191Hypercholesterolemia.Hyperglycemia/Hyperinsulinemia:Chronic stress-(pw6)-central nervous system-(pw27)-\u2191cortisol-(pw48)-liver-(pw14)-\u2191blood glucose-(pw54)-PI3K:MAPK-(pw69)-\u2191insulin resistance-(pw72)-\u2191Hyperglycemia/Hyperinsulinemia.Inflammatory state:Chronic stress-(pw6)-central nervous system-(pw27)-\u2191cortisol-(pw48)-liver-(pw14)-\u2191blood glucose-(pw54)-PI3K:MAPK-(pw69)-\u2191insulin resistance-(pw70)-\u2191angiotensin II-(pw88)-renin-(pw50)-\u2191TNF\u03b1-(pw41)-\u2191Inflammatory state.Hypertension:Chronic stress-(pw6)-central nervous system-(pw27)-\u2191cortisol-(pw48)-liver-(pw14)-\u2191blood glucose-(pw54)-PI3K:MAPK-(pw69)-\u2191insulin resistance-(pw70)-\u2191angiotensin II-(pw89)- \u2191Hypertension.n = 535, see Although the Covid-19 study is small  , shown iInflammatory state, Hypercholesterolemia, Hypertension and Hyperglycemia/Hyperinsulinemia  axis induced by elevated levels of corticotropin-releasing factor and adrenocorticotropic hormone , 24. Chrulinemia , 24.via central regulatory pathways. This results in increased plasma catecholamines -central nervous system-(pw27)-\u2191cortisol-(pw48)-liver-(pw12)-\u2191LDL-(pw33)-\u2191oxLDL-(pw51)-\u2191Hypercholesterolemia.Inflammatory state:Depression-(pw7b)-central nervous system-(pw27)-\u2191cortisol-(pw48)-liver-(pw14)-\u2191blood glucose-(pw54)-PI3K:MAPK-(pw69)-\u2191insulin resistance-(pw70)-\u2191angiotensin II-(pw88)-renin-(pw50)-\u2191TNF\u03b1-(pw41)-\u2191Inflammatory state.Hypertension:Depression-(pw7b)-central nervous system-(pw27)-\u2191cortisol-(pw48)-liver-(pw14)-\u2191blood glucose-(pw54)-PI3K:MAPK-(pw69)-\u2191insulin resistance-(pw70)-\u2191angiotensin II-(pw89)- \u2191Hypertension.Hyperglycemia/Hyperinsulinemia:Depression-(pw7b)-central nervous system-(pw26)-\u2191catecholamines / \u2193serotonin / \u2193BDNF-(pw44)-\u2191insulin resistance-(pw72)- \u2191Hyperglycemia / Hyperinsulinemia.Hypercoagulability:Depression-(pw7b)-central nervous system-(pw26)-\u2191catecholamines / \u2193serotonin / \u2193BDNF-(pw44)-\u2191insulin resistance-(pw72)-\u2191platelet factors-(pw73)-\u2191Hypercoagulability.Since depression can upregulate all five CHD hallmarks , 24, it Inflammatory state and Hypertension -central nervous system-(pw27)-\u2191cortisol-OSA-(pw42)-hypoxia-(pw61)-\u2191ROS-(pw85)-\u2191Inflammatory state.Hypertension:Apnoea-(pw9)-central nervous system-(pw27)-\u2191cortisol-OSA-(pw42)-\u2191hypoxia-(pw42)-\u2191)-oxia-(pSA-(pus systw70)-\u2191angiotensin II-(pw89)-\u2191Hypertension.Hypercholesterolemia:Apnoea-(pw9)-central nervous system-(pw27)-\u2191cortisol-(pw48)-visceral adiposity-(pw21)-\u2191TNF-\u03b1/IL-6-(pw56)-liver-(pw12)-\u2191LDL-(pw33)-\u2191oxLDL-(pw51)-\u2191Hypercholesterolemia.Hypercoagulability:Apnoea-(pw9)-central nervous system-(pw27)-\u2191cortisol-(pw47)-\u2191insulin resistance-(pw42)-\u2191platelet factors-(pw73)-\u2191Hypercoagulability.The activation of proinflammatory mediators namely, TNF-\u03b1, IL-6 and CRP induced by OSA are also elevated in severe Covid-19 patients without OSA \u201322. Therhealth factor that increases a person's risk for CHD with a RR of 1.45 (n = 568) and the data are statistically insignificant (95% CI of 0.44\u20132.71)  , see TabHyperglycemia/Hyperinsulinemia -central nervous system-(pw25)-(pw66)-\u2191ghrelin:leptin-(pw67)-\u2191insulin resistance-(pw72)-liver-(pw14)-\u2191blood glucose-(pw55)-\u2191Hyperglycemia/Hyperinsulinemia.Inflammatory state:Insomnia-(pw8b)-central nervous system-(pw25)-(pw66)-\u2191ghrelin:leptin-(pw67)-\u2191insulin resistance-(pw70)-\u2191angiotensin II-(pw88)-renin-(pw50)-\u2191TNF-\u03b1, IL-6-(pw41)-\u2191Inflammatory state.Hypercoagulability:Insomnia-(pw8b)-central nervous system-(pw25)-(pw66)-\u2191ghrelin:leptin-(pw67)-\u2191insulin resistance-(pw72)-\u2191platelet factors-(pw73)-\u2191Hypercoagulability.Unfortunately, the clinical data on insomnia and its effect on Covid-19 severity are small. Its effect may be underestimated.moderate alcohol consumption may influence CHD was described in detail in our previous paper   , 26, illModerate alcohol consumption may reduce fibrinogen levels, clotting factors, and platelet aggregation. Downregulation of these biomarkers reduces a state of Hypercoagulability -Liver-(pw49)- \u2193fibrinogen/clotting factors-(pw73)- \u2193Hypercoagulability and Alcohol-(pw1)-Liver-(pw49)-\u2191fibrinogen/clotting factors-(pw75)- \u2193platelet aggregation.Hypercholesterolemia:Alcohol-(pw1)-Liver-(pw10)-\u2191HDL-(pw31)-\u2193Hypercholesterolemia and Alcohol-(pw1)-Liver-(pw12)-\u2193LDL-(pw33)- oxLDL-(pw51)-\u2193Hypercholesterolemia.Hyperglycemia/Hyperinsulinemia:Alcohol-(pw1)-Liver-(pw14)-\u2193blood glucose-(pw55)-\u2193Hyperglycemia/Hyperinsulinemia.Inflammation:Alcohol-(pw1)-Liver-(pw14)-\u2193blood glucose-(pw54)-PI3K:MAPK-(pw69)-insulin resistance-(pw70)-Angiotensin II-(pw89)-\u2193Hypertension-(pw100)-\u2193ROS-(pw85)-\u2193Inflammatory state.moderate alcohol consumption plays in four of the five CHD hallmarks. The argument whether moderate alcohol consumption before infection decreases or increases Covid-19 severity has not yet been thoroughly explored.These pathways demonstrate an important role during Covid-19 could increase Covid-19 severity  increases the risk for CHD with a RR of 1.36 , see Figvia carbohydrate consumption. This may result in Hyperglycemia (Hyperglycemia resulting from HGDs can increase the risk of insulin resistance by upregulating the Phosphatidylinositol 3-kinase : Mitogen-activated protein kinase (PI3K:MAPK) ratio  ratio , 25. Subgulation , 25.Inflammatory state.Excessive intake of HGDs can result in increased adipose tissue, which enhances pro-inflammatory mediators such as CRP and TNF-\u03b1 , 25. TheHypercholesterolemia -gastro-intestines-(pw17)-\u2191blood glucose-(pw55)-\u2191Hyperglycemia.Hypercoagulability:Food-(pw2)-gastro-intestines-(pw17)-\u2191blood glucose-(pw54)-\u2191PI3K:MAPK-(pw69)-\u2191insulin resistance-(pw72)-\u2191platelet factors-(pw73)-\u2191Hypercoagulability.Inflammatory state:Food-(pw2)-gastro-intestines-(pw15)-plasma lipids-(pw34)-liver-(pw13)-TMAO/NLRP3-(pw52)-macrophage-(pw77)-\u2191Inflammatory state.Hypercholesterolemia:Food-(pw2)-gastro-intestines-(pw15)-plasma lipids-(pw34)-liver-(pw12)-\u2191LDL-(pw33)-oxLDL-(pw51)-\u2191Hypercholesterolemia.Hypertension:Food-(pw2)-gastro-intestines-(pw14)-blood glucose-(pw54)-\u2191angiotensin II-(pw89)-\u2191Hypertension.These pathways demonstrate the detrimental effect HGDs may have on an individual's \u201cbaseline\u201d vascular system before infection from SARS-CoV-2. It could potentially increase the risk of developing severe Covid-19 complications.integrated CHD/Covid-19 model shows that similar outcomes for different health factors are seen in CHD and Covid-19. The next question is: Since we know that various pharmaceutical interventions decreases one's risk for CHD, will they also work for Covid-19? If they do then this will further show validity of the proposed integrated CHD/Covid-19 model.The pharmaceutical interventions are shown in denote antagonize or inhibit and pointed blue arrows  denote up-regulate or facilitate. The question is whether these pharmaceuticals would also decrease one's risk for severe Covid-19. This was investigated, despite the limited clinical data available for Covid-19. The data were extracted from literature and are summarized in The Pharmaceutical Interventions on Covid-19 Severity, No risk value was available for antidepressants' effect on Covid-19 severity. However, its effect on Covid-19 severity is still discussed in this section as depression was shown to increase the odds of developing severe Covid-19 complications by 2.68  (The use of statins decreases the risk of CHD with a RR of 0.78 . This tr 13 981)   investigated heparin's effect in Covid-19 patients , this value is not statistically significant with the 95% CI of 0.71\u20131.15 presented in For Covid-19, direct thrombin inhibitors are shown to slightly reduce the risk of developing severe disease with a HR of 0.90 , see Tabpharmaceutical interventions in The antihypertensive The respective reduction of CHD risks for each pharmaceutical , 113 is Angiotensin-renin inhibitors: 1.09 (OR of 0.92)Calcium channel blockers: 1.20 (OR of 0.83)ACE inhibitors: 1.27 (OR of 0.79)\u03b2-blockers: 1.46 (RR of 0.69)Diuretics: 1.27 (RR of 0.79)The reduction in CHD risk is small for angiotensin-renin inhibitors with an OR close to one (0.92) . However*).The risk data for calcium channel blockers (OR of 0.94) , ACE inhpharmaceutical interventions is \u03b2-blockers, which reduced the risk of CHD (RR of 0.69). However, its use increases ones odds of developing severe Covid-19 (OR of 1.23) (The most interesting of the antihypertensive of 1.23) , see Figof 1.23) , see TabBiguanides such as metformin has been used for many decades to treat type 2 diabetes and its use decreases the odds of developing CHD, with a OR of 0.74 , see Tabn = 1 800 005) showed that the use of metformin decreased Covid-19-related mortality by 1.30-fold (HR of 0.77) (Elevated blood glucose levels at admission is an independent predictor of Covid-19 severity irrespective of diabetes . Therefoof 0.77) , see FigWe have done a detailed study of the mechanisms by which SSRI antidepressants may reduce CHD risk . We showSelective serotonin uptake inhibitors (SSRIs) such as sertraline has shown to decrease the risk of CHD, with a HR of 0.48 , see TabA similar SSRI antidepressant, fluvoxamine's effect on Covid-19 severity is currently being investigated in a clinical trial (NCT04727424). This study was initiated by results from a small double-blind, randomized clinical trial of 152 Covid-19 positive patients treated with fluvoxamine . The outThe study did not report any risk data. For this reason, the data could not be added to Frontiers. The resulting integrated CHD/Covid-19 model may provide insight into the various research questions, some also requested by Frontiers.The aim of this paper was to use a systems approach to explore the mechanisms between severe Covid-19 and its cardiovascular complications, as requested by death spiral before infection of SARS-CoV-2.Although aspects of this has been proposed elsewhere , 145\u2013148death spiral was summarized as follows: Increased inflammation at the lungs causes EC injury, which can result in vascular leakage and/or activation of the coagulation cascade at the lungs, thereby causing hypoxia which can further increase inflammation, creating two closed positive feedback loops and causing severe Covid-19 through a death spiral  have a high risk of developing severe Covid-19 \u201314. The Hypercholesterolemia, Hyperglycemia/Hyperinsulinemia and Hypertension can fuel the death spiral.This question was answered in this paper by visually \u201310 detaihealth factors ]]5)] haveFrontiers in their request for papers was the following: \u201cHow can computational analysis help to assess the risk of COVID-19 in cardiovascular disease?\u201d We speculate that to achieve such an outcome, at least the following must be done:One of the research questions posed by Step 1: Development of a fully integrated network model for the disease, accounting for all effects including cross linking.Step 2: Characterization of each interaction  is needed to solve the network.Inn1 \u2192  are the inputs (1 to n) to a node and outn1 \u2192  are the outputs (1 to n) from the node and f (1 to n) are the resulting transfer functions. The inputs and outputs are typically measured. More detail of this process is given in  and a CHD simulation model (B) proposed in  are show network , therebyThe question is: can the risk for Covid-19 severity in CHD then be established for any specific individual by inputting the measured biomarkers of that person into the simulation model based on Fortunately, there are numerous clinical trials currently underway that focus on treatments for Covid-19 with respect to the CHD hallmarks, namely the following:Hypercoagulation (A) Hypercholesterolemia (B) Hyperglycemia /Hyperinsulinemia (Diabetes) (C) Inflammation (D) Hypertension (E) The clinical trial numbers and respective treatments are available as If we can successfully develop a simulation model, could the best control strategy  be calculated for each individual Covid-19 or CHD patient? This would be similar to identifying the optimum control strategies, which we routinely calculate in engineering, for each individual mine or industrial complex.However, we acknowledge that there are many assumptions and restrictions relevant to a CHD/Covid-19 computational analysis, which is completely speculative at present. For example, research is needed to investigate how individualized predictions will be feasible. The full details on the research question of computational analysis will be the purpose of future papers.pharmaceutical interventions which mediate CHD also mediate the effects of Covid-19.We have shown in this paper that the late-stage consequences of severe Covid-19 is often accelerated cardiovascular disease. We have also shown that most pharmaceutical interventions that reduced Covid-19 severity which could potentially be of value for vascular disease? This is an important question as approximately five times more people died during the past year from cardiovascular disease than from Covid-19.The question arises if the reverse is true. Are there any reported Such a repurposed drug should preferably treat most of the hallmarks of cardiovascular disease. We investigated such a drug namely, ivermectin \u2013155. AltHypercoagulability: (1992) by increasing prothrombin time in 6.7% (ivermectin group) vs. 1.4% (control group) of participants in vivo (humans) ((A) (humans) .Hypercholesterolemia: cholesterol (2013) decreased by 1.5-fold in vivo (mice) ((B) o (mice) .Hyperglycemia: fasting blood glucose (2013) decreased by 1.4-fold in vivo (mice) ((C) o (mice) .Hyperinsulinemia: fasting insulin (2013) decreased by 2.0-fold in vivo (mice) ((D) o (mice) .Inflammation: (2004) decreased IL-1\u03b2 and TNF-\u03b1 by 1.27-fold in vitro ((E) in vitro .Inflammation  before the virus strikes, especially in vascular compromised individuals, rather than only help If well-designed clinical trials show that ivermectin could be a potential cardiovascular drug, could it be an ideal, inexpensive, drug for low- and middle-income countries where a high percentage of global cardiovascular related deaths occur ?Other research questions that should be investigated in future research are the following:Why would \u03b2 -blockers have an opposite effect on Covid-19 severity than on CHD?There exists an anomaly between statin's cholesterol lowering effect and low cholesterol levels seen in end-stage Covid-19. How can this drug help decrease Covid-19 severity while it further decreases cholesterol? Can statin's anti-inflammatory effect be so large that it overrides its cholesterol lowering effect? Would it then be better to drop statins and rather only use anti-inflammatory medication? Or does it depend on the stage of the disease, beneficial at first but not in the end stage?pharmaceutical interventions and Covid-19 mean that other CHD pharmaceuticals not investigated in detail for Covid-19 could also help reduce Covid-19 severity?Does a high correlation of most CHD related Are there pathways shown in the proposed model  that do Could the model be extended to include cerebrovascular disease and other cardiac diseases such as heart failure, valvular heart disease and peripheral artery disease?Frontiers therefore requested papers on how a systems approach can explore the mechanisms of cardiovascular complications in Covid-19.Covid-19 data show that disease severity mostly occurs in patients with pre-existing cardiovascular comorbidities i.e., in patients with poor initial vascular \u201cbaselines.\u201d integrated CHD/Covid-19 model, depicted in Frontiers request for research:This study attempted to fulfill this request by integrating pathways for severe Covid-19 into an existing coronary heart disease (CHD) model. The resulting death spiral seen in some critical Covid-19 patients.The integrated CHD/Covid-19 pathogenesis of the Hyperglycemia/Hyperinsulinemia, Hypercholesterolemia and/or Hypertension may fuel the death spiral.The comprehensive mechanisms of how underlying CHD comorbidities namely, health factors, which effect CHD risk and Covid-19 severity.The detailed pathogeneses of different pharmaceutical interventions may influence Covid-19 severity.The mechanisms of how chronic CHD The proposed model shows many pathways that currently do not have pharmaceuticals which influence them. This information can be the focus of future drug discovery.The proposed model can be further developed as a computational tool not only for Covid-19 application but also for cardiovascular disease.integrated CHD/Covid-19 model, also led to various research questions that can form the basis for future research. This includes potential repurposing of an existing drug for cardiovascular disease.Insights into the hallmarks of CHD, shown in the Although the details in this study are complex the message is simple. Studies such as this one not only highlight the value of a cardiovascular healthy lifestyle in general but also specifically for Covid-19. With the sharp focus on Covid-19 we hope that this \u201chealthy living\u201d message will be intensified, thus help to reduce cardiovascular deaths, the prime killer of man.The original contributions presented in the study are included in the article/death spiral and potential use of ivermectin for CHD based on MM's Ph.D. AM and AG developed the integrated CHD/Covid-19 model from literature. MM developed the CHD-based model and provided expert opinion for the integration of the model with Covid-19. All authors have assisted in revisions and have approved the final manuscript.AM developed the first draft (of more than 30) of the manuscript and compiled and analyzed the Covid-19 risk factor data. EM was the principal investigator. During level 5 Lockdown in May 2020 he initiated the original ideas and research including the The research was funded by EM and HumanSim (Pty) Ltd.This study received funding from HumanSim (Pty) Ltd. The funder was not involved in the study design, collection, analysis,interpretation of data, the writing of this article or the decision to submit it for publication. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the author and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Late-life depression is a comorbidity which may co-occur in older adults with hearing loss- each as prevalent and independent modifiable risk factors for dementia. We used data from 1,820 participants  from the Health Aging and Body Composition Study to test if the hearing loss-dementia/cognitive decline  relationship differed in hearing impaired participants who also had depressive symptoms. Depressive symptoms were defined as CES-D 10 \u226510) at one or more visits from years 1-5. Algorithmic incident dementia defined using medication use, hospitalizations and cognitive test scores. Audiometric hearing loss was measured at year 5 and categorized as normal/mild vs \u2265moderate loss. In linear mixed models adjusted for demographic and clinical covariates, presence of both hearing loss and depressive symptoms (vs. having neither) was associated with faster rates of decline in 3MS  and DSST  over 10 years of follow-up. Both hearing loss and depressive symptoms (vs. neither) was associated with increased risk (hazard ratio (HR):2.91, 95%CI: 1.59, 5.33) of incident dementia in multivariable-adjusted Cox proportional hazards models. Comorbid conditions among hearing impaired older adults should be considered and may aid in dementia prevention and management strategies."}
+{"text": "Therapeutic antibodies that target immune checkpoints have revolutionized cancer therapy. While these checkpoints restrain T cell activation in response to antigen engagement, checkpoint inhibitors de-repress such tumor-associated T cells, and have generated major clinical responses in multiple tumor types. Nonetheless, the vast majority of cancers remain resistant to this therapeutic approach as currently deployed, either through intrinsic or acquired resistance mechanisms. One key question involves the identity of the tumor targets which effector T cells recognize. Tumor-specific mutant epitopes  represent a favored example, whose recognition has been demonstrated in certain contexts. While potentially helpful in identifying likely therapeutic opportunities (such as cancers harboring DNA repair defects), numerous cancers are relatively deficient in neoantigen loads. This commentary discusses the prospect that a phenomenon of \u201cepitope spreading\u201d may occur in certain high mutation contexts, giving rise to T cell responses against non-mutated/wild-type lineage proteins. Recent evidence is also discussed that suggests this mechanism may be exploited to purposely trigger epitope spreading and induce systemic tumor eradication in neoantigen-deficient cancers. Immune checkpoint blockade, using anti-PD-1, anti-PD-L1, and anti-CTLA-4 antibodies, has transformed treatment of many kinds of cancer including melanoma. However, durable clinical response with significant tumor regression is elicited in only a small subset of cancer patients. Most cancer patients do not respond to immune checkpoint blockade at all (primary resistance); while other patients respond initially, they develop resistance over time and the cancers ultimately relapse (acquired resistance) [+ T cells) distinguish between normal cells and cancer cells for those patients who respond positively to immune checkpoint blockade? (3) How can toxicity associated with checkpoint blockade immunotherapy be understood, minimized, and/or eliminated? Answering these questions will not only provide unprecedented mechanistic insights into cancer immunology, but also remove barriers for improvements to checkpoint blockade immunotherapy.Central questions in the field of immune checkpoint blockade for cancer treatment are: (1) Why do the majority of cancer patients\u2019 tumors resist checkpoint blockade immunotherapy? What are the resistance mechanisms? How can we improve treatment efficacy? (2) How do cytotoxic T cells . It is plausible that the CD8+ T cells compared with parental D4M.3A.3 melanomas. Glycoprotein 100 (gp100) is a wild-type melanocyte and melanoma lineage antigen. Immunohistochemistry results demonstrated that UV2 melanomas had higher tumor-infiltrating T cells compared with parental D4M.3A.3 melanomas. These results were corroborated by flow cytometry, showing that UV2 melanomas contained higher number of CD8+ T cells and greater immune cytolytic activity compared with parental D4M.3A.3 melanomas.To understand this question, the authors utilized a mouse melanoma cell line containing BRAF (V600E) and PTEN homozygous loss  but no UV-exposure or corresponding UV mutational load. They generated additional cell lines (D4M-UV2 and D4M-UV3) by irradiating the parental line with UV, followed by single cell cloning and exome sequencing of the derivative lines, which indeed harbored significant genomic UV mutational loads in the same general range as human cutaneous melanomas. Parental D4M.3A.3 and the UV2 line were implanted into syngeneic C57BL/6 mice and the corresponding tumors were then treated with anti-PD1. The authors found that after anti-PD1 treatment, mice bearing UV2 melanomas had higher gp100-specific CD8Conventional wisdom would predict that immune checkpoint blockade for melanomas with more neoantigens would exhibit expansion of mainly neoantigen-specific tumor infiltrating T cells. Interestingly, after anti-PD-1 treatment, melanomas with higher mutational loads exhibited a significant increase in tumor infiltrating T cells targeting the wild-type melanocyte antigen gp100. These results suggest that epitope spreading to wild-type lineage self-antigens was enhanced by the pre-existing higher neoantigen burden. Additionally, the authors demonstrated that mice cured from UV-mutated melanomas by anti-PD-1 were capable of resisting challenges by the parental melanoma which lacks UV mutations. This observation demonstrated the functional importance of epitope spreading and anti-tumor properties of lineage directed immunity against wild-type antigens.in vivo model of neoantigen-deficient, poorly inflamed, and immunotherapy-resistant melanoma. Since epitope spreading was capable of triggering functional immunity against the neoantigen-poor parental melanoma, the authors tested whether non-mutational pro-inflammatory treatments might be capable of inducing epitope spreading towards wild-type melanocyte antigens on melanomas after anti-PD-1 treatment. To this end, they utilized a model consisting of the parental (neoantigen-poor) melanoma engrafted as two tumors on the flanks of syngeneic mice. They then treated one of the two/bilateral tumors with the triple combination of (1) ablative fractional photothermolysis (aFP), which is a cosmetic carbon dioxide laser producing nanoscale columns of tumor ablation over less than 5% of the tumor and aiming to induce tumor inflammation unilaterally; (2) topical imiquimod, a Toll-like receptor 7 (TLR7) agonist which activates innate immune signaling; and (3) anti-PD-1. Quadruple treatments (aFP + imiquimod + anti-PD-1 + anti-CTLA-4) were also tested and showed the strongest responses, resulting in complete regression of bilateral melanomas in 75% of mice with parental D4M.3A.3 melanomas. Triple treatments (aFP + imiquimod + anti-PD-1), any combination of double treatments, and single treatment induced complete bilateral regression of melanomas in 50%, 10%, and 0% of mice with D4M.3A.3 melanomas, respectively. One in 24 evaluable mice with complete response against melanoma developed vitiligo and none exhibited signs of gross toxicity. Importantly, these combination treatments were delivered locally to one of two tumors, yet they induced epitope spreading and complete regressions both locally as well as against contralateral tumors, thus demonstrating systemic immune activation.As described above, the parental D4M.3A.3 melanoma cell line exhibits a poor response to immune checkpoint inhibitors and thus serves as an + T cells; (3) Triple therapy dramatically increases the number of gp100 tetramer-positive CD8+ tumor infiltrating lymphocytes; and (4) Triple therapy modulates expression of genes associated with immune signaling cascades and pigmentation. These data suggest that a cosmetic laser (aFP) plus TLR activation dramatically produces pro-inflammatory effects that enhance immune attack on wild-type melanocyte antigens on melanomas, resulting in improved anti-PD-1 immunotherapy efficacy. Similar efficacy was also observed for this combination treatment when applied to another poorly immunogenic tumor, pancreatic adenocarcinoma. Lo, et al. [The authors performed RNA-sequencing as well as extensive immunophenotyping by flow cytometry to decipher molecular mechanisms underlying triple therapy (aFP + imiquimod + anti-PD-1) responses against melanomas with low mutational burden. The data suggest that: (1) Imiquimod enhances antigen presentation and activates the T cell compartment; 2) Triple therapy efficacy requires cross-priming of antitumor CD8 Triple t+ T cells capable of recognizing wild-type melanocyte antigens and boosting immune response. In addition to elucidating a mechanism likely underlying much antitumor efficacy by immune checkpoint inhibitors, these data also suggest new treatment opportunity for cancer harboring low neoantigen loads.Mechanistically, either UV-irradiation or aFP plus imiquimod treatment can improve anti-PD-1 therapeutic efficacy in poorly immunogenic melanomas by expansion of CD8Further studies are required to shed light on the following important questions raised by this study: (1) Can T cell populations specific for melanocyte antigens MART-1, tyrosinase, and other wild-type melanocyte antigens be used as biomarkers for monitoring responses to immune checkpoint blockade? (2) What comprehensive set of melanocyte antigens is targeted by the immune response after combinatorial immunotherapy? (3) What are fundamental principles or general rules/approaches for designing further combinatorial pro-inflammatory approaches that may enhance cancer immunotherapy? In which contexts will such an approach become detrimental due to elicitation of autoimmune responses? Decoding these questions will not only advance fundamental immunology and cancer biology, but also provide a roadmap for improving cancer immunotherapy using immune checkpoint blockade."}
+{"text": "Muller glia (MG) play a central role in reactive gliosis, a stress response associated with rare and common retinal degenerative diseases, including age-related macular degeneration (AMD). The posttranslational modification citrullination\u200b targeting glial fibrillary acidic protein (GFAP) in MG was initially discovered in a panocular chemical injury model. Here, we report in the paradigms of retinal laser injury, a genetic model of spontaneous retinal degeneration (JR5558 mice) and human wet-AMD tissues that MG citrullination is broadly conserved. After laser injury, GFAP polymers that accumulate in reactive MG are citrullinated in MG endfeet and glial cell processes. The enzyme responsible for citrullination, peptidyl arginine deiminase-4 (PAD4), localizes to endfeet and associates with GFAP polymers. Glial cell\u2013specific PAD4 deficiency attenuates retinal hypercitrullination in injured retinas, indicating PAD4 requirement for MG citrullination. In retinas of 1-mo-old JR5558 mice, hypercitrullinated GFAP and PAD4 accumulate in MG endfeet/cell processes in a lesion-specific manner. Finally, we show that human donor maculae from patients with wet-AMD also feature the canonical endfeet localization of hypercitrullinated GFAP. Thus, we propose that endfeet are a \u201ccitrullination bunker\u201d that initiates and sustains citrullination in retinal degeneration. Muller glia (MG) are the principal reactive cells of the retina that respond to stress via a process known as reactive gliosis . The posPadi4 gene expression by crossing ERT2GFAP-Cre with flox/floxPadi4 mice and administered tamoxifen to induce PAD4 deficiency in glial cells  (SI Appendix). Immunostaining of retinas from control and PAD4cKO mice subjected to laser injury (SI Appendix) revealed loss of citrullinated GFAP (cit-GFAP) in PAD4cKO retinas compared to control injured retinas as detected by a site-specific (R270 and R416) anticitrullinated GFAP antibody , a pathological process that occurs in wet-AMD and pathologic myopia, to assess retinal gliosis . We deteantibody O and P. antibody Q confirmantibody U, includantibody Q, arrow,antibody S.rd8Crb1/m1JJak3  double mutant mouse (JR5558 line) develops retinal lesions leading to adult-onset retinal degeneration . The control age-matched donor samples revealed the expected GFAP staining in the ganglion cell layer astrocytes, with some filamentous GFAP staining suggestive of minimal age-related gliosis . S. SSI App gliosis K, but in gliosis N. Taken Gfap mRNA transport to the endfeet for its localized translation . JR5558 mice were purchased from The Jackson Laboratory.C57BL/6J mice and PAD4cKO mice were subjected to laser injuries as described  . Human donor eyes from deidentified subjects , procured within 8 h of death, were dissected in buffered formalin and then the posterior eye cup was validated for disease stage (SI Appendix). Circular 8-mm tissue punches of the macula were cryopreserved and sectioned. Six different sets of sections from each donor eye were obtained and randomly chosen for analysis to ensure adequate representation of the macula tissues.Mouse retinas from control and injured mice were subjected to WB and immunostaining (P < 0.05 using PRISM software.Gel bands for WBs were normalized against stain-free gels using FIJI software. Data were analyzed by one-way ANOVA for significance of Supplementary File"}
+{"text": "Scientific Reports 10.1038/s41598-021-90554-3, published online 26 May 2021Correction to: The original version of this Article contained an error in the Data Availability section.\u201cAll sequencing data will be available on GEO upon publication.\u201dnow reads:\u201cAll sequencing data is available on GEO (GSE164741).\u201dThe original Article has been corrected."}
+{"text": "Maribacter dokdonensis 62\u20131, a novel strain of this flavobacterial species, isolated from alginate-supplemented seawater collected at the Patagonian continental shelf. M. dokdonensis 62\u20131 harbors a diverse array of CAZymes in multiple polysaccharide utilization loci (PUL). Two PUL encoding polysaccharide lyases from families 6, 7, 12, and 17 allow substantial growth with alginate as sole carbon source, with simultaneous utilization of mannuronate and guluronate as demonstrated by HPLC. Furthermore, strain 62-1 harbors a mixed-feature PUL encoding both ulvan- and fucoidan-targeting CAZymes. Core-genome phylogeny and pangenome analysis revealed variable occurrence of these PUL in related Maribacter and Zobellia strains, indicating specialization to certain \u201cpolysaccharide niches.\u201d Furthermore, lineage- and strain-specific genomic signatures for exopolysaccharide synthesis possibly mediate distinct strategies for surface attachment and host interaction. The wide detection of CAZyme homologs in algae-derived metagenomes suggests global occurrence in algal holobionts, supported by sharing multiple adaptive features with the hydrolytic model flavobacterium Zobellia galactanivorans. Comparison with Alteromonas sp. 76-1 isolated from the same seawater sample revealed that these co-occurring strains target similar polysaccharides but with different genomic repertoires, coincident with differing growth behavior on alginate that might mediate ecological specialization. Altogether, our study contributes to the perception of Maribacter as versatile flavobacterial polysaccharide degrader, with implications for biogeochemical cycles, niche specialization and bacteria-algae interactions in the oceans.Carbohydrate-active enzymes (CAZymes) are an important feature of bacteria in productive marine systems such as continental shelves, where phytoplankton and macroalgae produce diverse polysaccharides. We herein describe  Continental shelves are productive marine systems, where photosynthesis by pelagic phytoplankton and benthic macroalgae yields considerable amounts of organic matter. Polysaccharides constitute a major fraction of the algae-derived organic matter, with important roles in nutrient cycles and microbial metabolism . ConsequCultured bacterial strains are a valuable resource for studying the ecological and biogeochemical implications of microbial polysaccharide degradation, complementing molecular and metagenomic approaches on community level . CultureFlavobacteriaceae and Cryomorphaceae, are major contributors to marine polysaccharide degradation. Comparable to the human gut, marine flavobacteria can degrade various polysaccharides through dedicated genetic machineries (susCD genes in polysaccharide utilization loci (PUL) for orchestrated uptake and degradation  amended with 0.001% sodium alginate . Purity R2 = 0.97). Glucose concentrations were measured using samples diluted to 0.001% with MilliQ followed by HPLC with NaOH (18 mM) as eluent and a Carbopac PA 1 column (Thermo Fisher Scientific). A calibration curve was generated using 24 concentrations from 0.025 to 10 \u03bcM glucose (R2 = 0.99).At each OD measurement, subsamples of 5 mL were filtered through 0.22 \u03bcm polycarbonate filters into combusted glass vials and stored at \u221220\u00b0C. Alginate concentrations were quantified by High Performance Liquid Chromatography (HPLC) of its monomers mannuronate and guluronate after chemical hydrolysis  in combusted and sealed glass ampoules. Samples were neutralized with 6 N NaOH, desalted using DionexOnGuard II Ag/H cartridges , and eluted with 100 mM sodium acetate tri-hydrate in 100 mM NaOH. Concentrations were determined in three dilutions per sample  using a Carbopac PA 1 column (Thermo Fisher Scientific) and pulsed amperometric detection according to Capnocytophaga ochracea DSM 7271 as outgroup. The resulting nucleotide alignment was visually confirmed for consistency and the best substitution model (GTR + G) computed using ModelTest-NG  according to the manufacturer\u2019s instructions. The genome was sequenced with Illumina technology using a GAIIx sequencing platform on paired-end libraries prepared with the Nextera XT DNA Kit . A total of 83 contigs  were assembled using SPAdes v3.0 , followelTest-NG . A maximlTest-NG  on the ClTest-NG .e-value < 10\u201315 and > 65% query coverage. Gene annotations and PUL boundaries were manually curated based on the CAZy and UniprotKB-Swissprot databases  were identified by searching homologs from Gramella forsetii (NCBI assembly GCA_000060345.1). Putative kduI and kduD genes for processing unsaturated uronates were identified by searching homologs from Gramella flava (NCBI assembly GCA_001951155.1). Signal peptides were predicted using SignalP v5.0 , including an entire additional PUL for alginate degradation. Moreover, one PL7 and one PL12 are unique to lineage 1 (see detailed paragraph below). In contrast, a sizeable PUL encoding a PL10 pectate lyase with CE8 methylesterase domain is restricted to lineage 3 . Furthermore, specific O-antigen and GT variants occur on sublineage- and strain-level , presumachanisms .The array of predicted alginate lyase genes allowed considerable growth with alginate as sole nutrient source . Growth susCD pair and all genes for downstream processing of alginate monomers . The co-localization of PL families with structural and catalytic diversity . In contrast, lineages 2 and 3 encode a PL7 in this position, or solely harbor the PL6 and PL17 (Flavivirga eckloniae (locus tags C1H87_08155-08120), with 65% amino acid identity between the respective PL7 lyases. The original isolation of F. eckloniae from the alginate-rich macroalga Ecklonia  within an exopolysaccharide-related cluster, including several unique GTs , originally annotated as heparinase and PL8 but confirmed as PL33 and PL40 using the latest CAZy database  and the PL12 within the EPS gene cluster (unique to strain 62\u20131) in 102 microbial metagenomes from marine plants. The co-detection of PL33 and PL40 homologs on diverse algae and seagrasses from global locations  and advantageous traits  indicates versatile lifestyles, which potentially change depending on physicochemical conditions and algal health  can be found in the article/LW conducted genomic analyses and contributed to writing. MM performed growth experiments and HPLC. JK contributed to genomic analyses. RD performed genome sequencing. MS co-organized the experiments yielding the isolation of strain 62\u20131. MW designed research and wrote the manuscript. All authors contributed to the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Scientific Reports 10.1038/s41598-021-85195-5, published online 11 March 2021Correction to: The original version of this Article omitted the Funding section. The Funding section now reads:\u201cThis work was supported by GIST Research Institute (GRI) grant funded by the GIST.\u201dThe original Article has been corrected."}
+{"text": "Traumatic escape from Vietnam in 1975 brought 1.3 million Vietnamese refugees to the U.S. Today, Vietnamese are the largest Asian subethnic group in Houston, Texas , making Houston the 3rd largest Vietnamese-populated city in the U.S. Despite these numbers, health research on Vietnamese population is limited. To address this gap, we developed the Vietnamese Aging and Care Survey and collected data on Vietnamese older adults (\u226565 years) and their caregivers (N=199). The purpose of this study was to examine the association between caregivers\u2019 caregiving characteristics and care recipients\u2019 mental health (N=58 dyads). Descriptive statistics and logistic regression models were used. Caregivers were on average 53 years-old, Vietnam-born (97%), and working (66%). The majority (84%) lived with their care recipients and provided care for 20+ hours/week (69%) in good/excellent health (76%). Care recipients were on average 75 years-old, Vietnam-born (100%) in fair/poor health (81%). Regression results showed stressed caregivers with more-depressed care recipients  but positive caregiving experiences  and burdened caregivers  with less-depressed care recipients. We found the association between stressed caregivers and depressed care recipients (Life Stress Paradigm), but care recipients becoming a \u201chelpful company\u201d reduces caregiver burden and care recipients\u2019 depression . Vietnamese families live in multigenerational households within ethnic enclaves and remain a tightly-knit family unit showing resilience to their low socioeconomic status . Leveraging a family as their strength, healthcare professionals should take a caregiver-care recipient dyad approach when planning COVID-19 pandemic interventions in Vietnamese communities."}
+{"text": "ABSTRACT IMPACT: Rapid launch of a virtual internship can address clinical and translational science training needs of the New Jersey Alliance for Clinical and Translational Science (NJ ACTS) workforce during a pandemic. OBJECTIVES/GOALS: The global pandemic has necessitated innovate strategies for training clinical and translational scientists. With trainees largely restricted from campus, the Workforce Development Core of the NJ ACTS Hub sought to develop and evaluate a virtual 8-week internship program for professional and graduate students within the NJ ACTS community. METHODS/STUDY POPULATION: Establishment of the internship required a systematic approach to 1) recruiting projects and supervisors, 2) collecting and evaluating 90 applications, 3) screening and selecting finalists, and 4) onboarding interns that spanned 7 weeks. Core Leads and Researchers within NJ ACTS developed 8 projects to be performed remotely by 11 interns. Leads and co-leads from the Team Science, Special Populations, Community Engagement, Informatics, and TL1 Cores and Programs designed projects. During the internship, participants engaged in a series of career development training and one-on-one mentoring through weekly meetings. The internship culminated in a final symposium open to the entire clinical and translational science community. RESULTS/ANTICIPATED RESULTS: Interns spanned different educational programs - pharmacy (36%), medicine (18%), and undergrad (9%)/graduate education (36%). Interns included women (63%), students from underrepresented backgrounds (27%) and students who were first in their family to pursue advanced education (18%). Project topics included competency assessment, COVID-19 clinical trials, marketing materials, community engagement salons, eSource for clinical trials, team science projects, and REDCap utilization. Using a 4-point Likert scale to evaluate competencies, the baseline strengths of interns included team-based science (mean/SD: 3.5 \u00b10.7). Trainings were designed to address gaps in intern skills including developing written and graphical abstracts (mean/SD: 2.2 \u00b10.9) and effective LinkedIn pages (mean/SD: 2.4 \u00b11.0). DISCUSSION/SIGNIFICANCE OF FINDINGS: Taken together, the rapid development and launch of a virtual internship program can increase participation of trainees in CTSA Hub research activities and address gaps in their clinical and translational skill set. Plans are to host virtual internships each semester to enhance workforce training and collaboration across Hub Cores."}
+{"text": "Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited targeted therapeutic options. A defining feature of TNBC is the propensity to metastasize and acquire resistance to cytotoxic agents. Mitogen activated protein kinase (MAPK) and extracellular regulated kinase (ERK) signaling pathways have integral roles in cancer development and progression. While MEK5/ERK5 signaling drives mesenchymal and migratory cell phenotypes in breast cancer, the specific mechanisms underlying these actions remain under-characterized. To elucidate the mechanisms through which MEK5 regulates the mesenchymal and migratory phenotype, we generated stably transfected constitutively active MEK5 (MEK5-ca) TNBC cells. Downstream signaling pathways and candidate targets of MEK5-ca cells were based on RNA sequencing and confirmed using qPCR and Western blot analyses. MEK5 activation drove a mesenchymal cell phenotype independent of cell proliferation effects. Transwell migration assays demonstrated MEK5 activation significantly increased breast cancer cell migration. In this study, we provide supporting evidence that MEK5 functions through FRA-1 to regulate the mesenchymal and migratory phenotype in TNBC. Triple negative breast cancer (TNBC) represents a particularly aggressive subtype of breastcancer. Defined by a lack of targetable receptors, treatment options for patients presentingwith TNBC are limited to cytotoxic agents, such as anthracyclines and taxanes , 2.AlthAberrant MAPK signaling has been broadly shown to mediate chemoresistance in numerousmalignancies -7. ActivEMT plays an integral role in regulating various processes crucial to development,progression and recurrence of breast tumors, including metastasis, maintenance of breastcancer stem cells and acquisition of drug resistance -20. In bCharacterizing signaling pathways that mediate EMT in breast cancer biology provides apromising avenue for novel therapies. Given the clinical relevance and significantregulatory roles of the MEK5/ERK5 signaling pathway in breast cancer, it is a promisingtherapeutic target , 25, 26.etal., and lists 30 genes whose gene expression profile is predictive of completepathologic response to chemotherapy treatment in breast cancer , followed by analysis of significantlydown-regulated genes. Based on -log calculated from output data, top regulatedpathways were determined. MDA-MB-231 transfected cells were extracted for total RNA. Changes in gene expressionwere determined using next generation sequencing as described . Genes sStatistical analyses were performed using Graphpad Prism software . Data were subjected to unpaired Student\u2019s t-test, with p-value <0.05 considered statistically significant. Studies involving more than two groups wereanalyzed by one-way analysis of variance (ANOVA) followed by Tukey\u2019s post-hoc multiplecomparison tests. *, p < 0.05; **, p < 0.01; ***, p < 0.001."}
+{"text": "Communication is fundamental for dementia care and identifying communication behaviors is key to identifying strategies that facilitate or impede communication. To measure caregiver nonverbal communication, we adapted the Verbal and Nonverbal Interaction Scale for Caregivers (VNVIS-CG) for second-by-second behavioral coding of video observations. The VNVIS-CG was adapted for computer-assisted Noldus Observer coding of video interactions captured at home by family caregivers from the FamTechCare clinical trial. Operational definitions for nonverbal communication behaviors were developed and inter-rater reliability was excellent (Kappa = .88) using two independent coders. Videos N=232 were coded featuring 51 dyads; caregivers who were primarily female (80%) spouses (69%) of men (55%) diagnosed with moderate to severe dementia (64.7%). Mean caregiver age was 65 years. Emotional tone conveyed by caregivers was primarily respectful, occurring 68.1% of the time, followed by overly nurturing (9%), bossy, harsh, or antagonistic (6.2%), and silence occurred 16.7 % of the time. Caregiver gestures and positive postures  were the most commonly occurring overt behaviors (46.5%), followed by changing the environment to help the PWD (19.9%), and expressing laughter/joy (18.9%). The least common nonverbal behaviors were negative posture, aggression, compassion, and rejecting. The adapted behavioral coding scheme provides a reliable measure that characterizes dementia caregiver nonverbal communication behaviors for analysis of video observations. Ongoing research will identify strategies that facilitate communication as well as determine how strategies vary by dementia stage, diagnosis, and dyad characteristics."}
+{"text": "Exercise decreases mortality and hospital admissions. Exercise adherence is challenging, and little is known about exercise adherence especially in older adults with heart disease. To gain an understanding of long-term exercise behaviors in older adults we conducted a cross-sectional study of individuals diagnosed between 2016-2020 with myocardial infarction (MI)/angina. Emails were sent in 2020 to recruit participants. Exercise adherence was measured using the Exercise Adherence Rating Scale (EARS), Godin\u2019s Leisure-Time Activity Scale (GLTEQ) for exercise intensity, and self-report for impact of COVID-19. Descriptive statistics and t-tests were used to analyze data. Eight-hundred and seven individuals (x \u00ae age 67.3) responded to the on-line survey. The majority were males (68.8%), married, (68.9%), and retired (59.3%). Co-morbidities included hypertension (32%), hyperlipidemia (21%), diabetes (12%), and depression (6.2%). Long-term exercise behaviors were independently observed in participants \u226565yr (n=526) and <65yr (n=281). Females \u226565yo demonstrated higher exercise adherence scores compared with males \u226565yo . Conversely, males scored higher in exercise intensity . Gender related exercise adherence and exercise intensity did not differ significantly in <65yo . Exercise frequency decreased in both age groups after COVID-19 Pandemic started, however the decrease was significant only in older adults (p=.014) indicating they were at greater risk for exercise problems when faced with environmental barriers. Additional research is recommended as to the impact of environmental factors on exercise adherence in older adults and potential interventions."}
+{"text": "Adult mammalian hearts show limited capacity to proliferate after injury, while zebrafish are capable to completely regenerate injured hearts through the proliferation of spared cardiomyocytes. BMP and Notch signaling pathways have been implicated in cardiomyocyte proliferation during zebrafish heart regeneration. However, the molecular mechanism underneath this process as well as the interaction between these two pathways remains to be further explored. In this study we showed BMP signaling was activated after ventricle ablation and acted epistatic downstream of Notch signaling. Inhibition of both signaling pathways differentially influenced ventricle regeneration and cardiomyocyte proliferation, as revealed by time-lapse analysis using a cardiomyocyte-specific FUCCI (fluorescent ubiquitylation-based cell cycle indicator) system. Further experiments revealed that inhibition of BMP and Notch signaling led to cell-cycle arrest at different phases. Overall, our results shed light on the interaction between BMP and Notch signaling pathways and their functions in cardiomyocyte proliferation during cardiac regeneration. Myocardial infarction (MI) is a leading cause of death worldwide Zebrafish cardiac regeneration involves multiple signaling pathways Notch signaling pathway also plays important roles in cardiac regeneration Tg(vmhc:mCherry-NTR) with metronidazole (MTZ) at 3 days post fertilization (dpf) in situ hybridization (WISH) staining revealed that gene expressions of several BMP signaling components were dramatically increased in ablated hearts compared to that in control hearts at 5 dpf/ 2 days post MTZ-treatment (dpt)  Fig. A-D'. BMPTg(Bre:dGFP) which expressed destabilized GFP in BMP-activated cells Tg larvae displayed weak GFP signal in the ventricle at 4 dpf, besides other extracardiac signals. After ventricle injury, BMP signaling was activated in the ablated heart, mainly in the atrium, at 1 dpt. The signal intensity was gradually enhanced in the atrium and extended to the ventricle at 2 dpt  larvae. The results suggested that BMP signaling was strongly activated in myocardium during ventricle regeneration, while a weaker epicardial BMP signal could be detected occasionally  that inhibition of BMP signaling by DM treatment did not affect the activation of Notch signaling in the endocardium around atrioventricular canal  or early stage (0-2 dpt) of ventricle regeneration significantly reduced the heart recovery rates  with Tg(vmhc:mCherry-NTR) so that cardiomyocytes in S/G2/M phases would be labelled with green fluorescence  and recorded the change in zGem+ cardiomyocyte pattern by 12-hour-interval living imaging  fish. The overlapped signals of pH3 and EdU with zGem+ could help to eliminate the interference caused by proliferative cells in adjacent tissues, such as endocardium, epicardium and blood cells. Proliferating cardiomyocytes were in different cell-cycle stages , Tg(Bre:dGFP), Tg(tp1:dGFP), Tg(myl7:mAG-zGeminin).Zebrafish were maintained under standard conditions in situ hybridization was performed as previously described notch1b, nkx2.5, gata4, tbx20. The probes for bmp10, bmpr1aa, id2b and smad1 were amplified by PCR with the following primers: bmp10 F-GCAGCCAGCAAGTAAGAGGA and R-GGTAGAGCAGGGAGATGGGA, bmpr1aa F-TAGCCAACCCCAATGCTTAC and R-GCCCATTTGTCTCGCAGGTAT, id2b F-TCGTGCCGAGTTTACCG and R-GCAATACCATACAGCTCCAGAT, smad1 F-CACGCTTCCGTAACCCACTCC and R-GCTCAAACATTCGGCATACACCT.Whole-mount Tg(vmhc:mCherry-NTR) larvae were treated with 6 mM MTZ  in E3 water at 3 dpf for four hours as previously described The larvae were incubated with 500 \u03bcM EdU for 1 h in E3 water with 2% DMSO to facilitate EdU solubilization. After pulse labeling, larvae were rinsed with E3 water, anaesthetized with 0.2% tricaine and fixed in 4% PFA. The CLICK-IT reaction for EdU labeling was performed according to the manufacturer's instruction (Thermo Fisher Scientific).Immunofluorescence staining on whole-mount larvae was performed as previously described Live imaging and immunostaining images were obtained using a Zeiss LSM880 confocal microscope or an Olympus IX83 inverted microscope. The numbers of differentially marked cardiomyocytes were counted with ZEN software or cellSens software.P < 0.05 determined by Student's t-test between two groups, ANOVA analysis between more than two groups or Binomial test in quantification of the percentage of recovered hearts.Values were presented as mean \u00b1 SD. Statistical significance was defined as a threshold of"}
+{"text": "Scientific Reports 10.1038/s41598-021-89565-x, published online 12 May 2021Correction to: The original version of the Article contained an error in the Author Information section.\u201cThese authors contributed equally: Qingquan Liu, Yiru Wang, Xiaolin Guo and Yongman Lv.\u201dnow reads:\u201cThese authors contributed equally: Qingquan Liu and Yiru Wang. These authors jointly supervised this work: Xiaolin Guo and Yongman Lv.\u201dThe original Article has been corrected."}
+{"text": "Infertility is rarely life threatening, however, it poses a serious global health issue posing far-reaching socio-economic impacts affecting 12\u201315% of couples worldwide where male factor accounts for 70%. Functional spermatogenesis which is the result of several concerted coordinated events to produce sperms is at the core of male fertility, Alternative splicing and microRNA (miRNA) mediated RNA silencing (RNAi) constitute two conserved post-transcriptional gene (re)programming machinery across species. The former by diversifying transcriptome signature and the latter by repressing target mRNA activity orchestrate a spectrum of testicular events, and their dysfunctions has several implications in male infertility. This review recapitulates the knowledge of these mechanistic events in regulation of spermatogenesis and testicular homoeostasis. In addition, miRNA payload in sperm, vulnerable to paternal inputs, including unhealthy diet, infection and trauma, creates epigenetic memory to initiate intergenerational phenotype. Naive zygote injection of sperm miRNAs from stressed father recapitulates phenotypes of offspring of stressed father. The epigenetic inheritance of paternal pathologies through miRNA could be a tantalizing avenue to better appreciate \u2018Paternal Origins of Health and Disease\u2019 and the power of tiny sperm. Until puberty, the exquisite stem cell driven spermatogenesis in mammal is initiated to continuously produce haploid male gametes . SpermatThe crunch of biology is that DNA decodes phenotype. However, the aetiology of diseases including infertility in most cases is non-DNA sequence-associated , 4. BeyoDicer, a necessary endoribonuclease for miRNA biogenesis, has preimplantation development defects that can be rescued by injection of naive sperm RNAs [Unlike alternative splicing that diversifies mRNA variants, non-coding RNAs (ncRNAs), the abundant functional RNA transcripts without protein-coding property, are tire post-transcriptional regulators of gene expression. The landscape of ncRNAs has not yet fully deciphered but novel subspecies is emerging . miRNA term RNAs .Table 1.The concept of \u2018Developmental Origins of Health and Disease\u2019 captures the influences on health in adulthood of foetal life experience . IntensiBcas2 null mice, its further differentiation is dampened [in vivo study still needs to better characterize its relevance.Spermatogonial stem cells (SSCs), the heterogeneous undifferentiated spermatogonia comprising 0.01\u20131% of testicle cell populations, host properties of stemness maintenance and differentiation into spermatocytes that commence meiosis. Spermatogonia differentiation is under fine-tuning regulation of a myriad of signalling pathways . In partdampened . Epitheldampened . The inv6-methyl-adenosine (m6A) modification of mRNA is prevalent across organisms and represents a mechanism for post-transcriptional gene regulation. Emerging evidence suggests m6A modification intervenes mRNA alternative splicing, translational efficiency and stability [6A \u2018writer\u2019, methyltransferase-like 3/14 (Mettl3/14) regulate the expression and splicing of spermatogenesis-related genes required for alternative splicing of genes for SSCs maintenance (Dazl) and differentiation (Sohlh1), and its deficiency compromises spermatogonial differentiation [Mettl3/14 depletion is reported by another study [Ntability . Being tntiation . The SSCer study . A glimpTAp73 increases DNA damage induced spermatogonia death which can\u2019t be phenocopied by \u0394Np73 depletion, implying functional non-redundancy between them [Alternative splicing confers gene pleiotropy of several determinants in SSCs. The stem cell factor (SCF) c-kit is specifically expressed in differentiating spermatogonia to support survival and proliferation of pre-meiotic germ cells . Howevereen them ,38.Several multifaceted RNA helicases, such as MOV10 and DDX5, have been implicated in alternative splicing in spermatogonia ,40. MOV1The differentiated type B spermatogonia further differentiates into prepachytene spermatocytes which pass through the blood-testis barrier (BTB) becoming residents at the apical compartment wherein they transform into primary spermatocytes for meiosis . MultiplDazl, Ehmt2 and Hmga1, and its deficiency causes alternative splicing catastrophe in male germline leading to compromised spermatogenesis with rare meiotic spermatocytes [Mvh, Sycp3, Tpx-1 and Tex19.1, and thereby regulates their translation [Bcas2 depletion favours the exon 8 deleted DAZL (Dazl-\u03948) production instead, which dwindles the functional full-length DAZL reservoir [Pachytene spermatocytes undergo two consecutive meiotic divisions without an interval of DNA synthesis to produce haploid gametes . BCAS2 patocytes . The RNAnslation 3245, 46.eservoir . Spo11, eservoir , encodeseservoir ,48. The eservoir .RanBP9 are both sterile [RanBP9 deficient mice [Importantly, RBPs, by interacting with distinct partners, broadens the regulatory kingdom of alternative splicing. Ran-Binding Protein 9 (RanBP9), also called RanBPM, a multi-modular scaffolding protein belongs to RBP family, is essential for mammal gametogenesis as male and female lacking  sterile ,51. Defeent mice . RanBP9 ent mice ,52. Moreent mice , providiSam68 ablation compromises pachytene spermatocytes survival and spermatocytes meiosis [Sgce exon 8 in meiotic spermatocytes via affecting phosphorylated Pol II and U2AF65 recruitment, leading to exon skipping [The Src-associated substrate in mitosis of 68 kDa (Sam68), a signal transducer and RBPs activator, is a ubiquitous splicing factor for specific mRNAs.  meiosis . In addi meiosis . In addiskipping .TLE4-T in cooperation with SR-like protein TRA2b [Beyond the ubiquitously expressed splicing factors, a plethora of testis-specific ones, such as RNA-binding motif on Y chromosome (RBMY), heterogeneous nuclear ribonucleoprotein G-T (hnRNPG-T), signal transduction and activation of RNA (T-STAR) and homeodomain-interacting protein kinase 3 (HIPK3) have been identified in mammalian testis ,57. RBMYin TRA2b ,58. Furtin TRA2b . Althougin TRA2b .In parallel to exon skipping by which alternative splicing generates transcript variants, the choice between mutually exclusive exons, use of alternative splice sites and intron retention intricately create transcripts differ in untranslated region (UTR). The length of 3\u02b9UTR influences mRNAs stability and translation likely due to longer 3\u02b9UTRs have more propensity of RBPs binding while shorter ones loss the priority ,62, makiIntron retention (IR) is the most represented pattern of alternative splicing that contributes to the plasticity of transcriptome and the regulation of gene expression ,66. IR iBrdt bromodomain deletion (\u0394BDBrdt) with the up-regulated genes are enriched for splicing genes [Testis-specific double bromodomain-containing protein (BRDT), a bromodomain and extra-terminal motif (BET) family member, is the only BET protein highly expressed throughout the transcriptionally active pachytene stage and in haploid spherical spermatids along with BRD2/3 which is required for production of fertile sperms . BRDT hang genes .Srsf2), Asp\u2013Glu\u2013Ala\u2013Asp (DEAD)-box polypeptide 5 (Ddx5) and heterogeneous nuclear ribonucleoprotein K (Hnrnpk) is the 3\u02b9UTR truncation while the major spliceosome components, such as TAR DNA binding protein (Tardbp), are with longer 3\u02b9UTR accompanied by reduced protein expression Brdt depletion severely disrupts chromatin modifications involved in meiotic sex chromosome inactivation (MSCI) which epigenetically reprograms and transcriptionally ceases XY body, the chromatin configuration, and the crossover dynamics in spermatocytes, entitling BRDT an essential reprogramming and chromatin organization factor in spermatocytes meiosis [One commonality to most of those splicing genes including Serine/arginine-rich splicing factor 2 6A modifi of mRNA . Alkbh5  meiosis . The pheke stage . The evi6A modification factors in spermatocytogenesis are emerging. YT521-B homology domain-containing 2 (YTHDC2), a m6A \u2018reader\u2019 that recognizes m6A marks, functions in RNA splicing, mRNA decay and translation control, and is essential for male fertility [6A \u2018reader\u2019, YTHDC2 has 3\u02b9-5\u02b9 RNA helicase activity to regulate the abundance of m6A-modified transcripts, which ensures the programming of mitotic spermatogonia to meiotic spermatocytes [Attractively, novel mertility ,78,79. Yertility . Beyond atocytes .The final differentiation of spermatogonia is an extraordinarily integrated process termed spermiogenesis, through which the haploid spherical spermatid (rST) transforms into highly specialized tadpole-shaped spermatid prior to leaving seminiferous epithelium for further maturation in epididymis.Ptbp2 depleted germ cells arrests at spermatid differentiation accompanied by apoptotic death of spermatocytes [Spermatids elongation is one hallmark for spermatogenesis. Transcription cessation gradually takes place from rST onwards, but alternative splicing again deems its power. PTBP2 is a key splicing factor in nervous system, but also functions in germ cell. PTBP2 persists through spermatocytes to elongating spermatids, and spermatogenesis of atocytes ,83. Inteatocytes , suggestatocytes ,85. Prioatocytes ,87. Alteatocytes . Its impMrg15 null mice arrests at spherical spermatid stage but with normal histone methylation [Ptbp2 and Mrg15 null spermatids are non-overlapping, suggesting MRG15 and PTBP2 are specialized for splicing events.Interregulation of histone modification and alternative splicing is evident by chromatin-binding protein dependent recruitment of splicing factors . MORF-rehylation , which fRbm5 mutant mouse, splicing defects alter the expression of genes involved in MAPK/ERK and JAK/STAT signalling required for spermatid differentiation including germ cell adhesion, spermatid head shaping, and acrosome and tail formation [FAS, Caspase2 and c-FLIP are additional splicing clients of RBM5 [RBM5 (RNA binding motif 5) is another novel splicing factor highly enriched in testis, especially in spermatocytes and spherical spermatids, and is required for spermatid differentiation. RBM5 directly complexes with several partners implicated in pre-mRNA splicing, such as hnRNP, SR proteins, SFPQ and RNA helicase DDX5, and several RBPs include PABP1, DDX4, PSPC1 and ELAV1 that regulates various RNA processing events are also RBM5 putative partners . In Rbm5ormation . More be of RBM5 ,93.Acrbp null mice lacking both isoforms loss fecundity due to acrosome fragmentation. ACRBP-V5 functions in formation and configuration of acrosomal granules during early spermiogenesis while ACRBP-W functions in retention of the inactive proACR in acrosome until acrosomal exocytosis [The formation of acrosome, a Golgi-derived exocytotic organelle the contents which are indispensable for natural fertilization, is another remarkable event in spermiogenesis. The acrosomal protein ACRBP/sp32 is a binding protein for precursor ACR (proACR) and intermediate ACR ,95. In mocytosis , furtherFertility is constantly challenged by environmental insults, such as malnutrition, diabetes, stress, infections and xenobiotics. Numerous miRNAs have either ubiquitous or developmental dependent expression in testis, and regulates a myriad of events by targeting genes in different pathways . We high+ dependent deacetylase, have been in limelight over recent years due to their activities towards diverse pathways coping with cellular energetic, metabolic and redox crises [Sirtuins (Sirt1-7), a family of NADx crises . Among tx crises ,98.\u2212/\u2212Sirt1 mice are sterile with decreased testes size and rare presence of spermatozoa due to spermatogenic arrest at late-meiotic prophase followed by germ cells degeneration, and even a scarcity of spermatozoa can be retrieved they are immotile with morphological anomalies [\u2212/\u2212Sirt1 mice, therefore is ascribe to up-regulated p53 activity. Upon oxidative stress, Sirt1 deacetylates and activates PGC1\u03b1 to augment antioxidative response [\u2212/\u2212Sirt1 mice.Converging evidence suggests Sirt1 is a determinant for male and female fertility. Sirt1 is highly expressed from spermatotonia to spherical spermatids . Sirt1\u2212/nomalies ,100. P53nomalies , germ ceresponse . In this\u2212/\u2212Sirt1 mice could be a consequence of dysfunctions in hypothalamic-pituitary axis (HPA) [in vitro GnRH neuronal migration, and GnRH neurons in \u2212/\u2212Sirt1 mice loss migration from vomeronasal organ to colonize in hypothalamus, leading to hypogonadotropic hypogonadism reminiscent of human congenital Kallmann\u2019s Syndrome that causes male infertility [Sirt1 knockout (cKOSirt1) mice whereby novel roles of Sirt1 in acrosome biogenesis and histone to protamine transition are discovered [Notably, spermatogenesis defects in is (HPA) . HPA relertility . The dirscovered .Multiple miRNAs that target Sirt1 mRNA are reported. Given its relevance to reproductive health, perturbation in Sirt1 activity might underlie the molecular bases for fertility impairments, which is evident by miR-34a in diabetes mellitus (DM) induced testicular apoptotic cell death (TACD) . ObesityBesides Sirt1, Sirt2-7 are also of cellular importance. Sirt2 is primarily in cytoplasmic where it deacetylates \u0251-tubulin and checkpoint protein BubR1 to regulate cell division while Sirt3-5 are mitochondrial proteins to maintain mitochondrial functionality . Sirt6 iNuclear factor erythroid 2-related factor 2 (Nrf2) is a ubiquitous stress-rectifying transcription factor that harnesses a spectrum of signalling involved in regulation of redox homoeostasis, autophagy, detoxification, mitochondrial biogenesis and metabolic reprogramming . Nrf2 haGenerally, Nrf2 results in favourable outcomes, however, its hyperactivation is pronounced by chemotherapeutic drug resistance . Nrf2 ac\u2212/\u2212Nrf2 mice are viable presumably due to the compensation effect of Nrf1 as mice carrying combinatorial deletion for Nrf1 and Nrf2 die days after birth [\u2212/\u2212Keap1 mice with Nrf2 hyperactivation also die before weaning [\u2212/\u2212Nrf2 mice have compromised fecundity with declined spermatid output due to oxidative damage [in vitro hypoxic/reoxygenation modelized Leydig cell (TM3) [Although well studied in other fields, Nrf2 signalling in reproductive biology is mysterious. Even with decreased foetal weight and increased susceptibility to hyperoxia, er birth . Interes weaning . Nrf2\u2212/\u2212e damage . In addie damage ,125. MiRll (TM3) . FurtherDicer cKO sperm origin have preimplantation defects that can be ameliorated by injection of naive sperm RNAs [The study of paternal experiences and heritability to offspring is a topic of interest since long. While previously considered has limited contribution except paternal genome to embryo in light of the facts that (1) negligible size compared with oocyte; (2) transcriptionally inert; (3) limited remnant of cytoplasm with compromised translation machinery, sperm now is believed to preserve important epigenetic codes to shape embryonic development and offspring health. Indeed, embryos of erm RNAs . More reerm RNAs . In addierm RNAs ,21. The Given the prevalence of obesity pandemic, the influences on offspring health of parental obesity have attracted considerable attentions. Obesity up-regulates miR-122/155 in men\u2019s sperm , and humOf note, physical intervention is a common recommendation for preconception care, but paternal long-term physical activity predisposes offspring to higher susceptibility to HFD induced pathologies of glucose intolerance and insulin resistance, and modifies DNA methylation and miRNA repertoire in paternal sperm . That isTraumatic stress is an environmental stimuli living with most individuals that has intergenerational influences. Early life trauma correlates with down-regulation of several miR-34/449 family members that program neurodevelopment and spermatogenesis, in sperm of both humans and mice, and the phenomena persist over generations in mice . When exOver evolution, pathogens are co-evolving with us. They hijack host cellular machinery and reshapes host epigenome to create a conducive microenvironment for its pathogenesis . NumerouInfertility affects nearly 48.5 million reproductive-age couples worldwide, and around 2% of men present with compromised sperm parameters . Spermat+, have promising health benefits and can juvenilize metabolism and rhythm system [Oxidative stress represents a culprit of ageing and many pathologies including infertility ,112. Altm system ,140. Nrfm system . WhetherIn testes, Sertoli cells in seminiferous tubule support germ cells development, and construct an immuno-privilege niche for them . Sertoli6A mRNA modification [Although miRNA matters for epigenetic inheritance, it is not the sole reason . Mammalification , implicafication ,149. Thu"}
+{"text": "Cortisol is a primary stress hormone associated with sleep. We examined daily cortisol as the potential mechanism linking prior night\u2019s sleep and daily mood among 173 dementia family caregivers (M (SD) age = 61.97 (10.66)) who used adult day services (ADS) at least two days a week. Caregivers self-reported sleep characteristics  and affect  across eight consecutive ADS/non-ADS days. Salivary cortisol was collected five times each day. Multilevel mediation analysis suggested that daily cortisol total output (assessed as \u201carea under the curve\u201d) mediated prior nights\u2019 total time in bed and daily anxiety, but only on high-stress (non-ADS) days. Mediation was non-significant on low-stress (ADS) days, and at the between-person level. ADS use is respite from a chronically stressful role. Reducing exposure to stress via respite may protect against harmful processes related to sleep, cortisol reactivity, and daily anxiety."}
+{"text": "Correction to: BMC Neurol 19, 304 (2019)https://doi.org/10.1186/s12883-019-1542-9Following publication of the original article , the autThe sentence currently reads:\u201cThe lumbar ponction revealed a clear pleocytose  and elevated protein levels  without any evidence of tumor cells. We documented the presence of serum anti-neuronal Hu antibodies\u2026\u201dThe sentence should read:did not reveal a pleocytosis  but elevated protein levels  without any evidence of tumor cells. We documented the presence in the serum and in the cerebrospinal fluid (CSF) of anti-neuronal Hu antibodies\u2026\u201d\u201cThe lumbar ponction The original article  has been"}
+{"text": "P\u2009<\u20090.0001), implying a tumor-suppressive role. Colon-specific Znf545 knockout in mice accelerated CRC in ApcMin/+ and azoxymethane/dextran sulfate sodium-induced CRC. Mechanistically, we demonstrated that ZNF545 uses its two zinc finger clusters to bind to minimal rDNA promoter, where it assembled transcriptional repressor complex by interacting with KAP1. Znf545 deletion in mouse embryonic fibroblasts not only increased rRNA transcription rate and the nucleolar size and number but also altered the nucleolar composition and architecture with an increased number of fibrillar centers surrounded by net-like dense fibrillar components. Consequently, Znf545 deletion promoted the gene expression of translation machinery, protein translation, and cell growth. Consistent with its tumor-suppressive role, ZNF545 overexpression in CRC cells induced growth arrest and apoptosis. Finally, administration of rRNA synthesis inhibitor, CX-5461, inhibited CRC development in Znf545\u0394/\u0394ApcMin/+ mice. In conclusion, ZNF545 suppresses CRC through repressing rRNA transcription and protein translation. Targeting rRNA biosynthesis in ZNF545-silenced tumors is a potential therapeutic strategy for CRC.Ribosome biogenesis plays a pivotal role in tumorigenesis by supporting robust protein translation. We investigate the functional and molecular mechanism of Zinc finger protein 545 (ZNF545), a transcriptional repressor for ribosomal RNA (rRNA), in colorectal cancer (CRC). ZNF545 was silenced in CRC compared to adjacent normal tissues ( Colorectal cancer (CRC) is the third most common cancer worldwide and the third leading cause of cancer-related deaths . NeverthKr\u00fcppel-associated box zinc finger proteins (KRAB-ZFP) are the largest subgroup of the C2H2-type zinc finger protein (ZFP) family, which constitute the largest family ~350 genes) of transcriptional repressors in the human genome 0 genes o. DespiteZnf545 knockout mice  by crossing Znf545flox/flox mice to CDX2P-CreERT2 mice  , Znf545\u2212/+ mice (Znf545flox/+CDX2P-CreERT2), and wild type (WT) mice (CDX2P-CreERT2) were treated with tamoxifen, followed by carcinogen AOM and three cycles of DSS treatment to induce colon cancer , all the Znf545\u2212/\u2212 mice had multiple tumors  and burden  compared to WT mice  was crossed with ApcMin/+, a model of spontaneous CRC, to generate Znf545\u0394/\u0394ApcMin/+, Znf545\u0394/+ApcMin/+ and ApcMin/+ mice  and Znf545\u0394/+ApcMin/+ (77%) mice developed colon tumors, whilst <50% of ApcMin/+ mice harbored visible tumors in the colon  and burden (P\u2009<\u20090.0001)  Fig. . NotablyP\u2009<\u20090.0001)   of ZNF545, we performed the electrophoretic mobility shift assay (EMSA) using six ~60\u2009bp overlapping biotinylated DNA probes spanning the minimal rDNA promoter region Fig. . Probe 2ZNF545 protein contains twelve C2H2 zinc fingers arranged in two distinct clusters which are separated by a degenerate zinc finger motif (Z5): the first cluster, referred to as \u201cHand 1\u201d, containing zinc fingers 1 to 4, and the second cluster in the C-terminus, referred to as \u201cHand 2\u201d, containing zinc fingers 6 to 13 Fig. . All ZNFAs \u201cHand 1\u201d and \u201cHand 2\u201d bound to rDNA promoters independently of each other, we determined whether either of the zinc finger clusters coupled to transcriptional repression KRAB domain (KRAB-Hand1 or KRAB-Hand2) retains the rRNA suppressive effect of full-length ZNF545 Fig. . Indeed,Next, we sought to identify the potential interaction between ZNF545 and its transcriptional corepressors. We performed rapid immunoprecipitation mass spectrometry of endogenous protein (RIME) profiling assay to probe chromatin-associated protein complex involving ZNF545. Flag-tagged ZNF545 and empty vector overexpressing cells were cross-linked, extracted, and sonicated, followed by anti-Flag pulldown and liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis Fig. . LC-MS/MZnf545\u0394/\u0394 and WT mice to evaluate the effect of ZNF545 loss on the nucleolus  compared to WT MEFs  analysis, which relies on the metabolic incorporation of isotopically labeled specific amino acids into cellular proteins [Znf545 were most significantly enriched in the cytoplasmic translation pathway . Indeed, Znf545\u0394/\u0394 MEFs showed increased glycolysis as measured by L-lactate production . We next evaluated whether CX-5461 can be used for the treatment of Znf545 knockout-induced CRC in mice. CX-5461 was administered orally (50\u2009mg/kg) to Znf545\u0394/\u0394ApcMin/+ mice every 3 days for 30 days at 2 months old , tumor number (P\u2009<\u20090.05), and tumor burden (P\u2009<\u20090.05)  Fig. , inferriZnf545 in mice promotes colorectal tumorigenesis in two CRC models. Mechanistically, we showed that ZNF545 binds to the minimal rDNA promoter and recruits corepressors to mediate repressive histone modifications, leading to suppressed rRNA transcription, ribosome biogenesis and protein translation. Our results suggest that ZNF545 serves as a guardian against dysregulated ribosome activity in colorectal carcinogenesis, and its silencing is pivotal to CRC development.Ribosome biogenesis plays a pivotal role in tumorigenesis by supporting robust protein translation in rapidly proliferating cancer cells. In this study, we identified ZNF545 as a repressor of ribosome biogenesis that suppresses CRC development. Consistent with its functional role as a tumor suppressor, knockout of Znf545 knockout mice. Znf545 knockout increased the tumor number and tumor load in both genetically- (ApcMin/+) or carcinogen- (AOM/DSS) driven CRC mouse models. Consistent with its tumor suppressive effect in vivo, the ectopic expression of ZNF545 in CRC cell lines suppressed cell growth and induced apoptosis. Collectively, our findings provide evidence that ZNF545 functions as a tumor suppressor in CRC.We investigated the tumor suppressive potential of ZNF545 by first establishing rRNA is an essential component of the ribosomes and it is frequently hijacked by cancer cells to boost ribosome biogenesis. Given that ZNF545 functions as a transcription repressor for rDNA, we next elucidated the direct binding of ZNF545 to rDNA and its consequential effect on rRNA-dependent ribosome biogenesis. Several lines of evidence suggest ZNF545 as a critical gatekeeper for preventing excess rRNA transcription: (1) ZNF545 directly binds to rRNA minimal promoter region, the site for Pol I pre-initiation complex formation;  (2) eithElevated rRNA transcription following ZNF545 loss has a major effect on the nucleolus, the principal site of ribosome biogenesis. ZN545-null cells demonstrated enlarged nucleolar size, increased nucleolar number and altered nucleolar microarchitecture, reflecting abnormal activation of nucleolus. Disrupted nucleolus homeostasis is increasingly recognized as a hallmark of cancers and a morphological cue for the early diagnosis of precancerous lesions . Apart fIn light of the pro-tumorigenic role of dysregulated ribosome biogenesis, a number of drugs targeting rRNA synthesis have been developed that demonstrated high selectivity for transformed cells . Our datIn summary, ZNF545 is a tumor suppressor in CRC through transcriptional repression of rRNA transcription. Loss of ZNF545 expression resulted in increased rRNA transcription and ribosome biogenesis, nucleolar abnormality, consequently contributing to colorectal tumorigenesis. Finally, we demonstrate that rRNA biogenesis is a potential vulnerability of ZNF545-null CRC tumors that could be targeted using established rRNA synthesis inhibitors such as CX-5461.A total of 143 patients with histologically confirmed CRC who underwent surgery at Prince of Wales Hospital, the Chinese University of Hong Kong, were obtained as described previously . Biopsy Eight colon cancer cell lines HCT116 (Cat. #CCL-247), HT-29 (Cat. #HTB-38), Caco-2 (Cat. #HTB-37), LoVo (Cat. #CCL-229), SW480 (Cat. #CCL-228), SW620 (Cat. #CCL-227) and LS 180 (Cat. #CL-187) were obtained from the American Type Culture Collection (ATCC). Cell lines were maintained according to protocols from ATCC. The primary immortalized human colonic epithelial cell HCEC 1CT was obtained from Dr. Jerry W. Shay  and cultured on low oxygen. All cell lines were authenticated by short tandem repeat (STR) every 6 months and tested for mycoplasma contamination using LookOut\u00ae Mycoplasma PCR Detection Kit .Znf545-deficient C57BL/6J mice containing a \u201cknockout-first\u201d allele was generated by Beijing Biocytogen Co., Ltd, Beijing, China  was generated by cross-mating mice harboring \u201cknockout-first\u201d allele with mice expressing Flp (B6.129S4-Gt(ROSA)26Sortm1(FLP1)Dym/RainJ; Beijing Biocytogen Co., Ltd). Constitutive Znf545 knockout mice (Znf545\u0394/+ and Znf545\u0394/\u0394) were generated by cross-mating Znf545flox/flox mice with mice expressing the cytomegalovirus (CMV) promoter\u2212Cre (CMV-Cre) (B6.C-Tg(CMV-cre)1Cgn/J; Beijing Biocytogen Co. Ltd). Genotyping was performed by PCR of tail-snip DNA using genotyping primers . Znf545flox/flox mice was bred to CDX2-CreERT2 to generate Znf545flox/+CDX2-CreERT2 and Znf545flox/floxCDX2-CreERT2 mice (colon epithelium-specific Znf545\u2212/+ and Znf545\u2212/\u2212 mice) . Value of P\u2009<\u20090.05 was taken as statistical significance.Data are presented as mean\u2009\u00b1\u2009standard deviation (SD). The two-sided Student\u2019s Supplementary Materials and MethodsSupplementary Table 1Supplementary Table 2Supplementary Table 3Supplementary Table 4"}
+{"text": "Upadacitinib (UPA), an oral selective and reversible JAK inhibitor, demonstrated significantly greater efficacy compared with placebo (PBO) for induction of remission in patients with moderately to severely active ulcerative colitis (UC) in two phase 3 induction trials.Evaluate safety and efficacy of 52 weeks of UPA 15 mg QD (UPA15) and 30mg QD (UPA30) compared to placebo in patients achieving clinical response following UPA 45 mg treatment in the induction trials.The primary analysis (n=451) evaluated efficacy and safety of UPA15 and UPA30 compared to PBO as maintenance therapy. The primary endpoint was clinical remission via adapted Mayo score at wk 52. Ranked secondary endpoints included endoscopic improvement, maintenance of clinical remission, corticosteroid-free clinical remission, maintenance of endoscopic improvement, endoscopic remission, maintenance of clinical response and Histologic-endoscopic mucosal improvement (HEMI).Baseline characteristics were similar between all treatment groups. Both UPA15 and UPA30 met the primary endpoint, and all secondary endpoints. Significantly greater percentages of patients receiving UPA15 and UPA30 vs. PBO achieved clinical remission , endoscopic improvement , maintenance of clinical remission , corticosteroid-free clinical remission , maintenance of endoscopic improvement , endoscopic remission,  and HEMI  . UPA15 and UPA30 were both well-tolerated and no new safety signals were observed. Rates for serious adverse events (AEs) and AEs leading to treatment discontinuation were similar between UPA15 and UPA30 groups and lower compared to the PBO group. Most common AEs were nasopharyngitis and creatine phosphokinase elevation among UPA groups and UC exacerbation within the PBO group (30.2%). Herpes zoster was only reported in UPA groups (3.9%-4.1%). Similar rates of malignancy excluding NMSC were seen within all groups (0.7%-1.3%). MACE were only reported among patients receiving PBO (0.7%), while VTE were only found with UPA30 (1.3%).In patients responding to UPA induction therapy, both UPA15 and UPA30 were safe and effective as maintenance treatment at 52 wk for all primary and secondary endpoints. Patients receiving UPA30 responded approximately 10% better for most endpoints compared to those receiving UPA15. Both doses were well-tolerated, with no new safety signals observed.AbbVie"}
+{"text": "Scientific Reports 10.1038/srep40721, published online 12 January 2017.Correction to: The original version of this Article contains an error in the Abstract.\u201cMoreover, ACB had significantly higher risk of falling versus FNB.\u201dshould read:\u201cMoreover, ACB had significantly lower risk of falling versus FNB.\u201d"}
+{"text": "Accurate diagnosis of rCDI is challenging because of limitations in test performance and alternative causes of recurrent diarrhea, such as post-infectious irritable bowel syndrome (IBS). Stool enzyme immunoassay (EIA) toxin testing (TOX) is the best predictor of active disease, but may miss cases of CDI when toxins are below the limit of detection. In contrast, glutamate dehydrogenase (GDH) or PCR have high sensitivity but cannot differentiate colonization from infection, leading to possible overdiagnosis due to low specificity. In ECOSPOR III, SER-109, an investigational purified microbiome therapeutic, was superior to placebo in reducing rCDI . We examined diagnostic testing patterns among screened subjects. Patients with \u22652 prior episodes and \u22653 unformed bowel movements over 48 hours were screened. To ensure enrollment of patients with active CDI, toxin testing was required at entry via a local certified or central lab . Subjects with discordant GDH+/TOX- tests at the central lab had reflex confirmatory testing with a cell cytotoxicity neutralization assay (CCNA), considered the \u201cgold standard\u201d for toxin testing.The leading reason for screen failure among 281 subjects screened was a negative toxin test . Of 182 patients enrolled, 59 (32.4%) qualified with EIA TOX+ at the local lab  and 122 (67.0%) qualified by the central lab (Table 1). Of these 122 subjects, 87 qualified by GDH+/TOX+ but 35 required additional reflex testing by CCNA due to discordant GDH+/TOX-results; all 35 were positive. Diagnostic Testing for Qualifying C. difficile Episode in ITT PopulationThese diagnostic testing patterns suggest a subset of patients with suspected rCDI have toxin concentrations below the EIA threshold for detection or may have an alternative cause of diarrhea, such as post-infectious IBS. Thus, the limitations of EIA toxin testing need to be considered in clinical practice when evaluating patients with compatible symptoms of rCDI and a high prior probability of infection. In contrast, in trials of investigational agents, toxin testing assures enrollment of patients with active disease and accurate estimates of efficacy. Matthew Sims, MD, PhD, FACP, FIDSA, Astra Zeneca (Independent Contractor)Diasorin Molecular (Independent Contractor)Epigenomics Inc (Independent Contractor)Finch (Independent Contractor)Genentech (Independent Contractor)Janssen Pharmaceuticals NV (Independent Contractor)Kinevant Sciences gmBH (Independent Contractor)Leonard-Meron Biosciences (Independent Contractor)Merck and Co (Independent Contractor)OpGen (Independent Contractor)Prenosis (Independent Contractor)Regeneron Pharmaceuticals Inc (Independent Contractor)Seres Therapeutics Inc (Independent Contractor)Shire (Independent Contractor)Summit Therapeutics (Independent Contractor) Sahil Khanna, MBBS, MS, Seres (Grant/Research Support) Darrell Pardi, MD, seres (Consultant)Vedanta (Consultant) Paul Feuerstadt, MD, FACG, Ferring/Rebiotix Pharmaceuticals Finch Pharmaceuticals (Scientific Research Study Investigator)Merck and Co (Speaker's Bureau)SERES Therapeutics Takeda Pharmaceuticals (Consultant) Elaine E. Wang, MD, Seres Therapeutics (Employee) Elaine E. Wang, MD, Seres Therapeutics  Barbara McGovern, MD, Seres Therapeutics  Lisa von Moltke, MD, Seres Therapeutics"}
+{"text": "ABSTRACT IMPACT: The integration of patient-reported outcome measures into clinical care is feasible and can facilitate patient-centered care for individuals with systemic lupus erythematosus. OBJECTIVES/GOALS: Patient-reported outcome measures (PROMs) are powerful tools which can facilitate patient-centered care by highlighting individuals\u2019 experience of illness. The aim of this study was to assess the feasibility and impact of implementing web-based PROMs in the routine clinical care of outpatients with systemic lupus erythematosus (SLE). METHODS/STUDY POPULATION: Outpatients with SLE were enrolled in this longitudinal cohort study at two academic medical centers. Participants completed PROMIS computerized adaptive tests assessing multiple quality of life domains at enrollment and prior to two consecutive routinely scheduled rheumatology visits using the ArthritisPower research registry mobile or web-based application. Score reports were shared with patients and providers before the visits. Patients and rheumatologists completed post-visit surveys evaluating the utility of PROMs in the clinical encounters. Proportions with confidence intervals were calculated to evaluate survey completion rates and responses. RESULTS/ANTICIPATED RESULTS: A total of 105 SLE patients and 16 rheumatologists participated in the study. Subjects completed PROMs in 159 of 184 eligible encounters , including 90% of visit 1\u2019s (95% CI 82 - 95) and 82% of visit 2\u2019s (95% CI 72 - 90. Patients and rheumatologists found that PROMs were useful (91% and 83% of encounters respectively) and improved communication (86% and 72%). Rheumatologists reported that PROMs impacted patient management in 51% of visits, primarily by guiding conversations (84%), but also by influencing medication changes (15%) and prompting referrals (10%). There was no statistically significant difference in visit length before (mean=19.5 min) and after (mean=20.4 min) implementation of PROMs (p=0.52). DISCUSSION/SIGNIFICANCE OF FINDINGS: The remote capture and integration of web-based PROMs into clinical care was feasible in a diverse cohort of SLE outpatients. PROMs were useful to SLE patients and rheumatologists and promoted patient-centered care by facilitating communication."}
+{"text": "Respiratory virus infections are associated with significant and specific local and systemic inflammatory response patterns, which may lead to reactivation of latent viruses. We examined whether viral upper (URTI) or lower respiratory tract infection (LRTI) with common respiratory viruses increased the risk of CMV viremia after allogeneic hematopoietic cell transplantation (HCT). We retrospectively analyzed patients undergoing allogeneic HCT between 4/2008 and 9/2018. CMV surveillance was performed weekly and the presence of upper and lower respiratory symptoms were evaluated by multiplex respiratory viral PCR. We used Cox proportional hazards models to evaluate risk factors for development of any CMV viremia or high level CMV viremia in the first 100 days post-HCT. Each respiratory virus infection episode was considered positive for 30 days beginning the day of diagnosis.Figures 1 and 2), and PIV or RSV URTI increased the risk of high level CMV viremia; all other viruses showed no association in univariable models. Among 2,545 patients , 1,221 and 247 developed CMV viremia and high level CMV viremia, respectively, in the first 100 days post-HCT. Infections due to human rhinoviruses  were most frequent, followed by parainfluenza viruses 1-4 , seasonal human coronaviruses , respiratory syncytial virus , influenza A/B , human metapneumovirus , and adenovirus . In adjusted models, RSV LRTI was associated with increased risk of developing CMV viremia at all levels Ansun Biopharma (Scientific Research Study Investigator)Kyorin Pharmaceutical (Advisor or Review Panel member) Janet A. Englund, MD, AstraZeneca GlaxoSmithKline (Research Grant or Support)Meissa Vaccines (Consultant)Pfizer (Research Grant or Support)Sanofi Pasteur (Consultant)Teva Pharmaceuticals (Consultant) Michael Boeckh, MD PhD, AlloVir (Consultant)Ansun Biopharma (Grant/Research Support)Astellas (Grant/Research Support)EvrysBio Gilead Sciences GlaxoSmithKline (Consultant)Helocyte Janssen (Grant/Research Support)Kyorin (Consultant)Merck Moderna (Consultant)Symbio (Consultant)Takeda (formerly known as Shire) VirBio"}
+{"text": "Photo-supported verbal assessments have shown to improve comprehension and expression of choices by older adults living with cognitive-communication challenges. The purpose of this study was to assess content validity (CV) of photographs used to supplement the Preferences for Everyday Living Inventory-Nursing Home (PELI-NH) from the perspective of older adults, using cognitive interviewing methods. Participants (N=21) were average age 75 (SD=5.67), mostly male (62%) and white (90%), living in residential communities (86%), with no known cognitive or communication deficits. Interview data was used to iteratively assess and revise photographs. A total of 46 photographs demonstrated CV; 26 demonstrated CV after revisions; 3 did not demonstrate CV after revisions. Content analysis revealed thematic codes describing participants\u2019 photograph preferences including image quality, context, subject diversity, and relevance to long-term care. Discussion will include implications for clinicians and researchers on how to evaluate and improve CV of photo-supported verbal assessments."}
+{"text": "Detecting severe acute respiratory syndrome coronavirus 2 in deceased patients is key when considering appropriate safety measures to prevent infection during postmortem examinations. A prospective cohort study comparing a rapid antigen test with quantitative reverse transcription PCR showed the rapid test\u2019s usability as a tool to guide autopsy practice. Rapid detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is essential to prevent viral dissemination. Rapid antigen tests (RATs) have recently been approved and are now widely used in the current coronavirus disease (COVID-19) pandemic (https://www.roche.com) in 30 consecutive deceased COVID-19 patients at the University Hospital, Medical University of Graz , during November 28\u2013December 23, 2020. We tested each corpse with nasopharyngeal swabs for RAT (using the manufacturer\u2019s kit) and eSwabs (https://www.copanusa.com) for quantitative reverse transcription PCR (qRT-PCR) targeted to the viral envelope (E) and nucleocapsid (N) genes of SARS-CoV-2. Furthermore, we used virus isolation from lung tissue swabs from an additional cohort of deceased COVID-19 patients (n = 11) to compare molecular detection and virus cultivability , and 51.2% were female. The median disease duration  was 11 days (range 1\u201343 days). The median postmortem interval (time between death and specimen sampling) was 23 hours    Table 1.t values (t values or RAT results (t values and negative RATs. RAT and cultivation results closely mirrored each other with respect to viral load (Furthermore, we determined parameters that influenced test performance. We noted a significant positive correlation between disease duration and Ct values , panel Dt values , panel EAlthough RAT had an overall lower sensitivity than qRT-PCR in this study, our data suggest that viral loads of false-negative RAT cases are probably below the threshold of cultivability. Because culture is regarded as a measure of virus viability and infectivity (In conclusion, RAT should not be seen as a potential replacement for but rather as an addition to current postmortem testing strategies. Especially when qRT-PCR is not readily available, RAT might be useful in selecting the most hazardous corpses that should be examined under special conditions (e.g., Biosafety Level 3 [Additional information on materials and methods involved in postmortem detection and cultivation of SARS-CoV-2."}
+{"text": "Antibodies was able to maintain its standards for the high quality of its published papers. Thanks to the contribution of our reviewers, in 2021, the median time to first decision was 20 days and the median time to publication was 79.5 days. The editors would like to extend their gratitude and recognition to the following reviewers for their precious time and dedication, regardless of whether the papers they reviewed were finally published:Ailin WangJurgen SanesAkiyoshi TakamiKalra Rajkumar SinghAlessandra VillaKarin HufnaglAli R. JazirehiKatja KlauszAlicja Maria Sochaj-GregorczykKirstie BertramAnastasia SveshnikovaKoichi KatoAndrew ScottLina BaranauskieneAngelica BiancoLuis Alvarez-VallinaAnn WhiteMaciej W\u0142odarczykAnshu AgrawalMahendra DeonarainAnton LennikovMaria Antonietta CiardielloAntu K. DeyMarta KarazniewiczArne SkerraMd Kausar AlamBas De LaatMichal ZmijewskiBehnoush Abedi ArdekaniMichele BernasconiBin ZhanMing-Ching HsiehBingchun ZhaoNaga Venkata Sabarinath NeerukondaCatalina FlorezNicolae GicaChichun HoNima TaefehshokrChihyang WangNuria \u00c1lvarez-S\u00e1nchezChristiane StadlerOleksandr KonievChuan ChenOxana SerovaClaudia Kitzm\u00fcllerParameswaran RamakrishnanCollynn WoellerPaulina \u017barnowiecCory L. BrooksPhilippe BillialdDavid BrandonPierre Roug\u00e9David VancePio ContiDebmalya BarhPriyanka KhareDennis R. GouletQuirina Santos-CostaDhaval K. ShahRatnadeep MukherjeeDidier BoquetRobert H. CarnahanDiego MoricoliRonald P. TaylorDominic NarangRoss ChelohaEduardo Ruiz-L\u00f3pezRossella SartoriusEls VerhoeyenRyo MisakiFrancesco GiansantiScott DessainFrank KrauseShyh-Chyi LoGiada Maria VecchioSiva Krishna AngalakurthiGillian LoweStefanie K. WculekGiulia PezzoniStefano AngiariGordana Wozniak-KnoppSukmook LeeGregory IppolitoSushobhana BandyopadhyayGuangai XueSwati JainHarald KolmarSylvie BouvierHongnan CaoTae Hyun KangHuub SchellekensTal Noy-PoratIgnazio CaruanaTaru S. DuttJarmila CelakovskaTilman SchlothauerJeffrey V. LeytonTobias BerglerJohann BauerTomoyuki IgawaJohn De KruifTsvetelina VelikovaJordi Martorell-Marug\u00e1nUtkarsh H. AcharyaJoseph KauerWei SunRigorous peer-reviews are the basis of high-quality academic publishing. Thanks to the great efforts of our reviewers,"}
+{"text": "However, compared to VZV, the transcriptome and the full coding potential of SVV remains incompletely understood. Here, we performed nanopore direct RNA sequencing to annotate the SVV transcriptome in lytically SVV-infected African green monkey (AGM) and rhesus macaque (RM) kidney epithelial cells. We refined structures of canonical SVV transcripts and uncovered numerous RNA isoforms, splicing events, fusion transcripts and non-coding RNAs, mostly unique to SVV. We verified the expression of canonical and newly identified SVV transcripts in vivo, using lung samples from acutely SVV-infected cynomolgus macaques. Expression of selected transcript isoforms, including those located in the unique left-end of the SVV genome, was confirmed by reverse transcription PCR. Finally, we performed detailed characterization of the SVV homologue of the VZV latency-associated transcript (VLT), located antisense to ORF61. Analogous to VZV VLT, SVV VLT is multiply spliced and numerous isoforms are generated using alternative transcription start sites and extensive splicing. Conversely, low level expression of a single spliced SVV VLT isoform defines in vivo latency. Notably, the genomic location of VLT core exons is highly conserved between SVV and VZV. This work thus highlights the complexity of lytic SVV gene expression and provides new insights into the molecular biology underlying lytic and latent SVV infection. The identification of the SVV VLT homolog further underlines the value of the SVV non-human primate model to develop new strategies for prevention of herpes zoster.Primary infection with varicella-zoster virus (VZV) causes varicella and the establishment of lifelong latency in sensory ganglion neurons. In one-third of infected individuals VZV reactivates from latency to cause herpes zoster, often complicated by difficult-to-treat chronic pain. Experimental infection of non-human primates with simian varicella virus (SVV) recapitulates most features of human VZV disease, thereby providing the opportunity to study the pathogenesis of varicella and herpes zoster  Varicella-zoster virus (VZV)\u2013a ubiquitous human pathogen\u2013infects most individuals during childhood, leading to chickenpox, after which the virus persists in the host for decades. Later in life, VZV reactivates to cause shingles, frequently associated with difficult-to-treat chronic pain. Our limited understanding of the viral life-cycle hampers the development of more effective treatment options. Simian varicella virus (SVV) is the non-human primate homologue of VZV and causes a natural disease in Old World monkeys with clinical, pathological, and immunological features resembling human VZV infection. However, it is unclear how similar both viruses are at the molecular level. Here, we have revisited the genome-wide transcriptional activity of SVV during lytic infection of kidney epithelial cells derived from two non-human primate species and validated expression of newly identified viral transcripts in lung tissue from SVV-infected animals. Together, this has led to the identification of numerous alternative RNA isoforms, mostly unique to SVV, and some of which may have functional implications for the virus. Notably, we defined the SVV latency-associated transcript, which is highly similar to its VZV counterpart. In conclusion, our study shows the value of understanding the molecular biology of a given animal model and identifies potentially conserved mechanism of latency. Varicella-zoster virus (VZV) is an endemic human neurotropic alphaherpesvirus and causative agent of both varicella and herpes zoster . Althougin vivo  and rhesus macaque kidney epithelial cells LLC-MK2 cells [ATCC no. CCL-7] were cultured in DMEM (Lonza) containing 10% heat-inactivated fetal bovine serum  and penicillin-streptomycin/L-Glutamine (Lonza). Low-passage wild-type SVV Delta herpesvirus strain was isolated from an acutely infected AGM  and propFormalin-fixed and paraffin-embedded (FFPE) skin and ganglia samples were obtained from acutely SVV-infected AGM at 9 dpi and latently infected Chinese rhesus macaques at 21 dpi ,40. RNA in vivo SVV-infected CM. Sequencing was performed on a MinION MkIb using R9.4.1 (rev D) flow cells (Oxford Nanopore Technologies Ltd.) for 18\u201322 hrs (one library per flowcell). Raw fast5 datasets were then basecalled using Guppy v3.6.0 (-f FLO-MIN106 -k SQK-RNA002 / SQK-PCS109) with only reads passing filter used for subsequent analyses. Sequence reads were aligned against the SVV reference genome (NC_002686.2), using MiniMap2 [Nanopore dRNA-Seq libraries were prepared for each sample using between 500\u20131,000 ng of poly(A) RNA that was previously isolated from 30\u201350 \u03bcg of total RNA using the Dynabeads mRNA Purification Kit . The poly(A) RNA was spiked with 0.5 \u03bcL of a synthetic Enolase 2 (ENO2) calibration RNA (Oxford Nanopore Technologies Ltd.) and dRNA-Seq libraries prepared according to the standard SQK-RNA002 protocol (Oxford Nanopore Technologies Ltd.). A Nanopore SQK-PCS109 PCR-cDNA library was prepared, according to manufacturer\u2019s instructions, using 200ng of total RNA collected from an MiniMap2   as well as cleavage and polyadenylation sites (CPAS) were identified using a peak-calling strategy ,50. BrieRNA abundance counts were estimated by realigning sequence reads against our updated SVV transcriptome annotation using parameters optimized for transcriptome alignments (minimap2 -ax map-ont -p 0.99). RNA abundance counts were generated by counting alignments against a given RNA only if the alignment 5\u2032 end was located within the first 50\u2009nt of the RNA and the alignment was not marked as supplementary. Transcript per million (TPM) counts were generated by dividing the RNA abundance count for a given transcript by the total number of sequence reads (one read = one RNA) present in the data set and subsequently multiplying by 1 million.CPC 2.0  was usehttps://www.bioinformatics.babraham.ac.uk/projects/trim_galore/)  and aligned against the SVV reference genome using BBmap (https://sourceforge.net/projects/bbmap/) with post-alignment processing performed using SAMtools and BEDtools.Stranded RNA libraries were prepared from poly(A)-selected RNA using the NEBNext Ultra II Directional RNA Library Prep Kit for Illumina (New England Biolabs) and sequenced using a NextSeq 550. Sequence reads were trimmed using TrimGalore (https://sourceforge.net/projects/bbmap/). Filtered reads were subsequently assembled into a single circular contig using canu [Sequencing libraries were prepared for SVV Delta and unrelated samples using the Nanopore native genomic DNA by ligation kit (SQK-LSK109) and native barcoding kit (EXP-NBD104). 1,000 ng of purified genomic DNA was used per sample and five samples were multiplexed and sequenced on a single MIN106 flowcell for 24 hours. Demultiplexing and high-accuracy basecalling were performed using Guppy v4.2.2 . The SVV dataset  was subsing canu  and poliing canu  to produing canu .https://github.com/genome/bam-readcount) followed by processing with a custom script  available at https://github.com/DepledgeLab/vzv-2.0/tree/master/extras. Only variant SNPs and indels present at a frequency > 20% were retained for analysis.A second strategy for identifying SNPs and indels utilized the Illumina RNA-Seq dataset . Here, thttps://github.com/depledgelab/SVV-2.0.A total of 55 SNPs were identified by nanopore sequencing and 50 by Illumina sequencing, 49 of which overlapped between datasets . By contBS-C-1 and LLC-MK2 cells were infected with cell-associated SVV by cocultivation of uninfected and SVV-infected BS-C-1 or LLC-MK2 cells in a 8:1 ratio for 96 hrs. Cells were harvested in 1 mL Trizol, mixed with 200 \u03bcL chloroform, centrifuged for 15 min at 12,000xg at 4\u00b0C and RNA was extracted from the aqueous with the RNeasy Mini Kit (Qiagen) including on-column DNAse treatment according to manufacturer\u2019s instructions. Similarly, RNA extraction from tissue samples was performed by homogenizing frozen tissue samples in 1 ml TRIzol using the MP Fastprep-24  and the RNeasy Mini Kit (Qiagen). cDNA synthesis was performed using a maximum of 5 \u03bcg of total RNA, oligo(dT) primers and Superscript IV reverse transcriptase (both Thermo Fisher). qPCR was performed in duplicate on RT- and RT+ cDNA on an ABI Taqman qPCR system using Taqman 2x Universal Master Mix or 4x Taqman Fast Advanced Master Mix (both Applied Biosystems). Relative expression was determined by normalization to \u03b2-actin using the 2^(-deltaCt) method. Primer probe sets directed to GAPDH, SVV ORF29, SVV ORF40, SVV ORF61, SVV ORF63 have been described before , and priPCR was performed on both RT- and RT+ cDNA samples with Amplitaq Gold DNA Polymerase (Thermo Fisher Scientific) or PfuUltra II Fusion High-fidelity DNA polymerase (Agilent) and primer pairs corresponding to the newly identified SVV transcripts . PCR amp5\u2019RACE was performed on 5 \u03bcg RNA isolated from ganglia at 13 and 21 dpi, and on 10 \u03bcg RNA isolated from lytically infected B-SC-1 cells, with the FirstChoice RLM-RACE Kit (ThermoFisher Scientific) according to manufacturer\u2019s instructions. Finally, cDNA was generated in a total volume of 20 \u03bcL. Nested PCR reactions were performed, and cloned into pC4-TOPOvector using the TOPO-TA Cloning kit (ThermoFisher Scientific). Finally, individual colonies were picked and sequenced on the ABI Prism 3130 XL Genetic Analyzer using supplied M13 forward and reverse primers.ISH was performed using the RNAScope 2.5 HD Assay and probes directed to SVV VLT , SVV ORF63 (cat# 438091), universally expressed positive control gene ubiquitin C (UBC) and negative control bacterial transcript DapB . Staining was visualized using FastRed as a substrate, nuclei were stained with hematoxylin and slides were mounted with Ecomount . ISH was performed on normal skin and varicella skin rash of n = 2 animals (AGM 269 and 279 in ), with nS1 FigCoverage plot denoting two major transcription units (TU) in the SVV genome. The first TU includes RNAs 18\u20131 and 19\u20131 while the second TU consists of a single RNA (20\u20131). To define RNAs and TUs, Nanopore dRNA-Seq (light blue) of lytically SVV-infected BS-C-1 cells was integrated with pileup data that maps the pileup of 5\u2019 (red) and 3\u2019 (black) ends of polyadenylated RNAs mapping to this region. Rows denoted by transcription start sites  and cleavage and polyadenylation sites  indicate positions of putative TSS and CPAS identified using HOMER . TSS and(TIF)Click here for additional data file.S2 Fig(A) Schematic representation of the 3\u2019end of RNA15 and RNA16. The nucleotide sequence including polyadenylation site, cleavage site and U-rich DSE are indicated. The transparent box indicates the predicted CDS of RNA15, extending beyond the 3\u2019end as defined by dRNA-seq. (B) Schematic representation of all RNA15 and RNA16 isoforms (purple boxes), the DNA sequence and the amino acids encoded by all three open reading frames with start codons (M) highlighted in green and stop codons (*) in red. The bottom row of amino acids indicates the open reading frame from which pORF15 is translated.(TIF)Click here for additional data file.S3 Fig(A) Schematic outline of sequencing and assembly approaches used to assembly the SVV Delta-EMC genome and perform comparative analysis vs. the canonical SVV Delta assembly. Venn diagrams indicate the numbers of SNPs and Indels identified by Nanopore gDNA sequencing and high-coverage Illumina RNA-Seq. (B) Schematic overview of the SVV Delta-EMC genome. SNPs and Indel differences relatively to the canonical SVV Delta genome (GenBank NC_002686.2) are highlighted by black (non-synonymous SNP), grey (synonymous SNP), red (SNP in non-coding region), and green (Indel) vertical lines. CDS impacted by non-synonymous SNPs and Indels are highlighted in black and green, respectively. Note the cross-hatched ORF52 contains both a non-synonymous SNP and an Indel.(TIF)Click here for additional data file.S4 Fig(A) Minimal structural requirements to encode for each SVV pVLT variant: exons (grey boxes), introns (dashed line) and ATG (green arrow). Many other isoforms with longer 5\u2019 UTRs can also encode for these pVLT variants. (B) Total number of annotated VLT isoforms encoding for indicated SVV pVLT variants. (C) Multiple sequence alignment by Clustal Omega of all SVV pVLT variants and VZV pVLT indicates a similar core of the protein with diversification at the N- and C-terminus. Colors are added for visual comparison. (D) Pairwise sequence alignment by EMBOSS Needle of SVV pVLT (145 aa) and VZV pVLT. Lines indicate identical amino acids (aa) and double and single points degree of structural similarity. (E) Percentage amino acid identity between SVV and VZV pVLT and VLT surrounding proteins  in both viruses.(TIF)Click here for additional data file.S5 Fig(A) RT-PCR confirmation of the core of SVV VLT indicates 3 major isoforms in LLC-MK2 cells. (B) RT-PCR confirmation of 4 upstream exons represented by cluster C, D, E and G see  in LLC-M(TIF)Click here for additional data file.S1 Table(XLSX)Click here for additional data file.S2 Table(XLSX)Click here for additional data file.S3 Table(XLSX)Click here for additional data file.S4 Table(XLSX)Click here for additional data file.S5 Table(XLSX)Click here for additional data file.S6 Table(XLSX)Click here for additional data file."}
+{"text": "Circulating tumor cells (CTCs) are liquid biopsies that represent micrometastatic disease and may offer unique insights into future recurrences in non-small cell lung cancer (NSCLC). Due to CTC rarity and limited stability, no stable CTC-derived xenograft (CDX) models have ever been generated from non-metastatic NSCLC patients directly. Alternative strategies are needed to molecularly characterize CTCs and means of potential future metastases in this potentially curable patient group.Surgically resected NSCLC primary tumor tissues from non-metastatic patients were implanted subcutaneously in immunodeficient mice to establish primary tumor patient-derived xenograft (ptPDX) models. CTCs were isolated as liquid biopsies from the blood of ptPDX mice and re-implanted subcutaneously into na\u00efve immunodeficient mice to generate liquid biopsy CTC-derived xenograft (CDX) tumor models. Single cell RNA sequencing was performed and validated in an external dataset of non-xenografted human NSCLC primary tumor and metastases tissues. Drug response testing in CDX models was performed with standard of care chemotherapy (carboplatin/paclitaxel). Blockade of MYC, which has a known role in drug resistance, was performed with a MYC/MAX dimerization inhibitor (10058-F4).Out of ten ptPDX, two (20%) stable liquid biopsy CDX mouse models were generated. Single cell RNA sequencing analysis revealed an additional regenerative alveolar epithelial type II (AT2)-like cell population in CDX tumors that was also identified in non-xenografted NSCLC patients\u2019 metastases tissues. Drug testing using these CDX models revealed different treatment responses to carboplatin/paclitaxel. MYC target genes and c-MYC protein were upregulated in the chemoresistant CDX model, while MYC/MAX dimerization blocking could overcome chemoresistance to carboplatin/paclitaxel.To overcome the lack of liquid biopsy CDX models from non-metastatic NSCLC patients, CDX models can be generated with CTCs from ptPDX models that were originally established from patients\u2019 primary tumors. Single cell analyses can identify distinct drug responses and cell heterogeneities in CDX tumors that can be validated in NSCLC metastases tissues. CDX models deserve further development and study to discover personalized strategies against micrometastases in non-metastatic NSCLC patients.The online version contains supplementary material available at 10.1186/s12943-022-01553-5. Non-small cell lung cancer (NSCLC) is a devastating disease with high mortality. Even patients with early-stage disease amenable to resection have a 50% mortality rate . Cancer Primary tumor tissues from non-metastatic NSCLC patients were collected at the time of lung resection Table . Ten ptPDue to the rarity and instability of micrometastatic CTCs, stable CTC expansion models from non-metastatic NSCLC patients are lacking. Although xenograft models represent a clonal cell selection, ptPDX-derived CDX liquid biopsy models can still be a valuable tool to molecularly study and predict the risk of future recurrences and metastases after curative resection of localized NSCLCs in individual patients.To generate global atlases of the transcriptomic landscape, ptPDX and CDX tumors were profiled by single nuclear RNA-sequencing (snRNA-seq) Figs.\u00a0C, S3, S4To validate our findings, we utilized an external single cell sequencing data set consisting of eight NSCLC primary tumors and five metastases . This anSingle cell sequencing demonstrated the existence of an additional AT2-like cell population in metastatic CDX and, importantly, also in non-xenografted NSCLC metastases tissues. It is well reported that AT2 cells, apart from their regenerative stem cell capacity in non-cancerous lung, are found in lung cancers and have been linked to tumor initiation demonstrated in preclinical models , 14. A rTo explore the similarities and differences of the patient-matched PDX/CDX models, we aggregated snRNA-seq of PDX and CDX samples. MU150 PDX was strikingly different than MU150 CDX, as determined by DEGs following aggregation Fig.  A. Gene p\u00a0<\u20090.01; Student\u2019s t-test)   Fig. E/F. Blocst) Fig. G 22]. B. Bp\u00a0<\u20090.Liquid biopsy CDX mouse models generated from non-metastatic NSCLC ptPDX offer valuable drug sensitivity testing platforms, possibly in a time window before patients develop incurable recurrence. They can also be used to study strategies of chemoresistance reversal, such as by MYC inhibition. CDX models also allow identification of distinct single cell heterogeneity that matches non-xenografted NSCLC metastases.Liquid biopsy CDX mouse models provide a platform to study progression from non-metastatic to metastatic NSCLC disease. The strategy of using ptPDX models allowed CDX to be established, overcoming the difficulty of developing these models directly from NSCLC patients with limited disease. CTC isolated from ptPDX were phenotypically the same as those isolated from patients, and CDX established from these CTCs expressed diagnostic pathology markers similar to the patient primary tumor. Thus, as we demonstrate above, these CDX models provide an opportunity to study drug responses and targets for radiographically undetectable micrometastases after curative resection - a critical clinical gap . AdditioAdditional file 1: Supplementary Figure\u00a01. ptPDX-derived CTCs are similar in morphology and traditionally defined CTC marker expression to patient CTCs. CTCs from matched patient and ptPDX blood were enriched on a microfilter and stained with CK 8/18/19-FITC, EpCAM-PE, CD45-Cy5 and DAPI for nuclei identification. Arrowhead showing a white blood cell (WBC) captured with CTC. Scale bar, 10\u2009\u03bcm. Supplementary Figure\u00a02. Histopathology and immunohistochemistry staining of patient-matched primary tumor, ptPDX and CDX tumor tissues. Immunohistochemical staining of patient-matched primary, ptPDX and CDX tumor tissues. A: Representative images of hematoxylin and eosin (H&E) stained and immunostained (CK7 and Napsin A) patient-matched tumor tissues from MU150. B: Representative images of H&E stained and immunostained (CK5/6 and p40) patient-matched tumor tissues from MU197. For both sets of staining, human aorta served as negative control tissue and IgG served as isotype control. Scale bar, 20\u2009\u03bcm. Supplementary Figure\u00a03. Bright field images of extracted nuclei suspension from automated cell counter after staining with trypan blue. Snap-frozen matched ptPDX and CDX tumor tissues were minced on ice and homogenized. Lysate was transferred through 70\u2009\u03bcm cell strainer, homogenized again a few strokes, and passed through 40\u2009\u03bcm cell strainer. Nuclei were counted after staining with Trypan blue using Countess II FL Automated Cell Counter to check the quality. Supplementary Figure\u00a04. Pre-processing and filtering of snRNA-seq data matrix. Cells were filtered based on RNA transcript count, percentage of mitochondrial (mt)/ribosomal (rb) genes, percentage of mouse reads mapped in alignment to combined human-mouse reference genome. Red dotted line indicates the set cut-off applied to remove outliers. Supplementary Figure\u00a05. Heatmaps using differentially expressed genes (DEGs) of all clusters of ptPDX and CDX tumor tissues for cell type annotation. DEGs  of all clusters of patient primary and metastatic tumor tissues for cell type annotation. DEGs having p adj of less than 0.05 of each cluster expressing cell type canonical markers  between MU150 PDX versus MU150 CDX. Genes were grouped into upregulated (Up), downregulated (down), normal and not significant based on the average log fold change and adjusted p value (p adj). B: Gene set enrichment analysis and pathway enrichment analysis performed using top 100 (up/down regulated) DEGs between MU150 PDX versus MU150 CDX. C: Tumor growth kinetics of MU150 PDX and MU150 CDX. D: Volcano plot showing the DEGs between MU197 PDX versus MU197 CDX. E: Gene set enrichment analysis and pathway enrichment analysis performed using top 100 (up/down regulated) DEGs between MU197 PDX versus MU197. F: Tumor growth kinetics of MU197 PDX and MU197 CDX. DEGs after integration are provided in  between MU150 (PDX\u2009+\u2009CDX) versus MU197 (PDX\u2009+\u2009CDX). Genes were grouped into upregulated (Up), downregulated (down), normal and not significant based on the average log fold change and adjusted p value (p adj). B: Heatmap showing top 100 DEGs. C: Gene set enrichment analysis and pathway enrichment analysis performed using top 100 (up/down regulated) DEGs between MU150 (PDX\u2009+\u2009CDX) versus MU197 (PDX\u2009+\u2009CDX). D: Volcano plot showing the differentially expressed genes (DEGs) between MU150 CDX versus MU197 CDX. E: Heatmap showing top 100 DEGs. F: Gene set enrichment analysis and pathway enrichment analysis performed using top 100 (up/down regulated) DEGs between MU150 CDX versus MU197 CDX. G: Tumor growth kinetics of MU150/197 PDXs. H: Tumor growth kinetics of MU150/197 CDXs. DEGs after integration are provided in  and carboplatin/paclitaxel doublet. Cell proliferation was monitored from day 1 to day 4 by performing cell proliferation assay on each day. A: Effect of increasing concentrations of MYC blocker on cell proliferation (absorbance at 490\u2009nm) measured using the CellTiter 96\u00ae Aqueous One solution. B: Effect of increasing concentrations of doublet carboplatin/paclitaxel treatments on cell proliferation.Additional file 2.\u00a0Differentially expressed genes and cell type\u00a0canonical markers.Additional file 3: Supplementary Table\u00a01. Clinicopathological information and survival status of the NSCLC patients enrolled for ptPDX (N\u00a0=\u200910) and CDX (N\u00a0=\u20092) model development. Supplementary Table\u00a02. Total counts of ptPDX individual CTCs and CTC clusters that were detected at the time of injection to na\u00efve NSG mice to develop CDX models.Additional file 4.\u00a0Supplementary methods."}
+{"text": "To date, 106 patients have completed behavioral health assessments across three sites: a rural primary care clinic (n = 32), urban federally qualified health center (n = 33), and state-certified residential rehabilitation facility (n = 41). Patients ranged from 18 to 65 years of age . Approximately 51% were female and 75% were non-Hispanic White (followed by 22% African American). Over 60% had a high school degree or less and found it at least somewhat difficult to pay for basic needs. Most patients endorsed substantial (44%) or severe (39%) drug use, with 40% endorsing opioid use. There were no significant differences in substance use by age group. Moderate to severe symptoms of depression (43%) and anxiety (49%) were common. Approximately 70% endorsed adverse childhood experiences, and 44% reported clinically significant post-traumatic stress symptoms. Measures of cognitive functioning and objective health literacy are currently being collected."}
+{"text": "Guidelines for physical activity emphasize multiple fitness components among people aged >65. The age-related increase in variability of fitness components necessitates accurate individualized assessment prior to optimal prescription for personalized exercise program. Accordingly, we tested feasibility and effectiveness of a novel tool designed to remotely assess balance, flexibility, and strength using smartphone sensors (accelerometer/gyroscope), and subsequently remotely deliver personalized exercise programs via smartphone. This pilot study enrolled 52 healthy volunteers  aged 65+, with normal cognition and low fall-risk. Baseline preliminary data from smartphone fitness assessment were analyzed to generate 42 fitness digital-markers, used to generate personalized exercise programs (5 times/week for 6 weeks). Programs included graded exercises for upper/lower body, flexibility, strength, and balance . Fitness was remotely assessed at baseline and after six weeks. Average age was 74.7\u00b16.4 years; adherence was 3.6\u00b11.7 exercise sessions/week. Significant improvement for pre/post testing was observed for 10/12 digital-markers of strength/flexibility for upper/lower body . Balance improved significantly for 6/10 measures of tandem-stance, with consistent (non-significant) trends observed across 20 balance digital-markers of tandem-walk and one leg-stance. Balance showed greatest improvement among the 37 participants exercising \u22653/week. These preliminary results serve as proof of concept among people aged >65: high adherence and improved fitness confirm the potential benefits and niche for remote fitness assessment used to generate personalized exercise programs. Future research is required to confirm the benefits among specific patient groups, such as those with frailty, deconditioning, cognitive and functional impairment."}
+{"text": "ABSTRACT IMPACT: Our proposed jaw-specific control mechanism of tooth development is expected to address the site-specific prevalence of tooth agenesis in humans. OBJECTIVES/GOALS: To determine the molecular mechanisms that control jaw-specific tooth development. To identify the molecular basis of the site-specific prevalence of humans tooth agenesis cases. METHODS/STUDY POPULATION: We used three different genetically engineered mouse lines: Msx1 ^\u2019/ ^\u2019, Dkk2 ^\u2019/ ^\u2019, and Sostdc1 ^\u2019/ ^\u2019 mice. We used developmental mouse genetics approaches, basically generating different combinations of compound mutant mice. We examined their tooth development by using gross, histology, and mRNA expression analyses. RESULTS/ANTICIPATED RESULTS: We identified that Sostdc1, a secreted Wnt inhibitor, also plays an important role in regulating the Msx1-dependent odontogenic pathway. Sostdc1 mRNA showed similar expression patterns in the developing tooth germs between control and Msx1-null molar buds. Remarkably, by deleting the Sostdc1 gene, as well as the Dkk2 gene, in the Msx1-null background mouse, molar tooth development was rescued in the maxillary jaw, but not in the mandibular jaw. Furthermore, tooth developmental rescue could be achieved in both the maxillary and mandibular molars by combinedly deleting Dkk2 and Sostdc1 in Msx1-null mice. DISCUSSION/SIGNIFICANCE OF FINDINGS: Our study demonstrates that secreted Wnt inhibitors Dkk2 and Sostdc1 synergistically regulate the Msx1-dependent odontogenic pathway and further control early tooth morphogenesis. These mouse model will be used to further address the site-specific prevalence of tooth agenesis in humans."}
+{"text": "Fever with neutropenia (FN) is common and the timing of antibiotic cessation in patients without an identified fever source is uncertain. Absolute neutrophile count (ANC) recovery has been used clinically to represent bone marrow recovery (BMR) but other options should be considered. We hypothesized that absolute monocyte count (AMC), and absolute phagocyte count (APC) are more sensitive, and an earlier safe marker of antibiotic cessation (AC) compared with ANC A retrospective review was performed for FN episodes (FNEs) at UCM Comer Children\u2019s Hospital between 2009 and 2016 in pediatric oncology patients. Eligible FNEs who were a febrile for 24 hours, had no bacterial source identified at time of AC, and did not receive chemotherapy 10 days following AC. Ten-day post-AC outcomes, length of stay and cost were assessed and compared among different BMR parameters (ANC vs AMC).A total of 928 FN episodes (FNEs) were identified. 391 eligible FNEs occurred in 235 patients. Three groups were compared based on ANC (cells/\u03bcL) at the time of AC : < 200 in 102 (26%), 200-500 in 111 (28%), and >500 /uL in 178 (46%)  with an overall ten-day recurrent fever rate 7.4% (29/391) and readmission rate of 5.6% (22/391). No significant differences in recurrent fever rates were identified among 3 ANC groups  and readmission (Table 1).In subset analysis of AMC for each ANC group, patients with AMC >100 at AC have favorable outcomes, regardless ANC threshold (P< 0.01) (Table 1). Median of length of stay of FN was 3 days shorter using AMC >100/uL for BMR compared with any threshold of ANC (P< 0.01) and decrease overall FN cost stay (P< 0.01) (Table 2). Similar analysis show APC >300/uL at time of AC has favourable outcomes and decrease LOS regardless ANC threshold (data not shown here).Our results suggest that a AMC > 100 /uL regardless of ANC/uL, is a safe threshold value for empiric AC and discharge. This approach may shorten length of stay, reduce burden of cost of febrile neutropenia cost and potential long term antibiotics side effects. Lara Danziger-Isakov, MD, MPH, Ansun  Involved: Self): Scientific Research Study Investigator; Astellas  Involved: Self): Scientific Research Study Investigator; Merck  Involved: Self): Consultant, Scientific Research Study Investigator; Pfizer  Involved: Self): Scientific Research Study Investigator; Shire  Involved: Self): Consultant, Scientific Research Study Investigator; Viracor: Grant/Research Support"}
+{"text": "Clostridioides difficile infection (rCDI), and their proposed mechanisms include restoration of the microbiota and microbiota-mediated functions, including bile acid metabolism. RBX2660\u2014a broad-consortium investigational live biotherapeutic\u2014has been evaluated in >600 participants in 6 clinical trials, with consistent reduction of rCDI recurrence. Here we report that fecal bile acid compositions were significantly restored in treatment-responsive participants in PUNCH CD3\u2014a Phase 3 randomized, double-blinded, placebo-controlled trial of RBX2660.Microbiota-based treatments are increasingly evaluated as a strategy to reduce recurrence of PUNCH CD3 participants received a single dose of RBX2660 or placebo between 24 to 72 hours after completing rCDI antibiotic treatment. Clinical response was the absence of CDI recurrence at eight weeks after treatment. Participants voluntarily submitted stool samples prior to blinded study treatment (baseline), 1, 4 and 8 weeks, 3 and 6 months after receiving study treatment. A liquid chromatography tandem mass spectrometry method was developed to extract and quantify 33 bile acids from all participant fecal samples received up to the 8-week time point. Mean bile acid compositions were fit to a Dirichlet multinomial distribution and compared across time points and between RBX2660- and placebo-treated participants.Clinically, RBX2660 demonstrated superior efficacy versus placebo (70.4% versus 58.1%). RBX2660-treated clinical responders\u2019 bile acid compositions shifted significantly from before to after treatment. Specifically, primary bile acids predominated before treatment, whereas secondary bile acids predominated after treatment . These changes trended higher among RBX2660 responders compared to placebo responders. Importantly, median levels of lithocholic acid (LCA) and deoxycholic acid (DCA) showed large, significant increases after treatment .A. Bile acid compositions before (BL) and up to 8 weeks after RBX2660 treatment among treatment responders. Compositions are shown as the fraction of total bile acids classified as primary or secondary conjugated or deconjugated bile acids. B. Concentrations of lithocholic acid (LCA) and deoxycholic acid (DCA) among RBX2660 treatment responders, shown with individual samples and time point group median with interquartile ranges.Among PUNCH CD3 clinical responders, RBX2660 significantly restored bile acids from less to more healthy compositions. These clinically correlated bile acid shifts are highly consistent with results from a prior trial of RBX2660.Romeo Papazyan, PhD, Ferring Research Institute (Employee) Bryan Fuchs, PhD, Ferring Pharmaceuticals (Employee) Ken Blount, PhD, Rebiotix Inc., a Ferring Company (Employee)"}
+{"text": "Pseudomonas aeruginosa (PA) are a therapeutic challenge. Data demonstrating the pharmacokinetic/pharmacodynamic (PK/PD) properties of newer beta-lactamase inhibitors remains scarce. A clinical challenge lies in selecting an antimicrobial regimen that diffuses across the blood brain barrier and maintains concentrations to achieve PD targets associated with bacterial killing. These complexities compelled us to quantify the pharmacological properties of ceftazidime/avibactam (CZA). Utilizing therapeutic drug monitoring (TDM), we evaluated the adequacy of therapy and aimed to guide precise CNS dosing in the treatment of three patients with neurosurgical meningitis.Central nervous system (CNS) infections caused by carbapenem-resistant Enterobacterales (CRE) and Difficult-to-treat resistant (DTR)-Bacterial identification and susceptibility testing were performed using MicroScan. TDM of CZA was implemented using a dose of 2.5 g infused intravenously over 2-hours, every 8 hours. The concentrations of ceftazidime and avibactam were determined by liquid chromatography/mass spectrometry. For patients 2 and 3, four unique CSF and plasma samples spanning the dosing interval were obtained; including trough values. (See table)blaKPCKp (0.25\u03bcg/mL), DTR PA (4 \u03bcg/mL), and blaKPCE. cloacae (0.25 \u03bcg/mL), respectively. Measured plasma and CSF concentrations of avibactam (AVI) and ceftazidime (CAZ) are shown in Table 1.Bacterial identification and CZA MICs for patients 1, 2, and 3 revealed Table 1a. Therapeutic Drug Monitoring of CAZ-AVI depicting dosing, time of samples, and measured concentrations in CSF and Human Plasma (HP)Table 1b. Therapeutic Drug Monitoring of CAZ-AVI concentrations in CSF and Human Plasma (HP) pertaining to patient 2 and 3Measuring CZA concentration levels in CSF was achieved in 3 patients with complicated CNS infections. Post-infusion concentrations indicated that adequate CAZ and AVI exposures were attained in the CSF. Notably, avibactam was shown to achieve concentrations \u22651 \u00b5g/ml in the CSF throughout the dosing interval. For avibactam and ceftazidime, the PK/PD target correlated with bacterial killing is ~50% fT >MIC. In 2 out of 3 patients, concentrations were determined to be above the respective MICs throughout the entire dosing interval in the CSF. All patients attained clinical and microbiological cure. A novel CZA TDM method was successfully employed to establish that CZA maintains therapeutic CSF concentrations that exceed the MIC throughout the dosing interval. Robert A. Bonomo, MD, entasis (Research Grant or Support)Merck (Grant/Research Support)NIH (Grant/Research Support)VA Merit Award (Grant/Research Support)VenatoRx (Grant/Research Support)"}
+{"text": "Plasmodium berghei  ANKA. The course of parasitemia in postpartum mice infected with Pb ANKA was similar to the course in infected virgin mice. However, infected postpartum mice died earlier than did infected virgin mice. In addition, the weight of pups from mice infected with Pb ANKA was significantly reduced compared with pups from uninfected mice. The macroscopic and histological analyses showed apparent changes, such as destruction of the alveolus wall and extensive presence of leukocytes, in mammary gland tissue in mice infected during the postpartum period. The findings suggest that women during the postpartum period are more vulnerable to complications when infected with malaria parasites, particularly women who do not acquire protective immunity against malaria parasites. Based on the proteomic analysis, IFN-\u03b3 signaling pathway-related proteins in mammary gland tissue of the infected postpartum mice were increased. Our results indicate that inflammation induced by IFN-\u03b3, a proinflammatory cytokine, may contribute to negative histological changes in mammary gland tissue of postpartum mice infected with Pb ANKA. In IFN-\u03b3 receptor 1-deficient (IFNGR1-KO) mice, the histological changes in mammary gland tissue of the infected postpartum wild-type mice were improved to almost normal mammary gland structure. Furthermore, weight loss in pups delivered by infected IFNGR1-KO postpartum mice was not observed. Taken together, these findings indicate that inflammation induced by IFN-\u03b3 is associated with development of mastitis in postpartum mice infected with Pb ANKA. The present study results may increase our understanding of how disease aggravation occurs during postpartum malaria.Mastitis is an inflammation of the mammary gland in the breast and is typically due to bacterial infection. In malaria-endemic areas, mastitis with accompanying fever can be challenging to differentiate from malaria. At the same time, it is unclear whether malaria infection is directly involved in the development of mastitis. In the present study, whether mastitis develops during infection with malaria parasites was investigated using a rodent malaria model with  Plasmodium, and it is the major parasitic disease in tropical and subtropical regions ) cause development of cerebral and placental malaria  \u00d7 100.Methanol-fixed tail blood smears stained with 3% Giemsa diluted with phosphate buffer (pH 7.2) for 45 min were observed under a microscope. The number of infected erythrocytes in 250 erythrocytes was counted when parasitemia exceeded 10% and 1 \u00d7 10To measure hematological changes, blood (200 \u03bcL) was obtained from mice and assessed using an automated hematology analyzer, Sysmex XT-2000i .4 erythrocytes that had been infected with Pb ANKA. Mice were checked twice daily. On days 7\u20138 post-infection, neurological signs, such as cerebral paralysis and depression, were monitored. After death, a surgical incision in the skin of the head was made and intracranial cerebral hemorrhage was confirmed in mice that developed experimental cerebral malaria (ECM) as previously described [Pb ANKA was defined based on ECM, mortality rate, and parasitemia.Female C57BL/6 (B6) mice on day 12 post-mating (pregnant), on day 7 post-delivery (postpartum), on day 1 post-blood loss (blood loss), and from age-matched virgin mice (virgin) were injected with 1 \u00d7 10escribed \u201335. The Ex vivo bioluminescence imaging data were analyzed using the M3 software (Biospace) with size-constant regions of interest (ROIs).Bioluminescence imaging was performed using a Photon IMAGER system  as previously described . Mice weMammary gland tissues were obtained from uninfected and infected mice on day 7 post-infection. The mammary gland tissues were fixed in 10% buffered formalin and embedded in paraffin. Sections 6 \u03bcm thick were stained with hematoxylin and eosin (H&E) as previously described \u201337. The Proteins were extracted using Mammalian Protein Extraction Reagent  according to the manufacturer\u2019s protocol and treated with trypsin. Comparative proteomic analyses were performed as previously described , 38. Allvia peptide sequence analysis using Percolator [Peptide mass data were matched by searching the NCBInr database. The false discovery rate (FDR)  was calcrcolator . High-corcolator , 38. Nort-test and one- and two-way ANOVAs with Fisher\u2019s protected least significant difference (PLSD) post hoc test were performed using Statcel program . Survival curves were compared using a log-rank test. P-values < 0.05 were considered statistically significant.For time-series comparisons, Student\u2019s To investigate hematological changes during pregnancy and the postpartum period, blood was obtained from uninfected female C57BL/6 (B6) mice on day 15 post-mating (pregnant), on day 10 post-delivery (postpartum), from virgin mice on day 1 post-blood loss (blood loss), and from age-matched virgin mice (control), then subjected to analysis Tables . In pregPb ANKA. In a previous study, a rapid increase in parasitemia was observed in mice with reticulocytemia because Pb ANKA invades reticulocytes [Pb ANKA rapidly increased, compared with infected virgin and postpartum mice, beginning on day 3 post-infection (Pb ANKA (Pb ANKA was similar to the course in infected virgin mice (Pb ANKA developed ECM (data not shown) and died earlier than did infected virgin mice (on day 7 post-infection)  .Erythrocytes infected with malaria parasites bind to vascular endothelial cells, resulting in erythrocyte accumulation in organs, such as adipose tissue . As the Pb ANKA lacking SBP1 or MAHRP1a exhibited reduced sequestration and parasitemia in mice [Pb ANKA bind to vascular endothelial cells of organs, mice were infected with purified schizonts of Pb ANKA. During synchronized infection, pregnant mice showed high luciferase activity levels in the mammary gland, compared with control mice and infected postpartum mice, after perfusion  ANKA parasites. At 22 h post-infection, D-luciferin (1.5 mg) was injected into the tail vein of mice and the organs of mice from each group removed after perfusion. Representative data are shown. Right panel, fold change indicates the change in luciferase activity in each group, compared with virgin mice. Dotted lines indicate significant difference (\u2265 2-fold or \u2264 0.5-fold). Results are expressed as means \u00b1 standard deviation (SD) of three mice. Experiments were performed in duplicate with similar results.For bioluminescence analysis, erythrocytes infected with fugation . Left pa(TIF)Click here for additional data file.S2 Fig4 infected erythrocytes of Plasmodium berghei (Pb) ANKA. Representative hematoxylin and eosin (H&E)-stained placental sections are shown. (A and B) Uninfected wild-type virgin mouse. (C and D) Uninfected wild-type pregnant mouse on day 17 post-mating. (E and F) Infected wild-type pregnant mouse on day 17 post-mating (on day 5 post-infection). (G and H) Infected IFNGR1KO pregnant mouse on day 17 post-mating (on day 5 post-infection).  The scale bar represents 1,500 \u03bcm.  The scale bar represents 50 \u03bcm.  Numerous developing mammary glands were observed compared with A. Arrows indicate schizonts in vessels around mammary glands. Experiments were performed in triplicate with similar results.Pregnant B6 mice on day on day 12 post-mating were injected with 1 \u00d7 10(TIF)Click here for additional data file.S3 Fig(A and B) Venn diagram of protein levels in mammary gland tissue of uninfected and infected pregnant mice that changed 0.5-fold (A) or 2-fold (B) compared with uninfected virgin mice. (C and D) Fold change indicates the change in protein levels compared with uninfected virgin mice. (C) Protein levels that were significantly decreased and unchanged in mammary gland tissue of infected pregnant mice. Asterisks indicate proteins with significantly lower levels than in uninfected virgin mice (\u2264 0.5-fold change). Hash marks indicate proteins with significantly lower levels than in uninfected pregnant mice (\u2264 0.5-fold change). The dagger indicates the notable protein levels that were comparable with mammary gland tissue of uninfected virgin mice. (D) Proteins levels that were significantly increased in mammary gland tissue of infected pregnant mice, compared with uninfected virgin mice (\u2265 2-fold change). The IFN-\u03b3 signaling pathway-related proteins, antigen processing-related proteins, and other proteins obtained from the 59 increased proteins in mammary gland tissue of infected pregnant mice. Hash marks indicate proteins with significantly higher levels than in uninfected pregnant mice (\u2265 2-fold change). (TIF)Click here for additional data file.S1 TablePb ANKA on day 6 post-infection was compared with the proteomes in uninfected virgin and postpartum mice, as well as infected virgin and postpartum mice. Proteins showing one or two peptide spectral matches (PSMs) were excluded. Protein levels were normalized to actin, cytoplasmic 1 (Accession: P60710).The proteome of mammary gland tissues in postpartum mice infected with (XLSX)Click here for additional data file.S2 TablePb ANKA on day 5 post-infection was compared with the proteomes in uninfected virgin and pregnant mice, as well as infected virgin and pregnant mice. Proteins showing one or two peptide spectral matches (PSMs) were excluded. Protein levels were normalized to actin, cytoplasmic 1 (Accession: P60710).The proteome of mammary gland tissues in pregnant mice infected with (XLSX)Click here for additional data file.S3 Table4 erythrocytes that had been infected with luciferase-expressing Plasmodium berghei (Pb) ANKA. The number, survival rate, and weight of pups were measured on day 0 post-delivery. Experiments using three mice were performed in duplicate with similar results. Asterisks indicate a significant difference .Mice on day 12 post-mating were injected with 1 \u00d7 10(XLSX)Click here for additional data file."}
+{"text": "Informal caregivers of people with Alzheimer\u2019s disease and related dementias (ADRD) are a vulnerable, often isolated population with high rates of financial strain and need for community resource supports. Little is known about how best to connect these caregivers to resources, especially during the COVID-19 pandemic. CommunityRx-Caregiver is an evidence-based intervention that connects caregivers to community resources for basic needs, wellness, and caregiving. Using preliminary data from a randomized trial of CommunityRx-Caregiver (N=344), we examined caregivers\u2019 baseline confidence in finding community resources and their engagement in the CommunityRx-Caregiver intervention. Caregivers enrolled December 2020-February 2021 (n=26) received (1) personalized lists of community resources via text message , (2) access to an online resource portal (FindRx) and (3) automated texts offering support for finding resources. Most caregivers were female (65%), Black (92%), >60 years old (64%) and 44% reported very good or excellent health. Nearly half of caregivers (46%) were completely confident in finding community resources. Overall, 81% of caregivers engaged with a text message or the FindRx. Nearly two-thirds (65%) of caregivers responded to at least one text message. More than a quarter (27%) used the FindRx tool; 5/7 of those shared FindRx resources with others. Caregivers sought resources including in-home personal care, exercise classes and support groups. Caregivers of people with ADRD, many of whom had low confidence in finding resources, engaged with a multi-modal information technology-based intervention to obtain community resource support. These preliminary findings suggest caregivers were receptive to a remotely-delivered community referral intervention during the COVID-19 pandemic."}
+{"text": "Physical activity (PA) guidelines recommend 150 minutes of moderate-intensity or 75 minutes of vigorous-intensity PA, in addition to muscle strengthening activities, each week. Many questionnaires ascertain PA frequency, duration, and intensity to benchmark achievement of PA recommendations. However, most scoring algorithms utilize absolute intensity estimates when exertion may be influenced by age or other sociodemographic or health characteristics. This study compared PA estimates with and without adjustments for perceived exertion and determined if that difference was associated with individual characteristics. Women  from the longitudinal Study of Women\u2019s Health Across the Nation who completed \u22653 Kaiser Physical Activity Surveys (KPAS) across 8 biennial visits were included (baseline age: 46.4\u00b12.7 years). KPAS responses were converted to metabolic equivalent of a task (METs) using the Compendium of Physical Activities to estimate absolute and perceived intensity-adjusted MET values. Latent class growth modeling identified subgroups of participants following similar patterns of change in the difference between absolute intensity-based and perceived intensity-adjusted estimates across time. Four major trajectory classes emerged with patterns reflecting: (1) lessening high-intensity exercise (2.2%); (2) increasingly high-intensity exercise (3.1%); (3) consistently moderate-intensity exercise (92.0%); and (4) consistently low-intensity exercise (2.8%). Consistently low-intensity exercisers, for whom absolute intensity-based estimates exceeded perceived intensity-adjusted estimates, were more likely to be Japanese or Chinese (p<0.001) and have lower BMI (p=0.05). However, for most participants, absolute intensity-based estimates approximated perceived intensity-adjusted estimates over time, suggesting that traditional PA scoring techniques may provide sufficient estimates for PA in longitudinal cohort studies of mid-life and older adult women."}
+{"text": "Shorter courses of intravenous (IV) antibiotics for young infants with urinary tract infection (UTI) have myriad advantages. As practice shifts toward shorter IV treatment course, this study aimed to determine the safety of early IV-to-oral antibiotic switch, and identify risk factors for bacteraemia with UTI.Retrospective audit of infants aged \u226490 days with a positive urine culture at a quaternary paediatric hospital over four years (2016-2020). Data were collected from the hospital electronic medical record and laboratory information system. Short-course IV antibiotic duration was defined as < 48 hours for nonbacteraemic UTI and < 7 days for bacteraemic UTI. Multivariate analysis was used to determine patient factors predicting bacteraemia.Among 427 infants with nonbacteraemic UTI, 257 (60.2%) were treated for < 48 hours. Clinicians prescribed shorter IV courses to infants who were female, aged >30 days, afebrile, and those without bacteraemia or cerebrospinal fluid pleocytosis. Treatment failure (30-day UTI recurrence) occurred in 6/451 (1.3%) infants. All had nonbacteraemic UTI and only one received < 48 hours of IV antibiotics. None had serious complications . Follow-up audiology was performed in 21/31 (68%) infants with cerebrospinal fluid pleocytosis, and one had sensorineural hearing loss. Bacteraemia occurred in 24/451 (5.3%) infants, with 10 receiving < 7 days IV antibiotics with no treatment failure, meningitis or death. Fever and pyelonephritis were independent predictors of bacteraemia.Short course IV antibiotics for < 48 hours for young infants with nonbacteraemic UTI are safe provided bacterial meningitis has been excluded. Treatment failure and serious complications were rare in young infants with UTI. All Authors: No reported disclosures"}
+{"text": "DISCUSSION/SIGNIFICANCE OF IMPACT: Our results show that Rab27B is important in NSCLC TIC growth and invasion. Further studies are needed to determine the mechanism of Rab27B action. TICs have been linked to enhanced tumorigenic properties, suggesting that Rab27B could be a good candidate for therapeutic targeting of NSCLC TICs.OBJECTIVES/GOALS: Rab27B, a small GTPase, functions in exosome formation and secretion. Rab27B is overexpressed in non-small cell lung cancer (NSCLC) and predicts patient survival; however, little is known about its importance in NSCLC cells. Here, we investigated the role of Rab27B in NSCLC tumor initiating cells. METHODS/STUDY POPULATION: Tumor initiating cells (TICs) were enriched in a panel of NSCLC cell lines using low adherence spheroid cultures. QPCR and immunoblot analysis were used to compare Rab27B mRNA and protein expression, respectively, in adherent bulk cancer cells and TIC cultures. Lentiviral-packaged short hairpin RNAs (shRNAs) were used to knockdown Rab27B in PC9 and H1299 NSCLC TICs. The effects of Rab27B knockdown on PC9 and H1299 TIC expansion, transformed growth, and invasion were analyzed by MTT cell proliferation, soft agar colony formation, and Boyden chamber assays respectively. RESULTS/ANTICIPATED RESULTS: Quantitative PCR and immunoblot analysis showed that Rab27B expression is elevated in NSCLC TICs when compared to adherent bulk cancer cells. Efficient knockdown of Rab27B was achieved in PC9 and H1299 NSCLC TICs using two independent shRNA constructs. Rab27B knockdown cells exhibited decreased expansion as spheroid cultures, transformed growth, and invasion when compared to non-target shRNA control cells. Future experiments will focus on determining the importance of Rab27B in TIC exosome production and"}
+{"text": "ABSTRACT IMPACT: This work will help to understand a novel therapeutic approach to a common type of acute myeloid leukemia. OBJECTIVES/GOALS: FMS-like tyrosine kinase 3 (or FLT3) mutations occur in \u02dc30% of acute myeloid leukemia (AML) cases. FLT3 tyrosine kinase domain (TKD) mutations are particularly important in relapsed/refractory FLT3 mutant AML, which portends poor prognosis. This study describes a therapeutic approach to overcoming resistance conferred by FLT3-TKD mutations. METHODS/STUDY POPULATION: To understand the efficacy of a novel type 1 FLT3 inhibitor (NCGC1481), as a monotherapy and combination therapy, several assays were utilized to interrogate functionality of these therapies. Cell lines and patient samples containing aspartate 835 to tyrosine mutations  and phenylalanine 691 to leucine (F691L) were utilized to examine the effects of NCGC1481 with and without other targeted therapies like MEK inhibitors. Specifically, assays measuring viability, cell death using flow cytometry, in vitro clonogenicity, cellular signaling, and xenograft survival were examined in these FLT3-TKD AML models. Synergy was also measured using well described methods, which also allowed for appropriate dose finding for drug combination experiments. RESULTS/ANTICIPATED RESULTS: Our novel type 1 FLT3 inhibitor (NCGC1481) was particularly effective in the most common FLT3 TKD mutant, D835Y. NCGC1481 reduced viability and cell signaling, while also inducing cell death and prolonging xenograft survival in the FLT3-D835Y model system. In contrast, clinically approved FLT3 inhibitors were less effective at suppressing AML cells expressing FLT3-D835Y. In the case of FLT3-F691L, most of the FLT3 inhibitors tested, including NCGC1481, suppressed canonical FLT3 signaling, but did not significantly reduce viability or leukemic clonogenicity. However, when NCGC1481 was combined with other targeted agents like MEK inhibitors, at synergistic doses, eradication of the FLT3-F691L AML clone was substantially increased. DISCUSSION/SIGNIFICANCE OF FINDINGS: In AML, response to FLT3 inhibitor therapy is often short-lived, with resistance sometimes occurring via FLT3-TKD mutations. Given the dismal prognosis of relapsed FLT3 mutant AML, novel therapies are necessary. This study describes efficacy of a novel FLT3 inhibitor, along with its synergistic activity when combined with other targeted agents."}
+{"text": "OBJECTIVES/GOALS: To describe preliminary results of Alzheimer\u2019s and dementia caregivers\u2019 (CGs) mobile app use and intention to adopt mHealth apps for their own chronic condition self-management. To discuss implications for designing and implementing mHealth interventions for CGs. METHODS/STUDY POPULATION: This study aims to recruit 110 racially and ethnically diverse family caregivers (CGs) who have a chronic condition, provide care for persons with Alzheimer\u2019s disease or related dementias, and have access to a mobile device. This is a cross-sectional correlational study collecting data with computer-assisted telephone interviews stored through REDCap. The study survey was created using existing surveys about mobile app use; relevant, well-validated research instruments; and questions from the U.S. Census and other national surveys. CGs are being actively recruited from the Baltimore-Washington metropolitan area using various recruitment strategies that have been effective in prior studies. RESULTS/ANTICIPATED RESULTS: The majority of CGs used websites (86%), mobile devices (68%) or apps (53%) to manage their own health. CGs using health-related apps were tracking their exercise (60%), diet (60%), medical records (50%), and physical health measures (50%). More than 4 out of 5 (82%) predicted they would use mobile apps to self-manage their chronic condition, though only 68% actually planned to use them. 86% of CGs were using mobile apps for non-health related purposes, with the most popular app being weather (90%), followed by social media (74%), music/entertainment (68%), and banking/business apps (63%). CGs used weather and social media apps most often (2 or more times/day) and spent 9 hours/week on apps. DISCUSSION/SIGNIFICANCE OF IMPACT: Websites and mobile apps appear to be feasible modes to deliver health interventions to CGs. Researchers should consider including features of apps most frequently used by CGs, such as the weather, ways to connect with others, and music/entertainment, when delivering mHealth interventions to CGs."}
+{"text": "Brain Communications 2021; 3(2): doi:10.1093/braincomms/fcab060.Margot Juli\u00ebtte Overman, Giovanna Zamboni, Christopher Butler and Samrah Ahmed; Splenial white matter integrity is associated with memory impairments in posterior cortical atrophy. In the originally published version of this manuscript, the graphical abstract was mistakenly used as Figure The correct Figure This error has been corrected online."}
+{"text": "This quality improvement study describes the results of a mass preprocedure SARS-CoV-2 testing strategy during a period of high community transmission in Connecticut. Furthermore, patients with COVID-19 have increased risks of postprocedural complications, and current guidelines suggest that testing asymptomatic patients prior to preplanned procedures may help to mitigate these risks.3 We describe our mass preprocedure SARS-CoV-2 nucleic acid amplification testing (NAAT) during a period of high community transmission.4Systematic management of procedures during the COVID-19 crisis is a priority to (1) detect and care appropriately for patients with COVID-19, (2) prevent outbreaks, and (3) safely maintain routine health care activities. SARS-CoV-2 presents unique challenges, as an estimated 50% of infections occur through asymptomatic transmission, and clinical screening may miss contagious patients.SQUIRE) reporting guideline.5This quality improvement project was exempt from institutional review board review and informed consent, per Yale University institutional review board policy. We followed the Standards for Quality Improvement Reporting Excellence  from August 1 to November 30, 2020. The primary outcome was a positive preprocedure SARS-CoV-2 test. Patients received NAAT on nasopharyngeal or deep midturbinate nasal swabs on a US Food and Drug Administration\u2013authorized platform. Patients testing positive in the prior 90 days were not required to undergo repeated testing but could be tested at clinician\u2019s discretion. To evaluate for missed infections, we reviewed results up to 7 days after the preprocedure test when available. HCP wore respirators , eye protection, gowns, and gloves for all AGPs regardless of patient COVID-19 status. Data were collected and analyzed in Excel version 16.49 (Microsoft Corp).6 Six patients (19.4%) confirmed positive household contacts after being informed of their positive test. During the evaluation, community SARS-CoV-2 rates ranged between 5 and 179 daily positive tests per 100\u2009000 individuals.4A total of 75\u2009528 preprocedure tests were performed. The median (interquartile range [IQR]) age of participants was 59 (44-69) years and 33\u2009746 (44.7%) were male patients. A total of 318 (0.4%) tested positive . The medWith preprocedure testing, we detected asymptomatic patients with SARS-CoV-2 who were missed by clinical screening alone. Testing programs like this one can reduce potential transmission events while providing an additional layer of HCP safety. Postprocedural infectious complications of COVID-19 in this higher-risk population are also mitigated when COVID-19 status is known and procedural delay is possible. Additionally, the resource burden of performing procedures using COVID-19 precautions is reduced.6 While the incidence of such conversions was low, occurrences were more common during higher community prevalence. Some patients had known, although previously undisclosed, COVID-19 household contacts. Obtaining preprocedure SARS-CoV-2 rapid antigen tests may aid in detection while obviating the logistic challenges of NAAT.The optimal timing for preprocedural testing is unknown. In rare circumstances, patients who initially tested negative later tested positive, reflecting either low viral burden early in the disease course, false-negative laboratory errors, suboptimal specimen collection, nosocomial transmission, or variable viral particle shedding in an individual long recovered from COVID-19.Limitations of this study include underreporting bias; few patients had indications for postprocedure testing, and we may not have identified all patients testing positive after the initial preprocedure negative test result. While institutions should weigh the burden of preprocedure testing against managing patients with occult infections, universal preprocedure SARS-CoV-2 testing should be considered."}
+{"text": "There have been reports of COVID-19 infection characterized by prolonged viral replication [chronic active COVID-19 (CAC)] among immunocompromised patients, including those receiving B-cell depleting therapies (BCDTs). We aimed to characterize the severity and incidence of CAC among patients on BCDTs with COVID-19, and to identify associated risk factors.We retrospectively reviewed all patients who received an anti-CD20 BCDT within 1 year of a positive COVID test at University of Utah Health. Demographics, comorbidities, indications, and timing of BCDT were documented. Chart review was performed to characterize the clinical course, including need for hospitalization, COVID-specific therapies, need for ICU and ventilatory support, and mortality. We defined CAC as: (1) despite initial clinical improvement, progression of illness extending beyond 14 days, characterized by ongoing fevers or progressive respiratory failure; or (2) ongoing symptoms with demonstration of absent seroconversion \u2265 14 days into illness. In some patients the diagnosis of CAC was supported by low viral PCR crossing thresholds that occurred \u2265 14 days into illness. Logistic models were used to identify risk factors for CAC among the cohort of patients who survived through the initial period of infection.We identified 66 individuals who received a BCDT within 1 year of a positive COVID test; 29 (44%) were hospitalized, 4 (6%) required ventilation, and 7 (11%) died within 60 days. Among 63 patients who survived their initial COVID course, 16 (25%) had courses compatible with CAC. Nine (56%) who received a BCDT within 1 month before or 2 weeks after their COVID diagnosis developed CAC; OR 7.4 .We clinically observed COVID-19 infection lasting longer than the typical course and propose a definition for CAC. Incidence of CAC was highest among patients who received BCDT within 30 days before or 2 weeks after COVID-19 diagnosis. High suspicion for CAC is warranted among patients receiving these therapies. Additional study is needed to better define risk for CAC among varying immunosuppressed populations and determine whether COVID-specific treatments early in disease may benefit these patients. Hannah Imlay, MD, MS, Gilead Sciences, Inc. (Scientific Research Study Investigator)"}
+{"text": "Dear Editor,A 61-year-old-man of the South of Spain presented at the Dermatology Department at Hospital Regional Universitario de Malaga with multiple painful erythemato-violaceous nodules on the chin, on the trunk, and the scalp . The patThe abdominal-pelvic CT image showed diffuse wall bladder thickening after therapy have been finished.Multiple brain lesions compatible with metastasis were observed in the cranial MRI. Computerized tomography showed mediastinal lymph nodes, subcutaneous nodules, and pulmonary parenchyma infiltration compatible with carcinomatous lymphangitis. The scintigraphy image showed multiple bone metastases.The patient started treatment with pembrolizumab, oral corticosteroids and holocranial radiotherapy (20 Gy), but he died seven months later.The urothelial carcinomas are the second most common genitourinary tumors.The diagnosis requires a high index of clinical suspicion and histological confirmation.The clinical presentation is quite diverse, and most commonly includes isolated nodular subcutaneous metastases. However, patients also present with diffuse, erythematous, raised infiltrates within the skin. Zosteriform pattern, extramammary Paget\u2019s disease, have been documented. Erythema gyratum repens and acanthosis nigricans as paraneoplastic disorders have been reported.5A case of urothelial cutaneous metastasis mimicking condylomata acuminate has been reported. Penile metastasis from primary bladder cancer is an extremely rare event.Prognosis of patients with bladder cancer cutaneous spreading is generally poor with less than 1-year median survival.The optimal treatment of urothelial bladder cancer with micropapillary variant histology remains not clear.Optimal management of patients with cT1  remains divergent. Each case should be discussed individually considering other clinicopathological factors and discuss management options as part of a shared decision-making process.None declared.Elisabeth G\u00f3mez-Moyano: Data curation; formal analysis; investigation; methodology; project administration; software; supervision; validation; visualization; roles/writing \u2013 original draft; writing \u2013 review.Silvestre Mart\u00ednez Garcia: Formal analysis; investigation; methodology; project administration; software; supervision; validation; visualization; roles/writing \u2013 original draft; writing \u2013 review.David Hernandez Alcaraz: Formal analysis; investigation; methodology; project administration; supervision validation; visualization; roles/writing \u2013 original draft; writing \u2013 review.Maria Ayala-Blanca: Investigation; methodology; project administration; supervision; validation; visualization; roles/writing \u2013 original draft; writing \u2013 review.None declared."}
+{"text": "Insufficient serum 25-hydroxyvitamin D (25(OH)D) concentrations are associated with increased respiratory tract infections, influenza, and other infectious diseases. As the world deals with the COVID-19 pandemic, the interest of adequate serum levels to reduce the risk of infection has surfaced. This study determined if the number of infections per year are associated with serum 25(OH)D concentrations in long-term care (LTC). Participants (\u2265 65 years) in a cross-sectional study were recruited across five LTC communities in Texas. Medical records were used to collect a one-year medical history using double-blind protocols. Blood draws were collected to measure serum 25(OH)D concentrations. Medical records were used to classify infections based upon documentation of signs and symptoms of infection concurrent with either a physician\u2019s note or antibiotic/antiviral medication prescription. Race, BMI, sex, age, and liver and renal disease diagnoses were used as confounders. Of the 177 participants  69% had \u22651 infection over year and 55% had insufficient serum 25(OH)D concentrations <30 mg/mL (mean 32.6 ng/mL). Linear regression did not show a significant association between serum 25(OH)D concentrations and number of infections . Additionally, insufficient serum concentration did not increase the odds of having an infection . This study did not show a significant association between infection rates and serum 25(OH)D concentrations. However, further research is needed to determine if vitamin D supplementation could be an effective therapeutic intervention to reduce infection rates, including COVID-19."}
+{"text": "These data suggest pharmacologic activation of the BDNF pathway with either BDNF or 7,8-DHF may be beneficial for treatment of radiation or chemotherapy induced myelosuppression.Brain-derived neurotrophic factor (BDNF) is a member of the nerve growth factor family which has been extensively studied for its roles in neural development, long-term memory, brain injury, and neurodegenerative diseases. BDNF signaling through tropomyosin receptor kinase B (TrkB) stimulates neuronal cell survival. For this reason, small molecule TrkB agonists are under pre-clinical develoment for the treatment of a range of neurodegenerative diseases and injuries. Our laboratory recently reported BDNF is secreted by pro-regenerative endothelial progenitor cells (EPCs) which support hematopoietic reconstitution following total body irradiation (TBI). Here we report BDNF-TrkB signaling plays a novel regenerative role in bone marrow and thymic regeneration following radiation injury. Exogenous administration of BDNF or TrkB agonist 7,8-dihydroxyflavone  following myelosuppressive radiation injury promoted faster recovery of mature blood cells and hematopoietic stem cells capable of multi-lineage reconstitution. BDNF promotes hematopoietic regeneration via activation of PDGFR\u03b1 Bone marrow vascular and perivascular stromal cells are known to regulate hematopoietic regeneration following radiation injury . RecentlBDNF has been well characterized as a growth factor for neurons where it has been shown to promote neural cell survival and regeneration through activation of its most high affinity receptor, tropomyosin receptor kinase B (TrkB). Systemic BDNF administration promotes neurogenesis following ischemic stroke , 4. The Expression of neurotrophins and their receptors in human bone marrow were first noted by Labuoyrie et al. in 1999 . Since tAll experimental procedures were carried out according to the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals and approved by the Institutional Animal Care and Use Committee (IACUC) of the Medical College of Wisconsin. Equal numbers of male and female C57BL/6 or B6SJL mice 4\u201310 weeks were purchased from Jackson labs. For imaging studies, BDNF-TdTomato reporter mice were generated by crossing BDNF-Cre (Jackson labs strain 030189 with Rosa26 TdTomato (Jackson labs strain 007914) mice , 23. MicRecombinant human BDNF (100% sequence homology with mouse BDNF) and the small molecule agonist 7,8-dihydroxyflavone  were purchased from Biotechne . Mice were dosed starting at 24 hours after TBI and drug treatment was administered every other day through day 10. BDNF was reconstituted in sterile PBS and administered subcutaneously at 0.5 mg/kg , 4. 7,8-For isolation of hematopoietic cell populations, bone marrow from individual femurs was flushed using an insulin syringe into 5 ml of sterile PBS + 10% FBS. Cell pellets were lysed with ACK buffer and filtered. Prior to FACS sorting stem cell populations, column purification was performed to enrich for lineage negative cells . For analysis of thymocyte populations, thymi were dissected, cleaned of excess fat and connective tissue, and triturated by passing through 40\u03bcm strainer. Viable cells were enumerated by trypan blue exclusion on a Countess cell counter. For isolation of endothelial and stromal cell populations, long bones were harvested and crushed with a mortar and pestle in PBS. The crushed bone product was then digested at 37 C for 10 minutes in a collagenase/dispase buffer , 1 unit/ml Dispase II . Following digestion, bones were rinsed in ice-cold complete media (IMDM + 10% FBS), filtered, and then column depleted of lineage committed hematopoietic cells .FACS sorting was performed at the Versiti Blood Research Institute Flow Cytometry Shared Resource. Flow cytometric analysis was performed using a Miltenyi MACSQuant 10 instrument.The lineage-Sca-1+c-Kit+ (LSK) expressing hematopoietic stem and progenitor cell population were labeled with PE anti-mouse CD117 , APC/Cyanine7 anti-mouse Ly-6A/E , and Pacific Blue anti-mouse Lineage Cocktail (Biolegend 133310). Common myeloid progenitor (CMP: lineage-c-Kit+ Sca-1-CD34+CD16/32-) and common lymphoid progenitor (CLP: LSK IL-7R\u03b1+) subsets were discriminated using by the addition of the following antibodies to the LSK panel: Brilliant Violet 510 anti-mouse CD16/32 (Biolegend 101333), PE/Cyanine7 anti-mouse CD34 (128618), APC anti-mouse CD127 . Discrimination of donor B6.SJL versus recipient C57BL/6 blood cell lineages was performed using: FITC anti-mouse CD45.1 (Biolegend 110706), PE anti-mouse CD45.2 (Biolegend 109808), Pacific Blue anti-mouse CD3 (Biolegend 155612), APC/Cyanine7 anti-mouse B220 (Biolegend 103224), Brilliant Violet 510 anti-mouse TER-119 (Biolegend 116237), PE-Cy7 Cd11b (Biolegend 101216) and APC anti-mouse Gr-1 (Biolegend 108412) antibodies. Thymocytes were analyzed for double negative (CD4- CD8-) and double positive (CD4+ CD8+) populations using CD4-VioBlue (Miltenyi 130-118-568), CD8a-PE/VIO770 (130-118-946), CD44-APC , CD25 PE (130-120-696).For FACS-sorting CD31 and PDGFR\u03b1 populations, the following antibodies were used: FITC anti-mouse CD45 (Biolegend 103108), APC anti-mouse CD31 (Miltenyi 130-123-813), and PE-Vio770 CD140a . For analysis of endothelial cell death and mitochondrial ROS generation, the following antibodies were used: BV421 anti-mouse CD45 (Biolegend 103133), AF647 anti-mouse VE-Cadherin (Biolegend 138006). For these studies, mice were intravenously labeled with VE-Cadherin antibody (25 ug/mouse) via IV injection. Fifteen minutes following injection, mice were sacrificed, long bones were harvested and digested as described above. Endothelial cells were identified as the CD45- 7AAD- VE-Cadherin+ cell population. To discriminate apoptotic cells within this population, the CellEvent\u2122 Caspase-3/7 Green Flow Cytometry Assay Kit  was used per manufacturer\u2019s instructions. Mitochondrial ROS was measured using MitoSOX Red .Bone marrow supernatants were obtained by flushing both femurs from a single mouse into a total volume of 400 ul cold PBS. Cells and debris were pelleted by centrifugation and the remaining supernatant was assayed at 1X for mature BDNF and pro-BDNF using the Mature BDNF/proBDNF Combo Rapid ELISA Kit purchased from Biosensis (BEK-2211/2217) per manufacturer\u2019s instructions. Absorbance at 450 nm was measured on a Biotek plate reader.Complete blood counts were determined using a Heska Element 5 Veterinary Hematology Analyzer.Congenic transplantation studies were performed using 500,000 whole bone marrow (WBM) cells isolated from B6.SJL at day 7 following 5 Gy TBI. Donor B6.SJL cells were transplanted into 9 Gy irradiated C57BL/6 mice along with a host competitor cell dose of 200,000 C57BL/6 WBM cells.Evans Blue Dye (EBD) extravasation in the bone marrow space was assessed as previously described , 26. BriMice were intravenously labeled with VE-Cadherin antibody  via IV injection. Fifteen minutes following injection, mice were sacrificed and long bones were harvested. Whole femurs from VE-cadherin-labeled mice were fixed overnight in 4% paraformaldehyde, decalcified for 72 hours in EDTA/PBS, incubated for 2 hours in 20% sucrose, and then embedded in OCT medium. Femurs were sectioned at 8 um. Sections were re-hydrated in PBS and mounted in ProLong Gold Antifade with DAPI. Slides were imaged at 20X using an EVOS M500 imaging system.Human primary bone marrow mesenchymal stromal cells were purchased from Stem Cell Technologies (70022) and cultured to confluence in MesenCult\u2122 Proliferation Kit . After reaching confluence the media was replaced with serum free basal medium with or without 100 ng/ml BDNF. The cells were irradiated in vitro with 8 Gy. At 24 hours, the cell culture supernatant was collected and concentrated 2-fold. A human cytokine 71-plex Discovery assay was performed by Eve Technologies. Samples that were out of the detection range were excluded from analysis.Values are reported as mean \u00b1 SEM, unless stated otherwise. All comparisons were performed using GraphPad Prism 9.0. All data were checked for normal distribution and similar variance between groups. Data are derived from multiple independent experiments from distinct mice or cell culture plates. Sample size for in vitro studies was chosen based on observed effect sizes and standard errors from prior studies.Bdnf and TrkB mRNA levels were measured in the thymus, spleen, and bone marrow of pediatric (4 week old) and adult (12 week old) C57BL/6 mice . Interestingly, mRNA levels of TrkB rose in the thymus but declined in the BM PDGFR\u03b1+ with age. It is also worth noting that TrkB was not detectable within the CD31+ endothelial cell fraction. We then performed an additional analysis to determine if TrkB or the low affinity neurotrophin receptor p75NTR (NGFR) were expressed in FACS sorted bone marrow hematopoietic progenitor cell populations (TrkB or p75NTR transcript was detectable in the common myeloid progenitor (CMP) or common lymphoid progenitor (CLP) subsets. Within the stem cell-enriched lineage negative sca-1+ c-kit+ (LSK) fraction, only p75NTR was detectable at low levels.L/6 mice . Consistulations , 18. Herulations . NeitherTrkB transcript expression in bone marrow PDGFR\u03b1+ MSCs, we evaluated whether BDNF treatment induces activation of irradiated human MSCs ex vivo. Primary human MSCs were exposed to 8 Gy irradiation and cultured for 24 hours with or without 100 ng/ml recombinant human BDNF. The cell culture supernatant was screened for differential expression of a panel of 71 human cytokines. Of the 71-cytokines, IL-6 and LIF were significantly increased by BDNF treatment. , neutrophil (NEU), lymphocyte (LYMPH), platelet (PLT) and hemoglobin (Hgb) counts are suppressed in mice receiving 5 Gy at day 10 following TBI . HoweverWe next evaluated the bone marrow at day 10 following 5 Gy for differences in hematopoietic progenitor and stem cell content. At this dose and time point, radiation injury ablates the myeloid progenitor-enriched population of lineage-c-Kit+Sca-1- cells (MP) as well as the HSC and multipotent progenitor enriched population of lineage-Sca-1+c-Kit+ (LSK) cells . TreatmeSince BDNF and its receptor TrkB are expressed in the thymus, we next evaluated whether exogenous BDNF administration following radiation injury regulated both early (day 10) and late (day 120) recovery of the thymus. At day 10 following radiation, there is a decrease in total thymus mass compared to day 0 non-irradiated controls (dotted line) in both the saline and BDNF treated groups . HoweverBdnf transcript levels with increasing age. Additionally, we observed dynamic regulation of TrkB transcript expression with age in the thymus and bone marrow.Labyourie et al. first characterized expression of neurotrophins and the Trk family receptors in adult and fetal human bone marrow where they found transcript levels of the four members of the neurotrophin family  were increased in the fetal bone marrow compared to adult bone marrow . These din vivo [Our prior data demonstrated endothelial progenitor cells expressing high levels of BDNF promote hematopoietic reconstitution following ablative radiation injury in vivo . Based oAdditionally, we have seen that BDNF administration in vivo markedly increases the regeneration of the thymus following radiation injury. BDNF protein levels are known to decline in the thymus with age . Prior sSince agonism of BDNF-TrkB signaling supports regeneration of both the bone marrow and thymus following radiation injury, these data would support the therapeutic use of BDNF or 7,8-DHF for the treatment of radiation-induced neutropenia and lymphocytopenia. However, it should be noted that BDNF and TrkB upregulation are associated with tumor cell survival in a number of solid cancers , 33 and TrkB expression. Therefore, it is unlikely that exogenous BDNF administration is mitigating radiation injury to the bone marrow by acting directly on the hematopoieitic stem or progenitor cell compartment. Instead, our data indicate BDNF acts on TrkB+ bone marrow MSCs to promote the release of regenerative hematopoietic cytokines. This finding is supported by data from a recent lung injury study by Paris et al. which demonstrated BDNF promoted alveolar regeneration via activation of TrkB expressing pulmonary mesenchymal cells [Prior publications have demonstrated TrkB is expressed on human CD34+ cells 16, 17), murine B-lympocytes (18), as well as murine thymocytes (19). However, in our transcriptional analysis of bone marrow hematopoietic stem and progenitor cell populations, we did not detect , 17, mural cells . In thesal cells . This isal cells , 38. Heral cells  and bothal cells , 41.Our data with the TrkB specific agonist 7,8-DHF would suggest the regenerative activity of BDNF in the bone marrow is mediated primarily via activation of TrkB. However, BDNF is also known to bind and activate the low-affinity nerve growth factor receptor (p75NTR or NGFR). Recently, Severe et al. have reported that bone marrow stromal cell fractions expressing NGFR are resistant to radiation injury and express high levels of SDF1 . TherefoIn conclusion, our data support a novel role of BDNF in regulating bone marrow regeneration and hematologic reconstitution following myelosuppressive radiation injury through the TrkB receptor. Pharmacologic treatment with BDNF or TrkB receptor agonist may have therapeutic benefit for treatment of radiation or chemotherapy induced myelosuppression.S1 FigRight, %Lin-VE-Cad+ ECs.(PDF)Click here for additional data file.S2 FigRight, analysis of thymocyte precursor subsets within the DN population: DN1, DN2, DN3, and DN4 based on CD44 and CD25 staining.(PDF)Click here for additional data file."}
+{"text": "Background: Recent evidence indicates that host-gut microbiota crosstalk has nonnegligible effects on host skeletal muscle, yet gut microbiota-regulating mechanisms remain obscure.Methods: C57BL/6 mice were treated with a cocktail of antibiotics (Abx) to depress gut microbiota for 4 weeks. The profiles of gut microbiota and microbial bile acids were measured by 16S rRNA sequencing and ultra-performance liquid chromatography (UPLC), respectively. We performed qPCR, western blot and ELISA assays in different tissue samples to evaluate FXR-FGF15/19 signaling.Results: Abx treatment induced skeletal muscle atrophy in mice. These effects were associated with microbial dysbiosis and aberrant bile acid (BA) metabolism in intestine. Ileal farnesoid X receptor (FXR)-fibroblast growth factor 15 (FGF15) signaling was inhibited in response to microbial BA disturbance. Mechanistically, circulating FGF15 was decreased, which downregulated skeletal muscle protein synthesis through the extracellular-signal-regulated protein kinase 1/2 (ERK1/2) signaling pathway. Treating Abx mice with FGF19 (human FGF15 ortholog) partly reversed skeletal muscle loss.Conclusions: These findings indicate that the BA-FXR-FGF15/19 axis acts as a regulator of gut microbiota to mediate host skeletal muscle. The BA pool size was significantly decreased in caecum but increased in ileum , which sAsbt) was increased in ileum of Abx mice (Ost\u03b1) and solute carrier family 51, beta subunit (Ost\u03b2) were also upregulated in ileum of Abx mice  remained unaltered in Abx mice. FGF15 (the mouse FGF19 ortholog) is a BA-FXR-induced enterokine secreted from distal ileum. It governs BA homeostasis by inhibiting bile acid synthesis enzymes such as cholesterol-7a-hydroxylase (Cyp7a1) in liver [Cyp7a1 expression in Abx mice liver , indicating total BA pool size was increased after antibiotic treatment. Cyp7a1 is also regulated by hepatic FXR-SHP signalling, but hepatic FXR signalling was comparable in Veh and Abx mice . Taken together, deleting gut microbiota by antibiotic treatment altered microbial BA metabolism to remodel ileal FXR-FGF15 signalling.We further sought to analyse BA-related signalling pathways in two groups of mice. The protein level of BA reabsorption gene solute carrier family 10, member 2  and muscle ring finger-1 (Murf-1), two well-known MPB-related genes expressed at comparable levels in muscles of Veh mice and Abx mice . Thus, we assumed that gut microbiota might mediate host MPS via FGF15/19-ERK signalling in an insulin independent way.Skeletal muscle mass depends on the balance between muscle protein synthesis (MPS) and muscle protein breakdown (MPB). We firstly found that muscle atrophy F-box . We used surface sensing of translation (SUnSET) method in\u00a0vivo to estimate MPS rate in the three groups of mice [Figure S5). Collectively, we suggest that depleting gut microbiota disturbed gut microbiota-BA-FXR-FGF15/19-ERK signalling axis, which in turn decreased MPS, thereby inducing host skeletal muscle atrophy.To further verify whether skeletal muscle atrophy in Abx mice was caused by decreased FGF15, another subset of mice were given the same antibiotic treatment with recombinant FGF19 injected subcutaneously for 4\u2009weeks. The concentration of plasma FGF19 was undetectable in both vehicle- and PBS-treated mice (VP mice) and antibiotic- and PBS-treated mice (AP mice), but increased in antibiotic- and FGF19-treated mice (AF) mice ( of mice . PuromycHow gut microbiota influences skeletal muscle mass remains elusive. In this study, we demonstrated that deleting gut microbiota by antibiotics can induce skeletal muscle atrophy in mice, resulting in altered body composition, reduced muscle mass and smaller myofibers size. As a result of microbial dysbiosis, which is characterised by lacking bacteria possessing BSH, the microbial metabolism of BA was strikingly obstructed so that conjugated primary BAs including T\u03b2MCA were increased. Ileal FXR-FGF15 signalling was subsequently inhibited because of FXR antagonist T\u03b2MCA accumulation. Finally, ERK signalling cascades were downregulated so that protein synthesis was impaired in muscle because of decreased circulating FGF15. Further FGF19 treatment at least in part reversed antibiotic-induced muscle loss in mice. These results suggested that the crosstalk between gut microbiota and host skeletal muscle might partly depend on BA-FXR-FGF15/19 signalling .Our study confirms the results of earlier studies showing that gut microbiota plays an important role in the regulation of host skeletal muscle. Backhed team reported for the first time that compared with conventionalised mice, whole body lean mass was increased and fat mass was decreased in GF mice . AnotherLactobacilli and the number of Enterobacteriaceae was significantly higher in samples from very frail volunteers [ob/ob mice with prebiotic induced significant changes in the gut microbiota, with Lactobacilli and Bifidobacteria being increased, thereby improving metabolic disorders with a higher muscle mass [Lactobacillus and Bifidobacterium to aged mice resulted in increased muscle mass and grip strength [Bifidobacterium and Lactobacillus [The normal microbiomes in mice and humans are dominated by Firmicutes and Bacteroidetes, which harbour bacteria expressing BSH, a necessary microbial hydrolase that catalyses BA deconjugation. After antibiotic treatment, the Abx mice microbiome had a compositional shift to Proteobacteria and lacked bacteria stains expressing BSH. Previous data have reported that the elderly with high frailty scores, which indicate weak muscle performance, showed a significant reduction in the number of lunteers . Feedingcle mass . Directlstrength , and thibacillus , were deRecently, different studies found that the impacts of gut microbiota on host skeletal muscle were based on changing the expression of genes involved in the muscle peripheral circadian rhythm machinery , alterinvia ERK signalling, a pathway that regulates protein synthesis. We also revealed that muscle ERK signalling was inhibited by decreased FGF15 in Abx mice, independent of the insulin signalling pathway, which was also supported by a previous study [via FGF15/19-ERK pathway. Taken together, the impairment of protein synthesis in Abx mice muscles was associated with an inhibited FGF15/19 pathway.Interestingly, previous studies found that FGF15/19 was an activator of protein synthesis in liver and skeletal muscle ,32. TreaNevertheless, this study had several limitations of note. Firstly, GF mice were a better animal model to investigate gut microbiota-skeletal muscle axis. However, these mice not only have compensatory mechanisms to balance the absence of microbiota but also have a dramatically different bile acid profile . SecondlIn summary, we demonstrated for the first time that gut microbiota has a profound effect on mice skeletal muscle at least in part by BA-FXR-FGF15/19 signalling. On the one hand, antibiotics should be used with caution in clinical work, and whether antibiotic treatment induces skeletal muscle atrophy in human awaits further investigation. On the other hand, one inspiring discovery from our study is that bacteria-related FXR-FGF15/19 signalling could be potential targets for treating skeletal muscle atrophy.Click here for additional data file."}
+{"text": "Patients with COVID-19 receive high rates of antibiotic therapy, despite viral origin of infection. Reports of bacterial coinfection range from 3.5 to 8% in the early phase of infection. This study aimed to evaluate the relationship between diagnostic tests and antibiotic utilization in patients admitted with COVID-19 at the University of Maryland Medical Center to better inform future prescribing practices.Retrospective cohort study of adult patients with a positive SARS-CoV-2 PCR on admission from March 2020 through June 2020. Associations between diagnostic tests employed and antibiotic initiation and duration were explored using bivariate analysis (SPSS\u00ae). P=0.025), any degree of oxygen requirement on admission , and performance of blood cultures  were associated with antibiotic initiation. Positive bacterial diagnostic respiratory culture  and positive blood culture  were associated with longer antibiotic duration. Patients who did not have respiratory cultures performed had similar antibiotic durations as those with negative respiratory cultures.Baseline characteristics of 224 included patients are reported in Table 1. Excluding SARS-CoV-2 PCRs, most frequently performed diagnostic tests included blood cultures (65.6%), MRSA nasal surveillance (45.1%), respiratory cultures (36.2%), respiratory viral panel (RVP) (33.0%), and Legionella (28.6%) and pneumococcal (26.3%) urine antigens. Positivity of RVP, Legionella, pneumococcus, blood, and respiratory tests were low . A total of 62% of patients were initiated on antibacterial therapy with a median cumulative antibiotic duration of 77.9 hours . History of chronic respiratory disease"}
+{"text": "Drosophila melanogaster insulin/IGF signaling system slow aging, while also affecting growth and reproduction. To understand this pleiotropy, we produced an allelic series of single codon substitutions in the Drosophila insulin receptor, InR. We generated InR substitutions using homologous recombination and related each to emerging models of receptor tyrosine kinase structure and function. Three mutations when combined as trans-heterozygotes extended lifespan while retarding growth and fecundity. These genotypes reduced insulin-stimulated Akt phosphorylation, suggesting they impede kinase catalytic domain function. Among these genotypes, longevity was negatively correlated with egg production, consistent with life-history trade-off theory. In contrast, one mutation (InR353) was located in the kinase insert domain, a poorly characterized element found in all receptor tyrosine kinases. Remarkably, wild-type heterozygotes with InR353 robustly extended lifespan without affecting growth or reproduction and retained capacity to fully phosphorylate Akt. The Drosophila insulin receptor kinase insert domain contains a previously unrecognized SH2 binding motif. We propose the kinase insert domain interacts with SH2-associated adapter proteins to affect aging through mechanisms that retain insulin sensitivity and are independent of reproduction.Mutations of the  Early work extended lifespan through mutations of the insulin-like receptors osophila , which cC elegans and Drosophila while these invertebrates produce many insulin-like ligands  when heterozygous over a P-element insertion allele   . We thenDrosophila InR mediates aging in independent ways. One affects reproduction and thereby extends lifespan through reduced survival costs, the other affects mechanisms to assure longevity independent of reproduction. (2) The biochemical impact of substitutions within InR may be understood in a context of asymmetric transphosphorylation (We propose three conclusions. (1) rylation  that robInR is on the third chromosome. Lines with EMS-induced mutations in InR, balanced by the third chromosome inversion InR+TM3, were provided by M. Frasch (The Mount Sinai School of Medicine)   background using the balancer stock Sam 1; Sam 2; InR+TM3/TM6B .The Drosophila insulin/IGF-receptor Drosophila melanogaster caught at the Raleigh Farmer\u2019s Market  . In addition, the InRNC442 line was used to normalize survival data across test blocks.Iso-female lines were established from wild-type InRE19 (using adult InRE19/InR+TM3) and the nine viable Frasch InR EMS-alleles (using InREMS/InR+TM3), and between the 18 InRNC wild-type alleles (using InRNC/InR+TM3). Offspring from reciprocal crosses were pooled to measure phenotypes. Phenotypes of every InREMS/InRE19 and InRNC/InRE19 offspring were compared to a contemporaneous cohort of the allele when complemented by wild-type InR (InREMS/InR+TM3 or InRNC/InR+TM3).Quantitative complementation testing measures the phenotypic difference of one allele complemented to a standard hypomorph relative to when it is complemented to a standard wild-type allele . We madeSupplementary Methods). Cohorts were initiated with three replicate demography cages of \u223c150 newly eclosed adults at \u223c1:1 sex ratio per genotype. In total, we assessed the lifespan of 16,057 males and 17,223 females. Each 2 days, food vials were changed and dead flies were removed and counted. Life tables collected in five test blocks (j\u2009=\u20091\u20135) were made with data from replicate cages combined. Within each test block, we included the wild-derived line InRNC442 to normalized genotypes across blocks. One life table was generated for each InREMS allele and InRNC allele expect for duplicates generated in independent blocks for InR211(EMS), InR74(EMS), and InR353(EMS).Life tables (number of deaths per 2-day census period) were generated for adult offspring of each genotype (details in ij)\u03b2 within each block j for each InR allele i (EMS or NC) when complemented to InRE19 relative to when complemented to +TM3InR. In each block, we estimated adjusted mortality coefficient for each InR allele as iInR/InRE19 relative to iInR/(+TM3InR); values near zero indicate there is no effect on mortality and values greater than zero indicate there is increased mortality. The transformation InR allele complemented to InRE19 relative to when it is complemented to +TM3InR. Life expectancy was also standardized among blocks: for each block j we calculated the difference in life expectancy between InRNC442/InRE19 and InRNC442/(+TM3InR) denoted InR allele i is We used proportional hazard analysis  to conduInREMS mutant and InRNC wild-type allele when complemented to InRE19 and to +TM3InR. Adults were reared simultaneously on standard diet from vials seeded with 100 eggs, and collected across three replicate vials. The relative body size of each tested iInR allele was measured as (mean of iInR/InRE19)/(mean of iInR/+TM3InR).Head capsule width was measured from 20 females from each InRE19, InR211, InR74, and InR353 based on their ability to reduce mortality, and InR246 as a contrast where QCT showed effects body size but not mortality. Ron Kohanski  provided cDNA sequences for the InRE19, InR74, and InR246 alleles that respectively contained codon substitutions as Val810Asp, Ile1543Phe, and Val1384Met (InR353 and InR211 were reported by wDah background. We made five single replacement lines (designated InRE19(HR), InR74(HR), InR211(HR), InR246(HR), InR353(HR)). We produced independent, replicate accessions for InRE19(HR) (denoted InRE19(HR)-2, InRE19(HR)-14, InRE19(HR)-22) and for 353InR(HR) (denoted InR353(HR)-8, InR353(HR)-15, InR353(HR)-20). We replaced the native wDah sequence with itself to produce the wild-type control InR+(HR) (accession denoted \u201c29B\u201d). We generated a double substitution allele ), and a null InR allele (InRnull(HR)).To validate and extend the results of QCT, we focused on the EMS alleles l1384Met . Codon sSupplementary Materials. Targeting arms for InR cloned from wDah . Targeting arms contained single nucleotide substitutions to produce the desired amino acid replacements. Flies with the +white eye color marker mapped to the first or second chromosomes were used for homologous recombination. These lines were crossed to flies expressing flipase and the restriction enzyme I-Sce1 to execute excision and linearization of the transgenic construct. Candidate insertion lines were selected based on +white mapped to chromosome 3. Chromosomes with replaced alleles were crossed to flies expressing cre recombinase to remove the +white marker. The +white marker was retained in an accession of the wild-type replacement allele to produce InRnull(HR). All replacement alleles were validated by sequencing.Detailed methods for the homologous recombination are provided in the InR(HR) alleles. Four females and males were housed for mating and to lay eggs over 24\u2009h in replicate vials with yeast-supplemented standard media. We recorded stage of lethality  and the number of emerging adults each subsequent 24\u2009h. Adult size (thorax length) was measured from 20 off-spring females of every viable cross.Reciprocal crosses were made among all Newly eclosed males and females were collected, transferred to bottles with fresh medium and kept at 25\u00b0C for 2 days (details in Supplementary Methods). Mated females were transferred to demography cages maintained at 25\u00b0C at an initial density of 125 females per cage. Three to five replicate cages were initiated for each genotype. Food was changed every two days, at which time dead flies were removed and counted. Life tables were constructed with genotype replicate cages combined for survival analysis. In total, we assessed the lifespan of 17,184 homologous recombination females.wDah males into three replicate demography cages, modified for egg collection (details in Supplementary Methods). For the following 15\u2009days, egg plates were supplemented with yeast paste and changed twice a day at which time eggs were counted. Dead females were removed and counted daily. Daily fecundity (mean eggs per day) is the number of eggs summed across replicate cages per surviving female. Average fecundity is the mean of daily fecundity across the sample period. Ovariole number was measured from fifteen 10-day old females of each genotype. Ovaries were dissected in PBS, fixed with 4% paraformaldehyde, and scored for total number of ovarioles across both ovaries.Fifteen newly eclosed females of each genotype were placed with 15 4-Akt Cat#4054, pan-Akt Cat#4691). Blots were imaged and quantified with ImageLab (Bio-Rad).We evaluated the ability of IRs to induce phosphorylation of Akt from larval fat bodies stimulated by human insulin, as in Supplementary Figure S1 provide amino acid sequence annotation of Drosophila InR, and human IR and IGF1R. We number the human IR as the mature long isoform of Drosophila InR beginning at the first translation initiation site in wDah wildtype (deposited in GenBank as accession MT_563159), which is +45 amino acids relative to the TIS reported by wDah sequence also differs from that of Fernandez by an insertion/deletion (wDah lacks H144) and the substitution H146Q. This H144/H146 polymorphism segregates along latitudinal clines of Drosophila populations , eclosion time distribution , and the verified sequence alignments of the homologous recombination alleles . Supplementary Figure S3 provides conceptual diagrams of dimer complementation and a model for receptor domain function in aging. Tables in the Supplemental Materials provide survival statistics of the QCT (Supplementary Table S1), survival data for wild-type alleles in QCT (Supplementary Table S2), survival data of hemizygotes (Supplementary Table S3), and survival data of all HR alleles and accessions (Supplementary Table S4). https://doi.org/10.25386/genetics.13377023.Supplementary material is available at figshare DOI: InR EMS alleles  affect aging. InRE19 relative to when complemented to wild-type InR (InR+TM3) (Supplementary Table S1). Mortality rates in all cohorts increased exponentially once the death rate exceeded the lower limit of demographic power (InRNC442 measured in each to control for block effects (Supplementary Table S2). Relative to InRNC442 within each block, the EMS mutations variously reduced mortality (block adjusted i\u03b2adj = -1.80), had little effect (i\u03b2adj \u00a0i\u03b2adj = 1.64) (Supplementary Table S1). Because InRNC442 is just one instance of a wild-type allele, we applied QCT to a collection of 18 wild-type InR alleles extracted from the North Carolina Market population (NC series) and evaluated how each EMS mutant performed relative to the wild-type distribution (Supplementary Table S1). Six EMS InR mutants did not significantly reduce mortality relative to wild-type alleles , while InR327 strongly increased mortally. InR74 and InR211 significantly reduced mortality in males and females. The InR353 allele reduced female mortality but not significantly so relative to the wild-type distribution. The transformation InR74 and InR211 alleles reduced male and female mortality 2.6- to 6-fold, while InR353 reduced female mortality about 2-fold  used for complementation; each tested InR may contain unidentified substitutions; allelic effects are relative rather than absolute; and the measured effect of InR is confounded by a deleterious effect of the TM3 balancer chromosome. Our newly generated series of homologous recombination InR alleles resolves these issues.Quantitative complementation testing has limitations: it only measures recessive allelic effects; it confounds epistatic interactions with potential co-segregating mutations; the tested alleles were not derived from the wild-type Supplementary Figure S2). Every mutation had normal size and development time when heterozygous with +InR(HR). All mutations were homozygous lethal except for rare escapes in the case of InRE19(HR)/InRE19(HR). As expected from our QCT, all kinase domain mutations (InR74(HR), InR211(HR), InR246(HR), and InR353(HR)) produced small adults with delayed development when heterozygous with InRE19(HR) (an ectodomain mutation). Several kinase domain mutations were viable as trans-heterozygotes: InR74(HR)/InR353(HR) and InR74(HR)/InR211(HR), and these adults were small and developed slowly.We evaluated viability, eclosion time, and adult size for all allele combinations . Because homozygotes of mutant alleles are inviable, we infer homodimeric mutant receptors are nonfunctional. Viable mutant trans-heterozygotes must produce functional heterodimers, but they will also make fewer functional dimers because half of all potential receptors are mutant homodimers. To determine if simply having fewer functional receptors extends longevity, we evaluated the survival of hemizygote +InR(HR)/InRnull(HR) adults, which produce about 25% less InR mRNA (quantitative PCR in Supplementary Table S3). These adults increased life expectancy between 2 and 4\u2009days when tested in replicate trials (Supplementary Table S3). This difference provides an approximate benchmark: we may infer a genotype affects receptor function when its gain in longevity is more than that caused by numerical loss of receptors modeled in InR hemizygotes.Insulin receptors are preformed dimers assembled with protomers translated from either allele (InRE19(HR)/InR+(HR) does not extend lifespan (InRE19(HR) accessions was 43.3 days, compared to 44 days for wildtype (Supplementary Table S4). Likewise, the intracellular kinase domain alleles InR74(HR), InR211(HR), and InR246(HR) when heterozygous with +InR(HR) did not extend lifespan more than expected from InR hemizygotes (Supplementary Table S4). In contrast, in replicated trials with independent accessions, InR+(HR)/InR353(HR) increased life expectancy on average 12.5\u2009days by decreasing mortality about fourfold (Supplementary Table S4).The heterozygote lifespan : median InRE19 relative to when complemented to InR+. From the homologous recombination alleles, we now estimate the absolute allelic effect of each mutation. Across replicate trials, the genotypes InR74(HR)/InRE19(HR) and InR211(HR)/InRE19(HR) extended lifespan 6\u201314\u2009days (InR74(HR)/InR211(HR) extended lifespan (InR hemizygote (Supplementary Table S4).In QCT, kinase domain alleles reduced mortality when complemented to \u201314\u2009days . We alsolifespan . In everInRE19(HR)/InR74(HR) slowed aging, we asked if the mutations of these individual alleles extend lifespan when the substitutions were on the same protomer. They did not: InRE19,74(HR) had little effect on survival when heterozygous over a wild-type allele  when heterozygous with InR211(HR). These adults extended longevity to the same extent as trans-heterozygote InR74(HR)/InR211(HR)  . LongeviInR246 allele did not slow aging although it reduced body size. These observations are confirmed with InR246(HR)/InRE19(HR): adults were small (InR246(HR)/InRE19(HR) intersects that of wildtype, suggesting the mutant genotype may have high age-independent mortality which obscures a beneficial effect of reduced demographic aging.In QCT, the re small  but not re small . HoweverInR353(HR) extended lifespan when heterozygous with wildtype (10\u201316\u2009days), InR353(HR) also slowed aging when heterozygous with InRE19(HR) (14\u201315\u2009days). When heterozygous with InR74(HR), InR353(HR) extended lifespan 21\u201322\u2009days, an effect caused by decreasing age-dependent mortality sixfold (Supplementary Table S4).While InR74(HR)/InR211(HR); \u00a0InR74(HR)/InR353(HR); InRE19(HR)/InR353(HR)) and document a dominant longevity benefit conferred by InR353(HR) (InR+(HR)/InR353(HR)).The homologous recombination alleles validate inferences from QCT but now measure absolute effects and are tested in an independent genetic background. We describe new trans-heterozygous genotypes that extend lifespan /InR246(HR) females. Fecundity was reduced in all long-lived trans-heterozygotes. In contrast, long-lived +InR(HR)/InR353(HR) females produced more eggs than wildtype. The elevated fecundity of +InR(HR)/InR353(HR) could arise because these females have more ovarioles (subunits of the ovary) or produce more eggs per ovariole. We therefore measured ovariole number for all genotypes and regressed this trait against daily egg production. Fecundity positively associates with ovariole number with a slope less than one (InR353(HR) allele as a covariate , but the regression intercept for genotypes with one InR353(HR) allele is \u223c12\u2009days greater than genotypes without this allele (P\u2009=\u20090.013). The InR353(HR) allele confers longevity that is additive to and independent of how reproduction associates with survival.Drosophila insulin signaling modulates fecundity , we deteoduction . Fecundithan one : differeovariate . A strikInR353(HR) substitution (R1466C) lies in the kinase insert domain, a region of receptor tyrosine kinases thought to modulate substrate interaction rather than receptor kinase activity (+InR(HR)/InRnull(HR) was moderately insulin resistant. Fat body from trans-heterozygotes involving InRE19(HR), InR74(HR), InR246(HR), and InR211(HR) induced little pAkt; they were insulin resistant. In contrast, fat body from +InR(HR)/InR353(HR) induced wild-type levels of pAkt. The InR353(HR) allele dominantly extends lifespan without loss of insulin-stimulated kinase activity.The activity . We theractivity . Fat bodDrosophila InR alleles modulate aging, growth, and reproduction.Mutations of insulin/IGF receptors are thought to slow aging and reduce growth because they diminish the total amount of insulin signaling. Alternatively, mutations of the IR may alter protein-receptor interactions in specific domains that control particular phenotypes, as proposed for receptor tyrosine kinases in general by InR mutations that slow aging. Three alleles reduced mortality more than expected from a sample of natural wild-type alleles. We also quantify how alleles affect growth. While all alleles significantly reduced adult size, there was no association between relative size and relative mortality among genotypes.We used QCT to identify EMS InR mutations do not share a common genetic background. Epistatic interactions with unknown second site mutations on the third chromosome could affect traits attributed to InR. QCT only estimates recessive effects of the InR mutations, and we could not evaluate complementation besides with InRE19. Unidentified polymorphisms within each InR locus might influence the complementation. Finally, QCT measures relative rather than absolute allelic effects, and these relative effects were confounded by how the balancer haplotype itself reduced lifespan.As noted, QCT has caveats . The EMSInR substitutions of selected EMS alleles. These new alleles provide single, defined substitutions derived from a common wild-type progenitor in a controlled genetic background. We produced five homologous recombination (HR) alleles (InR74(HR), InR211(HR), InR246(HR), InR353(HR), InRE19(HR)), an HR-derived wild-type allele, a null allele, and a cis-allele with the E19 and 74 substitutions upon the same protomer ).To address these issues, we used ends-out homologous recombination to reconstitute the putatively causal Supplementary Figure S3). Thus, the lifespan of trans-heterozygote adults may be slowed simply because they have fewer functional receptors. To test this idea, we studied the hemizygote InR+(HR)/InRnull(HR). This genotype reduced InR mRNA about 25% and presumably this reduced the total number of receptors. Hemizygotes moderately impaired phosphorylation of Akt and only modestly affected longevity. The number of receptors in these hemizygotes is expected to be similar to that of recessive lethal alleles when heterozygous with wildtype (InR+(HR)/InRE19(HR), InR+(HR)/InR74(HR), InR+(HR)/InR211(HR)) due to their loss of mutant-mutant dimers . Yet, those adults have normal longevity. Together these data suggest that genotypes with robustly extended lifespan either further reduce the quantity of receptors, or alter the quality or quantity of signaling from their functional receptors.InR is a dimeric transmembrane receptor. Flies with two wild-type alleles generate normal protomers so that every dimer is functional. On the other hand, trans-heterozygotes produce some functional dimers with protomers of complementing alleles, as well as nonfunctional homodimers from protomers of each single mutant allele (InRE19(HR) substitution Val810Asp occurs in a linker sequence between the L2 and FnIII-1 ectodomains, corresponding to Phe475 of human IR and to Phe495 of human IGF-1R . Insulin induces a hinge motion in this linker to swing the fibronectin domain inward, bringing together the intracellular kinase domains of each protomer (810Asp substitution of Drosophila InR will destabilize the fibronectin domain movement (+InR(HR)E19/InR(HR) genotype has wild-type traits because the Val810Asp protomer retains its ability to transphosphorylate the complementing wild-type kinase domain, which is sufficient for full receptor kinase function.The Drosophila insulin/IGF-like receptor is homologous to that of human IR and IGF1R , a seven amino acid sequence containing three tyrosine residues that participate in transphosphorylation  and 13 final residues (InR74(HR) is an Ile1543Phe substitution within the MTRDI motif. This change may reduce the ability for Tyr1544 to be phosphorylated and thus diminish the domain catalytic activity or destabilize the loop binding platform (The activation loop (A-loop) of the InR+(HR)/InR74(HR) has normal phenotypes, suggesting that the Ile1543Phe protomer can transactivate its complementing wild-type protomer to provide full receptor function. In contrast, only the Ile1543Phe protomer can be transactivated in InRE19(HR)/InR74(HR) adults, and the lone hypomorphic function of Ile1543Phe increases life span. This conclusion is consistent with how InRE19(HR)/InR74(HR) reduces insulin-stimulated kinase signaling (pAkt). To further test this explanation, we produced a double mutant where Val810Asp and Ile1543Phe were on the same protomer ). This allele was homozygous lethal but the genotype InR+/InRE19,74(HR) had normal growth and lifespan. The data show that aging is slowed when receptors only activate a protomer with a Ile1543Phe kinase domain.InR246(HR) allele is a Val1384Met substitution at the invariant ATP binding loop of the N-terminal lobe  (InRE19(HR)/InR246(HR) fat body. The normal traits of the heterozygote +InR(HR)/InR246(HR) suggests the InR246(HR) protomer fully transactivates wild-type protomers within heterodimers. In contrast, InRE19(HR)/InR246(HR) adults are small, as expected from their loss of kinase activity. It is unclear why this genotype does not also extend longevity although their cross-over survival pattern suggests these adults suffer high age-independent mortality that could obscure slow demographic aging.The gure S1) . This su1598Arg substitution of InR211(HR) is in the kinase domain C-terminal lobe, a site conserved in human IR (Gly1212 Ebina) and IGF1R (Gly1215). These sites are three conserved residues from the substitution found in daf-2(e1370), the canonical IR longevity allele of C. elegans . The homologous amino acid segment in human fibroblast growth factor receptor FGFR3 stabilizes the dimer interface during transphosphorylation  allele is exceptional. The heterozygote InR+(HR)/InR353(HR) extends lifespan yet adults have normal size and elevated fecundity. InR353(HR) combined with InRE19(HR) and InR74(HR) likewise produce long-lived adults, although these are small and have reduced fecundity.The InR353(HR) contains the substitution Arg1466Cys. This arginine resides at a site found in human IRs (Arg1092)  where Arg1092 stabilizes kinase domain dimerization   (SupplemInR+(HR)/353InR(HR) has wild-type insulin sensitivity, demonstrating these receptors retain kinase catalytic activity unlike other longevity assurance mutations of InR. How then are InR+(HR)/353InR(HR) adults long-lived? The KID of Drosophila InR is 12 amino acids longer than the KID of human IR  (Drosophila Chico (homolog of IRS1-4) where it recruits Grb2/Drk (Grb2/Downstream-of-kinase)   as do nuDrosophila InR kinase insert domain regulates lifespan through its interaction with adaptor proteins. Drosophila InR has been previously recognized to contain adaptor protein binding sites in the C-terminal tail and in the juxtamembrane domain /353InR(HR) presents a paradox: adults are highly fecund and yet long-lived. This positive association, which has been seen in other genetic manipulations of C. elegans and Drosophila .Drosophila limits the rate of egg production within ovarioles (E19InR(HR), 74InR(HR), 211InR(HR) may be long-lived, in part, because their reduced egg production mitigates survival costs-of-reproduction. Genotypes with these alleles are also insulin resistant and small. We propose these growth and life history phenotypes are caused by how each amino acid substitution reduces insulin-stimulated kinase catalytic activity.The first mechanism involves reproductive costs . Reducedvarioles  and incr1466Cys substitution destabilizes this interaction to induce systems that promote somatic survival while maintaining kinase catalytic activity. Thus, +InR(HR)/InR353(HR) gains about 12\u2009days of longevity. The genotypes InRE19(HR)/InR353(HR) and InR74(HR)/InR353(HR) also gain this reproduction-independent longevity, but now in addition to benefits conferred by reduced costs-of-reproduction.The second mechanism confers longevity assurance independent of reproductive costs. We propose the kinase insert domain recruits substrate proteins through its SH2 binding motif. The ArgDrosophila chico to regulate aging  extends fly lifespan without reducing growth or fertility and maintains its ability for insulin to stimulate Akt phosphorylation. Chico mutated at the p85/p60 sites, on the other hand, extends life span but represses growth and reproduction. This suite of traits is seen in genotypes with the alleles E19InR(HR), 74InR(HR), and 211InR(HR), which also do not phosphorylate Akt in response to insulin.Our explanation is consistent with how we currently understand Drosophila IR appears to regulate aging through distinct systems modulated through structure-defined domains. This view reflects an emerging concept whereby protein tyrosine receptors control varied phenotypes through the action of specific protein interactions regulated by structural domains (The  domains . Future"}
+{"text": "Hepatitis C infection (HCV) is a curable disease that can be effectively managed by non-specialists. Delaware has high HCV rates but limited resources to care for individuals with HCV. Successful HCV micro-elimination starts with universal HCV screening and case identification. ChristianaCare (CC) and Westside Family Healthcare (WFH), Delaware\u2019s largest federally qualified health center (FQHC), created a multidisciplinary initiative to support comprehensive HCV care from July 2018-2020 . As part of this partnership, universal opt-out HCV screening in eligible (no prior HCV RNA result) adults \u2265 18 years was implemented at a pilot site in Wilmington in 2019. To characterize screening practices, pre- (risk-based screening) and post-intervention  electronic health record data was collected following the first 6 months of the intervention (Jan-June 2019). An HCV dashboard was created and updated monthly to evaluate trends in 2019 screening rates. Collaboration was supported through a 2-year CC Harrington grant. Figure 1. Components of Federally Qualified Health Center HCV Medical Care ModelTable 1. Pilot Site Patient CharacteristicsPre- and post-intervention patient characteristics and screening data are presented in Table 1 and Figure 2 respectively. 39% of patients had screening ordered during the first 6 months of universal screening, a 4% increase from baseline. HCV seroprevalence [amongst resulted tests] remained unchanged from baseline at 5%. During the universal screening period, 2.5% (12/482) of individuals with resulted tests had HCV compared to 4.0% (29/795) tested during risk-based screening. HCV dashboard data demonstrated a trend of increased ordering and fulfillment of screening tests . Figure 3. 2019 HCV DashboardThe early adoption of universal HCV screening in adults (prior to 2020 USPSTF update) at an urban FQHC, together with an initiative to provide multidisciplinary HCV care at this FQHC , led to increasing rates of ordered screening. The presented 6-month data does not fully account for lag times between test ordering and fulfillment, resulting in under-reporting of universal HCV screening rates. Multidisciplinary care models to address HCV in patients\u2019 medical homes are vital to HCV eradication with the robust implementation of universal HCV screening a vital first step in this continuum. Deborah A. Kahal, MD,MPH, FACP, Gilead (Speaker\u2019s Bureau)Viiv (Speaker\u2019s Bureau)"}
+{"text": "The Calgary Bile Leak Rule was developed to identify patients in whom biliary stent removal via gastroscopy could be safely performed in lieu of ERCP for post-surgical bile leaks.This study aimed to evaluate a Modified Calgary Bile Leak Rule (MCBLR) for a cohort of patients who underwent laparoscopic cholecystectomy complicated by bile leak.This retrospective cohort study included patients who underwent ERCP for management of laparoscopic cholecystectomy-induced bile leaks between 2005 and 2017. The primary outcome was defined as the absence of persisting bile leak or other pathology on follow-up ERCP. The MCBLR includes a) normal post-surgical serum alkaline phosphatase, b) small or absent leak with no other biliary pathology on initial ERCP, and c) time between initial and follow-up ERCP was 4\u20138 weeks. Test performance of the prediction rule was analyzed by calculating sensitivity, specificity, positive predictive value and negative predictive value.124 cases met inclusion criteria, of which 116 (94%) of bile leak cases had no leak identified during the follow-up ERCP. 8 (6.4%) had a persisting bile leak on follow-up ERCP. Bivariate analysis found no factors significantly associated with the primary outcome. The MCBLR demonstrated a sensitivity of 100% (95% CI 63% - 100%), a specificity of 35% (95% CI 26% - 44%), a positive predictive value of 10% (95% CI 4% - 18%), and a negative predictive value of 100.0% (91% to 100%).The MCBLR demonstrated high sensitivity and negative predictive value for determining the need for repeat ERCP following endoscopic management of laparoscopic cholecystectomy-induced bile leaks.None"}
+{"text": "Bacillus thuringiensis is a typical pesticide, with global application for over 40 years. Here, we report the draft genome sequence of B. thuringiensis ZZQ-130 from a salt lake; this strain has 31 pesticidal genes, including five cry genes, one vip gene, two vpa genes, and two vpb genes. Tribolium castaneum is a stored grain pest which is responsible for global grain losses (Bacillus thuringiensis (Bt) is the most useful bacterial pesticide, with plentiful pesticidal proteins such as crystal proteins (Cry), cytolytic proteins (Cyt), and vegetative insecticidal proteins (Vip) .n losses . Biopestns (Vip) . IdentifGenomic DNA from ZZQ-130 at the logarithmic growth phase in liquid salty 6%) LB medium was isolated as per the previously modified alkaline lysis method of Andrup et al. ; then, t% LB mediN50 value of 119,425\u2009bp and a GC content of 34.72%. Whole-genome alignment and assembly improvement were conducted using RagTag  , one rank 4 vip gene (K7H03_22005), one rank 1  vpa (Vip2\u2014the active component of the Vpa/Vpb binary toxin) gene (K7H03_29570), one rank 2  vpa gene (K7H03_27065), and two rank 2 vpb (Vip1\u2014the binding component of the Vpa/Vpb binary toxin) genes (K7H03_29535 and K7H03_29120), were identified. All the rank 4 cry and vip genes may be responsible for the pesticidal activity, although their novelty has decreased. The genes above ranks 1 and 2 may encode novel pesticidal proteins and mechanisms and need further research.To analyze the pesticidal factors, a whole genomic search of bacterial pesticidal proteins was performed using BLASTP within the online pipeline BtToxin_Digger (dex.php) . Thirty-JAIOAD000000000 and assembly accession number GCA_020005185.1. The raw draft genome data have been deposited in the NCBI Sequence Read Archive under accession number SRR15827360, BioSample accession number SAMN21033747, and BioProject accession number PRJNA758751.The whole-genome shotgun project of strain ZZQ-130 has been submitted to GenBank under accession number"}
+{"text": "The COVID-19 pandemic may have adverse health implications, particularly among older adults with chronic conditions who are at increased risk of severe illness. This cross-sectional study examined the early health impacts of the pandemic among adults aged 50 and older with chronic conditions. Participants included 700 adults  from Michigan (82.4%) and 33 other U.S. states who reported at least one chronic condition and completed an anonymous online survey between May 14 and July 9, 2020. Of these, 488 also provided open-ended responses. Individuals reported lower illness self-efficacy, less consumption of fruits, vegetables, and fried foods, and lower physical activity, along with greater alcohol use since the pandemic. About half (42.7%) reported worsened sleep. One in five (20.1%) reported at least some difficulty obtaining medications and over half (60.4%) reported at least some difficulty receiving routine care. Almost two-thirds (63.9%) had delayed preventative care and one in five (19.3%) had delayed essential medical treatment. Nearly half (42.6%) avoided contacting care providers about a physical health concern and one in eight (12.9%) avoided reporting mental health concerns. Qualitative data revealed that the pandemic has influenced how participants cared for their physical health through following guidelines related to COVID-19; coping with daily routine changes; greater awareness of self-care; mental health impacts; and health care disruptions. Older adults with chronic conditions report distinct pandemic-related challenges for self-care and health care that should be addressed in interventions to maintain their health and functioning."}
+{"text": "ABSTRACT IMPACT: This is the first study to use QUINT analyses to examine heterogeneity of treatment effect for group medical visits among individuals with type 2 diabetes. QUINT is a data driven method that assumes no a priori assumptions regarding effect moderators - an important step in the path towards personalized medicine. OBJECTIVES/GOALS: To examine heterogeneity of treatment effect (HTE) in Jump Start, a trial that compared the effectiveness of group medical visits (GMVs) focused on medication management only versus the addition of intensive weight management (WM) on glycemic control for patients with type 2 diabetes and body mass index >=27kg/m^2. METHODS/STUDY POPULATION: Jump Start patients (n=263) were randomized to a GMV-based medication management plus low carbohydrate diet-focused WM program  or GMV-based medication management only  for diabetes control. We used QUalitative INteraction Trees (QUINT), a tree-based clustering method, to determine if there were subgroups of patients who derived greater benefit from either WM/GMV or GMV. Subgroup predictors included 32 baseline demographic, clinical, and psychosocial factors. Outcome was hemoglobin A1c (HbA1c). We conducted internal validation via bootstrap resampling to estimate bias in the range of mean outcome differences among arms. RESULTS/ANTICIPATED RESULTS: QUINT analyses indicated that for patients who had not previously attempted weight loss, WM/GMV resulted in better glycemic control than GMV alone (mean difference in HbA1c improvement = 1.48%). For patients who had previously attempted weight loss and had lower cholesterol and blood urea nitrogen levels, GMV alone was better than WM/GMV (mean difference in HbA1c improvement = 1.51%). Internal validation resulted in moderate corrections in the mean HbA1c differences between arms; however, differences remained in the clinically significant range. DISCUSSION/SIGNIFICANCE OF FINDINGS: Among patients with diabetes and BMI>=27kg/m^2, a low-carbohydrate, weight loss focus may better improve HbA1c in those who have never attempted weight loss. A medication management focus may be better in those who have attempted weight loss and have lower cholesterol and blood urea nitrogen."}
+{"text": "Audiology Research was able to maintain its standards for the high quality of its published papers. Thanks to the contribution of our reviewers, in 2021, the median time to first decision was 21 days and the median time to publication was 57.5 days. The editors would like to extend their gratitude and recognition to the following reviewers for their precious time and dedication, regardless of whether the papers they reviewed were finally published:Adam SheppardJos\u00e9e Lagac\u00e9Agnieszka J. SzczepekKatarina Trebusak PodkrajsekAgnieszka Janik McErleanKiran K. SriperumbudurAlessandra FiorettiKoji NishimuraAlexander J. BilligLuca BruschiniAli A. DaneshLuca VerrecchiaAllegra CattaniMarcello CherchiAnke TropitzschMarwan El MobadderAugusto CasaniMatias MorinBenjamin BoeckingMelissa TesherChiara VisentinMike MaslinChip HahnMin Young LeeChristian ByaertMing ZhangChristian Gigu\u00e8reM\u00f3nica ChamorroChristopher PastrasNicolas Perez-FernandezCristiano BalzanelliPasqua Irena SciancaleporeDaniel B. PolleyPasqualina Maria PicciottiDelia HorhatPeter V. PaulDominika Ozi\u0119b\u0142oRichard C. DowellEkaterina GarbarukRobert J. MorellEleonora M.C. TreccaRoberto TeggiEliane SchochatRuggero LapennaFabrice GiraudetSaba BattelinoFaris F. BrkicSalvatore MartellucciFei ZhaoSamue AtchersonFrancesca AtturoSergio Cuevas-CovarrubiasFrancesco GaziaSeyed Alireza RohaniGeorge TavartkiladzeShunsuke KidaniGerrit PaascheSimona SacchiniGiampiero NeriSung Kwang HongGiuseppe AttanasioTang-Chuan WangHenning SchepkerToshihisa MurofushiHero P. WitVijaya Kumar NarneHiroshi Inui InuiVincenzo De CeglieIan CurthoysVirginia CorazziInna BelyantsevaWieslaw KonopkaJan de LaatWiktor JedrzejczakJerzy TomikXiying GuanJohannes FellingerYael ZaltzJose Antonio Lopez-EscamezRigorous peer-reviews are the basis of high-quality academic publishing. Thanks to the great efforts of our reviewers,"}
+{"text": "Spine vBMD loss trended higher with CR+AT , and similarly for vertebral bone strength. Hip vBMD losses trended lower with CR+RT . Hip vBMD and trunk muscle losses were positively correlated (r=0.53), and spine vBMD loss tended to increase with trunk muscle loss (r=0.21) and fat infiltration (r=0.17). Collectively, aerobic training was less effective at preserving muscle-bone health during CR.Caloric restriction (CR) can exacerbate muscle and bone loss. We examined 18-month changes in computed tomography (CT)-derived trunk muscle, and volumetric bone mineral density (vBMD) and finite element-estimated bone strength of the spine and hip in 55 older adults randomized to CR alone or CR plus aerobic (CR+AT) or resistance (CR+RT) training. Trunk muscle area loss trended higher with CR+AT [\u221216.8 cm"}
+{"text": "We sought to determine effects of age, HIV serostatus, and smoking on the associations between pulmonary function and physical function impairments using Multicenter AIDS Cohort Study data. Associations between physical function outcomes gait speed (m/sec) and grip strength (kg) with normalized pulmonary function tests  and forced expiratory volume in one second ) were examined. Adjusted mixed-effects models included interaction terms to assess effect modification. 574(55%) were HIV+, with median age 57 and mean cumulative smoking pack-years 12.2(SD=19.0). 349(33%) had impaired DLCO (<80% of predicted) and 130(13%) had impaired FEV1 (<80% of predicted). Participants with impaired DLCO had weaker grip strength than those with normal DLCO . Participants with impaired DLCO had slower gait speed than those with normal DLCO . Age modified the DLCO effect on gait (p-interaction=0.01) but not grip (p-interaction=0.09). The association between decreased DLCO and slower gait was more pronounced in older participants. Smoking or HIV serostatus did not significantly modify the DLCO effect on gait  or grip . As with DLCO, participants with impaired FEV1 had weaker grip strength  than those with normal FEV1. FEV1 was not associated with gait speed(p=0.98). Age, HIV serostatus or smoking did not modify the associations between FEV1 and gait speed or grip strength . Associations between lower DLCO/FEV1 and decreased physical function suggest that interventions to improve pulmonary function may also preserve physical function with aging."}
+{"text": "Background: Few studies have attempted to assess the effectiveness of formulary management in reducing the antipsychotic costs and utilization across U.S. state Medicaid programs, despite concerns about the potential impact of such formulary management on Medicaid patient health outcomes.Objectives: Compare antipsychotic utilization and total costs across Medicaid states with preferred drug list (PDL) programs vs.\u00a0states without PDLs in place.Methods: The following data from 48 Medicaid fee-for-service (FFS) programs were collected for calendar year 2010: antipsychotic prescription use ; formulary management , and patient enrollment (MediMedia). For each program, the total antipsychotic cost per capita was estimated by multiplying antipsychotic utilization by list price (First DataBank), then dividing by program enrollment. To control for differences in the prevalence of antipsychotic use among Medicaid patients across states, cost estimates were adjusted using state-level mental-health illness prevalence data . Volume-based market share of branded antipsychotics was also calculated to compare branded vs.\u00a0generic antipsychotic use across states. Significance of difference between the means of PDL and non-PDL states was tested using a two-sided, two sample t-test, assuming unequal variances between samples.Results: Among the 48 states studied, 33 (68.8%) used PDLs as a means to limit access to branded antipsychotic medications, including those states with the largest populations with a mental-health illness . In our analyses, the average difference in antipsychotic costs per capita between PDL and non-PDL states was less than $0.6M or 1.5% (p=0.95). The average difference in antipsychotic utilization per capita was less than 2.8% (p=0.91) and in branded antipsychotic market share was 0.7% (p=0.59).Conclusions: Although a majority of Medicaid states use PDLs to manage antipsychotic utilization, this analysis found no evidence of significant advantages for these Medicaid programs in terms of lowering percapita antipsychotic costs or increasing generic utilization."}
+{"text": "This study aimed to assess how the COVID-19 pandemic has impacted caregiver (CG)-related risk factors for elder mistreatment (EM) in a community sample of CGs. A non-probability sample of 433 CGs caring for care recipients (CRs) age \u226560 years completed a survey on COVID-19 impacts in April-May 2020. Compared to before COVID\u201019, over 40% of caregivers reported doing worse financially, 16% were experiencing new financial hardship, 19.4% were a lot more worried about their financial situation, 15% reported drinking more alcohol, and 64% had somewhat or greatly increased feelings of social isolation and loneliness. CGs reported that COVID\u201019 had made caregiving more physically (18.7%), emotionally (48.5%) and financially (14.5%) difficult and interfered with their own healthcare (19%). Differences found between younger and older caregivers will be presented and implications of these increased CG-related EM risk factors for healthcare and social service providers discussed."}
+{"text": "Mobility limitation affects one-third of older adults; yet, the impact of shoulder dysfunction which effects roughly 20%, is inadequately documented. As arm swing is a fundamental component of ambulation, we investigated the cross-sectional association between shoulder range of motion (ROM) and walking endurance using time to walk 400m as quickly as possible and lower extremity performance using the expanded Short Physical Performance Battery (e-SPPB). Data are from 614 men (50.5%) and women aged \u2265 60 years (mean 71.8 \u00b18 years) in the Baltimore Longitudinal Study of Aging (BLSA) who performed bilateral shoulder elevation and/or bilateral shoulder external rotation (ER) during nurse-administered physical examination. We examined odds of poor 400m-walk and e-SPPB performance defined as the worst quartile associated with abnormal shoulder elevation (\u22649%) relative to bilateral normal shoulder elevation and abnormal shoulder external rotation (\u22645%) relative to bilateral normal shoulder external rotation (ER) in separate analyses. Analyses were adjusted for age, sex, weight and height. Adjusted odds  of poor 400m-walk performance associated with abnormal shoulder elevation (N=254) were 4.7  and with abnormal shoulder ER (n=401) were 4.8 . Adjusted odds of poor e-SPPB performance associated with abnormal shoulder elevation (N=462) were 3.5  and with abnormal shoulder ER (n=457) were 2.9 . Results suggest abnormal shoulder ROM is associated with poorer walking endurance capacity and lower-extremity functional performance in the relatively healthy older adults. Future research is warranted to develop novel screening paradigms that mitigate mobility limitation and functional decline in older adults with shoulder dysfunction."}
+{"text": "Older adults often find it difficult to use everyday technology proficiently. We hypothesized that these difficulties would be exacerbated in those with subjective cognitive decline (SCD), that is, self-perceived worsening of cognitive functions that has been associated with increased risk of future dementia. Here we investigated the relationship between SCD symptom burden and technology proficiency. A nation-wide sample of adults (N=483) ages 50-79  completed an online survey via a crowdsourcing website, Amazon Mechanical Turk. The survey included the Subjective Cognitive Decline Questionnaire (SCD-Q MyCog) , questions about respondents\u2019 proficiency with computer, smartphone, and tablet , and the PROMIS depression  and anxiety  scales. Linear regression was used to examine the ability of technology proficiency to predict SCD score. We also probed the interaction of technology proficiency with age ( <70 vs. >70 years), and adjusted for covariates. We found that the age/technology interaction (B=-0.80), older age (B=7.49), lower education (B=-1.08), higher depression (B=0.20) and anxiety (B=0.16) symptoms predicted higher SCD burden (R-squared=.16). For respondents >70 years low technology proficiency predicted high SCD burden (B=-.79) whereas for those <70 years no relationship was found. Our study draws attention to older adults\u2019 self-experienced cognitive function in the digital era. The association between low technology proficiency and SCD may signal the adverse impact of the digital era on those who experienced technology only later in life. It is equally possible that declining technology proficiency is an indicator of emerging neurodegenerative disease."}
+{"text": "Staphylococcus aureus infections. Multiple strategies for calculating AUC exist, including first order pharmacokinetic (foPK) equations and Bayesian models. Most clinical applications of foPK assume unchanged patient status and project ideal administration times to estimate exposure. Bayesian modeling provides the best estimate of true drug exposure and can incorporate changing patient covariates and exact doses. We compared two commonly used foPK methods to Bayesian estimates of VAN AUC.Recent vancomycin (VAN) guidelines recommend targeting an area under the curve (AUC) concentration of 400-600 for treatment of methicillin resistant Graphs depict calculated AUCs using the three different methods: 1) Population PK estimated (foPOPPK) 2) Two-level first dose estimated (foFDPK) 3) Bayesian estimated.First order equations were performed using population PK estimates (foPOPPK) to estimate steady state (SS) AUC and initial doses. Two concentrations after first dose were used to estimate SS AUC (foFDPK). A 2-compartment Bayesian model allometrically scaled for weight and adjusted for creatinine clearance was used to determine 24-48 hour AUCs. Differences between AUCs were compared using a mixed-effects analysis, and correlation of foPK equations to Bayesian estimates was described using Spearman\u2019s correlation. Patient results from each method were classified as below (< 400), within (400-600), or above ( >600) targets.65 adult patients were included. The median and IQR for calculated AUCs using foPOPPK, foFDPK, and Bayesian methods were 495.6 (IQR: 76.6), 498.2 (IQR: 107.4), and 472.1 (IQR: 177.9), respectively with p >0.65 for both foPK methods vs. the Bayesian method. AUCs predicted by foPK equations were poorly correlated with Bayesian AUCs , while AUCs from foFDPK better correlated with Bayesian AUCs . AUCs were within, above, and below target for 54%, 20%, and 26% for the Bayesian model; 95%, 5% and 0% for foPOPPK; and 74%, 12%, and 14% for foFDPK. foPK AUC estimates concurred with Bayesian estimates only 52% of the time.AUCs calculated by the three methods did not differ on average, but dosing recommendations for foPK at the patient level varied substantially compared to the Bayesian method. This difference is because Bayesian estimation incorporates actual patient exposures while foPK equations rely on idealized dose timing to predict AUCs.Kimberly C. Claeys, PharmD, GenMark (Speaker\u2019s Bureau) Marc H. Scheetz, PharmD, MSc, Nevakar (Grant/Research Support)SuperTrans Medical (Consultant)US Patent #10688195B2"}
+{"text": "Stenotrophomonas maltophilia enables early optimization of antimicrobial therapy.The ePlex BCID Gram-Negative (GN) panel utilizes electrowetting technology to detect the most common causes of GN bacteremia (21 targets) and 6 antimicrobial resistance genes from positive blood culture bottles. Rapid detection of extended spectrum \u03b2-lactamases , carbapenemases , and highly resistant bacteria such as In this prospective study, we evaluated the performance of the BCID-GN panel compared to traditional standard of care culture and susceptibility testing with organism identification using the BioMerieux Vitek MS Matrix Assisted Laser Desorption Ionization (MALDI) Time of Flight mass spectrometry. Samples submitted for standard of care testing in Biomerieux BacT/Alert resin FA/FN blood culture bottles on the BacT/Alert VIRTUO automated blood culture system with GN bacteria on direct exam (n=108) were included. Enterobacterales, 1 ESBL E.coli) and a negative percent agreement (NPA) of 105/105 (100%). Consistent with alternative resistance mechanisms, only 8/12 (66.7%) of Enterobacterales with resistance to 3rd generation cephalosporins harbored the CTX-M gene. In contrast, 8/8 (100%) of isolates from samples harboring the CTX-M gene were resistant to 3rd generation cephalosporins. All but two GN bacteria identified by MALDI were represented on the BCID-GN Panel  and most tests  yielded valid results. Discordant analyses revealed a positive percent agreement (PPA) of 102/105 (97.2%) with 3 false negatives  of samples. The BCID-GN Panel provides rapid accurate detection of resistant gram negative bacteria enabling high quality data driven optimization of antimicrobial therapy. Detection of 1 Todd P. McCarty, MD, Cidara (Grant/Research Support)GenMark T2 Biosystems (Consultant) Sixto M. Leal, Jr., MD, PhD, Abnova (Grant/Research Support)AltImmune (Grant/Research Support)Amplyx Pharmaceuticals (Grant/Research Support)Astellas Pharmaceuticals (Grant/Research Support)CNINE Dx (Grant/Research Support)GenMark Diagnostics IHMA (Grant/Research Support)IMMY Dx (Grant/Research Support)JMI/Sentry (Grant/Research Support)mFluiDx Dx (Grant/Research Support)SpeeDx Dx (Grant/Research Support)Tetraphase Pharmaceuticals (Grant/Research Support)"}
+{"text": "Antibiotic use among patients with COVID-19 is common, exceeds the prevalence of probable bacterial co-infection, and promotes development of resistant organisms. Lack of diagnostic microbiological data may prolong empiric broad-spectrum therapy. Here we evaluate the use of the BioFire FilmArray pneumonia panel (PP), a novel rapid diagnostic test, and antibiotic decisions among intensive care unit (ICU) patients with COVID-19.We conducted a retrospective review of adult ICU patients admitted with COVID-19 between January 2020 and May 2021 at an academic medical center. ICU patients who underwent bronchoscopy/bronchoalveolar lavage (BAL) with PP (PP group) were matched by age (< 65 or \u226565), BMI (< 30 or \u226530), and BAL date (within 60 days) to ICU patients who did not undergo BAL (no-BAL group). PP patients were matched by age and BMI to ICU patients who underwent BAL without PP (no-PP group). Antibiotic use was compared between groups. Chi squared analysis, t-test, and ANOVA were used for comparisons as appropriate. 65 patients were included; the majority were male (65%), < 65 years (86%), and had BMI \u226530 (54%) (Table 1). Only 17 no-PP matches were identified for PP patients due to infrequent BALs. Similar proportion of patients in PP and no-PP groups had organisms identified from BAL . Among PP patients with a detected organism, all (n=13) had subsequent changes in antibiotic regimen \u226472 hours after BAL; 10/13 (77%) had a change targeted to detected organism and 5/13 (39%) had antibiotic narrowing. Among PP patients with no detected organism, only 4/11 (36%) had antibiotic narrowing or maintenance off antibiotics. In all groups, average antibiotic use exceeded 70% of admission duration.Table 1. Patient characteristics and antibiotic management. Abbreviations: BAL - bronchoalveolar lavageRapid, highly sensitive diagnostic tests have potential to guide clinical decisions and promote antibiotic stewardship among patients with severe viral pneumonia and suspected bacterial co-infection. In this descriptive analysis, antibiotic management did not differ significantly with use of PP. While most patients with detected organism on PP had targeted antibiotic changes, a negative PP did not appear to influence antibiotic narrowing. Larger studies and provider education are needed to evaluate potential of the PP for antibiotic stewardship. Jason Zucker, MD, MS, Nothing to disclose Daniel A. Green, M.D., BioFire  Deborah Theodore, MD, BioFire Diagnostics"}
+{"text": "Actigraphy can objectively measure sleep in studies on Bipolar Disorder (BD) where subjective sleep ratings might be influenced by affect. Actigraphy data are complex necessitating data reduction approaches. We created a composite score of actigraphy sleep metrics  in BD. We computed z-scores of sleep measures for n=51 BD vs. n=80 healthy subjects and averaged scores. We examined associations with participant characteristics and used LASSO to identify metrics best explaining composite variability. Higher composite scores (better sleep) were seen in employed vs. unemployed , and correlated with higher medication load , lower mania symptomatology  and lower interleukin (IL)-6 levels . TST best explained variability in medication load and PS best explained employment, mania symptoms and IL-6. Given observed specificity of associations, selecting theory-driven sleep metrics may be more appropriate than a composite."}
+{"text": "Leishmania (Mundinia) orientalis is a kinetoplastid parasite first isolated in 2014 in Thailand. We report the complete genome sequence of L. (M.) orientalis, sequenced using combined short-read and long-read technologies. This will facilitate greater understanding of this novel pathogen and its relationship to other members of the subgenus Mundinia. Leishmania  orientalis, isolate LSCM4, strain LV768 (WHO code MHOM/TH/2014/LSCM4), originally obtained from a cutaneous biopsy specimen from a 57-year-old woman from northern Thailand  orientalis axenic amastigotes  BGI  for DNBSEQ libraries, producing paired-end reads  using the Illumina HiSeq platform, and (ii) Aberystwyth University  for TruSeq Nano DNA libraries, producing paired-end reads (300\u2009bp) using the Illumina MiSeq platform. We performed long-read library preparation and sequencing according to the Nanopore protocol (SQK-LSK109) on R9 flow cells (FLO-MIN106). The read quality was assessed using MultiQC , incorpoLeishmania major Friedlin strain genome (GenBank accession number GCA_000002725.2)   as a refhttps://github.com/hatimalmutairi/LGAAP), including the software versions and parameters used . We carried out functional annotation and prediction using the MAKER2 (Leishmania tarentolae. We assessed the assembly completeness using BUSCO , with the MAKER2  annotatie MAKER2  gene preGCA_017916335.1. The master record for the whole-genome sequencing project is available under accession number JAFHLR000000000.1. The raw sequence reads are available at PRJNA691532.The assembly and annotations are available under GenBank assembly accession number"}
+{"text": "We report on a 56 year-old male with prolonged COVID-19 pneumonia who initially improved with dexamethasone and intubation but quickly decompensated. Clinical and radiologic features were consistent with VAP. Tracheal aspirate cultures grew carbapenem-resistant Enterobacter cloacae; meropenem (MEM) MIC was >8 ug/ml (resistant) while ceftazidime-avibactam (CZA) MIC was 2/4 ug/ml (susceptible). Lateral flow antigen assay detected a KPC enzyme. The patient was treated with CZA with steady improvement in respiratory function over the next two weeks. He then experienced an episode of tachycardia, prompting repeat culture. At this point the patient had been extubated: sputum culture grew KPC+ E. cloacae that now showed CZA-resistance (MIC >8/4 ug/ml) and paradoxical decrease in MEM MIC (4 ug/ml); meropenem-vaborbactam (< 2/8 ug/ml) was susceptible.The pre- & post-CZA therapy E. cloacae isolates underwent whole genome sequencing using the Illumina 150bp paired end protocol; sequences were quality trimmed and compared.blaKPC3 gene was identified in the post-CZA therapy isolate, an R163S mutation in the omega loop of the enzyme. ompC and ompF porin genes were analyzed to rule-out decreased influx as a mechanism for CZA-resistance: the pre- and post-CZA isolates had identical porin sequences.A point mutation in the plasmid This case highlights emerging mutations within KPC carbapenemases that lead to resistance to \u2018last-line\u2019 antimicrobials like CZA. The presumptive mechanism is increased KPC active site promiscuity due to increased omega loop flexibility, allowing increased ceftazidime binding and hydrolysis, and decreased avibactam binding and beta lactamase inhibition. Paradoxically, MEM susceptibility improves after such omega loop mutations, likely due to decreased active site binding affinity, a \u2018seesaw\u2019 effect between MEM and CZA. While authors have reported MEM MICs falling into the \u2018susceptible\u2019 category after an omega loop variant, these bacteria invariably develop secondary mutations leading to MEM treatment failure. Fortunately, given our patient\u2019s improved respiratory status, the post-CZA E. cloacae isolate was felt to reflect colonization and the patient was discharged home without antimicrobial therapy.Romney Humphries, PhD D(ABMM), Accelerate Diagnostics  Involved: Self): Consultant, Shareholder; IHMA  Involved: Self): Consultant; Melinta  Involved: Self): Consultant; Momentum  Involved: Self): Grant/Research Support; Pattern  Involved: Self): Consultant; QPex  Involved: Self): Consultant; ThermoFisher  Involved: Self): Consultant; Torus  Involved: Self): Consultant"}
+{"text": "In addition to routine facility follow-up, CDPH actively monitored facilities with breakthrough infections for 28 days to identify whether any new cases occurred in close contacts of the person with breakthrough infection.During the investigation period, an estimated 7,931 SNF residents and 6,834 staff members received two doses of COVID-19 vaccine. A total of 627 confirmed SARS-CoV-2 infections were identified across 75 of the 78 Chicago-based SNFs, including 353 (56%) among residents and 274 (44%) among staff members during the investigation period . Three fAmong the 22 breakthrough infections, 18 (82%) were detected in persons who received testing as part of routine screening, and four (18%) occurred in residents who received testing before a hospital admission or procedure. Among the 18 breakthrough infections identified during routine screening, 14 were detected (across 10 facilities) while residents were receiving weekly testing from the facilities; staff members at all facilities were receiving testing at least weekly. The median interval from second dose to collection of a positive SARS-CoV-2 specimen was 29 days (interquartile range [IQR]\u00a0=\u00a023\u201342 days). The median interval between most recent positive NAAT result and last known negative test result was 7 days (IQR\u00a0=\u00a07\u201314 days). Two-dose vaccination coverage among residents and staff members at facilities with breakthrough infections ranged from 62% to 96% and 18% to 85%, respectively. Among the 15 facilities with breakthrough cases, attack ratesAmong the 22 persons with breakthrough infections, 14  were asymptomatic . Three s\u03b2-hemolytic streptococcal bacteremia and a Pseudomonas urinary tract infection and died 7 days after hospital admission. The death certificate listed complications of COVID-19 infection as primary cause of death; underlying conditions were hypertension, diabetes mellitus, and chronic kidney disease.Resident A1 received a diagnosis of pneumonia 9 days after receiving the second COVID-19 vaccine dose and 7 days before receiving a positive SARS-CoV-2 test result . Althoughttps://stacks.cdc.gov/view/cdc/105130) and at least one negative NAAT result <14 days before the postvaccination positive test result. Five persons were asymptomatic during the second infection. Paired specimens for sequence comparison were unavailable.Among 12 available specimens from seven patients with breakthrough infections, RT-PCR cycle threshold values were >28, indicating low levels of detectable virus. Six persons with breakthrough infections had a previous positive SARS-CoV-2 test result >90 days before the most recent test, including five persons who had negative test results (range\u00a0=\u00a01\u201343 tests) between the positive results . Fourteen (64%) were asymptomatic, available RT-PCR cycle threshold values suggest low viral loads, and no facility-associated secondary transmission was detected. Two residents with breakthrough infections experienced COVID-related hospitalizations, one of whom died because of multiple concurrent infections. Although rare, postvaccination breakthrough infection can occur because COVID-19 vaccines do not offer 100% protection  are recommended to receive COVID-19 vaccine as a priority group.Twenty-two possible breakthrough SARS-CoV-2 infections occurred among fully vaccinated persons \u226514 days after their second dose of COVID-19 vaccine. Two thirds of persons were asymptomatic. A minority of persons with breakthrough infection experienced mild to moderate COVID-19\u2013like symptoms; two COVID-19\u2013related hospitalizations and one death occurred. No facility-associated secondary transmission was identified.SNFs should prioritize vaccination and follow recommended COVID-19 infection prevention and control practices, including following work restrictions, isolation, quarantine, testing of residents and staff members, and use of personal protective equipment."}
+{"text": "Children had higher frequencies of B cells with convergent BCR heavy chains against previously encountered pathogens and higher frequencies of class-switched convergent B cell clones against SARS-CoV-2 and related coronaviruses. These findings suggest that encounters with coronaviruses in early life may produce cross-reactive memory B cell populations that contribute to divergent COVID-19 susceptibilities.It remains unclear whether B cell repertoires against coronaviruses and other pathogens differ between adults and children and how important these distinctions are. Yang Science, this issue p. 738 Blood taken from children before the COVID-19 pandemic contains memory B cells that bind SARS-CoV-2. Vaccination and infection promote the formation, tissue distribution, and clonal evolution of B cells, which encode humoral immune memory. We evaluated pediatric and adult blood and deceased adult organ donor tissues to determine convergent antigen-specific antibody genes of similar sequences shared between individuals. B cell memory varied for different pathogens. Polysaccharide antigenspecific clones were not exclusive to the spleen. Adults had higher clone frequencies and greater class switching in lymphoid tissues than blood, while pediatric blood had abundant class-switched convergent clones. Consistent with reported serology, prepandemic children had class-switched convergent clones to severe acute respiratory syndrome coronavirus 2 with weak cross-reactivity to other coronaviruses, while adult blood or tissues showed few such clones. These results highlight the prominence of early childhood B cell clonal expansions and cross-reactivity for future responses to novel pathogens. The clonal identity of a B cell can be traced by the sequence of its B cell receptor (BCR), which determines its antigen specificity , Pneumococcus pneumoniae (PP), and tetanus toxoid (TT) at 2, 4, 6, and 12 to 15 months, had influenza virus (flu) vaccination, and were very likely exposed to respiratory syncytial virus (RSV) but were not vaccinated against Neisseria meningitidis (NM)  repertoires specific to six common pathogens as well as two viruses not encountered by the participants, Ebola virus (EBOV) and SARS-CoV-2, in pre-COVID-19 pandemic individuals. We analyzed 12 cord blood (CB) samples; 93 blood samples from 51 children aged 1 to 3 years (B cell clones fell into three groups: (i) nave clones containing only unmutated IgM or IgD ; (ii) antigen-experienced IgM or IgD with median SHM over 1% and without class-switched members ; and (iii) antigen-experienced clones with class-switched members . As we hypothesized, CB samples showed the lowest convergent IGH frequencies, consistent with limited fetal pathogen or vaccine exposures . ConvergP = 0.0001181, Fishers exact test). B cells specific for bacterial capsular polysaccharides are reported to be enriched in the spleen, and splenectomized patients are vulnerable to these bacteria , and mesenteric lymph nodes (MSLN) of eight adult deceased organ donors. Lymph nodes and spleen showed greater clonal sharing with each other than with blood (fig. S6A), suggesting larger clone sizes in lymphoid tissues and limited recirculation. Each tissue was dominated by different clones (fig. S6B), and SHM correlated with the number of tissues a clone occupied (fig. S7), consistent with greater prior antigen exposure leading to wider tissue distribution . Adult lbacteria . Thus, mRecent reports describe SARS-CoV-2binding antibodies in prepandemic childrens blood . Adult fThree convergent clones from five children in this study, but none from adults, had IGH sequences highly similar to SARS-CoV-2 S-binding clones isolated from a prepandemic donor that were reported to weakly bind other human coronavirus (HCoV) spikes . Three oChildhood immune responses are particularly important in an individuals life, as they form the initial memory B cell pool that shapes future responses ("}
+{"text": "Letermovir (LTV) is effective for prevention (ppx) of primary clinically significant CMV infection (csCMVi) in the first 100 days after hematopoietic cell transplant (HCT). Data on LTV for secondary ppx is limited. We report on the efficacy and safety of LTV administered for 14 weeks as secondary CMV ppx.Patients (pts) enrolled in an open label study of LTV  from August 2019 through February 2021 were analyzed. Key eligibility criteria were: CMV high risk (receipt of mismatched and/or T-cell depleted HCT and/or graft versus host disease (GVHD) requiring systemic immunosuppressants) AND prior csCMVi with either undetectable CMV (\u2264 136 IU/mL) or \u2265 2 consecutive values < 300 IU/mL at enrollment. Pts with breakthrough csCMVi on LTV or history of LTV resistance were excluded. LTV was administered for 14 weeks or csCMVi whichever occurred first. The study duration was 24 weeks. CMV was monitored per standards of care. The primary endpoint was csCMVi by week 14. Secondary endpoints were csCMVi by week 24, LTV resistance, CMV end-organ disease (EOD) and adverse events (AE) at least possibly related to LTV. Of 20 pts analyzed, the median age was 58 years (interquartile range [IQR] 46-63); 17 (85%) pts were CMV seropositive, 7 (35%) received mismatched HCT , 9 (45%) received CD34 selected allograft and 9 (45%) had GVHD at enrollment. Fourteen (70%) pts had received prior LTV. The median time from HCT to enrollment was 156 (IQR 37-244) and 55 (IQR 40-69) days for pts with and without prior LTV, respectively (P=0.16). CMV at enrollment was < 136IU/mL for 8 (40%) pts. By week 14, 4 (20%) pts developed csCMVi at median 48 days (range 40-66). Resistance testing performed in 3 of the 4 pts, identified LTV resistance mutations in 2 pts. There were no AEs related to LTV, and none developed EOD. Two pts developed csCMVi in the follow up phase. Three pts died during follow up , and four pts are in follow up.LTV secondary prophylaxis was safe and prevented recurrent csCMVi in 80% of high risk patients, including patients with prior LTV exposure. Our data supports the utility of LTV for secondary CMV prevention following HCT.Boglarka Gyurkocza, MD, Actinium Pharma, Inc.  Genovefa Papanicolaou, MD, ADMA biologics and Siemens Healthineers AlloVir Amplyx Astellas Behring Chimerix Cidara Merck & Co Partners Therapeutics Shionogi Shire/Takeda  Genovefa Papanicolaou, MD, allovir  Involved: Self): Consultant; amplyx  Involved: Self): Consultant; behring  Involved: Self): Consultant; Merck&Co  Involved: Self): Consultant, Investigator and received funding and consulting fees from Merck, Chimerix, Shire and Astellas, Research Grant or Support; octapharma  Involved: Self): Consultant; Partners Therapeutics  Involved: Self): Consultant; takeda  Involved: Self): Consultant, Scientific Research Study Investigator"}
+{"text": "Leishmania (Mundinia) martiniquensis is a kinetoplastid parasite that was first isolated in 1995 on Martinique. We report the first complete genome for Leishmania martiniquensis from Asia, isolate LSCM1, strain LV760, which was sequenced using combined short-read and long-read technologies. This will facilitate greater understanding of the evolution of the geographically dispersed subgenus Mundinia. Leishmania infect a wide range of hosts, including humans. After malaria, leishmaniasis is the second most common cause of death due to parasitic infection  martiniquensis MAR LEM2494 (GenBank accession number GCA_000409445.2). We now report the complete genome of L. (M.) martiniquensis isolate Chiang Mai 1, strain LV760 (WHO code MHOM/TH/2012/LSCM1), which was originally obtained by bone marrow aspiration from a 52-year-old male patient from northern Thailand  orientalis axenic amastigotes  (DNBseq libraries producing paired-end reads [270\u2009bp and 500\u2009bp] using the Illumina HiSeq platform) and Aberystwyth University  (TruSeq Nano DNA libraries producing paired-end reads [300\u2009bp] using the Illumina MiSeq platform). We performed long-read library preparation and sequencing according to the Nanopore protocol (SQK-LSK109) on R9 flow cells (FLO-MIN106). Read quality was assessed using MultiQC .Leishmania major Friedlin strain genome (GCA_000002725.2)   as a refhttps://github.com/hatimalmutairi/LGAAP). The analysis workflow for assembly and annotation, including software versions and parameters used, was performed using Snakemake  and is aEuglenozoa, containing 130 single-copy orthologues from 31 species, and we found 128 of the orthologues to be present (98.5% completeness). We carried out functional annotation and prediction using the MAKER2 (We assessed assembly completeness with BUSCO  using the MAKER2  annotatie MAKER2  gene preGCA_017916325.1. The master record for the whole-genome sequencing project is available under accession number JAFEUZ000000000.1. Raw sequence reads are available under accession number PRJNA691531.The assembly and annotations are available under GenBank assembly accession number"}
+{"text": "Asian Americans have the lowest mental health service utilization rate among all racial/ethnic groups. One important yet understudied aspect of this group\u2019s mental health service use is its potential associations with immigration-related factors such as migration reasons, years in U.S., acculturation, and ethnic enclave residence. Using data from the Population-based Study of Chinese Elderly in Chicago , this study investigates whether and how immigration-related factors shape mental health service utilization. Four categories of help-seeking behaviors for depressive symptoms were examined, including not seeking help (23.5%), seeking help from informal source(s) only (40%), seeking help from both informal and formal sources (28.7%), and seeking help from formal source(s) only (8.8%). Results of logistic regressions showed that U.S. Chinese older adults who migrated for family reasons were less likely to seek help from informal sources only than those who migrated for other reasons [Odds Ratio (OR)=0.64, 95% Confidence Interval (CI)=0.42-0.99). Less acculturated older immigrants  and those who lived in Chinatown  were more likely to seek help from formal sources only (relative to not seeking any help). Our findings showed that majority of the older Chinese Americans with depressive symptoms either did not seek help or sought help from informal sources only. Their help-seeking behaviors were shaped by their migration and acculturation experiences. Leveraging informal support networks and ethnicity-specific resources in Chinatown represent a culturally appropriate approach to facilitate mental health help-seeking among U.S. Chinese older adults."}
+{"text": "Data on COVID-19 vaccination among LGBT persons are limited, in part because of the lack of routine data collection on sexual orientation and gender identity at the national and state levels. During August 29\u2013October 30, 2021, data from the National Immunization Survey Adult COVID Module (NIS-ACM) were analyzed to assess COVID-19 vaccination coverage and confidence in COVID-19 vaccines among LGBT adults aged \u226518 years. By sexual orientation, gay or lesbian adults reported higher vaccination coverage overall (85.4%) than did heterosexual adults (76.3%). By race/ethnicity, adult gay or lesbian non-Hispanic White men (94.1%) and women (88.5%), and Hispanic men (82.5%) reported higher vaccination coverage than that reported by non-Hispanic White heterosexual men (74.2%) and women (78. 6%). Among non-Hispanic Black adults, vaccination coverage was lower among gay or lesbian women (57.9%) and bisexual women (62.1%) than among heterosexual women (75.6%). Vaccination coverage was lowest among non-Hispanic Black LGBT persons across all categories of sexual orientation and gender identity. Among gay or lesbian adults and bisexual adults, vaccination coverage was lower among women  than among men . By gender identity, similar percentages of adults who identified as transgender or nonbinary and those who did not identify as transgender or nonbinary were vaccinated. Gay or lesbian adults and bisexual adults were more confident than were heterosexual adults in COVID-19 vaccine safety and protection; transgender or nonbinary adults were more confident in COVID-19 vaccine protection, but not safety, than were adults who did not identify as transgender or nonbinary. To prevent serious illness and death, it is important that all persons in the United States, including those in the LGBT community, stay up to date with recommended COVID-19 vaccinations.Lesbian, gay, bisexual, and transgender (LGBT) populations have higher prevalences of health conditions associated with severe COVID-19 illness compared with non-LGBT populations  identified as gay or lesbian and 4,395 (3.1%) as bisexual; of the 142,523 survey respondents with nonmissing responses to the gender identity question, 5,594 (3.9%) identified as transgender or nonbinary. Receipt of \u22651 dose of a COVID-19 vaccine was higher among gay or lesbian adults (85.4%) than among heterosexual  or bisexual (76.3%) adults . Among gAmong non-Hispanic White adults, the percentage who reported receiving \u22651 COVID-19 vaccine dose was higher among gay or lesbian adults (91.7%) than among heterosexual adults (76.5%), higher among gay men (94.1%) and bisexual men (81.4%) than among heterosexual men (74.2%), and higher among gay or lesbian women (88.5%) than among heterosexual women (78.6%) . The percentage of non-Hispanic White bisexual women who reported receiving \u22651 COVID-19 vaccine dose (74.6%) was lower than that among heterosexual women (p<0.05). Among Hispanic adults, the percentage who reported receiving \u22651 COVID-19 vaccine dose was higher among gay men (82.9%) than among heterosexual men . Among non-Hispanic Black adults, coverage was lower among gay or lesbian women (57.9%) and bisexual women (62.1%) than among heterosexual women (75.6%) (p<0.05). Receipt of \u22651 COVID-19 vaccine dose was highest among non-Hispanic White gay men (94.1%) and lowest among non-Hispanic Black gay or lesbian women (57.9%). There were no statistically significant differences by race/ethnicity among adults who identified as transgender or nonbinary compared with those who did not identify as transgender or nonbinary.By urbanicity,Among both vaccinated and unvaccinated respondents, a higher percentage of gay or lesbian adults and bisexual adults reported they were very or moderately concerned about COVID-19  than were heterosexual adults (48.1%)  . Higher In this assessment of self-reported COVID-19 vaccination coverage and beliefs about COVID-19 vaccines among NIS-ACM survey respondents, receipt of \u22651 COVID-19 vaccine dose and vaccine confidence were higher among gay or lesbian adults than among heterosexual adults. In another large U.S. survey conducted during May\u2013June 2021, 92% of LGBT respondents reported receiving \u22651 dose of a COVID-19 vaccine , which can increase the potential for bias if systematic differences exist between respondents and nonrespondents, even after adjusting for nonresponse. Second, COVID-19 vaccination was self-reported and is therefore subject to recall or social desirability bias. Third, receipt of \u22651 doses of COVID-19 vaccine was assessed versus receipt of all recommended COVID-19 vaccinations. Fourth, survey respondents might not have identified as one of the sexual orientation categories provided or as transgender or nonbinary, and therefore might not have selected lesbian, gay, bisexual, or transgender or nonbinary. Fifth, the survey excluded institutionalized persons and those with no access to cellular telephones; however, 97.0% of Americans own some type of cellular phone  persons are at increased risk for severe COVID-19 illness because of a higher prevalence of comorbidities.COVID-19 vaccination coverage and vaccine confidence were higher among gay or lesbian adults than among heterosexual adults and higher among gay men than gay or lesbian women. There were no significant differences in vaccination coverage among persons based on gender identity. Vaccination coverage was lowest among non-Hispanic Black LGBT persons across all categories of sexual orientation and gender identity.To prevent serious illness and death, all persons in the United States, including those in the LGBT community, should stay up to date with recommended COVID-19 vaccinations."}
+{"text": "Over 93 million Americans are obese and 66 million suffer from metabolic disease. Roughly 40% of obese people do not have metabolic abnormalities , while approximately 15% of lean do . African green monkeys (AGMs) demonstrate naturally occurring obesity and metabolic syndrome (MetS) without diet manipulation, and MetS criteria are heritable. Age-matched maternal AGMs were classified by adjusted MetS criteria  >100 mg/dL, SBP/DBP >135/85mmHg, and HDL-c <50mg/dL) and classified as metabolically healthy lean (MHL), MHO, MUL or metabolically unhealthy obese (MUO). Age, weight and sex-matched pre-pubertal juvenile offspring from these mothers were additionally selected  for evaluation. We assessed monocyte subtypes by flow cytometry, and subcutaneous adipose gene expression patterns by RNAseq. Non-classical monocytes were increased in obese and unhealthy mothers  compared to MHL. MUL and MUO juvenile offspring also had more non-classical monocytes compared to MHL (p=0.05 and p=0.07). Monocyte chemoattractant protein-1 (MCP)-1 was measured in plasma and found to be elevated in MUO juveniles (p=0.02). Patterns of increased cytokine and extracellular matrix gene expression were seen in MUL and MUO juveniles\u2019 adipose (6-7/group), mirroring obese and unhealthy mothers\u2019 adipose gene expression patterns. Maternal health and obesity influence offspring immune cells and adipose gene expression prior to weight gain and metabolic disease onset. Our data underscore maternal monocyte and adipose profiles as inherited phenotypes that present prior to adipose expansion and may be targets to improve intergenerational health trajectories."}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-020-70032-y, published online 20 August 2020Correction to: This Article contained errors.The version of this Article previously published quoted an incorrect email address for Hanan H. Abd-Elhafeez. Correspondence and requests for materials should be addressed to hhnnzz91@aun.edu.egFurthermore, the legend of Figure 14,A) scanned sample of the intestinal blub. Note the epithelium , lamina propria , muscle .  TCs network (blue colored) in the lamina propria. Note connected teloped (pink colored). (D\u2013F) TCs (blue colored) between muscle bundles (red colored).  TC network between muscle fibers (reddish brown colored). Note serosa (violet colored). (H) TCs in serosa.\u201d\u201cScanned muscular TCs. (now reads:A) scanned sample of the intestinal blub. Note the epithelium (ep), lamina propria , muscle .  TCs network (blue colored) in the lamina propria. Note connected teloped (pink colored). (D\u2013F) TCs (blue colored) between muscle bundles (red colored).  TC network between muscle fibers (brown colored). Note connetced teloped (pink colored). (H) TCs (blue color) in serosa.\u201d\u201cScanned muscular TCs. (Lastly, in the Conclusion section,\u201cThe current study presented the relation of TCs with different types of immune cells in the intestinal bulb of the Grass carp [17].\u201dnow reads:\u201cThe current study presented the relation of TCs with different types of immune cells in the intestinal bulb of the Grass carp.\u201dThese errors have now been corrected in the PDF and HTML versions of the Article."}
+{"text": "IDSA guidelines do not recommend oral antibiotic suppression after 2SE. However, a recent randomized trial suggested that oral antibiotics for 3 months after arthroplasty reimplantation may prevent recurrent PJI. Objective: To compare rates of treatment failure  and adverse reactions (ARs) among patients who received < 1 month of antibiotics directly after reimplantation to those who received 1-3 months of antibiotics following reimplantation (extended antibiotics). Clostridioides difficile infections (CDI), or antibiotic associated diarrhea (AAD) during or 72 hours after antibiotics. Chi-square tests were used to compare outcomes. Cumulative incidence function curves were created to compare TF rates between those who did and did not receive extended antibiotic treatment, incorporating the competing risks of TF and death.This retrospective cohort study included patients with hip, knee, or shoulder PJI who underwent 2SE at 83 VA hospitals between the years 2003-2017. PJI was defined using administrative codes and microbiology data. Patients were followed for 5 years to assess treatment failure (TF) and ARs. TF was defined as recurrent PJI, debridement, or reoperation. ARs included Of the 433 patients, most (97%) received < 1 month of oral antibiotics and 3% received extended antibiotics. The 15 patients who received extended antibiotics had similar rates of TF and ARs compared with patients who received < 1 month of oral antibiotics (Table). However, there was a trend toward higher rates of CDI (6.7% vs. 3.8%) and AAD (13.3% vs. 9.6%) among those who received extended antibiotics. There was no difference in TF comparing extended antibiotics with < 1 month of antibiotics, accounting for death . Table: Treatment Failure and Adverse Reactions Among Those Who Did and Did Not Receive Extended AntibioticsFew patients received extended oral antibiotics in the study period. There were no statistically significant differences in TF or ARs between the 2 groups. Yet, there was a trend toward higher rates of ARs among the extended antibiotic group. Future prospective studies should assess both the potential benefits and ARs associated with extended antibiotics among patients undergoing 2SE surgery.Marin L. Schweizer, PhD, 3M (Grant/Research Support)PDI (Grant/Research Support) Bruce Alexander, PharmD, Bruce Alexander Consulting (Independent Contractor) Daniel Suh, MS MPH, General Electric (Shareholder)Merck (Shareholder)Moderna (Shareholder)Smile Direct Club (Shareholder) Aaron J. Tande, MD, UpToDate.com  Andrew Pugely, MD, MBA, Globus Medical (Research Grant or Support)Medtronic (Consultant)United Healthcare (Consultant)"}
+{"text": "Early-onset neonatal sepsis, defined as sepsis within 72 hours of birth, results in significant infant morbidity and mortality. Readmissions associated with neonatal sepsis have not previously been well-described. Early-onset neonatal sepsis is a mandatory reportable condition in Connecticut, allowing for expanded data collection through public health surveillance to evaluate readmissions. Infants with early-onset neonatal sepsis born in Connecticut during 2007\u20132016 were identified from statewide surveillance data and matched with a statewide hospital discharge database. We describe readmission rates, causes and timing of readmissions, and demographic and clinical factors associated with readmission among this group.Among 250 infants with early-onset neonatal sepsis matched to discharge data, 208 (82%) infants survived their initial hospitalization at birth. During the first year of life, 49 (23.6%) infants were readmitted. The most frequent reasons for readmissions were pulmonary complications (19%), systemic symptoms (17%), and gastrointestinal illness (13%). Infants with initial hospitalizations lasting longer than 30 days after birth were associated with higher rates of readmission compared to those discharged within 30 days after birth . Higher readmission rates were observed among non-white infants . Summary of early-onset neonatal sepsis cases and return hospital visits in Connecticut, 2007-2016Demographic and clinical factors for Connecticut neonatal sepsis cases, 2007-2016Reason for one-year readmissions of Connecticut neonatal sepsis cases, 2007-2016The top three reasons for readmission include pulmonary (19%), systemic (17%), and GI problems (13%).Given the high proportion of infants diagnosed with early-onset neonatal sepsis who are readmitted within the first year of life, further efforts are needed to prevent readmissions among this vulnerable patient population. Non-white infants and infants with prolonged initial hospitalizations after birth might be at higher risk for readmission. These groups warrant intensified strategies to prevent readmission.Vivian Leung, MD, Nothing to disclose"}
+{"text": "Tripidium ravennae is a cold-hardy, diploid species in the sugarcane complex (Poaceae subtribe Saccharinae) with considerable potential as a genetic resource for developing improved bioenergy and ornamental grasses. An improved understanding of the genetic regulation of reproductive processes  will enable future applications of precision breeding and gene editing of floral and seed development. In particular, the ability to silence reproductive processes would allow for developing seedless forms of valuable but potentially invasive plants. The objective of this research was to characterize the gene expression environment of reproductive development in T. ravennae.p-value <\u20090.05). The differential expression of floral integrators observed in the early phases of inflorescence development diminished prior to inflorescence determinacy regulation. Differential expression analysis did not identify many unique genes at mid-inflorescence development stages, though typical biological processes involved in plant growth and development expressed abundantly. The increase in inflorescence determinacy regulatory elements and putative homeotic floral development unigenes at mid-inflorescence development coincided with the expression of multiple meiosis annotations and multicellular organism developmental processes. Analysis of seed development identified multiple unigenes involved in oxidative-reductive processes.During the early phases of inflorescence development, multiple key canonical floral integrators and pathways were identified. Annotations of type II subfamily of MADS-box transcription factors, in particular, were over-represented in the GO enrichment analyses and tests for differential expression (FDR T. ravennae. These results provide insights into the molecular regulation of reproductive development and provide a foundation for future investigations and analyses, including genome annotation, functional genomics characterization, gene family evolutionary studies, comparative genomics, and precision breeding.Reproduction in grasses is a dynamic system involving the sequential coordination of complex gene regulatory networks and developmental processes. This research identified differentially expressed transcripts associated with floral induction, inflorescence development, and seed development in The online version contains supplementary material available at 10.1186/s12864-021-07641-y. Poaceae subtribe Saccharinae, also known as the sugarcane complex, have gained attention for their broad adaptability, pest resistance, high biomass yields, and potential for perennially sequestering large amounts of carbon with few inputs on marginal lands [The need for and importance of alternative energy sources becomes increasingly essential as global energy demands grow with concomitant fossil fuel reserve depletion. Bioenergy crops suitable as fuel for heat, electric power generation, and processing into cellulosic ethanol continue to attract attention as alternative fuel sources. Members of the grass family al lands \u20135.Saccharinae are diverse, spanning numerous genera include Erianthus, Miscanthus, Saccharum, and Tripidium [Saccharum L. [Erianthus (L.) P. Beauv [Erianthus into Tripidium based on both molecular and morphological features. The genus Tripidium currently circumscribes all the Old-World members of Erianthus sect. Ripidium resolving the debate over Tripidium spp. taxonomy since the partial treatment of the group by Vald\u00e9s and Scholz [Tripidium ravennae (L.) H. Scholz  is diploid (2n\u2009=\u20092x\u2009=\u200920) and cold-hardy to USDA Zone 5b [T. ravennae as a landscape ornamental or on marginal lands and riparian areas for erosion control purposes [The ripidium \u20138. Thougharum L. , then ErP. Beauv ., Vald\u00e9sP. Beauv  transferd Scholz , 7. Trip Zone 5b \u201312. The purposes \u201315 creatpurposes , 17.Tripidium hybrids with significantly higher biomass yields than Miscanthus \u00d7giganteus and cold hardiness to USDA Zone 6b/7a. However, plant biotechnology has considerable potential to augment conventional breeding and make value-added improvements in elite clonally propagated cultivars without compromising other genetically complex and desirable traits. For example, silencing key reproductive processes could reduce reseeding and invasive potential of valuable bioenergy grass clones.Conventional breeding is well suited for improving complex traits such as yield and cold-hardiness. Maren et al.  recentlyTriticum spp.) [Hordeum vulgare) [Panicoideae (including Tripidium spp.), Aristidoideae, Chloridoideae, Micrairoideae, Arundinoideae, and Danthonioideae (PACMAD) clade of the Poaceae is limited [T. ravennae. The aim of this study was to characterize the genetic control and differentially expressed transcripts in reproductive development pathways of the diploid perennial bioenergy grass T. ravennae.The role of plant reproduction in crop production and yield encouraged extensive research into the genetics of flowering among agricultural cereals such as wheat (um spp.) \u201320 and bvulgare) \u201323. Howe limited . A found limited , 26. The limited , inflore limited , 29, and limited , 31 invoT. ravennae  and cluster-based enrichment reduced the contig set by 68%, yielding a transcriptome assembly with 105,307 unitigs  between two or more samples. Of those unigenes, 36,127 were transcribed and differentially expressed in at least one of the 78 pair-wise tests of differential expression.Sequencing of vegetative, developing inflorescence, floret, and seed tissues yielded 687 million raw reads . Among the unigenes involved in plant reproduction and morphogenesis, MADS-box transcription factors and other floral integrators were prominent in all inflorescence samples. Transcriptome assembly sequences were named as \u201cTrav\u201d followed by a seven-digit number, which have been put in parenthesis here and thereafter. MADS-box transcription factor 18 (MADS18 \u2013 Trav0007787) [Sorghum bicolor MADS22-X2 (SbMADS22-X2 \u2013 Trav0022274) [MADS-box protein SUPPRESSOR OF OVEREXPRESSION OF CO 1 (SOC1 \u2013 Trav0019736) [MADS14-X2 (Trav0004731) [CAFFEIC ACID O-METHYLTRANSFERASE (COMT \u2013 Trav0002740) [CONSTANS-like unigenes [, HEADING DATE 3B-like (HD3B)-like (Trav0007479) [, MADS47-X1 (Trav0004133), MADS50 (Trav0015948), MADS55 (Trav0005904), MADS56 (Trav0017955) [, and GRAIN NUMBER, PLANT HEIGHT, AND HEADING DATE7 (Ghd7 \u2013 Trav0011675) [PARTING DANCERS isoform X1 (PTD)-X1 (Trav0016008) [, CHROMOSOME TRANSMISSION FIDELITY 7 (CTF7 \u2013 Trav0008006) [, POLLEN DEFECTIVE IN GUIDANCE 1 (POD1 \u2013 Trav0005801) [SELF-PRUNING (SP \u2013 Trav0029292) [, AGAMOUS LIKE 6-like MADS-box transcription factor (AGL6)-like (Trav0022760) [MADS3-X1 (Trav0008160), MADS7 (Trav0000111), and MADS8 (Trav0000081) [ETERNAL TAPETUM 1 (EAT1 \u2013 Trav0038135) [, MEIOSIS ARRESTED AT LEPTOTENE 1 (MEL1 \u2013 Trav0018140) [Expansin-B9 and -B11 (EXPB9 \u2013 Trav0000513 & EXPB11 \u2013 Trav0000400) [FLOWERING LOCUS T protein (FT \u2013 Trav0015919) [floral homeotic protein AGAMOUS-like (AG)-like (Trav0011776) [Differential expression analysis of inflorescence samples identified 3463 unigenes with an absolute two-fold minimum change in expression (FDR 0007787) , Sorghum0022274) , MADS-bo0019736) , and MAD0004731) , 36, the0002740) , 38. Sevunigenes , 34, 35,Trav00041, MADS50 0017955) \u201341, and 0011675) , 42, 43 0016008) , CHROMOS0008006) , POLLEN Trav00159, MADS55 Trav00041, MADS50 0000081) \u201341. The 0038135) , 50, MEI0018140) , Expansi0000400) , FLOWERI0015919) , and flo0011776) .Throughout inflorescence development, multiple unigenes and those possessing functional annotations were revealed in the differential expression analyses. Relative to vegetative controls, inflorescence samples at the earliest stages of development had the greatest abundance of DEGs, corresponding with the floral transition Fig. . The folp\u2009<\u20090.05; Figs.\u00a0AGL6-like [protein DROOPING LEAF (DL)-X1 (Trav0014582) [AG-like (Trav0011776) [NUCLEOSTEMIN LIKE 1 (NSN1 \u2013 Trav0003163) [SOMATIC EMBRYOGENESIS RECEPTOR KINASE 2 (SERK2 \u2013 Trav0003828) [FLOWERING PROMOTING FACTOR 1-LIKE 2 (FPF1)-2 (Trav0026700) [BTB/POZ AND TAZ DOMAIN-CONTAINING PROTEIN 3 (BT3 \u2013 Trav0015326) [NUCLEAR FUSION DEFECTIVE 4 (NFD4)-X2 (Trav0000417) [putative receptor protein CRINKLY 4 (CR4 \u2013 Trav0011689) [Differential gene expression profiling of floret development identified 5988 unigenes with the absolute minimum two-fold change in expression   and AG-l0011776) . As flor0003163) , 57, SOM0015326) . Relativ0000417) , and put0011689) .Fig. 5HTripidium.Floral tissue samples can provide detailed information to identify genes of interest for future applications of precision breeding and gene editing of reproductive processes. The utility of full-length transcripts to key floral integrators and the potential they have in the identification of multiple gene-editing mutation regions may be a key asset in precision breeding and gene editing. DEG analysis revealed tissue-specific gene expression dynamics in all floral samples. Within flower specific tissues, stamen tissues yielded the greatest abundance of upregulated differential gene expression Fig.\u00a0. Gene exp\u2009<\u20090.05; Figs.\u00a0VIVIPAROUS 1 (VP1 \u2013 Trav0080007) [WUSCHEL-related homeobox\u00a06 (WOX6 \u2013 Trav0041173) [LATE EMBRYOGENESIS ABUNDANT 18 (LEA18 \u2013 Trav0122482) [SUCROSE SYNTHASE 3 (SUS3 \u2013 Trav0008473) [OIL BODY-ASSOCIATED PROTEIN 1A (OBAP1A \u2013 Trav0053823) [VICILIN-like (VIC)-like (Trav0081216) [LATE EMBRYOGENESIS ABUNDANT EMB564 (LEA-EMB564 \u2013 Trav0096979) [Rab25-like (Rab25 \u2013 Trav0064814) [Differential gene expression profiling of seed development identified 1266 unigenes with an absolute minimum two-fold change in expression (FDR 0080007) , WUSCHEL0041173) , LATE EM0122482) , and SUC0053823) , VICILIN0081216) , LATE EM0096979) , and dehSeed production is a significant contributor to the successful cultivation of many plants. In developing seed samples, a variety of genes with increased expression levels involved in homeostatic regulatory roles for metal ion uptake, redox processes, heat shock, and genes known to interact under abiotic stress were found in the dataset. Fold changes in gene expression between late inflorescence stage development controls and mature seeds varied considerably and were expressed at as much as a 16,000-fold difference  is involved in the lignin biosynthetic pathway [Tripidium, unigenes designated with this annotation expressed abundantly in vegetative meristematic tissues and declined throughout inflorescence, floral, and seed development. NUCLEAR FUSION DEFECTIVE 4 (NFD4 \u2013 Trav0032568) is a gene of interest for its role in karyogamy or nuclear fusion following pollination and during female gametophyte formation [PARTING DANCERS 1 (PTD1 \u2013 Trav0016008) is essential in cross-over formation during meiosis [PTD1 in rice place the highest activity in anthers and pistils at heading [Tripidium and rice. CTF7 functions in the plant body during double-stranded break repair associated with cell division. The expression dynamics of this DNA repair associated protein expressed abundantly during active phases of inflorescence growth. RNA-DIRECTED DNA METHYLATION 4 (RDDM4 \u2013 Trav0015779) is putatively involved in the epigenetic modification system of plants [RDDM4 in Tripidium was relatively consistent throughout inflorescence, diminished in anthesis floral samples, and increased in mature seeds. POLLEN DEFECTIVE IN GUIDANCE 1 (POD1 \u2013 Trav0014920) dysfunction in Arabidopsis has demonstrated major impacts on vegetative and reproductive growth [POD1 in Tripidium demonstrated relatively consistent expression throughout inflorescence and floral development.The expression patterns between RNA-Seq data and qPCR data demonstrated a positive mean Spearman rank correlation Fig.\u00a0. Overall pathway . In Tripormation . Overall meiosis . Reports heading . The notf plants . Expresse growth , 47. TheThis study aimed to scrutinize the gene regulatory environment of developing inflorescences, flowers, and seeds to maximize the knowledge base for transgenic and gene editing based plant improvements. Our approach examined both within and between-group testing to identify transcript abundance changes specific to a given stage of development.Tripidium [The abundance of differentially expressed unigenes revealed the magnitude of gene expression changes involved in floral induction. The transition from the vegetative meristem to the reproductive meristem follows an abundance of regulatory changes coinciding with the increased expression of homeobox genes, MADS-box transcription factors, and plant hormones . The memripidium \u201373.MADS18, SbMADS22-X2, MADS-box protein SOC1, and MADS14-X2 [Tripidium. FLOWERING LOCUS T (FT), HEADING DATE 3A (HD3A) [VERNALIZATION 3 (VRN3) [Arabidopsis, rice, and wheat [Tripidium florigen transcript identified FT (TrFT \u2013 Trav0056419) within the transcriptome. Within inflorescence development samples, TrFT demonstrated the highest expression levels in the floral transition (20P), as reported in Sorghum bicolor [SELF-PRUNING (SP) is the homolog of CENTRORADIALIS and TERMINAL FLOWER 1 of Arabidopsis and functionally maintains floral meristem indeterminacy [SP expression patterning in Tripidium followed expectations with consistent expression throughout inflorescence development. The floral homeotic protein AG-like genes increased in expression in Tripidium inflorescences throughout maturation. AG-like genes are broadly involved in floral development and coordination of the floral body plan; therefore, it might have a role in Tripidium floral transition and organization. Concomitant decreases in WUSCHEL-related homeobox expression were observed as AGL increased, capitulating the relationship between these two interacting genes in Tripidium [Many of the classic ABC(D) E model MADS-box transcription factors are essential in the fate of meristem identity and determinacy , 74, 75.ADS14-X2 , 40 in iA (HD3A) , and VER3 (VRN3)  are synond wheat , 53, 78.erminacy . The SP ripidium .CONSTANS-like 9 (COL9) and CONSTANS1 (CO1) expression increases in the early weeks of plant development and diminished following the floral transition [COL9 abundance represses EARLY HEADING DATE 1, delaying flowering in rice, COL9 (Trav0008717) expression diminished in Tripidium with concomitant increased HEADING DATE 3 (HD3)-like transcription from early to mid-inflorescence stages of development [Grain number, plant height, and heading date 7 (Ghd7) is a photoperiodic responsive gene with upstream repressive effects on EHD1 and subsequently HD3A in rice [Ghd7 in Tripidium support a role throughout inflorescence development [In rice and barley, their respective ansition , 35. As elopment , 80, 81. in rice . The traelopment , 43, 76.AGL6-like MADS-box transcription factor is active in perianth and gynoecium development in rice with pleiotropic effects on lodicules, stamens, and carpels [Tripidium, the expression of AGL6-like follows similar patterns of expression in developing inflorescences and floral tissues reported in Oryza sativa [YABBY genes DL1 and DL2 in rice carpel specification and maize [Tripidium floral determinism [TaAGL6 acts on staminate floral development by working on TaAPETALA3 [Tripidium, the homeotic activity of staminate floral development could be identified by the dramatic increase in transcript abundance of floral homeotic protein AG-like in samples at 80\u2009cm of growth.The identity genetics of floral development in grasses consists of several MADS-box transcription factors and their interacting proteins in articulating the floral body plan. The translation of floral homeotic class genes from the core eudicots to the monocots is tenuous due to various synonyms applied with computationally derived annotations. The road map best suited to this disambiguation lies in the consensus between expression dynamics and functional genomics. The  carpels . In Tripa sativa , supportnd maize , 83, 84.erminism , 83, 84.APETALA3 . In TripEAT1 is a constituent of the TAPETUM DEGENERATION RETARDATION (TDR) heterodimer significant in tapetum development [EAT1 follows a distribution significant in both early and post-meiosis cells [Tripidium, support mid-inflorescence stage microsporogenesis. The conformity of expression patterns of the POD1 transcript to those reported by Dai et al. [Tripidium. It is noteworthy that the sampling strategy employed in this study was sufficient to successfully identify unigenes of protein PTD, CTF7, and SHORTAGE IN CHIASMATA I. Differential expression analysis of meiotic unigenes in developing inflorescences highlights their significance in the reproductive process as well as the abundance of meiocytes captured here. A more comprehensive characterization of the regulatory dynamics of meiocytes involved in mega- and microsporogenesis will require additional examination in Tripidium [As inflorescences matured into the middle stages of development and beyond, transcript abundance increased. Among the changes in transcript abundance, multiple meiotic genes delineated the next phase in reproduction. Transcription factor elopment , 87. Intis cells . This exi et al.  furthermripidium , 45, 88.The translational dynamics of floral development is foundational to plant reproduction. When the inflorescence has emerged from the flag leaf, the changes in floral morphology are apparent, but many of the morphological changes are manifestations of the developmental design laid out during inflorescence development. Many of the genes responsible for gamete production and flower development were highly expressed at the mid-inflorescence stages of development. One of the primary benefits of the sampling strategy and data analysis approaches used in this study has been to sample multiple stages of development and to compare all possible pair-wise comparisons. This has enabled the capitulation for several canonical floral genes in a novel species as well as highlighted the sequence identity of multiple novel genes.Tripidium is an enigmatic plant with considerable potential as a landscape and bioenergy crop given its ornamental merit and high biomass production on marginal lands with minimal inputs. A greater understanding of gene expression throughout reproductive development provides context for gene function analysis in these basic biological processes. This research focused on the molecular genetics of plant reproduction in T. ravennae, including identifying diverse genes related to inflorescence, flower, and seed development. The expression dynamics of unigenes detailed in this study provide a guide for future biological studies on functional and comparative genomics and the development of biotechnology applications, including precision breeding.Vegetative and inflorescence meristems as well as floral development tissues were collected from three plants on the week of August 9th, 2017, from the North Carolina Arboretum, Asheville, NC. Inflorescence meristematic tissue from reproductive culms was collected at various heights from the ground, representing floral development progression. Inflorescences had emerged from more developed culms, but inflorescence meristems at earlier development stages were apparent within the leaf sheath of immature culms. Floral development tissues were collected at the floret boot stage, pre-anthesis, anthesis stages, and mature stamens. Spikelets containing immature and mature seeds were collected from the same plants in September and October of 2017. Culm segments, inflorescences, and developing seed samples containing target tissues were collected and immediately placed in 15 or 50\u2009mL centrifuge tubes vials with 5\u201320\u2009mL of RNAlater\u00ae Stabilization Solution . Centrifuge tubes containing sample tissue were frozen in the field on a dry ice bed before transport to the laboratory and stored at \u2212\u200980\u2009\u00b0C . DNA was digested on-column with the Sigma-Aldrich DNase10 (DNASE10) kit per the manufacturer\u2019s instructions. RNA concentration and integrity were quantitated with the QubitTM fluorimeter (Life TechnologiesTM) and the 2100 Bioanalyzer (Agilent) before library preparation, respectively. RNA samples were poly-adenylation purified, and cDNA libraries were prepared using the BiooScientific (a PerkinElmer Co.) NEXTFlex Rapid Directional RNA-Seq kit with a target insert size of 200\u2013300\u2009bp. Libraries were sequenced using the Illumina HiSeq 4000, 150\u2009bp PE by Novogene . The RNA of all samples was mixed and used to construct Pacific Biosciences Iso-Seq libraries (Protocol # 101\u2013070-200 version 6) with three size fractions . The libraries were sequenced with four cells of a PacBio Sequel I system at NC State Genomic Sciences Laboratory.T. ravennae  as well as multiple reference genomic assemblies within the Andropogoneae tribe, including Sorghum bicolor [Saccharum officinarum [Zea mays [Read quality was inspected for quality with FastQC. Trimming was conducted with CLC Genomics WB  to remove adapter sequences and low-quality reads (Q\u2009<\u200920). Multiple de novo transcriptome assemblies were constructed with the CLC \u2013 GWB using different k-mer (word size) and the bubble size of de Bruijn graph combinations and assessed for the number of contiguity and N50  similar to that performed in DESeq and EdgeR , 99. In actiVenn . TPM noractiVenn . Negativp\u2009\u2264\u20090.05; CLC-GWB) aided in selecting sequences from the test set for over-representation (Supplementary Table\u00a0p\u2009\u2264\u20090.05) within the subset of relevant inflorescence samples. Final transcript selections were made on the unique mapping  of the 5-07-23, . Relativt method .Additional file 1: Table S1. Sequencing statistics. Figure S1a-c. Transcriptome assembly. Figure S2. Annotation statistics for primary de novo assembly. Figure S3. Annotation statistics for cluster enriched assembly. Figure S4. Annotation statistics for PB Iso-Seq sequences. Table S2. GO-term enrichment for upregulated transcripts during inflorescence development. Table S3. GO-term enrichment for upregulated transcripts during flower development. Table S4. GO-term enrichment for upregulated transcripts during seed development. Table S5. Excel workbook including summaries of DEG\u2019s in inflorescence development. Table S6. Excel workbook including summaries of DEG\u2019s in floral development. Table S7. Excel workbook including summaries of DEG\u2019s in seed development. Supplemental List 1. List of FASTA formatted sequences associated with Fig. Table S8. Table export of annotations for the cluster enriched de novo transcriptome assembly. Table S9. Table export of annotations for the collapsed Iso-seq transcript set."}
+{"text": "The Veterans Health Administration (VA) is increasingly purchasing long-term care for eligible Veterans from non-VA, community nursing homes (CNHs). Antipsychotics present safety risks for older adults, but it is unknown how the prevalent use of antipsychotics at CNHs influences whether newly admitted Veterans will initiate antipsychotic therapy. This study used 2013-2016 VA data, Medicare claims, Nursing Home Compare, and Minimum Data Set (MDS) assessments. We identified 10,531 long-stay CNH episodes for Veterans not prescribed antipsychotics 6 months before CNH admission. We categorized Veterans by whether, 12 months before admission, they were diagnosed with FDA-approved indications  for antipsychotic use. The exposure was the proportion of all CNH residents prescribed antipsychotics in the quarter preceding a Veteran\u2019s admission. Using adjusted logistic regression, we analyzed two outcomes measured using MDS assessments collected ~100 days after CNH admission: 1) new antipsychotic use, and 2) new diagnosis for an FDA-approved indication among Veterans without these conditions at admission. Among antipsychotic-na\u00efve Veterans admitted to CNHs, 7,924 (75.2%) lacked an antipsychotic indication. Prevalent antipsychotic use in CNHs ranged 0%-10.9% (quintile 1) and 25.7%-91.4% (quintile 5). The odds of initiating antipsychotic use increased with higher CNH antipsychotic use rates , as did the odds of acquiring a new indication . Provider practices may be influencing new diagnoses indicating antipsychotic use at CNHs with high antipsychotic use. It may be important for VA to consider antipsychotic use when contracting with CNHs."}
+{"text": "Scientific reports 10.1038/s41598-021-99752-5, published online 13 October 2021Correction to: The Competing interests section in the original version of this Article was incorrect.\u201cThe authors declare no competing interests.\u201dnow reads:\u201cGabor Marth is a founder and chief scientific officer of Frameshift Labs, Inc. and Alistair Ward is a founder and chief executive officer of Frameshift Labs, Inc.\u201dThe original Article has been corrected."}
+{"text": "Obesity is a worldwide epidemic associated with increased risk and progression of colon cancer. Here, we aimed to determine the role of adipose triglyceride lipase (ATGL), responsible for intracellular lipid droplet (LD) utilization, in obesity-driven colonic tumorigenesis. In local colon cancer patients, significantly increased ATGL levels in tumor tissue, compared to controls, were augmented in obese individuals. Elevated ATGL levels in human colon cancer cells (CCC) relative to non-transformed were augmented by an obesity mediator, oleic acid (OA). In CCC and colonospheres, enriched in colon cancer stem cells (CCSC), inhibition of ATGL prevented LDs utilization and inhibited OA-stimulated growth through retinoblastoma-mediated cell cycle arrest. Further, transcriptomic analysis of CCC, with inhibited ATGL, revealed targeted pathways driving tumorigenesis, and high-fat-diet obesity facilitated tumorigenic pathways. Inhibition of ATGL in colonospheres revealed targeted pathways in human colonic tumor crypt base cells (enriched in CCSC) derived from colon cancer patients. In CCC and colonospheres, we validated selected transcripts targeted by ATGL inhibition, some with emerging roles in colonic tumorigeneses  and others with established roles (MYC and MUC2). These findings demonstrate obesity-promoted, ATGL-mediated colonic tumorigenesis and establish the therapeutic significance of ATGL in obesity-reinforced colon cancer progression. Obesity affects half a billion individuals in both the industrialized and developing world , 2. ThisColon cancer, the second leading cause of cancer-related death worldwide , is initAdipose triglyceride lipase (ATGL), otherwise known as PNPLA2, is an LD-associated rate-limiting enzyme exclusively responsible for LDs utilization by breaking down their stored triglycerides , 31. ATGHere, we found in local colon cancer patients that increased levels of ATGL in tumor tissue, compared to matched control, were augmented by obesity. Blockade of ATGL in colon cancer cells and colonospheres, enriched in colon cancer stem cells, inhibited growth. Further, blockade of ATGL targeted metabolic and growth pathways in colon cancer cells and colonospheres. These findings identify a novel mechanism of increased ATGL-mediated LDs utilization in colon cancer progression and establish a platform for new diagnostic and therapeutic importance in colonic tumorigenesis, especially when driven by obesity.www.louisianacancercenter.org), processed in compliance with NIH regulations and institutional guidelines. Human colonic tumor tissue was acquired from ten patients, three female and seven male, ages 39\u201367 of both African American (n\u2009=\u20095) and Caucasian (n\u2009=\u20095) ethnic backgrounds. Body mass index (BMI), as calculated (kilogram/meters2), ranged from 23 to 40 and was determined on de-identified patient tumor samples at the time of tissue collection. The de-identified patient samples, used in this study, were approved by the institutional review board (IRB) at Tulane University, which waived the requirement for informed consent for sample collection.Primary human colon tumor tissue samples were obtained from local patients through the Louisiana Cancer Research Consortium Biospecimen core (n\u2009=\u200943) and colonic tumors samples (n\u2009=\u200972) (GSE20916 and GSE62322). Further, publicly available transcriptomes from human colonic tumor crypts relative to control crypts from colon cancer patients (n\u2009=\u20095) (GSE20916). Additionally, we utilized publicly available transcriptomic data obtained from colon cancer patients (TCGA), normal colon (n\u2009=\u200941), and tumors (n\u2009=\u2009457). These data are acquired using NCBI\u2019s GEO2R.Publicly available transcriptomes obtained from colon cancer patients included control (n\u2009=\u20093 for each group) were acquired before [Transcriptomic data from colon and colonic tumors of high-fat-diet obese mice . HT29 and HCT116 cells were propagated in complete McCoy\u2019s 5\u2009A media  containing 10% fetal bovine serum (FBS) . SW620 cells were grown in Leibovitz L-15 media (ATCC) containing 10% FBS. Mouse colon cancer CMT93 cells (ATCC) were propagated in DMEM (Sigma) containing 10% FBS. Human non-transformed colonic NCM460 cells were obtained from INCELL Corporation  and were grown in an M3Base medium (INCELL) containing 10% FBS. All colon cancer cell lines have been authenticated by ATCC through a short tandem repeat (STR) DNA profile and were tested for mycoplasma contamination. Cells were serum starved overnight prior to experimental procedures and were serum starved for three days to synchronize cells in the cell cycle prior to treatments.6 human colon cancer cells were plated in 24-well ultra-low attachment plates  and propagated in stem cell media (DMEM-F12 with 5\u2009mM HEPES)  supplemented with ITS liquid media complement (Sigma), bovine serum albumin  (Sigma), l-glutamine (2\u2009nM) (Sigma), epidermal growth factor  , and basic fibroblast growth factor  (Invitrogen) [A total of 5\u2009\u00d7\u200910itrogen) . Colonosl-glutamine (2\u2009nM) (Sigma), epidermal growth factor  (Invitrogen), basic fibroblast growth factor  (Invitrogen), 12-carbon chain saturated fatty acid analog with orange-red fluorescently labeled probe C12 (1\u2009\u00b5M) (Invitrogen), and BrdU (10\u2009\u00b5M) (Sigma). The following specific antibodies against protein were used: conjugated phycoerythrin (PE) CD133 , ATGL , CD133 (Abcam), phosphorylated retinoblastoma (pRb Ser807/811) , total retinoblastoma , MYC (Abcam), \u03b2-actin , BODIPY 493/503 (1\u2009\u00b5g/mL) (Invitrogen), DAPI (1\u2009\u00b5g/mL) (Invitrogen), and BrdU .The following reagents were utilized for our study: Oleic acid (OA) (300\u2009\u00b5M) (Sigma), atglistatin (40\u2009\u00b5M) , doxycycline  (Sigma), puromycin (250\u2009ng/ml) (Sigma), bovine serum albumin  (Sigma), For generating stable short hairpin RNA (shRNA) knockdown cell lines, ATGL-specific shRNA (shATGL) and control shRNA were cloned into the TET-ON all in one LT3GEPIR vector using the following nucleotide shRNA guide sequences: 5\u2032-TCTCAATCTGACATCTACGA-3\u2032 (shATGL), 5\u2032-TAGATAAGCATTATAATTCCTA-3\u2032 (shCon) . SequencHuman colon cancer cells were transfected with ATGL-specific pooled siRNA (MISSION esiRNA EHU003547) (Sigma) or equal amounts of negative-control scramble oligonucleotides using lipofectamine 3000 according to manufacturer\u2019s instructions (Invitrogen). The efficiency of the knockdown validated by immunoblot was more than 60%.Human colon cancer cells, serum starved for three days followed by treatments, fixed (ethanol), permeabilized (Triton-x 100), and stained for DNA (Propidium Iodide) were used for flow cytometry analysis . The experiment was performed four independent times and data were analyzed using SpectroFlo and Modfit software. Flow cytometry analysis was also performed using conjugated phycoerythrin (PE) anti-human CD133 antibody  for the colon cancer stem cells population. The experiment was performed three independent times and data were acquired using BD FACS Aria III and results were analyzed by BD FACSDiva software.Protein extraction and immunoblot were performed as described previously . The folExperimental cells grown on coverslips were fixed with 3.7% paraformaldehyde and immunofluorescently stained for LDs as previously described . Briefly12 (1\u2009\u00b5M) (Invitrogen). After washing (ten times with PBS), colonospheres were propagated in their media for 48\u2009h and LDs were imaged using a fluorescent microscope (Olympus DP80 with CellSens Dimension camera software) (independent experiments three times by different investigators).Human colonospheres were incubated (overnight) with a 12-carbon chain saturated fatty acid analog with orange-red fluorescently labeled probe CHuman colon cancer cells, siRNA transfected and grown on coverslips, were treated with OA and with BrdU (10\u2009\u00b5M) (Sigma) for the final 6\u2009h. Cells were fixed with 3.7% paraformaldehyde and stained with anti-BrdU antibody  and visualized using the slide scanner Aperio CS2 (Leica) and Image Scope software (independent experiments four times). BrdU positive cells were counted as a percentage of total cells per high power field.3) were plated in a six-well plate. After 8 days, cells were washed and stained with 0.5% crystal violet following incubation with methanol (20\u2009min) and quantified (OD570 nm) (independent experiments more than five times).Colon cancer cells (104) were plated in the upper chamber of a 24-well transwell  in serum-free media. Media containing a 10% FBS was added to the lower chamber of these transwells followed by treatment with atglistatin. After 24\u2009h, the upper side of membranes from the transwell insert were scrubbed to remove non-migrated cells. Cells on the lower side of membranes were fixed in formalin and stained with crystal violet. Membranes were excised from the transwell insert and mounted on glass slides. The number of migrated cells were visualized by microscopy and counted per high power field (independent experiments two times).Colon cancer cells  were visualized and quantified using light microscopy (independent experiments three times by different investigators).Isolation of total RNA was accomplished using the miRNeasy kit  according to the manufacturer\u2019s instructions. RNA quality was determined by an Agilent Bioanalyzer  and samples with RNA integrity numbers (RIN) >7 were used. For qPCR, RNA treated with DNase was reverse transcribed to cDNA with the qScript cDNA SuperMix synthesis system  according to the manufacturer\u2019s protocol.cDNA generated from human colon cancer cells and colonospheres was utilized for qPCR as previously described  (indepenn\u2009=\u20093 for each group) was accomplished as described previously [RNA sequencing (RNAseq) of experimental colon cancer cells and colonospheres  [RNAseq data analysis was performed using Ingenuity Pathway Analysis (IPA) . Differentially expressed genes (DEGs) entered into IPA met an expression threshold of >|1.5|\u2009-fold change with respect to control and a false discovery rate (FDR) <0.05. Clustered heatmaps were generated reflecting z-scaled transcripts per million (TPM) values for the top genes across all samples using a Python data visualization package (Seaborn). Expression of select transcripts was based on data generated by the TCGA research network, (o/timer) .http://medicine.tulane.edu/departments/pathologylaboratorymedicine/research/histology-laboratory) as described previously [Processing and immunohistostaining for human colon cancer and matched normal tissue were performed by The Pathology Core Laboratory at Tulane University Health Sciences Center  and Student Newman\u2013Keuls post-test using Graph Pad Instat 3 software (Graph Pad Software). A p value <0.05 was considered significant. Investigators were blinded to group allocation during the experiment. After assessing the outcomes, investigators traced back the group (samples) allocation for assembly of data and generated figures.To ensure statistical significance and data reproducibility, all experiments included a minimum of three samples per group and were repeated independently by the same or different researchers. All data are means\u2009\u00b1\u2009SE for a series of experiments. Data meet the normal distribution and statistical analysis was performed by Student\u2019s unpaired Since elevated LDs levels in colonic tumor tissue are critical for colon cancer cells growth \u201324, it iFurthermore, in human colon cancer cells (CCC), HT29, HCT116, and SW620, ATGL levels (mRNA and protein) were elevated relative to non-transformed colonic NCM460 cells Fig. . Among tNext, we determined the role of increased ATGL in colon cancer progression. We utilized atglistatin, a specific pharmacological inhibitor , or siRNHuman CCC, stimulated to migrate following confluency disruption, had increased LDs accumulation in cells close to the migratory front that was further elevated with ATGL inhibition (atglistatin) Fig. . FurtherMoreover, in HT29 cells with silenced ATGL (siRNA), OA-stimulated BrdU incorporation into newly synthesized DNA (6\u2009h) was significantly attenuated Fig. . In anotp\u2009<\u20090.05) or similar trends such as protein transport protein 24D (SEC24D) and pappalysin 2 (PAPPA2). These DEGs, significantly altered in human colon cancer tissue (TCGA)   Fig. , similar05) Fig. . Togethe12) that is shown to be stored in LDs [12 from media, we found a significant decrease in intracellular LDs-C12 (red) during the growth of colonospheres (48\u2009h)  , 55\u201357. d in LDs , 58. Aft\u2009h) Fig. . These d\u2009h) Fig. . Similar\u2009h) Fig. . These dp\u2009<\u20090.05) or trending alteration in colonospheres from both cell lines included: kruppel like factor 6 (KLF6), serine palmitoyltransferase long chain base subunit 2 (SPTLC2), phosphoglycerate mutase 1 (PGAM1), acetyl-CoA carboxylase alpha (ACACA), sequestosome 1 (SQSTM1), protein transport protein 24D (SEC24D), E74 Like ETS Transcription Factor 3 (ELF3), and ATP Binding Cassette Subfamily G Member 1 (ABCG1). Their altered levels were also found in colon cancer patients (TCGA) , relative to adherent HT29 cells, have 1265 differentially expressed genes   as well as their obesity-stimulated growth. Targeting ATGL-mediated LDs utilization in colon cancer cells led to cell cycle arrest effectively attenuating their growth facilitated by an obesity mediator. Emerging findings revealed that obesity promotes the expansion of cancer stem cells in breast and cervical tumors , 66. In We identified ATGL-mediated systemic transcriptional remodeling in human colon cancer cells and colonospheres associated with cancer growth and metabolism. Emerging findings revealed the importance of metabolic processes associated with cancer stem cells , 27, theColon cancer incidents have been consistently increasing, especially among young adults, mainly due to obesity , 10, 56,Supplemental"}
+{"text": "The MIP (c) and axial (D) PET/CT fused images detected an intense hypermetabolism on the left axillary lymph nodes up to the left supraclavicular area. The patient revealed she had received the first of dose Pfizer BNT162b2mRNA vaccine against COVID-19 on the left shoulder intramuscular 4\u2009days before FDG examination. In order to exclude a Virchow nodule due to her digestive cancer history, we performed a cervical echography with supraclavicular node cytological biopsy sample. Echography (E) showed a 14-mm-long axis normal lymph node with its central hilum. Cytological analysis revealed activated lymphoid cells without tumor cells.We present the case of a 64-year-old female with well-differentiated appendicular adenocarcinoma associated with peritoneal carcinosis initially treated by surgery and chemotherapy benefited from a 18F-FDG PET/CT following influenza and COVID-19 vaccination (Burger et al. 18F-FDG PET/CT scan.Several previous reports have demonstrated axillary lymph nodal activation on Nuclear physicians should be careful when cancers staging and re-staging. This is especially important for patients with breast cancer having been vaccinated on the homolateral upper limb, digestive cancer patients vaccinated on the left side, or with lung or head and neck carcinoma."}
+{"text": "Inflammatory breast cancer (IBC) is a rare, aggressive cancer found in all the molecular breast cancer subtypes. Despite extensive previous efforts to screen for transcriptional differences between IBC and non-IBC patients, a robust IBC-specific molecular signature has been elusive. We report a novel IBC-specific gene signature  that achieves 100% accuracy in discovery and validation samples (45/45 correct classification) and remarkably only misclassified one sample (60/61 correct classification) in an independent dataset. G59 is independent of ER/HER2 status, molecular subtypes and is specific to untreated IBC samples, with most of the genes being enriched for plasma membrane cellular component proteins, interleukin (IL), and chemokine signaling pathways. Our finding suggests the existence of an IBC-specific molecular signature, paving the way for the identification and validation of targetable genomic drivers of IBC.The online version contains supplementary material available at 10.1186/s13058-021-01467-y. IBC is a rare form of breast cancer associated with poor prognosis compared to other subtypes, and this is attributed to its therapy resistance and a high metastatic potential \u20133. MoreoIn this report, we reanalyzed publicly available gene expression datasets using the nonparametric machine learning random forest (RF) approach. RF is superior to classic statistical approaches used previously on these datasets because (1) It can handle many predictors at once while assigning each a predictor importance score. (2) It uses bootstrap-aggregated (bagged) decision trees to minimize overfitting, allowing for a robust model that can be validated in independent datasets. By restricting our analysis to microdissected IBC tumor epithelium and matching IBC samples with similar receptor-status to non-IBC samples, we have identified an IBC signature of 59 genes that only misclassified one patient out of a total 106 patients in pre-treatment datasets.https://www.cbioportal.org/study/summary?id=brca_tcga). GSE45581 was used for discovery and comprised 20 IBC, 20 non-IBC, and 5 normal microdissected patient epithelium samples. GSE5847 is primarily post-treatment samples dataset, comprised of 13 IBC and 35 non-IBC microdissected patient samples. GSE111477 is a dataset of 33 IBC and 28 non-IBC pre-treatment patient samples comprised primarily of the epithelial tissue.All analysis was carried out on MATLAB R2018b (MathWorks). Three microarray datasets were downloaded under accession number GSE45581 , GSE5847IBC-specific signature identification and validation using ensemble of decision trees based bagging is detailed in Additional file The IBC signature genes   Fig.\u00a0d.Having verified G59 signature in two pre-treatment datasets and shown higher specificity in the TCGA dataset, we performed gene ontology and pathway enrichment analysis of the genes. Protein-coding genes presented 88% 52/59) of the gene set  in GSE45581 and (60/61) 98.4% in GSE111477) in its prediction [The low prediction accuracy in primarily post-treatment tumor samples highlights the fact that chemotherapy induces changes in gene expression . InteresG59 is a more curated version of the 132 gene list selected by Dr. Woodward  for IBC Our finding highlights the need to integrate contemporary statistical approaches to identify molecular signatures previously missed by traditional statistical methods. Most important, the IBC-specific molecular signature we have identified paves the way for IBC functional studies, validation, and potentially successful therapeutic interventions.Additional file 1. Supplementary Methods and Tables. Supplementary Methods details genes signature identification, validation and comparison with other IBC\u00a0signatures, PAM50 subtyping and ROR scores, Gene ontology and pathway analysis. Table S1 details gene information for the G59 IBC signature. Table S2 shows distribution of clinical and molecular features in IBC/non-IBC predicted samples. Table S3 has cellular components for the G59 IBC signature. Table S4 has pathways analysis for the G59 IBC signature."}
+{"text": "COVID-19 has the potential to exacerbate stresses of family caregiving. While studies during COVID-19 have focused on caregivers of those with memory / cognitive issues like Alzheimer\u2019s Disease, less attention has been paid to those caring for persons with emotional / developmental / behavioral disorders. This paper compares family caregivers of persons with emotional / developmental / behavioral disorders (EDB); physical conditions (PH); and memory / cognitive problems (MC) during the early phase of the pandemic. We focus on demographics, caregiving context, COVID-related caregiver stressors, and validated physical, psychosocial, and financial well-being outcomes. We conducted a cross-sectional national online survey during April-May, 2020 (n = 556). The sample included 274 PH (50%), 141 MC (25%), and 141 EDB (25%) caregivers. EDB caregivers were younger, with younger care recipients who were more likely to be their child. EDB caregivers reported more COVID-related caregiver stressors than MC or PH caregivers, including increased caregiving duties (p<.01); more family disagreements about care provision (p=.05); and worsened mental health of the care recipient (p<.01). In multivariate regression models, EDB caregivers had significantly higher anxiety; depression; and fatigue ; more sleep disturbance (p=.05); less social participation (p<.05); and poorer overall financial well-being (p<.05). MC caregivers also reported more negative outcomes, but effects were consistently strongest for EDB caregivers. This study shows that EDB caregivers are at significantly elevated risk for negative impacts due to COVID-19 and should receive increased support and attention during this public health crisis."}
+{"text": "We describe enterococci in raw-frozen dog food commercialized in Europe as a source of genes encoding resistance to the antibiotic drug linezolid and of strains and plasmids enriched in antibiotic-resistance and virulence genes in hospitalized patients. Whole-genome sequencing was fundamental to linking isolates from dog food to human cases across Europe. Salmonella and Listeria , but awareness about this issue is not as evident in Europe. Eating raw meat has been considered a risk factor for carriage of clinically relevant ampicillin-resistant (AmpR) Enterococcus faecium and optrA-positive linezolid-resistant E. faecalis in dogs  genes because linezolid is a last-resort drug to treat gram-positive infections  and typed representative isolates by multilocus sequence typing  and whole-genome sequencing  using the Hi Seq 2500 Sequencing System . We deposited assemblies  in GenBank (Bioproject PRJNA663240) and characterized them using in silico tools (http://www.genomicepidemiology.org) and in-house databases .We purchased 14 raw-frozen dog food samples from the 2 commercially available brands in Portugal in specialized stores (September 2019\u2013January 2020). Brand A (produced in Europe) is available in specialized stores, brand B (produced in the United Kingdom) in specialized stores and online; both are commercialized across different countries in Europe. We enriched samples (25 g) in buffered peptone water (1:10), then in brain\u2013heart infusion broth with or without different antibiotic drugs , and plated them onto Slanetz-Bartley agar with and without the same drug concentrations. We identified isolates with different morphologies per plate by PCR. We performed antibiotic susceptibility testing by disk diffusion using European Committee on Antimicrobial Susceptibility Testing (EUCAST) , poxtA (2 E. faecium), optrA+poxtA  or optrA+cfrD . Of those, 15 expressed LinR (MIC\u00a0=\u00a08 mg/L), whereas 5 were susceptible (MIC\u00a0=\u00a04 mg/L)  .E. faecium isolates (n = 39) were mostly MDR (70%), expressing resistance to tetracycline (85%), quinupristin/dalfopristin (72%), erythromycin (64%), ciprofloxacin (59%), streptomycin (57%), ampicillin (56%), gentamicin (23%), chloramphenicol (21%), or linezolid (10%). We compared selected dog food AmpR E. faecium genomes with 7,660 available GenBank E. faecium genomes by complex types (CTs) through core-genome multilocus sequence typing . Those data . ST80 E. faecium from brand A was phylogenetically related to other strains from Germany and Netherlands; ST1091 and ST1263 from brand B were phylogenetically related to UK strains  in ST80 and ST1263 dog food AmpR E. faecium . ST1263 E. faecium was able to transfer poxtA by conjugation  recovered were mostly MDR (75%), resistant to chloramphenicol (83%), tetracycline (79%), erythromycin (75%), streptomycin (63%), gentamicin (31%), linezolid (21%), or ciprofloxacin (10%). ST40, ST674, ST1008, and ST1009 sequences corresponded to novel complex types carrying antimicrobial resistance (aac(6')-aph(2\u2033)/ant(6)-Ia/aph3\u2033-III/erm(B)/tet(M),tet(L),dfr(G)) and virulence (ace/gelE/elrA) genes linked to clinically relevant MDR lineages  identical to others from non\u2013clonally related E. faecalis in hospitalized patients in Spain and China . Similarly to pAPT110 in this study transferring optrA in high rates . Sgh rates , pEF1074E. faecium and E. faecalis with linezolid-resistance genes (optrA/poxtA/cfrD) we identified were unexpectedly high. Our data suggest that raw dog food could be a sentinel of emerging antimicrobial resistance traits because this type of food may accumulate raw ingredients of different origins, namely from animals associated with intensive farming, adding a new concern to the global health burden of antimicrobial resistance.In conclusion, the diversity and rate of Additional information about drug-resistant enterococci in raw commercial dog food, Europe, 2019\u20132020."}
+{"text": "Hamp (encoding hepcidin) KO mice (modeling type 2B HH). Here, we tested the hypothesis that Dmt1 silencing combined with dietary iron restriction (which may be recommended for HH patients) will mitigate iron loading once already established. Accordingly, adult Hamp KO mice were switched to a low-iron (LFe) diet and (non-toxic) folic acid-coupled, ginger nanoparticle-derived lipid vectors (FA-GDLVs) were used to deliver negative-control (NC) or Dmt1 siRNA by oral, intragastric gavage daily for 21 days. The LFe diet reduced body iron burden, and experimental interventions potentiated iron losses. For example, Dmt1 siRNA treatment suppressed duodenal Dmt1 mRNA expression (by ~50%) and reduced serum and liver non-heme iron levels . Interestingly, some iron-related parameters were repressed similarly by FA-GDLVs carrying either siRNA, including 59Fe (as FeCl3) absorption (~20% lower), pancreatic non-heme iron (reduced by ~65%), and serum ferritin (decreased 40\u201350%). Ginger may thus contain bioactive lipids that also influence iron homeostasis. In conclusion, the combinatorial approach of FA-GDLV and Dmt1 siRNA treatment, with dietary iron restriction, mitigated pre-existing iron overload in a murine model of HH.Intestinal iron transport requires an iron importer (Dmt1) and an iron exporter (Fpn1). The hormone hepcidin regulates iron absorption by modulating Fpn1 protein levels on the basolateral surface of duodenal enterocytes. In the genetic, iron-loading disorder hereditary hemochromatosis (HH), hepcidin production is low and Fpn1 protein expression is elevated. High Fpn1-mediated iron export depletes intracellular iron, causing a paradoxical increase in Dmt1-mediated iron import. Increased activity of both transporters causes excessive iron absorption, thus initiating body iron loading. Logically then, silencing of intestinal Dmt1 or Fpn1 could be an effective therapeutic intervention in HH. It was previously established that Dmt1 knock down prevented iron-loading in weanling  Hamp gene (encoding hepcidin) is transactivated in hepatocytes when iron stores are replete and during inflammation; increased hepcidin suppresses intestinal iron absorption and lowers serum iron. During iron depletion, hypoxia and when erythroid demand is elevated, Hamp transcription is downregulated, thus increasing intestinal iron transport and raising serum iron.Iron is an essential trace mineral with numerous notable biological functions. Iron homeostasis is unique among the dietary minerals as iron-excretory systems do not exist in humans or other mammals. Modulation of the rate of intestinal transport is thus critical to maintain overall body iron levels. Sophisticated homeostatic regulators of iron absorption have developed through evolutionary time, which collectively influence iron absorption in relation to body iron stores, erythroid demand, tissue oxygenation, and during infection and inflammation . HepcidiHamp is impaired in the genetic disease hereditary hemochromatosis (HH)  iron) and ferroportin 1 (Fpn1) (the main iron exporter). The activity of both transporters is inappropriately elevated in HH ,8,9. LowA-GDLVs)  to delivGinger-derived nanoparticles were isolated according to established protocols ,12,13,14Hamp\u2212/\u2212) mice on the C57BL/6 genetic background were bred in our animal facility. Female Hamp\u2212/\u2212 mice were weaned onto a standard chow diet and then, at 5 weeks of age, were switched to low-iron diet  for the remainder of the experiment . One day after the dietary switch, mice were given saline (control) or freshly made NC-siRNA or Dmt1-siRNA loaded FA-GDLVs daily (3.75 nmol/dose) by oral, intragastric gavage for 21 days. On each day of the experiment, mice were fasted for three hours before receiving the gavage treatment and then given food immediately thereafter. Water was always provided ad libitum. Our previous studies demonstrated that orally administered GDLVs/siRNAs are non-toxic and non-inflammatory in mice . R. RHamp Kcytosis) .Hamp\u2212/\u2212 mice, but concurrent knockdown of Dmt1 was necessary to bring values into the same range as in WT controls. In other tissues, low iron intake reduced tissue iron levels closer to WT levels, with FA-GDLV administration potentiating the effect of the low-iron diet only in pancreas (but not in heart or kidneys). Silencing intestinal Dmt1 is thus effective at reducing hepatic iron stores, while FA-GDLV/NC siRNA exposure reduced pancreatic iron loading. The latter observation suggested that ginger contains bioactive lipids [In sum, dietary iron restriction reduced hepatic non-heme iron levels in e lipids  that infe lipids .Hamp\u2212/\u2212 mice. Here, control  mice had similar serum ferritin levels of ~1000 ng/mL, indicating that dietary iron restriction did not decrease these levels. FA-GDLVs/NC siRNA treatment reduced serum ferritin by ~20%, while FA-GDLVs/Dmt1 siRNA exposure further reduced it (by ~50%) to just over 500 ng/mL  . In the absence of inflammation or malignant disease, serum ferritin is a reliable indicator of body iron stores . Moreovefferent) A. In the\u2212/\u2212 mice  to ~220 Hamp KO mice have elevated intestinal iron absorption [Hamp KO mice in the current investigation absorbed >45% of the radioactive iron dose, indicative of elevated iron absorption  [59Fe activity in liver was also reduced in both FA-GDLV treatment groups   and decreased non-heme iron levels in serum (by ~50%) and liver (by ~85%). Serum ferritin and pancreatic non-heme iron were reduced (by ~50%) in mice receiving FA-GDLVs carrying either siRNA . Given these observations, the next obvious step was to assess intestinal iron absorption. A well-established, oral gavage, radiotracer approach was thus utilized. sorption , presumahe dose) . Iron ab1, ~70%) B. Surprid kidney C\u2013G. 59Feeatments H, I. TheHamp expression, underlies iron loading in HH. Blocking iron absorption is thus a plausible therapeutic intervention. Targeting intestinal Dmt1 has been previously considered, as small molecule inhibitors have been identified [Hamp\u2212/\u2212 mice [Inappropriately elevated intestinal iron absorption, due to impaired hepatic entified ,42,43,44\u2212/\u2212 mice , providiWe previously established that GDLVs ,26 and F59Fe radiotracer absorption studies can be challenging, since this method offers a \u2018snapshot\u2019 of where dietary iron is being distributed during a single 24-h period . Since percent iron absorption is calculated from whole body 59Fe activity (minus 59Fe in the GI tract), reductions in absorption are reflected by decreases in whole-body 59Fe accumulation. Mice treated with FA-GDLVs/Dmt1 siRNA assimilated less 59Fe from the gavage dose than controls, indicating that vectorial iron transport was reduced. Consistent with this, 59Fe activity in the liver was decreased; however, 59Fe levels were paradoxically elevated in blood and several tissues tested. The significance of this latter observation is unclear, but nonetheless, iron transfer from the gut to the body was inhibited by FA-GDLV and Dmt1 siRNA treatment.As part of this investigation, iron absorption was quantified using a well-established experimental approach. Interpretation of Hamp\u2212/\u2212 mice that were fully iron loaded  [59Fe activity in liver was reduced by ~3-fold. FA-GDLVs carrying the NC siRNA also influenced many of the iron-related parameters reported here . Mitigation of iron loading in Hamp\u2212/\u2212 mice was thus most likely due to suppression of duodenal Dmt1 iron import activity and a concomitant reduction in iron transfer to the portal blood circulation. We say this is most likely based upon two facts: (1) DMT1 is the predominant (and probably the only) transporter of enteral non-heme iron in mice (which is the only form of iron present in mouse chow). This is nicely exemplified by the phenotype of the intestine specific Dmt1 KO [Our experimental approach here utilized dietary iron restriction (which could improve iron status in HH patients) , plus suWT mice) . Dietary Dmt1 KO . These m Dmt1 KO . AdditioThis investigation has demonstrated that intestinal Dmt1 is a valid therapeutic target to mitigate iron loading once already established in a murine model of early-onset, severe HH. Attenuation of duodenal Dmt1 expression and inhibition of vectorial iron transfer across the intestinal mucosa potentiated the iron-lowering effect of dietary iron restriction. Unique chemical properties of FA-GDLVs may have also contributed to the positive outcomes of this investigation; however, this is currently not clear and requires further investigation. This combinatorial approach of dietary iron restriction and inhibition of intestinal iron absorption could be further developed and utilized as an adjunctive treatment in HH (or other genetic iron-loading disorders), possibly reducing reliance on phlebotomy."}
+{"text": "Khirganga, a pristine hot spring that lies in the Parvati Valley within the Northern Himalayas characterised with unique white colour microbial mat and divine water with healing abilities. Here, we report 41 metagenome-assembled genomes (MAGs) reconstructed from the microbial mat, sediment and water samples of hot spring passed through Genome Standards Consortium (GSC) and Minimum Information of Metagenome-assembled Genome (MIMAG). The genome sizes, GC content, coding sequences and accession number are summarized in A total of 41 Metagenome-Assembled Genomes (MAGs) deconvoluted from water (n=24), microbial mat (n=12) and sediment samples (n=5) which are further described in 22.1Khirganga hot spring is a meso-thermic extreme environment characterised by white colour microbial mat deposited in and around the flowing hot water stream 2.2Total community DNA from water  and sediment  samples were extracted using PowerMax Soil DNA isolation kit  following the manufacturer's instructions. DNA extraction from microbial mat  samples described elsewhere 2.320 quality cut-off were discarded using SolexaQA k-mer 31, max. k-mer 93 and other default parameters. The metagenome-assembled genomes (MAGs) were reconstructed combining contigs based on tetra-nucleotide frequency and genome abundance probabilities using MetaBAT v2 (Metagenomic Binning with Abundance and Tetranucleotide Frequencies) minContig (minimum contig size) =2500 bp, and minS (minimum score of edge for binning) =60.Community DNA was sequenced at Beijing Genome Institute (BGI), Hongkong, China at Illumina Hiseq 2000 platform and 2\u00a0\u00d7\u00a0100bp paired-end libraries with insert size of 350bp were generated. Reads with <Q2.4Additional genome functional annotation was performed automatically using the Prokaryotic Genome Annotation Pipeline (PGAP) 3The raw sequence data were deposited at the National Centre for Biotechnology Information (NCBI) database under the project number PRJNA673998. The sequences of metagenomes are available with SAMN16657637; SAMN16632777 for microbial mat,\u00a0SAMN16657991; SAMN16673719 for sediment, and SAMN16683881; SAMN16683882 for water. The sequences of MAGs are available at GenBank under the genome accessions summarized in The work did not involve human subjects, animals, cell lines or endangered species of wild fauna and flora.Shekhar Nagar: Conceptualization, Data curation, Writing \u2013 original draft, Methodology, Software; Chandni Talwar: Conceptualization, Data curation, Writing \u2013 original draft; Meghali Bharti: Conceptualization, Validation; Sheetal Yadav: Validation; Sneha Siwach: Validation; Ram Krishan Negi: Conceptualization, Validation, Supervision.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."}
+{"text": "Some COVID-19 patients with similar quantitative CT measurements had variable clinical presentation and outcome. The absence of reasonable clinical explanations, such as pre-existing comorbidities or vascular complications, adds to the confusion. The authors believed that neglecting the impact of certain severe morphologic features could be an alternative radiological explanation. This study aims to optimize the initial CT staging of COVID-19 and propose a new combined morphologic/volumetric CT severity index (CTSI) to solve this clinico-radiological mismatch.This multi-center study included two major steps. The first step of the study entailed a standardized combined morphologic/volumetric CT severity analyses to propose a new optimized CTSI. This was conducted retrospectively during the period from June till September 2020. It included 379 acutely symptomatic COVID-19 patients. They were clinically classified according to their oxygen saturation and respiratory therapeutic requirements into three groups: group A (mild 298/79%), group B (borderline severity 57/15%), and group C . The morphologic and volumetric assessment of their HRCT was analyzed according to severity, by two consultant radiologists in consensus. A new 25 point-CTSI has been created, combining eight morphological CT patterns  and four grades of volumetric scores . The addition of the M5 pattern (air bubble sign), M6 pattern , or M7 pattern (crazy-paving) proved to increase the clinical severity. The second step of the study entailed a standardized blinded/independent validation analysis for the proposed CTSI. This was prospectively conducted on other 132 patients during October 2020 and independently performed by other two consultant radiologists. Validation results reached 80.2% sensitivity, 91.8% specificity, AUROC-curve = 0.8356, and 90.9% accuracy.A new optimized CTSI with accepted validation is proposed for initial staging of COVID-19 patients, using combined morphologic/volumetric assessment instead of the quantitative assessment alone. It could solve the clinico-radiological mismatch among patients with similar quantitative CT results and variable clinical presentation during the absence of pre-existing comorbidities or vascular complications. Progression to ARDS and coagulation dysfunction was reported in severe cases  (mild): patients with 95\u2013100% O2 saturation/RA plus type II or III dyspnea and/or tachypnea (RR \u2265 30/min) or both.Group [B] (borderline severe): patients with 93\u201394% O2 saturation/RA up to ARDS.Group [C] : patients with < 93% OThe patients in group [B] and [C] could be indicated for initial high flow nasal oxygen therapy up to mechanical ventilation.Patients were clinically classified according to the clinical symptoms, oxygen saturation, and respiratory therapeutic requirements into three groups :Group  (mild 298/79% patients). Group [B] (borderline severity 57/15% patients). Group [C] .It was conducted retrospectively during the period from June till September 2020. It included 379 acutely symptomatic COVID-19 patients. They were 242 males and 137 females (63.9%:36.1%). Their age ranged from 10 to 80 years (mean age 45.42 \u00b1 20.1 SD)CT images were analyzed in consensus with the availability of medical records by two expert consultant radiologists . They performed combined CT volumetric and morphologic assessment followed by severity analysis and a new combined CTSI proposal.[I] Volumetric/quantitative assessment [size of lesions (S)][S1] Patchy lesions involving (< 15% of lung volume),[S2] Patchy lesions involving (15\u201325% of lung volume),[S3] Patchy lesions involving (25\u201350% of lung volume),[S4] Diffuse lung involvement (> 50% of lung volume).[II] Morphologic assessment (M)OsiriX MD 11.0 software  was utilized for imaging review and volumetric/quantitative assessment of all patients, so the variability of the used MSCT machines would not impact the quantitative assessment. It was utilized for automated calculation of the total and pathological lung volumes based on threshold interval adjustment during the region of interest (ROI) 2D/3D color-coded reconstruction. (0:\u2212 1024 Hu) the interval was set for total lung volume calculation and (0: \u2212 700 Hu) interval was almost set for pathological lung volume calculation. Lesions were classified into four grades:[M1] Pure ground-glass opacities (GGOs) or solid nodules with peri-focal GG .[M2] GGOs with a peripheral organization \u201cAtoll or reversed halo sign.\u201d[M3] GGOs mixed with consolidative changes.[M4] Homogeneous or \u201ccurvilinear\u201d consolidations; the latter is parallel to the pleural lining.[M5] GGOs with \u201cair bubble sign\u201d; are small air-filled spaces within the ground-glass or consolidative changes, representing a cut section of sub-segmental bronchiolectasis sequel to fibrosis with focal air trapping.[M6] GGOs with \u201cearly secondary fibrotic changes\u201d and architectural distortion; are irregular linear streaks and atelectatic plates, representing early scarring of cellular components, which could be associated with bronchial wall thickening and bronchiectatic changes.[M7] Patchy GGOs with smooth septal thickening \u201ccrazy-paving pattern,\u201d[M8] Diffuse alveolar damage (DAD) pattern, showing diffuse lung involvement with either of the above-mentioned CT patterns or mixed (notably crazy-paving pattern and air bubble sign).Eight morphologic HRCT patterns were traced:Extra-parenchymal HRCT findings were also assessed, including significant nodal enlargement (short axis > 1 cm) and pleuro-pericardial effusions.The overall time for this combined quantitative and morphologic CT assessment was estimated and ranged from 6 to 12 min.\u2756 Prevalence of HRCT characteristics among the total number of patients.P value measurements were performed using an online calculator (https://www.socscistatistics.com). P value (< 0.05) was considered statistically significant.\u2756 Statistical analysis of significant relation between each HRCT volumetric or morphologic characteristic and clinical severity. Chi-square tests and \u2756 Calculation of the severity ratio for each HRCT abnormality among each group from the following equation [Severity ratio = Prevalence rate of HRCT finding among the total number of each patients\u2019 group/Prevalence rate of each patients' group among total sample size]. The total severity index is then summed and the CTSI model is created.[III] Statistical severity analyses and CTSI proposalIt was conducted prospectively during October 2020 on other 132 patients. They included 72 males and 60 females (54.5%:45.5%). Their age ranged from 22 to 67 years (mean age 41.13 \u00b1 11.69 SD). CT images were analyzed independently by two expert consultant radiologists . They were blinded from the clinical records.\u2756 Inter-observer agreement (IOA) using Cohen\u2019s Kappa test.http://araw.mede.uic.edu/cgi-bin/testcalc.pl).\u2756 Prevalence, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), using an online diagnostic test calculator (\u2756 Receiver operating characteristics (ROC) curve, area under the curve (AUC), confidence interval, and accuracy, using QI Macros 2020 Excel software.The following statistical methods were utilized:A flow diagram is demonstrating the study methodology including patients\u2019 selection, study design, and steps together with final clinical and radiological results Fig. .Fig. 1AP values ranged from 0.00017 to < 0.0001)  Table . [S1] le1) Table .Table 1P values ranged from 0.02930 to < 0.0001) .Trivial percentages of other extra-parenchymal CT signs were depicted and detailed in Table . No signAll patients with > 50% lung involvement S4] were clinically severe or critical. Around 67% of patients with 25\u201350% lung involvement S3] were borderline, while the remaining 33% were clinically severe or critical because of the additive effect of either [M6] pattern  or [M7] pattern (patchy GGOs with crazy-paving pattern)  /S (1-4)]. Distribution prevalence for our patients regarding new CT coding was grouped  with delayed recovery had followed up CT scans. Radiological improvement was noted among all of them regarding the morphological CT features (depicted by resolution or regression in the density of ground glass or consolidation lesions). Around 91/104 patients (87.5%) also showed regression in quantitative measurements, while 13/104 patients (12.5%) showed the stationary course of which, but with morphological improvement.2 saturation dropped below 93%). The radiological progressive course was depicted regarding both quantitative measurements and morphological features of parenchymal fibrosis and crazy paving pattern. One patient who had a previous \u201cair bubble sign\u201d developed pneumothorax. The vascular assessment was unremarkable. Thirty-one patients received high flow nasal oxygen while 6 patients needed mechanical ventilation later on.37/57 patients (65%) with borderline severity had a follow-up assessment with CT pulmonary angiography protocol after the deterioration of clinical condition into severe/critical status  showed deterioration in the clinical condition regarding the OAccepted inter-observer agreement (IOA) was achieved (ranging from 81.3%:100%). High accuracy for the proposed new CTSI was reached (ranging from 90.1%:91.7%). High degrees of specificity and NPV were estimated . Moderate to a high degree of sensitivity and PPV were estimated . Based on AUROC curve measurements (ranging from 0.7765: 0.9003) and confidence intervals (ranging from 0.684:0.832), the proposed CTSI expressed excellent, good, and fair validity for evaluation of mild, borderline, and severe patients, respectively. A detailed review of all validation analysis measurements was grouped . The overall time for every HRCT evaluation along with CTSI estimation and CT reporting was also very reasonable and did not exceed 12 min.However, this study was limited by the low percentage of severe cases in addition to the limited clinical indication/value for CT assessment of mechanically ventilated patients.Based on severity analysis, HRCT morphological features should share in CT severity scoring of COVID-19 patients (notably the pulmonary fibrosis and \u201ccrazy-paving pattern\u201d). A new optimized CTSI with accepted validation is proposed for the initial staging of COVID-19 patients, using combined morphologic/volumetric assessment instead of the quantitative assessment alone. It could solve the clinico-radiological mismatch among patients with similar quantitative CT results and variable clinical presentation during the absence of pre-existing comorbidities or vascular complications."}
+{"text": "Pseudomonas aeruginosa (CRPA) have high in-hospital mortality rates. It is unknown if patients with CRPA treated with ceftolozane/tazobactam (C/T) have improved clinical outcomes compared to those treated with polymyxins. Patients with carbapenem-resistant The CDC-funded, Georgia Emerging Infections Program performed active population- and laboratory-based surveillance for CRPA isolated from sterile sites, urine, lower respiratory tract and wounds in metropolitan Atlanta, GA from 8/1/2016\u20137/31/2018. We reviewed charts of adults without cystic fibrosis who were hospitalized within 1 week of CRPA culture. Using a desirability of outcome ranking (DOOR) analysis which incorporates both benefits and risks into a single outcome, we estimated the probability that a patient treated first with C/T would have a more desirable clinical outcome at 30-days than a patient treated with polymyxins (polymyxin B or colistin). We adjusted for confounding using inverse probability of treatment weighting (IPTW) based on culture source and need for dialysis at baseline. A partial credit analysis allowed for variable weighting of DOOR ranks and calculation of differences in mean partial credit scores. Among 710 cases from 18 different hospitals, we identified 73 patients treated for CRPA infections with polymyxins (n=31) or C/T (n=42). Most patients were male (64%) and Black (80%), and those receiving polymyxins were more likely to have required dialysis at baseline  (Table 1). At 30 days after culture, 34 (47%) were alive with no adverse events, 21 (29%) were alive with \u2265 1 adverse event, and 18 (25%) had died. Patients first treated with C/T had a lower 30-day mortality rate than those treated with polymyxins . Additionally, those receiving C/T had better overall clinical outcomes, with an adjusted DOOR probability of having an improved outcome of 67% (95% CI 53%\u201380%) compared to those receiving polymyxins . Partial credit analyses indicated consistent results across different patient values of survival with adverse events .Figure 1: Inverse probability of treatment weighting-adjusted desirability of outcome ranking (DOOR) distributions by treatment group, accounting for adverse events and survival status that occurred up to 30 days after CRPA culture.1. Percentages are adjusted using inverse probability of treatment weighting, controlling for culture source and need for dialysis at baseline 2. Adverse events measured included: acute kidney injury, discharge to higher acuity location than previous residence, or being hospitalized 30 days after cultureFigure 2: Inverse probability of treatment weighting-adjusted partial credit analysis.This displays the difference (ceftolozane/tazobactam minus polymyxin) in mean partial credit scores (black line) and associated 95% confidence bands (gray lines) as a function of the partial credit score assigned to an individual having at least one adverse event (range 0 \u2013 100%). A score of 100% is assigned to patients alive with no adverse events and a score of 0% is assigned to patients who die. A difference in mean partial credit scores of approximately zero suggests there was no difference observed between treatment groups.These findings support the recent Infectious Diseases Society of America guidance favoring C/T over polymyxins for treatment of CRPA infections.David van Duin, MD, PhD, Entasis (Advisor or Review Panel member)genentech (Advisor or Review Panel member)Karius (Advisor or Review Panel member)Merck Pfizer Qpex (Advisor or Review Panel member)Shionogi Utility (Advisor or Review Panel member) Scott R. Evans, PhD, Abbvie (Consultant)Advantagene (Consultant)Alexion (Consultant)Amgen (Consultant)AstraZeneca (Consultant)Atricure (Consultant)Breast International Group (Consultant)Cardinal Health (Consultant)Clover (Consultant)FHI Clinical (Consultant)Genentech (Consultant)Gilead (Consultant)Horizon (Consultant)International Drug Development Institute (Consultant)Lung Biotech (Consultant)Microbiotix (Consultant)Neovasc (Consultant)Nobel Pharma (Consultant)Novartis (Consultant)Nuvelution (Consultant)Pfizer (Consultant)Rakuten (Consultant)Roche (Consultant)Roivant (Consultant)SAB Biopharm (Consultant)Shire (Consultant)Stryker (Consultant)SVB Leerink (Consultant)Takeda (Consultant)Teva (Consultant)Tracon (Consultant)Vir (Consultant)"}
+{"text": "Previous studies showed that type 2 short bowel syndrome (SBS) rats were accompanied by severe intestinal bacterial dysbiosis. Limited data are available for intestinal fungal dysbiosis. Moreover, no effective therapeutic drugs are available for these microbiota dysbiosis. The aims of our study were to investigate the therapeutic potential of glucagon-like peptide 2 (GLP-2) for these microbiota dysbiosis in type 2 SBS rats.n\u00a0=\u20095) or GLP-2 . The Sham group rats which underwent transection and re-anastomosis were given a saline placebo . 16S rRNA and ITS sequencing were applied to evaluate the colonic bacterial and fungal composition at 22\u2009days after surgery, respectively.8-week-old male SD rats which underwent 80% small bowel resection, ileocecum resection, partial colon resection and jejunocolostomy, were treated with saline  significantly decreased. GLP-2 treatment significantly decreased Debaryomyces and Meyerozyma, and increased Penicillium. Moreover, GLP-2 partially restored the bacteria-fungi interkingdom interaction network of SBS rats.Our study confirms the bacterial and fungal dysbiosis in type 2 SBS rats, and GLP-2 partially ameliorated these microbiota dysbiosis.The online version contains supplementary material available at 10.1186/s12879-021-06270-w. Short bowel syndrome (SBS), a main cause of intestinal failure, refers to a kind of disease presented as severe malnutrition, diarrhea, water and electrolyte disorder mainly resulting from massive small bowel resection , 2. The Apart from bacteria, intestinal fungi are an indispensable part of intestinal microbiota. However, due to the restriction of techniques in the past, research on intestinal fungi dysbiosis in SBS patients and rats is still lacking. The development of high-throughput technology provides sufficient technical support for the study of fungal microbiota, which enables researchers to accurately understand the composition of intestinal fungi through internal transcribed spacer (ITS) sequencing \u201311. ReceTheranostics further demonstrated that GLP-2 exerted its gut mucosal hyperplasia promoting effect through modulating exosomal miRNAs transportation in small intestinal microenvironment , [C] and [E] Anosim similarity analysis based on weighted_unifrac distance rarefaction curves of each sample. [B], [D] and [F] Anosim similarity analysis based on Bray_curtis_OTU distance rarefaction curves of each sample.Additional file 2: Figure S2. Anosim similarity analysis of intestinal fungi. [A], [C] and [E] Anosim similarity analysis based on weighted_unifrac distance rarefaction curves of each sample. [B], [D] and [F] Anosim similarity analysis based on Bray_curtis_OTU distance rarefaction curves of each sample.Additional file 3:"}
+{"text": "Scientific Reports 10.1038/s41598-021-90617-5, published online 27 May 2021Correction to: The original version of this Article contained errors in Table 1 and the accompanying table legend.\u03c3abs were incomplete and omitted the term (Mm\u22121).The Table headings indicating the light absorption coefficients The correct and incorrect headings appear below.Incorrect:Correct:In addition, the Table legend was incorrectly given.www.climate-data.org, accessed October 2018. Tidal pattern data from data.shom.fr, accessed October 2018.\u201d\u201cBiogeographic region follows the biogeographic provinces in Bowen and others (2016). Climate data from now reads:\u201cAerosol light absorption properties.\u201dThe original Article has been corrected."}
+{"text": "Higher level of and greater longitudinal increase in perceived fatigability are linked to cognitive decline and lower brain volumes in older adults. However, it remains unclear whether perceived fatigability is associated with Alzheimer\u2019s disease-related brain pathology. In the BLSA, 163 participants without neurological disease or cognitive impairment  were assessed for perceived fatigability using rating of perceived exertion after a 5-minute (0.67 m/s) treadmill walk and A\u00df burden using 11C-Pittsburgh compound B (PiB) positron emission tomography. Forty-four participants were PiB+ based on a mean cortical distribution volume ratio (DVR) cut point of 1.066. After adjusting for demographics, body composition, comorbidities and ApoE-e4, higher perceived fatigability was not associated with PiB+ status . Results suggest perceived fatigability may contribute to cognitive decline through pathways other than A\u00df pathology. Future studies should target other mechanisms linking perceived fatigability and cognitive decline."}
+{"text": "Scientific Reports 10.1038/s41598-021-92635-9, published online 25 June 2021Correction to: The original version of the Article contained an error in the Author Information section.\u201cThese authors contributed equally: Leandri de Kock and P.J. Nico de Bruyn.\u201dnow reads:\u201cThese authors contributed equally: Leandri de Kock and W. Chris Oosthuizen.\u201dThe original Article has been corrected."}
+{"text": "Upper tract urothelial carcinoma (UTUC) represents 5% of all urothelial malignancies \u20133. AcWe developed a novel UTUC biopsy technique termed the \u201cform tackle\u201d biopsy. Ureteroscope is passed into ureter/renal collecting system. Cold-cup forceps are opened and pressed into the lesion base  then closed. Ureteroscope/forceps are advanced forward 3-10mm and then extracted from the patient. We compared standard versus novel upper tract biopsy techniques in a series of patients with lesions \u22651cm. In each procedure, two standard and two novel biopsies were obtained from the same lesion. The primary study aim was diagnosis of malignancy. IRB approved: 21-006907.Fourteen procedures performed on 12 patients between June 2020 and March 2021. Twenty-eight specimens sent  (Two biopsies per specimen). Ten procedures with concordant pathology. In 4 procedures the novel biopsy technique resulted in a diagnosis of UTUC  in the setting of a benign standard biopsy. Significant difference in pathologic diagnoses was detected between standard and novel upper tract biopsy techniques (p=0.008).The \u201cform tackle\u201d upper tract ureteroscopic biopsy technique provides higher tissue yield which may increase diagnostic accuracy. Further study on additional patients required. Early results are encouraging."}
+{"text": "Cleft palate repair surgeries lack a regenerative reconstructive option and, in many cases, develop complications including oronasal fistula (ONF). Our group has developed a novel murine phenocopy of ONF to study the oral cavity wound healing program. Using this model, our team previously identified that delivery of FTY720 on a nanofiber scaffold had a unique immunomodulatory effect directing macrophages and monocytes into a pro-regenerative state during ONF healing. Here, the objective of this study was to determine the effects of local biomaterial-based FTY720 delivery in the ONF model on the early bulk gene expression and neutrophil phenotypic response within the regenerating tissue.Using a mouse model of ONF formation, a palate defect was created and was treated with FTY720 nanofiber scaffolds or (blank) vehicle control nanofibers. At 1 and 3 days post-implantation, ONF oral mucosal tissue from the defect region was collected for RNA sequencing analysis or flow cytometry. For the RNA-seq expression profiling, intracellular pathways were assessed using the KEGG Pathway database and Gene Ontology (GO) Terms enrichment interactive graph. To assess the effects of FTY720 on different neutrophil subpopulations, flow cytometry data was analyzed using pseudotime analysis based on Spanning-tree Progression Analysis of Density-normalized Events (SPADE).+Ly6G+ neutrophils at both day 1 and day 3 post-injury showed significantly distinct subpopulations of neutrophils in oral mucosal defect tissue from the FTY720 scaffold treatment group compared to the vehicle control group (blank). Increased expression of CD88 and Vav1, among other genes, were found and staining of the ONF area demonstrated increased VAV1 staining in FTY720\u2010treated healing oral mucosa.RNA sequencing analysis of palate mucosa injured tissue identified 669 genes that were differentially expressed (DE) during the first 3 days of ONF wound healing after local delivery of FTY720, including multiple genes in the sphingolipid signaling pathway. Evaluation of the DE genes at the KEGG Pathway database also identified the inflammatory immune response pathways , and the Gene Ontology enrichment analysis identified neutrophil chemotaxis and migration terms. SPADE dendrograms of CD11bTreatment of oral mucosal defects using FTY720 scaffolds is a promising new immunotherapy to improve healing outcomes and reducing ONF formation during cleft palate surgical repair. Local delivery of FTY720 nanofiber scaffolds during ONF healing significantly shifted early gene transcription associated with immune cell recruitment and modulation of the immune microenvironment results in distinct neutrophil subpopulations in the oral mucosal defect tissue that provides a critical shift toward pro-regenerative immune signaling.The online version contains supplementary material available at 10.1007/s40883-021-00208-z. Cleft palate patients (1:1000 live births) all undergo palate repair; 60% develop complications including oronasal fistula (ONF) formation which is associated with poor feeding and speech. Currently, cleft palate repair surgeries lack a regenerative reconstructive option, require multiple re-repairs due to ONF and increase cost and morbidity. FTY720, an active biolipid that activates sphingosine pathway, attracts pro-regenerative neutrophils, monocytes and macrophages to the oral wound site improving the ONF healing. The comprehensive understanding of the inflammatory signaling pathways controlled by FTY720 during ONF formation provide therapeutic targets for an effective immunomodulatory strategy to improve oral cavity wound healing, reducing ONF formation.Abnormal craniofacial development can result in orofacial clefts, where there is continuity between the oral and nasal spaces. Cleft palate patients (1:1000 live births) all undergo surgical palate repair; however, 60% develop complications including oronasal fistula (ONF) formation. ONF formation leads to poor feeding, speech, and dental problems . Persistlo pro-regenerative monocytes associated with improved wound healing in soft tissues. FTY720 also increases the generation of pro-regenerative M2 macrophages in the site of the injury improving the healing outcomes and tissue regeneration  and poly (lactic-co-glycolic-acid) . These polymers were then dissolved in a 1:3 volume ratio solution of methanol to chloroform to achieve an 18% polymer concentration for blank fibers, and 20% polymer concentration for FTY720-loaded fibers. For FTY720 loaded fibers, drug was added into the solution at a 1:200 drug:polymer weight ratio. The solution was then agitated for 2 + hours until the polymer was fully dissolved and then 2 mL of polymer solution was loaded into a 3 mL syringe with a 10 mm diameter. Electrospinning was performed at a flow rate of 1 mL/hr, at applied voltage of 19 kV for both blank and FTY720 fibers , 18. Thein vivo experiments were performed using procedural guidelines with appropriate approvals from the Institutional Animal Care and Use Committee of Emory University. C57BL/6 mice  were used. All mice were 8\u201312-week females and had a weight of 20\u201325 g. To create an ONF, the mice were anesthetized with Isoflurane 3% and Ketamine/Xylazine 100 mg/kg/10 mg/kg, and a retractor was used to open their mouth  controlled at < 0.05. Volcano plots were generated using EnhancedVolcano, and heat maps were generated using GraphPad Prizm.Oral mucosal tissues were harvested and whole-genome RNA was isolated using the Qiagen RNeasy kit  according to the manufacturer\u2019s protocols. Quality Control (QC) was done using a bioanalyzer to determine the RNA Integrity Number (RIN) of the samples. Thereafter, a New England Biolab\u2019s (NEB) mRNA isolation module in conjunction with their Ultra II RNA directional kit  was used to generate sequencing libraries. QC was then performed on these libraries using the bioanalyzer, and the library was quantified using fluorometric methods. Paired-end 75 base pairs (PE75) sequencing was performed on the Illumina NEXTSeq instrument to obtain a sequencing depth of 30000 reads per sample. The transcripts obtained were aligned and annotated by comparing them to the genome-wide mouse database (mm9) along with elimination of duplicate reads, using the strand next-generation sequencing (NGS) application. The RNA levels were calculated in reads per kilobase per million mapped reads (RPKM). Genes expressed at >1.5 RPKM were included in further analyses . Gene quhttps://tools.dice-database.org/GOnet/ (https://david.ncifcrf.gov/) (q\u22640.05.Gene Ontology (GO) analysis was performed using g/GOnet/ . The apprf.gov/) , 24. Therf.gov/) . GO annoMice were euthanized at postoperative day 3, and palate tissue was harvested and fixed with 10% buffered formalin. Paraffin-embedded tissues were cut in 10 \u03bcm sections and stained with anti-VAV1/Alexa568  or anti-CD88/Alexa488 . Images were acquired using the \u00d710 objective on an Olympus F1000 microscope.For analysis of immune infiltrate, oral mucosal tissues were harvested and digested in 1 mg/ml collagenase I (Sigma) for 45 min at 37 \u00b0C. The digested palate mucosa was filtered through a cell strainer to obtain a single-cell suspension. Single-cell suspensions from palatal samples were stained for live cells using Zombie NIR (Biolegend) dyes in cell-culture grade PBS per manufacturer instructions. Cells were then stained with cell phenotyping antibodies in a 1:1 vol ratio of 3% FBS and Brilliant Stain Buffer (BD Biosciences) according to standard procedures and analyzed on a FACS AriaIIIu flow cytometer (BD Biosciences). The following antibodies were used for cell phenotyping: Zombie NIR Fixable Viability Kit (BioLegend), BV606-conjugated CD45 (BioLegend), PE-conjugated MERTK (BioLegend), PerCP-Cy5.5-conjugated CD64 (BioLegend), APC-conjugated Ly6C (BioLegend), PE-Cy7-conjugated Ly6G (BioLegend), FITC-conjugated CD11b (BioLegend), and APC-Cy7-conjugated CD206 (BioLegend).Spanning-tree progression analysis of density-normalized events (SPADE) is a nonlinear dimensionality reduction method that orders the progress of immune cell subsets through biological processes based on molecular marker similarities . SPADE cp-value (q) was calculated. From a total of 24421 variables, 3513 of genes were filtered for mean normalized counts <2. The volcano plot showed that more genes were significantly upregulated than downregulated  receptors and altering intracellular sphingolipid . In thisKEGG analysis of differentially expressed genes from the mucosal defect tissue treated with FTY720 scaffolds identified significant changes in chemokine signaling and leukocyte migration in the first 3 days after injury - and MCP-1-deficient mice in which endogenous H2O2 generation is impaired High Resolution Image (TIF 1964 kb)Supplemental Figure 2\u2013 Subpopulations of neutrophils at day 1 post injury during healing of wounded palate. A traditional gating strategy in which live, single cells were analyzed using CD11b+ as a general myeloid cell marker and Ly6G+ within the CD11b+ population as a neutrophil marker was used to visualize neutrophil heterogeneity in the myeloid cell compartment (PNG 392 kb)High Resolution Image (TIF 2220 kb)Supplemental Figure 3- Subpopulations of neutrophils at day 3 post injury during healing of wounded palate. A traditional gating strategy in which live, single cells were analyzed using CD11b+ as a general myeloid cell marker and Ly6G+ within the CD11b+ population as a neutrophil marker was used to visualize neutrophil heterogeneity in the myeloid cell compartment (PNG 342 kb)High Resolution Image (TIF 2190 kb)Supplemental Table 1\u2013 KEGG Pathways of the DE genes. (PNG 256 kb)High Resolution Image (TIF 952 kb)Supplemental Table 2\u2013 Nomenclature of the DE genes. (PNG 191 kb)High Resolution Image (TIF 1021 kb)"}
+{"text": "Poor sleep is a strong risk factor for dementia and is commonly reported among older adults with mild cognitive impairment (MCI). However, the neural underpinnings of poor sleep among older adults with MCI remains equivocal. The goal of this cross-sectional analysis was to explore the relationship between resting-state functional connectivity in the brain and sleep quality as measured by actigraphy. We hypothesize lower sleep efficiency and higher sleep fragmentation may be associated with aberrant functional connectivity of brain regions involved in somatosensory, somatomotor, and attentional processing. Thirty-six community-dwelling older adults with probable MCI between 65-85 years (mean=71.8 years) were assessed for sleep quality using a motion watch to quantify sleep efficiency and fragmentation over 14 days. All participants completed resting-state functional magnetic resonance imaging (fMRI) within 14 days of sleep monitoring. Independent associations between network connectivity and sleep quality were determined using general linear models. Examined networks included the somatosensory network (SMN), dorsal attention network (DAN), ventral attention network (VAN), frontoparietal network (FPN), and default mode network (DMN). Mean Montreal Cognitive Assessment score was 22.5 (SD=2.7) and Mini-Mental State Examination score was 28.3 (SD=1.5). Mean sleep efficiency and fragmentation index was 80.1% and 31.8 respectively. Higher sleep fragmentation correlated with increased connectivity between the SMN and insula, the SMN and posterior cingulate, as well as FPN and primary motor area . These results suggest aberrant functional connectivity between brain regions involved in attentional and somatosensory processes may be associated with disrupted sleep mechanisms in older adults with MCI."}
+{"text": "Cassiopea xamachana.Marine holobionts depend on microbial members for health and nutrient cycling. This is particularly evident in cnidarian-algae symbioses that facilitate energy and nutrient acquisition. However, this partnership is highly sensitive to environmental change\u2014including eutrophication\u2014that causes dysbiosis and contributes to global coral reef decline. Yet, some holobionts exhibit resistance to dysbiosis in eutrophic environments, including the obligate photosymbiotic scyphomedusa C. xamachana that stabilize symbiotic relationships. We combined labelled bicarbonate (13C) and nitrate (15N) with metabarcoding approaches to evaluate nutrient cycling and microbial community composition in symbiotic and aposymbiotic medusae.Our aim was to assess the mechanisms in C. xamachana as even at high heterotrophic feeding rates aposymbiotic medusae continuously lost weight. Heterotrophically acquired C and N were readily shared among host and algae. This was in sharp contrast to nitrate assimilation by Symbiodiniaceae, which appeared to be strongly restricted. Instead, the bacterial microbiome seemed to play a major role in the holobiont\u2019s DIN assimilation as uptake rates showed a significant positive relationship with phylogenetic diversity of medusa-associated bacteria. This is corroborated by inferred functional capacity that links the dominant bacterial taxa (~90 %) to nitrogen cycling. Observed bacterial community structure differed between apo- and symbiotic C. xamachana putatively highlighting enrichment of ammonium oxidizers and nitrite reducers and depletion of nitrogen-fixers in symbiotic medusae.C-fixation and cycling by algal Symbiodiniaceae was essential for C. xamachana. We found that the bacterial microbiome of symbiotic medusae was seemingly structured to increase DIN removal and enforce algal N-limitation\u2014a mechanism that would help to stabilize the host-algae relationship even under eutrophic conditions.Host, algal symbionts, and bacterial associates contribute to regulated nutrient assimilation and cycling in Video abstractThe online version contains supplementary material available at 10.1186/s40168-021-01075-0. Multicellular life depends on microorganisms for tight symbiosis, for their ability to drive biogeochemical processes, thus providing nutrients, or both . Hosts aCassiopea spp.), phototrophic C fixation can completely cover the host\u2019s energetic requirements  and (b) aposymbiotic C. xamachana (n = 12) [WWaposymbiotic = -1.440 + 0.100*BD]. Different colours indicate the number of days after start of the four-day menthol bleaching. Dashed vertical lines indicate minimum and maximum BD of medusae employed in the pulse-chase experiment. Figure S3. Net primary production (Pn) and host carbon enrichment. Host fraction enrichment expressed as AP13C light-incubated medusae (SymL) from all incubations  (n = 15).Additional file 2: Text S1. Extended Material and Methods. Text S2. OTU based bacterial analysis.Additional file 3: Table S2. ASV abundance table detailing ASV numbers over samples, including taxonomy and representative sequences. Number of ASVs 303, of which 7 are contaminants (marked with *), core microbiome members in bold, 'symbiome' members underlined for symbiotic samples and 'apobiome' members underlined for aposymbiotic samples. Table S3. Detailed stable isotope measurements of Cassiopea xamachana and its associated Symbiodiniaceae in symbiotic-light (SymL), symbiotic-dark (SymD), aposymbiotic-light (ApoL) treatments and upon heterotrophic feeding. Table S4. Stable isotope analysis enrichment statistics. Table S5. Stable isotope labelling of Isochrysis galbana and Artemia salina. 13C and 15N enriched Isochrysis galbana algae were employed to label Artemia salina as a heterotrophic food source for C. xamachana. Table S6. OTU abundance table detailing OTU numbers over samples, including taxonomy and representative sequences. Number of OTUs 697, of which 9 are contaminants (marked with *), core microbiome members in bold, 'symbiome' members underlined for symbiotic samples and 'apobiome' members underlined for aposymbiotic samples. Table S7. Closest blastn hits considered for presumably important OTUs . Table S8. Closest complete genomes of the 20 most abundant ASVs based on an NCBI blastn search (assessed November 2020). Considered gene homologs are related to nitrogen cycling and transport.Additional file 4: R-scripts employed to analyse the bacterial microbiome."}
+{"text": "Older adults may report high energy alongside tiredness or vice versa; little is known about whether discordant self-reported energy (SEL) and tiredness predict trajectories of mood, cognition, or gait speed. SEL  and tiredness (present/absent) were obtained in 2,613 older adults (aged 74.6\u00b1 2.87 years) and used to create four groups . Center for Epidemiologic Studies Depression Scale (CES-D) and gait speed were measured over 10 years; mixed effect models compared trajectories in these domains across each group with low energy/tired group as referent. Each group was significantly associated with CES-D and gait. Adjusting for demographics, the high SEL/not tired group showed the least decline in mood ; the high SEL/tired group showed the least decline in rapid gait . High SEL may indicate resilience for mood and gait speed decline."}
+{"text": "Veterans Health Administration\u2019s (VHA) large elderly population is at higher risk for influenza complications, including hospitalization and death. Herein we summarize VHA\u2019s national annual surveillance data for seasonal influenza activity and vaccinations.Influenza telephone triage, influenza-like-illness (ILI) encounters and antiviral prescriptions plus outpatient visits, laboratory testing, hospitalizations and deaths for influenza were obtained from VHA data sources (9/27/20-5/22/21) and compared to prior years and CDC FluView data. Influenza vaccinations were captured from 8/1/2020. Vaccination rates were calculated based on VHA users during the fiscal year. Surveillance metrics are presented (Table). Vaccinations were decreased and ILI was below average (0.3%-0.7% per week). Activity was highest 2020 Weeks 46-47 but remained low the entire season with no distinct peak seen, matching national influenza activity . Testing revealed 161 influenza positives from 440,553 tests performed (0.04%). Hospitalizations among laboratory-confirmed cases were similar to the prior season (16% vs 17%). Median length of stay (6 days) and deaths  were increased over prior seasons. Among 15 deaths where results were available, 4 had Influenza A, 10 had Influenza B and 1 had Influenza A+B. Nine were co-infected with COVID-19. Total influenza positives, outpatient visits, hospitalizations and antiviral use were extremely low compared to all prior season where national VHA data has been analyzed . Overall, influenza vaccination levels were decreased although percent receiving high-dose formulation was stable. Despite lower vaccination rates, the 2020-21 influenza season was of historically low activity, even with markedly increased testing performed in the setting of multiplex tests for influenza with COVID-19. Deaths were primarily seen with Influenza B and among those co-infected with COVID-19. This may also have contributed to increased length of stay. VHA influenza activity continues to track closely with national CDC data and may have been impacted by mitigation measures used to contain COVID-19, which were likely effective in curbing influenza activity. All Authors: No reported disclosures"}
+{"text": "OBJECTIVES/GOALS: The objective of the study was to determine whether CLP altered genes associated with mitochondrial function in the diaphragm. METHODS/STUDY POPULATION: A rodent cecal-ligation and puncture (CLP) model used to mimic sepsis-induced critical illness. The CLP model involved ligation of 50% of the cecum below the ileocecal valve in adult C57BL6 mice, followed by needle puncture of the cecum resulting in mid-grade sepsis. Mice survived for 48 hours or more, following injury. Diaphragm and limb muscles were harvested 24 hours following CLP (N = 6) and following a sham CLP procedure (N = 6). RESULTS/ANTICIPATED RESULTS: Gene expression of mitochondrial related genes , were significantly decreased in the diaphragm of CLP injured animals when compared to controls. In addition, ubiquitin ligases, genes associated with skeletal muscle atrophy murf1 and atrogin were increased in the diaphragm 24 hours after injury (p< 0.01). DISCUSSION/SIGNIFICANCE OF IMPACT: Our results indicate that sepsis-induced critical illness significantly impacts the expression of genes implicated in mitochondrial homeostasis and atrophy. Ongoing studies will identify whether CLP injury decreases skeletal muscle mitochondrial function."}
+{"text": "Oncogene activation through somatic gene amplification happens frequently in GBM, with over 70% of these tumors presenting amplification of at least one putative driver gene, oftentimes in small extrachromosomal circular DNA segments composed of chromatin (ecDNA). A molecularly diverse and representative panel of GBM patient-derived cancer stem-like cells (CSC) and orthotopic mouse xenografts (PDX), which retain the original genomic abnormalities and ecDNA amplifications, was employed to assess adaptive response to the absence of ecDNA amplification.We have isolated ecDNA negative cell populations from two patient-derived models. HF3035 harbors a MET amplification and HF3253 harbors a PDGFRA constitutively active genomic rearrangement and extrachromosomal amplification. We conducted paired, whole RNA-sequencing on 20 HF3253 populations  and 12 HF3035 population .Nonparametric differentially expressed gene (DEG) analysis using NOISeqBio (R/Bioconductor), identified 564 differentially expressed genes (482 upregulated in ecDNA(-)) employing a stringent false discovery rate of 0.05. Genes significantly associated with PDGF stimulation, central carbon metabolism, and H3K27me3 were downregulated in ecDNA(-), while genes significantly associated with astrocytic processes, neuronal differentiation, and EGFR signaling were upregulated in ecDNA(-) (EnrichR). We employed an additive linear model with PDX serving as a blocking factor to compare ecDNA+ and ecDNA- populations in both models (R/edgeR). 2071 genes were upregulated in ecDNA+ PDX specimens and 2365 genes were downregulated. Specifically, E2F targets were highly enriched in ecDNA+ populations, in addition to mRNA pre-processing. ecDNA loss primarily targeted glycogen metabolism, NTRK signaling, and inositol phosphate catabolism.We have identified PDX-specific and non-specific features to an adaptive response to the loss of ecDNA amplification. Notably, a signature adaptation is an upregulation of seemingly redundant receptor tyrosine kinases."}
+{"text": "Few studies have examined how the intersectionality of geographic context and race/ethnicity influences Alzheimer\u2019s disease and related dementia (ADRD) caregiving. Our aims were to determine whether 1) caregiver experiences and health differed across urban and rural areas; and 2) these links were moderated by caregiver race/ethnicity. We used data from the 2017 National Health and Aging Trends Study and National Study of Caregiving. The sample included caregivers (n=808) of care recipients ages 65+ with \u2018probable\u2019 ADRD (n=482). Geographic context was defined as care recipient\u2019s residence in metro (urban) or non-metro  counties. Outcomes included caregiving experiences  and health . Bivariate analyses indicated that non-metro ADRD caregivers were less racially/ethnically diverse (82.7% white) and more were spouses/partners (20.2%). Among racial/ethnic minority ADRD caregivers, non-metro context was associated with having more chronic conditions (p<.01), providing less care (p<.01), and not co-residing with care recipients (p<.001). Amid white ADRD caregivers, non-metro context was associated with not reporting caregiving was more than they could handle (p<.05) and finding financial assistance for caregiving (p<.05). Multivariate regression analyses demonstrated that non-metro minority ADRD caregivers had 3.09 times higher odds  of reporting anxiety in comparison to metro minority ADRD caregivers. Geographic context shapes ADRD caregiving experiences and caregiver health differently across racial/ethnic groups. Despite higher rates of ADRD and ADRD-related mortality in non-metro areas, findings suggest both positive and negative aspects of caregiving among White, Black, and Hispanic ADRD caregivers."}
+{"text": "Understanding of unmet needs and their predictors among bladder cancer (BC) survivors is critical to optimize health care planning for patients. This study compares between younger (<65 Years) and older (\u226565 Years) BC patients across seven domains of unmet needs  and their demographic, clinical, and psychosocial predictors. BC survivors  were recruited from the Bladder Cancer Advocacy Network and completed a questionnaire that included the needs assessment survey (BCNAS-32), hospital anxiety and depression scale (HADS), coping (BRIEF COPE), social provisions scale (SPS), and self-efficacy beliefs (GSE) scale. Although no significant group differences in all reported needs emerged, both groups reported more communication (IQR = 50 (62.5) and less sexuality needs (IQR =13 (52.1). Older patients reported higher depression and anxiety (IQR = 32 (11.5); N = 68) than younger patients (IQR = 28 (11.0); p < .01; N = 88). Multivariable analyses stratified by age showed significant effects of gender among older patients with women experiencing more psychological, care, communication, and sexuality needs than men. Multivariable analyses also showed age-related differences (p < .05) in the predictors of needs controlling for covariates . Among older patients both higher depression and anxiety and lower self-efficacy beliefs were associated with more psychological, care, and communication needs. Among younger patients, higher depression and anxiety were associated with more psychological, logistic, daily living, and communication needs. Results emphasize the importance of tailoring care planning for patients based on age."}
+{"text": "The VA Million Veteran Program (MVP) studies what factors influence Veteran health. Current procedures involve collection of venous blood at MVP enrollment sites. To examine home specimen collection options, MVP performed a pilot study comparing two blood specimen collection devices and evaluated SARS-CoV-2 antibody assays to determine known COVID-19 infection or vaccination.A sub-sample of MVP Veteran participants were asked to self-collect a capillary blood specimen using the Neoteryx Mitra Clamshell (up to 120uL dried blood) or Tasso-SST (up to 200uL liquid blood) per the vendor instructions. Veterans were randomly assigned to a device prior to consent. Eligibility included 30% of Veterans with known COVID-19 diagnosis or vaccination and sampling time was variable from these events. Veterans rated their device experience and shipped collected specimens directly to an MVP laboratory. Mitra tip (4) blood was eluted in 1 mL of 0.9% normal saline for 1 hour at room temperature shaking at 300 rpm. Tasso tubes were centrifuged per vendor instructions. All samples were stored at -80\u00b0C until tested with SARS-Cov-2 antibody (Ab) assays  Total Ab, Abbott NC IgG, and Abbott Spike IgG II) per vendor instructions. 312 MVP participants consented to the pilot (52%) of which 136 (43.6%) were sent Mitra and 176 (56.4%) were sent Tasso-SST (Table 1). Participants rated the Mitra Tasso-SST equally on average as 4.4 on a 0-5 usability scale. The Abbott IgG II assay had the highest sensitivity across both devices (87% Mitra and 98% Tasso-SST) for detecting known COVID infection and/or vaccination. The InBios IgG assay with the Tasso-SST had the best sensitivity (97%) and specificity (80%) for detecting known COVID-19 infection and/or vaccination (Table 2).Table 1. COVID-19 At-Home Capillary Blood Specimen Collection Pilot OutcomesVeterans successfully collected their own specimens and had no strong preference for either device. The Tasso-SST combined with the InBios Spike IgG assay provided the highest combination of sensitivity and specificity. Limitations included one collection device per subject, varied timing of testing, unknown infection or vaccination status among some, and Tasso collection volume and Mitra whole blood dilution may have affected comparison across assays or performance.All Authors: No reported disclosures"}
+{"text": "Teladorsagia circumcincta over the course of two separate trials performed over two\u00a0consecutive years.Growing evidence points towards a role of gastrointestinal (GI) helminth parasites of ruminants in modifying the composition of the host gut flora, with likely repercussions on the pathophysiology of worm infection and disease, and on animal growth and productivity. However, a thorough understanding of the mechanisms governing helminth-microbiota interactions and of their impact on host health and welfare relies on reproducibility and replicability of findings. To this aim, in this study, we analysed quantitative and qualitative fluctuations in the faecal microbiota composition of lambs vaccinated against, and experimentally infected with, the parasitic GI nematode Two trials were conducted under similar experimental conditions in 2017 and 2018, respectively. In each trial, lambs were randomly assigned to one of the following experimental groups: (i) vaccinated/infected, (ii) unvaccinated/infected and (iii) unvaccinated/uninfected. Faecal samples collected from individual animals were subjected to DNA extraction followed by high-throughput sequencing of the V3-V4 region of the bacterial 16S rRNA gene and bioinformatics and biostatistical analyses of sequence data.T. circumcincta were detected when comparing data from the two trials. Nevertheless, the abundance of Prevotella spp. was significantly linked to helminth infection in both trials.Substantial differences in the populations of bacteria affected by immunisation against and infection by T. circumcincta infection and/or vaccination. Nevertheless, our study calls for caution when interpreting data generated from in vivo helminth-microbiome interaction studies that may be influenced by several intrinsic and extrinsic host-, parasite- and environment-related factors.Despite the largely conflicting findings between the two trials, our data revealed that selected gut microbial populations are consistently affected by The online version contains supplementary material available at 10.1186/s13071-021-04688-4. It has been estimated that, by 2050, the global\u00a0human population will exceed 9 billion and that such a dramatic growth will exacerbate the already strained ability to meet the increasing demand of meat and dairy products ; thus, tTeladorsagia circumcincta, which resides in the abomasum or \u2018true stomach\u2019 ) and at 19, 47 and 57 dpi for Vac/  software   clustering together, and to the exclusion of samples from the Tc\u2212_18 group  were compared by sPLS-DA. Using this approach, the genera Lachnospiraceae NK4A136 group, Ruminococcus, Bacteroides, Oscillibacter, UCG-002 (family Oscillospiraceae), Eubacterium siraeum group, Phascolarctobacterium, Clostridia UCG-014 and RF39 were identified as discriminatory between Tc\u2212_18 and both Tc+_18 and Vac/Tc+_18 , albeit taking into account baseline differences between the gut microbiota composition of Tc+_18 and Vac/Tc+_18 animals and that of Tc\u2212_18.For the 2018 trial, PCoA analysis of microbial profiles of faecal samples collected at all time points revealed clustering according to experimental group along Principal Coordinate 1, with samples from oup Fig.\u00a0. This diTc+_18, Vac/Tc+_18 or Tc\u2212_18 over time  were not consistently supported by pairwise post hoc analysis (i.e. Tukey\u2019s test) . In contrast, the abundance of Bacteroidales BS11 gut group was significantly increased in Vac/Tc+_18 animals over time, with significant differences detected between 0 and 57 dpi by Tukey\u2019s test  were recorded for Tc+_18 and Vac/Tc+_18 were ordinated by CCA, following removal of samples from Tc\u2212_18 due to the aforementioned substantial differences in baseline microbial profiles  whose abundances differed between each pair of experimental groups at each time point  is available from Additional file T. circumcincta in both trials, whilst controlling for inter-experimental variability. In particular, the microbial taxa associated with T. circumcincta infection were identified by applying LEfSe to all samples collected post-experimental infection vs. samples from uninfected animals and samples collected pre-experimental infection from both the 2017 and 2018 trials. The genera Prevotella and Lachnospiraceae NC2004 group were associated with infected samples, while the genus Turicibacter was linked to samples from uninfected lambs [LDA score (log10)\u2009>\u20093]. To account for potential biases related to animal growth, the same test was applied to samples collected from Tc\u2212_18 animals at 0 dpi vs. 19\u2009+\u200947\u2009+\u200957 dpi .In addition, with the aim to identify faecal bacterial taxa potentially associated with vaccination against T. circumcincta over two separate studies conducted in consecutive years. Several inconsistencies were detected between bacterial taxa associated with infection and vaccination in the 2017 and 2018 trial, in line with the known challenges linked to the reproducibility of helminth-microbiome interaction data and vaccination studies in vivo . In rumiewed by , and dieiewed by \u201342. Whiliewed by \u201342. SuchT. circumcincta across trials, fluctuations in microbial alpha- and beta\u00a0diversity were similar over the course of the two experiments. In particular, no significant changes in faecal microbial alpha diversity were detected in either 2017 and 2018; this observation is in accordance with results from our previous study in T. circumcincta-infected sheep [Haemonchus contortus [Ostertagia ostertagi [T. circumcincta-infected animals (i.e. Vac/Tc+_17 and Adj/Tc+_17) and in all groups  over the course of the 2017 and 2018 trial, respectively, albeit with no consistent trend between consecutive time points. However, given the increase in microbial beta diversity observed in unvaccinated/uninfected lambs over time in the 2018 study, the hypothesis that such a finding might result from natural variations in gut microbiome composition occurring in early life cannot be excluded [Despite substantial differences in the gut microbial make-up of lambs infected with, and vaccinated against, ed sheep  as well ontortus  and cattstertagi , both ofexcluded , 44.T. circumcincta infection in the 2017 study, the genus Akkermansia was reduced in faecal samples from Vac/Tc+_17 and Adj/Tc+_17 animals. Reduced populations of Akkermansia, a known mucin degrader, have been linked to deterioration of GI health in humans  in comparison to goats fed a low-concentrate diet. In addition, Scott et al. [T. circumincta-parasitised sheep; this finding is consistent with a reduction in Muc5AC gene expression observed in sheep challenged with H. contortus [Akkermansia observed in our study might be directly linked to a reduction of Muc5AC-encoded mucin, a predominant component of abomasal mucus.Amongst the gut bacteria whose abundances varied significantly following iewed by ). Despitiewed by  demonstrt et al.  demonstrontortus . Thus, tT. circumcincta infection in lambs enrolled in the 2018 study. Amongst these, the genus Romboutsia was significantly expanded over time in the Tc+_18 and Vac/Tc+_18 groups, in accordance with data from our previously published trial [Romboutsia has recently been linked to a broad range of metabolic functions, including carbohydrate utilization and fermentation of single amino acids [Romboutsia in ruminants is scant, a single report described expanded populations of this genus of bacteria in the gut microbiota of diarrheic goats compared to healthy controls [Romboutsia in the gut microbiota of small ruminants and GI helminth infections is yet to be established.Several bacterial taxa were positively associated with ed trial . The genno acids . Whilst controls . HoweverT. circumcincta infection between the two studies, a small number of bacterial groups was consistently affected by helminth infection in both experiments. Amongst these, the order Burkholderiales and its genus Parasutterella were significantly expanded in faecal samples from Adj/Tc+_17 and Tc+_18. A bacterial genus closely related to Parasutterella, i.e. Sutterella, was also expanded in T. circumcincta-infected sheep enrolled in our previously published study [vs QIIME2-2020.2 and SILVA v.132 vs v.138) [Sutterella/Parasutterella in T. circumcincta-infected animals might contribute to abomasal inflammation during worm establishment [H. contortus was enriched in Burkholderiales compared with that of resistant animals [. [Burkholderiales that contribute to helminth-associated proinflammatory responses, as well as whether expansion of these bacteria represent cause or consequence of worm establishment, remain to be clarified. Additionally, the Bacteroidales BS11\u00a0gut group genus was expanded in the Vac/Tc+_17 and Vac/Tc+_18 groups. In our previous study [Bacteroidales BS11\u00a0gut group family in faecal samples from both vaccinated/infected and unvaccinated/infected sheep. Bacteria from the Bacteroidales BS11\u00a0gut group are known producers of short-chain fatty acids (SCFAs), which play key roles in gut homeostasis, strengthening of the gut barrier and protection against inflammation [. [T. circumcincta-derived molecules via vaccination might contribute to further expansion of Bacteroidales BS11\u00a0gut group bacteria, a hypothesis that requires thorough testing.Despite the fundamental differences in faecal bacterial taxa expanded upon ed study . Whilst s v.138) , the explishment \u201353; nevelishment , 55. In  animals . Howeverimals [.  was charimals [. . Thus, tus study , we recoammation , 58. Zaiammation  and Li eation [.  have demT. circumcincta. Of these, the genus Prevotella was significantly linked to helminth infection when controlling for differences between trials. This observation is in accordance with data from our previous investigation [H. contortus-infected goats [Prevotella might serve to counteract infection-induced protein loss\u00a0[Teladorsagia infection . Intereus study , the effT. circumcincta infection and/or vaccination. Nevertheless, our findings call for caution when interpreting data generated from in vivo helminth-microbiome interaction studies that may be influenced, amongst others, by factors including sampling site , parasite infective dose, sampling protocols, environmental conditions and diet [in vivo studies of the vertebrate gut microbiome often rely on analyses of faecal samples for both ethical and practical reasons, qualitative and quantitative changes in selected populations of low-abundant bacteria inhabiting proximal sections of the GI system (e.g. the abomasum) might remain undetected and thus overlooked. For small ruminants, the use of in vitro systems  might aAdditional file 1. Mean (\u00b1 standard error) values of (A) abomasal nematode burdens and cumulative faecal egg counts (cFEC) recovered from lambs infected with Teladorsagia circumcincta over the 2017 and 2018 trials, with (Vac/Tc+_17 and Vac/Tc+_18) or without (Adj/Tc+_17 and Tc+_18) prior immunisation.Additional file 2. Gut microbial profiles of lambs enrolled in the 2017 and 2018 trial, respectively, at phylum (A), family (B) and genus (C) level. Plots display the mean relative abundances  of each taxon, whilst tables show mean \u00b1 standard deviation (SD). \u2018Others\u2019 includes all taxa representing < 0.5% (A) or < 1% (B and C) of the whole bacterial population.Additional file 3. (A) Sparse Partial Least Squares (sPLS) regression applied to the faecal microbiota of lambs enrolled in each\u00a02017 and 2018 trial. (B) Top bacterial genera discriminating the faecal microbiota of samples collected in each trial, identified by sPLS-Discriminant Analysis (sPLS-DA).Additional file 4. Longitudinal changes in faecal microbial diversity of lambs experimentally infected with Teladorsagia circumcincta following adjuvant (Adj/Tc+_17) or vaccine (Vac/Tc+_17) administration, and of uninfected controls (Tc-_17), over the course of the 2017 trial. (A) Shannon index for alpha diversity; differences between time points were calculated by Mixed Effect Linear Regression (MELR). (B) ANOSIM plots depicting fluctuations in beta diversity over the course of the trial. Horizontal lines and asterisks indicate statistically significant differences between pairs of time points, calculated by permutational multivariate analysis of variance (PERMANOVA): *q < 0.05; **q < 0.01. ns: no sample available.Additional file 5. Longitudinal changes in differentially abundant microbial taxa (FDR-adjusted q < 0.05) in faeces of unimmunised uninfected lambs enrolled in the 2017 trial.Additional file 6. Faecal microbial profiles of lambs enrolled in the 2017 trial and infected with Teladorsagia circumcincta following adjuvant inoculation (Adj/Tc+_17) or immunisation (Vac/Tc+_17), as well as uninfected controls (Tc-_17), ordinated by Canonical Correspondence Analysis (CCA). Statistical differences between the microbial profiles of each experimental group at each time point post-trickle infection (dpi) are indicated at the top of each plot, whereas asterisks represent statistically significant differences between group pairs: **p < 0.01; ***p < 0.001.Additional file 7. Differences in microbial alpha (A) and beta (B) diversity between experimental groups of lambs enrolled in the 2017 trial. (A) Shannon index  calculated for each experimental group at each time point (dpi) and statistical differences between groups were assessed by ANOVA. (B) Overall and pairwise differences in Bray-Curtis dissimilarity between experimental groups were calculated by ANOSIM at each time point: **p < 0.01; ***p < 0.001. Adj/Tc+_17: lambs infected with Teladorsagia circumcincta following inoculation of the vaccine adjuvant; Vac/Tc+_17: lambs immunised against and subsequently experimentally infected with T. circumcincta; Tc-_17: uninfected lambs; ns: no sample available.Additional file 8. Differentially abudant microbial taxa (CSS+log) in faecal samples of lambs experimentally infected with Teladorsagia circumcincta following adjuvant (Adj/Tc+_17) or vaccine (Vac/Tc+_17) administration vs. uninfected controls (Tc-_17) . Results based on Linear Discriminant Analysis Effect Size (LEfSe)\u2014LDA score (log10) > 2.5.Additional file 9. Sparse Partial Least Squares Discriminant Analysis (sPLS-DA) applied to the faecal microbiota of lambs enrolled in the 2018 trial at 0 days post-trickle\u00a0infection, clustered by experimental group. (A) Comparison between infected (Tc+_18) vs. uninfected (Tc-_18) animals. (B) Comparison between vaccinated (Vac/Tc+_18) vs. uninfected (Tc-_18) animals. For each group pair compared, sPLS regression (left) and top bacterial genera discriminating the faecal microbiota of samples collected from each experimental\u00a0animal, identified by sPLS-Discriminant Analysis (sPLS-DA).Additional file 10. Differences in microbial alpha diversity between faecal samples of lambs infected with Teladorsagia circumcincta, either with (Vac/Tc+_18) or without prior immunisation (Tc+_18), and of uninfected controls (Tc-_18), enrolled in the 2018 trial. Horizontal lines indicate differences between time points: **p < 0.01; ***p < 0.001.Additional file 11. Longitudinal changes in faecal microbial diversity of lambs enrolled in the 2018 trial and infected with Teladorsagia circumcincta, either with (Vac/Tc+_18) or without prior immunisation (Vac/Tc+_18), and of uninfected controls (Tc-_18). (A) Shannon index for alpha diversity; differences between time points were calculated by Mixed Effect Linear Regression (MELR). (B) ANOSIM plots depicting fluctuations in beta diversity over the course of the trial. Horizontal lines and asterisks indicate statistically significant differences between pairs of time points, calculated by permutational multivariate analysis of variance (PERMANOVA): *q < 0.05; **q< 0.01.Additional file 12. Longitudinal changes in differentially abundant microbial taxa (FDR-adjusted q < 0.05) in faeces of unimmunised uninfected lambs enrolled in the 2018 trial.Additional file 13. Faecal microbial profiles of lambs enrolled in the 2018 trial and infected with Teladorsagia circumcincta, either without (Tc+_18) or following prior immunisation (Vac/Tc+_18), as well as uninfected controls (Tc-_18), ordinated by Canonical Correspondence Analysis (CCA). Statistical differences between the microbial profiles of each experimental group at each time point post-trickle infection (dpi) are indicated at the top of each plot, whereas asterisks represent statistically significant differences between group pairs: **p < 0.01; ***p < 0.001.Additional file 14. Differences in faecal microbial alpha (A) and beta (B) diversity between groups of lambs enrolled in the 2018 trial. (A) Shannon index  calculated for each experimental group at each time point and statistically significant differences between groups assessed by ANOVA. (B) Overall and pairwise differences in Bray-Curtis dissimilarity between experimental groups, calculated by ANOSIM at each time point: *p < 0.05; **p< 0.01; ***p < 0.001. Tc+_18: lambs infected with Teladorsagia circumcincta; Vac/Tc+_18: lambs vaccinated against and subsequently infected with T. circumcincta; Tc-_2018: uninfected lambs.Additional file 15. Differentially abundant microbial taxa (CSS+log) between faecal samples of lambs experimentally infected with Teladorsagia circumcincta, solely (Tc+_18) or following experimental vaccination (Vac/Tc+_18), vs. uninfected controls (Tc-_18) . Results based on Linear discriminant analysis Effect Size (LEfSe)\u2014LDA score (log10)\u00a0>\u00a02.5.Additional file 16. Differentially abundant faecal microbial genera (CSS+log) between samples collected at 0 and +19, +47 and +57 days post-infection (dpi) from uninfected animals in the 2018 trial (Tc-_18). Differences assessed by Linear discriminant analysis Effect Size (LEfSe)\u2014LDA score (log10) > 2.5."}
+{"text": "Best Practice Caregiving surveyed 324 healthcare and community organizations that replicated one or more of the 44 evidence-based programs about delivery organization characteristics, delivery staff, caregivers and persons with dementia served, funding sources, delivery challenges, perceived impact, and satisfaction. 211 (65.1%) organizations completed surveys about 30 different evidence-based programs. The most common types of organizations that delivered programs were healthcare organizations (23.8%) and Area Agencies on Aging (23.8%). Results showed on average organizations delivered programs for 49 months and served 68 families/year. The most common program delivery challenges were marketing (69.8%) and engaging participants (66.3%). Organizations generally agreed that programs had positive impacts on caregivers (59.5% strongly agree) but were less positive about benefits for persons with dementia (25.1% strongly agree). Discussion provides insights into successes and challenges organizations face when adopting evidence-based dementia caregiving programs in their communities."}
+{"text": "Guidelines recommends cytomegalovirus (CMV) prophylaxis by CMV serostatus/risk status, as the currently available antiviral agents may lead to myelosuppressive events in kidney transplant recipients (KTRs). Limited data exist for the United States (US) on the such clinical outcomes with CMV prophylaxis KTRs especially stratified by CMV risk strata. We examined the associations between clinical outcomes and CMV prophylaxis among adult KTRs stratified by CMV risk strata. We employed a retrospective cohort design using the US Renal Data System registry-linked Medicare data (2011-2017). The cohort included 22,918 adult KTRs with continuous Medicare Part A & B coverage for \u2265 6-month pre and \u2265 12-month post KT and Part D coverage for \u2265 12-month post- KT. CMV prophylaxis was defined as \u2265 1 prescription fill or medical claim for valacyclovir or valganciclovir at prophylaxis doses within 28 days post-KT. Table 1). CMV infection and myelosuppressive event rates were higher in high-risk than intermediate/low risk KTRs irrespective of CMV prophylaxis status. CMV prophylaxis was utilized by 75% of the cohort. In no CMV prophylaxis group, 52.2% and 34.2% of high and intermediate risk KTRs received valganciclovir (as either pre-emptive or deferred therapy), respectively. Among high risk KTRs, CMV prophylaxis group had significantly lower proportions of KTRs with CMV infection, opportunistic infections (OIs) including bacterial, and fungal infections, and new onset of diabetes mellitus (NODAT) compared to no prophylaxis group. There were no differences in the rates of acute rejection or death; however, a trend towards lower rate of graft-failure at 12-month post-KT. Nearly 40% of high-risk KTRs had myelosuppressive events ; however, their differences were non-significant except for thrombocytopenia by CMV prophylaxis status  Yuexin Tang, PhD, JnJ Merck & Co., Inc."}
+{"text": "This quality improvement study evaluates the association between waste-free formularies and prescription drug spending for 2 large self-insured employers. Employer 1, a large public employer, spends approximately $200 million annually on prescription drugs for more than 300\u2009000 beneficiaries. Employer 2, a publicly traded Fortune 500 company, spends approximately $100 million annually on prescription drugs for more than 60\u2009000 beneficiaries.Both employers hired external pharmacy consultants to perform a drug utilization review, identify wasteful drugs, and implement appropriate substitutions. Employer 1 gradually modified its formulary between January 2017 and December 2018, and employer 2 implemented its waste-free formulary in January 2019. This quality improvement study compared the following before and after waste-free formulary implementation: (1) average prerebate 30-day drug spending for the therapeutic classes targeted and not targeted by the waste-free formularies and (2) annual postrebate PMPM spending for all therapeutic classes.SQUIRE) reporting guideline.This study was exempt from institutional review board approval because it did not meet criteria for human subjects research, in accordance with the Common Rule. The study followed the Standards for Quality Improvement Reporting Excellence  were excluded from the original formularies and replaced with less expensive therapeutic alternatives of the same clinical value. The 14 remaining drugs (5%) were placed under prior authorization or step-therapy requirements. Substituted drugs belonged to 3 categories: multisource products (76 [26%]), me-too products (118 [40%]), and same-class products (85 [29%]) . All 14 Both employers notified beneficiaries who were affected by prescription drug coverage changes 90 days in advance. Employer 2 hired pharmacists to help beneficiaries navigate the transition. During the implementation phase, employer 1 received slightly higher-than-normal beneficiary complaints, whereas employer 2 did not.For the 2 large employers in this study, potentially wasteful drugs constituted a small percentage of all covered drugs (10%-14%) and were concentrated in a few therapeutic classes (3%-9%), but they represented a significant proportion of pharmaceutical claims (17%-29%). Within the targeted therapeutic classes, the prerebate savings surpassed 50%. Overall postrebate PMPM savings were 9% to 15%. To our knowledge, these results provide the first systematic evidence on the cost-saving potential of implementing waste-free formularies. Although approximately 300 drugs were identified as potentially wasteful between the 2 employers in this study, many more such drugs exist. As drug prices fluctuate and new drugs enter the market, the wasteful spending potential of covered drugs should be reassessed periodically.6 Public programs and private insurance plans interested in reducing wasteful prescription drug spending should consider implementing waste-free formularies, facilitated by effective communication and navigation efforts to ensure beneficiary satisfaction. The results of this study, limited by the experience of 2 large employers, may not be generalizable to small employers. Future studies examining clinical outcomes associated with the transition to waste-free formularies are warranted.The finding that the most common substitution among potentially wasteful drugs in the waste-free formulary was me-too drugs (118 [40%]), followed by same-class drugs (85 [29%]), suggests that cost-saving opportunities go beyond generic substitutions of multisource drugs. With effective communication, implementing waste-free formularies may not generate beneficiary dissatisfaction."}
+{"text": "Environmental factors influence older adult physical activity. However, the evidence about which factors lead to increased physical activity is mixed and few have studied how these factors affect those with frailty or living in retirement communities. This study investigated how environmental and weather factors influence physical activity among pre-frail and frail older adults residing in independent living retirement communities. We used ActivPal accelerometers to measure 7-day step counts among (n=108) pre-frail and frail residents in 9 independent living residences in metropolitan Chicago. We conducted environmental audits using the MAPS Abbreviated tool and collected National Weather Service Station data  during the ActivPal periods. Participants were on average 80.0 years, 74% female, and average daily step count was 3,450 . Four buildings were in suburban areas and 5 in urban areas and four were private-pay residences while 5 offered subsidized rent. ANOVA results showed private-pay buildings had higher total MAPS scores than subsidized buildings (p=0.001), and urban buildings had higher total MAPS scores than suburban buildings (p < 0.000). Mean step differences were non-significant between different building types: . Pearson product-moment correlations showed a positive association between steps and MAPS positive streetscape features (p=0.011). Multiple regression analysis showed higher temperature days, precipitation, and more minutes of daylight were associated with higher step counts (p=.04). Given the dramatic variation in individual step counts, future research should investigate personal factors that contribute to activity among independent living residents."}
+{"text": "VEGF-A knockdown (KDVEGF) in diabetic mice and in endothelial nitric oxide synthase knockout mice (\u2212/\u2212eNOS). Diabetes was induced with streptozotocin using the Animal Models of Diabetic Complications Consortium (AMDCC) protocol. Induction of podocyte KDVEGF led to diffuse glomerulosclerosis, foot process effacement, and GBM thickening in both diabetic mice with intact eNOS and in non-diabetic \u2212/\u2212:VEGFKDeNOS mice. KDVEGF diabetic mice developed mild proteinuria and maintained normal glomerular filtration rate (GFR), associated with extremely high NO and thiol urinary excretion. In \u2212/\u2212:VEGFKDeNOS (+dox) mice severe diffuse glomerulosclerosis was associated with microaneurisms, arteriolar hyalinosis, massive proteinuria, and renal failure. Collectively, data indicate that combined podocyte VEGF-A and eNOS deficiency result in diffuse glomerulosclerosis in mice; compensatory NO and thiol generation prevents severe proteinuria and GFR loss in KDVEGF diabetic mice with intact eNOS, whereas KDVEGF induction in \u2212/\u2212:VEGFKDeNOS mice causes massive proteinuria and renal failure mimicking DKD in the absence of diabetes. Mechanistically, we identify KDVEGF-induced abnormal S-nitrosylation of specific proteins, including \u03b23-integrin, laminin, and S-nitrosoglutathione reductase (GSNOR), as targetable molecular mechanisms involved in the development of advanced diffuse glomerulosclerosis and renal failure.Vascular endothelial growth factor-a (VEGF-A) and nitric oxide (NO) are essential for glomerular filtration barrier homeostasis, and are dysregulated in diabetic kidney disease (DKD). While NO availability is consistently low in diabetes, both high and low VEGF-A have been reported in patients with DKD. Here we examined the effect of inducible podocyte  Diabetic kidney disease (DKD) is a major complication of both type 1 and type 2 diabetes that leads to renal failure, and the single most frequent cause of end-stage renal disease (ESRD) worldwide . An incoVEGF-A gain-of-function in diabetic mice leads to the development of Kimmelstiel-Wilson-like nodular glomerulosclerosis and massive proteinuria  and nitric oxide (NO) are essential for glomerular filtration barrier homeostasis, and both are disregulated in diabetic nephropathy . Unlike teinuria . Similare models . Moreovediabetes . These fdiabetes . Endotheult mice . Short tneurisms , and VEGse model .VEGF-A knockdown (KDVEGF) in diabetic mice and in \u2212/\u2212:VEGFKDeNOS mice. We determined that in the setting of NO deficiency, caused either by diabetic milieu or eNOS knockout, KDVEGF results in diffuse glomerulosclerosis and proteinuria, mimicking human diabetic diffuse glomerulosclerosis of increasing severity. This phenotype is linked to the generation of NO and thiol mediated by changes in S-nitrosoglutathione reductase (GSNOR) and \u03b23-integrin S-nitrosylation that impairs their activity.Here we examined the effect of podocyte KDVEGF in eNOS KO mice (\u2212/\u2212:VEGFKDeNOS) by crossbreeding podocin-rtTA:tet-O-siVEGF mice (siVEGF) , and we backcrossed them >8 generations to a stable FVB background. In this study \u2212/\u2212:VEGFKDeNOS mice were fed standard or doxycycline-containing chow (Harlan-Teklad) for 1 month.We generated doxycycline-inducible podocyte (siVEGF)  with eNOeNOS\u2212/\u2212  (eNOS KOsiVEGF mice (KDVEGF) by intraperitoneal streptozotocin (STZ) using the low dose AMDCC  protocol, as previously described (KDVEGF (DM-KDVEGF) and non-diabetic (non-DM-KDVEGF) mice were fed standard (\u2212dox) or doxycycline containing chow (+dox) for 12\u00a0weeks to induce VEGF-A knockdown. At the end of the study 24\u00a0h urine was collected in metabolic cages; blood and kidney samples were obtained under anesthesia, as we previously described , and BP was measured under anesthesia and analyzed using PowerLab/8SP system  as previously described . Plasma Kidneys were processed for light microscopy and TEM or frozen in isopentane, mounted in OCT (Sakura). Histology was assessed by hematoxylin/eosin and periodic acid\u2013Schiff\u2019s reagent (PAS) stains. TEM was performed using standard techniques, as previously described . A renalImmunohistochemistry (IHC) was performed in frozen kidney sections using primary antibodies against laminin, nephrin, podocin, and S-nitroso-cysteine and appropriate Cy2 and Cy3 fluorescent-tagged secondary antibodies (Jackson ImmunoResearch Laboratories), visualized by confocal microscopy , as previously described . QuantitImmunoblotting was performed using the following primary antibodies: podocin , nephrin , laminin , \u03b23-integrin , VEGF receptor 2 ; actin (A2066. Sigma) or tubulin (Sigma) were used as a loading control. Signals were visualized by chemiluminescence, and quantified using ImageJ software .In situ Proximity Link Assays (PLA) were performed to identify specific S-nitrosylated proteins in kidney frozen sections using laminin rabbit polyclonal antibody  or \u03b23-integrin antibody  and S-nitrosocysteine mouse monoclonal antibody (AG Scientific) and Duolink II fluorescence protocol  , as previously described . Ascorba Sweden) , as prev Sweden) .p < 0.05) was determined using Prism 8 software by unpaired t test with Welch\u2019s correction and one-way Brown-Forsythe ANOVA to compare two or multiple experimental groups, respectively. Mann-Whitney test was used to analyze non-parametric variables.Data are expressed as mean \u00b1 SEM unless otherwise stated. Statistical significance (KDVEGF \u2212 dox mice (KDVEGF induction with doxycycline for 12\u00a0weeks prevented the development of glomerular hypertrophy in DM-KDVEGF + dox mice (KDVEGF (+dox) mice (KDVEGF (+dox) revealed diffuse glomerulosclerosis  mice  was simiox) mice , as quanclerosis  with lim\u2212/\u2212:VEGFKDeNOS (\u2212 dox) mice (KDVEGF (+dox) for 4\u00a0weeks in \u2212/\u2212:VEGFKDeNOS mice caused severe diffuse glomerulosclerosis (\u2212/\u2212:VEGFKDeNOS (+dox) mice. Significant tubulo-interstitial damage consisting of tubular atrophy and basement membrane thickening, tubular proteinaceous casts, and interstitial lymphocytic infiltrates were also observed in \u2212/\u2212:VEGFKDeNOS (+dox) (\u2212/\u2212:VEGFKDeNOS (\u2212dox) kidneys (KDVEGF (+dox) kidneys (\u2212/\u2212:VEGFKDeNOS (\u2212dox) kidneys, the severity and extension of the changes observed in \u2212/\u2212:VEGFKDeNOS (+dox) kidneys were obvious as demonstrated by highly significant score differences in all parameters.Glomerular histology was mostly normal in uninduced ox) mice , althougclerosis . Extensiclerosis , whereas (+dox)  but were kidneys  or in di kidneys . A semi-KDVEGF (+dox) mice (\u2212/\u2212:VEGFKDeNOS (\u2212dox) kidneys showed normal glomeruliar filtration barrier ultrastructure (\u2212/\u2212:VEGFKDeNOS mice with podocyte KDVEGF (+dox) revealed extensive foot process effacement, GBM thickening, severe mesangial sclerosis, and endotheliosis (KDVEGF (+dox) kidneys  mice . eNOS\u2212/\u2212tructure . In contheliosis , a more  kidneys .KDVEGF in \u2212/\u2212:VEGFKDeNOS (+dox) and diabetic mice resulted in nephrin downregulation, assessed by immunoblotting and immunohistochemistry (\u2212/\u2212:VEGFKDeNOS and diabetic mice subjected to KDVEGF (+dox) (KDVEGF resulted in \u03b23-integrin upregulation in \u2212/\u2212:VEGFKDeNOS (+dox) kidneys, whereas \u03b23-integrin protein expression was not altered in diabetic mice with intact eNOS  . Podocytact eNOS . Collectact eNOS .KDVEGF in \u2212/\u2212:VEGFKDeNOS (+dox) mice caused massive albuminuria >30-fold higher than that measured in uninduced genetically identical mice \u2212/\u2212:VEGFKDeNOS (\u2212dox), (\u2212/\u2212eNOS mice (data not shown). In contrast, mice with intact eNOS developed mild proteinuria when podocyte KDVEGF (+dox) was induced  mice , as reported in KDVEGF mice with intact eNOS  mice (KDVEGF) or intact eNOS (KDVEGF)  mice , red barVEGF-A and urinary excretion are similarly elevated in \u2212/\u2212:VEGFKDeNOS mice, irrespective of podocyte KDVEGF  than in non-diabetic mice (white bar), but KDVEGF did not significantly decrease plasma NO in any experimental group  in diabetic mice, irrespective of podocyte KDVEGF  and in DM-KDVEGF (+dox) kidneys, as detected by biotin-shift assay (BST) (\u2212/\u2212:VEGFKDeNOS \u2212 dox) or intact eNOS (KDVEGF \u2212 dox), but increased \u223c2.5 fold when KDVEGF was induced in \u2212/\u2212:VEGFKDeNOS (+ dox) mice (KDVEGF (DM-KDVEGF \u2212dox or + dox), than in non-diabetic mice (\u2212/\u2212:VEGFKDeNOS \u2212 dox or KDVEGF \u2212 dox) (\u2212/\u2212:VEGFKDeNOS (+ dox) mice and \u223c5-fold in diabetic DM-KDVEGF mice than in non-diabetic mice (S-nitrosoglutathione (GSNO) is the major source of cellular NO not generated by NOS . GSNO rediabetes . In contay (BST) , This SNox) mice . In cont \u2212 dox) . Urine Gtic mice . The remKDVEGF (+dox) alters S-nitrosylation of glomerular proteins in \u2212/\u2212:VEGFKDeNOS mice. Using immunohistochemistry we determined that S-nitrosylated proteins localized to glomeruli are significantly increased in \u2212/\u2212:VEGFKDeNOS kidneys with KDVEGF (+dox) as compared to uninduced \u2212/\u2212:VEGFKDeNOS (\u2212 dox) kidneys . Glomerular laminin S-nitrosylation (SNO-laminin) was increased significantly in \u2212/\u2212:VEGFKDeNOS mice with KDVEGF (+dox) as compared to uninduced \u2212/\u2212:VEGFKDeNOS (\u2212 dox) mice (\u2212/\u2212:VEGFKDeNOS (+ dox) mice .Specific S-nitrosylated proteins were detected ox) mice . Consistin situ PLA we detected \u03b23-integrin S-nitrosylation in glomeruli (\u2212/\u2212:VEGFKDeNOS (+dox) kidneys as compared to uninduced \u2212/\u2212:VEGFKDeNOS (\u2212dox) kidneys (\u2212/\u2212:VEGFKDeNOS (+dox) mice, a phenotype that mimics human advanced DKD with low VEGF.Next, we examined \u03b23-integrin, a transmembrane protein critically involved in maintaining glomerular filtration barrier integrity , whose alomeruli . Quantit kidneys . CollecteNOS knockout, podocyte VEGF-A knockdown results in diffuse glomerulosclerosis and proteinuria of increasing severity, leading to renal failure in \u2212/\u2212:VEGFKDeNOS mice. We show that podocyte KDVEGF and \u2212/\u2212eNOS induce severe diffuse glomerulosclerosis in the absence of diabetic milieu. Podocyte KDVEGF in diabetic mice prevents diabetes-induced glomerulomegaly but causes diabetic diffuse glomerulosclerosis. Mechanistically, we show that compensatory local NO and thiols generation prevent severe proteinuria and GFR loss in diabetic mice with intact eNOS, and we identify abnormal S-nitrosylation of specific proteins, including GSNOR, laminin, and \u03b23-integrin, as novel molecular pathways potentially involved in advanced diffuse glomerulosclerosis.This study demonstrates that in the setting of bioavailable NO deficiency, caused by diabetic milieu or by KDVEGF abrogates VEGF-A-mediated glomerular hypertrophy, leading to diffuse glomerulosclerosis with modest albuminuria and normal creatinine clearance. In contrast, \u2212/\u2212:VEGFKDeNOS mice have a decreased ability to increase NO when podocyte KDVEGF is induced, despite similarly elevated circulating VEGF-A, thereby becoming more susceptible than diabetic mice to deleterious effects of local KDVEGF, resulting in mesangiolysis, extensive podocyte foot process effacement, GBM thickening, and a notably severe diffuse glomerulosclerosis phenotype reminiscent of advanced diabetic diffuse glomerulosclerosis  and leading to renal failure, consistent with the more severe morphologic phenotype.High circulating VEGF-A in diabetic mice stimulates NOS leading to NO production, protecting the integrity of the glomerular endothelium and attenuating functional abnormalities of the glomerular filtration barrier . VEGF-A clerosis . MoreoveVEGF knockdown results in decreased glomerular size in non-diabetic mice . This phenotype is partially similar to that described in diabetic VEGF-A knockout mice  mice is associated with increased S-nitrosylation of glomerular proteins. As opposed to loss of laminin S-nitrosylation in the setting of excess VEGF-A (VEGF-A knockdown increased laminin S-nitrosylation in \u2212/\u2212:VEGFKDeNOS (+dox) mice associates with severe diffuse glomerulosclerosis, suggesting that laminin nitrosylation might prevent the development of glomerular nodules, probably by regulating the secretion or polymerization of 521-laminin heterotrimers  and diabetic KDVEGF (+ dox) mice. Consistent with GSNOR de-nitrosylation, we detected several fold increase in urine NO, GSH-, and Cys-thiols excretion in \u2212/\u2212:VEGFKDeNOS (+dox) and DM-KDVEGF (+dox) diabetic mice. The precise cellular origin of urine NO and thiols  remains to be determined. We posit that GSNOR de-nitrosylation underlies the compensatory mechanism providing an alternative NO source in diabetic and \u2212/\u2212:VEGFKDeNOS (+dox) mice (KDVEGF (+dox) mice, but does not prevent the development of diffuse glomerulosclerosis. The SNO-GSNOR mediated alternate source of NO supports renal function in \u2212/\u2212:VEGFKDeNOS (\u2212 dox) mice, but it fails to do so when podocyte KDVEGF is induced (+ dox), leading to massive proteinuria and renal failure, as well as severe diffuse glomerulosclerosis, suggesting incomplete compensation or an additional KDVEGF related pathway, including iNOS activation, which we have not evaluated. GSNOR function is influenced by subcellular localization and modulated by VEGF and NOS signaling  mice . This coignaling .KDVEGF increases \u03b23-integrin S-nitrosylation in \u2212/\u2212eNOS glomeruli might be linked to diffuse glomerulosclerosis. Laminin-521, the mature GBM laminin, binds \u03b1v\u03b23-integrin through interaction between \u03b15-laminin and \u03b23-integrin, transducing FGF and VEGF signals (KDVEGF decreases \u03b1v\u03b23-integrin activity in non-diabetic kidneys and cultured podocytes (KDVEGF increases glomerular \u03b23-integrin S-nitrosylation in \u2212/\u2212:VEGFKDeNOS (+dox) mice, likely decreasing \u03b23-integrin signaling. Decreased \u03b23-integrin inside-out activation disrupts nephrin-VEGFR2-\u03b23 integrin signaling in podocytes (\u2212/\u2212:VEGFKDeNOS (+ dox) mice.  mice. . Whetherx) mice.  and incrx) mice.  \u03b23-integx) mice.  probablyx) mice. . Thus, w failure .Collectively, these findings suggest that S-nitrosylation contributes to the tight regulation of glomerular homeostasis by modulating several important signaling pathways in DKD models. Our findings support a model whereby laminin S-nitrosylation is instrumental to prevent glomerular nodule development, while GSNOR denitrosylation and increased \u03b23-integrin S-nitrosylation lead to diffuse glomerulosclerosis in the setting of low podocyte VEGF-A.\u2212/\u2212:VEGFKDeNOS mice, perform a broad molecular phenotyping, confirm in cultured glomerular cell types the S-nitrosylation abnormalities identified in \u2212/\u2212:VEGFKDeNOS + dox kidneys and assess SNO-protein dysregulation in diabetic mice. Such additional studies will provide insight into how S-nitrosylation modulates several signaling pathways that are critical for glomerular homeostasis in DKD.Further studies are needed to address several limitations of this study: evaluate diabetic KDVEGF in \u2212/\u2212:VEGFKDeNOS mice causes renal failure, massive proteinuria, and severe diffuse glomerulosclerosis in the absence of diabetes. KDVEGF in diabetic mice with intact eNOS prevents diabetes-induced glomerulomegaly, causes diabetic diffuse glomerulosclerosis, and compensatory NO generation attenuates proteinuria and prevents GFR loss. Together, these models are reminiscent of human DKD phenotypes associated with low VEGF-A expression (KDVEGF in \u2212/\u2212:VEGFKDeNOS mice induces increased glomerular \u03b23-integrin S-nitrosylation, likely disrupting nephrin-VEGFR2-\u03b23-integrin signaling (In summary, pression . Mechaniignaling . Our obs"}
+{"text": "Selinexor, an oral selective inhibitor of nuclear export (SINE), was demonstrated to hinder the DNA damage repair (DDR) system by reducing DDR proteins while enhancing the killing of cancer cells by DDR-based therapeutics in vivo studies. In this single-center, multi-arm phase 1b study, selinexor with carboplatin, doxorubicin and cyclophosphamide (DC), irinotecan with fluorouracil and folinic acid (FOLFIRI), irinotecan, and capecitabine and oxaliplatin (XELOX), were employed as separate parallel arms. Eligible patients have relapsed/ metastatic refractory solid tumors following standard therapy or addition of selinexor to systemic therapy was appropriate. Nineteen patients were treated in the 5 arms. Tumor types included were colorectal (n\u2009 =\u20093), breast (n\u2009 =\u20093), neuroendocrine (n\u2009 =\u20092), ovarian (n\u2009 =\u20092), and pancreas cancers (n\u2009 =\u20092). All patients developed one treatment-related adverse events (TRAE). The most prevalent TRAE were thrombocytopenia (84%), nausea (68%), leukopenia (68%), neutropenia (63%), and fatigue (58%). The common grade 3/4 TRAE were neutropenia (42%), leukopenia (26%), and hyponatremia (21%). Three patients had dose-limiting toxicities (DLT) in 3 separate arms. Fourteen patients were evaluable for response. Although no patients achieved complete or partial response (CR or PR), seven patients attained stable disease (SD). Disease control rate (DCR) was 14%. The combination of oral selinexor with different standard chemotherapies showed limited clinical activity despite toxicity and DLT prevented further dose escalation. Optimizing supportive care, the utility of growth factors, and aggressive measures on antiemetics strategies remain tangible.Trial registration ClinicalTrials.gov Identifier: NCT02419495. Registered 14 April 2015, https://clinicaltrials.gov/ct2/show/NCT02419495). Sponsor(s): Karyopharm TherapeuticsThe online version contains supplementary material available at 10.1186/s40164-021-00251-0. To the editor,Selinexor KPT-330) is an oral selective inhibitor of nuclear export (SINE) and was shown to hinder the DNA damage repair (DDR) system by diminishing DDR proteins expression while enhancing the killing of cancer cells by DDR-based therapeutics in vivo preclinical models \u20133. Previ30 is an Eligible patients were adult (age \u2009\u2265\u200918\u00a0years) patients with histologically documented, relapsed/metastatic refractory solid tumors following standard therapy or adding selinexor to systemic therapy was appropriate. The primary aim was to evaluate the safety and tolerability of selinexor when given in combination with different standard chemotherapies and the secondary aim was to determine the preliminary antitumor activity .Nineteen patients with relapsed/refractory solid tumors were enrolled between July 2015 and January 2017. The demographic and clinical characteristics of all patients enrolled are summarized in Table All patients enrolled had measurable disease, but 5 patients had not completed their first restaging scans due to earlier withdrawal of consent and toxicity. Fourteen patients were considered efficacy evaluable patients  in all grades of severity. Figure S1. Waterfall plot of maximum change in tumor measurements (per RECIST v1.1) for evaluable patients. Figure S2. Kaplan-Meier plot showing progression-free survival (PFS) and overall survival (OS) for all treated patients."}
+{"text": "OBJECTIVES/GOALS: Estrogen monotherapy in postmenopausal women can reduce kidney function, while dual therapy combining estrogen with a progestin improves renal health. Using the female Long Evans rat as a novel animal model of postmenopausal cardiovascular disease, we found similar results where estrogen worsens renal health while co-administration of medroxyprogesterone acetate (MPA) was protective. MPA cross-activates glucocorticoid receptors (GR), which are targeted clinically for their anti-inflammatory actions. Therefore, our goal was to determine if estrogen monotherapy induces renal damage by increasing inflammation, while dual therapy with MPA opposes inflammation by cross-activating GR. METHODS/STUDY POPULATION: Female Long Evans rats underwent OVX at 11 months of age and received a subcutaneous implant containing E2, E2+MPA or vehicle for 40 days. RESULTS/ANTICIPATED RESULTS: Coadministration of MPA prevented the E2-induced increase in proteinuria  and decline in glomerular filtration rate . Co-administration of MPA significantly increased renal GR transcript levels compared with E2 alone . Inflammatory marker COX 2 renal transcript levels were significantly reduced by a similar degree in both mono and dual therapies compared with vehicle . Neither TNF-alpha and IL-6 mRNA nor urinary beta-microglobulin levels  were altered. DISCUSSION/SIGNIFICANCE OF IMPACT: Our results show that the effect of E2 on renal pro-inflammatory markers was not altered by the addition of MPA despite the significant increase in renal GR levels. Therefore, the renoprotective effects of MPA in midlife hormone therapy may be independent of renal GR-mediated changes in the immune profile."}
+{"text": "Scientific Reports 10.1038/s41598-021-85328-w, published online 05 April 2021Correction to: The original version of this Article contained an error in the Funding section.\u201cNo funding for this manuscript.\u201dnow reads:\u201cThis work was partially funded by the Ruth L. Kirschstein National Research Service Award (NRSA) Individual Fellowship F30CA250254 (AL).\u201dThe original Article has been corrected."}
+{"text": "NF2 mutated tumours harbouring recurrent mutations in genes including TRAF7, KLF4, AKT1 and SMO. Here, we aim to identify novel biomarkers and therapeutic targets of genetically stratified low-grade meningioma by characterising the proteomic landscape.Meningioma are the most common primary intracranial tumour. According to WHO, ~80% tumours are benign grade I. Although, some grade I tumour clinically show aggressive behaviour. Radio-surgery are the main therapeutic approaches, chemotherapies are ineffective. Accurate biomarkers for clinical management are lacking. The mutational profile of low-grade meningioma is well-defined, with non-AKT1E17K/TRAF7, KLF4K409Q/TRAF7 and NF2-/-. Proteins were separated by SDS-PAGE followed by in-gel tryptic digestion and sample preparation for LC-MS/MS analysis. Raw mass spectrometry data files were processed by MaxQuant and Perseus software. Quantitative phospho-proteomics was performed using TMT-10plex labelling approach followed by motif analysis using motif-X algorithm. GO enrichment analyses were performed using DAVID against all human proteins.Meningioma specimens were stratified according to mutational background: n=31). Hierarchical clustering analysis showed distinct proteomic profiles of mutational subgroups revealing clusters of differentially expressed proteins (DEPs). Comparative analysis showed 10 proteins were commonly significantly upregulated  among all mutational subtypes vs. normal meninges, indicating proteomic landscapes of mutational subtypes to be highly variable. In contrast, 257 proteins were commonly significantly downregulated  and enriched with molecular functions including aldehyde dehydrogenase and oxido-reductase. Mutational subtype-specific analysis identified 162 proteins significantly upregulated in AKT1E17K/TRAF7 vs. remaining sample groups to be enriched in the oxidative phosphorylation pathway. Lastly, analyses of 6600 phospho-sites (n=8) predicted regulatory kinases including EGFR and PKC\u03b1. Several of these up-regulated proteins and kinases already verified via WB. Further validation and functional verification will allow us to identify potential drug targets/biomarkers for meningioma.We have quantified 4162 proteins across all mutational meningioma subgroups and normal meninges ("}
+{"text": "OsSAHs) and verified their roles in SA metabolism and disease resistance. Recombinant OsSAH proteins catalyzed SA in vitro, while OsSAH3 protein showed only SA 5-hydroxylase (SA5H) activity, which was remarkably higher than that of other OsSAHs that presented both SA3H and SA5H activities. Amino acid substitutions revealed that three amino acids in the binding pocket affected SAH enzyme activity and/or specificity. Knockout OsSAH2 and OsSAH3 (sahKO) genes conferred enhanced resistance to both hemibiotrophic and necrotrophic pathogens, whereas overexpression of each OsSAH gene increased susceptibility to the pathogens. sahKO mutants showed increased SA and jasmonate levels compared to those of the wild type and OsSAH-overexpressing plants. Analysis of the OsSAH3 promoter indicated that its induction was mainly restricted around Magnaporthe oryzae infection sites. Taken together, our findings indicate that SA plays a vital role in immune signaling. Moreover, fine-tuning SA homeostasis through suppression of SA metabolism is an effective approach in studying broad-spectrum disease resistance in rice.Rice plants contain high basal levels of salicylic acid (SA), but some of their functions remain elusive. To elucidate the importance of SA homeostasis in rice immunity, we characterized four rice SA hydroxylase genes ( Plants have a sophisticated defense system against pathogen invasion. A general defense is the pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI), initiated by the recognition of PAMPs via pattern recognition receptors (PRRs) . ConversArabidopsis genome contains two ICS genes, responsible for 90% of SA synthesis under stimulation by pathogen challenge or UV radiation 6, 0.5 mM K4Fe[CN]6, 10 mM EDTA-2Na, 0.1% Triton X-100, 0.5 mg/mL X-gluc) for a designated time.GUS (beta-glucuronidase) staining was performed in the staining buffer . The relative transcript levels were quantified using SYBR Green PCR Master Mix (Takara) and normalized to OsUBQ. The relative expression level of each gene was analyzed using the delta-delta Ct method. Gene-specific primers used in qRT-PCR are listed in After removing possible DNA contaminations, two micrograms of total RNA were reverse transcribed with random hexamers and oligo(dT)OsSAH genes and revealed three amino acids affecting the enzyme hydroxylation activity and product specificity. Knockout of OsSAH genes increased SA homeostasis at an elevated level, and jasmonate content, conferring broad-spectrum disease resistance against both hemibiotrophic and necrotrophic pathogens. Our findings indicate that SA plays a crucial role in the rice immune signaling pathway.We showed the expression patterns of the four"}
+{"text": "Correction to: BMC Infect Dis 21, 338 (2021)https://doi.org/10.1186/s12879-021-06023-9In the original publication of this article  there waIncorrectp\u2009<\u20090.001), while Hispanic respondents were more willing than White respondents . Females were less likely than makes .Most respondents were willing to get the vaccine for themselves (75%) or their children (73%). Notably, Black respondents were less willing than White respondents , while Hispanic respondents were more willing than White respondents . Females were less likely than males .Most respondents were willing to get the vaccine for themselves (75%) or their children (73%). Notably, Black respondents were less willing than White respondents (47% vs. 79%,"}
+{"text": "Porcisia hertigi is a parasitic kinetoplastid first isolated from porcupines (Coendou rothschildi) in central Panama in 1965. We present the complete genome sequence of P. hertigi, isolate C119, strain LV43, sequenced using combined short- and long-read technologies. This complete genome sequence will contribute to our knowledge of the parasitic genus Porcisia. Porcisia hertigi was discovered in Central Panama (Coendou rothschildi) and later in Costa Rica , isolated from a porcupine in Panama in 1965. This new complete genome sequence will contribute to our understanding of the evolution of both the genus Porcisia and the subfamily Leishmaniinae.l Panama  in porcusta Rica . InitialPorcisia , within maniinae . To datea deanei  (strain in vitro culture system previously developed for Leishmania (Mundinia) orientalis axenic amastigotes  BGI  for DNBSEQ libraries, producing paired-end reads (270\u2009bp and 500\u2009bp) using the Illumina HiSeq platform, and (ii) Aberystwyth University  for TruSeq Nano DNA libraries, producing paired-end reads (300\u2009bp) using the Illumina MiSeq platform. We performed long-read library preparation and sequencing according to the Nanopore protocol (SQK-LSK109) on R9 flow cells (FLO-MIN106). The read quality was assessed using MultiQC (Leishmania major strain Friedlin genome (GenBank accession number GCA_000002725.2)   as a refhttps://github.com/hatimalmutairi/LGAAP), including the software versions and parameters used . We carried out functional annotation and prediction using the MAKER2 (We assessed the assembly completeness using BUSCO , with the MAKER2  annotatie MAKER2  gene preGCA_017918235.1. The master record for the whole-genome sequencing project is available at JAFJZO000000000.1. The raw sequence reads are available under BioProject accession number PRJNA691541.The assembly and annotations are available under GenBank assembly accession number"}
+{"text": "G12Cmutated NSCLC as well as be helpful to develop demographic subsets to predict targeted therapies and prognosis of lung cancer patients.The Kirsten rat sarcoma virus transforming protein (KRAS) mutations  and genomically drive nearly one-third of lung carcinomas. These mutations have complex functions in tumorigenesis, and influence the tumor response to chemotherapy and tyrosine kinase inhibitors resulting in a poorer patient prognosis. Recent attempts using targeted therapies against KRAS alone have met with little success. The existence of specific subsets of lung cancer based on KRAS mutations and coexisting mutations are suggested. Their interactions need further elaboration before newer promising targeted therapies for KRAS mutant lung cancers can be used as earlier lines of therapy. We summarize the existing knowledge of KRAS mutations and their coexisting mutations that is relevant to lung cancer treatment, in this review. We elaborate on the prognostic impact of clinical and pathologic characteristics of lung cancer patients associated with KRAS mutations. We briefly review the currently available techniques for KRAS mutation detection on biopsy and cytology samples. Finally, we discuss the new therapeutic strategies for targeting KRAS-mutant non-small cell lung cancer (NSCLC). These may herald a new era in the treatment of KRAS Lung cancer is the leading cause of cancer-related deaths among males worldwide . It accoIn lung adenocarcinomas, comprehensive molecular profiling has identified significant mutations in eighteen genes , includiPatients with newly diagnosed lung adenocarcinoma commonly undergo sequential molecular testing . They then undergo treatment with EGFR tyrosine kinase inhibitors- erlotinib, gefitinib, etc) and ALK/ROS1 TKIs  .KRAS mutKRAS mutations predominantly occur in codon 12, 13 in lung cancer. Codons 10, 61 and 146 are much less frequently mutated. The prevalence of KRAS mutations in early and advanced stage LADCs is similar . A heterLKB1/STK11co-mutations result in infiltration of neutrophils, leading to a pro-inflammatory cytokine milieu [Molecular heterogeneity is observed in up to one-third of KRAS-mutant lung cancers and defines their chemotherapy response, tissue spread and prognosis . The co-e milieu , 23.  PI3e milieu \u201360. These milieu  , TP53 alterations (KP), CDKN2A/CDKN2B (KC). These biologically distinct subsets have unique intracellular signaling patterns and are susceptible to different therapeutic strategies . KRAS alThe RAS family of protooncogenes includes three isoforms; Kirsten rat sarcoma virus oncogene (KRAS) (chromosome 12p12.1), Harvey rat sarcoma virus (HRAS) (11p15.5), Neuroblastoma Ras sarcoma virus (NRAS) (1p13.1) . KRAS  [G12V, 20\u201322%) [G12D or KRASG13D) are characterized by substitution of glycine with aspartate [G12A,7%) or glycine-arginine  are least frequent.KRAS mutations are heterogeneous in their frequency and spectrum in lung cancer and mainly show mutations in codons-12 89%), 13 (9%), and 61 (1%) . 40\u201360%) . In this 40\u201360%) . (ii) G\u2009 20\u201322%) , 88.  G\u2009Regardless of the site of mutation, RAS point mutations lock the mutant RAS into the GTP-bound oncogenic state, encoding oncoproteins, KRAS4A and KRAS4B . ResultiThus RAS oncogenic mutations not only contribute to cancer phenotype, progression and prognosis but are also indicative of their specific downstream signaling pathways Table\u00a0. For eg.The molecular methods of detecting oncogenic KRAS on clinical samples include: nucleic acid sequencing (Sanger/di-deoxy) , pyroseqSanger/dideoxy DNA sequencing method is the gold standard to detect KRAS mutations  and theiWhole exome sequencing (WES) identifies the disease causing variations in protein coding regions of mutated exons in tumor DNA as compared to normal DNA , 62, 108This sensitive DNA extension sequencing assay can detect <\u20095% mutant KRAS alleles among wild-type alleles. It measures the release of pyrophosphate moieties during the incorporation of a specific nucleotide into the synthesized DNA. By using the resulting program, the specific nucleic acid sequence for the target region can be detected . PyroseqPCR methods and high resolution melting curve assays provide a cost-effective, sensitive and reliable mutation analysis using low amounts of DNA . They caThis common laboratory method characterizes simple genetic variants such as point mutations. It utilizes allele-specific PCR-based K-RAS kits, to detect mutations in KRAS codons 12,13 etc., . In this method, the targeted alleles are amplified by amplification refractory mutation system (ARMS) and amplification products are detected with Scorpion probes . A fluorThis multiplexed single nucleotide probe extension assay detects point mutations from very small quantity of DNA . These iSSCP is a simple and sensitive assay for detection of SNP, based on the conformation of the single-stranded DNA (ssDNA). Any change in base pairs causes conformational change of the ssDNA and shifts DNA migration under non-denaturing electrophoresis conditions. The separated-out DNA bands are then visualized by incorporating radio-isotopes/ fluorescent dyes/ capillary-based or silver staining . SSCP anDGGE is another screening method. It separates the PCR products based on sequence differences and the DNA differential denaturing characteristics. In this denaturing gradient gel electrophoresis, PCR products migrate through increasingly higher concentrations of chemical denaturant in the polyacrylamide gel. This results in denaturation of the weaker melting domains of the double-stranded PCR product first and their separation .The KRAS mutated lung cancers are driven by sustained KRAS expression and signaling. These cancers are commonly associated with resistance to therapy and poor prognosis . They arKRAS protein requires membrane localization to become biologically active. Therefore, impairment of KRAS localization can serve as potential target for KRAS-mutant cancers . For memRAF, MEK, PI3K, mTOR are some of the downstream effectors of KRAS signaling. Their inhibitors are used as single agents or as combination therapy for treatment of lung cancer. The single agent therapies available for KRAS mutated LADCs are; BRAF inhibitor (Sorafenib) , MEK inhINK4A, p15INK4B, p18INK4C and p19INK4D, cause KRAS mutated lung cells to undergo senescence and prevent tumor growth128 (iii) TANK-binding kinase 1 (TBK1), serine-threonine kinase STK33 and polo-like kinase 1(PLK1) are other potential synthetic lethal therapeutic targets that have been identified in cell lines [The KRAS synthetic lethality approach involves the selective killing of KRAS mutated cancer cells by inhibition of a second protein. In every case, the interactions between mutated KRAS and other proteins on which KRAS mutated cancer cells have become dependent need to be identified first . Then thll lines \u201381. SomeG12C inhibitor therapy for lung cancer [RAS has been perceived to be \u201cundruggable\u201d due to its lack of deep pockets for binding of small molecule inhibitors. However, recent studies have shown some success in the direct inhibition of RAS , 133. Ththerascreen\u00ae KRAS RGQ PCR kit (tissue) and the Guardant360\u00ae CDx (plasma) as companion diagnostics. They have recommended that the tumor tissue should be tested if no mutation is detected in plasma specimen. Previously in the clinical trial of sotorasib conducted by Hong et al., 2020 a confirmed objective response in 32.2% patients and disease control (stable disease) in 88.1% NSCLC patients [G12C mutation that has shown promising activity [The Ras GTPase family inhibitor, sotorasib has recently been approved by US-FDA for treatment of KRAS mutated locally advanced or metastatic solid tumours  . Simultapatients  was obseactivity .G12C inhibitors have been identified [However, the mechanisms of acquired resistance to these therapies are currently unknown. Using in vitro deep mutational screening methods diverse genomic and histologic mechanisms imparting resistance to KRASentified . These aentified G12C and KRASG12D codon subtypes [KRAS mutant lung cancers have an immune resistant microenvironment. The immune resistance is caused by smoking that induces T-cell influx and PD-L1 expression by cancer cells and tumor infiltrating lymphocytes (TILs) . PD-L1 psubtypes . Identifsubtypes .Cancer cells harboring KRAS mutation show up-regulation of rate-limiting enzymes, shift of cancer cell metabolism toward anabolic pathways resulting in increased cancer cell growth. Therefore, recent studies are focusing on mutant KRAS-driven metabolic rewiring, including; (i) upregulation of enzymes involved in amino acid, fatty acid or nucleotide biosynthesis. Glucose and glutamine metabolism,(ii) deregulation of scavenging cellular pathways  , (iii) PThe KRAS driven lung cancers can be categorized into different subsets . This categorization is based on tumour histology, type of KRAS mutation (transversions/transitions) and presence of co-existing significant mutations in nearly eighteen genes identified so far. KRAS mutations have heterogeneous spectrum in lung cancer- transversions (80%)/ transitions (20%). KRAS mutations correlate with histology: transversions, more frequently develop adenocarcinoma while transitions more frequently have squamous cell carcinoma. These biologically distinct subsets have unique intracellular signaling patterns and are susceptible to different therapeutic strategies. Thus these subsets can be used to predict new targeted therapeutic strategies and improve the prognosis of lung cancer patients.A variety of molecular methods are now available for detecting oncogenic KRAS in clinical samples. These entail complete molecular profiling of each patient and identification of KRAS mutations and coexisting mutations. The biggest limiting factors in analysis are; small biopsy size, limited amount of DNA and intrinsic KRAS heterozygous status of tumors.G12C) mutation is the commonest in lung adenocarcinomas. Presently, there is renewed interest in therapeutic strategies inhibiting the functional output of mutated KRAS. Direct KRASG12C inhibitor therapy and immunotherapy with immune checkpoint inhibitors are being considered as one of the most promising treatment approaches. These may prove to be a step forward in personalized therapy and in improving prognosis of lung cancer patients.The G\u2009\u2192\u2009T transversion, in the first base of codon 12 (KRAS"}
+{"text": "Dear Editors,Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally, and the World Health Organization declared a pandemic on March 11, 2020. A widespread health emergency with social and economic disruptions remains in effect worldwide. Vaccination against SARS-CoV-2 is therefore an essential tool to control the global COVID-19 pandemic.Pioneering studies on vaccines against SARS-CoV-2 have verified their safety and efficacy in general populations . HoweverWe aimed to evaluate antibody response after the second dose of BNT162b2 mRNA vaccine (Pfizer/BioNTech). We measured IgG antibody titers to the S receptor-binding domain (RBD) in liver transplant recipients and healthy controls who had received two doses of BNT162b2 mRNA vaccine. We also analyzed how immunosuppressant regimens affected antibody responses.We included individuals who had received the second dose of BNT162b2 mRNA COVID-19 vaccine between March and August 2021. This study included 56 liver transplant patients and 42 healthy controls at Matsunami General Hospital. Blood was collected at least 14\u00a0days after the second vaccination. RBD-IgG titers were measured using the SARS-CoV-2 S-IgG (IC) Assay Reagent assay kit . Titers greater than 1.0 arbitrary units (AU)/mL were considered positive . This study conforms to the principles outlined in the 1975 Declaration of Helsinki and its later amendments. The study protocol was approved by the Ethics Committee of Matsunami General Hospital .n = 43) and 23.2% females (n = 13). None of participants had a prior polymerase chain reaction\u2013confirmed diagnosis of COVID-19, hospitalization and death between March, 2021 and September, 2021. Liver transplant recipients showed significantly decreased antibody titers as compared with healthy controls (p = 0.008). Median time between liver transplantation and BNT162b2 vaccination was 15.5\u00a0years. Calcineurin inhibitor-based immunosuppressive therapy was used in 91.1% (n = 51), mycophenolate mofetil in 58.9% (n = 33), steroids in 1.8% (n = 1), and mTOR inhibitors in 1.8% (n = 1) among liver transplant recipients.RBD-IgG antibody titers were measured in 56 liver transplant recipients. The median age of liver transplant recipients was 65.0\u00a0years, comprising 76.8% males (controls . Liver tp = 0.001), whereas the seroconversion rate was higher in recipients taking calcineurin inhibitor  than in those not taking calcineurin inhibitor .The overall seroconversion rate after the second vaccination was 86.7% in study participants. Liver transplant recipients showed a lower seroconversion rate  than healthy controls . The seroconversion rate was lower in recipients taking mycophenolate mofetil  than in those not taking mycophenolate mofetil .p for effect = 0.008, p for non-linearity = 0.24).A restricted cubic spline plot  shows thOur findings in liver transplant recipients confirmed suboptimal immunogenicity after the second dose of BNT162b2 vaccine, supporting findings from other studies of kidney transplant recipients , allogenThe seroconversion rate was as low as 63.6% (21/33) in patients taking mycophenolate mofetil. Even in patients with confirmed seroconversion, antibody levels were low, suggesting that the threshold for protective immunity had not been reached. Restricted cubic spline modeling also verified a linear dose-response relationship between mycophenolate mofetil dose and reduced antibody titers in our study. Reduced antibody responses among organ transplant recipients, including liver transplant recipients, suggest that these recipients may remain at high risk of COVID-19 even after the second and third doses of mRNA vaccine.Our findings have clinical implications for liver transplant recipients, emphasizing the need to consider a fourth dose of vaccination and the assessment of antibody titers even after the third dose of vaccination. Although a third vaccine dose was well tolerated by solid organ transplant recipients who had an insufficient antibody response after two dose of vaccination, the serological response was heterogeneous and a large proportion of recipients remain at risk for COVID-19 , 9. ApprLongevity of the antibody titer and the optimal period of monitoring antibody titers are still unveiled. Further longitudinal studies are warranted to investigate how cellular immune responses will be maintained or whether waning antibody titers still provide protection from breakthrough infections in transplant recipients with larger participants.In conclusion, we have revealed mycophenolate mofetil contributed the attenuated antibody acquisition against SARS-CoV-2 among liver transplant recipients with dose-dependent manner. For populations that prove unlikely to acquire antibodies, active measurement of RBD-IgG antibodies may be warranted to assess protective immunity against COVID-19 and the need for additional vaccination."}
+{"text": "The patient experienced intermittent fever, fatigue, and weight loss, but no cough, breathlessness, abdominal pain, or diarrhea. Physical examination revealed multiple plaques and nodular lesions with raised edges and a central crust . Abdominal ultrasonography showed splenomegaly (spleen length=15.9 cm). Skin biopsy revealed abundant fungal spores highlighted by positive periodic acid-Schiff (PAS) and Grocott's methenamine silver (GMS) stains . His blood culture revealed growth of Talaromyces marneffei, and hyphae were visualized on Gram stain. The skin lesions improved following treatment with intravenous amphotericin B for two weeks, followed by oral itraconazole as consolidation and maintenance therapy. Antiretroviral therapy and antifungal therapy were initiated.A 25-year-old man with newly diagnosed human immunodeficiency virus (HIV) infection (CD4 count = 53 cells/mml crust . Abdomi stains . His blTalaromyces marneffei endemic in Southeast Asia and the southern part of China3,Talaromycosis is a deep fungal infection caused by"}
+{"text": "A length of stay (LOS) of one day per percent total body surface area (TBSA) burn has been widely accepted in clinical practice but not validated in current pediatric burn studies. Additionally, TBSA burn data is often presented in ranges, which lacks granular details. The primary objective of this study is to validate our previous Pediatric Injury Quality Improvement Collaboration (PIQIC) findings by using a national burn registry to evaluate LOS per TBSA burn relative to burn mechanism, sociodemographic characteristics, and clinical factors which influence this ratio.We evaluated patients 0-18 years old who sustained a burn injury and whose demographics were submitted to the National Burn Repository (NBR) dataset from July 2008 through June 2018. Patients sustaining inhalation injury and electrical burns were excluded due to LOS being significantly increased unrelated to cutaneous injury. Mixed effects generalized additive regression models were then performed to identify characteristics associated with the LOS per TBSA ratio, a nonparametric variable.Among 51,561 pediatric burn patients, 45% were Non-Hispanic White, 58% were male, and the median age was 3 years old . The most common burn mechanism was scald (55.9%), followed by flame (19.4%), and contact (16.4%), with most burns occurring at home (82.2%). The median LOS per TBSA burn ratio across all cases was 0.9 . In adjusted models, scald burns and radiation burns had similar LOS per TBSA burn ratios , while all other burn mechanisms had a significantly higher LOS per TBSA burn ratio (p< 0.0001). Chemical burns had the highest ratio (predicted mean: 4.8), followed by contact burns . Non-Hispanic White patients had lower LOS per TBSA ratios than all other races and ethnicities (p< 0.05) with mean predicted values of 1.6. Native Americans and Hispanics had the highest ratios .These data substantiate evidence on variance in LOS per TBSA burn relative to burn mechanism, previously demonstrated by PIQIC centers. It also validates differences in LOS per TBSA burn ratios among race/ethnicity."}
+{"text": "There is growing interest in identifying factors protecting against aging-related decline. This cross-sectional study evaluated associations of self-reported resilience (ability to bounce back) with factors linked to aging-related decline among older adults with Type 2 diabetes (T2DM). Participants were 3,199 adults  enrolled in Look AHEAD , who were followed observationally after the 10-year intervention was discontinued. The following items were assessed approximately 14.4yrs post-randomization: Brief Resilience Scale; overnight hospitalizations in past year; physical functioning measured objectively  and via self-report ); a composite measure of phenotypic frailty based on having \u22653 of unintentional weight loss, low energy, slow gait, reduced grip strength, physical activity. Depressive symptoms (PHQ-9) and mental QOL (SF-36) were also measured. Logistic/linear regression was used to evaluate the association of these variables with resilience adjusted for age, race, and gender. Greater resilience was associated with lower BMI (p=.01), fewer hospitalizations (p=.02), better physical functioning , fewer depressive symptoms and greater mental QOL. Resilience is associated with better performance on indicators of overall functioning and risk for decline among older adults. Findings correspond with efforts to shift narrative on aging beyond \u2018loss and decline\u2019 to highlight opportunities to facilitate healthy aging."}
+{"text": "Pathways through which spousal support and strain influence older adults\u2019 well-being are poorly understood. We examined sleep quality and loneliness as mechanisms through which support and strain predict depressive symptoms across ten years utilizing National Social Life, Health, and Aging Project data. Our sample included partnered participants at waves 1 and 2 . Support  and strain  were measured at W1, loneliness (UCLA) and sleep quality (restless sleep) were measured at W2, and depression (CES-D) was measured at W3. We estimated latent-variable structural equation models, controlling for age, gender, and W1 depression. Indirect effects of support and strain on depressive symptoms through loneliness were significant. There was an additional trend-level indirect effect of spousal strain on depressive symptoms through restless sleep. Findings highlight multiple pathways through which marital quality predicts later-life well-being."}
+{"text": "Long-term hospital utilization trajectories in the context of surgery are understudied. Heart Failure (HF) is associated with an increased risk for rehospitalization after hip fracture surgery. This study aimed to examine whether older adults (>= 65 years old) have distinct patterns of long-term hospital utilization trajectories and whether HF influences these trajectories before and after hip fracture surgery. An initial cohort of 1,172 older adults hospitalized for hip fracture surgery between October 2015 and December 2018 was extracted from electronic health records. To adjust selection bias in baseline characteristics, we used propensity score 1:1 ratio matching to identify a final cohort of older adults with (n = 288) and without (n = 288) HF. Monthly frequencies of emergency department (ED) and inpatient encounters 1-year before and after the hip fracture surgery were used to identify distinct utilization trajectories from group-based trajectory analysis. Logistic regression models were used to compare the differences in ED and inpatient trajectories among patients with and without HF. High ED users (9.5%) had constant high ED use, and high inpatient users (20.1%) had significantly higher inpatient usage around the index hip fracture surgery hospitalization. Both low ED (90.5%) and inpatient (79.9%) users had low but slightly increased use around the index hospitalization. Compared with older adults without HF, older adults with HF were more likely to be long-term high inpatient user , but not significantly different in long-term ED utilization ."}
+{"text": "Neurological examination revealed hypotonia, areflexia, paralysis of bilateral lower limbs (power = 0/5), and sensory loss below the level of T12. Magnetic resonance imaging (MRI) showed spinal meningeal enhancement surrounding the conus medullaris from the upper T12 level with enhancement of the cauda equina nerve roots (2O) and colorless cerebrospinal fluid (CSF) with normal glucose and protein levels. Cryptococcal antigen was present in high titer in the CSF (1:1024), and CSF culture revealed Cryptococcus neoformans. The nerve conduction study demonstrated mixed sensory and motor axonal neuropathy of the bilateral lower limbs, sparing the upper limbs. The clinical, electrophysiological, and radiological findings were suggestive of cryptococcal meningoradiculitis. Intravenous amphotericin B and flucytosine were started. However, the patient did not achieve neurologic improvement and eventually succumbed to nosocomial infection. A 38-year-old man with newly diagnosed advanced acquired immunodeficiency syndrome (AIDS) (CD4 count = 17 cells/mmve roots . Lumbar C. neoformansCryptococcal meningitis is an important opportunistic infection caused by the encapsulated yeast"}
+{"text": "Neonatal treatment with ganciclovir/valganciclovir improves hearing outcomes, but its impact on neurodevelopmental outcomes remains an important knowledge gap. We describe the neurodevelopmental outcomes of children with cCMV infection and evaluate the effect of neonatal antiviral therapy on outcomes. Since 2013, infants with cCMV infection referred to Nationwide Children\u2019s Hospital\u2019s NEO-ID Clinic have had a complete evaluation at diagnosis as well as follow-up neurodevelopmental assessments. Pertinent demographic, clinical, laboratory, radiographic, and follow-up data were obtained and managed using REDCap. Neurodevelopmental assessments were performed using Bayley Scales of Infant and Toddler Development (BSID) III/IV  at ~ 24 months of age. The Gross Motor Function Classification System was used to classify functional motor impairment. Neurodevelopmental outcomes were compared by receipt of antiviral therapy in early infancy. 95 infants  with cCMV infection had follow-up neurodevelopmental assessments. 62% had central nervous system involvement, 37% had SNHL, 23% developed cerebral palsy (CP), and 6% were diagnosed with autism spectrum disorder. The majority had normal BSID scores (\u2265 85) in cognitive and motor domains  while 48% had normal scores in the language domain. 35% had severe impairment (< 70) in \u2265 1 domain (Table 2). 9 children had clinically inapparent cCMV infection; 2 (22%) had abnormalities on BSID testing . 11 (12%) children, including 6 who received antiviral therapy, had severe neurodevelopmental impairment, with CP and severe (< 70) BSID scores in both the cognitive and motor domains. Table 1. Demographic and Clinical Characteristics of 95 Children with Congenital CMV Infection by Receipt of Antiviral TreatmentTable 2. Neurodevelopmental Outcomes Based on Testing with the Bayley Scales of Infant and Toddler Development (BSID) III/IVA substantial proportion of children with cCMV infection had moderate (29%) or severe (33%) neurodevelopmental impairment, CP, or autism spectrum disorder, irrespective of antiviral treatment. Urgency exists for antenatal preventive strategies and vaccine development.Asuncion Mejias, MD, PhD, MsCS, Janssen Merck Roche (Advisor or Review Panel member)Sanofi (Advisor or Review Panel member)"}
+{"text": "Escherichia coli (STEC) causes proximal tubular defects in the kidney. However, factors altered by Shiga toxin (Stx) within the proximal tubules are yet to be shown. We determined Stx receptor Gb3 in murine and human kidneys and confirmed the receptor expression in the proximal tubules. Stx2-injected mouse kidney tissues and Stx2-treated human primary renal proximal tubular epithelial cell (RPTEC) were collected and microarray analysis was performed. We compared murine kidney and RPTEC arrays and selected common 58 genes that are differentially expressed vs. control . We found that the most highly expressed gene was GDF15, which may be involved in Stx2-induced weight loss. Genes associated with previously reported Stx2 activities such as src kinase Yes phosphorylation pathway activation, unfolded protein response (UPR) and ribotoxic stress response (RSR) showed differential expressions. Moreover, circadian clock genes were differentially expressed, suggesting Stx2-induced renal circadian rhythm disturbance. Circadian rhythm-regulated proximal tubular Na+-glucose transporter SGLT1 (SLC5A1) was down-regulated, indicating proximal tubular functional deterioration, and mice developed glucosuria confirming proximal tubular dysfunction. Stx2 alters gene expression in murine and human proximal tubules through known activities and newly investigated circadian rhythm disturbance, which may result in proximal tubular dysfunctions.Shiga toxin-producing  Escherichia coli (STEC) infection causes severe symptom hemolytic uremic syndrome (HUS), which is defined by the triad of acute renal failure, thrombocytopenia, and hemolytic anemia  [https://CRAN.R-project.org/package=gplots (last accessed on 4 January 2022)] [http://metascape.org (last accessed on 4 January 2022)] [https://string-db.org/ (last accessed on 4 January 2022)]  . The cuby 2022)] . Gene ony 2022)] . Connecty 2022)] . Associa"}
+{"text": "Enhanced biological phosphorus removal (EBPR) is an economically and environmentally significant wastewater treatment process for removing excess phosphorus by harnessing the metabolic physiologies of enriched microbial communities. We present a genome-resolved metagenomic data set consisting of 86 metagenome-assembled genome sequences from a photosynthetically operated lab-scale bioreactor simulating EBPR. Enhanced biological phosphorus removal (EBPR) is an economically and environmentally significant wastewater treatment process for removing excess phosphorus by harnessing the metabolic physiologies of enriched microbial communities. We present a genome-resolved metagenomic data set consisting of 86 metagenome-assembled genome sequences from a photosynthetically operated lab-scale bioreactor simulating EBPR. Candidatus Accumulibacter phosphatis\u201d (https://doi.org/10.6084/m9.figshare.14164307).A photobioreactor performing light-supported enhanced biological phosphorus removal (EBPR) was seeded from two lab-scale wastewater treatment systems, a photosynthetic nitrifying enrichment culture and an activated sludge EBPR bioreactor designed to enrich for the polyphosphate-accumulating organism \u201csphatis\u201d , 2. The Ca. Accumulibacter phosphatis\u201d draft genome sequences based on the ppk1 locus are available at https://doi.org/10.6084/m9.figshare.14164478.Default parameters were used for all software unless otherwise specified. The raw metagenomic reads were quality filtered and trimmed using bbduk as part of the BBTools v38.07 suite . MetagenPRJNA704939. The metagenomes are available under the SRA accession numbers SRR13786854, SRR13786855, and SRR13786856.The raw metagenomes for the 3 samples and genome assemblies for all 86 metagenome-assembled genomes (MAGs) are available at NCBI GenBank under BioProject accession number"}
+{"text": "A large body of research has documented how personality develops across adulthood, yet very little longitudinal work has examined whether these findings generalize beyond predominantly middle-class, highly-educated White American or Western European individuals. This pre-registered study uses longitudinal data from 1,110 Mexican-origin adults who completed a well-validated personality measure, the Big Five Inventory, up to 6 times across 12 years . Individuals generally maintained their rank ordering on the Big Five over time (rs=.66-.80), and all of the Big Five traits showed small, mean-level decreases across adulthood. These trajectories had few associations with sociodemographic factors  and cultural factors . Divergences between the present findings and previous research highlight the need to study personality development across diverse aging samples."}
+{"text": "Physical examination of the abdomen revealed a giant non-tender mass in the right quadrant. The patient was transfused with 4 units of blood. Abdomen computed tomography (CT) scan revealed a retroperitoneal mass of 20cm with calcification involving the liver, the kidney and surrounding the vena cava. He was referred to a multi-disciplinary team (MDT) to perform a CT scan fine-needle-aspiration (FNA) with a differential diagnosis of lymphoma, sarcoma or renal neoplasia.Retroperitoneal tumors give non-specific symptoms until they have reached a substantial size. Hystopathological types are: sarcomas such as liposarcoma (70%) and leiomyosarcoma (15%). Other retroperitoneal neoplasms include primary lymphoproliferative tumours (Hodgkin's and non-Hodgkin lymphoma) and epithelial tumours  or metastatic disease. A 57-year-old male was referred to the emergency department with acute onset of severe melena, right back pain and lipothymia. He had no medical history. On physical examination arterial blood pressure was 70/60mmHg, pulse rate was 100b/min, oxygen saturation of 90%. Blood exams demonstrated lymphocytes 61 x 10"}
+{"text": "RSV is the most frequent etiology of pediatric lower respiratory tract infection. Most children hospitalized for RSV are previously healthy without known risk factors. Children with mild disease managed as outpatients (OP) have higher viral loads than those hospitalized with severe disease. OP children have higher concentrations of the mucosal interferon (IFN), IFN\u03bb2/3, and IP-10, but no differences in IFN\u03bb1. We examined how RSV replication impacts cytokine production kinetics in the nasal mucosa.Primary infant human nasal epithelial (iHNE) cells were collected from nasopharyngeal swabs and cultured on an air-liquid interface. Cultures were infected with 0.1 or 0.001 multiplicity of infection (MOI) of RSV-A, or mock infected. Concentrations of IFN-related  and inflammatory  cytokines secreted to the apical and basolateral surfaces were quantified via immunoassay. Kinetics according to viral inocula were compared by ANOVA with Dunn post-hoc testing of the area under the curve (AUC) for each cytokine. Peak concentrations were compared according to MOI and secretion surface by 2-way ANOVA.AUC of IFNs in both surfaces of RSV infected cells were significantly higher than those of mock infected. The 0.1 MOI RSV inoculum resulted in significantly higher AUCs for all IFN cytokines on both surfaces than the 0.001 MOI. Peak IFN\u03bb1 concentrations were higher on the apical than basolateral side; peak IFN\u03bb2/3 concentrations were higher on the basolateral side than apical. AUCs of inflammatory cytokines in RSV infection were significantly higher on the basolateral, but not apical, surfaces than mock; all basolateral inflammatory cytokines were higher in the 0.1 MOI than the 0.001 MOI.Higher RSV inoculum induces higher concentrations of IFN-related cytokines on both sides of epithelial cells, and higher concentrations of inflammatory cytokines on the basolateral side. Differential secretion of IFN\u03bb1 and IFN\u03bb2/3 to the apical and basolateral surfaces suggests they may play different roles in immune response during RSV infection. These data support viral replication as an important factor influencing RSV pathogenesis and severity through cytokine production.Asuncion Mejias, MD, PhD, MsCS, Janssen Merck Roche (Advisor or Review Panel member)Sanofi (Advisor or Review Panel member) Octavio Ramilo, MD, Adagio (Consultant)Bill & Melinda Gates Foundation (Grant/Research Support)Janssen (Grant/Research Support)Lilly (Consultant)Merck NIH (Grant/Research Support)Pfizer (Consultant)SANOFI (Board Member)"}
+{"text": "During the COVID-19 pandemic, much of our social interaction has transitioned from in-person to online. This study examined older adults\u2019 social interaction during COVID-19, online and offline. Participants were recruited from community-dwelling older adults in Central Texas. Data collection took place via the telephone during June-August 2020 . Participants used a variety of communication modes, including phone or texting (used by 99% of the participants); email (44%); in person (35%); video chat (31%); social media (24%); and postal mail (4%). Most participants (77%) used more than one communication mode. Participants discussed their preferences for and challenges of technology  and its applications . Participants\u2019 self-reported experiences ranged from positive (50%), mixed (35%), to negative (15%). These findings will inform policy and community interventions to promote older adults\u2019 social interactions during the pandemic."}
+{"text": "Scientific Reports 10.1038/s41598-021-96851-1, published online 07 September 2021Correction to: The Funding section in the original version of this Article was incomplete.\u201cOpen Access funding enabled and organized by Projekt DEAL.\u201dnow reads:\u201cOpen Access funding enabled and organized by Projekt DEAL. The VolkswagenStiftung provided additional Open Access funding for this publication (Grant Number: 98 525).\u201dThe original Article has been corrected."}
+{"text": "Bacillus amyloliquefaciens spp. Importantly, WGS analysis of microbial representative strain, Bacillus sp. AM1 identified the four complete molecular pathways involved on BPA degradation indicating its versatility and high potential to degrade BPA. Pathways for Exopolysaccharide (EPS) and Polyhydroxyalkanates (PHA) biopolymer synthesis were also identified and phenotypically confirmed by transmission electronic microscopy (TEM). These microbial biopolymers could generally contribute to capture and/or deposit xenobiotics.Human gut microbiota harbors numerous microbial species with molecular enzymatic potential that impact on the eubiosis/dysbiosis and health/disease balances. Microbiota species isolation and description of their specific molecular features remain largely unexplored. In the present study, we focused on the cultivation and selection of species able to tolerate or biodegrade the endocrine disruptor bisphenol A (BPA), a xenobiotic extensively found in food plastic containers. Chemical xenobiotic addition methods for the directed isolation, culturing, Whole Genome Sequencing (WGS), phylogenomic identification, and specific gene-encoding searches have been applied to isolate microorganisms, assess their BPA metabolization potential, and describe encoded catabolic pathways. BPA-tolerant strains were isolated from 30% of infant fecal microbial culture libraries analyzed. Most isolated strains were phylogenetically related to the operational taxonomic group  The microorganisms that colonize the human gut are functionally diverse and highly variable . Four phBacillus genus are consistently identified in the human gut and are a source of enzymes with potential technological applications in the modern food sector  during 72 h and further spreading in BHI/MRS media incubated under aerobic and anaerobic conditions  following the manufacturing instructions. The isolated DNA was quantified using Nanodrop (Thermo Scientific) and biophotometer (Eppendorf\u00ae D30). The quality of DNA was monitored through gel electrophoreses. 16S RNA gene sequencing of selected bacterial strains was done by Sanger method (IPBLN Service). Forward and reverse sequences were provided separately. Reverse sequence was converted to complementary sequence with Chromas Pro 2.0 software . Sequences were inspected for maximum homology against GenBank using NCBI\u2019s BLASTn program. The collection of 16S RNA partial gene sequences is done using the Ezbiocloud platform. Genomic DNA was extracted using DNAeasy columns  of the University of Granada. Samples were fixed with 2.5% glutaraldehyde in sodium cacodylate buffer  for 24 h at 4 \u00b0C. After washing them three times in sodium cacodylate buffer  for 15 min, the post-fixation was carried out with 1% osmium tetroxide + 1% potassium ferricyanide in water for 2 h. It was washed again three times in water 15 min. And dehydration was realized using ascending ethanol gradients  for 15 min. Subsequently, the infiltration was carried out in a mixture of ethanol/resin (Epon 812) 2:1, 2:2 and 1:2 for 1 h and then it was the inclusion in pure resin overnight. After polymerization at 60 \u00b0C for 48 h, ultra-fine sections of 700 Angstrom were made (in a Leica Ultracut R ultramicrotome) deposited on copper grids and contrasted with uranyl acetate and lead citrate.The enzymatic assay were also determinate for starch, carboxymethyl cellulose, gelatin, inulin, tween 80, DNase supplemented media were used to test several enzymes production according to complementary methodologies previously described ,42.Bacillus sp. AM1 to 17 clinically important antibiotics, included those antibiotics recommending on the EFSA guidelines for testing antimicrobial susceptibility of the Bacillus species [The antimicrobial resistance patterns of  species , were co species .Bacillus sp. AM1 exposed to 25 ppb concentration of BPA at 30 \u00b0C during 72 h. Microbial preparations were measured through LC-MS/MS system for BPA quantification. Minimal medium 9 (M9) and M9 containing BPA (0.5 ppm) as sole carbon source were used for the isolation of BPA tolerant or biodegradation strain. M9 containing glucose (0.5 ppm) and M9 containing BPS (0.5 ppm) were also used to compare the growth ability. Chemicals, reagents, instrumentation and software for bisphenols determination were carried out by CIC services under validated procedures previously described by Garc\u00eda-C\u00f3rcoles et al. [BPA biodegradation capacity was tested in TSB liquid cultures of s et al. .Bacillus sp. AM1 (B1) selected for its phenotypic characteristics and its potential in biotechnology was inoculated in 2 mL nutrient broth, followed by overnight incubation at 37 \u00b0C. The cells were harvested by centrifugation at 5000\u00d7 g for 10 min. Genomic DNA was extracted using DNAeasy columns  as previously described.Genomic DNA extraction for WGS: Bacillus sp. AM1 (B1) strain was performed using the Nextera DNA Sample Preparation kit . Clusters generation and the sequencing were performed using the TruSeq\u2122 PE Cluster kit v2-cBot-HS and TruSeq SBS v3-HS (200 cycle) kit respectively . The sequencing was performed on the HiScan SQ sequencer .High-throughput sequencing: Shotgun library preparation of Genome assembly and annotation: Hybrid de novo assembly was performed with Illumina short reads  and Oxford Nanopore long reads (c.a. 1800X coverage) using Unicycler1 with the \u201cconservative\u201d option and threads 10 parameter .http://www.microbial-genomes.org accessed on 20 February 2021) that uses NCBI non-redundant prokaryotic genomes database, JSpeciesWS (http://jspecies.ribohost.com/jspeciesws accessed on 20 February 2021), and TrueBacTM ID system from the EzBioCloud server (https://www.ezbiocloud.net/contents/genome accessed on 20 February 2021). The species identification carried out in TrueBac-ID was based on the comparison of average nucleotide sequence identity (ANI) between the genomes of Bacillus sp. AM1 and the related type strains. For a reliable identification of the strains, the Type (Strain) Genome Server (TYGS) was employed. Prediction from identified Ribosomal Multilocus Sequence Typing (rMLST) alleles linked to genomes (53 rps genes) was used as a means of integrating microbial taxonomy and typing [Genome-based taxonomic classification and genome assembly were searched at Microbial Genomes Atlas (MiGA) online server . The functional annotation of genes was also carried out using web-based Rapid Annotation Using Subsystem Technology (RAST) annotation server (http://rast.theseed.org/FIG/rast.cgi accessed on 20 February 2021). Protein coding genes were scanned for their organization into operons using the web server Operon-mapper. Functional annotation of genes in terms of Kyoto Encyclopedia of Genes and Genomes (KEGG) orthology assignments and predictions of KEGG pathways were carried out through KEGG Automatic Annotation Server (KAAS) server (https://www.genome.jp/kegg/kaas/ accessed on 20 February 2021) using bi-directional best hit (BBH) method in GhostZ. Similarly, the Bacillus sp. AM1 genome were also scanned for cluster of orthologous groups (COGs) annotations using eggNOG-mapper v2 (http://eggnog-mapper.embl.de accessed on 20 February 2021). Automated Carbohydrate-active enzyme ANnotation web server, (dbCAN meta server (http://bcb.unl.edu/dbCAN2/blast.php accessed on 20 February 2021), was employed to annotate Carbohydrate-Active enZYmes (CAZy).Draft Bacillus sp. AM1 protein encoding genes.Specific genes and amino acid sequences of the BPA-tolerant representative microorganism were searched by screening according to phenotypic and chemical characteristics such as EPS, PHA, and other enzymes related to the BPA degradation pathways: quinol-enzymes, laccase, through BLAST (NCBI), EZBIOCLOUD, BRENDA, UNIPROT, and EXPASY. A more exhaustive and combined analysis using the KEGG database (Kyoto Encyclopedia of Genes and Genomes) allowed corroborating the identity of the enzymes involved in metabolic pathways of BPA degradation previously describe by Li et al. . EC numbBacillus sp. AM1 allowed taxonomic and phylogenomic identifications, relevant phenotypic features confirmation, and safety assessment aspects. Bacillus sp. AM1 WGS revealed the presence of a complete arsenal of genes that encode enzymes for versatile BPA degradation; this might open avenues for the investigation of the use of these strains for environment, feed and food industries, and/or to explore the clinical modulation impact on endocrine pathogenesis modulation by BPA-degrader species.This study is the first report on the isolation of BPA-degrading microbes from the human gut and its complete description of BPA biodegradation pathways. The isolation of strains belonging to the Firmicutes phyla from human microbiota able to biodegrade BPA was successful through a BPA-enriched media and a directed cultivation approach. WGS analyses of representative"}
+{"text": "Conserv Physiol 9(1): coab088; doi:10.1093/conphys/coab088In the originally published version of this manuscript, the incorrect Supplementary Materialwas included. This has been replaced with the correct information. The publisher apologizesfor the error."}
+{"text": "In many critical illnesses including burn injury (BI), muscle wasting (MW) with mitochondrial dysfunction (MD) leads to poor prognosis. Disturbed mitochondria can normally be turned over by autophagic degradation of mitochondria (mitophagy). We have previously observed that BI causes disturbed mitophagy response in skeletal muscles both in vivo and in the cultured myocytes, a potential mechanism for BI-induced MD. These previous findings have lead to the expectation that augmenting mitophagy will rescue mitochondrial functions and can help treating the BI-induced MW and MD. There have been, however, limited research tools to specifically intervene (or augment) mitophagy. In the current study, we have established mitophagy-compromised cell strains by CRISPR/Cas9-mediated knocking out of BNIP3L, a pivotal molecule mediating parkin-independent mitophagy induction. Deferiprone (DFP), a recently established mitophagy inducer, had previously been known to exert cellular and organ protective functions, but the mechanisms of its beneficial effects were not investigated in detail. Nor has its efficacy been tested on BI-induced MD.First, whether DFP stimulated mitophagy induction causes translocation of mitophagy markers into mitochondrial fraction, was tested by Western Blotting on the WT C2C12 cells against Parkin/PINK1- and BNIP3L- pathway molecules. Next we established BNIP3L knockout C2C12 myoblast cell like by CRISPR/Cas9-mediated gene deletion. Using both WT and BNIP3L knockout (KO) cell lines incubated in the BI or SB serum (from 30% rat burn at 3PBD) with or without DFP treatment, we tested whether DFP can rescue BI-induced upregulation of mitochondria-derived superoxide (SO) using MitoSOX staining.In WT C2C12 cells, mitophagy stimulation by DFP caused robust increase of the protein amount of BNIP3L in the mitochondrial fraction, but Parkin/PINK1 did not. KO completely abolished both basal and stimulated increase of BNIP3L. BI serum caused significant elevation of mitochondrial SO in WT myocytes ( >20 fold of SB), which was ameliorated by DFP-stimulated mitophagy augmentation (95% reduction). In KO C2C12 cells, however, DFP-induced SO reduction in BI serum was completely abolished, suggesting that DFP-mediated mitochondrial protection against BI was through augmenting mitophagy via BNIP3L pathway.By using BNIP3L KO C2C12 myocytes, mitochondrial protective role of BNIP3L-mediated mitophagy against BI-induced stress was demonstrated for the first time. Previously reported cellular and organ protective functions of DFP is likely through activation of this pathway. Augmentation of mitophagy will be a promising therapeutic approach in protecting BI-induced MW and MD."}
+{"text": "Oxidized low-density lipoprotein (oxLDL) induced a foam-cell-like phenotype of the vascular smooth muscle cells (VSMCs), leading to the inflammatory responses incorporating Toll-like receptor- (Tlr-) mediated cellular alterations. However, the role of Tlr4 in foam cell formation and underlying molecular pathways has not been comprehensively elucidated. To further investigate the mechanism, VSMCs were incubated with different doses of oxLDL, and then, the lipid, reactive oxygen species (ROS) accumulation, Tlr family genes, and the foam cell phenotype were explored. We observed that oxLDL induced foam cell-like phenotype in VSMCs and led to lipid and ROS accumulation in a dose-dependent manner. Furthermore, in the Tlr family, Tlr4 demonstrated the strongest upregulation under oxLDL stimulation. Simultaneously, oxLDL induced activation of Src, higher expression of Nox2, and lower expression of Mnsod, Sirt1, and Sirt3. By interfering the TLR4 expression, the phenotype alteration, lipid accumulation in VSMCs, and Src kinase activation induced by oxLDL were abolished. After interfering Src activation, the oxLDL-induced lipid accumulation and foam cell phenotype in VSMCs were also alleviated. Furthermore, the ROS accumulation, upregulated Nox2 expression, downregulated Sirt1, Sirt3, and Mnsod expression in VSMCs under oxLDL stimulation were also relieved after the knockdown of Tlr4. Additionally, overexpression of Sirt1 and Sirt3 ameliorated the ROS accumulation and foam cell-like marker expression in VSMCs. These results demonstrated that beyond its familiar role in regulating inflammation response, Tlr4 is a critical regulator in oxLDL-induced foam cell formation in VSMCs via regulating Src kinase activation as well as Sirt1 and Sirt3 expression. Coronary artery disease (CAD) is a leading health burden contributing to high morbidity and mortality worldwide . And athAlong with the continuous formation and necrosis of the foam cells, regional inflammatory storms induced by excessive cytokines caused damage to the vessels . oxLDL sAdditionally, excessive production of reactive oxygen species (ROS) was widely observed in atherosclerosis. Although it has been well-established that the broken oxidative homeostasis could promote the vascular inflammation response, the relationship between oxidative stress and foam cell formation in VSMCs has not been elucidated. Although a previous study showed that Tlr4 mediated ROS accumulation via regulating Nox2 , other mIn this study, we hypothesized that Tlr4 mediated oxLDL-induced foam cell formation via regulating lipid accumulation and ROS production in VSMCs. Based on cellular and molecular research, we aimed to clarify the mechanism underlying the ROS and lipid accumulation induced by oxLDL in VSMCs, thus deepening the insights about the formation of foam cell-like VSMCs during atherosclerosis.\u03b1Sma (Cat#ab52218), Mac2 (Cat#ab2785), Cd68 (Cat#ab31630), Nox2 (Cat#ab80508), Nox4 (Cat#ab14544), and Sirt4 (Cat#ab124521) were purchased from Abcam . Additionally, primary antibodies of \u03b2-actin (Cat#3700), p-Src Y418 (Cat#6943), t-Src (Cat#2123), Mnsod (Cat#13141), Sirt1 (Cat#2314), Sirt2 (Cat#12650), Sirt3 (Cat#5490), Sirt5 (Cat#8782), Sirt6 (Cat#12486), Sirt7 (Cat#5360), and tlr4 (Cat#14358) as well as the second antibody-conjunction HRP anti-mouse/rabbit (Cat#7076/Cat#7074) were gained from CST .Fetal bovine serum (Cat#16000), advanced DMEM/F-12 (Cat#12634010), and antibiotic-antimycotic (Cat#15240096) were obtained from Gibco . oxLDL (Cat#L34357), Nile Red (Cat#N1142), Image-IT\u2122 LIVE Green Reactive Oxygen Species Detection Kit (Cat#I36007), MitoSOX\u2122 Red Mitochondrial Superoxide Indicator (Cat#M36008), DAPI (Cat#D1306), TRIzol\u2122 Reagent (Cat#15596026), Goat anti-Rabbit secondary antibody conjunction with Alexa Fluor Plus 555 (Cat#A-21429), Goat anti-Mouse secondary antibody conjunction with Alexa Fluor Plus 488 (Cat#A-11001), and Lipofectamine\u2122 RNAi MAX transfection reagent (Cat#13778150) were purchased from Invitrogen . Tlr4 siRNA (Cat#sc-40261), Src siRNA (Cat#sc-29859), and negative control siRNA (Cat#sc-37007) were bought from Santa Cruz . Let-blank (Cat#GCNL), Let-Sirt1 (+) (Cat#GCD0161581), and Let-sirt3 (+) (Cat#GCD0201555) were acquired from Shanghai Genechem . Premix ex taq\u2122 DNA polymerase (Cat#RR039A) and primeScript\u2122 1st strand cDNA synthesis kit (Cat#6110A) were collected from TaKaRa . HDL and LDL/VLDL cholesterol assay kit (Cat#ab65390), H&E staining kit (Cat#ab245880), BCA protein assay kit (Cat#ab102536), PP2 (Cat#ab120308), PP3 (Cat#ab120617), and the primary antibody of Myh11 (Cat#ab53219), All animal experiments were conducted according to the Guide for the Care and Use of Laboratory Animals and approved by the Animal Care and Use Committee of Shanghai Jiao Tong University, China, which conform to the guidelines from Directive 2010/63/EU of the European Parliament on the protection of animals used for scientific purposes. Before obtaining the aortic tissues, the mice were firstly anesthetized and were euthanized humanely by intraperitoneal injection of sodium pentobarbital.2 in F12\u2009:\u2009DMEM (1\u2009:\u20091) medium with 20% fetal bovine serum and 1% antibiotic-antimycotic.Wild-type (C57BL/6) mice were purchased from the Model Animal Research Center of Nanjing University  and were euthanized at 4 weeks old. To obtain the primary smooth muscle cells, the aortas of the mice were dissected, and the adventitia was removed. The aortic explants were cultured after mechanical dissection and twice washing in PBS. The explant-derived VSMCs were cultured at 37\u00b0C, 5% COn = 3).VSMCs were cultured in 6-well plates and incubated with oxLDL for 72 hours. Afterwards, the VSMCs were washed by PBS twice and then were fixed in 4% paraformaldehyde/PBS for 15 minutes. Then, the cells were stained by 100\u2009ng/mL Nile Red for intracellular lipid detection . All cel\u03bcM carboxy-H2DCFDA working solution was used to label VSMCs for 30 minutes at 37\u00b0C in the dark. Afterwards, cells were gently washed in warm HBSS/Ca/Mg and incubated with Hoechst 33342 for another 5 minutes. After three times washes, the ROS signals were observed via a fluorescent microscope. Five fields of view were randomly acquired, and representative images were shown.Cellular ROS was detected by the carboxy-H2DCFDA kit. Based on the kit instruction, a 25\u2009After incubation with oxLDL, VSMCs were gently washed by warm Hanks buffer. The mitochondrial superoxide was detected using the MitoSOX\u2122 Red indicator. According to the manufacturer's recommendation, the MitoSOX\u2122 reagent was diluted into a working concentration and added to the six-well plates covering the VSMCs. After a 10-minute incubation in MitoSOX\u2122 reagent at 37\u00b0C in the dark, the cells were washed by Hanks buffer three times. Images were obtained by a fluorescence microscope using a green excitation light. Five fields of view were randomly acquired, and representative images were shown.\u03bcgs of total RNA undergone the reverse-transcription. Polymerase chain reactions (PCR) were carried out using Power SYBR Green PCR Master Mix  according to the manufacturer's recommendation in a StepOne System . Primers for the promoter sequences are listed in \u03b2-actin as the reference gene. The StepOne software v2.1 (Applied Biosystems) was used for data analysis.Total RNA was extracted by TRIzol reagent, and five \u03bcg) was applied in a 15% SDS-polyacrylamide gel and transferred to polyvinylidene fluoride (PVDF) membranes. The membranes were blocked by 5% milk for 1 hour at room temperature and then incubated with the primary antibody overnight at 4\u00b0C. After being washed three times in TBS buffer, the membrane was incubated with horseradish peroxidase- (HRP-) conjugated secondary antibodies at room temperature for 2 hours. Finally, images were captured in a Tanon-5500 chemiluminescent imaging system  and quantified by ImageJ software .VSMCs were lysed in Western & IP Cell lysate on ice for 15\u2009min. The total protein was collected after centrifugation. Protein concentration was measured using a BCA-protein assay kit. Equal quantification of protein (20\u2009RNA interference was conducted using the Oligofectamine reagent (Invitrogen). And cultured VSMCs were transfected with the targeting siRNA and negative control siRNA (non-targeting sequence) according to the instruction. Cells had 60%-70% confluency on the day of transfection. After transfecting for 48\u2009hours, the knockdown efficiency was tested by western blot.\u03bcmol/L) and PP3 (10\u2009\u03bcmol/L) were, respectively, added to VSMCs and incubated for 30\u2009min before oxLDL stimulation. PP3 served as the negative control for PP2.PP2 . Paired samples were compared using Student's paired \u03bcg/mL) of oxLDL for 48 hours, lipid accumulation, cellular ROS accumulation, mitochondrial superoxide generation, and foam cell formation were examined. The Nile Red staining and lipoprotein quantification showed that oxLDL induced lipid accumulation in VSMCs in a dose-dependent manner  of oxLDL resulted in significant elevation of Nox2 and remarkable decreased Mnsod, whereas the significant change of Nox4 expression was not observed  and elevated foam cell markers (Mac2 and Cd68) in NC VSMCs, TLR4 knockdown had interrupted most of these alterations, indicating that TLR4, at least partly, mediated the oxLDL-induced lipid and ROS accumulation and contributed to foam cell formation  . After 5 Figures . More im Figures .Notably, after knocking down the Tlr4 in VSMCs, the activation in the Tyr-418 phosphorylation site of Src kinase was deprived to a great extent, compared with the NC group, after 1-hour oxLDL treatment Figures . Such anInterestingly, we also observed that when Tlr4 in VSMCs was knocked down, the expression of Sirt1 and Sirt3 restored compared with the NC group after 48-hour oxLDL treatment accompanied by reduced Nox2 and elevated Mnsod expression, implying that Tlr4 contributed to Sirt1 and Sirt3 downregulation under oxLDL stimulation Figures .\u03b1Sma) loss and foam cell marker (Mac2 and Cd68) acquisition, which implied that Sirt1 and Sirt3 partly assist in VSMCs phenotype rebalancing under oxLDL stimulation ] or Sirt3 [Let-Sirt3(+)] overexpression was transfected SMCs. The Let-Sirt1(+) or Let-Sirt3(+) significantly increased the expression of Sirt1 and Sirt3, respectively, without mutual interference Figures . CompareIn this study, we demonstrated that oxLDL induced the transition of VSMCs to foam cells by promoting lipid accumulation and ROS production via raising the expression of a key linking molecule-Tlr4. Furthermore, oxLDL-induced lipid and ROS accumulation and phenotype alteration in VSMCs were at least partly attributed to Tlr4-regulated Src activation and Sirt1 and Sirt3 upregulation. Our findings unravelled a crucial role of Tlr4 in oxLDL-induced foam cell formation in VSMCs.The toll-like receptor family constitutes important members of pattern recognition receptors (PRRs), which identify particular ligands of receptor to evoke pathogen-associated molecular patterns (PAMPs) \u201323. Thes\u03baB activation [Foam cell phenotype and inflammation response are two significant interrelated alterations in VSMCs that exacerbated atherosclerosis progression . Our wortivation . Herein,Foam cell formation, characterized by the accumulation of intracellular lipids and the occurrence of inflammatory phenotype, is a hallmark in atherosclerosis progression . Lipid lROS was a well-known mediator that exerts severe intracellular oxidative stress and prompts an inflammatory response, structural reorganization, and even cell phenotype transition , 36. In Since previous studies showed that sirtuin family members were located in nuclear and mitochondrial organelles, maintaining redox homeostasis via regulating the oxidative stress-associated genes , we alsoOur study demonstrated that Tlr4 is a critical regulator in oxLDL-induced foam cell formation of VSMCs via mediating Src kinase as well as Sirt1 and Sirt3. Beyond the role of Tlr4 in the inflammation response of VSMCs, we added a more integrated mechanism about TLR4 in VSMC phenotype transition under oxLDL stimulation."}
+{"text": "Vancomycin is a broad-spectrum antibiotic commonly used in burn patients. Traditionally, vancomycin has been managed with a trough level dosing strategy. However, recent literature and practice changes have encouraged utilizing an area under the curve (AUC) dosing strategy. The objective of this study was to evaluate the likelihood of attaining therapeutic targets using population kinetics in burn patients utilizing AUC.This retrospective cohort included adult burn patients who received vancomycin dosed with an AUC strategy. Data collection covered 20 months following an institutional shift to AUC monitoring. Patients were excluded if they did not have pharmacokinetic (PK) data documented, received renal replacement therapy, or had a nonburn injury. The primary outcome was the difference between predicted and actual vancomycin AUC. Secondary outcomes included differences between additional PK parameters.The AUC analysis included 14 patients. Mean (SD) age was 47 (12) years, 57% were male, and mean (SD) TBSA was 30 (21). The mean (SD) AUC in the predicted and actual groups was 522 (42) and 455 (122) mg*h/L, respectively (p=0.05). A total of 6 patients were evaluated for additional PK analysis, summarized in Table 1.Actual patient-specific AUC was significantly lower than predicted AUC. This corroborates previous trough-based data indicating burn patients dosed using standard population estimates are at risk of being subtherapeutic, likely due to their hypermetabolic state. Our findings suggest AUC monitoring is an appropriate dosing strategy for burn patients and potentially more accurate than a traditional trough-based approach."}
+{"text": "Here, we report the draft genome sequences of four aerobic gaseous alkane-oxidizing bacteria isolated from soil by enrichment culture using isobutane (2-methylpropane) as the sole carbon and energy source. The sequences all reveal microorganisms with multiple alkane-oxidizing monooxygenases, including soluble di-iron monooxygenases (SDIMOs), copper-containing monooxygenases (CuMMOs), and alkane hydroxylases (AHs). Here, we report the draft genome sequences of four aerobic gaseous alkane-oxidizing bacteria isolated from soil by enrichment culture using isobutane (2-methylpropane) as the sole carbon and energy source. The sequences all reveal microorganisms with multiple alkane-oxidizing monooxygenases, including soluble di-iron monooxygenases (SDIMOs), copper-containing monooxygenases (CuMMOs), and alkane hydroxylases (AHs). Samples (5 g) from each site were incubated in sealed serum bottles (160\u2009ml) containing mineral salts medium (MSM)  sealed with screw caps and butyl rubber septa. The bottles contained MSM (100\u2009ml) and isobutane (10% [vol/vol] in air). After 7\u2009days, cells were harvested by centrifugation, and the sedimented cells were lysed in tubes (2\u2009ml) containing silica beads (0.1\u2009mm) using a FastPrep-24 bead beater  operated at 4 m/s for 20\u2009s. Total genomic DNA (gDNA) was extracted using a DNeasy UltraClean microbial kit . The DNA was sheared using a g-TUBE  and size selected (5\u2009kb) using the BluePippin size selection system . Sequencing libraries were prepared using the PacBio Express template prep kit v2.0 . The libraries were sequenced using a PacBio Sequel single-molecule real-time (SMRT) cell, and raw reads were processed with the PacBio Pipeline , and gen00\u2009ml seaA BLAST comparison of 16S rRNAs from the genome sequences against the NCBI 16S rRNA database revealed that the isolates were all examples of frequently encountered gaseous alkane-oxidizing genera. All four genomes encoded complete operons for a group 6 soluble di-iron monooxygenase (SDIMO) . CompletCP059893 to CP059895 (Mycolicibacterium sp. strain 2A), JACJDF000000000 (Rhodococcus sp. strain 3A), JACCFD000000000 (Rhodococcus sp. strain 4CI), and JACCFE000000000 (Rhodococcus sp. strain 4CII). The GenBank assembly numbers for the genomes are GCF_014295435 (Mycolicibacterium sp. strain 2A), GCF_014230115 (Rhodococcus sp. strain 3A), GCA_014230025 (Rhodococcus sp. strain 4CI), and GCA_014256275 (4CII). The BioProject accession number for the genomes is PRJNA644947. The Sequence Read Archive (SRA) numbers are SRX9122159 (Mycolicibacterium sp. strain 2A), SRX9122160 (Rhodococcus sp. strain 3A), SRX9122161 (Rhodococcus sp. strain 4CI), and SRX9122162 (Rhodococcus sp. strain 4CII).The complete genome sequences of the four isobutane-utilizing strains have been deposited in GenBank under the accession numbers"}
+{"text": "The scan revealed a solitary PSMA-positive thyroid lesion. On PET/ultrasound fusion imaging, a nodule with moderate risk of malignancy (TIRADS 4B) could be unambiguously correlated. Additional 124Iodine PET/ultrasound fusion imaging revealed normal iodine uptake within the PSMA-positive thyroid nodule. Fine-needle aspiration cytology was performed using an ultrasound needle-guidance system. The cytopathological investigation confirmed a benign thyroid nodule and excluded a thyroid carcinoma as well as a prostate cancer metastasis. Immunohistochemistry was positive for thyroglobulin staining.A 54-year-old male diagnosed with prostate cancer was referred for"}
+{"text": "Despite evidence of correspondence with intraoperative stimulation, there remains limited data on MRI diffusion tractography (DT)\u2019s sensitivity to predict morbidity after neurosurgical oncology treatment. Our aims were: (1) evaluate DT against subcortical stimulation mapping and performance changes during and after awake neurosurgery; (2) evaluate utility of early post-operative DT to predict recovery from post-surgical deficits.We retrospectively reviewed our first 100 awake neurosurgery procedures using DT- neuronavigation. Intra-operative stimulation and performance outcomes were assessed to classify DT predictions for sensitivity and specificity calculations. Post-operative DT data, available in 51 patients, were inspected for tract damage.91 adult brain tumor patients  underwent 100 awake surgeries with subcortical stimulation between 2014 and 2019. Sensitivity and specificity of pre-operative DT predictions were 92.2% and 69.2%, varying among tracts. Post-operative deficits occurred after 41 procedures (39%), but were prolonged (>\u20093\u00a0months) in only 4 patients (4%). Post-operative DT in general confirmed surgical preservation of tracts. Post-operative DT anticipated complete recovery in a patient with supplementary motor area syndrome, and indicated infarct-related damage to corticospinal fibers associated with delayed, partial recovery in a second patient.Pre-operative DT provided very accurate predictions of the spatial location of tracts in relation to a tumor. As expected, however, the presence of a tract did not inform its functional status, resulting in variable DT specificity among individual tracts. While prolonged deficits were rare, DT in the immediate post-operative period offered additional potential to monitor neurological deficits and anticipate recovery potential.The online version contains supplementary material available at 10.1007/s11060-021-03795-7. Surgery remains the first-line treatment for intrinsic brain tumors. Surgery has undergone increasing refinement with adjuncts that help maximize tumor resection and reduce morbidity. Evidence for the added value of emerging intra-operative approaches, however, remains low .Neuronavigation incorporating diffusion tractography (DT) has received particular attention for its potential to facilitate glioma surgery , 3. MaxiMRI-based diffusion tractography (DT) is the only technique available to estimate fiber tracts in vivo. Although an indirect technique , the topEvaluations against intra-operative electrical stimulation highlight that factors including tumor-associated edema and brain shift  reduce tConfirm DT sensitivity, specificity and accuracy for 5 primary fiber tracts, evaluated not only against intra-operative stimulation but also against behavioral change during/after surgery.Identify factors contributing to discrepancies between pre-surgically DT predicted tract locations and intra-operative stimulation.Explore if post-operative indications of fiber tract damage inform recovery potential.We analyzed findings in 100 patients at our institution who underwent awake surgery for intrinsic brain tumors using DT neuronavigation combined with subcortical stimulation. Our aims were to:We reviewed all adults undergoing awake surgery for intrinsic brain tumors at our institution between May 2014 and 31 May 2019. Patients were selected for awake surgery if intraoperative assessment of speech, sensorimotor or visual functions was felt to be important to achieve maximal resection without morbidity based on the location of the tumor. The first 100 surgeries using intra-operative subcortical stimulation were analyzed. Patients were reviewed at a multidisciplinary meeting and dedicated surgical neuro-oncology clinic to assess performance status and candidacy for awake neurosurgery.2, 32 directions, 2.5\u00a0mm3 resolution). 98 patients underwent post-operative MRI approximately 24\u00a0h after surgery, including post-operative DT in 51 patients. Two patients had post-operative CT. Post-operative MRIs were evaluated independently by a consultant neuroradiologist to determine extent of resection.Patients underwent MRI approximately 24\u00a0h before surgery on a 1.5\u00a0T Philips Achieva. Scans included volumetric pre- and post-Gadolinium T1-weighted scan, axial T2-weighted FLAIR and diffusion  or Medtronic StealthStation\u00ae S7  using standard processes. Tracts were selected based on tumor location and included the arcuate/superior longitudinal fasciculus (SLF), inferior fronto-occipital fasciculus (IFOF), corticospinal tract (CST), optic radiations (OR) and inferior longitudinal fasciculus (ILF). Tractography plans were exported to the neuronavigation system (see Online Resource).Patients were operated according to a Monitored Anesthesia Care (MAC) or Conscious sedation protocol (Online Resource). Subcortical stimulation was performed when approaching tumor margins, or where DT indicated proximal fibers. Stimulation started around 6\u20138\u00a0mA, descending to a lower voltage on approaching tracts. Surgical resection alternating with stimulation proceeded until functional margins were encountered or planned tumor resection was achieved. Subcortical stimulation was not always reliable/possible due to variable compliance levels or clinical events (e.g. seizures). In some cases, resection continued without stimulation, provided behavioral monitoring remained possible; in other words, patients maintained responses to test stimuli/instructions but did not comply sufficiently for stimulation and/or further stimulation was contraindicated by intra-operative focal seizures. Performance deterioration in specific tract-related functions of sudden onset, unrelated to seizures, pain, bleeding or dynamic brain traction was recorded as behavioral change without clear stimulation-induced response.Tract functionality was assessed using standard tests , 28, incImmediate post-operative neurological outcome was determined over 24\u201348\u00a0h of in-patient observation. Neurological status was determined using the World Health Organization (WHO) performance status, supplemented as appropriate with neuropsychological tests probing language function . Muscle power was measured using the Medical Research Council 5-point muscle scale. After discharge, patients returned for out-patient review within 2\u00a0weeks of surgery. Clinical reviews were 3 monthly for \u2018low-grade glioma\u2019 and bi-monthly for \u2018high-grade glioma\u2019 patients until the start of adjuvant treatment.True positive (TP) prediction was defined as a tract identified by DT and confirmed by intra-operative stimulation/behavioral change. DT findings were classified True negative (TN) if no tract was indicated near the tumor, nor found with stimulation. A False positive (FP) was defined as a tract identified by DT but not identified intra-operatively. Predictions were False Negative (FN) if no tract was located by DT but was found through stimulation. See Online Resource Fig. S1. Sensitivity was calculated as (TP)/(TP\u2009+\u2009FN); specificity as (TN)/(TN\u2009+\u2009FP) and accuracy as (TN\u2009+\u2009TP)/(TN\u2009+\u2009TP\u2009+\u2009FN\u2009+\u2009FP). Tracts were excluded from analysis if there was adjacent residual tumor on post-operative MRI or indications of atypicality (left-handedness or prior surgery combined with absence of expected symptoms intra-/post-operatively).A Fiber tracts were separately reconstructed from the post-operative scans and visually compared to pre-operative trajectories for gross evidence of surgical tract damage. We expected deficits would persist given evidence of tract injury, or be transient if tracts remained intact.Statistical analyses were performed using SPSS v25. Group comparisons consisted of independent samples t-tests. Chi-square tests compared the frequency of specific DT predictions  by performance outcome, and the contribution of histopathological diagnosis on DT predictions. Significance was set at p\u2009<\u20090.05.Table 143 tracts were evaluated during 100 surgeries , post-operative deficits (n\u2009=\u20094) or both (n\u2009=\u20093), each involving language tracts . Together, 107 DT predictions were classified \u2018TP\u2019.Stimulation was performed to verify 9 tracts which DT indicated should be remote from the surgical margins. For all 9, no stimulation-related behavioral changes occurred, confirming \u2018TN\u2019 predictions.One tract was not accurately predicted by DT. This patient showed malignant transformation of a known diffuse left temporo-fronto-insula astrocytoma. DT indicated white matter within the tumor. However, the IFOF was not reliably reconstructed due to confounding pathological signal in the temporo-parietal white matter Fig.\u00a0. Intra-oFour stimulation-silent but DT-predicted tracts  were not explained by identified clinical factors and classified \u2018FP\u2019 predictions. None experienced deficits.Stimulation induced seizures in two patients. Both recovered but had prolonged post-ictal states, limiting further stimulation mapping. One further patient developed an intra-operative supplementary motor area syndrome, precluding evaluation of the DT-predicted CST.19 additional DT-predicted tracts were not identified intra-operatively. Post-operative MRI revealed residual tumor adjacent to 11/19. For 6 others, the absence of stimulation-induced errors indicated atypical functional organization. Three \u2018silent\u2019 tracts  occurred in two left-handed patients operated for a newly diagnosed left hemisphere glioma. Neither patient had language symptoms before, during or after surgery, indicating right hemisphere dominance for language. The remaining three stimulation-silent tracts  occurred in three patients re-operated for tumor recurrence at 8, 3.7 and 3.4\u00a0years after initial surgery following full (n\u2009=\u20092) or partial (n\u2009=\u20091) behavioral recovery. Finally, substantial brain shift occurred in two glioblastomas. The pre-operative fiber tract locations (optic radiations in both) displayed on neuronavigation and the intra-operative location of stimulation visualized through the microscope became misaligned during surgery. The stimulation sites remained remote to predicted tracts, and neither patient experienced deficits. Since the DT predictions could not be conclusively verified these 22 tracts were omitted from sensitivity/specificity analyses.The frequency of DT tract predictions  did not differ by tumor grade (Notwithstanding minor wound leaks/infections (n\u2009=\u20094), surgical complication rates were low; 41/100 awake surgeries (41%) resulted in a post-operative performance decline, relating to 52 fiber tracts . Most declines were transient. Nine patients had persisting deficits (lasting\u2009>\u20093\u00a0months) but not all resulted from surgery: four arose from tumor progression and one patient deteriorated upon starting radiotherapy. Therefore, definite prolonged deficits occurred after four surgeries (4%), each involving sensorimotor functions. Tumor histological grade did not differ between patients with or without post-operative deficits .107 tracts were classified TP, 1 as FN, 9 TN, and 4 FP Fig.\u00a0, yieldinPost-operative DT was available in 51 patients, including 20 of those who experienced post-surgical performance declines. In 14/20 (70%), deficits recovered rapidly. Three patients had early tumor progression contributing to neurological decline. The remaining three patients were among the four reported above with de novo deficits persisting beyond 3\u00a0months: one experienced sensory symptoms without loss of mobility, one had persisting motor SMA syndrome, and one had residual lower limb weakness. Post-operative DT showed intact CST fibers in the patients with sensory symptoms and motor SMA syndrome. In contrast, the patient with persisting limb weakness had a small infarct involving the corona radiata, causing a post-operatively asymmetric, ipsilaterally reduced CST  reflected inherent differences between Our first study aim was to determine the sensitivity, specificity and accuracy of DTI in our sample of patients operated awake with subcortical stimulation. While numerous studies report using pre-operative DT for neuronavigation, few have quantified its sensitivity. Bello and colleagues  reportedOur second aim was to identify factors contributing to discrepancies between pre-operative DT and intra-operative stimulation. These included:DT failures were rare, affecting 1/143 tracts (<\u20091%). Insula gliomas can destroy the IFOF, and absence of IFOF in DT is predictive of achieving\u2009>\u200980% resection . Convers regions . NonetheBrain shift has been extensively described and affects neuronavigation based on pre-operative imaging. Excessive brain shift affected 2 (1%) of our tract evaluations. Intraoperative MRI  or more Residual tumor surrounded 11 DT-predicted tracts (8%). In these cases, stimulation likely did not reach the targeted tract.location of tracts, making no assumption about function, while stimulation evaluates tissue functionality without knowledge of tract locations. Which tract was stimulated is inferred from a patient\u2019s response [Functional variability. The arcuate, IFOF and CST generally produce consistent behavioral changes. Others, such as the ILF , appear response . HoweverThree main factors explained why subcortical stimulation did not elicit behavioral change for 22 DT-predicted tracts:Only four stimulation-silent DT-predicted tracts remained unexplained. In one left temporal glioblastoma patient, stimulation did not locate the ILF or optic radiations. Since the predicted IFOF, situated lateral to the optic radiations, was confirmed, optic fibers were likely not stimulated. Additionally, no visual symptoms were elicited through stimulation in a patient with a right medial parietal glioblastoma and near total resection. We did not conduct post-operative ophthalmological assessment and therefore cannot rule out subtle visual field deficits. Finally, the DT-predicted CST was not encountered in one patient with a left parietal glioblastoma who had gross total resection. Pre-operative DT indicated peri-tumoral edema displacing the CST. Due to an intra-operative cardiac event, resection stopped once visible tumor had been removed without attempting to reach functional boundaries. Classification of all four tracts as FP is therefore conservative, since resection likely did not reach at least two .Benefits of pre-operative DT in planning and performing glioma resections were reviewed recently , 37. DT post-operative DT to predict functional recovery. Recovery from surgical white matter damage is thought to be limited [transient deterioration after surgery, the main concern is to rule out damage to eloquent tracts producing lasting impairment. Very few (4%) of our patients experienced prolonged deficits. Nonetheless, post-operative DT distinguished a patient with a preserved CST who made a full recovery from another patient with a small infarct who required lengthy rehabilitation. Post-operative DT has rarely been reported, but another study demonstrated that post-operative language tract DT informed speech outcomes [The final aim of our study was to explore the potential for  limited . While poutcomes . TogetheDifferent tractography techniques produce varied results . DetermiSupplementary file1 (DOCX 662 KB)Below is the link to the electronic supplementary material."}
+{"text": "KRAB-ZFP) transcriptional repressors recruit TRIM28/KAP1 to heterochromatinize the mammalian genome while also guarding the host by silencing invading foreign genomes. However, how a KRAB-ZFP recognizes target sequences in the natural context of its own or foreign genomes is unclear. Our studies on B-lymphocytes permanently harboring the cancer-causing Epstein-Barr virus (EBV) have shown that SZF1, a KRAB-ZFP, binds to several lytic/replicative phase genes to silence them, thereby promoting the latent/quiescent phase of the virus. As a result, unless SZF1 and its binding partners are displaced from target regions on the viral genome, EBV remains dormant, i.e. refractory to lytic phase-inducing triggers. As SZF1 also heterochromatinizes the cellular genome, we performed in situ footprint mapping on both viral and host genomes in physically separated B-lymphocytes bearing latent or replicative/active EBV genomes. By analyzing footprints, we learned that SZF1 recognizes the host genome through a repeat sequence-bearing motif near centromeres. Remarkably, SZF1 does not use this motif to recognize the EBV genome. Instead, it uses distinct binding sites that lack obvious similarities to each other or the above motif, to silence the viral genome. Virus mutagenesis studies show that these distinct binding sites are not only key to maintaining the established latent phase but also silencing the lytic phase in newly-infected cells, thus enabling the virus to establish latency and transform cells. Notably, these binding sites on the viral genome, when also present on the human genome, are not used by SZF1 to silence host genes during latency. This differential approach towards target site recognition may reflect a strategy by which the host silences and regulates genomes of persistent invaders without jeopardizing its own homeostasis.Kr\u00fcppel-associated box-domain zinc finger protein  a mechanism for directing constitutive heterochromatin and ii) a strategy that allows the host to use the same heterochromatin machinery to regulate an invader without deregulating itself. Heterochromatin mediates functions ranging from gene regulation and regulation of imprinting control regions and endogenous retroviruses to maintenance of stem cell pluripotency \u20134. HeterThough TRIM28/KRAB-ZFP complexes engage both self and foreign genomes, how KRAB-ZFPs recognize target sequences on DNA in the natural context of the genome remains poorly understood. Further, whether KRAB-ZFPs like SZF1 target host and foreign genomes in a similar manner is also not known. While binding sites of some KRAB-ZFPs have been informatically inferred from ChIP-seq experiments utilizing overexpressed and tagged KRAB-ZFPs , definedUsing ChIP-exo, a high-resolution in situ strategy on isolated pure subpopulations of EBV-infected cells harboring latent versus lytic virus, we mapped SZF1 footprints on both self and viral genomes. Our analysis of the footprints on cellular genomes revealed a motif that was able to regulate gene expression. Footprints bearing this motif contained a repeat sequence and were enriched on pericentromeric regions of chromosomes. In contrast, viral genomes demonstrated no footprints bearing this motif. Experiments using virus mutants confirmed that SZF1 instead uses distinct non-consensus sequences to silence lytic genes on viral genomes, thereby shifting the balance towards latency. We found that such lytic silencing via interactions between SZF1 and non-consensus binding sites on the viral genomes is also needed to establish viral latency and transform newly infected B cells. Overall, the number of SZF1 footprints on the cell genome did not differ greatly between cells harboring latent or lytic viral genomes. That said, we found SZF1 to be enriched at the latent origin of replication (oriP) in lytic cells, though not contributing actively to viral genome replication arising from the lytic origins. The abovementioned non-consensus SZF1 binding sites identified on the viral genome were preferentially enriched in latent versus lytic cells, pointing towards SZF1-mediated differential host gene programming during latent and lytic states. Remarkably, although these non-consensus sites also mapped to the cell genome, they were not used by SZF1 to silence the host during latency. Thus, compared to self-genomes, the SZF1-TRIM28 machinery silences foreign herpesviral genomes using a different targeting strategy that may allow the host to shield itself from collateral damage.+ tumor/transformed B cell lines that were available, we chose HH514-16, a well-studied Burkitt lymphoma (BL)-derived cell line because these cells are tightly latent at baseline but can be readily triggered to support the lytic phase. As shown in To identify SZF1\u2019s footprints in the genomic context, we combined two approaches. The first is a cell-separation strategy that we developed to isolate latent cells in which EBV is refractory to lytic triggers from those that support the EBV lytic phase ,22\u2013this BZLF1 promoter , BGLF4 (early lytic) gene, and BDLF2 (late lytic) gene, respectively, that demonstrated between 44% and 99% repression of GFP. In contrast, the others did not silence GFP; an example of one such site associated with BALF1 is also shown  can transcriptionally activate kinetically downstream lytic genes Cell extracts were electrophoresed in 10% SDS-polyacrylamide gels, transferred onto nitrocellulose membranes, and blocked using 5% milk. Immunoblotting was performed using indicated antibodies at concentrations recommended by the manufacturer.+ and GFP- gates based on parallel untransfected control samples. As a transfection control in these experiments, cells were co-transfected with SignalSilence Control siRNA Cy5 Conjugate . FACS of HH514-16 cells for ChIP-exo was performed using a BD Aria II FACS instrument; again, staining and gate placement were performed as described in ChIP-Exo.HEK-293T cells were washed twice with 1x PBS and then subjected to flow cytometry. Flow cytometry data were acquired on a ThermoFisher Attune NxT Flow and analyzed using FlowJo software (Tree Star) with placement of GFPTotal RNA was isolated from HH514-16 cells by using an RNeasy kit (Qiagen) followed by DNase digestion (Promega). RNA was quantitated by using a NanoDrop instrument (Thermo Scientific). RNA (1\u03bcg) was converted to cDNA by using MuLV Reverse Transcriptase (New England Biolabs). Relative transcript levels of selected cellular genes were determined with gene-specific primers  and then Proteinase K overnight at 37\u00b0C. Absolute EBV genome copy number was determined with a standard curve obtained through qPCR using serially diluted BACmid p2089 as template. Primers targeting the EBV BALF5 gene were used to calculate relative released virus compared to wild type 293-BAC cells.Viral DNA in supernatant was measured using quantitative-PCR (qPCR) by amplifying EBV 6 primary B cells from three individual donors were infected at an MOI of 1  with each respective virus. Live cell counts were performed beginning on day 14 post infection.To assess changes in growth of primary B cells infected with wild type p2089 virus or SZF1-binding site mutant viruses, 5x10P values were calculated by comparing the means of two groups of interest using unpaired Student t test.S1 FigBZLF1p, BGLF4, and BDLF2. Coverage of the reads from lytic and refractory genomes were determined with Bedtools software (v2.30.0) and plotted in R. The lytic reads were normalized to refractory EBV genome copy number. Rightward and leftward strands are indicated by blue and red, respectively. Genome position numbers corresponding to the reference genome NC_007605 are indicated and validated SZF1 binding sites are indicated with brackets.Plots show read distributions at SZF1-binding sites and +/- 60 bp mapping to (TIF)Click here for additional data file.S1 TableTotal SZF1 ChIP-exo reads mapping to the human genome reference (Hg38/GRCh38) or EBV genome reference (NCBI Accession: NC_007605) for each experimental condition . Mapped and unique lytic reads were normalized based on EBV copy number in refractory cells.(XLSX)Click here for additional data file.S2 TablePeaks: overlapping clusters of reads with sigma = 5 exclusion zone = 10 (s5e10F1), or sigma = 20 exclusion zone = 40 (s20e40F1), excluding singletons. Singletons: peaks wherein all associated reads are located at a single chromosomal coordinate. Peak-median: median read count for all peaks, excluding singletons. Peak-mean: average read count for all peaks, excluding singletons. Median-std: median standard deviation for all peaks with standard deviation greater than zero. The standard deviation reflects the variance of read positions within each peak. A peak with a standard deviation = 0 defines a singleton peak and is excluded from further analysis. Mean-std: average standard deviation for all peaks with standard deviations greater than zero.SZF1 ChIP-exo sequence reads were mapped to either the EBV (NC_007605) or human (GRCh38) genome. Total indexed reads and unique read counts are shown for ChIP-exo sequence reads contributing to peak calling. (XLSX)Click here for additional data file.S3 TablePeak midpoint positions mapped to the EBV reference genome (NC_007605), listed in descending order based on number of contributing midpoint sequences. Immediate early, early, and late refer to kinetic classes of lytic genes; CDS, coding sequence. Sites corresponding to the bolded genes were analyzed via GFP repression assay in (XLSX)Click here for additional data file.S4 TableSZF1 binding sites within the EBV genome were mapped to the human genome with the requirement of 12 contiguous nucleotides sharing 100% identity. Neighboring genes within 100 kb of the potential binding sites, with the potential to be regulated via SZF1 binding, are shown. Sites with validated presence in peak-pair sequences, i.e. footprints determined from the SZF1 ChIP-exo data for each condition  are also shown.(XLSX)Click here for additional data file.S5 TableSequences derived from the top 27 motifs identified from Meme-suite analysis of SZF1 ChIP-exo read libraries mapped to Human (GRCh38) or EBV (NC_007605) genomes. Note: Fine grain peak-calling when sigma (s) = 5, exclusion zone (e) = 10; Coarse grain peak-calling sigma (s) = 20, exclusion zone (e) = 40; Untreated Human s5e10 and Lytic EBV s5e10 resulted in no motif hits. e values in bold indicate validated Motifs 1 and 2 while e value highlighted in grey indicates Motif 3 depicted in (XLSX)Click here for additional data file.S6 Table(XLSX)Click here for additional data file.S7 Table(XLSX)Click here for additional data file.S8 TableStart and end positions of motif 1 consensus (ATGGAATCGAATGGAATC) clustered on chromosomes 16 and 5 of the human genome (GRCh38) are shown along with any genes found within 100 kb upstream or downstream of the motif clusters. Additional SZF1 motif 1 clusters are shown in (XLSX)Click here for additional data file."}
+{"text": "Intratumor heterogeneity (ITH) is associated with tumor progression, unfavorable prognosis, immunosuppression, genomic instability, and therapeutic resistance. Thus, evaluation of ITH levels is valuable in cancer diagnosis and treatment.We proposed a new mRNA-based ITH evaluation algorithm (DEPTH2) without reference to normal controls. DEPTH2 evaluates ITH levels based on the standard deviations of absolute z-scored transcriptome levels in tumors, reflecting the asynchronous level of transcriptome alterations relative to the central tendency in a tumor.By analyzing 33 TCGA cancer types, we demonstrated that DEPTH2 ITH was effective in measuring ITH for its significant associations with tumor progression, unfavorable prognosis, genomic instability, reduced antitumor immunity and immunotherapy response, and altered drug response in diverse cancers. Compared to other five ITH evaluation algorithms , DEPTH2 ITH showed a stronger association with unfavorable clinical outcomes, and in characterizing other properties of ITH, such as its associations with genomic instability and antitumor immunosuppression, DEPTH2 also displayed competitive performance.DEPTH2 is expected to have a wider spectrum of applications in evaluating ITH in comparison to other algorithms.The online version contains supplementary material available at 10.1186/s12967-022-03355-1. Intratumor heterogeneity (ITH) refers to the differences of molecular and phenotypic profiles between different tumor cells within tumors. ITH has significant associations with tumor advancement, prognosis, immune evasion, and therapeutic responses . Many alIn this study, we proposed a novel algorithm to score ITH at the mRNA level. Similar to DEPTH, the novel algorithm, termed DEPTH2, measured ITH based on the perturbations of gene expression profiles. However, different from DEPTH and other ITH evaluation methods, DEPTH2 quantified ITH without reference to normal controls. It indicates that DEPTH2 can be applied to any gene expression profiles in tumors, regardless of whether the gene expression profiles in normal samples available or not. Furthermore, by analyzing transcriptomic profiles in more than 30 cancer types, we demonstrated that DEPTH2 is competitive in characterizing the properties of ITH compared with most established algorithms, including DEPTH.https://portal.gdc.cancer.gov/). The 33 cancer types included adrenocortical carcinoma (ACC), bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), cholangiocarcinoma (CHOL), colon adenocarcinoma (COAD), lymphoid neoplasm diffuse large B-cell lymphoma (DLBC), esophageal carcinoma (ESCA), glioblastoma multiforme (GBM), head and neck squamous cell carcinoma (HNSC), kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), acute myeloid leukemia (LAML), brain lower grade glioma (LGG), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), mesothelioma (MESO), ovarian serous cystadenocarcinoma (OV), pancreatic adenocarcinoma (PAAD), pheochromocytoma and paraganglioma (PCPG), prostate adenocarcinoma (PRAD), rectum adenocarcinoma (READ), sarcoma (SARC), skin cutaneous melanoma (SKCM), stomach adenocarcinoma (STAD), testicular germ cell tumors (TGCT), thyroid carcinoma (THCA), thymoma (THYM), uterine corpus endometrial carcinoma (UCEC), uterine carcinosarcoma (UCS), and uveal melanoma (UVM). For each RSEM normalized gene expression value, we added it to 1 and then log2-transformed. We downloaded transcriptomic data (Affymetrix Human Genome U219 array) for cancer cell lines and drug sensitivities  of these cell lines to 265 compounds from the Genomics of Drug Sensitivity in Cancer (GDSC) project (https://www.cancerrxgene.org/downloads). In addition, we downloaded 34 validation datasets from three resources: GEO (https://www.ncbi.nlm.nih.gov/geo/), ArrayExpress (https://www.ebi.ac.uk/arrayexpress/), and UCSC (https://xenabrowser.net/datapages/). We also downloaded gene expression profiles and clinical data for four cancer cohorts receiving anti-PD-1/PD-L1/CTLA-4 immunotherapies, including the Allen (melanoma)  tumors in diverse cancers . (E) Kaplan\u2013Meier curves showing that the tumors with higher tumor purity-adjusted DEPTH2 scores (>\u2009median) have more inferior overall survival and disease-specific survival than the tumors with lower tumor purity-adjusted DEPTH2 scores (<\u2009median) in 5 and 6 individual cancer types, respectively. The log-rank test P-values are shown."}
+{"text": "Tumors display widespread transcriptome alterations, but the full repertoire of isoform-level alternative splicing in cancer is unknown. We developed a long-read (LR) RNA sequencing and analytical platform that identifies and annotates full-length isoforms and infers tumor-specific splicing events. Application of this platform to breast cancer samples identifies thousands of previously unannotated isoforms; ~30% affect protein coding exons and are predicted to alter protein localization and function. We performed extensive cross-validation with -omics datasets to support transcription and translation of novel isoforms. We identified 3059 breast tumor\u2013specific splicing events, including 35 that are significantly associated with patient survival. Of these, 21 are absent from GENCODE and 10 are enriched in specific breast cancer subtypes. Together, our results demonstrate the complexity, cancer subtype specificity, and clinical relevance of previously unidentified isoforms and splicing events in breast cancer that are only annotatable by LR-seq and provide a rich resource of immuno-oncology therapeutic targets. Breast cancer long-read transcriptome profiling reveals patient-enriched isoforms, with implications for disease progression. CD44, a transmembrane glycoprotein that functions in cell division, viability, and adhesion, has been linked with tumor progression and epithelial-to-mesenchymal transition in breast and ovarian cancer models , transcription initiation, and polyadenylation in healthy and diseased cells  data and have identified a number of recurrent and tumor-specific splicing alterations across many cancer types, including breast (Long-read mRNA sequencing (LR-seq) is able to accurately capture full-length (FL) isoforms from start to end, eliminating the need for reference-based transcript reconstruction ], nine patient-derived xenograft (PDX) tumors, and four cancer cell lines  circular consensus sequencing (CCS) using the PacBio RSII and Sequel platforms were polished using the ToFU (Transcript Isoforms Full length and Unassembled) pipeline . An FL isoform consists of a single-mRNA molecule containing a polyadenylation [poly(A)] tail, where the entire transcript including cDNA adaptors at the 5\u2032 and 3\u2032 ends are successfully sequenced. After ToFU consensus clustering, 84% of CCS reads achieve 99.999% (Q50) accuracy (file S2). Overall, per library, we obtained an average of 546,000 CCS reads, which after processing resulted in ~21,000 FL polished isoforms (file S2). As a quality control step after ToFU, we filtered transcripts with inadequate splice junction support and those that contained signatures of poly(A) intrapriming or noncanonical junctions derived from reverse transcriptase template switching .Next, isoforms were classified into known or novel isoforms based on their splice junction match to a reference transcriptome (GENCODE v.30) using SQANTI. Known isoforms are classified as full-splice match (FSM), while novel isoforms include both transcripts that harbor a combination of known splice donors or acceptors that have not been previously cataloged in the same transcript [novel in catalog (NIC)] and isoforms containing at least one splice site not present in GENCODE v.30 [novel not in catalog (NNC)] . OverallOur comprehensive LR-seq breast cancer transcriptome contains 142,514 unique FL transcript isoforms  spanningTo assess the support for LR-seq isoforms by short-read sequencing, we performed RNA-seq and quantified isoform expression in 29 of our 30 LR-seq profiled breast samples. Briefly, 76\u2013base pair long paired-end RNA-seq libraries were sequenced at an average depth of 46 million reads per sample and mapped to our LR-seq breast cancer transcriptome using hisat2 and quantified using StringTie. While 89% of the annotated isoforms (FSM) were detected by RNA-seq [FPKM (fragments per kilobase per million mapped reads) > 0.5], NIC and NNC isoforms have average detection rates of 62 and 41%, respectively .CYTIP isoform originating from an alternative transcription start site supported by proximal CAGE and ATAC-seq peaks , ATAC-seq (assay for transposase-accessible chromatin using sequencing), and 3\u2032-seq. Previously unidentified 5\u2032 isoform regions substantially overlapped with CAGE-validated transcription start sites (FANTOM5 CAGE) and open chromatin regions detected by ATAC-seq in The Cancer Genome Atlas (TCGA) breast cancer tumors  (24). Sieq peaks . We alsoy 3\u2032-seq .Altogether, the integration of LR-seq with orthogonal data reveals that ~80% of our previously unidentified (NIC and NNC) breast cancer isoforms are validated by genomics (ATAC-seq) and/or transcriptomics  across independent samples.To assess the importance of novel isoforms from our LR-seq breast cancer transcriptome, we first examined the expression levels and gene pathways associated with these transcripts. Genes were binned into three groups based on our RNA-seq expression levels: low, average, and high based on FPKM cutoffs . Novel i2M checkpoint pathways), and development (myogenesis and EMT). Some cancer-related pathways were found to be enriched in a specific subtype such as glycolysis and mTORC1 signaling in HER2+ tumors, while others were shared. Myc targets were enriched in both HER2+ and TNBC tumors, while estrogen response was common to ER+/PR+ and TNBC. Notably, oncogenes are significantly overrepresented when isoforms from all tumors are combined  and selected genes with >2-fold increase for pathway enrichment analysis. We performed this analysis for all combined breast tumor isoforms and for isoforms in individual breast cancer subtypes to identify pathways that are common or specific to breast cancer subtypes (fig. S2A). When combining all tumors by subtype, spliced genes with novel isoforms are strongly associated with key breast cancer pathways, including estrogen, androgen, and interferon gamma response, mTORC1  signaling, and mitotic spindle regulation  exhibit a twofold increase in NIC + NNC isoforms compared to GENCODE v.30 , as well as genes known to be alternatively spliced in cancer such as CASP8, ENAH, BCL2L1, and STAT3 (fig. S4C). In summary, LR-seq profiling of breast tumors identifies novel spliced isoforms in genes previously associated with key cancer pathways and in known breast cancer oncogenes.We next examined individual genes that had a high gain of novel splice isoforms in our LR-seq breast cancer transcriptome. In total, 24 oncogenes including the human epidermal growth factor receptor 2 (ODE v.30 . ERBB2 it tumors . Many ofhttps://brca-isoforms.jax.org/), which includes Transdecoder for ORF predictions, as well as DeepLoc, TMHMM, and hmmer for localization predictions, and in-house scripts for comparative sequence analysis and nonsense-mediated mRNA decay (NMD) predictions .To understand the potential functional consequences of novel isoforms from our LR-seq breast cancer transcriptome at the protein level, we extracted open reading frames  and predicted domains, transmembrane regions, and subcellular localization using our ORF annotation pipeline  based on our ORF prediction, except for antisense and intergenic transcripts for which 74% have a predicted ORF (fig. S5A). However, NIC and NNC spliced isoforms are more likely to be targeted for mRNA degradation by the NMD pathway, because 11% of NIC and 20% of NNC translated ORFs contain premature termination codons compared to 3% of FSM ORFs (fig. S5B). Similarly, novel ORFs absent from the protein coding database UniProt are subject to NMD at equivalent rates  (fig. S5B).ESR1 (ER\u03b1), a clinical biomarker of hormone-positive breast cancers with several AS isoforms associated with cancer progression or treatment . Among those, seven novel protein isoforms are predicted to lack the DNA binding domain. Eleven ESR1 isoforms contained with novel regions affected by AS, including five protein isoforms with loss of the ligand-independent transactivation domain (AF1) and six protein isoforms with loss of the ligand-dependent transactivation domain (AF2) (fig. S5D). A unique ESR1 isoform was predicted by TMHMM to contain a transmembrane domain and by DeepLoc to be localized to the cell membrane (fig. S5D). Therefore, AS in breast cancer often leads to changes in protein localization that might affect spliced isoform function.To determine whether LR-seq isoforms encode novel protein sequences, we compared the ORF of an LR-seq isoform to its closest match in UniProt using global pairwise alignment. The majority of annotated FSM (79%) and incomplete splice match (ISM) (85%) LR-seq isoforms encode ORFs that are >99% identical to an entry in UniProt . In contBeyond transcript annotation, our pipeline leverages existing proteomics data for isoform validation . To detef1) and uniformity (pme) of ribosome occupancy across known and novel ORFs. To obtain sample-specific periodicity and uniformity cutoffs that are indicative of an isoform being translated, we selected as positive controls 343 single-ORF housekeeping genes that are found to be expressed in all tissues according to the Human Protein Atlas (fig. S6A). These cutoffs were applied to the remaining of our LR-seq transcripts and found that on average 53% of known isoforms (FSM) and 36% of novel isoforms (NIC and NNC) have evidence of active translation from the Ribo-seq data in breast cancer cell lines (fig. S6B). In sum, our analytical pipeline reveals that previously unannotated spliced LR-seq isoforms detected in breast cancer encode novel protein isoforms with changes in functional domains, transmembrane regions, and/or cellular localization and that the translation of novel isoforms can be confirmed with MS/MS and ribosomal profiling data.To determine whether novel isoforms were actively translated, we performed an isoform-specific ribosome profiling analysis using Ribo-seq (ribosome profiling) data from breast cancer cell lines  GTEx. We used SUPPA2 , using iGiven the heterogeneity of breast cancer, which can be classified into different subtypes based on gene expression and AS levels . OverallCYB561, a skipped exon in CEACAM1, and loss of an intron retention event in E2F4. Genes containing AS events associated with overall survival are known components of cancer-related pathways, including regulation of transcription , cell cycle (E2F4 and GTSE1), or cell-cell adhesion   .CYB561 and CEACAM1 are enriched in HER2+, and E2F4, AP2A2, MGAT4B, and DUXAP9 events are enriched in basal-like breast tumors  and TSS2 (known)  . Patientpulation , thus lipulation  and 5E. E2F4 affecting 215 (19%) of TCGA breast tumors (E2F4 isoforms in the TCGA cohort (fig. S8A). In the E2F4-S1 subpopulation, E2F4 switches from an intron-containing transcript in normal tissues that is not translated to a protein coding isoform in which the intron is spliced out in breast cancer patients (fig. S8). The E2F4 loss of intron retention is highly specific to breast cancer (E2F4 transcription factor is associated with cancer severity and poorer prognosis in breast cancer (E2F4 intron retention (E2F4-S1 subpopulation) have unfavorable prognosis when compared with patients where the intron is retained (fig. S8). Thus, this retained intron event might represent a regulatory mechanism by which splicing leads to up-regulation of the E2F4 oncogene in breast cancer.We also identified a loss of intron retention in the breast cancer oncogene CEACAM1, CYB561, and E2F4 as potentially playing a role in disease outcome.In summary, patient stratification using our novel GMM clustering analysis identified tumor-specific splicing events in breast cancer that are confined to patient subpopulations with variable prevalence. These patient subpopulations carry distinctive splice alterations compared to tumor adjacent and normal tissues (https://brca-isoforms.jax.org) that provides tools for querying, visualizing, and downloading data. We integrated LR-seq isoforms with orthogonal datasets to demonstrate the reliability of the approach and proposed an analysis framework to detect the functional consequences of spliced isoforms in cancer. Last, we used the resultant long-read breast cancer transcriptome to uncover novel isoforms associated with patient survival in TCGA using a GMM clustering approach to identify clusters of patients with similar splicing profiles.We performed LR-seq on 30 breast tumor and normal samples to define the FL isoform-level transcriptome of human breast cancers and developed an analytical pipeline to predict the functional consequences of cancer-associated splicing changes. We identified isoform-level diversity in tumors and developed a thorough LR-seq\u2013based breast cancer isoform catalog for quantitative and qualitative assessment of potential translation and subsequent protein domain effects. The data are made available through an interactive web portal  polymerase inhibitors in ovarian cancer  T cells. Isoforms also generate peptides that could be used for vaccination protocols, possibly in combination with checkpoint inhibitors.The study was conducted following approval by the Institutional Review Board(IRB) of The Jackson Laboratory for Genomic Medicine . Normal breast samples were acquired from the Maine Cancer Biospecimen Portal. Breast cancer tissue sections were contributed by K.P. Exempt primary tissues from patients with breast cancer were obtained from the Baylor University Medical Center (BUMC) Tissue Bank . Consecutive postsurgical tumor samples  were collected between years 2006 and 2013.The samples used in this research from BUMC were collected with appropriate informed consent, and the use of these samples was approved by The Jackson Laboratory (JAX) IRB (17-JGM-06). The use of deidentified samples from the Maine Cancer Biospecimen Portal and BUMC Tissue Bank was reviewed by The Jackson Laboratory (JAX) IRB (16-NHSR-15 and 2018-039) and determined to not meet the definition of human subjects research under HHS regulation 45 CFR 46.Snap-frozen PDX tumor samples were obtained from The Jackson Laboratory . Upon receipt, frozen PDX tumors were placed in cryomolds (VWR #4557), embedded in optimal cutting temperature (OCT) media (VWR #4583), and stored at \u221280\u00b0C before RNA extraction.2.Cell lines were purchased from the American Type Culture Collection . CAMA-1, T-47D, and BT-549 lines were cultured in Dulbecco\u2019s modified Eagle\u2019s medium (Thermo Fisher Scientific #11965118) supplemented with 10% fetal bovine serum (Gemini Bio #100-500). Hs578t was cultured in Dulbecco\u2019s modified Eagle\u2019s medium (Thermo Fisher Scientific #11965118) supplemented with 10% fetal bovine serum (Gemini Bio #100-500) and bovine insulin . Hs578Bst was cultured with Hybri-Care Medium (ATCC #46-X) and supplemented with sodium bicarbonate , mouse epidermal growth factor (EGF) , and 10% fetal bovine serum (Gemini Bio #100-500). MCF-7 was cultured in Eagle\u2019s minimum essential medium (ATCC #30-2003) supplemented with recombinant human insulin (0.01 mg/ml) and 10% fetal bovine serum. MDA-MB-231 and MDA-MB-468 lines were cultured in Leibovitz\u2019s L-15 medium (ATCC #30-2008), supplemented with 10% fetal bovine serum. HCC-1500 was cultured with RPMI 1640 medium (ATCC #30-2001) supplemented with 10% fetal bovine serum (Gemini Bio #100-500). MCF-10A was cultured in MEBMTM Mammary Epithelial Cell Growth Basal Medium (Lonza) supplemented with cholera toxin , 2.00 ml of Bovine Pituitary Extract (BPE) (Lonza), 0.50 ml of human epidermal growth factor (Lonza), 0.50 ml of insulin (Lonza), and 0.50 ml of hydrocortisone (Lonza). Cell lines were kept at 37\u00b0C with 5% COHigh-quality RNA was extracted from primary tumor tissues or cells. Briefly, using a Cryostat, four to five 0.3-\u03bcm tissue sections were cut from OCT-embedded tumors, mixed in 350 \u03bcl of RLT Lysis buffer containing 10% \u03b2-mercaptoethanol, and either frozen at \u221230\u00b0C or sent immediately for RNA extraction. For primary cells, cells were pelleted by centrifugation and then lysed with 350 \u03bcl of RLT + 10% \u03b2-mercaptoethanol. RNA was extracted using the RNeasy Mini Prep Kit following the manufacturer\u2019s instructions (Qiagen #74106). Samples were treated with deoxyribonuclease I (Qiagen #79254) and eluted in 30 to 50 \u03bcl of ribonuclease-free water. RNA quality and quantity were assessed using a Qubit 2.0 fluorometer (Thermo Fisher Scientific), and only samples with RNA integrity number > 8.0 were selected for sequencing.Following RNA extraction, FL cDNA synthesis from poly-A\u2013containing transcripts was performed using the Clontech SMARTer Polymerase Chain Reaction (PCR) Kit (Takara). The resulting cDNA was PCR-amplified to generate 1 to 2 \u03bcg of cDNA, and PCR products were purified using AMPure XP magnetic beads (Beckman Coulter). Size selection was performed using the Sage Science BluePippin System to remove small cDNA fragments that were preferentially sequenced by diffusion loading. Next, SMRTbell adapters were ligated to cDNA ends and purified by magnetic beads using the SMRTbell Template Prep Kit (Pacific Biosciences), followed by sequencing in a PacBio RSII or Sequel instrument. The list of clinical samples, PDXs, and cell lines sequenced in this study is provided in the file S1. File S2 provides additional information including equipment, size selection, and sequencing metrics for individual library runs.RNA was extracted using the Qiagen RNeasy Mini Prep kit and measured using a Qubit 2.0 fluorometer (Thermo Fisher Scientific). RNA underwent quality control testing using a 2100 Bioanalyzer  followed by cDNA library preparation using the KAPA Stranded mRNA-Seq kit (Roche) according to the manufacturer\u2019s instruction. Paired end sequencing was performed at 76 base pairs on each side of the DNA fragment on the Illumina NextSeq platform. In total, RNA-seq was performed for 29 tumor and control samples, with 10.7 to 142.4 million reads sequenced per sample (mean = 46.4 million).One microgram of RNA was reverse-transcribed using the SuperScript IV First-Strand Synthesis System with both oligod(T) and random hexamer primers per manufacturer instructions (Invitrogen #18091050). Touch-down PCR was used to amplify 200 ng of cDNA with Q5 High-Fidelity DNA Polymerase and the High-GC content buffer (New England Biolabs #M0491L), and primers are listed in file S4 on a Bio-Rad T100 Thermal Cycler (Bio-Rad #1861096). PCR products were separated in 2% agarose gel stained with SYBR Safe (Invitrogen) and imaged using ChemiDoc MP Imaging System (Bio-Rad).https://github.com/PacificBiosciences/IsoSeq_SA3nUP/wiki. Briefly, the pipeline generates nonredundant FL transcripts in the following steps: (i) classify reads as FL reads and non-FL reads based on the presence of adapters and polyA signal, (ii) identify isoform clusters for each transcript using FL read(s), and (iii) polish isoform sequences by performing error correction and obtaining a final consensus transcript using both FL and non-FL reads. FL transcripts were mapped to human (hg38) and mouse (mm10) genomes using gmap (https://github.com/Magdoll/cDNA_Cupcake) to create a nonredundant merged transcriptome. In addition to the samples sequenced in this study, a publicly available MCF7 cell line dataset (Raw PacBio Iso-seq data (BAM files) were processed using the ToFU pipeline  to obtain a comprehensive set of quality attributes for sequenced FL reads at both transcript and junction levels, which were applied for retaining high-quality transcripts and filtering out potential artifacts as detailed below.Our isoform annotation pipeline combined several tools for isoform transcript and ORF annotation as outlined in fig. S3A. Spliced isoforms were annotated with SQANTI  were filtered on the basis of 3\u2032 end reliability [no poly(A) intrapriming], noncanonical junctions or reverse-transcriptase switching (RT-switching) junctions, and splice junction read support as described below.SQANTI was used to flag transcripts with noncanonical junctions or junctions possibly derived from RT-switching.We used the SQANTI2 tool and the Intropolis dataset, a large compendium of RNA-seq samples containing ~21,000 human samples from the Short Read Archive .Gffcompare  It was located more than 100 base pairs away from an annotated TTS, (ii) the adenine percentage downstream of TTS > 80%, (iii) and no overlap with the polyA site database  = intersection/union, where AI and BI are the set of isoforms detected in given samples A and B, respectively.Hierarchical clustering of samples profiled by LR-seq was performed in R using the Jaccard pairwise similarity coefficient, which was defined as \u22125 to identify homologs in UniProt. Also, PFAM domains for all extracted ORFs were predicted using the hmmscan tool from hmmer v.3.1 (http://hmmer.org) using default parameters. Then, a single best ORF for each transcript was selected on the basis of significant sequence homology (blastp) and domain conservation (hmmer) to human proteins.We used sequence homology and domain conservation to human protein isoforms in UniProt to determine optimal coding sequences from FL LR-seq isoforms as described below. First, we assembled a comprehensive human proteome reference including both canonical (SwissProt + TrEmbl) and spliced isoforms (VarSplice) from UniProt release 2019-04, which contained 95,915 protein sequences. Possible coding sequences (ORFs) from LR-seq isoforms were predicted using Transdecoder  analysis was performed using a custom R script using the coding sequence predicted by Transdecoder. Specifically, an FL transcript was predicted as NMD sensitive when the stop codon occurred before the terminal exon and was located more than 55 nucleotides upstream of the last splice junction. Scripts for performing global alignment and NMD prediction were implemented using mclapply .Raw MS/MS datasets from TCGA breast cancer patients (230 samples from 125 tumors) were retrieved from the CPTAC database  and to compute signal periodicity (f1) and uniformity (proportion of maximum entropy or pme) of ribosome occupancy across all known and novel ORFs. We obtained a list of 343 single-ORF housekeeping genes that are found to be expressed in all tissues from the Human Protein Atlas and computed minimum f1 and pme cutoffs that classified as translated at least 80% of single-ORF housekeeping genes in each sample. ORFs with pme and f1 above the cutoffs and with at Ribo-seq coverage of at least 10 reads were considered actively translated in each sample.Ribo-seq and RNA-seq for HMEC, MCF-10A, T47D, ZR-75-1, SUM159PT, and MDA-MB-231 were obtained from Vaklavas \u2212t 250) for PSI calculation. For other types of events , the overlap threshold was set to 10 base pairs.AS events were extracted and quantified using SUPPA2 .The GMM clustering was implemented in R using the mclust package v. 5.4.1. The clustering approach consisted in fitting a mixture of Gaussian distributions to PSI values from AS events simultaneously in cancer and control samples, using the PSI matrix obtained from SUPPA2. Model fitting with mclust was performed using one to three Gaussian distributions , and the optimal fitting was determined using the Bayesian information criterion. For each AS event, samples were assigned to clusters (subpopulations) with highest probability, and the frequency of tumor and controls was computed within subpopulations. Subpopulations with high tumor purity (>90% breast tumor samples) were further analyzed for differential splicing and survival as described below. The Wilcox rank-sum test in R was used to determine differential splicing between a tumor-specific subpopulation and control tissues from TCGA and GTEx. Next, survival analysis was done using the pairwise_survdiff function from the survminer package v. 0.4.6, which performs pairwise comparisons between GMM-inferred subpopulations with corrections for multiple testing. Only subpopulations with at least 30 patients were included in the Kaplan-Meier analysis. Significant survival events were selected on the basis of the global t-Distributed stochastic neighbor embedding (t-SNE) was performed using the Rtsne package v. 0.13. The t-SNE representation was generated on the basis of the PSI matrix of exon skipping events. The PSI matrix was filtered to remove events with more than 80% of missing values. Samples with more than 80% of missing values were also removed. Missing values occurred for events in which neither the inclusion nor skipping forms are detected. Any remaining missing values were mean imputed. t-SNE with learning rate of 200 and perplexity of 50 was applied for all visualizations."}
+{"text": "This study highlights primary caregivers\u2019 experiences with health department policies designed to support people with cognitive impairment/Alzheimer\u2019s Disease and Related Dementias (ADRD). Caregivers were defined as individuals aged 45-85 that provide at least 10 hours of unpaid care. Five, 90-minute focus groups were conducted virtually with 24 caregivers of individuals with cognitive impairment/ADRD. Transcripts were analyzed thematically. Caregivers were primarily Black females (75%) with at least a high school education (42%). Care recipients were likely to be community-dwelling parents (71%), with moderate or advanced (79%) dementia. Caregivers described challenges with accessing resources intended for care recipients, especially as cognitive impairment worsened. Caregivers reported providing care 24/7 as traumatizing. Home-based personal aides and companionship services did not reduce this burden. COVID-19 impacted caregivers and care recipient\u2019s access to resources increasing burden. Policies need to be flexible for ever-changing needs of individuals with ADRD and support the overall well-being of the caregivers."}
+{"text": "TP63 affecting the translation initiation codon (p.1Met?). Sanger sequencing confirmed dominant inheritance of this unique variant in all six affected family members. In summary, our findings indicate that heterozygous variants in TP63 affecting the first translation initiation codon result in a novel phenotype dominated by a cleft tongue, expanding the complex genotypic and phenotypic spectrum of TP63-associated disorders.Variants in transcription factor p63 have been linked to several autosomal dominantly inherited malformation syndromes. These disorders show overlapping phenotypic characteristics with various combinations of the following features: ectodermal dysplasia, split-hand/foot malformation/syndactyly, lacrimal duct obstruction, hypoplastic breasts and/or nipples, ankyloblepharon filiforme adnatum, hypospadias and cleft lip/palate. We describe a family with six individuals presenting with a striking novel phenotype characterized by a furrowed or cleft tongue, a narrow face, reddish hair, freckles and various foot deformities. Whole-exome sequencing (WES) identified a novel heterozygous variant, c.3G>T, in  TP63 [MIM 603273] have been linked to several autosomal dominantly inherited malformation syndromes including ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC [MIM 106260]), acro-dermo-ungual-lacrimal-tooth syndrome (ADULT [MIM 103285]), ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome 3 (EEC3 [MIM 604292]), limb-mammary syndrome (LMS [MIM 603543]), split-hand/foot malformation type 4 (SHFM4 [MIM 605289]) and isolated orofacial cleft 8 (OFC8 [MIM 618149]) , Robinow syndrome [MIM 180700] or distal arthrogryposis type 5D [MIM 615065], are as well associated with other forms of orofacial clefts, e.g., cleft lip and/or cleft palate. Among the genetic causes associated with these phenotypes, pathogenic variants in et genes \u201335. Inteet genes , 37. Howis study . TherefoTP63 variant. Despite intensive efforts, we were not able to identify any additional genetic cause of this. Presenting these cases will contribute to identify further families with hereditary cleft tongue due to variants in TP63, which will help to gain further insights into p63-associated pathomechanisms and to answer these open questions.Additionally, we found by extensive research of the literature a further hint in line with our assumption. Pries et al. reported in 1974 three patients with EEC syndrome showing a furrow in the midline of the tongue , too. CoTP63 affecting the first translation initiation codon result in a novel phenotype dominated by a cleft tongue, expanding the complex genotypic and phenotypic spectrum of TP63-associated disorders.In summary, our findings indicate that heterozygous variants in"}
+{"text": "Fosfomycin combination therapy is a potential approach for treatment of multidrug-resistant (MDR) PA infections despite a lack of approved susceptibility breakpoints for this organism. While DD testing is commonly used for fosfomycin, growth of discrete inner colonies (IC) within the zone of inhibition has been observed for multiple organisms following DD. Criteria recommended by CLSI and EUCAST are contradictory for interpreting these inner colonies. We therefore sought to determine the frequency of inner colonies and MIC differences between PA parent-inner colony pairs from an international isolate collection.Escherichia coli (EC) breakpoints .A convenience collection of 198 clinical PA isolates from three U.S institutions (n = 82), two Australian institutions (n = 72), and the CDC & FDA Antibiotic Resistance Isolate Bank (n = 44) were included. Fosfomycin MIC values were determined in duplicate on separate days by DD and broth microdilution (BMD) testing. For parent isolates with discrete IC observed during DD, IC isolates were subcultured and MIC values were determined and then compared to their corresponding parent isolates. MIC values were interpreted using CLSI 50/90 values were 128/256 \u03bcg/mL and > 1024/ > 1024 \u03bcg/mL for the parent and IC isolates, respectively. A high frequency of 45% (89/198) of parent isolates displayed discrete IC which also demonstrated a higher frequency of resistance (97.8%) compared to the parent isolates (23.7%).Parent isolate BMD MIC values ranged from < 4 to > 256 \u03bcg/mL while IC isolate BMD MIC values ranged from 128 to > 1024 \u03bcg/mL. MICIC MIC values were higher overall compared to parent MIC values, with an average fold difference of ~18 between the parent-inner colony pairs. The frequency of IC found in this study (45%) is considerably higher than previously observed in EC clinical isolates. These data highlight the need to further investigate the importance of these IC and warrant caution for extrapolation of EC breakpoints for fosfomycin susceptibility testing against PA.All Authors: No reported disclosures"}
+{"text": "COVID-19 disproportionately impacted older adults in terms of fatalities, but also increased stress, isolation, and loneliness . We examined older adults\u2019 anxiety, depression, and barriers to mental healthcare during the COVID-19 pandemic and their perceptions of these variables prior to the pandemic. Further, we explored whether any perceived changes differed based on geographical location . Data were collected online between mid-June and mid-July of 2020 from 244 individuals aged 65-82 years . The sample was primarily White (91%) and female (60%); most (n=119) lived in suburban settings, with 63 in urban and 60 in rural settings. Repeated-measures ANOVAs at alpha=.01 showed that depressive symptoms, measured by the CESD-10 (p<.001), and anxiety symptoms, measured by the GAD-7 (p<.001), increased during the pandemic as did mental healthcare barriers related to transportation (p=.004) and beliefs that depression is a normal part of aging (p<.001). Only transportation concerns differed based on where older adults lived; those in rural (p<.001) and urban (p=.004) settings reported greater transportation barriers than those in suburban settings. No differences over time were found for barriers related to help-seeking (p=.403), stigma (p=.156), knowledge/fear (p=.180), finding a therapist (p=.030), ageism (p=.302), psychotherapist qualifications (p=.265), physician referrals (p=.207), or finances (p=.818). These findings highlight the impact of COVID-19 on older adults\u2019 perceptions of changes in their psychological well-being as well as their experience navigating mental health services."}
+{"text": "MANF supplementation increased restorative Ly6Clow macrophages and subsequently alleviated liver injury. Moreover, MANF could enhance IL-10 expression and phagocytosis in macrophages via p38 MAPK pathway. Altogether, MANF seems to be a critical immune modulator in promoting liver repair via reducing and reprogramming MoMFs. MANF perhaps promoted the phenotype conversion of pro-inflammatory MoMFs to pro-restorative Ly6Clow MoMFs via p38 MAPK pathway, particularly through enhancing IL-10 and phagocytosis.Acetaminophen (APAP)-induced liver injury (AILI) is the most frequent cause of acute liver failure; but the underlying mechanisms still remain obscure. Macrophages and endoplasmic reticulum (ER) stress play an important role in the pathogenesis of AILI. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a newly identified 18-kDa soluble protein, whose expression and secretion are stimulated by ER stress. To investigate the role of myeloid cell MANF in the pathogenesis of AILI, we assayed serum and liver samples from AILI model mice and patients with drug-induced liver injury (DILI). We demonstrated that the levels of MANF were elevated in patients with DILI and in mice with AILI. Moreover, myeloid-specific MANF knockout mice were generated and used. It was observed that a delayed liver recovery from myeloid-specific MANF gene knockout mice following APAP overdose compared to that from wild-type mice. MANF deficiency in myeloid cells resulted in increased infiltrating monocyte-derived macrophages (MoMFs) but reduced restorative Ly6C Drug-induced liver injury (DILI) is one of the major causes of liver diseases around the world. In Western society, the main cause of acute liver injury is acetaminophen (APAP) overdose . APAP is+ Ly-6Chi monocytes into injured liver [hi macrophages have a pro-inflammatory phenotype reflected by the expression of inflammatory cytokines. Hence, antagonists against CCL2 or CCR2 ameliorates the early but not the late phase of AILI via reducing the recruitment of monocytes [hi monocytes differentiate into Ly-6Clow restorative macrophages at the site of injury. Ly-6Clow macrophages express anti-inflammatory cytokines, regenerative growth factors and matrix degrading metalloproteinase to promote resolution from injury [Initial NAPQI-induced direct hepatocyte damage leads to the release of damage-associated molecular patterns (DAMP), which activates cytokines and chemokines formation in resident Kupffer cells for recruitment of neutrophils and circulating monocytes , 7. CCL2ed liver . These med liver . It has onocytes , 11. Intm injury \u201315. Signm injury \u201318.Mesencephalic astrocyte-derived neurotrophic factor (MANF), a new evolutionary conserved neurotrophic factor, is widely expressed in neuronal and non-neuronal tissues , 20. MANn\u2009=\u200924). In addition, 24 healthy blood samples were included as a control group. Normal liver samples were obtained from surgical resections of uninvolved liver tissues of angioma patients (n\u2009=\u200920). Informed consent was obtained from all subjects. This study was approved by the Ethics Committee of Anhui Medical University and the First Affiliated Hospital of University and Science and Technology.Liver tissues and blood samples of patients with drug-induced liver injury were collected from the First Affiliated Hospital of University and Science and Technology in this study  were prepared immediately before use by dissolving the compound in warmed PBS. After overnight fasting, 8\u201310 week old male mice were injected with APAP 300 (mg/kg) intraperitoneally. For the treatment, some of the mice were intravenously injected with recombinant human MANF  or recombinant mouse IL-10  0.5\u2009h after APAP administration.Serum ALT levels were measured using an ALT assay kit (Nanjing Jiancheng Bioengineering Institute) according to the manufacturer\u2019s instructions.Serum MANF levels were measured by using the MANF ELISA Kit 96\u2009T (Reddot Biotech Inc) according to the manufacturer\u2019s instructions.TM RT reagent Kit  (TaKaRa). Quantitative PCR was performed using SYBR Premix Ex TaqTM II (Tli RNaseH Plus) (TaKaRa) on a StepOnePlus Real-Time PCR System . Each test was repeated three times and the 2\u2212\u0394\u0394 Ct method was used to calculate the expression of mRNA with \u03b2-actin as an internal control. The primer sequences are listed in Supplementary Table Total RNA was purified from samples using TRIzol reagents  according to the manufacturer\u2019s instructions. First strand cDNA was synthesized using the PrimeScriptg for 10\u2009min at 4\u2009\u00b0C.Hepatic leukocytes were isolated as described previously . BrieflyLiver tissues were fixed in 10% formalin and paraffin-embedded following standard procedure. Embedded liver tissues were sectioned, and stained with hematoxylin and eosin (H&E) or subjected to immunohistochemical staining using anti-MANF antibody , anti-Cyp2E1 antibody  according to the manufacturers\u2019 protocols. The necrosis areas were outlined according to the cellular structure and color. The percentages of necrosis areas were averaged from 5 to 7 random view fields of each section (\u00d7200 magnification) using ImageJ software.Immunofluorescence staining was performed on frozen sections with rabbit anti-mouse F4/80 , FITC conjugated goat anti-rabbit IgG (H\u2009+\u2009L) , mouse anti-mouse MANF antibody, Rhodamine conjugated goat anti-mouse IgG (H\u2009+\u2009L) , and 4\u2032, 6\u2032-diamino-2-phenylindole (DAPI). The images were obtained by using Leica TCS SP8 confocal microscope.The following fluorochrome-conjugated monoclonal antibodies were used in this study: anti-mouse PE/Cy7-conjugated CD45 (Cat# 940335), APC-conjugated Ly6G (Cat# 560599), PE-conjugated CD11b (Cat# 553311), PE-conjugated CD19 (Cat# 553786), and APC/Cy7-conjugated NK1.1(Cat# 560618) . PerCP/Cy5.5-conjugated F4/80 (Cat# 157317), APC/Cy7-conjugated Ly6C (Cat# 128025), FITC-conjugated CD14 (Cat# 123308), , and PE/Cy7-conjugated CD3 (Cat# 25-0031-82) . Cells were blocked with FcR blocker (BD Pharmingen) and then incubated with the indicated antibodies under standard protocols. All samples were analyzed using flow cytometry  with FlowJo (version 7.6.1) software.Harvested cells were homogenized in RIPA buffer  supplemented with protease inhibitor cocktail . Proteins were separated on 10% SDS-PAGE gels and were then transferred to NC membranes . Membranes were blocked 2\u2009h in 5% nonfat milk and probed with the following primary antibodies against: P-AKT (Cat# 4060)/AKT (Cat# 4685), P-JNK (Cat# 9255)/JNK (Cat# 9252), P-ERK (Cat# 4370)/ERK (Cat# 4695), p-p38(Cat# 4511)/p38(Cat# 8690) . All membranes were subsequently incubated for 2\u2009h with Peroxidase-conjugated Goat anti-rabbit IgG (ZB-2301) . Protein bands were visualized with SuperSignal West Femto Maximum Sensitivity Substrate . Antibody concentrations used were based on the manufacture\u2019s recommendations.THP-1 cells and primary peritoneal macrophages were cultured in RPMI1640 media supplemented with 10% fetal bovine serum and penicillin-streptomycin. Cells were pretreated with various MAPK inhibitors or AKT inhibitor for 1\u2009h, followed by rhMANF (2\u2009\u03bcg/mL) treatment for 5\u2009h. The concentrations of the inhibitors used were as follows: c-Jun amino terminal kinase (JNK) inhibitor , p38 inhibitor , and ERK inhibitor , AKT inhibitor .For detecting phagocytosis of macrophages, mouse primary hepatocytes or human hepatocytes (LO2 cells) were treated with 20\u2009\u03bcM dexamethasone for 24\u2009h and then labeled with 1\u2009\u03bcM CFSE for 15\u2009min at 37\u2009\u00b0C. Mouse peritoneal macrophages, liver MoMFs (isolated from the same mouse as primary hepatocytes), or human monocytes (THP-1 cells) were challenged with CFSE-labeled apoptotic hepatocytes for 1\u2009h at a 1:5 ratio at 37\u2009\u00b0C or 4\u2009\u00b0C. The cells were washed and stained with cell surface markers. Stained cells were analyzed by flow cytometry.t-test. Comparisons among multiple groups were performed using two-way ANOVA followed by Tukey\u2019s post hoc test. P\u2009<\u20090.05 were considered significant. Sample sizes of all experiments were predetermined from preliminary experiments or from reports in the literature. No sample was excluded from the analyses. All mice used in this study were chosen randomly. Investigators were not blinded to the group allocation during the experiment and outcome assessment.Data are expressed as the means\u2009\u00b1\u2009SD and were analyzed using GraphPad Prism software . The variance was similar between the groups that were being statistically compared. Comparisons between two groups were performed using an unpaired Student\u2019s + macrophages was increased significantly after APAP challenge, whereas the expression of MANF in hepatocytes was increased mildly  was higher than that in hepatocytes (about 1.3-fold)  Fig. .Fig. 1InManf knockout mice (ManfHep-/-), and myeloid-specific Manf knockout (ManfMye-/-) mice, and treated these mice with APAP. Compared to WT mice, ManfMye-/- mice showed higher levels of serum alanine aminotransferase (ALT), larger areas of liver necrosis, and lower numbers of Ki67+ hepatocytes at the late phase post-APAP injection, whereas ManfHep-/- mice had comparable liver injury and regeneration to WT mice    Fig.  were incManfMye-/-mice had a lower percentage of Ly6Clow restorative MoMFs and a higher percentage of Ly6Chi MoMFs between 24 and 72\u2009h post-APAP application . Critically, rhMANF treatment greatly decreased ALT levels (Supplementary Fig. SManfMye-/-mice 24\u2009h and 48\u2009h after APAP administration. These data indicated that rhMANF induced macrophages to switch to a phenotype promoting liver injury resolution in vivo.The beneficial function of MANF in liver injury resolution prompted us to test whether MANF delivery is sufficient to elicit protective effects; thus, we treated WT mice and hi MoMFs secret inflammatory cytokines [low MoMFs secrete anti-inflammatory cytokines [Tnfa and Il1b levels and decreased Il10 levels in ManfMye-/- mice compared to WT mice after APAP treatment (Fig. Il10 levels in hepatic macrophages of APAP-treated ManfMye-/- mice were much lower than those in APAP-treated WT mice, and rhMANF dramatically up-regulated Il10 levels in hepatic macrophages of ManfMye-/- mice (Fig. Il10 levels in the liver of both WT mice and ManfMye-/- mice, whereas had no effect on hepatic Tnfa and Il1b levels (Supplementary Fig. SGiven that Ly6Cytokines , whereasytokines , we exament Fig. . Moreoveice Fig. . In addiManfMye-/- mice with IL-10 after APAP injection. As expected, treatment of mice with IL-10 significantly reduced liver injury at 24\u2009h after APAP injection, which was demonstrated by reduced ALT levels (Fig. It has been reported that macrophages secrete the anti-inflammatory molecule IL-10 that actively promote tissue repair , 26. To els Fig.  and lessels Fig. .ManfMye-/- mice was decreased compared with WT mice after APAP treatment (Fig. ManfMye-/- mice as compared with WT mice (Fig. Tnfa, Il1b, and Il6 mRNA expression in naive mouse peritoneal macrophages and human macrophages, although this effect did not selectively depend on p38 MAPK (Supplementary Fig. STnfa, Il1b, and Il6 expression, but not Il10 (Supplementary Fig. STo understand the mechanism by which MANF regulates IL-10 expression in macrophages, we screened several potential signaling pathways that are involved in IL-10 production in myeloid cells . Our datent Fig. . In vitrice Fig. . These rGpnmb, Cd5l, Macro, Mertk, Trem2, and CD81. The apoptotic hepatocyte uptake assay further demonstrated that rhMANF treatment greatly increased MoMF phagocytosis in vivo (Fig. It has been reported that phagocytosis drives the conversion of inflammatory macrophages to restorative macrophages , 18. We ivo Fig. . Given tivo Fig. . It is wivo Fig. .Fig. 7MAConsistent with the above findings, rhMANF treatment also activated AKT, JNK, p38, and ERK1/2 MAPK in human THP-1 monocytes Fig. . All of hi monocytes transition to pro-resolution Ly6Clow MoMFs. Mechanistically, the interaction of MANF with p38 resulted in increased IL-10 expression and enhanced phagocytosis in macrophages. The fact that rhMANF treatment was sufficient to regulate MoMF infiltration, macrophage programming, and liver repair, suggesting the therapeutic potential of rhMANF in treating APAP overdose-induced liver injury and other liver diseases.Recently, MANF has been described to have a function in regulating immune homeostasis in aging and protecting against liver damage . HoweverManfMye-/- mice showed increased inflammation and liver injury at the late phase after APAP injection, whereas no increase in inflammation and liver injury was observed in ManfHep-/- mice compared to WT mice, suggesting that the autocrine immunomodulatory function of MANF in myeloid cells was essential for the resolution of APAP-induced liver injury. Notably, rhMANF treatment was sufficient to promote liver repair in both WT mice and ManfMye-/- mice. A recent study showed that MANF deficiency in Cx3cr1-expressing monocytes or macrophages resulted in liver damage and inflammation, however, hepatocyte-specific ablation of MANF did not result in increased immune activation and liver damage [We demonstrated that MANF was highly elevated in DILI patients and in an AILI mouse model. Both hepatic macrophages and stressed hepatocytes expressed MANF in response to liver injury, however, the increase of MANF expression in macrophages was higher than that in hepatocytes. Furthermore, r damage , which sManfMye-/- mice had increased levels of CCL2 and CCL3 in the liver. MANF-deficient CD115+ monocytes expressed higher surface levels of CCR2, which augmented cell mobilization and influx, possibly explaining the increased monocyte infiltration during the late phase compared with WT mice. During AILI, bone marrow-derived monocytes are recruited in the damaged liver tissue [hi monocytes during the fibrosis regression phase accelerates resolution of toxic and metabolic liver fibrosis [ManfMye-/- mice.Our data showed that MANF could extensively inhibit monocyte infiltration during the resolution phase. r tissue . Generalr tissue . Blockinfibrosis . In thislow macrophages than that in Ly6Chi macrophages [ManfMye-/- mice showed decreased levels of Il10 in the liver especially in hepatic macrophages. Treatment of ManfMye-/- mice with recombinant IL-10 protected against AILI. Second, MANF promoted macrophage phagocytosis. rhMANF treatment upregulated the expression of phagocytosis-related genes in macrophages thus enhancing macrophage phagocytosis. It has been reported that induction of phagocytic behavior enhances the restorative phenotype of macrophages [On the other hand, MANF orchestrated liver repair by triggering hepatic macrophage transition into a reparative phenotype. First, MANF promoted MoMFs to produce IL-10, which is an anti-inflammatory cytokine and was expressed much higher in Ly6Crophages . Deficierophages . In our rophages , 18. Pharophages .Mechanically, our results demonstrated that MANF promoted macrophage transition into a reparative phenotype, possibly by interacting with p38 MAPK. The p38 MAPK pathway is well known for its role in transducing stress signals from environments such as pathogens, heat shock, growth factors, and cytokines . In thishi monocytes transition into restorative Ly6Clow macrophages at the site of injury [More recently, a series of studies suggested that inflammatory Ly6Cf injury , 30, 43.Reproducibility ChecklistMesencephalic astrocyte-derived neurotrophic factor reprograms macrophages to promote regression of acetaminophen-induced acute liver injury via p38 MAPK pathway"}
+{"text": "ABSTRACT IMPACT: By restoring the gut microbiota in patients with acute myeloid leukemia exposed to antibiotics, we will reduce infections during and after curative-intent chemotherapy. OBJECTIVES/GOALS: Infection is a leading cause of death in acute myeloid leukemia (AML). Antibiotics disrupt the gut microbiota, promoting secondary infections. Through a double-blind randomized placebo-controlled phase 2 trial, we will determine whether microbiota restoration using fecal microbiota transplantation (FMT) prevents infections in AML patients. METHODS/STUDY POPULATION: 72 intensively treated AML patients at our institution are randomized in a 2:1 ratio to FMT (arm A) or placebo (arm B). After completing each course of antibacterial antibiotics, patients receive one study treatment. Up to 3 study treatments are administered over 3 months. FMT is delivered as a third-party oral product containing microbiota (\u02dc5x10^11 bacteria) in 4-6 capsules. Stool samples are collected before and after each study treatment. The primary endpoint is 4-month overall infection rate. 16S rRNA gene sequencing of stool samples is used to determine specific taxa that are under- or over-represented in samples preceding infections and compare the two arms for key microbiome features including diversity and composition. Bloodstream infection within 7 days after FMT counts towards stopping rule. RESULTS/ANTICIPATED RESULTS: Five patients have been enrolled: 4 have received 1 dose and 1 received 2 doses. The only adverse event (possibly related to study treatment) has been grade 1 abdominal pain in 1 patient. Notably, no bloodstream infection has occurred. All planned samples have been collected and are sequenced in batches. We expect arm A patients to experience fewer infections and fewer intestinal blooms of pathobionts, and both arms to experience intestinal blooms before specific infections. An interim efficacy analysis will be performed at half total enrollment. DISCUSSION/SIGNIFICANCE OF FINDINGS: Current supportive care during intensive chemotherapy is fundamentally anti-microbial and results in dysbiosis, with detrimental consequences. We will establish the evidence for FMT as a restorative strategy in AML patients. This is the first randomized placebo-controlled trial of repeated FMT, with potential implications to other cancers."}
+{"text": "It is conserved between mycobacterium species, is up-regulated during dormancy, has a known 3D crystal structure and has no known human homologs. A model of Rv2421c in complex with nicotinic acid adenine dinucleotide and magnesium ion was constructed and subject tovirtual ligand screening against the Prestwick Chemical Library and the ZINC database, which yielded 155 potential hit molecules. Of the 155 compounds identified five were pursued further using an IC50 based 3D-QSAR study. The 3D-QSAR model validated the inhibition properties of the five compounds based on R2 value of 0.895 and Q2 value of 0.944 compared to known inhibitors of Rv2421c. Higher binding affinities was observed for the novel ZINC13544129 and two FDA approved compounds . Similarly, the total interaction energy was found to be the highest for Cromolyn disodium system (-418.88 kJ/mol) followed by Novobiocin (-379.19 kJ/mol) and Sulfasalazine with (-330.13 kJ/mol) compared to substrate DND having (-185.52 kJ/mol). Subsequent in vitro testing of the five compounds identified Novobiocin sodium salt with activity against Mycobacterium tuberculosis at 50 \u03bcM, 25\u03bcM and weakly at 10\u03bcM concentrations. Novobiocin salt interacts with a MG ion and active site residues His20, Thr86, Gly107 and Leu164 similar to substrate DND of Mycobacterium tuberculosis Rv2421c. Additional in silico structural analysis of known Novobiocin sodium salt derivatives against Rv2421c suggest Coumermycin as a promising alternative for the treatment of Mycobacterium tuberculosis based on large number of hydrogen bond interactions with Rv2421c similar in comparison to Novobiocin salt and substrate DND.Nicotinamide-nucleotide adenylyl transferase (Rv2421c) was selected as a potential drug target, because it has been shown,  Mycobacterium tuberculosis (M. tuberculosis) provides a useful resource to interrogate novel drug targets. The genome of M. tuberculosis is ~4.4Mb in size and codes for approximately 4000 proteins . DND active site residues are shown in black boxes.PDBID: 2QTR crystal Structure of nicotinate mono-nucleotide adenylyl transferase from (TIFF)Click here for additional data file.S2 FigA) The green structure represents Rv2421c and cyan is 3E27 solved in complex with nicotinic acid adenine dinucleotide (DND). Substrate DND (red) shown as a stick representation and MG (green) shown as a sphere RMSD = 1.261\u00c5.B) The green structure represents Rv2421c and in pink is 2QTN solved in complex with nicotinate mononucleotide (NCN). Substrates DND (green) and NCN (cyan) shown as stick representations. RMSD = 1.502\u00c5.(TIFF)Click here for additional data file.S3 FigA) substrate DND is displaying eight hydrogen bond interactions, one hydrophobic contact and one MG ionic interaction with Rv2421c residues. B) Carbenoxolone disodium salt is displaying two hydrogen bond interactions and three hydrophobic contacts with Rv2421c residues. C) Cromolyn disodium salt is displaying three hydrogen bond interactions and two hydrophobic contacts with Rv2421c residues. D) Sulfasalazine is displaying four hydrogen bond interactions, three hydrophobic contacts and one pi-pi stacking interaction with Rv2421c active site residues. The dashed yellow lines represent hydrogen bonds.(TIFF)Click here for additional data file.S4 FigE.coli inhibitor ZINC58655383 is displaying three hydrophobic contacts and one pi-pi stacking interaction with the binding site residues of Rv2421c. The dashed yellow lines represent hydrogen bonds.A) novel ZINC13544129 is displaying five hydrogen bond interactions and three hydrophobic contacts with Rv2421c residues. B) Novobiocin disodium salt is displaying four hydrogen bond interactions, two hydrophobic contacts and one MG ionic interaction with Rv2421c residues. C) The known NadD (TIFF)Click here for additional data file.S5 FigA) Similar binding pose for DND (blue stick) vs Novobiocin sodium salt (cyan stick). B) Different binding poses for Carbenoxolone disodium salt, Cromolyn disodium salt, Sulfasalazine, ZINC13544129, Novobiocin salt vs DND. Compound colouring schemes shown as sticks: DND is red, MG ion is green sphere, Carbenoxolone disodium salt is blue, ZINC13544129 is yellow, Cromolyn disodium salt is magenta, Novobiocin sodium salt is cyan, Sulfasalazine is orange and ZINC58655383 is in light pink.(TIFF)Click here for additional data file.S6 FigA) DND, B) Carbenoxolone disodium salt, C) Cromolyn disodium salt, D) Sulfasalazine, E) ZINC13544129 and F) Novobiocin salt.(TIFF)Click here for additional data file.S7 FigA) DND, B) Carbenoxolone disodium salt, C) Cromolyn disodium salt, D) Sulfasalazine, E) ZINC13544129 and F) Novobiocin salt.(TIFF)Click here for additional data file.S8 FigA) Structural depiction of active site residue fluctuation, B) DND, C) Carbenoxolone disodium salt, D) Cromolyn disodium salt, E) Sulfasalazine, F) ZINC13544129 and G) Novobiocin salt.(TIFF)Click here for additional data file."}
+{"text": "A 66-year-old man with a diagnosis of acute myeloid leukemia (AML) type M4 in 2017 who had undergone allogeneic hematopoietic stem cell transplantation in January 2018 presented with painless, nontender left hemiscrotal swelling. The patient underwent unilateral radical orchiectomy and histopathology revealed myeloperoxidase-, CD33-, and CD117-positive and CD34-negative infiltration of AML in the testis and local spread into the spermatic cord, rete testis, epididymis, tunica albuginea, and the surrounding soft tissue suggesting myeloid sarcoma (MS). F18-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) after left orchiectomy depicted moderate hypermetabolic metastatic retrocrural and paraaortic lymph nodes and multiple intense hypermetabolic foci along the course of the left testicular vein extending up to the left renal vein, suggesting testicular vein infiltration of MS (arrows in"}
+{"text": "Following publication of the original article , the autThe caption for Fig.\u00a04 originally read:Ultrasensitive detection of amyloid-beta-oligomers in mice CSF using a poly (PEDOT)-embedded Au nanoelectrode. Reprinted with permission from ref. [138].The caption for Fig.\u00a04 should read: Figure 4 Conceptual illustration for the detection of A\u03b242 using localized surface plasmon resonance (LSPR) technique. Reprinted with permission from Ref. [138]The original article  has been"}
+{"text": "Although the number of Prolonged Mechanical Ventilation (PMV) patients and their informal caregivers (CGs) is rising both at Home or Long Term Care (LTC), little is known concerning CG characteristics or strain. We enrolled 120 patients and 106 informal CGs: 34/46 and 72CGs/74 PMV patients from Home Hospital and LTC respectively. CGs were married (82%), female (60.4%), mean age 59 \u00b114 years; spouses (29%) or children (40%) of the PMV patient. The 13-item Modified Caregiver Strain Index (MCSI) (Maximum severity=26) was 13.6\u00b1 6.5, similar at Home vs. LTC . Most frequent complaints were distress concerning patient\u2019s changes (93%) or upsetting behaviours (82%), feeling overwhelmed (82%), sleep disturbance (69%) and emotional adjustments (67%). Home CGs reported significantly more physical and financial burden, confinement, and need for work adjustment, while LTC CGs reported greater emotional disturbance and upsetting patient behaviours. Hierarchical clustering identified three clusters of CG strain: burden , emotional (upsetting adjustment/ behaviours/overwhelmed) and disturbance (work/plans/confinement). Emotional strain was most frequent, irrespective of site of care; however CGs at Home vs. LTC experienced significantly higher burden and disturbance vs. higher emotional strain respectively. In multivariate models, after adjusting for numerous patient and CG variables, increasing CG strain was consistently associated with rising patient symptomatology. This relationship was pronounced among CGs of Home PMV patients, with a significant interaction variable of Home*Patient symptomatology. Our findings identify specific patterns of strain among caregivers of PMV patients whether at home or LTC, and highlight the importance of addressing their unique needs."}
+{"text": "Cancer-associated fibroblasts (CAFs) contribute notably to colorectal cancer (CRC) tumorigenesis, stiffness, angiogenesis, immunosuppression and metastasis, and could serve as a promising therapeutic target. Our purpose was to construct CAF-related prognostic signature for CRC.We performed bioinformatics analysis on single-cell transcriptome data derived from Gene Expression Omnibus (GEO) and identified 208 differentially expressed cell markers from fibroblasts cluster. Bulk gene expression data of CRC was obtained from The Cancer Genome Atlas (TCGA) and GEO databases. Univariate Cox regression and least absolute shrinkage operator (LASSO) analyses were performed on TCGA training cohort (n\u2009=\u2009308) for model construction, and was validated in TCGA validation (n\u2009=\u2009133), TCGA total (n\u2009=\u2009441), GSE39582 (n\u2009=\u2009470) and GSE17536 (n\u2009=\u2009177) datasets. Microenvironment Cell Populations-counter (MCP-counter) and Estimate the Proportion of Immune and Cancer cells (EPIC) methods were applied to evaluated CAFs infiltrations from bulk gene expression data. Real-time polymerase chain reaction (qPCR) was performed in tissue microarrays containing 80 colon cancer samples to further validate the prognostic value of the CAF model. pRRophetic and Tumor Immune Dysfunction and Exclusion (TIDE) algorithms were utilized to predict chemosensitivity and immunotherapy response. Human Protein Atlas (HPA) databases and immunohistochemistry were used to evaluate the protein expressions.A nine-gene prognostic CAF-related signature was established in training cohort. Kaplan\u2013Meier survival analyses revealed patients with higher CAF risk scores were correlated with adverse prognosis in each cohort. MCP-counter and EPIC results consistently revealed CAFs infiltrations were significantly higher in high CAF risk group. Patients with higher CAF risk scores were more prone to not respond to immunotherapy, but were more sensitive to several conventional chemotherapeutics, suggesting a potential strategy of combining chemotherapy with anti-CAF therapy to improve the efficacy of current T-cell based immunotherapies. Univariate and multivariate Cox regression analyses verified the CAF model was as an independent prognostic indicator in predicting overall survival, and a CAF-based nomogram was then built for clinical utility in predicting prognosis of CRC.To conclude, the CAF-related signature could serve as a robust prognostic indicator in CRC, which provides novel genomics evidence for anti-CAF immunotherapeutic strategies.The online version contains supplementary material available at 10.1186/s12935-021-02252-9. Colorectal cancer (CRC) is the most commonly diagnosed gastrointestinal cancer and is characterized by exhibiting cancer progression due to therapy resistance \u20133. CRC pAs the major TME stromal cellular constituents, cancer-associated fibroblasts (CAFs) were found not only to promote tumorigenesis and enhance the aggressiveness of cancer cells, but also to induce chronic inflammation by producing pro-inflammatory cytokines that are responsible for immune tolerance and tumor metastasis \u201312. PhysUnderstanding the heterogeneity and identifying the biomarkers of CAFs could be of great significance for survival prediction and CAF-based therapeutic guidance in CRC. Fibroblast activation protein (FAP), \u03b1-SMA (ACTA2), platelet derived growth factor receptor-\u03b2 (PDGFRB), caveolin 1 (CAV1) and podoplanin (PDPN) are the generally recognized fibroblasts markers in CRC , 24\u201326. https://www.ncbi.nlm.nih.gov/geo/) colorectal cancer cells datasets were analyzed to describe the CAF subset and its marker genes. In addition, through integrated bioinformatics transcriptome analyses at both single-cell and bulk levels, we aimed to discover promising CAF-targeting therapeutic hallmarks and design a CAF-associated gene signature to predict drug sensitivity and prognosis for CRC patients.Recently, substantial interest has been aroused around advances in single-cell RNA sequencing (scRNA-seq) technology, which is capable of profiling genes as well as discovering distinct oncogenic cellular populations and associated markers at single-cell resolution . Unequivhttps://www.ncbi.nlm.nih.gov/geo/). We randomly picked four tissues  as the discovery cohort, and sample GSM3855015 was chosen for hallmark validation. The bulk transcriptome RNA-seq data and corresponding clinical data were obtained from The Cancer Genome Atlas rectal adenocarcinoma (TCGA\u2010READ) and colon adenocarcinoma (TCGA\u2010COAD) through the UCSC Xena browser (GDC hub) (https://gdc.xenahubs.net) [The scRNA-seq files (raw unique molecular identifier (UMI) counts based on 10X Genomics technology) from five CRC tissues were accessed from GSE132257  via GEO ubs.net) . The batubs.net) . In totahttps://github.com/satijalab/seurat) [We utilized Seurat R package (version 3.0.2) and applied standard downstream processing for scRNA-seq data (/seurat) . Genes t/seurat) . Subsequ/seurat) .GO and KEGG pathway functional enrichment analyses were conducted through clusterProfiler R package (version 3.14.3) to assign various biological processes (BPs), molecular functions (MFs), cellular components (CCs) as well as pathways of identified marker genes in the interested cluster , P\u2009<\u20090.0i * Expi), where \u03b2i represented the LASSO coefficient of ith gene, and Expi was the ith candidate gene\u2019s expression value. Subsequently, patients were classified into high- and low-CAF risk groups by their median CAF scores, and their relationship with OS was evaluated via Kaplan\u2013Meier analysis. We generated heatmaps to visualize the association between CAF risk scores and candidate genes. Similarly, we validated our CAF signature in the TCGA validation and TCGA COAD/READ total cohorts, GSE39582 and GSE17536 external validation cohorts.We designed a prognostic signature across CRC patients by focusing on CAF marker genes, which were identified from the CAF-annotated scRNA-seq cluster. The main endpoint of this research was overall survival (OS), and prognostic CAF-related genes were investigated by univariate Cox regression model in the TCGA training dataset. Genes with P\u2009<\u20090.1 in univariate Cox analysis were regarded as candidate prognostic genes. To minimize overfitting risk, we then applied the least absolute shrinkage and selection operator (LASSO) Cox regression model via glmnet R package , and theThe relative infiltrations of 24 immune cell types were quantified via single sample gene set enrichment analysis (ssGSEA) with GSVA R package (version 1.34.0) . The genhttps://www.cancerrxgene.org/) [http://tide.dfci.harvard.edu/) algorithm was implemented to predict immune checkpoint blockade therapy response between two groups [To predict chemosensitivity between high- and low-CAF risk groups, we used pRRophetic R package (version 0.5) to extrapolate half-maximal inhibitory concentration IC50) values by building ridge regression model with ten-fold cross-validation , 50. Sev values bne.org/) . In addio groups .To explore the different KEGG pathways and hallmark gene sets between high- and low-CAF risk groups, GSEA was performed with The Molecular Signatures Database (MSigDB)  via fgsea R package (version 1.12.0) , 54. PatUnivariate and successive multivariate Cox regression analyses were performed to ascertain whether CAF model was independent of several clinical characteristics via survival R package. Subsequently, the nomogram was constructed based on the multivariate Cox regression coefficients of CAF signature and clinical variables in the TCGA training cohort. The concordance index (C-index) was calculated to validate the nomogram\u2019s predictive performance, and calibration curves were also plotted to examine the consistence between the predicted 1-, 3- and 5-year OS probabilities and the actual observations .https://www.proteinatlas.org/), which aims to create a human proteome-wide map through integrated omics technologies [The protein expressions of these CAF signature genes in CRC tissues were analyzed in HPA online database  and CXCL1 ) overnight at 4\u00a0\u00b0C, followed by incubation with secondary antibody  at room temperature for 30\u00a0min. Then, diaminobenzidine tetrachloride (DAB) staining  was applied for CEBPD and CXCL1 expressions visualizations.\u2212\u0394\u0394CT method. The primer sequences of these genes were listed in Additional file Tissue microarrays containing 80 colon cancer samples (HColA095Su01) with the corresponding clinicopathological information were purchased from Shanghai Outdo Biotech  for prognostic verification. The mRNA expressions of the nine signature genes were quantified by qPCR using SYBR Green Premix  on the 7500 Sequence Detection System . \u03b2-actin served as internal control for qPCR normalization, and the relative gene levels were calculated by 2https://www.r-project.org/). Wilcoxon test was applied for the comparisons between two groups. Survival analysis was performed using survival and survminer R packages. P-value less than 0.05 was regarded as statistical significance.All statistical analyses and visualization were performed using R software v3.6.3 , a total of 1771 high-quality cell samples were screened . As shown in Fig.\u00a0In the TCGA training cohort, by inputting the 208 differential CAF marker genes identified above into univariate Cox regression analysis, a total of 41 genes were exhibited with P\u2009<\u20090.1. LASSO Cox regression algorithm was then performed on these genes, the lambda.min was determined as the optimal lambda value by tenfold cross-validations, and 9 prognostic genes with non-zero coefficients were successfully identified Fig.\u00a0e. In TCGSubsequently, expression characteristics of the nine markers among clusters in single-cell RNA sequencing profile were visualized via violin and bubble plots, CSRP2, PPP1R14A and TPM2 were up-expressed mainly in fibroblasts, while SPINK1 was down-regulated and expressed exclusively in epithelial cells. The other six markers were upregulated in fibroblasts cluster and revealed multiple expression forms among clusters Fig.\u00a0b, c. MorBy running ssGSEA, MCP-counter, EPIC and ESTIMATE algorithms, we investigated the correlation of CAF risk score and TME constituents at bulk\u00a0RNA-sequencing level. As shown in Fig.\u00a0We next investigated the practicability of the model in guiding systemic therapies. Firstly, estimated IC50 values were calculated by pRRophetic algorithm to predict the different chemotherapy responses of CAF-associated high and low risk groups. Based on the GDSC cancer cell line database, we found that higher CAF risk score increased the sensitivity of 6 types of anticancer drugs  in TCGA COAD/READ, GSE39582 and GSE17536 datasets  in the TCGA training cohort, we built a prognostic nomogram for clinicians to quantitatively predict 1, 3 and 5-year OS probabilities of CRC patients Fig.\u00a0a. The C-Finally, with respect to CRC tissue protein expression levels, the immunohistochemical results from HPA database indicated that protein expression of CSRP2, HSPB1, PPP1R14A, S100A13, TIMP1 and TPM2 was higher in CRC stroma Fig.\u00a0a\u2013f, whilThe recognized tumor-promoting capacity of CAFs makes them a prospective immunotherapy target , 11, 57.In this study, we observed the immune and stromal cells infiltrations were more abundant in the high CAF risk group, especially several immunosuppressive types like fibroblasts, macrophages and mast cells. The effectiveness of most immunotherapies depends on the abundant infiltrations of CD8\u2009+\u2009T cells in the tumors . HoweverFor the CAF-related genes in this well-established signature, scRNA-seq displayed TIMP1 expressed mostly in fibroblasts, epithelial cells, macrophages and endothelial cells. Many studies have identified dysregulation of TIMP1 expressions contributed critically to pro-tumor inflammation initiation, matrix remodeling and fibrosis development \u201368. IlleSeveral limitations in this study should be acknowledged. First, it was a retrospective study based on public sequencing data, and the sample capacity of the tissue microarray verification cohort was insufficient. Hence, the prognostic and predictive efficacies of our CAF-related signature should be prospectively verified in large clinical trial. In addition, cross-validations at proteomics level are also necessary to serve the clinical applications. Secondly, the molecular mechanisms of how these CAF-related genes affect patient prognosis and therapeutic responses need to be clarified by further basic experimental studies.In summary, based on integrated single-cell and bulk RNA sequencing analysis, we constructed and validated a nine-gene CAF-related signature as an independent prognostic indicator for CRC patients. Our results also provided genomic evidence for future research directions on anti-CAF therapeutic strategies for those who might not benefit from immunotherapy.Additional file 1: Table 1. qRT-PCR primer sequences.Additional file 2: Figure S1. Validation analysis on single-cell RNA sequencing from 1771 cells of one CRC tissue (GSM3855015). (a) Post quality control filtering of each sequenced cell, which was plotted in violin plots to display their number of RNA features (nFeature_RNA) and absolute UMI counts (nCount_RNA). (b) Correlation analysis between nFeature and nCount. (c) Cells were clustered into 11 types via tSNE dimensionality reduction algorithm, each color represented the annotated phenotype of each cluster. (d) Heatmap depicting expressions of top 10 marker genes among 11 identified CRC cell clusters.Additional file 3: Figure S2. (a) Recognized and (b) the identified CAF markers expressions in single-cell clusters of GSM3855015 sample. (c) Bubble plot visualizing genes expression characteristics in single-cell RNA sequencing profile. Cell phenotypes were listed on y-axis, recognized CAF markers (left part of the dotted line) as well as the identified 9 prognostic markers (right part of the dotted line) were listed along the x-axis. Dot size reflects each gene\u2019s expressing percentage of each cluster\u2019s cells; dot color represents the expression level."}
+{"text": "Data describing central nervous MAC involvement (CNS-MAC) in disseminated infection is scarce. Disseminated Mycobacterium avium complex (MAC) infection occurs in 20-40% of patients with < 50 CD4/mmWe conducted a retrospective case series in the outpatient infectious diseases clinic in the hospital \u201cDr. Manuel Gea Gonzales\u201d in Mexico City. We reviewed all records from October 2020 to May 2021 and identified all culture proven MAC infections.3 and recent HIV diagnosis (1-4 months) that were referred to our institution with consumptive syndrome and fevers. All patients were receiving antiretroviral treatment (ART) with BIC/FTC/TAF and initiated ART in less than 1 month since HIV diagnosis. Opportunistic infections were ruled-out at the moment of CNS-MAC diagnosis . All patients exhibited non-specific neurologic symptoms at arrival (headache and bradipsiquia) mixed with more severe symptoms . All patients were treated with Clarithromycin/Levofloxacin/Ethambutol. Two patients achieved symptom remission and 1 patient was lost to follow-up. Of important note, all CSF analysis and CNS imaging studies carried-out were normal. No MAC bacilli were identified with direct Ziel-Neelsen staining of CSF.We found 7 cases of MAC, with disseminated infection (positive bone marrow cultures) with 3 out of those 7 meeting our definition for CNS-MAC . All cases of CNS-MAC infection occurred in patients with < 50 CD4/mm3 might represent a specific population that could benefit from routine targeted diagnostic test at presentation in order to establish CNS involvement.We found a high proportion of CNS-MAC in patients with disseminated MAC infection (42.8%) during the study period. All patients presented CNS symptoms and normal CSF characteristics. In our setting, patients with suspected disseminated MAC infection CD4 counts < 50 cells/mmAll Authors: No reported disclosures"}
+{"text": "Scientifc Reports 10.1038/s41598-021-92835-3, published online 30 June 2021Correction to: The Funding section in the original version of this Article was omitted. The Funding section now reads:\u201cThe authors acknowledge TU Wien Bibliothek for financial support through its Open Access Funding Programme.\u201dThe original Article has been corrected."}
+{"text": "Use driver behavior profiles to screen and index early warnings of cognitive decline and Alzheimer\u2019s disease (AD). Hypothesis: Real-world driver speed behavior profiles discriminate mild cognitive impairment (MCI).Sensors were installed in personal vehicles of 74 legally-licensed, active drivers  who completed 2, 3-month real-world driving assessments, including demographic and cognitive assessments, 1 year apart . MCI status was indexed using 8 neuropsychological tests , relevant to MCI and driving. Driving environment was indexed from state speed limit  and sunrise-sunset databases (time of day: day vs. night). Models: Data were randomly split into training (66%) and validation (33%) sets. An optimal mixed effects logistic regression model was determined from validation data AUC values.MCI drivers drove slower with optimal discrimination (estimated for every 5 mph decrease in speeding) in 1) residential roads , 2) interstate roads , and 3) night environments (MCI odds increased by 7% [95% CI: 2-12%]).Quantitative indices of real-world driver data provide \u201cground truth\u201d for screening and indexing phenotypes of cognitive decline, in line with ongoing efforts to link driver behavior with age-related cognitive decline and AD biomarkers. Behavioral biomarkers for diagnosing early warnings of dementia could ultimately bolster our ability to detect and intervene in early AD."}
+{"text": "Antimicrobial stewardship programs (ASP) have been essential during the coronavirus disease 2019 (COVID-19) pandemic response. Use of monoclonal antibodies for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has proven difficult to operationalize, despite being available through emergency use authorization (EUA). Utilizing existing ASP and multidisciplinary approach to lead the effort, we aim to describe our experience in operationalizing monoclonal antibody therapy.Retrospective study of SARS-CoV-2 infected adults receiving monoclonal antibody therapy under EUA (December 2020-April 2021). An algorithm developed by the ASP provided education and an interactive online tool allowing referring physicians and patients to assess eligibility prior to hospital arrival. Patients were screened and approved by existing ASP which included; Infectious Disease (ID) physicians, pharmacist, and ID Nurse. A multidisciplinary approach with ER staff and development of pharmacy workflow with order set were utilized as eligible patients received infusion in dedicated ER location. Data such as demographics, co-morbid condition, infusion related complications, hospitalization, and death were reviewed and collected regularly by the ASP team with frequent monitoring and regulatory reporting. Primary patient outcome was preventing hospitalization.107 patients received monoclonal antibody therapy. 47% patients were male, 50% White, and 79% non-Hispanic. 87% received monotherapy (bamlanivimab) and 13% received dual therapy (bamlanivimab/etesevimab). 17 patients required hospitalization post infusion. 1 death occurred. COVID-19 related hospitalization within 30-days was avoided in 84% of treated patients. No adverse event directly related to infusion were seen.Use of monoclonal antibody therapy under EUA for patients for SARS-CoV-2 infection led to decrease in hospitalization in this cohort. An existing ASP using an algorithmic approval process, frequent monitoring, and multidisciplinary approach successfully operationalized the use of monoclonal antibody therapy. ASP\u2019s provide benefit and versatility beyond monitoring of antimicrobials alone and should continue to receive support by hospital leadership.All Authors: No reported disclosures"}
+{"text": "Streptococcus pneumoniae is a leading cause of pneumonia, meningitis, and bacteremia. Serotype 1 is rarely carried but is commonly associated with invasive pneumococcal disease, and in the African \u201cmeningitis belt,\u201d it is prone to cause cyclical epidemics. We report the complete genome sequence of S. pneumoniae serotype 1 strain BVJ1JL, isolated in Malawi. Streptococcus pneumoniae, a Gram-positive bacterium, is a leading cause of childhood mortality worldwide  and confirmed genomically using PneumoCat  and 50\u2009units mutanolysin (Sigma-Aldrich). DNA was sheared using a g-TUBE device (Covaris) with a target length of 10\u2009kb, and library preparation was performed according to the protocol \u201cPreparing Multiplexed Microbial Libraries Using SMRTbell Express Template Prep Kit 2.0,\u201d with the Barcoded Overhang Adapter Kit-8A (Pacific Biosciences) at the University of Exeter, UK. The pooled samples were purified and size selected to remove SMRTbell templates of >3\u2009kb using AMPure PB beads (Pacific Biosciences). A 10-h capture using a 1M single-molecule real-time (SMRT) cell was performed on a PacBio Sequel instrument using Sequel v3 chemistry  and quantified using Quant-iT PicoGreen double-stranded DNA (dsDNA) kits (Invitrogen) according to the manufacturer\u2019s specifications. DNA was fragmented using an EpiSonic sonication system (EpiGentek), and libraries were constructed using the NEBNext Ultra DNA sample prep master mix kit (New England BioLabs [NEB]) with in-house adapters and barcode tags described at Oxford Genomics Centre, UK  obtained from a 9-year-old child in Blantyre, Malawi . The macrolide resistance genes mef and ermB were not detected.BVJ1JL belonged to sequence type 5012 (ST5012) and Global Pneumococcal Sequence Cluster 2 (GPSC2) lineage . ST5012 CP071871. The PacBio and Illumina raw reads are available in NCBI Sequence Read Archive (SRA) under accession numbers SRX10254117 and SRX10254116, respectively. The BioProject accession number is PRJNA695191, and the BioSample accession number is SAMN17602804.The assembled complete genome sequence has been deposited in GenBank under accession number"}
+{"text": "Patients with COVID-19 infection at highest risk for poor outcomes include immunocompromised patients, such as solid organ transplant (SOT) recipients. Monoclonal antibody (mAb) infusions were developed to promote passive immunity. Analysis of the first 200 patients who received SARS-CoV-2 mAb at our hospital showed a 27 % absolute reduction in hospitalization and emergency department (ED) visits. Understanding the role of SARS-CoV-2 mAb therapy in management of the SOT population is likely to inform decision making for these patients. We conducted a retrospective chart review of SOT patients diagnosed with COVID-19 who received mAb therapy between 11/18/20 and 04/26/21. Patients were excluded if they were < 18 years of age or if they weighed < 40 kg. We compared those patients who were hospitalized or visited the ED within 29 days of mAb therapy to those who recovered without further visits to our hospital.A total of 50 SOT patients receiving mAb therapy were included in this analysis. Bamlanivimab was given to 33 patients, while 9 patients received bamlanivimab/etesevimab and 8 patients received casirivimab/imdevimab. Twelve (24 %) patients were hospitalized or visited the ED within 29 days of mAb therapy; 38 patients did not. These 2 groups did not significantly differ by age, gender, body mass index, time from SOT, or other risk factors for severe COVID-19 illness per FDA Emergency Use Authorization guidance. Both groups were primarily made up of kidney transplant recipients . Significantly more patients in the hospitalization/ED group were receiving antimetabolites as part of their immunosuppression (IS) regimen prior to COVID-19 diagnosis . Patients in the hospitalization/ED group received mAbs within a median of 6 days (IQR 3.8) of symptom onset compared to 4 days (IQR 4) (p = 0.006). SOT recipients were more likely to be hospitalized or visit the ED due to COVID-19 after mAb if they were receiving antimetabolite IS or received mAb later after symptom onset. These data stress the importance of early mAb administration in all SOT patients, particularly in those on antimetabolite therapy. Lyndsey Bowman, PharmD, Veloxis Pharmaceuticals  Kami Kim, MD, Regeneron Pharmaceuticals Inc. (Scientific Research Study Investigator)Sanford Guide"}
+{"text": "Salmonellaenterica serovar Heidelberg outbreak in Australia during 2018\u20132019. Laboratory investigation of cases reported across 5 jurisdictions over a 7-month period could not identify a source of infection but detected indicators of severity and invasiveness. The hospitalization rate of 36% suggested a moderately severe clinical picture.We report a multistate  Salmonella enterica serovar Heidelberg is a frequently identified serotype among infections in humans in North America, East Africa, and Asia but is uncommon in Australia. An average of 37 cases of Salmonella Heidelberg were notified in Australia annually in 2009\u20132017, predominantly overseas acquired  were above the national historical 5-year mean (2.4 cases). New South Wales (NSW) and Victoria initiated separate investigations during December 2018\u2013February 2019; neither developed a hypothesis regarding potential sources of infection. In February\u2013March 2019, whole-genome sequencing (WGS) analysis of available isolates identified 36 highly related cases, 12 each from Queensland, NSW, and Victoria. Concurrent Salmonella Heidelberg infections with WGS pending were subsequently identified in other states: South Australia (SA) (N = 4) and Western Australia (WA) (N = 3). Queensland cases were not initially investigated because Salmonella Heidelberg is more common in this state; Queensland contributed 43% of cases in Australia during 2009\u20132017 : NSW , Victoria , Queensland , WA , and SA  . Case-paThirty-nine case-patients completed interviews using telephone-administered hypothesis-generating questionnaires. The remaining 20 patients were not investigated because they refused interviews, they could not be contacted, or their diagnosis dates precluded obtaining a reliable food history. Binomial probability analysis compared case-patient food exposures to background rates estimated from a Victoria population survey, accounting for seasonality, from November 2014\u2013October 2016 , macadamia nuts (p = 0.001), frozen vegetable products (p = 0.005), and lamb (p = 0.005). Global epidemiology suggests Salmonella Heidelberg cases at the Queensland Health Forensic and Scientific Services laboratory by generating core genome multilocus sequence typing (cgMLST) complex types  using Ridom SeqSphere+ version 5.1.0 (https://www.ridom.de) based on the EnteroBase Salmonella enterica scheme version 2.0 (https://enterobase.warwick.ac.uk). We determined single-nucleotide polymorphism (SNP) differences using Snippy package version 4.3.6 (https://github.com/tseemann/snippy) using Salmonella Heidelberg SL476 (GenBank accession no. NC_011083.1) as a reference. We conducted in silico WGS analysis for antimicrobial-resistance genes by the abricate program version 0.8.10 (https://github.com/tseemann/abricate), using the Resfinder database October 18, 2018, version (https://cge.cbs.dtu.dk/services/ResFinder) to further characterize strains. We investigated the presence of the saf operon using Ridom SeqSphere+ against the saf operon sequence from GenBank (accession no NZ_LS483494). We generated sequences for isolates on the Illumina NextSeq genome sequencing platform (https://www.illumina.com) using the Nextera XT library preparation kit; the WGS read files were deposited in the US National Center for Biotechnology Information (https://www.ncbi.nlm.nih.gov) Sequence Read Archive . We developed our hypothesis using a range of local and international sequence data sources to assess genetic relatedness to outbreak cases; we used 78 human sequences from 5 jurisdictional laboratories, 8 nonhuman Salmonella Heidelberg isolates from a Queensland culture collection from food and animals , and 86 international sequences downloaded from EnteroBase and the National Center for Biotechnology Information.We consolidated sequence data, including isolates sequenced in jurisdictional laboratories. We assessed genetic relatedness among isolates of Salmonella Heidelberg isolates available from this outbreak were all multilocus sequence type (ST) 15 and belonged to the same cgMLST complex type (2561); isolates differed within the complex type by 0\u20133 SNPs/cgMLST alleles, whereas the nearest nonoutbreak genomes had >34 SNP and >16 SNP allele differences  were hospitalized with a median duration of 4 (range 1\u201318) days, reported by 13 case-patients. Although direct comparison is difficult because of potential confounding by age, the hospitalization rate of 36% was high compared with the rate of 11.6% among 149 US outbreaks of Salmonella Heidelberg has frequently been associated with greater risk for invasive disease than have other commonly reported nontyphoidal Salmonella serotypes, including Typhimurium and Enteritidis (\u2013Salmonella Heidelberg is among the 4 most common serotypes isolated from blood; 12%\u201313% of Salmonella Heidelberg infections resulted in invasive disease in North America, higher than the US Salmonella average of 7% (\u2013Salmonella infection in Australia similarly found that almost 10% of Salmonella Heidelberg gastrointestinal infections during 2007\u20132016 were invasive disease, \u22485\u00d7 higher than Salmonella Typhimurium infections (Salmonella Heidelberg outbreak; recent genomic analyses indicated that most identified Salmonella virulence genes are present in most Salmonella Heidelberg strains. These studies highlighted potential contributions of saf fimbrial genes to increased severity via their role in bacterial aggregation, colonization, and biofilm formation (saf operon has been reported generally absent from the Salmonella Heidelberg serovar but was present in a previous outbreak associated with increased severity (saf operon was present in all Australia isolates in this study (Although this investigation was unable to capture invasiveness of the outbreak strain, is study  Figure.S. enterica serovar of unknown origins in Australia. Although Salmonella Heidelberg outbreaks are relatively uncommon in Australia, given this outbreak\u2019s comparatively high hospitalization rate and the presence of saf fimbrial genes in the implicated strain, future cases warrant prompt investigation to assess severity and invasiveness. A platform for real-time exchange of sequence data in Australia and use of routine WGS for salmonellosis cases, including comparison with local and international strain data, may enable more timely detection of outbreaks.We report a national outbreak investigation of a locally uncommon Salmonella enterica serovar Heidelberg outbreak, Australia, 2018\u20132019.Additional information about"}
+{"text": "Staphylococcus aureus bacteremia (SAB) are incompletely understood. We used Geographic Information Systems (GIS) and spatial statistics to analyze demographic and geographic epidemiology of SAB in the community.Risk factors for community-associated S. aureus Bacteremia Group Prospective Cohort Study (SABG-PCS) at Duke University Medical Center to obtain demographic and clinical data. We used the American Community Survey and U.S. Census to supply neighborhood variables. Secular trends in demographic and clinical characteristics of SAB patients prospectively enrolled between 1995 and 2015 (n = 2478) were determined using linear regressions. To characterize spatial patterns in Methicillin-resistant S. aureus (MRSA) bacteremia compared to Methicillin-susceptible S. aureus (MSSA) bacteremia, we used GIS mapping and selected a subgroup of patients (n = 667) living in and around Durham County, North Carolina. We then created generalized additive models (GAMs) using this subgroup to detect geographic heterogeneities in probabilities of MRSA infections compared to MSSA infections.We used the We found evidence of changing demographic and clinical characteristics of SAB patients over the 21-year period. The proportion of infections acquired in the community increased significantly (p < 0.0001). However, we did not detect spatial heterogeneities of MRSA infections in Durham County. Patient location of residence was not significantly associated with antimicrobial-resistant infections. Patient age and year of hospital admission were the only statistically significant covariates in our spatial models.S. aureus to identify robust risk factors for infection.We utilized a novel method to analyze SAB in the community using GIS and spatial statistics. Future research should prioritize community transmission of Vance G. Fowler, Jr., MD, MHS, Achaogen (Consultant)Advanced Liquid Logics (Grant/Research Support)Affinergy Affinium (Consultant)Akagera (Consultant)Allergan (Grant/Research Support)Amphliphi Biosciences (Consultant)Aridis (Consultant)Armata (Consultant)Basilea Bayer (Consultant)C3J (Consultant)Cerexa Contrafect Debiopharm Destiny (Consultant)Durata Genentech Green Cross Integrated Biotherapeutics (Consultant)Janssen Karius (Grant/Research Support)Locus (Grant/Research Support)Medical Biosurfaces (Grant/Research Support)Medicines Co. (Consultant)MedImmune Merck (Grant/Research Support)NIH (Grant/Research Support)Novadigm (Consultant)Novartis Pfizer (Grant/Research Support)Regeneron sepsis diagnostics Tetraphase (Consultant)Theravance Trius (Consultant)UpToDate Valanbio xBiotech (Consultant)"}
+{"text": "Mild Parkinsonian signs (MPS) affect up to 24% of community-dwelling older adults. We hypothesize that MPS are associated with Parkinson\u2019s-like alterations of functional connectivity (FC) in sensorimotor, executive, and reward cortico-striatal networks. Participants  without Parkinson\u2019s completed resting-state fMRI and Unified Parkinsonian Disease Rating Scale (UPDRS). FC between striatum and cortex was measured within each network. Logistic regression tested associations of each network\u2019s FC with MPS (UPDRS>0), adjusted for MPS risk factors, then including white matter hyperintensities (WMH). MPS was associated with lower cortical-striatal FC in the left executive cortico-striatal network . Association survived adjusting for risk factors  but was attenuated after including WMH . In stratified analyses, left executive cortico-striatal FC was associated with MPS only for those with higher WMH . Future work should examine whether higher FC protects against the influence of WMH on MPS."}
+{"text": "Typhula ishikariensis demonstrated Arabidopsis plants develop disease resistance through cold acclimation.A model plant\u2013pathogen system using Arabidopsis and its natural snow mold pathogen  Dear Editor,Triticum aestivum), rye , and forage grasses in heavy snow regions. The major snow mold pathogens of winter cereals include Typhula ishikariensis, Sclerotinia borealis, and Microdochium nivale  after cold acclimation (Hordeum vulgare) and meadow fescue (Festuca pratensis) acquire resistance to Bipolaris sorokiniana through cold acclimation  has an overwintering growth habit and naturally undergoes cold acclimation and vernalization  medium, respectively  and wheat (A rosette leaf on Col-0 plants was inoculated with nfection . A waternfection . The inonfection . SEM furnfection  and stomnfection . This obnd wheat . Stomatand wheat .2) were measured 2 d later.A quantitative assay system for pathogenicity and host resistance is required to investigate the host\u2013microbe interactions at a molecular level. A detached leaf assay to evaluate snow mold resistance in barley has been previously reported . We deveT. ishikariensis isolates belonging to biotype A  and biotype B  did not form lesions on leaves , ethylene-insensitive 2 (ein2), and salicylic acid induction-deficient 2 (sid2) were CA and then inoculated with WSL9-5 for evaluation of disease resistance under the mimicked snow-covered condition (jar1 mutant showed similar size legions with or without cold acclimation, indicating a lack of cold-induced disease resistance (ein2 and sid2 leaves were reduced when cold-acclimation was applied, suggesting that these mutants retain the cold-induced defense mechanism (ein2 mutant was of particular interest because CA ein2 showed much smaller lesion areas than CA Col-0 (To perform initial characterization of the molecular mechanisms responsible for cold-induced disease resistance, Arabidopsis plants defective in different hormone signaling pathways were analyzed. Arabidopsis mutants, ondition . Interessistance . These dechanism . The einCA Col-0 . This maCA Col-0 , cold-inTyphula snow molds that exhibit a significant level of virulence in Arabidopsis. Typhula ishikariensis WSL9-5 infects Arabidopsis primarily through epidermal penetration, and slowly spreads into the entire plant causing symptoms similar to those observed in cereals. We developed a detached-leaf inoculation method that enabled a quantitative assessment of pathogenicity and plant resistance in a short period of time. The Arabidopsis model system will be useful for addressing questions on plant\u2013snow mold interactions that occur when plants are covered by snow, including how does cold acclimation induce plant resistance, is the resistance signaling pathway common to freezing tolerance induction, how do host and pathogen genotypes and physiology affect the pathogenicity and disease development of snow molds, and how do environmental factors, such as nonfreezing low temperature, darkness, or humidity, affect disease development? Since these research topics have been barely examined, addressing these questions will contribute to the timely development of snow mold resistant cultivars in cereals and forage crops. In our present study, we successfully isolated two  Whole-plant leaf inoculation assay.. kiab027_Supplementary_DataClick here for additional data file."}
+{"text": "ABSTRACT IMPACT: Understanding gene expression changes after viral vaccination and booster may help predict vaccine efficacy. OBJECTIVES/GOALS: Utilize a systems biology approach to identify gene expression changes after administration of Zaire Ebola virus glycoprotein expressed in a Chimp Adeno3 vector (ChAd3-EBOZ) and either boosted \u02dc7 weeks later with modified vaccinia Ankara MVA expressing Zaire and Marburg GPs plus Tai forest NP (MVA-BN \u00aeFilo) or given saline (placebo). METHODS/STUDY POPULATION: As part of the phase 1b, open-label vaccination trial of ChAd3-EBO-Z in Mali, West Africa, peripheral blood mononuclear cells were isolated from eight volunteers for whole genome transcriptomics analysis. Four subjects received the MVA-BN \u00ae-Filo booster and four received saline. Samples were taken prior to receipt of the booster or placebo, as well as 1, 7, and 14 days afterwards. Significant differentially expressed genes were identified using RNA-seq between baseline and post-MVA-BN \u00aeFilo. Functional enrichment analysis against the GO Ontology Database and the Immune Signatures C7 collection of MSigDB (ImmuneSigDB) was performed. These differentially expressed genes were also examined for associations with Ebola antibody titers and cell-mediated immune responses. RESULTS/ANTICIPATED RESULTS: The majority of gene expression changes occurred on day 1 post-MVA-BN \u00ae-Filo administration. 870 genes had significantly different expression when day 1 samples were compared to pre-booster baseline (791 upregulated/79 downregulated). Those upregulated genes are mainly involved type I interferon and regulation of viral life cycle pathways. The downregulated genes are involved in regulation of cellular defense response, lymphocyte mediated immunity. Comparing to the C7 Immune Signatures collection datasets, we identified more than 100 upregulated genes from 6 studies of yellow fever vaccination that were also significantly upregulated in our study. The top enriched ontological pathway of those genes is cellular response to type I Interferon. DISCUSSION/SIGNIFICANCE OF FINDINGS: The use of a systems biology approach to compare gene expression changes among vaccine studies utilizing whole genome transcriptomics data allows the identification of genes involved in the immune response to vaccination and might aid in predicting vaccine efficacy."}
+{"text": "Pneumococcal vaccine recommendations for US adults are complex, varying by age and underlying conditions, and include both 23-valent polysaccharide vaccine (PPSV23) and 13-valent pneumococcal conjugate vaccine. The Advisory Committee on Immunization Practices (ACIP) will vote on new recommendations in October after the 15- (PCV15) and 20-valent (PCV20) conjugate vaccines are approved. Stakeholder acceptability is part of ACIP\u2019s evidence to recommendation framework, but few data are available on health care providers\u2019 (HCPs) preferences for potential recommendations.752 HCPs  were surveyed. Object case best-worst scaling (BWS) was used to elicit preferences for hypothetical recommendations for 1) adults 19-64 years with chronic conditions and 2) immunocompetent adults \u226565 years. Presented recommendations included combinations of PCV15/PCV20 either as routine or after shared clinical decision making (SCDM), and PPSV23 as routine, SCDM, or no recommendation. Following BWS, HCPs were asked to assume ACIP was considering implementing both of their preferred recommendations for the age/risk groups. HCPs were then given the opportunity to change their selections and propose recommendations not included in the BWS exercise. Additional information was collected using conventional survey items. Routine use of higher-valent PCVs in sequence with PPSV23 was most often preferred for both adults 19-64 with chronic conditions (40%) and immunocompetent adults \u226565 (49%) when elicited separately for each age/risk group. Most respondents (63%) revised their recommendations after considering implementation, which resulted in most (59%) favoring recommendations harmonized across the age/risk groups, and 75% favoring routine use of PCV15 or PCV20 among immunocompetent adults \u226565. When asked directly, HCPs generally approved of the idea of simplifying adult pneumococcal vaccine recommendations, harmonizing the interval between vaccines, and lowering the cutoff for age-based recommendations below 65 years.US HCPs generally prefer simplification of the adult pneumococcal recommendation, favoring broad routine use of both higher-valent PCVs and PPSV23.Jeffrey Vietri, PhD, Pfizer Inc  Kelley Meyers, PhD, RTI Health Solutions (Independent Contractor) Christine Poulos, PhD, Pfizer Inc  Erica Chilson, PharmD, Pfizer, Inc  Vincenza Snow, MD, Pfizer Vaccines (Employee)"}
+{"text": "Diabetic foot osteomyelitis (DFO) remains a significant comorbidity in diabetes and often requires both surgical and medical interventions. Surgical bone resection with proximal margins is performed for treatment at our institution to guide antimicrobial therapy. Optimal antibiotic duration often remains unclear, along with clinical outcomes with negative margins. We evaluate if negative bone margins predict outcomes of DFO at one year in our county hospital.A retrospectively cohort study assessed adult patients undergoing DFO amputations between 9/2016 to 9/2019. Patient data collected included demographics, smoking history, hemoglobin A1c (HbA1c), basic labs, microbiology, antibiotic duration, bone margin pathology. Physician review of records determined if intervention was successful. Primary outcome was met if no further amputation at the same site was required in the following 12 months.taphylococcus aureus was notable in positive vs negative margins . MSSA was significantly noted in positive margins . MRSA was similar regardless of margin results . Initial ESR, CRP and HbA1c were similar between groups.Of 92 patients, 57 had negative margins and 35 had positive margins for pathology confirmed osteomyelitis. Smoking history was significant in positive margins . Patients with negative margins had a successful outcome at 12 months compared to positive margins , but no significant differences in outcome at 6 months. Antibiotic days was reduced in negative margin individuals . Negative margins also demonstrated significant lower rates of readmission at 12 months (p=0.015). SS. aureus was significant in positive margins and likely warrant consideration for further aggressive intervention.Our study noted that negative proximal bone margins resulted in more successful outcomes at 12 months and less days of antimicrobial therapy. Patients with negative margins had lower rates of readmission at 12 months for surgical site complications. Negative proximal bone margins results can guide antibiotic therapy and improve outcomes of resections. Presence of Clinical Characteristics of Patients with Diabetic Foot OsteomyelitisClinical demographics, antibiotic usage, microbiology and results of patients presenting for diabetic foot osteomyelitis needing surgical amputation intervention. Abbreviations: HbA1c - Hemoglobin A1c; MSSA - methicillin-susceptible Staphylococcus aureus; MRSA - methicillin-resistant Staphylococcus aureus; CRP -C-reactive protein; ESR - erythrocyte sedimentation rateAll Authors: No reported disclosures"}
+{"text": "Severe burn injury is a devastating trauma with significant immune dysfunction that results in an ~12% mortality rate due to sepsis-induced organ failure, pneumonia, and other infections. Severe burn causes a biphasic immune response: an early (0-72 hrs) hyper-inflammatory state, with release of pro-inflammatory damage-associated molecular pattern molecules (DAMPs), such as HMGB1, and cytokines (e.g.IL-1b), followed by an immunosuppressive state (1-2 weeks post injury), associated with increased susceptibility to life-threatening infections. We have reported that early after severe burn injury HMGB1 and IL-1b are enriched in plasma microvesicles (MVs), suggesting a role for MVs in post-burn immune activation. Here we tested the impact of MVs isolated after burn injury on phenotypic and functional consequences TM) seen with their associated phase of post-burn immune dysfunction.We then assessed if the cargo of MVs following burn injury in humans could predict length of hospital stay. MVs isolated early from mice that underwent a 20% total body surface area (TBSA) burn injury (burn MVs) caused similar cytokine responses in na\u00efve mice to those seen in burned mice early after injury. Burn MVs transferred to RAW264.7 macrophages caused similar functional (i.e. cytokine secretion) and genetic changes (measured by NanoStringBurn MVs isolated early (24h) induced MCP-1, IL-12p70 and IFNg, while MVs isolated later (1 and 2 weeks) blunted RAW proinflammatory responses to bacterial endotoxin (LPS). Unbiased LC-MS / MS proteomic analysis of early EVS (< 72 h post-injury) showed similarities in human and mice.In our sample of large burn injury, EV SAA1 and CRP correlated with TBSA injury in both sexes and were correlated with length of hospital stay in women."}
+{"text": "Postural stability is a complex skill dependent upon the coordination of motor, sensory and cognitive systems. The purpose of this project was therefore to explore how older adults\u2019 balance performance is impacted by increased cognitive load, hearing loss, and simulated vision loss. Twenty-eight older adults between the ages of 50 and 93 years  were tested. Participants underwent standard sensory acuity and cognitive functioning tests. The balance trials varied as a function of cognitive load and visual challenge resulting in five conditions: (1) eyes closed, (2) normal vision clear goggles (NV) (3) simulated low vision (20/80) goggles (LV) (4) LV and math task, (5) NV and math task. Postural stability was assessed with three key center of pressure parameters: total path length (TPL), anterior-posterior amplitude (APA) and medial-lateral amplitude (MLA). A mixed-model ANOVA using hearing acuity as a covariate revealed significant effects of complexity in sway amplitude: , while TPL approached significance (p < .074). T-tests revealed significant (p < .05) decreases in balance performance across all 3 centre of pressure parameters when comparing single task NV to dual-task NV, NV vs. eyes closed and single task NV vs. LV dual-task. There were significant positive correlations between hearing acuity and balance (MLA) under single task NV (r = .491) and LV conditions (r = .497). Results suggest the attentional demands from increased cognitive load and sensory loss lead to decreases in older adults\u2019 single- and dual-task balance performance."}
+{"text": "Intestinal disorders such as environmental enteric dysfunction (EED) are prevalent in low- and middle-income countries (LMICs) and important contributors to childhood undernutrition and mortality. Autopsies are rarely performed in LMICs but minimally invasive tissue sampling is increasingly deployed as a more feasible and acceptable procedure, although protocols have been devoid of intestinal sampling to date. We sought to determine (1) the feasibility of postmortem intestinal sampling, (2) whether autolysis precludes enteric biopsies\u2019 utility, and (3) histopathologic features among children who died during hospitalization with acute illness or undernutrition.Transabdominal needle and endoscopic forceps upper and lower intestinal sampling were conducted among children aged 1 week to 59 months who died while hospitalized in Blantyre, Malawi. Autolysis ratings were determined for each hematoxylin and eosin slide, and upper and lower intestinal scoring systems were adapted to assess histopathologic features and their severity.Endoscopic and transabdominal sampling procedures were attempted in 28 and 14 cases, respectively, with >90% success obtaining targeted tissue. Varying degrees of autolysis were present in all samples and precluded histopathologic scoring of 6% of 122 biopsies. Greater autolysis in duodenal samples was seen with longer postmortem interval . Histopathologic features identified included duodenal Paneth and goblet cell depletion. Acute inflammation was absent but chronic inflammation was prevalent in both upper and lower enteric samples. Severe chronic rectal inflammation was identified in children as young as 5.5 weeks.Minimally invasive postmortem intestinal sampling is feasible and identifies histopathology that can inform mortality contributors. Undernutrition underlies 45% of child deaths and remains prevalent in low- and middle-income countries, including Malawi, where the under-5 year mortality rate is 42 per 1000 live births: 11% above the global average . Causes Accelerating mortality reductions requires improved cause of death (COD) understanding, particularly within populations in which undernutrition and infections are the leading mortality risk factors , 6. FullLack of gastrointestinal interrogation impedes understanding of intestinal infections, EED, and other enteric contributions to childhood deaths. The MITS in Malawi (MiM) study sought to assess postmortem endoscopic intestinal sampling feasibility, determine whether autolysis precludes enteric biopsy utility, and examine enteric histopathologic features among children who died during hospitalization with acute illness or undernutrition.MiM was conducted at Queen Elizabeth Central Hospital (QECH) in Blantyre, Malawi, a national referral and teaching hospital. MiM started as a substudy at the QECH site of the Childhood Acute Illness & Nutrition (CHAIN) study, which assessed risk factors for mortality among children hospitalized with acute illness or undernutrition in low- and middle-income countries . BecauseStudy staff approached parents/guardians of eligible children after a respectful period following death. Written informed consent was obtained from parents/guardians. Assistance with coffin purchase, transportation, and grief support was offered to all approached parents/guardians, regardless of consent to participation.MITS procedures commenced as soon as feasible after obtaining consent. A study gastroenterologist or endoscopist used Olympus GIF-P140, GIF XP-160, or GIF-160 gastroscopes and Olympus FB-231K.A or FB-230.K.A forceps. Gastric and duodenal fluid were aspirated, either prebiopsy (preferred) or postbiopsy after flushing with buffered saline. Biopsies were obtained from stomach, the first (D1), second (D2), and most distal accessible duodenal segments (D3/D4), rectum; and colon last as proximally as possible. Postendoscopy, standard MITS procedures were performed [Transabdominal intestinal needle sampling was initially considered impractical, but was adopted midstudy to assess feasibility. Bard Monopty 16G 100-mm needles were introduced just inferior to the umbilicus and right-side posterolateral for small bowel and ascending colon samples, respectively. All tissues were paraffin embedded, sectioned, and stained with hematoxylin and eosin.Z scores were calculated using World Health Organization Anthro software [z score <-3, or nutritional edema [Antemortem clinical data were collected during admission for coenrolled patients and otherwise extracted from medical records. Antemortem clinical test results were abstracted from laboratory reports. Because of incomplete antemortem anthropometric data, postmortem anthropometry was used, as is standard in MITS studies , 16. Twosoftware . Severe al edema , 19.A gastrointestinal pathologist (T-C.L.) rated each intestinal hematoxylin and eosin slide for autolysis, categorized as: (0) no autolysis; (1) <50% of tissue autolyzed; (2) 50%\u201375%; (3) >75% but <100%; and (4) complete autolysis. All sufficiently intact duodenal slides were scored using the EED Biopsy Consortium histology index, whereby 10 histologic parameters are assigned semiquantitative scores from 0  to 3 or 4 (severe pathology) . Lower iAnalysis was primarily descriptive because this study was designed to examine the feasibility of adding intestinal sampling to standard MITS procedures and not powered to comprehensively test associations with intestinal autolysis or histopathology. However, once feasibility was determined, we leveraged obtained tissues to explore such associations.t tests. Autolysis and histologic score intraindividual variability was determined with intraclass correlation coefficients (ICC) using a 2-way mixed effects model. We used univariate linear regression to explore the effect on autolysis by age, sex, admission diagnosis , nutritional status (per postmortem anthropometry), human immunodeficiency virus (HIV) status, exposure to antibiotics that are potentially more gut microbiome disruptive  versus less so  [We examined autolysis variability by anatomic location and sampling method  using paired oxazole) , refrigeWe used univariate linear regression to explore influences on histologic severity by age, sex, admission diagnosis , HIV status, nutritional status, length of hospital stay, higher dysbiotic potential antibiotics (described previously), and hepatic steatosis .Data were insufficient to relate blood culture results, blood gas acidosis, antibiotics (any use), and stomach pH to autolysis, and malaria diagnosis and acidosis to histologic severity. Analyses were conducted using Stata/SE 16.1. Significance was defined by 2-tailed alpha = .05. Graphics were generated using RStudio version 1.2.5019.The Malawi National Health Sciences Research Committee (NHSRC 1913) and Oxford University Ethics Committee (OxTREC 34-16) provided ethical approval. The University of Washington Institutional Review Board exempted the study from review (STUDY00003689).Seventy-five children eligible for this study died on enrollment days. Reasons for not seeking consent included: inability to mobilize a key study member within an appropriate time (n = 8), lack of notification by ward staff (n = 5), or unknown reasons (n = 4). Of 58 caregivers approached, 29 (50%) consented. Reasons for refusal were: lack of perceived benefit (n = 9), preference to immediately take body home (n = 7), cultural/religious concerns (n = 5), poor relationship with healthcare staff (n = 2), consenters unavailable (n = 2), child too young (n = 1), or unknown reasons (n = 3). Upper and lower endoscopic sampling was attempted for all but the final case because of corona virus disease 2019-related circumstances. Upper and lower endoscopy mean (range) duration were 34.4 (20-57) and 10.5 (6-20) minutes, respectively.At least 1 intestinal biopsy was endoscopically obtained from each of 28 cases, including: 21 D1 (75%), 20 D2 (71%), 23 D3/D4 (82%), 5 colon (18%), and 26 rectum (93%) . PresencP = .040).All intestinal samples displayed some autolysis . Thirty-P = .01), without meaningful change after adjusting for refrigeration (as percent of PMI)  higher with a 6-hour increased PMI  . No cleaP = .032). Endoscopically-obtained small intestine autolysis was 0.6 points lower in those with SAM . Antibiotic administration during hospitalization was universal, but those who received higher dysbiotic potential antibiotics had 0.5-point lower autolysis than those receiving other antibiotics, although this finding was limited to endoscopically obtained duodenal samples . Those with endoscopically visible gastric contents had 0.5-point lower autolysis (only assessed in D1) .Rectal autolysis was 0.5 points higher among children diagnosed with sepsis .Autolysis precluded scoring of 7 (6%) slides. At least 1 slide per case, totaling 115 slides (94%), were scored: 20 D1 (95%), 20 D2 (100%), 22 D3/D4 (96%), 5 colon (100%), and 26 rectal (100%) endoscopic biopsies and 11 transabdominal small (79%) and 11 large intestine samples (85%) , Table 2Of upper intestinal histology features, Paneth cell depletion was most severely abnormal (mean score = 2 of 3), followed by chronic inflammatory infiltration (mean score = 1.8 of 3) and goblet cell depletion (mean score = 2 of 4) . AutolysTo our knowledge, this is the first pediatric use of minimally invasive intestinal sampling. In 22 adults from Hong Kong, Fan et al assessed postmortem laparoscopic and thoracoscopic approaches to various organs and endoscopy of stomach and great vessels. They also visualized (without biopsying) the duodenum endoscopically in 1 patient . PostmorIn our study, jaw rigor mortis did not inhibit oral intubation, though occasionally instrumented jaw opening was required. Anal rigor mortis, when present, was easily overcome. Pyloric sphincter rigor mortis impeded duodenal intubation in 3 cases. This phenomenon arises 2 hours postmortem and resolves by 12\u201314 hours in uncooled bodies . It is eThe standard MITS procedure uses transcutaneous needle biopsies, but to our knowledge, this method had not been applied intestinally. We included transabdominal small and large bowel sampling for the last 14 cases with near universal success. Rapid needle firing likely facilitated intestinal tissue acquisition. Although likely more scalable than endoscopy, location within the upper intestine cannot be determined by blind biopsy nor can mucosa be grossly visualized. Preliminary data from an ongoing study suggest this approach unreliably yields samples in adults (unpublished). Moreover, preservation tended to be better in endoscopically sampled tissues than transabdominally. Therefore, endoscopic approach may be preferred, except in settings where precluded by resource strain.Sampling utility is an important consideration even if feasible and scalable. Intestine autolyzes early. Microbial colonization is less abundant in the duodenum but likely an important driver of large bowel autolysis . DigestiGreater small bowel autolysis was seen with longer PMI, corroborating prior studies suggesting tissues become histologically uninformative beyond 12\u201324 hours . Our datDespite autolysis prevalence, many histologic features were discernible. As expected, epithelial structure was generally undiscernible because luminal surfaces degrade first. However, inflammatory response was scorable in 94% of slides. Duodenal chronic inflammation was prevalent. All tissues were devoid of acute inflammation. This is consistent with findings from biopsies of Zambian and Pakistani children with EED, as was our finding of reduced Paneth and goblet cell density which are important in antimicrobial activity and mucin production, respectively . DepletiTransabdominally obtained small intestine had fewer histologic abnormalities than endoscopically obtained. Histopathology is a presampling phenomenon, so sampling method should not affect this. EED is thought to be a patchy duodenal disorder, as supported by our findings of intraindividual variation, possibly explained by sampling method difference. Because transabdominal sampling is blind, we cannot determine upper intestinal anatomic location and we may be scoring regions less affected than duodenum.We hoped to explore relationships with histopathology to further elucidate the role of EED and intestinal pathology in child mortality. Though EED is considered an underlying cause of undernutrition, our study was unable to detect such relationship, likely from lack of statistical power . FurtherWe acknowledge study limitations. Sample size was constrained because MiM was designed to assess feasibility; therefore, our assessment of relationships with autolysis and intestinal histopathology are exploratory. Additionally, participants died while at a referral hospital, where the majority of patients are from lower socioeconomic backgrounds and reside near Blantyre. Results may not generalize to community-based deaths or other populations.Despite these limitations, our study demonstrates that minimally invasive postmortem intestinal sampling is feasible and histologically informative. Biopsy ascertainment within 12 hours of death appears to improve tissue preservation. Preservation may also be affected by patient characteristics . Histologic interrogation successfully identified and quantified features of EED and rectal chronic inflammation. Future studies with larger sample sizes should elucidate factors affecting autolysis and enteric disease and its role in child mortality and undernutrition.Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.Supplementary materials are available at ciab790_suppl_Supplementary_Figure_1Click here for additional data file.ciab790_suppl_Supplementary_Figure_2Click here for additional data file.ciab790_suppl_Supplementary_Figure_3Click here for additional data file.ciab790_suppl_Supplementary_Figure_4Click here for additional data file.ciab790_suppl_Supplementary_Figure_5Click here for additional data file.ciab790_suppl_Supplementary_Figure_6Click here for additional data file.ciab790_suppl_Supplementary_Figure_LegendsClick here for additional data file."}
+{"text": "Latinos are twice as likely to develop Alzheimer\u2019s disease (AD) compared to non-Latino whites, yet, account for <2% of clinical trial participants in AD research. This randomized controlled trial examined the feasibility, acceptability and effects of a culturally-adapted timed-activity intervention designed to promote quality of life (QOL) and reduce behavioral symptoms in older Latinos with AD and their caregivers. Healthy Patterns [Pautas Saludables] was implemented among 40 Spanish-speaking dyads. Measures assessed at baseline and 4 weeks post-intervention, indicate improvements in sleep efficiency (p=.06) and QOL (p=.01) among intervention participants. Pautas Saludables was found to be feasible and acceptable. Intervention attendance rate was >90% with low attrition (n=0); no adverse events. Most (74%) rated timed-activity sessions as helpful and appropriate; 58% recommended refreshers. Results provide evidence that Latinos with AD will participate in clinical trials and can improve on key health outcomes, when interventions are adapted to meet their cultural needs."}
+{"text": "Scientific Reports 10.1038/s41598-021-82275-4, published online 09 February 2021Correction to: The original version of this Article contained an error in the Abstract.\u201cTDCS did not skill learning facilitate learning neither in explicit nor implicit parameters.\u201dnow reads:\u201cTDCS did not facilitate learning neither in explicit nor implicit parameters.\u201dThe original Article has been corrected."}
+{"text": "Escherichia coli Nissle (EcN) 1917 and Lacticaseibacillus rhamnosus GG (LGG) probiotics on immunogenicity and protective efficacy of oral attenuated (Att) HRV vaccine. EcN-colonized pigs had reduced virulent HRV (VirHRV) shedding and decreased diarrhea severity compared with the LGG-colonized group. They also had enhanced HRV-specific IgA antibody titers in serum and antibody secreting cell numbers in tissues pre/post VirHRV challenge, HRV-specific IgA antibody titers in intestinal contents, and B-cell subpopulations in tissues post VirHRV challenge. EcN colonization also enhanced T-cell immune response, promoted dendritic cells and NK cell function, reduced production of proinflammatory cytokines/Toll like receptor (TLR), and increased production of immunoregulatory cytokines/TLR expression in various tissues pre/post VirHRV challenge. Thus, EcN probiotic adjuvant with AttHRV vaccine enhances the immunogenicity and protective efficacy of AttHRV to a greater extent than LGG and it can be used as a safe and economical oral vaccine adjuvant.Human rotavirus (HRV) infection is a major cause of viral gastroenteritis in young children worldwide. Current oral vaccines perform poorly in developing countries where efficacious vaccines are needed the most. Therefore, an alternative affordable strategy to enhance efficacy of the current RV vaccines is necessary. This study evaluated the effects of colonization of neonatal gnotobiotic (Gn) pigs with  Studies have shown that there is reduced efficacy of HRV and other vaccines in developing countries, which presents a major concern and a global health challenge [Human rotavirus (HRV) is the leading cause of viral gastroenteritis in infants and children that results in significant morbidity and mortality, especially in developing countries ,2,3. Thehallenge ,5,6,7. Mhallenge ,9,10. ThHelicobacter pylori replication, allergies, and cancer [Escherichia coli Nissle (EcN) 1917 is a Gram-negative probiotic that was shown to be highly efficient in protecting gnotobiotic (Gn) piglets against HRV infection and disease by modulating innate and adaptive immunity, and directly protecting the intestinal epithelium by binding to HRV particles [Lacticaseibacillus rhamnosus GG (LGG) is a Gram-positive probiotic commonly used to treat or prevent RV diarrhea in children. Prophylactic supplementation of LGG to children significantly reduced the incidence of HRV disease [Lacticaseibacillus strains were demonstrated to significantly reduce diarrhea severity in hospitalized children [Bifidobacterium lactis resulted in a significant reduction in both fecal HRV shedding titers and diarrhea severity in the Gn piglet model of HRV infection [Commensal/probiotic colonization and their beneficial effects play a vital role early in life that may result in lifelong benefits . Thus, ed cancer ,21,22,23articles ,25. Lact disease . Furtherchildren . Previounfection .Gn pigs are immunocompetent at birth but immunologically immature . They arIn this study, we investigated the role of selected probiotics (EcN and LGG), on adaptive and innate immune responses to live oral attenuated (Att) HRV Wa (G1P ) vaccine7 fluorescent foci-forming units (FFU) [6 FFU as described previously [The cell culture adapted attenuated HRV (AttHRV) Wa G1P  strain pts (FFU) . Viruleneviously ,34.Lacticaseibacillus rhamnosus GG (LGG) a Gram-positive probiotic, was used in these experiments for comparison with the Gram-negative probiotic Escherichia coli Nissle (EcN) 1917 [n = 7) and LGG/AttHRV/VirHRV (n = 6). EcN and LGG inoculum was prepared as described previously [5 CFU/pig/timepoint in 0.1% peptone water. All pigs were orally vaccinated twice at 7 day intervals with AttHRV on post bacterial colonization day (PBCD) 3/post first vaccination day (PVD) 0, and PBCD 10/PVD 7(0) ). At PBCD 17/PVD 14 (7)/post challenge day (PCD) 0, a subset of pigs from each of the group was euthanized to assess immune vaccine responses pre challenge. The remaining pigs were challenged with homologous VirHRV Wa and euthanized at PBCD 24/PVD 21 (14)/PCD 7. All piglets were challenged with VirHRV at a dose of 1 \u00d7 106 FFU per piglet at PBCD 17 and were euthanized at PBCD 24/post VirHRV challenge day (PCD) 7. Systemic and intestinal tissues were collected to isolate mononuclear cells (MNCs) for subsequent immunological assays. Serum and intestinal contents were collected to determine the HRV specific and total antibody responses.This study was approved by the Ohio State University Institutional Animal Care and Use Committee. Piglets were derived from near-term sows (Landrace \u00d7 Yorkshire \u00d7 Duroc cross-bred) by hysterectomy and maintained in sterile isolators as described previously . All thecN) 1917 ,13,36. Neviously  and sequg for 10 min at 4 \u00b0C, and stored at \u221220 \u00b0C until quantification of infectious HRV by a cell culture immunofluorescence (CCIF) assay.Rectal swabs were collected daily after VirHRV challenge. Fecal consistency was scored as follows: 0, normal; 1, pasty/semi-liquid; 2, liquid; pigs with fecal scores more than 1 were considered diarrheic. Rectal swabs were suspended in 2 mL of MEM  supplemented with antibiotics/antimycotic, clarified by centrifugation at 800\u00d7 Systemic  and intestinal  tissues were collected to isolate MNCs as described previously ,37,38,39The HRV antibody and total immunoglobulin (Ig) isotype titers in serum, SIC, and LIC were detected by ELISA. To determine the intestinal antibody responses, SIC and LIC were collected with protease inhibitors in the medium. MNCs isolated from blood, spleen, duodenum, and ileum were analyzed by ELISPOT assay to quantitate numbers of HRV-specific antibody secreting as described previously ,39,40.Serum samples were collected and analyzed for proinflammatory  and T regulatory  cytokine levels as described previously with modifications ,38.+CD4+), cytotoxic T cells (CD3+CD8+), natural T regulatory cells (CD4+/CD8+CD25+FOXP3+), activated T regulatory cells (CD4+/CD8+CD25+FOXP3\u2212), and inducible T regulatory cells (CD4+/CD8+CD25\u2212FOXP3+) [+CD4\u2212CD11R1+) and plasmacytoid DCs , activated cDC (SWC3a+CD4\u2212CD11R1+MHC II+), activated pDC (SWC3a+CD4+CD11R1\u2212MHC II+), and CD103+ cDC (SWC3a+CD4\u2212) and CD103+ pDC (SWC3a+CD4+) marker expression on DCs and Toll-like receptor (TLR) expression on MNCs as reported previously [+CD2\u2212CD21\u2212), Ig-secreting B cells (CD79\u03b2+CD2+CD21\u2212), na\u00efve antibody-forming B cells (CD79\u03b2+CD2+CD21+), and activated antibody-forming B cells (CD79\u03b2+CD2\u2212CD21+) among systemic and intestinal CD79\u03b2+ B cells were analyzed using gating strategies as determined previously [+CD16+) were assessed among systemic and intestinal MNCs. The frequencies and tissue distribution of apoptotic MNCs were assessed with an annexin V apoptosis detection kit. APC and propidium iodide staining solution (eBioscience) were used to discriminate apoptotic and necrotic MNCs. Analysis and gating strategies were performed as described previously [Freshly isolated MNCs were stained to determine frequencies of T-cell subsets: T helper cells (CD3\u2212FOXP3+) ,40. MNCseviously ,24,41,42eviously ,24,43. Feviously ,44.\u2212\u0394\u0394Ct method [The IECs were isolated from jejunum (mid gut) using a modified protocol adapted from Paim et al. ,34,45. Tt method .10 transformed isotype ELISA antibody titers were analyzed using one-way ANOVA followed by Duncan\u2019s multiple range test. Correlation analysis was performed using nonparametric correlation Spearman\u2019s method . Values or error bars indicate the standard error of the mean.All statistical analyses were performed using GraphPad Prism version 6 . Logs method . Data reDiarrheal scores and HRV fecal shedding were recorded daily post VirHRV challenge. Analysis revealed that EcN colonization resulted in greater protection from diarrhea . MoreoveHRV shedding analysis revealed that 42.9% of EcN pigs shed compared with 66.7% LGG-colonized pigs, and the reduced shedding coincided with reduced diarrheal scores . FurtherAt PVD14(7) and pre challenge day 0, EcN colonization enhanced the effects of AttHRV vaccination, i.e., increasing the HRV-specific IgA and IgG antibody titers in serum: IgA and IgG ASCs in systemic and intestinal MNCs, and IgM ASCs in intestinal MNCs compared with LGG colonization . HoweverPost VirHRV challenge (PCD7), coincident with reduced fecal scores and HRV shedding titers, EcN colonization increased the HRV specific IgA antibody titers in serum, SIC, and LIC, as well as HRV-specific IgA ASCs in systemic, and intestinal MNCs compared with LGG colonized pigs . Similar+) in tissues (At PVD14(7) and pre challenge day 0, EcN compared with LGG colonization decreased the frequencies of B-cell subpopulations , resting/memory, Ig-secreting, IgA tissues . Interes tissues . These f+CD4+) in systemic MNCs, while EcN colonization increased them in intestinal MNCs pre challenge (PCD0). However, EcN colonization increased the frequencies of cytotoxic T cells (CD3+CD8+) in systemic and ileal MNCs pre challenge compared with LGG colonization (LGG colonization resulted in slightly elevated frequencies (percent) of T helper cells  and pre challenge day 0, LGG colonization increased the frequencies of HRV-specific CD3 vaccine . Post Vihallenge . Thus, o+ T regs in splenic and intestinal MNCs, activated CD8+ T regs in systemic and ileal MNCs, inducible CD4+/CD8+ T regs in systemic and intestinal MNCs, and natural CD4+/CD8+ T regs in spleen and ileum (At PVD14(7) and pre challenge day 0, EcN colonization resulted in slightly higher frequencies of activated CD4nd ileum  consiste+ T regs in splenic and intestinal MNCs, activated CD8+ T regs in spleen and duodenum, inducible CD4+ T regs in systemic and duodenal MNCs, inducible CD8+ T regs in spleen, natural CD4+ T regs in splenic and intestinal MNCs, and natural CD8+ T regs in systemic and intestinal MNCs  cytokine levels in serum in most cases compared with LGG colonization a,b. In c+ cDCs/pDCs in intestinal MNCs, activated cDCs in intestinal MNCs, and activated pDCs in duodenum (At PVD14(7) and pre challenge day 0, EcN colonization increased the frequencies of cDCs in splenic and intestinal MNCs, pDCs in systemic and ileal MNCs, CD103duodenum .+ cDCs in spleen and ileum, CD103+ pDCs in spleen and duodenum, activated cDCs in systemic MNCs, and activated pDCs in blood  and pre challenge day 0, EcN colonization decreased the frequencies of TLR4 -expressing MNCs in systemic and systemic/intestinal tissues, respectively. On the other hand, EcN colonization increased the frequencies of TLR3/TLR9 -expressing MNCs in systemic and intestinal tissues .Post VirHRV challenge, EcN colonization decreased the frequencies of TLR4-expressing MNCs in intestinal and systemic/intestinal tissues, coinciding with decreased diarrheal severity and HRV shedding titers. TLR3-expressing MNCs were increased in systemic and intestinal tissues, while TLR9-expressing MNCs were increased in the ileum of EcN-colonized pigs . These dAt PVD14(7) and pre challenge day 0, EcN colonization increased the frequencies of NK cells in blood and ileum MNCs . HoweverFrequencies of apoptotic MNCs were decreased in intestinal MNCs pre challenge . On the NK cell function in blood MNCs was enhanced in EcN-colonized pigs compared with LGG-colonized pigs both pre/post VirHRV challenge c,d. ThisGene expression levels of villin, SOX9, PCNA, MUC2, and CgA mRNA levels were assessed in jejunal epithelial cells. The relative mRNA levels of all the genes were increased in jejunal epithelial cells of EcN compared with LGG colonized pigs . This coProbiotic intervention is a potential strategy to immunomodulate adaptive and innate immunity to enteric infections and/or enhance efficacy of vaccines. Probiotic investigations in infants and children using vaccines have focused mainly on antibody responses, and a small number of studies have addressed T-cell responses . Using tOur study showed that EcN colonization resulted in significant reduction in HRV shedding, diarrheal scores, delayed onset, and duration of diarrhea compared with previously published observations  suggestiOur results suggest that the EcN probiotic, which effectively colonized the Gn piglets, beneficially immunomodulated B cell responses to oral AttHRV vaccine pre challenge. Interestingly in this study, HRV-specific IgA/IgG ASCs were elevated in both ileal and duodenal MNCs compared to our previous study where the effect was observed only in duodenum post VirHRV challenge  owing toEcN colonization enhanced total and HRV-specific IgA, IgG, and IgM antibody titers in serum and HRV specific IgA antibody titers in intestinal contents which coincided with reduced diarrheal scores and HRV shedding titers. Moreover, HRV-specific/total IgA antibody responses were correlated with HRV-specific/total IgG and IgM antibody responses, further confirming the enhancement of immune responses pre-challenge against HRV infection ,51,52. I+ Tregs in duodenum post VirHRV and natural CD8+ Tregs in ileum pre challenge. This suggests that EcN colonization pre challenge enhanced T-cell immunity and induced an anti-inflammatory environment, thereby inhibiting proinflammatory immune responses post VirHRV challenge. This also implies that blockade of proinflammatory signaling by EcN adjuvant with AttHRV can represent a therapeutic approach.In this study, resting/memory antibody-forming B cells were enhanced in systemic and intestinal MNCs post VirHRV challenge, contrary to a previous study where these cells were enhanced only in spleen post VirHRV challenge , suggest+ cells were not observed in our previous studies [Interestingly, cDCs, activated cDCs, and CD103 studies  indicati studies ; however studies ,54,55,56Compared with previous observations  where TL+ MNCs frequencies were increased in splenic (significantly) and other tissue MNCs of EcN-colonized pigs pre challenge, suggesting a possible synergistic effect of EcN colonization on AttHRV vaccine leading to upregulation of TLR3/9 expression, which contributed to the enhanced immunoglobulin responses [TLR9-expressing MNCs frequencies were increased in systemic and intestinal MNCs pre challenge and ileal MNCs post VirHRV challenge of EcN-colonized pigs; however, previously , TLR9-exesponses ,57,58. Tesponses ,60,61,62Furthermore, NK cell function was enhanced in EcN colonized pigs pre/post VirHRV challenge, suggesting that EcN colonization produced adjuvant effects with live oral AttHRV to promote innate immune responses pre challenge that alleviated HRV infection post VirHRV challenge.EcN mechanisms of action include direct antimicrobial impact, involvement in the bacterial\u2013epithelial crosstalk via biofilm formation, strengthening of tight junctions of intestinal epithelial cells, interactions with immune system by causing a decrease in proinflammatory cytokines and an increase in immunoregulatory cytokines, and binding to HRV particles via histo-blood group antigen-like bacterial glycans . On the There is a limitation of this study in that Gn piglets without other confounding microbiota were used to determine the specific beneficial effects of EcN on AttHRV against HRV-induced immunity. Whether the findings from this study using Gn pigs can be comparable to conventional pigs or other species with a normal gut microbiota is uncertain because of the reduced immune responses in germ-free, mono-colonized or dual-colonized versus conventional animals ,66. HoweIn future studies, we plan to delineate the impact of EcN probiotic in pigs transplanted with a human infant fecal microbiota and vaccinated with live oral AttHRV to determine its effect pre/post VirHRV challenge. Furthermore, additional studies are needed to evaluate the efficacy of EcN efficacy on AttHRV vaccine in malnourished Gn piglets transplanted with human infant fecal microbiota, as well as in a conventional pig model.Our results suggest that, compared with the Gram-positive LGG probiotic, the Gram-negative EcN probiotic had greater beneficial effects in promoting strong but balanced immunoregulatory/immunostimulatory efficacy of oral AttHRV vaccine in Gn piglets. EcN probiotic increased the effectiveness of live oral AttHRV vaccine by increasing both adaptive and innate immune responses. Our results suggest the possibility that low-cost dietary supplementation of EcN given together with RV vaccine can protect against HRV-associated diarrhea, HRV outbreaks, and other potentially enteric infections."}
+{"text": "Molecular rapid diagnostic tests (RDTs) for bloodstream infections (BSI) utilize a variety of technologies and differ substantially in organisms and resistance mechanisms detected. RDT platforms decrease time to optimal antibiotics; however, data on RDTs in special populations, such as immunocompromised are extremely limited. This study aimed to compare theoretical changes in antibiotics based on differences in panel identification of organisms and resistance targets among three commercially available RDT panels.3 at any time 30 days prior to BSI diagnosis. Verigene BC-GN was performed as standard of care. GenMark ePlex BCID and BioFire FilmArray BCID 2 results were assigned based on respective identifiable organism panels. Retrospective cohort of immunocompromised patients treated for gram-negative BSI at University of Maryland Medical Center from January 2018 to September 2020. Immunocompromised was defined as active hematologic or solid tumor malignancy at time of BSI diagnosis, history of hematopoietic stem cell transplantation (HSCT) or solid organ transplantation (SOT), or absolute neutrophil count (ANC) < 1000 cells/mma priori DOOR-MAT matrices. A partial credit scoring system (0 to 100) was applied to each decision based on final AST results. The mean and standard deviation (SD) were compared across panels using One-Way Repeated Measures ANOVA with modified Bonferroni for multiple comparisons.An infectious diseases clinician blinded to final antimicrobial susceptibility testing (AST) results used RDT results to assign antibiotic treatments for each platform. Decisions were referenced against P=0.6). A total of 146 patients met inclusion. Baseline characteristics are summarized in Table 1. The mean (SD) DOOR-MAT scores for the three RDT panels were: 86.1 (24.4) Verigene BC-GN vs. 88.5 (22.2) GenMark BCID vs. 87.2 (24.4) BioFire BCID 2. There was no statistically significant difference between the panels for DOOR-MAT score , GenMark (Speaker\u2019s Bureau) Kimberly C. Claeys, PharmD, GenMark (Speaker\u2019s Bureau)"}
+{"text": "Candida have been rarely reported. We describe SCV C. glabrata (CG) strains recovered from within a population causing bloodstream infection (BSI) in a patient (pt), which were not recognized by the micro lab. Pt J developed CG BSI shortly after liver transplant (OLTX), which was treated with voriconazole (VOR). VOR was also used for post-OLTX mold prophylaxis. 67 d after BSI, he developed intra-abdominal infection due to VOR-resistant CG. We hypothesized that BSI might be caused by an unrecognized mixed population of azole-susceptible and \u2013resistant strains. Bacterial small colony variants (SCVs) that are tolerant to commonly used antibiotics are well recognized. Clinical SCV Ten colonies from small (SCV) and large colonies (LC) from blood culture (BC) agar plates underwent Illumina NextSeq WGS and phenotype testing. CDR1 and PDR1 expression . Compared to LCs, SCVs grew slowly in YPD, did not grow on media containing glycerol as sole carbon source, and were less adherent to agar. SCVs stained poorly with rhodamine 123 by fluorescence flow cytometry and had fewer mitochrondria by transmission electron microscopy, consistent with WGS findings and respiratory deficiency. SCVs were less susceptible to macrophage (J774) phagocytosis, and they were significantly outgrown by other strains in competitive infections in vitro and during disseminated candidiasis in mice. LCs incubated with FLU in vitro yielded SCVs in concentration-dependent manner. Likewise, LCVs passed through spleens of mice following IV inoculation yielded SCVs in both presence and absence of FLU. BCs from pt J harbored a diverse population of genetically distinct CG strains, differing by unique SNPs and indels [Fig. 1]. Gene variants identified were enriched for biological processes involved in mitochondrial processes (2.5e-9), cell adhesion (3.3e-5), and respiration (3.5e-4). Unlike LC, SCVs were fluconazole (FLU) resistant (MIC: 128 \u00b5g/mL), and exhibited enhanced Venn diagram for 5 representative stranis of C.glabrataCG, if micro labs select single colonies from BCs for antifungal susceptibility testing, or in absence of prolonged incubation.Mitochondrial dysfunction and SCVs may be under-recognized determinants of azole resistance in Cornelius J. Clancy, MD, Merck (Grant/Research Support) Minh-Hong Nguyen, MD, Merck (Grant/Research Support)"}
+{"text": "PDGF-B homodimers induce DNA synthesis in adult zebrafish cardiomyocytes. In addition, we demonstrate that a chemical inhibitor of PDGF receptor decreases DNA synthesis of cardiomyocytes both in vitro and in vivo during regeneration. Our data indicate that zebrafish heart regeneration is associated with sequentially upregulated wound healing genes and growth factors and suggest that PDGF signaling is required.Mammalian hearts cannot regenerate. In contrast, zebrafish hearts regenerate even when up to 20% of the ventricle is amputated. The mechanism of zebrafish heart regeneration is not understood. To systematically characterize this process at the molecular level, we generated transcriptional profiles of zebrafish cardiac regeneration by microarray analyses. Distinct gene clusters were identified based on temporal expression patterns. Genes coding for wound response/inflammatory factors, secreted molecules, and matrix metalloproteinases are expressed in regenerating heart in sequential patterns. Comparisons of gene expression profiles between heart and fin regeneration revealed a set of regeneration core molecules as well as tissue-specific factors. The expression patterns of several secreted molecules around the wound suggest that they play important roles in heart regeneration. We found that both Comparison of gene expression in regenerating heart and fin points to common as well as tissue-specific mechanisms. PDGFs expressed in the heart induce DNA synthesis in cardiac myocytes. Injured mammalian hearts cannot regenerate; instead, they scar. Mammalian cardiomyocytes undergo hypertrophy to compensate for the loss of cardiac cells. Although it has been reported that cardiomyocytes in diseased human hearts can proliferate , most evZebrafish heart regeneration occurs over a 2-mo period . After ancp , tbx18 (T box-18), andatf3 (activating transcription factor 3).The differentially expressed genes were grouped into six clusters (I to VI). Each gene cluster is shown separately for illustrative purposes and the representative genes are indicated graphically by plotting dpa versus log(607 KB EPS)Click here for additional data file.Figure S2The alignments were performed using clustW. The gray boxes indicate homologous regions. The red boxes indicate conserved cysteine residues. Zebrafish PDGF-B shows high homology to other species.(404 KB EPS)Click here for additional data file.Table S1(44 KB DOC)Click here for additional data file.Table S2(27 KB DOC)Click here for additional data file.http://www.ncbi.nlm.nih.gov/Genbank) accession numbers for human, mouse, andXenopus PDGF-B used inmonopolar spindle (mps) 1 gene (NM_175042), heat shock protein 60 (hsp60) chaperone protein (NM_181330),pdgf-a (AF200950),pdgf-b (DQ647924),apoEb (NM_131098), vegf-c (AF466147),granulin-A (AF375477), MMP2 (NM_198067), MMP14a (NM_194416), MMP14b (NM_194414), acidic cysteine\u2013rich glycoprotein(sparc) (BG305371),thymosin \u03b24 (BI428446), insulin-like growth factor 2 (igf2) (AF250289),chemokine c-x-c ligand 12 (cxcl12) (NM_178307), andmidkine a (NM_131070).The GenBank ("}
+{"text": "Both biodegradable emboli and pharmacological agents can enhance regional therapy for hepatic targeting. Using a rat model with similar haemodynamic characteristics to human colorectal liver tumour and a radio-labelled marker of similar molecular weight to Adriamycin, we have combined the two approaches to see if the effect was addictive. Following induction of liver tumour in male hooded rats by intrahepatic injection of HSN sarcoma cells, the relative distribution of marker, 99mTc methylene diphosphonate (MDP), was studied in three groups given the following by injection into the hepatic artery. (1) Saline (Control) + MDP; (2) Degradable Starch Microspheres (DSM) + MDP; and (3) Angiotensin II + DSM + MDP. Both Degradable Starch Microspheres alone (P less than 0.001) and Degradable Starch Microspheres + Angiotensin II (P = 0.003) significantly increased the retention of marker in liver and tumour at 1 min following injection, with a 12-fold improvement over controls, but the tumour:liver ratio was unaltered. By 90 min the MDP levels in normal hepatic parenchyma had returned to control values. There was relatively less washout with significant retention in tumour tissue in both DSM (P = 0.03) and combination treated animals (P = 0.001), with a significantly improved (P = 0.001) tumour to liver ratio (5.22:1) in combination treated animal relative to those treated with DSM alone."}
+{"text": "There is abundant evidence that inhibitors of prostaglandin (PG) biosynthesis might increase the radioresponse of certain tumour cells. This study investigated specific PG binding sites, eicosanoid production as well as intracellular cAMP levels in cultured human hypernephroma cells derived from 11 patients upon nephrectomy. Scatchard analyses of the binding data revealed specific PGE1-, PGE2- as well as PGI2-binding sites . Significant (P < 0.01) increase in PG binding sites expressed on human hypernephroma cells  and inhibition of PG biosynthesis  were found after acetylsalicylic acid (ASA)-treatment (0.5 mg 10(-6) cells for 24 h). Following irradiation , PG binding sites  were significantly (P < 0.01) diminished. However, irradiation had no significant effect on PG binding sites in ASA-pretreated cells . Although there was no significant difference in the basal values for cAMP between control and ASA-treated group cells, the PG-induced cAMP-production was less pronounced in the control group. Taken together, the findings suggest that ASA may modify the radioresponse of cultured human hypernephroma cells by preventing the decrease of PG binding sites induced by irradiation."}
+{"text": "Glutathione S-transferase (GST) isoenzyme composition, isoenzyme quantities and enzymatic activity were investigated in benign (n = 4) ovarian tumours and malignant ovarian tumours, before (n = 20) and after (n = 16) chemotherapy. Enzymatic activity of GST in cytosols was measured by determining 1-chloro-2,4-dinitrobenzene conjugation with glutathione, cytosolic GST subunits were determined by wide pore reversed phase HPLC, using a S-hexylglutathione-agarose affinity column, and isoelectric focussing. Both GST activity and GST pi amount were not related to histopathologic type, differentiation grade, or tumour volume index in untreated malignant tumours. GST isoenzyme patterns were identical in benign tumours and malignant tumours before and after platinum/cyclophosphamide chemotherapy, while GST pi was the predominant transferase. Mean GST activity and GST pi amount were decreased (P < 0.05) in malignant ovarian tumours after platinum/cyclophosphamide chemotherapy compared to untreated ovarian malignant tumours. No relation was found in untreated ovarian tumours between GST pi amount and response to platinum/cyclophosphamide chemotherapy. Thus, within the limitations of the current study no arguments were found for a role of GST in in vivo drug resistance of malignant ovarian tumours to platinum/cyclophosphamide chemotherapy."}
+{"text": "Serum-free media conditioned by the androgen insensitive human prostate cancer cell line DU145 showed immunological transforming growth factor-alpha  activity, as well as competing activity in epidermal growth factor (EGF) radioreceptor assays (RRA). Furthermore, there were factors in the conditioned media which inhibited and stimulated DNA synthesis by DU145 cells in a dose-dependent fashion. Fractionation of the concentrated conditioned media by reverse-phase high performance liquid chromatography revealed several peaks containing EGF-like competitive activity only one of which demonstrated TGF alpha activity. However, none of the peaks corresponded to immunoreactive EGF. Measurement of EGF receptors on DU145 cells by competition and saturation analysis revealed high levels of receptors (mean +/- s.d. = 2.5 +/- 1 x 10(5) surface receptors per cell) which were of high affinity (Kd +/- s.d. = 1.0 +/- 0.5 nmol l-1). Although DU145 cells express high levels of EGF receptors, DNA synthesis was only minimally affected by exogenous EGF and TGF alpha."}
+{"text": "In order to evaluate long-term somatic morbidity after treatment for testicular cancer 149 patients with NED greater than or equal to 3 years answered a questionnaire. The patients had been treated with surgery only , cisplatin-based chemotherapy plus surgery (46 patients) or chemotherapy plus radiotherapy with or without surgery (32 patients). Raynaud-like phenomena were the most frequent side-effect occurring significantly more often after cisplatin-based chemotherapy than after surgery or radiotherapy (33/72 patients versus 5/68 patients). Peripheral sensory 'neuropathy' was reported by 18% of all the patients. Seventeen per cent and 11% complained of pulmonary symptoms and auditory symptoms, respectively. Gastrointestinal side-effects were more frequent after any type of cytotoxic therapy than after surgery only (34/47 patients versus 5/22 patients). Twenty-six patients had fathered children after treatment. About 80% of the patients were in full time wage-earning activity when they answered the questionnaire. In conclusion, 3-7 years after treatment for testicular cancer, 30-50% of the patients had minor somatic complaints whereas serious side-effects seldom occurred."}
+{"text": "Using an RNAse protection assay, expression of messenger RNA for isoforms of TGF-beta was determined in a series of breast cancers. Of 50 tumours, 45 (90%) expressed TGF-beta 1 mRNA, 39 (78%) expressed TGF-beta 2, and 47 (94%) expressed TGF-beta 3. Patterns of expression varied between different tumours: 37 (74%) cancers expressed all three TGF-beta isoforms, ten (20%) expressed only two isoforms and two expressed TGF-beta 1 alone. One sample showed no evidence of TGF-beta mRNA expression. Although most breast cancers expressed mRNA for at least one isoform of TGF-beta, there were differences in patterns of mRNA expression between individual tumours. The relatively small number of tumours examined precluded detailed analysis between expression and other clinical parameters, but a significant association was identified between one aspect of isoform expression and lymph node status, in that the majority of tumours expressing all three isoforms were associated with lymph node involvement, whereas tumours without one or more isoform were usually lymph node negative (P = 0.025 by Fisher's exact test)."}
+{"text": "Objective: We postulated that either oral or vaginal administration of the immune response modifier imiquimodwould decrease vaginal shedding of Chlamydia trachomatis, mouse pneumonitis strain (MoPn), in a murine model.Methods:  Female BALB/c mice were infected intravaginally withC. trachomatis  (MoPn) and were administeredimiquimod either orally (30 mg/kg) or vaginally (10 \u03bcl of 5%imiquimod cream) prior to infection and every secondday after infection for a total of four doses. The course of infection was monitored by collecting cervical\u2013vaginalswabs and isolation in HeLa 229 cell culture. To determine whether the drug affected T helper type 1 or T helpertype 2 immune response polarization, immunoglobulinG(IgG) subclass antibody responses were assessed at day 56after infection.Results: There was no significant difference in the course of infection when imiquimod-treated mice werecompared with sham-treated controls, regardless of whether the drug was administered orally or vaginally. IgGsubclass antibody responses, and by extension, T helper type 1 to T helper type 2 immune response polarization,were also unaffected.Conclusions: Imiquimod has no efficacy in controllingC. trachomatis  (MoPn) infection in the murine model."}
+{"text": "This rich source of proviral information, accumulated in a local database, and a collection of XRV sequences from the literature, allowed the reconstruction of a Pol based phylogenetic tree, more extensive than previously possible. The aim was to find traits useful for classification and evolutionary studies of retroviruses. Some of these traits have been used by others, but they are here tested in a wider context than before.Endogenous retroviral sequences (ERVs) are integral parts of most eukaryotic genomes and vastly outnumber exogenous retroviruses (XRVs). ERVs with a relatively complete structure were retrieved from the genetic archives of humans and chickens, diametrically opposite representatives of vertebrate retroviruses (over 3300 proviruses), and analyzed, using a bioinformatic program, RetroTectorIn the ERV collection we found sequences similar to the XRV-based genera: alpha-, beta-, gamma-, epsilon- and spumaretroviruses. However, the occurrence of intermediates between them indicated an evolutionary continuum and suggested that taxonomic changes eventually will be necessary. No delta or lentivirus representatives were found among ERVs. Classification based on Pol similarity is congruent with a number of structural traits. Acquisition of dUTPase occurred three times in retroviral evolution. Loss of one or two NC zinc fingers appears to have occurred several times during evolution. Nucleotide biases have been described earlier for lenti-, delta- and betaretroviruses and were here confirmed in a larger context.i.) translational strategy, ii.) number of Gag NC zinc finger motifs, iii.) presence of Pro N-terminal dUTPase (dUTPasePro), iv.) presence of Pro C-terminal G-patch and v.) presence of a GPY/F motif in the Pol integrase (IN) C-terminal domain. \"Local\" retroviral genomic properties useful for delineation of lower level taxa are i.) host species range, ii.) nucleotide compositional bias and iii.) LTR lengths.Pol similarities and other structural traits contribute to a better understanding of retroviral phylogeny. \"Global\" genomic properties useful in phylogenies are  Retroviral and related endogenous retroviral sequences (ERVs) are integral parts of most eukaryotic genomes, sometimes constituting over 50% of them . Their aRetroviridae borders to Pararetroviridae (e.g. Hepatitis B), Metaviridae (Gypsy-like) and Pseudoviridae (Copia-like). Together with the even more more distant relatives Mal-R , we have used Pol similarity for ERV classification. Pol is highly conserved, and its large size (800\u20131100 aa) provides adequate information for a relatively detailed classification. This is facilitated by the program RetroTector\u00a9 [Sperber G.O. et al. in preparation], which reconstructs probable Pol proteins (\"puteins\") from different reading frames in the often damaged gene candidates. The puteins are favored over nucleotide sequences since they are more conserved, easier to align and therefore allow phylogenetic inference and taxonomy over greater evolutionary distances. This is further discussed in the Methods and Results sections of this paper. A number of reliable distinguishing features must be defined to enable a durable retroviral taxonomy which can encompass the many new ERVs and XRVs, and to trace their evolution. In this study, we compared phylogenetic trees, based on Pol similarity, with distinct structural features of possible use as taxonomic and phylogenetic markers.In several papers ,20 and J and J20 \u00a9 (see methods), we screened the human hg16 . Based on experience from randomized data set scores (data not shown), this threshold separated false from true retroviral elements with a wide margin. We collected the sequences into an ERV databank, from which we extracted representative sequences for use in matching structural traits against sequence similarity based phylogenetic inference. Sequences scoring over 300 from the hg16 and gg01 genomes were analyzed for the presence of Pol. Those with a recognizable Pol were grouped into respective genera according to sequence similarity (Table Using the program RetroTectorman hg16  and chicman hg16  genomes submitted]) and chicken gg01 [submitted]) were included to provide a broad based phylogeny. The remaining representative ERVs, all with high RetroTector\u00a9 scores, were selected to contribute with different aspects, e.g. intermediate positions in the tree, while still keeping the size of the Pol tree manageable. Annotated exogenous retroviruses retrieved from GenBank were added to form a tree backbone structure useful for taxonomic reference  tree. We used the whole Pol and the principle of pairwise deletions in the alignment and distance matrix analyses to avoid problems with missing portions in RT as in e.g. the large HERV-H group . To recoken gg01  genome aken gg01 , not foue Figure . The phye Figure , and thee Figure . The consubmitted] and lentiviruses , RSV [NC001407], MMTV [NC001503], MPMV [NC001550], JSRV [M80216], HML1 (Chr19-21849393), HML2 (Chr11-101600013), HML3 (Chr1-48344461), HML4 (Chr8-75679221), HML5 [AC004536], HML6 (consensus), HML7 (Chr6-121300220), HML8 (Chr3-131452286), HML9 (Chr9-62700428), HML10 (Chr6-32017925), HERV-H (consensus), HERV-H/RGH2 [D11078], HERV-H/RTVLH2 [M18048], HERV-Fc1 [AL354685], HERV-Fc2 [AC019088], HERV-W (Chr7-9105739), ERV9 [AC073410], ERV3 (Chr7-63865366), HERV-E [M10976], MLV [NC001501], MoLV [AF033811], BaEV [D10032], GaLV [M26927], HERV-ADP [AC005741], HERV-FRD [AC004022], HERV-I (Chr16-72821350), HERV-T (Chr14-104635791), HERV-S [AC004385], FLV [NC001940], PERV [AJ293656], WDSV [NC001867], Xen1 [AJ506107], SnRV [NC001724], BLV [NC001414], HTLV-1 [NC001436], and HTLV-2 [NC001488], Gypsy [AJ000387], HERV-L (RepBase), HSRV [AF033816], HFV [NC001736], MER4like (Chr13-54208300), HERV-L66 (RepBase), HERV-L74 (RepBase), HERV-L40 (RepBase) and Python molurus [AAN77283].GenBank accession numbers or chromosomal positions in \u00a9, developed by us, to screen the downloaded genomic sequences for proviral integrations. Briefly, the program recognizes conserved retroviral consensus motifs and constructs putative proteins (\"puteins\") from the different reading frames in the gene candidates. Codon statistics, frequency of stop codons and alignment to known retroviral proteins are used to approximate an original ORF. Finally the puteins are validated and classified using alignments of earlier described proteins from the literature. The validity of the puteins used for alignment and phylogenetic inference, can be confirmed by inspection of excised parts of RT and IN from the full Pol alignment  . A conse\u00a9 analysis of the different genomes.Statistics were extracted from the ERV databank collected through the RetroTectorThe Pol FASTA sequences are included into the additional files .aa amino acidsCA CapsiddUTPase deoxyuridine triphosphataseEnv EnvelopeERVs Endogenous retroviral sequencesGag Group specific antigenHERVs Human endogenous retroviral sequencesIN IntegraseLTR Long terminal repeatMA MatrixNC NucleocapsidPBS Primer binding sitePol PolymerasePPT Polypurine tractPro ProteaseRNAse H Ribonuclease H enzymeRT Reverse transcriptaseXRV Exogenous retrovirusThe author(s) declare that they have no competing interests.PJ conceived the study, participated in its design and coordination, carried out the molecular genetic studies and drafted the manuscript. GOS developed algorithms and carried out the programming needed for the analyses. JB conceived the study, and participated in its design and coordination, participated in programming and helped to draft the manuscript. All authors read and approved the final manuscript.Pol similarity matrix. Pol NJ cladogram (1000 bootstraps and pairwise deletions) aligned to a similarity matrix based on PAM250.Click here for fileRetroviral genomic structures. RetroTector\u00a9 output of selected retroviral genomic structures described in the text.Click here for filedUTPase phylogenetic tree. Retroviral dUTPase acquisitions. Minimum Evolution (ME) tree (100 bootstraps).Click here for fileMotif consensus validations. WebLogo consensus of the partial dUTPasePro, C-terminal Pro (G-patch) and Pol (GPY/F) motifs.Click here for filePutein validations. Validation of puteins from Pol alignment. Excised parts of RT and IN are shown.Click here for filePol FASTA sequences. Pol FASTA sequences.Click here for file"}
+{"text": "We have investigated the possibility of a direct regulatory effect of gonadotrophin releasing hormone (GnRH) analogues on prostatic cancer cell growth. Here we report high affinity binding (Kd = 50 nM) of a GnRH analogue resulting in biphasic growth modulation of the human androgen-sensitive prostatic cancer cell line LNCaP. In contrast, the human androgen-insensitive prostatic cancer cell line DU145 showed low-affinity (Kd = 10 microM) binding without any biological response to the GnRH analogue. A GnRH-specific radioimmunoassay demonstrated GnRH-like immunoreactivity in the concentrated culture medium from both cell lines. Seventy-six human benign and malignant tumours were assayed following surgical resection. Nineteen of 22 (86%) malignant tumours and 49 of 54 (91%) benign tumours, exhibited high affinity GnRH-analogue binding. Fourteen of 19 (74%) malignant tumours and 17 of 49 (35%) benign tumours exhibiting high affinity binding contained GnRH-like immunoreactivity, suggesting that this system may be involved in prostatic epithelial cell growth in vivo."}
+{"text": "How different immune cell compartments contribute to a successful immune response is central to fully understanding the mechanisms behind normal processes such as tissue repair and the pathology of inflammatory diseases. However, the ability to observe and characterize such interactions, in real-time, within a living vertebrate has proved elusive. Recently, the zebrafish has been exploited to model aspects of human disease and to study specific immune cell compartments using fluorescent reporter transgenic lines. A number of blood-specific lines have provided a means to exploit the exquisite optical clarity that this vertebrate system offers and provide a level of insight into dynamic inflammatory processes previously unavailable.lysozyme C (lysC) gene to drive enhanced green fluorescent protein (EGFP) and DsRED2 expression in a manner that completely recapitulated the endogenous expression profile of lysC. Labeled cells were shown by co-expression studies and FACS analysis to represent a subset of macrophages and likely also granulocytes. Functional assays within transgenic larvae proved that these marked cells possess hallmark traits of myelomonocytic cells, including the ability to migrate to inflammatory sources and phagocytose bacteria.We used regulatory regions of the zebrafish These reporter lines will have utility in dissecting the genetic determinants of commitment to the myeloid lineage and in further defining how lysozyme-expressing cells participate during inflammation. A major challenge faced by researchers in various fields of immunology is understanding the cellular interactions that govern a successful immunological response. A typical vertebrate immune response depends upon the highly orchestrated migration and motility of various hematopoietic compartments and their subsequent interactions that ultimately control the magnitude of the response ,2. Currerag-dependent system that emerged with the evolution of the jawed vertebrates [Zebrafish, like mammals experience two separate waves of hematopoiesis. The first 'primitive wave' generates embryonic erythrocytes as well as early myeloid-derived macrophages and neutrophils from two distinct intraembryonic compartments, the caudally-located intermediate cell mass (ICM) and a rostral blood-forming region derived from cephalic mesoderm -19. Whettebrates ,22.Macrophages represent the main differentiated cell of the monocyte phagocyte system and an essential primary innate barrier to infection ,24. Theipu.1 migrate to initially populate the anterior yolk surface and then more posterior yolk regions [pu.1 has been demonstrated, by whole mount in situ hybridization, to mark the myeloid lineage up to 30 hours post fertilization (hpf) [myeloperoxidase (mpo) [In zebrafish, embryonic macrophage precursors originate from the rostral blood compartment and derive from lateral plate mesoderm . During  regions ,27-31. Ton (hpf) ,32. Onceon (hpf) ,28,29,33se (mpo) ,19, sugglysC promoter was used to drive macrophage expression of EGFP and DsRED2. Lysozyme is a cationic antibacterial enzyme capable of hydrolyzing specific linkages within the bacterial cell wall [lysozyme M gene, one of two lysozyme genes found in mice [lysC expression has been reported to specifically mark the macrophage compartment, based upon initial expression within cells on the yolk and co-localised expression with L-plastin [Tol2 transposon system to generate germline lysC::EGFP and lysC::DsRED2 transgenic founders [lysC and was consistent with the known ontogeny of the macrophage lineage. Inflammation, bacterial infection and phagocytic assays demonstrated that these labeled cells possessed hallmark traits of the macrophage lineage while time-lapse confocal microscopy revealed their highly dynamic morphology, proliferative potential and ability to roll along vascular endothelia. Within transgenic embryos, labeled cells expressed markers of the macrophage lineage, including L-plastin. Some fluorescent cells also contained transcripts for myeloperoxidase (mpo), raising questions regarding the macrophage-specificity of lysC previously reported [lysC::EGFP and lysC::DsRED2 reporter lines as having marked myelomonocytic compartments that will prove useful in defining the determinants of lineage commitment during myelopoiesis and in examining the contribution of innate immune cells during inflammatory events.To generate a macrophage reporter line, and facilitate direct observation of macrophage events in situ in real-time, we have generated novel transgenic lines in which the zebrafish ell wall . In humaell wall ,35. Regu in mice , have be in mice ,38. In z-plastin . We usedfounders . Approxireported , but conlysC promoter region was selected for generation of a reporter line, as expression of the lysC gene had been described as being specific to the zebrafish macrophage lineage [lysC transgenic reporter lines generated in this work, we have included a detailed expression analysis of lysC during embryonic/larval development that extends previous studies . A zebrafish genomic BAC clone was initially identified in silico as containing sequence of the Ensembl-predicted lysC gene. This BAC clone (I.D. zC250A24) was confirmed via amplification and sequence verification as containing the first coding exon of lysC. Fragments corresponding to sequence upstream of the initiation codon were cloned from this BAC (for details see Methods section) into EGFP- and DsRED2-encoding pT2KXIG\u0394in Tol2-containing vectors [lysC, we injected 1-cell stage zebrafish embryos with 30 pg of either construct (injection of higher doses resulted in toxicity). EGFP and DsRED2 expression was first observed exclusively on the yolk surface with EGFP first detectable around 24 hpf and DsRED2 approximately 4 hours later. This is most likely due to the longer time required for proper folding of the DsRED2 tetrameric protein (data not shown). A subset of these cells entered the circulation and could be seen moving over the yolk ventrally towards the embryonic heart. This expression pattern is consistent with the endogenous expression pattern of lysC, as detected by whole mount in situ hybridization as shown here and by others [The  lineage . To faci vectors . This gey others  and the y others .transposase transcript to induce transposition and generate germline transgenic founders. Six germline transgenic founders were identified for both the lysC::EGFP and lysC::DsRED2 lines. Both lines displayed correct Mendelian inheritance ratios in subsequent generations and identical reporter expression profiles of comparable intensities (data not shown).These constructs were then injected into 1-cell stage embryos along with capped lysC::EGFP transgenic animals. It is of note that the lysC::DsRED2 line possessed an identical expression profile throughout development , albeit commencing slightly later.Next we describe, in detail, reporter expression within stable lysC::EGFP line was first detectable by fluorescence microscopy at 22 hpf. This expression was restricted to a small collection of weakly expressing cells located over the anterior yolk  and by others [lysC::EGFP larva). Microangiography using red fluorescent microspheres revealed that EGFP-positive cells within the ventral tail region were largely excluded from the caudal vascular plexus and occupied mesenchymal tissue between the vascular endothelia . The first evidence of hematopoietic activity in the zebrafish kidney, the equivalent of mammalian bone marrow, occurs around 4 dpf where hematopoietic progenitors are closely associated with renal vasculature [I-FABP::RFP larvae [lysC.EGFP expression within the olk Fig. . This loy others . This loy others . Summed y others . This iny others . The prilia Fig. . This oblia Fig. ; inset. culature ,40. WithP larvae , a line P larvae . Of notelysC::EGFP line throughout embryonic/larval development. Previous studies have demonstrated specific colonization of the optic tectum by L-plastin-expressing macrophages [lysC::EGFP reporter line and the expression of lysC  suggest that these cells that mark the optic tectum represent a subset of macrophages that are lysozyme C-deficient. It is of note that within lysC::EGFP animals, fewer labeled cells were detected within the developing head when compared with those revealed by L-plastin and fms expression [In addition to the domains described above, EGFP-labeled cells were observed within the developing brain and retina  of cells within the myelomonocytic (FSChiSSChi) fraction were marked with EGFP and displayed typical myelomonocytic morphology  has been demonstrated to co-localize with that of the pan-myeloid marker pu.1 within cells considered to be macrophage progenitors on the yolk sac [fms is also observed in more mature macrophage populations [mpo were detected  exceeded that previously reported for monocytes/macrophages (24%) [mpo only within morphologically identified granulocytic neutrophils and not within the macrophage lineage [mpo may represent a specific marker of neutrophils [mpo expression, in the posterior ICM compartment [lysC and L-plastin that first appear over the yolk surface [mpo-expressing cells are also located over the yolk surface suggesting a separate anterior domain of granulopoiesis [mpo::EGFP reporter line, a distinct subset of cells expressing EGFP, in low levels, were identified and have been suggested as being macrophages based upon morphology [mpo and the macrophage marker L-plastin has been observed in a small subset of myeloid cells within the early zebrafish embryo [Unlike erythropoiesis, which generates a single mature cell type, myelopoiesis gives rise to monocyte/macrophage cells and several different types of granulocytes. In the zebrafish, a number of markers have been used to distinguish embryonic macrophages, including draculin , fms [43ms [lysC , while nysC [mpo ,19,49,50ipt Fig.  and 4B. -plastin , in thattin Fig.  and 4D. ail Fig.  as well ipt Fig. . In zebryolk sac . Expressted Fig. , raisinges (24%) . In mammes (24%) ,35,52-54partment ,19, is d surface ,33. Howeopoiesis . Whetherh embryo . Bennettmpo promoter fragment is reported to drive macrophage-specific expression [lysC::EGFP animals described here, in concert with their initial appearance on the yolk surface suggests that populations of macrophages and also some neutrophils are fluorescently marked.Recently a medaka transgenic line has been described in which a fugu pression  illustrapression . It seemlysC::EGFP larvae were transected and the response of EGFP-expressing cells monitored. As early as 2 hpi (hours post insult), EGFP-labeled cells had accumulated at the injury site and by 6 hpi a significant number of cells had assembled at the trauma region . Using DIC optics in live Mycobacterium marinum infection assays, infected macrophages have been observed to transfer phagocytosed bacteria via membrane tethers [In addition to expressing a large repertoire of cytokines during infection and wound repair, macrophages are phagocytes that function to clear wounds of cellular debris . To demodiameter . To ensu tethers .lysC reporter lines, we infected lysC::DsRED2 zebrafish larvae with GFP-expressing Salmonella enterica serovar Typhimurium. Following infection, a robust response was detected within the posterior extremities of the intestine . Labeled cells within this region were detected containing fluorescent bacteria  embryos were obtained from natural spawning between lysC::EGFP/DsRED2, fli1::EGFP [I-FABP::RFP [Zebrafish  staining, larvae were washed several times in PBS then transferred to blocking solution before binding of a rabbit anti-GFP-Alexa488 conjugated antibody (Molecular Probes) diluted 1:200 in blocking solution for 4 hours at room temperature. Larvae were then washed several times in PBS, fixed in 4% (w/v) PFA in PBS, mounted in 1% (w/v) low melting point agarose (Sigma) and images captured using a TCS SP2 confocal laser scanning microscope (Leica) through FITC (for Alexa488) and TRITC (for Fast Red stain) channels.Whole mount in situ hybridizations were performed essentially as described . PigmentlysC-containing BAC clone (zC250A24) obtained from the RZPD (German Resource Center for Genome Research) was digested with XhoI and EcoRI which cut approximately 11,040 bp and 330 bp from the lysC initiation codon, respectively. This generated a 10.7 kb genomic fragment encompassing regulatory elements of the lysC gene starting 330 bp from the initiation codon. The remaining 3' sequence was generated by amplification using the following primer set: LysPA, 5'-CACCGGTGTCACTAATAACACGATCG-3' (which corresponded to sequence starting 30 nucleotides upstream of the EcoRI site); LysPB, 5'-TATACCCGGGAGGTGTATGGTGGAG-3' (which corresponded to sequence starting 39 nucleotides upstream of the initiation codon and contained a SmaI restriction site). This 330 bp PCR fragment was then cloned into the pGEM-T Easy Vector (Promega), sequence verified then digested with EcoRI and SmaI. This restriction fragment was cloned, together with the 10.7 kb XhoI/EcoRI fragment, into XhoI/SmaI-linearized pBS/KS to generate 11kblysCP/pBSKS. The 11 kb lysC promoter fragment was then liberated from 11kblysCP/pBSKS using XhoI and SmaI and ligated into XhoI/BamHI(blunted)-linearized pT2KXIG\u0394in to generate pT2K/lysC::EGFP. The pT2K/lysC::DsRED2 construct was generated by first cloning the XhoI/SmaI-linearized 11 kb lysC promoter fragment from 11kblysCP/pBSKS together with a BamHI (blunted)/KpnI DsRED2-encoding construct into XhoI/KpnI-linearized pBS/KS to create 11kblysCP/DsRED2/pBSKS. This construct was then digested with SacII and XhoI to release 6.35 kb of lysC promoter sequence upstream of DsRED2 which was cloned into SacII/XhoI-linearized pCS2+. Subsequent digestion with ApaI/ClaI facilitated the cloning of this 6.35 kb lysC promoter/DsRED2-encoding fragment into similarly linearized pT2KXIG\u0394in.A lysC, the transient expression profile of injected embryos was examined under fluorescence microscopy.To confirm the efficiency with which the cloned lysC::EGFP/DsRED2 constructs could drive EGFP/DsRED2 expression and recapitulate the endogenous expression pattern of transposase transcript was generated using the mMESSAGE mMACHINE SP6 kit (Ambion Inc.) from the pCS-TP expression vector as previously described [transposase transcript (50 pg/embryo) at the 1-cell stage of development. These potential founders were then screened for reporter expression under fluorescence microscopy following 2 days of development. Only fluorescent embryos were selected to form the founder population. Once at sexual maturity, founders were intercrossed and F1 progeny screened for reporter expression. Pairs that generated a positive clutch were then individually outcrossed to wild type animals to identify the germline transgenic founder.Capped escribed . ZebrafiImages of whole transgenic embryos/larvae were generated using a DC200 digital camera and supporting software (Leica) connected to an MZFLIII fluorescence stereomicroscope equipped with GFP and DsRED filter sets (Leica).LysC::EGFP larvae to be injected were anaesthetized in tricaine as described [Microangiography was performed as described . In brieescribed  before blysC::EGFP adult fish were anaesthetized in tricaine before dissection of kidneys which were dissociated by teasing through a 40 \u03bcm cell strainer  in ice-cold 0.9 \u00d7 PBS supplemented with 5% FBS. Cells were washed several times and resuspended in 0.9 \u00d7 PBS/5% FBS before addition of propidium iodide to a final concentration of 1 \u03bcg/ml for exclusion of dead cells. FACS analysis was based on forward and side scatter characteristics, propidium iodide exclusion and GFP fluorescence using a FACS Vantage flow cytometer (Beckton Dickenson). Cytospin preparations were made using a Cytofuge 2 cytocentrifuge (StatSpin) followed by Leishman's staining for morphological analysis.Cell collection, FACS analysis and sorting was performed essentially as described . In brieAdult animals were anaesthetized in 4% paraformaldehyde, decalcified in 0.5 M EDTA (pH 7.8) for several days, dehydrated through an ethanol series, cleared in xylol overnight before infiltration and embedding in paraffin. Five-micrometer tissue sections were deparaffinized, rehydrated and immunohistochemical detection of EGFP performed as previously described  using a gata1ATGMO, 5'-CTGCAAGTGTAGTATTGAAGATGTC-3' [sclspliceMO, 5'-AATGCTCTTACCATCGTTGATTTCA-3' [Morpholino oligonucleotides  used in this study and their sequence are as follows: ATGTC-3'  and sclsTTTCA-3' . MOs werTTTCA-3' . EffectiTTTCA-3' ,68,69.lysC::EGFP larvae were anaesthetized in E3 medium supplemented with tricaine before the posterior portion of the developing caudal fin was transected with a sterile scalpel. Larvae were then left to recover in E3 medium before analysis under fluorescence microscopy using an MZFLIII stereo microscope equipped with a GFP filter set (Leica) during the progression of inflammation. The high resolution inflammation assay was performed by making a small incision in the ventral fin of anaesthetized 6 dpf lysC::DsRED2/fli1::EGFP compound transgenic larvae using a sterile scalpel followed by mounting in 1% low melting point agarose (Sigma) in E3 medium and time-lapse confocal microscopy using an Olympus FV1000 confocal microscope equipped with a heated chamber which was kept at 29\u00b0C and water-immersion lenses. Z-series were collected at 1 minute intervals and were no greater than 4 \u03bcm between each section as to ensure detection of all DsRED2-labeled cells. Projections of summed Z stacks, time-lapse animations and cell tracking were generated using ImageJ [The inflammation assay was conducted essentially as described . In brieg ImageJ .lysC::EGFP larvae. Larvae to be injected were anaesthetized in tricaine then mounted in 1% (w/v) low melting point agarose (Sigma) in E3 medium. The microspheres were diluted 3:1 in sterile distilled water then microinjected into the embryonic tissue of 4 dpf transgenic larvae using a FemtoJet pressure injection system (Eppendorf). Injections were typically 0.5 \u03bcl in volume and targeted just posterior to the swim bladder within the somitic tissues. The success of injections was confirmed through fluorescence microscopy using an MZFLIII stereo fluorescence microscope equipped with a DsRED filter set (Leica). Phagocytosis of the individual microspheres was detected using a TCS SP2 confocal laser-scanning microscope (Leica) using GFP and TRITC channels. Projections of summed Z stacks and time-lapse animations were generated using ImageJ [Red fluorescent microspheres of 2 \u03bcm diameter (Molecular Probes) were selected to monitor the phagocytic ability of EGFP-expressing cells within 4 dpf g ImageJ .Salmonella enterica serovar Typhimurium were used to infect zebrafish. To label Salmonella, the strain SM022 [rpsM::gfp fusion and linked kanamycin resistance genes from SM022 into the original parental Salmonella strain SL1344 [lysC::DsRED2 larvae  low melting point agarose (Sigma) and imaged using an Olympus FV1000 confocal microscope equipped with a heated chamber which was kept at 29\u00b0C.GFP-labeled in SM022  was recrin SM022  of the rn SL1344 . Five dpescribed ) were imCH carried out experimental work and drafted the manuscript. TS performed bacterial infection assay. MVF, PC and KC all provided significant contributions to the conception and design of the study as well as critically reviewing the manuscript. All authors read and approved the final manuscript.lysC expression during early embryonic/larval development. lysC expression within 22 hpf (A and B), 30 hpf (C-E), 36 hpf (F-H), 48 hpf (I-K), 4 dpf (L-N), 5 dpf (O and P) and 7 dpf (Q and R) zebrafish embryos and larvae. Arrow in D denotes lysC-expressing cell within head mesenchyme. Arrows in O-Q denote lysC transcripts within the developing pronephric glomerulus. Scale bars: 200 \u03bcm.Click here for filelysC::EGFP/lysC::DsRED2 compound transgenic larvaeCo-localized expression of EGFP and DsRED2 within . (A) Summed Z-stacks through ICM compartment of EGFP and DsRED2 expression (and merged images) within 48 hpf lysC::EGFP/lysC::DsRED2 larva. (B) Higher magnification within same region. Scale bars: 50 \u03bcm in A; 10 \u03bcm in B.Click here for filelysC::EGFP larvaMovie of dividing EGFP-labeled cell within ICM compartment of 52 hpf . Each frame represents summed Z-stacks through a single EGFP-labeled cell collected every 30 seconds over a 37 minute period. The dividing cell is initially marked by a blue dot.Click here for file Movie of labeled cell rolling along vascular endothelia. Each frame represents summed Z-stacks through a single DsRED2-expressing cell collected every 20 seconds (over an approximate 9 minute period) as it rolls along the luminal endothelium of the caudal vein within a 6 dpf lysC::DsRED2/fli1::EGFP compound transgenic larva, anterior to left. For reference the movement is tracked with a blue line.Click here for fileLabeled cells are located within the developing brain and retina. (A-C and D/E) Lateral and dorsal bright field, GFP and merged views (of summed Z-stacks), respectively, of EGFP-labeled cells within the developing hindbrain (A and D), midbrain (B), retina (C) and forebrain (E) within 36 hpf (A and B), 48 hpf (C) and 2.5 dpf (D and E) lysC::EGFP animals. Anterior to left in all images. Abbreviations: E, eye; Le, lens; Ol, olfactory organ; OV, otic vesicle; Re, retina. Scale bars: 100 \u03bcm in A/B/D and E; 25 \u03bcm in C.Click here for fileLabeled cells are restricted to the myeloid lineage. (A and B) EGFP expression within 48 hpf lysC::EGFP transgenic larvae. (C and D) EGFP expression within 48 hpf lysC::EGFP transgenic larvae following early delivery of scl-targeting MOs. Arrows in D denote pericardial edema. (E and F) EGFP expression within 28 hpf lysC::EGFP embryo and 28 hpf transgenic embryo following early delivery of gata1-targeting MOs, respectively. (A/C/E/F and B/D) Lateral views of tail/trunk and dorsal views of cranio-trunk region, respectively, anterior to left. Scale bars: 200 \u03bcm.Click here for fileMovie of tracked cell demonstrating retrograde chemotaxis. Each frame represents Z-stacks collected every minute during an inflammatory response within 6 dpf lysC::DsRED2/fli1::EGFP compound transgenic animals following wounding of the ventral fin. The migratory path of the DsRED2-labeled cell is highlighted by a blue line as it exits from the EGFP-labeled vasculature towards the wound and then back into the circulation. White polygon demarcates injury boundaries. Movie played at 7 frames/second.Click here for fileMovie of tracked cell that infiltrates the injury site and returns to the vasculature twice. Each frame represents Z-stacks collected every minute during an inflammatory response within 6 dpf lysC::DsRED2/fli1::EGFP compound transgenic animals following wounding of the ventral fin. The migratory path of the DsRED2-labeled cell is highlighted by a blue line as it returns to the circulation then re-visits the wound followed by migration back towards the vasculature. White polygon demarcates injury boundaries. Movie played at 7 frames/second.Click here for fileMovie of tracked cell that fails to infiltrate the wound. Each frame represents Z-stacks collected every minute during an inflammatory response within 6 dpf lysC::DsRED2/fli1::EGFP compound transgenic animals following wounding of the ventral fin. The migratory path of the DsRED2-labeled cell is highlighted by a blue line as it initially emerges from the caudal vein and migrates towards the injury only to cease this trajectory and return to the vasculature. White polygon demarcates injury boundaries. Movie played at 7 frames/second.Click here for filelysC::EGFP larvaMovie of interacting EGFP-labeled cells within 4 dpf . Time-lapse confocal microscopy of interacting EGFP-labeled cells within 4 dpf lysC::EGFP larva. Movie of two EGFP-expressing cells (one containing a phagocytosed microsphere) over an approximate 7.5 minute interval (imaged every 20 seconds). Movie played at 5 frames/second.Click here for fileSalmonella results in a robust inflammatory response within the posterior intestineInfection with GFP-expressing . Summed Z-stacks through the posterior intestine of 8 dpf lysC::DsRED2 larva following infection at 5 dpf with GFP-expressing Salmonella. Arrows denote autofluorescence of pigment cells. Scale bar: 50 \u03bcm.Click here for file"}
+{"text": "The controversial issue of enhanced pancreatic carcinogenesis following partial gastrectomy has been explored in male Wistar rats (n = 40) weighing 250-300 g. Animals were randomised to receive either 60% distal gastrectomy with Roux-en-Y reconstruction or gastrotomy and resuture (control). Immediately after operation each group was further divided into two subgroups, receiving i.p. injections of either saline or azaserine (30 mg kg-1 wk-1 for 3 weeks). At 15 months blood was obtained at 0, 5, 15 and 30 min after a fatty meal for cholecystokinin (CCK) assay; rats were then killed. Pancreatic wet weight was measured, and histological sections were examined for atypical acinar cell foci (AACF), the putative precursor lesion of carcinoma. There were no significant differences in body weight or pancreatic weight between controls and rats with gastrectomy. Only azaserine-treated rats had acidophilic AACF. Partial gastrectomy substantially increased the number of acidophilic AACF per pancreas , with a 9-fold increase in their volume (P less than 0.005). Basal and postprandial plasma CCK concentrations were higher after gastrectomy than in controls (P less than 0.05). Partial gastrectomy has an enhancing effect on azaserine-induced pancreatic carcinogenesis, probably by means of increased CCK release."}
+{"text": "Response to chemotherapy and survival was retrospectively analyzed in 28 patients with bulky retroperitoneal and disseminated seminoma treated between 1977 and 1983. The median age was 41 years (range: 23-52). All patients had histological evidence of pure testicular seminoma, however, 14 patients revealed moderate increases of human beta-chorionic gonadotropin levels. Prior radiotherapy had been given to 9/28 (32%) patients. Treatment consisted of at least four courses of simultaneous or sequentially alternating therapy with cisplatin, vinblastine, bleomycin plus/minus adriamycin (PVB +/- A), administration of ifosfamide or combination therapy with ifosfamide/cisplatin (IFS/DDP) or ifosfamide/etoposide (IFS/ETP). Twenty-five of 28 patients (89%) achieved a complete (CR), and 3/28 patients a partial remission. Relapse occurred in 1/8 CR patients after adjuvant postchemotherapeutic irradiation, and in 1/11 patients without any further radiotherapy. So far, 23/28 patients (82%) are free of disease after a median follow-up of 28+ (14+----82+) months. Marked myelosuppression was observed in previously irradiated patients, mainly after PVB +/- A therapy. In two patients, transient nephrotoxicity developed after PVB and IFS/DDP, respectively. After PVB +/- A chemotherapy, three patients revealed polyneuropathy, paralytic subileus and bleomycin-induced pneumonitis, respectively. In conclusion, the present series suggests a high probability of continuous CR in even bulky retroperitoneal and widespread metastatic seminoma. So far, no definite conclusions can be made on the therapeutic superiority of one of the different chemotherapeutic regimens used. However, this preliminary experience suggests that the combination of ifosfamide and etoposide or cisplatin may prove less toxic than sequentially alternating or simultaneous PVB +/- A chemotherapy."}
+{"text": "Several protocols that generate different types of neurons from human stem cells (hSCs) have been developed. Nevertheless, the cellular mechanisms that underlie the development of neurons We have designed a focused DNA (oligonucleotide-based) large-scale microarray platform (named \"NeuroStem Chip\") and used it to study gene expression patterns in hSCs as they differentiate into neurons. We have selected genes that are relevant to cells (i) being stem cells, (ii) becoming neurons, and (iii) being neurons. The NeuroStem Chip has over 1,300 pre-selected gene targets and multiple controls spotted in quadruplicates . In this study, we present the NeuroStem Chip in detail and describe the special advantages it offers to the fields of experimental neurology and stem cell biology. To illustrate the utility of NeuroStem Chip platform, we have characterized an undifferentiated population of pluripotent human embryonic stem cells . In addition, we have performed a comparative gene expression analysis of those cells versus a heterogeneous population of hESC-derived cells committed towards neuronal/dopaminergic differentiation pathway by co-culturing with PA6 stromal cells for 16 days and containing a few tyrosine hydroxylase-positive dopaminergic neurons.We characterized the gene expression profiles of undifferentiated and dopaminergic lineage-committed hESC-derived cells using a highly focused custom microarray platform (NeuroStem Chip) that can become an important research tool in human stem cell biology. We propose that the areas of application for NeuroStem microarray platform could be the following: (i) characterization of the expression of established, pre-selected gene targets in hSC lines, including newly derived ones, (ii) longitudinal quality control for maintained hSC populations, (iii) following gene expression changes during differentiation under defined cell culture conditions, and (iv) confirming the success of differentiation into specific neuronal subtypes. Modern DNA microarrays permit a comprehensive analysis of quantitative and qualitative changes in RNA transcript abundance, outlining the cross-sections of gene expression and alterations of these in response to genetic or environmental stimuli. Genome-scale microarrays (cDNA- or oligonucleotide-based) are most valuable when screening populations of cells for the novel genes reflecting potential diagnostic and prognostic markers or for an identification of novel therapeutic targets. On the other hand, custom microarray platforms that focus on specific pre-selected subset of genes relevant to a particular field of investigation can be less costly and more suitable for detection of smaller gene expression changes.substantia nigra dopaminergic neurons, which degenerate in Parkinson's disease (PD) )IVF dishes with hESCs grown atop hFCs and 4-well plate dishes with hESCs growing atop PA6 cells were fixed with 4% paraformaldehyde (PFA) for 15 minutes at the day of passage/harvest (Day 6 of hESC/hFC co-culturing) and Day 16 of co-culturing with PA6 cells, respectively. Cells were pre-incubated with blocking solution containing PBS, 0.5% Triton X-100 and 5% of donkey serum. They were then incubated with primary antibodies in blocking solution overnight at room temperature. After three washes with PBS, cells were incubated with the donkey anti-rabbit IgG conjugated with FITC or anti-mouse Cy3 . Cells were then washed once with PBS, incubated with 1:1000 DAPI in PBS for 10 minutes, followed by another wash with PBS. Coverslips were mounted onto glass slides with PVA mounting medium containing anti-fading reagent DABCO. The following primary antibodies were used: mouse anti-Oct3/4 ; rabbit anti-Ki67 ; rabbit anti-TH . Immunostained cell cultures were visualized using a Zeiss fluorescent microscope attached to a Nikon digital camera.Drosophila muscle segment homolog 1: 5'-CTC AAG CTG CCA GAA GAT GC-3', 5'-TCC AGC TCT GCC TCT TGT AG-3'; Pitx2, paired-like homeodomain transcription factor 2: 5'-ACC TTA CGG AAG CCC GAG TC-3', 5'-TGG ATA GGG AGG CGG ATG TA-3' [Using RT-PCR, all RNA samples used in this study were tested negative for the presence of gDNA (data not shown). The intron-spanning primers for RT-PCR were selected from published works or designed using Oligo 4.0 software (Molecular Biology Insight) or Clone Manager Suite 7.1  and ordered from TAG Copenhagen A/S, Denmark, as the following: Sox2, SRY-box 2: 5'-TAC CTC TTC CTC CC CTC CA-3', 5'-ACT CTC CTC TTT TGC ACC CC-3'; En1, Engrailed 1: 5'-AAG GGA CGA AAC TGC GAA CTC C-3', 5'-GAC ACG AAA GGA AAC ACA CAC TCT CG-3' ; Nanog: TG TA-3' . cDNA waRNA purification and fluorescent dye incorporationFor RNA purification of undifferentiated hESCs, the latter were mechanically separated from hFCs, collected in a 500 \u03bcl volume of VitroHES media, rinsed in PBS buffer and spun down at 300 rcf for 5 min. hESC-derived cells grown atop PA6 cells were harvested using a papain dissociation kit , rinsed in PBS buffer and spun down as described above. The resulting cell pellets were resuspended in RLT buffer , passed through the shredder column (Qiagen) and stored at -80\u00b0C until the RNA sample was purified following the RNeasy Micro Kit (Qiagen) protocol (without carrier RNA); with DNase I (Quiagen) treatment incorporated to the latter. RNA integrity was tested using both ND-1000 specrophotometer  and RNA Nano LabChip/2100 Bioanalyzer system .Fluorescent label (24 nmol of the Cyanine 3-CTP (Cy3); PerkinElmer, USA) was incorporated to 350\u2013500 ng of total RNA amplified using Low RNA Input Fluorescent Linear Amplification Kit (Agilent Technologies), generally following the kit manufacturer's protocol. Similarly, 24 nmols of the Cyanine 5-CTP  fluorescent label were incorporated to 400 ng sample of Human Universal Reference RNA ; in addition, dye-swap replicate amplification were performed. Amplified fluorescent cRNA samples were purified using RNeasy mini-columns (Quiagen), and fluorescence of the eluted products was measured using ND-1000 specrophotometer (NanoDrop).2), pre-hybridizedwith fluorescently labeled samples using the Pronto! Universal Microarray Hybridization Kit (Corning) and subsequently hybridized with test (Cy3-labeled)/reference (Cy5-labeled) RNA samples (or in reverse dye-labeling order) at 42\u00b0C for 17 h using a MAUI hybridization station  and the Pronto! Universal Microarray Hybridization Kit, generally following manufacturer's instructions, with several minor adaptations [Long oligonucleotide probes (69\u201371 nucleotides) matching gene targets of interest were selected from Operon V2 and V3 human AROS sets . Arrays were produced by the SweGene DNA Microarray Resource Centre, Department of Oncology at Lund University (Sweden) using a MicroGrid II 600R arrayer fitted with MicroSpot 10 K pins . Printing was performed in a temperature- (18\u201320\u00b0C) and humidity- (44\u201349% RH) controlled area on Corning UltraGAPS aminosilane slides  with 140 \u03bcm spot-to-spot centerdistance and 90\u2013110 \u03bcm average spot size. Following printing, arrays were dried for 48 hours andstored in a dessicator until used. Microarray slides were UV-cross-linked . After image formatting by Tiff Image Channel Splitter Utility (Agilent Technologies) and grid annotation, a complete set of spots was visually inspected for each slide. Using GenePix Pro (Molecular Devices Corp. USA) flags for artifactual spots were annotated for each spot. Median pixel intensity minus the median local background for both dyes was used to obtain a test over reference intensity ratio. Data normalization was performed per array subgrid using LOWESS curve fitting with a smoothing factor of 0.33 ,53. All Overall design of the project was performed by joint effort of all coauthors. S.V.A. developed the NeuroStem Chip design, participated in hESC growth and differentiation, and performed RNA sample purifications, fluorescent sample preparations, microarray hybridizations, microarray data formatting and RT-PCR experiments. N.S.C. performed all computer analysis of microarray data. A.S.C. participated in hESC growth and differentiation and performed extensive characterization of hESCs on all stages of differentiation protocol. All authors have contributed to the writing and approved the final manuscript.Genes up-regulated in hESC population, as compared to human universal reference RNA. Lists 101 genes up-regulated in hESC cells, as compared to universal reference RNA sample; sorted based on average Log2 ratio.Click here for fileTop 100 NeuroStem entries up-regulated in dopaminergic differentiation. Lists top 100 genes most up-regulated in hESC-derived cells, as compared to undifferentiated hESC sample; sorted based on average Log2 ratio.Click here for file"}
+{"text": "Hypoglycemia is a vary rare toxicity of rituximab. The exact mechanism of rituximab induced hypoglycemia is not clear.A 50 year old female presented with a left tonsillar non Hodgkin's lymphoma and was started on R-CHOP chemotherapy. Twenty four hours after the first rituximab infusion, she developed hypoglycemia which was managed by IV glucose infusion.Hypoglycemia following rituximab administration is rare. Possibilities of hypoglycemia should be kept in mind in patients developing symptoms like fatigue, restlessness, and sweating while on rituximab therapy. Hypoglycemia is a rare complication of rituximab treatment. The exact cause of this phenomenon is not known. We report here a case of non-Hodgkin's lymphoma developin hypoglycemia on being treated with R-CHOP chemotherapy3, erythrocyte sedimentation rate (ESR) was 50 mm/hour and random blood sugar (RBS) was 96 mg/dl. Renal and liver function tests were normal. VDRL, HIV and HBsAg were non-reactive. Chest X-ray, ultrasound scan of the abdomen, upper gastro-intestinal endoscopy, peripheral blood smear and bone marrow biopsy were normal. There was no past history of diabetes mellitus, hypo or hyperglycemic episodes. Biopsy and histopathological examination of the tonsillar mass was consistent with Non Hodgkin's lymphoma-diffuse large B cell type. Immunohistochemistry showed the tumor cells to be CD20 positive. She was treated using R-CHOP  chemotherapy on a three weekly schedule after obtaining informed consent. About 24 hours following rituximab, she developed hypoglycemic symptoms like fatigue, restlessness, sweating and drowsiness. There was no other rituximab infusion related toxicities. Her RBS at that time was 39 mg/dl. Her symptoms subsided following intravenous (IV) glucose administration and RBS became normal. During the next 48 hours, she developed three more symptomatic hypoglycemic episodes, with RBS nadir 54 mg/dl, 61 mg/dl and 70 mg/dl respectively and were managed with IV glucose administration. Three days after rituximab her hypoglycemic symptoms subsided completely and the RBS improved to normal range. During the subsequent courses of rituximab, she was given IV glucose support during the first 72 hours. There were no further episodes of symptomatic hypoglycemia.A 50-year-old female presented in January 2004 with a 4 cm left tonsillar mass. Her general and systemic examinations were unremarkable. There was no lymphadenopathy or hepato-splenomegaly. Her hemoglobin was 12.5 gm/dl, white blood cell (WBC) count was 7700/mmRituximab is a chimeric murine/human monoclonal antibody directed against CD-20 positive cells. Commonly observed toxicities are fever(55%), chills33%), asthenia(25%), lymphopenia (48%), nausea (23%), bronchospasm 10%), anemia (15%), neutropenia (15%), abdominal pain (14%), back pain (10%), flushing (5%), angio-edema (11%), peripheral edema (8%), night sweats (15%) hypotension (10%) and hypertension (6%). Metabolic complications like hyperkalemia, hyperuricemia, hyperphosphatemia and hypocalcemia have been observed 12\u201324 hours after an infusion due to an association with a reduction in tumor burden. Rarely hyperglycemia is also seen [0%, anemi3%, astheEven though its occurrence is rare, the possibility of hypoglymia should always be kept in mind.The author(s) declare that they have no competing interests.BMH literature review and preparation of draft manuscriptNG and VL helped in preparation of manuscriptMP helped in preparing the draft manuscript and edited the final version."}
+{"text": "Systemically administered radiolabelled anti-tumour antibody is ineffective in treating the majority of patients with liver metastasis from colorectal carcinoma. We have assessed whether agents which increase capillary permeability can increase tumour uptake of antibody isotope conjugate. We developed a xenograft model of colorectal carcinoma using an antibody directed against carcinoembryonic antigen (CEA). Tumours were grown subcutaneously in the hind limbs of athymic rats to derive their circulation from the femoral artery. Cannulae were placed in the common iliac artery and iliolumbar vein. Antibody was delivered systemically, regionally and regionally with histamine, leukotriene C4 and interleukin-2. Regionally administered anti-CEA antibody resulted in a significantly greater (P = 0.004) tumour to normal tissue ratio  compared to systematically administered antibody . The addition of vasoactive drugs produced an approximately 3-fold increase with an increase to a mean tumour:liver ratio of 3.24 (s.d. = 1.39) for histamine (P less than 0.001 compared to systemic delivery), 3.21  for leukotriene C4 and 3.80  for interleukin-2. The addition of histamine significantly (P = 0.004) increased the mean tumour to liver ratio  of non-specific antibody uptake compared with either systemic  or regional delivery  of non-specific antibody alone. Increasing tumour capillary permeability can produce a significant clinically useful increase in tumour uptake of antibody-isotope conjugate."}
+{"text": "Metastasis involves the emigration of tumor cells through the vascular endothelium, a process also known as diapedesis. The molecular mechanisms regulating tumor cell diapedesis are poorly understood, but may involve heterocellular gap junctional intercellular communication (GJIC) between tumor cells and endothelial cells.To test this hypothesis we expressed connexin 43 (Cx43) in GJIC-deficient mammary epithelial tumor cells (HBL100) and examined their ability to form gap junctions, establish heterocellular GJIC and migrate through monolayers of human microvascular endothelial cells (HMVEC) grown on matrigel-coated coverslips.HBL100 cells expressing Cx43 formed functional heterocellular gap junctions with HMVEC monolayers within 30 minutes. In addition, immunocytochemistry revealed Cx43 localized to contact sites between Cx43 expressing tumor cells and endothelial cells. Quantitative analysis of diapedesis revealed a two-fold increase in diapedesis of Cx43 expressing cells compared to empty vector control cells. The expression of a functionally inactive Cx43 chimeric protein in HBL100 cells failed to increase migration efficiency, suggesting that the observed up-regulation of diapedesis in Cx43 expressing cells required heterocellular GJIC. This finding is further supported by the observation that blocking homocellular and heterocellular GJIC with carbenoxolone in co-cultures also reduced diapedesis of Cx43 expressing HBL100 tumor cells.Collectively, our results suggest that heterocellular GJIC between breast tumor cells and endothelial cells may be an important regulatory step during metastasis. Tumor metastasis is a multi-step process that involves the dissociation of tumor cells from the primary tumor followed by their entry into the circulation, extravasation from the vascular system and proliferation into tumor masses at secondary tissue sites. Both cell-cell and cell-matrix interactions are important regulators at different stages of this metastatic cascade -4. For iExtravasation of malignant cells often involves transendothelial migration (diapedesis) into tissues prior to forming secondary tumors. In contrast to diapedesis of leukocytes during inflammatory responses, little is known about the molecular mechanisms that regulate tumor cell diapedesis. The integrity of the endothelium depends mainly on the organization of interendothelial junctions, and tumor cells must traverse these junctions to extravasate across the endothelial barrier. Our previous studies demonstrated that diapedesis of melanoma cells is in part regulated by adhesion receptors present on both the vascular endothelium and the tumor cell . A localen route to secondary metastatic sites outside the site of the primary diseased tissue. Previous studies have observed apparent gap junction formation between mammary tumor and vascular endothelial cells but the consequences of this interaction were not established [in vivo [These previous studies suggest that signaling via cell-cell and cell-matrix adhesion receptors facilitates tumor cell diapedesis. Another possible mechanism by which tumor cells may communicate with endothelial cells to cross the endothelial barrier involves gap junctions -17. Gap ablished ,16. In a[in vivo .Previous studies investigating GJIC between tumor cells and endothelial cells focused primarily on tumor cell adhesion to the endothelium during the initial stages of diapedesis -17. To a2.Human microvascular endothelial cells (HMVECs) derived from the lung were purchased from Cambrex Biosciences Inc.  and cultured according to supplier's instructions in endothelial growth medium , supplemented with 100 units/ml penicillin G sodium, and 100 \u03bcg/ml streptomycin sulphate . Wild-type transformed mammary epithelial cells (HBL100) and HBL100 cells expressing Cx43 or Cx43 with green fluorescent protein (GFP) tagged to the amino terminal (GFP-Cx43)  were rouet al. [HBL100 cells expressing Cx43 (HBL100Cx43) or empty vector (HBL100v) were engineered by retroviral infection as described by Qin et al. . Brieflyet al. .5 HBL100 cells with 2 \u03bcg of GFP-Cx43 using Metafectene . After 24 h, approximately 40% of cells expressed GFP-Cx43 and these cells were used for diapedesis assays.HBL100 cells expressing non-functional GFP-Cx43 (HBL100GFP-Cx43)  were gen5 HMVECs were seeded onto 12 mm glass coverslips coated with matrigel . HMVEC cells were allowed to settle for 2\u20133 h and form monolayers in a 37\u00b0C humidified chamber containing 5% CO2. Coverslips were then transferred to a 24-well plate and cultured for 48 h in EGM. The number of cells seeded produces an endothelial monolayer without requiring cell proliferation. Monolayers have intact adherens junctions as previously evaluated by VE-cadherin staining [4 cells were added to endothelial monolayers at a ratio of around 1:10 . Cells were then co-cultured for different times  before live observation or fixation and immunostaining. Diapedesis was quantified blinded to the investigators using a Leica IRE2-DM epifluorescence microscope  as previously described [The diapedesis assay was carried out as previously described . Brieflystaining ,35. HBL1escribed . BrieflyGJIC was evaluated using the preloading dye coupling assay as described previously  with theTo determine whether carbenoxolone (CBX) blocks gap junctional coupling, HMVEC monolayers were pretreated for 7 h with 150 \u03bcM CBX or the inactive analog glycyrrhizic acid (GZA). HMVEC were then loaded for 15 minutes with 10 \u03bcg/ml calcein-AM (Molecular Probes) in an Opti-MEM solution containing CBX or GZA. Cells were rinsed twice with Opti-MEM containing CBX or GZA and immersed in fresh media containing CBX or GZA. Because the fluorescent dye can only pass through gap junctions, recovery of fluorescence in the bleached cell will only occur if dye passes through gap junctions with adjoining unbleached cells. For each experimental condition, three individual cells were bleached for approximately 30 s using the Zeiss laser scanning confocal microscope (LSM) 410 and an argon laser at full power. To observe recovery of fluorescence, images were obtained every five minutes following photobleaching using the argon laser at 33% power until maximum recovery was reached (15 minutes). In control experiments, monolayers were left untreated or were treated with the inactive analog of CBX, GZA. Mean fluorescence intensity of bleached/unbleached cells in the same area was measured over time using scion imaging software and expressed as mean relative recovery (arbitrary units). Data represent three independent experiments.\u00ae 488 or Texas Red conjugated-phalloidin (Molecular Probes) diluted 1:50 in PBS with 1% (w/v) bovine serum albumin (BSA) followed by three washes in PBS. To examine the localization of F-actin and Cx43, cells were labeled with Texas red conjugated-phalloidin (1:50 dilution) and with monoclonal anti-Cx43  diluted 1:10 in 1% (w/v) BSA/PBS. Cells were incubated with Alexa Fluor\u00ae 488-conjugated goat-anti-mouse secondary antibody (Molecular Probes). Nuclei were stained using 10 \u03bcg/ml Hoechst 33342 (Sigma-Aldrich) diluted in PBS. Coverslips were mounted on glass slides using vectashield mounting media  and sealed with nail enamel. The inclusion of spacers made from plastic coverslips cut into strips prevented contact of co-cultures with the slides as described by Voura et al. [Cells were fixed at room temperature for 20 minutes with 2% or 4% (w/v) paraformaldehyde  and washed in cation free phosphate buffered saline (PBS). Cells were permeabilized for five minutes at 4\u00b0C using a buffer containing 15 mM Tris-HCL, 120 mM sodium chloride (NaCl), 25 mM potassium chloride (KCl), 2 mM EDTA, 2 mM EGTA, 0.5% (v/v) Triton X-100, pH 7.5. To label F-actin, co-cultures were incubated for 30 minutes at room temperature with Alexa Fluora et al. .Co-cultures were imaged using a Zeiss LSM 410 laser scanning confocal microscope system . Serial 0.7 \u03bcm optical sections of selected areas were recorded and evaluated with the LSM 410 software (Carl Zeiss Canada Ltd). Representative serial optical sections are presented in an apical to basal direction.4 cells per well) and cultured for 48 h. HBL100, HBL100v, or HBL100Cx43 cells (2.1 \u00d7 103), pre-labeled with DiI, were added to HMVEC monolayers and co-cultured for 1 h. Co-cultures were fixed with 2% (w/v) paraformaldehyde and washed twice with PBS to remove non-adherent cells. The PBS was replaced with water and fluorescence intensity of DiI was measured for each well at 549 nm excitation and 565 nm emission wavelengths using a SAFIRE fluorescent microplate reader . The number of adherent tumor cells was calculated and normalized based on a standard curve generated with known numbers of DiI-labeled tumor cells present in duplicate wells in the same microplate. Experiments were repeated three times with eight sample replicates per cell type.Adhesion to the endothelium was evaluated as previously described for leukocyte adhesion to the endothelium  with theHBL100, HBL100v, HBL100Cx43, HBL100GFP-Cx43, and HMVEC cells grown in culture dishes were lysed using the following buffer for protein collection: 10 mM Tris (pH 7.4), 150 mM NaCl, 1 mM EDTA, 0.1% (w/v) SDS, and 0.5% (v/v) Triton X-100. Protein concentration was determined with bicinchoninic acid (BCA) protein assay reagent . Protein (50 \u03bcg) for each cell type was separated in 12% SDS-polyacrylamide gels and transferred to nitrocellulose membranes. Nitrocellulose membranes were blocked with 5% non-fat dry milk in tris buffered saline (TBS) containing 5% Tween 20. Membranes were then probed for Cx43 protein, using a monoclonal anti-Cx43 antibody against amino-terminal amino acid residues 1\u201320  at a dilution of 1:500. Immunoblots were probed with appropriate secondary antibodies conjugated to horse radish peroxidase  at a dilution of 1:10,000. The protein was visualized using Supersignal West Pico Chemiluminescent substrate  by exposing the immunoblot to Amersham Hyperfilm  for 30 s.Comparisons between cell types and different time points or treatments were evaluated using a two-way analysis of variance followed by Bonferroni post-hoc test. A p-value of < 0.05 was considered to be significant. Comparisons between cell types at a single time point were evaluated using one-way analysis of variance followed by Tukey's multiple comparison post-hoc test. Data are presented as means +/- SEM.in vitro assay in which tumor cells were allowed to migrate through a monolayer of endothelial cells grown on matrigel as we have previously described [Previous work suggested that GJIC between tumor cells and endothelial cells may affect diapedesis during metastasis -17. To aescribed ,39-41. Tescribed ,42 and oescribed . At siteescribed  but veryescribed ,35. The escribed . No openTo explore if Cx43 expression in HBL100 cells affects any aspects of diapedesis, cells were engineered to express functional Cx43, non-functional GFP-Cx43 or the empty retroviral vector as a control. Cx43 was absent in both wild-type and empty vector HBL100v control cell lines used Fig.  but exprTo determine whether HBL100 cells engineered to exogenously express Cx43 formed gap junctions and established GJIC with HMVEC cells, we co-cultured HBL100Cx43 with HMVEC monolayers, localized Cx43 in these cultures Fig. , and assPreloading dye transfer studies to assess whether Cx43 is being assembled into functional gap junctions at tumor/endothelial cell interfaces revealed that dye spread extensively from Cx43 expressing HBL100 cells to endothelial cells Fig. , whereasTo compare the efficiency of diapedesis of Cx43 deficient tumor cells with those that exogenously express Cx43, we co-cultured HBL100, HBL100v or HBL100Cx43 cells with HMVEC for 1, 5 and 7 h. At all time points HBL100Cx43 cells showed an up to two-fold increase in diapedesis efficiency compared to cells lacking Cx43 Fig. . This inTo determine whether the increase in diapedesis efficiency was due to increased adhesive properties of Cx43 expressing tumor cells, we co-cultured HBL100, HBL100v and HBL100Cx43 cells on endothelial cells and compared the number of DiI labeled tumor cells adherent to HMVEC monolayers using fluorescence intensity measurements. No significant difference in the ability of tumor cells to adhere to the endothelium was observed between HBL100 breast tumor cells expressing Cx43 and tumor cells lacking Cx43 expression Fig. , suggestTo determine whether GJIC was required to increase HBL100 tumor cell diapedesis, we chemically blocked gap junctional coupling using CBX. HMVEC monolayers were preloaded with calcein dye and fluorescence recovery after photobleaching (FRAP) analysis was first used to determine whether CBX effectively blocked gap junctions in endothelial cells. Individual cells within the calcein-AM loaded monolayer were bleached and recovery of fluorescence was quantified. Our results demonstrated that, in the presence of 150 \u03bcM CBX, fluorescence recovery in the bleached cell was prevented . Previous studies showed that GFP fused to the amino terminus of Cx43 (GFP-Cx43) results in a chimeric connexin that can traffic and form gap junction-like structures at cell-cell contacts, but these structures are not functional  and alsoin vitro cell culture model to evaluate the role of Cx43 expression in diapedesis of breast tumor cells through the endothelium by confocal microscopy. Our in vitro cell culture model enables us to dissect various stages of diapedesis and to examine the molecules or mechanisms involved in each of these stages [Previous work by Kramer and Nicolson  evaluatee stages ,37,39-41e stages  but diffe stages . ExogenoInterestingly, glioma cells engineered to express Cx43 formed bigger homocellular aggregates compared to control cells , suggestet al. [In our study we demonstrated that HBL100 breast cancer cells engineered to express Cx43 were able to localize Cx43 protein to cell-cell contacts during diapedesis, forming communication competent gap junctions with endothelial cells Fig. . Previouet al.  using meet al. . Althouget al. -17 it waet al. , our stuet al. ,46-49. Iet al. ,50-52. Iet al. ,54 and tet al. ,56. Incrin vivo [Our study shows that HBL100 breast tumor cells expressing Cx43 migrated more efficiently through the endothelium than their counterparts lacking Cx43 expression. This finding suggests that gap junctions and/or Cx43 expression in these cells may affect the motile behavior of cells by changing the kinetics of diapedesis of individual cells. The fact that Cx43 expression can influence the motile behavior of cells has been previously demonstrated . For exain vivo .Cellular motility may also be affected by changes in cadherin expression. Down regulation of E-cadherin expression or function correlates with tumor development and malignancy ,59, whilIt was important to distinguish whether the observed increase in diapedesis efficiency was due to enhanced expression of Cx43 in the tumor cell or due to the exchange of signals between tumor and endothelial cells via functional gap junctions. Two approaches were used to examine this issue. First, we blocked homocellular and heterocellular GJIC. In the presence of the gap junctional blocker, diapedesis efficiencies were significantly reduced in both the control HBL100v cells and the Cx43 expressing HBL100 cells (HBL100Cx43) Fig. , suggestet al. [3), through gap junctions that directly trigger the weakening of inter-endothelial junctions. IP3 can pass between adjacent cells through gap junctions [Several possible scenarios could explain how GJIC might modulate tumor cell diapedesis. Tumor cells might send signals to the endothelium, resulting in the release of endothelial proteolytic enzymes, facilitating endothelial cell retraction. A recent study by Bazarbachi et al.  demonstret al. . Tumor cunctions  and reguunctions . Interesunctions  and elevunctions ,68, whicunctions . Endothein vitro). Furthermore, squamous cell carcinomas exhibited reduced levels of Cx26 and Cx43 expression at early stages of mouse skin carcinogenesis and sites of invasion, although Cx26 expression was partially restored in these cells at metastatic sites within the lymph nodes [Although it has been suggested that extravasation may not be a limiting factor for metastasis -72, metaph nodes .Our work supports the hypothesis that heterocellular gap junctional coupling between tumor cells and endothelium may regulate the extravasation of at least some poorly invasive tumor cells such as HBL100 breast tumor cells, and that homocellular GJIC amongst endothelial cells may play an active role in this process. These studies would suggest that even though extravasation may not necessarily be a rate limiting step in metastasis, there might be therapeutic advantages to designing drugs or reagents that inhibit vascular homocellular and heterocellular GJIC as a means of reducing metastatic spread of tumor cells.3 = inositol triphosphate; LSCM = laser scanning confocal microscopy; PBS = phosphate buffered saline; VE = vascular endothelial; VEGF = vascular endothelial growth factor.BSA = bovine serum albumin; CBX = carbenoxolone; Cx = connexin; DiI = dioctadecyl-3, 3,3', 3'-tetramethylindocarbocyanine percholate; D-MEM = Dulbecco's modified Eagles medium; EGM = endothelial growth media; FBS = fetal bovine serum; FRAP = fluorescence recovery after photobleaching; GFP = green fluorescent protein; GJIC = gap junctional intercellular communication; GZA = glycyrrhizic acid; HBL100Cx43 = HBL100 cells expressing Cx43; HBSS = Hanks balances salt solution; HMVEC = human microvascular endothelial cell; IL = interleukin; IPThe author(s) declare that they have no competing interests.MAP participated in the design of the study, carried out the imaging, immunocytochemistry, immunoblotting, and migration assays in this study, and drafted the manuscript. QS carried out the molecular biology of the study. DWL participated in the design of the study. MS conceived the study, and participated in its design and coordination and revised the manuscript. All authors read and approved the final manuscript."}
+{"text": "A type I interferon resistant variant (beta-MIP101) of the poorly differentiated human colon cancer cell MIP101 has a more aggressive phenotype in vivo in the nude mouse. Subcutaneous tumours grew at twice the rate of MIP101, but with similar morphology. beta-MIP101 also produced liver metastases at a higher frequency. beta-MIP101 tumours were diploid while MIP101 tumours were aneuploid. Both cell lines had doubling times of approximately 25 h in vitro."}
+{"text": "KIT/PDGFRA mutations. Both ICC and GIST possess primary cilia (PC), which coordinate PDGFRA and Hedgehog signaling, regulators of gastrointestinal mesenchymal development. Therefore, we hypothesized that Hedgehog signaling may be altered in human GIST and controls KIT expression. Quantitative RT-PCR, microarrays, and next generation sequencing were used to describe Hedgehog/PC-related genes in purified human ICC and GIST. Genetic and pharmacologic approaches were employed to investigate the effects of GLI manipulation on KIT expression and GIST cell viability. We report that Hedgehog pathway and PC components are expressed in ICC and GIST and subject to dysregulation during GIST oncogenesis, irrespective of KIT/PDGFRA mutation status. Using genomic profiling, 10.2% of 186 GIST studied had potentially deleterious genomic alterations in 5 Hedgehog-related genes analyzed, including in the PTCH1 tumor suppressor (1.6%). Expression of the predominantly repressive GLI isoform, GLI3, was inversely correlated with KIT mRNA levels in GIST cells and non-KIT/non-PDGFRA mutant GIST. Overexpression of the 83-kDa repressive form of GLI3 or small interfering RNA-mediated knockdown of the activating isoforms GLI1/2 reduced KIT mRNA. Treatment with GLI1/2 inhibitors, including arsenic trioxide, significantly increased GLI3 binding to the KIT promoter, decreased KIT expression, and reduced viability in imatinib-sensitive and imatinib-resistant GIST cells. These data offer new evidence that genes necessary for Hedgehog signaling and PC function in ICC are dysregulated in GIST. Hedgehog signaling activates KIT expression irrespective of mutation status, offering a novel approach to treat imatinib-resistant GIST.Gastrointestinal stromal tumors (GIST) arise within the interstitial cell of Cajal (ICC) lineage due to activating  Al. Al46]. \u00ae) for hybridization to the Affymetrix GeneChip Human Genome U133 Plus 2.0 array .Total RNA was prepared from FACS-purified human ICC using the Total RNA Purification Kit  and purified using the MinElute Reaction Cleanup Kit . RNA quality was assessed with the Agilent RNA 6000 Pico Kit . The Ovation Pico WTA system  was used to prepare cDNA by single primer isothermal amplification (SPIAhttp://www.ncbi.nlm.nih.gov/geo/) and are accessible through GEO Series accession numbers GSE17743 [+ cells (n=3), and NOT ICC (n=1), as well as unfractionated gastric tunica muscularis tissues (n=4) generated in this study are accessible through GEO SuperSeries accession number GSE77839. Microarray data previously generated from mouse small intestinal myenteric ICC (ICC-MY) and deep muscular plexus ICC (ICC-DMP), as well as their source tissues are accessible through GSE7809; gene expression data from 2XSCS2F10 ICC-SC and their source tissue are accessible through GSE60854.The human GIST microarray data from 69 patients discussed in the current study were retrieved from the National Center for Biotechnology Information Gene Expression Omnibus . Probe-level data were pre-processed by robust multiple-array analysis (RMA) and analyzed for differential gene expression by the empirical Bayes approach with Benjamini-Hochberg adjustment using software packages in Bioconductor . Gene expression data for human GIST , purified human ICC, NOT ICC, HP+ cells, as well as human gastric tunica muscularis tissues were also quantified using the MAS5 algorithm in the Bioconductor package affy. Significance of expression was determined by Wilcoxon signed-rank test, and heat maps were assembled using probe set expression values with the lowest P-value. Unsupervised hierarchical clustering was performed using gplots.Gene expression was compared between human gastric ICC, human gastric GIST, mouse gastric 2xSCS2F10 ICC-SC, mouse intestinal ICC-MY/ICC-DMP and their respective unfractionated source tissues, as well as between human gastric ICC and gastric ctor.org/). DifferKIT exon 11 (V560-Y579\u03945: imatinib-sensitive) mutation [KIT exon 13 (K642E: imatinib-sensitive) mutation [KIT exon 11 (homozygous V560D: imatinib-sensitive) and KIT exon 17 (heterozygous D820A: imatinib-resistant) mutations from Dr. J. Fletcher  [We obtained the GIST-T1 line containing a mutation  from Dr.mutation  from Dr.ton, MA) . All celt-test . Statistical significance was accepted at the 5% level.Statistical analyses were performed using GraphPad Prism 4  or SigmaPlot 10 . Results are expressed as the mean \u00b1 SEM or SD as appropriate. Comparisons between two groups were performed using the Student's Standard methods  and additional details are described in the"}
+{"text": "A near-saturation transposon library of the M1T1 GAS 5448 strain was injected subcutaneously into mice, producing suppurative inflammation at 24 h that progressed to prominent abscesses with tissue necrosis at 48 h. The library composition was monitored en masse by Tn-seq and ratios of mutant abundance comparing the output  versus input (T0) mutant pools were calculated for each gene. We identified a total of 273 subcutaneous fitness (scf) genes with 147 genes (55 of unknown function) critical for the M1T1 GAS 5448 fitness in vivo; and 126 genes (53 of unknown function) potentially linked to in vivo fitness advantage. Selected scf genes were validated in competitive subcutaneous infection with parental 5448. Two uncharacterized genes, scfA and scfB, encoding putative membrane-associated proteins and conserved among Gram-positive pathogens, were further characterized. Defined scfAB mutants in GAS were outcompeted by wild type 5448 in vivo, attenuated for lesion formation in the soft tissue infection model and dissemination to the bloodstream. We hypothesize that scfAB play an integral role in enhancing adaptation and fitness of GAS during localized skin infection, and potentially in propagation to other deeper host environments.The Group A Streptococcus remains a significant human pathogen causing a wide array of disease ranging from self-limiting to life-threatening invasive infections. Epithelium (skin or throat) colonization with progression to the subepithelial tissues is the common step in all GAS infections. Here, we used transposon-sequencing (Tn-seq) to define the GAS 5448 genetic requirements for  in vivo transposon sequencing (Tn-seq), identifying 273 subcutaneous fitness (scf) genes with 108 of those previously of \u201cunknown function\u201d. Two yet uncharacterized genes, scfA and scfB, were shown to be critical during GAS 5448 soft tissue infection and dissemination into the bloodstream. Thus, this study improves the functional annotation of the GAS genome, providing new insights into GAS pathophysiology and enhancing the development of novel GAS therapeutics.The WHO ranks the Group A Streptococcus (GAS) in the top 10 leading causes of morbidity and mortality from infectious diseases worldwide. GAS is a strict human pathogen causing both benign superficial infections as well as life-threatening invasive diseases. All GAS infections begin by colonization of an epithelium (throat or skin) followed by propagation into subepithelial tissues. The genetic requirements for M1T1 GAS 5448 within this niche were interrogated by  Streptococcus pyogenes, GAS) is a strict human pathogen of high prevalence worldwide , RS08410/mga (TA4), RS09015 (TA412) and RS09010 (TA471), respectively. Additional mutant strains in GAS 5448 .When available, selected . MutantsGAS 5448  were proGAS 5448  and the  plasmid  was then plasmid . For simM/RW)/(RM0/RW0), with RM0 and RW0 correspond to the ratio of the mutant and the ratio of the wild-type, respectively, in the initial inoculum (T0); and RM and RW correspond to the ratio of the mutant and the ratio of the wild-type, respectively, at the end of the competition growth assay. Unpaired student\u2019s t-test was used to evaluate the significance of differences between groups; a p value of <0.05 was considered statistically significant.Competition growth assays in THY were carried after inoculation of 10 ml of broth with comparable amounts of exponentially-grown cells of GAS 5448 and the tested mutant strain (close to a 1:1 ratio). At different time intervals , samples were collected, serial diluted (10-fold increments), cell suspension plated on either THY (whole population) or THY containing the appropriate antibiotic (mutant population) and cell counts determined. Competition index (CI) was calculated using the following formula: CI = (RhrBR mice (Charles River Laboratories) were infected with GAS in AAALAC-accredited ABSL-2 facilities and following protocols approved by the University of Maryland IACUC (R-16-05) for humane treatment of animal subjects in accordance with guidelines set up by the Office of Laboratory Animal Welfare at NIH, Public Health Service, and the Guide for the Care and Use of Laboratory Animals; with every effort to limit distress and pain to animals taken.Crl:SKH1-Krmit mutant library were diluted 1:20 to a final volume of 80 ml of THY broth and grown to late-logarithmic phase, GAS cell chains were disrupted by vortexing the culture for 10 min, and cells centrifuged at 6000 \u00d7 g for 10 min and resuspended in saline to produce the infection inoculum (ca. 109 CFU/ml). Initial CFU counts of the infectious dose were confirmed by serial dilutions plated onto THY agar (THYA) plates. Five-week-old, outbred, immunocompetent, hairless female Crl:SKH1-hrBR mice (Charles River Laboratories) received subcutaneous injections of ca. 108 CFU (0.1 ml) of 5448 (or 5448 Krmit mutant library) at the base of the neck. At different times , mice were euthanized by CO2 asphyxiation and skin lesions were excised.Overnight cultures of GAS 5448 or the GAS 5448 For microscopy analyses, lesions were fixed with fresh 4% paraformaldehyde for 24 hours at 4\u00b0C, stored in 70% ethanol at room temperature, then paraffin embedded for sectioning and stained using a hematoxylin and eosin stain (H&E stain) for histology observations.To quantify bacterial load, the lesion was placed into a sterile 2-ml screw-cap microtube containing 1.4 mm ceramic spheres  and 1 ml of sterile saline; and skin tissues were homogenized using three successive 45-second bursts with a FastPrep FP120 BeadBeater (BioSpec Products) as recommended by the manufacturer. Tissue homogenates  were serially diluted (10-fold increments) in saline, plated onto THY agar, and CFU counts determined after overnight incubation at 37\u00b0C.Krmit mutant library and were transferred into 150 ml THY+Km and cultured at 37\u00b0C for 4 h. GAS cells were collected by centrifugation at 6000 \u00d7 g for 10 min and GAS gDNA extracted as above. Tn-seq was carried using the MmeI protocol [et al. [MmeI adapters (Krmit insertion tags were sequenced (50-nt single end reads) on an Illumina HiSeq 1500 platform in the Institute for Bioscience and Biotechnology Research (IBBR) Sequencing Facility located at the University of Maryland, College Park. Tn-seq read datasets were analyzed  as previously described [Tissue homogenates  were produced as described above using the skin lesions from mice infected with the GAS 5448protocol  with mod [et al. . In thisadapters  were useescribed  using thescribed , 70.scfAB locus were obtained by replacing the corresponding open reading frames (ORF) with the promoterless aphA3 gene using allelic exchange as previously described [scfA mutation, DNA fragments flanking the scfA gene were amplified using the primer pairs oAX0478.1 and oAX0478.2 (before the 5\u2032 end of scfA) (PCR 5\u2019scfA) and oAX0478.3 and oAX0478.4 (within the 3\u2032 end of scfA) (PCR 3\u2019scfA) and subsequently ligated by PCR-splicing by overlap extension (SOE) to the aphA3 cassette. The resulting PCR product then was digested by BamHI and cloned into the BamHI-digested pCRS [scfA by the aphA3 cassette was conducted as previously described [scfA. The same approach was carried out to mutate scfB using scfB flanking DNA fragments amplified with primers oAX0477.1 and oAX0477.2 (PCR 5\u2019scfB) and oAX0478.3 and oAX0478.4 (PCR 3\u2019scfB) to produce the pAX0477K plasmid and generate GAS strain 5448\u0394scfB . Mice were anesthetized with ketamine, fur was removed from a ~3-cm2 area of the haunch with Nair (Carter Products), and 100 \u03bcl of a cell suspension in saline injected under the back skin. Mice were monitored twice daily for 2 days, euthanized by CO2 asphyxiation. Skin lesions lysates, CFU counts  and competition indexes were obtained as described above. Unpaired student\u2019s t-test was used to evaluate the significance of differences between groups; a p value of <0.05 was considered statistically significant.Subcutaneous infections were carried out using 5- to 6-week-old female CD-1 mice (Charles River Laboratories). Cell suspensions of exponentially growing GAS cells were obtained by mixing equal amounts of GAS 5448 and the tested mutant strain (close to a 1:1 ratio) in saline . RNA extraction, RNA-seq library preparation and massive parallel DNA sequencing were carried out as previously described . Read anscfA, scfB and scfAB mutants were produced and injected subcutaneously in CD1 mice (108\u2212109 CFUs) as described above. Mice were monitored twice daily for up to 5 days, euthanized by CO2 asphyxiation. Skin lesions and/or spleen were surgically harvested and cell lysates produced with the FastPrep FP120 BeadBeater and CFU counts determined as described above.Cells suspensions in saline of pure cultures of GAS 5448, Illumina sequencing reads from the RNA-seq and Tn-seq analyses were deposited in the NCBI Sequence Read Archive (SRA) under the accession number (PRJNA391181).S1 Text(DOCX)Click here for additional data file.S1 Figin vitro at 24 (light shade), 48 h (dark shade), and both (hatched).Venn diagrams comparing the number of genes showing either decreased (orange) or increased (green) fitness from the Tn-seq analyses of M1T1 GAS 5448 grown in THY for 24 h (A) and 48 h (B). (C) Clusters of Orthologous Genes (COG) categories are indicated with their relative abundance for the same genes showing either decreased (orange) or increased (green) fitness (EPS)Click here for additional data file.S2 Figca. 12 \u03bcm) and features. (B) 12 HPI lesion with inflammatory infiltration (black arrows) in the dermis (both PD and RD) and PCM with early necrosis indicated. (C) Magnification of (B). (D) 24 HPI lesion with PCM inflammation and infiltration (black arrow); Hypo: hypodermis. (F) Magnification of (D) showing monocytes, macrophages, lymphocytes and neutrophils  and visible GAS chains (black arrows). (E) 48 h HPI lesion showing extensive inflammation, tissue damage and abscess formation with pseudo-capsule (CAP) surrounding necrotic debris (Nec). (G) Magnification of (E) shows visible GAS chains (black arrows). Scale bars (in red) represent 100 \u03bcm on panels A, B, D and E; and 10 \u03bcm on panels C, F and G.H&E stains of skin and associated soft tissues samples collected at 12, 24 and 48 HPI. Specific regions are indicated as follows: epidermis (EP), sebaceous gland (SG), hair shaft (HS), papillary dermis (PD), reticular dermis (RD), and panniculus carnosus muscle (PCM). (A) Non-infected tissues displaying normal epidermal thickness ((EPS)Click here for additional data file.S3 FigKrmit libraries injected subcutaneously into immunocompetent Crl:SKH1-hrBR hairless mice were isolated from homogenized lesions and plated onto 5% TSA blood agar plates to look for mucoid (capsule-overproducing) colonies. (A) After 12 HPI, most colonies display a non-mucoid phenotype. (B) After 48 HPI, mucoid colonies (grey arrows) are distinguishable from the remaining colonies (white arrows). (C) AP-PCR analyses on gDNA isolated from selected mucoid mutants show Krmit insertions at different locations within the covS gene (green arrow heads) as indicated.GAS 5448 (EPS)Click here for additional data file.S4 Figwww.microbesonline.org/) using the MGAS5005 genome as reference and the RS06890 homolog (M5005_Spy0477) as the query for the genome alignment. The graphic display presents genome alignments based on the 24 highest homologs to RS06890/M5005_Spy0477. Colored arrows depict homologous genes found within the display window of the different aligned genomes, while grey arrows represent genes that do not have a homolog in the displayed genome window.Genome alignment was generated using the Orthology Browser from the Microbes Online resource ((EPS)Click here for additional data file.S5 FigscfA and scfB genes in the \u0394scfA and \u0394scfB mutants compared to wild-type 5448 grown in THY to late log phase. Error bars represent the standard errors from at least three biological replicates. Dashed lines indicate 2-fold significance. Significance was determined using comparisons of transcript levels relative to those of the gyrA gene.Real-time quantitative PCR (qRT-PCR) analyses of relative transcript levels for (EPS)Click here for additional data file.S1 Table(XLSX)Click here for additional data file.S2 Table(XLSX)Click here for additional data file.S3 Table(XLSX)Click here for additional data file.S4 Table(PDF)Click here for additional data file.S5 Table(PDF)Click here for additional data file."}
+{"text": "Aag-transgenic mice (AagTg) was abrogated in the absence of Poly(ADP-ribose) polymerase-1 (Parp1). Here we report that Parp1-deficient mice expressing increased Aag (\u2212/\u2212)AagTg/Parp1 develop sex-dependent kidney failure upon exposure to the alkylating agent, methyl methanesulfonate (MMS), and suffer increased whole-animal lethality compared to AagTg and wild-type mice. Macroscopic, histological, electron microscopic and immunohistochemical analyses revealed morphological kidney damage including dilated tubules, proteinaceous casts, vacuolation, collapse of the glomerular tuft, and deterioration of podocyte structure. Moreover, mice exhibited clinical signs of kidney disease indicating functional damage, including elevated blood nitrogen urea and creatinine, hypoproteinemia and proteinuria. Pharmacological Parp inhibition in AagTg mice also resulted in sensitivity to MMS-induced nephrotoxicity. These findings provide in vivo evidence that Parp1 modulates Aag-dependent MMS-induced nephrotoxicity in a sex-dependent manner and highlight the critical roles that Aag-initiated BER and Parp1 may play in determining the side-effects of chemotherapeutic alkylating agents.Nephrotoxicity is a common toxic side-effect of chemotherapeutic alkylating agents. Although the base excision repair (BER) pathway is essential in repairing DNA alkylation damage, under certain conditions the initiation of BER produces toxic repair intermediates that damage healthy tissues. We have shown that the alkyladenine DNA glycosylase, Aag (a.k.a. Mpg), an enzyme that initiates BER, mediates alkylation-induced whole-animal lethality and cytotoxicity in the pancreas, spleen, retina, and cerebellum, but not in the kidney. Cytotoxicity in both wild-type and  The kidney is essential for excretion of waste and maintenance of proper osmotic and oncotic pressure; these functions require a properly functioning filtration unit comprised of the glomerulus and surrounding Bowman's capsule. Blood is filtered within the filtration unit; protein, cells, and specific concentrations of chemicals are retained, whereas waste and extra fluid is passed to the renal tubules to become urine. One common feature of glomerular dysfunction is loss of protein from the blood (hypoproteinemia) accompanied by increased urinary protein (proteinuria). Glomerular dysfunction can cause chronic kidney disease and eventually end-stage renal disease (ESRD), requiring dialysis or kidney transplantation. Various causes include genetic mutations, autoimmunity, infections, environmental exposures or any combination thereof (reviewed in \u20134). PathThe glomerular filtration unit has three layers: the visceral epithelial cells (podocytes), the glomerular basement membrane, and parietal endothelial cells; proper communication and function of all three components is required for glomerular function. Podocytes, the most essential cell-type for glomerular filtration, possess interdigitating foot processes that form filtration slits called slit diaphragms (reviewed in ). Loss oSome cancer chemotherapeutic agents, including alkylating agents, induce nephrotoxicity. For example, oxazaphosphorines, used in the treatment of certain leukemias, lymphomas and solid tumors, result in significant nephrotoxicity \u201310. SuchO6-alkylguanine , 7-alkylguanine  and 3alkyladenine . The induction of cell death in rapidly-dividing cells by these toxic DNA lesions underlies the effectiveness of alkylators as cancer chemotherapeutic agents. The base excision repair (BER) pathway repairs many alkylated DNA base lesions [Alkylating agents represent one class of commonly-utilized chemotherapeutic agents that generate numerous types of alkylated DNA base lesions, including  lesions . BER is in vivo alkylation sensitivity. Modest increases in Aag activity in a transgenic mouse model (AagTg mice) increased susceptibility to the alkylating agent, methyl methanesulfonate (MMS), for both whole-animal survival and tissue damage in a specific subset of tissues [AagTg mice, is entirely Parp1-dependent, being wholly prevented by Parp1 deficiency. Here, we show that although Parp1 deficiency protects against Aag-dependent, MMS-mediated tissue degeneration in the pancreas, spleen, retina, and cerebellum [\u2212/\u2212AagTg/Parp1 mice exhibit greater morbidity and lethality following MMS treatment as compared to AagTg mice. Strikingly, following MMS treatment, \u2212/\u2212AagTg/Parp1 mice exhibit severe glomerular damage, suggesting a novel role for Aag and Parp1 in modulating the renal toxicity of alkylating agents.Although BER can repair DNA alkylation damage, under certain conditions the initiation of BER can generate toxic repair intermediates that cause damage to healthy tissues. Recently, using mouse genetic models, we demonstrated the importance of both Aag and Parp1 in modulating  tissues , 13. Therebellum , Parp1 dAagTg/\u2212/\u2212Parp1 mice represent a new model of glomerular disease and may provide insight into many types of human glomerular diseases. Further, the induction of nephrotoxicity by MMS is novel and the importance of Parp1 and Aag in modulating responses is especially relevant, given the recent surge in the use of PARP inhibitors for multiple clinical indications and the wide range of AAG activity in the human population [Numerous animal models of acquired podocyte diseases have been described . MMpulation , 16, 17.AagTg mice, expressing higher than WT levels of Aag, display increased sensitivity to MMS toxicity compared to WT mice, at the whole-animal level and in numerous tissues including the cerebellum, retina, and pancreas, but not kidney [AagTg mice [AagTg mice, we determined the LD50 of the alkylating agent MMS in WT, \u2212/\u2212Parp1, AagTg, and AagTg/\u2212/\u2212Parp1 mice. Surprisingly, although alkylation-induced damage in numerous tissues is suppressed in AagTg/\u2212/\u2212Parp1 mice [50 for AagTg mice is 80 mg/kg as we previously reported [AagTg/\u2212/\u2212Parp1 mice (Table \u2212/\u2212Parp1 mice exhibit the same whole-body sensitivity to MMS as WT (LD50 200 mg/kg). Remarkably, during a 30-day (d) survival experiment post-MMS treatment , we observed that \u2212/\u2212AagTg/Parp1 mice began to lose significant body weight  mice. Moreover, no other tissues from MMS-treated \u2212/\u2212AagTg/Parp1 mice revealed histological abnormalities (not shown) at 14d. \u2212/\u2212AagTg/Parp1 kidneys stained with PAS, toludine blue and phosphotungstic acid-hematoxilin (PTAH) 14d post-MMS showed no evidence of abnormal glomerular cellular accumulations, intravascular fibrin thrombi, matrix deposits, or significant fibrosis , a clinically-relevant PARP inhibitor, exhibit MMS-mediated renal toxicity similar to \u2212/\u2212AagTg/Parp1 mice .e Figure  indicatiAagTg mice combined with either the \u2212/\u2212Parp1 allele or Parp inhibition are susceptible to MMS-mediated renal toxicity, we determined whether this toxicity correlates with the accumulation of BER intermediates and lack of Parp activity. The Aag glycosylase generates potentially toxic abasic (AP) sites that can block replication and transcription [AagTg kidney DNA contained twice as many AP sites as WT kidney DNA , vacuolation (p = 0.001) and capillary lumen collapse (p < 0.05). At 14d post-MMS, additional glomerular pathological abnormalities appear, including crescent formation    in ) Figure ; this tr) Figure . Levels ) Figure .\u2212/\u2212AagTg/Parp1 mice compared to treated WT mice or untreated \u2212/\u2212AagTg/Parp1 mice  protein, a podocyte marker. MMS-treated \u2212/\u2212AagTg/Parp1 mouse kidneys exhibited a decreased number of WT1-stained cells. No significant change was observed in MMS-treated WT mice  showed ultrastructural alterations consistent with the main histological alterations observed in the podocytes and PECs. As shown in Figure \u2212/\u2212AagTg/Parp1 mice exhibit severe morphological and functional podocyte damage post-MMS.Electron-microscopy Figure  revealed\u2212/\u2212AagTg/Parp1 mice. MMS-induced whole-animal toxicity was reduced in \u2212/\u2212AagTg/Parp1 female mice. The MMS LD50 for \u2212/\u2212AagTg/Parp1 female mice is 80 mg/kg, whereas that for \u2212/\u2212AagTg/Parp1 male mice is 66 mg/kg. Furthermore, in contrast with the morbidity observed in male \u2212/\u2212AagTg/Parp1 mice, female \u2212/\u2212AagTg/Parp1 mice exhibited no body weight decrease and survived 30d post-MMS  completely protected 6 out of 8 male mice against MMS-induced kidney damage  [Although protected from MMS-induced toxicity in a variety of tissues, d retina , but enhhocytes) , 16, 17 hocytes) .\u2212/\u2212Parp1 and Parp-inhibited AagTg mice, several other models of kidney damage have demonstrated protection under conditions of genetic or pharmacologic Parp depletion. Parp1 depletion protects against nephrotoxicity induced by the chemotherapeutic agent, cisplatin [\u2212/\u2212AagTg/Parp1 mice was unexpected and to our knowledge has not been previously described. This finding suggests that Parp1 deletion or Parp inhibition may not give rise to the same outcomes across all tissues and experimental models, making it increasingly important to consider the clinical consequences of PARP inhibition in cancer treatment.In contrast to our finding that MMS induces nephrotoxicity in isplatin , 32, diaisplatin , 34 and isplatin , 36. TheParp1 is a multi-functional protein, exhibiting many functions independent of its role in DNA repair . It is p\u2212/\u2212AagTg/Parp1 mice were completely protected from MMS-mediated nephrotoxicity. Males  are more prone to kidney disease [in vitro and in vivo [\u2212/\u2212AagTg/Parp1 mice from MMS-mediated kidney disease. Additionally, it has been described previously that female and male mice exhibit different responses to Parp1 deletion or Parp inhibition in mouse models of endotoxemia and nephrotoxic serum-induced nephritis [Strikingly, female  disease , 42. Ind disease . Consist disease \u201346, but  disease . Specifi in vivo , 49. Not in vivo \u201353. Here in vivo , 55 may ephritis , 57. Theephritis \u201361.The sexual dimorphism in our model may be explained by the interaction of Aag and Parp1 with estrogen receptor-\u03b1 (ER\u03b1) , 63. A dNumerous existing models of acquired podocyte diseases are used to explore human renal diseases, however all models have both advantages and disadvantages . We pres\u2212/\u2212Parp1 mice were purchased from Jackson Laboratories [Aag transgenic (AagTg) mice were described previously [ratories . Aag traeviously , 13, 65.50 was determined as in Deichmann and LeBlanc [Approximate LD LeBlanc . MMS wasin vivo Pharmacodynamic Assay II (Trevigen) according to the manufacturer's instructions.DNA was isolated using Roche kit according to the manufacturer's instructions with precautions taken to avoid overheating of the DNA solution (proteinase K step 10 min at 55\u00b0C). AP sites were determined by using the DNA Damage Quantification Kit (Dojindo) and performed according to the manufacturer's instructions. Parp activity was determined by using the HT PARP via cardiac puncture and placed in BD microtainer serum separator tubes (VWR). Blood samples were then centrifuged for 5 minutes at 2000 x g to separate serum. Idexx Laboratories, Inc.  performed serum chemistry analysis.Whole blood was collected Two \u03bcL of urine was denatured and run on a SDS-PAGE gel and proteins were visualized using ProteoSilver Plus Silver Staining Kit (Sigma).Tissue processing and imaging was performed by the W.M. Keck Microscopy Facility at the Whitehead Institute (MIT). Kidney cortex was fixed in 2.5% gluteraldehyde, 3% paraformaldehyde with 5% sucrose in 0.1 M sodium cacodylate buffer (pH 7.4), post-fixed in 1% osmium tetroxidein veronal-acetate buffer, stained in block overnight with 0.5% uranyl acetate in veronal-acetate buffer (pH 6.0) and then embedded in Embed-812 resin. Ultrathin sections were cut from blocks on a Leica Ultracut UCT microtome with a Diatome diamond knife. The sections were examined using a FEI Tecnai Spirit at 80 keV.Tissues were processed by the Histology Core Facility at the David H. Koch Institute for Integrative Cancer Research (MIT); they were paraffin-embedded, sectioned at 5 \u03bcm, and stained with hematoxylin and eosin (H&E), or Periodic Acid-Schiff (PAS). Phosphotungstic acid-haematoxylin (PTAH) staining was performed at the Division of Comparative Medicine (MIT). All H&E stained slides were blindly analyzed by a pathologist (R.T.B). Renal lesions were blindly scored by a pathologist (S.M.) using criteria listed in Deparaffinized tissue sections (5 \u03bcm) were thermally processed for epitope retrieval using a Prestige Medical 2100-Retriver. Sections were permeabilized in PBS-T , incubated with 1x PBS-T plus 10% goat serum for 1 hour and then stained with either anti-WT1antibody (Santa Cruz) or anti-podocin (Sigma) overnight at 4\u00b0C. Nuclear counterstaining was done using DAPI. The number of glomerular DAPI- and WT1-stained cells were counted using ImageJ.Statistical analyses were performed using GraphPad Prism software. Statistical significance was determined using unpaired t-test. Kaplan-Meier survival curves were generated and survival differences determined using the Log-Rank test. Data are represented as mean +/\u2212 SEM. A p-value is considered significant if less than 0.05."}
+{"text": "A 35-year-old woman, gravida 4 para 3 estimated at 9+1 weeks gestational age by uncertain last menstrual period, presented with vaginal bleeding. She endorsed unprotected intercourse eight weeks prior and took Plan B One-Step (\u201cmorning-after pill\u201d) within 48 hours. Quantitative human chorionic gonadotropin (hcg) resulted at 30 mIU/ml. Bedside transabdominal ultrasound was concerning for ectopic pregnancy . Is thisRadiology performed a transvaginal ultrasound, which was negative for intrauterine or ectopic pregnancy. Obstetric consultants were uncertain if the structure seen at bedside represented an ectopic . RadioloThe daughter cyst sign indicates an uncomplicated ovarian cyst.are limited to case reports involving pediatric females with McCune \u2013Albright Syndrome and precocious puberty, as well as fetuses with incidental cysts mimicking ectopic pregnancy.VideoPoint-of-care transabdominal ultrasound video clip demonstrating the uterus and daughter cyst in the axial plane."}
+{"text": "During recent years, systematic reviews of observational studies have compared digoxin to no digoxin in patients with atrial fibrillation or atrial flutter, and the results of these reviews suggested that digoxin seems to increase the risk of all-cause mortality regardless of concomitant heart failure. Our objective was to assess the benefits and harms of digoxin for atrial fibrillation and atrial flutter based on randomized clinical trials.We searched CENTRAL, MEDLINE, Embase, LILACS, SCI-Expanded, BIOSIS for eligible trials comparing digoxin versus placebo, no intervention, or other medical interventions in patients with atrial fibrillation or atrial flutter in October 2016. Our primary outcomes were all-cause mortality, serious adverse events, and quality of life. Our secondary outcomes were heart failure, stroke, heart rate control, and conversion to sinus rhythm. We performed both random-effects and fixed-effect meta-analyses and chose the more conservative result as our primary result. We used Trial Sequential Analysis (TSA) to control for random errors. We used GRADE to assess the quality of the body of evidence.2 = 0%); serious adverse events ; quality of life; heart failure ; and stroke . Our analyses on acute heart rate control (within 6 hours of treatment onset) showed firm evidence of digoxin being superior compared with placebo (mean difference (MD), -12.0 beats per minute (bpm); TSA-adjusted CI, -17.2 to -6.76; I2 = 0%) and inferior compared with beta blockers . Meta-analyses on acute heart rate control showed that digoxin was inferior compared with both calcium antagonists  and with amiodarone , but in both comparisons TSAs showed that we lacked information. Meta-analysis on acute conversion to sinus rhythm showed that digoxin compared with amiodarone reduced the probability of converting atrial fibrillation to sinus rhythm, but TSA showed that we lacked information .28 trials (n = 2223 participants) were included. All were at high risk of bias and reported only short-term follow-up. When digoxin was compared with all control interventions in one analysis, we found no evidence of a difference on all-cause mortality (risk ratio (RR), 0.82; TSA-adjusted confidence interval (CI), 0.02 to 31.2; IThe clinical effects of digoxin on all-cause mortality, serious adverse events, quality of life, heart failure, and stroke are unclear based on current evidence. Digoxin seems to be superior compared with placebo in reducing the heart rate, but inferior compared with beta blockers. The long-term effect of digoxin is unclear, as no trials reported long-term follow-up. More trials at low risk of bias and low risk of random errors assessing the clinical effects of digoxin are needed.PROSPERO CRD42016052935 Atrial fibrillation is the most common arrhythmia of the heart with a prevalence of approximately 2% in the western world , 2. AtriDuring recent years, systematic reviews of observational studies have compared digoxin to no digoxin  in patients with atrial fibrillation or atrial flutter, and these reviews suggested that digoxin seems to increase the risk of all-cause mortality regardless of concomitant heart failure \u201320. The Therefore, the aim of this systematic review was to evaluate the beneficial and harmful effects of digoxin for atrial fibrillation and atrial flutter in randomized clinical trials , 22. FurWe conducted this systematic review based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines (PRISMA)  23], an, an23], We searched for randomized clinical trials comparing digoxin versus placebo, no intervention, or other medical interventions in patients with atrial fibrillation or atrial flutter. We searched for eligible trials in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS, Science Citation Index Expanded on Web of Science, BIOSIS, Google Scholar, clinicaltrials.gov, Trip Medical Database (TRIP), WHO International Clinical Trials Registry Platform (ICTRP), International Standard Randomised Controlled Trial Number (ISRCTN), EU Clinical Trial Register (EUCTR), and Chinese Clinical Trial Registry (ChiCTR) in October 2016. The search strategy can be found in the supplementary material . AdditioCochrane Handbook for Systematic Reviews of Interventions and Lundh et al. .\u201385.54\u201385All 28 trials were at high risk of bias . All triWe have reported the baseline characteristics of the participants in 2 = 0%; 522 participants; 6 trials; very low quality of evidence; 2 = 51%; 462 participants; 4 trials; very low quality of evidence; 2 = 17%; 325 participants; 3 trials; very low quality of evidence; 2 = 0%; 1210 participants; 13 trials; very low quality of evidence; When digoxin was compared with all control interventions in one analysis, our analyses on all-cause mortality , atrial fibrillation symptom severity score (AF-SSS), SF-36 physical component score (SF-36 PCS), and SF-36 mental component score (SF-36 MCS). Our analyses showed no evidence of a difference between the digoxin versus the control group on AF-SFS ; TSA-adjusted CI, -17.2 to -6.76; P < 0.00001; I2 = 0%; 453 participants; 4 trials; very low quality of evidence; 2 = 3%; 484 participants; 6 trials; very low quality of evidence; Our analyses showed no evidence of a difference on the probability of converting the atrial fibrillation to sinus rhythm both within 6 hours of treatment onset . None oWhen digoxin was compared with all control interventions in one analysis, our analyses showed no evidence of a difference on all-cause mortality, quality of life, stroke, and heart failure. Meta-analysis on serious adverse events suggested that digoxin might have a harmful effect, but TSA showed that there was not enough information to confirm or reject a RRR of 22.5%. When we deal with harms, it should be considered if we need the same statistical backing as if we were dealing with benefits . Our anaOur review has several strengths. We are the first to conduct a systematic review with meta-analysis of randomized clinical trials comparing digoxin versus placebo, no intervention, or other medical interventions for atrial fibrillation and atrial flutter , 25. We Our review also has several limitations. All trials were at high risk of bias and especially the risk of incomplete blinding of participants and personnel and for-profit bias might bias our review results. Our assessment of especially publication bias was also uncertain, as a relatively low number of trials were included. Furthermore, some of the performed meta-analyses had considerable statistical heterogeneity. Hence, publication bias and heterogeneity might further bias our results. Large meta-epidemiological studies have shown that trials at high risk of bias tend to overestimate benefits and underestimate harms of experimental interventions \u201333. FurtThe potential relevance of heart rate control as a surrogate outcome is questionable. Heart rate reduction alone is believed to reduce the risk for cardiovascular events and death, and increase the quality of life, but its clinical relevance has not yet been fully established for patients with atrial fibrillation and atrial flutter , 109. MoWe have identified one systematic review of randomized clinical trials assessing the effect of digoxin versus other medical interventions for atrial fibrillation and atrial flutter by Al-Khatib et al. . They inWe have identified four systematic reviews of observational studies assessing the effect of digoxin for atrial fibrillation and atrial flutter \u201320. The Current guidelines recommend that beta blockers and calcium antagonists should be preferred over digoxin for acute rate control in patients with normal ejection fraction , 113. OuFor long-term heart rate control, guidelines recommend that the choice of rate control drug should be made individually for each patient , 113. HoWe identified one ongoing trial see  that migThe clinical effects of digoxin on all-cause mortality, serious adverse events, quality of life, heart failure, and stroke are unclear based on current evidence. Digoxin may increase the risk of a serious adverse event, but no firm evidence was available. Our systematic review could neither confirm nor reject the findings from recent systematic reviews of observational studies showing that digoxin compared to no digoxin increased the risk of death. The increased risk of death found in observational studies might be caused by selection, prescription biases, or due to a longer follow-up , 22. BasWe changed our assessment time-point for heart rate control and conversion to sinus rhythm. According to the protocol, we would use the trial results reported within 48 hours after treatment onset. However, in this review, we had two assessment time-points. We both performed meta-analyses within 6 hours of treatment onset and meta-analyses 6 to 24 hours after treatment onset. We made this change so we were able to investigate the effect of digoxin on heart rate control and conversion to sinus rhythm in both the acute and subacute phase.We performed TSAs on all meta-analysis results. If the TSA could not be conducted because of too little information, we conducted a more lenient TSA by increasing the anticipated intervention effect. In the protocol, we did not mention that we would perform these analyses.S1 Text(DOCX)Click here for additional data file.S2 Text(PDF)Click here for additional data file.S3 Text(PDF)Click here for additional data file.S1 Fig(TIF)Click here for additional data file.S2 Fig(TIF)Click here for additional data file.S3 Fig(TIF)Click here for additional data file.S4 Fig(TIF)Click here for additional data file.S5 Fig(TIF)Click here for additional data file.S6 Fig(TIF)Click here for additional data file.S7 Fig(TIF)Click here for additional data file.S8 Fig(TIF)Click here for additional data file.S9 Fig(TIF)Click here for additional data file.S10 Fig(TIF)Click here for additional data file.S11 Fig(TIF)Click here for additional data file.S12 Fig(TIF)Click here for additional data file.S13 Fig(TIF)Click here for additional data file.S14 Fig(TIF)Click here for additional data file.S15 Fig(TIF)Click here for additional data file.S16 Fig(TIF)Click here for additional data file.S17 Fig(TIF)Click here for additional data file.S18 Fig(TIF)Click here for additional data file.S19 Fig(TIF)Click here for additional data file.S20 Fig(TIF)Click here for additional data file.S21 Fig(TIF)Click here for additional data file.S22 Fig(TIF)Click here for additional data file.S23 Fig(TIF)Click here for additional data file.S24 Fig(TIF)Click here for additional data file.S25 Fig(TIF)Click here for additional data file.S26 Fig(TIF)Click here for additional data file.S27 Fig(TIF)Click here for additional data file.S28 Fig(TIF)Click here for additional data file.S29 Fig(TIF)Click here for additional data file.S30 Fig(TIF)Click here for additional data file.S31 Fig(TIF)Click here for additional data file.S32 Fig(TIF)Click here for additional data file.S33 Fig(TIF)Click here for additional data file.S34 Fig(TIF)Click here for additional data file.S35 Fig(TIF)Click here for additional data file.S36 Fig(TIF)Click here for additional data file.S37 Fig(TIF)Click here for additional data file.S38 Fig(TIF)Click here for additional data file.S39 Fig(TIF)Click here for additional data file.S40 Fig(TIF)Click here for additional data file.S41 Fig(TIF)Click here for additional data file.S42 Fig(TIF)Click here for additional data file.S43 Fig(TIF)Click here for additional data file.S44 Fig(TIF)Click here for additional data file.S45 Fig(TIF)Click here for additional data file.S46 Fig(TIF)Click here for additional data file.S47 Fig(TIF)Click here for additional data file.S48 Fig(TIF)Click here for additional data file.S49 Fig(TIF)Click here for additional data file.S50 Fig(TIF)Click here for additional data file.S51 Fig(TIF)Click here for additional data file.S52 Fig(TIF)Click here for additional data file.S53 Fig(TIF)Click here for additional data file.S54 Fig(TIF)Click here for additional data file.S55 Fig(TIF)Click here for additional data file.S56 Fig(TIF)Click here for additional data file.S57 Fig(TIF)Click here for additional data file.S58 Fig(TIF)Click here for additional data file.S59 Fig(TIF)Click here for additional data file.S60 Fig(TIF)Click here for additional data file.S61 Fig(TIF)Click here for additional data file.S62 Fig(TIF)Click here for additional data file.S63 Fig(TIF)Click here for additional data file.S64 Fig(TIF)Click here for additional data file.S65 Fig(TIF)Click here for additional data file.S66 Fig(TIF)Click here for additional data file.S67 Fig(TIF)Click here for additional data file.S68 Fig(TIF)Click here for additional data file.S69 Fig(TIF)Click here for additional data file.S70 Fig(TIF)Click here for additional data file.S71 Fig(TIF)Click here for additional data file.S72 Fig(TIF)Click here for additional data file.S73 Fig(TIF)Click here for additional data file.S74 Fig(TIF)Click here for additional data file.S75 Fig(TIF)Click here for additional data file.S76 Fig(TIF)Click here for additional data file.S77 Fig(TIF)Click here for additional data file.S78 Fig(TIF)Click here for additional data file.S79 Fig(TIF)Click here for additional data file.S80 Fig(TIF)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file."}
+{"text": "Graft-versus-host response after allogeneic hematopoietic stem cell transplantation  represents one of the most intense inflammatory responses observed in humans. Host conditioning facilitates engraftment of donor cells, but the tissue injury caused from it primes the critical first steps in the development of acute graft-versus-host disease (GVHD). Tissue injuries release pro-inflammatory cytokines  through widespread stimulation of pattern recognition receptors (PRRs) by the release of danger stimuli, such as damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). DAMPs and PAMPs function as potent stimulators for host and donor-derived antigen presenting cells (APCs) that in turn activate and amplify the responses of alloreactive donor T cells. Emerging data also point towards a role for suppression of DAMP induced inflammation by the APCs and donor T cells in mitigating GVHD severity. In this review, we summarize the current understanding on the role of danger stimuli, such as the DAMPs and PAMPs, in GVHD. In addition, activated APCs produce an abundance of T-cell stimulating cytokines, such as IL-12, which further escalate the inflammatory response. In this review, we describe several encouraging investigations that have been conducted in both experimental bone marrow transplantation (BMT) models and humans over the last two decades. We further summarize the updated findings of how DAMPs and PAMPs amplify or mitigate GVHD and explore potential new strategies for the regulation of these \u201cdanger signals\u201d in the regulation of GVHD.Allogeneic hematopoietic stem cell transplantation  has become widely used as a curative therapy for a variety of life-threatening hematological malignancies and congenital immune deficiencies . HoweverPAMPs are non-host derive molecules derived from microbes and are recognized by pattern recognition receptors (PRRs) that initiate and sustain the innate immune responses for protecting host from foreign pathogens . DAMPs aDanger signaling is transmitted through PRRs when they bind PAPMs and DAMPs. Several signaling pathways, such as toll-like receptor (TLR), Nucleotide-binding oligomerization domain (NOD)-like receptor (NLR), and retinoic acid-inducible gene 1 (RIG-I) signaling, are recognized. The detailed mechanisms are recently reviewed in several articles \u20137. In thToll-like receptors are one of the PRRs and play a key role in innate immune responses by recognizing PAMPs as well as DAMPs\u2009. TLRs ar\u2212/\u2212 animals were used as either donor or recipient, acute GVHD severity and mortality were significantly ameliorated in MHC-mismatched B6 into BALB/c model by altering DC functions in TLR4\u2212/\u2212 APCs  also showed significantly less intestinal GVHD, but reduction was appeared dependent on conditioning intensity . TLR4 signaling is transmitted through intracellular adaptor molecules myeloid differentiation primary response gene 88 (MyD88) and Toll/IL-1receptor (TIR)-domain-containing adaptor-inducing interferon \u03b2 (TRIF) that activate NF-\u03baB signaling that potently enhances expression of pro-inflammatory cytokines. The role of TLR4 in APCs for mediating acute GVHD remains controversial. Mutations in TLR4 are involved in the reduction of GVHD responses by hyporesponsiveness of APCs to LPS stimulation while over activation of TLR4 signaling results in exacerbation of GVHD . When TL\u2212/\u2212 APCs . This fi\u2212/\u2212 APCs . TLR2/4\u2212ntensity . In minontensity . In addintensity , 15. Whi\u2212/\u2212 animals were used as the host, acute GVHD was significantly improved (\u2212/\u2212 T cell depleted BM (TCD-BM) cells showed greater intestinal GVHD (\u2212/\u2212 donor T cells reduced graft-versus-tumor (GVT) activity through the expansion of Foxp3- and IL-4-producing T cells in MHC-mismatched haploidentical B6 into B6D2F1 model  from gram-positive bacteria as well as zymosan from yeast. Intriguingly, granulocyte-colony stimulating factor (G-CSF) mobilized donor grafts showed the increase level of TLR2 expression on myeloid cell populations , but uprute GVHD , 20.TLR5 recognizes flagellin that is an essential component of bacterial flagella from both gram-negative and -positive bacteria and regulates immunity \u201326. CBLBTLR7 recognizes endosomal single strand ribonucleic acids (RNAs) leading to production of type I interferons (IFNs), pro-inflammatory cytokines, as well as regulatory cytokines , 32. TLR\u2212/\u2212 animals were used as hosts, acute GVHD severity and mortality was ameliorated. This was dependent on the expression of TLR9 expression on the non-hematopoietic cells (TLR9 recognizes unmethylated cytosine-phophorothionate-guanine (CpG) dinucleatides in the bacterial DNA and triggers a Th1-mediated inflammatory response . CpG-medic cells , 14. Howic cells , 43. Donic cells .\u2212/\u2212 hematopoietic cells, we have already demonstrated that TLR3 deficiency in host APCs showed equivalent GVHD severity and mortality to WT animals but impaired GVT activity in MHC-matched multiple minor mismatched BMT model. Activation of TLR3 by polyinosine-polycytidylic acid (Poly I:C) improved GVT activity without enhancing GVHD (TLR3 recognizes double-stranded RNA (dsRNA), which is produced by most of viruses. It signals through interferon regulatory factor (IRF)3 and activates NF-\u03baB and enhances production of type I IFNs , 46. TLRing GVHD . Becauseing GVHD , 50, TLR\u2212/\u2212 recipient animals showed exacerbated GVHD severity and morality, particularly intestinal GVHD. This was due to host APC activation in experimental BMT  tripeptide from gram-negative bacterial PGN , 52, whintal BMT . By contMT model .+ T cells promotes IFN-\u03b3 production and Th1 differentiation by enhancing caspase 1-dependent IL-1\u03b2 secretion mediated through intracellular C5 activation  (ASC), which has pyrin domain (PYD) and CARD, pro-caspase 1, and certain receptor proteins, such as NLR family members , the protein absent in melanoma 2 (AIM2) , 74. Onctivation . These dtivation . We recetivation , 84. Absallo-BMT . These rRIG-I, melanoma differentiation-associated gene 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2) are known as RIG-I-like receptors (RLRs). RIG-I and MDA5 contain a DExD/H box RNA helicase domain and CARD, but LGP2 has no CARD-like domain. These receptors bind to intracellular dsRNA or ssRNA and trigger innate antiviral responses by producing type I IFNs \u201391. TherC-type lectin receptors (CLRs) are expressed on myeloid-derived APCs as soluble or transmembrane embedded proteins. They directly activate NF-\u03baB through spleen tyrosine kinase (SYK)  or indirBoth exogenous and endogenous danger signal proteins are released from damaged tissues and abnormal intestinal microbial colonies after conditioning. In addition, blood stream infection (BSI) caused by gut translocation of colonized bacteria is another critical source of PAMPs after allo-HCT . ExperimLipopolysaccharides (endotoxin) are membrane component of many gram-negative bacteria representing one of the earliest and most investigated PAMPs in GVHD. The role of LPS in GVHD is complex and controversial. LPS translocation due to gastrointestinal (GI) tract damage is correlated with conditioning intensity  and show+ T cell and NK cell dependent model  that is stored within cytoplasm and mitochondria  as the primary energy source chondria . Once cechondria , 133. Inced GVHD . Anotherced GVHD . Increasced GVHD . In lineced GVHD . Loss ofted GVHD , 139. Thted GVHD . The immted GVHD .+ T cell cytotoxic functions, and is recognized as an endogenous DAMP (Uric acid is a metabolite of purine nucleotide and hyperuricemia is known to lead gout . Uric acous DAMP . Recent ous DAMP . Patientous DAMP . Howeverous DAMP .in vitro (in vivo effects on GVHD were not studied.Heat shock proteins (HSPs) work as molecular chaperones that enhance protein folding and intracellular transportation . HSPs hain vitro , but theHeparan sulfate proteoglycans (HSPGs) are component of extracellular matrix and play fundamental role in cell development, metabolism, and immunity , 157. HScandida species exacerbated GVHD in clinical studies  is a component of fungal cell wall as a known DAMP. The \u03b1-mannan is recognized by dectin1 and dectin2, which is one of the CLRs and activates NF-\u03baB signaling through SYK and produces pro-inflammatory cytokines and effector T cell differentiation . \u03b1-manna studies , 101.\u201cDanger signals\u201d are indispensable role in initiating and developing acute GVHD. Regulating danger signal in an efficient manner in early phase of allo-SCT would ameliorate GVHD and have a great therapeutic strategy. Herein, we summarize potential therapeutic strategies for prevention and treatment of GVHD through modulating this signaling pathway. The studies are also summarized in Table P2X7 receptor on APCs binds to extracellular ATPs, which released from damaged tissues by conditioning, and activates APCs to produce pro-inflammatory cytokines. Therefore, P2X7R plays a key role in DAMPs-mediated inflammatory responses. Systemic administration of the broad-spectrum P2X7R antagonist, pyridoxal-phosphate-6-azophenyl-2\u2032,4\u2032-disulfonic acid (PPADS), or an ATP diphosphohydrolase, apyrase attenuated GVHD by suppressing APC activation . AdditioSerine protease inhibitor alpha-1 antitrypsin (AAT) attenuates GVHD by inhibiting HS, one of the DAMPs, and reducing HS mediated allogenic T cell responses in murine model . ClinicaSialic acid-binding immunoglobulin like lectins (Siglecs) have an immunoreceptor tyrosine-based inhibitory motifs (ITIM) or ITIM-like regions in their intracellular domains and negatively regulate DAMPs-mediated innate inflammatory responses , 178 or Danger signals mediate inflammatory responses through a multitude of PRRs that play a key role in the pathogenesis of GVHD. Once danger signals are released after conditioning, multiple innate immune signaling pathways are activated and amplified. Therefore, regulating danger signaling pathways in an effective manner is complex. Preclinical data suggest that targeting one specific signaling pathway or molecule may have only limited effects in reducing GVHD. In addition, the specific timing of regulation by blockade using antagonists may be a critical factor to consider. However, it is plausible that stimulating the negative regulating pathway that is commonly employed by several DAMPs may be a more rational way to mitigate GVHD. Thus exploring novel mechanisms of negative regulation of danger DAMP signaling that mediate lethal inflammatory responses should be carefully examined as new strategy of the prevention and treatment of GVHD. One potential benefit of regulating danger signaling is that GVT responses may be preserved due to selective attenuation of APCs with presumably limited effects on donor tumor-specific T cells necessary for mediating GVT responses. Clinical trials that investigate critical mediators of the danger response hold promise in the prevention of GVHD without affecting GVT responses.The review article was designed and written by TT and PR. Both NM and JM helped with designing figures. together with the help of co-authors NM and JM. All of them performed literature review and critically discussed the published literature.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Angioimmunoblastic T-cell lymphoma (AITL) is one of the most common subtypes of peripheral T-cell lymphoma. Advances in understanding the mutational landscape of AITL have not resulted in improved prognosis nor consensus regarding optimal first-line and second-line treatment.The recently proposed multistep tumorigenesis model for AITL provides a theoretical framework of AITL oncogenesis. In this model, early mutations in epigenetic modifiers interact with late cooperative mutations to enable malignant transformation. Frequent mutations in epigenetic modifiers suggest that aberrant DNA methylation contributes to AITL oncogenesis. Several research groups have reported findings suggesting that inappropriate costimulation acts as a late cooperative mutation. Drugs targeting inappropriate costimulation have already been approved for the treatment of several malignancies or autoimmune diseases. Additionally, aberrant DNA methylation was recently shown to potentiate inappropriate costimulation in a subset of AITL cases. Therefore, drugs targeting inappropriate costimulation and hypomethylating agents might have synergistic effects. Both offer promising new therapeutic options in AITL treatment.This commentary summarizes the main findings on aberrant DNA methylation and inappropriate costimulation in AITL and proposes several already approved drugs for AITL treatment. Hopefully, these will contribute to improving the still dismal prognosis of AITL patients. Peripheral T-cell lymphoma (PTCL) constitutes a heterogeneous group of non-Hodgkin lymphomas generally characterized by an aggressive clinical course and poor prognosis . AngioimVaries sequencing studies have been conducted to investigate the mutational landscape of AITL. TET2, IDH2 and DNMT3A are mutated in 30\u201380%, 20\u201345% and 10\u201330% of investigated AITL cases, respectively \u201317. Beca2+- and 2-oxoglutarate (2OG)-dependent dioxygenase involved in DNA demethylation. Most cytosine derivatives generated by TET2, especially 5-hydroxymethylcytosine resulting in DNA hydroxymethylation, are stable epigenetic marks [FH) [FH-like features [FH differentiation and renders affected cells susceptible for malignant transformation after acquiring late cooperative mutations. Isocitrate dehydrogenase 2 (IDH2) is a potential regulator of TET2. Wildtype IDH2 catalyzes the two-step interconversion of isocitrate to 2OG. Mutant IDH2, in AITL restricted to R172 residue mutations, catalyzes the reduction of 2OG to (R)-2-hydroxyglutarate (2HG). 2HG has been identified as an oncometabolite potentially contributing to malignant transformation by competitively inhibiting 2OG-dependent enzymes. As these enzymes are involved in many cellular functions including DNA and histone modification, cellular energy metabolism and differentiation, further research is warranted to evaluate the oncogenic potential of downstream targets of mutant IDH2 [+ T-cells [FH with both increased expression of the Inducible T-cell CoStimulator (ICOS) receptor and increased ICOS-dependent signaling. Blocking ICOS signaling using an anti-ICOS antibody prevented mutant Rhoa-induced TFH phenotype [FH phenotype, likely via stabilization of Bcl6 [FH phenotype via increased ICOS signaling. This mechanism might explain why this mutation is so frequently encountered in AITL.Ten-Eleven Translocation 2 (TET2) is a Feic marks . Preciseic marks . Additioic marks . B cell rks [FH) . Intron1rks [FH) . Accordirks [FH) . Similarfeatures . Deregulant IDH2 . A recenant IDH2 . Using aant IDH2 . How thiant IDH2 . Among dant IDH2 . SIT1 isant IDH2 . Diacylgant IDH2 . As the ant IDH2 , 29. It ant IDH2 . These dant IDH2 , 12, 14.ant IDH2 , 12, 14. T-cells . E\ufeffxpreshenotype . ICOS is of Bcl6 . It seemFH phenotype-inducing capacities of mutant Rhoa in vivo, also explored the potentially synergistic effect of mutations in TET2 and RHOA. Expression of mutant Rhoa in HSCs derived from TET2-deficient mice resulted in the development of AITL. Neoplastic cells were heavily dependent upon ICOS signaling for growth and proliferation in vivo [Mutations in TET2 and DNMT3A are not only found in AITL but also in myeloid malignancies and even non-malignant HSCs. It is currently presumed that these mutations are acquired during an early stage of hematopoietic differentiation. Mutant HSCs cause clonal hematopoiesis and eventually give rise to preleukemic/prelymphoma stem cells with an increased risk for subsequent hematologic malignancies . What ki in vivo . These aT cell activation is determined by engagement of co-stimulatory and co-inhibitory molecules in combination with T cell receptor activation. As binding affinity of co-inhibitory molecules is generally higher compared to co-stimulatory molecules, T cell activation is mitigated when expression of ligands is low. This interplay functions to ensure appropriate T cell activation . EngagemTwo research groups identified missense mutations in the gene encoding co-stimulatory molecule CD28 , 6. MutaA recently published study expanded upon these earlier findings indicating inappropriate costimulation as potential cooperative mutation in AITL oncogenesis. Vallois et al. showed that 50% 36/72) of investigated AITL cases had mutations in components of T cell receptor signaling or costimulatory pathways, other than RHOA . Intrigu2 of inveTargeting inappropriate costimulation in AITL might prove an effective therapeutic approach. Two strategies could potentially be effective in blocking inappropriate costimulation: 1) preventing ligand-coreceptor interaction and 2) inhibition of intracellular signaling pathways downstream of co-stimulatory molecule CD28  is a CTLA-4-specific monoclonal antibody which can potentially be effective in CTLA4-CD28 fusion gene-positive AITL patients. Ipilimumab has already been approved for the treatment of malignant melanoma . AbataceFH differentiation which could also explain the efficacy of everolimus in AITL [Various components of the PI3K/Akt/mTOR signaling pathway have been targeted by specific inhibitors. Idelalisib  inhibits class I PI3K isoform p110\u03b4, the main PI3K isoform expressed in leukocytes. Idelalisib is already approved for the treatment of certain hematological malignancies (e.g. follicular B-cell non-Hodgkin lymphoma). In vitro data has shown that p110\u03b4 is the main PI3K isoform responsible for PI3K activity at the immune synapse . Because in AITL .Most of the approved Ras/Raf/MAPK/ERK signaling pathway inhibitors target frequently mutated components. Sorafenib , a multikinase inhibitor (including Raf), and trametinib  and cobimetinib , both MEK inhibitors, are currently the only approved non-BRAF mutant-selective Ras/Raf/MAPK/ERK signaling pathway inhibitors . SorafenTET2 and DNMT3A are among the most frequently mutated genes in AITL \u201317. The Azacitidine  and decitabine  are currently the only two approved hypomethylating agents for the treatment of myelodysplastic syndromes and acute myeloid leukemia . AzacitiCombined targeting of inappropriate costimulation and aberrant DNA methylation may prove to increase therapeutic efficacy in some AITL cases. Several negative regulators of T cell receptor signaling  have shown to be hypermethylated and downregulated in mutant IDH2 AITL cases . As prevAdvances in understanding the mutational landscape of AITL have not resulted in improved prognosis nor consensus regarding optimal first-line and second-line treatment. However, these findings have resulted in a multistep tumorigenesis model for AITL which provides us with a theoretical framework for AITL oncogenesis. Several research groups have identified mutations in costimulatory pathways resulting in inappropriate costimulation, potentially contributing to AITL oncogenesis. We propose that inappropriate costimulation can be regarded as a new cooperative mutation for AITL development from prelymphoma stem cells. This insight opens new therapeutic options for AITL treatment. We have proposed several candidate drugs with the potential to block inappropriate costimulation which have already been approved for the treatment of other malignancies or autoimmune disorders. Furthermore, we provided an overview of the current knowledge regarding aberrant DNA methylation in AITL. Hypomethylating agents are already being used to treat other hematological disorders and first prospective data for the use of hypomethylating agents in AITL treatment are promising. Additionally, studies have shown that aberrant DNA methylation can increase signaling through costimulatory pathways and therefore potentiate inappropriate costimulation. Together with the fact that aberrant DNA methylation contributes to AITL oncogenesis, these findings provide a biological and theoretical rationale for the simultaneous use of hypomethylating agents and drugs targeting inappropriate costimulation in a subset of AITL cases. Pre-clinical studies and clinical trials should be readily conducted to investigate the efficacy of these already approved drugs and their potential synergistic effect. Hopefully, these insights will contribute to improving the still dismal prognosis of AITL patients."}
+{"text": "China is the largest royal jelly producer and exporter in the world, and highroyal jelly-yielding strains have been bred in the country for approximatelythree decades. However, information on the molecular mechanism underlying highroyal jelly production is scarce. Here, a cDNA microarray was used to screen andidentify differentially expressed genes (DEGs) to obtain an overview on thechanges in gene expression levels between high and low royal jelly producingbees. We developed a honey bee gene chip that covered 11,689 genes, and thischip was hybridised with cDNA generated from RNA isolated from heads of nursingbees. A total of 369 DEGs were identified between high and low royal jellyproducing bees. Amongst these DEGs, 201 (54.47%) genes were up-regulated,whereas 168 (45.53%) were down-regulated in high royal jelly-yielding bees. Geneontology (GO) analyses showed that they are mainly involved in four keybiological processes, and pathway analyses revealed that they belong to a totalof 46 biological pathways. These results provide a genetic basis for furtherstudies on the molecular mechanisms involved in high royal jelly production. Apis mellifera) is an important insect that generateshigh economic and ecological values for humans as a key pollinator of crops   in specific biological processes. Microarrays have beenextensively used in the study of honey bees, including age-related division oflabour (rasitism . DozensApis mellifera ligustica), wereobtained from the experimental apiary of Zhejiang University, Hangzhou, China.Local Italian bees with a low royal jelly-producing trait were obtained fromMiao Siwei Apiary, Simao County, Yunnan Province.High royal jelly-producing colonies (Zhenongda No. 1), which were derived from anItalian honey bee subspecies  and genesequences obtained from our lab sequence results, not yet deposited in NCBI.Each gene had a 60 bp sequence included in the oligonucleotide microarrayconstruction done by Advanced Throughput Inc. . The details ofprobes are provided as Supplementary material (TableS1).A honey bee chip was designed following the Agilent eArray Design guidelines. Itcontained 11,689 genes from GenBank  according to theprocedures of a previous study  was used togenerate fluorescent cRNA according to the manufacturer's instructions. Aliquotsof 200 ng of total RNA from each sample were used in a protocol described byTableS2. DEGs with at least twofold changesbetween high royal jelly producing bees and low royal jelly producing bees werescreened for analysis following methods described previously . The PCRmix  consisted of 2 \u03bcL of 250 ng/\u03bcL cDNA template, 10 \u03bcLTHUNDERBIRD SYBR qPCR Mix , 1 \u03bcL of 10 \u03bcM forwardprimer, 1 \u03bcL of 10 \u03bcM reverse primer and 6 \u03bcL of nuclease-free water. Thereactions were run as follows: 95 \u00b0C for 1 min, 40 cycles of 15 s at 95 \u00b0C and45 s at 60 \u00b0C. GAPDH  was used as an internal control gene because of its stableexpression level in the heads of honey bees  software . IndepenTableS4). Amongst these modulated genes, 201(54.47%) were up-regulated, whereas 168 (45.53%) were down-regulated in highroyal jelly producing bees. Hierarchical clustering analysis showed that fourhigh royal jelly bee colonies were clustered, and the other four low royal jellybee colonies were clustered, indicating that the samples used for microarray arereliable , 35 nutrient anabolic pathways and seven protein processes andmodifications (TableS5).We mapped DEGs to the reference canonical pathways in KEGG to identify thebiological pathways that participate in royal jelly production. They wereinvolved in 46 KEGG metabolic pathways, including 4 signalling pathways(hex71) (GI: 149939402);hypothetical protein LOC726515 (LOC726515) (GI: 110759535); similar to lethal(1) G0168 CG33206-PA, isoform A (LOC411348) (GI: 110750767); similar toSHC-adaptor protein CG3715-PA (LOC412172) (GI: 66520065); similar to CG1998-PA,transcript variant 1 (LOC409360) (GI: 110749006); similar to LDLa domaincontaining chitin binding protein 1 CG8756-PD, isoform D, transcript variant 1(LOC551323) (GI: 110760992) and similar to multidrug resistance-associatedprotein 5 (LOC413947) (GI: 66538119). As they were significantly up-regulated inhigh royal jelly producing bees, these genes could play an important role inroyal jelly production of Apis mellifera.Ten genes were randomly selected for confirmation using qRT-PCR to verify theaccuracy of the identification of the DEG in the chip data. The 10 genes weresignificantly up-regulated in high royal jelly producing bees via qRT-PCRanalysis , which wIn this study, 369 DEGs were identified between high royal jelly producing bees andlow royal jelly producing bees using chip analysis. The KEGG pathway of 201up-regulated genes in the high royal jelly producing bees were involved in proteinsynthesis , amino acid metabolism, nucleotide and fatty acid metabolism , sugar metabolism , signal transduction, oxidation, transporter (ABC transporters). Thissuggests that repeated selection pressure for high royal jelly production hasaffected different pathways.Compared to the proteome data on hypopharyngeal gland development comparing Italianand royal jelly producing worker honeybees , and is decreased whennurse bees become forage bees (18 to 28 days old) family. Ammonia transport across biological membranes is a critical feature ofnitrogen metabolism, and Amt plays an important role in olfactory signalling  and HSP60 (GI: 110763844) were also up-regulated in the high royal jellyproducing bees. HSPs function as binding proteins and molecular chaperones andassist in the folding and processing of new proteins. Several heat shock proteinsare expressed in the early development of hypopharyngeal glands in adult workerhoney bees, and these proteins reach their peak expression levels between the age of6 and 12 days (In this study, we measured the production of royal jelly in high royal jellyproducing bees and low royal jelly producing bee, putting in evidence a significantdifference between the two groups. A total of 369 DEGs were identified between highroyal jelly producing bees and low royal jelly producing bees using a cDNAmicroarray. These DEGs are involved in 46 pathways. This is first comprehensivetranscriptome database revealing genes that are differentially expressed betweenhigh royal jelly bees and low royal jelly bees. Our results provide new insightsinto the molecular mechanism of royal jelly secretion and also serve as an extensivenovel resource for screening molecular markers to accelerate molecular breeding ofhigh royal jelly bees."}
+{"text": "Problems such as heterogeneity of the ribosomal operon and the inability to differentiate closely related phytoplasma strains has motivated the search for additional markers capable of providing finer differentiation of phytoplasma strains. In this study we developed and validated a scheme to classify phytoplasmas based on the use of cpn60 universal target (cpn60 UT) sequences. Ninety-six cpn60 UT sequences from strains belonging to 19 16Sr subgroups were subjected to in silico RFLP using pDRAW32 software, resulting in 25 distinctive RFLP profiles. Based on these results we delineated cpn60 UT groups and subgroups, and established a threshold similarity coefficient for groups and subgroups classifying all the strains analysed in this study. The nucleotide identity among the reference strains, the correspondence between in vitro and in silico RFLP, and the phylogenetic relationships of phytoplasma strains based on cpn60 UT sequences are also discussed.Phytoplasmas are unculturable, phytopathogenic bacteria that cause economic losses worldwide. As unculturable micro-organisms, phytoplasma taxonomy has been based on the use of the 16S rRNA-encoding gene to establish 16Sr groups and subgroups based on the restriction fragment length polymorphism (RFLP) pattern resulting from the digestion of amplicon ( Mollicutes, derived from an Acholeplasma-like ancestor , proposed the provisional genus \u2018Candidatus Phytoplasma\u2019  RFLP as an alternative to the actual (in vitro) RFLP, along with the development of the interactive online phytoplasma classification tool iPhyClassifier, increased the accuracy of phytoplasma classification based on 16S rRNA gene sequences  operon, tuf, rplV (rpl22)\u2013rpsC (rps3), secY, map, uvrB\u2013degV, nusA, secA, and rpoB genes have been used to identify and characterize phytoplasmas  (rpoB (tuf (cpn60 gene sequences (500 to 550 bp), have been useful to identify novel species such as Lactobacillus selangorensis   from the major groups of phytoplasmas  . All the genomes , genes ecpn60 UT sequences with seven endonucleases. This new classification scheme, besides being phylogenetically valid, allowed a finer differentiation of phytoplasma strains inside the same 16Sr RFLP subgroups, with the identification of cpn60 UT groups and subgroups.In this study, following the strategy previously used in the phytoplasma classification scheme based on the 16S rRNA gene, we suggest a complementary, coherent system to classify phytoplasmas based on RFLP analysis of cpn60 UT sequences were retrieved from the cpnDB , and one sequence from Cyanobacteria used as outgroup, were aligned with clustal x version 1.63b . Aligning nucleotides 1\u201358 of all phytoplasma sequences and displaying them using Weblogo  operon . After comparing the RFLP patterns obtained for each strain, we detected 25 different RFLP patterns from 19 16Sr subgroups, which points to the increased diversity observed using cpn60 UT as an additional marker to differentiate phytoplasmas. The highest diversity was detected inside the 16SrI group. We detected two cpn60 RFLP profiles among the strain members of the 16SrI-A subgroup and six distinctive RFLP profiles within the members of the 16SrI-B subgroup, while for the rest of the subgroups we detected only one cpn60 RFLP pattern for each corresponding 16Sr subgroup. The virtual 4\u2009% agarose gel electrophoresis patterns observed for each of the 25 reference strains detected in this study are presented in Since the development of the first coherent scheme to differentiate phytoplasmas, the use of RFLP has contributed to an understanding of phytoplasma diversity and has been used to differentiate strains that are phylogenetically closely related. This strategy has been used not only with the 16S rRNA gene, but also with cpn60 UT-based subgroups. To maintain consistency with the established nomenclature based on the 16S rRNA-encoding gene, we named the strains from group 16SrI as cpn60 UT I, 16SrII as cpn60 UT II, and so on. To name subgroups, for example the 16SrI-B, which had until now six different RFLP patterns among strains, we named the cpn60 UT subgroups as cpn60 UT I-IB, cpn60 UT I-IIB, cpn60 UT I-IIIB, (\u2026), cpn60 UT I-VIB. All 96 strains analysed in this study were reclassified based on their cpn60 UT RFLP patterns (Table S1).Based on the RFLP patterns observed, we separated the strains into cpn60 UT groups and subgroups, we calculated the similarity coefficients (F) among the 25 reference strains with unique RFLP patterns. We used the formula F=2Nxy / (Nx+Ny)  , where Ncpn60 UT group varied from 0.97 to 0.62, while F values lower than 0.62 belonged to strains classified in a different cpn60 UT group (cpn60 UT subgroups inside the cpn60 UT I-A group (cpn60 UT I-IA and cpn60 UT I-IIA), and six subgroups inside the cpn60 UT I-B group (cpn60 UT I-IB to cpn60 UT I-VIB). We suggest 0.97 as the threshold similarity coefficient to delineate new subgroups based on the use of the seven endonucleases previously mentioned, while 0.60 can be considered as the threshold similarity coefficient to delineate new groups. The threshold to delineate new cpn60 UT subgroups (0.97), corresponds with the threshold to delineate new 16S rRNA gene subgroups (The similarity coefficients among the 25 reference strains are shown in UT group . Based ocpn60 UT I-IA is represented by Brassica spp. phytoplasma strain AY-Ruta (GenBank accession no. KJ940011), and cpn60 UT I-IIA is represented by Grey dogwood stunt phytoplasma strain GD (GenBank accession no. AB599694). The subgroup cpn60 UT I-IB is represented by Linum usitatissimum phytoplasma strain SF1 (GenBank accession no. KJ940013); cpn60 UT I-IIB is represented by Aster yellow phytoplasma strain AY-J (GenBank accession no. AB599689); cpn60 UT I-IIIB and cpn60 UT I-IVB are represented by Maize bushy stunt phytoplasma, strains MBS-Ver (GenBank accession no. KT444673) and MBS-Pueb (GenBank accession no. KT444672), respectively. Subgroup cpn60 UT I-VB is represented by Iceland poppy yellows phytoplasma strain IPY (GenBank accession no. AB242234), and the subgroup cpn60 UT I-VIB is represented by Eggplant dwarf phytoplasma strain ED (GenBank accession no. AB242231). Subgroup cpn60 UT I-IC is represented by Aster Yellow phytoplasma strain AY-Col (GenBank accession no. KJ939994); cpn60 UT I-IE is represented by Blueberry stunt phytoplasma strain BbSP (GenBank accession no. KU523402); cpn60 UT I-IF is represented by Apricot chlorotic leafroll phytoplasma strain AY-A (GenBank accession no. AB599699); and cpn60 UT I-IP represented by Populus decline phytoplasma strain PopD (GenBank accession no. AB599710).Subgroup cpn60 UT II, V, VII, and XIII, we only had strains from one subgroup, so we were not able to detect more than one RFLP pattern. The subgroup cpn60 UT II-IA is represented by Peanut witches\u2019-broom phytoplasma strain PnWB (GenBank accession no. NZ_AMWZ00000000); subgroup cpn60 UT V-IA is represented by the Flavescence doree phytoplasma strain FD (GenBank accession no. KJ939992); the subgroup cpn60 UT VII-IA, on the other hand, is represented by Ash Yellow phytoplasma strain AshY (GenBank accession no. KJ939978). Subgroup cpn60 UT IX-IH and cpn60 UT IX-IB are represented by Catharanthus roseus phoenicium phytoplasma strain Cr (GenBank accession no. KJ939989) and Almond witches\u2019-broom strain SA213 (GenBank accession no. KND62606), respectively. Inside the group cpn60 UT X, we were able to differentiate members of the subgroups cpn60 UT X-IA, represented by Apple proliferation phytoplasma (GenBank accession no. KJ939977), members of the subgroup cpn60 UT X-IC represented by Pear decline phytoplasma strain 12MG305 (GenBank accession no. KJ940000), and members of the subgroup cpn60 UT X-IF represented by the European stone fruit phytoplasma strain ESFY (GenBank accession no. KJ940007). Inside the group cpn60 UT XII we identified two subgroups, subgroup cpn60 UT XII-IA, represented by Bois noir phytoplasma strain BN44948 (GenBank accession no. KJ939979), and subgroup cpn60 UT XII-IB, represented by Strawberry lethal yellow strain AT (GenBank accession no. NC_011047). Subgroup cpn60 UT XIII-IA was represented by Mexican periwinkle virescence strain MPV-S83 (GenBank accession no. KT444668). Finally, we identified two subgroups inside the group cpn60 UT XIV, subgroup cpn60 UT XIV-IA, represented by Bermuda white leaf phytoplasma strain AL85/11 (GenBank accession no. KF383984), and subgroup cpn60 UT XIV-IC represented by Bermuda white leaf phytoplasma strain RS59/11 (GenBank accession no. KF383985).Inside the groups cpn60 UT-subgroups. Subgroups from the group cpn60 UT I can be differentiated through the use of AluI, MseI and RsaI . Moreover, we observed correspondence between the in silico and in vitro RFLP for 12 phytoplasma strains representing the three major phylogenetic subclades into which phytoplasmas are grouped [ algorithm available in the mega6 software package (cpn60 UT groups and subgroups, supporting the results obtained through the RFLP analysis, the calculation of F value and the nucleotide identity among the reference strains. Phylogenetic analysis of cpn60 UT sequences showed a better resolution of the subgroup B, identified inside the group cpn60 UT I (cpn60 UT XII (Phylogenetic analysis of  package  and amin package  sequencen60 UT I , while t0 UT XII .cpn60 UT sequences to act as an additional marker to differentiate phytoplasmas. Strains that are closely related based on 16S rRNA gene sequence classification were differentiated as members of new subgroups, contributing to a better identification of the strains. Previous studies mentioned a high nucleotide similarity between the cpn60-encoding genes amplified from members of the 16SrI-B subgroup(The present study confirms previously published work  showing cpn60 is present in a single copy in the phytoplasma genome, which obviates the taxonomic complications related with the occasional presence of heterogeneous ribosomal operons (cpn60 do not tend to invade cells (cpn60 UT among the additional markers used to characterize phytoplasma strains will improve the understanding of phytoplasmas. This study, supported by the cpnDB (cpn60 UT sequence amplified from phytoplasmas.Protein-encoding genes are known to provide a better strain resolution compared to rRNA-encoding genes . Unlike de cells , so phyt"}
+{"text": "Sharpincpdm/cpdm) mice display multi-organ inflammation and chronic proliferative dermatitis (cpdm) due to TNF-induced keratinocyte apoptosis. In cells, SHARPIN also inhibits integrins independently of LUBAC, but it has remained enigmatic whether elevated integrin activity levels in the dermis of Sharpincpdm/cpdm mice is due to increased integrin activity or is secondary to inflammation. In addition, the functional contribution of increased integrin activation to the Sharpincpdm/cpdm phenotype has not been investigated. Here, we find increased integrin activity in keratinocytes from Tnfr1-/-Sharpincpdm/cpdm double knockout mice, which do not display chronic inflammation or proliferative dermatitis, thus suggesting that SHARPIN indeed acts as an integrin inhibitor in vivo. In addition, we present evidence for a functional contribution of integrin activity to the Sharpincpdm/cpdm skin phenotype. Treatment with an integrin beta 1 function blocking antibody reduced epidermal hyperproliferation and epidermal thickness in Sharpincpdm/cpdm mice. Our data indicate that, while TNF-induced cell death triggers the chronic inflammation and proliferative dermatitis, absence of SHARPIN-dependent integrin inhibition exacerbates the epidermal hyperproliferation in Sharpincpdm/cpdm mice.SHARPIN (Shank-Associated RH Domain-Interacting Protein) is a component of the linear ubiquitin chain assembly complex (LUBAC), which enhances TNF-induced NF-\u03baB activity. SHARPIN-deficient ( Sharpincpdm/cpdm) display progressive multi-organ inflammation, which most prominently manifests with chronic eosinophilic hyperproliferative dermatitis characterized by skin thickening, keratinocyte hyperproliferation and severe inflammation  supplemented with 10% fetal bovine serum (FBS)  or isotype IgG control antibody. Theamount of cells) in each well was quantified with Cell Proliferation Reagent WST-1  according to the manufacturer\u2019s instructions and a BioTek Synergy H1 Hybrid Multi-Mode Microplate Reader. The relative proliferation was calculated by normalizing the amount of cells in each time point to day zero  or by su\u00ae Ultra filter centrifugation and directly conjugated to Alexa Fluor 647 with APEX\u00ae antibody labelling kit (Thermo Fischer Scientific). Cells were fixed with 2% paraformaldehyde in PBS for 10 min at RT, after which they were centrifuged and washed with cold Tyrodes buffer . The cells were stained with directly fluorochrome-conjugated antibodies  in 100 \u03bcl Tyrodes for 30 min RT, washed with Tyrodes and resuspended in PBS. Filtered cells were analysed using BD LSRFortessa (BD Biosciences) and FlowJo analysis software (Tree Star).The active conformation specific Itgb1 antibody  was concentrated with an AmiconProtein content in primary mouse keratinocytes was analysed by immunoblotting using standard western blotting techniques and the Odyssey LICOR imaging system.All statistical analyses were performed using GraphPad Prism . Normal distribution was assumed for the data and unpaired Student's t-test was used for all experiments. A p < 0.05 was considered significant.S1 FigSharpin+/+, Sharpin+/- and Sharpincpdm/cpdm mice, as well as mouse embryonic fibroblast (MEF). Keratinocyte isolation purity was evaluated by measuring the Krt14/vimentin ratio, normalized to GAPDH, with MEFs serving as a control fibroblast cell line. Molecular weight markers are indicated (KDa). All numerical data are mean \u00b1 s.e.m. Scale bars represent 20 \u03bcm. FACS analysis (A) and quantification (B) of active Itgb1  labelling specificity compared to isotype IgG control  in primary mouse keratinocytes using AlexaFluor647 conjugated anti-rat secondary antibody. Samples were analyzed by flow cytometry at SSC/FSC and APC-A channels, and background fluorescence was subtracted before normalization to Isotype IgG . (C) Quantification of dermal skin thickness from skin sections similar to those depicted in (TIF)Click here for additional data file.S2 FigSharpin+/? and Sharpincpdm/cpdm mice treated with PBS (control) or anti-Itgb1 (Itgb1 function blocking antibody). (A) Quantification of immune cell populations from peripheral blood. WBC, white blood cells; LUC, large unstained cells.  Representative skin sections stained for Tnf and nuclei (DAPI) (B) and quantification of dermal Tnf levels (C) . Dotted line marks the basement membrane. All numerical data are mean \u00b1 s.e.m. Scale bars represent 20 \u03bcm.Experiments show data from (TIF)Click here for additional data file."}
+{"text": "Targeting CD38, a common blood cell membrane receptor highly expressed on many B- and T-cell cancers, has achieved significant clinical activity with an acceptable safety profile in multiple myeloma (MM). Specifically, daratumumab (dara) was the first naked CD38 monoclonal antibody (mAb) approved for the treatment of relapsed and refractory MM (RRMM) in 2015. Importantly, it induces high response rates in two phase III trials in RRMM when combined with bortezomib or lenalidomide plus dexamethasone [Isatuximab (Isa), a novel humanized IgG1-kappa CD38 mAb targeting a completely different epitope in CD38 molecule than dara, achieves significant responses when combined with lenalidomide and dexamethasone in heavily pretreated patients with RRMM . Isa, liSince CD38 is widely expressed on hematopoietic cells, it is crucial to study how isa impacts on various CD38-expressing subsets to influence clinical responses. We recently defined the effects of isa on myeloma-supporting osteoclasts (OCs) and immune cell subsets in the bone marrow microenvironment , 5. BesihighFoxp3+) when compared with conventional T effector cells  [high subsets are defined in Tregs versus Tcons, associated with significantly enhanced CD38 targeting by isa on Treg vs Tcon. As seen in CD38high MM cells, isa preferentially targets Tregs vs Tcon via triggering apoptosis and decreasing proliferation   are defined within bone marrow (BM) more distinctly than peripheral blood (PB) in MM patients [high subsets, which were rapidly depleted by dara in a recent correlative study [In addition to Treg, we found that B regulatory cells (Bregs) also express significantly higher CD38 when compared with normal T, B, NK, and monocytes . Importapatients . MM Bregve study .It remains to be determined whether differential effects of isa on Tregs vs Tcons can improve its therapeutic window. Nevertheless, early results from ongoing phase III dara-based combination trials in newly diagnosed MM patients whose immune function are relatively more intact than RRMM demonstrate significantly improved overall response rate and progression-free survival . Such un"}
+{"text": "The mortality due to cardiogenic shock complicating acute myocardialinfarction (AMI) is high even in patients with early revascularization.Infusion of low dose recombinant human brain natriuretic peptide (rhBNP) atthe time of AMI is well tolerated and could improve cardiac function. The objective of this study was to evaluate the hemodynamic effects of rhBNPin AMI patients revascularized by emergency percutaneous coronaryintervention (PCI) who developed cardiogenic shock.\u22121 min\u22121 for 72 hours. A total of 48 patients with acute ST segment elevation myocardial infarction(STEMI) complicated by cardiogenic shock and whose hemodynamic status wasimproved following emergency PCI were enrolled. Patients were randomlyassigned to rhBNP (n=25) and control (n=23) groups. In addition to standardtherapy, study group individuals received rhBNP by continuous infusion at0.005 \u00b5g kg Baseline characteristics, medications, and peak of cardiac troponin I (cTnI)were similar between both groups. rhBNP treatment resulted in consistentlyimproved pulmonary capillary wedge pressure (PCWP) compared to the controlgroup. Respectively, 7 and 9 patients died in experimental and controlgroups. No drug-related serious adverse events occurred in either group. When added to standard care in stable patients with cardiogenic shockcomplicating anterior STEMI, low dose rhBNP improves PCWP and is welltolerated. Despite this progress,cardiogenic shock continues to be associated with a high short-term mortalityrate.Vasopressors and inotropes are used to improve the hemodynamic status, but theinformation about comparative effective outcomes is limited; indeed, some of themcould induce decreased survival rate that may be associated with the deleteriouscellular effects of these drugs,7.Cardiogenic shock complicates 6-10% of all ST segment elevation myocardial infarction(STEMI) cases and remains a leading cause of death, with hospital mortality ratesapproaching 50%,9. BNP can act via the natriuretic peptide receptorA/guanylyl cyclase/cyclic guanosine monophosphate (cGMP) signaling pathway,maintaining cardio-renal homeostasis through diuresis, natriuresis, vasodilation,and inhibition of aldosterone synthesis and renin secretion under physiological andpathological conditions. Interestingly, exogenous BNP infusion may result incoronary vasodilatation with reduced myocardial oxygen consumption, enhanced myocardialrelaxation, suppressed synthesis and release ofaldosterone, induced vascular regeneration, delayed adrenergicactivation and inhibited cardiac fibroblast collagen synthesis-17.B type natriuretic peptide (BNP), released due to altered chamber loading and myocytestretch, has been detected in acute myocardial infarction (AMI). Low-dose rhBNP administration could avoid hypotensionin patients with cardio-renal disease. Indeed, Brunner-La Rocca etal. havereported that in humans withheart failure, low-dose rhBNP suppresses the adrenergicoutflow without hypotension. Chen et al. reported that 72 hours of infusion of low-doserhBNP at the time of anterior AMI is well tolerated, and may suppress aldosteroneand preserve ventricular function and structure in patients with anterior AMI.rhBNP (Recombinant human brain natriuretic peptide) was approved by the U. S. Foodand Drug Administration (FDA) for the management of acute decompensated heartfailure in 2001. Recently, a small study showed that rhBNP, given soon after AMI,induces a trend towards favorable ventricular remodeling, but blood pressure waslower with rhBNP over the first 8-12 hours of infusion without clinicallysignificant hypotensionThere are currently no reports on low-dose rhBNP administration in patients withcardiogenic shock complicating STEMI after successful early revascularization. Weproposed a pilot study to evaluate the safety and efficacy of low dose rhBNP in thesetting of STEMI complicated with cardiogenic shock. This study was designed toevaluate the hemodynamic, neuro-hormonal, and renal effects of rhBNP given as a72-hour infusion to AMI patients revascularized by emergency PCI who developedcardiogenic shock, but were stable after appropriate medical intervention.th People'sHospital, China, with cardiogenic shock complicating a first anterior AMI fromMarch 2009 to March 2013. Patients were eligible for the trial if they presentedwith: (1) anterior STEMI complicated by cardiogenic shock; (2) successful earlyrevascularization performed with stable hemodynamic status in the 1sthour post-intervention. Anterior STEMI was diagnosed by the following criteria:prolonged chest pain >30 minutes; positive troponin I; ST-segment elevation 2mv in two or more adjacent anterior precordial leads. A patient was consideredto be in cardiogenic shock if: (1) systolic blood pressure was less than 90 mmHgfor more than 30 minutes or catecholamine infusion was required to maintain asystolic pressure above 90 mmHg; (2) clinical signs of pulmonary congestion werepresent; or (3) there was evidence of impaired end organ perfusion. Thediagnosis of impaired end organ perfusion required at least one of thefollowing: altered mental status; cold, clammy skin and extremities; oliguriawith urine output of less than 30 ml per hour; serum lactate level higher than2.0 mmol per liter. All patients got successful revascularization  and intra-aortic balloon pump (IABP) support within 24hof onset of chest pain, were enrolled, and sent to Coronary Care Unit forhemodynamic monitoring.The study group included patients admitted to Shanghai 62; previous knownintolerance history to rhBNP.Exclusion criteria were: SBP < 90 mmHg within first hour post-interventionalthough 12 mg/kg \u00d7 min dopamine and 1:1 IABP supporting; pulmonarycapillary wedge pressure (PCWP) < 18 mmHg; acute inferior, posterior andright ventricle myocardial infarction; previous history of myocardialinfarction; previous eletrocardiograma (ECG) suggesting an old myocardialinfarction; previous history of chronic heart failure or decreased leftventricular ejection fraction (LVEF); hypertrophic cardiomyopathy;hemodynamically significant mitral regurgitation; other hemodynamicallysignificant valvular or congenital heart diseases; estimate glomerularfiltration rate (eGFR) < 15 mL/min per 1.73 mth People's Hospital.Documented informed consent was obtained from each patient or his/herguardian.This was a randomized , open-label, parallel group study.Patients were assigned to rhBNP or control group at a 1:1 ratio. The primaryendpoints were absolute changes in PCWP from baseline to 72 hours afterrandomization compared to the control group. Secondary endpoints includedcomparisons between rhBNP and control groups of the following hemodynamic andclinical effects: cardiac index, in hospital mortality, 72 hours urine output,and safety profile . The trial protocol wasapproved by the ethics committee of Shanghai 6Each patient was monitored hemodynamically using a pulmonary artery Swan-Ganzthermodilution catheter (bedside chest X-ray was done to check its position).Arterial blood pressure was measured with IABP. Baseline heart rate, bloodpressure, right atrial pressure (RAP), PCWP and cardiac index (CI) were recordedthree times within a 5 minutes period using the bedside patient monitor.Measurements were carried out by another research team member blinded totreatment allocation. Additional measurements were performed 15 min and then 3,24, 48 and 72h after starting drug administration. Echocardiography wasperformed immediately after operation and read in random order with no patientidentifiers.-1min-1 without aloading dose. The infusion dosage was decreased to 0.003 mgkg-1min-1 if SBP < 85 mmHg more than 20 minutesdespite dopamine titration. If symptomatic hypotension or systolic bloodpressure < 75 mmHg occurred, rhBNP infusion was interrupted for 30-60 minutesand the dosage of dopamine increased. rhBNP treatment would restart at 0.003 mgkg-1min-1 when the dose-limiting event had resolved.Infusion of rhBNP was discontinued for recurrent symptomatic hypotension;sustained hypotension despite rhBNP dosage decrease to 0.003 mgkg-1min-1 or dopamine dosage increase to more than 12mg kg-1min-1.All the patients were given dopamine (3-12 mg/kg \u00d7 min) after diagnosis ofcardiogenic shock, at dosage adjusted to achieve a satisfactory blood pressure(SBP < 90 mmHg). Patients with stable blood pressure (SBP < 90 mmHg)within 1 hour post-intervention were enrolled and randomized. In the rhBNPgroup, rhBNP treatment was initiated after randomization for 72 hours with acontinuous infusion of 0.005 mg kgIn addition to standard medical treatment, dobutamine and norepinephrine werepermitted for intractable hypotension and pump failure based on investigator'sclinical judgment. Statin, aspirin and clopidogrel were given before emergencyPCI. IIb/IIIa receptor antagonist (Tirofiban) was administered during theprocedure and next 24 hours according to the physician's judgment. Enoxaparinwas given from 6 to 72 hours after emergency PCI. Low dose of angiotensinconverting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) aswell as beta-blocker therapy were started 24h after randomization if patientstolerated. Blood for measurement of N-terminal brain natriuretic peptide(NT-proBNP), BNP, cGMP and creatinine levels was drawn before the initiation ofIV rhBNP, then at 72 hours and 1 week after randomization.. We calculated that asample size of 21 patients would be needed in each group for a statistical powerof 80% at significance level of 0.05 (with a two-sided t-test).We postulated an expected change of PCWP as -3.8 mmHg from Vasodilation in theManagement of Acute Congestive Heart Failure (VMAC) studyP <0.05 wasconsidered statistically significant.Data were statistically processed and analyzed using the Statistical Package forthe Social Sciences (SPSS) 16.0 software package. Descriptive statistics werepresented as mean\u00b1standard deviation for continuous data and aspercentages for categorical data. Analyses of continuous data were performed bytwo-sample t-test and categorical data by Chi-Square test. One way analysis ofvariance (ANOVA) was used to evaluate the differences among groups aftertreatment. The changes in renal function from baseline to after drugadministration were analyzed by paired t-test. 2 (n=2) or significant mitral valve regurgitation(n=1).A total of 65 patients were screened, of whom 17 were excluded because of hypotension(n=8), death before randomization (n=3), PCWP < 18 mmHg (n=3), eGFR < 15mL/min per 1.73 mA total of 16 patients died in hospital. In the rhBNP group, 5 patients died within72h of randomization , and 1 patient died at each day 4 (cardiac rupture) and 10(pump failure) after randomization. In the control group, 8 patients died within 72hafter randomization [pump failure (n=5); MSOF (n=2); ventricular fibrillation(n=1) and 1 died at day 6 (pump failure). These findings indicated that there was nosignificant difference in in-hospital mortality between the two groups . No re-infarctions or cerebrovascular accidents were observed ineither group.-1min-1 in 3 patients because ofasymptomatic hypotension. In 2 patients of the study group, rhBNP infusion wasdiscontinued for symptomatic hypotension, which resolved with no clinicalconsequences after infusion was stopped. The 72h urine volume after randomizationshowed no statistically significant difference between these two groups .Hemodynamic characteristics at 3 and 72h after randomization were analyzed in livepatients . After rAs shown in ,17,20-22. Recently, a large multicenter clinicaltrial using atrial natriuretic peptide (ANP) at the time of myocardial reperfusionwith AMI was reported that ANP (carparitide) could reduce infarct size, improveejection fraction and decrease the rate of new-onset heart failure. Meta-analysis suggestedthat ANP/BNP infusion might be effective in protecting left ventricular function inpatients with AMI. Thus natriuretic peptides (ANP and BNP) seem to belogical adjuncts to standard care for the treatment of AMI. Additionally, BNP hasproven effects on acute decompensated heart failure, and should not decrease bloodpressure at low dose,15. Therefore, wehypothesized that BNP would be safe and effective for the treatment of STEMIpatients with cardiogenic shock. In this study, 48 patients with cardiogenic shockcomplicating anterior STEMI, successful emergency PCI, and stable hemodynamic statuspost intervention were enrolled. The major findings of this study are: (1) incomparison with controls, administration of low-dose rhBNP for 72 hours isassociated with PCWP reduction; (2) low dose rhBNP treatment is unlikely to belimited by hypotension in this clinical setting; (3) low dose rhBNP does notsignificantly affect the renal function. Patients with STEMI complicated bycardiogenic shock can benefit from the hemodynamic effects of rhBNP. On the otherhand, the long-term benefits of remodeling inhibition and cardio-protection need tobe confirmed by further studies. Mortality in this study was lower than whatreported for the SHOCK trial. In this work, patients who remained unstable afteremergency PCI were excluded,which may explain the discrepancy.Animal and clinical studies have shown that BNP infusion limits infarct size,improves cardiac remodeling and protects cardiomyocytes-26. In our hospital,emergency PCI is the first choice for these patients. IABP was the most widely usedform of mechanical hemodynamic support in this clinical setting at the time of thepresent trial. In the current U.S. and European guidelines, IABP in the treatment ofcardiogenic shock is still given IIa and IIb recommendations, respectively, althoughrecent clinical trials showed IABP use does not significantly reduce the 30-daymortality rate in these patients-28.Mechanical left ventricular assist devices (LVADs) have been used in cardiogenicshock patients not responding to standard therapy, but evidence regarding theirbenefits is limited. In this study, all patients were submitted to emergency PCI andIABP support, and no LVADs were used. The Sepsis Occurrence in Acutely Ill Patients(SOAP) II study was published during the early phase of this trial, with a subgroupanalysis showing that dopamine, as compared with norepinephrine, was associated withincreased mortality rate at 28 days in patients with cardiogenicshock.However, dopamine is still given a IIa recommendation for AMI patients with CS inthe current European Society of Cardiology STEMI guideline. Here, norepinephrine anddobutamine were permitted for intractable hypotension and pump failure. All studypatients were treated by the same medical team, to limit biases.In the American College of Cardiology/American Heart Association and European Societyof Cardiology guidelines for STEMI, emergency revascularization by PCI or CABG forthe cardiogenic shock complicating AMI is given a class IBrecommendation-1min-1) might be detrimentalto renal function in patients with acute decompensated heartfailure;meanwhile, the multicenter randomized control trial Acute Study of ClinicalEffectiveness of Nesiritide and Decompensated Heart Failure (ASCEND-HF) confirmedits renal safety. Recently, a small study reported that low-dose rhBNPimproves renal function in heart failure patients following AMI. We demonstrated hereinthat renal function before and after treatment was similar between both groups.The effect of rhBNP on renal function is controversial. A meta-analysis showed thatstandard rhBNP dose (0.01 mg kg showed no evidence thatnesiritide increases urine output in patients with acute decompensated heartfailure. Here, we found no evidence that rhBNP increases urine output in thecardiogenic shock patients assessed.BNP is a biologically active hormone affecting diuresis and natriuresis. However,increased urine output with physiological and common pharmacological doses of rhBNPhas been proven only in normal individuals. The ASCEND-HF trial. Based on our results, further clinicaltrial could be planned on rhBNP treatment for AMI patients with or withoutcardiogenic shock.Some small scale clinical trials suggested rhBNP infusion might protect leftventricular function in patients with AMI, but there is no randomized clinical trialwhich with large sample on these patientsWhen added to standard care in stable patients with cardiogenic shock complicatinganterior STEMI, low dose of rhBNP improves PCWP and is well tolerated.-1min-1 after randomization.Further adequately powered trials are needed to test the short and long-termbenefits of rhBNP infusion in this clinical setting.This was a small open control randomized pilot study. There was no clinical data forPCWP changes after 72h infusion of low dose rhBNP, so we postulated an expected PCWPchange of -3.8 mmHg as shown in the VMAC study, which was designed with 3 hoursrhBNP infusion at 0.01 mg kg"}
+{"text": "Left ventricular systole involves coordinated contraction of longitudinal, circumferential, and radial myocardial fibers. Longitudinal fiber dysfunction appears to be an early marker for a number of pathological states. We hypothesized that reduced mitral annular plane systolic excursion (MAPSE) measured during cine-Cardiac Magnetic Resonance (CMR) imaging reflects changes in longitudinal fiber function and may be an early marker for adverse cardiovascular outcomes.400 consecutive patients with known or suspected coronary artery disease undergoing CMR were prospectively enrolled. Lateral MAPSE was measured in the 4-chamber cine view by two independent observers. Patients were prospectively followed for major adverse cardiac events (MACE) - death, non-fatal myocardial infarction, hospitalization for heart failure or chest pain, and late revascularization. Cox proportional hazards regression modeling was used to identify factors independently associated with MACE.The mean age of the study population was 58\u00b1 15) years, with a mean ejection fraction of 59(\u00b1 14%). 31% of the individuals had known coronary artery disease and 33% were diabetic. 72 MACE occurred during a median follow-up of 14.5 months. By Kaplan-Meier analysis, patients with lateral MAPSE \u22641.11 cm (median) experienced significantly higher incidence of MACE than patients with a MAPSE >1.11 cm (p = 0.0270) (Figure 5 years, Longitudinal fiber dysfunction assessed with lateral MAPSE during cine-CMR is an independent predictor of MACE in patients with known or suspected coronary artery disease."}
+{"text": "Pol regions including whole protease and partial reverse transcriptase (RT) were amplified and sequenced to establish the profile of genotype distribution and drug resistance mutations (DRMs). Viral loads were determined using the ROCHE COBAS system. Of the 259 HIV-1 positive samples tested by the Lag-avidity assay, 23.6% (61/259) were identified as recent infections. A total of 205 amplified sequences displayed the following genotype distributions: circulating recombinant form (CRF) 07_BC (61.5%), CRF08_BC (8.3%), CRF01_AE (20%), B (6.3%), and 01B (3.9%). There was no significant difference in genotype distribution between recent and long-term infections. 31 DRMs were identified from 27 samples including four protease inhibitors (PIs) accessory DRMs, two PIs major DRMs (M46I), two nucleoside RT inhibitors DRMs (K219R and K70Q), and 23 nonnucleoside RT inhibitors DRMs. 27 samples had DRMs, yielding a drug resistance prevalence of 13.2% (27/205). Our findings provide important information for developing strategies for comprehensive HIV control and improving anti-retroviral treatment in China.The increasing complexity and diversity of the human immunodeficiency virus-1 (HIV-1) infections challenge the disease control and anti-retrovirus treatment in China. The infection stages and molecular characteristics of HIV-1 from infected Chinese blood donors were examined to shed light on the HIV genotype distribution and the status of drug resistance mutations (DRMs) in the changing HIV epidemic in China. Western blot (WB) confirmed HIV-1 positive plasma samples were collected from blood donors at five Chinese blood centers from April 16, 2012, through June 30, 2014. The HIV infection stages were determined using the Lag-avidity assay. HIV  Accordign to updated Chinese government report, by the end of 2014, there were approximately 501,000 people living with human immunodeficiency virus Type 1 (HIV-1)  and 159,000 reported HIV related deaths in China [The genotypic characteristics and profile of drug resistance mutations (DRMs) of HIV may provide substantial information to monitor trends of the viral evolution, and to optimize treatment strategy when initiating anti-retroviral treatment (ART). Understanding the genomic diversity of variant HIV strains is also critical to improve blood donor screening assays in order to prevent unknown infected donations from getting into the blood supply, especially in a rapidly evolving and changing HIV epidemic. In China, the major subtypes of HIV-1 in the general population include: circulating recombinant form (CRF) 07_BC, CRF08_BC, CRF01_AE and subtype B, while HIV-2 is seldom reported, 6. DataClassification of the HIV recent and long-term (or chronic) infection by laboratory detection of biological markers is an important tool for accurate estimation of HIV incidence. Despite the potential, unavoidable misclassifications, severalThe HIV molecular surveillance among blood donors was launched as a part of the Recipient Epidemiology and Donor Evaluation Study (REDS-III) funded by the US NHBLI since 2012. In this study, we performed multiple laboratory-based testing to determine the HIV infection stages, genotype diversity and characteristics of HIV-1 DRMs among infected blood donors from five RED-III Chinese blood centers . The implications of possible correlation between infection stages (e.g. recent/long-term infection), HIV genotypes and DRMs were investigated. Such information can be combined with data from the general Chinese population and high risk populations to help improve HIV screening strategies and safeguard the blood supply in China.This study was approved by institutional review board (IRB) of Johns Hopkins Medicine, NA_00080591/ CR00012868 From April 2012 to June 2014, a total of 265 HIV western blot (WB) confirmed positive donor samples were collected from five REDS-III blood centers: Chongqing (n = 153), Urumqi (n = 53), Liuzhou (n = 31), Luoyang (n = 17) and Mianyang (n = 11). The annual donations from five blood centers were approximately: Chongqing, 100,000; Liuzhou, 65,000; Urumqi, 40,000; Luoyang, 75,000; and Mianyang, 45,000 respectively. During the study period, approximate 90% HIV screening reactive samples underwent confirmatory testing and all available samples with confirmatory testing results from these five blood centers were included in this study. Routine parallel enzyme-linked immunosorbent assay (ELISA) screening was performed on all donations at each blood center using two of the following six assays at each center: Kehua Bio-engineering Co. Ltd. Shanghai; KINGHWAWK PHARMACEUTICAL. Inc. Beijing; Wantai Biological Pharmacy Enterprise CO., LTD., Beijing; Biomerieux., Inc., Shanghai; ZHUHAI LIVZON DIAGNOSTIC., INC., Zhuhai; Bio-Rad, Inc., Hercules, CA). ELISA screening reactive plasma samples were then collected, frozen, and stored at \u221220\u00b0C at each blood center before being shipped in batches to the Chinese Institute of Blood Transfusion (IBT) via cold chain transportation for WB confirmatory testing . Written consents from donors were obtained to have their blood samples tested for research purposes at the time of donation.The single-well LAg-Avidity EIA  was implemented to determine the HIV infection stages following the manufacturer\u2019s specification. This assay classifies HIV infection stages into recent infection and long-term infection based on avidity of HIV antibodies. It has Two methods were applied for HIV-1 RNA extraction, amplification and sequencing at IBT:pol region including the entire protease gene (297 nucleotides encoding 99 amino acids) and partial reverse transcriptase gene (the first 241 amino acids) were amplified by reverse transcription nested polymerase chain reaction (RT-nest-PCR) using previously reported method[HIV-1 RNA was extracted from 350\u03bcL of plasma using a viral RNA isolation kit  and eluted to a 75\u03bcL suspension according to the manufacturer\u2019s manual. Approximately 1022bp of the HIV-1 ed method. Both DNpol segment including the whole protease gene and partial polymerase gene was amplified. The PCR products were purified and sequenced by AB 3730 DNA Analyzer  with modules inserted in the Viroseq assay.According to the method using Abbott HIV-1 genotyping assay , the plasma samples were extracted for HIV-1 RNA and underwent RT-PCR with RNA extraction and RT-PCR modules inserted in the assay package. The length of 1302 nucleotides HIV-1 The HIV-1 viral load testing was performed using individual HIV-1 nucleic acid testing (NAT) assay . The lower limit of detection was 20 copies/ml, given by the manual of the assay.http://www.mbio.ncsu.edu/BioEdit/bioedit.html). The phylogenetic tree was built with tool of MEGA 6.06 (http://www.megasoftware.net) by the neighbor-joining method under Kimura\u2019s two parameter correction (1000 replicates). The HIV-1 reference sequences were collected from the Los Alamos database (http://www.hiv.lanl.gov) as the following (Accession Number): CRF07_BC, AF503396, JF906665, HQ215583, JQ901027, JQ901094, EF122515; CRF01_AE, AY008714, U51189, JF906597, JQ028206; CRF08_BC, AF286229, AY008717; Subtype B, K03455, U71182; Subtype 01B, KF857447, AY358072, KC183783 and SIVcpz as an outgroup X52154.Sequences were edited and aligned by BioEdit, v7.0.4.1 (http://www.hiv.lanl.gov). The DRMs were analyzed by submitting the sequences to the Stanford HIVdb Program Genotypic Resistance Interpretation Algorithm . HIVdb is an expert system that accepts user-submitted HIV-1 protease, reverse transcriptase (RT) and integrase sequences or mutations and returns inferred levels of resistance to 22 FDA-approved anti-retroviral drugs including 8 protease inhibitors (PIs), 7 nucleoside RT inhibitors (NRTIs), 4 non-nucleoside RT inhibitors (NNRTIs), and 3 integrase strand transfer inhibitors (INSTIs). The HIVdb system assigns a drug penalty score and a comment to each HIV DRM; five levels of inferred drug resisitance: susceptible, potential low-level resistance (PLLR), low-level resistance (LLR), intermediate resistance (IR), and high-level resistance (HLR) are reported based on the total score derived by adding the scores of each DRM associated with resistance to the specific drug.The HIV subtypes were then determined by subtypes reference sets from the Los Alamos HIV-1 sequence database . Chi-square tests (or Fisher\u2019s exact test if a cell in the cross table has fewer than 5 observations) were conducted on all testing outcomes by blood center, donor demographic categories, and long term vs. recent HIV infection. P<0.05 was considered statistically significant.The HIV-1 sequences in the study can be retrieved from GenBank with accession numbers from KU954560 to KU954764 pol region of HIV-1 for further genotyping and DRMs analysis; 3) 245 were available for HIV individual viral load testing. Summary of the HIV testing and analysis is displayed in Among 265 initial HIV confirmatory positive samples from blood donors enrolled in this study, 1) 259 were available for Lag-avidity testing to identify HIV infection stages; 2) 260 were available for amplification on Of 259 initial HIV confirmatory positive samples tested by Lag-avidity assay, 61(23.6%) were identified as recent infection and 198 (76.4%) as long-term infection . The recOf the 259 samples with Lag-avidity results, 55 recent infection and 179 long-term infection samples underwent viral load testing. The viral loads of recent infections  were lower than those of long-term infections (10300\u00b153062 copies/ml) at the marginal level of statistical significance (P = 0.07). The proportion of repeat donors among recent infections was higher than that of long-term infections with no statistical significance . The 12 repeat donors with recent infection were 10 whole blood donors with an average inter-donation interval of 299.4\u00b1165.1 days (from their last negative donations) and two apheresis donors with 36 and 86 days inter-donation intervals.pol region of HIV-1, 205 HIV partial pol sequences were amplified, sequenced and analyzed for HIV subtype. Among them, 177 were amplified using IBT\u2019s RT-nest-PCR procedure and 28 samples that failed to be amplified by IBT\u2019s procedure were successfully amplified using Abbott Viroseq assay  Twenty-seven samples were interpreted as having HIV-1 drug resistance (DR) with potential low-level resistance (PLLR) or above and the rate of HIV-1 DR rate was 13.2% (27/205). The characteristics of donors with DR were shown in 5 copies/ml, and 3 were repeated viral loads not detected (VLND)  . After rThe rate of HIV recent infections varied worldwide due to differences in HIV prevalence, infection risks, and the use of different laboratory detection assays. In thisIn our study, samples with recent infections bear relatively lower viral loads than those with long-term infections, perhaps because low-level viremia may appear in early primary HIV-1 infections among blood donors. The comBlood donors in this study were from regions with the highest HIV prevalence rates in China, including four blood centers located in vast western China and one (Luoyang) in central region. The most frequently observed subtypes among blood donors from western China were subtype CRF07_BC (61.5%) and CRF01_AE (20%), which was different than the HIV subtypes found in our previous REDS-II study with two major subtypes CRF08_BC (41.6%) and CRF01_AE (32.7%). Most ofThe DRMs prevalence rate reported here  was lower than the published results from other studies about Chinese blood donors or anti-retroviral-naive populations that varied from 17% to 37.8%, 39, 40.The prevalence of HIV-1 DR (13.2%) was similar to those reported in studies performed in the United States  can indicate false positive western blot results. TherefoThere are several limitations in this study including: 1) The unbalanced number of HIV infected donors from five blood centers may make it difficult to compare the status of HIV-1 genotypic distribution and DRMs between each site; 2) The length of study period and sample size were limited. More samples should be included to obtain more comprehensive profile of HIV infections among blood donors in China in our future efforts; 3) Information of the HIV infection risk factors from infected donors is limited and urgently awaited to help on illuminating the relations between HIV transmission routes, HIV-1 genotype diversity, as well as profile of HIV DRMs and drug resistance. 4) Full genome sequences of HIV strains from infected donors should be obtained to give more comprehensive HIV genomic information for genotyping and evaluation on the virus evolution. However, our results may provide an important contemporary picture of HIV infections among donors in parts of China with comparatively high prevalence of HIV infections, especially regions with increasing infection risk of MSM.In conclusion, our results on the recency rate of HIV infection among Chinese blood donors reminds us the importance of timely surveillance and update on information of HIV risk factors among donors. The increasing prevalence of HIV-1 DR among Chinese donors compared to our previous REDS-II study indicates the urgent need to improve HIV antiviral therapeutic strategy and implement comprehensive HIV control programs in China.S1 Fig(JPG)Click here for additional data file.S1 Text(PDF)Click here for additional data file.S2 Text(TXT)Click here for additional data file.S3 Text(PDF)Click here for additional data file."}
+{"text": "A 68-year-old woman was admitted in our acute cardiac care unit due to cardiogenic shock.The transthoracic echocardiography (TTE) showed severe aortic stenosis, severe leftventricle (LV) systolic dysfunction (ejection fraction 20%) and a large apical thrombus-B. We peThe case was discussed by our heart team and she was considered to be at high operativerisk . Therefore, we havedecided to implant a transcatheter aortic valve (TAVI) using an embolic protectionsystem. Aortic annulus sizing was performed intra-procedure using transoesophagealechocardiography, which also showed the apical thrombus . Firstly"}
+{"text": "P < 0.0001) positive correlation and association between PTEN and USP18 protein expression profiles in human lung cancers. Taken together, this study identified PTEN as a previously unrecognized substrate of the ISGylation post-translational modification pathway. The deconjugase USP18 serves as a novel regulator of PTEN stability. This indicates inhibition of ISGylation is therapeutically relevant in cancers.The ubiquitin-like modifier interferon-stimulated gene 15 (ISG15) is implicated in both oncogenic and tumor suppressive programs. Yet, few ISGylation substrates are known and functionally validated in cancer biology. We previously found specific oncoproteins were substrates of ISGylation and were stabilized by the ISG15-specific deubiquitinase (DUB) ubiquitin specific peptidase 18 (USP18). Using reverse-phase protein arrays (RPPAs), this study reports that engineered loss of the DUB USP18 destabilized the tumor suppressor protein phosphatase and tensin homologue (PTEN) in both murine and human lung cancer cell lines. In contrast, engineered gain of USP18 expression in these same lung cancer cell lines stabilized PTEN protein. Using the protein synthesis inhibitor cycloheximide (CHX), USP18 knockdown was shown to destabilize PTEN whereas USP18 overexpression stabilized PTEN protein. Interestingly, repression of USP18 decreased cytoplasmic PTEN relative to nuclear PTEN protein levels. We sought to identify mechanisms engaged in this PTEN protein destabilization using immunoprecipitation assays and found ISG15 directly conjugated with PTEN. To confirm translational relevance of this work, USP18 and PTEN immunohistochemical expression were compared in comprehensive lung cancer arrays. There was a significant ( Lung cancer is the most common cause of cancer death for men and women . DespitePTEN are found in only 4-8% of cases [PTEN mutations are rare in lung cancer, PTEN protein is often lost in these tumors [PTEN mRNA and PTEN protein expression in studied cancers, implying that aberrant post-transcriptional or post-translational regulators of PTEN are engaged for its repression in tumorigenesis [The phosphatase and tensin homologue (PTEN) protein is a major tumor suppressor commonly lost in multiple cancer-types . PTEN fuof cases . Even the tumors . Interesigenesis . In contigenesis . This imFVB-Usp18 knockout mice [The interferon-stimulated gene 15 (ISG15) protein was the first ULM identified and was initially identified as part of ubiquitin-stimulated immune response . Similarout mice . Thus, iThe experiments reported here indicate the PTEN tumor suppressor is a previously unrecognized target of ISGylation. Reverse-phase protein arrays (RPPAs) of lung cancer cell lines engineered with repressed USP18 expression uncovered PTEN as a potential target of the ISGylation pathway. Immunoblotting of PTEN levels in murine and human lung cancer cell lines with engineered knockdown versus overexpression of USP18 (as compared to controls) established USP18 as a regulator of PTEN protein levels and stability. Immunoprecipitation (IP) assays confirmed that ISG15 directly complexed with PTEN protein and this conjugation was attenuated by engineered overexpression of USP18. The translational relevance of this work was confirmed in human lung cancer arrays that revealed USP18 and PTEN immunostaining were positively correlated. These findings not only contribute to the understanding of the functional consequences of ISGylation, but also advance our knowledge of how PTEN is post-translationally regulated in tumorigenesis.Putative ISGylation substrates have been uncovered, however few were confirmed as direct protein targets . We prevDiverse proteins on this array were affected by USP18 knockdown. Only a small number of these proteins showed substantial differences in expression profiles between USP18 knockdown and vector controls Figure . To idenARID1A exhibits up to a 50% mutation frequency in diverse cancers [ARID1A mRNA correlates with reduced ARID1A protein levels in the majority of tumors analyzed with ARID1A mutations [PTEN mRNA and protein are altered despite genetic alterations in the PTEN gene [PTEN was mutated or altered in only ~2% of lung adenocarcinoma cases  decreased cytosolic relative to nuclear PTEN protein levels  correlation between PTEN and USP18 expression in human lung cancers  indicated the importance of PTMs in regulating PTEN in oncogenesis [In the search for novel targets of ISGylation in lung cancer, RPPAs uncovered PTEN as a previously unrecognized candidate ISG15 substrate. This extended prior work by showing USP18 regulates protein levels of the PTEN tumor suppressor. The frequent loss of PTEN at the mRNA and protein levels as compared to its infrequent mutations  associated in human lung cancers, it is not surprising that the ISGylation can affect PTEN expression in malignant tissues.Engineered loss versus gain of USP18 expression respectively decreased and increased PTEN protein levels and stability in murine and human lung cancers. Yet, manipulation of USP18 levels did not alter proteins , 17, IP proteins . Given tISG15 is known to destabilize substrate proteins through the 20S proteasome . Similartrans-retinoic [Usp18 led to development of leiomyosarcomas, but this is a strain specific effect [Ubiquitin-like pathways and specific DUBs are reported to affect both oncogenes and tumor suppressors , 39. In retinoic , 40. In retinoic , 40. We retinoic . Likewisc effect . Thus, wDifferent cellular and tumor contexts determine whether a DUB has a net oncogenic or tumor suppressive effect . For exaThis study elucidated PTEN as a new substrate of ISGylation. Additional studies are needed to delineate the precise functional consequences of this ISGylation, uncover other ISGylated substrates, and learn in which cancers USP18 exerts a net oncogenic or tumor suppressive effect. As these studies unfold, it is important to keep in mind that engineered loss of USP18 does reduce lung cancer formation in mouse models . This is why identifying an inhibitor of USP18 is an important next step in the investigations of this DUB. Likewise, it will be necessary to discover the antineoplastic effects of an inhibitor of USP18. Such an inhibitor could act as a single agent or in combination with another chemotherapeutic agent in lung and potentially other cancers.2. Cell lines were obtained from American Type Culture Collection (ATCC) except for ED1 [Murine (ED1 and LKR13) and human (HOP62 and H522) lung cancer cell lines were cultured in RPMI 1640 medium (Invitrogen) supplemented with 10% fetal bovine serum (FBS) (Thermo Scientific). 293T cells were cultured in DMEM medium (Invitrogen) supplemented with 10% FBS. Cells were cultured at 37\u00b0C in a humidified incubator with 5% CO for ED1  and LKR1 for ED1 .The plasmids pCMV-HA-ISG15, pSG5-UBE1L, pCMV2-UBCH8, and pcDNA4-USP18 were described before , 19. Fulimagej.nih.gov/ij). Antibodies used for immunoblot analyses were: anti-USP18 , anti-ISG15 , anti-\u00df-Actin , anti-GFP (Santa Cruz Biotechnology #sc-8334), and anti-PTEN . Two different antibodies were derived to recognize USP18 [Cells were washed with phosphate buffered saline (PBS) (Corning) and lysed with ice-cold Pierce RIPA Lysis and Extraction Buffer (Thermo Scientific) supplemented with Halt Protease and Phosphatase Inhibitor Cocktail (Thermo Scientific). IP reactions were completed with the Pierce HA-Tag IP/Co-IP Kit (Thermo Scientific). Proteins were resolved on SDS-PAGE before transfer to nitrocellulose membranes (Whatman). Membranes were blocked in 5% nonfat milk dissolved in Tris-buffered saline with 0.1% Tween 20 for at least 1 hour before overnight incubation at 4\u00b0C with primary antibody diluted in 5% nonfat milk or 5% bovine serum albumin. This was followed by 40 minute incubation with secondary antibody diluted in 5% nonfat milk at room temperature. Antibody binding was visualized by Luminata Forte (EMD Millipore) and quantified by ImageJ software  and reverse primer (5\u2032-CTACTTTGATATCACCACACAC-3\u2032); murine Gapdh forward primer (5\u2032-AGGTCGGTGTGAACGGATTTG-3\u2032) and reverse primer (5\u2032-TGTAGACCATGTAGTTGAGGTCA-3\u2032). Assays were performed using previously optimized methods [For qRT-PCR assays, primers were: murine  methods , 20.Lentiviral pCMV-dR8.2 dvpr and pMD2.G plasmids were purchased (Addgene). Five candidate TRC pLKO.1 lentiviral shRNAs repressing USP18 were purchased (GE Dharmacon). The different shRNA lentiviral particles used for individual USP18 knockdown experiments in murine and human cell lines were generated in 293T cells, as before . RepressED1 and HOP62 lung cancer cells with stable knockdown of USP18 were cultured on coverslips (Fisherbrand). After 24 hours, cells were washed (three times for five minutes each with PBS) and fixed with 4% paraformaldehyde (PFA) (Electron Microscopy Sciences) for 20 minutes at room temperature. Cells were washed again and permeabilized with 0.1% TritonX-100 (Fisherbrand) for 5 minutes at room temperature before blocking with 3% bovine serum albumin (PBS-BSA) for 1 hour at room temperature. Cells were incubated with a murine monoclonal antibody that recognized PTEN (Thermo Scientific #32-5800) or a murine monoclonal antibody isotype control (Biolegend #401602) diluted at 1:10 in 3% PBS-BSA and rabbit monoclonal anti-Sodium Potassium ATPase (Alexa Fluor 647) antibody (Abcam #198367) diluted at 1:100 in 3% PBS-BSA overnight at 4\u00b0C. The following day, cells were washed and incubated with a FITC-conjugated goat anti-mouse IgG secondary antibody (Thermo Scientific #F2761) diluted at 1:1000 in 3% PBS-BSA for 1 hour in the dark at room temperature. Cells were washed before mounting on coverslips (Fisherbrand) with Prolong Gold Anti-Fade Reagent with DAPI (Thermo Scientific). Fluorescence was examined using a confocal microscope (Leica Microsystems) and quantitated by using ImageJ (Fiji) software (version 2.0.0-rc-43/1.50e).RPPA analyses were performed in cell lysates from ED1 and HOP62 lung cancer cells stably transfected with vector control or with one of two individual USP18 shRNAs and subsequently analyzed in the RPPA core facility at MD Anderson Cancer Center. Samples were serially diluted and probed with 304 antibodies and arrayed on nitrocellulose-coated slides. Relative protein levels were normalized for protein loading and determined by interpolation of each dilution curve from the standard curve . NormaliExpression and mutation data for lung adenocarcinomas and expression data for normal lung tissues were obtained from public repositories of TCGA. To compare expression levels, transcripts per million units were used, which was previously found as optimal for comparing expression data from RNA sequencing .n = 507) from surgically resected lung tumors were used in this array. Immunostaining was performed on formalin-fixed paraffin-embedded sections using a Leica BOND-MAXTM automated stainer and Leica Bond Polymer Refine Detection reagents (Leica Microsystems) to detect USP18 expression using a described antibody [A lung cancer microarray was developed at MD Anderson Cancer Center. Primary non-small cell lung cancer cases (antibody , 20 and antibody . SpecifiThe Institutional Review Board reviewed and approved studies conducted with human lung cancer microarrays.t test compared differences between two studied groups. Spearman rank correlation measured the strength of association between two variables. Fisher's exact test evaluated the association between two categorical variables. Results of independent experiments were pooled to assess statistical significance. Statistical significance was defined as P < 0.05, unless otherwise noted.Two-tailed Student's"}
+{"text": "A 34-year-old man was referred to our institution after an echocardiography performed atanother center because of tachycardia , which showed heterogeneouspericardial mass infiltrating the right chambers. Thoracic computed tomography (CT) andcardiac magnetic resonance (MR) imaging were performed for more accurate assessment ofthe exact tumor location, size, and potential infiltration of other cardiac andmediastinal structures. CT  and MRi"}
+{"text": "Subsequently, attempt has been made to narrow-down identified grain size/weight metaQTLs through individual SNP- as well as haplotype-based regional association analysis. The study identified six different metaQTL regions, three of which were successfully revalidated, and substantially scaled-down along with GS3 QTL interval (positive control) by regional association analysis. Consequently, two potential candidate genes within two reduced metaQTLs were identified based on their differential expression profiles in different tissues/stages of rice accessions during seed development. The developed strategy has broader practical utility for rapid delineation of candidate genes and natural alleles underlying QTLs associated with complex agronomic traits in rice as well as major crop plants enriched with useful genetic and genomic information.Molecular mapping studies which aim to identify genetic basis of diverse agronomic traits are vital for marker-assisted crop improvement. Numerous Quantitative Trait Loci (QTLs) mapped in rice span long genomic intervals with hundreds to thousands of genes, which limits their utilization for marker-assisted genetic enhancement of rice. Although potent, fine mapping of QTLs is challenging task as it requires screening of large number of segregants to identify suitable recombination events. Association mapping offers much higher resolution as compared to QTL mapping, but detects considerable number of spurious QTLs. Therefore, combined use of QTL and association mapping strategies can provide advantages associated with both these methods. In the current study, we utilized meta-analysis approach to identify metaQTLs associated with grain size/weight in diverse Indian  However, mere detection of QTLs is usually insufficient for their utilization in crop improvement programs. This is mainly because, confidence intervals for QTLs identified primarily by QTL mapping usually span tens of map units (cM) or hundreds of genes making it difficult to introgress these large genomic regions  for genetic enhancement of elite crop varieties. Therefore, fine mapping and subsequent map-based cloning of these large QTL genomic intervals to one or few genes responsible for observed phenotypic trait variation are essential. However, fine mapping/positional cloning studies to scale-down a QTL region to candidate genes require development, maintenance and precise multi-location/year field phenotyping of large size  advanced generation back-cross and/or RIL (recombinant inbred line) mapping populations. Further, it also requires screening of thousands of mapping individuals from developed mapping populations to identify suitable recombination events within trait-associated QTL intervals. Consequently, fine mapping of these QTLs into potential genes influencing phenotypic trait variation in crop plants requires considerable cost, labor, time and resources. This ultimately impedes fine mapping of majority of the identified QTLs into single gene and essentially affects efficient utilization of identified QTLs for crop improvement.The major goal of contemporary molecular breeding is to understand complex inheritance pattern and genetic basis of agronomically important traits for rapid genomics-assisted crop improvement. Quantitative trait loci (QTLs) mapping is the most commonly adopted strategy for identifying QTLs (a genomic region with one or multiple genes) regulating different complex traits of agronomic importance in crop plants. Till date, genome scans for QTLs have been conducted for variety of agronomic traits in most of the major food crops, which resulted in identification of numerous QTLsAssociation mapping is a proficient complementary approach to QTL mapping for rapid identification of genomic regions (genes) associated with complex quantitative traits. This strategy takes advantage of numerous historical recombinations accumulated within natural germplasm accessions during evolution/domestication and therefore, usually offers a much higher resolution as compared to QTL mapping . AlthougGS3, GS5, qGL3, GW2, GW5, GW8, and TGW6, etc.) regulating grain size/weight are now well-known; however, majority of these QTLs/genes (except few like GS3) have failed to precisely explain grain size/weight trait variation existing within Indian indica and aromatic germplasm accessions of rice  and grain width (GWi)] is one of the most important determinant of grain weight (GWt) and grain yield in rice, besides serving as a vital determinant of consumer preference especially for Basmati trade and commerce. Globally, more than 400 major QTLs regulating grain size/weight have been identified so far, predominantly by traditional linkage/QTL mapping approach and in few cases by genome-wide association studies (GWAS) using diverse bi-parental mapping populations and natural germplasm accessions, respectively . Genes u of rice . This caomosomes . Unlike 3). Exploitation of these diverse genetic resources for various high-throughput genetic analysis and genomics-assisted crop improvement of rice is now conceivable with advent of next-generation sequencing (NGS)-led structural, functional and comparative genomic strategies. Numerous (Millions) sequence variants including SNPs (single nucleotide polymorphisms) and InDels (insertions\u2013deletions) for thousands of resequenced rice accessions belonging to different indica, japonica, aus, aromatic and wild populations are available at a genome-wide scale in public-domain  to validate and narrow-down long confidence intervals of six important metaQTL regions governing grain size/weight in Indian indica and aromatic rice accessions. This study will take us one step closer toward identifying functionally relevant potential genes/alleles underlying known grain size/weight QTLs mapped on Indian germplasm accessions-derived low-density genetic linkage maps. This will essentially assist us to select superior natural allelic variants from the potential QTLs/genes detected for grain size/weight and their effective deployment in yield improvement especially of Indian indica and aromatic rice accessions.Keeping above prospects in view, the current study employed an integrated strategy combining traditional metaQTL analysis and regional association mapping  and GWt QTLs, which have been identified and mapped on different rice chromosomes using multiple preliminary and advanced generation mapping populations generated by inter-crossing among diverse Indian indica and aromatic rice accessions. The search resulted in identification of seven studies with 64 major/minor QTLs governing grain size and GWt traits mapped genetically on 12 rice chromosomes  was found to be the shortest, spanning 0.33 Mb with 42 genes whereas another mQTL located on same chromosome (OsmQTL5.2) was longest spanning 3.48 Mb containing 526 genes . The efficacy of meta-analysis in refining the confidence intervals for previously known QTLs as well as for validating their effects across different genetic backgrounds and environments is well-demonstrated  detected six different mQTL (metaQTLs) regions (with at least one of the overlapping QTL exhibited a LOD score \u2265 4 and phenotypic variance \u2265 10) that were mapped on four different rice chromosomes. The confidence marker intervals for these six mQTLs ranged from 0.33 to 3.48 Mb. The structural annotation of the identified mQTLs revealed the presence of various protein-coding genes ranging from 42 to 526. A mQTL mapped on chromosome 5  for selected mQTL genomic regions were retrieved from RiceVarMap database5. SNPs as well as accessions with greater than 1% missing data or minor allele frequency (MAF) < 5% were discarded. Filtered high-quality SNPs and accessions were further considered for association analysis  with normal frequency distribution for all three gain size/weight traits among selected rice accessions were observed. To begin with the regional association analysis was performed in a known mQTL region, which harbors GS3, a major gene regulating grain size especially in indica population, has been cloned and characterized earlier by fine mapping/map-based isolation, association mapping and functional genomic approaches  data of 505 accessions belonging to three different rice populations (proaches . These pindica subset (365) of total 505 accessions were integrated using a CMLM interface of GAPIT independently. This analysis successfully revealed significant association  of a known causal non-synonymous SNP (C/A at 16732087 bp on chromosome 3) reported previously in a G-protein \u03b3 subunit gene underlying a major GS3 mQTL with grain size trait in indica population  . The concerned SNP explained about 10% variation in GWi phenotype with A-allele positively affecting the grain size in rice. Like-wise, genetic association analysis was conducted for a GS3 mQTL region for all three grain size/weight traits  using hapQTL  between G-protein \u03b3 subunit gene-derived known causal non-synonymous SNP (C/A at 16732087 bp on chromosome 3) underlying a GS3 QTL with grain size in indica subpopulation  . Subsequently, haplotype block was constructed around this significant trait-associated SNP that harbors five protein coding genes including the one coding for known G-protein \u03b3 subunit gene . These outcomes are in accordance with earlier rice grain size trait association mapping studies  but also targeting diverse major/minor grain size/weight mQTLs for which major effect genes are unknown in rice.For regional association analysis, the SNP genotyping information and grain size/weight  phenotyping data of all 505 accessions as well as g hapQTL , which e studies . Hencefoindica, japonica, and aus populations) were combined with their relative kinship matrix (K) and PCA [principal component (PC) analysis] information using P3D/compressed mixed linear model (CMLM) in GAPIT (10 (P)-value for each SNP marker-trait association. The P-value threshold of significance was corrected for multiple comparisons based on false discovery rate (FDR cut-off \u2264 0.05)  and grain size/weight phenotyping  data for all 505 accessions (representing in GAPIT . The qua \u2264 0.05) . FurtherOsmQTL regions with grain size/weight-related phenotyping information  of all 505 accessions successfully detected significant association of a genomic locus underlying OsmQTL5.3 with GL in rice . However, significant association could not be detected for any other OsmQTL regions with any of grain size/weight phenotypes when analysis was performed for indica subpopulation. A most significant SNP (G/T) (SNP ID: sf0518872800) within OsmQTL5.3 was found to be located in the intergenic region between LOC_Os05g32430 (encoding NLI interacting factor-like phosphatase protein) and LOC_Os05g32440 (unknown expressed protein). Considering the known estimated average LD decay rate in rice .The integration of SNP genotyping data from six selected  in rice , 20 protindica, japonica, and aus) using hapQTL. To determine population structure, PCA was performed with filtered high-quality SNPs using TASSEL 5.0 and top three PCs were used as covariates in regression model during analysis. Threshold for significance BF (Bayesian factor) was selected as maximum log10 BF (bayes factor) under null for all three grain size/weight phenotypes combined plus one (K = 10) value, were defined as trait-associated LD blocks. Like-wise, haplotype-based association analysis (with no PC covariates) was performed independently by integrating genotyping data with grain size/weight phenotyping information of 365 indica accessions as per aforementioned methods.Haplotype-based regional association analysis was performed by integrating high-quality SNP (for each of the selected mQTL genomic regions) genotyping data with grain size/weight phenotyping information  of all 505 rice accessions belonging to three different rice populations  with GL . The outcome is agreed-well with our aforementioned CMLM-based association analysis with all 505 accessions, thereby further augmenting the authenticity of detected marker-trait association in rice. In addition, hapQTL analysis detected association of OsmQTL3.1 (SNP G/A at 327811770 bp on chromosome 3 with log10 BF of 6.36 for haplotype) and OsmQTL7.1 (SNP A/G at 22700042 bp on chromosome 7 with log10 BF of 6.51 for haplotype) with GWi and GL, respectively. Subsequent analysis with indica subpopulation could only detect significant association of OsmQTL3.1 (SNP T/C at 27686607 bp on chromosome 3 with log10 BF of 5.81 for the haplotype) with GWi and OsmQTL5.3 (SNP G/A at 18859830 bp on chromosome 5 with log10 BF of 5.17 for the haplotype) with GWt . Interestingly, two additional novel marker-trait associations  aside those identified using GAPIT were detected using hapQTL . This highlights the power of haplotype-led association strategies in detecting novel associations, which are difficult to detect with individual SNP-based association methods due to its inability to deal with allelic as well as locus heterozygosity (OsmQTL3.1 (G/A at 327811770 bp on chromosome 3) spanned from 27.68 to 27.94 Mb containing 34 genes whereas those calculated around the MSP within OsmQTL5.3 (T/G at 18872800 bp on chromosome 5) and OsmQTL7.1 extended from 18.84 to 18.97 Mb and 22.60 to 23.06 Mb harboring 12 and 58 rice genes, respectively . Like-wise, LD bocks were also estimated around MSPs detected with indica subpopulation using 365 indica accessions. The LD block around MSP detected within OsmQTL3.1 (T/C at 27686607 bp on chromosome 3) extended from 27.67 to 27.71 Mb with only four genes, whereas those around MSP detected within OsmQTL5.3 (T/G at 18872800 bp on chromosome 5) spanned from 18.72 to 18.95 Mb with 37 genes .The haplotype-based association analysis of six selected zygosity . The mLHOsmQTL3.1, OsmQTL5.3, and OsmQTL7.1 from 0.68 (108 genes), 0.33 (42 genes), and 2.40 (394 genes) Mb to 0.25 (34 genes), 0.13 (12 genes), and 0.46 (58 genes) Mb, respectively . In case of similar analysis with indica subpopulation, the intervals for OsmQTL3.1 and OsmQTL5.3 were scaled-down from 2.4 (108 genes) and 0.33 (42 genes) Mb to 0.03 (4 genes) and 0.23 (27 genes) Mb, respectively . In case of OsmQTL5.3, mLHS calculation with all 505 accessions produced smaller LD block as compared to those calculated with 365 indica accessions, showing evidence of inverse correlation between number of accessions used for mLHS calculation and size of LD block as suggested previously   . This pr in rice .in silico expression profiling of these genes were performed utilizing the whole genome microarray profiling data for diverse vegetative and reproductive stages of Nipponbare cultivar available at RiceXPro database6. This includes microarray expression profiles of different tissues such as total inflorescence, floral organs  at early reproductive development stages, embryo and endosperm during early grain development stages as well as seed maturation stages.Integration of expression profiling-based functional evidences with association analysis is very popular approach for further delineating candidate genes within associated LD blocks and has been successfully employed in variety of crops . In ordein silico expression analysis. Most of the genes displayed differential expression when compared between various tissues at different stages of reproductive development. Some of the genes within the delineated genomic intervals were found to express at very high levels in spikelet hull  during early reproductive development stages and therefore, can be involved in spikelet hull development and essentially in seed development. For instance, one gene (LOC_Os05g32460) delineated within reduced OsmQTL5.3 region (0.1 Mb), which codes for VQ domain-containing protein and another gene (LOC_Os03g48660) located within reduced OsmQTL3.1 interval (0.13 Mb) encoding DUF966 protein were found to be highly expressed in both lemma and palea during early stages of seed development and in endosperm during seed maturation  were compared with aforesaid various vegetative and reproductive tissues using global Arabidopsis known grain size/weight orthologs (Collectively, the outcomes of the present study indicate the potential utility of high-resolution association mapping in reduction of grain size/weight mQTL intervals derived from diverse QTL mapping studies in rice. The reduced grain size/weight major mQTLs can be directly utilized in MAS for rice genetic improvement given their consistent effects in different genetic backgrounds and environments. Moreover, two potential candidate genes exhibiting similarity with earlier characterized rthologs , delineaAD written the manuscript and performed all analysis. RS helped in data analysis. AS, SP, and AT conceptualized and guided the study.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Viperin is an interferon-inducible antiviral protein, responsible for antiviral response to a variety of viral infections. Here, we show that silencing viperin by antisense oligonucleotides (ASO) protects against diet-induced glucose intolerance, and yet exacerbates adipose tissue inflammation. In high-fat diet-fed mice, viperin ASO improves glucose homeostasis, reduces plasma triglyceride concentrations and ameliorates diet-induced hepatic steatosis. Peripheral delivery of viperin by adeno-associated virus elevates fasting plasma glucose and insulin concentrations and reduces insulin-stimulated glucose uptake in skeletal muscle. Viperin overexpression reduces epinephrine- stimulated lipolysis in white adipose tissue, whereas viperin ASO increases expression of lipolytic genes. Targeting viperin by antisense oligonucleotides promotes reciprocal regulation of hepatic and adipose lipogenesis by reducing hepatic lipid content and increasing triacylglycerol content in adipose tissue. These findings reveal viperin as an important target to improve glucose metabolism, and suggest that suppressing antiviral potential may improve the metabolic adaptability to high-fat diet. Type 2 diabetes and obesity are associated with chronic inflammation characterized by increased proinflammatory responses and macrophage infiltration into adipose tissues , 2. TherSuccessful antiviral therapy can induce remission of type 2 diabetes. Recent case reports in humans suggest that antiviral treatment of HCV improved glycemic control in type 2 diabetes , 13. VipWe evaluated the expression pattern of viperin in several tissues of insulin-resistant mice, which indicated that adipose tissues express the lower levels of viperin. However, specific knockdown of viperin with antisense oligonucleotides (ASO) in HFD-fed mice ameliorated glucose tolerance and enhanced adipose tissue inflammation. Viperin overexpression elevated fasting plasma glucose and inhibited adipocyte lipolysis. Silencing viperin induced reciprocal regulation of hepatic and adipose lipid metabolism under the challenge of high-fat diet. These findings suggest a previously unknown function for viperin in linking glucose metabolism to antiviral activity.-/- mice (db/db mice). In the two mouse models of insulin resistance, viperin expression was consistently decreased in WAT and BAT - and HFD-fed mice with viperin ASO twice a week for 4 weeks. Antisense oligonucleotides (ASOs) are well designed to bind to the target RNA and reduce expression of the target gene primarily in liver and adipose tissue -glucose uptake was measured after incubation. For ex vivo analysis of epinephrine- stimulated lactic acid release, intact muscles were incubated for 15 min with epinephrine 2, 5, 10, 20, 30, or 40\u03bcg/mL, and then lactic acid content in culture medium was measured after incubation. For ex vivo analysis of epinephrine-stimulated glycerol release, WAT and liver were respectively incubated for 180 min with epinephrine. Glycerol contents in culture medium were measured per 30 min. Lactic acid and glycerol contents were measured using spectrophotometer following the manufacturers\u2019 protocols (Nanjing Jianchen Biotech).Intactgastrocnemius muscle and epididymal fat (WAT) from mice were preincubated for 2 h at 30\u00b0C in oxygenated (95% O2 and 5% CO2) Krebs-Ringer bicarbonate HEPES buffer (KRBH) containing (mM): 129 NaCl, 5 NaHCOPlasma concentrations of insulin were measured by ELISA. Plasma glucose, triglycerides , free fatty acid (NEFA), and cholesterol were determined with enzymatic colorimetric assay following the manufacturers\u2019 protocols (Nanjing Jianchen Biotech).Tissue TAG was extracted using the method described previously . Pieces -\u0394\u0394ct relative to the control group, respectively.Total RNA was isolated from tissues using TRIzol (Invitrogen), according to the manufacturer's instructions. RNA was reverse-transcribed . cDNA was amplified by real-time PCR in a total reaction volume of 20\u03bcl using SYBR Green Realtime PCR Master Mix . Real-time PCR reactions were cycled in StepOne\u2122 Real-Time PCR System (Applied Biosystems). Target gene expression was normalized to housekeeping gene 18S or GAPDH and expressed as 2For frozen tissue, lysates were prepared using a RIPA lysis buffer (50mM Tris (pH7.4), 150mM NaCl, 2mM EDTA, 1% Nonidet P-40, 50mM NaF, 0.1% SDS and 0.5% sodium deoxycholate with PhosStop Phosphatase-Inhibitor Cocktail tablet and protease-inhibitor cocktail tablet (Roche). The homogenate was centrifuged at 4\u00b0C for 10 min at 14,000g and the supernatant was used for western blot. The protein content of the supernatant was quantified using bicinchoninic acid reagents and BSA standards. Equal amounts of protein were separated using a polyacrylamide SDS-PAGE gel. After SDS-PAGE, proteins were transferred to PVDF membrane. The membrane was blocked for 1 h at room temperature followed by incubation overnight at 4\u00b0C with viperin antibody (Abcam), phospho-PKC\u03bc, phospho-ACC, phospho-Akt, or GAPDH antibodies . After overnight incubation, the blots were incubated with HRP- conjugated secondary antibodies at a dilution of 1:5,000 for 1 h at room temperature. Bands were visualized by ECL plus (Thermo Scientific) according to the manufacturer's instructions and quantified using Image lab software.Data are shown as Mean \u00b1 SEM. Differences between groups were analysed statistically using Student's t test, and differences among the four groups were analysed with analysis of variance followed by post-hoc Bonferroni tests in Graphpad Prism 5.0. P-value < 0.05 was considered significant."}
+{"text": "Little surveillance data is undertaken on the antimicrobial susceptibility of isolates from acute dento-alveolar infections. We present data collated from routine diagnostic microbiology specimens submitted over a 27 year period in Glasgow, UK. Over the study period isolates were identified using the API system, VITEK 2 and MALDI-TOF. Antimicrobial susceptibility tests were undertaken using combinations of Stokes method and/or E-tests. Baseline data based on Lewis et al.,  and compared to isolates from 1998-2015. From 621 specimens, we isolated Anginosus group streptococci (n = 196), Mitis group Streptococci (n = 448), anaerobic streptococci (n = 116), Fusobacteria (n = 121) and Prevotella (n = 140) species. No discernable increase in resistance patterns over the 27 year time period of analysis was observed. A 6 month audit (May-Oct 2016) in Glasgow recorded 37 patients hospital admissions for 142 bed days (mean 3.5 days) to incise and drain severe odontogenic infections. But, dental practitioners in England (2015) prescribed 10,717 items of cephalosporins and 18, 630 items of augmentin  \u2013 why?Diagnostic oral microbiology matters in guiding antimicrobial stewardship programs but more collaborative working on processing methods and routine susceptibility data would help overcome limited data from single centers."}
+{"text": "Achromobacter species are being increasingly isolated from therespiratory tract of cystic fibrosis patients. Recent reports indicate thatAchromobacter ruhlandii is a potential human pathogen in cysticfibrosis-related infections. Here we report the draft genome of four A.ruhlandii strains isolated from cystic fibrosis patients in Brazil. Thisreport describes A. ruhlandii as a potential opportunistic pathogenin cystic fibrosis and provides a framework to for additional enquires into potentialvirulence factors and resistance mechanisms within this species. Achromobacter ruhlandii is a Gram-negative bacterium naturally found insoil ,causing infection in cystic fibrosis patients in Copenhagen  andHospital Universit\u00e1rio Pedro Ernesto (HUPE-UERJ), in 2007 and 2008. The isolates wereidentified to species level by sequencing seven housekeeping genes that were subsequentlysubmitted to the Achromobacter MLST database where they were assigned tospecific STs . Furthermore, thespecies specific marker genes for A. xylosoxidans (blaOXA-114) and for A. ruhlandii (blaOXA-258) were amplified and sequenced to confirm species assignment . The four samples were susceptible to antibiotics with the exception of strain 7022that was resistant to trimethoprim/sulfamethoxazole.Here we describe draft genome sequences of four signment . Accordide novo into scaffolds with Spades 3.5 genomeassembler . Sequencing was performed for each isolate with the500 cycle MiSeq Reagent v2 kit on a MiSeq benchtop instrument (Illumina). Paired-endsequence reads obtained for each of the isolates ranged from 2,017,226 to 3,232,222. Readswere corrected and assembled ssembler . The RapA. ruhlandii strains were compared with the genome of A.xylosoxidans NH-44784-1996  were annotated, however, only strain 7022 showed the presence of SHV-5aand APH(3\u2019)-II. Furthermore, we also observed two resistance genes that are usuallyassociated with mobile elements, sul1 and dfra26. However, in these genomes they could benot associated with these elements, being randomly located in the chromosome (A. ruhlandii samples with other genomic sequences of different speciesfound in the databases demonstrated the presence of IS and transposable elements that wererelated to ISBcen18 (Burkholderia cenocepacia J2315), ISPa43(Pseudomonas aeruginosa), TnAs2 , TnAs3 , ISRme12 , ISBmu5(Burkholderia multivorans ATCC 17616), ISBcen10 (Burkholderiacenocepacia J2315), ISStma15 , ISPst3 (Pseudomonas stutzeri OM1), IS408 (Burkholderiacenocepacia ATCC17616),ISPa38 (Pseudomonas aeruginosa DK2),ISPa39 (Pseudomonas aeruginosa DK2), ISPa40 (Pseudomonasaeruginosa DK2), ISBcen23 (Burkholderia cenocepacia HI2424),IS1474 and IS1162 (Pseudomonas fluorescens ST plasmid pEG). This illustrates thepotential ability of A. ruhlandii to carry genetic and transferableelements that could contribute to the dissemination/acquisition of antimicrobial resistancemechanisms.Genes responsible for resistance to antibiotics  and five incomplete prophage regionswere also detected in our  strains .This whole Genome Shotgun project has been deposited at DDBJ/ENA/GenBankunder the accessionLVKM00000000, LVKO00000000, LVKN00000000 and LVKP00000000. The version described in thispaper is version LVKM01000000, LVKO01000000, LVKN01000000 and LVKP01000000."}
+{"text": "FLT PET  images were acquired according to standard protocols. FLT uptake was quantified using standardised uptake values (SUV). Mean follow-up was 35 months (range 24-49). FLT uptake was correlated with survival using Martingale residual analysis.p = 0.045). The corresponding estimated hazard ratio per one-point increment of SUVmean was 1.298 .Twenty-two patients died during follow-up. Mean overall survival was 18.8 months . FLT PET showed a mean SUV of 2.5 (range: 1.1 - 6.5). Martingale residual analysis revealed significant correlation between survival and FLT uptake (FLT PET allows risk stratification for death in patients with resectable pancreatic cancer prior to surgery. Pancreatic cancer (PC) accounts for approximately 36,800 cancer deaths per year in the United States . In induDespite improvements in chemotherapy, surgical resection remains the only potentially curative treatment available for PC patients . However18F] fluorothymidine (FLT), derived from the cytostatic drug azidovudine, has recently been developed for clinical positron emission tomography (PET) and allows in vivo imaging of proliferative activity in malignant tumours. The tracer has been shown to correlate with the Ki-67 labelling index in tumours ex vivo  fluorothymidine has been shown to reflect proliferation-dependent retention of nucleosides in a number of different tumours, assessed non-invasively by PET  fluorothymidine was synthesised as described previously [3\u2019-Deoxy-3\u2019-[eviously . Imaging(HW and JCS) blinded to the clinical data and the results of other imaging studies. Discordant readings from the two observers were resolved by consensus. Circular regions of interest (ROIs) with a diameter of 1.5 cm were placed in the area with the highest tumour uptake as described previously [All FLT PET scans were evaluated by two experienced nuclear medicine physicians/radiologists eviously . In caseeviously .The histopathology served as the reference standard in all patients. Mean follow-up time was 35 months (range 24\u201349). Follow-up imaging was done using contrast enhanced CT chest-abdomen-pelvis, covering all regions except for the upper and lower extremities every 3 months.U test was used to compare quantitative data between two independent samples. Spearman correlation coefficients were calculated to quantify bivariate correlations of measurement data. Exact two-sided 95 percent confidence intervals (CI) were reported for normally distributed estimates. Martingale residual analysis was performed to assess prognostic impact of continuous variables with regard to overall survival [p-value for the log-rank test for equal survival curves . Quantitative values were expressed as mean \u00b1 standard deviation and range. The Mann-Whitney survival . Smoothil curves . All anaFLT PET allows risk stratification for death in patients with resectable PC prior to surgery. The data presented here justify further evaluation in larger cohorts to confirm preoperative FLT PET as a predictive tool in the management of patients with pancreatic cancer."}
+{"text": "Obesity is a highly prevalent risk factor for cardiometabolic diseases. Observationalstudies suggest that obesity is associated with psychiatric traits, but causalinference from such studies has several limitations. We used two-sample Mendelianrandomization methods  to evaluate the association of body mass index (BMI) with threepsychiatric traits using data from the Genetic Investigation of AnthropometricTraits and Psychiatric Genomics consortia. Causal odds ratio estimates per1-standard deviation increment in BMI ranged from 0.88  to 1.23 for bipolar disorder; 0.93  to 1.41 for schizophrenia; and 1.15  to 1.40  formajor depressive disorder. Analyses removing potentially influential SNPs suggestedthat the effect estimates for depression might be underestimated. Our findings donot support the notion that higher BMI increases risk of bipolar disorder andschizophrenia. Although the point estimates for depression were consistent in allsensitivity analyses, the overall statistical evidence was weak. However, the factthat SNP-depression associations were estimated in relatively small samples reducedpower to detect causal effects. This should be re-addressed when SNP-depressionassociations from larger studies become available. Obesity is a major public health concern with well-established risk-increasing effects oncardiometabolic diseasesPsychiatric disorders are one of the main causes of years lived with disabilityglobally357610Cohort studies provide support that obesity both predicts and can be predicted bydepression3121517Most of the evidence regarding the association of obesity with psychiatric disorderscomes from observational studies, which present several limitations for causalinference, including residual confounding, measurement error and reverse causation202122Mendelian randomization relies on assuming that any association between the geneticinstrument(s) and the health outcome is entirely mediated by the exposure 2122FTO and MC4R variantsas genetic instruments252725292526293133Previous Mendelian studies on this topic yielded inconsistent findings. However, suchstudies have some limitations, including using only Currently, many GWAS consortia make summary-level results freely available. Such data canbe used to obtain causal effect estimates based on multiple single nucleotidepolymorphisms (SNPs) using the inverse-variance weighting (IVW) methodA flowchart depicting the selection process of the genetic variants used inMendelian randomization analysis is shown in Mendelian randomization results for each psychiatric disorder are shown in TRIM66), rs12401738 (FUBP1), rs9925964(KAT8), rs11191560 (NT5C2), rs11057405 (CLIP1) inbipolar disorder; rs13107325 (SLC39A8), rs11191560 (NT5C2),rs9400239 (FOXO3) and rs4787491 (INO80E) in schizophrenia; andrs571312 (MC4R), rs1462433 (HNF4G), rs6785875 (FHIT) andrs11191560 (NT5C2) in major depressive disorder .The following SNPs \u2013 rs number (gene locus) \u2013 were classified asinfluential: rs4256980  for bipolar disorder, 0.49 and68.8%(P\u2009=\u20099.9\u2009\u00d7\u200910\u221224)for schizophrenia, and 0.20 and 18.4% (P\u2009=\u20090.073) formajor depressive disorder. In a random effects meta-regression model, includingan indicator variable of influentiality status reduced\u03c42 and 2Ivalues of major depressive disorder ratio estimates to 0.14 and 13.4%,respectively, with an adjusted-R2 value (which indicates theamount of heterogeneity explained by the moderators) of 29.3%(P\u2009=\u20090.028), and the test of residual between-instrumentsheterogeneity yielded P\u2009=\u20090.152. Regarding bipolardisorder and schizophrenia, the same procedure had a substantially smallerinfluence, with adjusted-R2 values of 1.1%and 2.4% , respectively. When an indicatorof belonging to a neuronal-related biological category was used instead ofinfluentiality status, all adjusted-R2 values were 0%.Values of the meta-analytical measures of heterogeneity2 and residual2I values for the selected moderators togetherwere 32.9% and 21.5% for bipolar disorder, 8.3% and 66.7% for schizophrenia and68.8% and 6.5% for major depressive disorder. Mendelian randomization odds ratioestimates excluding each and both of the selected biological categories areshown in The results of the forward selection process of biological moderators ofindividual-SNP ratio estimates using random effects meta-regression are shown inIn the present study, we evaluated the association between BMI-associated SNPs andthree psychiatric disorders by Mendelian randomization using summary-level data.Only major depressive disorder presented consistent causal effect estimates usingthe three Mendelian randomization methods and in all sensitivity analyses. The factthat removing influential variants increased, rather than attenuated, the odds ratioestimates is also reassuring because it suggests that the true causal effect mightbe greater than that estimated using all variants simultaneously. However, theoverall statistical evidence for any meaningful associations was weak.Our findings suggest that the commonly positive association between obesity andpsychiatric disorders reported in observational studies3456731213FTO variant rs1421085and common mental disorders was detected in the British Whitehall II studyFTO andMC4R variants were inversely associated with psychological distress in amuch larger Danish cohortFTOMC4RFTO might not be a valid instrument for BMI when mental disorders arethe outcome25MC4R variant rs571312 was identified as an influential  instrument in major depressive disorder analysis, but not in the remainingoutcomes. In the Young Finns cohort, BMI instrumented by a 31-SNP allele score waspositively associated with depressive symptoms29Mendelian randomization studies on the association between obesity and psychiatricdisorders are scarce, with no studies for bipolar disorders and schizophrenia. Apositive association between BMI instrumented using the Obesity and psychiatric disorders may share several dysregulated physiologicalpathways, including inflammation13European ancestry was predominant in all datasets, which increases the plausibilityof the assumption that the two datasets are samples from the same or comparablepopulations. Regarding power, two-sample Mendelian randomization power depends moreon the precision of SNP-outcome than SNP-exposure associationsI2 statistic, and that excluding four influential SNPsincreased the magnitude of the causal effect estimates and further attenuated theI2 statistic.It is impossible to prove empirically whether Mendelian randomization results mostlyreflect causal effects of the exposure or violations of instrumental variableassumptions. In the present study, three Mendelian randomization methods \u2013each with different assumptions regarding horizontal pleiotropy \u2013 were used,and all of them were consistent regarding major depressive disorder, but not whenanalyzing bipolar disorder and shcizophrenia. Moreover, both MR-Egger regression andthe weighted median approach  point estimates were stronger than the IVW one. It was alsoreassuring that major depressive disorder presented the smallest heterogeneity inindividual-SNP ratio estimates measured using the conventionalIn general, our findings do not corroborate the notion that BMI has a causal effecton bipolar disorder or schizophrenia. Regarding major depressive disorder, althoughthe point estimates were consistent across a range of analyses, the overallstatistical evidence was weak. Re-addressing this research question onceSNP-depression associations from larger GWAS become available would be warranted toobtain more precise Mendelian randomization estimates . Given the high prevalence of both obesity and depressionworldwide, understanding the mechanisms underlying associations between BMI anddepression, with identification and quantification of causal effects, is of publichealth relevance. Analyses involving schizophrenia were less prone to power issuesbecause SNP-schizophrenia associations were estimated in a relatively large sample.Bipolar disorder, similarly to major depressive disorder, require furtherinvestigation once more precise SNP-outcome associations are available.The final datasets were provided in Supplementary Tables S3\u2013S6.https://www.broadinstitute.org/collaboration/giant/index.php/GIANT_consortium_data_files).Locke and colleagues\u2019, under the GIANT consortium, identified 97BMI-associated single nucleotide polymorphisms (SNPs)2 . In studies of unrelated individuals, residuals were calculatedwithin sex and (when relevant) case/control strata. In family studies,residuals were sex-adjusted rather than sex-specific.The outcome was obtained by applying an inverse normal transformation to BMIresiduals on age and ager2\u2009>\u20090.2. For variants withoutgenes mapping to this interval, the nearest gene was used. This resulted in405 genes, which were annotated based on a manual literature review usingseveral venues. Through this process, those 405 genes were manually curatedinto 25 biological categories containing at least three genes, to which eachof the 97 BMI-associated variants were assigned , which performedlogistic regression adjusting for ancestry-informative principal componentsand assuming an additive effect.Log odds ratio and standard error estimates of SNPs-psychiatric disordersassociations were obtained from the Psychiatric Genomics Consortium (PGC). Aproxy was defined as a genetic variant within 500 kb of the index SNPand in high linkage disequilibrium(r2\u2009>\u20090.8) with it. If therewas more than one proxy available for the same index SNP, the variantwith the higher r2 was selected. Using 1000Genomes Pilot 1 (CEU population) as the reference panel, 26 proxiesavailable in both SNP-BMI and SNP-major depressive disorder datasetswere identified. An additional search using HapMap release 22 (CEUpopulation) as the reference panel yielded two additional proxies, thustotalizing 28 proxy variants and 90 BMI-associated SNPs. Afterharmonization, the correlation between effect allele frequencies was0.989.Only 62 BMI-associated SNPs were available. Proxies for missing variantswere identified using the SNP Annotation and Proxy Search tool , and threefamily-based studies comprising 1,235 parent affected-offspring Europeanancestry triosIVW method, consisting of a linear regression of SNP-outcome (dependentvariable) on SNP-exposure coefficients (independent variable), weightingby the inverse of the squared SNP-outcome standard errors. The interceptis constrained at zero, which follows from the assumption thatSNP-outcome associations are entirely mediated by the exposure2I statistic \u2013 MR-Egger regression, which differs from the IVW method because theintercept is not constrained. This yields a causal effect estimaterobust against horizontal pleiotropy under the InSIDE (InstrumentStrength Independent on Direct Effect) assumption, which requires thatthe SNP-exposure and direct SNP-outcome associations are independent.The intercept provides a test for directional horizontal pleiotropyWeighted median method, which provides a valid causal estimate if atleast 50% of the weights  come from valid instruments,regardless of whether or not horizontal pleiotropic effects of theremaining variants respect the InSIDE assumptionIn Mendelian randomization analyses, all BMI-associated SNPs available for eachpsychiatric disorder were used .The folet al.36Point estimates and standard errors were calculated for the IVW, MR-Egger andweighted median methods using the code provided by Bowden Sample overlap between GIANT and PGC datasets can bias causal effect estimatesfrom Mendelian randomization towards the observational (and possibly confounded)estimate33Mendelian randomization analyses were also performed within SNP subgroups ofbiological function: neuronal-related ; and non-neuronal (comprisingthe remaining categories). Consistency among different biological subgroupswould argue against the role of horizontal pleiotropy in the results.To evaluate if the results were substantially driven by a few instruments, theanalyses were repeated excluding influential SNPs. A SNP was classified asinfluential if at least one of two tests of influence  yielded aP-value\u2009<\u20090.05. These were calculated separately for IVW orMR-Egger regression, but the same SNPs were classified as influential usingeither Mendelian randomization method. The null distributions of these testswere: Student\u2019s t-distribution with degrees of freedom equal to thenumber of SNPs minus 2, for studentized residuals; or the F-statistic with jointdegrees of freedom equal to  (for IVW) or  (for MR-Egger regression), for Cook\u2019s distance2\u03c4, until no additional covariates reachedP\u2009<\u20095%.In exploratory analysis aimed at identifying factors associated with horizontalpleiotropy, individual-SNP ratio estimates  were used to calculatebetween-instrument heterogeneity, which corresponds to horizontal pleiotropy inthe Mendelian randomization contextTwo additional sensitivity analyses were performed: (i) IVW estimates withinsubgroups of SNPs excluding one biological category at a time; (ii) estimationof causal effects using the three Mendelian randomization methods after removingSNPs belonging to the biological categories identified in the forward selectionprocess described above.www.r-project.org).Analyses were performed using R 3.2.4 ."}
+{"text": "Arthrobacter sp. strain EpSL27, isolated from the stem and leaves of the medicinal plant Echinacea purpurea and able to inhibit human-pathogenic bacterial strains. The genome sequencing of this strain may lead to the identification of genes involved in the production of antimicrobial molecules.We announce here the draft genome sequence of  Echinacea purpurea and Echinacea angustifolia have been characterized, highlighting the specific composition of such communities within plants\u2019 compartments  and is able to degrade diesel fuel. Among such notable biotechnological potentialities, Arthrobacter sp. EpSL27 has also been found to show strong inhibition activity toward human-pathogenic bacteria from the Burkholderia cepacia complex  method (Arthrobacter\u00a0arilaitensis Re117 (Arthrobacter Rue61a (Arthrobacter sp. strain FB24 (Arthrobacter aurescens TC1 (Arthrobacter chlorophenolicus A6. The resulting scaffolds were then annotated using the NCBI Prokaryotic Genome Annotation Pipeline (PGAAP) , and 91 are pseudogenes.) method , and its) method . Assembl) method , with k-) method , using tr Rue61a , Arthrobain FB24 , Arthrobcens TC1 , and Art (PGAAP) . The finMycobacterium tuberculosis kasA mutant), fluoroquinolones (mfd), amynocoumarin (Streptomyces rishiriensis parY mutant), rifamycin (rphB), mupirocin (Bifidobacterium intrinsic ileS), and fosfomycin (Chlamydia trachlomatis intrinsic murA). antiSMASH  database under accession number"}
+{"text": "Profound FER deficits exist in Sz, causing social disability, though can be partly remediated with computer-based training. Neurostimulation might augment remediation if critical nodes were identified. We aimed to 1) briefly recapitulate FER deficits of Sz in HV using rTMS to rpSTS, 2) identify connectivity patterns of rpSTS regressed by FER, and 3) apply TMS to rpSTS with fMRI as readout.http://faces.mpdl.mpg.de/) for emotion or gender identification (button press). 14 Sz patients completed these tasks without TMS. 2) Whole-brain resting-connectivity analyses, seeded by rpSTS, was applied in 27 Sz and 35 HV who also completed the UPenn FER task. 3) BOLD fMRI was obtained in 4 HV pre- and post-TMS to rpSTS .1) Nine healthy volunteers had rTMS  to rpSTS or rOFA  concurrent  with stimuli (1) In HV, rTMS to rpSTS only (not OFA) significantly slowed reaction time for FER only (not gender identification): overall F test for logRT (p=.001) with post-hoc rpSTS vs.OFA (p=.005) and rpSTS vs. non-stim trials (p=.004). rpSTS recapitulated slowed RT ad lower FER accuracy of Sz. 2) In both HV and Sz, rpSTS had significant resting connectivity with V1 (p= .00013), positively modulated by FER accuracy. 3) Analyses are ongoing.rpSTS is a critical node in the FER circuit with connectivity to primary visual cortex modulated by FER, whose disruption recapitulates FER deficits, making it a candidate target for remediatory neurostimulation."}
+{"text": "Pseudomonas syringae pv. actinidiae. Comparison with the genome sequence of a copper-sensitive biovar 5 isolate indicates that copper resistance is encoded on a plasmid.We present the first complete genome sequence of a copper-resistant biovar 5 strain of a bacterial pathogen of kiwifruit,  Pseudomonas syringae pv. actinidiae causes bacterial canker of kiwifruit, a disease that is devastating kiwifruit orchards throughout the world . Four pPaCu1 clones present in GenBank  are highly similar (99.9% identity) to pMAFF212063-A. There are also highly similar plasmids (differing at only 5 single nucleotide polymorphisms [SNPs]) in copper-resistant P.\u00a0syringae pv. syringae from mango buds in Spain (pPs0081) and from sweet cherry in the United States (pPs6-9)   from a New Zealand isolate of P. syringae pv. actinidiae biovar 3 is identical to pMAFF212063-A over a >20-kb region that includes the copper resistance genes. This indicates that the copper resistance determinant can occur on diverse mobile elements.Copper resistance is therefore encoded on plasmid pMAFF212063-A. This element carries a copper resistance operon encoding CopA, CopB, CopC, CopD, and the regulatory CopRS pair. Nakajima et al.  describePseudomonas syringae, there must be a method of mitigating the effects of the various restriction systems.Analysis of the methylation patterns identified by the PacBio analysis showed that strain MAFF212063 has unique restriction systems, a type I GGYANNNNNNTTTC site (99.4% methylation), a type II site CTCGAG (75.7%), and two type III sites recognizing CCTTNAG (98.3%) and GAAGAT (96.2%). Given that the copper resistance plasmids have been transferred between strains of CP024712 (MAFF212063 chromosome), CP024713 (plasmid pMAFF212063-A), and CP024714 (plasmid pMAFF212063-B). The whole-genome sequencing (WGS) project for MAFF212054 has been deposited under the GenBank accession number PESZ00000000.The genome sequences described here have been deposited in DDBJ/ENA/GenBank under the accession numbers"}
+{"text": "Maeg loss-of-function embryos showed reduced endothelial cell number and filopodia extensions of intersegmental vessels (ISVs). Maeg gain-of-function induced ectopic sprouting evolving into a hyperbranched and functional perfused vasculature. Mechanistically we demonstrate that Maeg promotes angiogenesis dependent on RGD domain and stimulates activation of Akt and Erk signaling in vivo. Loss of Maeg or Itgb1, augmented expression of Notch receptors, and inhibiting Notch signaling or Dll4 partially rescued angiogenic phenotypes suggesting that Notch acts downstream of Itgb1. We conclude that Maeg acts as a positive regulator of angiogenic cell behavior and formation of functional vessels.MAM and EGF containing gene (MAEG), also called Epidermal Growth Factor-like domain multiple 6 (EGFL6), belongs to the epidermal growth factor repeat superfamily. The role of Maeg in zebrafish angiogenesis remains unclear. It was demonstrated that  The ein vivo studies of the vascular development [in situ hybridization, and immunostaining. Then we examined whether zebrafish maeg regulates angiogenesis in vivo through loss- and gain-of-function analysis. Further more, we investigated the potential mechanism underlying maeg regulating zebrafish embryonic angiogenesis.The vascular network develops in a conserved manner in all vertebrates. The zebrafish (Danio rerio) model system offers distinct advantages for elopment . In the in situ hybridization (WISH) analysis using digoxigenin-labeled antisense probes. Consistent with previous report [maeg reached its peak at around 22~26 hpf and decreased hereafter  and 8 types of mutations  and Tg(kdrl:EGFP) transgenic lines for studying angiogenesis. Homozygous maeg mutant individuals (maeg\u2212/\u2212) were obtained in F3 offspring.To do the loss of function analysis on g Figure . Then weing site . To evals Figure . The rems Figure , S1C. Ths Figure . The Maes Figure . For themaeg\u2212/\u2212Tg(kdrl:EGFP) zebrafish embryo at different stages using in vivo confocal imaging. In the maeg mutants, although the position of the initial sprout formation was not affected , which are formed via vasculogenesis , whose specificity were validated by Western Blot and RT-PCR analysis as previous reported [maeg phenocopied the angiogenic defects of maeg mutants  embryos. Confocal imaging analysis of the fluorescence labeled neurons in Tg(huC:EGFP) embryos revealed normal hindbrain development in maeg loss of function zebrafish  embryos, in which EGFP accumulates in nucleus in ECs [maeg, the ISV tip cells migrated from DA later than the stage of control  was reported to be one of the receptor for Maeg recognizing the RGD motif [itgb1 isoforms in zebrafish, including itgb1a, itgb1b, itgb1b.1, and itgb1b.2 [Tg(kdrl:EGFP) transgenic embryos at 24 hpf by fluorescence-activated cell sorting (FACs) (itgb1 isoforms were determined by RT-PCR Assay (itgb1a was expressed in ECs of 24 hpf zebrafish embryos (in situ hybridization data (itgb1a using a translation blocking MO in Tg(kdrl:EGFP) zebrafish embryos and observed that itgb1a morphants phenocopied the angiogenic defects of maeg mutants  . The purg (FACs) . The expCR Assay , showing embryos . These rion data . Subsequs Figure . In addis Figure . Taken tmaeg promoted zebrafish embryonic branching angiogenesis involving Notch signaling. Then we examined the expression level of Notch receptors and ligands in maeg deficiency embryos. Our data sets showed that the expression level of the notch1a and notch1b was elevated  cells [EGF-like proteins have been suggested to play a variety of roles in angiogenesis and endothelial cell behaviors. BTC, a member of the EGF family, induces angiogenesis through activation of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3\u2032-kinase (PI3K) in human umbilical vein endothelial cells (HUVECs) . In addiin vivo. HB-EGF in vivo-10. Mostin vivo, 17. Itsin vivo-16, 36. o Figure . Zebrafie) cells . This dimaeg in zebrafish embryos impaired ISV out growth and tip cell behaviors that is reminiscent of Notch activation. In Maeg mutants, Notch signaling was upregulated and this result was consistent with previous studies that Egf-like family members have been implicated in the modulation of Notch signaling. Nueda et al revealed that the EGF-like protein DLK1 Inhibits Notch signaling and potentiates adipogenesis of mesenchymal cells [maeg and itgb1 deficiency embryos, suggesting Maeg-Itgb1 modulates angiogenesis upstream of Notch signaling  and ethically approved by the Administration Committee of Experimental Animals, Jiangsu Province, China  2007\u20130021).All animal experimentation was carried out in accordance with the NIH Guidelines for the care and use of laboratory animals (Tg(fli1a:nEGFP), Tg(kdrl:EGFP), Tg(kdrl:ras-mCherry) and Tg(huC:EGFP) were used as described in our previous work [Zebrafish embryos and adult were raised and maintained under the conditions as we previously described -40. AB aous work -42. Embrhttps://tale-nt.cac.cornell.edu/) [in vitro using the linearized constructs as templates with SP6 mMESSAGE mMACHINE Kit (Ambion), purified with RNeasy Mini Kit (Qiagen), and dissolved in RNase free Ultrapure water (Life Technologies). Equal amounts (100 ng/\u03bcl) of Left and Right TALEN mRNA were injected together into the cytoplasm of 1-cell stage zebrafish embryos.We designed a pair of TALENs targeting the first exon of Maeg using online tools TALE-NT (ll.edu/) . Left armaeg TALEN pair is functional since the melting curve for TALEN mRNA injected embryos is shifted when WT is compared. To identify germ line-transmitted mutations, the microinjected founder (F0) embryos were raised to adulthood. The F0 fish were then outcrossed with wild-type zebrafish to produce F1. 16 of F1 embryos at 24 hpf were collected for genomic DNA extraction respectively. Subsequently, the genomic DNAs were subjected to perform HRMA. Siblings of the F1 embryos that potentially carry heritable mutations were raised to adulthood and individual F1 mutants were identified via PCR amplification and sequencing with fin-clipped DNAs. The primers for genotyping are listed in supplemental data  at 28.5 \u00b0C. 20 embryos at 24hpf after TALEN mRNA injection were collected and their genomic DNA were extracted and subjected to perform high-resolution melting assay (HRMA) . Primerstal data .maeg and dll4 were the same as previously described [itgb1a (ENSDART00000039700) translation-blocking MO are listed in supplemental data (maeg and mCherry coding sequence were cloned into PCS2+ vector. The vector template was linearized with NotI Restriction Enzyme (NEB). Sense-capped mRNAs were synthesized with SP6 mMESSAGE mMACHINE Kit (Ambion), purified with RNeasy Mini Kit (Qiagen), and dissolved in RNase free Ultrapure Water (Life Technologies). 2nl maeg and mCherry mixture (1:1) was injected at 100ng/ \u03bcl into cytoplasm of 1/2-cell stage zebrafish embryos.Morpholino antisense oligos  were prepared at a stock concentration of 1 mM according to the manufacturer's instruction. MOs were diluted to 0.3mM and injected into one-cell stage embryos. MOs for targeting zebrafish escribed , 40. Thetal data . ZebrafiTissue was homogenized and frozen in TRIzol Reagent (Invitrogen) and stored at -80 \u00b0C. The RNA was extracted following the manufacturer's instruction. 1 \u03bcg of total RNA was reverse transcribed into cDNA by the use of Transcriptor First Strand cDNA Synthesis Kit (Roche) according to the manufacturer's instructions. Synthesized cDNA was stored at -20 \u00b0C. All PCR amplifications were carried out in a total volume of 50\u03bcl using specific primers and Advantage 2 Polymerase Kit (Clontech). The primers for PCR are listed in supplemental data .in situ hybridization with antisense RNA probes was performed according to the previous description [Whole-mount cription , 40. Thecription , 30, 40.cription . The pricription .DAPT was purchased from (Sigma-Aldrich) and dissolved in DMSO. DAPT was used at a final concentration of 100 \u03bcM diluted as our pervious description . U0126 win situ-hybridized embryos was performed according to the previous description [in situ hybridization and photos in bright field were documented with an Olympus DP71 camera on an Olympus stereomicroscope MVX10, Leica imaging system on a Leica compound microscope and Zeiss SteREO Discovery V20 microscope with a Zeiss AxioCam HRc camera. For confocal imaging of blood vessel development in zebrafish embryos, they were anesthetized with egg water/0.16 mg/mL tricaine/1% 1- phenyl-2-thiourea (Sigma) and embedded in 0.6% low melting agarose. Confocal imaging was performed with a Leica TCS-SP5 LSM. Analysis was performed using Imaris software.Section of the whole-mount cription . The res2 test were used (P<0.05). When we did the One-Way ANOVA for multiple comparisons test, we chose correction for multiple comparisons.Statistical analysis was performed using GraphPad Prism\u00ae version 6.0c. One-Way ANOVA , Fisher's exact test, Student's t-test, Mann Whitney U-test, and \u03c7"}
+{"text": "Global transcriptional profiling of adult flies overexpressing Nub-PB in immunocompetent tissues revealed that this form is a strong transcriptional activator of a large set of immune genes. Further genetic analyses showed that Nub-PB is sufficient to drive expression both independently and in conjunction with nuclear factor kappa B (NF-\u03baB), JNK and JAK/STAT pathways. Similar overexpression of Nub-PD did, conversely, repress expression of the same targets. Strikingly, isoform co-overexpression normalized immune gene transcription, suggesting antagonistic activities. RNAi-mediated knockdown of individual nub transcripts in enterocytes confirmed antagonistic regulation by the two isoforms and that both are necessary for normal immune gene transcription in the midgut. Furthermore, enterocyte-specific Nub-PB expression levels had a strong impact on gut bacterial load as well as host lifespan. Overexpression of Nub-PB enhanced bacterial clearance of ingested Erwinia carotovora carotovora 15. Nevertheless, flies quickly succumbed to the infection, suggesting a deleterious immune response. In line with this, prolonged overexpression promoted a proinflammatory signature in the gut with induction of JNK and JAK/STAT pathways, increased apoptosis and stem cell proliferation. These findings highlight a novel regulatory mechanism of host-microbe interactions mediated by antagonistic transcription factor isoforms.Gut immunity is regulated by intricate and dynamic mechanisms to ensure homeostasis despite a constantly changing microbial environment. Several regulatory factors have been described to participate in feedback responses to prevent aberrant immune activity. Little is, however, known about how transcriptional programs are directly tuned to efficiently adapt host gut tissues to the current microbiome. Here we show that the POU/Oct gene  via two isoforms encoded from the same gene. Balanced expression of the two forms was necessary for ensuring normal immune gene expression and maintaining immunological homeostasis in the Drosophila gut. We performed genetic manipulations to skew the balance of these isoforms. This resulted in a dysregulated immune system, changed levels of gut bacteria and altered host lifespan. Moreover, when we overexpressed the activating form flies quickly succumbed to oral bacterial infection despite an enhanced immune response. We suggest that antagonistically acting transcription factor isoforms may constitute a general mechanism for adjusting gene expression in various biological processes.The numerous human diseases caused by aberrations in intestinal immunity and integrity urge a better understanding of the regulatory interactions that balance the output of host-microbe interactions. In this study, we discovered a novel phenomenon of transcriptional antagonism exerted  Drosophila and mammals ; UAS-nub-RB; UAS-bsk-IR from (H) and (L); (V) w1118; c564-Gal4; RelE20, es from (M) and (R); -Gal4-driven RNAi of nub-RB in midguts (C) or abdominothoracic carcasses (D). Asterisks denote significant differences, determined by Student\u2019s unpaired t-test .(A) Western blot of Nub from dissected midguts or corresponding carcasses in OregonR flies. (B) Western blot from whole fly extracts following five days incubation at 29 \u00b0C to achieve full effect of the NP1(TIF)Click here for additional data file.S6 FigpBonferroni-corrected<0.0083). (D) Relative lifespan extension in GF conditions for respective genotype (pBonferroni-corrected<0.0125 was considered significant).(A-B) Lifespan analysis of females and males of the denoted genotypes. Flies were conditionally reared (CR) or maintained on antibiotic-supplemented food to become germ free (GF). The number of dead flies were recorded daily. (C) Statistics from the three individual experiments under CR conditions. Group letters denote significant differences ((TIF)Click here for additional data file.S7 FigEcc15 counts and relative bacterial clearance in flies overexpressing nub-RD in enterocytes, compared to controls. (C) Feeding rates following nub-RD overexpression. See (A-B) (TIF)Click here for additional data file.S1 Table(XLSX)Click here for additional data file.S2 Table(XLSX)Click here for additional data file.S3 Table(XLSX)Click here for additional data file.S4 Table(XLSX)Click here for additional data file.S5 Table(XLSX)Click here for additional data file.S6 Table*, verified by RT-qPCR; italicized values, below threshold or not significant.(XLSX)Click here for additional data file."}
+{"text": "Methanohalophilus mahii strain DAL1, recovered from Marcellus Shale hydraulic fracturing-produced water using metagenomic contig binning. Genome annotation revealed several key methanogenesis genes and provides valuable information on archaeal activity associated with hydraulic fracturing-produced water environments.We report here the 1,882,100-bp draft genome sequence of  Archaea being detected at low quantities . Sequencing reads were quality trimmed (Q30) and de novo assembled into contigs using CLC Genomics Workbench version 8.5.1  and SPAdes version 3.5.1 , methyl coenzyme M reductase (mcr), and methenyl-tetrahydromethanopterin cyclohydrolase (mch). Moreover, the coenzyme M methyltransferase (mtbA) and the trimethylamine methyltransferase (mttB) genes were identified. These observations suggest Methanohalophilus mahii strain DAL1 to have the genetic potential for hydrogenotrophic (CO2 to methane) and methyl reduction (trimethylamine to methane) methanogenesis (The draft genome was annotated by Rapid Annotations using Subsystems Technology (RAST) , 17, revMethanohalophilus accumulate potassium ions and uptake glycine and betaine in response to osmotic stress (\u2013Annotation also revealed the potassium uptake proteins TrkA and TrkH and the osmoprotectant transporter ProP. These findings agree with previous observations that members of the genus c stress \u201324.Methanohalophilus mahii sp. DAL1 draft genome indicates the potential for methanogenic activity associated with Marcellus Shale hydraulic fracturing operations.The analysis of the MAFX00000000. The version described in this paper is version MAFX01000000.This whole-genome shotgun project has been deposited at DDBJ/ENA/GenBank under the accession no."}
+{"text": "Children with heart disease may require repeated X-Ray cardiac catheterization procedures, are more radiosensitive, and more likely to survive to experience oncologic risks of medical radiation. Cardiovascular magnetic resonance (CMR) is radiation-free and offers information about structure, function, and perfusion but not hemodynamics. We intend to perform complete radiation-free diagnostic right heart catheterization entirely using CMR fluoroscopy guidance in an unselected cohort of pediatric patients; we report the feasibility and safety.We performed 50 CMR fluoroscopy guided comprehensive transfemoral right heart catheterizations in 39 pediatric (12.7 \u00b1 4.7 years) subjects referred for clinically indicated cardiac catheterization. CMR guided catheterizations were assessed by completion (success/failure), procedure time, and safety events . Pre and post CMR body temperature was recorded. Concurrent invasive hemodynamic and diagnostic CMR data were collected.During a twenty-two month period (3/2015 \u2013 12/2016), enrolled subjects had the following clinical indications: post-heart transplant 33%, shunt 28%, pulmonary hypertension 18%, cardiomyopathy 15%, valvular heart disease 3%, and other 3%. Radiation-free CMR guided right heart catheterization attempts were all successful using passive catheters. In two subjects with septal defects, right and left heart catheterization were performed. There were no complications. One subject had six such procedures. Most subjects (51%) had undergone multiple (5.5 \u00b1 5) previous X-Ray cardiac catheterizations. Retained thoracic surgical or transcatheter implants (36%) did not preclude successful CMR fluoroscopy heart catheterization. During the procedure, two subjects were receiving vasopressor infusions at baseline because of poor cardiac function, and in ten procedures, multiple hemodynamic conditions were tested.Comprehensive CMR fluoroscopy guided right heart catheterization was feasible and safe in this small cohort of pediatric subjects. This includes subjects with previous metallic implants, those requiring continuous vasopressor medication infusions, and those requiring pharmacologic provocation. Children requiring multiple, serial X-Ray cardiac catheterizations may benefit most from radiation sparing. This is a step toward wholly CMR guided diagnostic (right and left heart) cardiac catheterization and future CMR guided cardiac intervention.NCT02739087 registered February 17, 2016ClinicalTrials.gov The online version of this article (doi:10.1186/s12968-017-0374-2) contains supplementary material, which is available to authorized users. Children with congenital and acquired heart disease often require serial X-Ray cardiac catheterization, accruing significant radiation exposure . GrowingClinical cardiovascular magnetic resonance (CMR) catheterization was first reported over a decade ago using adjunctive X-Ray  and has Similarly, we intend to enable CMR fluoroscopy catheterization as the preferred clinical standard for children. In this report, we pursued complete diagnostic right heart catheterization in children, solely guided by real-time cardiac CMR using commercially available catheters, with the specific aims of feasibility  and safety .The protocol was approved by the Institutional Review Board, and was performed in the combined NHLBI/Children\u2019s National Medical Center MRI catheterization suite at Children\u2019s National Health System in Washington DC (NCT02739087). Patients referred for medically necessary cardiac catheterization were invited to participate in this study Fig. . PatientAera and Artis Zee; Siemens, Erlangen, Germany; Fig. Magnevist 0.1 mM, Bayer Healthcare, Tarrytown, NY). Right heart catheterization included catheter access to the superior vena cava, inferior vena cava, right atrium, right ventricle, and typically both branch pulmonary arteries including distal pulmonary capillary wedge position. Left heart catheterization, when attempted, was performed by advancing catheter through an atrial septal defect into the left atrium and antegrade across the mitral valve into the left ventricle. Catheters were advanced to ventricular chambers with balloon inflated (without a guidewire) to minimize ventricular ectopy, and without a guidewire absent an CMR-safe commercial option. Continuous simultaneous pressure waveforms confirmed catheter tip localization as is standard practice with traditional X-Ray fluoroscopy.All subjects underwent general anesthesia per institutional clinical standard for cardiac catheterization. General anesthesia  was administered per anesthesiologist discretion as clinically indicated for each patient. Anesthesia and vascular access was obtained in the X-Ray room of the combined interventional cardiovascular magnetic resonance (CMR)/X-Ray fluoroscopy suite Interactive Front End, Siemens, Erlangen, Germany), wireless operator noise-cancelling communication headsets , hemodynamic recording system interface , and in-room shielded  LCD projectors to a rear-projection screen that can slide to the head or foot side of the patient as needed.The CMR room is outfitted for invasive cardiac catheterization as previously described  Fig. 2)2) with aR=1-3) in conjunction with the Gadgetron reconstruction engine  and a high-fidelity hemodynamic recording system interface  . (TIFF 888 kb)CMR Right Heart Catheterization imaging planes: caval view. Real-time CMR acquisition and display console Additional file 5: Figure S3.CMR Right Heart Catheterization imaging planes: pulmonary artery view. RPA = right pulmonary artery; LPA = left pulmonary artery. (TIFF 571 kb)"}
+{"text": "Bone metastases were osteoblastic, and osteolytic. IGR-CaP1 cells expressed the neuroendocrine marker synaptophysin, near equivalent levels of vimentin and e-cadherin, all of the EMT transcription factors, and activation of NOTCH and WNT pathways. In parallel, we created a new triple-targeted adenoviral vector containing a fiber knob RGD peptide, a hexon mutation, and an EC specific ROBO4 promoter (Ad.RGD.H5/3.ROBO4). This vector was expressed in metastatic microvessels tightly juxtaposed to IGR-CaP1 cells in bone and visceral niches. Thus, the combination of IGR-CaP1 cells and NSG mice produces a completely penetrant metastatic PCa model emulating end-stage human disease. In addition, the metastatic niche access provided by our novel Ad vector could be therapeutically leveraged for future disease control or cure.While modern therapies for metastatic prostate cancer (PCa) have improved survival they are associated with an increasingly prevalent entity, aggressive variant PCa (AVPCa), lacking androgen receptor (AR) expression, enriched for cancer stem cells (CSCs), and evidencing epithelial-mesenchymal plasticity with a varying extent of neuroendocrine transdifferentiation. Parallel work revealed that endothelial cells (ECs) create a perivascular CSC niche mediated by juxtacrine and membrane tethered signaling. There is increasing interest in pharmacological metastatic niche targeting, however, targeted access has been impossible. Here, we discovered that the Gleason 7 derived, androgen receptor negative, IGR-CaP1 cell line possessed some but not all of the molecular features of AVPCa. Intracardiac injection into NOD/SCID/IL2Rg\u2009 Despite enormous strides in therapeutic development, metastatic prostate cancer remains fatal. Treatment with abiraterone an inhibitor of cytochrome P450 17A1 -mediated androgen synthesis, or enzalutamide, which inhibits three androgen receptor (AR) functions; ligand binding, nuclear translocation, and DNA binding, have increased quality of life and life span. However, these more potent drugs and the newer taxanes, alone or in combination, also appear to foster an increasingly evident clinical and pathological entity, \u201caggressive variant prostate cancer (AVPCa)\u201d . AVPCa iWhile the proximate cause for AVPCa development is selection under AR signaling inhibition , 11, the-/\u2212 (NSG) mice [Here, we have used a recently described PCa cell line, IGR-CaP1, that forms osteoblastic metastases following intratibial or systemic arterial injection . We haveSG) mice  evidence5, into the left ventricle [In the original reports of the IGR-CaP1 cell line, nude (nu/nu) mice were the recipient immunodeficient hosts , 23. Howentricle , 23. To More detailed histopathological analysis revealed that IGR-CaP1 liver, kidney, and adrenal metastases were relatively well-circumscribed nodules of poorly differentiated carcinoma growing in sheets and nests with scant stroma and only focal gland-like spaces Figure . OccasioTo further explore the metastatic biology and the tumor-host niche interactions of experimental NSG host IGR-CaP1 metastatic tumors we used a combination of histopathology and molecular immunofluorescence analysis. Skeletal metastases were profoundly osteoblastic with marked new bone formation, particularly evident using Masson-trichrome staining Figure  and 2B. To globally investigate IGR-CaP1 cell alterations of bone morphology we used microCT analysis of tumor bearing (n=2 mice) versus non-tumor bearing (n=1) femur, tibia, and spine Figure . 3D rendT145  growth factor stimulation. Additional support for elevated c-MET-mediated signaling in IGR-CaP1 cells, was provided by the differentially elevated JAK\u2013STAT3, and markedly elevated c-RAF/MAPK kinase pathway phosphorylation, both downstream of c-MET receptor activation  activity and marker expression , and sinAs EMT can be a CSC precursor, IGR-CaP1 metastases were interrogated for molecules and signaling pathways known to regulate CSC niche maintenance and adherence. As both NOTCH and WNT have been shown to maintain the CSC phenotype in several types of cancer , includiAs AVPCa is the therapeutic terminus of widespread metastatic disease, new approaches to targeting resistance fostering niches are desperately needed for this increasingly frequent patient cohort . The cruPreviously, we had created and tested an endothelial cell (EC)-targeted Ad vector containing 3 kb of the ROBO4 enhancer/promoter . While tAs the major clinical challenge is systemic control or cure of multi-organ metastatic disease, we tested the RGD.H5/3.ROBO4-EGFP reporter vector administered intravenously to NSG mice bearing IGR-CaP1 experimental bone and visceral metastases 4 weeks post intracardiac administration. For these experiments, we created an IGR-CaP1 cell line constitutively expressing a histone 2B-red fluorescent protein (H2B-RFP) reporter. Intense RFP fluorescence, mediated by chromatin condensation, facilitated single cell metastatic detection Figures . ExpressThere are three crucial aspects of our study. Using the combination of the highly immunodeficient NSG mouse with the IGR-CaP1 cell line we have created a new and highly penetrant preclinical model of metastatic prostate cancer. Both the concomitant visceral and osseous metastases and our protein expression profiling of this model strongly suggested that it emulated some, but not all the biological and molecular features of AVPCa, which is increasingly the final stage of disease progression in the modern era of potent androgen blockade and chemotherapy . Pan-theA particularly outstanding feature of the model was exquisite osteotropism of the IGR-CaP1 cells in NSG hosts following intracardiac injection. Bone metastatic modeling can also be produced using direct intratibial injection . While tWhile the accelerated metastatic growth of the IGR-CaP1/NSG model offers the advantages of rapid phenotypic screening for genetic manipulations, it fails to recreate the usual pace of the slow progression of human metastatic prostate cancer. IGR-CaP1 cells were derived from an intermediate stage, Gleason 7 primary prostate cancer. During the serial cell passaging necessary for cell line establishment, they obviously were selected for loss of AR expression. AR expression loss could be due to outgrowth of an AR negative cell present in the primary cancer , 50, or The other compelling facet of IGR-CaP1 cells is that they shared some, but not all, of the molecular attributes of AVPCa. Detection of an IGR-CaP1 neuroendocrine marker subset had not been reported in the prior work with these cells . The eleAnother aggressive disease hallmark is EMT . IGR-CaPThe induction of multiple cell signaling and fate determination pathways evident in aggressive PCa highlights its associated therapeutic challenges. While small molecule and chemotherapeutic cocktails have successfully inhibited growth of subcutaneous xenografts, the clinical application of this approach could be fraught with toxicities particularly in susceptible organs with rapid cell turnover such as intestine, skin, and bone marrow. While the target repertoire of small molecule inhibitors is increasingly being narrowed, targeted delivery of therapeutics to specific cellular components of the metastatic microenvironment could obviate host toxicity, but enhance growth inhibitory efficacy. One approach is manipulation of vasculature to usurp EC angiocrine function . This coHere, we created a new adenovirus incorporating three genetic modifications designed to address three challenges of systemic vector administration; first pass target organ infection, hepatocyte sequestration, and cell type specific gene expression. The cyclized RGD peptide was used for enhanced tumor vessel infection/transduction. A serotype 3 domain was swapped into hexon replacing the native serotype 5 correspondent to obviate coagulation Factor X binding mediating hepatocyte sequestration. Biased tumor vascular endothelial expression was achieved with the use of the human ROBO4 promoter . This prReplication incompetent RGD.H5/3.ROBO4-EGFP adenovirus was created using a two-plasmid rescue method, as described previously . DetailsHuman prostate IGR-CaP1 cells were a generous gift from Anne Chauchereau, Institut Gustave Roussy . STR analysis by an independent laboratory confirmed their maintenance of the originally reported profile (data not shown), thus serving as validation of this cell line. LNCaP, PC3, DU145 cell lines were obtained directly from ATCC. The LNCaP derivative C4-2B cells were obtained from Christopher Maher at WUSTL. Details of cell line propagation and RSPO or WNT3a stimulation experiments are available in Supplementary Data.scid Il2rgtm1Wjl/SzJ (NSG) mice  were inbred in Washington University School of Medicine aseptic barrier mouse facility. To establish experimental tumor metastasis, NSG mice were anesthetized and injected with 5\u00d7105 parental, H2B-RFP-labeled, or CBR-Luciferase/mCherry-labeled IGR-CaP1 cells in 50 \u03bcl of PBS into the left cardiac ventricle using 30G needles. Tumor growth necessitated mouse sacrifice 4.5-5.5 weeks post injection. Further details of organ harvest and processing are presented in Supplementary Methods.Experimental procedures involving mice were carried out under a protocol approved by the Washington University Animal Studies Committee. Immunodeficient NOD.Cg-PrkdcIn vivo bioluminescence imaging (BLI) was performed on the weeks indicated on an IVIS Lumina . Mice were injected intraperitoneally with D-luciferin  and both dorsal and ventral sides were imaged 10min later using isoflurane anesthesia (2% vaporized in O2). Total photon flux (photons/sec) was measured from fixed regions of interest (RIOs) over the entire mouse using Living Image 2.6.Four-five weeks post tumor and 72 hour post Ad vector intravenous injection, mice were anesthetized with 2.5% 2, 2, 2-tribromoethanol , perfused via the left ventricle with phosphate-buffered saline (PBS) followed by 10% neutral buffered formalin. Bones and organs were harvested and processed as detailed further in Supplementary Methods.Details regarding immunofluorescence are presented in Supplementary Methods.Methods and details of bone processing and imaging for microCT are described in Supplementary Methods.Overall methods of protein extract preparation were similar to previous work  and provFluorescence and bright field microscope images were collected using a DP80 dual color/monochrome sensor CCD camera  with CellSens Dimension software (Olympus Soft Imaging Solutions) with Extended Focal Imaging (EFI) function. Wide-filed images were also collected using defined scanning area mode with multiple image alignment (MIA) algorithm. Imaging experiments were repeated at least three times on independent sets of vector-injected mice. Confocal fluorescence microscope images were collected using an Olympus FV1000 confocal microscope equipped with an UPlanApo 100\u00d7/1.35 numerical aperture oil immersion objective and analyzed with Fluoview version 1.7a software . Collected images were processed into standard tagged image file (TIF) format using CellSens Dimension software (Olympus Soft Imaging Solutions) with Extended Focal Imaging (EFI) function.Further Materials and Methods details are provided in the Supplementary Information."}
+{"text": "Fusarium oxysporum f. sp. ciceri Race 1 (Foc1) infection. Transcriptomic dissections using RNA-seq showed significantly differential expression of molecular transcripts between infected and control plants of both susceptible and resistant genotypes. Radar plot analyses showed maximum expressional undulations after infection in both susceptible and resistant plants. Gene ontology and functional clustering showed large number of transcripts controlling basic metabolism of plants. Network analyses demonstrated defense components like peptidyl cis/trans isomerase, MAP kinase, beta 1,3 glucanase, serine threonine kinase, patatin like protein, lactolylglutathione lyase, coproporphyrinogen III oxidase, sulfotransferases; reactive oxygen species regulating components like respiratory burst oxidase, superoxide dismutases, cytochrome b5 reductase, glutathione reductase, thioredoxin reductase, ATPase; metabolism regulating components, myo inositol phosphate, carboxylate synthase; transport related gamma tonoplast intrinsic protein, and structural component, ubiquitins to serve as important nodals of defense signaling network. These nodal molecules probably served as hub controllers of defense signaling. Functional characterization of these hub molecules would not only help in developing better understanding of chickpea-Foc1 interaction but also place them as promising candidates for resistance management programs against vascular wilt of legumes.Plants\u2019 reaction to underground microorganisms is complex as sessile nature of plants compels them to prioritize their responses to diverse microorganisms both pathogenic and symbiotic. Roots of important crops are directly exposed to diverse microorganisms, but investigations involving root pathogens are significantly less. Thus, more studies involving root pathogens and their target crops are necessitated to enrich the understanding of underground interactions. Present study reported the molecular complexities in chickpea during  Medicago and Lotus and soil inhabiting pathogens [Legumes are well known for their nutritive value consisting of easily digestible proteins .Besides,athogens ,3, but rathogens ,5,6,7. Hathogens .Fusarium wilt was known to be primarily managed by conventional breeding programs. But pathogenic variability and mutability have led to the breakdown of natural resistance over prolonged periods [Fusarium wilt of chickpea.Chickpea tops the Indian list of important pulse legumes . But, va periods . Besides periods . Hence, Fusarium resistance in chickpea as well as other legumes [in planta signaling network yet remains incomprehensible that necessitates more transcriptomic analytical results. Although, large body of information indicates towards simultaneous participation of many intricate metabolic events but lack of fully annotated host genome sequence fails to plug the gap in this particular defense network. Moreover, wide genomic diversification across model legumes and crop legumes fails to completely transfer the knowledge of metabolic events from model plants to crop plants [Previous reports on chickpea-Foc1 interaction documented transcriptomic alterations during pathogen attack \u201316. Besi legumes \u201319. Even legumes . Followi legumes . Reactiv legumes . With alp plants . Thus, iThe advent of next generation sequencing tools and techniques has made a paradigm shift in the field of functional genomics as it generates large data sets. In present study RNA-seq was performed at early time point  upon Foc1 invasion and differential transcriptomic dissection was performed. The analyses revealed induction as well as suppression of several defense responsive transcripts. Finally attempts were made to map the defense responsive components in an inter-connected defense regulatory network and identify the regulatory hubs that presumably control the entire defense signaling cascade in chickpea during Foc 1 attack.SRP041784 and BioProject ID PRJNA246444. Following adapter trimming 132.55 million, 89.6 million, 77.84 million, 89.86 million filtered reads were obtained for infected JG62 (represented by J4), uninfected JG62 (represented as JC), infected WR315 (represented as W4), uninfected WR315 (represented as WC), respectively. High quality (>Q20) bases were more than 96% for all the samples with low non ATGC characters (0.09%) for all the samples  between J4 and JC were 2090 while between W4 and WC were 881 . Fig 3 dRadar plot analysis explains the distribution of fold change of the entire transcripts as obtained from the base mean values of each transcript. The blue line explains the fold change value of transcripts that are found only in susceptible JG62 plants whereas red line demonstrates the expression values of transcripts found exclusively in resistant WR315 plants. The region where red and blue lines overlap with one another explains transcripts that are found in both JG62 and WR315 plants. Green line independently explains the transcripts that are found to be induced in JG62 and WR315 plants only after infection. All the transcripts undulate significantly but the transcripts that are found to be induced only after infection exhibit maximum expressional values. The surface distribution of the transcripts also exhibited defense, metabolism, signaling and ROS regulations with varied expressional values .Clustering of total annotated transcripts based on gene ontology showed varying distribution of transcripts across biological process, molecular function and cellular components . AmongstFunctional categorization demonstrates that among eight distinct categories the highest number of transcripts belongs to the metabolism group. Signaling and defense related transcripts are the other two major groups that are found to be induced after infection. Protein synthesis and degradation events were also found to be induced . BesidesMost of the selected transcripts showed up regulation in both JG62 and WR315 plants except SEO, PEC and HDH. Among the up regulated components of the transcripts EF1, MPK and PR1 displayed highest expressional induction and all the three transcripts show greater induction in susceptible plants as compared to the resistant plants. Besides, PR5B expression was found to be largely comparable in both JG62 and WR315 plants. In case of ASCEND the induction in JG62 is more than that of WR315 plants. Rest of the positively induced transcripts e.g. HSP, IFG, WR and ENOD the expression level of WR315 was more than that of JG62, whereas, other transcripts marginally varied among themselves. Contrarily, PTR5 induced in JG62 but the expression was dramatically reduced in WR315 plants. Among the down regulated transcripts except SEO, expression of other transcripts  were significantly low in case of susceptible (JG62) plants than that of resistant (WR315) plants .Network analyses was performed with only those set of TAIR protein homologues that showed interactions with at least a single neighbor while rest of the proteins showing no interconnections with relatives were eliminated. Interaction map showed the location of several defense responsive components such as TOR (Serine threonine protein kinase), ROC (Peptidylprolylcis trans isomerase), BGL2 (Beta glucosidase), ATGLX (Lactolylglutathionelyase), ST2A (Sulfotransferase), MPK6 (MAP kinase), CSLD3 (Cellulose synthase), PGIP  and LIN2 (Coproporphirinogen III oxidase). Storage component PLA2A (Patatin like protein) and ROS related component ATP1 (V type ATPase), VHA-A (V type ATPase), ATCBR (Cytochrome b5 reductase), RBOH (Respiratory burst oxidase), CSD/MSD (Manganese or copper superoxide dismutase), RSR4 (Reduced sugar response 4), NTRC/B (NTRC/ NADPH-dependent thioredoxinreductase C/B) were also found , S1 FileLarge number of metabolic components like MEE58(S-adenosyl-L-homocysteine hydrolase), CYT1(Cytokinesis defective 1), GLT1(Glucose transporter 1), MTO3 (Methionine over-accumulator 3), APR3(APS reductase 3), C4H(Cinnamate 4-hydroxylase), LOX1(Lipoxygenase 1), PCK1(Phosphoenolpyruvate carboxykinase), CWINV1, ADH1(Alcohol dehydrogenase), ACO1(ACC oxidase 1), MLS , ASN1(Glutamine-dependent asparagine synthase 1), RNR1(Ribonucleotide reductase 1), HOT5 (Sensitive to hot temperatures 5), SHM1(Serine hydroxymethyltransferase 1), FDH (Formate dehydrogenase), P5CS1(Delta1-pyrroline-5-carboxylate synthase 1), LIP1(Lipase 1), SDH1(Succinate dehydrogenase), RHM1(Rhamnose biosynthesis 1), AMY1 (Alpha-amylase-like), SBE2.2 (Starch branching enzyme 2.2), MTLPD2 (Lipoamide dehydrogenase 2), MIPS2 (Myo-inositol-1-phosphate synthase 2), IPP2 , GDH3 (Glutamate dehydrogenase 3),TIM , IVD , PMDH1 , ADSS (Adenylosuccinate synthase), GR (Glutathione reductase), SUS4 (Sucrose synthase 4) were found to interconnect in the metabolic regulatory pathway , S1 FileProtein synthesis and degradation related components FKBP15-2 (Peptidyl-prolyl cis-trans isomerase), UBQ1(Ubiquitin 1), UBQ10 (Ubiquitin 10), UBQ35 (Ubiquitin 35), PaB1(Proteasome subunit), HD (Histone deacetylase), RPT2A (Proteasome component), T6D22.3 (Elongation factor), EMB2780 (DNA polymerase), LBA1(Regulator of nonsense transcript like protein), RUB1 (Ubiquitin), PBE1(Proteasome components), ATHMG (FACT complex subunit SSRP1) were mapped in the interaction pathway. Besides several structural components like LHB1B1(Chlorophyll a/b binding protein), LHCA2 (Chlorophyll a/b binding protein), Delta TIP (Delta Tonoplanst intrinsic protein), Gamma TIP (Gamma Tonoplanst intrinsic protein), ELIP1(Early light inducible protein), GCP2(Tubulin gamma chain), FLA12 , IRX3 (Cellulose synthase), ATFH8 (Formin like protein), NFU4 (NifU like protein), TUA6 , SMC2 , F8L15.150 (KRR motif containing protein 1) were found , S1 FileTransport controlling components such as CHX20 (K+/N+ antiporter), SKD (Vacuolar sorting protein), NRT (Nitrate transporter), ATGCN (ABC transporter family protein), SUC 2 (Sugar transporter) were found to interact in the interaction pathway , S1 FileAmongst the several components mentioned above, PLA2 showed overlapping role in storage and defense. Besides, ATGLX1, ST2A, LIN2 and CSLD3, served as regulators of direct defense, as well as acted in regulating host metabolic activities. TOR, MIPS and LIP1 showed overlapping roles in regulating defense, metabolism as well as signaling, Gamma-TIP a structural component regulated metabolism and transport. RUB also being a structural component regulated protein synthesis and degradation.Fusarium interaction attempts have been made to develop an understanding of how roots trigger defense signaling cascades and tackle the scuffle with its invading pathogen using RNA-seq approach. This study reports a large number of transcripts with low non ATGC characters marking the library to be of good quality. Radar plot analyses showing maximum expressional values of defense, metabolism, signaling and ROS regulation related transcripts projected them as key regulators of defense in chickpea-Foc1 interaction. GO based analyses showed comparatively less number of transcripts related to direct defense as compared to transcripts regulating transcription, carbohydrate metabolism and proteolysis suggesting that imparting defense to a system is a complex phenomenon, probably controlled by multidimensional regulatory mechanism. Besides large number of transcripts regulating ATP binding suggested a constant need of energy to meet up internal as well as external requirements [Plants use above ground green tissues to convert solar energy to biological energy that directly or indirectly sustains all life forms on earth. But, the essentiality of roots in fuelling this life sustenance process remains mostly ill noticed . In addiirements . Abundanirements . The stuPhytopthora sojae [Glycine max, where the decisive role is determined by MKK4, the upstream factor of MPK6 [Arabidopsis thaliana during powdery mildew disease [Arabidopsis thaliana and Oryza sativa NTRs (Thioredoxin reductase) transfer reducing power to thioredoxin/peroxiredoxin system for scavenging ROS [Arabidopsis thaliana cytochrome b5 reductase) acts as important component of electron transport chain that regulates oxidoreductase activity and in the process regulates redox signaling [ROCs (Peptidyl proplyl cis trans isomerase), a class of plant immunophilins/cyclophilins are reported to catalyze the activation of several pathogen effectors by bringing about their conformational alterations and triggering R gene mediated host defense response . Soybeanra sojae . In presra sojae . TOR prora sojae . In presra sojae . Conversra sojae . They arra sojae . In presra sojae . They acra sojae . Interesra sojae . ATGLXs ra sojae . In presra sojae . The dow of MPK6 . MPK6 al of MPK6 , 35. The of MPK6 . Inducti of MPK6 . The PG- of MPK6 . The ind disease . The enh disease . PLA2A  decides the upshot of interaction. In present study several metabolic transcripts were found to be integrated in the defense regulatory network. MEE (S-adenosyl L-homocysteine hydrolase) maintains the methylation potentials in an organism. Downregulation of MEE was reported to lower Hsyringae . Upreguleraction . CYT1  is known to regulate polyamine and ethylene biosynthesis. Besides, MTO3 was reported to be co-expressed with ACO2 (ACC oxidase) during water stress in maize . In presin planta pathogen establishment [CWINV1  is believed to function as the key enzyme for reconstruction of damaged cell wall . Upregullishment . Intereslishment . Upregullishment . ASN (Gllishment . In preslishment . Upregullishment . Upregulin planta growth of Foc1. SETH2 (Glucosyltransferase 2) regulates GPI anchor biosynthesis and cell wall protection [2O2 production in sweet potato [2O2 levels reported to be hazardous for chickpea during Foc1 attack  is important component regulating drought stress via ABA dependent pathways. Sulphur acts in maintaining cellular redox balance and mitigates damage caused by ROS . In presotection . In prest potato . In the 1 attack . MLS  and MPK6 simultaneously during d tomato . In presegulated . Decreasoduction . Thus, osistance   involved in ubiquitin dependent catabolic process was reported to be induced during infection caused by thaliana . Howeverthaliana . Interesthaliana . In presthaliana . Additio in rice . Down re in rice . Increas. LBA1 (Regulator of nonsense transcript like protein) proteins initiate nonsense mediated mRNA decay (NMD) which is conserved mechanism that target aberrant mRNAs for decay. Pathogen responsive genes including SA responsive molecular markers genes and PR genes were upregulated in NMD deficient plants in Arabidopsis thaliana which showed partial resistance to Pseudomonas syringae [EMB2780 DNA polymerases are well known for their roles in DNA repair which ultimately affect the translation process and protein quantum. Studies show that homologous recombination based repair mechanism are enhanced in plants exposed to biotic stresses and often the changes incurred are conserved as epigenetic modifications for ensuring better adaptation over the generations . Upregulsyringae . EnhanceArabidopsis thaliana suggest that the downregulation of these proteins result in accumulation of ROS which is decreased by ABA under drought stressed condition [Many structural proteins are also altered during pathogen infection. LHB1B1 and LHCA2 (Chlorophyll a/b bonding proteins) are abundant class of proteins that are affected by light, oxidative stress, chlorophyll retrograde signaling, circadian clock and ABA. Reports on ondition . In presondition . HoweverMelamspora lini [Vitis vinifera during infection by biotrophic oomycete Plasmopara viticola [GCP2 (Gamma tubulin protein complex 2) contributes in microtubule nucleation that leads to the formation of organized microtubule arrays of cellular cytoskeleton . Pathogeora lini . Similarviticola . Howeverviticola . Mutatioviticola . DecremeIRX3 (Irregular xylem 3) belongs to cellulose synthase group of proteins that regulate synthesis of cellulose microfibrils that make up for primary cell walls. Downregulation of this class of protein leads to disruption of cell wall which makes the host susceptible to pathogen attack . Hence, Arabidopsis [Arabidopsis ABC transporter belonging to GCN superfamily) was also reported control stomatal and/or apoplastic defenses against Pseudomonas syringae p.v tomato DC3000 in Arabidopsis [+/proton  and NIA2 (Nitrate reductase) are known to control nitric oxide (NO) biosynthesis and transport. However, the role of NO in defense is quite mysterious as it has been found to favour both the invader and the host and at times reported to have dual roles which depends who takes command over whom and when during the course of pathogenetic events . NRT1.1 bidopsis . In the bidopsis . In presbidopsis . Upregul+/proton .Arabidopsis [Arabidopsis thaliana suggest that during water deficit conditions SUC2 are upregulated for allocating relatively more carbon to the roots for maintaining their normal metabolic activities [SKD (Suppressor of K+ transport growth defect 1) represent an ATP consuming vacuolar sorting protein 4 (VSP4). It is the core component of ESCRT pathway  that degrades plasma membrane proteins. Ubiquitination of appropriate plasma membrane protein cargos are important in regulating development and stress . Besidesbidopsis . In the tivities . Decremetivities . In the The present study highlights the regulatory complexities of defense responses in chickpea during Foc1 infection. The study identifies several differentially expressed components regulating the host-pathogen interaction network. However, amongst them, handful components were found to share overlapping roles. For example ROC7 regulated folding and synthesis of defense related proteins. MPK6 regulated defense response, signaling as well as ROS metabolism by interacting with RBOH, MSD and CSD. BGL2 had role in regulating defense and modulating metabolism by influencing the expression of CYT1. TOR was found to be a direct regulator of defense and ROS through its connection with ATCBR, RSR4, GR, NTRC/B and ATPase. ATGLX1, LIN2 and ST2A had overlapping role in defense and metabolism while PLA2A being a storage component also regulated defense. Gamma-TIP, a structural component regulated both metabolism and transport. MIPS and P5CS1 had roles controlling signaling as well as metabolism. RUB, a structural component regulated protein synthesis and degradation .Therefore, in the entire Chickpea-Foc1 interaction network, the above mentioned molecules with overlapping roles probably modulated the defense signaling network by forming signal controlling nodal hubs. These hub components with defined mode of action may pose themselves as promising candidates for resistant management programs of legumes using genetic engineering technique.Cicer arietinum L.) seeds obtained from International Crops Research Institute for Semi-Arid Tropics (ICRISAT), Patancheru, Andhra Pradesh, India were used for performing the experiments. Seeds were sown in mixture of sand: synthetic soil (1:1) and plantlets maintained under natural greenhouse conditions with temperatures ranging from 22\u201328\u00b0C, humidity 35\u201340%, and photoperiod of 16:8 hours day and light, respectively.Wilt susceptible (JG62) and wilt resistant (WR315) chickpea (Fusarium oxysporum f. sp. ciceri (Foc1), obtained from ICRISAT, purified and maintained according to Summerell, Salley & Leslie [Fungal strain of & Leslie . Spores Seeds of both JG62 and WR315 were surface sterilized and germinated in sterile synthetic soil. Fourteen days old seedlings were used for the infection assay. Infection with Foc1 was induced by sick soil method as described by Gupta et al . Optimal\u00b0C) in the presence of divalent cations and reverse transcribed with Superscript III Reverse transcriptase by priming with Random Hexamers. Second strand cDNA was synthesized in the presence of DNA Polymerase I and RnaseH. The cDNA was cleaned up using Agencourt Ampure XP SPRI beads (Beckman Coulter). Illumina Adapters were ligated to the cDNA molecules after end repair and addition of A base. SPRI cleanup was performed after ligation. The library was amplified using 11 cycles of PCR for enrichment of adapter ligated fragments. The prepared library was quantified using Nanodrop and validated for quality by running an aliquot on High Sensitivity Bioanalyzer Chip (Agilent).Library was constructed according to the Illumina TruSeq RNA library protocol outlined in \u201cTruSeq RNA Sample Preparation Guide\u201d . RNA purity was analysed by calculating RNA integrating number (RIN) for both uninfected and infected samples prior to mRNA preparation . RNA samhttp://genotypic.co.in/SeqQC.html) to generate high quality reads for use in assembly. The reads were filtered or trimmed for adapters, B trimming and other low quality read trimming by standard methodology (CASAVA 1.7User Guide). These high quality, filtered reads were used for further analyses.Illumina Hiseq 1000 platform was used to generate paired end short reads using Sequencing By Synthesis (SBS) method. Standard illumine pipeline (RTA-CASSAVA-OLB) was used to generate short reads in FASTQ format. Accuracy of base calling was reflected in the quality scores which were performed after filtering. Quality control was done using in-house program (Seqc V2.1- http://www.ebi.ac.uk/zerbino/velvet/). Draft assembly was built with fixed hash length for each sample. The values of the estimated insert length, insert length standard deviation and expected coverage for the all the draft assemblies were also calculated. The resulting contigs were assembled into transcripts by Oases-2.01 (http://www.ebi.ac.uk/zerbino/oases/), using the assembly of velvet that clustered them into small groups (loci). Paired end information was used to construct transcript isoforms. Assembly statistics were calculated using in-house Perl scripts. The transcripts from all assemblies were clustered (CD_HIT v 4.5.4 http://www.bioinformatics.org/cd-hit/) to generate a comprehensive de novo reference assembly. Sequence identity threshold and alignment coverage (for the shorter sequence) were both set to 80% to generate clusters. Such clustered transcripts are defined as reference transcripts in the present study.Contig assembly for all the uninduced and induced samples of JG62 and WR315 was carried out using a de Bruijn graph algorithm based de novo genome assembler Velvet-1.1.07 (Cicer arietinum [http://www.ebi.ac.uk/Tools/pfa/iprscan/) was used to scan Pfam database for identifying protein domains. Final annotation table was prepared giving preference to Swiss-Prot, PlantCyc and KOG databases following which GenBank Viridiplantae mRNA or TreEMBL annotations were assigned. Pfam annotations were assigned to only those trasnscripts that did not show matches with any of the above mentioned databases.Functional annotations of transcripts were carried out using Viridiplantae (Papilionoideae) database of mRNA datasets of NCBI. Although recent researches have identified the whole draft genome sequence of rietinum ,7, but thttp://www-huber.embl.de/users/anders/DESeq/). P value cutoff of 0.05 was used to filter statistically significant results. Fold change was calculated from the base mean value of treated samples with their corresponding control sample. P values were further adjusted maintaining standard parameters assigning specific Q values to P significant differential transcripts. Only Q significant transcripts were considered for downstream functional clustering and network generation.Differential expression analyses were performed by employing a negative binomial distribution model , metabolism, signaling, protein synthesis and degradation, transport, structural and storage.The functional categorization of Q significant annotated transcript was performed using ChartTool software package. The number of transcripts in each category was used as an input to generate pie chart of total transcripts. Pyramiding of each category was also performed using individual transcript number of each group. The area of each stage of the pyramid corresponds to the abundance of transcript group of the category.The expression patterns of the transcripts from the base mean value were demonstrated through radar plot analyses using Excel Stat software plug in. The fold change value of susceptible JG62 plants and resistant WR315 plants were obtained from base mean values of each transcripts after infection and its cognate control values. The transcripts that are expressed only after infection in both the susceptible and resistant plants without any cognate control values, the fold change was calculated by normalizing the data with base mean values of susceptible JG62 plants. A surface plot using all the fold change values of the entire transcript set was also performed.C-\u0394\u0394T method [Twenty transcripts from the NGS dataset were randomly selected and quantitative real time PCR (qRT-PCR) was carried out on Bio-Rad iCycler (Bio Rad iQ5) using SyBr green technology. Total reaction volume of 20 \u03bcl comprised of SyBr green qPCR Supermix (2X) (BioRad), 25ng cDNA and 0.3 \u03bcM sequence specific forward and reverse primers . PCR cycT method .All expeInteraction network was generated using Pathway studio version 10.1 in two different ways. Initial network was generated by importing the entire experiment set bearing differential transcripts with significant P values (<0.05). Further sub networks were generated according to different sub divisional functional classes such as direct defense, reactive oxygen species generation (ROS), metabolism, signaling, protein synthesis and degradation, transport, structural and storage. In both cases differential transcripts identified by RNA-seq studies were subjected to BLAST analyses at TAIR database (The Arabidopsis Information Resource) and their homologous genes , (B) and WR315 control (E), (F); JG62infected (C), (D) and WR315 infected (G), (H) at 48 hours post infection stained with Trypan blue and lactophenol. Bars represents 10\u03bc respectively.Sectional views of control and infected roots of chickpea plants JG62 (TIF)Click here for additional data file.S2 FigThe bars here represent the number of reads obtained for samples JC (uninduced susceptible), J4 (induced susceptible), WC (Uninducedresistant), W4 (induced resistant). Blue bar represents raw reads and red represents processed reads.(TIF)Click here for additional data file.S3 FigThe bars here represent the number of contigs of variable base pairs for J4 represented by blue bar, JC represented by red bar, W4 represented by green bar, WC represented by violet bar.(TIF)Click here for additional data file.S4 FigThe bars here represent the number of transcripts of variable base pairs for J4 represented by blue bar, JC represented by red bar, W4 represented by green bar, WC represented by violet bar.(TIF)Click here for additional data file.S5 FigA. Percentage of transcript down regulated only in JG62 (blue), only in WR315 (red) and in both JG62 and WR315 (green). B. Percentage of transcript upregulated only in JG62 (blue), only in WR315 (red) and in both JG62 and WR315 (green).(TIF)Click here for additional data file.S6 FigA. represents RNA integrity of JC (uninduced susceptible), B. represents RNA integrity of J4, C. represents RNA integrity of WC (uninducedreesistant), D. represents RNA integrity of W4 (induced resistant).(TIF)Click here for additional data file.S1 TableTable containing read statistics of JC, J4, WC, and W4.(XLS)Click here for additional data file.S2 TableTable containing contig statistics of JC, J4, WC, and W4.(XLS)Click here for additional data file.S3 TableTable containing transcript statistics of JC, J4, WC, and W4.(XLS)Click here for additional data file.S4 TableTable containing representative transcript number and sizes between of JC and J4, WC and W4 respectively.(XLS)Click here for additional data file.S5 TableTable containing transcript annotation statistics.(XLSX)Click here for additional data file.S6 Table(XLS)Click here for additional data file.S7 Table(XLS)Click here for additional data file.S8 TableTable includes gene list of down regulated and up regulated transcripts in chickpea upon foc1 infection.(XLSX)Click here for additional data file.S9 TableTable containing list of protein names and their abbreviation used in the Radar plot.(XLSX)Click here for additional data file.S10 TableTable includes list of primer pairs sequences used for qRT-PCR for representative transcripts with their respective abbreviations.(XLSX)Click here for additional data file.S11 TableTable containing list of proteins, their abbreviations used for pathway construction and TAIR homologous IDs of the identified proteins used as input for network generation.(DOC)Click here for additional data file.S1 FileThe document shows interaction of proteins belonging to different biological classes such as defense, metabolism, protein synthesis and degradation, reactive oxygen species generation, signaling and storage in chickpea obtained post infection with Foc1.(PDF)Click here for additional data file."}
+{"text": "Escherichia coli NB8 is a clinical pyelonephritis isolate. Here, we report the draft genome sequence of uropathogenic E.\u00a0coli NB8, which contains drug resistance genes encoding resistance to beta-lactams, aminoglycosides, quinolones, macrolides, colistin, sulfonamide-trimethoprim, and tetracycline. NB8 infects the kidney and bladder, making it an important tool for studying E.\u00a0coli pathogenesis. Escherichia coli is the predominant species, leading to 75% to 95% of UTIs in otherwise healthy young women (De novo assembly was done with Edena version 3 (Escherichia coli SE15 (GenBank accession no. NC_013654). The de novo assemblies and alignment-based contigs were merged using Gap4 (Urinary tract infections (UTIs) account for more than 7 million office visits and 1 million hospitalizations annually in the United States, making them the most common bacterial infections acquired in the community and in hospitals , aminoglycosides , macrolides [mph(2\u2032)-I and macA], colistin (arnA), sulfonamide-trimethoprim , and tetracycline [tet(A) and two copies of tet(C)]. Further analysis discovered mutations encoding amino acid substitutions at TCG(S)\u221283\u2192TTG(L),GAC(D)\u221287\u2192AAC(N) within the quinolone resistance-determining regions (QRDR) of gyrA, and AGC(S)\u221280\u2192ATT(I) of parC. In addition, the genome encodes numerous transposases and insertion sequences, highlighting the importance of genomic exchange in creating the NB8 pathogenic phenotype.The draft genome sequence of UPEC NB8 will aid in precise genetic manipulation and thereby further improve the study of UPEC virulence.E.\u00a0coli NB8 have been deposited at DDBJ/EMBL/GenBank under the accession no. LBIS00000000.The genome sequences of the uropathogenic"}
+{"text": "The generation of full thickness human skin from dissociated cells is an attractive approach not only for treating skin diseases, but also for treating many systemic disorders. However, it is currently not possible to obtain an unlimited number of skin dermal cells. The goal of this study was to develop a procedure to produce skin dermal stem cells from induced pluripotent stem cells (iPSCs). Skin-derived precursor cells (SKPs) were isolated as adult dermal precursors that could differentiate into both neural and mesodermal progenies and could reconstitute the dermis. Thus, we attempted to generate SKPs from iPSCs that could reconstitute the skin dermis. Human iPSCs were initially cultured with recombinant noggin and SB431542, an inhibitor of activin/nodal and TGF\u03b2 signaling, to induce neural crest progenitor cells. Those cells were then treated with SKP medium that included CHIR99021, a WNT signal activator. The induction efficacy from neural crest progenitor cells to SKPs was more than 97%. No other modifiers tested were able to induce those cells. Those human iPSC-derived SKPs (hiPSC-SKPs) showed a similar gene expression signature to SKPs isolated from human skin dermis. Human iPSC-SKPs differentiated into neural and mesodermal progenies, including adipocytes, skeletogenic cell types and Schwann cells. Moreover, they could be induced to follicular type keratinization when co-cultured with human epidermal keratinocytes. We here provide a new efficient protocol to create human skin dermal stem cells from hiPSCs that could contribute to the treatment of various skin disorders. An important goal of current bioengineering efforts is to generate or reconstitute fully organized and functional organ systems from dissociated cells that have been propagated under defined tissue culture conditions. Stem cells (SCs) have the unique capacity to self-renew and to differentiate into the cell lineages that constitute their tissue of origin. Within the tissue, SCs reside in a specialized environment (termed the niche) and regulate their proliferation and differentiation to maintain and regenerate tissue \u20133.Several kinds of SCs reside in the skin and they will be useful in the treatment of diseases and other skin problems such as burn wounds, chronic wounds and ulcers. Epithelial SCs reside in the bulge region of the hair follicle (HF), a specialized portion of the outer root sheath epithelium defined as the insertion site of the arrector pili muscle \u20137. BulgeOn the other hand, despite the remarkable regenerative capacity of the skin dermis, adult dermal SCs have not yet been fully defined. Skin-derived precursor cells (SKPs) have been isolated as a self-renewing, multipotent precursor population from the dermis of rodents and humans . SKPs caThus, SKPs are attractive tools for regenerating the skin dermis, however, isolating SKPs from human skin requires invasive surgical procedures and the cells isolated may have limited or variable abilities to proliferate and/or differentiate depending on the age of the donor and the culture conditions. Mesenchymal stem cells (MSCs), defined as cells that self-renew and are able to give rise to multiple mesenchymal tissues, also have the same problems. Therefore, there have been many studies that generated MSCs from pluripotent stem cells . TherefoIn this report, we provide an efficient induction protocol of SKPs from human iPSCs. The human iPSC-derived SKPs (hiPSC-SKPs) express several genes and proteins that have been previously reported to be expressed by human SKPs . As for A human iPS cell line (201B7) generated by introducing four transcription factors  into human skin fibroblasts  was usedWhen hiPSC colonies reached 80\u201390% confluence, they were dissociated into small cell clumps by pipetting several times and were then plated on SNL feeder cells in hiPSC medium without bFGF, including 500 ng/ml noggin (R&D Systems) and 10 \u03bcM SB431542 (Tocris Bioscience). After 5 days of culture, the hiPSC medium was removed and the cells were washed with D-PBS, after which they were cultured for 3\u20135 days in SKPs medium containing DMEM/F12 (Life Technologies), 2% B27 supplement (Life Technologies), 100 units/ml penicillin and 100 \u03bcg/ml streptomycin (Life Technologies), 40 ng/ml bFGF (Wako), 20 ng/ml EGF (R&D Systems) and 3 \u03bcM CHIR99021 . When cells reached 80% confluence, they were dissociated using Accutase cell detachment solution (BD Biosciences) and were subcultured in new dishes in SKPs medium without CHIR99021. Do as CHIR99021, 5 \u03bcM Wnt-C59 (Cellagen Technology), 5 \u03bcM DAPT (Cellagen Technology), 1 \u03bcM Hh-Ag1.5 (Cellagen Technology), 5 \u03bcM PD0325901 (Bio Vision) were treated for 3\u20135 days, respectively.4 cells/cm2 and allowed to adhere overnight in SKPs medium. Adipogenic differentiation was induced for 2 weeks using medium consisting of MEM (Life Technologies), 15% rabbit serum (Sigma Aldrich), 0.45 nM IBMX (3-isobutyl-1-methylxanthine) (Sigma Aldrich), 2.07 \u03bcM insulin (Sigma Aldrich) and 100 nM dexamethasone (Sigma Aldrich); all media were changed every 3\u20134 days. The cells were stained with oil red-O solution (ScienCell Research Laboratories).For adipogenic and osteogenic differentiation, cells were seeded at 3x10Osteogenic differentiation was induced for 2 weeks using medium consisting of MEM (Life Technologies), 10% fetal bovine serum (Hyclone Laboratories), 100 nM dexamethasone (Sigma Aldrich), 10 mM \u03b2-glucerophosphatase (Sigma Aldrich) and 50 \u03bcM L-ascorbic acid-2 phosphate (Sigma Aldrich); all media were changed every 3\u20134 days. Alkaline phosphatase (ALP) activity was determined using a Vector Blue Alkaline Phosphatase Substrate kit (Vector Laboratories).4 cells/cm2 on dishes coated with 0.02 mg/ml laminin (Sigma Aldrich) and 0.1 mg/ml poly-L-lysine (Sigma Aldrich) and were allowed to adhere overnight in SKPs medium. Cells were then cultured in Schwann cell differentiation medium consisting of DMEM/F12 (Life Technologies), N2 supplement (Life Technologies), 5 \u03bcM forskolin (Sigma Aldrich) and 50 ng/ml heregulin-1 \u03b2 (Peprotech) for 3 weeks; all media were changed every 2\u20133 days. Immunofluorescent analysis was used to examine the expression of S100\u03b2 (Sigma Aldrich).For Schwann cell differentiation, cells were seeded at 0.5x10RNAs were prepared from 3 sets each of 5 day (NC) and 9 day (iPS-SKPs) cells in culture using RNeasy (Qiagen). The RNA samples were hybridized to Affimetrix GeneChip Human Genome U133 plus 2.0 Arrays and were analyzed using an Affimetrix GeneChip system. Microarray data were analyzed using GeneSpring software (Agilent Technologies).Total RNAs were extracted using RNeasy (Qiagen). cDNAs were synthesized by reverse transcription of 1 \u03bcg total RNA using a high capacity RNA-to cDNA kit (Applied Biosystems). PCR analysis was performed with KOD DNA polymerase (Toyobo) using the primers listed in Cells were fixed with 4% paraformaldehyde (Wako) for 15 min, permeabilized with 0.1% Triton X-100 for 5 min and blocked with 10% goat serum (Nichirei Bioscience) in PBS for 1 hr at room temperature (RT). Cells were incubated with primary antibodies for 2 hr at RT before incubation with appropriate secondary antibodies for 1 hr at RT, prior to counterstaining with 4\u2019,6-diamidino-2-phenylindole (DAPI)(Dojindo Laboratories). Samples were observed using a Leica fluorescent microscope (Leica Microsystems). The primary antibodies used were: anti-nestin antibody , anti-fibronectin antibody , anti-\u03b1SMA antibody , anti-S100\u03b2 antibody  and anti-trichohyalin antibody . Secondary antibodies used were: Alexa Fluor 488-conjugated goat anti-mouse (1:200) and Alexa Fluor 546-conjugated goat anti-rabbit .After cells were detached and collected, they were fixed and permeabilized with cytofix buffer for 20 min. After washing with Phosflow Perm/Wash buffer, cells were incubated for 30 min with the anti-nestin antibody conjugated with PerCP-CyTM5.5 and with the anti-fibronectin antibody conjugated with Alexa fluor 488 (both from BD Biosciences). Isotype-matched monoclonal antibodies (mAbs) were used as negative controls. In order to calculate the differentiation efficiency of iPSCs into SKPs, stained cells were analyzed using BD FACSVerse with FACSuite software (BD Biosciences)4 cells of each cell type were mixed and cultured in 96-well-round-bottom assay plates (Cell Seed) containing 200 \u03bcl Amniomax C-100 medium (Life Technologies) with medium changes every 1\u20132 days. After 7 days in culture, cell aggregates were embedded in OCT compound  and then frozen sections were stained.Human primary keratinocytes (J-TEC) were cultured in keratinocyte medium (J-TEC). Human primary fibroblasts (Kurabo) were cultured in DMEM (LifeTechnologies) including 5% fetal bovine serum (Hyclone Laboratories). Human dermal papilla cells (Cell Applications) were cultured in dermal papilla cell medium (Cell Applications). Four x 10To generate SKPs from hiPSCs, we established a step-wise differentiation protocol in which hiPSCs were initially differentiated to the multipotent neural crest stage as precursor cells of SKPs . Human iWe next performed gene expression analysis to characterize which signals were regulated during the NC to iPSC-SKPs differentiation . The up-In order to characterize hiPSC-SKPs, we examined their expression patterns of genes that have been well characterized for SKPs , 23. RT-To determine whether hiPSC-SKPs are also functionally similar to traditional SKPs, we examined the differentiation potentials of hiPSC-SKPs. hiPSC-SKPs were cultured in each differentiation medium for 2 or 3 weeks. Adipogenic differentiation was conducted in adipogenic differentiation medium. After 2 weeks of differentiation in that medium, the hiPSC-SKPs displayed significant lipid accumulation in the cytoplasm, which was positively stained with oil Red-O . The mRNHuman epidermal keratinocytes and dermal fibroblasts, dermal papilla cells or hiPSC-SKPs were mixed and co-cultured in 96-well-round-bottom assay plates. After 7 days in culture, aggregates consisting of epidermal keratinocytes and hiPSC-SKPs expressed trichohyalin , an HF sIn the present study, we developed a simple and efficient method to induce hSKPs from hiPSCs. The induction efficiency of this method is very high (over 95%) in a short period and the hiPSC-SKPs exhibit SKP characteristics under maintenance culture conditions.SKPs were originally isolated as adult SCs capable of generating neural cell types from mammalian skin . SKPs alIn this study, hiPSC-SKPs exhibit many of the differentiation properties attributed to SKPs previously reported for multiple cell lineages including adipocytes, skeletogenic cell types and Schwann cells. Thus, our induction method can induce multipotent SCs similar to SKPs. However, hiPSC-SKPs also are able to differentiate into osteogenic cells unlike SKPs. An osteogenic differentiation property was reported in mSKPs that were formed from neonatal and adult fibroblasts in culture . In addide novo HF development and hair growth [in vivo experiments. Our data show that hiPSC-SKPs express CD133, a dermal papilla marker, display follicular mesenchymal-epithelial interactions with human epidermal keratinocytes and induce trichohyalin expression in spheroid cultures in vitro (SKPs reside within the dermal papilla and dermal sheath of HFs. It has also been reported that SKPs can induce HF morphogenesis in rodents . Howeverr growth \u201326. Hower growth \u201328. Thusin vitro . In anotIn conclusion, we have developed a simple protocol to generate hiPSC-SKPs. Our study provides a substantial contribution to the development of skin tissue regeneration, including the dermis and HFs, that are lost due to injury or diseases such as inherited disorders and androgenic alopecia."}
+{"text": "Prognostic implications of several non-invasive imaging techniques have been thefocus of some landmark studies published in 2015. Non-invasive characterization ofatherosclerosis processes and vulnerable plaques have been possible with advances incardiac magnetic resonance imaging and nuclear imaging techniques. In addition,3-dimensional echocardiography and multidetector-row computed tomography haveimproved our understanding of valvular heart disease. Finally, data on the clinicalrole of integration of non-invasive imaging techniques (fusion imaging) areaccumulating and its use is expected to increase in the coming years. The currentreview provides a summary of selected articles on prognostic impact of currentnon-invasive imaging techniques and technological innovations.1 In addition, this position document includes referencevalues for chamber quantification with three-dimensional (3D) echocardiographyand myocardial deformation with strain imaging. These normative data permitdifferentiation between normal and abnormal findings. From a clinicalperspective however, definition of the degree of abnormality  may be more meaningful. The document acknowledges the difficulties todetermine cut-off values that define the degree of abnormality and providesexperience-based partition values only for left ventricular (LV) size, functionand mass, and for left atrial (LA) volume.In 2015, the new recommendations for cardiac chamber quantification usingechocardiography in adults were published providing updated normative values forall four cardiac chambers based on multiple databases compiling data from alarge number of normal subjects.2 On multivariable analysis, each1 standard deviation (SD) change in LV GS was independently associated withall-cause mortality  compared with LVEF, indicating that the HR per each 1 SD change in LVGLS was 1.62 times greater than that of LVEF . Inpatients with MI, regional LV longitudinal strain may clinically be moremeaningful than GLS. A subanalysis of the VALIANT  trial including 248 patients with LV systolic dysfunction,heart failure, or both demonstrated that regional LV longitudinal strain wassignificantly impaired even in segments with normal wall motion score indexcompared with healthy controls .3 Abnormallongitudinal strain segments were defined as having a strain value higher (lessnegative) than the 95% percentile of corresponding normal control segments. Anincreasing number of LV segments with abnormal regional strain was associatedwith an increased risk of all-cause mortality .Data showing the prognostic value of LV global longitudinal strain (GLS) areaccumulating. A recent meta-analysis pooling data from 16 studies (n = 5721),encompassing different cardiac diseases , showed that theprognostic value of LV GLS exceeds that of LV ejection fraction (EF).4 The presence of persistent or worsened LV dyssynchrony wasassociated with increased risk of all-cause mortality and heart failurehospitalization . These results were alsoobserved in the large multicentre registry PREDICT-CRT.5 Left ventricular apical rockingand septal flash visualized on echocardiography are markers of left bundlebranch block-induced LV dyssynchrony. In 1060 patients treated with CRT,correction of apical rocking and septal flash at 6-12 months echocardiographywas associated with LV reverse remodelling and better survival at long-termfollow-up. In contrast, patients who still exhibited LV apical rocking or septalflash at follow-up showed less LV reverse remodelling and worse outcome.Echocardiographic assessment of heart failure patients who are candidates forcardiac resynchronization therapy (CRT) remains of interest. Results of theEchoCRT (CRT in heart failure with narrow QRS complex) substudy showed that 77%of the 614 patients with echocardiographic follow-up at 6 months had persistentor worsened LV dyssynchrony (\u2265130 ms as measured with STE or \u226580ms using tissue Doppler imaging).7 In 96 patients with heartfailure with preserved LVEF and 46 controls who underwent clinically indicatedright-sided heart catheterization and transthoracic echocardiography, Melenovskyand coworkers showed that male gender, LVEF, atrial fibrillation, coronaryartery disease (CAD), and systemic systolic blood pressure were independentlyassociated with RV dysfunction after adjusting for RV pulmonary arterial pressures.6 Patients with RV dysfunction showed lower 2-yearsurvival compared with patients without (56 vs. 93%). Right ventriculardysfunction was the strongest associate of all-cause mortality in a modelcorrected for systolic pulmonary artery pressure . Advances in 3D strain imaging have allowed characterization of RVremodelling in patients with pulmonary hypertension.7 Right ventricular morphological and functionaldata of 92 patients with pulmonary hypertension were analysed with novel 3Dmotion tracking echocardiography. Based on pressure-volume loops obtained duringright-sided heart catheterization, patients were divided into three groups: RVadapted, RV adapated-remodelled, and RV adverse-remodelled. A progressiveimpairment in RVEF and global area strain was observed across the three groupswith the RV adverse-remodelled group having the worst values. Patients withinthe RV adapted group showed better 6-month free-survival from hospitalization,death, or lung transplantation compared with the other groups , whereas patients within the RV adverse-remodelled groupshowed the worst outcome .The prognostic value of right ventricular (RV) function was also evaluated inseveral studies.8 Insufficient leaflet remodelling relative toannular and LV dilatation resulted in reduced coaptation, which wasindependently associated with MR severity in patients with functional MR. 9 The authors demonstrated important differencesin LV remodelling, annular, and valvular dimensions, associated with differencesin MR severity between patients with fibro-elastic deficiency and diffusemyxomatous degeneration.Three-dimensional echocardiography is increasingly used in heart valve disease.Debonnaire and coworkers demonstrated that 3D transoesophageal echocardiographycould adequately depict mitral valve leaflet remodelling in patients with LVdysfunction and functional mitral regurgitation (MR).10 In 353 patients with variousdegrees of isolated functional TR, the effective regurgitant orifice area (EROA)was calculated with the proximal flow convergence method. An EROA \u226540mm2 defined severe TR and was observed in 40% of patients. Duringa mean follow-up of 5.8 years, 82 patients died. An EROA \u226540mm2 was independently associated with all-cause mortality  after adjusting for clinicalcharacteristics, LVEF, RV size, RV function, and RV systolic pressure.Finally, the incremental value of quantification of tricuspid regurgitation (TR)to predict survival was demonstrated by Topilsky et al.11 A CACS = 0 was associated with an invariablylow death rate of 4.7% (i.e. 0.3%/year on average), and thereby extends thewarranty period of zero CACS over a period of almost 15 years, particularly inlow and intermediate risk patients, and regardless of gender. In a recentpublication from the COronary CT Angiography EvaluatioN For Clinical Outcomes:An InteRnational Multicenter registry, investigators observed in 3217asymptomatic subjects that CT coronary angiography (CTCA) possessed incrementalprognostic value over FRS only in patients with a CACS >100 , but not among those with CACS\u2264100.12However, in high and very high CACS subgroups (i.e. >400 and >1000), theincremental value of CTCA was lost again, probably through less reliable CTCAinterpretation. However, conclusions in these subgroups were limited due to lowsample sizes and event rates.Very long-term prognostic data for coronary artery calcium score (CACS) werepublished by Valenti and coworkers in 9715 asymptomatic subjects followed for14.6 years: CACS emerged as the strongest predictor of death, and wasindependent from Framingham risk score (FRS) or National Cholesterol EducationProgram Adult Treatment Panel III risk category.13 A total of955 patients with vascular risk factors were included, of which 74 (8%) suffereda perioperative event (cardiovascular death/MI). Computed tomography coronaryangiography findings provided independent prognostic information over revisedcardiac risk indices with increasing HRs for non-obstructive , obstructive , and extensive obstructive  disease. However, the c-index increased only from 0.62 to 0.66 whenadding CTCA to the clinical risk prediction models, mostly because ofreclassification of a sizable number of patients (~10%) into a higher-riskcategory who would not suffer any subsequent event. Thus, the results of thecoronary CTA VISION raise concerns about overestimation of risk by CTCA comparedwith clinical risk indices.The Coronary computed tomography angiography (CTA) vascular events in non-cardiacsurgery patients cohort evaluation (VISION) study assessed the value of CTCA forpredicting the risk of cardiovascular complications of non-cardiacsurgery.14The overall diagnostic yield was similar for TRO CT compared with CTCA only and was driven mainly by CAD detection ; TRO CT, however, yielded slightly more PE  and AD  diagnoses, although at a higher medianradiation  and mean contrast dose , and higher non-diagnostic image qualityrate . Thus, although TRO CT may be useful inselected patients ,the study does not support its indiscriminate use in emergency departments.The diagnostic yield of CT for triple rule-out (TRO) of MI, pulmonary embolism(PE), and aortic dissection (AD) in patients with acute chest pain is a debatedissue, and was investigated in the Advanced Cardiovascular Imaging Consortiumdatabase in 12 834 patients.15 At 25 monthsfollow-up, there were no differences in the primary endpoint of death, MI,hospitalization for unstable angina, or major procedural complications. However,CTCA resulted in fewer catheterizations showing no obstructive CAD , although more patients in the CTCA group underwentcatheterization (12.2 vs. 8.1%) and were revascularized  within 90 days of randomization. The Scottish COmputed Tomography of theHEART trial randomized 4146 patients to standard care (SC)  plus CACS and CTCA vs. SC alone.16 The use of CTCA increaseddiagnostic certainty [relative risk (RR) 1.79; p < 0.001) for the primaryendpoint of angina due to CAD, resulted in cancellation of 121 functional testsand 29 invasive angiograms, and more changes in preventive and antianginal drugtherapies. At follow-up of 1.7 years, there was a numerical  38% reduction of the composite endpoint of CAD death/MI in the CTCAgroup (p = 0.053).The results of two large randomized CT studies were eagerly awaited in 2015: inthe prospective multicenter imaging study for evaluation of chest pain trial, 10003 symptomatic patients with intermediate CAD pretest probability wererandomized to a strategy of initial anatomical testing with CTCA vs. traditionalfunctional testing .CT) continuesto raise interest in 2015 through its latest publication, the ProspectiveLongitudinAl Trial of FFRct: Outcome and Resource IMpacts study.17 In this trial, 584 symptomaticpatients with intermediate CAD pretest probability were prospectively (but notrandomly) assigned to receive either usual testing  or CTCA (n = 297) with additionalFFRCT where requested. Among those with intended ICA (n = 380),FFRCT resulted in a significant reduction in the number ofinvasive catheterizations showing no obstructive CAD (from 73 to 12%) andavoided ICA in 117 (61%) patients, while no differences were noted in the groupof patients with intended non-invasive testing  were not significant .18However, in the non-invasive arm, patients undergoing FFRCT showedbetter scores on quality-of-life questionnaires compared with patientsundergoing usual care, whereas in the invasive arm, there were no differencesbetween FFRCT and ICA.Computed tomography-derived fractional flow reserve (FFR testing . Althoug19Seventy-seven patients with stable angina and significant coronary arterylesions (>70% stenosis on invasive angiography) underwent 1.5T MRI 48 h priorto PCI and coronary plaque composition was assessed with non-contrastT1-weighted MRI. High-intensity plaques (considered vulnerable plaques) weredefined by a 'coronary plaque to myocardium signal intensity' ratio of\u22651.4. Percutaneous coronary intervention-related myocardial injury wasdefined as an increased high-sensitivity cardiac troponin T >5 times the 99thpercentile upper reference limit. Patients with high-intensity plaques (n = 31)showed greater plaque burden, larger lipid pool, more frequently positiveremodelling, ultrasound attenuation, and intracoronary thrombus on intravascularultrasound analysis, compared with patients without high-intensity plaques(20Characterization of coronary artery plaques with non-contrast T1-weightedmagnetic resonance imaging (MRI) has provided novel insights into thepathophysiology of percutaneous coronary intervention (PCI)-related myocardialinjury, a procedural complication which has important prognosticimplications. plaques. Importa21Patients underwent cine CMR, native T1 mapping, T2 mapping, T2* mapping and lategadolinium contrast-enhanced (LGE) sequences 2 days after index MI and at 6months follow-up. Native T1 times were measured in the infarct zone, injuredmyocardium, and remote myocardium. The infarct zone region was defined asmyocardium with pixel values (T1 or T2) >2 SD from the remote zone onT2-weighted CMR sequences. The hypo-intense infarct core was defined as areaswithin the infarct zone with pixel T1 values <2 SD of the values observed inperiphery of the infarct zone. Infarct core native T1 was significantlyassociated with native T2 . Native T1 values within theinfarct core were associated with LV adverse remodelling at 6 months follow-up and were independentpredictors of all-cause mortality or heart failure hospitalization .In survivors of ST-segment elevation acute MI (STEMI), assessment of infarct sizeand microvascular obstruction with contrast-enhanced CMR has importantprognostic value. Interestingly, non-contrast CMR-derived parameters such asnative T1 mapping permit characterization of the infarct core tissue. After MI,there is an increase in water content in the ischaemic area that will result inlonger native T1 times. Carrick and coworkers investigated in 300 survivors ofSTEMI, the correlation between native T1 time of the infarct core, infarct sizeand microvascular obstruction and the prognostic implications of native T1 timein terms of LV adverse remodelling (\u2265 20% increase in end-diastolicvolume at 6 months follow-up), all-cause mortality and heart failurehospitalization.26 In 65 patients who underwentpotentially cardiotoxic chemotherapy, LVEF decreased significantly after 3months of therapy  whilemyocardial T1-weighted LGE-signal intensity increased  without an increase in myocardial oedema onT2-weighted CMR sequences.22Whether these changes may predict irreversible myocardial damage afterwithdrawal of chemotherapy, remains unknown. The presence of subclinical diffusemyocardial fibrosis was evaluated measuring the ECV in 35 patients withasymptomatic moderate and severe primary MR and preserved LVEF.23 Compared with controls,patients with MR exhibited larger ECV . Increasing myocardial ECV was significantly associated withlarger LV end-systolic volume index  and left atrialvolume index , lower LVEF  andworse functional capacity as measured with peak oxygen consumption . In 139 patients with hypertrophic cardiomyopathy (HCM), Ellims etal. investigated the correlations of macroscopic myocardial fibrosis (assessedwith LGE CMR) and diffuse myocardial fibrosis (assessed with post-contrast T1mapping) with LV function and genotype.24 The presence of LGE was associated with LVEF andpresence of LV outflow tract obstruction whereas shorter post-contrastT1-mapping values (more diffuse fibrosis) were significantly associated with LVdiastolic dysfunction and dyspnoea symptoms. Interestingly, patients withidentifiable HCM genetic mutations showed larger extent of LGE  but longer post-contrast T1-mapping values  compared with patients withoutmutations. Using LGE CMR, Nadel et al. investigated in 106 patients withbiopsy-proven extracardiac or cardiac sarcoidosis the association between thepresence of focal macroscopic fibrosis and occurrence of the composite endpointall-cause mortality, sudden cardiac death, ventricular tachycarrhyhtmia orventricular fibrillation.25Thirty-two (30%) patients showed focal myocardial fibrosis on LGE CMR which wasof patchy distribution in the majority of patients (72%) followed bysubepicardial (59%) and midwall (25%) distribution. During a mean follow-up of37 months, 16 patients reached this composite endpoint. The presence of focalmyocardial fibrosis on LGE CMR was independently associated with the compositeendpoint . In 100 patients with systemiclight-chain amyloidosis, Banypersad and coworkers evaluated the prognostic valueof ECV, pre-contrast (native), and post-contrast T1 values.26 During a median follow-up of23 months, 25% of patients died. A cut-off value of ECV \u22650.45  and a cut-off value of native T1 time \u22651044ms  were independently associated withall-cause mortality, whereas post-contrast T1 mapping values were not predictiveof mortality.Several CMR-derived variables have been used to define and quantify the presenceof myocardial fibrosis . While focal macroscopic fibrosis iscommonly assessed with LGE CMR, diffuse fibrosis can be characterized bycalculating the extracellular volume (ECV), after primed contrast infusion oradministration of bolus of gadolinium, post-contrast T1-mapping values andpre-contrast (native) T1-mapping values. In addition, changes in T1-weightedLGE-signal intensity have been associated with myocardial injury. These measureshave been correlated with LV function and prognosis in several cardiacdiseases.28 Van der Falk et al. aimed atassessing the role of leukocytes in atherogenesis by performing single photonemission computed tomography (SPECT)-CT with 99mTechnetium-labeledperipheral blood mononuclear cells (PBMC).27 In 10 patients with known cardiovascular disease and 5healthy controls, a markedly enhanced accumulation of PBMC was found in patientswith advanced atherosclerotic lesions. This represents a novel-imaging approachto visualize leukocyte migration and PBMC accumulation to atherosclerosis inhumans, potentially lending support to strategies aimed at attenuating leukocyterecruitment as a therapeutic target in patients with cardiovascular disease. VanWik et al. demonstrated that lipoprotein apheresis leads to a marked reductionof arterial wall inflammation in patients with familial hypercholesterolaemia(FH) characterized by severely elevated plasma low-density lipoproteincholesterol levels.2818-F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) was used toassess the target-to-background ratio (TBR) of FDG uptake within the arterialwall in 24 patients with known FH and in 14 normolipidemic controls. A secondPET scan was acquired after 3 days in 12 patients in whom lipoprotein apheresiswas performed and demonstrated a significant reduction of TBR compared with thebaseline scan . Thesesuggest that apoprotein B-containing lipoproteins play a role in arterial wallinflammation and support the concept of a beneficial effect of lipoproteinapheresis.In patients with cardiovascular risk factors, characterization of inflammationand lipid accumulation in the arterial wall using nuclear imaging has been thetarget of several studies.29 Carotid FDG uptake and CIMT were measured in1089 asymptomatic adults who underwent PET imaging. Cardio-cerebrovascularevents occurred in 19 participants (1.74%) during an average follow-up of 4.2years. Multivariate Cox regression analysis revealed that high carotid FDGuptake  and high CIMT  were independent predictors of these events. Furthermore,carotid FDG uptake improved discrimination of risk prediction when added to theFRS independently CIMT.In addition, Moon et al. sought to investigate the added prognostic value ofFDG-PET over the FRS and carotid intima-media thickness (CIMT) for theprediction of future cardio-cerebrovascular events.30 Littleis known on the potential role of nuclear myocardial perfusion imaging (MPI) inthis context. Cremer et al. reported on the yield of SPECT-MPI for detectingischaemia, its prognostic value for short-term events, and its impact ondownstream resource utilization.31 Among 5354 patients referred from the emergency departmentafter negative troponin T tests and non-diagnostic ECGs, only 6.1% of patientswith a thrombolysis in myocardial infarction (TIMI) score \u2264 2 presentedwith > 5% ischaemic myocardium, while 19.6% of patients with TIMI scores\u2265 3 had >5%. Furthermore, short-term adverse events were rare at 30days with only 0.1% mortality and 0.1% of patients undergoing revascularizationfor acute MI. These findings suggest that SPECT-MPI before discharge after twonegative troponins should be helpful in patients with TIMI scores \u22653.In patients with suspected acute coronary syndrome and negative cardiacbiomarkers routine exercise testing is recommended by currentguidelines.32 All patients underwent heparinpre-treatment to suppress FDG uptake in remote myocardium. The metabolic rate ofglucose was significantly increased in infarcted vs. remote myocardium . Regionally, FDG score was highest insegments with LGE vs. oedema only and to remote myocardium . Thus, increased FDG uptake after heparin-induced suppression ofmyocyte uptake appears to reflect inflammatory activity in acutely infarctedmyocardial tissue.In the field of acute MI, it has been shown that FDG-PET may be able to detectinflammation in the acutely infarcted myocardium, if information on latecontrast enhancement (scar tissue) from concomitant CMR or CT is integrated.Wollenweber et al. have translated these concepts into 15 patients early afterMI by performing PET and CMR within 7 days of first MI.33 Patient effective radiationdose ranged between 0.8 and 35.6 mSv (median 10.0 mSv). Average laboratoryeffective dose ranged from 2.2 to 24.4 mSv (median 10.4 mSv) and only 30% of alllaboratories achieved a median effective dose of \u2264 9 mSv as recommendedby guidelines. The lowest effective dose (median 8.0 mSv) was administered inEurope, coinciding with the highest best-practice adherence rate.Finally, the radiation burden associated with nuclear imaging remains of concernand was the objective of the INCAPS Investigators Group which conducted anobservational cross-sectional study of nuclear MPI protocols in 308 nuclearcardiology laboratories in 65 countries around the world, characterizing patientradiation doses and the use of radiation optimizing 'best practices'.34The number of studies published on the use of integrated or fusion imaging isincreasing, indicating increasing use of integrated PET-CT and PET-MRIequipment, but also the fusion of independently obtained data from (for example)SPECT and fluoroscopy. Zhou and colleagues developed a 3D fusion tool kit tofuse LV venous anatomy (derived from fluoroscopy) with SPECT-MPI  to guide LV lead placement in CRT.36 Valenta and colleagues evaluated 24 patientswith PET-CT using N13-ammonia to assess different myocardial blood flowvariables (flow reserve and flow gradients), which were related with CTCA,resulting in better understanding of the haemodynamic significance of coronarystenoses.35 Dey et al.reported on PET-CT data from 51 patients: CTCA  wasfused with myocardial flow reserve (derived from rest-stress N13-ammoniaPET).36 Prediction ofreduced myocardial flow reserve (indicating ischaemia) was optimal when CTCAstenosis severity was integrated with various other CTCA variables, includingtotal  plaque burden. These findings indicate that an integratedCTCA score  may better predict reduced myocardial flow reserve.Fusion imaging with PET-CT has been applied in patients with suspectedCAD.18F-FDG-PET-CT in the diagnosis of cardiac implantableelectronic device generator pocket infection.37 To this end, 46 patients with suspectedgenerator pocket infection and 40 without any infection underwent PET imaging,and FDG activity in the region of the generator pocket  but the small valve area (indicating severestenosis) may be related to the assumption of a circular shape of the LV outflowtract with 2D echocardiography . Since this parameter contributes significantly to the calculation of theaortic valve area (2/m2) and preserved LVEF (\u2265 50%), this fusionapproach was applied and reclassified 52% of patients with low gradient butsevere aortic stenosis and preserved LVEF into moderate aortic stenosis (Fusion imaging of CT and echocardiography in heart valve disease was reported byKamperidis et al.lve area , this mastenosis 5."}
+{"text": "This effect has been associated with differences in folding of the aggregates, manifested in part by reduced solvent exclusion and protease-resistance in rPrP amyloids, especially within residues ~90\u2013160. Substitution of 4 lysines within residues 101\u2013110 of rPrP  with alanines (K4A) or asparagines (K4N) allows formation of aggregates with extended proteinase K (PK) resistant cores reminiscent of PrPSc, particularly when seeded with PrPSc. Here we have compared the infectivity of rPrP aggregates made with K4N, K4A or wild-type (WT) rPrP, after seeding with scrapie brain homogenate (ScBH) or normal brain homogenate (NBH). None of these preparations caused clinical disease on first passage into rodents. However, the ScBH-seeded fibrils (only) led to a subclinical pathogenesis as indicated by increases in prion seeding activity, neuropathology, and abnormal PrP in the brain. Seeding activities usually accumulated to much higher levels in animals inoculated with ScBH-seeded fibrils made with the K4N, rather than WT, rPrP molecules. Brain homogenates from subclinical animals induced clinical disease on second passage into \u201chamsterized\u201d Tg7 mice, with shorter incubation times in animals inoculated with ScBH-seeded K4N rPrP fibrils. On second passage from animals inoculated with ScBH-seeded WT fibrils, we detected an additional PK resistant PrP fragment that was similar to that of bona fide PrPSc. Together these data indicate that both the central lysine cluster and scrapie seeding of rPrP aggregates influence the induction of PrP misfolding, neuropathology and clinical manifestations upon passage in vivo. We confirm that some rPrP aggregates can initiate further aggregation without typical pathogenesis in vivo. We also provide evidence that there is little, if any, biohazard associated with routine RT-QuIC assays.Mammalian prion structures and replication mechanisms are poorly understood. Most synthetic recombinant prion protein (rPrP) amyloids prepared without cofactors are non-infectious or much less infectious than  bona fide tissue-derived prions. Substitution of a central cluster of 4 positively charged lysines within residues 101\u2013110 of the prion protein with uncharged residues allows the formation of synthetic recombinant prion aggregates with larger tightly packed cores. Inoculation of these mutant and wild-type synthetic aggregates into animals demonstrated that both the central lysine cluster as well as templating with bona fide prions, strongly influence both the initiation of self-propagating transmissible misfolding of the endogenous prion protein and the resultant neuropathological and clinical outcomes. The results also confirm that some recombinant prion protein aggregates can replicate in vivo without causing classical prion disease pathogenesis.Differences in the folding and packing of the prion protein into aggregates are thought to be the molecular basis for variability in prion transmissibility. Recombinant prion protein aggregates prepared without non-protein cofactors typically are less tightly packed within residues ~90\u2013160 and are much less infectious than  C) into TSE-associated  forms. PrPSc is often resistant to digestion by proteinase K (PK) and, as such, may also be called PrPRes. PK digestion typically leaves a resistant core of residues ~90\u2013231, attributed to ordered aggregation and the transformation of PrPC\u2019s alpha-helical and natively disordered regions into tightly packed assemblies with high beta-sheet content  were inoculated into wild-type hamsters. The fact that the ScBH(WT)RTQ products failed to propagate above discernable input levels in wild-type animals suggests that there is little, if any, biohazard associated with performing RT-QuIC assays under routine clinical circumstances in which WT rPrP substrates would be used by humans expressing normal amounts of PrPC. Indeed, in our bioassays 2.5 \u03bcg of RT-QuIC reaction product was inoculated directly into the brains of hamsters without any apparent pathological effect, making these RT-QuIC products at least 106\u2212109-fold less pathogenic than bona fide 263K PrPSc RTQ products were shaken rather than sonicated and contained only 0.002% SDS. Whether sonication, the much higher detergent content, or the use of N-terminally truncated PrP in the Kim et al study was most responsible for the greater pathogenicity of the rPrP PMCA products is not clear. Notably, SDS has an anionic moiety that might ion-pair with the cationic CLC to facilitate tighter packing in this region. The hydrophobic tail of SDS could also play an important role, analogous to previously observed effects of detergents  & B [A458-2]) and Tg7 mice (C [B991-1] & D [B987-3]) inoculated with ScBH(WT)(TIF)Click here for additional data file.S3 FigPrP antibodies R30 , 3F4 , mAB132 , R18 , and R20  were used. (F) Diagram outlining the location of antibody epitopes. The locations of the central lysine cluster (CLC), signal peptide (SP), glycosylphosphatidylinositol (GPI) anchor, and proteinase K (PK) cleavage site are also indicated.(TIF)Click here for additional data file.S4 FigSen)P1 as well as areas commonly affected by 263K scrapie are displayed. Slides were stained using a PrP antibody (EP1802Y), anti-GFAP antibody, or hematoxylin and eosin. Scale bar indicates 50 microns.Brain regions affected in ScBH(PrP(TIF)Click here for additional data file.S5 FigSlides were stained using a PrP antibody (EP1802Y), GFAP antibody, or hematoxylin and eosin. Animal numbers are displayed below images. Red arrow heads denote PrP aggregates and black arrows denote vacuolization (spongiosis). Scale bar indicates 50 microns.(TIF)Click here for additional data file.S6 FigP2 brain homogenate (A [C204-2]) and one ScBH(K4N)P2 brain homogenate (B [C208-2]). Each sample was assayed down to 10\u221210 brain tissue dilutions. SD50 per mg of brain homogenate is displayed above each panel. The animal number used to inoculate the P2 animal assayed is displayed in parentheses. Each trace is an average of four replicate wells.Representative end-point dilution RT-QuIC analysis of one ScBH(WT)(TIF)Click here for additional data file.S7 Fig4N)P2 Tg7 mice that had acute TSE disease at 143 dpi and ScBH(K4N)P2 Tg7 mice that had a prolonged clinical course out to 433 dpi is shown. Red arrow heads denote PrP aggregates and black arrow heads denote vacuolization (spongiosis). Slides were stained using a PrP antibody (EP1802Y), GFAP antibody, or hematoxylin and eosin. Animal numbers are displayed below images. Scale bar indicates 50 microns.A comparison between ScBH(K(TIF)Click here for additional data file.S1 TableThe table summarizes the individual animal data for A) Hamsters, B) Tg7 P1 mice, and C) Tg7 P2 mice.(XLSX)Click here for additional data file.S2 TableThe table describes the histopathology as it pertains to spongiosis, astrogliosis and PrP deposition for each ScBH animal.(PDF)Click here for additional data file."}
+{"text": "To explore the value of whole-lesion apparent diffusion coefficient (ADC) histogram and texture analysis in predicting tumor recurrence of advanced cervical cancer treated with concurrent chemo-radiotherapy (CCRT).2) were performed before CCRT (pre-CCRT) and at the end of 2nd week of CCRT (mid-CCRT). ADC histogram and texture features were derived from the whole volume of cervical cancers.36 women with pathologically confirmed advanced cervical squamous carcinomas were enrolled in this prospective study. 3.0 T pelvic MR examinations including diffusion weighted imaging .With a mean follow-up of 25 months , 10/36 (27.8%) patients ended with recurrence. Pre-CCRT 75th, 90th, correlation, autocorrelation and mid-CCRT ADCPre- and mid-treatment whole-lesion ADC histogram and texture analysis hold great potential in predicting tumor recurrence of advanced cervical cancer treated with CCRT. Cervical cancer is the fourth most common gynecologic malignancy, and the fourth leading cause of cancer related deaths in women all over the world . AlthougThe predictive efficiency of morphological indexes such as maximal tumor diameter (MTD) seemed limited based on previous studies, since treatment induced morphologic alterations occurred after tumor molecular and biological changes . Functiomean and ADC percentiles were significantly lower in cervical cancers with recurrence compared to those without recurrence  response (%) = (pre-CCRT MTD [area or volume] \u2013 mid-CCRT MTD [area or volume])/pre-CCRT MTD [area or volume] * 100.ADC response (%) = |mid-CCRT ADC \u2013 pre-CCRT ADC|/pre-CCRT ADC After the completion of CCRT, follow-ups were performed 1 month, 3 months and afterwards every 6 months. Each visit contained medical records review, gynecological examinations and serum tumor markers detection. MR examinations were also performed for suspected tumor recurrence. Patients\u2019 outcomes were divided into 2 groups: recurrence group, including recurrences, which were considered to be biopsy-proven or clinically diagnosed (by gynaecologists) replaces including pelvic recurrence and distant metastasis, or any lesion that was significantly enlarged at the latest follow-up, or deaths caused by cervical cancer; nonrecurrence group, that is, any patient who showed negative physical examination, negative tissue biopsy or negative imaging findings within the normal range of tumor markersin the follow-up process.Statistical analyses were performed using SPSS 22.0 software . Independent samples t test was used to compare ADC histogram parameters and their change rates between the recurrence and nonrecurrence group. As some ADC texture parameters groups did not verify the normality assumption after performing Shapiro-Wilk test, Mann\u2013Whitney U test was used to compare ADC texture parameters between the recurrence and nonrecurrence group. The predictive values of those parameters were tested by receiver operating characteristic (ROC) analysis, and were compared by multivariate stepwise logistic regression analysis. Two-tailed P values less than 0.05 were considered statistically significant. Dunn-Sid\u00e1k correction was performed to adjust the significance level for ADC histogram parameters and texture features. Inter-observer reproducibility of ADC parameters was measured by calculating the intra-class correlation coefficient (ICC) with 95% confidence interval."}
+{"text": "Alba) extract (250 \u03bcg/ml) for 48 h to measure apoptosis, reactive oxygen species (ROS), oxidative phosphorylation  and glycolysis  as well as fibrosis associated gene and/or protein expression. In leiomyoma cells, strawberry increased the percentage of apoptotic and dead cells. Strawberry significantly increased ROS concentration in leiomyoma cells, while decreased it in myometrial cells. After strawberry treatment, leiomyoma cells showed a significant decreased rate of ECAR, while OCR was unchanged in both myometrial and leiomyoma cells. Strawberry significantly decreased collagen1A1, fibronectin and versican mRNA expression in leiomyoma cells. The reduced protein expression of fibronectin was observed by strawberry extract in leiomyoma cells as well. Furthermore, strawberry was able to reduce activin A induced fibronectin, collagen1A1, and versican as well as activin A and PAI-1 mRNA expression in leiomyoma cells. This study suggests that strawberry can be developed as therapeutic and/or preventive agent for uterine leiomyomas.Uterine leiomyomas are highly prevalent benign tumors in reproductive aged women. Unfortunately, medical treatments are still limited and no preventive therapies have been developed. In the present study, we investigated the therapeutic effects of strawberry extract on uterine leiomyoma cells. Leiomyoma and myometrial cells were treated with strawberry (cultivar  Uterine leiomyomas (fibroids or myomas) are benign smooth muscle tumors originating from the myometrium . They arAlthough leiomyoma treatment has mainly been surgical some medical therapies are available for women who wish to preserve their uterus. These include gonadotropin-releasing hormone (GnRH) agonists (leuprolide acetate), GnRH antagonists (cetrorelix acetate), selective progesterone receptor modulators (ulipristate acetate and asoprisnil), antiprogestin (mifepristone), etc. . HoweverCamellia sinensis (L.) Kuntze], has shown interesting results during in vivo and course of clinical trial. EGCG was reported to dramatically reduce the volume and weight of tumors of female mice (implanted with fibroid tumor cells) , membranes were incubated overnight with primary antibody as 1: 10000 dilutions for monoclonal mouse anti-human fibronectin (Sigma-Aldrich) or 1: 3000 dilutions for monoclonal mouse Tubulin (Sigma-Aldrich). Membranes were washed four times (10 min for each) in TBST and incubated with 1:1000 dilutions of horseradish peroxidase linked anti-mouse IgG (Amershan) against anti-human fibronectin and tubulin for 2 h. Membranes were washed four times (10 min for each) in TBST, and immunoreactive proteins were visualized using Super Signal West Pico chemiluminescent substrate (Pierce). The bands were quantified by scanning and analysis using Java-based image processing program, ImageJ 1.49n . The data were analyzed using non-parametric \u2018Kruskal-Wallis\u2019 ANOVA, followed by post hoc \u2018Dunn\u2019 test for multiple comparisons. Results are expressed as mean\u00b1SD. Differences were considered significant when p < 0.05."}
+{"text": "Epicoccum sorghinum is associated with grain mold of sorghum and produces the mycotoxin tenuazonic acid. This fungus can have serious economic impact on sorghum production. Here, we report the draft genome sequence of E.\u00a0sorghinum (USPMTOX48).The facultative plant pathogen  Epicoccumsorghinum (Sacc.)  (orghina)  is one oorghina) . The preorghina) . This fuorghina) , 5. The E.\u00a0sorghinum, we report the draft genome sequence of Epicoccum sorghinum strain USPMTOX48, which was recovered from contaminated sorghum grains (Sorghumbicolor [L.] Moench cv. DKB 550) cultured in Votuporanga, Brazil, in 2013. A polyphasic approach consisting of molecular and morphological characterization was performed for species identification  totaling 5,878\u00a0Mbp (176\u00d7 genome coverage). Raw data underwent quality control using FaQCs, which trimmed and filtered the reads . The genhttp://www.repeatmasker.org). Genes were then modeled by combining several gene annotations methods as inputs into MAKER2, namely: (i) BLASTx alignment of proteins of a related species, Phoma tracheiphila; (ii) Augustus  (ab initio models trained on Hidden Markov Models of the CEGMA core eukaryotic genes (ab initio gene models (Gene annotation was carried out using the MAKER2 training and annotation pipeline . BrieflyAugustus  ab initi (BUSCO) ; (iii) S (BUSCO)  ab initiic genes ; and  has been deposited at DDBJ/EMBL/GenBank under the accession no. MIEO00000000. The version described in this paper is version MIEO01000000.The draft genome sequence of"}
+{"text": "We compared heart deformation analysis (HDA) of SSFP images and cine Displacement Encoding with Stimulated Echoes (DENSE) for the assessment of global and segmental circumferential strain (Ecc) and derivative indices in healthy volunteers and heart failure (HF) patients with left bundle branch block (LBBB).Post-processing methods have been developed to quantify myocardial strain from steady-state free-precession (SSFP) cine images. In the left ventricle (LV), global strain measurements from SSFP in healthy volunteers3,4. The mean and standard deviation of global Ecc were compared and the correlation between HDA and cine DENSE was assessed. The circumferential uniformity ratio estimate computed with singular value decomposition (CURE-SVD) is a quantitative index of mechanical dyssynchrony based on segmental Ecc, where values near 1 indicate synchrony and lower values indicate dyssynchrony5. CURE-SVD was computed for all subjects using HDA and DENSEImaging was performed on a 1.5T Siemens Avanto MR system in 3 short-axis planes in 6 volunteers and 29 patients with HF-LBBB. Ecc was computed from SSFP images using HDA  and from cine DENSE using previously described methods2 = 0.29, p = 0.002) than HDA , Fig. Fig. HDA and cine DENSE show good agreement for global Ecc. For regional Ecc, HDA shows greater variability including apparent false-positive segmental dysfunction in some volunteers. While HDA measurements of dyssynchrony can discriminate HF-LBBB from healthy volunteers (p < 0.01), it underestimates the degree of synchrony in volunteers and the degree of dyssynchrony in patients compared to cine DENSE. CURE-SVD by cine DENSE has a better correlation to LV remodeling compared to HDA."}
+{"text": "Lymantria dispar) is a serious pest of forestand shade trees in many Asian and some European countries. However, there have beenfew studies of L. dispar genetic information and comprehensivegenetic analyses of this species are needed in order to understand its genetic andmetabolic sensitivities, such as the molting mechanism during larval development. Inthis study, high-throughput sequencing technology was used to sequence thetranscriptome of the Asian subspecies of the gyspy moth, after which a comprehensiveanalysis of chitin metabolism was undertaken. We generated 37,750,380 high-qualityreads and assembled them into contigs. A total of 37,098 unigenes were identified, ofwhich 15,901 were annotated in the NCBI non-redundant protein database and 9,613 wereannotated in the Swiss-Prot database. We mapped 4,329 unigenes onto 317 pathwaysusing the Kyoto Encyclopedia of Genes and Genomes Pathway database. Chitin metabolismunigenes were found in the transcriptome and the data indicated that a variety ofenzymes was involved in chitin catabolic and biosynthetic pathways.The Asian gypsy moth ( Lymantria dispar (Linnaeus) (Lepidoptera:Lymantriidae), is one of the most destructive polyphagous pests in forests,agro-ecosystems, shade trees and shrubs, with more than 500 host plants identified sofar  and chemical pheromones to disrupt mating (Disparlure), biological control(using Bacillus thuringiensis), and the use of transgenic host plants.Pesticides remain the most rapid and effective strategy for combating the pest, butgypsy moth insecticide resistance is a growing concern although the underlying causesare currently unknown. Limited genetic information exists for gypsy moths in general,especially the Asian subspecies. Comprehensive analyses are therefore needed to revealgenetic sensitivities of the pest, improve bioinsecticide selection, recognize genesthat are determinants of disease and resistance development, and facilitate targetedpest management  and the Lymantriadispar (L. Dispar) larval midgut in response to infectionby B. thuringiensis have been undertaken -N-acetylglucosamineresidues and is a vital component of the insect cuticle and peritrophic membrane (PM). Theeggs were placed in an incubator for incubation and rearing. Whole insect samples(gut and epidermis) were immediately frozen and stored in liquid nitrogen untilanalysis. Total RNA was extracted from these samples using RNAiso reagents   according to the manufacturer'sinstructions. Poly-(A) mRNA was isolated from total RNA using poly-T oligo-attachedmagnetic beads. The mRNA was fragmented with an RNA fragmentation kit  before cDNA synthesis in order to avoid priming bias. The cleavedRNA fragments were transcribed into first-strand cDNA using reverse transcriptase (Invitrogen) and random hexamer primers, followed bysecond-strand cDNA synthesis using DNA polymerase I and RNase H (Invitrogen). Thedouble-stranded cDNA was end-repaired using T4 DNA polymerase , Klenow fragment (NEB) and T4 polynucleotidekinase (NEB). Base addition was done using Klenow 39 to 59 exopolymerase (NEB) toprepare the DNA fragments for ligation to the adaptors. The products of ligation werepurified using a MinElute PCR purification kit according to the manufacturer's instructions, and eluted in 10 mL of QIAGEN EBbuffer. The eluted adaptor-ligated fragments of the ligation reaction were separatedon an agarose gel to select a size range of templates for downstream enrichment. Thedesired range of cDNA fragments was excised and retrieved using a gel extraction kit. PCR was used for selective enrichmentand amplification of the cDNA fragments using a Phusion master mix (NEB) with twoprimers (primers PE 1.0 and PE 2.0) generated with an mRNASeq sample preparation kit(Illumina). The amplified products were purified using a QIAquick PCR purificationkit (QIAGEN) according to the manufacturer's instructions and eluted in 30 mL ofQIAGEN EB buffer. Libraries were prepared from a 150-200 bp size pool after adaptorligation and agarose gel separation. After accurate quantitation (Qubit) of the150-200 bp size pool, bridge PCR was done on the surface of the flow cell to amplifyDNA fragments as a single DNA molecule cluster (this process was done with a ClusterStation). Each attached DNA fragment underwent multiple rounds of amplification tocreate a cluster of identical DNA fragments. With each sequencing cycle, afluorescently-labeled base was incorporated into each fragment in the cluster andimages of the flow cell surface were captured (Pair-end raw reads were trimmed with BWA trimming mode at a threshold of Q20 (P =0.01) as implemented by SolexaQA (\u22125. Gene names were assigned to each assembled sequence based on thebest BLAST hit (highest score). Searches were limited to the first 10 significanthits for each query in order to increase computational speed. Open reading frames(ORFs) were predicted using the \"getorf\" program of the EMBOSS software package non-redundant protein (Nr) database and Swiss-Prot database using BLASTx with an E-value cutoff of <10To annotate the assembled sequences with Gene Ontology (GO) terms describingbiological processes, molecular functions and cellular components, the Swiss-ProtBLAST results were imported into Blast2GO , a softwhttp://www.genome.jp/kegg/kaas/). The bi-directional best hit methodwas used to obtain a KEGG orthology (KO) assignment. The output of the KEGG analysisincluded KO assignments and KEGG pathways that were populated with the KOassignments.The unigene sequences were also aligned to the Clusters of Orthologous Group (COG)database to predict and classify functions  were assigned to47,166, 35,597 and 16,594 GO terms, respectively. In the \"biological process\"category, the unigenes related to \"metabolic processes\" (18.75%), \"cellularprocesses\" (21.42%), \"single-organism process\" (13.97%), \"biological regulation\"(9.90%), \"regulation of biological process\" (9.17%), \"response to stimulus\" (7.61%)and \"multicellular organismal process\" (6.48%) were predominant. The most abundantclasses were \"cell parts\" (20.67%) and \"cell\" (20.67%), \"organelle\" (15.26%),\"membrane\" (9.63%), and \"organelle part\" (8.34%). Most of the genes in the \"molecularfunction\" category were involved in \"binding\" (20.24%) and \"catalytic activities\"(15.78%) .KOG classification showed that 7,302 unigenes were clustered into 25 functionalcategories. \"General function prediction only\" (14.13%) was the major KOG category,followed by \"signal transduction mechanisms\" (11.73%), \"transcription\" (8.46%),\"posttranslational modification, protein turnover, chaperones\" (8.34%), \"translation,ribosomal structure and biogenesis\" (5.24%), \"intracellular trafficking, secretionand vesicular transport\" (4.83%) and \"lipid transport and metabolism\"(4.67%) .KEGG analysis showed that 4,329 unigenes were assigned to 317 pathways. The majorpathways that contained > 100 unigenes were ribosome (ko03010) , RNA transport (ko03013) , protein processing inendoplasmic reticulum (ko04141) , purine metabolism (ko00230) , oxidative phosphorylation (ko00190)  and spliceosome (ko03040) .\u221250), while theremaining 41.28% showed weak homology   protein database  .Bombyx mori(42% of unigenes), Danaus plexippus (28%), Papiliopolytes (7%), Papilio xuthus (2%), Helicoverpaarmigera (1%), Tribolium castaneum (1%),Acyrthosiphon pisum (1%), Manduca sexta (1%),Spodoptera frugiperda (1%) and Fibroporiaradiculosa (1%)  . InsummLeptinotarsa decemlineata (538 bp), and the N50 length of theL. dispar transcriptome (1391 bp) was significantly longer than thatof L. decemlineata (570 bp) (The mean unigene length identified in the Asian gypsy moth (788 bp) was much longer thanthat of L. dispar unigenes were mainly relatedto cellular processes (21.42%), metabolic processes (18.75%), single-organism processes(13.97%) and biological regulation (9.90%). The high number of unigenes related to\"cellular process\" and \"metabolic processes\" indicated that the Asian gypsy moth ismetabolically active. Based on sequence homology, the results revealed that 24 unigeneswere related to the chitin catabolic process (GO: 0006032) and 86 unigenes were relatedto the chitin metabolic process (GO: 0006030); only three unigenes related to the chitinbiosynthetic process (GO: 0006031) were identified. These results suggest that thechitin metabolic process is a sophisticated and dynamically cyclic process containingunique genetic information on chitin metabolism in this moth. One important feature ofthe epidermis was that two closely-related processes, namely, chitin synthesis anddegradation, occurred almost simultaneously during metamorphosis. Chitin is digested toGlcNAc in the larval cuticle by a binary enzyme system composed of endochitinase(commonly referred to as chitinase) and exochitinase (\u03b2-N-acetylglucosaminidase). Theformer enzyme hydrolyzes chitin into oligosaccharides while the latter further degradesthe oligomers to monomers. The synthesis of chitin relies on two key enzymes, chitinsynthase (CHS) and glutamine-fructose-6-phosphate aminotransferase (GFAT), whichprovides the GlcNAc precursor for the chitin biosynthetic pathway. Insect epidermalmetamorphosis is a complicated process involving multiple genes and pathways  using the Illumina platform. Our analysis provided37,098 unigenes, of which 42.86% were aligned to sequences in the Nr database. Althougha reference genome sequence for"}
+{"text": "Staphylococcus aureus isolates from dairy farms located in Victoria, Australia. Two novel sequence types (ST3183 and ST3184) were identified among these isolates.This study describes draft whole genomes of 15  Staphylococcus aureus is a Gram-positive bacterium that can cause mastitis in dairy cattle and food poisoning in humans. Draft genome sequences were generated for 15 S.\u00a0aureus isolates recovered from raw milk or their associated milk filters from dairy farms in Victoria  and sent to the Ramaciotti Centre for Genomics  for library preparation  and whole-genome sequencing on the Illumina MiSeq platform. Quality filtering and adapter trimming was done on Trimmomatic version 0.22 software. The preprocessed reads were then S.\u00a0aureus multilocus sequence type database (http://saureus.mlst.net)  and MAQR00000000 (sa14-004), harbored the enterotoxin gene cluster (egc) variant 1, which carries seg to sei along with yent1 and yent2. A diverse range of staphylococcal enterotoxins were found among bovine isolates, which included sec-sed, seg-sej, sel-seo, and ser; this was in contrast to caprine and ovine samples, which contained only sec and sel. A high proportion of caprine and ovine isolates contained TSST-1 (n = 4), relative to bovine isolates (n = 1).Multilocus sequence types were assigned according to the lst.net) . Seven slst.net) . All oviThis whole-genome shotgun project has been deposited at DDBJ/ENA/GenBank under the accession numbers listed in"}
+{"text": "Cartilage tissue engineering using stem cells and biomaterials is considered a promising approach despite poor outcomes. Wehypothesise that articular cartilage fragments provides native environmental cues to enhance stem cell differentiation. As such weevaluated the chondrogenic differentiation and repair of critical size defect in a human explant osteochondral model (OD) using bonemarrow derived mesenchymal stem cells (BM-MSCs) and homogenised cartilage. BM-MSCs were established from the bone-marrowplugs of patients undergoing total knee arthroplasty and characterized. Osteochondral tissue was trimmed and a central drill defect(\u223c2mm) was made. Chondrogenic repair was evaluated by filling the OD defect area with either BM-MSCs (Group II), homogenizedcartilage (Group III) or a combination of both BM-MSCs and homogenized cartilage (Group IV). OD with no added cell or tissueserved as control (Group I). Samples were maintained in chondrogenic differentiation medium for 28 days. Microscopic imagesshowed maximal OD closure in Group IV. Partial OD closure was observed in Group II and to a lesser extent in Group III.Haematoxylin-eosin staining revealed immature cartilaginous matrix in Group II and more mature matrix in Group IV. Sircol\u2122 Assayshowed increased collagen deposition in both Group II and Group IV. Immunostaining for both groups revealed positive staining fortype II collagen. Combining BM-MSCs and homogenised cartilage demonstrated enhanced cartilage formation and defect filling in ahuman ex-vivo osteochondral model. Osteoarthritis (OA) is a progressive degenerative disease of thejoint characterized by gradual degradation of the cartilaginousextracellular matrix (ECM) and sclerosis of bone. The ECM ofcartilage is highly specialized structure that is mainly composedof type II collagen that provides tensile strength andproteoglycans that provide compressive stiffness . TheimbMesenchymal stem cells (MSCs) are considered a promisingcandidate for cartilage regeneration, due to their self-renewalcapacity and potential to differentiate into chondrocytes, as wellas other cell types . MoreoveThe present study was approved by the Ethical Committee forScientific Research of King Abdulaziz University, Jeddah, SaudiArabia [No. 113-157]. Informed consent was obtained from allpatients before bone marrow aspiration, and collection ofosteochondral plugs and cartilage from undamaged areas frompatients undergoing total knee arthroplasty.BM-MSCs were isolated from six patients according to earlierestablished protocols . BrieflyBM-MSCs were plated at a seeding density of 2x104 cells per wellin a 24 well plate and cultured under standard culture conditionsfor 72 h. Cell morphology was imaged using a phase contrastmicroscope and cell proliferation was determined at 24 h, 48 hand 72 h using MTT reagent -2,5-diphenyltetrazolium bromide; Sigma, MO) and absorbance wasobtained at 570 nm (reference 630 nm) using a spectrophotometer.The derived BM-MSCs were characterized for their expression ofMSC related surface antigens using fluorescence-activated cellsorting (FACS) analysis. Briefly, BM-MSCs was aliquoted andstained with MSC isotype, positive  and negative  antibodies (Miltenyi Biotec) at1:10 dilution for 15 min at 4\u00b0C. The cells were then washed oncewith 3% (v/v), centrifuged (500 g for 5 min) and the pelletresuspended in 3% (v/v) FBS and analysed using FACS Aria III(BD Biosciences).Expanded BM-MSCs (2 x 104 cells/well) were seeded into a 24well plate and allowed to reach confluence. They were thencultured using StemPro\u00b0 adipocyte, osteoblast and chondrocytedifferentiation media for up to 21 days with fresh media changesevery 3 - 4 days. Following differentiation, the cells were fixed in 4% formaldehyde solution for 30 minutes and rinsed with PBStwice. The cells were then stained with oil Red O (adipocytes),Alizarin red (osteoblasts) or Alcian blue (chondrocytes) (Sigma),washed and analysed for positive staining using lightmicroscopy.Osteochondral bone samples that were obtained from patientsundergoing total knee arthroplasty were trimmed to 1cm (w) x1cm (b) x 1cm (h) and a central drill defect (\u223c2 mm) was made.Chondrogenic repair was conducted by seeding theosteochondral defect (OD) with BM-MSCs (1x106cells) pellet(Group-II), homogenized cartilage pellet (Group-III) or acombination of both BM-MSCs (0.5x106cells) and homogenizedcartilage pellet (Group-IV). OD with no added cell or tissueserved as control (Group-I). Fresh undamaged articular cartilagefrom the femoral condyles were finely homogenized and pelletedby centrifugation. The pellet was re-suspended in 5 ml of PBSand aliquots of 250 \u03bcl were pelleted and used either separately(Group-III) or together with MSCs (Group-IV) respectively.Similar sized cell pellets were used for all experimentalconditions. Samples from all four groups were maintained instandard BM-MSC chondrogenic medium up to 28 days. Tissueformation and repair of the central drill defect was analysed byphase contrast imaging, histology, immuno-histo-chemistry andbiochemical analysis.Histological analysis was performed following the differentiationperiod of 28 days. Briefly, the ex-vivo samples were fixed in 10%(v/v) neutral buffered formalin for 24 h at 4\u00b0C, demineralizedusing an aqueous mixture of 5% (v/v) formic acid and 5% (v/v)formalin. Demineralized samples were post-fixed in 70% (v/v)ethanol before being embedded in paraffin. Tissue weresectioned at 10 \u03bcm thickness and stained with Toluidine blue forhistological analysis. For type II collagen immunostaining, thetissue sections were deparaffinized in xylene, washed in gradedseries of ethanol  and rehydrated. Antigenretrieval was done by heating the tissue in sodium citrate buffer(pH 6.0) using microwave for 15 min and the tissue was left tocool for at least 30 min. The tissue was blocked with peroxidasebefore incubating with mouse monoclonal anti-collagen II(Abcam) at 1:100 dilution at 4\u00b0C overnight. The sections werewashed and incubated with respective secondary goat antimouseantibodies for 30 min . The tissue was finally counterstained with DAPI andanalysed using fluorescent microscope (EVOS).Secreted collagen levels from all groups were evaluated usingSircol (collagen assay) kit (Bioclor) according to themanufacturer\u05f3s instructions. Briefly, 1 ml of the Sircol reagentwas mixed with 100 \u03bcl of the standards and samples  to form collagen-dye complex. Theywere then centrifuged at 12000 rpm for 10 min and thesupernatant removed. Unbound dye was removed by layering750 \u03bcl of ice-cold acid-salt wash reagent (Kit content) followed by centrifugation (12000 rpm for 10 min) and removal of thesupernatant. Alkali reagent (250 \u03bcl) was added to dissolve thebound dye and absorbance at 555 nm was spectrophotometricallymeasured using a micro-plate ELISA reader(\u03bcQuant-BioTek) to determine collagen concentration.Comparisons between treatment and control for cell proliferationand collagen assays were analysed using One-Way ANOVA testwith the Statistical Package for Social Sciences (SPSS 21). Theresults were expressed as mean \u00b1 standard error of the mean(SEM) from three different replicates for individual assays and avalue of p<0.05 was considered to be statistically significant.BM-MSCs adhered to the culture surface as multiple patches asearly as day 4, while the non-adherent cells were gradually lostwith changing of media. The cell numbers continued to increasereaching up to 70% - 80% confluence by the second week. TheBM-MSCs showed characteristic spindle shape in culture . The iniPrimary cultures from bone marrow aspirates analysed forsurface marker expression demonstrated high percentages ofMSC related positive markers, namely CD73 (98.6%), CD90(97.7%), CD105 (98.7%), CD44 (90.8%) and CD29 (91.6%)compared to their respective isotype matched controls. The cellswere negative for CD34 and CD45, the haematopoietic stem cellsrelated surface markers .Primary cultures of BM-MSCs showed differentiation intoadipocytes, chondrocytes and osteoblasts upon culture inrespective differentiation medium (StemPro\u00b0; Phase contrast  and H&E Toluidine blue staining ofGroup-IV demonstrated positive staining of proteoglycansindicative of chondrogenic differentiation . ImmunohWe have demonstrated in this study for the first time thatcartilage repair in an ex vivo human osteochondral defect modelcan be achieved using a mixture of BM-MSCs and homogenisednative cartilage. The repair tissue of mixed BM-MSCs andhomogenised cartilage appears to be stable, integrating withsurrounding host tissue and capable of turnover. This findingsuggests it will be possible to develop a method for robustcartilage repair using native tissue and BM-MSCs.The BM-MSCs derived and used in this study satisfied theminimal criteria for MSCs as stated in the position paper . TheexpThe osteochondral length is comprised of highly organizedstructures: the elongated chondrocytes and collagen fibrils thatrun parallel in the upper zone, the intermediate zone of roundchondrocytes and less of collagen fibrils, and the deep zonewhere chondrocytes and collagen fibrils are arranged in verticalcolumns perpendicular to the articular surface , 13. DeeA recent study has highlighted the importance of having ahealthy BM-MSC in the subchondral niche to avoid progressionof osteoarthritis and suggested that manipulation of subchondralMSCs could be a treatment option for osteoarthritis . AnearlThe results from the present study showed that the combinationof BM-MSCs and cartilage fragments provides better cartilagerepair. This is in part due to the presence of micro-environmentalcues provided by the native cartilage tissue, which facilitatedeffective interaction between the bone and cartilage in thishuman ex-vivo osteochondral defect model. Further analysis ofsub-fragments could help design more effective methods tounderstand the signaling mechanisms involved in enhancedcartilage repair and pave way for the delivery of therapeuticchondrogenic MSCs."}
+{"text": "The interplay between viral and host proteins has been well studied to elucidate virus-host interactions and their relevance to virulence. Mammalian genes encode apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) proteins, which act as intrinsic restriction factors against lentiviruses. To overcome APOBEC3-mediated antiviral actions, lentiviruses have evolutionarily acquired an accessory protein, viral infectivity factor (Vif), and Vif degrades host APOBEC3 proteins via a ubiquitin/proteasome-dependent pathway. Although the Vif-APOBEC3 interaction and its evolutionary significance, particularly those of primate lentiviruses (including HIV) and primates (including humans), have been well investigated, those of nonprimate lentiviruses and nonprimates are poorly understood. Moreover, the factors that determine lentiviral pathogenicity remain unclear. Here, we focus on feline immunodeficiency virus (FIV), a pathogenic lentivirus in domestic cats, and the interaction between FIV Vif and feline APOBEC3 in terms of viral virulence and evolution. We reveal the significantly reduced diversity of FIV subtype B compared to that of other subtypes, which may associate with the low pathogenicity of this subtype. We also demonstrate that FIV subtype B Vif is less active with regard to feline APOBEC3 degradation. More intriguingly, we further reveal that FIV protease cleaves feline APOBEC3 in released virions. Taken together, our findings provide evidence that a lentivirus encodes two types of anti-APOBEC3 factors, Vif and viral protease.IMPORTANCE During the history of mammalian evolution, mammals coevolved with retroviruses, including lentiviruses. All pathogenic lentiviruses, excluding equine infectious anemia virus, have acquired the vif gene via evolution to combat APOBEC3 proteins, which are intrinsic restriction factors against exogenous lentiviruses. Here we demonstrate that FIV, a pathogenic lentivirus in domestic cats, antagonizes feline APOBEC3 proteins by both Vif and a viral protease. Furthermore, the Vif proteins of an FIV subtype (subtype B) have attenuated their anti-APOBEC3 activity through evolution. Our findings can be a clue to elucidate the complicated evolutionary processes by which lentiviruses adapt to mammals. Viruses undergo drastic changes in virulence in response to alterations to their genetic information and cross-species transmission events, and elucidating the coevolutionary relationships between viruses and their hosts remains one of the most important undertakings in the fields of virology and evolutionary biology. For example, infection with a human lentivirus, human immunodeficiency virus type 1 (HIV-1), results in AIDS, while simian immunodeficiency viruses (SIVs), the evolutionary relatives of HIV-1, naturally infect more than 40 species of Old World monkeys (OWMs) in Africa but cause no known disorders 14. HoweveA3 genes in their genomes , recruits the cellular ubiquitin E3 ligase complex and degrades A3 proteins via a ubiquitin/proteasome-dependent pathway, thereby impeding A3 packaging into nascent viral particles , 7. Althal hosts \u201315, sugg genomes , and the genomes . Thus, AFelis catus) exhibiting AIDS-like symptoms , a feline lentivirus, was first discovered in 1987 in domestic cats    were cotdeleted) . Consisteted) 19\u2013, feline  deleted . In the  deleted . In cont deleted . Moreove deleted .A3Z3 gene in domestic cats (Given the unique phenotype of the FIV subtype B (strain TM2) Vif , it is ptic cats , and imptic cats . Based otic cats , similartic cats  and supptic cats . Therefovif sequences of FIV strains Aomori and Kyo1, which are classified into subtype B  assay with FIV Vif and feline A3. As shown in To identify the region of FIV Vif that determines the ability to degrade the feline A3 protein, we constructed two types of Vif proteins, swapping derivatives based on FIV Petaluma (subtype A) and TM2 (subtype B), which were designated the PT and TP derivatives, respectively , top. AsTo further identify the responsible amino acid(s) at the single residue level, a series of Vif mutants was constructed , bottom.vif sequences are listed in http://www.hiv.lanl.gov/content/sequence/VESPA/vespa.html) , while the Vif proteins of subtype B (n = 8) encoded lysine at this position  . As showpa.html) , was composition . Therefoposition  and A3Z2position  is deterposition , were hiposition . Therefovif. On the basis of this phylogenetic tree  of FIV demonstrated similar topologies, and FIV subtype B was most recently separated from subtype D , and the amino acid sequence identity between the PRs of Petaluma and TM2 (subtype B) is 90.0%. To investigate whether the PR of subtype B FIV cleaves feline A3Z2Z3, we next constructed a plasmid, pFP93prTM2  in England and Australia . Reverse transcription (RT) was performed using SuperScript III reverse transcriptase (Thermo Fisher Scientific), and RT-PCR was performed using PrimeSTAR GXL DNA polymerase (TaKaRa) and the following primers: FIV vif Fwd (CAG TRT TAT TAA AGG ATG AAG AGA RGG G) and FIV vif Rev (CTA AAK GGG TTT AYT CCT GGR TTA ART GG). The resulting products were purified by gel extraction and then cloned using a Zero Blunt TOPO cloning kit (Thermo Fisher Scientific). Nucleotide sequences were determined by a DNA sequencing service (Fasmac), and the data were analyzed using Sequencher (v 5.1) software (Gene Codes Corporation). All FIV env (n = 326) were obtained from the GenBank/EMBL/DDBJ sequence database and were aligned using the MAFFT program  method with the PhyML program , pol (n = 47), and env (n = 326) gene sequences from the GenBank/EMBL/DDBJ sequence database, and the accession numbers are available upon request. These genes were individually aligned with an FIV sequence derived from a puma  using the MAFFT program  was employed to construct the trees for these FIV genes with 100 bootstrap replicates. The FIVpco sequence was specified as the root of each tree.The sequences of the V3-V5 region of FIV  program . The bes program , and the program  (GTR+G)  program   and synthesized by the GeneArt gene synthesis service (Thermo Fisher Scientific). The obtained DNA fragments were inserted into the BamHI/SalI sites of the pDON-AI plasmid (TaKaRa). To construct the expression plasmids for a series of FIV Vif derivatives, the following primers were used: PT insert Fwd (TGG CCC TTC GTG AAC ATG TGG ATC AAG ACC GGC), PT insert Rev (ATG CGT TAA CGT CGA CTC ATT TGT CGT CGT CGT C), PT vector Fwd (GTC GAC GTT AAC GCA TGC), PT vector Rev (GTT CAC GAA GGG CCA TTC), TP insert Fwd (TGG CCC TTC GTG AAC ATG TGG ATC AAG ACC GGC), TP insert Rev (ATG CGT TAA CGT CGA CTC ATT TGT CGT CGT CGT C), TP vector Fwd (GTC GAC GTT AAC GCA TGC), TP vector Rev (GTT CAC GAA GGG CCA CTC), P-mu#1 Fwd (GAA CAT CTG CAA GGG CGG CGA GGT GTC CCA CGG ATG GGG ACC), P-mu#1 Rev (GGT CCC CAT CCG TGG GAC ACC TCG CCG CCC TTG CAG ATG TTC), P-mu#2 Fwd (GGC GAG CGG AAG ATC AAG GCC ACC CCC), P-mu#2 Rev (GGG GGT GGC CTT GAT CTT CCG CTC GCC), P-mu#3 Fwd (GCG GAA GAT CGA GAT CAC CCC CGT GAT G), P-mu#3 Rev (CAT CAC GGG GGT GAT CTC GAT CTT CCG C), P-mu#4 Fwd (GGC GAG ATC GAC CCC CAG AAG TGG TGC GGC), P-mu#4 Rev (GCC GCA CCA CTT CTG GGG GTC GAT CTC GCC), P-mu#5 Fwd (CCA TGC TGG CTT GTG GCA AAG AGG CCA AAG AAT GGC GGG GCT GC), P-mu#5 Rev (GCA GCC CCG CCA TTC TTT GGC CTC TTT GCC ACA AGC CAG CAT GG), P-mu#6 Fwd (GAT TCG TGT CCC CCT TCC GGA CCC CTG CC), P-mu#6 Rev (GGC AGG GGT CCG GAA GGG GGA CAC GAA TC), P-mu#7 Fwd (CTG GAA GTG ATC CAG AAC AAG CCC AAG CGG AAT CTG CTG TG), P-mu#7 Rev (CAC AGC AGA TTC CGC TTG GGC TTG TTC TGG ATC ACT TCC AG), P-mu#8 Fwd (GGA AGT GAT CCA GAA CAA GCC CAG CTG G), P-mu#8 Rev (CCA GCT GGG CTT GTT CTG GAT CAC TTC C), P-mu#9 Fwd (CCA GAG CAA GCC CAA GTG GAA TCT GCT G), P-mu#9 Rev (CAG CAG ATT CCA CTT GGG CTT GCT CTG G), P-mu#10 Fwd (GCA AGC CCA GCC GGA ATC TGC TGT GGA G), P-mu#10 Rev (CTC CAC AGC AGA TTC CGG CTG GGC TTG C), T-mu#1 Fwd (GAA CAT CTG CAT CGG CGG CGA GAT CAG CCC AGG CTG GGG ACC), T-mu#1 Rev (GGT CCC CAG CCT GGG CTG ATC TCG CCG CCG ATG CAG ATG TTC), T-mu#2 Fwd (GGC GAG CGG AAG ATC GAG GCC ACC CCC GTG ATG ATC), T-mu#2 Rev (GAT CAT CAC GGG GGT GGC CTC GAT CTT CCG CTC GCC), T-mu#3 Fwd (GGC GAG ATC GAC CCC AAG AAG TGG TGC GGC), T-mu#3 Rev (GCC GCA CCA CTT CTT GGG GTC GAT CTC GCC), T-mu#4 Fwd (CCA TGC TGG CCT GCG GCG TGC CCG CCA AAA AGT GGC GGG GCT GC), T-mu#4 Rev (GCA GCC CCG CCA CTT TTT GGC GGG CAC GCC GCA GGC CAG CAT GG), T-mu#5 Fwd (GAT TCG TGT CCC CCT ACC GGA CCC CCT GC), T-mu#5 Rev (GCA GGG GGT CCG GTA GGG GGA CAC GAA TC), T-mu#6 Fwd (CTG GAA GTG GTG CAG AGC AAG CCC AGC TGG AAC CTG CTG TG), T-mu#6 Rev (CAC AGC AGG TTC CAG CTG GGC TTG CTC TGC ACC ACT TCC AG), Petaluma vif His insert Fwd (ACC GAG CTC GGA TCC GCC ACC ATG AGC GAA GAG G), Petaluma vif His insert Rev (TGA GAT GAG TTT TTG TTC CAG CTC GCC GCT CCA CAG), TM219 vif His insert Fwd (ACC GAG CTC GGA TCC GCC ACC ATG AGC GAC GAG), TM219 vif His insert Rev (TGA GAT GAG TTT TTG TTC CAG CTC GCC GGT CCA CAG), C36 vif His insert Fwd (ACC GAG CTC GGA TCC GCC ACC ATG AGC GAA GAG G), C36 vif His insert Rev (TGA GAT GAG TTT TTG TTC CAG CTC GCC CAG CCA CAG), Shizuoka vif His insert Fwd (ACC GAG CTC GGA TCC GCC ACC ATG AGC GAA GAG G), Shizuoka vif His insert Rev (TGA GAT GAG TTT TTG TTC CAG CTC GCC GGT CCA CAG), vif His vector Fwd (GAA CAA AAA CTC ATC TCA GAA GAG GAT CTG AAT ATG CAT ACC GGT CAT CAT CAC CAT CAC CAT TGA GTC GAC GTT AAC GCA TGC), and vif His vector Rev (GGA TCC GAG CTC GGT ACC). The expression plasmids for a series of FIV Vif proteins, feline A3 derivatives, and pFP93 derivatives  (HA-tagged feline A3 expression plasmids (based on pcDNA3.1) were kindly provided by Carsten M\u00fcnk or prepared in our previous studies , 60, 68.oeschla)  were conHEK293T cells  were cultured in Dulbecco modified Eagle medium (Sigma-Aldrich) supplemented with 10% heat-inactivated fetal calf serum and antibiotics (Thermo Fisher Scientific). Transfection was performed using the Lipofectamine 2000 (Thermo Fisher Scientific) or the PEI Max  reagent according to the manufacturers' procedures. The anti-FIV activities of feline A3 proteins were evaluated as previously described . To analg for 1 h at 4\u00b0C using a TL-100 instrument (Beckman), and the pellet was lysed with 1\u00d7 SDS buffer. Transfected cells were lysed with radioimmunoprecipitation assay (RIPA) buffer containing a protease inhibitor cocktail (Roche). To quantify the amount of feline A3Z2Z3 and cleaved A3Z3 in the released viral particle  and feline A3Z2Z3-HA (2 \u03bcg) were cotransfected into HEK293T cells in a 6-cm dish (Nunc) using the PEI Max reagent . The transfected cells were treated with the proteasome inhibitor MG132 (10 \u03bcM) at 24 h after transfection. The transfected cells were harvested 16 h later and resuspended in lysis buffer  containing a protease inhibitor cocktail (Roche) and MG132 (12.5 \u03bcM) at 4\u00b0C for 30 min. To perform the coimmunoprecipitation (co-IP) assay, cell lysates were mixed with magnetic beads conjugated to an anti-HA monoclonal antibody  and incubated at 4\u00b0C for 3 h. Then, the magnetic beads were washed with RIPA buffer and PBS and analyzed by Western blotting as described above.t test and Bonferroni's multiple-comparison test.The data are expressed as averages with the standard deviations (SDs), and statistically significant differences were determined using Student's vif sequences are available under GenBank/EMBL/DDBJ accession numbers LC177497 to LC177511 and LC179607 to LC179612.FIV"}
+{"text": "One nNOS siRNA vector significantly reduced the number of degenerating hippocampal neurons and showed a tendency to improve working memory. GPx-1 siRNA treatment did not alter TBI-induced neurodegeneration or working memory deficits. Nevertheless, microarray analysis of laser captured, virus-infected neurons showed that knockdown of nNOS or GPx-1 was specific and had broad effects on downstream genes. Since nNOS knockdown only modestly ameliorated TBI-induced working memory deficits, despite widespread genomic changes, manipulating expression levels of single genes may not be sufficient to alter functional outcome after TBI.Virally mediated RNA interference (RNAi) to knock down injury-induced genes could improve functional outcome after traumatic brain injury (TBI); however, little is known about the consequences of gene knockdown on downstream cell signaling pathways and how RNAi influences neurodegeneration and behavior. Here, we assessed the effects of adeno-associated virus (AAV) siRNA vectors that target two genes with opposing roles in TBI pathogenesis: the allegedly detrimental neuronal nitric oxide synthase (nNOS) and the potentially protective glutathione peroxidase 1 (GPx-1). In rat hippocampal progenitor cells, three siRNAs that target different regions of each gene  effectively knocked down gene expression. However,  Although acute and chronic neurodegeneration and long term deficits in cognitive function are hallmarks of traumatic brain injury (TBI) survivors, there are currently no treatments to address these debilitating repercussions \u20133. Thus,in vivo gene silencing via RNAi can improve functional outcome after TBI and can illuminate how a gene regulates specific brain functions, including behavior  would improve and that knocking down GPx-1 [GPx-1 (2)] would worsen neurobehavioral outcome. If an AAV construct that knocked down gene expression did not show promise in the behavioral tests, we reasoned that downstream analyses, i.e. microarray analysis may be moot. The nNOS (3) and GPx-1 (2) siRNA AAV constructs were subsequently used for stereological and microarray analysis in the hippocampus two weeks post-sham or FPI injury. Two weeks after stereotaxic injection, we found that the majority of pyramidal neurons in the CA1-CA3 subfields were infected with recombinant viruses . Injectiin vivo with all three viral vectors by qPCR analysis of laser captured pyramidal neurons 15 days after injury/sham surgery. Because the LCM staining protocol washed out GFP fluorescence, we viewed frozen sections not subjected to ethanol fixation and dehydration protocols of LCM. These sections clearly showed GFP fluorescence associated with AAV transduction in hippocampal neurons. We then laser captured neurons from the same regions in immediately adjacent sections. The clean laser capture of hippocampal cells\u2014the region of the hippocampus captured on macrocaps\u2013is seen in nissl-stained coronal sections . Although the TBI+NOS (2) group was lower than TBI+SV, this result did not reach statistical significance  and GPx-1(2), were significantly knocked down In vivo delivery of AAV-nNOS (3) siRNA reduced numbers of dying, degenerating hippocampal neurons, but the GPx-1 (2) vector had no discernable effects on TBI-induced neurodegeneration , a marker of neurodegeneration , and detneration .P = 0.10) or TBI+SV (P = 0.23), TBI+SV was significantly different from SHAM (P = 0.01) (upper). Comparison of TBI + GPx-1(1), TBI+GPx-1(2), and TBI+GPx-1(3) to TBI + SV revealed no statistically significant differences (middle). Comparison of TBI+ nNOS(1), TBI+nNOS(2), TBI+nNOS(3) to TBI+SV revealed no statistically significant differences (lower), suggesting a possible protective effect of nNOS(3) siRNA.We compared the effects of virus treatments on hippocampal-dependent working memory using the Morris Water Maze (MWM) test. Cell injury induced by viral injection alone can cause additional off-target effects; therefore, MWM results of nNOS or GPx-1 siRNA treated TBI rats were compared to TBI rats with scrambled AAV siRNA. TBI rats with scrambled siRNA AAV treatment performed significantly worse than sham injured rats. To simplify, only the results of Trial 2 are shown in  = 0.01) upper. Cferences . Neverthferences middle. ferences . Howeverferences lower, sThe TBI alone group and the TBI plus scrambled AAV (SV) siRNA group showed significantly worse latencies then the sham alone group (p<0.05). The TBI alone group and TBI plus SV group showed no differences within the groups; thus TBI plus SV was used as the control group for the nNos and GPX-1 constructs. Even though overall swim times across trials and days of all 3 TBI+nNOS groups were observed to be shorter than TBI+SV group, this was not statistically significant. All 3 of the GPX-1 constructs were not significantly different from TBI plus SV Click here for additional data file.S2 Fig(PDF)Click here for additional data file.S3 Fig(PDF)Click here for additional data file.S4 Fig(PDF)Click here for additional data file.S5 Fig(PDF)Click here for additional data file.S6 Fig(PDF)Click here for additional data file.S7 Fig(PDF)Click here for additional data file.S8 Fig(PDF)Click here for additional data file."}
+{"text": "Substantial advances have been made in the treatment of testicular cancer and these have been among the great achievements in modern medicine. The introduction and refinement of cisplatin-based combination chemotherapy revolutionized the treatment of germ-cell tumors (GCT) and patients who once had a dismal prognosis are now curable even in the presence of metastatic disease. Despite 2 plus etoposide 750 mg/m2 on days -5,-4, -3 followed by stem-cell infusion on day 0. Remission rates were higher when HDCT was utilized as initial salvage vs. \u22653rd line therapy (63% vs. 49%). Notably, patients with relapsed seminoma had a 90% cure rate. Cures were also achieved in patients with poor prognostic features: platinum refractory defined as progression \u22644 weeks after first-line platinum-based chemotherapy (33%), primary mediastinal non-seminomatous GCT (PMNSGCT) (23%), and progressive brain metastasis at initiation of HDCT (40%). There were 9 treatment-related deaths (2.5%) with 6 occurring \u226430 days from completion of HDCT. Secondary leukemia developed in 5 patients.In a series of 364 consecutive patients with relapsed GCT treated at Indiana University from 2004-2014, HDCT plus PBSCT achieved cures in 60% of patients. 94% of pThe choice of initial salvage chemotherapy for relapsed GCT remains unsettled. In our opinion, patients who experience relapse after initial chemotherapy require multi-disciplinary expertise and should be referred to centers of testicular cancer excellence. Although there are no phase 3 studies demonstrating the superiority of one approach over another, a large multi-national retrospective analysis including 1,594 patients with relapsed GCT was published in 2011. This stuAt Indiana University, our preferred approach is to use tandem HDCT with carboplatin-etoposide plus PBSCT for most patients as second-line chemotherapy. There are special considerations in certain patient populations. (1) For patients who relapse with anatomically confined disease, salvage surgery is our preferred approach. When performed by experienced surgeons, this has potential for cure with significantly less long-term morbidity compared to salvage chemotherapy. (2) Pati"}
+{"text": "In evidence-based medicine, multicenter, prospective, randomized controlled trials (RCTs) are the gold standard for evaluating treatment benefits and ensuring the effectiveness of interventions. Patient-centered outcomes, such as mortality, are most often the preferred evaluated outcomes. While there is currently agreement on how to classify renal dysfunction in critically ill patients , the application frequency of this new classification system in RCTs has not previously been evaluated. In this study, we aim to assess the definition of renal dysfunction in multicenter RCTs involving critically ill patients that included mortality as a primary endpoint.A comprehensive search was conducted for publications reporting multicenter randomized controlled trials (RCTs) involving adult patients in intensive care units (ICUs) that included mortality as a primary outcome. MEDLINE and PUBMED were queried for relevant articles in core clinical journals published between May 2004 and December 2017.Of 418 articles reviewed, 46 multicenter RCTs with a primary endpoint related to mortality were included. Thirty-six (78.3%) of the trial reports provided information on renal function in the participants. Only seven articles (15.2%) included mean or median serum creatinine levels, mean creatinine clearance or estimated glomerular filtration rates. Sequential organ failure assessment (SOFA) score was the most commonly used definition of renal dysfunction . Risk, Injury, Failure, Loss, End-stage renal disease (RIFLE), Acute Kidney Injury Network (AKIN) and Kidney Disease Improving Global Outcomes (KDIGO) criteria were used in five (10.9%) trials. In thirteen trials (28.3%), no renal dysfunction criteria were reported. Only one trial excluded patients with renal dysfunction, and it used urinary output or need for renal replacement therapy (RRT) as criteria for this diagnosis.The presence of renal dysfunction was included as a baseline patient characteristic in most RCTs. The RIFLE, AKIN and KDIGO classification systems were infrequently used; renal dysfunction was generally defined using the SOFA score. Acute renal dysfunction affects one in five hospitalized patients  and occuSince 2004, the severity of kidney injury has been determined by several new classification systems: Risk, Injury, Failure, Loss, End-stage renal disease (RIFLE), Acute Kidney Injury (AKI) Network (AKIN) and Kidney Disease Improving Global Outcomes (KDIGO) . These sIn evidence-based medicine, multicenter, prospective, randomized controlled trials (RCTs) are the gold standard for evaluating treatment benefits and ensuring the effectiveness of interventions. Patient-centered outcomes, such as mortality, are most often the preferred evaluated outcomes . While t01 \u201cintensive care\u201d[MeSH Terms] OR Intensive care[Text Word]02 \u201ccritical care\u201d[MeSH Terms] OR critical care[Text Word]03  OR \u201ccritical illness\u201d[MeSH Terms] OR critically ill[Text Word]04 \u201csepsis\u201d[MeSH Terms] OR sepsis[Text Word]05 \u201cartificial respiration\u201d[Text Word] OR \u201crespiration, artificial\u201d[MeSH Terms] OR mechanical ventilation[Text Word]06 \u201cadult respiratory distress syndrome\u201d[Text Word] OR \u201crespiratory distress syndrome, adult\u201d[MeSH Terms] OR A RDS[Text Word]07 (#01OR#02OR#03OR#04OR#05OR#06)08 \u201crandomized controlled trial\u201d[Publication Type] OR \u201crandomized controlled trials\u201d[MeSH Terms] OR \u201crandomized controlled trial\u201d[Text Word] OR \u201crandomised controlled trial\u201d[Text Word]09 #07 AND #0810 (\u201cMulticenter Studies\u201d[MeSH] OR \u201cMulticenter Study\u201d[Publication Type]) OR multicenter[All Fields]11. End Point Mortality12 #09 AND #10A comprehensive search was conducted for publications reporting multicenter RCTs involving adult patients in intensive-care units (ICUs), with mortality as a primary outcome. The search was conducted in the MEDLINE database via the PubMed interface, including articles in the core clinical journals subset published May 2004 to December 2017 (In the list below). MEDLINE offers the \u201cCore Clinical Journals\u201d filter to limit searches to clinically useful journals , 15. EliThe following data were extracted: (1) subject of study, (2) number of patients, (3) number of centers, (4) conditions studied, (5) allocation concealment, (6) exclusion of chronic kidney disease, (7) exclusion of acute renal dysfunction, (8) chronic kidney disease (CKD) criteria, (9) baseline acute renal dysfunction criteria, and (10) acute renal dysfunction as outcome (11) mortality. Two authors (RHP and PB) evaluated the selected studies for quality using the Consolidated Standards of Reporting Trials (CONSORT) checklist.Analyses were performed in SPSS 21.0 . Categorical variables are described as number (percentage).The selection and exclusion of RCTs are summarized in Fig. CKD chronic kidney disease, PEEP positive end-expiratory pressure; SOFA sequential organ failure assessment, MV mechanical ventilation, MODS multiple organ dysfunction score, GFR glomerular filtration rate; LODS logistic organ dysfunction score, UO urine output, RRT renal replacement therapy, KDIGO Kidney Disease Improving Global Outcomes; RIFLE Risk, Injury, Failure, Loss of kidney function, End-stage kidney disease, TAK-242 a small-molecule inhibitor of Toll-like receptor-4-mediated, ARDS acute respiratory distress syndrome, IABP intraaortic balloon pump, Cr creatinineThe distribution of the number of studies per year of publication, stratified by the acute renal dysfunction criteria used as a baseline and outcome measure is described in Figs. A wide range of conditions in critically ill patients was studied in the 46 RCTs, including sepsis (13 RCTs), acute respiratory distress syndrome (11 RCTs), shock (5 RCTs), nutrition (4 RCTs), anemia (5 RCTs), surgery (3 RCTs), respiratory failure (2 RCTs), pneumonia (2 RCTs), renal replacement therapy (1 RCT), and quality improvement (1 RCT).The RCTs assessed a range of interventions in critically ill patients Table , includiThirty-six trial reports (78.3%) provided information on acute renal (dys)function in the participants. Only seven articles 15.2%) contained mean or median serum creatinine levels, mean creatinine clearance or estimated glomerular filtration rates (eGFRs). The SOFA score was the most commonly used definition of acute renal dysfunction, in 20 studies (43.5%): RIFLE/AKIN/KDIGO criteria were used in 5 trials (10.9%). In thirteen trials (28.3%) no criteria for defining acute renal dysfunction were reported. Only one trial (2.2%) excluded patients with acute renal dysfunction, using urinary output or need for RRT as criteria for this diagnosis. As shown in Fig. % containMost of the trials studied acute renal dysfunction as a secondary outcome, which was reported in 33 trials (71.7%). The renal SOFA score was the most commonly used definition, in 19 trials (41.3%), followed by the need for RRT, used in 10 trials (21.7%) and RIFLE/AKIN/KDIGO criteria used in 5 trials (10.9%). Only six articles (13.0%) included serum creatinine levels, mean creatinine clearance, or GFR (eGFR) values as secondary outcomes.Five trials (10%) reported progression to more severe stages of acute renal dysfunction. No trial reported progression to chronic kidney disease. Thirty-three trials (71.7%) evaluated organ dysfunction in addition to renal dysfunction.Our results demonstrated that patients with acute renal dysfunction were often included in multicenter RCTs involving critically ill patients that included mortality as a primary endpoint. However, current classification systems, such as RIFLE/AKIN/KDIGO, were not frequently used to define renal dysfunction in the descriptions of patient baseline characteristics or as secondary outcomes.Despite the advances from widespread use of new classification systems and the development of new biomarkers for early renal dysfunction detection, little progress has been made in developing evidence-based interventions for renal dysfunction prevention and treatment . For criA single definition of acute renal dysfunction would be useful for clinical practice, research, and public health . This deAlthough the acute renal dysfunction (RIFLE/AKIN/KDIGO) classification systems have been compared and validated , they doThe renal SOFA score was the most commonly used system to quantify renal function at baseline or as a secondary outcome. It may be more convenient to study changes in the SOFA score over time. Such changes have been assessed in critically ill patients over 48 h  or durinIn addition to the new definitions of renal dysfunction, the SOFA score has been validated as a tool for assessing sequential organ dysfunction and is a good prognostic indicator. Furthermore, this score is familiar to critical care physicians and has been used for years in critical care settings and for different clinical conditions . To dateTo our knowledge, the present manuscript is the first to describe the characterization of acute renal dysfunction in RCTs of critically ill patients. We have utilized an extensive search covering a period of 13 years following publication of current renal dysfunction definitions.Nonetheless, our study does have several limitations. First, we have limited our sample to papers published in high-impact journals because these are typically multicenter studies with a better opportunity for impacting clinical practice . We defiThe presence of renal dysfunction was included as a baseline patient characteristic and as an outcome measure in most multicenter RCTs involving critically ill patients with mortality as a primary endpoint that were published in core clinical journals in the study period. The analyzed RCTs generally defined acute renal dysfunction using the SOFA score, with a less frequent utilization of the RIFLE, AKIN and KDIGO classification systems. There is a need for further evaluation of the validity and barriers for utilization of each score to better inform clinical practice."}
+{"text": "Toxoplasma gondii susceptible conventionally colonized mice develop acute ileitis due to an underlying T helper cell (Th) -1 type immunopathology. We here addressed whether mice harboring a human intestinal microbiota developed intestinal, extra-intestinal and systemic sequelae upon ileitis induction.Within seven days following peroral high dose infection with T. gondii strain ME49 by gavage human microbiota associated (hma) mice displayed severe clinical, macroscopic and microscopic sequelae indicating acute ileitis. In diseased hma mice increased numbers of innate and adaptive immune cells within the ileal mucosa and lamina propria and elevated intestinal secretion of pro-inflammatory mediators including IFN-\u03b3, IL-12 and nitric oxide could be observed at day 7 p.i. Ileitis development was accompanied by substantial shifts in intestinal microbiota composition of hma mice characterized by elevated total bacterial loads and increased numbers of intestinal Gram-negative commensals such as enterobacteria and Bacteroides / Prevotella species overgrowing the small and large intestinal lumen. Furthermore, viable bacteria translocated from the inflamed ileum to extra-intestinal including systemic compartments. Notably, pro-inflammatory immune responses were not restricted to the intestinal tract as indicated by increased pro-inflammatory cytokine secretion in extra-intestinal (i.e. liver and kidney) and systemic compartments including spleen and serum.Secondary abiotic mice were generated by broad-spectrum antibiotic treatment and associated with a complex human intestinal microbiota following peroral fecal microbiota transplantation. Within three weeks the human microbiota had stably established in the murine intestinal tract as assessed by quantitative cultural and culture-independent (i.e. molecular 16S rRNA based) methods. At day 7 post infection (p.i.) with 50 cysts of T. gondii infection. Thus, hma mice constitute a suitable model to further dissect the interactions between pathogens, human microbiota and vertebrate host immunity during acute intestinal inflammation.With respect to the intestinal microbiota composition \u201chumanized\u201d mice display acute ileitis following peroral high dose  Toxoplasma gondii strain ME49 susceptible mice develop severe ileitis and succumb to infection [T. gondii infection, whereas upon reconstitution with the murine intestinal microbiota mice were suffering from overt disease [Bacteroides / Prevotella spp. [E. coli further perpetuate the fatal immunopathological process [T. gondii infection model resembles key features of inflammatory bowel diseases (IBD) in humans such as Crohn\u2019s disease during the acute stage [Within one week following peroral infection with a high dose (i.e. 50 to 100 cysts) of the intracellular parasite nfection . Diseasenfection \u20137. Ileitnfection , given tlla spp. , 9, 10.  process . Overallte stage , 9, 12.T. gondii induced ileitis.Given the importance of the host specific intestinal microbiota in susceptibility towards distinct immunopathological diseases, their onset, progression and outcome , 13, 14,All animal experiments were conducted according to the European Guidelines for animal welfare (2010/63/EU) with approval of the commission for animal experiments headed by the \u201cLandesamt f\u00fcr Gesundheit und Soziales\u201d . Animal welfare was monitored twice daily by assessment of clinical conditions and weight loss of mice. Mice suffering from weight loss >20% were euthanized by isoflurane treatment  in accordance with the guidelines of the local authorities (\u201chuman end points\u201d).ad libitum).Female C57BL/6j mice were bred under specific pathogen-free conditions in the Forschungseinrichtungen f\u00fcr Experimentelle Medizin . Secondary abiotic mice with a virtually depleted microbiota were generated as described previously . In briead libitum). Fresh fecal samples free of enteropathogenic bacteria, viruses and parasites were collected from five individual healthy volunteers, dissolved in sterile phosphate buffered saline ), aliquoted and stored at -80\u00b0C as described earlier [T. gondii infection individual fecal samples were collected for quantitative cultural and molecular analyses of main intestinal bacterial communities as described elsewhere [Three days prior reassociation of secondary abiotic mice with a complex human intestinal microbiota, antibiotic cocktail was replaced by autoclaved tap water  by gavage as described previously [In order to induce acute ileitis, hma were perorally subjected to high-dose eviously , 16, 17.Mice were sacrificed seven days after ileitis induction by isoflurane treatment . Cardiac blood, tissue samples from spleen, liver, lung, kidney, mesenteric lymph nodes (MLN), ileum and colon were removed under sterile conditions. Colonic and ileal samples from each mouse were collected in parallel for microbiological, immunological, immunohistochemical and histopathological analyses.Ex vivo biopsies derived from the terminal ileum were immediately fixed in 5% formalin and embedded in paraffin. Sections (5 \u03bcm) were stained with hematoxylin and eosin (H&E) and subjected to a standardized histopathological scoring system ranging from 0 to 6 as described earlier [Small intestinal lengths were determined by measuring the distance from the duodenum leaving the stomach to the ileal-caecal transition.  earlier , 11.ex vivo biopsies were used for in situ immunohistochemical analyses as described previously [2; 400 x magnification) were determined by an independent and blinded investigator.Five \u03bcm thin paraffin sections of ileal eviously , 18, 19.ex vivo biopsies were homogenized in sterile phosphate buffered saline  and analyzed in serial dilutions on respective solid media as described earlier [For comprehensive quantitative survey of the microbiota composition in fecal human donor suspensions and intestinal  luminal contents as well as of viable bacteria translocating from the intestines to extra-intestinal compartments including MLN, liver, lung and spleen, respective intestinal samples and  earlier , 11, 20.DNA was extracted from the human donor suspension and intestinal luminal content as described previously . In brieEx vivo biopsies of approximately 1cm2  were washed in PBS and placed in 24-flat-bottom well culture plates  containing 500 mL serum-free RPMI 1640 medium  supplemented with penicillin  and streptomycin . After 18 hours at 37\u00b0C, culture supernatants and serum samples were tested for IFN-\u03b3, TNF, MCP, IL-12p70, IL-6 and IL-10 by the Mouse Inflammation Cytometric Bead Assay  on a BD FACSCanto II flow cytometer (BD Bioscience). Nitric oxide (NO) was measured by the Griess reaction as described earlier [ earlier .p) values \u22640.05 were considered significant. Experiments were repeated at least twice.Mean values, medians, standard deviations (SD) and levels of significance were determined using appropriate tests as indicated . Two-sided probability  \u201chumanized\u201d mice. To assure stable intestinal colonization of mice with a complex human microbiota, we initially generated secondary abiotic animals by quintuple antibiotic treatment for eight weeks. Subsequently, mice with a virtually depleted intestinal microbiota were subjected to peroral transplantation of human microbiota generated from five healthy human individuals on three consecutive days. Quantitative cultural as well as culture-independent (i.e. 16S rRNA based molecular) analyses revealed comparable microbiota compositions of respective human fecal suspensions , Clostridium leptum (p<0.05), but not C. coccoides (n.s.), whereas decreased 16S rRNA copies of lactobacilli (p<0.05) could be determined at day 7 p.i. as compared to uninfected hma control mice  of rol mice . NotablyT. gondii infection hma were clinically severely compromised and exhibited wasting and bloody diarrhea in almost 90% of cases  ilea to extra-intestinal including systemic compartments. As assessed by direct plating, commensals such as enterobacteria, enterococci and .i. Figs . Remarka.i. Figs . Of note.i. Figs .T. gondii induced inflammatory responses could also be observed in extra-intestinal compartments. In fact, IFN-\u03b3 and nitric oxide concentrations were multifold higher in ex vivo biopsies derived from liver and kidney of hma mice at day 7 p.i. as compared to noninfected hma control animals  methods to also assess fastidious or even uncultivable bacteria including bifidobacteria, clostridia and Mouse Intestinal Bacteroides. One needs to take into consideration, however, that it can not be distinguished whether amplified 16S rRNA gene copies were derived form viable or \u201cdead\u201d bacterial cells. The here presented comprehensive survey of the intestinal microbiota in \u201chumanized\u201d mice was further supported by our previous studies where the human microbiota composition was stable in the murine gastrointestinal tract for at least six weeks following FMT [T. gondii resulted in severe macroscopic and microscopic pro-inflammatory sequelae as indicated by wasting, bloody diarrhea and acute transmural ileitis with both apoptosis and necrosis that were comparable to disease outcomes in T. gondii infected conventionally colonized mice as shown in several previous reports [T. gondii infection [T. gondii infection resulted in enhanced secretion of pro-inflammatory mediators (including IFN-\u03b3 and nitric oxide) also in the large intestines.In the present study we surveyed the suitability of (with respect to the microbiota) \u201chumanized\u201d mice to study the interactions between pathogen, human commensal microbiota and host immunity during acute wing FMT , 25. In wing FMT . High do reports , 27\u201331. T. gondii induced ileitis could be proven by our previous and actual in vivo studies, given that secondary abiotic mice were virtually unaffected from T. gondii infection, whereas with a complex microbiota recolonized mice  Numbers of viable enterobacteria (EB), enterococci (EC), Gram-positive rods (GPR), Bacteroides / Prevotella species (B/P), Clostridium / Eubacterium species (C/E) and the total bacterial load (TL) were determined by culture and expressed as colony forming units (CFU) per ml suspension. (B) 16S rRNA of the main intestinal bacterial commensals including enterobacteria (EB), enterococci (EC), lactobacilli (LB), bifidobacteria (Bif), Bacteroides / Prevotella species (B/P), Clostridium coccoides group (Clocc), Clostridium leptum group (Clept), Mouse Intestinal Bacteroides (MIB) and the total eubacterial load (TL) were analyzed by quantitative RT-PCR and expressed as gene numbers per ng DNA. Data shown are representative for at least three independent experiments.Before fecal microbiota transplantation of secondary abiotic mice, main intestinal bacterial groups were quantitatively assessed in human donor fecal suspensions. (TIFF)Click here for additional data file.S2 FigT. gondii strain ME49 to induce acute ileitis. Noninfected mice served as respective naive controls. Small intestinal immunohistopathological changes were assessed at day (d) 7 following ileitis induction in ileal paraffin sections stained with (A) hematoxylin & eosin or antibodies against (B) caspase-3, (C) CD3, (D) FOXP3, (E) B220 or (F) F4/80. Representative photomicrographs from three independent experiments are shown .Human microbiota associated (hma) and conventionally colonized (SPF) mice were perorally infected with (PDF)Click here for additional data file."}
+{"text": "An European society growing older sets the need to explore treatment options for elderly patients. Here we aimed to gather evidence on the effectiveness of a modified cognitive behavioural therapy (mCBT) in elderly schizophrenia patients as compared to treatment as usual (TAU).43 schizophrenia patients > 55y (mean 60 y), were assessed in a randomized, single blind controlled pilot trial with parallel groups: TAU+mCBT vs. TAU and intention to treat (ITT) last observation carried forward (LOCF) analysis. Subjects were recruited in Germany among in- and outpatients. MCBT comprised 30 sessions in 9 month, and a 6 month follow-up including a) physical and social activation, b) problem solving c) social skills. Primary outcomes were pre/post change in either PANSS total score, UPSA-brief score or Calgary Depression Scale for Schizophrenia.From 43 patients, 40 were randomized. 15 mCBT and 16 TAU-patients comprised the ITT sample. None of the primary outcome measures reached significance. When assessing effect sizes we found little pre-/post change in PANSS total score (d=0.14) and the UPSA-brief (d=0.14). Depression symptoms however improved with treatment (pre/post d=0.75 and pre/FU d=0.52). Among secondary outcomes, global assessment of functioning significantly improved in the mCBT-group pre/post (d=.074) and pre/follow-up (d=.080).Our results provide evidence for the feasibility of a sufficiently powered phase-III study targeting depressive symptoms and global functioning in long-term treated elderly schizophrenia patients. A history of about twenty years of pharmacological treatment does not imply there is no room for improvement in depression and global functioning following a modified cognitive behavioral therapy in this specific patient group. Supported by the German Federal Ministry of Education and Research (BMBF-01GV0909); ICTRP/DRKS: DRKS00003623."}
+{"text": "Cucurbit aphid-borne yellows virus (CABYV) from Papua New Guinea. We compared it with 36 complete CABYV genomes from other world regions. It most resembled the genome of South Korean isolate GS6.Analysis of an RNA-Seq library from cucumber leaf RNA revealed the first complete genome sequence of  Cucurbit aphid-borne yellows virus (CABYV) was obtained from cucumber (Cucumis sativus) sample 10PN from Zage Village, Goroka, Eastern Highlands Province, PNG. CABYV was first described in 1992 causing yellow leaf symptoms in cucurbit plants in France  and six open reading frames (ORFs) organized into two clusters, as with other poleroviruses (CABYV isolate 10PN yielded 19,041,390 reads and, after trimming, 19,038,589 reads remained. oviruses  revealedMG780352.The complete genome sequence of CABYV isolate 10PN has been deposited in GenBank with the accession number"}
+{"text": "Cicer arietinum desi accession ICC 4958 \u00d7 C reticulatum wild accession ICC 17160)- and intra (ICC 4958 \u00d7 C. arietinum kabuli accession ICC 8261)-specific RIL mapping populations to identify the major QTL genomic regions governing flowering time in chickpea. The whole genome resequencing discovered 1635117 and 592486 SNPs exhibiting differentiation between early- and late-flowering mapping parents and bulks, constituted by pooling the homozygous individuals of extreme flowering time phenotypic trait from each of two aforesaid RIL populations. The multiple QTL-seq analysis using these mined SNPs in two RIL mapping populations narrowed-down two longer (907.1 kb and 1.99 Mb) major flowering time QTL genomic regions into the high-resolution shorter (757.7 kb and 1.39 Mb) QTL intervals on chickpea chromosome 4. This essentially identified regulatory as well as coding (non-synonymous/synonymous) novel SNP allelic variants from two efl1 (early flowering 1) and GI (GIGANTEA) genes regulating flowering time in chickpea. Interestingly, strong natural allelic diversity reduction (88\u201391%) of two known flowering genes especially mapped at major QTL intervals as compared to that of background genomic regions  in cultivated vis-\u00e0-vis wild Cicer gene pools was evident inferring the significant impact of evolutionary bottlenecks on these loci during chickpea domestication. Higher association potential of coding non-synonymous and regulatory SNP alleles mined from efl1 (36\u201349%) and GI (33\u201342%) flowering genes for early and late flowering time differentiation among chickpea accessions was evident. The robustness and validity of two functional allelic variants-containing genes localized at major flowering time QTLs was apparent by their identification from multiple intra-/inter-specific mapping populations of chickpea. The functionally relevant molecular tags delineated can be of immense use for deciphering the natural allelic diversity-based domestication pattern of flowering time and expediting genomics-aided crop improvement to develop early flowering cultivars of chickpea.Identification of functionally relevant potential genomic loci using an economical, simpler and user-friendly genomics-assisted breeding strategy is vital for rapid genetic dissection of complex flowering time quantitative trait in chickpea. A high-throughput multiple QTL-seq strategy was employed in two inter ( Cicer arietinum L.) is one of the vital food legume crops represented by two of its major cultivar types- desi and kabuli (C. reticulatum at Fertile Crescent around 10000 years ago (desi and kabuli accessions (Chickpea (d kabuli  which arears ago . Developears ago . The numears ago . Therefocessions . The genefl) gene loci/allelic variants  controlling varied flowering time trait adaptation characteristics in multiple chickpea accessions  and FT (flowering time) gene families] within the low-resolution major flowering time QTL regions mapped on chickpea chromosomes (Significant progress has been made to decipher the complex genetic inheritance characteristics and molecular genetic dissection of flowering time trait in chickpea . This incessions . Additioomosomes .desi chickpea accession (ICC 4958) through NGS (next-generation sequencing)-based global transcriptome sequencing strategy  and SNP (single nucleotide polymorphism) markers among mapping individuals of diverse inter-/intra-specific populations is found much expedient in chickpea . This apdesi, kabuli and wild accessions that are most commonly utilized as parents for generating diverse intra- and inter-specific mapping populations of chickpea  and (ICC 4958 \u00d7 C. arietinum kabuli accession ICC 8261)- at a genome-wide scale to delineate major genomic (gene) regions and novel natural allelic variants underlying the QTLs associated with flowering time in chickpea.Considering usefulness and broader practical applicability, multiple QTL-seq assay can be employed for rapid genome-wide scanning and fine-mapping  of trait-linked major genes and natural allelic-variants colocalized at robust QTLs  in chickpea with minimal resource expenses. This will collectively enrich our understanding on complex genetic architecture and evolutionary pattern influencing flowering time quantitative trait variation during domestication of chickpea in order to expedite its genomics-assisted crop improvement. In view of afore-mentioned possibilities, a multiple QTL-seq strategy was employed in two inter- and intra-specific RIL (recombinant inbred lines) mapping populations-  and - with contrasting flowering time trait were developed by single seed descent method. As per field phenotyping at International Crops Research Institute for the Semi-Arid Tropics (ICRISAT), ICC 4958  is an early flowering chickpea accession with DTF (days to 50% flowering time) of 43 days. In contrast, ICC 17163 (wild accession) and ICC 8261  originated from Turkey are late flowering chickpea accessions with DTF of 85 and 61 days, respectively. The desi chickpea accession ICC 4958 was considered as a common parent for both mapping populations generated.Two inter- and intra-specific F0C following 2 (broad-sense heritability) of DTF trait among RIL individuals were determined as per For phenotyping, the mapping individuals and parents of both RIL populations were grown and phenotyped in the field as per RCBD (randomized complete block design) with two replications at two diverse eco-geographical regions  of India for two successive years (2013 and 2014) during crop growing season. In addition, these parents and RIL individuals were grown in the greenhouse to determine the flowering time response of these mapping individuals under both long- and short-day conditions at 22 \u00b1 2We selected 10 of each early and late flowering homozygous mapping individuals belonging to two extreme ends of DTF normal frequency distribution curve from each of the two RIL populations of ICC 4958 \u00d7 ICC 17163 and ICC 4958 \u00d7 ICC 8261 for QTL-seq study. Prior to inclusion of these selected 20 RIL mapping individuals in QTL-seq analysis, the homozygous genetic constitution of these individuals from both RIL populations for either of the early and late flowering trait was assured using their DTF field phenotyping data and genome-wide SSR markers-based genotyping information as per The genomic DNA was isolated from constituted DNA bulks- early days to 50% flowering time bulk (EDTFB) and late days to 50% flowering time bulk (LDTFB) as well as parents of mapping populations using QIAGEN DNeasy kit  following manufacturer\u2019s instructions. The quantity and quality of isolated genomic DNA was ensured by Qubit 2.0 Fluorometer  and Bioanalyzer 2100 , respectively. About 1 \u03bcg of high-quality genomic DNA of each sample was utilized for library preparation using Illumina TruSeq DNA PCR-Free Library Preparation Kit according to the manufacturer\u2019s protocol. The libraries were processed for paired-end sequencing (100-nucleotide long reads) using Illumina HiSeq2000 platform  and raw sequence data were filtered through standard Illumina pipeline. The FASTQ sequences were further processed through NGS QC Toolkit v2.3  to removdesi (ICC 4958) chickpea genome are freely available in public domain  chromosome pseudomolecule (334 Mb) and scaffolds of c domain . Accordidesi chickpea genome using BWA with default parameters (desi chickpea genome following desi genome) between EDTFB and LDTFB was measured as \u0394 (SNP-index). Following the representation of genomic fragments obtained from ICC 4958 (early DTF) and ICC 17163/ICC 8261 (late DTF) in entire genome sequences, the SNP-index was calculated as \u201c0\u201d and \u201c1,\u201d respectively. The major genomic regions underlying QTL-seq derived DTF QTLs were ascertained by \u0394 (SNP-index) which is altogether different from 0 at a 99% significance level and thereby, considered to be highly significant QTLs governing flowering time in chickpea. A 10 Mb window-size and 1 kb increment sliding window approach was used to evaluate the mean distribution of \u0394 (SNP-index) of SNPs physically mapped across chromosomes in a target genomic interval. The SNP-index plots of EDTFB and LDTFB for two individual RIL mapping populations and null hypothesis statistical confidence intervals of \u0394 (SNP-index) were obtained to determine the accuracy and validity of QTL-seq derived QTLs following High-quality sequence reads generated from parental accessions and bulks (EDTFB and LDTFB) were mapped onto reference rameters . Consequrameters . The mindesi and 53 kabuli accessions) and 79 wild chickpea accessions  (Table 1). A wider phenotypic variation (varied from 25.7 to 70.9 days with 46.1 to 53.9 days mean \u00b1 8.1\u20139.2 days SD) for DTF with 17.2\u201319.5% CV and 79\u201383% H2 was detected among 204 individuals and parents of an another intra-specific RIL mapping population [ICC 4958 (32.5\u201349.7 mean \u00b1 2.7\u20133.6 SD) \u00d7 ICC 8261 (57.9\u201367.5 mean \u00b1 2.8\u20134.1 SD)] phenotyped similarly in field at two different geographical locations and in green house (long- and short-day photoperiod) for 2 years (Table 1). A significant (P < 0.0001) difference in DTF of individuals representing both RIL mapping populations grown under long- and short-day photoperiod conditions at green-house across 2 years was apparent. We observed a continuous variation-based normal frequency distribution along with a bi-directional transgressive segregation of DTF trait in these two RIL mapping populations .A significant difference of DTF trait was observed on phenotyping in field at two diverse geographical locations and in green house (long- and short-day photoperiod conditions) for 2 years. This varied from 25.8 to 99.5 days with 47.1 to 57.8 days mean \u00b1 13.5\u201316.1 days standard deviation (SD) of DTF trait with 25.6\u201332.1% CV and 79\u201386% H2 with accession number SRR2229140 for unrestricted public access. About 86.5 to 90.1% sequence reads of these were mapped to unique physical locations of reference desi genome with a 73.6% mean coverage (Supplementary Table desi chickpea genome (estimated genome size \u223c740 Mb). For QTL-seq analysis, we compared the individual normalized sequence reads generated from mapping parents and bulks (EDTFB and LDTFB) with that of reference desi genomic sequences including pseudomolecules to discover homozygous high-quality SNPs.For QTL-seq study, we performed high-throughput whole genome NGS resequencing of early and late flowering parents as well as bulks- EDTFB (mean DTF: 22.7\u201328.6 days) and LDTFB (63.0\u201395.1 days)- of two RIL mapping populations [(ICC 4958 \u00d7 ICC 17163) and (ICC 4958 \u00d7 ICC 8261)]. Considering the significant effect of long- and short-day photoperiod on DTF response in two RIL mapping populations across 2 years at green house, early and late flowering bulks- EDTFB (mean DTF: 25.3\u201330.1) and LDTFB (69.9\u201394.6) constituted from two RIL mapping populations were made at these two different photoperiod conditions separately and sequenced at a genome-wide scale for QTL-seq study. This produced 173.8 million high-quality average sequence reads (ranged from 167.4 to 181.4 million reads) with a \u223c30-fold sequencing-depth coverage. The sequencing data generated in the present study were submitted to NCBI-sequence read archive (SRA) databasedesi genome .We discovered 1635117 SNPs (with an average map-density of 0.20 kb) revealing polymorphism between early (ICC 4958 and EDTFB) and late (ICC 17163 and LDTFB) flowering mapping parents and bulks according to their congruent physical positions (bp) on the reference pseudomolecule of aDTF4.1Caq: 46023168 to 46780835 bp and aDTF4.2Caq: 26100745 to 28089632 bp) on chromosome 4 demonstrating the mean SNP-index of \u2265 0.8 in EDTFB and \u2264 0.2 in LDTFB in accordance with the SNP-index measurement criteria defined in QTL-seq analysis . The comprehensive analysis of these selected DTF QTL genomic regions indicated the presence of majority of the SNP alleles derived from early (ICC 4958) and late (ICC 17163) flowering mapping parents in the early and late flowering mapping individuals composing the EDTFB and LDTFB bulks, respectively. Summarily, the QTL-seq assay in an inter-specific mapping population (ICC 4958 \u00d7 ICC 17163) assured the occurrences of two major DTF QTLs- aDTF4.1Caq and aDTF4.2Caq- at the 1.99 Mb [26100745 (SNP_1A) to 28089632 (SNP_2A) bp with a \u0394 (SNP-index): 0.8] and 757.7 kb [46023168 (SNP_3A) to 46780835 (SNP_4A) bp with a \u0394 (SNP-index): 0.9] genomic intervals, respectively, on chickpea chromosome 4 .We identified two major genomic regions  were further validated by resequencing of PCR fragments amplified from the parents (ICC 4958 and ICC 17163) and mapping individuals forming the EDTFB and LDTFB bulks. Accordingly, two major DTF QTLs were detected on similar aforesaid physical positions of chromosome 4 by the QTL-seq analysis of early- and late-flowering bulks (EDTFB and LDTFB) constituted from a RIL mapping population (ICC 4958 \u00d7 ICC 17163) using the long- and short-day photoperiod-based greenhouse DTF phenotyping data of chickpea.The detailed structural annotation of 16397 and 2542 SNPs at desi genome (pseudomolecule)  were found polymorphic between early (ICC 4958 and EDTFB) and late (ICC 8261 and LDTFB) flowering mapping parents and bulks as per their congruent physical locations (bp) on the reference Figure 2B). This essentially detected two major genomic regions (bDTF4.1Caq: 45600294 to 46991993 bp and bDTF4.2Caq: 26500027 to 27407090 bp) on chromosome 4 revealing the mean SNP-index of \u2265 0.8 in EDTFB and \u2264 0.2 in LDTFB . The accuracy of these major genomic regions underlying DTF QTLs was ascertained by a valid 99% \u0394 (SNP-index) significance level. The comprehensive analysis of these DTF QTL genomic regions inferred the occurrence of majority of the SNP alleles derived from parents (ICC 4958 and ICC 8261) in early and late flowering mapping individuals forming the EDTFB and LDTFB bulks, respectively. Overall, the QTL-seq in an intra-specific mapping population (ICC 4958 \u00d7 ICC 8261) identified two major DTF QTLs- bDTF4.1Caq and bDTF4.2Caq- at the 907.1 kb [26500027 (SNP_1B) to 27407090 (SNP_2B) bp with a \u0394 (SNP-index): 0.9] and 1.39 Mb [45600294 (SNP_3B) to 46991993 (SNP_4B) bp with a \u0394 (SNP-index): 0.8] genomic intervals, respectively, on chickpea chromosome 4 .The SNP-index of individual SNPs exhibiting differentiation between early (ICC 4958 and EDTFB) and late (ICC 8261 and LDTFB) flowering mapping parents and bulks was estimated. The mean SNP-index  as well as \u0394 (SNP-index) of EDTFB and LDTFB were measured and further plotted across chromosomes as per aforesaid methods  were validated by resequencing of PCR fragments amplified from the parents (ICC 4958 and ICC 8261) and mapping individuals composing the EDTFB and LDTFB bulks. Like-wise, we detected two major DTF QTLs on similar aforementioned physical positions of chromosome 4 by the QTL-seq analysis of EDTFB and LDTFB bulks constituted from a RIL mapping population (ICC 4958 \u00d7 ICC 8261) using the long- and short-day photoperiod-based greenhouse DTF phenotyping data of chickpea.The detailed structural annotation of 7302 and 3177 SNPs at aDTF4.1, CaqaDTF4.2, CaqbDTF4.1Caq and bDTF4.2Caq) identified and mapped by QTL-seq in two intra-/inter-specific RIL mapping populations of ICC 4958 \u00d7 ICC 17163 and ICC 4958 \u00d7 ICC 8261. Based on these analyses, two consensus major short physical genomic intervals of 757.7 kb [46023168 (SNP_3A) to 46780835 (SNP_4A) bp] and 907.1 kb [26500027 (SNP_1B) to 27407090 (SNP_2B) bp] harboring the major DTF QTLs were detected on chromosome 4 . Our comprehensive multiple QTL-seq analysis in two inter-/intra-specific RIL mapping populations ascertained the validity of novel natural allelic variants-containing similar efl1 and GI genes with a highest \u0394 (SNP-index) of 1.0 at aDTF4.2Caq and bDTF4.1Caq QTL regions governing flowering time in chickpea. Henceforth, these strong flowering time-associated efl1 and GI genes localized at a major DTF QTL interval (aDTF4.2Caq and bDTF4.1Caq) were considered as the potential candidates for flowering time regulation in chickpea. This essentially identified two upstream regulatory [46630632 (G/A) and 46630495 (C/T) bp] and one non-synonymous [Asparagine (AAT) to Serine (AGT)] coding [46618224 (A/G) bp] SNP allelic variants from a efl1 desi gene (Ca11444) as well as two synonymous coding [27092669 (G/A) bp] and downstream regulatory [27096726 (C/T) bp] SNP alleles from a GI desi gene (Ca10198) regulating flowering time in chickpea  and GI (31) localized at two major DTF QTL regions (identified by multiple QTL-seq) were genotyped in 93 desi and kabuli cultivated and 79 wild chickpea accessions to determine their natural/functional allelic diversity-based domestication pattern based on multiple nucleotide diversity parameters (\ud835\udf03\u03c0 and Tajima\u2019s D) (Supplementary Table efl1 (36\u201349% phenotypic variation explained) and GI (33\u201342%) flowering genes exhibited significantly higher association potential for early and late DTF differentiation among chickpea accessions (Table 3). Notably, only 9 to 12% of natural allelic variation-based functional diversity level estimated in efl1 and GI flowering genes among wild gene pool was retained and thus got preserved in cultivated chickpea. The relative mean natural allelic diversity of two flowering genes (efl1 and GI) localized at major DTF QTL regions between cultivated and wild chickpea varied from 88 to 91% (\ud835\udf03\u03c0Cc/\ud835\udf03\u03c0Cw). This was much higher than the relative mean natural allelic diversity level (\ud835\udf03\u03c0Cc/\ud835\udf03\u03c0Cw: 61.8%) estimated by using 7116 genome-wide SNPs localized at genomic regions where no DTF QTLs were mapped.The novel SNP allelic variants discovered from the coding (synonymous and non-synonymous) and non-coding regulatory sequence regions of two flowering genes, A broader phenotypic variation coupled with bi-directional transgressive segregation  of DTF trait among RIL individuals and parents of inter (ICC 4958 \u00d7 ICC 17163)- and intra (ICC 4958 \u00d7 ICC 8261)-specific mapping population phenotyped in field and green house (long- and short-day) conditions at two different geographical locations/years was evident. This infers the complex genetic inheritance pattern of flowering time quantitative trait in chickpea. Therefore, genetic dissection of this complex quantitative trait employing various genomics-assisted breeding strategies is essential for genetic enhancement and to develop early flowering high seed and pod-yielding stress tolerant cultivars of chickpea during present scenario of climate change. To accomplish these, our study selectively employed a rapid, cost-efficient and NGS-led high-throughput multiple QTL-seq assay in two inter- and intra-specific RIL mapping population exhibiting a much wider flowering time trait variation including a higher heritability (consistent phenotypic expression) for flowering time in field and green house (long- and short-day) across two diverse geographical locations/years in order to identify major flowering time QTLs in chickpea.aDTF4.1Caq and aDTF4.2Caq QTLs, respectively, mapped on chromosome 4 governing flowering time in chickpea. Like-wise, 907.1 kb and 1.39 Mb, two major genomic intervals of bDTF4.1Caq and bDTF4.2Caq QTLs, respectively, mapped on chromosome 4 were detected by QTL-seq analysis in an intra-specific RIL mapping population (ICC 4958 \u00d7 ICC 8261). These analyses altogether led to identify two consensus major short physical genomic regions of 757.7 kb and 907.1 kb harboring aDTF4.2Caq and bDTF4.1Caq QTLs, respectively, on chromosome 4 of chickpea. The validation of these major DTF QTLs across two diverse intra-/inter-specific chickpea mapping population was apparent implicating the robustness of identified QTLs in regulating flowering time in chickpea. The aforesaid outcomes also inferred the efficacy of multiple QTL-seq assay to narrow-down the longer major DTF QTL intervals detected by QTL-seq in an individual mapping population into shorter major QTL regions in multiple mapping populations of chickpea. This suggests the potential utility of multiple QTL-seq over NGS-based QTL-seq assay and other conventional QTL mapping approaches in high-resolution molecular/fine mapping of major genomic regions harboring QTLs governing diverse agronomic traits including flowering time in chickpea. As per congruent physical positions (bp) on desi chromosome 4, two short interval DTF QTLs (aDTF4.2Caq and bDTF4.1Caq) revealed correspondence with the two earlier identified known major flowering time QTLs (CaqDF4.1 and CaqDF4.2) that are identified and mapped on an intra-specific high-density genetic linkage map (ICC 16374 \u00d7 ICC 762) of chickpea  detected 1.99 Mb and 757.7 kb two major genomic regions underlying chickpea .aDTF4.2Caq and bDTF4.1Caq QTL regions detected novel natural allelic variants-containing two strong flowering time-associated efl1 and GI genes with highest \u0394 (SNP-index) of 1.0 and thereby, considered as the potential candidates for flowering time regulation in chickpea. Two potential candidate genes, efl1 and GI underlying these major QTLs  regulating flowering time have been delineated by deploying an integrated genomics-assisted breeding strategy involving candidate gene-based trait association mapping, GWAS, QTL mapping, differential transcript expression profiling and gene-specific molecular haplotyping in chickpea  of chickpea. The detection of altogether different natural allelic variants from two similar efl1 and GI flowering genes localized at two major DTF QTL regions between past and present studies collectively infers the population/cultivar-specific genetic inheritance pattern of complex flowering time quantitative trait in diverse genetic backgrounds of chickpea. The above clues collectively suggest the accuracy, robustness and wider practical applicability of multiple QTL-seq approach for fast genome-wide scanning and mapping of high-resolution major flowering time QTLs as well as delineation of candidate genes and novel natural alleles underlying these major QTLs governing flowering time in chickpea.Despite of identifying similar flowering time efl1 and GI genes (detected by multiple QTL-seq) among diverse desi and kabuli cultivated and wild accessions has detected multiple novel natural allelic variants including haplotypes in these flowering time genes exhibiting varied potential characteristics for flowering time trait regulation and evolutionary pattern in domesticated chickpea (The quantitative flowering time trait is primarily governed by complex regulatory networks/pathways involving a diverse array of genes in plant species including legumes . The molchickpea . Therefoefl1 and GI) genes localized at two major DTF QTL regions among Cicer cultivated (desi and kabuli) and wild genepools. This exhibited a significant reduction of natural/functional allelic diversity in cultivated desi and kabuli accessions from diverse geographical regions of the world as compared to annual and perennial wild accessions belonging to primary, secondary and tertiary gene pools of chickpea. However, this observed background allelic diversity reduction in cultivated than that of wild chickpea was much stronger especially at major DTF QTL regions where efl1 and GI flowering genes were mapped. This implicates that these genes were targeted by artificial selection which was further evident from their non-neutral evolution during chickpea domestication based on significant variation of Tajima\u2019s D between cultivated (\u20131.12) and wild (0.26) accessions, respectively. Interestingly, all these natural allelic variants-containing two potential genes localized within flowering time major QTL intervals have been commonly identified and mapped on multiple independent chickpea mapping populations by earlier and our present studies (efl1 and GI) during chickpea domestication leading toward reduction of genetic diversity in cultivated chickpea as compared to that of wild Cicer genepool  localized at two major DTF QTL regions by using the long- and short-day phenotyping data of both RIL populations separately in multiple QTL-seq assay. This further infers the efficacy of strategy (multiple QTL-seq) implemented in our study to detect potential molecular signatures regulating flowering time in chickpea. It is, therefore, essential to perform a comprehensive analysis using all natural/functional allelic variants discovered and potential locus targeted by natural and/or artificial selection in two flowering genes (efl1 and GI) to delve deeper into the complex flowering time trait evolution and domestication in chickpea. This will be useful to understand the molecular mechanism influencing fixation of such complex flowering time quantitative trait in domesticated cultivars that are adapted to multiple agro-ecological regions of the world and further pave the way for genetic enhancement to develop early flowering high seed/pod-yielding varieties of chickpea amidst current climate change scenario.The most crucial evolutionary bottleneck, vernalization, is a vital key module of flowering time during chickpea domestication culminating into existence of currently cultivated vernalization insensitive iculatum . The majcumented . In the RS, AD, and UB conducted all experiments and drafted the manuscript. HU, RK, PS, ST, and CB helped in development, advancement and phenotyping of mapping populations. AT and SP conceived and designed the study, guided data analysis and interpretation, participated in drafting and correcting the manuscript critically and gave the final approval of the version to be published. All authors have read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Growing global demands for crustacean food crop species have driven large investments in aquaculture research worldwide. However, large-scale production is susceptible to pathogen-mediated destruction particularly in developing economies. Thus, a thorough understanding of the immune system components of food crop species is imperative for research to combat pathogens.Through a comparative genomics approach utilising extant data from 55 species, we describe the innate immune system of the class Malacostraca, which includes all food crop species. We identify 7407 malacostracan genes from 39 gene families implicated in different aspects of host defence and demonstrate dynamic evolution of innate immunity components within this group. Malacostracans have achieved flexibility in recognising infectious agents through divergent evolution and expansion of pathogen recognition receptors genes. Antiviral RNAi, Toll and JAK-STAT signal transduction pathways have remained conserved within Malacostraca, although the Imd pathway appears to lack several key components. Immune effectors such as the antimicrobial peptides (AMPs) have unique evolutionary profiles, with many malacostracan AMPs not found in other arthropods. Lastly, we describe four putative novel immune gene families, potentially representing important evolutionary novelties of the malacostracan immune system.Our analyses across the broader Malacostraca have allowed us to not only draw analogies with other arthropods but also to identify evolutionary novelties in immune modulation components and form strong hypotheses as to when key pathways have evolved or diverged. This will serve as a key resource for future immunology research in crustacean food crops.The online version of this article (doi:10.1186/s12864-017-3769-4) contains supplementary material, which is available to authorized users. Cancer magister . Representative species are shown at each branch. Species denoted in purple are edible food crops. (PDF 153 kb)Additional file 2: Table S1.A complete list of all 69 malacostracan transcriptome datasets used in this study along with information on tissue types, developmental stages, accession IDs and total number of transcripts for each transcriptome. (PDF 65 kb)Additional file 3: Table S2.List of species used in graphs along with their corresponding number IDs. (PDF 46 kb)Additional file 4: Table S3.Malacostracans pattern recognition receptors and proPOs. (PDF 639 kb)Additional file 5: Figure S2.Bombyx mori (NP_001159614.1). Two conserved Glu active site residues are labeled as E188 and E193 based on positions in the B. mori protein. (PDF 924 kb)Multiple sequence alignment of the \u03b2-glucanase domains of Gram negative binding proteins of malacostracans together with the \u03b2-glucanase protein from Additional file 6: Figure S3.n=1000) for all trees can be found in Supplementary figure\u00a0TEP family transcripts. The y-axes represent total number of genes identified in all 55 malacostracan species for each family. Each species is represented by a number on the X-axes and a complete list of species is available in Additional file Thioester-containing protein (TEPs) family. (A) Phylogenetic tree of the TEP family is constructed using the maximum-likelihood method from an amino acid multiple sequence alignment. Amino acid sequences include the macroglobulin complement related proteins, the vertebrate C3, C4 and C5 complement factors, arthropod TEPs and the alpha-2 macroglobulin family. Taxa labels are depicted as their respective colour codes. Bootstrap support values  CLIP-domain serine protease transcripts in malacostracans. The y-axes represent total number of genes identified in all 55 malacostracan species for each family. Each species is represented by a number on the X-axes and a complete list of species is available in Additional file Prophenoloxidase activation system. (A) Phylogenetic tree of prophenoloxidase (proPO) is constructed using the maximum-likelihood method from an amino acid multiple sequence alignment. Taxa labels are depicted as their respective colour codes. Bootstrap support values (n=1000) for all trees can be found in Additional file Additional file 8: Figure S5.n=1000) for all trees can be found in Additional file TLR transcripts. The y-axes represent total number of genes identified in all 55 malacostracan species for each family. Each species is represented by a number on the X-axes and a complete list of species is available in Additional file Malacostracans Toll-like receptors (TLRs). (A) Phylogenetic tree of TLRs is constructed using the maximum-likelihood method from an amino acid multiple sequence alignment of toll-IL-1 receptor (TIR) domains. Taxa labels are depicted as their respective colour codes. Bootstrap support values Additional file 10: Figure S6.n=1000) for all trees can be found in Additional file Additional members of the IMD pathway. Phylogenetic trees of (A) PGRP, (B) I\u03baB kinase \u03b2 (IKKb); also known as immune response deficient-5 (IRD-5) and (C) TAK1 are constructed using the maximum-likelihood method from an amino acid multiple sequence alignment. Taxa labels are depicted as their respective colour codes. Bootstrap support values Additional file 12: Figure S7.n=1000) for all trees can be found in Additional file JAK-STAT pathway members in malacostracans. (A) Activation of the JAK-STAT signalling occurs through the binding of ligands such as cytokines to the cytokine receptor Domeless. Conserved protein domains of Domeless are shown in the figure inset. This binding activates the phosphorylation of the Janus kinase (JAK) proteins, which creates docking sites for Signal Transducer and Activator of Transcription (STAT) proteins through their Src Homology 2 (SH2) domains. STATs are phosphorylated by JAKs and activated STATs dimerise and are translocated to the nucleus to induce transcription. JAK-STAT transduction is controlled by suppressors of cytokine signalling (SOCS) and protein inhibitors of activated STAT (PIAS). SOCS proteins inhibit STATs phosphorylation via two mechanisms; 1) by competing with STATs for phosphotyrosine binding sites on cytokine receptors and (2) by binding to JAKs and preventing the recruitment of STATs onto the Domeless receptor. PIAS, also known as the E3 SUMO-protein ligase PIAS, is a transcriptional co-regulator that has the ability to inhibit STAT function. Phylogenetic trees of (B) JAK, (C) STAT and (D) PIAS are constructed using the maximum-likelihood method from an amino acid multiple sequence alignment. Two groups of PIAS proteins have been identified in malacostracans. Taxa labels are depicted as their respective colour codes. Bootstrap support values Additional file 14: Figure S8.n=1000) for all trees can be found in Additional file Suppressor of cytokine signalling (SOCS) gene family in malacostracans. Phylogenetic tree of the SOCS gene family is constructed using the maximum-likelihood method from an amino acid multiple sequence alignment. Seven main groups of SOCS proteins are identified in malacostracans. Taxa labels are depicted as their respective colour codes. Bootstrap support values Additional file 16: Table S8.Malacostracans antiviral RNAi pathway genes. (PDF 378 kb)Additional file 17: Figure S9.Argonaute and Piwi gene families in malacostracans. Phylogenetic tree of the Argonaute and Piwi family is constructed using the maximum-likelihood method from an amino acid multiple sequence alignment. Seven main groups of SOCS proteins are identified in malacostracans. Taxa labels are depicted as their respective colour codes. Bootstrap support values (n=1000) for all trees can be found in Additional file Additional file 18: Table S9.Four novel malacostracan gene families. (PDF 231 kb)Additional file 19: Table S10.Parhyale hawaiensis. (PDF 33 kb)Primer sequences used for RT-PCR of novel malacostracan genes in Additional file 20: Figure S10.Novel gene family with potential innate immunity function characterised by the chitin binding peritrophin-A domain (pfam01607) found only in malacostracans. (A) Phylogenetic tree of proteins containing the chitin binding peritrophin-A domain is constructed using the maximum-likelihood method from an amino acid multiple sequence alignment. Taxa labels are depicted as their respective colour codes. Node labels represent bootstrap support values from 1000 replicates. Scale bar represents substitution per site. (B) Multiple sequence alignment of peritrophin-A proteins showing the conserved peritrophin-A domain marked with a blue box, conserved cysteine residues marked in red boxes and conserved aromatic amino acids indicated by blue asterisks. The yellow shaded box represents a group of proteins with additional isopod-specific sequences. (PDF 5816 kb)Additional file 21: Figure S11.Novel gene family with potential innate immunity function characterised by the death domain (pfam00531) found only in malacostracans. (A) Phylogenetic tree of proteins containing the death domain is constructed using the maximum-likelihood method from an amino acid multiple sequence alignment. Taxa labels are depicted as their respective colour codes. Node labels represent bootstrap support values from 1000 replicates. Scale bar represents substitution per site. (B) Multiple sequence alignment of the death domain family showing the death domain marked with a red box and a novel gene-family-specific motif marked with a blue box. (PDF 3603 kb)Additional file 22: Figure S12.Novel gene family with potential innate immunity function characterised by the ML domain (pfam02221) found only in malacostracans. (A) Phylogenetic tree of proteins containing the ML domain is constructed using the maximum-likelihood method from an amino acid multiple sequence alignment. Taxa labels are depicted as their respective colour codes. Node labels represent bootstrap support values from 1000 replicates. Scale bar represents substitution per site. (B) Multiple sequence alignment of the ML family showing the ML domain characterised by six conserved cysteine residues marked with red asterisks. Transmembrane domains were predicted using the Phobius program  and are annotated with a pink box. (PDF 3188 kb)Additional file 23: Figure S13.Novel gene family with potential innate immunity function characterised by the Von Willebrand factor type A domain (pfam05762) found only in malacostracans. (A) Phylogenetic tree of proteins containing the Von Willebrand factor type A domain is constructed using the maximum-likelihood method from an amino acid multiple sequence alignment. Taxa labels are depicted as their respective colour codes. Node labels represent bootstrap support values from 1000 replicates. Scale bar represents substitution per site. (B) Multiple sequence alignment of the Von Willebrand factor type A domain from this gene family. (PDF 5243 kb)Additional file 25:Fasta files of all sequences. (ZIP 3690 kb)Additional file 26: Figure S14.Phylogenetic trees presented in this study with node labels representing bootstrap support values from 1000 replicates. Scale bars represent substitution per site. (PDF 11640 kb)Additional file 24:Supplementary references (DOCX 31 kb)"}
+{"text": "A 65-year-old woman, non-smoker presented with a two-month history of cough. She also complained of arthralgia and weight loss. The clinical examination revealed a febrile patient. The chest radiograph and the scanner revealed right upper lobar mass, with spiculated contours . Biology showed an inflammatory syndrome. Polymerase chain reaction for Mycobacterium tuberculosis and tumor markers was negative. A lung biopsy showed non caseous granulomatous vasculitis. The cytoplasmic antineutrophil cytoplasmic antibody (cANCA/PR3/ANCA) showed a positive result; Wegener's granulomatosis was finally confirmed. The patient was treated with prednisone and cyclophosphamide with favorable outcome. A follow-up chest radiography two weeks after treatment showed resolving pulmonary lesions (C)."}
+{"text": "Enho (energy homeostasis) gene expression was significantly upregulated. Further metabolic studies employing a human hepatocellular line revealed that MTX treatment preserved robust oxidative phosphorylation, but also promoted mitochondrial uncoupling with a surge in proton leak. This is the first report that certain optimally dosed chemotherapeutic agents can induce weight loss in morbidly obese mice without reduced dietary intake, apparently by depleting stores of adipocytes and their progenitors, curtailment of lipogenesis, and inconspicuous disposal of incoming dietary lipid via a steady state partial uncoupling of mitochondrial oxidative phosphorylation.Morbidly obese patients who accomplish substantial weight loss often display a long-term decline in their resting metabolism, causing even relatively restrained caloric intake to trigger a relapse to the obese state. Paradoxically, we observed that morbidly obese mice receiving chemotherapy for cancer experienced spontaneous weight reduction despite unabated ingestion of their high fat diet (HFD). This response to chemotherapy could also be achieved in morbidly obese mice without cancer. Optimally dosed methotrexate (MTX) or cyclophosphamide (CY) enabled the mice to completely and safely normalize their body weight despite continued consumption of obesogenic quantities of HFD. Weight reduction was not attributable to decreased HFD intake, enhanced energy expenditure or malabsorption. MTX or CY dosing significantly depleted both adipose tissue and preadipocyte progenitors. Remarkably, however, despite continued high fat feeding, a compensatory increase in hepatocyte lipid storage was not observed, but rather the opposite. Gene microarray liver analyses demonstrated that HFD mice receiving MTX or CY experienced significantly inhibited lipogenesis and lipid storage, whereas  Obesity affects more than one-third of the adult population in the United States, and is identified as a major global health and economic concern by the World Health Organization , 2. ExceApart from these concerns, there is a tendency for obese patients with malignancies to be undertreated with chemotherapy, due to apprehension about their ability to tolerate its comorbidities \u20139. RecenOur own effort to observe whether chemotherapy's anti-tumor efficacy varied for normal versus obese mice evidenced no significant differences, consistent with the ASCO analysis. Surprisingly, however, the weekly weighing of mice to adjust their chemotherapy doses revealed that chemotherapy-treated obese mice had an unsuspected and remarkable tendency for weight reduction despite their continued avid ingestion of HFD. This paraphenomenon was also observed in non-tumor-bearing obese mice, with two chemotherapeutic agents, cyclophosphamide and methotrexate, proving to be particularly well tolerated during weeks of treatment, facilitating complete weight normalization despite unabated HFD intake. Explanations such as malabsorption, decreased caloric intake, increased energy expenditure, or ketotic excretion of calories were effectively ruled out as explanations for weight normalization. Instead, a pronounced loss of lipid stores associated with a log-fold cytoreduction of adipocyte progenitors was evident. Remarkably, despite continued high fat feeding, a compensatory increase in hepatocyte lipid storage was not observed during chemotherapy, but rather a stable background increase in uncoupled oxidative phosphorylation which could inconspicuously dissipate calories through a steady-state proton leak.5 MC38 colorectal tumor cells were injected subcutaneously. Two weeks after implantation, MC38 tumors averaged 6mm in diameter, at which time cyclophosphamide 100 mg/kg (CY100) was given to the chemotherapy cohorts for 5 weekly treatments , remaining on the same diet at all stages of treatment. Eight weeks later, mice were individually housed to precisely monitor food intake. At 10 weeks on diet, 5\u00d710s Figure , arrows.HFD-fed mice were morbidly obese and weighed significantly more than LFD-fed mice prior to chemotherapy  Figure . In contNonetheless, during chemotherapy, we observed strikingly different weight trends in the two dietary cohorts. Prior to chemotherapy, HFD-fed obese mice consumed approximately 10% fewer kcal than non-obese LFD-fed mice  lowWe examined the mechanisms by which optimal weekly dosing of MTX or CY accomplished complete weight normalization of HFD obese mice. Preceding chemotherapy treatment, mice fed on HFD nearly doubled in body weight after 10 weeks compared to only a 17% gain in the LFD cohort Figure . Mice fe2); however, there was no significant difference in lean body mass energy expenditure between the chemotherapy treated and non-treated groups within either the HFD or LFD-fed groups (Mice were housed in metabolic cages (CLAMS) for 72h to test possible differences in energy expenditure. The results showed that HFD-fed mice had significantly higher lean body mass energy expenditure compared to LFD-fed mice ; hd groups . TherefoTo examine whether there was a difference in energy excretion, fecal matters from singly housed mice kept in bedding-free cages were collected every 24h during a 3 day collection period. Collected sample weight from all mice, regardless of diet or chemotherapy treatment, averaged 1.7 \u00b1 0.06 g. Bomb calorimetry revealed that there were no significant differences between pre- and post-chemotherapy regarding calories lost fecally in each group, nor were there significant differences between HFD and LFD respective treatment groups Figure . Therefop<0.004). When mice were treated with 5-weekly doses of MTX 12.5-50 mg/kg (MTX12.5-MTX50) or CY 100-200 mg/kg (CY100-CY200), eWAT displayed significant reductions: for example, HFD mice receiving MTX50 lost 44% and CY200 lost 48% of eWAT weight compared to non-treated HFD mice, reducing eWAT to levels indistinguishable from LFD mice not receiving chemotherapy . Livers from HFD mice treated with MTX50 or CY200 displayed 44% or 31% (p<0.02) average decrease in weight compared to HFD non-treated mice . Chemotherapy-induced TG reductions were also seen in the LFD-fed groups . These data indicated that optimized doses of MTX or CY facilitated the catabolism and/or clearance of liver TG in HFD-fed mice to the levels observed in LFD-fed mice not receiving chemotherapy.Intracellular liver triglycerides (TG) were extracted and normalized to liver weight for quantitative comparisons Figure . Mice fep\u2264 0.015 cut-off  in response to HFD and/or methotrexate treatment  that were found to be differentially expressed when comparing LFD, HFD and methotrexate 50 mg/kg treatment were selected for GeneSpring gene ontology (GO) analysis. There were 113 transcripts differentially regulated in the metabolic process and 55 genes that made the f Figure . Of thost Figure .de novo fat synthesis , catalyst of the last step in the FA biosynthetic pathway, was 2.7-fold reduced in MTX50-treated obese mice compared to long-term HFD-fed control mice , catalyst of the biosynthesis of monounsaturated FA, showed a 2.6-fold decrease in livers of HFD-fed mice compared to LFD-fed mice. Furthermore, Scd1 was 14.5-fold reduced in HFD MTX50-treated mice compared to HFD-fed control. Acetyl-CoA carboxylase \u03b2 (Acacb), which catalyzes the carboxylation of acetyl-CoA to the malonyl-CoA pool, was 2.4-fold reduced in chemotherapy-treated mice compared to controls. Elongation of very long chain fatty acids protein (Elovl), a family of microsomal enzymes, displayed differential hepatic expression in three of seven isoforms. Elovl3, Elov5 and Elov6 were respectively downregulated 3.5-fold, 2.4- fold and 3.0-fold in HFD MTX50-treated mice compared to HFD-fed control mice. Glycerol-3-phospate acyltransferase 1-mitochondrial (Gpam), an enzyme on the outer mitochondrial membrane that promotes triglyceride synthesis, was slightly reduced in HFD-fed mice compared to LFD-fed mice; however, when treated with methotrexate, obese mice displayed a 2.1-fold reduction in gene expression compared to HFD-fed controls. Monoacylglycerol acyltransferase 1 (Mogat1), an enzyme converting monoacylglycerol to diacylglycerol, was significantly upregulated (5-fold) in obese mice compared to non-obese controls, but when HFD-fed mice were treated with MTX there was a 3.7-fold decreased expression.Key lipogenic enzymes were significantly downregulated in livers after chemotherapy treatment, consistent with suppression of s Figure  and 5D. Fitm1), a strong promoter of intracellular lipid accumulation [Enho) gene, known to be down regulated in obesity, hepatosteatosis and insulin resistance [Enho expression, surpassing levels seen in LFD control mice. LFD MTX50 mice also displayed significantly increased Enho expression (3.7-fold increase) compared to LFD control.These analyses suggested that MTX affects hepatocytes not only by effectively blocking the generation of lipids, but also by impairing the retention of lipids. Fat storage-inducing transmembrane protein 1  MTX-exposed HepG2 cells showed a significant (MTX-6hrs p<0.03) sustained 2-fold increase in OCR , an indicator of mitochondrial respiration, and extracellular acidification rates (ECAR), a measure of glycolytic energy metabolism, were measured in HepG2 cells treated with or without a nontoxic dose of 10 \u03bcM MTX. , nor upregulated expression of dihydrofolate reductase (Dhfr), a main target of MTX [During the period that HFD mice received five optimized weekly doses of MTX or CY they continued to follow a weight normalization trend which did not reverse until the chemotherapy was terminated, even in non tumor-challenged mice. Therefore, there was no evidence that resistance to chemotherapy developed when normal body cellular constituents were the targets of chemotherapy. Consistent with such lack of resistance, our liver gene arrays for HFD mice demonstrated no significant MTX-attributable downregulation of t of MTX .A key question in the present studies is what becomes of the excessive dietary lard continuously consumed by obese mice receiving MTX or CY, yet accompanied by normalizing weight loss. Common explanations such as malabsorption, increased activity, decreased feeding or diet-induced urinary ketosis were effectively ruled out. Incoming dietary fat storage was thwarted by reduced or unavailable adipocyte storage, due to chemotherapy's depletion of ASC. Despite this additional pressure on the liver to process the continuing glut of incoming dietary TG, CY or MTX treatment was paradoxically also associated with depletion of hepatic lipid stores. In depth analysis of MTX additionally demonstrated this agent's inhibition of hepatic lipogenesis and overall enhancement of mitochondrial respiration, but perhaps most importantly, also revealed a persistence of mitochondrial uncoupling in the face of enhanced overall oxygen consumption, generating a significantly enhanced steady state proton leak. This leak is probably the best candidate mechanism to explain the catabolic dissipation of ingested lipid in a manner which promotes weight loss rather than worsening obesity.The favorable metabolic effects of MTX or CY chemotherapy upon HFD-fed obese mice is in stunning contrast to the plight of markedly obese patients who achieve impressive weight loss through dietary restraint and intensive exercise, but who subsequently display a poorly understood long-term reduction in their resting metabolism which causes even relatively moderate caloric intake to provoke recurrent obesity . Our finad libitum prior to treatment or CLAMS  study. At week 8 on diet mice were housed individually to measure food intake. Mice and food were weighed weekly.Animal work was performed in accordance of Mayo Clinic Institutional Animal Care and Use Committee. C57BL/6 male mice were purchased from Jackson Laboratories. Starting at 6 weeks of age mice were started on either the control,10% kcal fat energy diet (LFD) or 60% kcal fat energy diet (HFD)  for 10 weeks 2. Cells were fed every 2-3 days. MC38 cells (5\u00d7105) were injected subcutaneously into right flank after 10 weeks on diet. If maximal tumor burden was reached, 2000 mm3, mice were euthanized.HepG2  and MC38 colon carcinoma (NCI/NIH) cells were cultured in complete growth medium: DMEM  supplemented with 10% fetal bovine serum (Gibco), 1000 U/ml penicillin-streptomycin and 2 mM L-glutamine (Gibco) at 37\u00b0C/5% COMice were randomized by body weight and then given weight-based chemotherapy (mg/kg) intraperitoneal (i.p.) x5 weekly injections (except gemcitabine which was given i.p. twice weekly) and tissue harvest was performed 1 week post final treatment. Maximum tolerated doses (MTD) were determined for each of the following chemotherapy compounds: cyclophosphamide , 5-fluorouracil , gemcitabine , irinotecan , paclitaxel  and methotrexate  .6 cell in 100 \u03bcl volume) with CD31-PE , CD34-FITC (BD Biosciences cat# 553373), CD45-APC-Cy7  and CD140a-BV421 (BD Pharmingen cat# 562774) and cell sorted with FACS Aria and analyzed with FACS Diva for CD31\u2212, CD34+, CD45\u2212 and CD140a+ preadipocytes [Stromal vascular fraction from epididymal white adipose tissue was isolated using collagenase type VIII (Sigma) digestion. Isolated cells were stained .Triglycerides (TG) were extracted from flash frozen liver samples and were measured using the Triglyceride Quantification Kit protocol .Liver sections were fixed in 10% formalin and paraffin embedded (FFPE). 4 micron thick liver samples were stained with hematoxylin and counterstained with eosin (H&E). Microscopy performed using Leica DMRB (20x objective) with Olympus DP71 camera and images analyzed with cellSens Entry 1.12 software.RNA was isolated using RNeasy mini kit  according to manufacturer's instructions. RNA quantity and integrity were verified with the Nanodrop (Thermo Scientific) and Bioanalyzer using the Nano chip (Agilent). Using the Quick Amp Labeling kit, one color (Agilent), 200 ng RNA per sample was labeled. Dye incorporation and amplified RNA amounts were verified with Nanodrop. Then, 1.65 \u03bcg of each sample was hybridized to a 4\u00d744K mouse whole genome slide (Agilent), washed, and feature extracted according to manufacturer's (Agilent) instructions.p-value \u22640.015 rather than 0.02 for greater stringency [Gene expression imaging, quality control, fold change, GO (gene ontology), and clustering analysis was performed with GeneSpring GX 13.0 . Differentially regulated gene lists, 2-fold change or greater, were selected between LFD and HFD and between methotrexate treated and non-treated mice. Metabolic process list was generated using GO analysis with p-value\u22640.05. Hierarchical clustering analysis was performed using gene lists that were differentially regulated with a ringency . Every thttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE87729), food intake and spontaneous locomotor activity were measured.Mice fed on LFD or HFD for 10 weeks prior to placement into a 12 chamber Oxymax/CLAMS  with free access to food and water. Mice were allowed to acclimate in individual metabolic cages at 22\u00b0C for 16h before measurements were taken. 72h metabolic profiles were generated in successive 26min cycles. Oxygen consumption, COe Extracellular Flux Analyzer was used to monitor the oxygen consumption rate  and extracellular acidification rate  in intact HepG2 cells.Human hepatocellular HepG2 cells were untreated or treated with MTX 10 \u03bcM for either 6h or 12h prior to extracellular flux analysis. HepG2 cells were washed with PBS and cells were seeded at 40000 cells/well in XF96-well cell culture microplate . Seahorse Bioscience XF96t-test, with p\u2264 0.05 considered significant. In Seahorse experiments, 6 wells were concurrently performed and similarly analyzed for each condition by Student's t-test. Therapeutic impact of diet and chemotherapy upon tumor growth was analyzed in a binary fashion  by Fisher's exact-test. Statistical analyses of microarrays are described above.Within individual experiments, each treatment condition (e.g. HFD vs LFD with or without chemotherapy) was tested in individual groups of mice to determine means \u00b1SD for various parameters at particular time points, such as weight or kcal consumed. Such groups were compared via unpaired Student's"}
+{"text": "Pseudomonas putida KF715 (NBRC 110667) utilizes biphenyl as a sole source of carbon and degrades polychlorinated biphenyls (PCBs). Here, we report a complete genome sequence of the KF715 strain, which comprises a circular chromosome and four plasmids. Biphenyl catabolic genes were located on the largest plasmid, pKF715A. Pseudomonas putida KF715, from the soil near a biphenyl manufacturing plant in Kitakyushu, Japan, by enrichment culture with biphenyl as the sole source of carbon  in the P.\u00a0putida KF715 strain can be transferred frequently by conjugation to various Pseudomonas putida strains  have been used widely for a variety of industrial purposes and have become serious environmental contaminants due to their chemical and physical stability. Biphenyl-utilizing bacteria can cometabolize PCBs into chlorobenzoic acids using biphenyl-catabolic enzymes. We have isolated 14 PCB-degrading bacterial strains (KF strains), including es KF707 , 3. We at medium .http://www.ige.tohoku.ac.jp/joho/gf_e/). Remaining gaps between contigs were closed using custom primer working and PCR amplification with standard Sanger technology. The genome of KF715 consists of a circular chromosome  and four circular plasmids named pKF715A , pKF715B , pKF715C , and pKF715D .The genome sequence was determined by the National Institute of Technology and Evaluation (NITE). The draft genome was sequenced using 454\u00a0GS FLX+ (Roche) and HiSeq 1000 (Illumina) systems, with a standard fragment library and a paired-end library, respectively. The reads obtained by the two systems were assembled using Newbler version 2.8 (Roche), which generated the initial draft sequence data consisting of 282 contigs. The finishing was facilitated using two computer programs, GenoFinisher and AceFile Viewer ( Pseudomonas putida strains (5.77 to 6.36\u00a0Mb) (n = 240) involved in the metabolism of aromatic compounds. The bph-sal element containing the biphenyl metabolism cluster bphR1A1A2A3A4BC is found on the largest plasmid, pKF715A. This suggests that the bph-sal element spread frequently by plasmid-mediated horizontal transfer between KF strains in the natural environment.The complete genome sequence of the KF715 strain annotated using the Rapid Annotations using Subsystems Technology (RAST) server (6.36\u00a0Mb) . This RAAP015029 (chromosome) and AP015030, AP015031, AP015032, and AP015033 (plasmids).The sequences with the annotation of KF715 have been deposited at DDBJ/EMBL/GenBank under accession numbers"}
+{"text": "There were no other predictors of PONV/PDNV  in these patients. The low incidence of vomiting (2-5%) suggests the potential importance of aprepitant in a multimodal antiemetic regimen. However, there may be the potential that too many unique antiemetic mechanisms combined with preoperative aprepitant may actually increase the incidence of perioperative nausea.Postoperative and postdischarge nausea and vomiting  add morbidity to perioperative outcomes. Combining some antiemetic agents of different mechanisms is more effective than using single agents, although this concept has not yet been tested extensively with aprepitant. Consecutive high-risk patients for PONV (n = 100) were given preoperative aprepitant 40 mg before surgery and were followed perioperatively. Female patients receiving general anesthesia (n = 81) were selected for data analysis. The primary endpoints were PONV/PDNV in the 48 h after surgery. For patients included in the data analysis, using Apfel PONV risk factors, the median risk count was four out of four. PONV and PDNV incidences were 21% (95% CI: 14-31%) and 37% (95% CI: 27-48%), respectively. Two patients experienced PACU (postanesthesia care unit) vomiting and two patients experienced emesis postdischarge. When using regression modeling and comparing patients who received one or two vs. three or four mechanistically unique antiemetics (added to preoperative aprepitant), while adjusting for surgical case duration, the three or four additional antiemetic group showed more PONV/PDNV (Odds Ratio 3.73, 95% CI 1.3-10.9,"}
+{"text": "Adult-onset Still disease (AOSD) is a rare systemic inflammatory disorder. A few patients develop organ complications that can be life-threatening. Our objectives were to describe the disease course and phenotype of life-threatening AOSD, including response to therapy and long-term outcome.A multicenter case series of intensive care medicine (ICU) patients with life-threatening AOSD and a systematic literature review.. After ICU discharge, most patients required additional treatment. Literature analysis included 79 cases of AOSD with organ manifestations, which mainly included reactive hemophagocytic syndrome (42%), acute respiratory failure (34%), and cardiac complications (23%). Response rate to corticosteroids was 68%. Response rates to IVIgs, cyclosporin, and anakinra were 50%, 80%, and 100%, respectively.Twenty patients were included. ICU admission mostly occurred at disease onset (90%). Disease manifestations included fever (100%), sore throat (65%), skin rash (65%), and arthromyalgia (55%). Serum ferritin was markedly high . Acute respiratory failure, shock and multiple organ failure occurred in 15 (75%), 10 (50%), and 7 (35%) cases, respectively. Hemophagocytosis was demonstrated in eight cases. Two patients died. Treatment delay was significant. All patients received corticosteroids. Response rate was 50%. As second-line, intravenous immunoglobulins were ineffective. Anakinra was highly effectiveAOSD should be recognized as a rare cause of sepsis mimic in patients with fever of unknown origin admitted to the ICU. The diagnosis relies on a few simple clinical clues. Early intensive treatment may be discussed. IVIgs should be abandoned. Long-term prognosis is favorable.The online version of this article (10.1186/s13054-018-2012-2) contains supplementary material, which is available to authorized users. Adult-onset Still disease (AOSD) is a rare systemic inflammatory disorder of unknown etiology. Its prevalence is less than 1/100,000 and it affects predominantly young people , 3.While differential diagnosis is broad  there is no single biological nor pathological finding specific for AOSD . Thus itA few patients develop organ complications that can be life-threatening, including reactive hemophagocytic syndrome (RHS), cardiac failure, respiratory distress, coagulopathy, severe hepatitis, and multiple organ failure (MOF) . Data reOur objectives were: (i) to describe the disease course and phenotype of life-threatening AOSD (i.e. cases with organ failure leading to ICU admission) (ii) to analyze the response to therapy and long-term outcome of these patients.We report a multicenter case series of 20 intensive care unit (ICU) patients with life-threatening AOSD as well as a systematic literature review of organ manifestation of AOSD.French Intensive Care Society and the French Internal Medicine Society. Inclusion criteria were: (i) admission to ICU due to AOSD-related organ failure. (ii) AOSD diagnosis fulfilling the Yamaguchi  level: 328 mg/L (100\u2013495)) contrasting with fibrinogen levels (median: 3.8 g/L (1.1\u20137.1)). Prothrombin activity  was \u226450% in eight cases (40%). Ten patients (50%) had elevated liver enzymes (median aspartate aminotransferase [ASAT] level: 85.5 UI/L (31\u20132963)). Serum ferritin was markedly elevated )  from 11 centers were included. Patients\u2019 ethnicity was mostly Caucasian . Median age was 36 years (18\u201364). ICU admission mostly occurred during the initial AOSD flare (90%). Patients exhibited a combination of fever, evanescent skin rash, sore throat, arthromyalgia, serositis Fig.  and b, a4)) Fig. .Fig. 1PhMedian time between fever onset and hospitalization was 10 days (1\u201361) Fig. . Median Organ involvement mainly affected the respiratory, cardiocirculatory and hematologic systems Fig. . The medFifteen patients (75%) suffered acute respiratory distress (ARF) requiring mechanical ventilation . One patient required pleural drainage. Upon chest computed tomography (CT), 12 patients (60%) exhibited parenchymal lesions, including pulmonary condensations (35%), bilateral micronodular infiltrates (15%) and/or interstitial pneumonia (10%). Pleural effusions were frequent . Respiratory distress fulfilled the acute respiratory distress syndrome (ARDS) criteria in two patients, who were treated by prone position and neuromuscular blocking agents. Four patients had tracheostomy for weaning from mechanical ventilation (20%).Ten patients had shock requiring vasopressors. Five had non-cardiogenic shock, with MOF in four cases. Norepinephrine was administered for a median of 8 days (2\u201315). Four other patients had cardiogenic shock requiring dobutamine for a median of 3 days (2\u20138) and one patient had mixed shock. One patient needed an extracorporeal life support system for 7 days.Pericarditis occurred in ten patients (50%) with cardiac tamponade in three (drainage in two cases). Five patients (25%) had < 45% left ventricular ejection fraction. Their median was 40 (25\u201345). No patients had ventricular heart rhythm disorder. Eight patients had evidence of myocarditis (40%), which was occasionally proven by magnetic resonance imaging (MRI) or endomyocardial biopsy (one case each).9/L. Fourteen patients underwent bone marrow examination. Hemophagocytosis was seen in eight cases and correlated with thrombocytopenia and liver enzyme elevation. In contrast, hemoglobin, leukocyte,\u00a0fibrinogen and ferritin levels did not predict hemophagocytosis , severe hepatitis (n = 2), myocarditis (n = 1) or ARF (n = 1). One patient had TMA (5%), with thrombocytopenia, hemolytic anemia, and schizocytosis. TMA was confirmed by renal biopsy and it was complicated by AKI requiring RRT, and status epilepticus. A disintegrin and metalloprotease with thrombospondin type I repeats-13 (ADAMTS 13) activity was 35%.Ten patients (50%) had DIC in the context of MOF (Liver enzyme elevation above 3 \u00d7 ULN occurred in ten patients (50%). One patient had hepatic encephalopathy and two had hepatic failure with PA < 50%. None received a liver transplant. Neurological impairment occurred in five patients (25%), in association with other organ failure. AKI occurred in seven patients ). All seven patients required RRT (median duration = 8 days (4\u201330)). AKI occurred in the event of MOF for six patients  and TMA for one (14.3%). MOF occurred in seven patients (35%), with hemophagocytosis for five patients.p = 0,017) and tended to exhibit a less severe clinical picture. An additional table shows this in more details , within a median of 6 days 1\u201336). These patients had lower ferritin level . Ten patients (50%) suffered at least one complication, including infection, hemorrhage, distal necrosis, and ICU neuropathy (Table \u201382. Ten Staphylococci (n = 3), Pseudomonas aeruginosa (n = 3), Corynebacterium jekeium (n = 1), Candida albicans (n = 1). Ventilator-associated pneumonia occurred in two patients (5%), caused by Pseudomonas aeruginosa plus Klebsiella pneumonia in one, Enterobacter aerogenes in the other.Seven patients developed ten infectious complications. Six patients (30%) developed catheter-related infection, with suppurative thrombophlebitis in two cases. Causal agents included n = 1), peptic ulcer (n = 1), and intestinal necrosis (n = 1); liver biopsy (n = 1); lower limb (n = 1); and diffuse hemorrhage (n = 1). Distal extremity necrosis occurred in two patients (10%), caused by DIC for one, and TMA for the other. Three patients (15%) had atrial fibrillation, complicated by pulmonary edema. One patient had hypoxic cardiocirculatory arrest, with full recovery. One patient had hypertensive emergency. Three patients (15%) developed ICU neuropathy. Four patients (20%) needed tracheotomy.Six patients (30%) experienced hemorrhages in the context of hemostasis disorders, thrombocytopenia and/or organ lesions: digestive hemorrhage by angiodysplasia (Two patients (10%) died in the ICU. Both had MOF and hemophagocytosis. A 19-year-old man, with a previous history of AOSD died after ineffective CS then IVIgs treatment. Treatment had begun 17 days after first signs. A 37-year-old woman with new-onset AOSD died after 2 months in the ICU. This patient presented with hemophagocytosis uncontrolled by CS, anakinra, cyclosporine, and etoposide. She underwent diagnostic splenectomy and suffered repeated infections, notably invasive candidiasis. Autopsy disclosed hepatosplenic hemophagocytosis. Treatment had begun 32 days after fever onset.n = 10) and/or methotrexate (n = 5). Detailed long-term treatment data are reported in Table After leaving the ICU, 11 patients with persistent disease activity required additional treatment before discharge. At 3 months, all patients were on CS and 16/18 (89%) received additional treatment, mostly anakinra . The spectrum of organ complications were as follows: 33 RHS (42%); 27 ARF (34%) including six ARDS (8%); 18 cardiac complications (23%) including six tamponades (8%), 12 myocarditis (15%), complicated by cardiogenic shock in five cases (6%); 16 MOF (20.3%); 13 TMA (16.5%); four fulminant hepatitis (5.1%) with two liver transplantations. As in our series, neurologic and renal impairment resulted from other organ manifestations.We performed a systematic review of published data describing AOSD patients with organ complications, which included 79 cases from 62 publications. Median age at life-threatening episode was 38 years. Fifty patients were female (63.3%). Organ complication mostly occurred at diagnosis . Response rate was 68%. The efficacy of second-line treatments is reported in Table Herein, we report on the first study focusing on AOSD patients requiring ICU admission due to AOSD-related organ failure. Our objectives were to describe the phenotypic spectrum, response to therapy and long-term outcome of this infrequent subgroup of patients with life-threatening AOSD.Until now, most studies about AOSD have focused on the long-term risk of developing further systemic flare(s) and/or a chronic polyarthritis. Similarly, most data regarding therapeutics focuses on patients with refractory, chronic, and non-life-threatening disease , 21, 22.Both in our series and in published cases, we found that three key AOSD organ manifestations can lead to ICU admission. The most frequent is respiratory failure due to lung damage and/or pleural effusion. The second is cardiocirculatory failure . The third complication is hematologic disorders, including RHS and/or DIC. The majority of patients exhibit a combination of organ manifestations and one-third has MOF. These complications occurred mostly during the first flare. Expectedly, patients had usual signs of AOSD. Half of them exhibited the classic triad of high-grade fever with evanescent maculopapular rash and arthromyalgia . Other cRHS is the most frequent AOSD complication , 17\u201319. AOSD, RHS, and sepsis share pathophysiological aspects, including the prominent role of pro-inflammatory cytokines IL-1, IL-6, and IL-18 , 28\u201333. Our second objective was to assess the prognosis and response to therapy. Two patients of ours succumbed to AOSD (10%). Yet, mortality may be higher since some patients with fatal AOSD have certainly been missed. A significant proportion of patients experienced classical ICU complications and/or sequelae such as distal necrosis or neuropathy, but long-term prognosis was favorable.Overall, only half the patients responded to CS. We found that these patients tend to have a less severe disease, and lower ferritin levels. IVIgs were frequently used as second-line therapy in patients who failed CS. Indeed, persisting or recurrent fever under CS in an ICU patient raises the issue of superimposed infection. In such circumstances IVIgs are an appealing therapy even if little data are available regarding their use in AOSD. Our study and literature data show that IVIgs are rarely effective, with an overall response rate of only 41%. By contrast, we found that IL-1-targeting therapy with anakinra was highly effective. In our series, five patients (25%) received anakinra in the ICU, with a response rate of 80%. One of the limitations of its use is the lack of data for patients with severe renal failure. Indeed, the only patient that did not fulfill our response criteria (i.e leaving ICU without further treatment) died after anakinra was stopped due to persistent fever, infections, and AKI requiring RRT. Twenty years ago, a phase III randomized controlled trial investigated the efficacy of anakinra in ICU patients with severe sepsis . In thisOur series have several limitations owing to its retrospective nature, limited size, and heterogeneity. However, retrospective studies are essential tools for the study of such rare diseases. They can also provide meaningful information regarding the efficacy and safety of therapeutic strategies in complex yet real-life situations.AOSD should be recognized as a potential sepsis mimic in patients with fever of unknown origin admitted to ICU. In the absence of diagnostic gold standard, intensivists should be aware of the clinical and biological clue to this diagnosis. Fifty percent of patients are refractory to CS, thus early intensive treatment may be discussed on an individual patient basis . WhetherAdditional file 1:Flow chart of life-threatening adult-onset Still disease. (PDF 363 kb)Additional file 2:Additional information about the manuscript methods and literature review references are provided. (DOCX 27 kb)Additional file 3:Comparison of patients according to response to corticosteroids in the ICU. (DOCX 14 kb)Additional file 4:Treatment of 20 AOSD in the ICU: treatments, timing and outcome. (PDF 510 kb)Additional file 5:Example of two patients treated by anakinra. (PDF 265 kb)"}
+{"text": "Gracula religiosa), demonstrating close homology with Usutu viruses circulating in Europe.The complete and annotated coding sequence and partial noncoding sequence of an Usutu virus genome were sequenced from RNA extracted from a clinical brain tissue sample obtained from a common hill myna ( Turdus merula) and great grey owls (Strix nebulosa) in Austria  that died 24\u00a0h after the first demonstration of clinical symptoms tested positive using an in-house Usutu virus real-time reverse transcription-PCR (RT-PCR) (data not shown). During autopsy, a swollen liver and spleen were detected as sole macroscopic lesions. The brain tissue was homogenized in phosphate-buffered saline (10% [wt/vol]), pretreated by 0.45-\u00b5M-pore-size selective filtration and nuclease, and RNA was extracted as previously described . Stretches containing unidentified nucleotides (N) were trimmed using Cutadapt version 1.3    . De novoge.net/) . The proge.net/) .The nearly complete genome of Usutu virus strain Gracula religiosa/U1609393/Belgium/2016 was obtained with an average coverage of 493\u00d7 and contains a single 10,305-nucleotide (nt) open reading frame (ORF) encoding a polypeptide precursor protein, sharing a high nucleotide homology with Usutu viruses circulating in wild birds and mosquitoes in Germany in 2011 to 2013 and Usutu viruses circulating in 2011 to 2015 in central and western Europe in general.KY315178.The complete coding sequence of Usutu virus strain Gracula religiosa/U1609393/Belgium/2016 was assigned DDBJ/EMBL/GenBank accession no."}
+{"text": "Cardiac growth after heart transplantation (HTx) in children has been reported to be normal in the long-term follow-up. The aim of our study was to evaluate ventricular volumes, mass and function in a cohort of pediatric HTx patients using cardiac magnetic resonance (CMR).Seventy-five pediatric HTx patients  were assessed by CMR 11.2 \u00b1 5.4 years after HTx . Right (RV) and left ventricular (LV) volumes and LV mass were derived from short-axis cine images. The results were compared with a healthy reference population of 79 patients  from the German Competence Network for Congenital Heart Defects. LV strain measurements were performed using CMR feature tracking (FT) software  and were compared with a group of 46 healthy controls .Both LV and RV enddiastolic and -systolic volumes were significantly smaller in the HTx group compared to healthy controls while LV mass was significantly higher in HTx patients. RV and LV ejection fraction were both reduced in HTx patients. While LV longitudinal (LS) and radial strain (RS) were significantly reduced, LV circumferential strain (CS) was preserved in the HTx group. LV-CS and LV-RS correlated with LV enddiastolic volume . LV mass was inversely related to diastolic LV function assessed by early diastolic strain rate .Compared to healthy references, children and adolescents after HTx show impaired cardiac growth, increased myocardial mass and reduced global systolic pump function. Smaller LV dimensions are associated with impaired systolic strain while higher LV myocardial mass is related to diastolic function."}
+{"text": "Meloidogyne spp.) are the most damaging plant parasites causing severe losses to crop production. The present study reports genome-wide identification and characterization of both tomato and RKN miRNAs simultaneously from RKN-infected susceptible tomato roots using high-throughput sequencing technique. RNAseq data from 11 small RNA libraries derived from 5 disease development stages identified 281 novel miRNAs of tomato in addition to 52 conserved and 4 variants of conserved miRNAs. Additionally, the same set of RNAseq data identified 38 conserved and 290 novel RKN miRNAs. Both tomato and RKN miRNAs showed differential expression at 5 stages of disease development based on digital expression profiles. In tomato, further validation through qRT-PCR confirmed that majority of miRNAs were significantly upregulated during susceptible response whereas downregulated during resistance response. The predicted targets of 8 conserved and 1 novel miRNAs were validated through 5\u2019RLM-RACE. A negative correlation between expression profiles of a few conserved miRNAs  and their targets  was confirmed. A novel Sly_miRNA996 also showed a negative correlation with its target MYB-like transcription factor. These results indicate that the conserved and novel tomato miRNAs are involved in regulating developmental changes in host root during RKN infection. In RKN, the targets of conserved miRNAs were also predicted and a few of their predicted target genes are known to be involved in nematode parasitism. Further, the potential roles of both tomato and RKN miRNAs have been discussed.Root-knot nematodes (RKNs,  Meloidogyne spp.) are the most damaging plant pathogens worldwide. They have a wide host range causing agricultural losses of billions of dollars annually  and RKN  and their targets that can be further functionally characterized to get better insights into plant-nematode interaction. Finally, this study and previous studies strongly support for a wide range of roles of plant miRNAs during disease progression  and of RS1 Fig(TIF)Click here for additional data file.S2 Fig(A) Tomato miRNAs and (B) RKN miRNAs prepared through Mfold web server.(TIF)Click here for additional data file.S3 Fig(TIF)Click here for additional data file.S4 FigA) Sequence alignment of three RKN miRNAs (identified in our study but not reported previously) was done on the basis of same seed sequence and 80% homology within the mature miRNA sequence (21-24nt). (B) Sequence alignment of additional three miRNAs identified from our sequencing data when mapped on C. elegans genome with no mismatches. The nucleotides highlighted in black are same. miR- miRNA sequences of RKN identified from our sequencing data. min-miR\u2014miRNA sequences of RKN identified by Zhang et al. 2016. MI-miR\u2014miRNA sequences of RKN identified by Subramanian et al. 2016. cel-miR\u2013C. elegans, prd-miR\u2013P. redivivus, asu-miR\u2013A. suum, bma-miR\u2013B. malayi miRNA sequences.((TIF)Click here for additional data file.S5 Fig(TIF)Click here for additional data file.S1 Table(XLS)Click here for additional data file.S2 Table(XLS)Click here for additional data file.S3 Table(XLS)Click here for additional data file.S4 Table(XLS)Click here for additional data file.S5 Table(XLS)Click here for additional data file.S6 Table(XLS)Click here for additional data file.S7 Table(XLS)Click here for additional data file.S8 Table(XLS)Click here for additional data file.S9 Table(XLS)Click here for additional data file.S10 Table(XLS)Click here for additional data file.S11 Table(XLS)Click here for additional data file.S12 Table(XLS)Click here for additional data file.S13 Table(XLS)Click here for additional data file.S14 Table(XLS)Click here for additional data file.S15 Table(XLS)Click here for additional data file.S16 Table(DOC)Click here for additional data file.S17 Table(XLS)Click here for additional data file."}
+{"text": "Obba rivulosa , a polypore known for its lignin-decomposing ability. The genome is based on the homokaryon 3A-2 originating in Finland. The genome is typical in size and carbohydrate active enzyme (CAZy) content for wood-decomposing basidiomycetes.We report here the first genome sequence of the white-rot fungus  Obba rivulosa (= Physisporinus rivulosus) is a conifer-dwelling polypore, a selective delignifier that targets lignin over cellulose in the early stages of wood decomposition (Obba rivulosa is a close relative of Gelatoporia subvermispora (= Ceriporiopsis subvermispora), whose draft genome sequence has been published   .O.\u00a0rivulosa differ slightly genetically . Both the genome and transcriptome were sequenced using Illumina platforms. DNA was sheared to 270 bp using the Covaris E210 (Covaris) and size-selected using SPRI beads (Beckman Coulter). The fragments were treated with end repair, A-tailing, and ligation of Illumina adapters using the TruSeq sample prep kit (Illumina). Stranded cDNA libraries were generated using the TruSeq stranded RNA LT kit. mRNA was purified from total RNA using magnetic beads containing poly(T) oligonucleotides, fragmented, and reverse transcribed using random hexamers and SSII (Invitrogen), followed by second-strand synthesis. The fragmented cDNA was treated with end repair, A-tailing, adapter ligation, and eight cycles of PCR. Both libraries were quantified using Kapa Biosystems\u2019 next-generation sequencing library quantitative PCR (qPCR) kit and run on a Roche LightCycler 480 real-time PCR instrument. The quantified library was then prepared for sequencing on the Illumina HiSeq sequencing platform utilizing a TruSeq paired-end cluster kit, version 4, and Illumina\u2019s cBot instrument to generate clustered flow cells for sequencing on the Illumina HiSeq 2500 using HiSeq and TruSeq SBS sequencing kits, version 4, following a 2 \u00d7 150 indexed run recipe.in silico long mate-pair library with 3-kbp insert, which was then assembled with the original Illumina library with AllPaths-LG release 46652  . A single lignin peroxidase gene, but no versatile peroxidase, was detected. Among e (CAZy)  profile MAXV00000000. The version described in this paper is MAXV01000000. The annotated genome is available via the JGI fungal genome portal MycoCosm (http://genome.jgi.doe.gov/Obbri1) (This whole-genome shotgun project has been deposited at DDBJ/ENA/GenBank under the accession no. /Obbri1) ."}
+{"text": "Staphylococcus haemolyticus is a coagulase-negative staphylococcal species that is part of the skin microbiome and an opportunistic human pathogen. The strain SGAir0252 was isolated from tropical air samples collected in Singapore, and its complete genome comprises one chromosome of 2.63\u2009Mb and one plasmid of 41.6\u2009kb. Staphylococcus genus is associated with several bacterial infections in humans and other animals and is described as part of the human skin microbiome (Staphylococcus haemolyticus is included in the coagulase-negative staphylococci (CoNS) group and is one of the most important human-associated pathogens . This air sampler collects bioaerosol particles at a flow rate of 28.3\u2009liter/min. Viable air particles were collected on Trypticase soy agar  media plates placed below the sampler and incubated overnight at 30\u00b0C. Further isolation was conducted in Luria-Bertani (LB) broth incubated at room temperature overnight. DNA was extracted using a Wizard Genomic DNA purification kit (Promega), following the manufacturer\u2019s protocol. A whole-genome shotgun (WGS) library was prepared with the SMRTbell template prep kit 1.0 (Pacific Biosciences), using a 15-kb cutoff. Single-molecule real-time (SMRT) sequencing was performed on a PacBio RS II (Pacific Biosciences) sequencer. Additional WGS libraries were prepared with a TruSeq Nano DNA library preparation kit and sequenced on an Illumina MiSeq instrument to generate 300-bp paired-end reads. The total number of long reads obtained with the PacBio RSII platform was 23,264 (71.33-fold coverage), whereas the Illumina MiSeq platform provided 653,569 (121.27-fold coverage) short reads.De novo genome assembly of long reads was performed using the Hierarchical Genome Assembly Process version 3 (HGAP3) implemented in the SMRT analysis algorithm version 2.3.0 .The Phylum-specific Automated Phylogenomic Inference Pipeline (Phyla_AMPHORA)  predicteMultilevel genome annotation was conducted by the NCBI Prokaryotic Genome Annotation Pipeline (PGAP) . The com9\u2013Staphylococcus haemolyticus strain SGAir0252, including the plasmid pSGAir0252, is available in GenBank under the accession numbers CP025031 (chromosome) and CP025033 (pSGAir0252).The complete genome sequence of"}
+{"text": "Genome wide association studies (GWAS) already have identified tens of susceptible loci for nonsyndromic cleft lip with or without cleft palate (NSCL/P). However, whether these loci associated with nonsyndromic cleft palate only (NSCPO) remains unknown.p values in published GWASs, genotyping by using SNPscan among 144 NSCPO trios from Western Han Chinese. We performed the transmission disequilibrium test (TDT) on individual SNPs and gene-gene (GxG) interaction analyses on the family data; Parent-of-Origin effects were assessed by separately considering transmissions from heterozygous fathers versus heterozygous mothers to affected offspring.In this study, we replicated 38 SNPs (Single nucleotide polymorphisms) which has the most significant p=0.025, ORtransmission=3.00, 95%CI: 1.09-8.25) and G allele at rs2485893 (10kb 3\u2019 of SYT14) were associated with NSCPO . Genotypic TDT based on 3 pseudo controls further confirmed that rs742071  and rs2485893 were associated with NSCPO under additive model . Genotypic TDT for epistatic interactions showed that rs4844913 (37kb 3\u2019 of DIEXF) interacted with rs11119388 (SYT14)  and rs6072081 (53kb 3\u2019 of MAFB) interacted with rs6102085 (33kb 3\u2019 of MAFB)  for NSCPO, suggesting they may act in the same pathway in the etiology of NSCPO.Allelic TDT results showed that T allele at rs742071 (PAX7) (In this study, we found that rs742071 and rs2485893 were associated NSCPO from Han Chinese population; also, interactions of rs4844913:rs11119388 and rs6072081:rs6102085 for NSCPO were identified, gene-gene interactions have been proposed as a potential source of the remaining heritability, these findings provided new insights of the previous GWAS.Key words:GWAS, NSCPO, TDT, parent-of-origin effects, epistatic interactions. Cleft palate (CP) is a common birth defect, which has a lower birth prevalence compared to cleft lip with/without cleft palate (CL/P): 1/2500 live births vs. 1/700; but CP shows less variability in birth prevalence across populations compared to CL/P , affected individuals have no other physical or developmental anomalies. Most studies suggest that about 50% of CP is nonsyndromic . Both poGenome wide association studies entail the matching of a given human genome sequence with an annotated, high-resolution map of common genetic variation; They are contributing a lot to our understanding of diseases to which there is a genetic predisposition . Genome However, whether these loci associated with nonsyndromic cleft palate only for Han Chinese remains unknown. In this study, we replicated 38 SNPs from 19 genes/ regions of 11 chromosomes from previous GWAS -10 and o- SamplesOur samples consisted of 144 complete case-parent trios with nonsydromic cleft palate only (NSCPO), 59 males, 82 females and 3 unknown gender of the probands. All subjects were self-identified as Western Han Chinese, they were recruited between 2008 and 2013 from the Cleft Surgery Department of West China Hospital of Stomatology, Sichuan University. Written informed consent was obtained from parents on behalf of the children and all affected individuals old enough to give their own consent in this study. The consent procedure and this study approved by the Hospital Ethics Committee (HEC) of West China Hospital of Stomatology, Sichuan University.- GenotypingVenous blood samples were drawn from participants and DNA was extracted by phenol chloroform extraction protocol. The SNP genotyping work was performed using a custom-by-design 2x48-Plex SNPscanTM Kit .- Statistical analysis p=0.0013.The unaffected parents were underwent Hardy-Weinberg Equilibrium (HWE) analysis and minor allele frequency (MAF) determination. HWE, MAF, allelic TDT and parent-of-origin effects, were calculated using PLINK . Pairwis- Transmission Disequilibrium Testp >0.05)  and G allele at rs2485893 (10kb 3\u2019 of SYT14) were associated with NSCPO   and rs2485893 are associated with NSCPO under additive model  (All SNPs were passed the HWE test (p >0.05) . Allelic42-0.85) . Genotyp47-0.92) .- Parent-of-Origin Effectsp=0.026), allele A at rs8001641 (p=0.018) and allele G at rs17563 (p=0.045) compared with the paternal . However, we found an excess of maternal transmission of the allele G at rs2485893  and rs6072081 (53kb 3\u2019 of MAFB) interacted with rs6102085 (33kb 3\u2019 of MAFB) (p= 3.60E-04) for NSCPO  interacted with rs11119388 (SYT14)  of SNPs on chromosome 1 based the association results above. There were strong LD between six pairs of SNPs  with D\u2019>0.93 and r2>0.80, which distributed on two haplotypes  and rs6072081 interacts with rs6102085 for NSCPO, which provided new insights for the previous GWASs.In summary, we replicated 38 SNPs contributing to NSCL/P to investigate their roles in NSCPO among Han Chinese population. In this study, we found that rs742071 and rs2485893 were associated NSCPO from Han Chinese population; also, interactions of rs4844913:rs11119388 and rs6072081:rs6102085 for NSCPO were identified, which may provide new insights for the previous GWASs."}
+{"text": "Xanthomonas fragariae is a worldwide-spread plant bacterial disease causing angular leaf spots, thus reducing the yield of production for strawberry fruits. Three isolates with various geographic and time origins were sequenced with long-read technology (PacBio) to generate finished genome sequences of virulent strains and observe the variability in their contents. Xanthomonas fragariae is a bacterium under quarantine status in Europe (X.\u00a0fragariae genome (LMG 25863) was published in 2013 , all these contigs were found to be circular. To control the assembly and correct possible misassigned bases, raw reads were mapped against the manually edited HGAP assemblies with the SMRT Analysis software version 2.3.0 using the RS_Bridge Mapper protocol. The final assemblies were similar in size  and in the same range as those previously described , and PD 5205 also contains two plasmids (30.469 and 20.830 kb), whereas only one plasmid (21.045 kb) was detected in NBC 2815. A 10-kb insertion was observed in the 27.107-kb plasmid harbored by PD 885T compared to other 21-kb plasmids. This insertion contains genes encoding a type IV secretion protein, VirB5, and VirB6, which are absent from all other Xanthomonas fragariae replicons and chromosomes sequenced so far. A 1-kb insertion containing two genes coding for transposase proteins was detected in the plasmid PD 5205 (30.469 kb) compared to other 29-kb plasmids.The sequenced strains harbored plasmids with the same backbones as the two plasmids described by Henry and Leveau , approxiT, NBC 2815, and PD 5202 have been deposited at DDBJ/ENA/GenBank under the accession numbers LT853882 (PD 885T chromosome), LT853883 (plasmid pPD885-29), LT853884 (plasmid pPD885-27), LT853885 (PD 5205 chromosome), LT853886 (plasmid pPD5205-30), LT853887 (plasmid pPD5205-21), LT853880 (NBC 2815 chromosome), and LT853881 (plasmid pNBC2815-21).The complete genome sequences for PD 885"}
+{"text": "HCM variant locations predict impaired IHM formation and stability, and attenuation of the SRX state - accounting for altered contractility, reduced diastolic relaxation, and increased energy consumption, that fully characterizes HCM pathogenesis.Cardiac \u03b2-myosin variants cause hypertrophic (HCM) or dilated (DCM) cardiomyopathy by disrupting sarcomere contraction and relaxation. The locations of variants on isolated myosin head structures predict contractility effects but not the prominent relaxation and energetic deficits that characterize HCM. During relaxation, pairs of myosins form interacting-heads motif (IHM) structures that with other sarcomere proteins establish an energy-saving, super-relaxed (SRX) state. Using a human \u03b2-cardiac myosin IHM quasi-atomic model, we defined interactions sites between adjacent myosin heads and associated protein partners, and then analyzed rare variants from 6112 HCM and 1315 DCM patients and 33,370 ExAC controls. HCM variants, 72% that changed electrostatic charges, disproportionately altered IHM interaction residues (expected 23%; HCM 54%, p=2.6\u00d710DOI:http://dx.doi.org/10.7554/eLife.24634.001 Vertebrate skeletal and cardiac muscles produce force through a chemo-mechanical cycle that contracts and relaxes the sarcomere, the contractile unit in all muscle cells. Sarcomeres are composed of inter-digitating thick filaments that contain myosin, comprising a globular head  and \u03b1-helical tail, and thin filaments that contain actin. Interactions between myosin and actin generate the contractile force underpinning sarcomere contraction.Myosin heads comprise a motor domain (MD) that hydrolyses ATP, a regulatory domain (RD) that includes the essential (ELC) and regulatory (RLC) light chains, and a proximal S2 subfragment. Myosin tails are packed in antiparallel formation and shape the thick filament\u2019s backbone, from which myosin heads protrudes every 14.3 nm as crowns formed by three pairs of heads. In some crowns  the S2 fAfter contraction, myosin heads rebind ATP, detach from actin, and assume a relaxed pre-powerstroke state . During The IHM appears to form through key interactions  involvinThe dynamic structure of the IHM  enables The asymmetric IHM structure imposes functional consequences on the sarcomere. The blocked myosin head has a pre-powerstroke state  while doThe IHM structure could account for super-relaxation . When tMYH7  and MYPBC3 (encoding MyBP-C) and rarely in MYL2 and MYL3 that encode the ELC and RLC, respectively. Distinct variants in sarcomere genes also cause DCM, albeit less frequently. Variant location is not highly predictive of whether it will trigger HCM or DCM (Hypertrophic (HCM) and dilated (DCM) cardiomyopathies are heart muscle diseases caused by variants in genes encoding sarcomere proteins , most coM or DCM .MYH7 variants increase myofibrillar Ca2+-sensitivity and sarcomere power, therein explaining hyperdynamic contraction  substitutions, and as such the locations of these substitutions inform physiologically important domains in myosin. Because myosin sequences are highly conserved across species, the impact of MYH7 variants on MD properties have been studied in the context of a variety of vertebrate molecular myosin structures. Early analyses, employing the chicken skeletal S1 myosin (2) structural feature that is proposed to bind MyBP-C  conditions  Figure . In addinditions  and the nditions . Figure nditions . Relativ -1; see , reveale4, PDB 1BR1;  By further assuming that the myosin parallel and perpendicular populations are roughly similar [\u2026]\u201d"}
+{"text": "Dasatinib (DAS), a second-generation tyrosine kinase inhibitor, is highly effective in treating chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. However, its clinical use is limited due to serious adverse effects. DAS can disrupt endothelial barrier integrity and increase endothelial permeability which may cause peripheral edema and pleural effusion. Albumin nanoparticles (NPs) as a drug carrier may serve as a useful tool for cell-selective drug delivery to reduce DAS-induced endothelial hyperpermeability and maintain endothelial barrier integrity. In this study, we reported that DAS-loaded NPs exhibited potent anti-leukemia efficacy as DAS alone. Importantly, albumin NPs as a drug carrier markedly reduced DAS-induced endothelial hyperpermeability by restraining the inhibition of Lyn kinase signaling pathway in endothelial cells. Therefore, albumin NPs could be a potential tool to improve anti-leukemia efficacy of DAS through its cell-selective effects. Chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) are the most common types of leukemia with increasing morbidity \u20133. DasatNanoparticles (NPs) as a drug delivery system could enhance drug bioavailability, increase specificity, improve tissue selectivity and prolong pharmacological effect resulting in higher therapeutic efficacy \u201314. MeanAvoiding direct interaction of DAS with Lyn kinase in endothelial cells may be a useful approach to prevent DAS-induced endothelial hyperpermeability. In this study, we investigated the possibility that the DAS-induced endothelial hyperpermeability could be prevented by employing albumin NPs as a drug carrier. Human leukemic K562 cells and human pulmonary artery endothelial cells (HPAECs) were used to investigate anti-leukemia activity of DAS and DAS-loaded NPs, and their adverse effects on endothelial barrier function. Moreover, we investigated the effects DAS-loaded NPs on Lyn-mediated cell signaling in endothelial cells, including Lyn phosphorylation, VE-cadherin localization, and focal adhesion kinase (FAK) modulation.The results of dynamic light scattering showed that albumin NPs with and without DAS loading were similar in size and polydispersity index (PDI). The average diameter of DAS-loaded albumin NPs was 148.0 \u00b1 0.5 nm, and the PDI was 0.163 \u00b1 0.016 Figure . The ZetOur results showed that both DAS and DAS-loaded NPs significantly inhibited the viability of K562 cells compared to vehicle treated corresponding controls Figure . FurtherDAS is known to possess potent anti-leukemia activity through its inhibition of Src family kinases including Lyn \u201325. To fTo assess the effect of DAS and DAS-loaded NPs on endothelial barrier function, basal TER, an assay for endothelial barrier integrity, was measured at a different time points in HPAECs. Under the treatment of DAS, basal TER began to decrease from 0.5 h, reached its lowest point at 0.8 h Figure , indicatThe subcellular distribution of VE-cadherin, as a molecular marker of vascular endothelial adherent junctions, was examined in HPAECs monolayers to visualize the effect of DAS and DAS-loaded NPs on the integrity of endothelial junctions. DAS caused the distinct discontinuities in VE-cadherin distribution between the cells and formation of numerous interendothelial junctional gaps (White arrow) at 2 h, indicating the DAS disrupted adherent junction integrity Figure . InteresWe then examined the effect of DAS and DAS-loaded NPs on Lyn kinase signaling in endothelial cells. DAS treatment significantly decreased the phosphorylation of Lyn kinase in HPAECs Figure , while tWe previously reported that Lyn kinase-mediated regulation of FAK activity plays a pivotal role in maintaining endothelial barrier function . To confTo address the cell-selective effects of DAS NPs, we examined the uptake of Alexa Fluor 488 conjugated albumin NPs by K562 cells and HPAECs. Our results showed that Alexa Fluor 488-conjugated albumin NPs were efficiently internalized by K562 cells, while little green fluorescence was observed in HPAECs, indicating that albumin NPs failed to enter HPAECs  and 8% glutaraldehyde solution were purchased from Sigma\u2013Aldrich Company . DAS (Purity: > 99%) was purchased from Cell Signaling Technology . All other chemicals were purchased from Fisher Scientific . Rabbit polyclonal antibodies against phosphorylated FAK at residues Tyr397, 576/577, and 925, phosphorylated Lyn and total FAK, and a rabbit monoclonal antibody against total Lyn were obtained from Cell Signaling Technology . A goat polyclonal antibody against VE-Cadherin was obtained from Santa Cruz Biotechnology .Albumin NPs were prepared according to a modified desolvation method . BrieflyThe size and Zeta potential distribution of DAS-loaded albumin NPs were measured using a Malvern Zetasizer Nano ZS Instrument . To evaluate the loading efficiency of DAS in albumin NPs, the supernatant (containing unbound DAS) after centrifugation of a suspension of DAS-loaded albumin NPs was collected and centrifuged using 10 kDa Microcon  to separate unbound DAS (Molecular Weight: 488.01 Da) from free HSA (Molecular Weight: 66478 Da) molecules. DAS molecules in filtrate were quantified by measuring the absorbance at 282 nm. The loading yield of DAS in albumin NPs was calculated with the following equation: loading yield (%) = (drug used\u2013unloaded drug)/drug used.2.Primary HPAECs were purchased from Lonza Walkersville Inc. . These cells were cultured with endothelial growth medium-2  and supplemented with 10% fetal bovine serum (FBS). Human leukemic K562 cells  were cultured with Iscove's Modified Dulbecco's Medium  supplemented with 10% heat-inactivated fetal bovine serum (FBS), penicillin and streptomycin (1%) and cultured at 37\u00b0C in a humidified incubator with 5% COCellTiter 96 Aqueous Non-Radioactive cell proliferation Assay Kit  was used for growth inhibition assay as previously described . 10,000 Real-time changes in transendothelial electrical resistance (TER) across endothelial monolayers were measured to evaluate the endothelial barrier function as previously described . BrieflyTo assess the effect of DAS and DAS-loaded NPs on adherent junctions between endothelial cells, HPAECs cultured onto 0.2% gelatin-coated coverslips were incubated with DMSO, NPs, DAS (100 nM) or DAS-loaded NPs (100 nM as DAS) for 2 h. Cells were fixed with 4% paraformaldehyde for 20 minutes, followed by permeabilization with 0.1% Triton \u00d7-100. Thereafter, cells were incubated with primary antibody against endogenous VE-cadherin for 1 h, followed by incubation with Alexa-Fluor 594 labeled donkey anti-goat secondary antibody, using Hanks balanced salt solution containing 1% bovine serum albumin as a blocking buffer. Images were acquired using an Olympus BX43 microscope .5 cells in 1 ml of medium. HPAECs were cultured onto 0.2% gelatin-coated coverslips placed in 24-well culture plates. K562 cells and HPAECs were cultured for 24 h, then exposed to the Alexa Fluor 488-conjugated albumin NPs (40 \u03bcg) for 2 h. The cells were washed three times with phosphate-buffered saline and fixed with \u221220\u00b0C 100% methanol for 10 minutes. After fixation, the cells were washed three times with phosphate-buffered saline. The coverslips with HPAECs were put on the slides coated with DAPI for nuclear staining. K562 cells were smeared on the surface of the slides and stained with DAPI. The uptake of albumin NPs by K562 cells and HPAECs was visualized using an Olympus BX43 microscope .Alexa Fluor 488 Protein Labeling Kit  was used to label albumin NPs. In brief, 0.5 ml of 2 mg/ml albumin NPs suspended in phosphate-buffered saline was mixed with 50 \u03bcl of 1 M sodium bicarbonate solution. Then, the mixture was transferred to the provided vial of Alexa Fluor 488 reactive dye and reacted for 1 h at room temperature. After reaction, the Alexa Fluor 488 conjugated albumin NPs were purified by three cycles of centrifugation  and re-suspended in phosphate-buffered saline. K562 cells were seeded onto 24-well culture plates, with approximately 2.5 \u00d7 10Approximately 4 \u00d7 105 HPAECs or K562 cells were seeded into 6-well plates in serum-containing medium. After culture for 24 h, cells were exposed to DMSO, NPs, DAS (100 nM) or DAS-loaded NPs (100 nM as DAS) for 2 h. The cells were lysed for protein extraction using cell lysis buffer with protease inhibitor and phosphatase inhibitor . The total protein concentration was measured by BCA Protein Assay Kit . Isolated proteins (30 \u03bcg/Lane) were separated by SDS-PAGE and transferred to a polyvinylidene fluoride (PVDF) membrane for immunoblotting assay as described previously [eviously .P < 0.05) between the indicated groups.Statistics were performed using GraphPad Prism 6 software . Data were expressed as mean \u00b1 SEM. A one-way analysis of variance followed by Turkey's test (multiple groups) was performed to determine the statistical significance ("}
+{"text": "AR amplifications predicted reduced time on therapy, independent of therapy type . Our screening approach enables robust, broadly applicable cfDNA-based precision oncology for patients with advanced cancer through scalable identification of therapeutically relevant CNAs and pre-/post-treatment genomic profiles, enabling cfDNA- or tissue-based precision oncology workflow optimization.Current cell-free DNA (cfDNA) next generation sequencing (NGS) precision oncology workflows are typically limited to targeted and/or disease-specific applications. In advanced cancer, disease burden and cfDNA tumor content are often elevated, yielding unique precision oncology opportunities. We sought to demonstrate the utility of a pan-cancer, rapid, inexpensive, whole genome NGS of cfDNA approach (PRINCe) as a precision oncology screening strategy via ultra-low coverage (~0.01x) tumor content determination through genome-wide copy number alteration (CNA) profiling. We applied PRINCe to a retrospective cohort of 124 cfDNA samples from 100 patients with advanced cancers, including 76 men with metastatic castration-resistant prostate cancer (mCRPC), enabling cfDNA tumor content approximation and actionable focal CNA detection, while facilitating concordance analyses between cfDNA and tissue-based NGS profiles and assessment of cfDNA alteration associations with mCRPC treatment outcomes. Therapeutically relevant focal CNAs were present in 42 (34%) cfDNA samples, including 36 of 93 (39%) mCRPC patient samples harboring AR amplification. PRINCe identified pre-treatment cfDNA CNA profiles facilitating disease monitoring. Combining PRINCe with routine targeted NGS of cfDNA enabled mutation and CNA assessment with coverages tuned to cfDNA tumor content. In mCRPC, genome-wide PRINCe cfDNA and matched tissue CNA profiles showed high concordance (median Pearson correlation = 0.87), and PRINCe detectable  Clinical and commercial next-generation sequencing (NGS) based precision oncology strategies have expanded rapidly , 2. BothMyriad noninvasive (\u2018liquid biopsy\u2019) approaches for identifying and tracking clinically relevant genomic alterations from cell-free DNA (cfDNA) have emerged as viable and potentially more broadly applicable alternatives to tissue-based assays using technologies including quantitative PCR (qPCR), digital droplet PCR (ddPCR), targeted DNA sequencing, and whole exome (WES) or whole genome sequencing (WGS) , 10\u201331. Genome-wide copy number profiles derived from low-pass cfDNA whole genome sequencing (WGS) are routinely used to detect large-scale aneuploidy events in clinical applications such as screening for fetal anomalies during pregnancy \u201336. MultHere, as part of an effort to facilitate precision medicine for all patients with advanced cancer, we propose a comprehensive approach deploying rapid, inexpensive, ultra-low pass cfDNA WGS as a broadly applicable potential screening strategy through: 1) directly identifying actionable CNAs, 2) informing needed sequencing depth for additional comprehensive/targeted cfDNA assessment (through cfDNA tumor content approximation) and 3) reserving ultra-deep cfDNA sequencing or tissue-based profiling for patients with low cfDNA tumor content. We show that with effective whole-genome coverage as low as 0.01\u00d7  per sample on a benchtop Ion Torrent sequencer from as little as 10 pg of double-stranded DNA, we can recapitulate known whole-genome copy number profiles in cell lines and advanced prostate, colon, lung, and breast cancer patient samples, while retaining the ability to identify both focal and broad CNAs with megabase-level resolution. To confirm the utility of this screening approach to guide additional precision oncology assessment, we also paired this ultra-low-pass WGS with targeted multiplexed PCR based NGS of the same cfDNA, validating CNAs and identifying clinically relevant somatic mutation profiles at depth tuned by WGS-informed cfDNA tumor content approximation. Further, we directly compare cfDNA copy-number and mutational profiles with molecular profiles from synchronous or asynchronous tissue samples, highlighting high overall concordance and unique considerations for comprehensive precision oncology workflows, while exploring associations between putative cfDNA biomarkers and therapeutic outcomes in patients with mCRPC.n = 129) profiled as part of the MI-ONCOSEQ project ; Figure p = 0.72, two sample t-test) (TMPRSS2:ERG fusion isoform expression confirmed by tissue-based RNAseq in 5 of 6 men (AR amplifications and 11 of 12 (92%) patient-matched high tumor content cfDNA samples show concordant detectable AR amplifications , of which 18 (82%) had a cfDNA sample w/high cfDNA tumor content amenable to analysis Figure . Despiteof 6 men . Of 18 mrange: 0.4\u20130.95; FAR amplification in the cfDNA that was absent in the tissue based profiling of a prostatic neuroendocrine/small cell carcinoma focus , consistent with circulating evidence of both AR-driven and AR-independent clones , PRINCe assessment of synchronous (same-day) specimens detected a clear focal s Figure . FurtherAR amplification has been reported as a biomarker predicting therapeutic resistance to second generation anti-androgens  in several studies [AR splice variant (AR-V7) has been reported as predictive of abiraterone/enzalutamide resistance and taxane chemotherapy sensitivity [AR amplification in samples from patients with limited PSA response   may be a potentially prognostic marker for resistance to both second generation anti-androgen therapy and taxane chemotherapies. These results are consistent with those seen when restricting analyses to samples from patients on or starting therapy separately  as a more general poor prognostic factor, similar to circulating tumor cell (CTC) count [cfDNA detectable  studies , 52, 53,sitivity , 64. Whie Figure , with boparately , and toglutamide , 52, 53,C) count , 66.Many comprehensive precision oncology NGS approaches carry up-front coverage and sequencing requirements (aimed at maximizing sensitivity and specificity) that limit clinical implementation across cancer types in the current era of limited reimbursement, particularly using cfDNA (where estimated tumor content can be < 0.01% in early stage disease ). Given As CNAs may not be informative in all cancers, and many patients may have insufficient tumor content to identify high level CNAs, results from our approach can be used to guide additional precision oncology NGS profiling of the same cfDNA sample or fresh frozen or archived FFPE tissue-based NGS profiling, with sequencing approach and coverage tuned to tumor content. Supporting this tiered approach, we performed targeted multiplexed PCR based NGS on residual unamplified cfDNA from 61 cfDNA samples from patients with advanced cancer, confirming focal amplifications and identifying potentially informative mutations and indels at high concordance with known putative clonal alterations  in cfDNA samples with high tumor content. Comparisons between cfDNA and comprehensive tissue-based profiling in a subset of patients highlight substantial concordance for both somatic mutational and copy-number profiles, while elucidating important potentially complementary utility for cfDNA-based profiling strategies.PTEN deletion) can clearly be detected at 0.01\u20130.1x genome-wide coverages with sufficient cfDNA tumor content  is more appropriate, though our ability to detect known early broad copy-number events  in prostate carcinoma progression at low cfDNA tumor content see  suggestst Figure . ImportaAR amplification not only predicts poor response to second generation anti-androgens, consistent with other published reports [AR amplification may be a more general poor prognostic factor, unlike AR-v7, which has been reported to confer resistance to anti-androgens and sensitivity to taxanes [Applied to a large mCRPC cohort, our approach showed high overall concordance between our cfDNA genome-wide CNA profiles with tissue-based profiles derived from whole exome sequencing in a precision medicine program . In addi reports , 53, but taxanes , 64. An In summary, we have demonstrated the feasibility and potential utility of PRINCe, a broadly applicable, rapid, inexpensive cfDNA WGS screening assay for precision oncology that can robustly detect clinically informative CNAs from cfDNA at low tumor content using effective whole-genome coverage as low as 0.01\u00d7. This screen, while most informative in those patients with actionable CNAs and tumor content > 10%, can nevertheless be used to guide additional testing in all patients based on cfDNA tumor content approximation. Our approach highlights important potential clinical utility when paired with targeted cfDNA NGS and/or tissue-based workflows, and demonstrates unique possibilities for inexpensive disease monitoring. More generally, our study supports the potential utility of tiered approaches in precision oncology, rather than using costlier front-line approaches defined by performance necessary in the extremes.TCGA pan-cancer copy number analyses were run on somatic segmented Affymetrix SNP6 array-based copy-number calls for 11,576 tumor samples across 32 tumor types contained in the January 28, 2016 TCGA GDAC Firehose standard data run (stddata__2016_01_28)   using K2 EDTA blood collection tubes  , and cfDin vitro dilution experiments using serially diluted genomic DNA from 1) VCaP cells (metastatic prostate cancer cell line) with normal male human cell-free genomic DNA at 50%, 25%, 10%, 5%, 1% and 0% dilutions, and 2) UMUC-5 cells  with normal male human cell-free genomic DNA at 50%, 10%, 5%, 0% dilutions. Cell line DNA was fragmented to approximately 180 bp by Covaris AFA  focused ultrasonication. Library preparation and sequencing from undiluted and serial dilution samples was performed as for patient samples described below.We carried out Whole genome amplified (WGA) libraries were prepared from either cell-free DNA (cfDNA) isolated from plasma samples . Genome-wide copy number alterations were first called from aligned, non-PCR-duplicate reads using the QDNASeq R package (version 1.6.1) . SegmentFor 61 patient cfDNA samples see  and bothin silico dilution and downsampling experiments on artificial cfDNA VCaP and UMUC-5 WGS data and patient cfDNA samples (see Supplementary Methods). Using computational experiments on in vitro and in silico VCaP and UMUC-5 cell line dilution data as described in Supplementary Methods, a heuristic least squares based distance metric (LSS) was used to approximate tumor content from whole-genome copy-number data, and guide tumor content approximation for patient samples, with low tumor content samples (LSS < 0.1) specifically scanned for focal CNAs as described (see Supplementary Methods).To establish theoretical segment-level copy-number distributions for tumor content approximation and examine efficacy across variable effect whole-genome coverages (0.005\u20130.01x), we carried out serial in vitro dilutions were compared to publically available COSMIC and targeted NGS copy-number calls, respectively (see Supplementary Methods).To evaluate the capacity of low-pass cfDNA WGS to detect copy-number alterations across variable tumor content, segmented cfDNA WGS copy-number calls for VCaP and UMUC-5 Segmented log2 copy number ratio and point mutation data from whole-exome sequencing of fresh frozen tissue specimens , 45 was All clinical and outcome information was collected, retrieved, and analyzed from internal patient tracking databases and University of Michigan Health System (UMHS) electronic health records by IRB-approved personnel.All statistical analyses described were carried out in R (3.2.3)."}
+{"text": "Scientific Reports7: Article number: 4464010.1038/srep44640; published online: 03152017; updated: 06302017The original version of this Article contained a typographical error in the Abstract.Ac workers responded less strongly to QMP than Ac workers, and 9-HDA and 10-HDA consistently elicited stronger antennal and retinue formation responses\u201d.\u201cThus, now reads:Ac workers responded less strongly to QMP than Am workers, and 9-HDA and 10-HDA consistently elicited stronger antennal and retinue formation responses\u201d.\u201cThus, This has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "GFI1 cause severe congenital neutropenia (SCN). Neutropenia is associated with low bone mass, but the underlying mechanisms are poorly characterized. Using Gfi1 knock-out mice (Gfi1-ko/ko) as SCN model, we studied the relationship between neutropenia and bone mass upon different pathogen load conditions. Our analysis reveals that Gfi1-ko/ko mice kept under strict specific pathogen free (SPF) conditions demonstrate normal bone mass and survival. However, Gfi1-ko/ko mice with early (nonSPF) or late (SPF+nonSPF) pathogen exposure develop low bone mass. Gfi1-ko/ko mice demonstrate a striking rise of systemic inflammatory markers according to elevated pathogen exposure and reduced bone mass. Elevated inflammatory cytokines include for instance Il-1b, Il-6, and Tnf-alpha that regulate osteoclast development. We conclude that low bone mass, due to low neutrophil counts, is caused by the degree of systemic inflammation promoting osteoclastogenesis.Gfi1 is a key molecule in hematopoietic lineage development and mutations in  ELANE), growth factor independence 1 transcription repressor (GFI1), HCLS1-associated protein X-1 (HAX1), glucose-6-phosphatase 3 (G6PC3), Wiskott-Aldrich syndrome protein (WAS), and vacuolar protein sorting 45 homolog (VPS45) genes [ELANE gene [HAX1), hepatospleno- and nephromegaly (VPS45), or complex defects of organ development (G6PC3) [Neutrophils are the predominant innate immune cell subtype that mediates initial response to infection . Via che (G6PC3) .WAS, have been linked with bone cell function or bone phenotypes. The WAS protein, however, is implicated in osteoclast sealing zone formation suggesting an impact at late differentiation stages [Low bone mass upon development of neutropenia has originally been addressed in a genetically undefined cohort of chronic idiopathic neutropenia patients . In thatn stages .GFI1 mutations demonstrate low neutrophil numbers, elevated monocytic cells, and diminished naive T lymphocytes in the peripheral blood [Gfi1 knock-out mouse models (Gfi1-ko/ko) showing defects of the adaptive and innate immune system such as reduced lymphocyte numbers, neutropenia, and immature monocyte accumulation [ELA2, P21/WAF, GFI1B, cMyc, IL-2, and IL-6R [SCN patients affected by dominant negative al blood . This phmulation , 14. In mulation . Serum lmulation . Gfi1 tand IL-6R . Recentlnd IL-6R . This stHere, we study the impact of severe congenital neutropenia on bone tissue in a Gfi1 knock-out model, lacking a key transcription factor of neutrophil differentiation. The overall study design was a series of controlled laboratory experiments in mice as described below. Our main objective was to assess the effect of neutropenia in combination with different housing conditions of variable pathogen load, on bone tissue development during early adulthood of Gfi1-ko/ko mice.in vitro assays, microCT, and histological analysis were blinded for group allocation. Sample sizes were selected to minimize the number of animals needed while obtaining a statistically significant result. No samples or data were excluded from the data analysis. If not otherwise indicated values of Gfi1-ko/ko mice were calculated vs. Gfi1-wt/wt mice of identical housing conditions and age.The personnel performing the Gfi1-ko/ko mice, generated by Karsunky and colleagues, were bred under different conditions and genotyped as described previously  according to standard laboratory procedures . For hisImmunodetection of proteins within mineralized bone tissue was achieved according to a standard procedure. Briefly, frozen tissue was sectioned (5\u03bcm) on a cryostat . Subsequently, sections were fixed, permeabilized and antibodies were incubated in PBS buffered 3% BSA. The following antibodies were used for immunodetection: osteocalcin  and anti-mouseAlexa555 . Sections were analyzed with epifluorescence microscopy Olympus BX60 .Bone samples (vertebra) were analyzed with low (6 \u03bcm voxel) resolution with a microCT from Skyscan 1172  . For vol\u2122 (16-Plex) Mouse Cytokine ELISA  according to manufactures protocol.Plasma was collected after decapitation with standard protocols utilizing Li-Heparin capillary tubes . Biochemical analysis of bone parameters was achieved with enzyme linked immunoassays detecting osteocalcin, Rankl, Opg, and rat-laps (CTX-I). Analysis was performed according to manufacture instructions. Cytokine profiles were generated using the quantitative Q-PlexCortical bone was mechanically cleaned from adjacent muscle and connective tissue and the bone marrow was removed by centrifugation. Separated cortical bone tissue was mechanically crashed after liquid nitrogen incubation and mRNA lysates were generated with Trizol reagent . For mRNA expression analysis, full RNA was isolated according to a laboratory standard protocol and 1\u03bcg RNA was transcribed into cDNA with RevertAid H Minus First Strand cDNA synthesis kit and random hexamer primers  , 22. ExpImmediately after euthanization peripheral blood and bone marrow was supplemented with EDTA to prevent coagulation. Subsequently, cells were distributed on coated glass slides and air dried. Blood and bone marrow cell counts were performed according to standard protocols , 14, 23.For analysis of mesenchymal progenitor cells (MPCs), bone marrow was removed from murine tibia and femur as described earlier , 25. BriOsteogenic differentiation of confluent bone marrow-derived mesenchymal progenitor cells was induced with osteogenic media as described previously . Briefly\u00ae SPSS\u00ae 22.0 software package  and Microsoft Excel was used for statistical evaluation. Results are presented as mean \u00b1 standard deviation (S. D.). Statistical significance between Gfi1-ko/ko mice and Gfi1-wt/wt mice  was calculated using the unpaired two-sided Student\u2019s t-test . Detailed information about error bars, sample sizes, and number of technical replicates are included in all figure legends. If not otherwise indicated values of Gfi1-ko/ko mice were calculated vs. Gfi1-wt/wt mice of identical housing conditions and age.The IBMPasteurellaceae, Pasteurella pneumotropica, Heliobacter spp.) and parasites (Trichomonas sp. and Flagella) were present in the nonSPF and SPF+nonSPF facility , which promotes osteoclast formation, are significantly lower in nonSPF Gfi1-ko/ko mice compared to their corresponding wild-type controls . In contin vitro differentiated osteoclasts or osteoblasts show almost absent Gfi1 expression , alkaline phosphatase 2 (Akp2), Cd73, and Cd90  exhibit growth retardation associated with osteoporosis and premature death immediately after weaning . Our obsablation . Unexpecablation  and 55% ablation  in previablation , 14. NotEarly (nonSPF) and late (SPF+nonSPF) pathogen exposure of Gfi1-ko/ko mice results in osteoporosis and osteopenia, respectively. Diminished bone mass develops if bone resorption exceeds formation and can be a result of either excessive osteoclast and/ or decreased osteoblast activity . Early hInflammation involves the activation of innate and adaptive immune cells leading to production of inflammatory cytokines . Some ofIn a chronic inflammatory condition (SPF) Gfi1 neutropenia mildly favors osteoclastogenesis but only a boosted inflammation (SPF+nonSPF) efficiently stimulates osteoclast formation and activity , 45. SinOur study demonstrates a critical impact of a defective innate immune system due to neutropenia and systemic inflammation for bone development. Our findings support studies showing: (i) osteoporosis in SCN patients , 10, Click here for additional data file.S2 Fig(DOCX)Click here for additional data file.S3 Fig(DOCX)Click here for additional data file.S4 Fig(DOCX)Click here for additional data file.S5 Fig(DOCX)Click here for additional data file.S6 Fig(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S5 Table(DOCX)Click here for additional data file."}
+{"text": "Late Gadolinium Enhancement (LGE) MRI accurately delineates regions of irreversible injury following myocardial infarction (MI). However, markers of tissue abnormalities in the remote, non-infarcted myocardium remain poorly investigated. In this study we explore the utility of 4D strain analysis and native T1 mapping to identify alterations in tissue function or characteristics in diabetics following MI.91 consecutive patients \u22653 months post MI were enrolled. All patients underwent an imaging protocol at 1.5T using standard multi-planar cine imaging, pre-contrast T1 mapping (shMOLLI) and LGE imaging. An additional 40 normal controls were studied. 4D Strain analysis using a deformation field approach was performed using in-house software  to obtain segmental estimates of Peak and Time to Peak strain of the left ventricle (LV). Strains were calculated in Radial (Err), Circumferential (Ecc), Longitudinal (Ell) and Principal directions (Emin and Emax). Strain systolic amplitude and time to peak (ttp) indexed by RR duration were also obtained. Spatially matched segmental estimates of %LGE and native T1 (ms) were obtained using cvi42 . Segmental strain values of the study population were indexed to reference segmental values obtained from normal controls. All segments with <5 LGE% were considered eligible as non-infarcted or \"remote\" myocardium and their indexed strain values then compared between study patients with (N = 29) and without (N = 62) type 2 diabetes. Finally, native T1 of remote tissue was compared for the same cohorts.Mean age was 60.6+/-9.6 with mean LV EF of 42.1+/-7.1%. Mean Segmental values for remote myocardial strain were significantly reduced in the study cohort versus normal controls using Peak Longitudinal (Ell), Minimum Principal (Emin) and Max Principal (Emax) Strain (p < 0.05). Diabetics showed a significant (p < 0.05) reduction in remote tissue strains relative to non-diabetics , as well as significant increase in time to peak systolic strain . A trend towards longer native T1 values, suggestive of interstitial fibrosis, was found among remote myocardium of diabetics versus non-diabetics .4D strain analysis demonstrates impaired myocardial performance, consistent with underlying tissue remodelling, in remote myocardial segments in diabetics following acute myocardial infarction. This finding was associated with a trend towards prolonged native T1 values, a surrogate marker of interstitial fibrosis. Study into the prognostic utility of this marker for future adverse cardiovascular events is required."}
+{"text": "In this retrospective study, we analyzed prognostic factors associated with survival outcomes in 73 locally advanced gastric cancer patients treated with neoadjuvant chemotherapy (NAC) followed by surgical resection. Median disease-free survival (DFS) for 64 patients that received R0 resection was 685 days, whereas median overall survival (OS) for 73 patients was 930 days. Multivariate analysis demonstrated that post-treatment nodal stages (P = 0.002), nervous invasion (P = 0.0492) and serum CA199 levels (P = 0.0398) were independent prognostic factors for DFS. Nodal stages (P = 0.0007), presence of nervous invasion (P = 0.0259) and non-radical resection (P = 0.0165) were independent prognostic factors for OS. These results indicate that post-treatment nodal stages, neural invasion and serum CA199 levels are all associated with poor DFS. Moreover, post-treatment nodal stage, resection type and neural invasion status are independent prognostic factors for OS. Gastric cancer ranks fifth among most malignant cancers and third among cancer related deaths worldwide . China hTherefore, we analyzed the relevant prognostic factors associated with survival by reviewing medical records of 73 locally advanced gastric cancer patients that were treated with neoadjuvant chemotherapy followed by curative-intent surgery. Our analysis included the prognostic status of pathological response to NAC and post-therapy node status .Table Median DFS for 64 patients that received R0 resection was 685 days Figure . UnivariMultivariate analysis by stepwise Cox model showed that post-treatment nodal stage, nervous invasion and serum CA199 levels were independent prognostic factors for DFS Table . Higher Kaplan-Meier survival analysis showed a median OS of 930 days Figure . UnivariMultivariate analyses showed that higher nodal stages , presence of nervous invasion  and non-radical resection  were independent prognostic factors for poor OS  staging system had better prognostic power than the TNM system by reviewing 219 patients that underwent gastrectomy for node-positive (M0) cancer ; clinical response ; graded pathologic response (minor vs. moderate vs. major); resection type (R0 vs. R1+R2); Nodal stage ; lymph node metastasis ratio ;presence or absence of vascular invasion; presence or absence of nervous invasion; and if regimen of AC was the same as NAC or not.Multivariate analysis of prognostic factors was performed by the stepwise Cox proportional hazard model with the variables identified as significant factors in the univariate analyses and hazard ratio (HR) and their95% confidence intervals (CIs) were calculated. A two-sided P < 0.05 was considered statistically significant."}
+{"text": "Drosophila melanogaster and D. simulans is caused by a lethal interaction of the proteins encoded by the Hmr and Lhr genes. In D. melanogaster the loss of HMR results in mitotic defects, an increase in transcription of transposable elements and a deregulation of heterochromatic genes. To better understand the molecular mechanisms that mediate HMR\u2019s function, we measured genome-wide localization of HMR in D. melanogaster tissue culture cells by chromatin immunoprecipitation. Interestingly, we find HMR localizing to genomic insulator sites that can be classified into two groups. One group belongs to gypsy insulators and another one borders HP1a bound regions at active genes. The transcription of the latter group genes is strongly affected in larvae and ovaries of Hmr mutant flies. Our data suggest a novel link between HMR and insulator proteins, a finding that implicates a potential role for genome organization in the formation of species.Hybrid incompatibility between  Hybrid male rescue (Hmr) and Lethal hybrid rescue (Lhr). Hmr and Lhr cause hybrid incompatibility between the closely related fly species Drosophila melanogaster and D. simulans. Hmr diverged in both Drosophila sibling species under positive selection [D. melanogaster and D. simulans is their substantial difference in protein amounts [Biodiversity is the result of the emergence and the extinction of species. New species form by pre- and post-zygotic isolation mediated by genetic incompatibility . One of election . HMR andelection . A reducelection \u20135. The m amounts ,6, which amounts . High le amounts . Such sp amounts ,8, the p amounts  or compo amounts ,11. In m amounts \u201314. This amounts .cis-regulatory functions, thereby contributing to the evolution of new, species-specific, phenotypic traits [cis-regulatory elements that show signs of transposon ancestry [Drosophila genome harbours a large variety of insulator proteins such as CTCF, BEAF-32, Su(Hw), Mod(mdg4) and CP190, which all affect nuclear architecture [Drosophila species underwent multiple genomic rearrangements and transposon invasions [Eukaryotic genomes of closely related species differ mostly in the amount and sequence of repetitive DNA \u201318. Thisc traits \u201321. Genoancestry ,23. A stancestry . In factitecture . Differenvasions ,27, whicnvasions ,27. The nvasions , the spenvasions  but is aD. melanogaster embryonic S2 cell line. We demonstrate an extensive colocalization of HMR with a subset of insulator sites across the genome. HMR\u2019s binding to genomic gypsy insulators, which constitute the major group of its binding sites, is dependent on the residing insulator protein complex. In a second group, HMR borders heterochromatin together with the insulator protein BEAF-32. In agreement with previous low-resolution techniques in cell lines and fly tissue [Hmr mutant larvae and ovaries. Altogether, our data provide evidence for a functional link between HMR and insulator proteins, which potentially results in hybrid incompatibilities due to the adaptive evolution of these genome-organizing complexes.Various studies describe HMR\u2019s localization to heterochromatin, but the molecular details on HMR\u2019s binding sites and its recruitment to these sites are not well understood. To get new insights into HMR\u2019s association to chromatin, we measured HMR\u2019s genome-wide localization by chromatin immunoprecipitation (ChIP) in the D. melanogaster S2-DRSC cells were obtained from the DGRC and grown at 26\u00b0C in Schneider's Drosophila medium (Invitrogen) supplemented with 10% fetal calf serum and antibiotics (100 units/mL penicillin and 100 \u03bcg/mL streptomycin).For RNAi experiments cells were incubated in serum-free medium containing 10 mg/mL dsRNA. After 1 hr of incubation, the serum-containing medium was supplied. Samples were taken after 7 days. The dsRNA was prepared using the MEGAScript T7 Transcription Kit (Thermo Fisher Scientific) following the manufacturers instructions with primers listed in 6 cells was incubated with following antibodies precoupled to Protein A/G Sepharose: rat anti-HMR 2C10 (RRID: AB2569849) [For chromatin immunoprecipitation (ChIP) cells were crosslinked with 1% formaldehyde for 5 min at room temperature. Upon cell lysis, protease inhibitors and proteasome inhibitor MG-132 (Enzo Life Sciences) were applied. The chromatin was isolated and sheared with adaptive focused acoustics (Covaris) to an average size of 200 base pair (bp). For each ChIP reaction, chromatin isolated from 1\u20132 x 102569849) , rabbit D. melanogaster genome assembly (dm3) using Bowtie 2.2.6 with unique mapping criteria and exclusion of chromosome Uextra [D. melanogaster larvae and ovaries, RNA-Seq data were taken from NCBI BioProject PRJNA236022 [The raw reads were aligned to the e Uextra . The rawe Uextra  and reade Uextra . Sequence Uextra  and IGV e Uextra  genome ve Uextra  and ChIPe Uextra . For dowe Uextra . For repe Uextra  using Boe Uextra . Only une Uextra , BEAF-32e Uextra . RNA expNA236022  and analNA236022 . An exteSamples were boiled in loading buffer, separated on SDS-PAGE gels (Serva), processed for western blot using standard protocols and detected using rat anti-HMR 2C10 (1:20) (RRID: AB2569849), rabbit anti-CP190 (RRID: AB2615894) , rabbit ChIP-Seq data from this study are publicly available at NCBI GEO (GSE86106).D. melanogaster S2 cells. We used a highly specific monoclonal antibody against HMR [cas9 system to edit the HMR locus in S2 cells such that the cell line exclusively expresses an HMR allele, which carries a double FLAG-tag at the C-terminus. ChIP-qPCR using HMR and FLAG antibody in wild type and HMR-Flag2 expressing cells showed specific and reproducible enrichment of HMR at selected HMR binding sites , Mod(mdg4) and CP190 [gypsy-like family of insulators (gypsy-like elements classified as bound by Su(Hw), Mod(mdg4) and CP190 are also bound by HMR.We next asked whether HMR binding sites are enriched for specific DNA sequence motifs. A motif analysis of HMR-bound regions revealed three DNA sequence motifs that were significantly enriched and present in up to 26% of all HMR peaks . These mnd CP190 \u201348. Conssulators . Howevergypsy-like insulators , Mod(mdg4) and CP190  binding sites, but almost all those sites can be classified as gypsy-like sites bound by CP190 and mod(mdg4) in addition to Su(Hw).HMR localizes to centromeric and pericentromeric regions in elements \u20135. Mutatd larvae . Such a d larvae , where Hd larvae . To bettgypsy insulator sites along the chromosome arms, we observe dense clusters of HMR binding sites around the centromere and on the 4th chromosome where it potentially serves to separate HP1a binding domains from highly active genes. This dense clustering of binding sites around the centromere correlates well with the strong colocalization of HMR signals with the centromeric H3 variant CID in immunolocalization experiments [Drosophila embryos, HMR has been suggested to be a bona-fide heterochromatin component [Drosophila centromere. However, the fact that the purification of chromatin containing the centromeric H3 variant CID did not identify HMR [Besides dispersed binding of HMR at genomic omponent ,54. Howeomponent . Unfortuomponent ,57. In atify HMR , suggestHmr gene, flies in which BEAF-32 is only contributed maternally have defects in female fertility [The genomic sites, where we find HMR bound next to an HP1a domain, are highly enriched for recognition sites of the insulator protein BEAF-32. Interestingly, a depletion of BEAF-32 in S2 cells results in an increased rate of mitotic defects , which iertility ,60. BEAFertility  has beenertility . Strikinertility , HMR maygypsy or gtwin retrotransposons and to similar sites within the genome that are presumably derived from these elements. These sites are occupied by insulator proteins Su(Hw), CP190 and Mod(mdg4) and often display enhancer blocking activity in transgenic assays [gypsy-like insulator sites but has weak effect on HMR binding to sites containing BEAF-32 recognition motifs. Notably, in contrast to BEAF-32, CP190 is not required for oogenesis [Hmr mutant flies.Although HMR depletion has a substantial effect on the transcription of multiple transposons, we find HMR only enriched at the 5' insulator region of the c assays ,63\u201365. Ac assays . Howeverogenesis , suggestin vivo [How can we integrate our findings with the lethal phenotype of increased HMR/LHR levels in male hybrids? It is tempting to speculate that multiple additional binding sites that are observed in hybrids and on polytene chromosomes of fly strains over-expressing HMR  constituin vivo ,67,68, min vivo . Such a in vivo ,71.cis-regulatory elements bound by insulator proteins. We speculate that divergent evolution of such genomic elements and their corresponding binding factors in sibling species is triggering hybrid incompatibilities.Altogether, our data provide a novel link between HMR and S1 Fig(A) Venn diagram showing the lack of overlap between HMR peaks  and control IgG (anti-FLAG) ChIP peaks . (B) Changes in HMR ChIP enrichment upon HMR RNAi versus a control RNAi (GST) in two biological replicates. Each data point represents a mapped HMR peak. The scatter plot on the left displays fold changes of normalized HMR ChIP tag number mapped to a 200 bp HMR peak region in two biological replicates. Peak regions with less than 50 aligned tags were excluded from the analysis. The histogram on the right shows the frequency of peaks displaying a reduction of HMR binding upon knock-down. Shown are average values of replicate 1 and replicate 2. (C) ChIP-qPCR showing specific HMR enrichment at HMR binding sites. HMR ChIP is enriched for HMR binding sites in both wild type and HMR-Flag2 expressing cells. FLAG ChIP is enriched for HMR binding sites only in HMR-Flag2 expressing cells but not in wild type cells lacking the Flag2 epitope. Data are represented as mean \u00b1 SD of three technical replicates. (D) Genome browser view of HMR ChIP, HP1a ChIP and control IgG ChIP signal at a large centromere-proximal region at the right arm of the 2nd chromosome.(TIF)Click here for additional data file.S2 Fig(A) Sequence motifs identified within Su(Hw) [gypsy-insulator proteins CP190, Mod(mdg4), Su(Hw) [gypsy-twin repeat.n Su(Hw)  and BEAFn Su(Hw)  peak regn Su(Hw)  and BEAFn Su(Hw) . (C) Su  across t(TIF)Click here for additional data file.S3 FigComposite analysis of HMR ChIP signal and Histone H3 ChIP signal at genomic HMR peak positions according to the groups defined in (TIF)Click here for additional data file.S4 Fig(A) Composite analysis of HMR, HP1a and BEAF-32 ChIP signals at class 1 genomic sites relative to the transcriptional start site (TSS) and the gene body. Shown are normalised and scaled read density plots (B) Peak overlap of HMR with peaks of the insulator proteins CP190, Mod(mdg4), Su(Hw), CTCF [(C) Composite analysis of HP1a and H3K9me3 ChIP signals at class 1 HMR binding sites after HMR knockdown. Class 1 is defined in (D) Western Blot analysis on cell lysates to assay protein levels after HMR knockdown. Tubulin protein detection served as control. (E) Same as described in D. melanogaster male larvae [w), CTCF  and BEAFw), CTCF  for clas0, Modmdg, Su(Hw),(TIF)Click here for additional data file.S1 TableList of primers used in this study. Primers used in ChIP Real-Time PCR were designed with help of Primer3.(DOCX)Click here for additional data file.S2 TableChIP-Seq sample overview and number of uniquely aligned sequence reads. The percentage of uniquely mapped reads in ChIP-Seq experiments can largely vary and depends on the nature of the ChIPed protein. Proteins that bind repetitive regions (such as HMR or HP1a) give substantially lower percentages of uniquely mapped reads.(DOCX)Click here for additional data file.S3 TableHMR peak list derived from HOMER peak calling on three biological replicates . First t(XLSX)Click here for additional data file.S1 MethodsHmr gene editing using CRISPR/cas9, extended ChIP Real-Time PCR methods, extended ChIP-seq data analysis methods.(DOCX)Click here for additional data file."}
+{"text": "Date palm cultivars differently tolerate salinity and drought stress. This study was carried out to study the response of date palm to severe salinity and drought based on leaf proteome analysis. Eighteen-month-old date palm plants were subjected to severe salt (48\u2009g/L NaCl) and drought (82.5\u2009g/L PEG or no irrigation) conditions for one month. Using a protein 2D electrophoresis method, 55 protein spots were analyzed using mass spectrometry. ATP synthase CF1 alpha chains were significantly upregulated under all three stress conditions. Changes in the abundance of RubisCO activase and one of the RubisCO fragments were significant in the same spots only for salt stress and drought stress with no irrigation, and oxygen-evolving enhancer protein 2 was changed in different spots. Transketolase was significantly changed only in drought stress with PEG. The expression of salt and drought stress genes of the chosen protein spots was either overexpressed or downexpressed as revealed by the high or low protein abundance, respectively. In addition, all drought tolerance genes due to no irrigation were downregulated. In conclusion, the proteome analysis of date palm under salinity and drought conditions indicated that both salinity and drought tolerance genes were differentially expressed resulting in high or low protein abundance of the chosen protein spots as a result of exposure to drought and salinity stress condition.  Phoenix dactylifera L.) can adapt to extreme drought, heat, and relatively high levels of soil salinity  and transketolase (TRK), chloroplastic [Phoenix dactylifera], whereas those with high protein abundance in the NaCl treated group were uncharacterized protein LOC103705614 [Phoenix dactylifera], chaperonin hsp60 [Arabidopsis thaliana], chaperonin CPN60-2, mitochondrial-like [Phoenix dactylifera], serine acetyltransferase 1, chloroplastic-like [Brassica napus], beta-glucosidase 12-like [Phoenix dactylifera], ATP synthase CF1 alpha chain (ATPase) [Phoenix dactylifera], ATP synthase subunit beta, mitochondrial-like [Phoenix dactylifera], ATP synthase beta subunit [Toronia toru], serine acetyltransferase 1 (SAT1), chloroplastic-like [Brassica napus], and ribulose-1,5-bisphosphate carboxylase.The spots with higher protein abundance in PEG treated group (which are listed in p < 0.05) as a result of salinity and drought stress using either PEG or no irrigation compared to the control is as follows:Phoenix dactylifera], elongation factor TuA (EFTuA), chloroplastic-like [Phoenix dactylifera], ATP synthase CF1 alpha chain [Phoenix dactylifera], and ribulose-1,5-bisphosphate carboxylase/oxygenase large subunit [Villarsia albiflora]).Four proteins were significantly changed in all studied salinity and drought treatments (oxygen-evolving enhancer protein 1 (OEE1), chloroplastic [Ulva lactuca], ribulose bisphosphate carboxylase/oxygenase activase 2, chloroplastic isoform X1 [Phoenix dactylifera], ribulose bisphosphate carboxylase/oxygenase activase 2, chloroplastic isoform X1 [Phoenix dactylifera], ribulose-1,5-bisphosphate carboxylase/oxygenase large subunit, partial (plastid) [Torilis japonica], ribulose-1,5-bisphosphate carboxylase/oxygenase, partial (chloroplast) [Eriophorum viridicarinatum], ribulose-1,5-bisphosphate carboxylase/oxygenase large subunit, partial (chloroplast) [Eucalyptus stoatei], ribulose-1,5-bisphosphate carboxylase/oxygenase large subunit [Pimelea longiflora subsp. eyrei], ribulose-1,5-bisphosphate carboxylase/oxygenase large subunit (RubisCO) [Andreaea rothii], and ribulose-1,5-bisphosphate carboxylase [Euonymus bungeanus]).Nine proteins were changed in both no irrigation and NaCl treated groups  [Phoenix dactylifera] was found to be significantly changed only in drought stress with PEG and NaCl treated groups, whereas glucose-methanol-choline (GMC) oxidoreductase, putative [Ricinus communis] was found to be significantly changed only in drought stress either PEG or No Irrigation.ATP synthase subunit d, mitochondrial [Moraea fugax], chlorophyll a-b binding protein 6, chloroplastic [Vitis vinifera], phosphoglycerate kinase (PGK), cytosolic [Glycine max], ribulose-1,5-bisphosphate carboxylase/oxygenase large subunit [Zantedeschia aethiopica], ribulose-1,5-bisphosphate carboxylase, glyceraldehyde-3-phosphate dehydrogenase B (GPDB), chloroplastic [Phoenix dactylifera], dehydroascorbate (DHA) reductase-like [Phoenix dactylifera], serine acetyltransferase 1 (SAT1), chloroplastic-like [Brassica napus], ATP synthase beta subunit [Toronia toru], ATP synthase subunit beta, mitochondrial-like [Phoenix dactylifera], ATP synthase CF1 alpha chain [Phoenix dactylifera], beta-glucosidase 12-like [Phoenix dactylifera], chaperonin CPN60-2, mitochondrial-like [Phoenix dactylifera], chaperonin hsp60 [Arabidopsis thaliana], and uncharacterized protein LOC103705614 [Phoenix dactylifera]).17 other proteins were significantly changed only in NaCl treated group .Five proteins were significantly changed only under drought condition exerted by PEG .Five more proteins were also significantly changed only under drought condition exerted by no irrigation  and drought stress exerted by PEG (82.5\u2009g/L) or no irrigation for one month as revealed by proteome analysis of leaves. Proteome analysis of roots and leaves revealed a synergetic responsive network under stress . The DIGa et al.  reporteda et al.  stated ta et al. .The current results indicate that the high concentration of NaCl has an inhibitory effect on date palm biosynthesis resulting in reduction in plant growth under high salinity. Mechanisms that contribute to date palm salt tolerance were described through miRNA-mediated gene expressions that are important for adaptation to salinity , whereasDrought stress with PEG showed three spots with higher protein abundance and six spots with lower protein abundance compared to control plants. Golldack et al.  ascribed2, and photosystem II activities often decline in parallel by drought stress. In addition, Bota et al. [Drought stress with no irrigation did not show any spots with higher protein abundance and showed 19 spots with lower protein abundance compared to control plants. Six spots showed lower protein abundance in salt stress and drought stress due to no irrigation. Only one spot showed lower protein abundance in all three studied stresses. Drought stress primarily results in a reduced rate of photosynthesis , 15, 16.a et al.  reportedThe proteome analysis of date palm under salinity and drought conditions indicated that both salinity and drought tolerance genes were differentially expressed resulting in high or low protein abundance of the chosen protein spots as a result of exposure to drought and salinity stress condition. In addition, drought stress due to no irrigation caused downexpression of all genes controlling drought tolerance.MS analysis of the significantly changed spots and their behavior in other studied stresses."}
+{"text": "BRAF gene, causing constitutive activation of BRAF, have been found in various types of human cancers such as malignant melanoma, and colorectal cancer. BRAF V600E and V600K, most commonly observed mutations in these cancers, may predict response to targeted therapies. Many techniques suffer from a lack of diagnostic sensitivity in mutation analysis in clinical samples with a low cancer cell percentage or poor-quality fragmented DNA. Here we present allele-specific real-time PCR assay for amplifying 35- to 45-base target sequences in BRAF gene. Forward primer designed for BRAF V600E detection is capable of recognizing both types of BRAF V600E mutation, i.e. V600E1 (c.1799T>A) and V600E2 (c.1799_1800delTGinsAA), as well as complex tandem mutation caused by nucleotide changes in codons 600 and 601. We utilized this assay to analyze Thai formalin-fixed paraffin-embedded tissues. Forty-eight percent of 178 Thai colorectal cancer tissues has KRAS mutation detected by highly sensitive commercial assays. Although these DNA samples contain low overall yield of amplifiable DNA, our newly-developed assay successfully revealed BRAF V600 mutations in 6 of 93 formalin-fixed paraffin-embedded colorectal cancer tissues which KRAS mutation was not detected. Ultra-short PCR assay with forward mutation-specific primers is potentially useful to detect BRAF V600 mutations in highly fragmented DNA specimens from cancer patients.The protein kinase BRAF is one of the key players in regulating cellular responses to extracellular signals. Somatic mutations of the  BRAF), is located on chromosome 7q34. The cytoplasmic serine-threonine kinase encoded by this gene mediates the activation of the mitogen-activated protein kinase (MAPK) signaling pathway involved in cell growth, survival and differentiation. About half of nonacral cutaneous melanomas harbor gain-of-function BRAF mutations, rendering the MAPK pathway constitutively active , complex tandem BRAF mutations, as PCR template. We demonstrate that our assay can detect these mutations presented in the oligonucleotide templates   or BRAF F V600K)  in DNA remplates . This deBRAF mutations in shorter DNA fragments (BRAF mutation detection and found that our assay can detect BRAF V600D (c.1799_1800delTGinsAT) mutations (BRAF V600M (c.1798G>A) and V600R (c.1798_1799delGTinsAG) mutations were also picked up with less efficiency while BRAF V600G (c.1799T>G) and V600A (c.1799T>C) mutations were barely amplified. No amplifications were found in any of the wild-type templates.The accuracy of PCR-based diagnostic assays depends greatly on the DNA quality of specimens. Targeting short genomic DNA region will ensure that our assay efficiently detect mutations in clinical specimens containing highly fragmented genomic DNA. We examined the ability of our assay to identify ragments . Althougutations . The BRABRAF V600E mutant alleles (34\u201366%) and the rest of FFPE samples contain only BRAF wild-type cells. Mutation analysis results were shown in We examine our assay performance using DNA extracted from FFPE cell block sections used for EQA schemes which mimic processed tissue sample quality. For 30 samples tested, six samples have In our study, DNA quality is demonstrated by amplification of 200-bp target using quantitative PCR (qPCR), the most suitable technique for checking the quality of FFPE-DNA. PCR amplification is affected by the quality of DNA samples. The FFPE reference standards (cell block sections) contain good quantities of amplifiable DNA with the length of fragments of 200 nucleotides . Our DNAKRAS Mutation Detection Kit to provide a KRAS mutation testing service. All of our 178 colorectal cancer specimens tested by these techniques in the years 2013\u20132017 are FFPE tissues. Three-fifths (106 samples) of 178 FFPE specimens are from male patients . Three samples contain KRAS mutations at codons 59, 61, 117, or 146. We found no significant association between KRAS mutation status and sex or tumor location (metastatic versus primary tumors) (KRAS mutation rate is significantly high in CRC patients aged over 70 (65.5%) .The lower limits of detection of cobas\u00ae KRAS Mutation Test and AmoyDx\u00ae  alleles  Tables. is 47.8% . Forty-e tumors) . The KRAKRAS and BRAF mutations were nearly mutually exclusive [BRAF mutation analysis using our ultra-short allele-specific PCR assays in FFPE DNA samples that KRAS mutations were not detected. Ninety-three DNA samples used for further BRAF mutation detection have similar characteristics to 178 samples analyzed for KRAS mutation. Ten out of 93 FFPE specimens (10.8%) were taken from the patients aged over 70 years. Approximately three-fifths (58 samples) of specimens are from male patients. Thirteen percent (12 samples) of the tissues was collected from metastatic sites. The most common metastatic site is liver (7 samples).xclusive . We perfBRAF gene were detected in 6 samples (6.5%). Information on these cases was shown in BRAF gene was found in 4 male (6.9%) and 2 female (5.7%) patients. All patients except one were over 50 years of age. BRAF mutation-negative CRC were not included in this table. Detection of BRAF V600E mutation in one of those specimens is demonstrated in Mutations of BRAF mutation was detected by our assay using the GeneReader next generation sequencing system and GeneRead QIAact Actionable Insights Tumor Panel. The average amplicon size for this panel is 134 bp. The BRAF V600E mutation was found in five out of six samples. It is noteworthy that PCR amplification of 200-bp fragment of a discordant sample , technique involves antigen\u2013antibody reactions, is widely used in many laboratories. The recently developed monoclonal VE1 antibody has permitted the use of IHC to assess BRAF V600E mutation status in the FFPE tissue in cancers \u201346. Thispossible . Immunohreported , 51. FalRAF gene , 52. In BRAF mutations in the total of 93 clinical specimens. We report here that BRAF V600 mutations are found at approximately 6.5% (6 out of 93) in Thai colorectal cancer patients with no KRAS mutations detected in codons 12, 13, 59, 61, 117 or 146. Mutations of BRAF gene in KRAS mutation-negative CRC tissues have been studied in other Asian patients, including Chinese, Taiwanese, Japanese, and Korean [BRAF V600 mutations in these populations vary from around 1% to 10%.In this study, we analyzed d Korean \u201311. The KRAS mutation status, we used cobas\u00ae KRAS Mutation Test and AmoyDx\u00ae KRAS Mutation Detection Kit which are among the most sensitive methods available in clinical molecular laboratories. This study support the claimed detection limits of <5% and 1\u20135% mutant DNA in a background of wild-type DNA for cobas\u00ae KRAS Mutation Test and AmoyDx\u00ae KRAS Mutation Detection Kit respectively.The DNA present in formalin-fixed material is generally fragmented . This stKRAS and BRAF mutation assays in Thai CRC tissues. Two reports have been published on the prevalence of BRAF mutations at codon 600 in Thai CRC patients. The first study performed Sanger sequencing to analyze 133 frozen tissues and 67 FFPE tissues [BRAF V600 mutation was detected in any of the specimens, while overall incidence of KRAS mutations was 23%. This prevalence of KRAS mutations in these patients from southern Thailand is quite low compared to our finding (44%). It is likely caused by a difference in detection limits of techniques. It should be highlighted that the LOD of Sanger sequencing for mutations of both BRAF and KRAS genes at their laboratory and the estimation of tumor cell percentage were not mentioned. Another study utilized two-round allele-specific PCR and high sensitivity DHPLC to analyze 211 specimens obtained from newly diagnosed CRC patients [BRAF V600E mutation has been reported in 10.9% of these Thai CRC patients. Although they use sensitive assay with a detection limit of at least 0.5% V600E tumor cells, the copy number of mutant versus wild-type alleles in their cells, cross-reactivity with non-target BRAF mutations, and KRAS mutation status were not clearly described.To the best of our knowledge, this is the first report investigating mutations by highly sensitive  tissues . No BRAFpatients . BRAF V6KRAS mutations in this study appears similar to that in two recent studies in Thai FFPE CRC tissues. Overall prevalence of KRAS codon 61 mutation detected by pyrosequencing in one study was 1.7% [KRAS exon 2 mutations in 120 of 270 specimens (44.4%) [KRAS mutations in our CRC patients aged over 70 years is higher than that in the rest of study population .The frequency of was 1.7% . In anot (44.4%) . They foBRAF gene. This finding suggests that alcohol may have restricted effects on development of CRC cells originating via specific molecular pathways [BRAF or KRAS mutated tumors were more likely to have an elevated serum level of carbohydrate antigen (CA19-9) and carcinoma embryonic antigen (CEA) [BRAF or KRAS genes may enhance an important role of these blood biomarkers for precise risk stratification of CRC patients.Our simple mutation detection assay may help facilitate the studies in the emerging field of 'molecular pathological epidemiology', which investigate interactive effects of various factors and tumor molecular changes , 59. Intpathways . Anotheren (CEA) . MutatioBRAF mutation status in existing DNA from CRC samples that lack KRAS activating mutations by AS-PCR is technically easy and economically favorable. Ultra-short PCR assay with mutation-specific forward primers was proved to be feasible in detecting low abundant BRAF V600 mutations in various conditions of DNA samples, i.e. intact genomic DNA, short single-stranded DNA, and DNA from FFPE sections. Molecular assay with specific primers targeting short DNA fragments is therefore particularly useful tool for mutation analyses in a range of clinical matrices, including poor-quality tissues, effusion, plasma and urine.In summary, assessment of S1 Table(TIF)Click here for additional data file.S2 Table(TIF)Click here for additional data file.S3 Table(TIF)Click here for additional data file.S4 Table(TIF)Click here for additional data file."}
+{"text": "A territory-wide specialized early intervention (EI) service for psychosis (EASY) has been implemented in Hong Kong since 2001, providing 2-year phase-specific early assessment and clinical care to young people aged 15\u201325 years presenting with first-episode psychosis (FEP). Previous evaluation demonstrated superiority of EASY programme over standard care in outcome improvement in FEP. Recently, EASY has been extended to provide 3-year EI service to FEP patients aged 15 to 64 years. However, effectiveness of EI on adult FEP populations has not been well examined.This study adopted case versus historical-control design, comparing patients received 3-year EASY treatment (EI group) with those managed by standard psychiatric care (SC group) prior to implementation of EASY extension in terms of treatment delay and outcomes in symptom and functioning. In total, 320 Chinese adult FEP patients aged 26\u201355 years  were included in the study. Retrospective record review detailing service utilization over 3-year treatment period was conducted. Follow-up interview assessment (on average 48.3 months after service entry) encompassing premorbid adjustment, duration of untreated psychosis (DUP), clinical , functional  and treatment profiles was administered. Comparison analyses on DUP and service utilization were based on record review data of 320 patients. Clinical and functional outcome analyses focused on data collected from follow-up interview assessment .EI and SC groups were comparable regarding demographics, premorbid and baseline characteristics, except the use of second-generation antipsychotic (SGA) treatment (EI patients were more likely to receive SGA than SC patients). EI patients had significantly shorter DUP than SC counterparts (p=0.015). Regarding follow-up outcomes, EI patients displayed lower levels of negative (p=0.044) and depressive symptoms (p=0.055), higher scores in RFS immediate social network (p=0.027) and lower rates of service disengagement (p=0.048) than SC patients even when SGA use and DUP were adjusted as covariates in analysis of covariance for comparison. There were no significant group differences in admission and suicide rates.Our results indicate that extended EASY service achieve favorable outcomes in adult FEP patients on shortening of treatment delay and improvement in negative symptoms and social functioning, and service disengagement reduction. Further evaluation is required to assess the sustainability of positive effects."}
+{"text": "Since TCR signaling is a critical first step in T cell activation, differentiation, and effector function, its inhibition may contribute towards HCV persistence in vivo. The effect of HCV infection on PTPRE expression in vivo has not been examined. Here, we found that PTPRE levels were significantly reduced in liver tissue and peripheral blood mononuclear cells (PBMCs) obtained from HCV-infected humans compared to uninfected controls. Loss of PTPRE expression impaired antigen-specific TCR signaling, and curative HCV therapy restored PTPRE expression in PBMCs; restoring antigen-specific TCR signaling defects. The extent of PTPRE expression correlated with the amount of sequence complementarity between the HCV E2 vsRNA and the PTPRE 3\u2019 UTR target sites. Transfection of a hepatocyte cell line with full-length HCV RNA or with synthetic HCV vsRNA duplexes inhibited PTPRE expression, recapitulating the in vivo observation. Together, these data demonstrate that HCV infection reduces PTPRE expression in the liver and PBMCs of infected humans, and suggest that the HCV E2 vsRNA is a novel viral factor that may contribute towards viral persistence.Among human RNA viruses, hepatitis C virus (HCV) is unusual in that it causes persistent infection in the majority of infected people. To establish persistence, HCV evades host innate and adaptive immune responses by multiple mechanisms. Recent studies identified virus genome-derived small RNAs (vsRNAs) in HCV-infected cells; however, their biological significance during human HCV infection is unknown. One such vsRNA arising from the hepatitis C virus (HCV) E2 coding region impairs T cell receptor (TCR) signaling by reducing expression of a Src-kinase regulatory phosphatase (PTPRE)  in vitro, and leads to impaired T cell function. Here, we show that PTPRE expression is reduced in liver tissues and peripheral blood mononuclear cells (PBMCs) obtained from HCV-infected humans. Furthermore, serum from HCV infected individuals reduced antigen-specific TCR signaling, and curative anti-HCV therapy restored PTPRE expression in HCV-infected humans coincident to rescuing antigen-specific TCR-signaling defects. Transfection of a hepatocyte cell line with HCV genomic RNA or synthetic vsRNA duplexes inhibited PTPRE expression, recapitulating the in vivo observations. Together, these data suggest that HCV genomic RNA is processed into short, regulatory HCV RNA sequences that regulate PTPRE levels in HCV-infected humans, contributing to HCV immune evasion in vivo.The mechanism by which hepatitis C virus (HCV) establishes persistent human infection is complex and incompletely understood. Recent studies identified virus-derived small RNAs (vsRNAs) in HCV-infected cells; however, their biological significance is unclear. One HCV vsRNA arising from the E2 coding region reduces expression of a Src-kinase regulatory phosphtase (PTPRE) both in hepatocytes and lymphocytes  Althougcination \u201320.We recently reported that incubation of peripheral blood mononuclear cells (PBMCs) with plasma derived HCV, infectious cell culture derived HCV, and serum exosomes containing HCV RNA reduced IL-2 release and CD69 upregulation by T lymphocytes following activation through the T cell receptor (TCR) . Expressin vitro [PTPRE activates signaling by Src family tyrosine kinases \u201323, and in vitro .in vitro characterization of the HCV vsRNA effect on TCR signaling by showing that synthetic HCV genomic and vsRNA regulate PTPRE via one of the two potential target sites with complementarity within the PTPRE 3\u2019UTR, and that HCV regulates TCR and PTPRE expression in human liver tissue and PBMCs during HCV infection. Importantly, curative HCV therapy restored both PTPRE levels and T cell activation following TCR stimulation. The data provide the first in vivo evidence of a functional vsRNA generated from the HCV genome, and identify PTPRE as a novel cellular factor regulating T cell activation.Although DNA viruses and retroviruses generate functional vsRNAs , 27, theTo determine if HCV RNA-containing sera inhibits antigen-specific TCR signaling, PBMCs from three healthy blood donors were incubated in sera obtained from 5 HCV infected donors before and following curative HCV therapy. Sera pooled from 5 HCV uninfected individuals served as the negative control. Following overnight incubation, cells were stimulated with either viral T-cell antigenic peptides from CMV, EBV, and influenza  or anti-CD3 antibody. Incubation of PBMCs in HCV infected patient serum reduced, but did not abolish IL-2 release following antigen-specific T cell receptor stimulation  . Jurkat in vitro transcribed, full-length, infectious HCV RNA or a synthetic RNA duplex comprised of the HCV vsRNA sequence to determine if transfection of HCV RNA was sufficient to regulate PTPRE expression.Stable expression of a short region of HCV E2 RNA in Jurkat cells negatively regulates TCR signaling, PTPRE expression, and Lck phosphorylation following TCR activation . Here, wBioinformatic analyses identified several genes predicted to be targeted by the HCV vsRNA based on the putative seed sequence, including PTPRE, Vesicle-associated membrane protein-A (VAPA), and growth factor receptor-bound protein 2 (Grb2) \u201338. Likehttp://hcv.lanl.gov/content/sequence/HCV/ToolsOutline.html). In addition, PTPRE Site 2 was complementary to 9 HCV E2 conserved bases in the majority of these isolates  transcribed from an infectious clone (kindly provided by Drs. Rice and Wakita) . PTPRE lisolates . These r6 infectious units). GFP . GFP  and PTPRts). GFP  were monts). GFP . Since sts). GFP . HCVcc\u2019sTo further examine RNA-mediated regulation of PTPRE, two RNA duplexes containing the conserved HCV vsRNA targeting sequence were synthesized. The 8 nt HCV sequence was placed at either the 5\u2019 end (vsRNA-1) or the 3\u2019 end (vsRNA-2) of the HCV sequence . These vhttp://www.proteinatlas.org/ENSG00000132334-PTPRE/tissue). HCVgRNA and synthetic HCV vsRNA duplexes are sufficient to reduce PTPRE levels in cells of hepatocyte origin  following TCR stimulation is required for TCR-mediated activation and proliferation . We examin vitro (vsRNA sequences kindly provided by Drs. Fire and Parameswaran)[2 0.56, p<0.01 Spearman Correlation).Andrew Fire\u2019s group identified HCV vsRNAs in HCV-infected Huh7.5 cells , one of meswaran). Since Pmeswaran). Examinimeswaran), the 8 nin vitro [Virus derived small RNAs (vsRNAs) encoded by DNA viruses and retroviruses play an important role in viral replication and may contribute to immune evasion , 27. Altin vitro , 57, 58,in vitro , 30. HCVin vitro . Previouin vitro , 59.Although several mechanisms may contribute to HCV immune evasion, we recently found that expression of full-length HCV E2 coding RNA with a frame-shift to abolish translation in Jurkat cells reduced TCR signaling and Lck activation following TCR stimulation with anti-CD3/CD28 . Placingin vitro transcribed full-length HCV genome and short synthetic HCV E2 vsRNAs were sufficient to regulate PTPRE expression following transfection into Huh7.5 cells, and that one of the two complementary sequences in the PTPRE 3\u2019UTR is sufficient to regulate upstream protein expression. We also observed that PTPRE levels were reduced in liver biopsy tissues and cell lines of hepatocyte origin that support HCV replication, and that HCV infection was associated with both reduced PTPRE levels in PBMCs, and with reduced Lck activation following TCR stimulation. PTPRE levels and Lck phosphorylation were restored by curative HCV therapy. Further supporting a functional role for the HCV vsRNA, the extent of sequence complementarity between the HCV E2 RNA sequences correlated directly with the level of reduction of PTPRE expression in lymphocytes. Although complete blockade of TCR signaling would render an infected person severely immune compromised, HCV effects on TCR signaling are incomplete. This regulator of TCR signaling likely contributes to both establishment of infection and persistent viremia.Here, we expand the earlier findings to show that HCV containing serum inhibits both antigen-specific (CEF-mediated) TCR signaling, and PTPRE expression, and that T cell function and PTPRE levels are restored following curative HCV therapy, providing novel insights into antigen-specific and non-specific modulation of T cells by HCV RNA. We also demonstrated that in vitro, and that HCV infection regulates TCR activation and PTPRE expression in vivo.Although there are many vsRNAs detected in HCV infected cells for which no function has been determined , these dAmong potential targets identified by bioinformatics, VAPA, a proviral factor required for HCV replication \u201342, and Our data also identified PTPRE as a novel factor regulated by HCV vsRNA in hepatocytes. This phosphatase activates Src-kinase signaling, and previous studies demonstrate an inhibitory role of Src-kinases in HCV replication , 25. ThuHCV-infected subjects recruited from the University of Iowa Hepatology Clinic or healthy blood donors were invited to participate in this study. Characteristics of subjects are described in 2. HCV genomic RNA (gRNA) was transcribed from J6/JFH infectious clone as described [Human cell lines Huh7 cells (obtained from the American Type Culture Collection) Huh-7.5 (kindly provided by Dr. Charles Rice), and Huh7D (kindly provided by Dr. Dino Feigelstock), were cultured in Dulbecco's modified Eagle's medium containing 10% fetal bovine serum, 1% penicillin-streptomycin and 1% L-glutamine at 37\u00b0C in a 5% COescribed . PBMC isescribed , 60.Coding sequence for eGFP were ligated into a modified pTRE2-HGY plasmid  expressing GFP with an EMC IRES element directing translation as previously described . The two6 cells/ml) obtained from HCV-negative donors were resuspended in 200 \u03bcl serum obtained from HCV-infected donors before or after curative HCV therapy and incubated for 24 hrs prior to stimulation with plate-bound anti-CD3 . Alternatively, antigen-specific TCR-mediated activation was stimulated using pooled synthetic peptides (20 \u03bcg/ml) with sequences derived from human cytomegalovirus, Epstein-Barr virus, and influenza viruses [PBMCs (2\u00d710GT Group), 63. TCRGT Group), 65, or Plasma RNA was isolated from HCV-infected humans  and cDNA generated using random hexamer primers as described . HCV E2 Huh7.5 cells were transfected by electroporation (Bio-Rad Gene Pulser Xcell) using 10\u03bcg HCV genomic RNA (gRNA). HCV and control vsRNA duplexes were purchased from Integrated DNA Technologies and used at 1\u03bcM concentrations. Cells and HCV RNA were mixed in cold PBS (500\u03bcL) transferred to a 4 mm gap-width electroporation cuvette and pulsed once at 270V and 950 \u03bcF capacitance. Transfected cells were maintained in complete medium for 96 hours at 37\u00b0C.Cell lysates were separated by SDS-PAGE gel electrophoresis, transferred to nitrocellulose membranes, and proteins detected by chemiluminescence as described , 68. PriP values less than 0.05 were considered statistically significant.Statistics were performed using GraphPad software V4.0 (GraphPad Software Inc.). Student\u2019s t test was used to compare results between groups. This study was approved by the University of Iowa Institutional Review Board (IRB-01) and all subjects provided written informed consent.S1 FigAlthough the HCV infected subjects were shown to have lower PTPRE expression relative to actin, there was no correlation observed between PTPRE expression levels and fibrosis score in either HCV infected or HCV uninfected subjects. ND = no data as there were no subjects with HCV with no fibrosis detected on biopsy.(TIF)Click here for additional data file.S1 TableALD = alcoholic liver disease; HH = hereditary hemochromatosis; LAE = liver enzyme elevation; NASH = non-alcoholic steato-hepatitis; PSC = primary sclerosing cholangitis; RCC = renal cell carcinoma with elevated liver enzymes; Tx = liver transplant organ biopsy. *PTPRE relative to Actin by immune blot.(DOCX)Click here for additional data file.S2 TableL = Ledipasvir; S = Sofosbuvir; R = Ribavirin; V = Ombitasvir+ Paritaprevir+ Ritonavir+ Dasabuvir.(DOCX)Click here for additional data file."}
+{"text": "Echocardiography has shown that patients with constrictive pericarditis or hemodynamically significant pericardial effusion show an increased respiratory variation in early transmitral inflow velocity. The methodology for quantification of respiratory variation in early transmitral inflow velocity using real time phase contrast (RT-PC) cardiovascular magnetic resonance (CMR) images is currently cumbersome and manual. The aim of this study was to develop a method for quantifying the respiratory variation in early transmitral inflow velocity using semi-automatic analysis of RT-PC CMR images.Clinically referred patients  with sinus rhythm and no pericardial effusion or pericardial thickening underwent RT-PC CMR (1.5T Siemens Aera) of short-axis through-plane transmitral inflow velocities over two 30 s acquisitions during free breathing. Image acquisition parameters were: repetition time 12 ms, water excitation pulse with flip angle 15\u00b0, slice thickness 11 mm, matrix 84 \u00d7 128, echo-planar imaging factor 7, temporal sensitivity encoding rate 3, aliasing velocity 150 cm/s, shared velocity encoding enabled and temporal resolution 60 ms. One patient with hemodynamically significant pericardial effusion was imaged to illustrate clinical feasibility. Image analysis was performed using an in-house developed plugin to Segment . The user manually delineated a region of interest encompassing the mitral orifice, and the software then automatically identified the contiguous 10 s period of time with the lowest variation in per-beat peak early transmitral inflow velocity.Automatic analysis of RT-PC data yielded a respiratory variation in early mitral inflow velocity of mean \u00b1 SD 16 \u00b1 5%, 95% normal limits 6-26%. The patient with pericardial effusion (20 mm) had an inflow variation of 34%.This study has demonstrated clinical feasibility and presented normal values for semi-automatic analysis of the respiratory variation in early transmitral inflow velocity using RT-PC CMR. Further studies in patients with echocardiographically verified hemodynamically significant pericardial disease are justified."}
+{"text": "Archangium sp. strain Cb G35 has been obtained. Analysis of the genome using antiSMASH predicts 49 natural product biosynthetic pathways. This genome will contribute to the investigation of myxobacterial secondary metabolite biosynthetic pathways.In an effort to explore myxobacterial natural product biosynthetic pathways, the draft genome sequence of  Archangium sp. strain Cb G35 (DSM 52696) was reported to produce the antibiotic roimatacene, as well as six novel p-hydroxyacetophenone amides  in Braunschweig (DSM 52696). Archangium sp. Cb G35 has been referenced as Cystobacter ferrugineus strain Cb G35 and Cystobacter gracilis strain Cb G35 prior to a suggested reclassification , including pathways for 10 hybrid nonribosomal peptide polyketides, six nonribosomal peptides, six bacteriocins, five polyketides, five terpenes, four lantipeptides, and two microviridins (MPOI00000000.This whole-genome shotgun project has been deposited in DDBJ/ENA/GenBank under the accession number"}
+{"text": "We report here the complete genome sequences of 12 bacterial species of stable defined moderately diverse mouse microbiota 2 (sDMDMm2) used to colonize germ-free mice with defined microbes. Whole-genome sequencing of these species was performed using the PacBio sequencing platform yielding circularized genome sequences of all 12 species. Isobiotic animal models with a defined stable composition are being developed to study host-microbial mutualism under reproducible conditions . The com12) gnotobiotic mouse model has been maintained successfully for over five generations in the clean mouse facility of the University of Bern and LMU Munich. These bacterial strains are publically available from the German Type Culture Collection (DSMZ)   coveringn (DSMZ) .2S, 0.001% hemin, and 0.00005% menadione) in an anaerobic chamber , except for Akkermansia muciniphila YL44 (further supplementation of 0.025% mucin to the BHI medium) and Lactobacillus reuteri I49 . Genomic DNA was purified by standard phenol-chloroform extraction. Whole-genome sequencing was carried out using PacBio RS II sequencing platform with a 10-kb insert library and XL/C2 chemistry  medium (Oxoid) supplemented with four chemicals (0.025% cysteine, 0.025% Narization . The assrization .All 12 assembled sequences have been deposited in DDBJ/ENA/GenBank under the accession numbers as provided in"}
+{"text": "Induced pluripotent stem cells (iPSC) can be differentiated into cardiomyocytes and represent a possible autologous cell source for myocardial repair. We analyzed the engraftment and functional effects of murine iPSC-derived cardiomyocytes (iPSC-CMs) in a murine model of myocardial infarction.\u2122 resistance gene under control of the cardiac-specific \u03b1-myosin heavy chain  promoter. Thus, CM selection was performed during in vitro differentiation. iPSC-CM aggregates  were transplanted on day 14 after LAD ligation into the hearts of previously LAD-ligated mice . Animals were treated with placebo  or iPSC-CMs (n = 35). Myocardial remodeling and function were evaluated by magnetic resonance imaging (MRI), conductance catheter (CC) analysis and histological morphometry. In vitro and in vivo differentiation was investigated. Follow up was 28 days . iPSC-CM purity was >99%. Transplanted iPSC-CMs formed mature grafts within the myocardium, expressed cardiac markers and exhibited sarcomeric structures. Intramyocardial transplantation of iPSC-CMs significantly improved myocardial remodeling and left ventricular function 28 days after LAD-ligation.To maximize cardiomyocyte yield and purity a genetic purification protocol was applied. Murine iPSCs were genetically modified to express a ZeocinWe conclude that iPSCs can effectively be differentiated into cardiomyocytes and genetically enriched to high purity. iPSC derived cardiomyocytes engraft within the myocardium of LAD-ligated mice and contribute to improve left ventricular function. However, the process of harvesting CMs from iPSCs faces several hurdles: Standard protocols are based on spontaneous differentiation or directed differentiation of pluripotent stem cells (PSCs) being hampered by high cell heterogenicity and limited cardiomyocyte maturation with poor purity [in vivo [Cardiovascular diseases represent the most important burden of the present century with increasing numbers of afflicted patients worldwide . Once dar purity . Further[in vivo ,29. To o[in vivo ,31. Fina[in vivo \u201334.in vivo and to engraft after transplantion intramyocardial transplantation in an acute myocardial infarction model in mice.Addressing these challenges, our group has recently reported a novel method for efficient cardiac differentiation followed by a genetic purification method to produce high numbers of ultrapure (>99%) CMs from murine and human iPSCs . The pur\u2122 resistance gene under control of the cardiac-specific \u03b1-MHC (MYH6) promoter. Cardiac differentiation was initiated by hanging drop technique. On differentiation day (dd) 3, embryoid bodies were transferred into dynamic suspension culture. Differentiation medium was supplemented with 400 \u03bcg/mL Zeocin\u2122 from dd7 to dd14 to initiate cardiomyocyte (CM) selection. Resulting CM enriched aggregates  were characterized by immunostaining. Undifferentiated, non-selected iPSCs served as controls. Before transplantation, CBs were marked for histological detection with a vitality sensitive fluorescence marker  as described in the Supporting Information.Genetic cardiomyocyte purification was established by Kensah et al.  and is dGuide for the Care and Use of Laboratory Animals  and in accordance with federal regulations. The study protocol was approved by state authorities (Nieders\u00e4chsisches Amt f\u00fcr Verbraucherschutz und Lebensmittelsicherheit). Inhalative anesthesia with 2.5% vaporized isoflurane  was used in all experiments. Animals received prophylactic oral antibiotic and analgesic drugs and kept under special care in the central animal laboratory of our institution. Monitoring of the animals included daily visits.Surgery and animal care were provided following the 6 viable iPSC-CMs) in phosphate buffered saline (PBS) or PBS alone were injected into the anterior left ventricle of LAD ligated mice shortly after MI induction. Animals were divided into a sham-operated group , a placebo treated infarct group  and three infarct groups treated with iPSC-derived CMs .A total of 70 immunodeficient SCID beige mice  were used. Myocardial infarction (MI) was induced as described in the Supporting Information and performed as previously described . AliquotA 7 Tesla scanning system  was used for magnetic resonance imaging (MRI) as detailed in the Supporting Information. On postoperative day 2 (POD 2) infarct size was determined by contrast enhanced MRI. Cardiac function was evaluated on POD 27.On POD 28 conductance catheter (CC) analysis was performed to record LV pressure-volume loops as described recently  and detaHearts were processed in standard fashion and histological morphometry as well as immunostaining was performed as described in the Supporting Information. iPSC-CM grafts were detected by their cell tracer staining. Graft size was measured using a pixel-based approach. Data were obtained by computer-assisted morphometry . An overview of all used antibodies for immunostaining is described in Table A in P<0.05. All reported P values are two-sided.GraphPad Prism 6.01 was used for statistical analysis. If not stated otherwise, data are given as mean\u00b1SEM. Differences in mortality were analysed by Fisher\u2019s exact test. Comparison of continuous variables was performed with Student\u2019s T-test or one-way ANOVA followed by Tukey's multiple comparison test. Linear regression analysis was performed to correlate continuous data. Differences were considered significant at \u00ae under dynamic suspension culture conditions, murine iPSCs formed spontaneously beating aggregates of almost pure cardiomyocytes  per animal were used. iPSC-CM grafts were readily visible within the host myocardium . After intramyocardial injection into ischemic myocardium, iPSC derived CMs exhibited an authentic adult CM appearance despite their original spherical organisation within CBs. We believe that their alignment and longitudinal organisation is induced by the directed strain within in the host\u2019s myocardium. This finding has also been described for BCTs and indicates a viable CM response after transplantation [in vivo. In our model, CMs were indirectly connected to the host myocardium after injection into the infarct area because of a surrounding cellular infiltration after 7 days and scar formation after 28 days. CM graft appearance changed over a period of 28 days towards an unorganized morphology and reduced size indicating late cell death. Impaired CM viability in models of myocardial infarction has been frequently described and attributed to the cytotoxic environment after myocardial infarction or dissociation of CMs [We used a genetically engineered iPSC clone especially developed for maocardial regeneration . Similarp before . Using aantation . This sen of CMs ,35,47. Opos iPSC derived progenitor cells [We could show that direct intramyocardial transplantation of iPSC derived CMs as three-dimensional CBs results in a significant functional improvement and attenuated adverse remodelling 28 days after acute myocardial infarction as determined by a combination of MRI, pressure-volume loop analysis and histological morphology assessment. LV thickness in the infarct zone was preserved despite decreasing iPSC-CM graft size thereby preventing progressive LV dilatation. In contrast to former studies by our group using adult cardiac stem cells  and Flk-or cells  in the sS1 FigUndifferentiated IPSCs showed a marked Oct3/4-mediated eGFP expression and a high proportion of mitotically active Ki-67 positive cells. Most cells were positive for both markers. Few cells were Oct3/4-eGFP negative and Ki-67 positive (arrowheads). Rarely cells were Oct3/4-eGFP positive and Ki-67 negative (*). Scale bar: 50\u03bcm.(TIF)Click here for additional data file.S2 FigDifferentiated CBs at dd14 lost the intrinsic Oct3/4-mediated eGFP signal compared to undifferentiated IPSCs  and were(TIF)Click here for additional data file.S3 FigReseeded IPSC-CMs showed a low proportion of Ki-67 positive cells . Scale bar: 100\u03bcm.(TIF)Click here for additional data file.S4 FigDifferentiated CBs on dd14 were positive for Connexin 45. Scale bar: 100\u03bcm.(TIF)Click here for additional data file.S5 FigDifferentiated CBs on dd14 were positive for Connexin 40. Scale bar: 100\u03bcm.(TIF)Click here for additional data file.S6 Fig28) and infarcted animals  were statistically not significant.  Most deceased animals died perioperatively. Hence, mortality within the 7 day group (IPSC-CM7) was similar to 28 day myocardial infarction groups .Differences between non-infarcted animals (Sham(TIF)Click here for additional data file.S7 FigA: MRI LV-EF (%) vs. CC LV-EF (%). B: MRI EDV (\u03bcl) vs. CC EDV (\u03bcl). Volume values were typically underestimated by CC evaluation.(TIF)Click here for additional data file.S8 FigExpansion Index (EI) correlated well with Infarct Size.(TIF)Click here for additional data file.S1 File(DOCX)Click here for additional data file.S1 Video(MPG)Click here for additional data file.S2 VideoCBs remain vital and contracting.(MPG)Click here for additional data file."}
+{"text": "EGFR-mutated lung adenocarcinoma (LADC). Surgically resected tumors (EGFR-mutated LADCs with (21) and without (79) lymph node metastasis and EGFR wild-type LADCs with (26) and without (108) lymph node metastasis) and biopsy samples from inoperably advanced tumors (EGFR-mutated LADCs (78) and EGFR wild-type LADCs (99)) were examined. In surgically resected tumors, the EGFR-mutated LADCs with lymph node metastasis had the micropapillary element in a significantly greater proportion than others (Mann-Whitney tests P \u22640.026). The proportion of micropapillary element was higher in the EGFR-mutated LADC at the advanced stage  than in the tumor at the early stage (stage I) . In the biopsy samples from inoperably advanced LADCs (177), EGFR-mutated tumors also had micropapillary element at a higher frequency than EGFR-wild type tumors (53/78 (68%), versus 30/99 (30%), Pearson x2 test, P<0.0001). In stage I EGFR-mutated LADCs (84), the tumors with the micropapillary element (34) exhibited a significantly higher recurrence rate than tumors without micropapillary element (50) . The micropapillary element may be an exclusive determinant of malignant potential in EGFR-mutated LADC. It is suggested that EGFR-mutated LADC may develop through a distinct histogenesis, in which the micropapillary element is important for promoting progression.The purpose of this study was to define histological features determining the malignant potential of  EGFR, KRAS, ALK, RET, and ROS genes, mutations of which are mutually exclusive, and are crucial determinants indicating a favorable response to different molecular targeting agents  3]  [3] EGFR  [3] EGFg agents  5] 6]. [6].EGFR. [6].EGFEGFR is the most common driver oncogene in LADCs, and mutations in this gene are seen in 20 to 50% of LADCs in Asians and 5 to 10% LADCs in Westerners  9]. [9].EGFR. [9].EGF subtype  10] [11 [11EGFR  subtype  13]. Th. ThEGFR  subtype  15] . Th. ThEGFR 2 test or Fisher\u2019s exact test were used in combination with the Mann-Whitney test to analyze categorical and continuous variables, respectively. Recurrence curves were plotted using the Kaplan-Meier method and the absolute risk of recurrence at five years was estimated. Differences in the recurrence-free survival (RFS) were analyzed using the log-rank test. The Fleiss kappa statistic was used to measure interobserver agreement )2 \u00d7 (percentage of the mPAP element [%])/100]. The mPAP EV was found to be significantly correlated with RFS  was obtained when the mPAP EV cut-off value was set at 15 , vascular invasion (P = 0.011) and mPAP EV  were associated with worse RFS. Multivariate analysis revealed that the mPAP EV (P = 0.004) and lymphatic canal invasion (P = 0.009) were independent predictors of disease recurrence . The mPAP EV may be fit for clinical use.We additionally evaluated a prognostic impact of mPAP element for with RFS . The lowcurrence . These rEGFR mutations (major or minor mutations) between tumors with mPAP and those without mPAP was found  treatment . Cl. ClEGFR-T study)  34] [35 [35EGFR-EGFR-mutated LADC may develop through a distinct carcinogenetic pathway, in which the mPAP element may play an important role in promoting progression. The mPAP element also has prognostic value. We hope that our efforts will increase current knowledge about the carcinogenesis of EGFR-mutated LADC and lead to improvements in the therapeutic strategies for such tumors.In summary,"}
+{"text": "Potyvirus species in sweet potatoes have been detected mostly by serology. Here, we report the complete genome sequences of two Potyvirus species, Sweet potato feathery mottle virus strain (SPFMV-UNB-01) and Sweet potato virus G strain (SPVG-UNB-01).In Brazil,  Ipomoea batatas Lam.)   is a tubas Lam.)  belonginood crop .Potyvirus (family Potyviridae), Sweet potato feathery mottle virus (SPFMV), Sweet potato latent virus (SPLV), Sweet potato mild speckling virus (SPMSV), and Sweet potato virus G (SPVG)  .Ipomoea setosa and kept in a greenhouse at the Experimental Station of Biology of the Universidade de Bras\u00edlia (EEB-UnB). The virus enrichment process with semipurification of particles was carried out using leaves of I. setosa. Samples were weighed individually, to 1\u00a0g of each plant, and then pooled, forming a sample composed of 10 plants (10\u00a0g). From the purified particles, RNA extraction was performed using Trizol reagent following the manufacturer\u2019s instructions. The composite sample was sent for sequencing on the Illumina MiSeq platform at the Universidade Cat\u00f3lica de Bras\u00edlia (UCB).In this study, 40 sweet potato plants from distinct producing regions in Brazil were grafted on de novo assembled using CLC Genomics Workbench version 8.0. The resulting contigs were compared to the viral RefSeq database available in GenBank using a BLASTx search  were trimmed and MF185715 (strain SPFMV-UNB-01) and MF185716 (strain SPVG-UNB-01).The sequences reported here have been deposited in GenBank under the accession numbers"}
+{"text": "Cardiac metastases (CMET) impact management and clinical outcomes of patients with systemic neoplasms. CMR is well validated for evaluation of cardiac masses and increasingly used to assess oncologic patients, among whom pattern, tissue characteristics, and optimal diagnostic strategies for CMET are not known.The population comprised consecutive adults (\u226518 yo) with metastatic systemic neoplasms who underwent contrast-enhanced CMR between 1/2012 - 8/2015. Patients with primary cardiac neoplasms were excluded. CMR was performed using 1.5T (88%) and 3T (12%) clinical (GE) scanners. A standard contrast-enhanced CMR protocol was applied: Cine-CMR (SSFP) was used to assess cardiac structure and morphology. DE-CMR  was used for tissue characterization; long TI (600 msec) DE-CMR was employed to confirm tissue properties of visualized masses. CMET was defined using established criteria as a discrete, irregularly contoured mass with discrete borders independent of cardiac chambers, myocardium, or central catheters. CMET was further categorized based on enhancement pattern . Transthoracic echocardiography (echo), if performed clinically within 30 days of CMR, was used to test conventional imaging for CMET.115 patients  with metastatic extra-cardiac primary neoplasms were studied; 29% (n=33) had CMET on CMR. Sarcoma (21% [n=7]) and melanoma (12% [n=4]) were the two leading primary cancer etiologies; atypical primaries also occurred . CMET location markedly varied ; 21% of cases involved multiple cardiac locations. 76% were due to hematogenous or lymphatic spread; 24% were due to direct invasion. DE-CMR demonstrated CMET enhancement in 83% of cases; enhancement pattern was variable . CMET often occurred in absence of pericardial (27%) or pleural (48%) effusions. 67% of the population underwent echo within 30 (6.7 \u00b1 8.0) days of CMR, including 61% (n=20) of patients with CMET by CMR. As shown (Table CMET vary in location and enhancement pattern on CMR, often presenting without typical adjunctive findings such as pericardial or pleural effusions. Conventional screening via echo can be limited for CMET detection; incremental utility of CMR is typically provided for neoplasms that are intramyocardial or atypical in location."}
+{"text": "Recent advances in genome editing technologies have enabled the rapid and precise manipulation of genomes, including the targeted introduction, alteration, and removal of genomic sequences. However, respective methods have been described mainly in non-differentiated or haploid cell types. Genome editing of well-differentiated renal epithelial cells has been hampered by a range of technological issues, including optimal design, efficient expression of multiple genome editing constructs, attainable mutation rates, and best screening strategies. Here, we present an easily implementable workflow for the rapid generation of targeted heterozygous and homozygous genomic sequence alterations in renal cells using transcription activator-like effector nucleases (TALENs) and the clustered regularly interspaced short palindromic repeat (CRISPR) system. We demonstrate the versatility of established protocols by generating novel cellular models for studying autosomal dominant polycystic kidney disease (ADPKD). Furthermore, we show that cell culture-validated genetic modifications can be readily applied to mouse embryonic stem cells (mESCs) for the generation of corresponding mouse models. The described procedure for efficient genome editing can be applied to any cell type to study physiological and pathophysiological functions in the context of precisely engineered genotypes.The online version of this article (doi:10.1007/s00424-016-1924-4) contains supplementary material, which is available to authorized users. Analyses of epithelial physiology in genetically tractable model organisms have provided important biological insights. However, the complex interaction of multiple cell types and finite experimental resolution of specific cellular functions within tissues have made complementary cell culture-based approaches desirable. Wild-type renal cells have been characterized extensively, but considerable limitations concerning the genetic tractability of cultured cells have confounded molecular studies: the majority of isolated primary cells are heterogenous and have a finite replicative capacity; the generation of immortalized, differentiated renal epithelial cells from patients or mouse models has proven difficult; murine embryonic fibroblasts (MEFs) from genetically modified mice lack the epithelial characteristics of renal tubular cells; and the physiological relevance of heterologous expression systems has been questioned . We therGenome editing of MDCK, mIMCD3, and mES cells\u2014See Pkd1 and human PKD2 cDNA have been described previously [Mouse eviously . All DNAConstitutive gene expression was achieved by pLXSN-mediated (Clontech) retroviral transduction.mRNA of a confluent 35\u00a0mm cell culture dish was isolated  and reversely transcribed to complementary DNA  according to the manufacturer\u2019s protocols , 6. Olig698\u2013799 antibodies have been described previously [Mouse anti-beta-Actin , goat anti-TRPP2 , mouse anti-Polycystin-1 , chicken anti-GFP , mouse anti-Flag M2 , rabbit anti-V5 epitope tag (Merck Millipore), and mouse anti-V5-Tag  antibodies were obtained commercially. Mouse anti-TRPP2Cells were harvested 5\u00a0days after epithelial confluency. Proteins were isolated and processed as described previously , 13. CheIndirect immunofluorescence staining of cells has been described previously . Cells wwww.atcc.org). Of those, Madin-Darby Canine Kidney (MDCK) cells and mouse Inner Medullary Collecting Duct 3 (mIMCD3) cells are most widely used to study renal epithelial biology (\u2265 5\u2032000 entries on www.ncbi.nlm.nih.gov) [To date, American Type Culture Collection lists 21 mammalian renal epithelial cell lines (nih.gov) , 22. Botnih.gov) , 10. FurTo take advantage of well-characterized cell lines, we have developed a widely applicable workflow for the efficient generation of targeted alleles using genome editing technology Fig. a. Duringpolycystic kidney disease 1 (PKD1) and PKD2, suggest that both genes are part of an epithelial morphogenetic program to maintain kidney structure [PKD1 and PKD2  deland PKD2 a\u2013d; (2) and PKD2 a, b; (3)and PKD2 c, d; andion Fig. a\u2013d. The ult Fig. b. HA- anreported . Here, wreported , 28.Fig.Laminin subunit alpha 5 (Lama5). Basal lamina biogenesis is a core epithelial function, but its visualization in vivo has been difficult. The generation of fluorescent laminin fusion proteins showing sufficient brightness and proper localization to the basal lamina has been particularly challenging. To visualize basal lamina, we genetically fused eGFP to the 3\u2032-end of the Lama5 coding sequence  that can be studied in 3D culture  suggest that genomic alterations in mESCs can be readily tested in mIMCD3 cells and successively used for the establishment of novel mouse alleles ESM 2(PDF 609\u00a0kb)ESM 3(PDF 230\u00a0kb)"}
+{"text": "Formation of stable kinetochore-microtubule attachments is essential for accurate chromosome segregation in human cells. This process is monitored by the spindle assembly checkpoint (SAC) that delays sister chromatid separation in the presence of unattached or improperly-attached kinetochores . KinetocThe endosomal sorting complex required for transport (ESCRT) machinery promotes budding and severing of narrow cytosol-filled membrane invaginations from their inner face . Functioin vitro and promotes localization of RZZ and Mad1-Mad2 complexes to prometaphase kinetochores. Furthermore, constitutive Chmp4c kinetochore targeting induces an RZZ-dependent checkpoint metaphase arrest, suggesting that Chmp4c kinetochore localization dictates spindle checkpoint activity. These results show that Chmp4c acts as a loading factor for the RZZ to unattached kinetochores (In a recent study, we identified novel Chmp4c functions at kinetochores that are independent from its membrane-directed activities . Chmp4c tochores . Howevertochores  2,3]. S,3. Sin vChmp4c also promotes cold-stable kinetochore-microtubules and Chmp4c-deficient cells exhibit reduced average centromere distance compared with controls . These rThe work by Petsalaki et al.  clearly"}
+{"text": "The strong association between non-progression and maintenance of HIV-specific CD8+ T cell cytokine production and proliferative capacities suggests that invigorating CD8+ T cell immune responses would reduce viremia and slow disease progression. A series of studies have demonstrated that sequence variants of native immunogenic peptides can generate more robust CD8+ T cell responses and that stimulation with these \u2018heteroclitic\u2019 peptides can steer responses away from the phenotypic and functional attributes of exhaustion acquired during chronic HIV infection. Incorporation of heteroclitic peptide stimulation within therapeutic vaccines could favour induction of more effective cellular antiviral responses, and in combination with \u2018shock and kill\u2019 strategies, contribute towards HIV cure.Chronic infection with human immunodeficiency virus (HIV) causes HIV-specific CD8 Recognition by, and activation of CD8+ T cells is governed via interaction between the T cell receptor (TCR) and antigen-derived peptides bound within cognate class I major histocompatibility complexes (MHC-I). Stabilizing derivations that fasten antigenic peptides to MHC (pMHC) molecules more securely, or enhance TCR binding to the pMHC complex, increase peptide immunogenicity [Cytotoxic CD8genicity , 2.+ T cells are critical for limiting HIV replication in vivo [+ T cells with a superior functional profile than those from progressors [+ T cell cytolysis and cytokine production wanes during progressive chronic HIV infection as T cells fail to recognize viral escape variants, become progressively exhausted and ultimately sustain dysfunctional immune responses against HIV [+ T cell potency would promote clearance of virus-infected cells, reduce viremia, and slow disease progression. Here, we review recent research that exploits the TCR:pMHC interaction axis to modulate HIV-specific CD8+ T cell responses in vitro and discuss potential therapeutic application of this approach.During early infection, human immunodeficiency virus (HIV)-specific CD8 in vivo . Long tegressors . Thus, iinst HIV , 6. Main+ T cell-based HIV vaccine therapy. As individual T cell clones recognize series\u2019 of related peptides, constructing heteroclitic sequence variants that increase TCR:pMHC avidity, relative to reference peptides, can produce more potent CD8+ T cell responses [c proliferated to a greater extent following restimulation with moth cytochrome c than with pigeon cytochrome c [Methods of augmenting TCR:pMHC complex avidity are varied and can involve either modifying the TCR or MHC-I complexes themselves, or creating peptide sequence variants , 2. Augmesponses . Solingechrome c . Mappingchrome c .+ T cell response. As the TCR does not directly interact with buried anchor residues, substitutions here are unlikely to negatively affect TCR recognition, unless they have indirect effects on orientation of the peptide towards the TCR. For example, some modifications in anchor residues alter peptide conformation by creating a \u2018bubble\u2019, which can adversely affect the TCR recognition platform [Anchor modified heteroclitic peptides in the context of many MHC-I molecules have aa substitutions involving N- and C-terminus anchors that penetrate the floor of the MHC-I peptide-binding groove to secure the peptide position and orientation . Anchor platform .Heteroclitic peptides can also arise from conservative and semi-conservative aa substitutions at positions directly interacting with the TCR. Modifying the TCR recognition sequence appropriately should increase T cell sensitivity to antigen and substitution of aa at non-anchor positions was found to produce variant peptides more immunogenic than their native counterparts . T cells+ T cells (CTL) are critical for controlling certain cancers, HIV and many other viral infections [+ T cell responses against HLA B*57-restricted HIV Gag protein peptide epitopes [+ T cell cytotoxic responses than stimulation with reference peptide [Cytotoxic CD8fections . They prfections . Studiesfections . Long-teepitopes . As CTL  peptide , 16.+ T cells. Heteroclitic peptides with aa substitutions in the TCR recognition motif of immunodominant HIV Gag and Nef epitopes enhanced CD8+ T cell IFN-\u03b3 and/or IL-2 production in vitro, relative to the native peptides [Cytokine production is instrumental to T cell development, differentiation and effector functions . During peptides . In somepeptides .+ T cells producing IL-2 retain high proliferative capacity [+ T cell IL-2 production after in vitro heteroclitic peptide stimulation could suggest that heteroclitic variant peptides could not only reconstitute antigen-specific T cell cytokine production and cytotoxicity, but also support clonotypic proliferation of HIV-specific CD8+ T cells no longer, or never activated by native peptides. Adegoke et al. examined HIV-specific CD8+ T cell proliferation in vitro using HIV-specific heteroclitic peptides previously shown to increase T cell cytokine responses. They observed increased HIV-specific CD8+ T cell proliferation against heteroclitic peptides in more than 25% of the cases where cytokine production was enhanced [+ T cell proliferation driven by either heteroclitic anti-tumour or self-peptides has also been observed, further demonstrating that apparent T cell insufficiency and even T cell tolerance can be overcome by using sequence variants of the reference peptides lacking desired activity [Memory CD8capacity . Any biaenhanced . CD8+ T activity \u201322.+ T cell cytokine production and proliferation, probing their potential role in managing HIV-specific T cell exhaustion could also be informative. T cell exhaustion occurs with antigen persistence during malignancy or chronic infections and is defined by successive loss of IL-2, TNF-\u03b1 and IFN-\u03b3 production, poor cytotoxic and proliferative capacity, and increased expression of inhibitory receptors such as programmed cell death (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or T cell immunoglobulin and mucin-domain containing-3 (TIM-3) [+ T cells could be a beneficial adjunct to current HIV treatment. In some cases, the same heteroclitic peptides that boosted HIV-specific CD8+ T cell proliferation also stimulated a proliferating population of HIV-specific T cells expressing less PD-1 than those proliferating following stimulation with native peptides [+ T cell responses away from the exhaustive phenotype, potentially restoring clonogenicity, cytotoxicity and cytokine production to levels associated with long-term non progression.As HIV-specific heteroclitic peptides can restore CD8 (TIM-3) \u201325. Effepeptides . With thgag) or enzymatic (pol) proteins, stimulate stronger immune responses [env gene, choosing epitopes from gag- or pol\u2013derived HLA-restricted immunodominant proteins would provide optimal and prolonged CD8+ T cell responses [+ T cell responses, thwart T cell exhaustion and reduce viremia in cases of disease progression.Synthetic peptide variants can enhance MHC interaction with the TCR by reducing adverse interactions or by increasing favourable ones. Consequently, variant peptides have a significantly better capacity to boost weak immune responses than their naturally occurring counterparts. Amino acid substitutions within defined HIV epitopes, such as those within genes encoding structural  targeting various stages of the viral life cycle. Efficacy requires strict adherence and this, coupled with high cost, limits the global use of cART. Although cART has undergone great improvements in reducing toxicity and resistance, stimulating more effective CD8Beyond contributing towards long term viral control, heteroclitic peptides could also play an important role in cure strategies for HIV infection. With the exception of extremely rare cases, HIV has been impossible to cure and recurrence of viremia in patients off cART is attributed to HIV reactivation from viral reservoirs \u201330. To o"}
+{"text": "Previous studies have demonstrated that saturated fatty acids (SFAs) are more lipotoxic than unsaturated fatty acids (UFAs) in inhibiting hepatic autophagy and promoting non-alcoholic steatohepatitis (NASH). However, there have been few studies have investigated the effects of carbon chain length on SFA-induced autophagy impairment and lipotoxicity. To investigate whether SFAs with shorter carbon chain lengths have differential effects on hepatic autophagy and NASH development, we partially replaced lard with coconut oil to elevate the ratio of medium-chain fatty acids (MCFAs) to long-chain fatty acids (LCFAs) in a mouse high-fat diet (HFD) and fed mice for 16 weeks. In addition, we treated HepG2 cells with different combinations of fatty acids to study the mechanisms of MCFAs-mediated hepatic protections. Our results showed that increasing dietary MCFA/LCFA ratio mitigated HFD-induced Type 2 diabetes and NASH in mice. Importantly, we demonstrated that increased MCFA ratio exerted its protective effects by restoring Rubicon-suppressed autophagy. Our study suggests that the relative amount of LCFAs and MCFAs in the diet, in addition to the amount of SFAs, can significantly contribute to autophagy impairment and hepatic lipotoxicity. Collectively, we propose that increasing dietary MCFAs could be an alternative therapeutic and prevention strategy for Type 2 diabetes and NASH. Thus, NASH is currently considered to be the determining stage in the progression of non-alcoholic fatty liver diseases (NAFLD), and its prevention is becoming an important clinical issue. Although previous clinical and animal studies have suggested obesity, insulin resistance, and Type 2 diabetes are important risk factors for NASH9. Autophagy is an important cellular process regulating metabolic homeostasis and stress responses. Under different nutrient conditions, the AMPK/mTOR/ULK1 pathway is tightly controlled to regulate early-stage induction of autophagy10. During early-stage autophagy induction, the newly synthesized double-membrane autophagosomes engulf damaged and redundant intracellular components such as organelles and proteins. Mature autophagosomes then will fuse with lysosomes to form autolysosomes for cargo degradation11. Although impaired autophagy was found to be highly correlated with NAFLD progression, the major triggers and molecular mechanisms that lead to decreased autophagy remain unclear. According to previous studies, both early-stage and late-stage autophagy suppression occur during NAFLD development. Previously, fatty acids were shown to inhibit AMPK- or mTOR-regulated autophagy in rat and human hepatocytes13. Additionally, recent studies demonstrated late-stage inhibition of autophagy via impaired lysosomal acidification15 or reduced autophagosome-lysosome fusion16.Recent studies have found that hepatic autophagy plays an important role in human and mouse NAFLD progression by regulating lipid metabolism, endoplasmic reticulum (ER) stress, and cell apoptosis in hepatocytes20. Additionally, many recent studies have shown the protective effects of unsaturated fatty acids (UFAs) on NAFLD23. However, little is known currently about the role of fatty acid carbon chain length on NASH development. Medium-chain fatty acids (MCFAs) are fatty acids containing 6 to 12 carbons that are commonly found in coconut oil and animal milk24. Previous reports indicated that MCFAs improved Type 2 diabetes and NAFLD26, but the molecular mechanisms underlying these effects were not well characterized. Accordingly, we investigated the potential protective effects of MCFAs on NASH using mouse and cell culture models. In particular, we examined whether increasing the MCFA/long chain fatty acid (LCFA) ratio in HFD protected against Type 2 diabetes and NASH by regulating autophagy.The roles of saturated fatty acids (SFAs) in promoting insulin resistance, autophagy impairment, and NAFLD have been well characterizedth week, the MCFAD group had higher weight gain than the SDHFD group. Surprisingly, despite the increased weight gain, 15-week MCFAD-fed mice showed significantly improved oral glucose tolerance than SDHFD-fed mice , standard high-fat diet (SDHFD), or MCFA-rich high-fat diet (MCFAD) for 16 weeks. As shown in Fig.\u00a0ice Fig.\u00a0. To furtHFD Fig.\u00a0. AlthougHFD Fig.\u00a0.Figure 127. We found that MCFAD-fed mice had significantly larger adipose cell size compared to SDHFD-fed mice  to simulate the lipotoxicity caused by LCFAs. To evaluate the protective effects of increasing MCFA/LCFA ratio on hepatic cells, we replaced half of the OA in SDF mixture with capric acid  or lauric acid , which were designated as MCFA mixture 1 (MCF1) and MCFA mixture 2 (MCF2), respectively. Similar to our in vivo findings, increasing the MCFA ratio significantly decreased the amount of fat accumulation in HepG2 cells during fat loading  and fed to mice for 16 weeks. The MCFAD contains approximately same amount of long-chain saturated fatty acids (LCSFAs) compared to SDHFD but halved long-chain unsaturated fatty acids (LCUFAs) replaced by MCFAs. Consistent with previous studies39, our data showed that increasing dietary MCFA ratio significantly improved HFD-induced insulin resistance in mice, but led to more body weight gain , in the context of autophagy inhibition by chronic administration of LCFAs, MCFAs were able to stimulate autophagy  were previously reported to activate mTOR/AMPK-mediated autophagy and regulate cellular lipid metabolism50, we found that MCFAs restored autophagy in fat-loaded hepatic cells independently of regulating AMPK and mTOR signaling , standard high-fat diet (SDHFD), or MCFA-rich high-fat diet (MCFAD) for 16 weeks. The CTD , SDHFD , and customized MCFAD were purchased from Research Diets. The MCFAD was made by replacing half the lard in the D12492 diet with hydrogenated coconut oil. Briefly, the MCFAD contains approximately same amount of long-chain saturated fatty acids (LCSFAs) compared to SDHFD but halved long-chain unsaturated fatty acids (LCUFAs), which is replaced by MCFAs. Detailed formulas of diets used in this study are shown in Table\u00a06-hour starved mice were orally administrated a single dose of glucose (2\u2009g/kg body weight). Before and at the 15, 30, 45, 60, 90, and 120\u2009minute time points after glucose gavage, blood from mouse tails were collected and analyzed using Bayer\u2019s Elite Glucometer with test strips. Blood glucose data were then plotted and calculated as area under curve values for statistical analyses.52. Default parameters in Adiposoft were set for auto-detection of adipocytes.Mouse liver and adipose tissues were fixed, embedded in paraffin, and trimmed as 5-\u03bcm-thick sections. After the sections were made, H&E and Sirius Red staining were performed following standard protocols. To quantify the adipocyte size, images of H&E-stained adipose sections were randomly taken from each section and then analyzed using Adiposoft softwareFor hepatic triglyceride (TG) measurement, assay Kit (K622) from BioVision was used following the manufacturer\u2019s protocol.in vitro samples, cells were directly lysed and harvested in Laemmli buffer. Protein lysates were boiled at 98\u2009\u00b0C for 5\u2009minutes and subjected to Western blotting analysis as previously described53.Mouse liver tissues were homogenized and extracted in Pierce IP Lysis Buffer (87787) added with Complete EDTA-free Protease Inhibitor Cocktail and PhosSTOP (Roche) for protein quantification. After protein estimation, samples were diluted and mixed with Laemmli Sample Buffer (Bio-Rad) and. For For Dot blotting analysis, undenatured liver lysates were carefully dotted on activated methanol membranes (20 \u03bcg proteins per dot) and fixed by air-drying for 1.5\u2009hours at RT. Dotted membranes were then blocked, incubated with anti-collagen I antibody and secondary HRP-conjugated antibody, and visualized as in Western blotting analysis.To determine the liver hydroxyproline levels, commercial assay kit purchased from BioVision (K226) were used following manufacture recommended protocol.2. To make the fatty-acid-containing medium, fatty acid stocks (100\u2009mM in ethanol) were added into 1% BSA-containing medium and incubated for 30\u2009minutes at 37\u2009\u00b0C before use. For autophagic flux analyses, cells were treated with or without Bafilomycin A1 (50\u2009nM), for another 3\u2009hours before harvest. Autophagy flux was then quantified by measuring the amount of Bafilomycin A1-induced LC3 II protein accumulation.HepG2 cells were purchased from Taiwan Bioresource Collection and Research Center (BCRC number: RM60025) and cultured in DMEM medium (Sigma-Aldrich) supplemented with 10% FBS and 1% penicillin-streptomycin (Gibco). Cells were maintained at 37\u2009\u00b0C with 5% COTo knock down Rubicon, predesigned siGENOME non-targeting siRNA or SMARTpool Rubicon specific siRNAs (Dharmacon) were reversely transfected into HepG2 cells using Lipofectamine RNAiMAX Transfection Reagent (Thermo Scientific). For Rubicon overexpression, the EGFP-Rubicon plasmid  was reversely transfected into HepG2 cells using Lipofectamine 3000 Reagent (Thermo Scientific). Transfection procedures were carried out following manufacture\u2019s protocol.To quantify intracellular fat accumulation, fluorescent Nile Red staining was used. Briefly, cells grown in black 96-well plates were fixed with 4% paraformaldehyde and stained with Nile red (1 \u03bcg/mL) and Hoechst 33342 (2 \u03bcg/mL) in PBS for 30\u2009minutes in the dark. The fluorescence of Nile Red  and Hoechst 33342  was measured using Biotek Synergy H1 Multi-Mode Reader for intracellular fat quantification and cell number normalization respectively.ACTB or Actb were used as internal controls.Total RNA from mouse livers or HepG2 cells was extracted using TRIzol Reagent (Thermo Scientific) following the manufacturer\u2019s protocol. After RNA extraction, the PrimeScript RT Reagent Kit purchased from Takara Bio was used for first-strand cDNA synthesis. To quantify mRNA expression levels, qPCR analyses were performed using the QuantStudio 3 System with Fast SYBR Green Master Mix reagent (Applied Biosystems) and gene-specific primer pairs (Supplementary Table\u00a0In vivo (n\u2009=\u20094\u20136) or in vitro data obtained from at least three independent experiments were pooled and expressed as the mean\u2009\u00b1\u2009standard error of the mean (SEM). Statistically significant differences (p\u2009<\u20090.05) were determined by Student\u2019s t-tests or ANOVA followed by Holm-Sidak test.In this study, statistical analyses were conducted and plots were generated using SigmaPlot software . No datasets were generated or analyzed during the current study.supplementary information"}
+{"text": "Cabozantinib, a c-MET and vascular endothelial growth factor receptor 2 inhibitor, demonstrated to prolong progression free survival and improve skeletal disease-related endpoints in castration-resistant prostate cancer and in metastatic renal carcinoma. Our purpose is to investigate the direct effect of cabozantinib on bone microenvironment using a total human model of primary osteoclasts and osteoblasts.Osteoclasts were differentiated from monocytes isolated from healthy donors; osteoblasts were derived from human mesenchymal stem cells obtained from bone fragments of orthopedic surgery patients. Osteoclast activity was evaluated by tartrate resistant acid phosphatase (TRAP) staining and bone resorption assays and osteoblast differentiation was detected by alkaline phosphatase and alizarin red staining.TRAP (p=0.006), CATHEPSIN K (p=0.004) and Receptor Activator of Nuclear Factor k B (RANK) (p=0.001). Cabozantinib treatment has no effect on osteoblast viability or differentiation, but increases osteoprotegerin mRNA (p=0.015) and protein levels (p=0.004) and down-modulates Receptor Activator of Nuclear Factor k B Ligand (RANKL) at both mRNA (p<0.001) and protein levels (p=0.043). Direct cell-to-cell contact between cabozantinib pre-treated osteoblasts and untreated osteoclasts confirmed the indirect anti-resorptive effect of cabozantinib.Our results show that non-cytotoxic doses of cabozantinib significantly inhibit osteoclast differentiation (p=0.0145) and bone resorption activity (p=0.0252). Moreover, cabozantinib down-modulates the expression of osteoclast marker genes, We demonstrate that cabozantinib inhibits osteoclast functions \u201cdirectly\u201d and \u201cindirectly\u201d reducing the RANKL/osteoprotegerin ratio in osteoblasts. Cabozantinib is an orally bioavailable receptor tyrosine kinase inhibitor with a strong activity against c-MET and vascular endothelial growth factor receptor 2 (VEGFR2) that promote tumour progression and angiogenesis. Osteoclasts and osteoblasts also express c-MET and VEGFR2 \u20134 and sePre-clinical studies in animal models of prostate cancer bone metastases showed that cabozantinib inhibits tumour proliferation and bone resorption, indicating that both the tumour and bone microenvironment may represent cabozantinib targets \u201311. MoreOverall, these clinical and preclinical data support the hypothesis that bone microenvironment may represent a potential mediator of observed treatment responses, but it is not yet clear if cabozantinib acts on bone metastases directly or indirectly regulating osteoclasts and osteoblasts, or both.Previous works explored the biological activity of cabozantinib on bone tissue using only murine models or established cell lines , 20. CelThis is the first study investigating cabozantinib effect on bone microenvironment using a total human primary model.c-MET and VEGFR2 levels at different stages of osteoclast/osteoblast differentiation by real-time PCR. In particular c-MET and VEGFR2 gene expression was assessed at three different time-points in osteoclasts and osteoblasts .We evaluated c-MET mRNA levels were significantly increased in the early stages of osteoclast differentiation , while VEGFR2 was more expressed in mature osteoclasts  (c-MET and VEGFR2 mRNA levels remained unchanged during the osteoblast maturation process (We found that < 0.001) . Both c- process .C-MET protein expression decreased during osteoclast differentiation , but wasCabozantinib was administered to osteoclasts at a non-cytotoxic concentration  , every 3(p = 0.0145)  positive osteoclasts compared to control (DMSO) ) Figure .We assessed the effect of cabozantinib treatment on osteoclast activity by seeding monocytes on wells coated with inorganic calcium phosphate that mimic bone matrix and, then, evaluating the reabsorbed areas (pits) produced by mature osteoclasts. We found that cabozantinib significantly inhibited osteoclast function reducing their capacity to reabsorb bone matrix (p = 0.0252) Figure .The effect of cabozantinib on osteoblasts was evaluated via treating the cells from day 21 to day 28 of the differentiation protocol at different concentrations . Live and Dead analyses showed that cabozantinib treatment has no cytotoxic effects at these doses Figure  or in AlTartrate Resistant Acid Phosphatase (TRAP) (p = 0.006), CATHEPSIN K (p= 0.004) and Receptor Activator of Nuclear Factor (RANK) (p = 0.001) but it did not affect METALLOPROTEINASE-9 (MMP-9) expression, a type IV collagenase highly expressed in activated osteoclasts ..(p = 0.0We set up an osteoblast/ osteoclast direct co-culture to investigate if osteoblasts pre-treated with cabozantinib exerted an inhibitory effect on osteoclast differentiation. The results showed that the number of TRAP\u2013positive cells (osteoclasts) were significantly reduced in cabozantinib 5 \u03bcM) pre-treated osteoblast compared to untreated osteoblasts  to evaluate the effect of cabozantinib in a more physiological system. Our results show that cabozantinib pre-treated osteoblasts are able to reduce the number of osteoclasts differentiated directly on the osteoblast layer. Therefore, cabozantinib could act at multiple levels in the bone metastatic process, targeting cancer cells [Cabozantinib does not inhibit osteoblast differentiation and bone matrix deposition, but, most interestingly, we observed a down-modulation of er cells \u201313, boneer cells , cabozanin vitro results provide the evidence of potential effects of Cabozantinib on both osteoblasts and osteoclasts as components of its in vivo efficacy in reducing tumour burden, prolonging skeletal PFS, decreasing new bone metastases onset and delaying the appearance of SREs as demonstrated in metastatic prostate cancer patients [Our patients \u201314 and mpatients .s activity on skeletal disease-related endpoints and its potential synergism with standard antiresorptive agents [From a clinical perspective, these results could represent the biological rationale to design novel clinical trials in order to investigate Cabozantinib'e agents \u201326 in pa+ monocytes were differentiated in osteoclasts in presence of 25 ng/mL macrophage-colony stimulating factor (M-CSF) and 50 ng/mL receptor activator of Nuclear Factor kappa-B ligand (RANKL) (R&D Systems). Cabozantinib  was added every 3 days to the culture medium starting from day 0 to the end of the differentiation protocol (day 12).Primary human osteoclasts were differentiated from human peripheral blood mononuclear cells (PBMCs) of ten male healthy blood donors following signed informed consent as previously described . The proPrimary human osteoblasts were differentiated from human mesenchymal stem cells (hMSCs). Bone fragments of non-oncological orthopedic surgery patients were collected following the approval by Ethical Committee of Campus Bio-Medico University of Rome (Prot 21/15 OSS) in accordance with the Declaration of Helsinki principles. The informed consent was obtained from all subjects. Bone fragments were digested with Collagenase II (1.5 mg/mL)/ Tripsin (1X) mix solution for 2 hours at 37\u00b0C and placed in a culture flask with alpha MEM (Euroclone) supplemented with 20% fetal bovine serum , 100 units/ml penicillin, 100 mg/ml streptomycin and amphotericin B (250ng/mL)  in order to allow HMSCs migration to the flask surface. osteoblast differentiation was achieved by culturing hMSCs in basal medium supplemented with 10 mM beta-glycerophosphate (Sigma-Aldrich), 50 \u03bcM ascorbic acid (Sigma-Aldrich) and 100 nM dexamethasone. Cabozantinib was administrated to mature osteoblasts from day 21 to day 28 (every three days) at different concentrations .At the end of the osteoclasts differentiation protocol (day 12), culture medium was removed and cells were fixed with 4% formaldehyde for 5 minute and stained with leukocyte acid phosphatase (TRAP) kit (Sigma-Aldrich) according to the manufacturer's instructions. Stained positive cells (>3 nuclei) were then counted. Osteoclast activity was assessed by culturing cells on plates coated with a synthetic inorganic bone mimetic matrix . At day 12 the culture medium was removed and plates filled with sodium hypochlorite solution to evaluate the ability of mature osteoclasts to reabsorb this substrate; the pits produced by osteoclasts were quantified by ImageJ software .On day 21, cells were fixed with 4% formaldehyde for 5 minutes and stained with an alkaline phosphatase (ALP) kit (Sigma-Aldrich) according to the manufacturer's protocol. ALP positivity was quantified by ImageJ software. In order to detect bone matrix deposition as a marker of osteoblastic activity, cells were fixed with 4% formaldehyde for 20 minute and stained with alizarin red for 1 hour at room temperature. Alizarin red fluorescence was detected at 470 nm and quantified by spectrofluorimeter (Tecan Infinite M200Pro).Cell viability was performed on osteoblasts treated with cabozantinib using LIVE/DEAD Viability/Cytoxicity Kit (Thermo Fisher Scientific) according to the manufacturer's protocol.\u22127 M) adding neither cabozantinib nor others pro- osteoblasts/osteoclasts cytokines. At day 12, osteoclasts were detected on osteoblasts layer using TRAP staining kit (Sigma-Aldrich) and counted.In order to evaluate the \u201cindirect\u201d effect of cabozantinib on osteoclasts differentiation, we seeded monocytes directly on osteoblasts untreated or previously treated with cabozantinib. osteoblasts/osteoclasts co-culture was performed in basal medium supplemented with Vit D (10c-MET (Hs01565584_m1), Vascular Endothelial Growth Factor Receptor 2, (VEGFR2) (Hs00911700_m1), Tartrate Resistant Acid Phosphatase (TRAP) (Hs00356261_m1), Cathepsin-K (CAT K) (Hs00166156_m1), Metalloproteinase-9, (MMP-9) (Hs00234579_m1), Receptor Activator of Nuclear Factor (NF)-\u03baB (RANK) (Hs00921372_m1), Alkaline Phosphatase (ALP) (Hs01029144_m1), Osteocalcin (OCN) (Hs00234160_m1), Receptor Activator of Nuclear Factor (NF)-\u03baB Ligand (RANKL) (Hs00243522_m1), Osteoprotegerin (OPG), (Hs00900358_m1) and Runt-related transcription factor 2 (RUNX2) (Hs00231692_m1) expression levels were normalized to the endogenous housekeeping gene Glucuronidase Beta (GUS\u03b2) (Hs99999908_m1) in both untreated and treated samples using the \u0394CT calculation. Subsequently the relative expression levels in treated samples were normalized to the mRNA levels detected in control samples using the \u0394\u0394CT calculation [Total RNA was extracted from osteoclasts and osteoblasts at the end of the differentiation protocol using the Trizol reagent (Invitrogen) according to the manufacturer's instructions. RNA was treated with DNase buffer and DNase  to avoid genomic DNA contamination. cDNA was produced using the High Capacity cDNA Reverse Transcription kit (Applied Biosystems) according to the manufacturer's instructions. mRNA levels were measured by quantitative real-time polymerase chain reaction (qRT-PCR) using TaqMan Gene Expression Assays in 7900HT Real-Time PCR System (Applied Biosystems). culation .Cell lysates were obtained using radioimmunoprecipitation assay buffer (RIPA buffer) (Sigma-Aldrich) and quantified using DC protein assay kit (Bio-Rad). Total protein extract (20 mg) from each sample was loaded on 10% SDS-PAGE gels, transferred onto nitrocellulose membranes through the Trans- Blot Turbo Transfer System (Bio-Rad) and incubated in a blocking buffer (TBST 1X with 5% non-fat dry milk) for one hour. Rabbit monoclonal anti-human c-MET , rabbit monoclonal anti-human VEGFR2  and mouse anti-human Actin-\u03b2 (A1978 - Sigma-Aldrich) were incubated for 2 hours at room temperature. Anti-rabbit/mouse HRT-coniugated antibody (Abcam) was used and the chemiluminescence signal detected using ChemiDoc (Bio-Rad) and Quantity One software (Bio-Rad) to quantify the bands\u2019 signal intensity.Osteoblasts conditioned media (CM) of both treated with cabozantinib or untreated were collected to evaluate the soluble OPG and RANKL protein secretion levels using Human Osteoprotegerin ELISA Kit (RayBio\u00ae) and the Total sRANKL ELISA kit (ImmunDiagnostik). Then cells were harvested and counted. RANKL and OPG levels were normalized to cell numbers in each well.Data were analyzed using the Student t test and One-Way ANOVA test followed by Tukey's multiple comparison tests. The graphics processing and statistical tests were performed using the program GraphPad Prism ."}
+{"text": "Incomplete understanding of TB transmission dynamics in high HIV prevalence settings remains an obstacle for prevention. Understanding where transmission occurs could provide a platform for case finding and interrupting transmission.Mycobacterium tuberculosis culture-positive specimens underwent 24-loci MIRU-VNTR and spoligotyping. We sought to identify epidemiologic links between genotype-matched cases by analyzing social networks and mapping locations where cases reported spending \u226512 hours over the one-month pre-treatment. Sites of spatial overlap (\u2264100m) between genotype-matched cases were considered potential transmission sites. We analyzed social networks stratified by genotype clustering status, with cases linked by shared locations, and compared network density by location type between clustered vs. non-clustered cases.From 2012\u20132015, we sought to recruit all adults starting TB treatment in a Ugandan community. Participants underwent household (HH) contact investigation, and provided names of social contacts, sites of work, healthcare and socializing, and two sputum samples. Of 173 adults with TB, 131 (76%) were enrolled, 108 provided sputum, and 84/131 (78%) were MTB culture-positive: 52% (66/131) tested HIV-positive. Of 118 adult HH contacts, 105 (89%) were screened and 3 (2.5%) diagnosed with active TB. Overall, 33 TB cases (39%) belonged to 15 distinct MTB genotype-matched clusters. Within each cluster, no cases shared a HH or reported shared non-HH contacts. In 6/15 (40%) clusters, potential epidemiologic links were identified by spatial overlap at specific locations: 5/6 involved health care settings. Genotype-clustered TB social networks had significantly greater network density based on shared clinics (p<0.001) and decreased density based on shared marketplaces (p<0.001), compared to non-clustered networks.In this molecular epidemiologic study, links between MTB genotype-matched cases were only identifiable via shared locations, healthcare locations in particular, rather than named contacts. This suggests most transmission is occurring between casual contacts, and emphasizes the need for improved infection control in healthcare settings in rural Africa. Tuberculosis (TB) remains a leading cause of death worldwide, despite the availability of effective antibiotics for drug-sensitive TB for decades, in part due to ongoing transmission from undiagnosed disease. IncompleMycobacterium tuberculosis (MTB) genotypic clustering, suggesting that most incident TB disease is a result of rapid progression to disease following recent transmission.) than HIV-uninfected/status unknown contacts (13/85 [15%]). Among symptomatic contacts, 16/20 (80%) accepted a referral voucher for evaluation at the hospital. Of the four symptomatic contacts that declined referral, one had recently initiated TB treatment outside of the study community. Of the 16 household contacts provided a transport voucher, 11 presented for evaluation, of whom three were diagnosed with active TB and enrolled. Therefore, overall 4/105 (4%) adult household contacts were found to have co-prevalent active TB at the time of household contact investigation, with a yield of 3/105 (3%) new active TB diagnoses, and 3/20 (15%) new diagnoses among symptomatic contacts. One of the 13 adult household contacts who could not be found for enrollment and symptom screening presented to care eight months after attempted household investigation, and was diagnosed with active TB and enrolled as a TB index case.Enrolled TB cases reported a total of 343 household contacts; 23 (18%) of 131 cases reported living alone. Median household size was three persons (IQR: 2\u20134 persons) among 108 TB cases who did not live alone. Of 343 household contacts, 118 (34%) were adults (\u226518 years), the majority of whom (75/118 [71%]) were women; 105/118 (89%) adult household contacts underwent an interview and TB symptom screening. Of the 105 household contacts interviewed, 85 (81%) reported ever testing for HIV, and 20 (19%) self-reported being HIV positive  of TB index case participants. Of the 23 participants that were unable to produce sputum for culture despite attempted induction with hypertonic saline, four had a diagnosis of extra-pulmonary TB, and 14 had been diagnosed with smear-negative pulmonary TB based on clinical suspicion in local clinics at the time of diagnosis, prior to study enrollment. Of 108 participants with sputum obtained for culture, 104 had valid results (four participant samples were contaminated), and 84 (81%) grew MTB. In summary, among 104 cases with sputum results: 79 (76%) cases were both acid-fast bacilli (AFB) smear-positive and MTB culture-positive, 5 (4.8%) cases were AFB smear-negative and MTB culture-positive, 12 (11.5%) cases were AFB smear-positive and MTB culture-negative, 8 (7.7%) cases were AFB smear-negative and MTB culture negative. Among 27 TB cases without MTB culture results, 4 (15%) had a record of AFB smear positivity prior to study enrollment by local non-study laboratories, and 23 (85%) were clinically defined TB cases without microbiological evidence of disease.Table 2and Fig 1and S1 Table).Of the 84 participants with culture-confirmed TB, 33 cases  belonged to 15 distinct MTB genotypic clusters by 24-locus MIRU-VNTR and spoligotyping. Genotypic clusters ranged in size from 2\u20133 TB cases. The proportion of TB cases attributable to recent transmission by the \u201cn-1\u201d method is 21%. Within each of the 15 genotypic clusters, none of the genotype-matched TB cases shared a household or named one another as non-household social contacts. Of the 4 household contacts who were later enrolled as TB index cases, two were unable to produce sputum for culture, one was MTB culture negative, and one grew MTB on culture with a different genotype than the other household member enrolled. Within each cluster, none of the cases reported any shared non-household contacts. TB cases in six of the 15 clusters reported potential epidemiologic links based on either co-location at a shared site or time spent at geographically adjacent locations (within 100 meters distance), based on GPS coordinates of sites of work, clinic, socializing, and households (Table 3). When examining person-time at location types prior to TB diagnosis, a significantly greater proportion of non-clustered cases (76%) reported spending time socializing at bars/restaurants than clustered cases (55%); otherwise no significant differences in person-time were observed at other location types (Table 4). Finally, when examining social networks that linked TB cases to one another based on time spent at specific locations within the community during the study period, stratified by genotype clustering status, genotype-clustered TB case social networks had a significantly greater network density (i.e. greater connectedness of nodes) based on shared medical clinics, and a significantly decreased network density based on shared marketplaces, compared to non-clustered TB case social networks .When comparing demographic and clinical characteristics of adults with TB disease within MTB genotype clusters (N = 33) to adults with TB that were not identified as part of a genotypic cluster , a significantly greater proportion of patients within genotype clusters reported longer cough durations and significantly less tobacco use than non-clustered TB cases in unadjusted analyses  of MTB genotypic clusters. These potential epidemiologic links were only identifiable through time spent at shared locations, and health care locations in particular, rather than through named social contacts in this community. This suggests that high rates of transmission events are occurring between \u201ccasual\u201d contacts and that nosocomial transmission remains a major source of TB spread in rural Africa, emphasizing the continuing need for improved infection control measures in health care settings.The finding that 39% of participants with culture-confirmed TB disease belonged to genotype-matched clusters falls within range of prior estimates from east Africa,, 15 and Potential epidemiologic links between cases could not be identified in 60% of genotype-matched TB clusters in this community despite our use of household contact investigation, ascertainment of social contacts , and GPS mapping of homes, and social, work and clinical locations frequented by TB cases. No direct epidemiologic links between genotype-matched cases were identified via named contacts. Other molecular epidemiologic studies from sub-Saharan Africa have reported similar challenges in identifying epidemiologic links within MTB genotype clusters, as well as low rates of transmission attributable to known, close contacts., 17\u201319 IDespite the lack of shared households among genotype-matched TB cases, co-prevalent active TB was relatively common among adult household contacts (4%), and the yield of adult household contact investigation was relatively high (3%) for the detection of secondary TB cases, compared to other methods of active TB case finding. Our estiTB cases belonging to genotype clusters had greater network densities based on shared clinics compared to non-clustered cases, suggesting a relatively greater contribution of clinical settings in promoting recent TB transmission within this community compared to other location types. Conversely, the higher rates of tobacco use and the greater person-time spent at drinking venues observed among non-clustered TB cases may reflect either higher rates of reactivation TB among persons engaging in tobacco and alcohol use in this setting,, 23 or cTB incidence declined steadily over the three years of the study. There were no changes in TB diagnostic capacity at clinics in the study community over this time period. Similar declines in TB case detection rates have been reported across east Africa., 25 ThesOur study has several limitations. Incomplete sampling can result in underestimation of the proportion of incident TB cases attributable to recent transmission, in part due to misclassification of TB cases as \u201cnon-clustered\u201d that truly occurred within recent TB transmission networks. Several factors that contributed to incomplete sampling in this study included incomplete case detection at local clinics, incomplete enrollment of diagnosed TB cases, an inability to collect sputum from all study participants, and using data from three years of TB surveillance in this community rather than a longer time frame. Continuing enrollment for a longer time period may have reduced \u201cclustered\u201d vs. \u201cnon-clustered\u201d TB case misclassification. The incoIn conclusion, identifying potential epidemiologic links identified between MTB culture-positive, genotype-matched TB patients proved challenging, but possible, in a rural African setting, with a combination of molecular epidemiologic tools, and social network and GIS analyses. Our findings suggest most transmission is occurring between casual contacts, and emphasizes the need for improved infection control in health care settings in rural Africa.S1 Questionnaire(PDF)Click here for additional data file.S2 Questionnaire(PDF)Click here for additional data file.S3 Questionnaire(PDF)Click here for additional data file.S1 Dataset(DTA)Click here for additional data file.S2 Dataset(DTA)Click here for additional data file.S1 Table(XLSX)Click here for additional data file.S2 Table(XLSX)Click here for additional data file."}
+{"text": "Severe degenerative calcific aortic stenosis (cAS) affects 3% of the over 75 year-olds and leads to heart failure and death unless the valve is replaced. Coexisting cardiac amyloid - typically wild-type Transthyretin (wtATTR) has been reported but has not been systematically studied: its prevalence and prognostic significance are unknown. Multiparametric CMR  has high sensitivity and specificity for cardiac amyloidosis. We sought, in cAS, to define the prevalence of occult cardiac amyloid by biopsy, subtype it, explore its CMR presentation and understand its prognostic significance.As part of the RELIEF-AS study (NCT 02174471), 146 patients with severe AS awaiting aortic valve replacement (AVR) underwent CMR  and intra-operative myocardial biopsies. 108 patients had calcific AS (cAS) ; the remainder had bicuspid (36), rheumatic (1) or unicuspid AS (1). Biopsies were screened for cardiac amyloid by congo red staining; if positive, tissue was fully sub-typed , and patients underwent full clinical amyloid assessment including genotyping and DPD (bone tracer) scintigraphy.p = 0.001, univariable Cox regression analysis).Myocardial biopsy identified amyloid depositions in 6 out of 108 cAS patients ; none in the other cohorts. All were TTR. All were by genotyping wild-type. Two had definite cardiac amyloidosis by CMR and DPD, but were not recognized by routine pre-operative work-up  has a prevalence of 6% in cAS undergoing surgical AVR (mean age 75). It has a poor outcome even when at low levels of infiltration. Multiparametric CMR becomes diagnostic in 1/3, but early disease looks like the changes of AS - here, DPD scanning adds value."}
+{"text": "For the eleventh year running, NAR and Oxford Journals have provided sponsorship and awarded travel bursaries and prizes to students and junior scientists in recognition of their outstanding achievements. This year, sponsorship and prizes were given at 9 different meetings. A list of the awards is presented below. Our warm congratulations go to the prize winners.Student New Investigator Poster SessionEnvironmental Mutagenesis and Genomics SocietyKansas City, MO, USASeptember 24\u201328, 2016Poster PrizesSifrARN meeting, French Society for Biochemistry and Molecular BiologyToulouse, FranceMarch 8\u201310, 2016Jonathan Jagodnik International Society for Computational Biology Student Council MeetingOrlando, FL, USAJuly 8\u201312, 2016Urszula Czerwinska FASEB meeting on Post-transcriptional control of gene expression: Mechanisms of RNA decayLisbon, PortugalJuly 10\u201315, 2016Jeffrey Mugridge Cap recognition and catalytic activation of the Dcp1/Dcp2 mRNA decapping complexInternational Biennial Conference on \u2018LARPs\u2019Stockton House, Wiltshire, UKSeptember 14\u201317, 2016Roni Lahr LARP1 interacts directly with 5\u2019UTRs encoding translation machineryInternational Retroviral NucleoCapsid and Assembly SymposiumMontpellier, FranceSeptember 18\u201321, 2016Assia Mouhand The C-terminal domain of Gag: multiple interactions and role for the assembly and budding of HIV-1RNA Biochemistry of the German Society for Molecular Biology and Biochemistry MeetingBonn, GermanyOctober 6\u20139, 2016Indira Memet Interactions and functions of the NF\u03baB-repressing factor in human ribosome biogenesisElke Duchardt-Ferner (Institute for Molecular Biosciences and Center of Biomolecular Magnetic Resonance (BMRZ), Goethe University, Frankfurt, Germany)Structure and Folding of Tetramethylrhodamine Binding RNA AptamersOligonucleotide Therapeutics SocietyMontreal, Quebec, CanadaSeptember 25\u201328, 2016Yazan Abbas RNA binding by Interferon Induced Proteins with Tetratricopeptide RepeatsHala Abou Assi Trapping G-quadruplex/i-Motif Intermediates of Human Telomeric DNAAnnabelle Biscans Synthesis and Optimization of Docosahexaenoic Acid Conjugated Oligonucleotides for siRNA applicationsJovanka Bogojeski Novel Tailed siRNA containing 2\u2032-N-Acyl-L-Phenylalanine Sugar Modifications Self-Delivers to Reduce DRR Expression in Malignant GlioblastomasAmy E. Brinegar Redirected splicing by morpholinos to determine function on calcineurin splicing in skeletal muscle developmentAndrew Coles Polyunsaturated Fatty Acid Conjugated hsiRNAs Enables Systemic Delivery and Efficacy in Mouse TissuesLaura Croft Targeting DNA damage response pathways with antisense oligonucleotidesSuzan Hammond Peptide conjugated antisense oligonucleotides cross the blood brain barrier to enhance their therapeutic efficacy for spinal muscular atrophyMasahiko Horiba Synthesis of 2\u2019-O,4\u2019-C-Spirocyclopropylene Bridged Nucleic Acids (scpBNA) Bearing Purine BasesZachary Kartje Nucleotide Substitutions Tune CRISPR/Cas9 Cleavage ActivityKassie Manning Evaluating antisense therapy for the treatment of myotonic dystrophyLouise Usher Translationally relevant assays for documenting the mechanism of action of oligonucleotide therapeutics in the clinicInternational Society for Computational Biology Latin American ConferenceBuenos Aires, ArgentinaNovember 21\u201323, 2016Emilio Fenoy NetPhosPan: a pan specific predictor for phosphorylation site predictionsLionel Uran Landaburu Updates to the TDR Targets chemogenomics databaseLaura Forero Identification of Bacteriophage crAssphage Through Hidden Markov Models"}
+{"text": "Mycobacterium tuberculosis culture-confirmed tuberculosis cases diagnosed between 2009 and 2013 in New South Wales (NSW), Australia, were examined and clusters identified. The relatedness of cases within the largest MIRU-24 clusters was assessed using whole genome sequencing and phylogenetic analyses. Of 1841 culture-confirmed TB cases, 91.9% (1692/1841) had complete demographic and genotyping data. East-African Indian  and Beijing  lineage strains predominated. The overall rate of MIRU-24 clustering was 20.1% (340/1692) and was highest among Beijing lineage strains . One Beijing and three East-African Indian (EAI) clonal complexes were responsible for the majority of observed clusters. Whole genome sequencing of the 4 largest clusters (30 isolates) demonstrated diverse single nucleotide polymorphisms (SNPs) within identified clusters. All sequenced EAI strains and 70% of Beijing lineage strains clustered by MIRU-24 typing demonstrated distinct SNP profiles. The superior resolution provided by whole genome sequencing demonstrated limited M. tuberculosis transmission within NSW, even within identified MIRU-24 clusters. Routine whole genome sequencing could provide valuable public health guidance in low burden settings.Australia has a low tuberculosis incidence rate with most cases occurring among recent immigrants. Given suboptimal cluster resolution achieved with 24-locus mycobacterium interspersed repetitive unit (MIRU-24) genotyping, the added value of whole genome sequencing was explored. MIRU-24 profiles of all  Mycobacterium tuberculosis is a highly successful human pathogen. Estimates suggest that up to a third of global people are infected and that 9 million developed active disease in 2014 [M. tuberculosis with evidence of ongoing adaptation and genetic diversification throughout human history [M. tuberculosis strain lineages have been identified with distinct geographic distribution patterns, shaped by ancient human migration pathways [pathways . More reM. tuberculosis strain lineages have been associated with variable virulence, transmissibility, disease phenotypes and drug resistance profiles [M. tuberculosis evolution and transmission [Traditional genotyping methods such as mycobacterial interspersed repetitive unit (MIRU) analysis provided new insight into pathogen diversity and strain-specific transmission dynamics . Differeprofiles \u20137. Molecprofiles ,9. More smission ,11.Australia is a low TB incidence setting with a stable incidence of 5\u20136 per 100,000 . The mosDespite these insights, the existence of clusters with identical MIRU-24 profiles provided a public health dilemma, since genotypic clustering is suggestive of local transmission that may require targeted public health intervention . In ordeM. tuberculosis isolates 24-loci MIRU (MIRU-24) genotypes and demographic data were reviewed. MIRU-24 genotyping was performed as described earlier [miru-vntrplus.org online database, (b) to build a minimum spanning tree using Bionumerics v.5 , (c) to calculate allelic richness (AR) using HP-RARE software v.1 [Routine surveillance data collected between 2009 and 2013 at the Mycobacterium Reference Laboratory, NSW containing all culture confirmed ware v.1  and finaware v.1 . In addiware v.1 . Two or M. tuberculosis were initially stored at -80\u00b0C and then recovered on Middlebrook agar. Genomic DNA was extracted using Wizard Genomic DNA purification kit  and libraries were prepared using Ion Xpress Plus Fragment Library kit . Sequencing was performed on an Ion Torrent Personal Genome Machine  with the Ion 318 chip kit (Life Technologies) as per manufacturer\u2019s instructions. A reference genome for mapping was prepared from NC_000962.3 [cysA genes, insertion sequences, transposases and prophage components, with gaps representing 6.3% of NC_000962.3.RRE). Single nucleotide polymorphisms (SNPs) were called using the mem algorithm of the mapper bwa [freebayes [mrbayes [The largest four MIRU-24 clusters identified during the study period were selected for WGS. These 4 clusters belonged to EAI Lineage 1 (clusters A and B with 5 and 4 isolates each) and Beijing Lineage 2 (clusters C and D with 11 and 10 isolates each) strains. Selected cultures of 000962.3  by substpper bwa , followereebayes  operatinreebayes ; the resM. tuberculosis lineages were explored using descriptive statistics, using \u03c72 and One-way ANOVA tests where applicable. All statistical analyses were performed using SPSS 23.0  and p-values less than 0.05 were considered significant. The study was approved by the Human Research Ethics Committee of the University of Sydney (project number 2013/126).Demographic and clinical characteristics of different M. tuberculosis population structure included 17 different strain families, with Lineage 1  and Lineage 2  accounting for more than half of all strains identified. Demographic, clinical and MIRU-24 clustering characteristics of the predominant strain families compared to minority strains are presented in A total of 1841 culture-confirmed TB cases were identified; 72% of all TB cases in NSW during the study period. Of these, 1692 (91.9%) had complete demographic and MIRU-24 genotyping data. The The TB incidence in NSW showed a decrease from 6.5/100,000 population in 2009 to 5.5/100,000 population in 2013 . Apart fMIRU-24 based minimum spanning tree analysis of Beijing lineage strains identified a single clonal complex with four large nodes, while three independent complexes, each with 1\u20132 large nodes, were observed among EAI lineage strains . The HGDAll generated raw reads from whole-genome sequencing were submitted to the European Nucleotide Archive of the European Bioinformatics Institute under study accession number PRJEB11778. The ENA sample identification numbers are listed in M. tuberculosis genotype clusters identified with routine MIRU-24 typing were not indicative of local transmission in this low TB incidence setting dominated by imported disease. The use of WGS-defined SNP clusters reduced the MIRU-24 potential secondary case rate for Beijing lineage strains by 79% (from 19/19 to 4/19) with a further 16% reduction (from 4/19 to 1/19) once likely laboratory contamination events were excluded. Overall SNP-based analysis of the four large MIRU-24 clusters  suggested only a single case of local transmission . The fact that laboratory contaminated isolates were clustered by WGS allowed for a critical review of specimen collection and processing methods and offered practical guidance to public health authorities. We reconfirmed previous observations [WGS demonstrated that large rvations , particuM. tuberculosis strains into Australia, which may influence pre- and post-immigration screening practices [Interestingly, WGS also demonstrated added value in the evaluation of EAI lineage clusters, despite higher MIRU-24 allelic diversity observed in these strains. Not a single transmission chain was identified within the largest MIRU-24 clusters selected . The observation that EAI lineage strains were more prevalent than Beijing among patients with non-respiratory TB and demonstrated equal spread across the age spectrum, support previous observations that suggested reduced transmissibility of EAI strains ,29. The ractices  and direractices .-5 to 1x10-2 per locus per year) and the fact that it considers less than 1% of the M. tuberculosis genome, compared to an estimated SNP mutation rate of 0.3 SNP per genome per year [The sub-optimal resolution associated with MIRU-24 genotyping could be attributable to a slow molecular clock Click here for additional data file.S1 Fig(PPTX)Click here for additional data file.S2 Fig(PPTX)Click here for additional data file.S3 Fig(PPTX)Click here for additional data file.S1 File(ZIP)Click here for additional data file.S2 File(ZIP)Click here for additional data file."}
+{"text": "Mortality and morbidity in patients with ST elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI) are still high  Specifications TableValue of the data\u2022The use of cyclosporine or nicorandil at the time of primary percutaneous coronary angioplasty (PCI) on fatal  death) and non fatal ) outcomes, show the absence of any potential benefit.\u2022Excluding a trial on metoprolol \u2022The analysis on follow-up length shows effects on hospital readmission for HF for trials with longer follow-up.\u2022These additional analyses should be the basis to plan further randomized clinical trials (RCTs) on reperfusion injury in ST elevation myocardial infarction (STEMI) patients undergoing PCI, focusing attention on other molecular mitochondrial targets.\u2022New RCTs on reperfusion injury should have a longer follow-up analysis.1p=0.33; p=0.16; p=0.95, respectively)   (p=0.03)  . The sam for HF) . After tctively) . Finally(p=0.03) , Fig. 6.22.1A systematic review and meta-analysis was performed following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) criteria Papers were retrieved in MEDLINE, Cochrane Library, Google Scholar and Biomed Central. The terms searched were: (reperfusion injury) AND ((PCI) OR (percutaneous coronary intervention) OR  OR (STEMI) OR ) 2.2Detailed description of selection criteria of the papers is described elsewhere 2.3We performed a pre-hoc stratification of studies according to mechanism of action targeting a mitochondrial component/pathway (direct/selective vs. indirect/unspecific) according to a recent overview 2.42 statistic 2 test has been used. Prometa  and RevMan 5  software were used for statistical analyses.The endpoints were expressed as odds ratio (OR). Point estimates and standard errors were calculated and combined by the generic inverse variance method"}
+{"text": "Adherence to antipsychotic treatment is essential in treating schizophrenia symptoms and in preventing costly relapse. This study aimed to compare medication adherence and discontinuation in patients with schizophrenia treated with aripiprazole once-monthly long-acting injectable antipsychotic  to those who changed to a different oral antipsychotic.This retrospective cohort analysis used the Truven Health Analytics MarketScan\u00ae Medicaid, commercial, and supplemental Medicare claims databases. In patients \u226518 years old with schizophrenia, two mutually exclusive cohorts were created: the AOM 400 cohort, patients who initiated AOM 400 between 01/01/2013-06/30/2015 (the ID period); and the oral cohort, patients who changed to a different oral antipsychotic during the ID period. AOM 400 or new oral therapy initiation was the index date. Patients were followed for \u22651 year. Primary outcome measures were adherence (proportion of days covered [PDC]) during 1-year post-index and index medication discontinuation (gap \u226560 days) during entire follow-up. Cox regression and linear regression models were used to estimate risk of discontinuation and PDC, respectively, adjusting for demographic and clinical characteristics, insurance type, baseline medication, and baseline ED visits or hospitalizations.The study sample consisted of 408 (10.8%) AOM 400 patients and 3,361 (89.2%) oral antipsychotic patients. AOM 400 patients had better medication adherence  than the oral cohort. Sixty-three percent of AOM 400 patients were partially (PDC 40%-79%) to fully adherent (PDC >80%) vs. 51.1% of oral antipsychotic patients (p<0.001). AOM 400 patients also had a lower medication discontinuation rate  within 1 year. Median time to discontinuation of AOM 400 was 193 days vs. 89 days for oral antipsychotics (p<0.001). In the Cox model, oral antipsychotic patients discontinued their index treatment at a higher rate than AOM 400 patients .This real-world study suggests that patients with schizophrenia initiating AOM 400 had better medication adherence and lower discontinuation risk than patients who changed to different oral antipsychotics."}
+{"text": "Microbiome analysis of TCS contaminated soil samples was also performed to investigate the abundance of TCS-resistant pathogens. We experimentally confirmed that TCS resistance could be accurately predicted using genome-wide in silico analysis against TRG database. Predicted TCS resistant phenotypes were observed in all of the tested bacterial strains (N = 17), and heterologous expression of selected TCS resistant genes from those strains conferred expected levels of TCS resistance in an alternative host Escherichia coli. Moreover, genome-wide analysis revealed that potential TCS resistance determinants were abundant among the majority of human-associated pathogens (79%) and soil-borne plant pathogenic bacteria (98%). These included a variety of enoyl-acyl carrier protein reductase (ENRs) homologues, AcrB efflux pumps, and ENR substitutions. FabI ENR, which is the only known effective target for TCS, was either co-localized with other TCS resistance determinants or had TCS resistance-associated substitutions. Furthermore, microbiome analysis revealed that pathogenic genera with intrinsic TCS-resistant determinants exist in TCS contaminated environments. We conclude that TCS may not be as effective against the majority of bacterial pathogens as previously presumed. Further, the excessive use of this biocide in natural environments may selectively enrich for not only TCS-resistant bacterial pathogens, but possibly for additional resistance to multiple antibiotics.The substantial use of triclosan (TCS) has been aimed to kill pathogenic bacteria, but TCS resistance seems to be prevalent in microbial species and limited knowledge exists about TCS resistance determinants in a majority of pathogenic bacteria. We aimed to evaluate the distribution of TCS resistance determinants in major pathogenic bacteria (N = 231) and to assess the enrichment of potentially pathogenic genera in TCS contaminated environments. A TCS-resistant gene (TRG) database was constructed and experimentally validated to predict TCS resistance in major pathogenic bacteria. Genome-wide  The surge of pathogenic bacteria resistant to antimicrobials is a major concern for global public health , which cThe biocide triclosan [5-chloro-2-phenol] (TCS) is widely used in a variety of personal care products . TCS bloThe majority of enzymes involved in type II fatty acid synthesis are relatively conserved among bacteria  with theEscherichia coli or a few other human pathogens, the majority of which were resistant to TCS because of the presence of TCS resistance determinants in their genomes. However, our understanding of TCS resistance and TCS resistance determinants among the majority of other human pathogens and soil-borne plant pathogens, which constitute pools of potentially transferrable resistance determinants, is limited. Considering the excessive ongoing use of this biocide, there is a dire need to determine whether the majority of human pathogenic bacteria are resistant to TCS.For over 40 years, TCS has been globally incorporated into a variety of consumer products  under thIn silico genome-wide studies have been widely used to uncover various aspects of the genome, such as antimicrobial resistance [in silico genome analysis of the 183 FabI carrying most common human pathogens [sistance \u201343 and asistance \u201345. In tathogens , 17 and TM Bacterial Genomic DNA Purification Kit (ELPIS BIOTECH) according to the manufacturer\u2019s protocol. pGEM-T Easy (Promega) vector was used for further subcloning of representative TCS resistant determinants in E. coli DH5\u03b1. Recombinant plasmid DNA was isolated using FavorPrep plasmid extraction mini kit (Favorgen Biotech Corp).The bacterial strains used in this study were listed in Standard recombinant DNA techniques were carried out as described previously . PrimersTo test if TCS resistance of bacterial pathogen can be inferred from the presence of putative TCS resistance genes, 17 different laboratory strains were selected for which the whole genome sequence (WGS) information was available . Compara600 of 1.0, and the bacterial suspensions were further serially diluted 1\u00d7105 colony-forming units (CFU)/ml. These cell suspensions (1\u00d7105 CFU/ml) were spreaded onto corresponding growth media containing TCS in the range of 0.5\u2013600 \u03bcg/ml. The culture plates were incubated at optimal growth temperature . A negative and positive control E. coli DH5\u03b1 carrying either pGEM-T Easy alone or a metagenomic TCS resistant 7-AHSDH like ENR in pGEM-T Easy, respectively were also included in the experiment.To validate whether the predicted potential TCS resistance determinants confer resistance to TCS, candidate TCS resistance determinants including FabL, FabK, FabI, AcrB and FabV from selected bacterial strains were cloned and investigated for TCS resistance in oli DH5\u03b1 . All of oli DH5\u03b1 . PCR ampoli DH5\u03b1  for 30 soli DH5\u03b1 . Recombiin silico analysis was performed on selected human pathogenic bacterial strains (N = 183) and soil-borne plant pathogenic bacteria (N = 48). Many of the human pathogens selected are well-known pathogens that have been previously listed [in silico study to include 48 soil-borne plant pathogens  misubtilis , (iii) T cholera , (iv) TCneumonia , (v) TCSneumonia , and  and the TRG reference database (query sequences) using NCBI BLASTp analysis. Annotated sequence reads were selected that had \u2265 27% amino acid sequence identity with the query sequence \u201336. Protnd S241F , 37\u201339.th August 2009 from alluvial soil (AS) and industrially contaminated soil (ICS) were stored in sterile zipper bags at -80\u00b0C and processed for DNA extraction and subsequent MiSeq sequence analysis [Previously collected soil samples dated 19analysis . ICS samanalysis . AS sampanalysis .TM SPIN kit for soil  according to the manufacturer\u2019s protocol. Extracted DNA samples were quantified using a NanoDrop 2000 spectrophotometer . PCR amplification of the 16S rRNA gene was performed from extracted DNA of each sample using barcoded PCR forward (5'- TCGTCGGCAGCGTCAGATGTGTATAAGAGACAGCCTACGGGNGGCWGCAG-3') and reverse (5'-GTCTCGTGGGCTCGGAGATGTGTATAAGAGACAGGACTACHVGGGTATCTAATCC-3') universal primers [http://www.r-project.org/) using Vegan and ggplot2 packages. Details regarding the ICS and AS samples, raw sequence data, and analyzed data are provided in SI  [Bacillus subtilis (FabI and FabL) [Enterococcus faecalis (FabI and FabK) [Another major concern associated with FabI-mediated TCS resistance is that FabI is not always present as a single ENR in a number of microorganisms . Our in s Tables  Tables. s Tables . Other Ts Tables . In regas Tables . Becausend FabV) \u201367, Bacind FabL) , and Entnd FabK) . These oin silico genome comparisons revealed that completely TCS-tolerant ENRs were predominant in most examined pathogens both in human-associated (42%) and soil-borne plant pathogens (52%) (Our ns (52%)  Tables. ns (52%) , and thans (52%)  Tables. in silico analysis revealed that genes encoding the AcrB efflux pump were present in the majority of the human pathogenic bacteria (58.4%) and plant pathogens (87.5%) examined in this study , Clostridium (ranked 3rd), Mycobacterium (ranked 8th), and Pseudomonas (ranked 12th) were among the top 20 abundant genera  Principal coordinate analysis (PCoA) plot representing differences in microbial community among AS and ICS samples. Each point represents individual sample. The variance explained by the PCoA is indicated on the axes. (b) Percent relative abundance revealed relatively similar microbial community structure among similar sample types.(TIF)Click here for additional data file.S1 Table(XLSX)Click here for additional data file.S2 Table(XLSX)Click here for additional data file.S3 Table(XLSX)Click here for additional data file.S4 Table(XLSX)Click here for additional data file.S5 Table(XLSX)Click here for additional data file.S6 Table(XLSX)Click here for additional data file.S7 Table(XLSX)Click here for additional data file.S8 Table(XLSX)Click here for additional data file.S9 Table(XLSX)Click here for additional data file.S10 Table(XLSX)Click here for additional data file.S11 Table(XLSX)Click here for additional data file.S12 Table(XLSX)Click here for additional data file.S13 Table(XLSX)Click here for additional data file.S14 Table(XLSX)Click here for additional data file.S15 Table(XLSX)Click here for additional data file.S16 Table(XLSX)Click here for additional data file.S17 Table(XLSX)Click here for additional data file.S18 Table(XLSX)Click here for additional data file."}
+{"text": "Pseudomonas stutzeri strain SGAir0442 was isolated from tropical air samples collected in Singapore. It is a Gram-negative denitrifying bacterium and an opportunistic human pathogen. Its complete genome consists of one chromosome of 4.52\u2009Mb, containing 4,129 protein-coding genes, 12 rRNA subunits, and 62 tRNAs. Pseudomonas stutzeri is a rod-shaped, single polar flagellated bacterium  using an Andersen single-stage Impactor (SKC BioStage). Strain SGAir0442 was isolated from trypticase soy agar (TSA) (Becton Dickinson) incubated at 30\u02daC after impacting airborne microorganisms onto agar. The strain was streaked several times to obtain an axenic culture. The isolated strain was cultured in Luria-Bertani (LB) broth overnight at room temperature prior to DNA extraction. Genomic DNA of the strain was extracted using a Wizard genomic DNA purification kit (Promega) based on the manufacturer\u2019s recommended protocol. A SMRTbell template prep kit 1.0 (Pacific Biosciences) was used to construct a whole-genome shotgun (WGS) library, followed by single-molecule real-time (SMRT) sequencing conducted on a PacBio RS II (Pacific Biosciences) sequencer. Additional WGS libraries were constructed using a TruSeq Nano DNA library preparation kit (Illumina), and 300-bp paired-end short reads were generated on an Illumina MiSeq sequencer.de novo genome assembly of long reads. The complete processing of the assembly includes preassembly, de novo assembly with HGAP3, polishing with Quiver , while the total number of short reads obtained with the Illumina MiSeq sequencer was 829,385 (110.35-fold coverage). The Hierarchical Genome Assembly Process version 3 (HGAP3)  (Pseudomonas stutzeri DSM4166 (GenBank assembly accession number GCA_000195105).The complete genome presented 98.3% identity with the AMPHORA) . FurtherAMPHORA) , which rAnnotation of the genome was performed with NCBI\u2019s Prokaryotic Genome Annotation Pipeline (PGAP) version 4.2 . The com15\u2013Pseudomonas stutzeri strain SGAir0442 has been deposited in DDBJ/EMBL/GenBank under the accession number CP025149.The complete genome sequence of"}
+{"text": "PARK2 mutations are the most common cause of early-onset Parkinson\u2019s disease. No genotype-phenotype correlation exists, and phenotypic variability is quite common. We report two siblings with confirmed identical compound heterozygous mutations in the PARK2 gene manifesting strikingly different phenotypes. The older brother demonstrated marked parkinsonism by his mid-20\u2019s, whereas the younger brother developed exercise-induced dystonia in his mid-30\u2019s with no subsequent clinical progression, highlighting the clinical heterogeneity of the disease and implying the role of other genetic and/or environmental factors in disease progression. The younger sibling, despite his mild symptoms, had a clearly abnormal dopamine transporter (DaT)-SPECT scan. To our knowledge, this is the first such reported case of an abnormal DaT-SPECT scan in a patient with biallelic PARK2 mutations who does not meet the clinical criteria for Parkinson\u2019s disease. SNCA, LRRK2, VPS35, and EIF4G1) are associated with autosomal dominant inheritance patterns and three ) with recessive inheritance patterns fluorodopa PET and DaT scans, which can assess presynaptic dopaminergic deficit [18F]fluorodopa PET studies in parkin-related PD have produced mixed results. One study found no significant difference in striatal uptake between parkin and non-parkin early-onset PD patients flpatients . In contonset PD .PARK2 mutations not meeting criteria for PD. Notably, patients with non-degenerative causes of dopa-responsive dystonia  have normal DaT scans [18F]dopa PET scan that showed more-than-expected presynaptic dopaminergic deficit, relative to a patient with idiopathic PD and similar motor impairment [PARK2 mutation have significant reduction in striatal [18F]dopa uptake [PARK2 mutations remains unclear, but prior literature has reported such patients manifesting extrapyramidal symptoms [PARK2 mutations in late-onset PD [DaT scans has demonstrated more severe and symmetric loss of striatal signal in patients with parkin-related PD as compared to those with non-parkin-related PD, though notably the parkin-related PD patients had significantly earlier age-of-onset (31 vs. 39 years) and longer disease duration (15 versus 6 years) . The autaT scans . In a caa uptake . The impsymptoms . Investionset PD .PARK2 mutations, further emphasizing the role of other genetic and/or environmental factors in disease manifestation. It also further supports that loss of DaT expression precedes clinical manifestations of PD.This case report highlights phenotypic diversity in patients with identical compound heterozygous"}
+{"text": "Muscle-restricted Cas9 expression enables direct editing of the mutation, multi-exon deletion or complete gene correction via homologous recombination in myogenic cells. Treated muscles express dystrophin in up to 70% of the myogenic area and increased force generation following intramuscular delivery. Furthermore, systemic administration of the vectors results in widespread expression of dystrophin in both skeletal and cardiac muscles. Our results demonstrate that AAV-mediated muscle-specific gene editing has significant potential for therapy of neuromuscular disorders.Gene replacement therapies utilizing adeno-associated viral (AAV) vectors hold great promise for treating Duchenne muscular dystrophy (DMD). A related approach uses AAV vectors to edit specific regions of the DMD gene using CRISPR/Cas9. Here we develop multiple approaches for editing the mutation in dystrophic  CRISPR/Cas9-mediated gene editing is an emerging strategy to treat Duchenne muscular dystrophy. Here the authors develop multiple CRISPR/Cas9-based approaches to correct different dystrophin gene mutations, and show significant restoration of dystrophin expression in skeletal and cardiac muscle in mice. Duchenne muscular dystrophy (DMD) is among the most common human genetic disorders, affecting approximately 1:5,000 newborn males11358910DMD gene modification using the CRISPR/Cas9 system has previously been demonstrated in patient-derived induced pluripotent stem cells (iPSCs) and murine germline manipulation studies13in vivo excision of exon 23 of the murine Dmd gene1516mdxScSn mouseDMD gene1http://www.dmd.nl), which can involve any of the 79 exons that encode the muscle transcript7mdx4cv mouse model that harbours a nonsense mutation within exon 53  to the mRNA; therefore a much larger genomic region containing both exons 52 and 53 must be removed or the mutation itself must be directly targeted. Exon 53 editing is thus an instructive additional Duchenne muscular dystrophy (DMD) target since editing different regions of the enormous DMD locus could generate different results due to effects on pre-messenger RNA (mRNA) splicing and the stability and/or functional properties of modified dystrophins that are not predictableDmd gene in dystrophic mdx4cv mice. Treated muscles display robust and widespread dystrophin expression following both local and systemic delivery, resulting in significant morphometric and pathophysiological amelioration of the dystrophic phenotype. Further, we demonstrate successful and novel in vivo induction of homology-directed repair (HDR)-mediated Dmd gene correction. Our results indicate that AAV-CRISPR/Cas9-mediated gene editing has significant potential for the development of future therapies for DMD.The potential for  53 ref. . ImportaStreptococcus pyogenes (SpCas9)Staphylococcus aureus (SaCas9)25Induction of dystrophin expression was tested following AAV6-mediated delivery of CRISPR/Cas9 components derived from either The overall approaches used in strategy 1 (\u03945253) are potentially applicable to a majority of DMD patients with mutations affecting one or more exons whose removal via editing would allow production of a mRNA with an ORF. For this, we designed sgRNAs to direct Cas9-mediated DNA cleavage within the introns flanking exons 52\u201353 . Followiin vitro using the T7 endonuclease 1 assay in mdx4cv-derived primary dermal fibroblasts. The respective targeting efficiencies for sgRNA-i51 and sgRNA-i53 were 9 and 16%, while a combined targeting efficiency of 8% was observed for the 5\u2032 and 3\u2032 sgRNAs within exon 53  muscles with 5 \u00d7 1010 vector genomes (v.g.) of the AAV6 CK8-nuclease plus targeting vectors and sacrificed at 4 weeks post-injection. In vivo targeting efficiency was estimated via deep sequencing across target regions within the dystrophin gene. For strategy 1 PCR amplification of the genomic DNA region spanning the intron 51\u201353 target sites revealed low levels of a unique \u03945253 deletion product whose sequence was verified following isolation and cloning  and 36% (mRNA) of the edited sequences carried insertions, deletions or substitutions that did not shift the reading frame  or 1.5\u201322.9%  for strategy 1 and 1.8\u20138.4%  for strategy 2, as compared with wild-type (WT) dystrophin levels  and 45% (53*) of myofibers expressed dystrophin . Of note muscles , constit muscles .in situ measurements of muscle force generation at 18 weeks post-transduction of 2-week-old male mdx4cv mice. Encouragingly, the observed dystrophin levels in muscles treated using strategy 1 were maintained at this later time point, resulting in significant increases in specific force generating capacity and protection from contraction-induced injury , an important component of the dystrophin-glycoprotein complex that modulates muscle performance 11. To asd injury . Convers12 v.g. per mouse. Both single- and dual-vector approaches yielded widespread dystrophin expression in the heart, with up to 34% of cardiac myofibers expressing dystrophin at 4 weeks post-transduction  cells and eliminating the impact of possible off-target events affecting genes expressed in mitotically active non-muscle cells, such as hepatocytes. Although HDR is believed to occur infrequently in post-mitotic tissues, at least a fraction of myogenic cells in dystrophic muscles displayed successful HDR-mediated gene correction following CRISPR/Cas9 delivery, as demonstrated by the presence of HDR-derived transcripts. Whether targeting of post-mitotic myonuclei or proliferating myogenic progenitors is responsible for these HDR events is currently unclear. However, MCK regulatory regions are not transcriptionally active in satellite cells or proliferating myoblasts26293034Our results demonstrate that muscle-specific CRISPR/Cas9-mediated gene editing is effective in inducing dystrophin expression in dystrophic in vivo, dystrophin correction could be permanent by ensuring continued generation of dystrophin expressing myofibers during normal muscle turnover. While our previous results indicated that satellite cell transduction using AAV6, 8 or 9 is very low compared with myofibers24For excision of exons 52\u201353, both single- and dual-vector approaches were able to induce dystrophin expression with similar efficiencies, despite an apparent higher frequency of editing with the dual vectors. It is possible that the difference in overall gene editing efficiency stems from a difference in the propensity for indel formation between Sp- and SaCas9 following DNA cleavage at the chosen target sites. For instances when DNA cleavage did not result in deletion of the intervening 45\u2009kb segment, SpCas9 may have generated indels at the cut sites at higher frequencies than SaCas9, resulting in a perceived higher editing efficiency. Actual deletion of the intervening sequence may in fact have been comparable, which the downstream (mRNA and protein) data reflect. Nevertheless, a dual-vector approach currently offers more flexibility in terms of allowing for variations in the ratio between administered nuclease versus targeting components, which may prove important for efficiency. If efficient transduction of myogenic stem cells (satellite cells) can be achieved Initial results from CRISPR/Cas9-mediated gene editing strategies are encouraging for the development of future treatments for DMD, but further studies are needed to enhance dystrophin production bodywide, as will be needed to treat or prevent dystrophy in patients37in vitro studies in fibroblasts) or the muscle-specific creatine kinase 8 (CK8) regulatory cassette (RC)24in vivo studies). (Sp)sgRNA target sequences were selected using the online software ZiFiT Targeter ( http://zifit.partners.org/ZiFiT/) and inserted into pLentiCRISPRv1 following BsmB1 restriction enzyme digestion. Two targeting constructs to work in conjunction with SpCas9 were generated by PCR cloning of the U6-(Sp)sgRNA expression cassette from pLentiCRISPRv1 followed by insertion into pAAV plasmids on either side of a CMV-mCherry expression cassette and a HDR template spanning positions X84575274 to X84576081 of the murine DMD gene cloned from C57BL/6 genomic DNA. The corresponding protospacer adjacent motif (PAM) sites at positions X84575612 (G-A) and X84575639 (G-A) within the HDR template were mutated using PCR-mediated mutagenesis while preserving the encoded amino acids (silent mutations) to eliminate or reduce targeting of the DNA repair template by Cas9. The modified HDR sequence, guide RNA sequences as well as primer sequences for cloning and PCR amplification of genomic DNA and complementary DNA (cDNA) are provided in Plasmids containing regulatory cassettes for expression of Cas9 or gRNAs flanked by AAV serotype 2 inverted terminal repeats (ITRs) were generated using standard cloning techniques. The spCas9 nuclease expression cassette was generated by PCR cloning of NLS-SpCas9-NLS from LentiCRISPRv1 ref. , and insmdx4cv miceL-Glutamine and 15% fetal bovine serum (Thermo Fisher Scientific) before harvest and DNA isolation .Primary dermal fibroblasts were isolated from 3-week-old male 10 v.g. of each vector (nuclease and targeting) was performed via longitudinal injection into tibialis anterior (TA) muscles of 2\u201312-week-old male C57BL/6-mdx4cv (mdx4cv) mice. For strategy 1, systemic delivery of 1 \u00d7 1012 v.g. (low dose) to 1 \u00d7 1013 v.g. (high dose) was performed via retro-orbital injection into 11 week-old male mdx4cv mice (n=3). Both dual- and single-vector approaches were evaluated at the low dose of 1 \u00d7 1012 v.g. of each vector, while the dual-vector approach was also evaluated at a high dose of 1 \u00d7 1013 v.g. of the nuclease vector and 4 \u00d7 1012 v.g. of the targeting vector. The mdx4cv mouse model of DMD harbours a nonsense C to T mutation in exon 53 leading to a loss of dystrophin expressionmdxscsn mouse strain, which provides much greater assurance that dystrophin-corrected fibres resulted from gene targeting rather than spontaneous reversion.All animal experiments were approved by the Institutional Animal Care and Use Committee of the University of Washington. Intramuscular delivery of 2.5\u20135 \u00d7 10mdx4cv and WT mice, except for mice undergoing physiological measurements which were analysed at 18 weeks post-transduction. Medial portions of TA muscles were embedded in Optimal Cutting Temperature (O.C.T.) compound  and fresh frozen in liquid nitrogen cooled isopentane for immunofluorescence analysis. The remaining portions of TA muscles were snap frozen in liquid nitrogen and ground to a powder under liquid nitrogen in a mortar kept on dry ice for subsequent extraction of DNA, RNA and protein.Muscles were collected and analysed at 4 weeks post-transduction and compared with age-matched male non-injected http://depts.washington.edu/if/). Confocal micrographs covering the entirety of injected TA muscle sections were acquired and montaged using the Fiji toolset (ImageJ) and Photoshop (Adobe). Quantification of dystrophin-positive myofibers and dystrophin-positive muscle cross-sectional area was performed via semi-automated tracing and measurement of 1,250 to 3,500 individual myofibers per TA using Adobe Photoshop (n=5 TAs per treatment group). Automated quantification of central nucleation was performed using software developed in-house by Rainer Ng (CHAMP) running on the Matlab platform.TA cross-sections (10\u2009\u03bcm) were co-stained with antibodies raised against alpha 2-laminin  and the C-terminal domain of dystrophin . Serial sections were stained with antibodies raised against neuronal nitric oxide synthase . Slides were mounted using ProLong Gold with DAPI (Thermo Fisher Scientific) and imaged via Leica SPV confocal microscope at the University of Washington Biology Imaging Facility ( mdx4cv (30\u2009\u03bcg) and treated mdx4cv (30\u2009\u03bcg) mice were denatured at 99 degrees Celsius for 10\u2009min, quenched on ice and separated via gel electrophoresis after loading onto Bolt 4\u201312% Bis-Tris polyacrylamide gels (Invitrogen). Protein transfer to 0.45\u2009\u03bcm PVDF membranes was performed overnight at constant 34\u2009volts at 4\u2009\u00b0Celsius in Towbin\u2019s buffer containing 20% methanol. Blots were blocked for 1 hour at room temperature in 5% non-fat dry milk before overnight incubation with antibodies raised against the C-terminal domain of dystrophin , anti-SpCas9 , anti-HA  for detection of HA-tagged saCas9 and Gapdh . Horseradish-peroxidase conjugated secondary antibody staining  was performed for 1\u2009h at room temperature before signal development using Clarity Western ECL substrate (BioRad) and visualization using a Chemidoc MP imaging system (BioRad). Gel- and blot- band densitometry measurements were performed on unsaturated images using ImageJ software .DNA and RNA were isolated using Trizol reagent (Invitrogen) according to the manufacturer\u2019s recommendations. Approximately 500\u2009bp amplicons across the targeted regions of genomic DNA were generated by PCR using Phusion proof-reading polymerase  and analysed for targeting efficiency using T7 endonuclease 1 (NEB), next generation sequencing  or Sanger sequencing  of subclones of PCR amplicons . The T7 endonuclease assay was performed by denaturing and re-annealing the amplified PCR product followed by treatment with T7 endonuclease 1 to cleave indel-derived heteroduplex PCR products. Analysis of dystrophin-targeted transcripts by RT\u2013PCR of the target regions was performed on cDNA made using Superscript III first-strand synthesis supermix (Invitrogen). Specific indel mutations or deletions in the dystrophin transcript were identified by Sanger sequencing of individual subclones of RT\u2013PCR fragments. Muscle proteins were extracted in radioimmunoprecipitation analysis buffer (RIPA) supplemented with 5\u2009mM EDTA and 3% protease inhibitor cocktail , for 1 hour on ice with gentle agitation every 15\u2009min. Total protein concentration was determined using Pierce BCA assay kit (Thermo Fisher). Muscle lysates from WT (10 and 1\u2009\u03bcg), untreated http://www.rgenome.net/cas-offinder/) was used to identify potential off-target sites for SaCas9, using a mismatch number of \u22643, DNA bulge size \u22641 and RNA bulge size \u22641. For Strategy B, genomic deep sequencing was performed on a \u223c230\u2009bp nested PCR product generated from an initial \u223c500\u2009bp product amplified across exon spanning both target sites. To eliminate false detection of the HDR template DNA present in AAV vectors, the primer pair used to generate the 500\u2009bp product was designed with one primer annealing outside of the region complimentary to the HDR template. The resulting PCR product was isolated following gel electrophoresis  before performing nested PCR followed by a second gel extraction. For each site analysed, amplicons from 4\u20135 mice were pooled and subjected to standard Illumina library preparation ), and QC\u2019d using a BioAnalyzer before paired end (PE150) sequencing on an Illumina MiSeq system . Libraries were barcoded for multiplexed sequencing and subsequent reads were parsed and QC\u2019d using custom scripts , phred33 score \u2265 30) and standard Illumina tools. On-target paired end (PE150) sequencing of DNA amplicons generated from muscles treated according to strategy 2 (53*) was performed by submitting the samples to BGI International . Uniquely mapping read pairs were used for downstream analysis using the CRISPResso software pipelineApproximately 200\u2013250\u2009bp PCR products were generated across target-, and the top predicted off-target sites for each sgRNA using Platinum Taq High-Fidelity polymerase (Invitrogen) or Phusion High-Fidelity Polymerase (NEB). Potential off-target sites were identified using ZiFiT Targeter software for SpCas9. CRISPR Rgen tools Cas-OFFinder software  and assayed in situ for force generationL0) the maximum isometric tetanic force was measured during electrical stimulation using Dynamic Muscle Control v5.420 software (Aurora Scientific). Muscle cross-sectional area (CSA) was calculated by dividing muscle mass (mg) by fibre length (mm) and 1.06\u2009mg\u2009mm\u22123 . Specific force values were obtained by normalizing maximum isometric tetanic force production to CSA. Protection against contraction-induced injury was evaluated by measuring force production during progressive lengthening contractions beyond optimal fibre lengthEighteen weeks post-transduction, treated post hoc tests unless otherwise stated. Statistical significance was set to P<0.05.Data values are represented as mean\u00b1s.e.m. and were analysed in Excel (Microsoft) and Prism6 (GraphPad). Measurements were analysed for statistical significance using one-way analysis of variance (ANOVA) multiple comparison tests with Turkey\u2019s https://www.ncbi.nlm.nih.gov/bioproject/PRJNA358248).Sequence data supporting the findings of this study have been deposited in the sequence read archive (SRA) with the BioProject accession code PRJNA358248 .Publisher\u2019s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Supplementary Figures and Supplementary Tables."}
+{"text": "The effectiveness of cardiology-led palliative care is unknown; we haveinsufficient information to conduct a full trial.To assess the feasibility  of a clinical trial ofpalliative cardiology effectiveness.Non-randomised feasibility.Unmatched symptomatic heart failure patients on optimal cardiac treatmentfrom (1) cardiology-led palliative service (caring together group) and (2)heart failure liaison service .Symptoms , Kansas City CardiomyopathyQuestionnaire, performance, understanding of disease, anticipatory careplanning, cost-effectiveness, survival and carer burden.A total of 77 participants  were enrolled ). The caringtogether group scored worse in Edmonton Symptom Assessment Scale (43.5 vs35.2) and Kansas City Cardiomyopathy Questionnaire (35.4 vs 39.9). Thecaring together group had a lower consent/screen ratio (1:1.7 vs 1: 2.8) andfew died before approach (0.08% vs 16%) or declined invitation (17% vs37%).At 4\u2009months, 74% in the caring together group and 71% in the usual care groupprovided data. Most attrition was due to death or deterioration. Dataquality in self-report measures was otherwise good.There was no difference in survival. Symptoms and quality of life improved inboth groups. A future trial requires 141  todetect a minimal clinical difference (1 point) in Edmonton SymptomAssessment Scale score for breathlessness (80% power). More participants are needed to detect a 10.5 change inKansas City Cardiomyopathy Questionnaire score .A trial to test the clinical effectiveness (improvement in breathlessness) ofcardiology-led palliative care is feasible. What is already known about the topic?Compared with people with cancer, those with advanced heart failure haveequivalent palliative care needs with poorer access to specialist palliativecare.A palliative care approach led by cardiology teams and access to specialistpalliative care according to need rather than prognosis is recommended butpoorly implemented.The evidence base for palliative care in heart failure is less robust thanthat for cancer and there are no published prospectively collected data forcardiology-led palliative care services.What this paper adds?Novel prospectively collected data for cardiology-led palliative careservices which show that a future trial of cardiology-led palliative care isfeasible in terms of recruitment to a clinical study (note: willingness torandomisation was not tested), data quality and sample size.Data generating a hypothesis that cardiology-led palliative care may safelyimprove advance care planning and patients\u2019 understanding of theircondition, enable care at home and reduce costs.Implications for practice, theory or policyFindings should be tested in an adequately powered randomised controlledtrial.Future studies should identify and randomise patients with more severe orcomplex palliative care needs to ensure optimal use of finite specialistpalliative care resources.16 Palliative care isrecommended,710 but poorlyimplemented.1115Compared with people with cancer, those with advanced heart failure have equivalentpalliative care needs with poorer access to specialist palliative care.1619 reportcost-effective21 benefit with specialist palliative care without compromisingsurvival. However, most palliative concerns in people with heart failure can bemanaged by the usual care team using a patient-centred approach with access tospecialist palliative care for complex issues only.23 Previous integrated servicedescriptions do not include patient-reported outcomes,2427 and the effectiveness ofcardiology-led palliative care is untested.Phase III trials of specialist palliative care for people with heartfailure28).A partnership between two charities (Marie Curie and British Heart Foundation) and aScottish NHS health board developed cardiology-led models of heart failurepalliative care (\u2018The Caring Together (CT) Programme\u2019The study objectives were to assess the feasibility of a future randomised controlledtrial (RCT) in terms of (1) recruitment/retention, (2) data quality, (3)variability/sample size estimation and (4) safety.Expanded methods are available online.This prospective feasibility cohort single-site study  used two heart failure outpatient groups. Theparticipants continued 2\u2009monthly measures until the last recruit completed4\u2009months\u2019 follow-up.Ethical and institutional approvals were obtained prior to recruitment. The participantsgave written informed consent.29Participants were adults with symptomatic heart failure  and family carers. Participantswith at least one CT clinic attendance formed the caring together group (CTG). Aconvenience unmatched usual care group (UCG) was formed from heart failureliaison nurse service patients fulfilling CT criteria but who had not beenreferred. The risk of contamination was deemed to be minimal.The liaison nurse service and other consultant cardiologists\u2019 clinics provideeducation, self-care promotion, medical therapy up-titration and patient/familysupport (HFrEF only).Recruitment: screen-to-consent ratio, reasons for non-consent,recruitment rate, retention.30 Australian-modified Karnofsky Performance Status (AKPS);31 Charlson et al.\u2019s32 comorbidity index; medication-optimised cardiactreatment; pulse, heart rate, presence/absence of oedema andjugular venous pressure; urea and electrolytes; andechocardiogram .(a)\u2003Demographic and clinical measures at baseline: New YorkHeart Association (NYHA) status;33 Kansas City Cardiomyopathy Questionnaire(KCCQ-12),3436EuroQol EQ-5D-5L,37 Hospital Anxiety and Depression Scale (HADS),38 patient understanding (Likert), health serviceutilisation and costs (including medication) and Zarit 6caregiver burden (carers).39(b)\u2003Patient measures at baseline and follow-up: AKPS,Edmonton Symptom Assessment Scale \u2013 revised (ESAS-r),(c)\u2003Clinical measures at baseline and follow-up: survival,clinical documentation of anticipatory care planning(ACP).Data quality of protocol measures.Candidate primary outcome data variability for power estimation.Safety: survival (6\u2009months) and outcomes (4\u2009months).Data were not collected on willingness to be randomised.Data are presented using descriptive statistics. Sample size estimations wereconducted based on variability data around candidate primary outcomes.t tests (continuous) andFisher\u2019s exact tests , unless otherwise stated. No adjustments weremade for multiple comparisons. Missing data were not imputed. A \u2018per-protocol\u2019(PP) repeated-measures model analysis excluded UCG participants referred to CT.Two random-effects repeated-measures regression models with (1) the KCCQ-12 and(2) the EQ-5D-5L, as the dependent outcomes adjusted for age, sex and baselineESAS-r scores, were used. The estimated between-group differences were reportedwith 95% confidence intervals (CIs) and p values. PP analysiswas completed for the initial repeated-measures model (data available).Safety assessment: (1) Cox proportional hazards models were used forbetween-group survival differences and (2) Group 4\u2009month outcomes comparison bystudy entry group used two-sample Incremental costs and outcomes associated with CTG were determined. Resource useitems included health service utilisation and medication. Analyses wereconducted using SAS for Windows version 9.3. Formal power calculation wasinappropriate.A total of 77 participants (43 CTG and 34 UCG) were recruited (8 April to 18 December2015). A follow-up of 4\u2009months is presented except for the repeated-measures model,survival and health service utilisation (8\u2009months) and study flow (10\u2009months).Most attrition was due to death or deterioration; those providing follow-up datahad better performance status, symptom scores and quality of life (QoL) atbaseline (data available). Data quality was otherwise good  and 3.Both groups were on optimal tolerated cardiac treatment.There were clinically important between-group differences  and 5. NMore UCG participants had prior admissions (47.1% vs 32.6%). All CTG participants hadattended CT at least once :2\u201321\u2009months).p\u2009<\u20090.001). Two UCG participantswere transferred to CTG, but there were no differences in the PP analysisfindings.Overall, the ESAS-r and KCCQ-12 scores improved. At 4\u2009months, adjusted symptomimprovement was greater in the UCG (0.046). ACP documentation and understandingremained better in the CTG . CTparticipants commented on excellent, individually tailored, coordinated care.UCG participants commented on fragmented care, poor communication and differentunfamiliar doctors.There was no between-group difference in survival .p\u2009=\u20090.50)or KCCQ-12 (p\u2009=\u20090.08) at 4\u2009months after adjustment for age, sexor baseline individual ESAS-r .There were no between-group differences in EQ-5D-5L 41 were used. UCG was taken as the population of interest and ESAS(breathlessness) as the symptom most highly correlated with KCCQ-12 (dataavailable). eTable 2 shows the estimated sample sizes . To detect a difference of 10.5 points (KCCQ-12) and 1 point (ESASbreathlessness), the sample sizes of 176 and 141, respectively, are needed .Important clinical differences for KCCQ-1242 attrition was high (27% at 4\u2009months) mostly due to death ordeterioration. Further feasibility work should test the willingness to berandomised.It is feasible to recruit and collect data for a clinical study. As reportedpreviously in palliative studies,43 or historical controls.27This the first study to provide patient report and cost-effectiveness data from acardiology-led palliative heart failure service. Other studies report thecomponents only The major limitations are as follows: (1) non-randomisation, (2) cost neutralitywas assumed and opportunity costs were not considered, (3) missing data and (4)CT participants were already receiving cardiology-led palliative care (possibleunderestimated benefit).This study provides useful feasibility and early safety data; the UCG did notappear to be disadvantaged in terms of survival or 4-month outcomes. Willingnessto be randomised was not tested but could be built into a pilot embedded into aphase III trial. Recruitment appeared to be easier from patients known to theresearch team (UCG). This should be taken into account when researchers aredependent on other clinical teams to identify potential participants althougheligible patients may be more inclined to participate in an interventiontrial.7 encourages problem-driven palliative care independent of prognosis,citing benefits as improved patient/carer understanding, symptoms/sufferingrelief, patient-centred decision-making, improved communication, better ACP andbereavement support. Although the study was not designed to assesseffectiveness, the data on patient understanding, ACP documentation, fewernights in hospital and being shifted from secondary to community care showpromise \u2013 consistent with Component 5 (A recent US statementponent 5 .A clinical trial investigating the cost-effectiveness of cardiology-led heart failurepalliative care is feasible. A future trial should recruit from usualcommunity-based care eligible for but not referred to cardiology palliative care,and identify those needing more intensive palliative care."}
+{"text": "A 78-year-old male was hospitalized in October 2013 due to renal failure. Soon thereafter, light-chain deposition disease was confirmed . A high-dose DEXA protocol was introduced and he received 11 protocols during the following 12 months. In October 2014 he commenced maintenance hemodialysis (HD) via a distal arteriovenous fistula (AVF). In March 2015 he noticed swelling of the fistula region. Although the AVF was functional, local findings on the skin deteriorated within 1 month . MultislPresentation of extramedullary subcutaneous light-chain deposition surrounding an AVF may be a potential link between light-chain deposition disease and augmented circulation, thus giving a preferential site for tumor growth . Hematog"}
+{"text": "Chitinophaga comprises microorganisms capable of degrading plant-derived carbohydrates, serving as a source of new tools for the characterization and degradation of plant biomass. Here, we report the draft genome assembly of a Chitinophaga strain with 8.2\u00a0Mbp and 7,173 open reading frames (ORFs), isolated from a bacterial consortium that is able to degrade lignocellulose. Chitinophagaceae family was first described in 1981 by Sangkhobol and Skerman . The library was constructed using the Ion Xpress Plus fragment library kit (Thermo Fisher Scientific), under conditions recommended by the manufacturer. Single-read sequencing (1 \u00d7 200 bp) was performed on an Ion Torrent proton sequencer (Thermo Fisher Scientific) on a separate PI chip, according to the manufacturer\u2019s protocols.Genomic DNA from isolate CB10 was extracted using the Wizard genomic DNA purification kit (Promega). Chitinophagaceae family bacterium with a total of 59,136,612 reads sequenced, which had 22,401,727 reads with a Phred quality greater than 20 identified using Prinseq (http://prinseq.sourceforge.net). The organization of contigs was performed using the SPAdes program , virulence, disease, and defense (145 ORFs), potassium metabolism (19 ORFs), phages, prophages, transposable elements, and plasmids (8 ORFs), membrane transport (186 ORFs), iron acquisition and metabolism (16 ORFs), RNA metabolism (169 ORFs), protein metabolism (243 ORFs), cell division and cell cycle (41 ORFs), regulation and cell signaling (47 ORFs), secondary metabolism (24 ORFs), DNA metabolism (116 ORFs), dormancy and sporulation (six ORFs), stress response (119 ORFs), sulfur metabolism (48 ORFs), phosphorus metabolism (38 ORFs), and central carbohydrate metabolism (170 ORFs).Chitinophaga strain from the NCBI databases (The partial genome analysis shows 75% similarity to the genome of a atabases .MLAV00000000.The draft genome sequence has been deposited in NCBI GenBank under the accession number"}
+{"text": "Nature Communications8: Article number: 13914; DOI: 10.1038/ncomms13914 (2017); Published 01092017; Updated 04192017This Article contains typographical errors in Equation 1, where the fraction line incorrectly extends across the entire equation. The correct form of Equation 1 is as follows:"}
+{"text": "V600E mutation. Small molecule inhibitors that selectively target BRAFV600E are FDA approved for melanoma and have shown significant efficacy in treating BRAFV600E glioma in pre-clinical trials. Despite showing initial anti-tumor activity, acquired drug resistance significantly limits the benefit from being treated with BRAFV600E inhibitors. Here, we have identified molecular responses to BRAFV600E inhibitor treatment in human glioma models that have substantial clinical implications. Specifically, we show that BRAFV600E inhibitor resistant cells upregulate pro-survival mediators such as Wnt, and additionally increase receptor tyrosine kinase activity, including EGFR and Axl, promoting resistance to BRAFV600E inhibition. Our results suggest strategies to circumvent acquired resistance to BRAFV600E inhibitor therapy, and thereby improve outcomes for patients with BRAFV600E gliomas.Activating mutation of BRAF is a common finding in pediatric gliomas. As many as 14% of high grade and up to 66% of certain subtypes of low grade pediatric glioma have the BRAF V600E mutation is found in as many as 14% of high grade and up to 66% of certain subtypes of pediatric low grade glioma. Interestingly, this mutation is much less frequent in adult glioma [Oncogenic BRAF mutation occurs in approximately 8% of human cancers . These iV600E selective small molecule inhibitors have been developed. Vemurafenib (Zelboraf) and dabrafenib (Tafinlar) are BRAFV600E selective, ATP-competitive small molecule inhibitors that are FDA-approved for the treatment of melanoma [V600E-mutant glioma [et al reported a case of complete regression in a pediatric patient treated with vemurafenib for recurrent BRAFV600E giloblastoma multiforme [et al documented partial and transient response to vemurafenib in two out of three pediatric patients with high grade BRAFV600E glioma [et al reported moderate single agent activity of vemurefinib against recurrent pleomorphic xanthoastrocytoma, which is a subtype of glioma with an especially high incidence of BRAFV600E mutation [V600E glioma .A number of BRAFmelanoma . We havet glioma . Clinicaltiforme . Bautistmutation . CombineV600E inhibitor monotherapy indicate that orthotopic glioma xenograft growth is delayed and/or slowed down, but not stopped, when treating mice with PLX4720, suggesting a tumor adaptive response to BRAFV600E inhibitor therapy [V600E inhibitors has been observed in a number of cancer types. In melanoma, acquired resistance can be mediated through (i) upregulation of receptor tyrosine kinase (RTK) signaling, including EGFR, insulin-like growth factor 1 receptor (IGF1R) and platelet derived growth factor beta (PDGF-B) [V600E [V600E [Results from our preclinical studies using BRAF therapy . In fact(PDGF-B) \u201312; (ii)(PDGF-B) , 13; (ii(PDGF-B) ; (iv) Ra(PDGF-B) , 13; (v)) [V600E ; (vi) amE [V600E ; (vii) eE [V600E , 18;  by culturing parental AM-38 and DBTRG-05MG cells in the presence of increasing inhibitor concentrations. RGCs that had adapted to 5 uM inhibitor showed a reduced G1 phase cell cycle population, relative to corresponding treatment na\u00efve parental cells (TNPCs) upon initial exposure to PLX4720 Figure , and TNPV600E inhibitor resistance [Because increased CRAF and IGF1R activity have each been implicated in melanoma BRAFsistance , 21, we V600E inhibitor resistance in melanoma [V600E inhibition might be an approach to overcome drug resistance. In agreement with our previous report, TNPCs treated with PLX4720 showed increased Ras activity compared to DMSO treated control cells, most likely due to feedback activation of upstream RTK upon MAPK pathway inhibition [Elevated Ras activity has been observed in association with BRAFmelanoma . Our comhibition   significantly reduced RGC cell viability determined by WST-1 Figure  and coloTo investigate if Axl activity confers PLX4720 resistance, we expressed exogenous wild-type and kinase-dead K567R Axl in TNPC, then examined the response to PLX4720 treatment. TNPCs expressing exogenous wild-type Axl showed significantly higher levels of phospho-Axl compared to vector or kinase dead K567R Axl transfected TNPC Figure . Upon trper se is more effective in reducing RGC cell viability than PLX4720, as RGC cells have bypassed PLX4720 through upstream RTK activation [To study the importance of EGFR to RGC PLX4720 resistance, we used EGFR siRNA and small molecule inhibition (HKI-272) to reduce EGFR activity in RGCs Figure  then exativation .V600E cell response to PLX4720, we expressed exogenous EGFR in TNPC , we found many involved with Wnt pathway signaling, with higher expression consistently associated with RGC Table .V600E inhibitor to previously untreated cells.We compared Wnt pathway transcriptional activity in corresponding TNPC-RGC cell pairs using a Cignal TCF/LEF reporter assay. RGC showed an almost two-fold higher level of Wnt pathway activity associated transcription compared to TNPC maintained in PLX4720 free media Figure . HoweverCanonical Wnt signaling is mediated by beta-catenin, which is a transcription factor that activates Wnt responsive genes. To investigate if canonical Wnt pathway inhibition affects PLX4720 resistant glioma cell viability, we suppressed Wnt signaling by treating RGC with Wnt inhibitor FH535, and also by knocking down RCG beta-catenin via siRNA transfection . 10 uM FWe next examined combined pharmacologic inhibition by incubating RGCs and TNPCs with HKI-272 or foretinib or FH535, both in the presence and absence of PLX4720. HKI-272 and foretinib treatments resulted in a significant reduction in RGC and TNPC viability in both AM38 and DBTRG-05MG cells , howeverV600E-mutant glioma [V600E inhibitor treatment. We have previously shown in a BRAFV600E glioma model that BRAF monotherapy is inefficient in suppressing tumor growth, whereas combination with EGFR inhibitor confers significant anti-tumor efficacy, suggesting that both BRAF oncogene as well as primary resistance mechanisms have to be inhibited in vivo to prevent acute resistance from developing [V600E glioma adaptation and acquired resistance to BRAFV600E inhibition. Our results indicate an important role of Axl and EGFR signaling in conferring vemurafenib resistance in BRAFV600E glioma.Vemurafenib has shown promising results in preclinical and clinical studies of BRAFt glioma , 22. Howveloping . Here weV600E inhibitor treatment, likely a consequence of reduced expression of the EGFR phosphatase PTPN9 upon MAPK pathway inhibition [in vivo model of BRAFV600E glioma. Here, we show that Axl expression and activity are also increased in RGCs. Axl activity has been shown to contribute to tumor malignant phenotypes, including cell migration, survival and chemosensitivity [in vitro [V600E glioma, and that Axl inhibition is a therapeutic strategy deserving of further development for clinical translation.We have previously shown that EGFR is hyperactivated upon BRAFsitivity \u201325. As win vitro , 28. Trein vitro . Similarin vitro . Importaet al have shown that genetic and pharmacologic inhibition of Axl help prevent acquired resistance to EGFR inhibition, in EGFR\u2013mutant lung cancer models [In squamous cell carcinoma (SCC) cells Axl has been shown to dimerize with EGFR and promote ligand independent phosphorylation of EGFR, leading to increased activation of phospholipase C\u03b3 (PLC \u03b3) and protein kinase C \u03b6 (PKC\u03b6), as well as mTOR . Zang etr models . In breaV600E glioma cell growth and did not sensitize RGCs to BRAFV600E inhibition. Wnt 5A is an important component of the non-canonical Wnt signaling effects, which include cytoskeleton organization and function [We also observed increased expression of multiple Wnt pathway genes, including Wnt5A, FZD2, Dvl3 and WSP1, in RGCs, with elevated Wnt pathway-associated transcription in these cells confirmed by TCF/LEF reporter results. However, in contrast to previous report with U251 (BRAF wild-type) glioma cells , geneticfunction , potentiV600E glioma cell adaptation to BRAFV600E inhibitor treatment, our current work provides information important to improving the duration and/or extent of BRAFV600E glioma therapy by interfering with compensatory cell responses that involve increasing Axl and EGFR activities. Given the availability of clinically approved compounds for inhibiting these RTKs, there will certainly be opportunities for translating our observations to evaluate combination therapies for treating patients with BRAFV600E glioma.Irrespective of the nature of Wnt pathway involvement with BRAFAM38, DBTRG-05MG, LN229, NMC-G1 and U87MG cells were purchased from ATCC. 8MGBA, 42MGBA were obtained from DSMZ. ATRT lines BT12, BT16 and 794 was kindly provided by Dr N. Foreman (University of Colorado). CHLA-07-BSGBM was the provided by the courtesy of Dr Anat Erdreich-Epsten . SF188, SF9744, SF9841 and SF9867 were obtained from the Brain Tumor Research Center .EGFR has been described previously [Wild-type and K567RAxl in pcDNA3.1 (+) vector was kindly provided by Dr Trever Bivona  . pcDNA3.eviously . PLX4720All cell lines were maintained in DMEM supplemented with 10% fetal bovine serum, 1% penicillin and streptomycin, and 1% non-essential amino acid. PLX4720 resistant cells were generated by culturing parental AM38 and DBTRG-05MG cells in increasing concentrations of PLX4720 to achieve chronic selection. PLX4720 resistant cells were maintained in the presence of 5 uM PLX4720. For Axl, EGFR and B-catenin siRNA knock down experiments, cells were transfected with Dharmacon siGENOME non-target siRNA, Axl SMARTpool siRNA or EGFR SMARTpool siRNA following manufacturers instruction . For Axl and EGFR overexpression, transfection was achieved using the Amaza Basic Glial Cells Nucleofector Kit  following manufacturers instructions.Proteins were extracted from cells using cell lysis buffer  supplemented with proteinase  and phosSTOP phosphatase inhibitor cocktail (Roche). Proteins were resolved by SDS-PAGE and transferred onto polyvinylidene difluoride membranes, which were then probed with primary antibodies followed by horseradish peroxidase-conjugated secondary antibody, and visualized by ECL . Antibodies against phospho-ERK, phospho--Akt, total Akt, phosphor-CRAF, total CRAF, phospho-IGF1R, total IGF1R, phospho-MEK, total MEK, phospho EGFR, Ras, phospho Axl, total B-catenin were purchased from Cell Signaling Technology. Total EGFR and total ERK antibodies were purchased from Santa Cruz Biotechnology  and total Axl was obtained from R&D Systems . Antibody specific for p-EGFR (1173) was obtained from Novus Biologicals, and antibodies specific for Beta-Tubulin was from Milipore. Anti-Wnt5A antibody was purchased from Abcam .Cells were seeded onto 48-well plates at 2500 to 3000 cells per well. After 16 hours of seeding, cells were maintained in drug containing culture media for 72 hours. Cell viability was determined by WST-1 assay (Roche) according to manufacturer's instructions. 450 nm absorbance was measured using a microplate reader , with background reading at 800 nm subtracted. Percent viability was normalized against cell treated with 0.1% DMSO as control.Cells were treated with or without drugs for 24 hours before harvesting. The trypsinized cells were washed with PBS and fixed in ice-cold 70% ethanol overnight followed by staining with propidium iodide (20 ug/ml)  in PBS containing RNaseA (0.4 mg/ml) (Invitrogen). Fluorescence levels (488nm excitation) were measured by a FACSCalibur , and data was analyzed using the ModFit software .RNA was isolated using the RNeasy Mini kit  and quantified using a NanoDrop Spectrophotometer . The NuGEN Pico V2, based on Ribo-SPIA technology, was used for amplification, fragmentation and biotin-labeling. The labeled cDNA was hybridized to Human GeneChip Gene 2.0 ST microarrays . The signal intensity fluorescent images produced during Affymetrix GeneChip hybridizations were read using the Affymetrix Model 3000 Scanner and converted into GeneChip probe results files (CEL) using Command and Expression Console software (Affymetrix). The analysis of the microarray data was done by first normalizing for array-specific effects by Affymetrix's \u201cRobust Multi-Array\u201d (RMA) normalization. The normalized arrays values were then reported on a log2 scale. For statistical analyses, all array probesets where no experimental groups had an average log2 intensity greater than 3.0 were removed. This is a standard cutoff as below which expression is indistinguishable from background noise. Linear models were then fitted for each gene using the Bioconductor limma package in R . Moderat"}
+{"text": "Rare cases of invasive meningococcal disease caused by cnl isolates belonging to sequence types (ST) and clonal complexes (cc) ST-845 (cc845), ST-198 (cc198), ST-192 (cc192) and ST-53 (cc53) have been documented. The clinical significance of these isolates however remains unclear. We identified four invasive cnl meningococci through laboratory-based surveillance in South Africa from 2003 through 2013, which we aimed to characterize using whole genome data.The meningococcal capsule is an important virulence determinant. Unencapsulated meningococci lacking capsule biosynthesis genes and containing the capsule null locus  and contained cnl allele 2. One patient was an adolescent male with meningitis. The remaining two isolates were from recurrent disease episodes (8 months apart) in a male child with deficiency of the sixth complement component, and with the exception of two single nucleotide polymorphisms, contained identical core genomes. The ST-53 (cc53) isolate possessed alleles for NHBA peptide 191 and fHbp variant 2; whilst the ST-192 (cc192) isolates contained NHBA peptide 704 and fHbp variant 3. All four isolates lacked nadA. Comparison of the South African genomes to 61 additional cnl genomes on the PubMLST Neisseria database (http://pubmlst.org/neisseria/), determined that most putative virulence genes could be found in both invasive and carriage phenotypes.One isolate  contained cnl meningococci may be associated with host immunodeficiency and such patients may benefit from protein-based meningococcal vaccines.Although rare, invasive disease by The online version of this article (doi:10.1186/s12866-017-0942-5) contains supplementary material, which is available to authorized users. Neisseria meningitidis (meningococcus) is a commensal of the human upper respiratory tract, which occasionally causes meningitis and sepsis, particularly in infants and young adults. Meningococci may express one of twelve antigenically distinct capsules, however, invasive disease is mostly caused by serogroups A, B, C, W, X or Y. The polysaccharide capsule is an important virulence determinant and aids in evading the host immune response   and Burkina Faso isolates .The Wizard\u00ae Genomic DNA Purification Kit  was used to extract DNA from suspensions prepared from overnight cultures, according to manufacturer instructions. DNA was quantified using the Qubit\u00ae 2.0 fluorometer  and Qubit\u00ae dsDNA BR assay kit. Library preparation was performed using the Nextera XT DNA Library Prep Kit , and sequenced using the Illumina platform. The reads were ft level , 40. Thed 41961] . Sequenccnl allele (PubMLST Neisseria database locus identifier: NEIS2743)   \u201349. The me v1.0] . The degNeisseria database at the time of analysis (22 December 2016). A mutually exclusive gene or allele was defined as being present in all isolates in one group (carriage or invasive) and absent in the other.The Genome Comparator tool was used to examine 117 previously defined putative virulence loci, in 51 carriage and 14 invasive capsule null isolates with known epidemiology  was used as an encapsulated control. NCDC A7515, a N. lactamica strain (ATCC-23970\u2122) was used as an unencapsulated control.The South African isolates were visualized using a previously described TEM method that was adapted for Gram-negative bacteria by substituting ruthenium red with a 0.5% alcian blue pyridine variant (pH 7.2) . Ultrath"}
+{"text": "Loss of the pro-apoptotic Bcl-2 family protein Bax occurs in ~50%of hereditary nonpolyposis colorectal cancer (HNPCC) due to microsatelliteinstability (MSI). Recently, we found that some of the\u201cBax-negative\u201d MSI tumor cells contain a functional Bax isoform,Bax\u03942, which sensitizes cells to selective chemotherapeutics. Here weshow the detection of Bax microsatellite mutations and expression ofBax\u03942 proteins in human buccal cells. Our study provides a sensitive andnon-invasive approach and a potential clinical application in diagnosis andtreatment of MSI colon cancer patients. Over 90% of hereditary nonpolyposis colorectal cancer  patients have high microsatellite instability (MSI-H) ,2. As HNHuman buccal cells were collected through mouth-wash and all experiments wereperformed with Institutional Review Board (IRB) approval. Cells were collected fromtwo control-individuals with no cancer history (denoted Control-1 and Control-2) andanother two individuals from a family with HNPCC history (Patient-1 and Patient-2).Genomic DNA was isolated from their buccal cells and Bax microsatellite status wasdetermined by PCR with Bax specific primers and sequenced as described previously. The repTo analyze whether Bax  cells express Bax\u03942 protein, freshlyisolated buccal cells from both control and patient samples were washed and spunonto glass slides by Cytospin centrifugation. The cell morphology was visualized byCrystal Violet staining ("}
+{"text": "Semen Cassiae has potent anti-inflammatory activities. The aim of our study was to investigate whether Semen Cassiae plays a protective effect on lipopolysaccharide (LPS)-induced ALI and, if so, to elucidate its potential mechanism.Acute lung injury (ALI) is an inflammatory disorder. Semen Cassiae or vehicle 3\u00a0h after LPS challenge. Samples were harvested 24\u00a0h post-LPS administration. We also investigated the effects of Semen Cassiae on LPS stimulation in RAW 264.7 cells.Male Sprague\u2013Dawley rat lungs were injured by intratracheal instillation of LPS. Rats were treated with Semen Cassiae treated group. Moreover, Semen Cassiae markedly reduced pulmonary interleukin (IL)-6, tumor necrosis factor (TNF)-\u03b1, and 8-hydroxy-2\u2032-deoxyguanosine (8-OHdG) levels. The pulmonary soluble epoxide hydrolase (sEH) activity and the DNA binding activity of Nuclear factor (NF)-\u03baB were significantly inhibited in Semen Cassiae treated group. Furthermore, Semen Cassiae treatment significantly increased epoxyeicosatrienoic acids (EETs), and heme oxygenase-1 (HO-1) activity. Our in vitro study demonstrates that Semen Cassiae treatment may inhibit LPS induced I\u03baB\u03b1 phosphorylation and NF-\u03baB p65 nucleus translocation.LPS administration markedly induced pulmonary edema and polymorphonuclear neutrophil influxes. These changes were significantly attenuated in Semen Cassiae protects LPS-induced ALI in rats. Semen Cassiae can be developed as a novel treatment for ALI.The online version of this article (doi:10.1186/s12906-017-1747-7) contains supplementary material, which is available to authorized users. Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is severe disorder of lungs with high mortality , 2. The A recent study showed that soluble epoxide hydrolase (sEH) plays a prevailing role in the pathogenesis of acute lung injury (ALI) . sEH conHeme oxygenase (HO)-1, a rate-limiting enzyme in oxidative degradation of heme to biliverdin, plays an important effect in maintaining oxidative/antioxidant homeostasis . ElevatiSemen Cassiae, the seeds of Cassia tora, contains multiple active ingredients such as anthraquinone compounds, cassiaside, and sitosterol. Semen Cassiae is a traditional Chinese medicine that has been demonstrated with anti-inflammatory and antioxidant features . It has been reported that NF-\u03baB activity is increased in patients with ARDS , 21. In findings . The NF-Semen Cassiae protects LPS-induced ALI in rats. Semen Cassiae can be developed as a novel treatment for ALI."}
+{"text": "Sesarma reticulatum) grazing driven low marsh die-off. Geospatial analyses reveal that crab-driven die-off has led to an order of magnitude more marsh loss than sea-level rise between 2005 and 2013. However, field transplant experimental results suggest that sea-level rise will facilitate crab expansion into higher elevation marsh platforms by inundating and gradually softening now-tough high marsh peat, exposing large areas to crab-driven die-off. Taking interactive effects of marsh softening and concomitant overgrazing into account, we estimate that even modest levels of sea-level rise will lead to levels of salt marsh habitat loss that are 3x greater than the additive effects of sea-level rise and crab-driven die-off would predict. These findings highlight the importance of multiple stressor studies in enhancing mechanistic understanding of ecosystem vulnerabilities to future stress scenarios and encourage managers to focus on ameliorating local stressors to break detrimental synergisms, reduce future ecosystem loss, and enhance ecosystem resilience to global change.Climate change and other anthropogenic stressors are converging on coastal ecosystems worldwide. Understanding how these stressors interact to affect ecosystem structure and function has immediate implications for coastal planning, however few studies quantify stressor interactions. We examined past and potential future interactions between two leading stressors on New England salt marshes: sea-level rise and marsh crab ( Multiple anthropogenic stressors increasingly affect ecological systems at the population, community, and ecosystem level 2]. As e. As e2].Sesarma reticulatum) grazing-driven low marsh die-off  14].[14].13][.[14].13]tressor) . Sea levtressor) , althougtressor) .Spartina alterniflora, migrates to higher marsh elevations, displacing the high marsh dominant, Spartina patens (hereafter marsh hay) 23][[23][Spar[[23][Sparsh hay) . This sprsh hay) . A similrsh hay)  and incrrsh hay) 27]. At . At Sparrsh hay) . SLAMM mrsh hay) ; howeverS. reticulatum, from top-down control in New England salt marshes, leading to widespread consumption of low marsh cordgrass . Loc. Loc44]."}
+{"text": "Lelliottia nimipressuralis type strain SGAir0187 was isolated from tropical air samples collected in Singapore. The genome was assembled with an average coverage of 180-fold using Pacific Biosciences long reads and Illumina MiSeq paired-end reads. The genome measures 4.8\u2009Mb and contains 4,424 protein-coding genes, 83 tRNAs, and 25 rRNAs. Lelliottia genus includes environmental gammaproteobacteria, reclassified from the genus Enterobacter  and Reasoner\u2019s 2A (R2A) agar. Samples were grown and maintained on Trypticase soy agar (TSA)  at room temperature and in Luria-Bertani (LB) broth overnight until they were axenic. DNA was then extracted using the Wizard genomic DNA purification kit (Promega) following the manufacturer\u2019s instructions. The whole-genome shotgun library was then prepared for sequencing on a PacBio RS II instrument using the SMRTbell template prep kit version 1.0 and loaded onto a single-molecule real-time (SMRT) cell (Pacific Biosciences). Additional libraries were constructed using the TruSeq Nano DNA library preparation kit (Illumina) and used to generate 300-bp paired-end reads via the Illumina MiSeq platform.L. nimipressuralis.A total of 80,945 PacBio subreads were assembled using the PacBio SMRT Analysis version 2.3.0 package\u2019s Hierarchical Genome Assembly Process version 3 (HGAP3) , 8 noncoding RNAs (ncRNAs), and 122 pseudogenes. Results from functional analysis showed 647 genes involved in carbohydrate metabolism and 483 genes involved in metabolism of aromatic amino acids and derivatives. Six adhesion genes were predicted as mediators for the hyperadherence yidE gene, 85 genes were found to be potentially involved in resistance to antibiotic and toxic compounds, and 14 genes were found to be involved in invasion and intercellular resistance. These genes could aid the ability of L. nimipressuralis to colonize a plant host (Genome annotation was performed using NCBI\u2019s Prokaryotic Genome Annotation Pipeline version 4.3 , and fur7\u2013ant host .Enterobacter, and ANI resulted in 95.92% identity with Lelliottia nimipressuralis with 0.63 confidence.Isolate SGAir0187 was subjected to taxon assignment methods using Phyla-AMPHORA  for genoLelliottia nimipressuralis type strain SGAir0187 was submitted to DDBJ/EMBL/GenBank under the accession number CP025034.The genome sequence of"}
+{"text": "Both American and European guidelines for the management of hypertrophic cardiomyopathy (HCM) advise that HCM be considered when LV end-diastolic wall thickness (EDWT) \u226515 mm in \u22651 myocardial segment. Hypertensive heart disease (HHD) is a common cause of left ventricular hypertrophy (LVH). Distinguishing between HHD and HCM is a frequent clinical conundrum. We aimed to identify predictors of HHD versus HCM with EDWT \u226515 mm, using multi-parametric cardiac magnetic resonance (CMR) including pixel-wise myocardial segmental EDWT analysis.HCM with EDWT \u226515 mm were identified from 2481 consecutive clinical CMRs between 2014-15. Those without a diagnosis of HCM (n=2428), with concomitant hypertension (n=21), apical HCM only (n=2) and severe renal impairment (n=1) were excluded. Analysis of 464 myocardial segments from 29 HCM subjects was performed.HHD with EDWT \u226515 mm were identified from a separate prospectively maintained tertiary hypertension clinic database of 150 consecutive referrals. Hypertensive subjects with EDWT \u226415 mm (n=102), concomitant cardiac pathology (n= 17) and CMR contraindications (n=4) were excluded. Analysis of 432 segments from 27 HHD subjects were performed.EDWT was measured by pixel-wise analysis. Segmental distribution of EDWT \u226515 mm, mean segmental thickness, segmental distribution of late gadolinium enhancement (LGE) were recorded. EDWT asymmetry, defined as >1.5-fold the opposing segment, was documented. The prevalence of other potential discriminators including systolic anterior motion of the mitral valve (SAM) and aorto-septal angulation (AoSA) were measured.Unpaired T tests and multivariate logistic regression analysis was performed. Significance was set at two-tailed p < 0.05.HHD and HCM cohorts were matched in age  and gender . HHD had significantly increased indexed LV mass  and mass : volume ratio  compared to HCM but no significant difference in indexed LV volumes. There were no significant differences in the anatomical site or magnitude of maximal EDWT between HHD and HCM Figure . The preThere is a significant morphological overlap (location and magnitude of hypertrophy) between HHD and HCM. Both conventional EDWT \u226515 mm cut-off and LV asymmetry are poor discriminators. Elevated indexed LVM, absence of SAM and absence of midwall LGE are significant predictors of HHD. Tissue characterisation with LGE is unique to CMR and our findings support its extended use in cases of suspected HCM, particularly where there is concomitant hypertension."}
+{"text": "Vibrio cholerae O1 and occasionally O139. A growing body of evidence indicates that immune responses targeting the O-specific polysaccharide (OSP) of V. cholerae are involved in mediating protection against cholera. We therefore assessed whether antibody responses against OSP occur after vaccination with live attenuated oral cholera vaccine CVD 103-HgR, and whether such responses correlate with protection against cholera.Cholera is an acute voluminous dehydrating diarrheal disease caused by toxigenic strains of 8 colony-forming units (CFU) of oral cholera vaccine CVD 103-HgR and then orally challenged with approximately 1 \u00d7 105 CFU of wild-type V. cholerae O1 El Tor Inaba strain N16961, either 10 or 90 days post-vaccination.We assessed adult North American volunteers (n = 46) who were vaccinated with 5 \u00d7 10P = 0.002; r = \u22120.36, P = 0.01; respectively), and none of 27 vaccinees who developed a \u22651.5 fold increase in any antibody isotype targeting OSP on day 10 following vaccination compared to baseline developed moderate or severe cholera following experimental challenge, while 5 of 19 who did not develop such anti-OSP responses did (P = 0.01).Vaccination was associated with induction of significant serum IgM and IgA anti-OSP and vibriocidal antibody responses within 10 days of vaccination. There was significant correlation between anti-OSP and vibriocidal antibody responses. IgM and IgA anti-OSP responses on day 10 following vaccination were associated with lower post-challenge stool volume  of V. cholerae lipopolysaccharide (LPS). Despite this, no previous work has directly assessed correlation of OSP-immune responses and protection against cholera. In this study, we assessed adult North American volunteer\u2019s antibody responses targeting OSP after vaccination with live attenuated oral cholera vaccine CVD 103-HgR, and we assessed correlation of protection against cholera with such antibody responses. Oral vaccination was associated with the induction of significant IgM and IgA responses against OSP, and these responses correlated with vibriocidal responses. There was significant negative correlation of OSP responses and post-challenge stool volume, and none of the volunteers who developed an anti-OSP antibody responses of any isotype of \u22651.5 fold developed moderate or severe cholera following experimental challenge. In summary, vaccination with live attenuated oral cholera vaccine CVD 103-HgR induces antibodies that target V. cholerae OSP, and these responses highly correlate with protection against cholera.Cholera is a severe watery diarrheal disease, caused by pathogenic strains of  Vibrio cholerae can be characterized into over 200 serogroups [V. cholerae serogroups O1 and O139 are the causes of epidemic cholera, a severe dehydrating illness of humans [V. cholerae O1 and O139 are noninvasive intestinal pathogens that express cholera toxin within the intestine of infected humans. Cholera toxin (CT) is an ADP-ribosylating protein that binds to intestinal epithelial cells, resulting in increased intracellular cAMP, and subsequent chloride, sodium, and water excretion by intestinal epithelial cells, resulting in the secretory diarrhea characteristic of cholera [V. cholerae O1 are Ogawa and Inaba and serospecificity is mediated by the O-specific polysaccharide (OSP) component of lipopolysaccharide (LPS) [V. cholerae OSP, suggesting that OSP is the prime antigenic target assessed by the vibriocidal assay [rogroups . V. chol cholera . The mec cholera \u20137. Protede (LPS) , 8. Currde (LPS) . The vibal assay .V. cholerae O1 classical Inaba strain 569B [V. cholerae O1 organisms [V. cholerae O1 OSP occur after vaccination with CVD 103-HgR, and whether such responses to vaccination correlate with protection against cholera following subsequent experimental challenge with wild type V. cholerae O1 organisms.A live attenuated oral cholera vaccine, CVD 103-HgR  was recently FDA-approved in the United States. CVD 103-HgR is an engineered attenuated derivative of rganisms . We werehttp://clinicaltrials.gov/show/NCT01895855) that was approved by the Institutional Review Boards of the University of Maryland, Baltimore; Cincinnati Children\u2019s Hospital Medical Center, Ohio; and University of Vermont Burlington, Vermont. Written informed consent was obtained from participating healthy adults 18\u201345 years of age.This study involved analysis of anonymized samples from a previously reported clinical trial; this current use was approved by the Partners-Massachusetts General Hospital Institutional Review Board, Boston, Massachusetts. The serum samples were collected in a previously reported clinical trial (8 colony-forming units (CFU) of CVD 103-HgR, and then orally challenged on either day 10 (n = 26) or day 90 (n = 20) with 1 \u00d7 105 CFU of wild type V. cholerae O1 El Tor Inaba N16961, as previously described [The clinical study during which samples were collected has been previously described . We limiFor analyses using diarrhea following challenge as an efficacy endpoint, diarrhea was defined as the passage of \u22652 loose stools (grade 3\u20135) over a 48-hour period \u2265200 mL on volume or a single loose stool \u2265300 mL, as previously described . ModeratV. cholerae OSP purified from PIC018  and PIC158 (Ogawa El Tor), as previously described [Stored serum specimens were tested to measure IgM, IgA and IgG immune responses against escribed , 13, 14.2O2 (Sigma), and determined the optical density at 405 nm with a Vmax microplate kinetic reader . Plates were read for 5 min at 30s intervals, and the maximum slope for an optical density change of 0.2U was reported as millioptical density units per minute (mOD/min). We normalized ELISA units (EU) by calculating the ratio of the optical density of the test sample to that of a standard of convalescent-phase pooled sera (prepared from previously infected cholera patients) included on each plate.We measured OSP-specific IgM, IgA and IgG responses in stored serum using standard enzyme-linked immunosorbent assay (ELISA) protocols, as described previously , 16. In P values were two-tailed, with a value of \u22640.05 considered the threshold for statistical significance. We performed analyses using GraphPad Prism, version 5.01 .We analyzed differences in immune responses between groups using Mann-Whitney U tests. We used Fisher\u2019s exact tests to assess differences by responder frequency. We used Spearman\u2019s test to assess correlations of anti-OSP and vibriocidal antibody responses with cumulative diarrheal volume, as well as to assess correlations between immune responses. All Characteristics of study participants are described in V. cholerae O1 Inaba OSP within 7 days of oral vaccination with CVD 103-HgR, and these values remained elevated until at least day 28 following vaccination. The peak effect was seen at 10 days after vaccination. In the absence of wild type experimental challenge, anti-OSP Inaba IgM mean responses decreased to baseline by day 90 following vaccination. Elevated IgA anti-OSP Inaba mean increases were also present within 10 days following vaccination, and decreased to baseline by day 28. Anti-Ogawa IgM and IgA mean antibody increases were also induced following vaccination with CVD 103-HgR, although these responses were generally of lower magnitude and shorter duration than responses targeting Inaba OSP, consistent with the fact that CVD 103-HgR is an Inaba-based vaccine. Mean increases in anti-OSP IgG were not detected following vaccination.To assess anti-OSP responses following vaccination alone, we analyzed anti-OSP antibody responses in blood samples from both day 10 and day 90 challenge cohorts up to their respective days of challenge . We founWe found no significant boosting of IgM or IgA anti-OSP mean responses following challenge, when analyzing immune responses in the cohort of volunteers vaccinated with CVD 103-HgR challenged 10 days after vaccination . In compWe did not detect a difference in mean antibody responses targeting OSP following vaccination when considering cohorts by blood group O characterization .V. cholerae , for the purposes of assessing whether anti-OSP responses correlated with protection against cholera, we combined day 10 and day 90 challenge cohorts, and assessed outcome by post-vaccination day 10 immune responses. We found that IgM anti-OSP Inaba responses on day 10 following vaccination with CVD 103-HgR correlated with protection against moderate or severe diarrhea following subsequent experimental challenge  and IgA (P = 0.05)  . InteresV. cholerae O1 challenge and post-vaccination day 10 anti-Inaba OSP IgM responses  and anti-Inaba OSP IgA responses  , 5 of 22 , and 5 of 38 , who did not develop such anti-OSP responses did develop moderate or severe diarrhea. Fold increase of anti-OSP values was also associated with protection against all degrees of diarrhea  following wild type challenge. Six of 27 vaccinees who developed a \u22651.5 fold increase in any antibody isotype  targeting OSP on day 10 following vaccination compared to baseline developed mild diarrhea; none developed moderate or severe diarrhea following experimental challenge, while 11 of 19 who did not develop such anti-OSP responses did develop diarrhea  , but no P = 0.01) (P < 0.0001) (P = 0.03), and there was no correlation of IgG OSP responses and vibriocidal responses   Figs. Se 0.0001) . Serum Iesponses .V. cholerae O-specific polysaccharide (OSP), and that these responses correlate with protection against moderate or severe diarrhea following experimental challenge with wild type V. cholerae O1. Antibodies targeting OSP induced by vaccination with CVD 103-HgR were largely of the IgM and IgA isotypes. Since V. cholerae is a noninvasive mucosal pathogen of the human intestine, IgM and IgA immune responses would be predicted to be the most pertinent isotypes involved in mechanistically mediating protection against cholera, since both IgM and IgA are actively secreted into the intestinal lumen by intestinal epithelial cells [In this study, we found that recipients of live attenuated oral cholera vaccine CVD 103-HgR develop prominent immune responses targeting al cells \u201319.V. cholerae OSP is currently unknown, as is the duration of protection afforded by vaccination.Induction of IgA antibody is associated with oral and mucosal vaccination, especially in response to protein antigens that are antigenically processed by T cells , 21. OSPV. cholerae OSP highly correlated with vibriocidal responses in vaccine recipients. This would be expected, since we have previously shown that the vibriocidal response can largely be adsorbed away by V. cholerae OSP [V. cholerae. The vibriocidal assay assesses complement-dependent mediated bacterial cell lysis in an in vitro assay [V. cholerae OSP. Indeed, in our current analysis, we show that immune responses targeting V. cholerae OSP correlate with protection against experimental challenge with wild-type V. cholerae. This association was most clear when considering IgM responses targeting V. cholerae OSP, but also approached statistical significance (P = 0.06) when considering IgA responses targeting V. cholerae OSP. There was no association of mean IgG anti-OSP responses and protection against cholera. IgG is not actively transported into the intestinal lumen in appreciable quantities in the presence of an intact epithelium, and IgG responses would not be predicted to play a major role in mechanistically mediating protection against V. cholerae. The few vaccine recipients who did develop IgG responses targeting OSP in this study, also developed IgM and IgA anti-OSP responses.In our study, IgM and, less so, IgA antibody responses targeting erae OSP . It is mro assay , 26. Bacro assay , 28. Mucro assay \u201329. Our V. cholerae OSP or vibriocidal responses when vaccine recipients were experimentally challenged with wild-type V. cholerae just 10 days after vaccination. We did, however, find significant boosting of anti-V. cholerae immune responses and vibriocidal responses following experimental challenge with wild-type V. cholerae when 90 days had elapsed since vaccination. A possible explanation for this observation is that mucosal immune responses 10 days following vaccination may have been so prominent that there was minimal if any immunological and antigenic processing of V. cholerae by host immune cells; specifically, that intestinal IgM and IgA anti-OSP antibody levels may have been so prominent within 10 days of vaccination and bound with such high avidity to intra-luminal wild-type V. cholerae organisms that not only was clinical protection present, but V. cholerae organisms were also not presented to human immune cells in Peyer\u2019s patches or regional lymph nodes at an appreciable level. However, when experimental challenge was delayed for 90 days after vaccination, we did indeed find boosting of IgM and IgA responses targeting OSP, and new development of IgG responses targeting V. cholerae OSP. These observations might suggest that mucosal immune responses were then less prominent at this 90 day mark, and that this decrease allowed additional immunological processing and handling of V. cholerae organisms. Such a scenario could result in the observed rapid boosting of the IgM and IgA anti-OSP responses following the 90 day challenge to values that were actually higher than following primary immunization. This de facto boosting also appears to have led to isotype switching of the antibody response with development of IgG isotype antibodies targeting OSP. Whether there was antibody maturation and increased affinity afforded by this boosting was not assessed in this study. These observations agree with a prior analysis performed in North American volunteers who received a previous version of CVD 103-HgR and were then challenged with wild type V. cholerae O1 either 7, 30, or 180 days after vaccination [Interestingly, we found no boosting of immune responses targeting cholera gravis [V. cholerae OSP by A/B/O blood group. As such, CVD 103-HgR appears to be equivalently immunogenic with regard both to V. cholerae OSP as well as vibriocidal responses irrelevant of this major blood group category. These data suggest that the association of blood group and severity may not be directly due to differences in the ability to mount anti-OSP antibody responses.Although the mechanism has not been clearly elucidated, humans with blood group O are at increased risk of severe cholera, especially in its severest form: a gravis , 32. In V. cholerae Ogawa OSP, as well as Inaba OSP. V. cholerae can be classified into over 200 serogroups with V. cholerae O1 and O139 being able to cause epidemic cholera. V. cholerae O1 itself can be classified into a number of serotypes including Inaba and Ogawa, with the difference being the presence of a 2-O-methyl group in the non-reducing terminal sugar of the Ogawa OSP, which is absent from Inaba OSP [V. cholerae O1 Inaba provide more protection against Ogawa than previous Ogawa infection provides against Inaba [V. cholerae O1 serotype organism. We found that vaccination with CVD 103-HgR induced immune responses against both Inaba and Ogawa V. cholerae OSP, with responses being most prominent to the Inaba serotype. Our data suggest that CVD 103-HgR would provide protection against both Inaba and Ogawa serotype O1 organisms.We also assessed the ability of CVD 103-HgR to induce anti-OSP responses against naba OSP . Anti-Inst Inaba , 33, 34.V. cholerae OSP, nor did we assess antibody affinity or avidity. We also did not assess duration of immune responses via long-lived plasma cells or memory B cell responses targeting V. cholerae OSP. This volunteer study also did not include children, who may respond differently to vaccination with CVD 103-HgR, especially to T cell-independent antigens such as OSP, although the induction of IgM responses to OSP as occurred in adults in this study would presumably still occur. Our study is only one of correlations, and is not able to assess the possible mechanism of protection that may be afforded by antibodies targeting V. cholerae OSP. Despite these limitations, our analysis shows that CVD 103-HgR induces immune responses targeting V. cholerae OSP; these responses are likely largely mucosal in nature; mucosal immune responses appear to be very high level soon after vaccination; and boosting of anti-OSP immune responses can occur following repetitive exposure to V. cholerae. We also found that blood group did not appear to affect the ability to mount an anti-OSP immune response, and that immune responses induced by CVD 103-HgR included antibodies targeting both Inaba and Ogawa serotype V. cholerae. Most importantly, we found that anti-OSP immune responses correlated with protection against diarrhea following wild-type experimental challenge, especially moderate or severe diarrhea. These data further support the growing body of evidence that immune responses targeting V. cholerae OSP may be a critical component of providing protection against cholera. Establishing the mechanism of this protection is warranted.Our study has a number of limitations. We did not directly assess induction of mucosal immune responses targeting S1 Table(PDF)Click here for additional data file.S2 Table(PDF)Click here for additional data file.S1 FigV. cholerae O1 Inaba and Ogawa OSP 10 days after oral vaccination with CVD 103-HgR by O blood group status of vaccine recipient. X axis indicates the time points of samples while Y-axis denotes OSP specific antibody responses. Each single dot indicates an individual OSP antibody value, horizontal bars indicate the geometric mean (GM), and error bars indicate 95% confidence intervals. Responders were defined as having an increase in kinetic ELISA units \u2265 1.5-fold on day 10 post-vaccination compared with day 0 pre-vaccination.Serum IgM, IgA and IgG antibody responses targeting (PDF)Click here for additional data file.S2 FigV. cholerae O1 Inaba and Ogawa OSP 10 days after oral vaccination with CVD 103-HgR and subsequent development of mild (<3L), moderate (\u22653L) or severe (\u22655L) diarrhea versus no diarrhea following wild type V. cholerae O1 Inaba experimental infection 10 or 90 days after vaccination. X axis indicates the time points of samples while Y-axis denotes OSP specific antibody responses. Each single dot indicates an individual OSP antibody value, horizontal bars indicate the geometric mean (GM), and error bars indicate 95% confidence intervals. Responders were defined as having an increase in kinetic ELISA units \u2265 1.5-fold on day 10 post-vaccination compared with day 0 pre-vaccination. Ina indicates Inaba and Oga indicates Ogawa.Serum IgM, IgA and IgG antibody responses targeting (PDF)Click here for additional data file.S3 FigV. cholerae O1 Inaba and Ogawa OSP 10 days after oral vaccination with CVD 103-HgR and subsequent development of moderate (\u22653 \u2212 <5L) or severe (\u22655L) diarrhea versus no or mild (<3L) diarrhea following wild type V. cholerae O1 Inaba experimental infection 10 or 90 days after vaccination. X axis indicates the time points of samples while Y-axis denotes OSP-specific antibody responses. Each single dot indicates an individual OSP antibody value, horizontal bars indicate the geometric mean (GM), and error bars indicate 95% confidence intervals. Responders were defined as having an increase in kinetic ELISA units \u2265 1.5-fold on day 10 post-vaccination compared with day 0 pre-vaccination. Ina indicates Inaba and Oga indicates Ogawa.Serum IgM, IgA and IgG antibody responses targeting (PDF)Click here for additional data file.S4 FigV. cholerae challenge. Day 0 is pre-vaccination. In total, 46 vaccinees are included until day 10, then 20 vaccinees until day 90. Each single dot indicates an individual vibriocidal antibody titer, horizontal bars indicate the geometric mean (GM) and error bars indicate 95% confidence intervals (CI). P values represent significant differences of the mean between groups. Asterisks denote significance between responder and non-responder frequency at every time point with baseline (*** P < 0.0001). Responders were defined as having a \u22654-fold increase in vibriocidal titer compared to the baseline (day 0).Figure only contains results for samples collected prior to wild type experimental (PDF)Click here for additional data file.S5 FigEach single dot represents an individual vibriocidal antibody titer, horizontal bars represent the geometric mean (GM) and error bars represent 95% confidence intervals (CI). Responders were defined as having a \u2265 4-fold increase in vibriocidal value on day 10 post-vaccination compared with day 0 pre-vaccination.(PDF)Click here for additional data file.S6 FigV. cholerae O1 Inaba and Ogawa at different time points post-vaccination in recipients (N = 26) of oral cholera vaccine CVD 103-HgR who were then experimentally challenged with wild type V. cholerae O1 Inaba N16961 10 days after vaccination. Day 0 is pre-vaccination. Other dates are timed from vaccination. Each single dot denotes an individual vibriocidal antibody titer, horizontal bars denote the geometric mean (GM) and error bars denote 95% confidence intervals (CI). P values represent significant differences of the mean between groups. Asterisks denote significance between responder and non-responder frequency of every time point compared with baseline (*** P < 0.0001). Responders were defined as having a \u22654-fold increase in vibriocidal titer compared to the baseline (day 0).Serum vibriocidal antibody responses to (PDF)Click here for additional data file.S7 FigV. cholerae O1 Inaba and Ogawa at different time points post-vaccination in recipients (N = 20) of oral cholera vaccine CVD 103-HgR who were then experimentally challenged with wild type V. cholerae O1 Inaba N16961 90 days after vaccination. Day 0 is pre-vaccination. Other dates are timed from vaccination. Each single dot represents an individual vibriocidal antibody titer, horizontal bars represent the geometric mean (GM) and error bars represent 95% confidence intervals (CI). P values represent significant differences of the mean between groups. Asterisks denote significance between responder and non-responder frequency of every time point compared with baseline (*** P < 0.0001 and ** P < 0.01). Responders were defined as having a \u22654-fold increase in vibriocidal titer compared to the baseline (day 0).Serum vibriocidal antibody responses to (PDF)Click here for additional data file.S8 FigV. cholerae O1 Inaba and Ogawa 10 days post-vaccination and subsequent development of moderate (\u22653L) or severe (\u22655L) diarrhea versus no diarrhea following wild type V. cholerae O1 Inaba experimental infection 10 or 90 days after vaccination. Each single dot indicates an individual vibriocidal antibody titer, horizontal bars indicate the geometric mean (GM) and error bars indicate 95% confidence intervals (CI). Responders were defined as having \u22654-fold increase in vibriocidal value (day 10 post-vaccination compared to day 0 pre-vaccination). Asterisks denote significant difference (** P < 0.01) of responder frequency between no diarrhea versus moderate/severe diarrhea group in Fisher\u2019s exact test.Serum vibriocidal antibody responses to (PDF)Click here for additional data file.S9 FigV. cholerae O1 Inaba and Ogawa 10 days post-vaccination and subsequent development of mild (<3L), moderate (\u22653 \u2212 <5L) or severe (\u22655L) diarrhea versus no diarrhea following wild type V. cholerae O1 Inaba experimental infection 10 or 90 days after vaccination. Each single dot denotes an individual vibriocidal antibody titer, horizontal bars denote the geometric mean (GM) and error bars denote 95% confidence intervals (CI). Responders were defined as having \u22654-fold increase in vibriocidal value (day 10 post-vaccination compared to day 0 pre-vaccination). Asterisks denote significant difference  of responder frequency between no diarrhea versus mild/moderate/severe diarrhea group in Fisher\u2019s exact test.Serum vibriocidal antibody responses to (PDF)Click here for additional data file.S10 FigV. cholerae O1 Inaba and Ogawa 10 days post-vaccination and subsequent development of mild (<3 L), moderate (\u22653L) or severe (\u22655L) diarrhea versus no diarrhea following wild type V. cholerae O1 Inaba experimental infection 10 or 90 days after vaccination. Each single dot represents an individual vibriocidal antibody titer, horizontal bars represent the geometric mean (GM) and error bars represent 95% confidence intervals (CI). Responders were defined as having \u22654-fold increase in vibriocidal value (day 10 post-vaccination compared to day 0 pre-vaccination). Asterisks indicates significant difference (** P < 0.01) of responder frequency between no/mild diarrhea versus moderate/severe diarrhea group in Fisher\u2019s exact test.Serum vibriocidal antibody responses to (PDF)Click here for additional data file.S11 FigDashed horizontal lines mark moderate (3L) or severe (5L) diarrheal and dashed vertical line denotes 4-fold vibriocidal change value (day 10 post vaccination compared to day 0 pre-vaccination).(PDF)Click here for additional data file.S12 FigDashed horizontal lines mark moderate (3L) or severe (5L) diarrheal and dashed vertical line denotes 4-fold vibriocidal change value (day 10 post vaccination compared to day 0 pre-vaccination).(PDF)Click here for additional data file.S13 Fig(PDF)Click here for additional data file."}
+{"text": "To establish if using intensive treatment to reduce synovitis and attain remission in active rheumatoid arthritis (RA) improves all aspects of health-related quality of life (HRQoL).A secondary analysis of two randomised clinical trials (CARDERA and TACIT) was undertaken. CARDERA randomised 467 patients with early active RA to different disease-modifying antirheumatic drug (DMARD) regimens, including high-dose tapering corticosteroids. TACIT randomised 205 established patients with active RA to combination DMARDs (cDMARDs) or tumour necrosis factor-\u03b1 inhibitors (TNFis). Short-Form 36 (SF-36) measured HRQoL across eight domains, generating physical (PCS) and mental (MCS) component summary scores. Linear regression evaluated 6-month intensive treatment impacts. Mean SF-36 scores, stratified by end point disease activity category, were compared with age/gender-matched population scores.In CARDERA, intensive corticosteroid treatment gave significantly greater improvements in PCS but not MCS scores relative to placebo. In TACIT, all eight SF-36 domains had improvements from baseline exceeding minimal clinically important differences with cDMARDs and TNFis. Significantly greater improvements with TNFi relative to cDMARDs were reported in PCS only (p=0.034), after adjusting for covariates. Remission provided the best SF-36 profiles, but scores in physical functioning, role physical and general health in both trials remained below normative values. Patient global assessment of disease activity had a greater association with HRQoL than other disease activity score (DAS28) components.Intensive corticosteroid treatment in early RA improves physical but not mental health, relative to placebo. In established RA, cDMARDs and TNFi provide similar improvements in HRQoL. As remission optimises but fails to normalise HRQoL, a focus on treatment strategies targeting HRQoL is required.ISRCTN 32484878. TACIT was registered as ISRCTN 37438295; pre-results.CARDERA was registered as  An important treatment goal in rheumatoid arthritis (RA) is optimising health-related quality of life (HRQoL).It is uncertain if intensive treatment and remission improve all aspects of HRQoL, with previous placebo-controlled trials of tumour necrosis factor-\u03b1 inhibitors (TNFis) combined with methotrexate suggesting greater benefits on physical than mental health.This secondary analysis of two randomised clinical trials shows that in early active RA, intensive corticosteroid therapy improves physical but not mental HRQoL relative to placebo, and in established active RA, intensive treatment with combination disease-modifying antirheumatic drugs and TNFis has similar impacts on HRQoL.It also demonstrates that in patients with previously active RA, attaining remission substantially improves, but fails to normalise, HRQoL , and that the patient global assessment (PtGA) of disease activity has a strong association with HRQoL.In order to optimise HRQoL in RA, it may be helpful to place an increased focus on improving PtGA scores; additional treatments based on reducing pain, fatigue and improving mood, which are likely to improve PtGA scores, may be of benefit in HRQoL.Treating rheumatoid arthritis (RA) with disease-modifying antirheumatic drugs (DMARDs), biologics and corticosteroids is primarily intended to reduce synovitis. Efficacy is assessed by improving composite measures such as European League Against Rheumatism (EULAR) response criteria,3HRQoL is a broad, multidimensional concept spanning physical and mental health, function, social support and socioeconomic status.Our goal was to establish if using intensive treatment to reduce synovitis and attain remission improves all aspects of HRQoL. We undertook secondary analyses of two randomised clinical trials of intensive treatment in patients with early and established active RA. HRQoL was captured using the Short-Form 36 (SF-36). We had three aims: (1) establishing how intensive treatment with high-dose tapering corticosteroids, TNFi and combination DMARDs (cDMARDs) affects SF-36 domains; (2) evaluating the impact of remission and other disease activity score (DAS28)-defined disease activity categories on SF-36 domains and (3) evaluating which DAS28 components have the strongest associations with HRQoL.We studied patients in the Combination Anti-Rheumatic Drugs in Early RA (CARDERA) and TNFi versus combination intensive therapy with conventional DMARDs in established RA (TACIT) trials; their primary results have been reported.10CARDERA recruited 467 patients with active early RA (<2\u2005years duration) from 42 English centres. Patients were randomised to receive methotrexate alongside high-dose rapidly reducing corticosteroids,TACIT recruited 205 patients with active established RA (>1\u2005year duration) from 24 English centres. Patients were randomised to receive (a) TNFi , with a TNFi switch after 6\u2005months if DAS28(ESR) reduction was <1.2; (b) intensive cDMARDs, with TNFi initiated after 6\u2005months if DAS28(ESR) reduction was <1.2. Patients were assessed 6-monthly for 12\u2005months.SF-36 evaluated HRQoL in both trials. It measures HRQoL across eight domains: physical functioning (PF)\u2014ability to perform physical activities; role physical (RP)\u2014interference with work and other daily activities; bodily pain (BP); general health (GH)\u2014how individuals evaluate their health; vitality (VT)\u2014fatigue, pep and energy; social functioning (SF)\u2014interference with social activities; role emotional (RE)\u2014interference with work/daily activities due to emotional problems; general mental health (MH)\u2014nervousness and depression.14SF-36 scores were converted into the Short-Form 6D (SF-6D), a health utility measure ranging from 0.290  to 1.000 , using the Ara and Brazier algorithm.17We evaluated treatment effects on HRQoL over the first 6\u2005months in CARDERA and TACIT for two reasons. First, the COBRA corticosteroid regimen in CARDERA The impact of remission and DAS28 components on HRQoL was assessed at study end points  when remission rates were greatest.Treatment effects were evaluated using linear regression models including the 6-month changes in each SF-36 domain and summary score as the response variable. An unadjusted model included treatment  as the explanatory variable. An adjusted model included treatment, baseline SF-36 domain/summary score, age, sex and disease duration as explanatory variables.Mean SF-36 domain scores at the final time point in CARDERA and TACIT were plotted on spydergrams stratified by (a) DAS28(ESR) activity category: remission (DAS28(ESR) <2.6), low disease activity , moderate disease activity , high disease activity  and (b) remission versus non-remission according to each DAS28 component: tender joint count (TJC) \u22641, swollen joint count (SJC) \u22641, patient global assessment (PtGA) of disease activity on a 100\u2005mm visual analogue scale \u226410, erythrocyte sedimentation rate (ESR) \u226420\u2005mm/hour. These component cut-offs represent the preliminary American College of Rheumatology (ACR)/EULAR Boolean-based definition of RA remission for clinical trials.To minimise type I error from multiple testing , associations between DAS28(ESR) components and PCS and MCS were tested. Linear regression models used final time point PCS and MCS scores as response variables, and SJC, TJC, ESR and PtGA as explanatory variables, adjusted for covariates . Model 1 tested each DAS28(ESR) component separately. Model 2 included all DAS28(ESR) components as explanatory variables. To ensure multicollinearity between DAS28(ESR) components was not an issue in model 2, variance inflation factors (VIFs) were calculated for each predictor; VIF was <2 for all explanatory variables.In CARDERA, missing data had been imputed at all time points using last observation carried forward (LOCF) analysis.10.1136/rmdopen-2016-000270.supp1Supplementary tablesAge-matched and gender-matched US normative scores (A/G norms) were generated for CARDERA and TACIT protocol populations using data published in SF-36 manuals and updates.22Analyses were performed in R (V.3.1.3).CARDERA (ISRCTN 32484878 and Research Ethics Committee (REC) reference: MREC (1) 99/04) and TACIT (ISRCTN 37438295 and REC reference: MREC Ref 07/Q0505/57) were approved by research ethics committees. All patients provided informed written consent.In both trials, most patients were female, with a mean age in the sixth decade . As expeWithin-trial comparisons of baseline patient characteristics between treatment arms showed patients were well matched . SignifiIn CARDERA, 6-month increases in mean scores exceeding MCID were reported in all eight SF-36 domains with active and placebo corticosteroids, with the exception of GH in the placebo arm . Active In TACIT, 6-month increases in mean scores exceeding MCID were reported in all eight SF-36 domains with cDMARDs and TNFi . A totalIn both trials, increases in all SF-36 domains were observed with reducing DAS28(ESR) disease activity categories  and 3. RIn CARDERA , patientIn TACIT , patientIn both CARDERA and TACIT, PtGA-defined remission resulted in the highest mean domain scores and ESR-defined remission resulted in the lowest mean domain scores, compared with remission defined by other DAS28(ESR) components  and 3.In CARDERA, all four DAS28(ESR) components had significant associations with PCS and MCS scores at 24\u2005months in both models  except TJC, which did not have a significant association with PCS in model 2 p=0.977; . PtGA haIn TACIT, SJC, TJC and PtGA, but not ESR had significant associations with PCS and MCS scores in model 1 ; as in CSF-6D scores improved in CARDERA and TACIT with all treatments. In CARDERA, SF-6D scores increased from 0.594 to 0.669 (change 0.076) over 6\u2005months with active corticosteroids, and from 0.577 to 0.633 (change 0.057) with placebo. In TACIT, SF-6D scores increased from 0.548 to 0.629 (change 0.081) over 6\u2005months with TNFi and 0.574 to 0.626 (change 0.052) with cDMARDs. Improvements in both treatment arms in both trials exceeded MID.We have undertaken secondary analyses of two completed randomised clinical trials in early and established RA. Our first aim was to evaluate the effect of intensive treatments\u2014high-dose corticosteroids versus placebo in early RA, and cDMARDs versus TNFis in established RA\u2014on SF-36 domains during the first 6\u2005months of treatment. With all active treatments, there were improvements in all eight SF-36 domains, which exceeded MCIDs (5\u2005units). However, in early RA, corticosteroids only provided improvements beyond placebo in physical but not mental SF-36 domains. Furthermore, in established RA, there were similar improvements with cDMARDs and TNFis. These results show that in these two trials intensive treatments resulted in limited additional benefits on HRQoL compared with less intensive treatments.Our second aim was to evaluate the impact of remission and other DAS28-defined disease activity categories on SF-36 domains at trial end points. Patients in remission had better HRQoL profiles than patients in higher disease activity states. However, scores in PF, RP and GH in both trials remained below normative values, with large deficits observed in established RA patients enrolled to TACIT. The IMPROVED trial suggested that in patients with early inflammatory arthritis, attaining prompt remission normalises HRQoL.et alOur third aim was to assess which DAS28 components had the strongest associations with HRQoL at trial end points. In CARDERA and TACIT, PtGA had the strongest association with PCS and MCS scores; associations with SJC and ESR levels were weaker. Although different types of patient-reported outcomes such as PtGA and SF-36 component summary scores may be expected to be inter-related, our finding that PtGA was most strongly associated with physical and mental HRQoL compared with other DAS28 components is of clinical importance. It suggests that in order to optimise HRQoL in RA, it might be helpful to place an increased focus on improving PtGA scores. In routine practice, the PtGA is not a key driver of rheumatologists' treatment decisions, with DutchThe failure of TNFi to improve individual SF-36 domains beyond cDMARDs in TACIT was of interest. Although limited by a modest sample size, TACIT provided only little evidence that 6-months TNFi with DMARDs was superior to cDMARDs at improving HRQoL. Previous trials of TNFi with methotrexate versus methotrexate monotherapy in DMARD-IR patients show significant improvements in PCS and MCS scores with biologics, although the effects are greater on physical than mental health.et al,et al also found most SF-36 domains in RA patients in remission were below general population levels. Their findings therefore support our view that additional management strategies are needed to normalise HRQoL in addition to attaining remission.In CARDERA and TACIT SF-36, health profiles were superior in patients attaining remission, compared with those attaining LDA. This replicates previous work by Radner Our study has several strengths. As a secondary analysis of two clinical trials, assessments were standardised. Its main findings were similar in early and established RA patients receiving different intensive treatments. Patients were recruited from many English centres, which followed consistent healthcare approaches. It also has several limitations. As a post-hoc analysis, it did not test a prespecified hypothesis. It was restricted to assessing treatment impacts in active RA, limiting its generalisability to all RA populations. It focused on 6-month and 12-month HRQoL changes; longer time frames could show greater benefits. It used a generic HRQoL assessment (SF-36); disease-specific measures like RAQoLOur key finding that physical HRQoL remained impaired even when intensive treatment achieved remission could reflect several underlying drivers. Loss of lean muscle mass, which is linked with RA disability,Patient surveys suggest current RA management does not fully address their needs and expectations."}
+{"text": "Additional in vitro experiments using macrophages and kidney fibroblasts demonstrated NF-?BIZ and related cytokines participate in fibrosis. In particular, increased levels of NF-?BIZ-associated cytokines in macrophages significantly up-regulated TGF-\u03b2 induced kidney fibroblast activation. Moreover, experiments with NF-?BIZ knocked down macrophages showed reduced TGF-\u03b2- induced kidney fibroblast activation. The findings of the present study provide evidence regarding an involvement of NF-?BIZ in age-associated progressive renal fibrosis and provides potential targets for its prevention.Chronic inflammation is a major contributor to age-related nephropathic changes, including renal fibrosis. In this study, various experimental paradigms were designed to delineate the role played by NF-?BIZ  in age-associated renal fibrosis. Analyses based on RNA-sequencing findings obtained by next generation sequencing (NGS) revealed the upregulations of NF-?BIZ and of IL-6 and MCP-1 (both known to be regulated by NF-?BIZ) during aging. The up-regulation of NF-?BIZ in aged rat kidneys coincided with increased macrophage infiltration. In LPS-treated macrophages, oxidative stress was found to play a pivotal role in NF-?BIZ expression, suggesting age-related oxidative stress is associated with NF-?BIZ activation. Furthermore, these  Sections were then counterstained with 1 \u03bcg/ml Hoechst 5 min, mounted, and stored in dark at 4\u00b0C. Confocal images were obtained using a FV10i FLUOVIEW Confocal Microscope .The siRNAs of NF-\u03baBIZ and negative controls were purchased from Integrated DNA Technologies . Dicer-substrate siRNA methods were used to increase the potency of target gene knock-down. The selected NF-\u03baBIZ siRNA-targeting sequence (duplex1 in experiment) was AUAUUUGUAGUUCUUACUCACGUUGGG. TYE-563 fluorescently-labeled transfection control duplex was used for detecting the efficiency of transfection in peritoneal macrophages. Lipofectamine 3000 (Invitrogen) was used to transfect cells with siRNA. For siRNA transfection, cells were seeded in six-well plates, grown for 24 h to 60-70% confluence, and then transfected with 25 nM NF-\u03baBIZ siRNA or negative control siRNA using Lipofectamine 3000 (Invitrogen).post hoc test. The Student's t-test was used to analyze differences between two groups. P values of < 0.05 were considered statistically significant. Analyses were performed using GrapdPad Prism 5 .Analysis of variance (ANOVA) was used to analyze intergroup differences. Differences between group means were assessed using Fisher's protected least-significant difference"}
+{"text": "To assess the image quality of coronary CT angiography (CCTA) for suspected acute coronary syndrome (ACS) outside office hours.Patients with symptoms suggestive of an ACS underwent CCTA at the emergency department 24 hours, 7 days a week. A total of 118 patients, of whom 89 (75 %) presented during office hours (weekdays between 07:00 and 17:00) and 29 (25 %) outside office hours  underwent CCTA. Image quality was evaluated per coronary segment by two experienced readers and graded on an ordinal scale ranging from 1 to 3.There were no significant differences in acquisition parameters, beta-blocker administration or heart rate between patients presenting during office hours and outside office hours. The median quality score per patient was 30.5 [interquartile range 26.0\u201333.5] for patients presenting during office hours in comparison to 27.5 [19.75\u201332.0] for patients presenting outside office hours (p=0.043). The number of non-evaluable segments was lower for patients presenting during office hours .Image quality of CCTA outside office hours in the diagnosis of suspected ACS is diminished.Quality scores were higher for coronary-CTA during office hours.\u2022 There were no differences in acquisition parameters.\u2022 There was a non-significant trend towards higher heart rates outside office hours.\u2022 Coronary-CTA on the ED requires state-of-the-art scanner technology and sufficiently trained staff.\u2022 Coronary-CTA on the ED needs preparation time and optimisation of the procedure.\u2022  The optimal diagnostic work-up of suspected acute coronary syndrome (ACS) remains a topic of controversy . RecentlIn the multicentre randomised BEACON trial, we compared a diagnostic strategy with early CCTA to standard optimal care in patients suspected of acute coronary syndrome. At one institution, patients were enrolled 24 hours, 7 days a week. The study design, inclusion and exclusion criteria, and primary results have been reported previously . BrieflyStudy participants were divided into patients presenting during regular office hours (weekdays between 07:00 and 17:00) and outside office hours . Information regarding clinical characteristics, time of presentation, time between presentation and CT angiography, image quality, presence of coronary artery disease and clinical outcome were collected prospectively.After initial workup at the ED, consisting of a clinical evaluation including an ECG and laboratory tests, patients underwent CCTA. Image acquisition was performed on either a 128-slice single source scanner, present at the ED or a dual-source system, situated at the radiology department depending on physician preference and availability. We used ECG-synchronised axial or spiral scan protocols combined with radiation-minimising measures. During the day CT scans were performed by a cardiac dedicated technician team. At night the examinations were performed by a broader group of technicians, although all were trained to perform cardiac CT. If indicated and clinically acceptable, beta-blockers were administrated. All patients received sublingual nitroglycerin 1 min before scanning. First a coronary calcium scan was performed, and the Agatston calcium score calculated. Subsequent CCTA was evaluated according to SCCT criteria . For cliImage quality was evaluated per segment in accordance with the American Heart Association (AHA) classification , by two Values for effective radiation dose (mSv) were calculated by multiplying the dose-length product (DLP) with a conversion factor for cardiac CT of \u03ba = 0.017 mSv/mGy x cm .Continuous data are presented as means \u00b1 SD or medians with interquartile ranges as appropriate, and categorical variables as frequencies or percentages. Groups were compared using an independent-sample t-test or Mann-Whitney U-test for continuous variables, and chi-square or Fisher\u2019s exact-test for categorical variables. A two-sided p-value of <0.05 was considered statistically significant. Statistical analyses were performed using SPSS .A total of 118 patients with suspected acute coronary syndrome underwent CCTA. Eighty-nine (75 %) presented during office hours and 29 (25 %) outside office hours. Baseline characteristics are shown in Table The median Agatston calcium score was 1 [0\u201330] in patients presenting during office hours and 4 [0\u201348] in patients presenting outside office hours. CCTA identified 40 (45 %) patients presenting during office hours with no detectable CAD, compared to 11 (38 %) patients presenting outside office hours. Obstructive CAD  was found in 13 (15 %) patients presenting during office hours and five (17 %) presenting outside office hours. The scan was considered non-diagnostic in five (6 %) patients presenting during office-hours and in two (7 %) patients presenting outside office hours   patients were admitted, in comparison to 12 41 %) patients who presented outside office hours (p=0.085). The overall number of major adverse cardiac events  within 30 days after the index visit was low, and comparable between groups (9 (10 %) vs. 3 (10 %), p=0.320)). In addition, there was no difference in the rate of invasive coronary angiography and the rate of coronary revascularisation between patients presenting during and outside office hours  was lower than expected. Screening of all potential study candidates by the medical team may not have been concordant during regular hours and shifts. Quality of CCTA depends on the available technology and personnel. Therefore, extrapolation of our results to other centres may be limited. Larger studies with patients enrolled in different centres are needed to thoroughly address the performance of CCTA outside office hours.Image quality of CCTA outside office hours in the diagnosis of suspected ACS is diminished."}
+{"text": "CSRNP1 (P\u2009=\u20090.017), DISC1 (P\u2009=\u20090.012), and NR4A2 (P\u2009=\u20090.005); and a gene known to relate to HIV viremia, THBS1 (P\u2009=\u20090.003). This discovery cohort data unveils cell type-specific DNA methylation patterns related to HIV-associated CI and provide an immunoepigenetic DNA methylation \u201csignature\u201d potentially useful for corroborating clinical assessments, informing pathogenic mechanisms, and revealing new therapeutic targets against CI.Monocytes/macrophages contribute to the neuropathogenesis of HIV-related cognitive impairment (CI); however, considerable gaps in our understanding of the precise mechanisms driving this relationship remain. Furthermore, whether a distinct biological profile associated with HIV-related CI resides in immune cell populations remains unknown. Here, we profiled DNA methylomes and transcriptomes of monocytes derived from HIV-infected individuals with and without CI using genome-wide DNA methylation and gene expression profiling. We identified 1,032 CI-associated differentially methylated loci in monocytes. These loci related to gene networks linked to the central nervous system (CNS) and interactions with HIV. Most (70.6%) of these loci exhibited higher DNA methylation states in the CI group and were preferentially distributed over gene bodies and intergenic regions of the genome. CI-associated DNA methylation states at 12 CpG sites associated with neuropsychological testing performance scores. CI-associated DNA methylation also associated with gene expression differences including CNS genes  HIV-related cognitive impairment (CI) is characterized by debilitating impairments in cognitive, behavioral, and motor function with severity ranging from mild to severe (e.g. dementia)Many studies have focused on peripheral immune cells of the monocyte/macrophage lineage since these cells can be infected by HIV, functionally altered, and enter the central nervous system (CNS) either across a permeable blood brain barrier or potentially through the recently described meningeal lymphatic conduit3467812131522Herein, we utilized genome-wide DNA methylation profiling to evaluate and compare the DNA methylation states of circulating monocytes in a cohort of HIV-infected participants based on clinical diagnostic criteria for the presence or absence of CIP\u2009<\u20090.0001).We examined cryopreserved peripheral blood mononuclear cells (PBMC) specimens from 21 HIV-infected individuals enrolled in the Hawaii Aging with HIV Cohort study classified as having CI based on meeting criteria for HIV-associated Dementia  or Mild Cognitive Motor Disorder  using the American Academy of Neurology (AAN) 1991 as previously described 24. We raP\u2009<\u20090.0001) and matched non-impaired participants  (P\u2009<\u20090.0001) and non-impaired  monocyte samples post-enrichment methylation profile at the same CpG sites, providing evidence to confirm the enrichment of a majority cell population of monocytes (P\u2009<\u2009 0.0001) between percent monocyte enrichment values based on our FACS sorting results for the samples and the cell type-specific DNA methylation correlation  . As an aonocytes . We alsorelation , suggestP\u2009<\u20090.05). This comparative analysis identified 1,032 differentially methylated CpG loci (DML) associated with CI (Dataset 1), with 71% of loci exhibiting hypermethylated states between CI and Non-CI groups. In agreement with recent reports, this hypermethylation phenotype of monocytes extends methylation findings observed in PBMCs comparing HIV-infected versus non-infected participantsP\u2009=\u20090.0006) supporting the unsupervised hierarchical clustering analysis that stratified all CI samples from Non-CI  array. For the differential methylation analysis, we filtered probes showing absolute mean differences in methylation greater than 10% between CI-diagnosed and non-CI groups  and CpG shelf regions . The predominant differences were enriched in CpG sites located within gene bodies  and intergenic regions , but less than expected were located within gene promoters   . Since rP\u2009<\u20090.01, P\u2009<\u20090.05, 33CXCL12) gene , which interestingly is a ligand for HIV co-receptor CXCR4 and inhibits HIV-1 transmission by competing for CXCR4 bindingBDNF) gene  and fibroblast growth factor 2 (FGF2) gene  were identified as differentially methylated in CI  gene associates with neurocognitive impairments in HIV infected individuals dependent on methamphetaminecis-regulatory regions in the genome and assigns biological meaning to genomic locations. This analysis identified the top GO biological processes involved antigen processing and presentation of exogenous peptide antigen via MHC class I, regulation of T cell mediated cytotoxicity, and regulation of granule cell precursor proliferation . We used the Enrichr integrative web-based analysis tool to perform a gene list enrichment (amp.pharm.mssm.edu/Enrichr) of the 497 annotated genes associated with a DMLed in CI . Studiesferation . Additioferation , a bioloHLA-G gene was previously shown to be higher in monocytes from HIV participantsHLA-G gene was 32% significantly lower in methylation in CI compared to Non-CI samples  relationships . A positive relationship was identified between higher levels of methylation and increased neuropsychological function at a CpG  in the CNS linked gene FEZ Family Zinc Finger 2 (FEZF2). In contrast, we identified a negative relationship between higher levels of methylation and decreased neuropsychological function at CpGs (GRM8) , Glutathione S-Transferase Mu 1(GSTM1) , GTP-Binding Protein 8(GTPBP8) , RNA Binding Protein, Fox-1 Homolog(HRNBP3) , Lipopolysaccharide Specific Response-7 Protein(KIAA1704) , Seryl-TRNA-Synthetase 2, Mitochondrial(SARS2) , and Solute Carrier Family 25 Mitochondrial Carrier Member 16(SLC25A16) . These results suggest specific DNA methylation signatures of monocytes may have potential utility as a prospective biomarker or provide information for assessing the severity of CI in HIV.To examine whether DNA methylation of monocytes associated with neuropsychological function, we determined the correlations between individual\u2019s NPZ8 global neuropsychological score and the CI-associated DML identified in monocytes. After determining the correlation between NPZ8 and DNA methylation levels at all DML and correcting for multiple correlations with the Benjamini-Hochberg procedure, we identified 12 significant  has been shown to associate with transcriptionCSRNP1) gene contained a differentially methylated CpG in a region proximal to but downstream of the promoter (P\u2009=\u20090.017). CSRNP1 encodes a protein involved in the Wnt signaling pathwayDISC1) contained a hyper-methylated CpG (P\u2009=\u20090.012). DISC1 encodes a protein that is critical to brain function and genetic variants of this gene have been associated with neurocognitive deficits in schizophreniaKIAA1704 gene contained a differentially methylated CpG in the promoter region of the gene (P\u2009=\u20090.021). Moreover, for another overlapping gene, Nuclear Receptor Subfamily 4, Group A, Member 2(NR4A2), we observed a cluster of 3 significantly hypermethylated CpGs in the gene body region in CI compared to Non-CI, suggestive of a differentially methylated region (P\u2009=\u20090.005). This positive association between methylation and gene expression supports previous reports of DNA methylation\u2019s role in gene bodies related to the regulation of alternative splicing47NR4A2 regulates dopamine neurons in the brain during development56THBS1) gene, we identified 3 CpG loci significantly hypomethylated in CI compared to Non-CI individuals (P\u2009=\u20090.003). Confirming the widely accepted relationship between gene promoter methylation and expression, we observed significantly higher DNA methylation at the gene promoter of THBS1 in CI compared to Non-CI was related to significantly lower expression  and examined the overlap of differentially expressed (496) and methylated (497) genes. This analysis identified only 5 genes (1%) were differentially expressed and contained a differentially methylated CpG loci. The Cysteine-Serine-Rich Nuclear Protein 1 comparing CI versus Non-CI samples.We determined whether the CI-associated differential DNA methylation profile and perturbed biological processes identified in monocytes are distinct to this cell type or manifest in other immune cell types. Given CD8+ T cells have been associated with and proposed to play a role in the pathogenesis of CIPTPRD), Retinoic Acid Induced 1(RAI1), and Zinc Finger, X-Linked, Duplicated A (ZXDA) were significantly hypermethylated in CI compared to Non-CI from both monocytes and CD8+ T cells  and 33 CpGs (3.2%) overlapped , indicat T cells . PTPRD hCCR5, CXCR4, and IFNG in CD8+ T cells from the 1,431 differentially methylated loci comparing CI versus Non-CI samples  technology to profile the methylome of these clinical samples at single nucleotide resolution29Demographic and clinical data for participants were compared using nonparametric Wilcoxon-Mann-Whitney test. Informed consent was obtained from participants following procedures approved by the University of Hawaii Human Studies Institutional Review Board. All experiments were performed in accordance with relevant guidelines and regulations.Viably cryopreserved peripheral blood mononuclear cells (PBMCs) specimens (4\u20136 million cells) were thawed using AIM-V Serum Free Medium (Thermo Fisher) supplemented with 2% DNase, washed, and resuspended in buffer consisting of PBS, 3% BSA, and 1\u2009mM EDTA. An aliquot of all PBMCs were stained and quantified using the Countess Automated Cell Counter (Life technologies). PBMCs were used to negatively select for monocytes (CD14+) by magnetic bead separation (EasySep Human Monocyte Enrichment Kit without CD16 depletion) or T cells (EasySep Human CD8+ T Cell Enrichment Kit) according to manufacturer\u2019s instructions (StemCell Technologies). DNA and RNA were isolated from enriched monocytes or T cells using the AllPrep DNA/RNA kit (Qiagen) according to the manufacturer\u2019s recommendations for cells. Nucleic acid concentrations were determined using the Qubit DNA Broad Range or RNA Broad Range fluorescence assays (Life Technologies) and Qubit Instrument (Life Technologies).To confirm the enrichment for monocytes by negative selection, an aliquot  for all subjects pre- and post-enrichment was analyzed by a flow cytometer for monocytes, T cells, NK cells, and B cells . AliquotIllumina HumanMethylation450 BeadChip data was downloaded from GEO accession: GSE35069http://www.r-project.org) using the RnBeads 0.99.18 pipeline analysis package500\u2009ng of DNA per sample were bisulfite converted using the EZ DNA Methylation kit (Zymo Research) according to the manufacturer\u2019s instructions. Bisulfite-converted DNA samples were randomly assigned to a chip well on the Infinium HumanMethylation450 BeadChip, amplified, hybridized onto the array, stained, washed, and imaged with the Illumina iScan SQ instrument to obtain raw image intensities at the University of Hawaii Cancer Center Genomics Shared Resource. Raw Methylation array IDAT intensity data was preprocessed in R statistical programming language (The Ion AmpliSeq Transcriptome Human Gene Expression panel (Life Technologies) was utilized for gene expression profiling of monocytes. The panel uses targeted sequencing of 20,802 RefSeq genes. 100\u2009ng of total RNA was used from enriched monocytes of CI and Non-CI to construct sequencing libraries according to manufacturer\u2019s instructions. Indexed sequencing libraries were constructed using the Human Transcriptome AmpliSeq kit and quantified using the Ion Library Quantification kit on a StepOnePlus Real-Time PCR system. Eight multiplexed samples were templated using the Ion P1 Template OT2 200 Kit V3 with Ion OneTouch 2 Instrument, enriched, loaded on an Ion P1 semiconductor sequencing chip, and run on the Ion Proton Semiconductor Sequencer using the Ion P1 Sequencing 200 Kit V3. The Ion TorrentSuite software was used to map reads and the Ion ampliSeqRNA plugin was used to attain normalized read count data files (RPM) for each sample. Differential gene expression statistical analysis was performed on normalized (Reads Per Million reads) expression values assigned to each amplicon for all samples using the R statistical programming language package DESeq, which estimates variance-mean dependence in count data and tests for differential expression using a model based on negative binomial distribution.How to cite this article: Corley, M. J. et al. Comparative DNA Methylation Profiling Reveals an Immunoepigenetic Signature of HIV-related Cognitive Impairment. Sci. Rep.6, 33310; doi: 10.1038/srep33310 (2016)."}
+{"text": "Genome-wide quantification of enhancer activity in the human genome has proven to be a challenging problem. Recent efforts have led to the development of powerful tools for enhancer quantification. However, because of genome size and complexity, these tools have yet to be applied to the whole human genome.\u00a0In the current study, we use a human prostate cancer cell line, LNCaP as a model to perform whole human genome STARR-seq (WHG-STARR-seq) to reliably obtain an assessment of enhancer activity. This approach builds upon previously developed STARR-seq in the fly genome and CapSTARR-seq techniques in targeted human genomic regions. With an improved library preparation strategy, our approach greatly increases the library complexity per unit of starting material, which makes it feasible and cost-effective to explore the landscape of regulatory activity in the much larger human genome. In addition to our ability to identify active, accessible enhancers located in open chromatin regions, we can also detect sequences with the potential for enhancer activity that are located in inaccessible, closed chromatin regions. When treated with the histone deacetylase inhibitor, Trichostatin A, genes nearby this latter class of enhancers are up-regulated, demonstrating the potential for endogenous functionality of these regulatory elements.WHG-STARR-seq provides an improved approach to current pipelines for analysis of high complexity genomes to gain a better understanding of the intricacies of transcriptional regulation.The online version of this article (doi:10.1186/s13059-017-1345-5) contains supplementary material, which is available to authorized users. Enhancers are DNA elements that control the temporal and spatial expression of genes and thus are central to biological processes such as development, differentiation, and homeostasis . Enhancecis-regulatory elements located in non-coding regions of the genome  (Promega). Briefly, minP promoter was replaced with SCP1 promoter and a CmR-ccdB cassette was cloned between luc2 ORF and SV40 poly (A). The PCR product (homology arms added to DNA fragments) was introduced into the vector backbone (linearized by SphI and NdeI restriction enzymes) using Gibson Assembly Master Mix (NEB), followed by transformations into MegaX DH10B\u2122 T1R electrocompetent cells (ThermoFisher Scientific). A total of 32 Gibson Assembly and transformations were performed. All transformed E. coli cells were pooled to grow in 4 L LBAMP medium and harvested when Optical Density (OD) reached 1.0. The input plasmid library was extracted using Plasmid Mega Kit (Qiagen) and drop dialyzed before transfection.Generation of plasmid libraries was based on the method described by Arnold et al. . BrieflyInput plasmid library was electroporated into LNCaP cells using the Nucleofector\u2122 platform (Lonza) according to manufacturer\u2019s protocol (1 \u03bcg DNA/1 million cells). A total of 300 million cells were electroporated in each replicate and two biological replicates were generated. After transfection, cells were plated in phenol red free RPMI 1640 medium (ThermoFisher Scientific) supplemented with 10% charcoal-stripped FBS (Gemini) and 1.0% penicillin/streptomycin (ThermoFisher Scientific) for 72 h until harvest.Total RNA was extracted from transfected LNCaP cells using PerfectPure RNA Cultured Cell Kit (5PRIME), and followed by poly (A) tail mRNA isolation using Dynabeads\u00ae Oligo (dT) kit (ThermoFisher Scientific). mRNA was treated with TURBO\u2122 DNase (ThermoFisher Scientific) and purified by Agencourt RNAClean XP beads (Beckman Coulter). Target-specific first strand complementary DNA (cDNA) synthesis was performed with SuperScript III  to specifically reverse transcribe WHG-STARR-seq mRNAs (RT primer: 5\u2019- CAAACTCATCAATGTATCTTATCATG-3\u2019). All mRNA from the 150 million transfected cells was used in reverse transcription. After reverse transcription, reactions were treated with RNase A\u2009+\u2009H and pooled. In the final PCR amplification, every 5 \u03bcL cDNA reaction was used as a template in every 50 \u03bcL PCR reaction using Q5 High-Fidelity DNA polymerase (NEB) using the following program: 98 \u00b0C for 30s; 20 cycles of 98 \u00b0C for 10 secs, 65 \u00b0C for 30 secs and 72 \u00b0C for 30 secs. Illumina HiSeq platform compatible primers were used . For each replicate, we set up separate final PCR reactions using 16 different indexing primers. A total of 20 duplicated PCR reactions were performed for each indexing PCR. PCR products were cleaned up by AmPure XP beads  and submitted fro Illumina sequencing. Input library for sequencing was generated using similar PCR setup. Products from 12 duplicated PCR reactions were pooled .STARR-seq consists of two parts of data with different types of readouts. The input library is generated by directly amplifying inserts from the plasmid DNA used for cell transfection, served as reference of the original representation of insert fragments in starting plasmid pool. The output library measures the abundance of self-transcribed mRNA from insert fragments of the transfected plasmid pool.5 cells/replicate, three replicates/testing region). After transfection, cells were seeded in 24-well plates in phenol red free RPMI 1640 medium (ThermoFisher Scientific) supplemented with 10% charcoal-stripped FBS (Gemini) and 1% penicillin/streptomycin (ThermoFisher Scientific). Dual luciferase assays (Promega) were performed at 72 h post transfection following manufacturer\u2019s protocol.The vector backbone for the reporter assay used the input plasmid library backbone without a CmR-ccdB cassette. Candidate regions were PCR amplified from human genomic DNA (Promega) and cloned into the vector through Gibson Assembly reactions (vector linearized by KpnI and NheI restriction enzymes). Reporter plasmids were co-transfected with luciferase control vector pRL-CMV (Promega) into cells with Lipofectamine\u00ae 2000 (ThermoFisher Scientific) following the manufacturer\u2019s protocol (1.0\u2009\u00d7\u2009105 cells per well in phenol red free RPMI 1640 medium (ThermoFisher Scientific) supplemented with 10% charcoal-stripped FBS (Gemini) and 1% penicillin/streptomycin (ThermoFisher Scientific) for 72 h before treatment. Cells were treated with either 100 ng/mL TSA (Sigma Aldrich) or DMSO vehicle for 24 h before harvest to achieve three biological replicates.Seeded in six-well plates were 1.0\u2009\u00d7\u200910ATAC-seq was performed as previously described . Nuclei Total RNA was extracted from TSA/DMSO treated cells using PerfectPure RNA Cultured Cell Kit (5PRIME). RNA-seq library preparation was conducted using TruSeq Stranded mRNA Library Prep Kit (Illumina) according to manufacturer\u2019s protocol .http://broadinstitute.github.io/picard/). Uniquely mapped distinct fragments from the 16 different indexing libraries were pooled and all included for downstream analysis, since duplicated fragments coming from different indexing libraries are considered as biological duplicates. To identify enhancers, we combined data from two biological replicates and called enhancer peaks by MACS2  [Paired-end sequencing reads (2\u2009\u00d7\u2009100 bp) from Illumina Hiseq2000 were aligned to human genome hg19 by bowtie. Reads that are mapped to more than one location to the genome were filtered out. To exclude potential PCR amplification bias, fragments (inferred from paired-end reads) that have the same start and end positions were collapsed into distinct fragments by Picard (\u2009<\u20090.05) . An enhaSince it is difficult to dissect biological duplicates from PCR/sequencing duplicates in the sequencing reads and using total reads may inappropriately inflate statistical power in peak detection leading to false positives, we decided to use distinct fragments for peak calling and downstream analyses, similar to previous studies , 19. HowTo compare whole-genome STARR-seq enhancer signals with other epigenomics features, we gathered raw sequencing data for H3K4Me2 (GSE43720), H3K27Me3 (GSE62497), H3K27Ac (GSE51621), DNase I (GSE32970), and chromatin input  in LNCaP cells under vehicle-treated conditions. We combined the datasets for each epigenomics feature together and mapped the reads to human genome hg19 by Bowtie , filtereSingle-end reads of 50 bp from Illumina Hiseq2000 were mapped to the human genome hg19 by Tophat . Reads wPaired-end reads (2\u2009\u00d7\u200950 bp) were sequenced by Illumina Hiseq2000. Because of the existence of adaptor sequences in library molecules generated by ATAC-seq insertion events within 50 bp, we used Bowtie and Bowtie2  for eachhttp://fureylab.web.unc.edu/software/fseq/) to call peaks in both vehicle condition and TSA treatment. We then merged peaks across conditions and counted the ATAC-seq reads number for each peak in each condition. Genomic regions showing differential accessibility after TSA treatment were called by EdgeR . Three biological replicates were collected for each condition. We then overlapped closed active enhancers to TSA-induced sites to find closed, active enhancers that are opened up by TSA treatment.To identify TSA-induced chromatin accessibility change, we first used Fseq  at defauAdditional file 1:Supplemental figures. (PDF 10391 kb)Additional file 2: Table S1.Genomic coordinates and chromatin environment of the 15 regions validated by luciferase assay. (XLSX 43 kb)Additional file 3: Table S2.GO term analysis of the top 2000 active open enhancers and the top 2000 active closed enhancers. (XLSX 37 kb)Additional file 4: Table S3.Motif enrichment analysis of WHG-STARR-seq enhancers. (XLSX 24 kb)"}
+{"text": "KRAB domain Zinc finger proteins are one of the most abundant families of transcriptional regulators in higher vertebrates. The prevailing view is that KRAB domain proteins function as potent transcriptional repressors by recruiting TRIM28 and promoting heterochromatin spreading. However, the extent to which all KRAB domain proteins are TRIM28-dependent transcriptional repressors is currently unclear. Our studies on mouse ZFP568 revealed that TRIM28 recruitment by KRAB domain proteins is not sufficient to warrant transcriptional repressive activity. By using luciferase reporter assays and yeast two-hybrid experiments, we tested the ability of ZFP568 and other mouse KRAB domain proteins to repress transcription and bind TRIM28. We found that some mouse KRAB domain proteins are poor transcriptional repressors despite their ability to recruit TRIM28, while others showed strong KRAB-dependent transcriptional repression, but no TRIM28 binding. Together, our results show that the transcriptional repressive activity of KRAB-ZNF proteins does not correlate with their ability to recruit TRIM28, and provide evidence that KRAB domains can regulate transcription in a TRIM28-independent fashion. Our findings challenge the current understanding of the molecular mechanisms used by KRAB domain proteins to control gene expression and highlight that a high percentage of KRAB domain proteins in the mouse genome differ from the consensus KRAB sequence at amino acid residues that are critical for TRIM28 binding and/or repressive activity. Kr\u00fcppel-associated box (KRAB) domain proteins are one of the most abundant protein families in higher vertebrates, with as many as 381 human and 357 mouse protein coding genes \u20135. This Because most KRAB domain-containing proteins contain a variable number of Zinc Finger motifs (ZNF) in their carboxyl terminal end , it has In this study, we report the characterization of ZFP568 (NCBI Gene ID: 243905), a mouse KRAB-ZNF protein required for early embryonic morphogenesis ,29. Unlichato, a recessive lethal mutation in the mouse KRAB domain protein ZFP568 [chato mutation causes a Leucine to Proline (L64P) amino acid substitution in a conserved residue of the first KRAB motif of ZFP568  show similar developmental defects, including abnormal convergent extension and disrupted morphogenesis of extraembryonic tissues  severely impaired the repressive activity of GAL4DBD-ZFP568  all increased in response to ectopically expressed TRIM28  significantly decreased when TRIM28 siRNAs were transfected (KRAB1L-P and GAL4DBD-ZFP568KRAB1DV-AA) or in both the first and second KRAB domains  failed to respond to the decrease in TRIM28 caused by siRNAs . As shown in KRAB1L-P; \u2206KRAB2 mutants failed to recruit TRIM28 in yeast two-hybrid experiments. Therefore, although the second KRAB motif of ZFP568 could not bind TRIM28 on its own , #2 (19778) or non-silencing siRNA (Ambion) was transfected using Lipofectamine RNAiMax (Invitrogen). Cells were transfected with luciferase effectors and reporters 24 hours after siRNA transfection and luciferase was assayed after another 48 hours. For each luciferase assay, duplicate transfections and replicate lysates were measured for each condition (n = 4). Luminescence was quantified with a luminometer plate reader (BioTek). Firefly luciferase expression was normalized to Renilla to control for transfection efficiency. Fold repression was calculated compared to Gal4DBD. Lysates were analyzed by western blotting (not shown) to ensure consistent protein expression . Statistical analysis was performed using paired, two-tailed t-test.HEK293T cells  were transfected using Lipofectamine 2000 (Invitrogen) with pGL3-5XUAS Firefly luciferase reporter, a Gal4DBD effector and pRL Renilla luciferase plasmids. Total amount of DNA transfected was held constant by cotransfecting pCMV-MYC as needed. Cells were assayed with the Dual-Luciferase Reporter System (Promega) 24 hours after transfection. For small interfering RNA (siRNA) knockdown, 8 pmol of HEK293T cells were transfected with Lipofectamine 2000 (Invitrogen). Western blots were performed using standard protocols and analyzed using the Odyssey Digital Imager (LiCor). The following validated commercially available antibodies were used: rabbit polyclonal anti-TRIM28 , mouse monoclonal anti-Flag , normal mouse/rabbit IgG , goat anti-mouse and goat anti-rabbit IR secondary 800CW or 680LT dyes .Bait Gal4DBD (pGBKT7 DNA-BD) fusion plasmids with wild type or mutant KRAB-ZNF proteins and prey AD (pGADT7 AD) fusion plasmids with TRIM28 were sequentially transformed into AH109 yeast strain as specified in the Matchmaker GAL4 Two-Hybrid System 3 (Clontech). After transfection, yeast were plated in Leu-Trp- media to select for colonies containing bait and prey constructs, then colonies were re-plated to test for protein interactions onto Ade-His Leu-Trp- plates (high stringency media) or Leu-Trp- X-alpha-gal plates (low stringency media).Renilla luciferase are described in . Other constructs were generated as described in Plasmids pCDNA3.1-Gal4DBD, pGL35XUAS firefly luciferase and pRL http://weblogo.berkeley.edu/logo.cgi).Analysis of mouse KRAB-ZNF protein sequences was done using the dataset in  and reguS1 FigData were obtained from \u201313,25, a(TIF)Click here for additional data file.S2 Fig(TIF)Click here for additional data file.S3 Fig(A), as well as the human KRAB-ZNFs analyzed in [(B). Residues highlighted in grey indicate amino acids important for repressive activity . Resribed in \u201313,25). (TIF)Click here for additional data file.S1 TableThe 357 mouse KRAB domain proteins identified in the Corsinotti et al. 2013 study [(XLSX)Click here for additional data file.S2 Table(XLSX)Click here for additional data file."}
+{"text": "Emerging evidence suggests receptor tyrosine kinase ALK as a promising therapeutic target in neuroblastoma. However, clinical trials reveal that a limited proportion of ALK-positive neuroblastoma patients experience clinical benefits from Crizotinib, a clinically approved specific inhibitor of ALK. The precise molecular mechanisms of aberrant ALK activity in neuroblastoma remain elusive, limiting the clinical application of ALK as a therapeutic target in neuroblastoma. Here, we describe a deep quantitative phosphoproteomic approach in which Crizotinib-treated neuroblastoma cell lines bearing aberrant ALK are used to investigate downstream regulated phosphoproteins. We identified more than 19,500\u2014and quantitatively analyzed approximately 10,000\u2014phosphorylation sites from each cell line, ultimately detecting 450\u2013790 significantly-regulated phosphorylation sites. Multiple layers of bioinformatic analysis of the significantly-regulated phosphoproteins identified RAS/JNK as a downstream signaling pathway of ALK, independent of the ALK variant present. Further experiments demonstrated that ALK/JNK signaling could be inactivated by either ALK- or JNK-specific inhibitors, resulting in cell growth inhibition by induction of cell cycle arrest and cell apoptosis. Our study broadly defines the phosphoproteome in response to ALK inhibition and provides a resource for further clinical investigation of ALK as therapeutic target for the treatment of neuroblastoma. Neuroblastoma is the most common extracranial solid malignant tumor and accounts for approximately 10% of pediatric cancer related death . DespiteRecent studies reveal that approximately 8% of primary neuroblastomas have a mutation in the anaplastic lymphoma kinase (ALK) gene \u20137, whichMass spectrometry-based phosphoproteomics provides a powerful approach to gain more complete knowledge of a cell signaling network . In thisWe investigated the signaling pathways regulated by ALK in ALK-positive neuroblastoma by comparing the phosphoproteomes of ALK-positive neuroblastoma cell lines following inhibition of ALK by its specific inhibitor Crizotinib Figure . Dose-reOnly those phosphopeptides with a greater than two-fold change (either increased or decreased) in both replicates were considered for further analysis Figure . A complWe next investigated the function of ALK-regulated phosphorylation of proteins in neuroblastoma by applying several layers of bioinformatic analysis. The subcellular localization of signaling molecules plays a vital role in signal transduction, so we first investigated the subcellular localization of ALK-regulated phosphoproteins by querying the LOCATE database . In all We next performed Gene Ontology (GO) analysis of significantly regulated proteins. The most significant GO categories of the regulated phosphoproteins were similar across all three cell lines. For example, the significantly enriched molecular function GO terms, including GTPase regulator activity (GO:0030695), Ras GTPase activator activity (GO:0005099), and transcription factor binding (GO:0008134), were identified in all three cell lines, albeit with slightly differing but still significant p-values . The enrWe next performed KEGG pathway analysis to investigate the potential pathways connecting ALK and downstream transcription factors Figure . The neuin vitro by western blotting. The level of phosphorylation of JNK at Thr183 and Tyr185 reflects its activity . Pe. Pe46]. Cells were seeded in 6 well plates until the cell confluency up to 80%, a serial concentration of SP600125 and Crizotinib was employed to treat the cells for 4 hours. After washing twice with cold PBS, the cells were lysed with RIPA  lysis buffer containing 5X protein phosphatase inhibitor and PMSF. Protein concentration was determined by BCA kit . A 10% SDS-PAGE gel was used for gel electrophoresis. Each lane was loaded equal amounts of proteins. A PVDF membrane was used for protein transfer. Membrane was then blocked using 5% w/v BSA in TBST  for 1 hour in room temperature prior to incubation with primary antibody using 5% w/v BSA in TBST at 4\u00b0C for overnight. Membrane was washed thrice with TBST for 30 min, incubated with appropriate secondary antibody using TBST for 30 min in room temperature, and then washed thrice with TBST for 30 min. Proteins was visualized by electrogenerated chemiluminescence (ECL). Antibodies were purchased from Cell Signaling Technology  and used to direct against total JNK (#9252), Phospho-SAPK/JNK (#4668), total c-jun, phospho-c-Jun (Ser63) (#2361), phospho-ATF-2 (Thr71) (#5112), ALK (#3333), phospho-ALK (Tyr1507) (#14678), Cyclin A2 (#4656), phospho-cdc2 (Tyr15) (#4539), Myt1(#4282), phospho-Histone H3 (Ser10) (#3377) and Cyclin B1 (#12231). Anti-GADPH (#2118) were used as a loading control.4 cells were washed twice with cold PBS and resuspended with binding buffer, then stained with Annexin V-FITC and propidium iodide (PI) for 15 min in the dark. Analyze by flow cytometry within 1 hour. Cell cycle analysis was used PI staining and flow cytometry. 3*104 cells were harvested and fixed with cold 70% alcohol overnight at 4\u00b0C. After fix cells overnight, the cells were washed with PBS and resuspended with RNase. After incubation for 30 min at 37\u00b0C, PI was added to cells and analyze within 4 hours.Apoptosis was analyzed using Annexin V-FITC Apoptosis Detection Kit  and BD Biosciences FACSCalibur flow cytometry. Briefly, a total of 1.5*10The small interfering RNA (siRNA) specific for ALK was chemically synthesized . The sequence of ALK siRNA was CTGGTCATAGCTCCTTGGAAT. The sequences of ALK siRNA were previously reported . The siRWhen cells reached 80\u201390% confluent in 24-wells plates, plasmids were incubated in Opti-MEM  by using lipofectamine 2000  according to the protocol for transfection. As for NB1 cell, a total of 2.4ul lipofectamine 2000, 5ug pGL4.44[luc2P/AP1 RE/Hygro] vector and 0.2ug Renilla luciferase vector were used in each well. After incubating with SP600125 (40\u03bcM) and Crizotinib (1\u03bcM) for 24 hours, the cells were lysed and analyzed with Dual-Luciferase Reporter Assay System ."}
+{"text": "Thermus thermophilus HB8, we sought to first determine its preferred DNA-binding sequences in vitro using the combinatorial selection method Restriction Endonuclease Protection, Selection, and Amplification (REPSA) and then use this information to bioinformatically identify potential regulated genes. REPSA determined a consensus FadR-binding sequence 5\u00b4-TTRNACYNRGTNYAA-3\u00b4, which was further characterized using quantitative electrophoretic mobility shift assays. With this information, a search of the T. thermophilus HB8 genome found multiple operons potentially regulated by FadR. Several of these were identified as encoding proteins involved in fatty acid biosynthesis and degradation; however, others were novel and not previously identified as targets of FadR. The role of FadR in regulating these genes was validated by physical and functional methods, as well as comparative genomic approaches to further characterize regulons in related organisms. Taken together, our study demonstrates that a systematic approach involving REPSA, biophysical characterization of protein-DNA binding, and bioinformatics can be used to postulate biological roles for potential transcriptional regulators.One of the primary transcriptional regulators of fatty acid homeostasis in many prokaryotes is the protein FadR. To better understand its biological function in the extreme thermophile  Haemophilus influenza, in 1995 *[FadRfree]/[FadR-DNAcomplex] where [DNAfree] = [DNAtotal] * fraction unbound, [FadR-DNAcomplex] = [DNAtotal] * fraction in complex species, and [FadRfree] = [FadRtotal]\u2013[FadR-DNAcomplex]) with values for free DNA and DNA-FadR complex concentrations being obtained from the image analysis software.Electrophoretic mobility shift assays (EMSA) followed the procedures used previously with SbtR . QuantitAmplicon library preparation, Ion PGM individual sequencing particle (ISP) preparation, Ion PGM semiconductor sequencing, and Ion torrent sever sequence processing were all performed as previously described . A fastqP-values (7.0e-07) and Q-values (0.14) was used in this study, based on prior work with related REPSA-identified transcription factor binding sites. Additional bioinformatic gene expression analyses were performed using data from the National Center for Biotechnology Information Gene Expression Omnibus website (https://www.ncbi.nlm.nih.gov/geo/) [https://www.ncbi.nlm.nih.gov/geo/geo2r/), thereby allowing an assessment of the statistical significance of the comparison. Significance levels  were adjusted to correct for potential false positives using the Benjamini & Hochberg false discovery rate method [P-values are shown.Bioinformatics, including sequence data processing, duplicate finding, motif discovery, motif scanning, promoter identification, and operon identification were performed using the software, websites, and workflows previously described . For ourov/geo/) . Expresse method . Adjustehttps://blast.ncbi.nlm.nih.gov/Blast.cgi), discontiguous megablast BLASTn algorithm, and default parameters [T. thermophilus HB8 FadR binding site (see Thermus thermophilus HB8 (taxid:300852), Thermus thermophilus HB27 (taxid:262724), Thermus aquaticus Y51MC23 (taxid:498848), Deinococcus radiodurans R1 (taxid:243240), Deinococcus deserti VCD115 (taxid:546414), and Deinococcus geothermalis DSM 11300 (taxid:319795) served as search sets. The presence of FadR binding sites in individual alignments was performed using the intrinsic browser find function while mapping these sites to specific gene promoters was performed using the BLASTn-embedded Nucleotide Graphics function.For our comparative genomics studies, nucleotide BLAST sequence alignment searches for FadR binding sites in orthologous gene promoters were performed using the NCBI BLASTn website (rameters . For eacsite see  served ahttp://regpredict.lbl.gov/regpredict/), selecting the full set of Deinococcus-Thermus genomes, and determining regulon inference by known PWM using a training set composed of the putative FadR binding sites identified in T. thermophilus HB8 promoters (T. thermophilus HB27 genome explicitly identified and clusters of co-regulated orthologous operon member genes from other organisms indicated with a simplified measure: number of orthologous genes under strong (s), weak (w), or no (n) postulated FadR regulation. A negative sign (\u2013) indicated no orthologous operons were identified.Comparative genomics regulon inference analysis was performed using the RegPredict webserver Click here for additional data file.S1 Table(PDF)Click here for additional data file.S1 Text(FASTQ)Click here for additional data file.S2 Text(TXT)Click here for additional data file."}
+{"text": "Also, patients treated with higher (\u226510 mg BID) average RUX doses in the first 12 weeks achieved higher response rates (p=0.019). After adjustment for IPSS risk, patients in spleen response at 6 months showed only a trend for better survival compared to non-responders. At 6 months, symptoms response was achieved by 85.5% of 344 evaluable patients; only a higher (>20) Total Symptom Score significantly correlated with lower probability of response (p<0.001). Increased disease severity, a delay in RUX start and titrated doses <10 mg BID were associated with patients achievinglower response rates. An early treatment and higher RUX doses may achieve better therapeutic results.In patients with Myelofibrosis (MF) treated with ruxolitinib (RUX), the response is unpredictable at therapy start. We retrospectively evaluated the impact of clinical/laboratory factors on responses in 408 patients treated with RUX according to prescribing obligations in 18 Italian Hematology Centers. At 6 months, 114 out of 327 (34.9%) evaluable patients achieved a spleen response. By multivariable Cox proportional hazard regression model, pre-treatment factors negatively correlating with spleen response were: high/intermediate-2 IPSS risk ( Myelofibrosis (MF) is a chronic myeloproliferative neoplasm (MPN) primarily characterized by dysregulation of the JAK-STAT pathway, that is thought to be responsible for increased myeloproliferation and abnormal production of pro-inflammatory cytokines . MF can Ruxolitinib (RUX) is a potent and selective JAK1/JAK2 inhibitor that has demonstrated superiority over placebo , 6 and oHere, we report a large cohort of MF patients treated with RUX and evaluated for response according to the International Working Group for Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) criteria , with thp=0.048).Between June 2011 and Apr 2016, 408 patients with PMF , PET-MF  or PPV-MF  were treated with RUX in 18 Italian Hematology Centers and were included in the study. Overall, 160 patients received RUX as per compassionate or commercial use, while 248 (60.8%) patients were first enrolled in the JUMP trial  curve) and calibration (Hosmer-Lemeshow [H-L] test) were reported. Survival analysis was performed by means of Kaplan-Meier (KM) product-limit estimate and differences between KM estimates were evaluated using the Log-rank test. To assess spleen response role as independent predictor of survival a multivariable Cox proportional hazard regression model was fitted to the data adjusting for the IPSS score (intermediate-1 vs intermediate-2/high). All tests were 2-sided and a"}
+{"text": "BCL7A, BRWD3, and AUTS2 demonstrate significantly higher mutation frequencies among AA cases. These genes are all involved in translocations in B-cell malignancies. Moreover, we detected a significant difference in mutation frequency of TP53 and IRF4 with frequencies higher among CA cases. Our study provides rationale for interrogating diverse tumor cohorts to best understand tumor genomics across populations.Multiple Myeloma (MM) is a plasma cell malignancy with significantly greater incidence and mortality rates among African Americans (AA) compared to Caucasians (CA). The overall goal of this study is to elucidate differences in molecular alterations in MM as a function of self-reported race and genetic ancestry. Our study utilized somatic whole exome, RNA-sequencing, and correlated clinical data from 718 MM patients from the Multiple Myeloma Research Foundation CoMMpass study Interim Analysis 9. Somatic mutational analyses based upon self-reported race corrected for ancestry revealed significant differences in mutation frequency between groups. Of interest,  This study represents the largest comprehensive molecular analysis of ethnically defined newly diagnosed treatment na\u00efve Multiple Myeloma (MM). We revealed significant differences in mutation frequencies for important cancer genes between AA and CA MM. This study provides support for interrogating diverse tumor cohorts to best understand tumor genomics across populations. Multiple Myeloma (MM) is a malignancy of plasma cells provoked by immunoglobulin gene rearrangements, accounting for slightly more than 10% of all hematologic cancer diagnoses in the US . PathogeSeveral previous profiling studies have provided a view of the somatic landscape of MM , 13. HowRecently, a comprehensive longitudinal study (CoMMpass) was initiated with the overall goal to prospectively observe the natural history of MM through comprehensively profiling 1,000 MM cases at diagnosis, with multiple biological and clinical follow-up points throughout the course of clinical management. Genomic profiling includes whole exome sequencing of germline and MM tumors, low pass whole genome sequencing, and RNA sequencing of tumors. Data are publicly distributed as Interim Analyses throughout the course of the study. Interim Analysis 9 (IA9) includes whole exome sequencing (WES) data from bone marrow tumor extracts with matching normal from 796 newly diagnosed MM cases. Patient ethnicity was one of the demographic parameters collected for each patient that included self-identification categories for African American, Caucasian, Asian, Hispanic, Middle Eastern, Other, Declined, and Unknown. This enabled us to perform genomic analyses to assess potential somatic differences from tumors based upon self-reported race. Alternatively, genetic ancestry is characterized by population genetic informative markers derived from allele frequencies of single nucleotide variances across biogeographical distributions  and is aFor this study, we utilized a subset of the CoMMpass IA9 dataset comprised of high quality WES and RNA-seq data from 721 newly diagnosed MM patients that were self-reported as either AA (N = 128) or CA (N = 593) with longitudinal clinical follow-up . For theTo delineate genetic ancestry, we used a population stratification principal component analysis (PCA) to cluster MM patients by extracting 4,761 Ancestry Informative Markers (AIMs) SNP genotypes derived from germline WES CoMMpass IA9 data . This alAnalysis of demographics data stratified by race confirmed the previously reported finding by Waxman et al.  of a sigKRAS, NRAS, BRAF, TP53, DIS3, and FAM46C  versus CA (8.3%) MM, however the difference did not reach statistical significance (p = 0.09). In addition, we further examined differences in BRAF mutation frequency between AA and CA cases. Although we did not detect a difference in overall BRAF mutation frequency, we did observe a difference in BRAFV600E mutation between AA (0.8%) versus CA (4.34%), but this difference did not reach nonimnal significance   algorithm  with cusd FAM46C  . Th. ThIRF4 um test) .TP53 loss based upon mutational analysis data, an integrated somatic copy number and mutational analysis of the TP53 locus was performed. This analysis revealed a predominance of bi-allelic TP53 events among CA MM cases  poorer overall survival  as compared to AA (0.8%), although this differenece did not exceed nominal significance due to limited power. Furthermore, we did not observe a difference in overall survival in primary MM cases harboring any BRAF mutation, nor specifically BRAFV600E mutation compared to BRAF wildtype cases . These results are of clinical consequence as BRAF mutations, particularly BRAFV600E, can be targeted with select BRAF inhibitors, which has shown effect in mutation positive MM cases [BRAF mutations have also been reported in MM, generally at frequencies of 2.8%-5% \u201329. AlthMM cases , 29.BCL7A has been shown to be directly involved in a three-way gene translocation with Myc and IgH in high-grade B-cell non-Hodgkin lymphoma cell lines [BRWD3 is a bromodomain and WD repeat containing protein that is thought to have chromatin-modifying function, and may play a role JAK/STAT pathway activity [AUTS2 is involved in translocations with PAX5 in B-cell precursor acute lymphoblastic leukemia and other cancers [Three of the genes with significantly higher mutation frequency in AA are involved in other B-cell malignancies. ll lines . As a rell lines . The proactivity . Importaactivity . Finally cancers . These fTP53 mutation frequency among patients with higher European admixture in our dataset. Integrated mutation and copy number analysis demonstrated a trend towards higher TP53 bi-allelic inactivation in tumors derived from CA cases. This could have translational significance as bi-allelic TP53 inactivation is a universally validated predictor of poor outcome [IRF4 mutation frequency, which was also higher among CA MM cases. IRF4 is a credentialed MM oncogene, which is known to be an oncogenic fusion partner in MM, and is also among the known significantly mutated genes in MM [IRF4 mutations in CA cases could have strong clinical translational implications. Although the collection of longitudinal clinical data is ongoing for CoMMpass, one current limitation of this study is the limited long-term follow-up data from IA9. However, the CoMMpass study design will allow us to assess outcomes longitudinally, along with molecular profiles of both newly diagnosed and relapse disease in upwards of 1,000 MM cases.Another significant observation of our study was the difference in  outcome . We furtes in MM , 36. Mores in MM , 38. TheUltimately, our study represents among the most comprehensive (WES and RNAseq) genomics studies of a tumor type in patients of African descent, and sheds light on potential ancestry-related differences in biological mechanisms of myelomagenesis. Three genes that are known to be involved in B-cell malignancy translocations represent new candidate myeloma genes that may have been overlooked because of the lack of AA cases in most large genomic efforts. It is clear that there are molecular differences between MM tumors from AA and CA cases, and that it is absolutely critical to continue to delineate these observations to better improve clinical management of the disease. As the CoMMpass study matures, it will allow scientists to validate these findings as well as expand on studies such as recurrence, better elucidation of driving mutations, and clonal evolution during the course of treatment.Samples were obtained under Multiple Myeloma Research Foundation (MMRF) CoMMpass Study Network Institutional Review Board approved Informed Consent; Copernicus IRB (IRB # QUI1-11-217).The design of the study is to prospectively profile newly diagnosed, treatment naive MM from 1000 patients with longitudinal clinical follow up. Tumor specimens collected at diagnosis and relapse are interrogated by whole-exome, modified low pass whole-genome, and or RNA sequencing. The longitudinal component requires clinical follow-up of each patient with collection of clinical parameters four times annually over a period of 10 years. Furthermore, each patient participating into the study underwent an IMID and/or Proteasome inhibitor based treatment regimen at diagnosis determined by the treating oncologist.CoMMpass data are systematically analyzed and periodically released in the form of Interim Analyses on a biannual basis. Interim Analysis 9 (IA9) is comprised of 796 unique baseline newly diagnosed bone-marrow samples with high quality WES data of which, 75 have confirmed progression with comprehensive clinical annotation. In addition, IA9 is comprised of 520 bone marrow baseline samples that were analyzed by both whole-exome and RNAseq platforms. The data is publically available at dbGAP accession number phs000748.In this study, we performed our analysis on whole-exome data from 741 of treatment-na\u00efve bone marrow derived MM matched normal samples from IA9, from those cases who self-reported race as either African American or Caucasian. To ensure high quality WES data for downstream copy number analysis, we removed samples that had maximum segmentation count above 2,500 to be in concordance with GISTIC 2.0 recommendation of maximum segment counts . This reBone marrow aspirates and peripheral blood samples were collected from each patient. Bone marrow aspirates from each patient were subjected to immunomagnetic bead separation using the Miltenyi MACS Cell Separation System  to enrich for CD138-positive malignant MM plasma cells. Only clinically eligible samples with greater than 250,000 cells recovered after CD138 enrichment, which are greater than 80% monoclonal light chain restricted plasma cells move forward for nucleic acid extraction. Genomic DNA was extracted from purified CD138-positive plasma cells (tumor) and matched peripheral blood samples  using QIAamp DNA Mini Kit (Qiagen). Total RNA was extracted from CD138-positive plasma cells the using QiaAmp RNeasy Mini Kit (Qiagen). Nucleic acids were quality assessed using the Qubit 2.0 (Thermo Fisher) and Agilent Tape Station to determine quantity and integrity. Samples were stored at -80\u00b0C for subsequent molecular analyses.DNA samples were used for two different assays including whole exome sequencing (WES) and low pass long insert whole genome sequencing (WGS). WES was prioritized if material was limiting. For WES, 50ng-250ng of genomic DNA was fragmented to an average size of 180bp in length using a Covaris focused-ultrasonicator (Covaris). An Illumina sequencing technology compatible whole genome library was created using Kapa Biosystems Hyper Prep Kits. These libraries were then subjected to whole exome target enrichment using Agilent SureSelect V5+UTR hybrid capture kits.For RNA-sequencing, either 150ng or 500ng of total RNA was used to enrich for poly-adenylated RNA molecules, which were subsequently fragmented to a target size of 180bp by heat fragmentation. Fragmented molecules were then converted to cDNA using random primers with Superscript II (Invitrogen). After second strand synthesis, the resulting molecules were used for library prep using the Illumina TruSeqRNA library kit.Parallel sequencing of libraries was performed on Illumina HiSeq2000 or HiSeq2500 systems using version 3 or version 4 chemistry. WES was sequenced using paired-end 83x83bp reads while long-insert whole genome libraries were sequenced using paired-end 86x86bp reads. All sequencing reads were converted to industry standard FASTQ files using BCL2FASTQ v1.8.4.http://broadinstitute.github.io/picard/) to mark duplicate read pairs. Post alignment joint INDEL realignment and base quality scores recalibration was performed on the BAM files using GATK v3.1\u20131 [FASTQ files are processed using a custom semi-automated pipeline based upon industry standard software packages and programs. Sequencing reads are initially aligned to the GRCh37 human genome reference using v0.7.8 BWA-MEM aligner  to generK v3.1\u20131 .For WES data, final BAM files for each patient\u2019s constitutional and tumor data were used for germline and somatic variant detection, respectively. Variants were called from germline and tumor BAM files individually using GATK Haplotype Caller v3.1\u20131  and SAMTSomatic copy number analysis was performed on WES germline-tumor pairs. For these studies, we utilized the DNAcopy segmentation module in BioConductor . We alsoSomatic events were assembled in VCF and MAF formats and further annotated using SNPeff  to proviFor RNA-sequencing analysis, we employed the TopHat v2.0.11 for alignment of RNA-seq reads, CuffDiff v2.2.1 for differential expression analysis, and Salmon 0.7.2 for isoform quantification .www.goldenhelix.com) genotype tool. Exome specific genome-wide Ancestry Informative Markers (AIMs) were derived from Kosoy et al. [www.goldenhelix.com) Genotype PCA tool that implements eigenvalue technique described by Patterson et al. 2006 [Genotypes for germline variants with >98% detection across all samples with exome data, and used for somatic analysis, were deduced using the SNP & Variation Suite v8.4.1  algorithm  with adjMyeloma samples were further stratified by two subtypes: hyperdiploid or nonhyperdiploid. Hyperdeploidy was defined by presence of trisomy of at least three odd-numbered chromosomes . The resGene expression profile was performed on RNA extracted from CD138+ plasma cells as described above using HiSeq2500 sequencer . RNA-seq Sailfish TPM values were log2 transformed prior to the analysis. To determine the high-risk score, we utilized the UAMC 70-gene expression profile . The highttps://bitbucket.org/jtr4v/analysis-of-mutational-signatures).Mutation signature was deduced using all somatic point mutations except INDELs using a publically available tool (https://www.r-project.org) and GraphPad Prism 7 .Each event between the stratified populations was analyzed appropriately either using the Fisher\u2019s exact test , non-parS1 FigAnalysis was performed using Kaplan-Meier method with long-rank test for group comparisons.(TIF)Click here for additional data file.S2 FigSci. Signal. 2013Gao et al.  & Cancer Discov. 2012Cerami et al.  was applied to generate the mutation profile across the TP53 domains with top representing mutation profile among Caucasian, and bottom representing African American respectively.cBioPortal Mutation Mapper tool as described by (TIF)Click here for additional data file.S3 Fig(A) Comparison of nonsilent mutation frequency between ancestry and self-reporting using Wilcoxon, Mann-Whitney, and Unpaired t-test to determine statistical significance. (B) Mutation signature associated with African and European ancestry.(TIF)Click here for additional data file.S4 FigDifferentially altered events indicated by arrows. The red graph indicate copy number gains and blue is deletions for each stratified group.(TIF)Click here for additional data file.S5 FigKi67 expression profile in TPM across patients with MM.(TIF)Click here for additional data file.S1 Table(XLSX)Click here for additional data file.S2 Table(RNAseq) used in this study.(XLSX)Click here for additional data file.S3 Table(PDF)Click here for additional data file.S4 Table(PDF)Click here for additional data file.S5 Table25(1).(XLSX)Click here for additional data file.S6 Table(XLSX)Click here for additional data file."}
+{"text": "Dear Editor,Sir, we report here a rare case of Rathke cleft cyst (RCC) resembling sellar/suprasellar arachnoid cyst (SAC) on magnetic resonance (MR) imaging.A 75-year-old male was admitted to our hospital complaining of visual field disturbance. Laboratory evaluations including hormonal tests demonstrated no abnormalities. His consciousness level was clear and neurological examinations revealed no abnormalities except for bitemporal hemianopia. MR imaging disclosed a sellar/suprasellar cystic mass, which displayed low intensity on T1-weighted MR imaging, high intensity on T2-weighted MR imaging, and low intensity on fluid attenuated inversion recovery (FLAIR) imaging; no enhancement was evident after contrast medium administration . The intraoperative findings indicated that the cystic contents were clear like CSF Fig.\u00a0a. The meThe cystic contents of RCCs display various intensities on MR imaging depending on the nature of the cystic contents . On the Different surgical techniques have been selected for RCCs and SACs , 3, 4. D"}
+{"text": "BK polyomavirus is an important pathogen in kidney transplant patients. We report here two complete genome sequences, those of isolates CAMB-1035 and CAMB-1055, identified in two urine samples tested for urinary tract infection at a hospital in eastern England, United Kingdom. Variation and phylogenetic analyses indicate that both isolates belong to subtype Ib-1. BK polyomavirus (BKPyV) is a nonenveloped double-stranded DNA (dsDNA) virus and ubiquitous human pathogen, with up to 90% of adults worldwide being seropositive , 2. PrimTC], 26.7 and 27.5); therefore, a PCR amplification step with a set of six custom BKPyV-specific primers covering the complete genome was used. Libraries were prepared using the Ion Xpress Plus fragment library kit (Life Technologies), per the manufacturer\u2019s instructions, and then size selected by 2% E-Gel SizeSelect (Invitrogen). Fragment size and concentration were measured by an Agilent Bioanalyzer and a Qubit fluorometer, respectively. Libraries were amplified on the One Touch 2 with the Ion PGM template OT2 400 kit (Life Technologies) and sequenced on an Ion Torrent PGM sequencer using the 318 Chip kit version 2 and Ion PGM Hi-Q sequencing kit (Life Technologies). Sequencing reads were trimmed by base quality and human host sequences filtered as described previously  assay. DNA extraction and sequencing were performed as follows: nucleic acid was extracted using the PureLink viral RNA/DNA kit (Invitrogen) from 100 \u03bcl of urine, followed by OneStep PCR inhibitor removal column (Zymo Research). The qPCR indicated low viral concentrations (threshold cycle [After assembly using metaSPAdes (version 3.7.1) , each BKNearly 300 BKPyV strains have now been completely sequenced. BLASTn analysis of the two genomes showed >97% sequence identity to BKPyV-Dun and a characteristic genome organization of six genes encoding regulatory and structural proteins separated by a noncoding region. The highest sequence identity (>99.8%) was to isolates SJH-LG-152 (GenBank accession number JN192431) and SJH-LG-306 (GenBank accession number JN192437). Globally, there are four BKPyV subtypes (I to IV), with subtype I divided into four subgroups  clustereLT934539 (CAMB-1035) and LT960370 (CAMB-1055) and ENA study accession number PRJEB22539. The version described in this paper is the first version.All sequences are publicly available and can be found within the EBI European Nucleotide Archive under the chromosome accession numbers"}
+{"text": "We aimed to explore the potential molecular mechanism and independent prognostic genes for colon cancer (CC).Microarray datasets GSE17536 and GSE39582 were downloaded from Gene Expression Omnibus. Meanwhile, the whole CC-related dataset were downloaded from The Cancer Genome Atlas (TCGA) database. Differentially expressed mRNA (DEMs) were identified between cancer tissue samples and para-carcinoma tissue samples in TCGA dataset, followed by the KEGG pathway and GO function analyses. Furthermore, the clinical prognostic analysis including overall survival (OS) and disease-free survival (DFS) were performed in all three datasets.ULBP2) was associated with OS in CC patients. A total of 12 DEMs including Surfactant Associated 2 (SFTA2) were potential DFS prognostic genes in CC patients. Meanwhile, the GRP and Transmembrane Protein 37 (TMEM37) were two outstanding independent DFS prognostic genes in CC.A total of 633 up- and 321 down-regulated mRNAs were revealed in TCGA dataset. The up-regulated mRNAs were mainly assembled in functions including extracellular matrix and pathways including Wnt signaling. The down-regulated mRNAs were mainly assembled in functions like Digestion and pathways like Drug metabolism. Furthermore, up-regulation of UL16-binding protein 2 (ULBP2 might be a potential novel OS prognostic biomarker in CC, while GRP and TMEM37 could be served as the independent DFS prognostic genes in CC. Furthermore, functions including extracellular matrix and digestion, as well as pathways including Wnt signaling and drug metabolism might play important roles in the process of CC. Colon cancer (CC) is one of the best-understood neoplasms from a genetic perspective . GloballNumerous data indicate that the aberrant accumulation of genetic changes functions as vital roles in initiation and development of colon and rectal cancer , 8. MessIn previous studies, Smith et al. , 16 and http://www.ncbi.nlm.nih.gov/geo/) database. A total of 177 invasive murine CC cells sample were included in dataset GSE17536. Meanwhile, a total of 566 CC samples were included in GSE39582. The gene expression profile data of GSE17536 and GSE39582 were all generated based on the platform of Affymetrix Human Genome U133 Plus 2.0 Array (GPL570 [HG-U133_Plus_2]). Furthermore, the whole CC-related dataset in TCGA database (https://cancergenome.nih.gov/) were downloaded.Microarray dataset GSE17536 , 16 and Normalized RNA-seq data  of TCGA dataset were downloaded for the further investigation. Meanwhile, the CEL source files of GSE17536 and GSE39582 were processed into background adjustment , quantilThe DEMs were identified between cancer tissue samples and para-carcinoma tissue samples in TCGA dataset based on Student\u2019s t test . P valuehttp://www.geneontology.org) functional annotation , GSE17536  and GSE39582 . Furthermore, up-regulation of ULBP2 gene was associated with shorter OS of CC patients. The detail information was showed in Fig.\u00a0The relationship between DMEs and OS in each dataset was showed in Fig.\u00a0SFTA2), LEM Domain Containing 1 (LEMD1), Cartilage Oligomeric Matrix Protein (COMP), Kinesin Family Member 26B (KIF26B), Kallikrein Related Peptidase 10 (KLK10), Matrix Metallopeptidase 11 (MMP11), Gastrin Releasing Peptide (GRP), Twist Family BHLH Transcription Factor 1 (TWIST1), Regulator Of G Protein Signaling 16 (RGS16), Collagen Type VIII Alpha 1 Chain (COL8A1), Transmembrane Protein 37 (TMEM37), Rho GTPase Activating Protein 44 (ARHGAP44)  and Bone Marrow Stromal Cell Antigen 2 (BST2) are associated with the progression of CC [TMEM37 and CC. In the current study, independent DFS prognostic genes analysis showed that GRP and TMEM37 were two most outstanding mRNAs, which might be used as the independent DFS prognostic genes. However, a further clinical investigation based on a large scale of sample size is still needed to confirm the thesis speculation.Prognostic biomarkers for cancer have the power to change the course of a disease if they add value beyond knew prognostic factors . ULBP2, oprotein . A previr for CC . Demirko in vivo . In the r for OS . In thisrocesses . A Previcificity . MatkowsCC cells . MoreoveCC cells . Based oon of CC , 55. UnfULBP2 was a novel overall survival prognostic gene in CC.GRP was an independent disease-free survival prognostic gene in CC.TMEM37 was an independent disease-free survival prognostic gene in CC.Extracellular matrix and digestion functions were important for CC.Wnt signaling and drug metabolism pathways were vital for CC."}
+{"text": "Lactococcus lactis strains and have significant implications for the dairy processing industry. Here, we report the complete genome sequences of eight lactococcal prophages chemically induced from industrial lactococcal strains that propagate lytically on one of two laboratory strains.P335 group phages represent the most divergent phage group infecting dairy  Lactococcus lactis have been classified into 10 taxonomic groups based on morphology and genetic content . The mitomycin C-treated cultures were filtered , and phage enumeration was conducted by a plaque assay (L.\u00a0lactis 3107 [http://tubic.tju.edu.cn/Zcurve_V/). Functional annotation was performed using BLAST against sequences present in the NCBI and Pfam (http://pfam.xfam.org/) databases. Final annotations were revised using the HHpred tool (http://toolkit.tuebingen.mpg.de/hhpred) and manually edited using the Artemis software package (http://www.sanger.ac.uk/resources/software/artemis). These eight genomes were between 31 and 36\u00a0kb in length, with 35% G+C content. Since the exact genomic termini have not been determined experimentally, the integrase-coding genes were assumed as the first ORF in line with previously published P335 phage genomes. Between 48 and 52 ORFs were predicted for each phage, and four putative functional modules were identified: (1) the lysogenic cassette (negative strand), (2) the replication module, (3) the morphogenesis module, and (4) the lysis module; these are genomic features that are well described in lactococcal P335 phages (To assess the presence of temperate phages in our ue assay  employintis 3107 ). Eight 5 phages . CurrentGenBank accession numbers are listed in"}
+{"text": "E-cadherin (CDH1). So, here we provided novel evidence for enrichment of APLF in breast tumors, which could regulate metastasis-associated EMT in invasive breast cancer. We anticipate that APLF could be exploited as a biomarker for breast tumors and additionally could be targeted in sensitizing cancer cells towards DNA damaging agents.DNA damage-specific histone chaperone Aprataxin PNK-like factor (APLF) regulates mesenchymal-to-epithelial transition (MET) during cellular reprogramming. We investigated the role of APLF in epithelial-to-mesenchymal transition (EMT) linked to breast cancer invasiveness and metastasis. Here, we show that a significant manifestation of APLF is present in tumor sections of patients with invasive ductal carcinoma when compared to their normal adjacent tissues. APLF was significantly induced in triple negative breast cancer (TNBC) cells, MDAMB-231, in comparison to invasive MCF7 or normal MCF10A breast cells and supported by studies on invasive breast carcinoma in The Cancer Genome Atlas (TCGA). Functionally, APLF downregulation inhibited proliferative capacity, altered cell cycle behavior, induced apoptosis and impaired DNA repair ability of MDAMB-231 cells. Reduction in APLF level impeded invasive, migratory, tumorigenic and metastatic potential of TNBC cells with loss in expression of genes associated with EMT while upregulation of MET-specific gene The online version of this article (10.1186/s12943-018-0826-9) contains supplementary material, which is available to authorized users. Recently, we demonstrated that reduced expression of histone chaperone APLF could enhance the kinetics and efficiency of reprogramming of mouse embryonic fibroblasts to induced pluripotent stem cells . APLF acAPLF alterations, comprising of a large cohort of patient samples (n\u00a0=\u2009817), further demonstrated an upregulation of APLF mRNA in invasive ductal carcinoma (IDC) of basal origin (27%) and in patients with triple negative breast tumors (22%)  for invasive ductal breast carcinoma with 31 matched control and normal (adjacent tissue or ANT) sections were investigated for the expression of APLF. Tumor sections demonstrated significant enrichment in APLF expression compared to matched normal sections Fig.\u00a0. To ensu2%) Fig. . Thus, T2%) Fig. . Migratircinomas . Interes-kd hereafter). A significant depletion in APLF expression to 90% was observed in MDAMB-231 cells   belongs to the group of forkhead transcription factors and termed as \u201cpioneer factor\u201d in breast cancer . FOXA1 rlls Fig.\u00a0. It is kpromoter  in contrlls Fig. . So downFOXA1 promoter was observed in control and APLF-kd cells Additional file 2:GSEA of genes induced in breast cancer metastasis among different repair pathways related to Fig. 2M. (XLSX 42\u00a0kb)Additional file 3:Expression of EMT associated genes related to Figure S7B. (XLSX 10\u00a0kb)"}
+{"text": "Early life impairments leading to lower lung function by adulthood are considered as risk factors for chronic obstructive pulmonary disease (COPD). Recently, we compared the lung transcriptomic profile between two mouse strains with extreme total lung capacities to identify plausible pulmonary function determining genes using microarray analysis (GSE80078). Advancement of high-throughput techniques like deep sequencing (eg. RNA-seq) and microarray have resulted in an explosion of genomic data in the online public repositories which however remains under-exploited. Strategic curation of publicly available genomic data with a mouse-human translational approach can effectively implement \u201c3R- Tenet\u201d by reducing screening experiments with animals and performing mechanistic studies using physiologically relevant in vitro model systems. Therefore, we sought to analyze the association of functional variations within human orthologs of mouse lung function candidate genes in a publicly available COPD lung RNA-seq data-set.Association of missense single nucleotide polymorphisms, insertions, deletions, and splice junction variants were analyzed for susceptibility to COPD using RNA-seq data of a Korean population (GSE57148). Expression of the associated genes were studied using the Gene Paint (mouse embryo) and Human Protein Atlas  databases. The genes were also assessed for replication of the associations and expression in COPD\u2212/mouse cigarette smoke exposed lung tissues using other datasets.p\u00a0<\u2009\u00a00.05) of variations in 20 genes to higher COPD susceptibility have been detected within the investigated cohort. Association of HJURP, MCRS1 and TLR8 are novel in relation to COPD. The associated ADAM19 and KIT loci have been reported earlier. The remaining 15 genes have also been previously associated to COPD. Differential transcript expression levels of the associated genes in COPD- and/ or mouse emphysematous lung tissues have been detected.Significant association  contains supplementary material, which is available to authorized users. Genetic predisposition is considered to be an important risk factor for COPD susceptibility. This is evident from the fact that only 15\u201320% of smokers develop COPD  this was the largest available COPD RNA-seq dataset at the Gene expression Omnibus (GEO) database. The raw FASTQ files of paired end reads representing the transcriptome of control and cases were retrieved from the GEO database at the National Centre for Biological Information (NCBI) through accession number GSE57148 (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE57148)  in Genome Expression Omnibus (GEO) database. \u2193: Decreased \u2191: Increased \u2713: significantly altered. Table S4. Analysis of l transcript expression of the associated 20 genes in mouse cigarette smoke exposed lungs using available datasets  in Genome Expression Omnibus (GEO) database. \u2193: Decreased \u2191: Increased \u2713: significantly altered. Table S5. The difference in minor allele frequencies of the associated single nucleotide polymorphisms (SNPs) between Korean population and global population indicates the influence of ethnicity on the findings. The Korean population data was accessed from the KoreanDB: http://152.99.75.168/KRGDB/menuPages/firstInfo.jsp and http://152.99.75.168/KRGDB/browser/mainBrowser.jsp Global SNP data(dbSNP database): https://www.ncbi.nlm.nih.gov/SNP/. Figure S1. Analysis of protein domain and functional sites in the \u201cA Disintegrin and metallopeptidase domain 19\u201d (ADAM19). Figure S2. Transcript  and protein expression  domain of holliday junction recognition protein (HJURP). Figure S3. Transcript  and protein expression  domain of microspherule protein 1 (MCRS1). Figure S4. Protein expression  domain of toll like receptor 8 (TLR8). Figure S5. Gene-set enrichment analysis for the associated 20 genes for (A) cellular component enrichment (B) biological process enrichment (C) molecular function enrichment (D) diseases enrichment using Enrichr interactive enrichment analysis tool [71]. (PDF 1296 kb)"}
+{"text": "Comparative analysis of transcriptomes between microphyllum and cultivated desi cv. ICC4958 detected 12772 including 3242 root- and 1639 shoot-specific microphyllum genes with 85% expression validation success rate. Transcriptional reprogramming of microphyllum root-specific genes implicates their possible role in regulating differential natural adaptive characteristics between wild and cultivated chickpea. The transcript-derived 5698 including 282 in-silico polymorphic SSR and 127038 SNP markers annotated at a genome-wide scale exhibited high amplification and polymorphic potential among cultivated (desi and kabuli) and wild accessions suggesting their utility in chickpea genomics-assisted breeding applications. The functional significance of markers was assessed based on their localization in non-synonymous coding and regulatory regions of microphyllum root-specific genes differentially expressed predominantly in ICC 4958 roots under drought stress. A high-density 490 genic SSR- and SNP markers-anchored genetic linkage map identified six major QTLs regulating drought tolerance-related traits, yield per plant and harvest-index in chickpea. The integration of high-resolution QTL mapping with comparative transcriptome profiling delineated five microphyllum root-specific genes with non-synonymous and regulatory SNPs governing drought-responsive yield traits. Multiple potential key regulators and functionally relevant molecular tags delineated can drive translational research and drought tolerance-mediated chickpea genetic enhancement.The RNA-sequencing followed by  Cicer that includes 44 annual and perennial species, grouped into primary, secondary and tertiary gene pools based on their crossability with cultivated chickpea1Cicer species reportedly originated from the South Eastern Turkey and Syria (Fertile Crescent)3456Cicer gene pools are rich reservoir of potential genes and alleles for improving abiotic/biotic stress tolerance and yield component traits in cultivated chickpea (C. arietinum)128910C. reticulatum) of primary gene pool (contrasting characteristics of high crossability with cultivated gene pool) have been made for enhancing the seed and pod yield and stress tolerance in cultivated desi and kabuli chickpea128910111213141516Chickpea belongs to the genus C. microphyllum, a member of tertiary gene pool is presumed to have originated from India and Turkey. The recent marker-based genetic diversity and population genetic structure studies documented a higher admixture and close phylogenetic relationship of one contrasting C. microphyllum accession domesticated primarily in the natural habitat alongside glaciers of the Hindu Kush Himalayas with cultivated desi chickpea of Indian origin2C. microphyllum accession characterized by a peculiar feature of deep tap root system in the diverse rocky soil topography of Himalayan region, infers its strong adaptation towards drought and cold climatic conditions. Furthermore, this perennial wild accession exhibiting a vital characteristic of dense pod dehiscence is believed to serve as a potential source of pod borer resistance in chickpeaC. microphyllum accessions for pod borer resistance can be thus exploited to broaden the genetic basis of resistance with an objective of driving marker-assisted disease resistance breeding and crop improvement in cultivated chickpeaC. microphyllum accession revealing close evolutionary relationship with cultivated desi accessions is a potential natural source of novel genes and alleles especially related to drought, salinity and cold tolerance as well as pod borer resistance in chickpea.desi and kabuli) and wild (including C. reticulatum) chickpea accessions provide opportunity to characterize their global transcriptomes rapidly with use of limited resources19202122232425262728293031323334212227363721222736372122273637222325263239192021222324252627282930313233C. microphyllum accession contrasting for several a/biotic stress tolerance traits  can be an attractive strategy to understand its transcriptomic constitution aside scanning of functionally relevant molecular tags  and natural allelic variants at a genome-wide scale for expediting marker-assisted genetic enhancement in chickpea.The draft whole genome and transcriptome sequences available for diverse growth/development and stress-imposed tissues/stages of multiple cultivated  on a constructed high-density inter-specific genetic linkage map (transcript map) of chickpea. The high-resolution QTL mapping was further integrated with comparative transcriptome profiling to delineate candidate genes underlying major drought yield QTLs in chickpea.In view of aforesaid possibilities, the present study employed a RNA-seq strategy to optimize C. microphyllum accession, the transcriptome sequencing of root and shoot tissue samples-derived RNA-seq libraries was performed using an Illumina NGS (next-generation sequencing) platform. These libraries were constructed by using the high-quality RNA isolated from three independent biological replicates of root and shoot tissue samples, each comprising pooled tissues from three randomly selected seedlings of a C. microphyllum accession. The natural adaptation of C. microphyllum accession towards abiotic stress  tolerance in adverse agro-climatic conditions is primarily because of its inherent characteristic feature of deep tap root system required for survival of this perennial wild chickpea in the diverse rocky soil topography of Himalayan regionC. microphyllum were utilized specifically for transcriptome profiling to obtain the maximum representation of genes/transcripts differentially expressed/regulated in this hardy wild perennial accession as compared to a cultivated desi (ICC 4958) chickpea during natural adaptive climatic conditions. The RNA sequencing of both root (mean 54.7 million reads) and shoot (64.1) tissues of C. microphyllum accession generated on an average of ~118.7 million paired-end sequence reads across all three replicates of studied samples (C. microphyllum roots and shoots. All the C. microphyllum transcriptome sequence resource generated in the present study was submitted to NCBI-SRA (sequence read archive) database under BioProject ID PRJNA31486 with accession IDs SRR3340324\u20133340327 for unrestricted use.To generate the global transcriptome of a wild perennial  samples . Of thes samples . The seqC. microphyllum transcriptome, the filtered high-quality transcript sequence reads were mapped primarily on the reference draft genome sequences of desi (ICC 4958) chickpea. On an average 55% (ranging 49\u201361% in shoots and roots) of transcript sequence reads derived from root and shoot samples of C. microphyllum were mapped uniquely across the chickpea genome. Subsequently, to increase the mapping efficiency of uniquely mapped sequence-reads and generate the optimal assembly of C. microphyllum transcriptome, the de novo assembly using all high-quality non-redundant sequence reads (by removing the duplicate reads) obtained from both root and shoot samples was performed. The summary statistics defining the best de novo transcriptome assembly outputs of C. microphyllum optimized in our study, are mentioned in the de novo assembled high-quality transcript sequences uniquely suggests the use of at least 89% of transcript sequence reads in de novo assembly of C. microphyllum. The optimized assembly resulted in generation of 154352 unique transcript sequences with the average transcript and N50 length of ~896 and ~1641 bp, respectively  transcript sequence reads constituted by us on the C. microphyllum transcriptome is higher/comparable to that documented earlier in reference-, de novo- and hybrid (reference and de novo) assembly-based transcriptome studies in crop plants including chickpea192021222324252627283233343538de novo assembled transcripts of C. microphyllum were mapped to reference desi chickpea genome. The use of 154352 unique high-quality transcript sequences in Cufflink followed by Cuffmerge assembly generated 38149 putative gene loci. The comparison of these candidate gene loci with the genes annotated from desi chickpea genome based on BLAST homology searches (with 90% sequence identity and 70% query coverage) exhibited orthology of 11219 (29.4%) unique C. microphyllum genes with 8465 (27.8%) candidate protein-coding genes  annotated from desi genome.With an effort to constitute a reference-guided assembly of the ectively . The mapde novo assembled C. microphyllum transcriptome. This led to the mapping of ~89% transcript sequence reads on the C. microphyllum transcriptome. The abundance of transcripts (referred as genes) from each sample was estimated in accordance with FPKM (fragments per kilobase of exon per million fragments mapped) followed by differential expression profiling through Cuffdiff. This analysis identified 11621 genes exhibiting significant (\u2265two-fold at P\u2009\u2264\u20090.05) differential up - and down -regulated expression specifically in roots as compared to shoots of C. microphyllum. Remarkably, 2514 (21.6%) including 1597 (63.5%) and 917 (36.5%) genes showed a pronounced higher (\u226510-fold at P\u2009\u2264\u20090.05) differential up- and down-regulation, respectively in roots than that of C. microphyllum shoots. Higher accumulation of differentially regulated transcripts especially in the roots of C. microphyllum may underlie its deep tap root system-mediated inherent characteristics of natural adaptation towards drought, salinity and cold tolerance in adverse agro-climatic condition. Therefore, these differentially regulated molecular tags especially expressed in the roots of C. microphyllum have functional relevance to decipher the regulatory gene (TFs) networks and/or metabolic pathways controlling abiotic stress tolerance traits in wild as well as cultivated chickpea.To determine the transcriptome responses based on differential gene expression profiling, the high-quality transcript sequence reads generated from each root and shoot tissue sample were mapped on our optimized C. microphyllum and ICC 4958 by correlating the differential expression profiles of genes in the roots and shoots of these accessions was performed. The detail statistics regarding mapping of transcript sequence reads obtained from control unstressed root and shoot tissues of ICC 4958 on the C. microphyllum transcriptome, are mentioned in the C. microphyllum and ICC 4958 (C. microphyllum and ICC 4958. Higher number of root-specific genes (3685) as compared to shoot-specific genes (2100) were differentially expressed in C. microphyllum and ICC 4958. A total of 3242 root- and 1639 shoot-specific genes exhibiting pronounced higher differential expression specifically in C. microphyllum were identified  as compared to that of ICC 4958 . Therefore, these abundant root-specific differentially expressed genes especially scanned from the C. microphyllum could be vital to decipher the possible key regulatory pathway/mechanism governing superior root-responsive natural adaptive characteristic of this hardy wild chickpea accession in adverse climatic condition  as compared to a known cultivated drought tolerant desi accession ICC 4958.The comparative analysis of transcriptomes between ICC 4958 . This inentified . Notablyophyllum . InteresC. microphyllum and ICC 4958 indicated primary roles of 3229 (25.3%) genes in multiple cellular, biological and molecular processes in crop plants. This revealed enrichment of differentially expressed genes  involved in translation, ribosomal structure and biogenesis , post-translational modification, protein turnover and chaperones , and energy production and conversion  , NAC , YABBY , bHLH  and WRKY  TF families were predominately altered/regulated in roots and shoots of C. microphyllum and ICC 4958  of 441 TF-encoding genes were differentially regulated in both roots and shoots while 128 TFs commonly between roots and shoots, and 136 (30.8%) and 86 (19.5%) TFs differentially expressed particularly in roots and shoots of C. microphyllum, respectively  . Among 4ICC 4958 . Of thesectively .MYB, bHLH, NAC and WRKY in C. microphyllum  than that of ICC 4958  was observed. In contrast, we observed more than 2.5 times higher expression of root-specific genes especially belonging to genetic information processing  in C. microphyllum than that of ICC 4958. In this context, remarkable differential regulation/alteration of diverse class of gene transcripts especially in C. microphyllum roots might impart enhanced adaptation to this hardy wild chickpea in adverse climatic condition  than that of a known cultivated drought tolerant desi accession ICC 4958. The differential transcript accumulation and regulation of TF-encoding genes  representing diverse TF families have implicated their common and/or specific role in multiple adaptive trait mechanism functioning in many crop plants (including chickpea) during acute climatic adversities384243Despite higher root-specific gene expression, more than three times differential expression of TF-encoding genes specifically belonging to abundant class of TF gene families like C. microphyllum and ICC 4958 was performed using KEGG database. Of these, 2212 (17.3%) genes were found to be significantly enriched with diverse pathways related to metabolism , genetic information processing  and environmental information processing   are majorly known to elicit diverse cell signalling and transcriptional events, and thereby play crucial role in various plant adaptive abiotic stress responses384245464748C. microphyllum and cultivated desi ICC 4958 accessions could serve as an immense transcriptomic resource for elucidating the key gene regulatory mechanism involved in differential abiotic stress tolerance adaptation traits especially between cultivated and wild chickpea. This will assist us to select best suitable differentially induced/regulated potential genes  from C. microphyllum for developing climate resilient cultivars and thereby accelerate translational genomics in chickpea.To determine the possible gene regulatory pathways/interactions involved in natural adaptation responses, the pathway analysis of 12772 genes/TFs differentially expressed in roots and shoots of 3, 8.3%) . RemarkaC. microphyllum and ICC 4958 were used for differential expression profiling. For this, the RNA isolated from the root and shoot tissues of six drought tolerant  and sensitive  desi and kabuli chickpea accessions including a C. microphyllum accession (used for transcriptome sequencing) was amplified with the gene-specific and endogenous internal control (EF1\u03b1) primers using the semi-quantitative and quantitative RT-PCR assays. The up- and down-regulated differential expression profiles of genes observed in roots and shoots of both C. microphyllum and ICC 4958 by RT-PCR assay was strongly correlated (85%) with that of our RNA seq-led transcriptome profiling study  perfect and 663 (11.6%) compound genic SSR markers from the transcript sequences of C. microphyllum  in silico polymorphic genic SSR markers were found most abundant than that of tri-nucleotide class I  and class II  SSR markers (in silico polymorphic 257 (91.1%) and 25 (8.9%) SSR markers were physically mapped on the eight chromosomes and unanchored scaffolds of the desi chickpea genome, respectively (desi genes. Maximum proportion of polymorphic SSR markers were derived from the CDS (coding DNA sequence)  followed by DRRs (downstream regulatory regions)  and URRs (upstream regulatory regions)  of genes  chickpea to discover genic SNPs at a genome-wide scale. Accordingly, 127038 transcript-derived genic SNPs differentiating the C. microphyllum and ICC 4958 were discovered with an average density of one SNP per 2.80\u2009kb  and lowest (2.34\u2009kb) SNP map-density, respectively (The  2.80\u2009kb . Of thesectively . The A/Gectively . The codectively .C. microphyllum transcript-derived SSR markers and 96 in silico polymorphic (between C. microphyllum and ICC 4958) SSR markers physically mapped on chromosomes were genotyped in 96 wild and cultivated chickpea accessions using agarose gel-based assay  developed from the C. microphyllum transcriptome at a genome-wide scale for large-scale genotyping applications including QTL/eQTL (expression QTL) mapping and association analysis to identify potential genes/QTLs controlling important agronomic traits in chickpea.To experimentally validate the genic SSR markers, 192 ed assay . This inICC 4958  and S3. in silico between C. microphyllum and ICC 4958 exhibited the presence of 1124 (0.9%) SNPs common between our present and past studies11252650desi (ICC 4958) genome  SNPs were genotyped in 96 wild and cultivated chickpea accessions using the MALDI-TOF MassARRAY genotyping assay. This included six known drought tolerant and sensitive accessions selected in our study for differential expression profiling. One hundred eighty-three  of 192 non-synonymous and regulatory SNP loci were successfully validated (polymorphic between C. microphyllum and ICC 4958) and exhibited polymorphism among 96 wild and cultivated (desi and kabuli) chickpea accessions with 95.3% validation success rate. Notably, these experimentally validated informative SNPs were derived from diverse coding and regulatory sequence components of differentially expressed root-specific genes/TFs of C. microphyllum and ICC 4958  genome . InteresICC 4958  and S4. C. microphyllum with the control and stress -imposed root and shoot tissue samples of ICC 4958 was performed. The detail statistics regarding mapping of transcript sequence reads obtained from ICC 4958 on the C. microphyllum transcriptome are mentioned in the C. microphyllum genes that were differentially up- and down-regulated (\u2265two-fold at P\u2009\u2264\u20090.05) under at least one root and shoot tissue sample/stress condition of ICC 4958 during drought, salinity and cold stress, respectively  of regulatory SNPs as compared to non-synonymous SNPs in the abiotic stress-responsive differentially expressed genes representing abundant class of KOG and KEGG-based functional categories was observed  in both the roots and shoots of ICC 4958 and especially in the roots of ICC 4958, are provided in the Our global transcriptome sequencing-based comparative differential gene expression profiles in shoots and roots of se genes . This anophyllum . Notablyesponses . Of thesophyllum . The detC. microphyllum and ICC 4958  were genotyped among 190 individuals of a RIL mapping population (ICC 4958\u2009\u00d7\u2009ICC 17163). The linkage analysis utilizing 500 marker genotyping information mapped 490 genic marker loci onto eight LGs (linkage groups) of an inter-specific transcript map of chickpea (111725263240515253To construct a saturated inter-specific genetic linkage (transcript) map, 500 SSR and SNP markers derived from the drought-responsive differentially expressed root-specific genes of chickpea , Fig. 6.chickpea , Fig. 6.chickpea . LG6 conchickpea . Collect2) and harvest-index (HI: 12.9\u201341.7 with 9.3\u201310.6% CV and 80\u201381% H2) in 190 individuals and two parental accessions of an inter-specific mapping population (ICC 4958\u2009\u00d7\u2009ICC 17163) under rainfed and irrigated environments across two geographical locations was observed (\u22124) based on estimated Pearson\u2019s correlation coefficient (r) was observed. The QTL mapping using the genotyping information of 490 gene-derived SSR and SNP markers mapped on an inter-specific transcript map and field phenotyping data of 190 RIL mapping population identified six major genomic regions harbouring six significant (6.5\u201311.5 LOD) QTLs associated with YP and HI traits which were mapped on six chromosomes (except chromosomes 1 and 8) of chickpea  and HI -associated major QTLs genetically mapped on six chromosomes identified by high-resolution QTL mapping were selected to delineate candidate gene(s) regulating drought tolerance-related yield traits in chickpea (desi chickpea genome defined genomic regions (spanning 518931\u20134888587\u2009bp) harbouring such robust QTLs on six chromosomes  exhibited drought-responsive root-specific expression as well as pronounced up-regulated expression (6.4 to 46.8-fold) especially in ICC 4958 based on our comparative transcriptome profiling study. Our quantitative RT PCR-based gene expression profile validation data also revealed up-regulated (>10-fold) differential expression of these six SNPs-carrying genes especially in the roots of known drought tolerant  chickpea accessions as compared to that of sensitive  accessions (C. microphyllum accession in contrast to other two known drought tolerant cultivated accessions (ICC 4958 and ICC 296131) was observed implicating the efficacy of delineated genes in regulating drought tolerance of chickpea.Six robust YP  and one TF (WRKY72) with non-synonymous and URR SNPs regulating drought tolerance-related yield traits scaled-down in this study, by integrating high-resolution transcript-derived SSR and SNP markers-based QTL mapping with comparative transcriptome profiling are functionally relevant. Based on previous documentation, these six genes/TFs are known to play crucial role in various abiotic (drought) stress responses by regulating diverse DNA binding and transcriptional activity, hormonal cell signalling, transport, metabolism and accumulation of transcripts/proteins in crop plants5556575859606162636465666768C. microphyllum and ICC 4958 transcriptome profiles can be deployed for various functional and translational genomic (marker-assisted breeding and transgenics) research. This will provide multiple essential leads, which could accelerate genomics-assisted crop improvement to develop drought tolerant superior high-yielding cultivars of chickpea.The five C. microphyllum accession for the first time at a high-resolution scale. The optimized de novo high-quality transcriptome assembly and comprehensive transcript sequence data for root and shoot tissues of this wild accession were generated to provide a global view of its gene content. The gene-encoding transcripts differentially expressed between roots and shoots of C. microphyllum accession were correlated with that of an available whole genome transcript sequence data of a desi chickpea accession (ICC 4958) based on comparative transcriptome profiling to identify candidate genes, transcription factors (TFs) and key regulators/metabolic pathways especially governing inherent root-mediated natural adaptation characteristics of C. microphyllum in adverse agro-climatic condition. Based on these, numerous experimentally well-validated C. microphyllum transcript/gene-based SSR and SNP markers derived from the coding and regulatory sequence components of genome and/or root- and shoot-specific abiotic  stress-responsive differentially expressed genes of ICC 4958 were discovered to accelerate high-throughput genetic analysis in chickpea. These informative genic SSR and SNP markers were genotyped successfully in an advanced generation mapping population to construct a high-density inter-specific genetic linkage map (transcript map) and for molecular mapping of major QTLs governing two drought-responsive important yield traits (yield per plant and harvest-index) in chickpea. An integrated genomic approach by combining high-resolution drought yield QTL mapping with comparative transcriptome profiling was employed to delineate candidate gene(s) harbouring major QTLs regulating yield per plant and harvest-index in chickpea. Overall, this study provides a deep transcriptomic insight into the gene regulatory networks governing differential root-mediated natural adaptation responses in a hardy wild perennial C. microphyllum accession as compared to that of an already existing cultivated high-yielding drought stress tolerant desi chickpea accession (ICC 4958). The comprehensive transcriptome, informative genic SSR and SNP markers, differentially expressed genes, a high-resolution inter-specific genetic linkage/transcript map and major drought yield QTLs and potential genes/natural allelic variants especially generated in our study at a global scale can serve as a useful resource to drive translational genomics for genetic enhancement in chickpea.The current study utilized a RNA-seq strategy to sequence transcriptome of an Indian origin perennial wild C. microphyllum) accession were grown in the pots filled with soil between the temperature range of minimum 17\u2009\u00b1\u20091.5\u2009\u00b0C to maximum 20\u2009\u00b1\u20091.2\u2009\u00b0C at Palampur, Himachal Pradesh (latitude: 32.1\u00b0N and longitude: 76.5\u00b0E). At least three independent biological replicates of each root and shoot tissue sample were collected from the 10\u201315 days old seedlings (vegetative stage) of C. microphyllum accession and frozen instantly with liquid nitrogen. The total RNA was isolated from the tissues using an RNeasy Plant Mini Kit  following manufacturer\u2019s instruction. The quality and quantity of RNA samples was assessed by denaturing agarose gel-based assay, NANODROP 2000 Spectrophotometer  and Qubit\u00ae 3.0 Fluorometer  following the methods of Garg et al.et al.The seeds of one selected perennial wild  sequence reads for each sample. The raw Fastq sequences were filtered through the recommended Illumina pipeline and NGS QC Toolkit v2.3The total high-quality RNA isolated from three independent biological replicates of each root and shoot tissue sample of a de novo transcriptome assembly, the high-quality filtered sequence reads obtained from three independent biological replicates of root and shoot tissue samples of a C. microphyllum accession were analysed with Trinity (vr2012-05-18) and CLC Genomics Workbench (v4.7.2) tools. To obtain best transcriptome assembly, most vital parameters including k-mer and insert length, and expected coverage were optimized as per Garg et al.19C. microphyllum using the available draft genome sequence of its evolutionary close desi chickpea accession (ICC 4958)  and PFAM database v27.0 (http://pfam.sanger.ac.uk). The KOG -based functional annotation of the C. microphyllum transcripts and identification of TF-encoding genes from these transcripts were performed following the methods of Kujur et al.For CGAP v2.0 as a refC. microphyllum accession were mapped/aligned individually on the constituted de novo transcriptome assembly using Tophat (v2.0.0)http://www.clcbio.com) with default parameters. The Cufflinks (v2.0.2)C. microphyllum accession. The genes/transcripts revealing at least two-fold expression change with P value\u2009\u2264\u20090.05, were considered significant to be differentially expressed.For gene-encoding transcript expression analysis, all the high-quality sequence reads obtained from each of the root and shoot tissue samples of C. microphyllum transcript assembly and differential expression profiling of root and shoot (control/unstressed)-derived transcripts/genes between C. microphyllum and ICC 4958 were performed following the above-mentioned strategy. The heatmaps depicting the differential expression profiles of genes/transcripts (log2 fold-change) in unstressed control roots and shoots of C. microphyllum and ICC 4958 were constructed based on hierarchical clustering employing MultiExperiment Viewer (Mev v4.9). The KOG-based functional annotation of the C. microphyllum and ICC 4958 transcripts and TF-encoding gene identification from the differentially expressed transcripts were performed following the aforesaid strategy. The molecular interactions based on biochemical pathway mapping of differentially expressed genes/transcripts were performed using KEGG pathway database (http://www.genome.jp/kegg/pathway.html).For comparative transcriptome profiling, the raw transcriptome sequence data of control (unstressed) as well as drought, cold and salinity stress-imposed root and shoot tissue samples of ICC 4958 that are freely accessible at NCBI Gene Expression Omnibus (GEO) database (GSM1299261-GSM1299268) were retrievedC. microphyllum and ICC 4958 were selected to design primers using Primer Express (v3.0) . The RNA isolated from the root and shoot tissue samples of six drought tolerant and sensitive desi and kabuli chickpea accessions including a C. microphyllum accession (used for transcriptome sequencing) following aforesaid methods. In the RT-PCR assay, RNA isolated from three independent biological replicates of each root and shoot sample and two technical replicates of each biological replicate with no template and primer as control was used for expression study. For gene/transcript expression profiling, the isolated high-quality RNA was amplified with gene-specific primers using ABI 7500 Real-Time PCR System , following the methods as previously described by Kujur et al.et al.EF1\u03b1) was utilized in RT-PCR assay for normalization of gene/transcript expression value. The correlation between transcriptome sequencing and RT-PCR profiles assayed in roots and shoots of C. microphyllum and ICC 4958 was analysed through R program. The differential expression (fold change) profiles of genes/transcripts assayed in roots and shoots of drought tolerant and sensitive chickpea accessions was measured. Significant difference in gene/transcript expression among diverse tissues and/or accessions was determined by LSD-ANOVA significance test using SPSS 17.0 (http://www.spss.com/statistics). The significant difference in gene/transcript expression profile was visualized by a heat map using MeV.For experimental validation of gene expression through semi-quantitative and quantitative real-time (RT) PCR assays, the genes/transcripts exhibiting high root-specific differential expression especially in C. microphyllum transcripts were analysed with MISA  as per Kujur et al.in silico polymorphic genic SSRs based on variation of repeat-units length in the transcript/gene sequences between C. microphyllum and ICC 4958 (desi reference genome) were identified following the methods as described previously2776in silico polymorphic SSR repeats using the Primer3 interface module of MISA as per Kujur et al.To discover genic SSRs, the C. microphyllum and ICC 4958 were mined using Tophat and samtool. The high-quality genic SNPs differentiating the C. microphyllum and ICC 4958 accessions were screened following the criteria as defined by Jain et al.et al.in silico polymorphic SSR) and SNP markers were structurally and functionally annotated in the diverse coding and non-coding regulatory sequence components of desi chickpea (ICC 4958) genome as per Jain et al.et al.42C. microphyllum that were differentially expressed in the roots and shoots of ICC 4958 under drought, cold and salinity stresses.The genic SNPs in the transcript/gene sequences between C. microphyllum transcript-derived SSR markers and 96 in silico polymorphic SSR markers  were selected based on their localization especially in the diverse coding and regulatory sequence components of root-specific genes (TFs)/transcripts of C. microphyllum that were differentially expressed especially in the roots of ICC 4958 under drought stress. These SSR markers were genotyped in 96 wild and cultivated chickpea accessions22776For experimental validation of genic SSR markers, 192 C. microphyllum and ICC 4958 in silico, the genotyping information of SNPs differentiating these two chickpea accessions was compared/correlated with the available in silico SNP database according to their nature/types of SNP alleles and physical positions (bp) on the desi (ICC 4958) genome11252650C. microphyllum based on their drought-responsive differential expression especially in the roots of ICC 4958. These SNPs were further genotyped in 96 wild and cultivated chickpea accessions  using Sequenom MALDI-TOF (matrix-assisted laser desorption ionization-time of flight) MassARRAY as per Saxena et al.et al.To validate genic SNPs identified between 8 RIL (recombinant inbred line) mapping population derived from the inter-specific crosses between two parental chickpea accessions (C. arietinum desi accession ICC 4958\u2009\u00d7\u2009C. reticulatum wild accession ICC 17163) was developed to construct a genetic linkage map (transcript map) and for identification/mapping of major drought-responsive yield QTLs in chickpea. The genotyping data of drought-responsive root-specific differentially expressed gene-derived SSR (genotyped by gel-based assay) and SNP (Sequenom MALDI-TOF MassARRAY) markers revealing polymorphism between mapping parental accessions (ICC 4958 and ICC 17163) was utilized to generate an inter-specific genetic linkage map (transcript map) at a higher LOD (logarithm of odds) threshold (>4.0) with Kosambi mapping function following Saxena et al.et al.desi chickpea genome. The previously documented genic SNP markers mapped on eight LGs exhibiting polymorphism between two mapping parental accessions (ICC 4958 and ICC 17163) were used as anchor markers to define the identity of LGs/chromosomes of an inter-specific genetic map constructed in the present study. The identity of LGs was further ascertained by positions (cM) and groupings shared by anchor markers among eight LGs/chromosomes between current and past studies25A 190 Fet al.2) of YP and HI traits phenotyped in a RIL mapping population were measured as per Saxena et al.et al.et al.et al.The RIL mapping individuals and two parental accessions (ICC 4958 and ICC 17163) were grown in the field [as per randomized block design (RBD) with at least two replications] during crop growing season (minimum 13\u2009\u00b1\u20092.2\u2009\u00b0C and maximum 21\u2009\u00b1\u20092.5\u2009\u00b0C) for two consecutive years (2012 and 2013) under rainfed and irrigated environments at two diverse geographical locations  of India. Accordingly, these were phenotyped for two vital drought tolerance-related traits, namely yield (g) per plant (YP) and harvest-index (HI%) especially under rainfed and irrigated environments following Varshney How to cite this article: Srivastava, R. et al. Transcriptome landscape of perennial wild Cicer microphyllum uncovers functionally relevant molecular tags regulating agronomic traits in chickpea. Sci. Rep.6, 33616; doi: 10.1038/srep33616 (2016)."}
+{"text": "Following publication of the original article  the authSurvival-adjusted health-related quality of life (HRQL) among patients with metastatic breast cancer receiving paclitaxel plus bevacizumab versus paclitaxel alone: Results from Eastern Cooperative Oncology Group Study 2100 (E2100). Breast Cancer Research and Treatment, 2011. 130(3): p. 855\u2013861.Cella, D., et al.,"}
+{"text": "Chronic hepatitis C (CHC) is a major cause of liver disease worldwide which often leads to progressive liver inflammation, fibrosis, cirrhosis and hepatocellular carcinoma (HCC). CHC displays heterogeneous progression depending on a broad set of factors, some of them intrinsic to each individual such as the patient's genetic profile. This study aims to evaluate the contribution of certain genetic variants of crucial interferon alpha and lambda signaling pathways to the hepatic necroinflammatory activity (NIA) grade of CHC patients.IL-28B, IFNAR1-2, JAK-STAT and OAS1-3, among others) were genotyped using the Illumina GoldenGate\u00ae Genotyping Assay. Statistical association was determined by logistic regression and expressed as OR and 95% CI. Those SNPs significantly associated were further adjusted by other covariates.NIA was evaluated in 119 CHC patients by METAVIR scale and classified as low  or high grade . In a candidate gene approach, 64 SNPs located in 30 different genes related to interferon pathways (IL-28B (rs12979860), JAK1 (rs11576173 and rs1497056), TYK2 (rs280519), OAS1 (rs2057778), SOCS1 (rs33932899) and RNASEL (rs3738579) genes were significantly related to severe NIA grade (p<0.05). Regarding to clinical variables, elevated NIA was notably associated with aspartate aminotransferase (AST) serum levels >40 IU/L (p<0.05) but not with other clinical factors. Multivariate logistic regression analysis of these factors reflected that AST (>40 IU/L), TYK2 rs280519  and RNASEL rs3738579  were factors independently associated with elevated NIA (p<0.05). AST concentration showed a moderate AUC value (AUC = 0.63), similar to TYK2 (rs280519) and RNASEL (rs3738579) SNPs  in the ROC_AUC analysis. Interestingly, the model including all significant variables reached a considerable predictive value (AUC = 0.74).Seven SNPs located in The identified genetic variants in interferon signaling pathways may constitute useful prognostic markers of CHC progression. Further validation in larger cohorts of patients is needed. IL-28B rs12979860 polymorphism with the attainment of sustained virological response (SVR) in patients treated with the conventional antiviral therapy (pegylated-interferon and ribavirin) [IL-28B (rs12979860) for combination treatment outcome [Hepatitis C virus (HCV) is a major cause of liver-related morbidity and mortality, affecting 170 million people worldwide . Althougbavirin) . SimilarIL-28B C/C rs12979860 genotype and higher degree of hepatic inflammation and fibrosis in CHC patients has been described [On the other hand, the implication of inflammation in the progression of CHC and development of HCC is well established and several inflammatory signaling pathways link inflammation and cancer ,14. Therescribed \u201317. BaseThe study population included 119 patients of European descent from Hospital Universitario de La Princesa, Hospital Universitario San Cecilio de Granada and Hospital Universitario Central de Asturias. All patients gave their written informed consent to participate in the genetic analysis before their enrollment. This retrospective cohort study was approved by the local Ethics Committee of Hospital de La Princesa  and good clinical practice guidelines were followed.\u00ae assay  and the reverse-hybridization line probe assay , respectively. At Hospital Universitario San Cecilio, viral load was determined the by HCV Ampliprep TaqMan, Roche Molecular System (cutoff <15 IU/mL). Patients showed no evidence of HBV infection, HIV infection, alcoholism, autoimmune, or drug-induced liver disease. Patients\u2019 serum samples were also subjected to routine laboratory tests in the biochemical laboratory of each center using common commercial methods, measuring alanine transaminase (ALT), aspartate aminotransferase (AST) and gamma glutamyl transferase (GGT).Included patients had previous diagnosis of HCV infection, which was confirmed by the presence of detectable HCV RNA in serum. HCV RNA levels and HCV genotype were determined using the COBAS AMPLICORLiver biopsies, obtained for diagnostic purposes, were analyzed histologically according to the METAVIR classification system , which sDNA was isolated from whole blood samples from Hospital Universitario de La Princesa and Hospital Universitario San Cecilio by using a MagNA Pure DNA isolation kit  in accordance with the manufacturer\u2019s instructions and stored at \u221280\u00b0C until assay. Genomic DNA was extracted from peripheral blood samples from Hospital Universitario Central de Asturias with the Magtration-MagaZorb DNA Common Kit-200 N using the Magtration 12GC system  and the Maxwell 16 Blood Purification Kit using the Maxwell 16 Instrument .www.hapmap.org) for the CEU population. The specific location of each SNP  is detailed in  or location in key regulatory regions as described in the HapMap project, Release no. 27, Phase II and III . Associations between variables and NIA were assessed by Mann-Whitney U-test or Chi-squared test. Two-tailed p values below 0.05 were considered significant .Subsequently, significant clinical variables and SNPs were analyzed by multivariate logistic regression using a step-backward method, in which none of the variables was forced to be included into the model. ROC analyses were performed to discriminate the power of factors independently associated with inflammatory grade .Main clinical characteristics of the 119 patients included in the study are summarized in Genotype frequencies of each SNP and its association with necroinflammatory activity are detailed in . Of the IL-28B (rs12979860), JAK1 (rs11576173 and rs1497056), OAS1 (rs2057778), RNASEL (rs3738579), TYK2 (rs280519) and SOCS1 (rs33932899) genes were significantly related to severe NIA grade . In fact, IL-28B C/C genotype was more frequent in patients with severe NIA grade (38%) than in patients presenting moderate liver inflammation (25%). JAK1 rs14907056 G allele showed a higher frequency among patients with severe NIA grade (21% vs. 10% in moderate NIA). Additionally, JAK1 rs11576173 A/A genotype showed to be more frequent among patients with severe NIA, although this result could be doubtful because of the total number of patients carrying this genotype (n = 5). Similarly, rs2057778 C/C and rs33932899 G/G genotypes located in OAS1 and SOCS1, respectively, showed a slight relation to severe NIA grade; however, only 5 and 3 patients carried the risk genotypes (RNASEL (rs3738579), an interferon stimulated gene (ISG), displayed an association with liver inflammation, being the G allele related to severe NIA (p = 0.036). TYK2 rs280519 showed the stronger association with NIA grade: while the A/A genotype was present in near 30% of the patients with moderate NIA, only 8% of the patients with severe liver inflammation carried this genotype (p = 0.009).Seven SNPs located in IA grade , p<0.05.enotypes . One of TYK2 rs280519 and RNASEL rs3738579 were independent factors strongly associated with elevated NIA .Main clinical characteristics and the seven SNPs found in association with NIA grade were included in a multivariate logistic regression analysis . RegardiTYK2 rs280519 nor RNASEL rs3738579 SNPs were significantly related to other clinical variables such as viral load, AST, ALT, GGT or fibrosis stage . Nonetheless, the model including all the above variables showed the best predictive value (AUC = 0.74).ROC_AUC analysis of each variable associated with NIA in the multivariate analysis was performed to assess their putative predictive value . AST serIL-28B [As known, HCV clearance, CHC progression and response to treatment is driven by multiple and complex interactions among host, viral and environmental factors . Innate IL-28B \u201311.Interestingly, in this study we have inspected multiple SNPs located at numerous IFN related genes finding an independent association of some of them with the NIA of CHC patients. In particular, rs280519 and rs3738579 showed a significant influence in the grade of the disease and displayed a considerable individual predictive performance, which was substantially improved when they were simultaneously considered in addition to AST serum levels (AUC-ROC = 0.74).2>0.8) with other ten SNPs in European descent population . Interepulation . This po to date .TYK2 makes this SNP of particular interest for transcriptional regulation. Four SNPs were found in linkage disequilibrium with rs280519 in the last data released by The 1000 Genomes Project , all ofPhase 3 ,37). In . In TYK2Further validation of the above described genetic signature may entail a great interest for accurate prediction of CHC patients with higher risk of CHC progression, with special attention to the unexpected elevated occurrence/recurrence of hepatic and extrahepatic manifestations related to current IFN-free based therapies.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S1 Fig2 threshold = 0.8 and distance limit 500kb.Linkage disequilibrium plot of rs280519 was generated by using the SNP Annotation and Proxy Search tool . Plot w(PDF)Click here for additional data file."}
+{"text": "E. coli pathotypes are blended in hybrid strains. E. coli strains with hybrid enteroaggregative/uropathogenic (EAEC/UPEC) genotypes have sporadically emerged causing outbreaks of extraintestinal infections, however their association with routine infections is yet underappreciated. We assessed 258 isolates of E. coli recovered from 86 consecutive cases of extraintestinal infections seeking EAEC and hybrid genotype (EAEC/UPEC) strains. Extensive virulence genotyping was carried out to detect 21 virulence genes, including molecular predictors of EAEC and UPEC strains. Phylogenetic groups and sequence types (STs) were identified, as well as it was performed phylogenetic analyses in order to evaluate whether hybrid EAEC/UPEC strains belonged to intestinal or extraintestinal lineages of E. coli. Adhesion assays were performed to evaluate the biofilm formation by hybrid strains in human urine and cell culture medium (DMEM). Molecular predictors of UPEC were detected in more than 70% of the strains (chuA in 85% and fyuA in 78%). Otherwise, molecular predictors of EAEC (aatA and aggR) were detected in only 3.4% (9/258) of the strains and always along with the UPEC predictor fyuA. Additionally, the pyelonephritis-associated pilus (pap) gene was also detected in all of the hybrid EAEC/UPEC strains. EAEC/UPEC strains were recovered from two cases of community-onset urinary tract infections (UTI) and from a case of bacteremia. Analyses revealed that hybrid EAEC/UPEC strains were phylogenetically positioned in two different clades. Two representative strains, each recovered from UTI and bacteremia, were positioned into a characteristic UPEC clade marked by strains belonging to phylogenetic group D and ST3 (Warwick ST 69). Another hybrid EAEC/UPEC strain was classified as phylogroup A-ST478 and positioned in a commensal clade. Hybrid EAEC/UPEC strains formed biofilms at modest, but perceptible levels either in DMEM or in urine samples. We showed that different lineages of E. coli, at least phylogenetic group A and D, can acquire and gather EAEC and UPEC virulence genes promoting the emergence of hybrid EAEC/UPEC strains.Virulence genes from different  Escherichia coli colonizes the human intestine few hours after birth establishing a mutually beneficial relationship with its hosts. While they are restricted to the outer layer of intestinal mucus, these commensal E. coli strains rarely cause infections. However, some highly adapted E. coli lineages have evolved acquiring a broad range of virulence genes (VGs) that allows E. coli strains to adapt to, colonize and invade several anatomic sites  named as A, B1, B2, and D  strains are frequently classified as phylogroup B2 or D, while commensal strains are frequently sorted into phylogroup A or B1. Nevertheless, mechanisms of horizontal genetic transfer allows the exchange of VGs among phylogroups, which may promote the sporadic emergence of highly virulent strains belonging to commensal phylogroups A or B1. Additionally, each E. coli phylogroup may enclose heterogeneous groups of strains and different clonal populations, fact which imposes a more complex scenario in an attempt to establish epidemiological links between E. coli phylogroups and human infections  and sepsis/meningitis. Diarrheagenic E. coli (DEC) strains are sorted into six well-defined pathotypes, each displaying distinctive VG arrangements: enteropathogenic E. coli (EPEC), enterohemorrhagic E. coli (EHEC), enterotoxigenic E. coli (ETEC), enteroinvasive E. coli (EIEC), diffusely adherent E. coli (DAEC), and enteroaggregative E. coli (EAEC)  and aggR (the master virulence regulator in EAEC). Additionally, the pAA may harbor other EAEC-specific VGs, including alleles of aggregative adherence fimbriae , dispersin gene (aap), and the plasmid-encoded toxin gene (pet). EAEC prototype strain 042 has an archetypal pAA plasmid displaying a complete set of virulence genes: aatA, aggR, aafA, aap, and pet. However, epidemiological studies have shown that wild type strains maintain pAA plasmids with a virulence load quite different from the one from archetypal EAEC plasmids. As an example, wildtype EAEC strains collected in epidemiological approaches may show a low frequency for the detection of aggregative fimbriae genes and pet  was proposed to define typical EAEC strains  are the most common cause of bacterial infections in humans, mainly among women, and account for around 100 million cases a year  which can be combined into different genotypes. Despite that diversity, a set of four VGs has been reported as a predictor of UPEC strains. Any two of the genes chuA (heme receptor), yfcV (YfC fimbria) or vat (vacuolating autotransporter protein), when detected along with the gene fyuA (yersiniabactin siderophore receptor), can be used to differentiate UPEC strains from commensal and DEC strains  and fimbria F1C (focA) play a pivotal role in ascending UTIs since they promote the colonization of proximal and distal tubular cells from human kidney  pathotypes, EAEC virulence genes are among the most frequent markers of DEC strains reported in ExPEC strains isolated from sporadic cases of extraintestinal infections and outbreaks , under the registry number 782.067.E. coli-associated extraintestinal infections attended to in a tertiary hospital in Bras\u00edlia-DF, Brazil. Two hundred fifty eight isolates of E. coli (3 isolates for each sample) were isolated from 86 consecutive cases of extraintestinal infections including urinary tract infection (79 cases); bacteremia (1 case); pneumonia (1 case); surgical site infection (2 cases); peritoneal cavity infection (1 case); and mucosa infections (2 cases) , fimbriae curli (csgA gene), antigen 43 adhesin (ag43), plasmid-encoded type IV pilus (pilS), and the EAEC mucinase gene (pic) (Table aatA (formerly pCVD432 probe) aggR (EAEC virulon regulator gene) and aapA (dispersin gene)  and 17-2  were used as positive controls for the detection of EAEC markers. The Pasteur Institute-referenced strains FVL2  and FV34  were used as positive controls for UPEC markers. Primers designed in this study (Table FN554767.1 from EAEC 042 (primers aapA); EU637023.1 from E. coli C1010-00 (primers hdaB-A); KP202151.1 from E. coli plasmid pAA Agg5A (primers agg-5A); HG941718.1 from E. coli EC958 (primers fyuA); CP000243.1 from E. coli UTI89 (primers yfcV); AF280396.1 from E. coli hemin receptor ChuA (primers chuA); KR094957.1 from E. coli PAB72 (primers vat); AF298200.1 from E. coli AD110 (primers focA); AF483829.1 from E. coli 5383-2 (primers cnf); L04979.1 from E. coli curli gene (primers csgA); and, AF233272.1 from E. coli antigen 43 precursor gene (primers ag43).The detection of virulence genes was carried out by the polymerase chain reaction (PCR). Supernatants derived from bacterial suspension treated by boiling were used as the source of DNA template. All strains were tested for the presence of 8 virulence markers of UPEC (c) Table . In ordeE. coli phylogroups  was performed by PCR as described by Doumith et al.  . BigDye Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems\u2122) was employed in sequencing reactions and amplicons were analyzed with ABI-Prism 3500 Genetic Analyzer (Applied Biosystems\u2122). Clonal complexes (CC) were defined as groups of two or more independent isolates that shared identical alleles at six loci. The correspondence between STs assignment by Pasteur's scheme and Achtman's scheme was based on results published in previous studies  , supplemented with 0.5% of casamino acid and used as culture medium in biofilm assays.Healthy women with no history of consumption of antibiotics or anti-inflammatoreis within the last 15 days and with no clinical urinary symptoms were selected to donate urine samples. Donators were instructed, informed about the absence of health risk associated with the urine collection, and signed an informed consent term allowing the urine collection. Morning samples of urine (volume of 50 mL) were collected by spontaneous urination, centrifuged (3000 g/3 min), sterilized by ultrafiltration (0.22 \u03bcm) and preserved at \u221220\u00b0. Samples of sterile urine were pooled . Results with Cases of extraintestinal infections were predominantly associated with phylogroup B2 (37/86\u201343%) and D (33/86\u201338%), followed by the phylogroups B1 (6/86\u20136.9%) and A (5/86\u20135.8%) (Data not shown). In three cases of UTIs, different phylogroups were simultaneously recovered: A/B2; B1/D and B2/D.chuA (85%) and fyuA (78%) were predominantly detected among ExPEC strains. Additionally, the genes for UPEC-specific fimbriae pap and yfcV were detected in 47 and 41% of the strains, respectively  than in the intestinal groups (A and B1) (p < 0.001\u2014Fisher's exact test)  Table . MoreoveaatA and aggR were co-detected in 3.4% (9/258) of the ExPEC strains recovered from 3 out of 86 studied cases (3.4%). Besides aatA and aggR, the UPEC genes fyuA and pap were always found forming the genotypes of these strains, which highlighted their hybrid nature: hybrid EAEC/UPEC strains (Table aggA) were also detected in the EAEC/UPEC strains isolated from the UTI case 63 (Table aapA), although they did not harbor any of the EAEC-predictor markers aatA or aggR (Table The molecular predictors of EAEC n = 8) and was followed by ST43 (n = 3) (Warwick ST 131). Five STs were of single occurrence , and two STs were single-locus variants of ST43 and ST4 (Warwick ST73) (Table n = 11) belong to genetic lineages recognized by the epidemic potential (ST3 and ST43), including two of the hybrid EAEC/UPEC strains.Three hybrid EAEC/UPEC strains  had their allelic profiles and STs determined and compared with 19 contemporaneous UPEC strains, each from a different case chosen randomly Table  (Table 5dinB-icdA-pabB-polB-putP-trpA)  with positive results for molecular predictors of UPEC (fyuA and chuA) and UPEC-specific fimbria Pap as well . The prototype EAEC strain 042 was positioned in a separate clade, although it also belongs to phylogroup D. A different phylogenetic position was displayed by the EAEC/UPEC strain 63.1, which was positioned in a different major branch sharing a clade with the reference sequence of commensal strain K12. Endorsing that phylogenetic positioning is the fact that both strains belong to phylogroup A . Hybrid EAEC/UPEC formed biofilms at modest, but perceptible levels either in DMEM (median = 0.535 with Q3 = 0.731) or in urine (median = 0.270 with Q3 = 0.411). Just six strains showed an invariable ability to form biofilm despite the tested conditions (DMEM or human urine), including the hybrid EAEC/UPEC strain 63.1 (mean of 0.535 \u00b1 0.76 in DMEM and 0.553 \u00b1 0.026 in urine)  and 85.1 (genotype: aatA aggR aapA fyuA chuA pap csgA), the EAEC/UPEC strain 63.1 (genotype: aatA aggR aggA aapA fyuA vat focA pap csgA ag43) distinguishes from them for harboring the EAEC-specific fimbria AAF-I (aggA) and focA. In comparison to the prototype EAEC strains 17-2  and 042 (positive for AAF/II), the strain 63.1 formed biofilms at similar levels when tested in human urine  of EAEC/UPEC strains was tested and compared to the adherence of 77 UPEC strains Figure . In geneaatA  along with EAEC gene aggA (aggregative adherence fimbriae I \u2013 AAF/I), which highlighted the hybrid aspect of these strains  along with pap (UPEC pilus).EAEC is a heterogeneous category that has been recognized for gathering versatile pathogens since the late 1990's, when their epidemiological association with diarrhea involving children, adults, HIV-infected patients and travelers became more and more evident  was initially identified in the EAEC prototype strain 042 as a mucinase that displayed a pivotal role in the colonization of the intestinal mucus layer during diarrhea  can be acquired by UPEC strains. Concerning the EAEC/UPEC strains 17.1 and 85.1 (both classified as phylogroup D-ST3[ST69]), our findings conflict with the paradigm stablished in the literature that poses that diarrheagenic virulence markers are rarely detected in UPEC strains from phylogenetic group D-ST3[ST69]  may also include highly virulent UPEC strains. The hybrid EAEC/UPEC strain 63.1, characterized for having the most complete set of tested virulence genes for EAEC  and UPEC , besides being positive for csgA and ag43, was classified as phylogroup A. E. coli strains with similar genetic arrangements have already been associated with UTI outbreaks. In 1991, it was detected in Copenhagen an UTI outbreak involving a hybrid EAEC/UPEC strain   allowed a pronounced increase of bacterial adherence to human bladder epithelial cells as well as it allowed biofilm formation at levels significantly higher than those of UPEC prototype strains  showed an ability to produce invariable and perceptible biofilms in both DMEM and human urine. Although the biofilm levels had not been higher than those produced by the prototype EAEC strain 17-2 in DMEM, EAEC/UPEC strain 63.1 formed biofilms at higher levels than those formed by the strain 17-2 and at similar levels to those formed by prototype UPEC strains when tested with human urine.The formation of biofilms is considered to be a pivotal step during infection processes developed in human mucosas. EAEC strains are renowned for their prolific ability to form biofilms, which are in general supported by the aggregative adherence fimbriae (AAFs) coded on the plasmid pAA. Cases and outbreaks of UTI involving heteropathogenic EAEC/UPEC strains have endorsed the suspicion that EAEC virulence genes add uropathogenic properties to aatA aggR aapA fyuA chuA were recovered from diarrhea and included the prototype strain 042  with the grants No 193.000.019/2012 and 193.001.042/2015.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "We here report the case of a 68-year old female patient presenting with inflammatory poorly systematized bilateral lumbosciatica, without vesico-sphincteric disorders or associated general symptoms evolving for 4 months. Physical exam showed gait with little steps with trunk anteflexion, disappearance of lumbar lordosis, lumbar spine stiffness, positive bilateral Las\u00e8gue's test and hyperactive osteotendinous reflexes in lower limbs without motor and sensory deficit or saddle block anesthesia. Laboratory tests did not show any inflammatory syndrome. Lumbar spine X-rays were normal. Given the abnormal clinical picture, spinal MRI was performed which showed oval intracanalar mass behind L4 vertebral body, measuring 3 cm height with discrete hypersignal on T1 (A) and with hypersignal on T2 (B), enhanced after gadolinium administration and containing superior polar cystic component. The patient underwent tumor resection in orthopaedics. Histological examination of the surgical specimen revealed myxopapillary ependymomas."}
+{"text": "Reference 36 is incorrect. The correct reference is: Wang L, Michoel T (2017) Efficient and accurate causal inference with hidden confounders from genome-transcriptome variation data. PLoS Comput Biol 13(8): e1005703."}
+{"text": "Elasmosaurid plesiosaurians were globally prolific marine reptiles that dominated the Mesozoic seas for over 70 million years. Their iconic body-plan incorporated an exceedingly long neck and small skull equipped with prominent intermeshing \u2018fangs\u2019. How this bizarre dental apparatus was employed in feeding is uncertain, but fossilized gut contents indicate a diverse diet of small pelagic vertebrates, cephalopods and epifaunal benthos. Here we report the first plesiosaurian tooth formation rates as a mechanism for servicing the functional dentition. Multiple dentine thin sections were taken through isolated elasmosaurid teeth from the Upper Cretaceous of Sweden. These specimens revealed an average of 950 daily incremental lines of von Ebner, and infer a remarkably protracted tooth formation cycle of about 2\u20133 years\u2013other polyphyodont amniotes normally take ~1\u20132 years to form their teeth. Such delayed odontogenesis might reflect differences in crown length and function within an originally uneven tooth array. Indeed, slower replacement periodicity has been found to distinguish larger caniniform teeth in macrophagous pliosaurid plesiosaurians. However, the archetypal sauropterygian dental replacement system likely also imposed constraints via segregation of the developing tooth germs within discrete bony crypts; these partly resorbed to allow maturation of the replacement teeth within the primary alveoli after displacement of the functional crowns. Prolonged dental formation has otherwise been linked to tooth robustness and adaption for vigorous food processing. Conversely, elasmosaurids possessed narrow crowns with an elongate profile that denotes structural fragility. Their apparent predilection for easily subdued prey could thus have minimized this potential for damage, and was perhaps coupled with selective feeding strategies that ecologically optimized elasmosaurids towards more delicate middle trophic level aquatic predation. Liopleurodon [ca 330 mm versus an eight metre maximum body length in Hydrotherosaurus [Plesiosaurians (Plesiosauria) were highly diverse Mesozoic marine amniotes whose fossil record extended over 135 million years. During this vast timeframe the clade achieved a variety of body forms and feeding modes ranging from massive-skulled megacarnivores  and mesrosaurus . The funrosaurus , to amburosaurus \u201311, and rosaurus , passiverosaurus , 14. Irrrosaurus , and optrosaurus . In addirosaurus , 16). Hosensu [ca 45/10 mm in maximum crown height/basal diameter [Aristonectes [ca 20 mm in crown height [The teeth of elasmosaurids were distinctive amongst plesiosaurians in their elongate tapered profile and often labiolingually-compressed crowns  that wesensu ) with didiameter ) were altonectes , 20, 21)n height ) dental n height , 20 simin height , 22\u201324.Pliosaurus [Like other plesiosaurians , 25, andiosaurus ). The priosaurus . Therefoiosaurus .in situ elsmosaurid dentitions are exceptionally rare and not readily accessible for destructive analysis, we obtained a discrete sample of 131 isolated elasmosaurid teeth, historically referred to Scanisaurus [Belemnellocamax mammillatus belemnite zone at \u00c5sen and Iv\u00f6 Klack\u2013two geographically proximal localities (~ 6 km apart) in the northeastern Kristianstad Basin of Sk\u00e5ne in southern Sweden [Scanisaurus teeth exhibited damage from pre-burial abrasion, surface weathering and/or excavation, which precluded volumetric assessments of mean size based on complete teeth [in situ elasmosaurid dentitions .Lamit 109, Kittfort) and impregnated with EpoFix (Struers) prior to cutting on a 150 mm diamond blade, and abrasion to 0.2 mm on a Montasupal grinder  using silicon carbide. The resulting 25 mounted petrographic slides (Leitz DM RXE microscope equipped with a Leica DFC 550 camera and LAS v.4.2 software. Diagenetic modification was assessed using Field emission gun scanning electron microscopy (FEG-SEM) undertaken on uncoated slides with a Zeiss Supra 35-VP (Carl Zeiss SMT) incorporating a low vacuum VPSE detector, Robinson BSD backscattered electron-imaging attachment, and coupled EDX Apex 4 (Ametekh) EDS-detector for dispersive X-ray microanalysis. This detected high component phosphate, implying minimal elemental alteration in the samples from \u00c5sen (Four teeth from \u00c5sen (PMU 28757\u2013PMU 28760), and three from Iv\u00f6 Klack (PMU 28761\u2013PMU 28763) were selected for thin sectioning based on overall crown completeness and/or intact roots. These specimens were embedded in bicomponent epoxy resin  and belImageJ .All petrographic slides  and accompanying image metadata produced by the described study are publically accessible through the PMU fossil collection and digital archives.Microstructural examination of the thin (~120\u2013150 \u03bcm) prismatic enamel layers revealed discrete dark-coloured laminations . These mOdontocyte lacunae and radially arrayed dentinal tubules were observed extending from the pulp cavity . LongituDiscolouration from secondary minerals highlighted faint concentric staining up to ~50 \u03bcm in thickness, which was only visible in some transverse sections . OccasioScanisaurus concurs with previous reports of extended dental replacement cycles in plesiosaurians and other more basal sauropterygians [Scanisaurus could therefore indicate a comparable adaptation towards discretized tooth function, which in anisodont elasmosaurids presumably involved selective elongation of the premaxillary-maxillary and dentary \u2018fangs\u2019 via modified growth periods and rate of odontoblast/ameloblast differentiation during apical dentine secretion [Scanisaurus, which is frequently compared with homodont elasmosaurids such as Aristonectes [Our evidence for protracted tooth formation in dental remains attributed to the Late Cretaceous elasmosaurid erygians , 26\u201328. erygians ), but haerygians . The detecretion . Neverthecretion , 20, 21,ecretion , 50). Thtonectes , 34, butAnother important implication is the increased likelihood of severe tooth wear, breakage and/or related disease , 37. Cer"}
+{"text": "The pike-perch iridovirus (PPIV) was isolated in Finland from apparently healthy pike-perch fingerlings during routine disease surveillance. Our phylogenomic analysis revealed that PPIV is the first fish member of a clade of ranaviruses previously described from European and Chinese amphibians. Ranavirus (Pike-perch iridovirus (PPIV) was isolated in Finland in 1995 from apparently healthy pike-perch fingerlings during routine disease surveillance . A DNA library was prepared using the Nextera XT DNA kit (Illumina), and sequencing was performed using a version 3 chemistry 600-cycle kit on a MiSeq platform (Illumina). De novo assembly of 4,981,658 paired-end reads in SPAdes  with 10% fetal bovine serum (FBS) at 23\u00b0C. Inoculation of EPC cells at a high multiplicity of infection (MOI) provided sixth-passage material harvested after 48\u00a0h when CPE was extensive. Cell culture supernatant was clarified at 3,000 \u00d7 A total of 109 putative open reading frames (ORFs) were predicted using GeneMarkS  and GATUIridoviridae core genes  amphibians. An analysis of locally collinear blocks in Mauve (Maximum likelihood phylogenetic analysis based on concatenated amino acid sequences of the 26 re genes  revealedin Mauve  revealedWild amphibians were observed in the same ponds that yielded PPIV from asymptomatic pike-perch, leaving open the possibility of interclass transmission , 12. ExpKX574341.The complete genome sequence of PPIV has been deposited in GenBank under the accession no."}
+{"text": "NRAS and KRAS proto-oncogenes are among the most common in human cancer and frequently occur in acute myeloid leukemia (AML). An inducible NRAS(V12)-driven AML mouse model has established a critical role for continued NRAS(V12) expression in leukemia maintenance. In this model genetic suppression of NRAS(V12) expression results in rapid leukemia remission, but some mice undergo spontaneous relapse with NRAS(V12)-independent (NRI) AMLs providing an opportunity to identify mechanisms that bypass the requirement for Ras oncogene activity and drive leukemia relapse. We found that relapsed NRI AMLs are devoid of NRAS(V12) expression and signaling through the major oncogenic Ras effector pathways, phosphatidylinositol-3-kinase and mitogen-activated protein kinase, but express higher levels of an alternate Ras effector, Ralb, and exhibit NRI phosphorylation of the RALB effector TBK1, implicating RALB signaling in AML relapse. Functional studies confirmed that inhibiting CDK5-mediated RALB activation with a clinically relevant experimental drug, dinaciclib, led to potent RALB-dependent antileukemic effects in human AML cell lines, induced apoptosis in patient-derived AML samples in vitro and led to a 2-log reduction in the leukemic burden in patient-derived xenograft mice. Furthermore, dinaciclib potently suppressed the clonogenic potential of relapsed NRI AMLs in vitro and prevented the development of relapsed AML in vivo. Our findings demonstrate that Ras oncogene-independent activation of RALB signaling is a therapeutically targetable mechanism of escape from NRAS oncogene addiction in AML.Somatic mutations that lead to constitutive activation of  While the genetic landscape of AML has been extensively characterized, genetically based targeted therapies have yet to be realized and the optimal therapeutic target(s) are not known.3Despite aggressive combination chemotherapy, the majority of patients with acute myeloid leukemia (AML) die of relapsed treatment refractory disease.RAS proto-oncogenes are mutated in about 10\u201315% of human AML, and additional recurring AML mutations rely on Ras signaling for their oncogenic effects .6 A critical role for oncogenic Nras and Kras in leukemogenesis and maintenance of AML cells has been substantiated in genetically engineered mouse models.10 Furthermore, the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K) pathways downstream of Ras have been shown to regulate leukemic stem cell self-renewal in AML.11 In fact, the MAPK and PI3K pathways are active in the majority of patient-derived AML samples, further supporting a key role for Ras signaling in AML maintenance.13RAS mutations are among the most common molecular alterations in human cancer, and thus Ras has been the focus of intense interest for drug development.14 A major obstacle for targeted cancer treatment approaches has been the almost ubiquitous development of treatment resistance. For example, disruption of the post-translational modification of Ras with farnasyltransferase inhibitors demonstrated encouraging preclinical activity, but their clinical activity has been limited owing to resistance conferred by alternative biochemical pathways for the prenylation of Ras.15 Targeting BRAF and/or MEK has shown encouraging responses for BRAF(V600E) mutant non-small-cell lung cancer and melanoma, but responses have been variable and transient owing to treatment resistance.20 It has become clear that diverse mechanisms such as disruption of drug\u2013target interaction, mutations or amplifications that lead to activation of downstream signaling pathways, and/or activation of alternative growth and survival pathways can lead to resistance to most, if not all, targeted cancer therapies.22 Therefore, a better understanding of disease and context-specific resistance mechanisms will be essential to develop rational combination strategies for specific diseases.Oncogenic tetracycline-repressible NRAS(V12) and Mll-AF9-driven AML genetically engineered mouse model (tNM AML).8 The leukemia cells in this model are NRAS(V12)-dependent (NRD), and suppressing NRAS(V12) expression leads to rapid remission in leukemic mice, further highlighting the clinical potential of targeting oncogenic NRAS in AML.8 This model faithfully recapitulates the key challenge for clinically targeted cancer treatment, in that some mice spontaneously relapse with NRAS(V12)-independent (NRI) AML, providing a robust tool to study the mechanisms of relapse after Ras oncogene-targeted therapy. We interrogated key cancer signaling pathways, performed global gene expression analysis and performed functional studies to identify mechanisms that drive relapse with NRI AML and provide insight into the rational development of novel targeted treatment approaches for AML.To model Ras oncogene-targeted therapy for AML, we used a 8 In this system, suppression of NRAS(V12) expression resulted in rapid leukemia regression  in relapsed NRI AMLs in the presence of Dox treatment, thereby confirming the NRAS(V12) independence of the relapsed NRI AMLs (We confirmed leukemia . SimilarRI2 AMLs . WesternNRI AMLs .NRAS(V12) in both de novo NRD and relapsed NRI AML cells (NRAS(V12) suppression in de novo NRD AML, but was maintained at higher levels in relapsed NRI AMLs, even in the absence of NRAS(V12) expression  analyses of key cancer signaling pathways. Flow cytometric analysis confirmed a decrease in canonical oncogenic Ras effector signaling pathways\u2014MAPK and PI3K\u2014with decreased levels of phosphorylated ERK and AKT following Dox-mediated suppression of ML cells . Phosphopression . The exppression . Proapoppression , suggestpression .23 Of the 292 epitopes interrogated, 27 showed different levels of protein expression or phosphorylation between Dox-treated NRD AML and relapsed NRI AMLs .8 NRI1 and NRI2 AML cells were more similar to each other than NRD AML cells as determined by unsupervised clustering. Notably, NRI1 and NRI2 samples did not segregate in unsupervised clustering based on all identified transcripts . Bruton\u2019s tyrosine kinase, a member of the Tec kinase family, has been identified as a targetable pathway in AML.28 The PI3K signaling pathway was the most inhibited pathway in relapsed NRI AMLs compared with de novo NRD AML , consistent with their decreased dependence on canonical Ras signaling. The canonical nuclear factor-\u03baB signaling pathway was activated in relapsed NRI AMLs compared with de novo NRD AML  and NFKB1 was among the predicted activated upstream regulators in relapsed NRI AML cells . Other predicted upstream regulators that were activated in relapsed NRI AMLs included HOXA9 , CEBPA  and STAT3  that have established roles in AML.31We performed Ingenuity Pathway Analysis to identify enriched cellular processes, signaling pathways and predicted upstream regulators of differentially expressed genes . The Tecde novo NRD AML and relapsed NRI AMLs  independence for relapsed NRI AMLs we evaluated the differential expression of genes that are known to be associated with RALB activation and signaling 36 (AKT (myrAKT) or CRAF 22W, did not effectively rescue leukemic colony formation  inhibitors are lacking, dinaciclib, a cyclin-dependent kinase inhibitor, has been shown to inhibit CDK5-mediated activation of Ral signaling.P levels . DinacicP levels , but didll cycle . Dinacicll cycle . To veri(Q72L)36 . Notablyormation .37In vitro treatment of a panel of AML samples with dinaciclib uniformly resulted in decreased phosphorylation of TBK1 and increased cleavage of CASP3, while normal mononuclear cells from healthy donors were relatively insensitive to dinaciclib treatment  expression), or dinaciclib  in AML and represent putative mechanisms of resistance to therapeutically targeting oncogenic NRAS. In the NRAS(V12)-addicted tNM AML mouse model, some mice spontaneously relapsed with NRAS oncogene-independent AML despite continued suppression of NRAS(V12) expression. The spontaneous relapse seen after mimicking RAS oncogene-targeted cancer therapy closely resembles the major clinical challenge for targeted cancer therapies in general,40 and confirm that NRAS(V12)-addicted AML cells can acquire alternative mechanisms for maintained growth and survival and survive in the absence of the NRAS oncogene. With renewed efforts to therapeutically target oncogenic Ras proteins, our results have important implications for anticipating therapeutic challenges for such treatment strategies.42 Specifically, we found that relapsed AMLs developed an NRI mechanism to maintain signaling through RALB. The ability of inhibition of RALB signaling to suppress the clonogenic potential of relapsed NRI AML and to prevent AML relapse in leukemic mice supports further investigation of this pathway as a therapeutic target. Furthermore, the potent antileukemic effect of inhibiting RALB signaling in human AML, including patient-derived AML cells in vitro and in vivo, highlights the translational potential for our findings.In this study, we investigated potential mechanisms that bypass the requirement for 43 Consistent with this, we recently demonstrated a key role for RALB in AML cell survival.37 RALA or RALB activity are essential for cancer cell proliferation in a murine KRAS-driven non-small-cell lung cancer model.44 While RALB has a central role in innate immune signaling, chronically activated RALB associates with SEC5 in the exocyst complex and activates the noncanonical I\u03baB kinase family member TBK1, a critical mediator of RALB\u2019s oncogenic activity.45 The mechanism by which the RALB-TBK1 axis supports cancer cell survival remains unclear and are likely context and disease dependent, but have been shown to involve regulators of normal innate immune signaling in several models.46 A large-scale synthetic lethal RNAi screen uncovered a critical role for TBK1 in KRAS-driven transformation of epithelial cells through activation of nuclear factor-\u03baB antiapoptotic signals involving REL and BCL-xL.38 We found that upregulation of Cdk5 and Rgl2, activators of RALB signaling,35 as well as increased Ralb expression was associated with NRI activation of RALB-TBK1 signaling in relapsed AMLs. Activation of RALB signaling and upregulation of components of the nuclear factor-\u03baB transcriptional complex were accompanied by an altered balance of pro- and antiapoptotic mediators, consistent with previous reports suggesting that nuclear factor-\u03baB signaling downstream of RALB supports cancer cell survival.45 We have previously shown that RALB enhances expression of BCL2 in AML, providing a potential mechanism by which RALB drives NRI AML relapse.37 Consistent with this, BCL2 family inhibitors to suppressed the clonogenic potential of relapsed NRI AML cells; however, the precise mechanisms that promote AML cell survival downstream of RALB remain to be elucidated.There is mounting evidence that the activation and cellular localization of Ral GTPase effector proteins have an important role in Ras-driven transformation, proliferation, migration and survival.47 contributes to the antileukemic activity of dinaciclib. In fact, drugs that target multiple pathways may reduce the ability of AML cells to coopt alternate resistance pathways. Our findings support the further investigation of the critical targets of dinaciclib in AML. New small molecules that directly inhibit Ral function may provide additional tools to study the role and therapeutic potential of RALB signaling in AML as they become available.48While targeting RALB activation with dinaciclib demonstrated potent RALB-dependent antileukemic effects on AML cells, we cannot exclude the contribution of RALB-independent effects. It is possible that dinaciclib-mediated inhibition of CDK1, another protein that was enriched in relapse NRI AMLs, or CDK9, an alternate survival pathway for MLL-rearranged AMLs,RAS oncogene dependence of AML cells. The altered balance of pro- and antiapoptotic mediators in relapsed NRI AML cells that could be a direct or indirect result from enhanced RALB signaling warrants further investigation. YAP, a mediator of the Hippo signaling pathway that has been shown to mediate resistance to inhibition of MAPK signaling and promote Kras oncogene independence in oncogenic pancreatic cancer,25 was enriched in relapsed NRI AMLs. Overall, the broad deregulation of signaling and gene transcription observed provides a foundation for the ongoing rational development of targeted treatment approaches designed to mitigate or prevent relapse after Ras targeted treatment strategies.Our data also identified several other potential mechanisms that may bypass 41 Furthermore, our results support further characterization of RALB signaling as a key mediator of survival and NRAS-independent relapse in AML and as a valid therapeutic target.This work provides important insight into the mechanisms of response and resistance to targeted cancer treatment approaches in general, and particularly for renewed efforts to therapeutically target Ras signaling.P<0.05 using a t-test. For leukemic cell transplantation, 2 \u00d7 106 tNM AML cells, 4 \u00d7 106 THP1-luciferase AML cells or 2 \u00d7 106 patient-derived AML cells were injected via tail vein into 6\u201310-week-old recipient mice. Severe combined immunodeficiency (SCID) beige  mice did not receive any preconditioning before murine AML transplantation. NRG or NRGS  mice received 375\u2009cGy from an X-ray source 24\u2009h before human AML transplantation. Peripheral blood was obtained by retro-orbital blood sampling and leukocyte counts were monitored using a Hemavet 950 . THP1-luciferase mice were monitored using an IVIS 100 Imaging System . PDX mice were monitored by flow cytometry of peripheral blood stained for human CD45 and human CD33. Doxycycline-treated mice were given 4\u2009mg intraperitoneally doxycycline  followed by 5\u2009mg/ml in their water.All mouse studies were approved by the University of Minnesota Institutional Animal Care and Use Committee. Roughly equal number of male and female mice were used for all experiments and evenly allocated to experimental groups without systematic randomization or blinding. Group sizes were determined based on the number of mice required for 80% power to detect a difference in the mean AML burden of at least 1.5\u2009s.d. between experimental and control groups with in vitro studies inhibitors were diluted in the growth medium. For in vivo studies dinaciclib was diluted in 20% hydroxypropyl-\u03b2-cyclodextrin and administered intraperitoneally.Dinaciclib, ABT-737 and ABT-199 were purchased from Selleck Chemicals  and reconstituted in dimethyl sulfoxide (DMSO). For NRD and NRI AML cells were cultured in RPMI-1640  with 10% fetal bovine serum  with or without 1\u2009\u03bcg/ml doxycycline (Sigma-Aldrich) for 48\u2009h or inhibitors for 24\u2009h and then plated in IMDM (Lonza) with 30% fetal bovine serum, 1.275% methylcellulose  and 2\u2009ng/ml murine GM-CSF (R&D Systems). Human AML cells were treated with inhibitors for 24\u2009h and then plated in MethoCult H4034 . Colonies were scored after 7\u201314 days on an inverted microscope.Protein lysates were run on 10% polyacrylamide gel electrophoresis gels and transferred to a PVDF using the NuPAGE and iBlot Systems . RALB-GTP levels were determined using the RALB Activation Assay Kit . Blots were blocked and stained according to antibody manufacturer\u2019s recommendations. Blots were developed using the SuperSignal West Pico ECL  or Advansta Quantum ECL Kit  and signals were quantified using the LI-COR Imaging System .49 Briefly, for intracellular antigens cells were fixed with 2% paraformaldehyde  and permeabilized with 90% methanol (Sigma-Aldrich). Cells were stained with antibodies according to the manufacturer\u2019s recommendations. Cells were analyzed on an LSR II or Fortessa Digital Flow Cytometer  and analyzed using the FlowJo software .Flow cytometric analysis was performed as described previously.For western blotting, NRAS (F155) mouse monoclonal IgG1 (sc-31) and HRP-conjugated secondary antibodies were purchased from Santa Cruz Biotechnology ; BCL-xL rabbit polyclonal (2762) and GAPDH (14C10) rabbit monoclonal (2118) were purchased from Cell Signaling Technologies ; and BCL2 mouse monoclonal (610538) was purchased from BD Biosciences. For flow cytometry, c-MYC (9E10) Alexa Fluor 700, BAD (Y208), BAX (E63), BCL2 (E17), BCL-xL (E18) and BIM (Y36), and MCL1 (Y37) were purchased from Abcam/Epitomics ; phospho-4EBP1 (Thr46) and phospho-mTOR (Ser2448) were purchased from Thermo Fisher; cleaved caspase-3  phycoerythrin, cleaved PARP  Alexa Fluor 647, phospho-4E-BP1  Alexa Fluor 647, phospho-AKT  Alexa Fluor 488, phospho-p44/p42 MAPK  phycoerythrin, BCL-xL (54H6), BIM (C34C5), IkBa (L35A5), PTEN (138G6), phospho-JNK , phospho-S6 (Ser235/236) and phospho-TBK1  phycoerythrin were purchased from Cell Signaling Technologies; PUMA (RB1353-RB1354) was purchased from Novus Biologicals ; and phospho-TBK1  Alexa Fluor 488, cleaved PARP (Asp214), Ki67 (B56), phospho-AKT , phospho-STAT5 , human CD45 (2D1) FITC and human CD33 (P67.6) phycoerythrin were purchased from BD Biosciences.q-value of \u2a7d0.05.Total splenocytes were harvested from leukemic mice, snap frozen in liquid nitrogen and sent to the MD Anderson RPPA Core Facility for analysis. Briefly, protein lysates were serially diluted and arrayed on nitrocellulose-coated slides using an Aushon 2470 Arrayer . The slides were scanned, analyzed and quantified using Array-Pro Analyzer . Protein concentrations were normalized by median polish, which was corrected across samples by the linear expression values using the median expression levels of all antibody experiments to calculate a loading correction factor for each sample. Normalized protein values were used to evaluate differential target levels between NRD and NRI samples using a Benjamini\u2013Hochberg-corrected 50 Differential expression between NRD and NRI samples was determined using Cuffdiff.51 R (R core Team 2013) was used to visualize expression data. Genes with RNAseq expression variation over 0.2 were log transformed and mean centered. The resulting data was clustered using Pvclust package with correlation as distance metric and average clustering method.52 Differential transcript expression was defined using a Benjamini\u2013Hochberg-corrected q-value of \u2a7d0.01. The data discussed have been deposited in NCBI's Gene Expression Omnibus (GSE87870).Total splenocytes were harvested from leukemic mice and RNA was extracted using the RNeasy Midi Kit . RNA samples were quantified, quality checked and analyzed using the Illumina HiSeq 2000  at the University of Minnesota Genomics Core Facility. Raw data was mapped to the mouse mm9 genome using TOPHAT2 suite.m 2-mercaptoethanol (Sigma-Aldrich), 1% GlutaMAX (Thermo Fisher) and 10\u2009ng/ml each of stem cell factor, interleukin-3, interleukin-6, FLT3 (FMS-related tyrosine kinase 3) ligand and thrombopoietin .Cell lines were originally obtained from ATCC or DSMZ, maintained under standard cell culture conditions, tested monthly for mycoplasma contamination and authenticated by STR analysis at the University of Arizona Genomics Core. De-identified mobilized peripheral blood and AML patient samples were obtained after informed consent according to protocols approved by the University of Minnesota Institutional Review Board. Primary AML samples were cultured in IMDM (Thermo Fisher) supplemented with 20% fetal bovine serum , 100\u2009\u03bcViable cell numbers were determined using the CellTiter 96 Aqueous Non-Radioactive Cell Proliferation Assay . Half-maximal inhibitory concentrations were calculated using CalcuSyn 2.0 .53 by replacing eGFP with eBFP2 and luciferase with RALB(Q72L) (from Channing Der via Addgene plasmid no. 19721), myrAKT (from John Ohlfest) orCRAF W22 (from Channing Der via Addgene plasmid no. 12593). Vesicular stomatitis virus-G-pseudotyped lentivirus was produced by co-transfecting a 1:2:3 ratio of pMD2.G, pCMVDR8.2 (both from Dider Trono via Addgene nos 12259 and 8455) and lentiviral expression vector into HEK293 cells using X-treme Gene HP . Viral supernatant was harvested after 48\u2009h, filtered and used for transduction. Target cells were transduced by coculture with viral supernatant and 5 \u03bcg/ml polybrene overnight.Lentiviral expression vectors were generated using the Gateway cloning system (Thermo Fisher). BFP-expressing lentiviral vectors were generated from a previously described backbone,t-test corrected for multiple comparisons using the Holm\u2013Sidak method with PRISM software . Statistical significance was defined as P\u2a7d0.05.Unless otherwise indicated, statistical differences between two groups were determined using an unpaired, two-tailed"}
+{"text": "Existing cardiac magnetic resonance sequences are frequently suboptimal in the measurement of the aortic arch, particularly in the case of arch obstruction. Navigated three-dimensional (3-D) sampling perfection with application optimized contrast using different flip angle evolution (SPACE) is a novel turbo spin echo dark blood cardiac magnetic resonance sequence that yields a robust 3-D dataset and gates in systole in order to demonstrate the maximal aortic caliber. Additionally, it utilizes susceptibility for optimal blood suppression by orienting blood flow in the readout direction, thereby enhancing imaging in the setting of turbulence. We report our experience measuring the aortic arch using this sequence.Patients with congenital heart disease who were scheduled to undergo clinically indicated cardiac magnetic resonance imaging were prospectively enrolled and underwent navigated 3-D SPACE imaging. Aortic arch measurements were obtained from navigated 3-D SPACE images and other magnetic resonance sequences that were performed during the same study. Absolute agreement mixed-effects intraclass correlation coefficients (ICC) were used to determine agreement between navigated 3-D SPACE and other commonly used sequences as measured by a single blinded investigator and agreement between two blinded investigators in a randomly selected sub-sample of the navigated 3-D SPACE studies.Analysis was performed on 43 studies. The ICC for inter-observer agreement in 13 navigated 3-D SPACE sequences was 0.973 (p < 0.001). The ICCs for agreement between measurements derived from navigated 3D SPACE and those derived from steady state free precession Cine, two-dimensional dark blood imaging and gadolinium-enhanced magnetic resonance angiography were 0.734 (p < 0.001), 0.891 (p < 0.001) and 0.951 (p < 0.001) respectively.Navigated 3-D SPACE aortic arch measurements demonstrated excellent reliability between observers and validity in comparison to existing cardiac magnetic resonance sequences in patients with congenital heart disease. Given that the sequence's attributes are uniquely suited to measuring arch obstruction, it may be a useful tool in cases where accurate measurements of the aortic arch are clinically important"}
+{"text": "Here, we report the complete genome sequences of 15 chikungunya virus strains isolated from human plasma from infected patients in Puerto Rico. The results show that currently circulating chikungunya strains in Puerto Rico are closely related. Chikungunya virus (CHIKV) is an arthropod-borne alphavirus that causes febrile illness associated with severe acute and persistent arthralgia . Recent CHIKV sequence diversity in currently circulating strains of CHIKV could impact the efficacy of novel therapeutics targeting viral proteins. To determine the genetic diversity of CHIKV in the current epidemic in the Americas, we sequenced multiple CHIKV strains isolated from infected patients in Puerto Rico. Human serum samples from patients positive for CHIKV by quantitative reverse transcriptase PCR were obtained by the University of Puerto Rico. CHIKV infectious virus was amplified from serum samples by a single passage on C6/36 mosquito cells. The virus was purified from cell supernatants by centrifugation through a sucrose cushion. Genomic RNA was extracted from sucrose-purified virions using TRIzol (Thermo Fisher Scientific). Virion RNA was reverse-transcribed using random primers  and converted to double-stranded DNA using the NEBNext mRNA second-strand synthesis module (New England Biolabs). Sequencing libraries were prepared using the Nextera XT DNA library preparation kit (Illumina) and sequenced using a MiSeq version 3 reagent kit (150 cycle) (Illumina). Total reads were mapped to the CHIKV genome using Bowtie2 version 2.3.1 and a GenBank reference genome (accession no. EF452493.1). We obtained an average coverage depth of >10 at each nucleotide. The consensus genome sequences were derived from the most common nucleotide present at each coordinate.MF001505, MF001506, MF001507, MF001508, MF001509, MF001510, MF001511, MF001512, MF001513, MF001514, MF001515, MF001516, MF001517, MF001518, and MF001519.The complete genomic sequences for the 15 chikungunya virus genomes reported here have been deposited in GenBank under the accession numbers"}
+{"text": "Previously, we have shown that the first two of these RNA elements (A and B) are required for protease dimerization and activation. The D element functions as internal polypurine tract during reverse transcription. Peters et al., described the third element (C) as essential for gag expression suggesting that it might serve as an RNA export element for the unspliced genomic transcript.The foamy viral genome encodes four central purine-rich elements localized in the integrase-coding region of env splicing and demonstrate that the described C element composed of three GAA repeats known to bind SR proteins regulates env splicing, thus balancing the amount of gag/pol mRNAs. Deletion of the C element effectively promotes a splice site switch from a newly identified env splice acceptor to the intrinsically strong downstream localised env 3\u2032 splice acceptor permitting complete splicing of almost all LTR derived transcripts. We provide evidence that repression of this env splice acceptor is a prerequisite for gag expression. This repression is achieved by the C element, resulting in impaired branch point recognition and SF1/mBBP binding. Separating the branch point from the overlapping purine-rich C element, by insertion of only 20 nucleotides, liberated repression and fully restored splicing to the intrinsically strong env 3\u2032 splice site. This indicated that the cis-acting element might repress splicing by blocking the recognition of essential splice site signals.Here, we analysed env splice acceptor. It is essential for the formation of unspliced gag and singly spliced pol transcripts.The foamy viral purine-rich C element regulates splicing by suppressing the branch point recognition of the strongest The online version of this article (doi:10.1186/s12977-017-0337-6) contains supplementary material, which is available to authorized users. Complex retroviruses, beside the canonical genes, also encode additional regulatory genes whose expression extensively depends on alternative splicing. Thus, splicing needs to be carefully balanced to ensure regulated expression of all viral genes.At least three co-transcriptional modifications, namely capping, splicing and polyadenylation are essential to licence mRNA for nuclear export. Since retroviral pre-mRNAs are polycistronic they make extensive use of alternative splicing to regulate viral gene expression. Simple retroviruses, which encode exclusively cis-acting binding sites for regulatory proteins, such as serine/arginine-rich proteins (SR-proteins) and heterogeneous nuclear ribonucleoproteins (hnRNPs) acting in a position-dependent manner . T. Tpol waent pHSRVC+. The igag expression, we analysed two deletion mutants where the SpeI or the SexAI fragments of pHSRV13 harbouring the C element and known env 3\u2032ss had been removed   of 9.84) at position 5482 (aka 5478 in /[LTR transcripts] and the env splice transcripts as ratios of spliced transcripts divided by all transcripts in env [env spliced]/[LTR transcripts]. The transcript amounts were normalized to wild-type amounts.Probes and primers were designed with the Roche Universal Probe Library Assay Design Center software (http://www.umd.be/HSF3/). The strength of the 3\u2032ss was calculated using the MaxEntScore algorithm (http://genes.mit.edu/burgelab/maxent/Xmaxentscan_scoreseq_acc.html) [The analyses of the strength of splice sites and the localization of splice enhancer or silencer elements were performed with the human splice finder program (cc.html) .BHK21-ll cells were transfected and harvested two days post transfection. Western blotting analyses of cellular lysates were performed using Gag-specific monoclonal antibodies (SGG1) .http://imagej.net).For RNA affinity chromatography, wild-type and mutant substrate RNAs were synthesized (Wild-type 5\u2032-AAG TAC GAA TTT CCT GTA AAA GAG AAA GTT CTT CTT CTC TGG TCA AGT CAA GTG TAT CTT ACA TGG GTG ATC CTC ATG TCC TAT AGT GAG TCG TAT TA-3\u2032 Mutant: 5\u2032-AAG TAC GAA TTT CCT GTA AAA GAG AAA GTG GTT GTT TTC TGG TCA AGT CAA GTG TAT CTT ACA TGG GTG ATC CTC ATG TCC TAT AGT GAG TCG TAT TA-3\u2032). In vitro synthesized and immobilized RNAs encoding a MS2 stem loop followed by wild-type or Cn sequences and SA3 were incubated with HeLa nuclear extracts (NE) in buffer D . Recombinant MS2-MBP (1\u00a0\u00b5g) was added to monitor immobilized RNA amounts. Bound proteins were visualized by western blot analyses using SF1/mBBP  or MPB-antibodies (Tetracore) and quantified with the ImageJ software version 1.46 ("}
+{"text": "BCL2-like 11 (BIM) gene which impairs the expression of pro-apoptotic splice isoforms of BIM. SB939 (pracinostat) is a hydroxamic acid based HDAC inhibitor with favorable pharmacokinetic, physicochemical and pharmaceutical properties, and we investigated if this drug could overcome BIM deletion polymorphism-induced TKI resistance. We found that SB939 corrects BIM pre-mRNA splicing in CML cells with the BIM deletion polymorphism, and induces apoptotic cell death in CML cell lines and primary cells with the BIM deletion polymorphism. More importantly, SB939 both decreases the viability of CML cell lines and primary CML progenitors with the BIM deletion and restores TKI-sensitivity. Our results demonstrate that SB939 overcomes BIM deletion polymorphism-induced TKI resistance, and suggest that SB939 may be useful in treating CML patients with BIM deletion-associated TKI resistance.Chronic myeloid leukemia (CML) treatment has been improved by tyrosine kinase inhibitors (TKIs) such as imatinib mesylate (IM) but various factors can cause TKI resistance in patients with CML. One factor which contributes to TKI resistance is a germline intronic deletion polymorphism in the  BCL2-like 11 (BIM) gene that was sufficient to mediate TKI resistance in CML [BIM deletion polymorphism, splicing of BIM pre-mRNA is biased toward the inclusion of exon 3 (E3) and exclusion of exon 4 (E4). Since the pro-apoptotic BH3 domain is encoded by E4, the deletion promotes the expression of non-apoptotic BIM isoforms  over pro-apoptotic isoforms , thereby impairing the pro-apoptotic TKI response and confering partial TKI-resistance [Chronic myeloid leukemia (CML) is a disease defined by the presence of the BCR-ABL fusion protein, a constitutively active kinase produced by the 9,22 translocation which is sufficient to transform hematopoietic cells . ABL-spee in CML . In cellsistance .BIM deletion polymorphism-induced TKI resistance in non-small-cell lung cancer (NSCLC) when combined with an EGFR TKI [BIM polymorphism in CML. Our results indicate that SB939 does enhance IM lethality in CML cells, including those with the BIM deletion polymorphism.Cancer cells usually have aberrant histone acetylation profiles and it was reported that histone deacetylases (HDACs) activities are essential in establishing a tumor phenotype . AdditioEGFR TKI . HoweverEGFR TKI . AdditioEGFR TKI . In thisBIM deletion polymorphism were generated as previously described [The CML cell line K562 was purchased from ATCC. Genome\u2013edited K562 cells with or without the BIM exon 3 , BIM exon 4 .Total cellular RNA were extracted using RNeasy Mini Kit . Superscript III First-strand Synthesis System  were used to reverse transcribe the RNA which is then quantitatively analysed using the iQ5 Multicolor Real-Time Detection System  with a total reaction volume of 25 ul. Primers were annealed at 59\u00b0C for 20 s, and the amplicon was extended at 72\u00b0C for 30 s. The total number of cycles was 40. The following primers were used: We used the following antibodies for immunoblotting: BCR-ABL (#2862), p-BCR-ABL (#2861), BIM (#2819), CASPASE 3 (#9662), STAT5 (#9310), p-STAT5 (#9359), PARP (#9542)  and beta-ACTIN . The antibody dilutions used were 1 in 1,000, except for PARP , BIM (1 in 500) and \u03b2-ACTIN . HRP-conjugated secondary antibodies were specific to rabbit  or mouse IgG . The protein bands on the membrane were visualized using the Western Lightning chemiluminescence reagent .Apoptosis in CML cell lines and primary CML samples were measured by flow cytometry with the Annexin V-FITC antibody  and DAPI . Ten thousand events were recorded and the gated region and data were analysed using FlowJo software .Clinical CML samples were obtained from the Singapore General Hospital. Written informed consent and institutional review board approval were obtained from the relevant individuals and SingHealth Centralised Institutional Review Board (CIRB) respectively.Primary peripheral blood mononuclear cells (PBMCs) were subjected to drug treatment for 72 hours in StemPro , in drug-free methylcellulose . Colonies were counted after 10\u201314 days post-seeding.BIM deletion polymorphism, and overcoming BIM deletion polymorphism-mediated EGFR TKI resistance [BIM splicing and overcome TKI resistance in CML cell lines with the BIM deletion polymorphism. First, we evaluated the effects of SB939 on isogenic K562 cells with the BIM deletion polymorphism in heterozygous (BIMi2+/-) and homozygous (BIMi2-/-) configurations, as well as control cells without the deletion polymorphism (BIMi2+/+) [BIM deletion polymorphism-containing K562 cells had increased E3/E4-containing BIM transcript ratios compared to control cells [Earlier reports have shown that vorinostat is effective in correcting splicing in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) cell lines harboring the sistance . Hence, ol cells \u201315, whilBIM pre-mRNA splicing as well as BIM deletion polymorphism-induced TKI resistance. In all three K562 cell lines, we observed that SB939 consistently reduced the E3/E4 transcript ratio by approximately 50% but that imatinib had little effect, while the combination was as effective as SB939 alone  when compared to those with the BIM deletion polymorphism Click here for additional data file.S2 FigBIMEL, BIM extra long isoform; BIML, BIM long isoform; BIMS, BIM short isoform.(TIF)Click here for additional data file."}
+{"text": "We tested whether Trichostatin A (TSA), which reduces muscle degeneration in sapje mutants, would affect EtOH-treated zebrafish. We found that TSA and EtOH are a lethal combination. EtOH does, however, exacerbate muscle degeneration in sapje mutants. EtOH also disrupts adhesion of muscle fibers to their extracellular matrix at the myotendinous junction: some detached muscle fibers retain beta-Dystroglycan indicating failure of muscle end attachments. Overexpression of Paxillin, which reduces muscle degeneration in zebrafish deficient for beta-Dystroglycan, is not sufficient to rescue degeneration. Taken together, our results suggest that EtOH exposure has pleiotropic deleterious effects on skeletal muscle. Alcoholic myopathies are characterized by neuromusculoskeletal symptoms such as compromised movement and weakness. Although these symptoms have been attributed to neurological damage, EtOH may also target skeletal muscle. EtOH exposure during zebrafish primary muscle development or adulthood results in smaller muscle fibers. However, the effects of EtOH exposure on skeletal muscle during the growth period that follows primary muscle development are not well understood. We determined the effects of EtOH exposure on muscle during this phase of development. Strikingly, muscle fibers at this stage are acutely sensitive to EtOH treatment: EtOH induces muscle degeneration. The severity of EtOH-induced muscle damage varies but muscle becomes more refractory to EtOH as muscle develops. NF-kB induction in muscle indicates that EtOH triggers a pro-inflammatory response. EtOH-induced muscle damage is p53-independent. Uptake of Evans blue dye shows that EtOH treatment causes sarcolemmal instability before muscle fiber detachment. Dystrophin-null  Ethanol (EtOH) is a teratogen that can cause multisystemic diseases at any stage of life. The rate of lifetime alcohol use disorders is approximately 12% in the US . Childredystrophin [laminin a2 gene cause congenital muscular dystrophy with merosin deficiency [sapje mutant zebrafish is sarcolemmal damage. In contrast, the primary cause of muscle damage in laminin a2 mutant zebrafish is failure of adhesion of muscle fibers to the MTJ. We found that human influenza A virus causes both sarcolemmal damage and disrupts muscle fiber adhesion to the MTJ [Zebrafish are an ideal model for studying the effects of EtOH exposure on skeletal muscle after primary muscle development. Zebrafish skeletal muscle is structurally similar to that of other vertebrates, with individual muscle fibers and segmentally reiterated groups of muscle fibers surrounded by distinct and dynamic regions of extracellular matrix (ECM) ,15,16,17strophin . Mutatioficiency . Despiteficiency ,23,24. I the MTJ , indicatIn this study, we show that EtOH treatment after primary muscle development disrupts muscle homeostasis and causes muscle degeneration. Similar to previous reports ,9, the pmai1Tg(actb2:pxn-EGFP) [Tg(hsp70l:pxn-EGFP), nc1Tg(Nf-kB:EGFP) [M214Ktp53 [ta222asapje [Zebrafish embryos were retrieved from natural spawns of adult zebrafish maintained on a 14-h light/10-h dark cycle. Strains used in this study were AB, GFP)mai1 , Tg(hsp7EGFP)nc1 , tp53M21p53M214K , and sapjeta222a . Embryosjeta222a . All proEtOH dilutions were chosen based on . SolutioHeat shock was done at 6 or 24 hpf in a 37\u201338 degrees Celsius incubator for 1\u20132 h. All heat shock-treated embryos were screened using a GFP 470 filter on a Zeiss Discovery.V12 microscope to identify fluorescent transgenic embryos.w/v) was dissolved in a 0.9% saline solution. Injection needles were pulled from glass capillary tubes containing a filament on a Sutter Flaming/Brown Micropipette Puller. EBD solution was loaded into injection needles and injected into the circulation of anesthetized ~72 hpf zebrafish using a MPPI-3 pressure injector from ASI. EBD injected zebrafish were maintained in 1X ERM for 6 h before live imaging.Zebrafish were anesthetized in 0.16 mg/mL tricaine in 1X ERM and side mounted on 1% agarose-lined Petri dishes in a minimal volume of liquid. EBD . EtOH exposure also caused muscle damage. Control zebrafish had linear, organized muscle fibers at 24 hpf (Zebrafish primary muscle development entails the elongation of short muscle precursor cells into long myofibers that attach to the ECM at the MTJ and undergo fusion to generate myotubes . This prt 24 hpf J\u2013J1. EtOt 24 hpf . These dAlthough treatment with 2% EtOH diluted from a 95% (190 proof) stock resulted in fiber detachment, the penetrance of this phenotype varied across experimental replicates N,O. We aZebrafish primary muscle development is followed by a period of growth ,35. LessTg(NF-kB:EGFP) [Tg(NF-kB:EGFP) zebrafish were continuously exposed to 0 or 2% EtOH from 30 hpf on and then fixed at 3 dpf. Muscle fibers in control Tg(NF-kB:EGFP) zebrafish were long and linear   zebrafisd linear A1,A2 andd linear B3\u2013B6. ThM214Ktp53 mutant zebrafish [p = 0.19) or the average number of segments per embryo with fiber detachments (p = 0.29) in EtOH-treated, homozygous tp53 mutants and ABs. Therefore, EtOH-induced muscle degeneration could involve pro-inflammatory NF-kB-dependent signaling, but occurs independently of p53-mediated apoptosis. The transcription factor p53 induces apoptosis in various cell types in response to stress and is important for muscle homeostasis ,38. We uebrafish  to ask wn = 30 zebrafish over 3 trials). Beta-DG robustly localized to MTJs in untreated controls ) have normal muscle (p < 0.03 and 0.02 respectively). In contrast, Paxillin overexpression did not significantly change the phenotype of sapje mutants (p = 0.11). Muscle fibers in dystrophin-null neration ,40. Prevneration . Howeversapje mutant zebrafish suggests that the underlying mechanisms of muscle damage are distinct despite EBD uptake in both contexts. We asked whether the HDAC-inhibitor TSA, which significantly reduces muscle degeneration in sapje mutant zebrafish [The fact that Paxillin overexpression exacerbates muscle damage in EtOH-treated zebrafish but not ebrafish ,, would sapje mutant and EtOH-treated zebrafish, we asked whether EtOH treatment would additively worsen muscle damage in sapje mutant zebrafish. Wildtype zebrafish not exposed to EtOH displayed normal muscle .Given the differences between l muscle A. sapje during muscle development. EtOH treatment from 8 to 24 hpf causes abnormally wide MTJs and smaller slow-twitch muscle fibers [EtOH exposure can cause a wide range of symptoms in both fetal and adult organisms. Most of what is known about these diseases, such as in FASD, centers on the neurological defects . Our datWe report here that there is some variation in the penetrance and severity of skeletal muscle damage accompanying EtOH treatment between trials. We do not know if this variation is specific to this time point because previous reports have compiled trials. However, it has been shown that EtOH affects neurobehavioral responses differently in different strains of zebrafish . Althougv/v) whereas the EtOH dose used on zebrafish embryos is usually 1.5\u20132.5% EtOH. Together, these observations potentially contradict the idea that zebrafish develop a barrier to EtOH as they age.The decreasing muscle damage associated with increased age at initial EtOH exposure is likely due to either less EtOH ingestion and/or enhanced EtOH metabolism in older embryos. It was observed that the concentration of EtOH within zebrafish embryos was 2.7\u20134.2 fold lower in 24 hpf zebrafish and 5.8\u20136.2 fold less in 48 hpf zebrafish than the waterborne EtOH concentration . TherefoMuscle atrophy is a well-known symptom of many chemical or environmental insults and genetic perturbations. Previous studies showed that muscle fibers can detach before undergoing cell death via at least two distinct cellular etiologies in zebrafish models of genetic muscle diseases . Here, wsapje mutant zebrafish) [sapje mutant zebrafish. Although we did not observe a significant interaction, there was a clear trend towards worsening of the sapje phenotype (p = 0.06). Taken together these data highlight the utility of the zebrafish model to integrate gene environment interactions and suggest that environmental insults may have more pleiotropic deleterious effects on muscle tissue than genetic perturbations. One hallmark of many congenital muscular dystrophies is their phenotypic variation but the underlying causes of variation are not known. We previously showed that the human influenza A virus (IAV) damages muscle in zebrafish embryos. IAV infection significantly increases muscle degeneration and decreases survival in the zebrafish model of Duchenne Muscular Dystrophy (dystrophin-deficient brafish) . Here we"}
+{"text": "Claraia bivalves and algal buildups on the sea floor. Biostratigraphical correlation further shows that Boreal microconchids underwent progressive tube modification and unique taxic diversification concordant with changing habitats over time. We interpret this as a post-extinction recovery and adaptive radiation sequence that mirrored coeval subequatorial faunas, and thus confirms hard substrate ecosystem depletion as a hallmark of the earliest Triassic interval globally.The end-Permian mass extinction constituted the most devastating biotic crisis of the Phanerozoic. Its aftermath was characterized by harsh marine conditions incorporating volcanically induced oceanic warming, widespread anoxia and acidification. Bio-productivity accordingly experienced marked fluctuations. In particular, low palaeolatitude hard substrate communities from shallow seas fringing Western Pangaea and the Tethyan Realm were extremely impoverished, being dominated by monogeneric colonies of filter-feeding microconchid tubeworms. Here we present the first equivalent field data for Boreal hard substrate assemblages from the earliest Triassic (Induan) of East Greenland. This region bordered a discrete bio-realm situated at mid-high palaeolatitude (>30\u00b0N). Nevertheless, hard substrate biotas were compositionally identical to those from elsewhere, with microconchids encrusting  Archaeolithophyllum algae have also been reported in the earliest Triassic deposits of Jameson Land further to the south.M\u2009=\u20096.8\u2009\u03bcm; SD\u2009=\u20091.5), (3) \u2013 , and (4) \u2013 . These infer dysoxic (1), to anoxic (3\u20134) bottom watersClaraiaArchaeolithophyllum boundstones of interval (3), implying microbe-enriched local anoxia. In contrast, the absence of framboids from intervals (2) and (5), coupled with prevalent crystalline pyrite, suggests periodic oxic fluctuationsWe examined five discrete fossiliferous intervals  M\u2009=\u200929.4\u2009tubes/cm2, and (2) M\u2009=\u200922.9 tubes/cm2. Colonies attached to boundstones alternatively averaged only 11.8\u2009tubes/cm2, but this could reflect under-sampling of the unexposed bedding planes. Abundant microconchids (M\u2009=\u200929.4 tubes/cm2) were also scattered randomly across the mudstone layers in interval 5  formed squat spiral tubes, whereas those attached to algal filaments within boundstones from interval (3) displayed both spiral and helically uncoiled tubes  installed at the Faculty of Earth Sciences, University of Silesia, Sosnowiec, Poland. Uncoated ESEM samples were examined with back-scattered (BSE) imaging under low vacuum conditions. Samples for pyrite framboids were thin-sectioned and assessed by ESEM. More than 50 specimens were measured and interpreted following the procedures of Wignall and NewtonHow to cite this article: Zato\u0144, M. et al. Boreal earliest Triassic biotas elucidate globally depauperate hard substrate communities after the end-Permian mass extinction. Sci. Rep. 6, 36345; doi: 10.1038/srep36345 (2016).Publisher\u2019s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations."}
+{"text": "TP53 is the most frequently mutated gene in human cancer. One unusual feature that adds to the exceptional status of p53 is that the vast majority (75%) of p53 alterations are missense mutations in the DNA-binding domain.1 They fall into \u2018DNA-contact' and \u2018structural/conformational' mutant classes, which roughly \u2013 but not in every case \u2013 correlate with the degree of biophysical protein instability. Most if not all of these substitutions generate conformationally aberrant full-length mutant p53 (mutp53) proteins that have lost tumor suppressor functions and can have dominant-negative activities via hetero-oligomerization with wild-type p53. Importantly, however, many p53 mutants also acquire oncogenic gain-of-function (GOF) activities that actively promote malignant progression, cancer metabolism, stemness, invasion, metastasis and chemoresistance.34 For example, R248Q mutp53 knockin mice have significantly earlier tumor onset and shorter survival than p53-null mice.4 Moreover, germline Li-Fraumeni syndrome (LFS) patients carrying R248Q missense mutations have significantly earlier cancer onset (by 10.5 years) and higher tumor burden than LFS patients with TP53 loss-of-function (LOF) mutations.4 Similarly, sporadic human cancers across six major tumor entities show higher mortality (2-fold higher hazard ratios) for GOF mutant R282 and R248 patients, compared with p53 LOF mutant patients.5mutp53 GOF is strongly supported by knockin mouse models and the human data.2 Currently, about 11 million patients worldwide live with cancers expressing highly stabilized mutp53. This raises the question: Is mutp53 itself an important therapeutic target? Compelling genetic evidence suggests so. Thus, RNAi-mediated mutp53 depletion has strong cytotoxic effects in human cancer cell lines in vitro and in xenografts.3 In allografts, knockdown of mutp53 in KrasG12D pancreatic cancer cells strongly reduces their metastatic ability.6 Finally, in a conditional inactivatable (\u2018floxable') autochthonous mouse model expressing R248Q mutp53, we showed that allele ablation extends animal survival by 37%, induces regression or stagnation of advanced tumors and strongly suppresses metastasis.7 These data indicate that stabilized mutp53 is a tumor-specific vulnerability that can be pharmacologically exploited. Thus, understanding the mechanisms of mutp53 stabilization will be key for translation into therapy.mutp53 proteins undergo massive constitutive stabilization specifically in tumors , and this stabilization is prerequisite for GOF.9 Both classes of mutp53  require HSP90 for protection from degradation by their E3 ubiquitin ligases Mdm2 and CHIP  class mutp53 proteins. Moreover, statins specifically suppress growth of structural mutp53 cancer cells in vitro and in xenografts (cytostatic). Mechanistically, statins work via the mevalonate pathway/Hsp40/CHIP axis  promotes degradation of Hsp70-bound misfolded proteins. Hsp70 and Hsp90 are found in the same cancer-associated \u2018epichaperome' complex.12 Thus it is possible that other heat shock proteins besides Hsp90 and DNAJA1 protect mutp53 from statins-induced degradation.Both Hsp40 and CHIP interact with Hsp70, and Hsp70 cooperates with Hsp90 in stabilizing mutp53.13 Although this notion remains controversial, the findings of Parrales et al. might provide a possible mechanism. To resolve this important issue in future studies, the patients' mutp53 status, including structural versus DNA-contact class should be taken into account. One limitation is that the conformations of many \u2018non-hot-spot' mutp53 proteins are unknown. Interestingly, the majority of published studies analyzed patients who at the time of their cancer diagnosis had already been on statins, possibly suggesting that statins might exert anti-cancer effects in clinically advanced tumors.Statins are in wide clinical use as cholesterol-lowering drugs, but in epidemiological studies have long been suspected to have cancer chemoprevention ability.14 (14 Thus, by stimulating the mevalonate pathway, mutp53 further reinforces its own DNAJA1/MVP-mediated stability, which could further sensitize mutp53 to statins.Intriguingly, upregulation of the mevalonate pathway is one of mutp53's GOF. mutp53 upregulates expression of many mevalonate pathway genes by binding to and promoting the activity of the sterol biosynthesis master transcription factor SREBPIn sum, there are now two heat shock pathways mediating GOF mutp53 stabilization. Importantly, both are druggable and produce anti-tumoral effects. This further boosts the notion that indirect chaperone interception to degrade stabilized mutp53 is a more tangible strategy than the elusive long-term goal of identifying small molecules able to convert the many different aberrant conformations of mutp53 into a functional wild-type-like protein."}
+{"text": "Chrysemys picta TSD) before and during the thermosensitive period, and at equivalent stages in soft-shell turtles , to test whether TSD\u2019s and GSD\u2019s transcriptional circuitry is identical but deployed differently between mechanisms. Our data show that most elements of the mammalian urogenital network are active during turtle gonadogenesis, but their transcription is generally more thermoresponsive in TSD than GSD, and concordant with their sex-specific function in mammals . Notably, antagonistic elements in gonadogenesis  were thermosensitive only in TSD early-embryos. Cirbp showed warm-temperature upregulation in both turtles disputing its purported key TSD role. Genes that may convert thermal inputs into sex-specific development  were differentially regulated. Jak-Stat, Nf-\u03baB, retinoic-acid, Wnt, and Mapk-signaling  potentially mediate TSD thermosensitivity. Numerous species-specific ncRNAs (including Xist) were differentially-expressed, mostly upregulated at colder temperatures, as were unannotated loci that constitute novel TSD candidates. Cirbp showed warm-temperature upregulation in both turtles. Consistent transcription between turtles and alligator revealed putatively-critical reptilian TSD elements for male  and female (Crabp2 and Hspb1) gonadogenesis. In conclusion, while preliminary, our data helps illuminate the regulation and evolution of vertebrate sex determination, and contribute genomic resources to guide further research into this fundamental biological process.Vertebrate sexual fate is decided primarily by the individual\u2019s genotype (GSD), by the environmental temperature during development (TSD), or both. Turtles exhibit TSD and GSD, making them ideal to study the evolution of sex determination. Here we analyze temperature-specific gonadal transcriptomes  of painted turtles ( Organisms vary wildly in how they determine sex . VertebrWt1 , while Crabp2 and Hspb1 were upregulated at FPT in both taxa. Finally, differences in expression were observed in the transient receptor potential gene Trpc4ap and Tex15, which were both upregulated at MPT in the alligator but not in Chrysemys. No other genes in our categories of interest discussed above overlapped between the Chrysemys and alligator. These observations support the notion that significant transcriptional evolution has accrued even among TSD regulatory networks .networks  and leadNf2 and Prdx4  and Apalone spinifera [(c) and (dc)] at 26\u00b0C and 31\u00b0C respectively.Panels a-d illustrate modules of high (red) and low (yellow) co-expression for 981 genes of interest (described in (PDF)Click here for additional data file.S1 Table(XLSX)Click here for additional data file.S2 Table(XLSX)Click here for additional data file.S3 Table(XLSX)Click here for additional data file.S4 Table(XLSX)Click here for additional data file.S5 Table(XLSX)Click here for additional data file.S6 Table(XLSX)Click here for additional data file.S7 Table(XLSX)Click here for additional data file.S8 Table(XLSX)Click here for additional data file.S9 Table(XLSX)Click here for additional data file.S10 TableThe three biggest modules at each condition are indicated by turquoise, blue and brown colors in that order in S8 Fig.(XLSX)Click here for additional data file.S11 Table(XLSX)Click here for additional data file.S12 Table(XLSX)Click here for additional data file.S13 Table(XLSX)Click here for additional data file.S14 Table(XLSX)Click here for additional data file.S15 Table(XLSX)Click here for additional data file.S16 Table(XLSX)Click here for additional data file.S17 Table(XLSX)Click here for additional data file.S18 Table(XLSX)Click here for additional data file.S19 Table(XLSX)Click here for additional data file.S20 Table(XLSX)Click here for additional data file."}
+{"text": "Children with chronic kidney disease (CKD) have a significantly increased cardiovascular (CV) risk. The reasons for this remain unclear. However, abnormalities of systolic and diastolic myocardial function, the vascular system and autonomic dysfunction have been implicated. Conventional investigations like resting echocardiography offer limited assessment of the CV system (CVS). Comprehensive evaluation of the CVS using advanced cardiac magnetic resonance imaging (CMR) is feasible. Furthermore, exercise can unmask autonomic dysfunction not evident at rest. Hence, this study will use CMR to characterize CV response to isometric exercise in pediatric CKD.10 children (age 13 \u00b1 3 years) with CKD stages 2-4 and 10 matched healthy volunteers (HV) underwent an isometric stress CMR. This involved 3 minutes of static bicep flexion against a fixed weight (35% of maximum bicep strength). Left ventricular (LV) structure and function was assessed using real-time radial kt-SENSE sequence. Vascular haemodynamic properties of the aorta were evaluated with prospectively triggered segmented spiral phase contrast sequence and non-invasive blood pressure (BP) measurements. LV diastolic function was assessed by measuring cardiac timing intervals and LV inflow-outflow velocities using a high temporal resolution real-time spiral UNFOLDed-SENSE phase contrast sequence. Data was acquired at rest, exercise and recovery. In addition, a high temporal and spatial resolution, retrospectively gated, spiral tissue phase mapping sequence was used to assess radial and longitudinal LV function at rest. Image analysis was performed using in-house plug-ins for OsiriX software.At rest, patients had a significantly (p < 0.04) higher mean arterial BP , systemic vascular resistance  and lower total aortic compliance . Myocardial longitudinal systolic velocity was lower in CKD . There was no difference in LV mass, ejection fraction (EF), cardiac output (CO), myocardial performance index (Tei), diastolic parameters  and myocardial radial systolic velocities. Isometric exercise provoked a modest increase in MAP (13 \u00b1 11 mmHg), heart rate (HR 14 \u00b1 18 beats per min), and CO (0.86 \u00b1 1.49 ml/min). However, there were no differences in CV reactivity (heart rate & MAP) and LV function (EF & CO) between CKD and HV in exercise.Raised SVR and reduced TAC are present in early CKD and are the causes of hypertension in this population. This precedes diastolic dysfunction and LV hypertrophy. Reduction in longitudinal systolic velocity may be an early indicator of LV longitudinal function impairment. The CV and autonomic response to isometric stress is preserved in children with CKD despite these vascular abnormalities."}
+{"text": "Scientific Reports 10.1038/s41598-017-13184-8, published online 09 October 2017Correction to: The original version of this Article contained typographical errors in the title, where:\u201cMultiple similarly-well solutions exist for biomedical feature selection and classification problems\u201dnow reads:\u201cMultiple similarly effective solutions exist for biomedical feature selection and classification problems\u201dThis has now been corrected in the HTML and PDF versions of this Article."}
+{"text": "Trypanosoma cruziparasites at thick blood smear (A 47-year old previously healthy male presented fever and malaise for 30 days. Chagas\u2019disease was diagnosed by direct visualization of od smear .Benznidod smear , but parod smear . A seconod smear . LGE was"}
+{"text": "The inter\u00adlamellar regions contain hydrogen-bonded cyclic water hexa\u00admers which facilitate layer stacking into a pseudo-three-dimensional crystal structure.  The water hexamers themselves are formed by the operation of crystallographic inversion centers on sets of three crystallographically distinct water molecules of hydration.In the title compound, {[Cu DOI: 10.1107/S1600536808023131/sj2520Isup2.hkl            Structure factors: contains datablocks I. DOI:  crystallographic information; 3D view; checkCIF report            Additional supplementary materials:"}
+{"text": "Focal adhesion kinase (FAK) functions in cell migration and signaling through activation of the mitogen-activated protein kinase (MAPK) signaling cascade. Neuronal function of FAK has been suggested to control axonal branching; however, the underlying mechanism in this process is not clear.Drosophila FAK gene, Fak56. Null Fak56 mutants display overgrowth of larval neuromuscular junctions (NMJs). Localization of phospho-FAK and rescue experiments suggest that Fak56 is required in presynapses to restrict NMJ growth. Genetic analyses imply that FAK mediates the signaling pathway of the integrin \u03b1PS3\u03b2\u03bd heterodimer and functions redundantly with Src. At NMJs, Fak56 downregulates ERK activity, as shown by diphospho-ERK accumulation in Fak56 mutants, and suppression of Fak56 mutant NMJ phenotypes by reducing ERK activity.We have generated mutants for the We conclude that Fak56 is required to restrict NMJ growth during NMJ development. Fak56 mediates an extracellular signal through the integrin receptor. Unlike its conventional role in activating MAPK/ERK, Fak56 suppresses ERK activation in this process. These results suggest that Fak56 mediates a specific neuronal signaling pathway distinct from that in other cellular processes. Drosophila, various integrin subunits have been shown to function in motor axon pathfinding and target recognition, and synaptic morphogenesis at neuromuscular junctions (NMJs)  , FasII  and dp-ERK-1/2 . Alexa 488-, Cy3- and Cy5-conjugated secondary antibodies and TRITC-phalloidin were used (Jackson ImmunoResearch).In all experiments, wandering late third instar larvae were dissected for analysis of NMJ phenotypes. After dissection, tissues were incubated in fixative solution  for 20 minutes. For immunostaining, primary antibodies used were against synaptotagmin , HRP conjugated with TRITC , FAK . (A) Cumulative frequency plot reveals a significant shift in the distribution of mEJP amplitudes. (B) Representative traces and mean amplitudes of EJPs in wild-type and Fak56N30/K24.Electrophysiological recording of postsynaptic currents from wild-type and Click here for filesax4, witA12 and med13) for BMP signaling components into elav>Fak56RNAi.BMP/Gbb signaling-independent mechanism of Fak56 in NMJ growth. No alternations of NMJ phenotypes were detected by introducing mutant alleles (Click here for fileFak56CG1 mutant embryos. Expressions of phospho-ERK appear grossly normal during Drosophila embryogenesis.ERK phosphorylation in Click here for file"}
+{"text": "Isolated isletsmaintained in tissue culture were infected withfive well- characterised strains of CBV-4. Aliquotsof the culture medium were analysed with regardto virus replication and insulin content. Infectedand uninfected islets were examined by light microscopyto determine the degree of virus-inducedcytopathic effect (CPE). The results showed thatthe islet cells were susceptible to infection by allthe strains of CBV-4 although the outcome of theinfection differed. The virus titres obtained at 48and 72 hours post infection differed significantlybetween all the CBV-4 strains (p < 0.001), indicatingdifferent ability to replicate in islet cells. Pronouncedto weak CPE, which was partly due tothe origin (donor) of the islets, was induced byfour of the five CBV-4 strains. One strain (VD2921)replicated without causing CPE despite highvirus titres. One (V89-4557) of the CBV-4 strainsalways revealed pronounced CPE. Infection by this strain also caused functional impairment thatsignificantly affected insulin response to high glucoseat 48 hours post infection (p < 0.001). Replicationof another CBV-4 strain (JVB) in the islet cellssignificantly increased the release of insulin comparedto non-infected control cells (p < 0.001) indicatingdamage of the \u03b2-cells leading to leakage ofinsulin.The aim was to study whether different strains ofCoxsackievirus B4 (CBV-4) are able to infect humanpancreatic islet cells"}
+{"text": "Photodynamic therapy (PDT) utilizing Photofrin is proving to be effective for the treatmentof early stage lung cancers. The effect of PDT utilizing YAG-OPO laser as newlight source was evaluated in 26 patients (29 lesions) with early stage lung cancers. YAG-OPOlaser is solid state tunable laser which is easy to change wavelength between 620 and670 nm exciting various kinds of photosensitizers. Moreover, YAG-OPO laser is more reliable,smaller and has less consumables than argon-dye laser or excimer-dye laser. Asthe result of PDT with YAG-OPO laser, complete remission (CR) was obtained in 82.6%of the 29 lesions, partial remission (PR) in 13.8% and no change (NC) was obtained in3.4%. We conclude that PDT utilizing YAG-OPO laser is efficacious in the treatmentof early stage lung cancers and can achieve complete remission."}
+{"text": "Infectious work-up revealed only positive anti-streptolysin O (ASO) and anti-DNAse B titers. Autoimmune studies showed strongly positive anti-platelet IgM, elevated rheumatoid factor (RF), and positive cryocrit. Renal biopsy for evaluation of proteinuria and hematuria showed diffuse proliferative glomerulonephritis (DPGN) with membranoproliferative features consistent with cryoglobulinemia. Immunofixation showed polyclonal bands. Our patient was treated successfully with antibiotics, prednisone, and mycophenolate mofetil (MMF). This is the first report of a patient with partial DGS presenting with APS and type III mixed cryoglobulinemia possibly due to Streptococcal infection. We studied a 14 year-old boy with partial DiGeorge syndrome (DGS), status post complete repair of Tetralogy of Fallot, who developed antiphospholipid syndrome (APS) and type III mixed cryoglobulinemia. He presented with recurrent fever and dyspnea upon exertion secondary to right pulmonary embolus on chest computed tomography (CT). Coagulation studies revealed homozygous methylene tetrahydrofolate reductase 677TT mutations, elevated cardiolipin IgM antibodies, and elevated \u03b2"}
+{"text": "Zymomonas mobilis ZM4 (ZM4) produces near theoretical yields of ethanol with high specific productivity and recombinant strains are able to ferment both C-5 and C-6 sugars. Z. mobilis performs best under anaerobic conditions, but is an aerotolerant organism. However, the genetic and physiological basis of ZM4's response to various stresses is understood poorly.In this study, transcriptomic and metabolomic profiles for ZM4 aerobic and anaerobic fermentations were elucidated by microarray analysis and by high-performance liquid chromatography (HPLC), gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS) analyses. In the absence of oxygen, ZM4 consumed glucose more rapidly, had a higher growth rate, and ethanol was the major end-product. Greater amounts of other end-products such as acetate, lactate, and acetoin were detected under aerobic conditions and at 26 h there was only 1.7% of the amount of ethanol present aerobically as there was anaerobically. In the early exponential growth phase, significant differences in gene expression were not observed between aerobic and anaerobic conditions via microarray analysis. HPLC and GC analyses revealed minor differences in extracellular metabolite profiles at the corresponding early exponential phase time point.glk, zwf, pgl, pgk, and eno) and gene pdc, encoding a key enzyme leading to ethanol production, were at least 30-fold more abundant under anaerobic conditions in the stationary phase based on quantitative-PCR results. We also identified differentially expressed ZM4 genes predicted by The Institute for Genomic Research (TIGR) that were not predicted in the primary annotation.Differences in extracellular metabolite profiles between conditions became greater as the fermentations progressed. GC-MS analysis of stationary phase intracellular metabolites indicated that ZM4 contained lower levels of amino acids such as alanine, valine and lysine, and other metabolites like lactate, ribitol, and 4-hydroxybutanoate under anaerobic conditions relative to aerobic conditions. Stationary phase microarray analysis revealed that 166 genes were significantly differentially expressed by more than two-fold. Transcripts for Entner-Doudoroff (ED) pathway genes (Z. mobilis fermentations negatively influence fermentation performance. The maximum specific growth rates were not dramatically different between aerobic and anaerobic conditions, yet oxygen did affect the physiology of the cells leading to the buildup of metabolic byproducts that ultimately led to greater differences in transcriptomic profiles in stationary phase.High oxygen concentrations present during  Recent high oil prices, concerns over energy security, and environmental goals have reawakened interest in producing alternative fuels via large-scale industrial fermentations. The potential and challenges involved in supplanting a substantial amount of petroleum derived transportation fuels with fuels derived from renewable resources such as ethanol from lignocellulosic materials has been the focus of several studies and reviews -4. The d-1, > 1 g L-1 h-1, respectively); robust growth with simple, inexpensive growth requirements in conditions that retard contaminants (eg higher temperatures); and inhibitor tolerance, as reviewed previously  binding domain family protein (NT01ZM1467) as being up-regulated under aerobic conditions  encoding a ferredoxin showed six-fold induction, ZMO1732 (ahpC) encoding an alkyl hydroperoxide reductase showed 18-fold greater expression, ZMO0279 encoding a cold-shock protein was induced two-fold, and a glutathione S-transferase family protein encoded by ZMO1118 was induced eight-fold. The E. coli alternative sigma factor rpoH plays an important role in overcoming oxidative stress responses .Click here for fileAerobic up-regulated genes 26 h post inoculation. Expression profiles for significantly differentially expressed genes that were up-regulated under aerobic conditions at 26 h as detected by microarrays and real-time qPCR. The modified gene function categories are based on MultiFun categories .Click here for fileComparison of exponential growth phase gene expression measurements by microarray and qPCR. The gene expression ratios for wild-type Z. mobilis ZM4 under aerobic and anaerobic conditions after 3 h fermentation were log transformed in base 2 (log2<aerobic/anaerobic>). The microarray log2 ratio values (log2<aerobic/anaerobic>) were plotted against the qPCR log2 values. Comparison of the two methods indicated a level of concordance of R = 0.62.Click here for fileComparison of stationary growth phase gene expression measurements by microarray and qPCR. The gene expression ratios for wild-type Z. mobilis ZM4 under aerobic and anaerobic conditions after 26 h fermentation were log transformed in base 2 (log2<aerobic/anaerobic>). The microarray log2 ratio values (log2<aerobic/anaerobic>) were plotted against the qPCR log2 values. Comparison of the two methods indicated a high level of concordance (R = 0.92).Click here for file"}
+{"text": "Verbal working memory (VWM) engages frontal and temporal/parietal circuits subserving the phonological loop, as well as, superior and inferior cerebellar regions which have projections from these neocortical areas. Different cerebro-cerebellar circuits may be engaged for integrating aurally- and visually-presented information for VWM. The present fMRI study investigated load  and modality  dependent cerebro-cerebellar VWM activation using a Sternberg task. FMRI revealed modality-independent activations in left frontal (BA 6/9/44), insular, cingulate (BA 32), and bilateral inferior parietal/supramarginal (BA 40) regions, as well as in bilateral superior (HVI) and right inferior (HVIII) cerebellar regions. Visual presentation evoked prominent activations in right superior (HVI/CrusI) cerebellum, bilateral occipital (BA19) and left parietal (BA7/40) cortex while auditory presentation showed robust activations predominately in bilateral temporal regions (BA21/22). In the cerebellum, we noted a visual to auditory emphasis of function progressing from superior to inferior and from lateral to medial regions. These results extend our previous findings of fMRI activation in cerebro-cerebellar networks during VWM, and demonstrate both modality dependent commonalities and differences in activations with increasing memory load."}
+{"text": "A 59-year-old man with a history of longstanding systemic hypotension developed asymmetric non-arteritic anterior ischemic optic neuropathy (NAION) apparently precipitated by bilateral sequential acute primary angle closure. NAION is very rarely reported in association with raised intraocular pressure. In contrast to optical coherence tomography, the failure of scanning laser polarimetry to detect axonal swelling was another interesting finding. Possible reasoning for these observations is discussed. Nonarteritic Anterior Ischemic Optic Neuropathy (NAION) is a result of circulatory insufficiency within the Optic Nerve Head (ONH). An anatomically small optic disc with a correspondingly smaller optic cup resulting in \u2019crowding\u2019 of nerve fibers at the ONH is believed to play a causative role. ArteriosA 59-year-old gentleman was seen with a history of sudden onset pain, redness and diminution of vision of three weeks duration in the right eye (RE) and a week\u2019s duration in the left eye (LE). He had an associated history of abdominal pain, nausea and vomiting. He also gave a history of longstanding systemic hypotension.At presentation, he had visual acuities of 20/400 (RE), and 20/120 (LE). He had corneal edema and a shallow peripheral anterior chamber in both eyes with mid-dilated sluggish pupils. There were glaucomflecken in LE. The applanation pressures measured 44 mmHg (RE) and 46 mmHg (LE). He was treated with intravenous Mannitol 250 mL, Tablet Acetazolamide (250 mg) four times a day, and topical Prednisolone Acetate one-hourly, Timolol Maleate (0.5%) twice a day, Pilocarpine (2%) four times a day in both eyes (BE) after which corneal edema subsided. Gonioscopy confirmed bilateral angle closure. He underwent peripheral YAG laser -assisted iridotomy in both eyes (BE). Topical aqueous suppressants were continued.On the subsequent day, applanation pressures were 10 (RE) and 7 mmHg (LE). A relative afferent pupillary defect (RAPD) was evident in LE. Post-iridotomy gonioscopy revealed 360-degree peripheral anterior synechiae in BE. The right optic disc was moderate in size  with a pink neuroretinal rim and had a vertical cup-disc ratio of 0.4:1 while the left optic disc  showed pallid edema Fig. ,B. ColorOn subsequent follow-up a month later, the patient had no new symptoms. His visual acuities were 20/30 in RE and 20/40 in LE. The applanation pressures measured 13 (RE) and 12 (LE) mmHg. The right optic disc showed mild diffuse pallor and the left optic disc showed gross pallor with complete resolution of edema . Three mNAION is presumed to be a result of hypo-perfusion within the ONH. A signifOptic disc edema and hemorrhages have been reported following acute glaucoma. However,SLP measures form birefringence properties to estimate RNFL thickness. In contr"}
+{"text": "Bartonella henselae and B. vinsonii subspecies berkhoffii in the blood of 14 immunocompetent persons who had frequent animal contact and arthropod exposure.Using PCR in conjunction with pre-enrichment culture, we detected  Bartonella sp. from immunocompetent persons with serologic, pathologic, or molecular evidence of infection are often unsuccessful; several investigators have indicated that Bartonella isolation methods need to be improved  region and heme-binding protein (Pap31) gene have been described  procedure  of 40 extracted blood samples, 13 (33%) of 40 pre-enrichment cultures, and 5 isolates. For 7 persons, B. henselae DNA was amplified at multiple time points. Bartonella DNA was never amplified from any PCR control or uninoculated culture control.When reciprocal titers of antigens . B. hensisolates . For 5 pB. henselae ITS and Pap31 strains were sequenced, B. henselae Houston I (HI) (GenBank NC-005956) and B. henselae San Antonio 2 (SA2) (GenBank AF369529). Within the noncoding ITS region, B. henselae SA2 strains have a 30-bp insertion (ATT GCT TCT AAA AAG ATT GCT TCT AAA AAG) located 518 bases downstream from the 16S gene. Only B. vinsonii subsp. berkhoffii types I and II were detected\u00a0 is generally considered self-limiting  has proven problematic for other specialized laboratories that routinely culture for Bartonella spp. . Cats are considered the primary reservoir host for Bartonella infection in immunocompetent persons.Despite reporting chronic or episodic illness, most participants continued to effectively maintain daily professional and personal activities. The symptoms described in the study patients are very similar to those described in a community and hospital-based surveillance study of CSD patients, in whom CSD-associated arthropathy was an uncommon chronic syndrome affecting mostly young and middle-age women (Serologic and PCR results from blood collected at multiple time points from 14 persons with frequent animal and arthropod contact"}
+{"text": "Tumour-associated markers defined by monoclonal antibodies have proven useful to phenotype bladder tumours. In order to evaluate the prognostic value of such markers, we performed an immunohistochemical study on 57 transitional cell carcinomas  and ten healthy bladders using monoclonal antibodies against the external domain of the epidermal growth factor receptor (EGFR) and against the tumour-associated antigens T43, 19A211 and T138. Immunohistochemistry was performed on frozen sections using a two-step alkaline phosphatase method. The staining pattern obtained with each antibody was analysed according to the TNM classification, and results were analysed according to the subsequent clinical course. 19A211 preferentially stained superficial tumours, and T43, T138 and EGFR preferentially stained invasive tumours. Three monoclonal antibodies appeared to have prognostic value, since progression rate survival was significantly (log-rank test) associated with their expression of EGFR (P = 0.017), T138 (P = 0.0009) and T43 (P = 0.031). T138 expression was found to have an independent significant prognostic value using a stepwise logistic regression. T138 antibody may add significant information to classical pathological parameters."}
+{"text": "Immunosuppression is a risk factor for certain skin cancers. Autoimmune conditions can involve the skin, and may involve immunosuppressive therapies.We conducted a population-based case\u2013control study among elderly US adults using Surveillance, Epidemiology, and End Results-Medicare-linked data of 44\u2009613 skin cancer cases and 178\u2009452 frequency-matched controls. Medicare claims identified autoimmune conditions. Adjusted odds ratios (ORs) compared prevalence in cases and controls.N=1977; OR (95%CI): 1.39 (1.10\u20131.74)). Risk of cutaneous non-Hodgkin's lymphoma (N=2652) was increased with psoriasis (OR (95%CI): 3.20 (2.62\u20133.92)). Risk of Kaposi's sarcoma (N=773) was elevated with ulcerative colitis (OR (95%CI): 2.76 (1.42\u20135.39)), and risk of other sarcomas (N=1324) was elevated with Graves disease (2.62 (1.30\u20135.31)).The most frequent autoimmune condition was rheumatoid arthritis (2.29%), which was associated with slightly increased risk of Merkel cell carcinoma (These findings suggest that immune disturbances in the skin, arising from autoimmune conditions or their treatment, promote development of skin cancer. Established risk factors for skin cancer include exposure to solar ultraviolet radiation, white race, and advancing age . ImmunosAutoimmune conditions may also increase skin cancer risk. Chronic cutaneous inflammation that can characterise some autoimmune conditions  may plausibly cause DNA damage that could promote development of skin cancer. Immunosuppressive medications used to treat autoimmune conditions could have an additional role. This study aimed to investigate associations between autoimmune conditions and the subsequent risk of skin cancers among elderly US adults (aged 67 years and over).We selected subjects from the Surveillance, Epidemiology, and End Results (SEER)-Medicare data set, which links SEER cancer registry and Medicare claims data  .We used polytomous logistic regression to derive odds ratios (ORs) comparing the prevalence of each medical condition in skin cancer cases to controls (N=610), skin appendage carcinoma (N=316), and sweat gland adenocarcinoma (N=144). Of the 2652 cutaneous NHLs, 1854 were T-cell NHLs (of which 945 were mycosis fungoides/Sezary syndrome (MF/SS)) and 798 were B-cell NHLs. Among 1324 sarcomas, the most frequent histological subtypes were malignant fibrous histiocytoma (N=682), dermatofibrosarcoma (N=235), haemangiosarcoma (N=173), and leiomyosarcoma (N=121).Characteristics of 44\u2009613 skin cancer cases and 178\u2009452 controls  are shown in As shown in We evaluated the risk of non-keratinocytic skin cancers in patients with autoimmune conditions in a case\u2013control study among elderly US adults. Some associations that met our criterion for significance are likely to be explained by chronic inflammatory involvement of the skin or immune modulating therapies given for autoimmune conditions. The strong association that we observed between psoriasis and T-cell NHL (particularly MF/SS) is a biologically plausible manifestation of chronic inflammation (Our finding of elevated KS risk associated with ulcerative colitis is supported by several case reports in such patients receiving immunosuppressive drugs .The strength of our study is its large size, allowing us to evaluate associations between uncommon autoimmune conditions and skin cancers. Nonetheless, limitations of our study include that it was restricted to elderly adults, that basal and squamous cell skin cancers were not covered, and that we could not ascertain the presence of medical conditions below 65 years of age; we also had no data on immunosuppressive treatments.Several associations identified between autoimmune conditions and skin cancer risk suggest that such conditions affecting the skin, or treated with immunosuppression promote the development of skin cancer; their further investigation will require additional large studies."}
+{"text": "Dirofilaria repens (Onchocercidae). The patient's blood tests were within the normal limits. Neither eosinophilia nor microfilaremia were detected.A 55-year-old Polish male presented with discomfort, redness, itching, and swelling in the left eye that had begun three days before seeking medical help. Slit-lamp examination revealed an actively moving subconjunctival worm located inferotemporally . A complThe infection with ocular dirofilariasis probably occurred during a visit to Greece 8 months before the symptoms occurred.2The differential diagnosis of subconjunctival filariasis should include loaiasis."}
+{"text": "E. coli genomic DNA. These bacterial sequences act as\u2018mimotopes\u2019 (mimetic sequences of the true epitope), correspond to open reading frames,generate displayed peptides, and compete for binding during phage selection. The specificityof these mimotopes for IL-4 was confirmed by competition ELISA. Other E. colimimotopes were generated using additional antibodies. Mimotopes for a receptor tyrosinekinase gene were also selected using a breast cancer SKBR-3 cDNA phage display library,screened against an anti-erbB2 monoclonal antibody. Identification of mimotopes ingenomic and cDNA phage libraries is essential for phage display-based protein validationassays and two-hybrid phage approaches that examine protein-protein interactions. Thepredominance of E. coli mimotopes suggests that the E. coli genome may be useful togenerate peptide diversity biased towards protein coding sequences.In the post-genomic era, validation of candidate gene targets frequently requires proteinbasedstrategies. Phage display is a powerful tool to define protein-protein interactions bygenerating peptide binders against target antigens. Epitope phage display libraries have thepotential to enrich coding exon sequences from human genomic loci. We evaluated genomicand cDNA phage display strategies to identify genes in the 5q31 Interleukin gene clusterand to enrich cell surface receptor tyrosine kinase genes from a breast cancer cDNAlibrary. A genomic display library containing 2 \u00d7 Abbreviations used: IL, interleukin; ELISA, enzyme linked immunoabsorbant assay;PBS, phospho-buffered saline; cfu, colony forming units."}
+{"text": "Mammary teat removal (thelectomy) was performed unilaterally in female Sprague-Dawley rats at 35 days of age. They were given 7,12-dimethylbenz(a)anthracene (DMBA) when aged either 55 days or 79 days. One third were unmated; one third were mated one week and one third mated more than 3 weeks after DMBA administration. Animals were killed when tumour-positive or after one year, when mammary lesions had developed in 99% of rats. The mean latent period for adenocarcinomas was 18.9 +/- 2.0 weeks. Benign mammary tumours, mainly secretory adenomas, developed significantly later (39.2 +/- 1.7 weeks). The rapid unilateral involution of the thelectomized glands at parturition had no effect on the localization of either adenocarcinomas or benign mammary tumours. Pregnancy and delayed DMBA administration markedly reduced the incidence of adenocarcinomas; lactation had no significant effect. In a separate experiment, precocious puberty induced with pregnant-mare-serum gonadotrophin in 30-day-old female Sprague-Dawley rats enabled their first pregnancy and lactation to be completed by 80 days of age. Parity before carcinogen administration significantly delayed the development of adenocarcinomas."}
+{"text": "The bpt and formate ligands occupy the same C               2 symmetry, while the MnII ion resides on another crystallographic twofold rotation axis. Each bpt ligand acts as a cis-bis-chelate to ligate two MnII ions into a one-dimensional chain running along the crystallographic 41 screw axis. Adjacent MnII ions are further bridged by a \u03bc2-formate ligand, completing the distorted octa\u00adhedral coordination geometry of the cation.Owing to the presence of crystallographic twofold rotation axes (site symmetry 2, Wyckoff letters  DOI: 10.1107/S160053680802299X/si2099Isup2.hkl            Structure factors: contains datablocks I. DOI:  crystallographic information; 3D view; checkCIF report            Additional supplementary materials:"}
+{"text": "This study evaluates the degree and relevance of persisting ototoxicity after cisplatin-based standard-dose chemotherapy for testicular cancer, with emphasis on identification of potential factors for an increased risk of this late sequel. Hearing thresholds of 86 patients with a median age of 31 years (range 21-53 years) and a median follow-up time of 58 months (range 15-159 months) were assessed by conventional pure-tone audiometry. Interviews were conducted evaluating the patients' history with special regard to audiological risk factors, as well as circumstances of ototoxic symptoms. Details concerning treatment and patient variables were extracted retrospectively from the patients' charts. An additional screening programme assessed current body functions, blood parameters and other late toxicities. Symptomatic ototoxicity persisted in 20% of patients , while 10% had experienced completely reversible ototoxic symptoms for a duration of 1-18 months after treatment. Symptoms were bilateral in 81% of patients. Hearing thresholds were compatible with cisplatin-induced hearing loss in 42% of audiograms performed. Subjective (history) and objective (audiogram) findings were not always consistent. The following statistically significant risk factors for ototoxicity were established: high cumulative dose of cisplatin (P < 0.0001); history of noise exposure (P = 0.006). Additionally, high doses of vincristine (P = 0.001) seemed to result in reversible ototoxic symptoms. No other independent risk factors were identified. In conclusion, persisting ototoxicity represents a clinical sequel for approximately 20% of testicular cancer patients treated at standard dose but may affect more than 50% of patients receiving cumulative doses of cisplatin > 400 mg m(-2). Previous noise exposure may also result in a threefold increased risk for cisplatin ototoxicity. Future studies should use these risk factors as important stratification criteria for trials aiming at the evaluation and prevention of cisplatin-induced ototoxicity."}
+{"text": "Immune responses developing in irradiated environment are profoundly altered. The memory anti-arsonate response of A/J mice is dominated by a major clonotype encoded by a single gene segment combination called CRIA. In irradiated and autoreconstituted A/J mice, the level of anti-ARS antibodies upon secondary immunization is normal but devoid of CRIA antibodies. The affinity maturation process and the somatic mutation frequency are reduced. Isotype switching and development of germinal centers (GC) are delayed.            The primary antibody response of C57BL/6 mice to the hapten (4-hydroxy-3-nitrophenyl) acetyl(NP)-Keyhole Limpet Hemocyanin (KLH) is dominated by antibodies encoded by a family of closelyrelated VH genes associated with the expression of the \u03bb1 light chain.We investigated the anti-NPprimary response in irradiated and autoreconstituted C57BL/6 mice. We observed some splenicalterations as previously described in the irradiated A/J model. Germinal center reaction is delayedalthough the extrafollicular foci appearance is unchanged. Irradiated C57BL/6 mice are able to mounta primary anti-NP response dominated by \u03bb1 positive antibodies but fail to produce high affinityNP-binding IgGl antibodies. Following a second antigenic challenge, irradiated mice develop enlargedGC and foci. Furthermore, higher affinity NP-binding IgG1 antibodies are detected."}
+{"text": "Cisplatin (CDDP) is a potent anti-neoplastic agent with associated toxicities, especiallygastrointestinal and nephrotoxicity that are its dose-limiting factors in clinical oncology. In anattempt to elucidate its mechanism(s) of action, liver and kidney tissues from normal and CDDPtreated (1.8 mg/kg) dogs were evaluated for changes in various dehydrogenases  and nonspecific lipase enzymes. CDDP treatment induced an inhibitionof all the enzymes studied except G-6-PDH and nonspecific lipases, where there was a significantincrease. Supplemental pretreatments with calcium 2.50 mg  ergocalciferolplus 1000 mg of elemental calcium as Tums 500 /day seemed toretain enzyme levels close to normal with no apparent toxic side effects observed after CDDP.Calcium supplements post-CDDP treatment did not have any protective effect."}
+{"text": "Median survival and 5-year survival rate of all patients are 36 months and 46%, in R0 patients 68 months and 63% (R0-IIB/IIIA/IIIB: not yet reached and 67%). This multimodality treatment including surgery proved highly effective with 100% local control and remarkable long-term survival after complete resection, even in locally advanced SCLC stages IIB/IIIA patients. \u00a9 1999 Cancer Research CampaignFollowing mediastinoscopy, a prognostically orientated multimodality approach was chosen in selected small-cell lung cancer (SCLC) patients with hyperfractionated accelerated chemoradiotherapy (Hf-RTx) and definitive surgery (S). Stage IB/IIA patients had four cycles of cisplatin/etoposide (PE) and surgery. Stage IIB/IIIA patients had three cycles PE followed by one cycle concurrent chemoradiation including Hf-RTx and surgery. Most stage IIIB patients were not planned for surgery and had CTx followed by sequential RTx or one cycle concurrent CTx/RTx. Of 46 consecutive patients  43 (94%) showed an objective response. Twenty-three of patients (72%) planned for inclusion of S were completely resected (R0) . Overall toxicity was acceptable \u2013 one patient died of septicaemia, no perioperative deaths occurred. Median follow-up of patients alive ("}
+{"text": "Salmonellae deploy effectors that trigger localized actin reorganization to force their own entry into non-phagocytic host cells. Six effectors  can individually manipulate actin dynamics at the plasma membrane, which acts as a \u2018signaling hub\u2019 during Salmonella invasion. The extent of crosstalk between these spatially coincident effectors remains unknown. Here we describe trans and cisbinary entry effector interplay (BENEFIT) screens that systematically examine functional associations between effectors following their delivery into the host cell. The results reveal extensive ordered synergistic and antagonistic relationships and their relative potency, and illuminate an unexpectedly sophisticated signaling network evolved through longstanding pathogen\u2013host interaction.Bacterial pathogens have evolved a specialized type III secretion system (T3SS) to translocate virulence effector proteins directly into eukaryotic target cells.  Salmonella infection is the ability of bacteria to force their own entry (\u2018invade\u2019) into intestinal cells of their mammalian host from where they replicate, spread and cause damage. To achieve this invasion, Salmonella deliver a cocktail of proteins directly into host target cells. These proteins override host cell communications and remodel cell structure, tricking the normally dormant cells into engulfing the invaders. Although we are beginning to understand the functions of each delivered protein, little is known about how their activities are coordinated. Here we describe new techniques that systematically examine the interplay between the delivered bacterial proteins within the host cell. The results illuminate an unexpectedly complex network of interrelated relationships that must be precisely coordinated to promote bacterial invasion. The data provide new insights into how this important pathogen triggers invasion of host cells during infection.Critical to the onset of  Salmonella pathogenesis is bacterial invasion of non-phagocytic intestinal epithelial cells, an event that can be modelled using cultured cells Many bacterial pathogens employ type III secretion systems (T3SSs) to deliver virulence effector proteins directly into eukaryotic host cells Salmonella actin-binding proteins, SipC and SipA, control actin dynamics directly Effectors are delivered into the target cell via a cholesterol-binding plasma membrane-integral translocon comprising SipB and SipC, which is likely linked to the T3SS by SipD Listeria and Yersinia induce internalization by hijacking host receptor-mediated endocytosis Salmonella effectors are insufficient to promote bacterial internalization, although SopE, SopB and SipC do elicit generalized cell-wide cytoskeletal reorganization and membrane protrusions when expressed individually in cells Salmonellae without compromising target cell viability Discrete bacterial surface proteins of Salmonella entry effectors localize to the target cell plasma membrane both when expressed individually in cultured cells and after delivery via the bacterial T3SS, and consequently we proposed the plasma membrane as a critical interface for Salmonella effector action Salmonella effectors and their host targets within cultured cells.We have previously demonstrated that Salmonella T3SS S.typhimurium SL1344 strains each additionally expressing an individual plasmid-encoded epitope-tagged entry effector. This allowed the expression, secretion and delivery of an individual effector to be specifically enhanced (1.5\u20133.3-fold WT) in a WT background , we observed that a significant increase in bacterial invasion rate occurred with the dSopE, dSopB or dSipC strains . Each of these strains secrete the other entry effectors at WT levels When cultured cells were infected with the effector-augmented strains . In addition, SopE, SopB or SipC are each able to stimulate actin polymerization in cultured cells, although alone are insufficient to trigger bacterial entry Salmonella sopE or sopB deletion mutants exhibit only a modest decrease in invasion, whereas sipC null mutants are non-invasive, as SipC is not only an effector but also a translocator of other effectors Salmonella invasion rate.As effector\u2019) and infected with WT S.typhimurium , only mild rate increases  were evident. A comparable effect was observed when control Cdc42-dependent actin polymerization and macropinocytosis were induced with bradykinin . tSptP and tSipB conferred a limited resistance to invasion , consistent with their ability to counteract cytoskeletal and nuclear responses and to disrupt cellular endomembranes, respectively , these transfected effectors are unable to significantly influence invasion rate, either because the effectors distribute along the plasma membrane throughout the cell, rather than at specific pathogen contact sites as with the T3SS-delivered effectors, or because their premature activity inhibits WT entry. Together these data reveal that the spatio-temporal context of effector activity seems critical, as only cytoskeletal rearrangements induced by delivered stimulatory effectors can significantly increase bacterial invasion rate.However, when cultured cells were transfected with effectors :dSopE \u2013163%; tRac1(N17) \u2212238%), yet remained unaltered by tRhoA(N19) expression. Conversely, none of the expressed dominant negatives suppressed the enhanced invasion rate of the dSipC strain (e.g. tCdc42(N17) +19%; tRhoA(N19) +13%), indicating that SipC activity is Rho-family GTPase independent  screens to assess potential cross talk between pairs of effectors. In the first \u2018trans\u2019 BENEFIT screen, we investigated the effects of expressing individual bacterial effectors rather than dominant negative derivatives of host proteins in cells prior to infection with WT Salmonella or the effector-augmented strains  and effector B (\u2018t-effector\u2019 pre-expressed in the target cell by transient transfection) to be an increase (or decrease) in rate of at least one-fold of WT after correction for WT Salmonella invasion of cells expressing effector B , and invasion of control cells by WT Salmonella expressing augmented levels of effector A . This threshold is significantly different from the controls (Mann Whitney U p<0.05).Based on this transfection-infection approach, we next designed Salmonella invasion rates . Direct observation of infected cells in parallel revealed dramatic actin reorganization induced by these pairings . An extended screen including the dSipB and dSipD strains confirmed that unlike SipC, which is involved in both effector delivery and actin reorganization The results of this screen were striking, revealing reproducible changes in Salmonella strains, in particular dSopE , dSopB  or dSipC , and as with effector synergy, this functional antagonism was reversed  or annulled  using inverse pairings. Notably, although both tSptP and tSipB impede WT invasion , the effector-augmented strains were not significantly inhibited by tSipB expression , each infection was performed in duplicate, allowing the strain carrying the marker to be alternated. The mean invasion efficiency of each strain could then be calculated and controlled for the marker-induced variation ], and that the enhanced invasion rates observed with the dSopE, dSopB and dSipC strains  were recapitulated during mixed infection [e.g. the invasion rate of a mixed dSopE:dSopE strain input remains \u223c3-fold WT (304%) to which component strains contribute equivalently (152%\u2236152%)].At first, an identical multiplicity of infection to the cis BENEFIT screen using heterologous mixtures of effector-augmented WT strains. As previously, we conservatively defined functional interplay between effector A (\u2018d-effector\u2019) and effector B  to be reflected by an increase (or decrease) in invasion rate of at least one-fold of WT from the change recorded when WT Salmonella expressing augmented levels of either effector A or B enter cells independently . Such changes are statistically significantly different from the controls (Mann Whitney U p<0.05).Having experimentally verified these important assumptions, we next performed a complete trans BENEFIT screen, again illustrating that effector concentration is related to invasion rate, provided that host targets  remain in excess. Two significant synergistic relationships were immediately evident  and the dSipA (+153%) strains gain from a mixed dSipC:dSipA infection], or \u2018selfish\u2019 in which one strain exploits its partner . In contrast to the trans BENEFIT screen, no significant antagonistic effects were observed . tSipC-N localized along induced hyper-elongated filopodia 30\u201360 \u00b5m in length, an activity similar to the cellular actin-bundling protein fascin ). However, when cells expressing SipC-N or SipC-C were infected with effector-augmented S.typhimurium strains, SipC-SopB synergy was attenuated . Indeed, unlike tSipC, tSipC-N significantly inhibited invasion by the dSopE, dSopB and dSipC strains , as premature actin bundling is likely to intrinsically impede cytoskeletal plasticity required for bacterial invasion. tSipC-C also inhibited dSopE and dSipC invasion , but could still apparently engage in limited synergy with the dSopB strain, albeit below our imposed significance threshold . These data suggest a potential link to C-terminal domain function, but additionally imply that plasma membrane localization of this region is important for efficient synergy with SopB, reaffirming the view that the plasma membrane is a critical interface for effector interplay Initially, we wished to establish whether known SipC and SopB activities were required for synergy. The SipC N-terminal domain  directs actin filament bundling, whereas the C-terminal domain  induces actin nucleation Shigella flexneri IpgD C462S; S.typhimurium strains . When pre-expressed in cells, tSopB is a \u2018dominant-negative\u2019 inhibitor of the dSipA, dSipC, dSopE and dSopB strains . This effect was recapitulated using tIpgD , although inhibition of the dSipA and dSopB strains was somewhat reduced. Nevertheless, this functional substitution suggested that inhibition is driven by inositol phosphatase activity rather than an unknown SopB-specific function. In clear support of this, significant inhibition was alleviated using phosphatase-dead tSopBC462S , and invasion of the dSipC strain specifically but mildly enhanced .Next, we investigated whether SopB inositol phosphatase activity was required for SipC-SopB synergy by examining the effects of expressing the homologous invasion-associated inositol phosphatase S.typhimurium strain engineered to deliver increased levels of SopBC462S in the WT background (dSopBC462S), and included this in a trans BENEFIT screen where effector-transfected cells were infected with dSopE, dSopB or dSopBC462S strains , whereas the weaker tSopE synergy was abolished . The latter is a recognized relationship mediated by cellular inositol phosphates C462S invasion was not inhibited in cells expressing SipA, SopB or SptP . These combined findings suggested that SopB inositol phosphatase activity contributes to synergy with membrane localized SipC.To investigate the effect of SopB inositol phosphatase activity on SipC synergy during infection, we generated a 2] to promote membrane elasticity and vacuole formation 2 influence invasion the augmented dSopB strain, we expressed phosphatidylinositol-4-phosphate-5-kinase [PIP(5)K], which catalyzes the formation of PIP2, in cells prior to infection with the effector augmented S.typhimurium strains. Strikingly, excess PIP2 stimulated WT Salmonella invasion more than two-fold (2 either directly or via PIP(5)K stimulation. Indeed, the periphery of Salmonella-induced membrane ruffles are enriched for PIP2SopB additionally aids invasion by cleaving plasma membrane phosphatidylinositol-4,5-bisphosphate [PIPSalmonella effectors by radioactive counting of fractions separated by ion exchange chromatography P2], likely to be a stable breakdown product of PIP3). By comparison, no major alterations were observed when comparable tSipC or tSptP lysates were assayed ( and tSptP). These biochemical data demonstrate that SipC itself does not directly or indirectly generate PIP2, but do not preclude that SipC alters the local concentration or distribution of existing PIP2 in the membrane. To examine this possibility, the PIP2-binding plextrin-homology (PH) domain of phospholipase C\u03b4 fused to green fluorescent protein (PLC\u03b4-PH-GFP) was expressed in cultured cells prior to infection with effector-augmented strains to report PIP2 distribution during invasion 2, indicated by the diffuse reporter probe distribution , and additionally validate every cooperative  fused to C-terminal GFP was a kind gift from Phill Hawkins . pT:PIP(5)K was generated by PCR amplification of the cDNA encoding murine phosphatidylinositol-4-phosphate-5-kinase and cloning of the product into pcDNA3.1.Eukaryotic expression vectors pT:SopEcis\u2019 or \u2018trans\u2019binary entry effector interplay (BENEFIT) screens are a modification of the gentamicin protection assay, which measures the ability of Salmonella strains to invade cultured cells The \u2018S.typhimurium SL1344 cultures transformed with pB:sopEFLAG, pB:sopBFLAG, pB:sptPFLAG, pB:sipCFLAG, pB:sipA, pB:sipB, pB:sipD or vector control 4 serum-starved NIH3T3 fibroblasts, transfected 48 h previously with expression plasmids pT:sopEFLAG, pT:sopBFLAG, pT:C462SsopBFLAG, pT:sptPFLAG, pT:sipCFLAG, pT:sipCNFLAG, pT:sipCCFLAG, pT:sipA, pT:ipgDFLAG, pT:PIP(5)K or empty vector 2, 60 min), cells were repeatedly washed with warm PBS and extracellular bacteria killed with gentamicin . Cells were washed again with PBS and lysed in 10 mM Tris-Cl, pH 7.4, 0.5% (v/v) triton X-100. Serial lysate dilutions were plated onto LB agar and the percentage of intracellular bacteria compared to the original inoculum. Rates were referenced against invasion of WT S.typhimurium SL1344 and an isogenic invasion deficient mutant lacking invG, an essential structural component of the T3SS, assigned as 100% and 0% respectively, in each transfectant background. Functional interplay between effector A  and effector B (\u2018teffector\u2019 pre-expressed in the target cell by transient transfection) was defined as an increase (or decrease) in rate of at least one-fold (i.e. \u00b1100%) of WT after correction for WT Salmonella invasion of cells expressing effector B and invasion of control cells by WT Salmonella expressing augmented levels of effector A.Stationary phase S.typhimurium SL1344 cultures transformed with pB:sopEFLAG, pB:sopBFLAG, pB:sptPFLAG, pB:sipCFLAG, pB:sipA or empty vector 4 serum-starved NIH3T3 fibroblasts were infected. An antibiotic marker (spectinomycin) was introduced into one strain to allow the relative invasion efficiency of each strain to subsequently be calculated. Since selection conferred a marginal disadvantage (\u223c5%), each infection was performed in duplicate to allow the marker to be alternated. After incubation , cells were repeatedly washed with warm PBS and extracellular bacteria killed with gentamicin . Cells were washed again with PBS and lysed in 10 mM Tris-Cl pH 7.4, 0.5% (v/v) triton X-100. Serial dilutions were plated onto LB agar with and without spectinomycin and the percentage of intracellular bacteria compared to the original inoculum. In the cis assay, functional interplay between effector A  and effector B  was defined as an increase (or decrease) in rate of at least one-fold (i.e. \u00b1100%) of WT after correction for the rate expected when either strain invades cells independently.Stationary phase In both screens, the results presented are the mean\u00b1SEM of 4 independent experiments each performed in triplicate and the changes reported statistically significant from the controls (Mann Whitney U p<0.05).Infected or transfected cells were washed in PBS and fixed with 3.7% (v/v) paraformaldehyde for fluorescence microscopy. Fixed samples were permeabilized with 0.2% (v/v) triton X-100 in PBS, blocked with 3% (w/v) bovine serum albumin (BSA) in PBS , then incubated with appropriately diluted primary antibodies  in PBS . Samples were sequentially incubated with AlexaFluor 488-conjugated anti-rabbit or anti-mouse IgG secondary antibodies, according to manufacturer's instructions , then Texas Red-conjugated phalloidin  and 4\u2032,6\u2032-diamidino-2-phenylindole dihydrochloride  in PBS. Coverslips were mounted using ProLong Anti-fade reagent (Invitrogen), and visualized using a fluorescence microscope (Leica DM IRBE). Images were captured using a CCD digital camera (Hamamatsu) and processed using OpenLab software (Improvision). Where appropriate GFP fluorescence was observed directly in fixed cells. Bacterial DAPI signal was artificially enhanced to normalise the intensity to that of nuclear staining.S.typhimurium infection) were assayed by immunoblotting mechanical cell lysates or subcellular fractions with antibodies raised against purified effectors http://rsb.info.nih.gov/nih-image/), and intensity values compared to those derived by immunoblotting known concentrations of purified effectors. Cells were fractionated as previously described Effector protein concentrations in transfected cells or delivered into cells (measured 60 min after 32P]Pi ml\u22121 in 10 mM HEPES pH7.4 (diluted from an iso-osmotic stock) to allow labelling of cellular phosphoinositides . Cells were rapidly aspirated and fixed with 1 vol ice-cold 1.0 M HCl, and scraped into glass vials containing 4 vol CHCl3:MeOH , Folch carrier lipid and tetrabutylammonium sulphate . This was vortexed and centrifuged  to separate phases. The lower phase was removed into fresh tubes containing synthetic upper phase, mixed and centrifuged , then dried in vacuo. Dried lipids were deacylated by addition of monomethylamine reagent in vacuo. Deionized H2O and petroleum ether/n-butanol/ethyl formate [4\u223620\u22361 (v/v)] were then added, then the mixture vortexed and centrifuged . The upper organic phase was then removed, the lower water-soluble phase mixed with 1 vol petroleum ether/n-butanol/ethyl formate [4\u223620\u22361 (v/v)], and the mixture vortexed and centrifuged as previously. The lower phase and interface was then dried in vacuo. Labelled lipid species were then separated for analysis by high-performance liquid chromatography (HPLC). Dried lipids were resuspended in dH2O  and filtered (0.45 \u00b5m). Samples were loaded onto a pre-equilibrated Whatman Partisphere 5SAX column (12.5 cm) and developed at 1 mlmin\u22121 using a gradient of H2O (A) versus 1.25 M NaH2PO4 (B) . Fractions were collected every 30 s and scintillant added (Packard \u2018Ultima Gold\u2019). Lipid species were identified from the elution profile by comparison to labelled standards of known individual phosphoinositide species.Analysis was carried out as described 5P levels could be assessed relative to total cellular lipid 3\u2236CH3OH\u2236ammonium formate , CHCl3:CH3OH:ammonium formate , and finally resuspended in 0.1 vol CHCl3:MeOH:ammonium formate . Samples were incubated , centrifuged  and the supernatant discarded. Beads were washed twice with 1 vol 50 mM ammonium formate buffer and lipids eluted twice with 2 M triethylbicarbonate (TEAB) to which phosphatidylserine was added as an inert carrier (14.25 \u00b5M). Beads were incubated with 0.5 vol 2 M TEAB and phosphatidylserine (1 h), centrifuged  and supernatants collected. Beads were washed again with 0.2 vol 2 M TEAB and phosphatidylserine (1 h), and supernatants combined with the first. Tubes were dried in vacuo . Lipid phosphorylation with recombinant type II\u03b1 phosphatidylinositol kinase to determine PI(5)P mass was performed as previously 32P] ATP and 5 \u00b5M ATP to each sample, and PIP2 extracted and separated by thin layer chromatography. PI(5)P levels were determined from a standard curved with reference to known concentrations of synthetic PI(5)P, and expressed relative to amount of total phospholipids present in each sample.PI(5)P levels were assayed as described Figure S1S.typhimurium strains and cultured cells exogenously expressing SipB and SipD. A. Effector expression and secretion in S.typhimurium SL1344 wild-type compared with strains transformed with pTrc plasmids expressing SipB or SipD in trans in the wild-type background. Equivalent loadings of late exponential cell lysates (left) and filtered culture supernatants (right) were separated by SDS-PAGE and analyzed by immunoblotting with the appropriate effector antibody or RfaH (control). Densitometric analysis showed that plasmid-encoded SipB and SipD expression was specifically augmented in the absence of induction (\u223c4-fold wild-type), and that elevated expression correlated with increased effector secretion (\u223c3-fold wild-type). Effector expression from the plasmid did not interfere with the expression or secretion of other chromosomally-encoded entry effectors. B. Effect of exogenous SipB or SipD expression on S.typhimurium entry into cultured fibroblasts. Results of gentamicin protection assays using wild-type or strains exogenously expressing SipB (dSipB) or SipD (dSipD). Entry rates (after 60 min) were compared to wild-type (assigned as 100%) containing the empty plasmid. Results are the mean of four independent experiments each with three replications. Correspondingly, no significant change was observed in mean cells invaded per field , or in mean number of bacteria per fibroblast  with Salmonella strains expressing augmented levels of SipB or SipD as indicated. Left column shows triple fluorescence (merge) of cells stained with anti-SipB or anti-SipD/Alexafluor 488-conjugated anti-rabbit IgG to localize each effector (green), Texas Red-conjugated phalloidin to visualize F-actin (red), and DAPI to localize cell nuclei and bacteria (blue). Middle column shows individual effector channel (effector) and right column the DAPI channel from which the nuclear signal has been removed for clarity (indicated by dashed lines) (bacteria). Arrows indicate internalized bacteria, and areas indicated in merge are show at higher magnification in inserts. Scale bars, 2 \u00b5m. D. Immunofluorescence micrograph of fixed NIH3T3 fibroblast transiently expressing SipB. Left panel shows double fluorescence (merge) image of cell SipB stained 48 h after transfection with anti-SipB polyclonal antiserum/Alexafluor 488-conjugated anti-rabbit IgG to localize SipB (green), and Texas Red-conjugated phalloidin to visualize F-actin (red). SipB channel alone (effector) is shown in greyscale for clarity. Image is typical of >50 cells from three independent experiments. Scale bar, 2 \u00b5m. E. Localization of SipB and SipD in Salmonella-infected and effector-transfected fibroblasts. Cultured NIH3T3 fibroblasts were infected (60 min) with S.typhimurium strains expressing augmented levels of SipB (dSipB) or SipD (dSipD) in the wild-type background or were transiently transfected (48 h) with an expression vector encoding S.typhimurium SipB. Cells were mechanically fractionated Click here for additional data file.Figure S2Salmonella effectors. NIH3T3 fibroblasts were individually transfected with indicated effectors and analyzed by flow cytometry after 48 h. Cell number is expressed as the percentage of control cells, with apoptotic fraction shaded black. B. Effector concentration following delivery or transfection. Upper: Cells transfected with effectors (t-effector) or infected with effector-augmented (d-effector) S.typhimurium strains were mechanically fractionated prior to immunoblotting with appropriate anti-effector antibodies. Effector concentration in the internal membrane/cytoskeletal (IM/CS) and plasma membrane (PM) fractions was determined by densitometric analysis of band intensity and comparison to purified protein standards (e.g. SipC and SopE). To facilitate simultaneous quantification of effectors after transfection and infection, fractions from 2.7\u00d7106 and 5.4\u00d7106 cells were immunoblotted, respectively. Lower: Graph shows comparative concentrations of each transfected and delivered effector. Split bars represent relative concentration in the two subcellular fractions . C. Effector localization following delivery and transfection. Cells transfected with effectors  were infected with effector-augmented (d-effector) S.typhimurium strains . Infected transfectants were mechanically fractionated, each sub-fraction  separated by SDS-PAGE, and analyzed by immunoblotting with the appropriate anti-effector antibody.Intracellular effector concentration after T3SS-dependent delivery and transfection. A. Cell number and viability following transfection with (0.53 MB TIF)Click here for additional data file.Figure S3trans BENEFIT screening . Wild-type (WT) bacteria endogenously express, secrete and deliver sipA, sipC, sopE, sopB and sptP (abbreviated to acebp) and sipB and sipD (abbreviated separately as bd). Effector-augmented strains each express, secrete and deliver mildly increased levels of an individual plasmid-encoded effector in the WT background . Cultured cells were transfected with individual entry effectors (denoted t-effector) prior to infection. B. Upper: Cultured fibroblasts were transfected (t) with individual effectors prior to infection with WT or effector-augmented (d-effector) S.typhimurium strains. Invasion rates after 60 min were compared to WT (assigned as 100%). Results are mean\u00b1SEM of 4 independent experiments each performed in triplicate. Baselines \u2018wild-type\u2019 and \u2018\u0394invG\u2019 denote S.typhimurium SL1344 and S.typhimurium \u0394invG (T3SS deficient) invasion in each transfectant background, respectively. Lower: Table showing differences in invasion rates (%) after correction. Shading denotes a significant increase (green), significant decrease (red) or no significant change (grey) in invasion (Mann Whitney U p<0.05).The T3SS translocator SipB and SipD are not invasion effectors. A. Schematic illustrating (9.10 MB TIF)Click here for additional data file.Figure S4S.typhimurium strains. Cells were fixed 60 min post infection and double fluorescence stained to visualise F-actin and bacteria/cell nuclei. Arrows indicate internalized bacteria.Actin rearrangements induced during infection of transfected cells. Cultured fibroblasts were transfected with indicated effectors (t-effector) and subsequently infected with effector-augmented (d-effector) (1.66 MB TIF)Click here for additional data file.Figure S5S.typhimurium SL1344 or effector augmented (d-effector) strains were mixed pair wise (MOI 50) at 50\u223650, 90:10 and 10:90 ratios. Invasion of each strain was assessed using selectable markers after 60 min (Effector synergy is abolished by biasing the relative levels of each strain. r 60 min . Results(0.69 MB TIF)Click here for additional data file."}
+{"text": "Both cell death and, paradoxically, proliferation of immature Schwann cells was markedly enhanced, suggesting that their terminal differentiation is triggered by growth-arresting regulatory microRNAs. Using microRNA microarrays, we identified 16 microRNAs that are upregulated upon myelination and whose expression is controlled by Dicer in Schwann cells. This set of microRNAs appears to drive Schwann cell differentiation and myelination of peripheral nerves, thereby fulfilling a crucial function for survival of the organism.The myelin sheaths that surround the thick axons of the peripheral nervous system are produced by the highly specialized Schwann cells. Differentiation of Schwann cells and myelination occur in discrete steps. Each of these requires coordinated expression of specific proteins in a precise sequence, yet the regulatory mechanisms controlling protein expression during these events are incompletely understood. Here we report that Schwann cell-specific ablation of the enzyme Dicer1, which is required for the production of small non-coding regulatory microRNAs, fully arrests Schwann cell differentiation, resulting in early postnatal lethality. Dicer Proper myelination is essential for the efficient saltatory conduction of action potentials, the trophic support of axons, and the maintenance of axonal integrity in the peripheral nervous system (PNS). Defective PNS myelination occurs in hereditary peripheral neuropathies The mature myelin sheaths wrapped around the large-diameter axons of peripheral neurons arise from neural crest cells which subsequently develop into Schwann cell precursors (SCPs), immature Schwann cells, and finally mature myelinating or non-myelinating Schwann cells. Each stage of Schwann cell development is associated with a set of specific protein markers, the expression of which is thought to be driven primarily by axon-derived signals at the SCP stage and by the secretion of autocrine survival factors at the Schwann cell stage  system floxP sites (Dicer1fl/fl) to mice expressing the Cre recombinase under the control of the desert hedgehog promoter (Dhh-Cre).In order to determine which miRNAs might be required for peripheral myelination, we created a mouse line undergoing Schwann cell-specific deletion of Dicer1, by crossing mutants whose endogenous Dicer1 sequences were flanked by fl/fl mice to mice expressing Cre-recombinase specifically in Schwann cells . The Cre recombinase in these mice is already active in Schwann cells of the precursor stage at embryonic day 12/13 (E12/13) fl/fl Dhh-Cre+ mice lacking Dicer expression in Schwann cells exhibited a severe behavioral phenotype characterized by ataxia and hind limb paresis. In compliance with animal welfare regulations, mice were euthanized at the age of 25 days. Electron microscopy (EM) of 18-day old Dicerfl/fl Dhh-Cre+ sciatic nerves revealed a severe myelination defect when compared to control littermates Dicerwt/fl Dhh-Cre+ and Dicerfl/fl Dhh-Cre\u2212. In Dicerfl/fl Dhh-Cre+ sciatic nerves, most fibers remained unmyelinated; the few myelin sheaths present were abnormally thin  revealed no structural difference  and the microarray to identify miRNAs specifically expressed in Schwann cells. We chose two different developmental time points for analysis. The first time point was before the onset of myelination and before structural differences could be observed between Dicerfl/fl Dhh-Cre+ and Dicerwt/fl Dhh-Cre+ nerves (at E17). The second time point was p4, when myelination had already started in control mice and was already evidently impaired in Dicerfl/fl Dhh-Cre+ mice.To identify specific miRNAs involved in peripheral nerve myelination, we performed a differential microarray analysis of miRNA extracted from DicerAmong the 216 miRNAs expressed in peripheral nerves, we identified a total of 109 miRNAs which were either significantly developmentally up- or downregulated (p4 compared to E17) or significantly different between controls and mutants Fig. 4. fl/fl Dhh-Cre+ and Dicerwt/fl Dhh-Cre+ nerves. The mRNA expression of several transcription factors, cell surface receptors, and other molecules known to be involved in peripheral nerve myelination was significantly altered in p4 Dicerfl/fl Dhh-Cre+ nerves compared to Dicerwt/fl Dhh-Cre+  compared to the higher percentage of proliferating cells (11%) argues against compensatory proliferation.How can the above findings be mechanistically explained? In Dicer-less Schwann cells, a global reduction of all miRNAs may directly lead to both Schwann cell proliferation and death, maybe because certain miRNAs are necessary for exiting the cell cycle, terminal differentiation, and cell survival Fig. 6. fl/fl Dhh-Cre+ nerves showed a higher expression when compared to control Dicerwt/fl Dhh-Cre+ nerves. This suggests that other endoneural cells like fibroblast and endothelial cells or axonally transported miRNAs may contribute to the overall pool of miRNAs which are regulated in response to Schwann cell-specific lack of miRNA expression.By microRNA microarray, we identified numerous miRNAs that are expressed in peripheral nerves during development at E17 and p4. Among the 216 expressed miRNA, 109 were either up- or downregulated upon differentiation of immature Schwann cells at E17 into myelinating Schwann cells at p4, or differentially expressed as a consequence of Dicer depletion at E17 or at p4. Unexpectedly, for a number of miRNAs, Dicer mutant DicerIt is plausible to assume that miRNAs crucially involved in myelination should be upregulated as Schwann cell development progresses towards the myelinating phenotype. We therefore selected those miRNAs that were both (1) significantly upregulated upon myelination and (2) significantly decreased upon Dicer depletion in Schwann cells. Only 16 miRNAs met these criteria Table 1.Although downregulation of miRNAs might also be crucial during the development of peripheral myelin, such miRNAs are unlikely to be responsible for the observed phenotype following Dicer depletion in our study.in vitro, including miR-146, miR-23b, miR-24, and miR-27b in one study fl/fl Dhh-Cre+ peripheral nerves in our miRNA screen.Some of the upregulated miRNAs are important for oligodendrocyte differentiation, e.g. miR-338 in vitroin vivo at this time point of development. The miRNAs identified by Verrier et al. to be upregulated in differentiated Schwann cells showed no overlap with our main candidates in vivoAnother study analyzed and compared the miRNA expression pattern in proliferating and differentiated rat Schwann cells fl/fl Dhh-Cre+ nerves, with expression levels of Oct6, Egr2, and Sox10 in Dicerfl/fl Dhh-Cre+ p4 nerves closely matching those in Dicerwt/fl Dhh-Cre+ E17 nerves. The only exception was Brn2, which was further downregulated in Dicerfl/fl Dhh-Cre+ p4 nerves than in E17 nerves. This is in contrast to the recent study by Pereira et al., where Sox10 expression was not significantly reduced and Oct6 expression was only marginally reduced. The dramatic downregulation of Egr2 reported by Pereira et al., on the other hand, was consistent with our study fl/fl Dhh-Cre+ nerves, which is normally down-regulated after onset of myelination.The process of myelination requires the specific upregulation of pro-myelinating proteins and the coordinated downregulation of anti-myelinating proteins at specific stages of myelin maturation. Interestingly, we found that several transcripts  encoding pro-myelinating proteins fail to be upregulated in Dicerfl/fl Dhh-Cre+ mice might reflect the failure of Dicerfl/fl Dhh-Cre+ Schwann cells to downregulate anti-myelin signaling molecules. We tested the mRNA expression of the anti-myelinating factors Sox2 and c-Jun in Dicerfl/fl Dhh-Cre+ versus Dicerwt/fl Dhh-Cre+ nerves. We did not detect any significant difference in Sox2 or c-Jun mRNA expression between these two groups at the mRNA level; however, Pereira et al. reported elevated Sox2 in Dicerfl/fl Dhh-Cre+ nerves miRNA expression is normally associated with silencing of target mRNAs, either through enhanced mRNA degradation or translational inhibition of target transcripts. Therefore the Schwann cell differentiation defect observed in nerves of DicermiRNA-34a was recently shown to act as a tumor suppressor in human glioma cells by inhibiting cell proliferation Furthermore, we observed an increased phosphorylation of Erk in Dicer mutant nerves at p20. Activation of the Erk pathway is known to induce dedifferentiation of Schwann cells and Schwann cell proliferation, and might contribute to the observed failure of Schwann cells to myelinate fl/fl Dhh-Cre+ nerves fl/fl Dhh-Cre+ nerves compared to Dicerfl/fl Dhh-Cre+, were previously identified as a target of miR-34a, which we identified in our miRNA screen fl/fl Dhh-Cre+ nerves is unable to override anti-myelination signals, as the nerves nevertheless fail to myelinate.We also found altered mRNA expression of transcripts involved in Notch signaling, including Jagged1, Jagged2, and Notch3. In addition, Pereira et al. observed an increased expression of Notch1, and Hes1, as well as a reduced level of ErbB2 in DicerIt will be interesting to determine in the future whether miRNAs that are upregulated in both CNS and PNS myelination play analogous roles and/or target the same proteins in these cell types. Conversely, miRNAs that are distinctly upregulated in either oligodendrocytes or Schwann cells may target proteins and/or control processes that are specific to either PNS or CNS myelination.Clearly, miRNAs play a crucial role in the myelination process both in the CNS and the PNS. An important task that remains for future studies will be to positively identify Schwann cell-specific target transcripts of and the mode of regulation by miRNAs that are specifically upregulated in peripheral nerves during PNS myelination.fl/fl mice were obtained from Jackson Laboratory  fl/fl mice were crossed to Dhh-Cre, and subsequently, F1 mice were bred again to Dicerfl/fl mice to obtain Dicerfl/fl Dhh-Cre+ mice. For identifying Dhh-Cre transgene positive mice, the following primers were used: Cre fw: ACC CTG TTA CGT ATA GCC GA, Cre rev: CTC CGG TAT TGA AAC TCC AG. For distinguishing Dicer floxed and Dicer wild-type alleles, the following primers were used: DF1: CCT GAC AGT GAC GGT CCA AAG and DR1: CAT GAC TCT TCA ACT CAA ACT, producing a wild-type allele-specific product of 350bp and a floxed allele-specific product of 420bp. The recombined allele was amplified using DF1 primer and Ddel primer: CCT GAG CAA GGC AAG TCA TTC, the same primer set recognized also the wild-type allele (product size 1.3 kb).We housed mice and performed animal experiments in accordance with the Swiss Animal Protection Law and in compliance with the animal welfare regulations of the Canton of Zurich. The Committee on Animal Experimentation of the Cantonal Veterinary Office of the Canton of Zurich has specifically approved this study under license number 200/2007. DicerMice at the age of p4 or older were anesthetized and transcardially perfused with PBS followed by 3.9% glutaraldehyde in 0.1 M phosphate buffer, pH 7.4. Sciatic nerves of embryos (E17) were fixed with glutaraldehyde in situ for at least 5 minutes. At least n\u200a=\u200a4 mice of each genotype and age group  were analyzed. All nerves were then postfixed in glutaraldehyde in a test tube. Tissues were embedded in Epon using standard procedures. Semithin sections were stained with toluidine blue. Ultrathin sections were mounted on copper grids coated with Formvar membrane and contrasted with uranyl acetate/lead citrate. We examined the specimens using a Hitachi H-7650 transmission electron microscope operating at 80 kV. We took pictures with a digital CCD camera.fl/fl Dhh-Cre+ littermates and Dicerwt/fl Dhh-Cre+ were used and analyzed separately on individual arrays . Purity and quality of the isolated total RNA was determined using a NanoDrop ND 1000 (NanoDrop Technologies) and a Bioanalyzer 2100 (Agilent) respectively. Only those samples with a 260 nm/280 nm ratio between 1.6\u20132.1 and a 28S/18S ratio within 1.5\u20132 were further processed. Fluorescent miRNA with a sample input of 100ng of total RNA was generated. This method involves the ligation of one Cyanine 3-pCp molecule to the 3\u2032 end of an RNA molecule using a miRNA Complete Labeling and Hyb Kit (Agilent). The quality of Cy3- RNA was determined using a NanoDrop ND 1000. Only RNA samples with a dye incorporation rate >2 pmol/\u00b5g were considered for hybridization. Cy3-labeled RNA samples were mixed with an Agilent Blocking Solution and resuspended in Hybridization Buffer using a miRNA Complete Labeling and Hyb Kit (Agilent). Target RNA Samples (45\u00b5l) were hybridized to Mouse miRNA 8x15k OligoMicroarrays  for 20h at 55\u00b0C. Arrays were then washed using Agilent GE Wash Buffers 1 and 2 (Agilent), according to the manufacturer's instructions. An Agilent Microarray Scanner (Agilent p/n G2565BA) was used to measure the fluorescent intensity emitted by the labeled target. Raw data processing was performed using the Agilent Scan Control and the Agilent Feature Extraction Software Version 10.5.1.1. Quality control measures were considered before performing the statistical analysis. These included inspection of the array hybridization pattern , proper grid alignment and number of green feature non-uniformity outliers . Expression data was analyzed using R/Bioconductor. Briefly, median spot signals were log2-transformed and normalized using quantile normalization. Differential expression was assessed using t-test and fold-change analysis. miRNAs flagged as absent by the Feature Extraction Software in more than 50% of the samples in each of the 4 conditions were excluded from the results. All data is MIAME compliant and the raw data is available in the GEO archive under the accession GSE22023. For hierarchical clustering of the heatmap, we used as distance measure the euklidean distance of the normalized expression profiles of the miRNAs. Clusters were linked using the Ward's linkage rule that minimizes intra-cluster variance. A simplified version of the clustering tree is visualized on the left side of the heat map, including five groups of miRNAs.miRNA was extracted from sciatic nerves as described in the next section. Sciatic nerves of embryos at the gestational age of 17 days (E17) or newborns at the age of 4 days (p4) were used. For each time point, 4 pairs of Dicerfl/fl Dhh-Cre+ E17 n\u200a=\u200a4: 3 males, 1 female, Dicer+/fl Dhh-Cre+ E17 n\u200a=\u200a3: 3 males, Dicerfl/fl Dhh-Cre+ p4 n\u200a=\u200a4: 3 males, 1 female, and Dicer+/fl Dhh-Cre+ p4 n\u200a=\u200a4: 2 males, 2 females). Of each biological replicate, two (mRNA) or three (miRNA) technical replicates were performed. The following primers were used: c-jun fw: CCT TCT ACG ACG ATG CCC TC, c-jun rev: GGT TCA AGG TCA TGC TCT GTT T; Notch3 fw: CCA TCC TTG GAC TCA GGC, Notch3 rev: AGC TGG TGT TAG TAG CTC C; Jagged1 fw: GTT CTC CAA ATA ACT GTT CCC, Jagged1 rev: ATT TCA TTC TGA CAG TGA CCC; Jagged2 fw: TGC TGT CTG GCT TTG AAT GCC, Jagged2 rev: AGC ATT AAG GCA CGG TTT CCC; Delta1 fw: TTG TTC TTT CTC AGT GCC TCG, Delta1 rev: CCC TTC TTG TTG ACG AAC TCC; Sox2 fw: GCG GAG TGG AAA CTT TTG TCC, Sox2 rev: CGGGAAGCGTGTACTTATCCTT; Oct6 fw: TCG AGG TGG GTG TCA AAG G, Oct6 rev: GGC GCA TAA ACG TCG TCC A, Egr2 fw: AAT GGC TTG GGA CTG ACT TG, Egr2 rev: GCC AGA GAA ACC TCC ATT CA; Sox10 fw: AGA TGG GAA CCC AGA GCA C, Sox10 rev: CTC TGT CTT TGG GGT GGT TG; p75NTR fw: CTA GGG GTG TCC TTT GGA GGT, p75NTR rev: CAG GGT TCA CAC ACG GTC T; Brn2 fw: GCA GCG TCT AAC CAC TAC AGC, Brn2 rev: GCG GTG ATC CAC TGG TGA G; GAPDH fw: CCA CCC CAG CAA GGA GAC T; GAPDH rev: GAA ATT GTG AGG GAG ATG CT; Dicer fw: ACC AGC GCT TAG AAT TCC TGG GAG; Dicer rev: GCA GCA GAC TTG GCG ATC CTG TAG.RNA was extracted from sciatic nerves using miRNeasy (Qiagen) as described by the manufacturer using a polytron PT 3100 (kinematica). CDNA from mRNA was synthesized with QuantiTect, Reverse Transcription kit (Qiagen) and analyzed by real-time PCR using QuantiFast SYBR Green PCR kit (Qiagen). CDNA from miRNA was synthesized with TaqMan MicroRNA RT kit (Applied Biosystems) and analyzed using TaqMan MicroRNA Assays (Applied Biosystems) and Taqman Universal Master Mix II (Applied Biosystems). All samples were analyzed using a 7900HT Fast Real-Time PCR system (Applied Biosystems). Three to four biological replicates were used for each group analyzed (Dicer1 and IgG2a (Zymed) or anti-rabbit, and anti-rat IgG . We visualized proteins using SuperSignal West Pico Chemiluminescent Substrate System (Pierce) and Amersham Hyperfilm ECL films .Sciatic nerves were homogenized in nerve buffer  using a polytron PT 3100 (kinematica). For analysis of 18- and 4-day old mice three different lysates were used, each containing nerves pooled from three mice with the respective genotype of mixed gender. Protein concentration was determined using the BCA protein assay (Pierce). Proteins were boiled in LDS (Invitrogen) containing \u03b2-mercaptoethananol, and loaded onto a NuPAGE\u00ae Novex Bis-Tris Gel (Invitrogen). After electrophoretical separation, proteins were blotted onto nitrocellulose membranes (Schleicher & Schuell) using XCell II Blot Module (Invitrogen). Membranes were blocked using TBST containing Top-Block (Sigma), and decorated with antibodies against CNPase (Abcam), MBP (Serotec), PMP22, and Ras (Abcam), Erk, phospho-Erk, Akt, phospho-Akt , followed by incubation with the secondary anti-mouse IgGfl/fl Dhh-Cre+ and control Dicerwt/fl Dhh-Cre+ littermates). Longitudinal paraffin or frozen sections were incubated with the following antibodies: anti-S100 (Dako), anti-MIB1 (Dako), B220/CD45R for B-cells (Pharmingen), CD3 for T-cells , CD68 for macrophages (Serotec) or stained with haematoxylin-eosin. For detection of primary antibodies, a Ventana machine was used according to the manufacturer's protocol. Mounted slides were analyzed on an Axiophot microscope (Zeiss), equipped with a JVC digital camera . Rabbit immunoglobulin fraction (Dako) served as negative control for S100 staining (data not shown). For assessing proliferation, 940\u20131400 nuclei per mouse were counted and the \u201cMIB1 index\u201d was determined as the percentage of nuclei positive for MIB1 immunohistochemistry. CD3- and CD68-positive cells were quantified in relation to total number of nuclei.Sciatic nerves were fixed in 4% formalin and embedded in paraffin. For each genotype, at least four nerves were analyzed (22-day old Dicer"}
+{"text": "Therefore, chronic hypoxia may potentially be exploited to increase tumour cell radioresponse through the cytokine-inducible iNOS pathway. \u00a9 2001 Cancer Research Campaign http://www.bjcancer.comChronic hypoxia up-regulated the mRNA and protein expression of inducible nitric oxide synthase (iNOS) in EMT-6 tumour cells exposed to interferon (IFN)-gamma and interleukin (IL)-I beta. Low concentrations of cytokines (1\u2008unit ml"}
+{"text": "The highly resistant nature of glioblastoma multiforme (GBM) to chemotherapy prompted us to evaluate the efficacy of bicyclic triterpenoid Iripallidal against GBM in vitro.The effect of Iripallidal on proliferation and apoptosis in glioma cell lines was evaluated by MTS, colony formation and caspase-3 activity. The effect of iripallidal to regulate (i) Akt/mTOR and STAT3 signaling (ii) molecules associated with cell cycle and DNA damage was evaluated by Western blot analysis. The effect of Iripallidal on telomerase activity was also determined.Iripallidal (i) induced apoptosis, (ii) inhibited Akt/mTOR and STAT3 signaling, (iii) altered molecules associated with cell cycle and DNA damage, (iv) inhibited telomerase activity and colony forming efficiency of glioma cells. In addition, Iripallidal displayed anti-proliferative activity against non-glioma cancer cell lines of diverse origin.The ability of Iripallidal to serve as a dual-inhibitor of Akt/mTOR and STAT3 signaling warrants further investigation into its role as a therapeutic strategy against GBM. Iris pallida belongs to the terpenoid family as Paclitaxel. Paclitaxel is an effective chemotherapy for several types of neoplasms [Iripallidal [(-) -26-Hydroxy-22-\u03b1-methylcycloirid-16-enal NSC 631939]- a bicyclic triterpenoid isolated from Despite recent advances in understanding molecular mechanisms involved in GBM progression, the prognosis of the most malignant brain tumor continues to be dismal. Ras activation occurs in GBMs  and thisGlioblastoma cell lines A172, LN229, T98G and U87MG were obtained from American Type Culture Collection and cultured in DMEM supplemented with 10% fetal bovine serum. Peripheral blood mononuclear cells (PBMC) were isolated by Ficoll/Histopaque density gradient centrifugation. Adherent monocytes were purified from PBMC following adherence on glass petri-dish for three hours after flushing the non-adherent cells by extensive washing with PBS. All experiments with human PBMC were conducted under an approved institutional Human Ethics Committee protocol.On attaining semi-confluence, cells were switched to serum free media and after 6 hours, cells were treated with different concentration of Iripallidal  in serum free media for 24 hours. DMSO treated cells were used as controls. Iripallidal was purchased from Calbiochem, USA. All reagents were purchased from Sigma unless otherwise stated. Colon cancer cell line HT29, breast cancer line MCF-7, cervical cancer cell line HeLa, hepatocellular carcinoma cell line HepG2, acute myeloid leukemic cell line THP1 and human monocytes were similarly treated with Iripallidal.Viability of Iripallidal treated monocytes and cancer cell lines was assessed using the  (MTS) (Promega) as described earlier .The Colorimetric Assay kits for caspase 3 (Sigma) were used to determine its enzymatic activity in Iripallidal treated glioma cells as described previously .S6K (Thr389), cMyc (Santa Cruz), phospho-S6K (Ser235/236), pH2AX Ser139 (Upstate), cleaved-PARP and \u03b2 actin. Secondary antibodies were purchased from Vector Laboratories. After addition of chemiluminescence reagent (Amersham), blots were exposed to Chemigenius, Bioimaging System  for developing and images were captured using Genesnap software (Syngene). The blots were stripped and reprobed with anti-\u03b2-actin to determine equivalent loading as described [Protein from whole cell lysates were isolated as described previously . Proteinescribed .TeloTAGGG Telomerase PCR ELISA PLUS kit  as described previously [Telomerase activity was determined using the eviously .The soft agar colony formation assay was performed using CytoSelect\u2122 96-Well Cell Transformation Assay kit , as described previously .All comparisons between groups were performed using two-tailed Paired student's t-Test. All values of p less than 0.05 were taken as significant.To determine whether Iripallidal affects viability of glioma cells, MTS assay was performed on A172, LN229, T98G and U87MG glioma cells treated with different concentrations of Iripallidal for 24 hours. While no significant cell death was observed in cells treated with 10 \u03bcM Iripallidal, a ~50% decrease in cell viability was observed in all the glioma cell lines tested upon treatment with 20 \u03bcM Iripallidal Fig. . Since tAs aberrant activation of the PI3K/Akt occurs frequently in glioblastomas , therapemTOR activation results in phosphorylation of effector molecule p70S6K and S6 ribosomal protein, which subsequently leads to mTOR-dependent gene transcription that regulates cell growth, protein synthesis, and metabolism. We therefore determined the effect of Iripallidal on the status of p70S6K and pS6 kinase. Iripallidal inhibited phosphorylation of mTOR targets 70S6K and ribosomal protein S6 Fig. . These rAs mTOR inhibitor blocks STAT activation and glial differentiation  and sincInhibition of PI3-K/Akt/mTOR signaling effects cell cycle progression ,25. mTORAs maintained DNA breaks induce apoptosis  and sincInhibition of telomerase activity is an important anticancer modality since its inhibition causes apoptosis in human cancers . TelomerWe next evaluated whether Iripallidal also exhibits anti-proliferative property against other human malignancies, by testing its effects against a panel of non-glioma human cancer cell lines in vitro. Treatment with 20 \u03bcM Iripallidal reduced viability of MCF-7, HeLa, HepG2, THP1 and HT-29 cells lines by ~35% to 60%, as compared to their respective controls Fig. . These fIn vitro screening of compounds with anticancer properties by NCI identified Iridals for their anti-proliferative activity. Besides its ability to bind PKC\u03b1 and RasGRP3 , nothingIripallidal mediated decrease in STAT3 activation was concurrent with decreased cyclin D1 and increased p21 expression. While cyclin D1 overexpression and STAT3 activation are mutually exclusive events , p21 inhTaken together our studies suggest that (i) Iripallidal induces glioma cell apoptosis and (ii) inhibits Akt/mTOR and STAT3 pathway. This ability of Iripallidal to act as a multi-inhibitor that blocks Akt/mTOR and STAT3 pathways suggest that its potential as a chemotherapeutic agent against GBM should be further evaluated. Importantly, Iripallidal is not only a promising candidate for the treatment of GBM but a wide variety of malignancies, since it elicits cell death in many tumor cell types.\"Bicyclic triterpenoid Iripallidal as a novel anti-glioma and anti-neoplastic therapy in vitro\" has been filed for Indian patent (#2915/DEL/2008) and International Patent (PCT/IN09/000336) through Department of Biotechnology, Govt. of India.VS and ES designed the research; NK, VS, DD and SG performed the experiments, VS and ES analyzed the data; ES wrote the paper. All authors read and approved the final version of the manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/10/328/prepub"}
+{"text": "I order to study the time-course of myeloperoxidase (MPO) and eosinophil cationic protein (ECP) as parameters for monitoring inflammation in cystic fibrosis (CF), we investigated ten patients during both a 14-day intravenous antibiotic treatment and a corresponding self control. Modified Shwachman-Kulczycki score improved significantly (p < 0.008), C-reactive protein (CRP) levels decreased significantly (p < 0.05) during antibiotic treatment, while in the control phase there were no significant differences. Lung function parameters did not change significantly during antibiotic treatment or control phase. Serum MPO concentration (p < 0.006) and peripheral blood neutrophil granulocyte counts (p < 0.04) decreased significantly during antibiotic treatment, but not during the control phase. Sentm ECP concentration showed a tendency to decrease during antibiotic treatment, but this failed to reach significance. In general, sputum concentrations of MPO and ECP Were 500- to 1000-fold higher than in serum. However, neither MPO nor ECP in sputum showed a significan variation over time during antibiotic treatment or control phase. From our data we conclude that: (1) measurements of MPO, neutrophils and CRP in peripheral blood do correlate with clinical parameters such as the modified Shwachman-Kulczycki score; (2) neutrophils and MPO seem to reflect inflammatory changes induced by antibiotic treatment; (3) eosinophils may play a role in CF by an enhanced \u2018releasability\u2019 and (4) Sputum measurements of mediators of inflammation cannot be recommended."}
+{"text": "P = 0.03) increase in plasma VEGF level in 29 CLM patients  compared with 19 controls . There were significant correlations between plasma VEGF and tumour vessel count , tumour vessel volume , and CLM volume . A VEGF level in the upper quartile of the plasma VEGF distribution had a 70% sensitivity and 75% specificity in predicting an upper quartile liver metastasis tumour vessel count. No relation was identified between CLM and plasma bFGF levels. Plasma VEGF level predicted CLM vascularity, despite an overlap with normal levels and tumour volume-related variations. \u00a9 2000 Cancer Research CampaignThe extent to which plasma levels of angiogenic factors in healthy individuals and tumour volume-related variations in colorectal cancer affect the accuracy of circulating angiogenic factors as predictors of colorectal cancer vascularity is unknown. We used enzyme-linked immunosorbant assay to measure plasma vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) levels in colorectal liver metastasis (CLM) patients, and \u2018no cancer\u2019 controls. CLM volume was determined from computerized tomography scans, and tumour vessel count and vessel volume from anti-endothelial antibody-stained biopsies. There was a significant ("}
+{"text": "Infectious bronchitis virus (IBV) causes a costly respiratory viral disease of chickens. The role of wild birds in the epidemiology of IBV is poorly understood. We detected diverse coronaviruses by PCR in wildfowl and wading birds in England. Sequence analysis showed some viruses to be related to IBV. Infectious bronchitis virus (IBV), a group 3 coronavirus, causes a costly viral disease of chickens that is found worldwide (Anser anser), rock doves (Columba livia), mallards (Anas platyrhynchos), Chinese bulbuls (Pycnonotus sinensis), red-whiskered bulbuls (Pycnonotus jocosus), gray-backed thrushes (Turdus hortulorum), blackbirds (Turdus merula), white-rumped munias (Lonchura striata), and scaly-breasted munias (Lonchura punctulata)  following the manufacturer\u2019s instructions. Reverse transcription\u2013PCR was used to detect avian coronaviruses as previously described . Generalized linear modeling was used to calculate maximum-likelihood estimates of prevalence and confidence limits  (whooper swan/UK/p3/2005), 1 consisted of samples from red knots  (red knot/UK/p60/2006), and 1 contained samples from Eurasian oystercatchers  (oystercatcher/UK/p17/2006). PCR-positive pools were from birds sampled in estuarine, salt marsh, or standing water habitats  and waders (Charadriiformes). Coronaviruses have been detected previously in wildfowl species, rock doves, wild peafowl, and some passerine species . Sequences were aligned using the Clustal program within the MEGA 4.0 software package (10)."}
+{"text": "Colletotrichumfalcatum, Fusarium oxysporum, Curvularia pallescens . The O,O-diethylphosphate derivatives containing 2-chlorochalcone and 2-chlorochalcone semicarbazone exhibited 70-85% mycelial inhibition against all the test fungi at 1000 ppm. The screening results were correlated with structural features of the tested compounds.Ten newly synthesized organophosphorus derivatives containing substituted chalcones andsubstituted chalcone semicarbazones were tested for their antifungal efficacy against"}
+{"text": "Phylogenetic and genomic analysis of EVEs across multiple host species revealed novel information about the origin and evolution of diverse virus groups. Furthermore, several of the elements identified here encode intact open reading frames or are expressed as mRNA. For one element in the primate lineage, we provide statistically robust evidence for exaptation. Our findings establish that genetic material derived from all known viral genome types and replication strategies can enter the animal germ line, greatly broadening the scope of paleovirological studies and indicating a more significant evolutionary role for gene flow from virus to animal genomes than has previously been recognized.Integration into the nuclear genome of germ line cells can lead to vertical inheritance of retroviral genes as host alleles. For other viruses, germ line integration has only rarely been documented. Nonetheless, we identified endogenous viral elements (EVEs) derived from ten non-retroviral families by systematic  The presence of retrovirus sequences in animal genomes has been recognized since the 1970s, but is readily explained by the fact that these viruses integrate into chromosomal DNA as part of their normal replication cycle. Unexpectedly, however, we identified a large and diverse population of sequences in animal genomes that are derived from non-retroviral viruses. Analysis of these sequences\u2014which represent all known virus genome types and replication strategies\u2014reveals new information about the evolutionary history of viruses, in many cases providing the first and only direct evidence for their ancient origins. Additionally, we provide evidence that the functionality of one of these sequences has been maintained in the host genome over many millions of years, raising the possibility that captured viral sequences may have played a larger than expected role in host evolution. However, they can also increase in frequency, and some eventually reach fixation Viral infection of germ line cells  can lead to viral genes or genomes becoming integrated into chromosomes and inherited as host alleles In animal genomes, the majority of EVEs are derived from reverse transcribing RNA (rtRNA) viruses (i.e. retroviruses) exapted retroviral genes  in mammalian reproduction EVEs reveal complex evolutionary relationships between viruses and their hosts. For example, endogenous retroviruses have shaped vertebrate genome evolution, not only by acting as genetic parasites EVEs also constitute an invaluable resource for reconstructing the long-term history of virus and host evolution in silico approach to screen the genomes of mammals, birds and insect vector species for endogenous sequences derived from non-retroviral mammalian viruses. We identify sequences derived from a very broad range of viruses, revealing an extensive history of non-retroviral genome invasion ranging back to at least the late Mesozoic Era (\u223c93 million years ago). We demonstrate that these sequences can be highly informative; (i) revealing novel virus diversity; (ii) providing a timescale for virus evolution; (iii) indicating the likely host range of virus groups, and; (iv) identifying rare instances of horizontal transmission. Furthermore, using a novel approach, we show that at least some of the EVE sequences identified here are likely to have been exapted during their evolution. The implications of these findings are discussed.Despite the large quantity of published genome sequence data, the diversity of non-retroviral viruses in animal genomes has not been systematically explored. In this report, we use an in silico screening of genomes for endogenous non-retroviral insertions was developed. We selected all non-retroviral virus genera that infect mammals, and constructed a library of representative peptide sequences ) ) . The tBLes (Kb)) . Sequences (Kb)) , S6, S7.\u22129) to RNA viruses in the genomes of mammals and insect vectors (Reoviridae) and positive sense RNA (RNA+ve) viruses (Flaviviridae), as well as both segmented  and non-segmented  families of negative sense RNA (RNA-ve) viruses. Consistent with an integration process involving viral mRNA (rather than genomic RNA), all EVEs derived from RNA viruses had genetic structures that spanned a single viral transcript (or fragments derived from single transcripts). EVEs derived from different genes never occurred as contiguous sequences, and consequently we could not determine whether EVEs derived from distinct genes of a given virus family originated from the same or distinct virus lineages/infections.We identified numerous, highly significant matches  and 3\u2032 poly-A tails, consistent with LINE-mediated retrotransposition of viral mRNAs Mononegavirales  were identified. Matches to genes encoding the relatively conserved nucleoprotein (NP) and L-polymerase proteins predominated, but matches to more rapidly evolving glycoproteins were also identified (Numerous EVE sequences disclosing similarity to proteins derived from non-segmented RNA-ve virus families in the order entified . A subseentified  exhibiteEchinops telfairi)). Bornavirus nucleoprotein trees revealed an expansion of EBLNs in the New World branch of strepsirrhine primates, represented by the common marmoset   elements jacchus) .Myotis lucifugus), Tammar wallaby (Macropus eugenii), and gray short-tailed opossum (Monodelphis domestica) genomes. The majority of these matches comprised fragments of genes, although two full-length NP gene EVEs (displaying poly-A tails and TSDs) were identified in bats (Dipodymys ordii), guinea pig (Cavia porcellus) and common shrew (Sorex araneus) genomes. Additionally, fragments of the L-polymerase and VP35 gene were identified in the genomes of the opossum and Philippine tarsier (Tarsius syrichta) respectively. In phylogenies, EVEs derived from filovirus NP genes grouped into two well-supported clades , and in the genomes of both Aedes and Culex mosquitoes. Among these were insertions that encoded intact NP and GP ORFs (Drosophila sigma virus (Aedes and Culex was high (96%). A robust clade (100% bootstrap support) placed four Ixodes EVEs into a single group, suggesting they are likely derived from the same exogenous virus lineage, but their placement relative to other Rhabdoviruses was ambiguous, as they formed a clade with a number of distinct Rhabdoviruses with minimal bootstrap support (8%). Phylogenies constructed using L-polymerase sequences weakly grouped Ixodes and Aedes insertions with Lyssaviruses and Moussa virus, but not Drosophila sigma virus. Weak support for basal relationships was obtained with both trees, making it difficult to confidently place thenovel EVEs with respect to the known rhabdovirus diversity.EVEs related to rhabdoviruses were identified in the black-legged tick genome  Orthomyxoviridae (Bunyaviridae (Phlebovirus and Nairovirus genera) were identified in the I. scapularis genome. Nairovirus-derived EVEs were distantly related to Hazara virus  to segment 5 of the Liaoning virus genome  that was recently isolated from Aedes dorsalis mosquitoes A. aegyptii had a large inframe deletion, but encoded an otherwise intact ORF. This is the first EVE derived from a dsRNA virus to be described. As with other RNA virus EVEs in insect genomes, the mechanism of genomic integration was unclear. The intact ORFs and high level of identity to a circulating virus raise the possibility this EVE formed recently and is not fixed in the host population.In the s genome . LiaoninAedes mosquito contains several sequences exhibiting similarity to the viruses of the RNA+ve family Flaviviridae. Endogenous flaviviruses have previously been reported in the genomes of A. aegyptii and A. albopictus mosquitoes A. albopictus, and a range of smaller fragments at the 3\u2032 end of the flaviviral genome, mostly of the NS5 gene, have been described in both albopictus and aegyptii species. We have identified fragments that together span almost the entire flavivirus genome in A. aegyptii , includParvoviridae and Circoviridae - the first ssDNA virus EVEs to be described in mammals - and one family of reverse transcribing DNA (rtDNA) viruses (Hepadnaviridae) - the first rtDNA EVEs to be described. A single match to a double stranded DNA (dsDNA) virus family (Adenoviridae) was identified in the kangaroo rat genome, but this sequence was unambiguously viral across its entire length (\u223c17 Kb), encoding thirteen completely intact viral ORFs , and the zebrafinch (Taeniopygia guttata). In the zebrafinch genome, a total of 7 loci were identified on 7 distinct chromosomes  genome matched the Amdovirus genus (EVEs derived from viruses of the family  genomes . In totaus genus . Phylogeus genus .Loxodonta africana) encoded an intact NS1 gene (Trichosurus vulpecula).The majority of parvovirus EVEs were not intact, and are unlikely to express RNA or protein. However, a dependovirus EVE in the genome of the African elephant (NS1 gene . AdditioAdeno-associated virus 2 (AAV-2) integrates at a specific site in human chromosome 19 Circoviridae were identified in the genomes of the gray short-tailed opossum, and three species of the mammalian order Carnivora; domestic cat (Felis catus), dog (Canis familiaris) and panda (Ailuropoda melanoleuca) (EVEs disclosing significant similarity to the Rep gene of ssDNA family noleuca) . These snoleuca) . One cirParvo, Circo and Bornaviridae of 30, 68 and 93 million years respectively, demonstrating the ancient origins of these families  with respect to their known range as exogenous viruses (in vivo models M. lucifugus) and Asian primates (tarsier), but also in insectivores, rodents, and in both South American and Australian mammals  genome grouped robustly with avian dependoviruses  in NS1 trees (Highly discordant host ranges among closely related EVEs (or EVEs and exogenous viruses) can provide information about transmission events. In this regard, we note that a dependovirus EVE in the bottlenose dolphin  Richer sampling of animal genomes is likely to reveal an even greater diversity of EVEs. While EVEs that are very ancient (i.e. that inserted prior to the divergence of major host lineages) can be identified by selectively screening a small number of host species, identification of more recent insertions will often require richer sampling within orders and genera. Sampling of mammalian species for whole genome sequencing has generally been across, rather than within orders (primates are an exception). Consequently the majority of mammal species sampled in this study diverged more than 50 million years ago . Any mamin silico screening strategy employed here likely underestimates the actual diversity of EVEs for several reasons. Firstly, only low-coverage, incomplete genome data were available for most species. Furthermore, EVEs within the data we screened could have been overlooked because (i) screening was based on similarity searches, and is thus dependent on current (limited) knowledge of viral diversity, and (ii) more ancient EVEs may not be identified due to the divergence in both host and virus lineages subsequent to insertion .The Parvoviridae, Mononegavirales). This likely reflects a predisposition for germline integration among viruses with particular patterns of replication and infection. Notably, viruses that establish persistent infections and/or replicate within the nucleus are particularly well represented among the EVEs identified in this study. Nevertheless, these characteristics do not appear to be prerequisites for germ line integration  viruses appear to be better represented in the genomic fossil record than others  master species list (\u22129) to host proteins; or (iii) non-viral and highly repetitive (>50 copies per host genome). Insertions were considered endogenous when >100 bp of genomic flanking sequence could be identified either side of a viral match. Insertions for which >100 bp of unambiguous (i.e. >80% nucleotide identity) flanking sequence was identified in host sister taxa were considered orthologous insertions. PERL scripts were used to automate BLAST searches and sequence extraction. Putative EVE peptide sequences, and alignments of EVEs and exogenous retroviruses, are available online .Chromosome assemblies and whole genome shotgun assemblies of 44 species  were scries list ). Host gParvoviridae: dependovirus NS1 gene , Parvoviridae: parvovirus NS1 gene, , Circoviridae: Rep gene , Hepadnaviridae: polymerase gene , Orthomyxoviridae: GP gene , Reoviridae: VP5 gene , Bunyaviridae: phlebovirus NP gene , Bunyaviridae: nairovirus NP gene , Flaviviridae: mostly NS3 gene , Filoviridae: NP gene , Filoviridae: L gene , Bornaviridae: NP gene , Bornaviridae: L gene , Rhabdoviridae: NP gene , Rhabdoviridae: L gene .Putative EVE sequences inferred using BlastAlign were aligned with closely related viruses using MUSCLE and manually edited et alA Monte Carlo simulation procedure was employed to determine the probability that the bornavirus-derived element EBLN-1 has retained coding capacity over 54.1 million years under neutral evolution (i.e. not under purifying selection). A consensus EBLN-1 sequence was inferred, and the effects of neutral evolution were simulated using seq-gen Parvoviridae; AAV2 (NC_001401); Minute virus of mice (NC_001510.1); AMDV (NC_001662); Goose parvovirus (EU583390.1); Muscovy duck parvovirus (X75093.1); Porcine hokovirus (EU200671.1); Snake parvovirus (AY349010.1); Avian AAV ; AAV1 (AF063497.1); AAV4 (U89790); AAV2 (AY695375.1); Bovine AAV (AY388617.1); Caprine AAV (DQ335246.2); Bocavirus (M14363.1); Erythrovirus (AB126265.1); Aleutian mink disease virus (M20036.1); Porcine parvovirus (EU790642.1); Feline panleukopenia virus (EF988660.1); Canine parvovirus (EU310373.2); Rat parvovirus (AF036710.1); Hamster parvovirus (U34255.1); Minute virus of mice (DQ196317.1); Kilham rat virus (U79033.1); Circoviridae; Porcine circovirus 1 (NC_006266); Porcine circovirus 2 (GU325757); Cyclovirus PK5006 (GQ404856.1); Cyclovirus NG14 (GQ404855.1); Human stool-associated circular virus NG13 (GQ404856.1); Beak and feather disease virus (AY450436.1); Columbid circovirus (AF252610.1); Hepadnaviridae; duck HBV (NC_001344); Stork HBV (AJ251937.1|); Heron HBV (NC_001486); Ross' Goose HBV (AY494849.1); Crane HBV (AJ441113.1); Sheldgoose HBV (AY494852.1); Snow goose HBV (AF111000.1); Woodchuck HBV (AF410861.1); Flaviviridae; Kamiti river virus (NC_005064); Aedes flavivirus (NC_012932); Quang binh virus (NC_012671); Culex flavivirus (NC_008604); Nakiwogo virus (GQ165809). Reoviridae; Liaoning virus (NC_007736 - NC_007747); Kadipiro virus ; Banna virus . Bunyaviridae; Crimean-Congo hemorrhagic fever virus ; Uukuniemi virus ; Uukuniemi virus (M33551.1); Catch-me-cave virus (EU274384.1); Sandfly fever Naples virus (EF201832.1); Massilia virus (EU725773.1); Punta Toro virus (EF201834.1); Buenaventura virus (EF201839.1); Rift Valley fever virus (DQ380156.1); Phlebovirus sp. (EF201818.1); Icoaraci virus (EF076014.1). Orthomyxoviridae; Quaranfil virus (FJ861694.1); Johnston Atoll virus (FJ861696.1); Thogoto virus (M77280.1); Dhori virus (M34002.1). Bornaviridae; Borna disease virus (NC_001607); Avian BDV (FJ169441). Filoviridae; Reston ebola virus (NC_002549); Zaire ebola virus (NC_002549); Lake Victoria marburgvirus (NC_001608). Rhabdoviridae; vesicular stomatitis virus (NC_001560); Wongabel virus (NC_011639); Kotonkon virus (DQ457099); Adelaide river virus (U10363.1); Obodhiang virus (DQ457098.1); Bovine ephemeral fever virus (AF234533.1); Rochambeau virus (DQ457104.1); Mount elgon bat virus (DQ457103.1); Oita rhabdovirus (AB116386); Kern canyon virus (DQ457101.1); Sandjimba virus (DQ457102.1); Kolongo virus (DQ457100.1); Tupaia rhabdovirus (AY840978.1); Spring viremia of carp (DQ491000.1); Pike fry rhabdovirus (FJ872827.1); Cocal virus (EU373657.1); Vesicular stomatitis Indiana virus (AF473865.1); Isfahan virus (AJ810084.2); Chandipura virus (AY614728.1); Ngaingan virus (FJ715959.1); Wongabel virus (EF612701.1); Flanders virus (AF523194.1). Nyaviridae; Midway virus (NC_012702); Nyamanini virus (NC_012703).Figure S1Aedes aegyptii genome and Liaoning virus segment 5. Genomic regions, as determined by alignment to a repetitive element (RE) in the A. aegyptii genome, are indicated in blue, on coding viral regions are shown in red, and regions encoding viral proteins are shown in green.Sequence alignment of an EVE identified in the (0.40 MB PDF)Click here for additional data file.Figure S2Dipodymys ordii). The name of the corresponding protein in the most closely related virus  is indicated above each open reading frame (ORF). Arrows beneath ORFs indicate frames encoded in reverse direction relative to contig. Abbreviations: kd\u200a=\u200akiloDalton; pol\u200a=\u200aDNA polymerase; T\u200a=\u200aterminal protein; P\u200a=\u200apenton base; Mco\u200a=\u200aminor core; Mca\u200a=\u200aminor capsid; DB\u200a=\u200aDNA binding; Ma\u200a=\u200aMajor coat; H\u200a=\u200ahexon-associated; S\u200a=\u200ashaft.Genetic structure of an adenovirus related sequence identified in whole-genome shotgun sequence data for Ord's kangaroo rat ((0.27 MB PDF)Click here for additional data file.Figure S3Myotis lucifugus) genome. The element is a composite of two genomic contigs, which were assembled by identifying the empty pre-integration site in the closest relative (Pteropus vampyrus). The inset box shows an alignment the inverted repeats in the 5\u2032 and 3\u2032 untranslated regions. Abbreviations: IR\u200a=\u200ainverted repeat. NS1\u200a=\u200aNon-structural protein 1; VP2\u200a=\u200aViral protein 2; UTR\u200a=\u200auntranslated region.Genetic structure of a complete dependovirus genome identified in the little brown bat ((0.32 MB PDF)Click here for additional data file.Table S1Genome sequences screened for endogenous viral elements.(0.09 MB DOC)Click here for additional data file.Table S2in silico screening of host genomes.Viral reference sequences used for (0.14 MB DOC)Click here for additional data file.Table S3Endogenous viral elements related to negative sense RNA viruses.(0.40 MB DOC)Click here for additional data file.Table S4Endogenous viral elements related to doubled-stranded RNA viruses.(0.03 MB DOC)Click here for additional data file.Table S5Endogenous viral elements related to positive sense RNA viruses.(0.09 MB DOC)Click here for additional data file.Table S6Endogenous viral elements related to single stranded DNA viruses.(0.21 MB DOC)Click here for additional data file.Table S7Endogenous viral elements related to reverse transcribing DNA viruses.(0.04 MB DOC)Click here for additional data file."}
+{"text": "A sensitive flow cytometric assay has been developed using a monoclonal antibody, Myc 1-6E10, to quantitate c-myc oncoprotein levels in nuclei isolated from wax embedded testicular tumours. The oncoprotein (p62c-myc) level increased significantly with increasing teratoma differentiation. Patients with intermediate and undifferentiated tumours who developed recurrence had lower p62c-myc levels than those who were disease free since their initial treatment. Such quantitative biochemical methods may provide new prognostic indices for cancer patients."}
+{"text": "Management of variceal bleeding secondary to portal hypertension constitutes a challenging issue, particularly in child's C cirrhotic patients. Recently, transjugular placement of self-expanding metallic stents in the liver (TIPS), creating a shunt between the portal and hepatic branches has provided a safe and promisingtherapeutic approach in this clinical situation. We report here the case of a 66-year-old male cirrhotic patientwho developed a moderately severe clinical picture of a Coombsnegative hemolytic anemia , indirect 6.3 mg/dl (107.73 umol/L); serumLDH 1220 u/l, reticulocytes, 5.1%. serum ferritin, 1221 ug/1, schistocytes in peripheral blood smear) the weekafter undergoing a TIPS, suggesting the development ofa microangiopathic hemolytic anaemia secondary tored blood cell disruption by passing through the metallic network of the stent."}
+{"text": "Surprisingly, these metal complexes produce different interactionpatterns with DNA in spite of their profound structural similarity. Indeed, important modifications aredetected in the characteristic UV-Vis bands of [PtCl(Terpy)]Cl upon addition of ct-DNA, while the spectrumof [AuCl(Terpy)]Cl2 is almost unaffected. Gel electrophoresis studies confirm these findings:[PtCl(Terpy)]Cl \u2014 but not [AuCl(Terpy)]Cl2 \u2014 retards significantly the mobility of the supercoiled form of thepHV14 plasmid after a short incubation time. Ultrafiltration studies indicate that the affinity of[PtCl(Terpy)]Cl for ct-DNA is significantly greater than that of [AuCl(Terpy)]Cl2. On the other hand, both[AuCl(Terpy)]Cl2 and [PtCl(Terpy)]Cl induce important changes in the CD spectrum of ct-DNA, at highconcentration, and increase its Tm value. Remarkably, the analysed metal-complex/DNA interaction patternsdepend critically on the incubation times. We propose that [PtCl(Terpy)]Cl quickly intercalates DNA; then,formation of coordinative bonds progressively takes place with time. At variance, [AuCl(Terpy)]Cl2 firstinteracts electrostatically with the DNA surface, with subsequent slow formation of some coordinative bonds.The interactions of the parent complexes [AuCl(Terpy)]Cl"}
+{"text": "Fox and GATA regulatory genes specify tissue regions along the gut tube in a broad diversity of taxa, although little is known about gut regionalization within the Lophotrochozoa. In this study, we isolated FoxA and GATA456 orthologs and used whole mount in situ hybridization during larval gut formation in two marine worms: the segmented, polychaete annelid Chaetopterus, which develops a planktotrophic larva with a tripartite gut, and the non-segmented sipunculan Themiste lageniformis, which develops a lecithotrophic larva with a U-shaped gut.A through gut is present in almost all metazoans, and most likely represents an ancient innovation that enabled bilaterian animals to exploit a wide range of habitats. Molecular developmental studies indicate that FoxA and GATA456 transcripts are predominantly restricted to gut tissue, and together show regional expression spanning most of the alimentary canal in each of these lophotrochozoans, although neither FoxA nor GATA456 is expressed in the posterior intestine of Chaetopterus. In both species, FoxA is expressed at the blastula stage, transiently in presumptive endoderm before formation of a definitive gut tube, and throughout early larval development in discrete foregut and hindgut domains. GATA456 genes are expressed during endoderm formation, and in endoderm and mesoderm associated with the midgut in each species. Several species-specific differences were detected, including an overlap of FoxA and GATA456 expression in the intestinal system of Themiste, which is instead complimentary in Chaetopterus. Other differences include additional discrete expression domains of FoxA in ectodermal trunk cells in Themiste but not Chaetopterus, and expression of GATA456 in anterior ectoderm and midgut cells unique to Chaetopterus.FoxA and GATA456 transcription factors are part of an ancient patterning mechanism that was deployed during early evolution of the metazoan through gut. The common utilization of FoxA and GATA456 throughout gut formation by species with contrasting life history modes indicates that both genes are core components of a gut-specific gene regulatory network in spiralians. Despite a highly conserved pattern of early development, and probably similar ontogenic origins of gut tissue, there are molecular differences in gut regionalization between lophotrochozoan species.This study of gene expression in a sipunculan contributes new comparative developmental insights from lophotrochozoans, and shows that  Capitella teleta Blake, Grassle & Eckelbarger 2009, known for years as Capitella sp. I. In this paper, we extend that work with developmental data obtained from two additional marine worms.Formation of a through gut was a key innovation during the radiation of the Metazoa. Although the origins of an internal digestive tract are uncertain, it probably occurred early in animal evolution ,2. Consi7Chaetopterus variopedatus Cuvier 1827, sensu Enders (1909), which M. E. Petersen  suggested is most likely not C. variopedatus, but an undescribed species. We refer to this polychaete as Chaetopterus, a marine annelid that has been used both in classic ; LgFoxA [JGI protein ID:54814]; TlFoxA [GenBank:GU357822]; CtFoxA [GenBank:EF651787]; SpFoxA [GenBank:DQ459376]; PfHNF3 [GenBank:AB023019]; ChtFoxA [GenBank:GU357819]; Pdfkh [GenBank:AM114771]; HrFoxA [JGI protein ID:137725]; Dmfkh [GenBank:J03177]; Bmsgf1 [GenBank:NM_001043864];Pvfkh [GenBank:NM_001039414]; Atfkh [GenBank:BAC24088]; DrFoxA1 [GenBank:AAH65668]; MmFoxA1 [GenBank:AAH96524]; DrFoxA2 [GenBank:BC086703]; MmFoxA2 [GenBank:NM_010446]; CsHNF3 [GenBank:AB04958]; BfHNF3-1 [GenBank:X96519]; Nvfkh [GenBank:AY457634]; LgFoxB [JGI protein ID:75592]; Pdest [GenBank:CT033411]; Spfkh1 [GenBank:NP_999797]; XlFoxB [GenBank:AJ487619]; BfFoxB [GenBank:AJ506162]; CtFoxB [JGI protein ID:225366]; NvfkhB [GenBank:DQ17368]; SpFoxABlk [GenBank:XM_001186527]; CtFoxAB [JGI protein ID:131123]; CtFoxC [JGI protein ID:199610]; SpFoxC [GenBank:XM_001183474]; Dmcroc [GenBank:NM_079478]; BfFoxC [GenBank:CAH69694]; SpFoxG [GenBank:DQ286739].Tcfkh [GenBank:GATA transcription factors:BAE06473]; CbELT1 [GenBank:XM_002633918]; DmGRAIN [GenBank:NP_731211]; TcGRAIN [GenBank:NM_001164788]; SpGATAc [GenBank:AAC62960]; CiGATAb [GenBank:BAE06473]; DrGATA1 [GenBank:NM_131234]; MmGATA1 [GenBank:NP_032115]; DrGATA2 [GenBank:NM_131233]; MmGATA2 [GenBank:BC107009]; DrGATA3 [GenBank:BC162401]; MmGATA3 [GenBank:NM_008091]; LgGATAc [JGI protein ID:160340]; ChtGATA123a [GenBank:GU357821]; PdGATA123 [GenBank:ABK32792]; CtGATAa1[GenBank:EF651791]; NvGATA [GenBank:AY465174]; CtGATAb2 [GenBank:EF651789]; PdGATA456 [GenBank:ABK32792]; SpGATAe [GenBank:NM_001005725]; ChtGATA456a [GenBank:GU357820]; TlGATA456b [GenBank:GU357824]; DmPANNIER [GenBank:NM_057337]; AgPANNIER [GenBank:AF395080]; AaGatad [GenBank:AY745809]; DmSERPENT [GenBank:NP_732098]; AmSERPENT [GenBank:XM_001121273]; AaGata4 [GenBank:EAT37835]; TcGATA [GenBank:XM_968040]; DrGATA4 [GenBank:NM_131236]; MmGATA4 [GenBank:AF179424]; DrGATA5 [GenBank:BC116537]; MmGATA5 [GenBank:AK142213]; DrGATA6 [GenBank:BC067710]; MmGATA6 [GenBank:NM010258]; LgGATAb [JGI protein ID:167550]; LgGATAa [JGI protein ID:129788]; CtGATAb3 [GenBank:EF651790]; CtGATAb1 [GenBank:EF651788]; TlGATA456a [GenBank:GU357823].CeELT1 /ml alkaline phosphatase (AP) buffer. A detailed in situ hybridization protocol is available upon request.Specimens of both species were washed out of fixative into phosphate-buffered saline (PBS), dehydrated stepwise into 100% methanol, and stored at -20\u00b0C. Before hybridization, specimens were rehydrated stepwise from methanol into PBS with 0.1% Tween-20 detergent (PTw). Whole mount rotocols ,67 with Cht-FoxA; a 5' riboprobe of approximately 1490 bp was synthesized for Cht-GATA456a (each used at 0.5 ng/\u03bcl). A 3' riboprobe of 1569 bp was synthesized for Tl-FoxA (used at 1.0 ng/\u03bcl); and two 5' riboprobes of 1102 and 881 bp were synthesized for Tl-GATA456a and Tl-GATA456b, respectively (each used at 3.0 ng/\u03bcl). All of the antisense digoxigenin-labeled riboprobes (dig-11-UTP) were synthesized with a T7 MEGAscript kit  and detected by chromogenic staining (NBT/BCIP) of an anti-digoxigenin antibody-alkaline phosphatase conjugate . Color reactions were terminated in PTw, followed by a graded dilution series of hybridization buffer/PTw washes. Specimens were equilibrated and stored in glycerol  and mounted on coated slides . Microscopic analyses were performed on a compound light microscope  with DIC optics. Digital micrographs of riboprobe-labeled and non-labeled, fixed animals were captured with a stem-mounted, 4.0 megapixel digital camera .A 5' riboprobe of 737 bp was synthesized for T. lageniformis embryonic and larval stages were pretreated as previously described, fixed for 1.0 hour in 4% paraformaldehyde in FSW at RT, and washed in phosphate-buffered saline with 0.1% Triton X-100 (PBT). Embryos at stages 3 to 5 were blocked in PBS-T with 10% heat-inactivated goat serum (Sigma) for 1 hour at RT, followed by consecutive overnight treatments at 4\u00b0C with primary mouse anti-histone antibody  and secondary goat anti-mouse rhodamine antibody  in blocking buffer. Secondary antibody was co-incubated with 1:200 BODIPY FL-phallacidin (Molecular Probes). Labeled embryos at stages 3 to 4 were rinsed in PBS and mounted in SlowFade Gold (Molecular Probes). Pelagosphera larvae at stages 6 to 8 were treated with RNase A at 1.0 mg/ml PBS-T for 1 hr at 37\u00b0C, washed in PBS-T, and then labeled with propidium iodide (Sigma)] 5 \u03bcg/ml in PBS-T and 1:200 BODIPY FL-phallacidin for 2 hours at RT. Stage 5 pre-larvae and pelagosphera larvae were washed in PBS, dehydrated stepwise in isopropanol, cleared by emersion in 2:1 benzyl benzoate:benzyl alcohol, mounted on non-coated glass slides and sealed with clear nail polish. Visualization and imaging of all stages were performed using a confocal microscope .The authors declare that they have no competing interests.MJB performed molecular cloning, sequence analyses, gene expression protocols, microscopic imaging and writing of the manuscript. ECS provided critical analyses of the data, and helped to design the study and write the manuscript. Both authors read and approved the final manuscript."}
+{"text": "Each DyIII ion is coordinated by nine O atoms in a tricapped trigonal prismatic geometry. The DyO9 polyhedra form layers parallel to the bc plane. The rigid benzene rings of the anions link the layers along the a axis, forming a three-dimensional framework.The title dysprosium coordination polymer, {[Dy DOI: 10.1107/S1600536808017649/ci2601Isup2.hkl            Structure factors: contains datablocks I. DOI:  crystallographic information; 3D view; checkCIF report            Additional supplementary materials:"}
+{"text": "We sought to evaluate the geometric changes of the mitral leaflets, local and global LV remodeling in patients with left ventricular dysfunction and varying degrees of Functional mitral regurgitation (FMR).Functional mitral regurgitation (FMR) occurs as a consequence of systolic left ventricular (LV) dysfunction caused by ischemic or nonischemic cardiomyopathy. Mitral valve repair in ischemic MR is one of the most controversial topic in surgery and proper repairing requires an understanding of its mechanisms, as the exact mechanism of FMR are not well defined.136 consecutive patients mean age of 55 with systolic LV dysfunction and FMR underwent complete echocardiography and after assessing MR severity, LV volumes, Ejection Fraction, LV sphericity index, C-Septal distance, Mitral valve annulus, Interpapillary distance, Tenting distance and Tenting area were obtained.There was significant association between MR severity and echocardiogarphic indices . Severe MR occurred more frequently in dilated cardiomyopathy (DCM) patients compared to ischemic patients, (p < 0.001). Based on the model, only Mitral valve tenting distance (TnD)  and Interpapillary muscle distance (IPMD),  had significant associations with MR severity.Mitral annular dimensions and area, C-septal distance and sphericity index, although greater in patients with severe regurgitation, did not significantly contribute to FMR severity.Degree of LV enlargement and dysfunction were not primary determinants of FMR severity, therefore local LV remodeling and mitral valve apparatus deformation are the strongest predictors of functional MR severity. Functional Mitral Regurgitation (FMR) defined as a regurgitation that seen with structurally normal valve leaflets. It occurs as a consequence of systolic LV dysfunction caused by ischemic or nonischemic cardiomyopathy. Functional MR occurs in roughly 20\u201325% of patients following MI and 50% of those with CHF ,2. Any dThis study was conducted in Rajaei cardiovascular medical and research center, Tehran, Iran, where is one of the major referral center of cardiovascular diseases in the country.136 patients (mean age (SD) 55 (13.5) years, 85 (63%) male) with systolic LV dysfunction (mean EF (SD) 20% (8.7%)) and functional MR were enrolled. This study was approved by the ethics committee of Rajaei cardiovascular medical and research center. Inclusion criteria were: (1) systolic LV dysfunction (LVEF less than 50%); (2) structurally normal cardiac valves; (3)adequate 2D image for quantification of LV remodeling and mitral apparatus deformation; and (4)sinus rhythm. Exclusion criteria were (1) clinical or echocardiographic evidence of other cardiac diseases, such as organic valvular, pericardial, congenital, or infiltrative heart disease; (2) more than trace aortic regurgitation; (3) acute myocardial infarction; (4) suboptimal echocardiographic windows, leading to incomplete quantification of FMR or anatomic assessment; and (5) atrial fibrillation or flutter.All patients underwent complete transthoracic echocardiography for assessing MR severity and measuring the indices of global and local LV remodeling as well as mitral deformation indexes. All exams performed using Vivid seven (GE Vingmed ultrasound), with a 3S probe.14.ERO and MR volume assessed by PISA and VC methods . In patients with lesser degree of MR (less than mild to moderate) assessment of PISA wasnot done due to lesser accuracy in these patient. Measurements of LV indices: LV dimensions was measured at diastole and systole  in parasternal long axis view. LV volumes and EF were obtained by biplane Simpson's method. Patterns of regional wall motion abnormalities were assessed according to a 16 segment model [ERO \u2265 0.2 cmnt model . LV spheC-Septal distance was measured at mid-systolic parasternal long-axis view; The distance was measured between septum at hinge point of aortic valve cusp and coaptation point of mitral valve leaflets Figure .Mitral valve annulus was measured at mid-diastolic four-chamber and parasternal long-axis views. Mitral annular area was measured by formula; (MA area = d1 \u00d7 d2 \u00d7 \u03c0/4).Interpapillary distance was measured at diastolic mid parasternal short-axis view as a distance between two papillary muscles tips.Mitral Deformation Indexes: Tenting distance was measured as a distance between coaptation point of mitral leaflets and annular plane of MV at mid-systolic parasternal long axis view. Tenting area was measured as an area enclosed between leaflets and annular plane. Figure .One-way ANOVA (and Bonferroni post-hoc test) and chi-square tests were used for comparison of data among the groups. P-value < 0.05 considered as statistically significant. An ordinal logistic regression (OLR) model was fitted to study the adjusted association between severity of FMR and other echocardiogarphic and background determinants. The variables selected based on theoretic considerations and their statistically significant associations in bivariate analysis. STATA\u2122/SE 8  was used for data analysis.Of total 136 patients enrolled in this study, 85 (63%) were male. Mean (SD) age was 55(13.5) years. 51 patients (37.5%) presented with mild regurgitation, 39 patients (28.7%) with moderate and 46 patients (33.8%) with severe functional mitral regurgitation.104 (77%) patients categorized as ischemic cardiomyopathy (ICM) by documented history of infarction and/or coronary angiography and 32 (24%) of them as dilated cardiomyopathy (DCM). All of them had LV systolic dysfunction (mean (SD) EF = 23% (9%), range 10% to 50%). Mean (SD) of end-systolic diameter (ESD), end-systolic volume (ESV), end-diastolic diameter (EDD) and end-diastolic volume (EDV) of LV were: 5.50 (0.89) cm, 128.19 (53.22) ml, 6.49 (0.75) cm and 166.99 (57.71) ml, respectively. Mean volume (SD) of LA was 72.71 (26) ml. Also, the mean pressure (SD) of pulmonary artery (PAP) was 45 (15) mmHg.Associations between these characteristics and severity of FMR are shown in table All echocardiogarphic measurements of LV remodeling and mitral valve deformation are shown in table Based on OLR model, we estimated the values for tenting distance index, as an important predictor of FMR severity, in pre-defined probabilities of FMR. It can be seen that tenting distance 0.45 cm predicts mild FMR and 2.35 cm predicts severe FMR with 80% probability.The present study shows that mitral deformation in patients with systolic dysfunction provides reliable suggestion of valves subject to functional regurgitation, with a graded relationship between valve deformation indices and FMR severity. In early experimental studies, FMR has been attributed to global LV dilatation or sphericity. Later, animal studies have suggested complex alterations of spatial relationship between left ventricle and mitral apparatus to induce functional MR ,15. In pThe papillary muscles which are normally parallel to the LV long axis, displaced as a result of ischemia or heart failure, drawing the leaflets into the ventricle and restricting their motion toward closure ,8. In thWe sought that interpapillary muscle distance contributed independently to functional MR severity. Other studies also showed interpapillary distance and displacement of papillary muscles as a reliable indicator of FMR, correlated with regurgitation severity ,15-18. YWe didnot have gold standard to quantify MR severity. The limitations of PISA for quantitative MR assessment were previously reported, but were minimized in this study because we used both PISA and vena contracta methods for assessing MR severity.FMR: Functional mitral regurgitation; LV: Left ventricular; DCM: Dilated cardiomyopathy; ICM: Ischemic cardiomyopathy; IPMD: Interpapillary muscle distance; TnD: Tenting distance; TnV: Tenting volume; 2D: 2-Dimensional; PISA: Proximal isovelocity surface area; ERO: Effective regurgitant orifice; VC: vena contracta."}
+{"text": "Little is known about interventions that may prevent predegenerative changes in the diabetic retina. This study tested the hypothesis that immediate, systemic treatment with an insulin-like growth factor (IGF)-1 analog can prevent abnormal accumulations of type 1 IGF receptor, and phospho-Akt (Thr 308) immunoreactivity in predegenerative retinas of streptozotocin (STZ) diabetic rats. Type 1 IGF receptor immunoreactivity increased approximately 3-fold in both inner nuclear layer (INL) and ganglion cell layer (GCL) in retinas from STZ rats versus nondiabetic controls. Phospho-Akt (Thr 308) immunoreactivity increased 5-fold in GCL and 8-fold in INL of STZ rat retinas. In all cases, immunoreactive cells were significantly reduced in STZ des(1\u20133)IGF-1\u2013treated versus STZ rats. Preliminary results suggested that vascular endothelial growth factor (VEGF) levels may also be reduced. Hyperglycemia/ failure of weight gain in diabetic rats continued despite systemic des(1\u20133)IGF-1. These data show that an IGF-1 analog can prevent early retinal biochemical abnormalities implicated in the progression of diabetic retinopathy, despite ongoing hyperglycemia."}
+{"text": "Impaired vascular endothelium-dependent relaxationand augmented contractile responses have beenreported in several models of long-term hyperglycemia.However, the effects of short-term ambienthyperglycemia are poorly understood. Since oxidativestress has been implicated as a contributor toimpaired vascular function, we investigated thefollowing:in vitro (7 \u2013 10 days) on vascular relaxation to acetylcholine(Ach) and contractility to norepinephrine (NE)and KCl; (2) if NO-dependent cGMP generation isaffected under these conditions; and (3) aortic redoxstatus.Aims: (1) the effects of high glucose exposure Methods: Non-diabetic rat tail artery rings wereincubated in normal (5mM) (control NG) or high(20mM) glucose buffer (control HG). Vascular responsesto Ach, NE and KCl were compared tothose of streptozotocin (SZ) diabetic animals inthe same buffers . Ach stimulatedcGMP levels were quantitated as an indirectassessment of endothelial nitric oxide (NO)production and oxidative stress evaluated bymeasuring vascular glutathione and oxidizedglutathione.P = 0.002) but relaxednormally, when maintained in HG. Similarly, contractileresponses to NE were attenuated in diabeticrings in NG but similar to controls in HG. HGmarkedly augmented maximal contraction to KClcompared to control and diabetic vessels in NG(P < 0.0001). Diabetic vessels in a hyperosmolar, butnormoglycemic, milieu respond like those in HG.in vitro, HG for 2 hours changed neither relaxationnor contractile responses to NE and KCl in controlrings. Basal cGMP levels were lower in aortaefrom diabetic animals pre-incubated in NG than inHG/LG or in control rings in NG (P < 0.05). cGMPresponses to Ach were exaggerated in diabetic vesselsin HG  but not different between controland diabetic rings in NG. Vessels from diabeticanimals had lower levels of GISH (P < 0.0001) andhigher levels of GSSG (P < 0.0001) indicating oxidativestress.Results: Rings from diabetic rats in NG showedimpaired relaxation to Ach (per se does not cause abnormal vascular responses.Conclusions: Our data indicate that endothelium dependent relaxation is altered early in the diabetic state and that increased NO responses may compensate for augmented oxidative stress but the lack of effect of short-term exposure of normal vessels to HG suggests that short-term hyperglycemia"}
+{"text": "Immunoliposomes were prepared by conjugating anti-carcinoembryonic antigen (CEA) monoclonal antibody with liposomes containing [10B]compound. These immunoliposomes were shown to bind selectively to human pancreatic carcinoma cells (AsPC-1) bearing CEA on their surface. The cytotoxic effects of locally injected [10B]compound, multilamellar liposomes containing [10B]compound or [10B]immunoliposomes (anti-CEA) on human pancreatic carcinoma xenografts in nude mice were evaluated with thermal neutron irradiation. After thermal neutron irradiation of mice injected with [10B]solution, 10B-containing liposomes or [10B]immunoliposomes, AsPC-1 tumour growth was suppressed relative to controls. Injection of [10B]immunoliposomes caused the greatest tumour suppression with thermal neutron irradiation in vivo. Histopathologically, hyalinization and necrosis were found in 10B-treated tumours, while tumour tissue injected with saline or saline-containing immunoliposomes showed neither destruction nor necrosis. These results suggest that intratumoral injection of boronated immunoliposomes can increase the retention of 10B atoms by tumour cells, causing tumour growth suppression in vivo upon thermal neutron irradiation. Boron neutron capture therapy (BNCT) with intratumoral injection of immunoliposomes is able to destroy malignant cells in the marginal portion between normal tissues and cancer tissues from the side of 4He generation."}
+{"text": "We analysed 973 patients with stage I testicular tumours presenting between 1983 and 1994. The median ages at presentation for non-seminomatous germ cell tumour (teratoma) were 27 years, seminoma 36 years and combined tumour 33 years. These differences were statistically significant (Mann-Whitney P < 0.05), suggesting that combined tumours may have a separate natural history. We, therefore, analysed all stage I patients managed with surveillance  post orchidectomy. The actuarial 5 year relapse-free survival and anatomical patterns of relapse were identical for non-seminomatous germ cell tumour (NSGCT) and combined tumour and both were statistically distinct from seminoma . The association of seminoma within a histologically confirmed NSGCT has no influence on the clinical outcome."}
+{"text": "A series of colorectal carcinomas (n = 49) resected from patients with known clinical outcomes were analysed for E-cadherin expression using in situ hybridisation to measure mRNA. Patients surviving 5 years or longer (n = 31) exhibited significantly higher levels of E-cadherin mRNA than those surviving less than 5 years . These preliminary results from this small sample suggest that E-cadherin expression may be a useful prognostic marker in colorectal cancer patients."}
+{"text": "We describe here an improved method of encapsulating doxorubicin in liposomes using phosphatidylcholine, cholesterol and synthetic tetramyristoyl cardiolipin. With this new composition of lipids the entrapment of doxorubicin was found to be > 90%. Cytotoxicity studies using vincristine-resistant HL-60/VCR leukaemia cells showed that liposome-encapsulated doxorubicin reverses multidrug resistance 5-fold compared with conventional doxorubicin and at levels equivalent to that obtained using liposomes with natural cardiolipin. In normal mice, liposome-encapsulated doxorubicin was much less toxic than the conventional drug. A dose of 25 mg kg-1 i.v. of conventional doxorubicin produced 100% mortality in mice by day 14, whereas liposomal doxorubicin exhibited only 10% mortality by day 60. Liposomal doxorubicin demonstrated enhanced anti-tumour activity against murine ascitic L1210 leukaemia compared with conventional doxorubicin. At a dose of 15 mg kg-1, liposomal doxorubicin increased the median life span with 12 of 18 long-term (60 days) survivors compared with only 3 of 18 with conventional drug. Mice injected i.v. with liposomal doxorubicin had plasma levels 44-fold higher than conventional doxorubicin, producing significantly higher (P < 0.02) area under the plasma concentration curve. An altered tissue distribution was also observed with liposomal doxorubicin; cardiac tissue demonstrating at least 2-fold lower levels with liposomal doxorubicin probably accounting for its lower toxicity. This altered pharmacokinetics of liposome-encapsulated doxorubicin, providing enhanced therapeutic advantage and the ability to modulate multidrug resistance, could be useful in a clinical setting."}
+{"text": "This agent selectively inhibited L1210 DNA and purine syntheses, and DNA polymerase \u03b1, PRPP-amido transferase, IMP-dehydrogenase, dihydrofolate reductase, TMP-kinase and thymidylate synthetase activities. L1210 DNA strand scission was evident and DNA viscosity was reduced after 24 hr incubation. The nickel complexes were not L1210 DNA topoisomerase II inhibitors.Nickel(II) complexes of thiosemicarbazons were observed to be potent cytotoxic agents in human and rodent tissue cultured tumor cells. Each compound demonstrated a slightly different profile in the various histological types of tumors. The nickel complex of Appip demonstrated the most potent"}
+{"text": "Igh-6) congenic on theNZB/BlJ background was backcrossed 4 generations intothe NZO/HlLt background and was then intercrossed toproduce mice that initially segregated for wild-type versusthe mutant Igh-6 allele and thus permitted comparisonof syndrome development. A new flow cytometric assay(AIRA binding to transfected Chinese hamster ovarycells stably expressing mouse insulin receptor) showed IgMand IgG subclass AIRAs in serum from Igh-6 intact males,but not in Igh6null male serum. However, the absence ofB lymphocytes and antibodies distinguishing mutant fromwild-type males failed to significantly affect diabetes-freesurvival. The Igh6nullmales gained weight less rapidly thanwild-type males, probably accounting for a retardation, butnot prevention, of hyperglycemia. Thus, AIRA and the Blymphocytecomponent of the peri-insulitis in chronic diabeticswere not essential either to development of insulinresistance or to eventual pancreatic beta cell failure andloss. A new substrain, designated NZL, was generated byinbreeding Igh-6 wild-type segregants. Currently at the F10generation, NZL mice exhibit the same juvenile-onset obesityas NZO/HlLt males, but develop type 2 diabetes at ahigher frequency (> 80%). Also, unlike NZO/HlLt mice thatare difficult to breed, the NZL/Lt strain breeds well and thusoffers clear advantages to obesity/diabetes researchers.The New Zealand obese (NZO) mouse strain shares withthe related New Zealand black (NZB) strain a number ofimmunophenotypic traits. Among these is a high proportionof B-1 B lymphocytes, a subset associated with autoantibodyproduction. Approximately 50% of NZO/HlLtmales develop a chronic insulin-resistant type 2 diabetessyndrome associated with 2 unusual features: the presenceof B lymphocyte\u2013enriched peri-insular infiltrates andthe development of anti-insulin receptor autoantibodies(AIRAs). To establish the potential pathogenic contributionsofBlymphocytes and AIRAs in this model, a disrupted immunoglobulin heavy chain gene ("}
+{"text": "Of 40 eligible patients, 22 agreed to participate (feasibility 55%) and all complied with the full treatment schedule. All symptomatic patients achieved either complete (50%) or partial (50%) relief of tumour-related symptoms with pre-operative chemotherapy. Fifty-five per cent achieved objective tumour response, and a further 27% minor tumour shrinkage; none had progressive disease. Partial pathological response was seen in 50%. No severe (WHO grade III\u2013IV) toxicities occurred. No significant deterioration in quality of life was detected during chemotherapy. Pre-operative MVP chemotherapy is feasible in early stage NSCLC, and this study has now been initiated as a UK-wide Medical Research Council phase III trial. \u00a9 1999 Cancer Research CampaignSurgical resection offers the best chance for cure for early stage non-small-cell lung cancer , but the 5-year survival rates are only moderate, with systemic relapse being the major cause of death. Pre-operative (neo-adjuvant) chemotherapy has shown promise in small trials restricted to stage IIIA patients. We believe similar trials are now appropriate in all stages of operable lung cancer. A feasibility study was performed in 22 patients with early stage  resectable NSCLC; randomized to either three cycles of chemotherapy [mitomycin-C 8 mg m"}
+{"text": "DBA2 mice were inoculated i.p. with 10(5)L1210 cells. Animals subsequently treated with daunomycin  all died. The maximum increase in mean survival time observed was approximately 135%. Animals treated with N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers conjugated to daunomycin (DNM) showed a significant increase in mean survival time when the polymer-drug linkage was biodegradable . Such treatment also produced a number of long term survivors (greater than 50 days). In contrast, HPMA copolymer conjugated to DNM via a non-degradable linkage (Gly-Gly) produced no increase in survival time relative to untreated control animals. The effect observed with biodegradable HPMA copolymer-DNM conjugates was dependent on the concentration of conjugated drug administered (optimum greater than 5 mg kg-1); the frequency of administration (multiple doses were more effective than single); the timing of administration (single doses given on days 1 and 3 were most effective); and the site of tumour inoculation and route of drug administration. Biodegradable HPMA copolymer-DNM conjugates administered i.p. were active against L1210 inoculated s.c. at higher doses than required to curb a peritoneal tumour. Under certain experimental conditions polymer-DNM conjugates containing fucosylamine or galactosamine proved more active than conjugates without the carbohydrate moeity. The mechanism of drug-conjugate action in vivo is at present unclear. Radioiodination of polymer showed approximately 75% of polymer-drug conjugate to be excreted 24 h after i.p. administration. Synthesis of HPMA conjugates containing [3H]DNM showed that polymer containing Gly-Gly-[3H]DNM was excreted  in macromolecular form. In contrast polymer containing Gly-Phe-Leu-Gly-[3H]DNM was largely excreted in the form of low molecular weight species."}
+{"text": "We assessed factors which affect cisplatin concentrations in human surgical tumour specimens. Cisplatin 10 mg m-2 was given i.v. to 45 consenting patients undergoing surgical resection of neoplasms, and platinum was assayed in resected tumour and in deproteinated plasma by flameless atomic absorption spectrophotometry. By multiple stepwise regression analysis of normalised data, patient characteristics that emerged as being most closely associated (P < 0.05) with tumour platinum concentrations (after correcting for associations with other variables) were tumour 'source' [primary brain lymphomas, medulloblastomas and meningiomas ('type LMM') > 'others' > lung cancer > head/neck cancer > gliomas) or tumour 'type' , serum calcium and chloride (positive correlations) and bilirubin (negative). Tumour location  did not correlate with platinum concentrations. If values for a single outlier were omitted, high-grade gliomas had significantly higher platinum concentrations (P < 0.003) than low-grade gliomas. For intracranial tumours, the computerised tomographic scan feature that correlated most closely with platinum concentrations in multivariate analysis was the darkness of peritumoral oedema. Tumour source or type is a much more important correlate of human tumour cisplatin concentrations than is intracranial vs extracranial location. Serum calcium, chloride and bilirubin levels may affect tumour cisplatin uptake or retention. CT scan characteristics may help predict cisplatin concentrations in intracranial tumours."}
+{"text": "Xenopus tropicalis) PXR and that of a putative vitamin D receptor (VDR)/PXR cloned in this study from the chordate invertebrate sea squirt  were also investigated.The pregnane X receptor (PXR) shows the highest degree of cross-species sequence diversity of any of the vertebrate nuclear hormone receptors. In this study, we determined the pharmacophores for activation of human, mouse, rat, rabbit, chicken, and zebrafish PXRs, using a common set of sixteen ligands. In addition, we compared in detail the selectivity of human and zebrafish PXRs for steroidal compounds and xenobiotics. The ligand activation properties of the Western clawed frog  PXR was insensitive to vitamins and steroidal compounds and was activated only by benzoates.Using a common set of ligands, human, mouse, and rat PXRs share structurally similar pharmacophores consisting of hydrophobic features and widely spaced excluded volumes indicative of large binding pockets. Zebrafish PXR has the most sterically constrained pharmacophore of the PXRs analyzed, suggesting a smaller ligand-binding pocket than the other PXRs. Chicken PXR possesses a symmetrical pharmacophore with four hydrophobes, a hydrogen bond acceptor, as well as excluded volumes. Comparison of human and zebrafish PXRs for a wide range of possible activators revealed that zebrafish PXR is activated by a subset of human PXR agonists. The In contrast to other nuclear hormone receptors, PXRs show significant differences in ligand specificity across species. By pharmacophore analysis, certain PXRs share similar features such as human, mouse, and rat PXRs, suggesting overlap of function and perhaps common evolutionary forces. The Western clawed frog PXR, like that described for African clawed frog PXRs, has diverged considerably in ligand selectivity from fish, bird, and mammalian PXRs. The pregnane X receptor  is a member of the nuclear hormone receptor (NR) superfamily ,4 . Commonly used features in pharmacophore models include hydrophobic, hydrogen bond acceptor, hydrogen bond donor, and excluded volumes .In this study, we compare in detail the selectivity of human and zebrafish PXRs for steroid hormones and related compounds. We also compare human, mouse, rat, rabbit, chicken, frog, and zebrafish PXRs with a set of common compounds that activate most PXRs. These Ciona intestinalis  revealed a single gene [GenBank: BR000137] with close sequence similarity to the vertebrate VDRs, PXRs, and constitutive androstane receptors  carbazole , zebrafish), as well as the reporter constructs tk-UAS-Luc and CYP3A4-PXRE-Luc, and 'empty' vectors pCDNA, PsG5, and PM2 were generously provided by SA Kliewer, JT Moore, and LB Moore . The expression vectors were either full-length receptors  or GAL4/PXR chimeras that contain only the LBD of the PXR receptor . For the full-length expression vectors, the reporter plasmid was CYP3A4-PXRE-Luc, a construct that contains a promoter element from CYP3A4 (recognized by PXR DBDs) driving luciferase expression. For the GAL4/LBD expression constructs, the reporter plasmid was tk-UAS-Luc, which contains GAL4 DNA binding elements driving luciferase expression. The following transfection ratios of reporter, receptor, and \u03b2-galactosidase plasmids were used (ng/well): human, mouse, rabbit, and rat PXRs \u2013 25/2.7/20; chicken PXR \u2013 10/1/20; Xenopus tropicalis PXR, zebrafish PXR, and Ciona VDR/PXR \u2013 75/50/20.The creation of a HepG2 (human liver) cell line stably expressing the human Nareported . HepG2-NThe PXR activation assay was a luciferase-based reporter assay ,45. On dActivation of receptor by ligand was compared to receptor exposed to identical conditions without ligand ('vehicle control'). In general, dimethyl sulfoxide (Sigma) was used as vehicle and was adjusted to be 0.5% (v/v) in all wells. A control was also run with transfection of 'empty' vector  and reporter vector to control for activation of reporter vector by endogenous receptor(s). In experiments with a variety of activators, activation by endogenous receptors was not seen.Xenopus tropicalis PXR \u2013 n-propyl-p-hydroxybenzoate 50 \u03bcM; zebrafish PXR \u2013 20 \u03bcM 5\u03b1-androstan-3\u03b1-ol; and Ciona VDR/PXR \u2013 20 \u03bcM 6-formylindolo-carbazole. All comparisons to maximal activators were done within the same microplate. Luciferase data were normalized to the internal \u03b2-galactosidase control and represent means \u00b1 SD of the assays. Concentration-response curves were fitted using Kaleidagraph software . In combining data from multiple experiments, the pooled variance was calculated by the formula spooled = {[(n1-1)s12 + (n2-1)s22 + ... + (nk-1)sk2]/[N-k]}-1/2, where there are N total data points among k groups, with n replicates in the ith group.To facilitate more reliable cross-species comparisons, complete concentration-response curves for ligands were determined in the same microplate as determination of response to a maximal activator. This allows for determination of relative efficacy, \u03b5 defined as the maximal response to test ligand divided by maximal response to a reference maximal activator (note than \u03b5 can exceed 1). The following maximal activators and their concentrations were as follows: human PXR \u2013 10 \u03bcM rifampicin; mouse and rat PXRs \u2013 10 \u03bcM pregnenolone 16\u03b1-carbonitrile; rabbit PXR \u2013 50 \u03bcM 5\u03b2-pregnane-3,20-dione; chicken PXR \u2013 20 \u03bcM nifedipine; To test for cytotoxicity, two assays that have been well-validated in HepG2 cells were used: 3--2,5-diphenyltetrazolium bromide (MTT) reduction and alamar blue reduction. Both assays sensitively measure the ability of viable cells to metabolize the parent compound to a metabolite that can be detected by spectrophotometry or fluorometry . HepG2 cFor the alamar blue assays, alamar blue stock solution  was diluted 1:1 with cell growth medium and 50 \u03bcL of this was added to each well, yielding a final concentration of 10% alamar blue . The plates were exposed to an excitation wavelength of 530 nm, and the emission at 590 nm was recorded to determine whether any of the test drug concentrations fluoresce at the emission wavelength. Plates were returned to the incubator for 5 hr and the fluorescence was measured again. The percent viability was expressed as fluorescence counts in the presence of test compound as a percentage of that in the vehicle control (with subtraction of background fluorescence). Drug concentrations that cause > 30% loss of cell viability in the MTT assay or > 15% loss of cell viability in the alamar blue assay were not used in the determination of concentration-response curves for activation of PXRs.bold type were used for training as they are common to all species \u2013 molecules with no effect were given the arbitrary EC50 value of 10,000 \u03bcM (10 mM).Pharmacophore modelling was performed as described previously ,54. Brie50 values, after selection of the following features: hydrophobic, hydrogen bond acceptor, and hydrogen bond donor with up to 4 excluded volumes. After assessing all ten generated hypotheses, the hypothesis with the lowest energy cost was selected for further analysis as this possessed features representative of all the hypotheses and had the lowest total cost. The quality of the structure activity correlation between the estimated and observed activity values was estimated by means of an r value. Additionally 6-formylindolo-carbazole was aligned with carbamazepine and n-butyl-p-aminobenzoate with the HIPHOP alignment to ascertain the pharmacophore for Ciona VDR/PXR.Ten hypotheses were generated using these conformers for each of the molecules and the ECNM_00376], chimpanzee VDR [Ensembl:ENSPTRT00000009010], rhesus monkey VDR [Ensembl:ENSMMUT00000009414], cow VDR [Ensembl:ENSBTAT00000021832], dog VDR [Ensembl:ENCAFT00000014497], mouse VDR [GenBank: NM_008504], rat VDR [GenBank: NM_009504], chicken VDR [GenBank: AF011356], Japanese quail VDR [GenBank: U12641], Xenopus laevis VDR [GenBank: U91849], Atlantic salmon  VDR [GenBank: AJ780914], fugu VDR [Ensembl:NEWSINFRUT00000138841], bastard halibut  VDR [GenBank: AB037674], zebrafish VDR [GenBank: AF164512], medaka VDR [Ensembl:ENSORLT00000001311], stickleback fish (Gastrosteus aculeatus) VDR [Ensembl:ENSGACT00000006308], sea lamprey VDR [GenBank: AY249863], Ciona intestinalis VDR/PXR [GenBank: BR000137], human CAR [GenBank: NM_005122], chimpanzee CAR [ENSPTRT00000002884], rhesus CAR [GenBank: AY116212], cow CAR [Ensembl:ENSBTAT00000012145], dog CAR [Ensembl:ENSCAFT00000020528], pig CAR [GenBank: AB214979], Baikal seal (Phoca sibirica) CAR [GenBank: AB109553], Northern fur seal  CAR [GenBank: AB109554], mouse CAR [GenBank: NM_009803], rat CAR [GenBank: NM_022941], pig CAR [GenBank: AB214979], opossum CAR [Ensembl:ENSMODT00000006393], human PXR [GenBank: AF061056], chimpanzee PXR [ENSPTRT00000028510], rhesus monkey PXR [GenBank: AF454671], cow PXR [Ensembl:ENSBTAT00000026059], mouse PXR [AF031814], rat PXR [GenBank: NM_052980], rabbit PXR [GenBank: AF188476], opossum PXR [Ensembl:ENSMODT00000023109], chicken PXR [GenBank: AF276753], Xenopus laevis PXR\u03b1 [GenBank: BC041187], Xenopus laevis PXR\u03b2 [GenBank: AF305201], Xenopus tropicalis PXR [Ensembl:ENSXETT00000039109], fugu PXR [Ensembl:NEWSINFRUT00000171584], medaka PXR [Ensembl:ENSORLT00000022473], Tetraodon nigriviridis PXR [Ensembl:GSTENT00026021001], zebrafish PXR , domestic silkworm (Bombyx mori) ecdysone receptor [GenBank: L35266], ixotid tick (Amblyomma americanum) ecdysone receptor [GenBank: AF020187], and purple sea urchin (Strongylocentrotus purpuratus) liver X receptor [GenBank: XM_774904]. Sequences were aligned using ClustalW carbazole, and n-butyl-p-aminobenzoate as activators of Ciona VDR/PXR.HIPHOP model for Click here for fileReconstructed ancestral sequences. Detailed data for the reconstruction of ancestral sequences.Click here for fileComparison of ligand-binding residues between extant and reconstructed sequences. Conservation of ligand-binding residues in extant and reconstructed PXR sequences.Click here for fileIntrinsic disorder summary for PXRs, VDRs, and CARs. Summary data for intrinsic disorder predictions for PXR, VDR, and CAR sequences.Click here for fileIntrinsic disorder data for PXRs, VDRs, and CARs. Intrinsic disorder data for each amino acid residue of PXR, VDR, and CAR sequences analyzed.Click here for file"}
+{"text": "The expression of epidermal growth factor receptor (EGFR), oestrogen receptor (ER) and progesterone receptor (PR) was assayed by a radioreceptor method in 117 primary ovarian cancers. EGFR was not significantly related to any of the clinicopathological parameters examined. In patients with stage II-IV disease who underwent second-look surgery after primary chemotherapy, a significant correlation between high EGFR levels and poor response to chemotherapy was demonstrated (P = 0.031). Moreover, post-operative residual tumour showed an independent role in predicting chemotherapy response (P = 0.0007) and EGFR status showed a borderline significance (P = 0.052) in the multivariate analysis. No correlation between steroid hormone receptors and clinicopathological parameters was observed. Whereas a significant relationship was shown between EGFR positivity and a shorter overall survival (OS) (P = 0.0022) and progression-free survival (PFS) (P = 0.0033), patient survival was not related to steroid hormone receptor status. Among the parameters tested only stage, ascites and EGFR status retained an independent prognostic value in the multivariate analysis."}
+{"text": "Three Pt-creatinine complexes, cis-[Pt(NH3)2Cl(Creat)]+, cis-[Pt(NH3)2(H2O)(Creat)]2+ and cis-[Pt(NH3)2(Creat)2]2+, were synthesized and the platinum was shown to coordinate to the ring nitrogen, N(3). Human urine samples from patients on cisplatin chemotherapy were shown to contain cisplatin, its hydrolysis product and biotransformation products containing Pt-creatinine, Pt-urea and Pt-uric acid complexes. Urine from carboplatin patients shows fewer biotransformation products. Studies with control and diabetic (protected against cisplatin toxicity) rats showed systematic differences in the biotransformation products formed on administration of cisplatin.Cisplatin is an extremely effective cancer chemotherapeutic agent, but its use is often accompanied by toxicity. Second generation drugs such as carboplatin are becoming more widely used because of reduced toxicity. Since biotransformation products have been implicated in the toxic responses, we have begun to investigate the reactions of cisplatin and carboplatin with potential biological ligands. Reaction products were characterized using HPLC with inductivelycoupled plasma - mass spectrometry (HPLC-ICP-MS),"}
+{"text": "Tumor cell motility and invasion is governed by dynamic regulation of the cortical actin cytoskeleton. The actin-binding protein cortactin is commonly upregulated in multiple cancer types and is associated with increased cell migration. Cortactin regulates actin nucleation through the actin related protein (Arp)2/3 complex and stabilizes the cortical actin cytoskeleton. Cortactin is regulated by multiple phosphorylation events, including phosphorylation of S405 and S418 by extracellular regulated kinases (ERK)1/2. ERK1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the Arp2/3 regulator neuronal Wiskott-Aldrich syndrome protein (N-WASp), promoting actin polymerization and enhancing tumor cell movement.In this report we have developed phosphorylation-specific antibodies against phosphorylated cortactin S405 and S418 to analyze the subcellular localization of this cortactin form in tumor cells and patient samples by microscopy. We evaluated the interplay between cortactin S405 and S418 phosphorylation with cortactin tyrosine phosphorylation in regulating cortactin conformational forms by Western blotting. Cortactin is simultaneously phosphorylated at S405/418 and Y421 in tumor cells, and through the use of point mutant constructs we determined that serine and tyrosine phosphorylation events lack any co-dependency. Expression of S405/418 phosphorylation-null constructs impaired carcinoma motility and adhesion, and also inhibited lamellipodia persistence monitored by live cell imaging.Cortactin phosphorylated at S405/418 is localized to sites of dynamic actin assembly in tumor cells. Concurrent phosphorylation of cortactin by ERK1/2 and tyrosine kinases enables cells with the ability to regulate actin dynamics through N-WASp and other effector proteins by synchronizing upstream regulatory pathways, confirming cortactin as an important integration point in actin-based signal transduction. Reduced lamellipodia persistence in cells with S405/418A expression identifies an essential motility-based process reliant on ERK1/2 signaling, providing additional understanding as to how this pathway impacts tumor cell migration. Tumor cell motility and invasion is a central problem in cancer that is paramount in contributing to metastasis The actin binding protein cortactin is a major component of lamellipodia that regulates the lamellipodia actin network through several pro-migratory signaling pathways \u2212/\u2212 fibroblasts indicates that cortactin does not play a role in directly regulating lamellipodia protrusion or Arp2/3-based actin dynamics, but rather is important in mediating upstream activation of the small GTPases Rac1 and Cdc42, which in turn regulate WAVE2 and N-WASp activity Although the biochemical features of cortactin seem to point to a straightforward role in lamellipodia actin regulation, studies of cortactin function in lamellipodia have proven controversial, suggesting to a more complex role in cell migration. RNA interference studies have yielded conflicting results in regards to lamellipodia dynamics, with cortactin knockdown resulting in decreased lamellipodia stability and reduced persistence consistent with a role in lamellipodia actin network stabilization Besides regulating Arp2/3-based cortical actin networks by direct interactions, cortactin also functions as a key mediator in several kinase-based signal transduction cascades that indirectly govern Arp2/3 activity and cell movement. Cortactin is a well-defined target for Src kinase Besides tyrosine phosphorylation, cortactin is a target for multiple serine/threonine kinases In this study, we have generated site-specific antibodies against phosphorylated cortactin S405 and S418 to determine the spatial and temporal localization of cortactin in dynamic actin structures and human tumors, and to evaluate signaling interplay between cortactin tyrosine and serine phosphorylation events. We also determined the effects of S405/418 cortactin phosphorylation on EGF-induced cell migration, adhesion and lamellipodia dynamics in carcinoma cells.5\u2032-GCTTCGAGAGAATGTCTTC-3\u2032) was purchased from Thermo Scientific .For Myc-tagged human cortactin expression constructs, the wild-type human cortactin cDNA subcloned into pcDNA FLAG2AB 6 cells and two micrograms of plasmid construct or siRNA using the Nucleofector I device .The HNSCC cell lines 1483 st Century Biochemicals . Synthetic phosphorylated cortactin peptides containing the sequences NH2-KTQTPPV[pS]PAPQPTC-COOH (cortactin pS405) and NH2-TEERLPS[pS]PV-COOH (cortactin pS418) were produced, conjugated to keyhole limpet cyanine and injected into rabbits. Immune serum was screened by enzyme-linked immunosorbent assay against the appropriate phosphorylated cortactin peptide coupled to bovine serum albumin. High-titer bleeds were identified for each peptide, and immune serum was passed two successive times through chromatography columns containing agarose beads coupled to the equivalent non-phosphorylated peptide. The flow through material for each peptide was subsequently passed twice through chromatography columns containing beads conjugated to the matched phosphorylated cortactin peptide. After extensive washing, bound antibodies for each phosphorylation site were eluted, concentrated and screened for specificity by Western blotting against recombinant cortactin mutant proteins harboring alanine-serine point mutations at serine 405 or 418, respectively (Antibodies against phosphorylated serine 405 (pS405) and serine 418 (pS418) of human cortactin were produced by 21ectively . The antWestern blotting was conducted as described UMSCC2 cells were plated on fibronectin-coated coverslips  and allowed to attach before serum starvation for 16 h. Cells were stimulated with 100 nanograms/ml EGF (Millipore) for 1 h before fixation. UMSCC1 cells plated on FITC-gelatin (Sigma) for 8 h were processed for confocal microscopy using Zeiss LSM 510 Meta system  as described For immunohistochemistry, HNSCC tissue blocks were obtained from the West Virginia University Tissue Bank and used under approval of the West Virginia University Institutional Review Board. Five-micrometer sections from formalin-fixed, paraffin-embedded blocks were processed for immunostaining using the Discovery XT automated staining system . Briefly, after deparaffinization and antigen retrieval, sections were incubated with monoclonal rabbit anti-cortactin  at 1\u22362000, anti-pS418 cortactin at 1\u223625 and anti-pERK1/2 at 1\u2236100 dilutions. All primary antibodies were incubated in Dako diluent  for 1 h. Primary antibodies were detected with the Omnimap antibody horseradish peroxidase kit (Ventana). Slides were counterstained with hematoxylin and post-counterstained with bluing reagent (Ventana). Images were visualized with an Olympus AX70 microscope and captured using the MicroBrightfield system .Live cell imaging was conducted using MTLn3 cells starved for 3 h with serum-free media prior to stimulation with 100 nanograms/ml EGF. Cells were plated on delta-T4 glass bottom dishes (Fisher) coated with 10 micrograms/ml fibronectin (Sigma). Immediately following EGF addition, cells were imaged by differential interference contrast microscopy using a Nikon TE2000 inverted microscope equipped with a Roper CoolSNAP HQ charge-coupled device camera . Images were captured every 5 s for 15 min . A Nikon LiveScan SFC swept field microscope was used for imaging cells expressing mCherry-actin using the same parameters. In all cases, GFP-cortactin expressing cells were identified by fluorescence microcopy prior to imaging. Kymograms were produced by extracting 1 pixel-width strips from each movie frame at points of initial and maximal lamellipodia extension, and assembled using ImageJ (v1.40).5 cells were plated into 8-well electric cell substrate impedance sensing dishes . For motility measurements, cells were allowed to adhere overnight on 8W1E dishes to form a monolayer. Adhesion was assayed immediately after plating cells onto 8W10E dishes. Measurements were conducted for 24 h at 45 kHz, with reading taken at 1 min intervals. Cells treated with selumetinib were serum starved 24 h in the presence of drug prior to ECIS.To assay cell motility and adhesion, 5\u00d710Differences in mean groups for migration, adhesion and kymography between control and treated groups were evaluated using one way ANOVA, followed by Student-Newman-Keuls post hoc testing. All differences were considered significant at p\u22640.05. A minimum of three experimental groups were used for all analyses.We developed antibodies specific to phosphoserine 405 (pS405) and phosphoserine 418 (pS418) of human cortactin to facilitate analysis of these sites. To validate antibody specificity, epitope-tagged cortactin constructs containing wild-type (WT) cortactin, cortactin with individual serine to alanine mutations at codon 405 (S405A), codon 418 (S418A) or with both codons mutated in tandem  were produced and transfected into 1483 cells. Total cell lysates were blotted with anti-pS405 or anti-pS418 antibodies . The antTo determine the subcellular localization of serine phosphorylated cortactin, we conducted indirect immunofluoresence studies on cells producing lamellipodia and invadopodia, two actin-based structures that depend in part on N-WASp activity. While the anti-pS405 antibody yielded non-specific staining in our hands (data not shown), anti-pS418 specifically labeled lamellipodia and cytoplasmic puncta (presumably vesicles) in UMSCC2 cells. In cells with a motile phenotype, anti-pS418 localized with cortactin and F-actin in these regions , top rowIn solid human tumors, cortactin and cortactin phosphorylated on tyrosine 421 (pY421) localizes to invasive tumor fronts and to cell-cell junctions Previous biochemical work has implicated chemical inhibition of MEK and subsequent blocking of ERK1/2 activation as a major pathway responsible for cortactin S405/418 phosphorylation Based on sequence analysis, the largest and most prominent cortactin isoform (cortactin \u201cA\u201d or \u201cSV1\u201d) encodes a 61.5 kDa protein in vitro study evaluating the impact of cortactin phosphorylation on N-WASp activation determined that S405/418 phosphorylation by ERK1/2 enables the cortactin SH3 domain to stimulate N-WASp Arp2/3 activation, while Src phosphorylation downregulates N-WASp activity and counteracts the effects of S405/418 phosphorylation tsLa29-GFP tsLa29-GFP, the serine and tyrosine cortactin mutants were analyzed for phosphorylation at Y421 and S405 by SDS-PAGE and Western blotting . While the distinct 80 kDa and 85 kDa bands represent different post-translationally modified cortactin forms associated with pS405/418 phosphorylation, mutations at these sites have no effect on 80/85 kDa cortactin ratios, with the S405/418A mutant displaying a similar cortactin electrophoretic pattern to wild type cortactin , selumetinib (A), or saracatinib (B) for 16 h in serum free media. Cells were stimulated with 100 nanograms/ml EGF for 20 min, lysed and analyzed by Western blotting with anti-EGFR-pY1068, anti-EGFR, anti-pErk1/2, Erk1/2, anti-Src-pY418, and anti-Src antibodies as indicated.(0.23 MB TIF)Click here for additional data file.Video S1EGF-mediated extension of MTLn3 cells. Time lapse video microscopy of non-transfected mCherry-beta-actin transfected MTLn3 cells stimulated with 100 nanograms/ml EGF. Cells were visualized by swept-field fluorescence microscopy.(0.30 MB MOV)Click here for additional data file.Video S2Cortactin depletion enhances lamellipodia persistence MTLn3 cells stimulated with soluble EGF. MTLn3 cells were transfected with siRNA targeting cortactin. 48 h after transfection, cells were transfected with mCherry-beta-actin and stimulated with EGF. Cells were visualized by swept-field fluorescence microscopy.(0.15 MB MOV)Click here for additional data file.Video S3Expression of wild-type cortactin rescues siRNA-mediated enhancement of lamellipodia persistence. MTLn3 cells were transfected with siRNA targeting cortactin were co-transfected after 48 h with mCherry-beta-actin and GFP-tagged wild type cortactin. Cells were visualized by swept-field fluorescence microscopy. Red channel, mCherry; green channel; GFP fluorescence.(4.43 MB MOV)Click here for additional data file.Video S4Phosphorylation of cortactin S405/418 is required for lamellipodia persistence. MTLn3 cells transfected with siRNA targeting cortactin were co-transfected after 48 h with mCherry-beta-actin and GFP-labeled S405/418A cortactin. Cells were visualized by swept-field fluorescence microscopy. Red channel, mCherry; green channel; GFP fluorescence.(7.00 MB MOV)Click here for additional data file."}
+{"text": "Hyperinsulinemia has been shown to beassociated with diabetic angiopathy. Migrationand proliferation of vascular smooth musclecells (VSMC) are the processes required for thedevelopment of atherosclerosis. In this study,we attempted to determine whether insulinaffects mitogenic signaling induced by plateletderivedgrowth factor (PDGF) in a rat VSMCcell line (A10 cells). PDGF stimulated DNAsynthesis which was totally dependent on Ras,because transfection of dominant negative Rasresulted in complete loss of PDGF-stimulatedDNA synthesis. Initiation of DNA synthesiswas preceded by activation of Raf-1, MEK andMAP kinases (Erk 1 and Erk2). Treatment ofthe cells with PD98059, an inhibitor of MAPKkinase (MEK) attenuated but did not abolishPDGF-stimulated DNA synthesis, suggestingthat MAPK is required but not essential forDNA synthesis. PDGF also stimulated phosphorylationof protein kinase B (Akt/PKB) andp70 S6Kinase (p70S6K) in a wortmannin-sensitivemanner. Rapamycin, an inhibitor ofp70S6K, markedly suppressed DNA synthesis.Low concentrations of insulin (1-10 nmol/l)alone showed little mitogenic activity and nosignificant effect on MAPK activity. However,the presence of insulin enhanced both DNAsynthesis and MAPK activation by PDGF. Theenhancing effect of insulin was not seen in cellstreated with PD98059. Insulin was withouteffect on PDGF-stimulated activations of protein kinase B (Akt/PKB) and p70S6K. We concludethat insulin, at pathophysiologically relevantconcentrations, potentiates the PDGFstimulatedDNA synthesis, at least in part, bypotentiating activation of the MAPK cascade.These results are consistent with the notionthat hyperinsulinemia is a risk factor for thedevelopment of atherosclerosis."}
+{"text": "We have investigated the effects of localised tumour hyperthermia  on the acute toxicity and pharmacokinetics of the hypoxic cell sensitizer pimonidazole (Ro 03-8799) in mice. There were three treatment groups: unrestrained controls, sham-treated and LTH treated mice. LTH had minimal effects on the acute toxicity (LD50/7d) of pimonidazole with no significant difference between the three treatment groups. Pharmacokinetic studies were carried out at the maximum tolerated dose  of 437 micrograms g-1 i.v. in plasma, brain and tumour. Sham tumour treatment consistently increased plasma drug concentrations compared to unrestrained controls but had minimal effects on the elimination t1/2. The AUC0-infinitive was increased by 35% and the plasma clearance decreased by 26%. By contrast, LTH had minimal effects on these parameters compared to sham treatment. Brain pimonidazole concentrations were increased in restrained mice (sham and LTH treatments) compared to unrestrained controls, but average brain/plasma ratios were similar in all three groups at between 400 and 500%. Sham tumour treatment markedly reduced peak tumour pimonidazole concentrations compared to unrestrained controls giving a 29% lower AUC0-180min. Average tumour/plasma ratios were reduced from 236 to 129%. The most important finding was that LTH further reduced pimonidazole tumour concentrations, giving a 31% lower AUC0-180 min compared to sham treated tumours. Tumour/plasma ratios for pimonidazole were reduced by 41%. Plasma exposure to the pimonidazole N-oxide metabolite, Ro 31-0313, was unaltered by LTH. The markedly reduced drug concentrations in heated tumours may be a result of hyperthermia-stimulated bioreductive drug activation."}
+{"text": "Liver-function tests were normal. A hepatic nodule was detected on screening of upper abdominal and renal sonography. Contrast-enhanced computed tomography (CT) scan (3). A CT scan obtained 15 months later (3). An enzyme-linked immunosorbent assay (ELISA) for Toxocara canis was strongly positive, and optical density was 2.53 . He had several occasions of eating chops of uncooked cow's liver at restaurants before the initial blood test.A 54-year-old man with diabetes mellitus had a blood test and was found to have a blood eosinophilia  scan  showed aCT) scan \u20134 revealhs later  revealedT. canis takes place in two ways6As in dogs and animals, human infection of"}
+{"text": "P < .05) without reducingblood pressure (BP), whereas enalapril failed to significantly reduce UAE despite a reduction in BP. Combining thetwo treatments showed no further reduction in UAE comparedto monotherapy with nitrendipine, despite a lowerBP. When leaving diabetic rats untreated for 3 months, onlythe coadministration of nitrendipine and enalapril showeda significant reduction in UAE compared to monotherapyand placebo treatment, but showed no significant effecton BP.The objective of this study was to compare the effectof an angiotensin-converting enzyme (ACE) inhibitor anda calcium channel blocker on the development of renalchanges in diabetic rats. Diabetes was induced by an intravenousinjection of streptozotocin in normotensive Wistarrats. Treatment was commenced immediately in 1 set ofrats with 4 treatment arms: nitrendipine (250 mg/kg fodder),enalapril (35 mg/L drinking water), both treatmentsin combination, or placebo. Treatment was continued for 9weeks. Another set of rats was left with untreated diabetesfor 3 months followed by 7 weeks treatment as above. Whenstarting treatment right after induction of diabetes, nitrendipinesignificantly reduced urinary albumin excretion(UAE) to the nondiabetic level ("}
+{"text": "Protein kinases play a key role in intracellular signalling, participating at multiple levels along the transduction cascades that trigger mitogenic response. Because protein kinases are involved in mitogenic pathways, they are likely to play a role in the abnormal proliferation of malignant cells. In this study we compared activity of mitogen-activated protein (MAP) kinase and several renaturable kinases in homogenates of 30 surgically resected colorectal cancers and their adjacent normal tissues. Using sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) and membrane autophosphorylation assay on homogenates obtained from normal colon mucosa and adenocarcinoma, we identified at least four renaturable kinases . Compared with adjacent tissue, in most of the cancer samples only the 85-kDa kinase exhibited a higher level of autophosphorylation activity than those in normal matched tissue (P < 0.001). Moreover, the 85-kDa kinase from nearly all cancer homogenates showed faster electrophoretic mobility than the 85-kDa kinase from normal tissue homogenates. Interestingly, the 50-kDa kinase had significantly lower autophosphorylation activity in cancer tissues than those of normal tissue (P< 0.05). To assess p42-p44 MAP kinase activity, proteins were immunoprecipitated from adjacent colon mucosa and adenocarcinoma with anti-extracellular signal-related kinase (ERK) 1/2 antibodies, and MAP kinase activity was measured using MBP as a substrate. These studies revealed that MAP kinase activity in colorectal cancer was significantly higher (P < 0.001) than that in adjacent mucosa. Thus, the constitutive activity of MAP kinase and autophosphorylation activity of 85-kDa kinase are increased, whereas the autophosphorylation activity of another kinase, 50 kDa, is decreased in colorectal adenocarcinoma. However, although signal transduction pathways are markedly altered in this cancer, neither p42/p44 MAP kinase activity nor 85-kDa autokinase activity could be correlated with the established prognostic indicators."}
+{"text": "A 79-year-old male patient presented with a subacute cauda syndrome caused by an intradural metastasis of the lumbosacral caudate fibres from an adenocarcinoma of the prostate, which had been treated 5 years earlier with external beam radiation therapy. Diagnosis could not be established by repeated magnetic resonance images (MRIs) during a 2-year period of increasingly severe radicular pain. Eventually, a small tumour mass could be visualized on the fourth MRI. Repeated normal serum prostate-specific antigen (PSA) did not hint at a prostate cancer metastasis (range 2.4-5.1 ng ml(-1)); however, PSA in the cerebrospinal fluid was found to be elevated (29.1 ng ml(-1)). Empirical radiation therapy of the caudate region did not improve radicular pain. Therefore, an exploratory surgical procedure was conducted, which confirmed the suspicion of an intradural prostate cancer metastasis. In conclusion, PSA in the cerebrospinal fluid provides a useful diagnostic tool for detecting intradural prostate cancer metastasis."}
+{"text": "Spheroids incubated with ALA show significant fluorescence nonuniformity for all concentrations, with the outermost cells exhibiting greater porphyrin fluorescence. Comparable levels of fluorescence throughout the optical section are achieved with approximately 100-fold lower h-ALA concentrations, indicating that the interior cells maintain esterase activity and porphyrin synthesis and that h-ALA diffuses efficiently to the spheroid interior. Fluorescence gradients are less pronounced with h-ALA incubation, in part because of apparent saturation of esterase activity in the spheroid perimeter. Proliferating (Ki67 positive) and quiescent cell populations exhibit remarkably different h-ALA concentration dependencies. The incubation concentration resulting in maximum fluorescence with ALA is 10\u2008mM, while the optimal concentration for h-ALA is 200-fold lower at 0.05\u2008mM. Exceeding these optimal concentrations for both pro-drugs leads to an overall loss of fluorescence. \u00a9 2001 Cancer Research Campaign http://www.bjcancer.comSynthesis of protoporphyrin IX (PpIX) in intact murine mammary cancer cell spheroids is reported from optical sections obtained using a laser scanning confocal fluorescence microscope. EMT6 spheroids 275\u2013350"}
+{"text": "Chronic obstructive pulmonary disease (COPD) is characterized by chronic bronchitis, emphysema and irreversible airflow limitation. These changes are thought to be due to oxidative stress and an imbalance of proteases and antiproteases. Quercetin, a plant flavonoid, is a potent antioxidant and anti-inflammatory agent. We hypothesized that quercetin reduces lung inflammation and improves lung function in elastase/lipopolysaccharide (LPS)-exposed mice which show typical features of COPD, including airways inflammation, goblet cell metaplasia, and emphysema.Mice treated with elastase and LPS once a week for 4 weeks were subsequently administered 0.5 mg of quercetin dihydrate or 50% propylene glycol (vehicle) by gavage for 10 days. Lungs were examined for elastance, oxidative stress, inflammation, and matrix metalloproteinase (MMP) activity. Effects of quercetin on MMP transcription and activity were examined in LPS-exposed murine macrophages.in vivo and in vitro, while increasing expression of the histone deacetylase Sirt-1 and suppressing MMP promoter H4 acetylation. Finally, co-treatment with the Sirt-1 inhibitor sirtinol blocked the effects of quercetin on the lung phenotype.Quercetin-treated, elastase/LPS-exposed mice showed improved elastic recoil and decreased alveolar chord length compared to vehicle-treated controls. Quercetin-treated mice showed decreased levels of thiobarbituric acid reactive substances, a measure of lipid peroxidation caused by oxidative stress. Quercetin also reduced lung inflammation, goblet cell metaplasia, and mRNA expression of pro-inflammatory cytokines and muc5AC. Quercetin treatment decreased the expression and activity of MMP9 and MMP12 Quercetin prevents progression of emphysema in elastase/LPS-treated mice by reducing oxidative stress, lung inflammation and expression of MMP9 and MMP12. Chronic obstructive pulmonary disease (COPD) is a heterogeneous disorder characterized by small airway inflammation/fibrosis, mucus plugging and emphysema. COPD is the fourth leading cause of death worldwide and the prevalence is predicted to rise in the next two decades .Although the cellular and molecular mechanisms of COPD pathogenesis are not well known, oxidative stress, chronic inflammation and an imbalance of proteases and antiproteases are thought to play key roles in development and progression of the disease . TherefoInhalation of cigarette smoke and other environmental exposures can stimulate resident alveolar macrophages and lung epithelial cells to generate reactive oxygen species (ROS) and reactive nitric oxide species (RNS) in excess, thereby disturbing the oxidant to antioxidant balance, resulting in oxidative stress -4. ROS aThe histone deacetylases (HDACs) are transcriptional repressors which have been implicated in the resolution of inflammation as well as the regulation of MMP expression . In COPDLipopolysaccharide (LPS), a cell wall component of gram negative bacteria, is a potent inflammatory molecule and is present in appreciable amounts in cigarette smoke. It is also an active component in environmental and occupational exposures associated with the development of COPD -10. ExpeQuercetin is a 3,3',4',5,7-pentahydroxyflavone found in many plants. Based on its polyphenol structure, quercetin has potent antioxidant effects, combining with free radical species to form considerably less reactive phenoxy radicals ,17. QuerE. coli O26:B6  on day four of the week for four consecutive weeks. Control mice were exposed to PBS. Seven days after the last exposure to LPS, mice were orally gavaged with 300 \u03bcl of 50% propylene glycol (vehicle) or 0.2 mg of quercetin  dissolved in 50% propylene glycol, once a day for 10 days. We chose this dose of quercetin based on previous studies in which quercetin at 10 mg/kg body weight reduced airways responsiveness and lung inflammation in an allergic mouse model of asthma [Eight to ten weeks old C57BL/6 mice  were exposed to elastase and LPS for four consecutive weeks as described previously . Animalsf asthma ,20. In s2O And Pressure And Lung Volume Measured Continuously During Inflation And Deflation Of The Lungs. Static Elastance And Compliance Were Recorded By Inflating The Lungs To Full Capacity.Mice Were Anesthetized By Intraperitoneal Injection Of Ketamine (2.5-5 Mg/100 G Body Weight) And A Steel Cannula Was Inserted Into The Trachea And Connected To A Miniature Computerized Flexivent Ventilator . Sodium Pentabarbitol (2 Mg/100 G Body Weight) Was Also Given To Provide Further Sedation And Allow Stabilization On The Ventillator. To Determine Elastic Recoil, Lungs Were Gradually Inflated To 30 Cm HLungs Were Perfused With 20 Mm Edta And Inflation-Fixed With 10% Buffered Formalin, And Embedded In Paraffin. Five Micron Thick Sagittal Sections Were Stained With Hematoxylin And Eosin (H & E) Or Periodic-Acid Schiff'(Pas) Reagent. Alveolar Chord Length Was Determined Using Sagittal Sections Obtained At 5 Mm Intervals Through The Length Of The Lungs, And Diameter Of The Airspaces Was Measured In Random Areas Using Nih Image J Analysis Software .Mice Were Euthanized And Lungs Were Lavaged With Pbs. Bal Fluid Was Centrifuged And The Supernatant Was Collected For Determination Of Mmp Levels. Total And Differential Cell Counts In Bal Fluid Were Determined As Described Previously ,22.After Relevant Treatment, Mice Were Euthanized, Lungs Were Collected, Homogenized In Pbs Containing Complete Protease Inhibitors And Centrifuged . Cytokine Protein Levels In The Lung Homogenate Supernatants Were Measured Either By Elisa  Or Multiplex Immunoassay  ,22.Murine Alveolar Macrophages  Were Cultured In Rpmi1640 Supplemented With 10% Fetal Bovine Serum, Penicillin (100 Units/Ml), Streptomycin (100 \u03bcG/Ml), 1% Glutamine And 0.01% \u03b2-Mercaptoethanol. To Determine The Effect Of Quercetin On Mmp Expression, Cells Were Seeded In 6 Well Plates And Grown For 24 H. Cells Were Then Exposed To Cell Culture Media Containing 1 Ng/Ml Lps For 8 Hours A Day For Three Days. In Between Exposures To Lps, Cells Were Maintained In Cell Culture Media Alone. Cells Were Then Shifted To Serum-Free Media Containing Quercetin Dihydrate Or Dmso, Incubated For 24 H, And Media And Cells Were Harvested. Cells Exposed To Media Alone Instead Of Lps Were Used As Negative Controls.2 And 5\u03bcM Zncl2 And Stained With 0.5% Coomassie Blue.Mmp Activity Was Determined By Gelatin Zymography As Described.. BrieflyMice Were Sacrificed And Blood Was Collected By Cardiac Puncture In Tubes With Anticoagulant, Centrifuged And Plasma Was Collected. Levels Of Quercetin In Plasma Were Determined By Hplc As Described Previously .Chip Assays Were Performed With A Chip-It Kit  Following The Manufacturer'S Instructions. Briefly, Cells Were Fixed, Lysed And Chromatin Was Subjected To Enzymatic Shearing. Chromatin Fragments Of 100-1000 Bp Were Immunoprecipitated With An Antibody To Acetylhistone H4 Antibody. Chip And Input Dna Were Purified And Subjected To Qpcr Using Primers Specific For The Nf-\u03baB Binding Site In The Mmp9 And Mmp12 Promoters. Qpcr Conditions Were As Follows: 95\u00b0C For 15 Minutes; 95\u00b0C For 10 Seconds, 60\u00b0C For 30 Seconds, 72\u00b0C For 30 Seconds, Repeated For 50 Cycles, 72\u00b0C For 10 Minutes. The Primers Used For Qpcr Were Mmp9: Sense 5'-TTTAAACAGAAGAGGAAGGAT AGTGC-3' And Antisense 5'-CCTGATAGAGTCTTT GACTCAGCTTC-3'; Mmp12: Sense 5'-TTGCTGAATCATTTCATGGC-3' And Antisense 5'-AGTGCATAGGTATG TGAATGGG-3'.Mmp9, Mmp12, Sirt1, Inducible Nitric Oxide Synthase (Inos), Heme Oxygenase (Hmox)-1, And Muc5Ac Was Determined By Qpcr. All Pcr Reactions Were Performed In An Eppendorf Mastercycler  And Gene Expression Was Quantified Using The Comparative Ct Method.Expression Of Nuclear Proteins Were Resolved By 7.5% Sds-Polyacrylamine Gel Electrophoresis, Proteins Transferred To Nitrocellulose Membrane And Probed With Antibody To Sirt1 And \u03b2-Actin . Specific Bands Were Quantified By Densitometry Using Nih Imagej And Expressed As A Ratio Of Sirt1/B-Actin Which Is Normalized To Untreated Control Mice.The Amount Of Lipid Peroxidation Products In The Lungs Was Assayed As Thiobarburtic Acid Reacting Substances (Tbars)  Following Manufacturer'S Instructions.Statistical Analysis Of Significance Was Calculated By One-Way Analysis Of Variance Followed By Tukey'S Post Hoc Test, Anova On Ranks With Dunn'S Post Hoc Analysis Or By Mann-Whitney Test As Appropriate. Results Represent Mean \u00b1 Sd Or Sem, Or Range Of Data With Median.As observed previously , mice atNext, we examined the lung function of mice treated with quercetin (0.2 mg) or vehicle for 10 days starting one week after the four-week course of elastase/LPS-treatment. Compared to vehicle, mice receiving quercetin showed a rightward and downward shift in their volume-pressure curve Figure . Shifts iNOS mRNA and Hmox-1 mRNA determined. Compared to unexposed mice either treated with vehicle or quercetin, elastase/LPS-exposed mice treated with vehicle showed significantly increased levels of TBARS and iNos, and decreased levels of Hmox-1 mRNA. The ratio of iNos/Hmox-1 was increased . We examined whether reductions in S Figure . SimilarS Figure  and 5F. To determine the contribution of Sirt1 expression to the observed effects of quercetin on lung phenotype, elastase/LPS exposed mice were treated with polyethylene glycol or quercetin along with sirtinol, an inhibitor of Sirt1 activity . As obseChromatographic analysis of plasma obtained from mice treated with 0.2 mg quercetin for 10 days revealed a major peak which corresponded to quercetin aglycone and other minor peaks as we observed previously . Quantifin vitro cell culture system. Murine alveolar macrophages exposed to low levels of LPS for three days showed increased Mmp9 and Mmp12 mRNA levels, with a concomitant decrease in Sirt1 expression . On theal cells ,64. FurtIn summary, we have demonstrated that quercetin, a plant polyphenol, reduces oxidative stress, inflammation and MMP levels in elastase/LPS treated mice which show typical features of COPD. Quercetin also prevented progression of emphysema in these mice. Even after cessation of smoking, COPD patients show progressive emphysematous changes due to persistent oxidative stress and protease burden in the airways . The posThe authors declare that they have no competing interests.SG designed and performed the experiments, analyzed data and drafted the manuscript. ANF and SC and AC participated in the study design and assisted with ELISA and Western blot analysis. ATC carried out all the animal treatments, JRB determined the plasma quercetin levels. JLC, FJM, SZ and MBH participated in the review of the manuscript. US participated in study design, analysis of data and preparing the manuscript. All authors read and approved the final manuscript."}
+{"text": "Objective: Lactoferrin is a glycoprotein released from the secondary granules of activated neutrophils in the setting of infection. The purpose of this study was to determine if amniotic-fluid (AF) lactoferrin levels are elevated in preterm labor (PTL) patients with subclinical intraamniotic infection (IAI).Methods: AF samples were obtained from 186 pregnant patients withthe following characteristics: group 1 - term, no labor; group 2 - preterm, no labor; group 3 - PTL with IAI; group 4 - PTL without IAI. Lactoferrin levels were measured with an enzyme-linked immunosorbent assay (ELISA).Results: AF lactoferrin levels were elevated in normal gestation after 31 weeks (P < 0.0001). Lactoferrin levels were also higher in infected PTL patients compared with noninfected PTL patients at gestations \u226431 weeks (P = 0.005). An AF lactoferrin level of >2.5 \u03bcg/ml is highly suggestive of infection in PTL patients at <32 weeks, with an overall sensitivity of 82% and a specificity of 83%, when infection is defined as a positive AF culture or positive placental histology.Conclusions: AF lactoferrin levels increase after 31 weeks in normal gestations, but lactoferrin levels >2.5 \u03bcg/ml in PTL patients before this gestational age are highly suggestive of IAI. AF lactoferrin levels may be a useful clinical tool for selecting those PTL patients who might benefit from antimicrobial therapy, closer observation, or early delivery."}
+{"text": "This enzyme has been implicated in cellular immortalization and cellular senescence. Recently, a number of relevant genes have been cloned, including these encoding three major components of human telomerase: human telomerase RNA component (hTR), human telomerase reverse transcriptase (hTERT), and telomerase-associated protein-1 (TEP1). Also important are genes encoding human telomeric-repeat binding factor protein (TRF) 1 and 2. To clarify mechanisms regulating telomerase activity, we studied telomerase activity, the telomeric restriction fragment (TRF) length and gene expression of these telomerase components and the telomeric-repeat binding factor proteins in sequential observation following X-irradiation of cultured pancreatic cancer cells. We previously reported that PANC-1 cells are better able to tolerate thermal stress, antineoplastic drugs, and exposure to tumour necrosis factor than MIAPaCa-2 cells. MIAPaCa-2 and PANC-1 cells were exposed to X-irradiation, their telomerase activity was increased at 2 days and then decreased gradually. Of the three telomerase components, only hTERT mRNA expression showed parallel changes. TRF length was stable just before and after X-irradiation. Among binding factor proteins, TRF1 mRNA showed reciprocal changes possibly directed toward maintaining a stable telomere length. In this study, our results demonstrate that not only hTERT but also TRF1 are important regulator of telomerase activity. \u00a9 2001 Cancer Research Campaign"}
+{"text": "P< 0.01). The patients with positive mRNA before biopsy had higher sPSA (P< 0.001), and those after biopsy had higher sPSA and PSA density (PSAD) levels (P< 0.05). Positive PSA-mRNA cases had more cancer involved biopsy cores than the negative PSA-mRNA cases (P< 0.001). Although further investigations are needed, the present findings suggest that prostate biopsy might scatter prostate cells in the blood stream especially in cases with high sPSA and, thus, might contribute to tumour spreading in the cases of prostate cancer. \u00a9 2001 Cancer Research Campaign http://www.bjcancer.comTransrectal ultrasound (TRUS) guided prostate biopsy is standard diagnostic procedure for prostate cancer (PCa). However, possibility of dissemination of cancer cells by biopsy is not negligible. To investigate this possibility, we examined prostate specific antigen (PSA)-bearing cells in peripheral blood of the 108 patients before and after prostate biopsy. Peripheral blood samples were obtained from 108 patients with elevated serum PSA (sPSA) levels, who had undergone sextant prostate biopsy using TRUS. The presence of PSA-mRNA bearing cells was examined using the nested RT-PCR method enabling detection of one LNCaP cell diluted in 1\u2008ml of whole blood. Among 108 patients, 62 and 46 were diagnosed with benign prostatic hyperplasia (BPH) and PCa, respectively. PSA-mRNA was detected in 3 PCa cases but in no BPH patients before and after biopsy, and in 16 BPH (25.8%) and in 21 PCa (45.7%) patients only after biopsy ("}
+{"text": "Diffuse reflectance spectral analysis of PVC membranes containing thecalixarene hydroxamic acids show absorption bands at 485 nm and 504 nm followingcontact with aqueous solutions of Fe(III) and V(V) respectively. The pH dependency ofthis extractive selectivity is examined for Fe(III), Co(II), Pb(II), Mn(II), Cu(II) and Ni(II)using a solid phase extraction approach.   Spectrophotometric evidence for thecomplexation of Cu(II) in methanol by p-tertbutylcalix[4]arene tetraproline acid is alsoprovided.The functionalisation of macrocyclic p-tertbutylcalix[4]arenes at the lower rim withhydroxamic acid and proline hydroxamic acid groups gives the calixarenes chelatingproperties similar to siderophores.  The"}
+{"text": "Fifty-five consecutive patients with primary gastrointestinal intermediate or high grade non-Hodgkin's lymphoma were analysed to assess the efficacy of chemotherapy following surgical tumour resection. Histological subtypes were high grade (n = 18), intermediate grade (n = 36) and unclassified (n = 1). The majority of patients had gastric presentation (71%) and localised disease (84%). Surgery consisted of radical resection in 25 patients (45%) and partial or palliative excision in the remaining cases (22 and 8 respectively). Four subjects died within 3 months of surgery, two patients refused adjuvant chemotherapy and 49 completed the postoperative chemotherapeutic programme. Chemotherapy included either Fi2/74 (adriamycin + vincristine + bleomycin + cyclophosphamide + prednisone) or Fi3/74 (adriamycin + VM26 + bleomycin + cyclophosphamide + prednisone). Excluding the group who underwent radical tumour resection, postoperative chemotherapy induced complete remission in 81% of the remaining 30 patients. The 10-year cause-specific survival for the 53 treated patients was 76% (median follow-up 58 months) with a stable curve plateau after 80 months. Proportional-hazard multivariate statistics showed that survival was influenced by type of surgical resection (P less than 0.05) and stage (P less than 0.05), whereas age, sex and histological subtype were not influential. Our data indicate that chemotherapy following surgical resection of gastrointestinal lesion induces long-term remission in primary gastrointestinal lymphomas."}
+{"text": "Preincubation of etoposide-resistant human MCF7 breast cancer cells (MCF7/VP) with buthionine sulphoximine (BSO) resulted in their sensitisation to etoposide and vincristine. Chemosensitisation was accompanied by elevated intracellular drug levels. In contrast, simultaneous exposure to BSO did not result in increased drug accumulation. Similar, but quantitatively smaller, effects were also observed when sensitive wild-type MCF7/WT cells were treated with BSO. In agreement with its effect on drug accumulation, BSO pretreatment also increased VP-16-stimulated cleavable complex formation between DNA topoisomerase II and cellular DNA. BSO treatment also led to a significant increase in acid-precipitable VP-16 levels in MCF7/VP, but not MCF7/WT cells. In contrast, no clear effects of BSO on drug efflux were observed and drug retention was only minimally increased after BSO treatment of both MCF7/WT and MCF7/VP cells and no difference between the two cell lines was detected. Thus, chemosensitisation by BSO appeared to be mediated through increased intracellular drug concentrations and/or protein binding."}
+{"text": "Lifetime exercise activity has been linked to breast cancer risk among young women. However, no study has specifically evaluated whether lifetime exercise activity is related to the breast cancer risk of post-menopausal women. We conducted a population-based case-control study of post-menopausal white women  aged 55\u201364 who lived in Los Angeles County, California, USA to evaluate this relationship. Although neither exercise activity from menarche to age 40 years, nor exercise after age 40 separately predicted breast cancer risk, risk was lower among women who had exercised each week for at least 17.6 MET-hours  since menarche than among inactive women (odds ratio (OR) = 0.55; 95% confidence interval (CI) 0.37\u20130.83). Exercise activity was not protective for women who gained considerable (> 17%) weight during adulthood. However, among women with more stable weight, breast cancer risk was substantially reduced for those who consistently exercised at high levels throughout their lifetime , those who exercised more than 4 h per week for at least 12 years , and those who exercised vigorously (24.5 MET-hours per week) during the most recent 10 years . Strenuous exercise appears to reduce breast cancer risk among post-menopausal women who do not gain sizable amounts of weight during adulthood. \u00a9 1999 Cancer Research Campaign"}
+{"text": "The proposed metabolites demonstrated significant activity ascytotoxic, hypolipidemic, and anti-inflammatory agents. In cytotoxicity screens several of theproposed metabolites afforded better activity than the parent compound against the growth ofsuspended and solid tumor cell lines. Evaluation of in vivo hypolipidemic activity demonstratedthat the proposed metabolites of 1 were only moderately active and were generally less effectivethan the parent compound. Interestingly, L-phenylalanine methyl ester hydrochloride 3, whichcontains no boron atom, demonstrated equivalent hypolipidemic activity as the parent at 8mg/kg/day in CF1 male mice. As anti-inflammatory agents the proposed metabolitesdemonstrated variable capacities to reduce foot pad inflammation. These compounds weresimilarly effective as the parent 1 at blocking local pain and were generally better than the parentat protecting CF1 male mice from LPS induced sepsis.The metabolites of N-[(trimethylamineboryl)-carbonyl]-L-phenylalanine methyl ester"}
+{"text": "Novel immune-type receptor (NITR) genes are members of diversified multigene families that are found in bony fish and encode type I transmembrane proteins containing one or two extracellular immunoglobulin (Ig) domains. The majority of NITRs can be classified as inhibitory receptors that possess cytoplasmic immunoreceptor tyrosine-based inhibition motifs (ITIMs). A much smaller number of NITRs can be classified as activating receptors by the lack of cytoplasmic ITIMs and presence of a positively charged residue within their transmembrane domain, which permits partnering with an activating adaptor protein.Oryzias latipes) are located in three gene clusters on chromosomes 10, 18 and 21 and can be organized into 24 families including inhibitory and activating forms. The particularly large dataset acquired in medaka makes direct comparison possible to another complete dataset acquired in zebrafish in which NITRs are localized in two clusters on different chromosomes. The two largest medaka NITR gene clusters share conserved synteny with the two zebrafish NITR gene clusters. Shared synteny between NITRs and CD8A/CD8B is limited but consistent with a potential common ancestry.Forty-four NITR genes in medaka , T cell antigen receptor (TCR) and killer cell immunoglobulin-like receptor (KIR) genes. NITRs likely diverged along an independent pathway from that of the somatically rearranging antigen binding receptors but have undergone parallel evolution of V family diversity. The two major forms of novel immune-type receptors (NITRs) possess either one N-terminal ectodomain of the Ig variable (V) type, which may contain a joining (J) or J-like sequence or an N-terminal V domain plus a second C-terminal Ig domain of the intermediate (I) type. Most NITRs are predicted to encode type I transmembrane cell surface proteins that possess extracellular immunoglobulin (Ig) domains and can be classified as inhibitory or activating. A smaller number of NITR genes lack a transmembrane domain and are predicted to be secreted proteins ,2. NITRsSpheroides nephelus); more than 26 NITR genes were shown to be encoded in a single gene cluster . In gThe medaka genome encodes 44 NITR genes in 3 gene clusters. NITR genes in this species are divergent in sequence but structurally similar to those characterized in other fish species and include both inhibitory and activating forms. Comparative genomics reveals three possible scenarios in which the NITRs share a common genetic ancestry with CD8, CD28/CTLA4 or KIRs. A comparison of the complete sets of NITRs from medaka and zebrafish indicate that: 1) the two largest NITR gene clusters in medaka and zebrafish are derived from a whole chromosome duplication event, 2) as a gene family, the NITRs have experienced recent, species-specific \"birth and death\" events and 3) NITR family expansions have led to high levels of sequence variation between fish species.nitr1c and nitr3a as queries, putative medaka NITR genes were identified by searching version 1.0 of the medaka genome ; NITR1, transcript variant 2 [GenBank:EU419355]; NITR1, transcript variant 3 [GenBank:EU419356]; NITR2, transcript variant 1 [GenBank:EU419357]; NITR3, transcript variant 1 [GenBank:EU419358]; NITR4, transcript variant 1 [GenBank:EU419359]; NITR5, transcript variant 1 [GenBank:EU419360]; NITR5, transcript variant 2 [GenBank:EU419361]; NITR6, transcript variant 1 [GenBank:EU419362]; NITR8, transcript variant 1 [GenBank:EU419363]; NITR9, transcript variant 1 [GenBank:EU419364]; NITR11, transcript variant 1 [GenBank:EU419365]; NITR12, transcript variant 1 [GenBank:EU419366]; NITR14, transcript variant 1 [GenBank:EU419367]; NITR17, transcript variant 1 [GenBank:EU419368]; NITR18, transcript variant 1 [GenBank:EU419369]; NITR20, transcript variant 1 [GenBank:EU419370]; NITR22, transcript variant 1 [GenBank:EU419371]; NITR24, transcript variant 1 [GenBank:EU419372]; NITR24, transcript variant 2 [GenBank:EU419373]; and NITR24, transcript variant 3 [GenBank:EU419374].Sequence data described in this article have been deposited with the GenBank database under accession numbers: SD completed the gene prediction analyses. AKH, TMO and JAY cloned and sequenced the medaka NITR cDNAs. JAY conducted the phylogenetic analyses and comparative genomics. GWL and JAY interpreted data and wrote the manuscript. All authors have read and approved the final version of the manuscript.Predicted nucleotide sequence of NITRs based on the 1st draft of the medaka Hd-rR genome. Sequences are in FASTA format and include only full-length open reading frames. Predicted exons are color-coded .Click here for fileProtein sequences encoded by predicted NITR transcripts based on the 1st draft of the medaka Hd-rR genome. Sequences are in FASTA format and include translated sequences from Additional file 1. Predicted protein domains are color-coded .Click here for fileTetraodon nigroviridis encode multiple NITRs. Putative NITR genes and gene transcripts were identified from Tetraodon nigroviridis by a tBLASTn search using a Spheroides nephelus NITR1 protein sequence [GenBank:AAF28781] as a query. This strategy identified six candidate Tetraodon cDNAs  and a single genomic BAC clone B22K12 [GenBank:BX629355]. Only one of these cDNAs [GenBank:CR683680] appears to include an entire ORF. The partial protein sequences encoded by [GenBank:CR675622] and [GenBank:CR664265] are identical. The partial protein sequences encoded by [GenBank:CR725053] and [GenBank:CR724466] differ at three predicted amino acids residues; [GenBank:CR725053] is 10 amino acids longer at the amino-terminus. BAC B22K12 encodes 12 different NITR genes (designated by their nucleotide location in the reverse complement position within BAC B22K12). The predicted protein sequences of four representative NITR cDNAs are aligned relative to the predicted protein sequences of the NITRs encoded by BAC B22K12. Note that NITR-116851 (BAC B22K12) is predicted to encode a V domain and lacks an I domain.Click here for fileNITR10 amplified NITR24 transcripts. Primers designed to amplify NITR13 amplified NITR4 transcripts. Primers designed to amplify NITR16 amplified NITR1 transcripts.Oligonucleotide primer sequences used for nested 3' RACE. Predicted translational start sites are underlined. Primers designed to amplify Click here for fileClassification of medaka NITR cDNAs. Neighbor-joining tree of V domains encoded by out-bred, orange-red medaka NITR cDNAs (highlighted in yellow) and predicted NITR V domains from the genome of the inbred Hd-rR medaka. The number assigned to each interior branch corresponds to the bootstrap value. Branch lengths correspond to the number of amino acid substitutions estimated by Poisson correction, scale indicated below.Click here for fileNITR12 cDNA and genomic sequence. A partial alignment of NITR12 cDNA from out-bred, orange-red medaka to the predicted coding sequence of the NITR12a gene from inbred Hd-rR medaka. Predicted peptide sequence is shown above (cDNA) and below (genomic DNA) the alignment. The sequences shown include a portion of the transmembrane domain exon and the two cytoplasmic domain exons. Dashes indicate gaps in the nucleotide alignment. Asterisks indicate nucleotide identity. Stop codons are indicated by red highlighting in the nucleotide sequence and by dashes in the protein sequence. Downward arrowheads define predicted RNA splice sites. The NITR12 cDNA encodes additional nucleotide sequences that are not present in the genomic sequence (nucleotides highlighted in pink). Although the NITR12a genomic sequence is predicted to encode an ITIM (highlighted in yellow) and a second ITIM-like sequence , differences in the NITR12 cDNA alter the predicted ITIM sequence (LNYAAL to RYYAAL) and introduce a stop codon, preventing translation of the itim. The differences in predicted protein sequence likely reflect allelic variations between the out-bred, orange-red transcripts and Hd-rR genomic sequence.Variation between the medaka Click here for fileJoining (J) and J-like sequences in medaka NITRs. The consensus joining (J) sequence is FGXGTXLX(V/L). A J-like sequence possesses either motif FGXG or TXLX(V/L/I) or partial sequence of both motifs. Sequences were compiled from version 1.0 of the Hd-rR genomic sequence.Click here for fileITIM and ITIM-like sequences in medaka NITRs. Consensus ITIMs are defined as (S/I/V/L)xYxx(I/V/L) . An ITIMClick here for fileTransmembrane domains of activating NITRs. Transmembrane domains predicted by SMART software . ChargedClick here for fileCD8 locus does not display conserved synteny between medaka, zebrafish, stickleback and human. Although the CD8A and CD8B genes are tightly linked in (a) medaka, (b) zebrafish, (c) stickleback and (d) human, flanking genes are not well conserved between fish and human. Data were acquired using release NCBI 36 of the human genome, release 1.0 of the medaka genome, release Zv7 of the zebrafish genome and release 1.0 of the stickleback genome.The Click here for fileNITR24 is linked to CTLA4. (a) Human CTLA4 and CD28 are tightly linked. (b) In medaka CTLA4 is closely linked to NITR24. Gene names and chromosomal order were identified via Contig View within the Ensembl Genome Browser [CTLA4 and CD28 are not linked to NITR genes in zebrafish (not shown). Note that Ensembl misidentified medaka CTLA4 [CD28. Predicted protein structures are shown and structural features are as in Figure Medaka ka CTLA4  as CD28.Click here for file(a) Cladogram depicts conventional phylogenetic radiations of bony fish [Figure adapted from 35]. Colors denote species in which NITR genes and/or gene transcripts have been characterized. (b) Neighbor-joining tree of V domains encoded by 73 representative NITR genes. Ol, medaka (Oryzias latipes); Dr, zebrafish (Danio rerio); Ip, channel catfish ; Om, rainbow trout (Oncorhynchus mykiss); Sn, Southern pufferfish (Spheroides nephelus); Po Japanese flounder  and Tn, pufferfish (Tetraodon nigroviridis). Specific NITR gene numbers are indicated (e.g. medaka NITR8a = Ol 8a), except for Tetraodon sequences . Only one NITR gene family member is incorporated; additional family members are indicated in parenthesis. Activating NITR genes are indicated by a \"+\"; NITR families that possess both inhibitory and activating forms are indicated by a \"+/-\". NITR genes which encode a V and I domain in a single exon (\"V and I exons fused\") and \"No I domain\" are indicated. These labels are presented in parentheses for NITR families, which do not consistently conform to these definitions. Number assigned to each interior branch corresponds to the bootstrap value; bootstrap values less than 60 are not shown. Branch lengths correspond to number of amino acid substitutions estimated by Poisson correction, indicated below.Phylogenetic comparisons of published NITR V domains. Click here for file"}
+{"text": "A 34 months-old male patient with double inlet right ventricle with nonconfluent pulmonary arteries who underwent successful extracardiac fenestarated Fontan procedure using pre-designed T-shaped PTFE vascular graft after multi-step rehabilitation of the diminutive hilar pulmonary arteries. At first we performed 6 mm confluent pulmonary artery vascular graft implantation with 4 mm BT shunt at patient's 4 weeks old. At 9 months of patient, we upsized the confluent pulmonary arterial graft to 8 mm with bidirectional cavopulmonary connection, and, at 34 months, we performed extracardiac conduit Fontan procedure with pre-designed T-shape conduit including the confluent pulmonary arterial portion at last. Patient shows excellent functional status and development. Intrapericardial pulmonary artery creation is inevitable at neonatal period because patient had no confluent pulmonary artery and compliance of pulmonary vascular bed is not ready to accept pulmonary boold flow. Furthermore, adequate inflow pulmonary bed preparation for systemic venous return is crucial for definitive Fontan repair. In this situation, we thought multi-step approach would be helpful for the pulmonary bed growth.A 4 week-old male diagnosed with {S, X, D} type double inlet right ventricle, small left side atrioventricular valve, intact atrial septum, and non-confluent pulmonary arteries with diminutive hilar pulmonary arteries (2.7 and 3 mm diameter) supplied by bilateral patent ductuses was admitted to our unit. Because disconnected pulmonary arterial portion was too long and pulmonary artery hilar portion was too tiny to do unifocalization, we performed central pulmonary artery interposition between both pulmonary arterial hilar portion with 6 mm polytetrafluoroethylene(PTFE) vascular graft and left modified Blalock-Taussig shunt with 4 mm PTFE graft and ductus division under median full sternotomy. Postoperative arterial saturation was 85%.At 9 months, echocardiography and cardiac catheterizing showed that previous left modified BT shunt was stenotic at the anastomosis site with artificial confluent pulmonary artery (PTFE 6 mm vascular graft), and left pulmonary artery orifice was totally occluded, it's distal part was filled by collateral vessels. Both pulmonary arteries were relatively small to his weight and age. We changed 6 mm central pulmonary artery conduit wiht upsized 8 mm PTFE graft and right bidirectional cavopulmonary connection and atrial septectomy was performed concomitantly. During the interstage period after above 2 staged palliative operations, we used coumadin for anticoagulation, tried to maintain INR level between 1.5 and 2.0. At 32 months (14 kg), second cardiac catheterization revealed pressure gradient of 11 mmHg at anastomosis site between SVC (19 mmHg) and central pulmonary arterial conduit (8 mmHg), and multiple collaterals from both internal mammary arteries (fig. At 34 months(14.5 kg), extracardiac conduit Fontan operation was performed, replacing central pulmonary arterial tube graft with predesigned T-shaped conduit which was made of 12 mm and 20 mm sized PTFE grafts including 4.5 mm fenestration made of bovine pericardial skirt  and BT shunt (4 mm), pulmonary artery hilar area was well-grown for bidirectional cavo-pulmonary connection, at the 2Cardiac catheterization demonstrated 11 mmHg of pressure gradient between SVC and RPA and 92% of oxygen saturation at 32 months. Apparent facial edema lead to suspect SVC obstruction. From this, we decided to proceed the Fontan procedure with re-replacement of central pulmonary artery conduit. It is well known that pulmonary atresia with non-confluent pulmonary artery is risk factor for Fontan operation. In this condition, size of both pulmonary hilar and pulmonary artery resistance were very important for successful Fontan procedure [Pre-building T-shaped conduit composed of 12 mm PTFE tube for central pulmonary artery and 20 mm PTFE tube for extracardiac conduit outside the operation table was very helpful. This procedure shortened bypass time as well as the facilitated the anastomosis. Considering future growth-mismatch, enlargement of native hilar pulmonary arteries as large as possible was required to fit the end of 12 mm tube.2. Because the Z-value of left and right pulmonary arteries are -3 and -2 respectively with this conduit size at body surface area, so if there will not occur the stenosis in the conduit, we could use this conduit for a long time without conduit change. For extracardiac conduit, patient has 20 mm sized conduit now, this is about 85% of adult average IVC size, 24 mm. Also, if the stenotic complication may not occured, we could use this extracardiac conduit without change[Even though several options were reported graft material including pericardial roll, xenopericardium, etc, we used PTFE vascular graft, because pericardial conduit, especially, heterologous pericardial roll has several problem like calcification, thrombosis and bacterial infection -4. Havinut change. Untill We report a 34 months-old male patient with double inlet right ventricle associated with nonconfluent pulmonary arteries who underwent successful extracardiac fenestarated Fontan procedure using pre-designed T-shaped PTFE vascular graft after multi-step rehabilitation of the diminutive hilar pulmonary arteries."}
+{"text": "Haemophilus influenzae type b (Hib) polysaccharide (PRP) was measured in 42 children with acute lymphoblastic leukaemia (ALL) and 42 non-leukaemic hospital controls. Modelling anti-PRP concentrations as a function of age revealed that the slopes of the trend lines differed significantly between cases and controls (P = 0.05); anti-PRP concentrations were lower among younger cases, and higher among older cases, than among controls of the same ages. \u00a9 2001 Cancer Research Campaign http://www.bjcancer.comAntibody to"}
+{"text": "Ciona intestinalis (sea squirt). VDR genes have been detected in a wide range of vertebrates including jawless fish. To date, PXR genes have not been found in cartilaginous fish. In this study, the ligand selectivities of VDRs were compared in detail across a range of vertebrate species and compared with those of the Ciona VDR/PXR. In addition, several assays were used to search for evidence of PXR-mediated hepatic effects in three model non-mammalian species: sea lamprey (Petromyzon marinus), zebrafish (Danio rerio), and African clawed frog (Xenopus laevis).The vitamin D receptor (VDR) and pregnane X receptor (PXR) are nuclear hormone receptors of the NR1I subfamily that show contrasting patterns of cross-species variation. VDR and PXR are thought to have arisen from duplication of an ancestral gene, evident now as a single gene in the genome of the chordate invertebrate Human, mouse, frog, zebrafish, and lamprey VDRs were found to have similar ligand selectivities for vitamin D derivatives. In contrast, using cultured primary hepatocytes, only zebrafish showed evidence of PXR-mediated induction of enzyme expression, with increases in testosterone 6\u03b2-hydroxylation activity (a measure of cytochrome P450 3A activity in other species) and flurbiprofen 4-hydroxylation activity (measure of cytochrome P450 2C activity) following exposure to known PXR activators. A separate assay in vivo using zebrafish demonstrated increased hepatic transcription of another PXR target, multidrug resistance gene (ABCB5), following injection of the major zebrafish bile salt, 5\u03b1-cyprinol 27-sulfate. The PXR target function, testosterone hydroxylation, was detected in frog and sea lamprey primary hepatocytes, but was not inducible in these two species by a wide range of PXR activators in other animals. Analysis of the sea lamprey draft genome also did not show evidence of a PXR gene.Our results show tight conservation of ligand selectivity of VDRs across vertebrate species from Agnatha to mammals. Using a functional approach, we demonstrate classic PXR-mediated effects in zebrafish, but not in sea lamprey or African clawed frog liver cells. Using a genomic approach, we failed to find evidence of a PXR gene in lamprey, suggesting that VDR may be the original NR1I gene. The vitamin D receptor VDR, NR1I1) and pregnane X receptor  are members of the nuclear hormone receptor (NR) superfamily of ligand-activated transcription factors. NRs work in concert with co-activators and co-repressors to regulate gene expression I1 and pr. NRs sha2-vitamin D3  with high affinity and mediate classic calcitriol effects such as regulation of calcium and phosphate homeostasis  , zfVDR (amino acid residues 121\u2013453) [Genbank: AF164512], and lampVDR (amino acid residues 92\u2013406) [Genbank: AY249863] were inserted into the pM2-GAL4 vector to create GAL4/LBD chimeras. Details of the cloning of the ciVDR/PXR are being described in a separate report. The ciVDR/PXR LBD construct contains amino acid residues 57\u2013391 [Genbank: BR000137].Plasmids containing human VDR, zebrafish PXR, human organic anion transporting polypeptide (SLC21), as well as the reporter constructs tk-UAS-Luc and CYP3A4-PXRE-Luc, and 'empty' vectors pCDNA, PsG5, and PM2 were generously provided by SA Kliewer, JT Moore, and LB Moore . Mouse VDR (IMAGE clone 3710866) and pCMV-sport6 vectors were obtained from Invitrogen . The expression vectors were either full-length receptors  or GAL4/VDR chimeras that contain only the LBD of the VDR . For the full-length expression vectors, the reporter plasmid was CYP3A4-PXRE-Luc, a construct that contains a promoter element from CYP3A4 (recognized by VDR DBDs) driving luciferase expression. For the GAL4/LBD expression constructs, the reporter plasmid was tk-UAS-Luc, which contains GAL4 DNA binding elements driving luciferase expression. xlVDR was cloned by RT-PCR from total RNA extracted from the frog A6 cell line. zfVDR was cloned by RT-PCR from total RNA extracted from the ZFL liver cell line. lampVDR was cloned by PCR from a full-length sea lamprey VDR clone, described as the 'insertless' full-length cDNA -carbazole 20 \u03bcM; zebrafish PXR \u2013 20 \u03bcM 5\u03b1-androstan-3\u03b1-ol. All comparisons to maximal activators were done within the same microplate. Luciferase data were normalized to the internal \u03b2-galactosidase control and represent means \u00b1 SD of the assays.To facilitate more reliable cross-species comparisons, complete concentration-response curves for ligands were determined in the same microplate as determination of response to a maximal activator. This allows for determination of relative efficacy, \u03b5 defined as the maximal response to test ligand divided by maximal response to a reference maximal activator (note than \u03b5 can exceed 1). The maximal activators and their concentrations were as follows: hVDR, xlVDR, zfVDR \u2013 1 \u03bcM calcitriol (BIOMOL); mVDR and lampVDR \u2013 0.5 \u03bcM calcitriol; ciVDR/PXR \u2013 6-formylindolo- , rhesus monkey VDR [Ensembl: ENSMMUT00000009414], cow VDR [Ensembl: ENSBTAT00000021832], dog VDR [Ensembl: ENCAFT00000014497], mouse VDR [Genbank: NM_009504], chicken VDR [Genbank: AF011356], Japanese quail VDR [Genbank: U12641], Xenopus laevis VDR [Genbank: U91849], fugu VDR [Ensembl: NEWSINFRUT00000138841], bastard halibut [Genbank: AB037674], zebrafish VDR [Genbank: AF164512], medaka VDR [Ensembl: ENSORLT00000001311], sea lamprey VDR [Genbank: AY249863], Ciona intestinalis VDR/PXR [Genbank: BR000137], human CAR [Genbank: NM_005122], rhesus CAR [Genbank: AY116212], cow CAR [Ensembl: ENSBTAT00000012145], dog CAR [Ensembl: ENSCAFT00000020528], Baikal seal [Genbank: AB109553], mouse CAR [Genbank: NM_009803], pig CAR [Genbank: AB214979], opossum CAR [Ensembl: ENSMODT00000006393], human PXR [Genbank: AF061056], rhesus monkey PXR [Genbank: AF454671], cow PXR [Ensembl: ENSBTAT00000026059], mouse PXR [Genbank: AF031814], rabbit PXR [Genbank: AF188476], opossum PXR [Ensembl: ENSMODT00000023109], chicken PXR [Genbank: AF276753], Xenopus laevis PXR\u03b1 [Genbank: BC041187], Xenopus tropicalis PXR [Ensembl: ENSXETT00000039109], fugu PXR [Ensembl: NEWSINFRUT00000171584], medaka PXR [Ensembl: ENSORLT00000022473], Tetraodon nigriviridis PXR [Ensembl: GSTENT00026021001], zebrafish PXR , ixotid tick (Amblyomma americanum) ecdysone receptor [Genbank: AF020187], and purple sea urchin (Strongylocentrotus purpuratus) liver \u00d7 receptor [Genbank: XM_774904]. Sequences were aligned using ClustalW [The following sequences were used for phylogenetic analysis (some links are from the Ensembl database ): human ClustalW  and manuin vivo studies in zebrafish. LRH purified bile salts from bile of various animals and provided perspective on evolution of bile salt and steroids. NB provided zebrafish, expert guidance on zebrafish work, and key reagents for the zebrafish cell culture studies. SRM, JO, and RV performed the testosterone 6\u03b1-hydroxylation and flurbiprofen hydroxylation assays. MDK conceived of the study, performed the functional assays and phylogenetic analyses, and drafted the manuscript. All authors contributed to, read, and approved the final manuscript.EJR performed molecular biology, prepared all the primary cultures of zebrafish, African clawed frog, and sea lamprey cells, and helped draft the manuscript. ACDS and JJM performed the Sequence alignment of PXRs and VDRs.Click here for fileConservation of VDR and PXR ligand-binding residues across species.Click here for fileXenopus laevis, zebrafish, and sea lamprey VDRs.Additional data for Click here for fileEffect of compounds on testosterone hydroxylation in primary cultures of African clawed frog hepatocytes.Click here for file"}
+{"text": "Sir,in vitro application of EGFR-TKIs before chemotherapeutic agents represses EGFR degradation (We have read the recent interesting minireviews by radation  and RAB1radation . Thus, m"}
+{"text": "The hepatic subcellular distribution, binding and persistence of 3H-7,12-dimethylbenz(a)anthracene were compared in partially hepatectomized rats and in intact controls. By 2 weeks after injection, intact liver homogenates contained only 9% of the total radioactivity present 4 h after injection; regenerated liver contained 60% in spite of a tripling in liver mass during this time. Cell fractions isolated from regenerated liver had 9-59 fold greater hexane extractable specific activities than those from intact liver. The radioactivity present in hexane extracts co-chromatographed with a 3H-7,12-dimethylbenz(a)anthracene standard. Preliminary experiments demonstrated that liver microsomes isolated from DMBA treated partially hepatectomized animals metabolized less DMBA in vitro than did microsomes isolated from DMBA treated intact animals. The greater persistence of unmetabolized DMBA may be related to the greater carcinogenicity of this compound for regenerating, as compared with intact, rat liver."}
+{"text": "Salmonella enterica serotype Baildon, a rare serotype, was recovered from 86 persons in eight states; 87% of illnesses began during a 3-week period ending January 9, 1999. Raw restaurant-prepared tomatoes were implicated in multiple case-control studies. Contamination likely occurred on the farm or during packing; more effective disinfection and prevention strategies are needed."}
+{"text": "The Nd-YAG laser has good tissue penetration and coagulation effects thus has become animportant weapon for photoresection of tracheobronchial obstructive lesions since 1980.        Treatment of benign lesions including benign tumors and scar tissues using the Nd-YAG         laser has good results. In the treatment of malignant tumors however, it has a lowereffectivity rate when compared to benign lesions. From July 1984 to September 1995, atotal of 65 patients were treated with Nd-YAG laser for tracheobronchial obstruction.There were 32 (49%) malignant tumors and 33 (51%) benign lesions. 116 resections wereperformed in 48 patients using the non-contact Nd-YAG laser  before1992. Thereafter, another 41 resections were performed in 17 cases using contact Nd-YAG laser . The overall effectivity rate was 60%. The effectivity rate forbenign lesions was 81.3% and 39.4% for malignant tumor. The effectivity rate betweennon-contact and contact Nd-YAG laser was not significantly different."}
+{"text": "A sentinel group of primary-care physicians in Wales actively reported cases of acute bloody diarrhea from February 1997 through December 1998. The estimated annual rate was 18 cases per 100,000 population. Most (80%) cases were due to Campylobacter or Salmonella; however, 18% were undiagnosed."}
+{"text": "Enzyme-linked immunosorbent assay, Western blot, and virus neutralization assays indicated that red colobus monkeys in Kibale National Park, western Uganda, had antibodies to a virus that was similar, but not identical, to known orthopoxviruses. The presence of a novel poxvirus in this endangered primate raises public health and conservation concerns. Chordopoxviridae contains emerging pathogens of considerable concern, both because of their historic impact on global human health and because of their zoonotic potential  from Kibale National Park, western Uganda  were sampled from Kibale National Park, western Uganda (Macaca mulatta) immunoglobulin (Ig) G , which readily detected antibodies of other primate species, including red colobus monkeys and humans. By using this approach, samples from 8 (26%) of 31 red colobus plasma scored positive (>200 ELISA units [EU]), 21 (68%) of 31 scored seronegative (<100 EU), and 2 (6%) of 31 had equivocal results (100\u2013200 EU) (A vaccinia virus (VV) ELISA was used as an initial screening test to detect antipoxvirus antibodies. VV-reactive antibodies were detected with horseradish peroxidase (HRP)\u2013conjugated polyclonal goat anti\u2013rhesus macaque  .8 PFU/mL before addition to virus-coated ELISA plates ( A). However, analysis of samples from 10 red colobus with detectable anti-VV antibody responses , and probed with plasma  before addition of HRP-conjugated polyclonal goat antihuman Ig G  and chemiluminescent detection  . VV-immuOrthopoxvirus genus elicit cross-neutralizing antibodies against other members of the same genus. To determine if the red colobus were infected with an orthopoxvirus or a more distantly related poxvirus, plaque reduction neutralization assays were performed using 100 PFU of MPV, VV, or CPV. Plasma samples from all 31 red colobus were tested, and all exhibited a neutralizing titer 50 of <20 against MPV, VV, or CPV (data not shown). These findings suggest that although the monkeys were infected with a poxvirus with serologic cross-reactivity to VV   to determine the identity of the poxvirus/poxviruses that have infected the red colobus described here. In this light, we note that tanapox, a zoonosis of suspected primate origin -reactive antibodies in red colobus. Vaccinia virus (VV)-coated ELISA plates were used to test for antipoxvirus antibodies by endpoint dilution analysis as previously described (7). As positive controls, a representative VV-immune human (VV+ human) at 1 y postvaccination with DryVax  and a modified vaccinia Ankara (MVA)-immune rhesus macaque (MVA+ RM) at 2 months post-vaccination with MVA are included for comparison. Negative controls included 2 unvaccinated human participants (OPV- human) and 6 unvaccinated rhesus macaques (OPV- RM). The dashed line indicates the cut-off value for a seropositive antibody response (200 ELISA units)."}
+{"text": "In this paper we investigate the reactivity pattern of T cells from stomach carcinoma patients against autologous tumour cells. T cells obtained from the tumour environment, tumour-draining lymph nodes and peripheral blood were cloned in 78 patients with stomach cancer and anti-tumour cytotoxic T lymphocytes (CTLs) precursor frequencies were assessed in each sample by using limiting dilution analysis. When tumour-specific CTLs were tested for specific T-cell killing by using only low doses of Interleukin 2 (100 U ml-1), a moderate rate of proliferation frequency of T cells (0.047) and specific cytotoxicity (12%) were observed in lymph node populations. When both IL-2 and autologous tumour cells in mixed lymphocyte tumour cultures (MLTCs) were used for stimulation, a dramatic increase in number (0.1) and in specific lytic activity (46%) could be measured. No effect or specific activity to tumour cells was observed with peripheral blood lymphocytes and tumour-infiltrating lymphocytes."}
+{"text": "Bacterial meningitis (BM) is a severe infection responsible for high mortality and disabling sequelae. Early identification of patients at high risk of these outcomes is necessary to prevent their occurrence by adequate treatment as much as possible. For this reason, several prognostic models have been developed. The objective of this study is to summarize the evidence regarding prognostic factors predicting death or sequelae due to BM in children 0-18 years of age.A search in MEDLINE and EMBASE was conducted to identify prognostic studies on risk factors for mortality and sequelae after BM in children. Selection of abstracts, full-text articles and assessment of methodological quality using the QUIPS checklist was performed by two reviewers independently. Data on prognostic factors per outcome were summarized.Streptococcus pneumoniae, young age, male gender, several cerebrospinal fluid (CSF) parameters and white blood cell (WBC) count.Of the 31 studies identified, 15 were of moderate to high quality. Due to substantial heterogeneity in study characteristics and evaluated prognostic factors, no quantitative analysis was performed. Prognostic factors found to be statistically significant in more than one study of moderate or high quality are: complaints >48 hours before admission, coma/impaired consciousness, (prolonged duration of) seizures, (prolonged) fever, shock, peripheral circulatory failure, respiratory distress, absence of petechiae, causative pathogen Although several important prognostic factors for the prediction of mortality or sequelae after BM were identified, the inability to perform a pooled analysis makes the exact (independent) predictive value of these factors uncertain. This emphasizes the need for additional well-conducted prognostic studies. Bacterial meningitis (BM) is a severe infection of the central nervous system which occurs especially in children <5 years of age. Although the occurrence of negative consequences of BM in developed countries is strongly reduced by vaccination strategies, antibiotic treatment and good care facilities, BM is still responsible for substantial morbidity and mortality in both developing and developed countries -3.The mortality rate is approximately 5%, and the long-term morbidity, mainly consisting of persistent neurological sequelae, is 15% ,4-6. SenIn pediatric care, the goal must be to prevent these sequelae as much as possible. Therefore, early recognition of children with BM with high risk for the development of sequelae is mandatory ,12-15. Fth 2009 was conducted to identify prognostic studies on mortality or various sequelae after BM in children. The search focused on BM using terms for the 10 most common causative pathogens according to the Netherlands Reference Laboratory for Bacterial Meningitis . Th. Th39]. The QUIPS contains six categories assessing (1) bias due to patient selection, (2) attrition, (3) measurement of prognostic factors, (4) outcome measurement, (5) confounding on statistical analysis, and (6) confounding on presentation. The items on confounding were considered irrelevant for our study because in studies regarding prognosis, the design to predict a specific outcome based on a combination of several possible prognostic factors, confounding is not an issue. The remaining 17 items of the five categories were each scored to assess the quality of the included study. High quality ('+') was scored when there was low risk of bias, moderate quality ('+/-') with moderate risk, and low quality ('-') when there was high risk of bias.To strengthen the discriminative capacity of the QUIPS we developed a scoring algorithm. All five categories were given a maximum of 15 points each, equally divided over all items per category. For all items we assigned 5 points in case of low risk of bias and 2.5 and 0 in case of moderate and high risk of bias, respectively. Except for category 1 (patient selection bias) which contained five instead of three items. Here we assigned 3 points in case of low risk of bias and 1.5 and 0 in case of moderate and high risk of bias, respectively. A total score, with a maximum of 75 points, was calculated by summing up the scores per item. A priori, we chose to consider \u226560 points (\u226580% of the maximum attainable score) as high quality, between 45 and 60 points (\u226560% of the maximum attainable score) as moderate/high quality and <45 points as low quality studies.Of the selected studies, data were extracted regarding study population , causative pathogen, design (prospective or retrospective), duration of follow-up, method of analysis (uni- or multivariate), outcome measures and independent statistically significant prognostic factors from multivariate analysis or, if not available, from univariate analysis (p < 0.05). To facilitate interpretation and comparison of the results, data were categorized per outcome: (1) hearing loss, (2) mortality, (3) neurological sequelae, or (4) poor outcome when the original study made no distinction between mortality and neurological sequelae. Both short- and long-term outcomes were included.This review did not aim to analyze original study data, therefore only the data presented in the manuscripts was used. Authors were not approached for insight in their data.Due to heterogeneity in study design, study population and analyses of the included studies, no quantitative analysis was performed. Instead, the prognostic factors predictive for mortality or sequelae after BM were summarized per outcome category. Prognostic factors reported in different papers on the same cohort were counted once. Due to the large variety in proposed factors found, only those factors found significant (p < 0.05) in more than one study of moderate/high quality were presented.Figure The results of the quality assessment are presented in Table Studies of moderate/high quality scored well on patient selection, outcome measurement, statistical analysis and presentation, and relatively well on prognostic factor measurement. However, many moderate/high quality studies scored poor on attrition. Studies classified as low quality scored relatively well on patient selection, but poor on all other categories. A poor score on prognostic factor measurement was often due to the fact the studies did not mention all factors considered in their analysis but presented only those factors found significant.et al.  OR \"Meningitis, Bacterial/complications\"[Mh] OR \"Meningitis, Bacterial/diagnosis\"[Mh] OR \"Meningitis, Bacterial/epidemiology\"[Mh] OR \"Meningitis, Bacterial/physiopathology\"[Mh] OR \"Meningitis, Bacterial/psychology\"[Mh] OR \"Meningitis, Meningococcal\"[Mh] OR \"Meningitis, Meningococcal/complications\"[Mh] OR \"Meningitis, Meningococcal/diagnosis\"[Mh] OR \"Meningitis, Meningococcal/mortality\"[Mh] OR \"Meningitis, Pneumococcal\"[Mh] OR \"Meningitis, Pneumococcal/complications\"[Mh] OR \"Meningitis, Pneumococcal/diagnosis\"[Mh] OR \"Meningitis, Pneumococcal/mortality\"[Mh] OR \"Meningitis, Escherichia coli\"[Mh] OR \"Meningitis, Escherichia coli/complications\"[Mh] OR \"Meningitis, Escherichia coli/diagnosis\"[Mh] OR \"Meningitis, Escherichia coli/mortality\"[Mh] OR \"Meningitis, Haemophilus\"[Mh] OR \"Meningitis, Haemophilus/complications\"[Mh] OR \"Meningitis, Haemophilus/diagnosis\"[Mh] OR \"Meningitis, Haemophilus/mortality\"[Mh] OR \"Meningitis, Listeria\"[Mh] OR \"Meningitis, Listeria/complications\"[Mh] OR \"Meningitis, Listeria/diagnosis\"[Mh] OR \"Meningitis, Listeria/mortality\"[Mh] OR meningitis[tw] AND Morbidity[Mh:noexp] OR mortality[Mh:noexp] OR \"cause of death\"[Mh] OR survival rate [Mh] OR prognos*[tw] OR predict*[tw] OR course*[tw] OR longitudinal[tw] OR follow-up[tw] OR followup[tw] OR follow up[tw] OR cohort*[tw] OR survival[tw] OR cohort studies[mh] OR follow-up studies[mh] NOT #1 AND #2 NOT #3 OR ('epidemic meningitis'/exp OR 'epidemic meningitis')) OR ('meningitis'/de OR 'meningitis') AND  OR meningitides OR ('streptococcus'/de OR 'streptococcus') OR pneumoniae OR ('haemophilus'/de OR 'haemophilus') OR hib OR influenzae OR ('listeria'/de OR 'listeria') OR monocytogenes OR ('escherichia'/de OR 'escherichia') OR coli OR agalactiae OR pyogenes OR ('staphylococcus'/de OR 'staphylococcus') OR aureus OR ('cryptococcus'/de OR 'cryptococcus') OR neoformans)). include text word((('morbidity'/de OR 'morbidity') OR  OR ('cause of death'/exp OR 'cause of death') OR  OR  OR ('follow up'/exp OR 'follow up')) OR prognos* OR predict* OR course* OR cohort* OR longitudinal OR ('follow up'/de OR 'follow up') OR ('followup'/de OR 'followup') OR ). include text word(('literature'/exp OR 'literature'/de) OR ('case report'/exp OR 'case report'/de) OR ('directory'/exp OR 'directory'/de) OR  OR ('interview'/exp OR 'interview'/de) OR  OR ('reading'/exp OR 'reading'/de) OR ('publication'/exp OR 'publication'/de) OR ('patient education'/exp OR 'patient education'/de) OR ('organization'/exp OR 'organization'/de) OR ('consensus development'/exp OR 'consensus development'/de) OR ('practice guideline'/exp OR 'practice guideline'/de)) NOT  NOT ('human'/exp OR 'human'/de))#1 AND #2 NOT #3The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2334/10/232/prepub"}
+{"text": "The human restriction factor TRIM5\u03b1 may play an important role in regulation of the human immunodeficiency virus (HIV). It is unclear whether non-synonymous single nucleotide polymorphisms (nsSNP) in TRIM5\u03b1 affect the clinical course of HIV infection.We surveyed the literature for TRIM5\u03b1 nsSNPs and used comparative sequence analysis to predict the effect of each polymorphism on protein function. Twenty-eight nsSNPs were identified with available functional data, clinical data, or both. The four comparative method programs assessed included SIFT, PolyPhen, A-GVGD, and average BLOSUM62 pairwise score. Two common polymorphisms, H43Y and R136Q, were predicted to be benign based on comparative sequence analysis. The nsSNPs P323R, K324N, I328M, G330Q, R332P, I348V, and T369S were all predicted to affect protein function.Comparative sequence analysis offers a functional tool to analyze unknown nsSNPs in TRIM5\u03b1. Human immunodeficiency virus type 1 (HIV-1) infection depends on both viral and human genetic factors , APOBEC3tripartite motif restriction factor TRIM5\u03b1 is a cytoplasmic and nucleolic protein that restricts viral infection by interfering with the capsid protein, promoting premature disassembly [The assembly ,7. The rassembly . The SPRassembly ,10. The assembly ,10,11. Dassembly -16. The ) [) [) [Comparative sequence analysis is a powerful technique that can predict whether an nsSNP is likely to affect protein function. These methods rely on the fact that critical residues for function are conserved across different genomes and should not vary -19. Thes) ; (2) Pol) [) ; (3) A-G) [) [) .The accuracy of any one method for predicting a non-synonymous SNP as either deleterious (affecting protein function) or tolerant (benign) is approximately 80%. When all four methods agree, the predictive value is greater than 90% . The goaAmino acid sequence alignments were constructed using the standard program ClustalW as previously described . HomologHomo sapiens (gi 48994821), Pan paniscus (gi 122145800), Pan troglodytes (gi 60593103), Gorilla gorilla (gi 56480705), Pongo pygmaeus (gi 122143969), Pongo abelii (gi 75060761), Symphalangus syndactylus (gi 122143726), Nomascus leucogenys (gi 156079722), Hylobates lar (gi 122143029), Colobus guereza (gi 75060798), Macaca mulatto (gi 62548080), Bunopithecus hoolock (gi 122144995), Pygathrix nemaeus (gi 75060797), Cercocebus torquatus (gi 118772044), Macaca fascicularis (gi 75060455), Papio anubis (gi 162951988), Macaca assamensis (gi 122144997), Macaca nemestrina (gi 122146076), Erythrocebus patas (gi 75060791), Chlorocebus aethiops (gi 48994825), Cercopithecus tantalus (gi 47559193), Chlorocebus pygerythrus (gi 75060767), Erythrocebus patas (gi 58379053), Callithrix jacchus (gi 167427342), Callithrix pygmaea (gi 75060793), Pithecia pithecia (gi 75060790), Saguinus oedipus (gi 122145799), Saguinus labiatus (gi 75060764), Callicebus donacophilus (gi 75060786), Saimiri boliviensis (gi 58379043), Saimiri sciureus (gi 75060788), Ateles geoffroyi (gi 75060789), Lagothrix lagotricha (gi 75060785), Aotus trivirgatus (gi 51317461), Alouatta sara (gi 75060794), Equus caballus (gi 149719383), Bos taurus (gi 77736574), Mus musculus (gi 31982207), Rattus norvegicus (gi 109459178), and Gallus gallus (gi 150247142).The TRIM5\u03b1 sequence alignment consisted of 40 sequences: TRIM5\u03b1 nsSNPs were evaluated by four publicly available methods as previously described : 1) AverComparative sequence analysis is a powerful tool for the analysis of nsSNPs in the human genome. A large variety of organisms selected for sequence analysis means fewer sequences will be needed to make inferences secondary to long divergence times and increased number of mutations ,26. Too Twenty-eight amino acid mutations in TRIM5\u03b1 were identified in the literature, twenty-one of which are known to be nsSNPs in the human population Table . Eight oThe nsSNP H43Y of the RING region may be important in protein function, specifically E3 ligase activity ,16,23. USimilar to H43Y, data regarding R136Q has shown conflicting results . ClinicTwo limitations to this study are the paucity of TRIM5\u03b1 gene sequences available and the lack of structural data available on TRIM5\u03b1. Although the number of sequences is sufficient as discussed above, a greater variety of species would allow better alignments based on sensitivity and specificity plots . FurtherComparative sequence analysis suggests that neither H43Y nor R136Q affect TRIM5\u03b1 protein function. We identified other nsSNPs that may affect TRIM5\u03b1 activity and should be analyzed in further clinical and laboratory studies.The author declares that they have no competing interests.PC was the sole contributor to the contents of this article."}
+{"text": "After injection of 111In-labelled DTPA-D-Phe1-octreotide, intraoperative tumour localisation was performed using a scintillation detector in 23 patients with neuroendocrine tumours. Count rates from suspect tumour lesions and adjacent normal tissue were expressed as a ratio before (Rin situ) and after (Rex vivo) excision. 111In activity concentration ratios of tumour tissue to blood (T/B) were determined in a gamma counter. In patients with midgut carcinoids, , false Rin situ recordings were found in 4/29 macroscopically identified tumours. T/B ratios were all high (27-650). In patients with medullary thyroid carcinomas (eight out of ten scintigraphy positive), misleading Rin situ results were found in 4/37 macroscopically identified tumours. T/B ratios were lower (3-39) than those seen in midgut carcinoids. Two out of four patients with endocrine pancreatic tumours had positive scintigraphy, reliable intraoperative measurements and very high T/B ratios (910-1500). One patient with a gastric carcinoid had correct measurements in situ and ex vivo with high T/B ratios (71-210). In situ measurements added little information to preoperative scintigraphy and surgical findings using the present detection system. Rex vivo measurements were more reliable. The very high T/B ratios seen in midgut carcinoids and some endocrine pancreatic tumours would be favourable for future radiation therapy via somatostatin receptors."}
+{"text": "Thirty-five patients with prostate cancer were examined for micrometastases to the bone marrow using reverse transcription-polymerase chain reaction (RT-PCR) with primers specific for the prostate-specific antigen (PSA) gene. Of nine patients with bone metastases detectable by bone scan imaging, five patients had PSA mRNA expression in the bone marrow detectable by RT-PCR. Of 26 patients with negative bone scan findings, seven patients had PSA mRNA expression detectable in the bone marrow. RT-PCR could detect micrometastatic prostate cancer cells in the bone marrow that were not detectable by bone scan imaging. Of 16 patients with a serum PSA concentration of 25 ng ml(-1) or greater, only nine (56.3%) had bone metastases detected by bone scans. Of the remaining seven patients, five had micrometastases to the bone marrow detected by RT-PCR. Overall, 14 of 16 patients (87.5%) with a serum PSA concentration of 25 ng ml(-1) or greater had metastatic bone diseases including bone marrow micrometastases. Of 19 patients with a serum PSA concentration of less than 25 ng ml(-1), two (10.5%) had only micrometastatic disease detected by RT-PCR. A significant correlation was observed between the incidence of bone involvement and the serum PSA concentration. This study suggests that RT-PCR will potentially develop into a relevant tool to assess bone involvement including bone marrow micrometastases and establish a precise correlation between serum PSA concentration and metastatic bone disease in patients with prostate cancer."}
+{"text": "Biodistribution of chimeric mouse/human monoclonal antibody against non-specific cross-reacting antigen (chNCA Ab) was studied in athymic mice and patients with metastatic bone disease. 99mTc-chNCA Ab showed a high labelling efficiency, stability and also a high binding ratio to human granulocytes. Since NCA showed cross-reactivity with carcinoembryonic antigen (CEA), animal experiments showed that 99mTc-chNCA Ab was accumulated in the xenografted tumour which expressed CEA, suggesting the preserved immunoreactivity of labelled materials. In the clinical study, injected 99mTc-chNCA Ab formed a high molecular weight complex immediately after intravenous administration and was trapped mainly in liver. The first-phase plasma half-life was 6.4 +/- 1.1 min. None of the patients showed adverse reaction or human antimurine or anti-chimeric antibody in their serum. 99mTc-chNCA Ab demonstrated remarkably different biodistribution between patients and the animal model and showed different pharmacokinetics from other murine and chimeric Abs reported previously. For safety HPLC analysis should be performed before clinical radioimmunodetection or radioimmunotherapy by incubating radiolabelled MAb with human serum under strict conditions."}
+{"text": "Sixteen chronic myeloid leukaemia (CML) patients in remission were tested with solubilized membrane antigens from CML leukaemic cells, CML blasts, AML blasts and ALL blasts for cellular immunity in vitro by lymphocyte transformation (LT) and leucocyte migration inhibition (LMI) assays. Twelve CML patients in remission were tested with allogeneic PHA-transformed normal lymphoblasts. As controls, peripheral-blood leucocytes from 9 healthy persons were tested with the same antigen preparations. It was seen that 8/16 (50%) CML patients responded to CML antigens by both LT and LMI assays, while 5/16 (31%) patients reacted to CML blasts and 44% (7/16) patients reacted to AML blast antigens. It was interesting to note that 5/11 (45%) CML patients reacted to ALL blast antigens by both assays. One out of 12 patients reacted to PHA-transformed lymphoblasts. None of the healthy controls reacted to leukaemia-associated antigens. The results suggest the sharing of antigens between myeloid leukaemic cells, myeloid blasts and lymphoid blasts."}
+{"text": "The diaminocyclohexane platinum (Pt(DACH)) derivatives ormaplatin and oxaliplatin have caused severe and dose-limiting peripheral sensory neurotoxicity in a clinical trial. We hypothesized that this toxicity could vary in relation to the biotransformation and stereochemistry of these Pt(DACH) derivatives. We prepared pure R,R and S,S enantiomers of ormaplatin (Pt(DACH)Cl4), oxaliplatin (Pt(DACH)oxalato) and their metabolites (Pt(DACH)Cl2 and Pt(DACH)methionine) and assessed their peripheral sensory neurotoxicity and tissue distribution in the rat and in vitro anti-tumour activity in human ovarian carcinoma cell lines. The R,R enantiomers of Pt(DACH)Cl4, Pt(DACH)oxalato and Pt(DACH)Cl2, induced peripheral sensory neurotoxicity at significantly lower cumulative doses (18 +/- 5.7 vs 32 +/- 2.3 micromol kg(-1); P < 0.01) and at earlier times  during repeat-dose treatment than the S,S enantiomers. Pt(DACH)methionine enantiomers showed no biological activity. There was no difference between Pt(DACH) enantiomers in the platinum concentration in sciatic nerve, dorsal root ganglia, spinal cord, brain or blood at the end of each experiment. Three human ovarian carcinoma cell lines  showed no (or inconsistent) chiral discrimination in their sensitivity to Pt(DACH) enantiomers, whereas two cell lines (CH-1 and CH-1cisR) showed modest enantiomeric selectivity favouring the R,R isomer (more active). In conclusion, Pt(DACH) derivatives exhibit enantiomeric-selective peripheral sensory neurotoxicity during repeated dosing in rats favouring S,S isomers (less neurotoxic). They exhibited less chiral discrimination in their accumulation within peripheral nerves and in vitro anti-tumour activity."}
+{"text": "Greater fatigability in older adults may be moderated by physical activity (PA). However, what features of PA timing are most strongly related to fatigability remains unknown. We examined the relationship between variability of free-living activity patterns and perceived physical and mental fatigability using the Pittsburgh Fatigability Scale  in older adults from the Developmental Epidemiologic Cohort Study . We assessed PA using ActiGraph GT3X+ over 7 days. Mean activity, standard deviation (SD) of mean activity across days, and relative activity [(mean at each bin)/] were calculated across 24-hours in 4-hour bins , adjusting for estimated rise-time. Lower SD of PA from 0-4 hours after rising was associated with greater PFS physical scores . No measures of PA correlated with PFS mental scores. In older adults with lower physical fatigability, associations with greater variability in activity may indicate larger energy reserves."}
+{"text": "Variable differences of 0\u20135000 yr in radiocarbon age are apparent between organic carbon in differing grain-sizes and foraminifera of the same sediment layer. The magnitude of 14C differences co-varies with key paleoceanographic indices , which we interpret as evidence of Atlantic\u2013Mediterranean seawater exchange influencing grain-size specific carbon accumulation and translocation. These findings underscore an important link between regional hydrodynamics and interpretations of down-core sedimentary proxies.Ocean dynamics served an important role during past dramatic climate changes via impacts on deep-ocean carbon storage. Such changes are recorded in sedimentary proxies of hydrographic change on continental margins, which lie at the ocean\u2013atmosphere\u2013earth interface. However, interpretations of these records are challenging, given complex interplays among processes delivering particulate material to and from ocean margins. Here we report radiocarbon ( Marine sedimentary records and the proxies within play a central role in unlocking our understanding of past climates, yet interpreting the signals they contain can be complex. Here, the authors reveal and discuss the complex effects of hydrodynamics on carbon accumulation in the sediments off the Iberian margin. These slowdowns were accompanied by pronounced hydrographic changes3 throughout the sub-tropical Atlantic, which are exemplified by paleoceanographic reconstructions off the southwest Iberian margin4  ago, were related to periods of Atlantic meridional overturning circulation slowdownin4 Fig.\u00a0. Respect12, but debate persists about the nature of these changes vis-\u00e0-vis apparent disparities among proxies within singular or correlative sediment horizons;13 for instance, sea-surface temperatures (SSTs) reconstructed from co-deposited (organic) biomarkers and foraminifera15. There is some evidence suggesting particle re-suspension and lateral translocation (advection) of sediment16 within nepheloid layers17 drive apparent disparities among proxies with differing grain-size associations via sediment (hydrodynamic) sorting processes20, but this evidence remains inconclusive as sediment mobilization and advection is often stochastic16 and difficult to resolve21.Microfossils and biogeochemical data suggest that marked paleoceanographic changes occurred in sub-tropical Atlantic circulation at intermediate water depths during glacial termination14C ages measured for organic carbon (OC) in different grain-size classes and foraminifera separated from a 3.44 m-long sediment (Kasten) core recovered in 2013 during cruise JC089 aboard the RSS James Cook in the northeast Atlantic Ocean  data and 14C feature a consistent down-core difference against foraminifera radiocarbon ages of 1450 \u00b1 200 yr  is more variable, with down-core differences of between about 0\u20132000 yr  likewise is variable, with down-core differences of ~1000\u20133500 yr  and incomplete disaggregation of flocculates with effective diameters in excess of 100 \u03bcm (refs. 25), we will focus here on changes in down-core radiocarbon offsets apparent between coincident finer sediment fractions and foraminifera. Notwithstanding questions about the reliability of differently preserved tests (translucent versus frosty), prior studies suggest foraminiferal 14C dates are an accurate indication of initial deposition age in rapidly accumulating sediments because of their consistent high settling velocities, whereas co-deposited finer sediments are more subject to (re)suspension with attendant spatio-temporal biases on sedimentary proxies26.Radiocarbon ages of OC increase with depth in every grain-size class and feature a maximum average radiocarbon age of 20,600 \u00b1 900 yr, when coincident foraminifera reach their maximum calendar age of 21,725 yr BP  during the Last Glacial Maximum  transitions into more moderate offsets of ~2000 \u00b1 500 yr during preliminary glacial termination, and then rapidly peak to values of ~1500\u20133500 yr amid the middle of Heinrich Event 1 . After an interim of lower radiocarbon offset through the conclusion of HE1 and initial B\u00f8lling/Aller\u00f8d interstadial , the relative age differences among grain-size classes increase again at B/A-to-Younger Dryas  transition with moderate offsets of ~2000 \u00b1 500 yr. Low-to-intermediate average radiocarbon offsets subsequently persist through the mid-Holocene. Thereafter, respective offsets climb to significantly greater values amid the last few millennia, most likely due to anthropogenic impacts on sedimentary processes27 28.The organic carbon in all finer sediment fractions  has older radiocarbon ages as compared to coincident foraminifera, and the magnitude of their respective radiocarbon offsets change in step with complementary proxies of oceanographic variability since at least 25 kyr ago Fig.\u00a0. A lower29, including preferential bioturbation31, diagenetic alteration or downslope mobilization of foraminiferal tests8, and the differential lateral transfer of bottom and intermediate nepheloid layer sediment fractions32 via deeper water currents33. However, although benthic organisms can induce age or size-dependent depositional displacement31, bioturbation effects are unlikely to affect down-core records significantly, given ichnofabric evidence of low-moderate degree34 of mid-tier36 (limited to upper <10 cm of the substrate) bioturbation alongside relatively high sedimentation rates37 and lack of a deep mixed layer29 as indicated by 210Pb from multi-cores at SHAK06-5K  that lies well above SHAK06-5K (2646 mbsl). Thus, while at least the base of the MOW descended to at least 2600 mbsl , which is a sensitive recorder of MOW flow velocities42, and another site closer to the moat generated by the uppermost MOW , which is sensitive to both MOW flow velocities and flow-core depth42. Considered together, such differences should be a robust, though indirect, indicator of MOW flow-core depths43. Not too surprisingly, patterns of U1389\u2013U1386 differences show a stronger correlation with RFS\u2013C and RCS\u2013C trends as compared to either core alone  of OM in sediments and suspended particulate matter (SPM) through cyclic oxygen (re)exposure47. More specifically, paleoceanographic reconstructions of deglacial MOW fluctuations suggest that there was increased discharge of deep-and-intermediate waters48 with high amounts of fine sediment fractions and TOC49.There are significant low-to-moderate strength relationships apparent between radiocarbon offsets and XRF  trends at SHAK06-5K Fig.\u00a0 that hin44 between regional MOW and Atlantic seawater50, increased Zr/Al and Mn/Al ratios most likely parallel the enhanced lateral transport flux and deposition of finer sediments  as compared to vertical input of fresh hemipelagic materials48 because of the deeper, enhanced nepheloid layer developed between seawater masses with disparate densities17. This interpretation is consistent with the nominal differences in down-core sortable silt distributions  suspension of finer sediment from upper slopes at their contact with uppermost MOW flow 51 that then settles at MOW\u2013NADW interface52 along with SPM transported from up-current distal locations48. Aforementioned drivers also square with the moderate correlation strength between radiocarbon offsets and down-core sedimentation rate physical drivers would drive increased injection of turbid Mediterranean water masses into the Gulf of Cadiz at high velocities during periods of deglacial transgression49, alongside regional increases in rainfall (i.e. river discharge) and benthic dysoxia49. As such, times of stronger MOW flow would thus result in more advection of fine grained terrigenous clastic material to our site, which then would be admixed together with local hemipelagic rain in varying proportions53.Insomuch as nepheloid layer dynamics and bottom current flow velocities along the Iberian margin are each related to seawater density gradientssl) Fig.\u00a0. Thus, wate Fig.\u00a0 and infeate Fig.\u00a0, both of54, reconstructed densities (\u03c3) of important Atlantic-Mediterranean seawater masses are more certain. The contrast between reconstructed densities of MOW and NADW through Greenland stadials (\u03c3MOW \u2212 \u03c3NADW = 2.4 kg m\u22123) is much larger as compared to warmer  intervals41, such as the recent Holocene54 (\u03c3MOW \u2212 \u03c3NADW = 0.7 kg m\u22123). Considered together with evidence of low-moderate degree34 of mid-tier (< 10 cm of the substrate) bioturbation36, our data suggest that down-core radiocarbon age offsets among grain-size classes are consequent \u2013 at least in part \u2013 to differential hydrodynamic effects on sediment lateral transfer vis-\u00e0-vis differences in regional Atlantic-Mediterranean seawater densities and flow depths. All data considered together, we suggest there are competing influences of (hemi)pelagic dilution vs. advection of finer sediment fractions as a function of MOW depth and OM degradation extent that, in turn, are related to regional (Mediterranean) terrestrial hydroclimate, ocean circulation dynamics, and benthic oxygenation.Although the exact balance of MOW temperature-salinity parameters during glacial termination remains uncertain43, about 20\u201310 kyr ago; however, important details of these changes remain unclear. Increasing grain-sizes42 and increases in reworked nannofossil influx55  MOW50, and decreased formation of less dense, cold NADW57. Intervals associated with cold Arctic conditions56 show decreased percent total OC  could be one explanation of these observations, it does not befit the consistent low ratio values of bulk carbon-to-nitrogen (Supplementary Data\u00a014 (BIT) that together indicate negligible soil OM input throughout the last ~25 kyr. Decreased TOC% through these intervals also does not track the significant, though varied, disparities in relative abundances or reconstructed temperatures among principle oceanography proxies14  during glacial terminationx55 Fig.\u00a0 during dOC% Fig.\u00a0) togetheera Fig.\u00a0).59, such that CS fractions contain decreasing proportions of fresh organic matter and decreased TOC% through time via progressive pre-depositional degradation33. During progressive oxic degradation, residual OC in CS fractions will become increasingly pre-aged because of decreased fresh organic matter and its accumulative residence in nepheloid layers over repeated (re)suspension\u2013deposition cycles60.One approach to reconcile such apparent discrepancies invokes recent data suggesting grain-sizes of 10\u201363 \u03bcm  feature especially protracted lateral transport histories in ocean margin systems61) from coastal Atlantic sources (Gulf of C\u00e1diz)61 that then is entrained to more distal locations of the continental Iberian margin. Assuming grain-sizes of 2\u201310 \u03bcm  have similar sediment transport histories as coarser silt59, these combined data suggest that RFS\u2013C and RCS\u2013C trends , these data suggest there was increased lateral (re)suspension of finer sediment62  with relatively pre-aged OC58 derived from more remote allochthonous sources63 such as marginal Gulf of Cadiz drift deposits65.Our analyses reveal down-core coherence of TOCS\u2013C Fig.\u00a0. In cont YD Fig.\u00a0 follow a55, glycerol dialkyl glycerol tetraethers66 (GDGTs), and foraminifera67 from correlative down-core records at MD95-2042 (ref. 14). Although some of these disparities could be consequent to multiple or independent factors66 , degradation and hydrodynamic effects could have an intrinsic role in explaining such proxy paradoxes68.Differential lateral transfer dynamics among grain-size classes may help to explain apparent disparities among proxies during paleoceanographic reconstructions in drift deposits when a single age-depth model is adopted for all down-core records , this suggests a critical threshold for deceleration is crossed in the vicinity of SHAK06-5K that might lead to differential degradation58 and deposition of advected SPM from up-current locations65. Accepting previous studies showing prototypic organic matter aggregates and fine surface-sediments of the southwest Portuguese margin show average settling speeds of ~0.015 cm s\u20131 within associated MOW branches and spend ~50% of time in (re)suspension59, these combined data insinuate advective displacement distances of up to several hundreds of kilometres  that befit the results of bottom boundary (BOBO) landers53 and bottom-current circulation simulations65.Overall MOW flow velocities decline from >250 cm s70 as compared to coincident foraminifera in north Atlantic drift deposits20 that befit the combination of their differing grain-size associations59 and degradation recalcitrance70. Previous studies indicate alkenones, which are more recalcitrant to oxidation70, occur in association with sedimentary particles of <6 \u03bcm (refs. 72), but less-recalcitrant GDGTs69 are associated with sedimentary particles of 6\u201332 \u03bcm (ref. 73). Although sorting processes are subject to variable and differential influences among grain-sizes 60 and between sedimentary particles of the same size 74, analogous molecular sediment-fraction associations29 \u2013 and thus relative age offsets64 \u2013 are also implied for southwest Portuguese margin sites71, wherein down-core alkenone and GDGT-derived SST trends are offset (lagged), like RCS\u2013FS values, about 200 yr on average, and likewise are offset from coincident foraminifera-derived SSTs up to several hundreds of years , which are often used to reconstruct flow velocities9. Further work, especially paired 14C measurements of differing proxies  and their carrier phase , is essential to establish the occurrence and significance of these phenomena. Even so, our study provides support for significant hydrodynamic effects on organic carbon transport, degradation, and deposition on ocean margins, and interpretations of related climate records.The magnitude of time offset between organic sedimentary proxies of SST through deglaciation is consistent with the average radiocarbon age offsets of their corresponding grain-size classes  Fig.\u00a0. Stepwis55 Fig.\u00a0 despite To summarize, organic radiocarbon age differences among grain-size classes as compared to coincident foraminiferal tests in marine sediments of the northeast Atlantic margin reveal differential lateral transfer dynamics accompanying particle mobilization, as controlled by paleo-current densities vis-\u00e0-vis nepheloid layer dynamics. Intervals with intensified Mediterranean Outflow, which closely parallel increased Atlantic-Mediterranean seawater density contrasts, amid Heinrich Event 1 have much higher radiocarbon offsets among grain-size classes of ~1000\u20132500 yr and lower organic carbon concentrations as compared to intervals with more sluggish Mediterranean Outflow amid the mid-Holocene. In consequence, our results suggest differential lateral transfer dynamics can influence apparent lead\u2013lag patterns among proxies with differing grain-size associations; as such, hydrodynamic influences on organic carbon accumulation and transfer are important factors to consider in interpretations of diverse co-occurring proxies in down-core records, which can experience differential degradation and hydrodynamic (sorting) processes.75 and tube settling protocol76 to create a series of four grain-size sediment fractions: clay (<2 \u03bcm [C]), fine silt (2\u201310 \u03bcm [FS]), coarse silt (10\u201363 \u03bcm [CS]), and sand (>63 \u03bcm [S]). Although sediment-fraction recoveries were not monitored directly, previous studies demonstrate wet-sieve recovery percentages exceed 85% both for mass and bulk organic carbon in most instances60 and have a nominal influence on associated bulk sediment-fraction isotopic signatures77 despite small, though significant, losses of dissolved organic matter during rinsing. Likewise, measured total bulk organic compositions correlate with mass-balance calculations of the organic composition among grain-size sediment fractions  were sub-sampled, before storage at \u221220 \u00b0C. Sub-samples were separated through wetted fine-mesh sieves78 bulk sediment fractions were made on a mini-carbon dating system79 (MICADAS) following graphitization or via elemental analyser as detailed previously80. Radioactive carbon isotope compositions are shown as conventional 14C ages (R \u00b1 1\u03c3 s.d.) to calculate relative age relationships 81 among grain-size classes, where x and y represent discrete sediment fractions:Radiocarbon measurements of foraminiferal tests and decarbonated (hydrochloric acid fumigated)33, however, conventional 14C ages of foraminiferal tests were converted into calendar years in an age-depth model (CALIB 7.1)82 with a dynamic marine inorganic carbon reservoir correction  to within several hundred years83. XRF (Avaatech [University of Cambridge]) analyses were used for semi-quantitative analysis at 0.5 cm depth intervals on u-channel (sub)cores extracted from composite split-core scans of SHAK06-5K Kasten core material  test 14C ages were used to construct the age model for SHAK06-5K . To do so, surface reservoir ages estimated from at MD99-2334K 1 were subtracted from each conventional 14C date . Then, respective calendar ages were used to construct down-core sediment depth-age models after stratigraphic alignment  are derived from singular cores  and thus are internally consistent.Foraminiferal (Supplementary InformationPeer Review File"}
+{"text": "Recen = 2) and Arg299Cys (n = 1) mutations were among the RS-TB strains. We then compared Ultra raw results with available rpoB sequences of the strains.To determine the reliability of Ultra results for predicting specific mutations, we tested 13 rifampin-susceptible (RS)-TB strains and 104 RR-TB strains harboring 33 unique RR-conferring mutations from the Belgian Coordinated Collections of Microorganisms in the Institute of Tropical Medicine Antwerp according to a protocol previously described   mutations inside the rifampin resistance-determining region (RRDR) were correctly identified by Ultra. Of concern, mutation His445Arg gave a \u201cRIF Resistance Indeterminate\u201d result among 3/4 strains tested, while it was reported as RR in the initial validation study . The RR-The probe reactions observed were largely in agreement with previous results , althougmT  and GXAlert  , Ultra r"}
+{"text": "Glycine max (L.) Merr.] seed yield. Although a major gene for salt tolerance was identified and consistently mapped to chromosome (Chr.) 3 by linkage mapping studies, it does not fully explain genetic variability for tolerance in soybean germplasm. In this study, a genome-wide association study (GWAS) was performed to map genomic regions for salt tolerance in a diverse panel of 305 soybean accessions using a single nucleotide polymorphism (SNP) dataset derived from the SoySNP50K iSelect BeadChip. A second GWAS was also conducted in a subset of 234 accessions using another 3.7\u2009M SNP dataset derived from a whole-genome resequencing (WGRS) study. In addition, three gene-based markers (GBM) of the known gene, Glyma03g32900, on Chr. 3 were also integrated into the two datasets. Salt tolerance among soybean lines was evaluated by leaf scorch score (LSS), chlorophyll content ratio (CCR), leaf sodium content (LSC), and leaf chloride content (LCC).Salinity is an abiotic stress that negatively affects soybean [For both association studies, a major locus for salt tolerance on Chr. 3 was confirmed by a number of significant SNPs, of which three gene-based SNP markers, Salt-20, Salt14056 and Salt11655, had the highest association with all four traits studied. Also, additional genomic regions on Chrs. 1, 8, and 18 were found to be associated with various traits measured in the second GWAS using the WGRS-derived SNP dataset.A region identified on Chr. 8 was identified to be associated with all four traits and predicted as a new minor locus for salt tolerance in soybean. The candidate genes harbored in this minor locus may help reveal the molecular mechanism involved in salt tolerance and to improve tolerance in soybean cultivars. The significant SNPs will be useful for marker-assisted selection for salt tolerance in soybean breeding programs.The online version of this article (10.1186/s12864-019-5662-9) contains supplementary material, which is available to authorized users. In the worldwide crop agriculture, salinity is considered a major abiotic stress. The global extent of salt-affected soils amounts to 1128 million ha, of which 60% are saline soils, 26% are sodic soils, and 14% are saline-sodic soils . The UniAlthough soybean is classified as a moderately salt tolerant crop plant with a threshold of 5 dS/m, salt sensitive soybean cultivars were severely affected under salt stress and did not produce seeds at a soil salinity level of 8 dS/m , 7. SoybGlyma03g32900) underlying salt tolerance was identified on Chr. 3 and related to a sodium transporter  were unassociated SNPs, on the other hand, sharp curves at the end are the number of true associations. (JPG 4403 kb)Additional file 6:Figure S4. Manhattan plots showing association of SNPs distributed throughout 20 chromosomes with four traits. The results based on analyzing GWAS of leaf scorch score (LSS), chlorophyll content ratio (CCR), leaf sodium content (LSC) and leaf chloride content (LCC) using 37,573 SNPs from SoySNP50K dataset from the subset of 234 diverse accessions selected from the original 305 accessions. (JPG 2008 kb)Additional file 7:Figure S5. Quantile-quantile (Q-Q) plots showing the expected -log10(P) compared to the observed -log10(P). The results of statistical testing (EMMAX) for association across 2,280,225 polymorphic SNPs from 3.7\u2009M SNP dataset with leaf scorch score (A), chlorophyll content ratio (B), leaf sodium content (C) and leaf chloride content (D) in the subset of 234 soybean lines selected from the original population of 305 genotypes. SNPs matched with solid lines [expected -log10(P)\u2009=\u2009observed -log10(P)] were unassociated SNPs, on the other hand, sharp curves at the end presented the number of true associations. (JPG 4813 kb)Additional file 8:Table S3. The genes underlying the significant genomic regions associated with salt tolerance from Phytozome and Soybase databases. (XLSX 24 kb)Additional file 9:Figure S6. The significant SNPs underlying the known gene (Glyma03g32900) on Chr. 3 (red dots) associated with salt tolerance. The known gene (Glyma03g32900) named in SoyBase Wm82 Genome Browser version 1, and LD block in this genomic region. (JPG 647 kb)Additional file 10:Table S4. A core set of 305 soybean plant introductions (PIs) selected from the USDA Soybean Germplasm Collection. (XLSX 27 kb)"}
+{"text": "During August 9\u2013October 31, 2019, 96 patients were classified as having e-cigarette, or vaping, product use\u2013associated lung injury (EVALI) by the Minnesota Department of Health (MDH); other patients are being investigated for case classification and exposures. Among 58 patients interviewed, 53 (91%) reported obtaining tetrahydrocannabinol (THC)\u2013containing products from informal sources such as friends, family members, or in-person or online dealers. Using gas chromatography\u2013mass spectrometry (GCMS), the MDH Public Health Laboratory (PHL) analyzed 46 THC-containing e-cigarette, or vaping, products obtained from 12 EVALI patients for various potential toxicants, including vitamin E acetate, which has recently been detected in some THC-containing products and in samples of lung fluid from EVALI patients , toxicants of concern , and three vitamin E forms .Bronchoalveolar lavage (BAL) fluid samples from five EVALI patients were analyzed at CDC for active compounds and toxicants. MDH collaborated with the Minnesota Bureau of Criminal Apprehension Forensic Drug Chemistry Department, which had obtained six containers of bulk liquids, each labeled with a different flavor, and 100 cartridges  from a spring 2018 raid. PHL tested five bulk liquid samples and five cartridges held by the Minnesota Bureau of Criminal Apprehension. In September 2019, local law enforcement seized 75,000 cartridges intended for the illicit THC market , and 58 (60%) were male. Eighty-seven (91%) patients were hospitalized, including 26 (27%) in intensive care units. Three (3%) patients died. Among 58 (60%) interviewed EVALI patients, 53 (91%) reported using illicit THC-containing products obtained from informal sources in the 3 months before illness onset,Sixteen (28%) patients submitted 265 products, 67 of which were selected for testing because of available product volume and features that physically differentiated the cartridges; 46 contained THC, and 21 contained nicotine. Among the 46 assessed THC-containing products submitted by 12 patients, the most commonly detected compounds were vitamin E acetate , MCT , CBD , and alpha tocopherol . Eight (17%) THC-containing products did not contain either vitamin E acetate or MCT. THC-containing products used by 11 of 12 (92%) patients contained vitamin E acetate, and products from seven (58%) patients contained MCT. One patient who used medical cannabis submitted illicit THC-containing products; one tested product contained vitamin E acetate and another contained MCT. THC-containing products from one patient did not contain vitamin E acetate; however, this patient reported using multiple products daily, including Dank Vapes, which were not included among the products submitted for testing. Among 21 nicotine-containing products submitted by eight patients, 20 contained propylene glycol, and 15 contained glycerin but not the other analytes.Among the 21 patient-submitted THC-containing products that were categorized by identifiable brands, two of two Dank Vapes samples contained vitamin E acetate . In fiveVitamin E acetate was detected in all five patient BAL fluid specimens. One of these patients submitted four THC-containing cartridges labeled \u201cTKO Extract\u201d (two), \u201cRove\u201d (one), or \u201cDr. Zodiak\u201d (one), all of which contained vitamin E acetate. Although the other patients were known to be exposed to THC based on interview or testing of the BAL fluid, none of the other patients whose BAL fluid specimens were tested submitted THC-containing products for testing.Among products seized during the 2018 raid, all five bulk liquid samples tested negative for vitamin E acetate and MCT; two tested positive for THC . The bulThis report evaluated e-cigarette, or vaping, products used by EVALI patients and products intended for the illicit market and seized by law enforcement both before and during the current EVALI outbreak. The findings support a potential role for vitamin E acetate in lung injury in EVALI patients. Vitamin E acetate has been detected in a high proportion of THC-containing products associated with EVALI cases, including those tested at MDH PHL, New York -containing e-cigarette, or vaping, products also containing vitamin E acetate appear to be associated with e-cigarette, or vaping, product use\u2013associated lung injury (EVALI).Illicit THC-containing products submitted by 11 of 12 EVALI patients in Minnesota contained vitamin E acetate. Twenty THC-containing products seized during September 2019 contained vitamin E acetate; ten products seized during 2018, before the EVALI outbreak, did not contain vitamin E acetate.These data further support a potential role for vitamin E acetate in EVALI. While potential toxicants continue to be evaluated, vitamin E acetate should not be added to e-cigarette, or vaping, products."}
+{"text": "Paenibacillus elgii strain isolated from soil samples from Cerrado, Brazil, showed antimicrobial activity. Its genome sequence was acquired (GS20 FLX Titanium 454 platform) and comprises 108 contigs  and 6,810 predicted sequences.A  Paenibacillus elgii strain isolated from soil samples from Cerrado, Brazil, showed antimicrobial activity. Its genome sequence was acquired (GS20 FLX Titanium 454 platform) and comprises 108 contigs  and 6,810 predicted sequences. Here, we shed some light on the antimicrobial genes of the strain, including a nonribosomal peptide synthetase (NRPS) module identified as part of a pelgipeptin gene cluster.A  Paenibacillus genus wasdefined after an extensive comparison between DNA sequences encoding 16S rRNA  proteinase K, followed by a phenol-chloroform-isoamyl alcohol (25:24:1 [vol/vol/vol]) extraction . Approximately 0.5 g of cells was collected, and DNA was extracted using a modified cetyltrimethylammonium bromide (CTAB) protocol . Cells wtraction . The DNAGenomic sequence annotation was performed using the Prokaryotic Genome Annotation Pipeline (PGAP), a modified NCBI Prokaryotic Genome Automatic Annotation Pipeline (PGAAP) protocol \u201316. The \u2013P. elgii strain B69  comparison with other nstitute  revealedPaenibacillus elgii strain AC13 whole-genome shotgun project sequencing has been deposited at DDBJ/ENA/GenBank under the accession number PYHP00000000. The version described in this paper is version PYHP01000000.The"}
+{"text": "This study examines program planning strategies among older adults participating in programs promoting aging-in-community (AIC) programs. Older adults from three programs were recruited (n=290): a university-based lifelong learning program , a county neighborhood lunch program , and a village program (n=96). Mean age was 72.4 (SD=8.68) years and 78% female. Findings showed NLP participants were more likely to obtain health information from TV (p=.030), friends and neighbors (p=.016), family members (p<.001), or mailed advertisement (p<.001); while less likely to obtain health information online (p<.001). Village members preferred afternoon while NLP participants preferred morning programs (p=.025). Most desired frequency was weekly (45%) and delivered in small group modes (68%). NLP participants were more likely to report self as risk takers (29% vs. 17%) or old tradition (23% vs. 3-8%) towards new technology adoption (p<.001). Results have implications on tailored program planning for older adults in different AIC programs."}
+{"text": "Accelerated malignant behaviors induced by insufficient thermal ablation have been increasingly reported, however, the exact mechanisms are still unclear. Here, we investigated the importance of the extracellular matrix (ECM) in modulating the progression of residual hepatocellular carcinoma (HCC) after heat treatment.Heat-exposed residual HCC cells were cultured in different ECM gels. We used basement membrane gel (Matrigel) to simulate the normal microenvironment and collagen I to model the pathological stromal ECM. The alterations of morphology and parameters of proliferation, epithelial-mesenchymal transition (EMT) and stemness were analyzed in vitro and in vivo.p values all <\u20090.05). Importantly, collagen I induced the activation of ERK phosphorylation in heat-exposed residual HCC cells. ERK1/2 inhibitor reversed the collagen I-promoted ERK phosphorylation, cell proliferative, protrusive and spindle-like appearance of heat-treated residual HCC cells in vitro. Moreover, collagen I promoted the in vivo tumor progression of heat-exposed residual HCC cells, and sorafenib markedly reversed the collagen I-mediated protumor effects.Increased collagen I deposition was observed at the periablational zone after incomplete RFA of HCC in a xenograft model. The markers of cell proliferation, EMT, motility and progenitor-like traits of heat-exposed residual HCC cells were significantly induced by collagen I as compared to Matrigel  contains supplementary material, which is available to authorized users. Among the various thermal ablations, radiofrequency ablation (RFA) has gained worldwide use and been deemed as the first-line treatment for unresectable early-stage hepatocellular carcinoma (HCC) with the complete necrosis rate higher than 90% \u20134. HowevIn the previous studies, sublethal heat treatment induced residual HCC cells themselves displaying more malignant phenotypes \u201311. SincHere, we presented the importance of collagen I in modulating the progression of residual HCC after heat treatment. Collagen I endowed the heat-exposed residual HCC cells with higher malignancy through the activation of ERK signaling cascade. These unfavorable protumor effects driven by collagen I could be reversed by sorafenib. Our finding helps offer a new treatment strategy to thwart tumor progression of residual HCC after suboptimal RFA.2 humidified incubator chamber.Human HCC cell lines MHCC97H  and HepG2  were maintained in DMEM media supplemented with 10% fetal bovine serum  and 1% penicillin/streptomycin in a 5% COThe procedure of in vitro sublethal heat treatment was performed as we previously described .After exposed to sublethal heat treatment, HCC cells were seeded into 6-well plates pre-coated with growth factor-reduced basement membrane gel (Matrigel)  or with gel of collagen I  for desirable incubation periods.Preparation of collagen I gel was performed according to the manufacturer\u2019s instructions. Briefly, collagen I gels were made by neutralizing rat-tail collagen solution with chilled neutralization solution  according to the volume ratio of 9:1. The final concentration of collagen I was 3\u00a0mg/mL.Briefly, RNA was extracted using TRIZOL reagent  and subsequently, cDNA was synthesized and amplified using RevertAid First Strand cDNA synthesis kit and Maxima SYBR Green qPCR Master Mix kit (Thermo Fisher Scientific) according to the manufacturer\u2019s instruction. Primer sequences were presented in Additional\u00a0file\u00a0Western blot was carried out as previously described . Total pAs in the previous description , deparafAs previously described , images n\u2009=\u2009374) were downloaded from The Cancer Genome Atlas (TCGA) (http:// cancergenome.nih.gov/) and analyzed using R Statistical Software. The analyses of fragments per kilobase of transcript per million fragments (FPKM) values of genes in TCGA HCC patient samples and survival outcome were conducted as previously described [Publically available HCC data  (Permit Number: 201807002Z).The MHCC97H orthotopic nude mouse model was developed as previously described . At 4 we7 cells) suspended in Matrigel alone or together with collagen I solution (1:2) were subcutaneously injected into the upper right flank of mice . After 2 weeks, animals were sacrificed and tumor samples were collected.Heat-exposed residual HCC cells MHCC97H (2\u2009\u00d7\u2009107 cells) suspended in Matrigel with collagen I solution (1:2) were randomized into two groups: sorafenib group  and control group . The tumor weight was estimated following the formula: Tumor weight (mg)\u2009=\u2009Length(mm) X (Width(mm))2/2 [Another 8 mice with the tumors from heat-exposed residual HCC cells MHCC97H , HCC cells were seeded on the plates pre-coated with Matrigel gel or collagen I gel. Distinct morphological changes were observed. Heated-exposed residual HCC cells cultured on Matrigel showed less, rounded, and collective growth. In contrast, the cells cultured on collagen I exhibited proliferative, protrusive and spindle-like appearance Fig.\u00a0. CollageActivation of ERK has been associated with aggressive phenotypes of HCC \u201331. SignTo determine whether collagen I would aggravate the in vivo progression of heat-exposed residual HCC, we subcutaneously inoculated heat-treated residual MHCC97H cells mixed with Matrigel alone or together with collagen I into nude mice. Compared with the Matrigel group, tumors of the collagen I group showed the increased expression of proliferation markers , EMT , phosphorylated ERK1/2 and Nanog mRNA, and the decreased E-cadherin Fig.\u00a0. ConsistSorafenib is the first-line systemic therapy for advanced HCC . To asser\u2009=\u20090.11, P\u2009=\u20090.0338), or EMT marker Twist    was significantly overexpressed in HCC samples than adjacent non-tumoral tissues Fig.\u00a0. The pos01) Fig. . In addi02) Fig. . These rWhen RFA is used to treat medium or large HCC, local recurrence and progression occurs frequently due to the remaining of microscopic residual tumors at the periablational zone . Even moHCC occurs in the setting of cirrhotic liver with ECM richness , 36. In This study has several limitations. First, besides collagen I, we could not exclude the other factors in post-inflammation reaction after RFA that influence tumor progression of residual HCC , 49, 50,In summary Fig.\u00a0, we reveAdditional file 1:Table S1. Primers for quantitative RT-PCR. (DOCX 13 kb)"}
+{"text": "Metabolomics of skeletal muscle found acute EAA supplementation resulted in increased EAA metabolic products while long-term supplementation resulted in increased anaplerosis [flux into the tricarboxylic acid cycle (TCA) intermediate pool] and anaplerotic substrates [propionyl (p<0.01) and succinyl (p<0.01) carnitine] and intermediates of long-chain fatty acid metabolism [stearoyl (p<0.01) and myristoyl (p<0.05) carnitine]. However, tissue level respiratory capacity appeared to be unaffected by EAA supplementation. DISCUSSION/SIGNIFICANCE OF IMPACT: EAA supplementation has potential to improve lipid metabolism and plasma TG levels in non-diabetic older adults. Mitochondrial metabolomics suggest that insufficient TCA pool size may limit tissue fatty acid oxidation and may provide an additional route for nutritional therapy.OBJECTIVES/SPECIFIC AIMS: This study will assess the effect of essential amino acid (EAA) supplementation on plasma triglyceride (TG) in elderly adults. We will also explore the mechanisms mediating EAA mediated changes in fat metabolism and to suggest promising routes to refine therapy of hypertriglyceridemia. METHODS/STUDY POPULATION: In total, 7 nondiabetic male and female subjects ages 50\u201375 years with elevated plasma TG levels (130\u2013500 mg/dL) were recruited to participate in an acute (5 h) and long-term (8 wk) EAA supplementation study. We measured changes in regional and whole body fat metabolism, including changes in body composition, plasma TG levels, whole body fat metabolic rates, tissue mitochondrial respiratory capacity, and metabolomic profiles before and after supplementation. RESULTS/ANTICIPATED RESULTS: Long-term EAA supplementation decreased fasted plasma TG levels by 19% ("}
+{"text": "Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) has been used increasingly to support patients with cardiogenic shock (CS). There has been growing recognition of the favorable and unfavorable hemodynamic effects of this therapy and recent interest in the use of other percutaneous circulatory support devices to offset some of the potentially harmful hemodynamic effects. Herein, we provide visual evidence of the effects of intra-aortic balloon pump (IABP) counterpulsation for a patient with peripheral VA-ECMO cannulation.Enterobacter aerogenes pneumonia and rapidly fatal septic shock.A 68\u2009year old man who had undergone orthotopic heart transplantation presented with 2\u2009days of fatigue, orthopnea, and paroxysmal nocturnal dyspnea. On examination, he was tachycardic, hypotensive and hypoxic with cool extremities, consistent with CS. Transthoracic echocardiogram (TTE) showed new severe biventricular dysfunction with a left ventricular ejection fraction of 15%, right heart catheterization demonstrated elevated filling pressures and low output. An IABP was inserted via the left femoral artery with minimal improvement in hemodynamics. He was escalated to VA-ECMO. Repeat TTE demonstrated aortic valve (AV) opening with each cardiac cycle and mild MR. With placement of the IABP on standby Additional file 1: Video 1 (video\u00a00:03), the AV no longer opened. Re-initiation of balloon counterpulsation resulted in resumed AV opening with each beat Additional file 1: Video 1 (video\u00a00:17). He was treated for presumed acute allograft rejection with methylprednisolone, thymoglobulin, intravenous immunoglobulin and plasmapheresis with improvement in allograft function. However, he developed an This case visually demonstrates effective LV decompression by IABP counterpulsation in VA-ECMO support. While the overall effects of LV decompression in patients on VA-ECMO with IABP are still unclear, this report demonstrates one potential mechanism of benefit in the prevention of stagnation of blood flow that may lead to intra-cardiac or aortic root thrombus formation.The online version of this article (10.1186/s13019-019-0970-3) contains supplementary material, which is available to authorized users. An increasingly well-recognized effect of peripherally inserted veno-arterial extracorporeal membrane oxygenation (VA-ECMO) in patients with cardiogenic shock (CS) is that of retrograde aortic flow and the resultant additional afterload on the already failing left ventricle (LV) . This ca2), he was tachycardic, hypotensive  and hypoxic with cool extremities, consistent with CS. Dopamine was initiated at 10mcg/kg/min. Transthoracic echocardiogram (TTE) showed new severe biventricular dysfunction with LV ejection fraction of 15%. He was brought to the cardiac catheterization lab for endomyocardial biopsy and right heart catheterization (RHC) which demonstrated elevated filling pressures  22\u2009mmHg, mean pulmonary artery pressure (mPAP) 33\u2009mmHg, pulmonary capillary wedge pressure (PCWP) 36\u2009mmHg, pulmonary artery saturation (PA sat) 43%, and Fick cardiac index 1.5\u2009L/min/m2). An IABP was inserted via the left femoral artery. Balloon counterpulsation provided minimal improvement in his hemodynamic profile (PA sat 38%). As a result, VA-ECMO was initiated via the right femoral artery and vein with flow of 3.0\u2009L/min (1.6\u2009L/min/m2). Repeat TTE demonstrated aortic valve (AV) opening with each cardiac cycle. With placement of the IABP on standby Additional file Enterobacter aerogenes pneumonia and rapidly fatal septic shock.A 68\u2009year-old man with a history of hypertension, diabetes mellitus and heart transplantation due to ischemic cardiomyopathy presented with 2\u2009days of fatigue, orthopnea, and paroxysmal nocturnal dyspnea. On examination, he weighed 78\u2009kg"}
+{"text": "In vivo suppression of ANGPTL4 led to higher accumulation of cisplatin-DNA adducts in primary and metastasized tumors, and a reduced metastatic tumor load. ANGPTL4 empowered cancer cells metabolic flexibility during EMT, securing ample cellular energy that fuels multiple ABC transporters to confer EMT-mediated chemoresistance. It suggests that metabolic strategies aimed at suppressing ABC transporters along with energy deprivation of EMT cancer cells may overcome drug resistance.Overcoming multidrug resistance has always been a major challenge in cancer treatment. Recent evidence suggested epithelial-mesenchymal transition plays a role in MDR, but the mechanism behind this link remains unclear. We found that the expression of multiple ABC transporters was elevated in concordance with an increased drug efflux in cancer cells during EMT. The metastasis-related angiopoietin-like 4 (ANGPTL4) elevates cellular ATP to transcriptionally upregulate ABC transporters expression via the Myc and NF-\u03baB signaling pathways. ANGPTL4 deficiency reduced ICThe online version of this article (10.1186/s12943-018-0904-z) contains supplementary material, which is available to authorized users. Cytotoxic chemotherapy is one of the mainstays of cancer treatment. Despite being an important therapeutic option for most cancer patients, the development of multiple drug resistance (MDR) by tumors has emerged as a major obstacle that limits the efficacy of chemotherapy . Recent A well-established cause of MDR is the increased expression of ATP-binding cassette (ABC) transporters, that efflux various chemotherapeutic compounds from cells . Their bIn this study, we explore the attenuation of metabolic flexibility as a potential strategy to attenuate the activities of ABC transporters and to overcome MDR in metastatic cancer cells.2) or TGF\u03b21. EMT was initiated in MKN74Snai1ER, a MKN74 line carrying a Snai1-ER transgene, by 4-hydroxytamoxifen (4-OHT). Upon exposure to stimuli, the MKN74 cells underwent EMT after 48\u201396\u00a0h as confirmed by immunoblotting and qPCR of epithelial- and mesenchymal-associated genes , ABCC1 (MRP1) and ABCG2 (BCRP), across the EMT models Fig.\u00a0. Flow cySnai1ER:shANGPTL4 cells -inducible shANGPTL4 transgene. Conversely, recombinant cANGPTL4 (rh-cANGPTL4) treatment increased glycolysis"}
+{"text": "The aim of the study was to evaluate the treatment outcomes of endoscopic prelacrimal recess approaches (EPLAs) in managing different sinus pathologies, analyzing associated adverse events and post-treatment quality-of-life.We enrolled 21 consecutive patients (22 lesions) who received endoscopic sinus surgical procedures with EPLAs in two tertiary medical institutes between 2015 and 2018. Quality-of-life and self-rated symptom severity data were collected using the 22-item Sino-Nasal Outcomes Test (SNOT-22) and 10-point visual analog scales (VAS), respectively.P-value = 0.021). After EPLAs, non-papilloma patients had significant improvements in SNOT-22 and VAS , while those with papillomas had only marginally significant improvements in VAS . The most common adverse events was temporary cheek/tooth numbness (n = 11), and patients with sinonasal papillomas were more likely to have post-treatment complications than those with other disease entities.A total of 21 patients (mean age (standard deviation) 51.7 (14.5) years; 16(76.2%) male) were followed up for 12.7 months. The most common symptoms were nasal discharge and nasal airway obstructions. Nine lesions (40.9%) were sinonasal papilloma\u2019s, seven lesions were other types of neoplasms , two were trauma-related (9.1%), and four inflammatory diseases (18.2%). Patients with non-papilloma lesions had higher presurgical SNOT-22 than those with papillomas (EPLAs were found to effectively manage various sinus diseases. Short-term life-quality improvements were promising. Future large-scale studies with longer follow-up periods are recommended. Maxillary sinus is the largest of the paranasal sinuses . It is bMost diseases of the maxillary sinus can be managed by endoscope, which is used mostly to perform standard middle meatal antrostomy (MMA) . For benWe identified 21 adult patients receiving surgical procedures utilizing the endonasal endoscopic prelacrimcal recess approach (EPLA) from February 2015 to October 2018 in two tertiary care referral centers retrospectively. These patients may have also had additional endoscopic sinus surgeries or deviated septum corrections when deemed necessary by a surgeon based on pathology, extent of disease, or a patient\u2019s specific complaints prior to surgery. All patients enrolled in this study were recommended EPLAs because their diseases had been considered too difficult to treat using standard MMA alone. The protocol of this study was approved by the institutional review board of Kaohsiung Chang Gung Memorial Hospital (IRB No: 201900695B0). Written consents of the participants are not needed because of the retrospective nature of our study design.All patients received high-resolution sinus computed tomography scans  to assess degree of inflammation. Sinus disease was scored based on modified-Lund\u2013Mackay scores  of the dWe assessed interval changes in patient-reported outcomes between initial baseline evaluations and the last follow-up date. Functional outcome measurements included self-rated visual analog scale for current overall health (zero being worst imaginable and 10 as best imaginable) and self-rated 22-item Sino-Nasal Outcome Test (SNOT-22) to assess sinonasal symptom severity . Other oAll surgical procedures were performed with patients under general anesthesia. EPLA was performed before the other procedures for patients scheduled to receive endoscopic PLR approach for maxillary sinus lesions. To perform these procedures using the PLR approach, we first administered local anesthesia to the axilla of inferior turbinate using a 4 mm, 18 cm length zero degree rod-lens endoscope . A 15-blade was used to create a curvilinear incision from the lateral nasal cavity to the nasal floor, pathway crossing just anteriorly to the head of inferior turbinate. The inferior turbinate-nasolacrimal duct (IT-NLD) flap was then elevated subperiosteally by a suction elevator pulling it toward the mucosal portion of the naso-lacrimal duct and placed medially. Using a 4 mm chisel to remove the head of inferior concha bone and part of frontal process of maxillary bone, we penetrated the antero-medial aspect of maxillary sinus. The entrance was further enlarged using a Kerrison Rongeurs and/or drilling burr. When operating space was not easily accessible and a wider working area was needed, we drilled out part of the anterior maxillary wall to make way extent our surgical fulcrum laterally. All the diseased mucosa as well as neoplasms were removed. The underlying hyperplastic bones were drilled out and cauterized electrically in patients with sinonasal papillomas . AdditioU test. P-value < 0.05 was considered significant. All statistical operations were performed using IBM SPSS 22.0 statistical software .Categorical variables were expressed as frequency and percentage. Descriptive parametric data were expressed using mean, standard deviation (SD), and range. We used median and interquartile range (IQR) to express subjective metrics (VAS and SNOT-22 included). Their interval changes between different groups were tested using Wilcoxon signed rank test. The differences between two groups were tested using Mann\u2013Whitney n = 2), endoscopic sinus surgery (n = 14), and inferior meatotomies (n = 3). Inferior meatotomies were created for facilitating postoperative investigation in two patients with diffuse papilloma and in one patient with trauma-related maxillary mucocele. Five (71.4%) of these seven revision patients received at least two interventions  with 22 lesion sites received surgical procedures utilizing the endonasal endoscopic prelacrimcal recess approach (EPLA) at our two hospitals. The mean (standard deviation (SD)) age at diagnosis was 51.7 (14.5) years (range 17\u201381 years) and mean follow-up after surgery was 12.7 months (range 1.4\u201341.5 months). Fourteen patients underwent these procedures as primary surgeries; the other seven received these procedures as revisions . The othventions . As can Patient characteristics and disease features are summarized in P = 0.064). The mean (SD) values for pretreatment SNOT-22 and VAS are 32.6 (22.1) and 6.7 (3.4), respectively. Patients who did not have papillomas reported statistically higher VAS ratings and SNOT-22 scores than those with papillomas (Average AP diameter was 5.5 (1.4) mm, and mean PLR medial wall height 26.9 (4.2) mm (range 19\u201334.9 mm). AP diameter of three diseased sides is greater than 7 mm whereas the measurement of the remaining 19 sides ranged from 3 mm to 7 mm. We did not find difference of modified-Lund\u2013Mackay scores between patients with sinonasal papillomas and chronic rhinosinusitis (3.0 (IQR 2.0\u20133.5) vs. 4.0 (IQR 4.0\u20134.0), pillomas .P-values < 0.05), while individuals with papillomas also reported improved VAS ratings and SNOT-22 scores, though without statistical significance . Finally, 16 patients were enrolled in functional outcomes analysis measured at the last clinical visit after primary EPLAs. There were no significant differences in post-treatment patient-reported outcomes between those with sinonasal papillomas and those with other pathologies . Patientificance . There wn = 11 vs. n = 2). The most commonly seen complication was paresthesia (n = 11) of cheek and tooth, and all symptoms of this complication resolved within 6 months. Patients with AP diameter ranged from 3 mm to 7 mm tend to have higher prevalence of surgery-associated neural sequels, compared with individuals with AP diameter greater than 7 mm , though of no statistical significance (P = 1.00). One patient had delayed wound healing resulting from a prior submucosal turbinectomy allegedly caused by post-surgical scarring. Additionally, one patient developed epistaxis soon after the surgery. No nasal lacrimal ducts or negative esthetic issues  were found.A total of 11 patients had 13 adverse events. Papilloma patients had a significantly higher incidence of post-operative complications, compared to patients with other pathologies , which are locations that traditional surgical corridors can hardly access . In seleOne recent study has reported that operations employing EPLA to treat maxillary or retro-maxilla lesions can achieve outcomes comparable to those achieved by traditional open approaches performed by experienced hands . HoweverInitially EPLA for neoplastic lesions were designed to provide a corridor to allow the management of lesions within infratemporal and pterygopalatine fossa tumors . RecentlThe proposed mechanisms for relatively higher incidence of transient neural sequel in our sinonasal papilloma patients are illustrated as the follows. The first is the majority of our study population has type II PLR (AP diameter ranged from 3 mm to 7 mm) . In an iSome studies have reported greater/faster symptoms reduction and less disease recurrence following surgeries compared with appropriate pharmaceutical managements alone in certain subgroups of chronic rhinosinusitis . HoweverThis study has some limitations. One limitation is its relatively small sample size and a lack of a control cohort treated with other surgical strategies. This made further comparisons of multiple endpoints among different cohorts with maxillary lesions difficult. Another limitation is that because we only had access to post-operative outcomes approximate 6 months later, we could not determine whether reduced inflammation reached nadir after surgical treatment using EPLA. An additional limitation is that we remain unclear regarding the altered extent of nasal airway resistance and maxillary sinus mucociliary clearance post-operatively. Future investigations are needed to verify long-term rhinologic manifestations. Still another is we did not analyze influencing factors (e.g., laterality In conclusion, we found that in addition to tumors, EPLAs can be used to safely and efficaciously treat various lesions within the maxillary sinus. This approach might be used to replace invasive or time-consuming surgical strategies currently used to manage certain pathologies. We found most common adverse event to be transient cheek/tooth numbness but they usually subsided within 6 months. Thus, with adequate patient counseling, symptoms reduction and improvements in life quality can be expected after receiving surgical treatment of maxillary sinus lesions using EPLAs.10.7717/peerj.8331/supp-1Supplemental Information 1Click here for additional data file."}
+{"text": "OBJECTIVES/SPECIFIC AIMS: Test the hypothesis that neprilysin inhibition with sacubitril/valsartan will increase endogenous intact GLP-1 after a mixed meal compared with valsartan. METHODS/STUDY POPULATION: Adults 18\u201380 years with pre-diabetes or type 2 diabetes and elevated blood pressure. RESULTS/ANTICIPATED RESULTS: We anticipate higher intact GLP-1 area under the cure after the meal when subjects receive sacubitril/valsartan compared with valsartan. DISCUSSION/SIGNIFICANCE OF IMPACT: Neprilysin inhibition may be a target for anti-diabetes therapy by decreasing degradation of GLP-1."}
+{"text": "Paspalum notatum genotypes in order to identify molecular pathways under epigenetic control that might be involved in the transition from sexuality to agamospermy.Apomixis is considered an evolutionary deviation of the sexual reproductive pathway leading to the generation of clonal maternal progenies by seeds. Recent evidence from model and non-model species suggested that this trait could be modulated by epigenetic mechanisms involving small RNAs (sRNAs). Here we profiled floral sRNAs originated from apomictic and sexual Paspalum transcriptomic resources showed these routes are functional during reproductive development, with several members differentially expressed in apomictic and sexual plants. Triplicate floral sRNA libraries derived from apomictic and a sexual genotypes were characterized by using high-throughput sequencing technology. EdgeR was apply to compare the number of sRNA reads between sexual and apomictic libraries that map over all Paspalum floral transcripts. A total of 1525 transcripts showed differential sRNA representation, including genes related to meiosis, plant hormone signaling, biomolecules transport, transcription control and cell cycle. Survey for miRNA precursors on transcriptome and genome references allowed the discovery of 124 entities, including 40 conserved and 8 novel ones. Fifty-six clusters were differentially represented in apomictic and sexual plants. All differentially expressed miRNAs were up-regulated in apomictic libraries but miR2275, which showed different family members with opposed representation. Examination of predicted miRNAs targets detected 374 potential candidates. Considering sRNA, miRNAs and target surveys together, 14 genes previously described as related with auxin metabolism, transport and signaling were detected, including AMINO ACID/AUXIN PERMEASE 15, IAA-AMIDO SYNTHETASE GH3\u20138, IAA30, miR160, miR167, miR164, miR319, ARF2, ARF8, ARF10, ARF12, AFB2, PROLIFERATING CELL FACTOR 6 and NITRATE TRANSPORTER 1.1.The mining of genes participating in sRNA-directed pathways from floral Paspalum notatum plants. An integration of the small RNA profiling data presented here and previous transcriptomic information suggests that sRNA-mediated regulation of auxin pathways is pivotal in promoting apomixis. These results will underlie future functional characterization of the molecular components mediating the switch from sexuality to apomixis.This work provides a comprehensive survey of the sRNA differential representation in flowers of sexual and apomictic The online version of this article (10.1186/s12864-019-5881-0) contains supplementary material, which is available to authorized users. In plants, several small RNA pathways that likely diversified from a cellular defense mechanism against viruses and transposable elements are essential regulators of genome expression through mRNA cleavage, translational repression and DNA methylation . As suchCurrently, apomictic developments are viewed as the outcome of the deregulation of one or more developmental program/s involved in the sexual pathway , and theBABY BOOM-like controlling parthenogenesis in aposporous Pennisetum squamulatum [ORIGIN RECOGNITION COMPLEX3 promoting imbalanced endosperm development in aposporous Paspalum simplex [QUI GON JINN necessary for the emergence of 2n-ES in aposporous Paspalum notatum [Considering the prospects for the permanent fixation of any genotype regardless of genetic complexity, harnessing apomixis into agriculture would allow to dramatically accelerate plant breeding schemes and reduce the cost of improved varieties . Howeveramulatum , ORIGIN  simplex  or QUI G notatum . On the  notatum \u201324.P. simplex [Eragrostis curvula plants subjected to environmental stress [Arabidopsis thaliana and maize have shown that inactivation of members of the RNA-dependent DNA Methylation (RdDM) pathway results in reproductive phenotypes reminiscent of apomictic developments [Boechera holboelli and E. curvula RdDM members are deregulated in ovules of apomictic plants compared to sexual plants [Although a large amount of information indicates that apomixis is genetically determined , increas simplex . Moreovel stress , 29. Furl stress \u201332, and l stress  have beelopments \u201336. Intel plants , 37.Boechera [Hypericum and Hieracium [Citrus (which shows adventitious embryony) [Citrus (miRN23-5p) [SQUAMOSA PROMOTER BINDING PROTEIN LIKE11 and Cs9g06920 (an unknown protein containing the XS conserved domain) after miR156/157 (Boechera) and miRN23-5p (Citrus) decreased expression in apomictic ovules. Similarly, transcript expression differences between sexual and apomictic Hieracium ovules correlated poorly with 24-nt small RNAs abundances, since only two EXORDIUM-like genes could be identified among 40 differentially expressed targets [These observations led several research groups to explore small RNA components in reproductive organs of sexual and apomictic plants belonging to different genera, including diplosporous Boechera , aposporieracium , 40, andmbryony) . These wRN23-5p) \u201341. AlthPaspalum genus is an attractive biological system for studying apomixis, since it is both a model system for mining candidate gene(s) and an important target forage crop [Paspalum spp. , together with the existence of a wide range of cytotypes (with ploidy levels ranging from 2x to 16x), likely contributed to complex functional diversification and wide distribution across the Americas, from North Patagonia to Central Mexico [Paspalum species are a key endemic forage resource for South American grasslands and pasture agro-ecosystems, they remain largely undomesticated. Therefore, generating novel knowledge on the genetic and molecular determinants of apomixis is essential for breeding and delivering novel Paspalum cultivars adapted to the challenges of climate change and societal demands on agriculture [P. notatum [The age crop . The sopl Mexico . Moreoveiculture , 42. To  notatum  with smaSmall-RNA directed pathways all rely on the activities of DICER-LIKE (DCL) enzymes that generate 21\u201324-nt small RNAs by processing: 1) hairpins of single-stranded RNAs synthesized from RNA POLYMERASE II (Pol II); 2) long double-stranded RNAs (dsRNAs), whose biogenesis requires transcription by Pol II or RNA POLYMERASE IV (Pol IV) followed by dsRNA synthesis by RNA-DEPENDENT RNA POLYMERASEs (RDRs); and 3) long dsRNAs arising from the hybridization of sense and antisense transcripts, from the fold-back of an inverted-repeat sequences, or from the hybridization of unrelated RNA molecules with sequence complementarity .Paspalum reference floral transcriptome annotations [P. notatum genome (i.e. isotigs of isogroup 01605). Predicted P. notatum AGO proteins (PnAGOs) were aligned with O. sativa Japonica and A. thaliana AGO proteins and a phylogenetic tree was inferred after careful visual inspection and post-processing multiple alignments for masking gaps. As shown in Fig.\u00a0P. notatum transcript homologs to most of the genes encoding proteins involved in key phases of PTGS and RdDM [n\u2009=\u200967 hits)  and a sexual (C4-4x) genotype, in mixed samples representing four developmental stages, by using a triplicate Illumina small RNA sequencing assay. The total number of raw reads across libraries ranged from 1,558,547 to 2,996,675, with an average % GC of 54.67\u2009\u00b1\u20090.51  collected from the two genotypes used in this work (Q4117 and C4-4x) [t\u2009=\u20090.831, paired samples) and clustering analysis revealed high similarities between replicates  and thus selected for further analyses. The number of reads mapped in this set of transcripts for each library is provided   . In parttes Fig.  b. Out oes) Fig.  c.Table Paspalum reference transcriptome. Next, we focused in determining to which extent small-RNA target genes belong to this particular group. To achieve this, we first categorized O. sativa orthologs of annotated small RNA target genes (4560 unique genes) using the plant structure development stage ontologies provided Plant Ontology database [Paspalum reference transcriptome: within the class \u2018biological processes\u2019, the subclasses \u2018cellular process\u2019 (GO: 0009987) and \u2018metabolic process\u2019 (GO: 0008152) resulted predominant, representing 29.3 and 28.8% of the transcripts, respectively; within the class \u2018cellular component\u2019, the most represented subclasses were \u2018cell part\u2019 (GO: 0044464) and \u2018organelle/nucleus\u2019 (GO: 0043226), with 39.6 and 29.1% of the transcripts, respectively. Moreover, within the class molecular function, the subclasses \u2018catabolic activity\u2019 (GO: 0003824) and \u2018binding\u2019 (GO: 0005488) reached 50 and 27.8% of the total transcripts, respectively . Interestingly, among all differential transcripts, we detected several homologs of O. sativa genes encoding proteins involved in: 1) meiosis: MEIOSIS-SPECIFIC DNA RECOMBINASE, SYNAPTONEMAL COMPLEX (SC) ASSEMBLY; MALE-GAMETE-SPECIFIC HISTONE H3; 2) biomolecules transport: AMINO ACID/AUXIN PERMEASE 15; MULTIDRUG RESISTANCE 9; MRS2/MGT FAMILY MEMBER 9; ABC TRANSPORTER I FAMILY MEMBER 8; MONOSACCHARIDE TRANSPORTER 1; SORBITOL TRANSPORTER; AMMONIUM TRANSPORTER 3 MEMBER 1; METAL TOLERANCE PROTEIN 8.1; HIGH-AFFINITY POTASSIUM(K+) TRANSPORTER 13; AMINO ACID TRANSPORTER-LIKE 5; and BI-DIRECTIONAL AMINO ACID TRANSPORTER 1; 3) hormone signaling pathways: AMINO ACID/AUXIN PERMEASE 15; MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE; GIBBERELLIN-INSENSITIVE DWARF 2; INDOLE-3-ACETIC ACID (IAA)-AMIDO SYNTHETASE GH3\u20138; and IAA30; 4) transcriptional regulation: b-ZIP TRANSCRIPTION FACTOR 71; ETHYLENE RESPONSE FACTOR 77 (APETALA-2-LIKE TRANSCRIPTION FACTOR); FINGER PROTEIN WZF1; WRKY GENE 67; BEL1-LIKE HOMEODOMAIN GENE 6; MADS27; and GROWTH-REGULATING FACTOR 1, 3, 9, and 10; and 5) cell cycle and proliferation: CELL DIVISION CYCLE PROTEIN 20.1; and CELL DIVISION CONTROL PROTEIN 2 HOMOLOG 2  signaling, biomolecules transport, transcription control and cell cycle undergo differential epigenetic regulation during apomictic and sexual reproductive development.Next, edgeR was used to compare the number of sRNA reads between sexual and apomictic libraries that map over all P. notatum floral reference libraries (454/Roche FLX +) revealed a list of 3732  isotigs associated with apomixis [P. notatum. Besides, since our libraries originated from bulks, our approach did not allow to discriminate at which specific stage differential expression occurred. Nevertheless, we likely detected differential expression across all developmental stages and further investigations such as in situ hybridization or qPCR experiments should help in resolving temporal differences.Previous comparative transcriptome analyses of apomictic and sexual apomixis , which iP. notatum, we computed small RNA sequences with ShortStack using the Paspalum floral transcriptome and the closely related genomic sequences of O. sativa, Setaria italica and Sorghum bicolor as references. Percentages of unmapped reads varied from 58.0% in S. bicolor to 69.7% in P. notatum (Table\u00a0P. notatum transcriptome (16.7%), while it dropped down to 8.0% for heterologous genomic references , but three of them  were found across all four references  were detected Table . FoldingSmall RNA read counts derived from both apomictic and sexual libraries were normalized and analyzed for differential expression using edgeR. Out of the 124 candidate miRNA precursors, 9 showed highly significant differences between reproductive modes, being all of them over-represented in apomictic libraries . According to our annotation, these loci produce both conserved  and novel  miRNAs , exhibited congruent expression patterns among the various precursors detected across the references used. However, the four precursors we identified for the miR2275 family showed contrasting behavior: while no significant change was detected for osa-miR2275a and bdi-miR2275a , the two remaining precursors showed opposite changes, i.e. increased expression in apomictic libraries for ata-miR2275b-3p  and slightly decreased expression in apomictic libraries for zma-miR2275b-5p .Several of the miRNAs showing strong and modest differences in abundance between apomictic and sexual plants have been associated with many aspects of plant reproductive development, including: miR156, miR159, miR160, miR167, miR169, miR319, miR390, miR2118, and miR2275 \u201351. Of i, we computationally predicted binding sites for the 40 mature miRNAs reported in Table Paspalum transcriptome reference using TargetFinder. Using a cut off value of 4.0, 376 hits were identified representing 283 different transcripts, out of which 224 were unique hits (i.e. target of a single miRNA), while 40, 11, 5, and 3 were found 2, 3, 4 and 5 times, respectively  were targeted by miRNAs from a single family, but a few ones were targeted by members of two families . We identified targets for all predicted miRNA families but miR158. The number of targets varied greatly across families (from 1 to 78 for miR156) and accessions (from 1 to 19 for Pn_miR2)  family (miR156), the NAC  family (miR164), the HD-ZIP family (miR166), the GROWTH-REGULATING FACTOR family (miR396), and the AUXIN RESPONSE FACTOR (ARF) family  [O. sativa orthologs corresponding to molecular function (MF), cellular components (CC), and biological processes (BP) are shown in Fig. With the aim of identifying putative miRNAs targetsPaspalum reference transcriptome for candidate target transcripts already assessed for differential expression between apomixis and sexuality [n\u2009=\u200921; FC\u2009>\u20094) over moderate  and low  differences. However, despite increased expression in apomictic libraries affected most miRNA genes differentially expressed between apomictic and sexual libraries, no bias in direction change was observed for the predicted targets (18 downregulated vs. 16 upregulated).Next, to identify putative major molecular routes differentially modulated by miRNAs during sexual and apomictic developments, we mined the exuality . Out of Then, miRNA/target pairs with consistent opposed expression were identified by comparing changes in representation for miRNAs and their target transcripts  are key proteins involved in many developmental processes through the regulation of auxin responsive gene expression by targeting specific binding sites within their promoter , 55. The complex . Recent bidopsis  and miR1bidopsis . Furtherbidopsis , 60. TCPpromoter , 62. In promoter . NRTs bepromoter . Severalbidopsis , 66, incbidopsis . FurtherPaspalum floral reference transcriptomes revealed more 40 genes related to auxin metabolism and signaling showing differential expression [P. notatum apomictic biotypes, resulting in altered signaling pathways and ultimately affecting growth and development.In summary, sRNA, miRNA and target analyses identified 14 molecules related with auxin transport, metabolism and response and encoded by a gene that differed in expression between sexual and apomictic plants, including: AMINO ACID/AUXIN PERMEASE 15 (auxin influx carrier) ; INDOLE-pression . AltogetPaspalum transcriptomic resources allowed the detection of miRNAs from 22 known conserved plant families, predicted novel members for two conserved plant families (miR156 and miR171) and four novel Gramineae miRNA families, including one specific to P. notatum. Furthermore, an integration of differential representation analyses for small RNAs, miRNA genes and miRNA targets suggested that small RNA-dependent auxin-centered mechanisms might be involved in the switch from sexuality to apomixis. The differences we observed in small RNA targets and miRNA biogenesis provide novel, attractive hypotheses that will guide future functional research. With regards to this, addressing the roles of miR160, miR167 and miR319 during sexual reproduction appears critical to expand our understanding of the molecular mechanisms underlying apomixis in Paspalum species.Our analysis of the small RNA expressed on the floral transcriptome of sexual and apomictic genotypes indicated that numerous genes belonging to PO ontology classes associated with reproductive development are probably controlled by epigenetic mechanisms and differentially expressed between both reproductive types. Moreover, the analysis of the small reads data set combining several Gramineae genome references and Paspalum notatum tetraploid (2n\u2009=\u20094x\u2009=\u200940) genotypes were used to collect material for small RNA libraries construction: Q4117, a highly heterozygous natural accession collected from the State of Rio Grande do Sul (Southern Brazil) that reproduces through obligate aposporous apomixis [P. notatum is a perennial rhizomatous species, therefore allowing multiplication through vegetative replicas. Both genotypes (Q4117 and C4-4x) belong to the living Paspalum germplasm collection established at IBONE-CONICET-UNNE . Vegetative replicates were transferred and maintained in experimental plots at IICAR-CONICET-UNR . Replicates of both Q4117 and C4-4x were established in neighboring plots in order to guarantee identical growing environmental conditions.Two apomixis  and C4-4apomixis . Due to i. e. balanced mixes) of spikelets collected at four developmental stages: premeiosis, meiosis, postmeiosis and anthesis. The material was classified into different developmental stages categories by correlating micro- and megagametophyte development and following the P. notatum reproductive calendar, as recommended in previous work [Small RNAs libraries were produced in triplicate from evenly balanced bulks  provided by the Gramene database [\u2212\u200905, ID >\u200950%, and alignment length\u2009>\u2009200). For AGO proteins phylogenetic analysis, we used the MUSCLE alignment and the Neighbor-joining options of Geneious\u00ae10.0.9. Phylogenetic tree was inferred after careful visual inspection and post-processing multiple alignments for masking gaps and using bootstrap values (1000 replicates). A. thaliana and O. sativa Japonica sequences were recovered from the Gramene database [P. notatum protein sequences were predicted from selected transcripts.We re-annotated the database . For glodatabase  and P. nP. notatum reference floral transcriptome generated from Q4117 and C4-4x genotypes  [p-value <\u20090.05 (FDR) [Small RNA reads were aligned onto the 454/Roche FLX+ riptome) . Mappingriptome)  with theriptome)  using Q\u2009riptome) . Only trriptome)  was usedriptome) . Sexual 05 (FDR) . CompariP. notatum floral transcriptome, small RNA sequences were analyzed with ShortStack version v05 using default parameters [Paspalum, small RNA alignments were performed using the Paspalum reference transcriptome and three other genomic sequences of related grasses including: Oryza sativa Japonica (Assembly GCA_001433935.1), Sorghum bicolor v2 (Assembly: GCA_000003195.2) and Setaria italica JGIv2.0 (Assembly GCA_000263155.2). Briefly, we aligned the small RNA reads against each reference using Bowtie allowing two mismatches (\u2212n 2) and requiring 18 high quality bases to initiate the alignment (\u2212l 18). Then, candidate cluster  associated to small RNA sequences were identified with the default parameters. Putative miRNAs were then selected based on a DicerCall of 20\u201322. Mature miRNA sequences were compared against miRBase [P. notatum miRNAs (Pn_miRNAs). The secondary structure of the predicted novel miRNA genes was analyzed using RNAfold within the ViennaRNA Package [\u2212\u20091 [In order to predict miRNA genes expressed in the rameters . Since n miRBase  using th Package  and manuage [\u2212\u20091 . Multiplage [\u2212\u20091 . The phyp values (FDR)\u2009\u2264\u20090.05 and logFC \u2265 |1| were considered differentially expressed.Differential expression of miRNA precursors was carried out using edgeR . Only 20Paspalum reference transcriptome. Common ontologies (GO-Slim and PO) were established using the PANTHER [Paspalum targets between sexual and apomictic developments, we took advantage of former expression analysis, considering only those transcripts that showed at least 10 reads in one of the libraries [We used TargetFinder  with the PANTHER  and Plan PANTHER . Finallyibraries .Additional file 1:Paspalum floral transcripts involved in sRNA-directed pathways. Section 1. List of key rice genes involved in small RNA-directed pathways and their P. notatum homologs expressed in floral tissues. Section 2: Expression levels of floral P. notatum transcripts homologous to key genes involved in small RNA-directed pathways. (XLSX 22 kb)Lists of annotated Additional file 2:Paspalum notatum genotypes. (PDF 178 kb)General statistics for the sequencing of triplicate floral sRNA libraries. The sRNA libraries were originated from apomictic (Apo) and sexual (Sex) Additional file 3:P. notatum floral transcripts harboring sRNA derived from apomictic and sexual libraries. Section 1: Number of small RNA reads from apomictic (Apo) and sexual (Sex) libraries mapping onto the Paspalum transcriptome reference. Section 2: List of the 1000 P. notatum transcripts with highest small RNA coverage. Section 3: Classification of the Paspalum annotated small RNA targets into ontology classes, according to Plant Structure Development Stage Ontologies (www.planteome.org). Section 4. Functional classification and PANTHER overrepresentation test for annotated small RNA targets. Section 5: edgeR analysis of small RNA reads mapped over the P. notatum reference transcriptome. (XLSX 6165 kb)Lists of Additional file 4:P. notatum genotypes. Section 1. List of clusters harboring miRNAs detected in four references  with ShortStack v.3.8.5. Section 2. BLAST SSEARCH of mature miRNAs sequences of P. notatum against MirBase. Section 3. edgeR expression analysis of clusters harbouring miRNAs detected using the above-mentioned four references. (XLSX 51 kb)Lists of miRNA detected in floral samples of sexual and apomictic Additional file 5:Folding analysis of miRNA putative precursors. Secondary structures derived from folding 8 predicted miRNA precursors. (PDF 667 kb)Additional file 6:P. notatum floral transcriptome. (PDF 53 kb)Phylogenetic analysis of miRNA sequences. Phylogenetic analysis by maximum likelihood method of mature miRNA sequences expressed in the Additional file 7:Paspalum transcriptome reference and annotated after blastx on a rice peptide database . Section 2: miRNA targets with or without differential expression between sexual and apomictic libraries, as detected in the Paspalum transcriptome reference: read coverage analysis and annotation. (XLSX 68 kb)miRNA targets prediction. Section 1: miRNA targets detected in the"}
+{"text": "Substantial evidence suggests a protective effect of annual influenza immunization on cardiovascular diseases (CVD). The inflammatory mediator TNF-related weak inducer of apoptosis (TWEAK) is thought to be involved in the pathogenesis of CVD. We previously showed that administration of a standard-dose influenza vaccine reduced circulating TWEAK levels. This study aimed to test the hypothesis that a high-dose vaccine would have greater impact on TWEAK levels than the standard-dose. Two groups of participants matched on age and sex were included in the study. One group (n=25) received standard-dose vaccine during 2008-2009 season, the other group (n=25) received high-dose vaccine during 2014-2015 season. Soluble TWEAK (sTWEAK) levels were assessed using ELISA in serum samples collected immediately before vaccination and during the 4th week after vaccination. Vaccine-induced strain specific antibody titers were measured by hemagglutination inhibition assay. The participants had a mean age 86 years and 68% were women. Our preliminary results thus far demonstrated no statistically significant change in sTWEAK levels after vaccination in either group . Pre-vaccination sTWEAK levels tended to be negatively associated with age (unadjusted linear regression of log2(x) transformed TWEAK levels on age: estimate [\u00b1SE]=-4.6% [\u00b12.7%] change in TWEAK level per year, p=0.08). We continue to evaluate more pre- and post-vaccination samples. We have also begun exploring TWEAK expression by circulating immune cells (T and B lymphocytes and monocytes) and potential impact of influenza immunization in older adults."}
+{"text": "Glucocorticoid excess medication interrupts osteoblast homeostasis and exacerbates bone mass and microstructure loss ramping up the pathogenesis of osteoporotic disorders. Heat shock protein 60 (HSP60) is found to maintain protein function within cellular microenvironment upon encountering detrimental stress. In this study, we revealed that supraphysiological dexamethasone decreased HSP60 expression along with deregulated autophagy in osteoblasts cultures. This chaperonin is required to sustain autophagic markers Atg4, and Atg12 expression, LC3-II conversion, and autophagic puncta formation, and alleviated the glucocorticoid-induced loss of osteogenic gene expression and mineralized matrix accumulation. Regulator-associated protein of mTOR complex 1 (RPTOR) existed in HSP60 immunoprecipitate contributing to the HSP60-promoted autophagy and osteogenesis because knocking down RPTOR impaired autophagic influx and osteogenic activity. HSP60 shielded from RPTOR dysfunction by reducing the glucocorticoid-induced RPTOR de-phosphorylation, aggregation, and ubiquitination. In vivo, forced RPTOR expression attenuated the methylprednisolone-induced loss of osteoblast autophagy, bone mass, and trabecular microstructure in mice. HSP60 transgenic mice displayed increased cortical bone, mineral acquisition, and osteoblast proliferation along with higher osteogenesis of bone marrow mesenchymal cells than those of wild-type mice. HSP60 overexpression retained RPTOR signaling, sustained osteoblast autophagy, and compromised the severity of glucocorticoid-induced bone loss and sparse trabecular histopathology. Taken together, HSP60 is essential to maintain osteoblast autophagy, which facilitates mineralized matrix production. It fends off glucocorticoid-induced osteoblast apoptosis and bone loss by stabilizing RPTOR action to autophagy. This study offers a new insight into the mechanistic by which chaperonin protects against the glucocorticoid-induced osteoblast dysfunction and bone loss. Chronic glucocorticoid use damages survival and anabolism of bone cells aggravating excessive bone loss and microarchitecture porosity, prominent deleterious effects notorious for osteoporosis development3. Organelle deregulation and protein dysfunction speed up osteoblast apoptosis contributing to the progression of glucocorticoid-mediated osteoporosis. For example, high concentrations of glucocorticoid disrupt endoplasmic reticulum4 and deteriorates mitochondrial integrity5 inducing a burst of reactive oxygen radicals that drastically impedes osteoblast viability. Increased E3 ubiquitin ligase signaling ramps up glucocorticoid-induced osteopenia in mice6. The mechanism underlying the glucocorticoid-impaired intracellular homeostasis and organelle machinery in osteoblasts upon glucocorticoid stress has not been well investigated.Glucocorticoid medication is widely prescribed to lessen immune irregularity and malignant hematological disorders, like allergy, arthritis, and leukemia7. As regards the biological role of autophagy in skeletal metabolism, knockout mice deficient in autophagic vesicle builder Atg5 in osteoblasts show poor mineralization capacity and low bone mineral density8. Mice lacking Atg5 and Atg7 in chondrocytes exhibit bone undergrowth9. Poor autophagy slows down bone development in fibroblast growth factor knockout mice10. In addition, mice lacking upstream autophagy regulator mammalian target of rapamycin complex 1 (mTORC1) in osteoblasts display low bone mass and meager trabecular microstructure11, whereas osteoclast-specific mTORC1 knockout mice reveal high bone mineral density owing to impaired osteoclastic resorption capacity12. The role. of mTORC1 signaling components in the progression of glucocorticoid-induced osteoporosis remains elusive.Autophagy is a sophisticated intracellular program, including progressive autophagosome formation and lysosomal degradation, responsible for removing abandoned organelle or proteins to maintain regular physiological activity of cells upon experiencing adverse conditions13. HSP60 knockout causes intestinal epithelial stem cells to lose stemness and proliferation capacity14. Decreased HSP60 impairs mitochondrial integrity worsening the fused sarcoma-associated neurodegenerative disorders15, whereas increasing this chaperonin promotes mitochondrial energy expenditure of murine skeletal muscle during endurance training16. Upregulating HSP60 facilitates alveolar macrophage autophagy to augment inflammatory responses in lung tissue upon ischemia and reperfusion17. We previously found that mice overexpressing HSP60 exhibited minor responses to chondrocyte apoptosis and knee osteoarthritis progression18. Silencing HSP60 expression induced bone loss in rats19. Given that HSP60 participated in bone metabolism, we hypothesized that it may regulate osteoblast autophagy during the pathogenesis of glucocorticoid excess-induced osteoporotic skeletons.Heat shock protein 60 (HSP60) is a mitochondrial chaperonin, stabilizing protein function through chaperoning unfolded proteins into a folded stateThis study is undertaken to investigate molecular events underlying HSP60 action to glucocorticoid-impaired osteoblast autophagy and osteogenic differentiation, and utilized HSP60 transgenic mice to verify its regulatory functions to osteoblast autophagy, survival, and bone mass homeostasis in long-term glucocorticoid excess-treated skeletal tissue.20. Dexamethasone significantly reduced HSP60 mRNA expression and protein levels along with slight HSP60 immunofluorescence in cytoplasmic compartment as compared with vehicle group  or RNA interference (RNAi). Gain of RPTOR function Fig.\u00a0 attenuat22. Glucocorticoid or HSP60 RNAi decreased levels of phosphorylated ERK, phosphorylated Ser473-Akt, and phosphorylated RPTOR  driven by PGK promoter were bred for studysue Fig.\u00a0. They gasue Fig.\u00a0. With resue Fig.\u00a0. Bone misue Fig.\u00a0 and prolsue Fig.\u00a0, respectsue Fig.\u00a0. Consistsue Fig.\u00a0.Fig. 6AnWe verified whether HSP60 overexpression changed bone histology or osteoblast autophagy in skeletal tissue at 4 weeks after methylprednisolone treatment. Glucocorticoid escalated trabecular bone loss histopathology and significantly decreased BV/TV in wild-type mice. These adverse effects were significantly attenuated in HSP60Tg mice Fig.\u00a0. FurtherTo verify whether HSP60 changed osteogenic differentiation capacity, primary bone marrow mesenchymal cells were isolated and incubated in osteogenic medium. In the wild-type group, glucocorticoid significantly inhibited Runx2, collagen 1\u03b11, and osteocalcin expressions Fig.\u00a0, and min7. Deregulated autophagy ratchets up the pathogenesis of skeletal and arthritic disorders. For example, low autophagic breakdown of misfolded collagen worsens osteogenesis imperfecta in mice23. Overacted autophagy mediates metal implant particle-induced osteolysis24. Proteasome inhibitor bortezomib-suppressed autophagy weakens bone metastasis capacity of multiple myeloma cells25. Poor osteoblast autophagy of crystal urate increases chronic gout development26. Aberrant autophagy hinders osteogenesis of bone marrow mesenchymal stem cells worsening diabetes-induced bone mass loss27. The contribution of osteoblast autophagy to glucocorticoid-induced excessive bone catabolism has not been well defined. This study is the first uncovering HSP60 action indispensable in osteoblast autophagy for protecting skeletal tissue from glucocorticoid-induced osteoporosis. It also throws light on new mechanistic events by which mitochondrial chaperonin pathway preserves RPTOR function to autophagic influx within osteoblast microcompartment facilitating bone tissue homeostasis and microstructure integrity.Autophagy is involved in disposal of unwanted molecules to harmonize intracellular microenvironment, enabling cells to overcome deleterious conditions28, necroptosis of acute lymphoblastic leukemic cells29, and fat overproduction of adipose tissue30. Loss of HSP60 function also perturbs extracellular matrix metabolism and amplifies apoptotic programs32. This study showed that HSP60 maintained autophagic influx beneficial for fending off glucocorticoid-induced apoptosis and mineralized matrix underproduction, indicating that glucocorticoid stress cutoff a fine-tuned organelle crosstalk between autophagosome and mitochondria aggravating osteoblast dysfunction. These interesting findings prompted us to decipher the molecular event by which HSP60 regulated osteoblast autophagy.Analyses of osteoblast culture models revealed that HSP60 was required to osteogenesis because silencing this mitochondrial chaperonin largely led to mineralized matrix synthesis below baseline, overexpressing it enabled cell cultures to uphold osteogenic differentiation capacity upon supraphysiological glucocorticoid-mediated adverse stress. Increasing evidence reveals that high dose of therapeutic glucocorticoid disturbs mitochondrial machinery provoking cell damage or tissue deterioration, like skeletal muscle wasting33. On the contrary, bone tissue-specific RPTOR knockout mice show bone underdevelopment34 and poor osteogenic activity of preosteoblasts11. Activation of mTORC1 prevents from osteoporosis progression in mice overexpressing Wnt1 in osteocytes35. We uncovered its role in preserving osteoblast function and bone integrity because increasing RPTOR alleviated the severity of glucocorticoid-induced bone mass loss and microstructure deterioration. Together with our findings and other groups\u2019 investigations, this molecule appeared to serve different functions depending on bone cell types and deleterious stresses impacted on skeletal tissue. Given that HSP60 interacted with RPTOR, further experiments were performed to delineate in detail how HSP60 warded off the glucocorticoid-induced RPTOR loss.Of note, arrays of analyses uncovered that RPTOR interplayed with HSP60 protecting osteoblasts against the glucocorticoid-impaired autophagy and differentiation. The regulatory action of RPTOR to skeletal tissue metabolism and osteoporosis pathogenesis seems like inconclusive. For example, bone marrow mesenchymal stem cells from RPTOR knockout mice favorably turn out to be osteogenic lineages37. It also affects kinase phosphorylation38 and cellular protein degradation39. In this study, we conveyed a new insight into chaperone machinery protective against the glucocorticoid-mediated RPTOR dysfunction. In addition to RPTOR stability, analyses of increased survival regulators ERK and Akt, and decreased pro-apoptotic signaling Bax and cytochrome c release consolidated the experimental findings showing that HSP60 facilitated osteoblast survival. Investigations were in agreement with other groups\u2019 studies demonstrating that Akt and ERK pathways phosphorylate RPTOR facilitating mTOR1 activity and cell growth41. Although it warrants further analysis in the future to characterize how chaperonin activates these regulators, changes in various signaling pathways indicated that multiple reactions within intracellular environment participated in stabilizing RPTOR to curtail the glucocorticoid excess-induced loss of osteogenic activity.Profound results of immunoprecipitation analysis revealed that HSP60 sustained RPTOR function by controlling multiple post-translational modification reactions of RPTOR, like phosphorylation, aggregation, and ubiquitination. HSP60 is found to convert mitochondrial proteins into a folding status, which drives them away from aggregationIntriguing findings were that HSP60Tg mice showed moderate bone overgrowth phenotypes like thickened cortical bone and increased bone mineral accretion, concomitant with intensive osteoblast proliferation. These anabolic effects kept skeletal tissue away from methylprednisolone excess-induced bone mineral density loss and trabecular porosity histopathology. Consistent with the analyses of in vitro osteoblast models, overexpressing HSP60 improved RPTOR signaling and autophagy to delay glucocorticoid-mediated osteoblast dysfunction. Collective investigations of sustained osteoblast autophagy and high osteogenic differentiation of bone marrow mesenchymal cells in HSP60Tg mice underpinned the bone anabolic function of HSP60 able to drag the glucocorticoid excess-mediated bone deterioration.Limitation of this study is that other regulators existing in HSP60 immunoprecipitate may directly or indirectly modulate osteoblast autophagy to alter bone formation upon glucocorticoid stress. It also indicates that HSP60 plays an important role in dealing with the complex nature of intracellular organelle intercommunication during glucocorticoid-deregulated osteoblast behavior. Taken together, plausible investigations revealed that HSP60 is required to osteoblast survival and mineralized matrix anabolism compromising the development of glucocorticoid-mediated osteoporotic skeletons through sustaining RPTOR function to osteoblast autophagy as schemed in Fig.\u00a05 cells/well were incubated in 24-well plates containing osteogenic medium  (R&D System) with 1\u2009\u03bcM dexamethasone or vehicle dimethyl sulfoxide for 18 days. Medium was changed every 3 days. Mineralized matrix deposits in cell cultures were detected using von Kossa staining, and area of mineralized nodules in three random fields in each well was measured using Zeiss Inverted microscopy and image analysis software, as previously described 42.Murine MC3T3-E1 osteoblasts were maintained in Dulbecco's Modified Eagle's Medium (DMEM) and 10% fetal bovine serum. 1\u2009\u00d7\u200910TM 3000 Transfection Reagent  and transferred into cell cultures, according to the manufacturer\u2019s instructions.cDNA coded human HSP60 or RPTOR were constructed into vectors pUSEamp(\u2009+\u2009) . RNA interference targeting HSP60 (#11067) and RPTOR (#178055) were obtained from Applied Biosystems Biotechnology (ThermoFischer Scientific). Aliquots of 2\u2009\u03bcg cDNA, RNAi or scramble controls were mixed with Lipofectamine\u00ae 488 and donkey anti-mouse IgG conjugated Alexa Fluor\u00ae 675  were used as secondary antibodies. After counterstaining with 4\u2032,6-diamidino-2-phenylindole (DAPI) and covering with Prolong Gold Antifade Reagent , immunofluorescence was evaluated using an Olympus Laser Confocal Microscope system. In some experiments, autophagic puncta in cell cultures were detected using fluorescent monodansylcadaverin probe of Autophagy Detection Kits , according to the manufacturer\u2019s instructions. Number of puncta in 30 cells in three random fields of each well were counted.After removing culture medium and rinsing with phosphate-buffered saline (PBS), cell cultures were fixed with 4% formaldehyde in PBS and blocked with normal goat serum . HSP60 and RTPOR immunoreactivity in cell cultures were probed using HSP60  and RPTOR antibodies . Goat anti-mouse IgG conjugated Alexa Fluor\u00ae Two-Step cDNA Synthesis Kits (Sigma-Aldrich). For PCR analysis, 2\u2009\u00d7\u2009TaqMan\u00ae Universal PCR Master Mix along with primers for probing HSP60 , RPTOR , Atg4 , Atg12 , Runx2 , collagen 1\u03b11 , osteocalcin , and actin  were mixed with the reverse transcription products. Gradient thermal programs and threshold values (Ct) computation were performed using a ABI 7900 Detection System (Applied Biosystems). Expressions of mRNA were calculated using the equation 2-\u0394\u0394Ct, where \u0394Ct resembled the difference in Ct values between the gene of interest and actin, and \u0394\u0394Ct stood for the difference in \u0394Ct between the glucocorticoid and vehicle group.Cell cultures were mixed with Trizol reagent to extract total RNA. Reverse transcription of 1\u2009\u03bcg total RNA was performed using ReadScript6 cells were prepared using Mammalian Cell Extraction Kits . HSP60, RPTOR, Atg4 , Atg12 , LC3 , phosphorylated ERK (#9106), phosphorylated Ser473-Akt (#9721), phosphorylated RPTOR (#2083), Bax (#2774), cytochrome c (#12963), caspase3 (#9662), ubiquitin (#3936), and actin  antibodies were used for probing the designated proteins in lysates using immunoblotting protocols. In some experiments, protein aggregates in 100\u2009\u03bcg cell lysates were isolated after ultrahigh centrifugation at 10,000\u2009g at 4\u2009\u2103 for 30\u2009min, as previously described20. For positive controls, 100\u2009\u03bcg cell lysates were mixed with equal volume of ice-cold acetone. Pellets were separated by electrophoresis and stained using Coomassie blue, and RPTOR levels in the pellet was probed using immunoblotting protocols. In addition, HSP60 and RPTOR immunoprecipitates were isolated for immunoblotting probed using ubiquitin antibody.Lysates of 5\u2009\u00d7\u20091019. Peptides in the hydrolyte were eluted through an Acclaim PepMap 100 column using a high-performance liquid chromatography system . Peptide sequences were characterized using electrospray ionization mass spectrometry . Analytic results detected by tandem mass spectrometry was submitted to SWISS-PORT bioinformation resource portal (http://www.expaysy.com) to match the peptide homology.Aliquots of HSP60 immunoprecipitates were electrophoresed, and protein bands of interest in the gel were cut for trypsin hydrolysis, as previously described\u00ae PLA Fluorescence Kits (Sigma-Aldrich). In brief, formaldehyde-fixed cell cultures were blocked using Duolink\u00ae Blocking Solution and mixed with HSP60 and RPTOR antibodies, and secondary antibody Duolink\u00ae PLA probe. Specimens were incubated in a Duolink\u00ae ligation buffer containing 1\u2009U/\u03bcl ligase at 37\u2009\u2103 for 30\u2009min and followed by reacting with an amplification solution containing 2\u2009U/ml polymerase and counterstaining with DAPI. Fluorescent spots in cell cultures were detected using a Zeiss fluorescence microscope, and number of fluorescent spots were counted using image analysis system .Interaction between HSP60 and RPTOR in cell cultures was probed using Duolink9 infectious units/ml lentivirus particle suspension. Twelve-week-old male FVB mice were anesthetized through inhale isoflurane. Twenty-four mice were evenly divided into two groups and anesthetized to receive 50\u2009\u03bcl RPTOR or mock lentivirus particle suspension through tail vein injection. One week after administration, mice were intra-peritoneally injected with 10\u2009mg/kg/day methylprednisolone for 4 weeks. For control group, 12 mice were injected with normal saline only. At the end of experiment, mice were killed to dissect femurs and tibiae for study. Six mice were used for \u03bcCT and histological assay, and 6 animals for harvesting bone extract for immunoblotting.Animal use protocols were reviewed and approved by IACUC, Kaohsiung Chang Gung Memorial Hospital (IACUC Affidavit No. 2011062101). HEK293 cells were transferred with 1\u2009\u03bcg pMIF-cGFP-zeo plasmid coding RPTOR along with 1\u2009\u03bcg pPACKF1 plasmid . Culture supernatants were harvested, ultrahigh centrifuged, and titrated using LentiX qRT-PCR Titration Kits  to prepare 2\u2009\u00d7\u20091018. Siblings that did not express the construct were designated as wild-type mice. 36 male HSP60Tg and 36 wild-type mice (12-week old) were evenly divided into two groups to receive 10\u2009mg/kg/day methylprednisolone or vehicle for 4 weeks. After euthanasia, bone tissue was dissected for study. Six mice were used for \u03bcCT imaging and histomorphology, six mice for harvesting total RNA in bone tissue, and six animals for isolating bone marrow cells.HSP60 transgenic mice  were bred, as previously described19. BMD (g/cm3), BV/TV (%), Tb.Th (mm), Tb.N, and Ct.Th (mm) of 200 slices of images with 9\u2009\u03bcm voxel size between growth plate region and midshaft region of proximal tibiae were calculated using SKYSCAN\u00ae CT-Analysis software.Tibiae were X-ray scanned using a Skyscan 1176 \u03bcCT system , as previously describedSections of methylacrylate-embedded tibiae blocks were stained using von Kossa reagent. Fluorescent calcein intensity was evaluated using a fluorescence microscope. Three sections of each animal were selected for measuring BV/TV (%) and mineral apposition rate . Immunohistochemical assessment was performed using LC3 antibody and BioGenex Immunohistochemistry Detection Kits . TUNEL staining in sections was probed using In Situ TUNEL Detection Kits (Roche Diagnostics GmbH). Osteoblasts showing positive immunostaining or TUNEL staining in each field were counted. Three fields in each section, and three sections of each mice were selected for measurement.19. In total, 1\u2009\u00d7\u2009105 cells/well bone marrow mesenchymal cells were incubated in 24-well plates containing osteogenic medium for 18 days. Mineralized matrix formation was stained using von Kossa staining reagents, and area of mineralized matrix in three random fields in each well was measured. In some experiments, cell cultures were harvested for reverse transcription polymerase chain reaction assessment of osteogenic gene expression.Primary bone marrow mesenchymal cells were isolated, as previously describedP values were set at <0.05.Experiments of cell culture models were repeated five times. Parametric analysis of variance and Bonferroni post hoc test were utilized to examine whether experimental results among vehicle, mock-treated, and RPTOR-treated groups, as well as the investigations among vehicle- and glucocorticoid-treated HSP60Tg mice and wild-type mice were significant different as the"}
+{"text": "ERD15 (Early Response to Dehydration 15), RAB18 (ABA-responsive gene) in Arabidopsis, COX1 (regulates energy and carbohydrate metabolism), PKDP (protein kinase), AP2-EREBP (stress responsive pathway), Hsp20, bZIP1 and COC1  in Pseudomonas fluorescens treated rice, LbKT1, LbSKOR (encoding potassium channels) in Lycium, PtYUC3 and PtYUC8 (IAA biosynthesis) in AMF inoculated Poncirus, ADC, AIH, CPA, SPDS, SPMS and SAMDC (polyamine biosynthesis) in PGPR inoculated Arabidopsis, 14-3-3 genes  in AMF treated Solanum, ACO, ACS (ethylene biosynthesis), jasmonate MYC2 gene in chick pea, PR1 (SA regulated gene), pdf1.2 (JA marker genes) and VSP1 (ethylene-response gene) in Pseudomonas treated Arabidopsis plants. Moreover, the key role of miRNAs in MIST has also been recorded in Pseudomonas putida RA treated chick pea plants.Drought conditions marked by water deficit impede plant growth thus causing recurrent decline in agricultural productivity. Presently, research efforts are focussed towards harnessing the potential of microbes to enhance crop production during drought. Microbial communities, such as arbuscular mycorrhizal fungi (AMF) and plant growth-promoting rhizobacteria (PGPR) buddy up with plants to boost crop productivity during drought via microbial induced systemic tolerance (MIST). The present review summarizes MIST mechanisms during drought comprised of modulation in phytohormonal profiles, sturdy antioxidant defence, osmotic grapnel, bacterial exopolysaccharides (EPS) or AMF glomalin production, volatile organic compounds (VOCs), expression of fungal aquaporins and stress responsive genes, which alters various physiological processes such as hydraulic conductance, transpiration rate, stomatal conductivity and photosynthesis in host plants. Molecular studies have revealed microbial induced differential expression of various genes such as  This ist plants  or induct plants ,25,26 ant plants .In present review article, we address the various MIST mechanisms responsible for enhancing plant productivity during drought as a result of interplay between plant and microbes (both PGPR and AMF).Claroideoglomus etunicatum) colonized Pistacia vera seedlings in comparison to non-mycorrhizal inoculated plants that helped plants to survive during drought [Lactuca [Macademia [Loquat [Allium [Erythrina [Knautia [Poncirus trifoliata [Cyclobalanopsis [Glycine plants showed elevated proline aggregation in roots and reduced proline content in shoots during water deficit [P. vulgaris nodules primed with Rhizobium etli overexpressing trehalose-6-phosphate synthase gene showed upregulation of genes engaged in stress tolerance in comparison to non-inoculated counterparts [A. brasilense primed maize plants during drought [Bacillus subtilis inoculated Arabidopsis plants as compared to its xipotl mutant [Azospirillum brasilense during osmotic stress [Arabidopsis plants treated with the Spd-producing Bacillus megaterium BOFC15. Inoculated plants survived drought stress because of robust root system possessing longer primary roots and increased lateral roots in comparison to the control plants [Abiotic stresses can alter the osmolality levels in plant which impedes its growth and survival. Hence to counteract it, osmotic adjustment and conglomeration of compatible solute accumulation is a requisite to combat dehydration loss caused by osmotic stress during drought. Plants under water stress can survive either by reducing water loss or sustaining water uptake. Osmotic adjustment is defined as a biochemical mechanism that involves the amassment of compatible osmolytes or solutes like proline, sugars, polyamines, betaines, quaternary ammonium compounds, polyhydric alcohols, amino acids and water stress proteins like dehydrins. Compatible osmolytes aggregation lowers cell water potential thus averting water loss and maintaining turgor in metabolically rustling cells which shields enzymes, proteins and biomembranes against oxidative stress . Osmolyt drought . A 3 fol drought . Proline[Lactuca , Macademacademia , white cacademia , maize [academia , Loquat  [Loquat , Allium  [Allium  and rice [Allium . Raised rythrina , Knautia[Knautia  and Poncifoliata  and Cycllanopsis . In addi deficit . It was  deficit . Trehalo deficit . Macro aterparts . Similar drought . Glycinel mutant . Variousl mutant ,46. It wl mutant . Polyamic stress . Increasl plants . Some stl plants ,49 henceBacillus cereus AR156, Bacillus subtilis SM21 and Serratia spp. XY21) primed cucumber plants displayed lower MDA levels and decreased relative electrical conductivity in leaves in comparison to control plants [A. brasilense inoculated Arabidopsis plants during drought [Glomus species during drought stress [cAPX transcription levels in BBS consortium primed cucumber plants that abated oxidative stress damages [Pseudomonas treated mung bean plants however CAT activity first inflated over 15\u201336 days and later decreased [Pseudomonas putida GAP-P45 inoculation downsized APX, CAT, GPX contents in maize plants in contrast to uninoculated counterparts [Lavandula plants treated with Bacillus thuringiensis [F. mosseae [Pseudomonas showed higher aggregation of enzymatic and non-enzymatic antioxidants compared to plants inoculated singly either with PGPR or AM [Rhizophagus irregularis inoculated Robinia seedlings had raised activity of SOD, POD, CAT, APX and GR activities and higher transcript levels of Cu/Zn-SOD during drought stress [Poncirus trifoliata trees colonized by Glomus versiforme in contrast to uninoculated trees during a drought period of 12 days [Rhizophagus intraradices) inoculated Eleusine seedlings revealed 16% higher flavonoid content and 25% higher ascorbate level in the leaves during drought stress [Usually ROS production as metabolic products is minimal in plants growing under normal conditions. Skewness induced as a result of ROS overproduction and detoxification in plants as a consequence of increased photorespiration and disrupted photosynthetic machinery is a cardinal change during water deficit or drought stress. ROS such as superoxide anion radical, hydrogen peroxide, hydroxyl radicals and singlet oxygen causes oxidative stress in plants leading to catastrophic damages to lipids, proteins and nucleic acids. Despite the fact that raised ROS levels induce oxidative damages, their lower levels are essential for the plant as they are involved in signalling events that activates various defensive pathways. Hence it is essential to manage ROS via coordinated control of ROS generation and ROS quenching systems to control oxidative stress damages and signalling functions. Plants are rigged with intrinsic setup of antioxidant defensive network to quash excess ROS. Antioxidant gadgetry constitutes enzymatic group (superoxide dismutase (SOD), peroxidase (POX), ascorbate peroxidase (APX), glutathione reductase (GR), catalase (CAT), ascorbate peroxidase (APX) and guaiacol peroxidase (GPOD)) and non-enzymatic components  . Even thl plants . Identict stress . Similart stress , maize [t stress  and pistt stress . Varioust stress ,55,56,57 damages . Increasterparts . Identicngiensis . Higher  mosseae . It was  mosseae . Mycorrh mosseae . Mycorrh mosseae . Dual inPR or AM . Rhizopht stress . Ascorba 12 days . Researct stress . In addiCitrus tangerina seedlings than non-AMF seedlings during water deficit [2 diffusion in the mesophyll cells [Trifolium repens L.) showed reduced stomatal conductance and higher RWC [P. chlororaphis O6 treated plants [Arabidopsis mutant plants that reduced transpiration levels thus enhancing MIST to drought in host plants. ROS production damages the photosynthetic machinery hence reducing photosynthesis during water deficit, however microbial inoculation can enhance tolerance in host plants as it improves plant water stature which boosts photosynthesis via increased stomatal conductance [Tagetes erecta L. [Erythrina variegata Linn. [Ipomoea batatas (L.) Lam. [Glomus versiforme inoculated Poncirus [F. Mosseae colonized Erythrina hence confirming sugar removal to enhance sink strength of AMF fungi via increased photosynthesis.The altered physical and biological properties of soil due to water deficit impedes the plant growth. Among the chief physiological mechanisms for upgraded MIST in plants during water deficit conditions could be attributed to boost in hydraulic conductivity of roots or water relations. Extraradical hyphae of AMF are engaged in water uptake and nutrient translocation  which is deficit . As glom deficit ,75  Lam.  and citrL.) Lam. . MoreovePoncirus  and F. MAzospirillum inoculated wheat plants [Bacillus thuringiensis showed increase in length and density of root hairs and lateral roots by modifying hormonal contents due to production of IAA and 1-aminocyclopropane-1-carboxylate deaminase (ACCd) by rhizobacteria [B. thuringiensis inoculated Lavandula plants by restoring the various physiological and metabolic processes of the host plant [Phaseolus plants in contrast to non AM plants under both well-watered and drought stress conditions [Azospirillum lipoferum primed maize plants [Burkholdera cepacia SE4, Promicromonospora spp. SE188 and Acinetobacter calcoaceticus SE370) colonized cucumber plants [Pseudomonas putida treated soybean plants [Rhizophagus intraradices) treated maize plants subjected to drought stress. Elevation in ABA levels in response to drought response was observed in non AM plants in contrast to AM plants indicating less stress experienced by AM plants [A. brasilense inoculated maize plants [Phyllobacterium inoculated Arabidopsis [Bacillus treated Platycladus orientalis seedlings [P. putida primed soybean plants [Bacillus licheniformis K11 treated pepper [Pseudomonas primed Pisum plants [Pseudomonas fluorescens DR7 which possessed ACCd and EPS production ability [Phytohormonal alterations in microbial colonized host plants ensures plant survival during drought stress. Water deficit caused by drought negatively affects the root metabolism and photosynthetic activity in plants. It is observed that PGPR treated plants display remodelled root system architecture (RSA) comprised of increased root tips and surface area ,87 ultimt plants  and incrt plants ,90. Wheabacteria . IAA prost plant . Higher nditions . Similarnditions . Gibberee plants , rhizobar plants  and Pseun plants . Cytokinn plants ,95  and micronutrients  was recorded in shoots of Lavandula plants primed with B. thuringiensis. Raise in K+ levels reduced stomatal conductance necessary for sustaining turgor pressure during drought conditions [G. Versiforme treated trifoliate orange seedlings displayed increased K, Ca in leaves and P, Ca and iron levels in host roots during water deficit conditions [Pistachio plants colonized by G. intraradices and G. mosseae [Rhizophagus intraradices) inoculation conferred drought tolerance to host Zea plants [Trifolium plants by PGPR strains and AM raised the K levels (217% in Bacillus thuringiensis + AM and 348% in Pseudomonas putida + AM or Bacillus megaterium + Rhizophagus intraradices) which helped plant to cope drought stress as K affects the physiological processes such as water uptake and photosynthesis. In addition a significant increase of 89%, 131%, 79% and 62% in P, Ca, Mg, Zn was observed respectively in plants inoculated with the autochthonous bacteria and mycorrhiza [Bacillus sp. and Klebsiella showed increased P, K contents and more biomass production in bacterial treated plants in comparison to AM inoculated ones which was associated with uptake of macronutrient  [2+ was noticed in AMF trifoliate orange seedlings during well-watered and water deficit conditions which was due to boosted Calmodulin (CaM), a calcium sensor synthesis as it was able to bind more calcium ions. CaM levels induced as a result of AMF inoculation were related to SOD and CAT activities enhancing MIST in host plants to drought [Drought affects diffusion and mobility of nutrients in soil due to poor soil structure as a result of water deficit. l plants . Nitroge process . A signinditions . Major rnditions ,114,115.nditions  and marinditions  in companditions ,116. G. nditions . Similar mosseae . Researc mosseae . It was a plants . AM inoca plants ,85. Colo drought   induced stomatal closure in Arabidopsis plants thus contributing towards MIST in plants [B. thuringiensis colonized wheat stressed plants showed reduced emission of these VOCs in comparison to non-primed stressed counterparts.VOCs  production by PGPR strains can alter the expression of genes related to cell wall structure  and auxiolerance . Pseudomn plants  , clearly indicating role of AMF aquaporins in enhancing water transport through AMF hyphae to plant. Researchers utilized suppression subtractive hybridization (SSH) to identify various genes involved in drought tolerance in AMF colonized Cajanus cajan [R. irregularis) inoculation in maize plants for drought stress alleviation [RpTIP2;1 and RpPIP2;1 in roots, stem and leaves was observed in Rhizophagus irregularis treated Robinia plants which enhanced water flow inside plant tissues mitigating drought stress effects [OePIP1;2 and OeTIP1;2 led to increased hydraulic conductivity however vice versa was observed for OePIP1;3, OePIP2;4 and OeTIP1;3 [ZmPIP1;1, ZmPIP1;3, ZmPIP1;4, ZmPIP1;6, ZmPIP2;2, ZmPIP2;4, ZmTIP1;1 and ZmTIP2; and upregulation of ZmTIP4;1 genes was observed in AM colonized ds plants, hence concluding that downregulated expression of genes in ds cultivar is a possible way to reduce water deficit induced stress changes [LjNIP1 and LjXIP1 during AM symbiosis in roots of Lotus japonicus, however both of them related to different families of plant aquaporins. It was observed through laser microdissection that LjNIP1 having putative function as an aquaporin was expressed principally in arbuscule-containing cells. LjNIP1 and LjXIP1 both were unable to transport solutes like ammonium or urea however LjNIP1 was capable of transporting water [Funneliformis mosseae and Rhizophagus intraradices) under the water stress condition revealed different transcriptional patterns of 3 aquaporin genes in roots corresponding to different subfamilies viz. NIPs (NOD26-like intrinsic proteins), TIPs (tonoplast intrinsic proteins) and PIPs  and ABA-responsive gene, RAB18 (LEA) [cAPX (cytosolic ascorbate peroxidase), rbcS and rbcL  in leaves ultimately magnifying antioxidant and photosynthetic machinery of hosts to overcome drought [PR1 (SA regulated gene), pdf1.2 (JA marker genes) and VSP1 (ethylene-response gene) was noticed during transcriptosome analysis carried in Arabidopsis thaliana plants colonized by Pseudomonas chlororaphis O6 thus confirming MIST to drought stress [Cadhn (dehydrin-like protein), chaperones sHSP , VA (vacuolar H+ ATPase) and CaPR-10 (Pathogenesis-related protein 10) in Bacillus licheniformis K11 treated pepper plants [DREB2A (Dehydration responsive element binding), DHN (Dehydrin) was recorded in Vigna plants treated with Pseudomonas aeruginosa GGRJ21 in comparison to control plants [Pseudomonas putida MTCC5279 inoculated chick pea exposed to drought stress. Quantitative real-time qRT-PCR analysis revealed upregulation of transcription factor DREB1 (Dehydration responsive element binding gene) and NAC1 in uninoculated plants however PGPR inoculation downregulated its expression in both cultivars, both TFs are primarily involved in abiotic stress tolerance however NAC is also related to some developmental pathways. PGPR inoculation repressed expression of stress responsive LEA and dehydrins that are involved in protecting macromolecules. A significant decrease in expression of genes encoding ROS scavenging enzymes  and ethylene biosynthesis genes namely ACO and ACS by inoculated plants confirmed ability of PGPR strains to MIST via restoration of normal growth conditions. In addition upregulation of jasmonate MYC2 gene was observed in desi cultivar of chickpea establishing role of JA in drought stress tolerance [Bacillus amyloliquefaciens 5113 and Azospirillum brasilense NO40 eventually caused upregulated expression of stress genes such as APX1 (ascorbate peroxidise), SAMS1 (S-adenosyl-methionine synthetase involved in biosynthetic pathway and supply of methyl units) and HSP17.8 in wheat leaves [DREB2A and CAT1 was observed during study of gene expression analysed by RT-qPCR in untreated wheat plants however PGPR-inoculated host wheat plants displayed decreased transcript levels indicating enhanced drought tolerance due to rhizobacterial plant interactions [OsDREB1A, OsAP37, OsNAC6, OsGADPH, OsWRKY11 and OsDIL in rice plants inoculated by consortium of two PGPR strains Bacillus amyloliquefaciens Bk7 and Brevibacillus laterosporus B4 which pointed towards MIST to drought [TaCTR1 gene and increased expression of TaDREB2 gene, latter encodes for a transcription factor involved in drought tolerance [Glomus mosseae) inoculated Poncirus trifoliata seedlings and observed elevated mRNA levels of CSD1, MIOX1, GlX1 and TTC1 encoding various antioxidant enzymes involved in maintaining ROS homeostasis and abating oxidative stress in AMF plants in comparison to non AMF plants [ABA1, NCED3, and ABA3), signalling  and stress response  was displayed by AMF colonized plants illustrating ABA role in drought tolerance to host plants [d-myo-inositol-3-phosphate synthase (IPS) and 14-3GF  indicated co-expression of both genes led to crosstalks between host maize plants and AMF enhancing to MIST in plants [Solanum lycopersicum via regulation of 14-3-3 genes (TFT1-TFT12)  that altered the stomatal behaviour in host plants. An upregulation in expression of TFT2 and TFT3 was recorded in AM colonized wild-type (wt) which decreased transpiration rate ultimately enhancing WUE of host wt plants. Moreover upregulated expression of TFT5, TFT7, TFT9 and TFT10 in AM colonized not plants altered transpiration rate subsequently contributing towards better WUE and drought tolerance [Piriformospora indica inoculated barley plants during drought stress showed raised content of various proteins that are involved in photosynthetic stimulation, redox metabolism or antioxidant defence and energy metabolism hence increasing drought tolerance in host plants [Glomus masseae inoculation in wheat roots showed alteration of proteins associated to sugar metabolism, defence responses and cell wall rearrangement. In addition AMF association in durum wheat also showed elevation in 12-oxo-phytodienoic acid reductase and reduced jasmonate-induced protein both correlated to JA synthesis, thus enhancing wheat tolerance to osmotic stress [LbKT1, LbSKOR (encoding potassium channels) showed positive correlation with potassium contents and colonization rate of AMF in Rhizophagus irregularis colonized Lycium barbarum ultimately increasing potassium uptake in host plants during drought stress [COX1 (regulates energy and carbohydrate metabolism), PKDP, AP2-EREBP, Hsp20, bZIP1 and COC1 in Pseudomonas fluorescens strain (Pf1) inoculated rice plants during drought stress. Hsp20, bZIP1 and COC1 are chaperons engaged in (ABA) dependent signalling pathway; PKDP functions as protein kinase and AP2-EREBP is involved in developmental and stress defensive pathways [Arabidopsis plants primed with GAP-P45 showed variation in expression patterns of genes  related to biosynthesis of polyamines thus enhancing polyamine levels in plants that are crucial to abate osmotic stress during drought [Molecular studies have revealed that microbial treated or colonized plants display different expression of genes in comparison to non-colonized plants ultimately enhancing drought tolerance . MIST to18 (LEA) . BBS con drought . A signit stress . Gene prr plants . Upregull plants . The expolerance . Inoculat leaves . An upreractions . RT-qPCR drought . Enhanceolerance . ResearcF plants . A market plants . Upreguln plants . AM symbolerance . Proteomt plants . At protc stress . Two putt stress . RT qPCRpathways . Arabido drought .PtYUC3 and PtYUC8 genes were related to IAA biosynthesis in Poncirus trifoliata inoculated with AMF (Funneliformis mosseae) during both well-watered and drought stress conditions [PtABCB19 and PtLAX2 (root auxin-species influx carriers) and downregulated level of PtPIN1 and PtPIN3 (root auxin efflux carriers) was also noticed during drought stress. Key role of miRNAs in Pseudomonas putida RA mediated MIST was studied in chick pea plants [PtPIN1 and PtPIN3 led to reduced auxin efflux thereby boosting auxin accumulation in roots ultimately enhancing root hair growth in AM inoculated plants. GAMYB-like TF are encoded by genes of miR159 and both were found to be inversely related in AMF treated plants during drought stress. Treated plants displayed upregulated expression of miR159 and downregulated expression of its target GAMYB-like TF during drought. A similar inverse relation with downregulation in expression of miR169 and up-regulation in expression of its target, NF-YA1 responsible for altering expression of various stress genes was observed. Moreover declined expression of miR166 (drought responsive RNA) targeting ATHB15, a representative of Class III homeodomain-leucine zipper was observed that has key role in vascular development and abiotic stress tolerance. A basal expression of miR171 boosted the expression of NSP2 transcripts  and downregulation of miR167 related to ABA signalling was observed.It was observed that the upregulation of root nditions . Upregula plants . DownregEpigenomics, the study to determine entire set of epigenetic alterations that modify genetic material of a cell is the latest omics strategy that can be utilized to study drought tolerance strategies in plants. Epigenetics is the study involving heritable modifications in gene expression comprising epigenetic mechanisms of DNA methylation, histone modifications and small RNAs. Researchers utilized capillary electrophoresis concerted with methylation-sensitive amplification length polymorphism (CE-MSAP) to track DNA cytosine methylation alterations in Burkholderia phytofirmans strain PsJN primed two potato varieties (the Red Pontiac and Superior) . SuperioOverall above discussion has led to conclusion that microbial colonization can enhance drought tolerance in host plants that involves various MIST mechanisms. To summarize, microbial inoculated plants employ various MIST mechanisms to counteract drought stress thus ensuring enhanced crop productivity. Considerable research studies has been done to understand the interplay between microbes and plants to enhance MIST to drought in plants, however some aspects still needs to be investigated such as decoding hidden metabolic pathways behind MIST. In future research studies can be focussed on how nutritional uptake affects the various transport channels in microbial inoculated plants and how this can be related to phytohormones such as ABA and brassinosteroids which affect stomatal regulation. In addition studies should be focussed on unravelling the PIN family functions inducing root hair modifications via microbial inoculation under drought conditions."}
+{"text": "RET p.Cys634Arg mutation (a known MTC driver). A germ-line RET substitution (p.Cys630=) had also been found but was considered clinically irrelevant because of its synonymous nature. Next generation sequencing (NGS) of the tumor tissues revealed that the RET mutations were in cis. There was no evidence of gene amplification. Expression analysis found an increase of RET transcript in p.Cys630=;p.Cys634Arg patient compared with that found in 7 MTCs harboring p.Cys634 mutations. Minigene expression assays demonstrated that the presence of the synonymous RET mutation was sufficient to explain the increased RET mRNA level. In silico analyses and RNA immunoprecipitation experiments showed that the p.Cys630 = variant created new exonic splicing enhancer motifs that enhanced SRp55 recruitment to the mutant allele, leading to more efficient maturation of its pre-mRNA and an increased abundance of mature mRNA encoding a constitutively active RET receptor. These findings document a novel mechanism by which synonymous mutations can contribute to cancer progression.Synonymous mutations continue to be filtered out from most large-scale cancer genome studies, but several lines of evidence suggest they can play driver roles in neoplastic disease. We investigated a case of an aggressive, apparently sporadic medullary thyroid carcinoma (MTC) harboring a somatic  RET protooncogene (a well-known MTC driver). A second RET substitution (p.Cys630=) discovered in the germline had been considered clinically irrelevant because of its synonymous nature. Our next-generation sequencing analysis of the patient\u2019s cancer tissues revealed that the RET mutations were in cis. We also found that RET mRNA levels in patient\u2019s MTC were significantly higher than those found in seven other MTCs with various amino-acid substitutions at position 634 in RET. Subsequent experiments demonstrated that the presence of the synonymous mutation created new exonic splicing enhancer motifs in the mutant allele, which led to more efficient maturation of its transcript and increased expression of a constitutively active RET receptor.Synonymous mutations\u2014once considered \u201csilent\u201d because they do not alter the gene product\u2019s amino-acid sequence\u2014are now emerging as potential drivers of cancer. Our recent investigation of an aggressive medullary thyroid carcinoma (MTC) revealed a novel mechanism that could underlie such effects. The MTC analyzed harbored a somatic p.Cys634Arg mutation of the  It is now clear that synonymous mutations\u2014single-nucleotide substitutions that do not alter the amino acid encoded by the affected codon\u2014can play functionally relevant roles in human disease . Over thRET proto-oncogene [MIM: 164761] in an aggressive case of medullary thyroid carcinoma . MTC is a relatively rare neuroendocrine calcitonin-secreting tumor derived from the parafollicular C-cells of the thyroid. Hereditary forms, including multiple endocrine neoplasia types 2A and 2B , in which MTC is associated with other endocrinopathies, are almost invariably associated with germ-line point mutations in RET. The membrane tyrosine kinase receptor encoded by this gene is activated by the binding of ligand\u2014co-receptor complexes, which induces dimerization of RET proteins and autophosphorylation of intracellular tyrosine residues  in a previously healthy 29-year-old man (patient ID0110M). The postoperative course was characterized by rapid disease spread. Despite multiple surgical interventions and systemic vandetanib therapy  substitution, which had been identified by the preoperative Sanger sequencing analysis and considered clinically inconsequential because of its synonymous nature. Our NGS data showed that the synonymous substitution was in cis with the somatic RET p.Cys634Arg driver mutation, and subsequent experiments demonstrated that it exerted appreciable effects on RET pre-mRNA splicing.The case we analyzed involved an apparently sporadic MTC harboring a somatic  therapy , the pat therapy ) were diUsing the Ion Torrent PGM NGS platform, we simultaneously sequenced 409 cancer-related genes in DNA from the patient\u2019s preoperative blood specimen and formalin-fixed paraffin embedded (FFPE) samples of the primary and metastatic lesions. Coverage statistics and the variants identified in each tissue are reported in RET exon 11. AFs approaching 50% in all tissues  were consistent with mutation clonality and the absence of gene amplifications. The latter conclusion was also supported by Sanger sequencing data, which confirmed the presence of the p.Cys634Arg mutation in all four tissues and documented complete overlap between the mutant and wild-type (WT) peaks (RET c.1890C>T (p.Cys630=) substitution documented in the germ line preoperatively (cis with the somatic p.Cys634Arg mutation led us to re-consider its possible role in the disease.As shown in T) peaks . NGS andratively . The dishttp://gnomad.broadinstitute.org/) revealed the p.Cys630 = to be a very low-frequency single nucleotide variant (SNV), AF in the European population, 0.003% ) , although we cannot exclude the possibility of alternatively spliced transcripts that had already undergone nonsense-mediated decay (NMD) [We used RT-PCR to analyze 611Phe]) . These fay (NMD) . Sanger RET mRNA levels in patient ID0110M\u2019s MTC were significantly higher than those found in seven other MTCs with various amino-acid substitutions at position 634 in RET, including two with the missense p.Cys634Arg mutation present in patient ID0110M\u2019s tumor. Sanger sequencing analysis of the patient\u2019s cervical lymph node metastasis revealed no mutations within the 1000-bp region preceding the RET start codon or in the 3\u2032 UTR of RET transcript , the lymph node lesion with the p.Cys630=;Cys634Arg phenotype displayed increased expression of RET protein , and theRET transcript, we used the minigene approach, an important tool for the identification and in vivo analysis of regulatory elements that affect precursor RNA maturation  MTC. Due to the paucity of the tissues, we performed a single protein extraction. All fresh-frozen neoplastic tissue samples had pathologist-confirmed tumor cell contents > 80%.Surgical samples of neoplastic tissue and peripheral venous blood were collected from patient ID0110M. The blood sample was used for the preoperative mutational analysis of RET mutations were identified by Sanger sequencing of DNA from peripheral blood and FFPE samples of the primary and metastatic tumor tissues. Blood DNA was isolated using Qiagen\u2019s QIAmp-Blood MIDI Kit; FFPE-tissue DNA using NucleoSpin Tissue Kit (Macherey-Nagel GmbH & Co.). RET mutational analysis was also performed on cDNA from a cervical lymph-node metastasis and from the primary tumor. Total RNA was isolated from a fresh-frozen tissue sample of the nodal metastasis using Trizol reagent (Thermo Fisher Scientific) and from FFPE tissue sample of the primary tumor using RecoverAll Total Nucleic Acid Isolation kit (Ambion). After DNase treatment, the RNA was used to generate cDNA with the High Capacity cDNA Reverse Transcription kit (Thermo Fisher Scientific). Sanger sequencing analyses of DNA and cDNA were performed as previously described  according to a standard protocol) and real-time PCR. The RETcDNAF8 and RETcDNAR12 primers used for RT-PCR assays are reported in Total RNA was isolated from FFPE slides with NucleoSpin tissue (Macherey Nagel), from fresh-frozen tissues with Trizol reagent (Thermo Fisher Scientific), and from transfected cells with RNeasy Mini Kit (Qiagen). After DNase treatment and purification (precipitation with ethanol and sodium-acetate), RNAs were quantified with Nanodrop 2000 (Thermo Fisher Scientific) and used to synthesize cDNA with the High Capacity cDNA Reverse Transcription kit (Thermo Fisher Scientific). Qualitative changes in \u2212\u0394\u0394Ct method and normalized to the calibrator sample. In particular, TaqMan Gene Expression Assays-on-Demand Hs01120021_m1 and Hs99999905_m1 (Thermo Fisher Scientific) were used to quantify RET and GADPH (reference control) expression, respectively, in MTC samples. RET expression in patient ID0110M was used as the calibrator. The TaqMan Gene Expression Assay-on-Demand Hs01120021_m1 (Thermo Fisher Scientific) was used to quantify mature minigene exon 11\u201312 junction transcript levels. Immature minigene transcript levels were quantified with Taqman Gene Expression Assay AIWR4LA (Thermo Fisher Scientific) designed with the Taqman Gene Expression design tool (https://www.thermofisher.com/order/custom-genomic-products/tools/gene-expression/) and the minigene sequence as a template. The assay targeted the ligation sites . Thermo Fisher Scientific certifies the high amplification efficiency (of 90\u2013110%) of all Taqman gene expression assays. Immature minigene transcripts encoded by minigenes were used as reference control and the WT sample (ratio mature/immature) as a calibrator.Real-time PCR analyses were done with a 7900HT Fast Real-Time PCR System, and SDS 2.3 software (both from Thermo Fisher Scientific) was used to calculate Ct values . TaqMan The SensiMix SYBR kit (Bioline) was used with specific primer pairs to quantify minigene expression levels and the half-lives of immature and mature minigene transcripts using a standard protocol. A standard curve was used to assess primer efficiency. Slopes, Y-intercepts, and R^2 values were -3.836, 22.087, and 0.975 for Immature F2 and Immature R1 and -3.253, 111.48, and 0.645 for Mature F1 and RETrs11. Levels of immature and mature minigene transcripts in transfected HeLa cell extracts were expressed as nanograms of cDNA, the ratio of mature to immature transcript levels, or percentage of mature transcripts.Custom Taqman Gene Expression Assay AIWR4LA (Thermo Fisher Scientific) was used to quantify immature minigene transcript levels in RNA immunoprecipitate and IgG-precipitated extracts (negative controls). Results were normalized to input samples and expressed relative to IgG control.Total proteins were extracted on ice from fresh-frozen tissues and quantified using the Bradford method. The lysis buffer contained TrisHCl , NaCl (150 mM), Triton (1% v/v), EDTA (20 mM), phenylmethylsulfonyl fluoride (2 mM), protease and phosphatase inhibitors (Pierce), leupeptin (2 \u03bcg/ml), and glycerol (10% v/v). For Western blot analysis, 30 \u03bcg of proteins separated by SDS-PAGE, transferred to polyvinylidene fluoride membranes, and probed with the following primary antibodies : anti-RET (C31B4), anti-Tubulin (sc-8035), anti-Erk1/2 (cat.# 137F5), and anti-phospho-ERK1/2 (Thr202-Tyr204) antibody (cat.# 4370). Secondary antibodies (anti-mouse SC-2005 and anti-rabbit SC-2004) were HRP-conjugated and used at 1:5000 dilution. Membranes were incubated with ECL reagent , and chemiluminescence was quantified with Bio-Rad\u2019s Chemidoc MP Imaging system (Bio-rad). Band intensity was analyzed with the system\u2019s Image Lab Software and the results normalized to that of controls . Experiments were repeated twice.RET gene fragments containing exon 10, exon 11, or exon 12, each with flanking intronic sequences. Fragments were amplified using AmpliTaq Gold (Thermo Fisher Scientific). Primer sequences are shown in RET allele. Fragment 2 contained the last 128 nt of intron 10, all of exon 11, and the first 20 nt of intron 11. Four versions were created: one with the WT sequence (amplified from the DNA used for fragments 1 and 2); the second with the p.Cys630 = substitution (amplified from germ-line DNA from patient ID0110M); the third with the p.Cys634Arg mutation (amplified from DNA isolated from an MTC harboring this mutation); and the fourth containing both of the latter variations (amplified from somatic DNA isolated from patient ID0110M). Amplified fragments were cloned into a pGEM-T Easy Vector (Promega) linked by the XhoI restriction enzyme sites. The sequences of all fragments were verified by Sanger sequencing. The construct was subcloned into a pcDNA3.3-TOPO TA vector (Thermo Fisher Scientific) and used to transform JM109 competent cells (Promega), using the heat-shock procedure. The transformed cells were plated on Luria broth (LB) agar containing 100 mg/mL ampicillin and incubated overnight at 37\u00b0C. Positive colonies were suspended in 2 ml of LB supplemented with 100 mg/mL ampicillin. After 16 hours of incubation at 37\u00b0C with shaking, the bacterial mixture was used to isolate plasmids, as previously described [We used PCR to amplify three escribed .5) into 6-well culture plates containing Dulbecco\u2019s modified Eagle medium (DMEM) (Gibco by Thermo Fisher Scientific) supplemented with 10% fetal bovine serum (FBS), penicillin (100 U/mL), and streptomycin (100 \u03bcg/mL) and incubated at 37\u00b0C in a 5% CO2 incubator. Two hours before transfection, the medium was replaced with antibiotic- and FBS-free DMEM. The starved cells were then transfected with RET minigenes (2 \u03bcg) using OPTI-MEM medium and Lipofectamine 3000 . After a 24-h incubation, the transfected cells were harvested, RNA was isolated, and cDNA was generated and assayed to quantify minigene expression, as described above .The day before transfection, HeLa CCL-2 cells purchased from ATCC were seeded (0.8 x 105) into 12-well culture plates and, as described above, four minigenes were transfected in Hela cells. After 24-h from transfection; we treated HeLa cells with 10 \u03bcg/ml [For the treatment with Actinomycin D (Thermo Fisher Scientific), we plated HeLa cells (0.4x1010 \u03bcg/ml  of ActinRET: the Human Splicing Finder (http://www.umd.be/HSF3/); ESResearch (http://ibis.tau.ac.il/ssat/ESR.htm); Automated Splice Site And Exon Definition Analyses (ASSEDA) (http://splice.uwo.ca); and ESE Finder (http://krainer01.cshl.edu/cgi-bin/tools/ESE3/esefinder.cgi?process=home).Four platforms were used to identify altered splicing motifs and splicing factor binding sites in exon 11 of The results were obtained analyzing the entire sequence of exon 11 WT or with p.C630=;C634R variations in all queries of the four platforms.RET minigene-transfected HeLa CCL-2 cells with 1% formaldehyde for 10 minutes at room temperature to crosslink RNA-protein complexes. The cells were washed in glycine (125 mM) to stop the reaction, harvested, and resuspended in PBS diluted 1:1 with nuclear isolation buffer (NIB) consisting of sucrose (1.28 M), Tris-HCl pH 7.5 (40 mM), MgCl2 (20 mM), and Triton X-100 (4%). To lyse the nuclear membranes, we resuspended the nuclear pellet in RIP buffer containing KCl (150 mM), Tris pH 7.4 (25 mM), EDTA (5 mM), DTT (0.5 mM), NP-40 (0.5%), RNAase inhibitor (100 U/ml), and protease inhibitors. One tenth of the total volume of nuclear lysate was reserved for use as an input control. Chromatin was needle-sheared, antibody was added to the solution , and samples were incubated at 4\u00b0C with gentle rotation to enhance antibody-protein binding. One hour later, magnetic protein G beads  were added and the samples re-incubated for 1h at 4\u00b0C with gentle rotation. Unbound material was removed by two washes with RIP buffer and one in PBS. The de-crosslinking reaction was performed at 70\u00b0C for 10 minutes. RNA and protein were isolated with TRIzol reagent (Thermo Fisher Scientific). cDNA was generated with High Capacity cDNA Reverse Transcription kit (Thermo Fisher Scientific).We treated Real-time PCR was performed as described above in the paragraph \u201cRNA analysis\u201d.Statistical significance was assessed with the Student\u2019s t test, and results were considered significant when P values were <0.05.S1 Supplementary Note\u2014Case report(DOCX)Click here for additional data file.S1 Fig(A) Representative gel from one of three RT-PCR experiments. Black arrows indicate immature and mature transcript bands. (Lower mature transcript bands represent concatemers of primers.) (B) The amount of each transcript (mature and immature) measured by real-time PCR is reported as separated bars; numbers above bars indicate the percentage of mature transcript in each sample.(TIF)Click here for additional data file.S1 Table(DOC)Click here for additional data file.S2 Table(XLS)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOC)Click here for additional data file."}
+{"text": "There is still no consensus on the value of Manchester Acute Coronary Syndromes (MACS) decision rule in detecting acute coronary syndrome (ACS). Therefore, the purpose of the present systematic review and meta-analyzes is to summarize the clinical evidence in the evaluation of the value of MACS in the diagnosis of ACS.A literature search was performed on the Medline, Embase, Scopus, and Web of Science databases. Outcomes included acute myocardial infarction (AMI) and major adverse cardiac event (MACE). Data were analyzed in the STATA 14.0 statistical program and the results were reported as summary receiver operating characteristics (SROC), sensitivity, specificity, positive and negative likelihood ratio, and diagnostic odds ratio with 95% confidence interval (95% CI).Finally, 8 articles included in the meta-analysis. The area under the SROC of MACS was excellent in rule out of AMI  and MACE . The sensitivity and specificity of the troponin-only MACS/history electrocardiogram alone MACS (HE-MACS) in the rule out of AMI were0.99 (95% CI: 0.98-0.99) and 0.22 (95% CI: 0.11-0.37), respectively, and for the original MACS were in order 0.99 (95% CI: 0.98-0.99) and 0.26 (95% CI: 0.20-0.34),. The sensitivity and specificity of the troponin-only MACS / HE-MACS in the rule out of MACE were 0.94 (95% CI: 0.92-0.96) and 0.22 (95% CI: 0.12-0.39) compared to the 0.99 (95% CI: 0.98-0.99) and 0.27 (95% CI: 0.22-0.33) for the original MACS. The findings of this study showed that original MACS, troponin-only MACS, and HE-MACS are able to rule out AMI and MACE. However, further studies are needed in developing countries to confirm its external validity.  Acute coronary syndrome (ACS) is a leading cause of mortality and disability worldwide. According to the statistics, in 2017, about 18 million deaths from cardiovascular disease have occurred in the world, which has increased by 21.1% over the past 10 years (1). This increase in the burden of cardiovascular disease has led researchers to seek solutions to reduce the incidence of ACS.Early diagnosis of ACS is one of the most effective methods to reduce the burden of the disease (2). Currently, the patient\u2019 clinical examination, electrocardiography and serial troponin are the standard ACS diagnostic method. A golden standard for diagnosing ACS in emergency episodes is the serial troponin test (3). However, the long-term approach to diagnosing ACS (about 6-12 hours) is the most important weakness of the current guidelines. In order to overcome this problem, Body et al in 2014 provided the Manchester Acute Coronary Syndromes (MACS) decision rule to the diagnosis of ACS (4). In subsequent studies, the diagnostic value of this model was validated and modifications were made (5-9) . In receSearch strategyIn the present meta-analysis using the keywords related to Manchester Acute Coronary Syndromes score in combination with Acute Coronary Syndrome, a search was performed in the Medline, Embase, Scopus, and Web of Science databases. The search was completed by the end of October 2018. No language restrictions were applied. The Searcy query for Medline (via PubMed) has been reported.1- \"Decision Support Techniques\"[mh] OR \"Manchester Acute Coronary Syndromes\"[tiab] OR \"MACS prognostic modes\"[tiab] OR \"MACS prognostic models\"[tiab] OR \"MACS Rule\"[tiab] OR \"decision rule\"[tiab] OR \"Decision Support Techniques\"[tiab] OR \"Decision Support Technique\"[tiab] OR \"Technique, Decision Support\"[tiab] OR \"Techniques, Decision Support\"[tiab] OR \"Decision Support Technics\"[tiab] OR \"Decision Support Technic\"[tiab] OR \"Technic, Decision Support\"[tiab] OR \"Technics, Decision Support\"[tiab] OR \"Decision Aids\"[tiab] OR \"Aid, Decision\"[tiab] OR \"Aids, Decision\"[tiab] OR \"Decision Aid\"[tiab] OR \"Models, Decision Support\"[tiab] OR \"Decision Support Model\"[tiab] OR \"Decision Support Models\"[tiab] OR \"Model, Decision Support\"[tiab] OR \"Decision Analysis\"[tiab] OR \"Analyses, Decision\"[tiab] OR \"Decision Analyses\"[tiab] OR \"Analysis, Decision\"[tiab] OR \"Decision Modeling\"[tiab] OR \"Modeling, Decision\"[tiab] OR \"Clinical Prediction Rule\"[tiab] OR \"Clinical Prediction Rules\"[tiab] OR \"Prediction Rule, Clinical\"[tiab] OR \"Prediction Rules, Clinical\"[tiab] OR \"Rule, Clinical Prediction\"[tiab] OR \"Rules, Clinical Prediction\"[tiab]2- \"Acute Coronary Syndrome\"[mh] OR \"Myocardial Ischemia\"[mh] OR \"Angina Pectoris\"[mh] OR \"Angina, Stable\"[mh] OR \"Angina, Unstable\"[mh] OR \"Coronary Artery Disease\"[mh] OR \"Coronary Occlusion\"[mh] OR \"Coronary Stenosis\"[mh] OR \"Coronary Thrombosis\"[mh] OR \"Coronary Vasospasm\"[mh] OR \"Myocardial Infarction\"[mh] OR \"Anterior Wall Myocardial Infarction\"[mh] OR \"Inferior Wall Myocardial Infarction\"[mh] OR \"Non-ST Elevated Myocardial Infarction\"[mh] OR \"ST Elevation Myocardial Infarction\"[mh] OR \"Acute Coronary Syndrome\"[tiab] OR \"Myocardial Ischemia\"[tiab] OR \"Angina Pectoris\"[tiab] OR \"Angina, Stable\"[tiab] OR \"Angina, Unstable\"[tiab] OR \"Coronary Artery Disease\"[tiab] OR \"Coronary Occlusion\"[tiab] OR \"Coronary Stenosis\"[tiab] OR \"Coronary Thrombosis\"[tiab] OR \"Coronary Vasospasm\"[tiab] OR \"Myocardial Infarction\"[tiab] OR \"Anterior Wall Myocardial Infarction\"[tiab] OR \"Inferior Wall Myocardial Infarction\"[tiab] OR \"Non-ST Elevated Myocardial Infarction\"[tiab] OR \"ST Elevation Myocardial Infarction\"[tiab] OR \"Acute Coronary Syndromes\"[tiab] OR \"Coronary Syndrome, Acute\"[tiab] OR \"Coronary Syndromes, Acute\"[tiab] OR \"Syndrome, Acute Coronary\"[tiab] OR \"Syndromes, Acute Coronary\"[tiab] OR \"Ischemia, Myocardial\"[tiab] OR \"Ischemias, Myocardial\"[tiab] OR \"Myocardial Ischemias\"[tiab] OR \"Ischemic Heart Disease\"[tiab] OR \"Heart Disease, Ischemic\"[tiab] OR \"Disease, Ischemic Heart\"[tiab] OR \"Diseases, Ischemic Heart\"[tiab] OR \"Heart Diseases, Ischemic\"[tiab] OR \"Ischemic Heart Diseases\"[tiab] OR \"Anginas, Stable\"[tiab] OR \"Stable Angina\"[tiab] OR \"Stable Anginas\"[tiab] OR \"Chronic Stable Angina\"[tiab] OR \"Angina, Chronic Stable\"[tiab] OR \"Anginas, Chronic Stable\"[tiab] OR \"Chronic Stable Anginas\"[tiab] OR \"Stable Angina, Chronic\"[tiab] OR \"Stable Anginas, Chronic\"[tiab] OR \"Angina Pectoris, Stable\"[tiab] OR \"Angina Pectori, Stable\"[tiab] OR \"Pectori, Stable Angina\"[tiab] OR \"Pectoris, Stable Angina\"[tiab] OR \"Stable Angina Pectori\"[tiab] OR \"Stable Angina Pectoris\"[tiab] OR \"Anginas, Unstable\"[tiab] OR \"Unstable Anginas\"[tiab] OR \"Angina Pectoris, Unstable\"[tiab] OR \"Angina Pectori, Unstable\"[tiab] OR \"Unstable Angina Pectori\"[tiab] OR \"Unstable Angina Pectoris\"[tiab] OR \"Unstable Angina\"[tiab] OR \"Angina at Rest\"[tiab] OR \"Angina, Preinfarction\"[tiab] OR \"Anginas, Preinfarction\"[tiab] OR \"Preinfarction Angina\"[tiab] OR \"Preinfarction Anginas\"[tiab] OR \"Myocardial Preinfarction Syndrome\"[tiab] OR \"Myocardial Preinfarction Syndromes\"[tiab] OR \"Preinfarction Syndrome, Myocardial\"[tiab] OR \"Preinfarction Syndromes, Myocardial\"[tiab] OR \"Syndrome, Myocardial Preinfarction\"[tiab] OR \"Syndromes, Myocardial Preinfarction\"[tiab] OR \"Artery Disease, Coronary\"[tiab] OR \"Artery Diseases, Coronary\"[tiab] OR \"Coronary Artery Diseases\"[tiab] OR \"Disease, Coronary Artery\"[tiab] OR \"Diseases, Coronary Artery\"[tiab] OR \"Coronary Arteriosclerosis\"[tiab] OR \"Arterioscleroses, Coronary\"[tiab] OR \"Coronary Arterioscleroses\"[tiab] OR \"Atherosclerosis, Coronary\"[tiab] OR \"Atheroscleroses, Coronary\"[tiab] OR \"Coronary Atheroscleroses\"[tiab] OR \"Coronary Atherosclerosis\"[tiab] OR \"Arteriosclerosis, Coronary\"[tiab] OR \"Coronary Occlusions\"[tiab] OR \"Occlusion, Coronary\"[tiab] OR \"Occlusions, Coronary\"[tiab] OR \"Stenoses, Coronary\"[tiab] OR \"Stenosis, Coronary\"[tiab] OR \"Coronary Artery Stenosis\"[tiab] OR \"Artery Stenoses, Coronary\"[tiab] OR \"Artery Stenosis, Coronary\"[tiab] OR \"Coronary Artery Stenoses\"[tiab] OR \"Stenoses, Coronary Artery\"[tiab] OR \"Stenosis, Coronary Artery\"[tiab] OR \"Coronary Stenoses\"[tiab] OR \"Infarction, Myocardial\"[tiab] OR \"Infarctions, Myocardial\"[tiab] OR \"Myocardial Infarctions\"[tiab] OR \"Cardiovascular Stroke\"[tiab] OR \"Cardiovascular Strokes\"[tiab] OR \"Stroke, Cardiovascular\"[tiab] OR \"Strokes, Cardiovascular\"[tiab] OR \"Heart Attack\"[tiab] OR \"Heart Attacks\"[tiab] OR \"Myocardial Infarct\"[tiab] OR \"Infarct, Myocardial\"[tiab] OR \"Infarcts, Myocardial\"[tiab] OR \"Myocardial Infarcts\"[tiab]3- #1 and #2Selection criteriaInclusion criteria included relevant studies in the assessment of MACS in rule out of acute myocardial infarction (AMI) and major acute cardiac event (MACE). Exclusion criteria included the lack of the required data after contact with the authors, duplicate articles, and reviews.Data synthases and quality controlThe method of summarizing and collecting data has been reported by previous systematic reviews (10-25). In summary, two independent reviewers screened the titles and abstracts as well as full text of the articles and selected relevant studies. Any disagreement was resolved by discussion with the third reviewer.The collected data included the name of the first author , the year of study, the number of patients , the type of study , the type of MACS , the assessed outcome (AMI and MACE) and follow-up duration. MACE included all-cause mortality, AMI, and urgent coronary revascularization. Quality assessment of the articles was evaluated using the proposed method of Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) guideline (26).Statistical analysisAll analyzes were performed in the STATA 14.0 statistical program. Using the values reported in the relevant studies, we calculated true positive, true negative, false positive and false negative. Data were analyzed by \u201cmidas\u201d command and the results were reported as a summary receiver operating characteristic (SROC), sensitivity, specificity, positive and negative likelihood ratio, and diagnostic odds ratio with 95% confidence interval (95% CI). The publication bias was evaluated using Deeks' funnel plot asymmetry test. In all analyzes p <0.05 was considered a significant level.CharacteristicsThe search led to the achievement of 3175 non-repetitive records. After the initial screening, 21 articles were studied in detail, and finally, eight papers arrived at the quantitative analysis . Quality control of articles and risk of biasThe quality assessment showed that the applicability of patient selection was high risk and unclear in two studies. In addition, in one study, the risk of bias in patient selection was unclear. In other cases, the risk of bias were low. The value of MACS in rule out of AMIData from seven studies (15 separate experiments) included in this section. The analysis showed that the area under the SROC curve of MACS in the rule out of AMI was excellent  . The senThe sensitivity and specificity of troponin-only MACS / HE-MACS in the diagnosis of AMI was 0.99 (95% CI: 0.98-0.99) and 0.22 (95% CI: 0.11-0.37), respectively. These values for the original MACS were 0.99 (95% CI: 0.98-0.99) and 0.26 (95% CI: 0.20-0.34), respectively. In thesensitivity (0.99 vs. 0.99) and specificity (0.26 vs. 0.24) of MACS there was no differencebetween validation and derivation studies .Diagnostic value of MACS in MACE detectionData from eight studies (18 separate experiments) were included in this section. The analysis showed that the area under the SROC curve of MACS in the rule out of MACE was excellent  . The sensitivity, specificity and DOR of the MACS rule in prediction of MACE were 0.99 (95% CI: 0.98-0.99) and 0.25 (95% CI: 0.19-0.32), and 25.0 (95% CI: 13.0-43.0), respectively .The sensitivity and specificity of the troponin-only MACS / HE-MACS in the rule out of MACE was 0.94 (95% CI: 0.92-0.96) and 0.22 (95% CI: 0.12-0.39), respectively. These values for the original MACS were 0.99 (95% CI: 0.98-0.99) and 0.27 (95% CI: 0.22-0.33) respectively. The sensitivity (0.98 vs. 0.97) and specificity (0.27 vs. 0.25) of MACS were not different in the MACE prediction between the validation and derivation studies . The findings of this study showed that the MACS value is good in the screening of AMI and MACE. It was also found that the value of troponin-only / HE-MACS is similar to the original MACS. Since troponin-only MACS and HE-MACS have fewer variables and don\u2019t need to evaluate the heart-type fatty acid binding protein, it seems that the use of troponin-only / HE-MACS is better than the original MACS.The MACS sensitivity to rule out of ACS is very high, but its specificity is low. Therefore, MACS is a good screening tool for AMI diagnosis and MACE prediction. In line with the present review article, Reynard et al. by reviewing five studiesconcluded that MACS is a good model for rule out of ACS (26).In the present study, 8 articles included in the meta-analysis. Although data from 7658 patients were analyzed, 7 studies were conducted by a team in the UK . Only one study in Australia and New Zealand performed , that only 405 patients were examined (29). Therefore, external validation of MACS in other communities is also required to ensure it is generalized.The findings of this study indicate that the performance of troponin-only MACS or HE-MACS in rule out of ACS is not different from the original MACS. One of the main disadvantages of the original MACS is the need to evaluate the heart-type fatty acid binding protein (h-FABP), while in the other two models, it is not necessary to measure h-FABP . The value of the troponin-only MACS in rule out of ACS was evaluated in four studies, while the value of HE-MACS was examined only in one study. Since the HE-MACS method does not require measurement of high sensitivity troponin and h-FABP, so if the screening value of HE-MACS is confirmed, it will be easier to use for rule out the ACS. Further studies are needed to achieve this goal.The findings of this study showed that the original MACS, troponin-only MACS, and HE-MACS are capable to rule out AMI and MACE. However, further studies are needed in developing countries for external validation."}
+{"text": "Here we investigated how sensitivity to these slight timing differences depends on spatial relationships among stimuli. Stimuli comprised bilaterally presented plaid pairs that rotated, or radially expanded and contracted to simulate depth movement. Left and right hemifield stimuli initially moved in the same or opposite directions, then reversed directions at various asynchronies. College students judged whether the direction reversed first on the left or right\u2013a temporal order judgment (TOJ). TOJ thresholds remained similar across conditions that required tracking only one depth plane, or bilaterally synchronized depth planes. However, when stimuli required simultaneously tracking multiple depth planes\u2013counter-phased across hemifields\u2013TOJ thresholds doubled or tripled. This effect depended on perceptual set. Increasing the certainty with which participants simultaneously tracked multiple depth planes reduced TOJ thresholds by 45 percent. Even complete certainty, though, failed to reduce multiple-depth-plane TOJ thresholds to levels obtained with single or bilaterally synchronized depth planes. Overall, the results demonstrate that global depth perception can alter local timing sensitivity. More broadly, the findings reflect a coarse-to-fine  Both findings demonstrate motion-induced change blindness. In each case, global-direction reversals impaired sensitivity to local non-motion features, e.g., orientation and color. Here we investigated the ironic case of global-direction reversals impairing sensitivity to the timing of their constituent local-direction reversals.Motion can blind us to other visual features. For example, a recent wave of magician-inspired neuroscience \u20134 promptThe impetus for this study came from a serendipitous finding in our lab . The tasperceived global (cross-hemifield) counter-phase depth. Stated differently, changing the initial directions from same to opposite had qualitatively distinct perceptual consequences in the radial and rotational conditions. Radial-Opposite directions induced global (cross-hemifield) counter-phase depth percepts that did not occur in the other stimulus conditions. Therefore, global depth perception could have doubled or tripled TOJ thresholds uniquely in the Radial-Opposite condition.Why would plaid pairs with radially opposite directions induce \u201cblindness\u201d to the temporal order of local-direction reversals? An insight comes from participants\u2019 spontaneous reports about depth perceived in radially expanding and contracting stimuli. Specifically, numerous participants spontaneously described the Radial-Opposite stimuli as \u201c\u2026difficult because they move in and out\u201d. Some participants also offered accompanying hand gestures that signaled counter-phase depth movement; one hand moved nearer in depth while the other moved away in depth. These spontaneous, informal verbal and non-verbal reports demonstrate that, in our Radial-Opposite condition, participants The possibility that global (cross-hemifield) depth perception alters local (within hemifield) timing sensitivity framed the present study. In Experiment 1 we conducted a direct replication attempt to assess the reliability of the above-described, serendipitously-discovered doubling and tripling of Radial-Opposite TOJ thresholds . In Expehttps://osf.io/d72bv/] contains the complete data set and all software necessary for replicating the experiment and the statistical analyses.The Denison University Human Participant Committee approved all experiments reported here, which we conducted with the written informed consent of each participant. The experiments adhere to the October 2008 Declaration of Helsinki. To promote reproducibility, the Open Science Framework  contains the software for this procedure.For each threshold the following procedure generated error bars. First, we determined the standard error (SE) of each sigmoid estimate, expressed in the psychometric function\u2019s y-axis units . The SE required computing the square root of the mean squared differences between each psychometric function\u2019s observed and predicted  values . We thenhttps://osf.io/d72bv/] contains the raw data from all participants.The statistical analyses included data from each participant whose TOJ performance statistically exceeded chance . This inclusion criterion minimally required 57.5% correct TOJ performance across the 480 non-zero asynchrony trials for analysis.  This criterion resulted in excluding data from 24 participants. Data from the remaining 31 (56.36% of 55) participants appear in the Results. As noted above, the Open Science Framework  contains the raw data from all participants.The statistical analyses included data from each participant whose TOJ performance statistically exceeded chance . This inclusion criterion minimally required 60% correct TOJ performance across the 240 non-zero asynchrony trials for analysis.  This criterion resulted in excluding data from 31 participants. Data from the remaining 76 (71% of 107) participants appear in the Results. As noted above, the Open Science Framework [all Experiment 2 stimuli contained multiple simultaneous depth planes.The Depth Uncertainty (DU) hypothesis predicts large TOJ threshold elevations when cues to multiple simultaneous depth planes occur infrequently. This would explain the threshold spike in Experiment 1\u2019s Radial-Opposite condition  lower threshold-ranks than did Experiment 1\u2019s Radial-Opposite condition. The Common Fate (CF) hypothesis posits that spatially separated stimuli sharing a direction of motion become organized into a coherent perceptual unit. This Gestalt law of perceptual organization predicts high or low TOJ thresholds for stimulus pairs that respectively lack or share common fate motion. This correctly predicts the TOJ threshold pattern observed in Experiment 1 \u2013displayed for comparison in The Attentional Prior Entry (APE) hypothesis posits that looming stimuli become perceptually available sooner than do receding stimuli, which capture less attention \u201327. AtteExperiment 2\u2019s psychometric functions appear in receding side from left to right.  asynchronies. Moreover, a comparably modest rightward PSE shift also occurred in the Receding-Rotation condition after changing the initially In Experiment 2 we tested three hypotheses for the reliable and large threshold elevation associated with Radial-Opposite TOJs. Experiment 2 provided support for the Depth Uncertainty hypothesis. When the probability of trials containing multiple simultaneous depth planes changed from 25% to 100%, TOJ thresholds improved (decreased) by more than 100 ms. Experiment 2 also provided support for the Common Fate hypothesis, albeit a smaller effect size than for depth uncertainty. Specifically, differencing the results from Experiments 1 and 2 revealed that common fate motion cues conferred a threshold advantage between 36 and 68 ms. By contrast, Experiment 2\u2019s data disconfirmed the PSE shifts predicted by the Attentional Prior Entry hypothesis. Although important in other contexts \u201327, attemotion certainty. Specifically, we controlled depth-certainty by experimentally controlling the certainty of radial expansion, radial contraction, and rotational motion, i.e., two-dimensional motion. Our findings therefore extend those of earlier studies that similarly generated performance improvements by increasing the certainty of one-dimensional (linear) motion [The finding that radial-opposite TOJ thresholds improved with increasing depth-certainty relied on increasing ) motion \u201331.multiplicity differs from depth-plane certainty.Experiment 2\u2019s 100% certainty about motion and depth still failed to improve performance to the level attained with Experiment 1\u2019s less probable common fate motion. This performance gap points to the distinct depth requirements in the two experiments. Experiment 1\u2019s common-fate-motion conditions  never required tracking multiple depth planes simultaneously, whereas all of Experiment 2\u2019s conditions did. Depth-plane Taken together, Experiments 1 and 2 demonstrate that depth-plane multiplicity impaired TOJs even when depth-plane certainty improved TOJs. Previous visual search studies that manipulated binocular rather than monocular depth cues similarly reported a cost for tracking multiple depth planes simultaneously. Specifically, those studies found slowed reaction times for detecting targets among distractors at distinct stereoscopically defined depths , 33.spatial sequence in visual timing sensitivity. This follows because manipulating global (cross-hemifield) depth information generated large TOJ threshold variations while local (within hemifield) linear motion vectors remained constant.Experiment 2 also revealed a global-to-local (coarse-to-fine) Competing theories of perceptual learning in drum corps experts motivated a previous study on visual temporal order judgments (TOJs) . That thperceived depth. Insight about the role of perceived depth came from participants\u2019 spontaneous, qualitative verbal reports and hand gestures. These described the Radial-Opposite stimuli as \u201c\u2026moving in and out\u201d, counter-phased in depth across hemifields.The present Experiment 1 directly replicated the previous finding  that gloBuilding on the participants\u2019 qualitative insights, we conducted Experiment 2 to quantitatively evaluate how the Radial-Opposite threshold elevation depends on perceived depth. We found little evidence that the effect reflects attentional prior entry for stimuli looming in depth. Dissimilarly, depth certainty and common-fate-depth-motion each altered TOJs. Depth certainty improved (reduced) Radial-Opposite TOJ thresholds by 100+ ms compared to a condition having less depth certainty but otherwise identical Radial-Opposite directions. Evidence for a more modest influence of common-fate-depth-motion came from contrasting Experiment 1\u2019s Radial-Same and Experiment 2\u2019s Looming-Receding conditions. Both conditions required tracking multiple depth planes. However, Experiment 1\u2019s Radial-Same condition occurred with 25% probability and required tracking stimuli that loomed synchronously or receded synchronously across hemifields. By contrast, Experiment 2\u2019s Looming-Receding condition required tracking stimuli that loomed in one hemifield and receded in the other\u2013with 100% certainty. Despite this 100% depth certainty, Experiment 2\u2019s Looming-Receding condition generated TOJ thresholds 35+ ms higher (worse) than those of Experiment 1\u2019s less probable Radial-Same condition. Likewise, Experiment 2\u2019s Looming-Rotation and Receding-Rotation conditions each generated TOJ thresholds 35+ ms higher (worse) than those of Experiment 1\u2019s less probable Radial-Same condition. Taken together, Experiment 2 demonstrated that participants struggled to simultaneously track distinct left- and right-hemifield depth planes.time sampling can depend on spatially global relationships. This follows because TOJs varied markedly across conditions comprising the same local motion components, spatially rearranged to generate distinct depth relationships across hemifields.less efficiently across hemifields  than within hemifields  [The finding that distinct depth planes across hemifields doubled or tripled TOJ thresholds may seem surprising given earlier reports about bilateral task performance. Specifically, several studies have revealed independent left and right hemifield resources for attentionally tracking objects  and elemterally) , 38. GroRemoving common fate grouping cues from Experiment 2\u2019s stimuli increased TOJ thresholds to 125 ms or more. This comparatively sluggish temporal precision matches what one might expect from so-called \u201cattention-based\u201d motion perception , 40. Atttiming of local direction reversals (red arrow).Overall, our experiments demonstrate that global depth perception alters local timing sensitivity. The doubling or tripling of TOJ thresholds for our bilaterally presented stimuli reveal coarse-to-fine influences across spatial scales. More broadly, the coarse-to-fine spatial influences on the present TOJ task align with the coarse-to-fine spatial influences demonstrated for diverse visual phenomena. These phenomena include stereoscopic depth perception \u201349, hystS1 Movie(MP4)Click here for additional data file.S2 Movie(MP4)Click here for additional data file.S3 Movie(MP4)Click here for additional data file.S4 Movie(MP4)Click here for additional data file.S5 Movie(MP4)Click here for additional data file.S6 Movie(MP4)Click here for additional data file.S7 Movie(MP4)Click here for additional data file.S8 Movie(MP4)Click here for additional data file.S9 Movie(MP4)Click here for additional data file.S10 Movie(MP4)Click here for additional data file.S11 Movie(MP4)Click here for additional data file.S12 Movie(MP4)Click here for additional data file.S13 Movie(MP4)Click here for additional data file.S14 Movie(MP4)Click here for additional data file."}
+{"text": "Endoplasmic reticulum (ER) stress generated unfolded stress response (UPR) is a basic survival mechanism which protects cell under unfavourable conditions. Leishmania parasite modulates host macrophages in various ways to ensure its survival. Modulation of PI3K-Akt pathway in delayed apoptotic induction of host; enables parasite to stabilize the infection for further propagation.Infected RAW macrophages were exposed to campothecin or thagsigargin and phosphorylation status of PERK, Akt, BAD and Cyt-C was determined through western blotting using phospho specific antibody. Expression at transcriptional level for cIAP1 &2, ATF4, CHOP, ATF3, HO-1 and sXBP1 was determined using real time PCR. For inhibition studies, RAW macrophages were pre-treated with PERK inhibitor GSK2606414 before infection.L.donovani infection activates Akt mediated pathway which delays apoptotic induction of the host. Moreover, Leishmania infection results in phosphorylation and activation of host PERK enzyme and increased transcription of genes of inhibitor of apoptosis gene family (cIAP) mRNA. In our inhibition studies, we found that inhibition of infection induced PERK phosphorylation under apoptotic inducers reduces the Akt phosphorylation and fails to activate further downstream molecules involved in protection against apoptosis. Also, inhibition of PERK phosphorylation under oxidative exposure leads to increased Nitric Oxide production. Simultaneously, decreased transcription of cIAP mRNA upon PERK phosphorylation fates the host cell towards apoptosis hence decreased infection rate.Our studies in RAW macrophages showed that induction of host UPR against Overall the findings from the study suggests that Leishmania modulated host UPR and PERK phosphorylation delays apoptotic induction in host macrophage, hence supports parasite invasion at early stages of infection. Leishmania donovani in Indian subcontinent. Modulation of host in terms of delayed apoptotic induction is one of the aspects which favours disease establishment; however the mechanism is not clearly understood yet. In the present study, we tried to explore the connection between L.donovani infection induced UPR in host with delayed onset of apoptosis. We found that L.donovani infection phosphorylates the PERK and Akt molecule in host along with delayed apoptosis. Simultaneously, the levels of cellular IAP (cIAP1 & 2) genes were also up-regulated in infected macrophages. To assess the involvement of PERK in delayed apoptosis of host, we inhibited the phosphorylation of PERK under the exposure to apoptotic inducers. We found that PERK inhibition decreased the Akt phosphorylation and fails to activate other associated downstream molecules involved in delayed apoptosis of host. Also, a significant reduction in cIAP levels was observed. Under oxidative exposure, inhibition of PERK phosphorylation debilitates infected RAW cell\u2019s ability to maintain redox homeostasis leading to higher nitric oxide production. Altogether, L.donovani infection modulates host apoptosis in a PERK dependent manner and favours infection.Visceral Leishmaniasis or Kala-azar is one of the severe tropical neglected parasitic diseases caused by  Leishmania ability to defy the host immune response is a major cause for persistence of Leishmaniasis. Parasite modulates host in various aspects and hampers the activation of adaptive immune responses against infection  ethylenediamine dihydrochloride  and 5% phosphoric acid. The absorbance was measured by spectrophotometry at 540 nm [Nitric oxide (NO) concentration was determined by analysing nitrite content in cell supernatant with the Griess reaction. t 540 nm .U test for comparing two groups or Kruskal\u2013Wallis with Dunn\u2019s multiple comparison test for comparing three or more groups. A P- value of <0.05 was considered significant.Graph Pad Prism  was used to analyse the data statistically. Each experiment was repeated three times in separate sets and the results were expressed as Mean \u00b1 SD. Statistical differences were determined using Mann\u2013Whitney Leishmania infection is known to elicit ER stress and activates UPR response in host. [in host. . To ensuLeishmania infection induces ER stress in host macrophages, we further investigated the effect of generated ER stress on infection rate. RAW macrophages treated with thapsigargin (Thg) or tunicamycin (Tu) for 1 hour were infected with L. donovani. After 36 hours, the infection index showed significantly higher parasite burden in thapsigargin (Thg) or tunicamycin (Tu) treated cells compared with that in non-treated cells (UNS) (As ls (UNS) . The resL.donovani infection induces ER stress in host macrophages, we further investigated the status and involvement of the host PERK in mounting UPR. Western blotting using phospho anti-PERK antibody revealed that in infected RAW cells, host PERK was phosphorylated  or campothecin (6h/ 2mM) treated RAW cell and were taken as control  gene family, particularly cellular IAPs (cIAP1 and cIAP2), provides cell protection during infection and against a variety of apoptotic stimuli , 32, 33. control .L.donovani infection induces ER stress, phosphorylates host Akt molecule and delays host macrophage apoptosis which facilitates infection. Also, induced ER stress phosphorylates host PERK and leads to accumulation of cIAP mRNA. So to further explore the connection between L.donovani infections induced ER stress and host PERK phosphorylation mediated UPR in modulating host cell apoptosis, inhibition studies was carried out. For inhibiting PERK mediated UPR response, RAW 267.4 macrophages were pre-treated with GSK2606414, a specific inhibitor of PERK phosphorylation [Leishmania PERK [The above results reveal that rylation , 39, 40;The Akt mediated signalling pathway requires PERK phosphorylation.An ER stress-inducing agent activates the PI3K\u2013Akt signalling pathway  and 42. PERK inhibition regulate the expression of IAP mRNA.L.donovani infection induces cIAP1 and cIAP2 mRNA translation. Since IAP is directly related to anti-apoptotic mechanism, we determine the involvement of host PERK in regulation of cIAP expression under apoptotic stimulus. RAW macrophages untreated or pre-treated with GSK2606414 were allowed to infect by L.donovani promastigotes. After 4 hours post infection, infected cells were exposed to campothecin or thapsigargin for apoptotic induction. RNA was prepared and cDNA was reversed transcribed for further real time analysis of cIAP1 and cIAP2 mRNA levels. It was found that in GSK2606414 untreated cells, the level of cIAP1 and cIAP2 was significantly up-regulated by ~ 3.0 fold high compared to GSK pre-treated RAW macrophages  released cytochrome C in cytoplasmic protein fraction was determined through western blotting using anti-Cyt C antibody after campothecin (2mM/6h) exposure. It was observed that the level of cytochrome C in GSK2606414 pre-treated infected RAW cells (Cmpt+GSK) was ~ 2.1 folds higher than in GSK2606414 untreated infected RAW cells exposed to campothecin (Cmpt) as revealed by densitometric analysis  resulted in an increase in DNA fragmentation as compared to GSK2606414 untreated infected RAW cells (Cmpt or Thg). Control untreated macrophages (UNS) or L.donovani infected RAW cells (LD+RAW) did not show any DNA fragmentation. The DNA fragmentation assay revealed that inhibition of infection induced PERK phosphorylation resulted in an increased DNA fragmentation upon apoptotic induction.One of the important identification features of apoptosis in mammalian cells is the fragmentation of cell DNA in multiples of 180\u2013200 bp. Similarly we also measure the DNA fragmentation in Oxidative stress induces PERK Phosphorylation in RAW macrophages.L.donovani infection, phosphorylation status of PERK was determined. Western blot analysis using phospho-PERK antibody against protein lysates of RAW macrophages exposed to H2O2 either untreated (H2O2) or pre-treated with GSK2606414 (H2O2+GSK) or incubated with NAC (H2O2+NAC) revealed that the PERK enzyme was phosphorylated in H2O2 exposed RAW cells  has a crucial role in redox homeostasis of the cell , 45. To AW cells ; howeverAW cells . The resL. donovani-infected macrophages from oxidative stressPERK phosphorylation regulates HO-1 expression and protects .L.donovani infected host cells during oxidative exposure, GSK2606414 pre-treated or untreated infected RAW 267.4 macrophages (4hr) were exposed to H2O2 and nitrite production as an indirect measure of nitric oxide (NO) levels was determined in cell supernatants. It was observed that NO level in H2O2 exposed uninfected RAW cell (H2O2 +RAW) was ~ 5 folds higher compared to infected RAW macrophages (UNS) but was ~2 folds higher in case of L.donovani infected RAW (H2O2 +LD+RAW) macrophages (2O2+LD+RAW+GSK). Uninfected RAW macrophages without any treatment were taken as control (UNS). Leishmania infection promotes expression of heme oxygenase (HO-1), a key antioxidant enzyme of host which facilitates parasite survival during oxidative burst to maintain redox homeostasis of host cell [L. donovani promastigotes (4hr) were exposed to H2O2. Following exposure, total mRNA was isolated, cDNA was prepared and HO-1 expression was determined. It was observed that the level of HO-1 was ~ 3.2 folds higher compared in H2O2 exposed RAW (H2O2+RAW) macrophages than normal untreated RAW cells (UNS). However in infected RAW macrophages (H2O2+LD+RAW) the level of was ~ 5.4 folds higher which results in lower NO production Click here for additional data file.S2 FigRAW macrophages either thapsigargin exposed (LD+RAW+Thg) or GSK2606414 pre-treated or normal/ untreated RAW macrophages (LD+RAW) were infected with L. donovani in 10:1 MOI. After 4 h of infection, the cells were fixed with methanol and stained with Giemsa, and the infection index was calculated (percent L. donovani infected cells X number of amastigotes per cell). Uninfected RAW macrophages (RAW) were taken as control. (Significant difference * (P < 0.05).(TIF)Click here for additional data file."}
+{"text": "A 2014 report evaluating accuracy of serologic testing for transfusion-transmissible viruses at African blood center laboratories found sensitivities of 92%, 87%, and 90% for detecting infections with human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV), respectively  was used. Within each country, all non-NBTS laboratories were sorted by number of blood units tested annually, and five laboratories were chosen randomly from strata above and below the median. Assay types in use at study laboratories were RDT; EIA-3, which detects antibody or antigen; and EIA-4, which detects both antigen and antibody. Characteristics of participating NBTS and non-NBTS laboratories were compared by country, prevalence of assay types, and measures of laboratory expertise, such as annual volume of specimens tested.https://stacks.cdc.gov/view/cdc/82012) at the Institut National de la Transfusion Sanguine, coded to allow for blinded testing, and sent to national coordinators who distributed them to participating laboratories while maintaining the cold chain.Panels of 25 challenge specimens were prepared and characterized by the Institut National de la Transfusion Sanguine . Each panel included seven negative controls; seven specimens that contained HIV antigen and anti-HIV antibody (six HIV-1 and one HIV-2) (HIV-positive samples); six specimens containing hepatitis B surface antigen  (HBV-positive samples); and five specimens that contained HCV RNA and anti-HCV antibody (HCV-positive samples). All positive challenge specimens included viral genotypes that were specific to Africa. Plasma specimens were diluted with uninfected plasma to obtain specific antigen or antibody concentrations. The panels were confirmed to match their labels  was estimated using approximately 25% of specimens for which the challenge virus matched the assay virus , and specificity (correct detection of infection-negative status) was estimated using approximately 75% of specimens for which the challenge virus (or control) did not match the assay virus .The investigators used separate generalized estimating equation logit-binomial models to estimate mean sensitivity and specificity and 95% confidence intervals (CIs), each as a function of the three assay viruses , clustering outcomes within laboratories. Multivariable models added NBTS status, assay type , and all two-way interaction terms to the unadjusted model. The unadjusted model of specificity also included the identity of the challenge virus. All analyses were performed using SAS software .Laboratory characteristics. Among the seven countries, the number of participating laboratories ranged from one (Rwanda) to 20 (Nigeria), and the proportion that were NBTS laboratories ranged from 9%  to 100% (Rwanda) ((Rwanda) . Five noAmong NBTS laboratories, 90% used EIA-3 or EIA-4 assays, whereas among non-NBTS laboratories, 78%\u201382% used RDT assays. NBTS centers tested approximately 10 times more blood units than did non-NBTS laboratories, and higher proportions of NBTS than non-NBTS laboratories produced blood components (66% versus 35%) and received blood primarily from volunteer donors (100% versus 60%).Sensitivity. Unadjusted mean sensitivity for detecting HIV-positivity was 97% (95% CI\u00a0=\u00a095%\u201398%); for detecting HBV-positivity was 76% (95% CI\u00a0=\u00a071%\u201381%); and for detecting HCV-positivity was 80% (95% CI\u00a0=\u00a075%\u201386%) (75%\u201386%) . SensitiBased on the multivariable model, adjusted sensitivities uniformly exceeded 96% when EIA-3 was used; however, the sensitivity of EIA-4 to detect HCV-positivity was <85%, and RDT assay sensitivities to detect HBV- and HCV-positivity were <71%. Sensitivity for detecting HIV-positivity was \u226595% regardless of laboratory or assay type. Sensitivity varied significantly among assay types (p = 0.011) but not among assay target viruses (p = 0.30) or between NBTS laboratory status (p = 0.81), and none of the three pairwise interaction effects was statistically significant (p\u22650.25). These findings are reflected by observed sensitivity proportions  that shoSpecificity. Unadjusted mean testing specificity was 95% (95% CI\u00a0=\u00a093%\u201397%) for HIV-negative specimens, 96% (95% CI\u00a0=\u00a093%\u201398%) for HBV-negative specimens, and 95% (90%\u201398%) for HCV-negative specimens. Across all assay target viruses, mean specificity was 90%\u201392% in three countries  and \u226598% in the other four countries.Adjusted estimates based on the multivariable model showed that the targeted assays varied in specificity by assay type (p = 0.054) and interaction with NBTS status (p = 0.058). Specificity was relatively low at non-NBTS laboratories for RDT assays targeting HCV or HIV and at NBTS laboratories for EIA-4 assays targeting HIV .This investigation of testing proficiency of targeted assays for HIV, HBV, and HCV found specificities to be high overall, with clinically negligible variations by NBTS status or assay type. In contrast, clinically important variation in sensitivities within and between assay targets was found. The finding that non-EIA-3 tests had lower sensitivity than did other assay types for detecting HBV- and HCV-positive specimens but not HIV-positive specimens is consistent with findings from previous studies  following reports of deficiencies in viral marker screening at African blood center laboratories.Standardized proficiency testing conducted in seven African countries during 2017 found that proficiency in human immunodeficiency virus testing has improved, but testing proficiency for hepatitis B virus (HBV) and hepatitis C virus (HCV) needs to be improved.Most poor performance in hepatitis virus testing can be attributed to the use of rapid tests rather than the non-NBTS setting of the laboratories. Remediation should be focused on improving the quality of rapid tests or avoiding their use."}
+{"text": "One DLT (grade 3 neuropathy) was observed in a patient who received 125 mg/m2 of nab-paclitaxel. Other grade 3 toxicities included fatigue (11%), anemia (11%), and neutropenia (11%). No grade 4 toxicities were observed. With a median follow-up of 8 months (range 5\u201328 months), median survival was 19 months and median progression-free survival was 10 months. Following chemoradiation, 3 patients underwent surgical resection, all with negative margins and limited tumor viability. Of the 3 patients, 2 initially had borderline resectable tumors and 1 had an unresectable tumor. Tumor  and peripheral (circulating tumor cells and microvesicles) biomarkers were collected and are being analyzed. DISCUSSION/SIGNIFICANCE OF IMPACT: The combination of fractionated radiation and weekly nab-paclitaxel was safe and well tolerated. This regimen represents a potentially promising therapy for patients with unresectable and borderline resectable pancreatic cancer and warrants further investigation.OBJECTIVES/SPECIFIC AIMS: Patients with locally advanced pancreatic cancer typically have poor outcomes, with a median survival of ~16 months. Novel methods to improve local control are needed. Nab-paclitaxel (abraxane) has shown efficacy in pancreatic cancer and is FDA approved for metastatic disease in combination with gemcitabine. Nab-paclitaxel is also a promising radiosensitizer based on laboratory studies, but it has never been clinically tested with definitive radiotherapy for locally advanced disease. METHODS/STUDY POPULATION: We performed a phase 1 study using a 3+3 dose-escalation strategy to determine the safety and tolerability of dose escalated nab-paclitaxel with fractionated radiotherapy for patients with unresectable or borderline resectable pancreatic cancer. Following induction chemotherapy with 2 cycles of nab-paclitaxel and gemcitabine, patients were treated with weekly nab-paclitaxel and daily radiotherapy to a dose of 52.5 Gy in 25 fractions. Final dose-limiting toxicity (DLT) determination was performed at day 65 after the start of radiotherapy. RESULTS/ANTICIPATED RESULTS: Nine patients received nab-paclitaxel at a dose level of either 100 mg/m"}
+{"text": "Multi-omic profiling of pancreatic neuroendocrine tumors (PanNETs) was performed to correlate genomic, proteomic, and molecular pathway alterations with clinicopathologic factors and identify novel co-occurring pathogenic alterations of potential clinical relevance to PanNET management.PanNETs referred to Perthera, Inc. having undergone molecular profiling for precision matched therapeutic purposes were screened. Correlative analyses were performed using Fisher\u2019s exact test across individual pathogenic alterations or altered molecular pathways and clinicopathologic variables. Associations were visualized by hierarchical clustering. Prognostic associations with overall survival (OS) were identified using Cox regression for pathogenic alterations and pathway-level alterations. Hazard ratios (HR) and odds ratios (OR) were reported with 95% confidence intervals (CI).MEN1 alterations by next-generation sequencing (NGS) were less associated with having high-grade PanNETs and metastatic disease at diagnosis (p \u2264 0.05). Genomic alterations associated with increased replicative stress (primarily driven by RB1 and TP53) correlated with higher grade  and worse OS . Other significant associations included: ERCC1 protein expression with DAXX or MEN1 alterations (NGS), PTEN (NGS) with ARID1A or TP53 alterations (NGS), and history of diabetes coincided with cell cycle pathway alterations but was mutually exclusive with replicative stress pathway alterations.From 12/2014\u20131/2019, 46 patients with predominantly locally advanced and metastatic PanNETs were included. We identified several molecular signatures of potential clinical significance for therapeutic targeting and prognostication in PanNETs warranting prospective validation. Our findings are hypothesis generating and can inform larger molecular profiling efforts in PanNETs. MEN1 (44.1%), DAXX (25%), ATRX (17.6%), TSC2 (8.8%), PTEN (7.3%), and PIK3CA (1.4%) [Pancreatic neuroendocrine tumors (PanNETs) have been established as a molecularly targetable group of cancers with approved inhibitors of mTOR and VEGFR/PDGFR/c-Kit that are available in the treatment paradigm for unresectable or advanced, well-differentiated disease , 2. Comp, PTEN 7.%, and PMUTYH , CHEK2 (4%), and BRCA2 (1%)), chromatin modification (including MEN1 (41%), SETD2 (5%), and MLL3 (5%)), altered telomere length (including DAXX (22%) and ATRX (10%)), and mTOR signaling (including PTEN (7%), DEPDC5 (2%), EWSR1 fusion (3%), TSC1 (2%), and TSC2 (2%)).Recently, the Australian Pancreatic Cancer Genome Initiative (APGI) within the framework of the International Cancer Genome Consortium (ICGC) performed whole-genome sequencing of 102 localized, locally advanced, and metastatic PanNETs to further characterize pathogenic mechanisms and uncover novel mutations for therapeutic targeting . In thisDespite the results of these landmark studies that have provided a framework for defining the most frequently altered genes and molecular pathways in PanNETs, their relationships to clinicopathologic characteristics remain poorly described. In this study, we describe our experience in cataloging alterations identified through multiplatform profiling of a cohort of predominantly locally advanced and metastatic PanNETs. In particular, we focused our analysis on co-occurring alterations of known pathogenicity and correlating molecular and pathway alterations with various clinicopathologic factors. We believe these analyses to be important in further defining molecular signatures and patient subsets of potential clinical relevance to PanNET management.From 12/2014\u201312/2018, a total of 46 patients diagnosed with predominantly locally advanced and metastatic PanNETs were included in this study . The medMEN1 (41%), DAXX (28%), TP53 (20%), PTEN (18%), RB1 (13%), and ARID1A (11%) comprised the most frequently altered genes in our NGS cohort of 46 patients with PanNETs. PTEN (100%), mismatch repair (MMR) proteins (100%), TOP1 (64%), TUBB3 (64%), pAKT (58%), ERCC1 (27%), and TLE3 (25%) were among those most frequently expressed in our IHC cohort  were less associated with having high-grade PanNETs, while alterations in RB1 (NGS), TP53 (NGS), and the replicative stress pathway were associated with having high-grade PanNETs. Alterations in MEN1 (NGS) and age >54 were less associated with metastatic disease at diagnosis. A history of diabetes was significantly associated with having an altered cyclin-dependent kinase (CDK) but less associated with having an altered replicative stress pathway. Several co-occurring alterations reached statistical significance: RB1 (NGS) and TP53 (NGS), MEN1 (NGS) with ERCC1 expression (immunohistochemistry or IHC) PTEN (NGS) and ARID1A (NGS), DAXX (NGS) and ERCC1 (IHC), PTEN (NGS) and TP53 (NGS), and MEN1 (NGS) with DAXX (NGS).Comparisons of molecular alterations and clinicopathologic variables identified several significant correlations . AlteratMEN1 and DAXX, both components of the chromatin remodeling pathway, tend to co-occur in non-metastatic, well-differentiated/intermediate grade PanNETS. NGS alterations in TP53 and RB1 tended to co-occur in high-grade tumors. SETD2 was mutually exclusive of these alterations within other low-grade tumors. No other associations across clinicopathologic variables and genomic alterations/IHC expression reached statistical significance beyond those described in Cluster analysis allowed generation of a heatmap to visualize putative correlations across clinicopathologic variables in our PanNET cohort . Notablyp = 0.0198). This finding was primarily driven by alterations in TP53 and RB1. No variables were significantly correlated with progression-free survival (PFS) in our analysis.Molecular alterations in the replicative stress pathway were the only variables demonstrating significant correlation with worse OS in our PanNET cohort  and mTOR signaling (PTEN and TSC1/2) as key oncogenic drivers [DAXX/ATRX to prognostic variables [Beyond well-established germline mutations, PanNETs are increasingly recognized as molecularly-driven tumors with somatic mutations affecting chromatin remodeling  were less associated with having high-grade PanNETs and metastatic disease at diagnosis. NGS alterations in MEN1 and DAXX, both components of the chromatin remodeling pathway, tend to co-occur in non-metastatic and well-differentiated/intermediate-grade PanNETs as visualized by hierarchical clustering  grade 2 tumors had significantly worse OS compared to wild-type tumors [MEN1, DAXX, and ATRX, which may be tumor stage and grade-specific. SETD2 was mutually exclusive of DAXX and MEN1 alterations within low-grade tumors in our cohort; the prognostic significance of this alteration may need further validation in larger PanNET cohorts.Our potential positive prognostic signature with T cohort . In predsurvival , 7. Recee tumors . FurtherTP53 (NGS) and RB1 (NGS) alterations, of which both were significantly associated with high-grade disease on pairwise comparison  polymerase (PARP) inhibitors or checkpoint kinase 1 (CHEK1/CHK1) inhibitors or cell cycle pathways with CDK inhibitors have yet to be as established in PanNETs as in other cancers, but our findings suggest a potentially targetable subset of PanNET patients with DNA replicative stress pathway alterations and poor prognosis that are primarily driven by RB1 and TP53 [To sum, alterations in the DNA replicative stress pathway, in particular and TP53 \u201313. FutuDAXX or MEN1 alterations (NGS), and PTEN (NGS) with ARID1A or TP53 alterations (NGS). ERCC1 expression has been shown to be putative prognostic and predictive biomarkers across various solid malignancies [DAXX and MEN1). In separate studies of PanNET patients, loss of PTEN and ARID1A were associated with poorer prognosis [PTEN co-occurred with ARID1A as well as the unfavorable prognostic TP53 alteration.We identified several other significant correlations of potential clinical importance on pairwise comparisons : historygnancies , 15. In rognosis , 17. ThiThe rationale behind the associations between a history of diabetes and alterations in the CDK or replicative stress pathway are unclear, but an altered replicative stress pathway portended to a poorer OS in our cohort . Age >54Lastly, it should be noted that this study was limited by its retrospective design and heterogeneity across patient characteristics and tumor biology. Our decision to include pathogenic variations only for analysis likely further limited our sample size though we believed this decision was justified in conducting our survival and correlative analyses to prognostic variables. Nevertheless, we identified several molecular signatures through multi-omic profiling of potential clinical significance that are hypothesis generating and can inform future investigations of larger and ideally prospective design. Increasing efforts to molecularly profile PanNETs will enhance the possibility to stratify PanNET patients into molecularly-defined treatment subgroups based on prognostic and predictive biomarkers.\u00ae (KYT) program  were referred to Perthera, Inc.  between 12/2014\u201312/2018 by their treating physician at a partnering institution or via the Pancreatic Cancer Action Network\u2019s Know Your Tumor program . ParticiThe processing of formalin-fixed paraffin-embedded (FFPE) tissues was performed in accordance to requirements per specific platform as previously described , 20. NGSsurvival package. Statistical significance was defined by a Fisher\u2019s exact test (two-tailed) p \u2264 0.05.Real-world outcomes data including demographics information, clinicopathologic factors, and survival metrics were abstracted from medical records and analyzed alongside molecular testing results from commercial laboratories. Descriptive statistics and other statistical analyses were computed in an R/Bioconductor programming environment. OS and PFS were evaluated for pairwise correlative analyses between individual pathogenic alterations or altered molecular pathways and clinicopathologic variables. Odds ratios (ORs) and 95% CIs were calculated using Cox proportional hazards regression as implemented in the R Pathogenic alterations were grouped into the following molecular pathways: replicative stress , chromatin remodeling , cyclin-dependent kinase , WNT signaling , mTOR signaling , and receptor tyrosine kinase (RTK) signaling . Only pathogenic alterations were included for correlative and survival analyses, and variants of uncertain significance (VUS) were excluded."}
+{"text": "Eukaryotes acquired the trait of oxygenic photosynthesis through endosymbiosis of the cyanobacterial progenitor of plastid organelles. Despite recent advances in the phylogenomics of Cyanobacteria, the phylogenetic root of plastids remains controversial. Although a single origin of plastids by endosymbiosis is broadly supported, recent phylogenomic studies are contradictory on whether plastids branch early or late within Cyanobacteria. One underlying cause may be poor fit of evolutionary models to complex phylogenomic data.Using Posterior Predictive Analysis, we show that recently applied evolutionary models poorly fit three phylogenomic datasets curated from cyanobacteria and plastid genomes because of heterogeneities in both substitution processes across sites and of compositions across lineages. To circumvent these sources of bias, we developed CYANO-MLP, a machine learning algorithm that consistently and accurately phylogenetically classifies (\u201cphyloclassifies\u201d) cyanobacterial genomes to their clade of origin based on bioinformatically predicted function-informative features in tRNA gene complements. Classification of cyanobacterial genomes with CYANO-MLP is accurate and robust to deletion of clades, unbalanced sampling, and compositional heterogeneity in input tRNA data. CYANO-MLP consistently classifies plastid genomes into a late-branching cyanobacterial sub-clade containing single-cell, starch-producing, nitrogen-fixing ecotypes, consistent with metabolic and gene transfer data.Phylogenomic data of cyanobacteria and plastids exhibit both site-process heterogeneities and compositional heterogeneities across lineages. These aspects of the data require careful modeling to avoid bias in phylogenomic estimation. Furthermore, we show that amino acid recoding strategies may be insufficient to mitigate bias from compositional heterogeneities. However, the combination of our novel tRNA-specific strategy with machine learning in CYANO-MLP appears robust to these sources of bias with high accuracy in phyloclassification of cyanobacterial genomes. CYANO-MLP consistently classifies plastids as late-branching Cyanobacteria, consistent with independent evidence from signature-based approaches and some previous phylogenetic studies. Over one billion years ago \u20133 photosPhylogenetic inferences concerning plastid origin are complicated by large evolutionary distances that have accumulated over at least one billion years of vertical descent, by extreme genome reductions in plastids  and in sIn this study, we show first that recently published phylogenomic datasets previously assembled from cyanobacterial and plastid genomes to address the root of plastids poorly fit the evolutionary models and character recoding strategies applied to them, which may help explain why earlier studies have reached contradictory conclusions with strong support. Then we introduce our Cyanobacterial Multi-Layer Perceptron Phyloclassifier (\"CYANO-MLP\"), a machine learning algorithm for phylogenetic classification of cyanobacterial and plastid query genomes to one of eight cyanobacterial clades. To \"phyloclassify\" a query genome to its clade of origin, the input data vector of CYANO-MLP respectively scores the query tRNA gene complement against eight sub-clade-specific structure-function maps for tRNAs called function logos, and the Class-Informative Features (CIFs) they contain .The bioinformatic estimation of tRNA CIFs applies Molecular Information Theory  to datab\u0393  indicates variant of CYANO-MLP with clade X data excluded from training and BAL indicates clade balanced training data. Table S5 Mean probability plus and minus one standard deviation of classification for the indicated group (Grp. Class.) using the specified variant of CYANO-MLP. Where CYANO-MLP[!X] indicates variant of CYANO-MLP with clade X data excluded from training and BAL indicates clade balanced training data. Table S6 Number of plastid genomes and left-out cyanobacterial clade genomes classifying to each cyanobacterial clade for the indicated version of CYANO-MLP. The number outside of parentheses indicated number of plastid genomes and the number within parentheses is the left-out cyanobacterial clade genomes. Dashes indicate N/A values. [!X] indicates variant of CYANO-MLP with clade X data excluded from training and BAL indicates clade balanced training data. Table S7 Classification results for plastid genomes and the chromatophore of P. chromatophora using CYANO-MLP. Results are summarized by plastid groups. Number of genomes classifying to each Cyanobacterial clade and percent are shown. 408 out of the 433 plastid genomes scored against B2+3 with a probability of 98.5% or better. Table S8 Number of plastid genomes with indicated max classification probability with the indicated version of CYANO-MLP. Where CYANO-MLP[!X] indicates variant of CYANO-MLP with clade X data excluded from training and BAL indicates clade balanced training data. Table S9 Median, mean, and standard deviation of classification probability to Cyanobacteria clade B2+3 for plastid genome groups.Additional file 2Figure S1 Function Logos for Cyanobacterial Clade A. Figure S2 Function Logos for Cyanobacterial Clade B1. Figure S3 Function Logos for Cyanobacterial Clade B2+3. Figure S4 Function Logos for Cyanobacterial Clade C1. Figure S5 Function Logos for Cyanobacterial Clade C3. Figure S6 Function Logos for Cyanobacterial Clade E. Figure S7 Function Logos for Cyanobacterial Clade F. Figure S8 Function Logos for Cyanobacterial Clade G. Figure S9 Normalized confusion matrices for (A) CYANO-MLP[!A], (B) CYANO-MLP[!B1], (C) CYANO-MLP[!B2+3], (D) CYANO-MLP[!C1], and (E) CYANO-MLP-BAL[!B1]. Where CYANO-MLP[!X] indicates variant of CYANO-MLP with clade X data excluded from training and BAL indicates clade balanced training data. Figure S10 Classification results of 100 bootstrap replicates of each Rhodophyta derived plastid genome. Results are summarized by Red plastid group with boxes spanning from the 25th percentile (bottom) to the 75th percentile (top) of bootstrap replicates classifying to the indicated Cyanobacterial clade per genome with the bisecting line marking the median value. Error bars indicate the shorter of either \u00b1 the interquartile range or the span of bootstrap replicates per genome. Dots show bootstrap replicates for individual genomes. Plastid genome bootstrap replicates classifying to cyanobacteral clades (A) A, B1, B2+3, (B) C1, C3, E, F, or G. Figure S11 Classification results of 100 bootstrap replicates of each Chloroplastida derived plastid genome. (A) Bootstrap results for plastid genomes classifying to cyanobacterial clades A, B1, B2+3, C1, F, and G. (B) Bootstrap results for plastid genomes classifying to cyanobacterial clades C3 and E. Figure S12 Box plot of maximum classification probability of each plastid genome. Error bars are the lesser of 1.5 IQR or full range of data. CYANO-MLP[!X] indicates variant of CYANO-MLP with clade X data excluded from training and BAL indicates clade balanced training data."}
+{"text": "Centrosomes function as the main microtubule-organizing centers (MTOCs) and play an essential role during cellular mitosis. As such, centrosome number is tightly controlled, with centrosomes duplicated only once per cell cycle . Unsurpr+ mimetic cores that display differential selectivity towards poly- and mono-ADP-ribosyltranferases [R2 = 0.76) observed between PARP6 enzymatic inhibition and multipolar spindle induction potency. We recapitulated the mitotic phenotype with siRNA-based PARP6 knockdown. Together, these results link the suppression of PARP6 enzymatic activity to the induced multipolar spindle centrosome phenotype. We further showed that targeting PARP6 with the optimized small molecule inhibitor AZ0108 effectively induced spindle multipolarity and demonstrated promising anti-tumor activity in various breast cancer models in vitro and in vivo.We recently reported the involvement of mono-ADP-ribosyltransferase PARP6 in maintaining centrosome integrity during mitosis by demonstrating that pharmacological inhibition of PARP6 induced multipolar spindle formation and elicited therapeutic effects in breast cancer . This stnferases . We levein vitro enzymatic assays and mass spectrometric analysis in cells. Beyond its role in mediating DNA damage responses, Chk1 is also involved in regulating cell-cycle checkpoints such as mitosis. During undisturbed cell cycle, Chk1 was reported to localize to interphase centrosomes and modulate cyclinB-Cdk1 activity, thereby impacting centrosomic mitotic events [via ADP-ribosylation and provide a mechanistic basis for multipolar spindle induction through PARP6 inhibition.To gain mechanistic understanding of the mitotic phenotype associated with PARP6 inhibition, we sought to identify PARP6 enzyme substrates using a powerful high-content ProtoArray screen consisting of 9,000+ full length human proteins. Centrosome related proteins were enriched as screening hits, including Chk1, which was further confirmed as a specific PARP6 substrate by c events . Our expvia modulating Chk1 activity (Figure In summary, our study established PARP6 as a novel molecular target for therapeutic intervention in breast cancer and delineated its role in maintaining centrosome integrity"}
+{"text": "During 2008\u20132018, we collected samples from rodents and patients throughout the Czech Republic and characterized hantavirus isolates. We detected Dobrava-Belgrade and Puumala orthohantaviruses in patients and Dobrava-Belgrade, Tula, and Seewis orthohantaviruses in rodents. Increased knowledge of eco-epidemiology of hantaviruses will improve awareness among physicians and better outcomes of patients. The most prevalent hantaviruses in Europe are Tula virus, Puumala virus (PUUV), and Dobrava-Belgrade virus (DOBV), all orthohantaviruses; PUUV and DOBV cause hemorrhagic fever with renal syndrome , 37 wood mice (A. sylvaticus), 222 striped field mice (A. agrarius), 445 bank voles (Myodes glareolus), 40 common voles , and 189 field voles (Microtus agrestis). We trapped all rodents as specified by the Animal Protection Act No. 246/1992 of the Czech Republic. Moreover, we obtained 61 clinical samples acquired from patients with hantavirus infections during 2008\u20132018; these hantavirus diagnoses were based on serologic testing (detection of hantavirus-specific IgG and IgM) and clinical and laboratory findings .During 2010\u20132017, we collected 1,551 wild rodents from different locations of the Czech Republic: 618 yellow-necked mice (https://www.euroimmun.com). We isolated RNA from rodent lung samples and human serum, plasma, and whole blood samples using QIAamp Viral RNA Kit  and QIAzol (QIAGEN) or TRIzol . We screened rodent and human RNA samples for hantavirus RNA using a reverse transcription PCR that amplified a 390-bp fragment of the large (L) segment (https://blast.ncbi.nlm.nih.gov/Blast.cgi), aligned with BioEdit (https://megasoftware.net).We tested human serum samples by Anti-Hantavirus Pool 1 \u201cEurasia\u201d ELISA (IgG and IgM) and confirmed previous hantavirus results by immunoblot EUROLINE Anti-Hanta Profile 1 (IgG and IgM)  and 4 sequences  of Seewis virus in 3 A. flavicollis mice and 1 A. sylvaticus mouse (GenBank accession nos. MK605682\u20134). The Seewis virus sequences clustered with sequences derived from shrews from the Beskydy Mountain region . From 33 positive A. agrarius mice trapped in Petrovice u Karvin\u00e9, we recovered 10 Kurkino genotype sequences with 99.1%\u2013100% similarity (GenBank accession nos. MK605680\u20131). We detected Tula virus (GenBank accession no. MK605685) in 1 field vole trapped at Velk\u00e1 Stolov\u00e1 Mountain.Of 1,551 rodent samples, 43 (2.77%) were PCR positive for hantavirus. These 43 animals were from 3 sampled localities: Celadna in the Beskydy Mountain region , Petrovice u Karvin\u00e9 , and Velk\u00e1 Stolov\u00e1 Mountain . From 9 hantavirus-positive mice collected in 2010, we recovered 6 sequences: 2 identical sequences of DOBV Dobrava in 2 Of 61 seropositive patients, 32 were PCR positive for DOBV and 3 PCR positive for PUUV (acquired outside of the Czech Republic). We recovered partial L segment sequences from 28 of 32 DOBV-positive patients (GenBank accession nos. MK605641\u201365). Because of low quality, we manually shortened these sequences to 195 bp. We obtained partial (264-bp) M segment sequences from 6 patients (GenBank accession nos. MK605666\u201371) and partial (531-bp) S segment sequences from 7 patients (GenBank accession nos. MK605672\u20138). We constructed phylogenetic trees to compare the virus sequences from humans and rodents. Analysis of the L segment revealed that samples clustered into 2 separate groups by DOBV genotype (Dobrava or Kurkino), and virus sequences from the same areas (regardless of human or rodent origin) clustered into the same clades . ClusterApodemus spp. mice (Most Dobrava-positive patients were from the mountain regions Jeseniky (northwest Silesia) and Beskydy (south Silesia), whereas Kurkino cases occurred in the lowlands between these 2 mountain regions  Figure. Additional information on molecular epidemiology of hantaviruses in the Czech Republic."}
+{"text": "This provides a high-quality representative sequence for the RT255 lineage.Hybrid  de novo assembly of Illumina/Nanopore sequence data produced a complete circular sequence of the chromosome for a Clostridioides difficile ribotype 255 (RT255) isolate from an elderly patient with recurrent C. difficile infection (CDI). This provides a high-quality representative sequence for the RT255 lineage.Hybrid  Clostridioides difficile is the leading cause of antibiotic-associated diarrhea and poses an urgent public health threat with >300,000 nosocomial infections in the United States each year (C. difficile ribotype 255 (RT255) has emerged as the fifth most common RT in Texas and supersedes hypervirulent RTs 027 and 078 in Houston, TX  in Houston, TX. Cryo-frozen isolates were incubated on cycloserine-cefoxitin fructose agar (CCFA) plates under anaerobic conditions for 48 h. Isolates were confirmed to be C. difficile by Gram staining, typical odor, and presence of C. difficile antigen on microscreen latex agglutination (Microgen Bioproducts). Genomic DNA was extracted using the MasterPure complete DNA and RNA purification kit . The same DNA prep was used for both Illumina and Nanopore sequencing. For Illumina sequencing, libraries of fragmented genomic DNA were prepared using a NEXTflex rapid DNA-seq kit . Paired-end reads  were generated on the MiSeq platform  using the Illumina MiSeq reagent kit v2  and the PhiX control kit v3 . Raw reads were quality filtered and adapter trimmed with Trimmomatic v0.36 (C. difficile Mta-79 as sequence type 34 (ST34). Nanopore and Illumina reads were combined for hybrid de novo assembly using Unicycler v0.4.8-beta (https://sourceforge.net/projects/bbmap/). The assembly was annotated with the NCBI Prokaryotic Annotation Pipeline (C. difficile Mta-79 (RT255) has been deposited in NCBI under BioProject PRJNA556848. The Illumina paired-end FASTQ and ONT base-called FASTQ files are available in the Sequence Read Archive under accession numbers SRR9850531 and SRR9850530, respectively. The annotated genome is listed under the NCBI accession number CP042267.The genome sequence for"}
+{"text": "Pseudomonas aeruginosa isolates were cultured from intensive care unit wastewater. All isolates exhibited resistance to carbapenem and extended-spectrum beta-lactam antibiotics.Four multidrug-resistant  Pseudomonas aeruginosa isolates were cultured from intensive care unit wastewater. All isolates exhibited resistance to carbapenem and extended-spectrum beta-lactam antibiotics. Genome characterization revealed the presence of beta-lactamase resistance genes (blaPAO and blaOXA), and three out of the four isolates carried the blaNDM-1 gene encoding resistance against carbapenems.Four multidrug-resistant  Pseudomonas aeruginosa isolates  were cultured from wastewater onto selective chromogenic media, CHROMagar Klebsiella pneumoniae carbapenemase (KPC) agar  from hospital wastewater samples of a clinical isolation ward in Singapore as described in Haller et al. (2017) . de novo using VelvetOptimiser 2.2.4 . Using the standard protocol, indexed sequencing libraries were prepared using a New England Biolabs Next Ultra DNA library prep kit for Illumina  and sequenced as paired-end reads 2 \u00d7 151 bp) using the Illumina HiSeq 4000 platform. A total of 26.1 million paired-end reads were obtained from four samples. Quality controlled reads with Phred scores of >20 were retained and assembled 1 bp usinP. aeruginosa isolate, the assembled genomes were searched against the Resfinder 3.0 database using default parameters (aph(3\u2032)-IIb], beta-lactam (blaPAO and blaOXA), fosfomycin (fosA), and phenicol (catB7) antibiotics, while isolates WPB099, WPB100, and WPB101 encoded additional ARGs resistant to fluoroquinolone (crpP and qnrVC1), macrolide-lincosamide-streptogramin B (msrE), sulfonamide (sul2), and trimethoprim (dfrB5) antibiotics. The blaNDM-1 gene, which encodes the New Delhi metallo-beta-lactamase enzyme capable of hydrolyzing ESBL and carbapenem antibiotics, was detected in genomes of isolates WPB099, WPB100, and WPB101.To identify antibiotic-resistant genes (ARGs) carried by each rameters . All 4 iP. aeruginosa strains WPB098 to WPB101 were deposited in GenBank under accession numbers CP031876 to CP031879 (BioProject number PRJNA486613). Raw reads can be found in the NCBI Sequence Read Archive (SRA) under accession numbers SRR8002634 to SRR8002637.Whole-genome sequences of"}
+{"text": "Alzheimer\u2019s disease (AD) patients display widespread mitochondrial defects. Brain hypometabolism occurs alongside mitochondrial defects, and correlates well with cognitive decline. Numerous theories attempt to explain AD mitochondrial dysfunction. Groups propose AD mitochondrial defects stem from: (1) mitochondrial-nuclear DNA interactions/variations; (2) amyloid and neurofibrillary tangle interactions with mitochondria, and (3) mitochondrial quality control defects and oxidative damage. Cells respond to mitochondrial dysfunction through numerous retrograde responses including the Integrated Stress Response (ISR) involving eukaryotic initiation factor 2\u03b1 (eIF2\u03b1), activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP). AD brains activate the ISR and we hypothesize mitochondrial defects may contribute to ISR activation. Here we review current recognized contributions of the mitochondria to AD, with an emphasis on their potential contribution to brain stress responses. Sporadic Alzheimer\u2019s disease (AD) brains possess profound mitochondrial defects, including changes in number, morphology, and enzyme activity ,2,3. MitBrain glucose uptake studies provided some of the earliest evidence for AD metabolic defects. Changes in cerebral glucose utilization occur during AD, demonstrated by numerous studies using 18F]-2-fluoro-2-deoxy-D-glucose (FDG) coupled with positron emission tomography (PET) ,8,9,10. F-2-fluorClassically, AD brains display decreased temporo-parietal glucose uptake in both hemispheres . StudiesDecreased cerebral glucose utilization occurs early in AD and could prove useful diagnostically ,18,19. SA clear association between brain hypometabolism and dementia exists but researchers do not understand why AD brains display reduced glucose utilization. Glucose transporter studies in AD brains provide one potential explanation for decreased glucose utilization. Glucose transporters move glucose across cell membranes and into the cytoplasm. Neurons import glucose mainly through GLUT3, while astrocytes import glucose mainly through GLUT1 . Both GLAltered metabolism in AD coincides with numerous mitochondrial changes. AD platelet cytochrome oxidase (COX) activity studies provided early evidence for mitochondrial dysfunction. Parker et al. showed altered COX activity in AD platelets, later extending their findings to AD brain tissue ,27. At tFurther changes in mitochondrial enzymes exist in AD. Post-mortem AD brain tissue analysis finds that COX subunits decrease during disease progression. In one study, the authors analyzed COXIV (nuclear-encoded) and COXII  subunit levels in cerebellar Purkinje neurons, an area relatively preserved in AD subjects compared to age-matched controls. The study found decreased COXIV and COXII protein levels in AD Purkinje neurons relative to age matched controls, as well as COX subunit reductions in aged controls relative to young controls. Based upon this finding, the authors argue COX deficiency occurs during normal aging and accelerated COX deficiency contributes to AD progression . CottrelWhile the AD hippocampus contains many COX deficient neurons, studies also observe AD neurons displaying increases in COX and mtDNA. In AD neurons with increased COX and mtDNA, lysosomal structures tend to accumulate mitochondrial components. These findings suggest increases in COX and mtDNA do not reflect increased intact mitochondria. Instead, mtDNA and COX accumulation likely signals deficient mitochondrial degradation . AD neurAD mitochondria also display alterations in morphology. AD brain electron microscopy (EM) studies reveal changes in mitochondrial physical structure. Numerous AD brain regions display increased variability in mitochondrial shape and disrupted cristae, as well as decreased mitochondrial surface area . MitochoWhether metabolic and mitochondrial defects represent a cause or consequence of AD remains controversial. Numerous groups propose mitochondrial dysfunction initiates AD pathological cascades and therapeutics should target mitochondrial dysfunction ,47,48,49Somatic mtDNA mutations may contribute to AD and mtDNA inheritance may influence AD risk. Mitochondrial function relies on coordinated expression of genes from the nuclear and mitochondrial genomes. Inherited mtDNA polymorphisms cause a range of disorders known as primary mitochondrial diseases. Many of these diseases primarily affect cognition, demonstrating that neurons possess high sensitivity to mitochondrial defects. One of the most widely recognized mtDNA deletions, a 4997 bp deletion called the \u201ccommon deletion\u201d, increases in the brain during normal aging. Common deletion rates increase most drastically in regions with high metabolic activity, causing some to speculate that mtDNA somatic deletions dispose individuals to neurological disease . AD mtDNAD brains also display increased mtDNA oxidative damage. Interestingly, mtDNA oxidative damage occurs most heavily in the parietal lobe, which displays early and consistent hypometabolism . IncreasAD inheritance pattern studies implicate mtDNA inheritance as an AD risk factor. In a group of families with one AD affected parent and two affected siblings, Edland et al. discovered increased AD rates among individuals with a maternal AD history . These fCytoplasmic hybrid (cybrid) studies provide further evidence mtDNA contributes to AD mitochondrial abnormalities. Cybrid generation occurs by repopulating cells lacking mtDNA (\u03c10) with exogenous mtDNA. Exogenous mtDNA often comes from patient platelets, allowing creation of cybrids containing AD patient mtDNA. Cybrids, therefore, effectively model AD mitochondrial function on a stable nuclear background. AD cybrids recapitulate numerous AD features. Initial AD cybrid studies demonstrate COX activity deficits that recapitulate those of AD patient mitochondria. AD cybrid COX deficits provide strong evidence that mtDNA contributes to AD mitochondrial defects ,63. FurtAD cybrids display amyloid changes reminiscent of those observed in AD and possess increased sensitivity to amyloid beta fragments. AD cybrids release amyloid beta at greater rates than controls. Furthermore, AD cybrids contain increased intracellular amyloid beta. Elevations in amyloid beta coincide with increased cytochrome c release and caspase-3 activity, suggesting cell death pathway activation may contribute to elevated amyloid beta . AD cybrFurther studies demonstrate mitochondrial function influences AD pathology. Treating fibroblasts from control subjects with a mitochondrial membrane potential uncoupler (CCCP) triggers tau phosphorylation at sites altered in AD . ComplexCOX10 gene, which encodes a necessary COX assembly factor, in triple transgenic mice. COX10 deletion inhibits COX assembly, causing loss of function. COX10 deficient triple transgenic mice produce fewer amyloid plaques and amyloid beta than triple transgenic mice with functional COX [COX10 deletion likely stimulates different responses than those elicited by defective functioning of intact COX. Additional studies are needed to more fully examine mitochondrial dysfunction\u2019s effects on AD pathology.Studies question whether mitochondrial dysfunction triggers Alzheimer\u2019s pathology. Fukui et al. deleted the onal COX . This fiA reciprocal relationship exists between AD pathology and mitochondrial function. Amyloid beta treatment in cell culture causes mitochondrial dysfunction, including decreases in membrane potential, electron transport chain activity and oxygen consumption . AmyloidTau truncation also occurs in AD, potentially contributing to mitochondrial dysfunction. AD NFTs contain truncated tau and these truncated tau species may be toxic ,80. OverApolipoprotein E allele \u03b54 (apoE4) increases risk for AD. Relative to other apoE isoforms, apoE4 accumulates in endosomal compartments and stimulates cholesterol efflux less efficiently . FurtherEmerging evidence suggests mitochondria contribute to cellular proteostasis . In yeasCaenorhabditis elegans (C. elegans) provide most of the evidence for a mtUPR. mtDNA depletion by ethidium bromide, doxycycline treatment and mitochondrial ribosomal protein knockdown all trigger the mtUPR in C. elegans. Also, disrupting mitochondrial protein complexes and knocking down mitochondrial proteases and chaperones activates the mtUPR [C. elegans, Activating Transcription Factor associated with Stress-1 (ATFS-1) mediates mtUPR activation. ATFS-1 controls the mtUPR based on its subcellular localization. Functional mitochondria import and degrade ATFS-1. When mitochondrial dysfunction occurs, ATFS-1 accumulates in the nucleus due to a nuclear targeting sequence. Nuclear ATFS-1 activates mitochondrial protease and chaperone transcription. The mtUPR and ATFS-1 gained notoriety following discoveries of lifespan extension in C. elegans upon electron transport chain (ETC) gene knockdown [C. elegans lifespan studies suggest mtUPR activation and ATFS-1 activity do not facilitate the observed lifespan extension following mitochondrial insult [Mitochondria possess intrinsic mechanisms for responding to unfolded proteins. Mitochondrial protein misfolding triggers a compensatory mechanism termed the mitochondrial unfolded response (mtUPR). Mutant ornithine transcarbamylase (OTC) overexpression leads misfolded OTC to accumulate within mitochondria, stimulating the mtUPR . The mtUhe mtUPR . In C. enockdown . Groups l insult .C. elegans. However, distinct mitochondrial stress response pathways appear to predominate in mammalian cells. Studies examining diverse mitochondrial stressors suggest ATF5 activation occurs under specific circumstances. Paraquat treatment and mutant OTC overexpression stimulate mitochondrial chaperone and protease transcription in an ATF5-dependent manner. While ATF5 appears responsive to paraquat and mutant OTC, studies reveal activating transcription factor 4 (ATF4) responds to numerous mitochondrial stressors. Quiros et al. [In mammalian cells, activating transcription factor 5 (ATF5) may regulate an mtUPR similar to how ATFS-1 functions in s et al.  introducs et al. . In lines et al. . ATF4 clSaccharomyces cerevisiae have elucidated mitochondrial-nuclear communication pathways in great detail [2+) and ROS levels, activating nuclear factor kappa B (NF\u03baB). Although NF\u03baB activation is canonically associated with immune system function, diverse cellular stressors, including mitochondrial dysfunction, activate NF\u03baB [Mitochondrial dysfunction triggers numerous changes in nuclear gene expression ,96. Refet detail . While fate NF\u03baB . Mitochoate NF\u03baB ,99. c-Myate NF\u03baB . NF\u03baB anate NF\u03baB . Numerouate NF\u03baB ,102.Many studies show that mitochondrial stress activates ATF4 signaling, suggesting ATF4 plays a role in retrograde signaling. ATF4 activation occurs through a pathway known as the integrated stress response (ISR). The ISR begins with eukaryotic initiation factor 2 alpha (eIF2\u03b1) phosphorylation . Four kiOne of eIF2\u03b1 phosphorylation\u2019s most important effects is to pause general protein translation, assisting in cellular stress recovery. However, eIF2\u03b1 phosphorylation paradoxically increases protein translation from mRNAs possessing alternative open reading frames (ORFs). Numerous stress responsive factors contain alternative ORFs. Therefore, eIF2\u03b1 phosphorylation reduces cell protein loads while preferentially increasing stress response factors . ATF4 trSeveral reports show mitochondrial dysfunction stimulates the ISR in mammalian cells. Rotenone treated oligodendroglia increase eIF2\u03b1 phosphorylation as well as ATF4 and CHOP protein . EarlierFurther studies show mitochondrial stress induces the ISR in muscle and brain tissue. Deletor mice possessing a dominant Twinkle (helicase involved in mtDNA replication) mutation model mitochondrial myopathy. Deletor mice rapidly accumulate mtDNA mutations leading to OXPHOS deficiency. OXPHOS deficiency in deletor mice triggers ISR components resulting in altered one carbon metabolism, serine synthesis, and glutathione production pathways (transulfuration) . Quiros Inducible Drp1 knockout in mouse neurons also stimulates the ISR. Drp1 knockout disrupts mitochondrial fission causing mitochondrial dysfunction and ISR activation. Drp1 knockout neurons increase fibroblast growth factor 21 (Fgf21) plasma protein and mRNA levels. A cytokine associated with mitochondrial myopathies, Fgf21 release increases upon mitochondrial dysfunction. Neuronal Drp1 knockout mouse studies show that brain mitochondrial dysfunction triggers Fgf21 release in an ISR dependent manner . Some coAs referenced earlier, numerous signals could activate ISRs. Heme depletion, viral infection, endoplasmic reticulum stress, and amino acid starvation all stimulate eIF2\u03b1 kinases . DetermiMitochondria associate with the ER and assist in calcium maintenance, leading investigators to speculate whether mitochondrial dysfunction triggers ISR by causing ER stress. To determine whether mitochondrial dysfunction stimulates ER stress, studies examined classical ER stress markers not involved in the ISR. Studies found that mitochondrial dysfunction triggers the mtISR independently of general ER stress . AlthougDeclining mitochondrial function during aging could theoretically stimulate retrograde responses . AD braiDrosophila melanogaster models of neuronal mitochondrial dysfunction identify hypoxia inducible factor 1\u03b1, forkhead box O (FOXO) and ATF4 as key retrograde responders [Few studies focus on retrograde responses in the AD brain. In fact, many mammalian retrograde response studies use cancer cells which may respond differently to mitochondrial stress than postmitotic neurons. However, several lines of evidence suggest retrograde responses occur in neurons. sponders . Human psponders . Differesponders . The div2+ concentration [Postmortem AD brains generally display NF\u03baB activation and cyclic AMP response element binding protein (CREB) alterations, both of which can be affected by mitochondrial dysfunction and subsequent changes in Cantration . AD braintration ,132. Thentration . All of Another hypothetical consequence of AD mitochondrial dysfunction is ISR activation. Post-mortem AD brains display ISR activation. Given the well documented mitochondrial dysfunction in AD and evidence suggesting mitochondrial dysfunction stimulates the mtISR, it seems possible a mtISR occurs in AD brain. Numerous studies describe increased eIF2\u03b1 phosphorylation in AD brains, particularly in hippocampal neurons ,135 ATF4Several groups propose amyloid beta and tau alterations trigger the ISR. In embryonic rat hippocampal cultures, amyloid beta oligomer treatment induces axonal ATF4 and CHOP synthesis. ATF4 siRNA desensitizes rat hippocampal cultures to amyloid beta\u2019s negative effects, suggesting ATF4 potentiates amyloid beta toxicity . HoweverMitochondrial dysfunction occurs in AD. Mitochondrial and metabolic abnormalities present early in disease progression. Systemic AD metabolic changes may prove useful diagnostically, and mitochondrial dysfunction seems to be a reasonable therapeutic target. Mitochondria-specific stress responses help cells cope with mitochondrial dysfunction. Certain mitochondrial stress response components are activated in AD, although to what extent these stress responses contribute to retarding or promoting AD progression remains unclear."}
+{"text": "Timelapse videos were created by taking images every 20 minutes for 18 hours(phase-contrast) or every 10 minutes for 12 hours (darkfield). NucView reagentwas ordered from Biotium. Temozolomide was ordered through Abmole. All in vivowork was conducted according to protocols approved by the University ofPittsburgh\u2019s IACUC office. RESULTS/ANTICIPATED RESULTS:ECM hydrogels derived from porcine dermis, small intestine, or urinary bladderall decreased the viability of primary glioma cells in vitro, with urinarybladder extracellular matrix (UBM) having the most dramatic effects. The SSF ofUBM (UBM-SSF), devoid of the fibrillar, macromolecular components of ECM, wassufficient to recapitulate this detrimental effect upon neoplastic cells invitro and was used for the remainder of the experiments described herein. In acell viability assay normalized to the media treatment, non-neoplastic CHME5 andN1E-115 cells scored 103% and 114% after 48 hours whentreated with UBM-SSF and 2 primary high-grade glioma cell types scored17% and 30.5% with UBM-SSF (n=2).Phase-contrast time-lapse video showed CHME5 and HFF thriving in the presence ofUBM-SSF for 18 hours while most primary glioma cells shriveled and died withinthis time. Darkfield time-lapse video of wells containing Nucview dye,fluorescent upon cleavage by active caspase-3, confirmed that within 12 hoursmost primary glioma cells underwent apoptosis while CHME5 and HFF did not. Inculture with primary astrocytes, high grade primary glioma cells, and U-87 MGglioma cells for 24 hours, UBM-SSF was found to significantly increase thepopulation of primary astrocytes compared with media(p<0.05) while decreasing the 2 glioma cell types toapproximately one-third as many cells as the media control(p<0.0001). A dose-response of temozolomide from 0to 10,000 \u03bcM showed that when treating 2 non-neoplastic cell types(CHME5 and HFF) and 2 types of primary glioma cell there was no difference insurvivability at any concentration. Contrasted to this, a dose-response ofUBM-SSF from 350 to 7000 \u03bcg/mL showed that thenon-neoplastic cells survived significantly better than the glioma cells atconcentrations of 875 \u03bcg/mL and upward(p<0.05). In preliminary animal experiments, largeprimary glioma tumors in the flanks of athymic nude mice were resected andreplaced with either UBM SSF or Matrigel (an ECM product of neoplastic cellorigin). After 7 days the resection sites with UBM-SSF had little tumor regrowthif any compared with the dramatic recurrence seen in the Matrigel injectionsites (n=2). In a separate survival study comparing PBS to UBM-SSFinjections in the flank-resection model, all animals given PBS had to besacrificed at 9, 11, and 11 days (n=3) whereas animals given UBM-SSFwere sacrificed at 15, 24, and 39 days (n=3), indicating a moderateincrease in survival due to the UBM-SSF. DISCUSSION/SIGNIFICANCE OFIMPACT: Since the introduction of the pan-cytotoxic chemotherapeutic agent TMZin 2005, the standard of care for patients with glioblastoma multiforme has notimproved. These findings indicate that non-neoplastic ECM contains potentbioactive regulators capable of abrogating malignancy. Our in vitro data suggestthese molecules appear to have no deleterious effect on non-neoplastic cellswhile specifically inducing apoptosis in glioma cells. Our in vivo data suggestthat these molecules may be useful in delaying glioma recurrence, thus resultingin extended lifespan. Delivering soluble fractions of ECM to a tumor site mayrepresent a novel approach to glioma therapy, sidestepping traditional cytotoxictherapies in favor of utilizing putative endogenous anti-tumor pathways.OBJECTIVES/SPECIFIC AIMS: Gliomas are the most lethal and commonprimary tumor type in the central nervous system across all age groups; affectedadults have a life expectancy of just 14 months. As glioma cells invade thesurrounding normal parenchyma they remodel the composition and ultrastructure ofthe surrounding extracellular matrix (ECM), suggesting that the native  microenvironment is not ideal for their survivaland proliferation. Recent reports describe suppressive and/or lethaleffects of mammalian ECM hydrogels derived from normal (nonneoplastic) sourcesupon various cancer types. ECM-based bioscaffolds placed at sites of neoplastictissue resection in humans have never been reported to facilitate cancerrecurrence. The objective of the present research is to evaluate mammalian ECMas a novel approach to glioma therapy. METHODS/STUDY POPULATION: ECMhydrogels from porcine dermis, small intestine, and urinary bladder wereproduced as described previously. Primary glioma cells were graciously suppliedby Drs. Nduka Amankulor and Johnathan Engh, and U-87 MG were ordered throughATCC. Cells were plated onto tissue culture plastic at~60% confluence and allowed to attach for 24 hours beforetreatment. The saline-soluble fraction (SSF) of ECM was obtained by mixinglyophilized, comminuted ECM with 0.9% saline for 24 hours thenfiltering the resulting mixture through a 10 kDa molecular weight cutoff column.All assays and kits were followed according to the manufacturer\u2019sinstructions. Cell viability was measured via MTT assay(Vybrant"}
+{"text": "Many older adult Veterans with Depression and superimposed Neurocognitive Impairments may demonstrate behavioral agitation. To buffer patient agitation seen within a Veteran\u2019s Affairs residential extended care facility, psychological services were expanded to include the use of mobile technologies. To evaluate the effectiveness of adding technology supported psychological services, outcomes were gathered as part of continuous process improvement efforts. 28 Veterans with Depression and NCI who received technology enhanced services were rated by staff on observed agitation behaviors prior and following clinical encounters. In addition, a subset of 17 Veterans also provided subjective unit of distress (SUD\u2019s) ratings based on the Brief Interview for Mental Status inclusion criteria. Paired sample T-Tests were completed to assess if technology-enhanced interventions resulted in average reductions of clinician rated observations of Veteran agitation behaviors. Significant differences were found in observations of Veteran facial tension (t(27)=3.722, p=.001), agitated body movement (t(14)=2.020, p=.053), and threatening posture (t(27)=2.243, p=.044). Evaluation of a subset of those residents who also provided SUD\u2019s ratings show a significant change in self-reported distress after intervention (t(16)=4.3, p=.001). Effect size for this difference was large (d=1.042). These results suggest that mobile technologies can help reduce agitation and Veteran self-reported distress among older Veterans with Depression and superimposed Neurocognitive Impairments."}
+{"text": "Idiopathic Pulmonary Arterial Hypertension (IPAH) is a deadly and disabling disease characterized by severe vascular remodeling of small pulmonary vessels by fibroblasts, myofibroblasts and vascular smooth muscle cell proliferation. Recent studies suggest that the Natriuretic Peptide Clearance Receptor (NPR-C) signaling pathways may play a crucial role in the development of IPAH. Reduced expression or function of NPR-C signaling in pulmonary artery smooth muscle cells may contribute to the pulmonary vascular remodeling, which is characteristic of this disease. The likely mechanisms may involve an impaired interaction between NPR-C, specific growth factors and other signal transduction pathways including but not limited to Gq\u03b1/mitogen-activated protein kinase (MAPK)/PI3K and AKT signaling. The resulting failure of growth suppression in pulmonary artery smooth muscle cells provides critical clues to the cellular pathobiology of IPAH. The reciprocal regulation of NPR-C signaling in models of tissue remodeling may thus provide new insights to our understanding of IPAH. Pulmonary arterial hypertension (PAH) is a devastating disease, which if not interrupted, leads to progressive right-sided heart failure and death within 2 to 3 years after diagnosis ,2,3. AltNatriuretic peptides (NPs) constitute a family of at least four structurally related peptide hormones named Atrial Natriuretic Peptide (ANP), Brain Natriuretic Peptide (BNP), C-type Natriuretic Peptide (CNP), and Urodilatin (URO), which may regulate several biological processes including plasma volume and blood pressure control ,14,15. M4\u201323 may decrease the cAMP levels in VSMCs [4\u201323 may trigger inositol triphosphate (IP3) formation in A10 vascular smooth muscle cells [4\u201323 is a secondary event mediated through the AC/cAMP system coupled to NPR-C or a primary event is still not well understood. There may definitely be a cross-talk between NPR-C-mediated AC/cAMP and PLC signaling pathways as the inhibition of AC and decreased levels of cAMP triggered by NPRC activation may contribute to stimulation of PI turnover [4\u201323 as well as other vasoactive peptides may trigger the activation of constitutive nitric oxide synthase (NOS) smooth muscle cells [Various studies have demonstrated that NPR-C can inhibit the AC/cAMP signal transduction and elicit physiological functions . Natriurin VSMCs . Evidencin VSMCs . Murthy le cells . Whetherturnover ,25. The turnover . NPs antturnover . In additurnover . These oturnover . Finallyle cells .Npr3 exhibit alterations in cardiovascular system, and several evidences suggest that mutations in Npr3 may lead to cardiovascular diseases [-/-) by echocardiography [-/- mice exhibit important structural features including right atrial and ventricular enlargement, hypertrophy of the right ventricular free wall, tricuspid regurgitation as well as echocardiographic findings suggestive of right ventricular pressure overload manifested as abnormal motion of the interventricular septum, which are all findings typically seen in humans with PAH [Both heterozygous and homozygous knockout mice for diseases . Recent iography ,10. NPR-Group 3 Pulmonary hypertension (PH) includes PH due to lung diseases or hypoxia. Among the etiologies of group 3 PH, the strongest evidence favors hypoxic pulmonary vasoconstriction with remodeling of the pulmonary vascular bed. The pulmonary vascular remodeling is characterized by the proliferation, hypertrophy and extension of smooth muscle cells to previously unmuscularized pulmonary arterioles . The mecSeveral evidence also suggests a potential role of NPR-C signaling pathways in the pathophysiology of other cardiovascular diseases ,18. Alte4\u201323 may attenuate the enhanced proliferation of VSMC by decreasing the expression of cell cycle proteins [4\u201323 in VSMC was, again, mediated through the inhibition of MAP kinase/PI3-kinase/AKT signaling pathways [Excessive vascular smooth muscle cell (VSMC) proliferation contributes to tissue remodeling that occurs in several vasculopathies including but not limited to PH ,43. Evidproteins . The autpathways . Cahill pathways . Sangarapathways . Furtherpathways ,48, wherpathways . The actpathways , and indpathways . Pedram pathways . These opathways . OverallFor several decades, NPR-C has been considered a NP clearance receptor responsible for receptor-mediated NPs degradation . More re"}
+{"text": "Asian-Australas J Anim Sci 2018. Vol 31, No. 10 : 1627\u20131634.The following is the updated title of Nopalea cochenillifera Salm Dyck) cladodes plus urea replace wheat bran in steers\u2019 diet?Can cactus ("}
+{"text": "While PET intensity carries prognostic significance, the genetic abnormalities associated with increased intensity remain unspecified.NSCLC samples (N = 34) from 1999 to 2011 for which PET data were available were identified from a prospectively collected tumor bank. PET intensity was classified as mild, moderate, or intense based on SUVmax measurement or radiology report. Associations between genome-wide expression (RNAseq) and PET intensity were determined. Associations with overall survival were then validated in two external NSCLC cohorts.MYC, NF-\u03baB, and HIF-1. Using an external cohort of 25 tumors with PET and genomic profiling data, common genes and gene sets were validated for additional study (P<0.05). Of these common gene sets, 20% were associated with hypoxia or HIF-1 signaling. While HIF-1 expression did not correlate with poor survival in the NSCLC validation cohort (N = 442), established targets of hypoxia signaling  were significantly associated with poor overall survival.Overall survival was significantly worse in patients with PET-intense (N = 11) versus mild (N = 10) tumors (p = 0.039). Glycolytic gene expression patterns were markedly similar between intense and mild tumors. Gene ontology analysis demonstrated significant enhancement of cell-cycle and proliferative processes in FDG-intense tumors (p<0.001). Gene set enrichment analysis (GSEA) suggested associations between PET-intensity and canonical oncogenic signaling pathways including PET-intensity is associated with a variety of oncogenic alterations in operable NSCLC. Adjuvant targeting of these pathways may improve survival among patients with PET-intense tumors. FDG is a fluorescent glucose analog that accumulates at sites with elevated glucose metabolism, including many tumors. It has been well-established that the degree of FDG uptake by NSCLC tumors (i.e. the intensity) predicts survival, even among early stage surgical candidates . Our. Our3]. This study is limited by the number of patients. To compensate, two distinct cohorts were identified and analyzed separately. This study was also limited in its strength of radiographic data. It was not possible to quantify every PET image due to technical limitations. However, many physicians do not receive explicit SUV values in the radiology reports. Therefore, these findings are still generally applicable to physicians who are familiar with evaluating such imaging without quantification. Finally, the genetic analysis was limited due to the heterogeneity within the samples. Again, this may suggest that PET-intensity represents a convergence of many distinct genetic phenomena.In conclusion, preoperative FDG-PET intensity in NSCLC patients correlates with worse survival. These data show that a genetic signature consistent with hypoxia correlates with high intensity tumors. Further research is warranted to determine the therapeutic and clinical significance of these findings.S1 FigTP53, EGFR, and KRAS between high and low intensity tumors.(a) Representative cross-sectional FDG-PET scan images of high and low intensity tumors. (b) Percent mutation of common NSCLC mutations including (TIF)Click here for additional data file.S2 Fig(TIF)Click here for additional data file.S3 Fig(TIF)Click here for additional data file.S4 Fig(TIF)Click here for additional data file.S1 File(TIF)Click here for additional data file."}
+{"text": "OBJECTIVES/SPECIFIC AIMS: Assess the presence of contact activation at baseline in sera from common variable immunodeficiency (CVID) patients with and without inflammatory complications compared with healthy controls. METHODS/STUDY POPULATION: CVID patients were recruited in the outpatient setting and the measurement of cleaved plasma HK (cHK) levels was determined by Western blot analysis, under reducing conditions, with quantitation of total and cHK bands using an Odyssey imaging system (Licor). One-way ANOVA test for differences among the 3 studied groups will be applied. Biomarkers C3, C4, C1 inhibitor levels and hs-CRP were also measured. RESULTS/ANTICIPATED RESULTS: Participant enrollment continues and to date, 9 CVID patients were studied, 7 with and 2 without inflammatory complications. Repeated determinations of cleaved HK% (cHK%) revealed an average of 1.20% (range: 0.46%\u20132.66%) in CVID patients with inflammatory complications and those without complications averaged 1.07% (range: 0.79%\u20131.35%). Healthy controls had an average cHK of 1.15% (range: 0.60%\u20132.10%). DISCUSSION/SIGNIFICANCE OF IMPACT: Cleaved kininogen detected in the sera of CVID patients was found at similar levels compared with healthy controls (cHK<5%). Findings suggest that systemic activation of the contact system might be absent in CVID, however, future considerations include developing detection methods for local tissue activation."}
+{"text": "A 34-year old gravida03 para02 woman with fetal bilateral hydronephrosis (A), greatly distended bladder and mild polyhydramnios, detected during a prenatal ultrasound. Based on the ultrasonography findings, megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) was suspected. MMIHS is an unusual disorder with the incidence of 1:1500, characterized by a massively enlarged fetal urinary bladder, microcolon, hypoperistalsis throughout the intestinal tract and incomplete intestinal rotation. A female infant was born at 34 weeks of gestation by an emergency caesarean section because of breech presentation during labor. The neonate weighed 4.2 kg with an Apgar score of 4 in 1 min and 6 in 5 min. Physical examination showed massive distended abdomen (B) and bladder, as well as bilateral palpated enlarged kidneys. Abdominal plain x-ray showed a dilated stomach and minimal gas in the distal bowel segments (C). An abdominal ultrasound imaging showed dilated stomach with distal duodenal atresia. Fluoroscopy gastrografin revealed narrow bowel loops and jejunal malrotation at the right side. Kidney-urinary-bladder ultrasonography showed distended urinary bladder, bilaterally enlarged kidneys, with tortuous and dilated ureter. A vesicostomy was performed to facilitate the drainage of urine (D). Presence of ganglion cells on rectal biopsy excludes Hirschsprung disease. The condition is fatal and surgical correction often remained unsuccessful. MMIH is an autosomal recessive disorder so genetic counseling is suggested for future pregnancies."}
+{"text": "Streptomyces thermocarboxydus strain BPSAC147 is an endophytic actinobacterium isolated from root tissues of Rhynchotechum ellipticum in Mizoram, Northeast India. The strain showed potentially plant growth-promoting and biocontrol activities. Streptomyces thermocarboxydus strain BPSAC147 is an endophytic actinobacterium isolated from root tissues of Rhynchotechum ellipticum in Mizoram, Northeast India. The strain showed potentially plant growth-promoting and biocontrol activities. The draft genome consists of 7.37 Mb and encodes 7,060 putative open reading frames. Streptomyces thermocarboxydus BPSAC147 was isolated from root tissues of Rhynchotechum ellipticum cultivated in Mizoram, India. After surface sterilization, root fragments were placed onto petri plates containing tap water-yeast extract agar (TWYE) medium supplemented with nystatin and cycloheximide (60 \u03bcg/ml) to suppress fungal growth. Then, the plate was incubated at 28\u00b0C for 15 days . A Streptomyces thermocarboxydus isolate showed the ability to solubilize phosphate and produce indole-3-acetic acid (IAA), ammonia, cellulase, and amylase enzyme  and incubated at 28\u00b0C for 7 days at 150 rpm. Genomic DNA was extracted using a Purelink genomic DNA isolation kit , and 500 ng of good-quality genomic DNA was fragmented using an M220 instrument . Fragmented genomic DNA was end repaired and further processed for ligation of Illumina adaptors with a NEBNext Ultra DNA library preparation kit , per the recommendation of the manufacturer. The adaptor-ligated enriched library was purified using AMPure XP beads. Library size distribution was checked on an Agilent Tapestation D1000 DNA chip . The Streptomyces thermocarboxydus strain BPSAC147 genome was annotated on the PATRIC Web server  numbers, 1,072 with Gene Ontology (GO) assignments, and 969 proteins that were mapped to KEGG pathway.The b server  using thSTGO01000001 to STGO01000102. The version described in this paper is the first version, STGO01000000. The Sequence Read Archive accession number is SRS4499771, and the BioProject accession number is PRJNA527710.This whole-genome shotgun project has been deposited at DDBJ/EMBL/GenBank under accession numbers"}
+{"text": "Empirical data regarding the frequency of infection during fever episodes among women in long-term care facilities are lacking.We conducted a case-series analysis of women long-term care residents enrolled in a randomized trial evaluating cranberry capsules to reduce bacteriuria plus pyuria across twenty-one long-term care facilities in CT, USA. Fever episodes identified during adverse event surveillance were assessed using established guidelines for older adults. Among fever episodes, infections were classified using standardized infection surveillance definitions in long-term care residents.We identified 123 fever episodes among 80 women long-term care residents. Median age was 88 years , and 81% (N=65) had dementia. Among 123 fever episodes, 79 (64%) met criteria for 86 total infections .Data from this study suggest that approximately two-thirds of fever episodes involve infection among women in long-term care facilities. These data may guide provider assessments of fever in older adult women in long-term care facilities. Comorbid conditions affecting older adults may preclude reliable clinical assessment of infection . ConsequWe conducted a case series analysis of all adverse events in women residents enrolled in a randomized trial evaluating cranberry capsules to reduce bacteriuria plus pyuria across 21 long-term care facilities between August 2012 and October 2015 . Fever eFor all participants, we recorded demographics, comorbidities, and medications. Fever episodes were evaluated in a stepwise manner. Initially, we assessed whether temperatures exceeded 100 F. Among temperatures <100 F, we assessed whether two oral temperatures exceeded 99 F during the adverse event and subsequently whether temperatures were 2 F above baseline . Based on this hierarchy, fever episodes were identified and plotted against baseline temperatures. For all fever episodes, we identified related hospitalizations, deaths, diagnostic tests, infections and antimicrobials. Infections were classified using surveillance definitions [Among 3830 total adverse events, we identified 123 (3%) fever episodes among 80 women participants. Median age was 88 years , and 94% (N=75) were white. Of these 80 participants, 81% (N=65) had dementia, 34% (N=27) had congestive heart failure, and 20% (N=16) had daily bladder incontinence. Median number of medications was 11 .Clostridium difficile infections. Infections occurred among fever episodes managed with  and without  administration of antimicrobials  met criteria for 86 total infections . There were no crobials . Figure Among fever episodes in women long-term care residents, we show that approximately two-thirds met criteria for infection. Among fever episodes managed with empiric antimicrobials, the majority met surveillance criteria for infection. These findings have implications for providers managing long-term care residents admitted with fever and provide empiric data supporting the use of consensus-derived definitions for fever and infection.Our work highlights the complementary roles of antimicrobial and diagnostic stewardship. Whereas most fever episodes were managed judiciously with antimicrobials, with prompt discontinuation when infection was excluded, diagnostic testing may be inappropriate and occasionally excessive. In our sample, there were seven-fold more urine cultures ordered than urinary tract infections identified. Evidence suggests multifaceted interventions reduce inappropriate urine cultures in hospitals . The datOur study has limitations. First, it may lack generalizability as only women were enrolled. However, our study builds upon data evaluating the association between body temperature and infection limited to older adults receiving antimicrobials . Second,We show that approximately two-thirds of fever episodes involve infection among women in long-term care facilities when applying IDSA fever guidelines and established infection surveillance definitions. These data may guide provider assessments of fever in older women in long-term care facilities."}
+{"text": "Xanthomonas genus contains a large group of economically important plant pathogens, which cause severe diseases on many crops worldwide. The diffusible signal factor (DSF) - mediated quorum sensing (QS) system coordinates expression of virulence factors in plant pathogenic Xanthomonas spp. However, the regulatory effects of this system during the Xanthomonas- plant interactions remain unclear from both the pathogen and host aspects.The gram-negative in planta DSF- mediated QS regulon of X. citri subsp. citri (Xac), the causal agent of citrus canker. We also characterized the transcriptional responses of citrus plants to DSF-mediated Xac infection via comparing the gene expression patterns of citrus trigged by wild type Xac strain 306 with those trigged by its DSF- deficient (\u2206rpfF) mutant using the dual RNA-seq approach. Comparative global transcript profiles of Xac strain 306 and the \u2206rpfF mutant during host infection revealed that DSF- mediated QS specifically modulates bacterial adaptation, nutrition uptake and metabolisms, stress tolerance, virulence, and signal transduction to favor host infection. The transcriptional responses of citrus to DSF-mediated Xac infection are characterized by downregulation of photosynthesis genes and plant defense related genes, suggesting photosynthetically inactive reactions and repression of defense responses. Alterations of phytohormone metabolism and signaling pathways were also triggered by DSF-mediated Xac infection to benefit the pathogen.In this study, we investigated the Xanthomonas to promote infection on host plants.Collectively, our findings provide new insight into the DSF- mediated QS regulation during plant-pathogen interactions and advance the understanding of traits used by The online version of this article (10.1186/s12864-018-5384-4) contains supplementary material, which is available to authorized users. Xanthomonas comprises a large group of gram-negative plant pathogenic bacteria that have considerable agricultural impact worldwide, and therefore, is an important model genus for studying the host-pathogen interactions  between wild type Xac 306 and \u2206rpfF mutant strains in the conditions analyzed  genes, 1946 genes were identified as significantly DEGs between wild type Xac 306 infected and \u2206rpfF mutant strain infected plants, with 708 genes upregulated and 1238 downregulated in the wild type Xac 306 infected plants compared to \u2206rpfF mutant strain infected plants  between the wild type Xac and \u2206rpfF mutant Fig. , we spec6 genome . For eac) genome , for thenes, 202 .5% were Xac genes and 33 citrus genes  were observed between the data produced by the two approaches . The results showed that overrepresented COGs terms were mostly related to \u2018Carbohydrate transport and metabolism\u2019 , \u2018Amino acid transport and metabolism\u2019 , \u2018Inorganic ion transport and metabolism\u2019 , and \u2018Cell wall/membrane/envelope biogenesis\u2019  , for a drug resistance translocase (yieO /XAC2494), for an endoproteinase (argC/XAC2992), and for trehalose biosynthesis (XAC0425 and XAC0429) were upregulated by \u22652-fold on average. Bacterial endoproteinases are able to degrade host defense proteins [katE gene (XAC1211) encoding a catalase important for hydrogen peroxide torelance in Xac [A total 12 genes encoding enzymes involved in detoxification and stress tolerance of proteins , 38, andproteins , 40. Thee in Xac , was alsXac in planta transcriptome regulated by DSF/Rpf -mediated QS is dedicated to nutrition utilization , glycosyl transferase , glycosyl hydrolase (XAC3073), glycogen synthase (glgA /XAC0425 and glgY/XAC0429), glucose dehydrogenase (gcd/XAC1633/XAC3212), glucokinase (glk/XAC3120), and transporter (araJ/XAC1363 and yieO/XAC2494). In contrast, the expressions of fruBK and fruA encoding components of a fructose-specific phosphoenolpyruvate (PEP): carbohydrate phosphotransferase system (PTS) were downregulated.A significant portion of the ion Fig. . Of the ion Fig. . The carin planta, while a small portion (6/29) were upregulated (Table asnB/XAC1433), tyrosine (phhA/XAC0174), glutamine (glnA/XAC0204 and glnB/XAC0205), glycine (pucG/XAC0300 and amaB/XAC0301), threonine , histidine (hisGDCBHAFI/XAC1828\u20131835), and biosynthesis of isoleucine, leucine, and valine . Over-presented in the up-regulated genes are those for biosynthesis of methionine (metE/XAC0306) and lysine (dapA/XAC2547), for a metalloproteinase (XAC0465), and for glycine biosynthesis and cleavage (gcvP/XAC1214). Remarkably, the urea amidolyase and an allophanate hydrolase, which catalyze the release of ammonia from urea, showed distinctive expression levels (Log2Fold Change \u22655.9) upregulated by DSF/RPF QS in Xac during host infection.For the genes involved in uptake and metabolism of amino acids, most (23 out of 29) were downregulated by DSF/Rpf QS Xac during host infection (Table phoX/ XAC1578 and oprO/XAC1579) encoding phosphate transporter proteins were upregulated by an average of 2.6-fold by DSF/Rpf QS during infection. The genes for siderophore biosynthesis (entF/XAC3922) and for iron storage protein in the bacterioferritin family (bfr/XAC1149) [Xac [fecA/XAC0690, btuB/XAC1310, and fyuA/XAC3489, were downregulated two-fold on average. In addition, the two genes coding for ferric enterobactin receptors involved in siderophore uptake (bfeA/ XAC3168 and XAC 3169) were also downregulated two-fold on average   were upr entF/XAC922 and f49) [Xac , 43, incXac were differentially regulated by DSF/Rpf-mediated QS  and ntrC (XAC0208) encoding the NtrB/C two-component system, which interacts with the RpfC/G system responding to DSF signal to regulate sigma54-dependent promoters in vitro [tctE (XAC3482) and XAC3720, the transcriptional regulator genes acoR (XAC0654), tetR (XAC2014), iscR (XAC 2934), and cebR (XAC3487), the AbrB ambiactive repressor and activator (XAC1883), and the Trp operon repressor gene (trpR/XAC1827) were downregulated by the DSF/Rpf \u2013mediated QS. The homologues of these signal transduction and transcription factors constitute regulators of virulence and adaptation factors in many bacteria, including the human bacterial pathogens enterotoxigenic E. coli [P. aeruginosa [Bacillus subtilis strain 168 [E. coli negatively controls the type I fimbriae colonization factor synthesis and biofilm formation in response to both iron limitation and oxidative stress [trp repressor negatively regulates expression of genes involved in tryptophan biosynthesis, transport, and metabolism in response to intracellular levels of tryptophan, but also regulates transcription initiation in several other operons related to tryptophan metabolism that are important for expression of virulence factors in E. coli and P. aeruginosa [Xac by modulating biofilm formation and adhesion factor production, which are crucial for attachment and colonization of the tissues and for consequent invasion [The expression of 12 genes coding for signal transducers and/or transcriptional regulators in QS Table\u00a0. Of thesin vitro . In addi E. coli  and P. aruginosa , and therain 168 . For exae stress . The trpruginosa . Thus, tinvasion .Table 4SXanthomonas genus. Based on sequence similarity and conserved domain detected, we defined putative functions for 24 of the 44 genes, which are potentially involved in bacterial adaptation and pathogenesis (Table\u00a0Xac to the host environment. The genes encoding putative GH18_chitinase-like glycosyl hydrolase (XAC3073) and GT2 family glycosyltransferase (XAC3533) were also upregulated, involved in carbohydrate transport and metabolism. In contrast, the gene XAC3085 encoding a putative T3SS effector protein was downregulated, with an unknown function in Xac-citrus interaction.BLASTx analysis showed that 39 of the 44 genes within the DSF/Rpf QS regulon encoding hypothetical proteins had significant similarities only to sequences in bacteria within the is Table\u00a0. Some ofXac grown in culture medium in the exponential and/or stationary growth phase [in planta DSF/Rpf regulon, 26 of which showed similar trends in alteration of expression between the two environmental conditions , protein fate and protein synthesis , and signal transduction or transcriptional regulation, and some encode hypothetical proteins with unknown functions.Our previous work identified 180 genes constituting the DSF/RpfF regulon of th phase . Among tXac infection revealed that the protein families related to stress responses, signaling pathways, hormone metabolism, and cell wall modification were over-represented according to the gene ontology (GO) analysis , VI-2 (PsaH), and O subunit (PsaO). In addition, the genes for photosynthetic electron transport protein plastocyanin (PetE) and for an ATP synthase subunit  were downregulated in wild type Xac infected leaves  biosynthesis [Xac infected leaves, and gens for ABA-responsive (ABR) proteins were upregulated in wild type Xac infected leaves. Three genes involved in cytokinin biosynthesis , and UDP-Glycosyltransferase superfamily protein) were downregulated in wild type Xac infected leaves, while two genes involved in cytokinin metabolic process (UDP-glucosyl transferase 85A5 (UGT85A5) and DON-Glucosyltransferase) were upregulated in wild type Xac infected leaves.Significant transcriptional changes in response to DSF/Rpf-mediated on Table\u00a0. Transcrynthesis , was dowXac infected leaves compared to \u2206rpfF mutant infected leaves  were less abundant in wild type Xac infected leaves. One gene (Cs4g05190) involved in ethylene biosynthesis was upregulated in wild type Xac infected leaves. Two genes for gibberellic acid (GA) biosynthesis (the CYP701A cytochrome p450 family protein) and GA inactivation (GA2OX: gibberellin 2-oxidase) [Xac infected leaves  and ARM repeat superfamily proteins.A total of 17 genes encoding the ethylene response factor (ERF) transcription factors were differentially expressed in wild type oxidase)  were dowXac infected leaves compared to \u2206rpfF mutant infected leaves  encoding S-adenosyl-L-methionine-dependent methyl transferases superfamily proteins involved in SA metabolic process were downregulated in wild type Xac infected leaves. Furthermore, four genes involved in brassinosteroid (BR) biosynthesis or responses were repressed in wild type Xac infected leaves. They are a cycloartenol synthase 1 (CAS1) and a C-8 sterol isomerase involved in the biosynthesis of BR, and two leucine-rich receptor-like protein kinase family proteins involved in BR signaling pathways [Three genes involved in jasmonic acid (JA) biosynthesis or metabolisms were upregulated in wild type es Table . These ies Table . Notablyn planta , was uprpathways   were identified to be involved in plant defense responses, with 32 genes upregulated and 70 genes downregulated by DSF/Rpf-mediated Xac infection -triggered immunity (PTI) [Xac infection modulates cytokinin accumulation and thus avoids strong activation of cytokinin signaling to promote host susceptibility. Another interesting finding is the upregulation of genes involved in the biosynthesis of and response to ethylene in wild type Xac infected leaves. Xac infection activates ethylene biosynthesis and signaling in citrus plants [Xac infection is favored by the development of inadequate plant defenses.Gene expression data indicated that significant transcriptional alterations occurred in citrus plants in response to DSF/Rpf-mediated on Table . The reselopment ; and auxnacearum . Therefoty (PTI) . Our ress plants . Ethylens plants , thus itXac infected leaves, while genes for SA metabolic process and for BR biosynthesis or responses were downregulated  were upregulated in wild type ed Table . EarlierXac infection   , the causal agent of bacterial spot disease on pepper and tomato, was determined as a T3SS effector named XopK, whose function remains unknown but seems not to contribute to the virulence of the pathogen [Xac might suppress the DSF molecule elicited plant defense responses through the EPS and/or the T3SS effectors that are not affected by the DSF/Rpf-mediated QS during host infection. Another possible reason might be the functional interplay between the bacterial T2SS and T3SS in modulating plant defense responses and promoting disease as observed in the X. oryzae pv. oryzae \u2013 rice interactions, where the bacterial T2SS secreted virulence factors: the ClsA cellulase and CbsA cellobiosidase, induced innate rice defense responses that were suppressed by T3S effectors [engXCA/XAC0612) of the ClsA cellulase  to enable successful infection.It is not clear how the activity of DSF/Rpf-mediated QS triggers plant basal defenses and represses secondary defenses of citrus plants. One possible explanation might lie in the observations that the DSF signal molecule itself could elicit plant defense response in ffectors . Our resor XAC308 Additional file 2:Table S2. Summary of the RNA-seq data (DOCX 13 kb)Additional file 3:Table S3. Detail of the DEGs of Xanthomonas citri subsp. citri regulated by DSF/RpfF \u2013mediated QS (DOCX 35 kb)Additional file 4:Table S4. Detail of the DEGs of citrus in response to DSF/RpfF \u2013mediated Xac infection (XLSX 183 kb)Additional file 5:Table S5. Comparison of the in vitro and in planta DSF/Rpf-mediated QS regulons of Xanthomonas citri subsp. citri (XLSX 29 kb)Additional file 6:Table S6. Differentially expressed citrus genes related to plant defense responses (XLSX 17 kb)Additional file 7:Table S7. Differentially expressed citrus genes involved in plant secondary metabolisms (XLSX 11 kb)Additional file 8:Table S8. Differentially expressed citrus genes involved in cell wall modifications (XLSX 13 kb)"}
+{"text": "POSTN) promote invasive phenotypes of GBM cells. Since TW functional effects are regulated by phosphorylation and dimerization, we investigated how phosphorylation of serine 68 in TW regulates TW dimerization, POSTN expression, and invasion in glioma cells. Compared with wild-type TW, the hypophosphorylation mutant, TW(S68A), impaired TW heterodimerization with the E12 bHLH transcription factor and cell invasion in vitro but had no effect on TW homodimerization. Overexpression of TW:E12 forced dimerization constructs (FDCs) increased glioma cell invasion and upregulated pro-invasive proteins, including POSTN, in concert with cytoskeletal reorganization. By contrast, TW:TW homodimer FDCs inhibited POSTN expression and cell invasion in vitro. Further, phosphorylation of analogous PXSP phosphorylation sites in TW:E12 FDCs (TW S68 and E12 S139) coordinately regulated POSTN and PDGFRa mRNA expression. These results suggested that TW regulates pro-invasive phenotypes in part through coordinated phosphorylation events in TW and E12 that promote heterodimer formation and regulate downstream targets. This new mechanistic understanding provides potential therapeutic strategies to inhibit TW-POSTN signaling in GBM and other cancers.Diffuse invasion into adjacent brain matter by glioblastoma (GBM) is largely responsible for their dismal prognosis. Previously, we showed that the TWIST1 (TW) bHLH transcription factor and its regulated gene periostin ( Glioblastoma (GBM), the most common and malignant adult primary brain cancer, is essentially incurable with median survivals of only 12\u201316 months from diagnosis. Little progress has been realized in outcomes over four decades underscoring the critical need for new therapeutic approaches. One potential therapeutic target is mechanisms, which promote mesenchymal transition ,4,5,6. ASite-specific TW phosphorylation fundamentally alters developmental phenotypes and most commonly confers increased malignant phenotypes related to invasion and EMT ,13. For POSTN expression and mesenchymal phenotypes. For instance, developmental models demonstrate robust phenotypes dependent on TW phosphorylation mediated regulation of TW dimerization motifs [POSTN expression. However, similar mechanisms have not been established in cancer studies. Hong et al. found no evidence for an association between TW S68 phosphorylation and TW:E12 heteromdimerization in a yeast two-hybrid assay [POSTN expression are lacking.Multiple lines of evidence suggest potential interactions between site-specific TW phosphorylation and TW dimerization motifs in regulating n motifs ,20. Of in motifs . Togetheid assay . In a prid assay . In pancid assay . CollectPOSTN expression through site-specific TW phosphorylation dependent regulation of TW dimerization motifs. To test this hypothesis we studied the role of TW S68 phosphorylation in regulating TW dimerization motifs and POSTN expression using hypo-phosphorylation TW mutants and forced TW:TW homodimer or TW:E12 heterodimer constructs in GBM cells. Our results demonstrated a novel mechanism whereby coordinated TW and E12 phosphorylation are required for preferential formation of pro-invasive TW:E12 heterodimers that drive maximal transcriptional activation of POSTN expression. This new understanding may provide new targets for intervention that could be leveraged to inhibit the TW-POSTN signaling axis in GBM and other cancers.Therefore, here we sought to test the hypothesis that TW mediates mesenchymal changes and To establish the potential relevance of TW S68 phosphorylation for GBM functional phenotypes we first confirmed its presence in patient-derived GBM samples using a S68 phospho-specific TW antibody and normal brain samples A. HigherNext we used phosphoproteomics to estimate relative fraction of TW S68 phosphorylation in glioma cells. We used cells with exogenous TW overexpression in GBM8 glioma stem cells (undetectable endogenous TW) and U87MG cells (high endogenous TW) with CRISPR mediated TW knockout and subsequent overexpression of exogenous TW (U87-dTW-A + TW) . The choTo establish the functional relevance of the S68 phosphosite for GBM cells we then over-expressed an S68 hypophosphomutant (TW(S68A)) or WT TW in T98G cells and demonstrated similar expression levels of both proteins by Western blot F. We preTW functions as a homodimer or heterodimer, the latter most commonly generated through TW binding to E12. TW dimerization motifs profoundly influence TW regulated phenotypes with the TW:E12 heterodimer most often associated with increased malignancy ,22. To ePOSTN knockdown was associated with reduced FAK expression and membrane localization [POSTN in mouse cells is a direct transcriptional target of TW [POSTN expression.Arguably, the most consistent functional effect of TW expression in all cancers including glioma is to promote invasion ,9,10,25.lization  implicatet of TW  that pheet of TW ,24. TherPOSTN mRNA levels in T98G cells expressing TW or TW:E12 and TW:TW FDCs compared with empty vector controls. TW expression alone increased POSTN mRNA levels by ~25-fold while TW:E12 FDCs generated a ~190-fold induction of POSTN mRNA compared with the empty vector control  of TW:E12 and TW:TW in T98G cells. Expression of the FDCs was confirmed in T98G cells by Western blot A. Next w control B. By conol cells C. We shool cells C,E. To dol cells D. Furtheol cells E. Togethol cells F. These Further, consistent with our previously published results ,11 in adWe next examined whether changes in TW regulated pro-invasive downstream targets and pathways including PDGFRa, AKT, and ERK1/2 reflected the dimer specific invasive phenotypes. Our results demonstrated marked increases in PDGFRa and phospho-AKT expression in cells expressing TW:E12 FDCs and reduced ERK1/2 activation in cells expressing TW:TW FDCs D. The inPOSTN mRNA revealed that all mutant FDCs dramatically inhibited POSTN mRNA expression (PDGFRa mRNA expression in cells expressing TW(S68A):E12 mutant dimers compared to cells expressing WT TW:E12 dimers  sites in E12 analogous to that in TW  reasoning that such sites might be coordinately regulated through a common kinase. Analysis of E12 protein revealed a single candidate consensus phosphorylation site centered at position S139 harboring the same amino-acid sequence as centered at S68 in TW. Since phosphospecific antibody to E12 S139 is not available, we verified the specificity of the pMAPK/CDK substrate antibody to recognize phospho-PXSP sites using TW immunoprecipitated from T98G cells overexpressing WT TW or TW (S68A) mutants. The pMAPK/CDK substrate antibody clearly could not detect mutant TW confirming the specificity of the antibody to recognize only phosphorylated PXS*P A. Next wpression E. Simila2 dimers F. While ern blot G. Clear TW and its transcriptional target POSTN  comprisePOSTN [Several lines of evidence support the importance of a TW-POSTN signaling axis in cancer. Consistent with the observation in normal mouse cells that TW is a direct transcriptional regulator of POSTN  changes POSTN . Of clinPOSTN ,24. HoweUsing mass spectrometry and Western blotting TW S68 phosphorylation was confirmed in GBM cells and importantly in patient derived GBM samples. Over-expression of TW(S68A) hypo-phosphomutant markedly reduced TW mediated invasion of T98G cells indicating a role for TW S68 phosphorylation in GBM cell invasion. Similarly, Hong et al. (2011) reported inhibition of invasion of MCF-7 breast carcinoma cells expressing TW(S68A) vs. WT TW . ConsistPOSTN/PDGFRa), signaling pathways (ERK/AKT) and mesenchymal phenotypes, these studies demonstrate the importance of TW dimerization as a phenotypic switch regulating cancer malignancy.The significance of mechanisms that regulate TW:TW vs. TW:E12 dimer formation is underscored by the robust functional impact of specific TW dimer motifs which serve as phenotypic switches in cancer and development. With the one exception as noted above , the TW:POSTN. These differences suggest that additional factors, perhaps at the promoter level, may be involved in TW dimer specific regulation of POSTN. The POSTN promoter contains TW e-box sites, yet detection of TW interactions at the POSTN promoter has not been consistent [POSTN and other mesenchymal target gene expression at the transcriptional level.In cancer studies TW dimerization has not been linked to regulation of POSTN expression, however, in mouse cranial suture development, TW homodimers upregulate POSTN in the osteogenic front . This isnsistent ,32. TogePOSTN and PDGFRa expression was dependent on the capacity for phosphorylation of a PXSP site in E12 (S139) analogous to that in TW S68. While loss of phosphorylation capacity for the S139 PXSP site either in E12 alone or in TW:E12 double mutant dimer (TW(S68A)):E12(S139A)) was clearly sufficient to significantly inhibit POSTN expression, expression was not maximally reduced to the levels achieved by expression of TW:E12 FDCs with TW(S68A) mutant alone. Further studies to discern their unique effects on recruitment of transcriptional co-factors or engagement of the POSTN promoter may provide insight into the mechanisms underlying these observations. Regardless, this finding provides the first indication of a potential broader scope of TW regulation, not only through its site-specific phosphorylation but also through that of its binding partners. Given that TW dimer motifs function as potent transcriptional and phenotypic switches it is of interest to determine whether TW or other bHLH dimerization preferences are encoded through coordinated phosphorylation at analogous sites. If so, targeting the common upstream kinases may prove to be useful therapeutic strategies to inhibit TW dimer specific malignant phenotypes. For example, inhibition of MAP kinases that phosphorylate PXSP sites , reduced expression of pTWS68, and total TW [Here we also presented the novel finding that TW:E12 dimer regulation of total TW .POSTN and PDGFRa mRNA expression suggesting broad transcriptional relevance of the mechanism. Therefore, targeting TW:E12 heterodimerization through dimer disruption or dephosphorylation could be therapeutically relevant for GBM treatment. Future studies will validate the scope of these mechanisms in additional glioma cell lines by analysis of direct POSTN promoter interactions, effects of kinase inhibition and establishing in vivo phenotypes in xenograft models.In summary, the current study demonstrated a novel mechanism by which site-specific TW S68 phosphorylation and dimerization motifs promoted glioma cell invasion with concomitant upregulation of pro-invasive genes. TW and E12, but not TW, homodimerization activated pro-invasive phenotypes and molecular changes in glioma cells. The TW and E12 heterodimer activated POSTN, PDGFRa, FAK expression, AKT phosphorylation, and cytoskeletal changes consistent with pro-invasive cellular phenotype. We further showed that in the context of FDCs, TW:E12 heterodimers are fully transcriptionally active only in the presence of phosphorylation-competent sites at S139 in E12 and S68 in TW. For the first time we show that E12 S139 is required for TW S68-dependent regulation of Established human GBM cell lines (T98G and U87) were maintained in Dulbecco\u2019s modified Eagle\u2019s medium/F12 with 10% fetal bovine essence , while human GBM8, GBM4, and G131 stem-like cell line (GSC)  were maiTW expression constructs were described previously . QuickChAntibodies used for Western blot , TW rabbit antibody and POSTN rabbit antibody were provided by Dr. Glackin and Dr. M. Zhu, respectively) were validated on the Western blot by detection of target protein overexpression or knockdown. HA-tag antibody was validated by overexpression of HA-tagged TW protein. Phospho TW S68 antibody  was validated by overexpression of WT TW vs. TW with mutation of Serine at position 68 to alanine. Phospho-MAPK/CDK antibody  was validated by immunoprecipitation of WT and S68A mutant TW protein followed by detection of phosphorylation by Western blot.2EDTA, 1 mM EGTA, 1% Triton, 2.5 mM sodium pyrophosphate, 1 mM beta-glycerophosphate, 1 mM Na3VO4, 1 mM sodium fluoride, and 1 mM PMSF. After pre-clearing protein preparations were incubated with primary antibody overnight followed by incubation with Protein A or G agarose  as appropriate. For affinity purification nuclear extracts from cells expressing NTAP tag fusion proteins were incubated overnight with agarose beads conjugated with rabbit immunoglobulin . Immuno- and affinity precipitates were washed four times with washing buffer, resuspended in the RIPA buffer, vortexed, and heated to elute proteins. Gel loading buffer with \u03b2-mercaptoethanol was added to resolve proteins on the Western blot.Nuclear extracts were isolated as previously described  and dilu4 cells/mL) were allowed to adhere for 1 h. Cells were washed to remove floating cells, fixed and stained with 1% crystal violet . After cell lysis, absorbance was quantified at 550 nm. Differences in cell adhesion are shown as the fold change over T98G control cells accepted as 1. Adhesion assays were performed with five technical replicates. Three separate experiments were analyzed and the significance of differences was determined by Student\u2019s t-test. Results are presented as adhesion fold change over mean control accepted as 1. F-actin filaments were stained with phalloidin conjugated with Texas Red. Focal adhesion kinase was detected using FAK antibody  followed by secondary antibody Alexa Fluor 488 . Slides counterstained with DAPI were imaged using a DMi8 microscope to collect single cell images for quantitative analysis of FAK. To analyze the FAK distribution we used a MATLAB script to detect the dots in cells using segmentation method [Three independent invasion assays with three technical replicates were performed as previously described ,11. InvaPOSTN amplification: forward-AATCATCCATGGGAACCAGA, reverse-ATTGGTGGGAGCAAAGAGTG. Premade primers for PGDFRa amplification were purchased (MilliporeSigma).RNAeasy kit  with on column DNAse digest was used for total RNA extraction. A reverse transcription kit  was used to reverse transcribe 1 \u00b5g of total RNA. Quantitative PCR amplifications were performed using SYBR Green master mix in CFX380  and preset standard amplification cycle for 40 rounds. Following primers were used for The precipitated proteins were trypsinized directly off beads following reduction with 5 mM Dithiothreitol and alkylation with 15 mM iodoacetamide. Following \u201cstage-tip\u201d desalting , peptidep value. Results are presented as the mean \u00b1 s.e.m. Images were prepared using ImageJ, Adobe Creative Suite , and Microsoft Excel .An unpaired two-sided t-test was used to calculate the The current study demonstrated a novel mechanism by which site-specific TW S68 phosphorylation and dimerization motifs promoted glioma cell invasion with concomitant upregulation of pro-invasive genes. Pro-invasive TW and E12 heterodimerization is regulated by TW S68 phosphorylation. We further showed that in the context of forced dimerization constructs, TW:E12 heterodimers are fully transcriptionally active only in the presence of phosphorylation-competent sites at S139 in E12 and S68 in TW."}
+{"text": "Schisandra chinensis Baillon (SC) has been utilized for its antioxidants and anti-inflammatory activities in a broad variety of medical applications. However; SC uses for improving fertility in males and related disorders with proper scientific validation remain obscure. The present study aimed to investigate the effects of SC on varicocele (VC)-induced testicular dysfunction and the potential molecular mechanism associated with VC-induced germ cell apoptosis. The male Sprague\u2013Dawley rats were equally divided into four groups consisting of 10 rats in a normal control group (CTR), a control group administered SC 200 mg/kg (SC 200), a varicocele-induced control group (VC), and a varicocele-induced group administered SC 200 mg/kg (VC + SC 200). Rats were administrated 200 mg/kg SC once daily for 28 days after induction of varicocele rats and sham controls. At the end of the treatment period, body and reproductive organ weight, sperm parameters, histopathological damages, proinflammatory cytokines, apoptosis markers, biomarkers of oxidative stress, endoplasmic reticulum (ER) stress, and steroidogenic acute regulatory protein (StAR) were evaluated. The effects of SC extract on human sperm motility were also analyzed. SC treatment reduces VC-induced testicular dysfunction by significantly increasing testicular weight, sperm count and sperm motility, serum testosterone level, Johnsen score, spermatogenic cell density, testicular superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase level, and steroidogenic acute regulatory protein (StAR) level. Furthermore, the effects of SC on malondialdehyde (MDA) level, reactive oxygen species (ROS)/reactive nitrogen species (RNS) level, apoptotic index, serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels, Glucose-regulated protein-78 (Grp 78), phosphorylated c-Jun-N-terminal kinase (p-JNK), phosphorylated inositol-requiring transmembrane kinase/endoribonuclease 1\u03b1 (p-IRE1\u03b1), cleaved caspase 3, and Bax:Bcl2 in VC-induced rats were significantly decreased. Treatment with SC extracts also increased sperm motility in human sperm. Our findings suggest that the SC ameliorate testicular dysfunction in VC-induced rats via crosstalk between oxidative stress, ER stress, and mitochondrial-mediated testicular germ cell apoptosis signaling pathways. SC promotes spermatogenesis by upregulating abnormal sex hormones and decreasing proinflammatory cytokines . Varicocele (VC) is defined as an abnormal enlargement of the pampiniform plexus of the spermatic cord. It is the leading cause of infertility in men . The incA man with idiopathic infertility is associated with higher seminal reactive oxygen species (ROS) level and lower antioxidant activity . IncreasSchisandra chinensis Baillon (SC) is an oriental traditional Chinese medicine. SC is known to have five flavors  in classical Chinese medicine and has been used for over centuries by humans  at room temperature for 1 h. The membrane was washed three times with TBST (10 min each). Antigen\u2013antibody complexes were then visualized by ECL system  using an enhance chemiluminescence detection kit . Band intensity was analyzed using ImageJ software . Protein isolation from testis tissue and Western blot were conducted as described previously . Brieflyp-value <0.05 was considered statistically significant. Graph analyses were performed using GraphPad PRISM 6.0 . All results are presented as mean \u00b1 standard error of the mean (SEM). One-way analysis of variance (ANOVA) followed by Tukey\u2019s post hoc test  was used to determine statistical significance. A In conclusion , our res"}
+{"text": "Patients were allocated to the experimental arm in 2:1 ratio compared with standard of care arm. Standard of care influenza vaccination was considered single age-based vaccination (standard dose for those <65 y and high dosefor those \u226565 y) and patients in this arm received a saline placebo injection at 30 days to assist in blinding. Eligibility criteria allowed any patient with a PCD and no contraindication to trivalent inactivated influenza vaccine. The primary endpoint was laboratory-confirmed flu infection rate. Protocol-driven surveillance screened patients for flu-like illnesses and performed laboratory testing for influenza until the end of the flu season in May 2016. Secondary endpoints include HAI titer serologic response rates, clinical correlates of protection from influenza infection, and exploratory studies of cell-mediated immunity through characterization of T cell subpopulations, cytokine profiles, and flu-specific T-cell responsiveness. RESULTS/ANTICIPATED RESULTS: In total, 122 plasma cell disorder patients were enrolled (97 with disease requiring therapy and 25 with asymptomatic gammopathy). Of those 48 patients received a single standard of care influenza vaccination and 74 patients received 2 doses of Fluzone\u00ae high-dose vaccine. Median age was 67 years (range 42\u201390). This 2-dose vaccination strategy was safely tolerated in all patients with no grade 2 adverse events attributed to vaccine. With close clinical follow-up, only 4% of patients receiving 2 vaccine doses developed laboratory confirmed influenza Versus 8.3% of those receiving single vaccine. When compared to the expected CDC influenza infection rate of 10%\u201315%, 1 sample, 2-tailed binomial testing revealed patients receiving 2 vaccines experienced a significantly lower rate of infection than the expected rate (p<0.05) whereas those receiving single vaccine showed no significant difference (p=0.38). DISCUSSION/SIGNIFICANCE OF IMPACT: This randomized study demonstrates that the 2 dose strategy of Fluzone\u00ae high-dose influenza vaccine is safely tolerated in patients with plasma cell disorders and associated with significantly less than expected laboratory-confirmed influenza infections. The results suggest that this novel vaccination strategy may have a clinical benefit in reducing influenza infections in plasma cell disorder patients and thus may have practice changing implications. Final analyses of serologic responses, clinical correlates of response, and cell-mediated immune correlates may provide valuable insights into in vivo \u201cimmune-competence\u201d in patients with plasma cell disorders.OBJECTIVES/SPECIFIC AIMS: (1) Evaluate safety of a novel influenza vaccination strategy in patients with plasma cell disorders. (2) Measure laboratory-confirmed influenza infection rates following a novel influenza vaccination strategy in patients with plasma cell disorders. (3) Evaluate clinical correlates of response following a novel influenza vaccination strategy in patients with plasma cell disorders. METHODS/STUDY POPULATION: We conducted a double-blind, randomized study over the 2015\u201316 flu season, comparing 2 doses of Fluzone"}
+{"text": "Identification of novel clinical biomarker in clear cell renal carcinoma (ccRCC) is warranted. Integrating transcriptome (n=1669), DNA methylation (n=577) and copy number data (n=832), we developed a method to identify driver biomarkers by analyzing the omics-level dynamics of Epithelial-Mesenchymal Transition (EMT)-related genes in ccRCC. We first identified 504 expression dynamic changed genes involved in ccRCC-associated key pathways such as EMT, cell cycle, EGFR and PI3K/AKT signaling. Further analysis identified 229 (90 gene promoters) aberrant expression quantitative trait methylation (eQTM) and 256 genes with expression quantitative trait copy number (eQTCN) alterations. Among them, FOXM1 was affected by both eQTM and eQTCN. FOXM1 copy number amplification , occurred in an amplified peak in chromosome 12q13.3, was enriched in late-stage ccRCC samples and was associated with worse survival. FOXM1-overexpressed pT3 patients with distant metastasis showed ~25% shorter overall survival in both training (log-rank P=0.006) and validation (log-rank P=0.018) cohorts. The eQTM-gene hybrid signature (cg00044170 and FOXM1), superior to either gene expression or DNA methylation alone, showed great potential in diagnosing localized ccRCC in training (area under curve = 0.958) and validation datasets. FOXM1 could be a novel prognostic biomarker and shed light for early diagnosis at molecular level in ccRCC. Our approaches may be utilized for omics-level spectrum investigations in future studies encompassing larger gene sets, or gene signatures involved in specific biological function modules, which will uncover more staged behaviors of key modulators in cancer.https://portal.gdc.cancer.gov/repository) data portal and used for transcriptomic analysis. The samples with RNA Integrity Number > 7.0 were included. RSEM expected-counts data was re-analyzed using raw sequencing data of The Cancer Genome Atlas (TCGA) and The Genotype-Tissue Expression (GTEx) Consortium downloaded from UCSC Xena (http://xena.ucsc.edu/public) [HTSeq-counts data of RNA-sequencing (RNA-Seq) and miRNA-seq of ccRCC were downloaded from Genomic Data Commons  . Twenty /public) . All samDNA methylation profiles of 312 primary tumors and 155 control samples of Illumina Infinium DNA HumanMethylation450 BeadChip  were obtained from GDC legacy archive. Fourteen tumors and 96 controls of 9 studies from GEO database were obtained as GEO methylation dataset. Another dataset GSE105288 with expression-methylation data was composed of 9 primary tumors and 9 normal controls. The raw IDAT files were preprocessed using minfi package  in R sofTo identify genes correlated with EMT, we performed text mining based on abstracts of literatures in the PubMed database. Specifically, the search criteria \u201c) AND (cancer OR tumor OR carcinoma))\u201d were used. The abstracts of 24,832 articles were extracted as input to perform part-of-speech tagging, shallow parsing, and named entity recognition using both GENIA Tagger and Enju software (NaCTeM Software Tools) . Only geBatch effects of five potential confounding factors listed in the recent study  and the For count data from TCGA, DESeq2 R package (v1.10.1)  was usedWe performed differential expression and differential DNA methylation analysis based on eleven grouping methods: (1) all patients with ccRCC versus normal; (2) low-stage patients versus normal; (3) high-stage patients versus low-stage patients; (4) low-grade patients versus normal; (5) high-grade patients versus low-grade patients; (6) patients without lymph nodes metastasis versus normal; (7) patients with lymph nodes metastasis versus patients without it; (8) patients of progression free versus normal; and (9) recurred patients versus patients are progression free; (10) patients without distant metastasis versus normal; (11) patients with distant metastasis versus those without it.dist in R was used to compute the distance matrix and the function hclust was used for clustering. We utilized Euclidean as our distance metric with Ward linkage to cluster both the rows and the columns for gene expression clustering, while Euclidean as distance metric with Ward2 linkage was used for CNAs clustering. For each clustering, the number of clusters was determined using the same distance metric and linkage method by ConsensusClusterPlus package (v1.44.0) [cutree function.Log2 transformed count per million data of HTSeq-counts was used for gene expression pattern investigation. Gene-level CNAs was used for clustering. The function v1.44.0)  in R. ClIlluminaHumanMethylation450kanno.ilmn12.hg19 package. The matched samples (n=332) with gene expression data and methylation data of TCGA were used to perform Pearson correlation analysis and non-zero correlation. CpG-gene pairs with negative Pearson correlation and FDR <0.05 were considered as eQTMs. The eQTCNs analysis was based on genes obtained by GISTIC2.0 with CNA frequency >5% in ccRCC. The CNAs of genes with significant expression changes  between samples with CN deletions and samples with CN amplifications were considered as eQTCNs.GTEx project identified expression quantitative trait loci in ~53 human tissues that influence gene expression . SimilarThe univariate Cox proportional hazard regression was used to determine the prognosis-related genes. The genes with BH-adjusted P value <0.05 were considered as candidate variables and were subjected to multivariate Cox regression model. Variables with log-rank P-values <0.05 were considered associated with patient survival. The expression data and overall survival rate of pT3 ccRCC patients with distant metastasis from International Cancer Genome Consortium (n=50) cohort were used for overall survival validation. The logistic regression was used to determine diagnostic markers. We used the logistic model to distinguish localized tumors (AJCC stage I/II) and normal samples based on the eQTM methylation, gene expression, or expression-methylation signature levels . The epsilon values of samples were calculated based on the expression levels of specific gene and the methylation levels of corresponding eQTM. Moreover, receiver operating characteristic curves and area under curves were used to evaluate the performance of the classifier. The original methylation datasets and expression datasets were randomly divided into two subsets of equal sample size for training and testing, respectively. This step was repeated for 1000 times. The model with median sensitivity and specificity was eventually considered. In the early diagnosis analysis of FOXM1 methylation, cg00044170 methylation level was used as a classifier to distinguish localized ccRCC tumors (even pT1a tumors) and normal samples. In the early diagnosis analysis of FOXM1-cg00044170 signature, the epsilon values calculated from FOXM1 expression levels and cg00044170 methylation levels by our formula  was servSupplementary FiguresSupplementary TablesSupplementary CodeSupplementary Table 1Supplementary Table 3Supplementary Table 4Supplementary Table 5Supplementary Table 6Supplementary Table 7Supplementary Table 8Supplementary Code"}
+{"text": "Retinoic acid or folic acid co-supplementation with ethanol rescued Wnt signaling and retinal differentiation. Activating Wnt signaling using GSK3 inhibitor  restored retinal cell differentiation pathways. Ethanol exposed embryos were treated with Wnt agonist, which rescued Wnt-active cells in the CMZ, Notch-active cells in the retina, proliferation, and photoreceptor terminal differentiation. Our results illustrate the critical role of Wnt signaling in ethanol-induced retinal defects.Fetal alcohol spectrum disorder caused by prenatal alcohol exposure includes ocular abnormalities . Zebrafish embryos exposed to ethanol from gastrulation through somitogenesis show severe ocular defects, including microphthalmia and photoreceptor differentiation defects. Ethanol-treated zebrafish had an enlarged ciliary marginal zone (CMZ) relative to the retina size and reduced M\u00fcller glial cells (MGCs). Ethanol exposure produced immature photoreceptors with increased proliferation, indicating cell cycle exit failure. Signaling mechanisms in the CMZ were affected by embryonic ethanol exposure, including Wnt signaling in the CMZ, Notch signaling and  Vertebrate retina has six main cell types including, retinal ganglion cells (RGCs), bipolar cells, amacrine cells, horizontal cells, photoreceptors, and the major glial cell type, M\u00fcller glial cells (MGCs). Retinal cell types are born progressively as development proceeds: commencing with RGCs and ending with bipolar cells, rods, and MGCs. Retinal precursors exit cell cycle periodically and sequentially, as developmental signaling pathways regulate neurogenesis and gliogenesis \u20133. In zep57kip2) and proneural gene expression [Xenopus, and chick retinal models show that self-renewal and differentiation of multipotent retinal stem cells in the CMZ is tightly regulated by Wnt, Sox2 and Notch signaling [hes) genes. hes genes expression can actively repress neurogenesis. Notch and Sox2 signaling coordinate to determine proneural gene expression levels. As stem cell differentiation progresses into middle and central CMZ with reduced Notch activity, these mitotic precursor cells express proneural and other transcription factors, exit the cell cycle and undergo terminal differentiation. Following activation of proneural genes, other signaling pathways such as Shh, retinoic acid (RA), Fgf, and Bmp regulate proliferation, differentiation and patterning [neurod, crx, and rx1), migrate to the ONL, express rod-specific transcription factors, and finally terminally differentiate into rods [The CMZ stem and progenitor cells determine the growth and differentiation of the retina. Based on cell cycle and proneural gene marker expression patterns, the CMZ is roughly divided into three major zones: (i) peripheral CMZ with low expression of cell cycle activators; (ii) middle CMZ with high expression of Cyclin D1 and high proliferation; and (iii) central CMZ with high cell cycle inhibitor  [Tg(TP1bglob:eGFP) (referred to as Tg(TP1:GFP)) [Tg(TP1:mCherry) [Tg(gfap:GFP)mi2001 (referred to as Tg(gfap:GFP)) [Tg(Tcf/Lef-miniP:dGFP)isi01(referred to as Tg(Tcf/Lef-miniP:dGFP) [Tg(nrd:eGFP) expresses eGFP under the neurod gene promoter. Tg(TP1bglob:eGFP) (referred to as Tg(TP1:GFP)) and Tg(TP1:mCherry) express color variants of GFP under the regulation of repeated sequence elements that are activated by Notch intracellular domain binding, that is, gene expression is activated by Notch receptor signaling. Tg(gfap:GFP)mi2001 (referred to as Tg(gfap:GFP) expresses GFP under the gfap gene promoter. Tg(Tcf/Lef-miniP:dGFP)isi01(referred to as Tg(Tcf/Lef-miniP:dGFP) expresses GFP under the regulation of repeated sequence elements that bind Tcf/Lef DNA binding factors that complex with \u03b2-catenin to activate gene expression. The embryos were treated with 1-phenyl-2-thiourea (0.003%) from 6 hpf (shield) onward in order to prevent melanogenesis. Potential secondary effects of 1-phenyl-2-thiourea in larval to juvenile stage transition will need additional investigation [This work was conducted according to guidelines and supervision of the Indiana University Policy on Animal Care and Use. The IUPUI School of Science Institutional Animal Care and Use Committee (IACUC) reviewed and approved this study. Anesthesia was performed using tricaine, and euthanasia used anesthetic overdose with physical assurance. Zebrafish (rd:eGFP) ; Tg(TP1bP1:GFP)) ; Tg(TP1:mCherry) ; Tg(gfapap:GFP)) ; and Tg(iP:dGFP)  transgeniP:dGFP)  in accortigation .Zebrafish embryos were exposed to ethanol by incubation in embryo medium containing 100 mM (0.6% v/v) or 150 mM (0.9% v/v) ethanol (referred to as 100 EtOH and 150 EtOH respectively) from 2\u201324 hpf as previously described in , 44. TheBrightfield images for histological and ISH sections were captured using Axiovision camera ICc1 mounted on the Zeiss observer Z1 . Confocal images of whole mount immunofluorescence staining and FISH were collected using Zeiss Observer Z1 (40X 1.1 NA W). All zebrafish were deyolked and imaged from the ventral side. Z-sections analyzed always included the optic nerve for consistency. Confocal imaging allowed us to collect images that were not saturating the photomultiplier tube detector, and thus linear fluorescence intensity is linear within the entire dynamic range.Fixed zebrafish were used for whole mount immunostaining as previously described  using prrx1 , axin2 (Addgene), her6 . Dig-labeled riboprobes were synthesized using a Dig RNA labeling kit (Roche). Stained embryos were mounted for histological analysis (see below). Brightfield images were collected.Whole mount ISH was performed as previously described  using dicdkn1c  for plastic sections which was performed at the Indiana University Histology Core. Five \u03bcm ventral sections were obtained using Leica RM2265 microtome and were stained with hematoxylin and eosin (H&E). Whole mount ISH zebrafish were also similarly mounted in JB-4TM resin for 5 \u03bcm plastic sections. Brightfield images were collected.Four and 18 dpf (days post-fertilization) zebrafish larvae were fixed with 4% PFA and embedded in JB-4rsp15 endogenous control, which has been shown in our previous studies to remain unchanged after ethanol treatment. Thermal cycling was done using the 7300 Real Time PCR system (Applied Biosystems). Relative expression was calculated as described [Total RNA was extracted from 72 hpf ethanol-treated and untreated retinas using TRIzol reagent (Sigma). One microgram of total RNA was reverse transcribed to cDNA using M-MLV reverse transcriptase . Each PCR reaction was performed with 1 microliter of cDNA using Power SYBR Green PCR mix . Primer sets used are listed in escribed . Fold chTg(TP1:mCherry), Notch-reporter transgenic line was used to perform cell counts of nuclear-localized mCherry-positive cells representing the Notch-active cells. A single optic nerve-containing optical section was used in 72 hpf control and ethanol treated larvae. The measurements of total zpr-1 intensity per retina in the ONL and cell proliferation counts per retina were performed on zpr-1 and phosphoH3 stained fish, respectively, as described earlier [H&E stained histological sections containing optic nerve were used for image analyses. CMZ area and retinal area were measured using Image J software (NIH software). CMZ area was demarcated to the lamination in the retina.  earlier .Unpaired two-tailed student\u2019s t-test was used for comparisons between control and ethanol treated groups using GraphPad software (GraphPad). One-way ANOVA and post hoc Tukey HSD for individual comparisons were used for analyses in rescue experiments.In this study, zebrafish embryos were treated from 2\u201324 hpf with 100 and 150 mM ethanol . Previous studies show that zebrafish larvae treated with 166.67 mM (1% v/v) from 6\u201324 hpf, have an equilibrated ethanol concentration inside the embryo that ranges from 40\u201358 mM . This exHistology at 4 dpf and 18 dpf indicated a persistent microphthalmia in ethanol treated larvae . At thesrx1 expression, which labels multipotent retinal stem cell populations in the CMZ at 48 hpf, was analyzed using ISH  expression in control embryos is restricted to central CMZ, which was greatly reduced in size in ethanol treated fish , Notch activity was examined after ethanol exposure (Tg(TP1:mCherry), expressed in Notch active cells, and Tg(gfap:GFP), expressing GFP under gfap promoter were used. At 72 hpf, GFP expression and active Notch signaling was seen in central retina of control larvae , larvae expressing GFP under neuord promoter, were stained using phospho-Histone-3 (H3) antibody. Ethanol treated larvae showed an increased number of double positive cells in the INL and ONL, indicating more proliferative neural precursor cells  expressing cells in the INL, which are a subset of differentiated amacrine cells, could be seen in control larvae [neurod-reporter positive cells in the INL  double positive cells and finally mature photoreceptors were zpr-1 positive with minimal neurod expression , Wnt activity-reporter line; Tg(TP1:GFP), Tg(TP1:mCherry), Notch activity-reporter lines; and Tg (nrd:GFP), proneural gene expression transgenic line. Wnt-signaling reporter expression was not detected at 18 hpf (data not shown). Ethanol treatment from 2\u201324 hpf showed minimal difference in Wnt-active cells in the retina at 24 hpf (data not shown). At 48 hpf, peripheral retina (presumptive CMZ) contains Wnt-active cells in untreated retinas. Most Wnt-positive cells are also Alcama-positive. However, few cells are Wnt-negative and Alcama-positive  signaling pathways involved in retinal stem cell maintenance and cell differentiation were examined using transgenic reporter lines see , includipositive . After epositive . Not onlpositive .axin2 ISH, which is a transcriptional target of Wnt signaling. In control fish, peripheral CMZ showed axin2 expression (axin2 expression was reduced after ethanol treatment (axin2 gene expression levels in the retina using qPCR showed a significant decrease (p<0.05) after ethanol treatment (100 mM ethanol and 150 mM ethanol-treated fish showed 0.294 and 0.562-fold change respectively). These data show that ethanol exposure led to reduced Wnt activity, and an expanded neuroepithelial, immature compartment in the peripheral CMZ.Wnt signaling in the peripheral retina was also detected by pression . Howeverreatment . axin2 gher6, a downstream target of Notch signaling, was expressed in the CMZ in a compact layer in the control fish was expanded in 100 mM ethanol treated embryos  embryos were co-supplemented with RA or FA and ethanol. Both RA and FA co-supplementation could rescue Wnt-active cells in the peripheral CMZ  showed rescue of the Notch-active cells to control levels in the retina  and tested for rescue of Notch signaling, proliferation, and photoreceptor differentiation. Since the difference in Wnt signaling was seen after 24 hpf, embryos were treated with 350 and 500 nM LSN 2105786 from 32\u201348 hpf. At 48 hpf, LSN2105786 treatment produced a rescue of the Wnt activity in the CMZ . QuantifTg(TP1:GFP) and Tg(Tp1:mCherry) to count cells at 72 hpf. These experiments showed significantly fewer Notch-active cells in ethanol treated larvae, and Notch-active cell numbers was rescued to control levels by 500 nM LSN 2105786 treatment .Ethanol exposure reduced Wnt activity and  neurons . Further neurons . Ethanol neurons , and tre neurons , 81. Sinneurod-positive cells in the central CMZ of ethanol treated fish as compared to controls. Furthermore, ethanol-induced disruption of other signaling pathways, including RA, may lead to cell cycle exit failure and reduced terminal differentiation [In zebrafish, Wnt signaling hyperstimulation, during specific developmental time windows, led to reduced differentiation and increased proliferation in the retina, and conversely, reduced Wnt signaling led to increased retinal differentiation and reduced proliferation . Ethanolntiation .Central retina cells derived from the retinal neuroblasts, which are specified during retinal morphogenesis and not derived from the CMZ, showed ethanol-induced defects. Wnt agonist also rescues central retina, suggesting that there are additional targets of Wnt agonist in addition to the CMZ. Wnt signaling disruption is likely to be only one of the pathways affected by ethanol exposure. Additional studies dissecting the developmental pathways are needed to understand the complete genesis of retinal defects.Several studies have shown effects of nutrient compound supplementation on ethanol-induced defects , 44, 82.Ethanol effects on the peripheral CMZ compartment reveals a defect in the stem cell compartment that can lead to persistent retinal defects. Reduced Wnt signaling in this compartment and consequent reduction of Notch activity may underlie many ethanol-induced retinal cell differentiation defects. Restoration of the Wnt-active cells, using GSK3\u03b2 inhibitor treatment, RA, and FA co-supplementation, restored Notch-activity and terminal differentiation. Additional research examining specific members of the signaling pathways and lineage tracing will provide detailed mechanistic insight in ethanol-induced retinal defects and help identify therapeutic targets for FASD."}
+{"text": "The purpose of this secondary analysis was to assess the relationship between objective and subjective perceptions of motor function measures in older adults following a 12 week adapted tango or health education intervention. A quasi-experimental, two-group, repeated-measures design was used. The study took place in diverse senior independent living communities in an urban metropolitan area. 74 older adults participated  years; Education: n=12, age: 84.1 (7.86) years). Participants were assigned to 20 sessions of 90-minute tango (n = 62) or health education (n = 12) classes over 12 weeks. Motor function, depression, mental and physical quality of life were measured before and after intervention. At post-test, participants indicated their level of agreement with statements that they improved in the objectively measured domains of motor function. Correlations were performed between subjectively rated agreement, and changes in motor function and depression/quality of life. Tango subjective ratings were negatively correlated with empirically observed improvements in balance (r= -.423) and endurance (r= -.241); although their ratings moderately correlated positively with coordination (r=.319) and minimally correlated positively with lower body strength (r=.188). In Tango, decreased depression was positively correlated with self-perceived improved lower body strength (r=.271) and endurance (r= .254). Improved mental function was moderately (r=.423) positively correlated with self-perceived improved balance and coordination (r=.306). After rehabilitation, even in the presence of improved depression and quality of life, older adults may not perceive empirically observed motor function improvements, particularly in balance and lower body strength."}
+{"text": "Non-alcoholic fatty liver disease (NAFLD) is one of the main causes of chronic liver disease. NAFLD begins with excessive lipid accumulation in the liver and progresses to nonalcoholic steatohepatitis (NASH) and cirrhosis. NAFLD is closely linked to dysregulated hepatic lipid metabolism. Although recent studies have reported that epidermal growth factor receptor (EGFR) signaling regulates lipid metabolism, the roles of EGFR and EGFR inhibitors as modulators of lipid metabolism are largely unknown. Here, we investigated whether inhibiting EGFR using the EGFR tyrosine kinase inhibitor (TKI) PD153035 improves NAFLD. Our results demonstrate that EGFR was activated in liver tissues from high fat diet (HFD)-induced NAFLD mice. Inhibiting EGFR using PD153035 significantly reduced phosphatidylinositol-3-kinase/protein kinase B signaling and sterol responsive elementary binding protein 1 and 2 expression, which prevented HFD-induced hepatic steatosis and hypercholesterolemia by reducing de novo lipogenesis and cholesterol synthesis and enhancing fatty acid oxidation. Additionally, inhibiting EGFR improved HFD-induced glucose intolerance. In conclusion, these results indicate that EGFR plays an important role in NAFLD and is a potential therapeutic target. The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing rapidly worldwide and it is now the most common liver disease, with an estimated global prevalence of ~25% . NAFLD iThe epidermal growth factor receptor (EGFR) signaling pathway has been implicated in many human diseases, especially in cancer, as it plays a central role in regulating the survival, proliferation, migration, and differentiation of various tissues . SeveralMale C57BL/6J mice were purchased from Harlan . A high-fat diet (HFD) composed of 60% fat was purchased from Research Diets Inc. . The animals were maintained in a controlled environment . Eight-week-old male mice were fed a normal chow diet (NCD) or HFD for 8 consecutive weeks and then divided randomly into three groups: the NCD group were fed an NCD without treatment, the HFD group were fed a HFD without treatment, and the HFD+PD group were fed a HFD and treated with PD153035  for the final 4 weeks. All animals received humane care according to institutional guidelines, and all experimental procedures were approved by the Institutional Review Board of Chungnam National University School of Medicine .The Huh-7 hepatocellular carcinoma cell line was purchased from the American Type Culture Collection  and cultured according to the manufacturer\u2019s instructions. Cells were cultured in high-glucose Dulbecco\u2019s Modified Eagle\u2019s Medium  supplemented with 10% fetal bovine serum  and 1% penicillin-streptomycin. Huh-7 cells were stimulated with 10 ng/mL EGF  and treated with 10 \u03bcM gefitinib (Sigma). Huh-7 cells were incubated with 400 \u03bcM palmitic acid and 10 \u03bcM gefitinib for 24 h.Tissue samples were obtained from 18-week-old mice. Samples for light microscopy were fixed in 4% paraformaldehyde (PFA) for 1 h. Paraffin embedding, sectioning, and hematoxylin and eosin (H&E) and oil red O staining were performed according to standard protocols.Blood was collected from the heart under general anesthesia. Samples were centrifuged at 5,000 rpm for 5 min and the supernatants were collected. Serum insulin levels were measured by enzyme-linked immunosorbent assay  using kits obtained from the indicated supplier. Biochemical analyses, including measuring free fatty acid and total cholesterol levels, were performed using a Hitachi 7180 auto analyzer and Wako reagents .Livers from mice and Huh-7 cells were lysed in RIPA buffer . Western blotting was performed on 30\u201350-\u03bcg protein samples using commercially available antibodies against the following antigens: EGFR, phospho-EGFR (pEGFR), Akt, phospho-Akt (pAkt), fatty acid synthase (FASN), anti-sterol responsive elementary binding protein 1 (SREBP1), and SREBP2 . Secondary antibodies (goat anti-mouse and goat anti-rabbit) were obtained from Cell Signaling Technology, Inc. .Total RNA was isolated using TRIzol reagent  and cDNA was prepared from total RNA using M-MLV reverse transcription and oligo-dT primers (Invitrogen). The resulting cDNA was amplified on a Rotor-Gene 6000 real-time rotary analyzer with software version 1.7 . Real-time polymerase chain reaction (PCR) was performed using cDNA and QuantiTect SYBRGreen PCR Master Mix . All quantitative calculations were performed using the \u0394\u0394CT method. The comparative Ct method was used to quantify transcripts, which were normalized to 18sRNA expression. Values were expressed as fold changes vs. control groups.t-tests. P < 0.05 was considered statistically significant.Statistical analyses were performed using Stat Graph Prism 5 . Data are presented as the mean \u00b1 standard error of the mean (SEM). To compare values obtained from two or more groups, data from animal studies were analyzed using two-way repeated-measures analysis of variance followed by Bonferroni\u2019s correction for multiple comparisons, one-way analysis of variance followed by Tukey\u2019s post hoc test, or two-tailed Student\u2019s Male C57BL/6J mice were maintained on an NCD or HFD for 8 weeks. A significant increase in body weight was observed in the HFD group compared with the NCD group, as expected . At the To compare glucose homeostasis parameters among groups, glucose tolerance tests were performed. Treatment with PD153035 for 4 weeks improved glucose tolerance  and reduBecause NAFLD was strongly linked with dyslipidemia, we next investigate serum lipid levels in each group. HFD-fed mice exhibited significantly increased serum total cholesterol (TC), high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, triglyceride (TG), and non-esterified fatty acid (NEFA) levels compared with those of the NCD group . TreatmeThe most common cause of hepatomegaly is hepatic steatosis, which is also the hallmark feature of NAFLD . FurtherTo evaluate the intrahepatic lipid contents and the degree of liver damage, we performed H&E staining of liver tissues. Histopathological analysis of the livers in the HFD group revealed markedly increased hepatic steatosis , whereasTo understand the role of EGFR in regulating hepatic lipid metabolism, we investigated whether inhibiting EGFR alters the mRNA and protein expression of proteins associated with hepatic lipid metabolism pathways such as hepatic de novo lipogenesis (DNL) and cholesterol synthesis. First, we examined whether EGFR signaling is activated in the livers of HFD-fed mice. The phosphorylation of EGFR and its downstream protein Akt was increased in the livers of HFD-fed mice. Treatment with PD153035 effectively reduced the phosphorylation of both proteins .We then examined the expression of sterol regulatory element-binding protein-1 (SREBP-1), a critical transcription factor for lipogenesis . AbnormaHMG-CoA reductase (Hmgcr), mevalonate diphospho decarboxylase (Mvd), cytochrome P450 family 511 (Cyp51), 7-dehydrocholesterol reductase (Dhcr7), and cholestenol delta-isomerase (Ebp) were remarkably decreased by treatment with PD153035 (low density lipoprotein receptor (Ldlr) was increased following treatment with PD153035 , and insulin induced gene 1 (Insig1), were markedly decreased by treatment with PD153035 (acyl-CoA dehydrogenase-1 (Acad1), uncoupling protein-2 (Ucp2), carnitine palmitoyltransferase-1\u03b1 (Cpt1\u03b1), acyl-Coenzyme A oxidase-1 (Acox1), and fatty acid binding protein-1 (Fabp1) were decreased by treatment with PD153035 ; stage 2, non-alcoholic steatohepatitis (NASH); stage 3, fibrosis; and stage 4, cirrhosis. In the early stages of NAFLD, only hepatic TG accumulation, without abnormal liver function, is found. NASH is characterized by hepatic steatosis with inflammation, and persistent inflammation can ultimately lead to irreversible fibrotic change . TherefoEGFR, also known as ErbB1/HER1, is a member of the ErbB family of receptor tyrosine kinases. EGFR dimerization is a crucial initial step in EGFR signaling. EGFR dimerization stimulates the auto-phosphorylation of tyrosine residues, leading to the activation of several downstream pathways. Three major downstream signaling pathways activated by EGFR have been identified: (1) the rat sarcoma (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase (MAPK) pathway; (2) the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) pathway; and (3) the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway ,19. EGFRThe current study also confirmed that inhibiting EGFR improves glucose tolerance. Several studies have suggested that EGFR affects glycolysis and glucose transport through the downstream RAS/RAF/MAPK and PI3K/Akt pathways . In addiIn conclusion, we demonstrated that inhibiting EGFR significantly improved HFD-induced NAFLD. To our knowledge, this is the first time that the role of EGFR as a therapeutic target of NAFLD has been experimentally investigated. Furthermore, we confirmed that inhibiting EGFR reduces liver fat accumulation and hepatocellular damage by reducing DNL and cholesterol synthesis and by enhancing fatty acid oxidation. However, further studies are needed to address the clinical efficacy and safety of EGFR TKIs such as PD153035.S1 Table(XLSX)Click here for additional data file."}
+{"text": "Human intestinal epithelial organoids (IEOs) are increasingly being recognised as a highly promising translational research tool. However, our understanding of their epigenetic molecular characteristics and behaviour in culture remains limited.We performed genome-wide DNA methylation and transcriptomic profiling of human IEOs derived from paediatric/adult and fetal small and large bowel as well as matching purified human gut epithelium. Furthermore, organoids were subjected to in vitro differentiation and genome editing using CRISPR/Cas9 technology.We discovered stable epigenetic signatures which define regional differences in gut epithelial function, including induction of segment-specific genes during cellular differentiation. Established DNA methylation profiles were independent of cellular environment since organoids retained their regional DNA methylation over prolonged culture periods. In contrast to paediatric and adult organoids, fetal gut-derived organoids showed distinct dynamic changes of DNA methylation and gene expression in culture, indicative of an in vitro maturation. By applying CRISPR/Cas9 genome editing to fetal organoids, we demonstrate that this process is partly regulated by TET1, an enzyme involved in the DNA demethylation process. Lastly, generating IEOs from a child diagnosed with gastric heterotopia revealed persistent and distinct disease-associated DNA methylation differences, highlighting the use of organoids as disease-specific research models.Our study demonstrates striking similarities of epigenetic signatures in mucosa-derived IEOs with matching primary epithelium. Moreover, these results suggest that intestinal stem cell-intrinsic DNA methylation patterns establish and maintain regional gut specification and are involved in early epithelial development and disease. Human intestinal epithelial organoids (IEOs)\u00a0are emerging as translational research tool to study epithelial biology in health and disease.Early studies described that regional differences in intestinal or colonic IEOs are preserved in culture.Human IEOs from ileum and colon show a stable highly gut segment-specific epigenetic DNA methylation profile that closely reflects their tissue of origin.Intrinsically programmed DNA methylation signatures define regional identity of the human intestinal epithelium.Human fetal epithelium shows in\u00a0vitro maturation, indicated by greater epigenetic plasticity and transcriptional changes in culture.Human mucosa-derived IEOs are excellent models to investigate DNA methylation dynamics in GI health, development and disease.Demonstrating stable epigenetic signatures in IEOs that closely match those of primary cells further extends the use of these promising culture models as future translational research tool in disease modelling, drug discovery and regenerative medicine.The intestinal epithelium is a complex and highly dynamic tissue which performs a variety of functions including digestion and absorption of nutrients, barrier formation and maintenance of intestinal homeostasis. Dividing adult stem cells located at the crypt base give rise to all major epithelial cell lineages and enable complete renewal of the epithelial layer over 3\u20135 days. The identification of reliable markers and key signalling pathways in adult intestinal stem cells has enabled long-term in\u00a0vitro propagation of intestinal stem cells within self-organising three-dimensional intestinal epithelial organoids (IEOs).Epigenetic mechanisms are critical regulators of mammalian development, cellular differentiation and tissue-specific functions. One of the main epigenetic mechanisms is DNA methylation of cytosine in the context of CpG dinucleotides. The role of DNA methylation during intestinal development and homeostasis has been studied in freshly isolated human epithelial cells, biopsies and mouse tissues.Here, we demonstrate the presence of stable, gut segment-specific DNA methylation signatures in human IEOs, which closely reflect those of matching primary purified epithelium and determine regional transcription and cellular function. In contrast, fetal IEOs showed distinct changes in their DNA methylation profile over time towards the paediatric pattern, suggesting the existence of a cell-intrinsic maturation programme that allows development in\u00a0vitro without the requirement for other cellular components. Lastly, we demonstrate that IEOs from diseased tissue retains altered DNA methylation signatures, highlighting the potential of organoids to model pathophysiology.Intestinal biopsies were collected from the terminal ileum (TI) and sigmoid colon (SC) from children under 16 years of age as well as adults undergoing diagnostic endoscopy. All patients included had macroscopically and histologically normal mucosa. Fetal intestine was obtained with ethical approval (REC-96/085) and informed consent from elective terminations at 8\u201312-week gestational age. Fetal gut was dissected and divided into the proximal  and distal (large intestine) sections at the ileocaecal junction. Sample details are listed in online 10.1136/gutjnl-2017-314817.supp1Supplementary file 1Intestinal epithelial cells (IECs)\u00a0were purified by enzyme digestion and magnetic bead sorting for the epithelial cell adhesion molecule (EpCAM) and purity was assessed as described previously.et al and Fordham et alet alIEOs were cultured according to protocols by Sato DNA and RNA were extracted simultaneously from the same sample as described previously.Bisulfite-converted DNA was measured using the Infinium HumanMethylation450 BeadChip . The readout for each CpG is expressed as beta value (from 0=unmethylated\u2009to 1=fully methylated) or the log2-beta value . A subset of IEC samples formed part of previous publications.RNA sequencing was performed on the Illumina HiSeq 2500 platform. Further information is provided in the IEOs were in\u00a0vitro differentiated by culturing in differentiation medium \u00a0as described previously.Fluorescent and brightfield images were obtained using an EVOS FL system (Life Technologies). Organoids were stained using anti-FABP6, anti-MUC5B (Atlas Antibodies) or anti-EpCAM (abcam) antibodies. Further details are provided in the et al.Plasmid vectors for hCas9 #41815) and gRNA (#41824) were obtained via Addgene. The targeting vector was generated from human genomic DNA and assembly into pUC118-FLIP-Puro backbone (Addgene #84538). and gRNAStatistical analysis for qPCR and pyrosequencing data was performed using GraphPad Prism V.7.00 (GraphPad). Significance levels were determined using multiple t-test with Holm-Sidak correction.Bioinformatic analysis was performed in R software for statistical analysis V.3.2.3 using Bioconductor V.3.2 packages.minfisva,limmaDMRcateMinfi was used to generate multidimensional scaling (MDS) plots, which allow visualising similarity between large datasets by reducing complexity to a two-dimensional scale. RNA sequencing data were processed using fastq_illumina_filter, cutadapttophat2,bowtiesamtoolshtseq-count,RUVseq.DESeq2GOseq.DNA methylation data were analysed using Genome-wide data have been deposited in ArrayExpress, accessions E-MTAB-4957 (DNA methylation) and E-MTAB-5015 (RNA sequencing).To investigate DNA methylation and its role in regulating cellular function in human IEOs, we generated organoids from mucosal biopsies from healthy children and adolescents from the distal small bowel \u00a0and distal large bowel , special AT-rich sequence-binding protein 2 antisense 1 (SATB2-AS1)\u00a0and claudin 15 (CLDN15)  . We vali(CLDN15) .Organoids derived from the same gut segment and profiled after a range of culture periods  displayed close clustering in the MDS plot , indicatLYZ), the main glucose transporter solute carrier family 5 member 1 (SLC5A1), CLDN15, cystic fibrosis transmembrane conductance regulator (CFTR) as well as SATB2 . Unsupervised hierarchical clustering and sample relation analysis of transcriptomes revealed a clear, primary separation of samples according to gut segment . Howeveras SATB2 . We confas SATB2 .We hypothesised that the transcriptional differences between organoids and IEC might arise in part from the enrichment for the stem cell niche in maintenance\u00a0organoid culture. We therefore subjected organoids to in\u00a0vitro differentiation that mimics migration upwards from the intestinal crypt.FABP6), nuclear receptor subfamily 1 group H member 4 (NR1H4), mucins (MUC5B and MUC12) as well as TFF3  and large bowel markers in TI organoids   -inhibitor Aza-deoxycytidine (AdC). Treatment with DNMT-inhibitor reduced DNA methylation, primarily at highly methylated loci, and thereby altered gut segment-specific signatures . Importand MUC4) . Hence, In addition to paediatric mucosal biopsies, we established IEO cultures from human fetal proximal gut  and fetal distal gut  . EpithelTLR4) and the transcription factor paired-like homeodomain 1 (PITX1). These genes displayed dynamic DNA methylation and gene expression changes in fetal organoids during prolonged culture  encodes an enzyme that plays a key role in active demethylation of DNANext, we aimed to identify the mechanisms underlying the dynamic changes in DNA methylation suggestive of in\u00a0vitro maturation of fetal IEOs. Ten eleven translocation 1  of a paediatric patient . The preCDX2 and KRT7 (GATA2)\u00a0(see online Next, we generated IEOs from gastric, rectal and gastric heterotopic biopsy samples  and subjand KRT7  and the IEO cultures are rapidly emerging as powerful models to study intestinal epithelial cell biology. Studies on both human and murine organoids have demonstrated that organoids can retain regional functional properties even in heterotopic grafts.We have previously shown that DNA methylation profiles of the epithelium in the small and large bowel differ substantially.In addition to DNA methylation, we confirmed that transcriptional profiles of paediatric mucosa-derived organoids displayed major similarities with primary epithelium derived from the respective gut segment.The use of immature fetal epithelium represents another promising area within the field of IEOs.In addition to modelling human intestinal epithelial biology in health, IEOs also hold great promise for studying diseases. A number of reports have demonstrated that patient-derived organoids display distinct disease-associated phenotypes.In summary, our study demonstrates the critical importance of precise intestinal epithelial cell-intrinsic epigenetic regulation in defining regional gut specification during development, in homeostasis and disease pathogenesis.10.1136/gutjnl-2017-314817.supp3Supplementary file 410.1136/gutjnl-2017-314817.supp4Supplementary file 310.1136/gutjnl-2017-314817.supp5Supplementary file 510.1136/gutjnl-2017-314817.supp6Supplementary file 6"}
+{"text": "Since 2006, CDC has recommended routine, provider-initiated human immunodeficiency virus (HIV) screening  for all patients aged 13\u201364 years in all health care settings   persons reported receiving an HIV test offer from a health care provider. Among 194 (58%) persons who reported not receiving an HIV test offer, 156 (80%) reported high-risk sexual activity, and 71 (37%) reported never having had an HIV test in their lifetime . Among pSince 2006, CDC has recommended routine HIV screening for all persons aged 13\u201364 years  for all patients aged 13\u201364 years in all health care settings.In a sample of 333 health care\u2013seeking, heterosexual adults at increased risk for acquiring HIV infection, 194 (58%) reported not receiving an HIV test offer at a recent medical visit(s), and men (versus women) had a significantly lower prevalence of provider-initiated HIV test offers (32% versus 48%). Recent HIV testing was higher among recipients of provider-initiated offers compared with nonrecipients (71% versus 16%).Provider-initiated HIV test offers are an important strategy for increasing HIV testing among heterosexual populations. More provider-initiated HIV screening among heterosexual adults at increased risk for acquiring HIV infection, especially men, is needed."}
+{"text": "Medicago truncatula NODULE ROOT1 (MtNOOT1) is required for the maintenance of nodule identity, preventing the conversion to lateral root development. MtNOOT1 and its orthologs in other plant species -collectively called the NOOT-BOP-COCH-LIKE (NBCL) family- specify boundary formation in various aerial organs. However, MtNOOT1 is not only expressed in nodules and aerial organs, but also in developing roots, where its function remains elusive.Legumes can utilize atmospheric nitrogen by hosting nitrogen-fixing bacteria in special lateral root organs, called nodules. Legume nodules have a unique ontology, despite similarities in the gene networks controlling nodule and lateral root development. It has been shown that Mtnoot1 mutant seedlings display accelerated root elongation due to an enlarged root apical meristem. Also, Mtnoot1 mutant roots are thinner than wild-type and are delayed in xylem cell differentiation. We provide molecular evidence that the affected spatial development of Mtnoot1 mutant roots correlates with delayed induction of genes involved in xylem cell differentiation. This coincides with a basipetal shift of the root zone that is susceptible to rhizobium-secreted symbiotic signal molecules.We show that MtNOOT1 regulates the size of the root apical meristem and vascular differentiation. Our data demonstrate that MtNOOT1 not only functions as a homeotic gene in nodule development but also coordinates the spatial development of the root.Our data show that  Medicago truncatula (medicago) LCO signalling induces cell divisions in the pericycle and endodermis, followed by a coordinated mitotic activation of cortical cells. This will give rise to nodule primordia  (40\u2009cycles), 95\u2009\u00b0C for 10\u2009s, followed by melt curve analysis . The gene expression was normalized using Additional file 1: Figure S1. Medicago MtNOOT1 is expressed in the root tip. Expression profiles are derived from the Medicago truncatula Gene Expression Atlas [MtNOOT1 is targeted by the probe-sets Mtr.19586.1.S1_at, Mtr.27707.1.S1_s_at, and Mtr.39297.1.S1_s_at. Root 3\u2009mm tip: 3\u2009mm root tip [on Atlas . MtNOOT1root tip ; adj tiproot tip ; Nod: noroot tip ; dpi: daAdditional file 2: Figure S2. The primary root Mtnoot1 tnk507 mutant is longer than wild-type. Representative seedlings at 6 DAG are presented. (DOCX)Additional file 3: Figure S3. The Mtnoot1 NF2717 mutant allele shows a similar phenotype as the Mtnoot1 tnk507 allele. a Root length of the medicago Mtnoot1 mutant (NF2717) is markedly longer at 4 DAG and 6 DAG when compared to primary roots of wild-type medicago seedlings (WT). b The cross-sectional area is significantly reduced in the medicago Mtnoot1 mutant (NF2717) at zone 3 and zone 4. The data represent means + SD of two independent experiments, each experiment contains 15\u201320 roots. Student t-test was performed to assess significant differences (****: P\u00a0<\u20090.0001). Representative root cross sections of wild-type  and Mtnoot1 (NF2717)  vascular bundle at zone 3 stained with phloroglucinol-HCl to demonstrate lignin deposition at 6 DAG. Black arrow marks lignified metaxylem cells, which are not found in the Mtnoot1 mutant (NF2717). g Vascular xylem differentiation is delayed in the Mtnoot1 (NF2717) primary root at 6 DAG. The fraction of roots with lignified central metaxylem cells in zone 3 and zone 4 is decreased in the Mtnoot1 mutant when compared with wild-type seedlings. The presented data combines two independent experiments, each experiment contains 15\u201318 roots. Scale bar: 50\u2009\u03bcm , 100\u2009\u03bcm . (DOCX)Additional file 4: Figure S4. Maximum likelihood tree of VND6, VND7 and related proteins. The protein sequences of OG0006787 (red), OG0009959 (dark red), OG0004118 (purple), OG0001465 (green and blue) are obtained from van Velzen et al. (2018), except VND6, which was not included in OG0001465. Species include arabidopsis , Eucalyptus grandis (Egrandis), Fragaria vesca (Fvesca), Glycine max (Gmax), medicago (Mtruncatula), Populus trichocarpa (Ptrichocarpa), Parasponia andersonii (Pan) and Trema orientalis (Tor). Numbers at to the branches indicate support from 1000 ultrafast bootstrap replicates. OG0006787 including NAC1 was used as outgroup. (DOCX)Additional file 5: Figure S5. Maximum likelihood tree of SND1 and related proteins. The protein sequences of OG0009898 (red) and OG0001875 (green) are obtained from van Velzen et al. (2018). Species include arabidopsis , Eucalyptus grandis (Egrandis), Fragaria vesca (Fvesca), Glycine max (Gmax), medicago (Mtruncatula), Populus trichocarpa (Ptrichocarpa), Parasponia andersonii (Pan) and Trema orientalis (Tor). Numbers at to the branches indicate support from 1000 ultrafast bootstrap replicates. OG0009898 containing SMB was used as outgroup. (DOCX)Additional file 6: Figure S6. Maximum likelihood tree of MYB46, MYB83 and related proteins. The protein sequences of OG0000857 (red) and OG0001270 (green) are obtained from van Velzen et al. (2018). Species include arabidopsis , Eucalyptus grandis (Egrandis), Fragaria vesca (Fvesca), Glycine max (Gmax), medicago (Mtruncatula), Populus trichocarpa (Ptrichocarpa), Parasponia andersonii (Pan) and Trema orientalis (Tor). Numbers at the branches indicate support from 1000 ultrafast bootstrap replicates. OG0000857 containing MYB50 was used as outgroup. (DOCX)Additional file 7: Figure S7. Maximum likelihood tree of MYB58, MYB63 and MYB85 proteins. The protein sequences of OG0005384 (red) and OG0002420 (green) are obtained from van Velzen et al. (2018). Species include arabidopsis , Eucalyptus grandis (Egrandis), Fragaria vesca (Fvesca), Glycine max (Gmax), medicago (Mtruncatula), Populus trichocarpa (Ptrichocarpa), Parasponia andersonii (Pan) and Trema orientalis (Tor). Numbers at the branches indicate support from 1000 ultrafast bootstrap replicates. OG0005384 containing MYB58 and MYB63 was used as outgroup. (DOCX)Additional file 8: Figure S8. Maximum likelihood tree of XCP1 and related proteins. The protein sequences of OG0003401 (red) and OG0003952 (green) are obtained from van Velzen et al. (2018). Species include arabidopsis , Eucalyptus grandis (Egrandis), Fragaria vesca (Fvesca), Glycine max (Gmax), medicago (Mtruncatula), Populus trichocarpa (Ptrichocarpa), Parasponia andersonii (Pan) and Trema orientalis (Tor). Numbers at the branches indicate support from 1000 ultrafast bootstrap replicates. OG0003401 containing CEP1 was used as outgroup. (DOCX)Additional file 9: Figure S9. Maximum likelihood tree of APL and related proteins. The protein sequences of OG0009526 (red) and OG0006786 (green) are obtained from van Velzen et al. (2018). Species include arabidopsis , Eucalyptus grandis (Egrandis), Fragaria vesca (Fvesca), Glycine max (Gmax), medicago (Mtruncatula), Populus trichocarpa (Ptrichocarpa), Parasponia andersonii (Pan) and Trema orientalis (Tor). Numbers at the branches indicate support from 1000 ultrafast bootstrap replicates. OG0009526 containing sequences highly homologous to MtAPL was used as outgroup. (DOCX)Additional file 10: Figure S10. The NAC domain transcription factors MtVND6 and MtVND7, but not MtSND1, are lower expressed in zone 3 of Mtnoot1 tnk507 roots when compared to wild-type. The data represent means + SEM of three independent experiments. Student t-test was performed to assess significant differences (ns: not significant). (DOCX)Additional file 11: Table S1. qRT-PCR primers used in this study. (DOCX)"}
+{"text": "We examined opioid use in long-term care nursing home residents with dementia. This retrospective cohort study used Minimum Data Set linked Medicare data, 2011-2016, and included long-term care episodes for residents 65+ years who survived 100+ days each year . Cognitive status at first annual assessment was classified as none/mild, moderate and severe impairment. Overall opioid use, prolonged opioid use (prescription supply 90+ days) and long-acting opioid use were identified from Medicare part D. Descriptive statistics were used to describe opioid use by cognitive impairment. Cochrane Armitage trends test was used to determine trends in opioid use. 114,622 (19%) patients had severe and 129,257 (22%) had moderate dementia. Overall opioid , prolonged opioid  and long-acting opioid use  were lower in patients with advanced dementia. Opioid use was significantly higher in females and Whites and varied by states. Substantial increase was found in overall opioid and prolonged opioid use from 2011 to 2016, with greater increase in none/mild and moderate dementia patients. For example, prolonged opioid use increased by 69% in none/mild and 71% in moderate dementia patients compared to 52% in severe dementia patients (p<0.0001). Long-acting opioid use decreased, with a greater decline in none/mild (69%) and moderate (71%) dementia patients compared to severe dementia patients (58%) (p<0.0001). Contrary to decreasing opioid use in community setting, overall and prolonged opioid use increased in nursing home residents. Future studies should identify the reasons behind increased use."}
+{"text": "Drosophila melanogaster, Bactrocera dorsalis and Calliphora stygia. This research has revealed that these proteins play a crucial role in insect orientation, predation and oviposition. However, little is known about the chemosensory proteins of Chlorops oryzae, a major pest of rice crops throughout Asia.Chemosensory proteins are a family of insect-specific chemical sensors that sense specific chemical cues and regulate insect behavior. Chemosensory proteins have been identified and analyzed in many insect species, such as Chlorops oryzae larvae, pupae and adults identified a total of 104 chemosensory genes, including 25 odorant receptors (ORs), 26 odorant-binding proteins (OBPs), 19 ionotropic receptors (IRs), 23 gustatory receptors (GRs) and 11 sensory neuron membrane proteins (SNMPs). The sequences of these candidate chemosensory genes were confirmed and used to construct phylogenetic trees. Quantitative real-time PCR (qRT-PCR) confirmed that the expression of candidate OR genes in different developmental stages was consistent with the fragments per kilobase per million fragments (FPKM) values of differentially expressed genes (DEGs).Comparative transcription analysis of the genes of C. oryzae provides a foundation for the investigation of the function of chemosensory proteins in this species, which, in turn, could allow the development of new, improved methods of controlling this pest.The identification of chemosensory genes in The online version of this article (10.1186/s12864-018-5315-4) contains supplementary material, which is available to authorized users. Olfactory and gustatory systems play crucial roles in insect orientation, oviposition, host-identification, mate choice and predator avoidance \u201314. ChemChlorops oryzae (Diptera) cause significant economic damage to rice crops throughout Asia. Newly hatched larvae primarily burrow into the stem of rice plants and feed on the growing tips of developing leaves \u2009\u2212\u20091)*100 [\u2212\u0394\u0394Ct method was used to analyze gene expression profiles [We used qRT-PCR with three replicates for each treatment to verify the expression of candidate \u2212\u20091)*100 , 86. Theprofiles . Means aAdditional file 1:Table S1. Summary of the transcriptome sequencing data from the C. oryzae samples. (DOCX 15 kb)Additional file 2:Figure S1. Results of BLASTx matches of Chlorops oryzae transcriptome unigenes and Gene ontology classification. a: E-values, b: gene identity, c: insect species in which homologous genes were matched. d: Gene ontology classifications of C. oryzae unigenes. (TIF 192 kb)Additional file 3:Table S2. Primers of candidate ORs in C. oryzae used for qRT-PCR. (DOCX 16 kb)Additional file 4:Protein sequences of ORs used to construct phylogenetic tree. (DOCX 52 kb)Additional file 5:Protein sequences of GRs used to construct phylogenetic tree. (DOCX 49 kb)Additional file 6:Protein sequences of IRs used to construct phylogenetic tree. (DOCX 72 kb)Additional file 7:Protein sequences of OBPs used to construct phylogenetic tree. (DOCX 28 kb)Additional file 8:Protein sequences of SNMPs used to construct phylogenetic tree. (DOCX 17 kb)"}
+{"text": "African American older adults experience disproportionate burden from disabling chronic pain. Pain self-management interventions for this group are most effective when they integrate culturally-relevant preferences into intervention design. In the STEPS pilot trial, we collected focus group (n=23) and survey (n=57) data from African Americans age 60+ years about pain-management practices. Participants were recruited from the community and reported pain for 3+ months, with intensity >4 . The most frequently-used pain-management strategies were exercise (75%) and prayer/Bible reading (74%). Also commonly used were healthy eating (61%), OTC medications (65%), and herbal supplements (51%). Focus group themes provided more nuanced information, including reasons for avoiding prescription pain medications, positive experiences with topical treatments, the value of movement, and the role of social support. Findings reveal strong engagement in pain self-care in this population. Interventions can build on existing practices by incorporating spirituality and appealing options for physical activity."}
+{"text": "Even though one-third of older adults have maladaptive fall risk appraisal (FRA), no studies has examined this discrepancy between perceived fall risk and physical fall risk among older adults in Thailand. We examined the characteristics of fall risk appraisal (FRA). 433 community-dwelling older adults were randomly selected from two provinces in Southern Thailand. Physical fall risk was assessed by a full tandem stand test and perceived fall risk was assessed by the Fall-Efficacy Scale International. We classified FRA into: 1) Rational FRA means low physical fall risk and low perceived fall risk; 2) Irrational FRA means low physical fall risk but high-perceived fall risk; 3) Congruent FRA means high physical fall risk and high-perceived fall risk; and 4) Incongruent FRA means high physical fall risk but low perceived fall risk. Irrational FRA and Incongruent FRA are a maladaptive FRA. About 60% of the participants had maladaptive FRA, which consisted of irrational FRA (57.3%) and incongruent FRA (2.3%). 20.8% were in rational FRA and 19.6% in congruent FRA. Among those with rational FRA, incongruent FRA, irrational FRA, and congruent FRA, 27.8%, 60%, 41.1%, and 74.1% reported having at least one fall in the past year, respectively. After covariate adjustment, participants in the congruent FRA group were 3.29 times more likely (p=0.006) to fall than those in rational FRA. High proportion of participants had maladaptive FRA so screening individuals with maladaptive FRA and prevent them to transition into the congruent FRA group is important efforts to mitigate health and economic burdens."}
+{"text": "Resected specimens of PCLD by laparoscopic fenestration surgery were evaluated by scanning electron microscopy. Epithelium lining the largest cyst (26 cm in size) showed prominent villous proliferation with positivity of Ki-67, while the epithelium of the small cyst (3 cm in size) showed slight proliferation (smooth) with small positivity of Ki-67. A 69-year-old woman with ADPKD was admitted to our hospital for evaluation of abdominal distention due to PCLD. Resected specimens by laparoscopic fenestration surgery were evaluated by scanning electron microscopy. Epithelium lining the largest cyst (26\u00a0cm in size) Fig.\u00a0a showed"}
+{"text": "Skeletal muscle retains the ability to regenerate throughout life, but this decreases significantly with aging. The present study investigates whether aging-associated loss of muscle hypoxia signaling limits regenerative potential. Utilizing young (3 months) and old (22-24 months) mice, skeletal muscle from old mice exhibited a 40% decline in the cross-sectional area (CSA) of newly regenerating fibers following cryoinjury at day 10 (p < 0.01) post-injury as compared to young. Focused PCR array demonstrated a greater than 3-fold decline in expression of the majority of hypoxia signaling genes. In particular, aryl hydrocarbon receptor nuclear translocator (ARNT), which is required for downstream hypoxia signaling and the transcription of hypoxia response genes, is 5-fold lower for both gene expression (p < 0.01) and protein levels (p < 0.01) in old versus young mice. To determine the effects of ARNT on muscle regeneration, we utilized a genetically modified mouse which results in an 80% decrease in ARNT gene expression following activation, specifically in skeletal muscle. Compared to littermate controls, mice with a muscle specific knockdown of ARNT (mKO ARNT) exhibit a 30% decline in regenerating fiber sizes at day 10 (p < 0.01) following cryoinjury, without any loss of regenerative potential in FACS isolated satellite cells ex vivo. Administration of a pharmacologic hypoxia activator, ML228, induced a 30% increase in regenerating fiber CSA in both old mice and mKO ARNT mice (p < 0.01) as compared to treatment with vehicle control. These data suggest hypoxia signaling declines with aging in skeletal muscle and activation of hypoxia signaling may promote regeneration."}
+{"text": "Salmonella enterica serovar Schwarzengrund isolates from clinical sources were sequenced as part of a larger study to examine phenotypic and genotypic characteristics. The majority of the sequenced strains were isolated from human stool (n = 20) followed by urine (n = 3) and blood (n = 2).Twenty-seven  Salmonella enterica serovar Schwarzengrund isolates from clinical sources were sequenced as part of a larger study to examine phenotypic and genotypic characteristics. The majority of the sequenced strains were isolated from human stool (n = 20) followed by urine (n = 3) and blood (n = 2). Four isolate sequences contained plasmids of known incompatibility groups.Twenty-seven  Salmonella enterica serovar Schwarzengrund strains can cause salmonellosis in humans and infections in other animal species  and sequenced at the Division of Microbiology, National Center for Toxicological Research, U.S. Food and Drug Administration . Epidemiological information for these isolates is listed in Twenty-seven 2S were subsequently inoculated in motility-indole-lysine agar, triple sugar iron agar, and a urea agar plate (BD). Identification was confirmed using matrix-assisted laser desorption ionization\u2013time of flight mass (MALDI-TOF) spectrometry. Likewise, blood and other clinical isolates were identified using standard microbiological procedures.Stool samples were plated on Hektoen enteric agar, salmonella-shigella agar, and enrichment broths . The plate or broth was then incubated at 35\u00b0C for 18 to 24 h. Colonies that were suspiciously lactose negative and positive for Hde novo assembly were performed with CLC Genomics Workbench . Genome sequences from individual samples were examined simultaneously with individual annotation tools, such as Rapid Annotation using Subsystem Technology (RAST) , and DNA sequencing libraries were constructed with the Nextera XT DNA library preparation kit . Samples were multiplexed with a unique combination of two indexes of the Nextera XT index kit. Whole-genome sequencing (WGS) reactions were carried out on an Illumina MiSeq instrument with a 2 \u00d7 300 paired-end format . Trimminy (RAST)  and Pathy (RAST)  -Id, strA, and tet(B) resistance genes; MDH-18 and MDH-20 contained the aph(3\u2032)-Ia and blaCMY-2 genes; and MDH-25 contained the aac(3)-VIa, aadA1, and sul1 genes.Among 27 idFinder  analysesidFinder  analysesPRJNA312617.This whole-genome shotgun project is deposited at DDBJ/ENA/GenBank under the accession numbers listed in"}
+{"text": "ABCA4) were identified as contributing to the family\u2019s STGD1 phenotype. These variants may impact the ABCA4 protein structure and reduce the retinal-activated ATPase activity, leading to abnormal all-trans retinal accumulation in photoreceptor outer segments and in retinal pigment epithelium cells. The present study broadens the mutational spectrum of the ABCA4 responsible for STGD1. A combination of whole exome sequencing and Sanger sequencing is likely to be a time-saving and cost-efficient approach to screen pathogenic variants in genetic disorders caused by sizable genes, as well as avoiding misdiagnosis. These results perhaps refine genetic counseling and ABCA4-targetted treatments for families affected by STGD1.Stargardt disease  is a common hereditary juvenile or early adult onset macular degeneration. It ultimately leads to progressive central vision loss. Here, we sought to identify gene mutations associated with STGD1 in a three-generation Han Chinese pedigree by whole exome sequencing and Sanger sequencing. Two novel potentially pathogenic variants in a compound heterozygous state, c.3607G>T (p.(Gly1203Trp)) and c.6722T>C (p.(Leu2241Pro)), in the ATP binding cassette subfamily A member 4 gene ( ABCA4) mutations, although autosomal dominant STGD1-like phenotypes have been reported to be associated with mutations in the ELOVL fatty acid elongase 4 gene (ELOVL4), the prominin 1 gene (PROM1), the peripherin 2 gene (PRPH2), the bestrophin 1 gene (BEST1), and the crumbs 1 cell polarity complex component gene (CRB1) [Stargardt disease , also known as Stargardt\u2019s macular dystrophy or juvenile macular degeneration, was initially described by Karl Stargardt in 1909 . The peae (CRB1) .ABCA4 is an important membrane protein composed of two exocytoplasmic domains, two transmembrane domains, and two cytoplasmic domains, which transport all-trans retinal, a by-product of the retinoid cycle, from intra-disc space to photoreceptor cytoplasm to avoid abnormal accumulation of all-trans retinal in photoreceptors outer segments and in RPE cells [ABCA4 mutations primarily generate dysfunctional ABCA4 proteins (Rim proteins) resulting in photoreceptor disruption and degeneration [ABCA4, including missense, nonsense, small insertion and deletion, frameshift, and splicing, have been reported as causing STGD1 [ABCA4 are implicated in STGD1 [The photoreceptor cell-specific ABCA4 protein encoded by the PE cells ,14. As aPE cells ,14. ABCAneration . Currentng STGD1 . Geneticin STGD1 .ABCA4 of a Han Chinese family affected by STGD1, and also described associated clinical phenotypes.Next-generation sequencing technology has become a low cost and shorter time tool nowadays for screening pathogenic mutations of hereditary diseases . Using wA three-generation, seven-member Han Chinese pedigree with STGD1 and 100 ethnically matched independent unaffected individuals  were recruited for the present study. Ophthalmologic examinations were performed on all available individuals by two experienced ophthalmologists. The examinations included best corrected visual acuity (BCVA) assessed by the Snellen visual chart, slit-lamp biomicroscopy, microperimetry, fundus examination, fundus fluorescein angiography (FFA), and optical coherence tomography (OCT). All clinical diagnoses for STGD1 phenotype were based upon a family history of recessive inheritance, first or second decade onset, progressive bilateral central vision loss, macular atrophy or dystrophy with a beaten-bronze appearance, retinal yellowish flecks, and a lack of pigmented bone spicules ,21. ThisWhole exome sequencing was performed on the proband from the pedigree with STGD1. The gDNA of the proband was assessed for integrity using agarose gel electrophoresis and quantitated using NanoDrop 2000 . Approximately 3.0 \u00b5g of gDNA was sheared into fragments. The 3\u2032 end of DNA fragments were then ligated with an \u2018A\u2019 to repair. Illumina adapters were added to the DNA fragments and final 350\u2013450 base pairs including adapter products were applied to PCR amplification. The ultimate products were confirmed using an Agilent 2100 Bioanalyzer system . Protein coding regions in human gDNA were captured by an Agilent SureSelect Human All Exon V6 Kit  following the manufacturer\u2019s instructions. Exome libraries were sequenced on a HiSeq 2000 platform  by a commercial service from Novogene Bioinformatics Institute  in accordance with the manufacturer\u2019s protocols.http://bio-bwa.sourceforge.net/) [http://samtools.sourceforge.net/) and Picard tools (http://sourceforge.net/projects/picard/) were utilized to rank sequence alignment results and remove duplicate reads, respectively. Genome Analysis Toolkit program (http://software.broadinstitute.org/gatk/) was used to realign and detect single nucleotide polymorphism (SNP) and insertion/deletion (Indel) variations. SNPs and Indels were identified with SAMtools and annotated with ANNOVAR (ANNOtate VARiation) software (http://annovar.openbioinformatics.org/). The variants identified above were filtered against the following four databases: 1000 Genomes Project , Single Nucleotide Polymorphism Database 147 , Exome Aggregation Consortium , and National Heart, Lung and Blood Institute Exome Sequencing Project . Remaining variants with a minor allele frequency <0.001 were further processed according to the 700 Han Chinese controls in-house exome database from Novogene Bioinformatics Institute . After excluding synonymous variants, potential pathogenic impacts caused by non-synonymous variants located in exonic regions and in splicing sites were predicted using the following four tools: Polymorphism Phenotyping v2 (PolyPhen-2) (http://genetics.bwh.harvard.edu/pph2/), Sorting Intolerant from Tolerant (SIFT) (http://sift.jcvi.org/), MutationTaster software (http://www.mutationtaster.org/), and Combined Annotation Dependent Depletion (CADD) algorithm (http://cadd.gs.washington.edu/score). According to the American College of Medical Genetics and Genomics (ACMG) guidelines for variants interpretation, variants for STGD1 or STGD1-like phenotypes were classified as pathogenic, potentially pathogenic, unknown clinical significance, likely benign, or benign [After base calling, low-quality and adapter reads were removed from raw reads using Solexa QA package and Cutadapt program, respectively. Effective reads were mapped on to the human reference genome UCSC (GRCh37/hg19) with a Burrows\u2013Wheeler Aligner (BWA) (ge.net/) . SAMtoolr benign .http://primer3.ut.ee/) based on the genome sequences of human reference genome UCSC (GRCh37/hg19). These primers were then synthesized in Sangon Biotech (Shanghai) Co., Ltd. . Primer sequences for PCR and Sanger sequencing were as follows: 5\u2032-ACCCAAGTATGGCCCGTCCA-3\u2032, 5\u2032-TCCCATCCATCTGTTGCAGG-3\u2032; and 5\u2032-CAACCCACACTGGGTGTTCT-3\u2032, 5\u2032-TGCATCCCCTAGATTTGGAG-3\u2032.Potential variants identified by whole exome sequencing in the genes associated with STGD1 or STGD1-like phenotypes were selected for subsequent Sanger sequencing in the proband, available family members, and 100 unaffected individuals. Sequence results were then analyzed with Chromas software . Co-segregation of potential pathogenic variants with this disease phenotype was also analyzed. Primers were designed around potential missense variants with Primer3 software  in seven different species. Predictions for structures of wild-type and mutant proteins were performed by online SWISS-MODEL tool (http://www.swissmodel.expasy.org). Structures were visualized using PyMOL software  [Multiple sequence alignments were performed using the online Clustal Omega tool ( U.S.A.) .Seven members of a three-generation family with STGD1 were presented in the present study A. The prABCA4 variants, c.3607G>T (p.(Gly1203Trp)) in exon 24 and c.6722T>C (p.(Leu2241Pro)) in exon 48, were found in the proband. According to the variant classification guidelines of ACMG, these two variants are categorized as likely pathogenic variants. Sanger sequencing further verified both variants in the proband . These two variants are categorized as likely pathogenic variants in accordance with the variant classification guidelines of ACMG. The effects on protein function of the two missense variants (p.(Gly1203Trp) and p.(Leu2241Pro)) were predicted to be deleterious by online prediction programs  (ABCA4 variant (p.(Gly1203Trp) or p.(Leu2241Pro)) were asymptomatic, which may be due to reserving a partly normal ABCA4 protein, supporting that the compound heterozygous variants (p.(Gly1203Trp) and p.(Leu2241Pro)) were responsible for the STGD1 phenotype in this family.Genotypic multiplicity and phenotypic variability widely exist in inherited retinal disorders. Mutations in the  studies . In addiystrophy ,28. Due quencing ,30. Wholquencing ,31. In tin vitro  was alsond CADD) . Four faABCA4, located at chromosome 1p22.1, includes 50 exons and expresses a 2273-amino acid glycoprotein with a molecular mass of 256 kDa, located in outer segments of cone and rod photoreceptors [ABCA4 mutations usually result in decrease or loss of retinal-activated ATPase activity and/or NRPE flipping activity, as well as protein mislocalization caused by misfolding in photoreceptor cells [The eceptors ,14. ABCAor cells ,33. Inteor cells . These sor cells ,33. The or cells . This inor cells . Similaror cells . These fABCA4 mutations and are inherited as an AR form [Abca4 knockout mice revealed some clinical manifestations related to STGD1 including delayed dark adaptation, RPE layer thickening, outer retinal layers thinning, lipofuscin accumulation in RPE cells, and photoreceptor degeneration [Abca4 knockout mice, delivering mouse Abca4 with recombinant adeno-associated viral vectors and human ABCA4 with recombinant lentivirus vectors into RPE and photoreceptors cells could trigger dark adaptation recovery, RPE layer thinning, and retinal lipofuscin deposition decrease [ABCA4-associated hereditary retinal diseases like STGD1.Approximately, 90\u201395% of STGD1 patients harbor loss-of-function neration . Amazingdecrease ,38,39. Ndecrease . This shABCA4 responsible for a STGD1 phenotype in a three-generation Han Chinese family and broadened the mutational spectrum of ABCA4 in STGD1. A combination of whole exome sequencing and Sanger sequencing is likely to be a time-saving and cost-efficient approach to screen pathogenic variants in genetic disorders caused by sizable genes, as well as avoiding misdiagnosis. These results perhaps refine genetic counseling and ABCA4-targetted treatments for families affected by STGD1.Taken together, the present study identified two novel potentially pathogenic variants in a compound heterozygous state, c.3607G>T (p.(Gly1203Trp)) and c.6722T>C (p.(Leu2241Pro)), in"}
+{"text": "Saccharomyces cerevisiae with genetic and chemical tools to analyze CAT tails in aggregated and un-aggregated states. We found that enhancing CAT tail aggregation induces proteotoxic stress and antagonizes degradation of CAT-tailed proteins, while inhibiting aggregation reverses these effects. Our findings suggest that CAT tail aggregation harms RQC-compromised cells and that preventing aggregation can mitigate this toxicity.The Ribosome-associated Quality Control (RQC) pathway co-translationally marks incomplete polypeptides from stalled translation with two signals that trigger their proteasome-mediated degradation. The E3 ligase Ltn1 adds ubiquitin and Rqc2 directs the large ribosomal subunit to append carboxy-terminal alanine and threonine residues (CAT tails). When excessive amounts of incomplete polypeptides evade Ltn1, CAT-tailed proteins accumulate and can self-associate into aggregates. CAT tail aggregation has been hypothesized to either protect cells by sequestering potentially toxic incomplete polypeptides or harm cells by disrupting protein homeostasis. To distinguish between these possibilities, we modulated CAT tail aggregation in  Ribosome-associated Quality Control (RQC), begins when a set of factors recognize ribosomes that have stalled on the same mRNA and collided into each other . Tr. Tr42]. ase LTN1 . This reht smear . This sm\u0394 strain , consistRQC2, which has previously been shown to increase CAT tail aggregation [RQC2 with the TDH3 promoter increased Rqc2 levels 28.4-fold relative to the native promoter, as assessed by levels of red fluorescent protein (RFP)-tagged Rqc2 (RQC2overexpression and LTN1deletion strain (hereafter named \u201cROLD\u201d), a proportion of RQCsub remained in the well rather than migrating into an SDS-PAGE gel   but became more punctate in ROLD cells (56.9% of cells with inclusions)  induced the punctate RQCsub localization we observed in ROLD cells   panel B. the gel  panel C.lusions) . To testa allele  instead LD cells , confirmROLD cells with GuHCl, we observed that RQCsub still localized to inclusions by microscopy (ROLD cells to migrate into the resolving gel rather than remaining in the well (We next sought a tool to inhibit CAT tail aggregation. Millimolar concentrations of the chaotrope guanidinium hydrochloride (GuHCl) in yeast growth medium limit CAT tail aggregation and block propagation of aggregated yeast prions by inhibiting the ATPase activity of the chaperone Hsp104 ,43\u201349. Wcroscopy  panel D.the well . The preLONG [LONG includes an internal expression control, RFP followed by viral T2A peptides, at the N-terminus of GFP-linker-arginine  affects degradation of CATylated RQCsubLONG. The ratio of GFP:RFP at the single-cell level serves as an internal, expression-controlled readout of RQCsubLONG stability  that reduces CAT tail-mediated degradation, we inhibited aggregation with GuHCl and measured RQCsubLONG stability. We observed that GuHCl treatment had two effects on RQCsubLONG degradation in ROLD strains. First, increasing concentrations of GuHCl increased the magnitude of the effect of HUL5 deletion on the stability of RQCsubLONG  led to 22.6-fold activation RQC2-OE, RQC2 overexpression, ltn1\u0394, and ROLD) grew equally well in a spot assay in the absence and presence of 5 mM GuHCl  were related to RNA Polymerase III (Pol III). These hits included a non-essential polymerase biogenesis factor, BUD27 [RPC17. Disruption of each of these by deletion or a \u201cdecreased abundance by mRNA perturbation\u201d allele (DAmP) [ROLD cells compared to wt   nearly eed to wt  panel A.ignaling . Perturbectively . Furtherd strain  panel B.ROLD-induced Hsf1 activation by perturbing CAT tail synthesis. Pol III perturbation could block CAT tail synthesis by preventing ribosome stalling, a necessary prerequisite for the RQC pathway to initiate. We evaluated this possibility using a quantitative stalling reporter similar to one previously developed [BUD27 deletion did not alleviate stalling induced by (CGN)12  in wt or ROLD strains relative to control   . Thus, PROLD strain , consistent with a reduction in CAT tail aggregation  in each of these backgrounds with Hul5 (degradation intact) and without Hul5 (degradation blocked) defined the degree of degradation [LONG in ROLD hul5\u0394 and ROLD bud27\u0394 hul5\u0394 strains  and ROLkgrounds . rpc17-D at 37\u00b0C  panel F.BUD27 deletion enabled faster growth of ROLD cells in the presence of cycloheximide  and remains unclear. RQC2 overexpression has been proposed to enhance aggregation because endogenous Rqc2 is limiting for CATylation [RQC2 overexpression would enable CATylation of more escaped RQC substrates that could then nucleate CAT tail aggregates. Although pleiotropic [We exploited Tylation . Under siotropic , Pol IIIiotropic , Pol IIILTN1 allele induces a progressive neurodegeneration that shares phenotypic similarities with amyotrophic lateral sclerosis (ALS) [LTN1-hypomorphic mice harbor toxic CAT tail aggregates, as has been observed in a Drosophila model of Parkinson Disease [We report here that CAT tail aggregation modifies the toxicity associated with disrupted Ltn1 function. In mice, a hypomorphic is (ALS) . It is p Disease . As the S1 FigA) Flow cytometry of cells expressing Rqc2-RFP to assess the degree of Rqc2 overproduction by the TDH3 promoter. Error bars represent s.e.m. from three independent cultures. (B) Lysate IB of RQCsub expressed in ltn1\u0394 compared to ROLD. (C) Immunoblot of RQCsub immunoprecipitated from ltn1\u0394 and ROLD lysates with and without tobacco etch virus (TEV) protease treatment. Arrow denotes molecular weight of non-CATylated RQCsub. Asterisk indicates the full-length RQCsub protein product, produced when ribosomes translate through the stall sequence . (D) Microscopy of RQCsub expressed in ROLD grown in various concentrations of guanidinium hydrochloride (GuHCl).((TIF)Click here for additional data file.S2 FigA) Flow cytometry of cells expressing RQCsubLONG. Error bars indicate s.e.m. from three independent cultures. (B) and (C) Additional data to support LONG expressed in ROLD cells grown in indicated GuHCl concentrations with additional bortezomib treatment to inhibit the proteasome and HUL5 deletion to measure CAT tail degron activity. Error bars as in A. P-values are indicated above bars. Thick lines indicate paired t-tests, probing the significance of bortezomib (btz)-induced stabilization. Thin lines denote t-tests for particular contrast, measuring how significantly different HUL5 deletion-induced stabilization is under different conditions.((TIF)Click here for additional data file.S3 FigA) Flow cytometry of cells containing an integrated reporter for Hsf1 activation. Error bars indicate s.e.m. from three independent cultures. P-values from paired t-tests indicated above bars. (B) Flow cytometry of Pol III-perturbed cells containing an integrated reporter for Hsf1 activation. These data are also contained in A. (C) Above, schematic of stalling reporter with the same (CGN)12 stalling sequence contained in RQCsub or a non-stalling (Ser-Thr)6 sequence, similar to a reporter used in refs 11 and 12. Below, flow cytometry of stalling and non-stalling reporters expressed in indicated strains. Error bars as in A. (D) IB of lysates containing RQCsub derived from ROLD compared to ROLD bud27\u0394. (E) Additional data to support LONG expressed in indicated strains with bortezomib (btz) treatment to inhibit the proteasome and HUL5 deletion to block CAT tail degron activity. Error bars indicate s.e.m. from three independent cultures. P-values are given above bars. Results of paired t-tests measuring the significance of bortezomib-induced stabilization are indicated with thick lines. The result of a t-test for particular contrast is indicated with thin lines; this assesses how significantly different HUL5 deletion-induced stabilization is in ROLD compared to ROLD bud27\u0394. (F and G) Spot assay of yeast strains grown under indicated conditions.((TIF)Click here for additional data file.S1 Table(PDF)Click here for additional data file.S2 Table(PDF)Click here for additional data file.S1 Datasetltn1\u0394 rps0a\u0394 background (column 3). The interaction (difference) between these measurements is reported in column 4.Each row includes the name of a gene (column 1) that was disrupted with a hypomorphic allele  and measured in a strain with a GFP-fluorescent Hsf1 reporter in either a wt (column 2) or (XLS)Click here for additional data file.S1 Raw Images(TIF)Click here for additional data file."}
+{"text": "Mycoplasma mycoides subsp. mycoides is the etiological agent of contagious bovine pleuropneumonia (CBPP). While several findings on CBPP prevalence in Nigeria were documented, no data were reported about the genomic characterization of Nigerian M. mycoides subsp. mycoides strains. Here, we present the draft genome sequences of two novel M. mycoides subsp. mycoides strains isolated in Nigeria. Mycoplasma mycoides subsp. mycoides is the etiological agent of contagious bovine pleuropneumonia (CBPP). While several findings on CBPP prevalence in Nigeria were documented, no data were reported about the genomic characterization of Nigerian M. mycoides subsp. mycoides strains. Here, we present the draft genome sequences of two novel M. mycoides subsp. mycoides strains isolated in Nigeria. Mycoplasma mycoides subsp. mycoides is the causative agent of contagious bovine pleuropneumonia (CBPP), a severe contagious respiratory disease affecting cattle, which is included among the Office International des Epizooties (OIE) diseases , but the disease still remains endemic in sub-Saharan Africa, including Nigeria, where it causes, directly or indirectly, economic losses of about $2 billion annually  (The draft genome sequences of two novel Nigeria) . The AP12 in pleuropneumonia-like organism (PPLO) broth and agar (Difco) supplemented as previously described , according to the manufacturer\u2019s manual. The libraries were loaded onto an Illumina 300-cycle NextSeq 500/550 mid output reagent cartridge 2 kit and sequenced on an Illumina NextSeq 500 platform, producing 150-bp paired-end reads.The isolates were grown at 37\u00b0C under 5% COescribed . The gende novo assembly was carried out using SPAdes 3.11 (M. mycoides subsp. mycoides strain T1/44 (GenBank accession number CP014346) as a reference. Gaps were then filled using Pilon 1.23 . After trimming performed using Trimmomatic 0.35  and 2 contigs for the AP108 strain , were submitted to GenBank, and annotation using the Prokaryotic Genome Annotation Pipeline (PGAP) pipeline  was requVCPG00000000 (strain APF9) and VCPH00000000 (strain AP108). The Illumina raw reads were deposited in the NCBI Sequence Read Archive (SRA) under the accession numbers SAMN11775870 (strain APF9) and SAMN11775871 (strain AP108).The genome sequences were deposited in GenBank under the following accession numbers:"}
+{"text": "Effect sizes are based moderate to large (effect size 0.5\u20130.8) reductions of in vitro GBM growth in vascular gene (TGF-\u03b2 knockdown studies). In addition, tagged tumor-derived pericytes should comprise a greater proportion of new vasculature in pericyte-knockdown mice to overcome host pericyte depletion. Finally, tumors in transgenic mice should show increased hypoxia from limitations in angiogenesis. DISCUSSION/SIGNIFICANCE OF IMPACT: Feasibility studies show successful tracking of fluorescently tagged-patient derived GBM samples in transgenic mice with decreased vasculature. GBM grafts show no evidence of immunogenic response with cyclosporine protocol. Successful limitation of tumor size with reduced pericyte density will provide support to increasing study of blood-brain barrier, stem cell activity and inflammatory activity of pericyte microenvironments altering GBM behavior. Furthermore, implementation of known pericyte targeted therapies, such as imantinib, can be evaluated for GBM patient treatment efficacy. Studies with assembled clinical translational research scholar mentorship team will allow the principal investigator to develop an independent career with laboratory focused on contributing to improved patient outcomes, translating successful pericyte-targeted results to patient trials.OBJECTIVES/SPECIFIC AIMS: Glioblastoma (GBM) carries a prognosis of 14.6 months mean survival despite maximal surgical, chemotherapeutic, and radiation therapy. The pericyte is a recently characterized cell shown to be a critical component of cerebral vessel physiology and pathology. Importantly, alterations in pericyte densities have shown resulting changes in breast and lung tumor growth. We leverage transgenic pericyte-deficient mouse models to evaluate resulting behavior of implanted patient-derived GBM. METHODS/STUDY POPULATION: Patient-derived, green fluorescent protein labeled, GBM will be implanted in right frontal bregma of both 6-month old pericyte-deficient (PDGFR+/\u2212) mice and age-matched wild-type littermate controls , which are immunosuppressed via daily intraperitoneal cyclosporine injection. In total, 30 mice of both genders are included in tumor and control cohorts. Fixed cortical sections following 3-week period will be stained for pericytes (NG2), endothelium (CD31), hypoxia (piminidazole), and tumor size. One-way ANOVA with will used to compare groups using SAS software . RESULTS/ANTICIPATED RESULTS: Feasibility studies show robust in vitro growth of patient-derived GBM cells, showing continued growth over 10 cellular division passages. Lentivirally transduced GFP reveals reliable tumor tracking both in vitro and in vivo. Transgenic mice at 6 months display reproducibly decreased pericyte and microvascular density in triplicate. Wild-type mice tolerate tumor injection up to three weeks with visible tumor growth, peritumoral hypervascularity, and no evidence of mouse neural dysfunction. With current cohorts recently implanted with tumor, we anticipate a significant decrease in tumor size with Cohen\u2019s"}
+{"text": "Correction to: BMC Genomics (2019) 20:168https://doi.org/10.1186/s12864-019-5562-zFollowing the publication of this article , the autLeptospira species. Genes encoding for outer membrane protein (loa22), flagella motor switch protein (fliY), and hemolysins B and C (tlyB and tlyC) were conserved in all 24 Leptospira strains. Genes encoding was conserved only in pathogenic Leptospira strains. Strains CUDO5 and CUDO8 contained all of the 33 virulence genesFigure The correct figure and caption is reproduced in this Correction article:The original article has been corrected."}
+{"text": "AMP cancers showed 8 down- and 1 up-regulated miRNAs (FDR p<0.05). Most enriched pathways (p<0.01) were RAS and Nerve Growth Factor signaling. PDAC and AMP display different global miRNA expression profiles and miRNA regulated networks/tumorigenesis pathways. The immune response was enriched in PDAC, suggesting the existence of immune checkpoint pathways more relevant to PDAC than AMP.Despite progress in treatment strategies, only ~24% of pancreatic ductal adenocarcinoma (PDAC) patients survive >1 year. Our goal was to elucidate deregulated pathways modulated by microRNAs (miRNAs) in PDAC and Vater ampulla (AMP) cancers. Global miRNA expression was identified in 19 PDAC, 6 AMP and 25 paired, histologically normal pancreatic tissues using the GeneChip 4.0 miRNA arrays. Computational approaches were used for miRNA target prediction/identification of miRNA-regulated pathways. Target gene expression was validated in 178 pancreatic cancer and 4 pancreatic normal tissues from The Cancer Genome Atlas (TCGA). 20 miRNAs were significantly deregulated (FC\u22652 and  Pancreatic cancer is the fourth most frequent cause of cancer death, worldwide ,2. The mThe asymptomatic nature of PDAC is often associated with late diagnosis and poor patient prognosis. This disease is characterized by very aggressive and rapid tumor growth and high incidence of distant metastasis . DespiteMolecular mechanisms underlying pancreatic oncogenesis involve both genetic and epigenetic changes . The rolPrevious studies compared global miRNA expression profiles in PDAC and AMP and showed that miRNA expression profiles are distinct between PDAC and AMP tumors \u201320.Here we sought to elucidate deregulated mechanisms modulated by miRNAs in PDAC and AMP cancers by experimental analysis followed by application of systems biology approaches. Our study shows that PDAC and AMP display different global miRNA expression profiles, which reflect distinct miRNA-regulated networks and pathways of tumorigenesis. Notably, an enrichment of immune response pathways was found in PDAC, suggesting that immune checkpoint pathways are more relevant to PDAC than AMP. The identification of miRNAs as biomarkers of innate and adaptive immune response in PDAC opens avenues for investigation of novel therapeutic strategies.This study was performed in accordance with the national and international ethical guidelines and recommendations of the Declaration of Helsinki. This study was approved by the Research Ethics Committee of the Faculty of Medicine, UNESP, Botucatu, SP, Brazil (Protocol # 4382/2012-B).Formalin-fixed, paraffin-embedded (FFPE) tissue samples  from patients undergoing surgery for resection of PDAC (N = 19) or AMP (N = 6) cancers were retrospectively collected from the Dept. of Pathology, Faculty of Medicine, UNESP, Botucatu, SP, Brazil. Primary pancreatic ductal adenocarcinoma and pancreatic carcinoma of the ampulla of Vater were obtained from patients naive of chemo or radiotherapy before surgery. Exclusion criteria were: patients diagnosed with secondary pancreatic metastasis and with unresectable disease. Patient demographic and histopathological data are shown in Formalin-fixed, paraffin embedded (FFPE) tissue sections were obtained from surgically resected tumors . Tissue sections were prepared for needle macrodissection using the stereomicroscope Leica EZ4 , according to a previously reported protocol ,22. Tisswww.mirbase.org) was assayed according to the manufacturer\u00b4s protocol. Briefly, RNA samples were first subjected to poly-A tail incorporation to 3\u00b4-end, followed by a second step of ligation reaction and biotinylation of 3\u00b4-poly A tail of RNA. Biotin-labeled RNA was hybridized to the GeneChip miRNA 4.0 array cartridge, for each sample, and detected with Avidin-Streptavidin-Phycoerythrin (PE) conjugate, which binds to biotin-labeled RNA with strong affinity. miRNA array cartridges were then placed into hybridization oven trays and trays were loaded into the hybridization oven and incubated at 48\u00b0C with 60 rpm rotation for 16 hours. Upon hybridization, each array was filled with an array holding buffer and allowed to reach room temperature before washing and staining. Wash and stain steps were performed using the appropriate fluidics script for cartridge arrays on the fluidics station. Arrays were scanned and data exported for further analysis using the Expression Console software (Affymetrix) for data summarization, normalization, and quality control.GeneChip microRNA 4.0 array  containing probes representing 2,588 miRNAs  p-values [PDAC and AMP data were analyzed independently in order to identify significantly deregulated miRNAs  in each tumor subtype compared to their corresponding normal tissues. In order to decrease the small sample size effect of the AMP sample group , miRNA analysis for the AMP sample group did not rely in the p-values  to selecOriginal, raw data are publicly available on Gene Expression Omnibus (GEO), under accession number GSE125179.http://ophid.utoronto.ca/mirDIP/) [http://mirtarbase.mbc.nctu.edu.tw/php/index.php) [Deregulated miRNAs were subjected to target prediction analysis using two different bioinformatic tools: microRNA Data Integration Portal (mirDIP/) , using adex.php) .Validation of miRNA target gene expression in external data sources (TCGA)https://cancergenome.nih.gov/). Raw RNA sequencing (RNA-Seq) data (read counts) were used to calculate differential gene expression levels in pancreatic carcinoma samples (N = 178) relative to normal pancreatic tissues (N = 4). For AMP subtype, gene expression data were not available in TCGA (date of access: November 6th 2018). We used edgeR package [Next, predicted miRNA targets were validated using external data retrieved from The Cancer Genome Atlas (TCGA) ( package  in the dvs. low purity tumors). Gene expression data were analyzed using Xena Functional Genomics Explorer tool (https://xenabrowser.net/) [https://software.broadinstitute.org/morpheus/) [In addition, expression levels of miRNA target genes were analyzed using unsupervised clustering approaches, according to neoplastic cellularity of PDAC (high purity er.net/) . Morpheurpheus/)  was usedhttps://toppgene.cchmc.org/) [http://iid.ophid.utoronto.ca/iid/Search_By_Proteins/) [ToppGene Suite (mc.org/)  was usedoteins/)  to assemoteins/) , which cStudy design, methods of data analyses and results are shown in We identified 20 significantly deregulated miRNAs (FC\u22652 and p<0.05) being 15 down-regulated and 5 up-regulated in PDAC compared to matched normal pancreatic tissues from the same patients . Interesvs. Low Cellularity tumors are shown in Our comparative analyses stratifying the TCGA pancreatic tumor dataset into high and low epithelial cellularity tumors included 128 tumors histologically confirmed as pancreatic ductal adenocarcinoma and classified as High or Low cellularity tumors. Of the 128 PDAC tumors, 76 were High and 52 Low Purity/Cellularity samples (data extracted from TCGA). Expression levels of the 86 significantly deregulated genes in High vs. normal tissues (We identified 9 miRNAs (8 under- and 1 over-expressed) as significantly differentially expressed  in AMP  tissues . Target  tissues . These 7 tissues . Of thesRecently studies have provided evidence of an immune-related component of PDAC tumors. Here, we provide novel data on the potential role of miRNAs in the regulation of immune-related gene networks including pathways of adaptive and innate immune response involved in PDAC. We validated an inverse correlation in miRNA and target gene expression in these pathways using the pancreatic cancer TCGA dataset; these data suggest a potential role of miRNAs in the regulation of immune-related genes in PDAC tumorigenesis.Of note, our study used needle macrodissected samples including tumor cells and stromal cells, an important component of the tumor microenvironment. Another study  have alsvs. low cellularity tumors) impacts the analyses and interpretation of transcriptomic data including coding and non-coding RNAs [vs. low cellularity PDAC samples corroborate the current literature, showing that PDAC tumors are very complex and gene expression levels are associated with neoplastic epithelial cellularity in this carcinoma. Of note, our unsupervised hierarchical clustering results showed higher gene expression levels in low compared to high cellularity tumors. Since low cellularity tumors may contain tumor cells as well as stromal tissue; these data are in agreement with our miRNA data, which are reflective of miRNA alterations in tumor cells and stromal cells in PDAC.Recently, it has been shown that the neoplastic cellularity of PDAC  miRNAs identified in our study directly target genes in this pathway. Specifically, members of miR-216 family  and miR-217 target CD antigens including LILRB1 and LILRB4 , CD36, Cvs. normal  consortium data. This consortium provides small RNA sequencing data on 396 human samples across 118 cell types obtained from different organs . We sear. normal . The resg cancer . In pancignaling . In concIn AMP cancers, we highlight RAS, NGF and EGFR and axon guidance signaling pathways, since identified miRNAs modulate the expression of target genes with overlapping roles in all three pathways. Altered expression of genes in these pathways is associated with deregulated expression of 9 miRNAs: over-expression of miR-4429 and under-expression of miRNAs miR-20b-3p,miR-509-5p, miR-570-3p, miR-3925-5p, miR-3941, miR-4681, miR-6766-5p, and miR-6817-5p.KRAS, with roles in axon guidance pathway [MUC4 gene in neural invasion in PDAC [Interestingly, miR-323a-3p was also reported as over-expressed in pancreatic ampullary tumors and found to participate in interaction networks, modulating gene expression including  pathway . Results pathway \u201363. NGF  pathway . Notably pathway ,66. Gene pathway . Axon gu pathway ,68. Gene pathway . The axo in PDAC . ConsideIn conclusion, our study identified miRNA changes in tumor and stromal cells of PDAC and AMP; such changes likely contribute to modulate the translational efficiency of corresponding target genes; however, we highlight that there are other mechanisms that interplay for translational regulation influencing gene expression. Indeed, translational control of gene expression occurs through a highly complex and dynamic interplay between mRNA sequences (cis-regulators) and the translational machinery, or canonical translational factors . In addiIn addition, while functional studies may lead to a deeper understanding on the role of identified miRNAs on specific pathways, the coordinated functions of multiple miRNAs and their targets into regulatory networks have yet to be elucidated in the different subtypes of pancreatic cancer.Our results suggest that miRNA-modulated pathways of the adaptive and innate immune response may represent an opportunity for improved therapeutics to benefit patients with pancreatic ductal adenocarcinoma.Our data provide a comprehensive picture of distinct pathways modulated by miRNAs in different subtypes of pancreatic tumors. Adaptive and innate immune response pathways modulated by miRNAs may be useful as potential therapeutic strategies specifically benefiting patients with PDAC.S1 FigRepresentative example of macrodissected areas: Hematoxylin and Eosin (H&E) stained section showing in (A) adjacent normal tissue; normal pancreatic ducts are shown by the arrows and (B) pancreatic ductal adenocarcinoma cells and stromal component. Magnification: 200 \u03bcm.(TIF)Click here for additional data file.S2 FigGraphical representation of miRNA target genes (Y-axis) according to significantly enriched pathways (p<0.05) (X-axis).(TIF)Click here for additional data file.S3 FigGraphical representation of miRNA target genes (Y-axis) according to significantly enriched pathways (p<0.01) (X-axis).(TIF)Click here for additional data file.S1 Table(XLSX)Click here for additional data file.S2 Table(XLSX)Click here for additional data file.S3 Table(XLSX)Click here for additional data file.S4 Table(XLSX)Click here for additional data file.S5 Table(XLSX)Click here for additional data file."}
+{"text": "Scientific Data 5:170199 doi: 10.1038/sdata.2017.199 (2018); Published 9 January 2018; Updated 31 July 2018The Data Descriptor incorrectly states that hybridization for the miRNA expression microarray analysis was performed with an Affymetrix 450 Fluidics Station. This step was performed using an Affymetrix GeneChip Hybridization Oven 645."}
+{"text": "Correction to: BMC Med (2019) 17:145https://doi.org/10.1186/s12916-019-1373The original article  containsNIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust (as shown in the affiliations of this Correction article).1) Rafael Perera-Salazar should also be affiliated to 2) The following Acknowledgement statement should take precedence over that in the original article:"}
+{"text": "PTPRS is the most commonly mutated receptor tyrosine phosphatase in colorectal cancer (CRC). PTPRS has been shown to directly affect ERK and regulate its activation and nuclear localization. Here we identify that PTPRS may play a significant role in developing adaptive resistance to MEK/ERK inhibitors (MEKi/ERKi) through SRC activation. Moreover, we demonstrate a new clinical approach to averting adaptive resistance through the use of the SRC inhibitor, dasatinib. Our data suggest the potential for dasatinib to enhance the efficacy of MEKi and ERKi by preventing adaptive resistance pathways operating through SRC. Colorectal Cancer (CRC) is one of the leading causes of cancer deaths in the USA which could be surgically cured with early detection; however, many CRC tumors are not diagnosed until late stage when cure rates are low . While 8n = 468); similar results were reported for the Dana Farber CRC database [We recently discovered that protein tyrosine phosphatase receptor S (PTPRS) was the most frequently mutated gene (~10%) in the family of protein tyrosine phosphatases in our CRC tumor collection . Reduction of SRC activity has been shown to increase epithelial appearance \u201334, and In order to test the hypothesis that SRC activity was responsible for MEKi/ERKi resistance, we treated isogenic CRC cell lines +/\u2013 PTPRS with an ERK inhibitor in the presence or absence of dasatinib, an inhibitor of SRC. Using an integrated approach to compare gene mutations with global gene expression in our 468 human CRC tumor collection, we showed that mutations in PTPRS highly correlated with an increase in a validated RAS pathway activity signature , 19. We decrease in resistance. The lack of SRC activity in cells without PTPRS was thought possibly due to increased phosphorylation of Y-530 which would negatively regulate SRC activity [The loss of PTPRS not only brought about increased ERK and AKT activity, but we were surprised to find that the CRC cells without PTPRS activity, despite the increased ERK activity, became more sensitive to ERK inhibition as was seen in activity  and explactivity  show tha\u00ae Mycoplasma qPCR Detection Kit (Cat No. MP0040A-1KT). Cells were cultured using RPMI 1640 (Gibco) supplemented with 10% FBS and 1% penicillin and streptomycin, unless otherwise specified.The parental HCT116 CRC cell line (KRASG13D/+) and the engineered HCT116-WT KRAS cell line, were obtained from Horizon Discovery (Cat.No.HD104-008). All cell lines had monthly tests for mycoplasma contamination with Sigma LookOut\u00ae CLx Imaging System was used to image all immunoblots. Antibodies were typically duplexed using rabbit antibodies for phosphorylated antibodies and mouse antibodies for total protein. Li-Cor secondary antibodies, Goat anti-Rabbit IRDye 680RD and Goat anti-Mouse IRDye 800CW, were used with the duplexed primary antibodies.Cell lysates were obtained using 1x RIPA buffer  containing 10 mM PMSF, Protease Inhibitor Cocktail (M250 Amresco), Phosphatase Inhibitor Cocktail 2 (P5726 Millipore), and Phosphatase Inhibitor Cocktail 3 (P0044 Millipore). The LI-COR OdysseyRabbit primary antibodies were used unless specified and were sourced as follows: PTPRS (goat AF3430 R&D Systems); alpha-Tubulin (mouse sc-8035 Santa Cruz). All other antibodies were obtained from Cell Signaling: phospho-Erk1/2 T202/Y204 (Cat.No.4370); phosphor-Akt S473 (mouse 4051); Akt (4691); phosphor-src Y416 (2101) and Src (mouse 2105).Two PTPRS-specific siRNAs were obtained from Qiagen: PTPRS_5 siRNA ; PTPRS_7 siRNA .Two SRC siRNA duplexes were obtained from Origene:SR321884A: GGUUGUAAAUACUUUGCAUAUUGTCSR321884B: GCAAGGUGCCAAAUUCCCCAUCAAGScrambled siRNAs from Qiagen (SI03650325) and Origene (SR30004) were used as controls. Transfections were performed at 20\u201330% cell confluency using the RNAiMAX Lipofectamine (Life Tech) according to the provided protocol using 30 nM of siRNA.The CRISPR kit for PTPRS was purchased from Origene (Cat.No.KN211163) and used according to the product protocol. Cells were transfected using Lipofectamine3000. The gRNA sequence KN211163G1, PTPRS gRNA vector 1 in pCas-Guide vector, (target sequence: CTTGTGGTCCTGCTCGTTGG) proved the most effective at knocking out (KO) PTPRS expression and was thus used to create the HCT116 and HCT116-KRAS (\u2013/+) PTPRS KO cell lines. CRISPR cells were then grown for 7 passages and selected using puromycin (Life Technologies). Numerous colonies were isolated and tested for absence of PTPRS via Western blot and mRNA analysis.HCT116 PTPRS KO Cells and control cells were treated with the ERK inhibitors SCH772984 (942183-80-4 Santa Cruz Biotechnology), VX11-E (A3931 ApexBio), VRT752271 (B1106 ApexBio); MEK inhibitors Trametinib (A3018 ApexBio) and AZD8330 (A8374 ApexBio); PI3K inhibitor LY294002 , Dasatinib (CDS023389 Sigma) and the AKT inhibitor VIII (A6730 Sigma). All treatments were for 48 hours and the noted concentrations, unless specified otherwise. Following treatments, Annexin 5 apoptosis assay or a cell cycle analysis using Brdu and propidium iodide staining were performed as described previously [t test was used to determine the statistical significance of comparison as needed. All Western blot experiments were performed in triplicate. Quantitative analysis was performed with Licor Image Studio 5.2 (Licor). Band density was determined via median analysis on the \u201call\u201d setting. Numbers from each blot were normalized by dividing phosphorylation signal by total protein; then averaging the values of all three experiments .Cell culture experiments were done in triplicates, and mean and standard deviation were calculated as indicated. Two-tailed, paired"}
+{"text": "C) into abnormal conformers (PrPSc) is critical for prion disease pathogenesis our current understanding of the underlying molecular pathophysiology is rudimentary. Exploiting an electrophysiology paradigm, herein we report that at least modestly proteinase K (PK)-resistant PrPSc (PrPres) species are acutely synaptotoxic. Brief exposure to ex vivo PrPSc from two mouse-adapted prion strains (M1000 and MU02) prepared as crude brain homogenates (cM1000 and cMU02) and cell lysates from chronically M1000-infected RK13 cells (MoRK13-Inf) caused significant impairment of hippocampal CA1 region long-term potentiation (LTP), with the LTP disruption approximating that reported during the evolution of murine prion disease. Proof of PrPSc  species as the synaptotoxic agent was demonstrated by: significant rescue of LTP following selective immuno-depletion of total PrP from cM1000 (dM1000); modestly PK-treated cM1000 (PK+M1000) retaining full synaptotoxicity; and restoration of the LTP impairment when employing reconstituted, PK-eluted, immuno-precipitated M1000 preparations (PK+IP-M1000). Additional detailed electrophysiological analyses exemplified by impairment of post-tetanic potentiation (PTP) suggest possible heightened pre-synaptic vulnerability to the acute synaptotoxicity. This dysfunction correlated with cumulative insufficiency of replenishment of the readily releasable pool (RRP) of vesicles during repeated high-frequency stimulation utilised for induction of LTP. Broadly comparable results with LTP and PTP impairment were obtained utilizing hippocampal slices from PrPC knockout (PrPo/o) mice, with cM1000 serial dilution assessments revealing similar sensitivity of PrPo/o and wild type (WT) slices. Size fractionation chromatography demonstrated that synaptotoxic PrP correlated with PK-resistant species >100kDa, consistent with multimeric PrPSc, with levels of these species >6 ng/ml appearing sufficient to induce synaptic dysfunction. Biochemical analyses of hippocampal slices manifesting acute synaptotoxicity demonstrated reduced levels of multiple key synaptic proteins, albeit with noteworthy differences in PrPo/o slices, while such changes were absent in hippocampi demonstrating rescued LTP through treatment with dM1000. Our findings offer important new mechanistic insights into the synaptic impairment underlying prion disease, enhancing prospects for development of targeted effective therapies.Although misfolding of normal prion protein (PrP C) into disease-associated conformations (PrPSc) is the critical initiating step for prion diseases. Similar to other neurodegenerative disorders, progressive failure of brain synapses is considered a primary deleterious event underpinning prion disease evolution. Our current understanding of the underlying mechanisms associated with synaptic failure is rudimentary contributing to difficulties in developing effective treatments. Herein we report the use of an electrophysiology paradigm that allowed us to demonstrate that at least modestly proteinase K (PK)-resistant PrPSc species from two mouse-adapted prion strains (M1000 and MU02) are directly synaptotoxic causing significant acute impairment of hippocampal CA1 region long-term potentiation (LTP). Of note, the LTP disruption approximated that reported in prion animal models. Additional detailed analyses provided novel pathophysiological insights suggesting possible heightened pre-synaptic vulnerability to the acute synaptotoxicity through impairment of replenishment of the readily releasable pool of neurotransmitter vesicles, while biochemical analyses demonstrated reduced levels of multiple key pre-and post-synaptic proteins. Broadly similar acute synaptic dysfunction and dose-response susceptibility were observed in slices from mice not expressing PrPC albeit with minor but noteworthy differences in electrophysiological and biochemical findings. Our study offers important new mechanistic insights into the synaptic impairment underlying prion disease, enhancing prospects for development effective therapies.Misfolding of the normal prion protein (PrP C into disease-associated conformers (herein collectively designated PrPSc), with their subsequent aggregation and accumulation, appears critical to pathogenesis although the precise neurotoxic species and how such species provoke neuronal dysfunction and loss leading to the onset of clinical illness remain unresolved. The precise composition of the infectious unit or \u201cprion\u201d also remains to be determined, although considerable evidence supports that PrPSc is the major, if not exclusive, component (the \u201cprotein only\u201d hypothesis)  and as average LTP as a percentage of baseline [right panels]) not affected by: 0.5% (w/v in aCSF) cNBH in both (B) 12-week-old ; cMU02 ; MoRK13-Inf . Scatterplot: Student\u2019s t test; I-O curves: Two-way ANOVA with repeated measures; mean \u00b1 SEM; *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001.(A) Relative to the appropriate negative controls, there was a uniform and similar impairment of LTP (displayed as percentage change) caused by: 0.5% (w/v in aCSF) cM1000 (in both 12-week-old  and as average LTP as a percentage of baseline [right panels]) not affected by (B) 0.5% (w/v in aCSF) PrP immuno-depleted NBH (dNBH) in 12-week-old hippocampal slices (related to ex vivo PrP preparation detected by coomassie stain and western blotting probed with 8H4 antibody. (I) Quantification of the total protein in each ex vivo PrP preparation. Relative to the total protein level in 0.5% (w/v) cM1000 without PK treatment, modest PK treatment (5\u03bcg/mL PK) of the 0.5% (w/v) cM1000 and IP-M1000 significantly reduced the total protein level to only 10% and 20% respectively, while containing substantial level of modestly PK-resistant PrPSc (H column ii & iv). Similarly, total proteins in 0.5% (w/v) cNBH and IP-NBH were significantly reduced to 20% and 30% by modest PK treatment compared with those in cNBH before PK treatment. However, no PrP detected by 8H4 antibody in modestly PK-treated NBH preparations (H column vi & viii). Densitometry analysis was performed as described in  Scatterplot: Student\u2019s t test; I-O curves: Two-way ANOVA with repeated measures; mean \u00b1 SEM; *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001.(A) Relative to the appropriate negative controls, there was a uniform and similar impairment of LTP (displayed as percentage change) caused by 0.5%  PK-treated cM1000 (PK+M1000) Click here for additional data file.S4 FigSc prevented reduction in the PPF ratio after LTP except dM1000, where the PPF ratio was significantly rescued , thereby suggesting that PTP appears more sensitive to the acute synaptotoxic effects of PrPSc than LTP  Relative to aCSF-only technical controls where the paired pulse facilitation (PPF) ratio after LTP induction (PPF2) was significantly reduced compared with the PPF before LTP (PPF1), similar normal PPF results were obtained in the cNBH, MoRK13Un, dNBH, PK treated NBH, and PK-eluted IP-NBH controls (related to (TIF)Click here for additional data file.S5 FigSc adverse synaptic effects on LTP (displayed as percentage of baseline fEPSP amplitude over time (A) or and as average LTP as a percentage of baseline (B), PTP (C) or PPF ratios after LTP induction  in 12-week-old PrPo/o mice hippocampal slices relative to aCSF-only technical controls. (E & F) In comparison to cNBH, cM1000 impaired both LTP (E) and PTP (F) in 12-week old PrPo/o hippocampal slices (displayed as percentage change), with the changes comparable in degree to the disruption of LTP and PTP observed with 12-week-old WT hippocampal slices  Analogous to what was observed in WT hippocampal slices, cNBH did not harbour non-PrP(TIF)Click here for additional data file.S6 FigRelative to hippocampal slices from 12-week old wild type mice treated with aCSF, (A) slices treated with 1% (w/v) cNBH for five minutes following an eight to 10-minute stable baseline exhibited a disrupted baseline that did not recover back to normal baseline before the trains of high frequency stimulation (HFS), associated with disruption of the long-term potentiation (LTP). (B) However, hippocampal slices treated with 0.5% (w/v) cNBH did not affect the baseline and LTP.(TIF)Click here for additional data file."}
+{"text": "Furthermore, inferior wall LD was the primary source of prognostic information in GLD since only inferior LD remained significant when both measures were included in the same model: GLD ; inferior LD . Of all walls, only inferior wall LD remained as an independent predictor after multivariate adjustment. DISCUSSION/SIGNIFICANCE OF IMPACT: GLD provides independent prognostic information in ACS patients over and beyond all conventional echocardiographic measures. Regional inferior LD was the primary source of prognostic information gained from GLD. GLD proved to be a better predictor of cardiovascular events than conventional echocardiographic measures. This could lead to better risk stratification in the clinical setting and open up for earlier intervention in high-risk individuals.OBJECTIVES/SPECIFIC AIMS: To investigate the prognostic value of left ventricular mitral annular longitudinal displacement (LD) measured with color tissue Doppler imaging (TDI) in a large population suffering from acute coronary syndrome (ACS). METHODS/STUDY POPULATION: In total, 501 ACS patients underwent an echocardiography within 9 days after a percutaneous coronary intervention. Regional LD was obtained from the 6 mitral annular regions with TDI and GLD was calculated as an average. RESULTS/ANTICIPATED RESULTS: During a median follow-up time of 4.4 years 46 ACS patients suffered CVD. Mean value of GLD in the population was 8.11mm (\u00b12.4). GLD and LD obtained from the inferior wall remained significant independent predictors after multivariate adjustment for clinical parameters, GLD (HR: 1.43, 95% CI: 1.12\u20131.82,"}
+{"text": "We evaluated whether 90 days of nutritional supplementation  with Chlorella vulgaris (CV) and Fucus sp extracts in conjunction with aminosulphurate  supplementation could detox heavy metal levels in patients with long-term titanium dental implants  and/or amalgam fillings  compared to baseline levels  and untreated controls  of similar age . In this study, we compared levels of several heavy metals/oligoelements in these patients after 90 days (n = 16) of nutritional supplementation with CV and aminozuphrates extract with their own baseline levels  and untreated controls (n = 21); 16 patients averaging 44 age years old with long-term dental amalgams and titanium implants for at least 10 years (average: 12 years) were recruited, as well as 21 non-supplemented controls  of similar age. The following heavy metals were quantified in hair samples as index of chronic heavy metal exposure before and after 90 days supplementation using inductively coupled plasma-mass spectrometry (ICP-MS) and expressed as \u03bcg/g of hair . We also measured several oligoelements . The algae and nutraceutical supplementation during 90 consecutive days decreased Hg++, Ag, Sn, and Pb at 90 days as compared to baseline levels. The mercury levels at 90 days decreased as compared with the untreated controls. The supplementation contributed to reducing heavy metal levels. There were increased lithium (Li) and germanium (Ge) levels after supplementation in patients with long-term dental titanium implants and amalgams. They also (d90) increased manganesum (Mn++), phosphorum (P), and iron (Fe++) levels as compared with their own basal levels (d0) and the untreated controls. Finally, decreased SuperOxide Dismutase-1 (SOD-1) activity  was observed after 90 days of supplementation as compared with basal levels , suggesting antioxidant effects. Conversely, we detected increased SOD-1 activity after 90 days as compared with untreated controls. This SOD-1 regulation could induce antioxidant effects in these patients. The long-term treatment with algae extract and aminosulphurates for 90 consecutive days decreased certain heavy metal levels  as compared with basal levels. However, Hg++ and Sn reductions were observed after 90 days as compared with untreated controls . The dental amalgam restoration using activated nasal filters in conjunction with long-term nutritional supplementation enhanced heavy metals removal. Finally, the long-term supplementation with these algae and aminoazuphrates was safe and non-toxic in patients. These supplements prevented certain deficits in oligoelements without affecting their Na+/K+ ratios after long-term nutraceutical supplementation.The toxicity of heavy metals such as Hg Controls without dental materials did not receive these treatments.All supplemented patients received nutritional treatment by oral intake during 90 consecutive days with the following formulations: GREEN-FLOR ; .All ICP-MS heavy metal or oligoelements data were evaluated as percentiles  for non-parametric data  and expressed as \u03bcg/g of hair in all cases (except vadanium). The ANOVA  evaluated differences for vanadium levels, which were expressed as mean values \u00b1 standard error media (S.E.M). S.E.M was the variance divided by root square, and n = 21, non-supplemented). These untreated controls did not receive supplements and they did not carry dental materials. Saliva samples were taken at these study times for SOD-1 determination.These heavy metal/oligoelements were compared after 90 days of nutritional supplementation (d90) with their own basal levels (d0: before any supplementation) as well as untreated controls without dental materials  and the absence of a placebo group. However, we included untreated controls . This placebo group in patients with long-term dental implants and amalgam fillings could be not ethically justifiable since it is not possible to keep dental amalgam fillings, which release mercury in patients . The impn = 21) and the baseline patients   , were exDSM IV)] . All patients took the following nutritional supplementation during 90 consecutive days : GREEN-FLOR (2-0-2), ERGYTAURINE (1-0-1), and ERGYLIXIR formulation  following the patterns of their antioxidants properties see . The con++ and Zn++ levels were in the minority. Hair samples close to the scalp were taken from all subjects  to measure a plethora of heavy metals/oligoelements by ICP-MS . Doctor\u2019s Data is a pioneer laboratory specializing in the toxicology of heavy metals with over 35 years of experience, and they provide analytical tests for healthcare practitioners. ICP-MS values for heavy metals were expressed in \u03bcg/g of hair. In the weight of the dental amalgam fillings, mercury (Hg) was 50%, and silver (Ag) was 41%, Sn was approximately 5\u20138%, and CuThe saliva SOD-1 activity was measured following a modified protocol by  Caba\u00f1a-Mn = 16, d90: n = 16) and controls (control: n = 21). The Levene test identified whether or not there was homogeneity of variance depending on its significance. Correlations between variables were performed by Spearman\u2019s rank correlation. Differences were considered statistically significant if p < 0.05 and highly significant when p < 0.01.All data were analyzed by SPSS software (v17.0)  and Sigma Plot . Mean 25%, 75%, and median values (\u03bcg/g of hair) were estimated for heavy metals/oligoelements in the hair samples. Non-parametric tests were applied in cases without homogeneity of variance . The Bonferroni tests were applied for multiple comparisons when there was homogeneity of variance . All results were expressed as percentiles 25%, 75%, and median (\u03bcg/g of hair) according to Kruskal Wallis values  and Mann Whitney (MW) and Dunn\u2019s post hoc test in the case of non-parametric data between (d0: p \u2264 0.001) for SOD-1 activity . The parametric Dunn\u2019s non-analysis revealed decreased SOD-1 activity after 90 days of supplementation (d90) compared to their basal levels ; Conversely, increased activity SOD-1 activity was detected before any supplementation as compared with untreated controls  as well as titanium alloys (Ti-6Al-4V) in patients with long-term dental titanium implants and amalgams fillings after 90 days of nutritional supplementation as compared with their own basal levels  as well with non-supplemented controls . The Kruskal Wallis and Mann Whitney post hoc analyses revealed mercury (Hg++) and tin (Sn) reductions after 90 days of supplementation as compared with their own basal levels (d0) without reaching a significant effect in Zn++, Co, Ni, or Cu++ levels  without reaching a significant effect as compared to untreated the controls.p < 0.05); increased d90 vanadium (V) levels were observed as compared with basal levels . There were no effects in Ti or Co levels by treatment  levels decreased after 90 days of supplementation (d90) as compared with untreated controls (++), chromium (Cr), vanadium (V), phosphorum (P), and lithium levels (Li) after 90 days of supplementation (day 90) as compared with untreated controls . In addition, after 90 days , their selenium (Se) levels decreased in comparison to their basal levels ; however, they were higher than the control values (p < 0.05). These supplements could promote antihypertensive effects by rising certain oligoelements. Finally, there were no effects in other oligoelements  or for Be, Bi, Tl, To .Patients with long-term titanium implants and amalgam fillings increased germanium (Ge), manganesum  levels after 90 days of supplementation (day 90) as compared with baseline levels (d0: before any supplementation); the aluminium (Al) levels were reduced after 90 days in comparison to untreated controls see .p > 0.05, n.s) and oligoelements by treatment  after 90 days of supplementation as compared with their baseline (d0) and control levels.There was a lack of effect in several heavy metals  compared to their respective basal levels ; However, these Se/Hg++, Se/Ag, and Mo/Hg++, and Na+/K+ ratios decreased before any treatment (d0) as compared with non-supplemented patients  ratio and Se levels after 90 days of supplementation  as well as with Mo/Hg++ (d90) ratio after 90 days . Two outlier values were excluded for statistical analysis herein  and long-term algae and aminoazuphrates supplementation. The exposure derived from amalgam fillings exceeds that from food, air, or beverages. Chronic nutritional supplementation contributes to preventing mercury release peaks caused by dental amalgam restoration . A study of 12 patients demonstrated that the long-term presence of dental amalgam (at least five years) did not result in any remarkable changes in mercury or tin levels in the pulp tissue after comparing 12 restored amalgams and 12 non-restored patients. However, elevated blood mercury levels were observed even five years after the placement of the restoration . These dChlorella and Fucus algae extract supplementation in conjunction with aminosulphurates lowered certain heavy metal levels in patients with long-term titanium implants and dental amalgams restoration using activated carbon active nasal filter as well as the nutraceuticals. Preclinical findings suggest a role of Chlorella vulgaris as a heavy chelator in preventing toxicity of certain xenobiotics and accelerating dioxin excretion in rats [Chlorella sp [We determined that chronic nutritional  in rats ,35. The rella sp ,37,38. HChlorella sp promoted detoxification of heterocyclic amines  in six young Korean adults [++, Sn, and Pb accumulations were strongly reduced after 90 days of consecutive nutritional supplementation as compared with basal levels (before any supplementation). Interestingly, mercury and Sn levels reductions were observed after 90 days as compared with untreated controls .Supplementation with n adults . This ra++ levels could suggest enhanced antioxidant responses after 90 days of supplementation. In fact, Ala16Val MnSOD-2 polymorphism has been described in cells exposed to methylmercury [Although it was not possible to elucidate the exact nutraceutical involved in SOD-1 activation here, we must consider that SOD-1 activation decreased after 90 days as compared with their basal levels . Conversely, higher SOD-1 activity was observed after long-term supplementation (day 90) compared with untreated controls; this suggests algae and aminoazuphates treatment may activate SOD-1. In addition, increased Mnlmercury . We havelmercury ,42. The Cinara scolymus (artichoke) [Raphanus niger [Taraxacum officinale [Arctium lappa (dandelion root) [Vaccinium macrocarpo [Solidago virgaurea  [Rosmarinus officinallis [Scolymus hispanicus [Sambucus nigra (elderberry with antocianines) [Allium sativa in the ERGYTAURINE formulation) may enhance heavy metal removal by inducing antioxidant activities [Sambucus nigra (elderberry) contains antocyanines that supply 87% of the daily vitamin C levels necessary for humans [++, and Mg++ (ERGYTAURINE formulation) [Heavy metals detox requires (i) a healthy gut microbiome state , (ii) thtichoke) , Raphanuus niger , Taraxacficinale , Arctiumon root) , Vaccinicrocarpo , Solidagafzelin) , Rosmaricinallis , Scolymuspanicus , and Samianines) . In additivities ,55,56. Ativities . In addir humans . Vitaminulation)  are nece+/K+ ratio did not differ after 90 days as compared with their basal levels (before any supplementation), we can confirm that chronic algae and aminoazuphrates supplementation are safe and non-toxic for humans. The increased Se/Hg++ ratios suggest enhanced detoxification after 90 days compared to their basal levels (before any supplementation) as well as untreated controls. Surprisingly, a toxic effect has been demonstrated in autistic children who had elevated hair selenium levels [+/K+ and Se/Pb ratios could prevent mercury accumulation at 90 consecutive days of supplementation. In fact, antagonistic interaction between selenomethionine enantiomers and methylmercury toxicity was described with Chlorella sorokiniana [Chlorella vulgaris is largely influenced by amino acids, cysteine being the most effective in promoting the detoxification of mercury (Hg2+)\u2212 in Chlorella sp exposed to this metal [2) reduced MeHg cytotoxicity in Hepatic HepG2 cells by inducing MeHg-glutathione (GSH) and also formed MeHg-cysteine (Cys) complex in vitro [Parachlorella beijerinckii-fed mice; this continuous BP intake (10%) accelerated MeHg excretion and subsequently decreased tissue mercury accumulation by inducing the GSH metabolism [Because Se levels decreased after 90 days of supplementation, we cannot exclude the possibility that selenomercurials reflect the Se-heavy metal complex formation in order to prevent mercury toxicity  in patients with long-term dental amalgams and titanium alloys. As the Nam levels . These lokiniana . Mercuryis metal . The amiis metal  and alsois metal . This inin vitro . These itabolism . 2+ and Cd2+ was detected using a fixed bed column analysis with immobilized Chlorella algae biomass [Chlorella sp supplementation, 69% at eight days, and 77% at 12 days of treatment [pneumonitis-induced [Chlorella algae exposed to U [Other metals such as Pb, Cd, and U that are associated with occupational exposure were significantly decreased after three consecutive months of supplementation compared with their basal levels (before any supplementation) without affecting the untreated controls . The biosorption of Pb biomass . Pb levereatment . Althoug-induced , the lowsed to U ,69,70.Fucus spiralis or Fucus vesiculosus in GREEN-FLOR formulation) may enhance heavy metal removal in patients with long-term dental fillings and titanium alloys. In fact, the marine algae Ulva lactuca and Fucus vesiculosus can sequester Cd and Cu++ [++ and Cd levels here agreed with the enhanced Hg++, Cd++, and Pb removal by Fucus from contaminated salt waters exposed to heavy metals for seven days [Fucus sp algae is also traditionally used to prevent obesity or gastrointestinal diseases. As Fucus vesiculosus extracts reduced the blood glucose peak in mice fed with a normal diet [Spirulina platensis plus Misola extract treatment have a better hematocrite that those taking Misola alone [2+ ratios have been described in patients with long-term dental titanium implants and dental amalgams [Chlorella or Fucus vesiculosus treatment contribute to the removal of heavy metals in patients with long-term dental amalgam fillings and titanium implants. The absence of placebo, the non-RCT , the size sample (pilot study), as well as the Caucasian population (Spaniards) are limitations in this study. These polyphenols from Azorean brown algae . In addition, increased Mn++, Li, Ge, Cr and lower U levels, and decreased Se levels were observed after 90 days of supplementation as compared to their basal levels (before any supplementation). These findings suggest that these nutraceuticals promote beneficial effects in patients. The safety of long-term algae and aminoazuphrates supplementation were confirmed by the lack of effect in Ka+/K+ and Se/Pb ratios after 90 days compared to their basal levels (before any supplementation) and untreated controls. The SOD-1 activity could explain antioxidant and enhanced detoxification of certain heavy metals by nutritional supplementation in the present study.The aminosulphurates and"}
+{"text": "Right-sided colon cancer (RCC) has worse prognosis compared to left-sided colon cancer (LCC) and rectal cancer. The reason for this difference in outcomes is not well understood. We performed comparative somatic and proteomic analyses of RCC, LCC and rectal cancers to understand the unique molecular features of each tumor sub-types. Utilizing a novel in silico clonal evolution algorithm, we identified common tumor-initiating events involving APC, KRAS and TP53 genes in RCC, LCC and rectal cancers. However, the individual role-played by each event, their order in tumor development and selection of downstream somatic alterations were distinct in all three anatomical locations. Some similarities were noted between LCC and rectal cancer. Hotspot mutation analysis identified a nonsense mutation, APC R1450* specific to RCC. In addition, we discovered new significantly mutated genes at each tumor location, Further in silico proteomic analysis, developed by our group, found distinct central or hub proteins with unique interactomes among each location. Our study revealed significant differences between RCC, LCC and rectal cancers not only at somatic but also at proteomic level that may have therapeutic relevance in these highly complex and heterogeneous tumors.The online version of this article (10.1186/s12943-018-0923-9) contains supplementary material, which is available to authorized users. Often grouped as one disease, right-sided colon cancer  and left-sided colon cancer  represent clinically distinct entities with significant differences in their prognosis and treatment outcomes , 2. TherUnderstanding the mutational timing and evolutionary trajectory of tumors is key to investigate the molecular underpinnings of cancer development and progression. Thus, we applied the PiCnIc (Pipeline for Cancer Inference) algorithm to our data to study ensemble-level cancer progression models and predict the evolutionary mutational trajectories between RCC, LCC and rectal cancers in the TCGA cohort . Similarly, APC somatic mutations \u2018selected\u2019 for BRCA2 mutations and TCF7L2 somatic mutations or deletions, but this association also did not reach statistical significance .In LCC , significant differences were also noted between these two sites. Taken altogether, our results show non-adherence to the established Vogelstein linear progression model of colorectal cancer progression from normal mucosa to adenoma to carcinoma . Furtherp\u2009<\u20090.001, Fig.\u00a0p\u2009=\u20090.35). APC R1450* mutations are mutually exclusive from \u03b2-catenin destruction complex genes suggesting that they may be early events in right-sided colon cancer tumorigenesis  data, we examined RCC, LCC and rectal cancers by proteomic cancer co-expression subnetworks using association estimators methodology previously described by our group  CASP8 (apoptosis) PCNA (DNA repair) NRAS (RTK-RAS pathway) PEA15  DVL3 (cell proliferation and ATM-dependent DNA damage response) and PDPK1 (growth regulation) Additional file 2:Inclusion and exclusion criteria for somatic mutation analysis. MSI-H, POLE mutation samples, rectosigmoid and transverse colon cancers were excluded\u00a0 for analysis(highlighted green). (TIF 666 kb)Additional file 3:Methods section. (DOCX 52.9 kb)Additional file 4:Tables S1-S3.\u00a0PicNiC statistics (bic and aic) for RCC, LCC and rectal cancers. (XLSX 43 kb)Additional file 5:Somatic mutation analysis \u00a0for RCC, LCC and rectal cancers. (DOCX 433 kb)Additional file 6:Table S4. Proteomics pathway and gene level analysis results. (XLSX 47 kb)"}
+{"text": "AbstractOver three years (2013-2015), we sampled bees using nets and bowl traps on four diversified vegetable farms in Gallatin County, Montana, USA, as part of a study evaluating the use of wildflower strips for supporting wild bees and crop pollination services on farmlands . We docuLasioglossum  clematisellum (Cockerell 1904) with previously published records from New Mexico, Arizona, California and Utah and Melissodes (Eumelissodes) niveus Robertson 1895 which was reported to range from New York to Minnesota and Kansas, south to North Carolina, Alabama and Mississippi.We provide a species list of wild bees associated with diversified farmlands in Montana and increase the number of published bee species records in the state from 374 to at least 399. The list includes new distributional records for 25 wild bee species, including two species that represent considerable expansions of their known ranges,  Native bees are important pollinators of wild and cultivated plants in natural habitats and agricultural systems e.g. . In the 2) and diverse ecosystems, many of which are difficult to access, suggest there is much to learn about the wild bee fauna in this region.Montana\u2019s bee fauna is one of the least-studied amongst US states but see ; of the We report a checklist of bee species from a three-year study surveying the bee community on diversified vegetable farms in south-western Montana. This is the second study  in Gallatin County , tomatoes (Solanumlysopersicum L.), cucumbers (Cucumissativus L.) and strawberries (Fragariaxananassa Duchesne), marketed locally through Community Supported Agriculture (CSA) programmes, farmers\u2019 markets, food co-ops and restaurants; two of the farms were certified organic and two followed organic or sustainable practices. Elevations of the farms ranged from 1350-1511 m above sea level. The mean annual precipitation in the area is 469 mm, the mean annual daily high temperature is 12.89\u00b0C and the mean annual low temperature is -0.44\u00b0C  DC., Gaillardiaaristata Pursh, Geraniumviscosissimum Fisch. & C.A. Mey. Ex C.A. Mey., Helianthusmaximiliani Schrad., Heterothecavillosa (Pursh) Shinners, Monardafistulosa L., Penstemonconfertus Douglas ex Lindl. and Phaceliahastata Douglas ex Lehm.) during weekly timed observations in 2014 and 2015; 2) crops  during timed observations every other week in 2013 or weekly in 2014 and 2015; and 3) other prolific bloomers, which included primarily agricultural weeds  Scop.), during timed observations once or twice a month, depending on the amount of surrounding vegetation and time availability. We collected for a total of ca. 23 hours in 2013, 104 hours in 2014 and 85 hours in 2015. In all three years, the same experienced netter (15 years) was paired with a less-experienced netter (\u22641 year) for bee collections with both contributing equal amounts of time to collecting; in 2015 the same netter from 2014 assisted with bee collections. Bees were freeze-killed, pinned, and labelled. We also collected bees weekly using yellow, 350-ml Solo bowls filled with soapy water. Six bowls were deployed approximately 6 m apart along each of four, 33-m linear transects (24 bowls per farm) located at different distances from the wildflower strips and left out for approximately six hours during the height of bee activity. Samples were collected into 70% EtOH and later removed from the alcohol, washed, blow-dried, pinned and labelled. We used EstimateS  the established wildflower strips (stimateS  to generSpecies IdentificationWe identified bees to the lowest taxonomic level possible using published keys Table  followinaff. (\u2018has affinity with\u2019) are also treated as morphospecies.For genera where no taxonomic literature was available for species-level identifications, we grouped bees that appeared morphologically distinct into morphospecies. We assigned each morphospecies a unique number and the letter \u201cF\u201d for females and \u201cM\u201d for males. However, because we could not reliably associate male and female morphospecies as a single \u201cspecies\u201d and to avoid inflating species numbers, we included only female morphospecies in this checklist. Species names with Agapostemonangelicus Cockerell and Agapostemontexanus Cresson are indistinguishable from one another (Hylaeusmesillae (Cockerell) and Hylaeusrudbeckiae (Cockerell and Casad) and they have been included with the males for species counts. For the Chao1 analysis, we have distributed the numbers of females of angelicus/texanusA.  and mesillae/rudbeckiaeH.  according to the proportions of confirmed males of each species for each of the two genera.As females of  another , they haSphecodes were only identified to genus. Similarly, Lasioglossum of the subgenus Evylaeus were identified only to subgenus. Due to time and resource constraints, a randomly-chosen subsample of 66 of the 4,173 Lasioglossum  collected in this study were identified to species.Due to a paucity of regional keys and an inability to discern any distinctive characters amongst individuals, except for one morphospecies, bees in the genus Voucher specimens will be deposited in the Montana Entomology Collection (MTEC) at Montana State University, Bozeman, MT USA.RangeHymenoptera in America north of Mexico Table Viereck & Cockerell 1914Table Cockerell 1897Table Robertson 1891Table Smith 1853Table Cockerell 1922Table Cockerell 1896Table Viereck 1904Table Robertson 1895New species record for Montana ((Viereck 1904)Table Smith 1879Table Cockerell 1902Table Cockerell 1904Table Robertson 1895Table Smith 1879Table Cockerell 1906Table Table Table Table Cockerell 1899New species record for Montana (Cresson 1878Table Smith 1853Table Cockerell 1897New species record for Montana : Site 1.(Cresson 1878)Table Table Cockerell 1896New species record for Montana : Site 1.Cockerell 1896Table Cockerell 1896New species record for Montana (Timberlake 1956Table (Cockerell 1896)Table (Cockerell 1922)New species record for Montana : Site 1.(Crawford 1903)New species record for Montana : Site 1.Cresson 1869Table Kirby 1837Table Cresson 1878Table Linnaeus 1758Non-native to North America.Table Cresson 1874Table Greene 1858Table (De Geer 1773)Table Cresson 1863Table (Smith 1861)Table Cresson 1878Table Cresson 1864Table Cresson 1863Table Greene 1860Table Cresson 1878Table Kirby 1837Table Cresson 1878Table (Fabricius 1798)Table (Cresson 1878)Table Cresson 1878Table Cockerell 1924New species record for Montana : Site 3.Cresson 1878Table Cresson 1878Table Robertson 1905Table Cockerell 1906Table Cresson 1868Table Cockerell 1905Table Robertson 1895New species record for Montana : Site 1.Cockerell 1905Table Cockerell 1925New species record for Montana : Site 1.Cresson 1878New species record for Montana ((Cresson 1878)Table Table Viereck 1905Table Table Table Bidentate; Table Unidentate; Table Unidentate; Table Bidentate; Table Bidentate; Table Bidentate; Table Unidentate; Table Unidentate; Table Unidentate; Table Unidentate; Table Unidentate; Table Provancher 1895Table Cockerell 1897Table Cockerell 1901Table Cockerell 1906Table Cockerell 1898Table Swenk 1904Table Cockerell 1898Table Timberlake 1943Table Titus 1900Table Cockerell 1906Table (Smith 1853)Table (Linnaeus 1758)Table (Metz 1911)Table (Morawitz 1871)Non-native to North America.Table (Cockerell 1896)Table (Cockerell and Casad 1895)Table (Cresson 1869)Table (Cockerell 1896)Table (Cockerell 1896)Table (Smith 1853)New species record for Montana (Say 1837Table (Smith 1853)Table Cockerell 1924Table Crawford 1901Table Cresson 1872Table (Fabricius 1775)Table Say 1837Table (Christ 1791)Table Smith 1853Table Cockerell 1895Table (Sandhouse 1924)Table (Cockerell 1904)New species record for Montana : Site 1.(Robertson 1890)New species record for Montana : Site 4.(Smith 1853)New species record for Montana . The cloGibbs 2010Table (Crawford 1906)New species record for Montana : Site 2.(Crawford 1902)Table (Cockerell 1895)Table (Ellis 1913)Table (Lovell 1905)New species record for Montana : Site 3.(Smith 1853)Table Table Table Table Table (Crawford 1907)New species record for Montana : Site 4.McGinley 1986Table (Cockerell 1895)Table (Crawford 1902)Table (Smith 1848)Table (Cresson 1872)Table Table Table (Cresson 1878)New species record for Montana ((Cresson 1878)Table Bohart 1948Table Cresson 1878Table Cockerell 1907Table Schwarz 1940New species record for Montana : Site 3.Swenk 1914Table (Cockerell 1911)Table Table Cresson 1864Table Cresson 1864Table Parker & Griswold 2013New species record for Montana : Site 3.Cockerell 1898Table Cresson 1878New species record for Montana : Site 3.Table Cresson 1864Table Smith 1854Table Cresson 1878Table Say 1837Table Smith 1853Table Cockerell 1902Table (Robertson 1903)Table Spinola 1808Non-native to North America.Table (Fabricius 1787)Non-native to North America.Table Say 1837Table Thomson 1872Table Cresson 1878Table Cresson 1878Table Cockerell 1908Table Cresson 1879Table Say 1837Table Smith 1853Table Say 1823Table Smith 1853Table Cockerell 1898Table (Say 1837)Table Cresson 1864Table Michener 1938Table (Cresson 1872)Table (Cresson 1864)Table (Cockerell 1910)Table (Cockerell 1906)Table (Cresson 1864)Table (Cresson 1864)Table (Provancher 1888)New species record for Montana . The clo(Nylander 1848)Table Cresson 1878Table Cockerell 1900Table Cresson 1878Table Sandhouse 1924Table Cockerell 1907Table Cockerell 1906Table Cockerell 1897Table Cresson 1864Table Cockerell 1897Table Cockerell 1907Table Cockerell 1897Table Acanthosmioides Ashmead , we collected 12,203 bees representing 202 species and morphospecies from 32 genera and five families; the list includes wild native, wild non-native and managed non-native bee species . For example, a checklist of bees recently published reported 34 new Montana state records at a site ca. 260 km from ours . We highlight two bee species on this checklist, and Utah ; unpublisissippi . Our finApismellifera, colonies were located at one of our sites, as well as nearby sites and were captured in bowl traps and observed visiting our experimental crop strips and wildflower strips. We also captured alfalfa leafcutting bees, Megachilerotundata, in bowl traps and with nets from two non-native plant species, Lotuscorniculatus L. and Melilotusofficinalis (L.) Lam. Megachilerotundata are managed for alfalfa (Medicagosativa L.) seed production  of both intentionally and accidentally introduced non-natives on other bee species  and plants  require further study  were classified only to the generic or subgeneric level. In addition, only a fraction of the Lasioglossumin thesubgenusDialictus, which accounted for about 25% of the specimens collected in our study, were identified to species. Bees in the subgenusDialictus are very abundant in studies using bowl traps  documented in each of two studies conducted in montane wildland habitats in Montana . HoweverIn contrast, when we compared our study to another conducted in a highly-simplified, small grains-wheat farming system in north central (Chouteau County) Montana (i.e. the drylands of the Northern Great Plains), we found 73% of bee species were unique to our study compared to those reported by Supplementary material 1Supplementary Table 1Data type: weather dataFile: oo_230944.docxC. M. Delphia, T. Griswold, E. G. Reese, K. M. O'Neill, L. A. BurkleSupplementary material 2Supplementary Table 2Data type: occurenceFile: oo_230945.xlsxC. M. Delphia, T. Griswold, E. G. Reese, K. M. O'Neill, L. A. BurkleSupplementary material 3Supplementary Table 3Data type: checklistFile: oo_253349.xlsC. M. Delphia, T. Griswold, E. G. Reese, K. M. O'Neill, L. A. BurkleSupplementary material 4Supplementary Table 4Data type: checklistFile: oo_253350.xlsxC. M. Delphia, T. Griswold, E. G. Reese, K. M. O'Neill, L. A. BurkleSupplementary material 5Supplementary Table 5Data type: occurenceFile: oo_247377.xlsxC. M. Delphia, T. Griswold, E. G. Reese, K. M. O'Neill, L. A. BurkleSupplementary material 6Supplementary Table 6Data type: speciesBrief description: Raw data for Chao1 analysis.File: oo_247378.xlsxC. M. Delphia, T. Griswold, E. G. Reese, K. M. O'Neill, L. A. Burkle"}
+{"text": "Information regarding prokaryotic microbiota associated with anaerobic bulking is limited. Here, we provide 16S rRNA gene-based prokaryotic diversity profiles for anaerobic bulking and healthy granular sludge in a mesophilic expanded granular sludge bed (EGSB) reactor. These data were tabulated at the phylum level based on high-quality reads. Information regarding prokaryotic microbiota associated with anaerobic bulking is limited. Here, we provide 16S rRNA gene-based prokaryotic diversity profiles for anaerobic bulking and healthy granular sludge in a mesophilic expanded granular sludge bed (EGSB) reactor. These data were tabulated at the phylum level based on high-quality reads. Upflow anaerobic sludge blanket (UASB) and expanded granular sludge bed (EGSB) reactors are core anaerobic wastewater treatment reactors for medium- and high-strength organic wastewater . Healthy2\u20133)  and a 515F/806R primer set  were collected from a sampling port located 2\u2009m from the EGSB reactor bottom  . The com3) . Most ofimer set . High-quimer set . Merged imer set . Operatiimer set  and the imer set . The repEuryarchaeota , Bacteroidetes , Chloroflexi , Epsilonbacteraeota , Firmicutes , Proteobacteria , and Spirochaetes   belonged to to 2.6%) . These dDRP005108 and SRA run accession numbers DRR180014 to DRR180032.The 16S rRNA gene amplicon data set was deposited in the DDBJ Sequence Read Archive (SRA) under accession number"}
+{"text": "While preemptive therapy with ganciclovir (GCV) for cytomegalovirus (CMV) infection is used following allogeneic hematopoietic stem-cell transplantation (HSCT), risk factors for CMV infection in children undergoing HSCT are poorly understood.5 leukocytes during the antigenemia assay era and >1000\u200acopies/mL in the polymerase chain reaction era. Among 290 at-risk patients, 54 (18.6%) patients had primary CMV infection or CMV reactivation occurring at a median of 76 days  following HSCT. CMV reactivation occurred in 28.2% (44/156) of CMV-seropositive transplant recipients at a median of 26 days posttransplant.We studied CMV reactivation following allogeneic HSCT by retrospectively analyzing pediatric patients who received allogeneic HSCT and preemptive GCV therapy between 1998 and 2016. The level of viremia requiring preemptive GCV therapy was >1 CMV antigen-positive cells per 5\u200a\u00d7\u200a10Univariate and multivariate analyses revealed statistically significant relationships between CMV infection and grade III\u2013IV acute graft-vs-host disease, seronegative donor/seropositive recipient combination, and unrelated/mismatched donors. The remaining demographic factors were not predictive of CMV infection.The seronegative donor/seropositive recipient combination for HSCT was associated with an incomplete response to antiviral therapy. Human leukocyte antigen identical donors were the best choice for patients undergoing allogeneic HSCT to reduce the incidence of CMV disease and mortality. Prophylaxis and preemptive therapy are used to prevent CMV disease in patients undergoing HSCT. Although preemptive therapy is the most commonly used approach, some clinicians favor prophylactic therapy for high-risk patients such as CMV-negative donor CMV-positive recipient serostatus, cord blood products, unrelated or mismatched donor. cutoff values for the number of CMV antigen-positive cells required to initiate ganciclovir (GCV) therapy have not been clarified. Current strategies for mitigating the effect of CMV infection on outcomes include weekly measurement of CMV antigenemia or viral loads in peripheral blood through posttransplant day 100 and initiation of acyclovir prophylaxis in the peritransplant period in patients at risk for CMV infection.While the CMV antigenemia assay remains the gold standard,Because of the inconclusive results and weaknesses of previous studies as well as potential risks associated with early and long-term use of GCV in this high-risk patient population, we investigated risk factors contributing to treatment failure in pediatric patients at high risk for CMV reactivation.22.1We retrospectively reviewed the computerized database of Chang Gung Children's Hospital for all patients aged 0 to 20 years who underwent allogeneic HSCT between April 1998 and December 2016. Immunodeficient patients who were treated with intravenous immunoglobulin (IVIg) during pretransplantation and those treated for CMV infection before HSCT were excluded from this study. Informed consent was waived by the institution review board of Chang Gung Children's Hospital because of the retrospective nature of this study.2.25 leukocytes), or elevated CMV DNA levels (>1000\u200acopies/mL). CMV infection was defined as isolation of the CMV or detection of viral proteins or nucleic acids in any body fluid or tissue specimen. CMV disease was defined by the presence of signs and/or symptoms of end-organ disease along with CMV detection in related fluid or tissue samples. All cord blood units were considered seronegative. Monitoring was initiated after neutrophil engraftment using CMV antigenemia or plasma-based PCR assay and continued through day 100 posttransplant. Patients with positive CMV antigenemia or elevated CMV DNA levels by quantitative PCR were monitored weekly until normalization.All patients were routinely screened for CMV viremia at 1-week intervals until 50 days posttransplant, biweekly until 100 days posttransplant, and subsequently on follow-up whenever indicated clinically until 1 year posttransplant. Reactivation was defined as positive antigenemia (>1 CMV antigen-positive cell per 5\u200a\u00d7\u200a10Intravenous (IV) acyclovir followed by oral acyclovir and early IVIg administrations were recommended for all seropositive patients at our institution. CMV reactivation was preemptively treated with GCV as follows: induction with 5\u200amg/kg IV GCV twice daily for 2 weeks, followed by maintenance with 5\u200amg/kg IV GCV daily for an additional 6 weeks. Recommendations for IVIg replacement applied to all patients undergoing allogeneic HSCT.2.35 peripheral blood leukocytes.The CMV antigenemia assay was performed within 4\u200ahours of specimen collection using the MONOFLUO CMV kit . This assay utilizes monoclonal antibodies to detect CMV matrix phosphoprotein pp65, a late structural protein expressed in blood leukocytes during the early phase of the CMV replication cycle. Briefly, antigenemia was measured by immunoflurescence quantitation of pp65-positive leukocyte nuclei using cytospin preparations of 5\u200a\u00d7\u200a102.45 leukocytes in the antigenemia assay era and \u22651000\u200acopies/mL in the PCR era.Real-time PCR of plasma samples was performed to detect the highly conserved, nondrug target region of the CMV DNA polymerase (UL54) gene. Standard silica-based specimen preparation methods were used to capture CMV DNA and CMV quantitative standard (QS) DNA, and defined oligonucleotides were used as primers for amplification of CMV DNA and CMV QS DNA. Briefly, CMV DNA was isolated from 350\u200a\u03bcL EDTA plasma samples using the COBAS AmpliPrep/COBAS TaqMan CMV Test . The clinical significance of low CMV DNA levels (<100\u2013500\u200acopies/mL) may be difficult to interpret, particularly in whole blood samples, as low CMV DNA levels in whole blood or plasma do not always correlate with disease development. Therefore, the cutoff for viremia prompting preemptive therapy was >1 CMV antigen-positive cell per 5\u200a\u00d7\u200a102.5P-value <.05 on univariate analysis were included in the logistic regression model. Continuous variables between the 2 groups were performed using the nonparametric Mann\u2013Whitney U-test, and categorical variables were compared using the Chi-squared or Fisher exact test, as appropriate. All descriptive statistics calculated for the categorical variable were reported as percentages, and continuous variables were presented as medians. CMV antigenema and CMV DNA viral loads were log-converted to fit for parametric analyses. Differences in numerical variables between the 2 groups were assessed by Welch t-test. Variables with P-value <.10 by univariate analysis were included in multivariate logistic regression analysis. P < .05 was considered statistically significant.Statistical analyses were performed using SPSS version 20 . We set up 10 parameters for univariate analysis , peripheral blood (n\u200a=\u200a124), and umbilical cord blood (n\u200a=\u200a136). Conditioning therapy comprised a myeloablative regimen (n\u200a=\u200a256) or reduced-intensity conditioning (n\u200a=\u200a34). The donor stem-cell sources included 78 human leukocyte antigen (HLA)-identical siblings, 203 unrelated donors, and 9 haploidentical matched parental stem cells.Among 290 at-risk patients, 54 (18.6%) patients had primary CMV infection or CMV reactivation occurring at a median of 76 days  following HSCT. CMV reactivation was detected in 44 (28.2%) of 156 CMV-seropositive transplant recipients at a median of 26 days posttransplant. IV GCV was ultimately administered as preemptive therapy to 50 patients. Moreover, hyperimmune CMV immunoglobulin was administered in 10 of these 50 patients. One patient presented with a significantly higher CMV viral load and subsequently developed acute interstitial pneumonitis requiring rescue extracorporeal membrane oxygenation. He eventually succumbed to respiratory failure secondary to the possible emergence of CMV resistance.Univariate analyses revealed statistically significant relationships between CMV infection and grade III\u2013IV acute graft-vs-host disease, seronegative donor/seropositive recipient combination, and use of unrelated/mismatched donors. Multivariate logistic regression analysis showed that these 3 variables were independent risk factors for CMV infection Table . The rem4\u20139 Risk factors predicting CMV infection in pediatric patients undergoing HSCT are poorly understood, and factors involved with the recurrence of CMV viremia following an initial episode have not been reported. Two methods have been utilized to diagnose CMV infection: the CMV antigenemia assay to detect pp65 and PCR to detect CMV DNA. Both techniques can be used for early detection of CMV replication. The antigenemia assay is likely to be replaced with molecular methods, particularly for monitoring CMV replication after transplantation.,13 The present study featured a moderate CMV infection rate (22.8%), but patients with cord blood transplantation (CBT) did not show a statistically significant association with CMV reaction, despite a crude trend in increased numbers of CMV infection among CBT than adult stem-cell transplantation.A majority of CMV infections are caused by virus reactivation, which usually occurs within 3 months following transplantation. Molecular diagnostic methods have replaced or supplemented traditional methods, such as viral culture and antigen detection, for diagnosis of viral infections. As compared with the CMV antigenemia testing, quantitative PCR was associated with earlier detection of CMV infection. Although quantitative PCR for CMV has replaced antigenemia for routine monitoring, until recently, inter-laboratory correlation of viral loads was poor due to lack of an international standard. Higher maximum CMV PCR titers, although not available for every patient, trended toward significance in univariate analysis. However, a CMV DNA load of >1000\u200acopies/mL after 2 weeks of GCV treatment was reported to be suggestive of drug resistance.The incidence of CMV primary infection or reactivation in the present study was 18.6%, which was lower than the rate in historical controls (30%). Specimen deterioration with time after sample collection is a lesser concern in PCR-based assays than in other tests for CMV detection.,19 Allogeneic HSCT can potentially reduce the high relapse rate for patients with leukemia; however, CMV reactivation following HSCT should be addressed to improve patient outcomes.The CMV antigenemia assay is a labor-intensive and low-throughput method, which is not amenable to automation. Patient samples must be processed within 6\u200ahours, as delays were shown to significantly reduce the assay sensitivity.,21 GCV therapy is a relevant, clinically tailored treatment for patients with CMV reactivation. Further studies are required to determine the appropriate timing of preemptive antiviral strategies to improve CMV infection.This study has several limitations, most of which related to its retrospective design. The patients were treated with different protocols during the study period. Additionally, donors included both HLA-identical and alternative donors . The leukocyte-based CMV antigenemia assays were positive at an earlier time after HSCT and became negative more rapidly after initiation of GCV therapy than the plasma-based PCR assays.Conceptualization: Tang-Her Jaing, Shih-Hsiang Chen.Data curation: Tsung-Yen Chang, Yu-Chuan Wen, Ting-Jiuan Yu.Formal analysis: Tsung-Yen Chang, Yu-Chuan Wen, Pei-Kwei Tsay.Funding acquisition: Tang-Her Jaing.Investigation: Shih-Hsiang Chen, Ching-Fen Lee.Methodology: Ching-Fen Lee.Software: Pei-Kwei Tsay.Supervision: Chao-Ping Yang.Validation: Pei-Kwei Tsay.Writing \u2013 original draft: Tang-Her Jaing.Writing \u2013 review & editing: Tang-Her Jaing, Shih-Hsiang Chen."}
+{"text": "Bunyavirales: Arenaviridae), obtained from a wild rodent Oligoryzomys mattogrossae captured in Mato Grosso do Sul state, Brazil. The genome of this virus showed strong similarity to highly pathogenic mammarenavirus from South America.Here, we report the complete genome sequence of the Apor\u00e9 virus ( Arenaviridae family currently comprises 41 viral species, classified into three genera: mammarenavirus (35 species), reptarenavirus (five species), and hartmanivirus (one specie).,Mammarenaviruses are negative sense bi-segmented RNA viruses each segment encodes genes for two non-overlapping reading frames in ambisense polarity.Neacomys guianae), Cupixi virus , Flexal virus (unidentified oryzomyini rodent), Sabi\u00e1 virus , Oliveros virus (Necromys lasiurus), Latino virus , Pinhal virus  and Xapuri virus (Neacomys musseri).,,,Oligoryzomys mattogrossae (= Oligoryzomys fornesi), captured in Cassil\u00e2ndia municipality, Mato Grosso do Sul state, Midwest, Brazil.To date, eight mammarenavirus were detected in Brazil: Amapar\u00ed virus . Isolated RNA from one rodent liver sample was treated with DNAse I (Life Technologies) following the manufacturer\u2019s instructions and depleted of ribosomal RNA using NEBNext rRNA Depletion Kit (New England BioLabs inc). A library was constructed with the Nextera XT Library Preparation Kit (Illumina) using 2 x 250 bp paired-end protocol on the MiSeq platform (Illumina). Sequencing reads were assembled A classical arenavirus bi-segmented genome was identified, each segment encoding two open reading frames (ORFs) in an ambisense organisation with an intergenic region containing a predicted stem-loop region between the ORFs. Full S segment (3.4 kb) encoded genes for two inferred proteins: nucleoprotein (562 aa) and a glycoprotein precursor (GPC) (489 aa), which is normally post-translationally processed into the envelope glycoproteins G1 (197 aa) and G2 (234 aa) and the stable signal peptide (SSP - 58 aa). The L segment (7.2 kb) encoded genes for zinc-binding matrix protein (99 aa) and the RNA-dependent RNA polymerase (2155 aa). Additional features commonly observed in mammarenavirus genomes include the conservation of the 3\u2032-5\u2032 termini and the presence of an L-domain motif within the Z protein.,Nucleotide sequences and deduced amino acid of the new virus were compared to those of other mammarenaviruses species. A nucleotide sequence divergence of 28% for S and 25% and 26% for L segment was found between the new virus and Chapare (from Bolivia) and Sabi\u00e1 (from Brazil) viruses, respectively.O. mattogrossae, SABV and CHAPV. Thus, the results of the phylogenetic analysis also indicates that it represents a novel virus within the Clade B New World mammarenavirus  (Pairwise sequence comparison (PASC) was performed on both segments reinforcing the close relation between the new discovered virus from viridae) . Therefo,O. mattogrossae rodents and APOV.In recent years, novel arenaviruses have been identified expanding our knowledge about their genetic diversity, geographic range and host association. Herein we show that APOV is closely related to two highly pathogenic arenaviruses from South America that were recovered from fatal cases of hemorrhagic fever, whose reservoirs remain unknown.Nucleotide sequence accession numbers - The complete genome sequence of Apor\u00e9 virus has been deposited in GenBank under the following accession numbers: MF317490 for the S segment, and MF317491 for the L segment."}
+{"text": "Here, we aimed to investigate the mechanisms underlying by determining skeletal muscle mitochondrial respiratory capacity in NamptTg and WT mice. Body weight and body composition, tissue weight , skeletal muscle and liver glycogen content, VO2max, skeletal muscle mitochondrial respiratory capacity (measured by high-resolution respirometry), skeletal muscle gene expression (measured by microarray and qPCR), and skeletal muscle protein content (measured by Western blot) were determined following 6 weeks of voluntary exercise training (access to running wheel) in 13-week-old male NamptTg (exercised NamptTg) mice and WT (exercised WT) mice. Daily running distance and running time during the voluntary exercise training protocol were recorded. Daily running distance (p = 0.51) and running time (p = 0.85) were not significantly different between exercised NamptTg mice and exercised WT mice. VO2max was higher in exercised NamptTg mice compared to exercised WT mice (p = 0.02). Body weight (p = 0.92), fat mass (p = 0.49), lean mass (p = 0.91), tissue weight , and skeletal muscle (p = 0.72) and liver (p = 0.94) glycogen content were not significantly different between exercised NamptTg mice and exercised WT mice. Complex I oxidative phosphorylation (OXPHOS) respiratory capacity supported by fatty acid substrates (p < 0.01), maximal (complex I+II) OXPHOS respiratory capacity supported by glycolytic (p = 0.02) and fatty acid (p < 0.01) substrates, and maximal uncoupled respiratory capacity supported by fatty acid substrates (p < 0.01) was higher in exercised NamptTg mice compared to exercised WT mice. Transcriptomic analyses revealed differential expression for genes involved in oxidative metabolism in exercised NamptTg mice compared to exercised WT mice, specifically, enrichment for the gene set related to the SIRT3-mediated signaling pathway. SIRT3 protein content correlated with NAMPT protein content . In conclusion, NamptTg mice develop higher exercise capacity following voluntary exercise training compared to WT mice, which is paralleled by higher mitochondrial respiratory capacity in skeletal muscle. The changes in SIRT3 targets suggest that these effects are due to remodeling of mitochondrial function.Mice overexpressing NAMPT in skeletal muscle (NamptTg mice) develop higher exercise endurance and maximal aerobic capacity (VO NAD+ isxtension . NAMPT cMNAT1-3) .2max) in comparison to wild-type (WT) mice following 7 weeks of voluntary exercise training Pbef2Srs] NAMPT transgenic  (NamptTg2max) following voluntary exercise training. VO2max was also assessed at baseline. The other six exercised NamptTg and six exercised WT mice were used to analyze skeletal muscle (gastrocnemius) and liver glycogen content, to measure skeletal muscle mitochondrial respiratory capacity, and to perform skeletal muscle transcriptomic (microarray) analysis following voluntary exercise training. Tissue-specific measurements were performed after a 5 h fast and 20 min run .At week 7 of age, all mice were given access to running wheels (voluntary exercise training)  equipped with odometers  for 6 weeks . Running distance, running time, average running speed, and maximal running speed were recorded every 24 h for the first 4 weeks during which the mice had access to the running wheels. Six exercised NamptTg and six exercised WT mice were used to assess body weight, body composition, tissue weight , protein content, and aerobic capacity  for determination of fat mass and lean mass. Measurements are obtained in less than 1 min.2max tests were conducted as previously described . Mice were defined as exhausted when they spent more than five continuous seconds on the electric grid. VO2max was achieved when VO2 no longer increased despite an increase in treadmill speed. VO2max was expressed as the change in VO2 from resting (\u0394VO2max).VOescribed . Mice weTissues were collected immediately following euthanasia and snap-frozen in liquid nitrogen. Homogenates were prepared by Polytron homogenization in RIPA buffer containing protease inhibitor and phosphatase inhibitor cocktails . Protein content was quantified by bicinchoninic acid (BCA) assay . NAMPT protein content was analyzed in red and white quadriceps using 15 and 25 \u03bcg of protein, respectively, and was run on a 10% SDS-PAGE gel . LCAD protein content was analyzed in red quadriceps using 15 \u03bcg of protein and was run on a 10% SDS-PAGE gel . SIRT3 and mitofusin-2 (MFN2) were analyzed in red quadriceps using 40 \u03bcg of protein. Catalase (CAT) was analyzed in red quadriceps using 60 \u03bcg of protein. SIRT3, MFN2 and CAT were run on a 4\u201320% SDS-PAGE gel . Protein was transferred to a PVDF membrane  and membranes were incubated with antibodies against NAMPT , LCAD , SIRT3 , MFN2 , CAT  and \u03b1-tubulin  overnight at 4\u00b0C, and then proved with IRDye 680 goat anti-mouse IgG or IRDye 800CW goat anti-rabbit IgG . Bands were visualized using an Odyssey Digital Infrared Imaging System (LI-COR) and quantified using Odyssey Application Software version 3.0 (LI-COR). Original western blot images are shown in the Supplementary Material.2, 0.5 mM dithiothreitol, 0.3 mM ATP, 0.05 NADP, 1 U/ml hexokinase + glucose-6-phosphodehydrogenase). Samples were then incubated at room temperature for 5\u201310 min. 200 \u03bcl from each reaction mixture was transferred to a 96-well black plate and fluorescence was detected using a Biotek plate reader . Glycogen content was calculated by the following equation: (\u0394Fsample/\u0394Fstandard) \u00d7 (mM concentration standard \u00d7 ml standard volume) \u00d7 muscle dilution/mg of tissue \u00d7 1,000 = \u03bcmoles glucosyl units/grams tissue.Twenty micrograms of frozen skeletal muscle (gastrocnemius) and 40 mg of frozen liver tissue was incubated at 100\u00b0C (dry heat/oven) in 0.5 ml of 2N HCl for 2 h, then neutralized with 1.5 ml of 0.67N NaOH. Following neutralization, muscle samples were shaken until dissolved. Twenty microliters of the dissolved muscle samples and a glucose standard (0.473 mM) were then added to borosilicate tubes containing 1 ml of the reagent cocktail  copy number was quantified in \u223c20 mg mixed gastrocnemius muscle tissue, as described previously . Briefly2/ml. LEAK respiration was determined through the addition of pyruvate (5 mM), malate (4 mM) and glutamate (10 mM) for glycolytic substrates supported respiration (LEAKGlycolytic), and through the addition of malate (4 mM) and palmitoyl-carnitine (40 \u03bcM) for fatty acid substrates supported respiration (LEAK FattyAcid). ADP (2 mM) was added to elicited complex I oxidative phosphorylation (OXPHOS) (OXPHOSCI) respiratory capacity. The integrity of the mitochondrial outer membrane was assessed by addition of cytochrome c (10 \u03bcM). Any sample that showed an increase in respiration of more than 10% with the addition of cytochrome c was not included in the final analysis. Succinate (10 mM) was then added to elicit maximal (complex I+II) OXPHOS (Max OXPHOSCI+II) respiratory capacity. Titrations of the uncoupler fluoro-carbonyl cyanide phenylhydrazone (FCCP) (0.5 \u03bcM) were then added to determine election transfer system (ETS) capacity ). Rotenone (0.05 \u03bcM) was added to inhibit OXPHOSCI, thereby facilitating the evaluation of complex II OXPHOS (OXPHOSCII) respiratory capacity. The addition of antimycin A (2.5 \u03bcM) inhibited complex III resulting in residual oxygen consumption (ROX). The oxygen flux was corrected by subtracting ROX from each measured respiratory steady-state and was expressed as the rate of O2 consumption per mtDNA content (pmol/s/mtDNA) to measure intrinsic mitochondrial respiratory capacity  by high-resolution respirometry . Measurements were performed in quadruplicate, at 37\u00b0C, in the range of 300\u2013400 \u03bcM Ocapacity . mtDNA c2 immediately following dissection. RNA was extracted via column purification using the Qiagen miRNeasy Mini Kit (Qiagen). RNA quantity was determined using an ND-1000 Nanodrop spectrophotometer (Thermo Fisher Scientific). DNA was isolated from \u223c20 mg mixed gastrocnemius muscle tissue. Tissues were snap-frozen in liquid N2 immediately following dissection. DNA was extracted via column purification using the Qiagen DNeasy Mini Kit (Qiagen). DNA quantity was determined using an ND-1000 Nanodrop spectrophotometer (Thermo Fisher Scientific).Total RNA was isolated from \u223c20 mg red and white quadriceps muscle tissue. Tissues were snap-frozen in liquid N2-transformation were followed by gene differential analysis using the two-sample t-test. A heat-map was prepared using an unsupervised two-way cluster analysis . The combined effects of voluntary exercise training and elevated NAMPT in skeletal muscle were evaluated using a false discovery rate (FDR) of 0.05 and a fold-change cutoff of 1.3. For each of the genes (gene probes) on the microarray, differential gene expression was considered significant when the effective FDR  was below the lowest FDR as calculated by permutations of gene-specific test in significance analysis of microarrays (SAMs). For functional clustering and annotation of the differentially expressed genes with statistical significance, Gene Set Enrichment Analysis (GSEA) and the Database for Annotation, Visualization and Integrated Discovery (DAVID) was used. The over-represented gene ontology groups were found at \u2264 0.05 of Expression Analysis Systematic Explorer (EASE) score  score .\u00ae Gene expression assays. qRT-PCR reactions were performed using Taqman Fast Virus 1-step reaction mix Standard protocol . Data were normalized by dividing the target gene by the geometric mean of the internal control genes (RPLP0 and GAPDH).RT-qPCR was performed in skeletal muscle of six exercised NamptTg and six exercised WT mice . Total Rp < 0.05. Normality was analyzed using the Shapiro\u2013Wilk test. An unpaired Student\u2019s t-test was used to detect significant differences between groups when data was normally distributed. The appropriate non-parametric test was performed when normality was violated. Data were analyzed using JMP version 12  and GraphPad Prism version 6.07 . Statistical analyses for microarrays are presented in the transcriptomics methods section.Data are presented as mean \u00b1 standard deviation. Statistical significance was set at p < 0.01, Figure 1A). No significant differences were observed in body weight (p = 0.91), fat mass (p = 0.49), and lean mass (p = 0.91) between exercised NamptTg mice and exercised WT mice . Tissue weights for gastrocnemius (p = 0.20), quadriceps (p = 0.89), soleus (p = 0.82), heart (p = 0.90), liver (p = 0.38), and EWAT (p = 0.85) were not significantly different between exercised NamptTg mice and exercised WT mice . No significant differences were observed for glycogen content in gastrocnemius muscle (p = 0.72) and liver (p = 0.94) between exercised NamptTg mice and exercised WT mice .Nicotinamide phosphoribosyl transferase protein content was analyzed in red and white quadriceps muscle of exercised NamptTg mice and exercised WT mice. NAMPT protein content was \u223c7-fold higher in red quadriceps muscle and \u223c11-fold higher in white quadriceps muscle of exercised NamptTg mice compared to exercised WT mice . VO2max following voluntary exercise training was higher in exercised NamptTg mice in comparison to exercised WT mice . Higher VO2max following voluntary exercise training in exercised NamptTg mice compared to exercised WT mice could not be attributed to higher levels of activity during the voluntary exercise training protocol, as there were no significant differences in daily running distance , running time , average speed , or maximal speed  during the voluntary exercise training protocol.Baseline VOCI+IIGlycolytic in comparison to exercised WT mice , while LEAKGlycolytic , OXPHOSCIGlycolytic , OXPHOSCIIGlycolytic , and UncoupledETSGlycolytic  were not significantly different between exercised NamptTg mice and exercised WT mice. Supported by fatty acid substrates, exercised NamptTg mice showed higher OXPHOSCIFattyacid , Max OXPHOSCI+IIFattyacid , and UncoupledETSFattyacid  in comparison to exercised WT mice. LEAKFattyacid  and OXPHOSCIIFattyacid  were not significantly different between exercised NamptTg mice and exercised WT mice.Functional analysis of mitochondrial capacity was performed by measuring mitochondrial respiratory capacity supported by glycolytic  and fatty acid  substrates in permeabilized skeletal muscle fibers from exercised NamptTg mice and exercised WT mice. Supported by glycolytic substrates, exercised NamptTg mice showed higher Max OXPHOSFigure 4A. Of the 989 gene hits that were differentially expressed, 395 gene hits were differentially expressed in white skeletal muscle only, 286 gene hits were differentially expressed in red skeletal muscle only, and 308 gene hits were differentially expressed in both red and white skeletal muscle . GSEA, using gene sets previously established for NAD+ metabolism  . No significant gene enrichment was observed in white skeletal muscle (data not shown). Gene expression in skeletal muscle of exercised NamptTg mice and exercised WT mice was also classified into functional categories by DAVID functional annotation clustering (Table 1). In agreement with the results from the GSEA analysis, genes involved in oxidative metabolism were upregulated in red skeletal muscle of exercised NamptTg mice in comparison to exercised WT mice. In addition, DAVID functional annotation clustering showed upregulation for genes related to antioxidant pathways in exercised NamptTg mice in comparison to exercised WT mice (Table 1). Subsequent RT-qPCR analysis in exercised NamptTg mice and exercised WT mice confirmed higher gene expression for genes involved in mitochondrial oxidative metabolism. Gene expression in red quadriceps muscle for citrate synthase (CS) (p = 0.04), succinate dehydrogenase complex iron sulfur subunit b (SDHb) (p = 0.02), CAT (p = 0.01), mitochondrial superoxide dismutase 2 (MnSOD2) (p = 0.05), growth arrest and DNA-damage-inducible 45-alpha (GADD45A) (p < 0.01), mitofusin-2 (MFN2) (p = 0.05), and long-chain acyl-CoA dehydrogenase (LCAD) (p < 0.01) was higher in exercised NamptTg mice in comparison to exercised WT mice . RT-qPCR analysis showed less prominent gene expression differences in white quadriceps muscle of exercised NamptTg mice in comparison to exercised WT mice, with only significant higher gene expression for GADD45A .Comprehensive transcriptomic analysis was performed in red and white quadriceps muscle of exercised NamptTg mice and exercised WT mice. A gene \u2018hit list\u2019 was generated, followed by GSEA and the DAVID functional annotation clustering program. In total, 989 gene hits were differentially expressed in skeletal muscle of exercised NamptTg mice in comparison to exercised WT mice, and these expression differences are depicted in the heatmap in tabolism , showed p = 0.27), despite being on average \u223c30% higher in NamptTg mice compared to WT mice . CAT (p = 0.47), MFN2 (p = 0.28), and LCAD (p = 0.74) protein content in skeletal muscle were also not significantly different between NamptTg mice and WT mice . SIRT3 protein content in skeletal muscle significantly correlated with NAMPT protein content in skeletal muscle . Associations were also observed for SIRT3 protein content in skeletal muscle with CAT , MFN2 , and LCAD  protein content in skeletal muscle, albeit the first two did not reach statistical significance.Sirtuin-3 protein content in skeletal muscle was not significantly different between NamptTg mice and WT mice (2max) following voluntary exercise training was higher in NamptTg mice in comparison to WT mice, despite equivalent loads of voluntary running distance and running time. Higher aerobic capacity was paralleled by higher skeletal muscle mitochondrial respiratory capacity in exercised NamptTg mice in comparison to exercised WT mice. These functional observations of higher mitochondrial respiratory capacity in skeletal muscle were supported by a distinct gene expression profile in the skeletal muscle of exercised NamptTg mice in comparison to exercised WT mice, which revealed gene enrichment for mitochondrial oxidative metabolism in exercised NamptTg mice.Our data reveal that maximal aerobic capacity  restored skeletal muscle mitochondrial respiratory capacity in the mNKO mice  NMN administration increased maximal uncoupled mitochondrial respiratory capacity in skeletal muscle  OXPHOS and maximal uncoupled mitochondrial respiratory capacity in skeletal muscle  derivate] bypass NAMPT to produce NAD+, which might explain the discrepancy in results.Functional analysis of mitochondrial respiratory capacity revealed that following voluntary exercise training NamptTg mice developed higher mitochondrial respiratory capacity in comparison to WT mice. Specifically, complex I respiratory capacity supported by fatty acid substrates, maximal (complex I+II) OXPHOS respiratory capacity supported by glycolytic and fatty acid substrates, and maximal uncoupled respiratory capacity supported by fatty acid substrates was higher in exercised NamptTg mice in comparison to exercised WT mice. These data thus indicate that there was a larger effect of voluntary exercise training on mitochondrial respiratory capacity when NAMPT in skeletal muscle was elevated. A previous study found no difference in mitochondrial respiration in isolated skeletal muscle mitochondria of skeletal-muscle-specific NAMPT overexpressing mice in comparison to WT mice under sedentary conditions . The samNKO mice  and in bNKO mice . NR treaimproved  or did nimproved  maximal l muscle . Two-weel muscle . These f+ metabolism (+-dependent deacetylation of oxidative enzymes (+-precursor Acipimox for 2 weeks significantly increased enrichment of genes related to the TCA cycle and electron transport chain in skeletal muscle (+ concentrations, found that the most downregulated gene cluster in skeletal muscle corresponded to metabolic processes related to ATP production (We performed comprehensive transcriptomic analysis to look at distinct gene set enrichment in the skeletal muscle of exercised NamptTg mice and exercised WT mice that could explain higher skeletal muscle mitochondrial respiratory capacity in exercised NamptTg mice following voluntary exercise training. Using gene sets that were previously established for NADtabolism , we foun enzymes , and SIR enzymes . SIRT3 p enzymes . In humal muscle . A studyoduction . Thus, tin situ or ex vivo skeletal muscle contraction might bring deeper insight regarding the contribution of skeletal muscle function to the superior exercise performance phenotype observed in the NamptTg mouse model. Secondly, we did not measure SIRT3 enzyme activity nor acetylation levels of downstream targets of SIRT3. Exercise is known to increase SIRT3 deacetylation activity (This study has some limitations worth noting. While our data clearly demonstrates higher mitochondrial respiratory capacity in skeletal muscle, we did not measure exercise performance of the skeletal muscle directly. Analyzing activity , which cactivity . AssessmOur study shows that maximal aerobic capacity following voluntary exercise training in mice was higher when NAMPT in skeletal muscle was elevated. Higher exercise performance was paralleled by higher skeletal muscle mitochondrial respiratory capacity, which suggests a plausible mechanism that can explain, at least in part, the higher exercise performance phenotype observed in mice with elevated NAMPT in their skeletal muscle. The changes in SIRT3 targets suggest that these effects are due to remodeling of mitochondrial function.BB performed the experiments, analyzed the data, interpreted the results, and wrote and edited the manuscript. NS performed the experiments, analyzed the data, interpreted the results, and critically reviewed the manuscript. SC performed the experiments, analyzed the data, and critically reviewed the manuscript. MH and SG performed the experiments and critically reviewed the manuscript. JA interpreted the results of experiments and critically reviewed the manuscript. FY and HX performed the statistical analysis and critically reviewed the manuscript. J-LL performed the analysis and critically reviewed the manuscript. SG, LS, and SS designed the study. LS and SS performed the experiments, analyzed the data, interpreted the results, and critically reviewed and edited the manuscript. SS is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Moreover, pathways regulating blood development are highly conserved between zebrafish and mammals, and several discoveries made in fish were later translated to murine and human models. This review and accompanying poster provide an overview of zebrafish hematopoiesis and discuss the existing zebrafish models of blood disorders, such as myeloid and lymphoid malignancies, bone marrow failure syndromes and immunodeficiencies, with a focus on how these models were generated and how they can be applied for translational research.Zebrafish offer a powerful vertebrate model for studies of development and disease. The major advantages of this model include the possibilities of conducting reverse and forward genetic screens and of observing cellular processes by  Summary: This At A Glance article and poster summarize the last 20 years of research in zebrafish models for hematopoietic disorders, highlighting how these models were created and are being applied for translational research. Danio rerio) are increasingly used to study mechanisms regulating vertebrate tissue development and disease pathogenesis. Since especially blood cell types and their regulation are highly conserved  injection for downregulation. MOs are nonionic DNA analogs in which the ribose moiety has been substituted with an MO ring. They are generally designed to be complementary to the translational start site or a specific splice site in the pre-mRNA of the target gene, preventing translation or splicing of the pre-mRNA by a steric blocking mechanism. The technique is based on injecting these modified oligonucleotides, which then prevent expression of the targeted gene . Recently, serious concerns have been raised as to the specificity of MO effects  can be used for targeting a unique genomic locus. Transcription activator-like effector nucleases (TALENs) are suitable for knock-in strategies or for removing large spans of DNA to cause genomic deletions. TILLING  allows directed introduction of point mutations in a specific gene. The CRISPR /Cas9 system can cut at a specific location but also allows knock-ins or removal of existing genes/sequences  manipulation at all developmental stages and analyses of phenotypes that would die in utero in mice.casper .Lack of specific antibodies for experimental work.Fish are greatly influenced by their environment .Different morphology of certain blood cells.Lack of a fully functioning adaptive immune system.in vivo investigations mandatory. For human cells, these require analyses in xenograft models. These are naturally limited by incomplete interspecies protein cross-reactivity and the requirement for an immunosuppressed host animal to prevent graft rejection. Therefore, researchers have developed animal models for further in vivo assessment of genotype-phenotype relations in hematologic disorders. Here, we describe the currently available zebrafish models for hematopoietic disorders in more detail.Blood development is tightly regulated by complex interactions between hematopoietic stem cells (HSCs) and the microenvironment, making Myeloid malignancies are chronic or acute clonal diseases arising from hematopoietic stem and progenitor cells (HSPCs) characterized by uncontrolled proliferation and/or differentiation blocks in myeloid cells. Chronic myeloid neoplasms such as myeloproliferative neoplasms (MPNs), myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) all have an increased risk of transformation into acute myeloid leukemia (AML) . The genJAK2, MPL, CALR or CSF3R : granulocyte colony stimulating factor (receptor)GFP: green fluorescent proteinHOX: homeobox transcription factorHRAS: V-HA-RAS Harvey rat sarcoma viral oncogene homologhspa9b:heat-shock 70-kD protein 9 variant birf8:interferon regulatory factor 8JAK2: Janus kinase 2KRAS: V-KI-RAS2 Kirsten rat sarcoma viral oncogene homologlck:lymphocyte-specific protein-tyrosine kinaseLEF1: lymphoid enhancer-binding factor 1lmo2:LIM domain only protein 2; encodes Rhombotin-like 1MPL: myeloproliferative leukemia virus oncogeneMYST3: histone acetyltransferase KAT6AmTOR: mechanistic target of rapamycinNADPH: nicotinamide adenine dinucleotide phosphateNCOA2: nuclear receptor co-activator 2n-Myc: v-Myc avian myelocytomatosis viral-related oncogene, neuroblastoma-derivednola1:nucleolar protein family A, member 1nop10:H/ACA ribonucleoprotein complex subunit 3NUP98: nucleoporin 98prpf8:precursor mRNA-processing factorPTEN: phosphatase and tensin homologPTPRJ: receptor-type tyrosine-protein phosphatase etaRAC2: Ras-related C3 botulinum toxin substrate 2rad51:DNA repair protein RAD51 homolog 2rag2:recombination-activating gene 2RPL: ribosomal protein LRPS: ribosomal proteinRUNX1: Runt-related transcription factor 1scl:stem cell leukemic proteinsf3b1:splicing factor 3B, subunit 1slc4a1:solute carrier family 4 (anion exchanger), member 1spi1:spleen focus forming virus proviral integration oncogenesptb:erythroid beta-spectrinSRP54: signal recognition particle 54stat5.1:signal transducer and activator of transcription 1syk:spleen tyrosine kinaseTCR: T-cell receptorTEL: TEL1 oncogeneTERT: telomerase reverse transcriptaseTET2: Tet methylcytosine dioxygenase 2TOX: thymocyte selection-associated high mobility group box proteintp53:cellular tumor antigenp53ZAP70: zeta chain of T cell receptor associated protein kinase 70MPNs are classified into three subgroups \u2013 polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis \u00a0\u2013 all of which are accompanied by disease-related complications, such as thrombosis and hemorrhages, and mainly affect people above 50 years of age . Driver JAK2 gene (V617FJAK2 was created by site-directed mutagenesis (see poster: Myeloproliferative neoplasia). The mutant had a high degree of similarity to human PV, mainly characterized by erythroid expansion  (A major defining genetic event in human MPN is a gain-of-function mutation (V617F) in the AK2 gene . To modexpansion . Anotheroplasia) . Both liTET2, an epigenetic factor regulating DNA methylation. Somatic loss-of-function m/mtet2 zebrafish mutants engineered by zinc-finger nuclease (ZFN) genome editing develop normally during embryogenesis, but show progression to clonal myelodysplasia as they age and eventually develop MDS-like features at 24 months post-fertilization (asxl1 mutant (see poster: Myeloid neoplasms). Somatic loss-of-function mutations of this gene are common genetic abnormalities in human myeloid malignancies and induce clonal expansion of mutated HSPCs. The authors showed that half of the heterozygous fish developed MPN by 5 months of age. Interestingly, the combination of heterozygous loss of asxl1 with heterozygous loss of their previously generated tet2 mutant led to a more penetrant phenotype, while +/\u2212asxl1 together with complete loss of tet2 even caused AML ]  and espelization . Subsequused AML .sf3b1 in zebrafish leads to spliceosomal defects and thus MDS-like phenotypes  reporter line   , and thurps14 by introducing an early stop codon via non-homologous end joining -like disease . Ear and colleagues used clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 to target  joining . This te joining . Targetesyndrome , which wsyndrome . Besides disease .AML is defined as acute malignant disease characterized by uncontrolled proliferation and accumulation of leukemic blasts in the bone marrow (BM), peripheral blood (PB) and other organs . It is tAML1 (RUNX1)-ETO in zebrafish embryos. This disrupted normal hematopoiesis, with accumulation of immature hematopoietic blast cells in the intermediate cell mass (ICM), and circulating erythroid cells with dysplastic features , as is commonly observed in human AML. Owing to its specificity to early myeloid lineages, spi1-driven oncogene expression was used in several additional myeloid malignancy models, e.g. involving the oncogenic fusion proteins FLT3-ITD  are known to regulate and maintain neutrophil numbers during primitive and definitive hematopoiesis as shown by MO-mediated knockdown experiments  . csf3 lieriments . Variouseriments . Pazhakheriments , serving3/\u03bcl (mpl gene with TALENs (PTPRJ in inherited thrombocytopenia patients without a known genetic background. Ablation of zebrafish ptprja by CRISPR/Cas9 successfully recapitulated the patient phenotypes in zebrafish (see poster: Bone marrow failure syndromes)  .merlot and chablis strains share common features of HE, which, as shown by Shafizadeh et al., is due to protein 4.1 (P4.1) deficiency. As in HE patients, P4.1 defects led to elliptical erythroid cell morphology, reduced cell deformability and disrupted skeletal network  have been modeled in zebrafish. Genetic anemia models were mainly identified in large-scale genetic screens in the 1990s and later cloned and characterized . Heredit network . Another network . The zebregation .zinfandel presents with hypochromic microcytic anemia due to defects in embryonic globin production (sauternes is caused by disrupted heme biosynthesis (weissherbst enabled the discovery of a conserved vertebrate iron exporter, Ferroportin 1, whose mutation causes the hypochromic phenotype in this strain (weissherbst is the chianti strain. Unlike weissherbst, the underlying cause is not a lack in circulatory iron, but rather defective iron acquisition due to mutations in the gene encoding Transferrin receptor 1 in differentiating erythrocytes (Furthermore, various zebrafish models for hypochromic anemia exist. Hypochromic anemia is characterized by pale and small erythrocytes, normally caused by globin or iron deficiencies . Whilst oduction , hypochrynthesis . Anothers strain . A mutanhrocytes .chardonnay zebrafish mutant adds another important player to the understanding of iron metabolism, by revealing an essential role of the iron transporter DMT1 in iron homeostasis (dracula mutant, which was, like most anemic zebrafish strains, identified in a genetic screen, represents a very accurate model for erythropoietic protoporphyria. The dracula gene was shown to encode for Ferrochelatase, the terminal enzyme in the heme biosynthesis pathway, and its inactivation rendered erythrocytes highly light sensitive (in vivo hemolysis and regeneration (Finally, the eostasis . Moreoveensitive . Interesneration .ex utero embryogenesis, facilitating non-invasive in vivo analyses of zebrafish, enable the application of a wide variety of genetic and drug screening approaches (ex vivo characterization of zebrafish hematopoietic precursors (in vivo drug effects, and allows the drug to interact with any biological pathway and all respective niches. Owing to their small size and high fecundity, chemical screening in fish is easily feasible and can be performed in a high-throughput manner with different read-outs, such as morphology, behavior and cell state. Morphology screens are designed based on a chosen morphology change of interest. For example, Shafizadeh and colleagues used o-dianisidine staining to detect changes in hemoglobin synthesis after chemical treatment and identified compounds that reduced hemoglobin abundance and as such led to hemolytic anemia (in situ hybridization as a read-out has identified prostaglandin E2 as a novel compound to regulate HSC homeostasis (Drug screening of a whole organism allows concurrent observation of drug toxicity and c anemia . Behavioc anemia . One impeostasis . This coeostasis .The blood system is highly conserved between zebrafish and mammals. This high degree of conservation indicates that knowledge obtained from zebrafish is potentially transferrable to humans, and zebrafish models can be used for modeling human blood disorders. The high fecundity and proaches , and canproaches . This syproaches  or on thecursors , furtherecursors , the com"}
+{"text": "Zetaproteobacteria lack well-defined taxonomic divisions, making it difficult to compare them between studies. We designed ZetaHunter to reproducibly assign 16S rRNA gene sequences to previously described operational taxonomic units (OTUs) based on a curated database.Like many taxa, the  Zetaproteobacteria lack well-defined taxonomic divisions, making it difficult to compare them between studies. We designed ZetaHunter to reproducibly assign 16S rRNA gene sequences to previously described operational taxonomic units (OTUs) based on a curated database. While ZetaHunter can use any given database, we included a curated classification of publicly available Zetaproteobacteria.Like many taxa, the  Zetaproteobacteria, which is only accurately classified to this taxonomic level by standard small subunit rRNA (16S rRNA) gene classification tools. ZetaHunter allows for reproducible, higher-resolution comparisons across studies by using a curated data set with a defined taxonomy based on operational taxonomic units (OTUs). ZetaHunter comes with a curated database to identify the members of the Zetaproteobacteria, though it may be used with any curated 16S rRNA gene database.  (Zetaproteobacteria genomes from the Joint Genome Institute (JGI) Integrated Microbial Genomes (IMG) database (Zetaproteobacteria OTU (ZOTU) definitions include those reported by McAllister et al. . By default, ZetaHunter uses a curated database of release 18 (2) anddatabase . Zetapror et al.  at 97% ide novo binning, average neighbor, numbered by abundance)  . The defundance) ; and (v)undance)  showing in QIIME .Zetaproteobacteria, users need (i) a database of SINA-aligned 16S rRNA gene sequences, (ii) a sequence mask with asterisks at each informative alignment column to be used for taxonomic assignment, and (iii) a tab-delimited file assigning each sequence to a particular taxonomic group at the similarity threshold desired by the user.To use ZetaHunter for non-https://github.com/mooreryan/ZetaHunter) (Zetaproteobacteria and non-Zetaproteobacteria. Detailed example data sets are included in the ZetaHunter_examples GitHub repository (https://github.com/mooreryan/ZetaHunter_examples).ZetaHunter is available for download at (aHunter) , where i"}
+{"text": "Personality should manifest everyday as behaviors, affective states, and thoughts. Trait personality measures require retrospection and appraisal, processes affected by cognitive changes. Ecological momentary assessments (EMA), however, may identify sensitive everyday personality markers. We analyzed data from 178 individuals aged 20-79 who completed 3 EMA measurement bursts. Each burst, participants rated positive affect (PA), negative affect (NA), negative thoughts (URT), total social interactions, and interaction pleasantness up to 5x daily for 7 days. We tested for measurement invariance across bursts in a confirmatory factor analysis using 4 indicators of Neuroticism  and 4 indicators of Extraversion . Strict measurement invariance held, indicating that the association among these indicators remained stable across the 18 month observation period."}
+{"text": "Haemophilus influenzae (NTHi) is a major bacterial cause of exacerbations in chronic obstructive pulmonary disease (COPD). Here, we report high-depth coverage transcriptome sequencing (RNA-seq) data from two NTHi strains, each encoding a different phase-variable methyltransferase. modA phase variation results in gene expression differences. These data will serve as an important resource for future studies.Nontypeable  Haemophilus influenzae (NTHi) is a major bacterial cause of exacerbations in chronic obstructive pulmonary disease (COPD). Here, we report high-depth coverage transcriptome sequencing (RNA-seq) data from two NTHi strains, each encoding a different phase-variable methyltransferase. modA phase variation results in gene expression differences. These data will serve as an important resource for future studies.Nontypeable  Haemophilus influenzae (NTHi) is a human-adapted pathogen that causes exacerbations in chronic obstructive pulmonary disease (COPD)   according to the manufacturer\u2019s instructions. NTHi strains were grown to mid-log phase in brain heart infusion (BHI) broth  at 37\u00b0C aerobically with 150 rpm shaking.Nontypeable e (COPD) . Globalle (COPD) . Previoule genes \u20136. Thesevarions) , 8. ModAvarions) . Therefovarions)  and woulvarions)  revealed strains . Using mCP029620  and CP029621 ). Reads were mapped to the respective genome using Bowtie2 aligner (v2.3.3.1), and transcripts were assembled with the read alignment and reference annotation-based assembly option in Stringtie v1.3.3 (http://ccb.jhu.edu/software/stringtie/). The Gencode annotation containing both coding and noncoding sequences for each genome was used to map reads (http://www.gencodegenes.org/). Raw gene count values were analyzed with edgeR (https://bioconductor.org/packages/release/bioc/html/edgeR.html), and the subread package (http://subread.sourceforge.net/) was used to quantitate counts using the featureCounts v1.5.3 utility. Gene expression differences were expressed as log2 fold change of expression (logFC). Analysis also generated the following: average log count/million for each gene from all samples , quasi-likelihood F statistic for each gene from all samples , P values to determine statistically different expression, and the false-discovery rate/adjusted P value for multiple-hypothesis testing.All methods used for transcriptome sequencing (RNA-seq) are identical to those described previously , except modA15 and modA18 phase variation . For example, the universal stress protein UspA (DLJ98_08875) and the cold shock protein CspD (DLJ98_02355) are both upregulated when modA15 is off. In the ModA18 phasevarion, two hypothetical genes (DLK00_05505 and DLK00_05510), encoding proteins of unknown function, are upregulated when modA18 is on. These RNA-seq data will serve as a primary resource for studying the regulatory events resulting from genome-wide methylation differences by phase-variable methyltransferases during COPD and for determining the exact molecular mechanisms of modA-mediated gene expression differences.Multiple genes are differentially regulated commensurate with GSE129761 (modA15 on versus off) and GSE129764 (modA18 on versus off).These data have been deposited in the NCBI Gene Expression Omnibus under the accession numbers"}
+{"text": "Heart failure (HF) patients enroll in hospice at lower rates despite their worse prognosis. This multi-method study explores the characteristics and challenges associated with caring for HF patients. Data from qualitative interviews with hospice providers (n=32) and quantitative records  were used to identify care management issues and prognostic tools. Hospice providers described HF patients unique and often unpredictable symptomatology, their limited understanding and discordant hospice expectations, and difficulties managing symptoms at home. Providers also highlighted HF patients use of assistive medical devices and complex medication regimens. Palliative Performance Scale (PPSv2) scores at hospice enrollment were found to be strongly associated with hospice survival  and live discharge risk (PPSv2 50-70% AOR=5.68 [CI=3.66-8.79]). Findings underscore the need for specially-tailored trainings and protocols for providers to prevent unplanned discharges and support HF patients at end-of-life."}
+{"text": "Sling explant was not a significant predictor of 12 month (p=0.12) or 96 month failure (p=0.17). DISCUSSION/SIGNIFICANCE OF IMPACT: Sling revision during AUS placement helps expose the wider proximal urethra, allowing larger cuff size placement. This procedure appears safe, with low rates of erosion and short-term failure\u2014albeit with high rates of long-term urethral atrophy possibly due to more significant dissection causing devascularization. However, sling removal was not a significant predictor of failure. The transobturator sling\u2019s smaller profile may result in less trauma to urethra\u2014possibly explaining the improved outcomes.OBJECTIVES/SPECIFIC AIMS: Perineal urethral sling placement is an option for men with mild to moderate post-prostatectomy stress urinary incontinence (SUI). However, men with persistent incontinence after sling placement often require secondary artificial urinary sphincter (AUS) placement, made difficult by the sling occupying the proximal bulbar urethra. This proximal section has a thicker corpus spongiosum which may mitigate cuff-induced ischemia and subsequent urethral atrophy. The authors report a series of AUS placements after failed sling, using sling revision or removal to access the proximal urethra. METHODS/STUDY POPULATION: Cutting the sling arms during urethral cuff placement increased urethral exposure and mobility. If feasible, completely removing the sling allowed the most proximal cuff site; but if dissection was felt unsafe, the mesh was left in situ and the cuff placed distally. This study is a retrospective cohort design of patients with SUI who underwent AUS placement after failed sling from 2010 to 2016. Variables included baseline patient characteristics, SUI severity, intraoperative variables, and postoperative outcomes. AUS failure, defined as infection, erosion or urethral atrophy, was analyzed at 12 and 96 months using univariate and multivariable logistic regression. RESULTS/ANTICIPATED RESULTS: Over the study period, 29 patients underwent AUS placement after failed sling. At the time of AUS placement, mean urethral circumference was 6.2 cm and 68% of patients had a 4.5 cm cuff placed; no cases required a 3.5 cm cuff. Seventy-three percent of cases were after transobturator sling placement (27% bone-anchored) and 45% of slings were explanted. AUS failure rate at 12 and 96 months was 17.8% and 45%, respectively; atrophy was the most common indication. Prior transobturator sling placement had lower rates of both 12 month (9.1% vs. 57%,"}
+{"text": "We recently reported the efficacy and safety of docetaxel (DOC) plus ramucirumab (RAM) with primary prophylactic pegylated (PEG)-granulocyte-colony stimulating factor (G-CSF) for pretreated non-small cell lung cancer (NSCLC) . DOC+RAMIn our cohort, 10 (19%) of 52 patients receiving DOC+RAM with PEG-G-CSF moved to maintenance RAM monotherapy after intolerable toxicities following clinical response . Reasons for these movements were all adverse events (AEs) \u2265grade 2: 4 oral mucositis; 3 anorexia; 2 malaise; 2 numbness; 2 nail change; and 2 peripheral edema (some overlapping). Median cycles of DOC+RAM before RAM monotherapy was 6 . Median cycles of RAM monotherapy was 4 . Among these 10 patients, median progression-free survival (PFS) from DOC+RAM initiation was 7.0  months  and blocks the activation of the receptor, preventing tumor angiogenesis, growth, and proliferation. In salvage-line settings of gastric cancer, RAM monotherapy demonstrated survival benefit over placebo . This evIn patients suffering from intolerable toxicities following response to DOC+RAM, movement to RAM monotherapy could reduce severe AEs, improve quality of life, and prolong PFS. Further studies are warranted to evaluate this unique strategy of maintenance RAM monotherapy in pretreated NSCLC."}
+{"text": "Vasculogenic mimicry (VM) gives rise to tumor neovascularization that is critical for tumor growth and metastasis. Long non-coding RNAs (lncRNAs) have been implicated in diverse and fundamental biological processes. LINC00312 is associated with lung adenocarcinoma. In this study, we found that LINC00312 induced migration, invasion and VM of lung cancer cells by direct binding to the transcription factor Y-Box Binding Protein 1 (YBX1). Moreover, we demonstrated that YBX1 is associated with different fragments within 0\u20132410\u2009nt 5\u2019region of LINC00312. In addition, LINC00312 is associated with VM in 124 lung adenocarcinoma clinical specimens. The results suggest that LINC00312 is a promising therapeutic and diagnostic target for lung adenocarcinoma.The online version of this article (10.1186/s12943-018-0920-z) contains supplementary material, which is available to authorized users. Lung cancer is the most common cause of cancer related death in men and women. One of the most common types of lung cancer is NSCLC. Tumor neovascularization provides adequate blood and nutrition supply for tumor progression. Vasculogenic mimicry (VM) is one of the important sources of angiogenesis and nutritional supply in cancer . The lncp\u2009<\u20090.0001) , distant metastasis (p\u2009<\u20090.001), tumor node metastasis (TNM) stage (p\u2009=\u20090.042)  according to its secondary structure Additional file 2:Figure S1. LINC00312 promotes migration and invasion of ADC cells. (TIF 9436 kb)Additional file 3:Table S2. Proteins associated with biotinylated LINC00312 in RNA pull-down assay. (XLS 425 kb)Additional file 4:Figure S2. A. Secondary structure of LINC00312. B. PC-9 whole-cell lysates pulled down with truncated LINC00312 or antisense probe. C. LINC00312 fragment\u2013specific bands were excised and analyzed by Western blot assay. (TIF 1462 kb)Additional file 5:Figure S3. Functional annotations of differentially expressed genes between LINC00312 stably overexpressed pIRES2-LINC00312 and the vector control PC-9 cells. (A) Schematic presentation of top terms in the GO terms. (B) Schematic presentation of top terms in the KEGG terms. (TIF 4495 kb)"}
+{"text": "Global RNA sequencing technologies have revealed widespread RNA polymerase II (Pol II) transcription outside of gene promoters. Small 5\u2032-capped RNA sequencing (Start-seq) originally developed for the detection of promoter-proximal Pol II pausing has helped improve annotation of Transcription Start Sites (TSSs) of genes as well as identification of non-genic regulatory elements. However, apart from the most well studied genomes of human and mouse, mammalian transcription has not been profiled with sufficiently high precision.Rattus norgevicus) primary neural progenitor cells. Over 48 million uniquely mappable reads from two independent biological replicates allowed us to define the TSSs of 7365 known genes in the rn6 genome, reannotating 2503 TSSs by more than 5 base pairs, characterize promoter-associated antisense transcription, and profile Pol II pausing. By combining TSS data with polyA-selected RNA sequencing, we also identified thousands of potential new genes producing stable RNA as well as non-genic transcripts representing possible regulatory elements.We prepared and sequenced Start-seq libraries from rat  contains supplementary material, which is available to authorized users. Transcription of genes was thought to be regulated mainly through recruitment of the RNA polymerase to promoters. However, work over the last several years \u20133 has deC. elegans, and Drosophila . Time-pregnant rats were obtained from a commercial resource (Charles River). Pregnant dams were sacrificed by first deeply anesthetizing them (to minimize pain sensation during decapitation) by intraperitoneal injection of pentobarbital solution and then decapitated using a sharp guillotine. Embryonic animals were decapitated with a sharp pair of scissors, cortices were isolated and subsequently digested in Accutase (Gibco) for 5\u2009min at room temperature. Cultures of cortical neural progenitors were prepared from embryonic day 14 (E14) Sprague Dawley rats of either sex. Single cell suspension was achieved by triturating digested tissue through fire-polished Pasteur pipettes. Cells were washed with Hank\u2019s Balanced Salt Solution (HBSS) without calcium and magnesium, and then plated onto dishes coated with CELLstart (Gibco) in Knockout DMEM/F-12 (Gibco) supplemented with 2% StemPro Neural Supplement (Gibco), 2\u2009mM GlutaMAX (Gibco), 20\u2009ng/ml bFGF (Gibco), and 20\u2009ng/ml EGF (Gibco). Cells were passaged every 2\u20133\u2009days and routinely collected after the second passage.PolyA selected RNA libraries were prepared from 50\u2009ng of total RNA extracted from frozen cell pellets using Trizol reagent. In addition to the standard Trizol procedure, we included a chloroform extraction step of the aqueous phase after chloroform-induced separation of phases, to remove traces of phenol. RNA Integrity Numbers were calculated by Bioanalyzer and were always >\u20096.8, to meet the RNA quality guidelines for RNA sequencing service (Novogene). PolyA-selected RNA-sequencing libraries were prepared using NEBNext Ultra II library preparation kit with NEB beads, using 12\u2009cycles of amplification. Libraries were quantified on Bioanalyzer prior to sequencing.scRNAs were prepared based on our earlier procedure , 22, witStart-Seq libraries were sequenced on a MiSeq instrument for quality control locally and re-sequenced on HiSeq2500 using small RNA option (SE50) commercially (Novogene) to the depth of ~\u2009100\u2009M raw reads per sample. Raw files for Start-seq were mapped to rn6 genome using Hisat2. To filter out highly abundant species with multiple genomic copies such as tRNAs, only uniquely mappable Start-seq reads (Hisat2 mapping score\u2009>\u20093) were considered for analysis. Mapped reads were assigned to annotated genes using rn6 RefSeq annotation.PolyA-selective RNA sequencing was done to an average ~\u2009140\u2009M raw reads per replicate using a commercial company (Novogene) from Trizol-extracted RNA. Reads were aligned to the rn6 genome using STAR and expression levels (FPKM) were obtained using the Rsubread  and DESeRn6 annotated gene TSS locations were obtained from UCSC and deduplicated to produce a list of unique start site coordinates for each gene. Contaminating RNAs  and micro RNA species were removed from consideration for this study. The deeptools package  was usedAdditional file 1:Supplemental figures and supplemental figure legends. (DOCX 1323 kb)Additional file 2:The list of genes with rn6-based coordinates of TSSs (RefSeq and Start-Seq-based) alongside TSS-RNA signal and RNA-seq signal for each replicate. (XLSX 1592 kb)Additional file 3:Panther GO analysis of highest and lowest PI genes. (XLSX 19 kb)Additional file 4:Stringtie assembly of new transcripts, as a Gene Transfer Format (GTF) file. (TXT 11349 kb)Additional file 5:Regions of bidirectional transcription outside of known genes identified based on TSS-RNA. (TXT 211 kb)"}
+{"text": "The cement surface was studied by Fourier transform infrared spectroscopy (FT-IR), field emission gun scanning electron microscopy (FEG-SEM) and energy dispersive X-ray analysis (EDX). Release to the SBF media of ionic degradation products was monitored using inductively coupled plasma atomic emission spectroscopy (ICP-AES).Bioactivity evaluation FT-IR showed increasing formation of phosphate phase bands at 1097, 960, 607 and 570 cm-1 with prolonged SBF soaking. FEG-SEM analysis reveals that HP produces a effectively surface covering consisting in homogeneous spherical phosphate phase aggregates with an average diameter of 0.5-1.0 \u00b5m. EDX analysis comparing un-treated (hydrated), 24 h and 72 h SBF treated surfaces of MTA HP Repair revealed phosphate deposition after 24 h, with high phosphorous/silicon element ratio signal measured after 24 h, indicating a very high phosphate phase deposition for this material.in vitro in terms of crystalline calcium phosphate surface coating formation. The high bioactive response of MTA HP Repair makes it an interesting candidate for endodontic use as repair cement.The study shows that MTA HP Repair produces a quick and effective bioactive response  Key words:Bioactive endodontic cements, bioactive response, MTA HP Repair. Bioceramic endodontic cements (BECs), such as Mineral Trioxide Aggregate (MTA) and related materials, stimulate the natural remineralization process at the material-tooth interface . TherefoCalcium silicates (Ca3SiO5 and Ca2SiO4) are the base compounds of BECs, together with radiopacifying additives such as bismuth, zirconia, tantalum, or tungsten oxides . Calciumin vitro of the bioceramic endodontic cement MTA HP Repair (HP).MTA Repair HP  is a new BEC in which, bismuth oxide has been replaced by calcium tungstate (CaWO4) as radiopacifier and this modification of cement composition will alter the physico-chemical characteristics and the biomechanical properties of the bioceramic material ,11,12, aMTA HP Repair  was used in this study. The composition of the bioceramic as the manufacturer specifications is: tricalcium silicate (Ca3SiO5), dicalcium silicate (Ca2SiO4), calcium tungstate (CaWO4) as radiopacifier, tricalcium aluminate (3CaO.Al2O3), and calcium oxide (CaO).in vitro bioactivity evaluation was assessed, by soaking the cement disks in 13 mL of simulated body fluid (SBF) (The id (SBF)  during 4Fourier transform infrared (FT-IR) spectra of as-processed set material and the SBF treated samples were collected in transmission configuration in the 1300-400 cm-1 range using 4 cm-1 intervals in a Nicolet IS50 FT-IR . The microstructures were studied by field emission gun scanning electron microscopy (FEG-SEM) using a HITACHI S-4800 . Images were recorded at an accelerating voltage of 2 kV. Energy dispersive X-ray (EDX) analysis was carried out at 10 kV with an EDX Bruker XFlash 4010 detector. Concentrations of Si, Ca, P, W and Al ions in the soaking media were monitored after 72 and 168h by inductively coupled plasma atomic emission spectroscopy (ICP-AES) using the spectrometer Horiba Jobin Yvon . Control solutions consisting of pure SBF was simultaneously prepared and stored under the same conditions.The FT-IR absorbance spectra of MTA HP Repair after the analysed SBF treatment times, in comparison with the spectra of the as-set (SBF un-treated) sample, are shown in Figure Back-scatter FEG-SEM micrographs of the un-treated MTA HP Repair set material surface , as well as secondary images after 24 h  and 72 h  SBF treatment, at two different magnifications are presented in Figure Si, Ca, P, W and Al ionic product in solution after 72 and 168 h SBF soaking treatment are presented in in vitro indicates that MTA HP Repair forms a structured crystallized calcium phosphate coating layer after 72 h treatment. FEG-SEM observations of MTA HP Repair surface after 24 h only SBF treatment, shows a phosphate phase coating formed of homogeneous spheres with an average diameter in the 0.5-1.0 \u00b5m range. This high bioactive response might be associated to the high calcium aluminate content of this material (Calcium phosphate mineralization capacity of MTA HP Repair, a bioceramic cement with calcium tungstate as radiopacifier used in endodontic therapy, has been studied. Bioactivity assay material , and to material . Particuet al. (The clinical manifestation of bioactivity with the use of BECs has been attributed to phosphate phase\u2019s mineralization induction capacity  and compet al.  using MTin vitro in terms of HA surface coating formation. The high bioactivity response for HP is in good accordance with its high calcium aluminate content. Recently, a study carried out on human dental pulp stem cells has demonstrated the high biocompatibility and cytocompatibility of MTA Repair HP (The results of the present study indicates that MTA HP Repair produces a quick and effective bioactive response epair HP .in vitro indicates that MTA HP Repair produces a quick and effective bioactive response in vitro in terms of homogeneous calcium phosphate surface coating formation. MTA HP Repair stimulates the formation of a nanostructured calcium phosphate coating layer after 72 h treatment. The high bioactive response of MTA HP Repair makes it ideal for endodontic use as repair cement.Bioactivity essay"}
+{"text": "To assess the safety of, and subsequent allergy documentation associated with, an antimicrobial stewardship intervention consisting of test-dose challenge procedures prompted by an electronic guideline for hospitalized patients with reported \u03b2-lactam allergies.Retrospective cohort study.Large healthcare system consisting of 2 academic and 3 community acute-care hospitals between April 2016 and December 2017.We evaluated \u03b2-lactam antibiotic test-dose outcomes, including adverse drug reactions (ADRs), hypersensitivity reactions (HSRs), and electronic health record (EHR) allergy record updates. HSR predictors were examined using a multivariable logistic regression model. Modification of the EHR allergy record after test doses considered relevant allergy entries added, deleted, and/or specified.We identified 1,046 test-doses: 809 (77%) to cephalosporins, 148 (14%) to penicillins, and 89 (9%) to carbapenems. Overall, 78 patients  had signs or symptoms of an ADR, and 40  had confirmed HSRs. Most HSRs occurred at the second  step (68%) and required no treatment beyond drug discontinuation (58%); 3 HSR patients were treated with intramuscular epinephrine. Reported cephalosporin allergy history was associated with an increased odds of HSR . Allergies were updated for 474 patients (45%), with records specified (82%), deleted (16%), and added (8%).This antimicrobial stewardship intervention using \u03b2-lactam test-dose procedures was safe. Overall, 3.8% of patients with \u03b2-lactam allergy histories had an HSR; cephalosporin allergy histories conferred a 3-fold increased risk. Encouraging EHR documentation might improve this safe, effective, and practical acute-care antibiotic stewardship tool. Prior to this study, our results demonstrated that the guideline safely increased \u03b2-lactam antibiotic use at 2 academic medical centers.,,1 online).We developed \u03b2-lactam hypersensitivity pathways in 2013 at the Massachusetts General Hospital (MGH), which were modified and studied prospectively at the Brigham and Women\u2019s Hospital (BWH).We identified all PHS \u03b2-lactam antibiotic test doses performed from April 2016 through December 2017. Although \u03b2-lactam test doses were not performed at community hospital sites prior to April 2016, test doses at academic sites prior to guideline adoption occurred exclusively at the direction of an allergist. The \u03b2-lactam antibiotic test doses reviewed included those performed with and without preceding PST; PST was available at 3 sites by an allergy/immunology consultation. All patients receiving 1 or more test-dose challenge had their EHR reviewed by PHS house staff, with data entry and maintenance supported by research electronic data capture (RedCap) hosted by PHS.The EHR-abstracted data included characteristics of the test dose  and patient characteristics . Historical penicillin and cephalosporin reactions were recorded. Itching, flushing, rash, and hives were considered nonsevere cutaneous reactions; bronchospasm, shortness of breath, wheezing, anaphylaxis, angioedema, swelling, syncope, arrhythmia, hypotension, dizziness, and positive skin testing were considered severe IgE histories. Other EHR drug allergies were recorded.The primary outcome was a hypersensitivity reaction (HSR) resulting from a \u03b2-lactam antibiotic test dose. PHS house staff reviewers recorded reaction details including timing or onset, test-dose step, symptoms and presentation, treatment, and clinical context for all possible reactions. Allergy specialist coinvestigators  determined whether the signs and/or symptoms were consistent with an HSR. All reactions not consistent with HSRs were considered adverse drug reactions (ADRs). For all HSRs, allergy specialists determined whether objective findings were present and whether the pathways were followed correctly. Confirmed HSRs were grouped as follows. Nonsevere cutaneous reactions included itching, flushing, rash, tingling, and urticaria; severe IgE reactions included angioedema, swelling, bronchospasm, wheezing, hypotension, and anaphylaxis; and severe delayed immunologic reactions included organ-specific reactions and severe cutaneous adverse reactions. We assessed HSRs overall by drug class, and we separately considered direct challenges .Modification of the EHR allergy record after a test dose was determined by assessing whether the allergy module had a relevant allergy entry added, deleted, and/or specified .2 and Kruskal-Wallis tests. Confidence intervals (CIs) were calculated using exact  methods. The HSR and ADR predictors were identified using multivariable logistic regression models, and we reported adjusted odds ratios (aORs) with 95% confidence intervals (CIs). The selection of variables to include in multivariable models involved a priori knowledge of variable association with outcome. Statistical analyses were conducted using SAS version 9.4 software .We used descriptive statistics such as numbers with frequencies and medians with interquartile ranges. Univariable comparisons were made using \u03c7From April 2016 through December 2017, 1,046 test doses to \u03b2-lactams were administered to 942 patients across 5 PHS hospitals (Table P < .001). A PST prior to the test dose was performed for 38 patients (4%), most commonly prior to penicillin test doses (13%), compared to cephalosporins test doses (2%) and carbapenem test doses .Allergy/Immunology staff were consulted for 96 (9%) test-dose challenges administered, more often for penicillin test doses (19%) than for carbapenem test doses (16%) or cephalosporins . The overall median length of stay was 10 days  for patients receiving test doses.Patients were in the hospital a median of 2 days prior to their test dose ; patients received penicillin test doses later in the hospitalization  than patients who received cephalosporin  or carbapenem test doses  with a median age of 64 years . Patients receiving test doses had penicillin allergy histories (96%); 29% had cephalosporin allergy histories. Penicillin allergy histories included nonsevere cutaneous reactions (48%) and severe IgE-mediated reactions (20%). Cephalosporin allergy histories included nonsevere cutaneous reactions (17%) and severe IgE-mediated reactions (5%).We identified 78 ADRs , of which 40  were HSRs and 38  were non-HSRs .Most HSRs occurred after 24 hours from the initial test dose , but 14 (35%) occurred during the 1-hour test-dose observation period (Table 2 online). Female sex , allergy to cephalosporin antibiotics , and allergy consultation  were associated with significantly increased odds of an ADR.An allergy to cephalosporin antibiotics  was associated with increased odds of an HSR  or carbapenems [Fig. We identified 179 patients with mild penicillin reaction histories who received direct test-dose challenges. Of 76 patients direct challenged to penicillin, 3 had HSRs . Of 103 patients directly challenged with cephalosporins (first or second generation), 2 patients exhibited HSRs  [Fig. There were 135 patients with cephalosporin allergy histories directly challenged with \u03b2-lactams: 34 with penicillins , 86 with cephalosporins , and 15 with carbapenems . Of patients who had had an allergy/immunology consultation (n = 96), the EHR was updated for 59 (61%).Overall, EHR allergy sections of 474 of 1,046 patients (45%) were updated after the \u03b2-lactam antibiotic test-dose challenge. Among the updated cases, 37 (8%) had an allergy added, 75 (16%) had an allergy deleted, and 390 (82%) had an allergy specified (records could have >1 action). The PHS community hospitals updated the EHR more frequently after test doses than did PHS academic hospitals  can occur in patients with prior drug reactions.,The HSR rate observed in this study was 3.8%, which is similar to our prior study at MGH (3.9%) and comparable to the penicillin HSR rate observed previously by allergy specialists (1.5%\u20132.6%).,,This study provides insight into \u201creal world\u201d \u03b2-lactam cross reactivity in patients with specified IgE penicillin allergy histories, including patients with severe IgE histories. Prior observational studies of cephalosporins administered to penicillin allergy patients largely excluded patients with higher-risk penicillin allergy histories because they were selected out.,Allergy to cephalosporin antibiotics was associated with a significant 3-fold increased odds of HSR. Documented cephalosporin allergies may more often be true hypersensitivities that occurred more recently compared to documented penicillin allergies (often \u201cunknown\u201d and/or remote). The cephalosporin hypersensitivity pathway may not be as accurate as the penicillin hypersensitivity pathway in this US acute-care populaton.,Drug allergy documentation is important for quality and safety. However, EHR allergy documentation is often incomplete and inaccurate.Although the guideline can recommend \u03b2-lactam avoidance or administration of a full-dose \u03b2-lactam, we only reviewed \u03b2-lactams initiated by a test dose in this study. All data were abstracted and analyzed retrospectively, which can result in misclassification; however, HSR determination was rigorously determined by allergist coinvestigators. While evaluating HSRs occurring from direct challenges in patients with different allergy histories provides insight into beta-lactam cross-reactivity, patients in this study had an unknown true allergy status. Although we evaluated HSRs occurring from direct challenges in patients with different allergy histories provides insight into \u03b2-lactam cross reactivity, we were unable to obtain the true allergy statuses of patients included in this study. Finally, we report on a multisite intervention in which all hospitals are part of a single geographically localized large US healthcare system. However, non-PHS hospitals have also adopted this guideline.An electronic guideline with penicillin and cephalosporin hypersensitivity pathways encouraging \u03b2-lactam test-dose challenges was implemented in 5 hospitals with different resources using 1 EHR as an antibiotic stewardship tool. The ADR and HSR rates were low, and not higher than expected given a morbid inpatient population with prior reported drug allergies. Certain test-dose challenges may be omitted given their observed safety, and caution is prudent with cephalosporin-allergy challenged inpatients. Additional efforts to improve allergy documentation are important to the success of \u03b2-lactam allergy interventions."}
+{"text": "Cerebral amyloid angiopathy-related inflammation (CAA-ri) is an unusual cause of encephalopathy, seizures and focal neurological deficits.18F-florbetapir) demonstrated moderate widespread amyloid deposition; CSF analysis showed reduced amyloid-beta 1\u201342 and high-normal total tau. Formal neuropsychological testing suggested mild compromise in frontal functioning only. The patient was treated with 5 days of intravenous methylprednisolone (1\u00a0g daily), followed by an oral taper from prednisolone 60\u2009mg over 8 weeks. Follow-up MRI after 8 months showed almost complete resolution of the parenchymal abnormalities, but with persisting lobar microbleeds. At 24 months following symptom onset, he remains asymptomatic, with stable brain imaging.A 62-year-old man presented with a moderately severe non-radiating frontal headache. Brain MRI 9 months later showed multiple discrete regions of abnormal signal and mild swelling involving white matter and overlying cortex. Susceptibility-weighted imaging (SWI) demonstrated numerous cortical lobar microbleeds throughout both cerebral hemispheres. Repeat MRI another 9 months later showed resolution of many of the parenchymal abnormalities, but with several new regions containing more peripheral microbleeds. Amyloid-PET  within the temporal, parietal and occipital lobes, which largely resolved. SWI demonstrated progressive accumulation of lobar microbleeds, mainly in the affected areas. The patient remains asymptomatic with no change in his subjective cognitive symptoms, without having received immunosuppressive treatment.A 54-year-old woman presented with a bright flashing light in her left visual field and a sudden onset headache. After initial CT of the brain demonstrated right-sided occipital hypoattenuation, she was treated for ischaemic stroke and then antiepileptic drugs for presumed seizures. Approximately 6 months later, she developed worsening headache; MRI showed an area of abnormal signal and mild parenchymal swelling in the right temporo-occipital area. A diagnostic brain biopsy showed CAA-ri . After a further 8 months, she was still experiencing occasional left-sided visual flickering and some subtle memory difficulties. MRI \u00a0demonstrOne year after intravenous corticosteroid treatment, while still taking oral steroids, the patient developed headache and new left-sided visual disturbances. MRI showed recurrence and extension of the right-sided temporo-occipital region abnormalities, with local swelling and numerous new cortical microbleeds in the affected area. The patient was once again treated with intravenous corticosteroids (as previously); follow-up MRI 3 months after this showed almost complete regression of the right temporal abnormalities and no change in the appearance or number of peripheral microbleeds.We report three cases of CAA-ri  and the current clinico-radiological criteria require further validation, particularly for atypical cases, where amyloid-\u00a0Positron Emission Tomography (PET)"}
+{"text": "Neuroretinitis from neurosyphilis is an uncommon finding in previously healthy young individuals. A 37-year-old presented with three days of painless, unilateral vision loss with an associated diffuse erythematous non-pruritic truncal rash. Physical exam demonstrated vision loss in the left eye. Fundoscopic exam showed unilateral peripapillary hemorrhage, papilledema and venous engorgement. Labs showed positive syphilis antibody qualitative. Magnetic resonance imaging demonstrated 12 millimeters of high right frontal lobe cerebrospinal fluid density. The patient was treated with benzylpenicillin and within 18 hours had improvement of his vision. A 37-year-old male presented to the emergency department complaining of three days of painless left eye vision changes. He described the changes as a \u201cwhite out.\u201d He also noted a four-week-old diffuse, erythematous, nonpruritic truncal rash. Visual exam findings were notable for oculus sinister of 20/25. Oculus dexter was 20/20. There was no presence of ptosis. Bilateral fluorescein stain and slit lamp exam were unremarkable. A fundoscopic exam of the left eye revealed unilateral papilledema (UP) and bilateral retinal hemorrhage . Ocular Labs were significant for reactive hepatitis B, antinuclear antibody screen, rapid plasma reagin test with reflex, fluorescent treponemal antibody absorption test, sedimentation rate Westergren automated test, and c-reactive protein of 3.1 milligrams per deciliter (mg/dL) (0.0\u20133.1 mg/dL). Venereal disease research laboratory on cerebrospinal fluid (CSF) was nonreactive. Lyme antibody screen and Bartonella antibody panel were both negative. Syphilis antibody qualitative was positive. Rapid human immunodeficiency virus (HIV) test was negative. Syphilitic and UP findings prompted a lumbar puncture to rule out neurosyphilis, which subsequently revealed elevated lymphocytes 100% (40\u201380%) and protein 65.0 mg/dL (15.0\u201345.0 mg/dL).A magnetic resonance imaging of the brain revealed 12 millimeters of high right frontal lobe CSF density . The patCommon causes of UP and vision loss include anterior ischemic optic neuropathy (AION) and optic neuritis (ON).2Our patient\u2019s exam and symptoms were most consistent with neuroretinitis. Most cases of neuroretinitis are reported in ophthalmology literature and in association with cat scratch disease (CSD). Only about 1% of the 12,000 yearly cases of CSD present with neuroretinitis. Those who have reported cases of ophthalmological complaints not neuroretinitis specifically are individuals who are HIV positive.What do we already know about this clinical entity?Neuroretinitis is most commonly found in patients with cat scratch disease.What is the major impact of the image(s)?This case demonstrates a rare presentation of unilateral papilledema in an otherwise healthy patient.How might this improve emergency medicine practice?Unilateral papilledema in younger populations presenting without pain should prompt a thorough medical and physical examination with a widened differential diagnosis."}
+{"text": "Cerebellar Purkinje cells mediate accurate eye movement coordination. However, it remains unclear how oculomotor adaptation depends on the interplay between the characteristic Purkinje cell response patterns, namely tonic, bursting, and spike pauses. Here, a spiking cerebellar model assesses the role of Purkinje cell firing patterns in vestibular ocular reflex (VOR) adaptation. The model captures the cerebellar microcircuit properties and it incorporates spike-based synaptic plasticity at multiple cerebellar sites. A detailed Purkinje cell model reproduces the three spike-firing patterns that are shown to regulate the cerebellar output. Our results suggest that pauses following Purkinje complex spikes (bursts) encode transient disinhibition of target medial vestibular nuclei, critically gating the vestibular signals conveyed by mossy fibres. This gating mechanism accounts for early and coarse VOR acquisition, prior to the late reflex consolidation. In addition, properly timed and sized Purkinje cell bursts allow the ratio between long-term depression and potentiation (LTD/LTP) to be finely shaped at mossy fibre-medial vestibular nuclei synapses, which optimises VOR consolidation. Tonic Purkinje cell firing maintains the consolidated VOR through time. Importantly, pauses are crucial to facilitate VOR phase-reversal learning, by reshaping previously learnt synaptic weight distributions. Altogether, these results predict that Purkinje spike burst-pause dynamics are instrumental to VOR learning and reversal adaptation. Cerebellar Purkinje cells regulate accurate eye movement coordination. However, it remains unclear how cerebellar-dependent oculomotor adaptation depends on the interplay between Purkinje cell characteristic response patterns: tonic, high frequency bursting, and post-complex spike pauses. We explore the role of Purkinje spike burst-pause dynamics in VOR adaptation. A biophysical model of Purkinje cell is at the core of a spiking network model, which captures the cerebellar microcircuit properties and incorporates spike-based synaptic plasticity mechanisms at different cerebellar sites. We show that Purkinje spike burst-pause dynamics are critical for (1) gating the vestibular-motor response association during VOR acquisition; (2) mediating the LTD/LTP balance for VOR consolidation; (3) reshaping synaptic efficacy distributions for VOR phase-reversal adaptation; (4) explaining the reversal VOR gain discontinuities during sleeping. The cerebellum controls fine motor coordination including online adjustments of eye movements . Within Purkinje cells provide the major output of the cerebellum through MVN. Purkinje cells receive two main excitatory (glutamatergic) afferent currents . The firThe spiking cerebellar model presented here addresses these issues within a VOR adaptation framework . We simu+ spike output, CF-evoked bursts, and post-complex spike pauses. As evidenced in  .The sodium activation variable was replaced and approximated by its equilibrium function ng modes .Membrane Area and Membrane Capacitance are provided in Injected Current is the sum of all contributions received through individual synapses . We emulated the effect of the PF over the Purkinje cell through a spike train of 55 Hz and a synaptic weight of gexc = 8 \u03bcS. We used CF synaptic stimulations through an AMPA synapse with weight of gexc = 80 \u03bcS, .Cm denotes the membrane capacitance, EAMPA and EGABA are the reversal potential of each synaptic conductance, Erest is the resting potential, and Grest indicates the conductance responsible for the passive decay term towards the resting potential. Conductances gAMPA and gGABA integrate all the contributions received by each receptor type (AMPA and GABA) through individual synapses and they are defined as decaying exponential functions . At MF-MVN the LTD/LTP balance was more critical since N is within a narrower band range . The reddish area within the last plot indicates the optimal parameters range. LTP must exceed LTD at MF-MVN synapses for optimal VOR performance. This result is consistent with the unsupervised nature of the LTP for the kernel defined for MF-MVN STDP. Unsupervised LTP with larger values than LTD takes the MF-MVN synaptic weights to the upper bound of their synaptic efficacy, thus provoking more MVN activations. In the absence of LTD counteraction, the cerebellar output is, therefore, upper saturated. LTD driven by Purkinje cell activity blocks LTP at MF-MVN synapses, thus shaping the cerebellar compensatory output.synapses , 126. Fosynapses , 161. A (PDF)Click here for additional data file.S3 FigN where \u201311 \u2264 N \u2264 12 during a 10000 s simulation. (A) Final VOR gain and phase plotted as a function of the tested LTD/LTP range across time. (B) Combined VOR gain and phase  over time. A proper balance between LTD and LTP (ratio of approximately 0.4) makes the cerebellum perform optimally after 750 sec.Whilst LTD/LTP balance was fixed at PF-PC synapses, we modified the LTD/LTP balance at MF-MVN synapses by systematically varying the ratio by 1.5(PDF)Click here for additional data file.S4 Fig(A) Final VOR gain and phase plotted over the LTD/LTP range of tested values. (B) Combined VOR gain and phase  as a function of the LTD/LTP ratio. LTD/LTP at both PF-Purkinje cell synapses is well balanced for N values ranged between . Thus, the absence of bursting and pause dynamics leads to a wider range values for the LTD/LTP balance.Similar to (PDF)Click here for additional data file.S5 FigAverage VOR gain/phase calculated by taken gain values each 400 s over the last 4000 s of the VOR adaptation process (10000 s) over a range of frequencies within the natural head rotation range [0.05-5Hz]. Consistently with the known frequency spectrum of the vestibular system , VOR gai(PDF)Click here for additional data file.S6 FigTime course of the VOR phase. (A) VOR phase adaptation with (red curve) and without (green curve) Purkinje spike burst-pause dynamics. (B) Focus is on the phase-reversal period and comparison with experimental data [tal data .(PDF)Click here for additional data file.S7 FigVOR gain adaptation mediated by the model with Purkinje spike burst-pause dynamics Click here for additional data file.S8 Fig(A) Only the eye velocity movement corresponding to the sparser and more selective distribution of MF-MVN synaptic weights is able to counteract the head velocity movement in counter phase (B), as phase-reversal learning is achieved (C).(PDF)Click here for additional data file.S9 FigIn the model, CF responses follow a probabilistic Poisson process. Given the normalised error signal ns silent A singlens silent, 150. Thns silent.(PDF)Click here for additional data file."}
+{"text": "Scientific Reports 10.1038/s41598-017-03928-x, published online 16 June 2017Correction to: The Acknowledgements section in this Article is incomplete.\u201cThe authors thank Dr. Marjet Heitzer for helpful discussion and suggestions on the manuscript.\u201dshould read:\u201cGrant sponsor: FONDECYT; Grant number: 1140677(MAGR), 11150992(FS) and 11121518(CM). The authors thank Dr. Marjet Heitzer for helpful discussion and suggestions on the manuscript.\u201d"}
+{"text": "JC polyomavirus (JCPyV) may cause clinical syndromes such as progressive multifocal leukoencephalopathy in immunocompromised patients. Here, we report seven complete genome sequences of JCPyV genotype 7A, generated directly from urine samples from Vietnamese renal transplant recipients by using rolling-circle amplification and next-generation sequencing. JC polyomavirus (JCPyV) may cause clinical syndromes such as progressive multifocal leukoencephalopathy in immunocompromised patients. Here, we report seven complete genome sequences of JCPyV genotype 7A, generated directly from urine samples from Vietnamese renal transplant recipients by using rolling-circle amplification and next-generation sequencing. Betapolyomavirus genus of the Polyomaviridae family. In highly immunosuppressed individuals, JCPyV can cause severe disease, most commonly progressive multifocal leukoencephalopathy (JC polyomavirus (JCPyV) is a circular double-stranded DNA virus from the alopathy . JCPyV galopathy , 3. ThisSeven urine samples were collected from Vietnamese renal transplant recipients between 2015 and 2017. Viral DNA was extracted from 250 \u03bcl of urine  with the EZ1 DSP virus kit (Qiagen). To ensure sufficient polyomavirus DNA reads from the clinical specimens, a primer-directed rolling-circle amplification method was used to enrich DNA extracts for JCPyV . After eJ02226) using Burrows-Wheeler alignment (BWA-MEM v0.7.12) .Raw sequencing reads were trimmed with Trimmomatic v0.36  . Human rv0.7.12) . Referende novo assembly were performed in parallel to confirm the draft genome sequences, because indels and duplications are known to occur within the noncoding control region. Reference mapping resulted in high average coverages  and a GC content of 40.2%. De novo assembly produced a single contig spanning the length of the JCPyV genome for specimens VN-24 , VN-214 , VN-247 , and VN-291 . The remaining specimens produced a maximum of 3 contigs with BLAST+ identity to JCPyV  and LR215999 to LR216005 (genomes).Raw fastq files and final consensus draft JCPyV genomes have been deposited in the European Nucleotide Archive (ENA) under accession numbers"}
+{"text": "We present a cellular model of c9ALS/FTD where induced neurons (iNeurons) are generated within 2 weeks by direct conversion of patients\u2018 dermal fibroblasts through down-regulation of polypyrimidine-tract-binding protein 1 (PTB1). While sense (S) and anti-sense (AS) intranuclear RNA foci were observed in both fibroblasts and iNeurons, the accumulation of (S) and (AS) repeat-associated non-ATG translation (RANT) products were detected only in iNeurons. Importantly, anti-sense oligonucleotides (ASOs) against the (S) repeat transcript lead to decreased (S) RNA foci staining and a reduction of the corresponding RANT products without affecting its (AS) counterparts. ASOs treatment also rescued the cell viability upon stressful stimulus. The results indicate that iNeurons is an advantageous model that not only recapitulates c9ALS/FTD hallmark features but can also help uncover promising therapeutics.Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are incurable neurodegenerative conditions. A non-coding hexanucleotide (GGGGCC) repeat expansion in the  ALS is ALS/FTD) . Normal D) (exp] . ApproxiD) (exp]  and as aD) (exp]  while upD) (exp] .exp or anti-sense (AS) r(CCCCGG)exp can form nuclear foci in the CNS of c9ALS/FTD patients  r(GGGGCC)patients  which mapatients . Secondlpatients . Thirdly in 2011  in whichf72 gene , indicatf72 gene . The hapf72 gene . Neverthf72 gene .c9orf72 mRNA and protein as seen in c9ALS/FTD patients  derived from c9ALS/FTD patients. In these cells, RNA foci and accumulation of inclusions composed of c9RAN proteins, mainly poly GP, have been observed while maintaining the reduction of f72 mRNA . Althougf72 mRNA . PTB1 haf72 mRNA . Xue et f72 mRNA . We deverecently . In thisexp RNA sequence in iPSC differentiated neurons can significantly reduce (S) RNA foci and mitigate cellular toxicity with little effect on c9RAN products detected with a polyclonal antibody preferentially detecting poly GP (exp in our model and observed significant reduction of (S) RNA foci and c9RANT products accumulation without affecting (AS) RNA foci and c9RANT products. Thus, our c9ALS/FTD iNeuron model may be an efficient tool for validating therapeutic screenings.Several groups have recently shown that anti-sense oligonucleotides (ASOs) therapy targeting the r(GGGGCC) poly GP . TherefoProtocols were approved by the Mayo Clinic Institutional Review Board and Ethics Committee on human experimentation. Skin biopsies were collected after the participants gave written informed consent.c9orf72 repeat expansion was determined by PCR method as previously described  and three repeat expansion carriers . Fibroblasts were generated by ReGen Theranostics Inc., . The presence or absence of the escribed . These sFibroblasts were maintained in Dulbecco\u2019s modified Eagle\u2019s medium  supplemented with 10% heat-inactivated fetal bovine serum (Sigma), 100 units/ml penicillin, and 100 \u03bcg/ml streptomycin (Gibco) at 37\u00b0C, in an atmosphere containing 5% CO2 and 95% air. The shRNA against human PTB1 (shPTB) cloned into lentiviral plasmid pLKO.1 was a kind gift from Dr. Fu . Both shPTB and non-silencing shRNA in the pLKO.1 vector (Sigma) were packaged in HEK293FT cells using Virapower (Invitrogen). Viral particles were collected 48 and 72 h after transfection.For iNeurons production, our previously modified method  was furtCells were fixed with 4% paraformaldehyde, permeabilized with 0.5% Triton X-100/PBS and blocked with 5% skim milk in TBS-Tween20 (TBS-T) buffer. All antibodies were diluted in 5% skim milk/TBS-T. For neuronal markers analysis, following antibodies were used: mouse anti-MAP2 , mouse anti-Neurofilament H , mouse anti-neuronal nuclei , rabbit anti-Synapsin 1 , rabbit anti-MAP2 , mouse anti-Tuj1 , rabbit anti-postsynaptic density protein 95 , rabbit anti-Drebrin , rabbit anti-pan voltage-gated Na2 + channels , anti-vesicular glutamate transporter 1 , and goat polyclonal anti-PTB1 . Rabbit antibodies against c9RANT products, anti-poly(GP), anti-poly(GA), anti-poly(GR), anti-poly(PA), and anti-poly(PR), were generated as described previously  and usedFibroblasts were transduced with shPTB1 or non-silencing control shRNA. Cells were collected and lysed 5 days later and the samples were run on 4\u201320% Tris\u2013glycine polyacrylamide gel. Proteins were then transferred from the gel to nitrocellulose membranes following standard protocols and the immunoblot was completed using goat polyclonal anti-PTB1  and mouse monoclonal anti-\u03b2-actin .exp  (O-methyl RNA/DNA ASOs were generated by Integrated DNA Technologies (IDT). For quantification experiments, iNeurons were induced in 96-well plates and serial pictures were generated with BD Pathway Bio-imager (BD Biosciences). For each cell line and condition, the percentage of cells containing c9RANT inclusions was calculated from 6 wells in 4 independent experiments.Control anti-sense oligonucleotides  and ASOs targeting the r(GGGGCC)CGGCCCC)  in finalRNA FISH on fibroblasts and iNeurons to detect RNA foci consisting of the sense (S) transcript was performed using a modified method described previously . BrieflyThe iNeurons were grown in 96-well plates and treated with increasing concentrations of tunicamycin (Sigma) for 24 h or 10 \u03bcM glutamate (Sigma) for 8 h. Medium was collected and lactate dehydrogenase (LDH) levels using Cyto-tox 96 (Promega) were measured with Spectra Max M5e Microplate Reader (Molecular Devices).t-test for comparison between two sample groups. Two-way ANOVA Fisher\u2019s test was used for multiple comparisons with a 95% confidence level. We considered the difference between comparisons to be significant when P < 0.05 for all the statistical analyses.We used paired student\u2019s Effect of PTB1 downregulation in several cell types has been shown to result in direct conversion to neuron-like cells . In an ac9orf72-related pathologies, we analyzed them for the presence of RNA foci, usually found in c9ALS/FTD patients. As reported previously, HDFs of c9ALS/FTD patients contain intranuclear RNA foci (in situ hybridization (RNA FISH) by utilizing fluorescently labeled locked nucleic acid (LNA) oligonucleotides probes against the (S) and (AS) repeat RNA expansion (c9orf72 expansion carriers (C9 +) are consistent with results previously reported in iPSC derived neurons from c9orf72 ALS fibroblasts (To see whether iNeurons could serve as a useful cellular model for RNA foci . (S) andxpansion . RNA focxpansion . Interesxpansion  but is rxpansion . The perxpansion . The varroblasts .In contrast to the RNA foci, we were not able to detect RANT products in HDFs . We wereTo examine, whether our iNeuron model could be utilized as a tool for research related to experimental therapies, we treated the cells with ASOs. Specifically designed antisense oligonucleotides have been proven to mediate the target RNA molecules degradation through RNase H-based mechanism. Previously, it has been shown that a 3-day treatment with ASOs efficiently reduced the RNA foci formation, however, did not significantly affect poly(GP) accumulation .Control ASO or ASOs (5 \u03bcM) were applied to the cells 4 days post-transduction. Further differentiation steps including the media changes remained unmodified. ASOs reduced the staining of RNA foci formed from the (S) strand by more than 90% in three different C9 + iNeuron lines . The RNAImportantly, we also observed effect on c9RANT products translated from the (S) strand. The quantification was performed by counting cells containing inclusions by BD Pathway Bio-imager. In case of poly(GR) and poly(GA) peptides, the peptides translated only from the (S) strand, the inclusion formation was reduced by more than 85 and 75%, respectively, in all three C9 + iNeuron lines . Accordiexp did not cause cytotoxicity in iNeurons. However, the C9 + cells were more sensitive to the treatment with a well-known endoplasmic reticulum stress inducer, tunicamycin icamycin . This isc stress . Importac stress . Similarc stress , that hac stress . Our resThese results confirm that iNeurons are a suitable cellular disease model system for screening and performing experimental therapies for c9ALS/FTD.In this study, we characterize a cellular model of c9ALS/FTD and provide evidence that this model is suitable for experimental therapeutic attempts. Studying neurological diseases is very challenging as compared to other medical fields due to the inaccessibility of the CNS neurons affected by diseases. Most of the human brain studies in neurological patients have been performed on post-mortem tissues often depicting the end-stage of the disease. With improving cellular and animal models of the GGGGCC repeat expansion, we can uncover the pathomechanism related to c9ALS/FTD. Traditional approaches in modeling disease have multiple limitations often due to overexpression of the disease gene. Moreover, cellular and animal models often partially imitate the disease leading to limited phenotypic correlations between the genetic models and human diseases. Consequently, most of the successful experimental treatments fail to be introduced to clinics.New approaches in disease modeling are not only vital to recapitulate human neuropathologic conditions but also can reveal unknown aspects, which could greatly improve the benefits for patients. It is particularly true in disorders without definitive causative genes and mutations  as well as in sporadic neurological disorders caused by interactions of environmental and (multi)genetic risk factors. Another category comprises disorders where the cloning of the causing genes is problematic . The cell reprograming technology for producing iPSCs allows studying the development and progression of neurological diseases in human systems with the disease-specific pathways investigated before and during disease onset. Several reports have been published on employing iPSC technology in modeling neurological diseases, including PD, AD, spinal muscular atrophy or familial dysautonomia .Direct conversion of somatic cells bypassing the iPSC stage is an alternative approach which considerably shortens the process patient-specific neurons generation. There have been several methods published using various cocktails of transcription factors  . These mexp (We extended this finding and used shPTB1 in HDFs obtained from c9ALS/FTD patients. Within 2 weeks, we were able to generate iNeurons which expressed multiple neuronal markers . Importaexp . To testexp . We founexp . Importaexp  and glutexp .c9orf72 mRNA has been shown to be one of the pathological hallmarks of the c9ALS/FTD disease (c9orf72 mutation, including those involved in this study (Reduction of the  disease , probabl disease . We haveis study .The simplicity of the direct conversion strategy enables rapid production of iNeurons, as the whole procedure routinely takes 2\u20133 weeks. As the primary fibroblast cultures from punch biopsies can be established in 4\u20136 weeks, the patient-specific iNeurons can be generated within 2 months after the patient\u2019s visit. Therefore, this model represents a powerful tool not only for accurately recapitulating the pathology of c9ALS/FTD but also for individualized testing of potentially effective drugs in the future.POB conceived and designed the experiments. POB, JHD, and HS performed the experiments. POB andVManalyzed the data. POB and VM wrote the manuscript.POB is employed by the company Bioinova, Ltd.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Ugandan Passiflora virus (UPV) sequenced from a symptomatic sample of KH7 passion fruit (Passiflora edulis Sims) variety. UPV had limited amino acid identity with other potyviruses known to cause passion fruit woodiness disease (PWD).Here, we present the first near-complete genome of  Ugandan Passiflora virus (UPV) sequenced from a symptomatic sample of KH7 passion fruit (Passiflora edulis Sims) variety. UPV had limited amino acid identity with other potyviruses known to cause passion fruit woodiness disease (PWD). The closest relationship (71.2% amino acid similarity) was with Bean common mosaic necrosis virus.Here, we present the first near-complete genome of  Passiflora edulis Sims)  was reported to cause PWD in Uganda (Passion fruit woodiness disease (PWD) is globally the most economically important disease of passion fruit (is Sims) . PWD is is Sims) \u20134. Recenn Uganda . To deven Uganda . Howevern Uganda . Here, wFive leaf samples were collected from a single plant belonging to KH7 variety and showing PWD-like symptoms. The KH7 plants were collected from a farmer\u2019s field and maintained in an insect-proof screenhouse. Total RNA was extracted from the samples using a plant RNA miniprep kit (Zymo Research). An RNA quality check was done using Tris-acetate-EDTA (TAE)/formamide agarose gel electrophoresis  for quality control by first trimming with previously described quality parameter settings . The tri-2.2.29+ .De novo assembly yielded 43 contigs of >1,000 bp. The contig of interest was 9,670\u2009nt with 8,100,407 reads mapping to it with a coverage of 126,047\u00d7. The 9,670-nt contig (referred to here as KH7-1) had a G+C content of 40.73%. A BLASTN search revealed that KH7-1 resembled a Ugandan Passiflora virus isolate, UGM-19a (GenBank accession number FJ896000), with 99.36% nt identity over 1,718\u2009bp. Also, KH7-1 had a single ORF comprised of 10 mature proteins typical of potyviruses (Bean common mosaic necrosis virus isolates (ANO46357 and ARI46489). Although the UPV sequences currently present in GenBank originate solely from Uganda, we propose a more neutral name for this virus (Passiflora virus\u201d (PV). This is because with increasing human movement and world trade involving plants/plant products, this virus might be found elsewhere  remained after trimming. yviruses , 12. Paiyviruses  showed lis virus , withoutMK110656. Raw data were deposited in the SRA under BioSample number SAMN10717829, which is part of BioProject number PRJNA513986.The sequence described here was deposited in GenBank under accession number"}
+{"text": "Plants respond to abiotic stresses by activating a specific genetic program that supports survival by developing robust adaptive mechanisms. This leads to accelerated senescence and reduced growth, resulting in negative agro-economic impacts on crop productivity. Cytokinins (CKs) customarily regulate various biological processes in plants, including growth and development. In recent years, cytokinins have been implicated in adaptations to osmotic stresses with improved plant growth and yield. Endogenous CK content under osmotic stresses can be enhanced either by transforming plants with a bacterial isopentenyl transferase (IPT) gene under the control of a stress inducible promoter or by exogenous application of synthetic CKs. CKs counteract osmotic stress-induced premature senescence by redistributing soluble sugars and inhibiting the expression of senescence-associated genes. Elevated CK contents under osmotic stress antagonize abscisic acid (ABA) signaling and ABA mediated responses, delay leaf senescence, reduce reactive oxygen species (ROS) damage and lipid peroxidation, improve plant growth, and ameliorate osmotic stress adaptability in plants. Osmotic stresses in plants are caused by drought, salinity and high temperature. Drought is a major global problem that impacts 1\u20133% of all land. This number is predicted to increase to 30% by 2090 . ExogenoIPT (AtIPT1 to AtIPT9) genes and 7 CKX (AtCKX1 to AtCKX7) genes , retained relatively higher contents of chlorophyll, carotenoids, and soluble proteins compared to control plants [IPT gene (pHSP70::IPT), exhibited a 2\u20133-fold increase in root CK concentration and improved plant growth and yield under salinity stress (100\u2009mM NaCl for 22\u2009days). Enhanced CK concentrations in transgenic tomato plants delayed stomatal closure and leaf senescence and virtually doubled shoot growth compared to WT plants. Furthermore, ABA and toxic Na+ ion concentrations decreased by 20\u201340% and 30% respectively with concomitant increases in the essential K+ ion by 20% in mature leaves [IPT expressing rootstock (p35S::IPT); plant yield was enhanced by 30% compared to WT under salinity stress [IPT overexpressing plants may also be substantiated by improved N-use efficiency. Transgenic tobacco plants (pSARK::IPT) with increased CK biosynthesis, maintained adequate biomass and growth rates under limited N conditions compared to WT plants [pSAG12::IPT modified rice plants resulted in vigorous growth even after a long drought period that killed the control plants. The transgenic plants displayed improved photosynthetic activity and maintained high water contents during drought [pSAG12::IPT) in transgenic peanut plants also resulted in higher photosynthetic rates with improved stomatal conductance and transpiration, compared to WT control plants under limited irrigation conditions. All these CK mediated changes in transgenic peanut plants resulted in significantly higher yields than wild-type control plants in the field [AHK2, AHK3 and CRE1/AHK4 in Arabidopsis displayed rapid seed germination but the leaves of mutants formed fewer cells and had reduced chlorophyll content [ipt1, 3, 5 and 7 mutants showed better salt and drought tolerance but had reduced yield compared to WT [Leaf discs of l plants . Tomato e leaves . In anoty stress . High yiT plants . Higher  drought . Similargene pHSP0::IPT, e content . Arabidoed to WT .IPT modulations, exogenous applications of synthetic cytokinins have also proved equally beneficial in improving plant growth under stress environments. Foliar spray of CPPU enhanced salt tolerance in rice by maintaining rates of photosynthesis, soluble sugars and free proline concentration under salinity stress [\u22121 BAP significantly increased membrane stability index (MSI), photosynthetic pigment contents, chlorophyll stability index, and other growth parameters under drought and high temperature stress conditions [Elevated concentrations of CK under drought stress counteract drought-induced signaling and facilitate plants to act ordinarily ,99. Hency stress . Exogenoy stress . In a renditions .IPT [Reactive oxygen species (ROS) are generated in chloroplasts and mitochondrial electron transport chains in response to both abiotic and biotic stresses . DroughtIPT ,106,107 IPT ,109,110.IPT gene under control of the promoter of a small subunit of rubisco (pSSU::IPT) exhibited delayed senescence and predominance of zeatin and zeatin riboside type CKs [pSARK::IPT transgenic tobacco plants grown under limited nitrogen (N) conditions demonstrated reduced oxidative damage and higher biomass compared to WT plants [pSAG12::IPT chimeric gene and induced by 40% (w/v) polyethylene glycol (PEG) mediated osmotic stress for 20 h, revealed higher activities of SOD, CAT, APX, GPX and DHAR compared to control plants [Tobacco plants overexpressing the type CKs . The tratype CKs ,111. Furtype CKs . In anotT plants . Gerberal plants . Additiol plants .pSAG12::IPT modification in creeping bentgrass (Agrostis stolonifera L.) led to greater antioxidant enzyme activities of SOD, POD and CAT, with relatively lower lipid peroxidation in leaves under osmotic stress than NT plants [pSAG12::IPT gene cassette. Root physiological analysis of transgenic plants showed significantly lower contents of ROS (hydrogen peroxide and superoxide) and less lipid peroxidation compared to WT roots under drought stress. Enzymatic assays and transcript abundance analysis further revealed predominantly higher activities of SOD, POD, CAT and DHAR in roots of transgenic bentgrass under drought stress [2\u2212 and H2O2 concentration than control CK0 plants. The CK100 treatment boosted activities of SOD, APX, CAT and POD by 25%, 22%, 17%, and 24%, respectively compared to CK0 [pSARK::IPT transgenic tobacco plants showed less oxidative damage under limited N conditions. Nevertheless, enhancing the concentration of CK, either through exogenous application or endogenously via IPT modifications, always proved advantageous for the plant in terms of reducing oxidative damage.T plants . In anott stress . Antioxid to CK0 . Howeverd to CK0 , where ppSAG12::IPT overexpressing tobacco plants were allowed to undergo natural senescence and lipid peroxidation rate was determined by GS-MS using end product malondialdehyde (MDA). Though leaves of pSAG12::IPT remained green due to delayed senescence, lipid peroxidation was much higher compared to WT leaves of the same age [Plenty of evidences suggest that drought induces senescence of leaves with concurrent enhancement in ROS production. Both senescence and ROS production are moderated by higher CK levels inside the plant. However, when plants are not under stress, contrasting results deny the correlation of senescence progression with ROS-triggered lipid peroxidation. Recently, leaves of same age . ResultspSARK::IPT modified tobacco plants, performed under prolonged water deficit conditions, revealed repression of carotenoid pathway genes which are implicated in ABA biosynthesis [pSARK::IPT tobacco plants were further complemented by assessing expression of corresponding proteins using Western Blot [IPT (pSAG12::IPT) in creeping bentgrass under drought stress, exposed differential expression of 252 genes related to energy production, metabolism, stress defense, signaling, protein synthesis and transport and membrane transport. Substantially higher transcript levels were observed for genes encoding proteins like Mg-protoporphyrin IX, chloroplast localized ToxA binding protein (Pr ToxA), CAT, aquaporin Pip1\u20132, Leu-rich repeat (LRR) receptor kinases, universal stress protein (USP), and isoflavone reductase-like protein 5. Conversely, transgenic plants showed reduced transcript levels of genes encoding malate dehydrogenase, glycogen synthase kinase (GSK), DELLA proteins, and ATP binding cassette (ABC) transporters [IPT-transgenic creeping bentgrass was performed under drought stress. Among 127 differentially expressing TFs, 65 exhibited upregulation and 62 were downregulated in IPT-transgenic plants, compared to WT. The downstream genes of 15 TFs also expressed differentially in IPT-transgenic plants. Significant transcriptional upregulation was detected in central hubs of bHLH148, MYB4/4-like and WRKY28/53/71. These TFs are ascribed to trigger the genes involved in jasmonic acid (JA) signaling and suppress the genes associated with ABA signaling [A transcriptome study of ynthesis . By contern Blot . CK arbisporters . To idenignaling .Agrostis stolonifera, expressing IPT under control of two different inducible promoters (SAG12 and HSP18), were performed under heat stress (35 \u00b0C). Significant changes were detected in proteins related to energy metabolism, localization and storage, and stress defense. Transgenic plants displayed predominantly higher abundance of enolase, oxygen-evolving enhancer protein 2, putative oxygen-evolving complex, rubisco small subunit, Hsp90, and glycolate oxidase in leaves under heat stress, compared to NT plants. Similarly, root proteome revealed relatively higher abundance of Fd-GOGAT, nucleotide-sugar dehydratase, NAD-dependent isocitrate dehydrogenase, ferredoxin-NADP reductase precursor, putative heterogeneous nuclear ribonucleoprotein A2, ascorbate peroxidase, and dDTP-glucose 4\u20136-dehydratases-like protein [pSAG12::IPT) transgenic creeping bentgrass under drought stress revealed higher abundance of proteins involved in energy production during the processes of photosynthesis and respiration  and glyceraldehyde phosphate dehydrogenase (GAPDH)), compared to WT plants. Furthermore, transgenic plants showed higher abundance of proteins involved in methionine and glutamine synthesis, chloroplastic elongation factor (EF-Tu), protein disulphide isomerases (PDIs), and antioxidant enzymes , than WT plants [pSSU::IPT) and low (p35S:CKX1) endogenous CK were analyzed. Results revealed substantial quantitative differences in stroma proteins of both the transgenic plants but with no qualitative change in chloroplast proteome [Differential proteomic analyses of leaves and roots of  protein . In anotproteome .IPT overexpression caused the upregulation of BR (brassinosteroid)-biosynthesis (DWF5 and HYD1) and BR-signaling  genes under water deficit stress, suggesting a positive correlation between CK and BR [JAZ12, JAZ1, OPR2 and MES3) [OsPIN6 and OsPIN3a, was downregulated in IPT overexpressing rice plants [pSAG12::IPT transgenic eggplants displayed relatively higher contents of IAA and GA under drought stress [Contrasting observations revealed that CK-deficient plants display a strong stress-tolerant phenotype with increased cell membrane integrity and abscisic acid (ABA) hypersensitivity  but at tK and BR ,60. Convnd MES3) ,60, whilnd MES3) . Contrast stress . Nonethe"}
+{"text": "Salmonella enterica subsp. enterica serovar Gallinarum  strains isolated in Colombia in 2017 from layer breeders of different ages. The layer breeder flocks were presenting with an elevated mortality with lesions typical of fowl typhoid (FT).This report describes the genome sequences of four  Salmonella enterica subsp. enterica serovar Gallinarum  strains isolated in Colombia in 2017 from layer breeders of different ages. The layer breeder flocks were presenting with an elevated mortality with lesions typical of fowl typhoid (FT). These draft genome sequences revealed a highly conserved genome of Salmonella Gallinarum strains circulating in Colombia.This report describes the genome sequences of four  Salmonella enterica subsp. enterica serovar Gallinarum  is the etiological agent of fowl typhoid (FT) in poultry, affecting mainly layer hens close to the egg-laying phase  countries , 25 weeks old (isolate GDX58), 15 weeks old (isolate FTA303), and 1 week old (isolate Buga). Each production unit of layer breeder flocks was composed of 10,000 chickens, and mortality reached 40,000 chickens per week, for a total of 500,000 birds. Some moribund birds were sacrificed and subjected to necropsy examination and presented with liver and spleen enlargement, necrotic foci, and friability. Liver and spleen fragments were collected and cultured in tetrathionate for 48 h at 37\u00b0C and then cultured in MacConkey and xylose-lysine-tergitol 4 (XLT4) agar for 24 h at 37\u00b0C. Typical colonies were detected in both medium types and were subjected to biochemical testing using the API 20E kit . After biochemical identification, colonies were cultured in LB broth for 18 hours at 37\u00b0C for DNA extraction, using the ChargeSwitch genomic DNA (gDNA) mini bacteria kit . DNA concentration was determined by Qubit fluorometric quantitation and the double-stranded DNA (dsDNA) broad-range (BR) assay kit (Thermo Fisher Scientific) before being diluted to 0.5 ng/\u00b5l. A library was prepared using the Nextera XT DNA library preparation kit , and sequencing was performed using the MiSeq sequencing system , with a v2 kit, 500 cycles of amplification, and paired-end sequencing (2 \u00d7 250-bp reads). The de novo genome assembly of reads, adapter removal, and quality filtering were conducted using A5-miseq software version 20160825  -Iaa gene in all isolates, which is a chromosomally encoded aminoglycoside acetyltransferase that confers aminoglycosides. Outbreaks of FT in LA are recurrent due to several factors, such as chicken breeder suppliers, environmental contamination, installations, insects, wild bird reservoirs, hematophagous mites, and others. A genome comparison of different isolates from Colombia showed that the isolates are very similar. The currently described genomes of Salmonella Gallinarum isolates from layer breeder flocks can provide more information on Salmonella Gallinarum genetic evolution and genome organization and its pathobiological relationship with chickens for understanding certain outbreaks   and showsion 2.0  identifision 3.1  identifiutbreaks .QYTY00000000 (GDX7), QYTX00000000 (GDX58), QZND00000000 (FTA303), and RHEL00000000 (Buga) and Sequence Read Archive (SRA) accession numbers SRR8521149 (GDX7), SRR8521221 (GDX58), SRR8521219 (Buga), and SRR8521220 (FTA303).These annotated draft genome sequences have been recorded in DDBJ/EMBL/GenBank under accession numbers"}
+{"text": "Background\u2003Increased tibial slope has been shown to be associated with higher anterior cruciate ligament (ACL) reconstruction failure rate. Little is known about the correlation of tibial slope and anterior tibial translation in ACL deficient and reconstructed knees as well as the correlation of tibial slope and ACL reconstruction outcome.Purpose/Hypothesis\u2003The purpose of this study was to investigate the correlation of tibial slope with anterior tibial translation and ACL reconstruction outcome. It is hypothesized that increased medial tibial slope is associated with increased anterior tibial translation in the ACL deficient knee. Medial tibial slope is neither expected to affect anterior tibial translation in the ACL reconstructed knee nor short-term ACL reconstruction outcome.Materials and Methods\u2003A cohort of 104 patients with unilateral isolated ACL deficiency undergoing hamstring ACL reconstruction by a single surgeon between 2002 and 2004 was followed up prospectively. Preoperative data were collected including patient demographics, time to surgery, subjective and objective International Knee Documentation Committee (IKDC) outcome scores, as well as manual maximum anterior tibial translation measured with the KT-1000 measuring instrument. Medial tibial slope was assessed on long lateral X-rays using the method described by Dejour and Bonnin (1994). Intraoperative data were collected including meniscal integrity; postoperative data were collected at 1-year follow-up including manual maximum anterior tibial translation (KT-1000 measured), and subjective and objective IKDC scores.Results\u2003A significant positive correlation was seen between medial tibial slope in ACL deficient knees and KT-1000\u2013measured anterior tibial translation . The positive relationship increased when meniscal integrity was factored in . No significant correlation was seen between medial or lateral meniscal integrity and KT-1000\u2013measured anterior tibial translation . No significant correlation was seen between KT-1000\u2013measured anterior tibial translation and time to surgery. One year postoperatively, 82 patients were assessed, while 26 patients were lost to follow-up; no significant correlation was found between increased medial tibial slope and poor ACL reconstruction outcome measured by post-ACL reconstruction anterior tibial translation (KT-1000) or subjective and objective IKDC scores.Conclusion\u2003Increased medial tibial slope is associated with increased (KT-1000 measured) anterior tibial translation in ACL deficient knees. No significant correlation is found between increased medial tibial slope and poor short-term ACL reconstruction outcome. Rupture of the anterior cruciate ligament (ACL) represents a common knee injury, eventually resulting in long-term complications such as meniscal and chondral deterioration even after the ACL has been satisfactorily reconstructed and stable conditions are restored.t-tests.A cohort of 104 patients with unilateral isolated ACL deficiency undergoing hamstring ACL reconstruction by a single surgeon between 2002 and 2004 was followed up prospectively. Preoperative data were collected including patient demographics, time to surgery, subjective and objective IKDC outcome scores, as well as manual maximum anterior tibial translation measured with the KT-1000 measuring instrument. Furthermore, medial tibial slope was assessed on long lateral X-rays using the method described by Dejour and Bonnin which has shown acceptable inter- and intraobserver reliability.r\u2009=\u20090.24;p\u2009=\u20090.003). Meniscal integrity and meniscal treatment procedure (in per cent) are shown inr\u2009=\u2009\u221218;p\u2009=\u20090.06). No significant correlation was seen between KT-1000\u2013measured anterior tibial translation and time to surgery. One year postoperatively, 82 patients were assessed, while 22 patients were lost to follow-up; 93% of patients showed a post-ACL reconstruction anterior tibial translation (KT-1000 measured) of less than 3 mm. One patient showed a post-ACL reconstruction anterior tibial translation (KT-1000 measured) of more than 5\u2009mm and was defined as an ACL failure. Mean postoperative subjective IKDC score was 90 (63\u2013100). Seventy-four patients showed a normal objective IKDC score, three patients showed a nearly normal score, while one patient showed a severely abnormal objective IKDC score.In this study, 73 males and 31 females (mean age: 29 years) with unilateral isolated ACL deficiency were assessed; ACL injury was sustained sports related in 73 cases. Preoperative objective IKDC score was severely abnormal in 48 patients and abnormal in 56 patients. None of the patients showed a nearly normal or normal IKDC score. Mean preoperative subjective IKDC score was 54 (range: 24\u201379). Mean tibial slope in ACL deficient knee was 8.36 degrees (range: 0\u201317 degrees). Mean anterior tibial translation of ACL deficient knees measured by KT-1000 was 6.38\u2009mm (range: 3\u201319 mm). A significant positive correlation was seen between medial tibial slope of ACL deficient knees and the KT-1000\u2013measured anterior tibial translation  anterior tibial translation in ACL deficient knees. Second, no significant correlation was found between increased medial tibial slope and poor short-term ACL reconstruction outcome at 1-year follow-up measured by post-ACL reconstruction anterior tibial translation (KT-1000 measured) as well as subjective and objective IKDC scores. To date March 2017), three patients with ACL reconstruction failure have been identified with tibial slopes of 10, 11, and 17 degrees, respectively, which all lie above the average measured tibial slope of 8.36 degrees. The findings of this study support the findings of Dejour and Bonnin, who demonstrated a mean 6\u2009mm increase in anterior tibial translation for each 10 degrees increase in posterior tibial slope in ACL deficient knees., three pIncreased medial tibial slope is associated with increased (KT-1000 measured) anterior tibial translation in ACL deficient knees. No significant correlation is found between increased medial tibial slope and poor ACL reconstruction outcome."}
+{"text": "This case series documents local experience using accelerated theta-burst repetitive transcranial magnetic stimulation (rTMS) as a supplementary treatment for depression in both major depressive disorder (MDD) and bipolar disorder (BD).Z = -2.55, p = 0.011). The CGI severity scores also decreased significantly between baseline  and post-treatment .Nine consenting patients  received the accelerated theta-burst protocol consisting of three magnetic pulses delivered 20 ms apart and repeatedly delivered every 200 ms, resulting in a 5 Hz theta rhythm over the left dorsolateral prefrontal cortex (DLPFC). Treatment comprised 20 sessions delivered over 8 days. Accelerated theta burst rTMS treatment provides more stimuli over a shorter period of time, thus potentially increasing feasibility and cost-effectiveness. Improvement was monitored using the Centre for Epidemiological Studies Depression (CES-D) scale and the Clinical Global Impression (CGI) scale at baseline, day 5 and day 8 of rTMS treatment. All patients remained on their prescribed medication for the duration of rTMS treatment. We performed a Wilcoxon matched-pairs signed rank test to determine whether there was a difference in scores from baseline to post-treatment. The CES-D scores decreased significantly from baseline  to post-treatment (Mdn 17.0; IQR 11.0; 28.5; Five patients demonstrated at least a 50% symptom reduction on the CES-D scale. The most commonly reported adverse effect was mild headache, which lasted a few hours during and post-rTMS treatment.A limitation of these findings is that this was a small case series without a control arm; however, the findings suggest that the accelerated theta burst rTMS protocol for depression was well tolerated with most patients also experiencing symptomatic improvement by day 8."}
+{"text": "We found tumor specific TNC gene and protein overexpression that directly correlated with higher tumor grade , H3K27\u2009M mutation (p\u2009=\u20090.012), shorter progression free survival (p\u2009=\u20090.034), and poorer overall survival (0.041) in association with these factors. TNC knockdown via lentiviral shRNA transfection of HGG (n\u2009=\u20091) and DIPG (n\u2009=\u20093) cell lines resulted in decreased cell proliferation, migration, and invasion in vitro (p\u2009<\u20090.01), while TNC cDNA transfection resulted in increased cell migration, invasion and proliferation (p\u2009<\u20090.01) as well as altered cell morphology in H3K27\u2009M mutant DIPG lines. Whole transcriptome sequencing analysis (RNA-Seq) on DIPG (n\u2009=\u20093) and HGG (n\u2009=\u20092) cell lines after TNC cDNA, shRNA, and empty vector control transfection revealed the effects of TNC expression level on global gene expression profiles. Together, our findings reveal TNC expression in DIPG in association with H3K27\u2009M mutation and VEGF signaling, and suggest that TNC may contribute to DIPG tumor phenotype, and serve as a clinically detectable biomarker for DIPG.Diffuse intrinsic pontine glioma (DIPG), an infiltrative, high grade glioma (HGG) affecting young children, has the highest mortality rate of all pediatric cancers. Despite treatment, average survival is less than twelve months, and five-year survival under 5%. We previously detected increased expression of Tenascin-C (TNC) protein in DIPG cerebrospinal fluid and tumor tissue relative to normal specimens. TNC is an extracellular matrix (ECM) glycoprotein that mediates cell-matrix interactions, guides migrating neurons during normal brain development and is thought to maintain the periventricular stem cell niche in the developing brain. Tumor TNC expression is reported in adult glioma and other cancers. However, the pattern and effects of TNC expression in DIPG has not been previously explored. Here, we characterize TNC expression in patient derived pediatric supratentorial HGG (The online version of this article (10.1186/s40478-019-0727-1) contains supplementary material, which is available to authorized users. Brain tumors are the most common solid cancer in children. Approximately 15% of pediatric brain tumors arise in the brainstem, of which up to 80% are a subtype known as diffuse intrinsic pontine glioma (DIPG), an infiltrative, high grade glioma affecting young children . DIPG tyH3F3A and HIST1H3B, respectively) . O. O54]. Oresponse , 54, 61.response : measuriIn conclusion, we characterized TNC expression in pediatric glioma tissue and cell lines, including DIPG, with higher endogenous expression levels in tumors harboring the H3K27\u2009M mutation. TNC overexpression is associated with more malignant cell behavior, including increased cell proliferation and migration, and patterns of gene expression consistent with a pro-angiogenic, mesenchymal tumor phenotype. Our findings suggest TNC overexpression in pediatric high grade and diffuse midline glioma is clinically detectable and may significantly contribute to tumor biology. Given this, we are currently investigating the effects of TNC expression in vivo on tumor growth and animal survival in an animal xenograft model of pediatric glioma, and evaluating changes in TNC expression by DIPG cells in vitro in response to novel epigenetic therapies. Our results suggest TNC may serve as a feasible disease biomarker and novel therapeutic target for this challenging disease.Additional file 1:Figure S1. TNC expression in pediatric glioma cell lines modified via shRNA and cDNA transfection in vitro. Pediatric supratentorial high-grade glioma (HGG n\u2009=\u20091) and brainstem glioma (DIPG n\u2009=\u20093) cell lines were modified via lentiviral transfection of TNC cDNA and shRNA constructs. Two distinct shRNA constructs, 232 and 234, were generated. a)TNC transcript level after transfection, measured via qPCR, demonstrating TNC shRNA knockdown (left) and cDNA amplification (right), relative to empty vector controls . Y-axis: Normalized TNC mRNA expression level (percent GAPDH). b) TNC protein level after transfection, measured via western blot, demonstrating decreased protein expression after shRNA knockdown (upper panels) and increased expression cDNA amplification (lower panels), relative to empty vector controls. Densitometry analysis of western blot signal intensity confirms statistical significance of TNC expression patterns between transfected lines and empty vector controls . Y-axis: TNC protein band intensity . Error bars represent standard error of the mean. c) Fluorescent microscopy images showed transfection efficiency of >\u200995% in both cDNA and shRNA. Scale bar\u2009=\u2009200\u2009\u03bcm. (TIF 138230 kb)Additional file 2:Figure S2. Targeted gene expression analysis in pediatric glioma cell lines. Levels of TNC and related transcripts were measured via qPCR in pediatric supratentorial highgrade glioma (HGG n\u2009=\u20093) and brainstem glioma (DIPG n\u2009=\u20095) cell lines. a) Expression levels of TNC, Notch 1, Notch 2, MYCN and PDGFRA across cell lines studied. Values are normalized to GAPDH expression levels in each cell line. Y-axis: Relative gene expression to GAPDH. Error bars represent standard error of the mean. b) Correlation between TNC expression each gene of interest across cell lines, as measured by qPCR. Positive correlation was found between TNC and Notch 2, and between TNC and PDGFRA, but did not reach statistical significance. c) Correlation between TNC transcription and genes of interest  across cell lines, as measured by RNA-Seq. TNC expression positively correlated with Notch2 (R2\u2009=\u20090.817) and PDGFRA (R2\u2009=\u20090.820). Each data point represents one glioma cell line. (TIF 101751 kb)Additional file 3:Figure S3. Unsupervised hierarchical clustering of cell line gene expression profiles RNA-Seq analysis was performed in triplicate on DIPG (n\u2009=\u20093) and HGG (n\u2009=\u20092) cell lines after TNC cDNA, shRNA, and empty vector control transfection. Differentially expressed genes  were identified between cDNA and shRNA lines. a) Unsupervised analysis of resulting gene expression profiles by cell line (Y-axis) demonstrates clustering by technical replicate, followed by experimental condition. b) Scatterplot depicting differential TNC expression levels across shRNA and cDNA cell lines holds when adjusted for cell culture conditions (with or without serum FBS). c) Explicit modeling for differentially expressed genes both as means and as sums across technical replicates results in minimal change in data sets when adjusted for culture conditions. Together, these data demonstrate that observed transcriptomes and resulting cell functions are driven by induced differences in TNC expression. (TIF 136432 kb)Additional file 4:Figure S4. Relative TNC expression differs across single-cell subpopulations. Single cell RNA-Seq of H3K27\u2009M mutant pediatric glioma was performed by Filbin et al. [p\u2009=\u20090.0002). Y-axis: mean gene expression (in log2 TPM/10). Error bars represent standard error of the mean. Relative gene expression of the three DIPG subpopulations was normalized to all DIPG cells. Published data analyzed and presented with permission of the Dr. Mariella Filbin. (TIF 17718 kb)n et al. , revealiAdditional file 5:Online\u00a0Resource 1. Whole transcriptome (RNA-Seq) analysis of pediatric glioma cell lines. Whole transcriptome sequencing analysis (RNA-Seq) was performed in triplicate on DIPG (n\u2009=\u20093) and HGG (n\u2009=\u20092) cell lines after TNC cDNA, shRNA, and empty vector control transfection. (PDF 28227 kb)Additional file 6:Online\u00a0Resource 2. Differential gene expression analysis of RNA-Seq data Resulting transcriptomes of cell lines transfected with TNC cDNA were compared to TNC knockdown (shRNA) and controls. Gene count tables from HTSeq were used as input for EBSeq version 1.16.0 [n 1.16.0 . Genes w"}
+{"text": "Cap Analysis of Gene Expression (CAGE) is one of the most popular 5'-end sequencing methods. In a single experiment, CAGE can be used to locate and quantify the expression of both Transcription Start Sites (TSSs) and enhancers. This is workflow is a case study on how to use the CAGEfightR package to orchestrate analysis of CAGE data within the Bioconductor project. This workflow starts from BigWig-files and covers both basic CAGE analyses such as identifying, quantifying and annotating TSSs and enhancers, advanced analysis such as finding interacting TSS-enhancer pairs and enhancer clusters, to differential expression analysis and alternative TSS usage. R-code, discussion and references are intertwined to help provide guidelines for future CAGE studies of the same kind. Transcription Start Sites (TSSs) are focal points of this process: The TSS act as an integration point for a wide range of molecular cues from surrounding genomic areas to determine transcription and ultimately expression levels. These include proximal factors such as chromatin accessibility, chromatin modification, DNA methylation and transcription factor binding, and distal factors such as enhancer activity and chromatin confirmation5. CAGE is based on \u201ccap trapping\u201d: capturing capped full-length RNAs and sequencing only the first 20\u201330 nucleotides from the 5\u2019-end, so-called CAGE tags6. When mapped to a reference genome, the 5\u2019-ends of CAGE tag identify the actual TSS for respective RNA with basepair-level accuracy. Basepair-accurate TSSs identified this way are referred to as CAGE Transcription Start Sites (CTSSs). RNA polymerase rarely initiates from just a single nucleotide: this is manifested in CAGE data by the fact that CTSSs are mostly found in tightly spaced groups on the same strand. The majority of CAGE studies have merged such CTSSs into genomic blocks typically referred to as Tag Clusters (TCs), using a variety of clustering methods (see below). TCs are often interpreted as TSSs in the more general sense, given that most genes have many CTSSs, but only a few TCs that represent a few major transcripts with highly similar CTSSs8. Since the number of mapped CAGE tags in a given TC is indicative of the number of RNAs from that region, the number of CAGE tags falling in given TC can be seen as a measure of expression9.Cap Analysis of Gene Expression (CAGE) has emerged as one of the dominant high-throughput assays for studying TSSs10. Since CAGE captures all capped RNAs, it can also identify long non-coding RNA (lincRNA)11 and enhancers RNA (eRNA). It was previously shown that active enhancers are characterized by balanced bidirectional transcription, making it possible to predict enhancer regions and quantify their expression levels from CAGE data alone13. Thus, CAGE data can predict the locations and activity of mRNAs, lincRNAs and enhancers in a single assay, providing a comprehensive view of transcriptional regulation across both inter- and intragenic regions.As CAGE tags can be mapped to a reference genome without the need for transcript annotations, it can detect TSSs of known mRNAs, but also mRNA from novel alternative TSSs (that might be condition or tissue dependent)14. Only a few packages are dedicated to analyzing 5\u2019-end data in general and CAGE data in particular:TSRchitect15,icetea16,CAGEr17 andCAGEfightR18, seeBioconductor contains a vast collection of tools for analyzing transcriptomics datasets, in particular the widely used RNA-Seq and microarray assaysCAGEr was the first package solely dedicated to the analysis of CAGE data and was recently updated to more closely adhere to Bioconductor S4-class standards.CAGEr takes as input aligned reads in the form of BAM-files and can identify, quantify, characterize and annotate TSSs. TSSs are found in individual samples using either simple clustering of CTSSs (greedy or distance-based clustering) or the more advanced density-based paraclu clustering method19, and can be aggregated across samples to a set of consensus clusters. Several specialized routines for CAGE data is available, such as power law normalization of CTSS counts and fine-grained TSS shifts. Finally,CAGEr offers easy interface to the large collection of CAGE data from the FANTOM consortium10.TSRchitect andicetea are two more recent additions to Bioconductor. While being less comprehensive, they aim to be more general and handle more types of 5\u2019-end methods that are conceptually similar to CAGE . Both packages can identify, quantify and annotate TSSs, withTSRchitect using an X-means algorithm andicetea using a sliding window approach.icetea offers the unique feature of mapping reads to a reference genome by interfacing withRsubread. BothCAGEr,TSRchictet andicetea offers built-in capabilities for differential expression (DE) analysis via the popularDESeq2 oredgeR packages21.CAGEfightR is a recent addition to Bioconductor focused on analyzing CAGE data, but applicable to most 5\u2019-end data. It aims to be general and flexible to allow for easy interfacing with the wealth of other Bioconductor packages.CAGEfightR takes CTSSs stored in BigWig-files as input and uses only standard Bioconductor S4-classes  making it easy for users to learn and combineCAGEfightR with functions from other Bioconductor packages . In addition to TSS analysis,CAGEfightR is the only package on Bioconductor to also offer functions for enhancer analysis based on CAGE (and similarly scoped) data. This includes enhancer identification and quantification, linking enhancers to TSSs via correlation of expression and finding enhancer clusters, often referred to as stretch- or super enhancers.CAGEfightR package can be used to orchestrate an end-to-end analysis of CAGE data by making it easy to interface with a wide range of different Bioconductor packages. Highlights include TSS and enhancer candidate identification, differential expression, alternative TSS usage, enrichment of motifs, GO/KEGG terms and calculating TSS-enhancer correlations.In this workflow, we illustrate how the\u201cIdentification of Gene Transcription Start Sites and Enhancers Responding to Pulmonary Carbon Nanotube Exposure in Vivo\u201d by Bornholdtet al24. This study uses mouse as a model system to investigate how nanotubes affect lung tissue when inhaled. Inhaled nanotubes were previously found to produce a similar response to asbestos, potentially triggering an inflammatory response in the lung tissue leading to drastic changes in gene expression.This workflow uses data fromThe dataset consists of CAGE data from mouse lung biopsies: 5 mice whose lungs were instilled with water (Ctrl) and 6 mice wholes lungs were instilled with nanotubes (Nano), with CTSSs for each sample stored in BigWig-files, shown inThe data is acquired via the nanotubes data package:library(nanotubes)This workflow uses a large number of R-packages: Bioconductor packages are primarily used for data analysis while packages from the tidyverse are used to wrangle and plot the results. All these packages are loaded prior to beginning the workflow:# CRAN packages for data manipulation and plotting library(knitr)                                     library(kableExtra)                                library(pheatmap)                                  library(ggseqlogo)                                 library(viridis)                                   library(magrittr)                                  library(ggforce)                                   library(ggthemes)                                  library(tidyverse)                                 # CAGEfightR and related packages                  library(CAGEfightR)                                library(GenomicRanges)                             library(SummarizedExperiment)                      library(GenomicFeatures)                           library                              library(InteractionSet)                            library(Gviz)                                      # Bioconductor packages for differential expressionlibrary(DESeq2)                                    library(limma)                                     library(edgeR)                                     library(sva)                                       # Bioconductor packages for enrichment analyses    library(TFBSTools)                                 library(motifmatchr)                               library(pathview)                                  # Bioconductor data packages                       library(BSgenome.Mmusculus.UCSC.mm9)               library(TxDb.Mmusculus.UCSC.mm9.knownGene)         library(org.Mm.eg.db)                              library(JASPAR2016)                                We also set some script-wide settings for later convenience:# Rename these for easier access                              bsg <- BSgenome.Mmusculus.UCSC.mm9                            txdb <- TxDb.Mmusculus.UCSC.mm9.knownGene                     odb <- org.Mm.eg.db                                           # Script wide settings                                        register(MulticoreParam(3)) # Parallel execution when possibletheme_set(theme_light) # White theme for ggplot2 figures    The workflow is divided into 3 parts covering different parts of a typical CAGE data analysis:1. CAGEfightR to import CTSSs and find and quantify TSS and enhancer candidates.Shows how to use2. GenomicRanges andBiostrings. This part covers typical analyses made from CAGE data, from summarizing cluster annotation, TSS shapes and core promoter sequence analysis to more advanced spatial analyses (finding TSS-enhancer correlation links and clusters of enhancers).Shows examples of how to perform genomic analyses of CAGE dusters using core Bioconductor packages such as3. CAGEfightR can be used to prepare data for differential expression analysis with popular R packages, includingDESeq2,limma andedgeR25. Borrowing from RNA-Seq terminology, differential expression can be assessed at multiple different levels: Tag cluster- and enhancer-level, gene-level and differential TSS usage26. Once differential expression results have been obtained, they can be combined with other sources of information such as motifs from JASPAR27 and GO/KEGG terms30.Shows howCAGEfightR starts analysis from CTSSs, which is the number of CAGE tag 5\u2019-ends mapping to each basepair (bp) in the genome. CTSSs are normally stored as either BED-files or BigWig-files.CAGEfightR works on BigWig-files, since these can be efficiently imported and allow for random access.data.frame, sometimes called thedesign matrix.CAGEfightR can keep track of the design matrix throughout the analysis:Before starting the analysis, we recommend gathering all information  about the samples to be analyzed in a singledata(nanotubes)                                                              kable %>%    kable_styling(latex_options = \"hold_position\")                           Importing CTSSs.  We need to tellCAGEfightR where to find the BigWig-files containing CTSSs on the hard drive. Normally, one would supply the paths to each file (e.g. /CAGEdata/BigWigFiles/Sample1_plus.bw), but here we will use data from the nanotubes data package:# Setup paths to file on hard drive                      bw_plus <- system.file                 bw_minus <- system.file                 # Save as named BigWigFileList                           bw_plus <- BigWigFileList(bw_plus)                       bw_minus <- BigWigFileList(bw_minus)                     names(bw_plus) <- names(bw_minus) <- nanotubes$Name      CAGEfightR analysis, but it can be speed up by using multiple cores . We also need to specify the genome, which we can get from theBSgenome.Mmusculus.UCSC.mm9 genome package:The first step is quantifying CTSS usage across all samples. This is often one of the most time consuming step in aCTSSs <- quantifyCTSSs,                                               design = nanotubes)                           #> Checking supplied genome compatibility...                         #> Iterating over 28 genomic tiles in 11 samples using 3 worker(s)...#> Importing CTSSs from plus strand...                               #> Registered S3 method overwritten by \u2019pryr\u2019:                       #>   method      from                                                #>   print.bytes Rcpp                                                #> Importing CTSSs from minus strand...                              #> Merging strands...                                                #> ### CTSS summary ###                                              #> Number of samples: 11                                             #> Number of CTSSs: 9.339 millions                                   #> Sparsity: 81.68 %                                                 #> Final object size: 282 MB                                         RangedSummarizedExperiment, which is the standard representation of high-throughput experiments in Bioconductor. We can inspect both the ranges and the CTSS counts:The circa 9 million CTSSs are stored as# Get a summary                                                   CTSSs                                                             #> class: RangedSummarizedExperiment                              #> dim: 9338802 11                                                #> metadata(0):                                                   #> assays(1): counts                                              #> rownames: NULL                                                 #> rowData names(0):                                              #> colnames(11): C547 C548 ... N17 N18                            #> colData names(4): Class Name BigWigPlus BigWigMinus            # Extract CTSS positions                                          rowRanges(CTSSs)                                                  #> GPos object with 9338802 positions and 0 metadata columns:     #>                 seqnames       pos strand                      #>                    <Rle> <integer>  <Rle>                      #>         [1]         chr1   3024556      +                      #>         [2]         chr1   3025704      +                      #>         [3]         chr1   3025705      +                      #>         [4]         chr1   3028283      +                      #>         [5]         chr1   3146133      +                      #>         ...          ...       ...    ...                      #>   [9338798] chrUn_random   5810899      -                      #>   [9338799] chrUn_random   5813784      -                      #>   [9338800] chrUn_random   5880838      -                      #>   [9338801] chrUn_random   5893536      -                      #>   [9338802] chrUn_random   5894263      -                      #>   -------                                                      #>   seqinfo: 35 sequences (1 circular) from mm9 genome           # Extract CTSS counts                                             assay %>%                                            head                                                          #> 6 x 11 sparse Matrix of class \"dgCMatrix\"                      #>    ]#>                                                                #>  . . 1 . . . . . . . .                                     #>  . . . 1 . . . . . . .                                     #>  . . . . 1 . . . . . .                                     #>  . . . . 1 . . . . . .                                     #>  . . . . . . 1 . . . .                                     #>  . 1 . . . . . . . . .                                     Unidirectional and bidirectional clustering for finding TSS and enhancer candidates. CAGEfightR finds clusters by calculating the pooled CTSS signal across all samples: We first normalize CTSSs count in each sample to Tags-Per-Million (TPM) values, and them sum TPM values across samples:CTSSs <- CTSSs %>%                 calcTPM %>%                  calcPooled               #> Calculating library sizes...#> Calculating TPM...          CTSSs: The total number of tags in each library, a new assay calledTPM, and the pooled signal for eachCTSS.This will add several new pieces of information tounidirectional clustering to locate unidirectional clusters, often simply called Tag Clusters (TCs), which are candidates for TSSs. ThequickTSSs will both locate and quantify TCs in a single function call:We can useTCs <- quickTSSs(CTSSs)               #> Using existing score column!       #>                                    #>  - Running clusterUnidirectionally:#> Splitting by strand...             #> Slice-reduce to find clusters...   #> Calculating statistics...          #> Preparing output...                #> Tag clustering summary:            #>   Width   Count Percent            #>   Total 3602099 1e+02 %            #>     >=1 2983433 8e+01 %            #>    >=10  577786 2e+01 %            #>   >=100   40842 1e+00 %            #>  >=1000      38 1e-03 %            #>                                    #>  - Running quantifyClusters:       #> Finding overlaps...                #> Aggregating within clusters...     Note:quickTSSs runsCAGEfightR with default settings. If you have larger or more noisy datasets you most likely want to do a more robust analysis with different settings. See theCAGEfightR vignette for more information.Many of the identified TCs will only be very lowly expressed. To obtain likely biologically relevant TSSs, we keep only TSSs expressed at more than 1 TPM in at least 5 samples :TSSs <- TCs %>%                                                                 calcTPM %>%                                                               subsetBySupport                                           #> Calculating library sizes...                                             #> Warning in calcTotalTags: object already has a column named totalTags#> in colData: It will be overwritten!                                      #> Calculating TPM...                                                       #> Calculating support...                                                   #> Subsetting...                                                            #> Removed 3573214 out of 3602099 regions (99.2%)                           This removed a large number of very lowly expressed TCs, leaving us with almost 30.000 TSSs candidates for analysis.bidirectional clustering for identifying bidirectional clusters (BCs), which are candidate for enhancers. Similarly, we can usequickEnhancers to locate and quantify BCs:Then we turn toBCs <- quickEnhancers(CTSSs)                       #> Using existing score column!                    #>                                                 #>  - Running clusterBidirectionally:              #> Pre-filtering bidirectional candidate regions...#> Retaining for analysis: 68.3%                   #> Splitting by strand...                          #> Calculating windowed coverage on plus strand... #> Calculating windowed coverage on minus strand...#> Calculating balance score...                    #> Slice-reduce to find bidirectional clusters...  #> Calculating statistics...                       #> Preparing output...                             #> # Bidirectional clustering summary:             #> Number of bidirectional clusters: 106779        #> Maximum balance score: 1                        #> Minimum balance score: 0.950001090872574        #> Maximum width: 1866                             #> Minimum width: 401                              #>                                                 #>  - Running subsetByBidirectionality:            #> Calculating bidirectionality...                 #> Subsetting...                                   #> Removed 73250 out of 106779 regions (68.6%)     #>                                                 #>  - Running quantifyClusters:                    #> Finding overlaps...                             #> Aggregating within clusters...                  Note:quickEnhancers runsCAGEfightR with default settings. If you have larger or more noisy datasets you most likely want to do a more robust analysis with different settings. See theCAGEfightR vignette for more information.Again, we are not usually interested in very lowly expressed BCs. As they are overall lowly expressed, we will simply filter out BCs without at least 1 count in 5 samples:BCs <- subsetBySupport#> Calculating support...                                                    #> Subsetting...                                                             #> Removed 20017 out of 33529 regions (59.7%)                                Annotating clusters with transcript models. After having located unidirectional and bidirectional clusters, we can annotate them according to known transcript and gene models. These types of annotation are store viaTxDb-objects in Bioconductor. Here we will simply use UCSC transcripts included in theTxDb.Mmusculus.UCSC.mm9.knownGene package, but theCAGEfightR vignette includes examples of how to obtain aTxDb object from other sources .part of a transcript a TSS lies by using a hierarchical annotation scheme. As some TSSs might be very wide, we only use the TSS peak for annotation purposes:Starting with the TSS candidates, we can not only annotate a TSS with overlapping transcripts, but also in what# Annotate with transcript IDs                           TSSs <- assignTxID  #> Extracting transcripts...                             #> Finding hierachical overlaps...                       #> ### Overlap Summary: ###                              #> Features overlapping transcripts: 87.65 %             #> Number of unique transcripts: 31898                   # Annotate with transcript context                       TSSs <- assignTxType#> Finding hierachical overlaps with swapped ranges...   #> ### Overlap summary: ###                              #>       txType count percentage                         #> 1   promoter 13395       46.4                         #> 2   proximal  2246        7.8                         #> 3    fiveUTR  2112        7.3                         #> 4   threeUTR  1200        4.2                         #> 5        CDS  3356       11.6                         #> 6       exon   161        0.6                         #> 7     intron  2810        9.7                         #> 8  antisense  1294        4.5                         #> 9 intergenic  2311        8.0                         Almost half of TSSs were found at annotated promoters, while the other half is novel compared to the UCSC known transcripts.Transcript annotation is particularly useful for enhancer candidates, as bidirectional clustering might also detect bidirectional promoters. Therefore, a commonly used filtering approached is to only consider BCs in intergenic or intronic regions as enhancer candidates:# Annotate with transcript context                             BCs <- assignTxType        #> Finding hierachical overlaps with swapped ranges...         #> ### Overlap summary: ###                                    # Keep only non-exonic BCs as enhancer candidates              #>       txType count percentage                               #> 1   promoter   766        5.7                               #> 2   proximal  1649       12.2                               #> 3    fiveUTR    67        0.5                               #> 4   threeUTR   596        4.4                               #> 5        CDS   420        3.1                               #> 6       exon    71        0.5                               #> 7     intron  6815       50.4                               #> 8  antisense     0        0.0                               #> 9 intergenic  3128       23.1                                                           Enhancers <- subset)This leaves almost 10000 enhancer candidates for analysis.Merging into a single dataset. For many downstream analyses, in particular normalization and differential expression, it is useful to combine both TSS and enhancers candidates into a single dataset. This ensures that TSSs and enhancers do not overlap, so each CAGE tag is only counted once.CAGEfightR will only allow merging of clusters if they have the same sample and cluster information:We must first ensure that the enhancer and TSS candidates have the same information attached to them, since# Clean colData                             TSSs$totalTags <- NULL                      Enhancers$totalTags <- NULL                 # Clean rowData                             rowData(TSSs)$balance <- NA                 rowData(TSSs)$bidirectionality <- NA        rowData(Enhancers)$txID <- NA               # Add labels for making later retrieval easyrowData(TSSs)$clusterType <- \"TSS\"          rowData(Enhancers)$clusterType <- \"Enhancer\"Then the clusters can be merged: As enhancers are the most complicated type, we keep only enhancers if a TSS and enhancer overlaps:RSE <- combineClusters                                          #> Removing overlapping features from object1: 374                                             #> Keeping assays: counts                                                                      #> Keeping columns: score, thick, support, txID, txType, balance, bidirectionality, clusterType#> Merging metadata...                                                                         #> Stacking and re-sorting...                                                                  We finally calculate the total number of tags and TPM-scaled counts for the final merged dataset:RSE <- calcTPM(RSE)            #> Calculating library sizes...#> Calculating TPM...          Genome-browser figures of TSSs and enhancers. First we can simply plot some examples of TSSs and enhancers in a genome browser style figure using theGviz package31. It takes a bit of code to setup, but the resulting tracks can be reused for later examples:# Genome track                                   axis_track <- GenomeAxisTrack                  # Annotation track                               tx_track <- GeneRegionTrack       subsetByOverlaps. The following code demonstrates this using the first TSS:A good general strategy for quickly generating genome browser plots is to first define a region of interest, and then only plotting data within that region using# Extract 100 bp around the first TSS.        plot_region <- RSE %>%                            rowRanges %>%                                 subset(clusterType == \"TSS\") %>%              .[1] %>%                                      add(100) %>%                                  unstrand                                # CTSSs track                                 ctss_track <- CTSSs %>%                           rowRanges %>%                                 subsetByOverlaps(plot_region) %>%             trackCTSS(name = \"CTSSs\")                 #> Splitting pooled signal by strand...       #> Preparing track...                         # Cluster track                               cluster_track <- RSE %>%                          subsetByOverlaps(plot_region) %>%             trackClusters                #> Setting thick and thin features...         #> Merging and sorting...                     #> Preparing track...                         # Plot at tracks together                     plotTracks,                               from = start(plot_region),                    to=end(plot_region),                          chromosome = seqnames(plot_region))The top track shows the pooled CTSS signal and the middle track shows the identified TC with the thick bar indicating the TSS peak . The bottom track shows the known transcript model at this genomic location. In this case, the CAGE-defined TSS corresponds well to the annotation.We can also plot the first enhancer:# Make plotting region                                      plot_region <- RSE %>%                                          rowRanges %>%                                               subset(clusterType == \"Enhancer\") %>%                       .[1] %>%                                                    add(100) %>%                                                unstrand                                              # CTSSs track                                               ctss_track <- CTSSs %>%                                         rowRanges %>%                                               subsetByOverlaps(plot_region) %>%                           trackCTSS(name = \"CTSSs\")                               #> Splitting pooled signal by strand...                     #> Preparing track...                                       # Cluster track                                             cluster_track <- RSE %>%                                        rowRanges %>%                                               subsetByOverlaps(plot_region) %>%                           trackClusters                              #> Setting thick and thin features...                       #> Merging and sorting...                                   #> Preparing track...                                       # Plot at tracks together                                   plotTracks,                                             from = start(plot_region),                                  to=end(plot_region),                                        chromosome = as.character(seqnames(plot_region)))Here we see the bidirectional pattern characteristic of active enhancers. The bidirectional cluster is seen in the middle track, with the midpoint in thick marking the maximally balanced point within the bidirectional cluster.Location and expression of TSSs and enhancers. In addition to looking at single examples of TSSs and enhancers, we also want to get an overview of the number and expression of clusters in relation to transcript annotation. First we extract all of the necessary data from theRangedSummarizedExperiment into an ordinarydata.frame:cluster_info <- RSE %>%    rowData %>%          as.data.frame    ggplot2 to plot the number and expression levels of clusters in each annotation category:Then we use# Number of clusters                                        ggplot) +         geom_bar +     scale_fill_colorblind(\"Cluster type\") +                     labs +               theme)# Expression of clusters                                                 ggplot),                                                 fill=clusterType)) +                                geom_violin) +          scale_fill_colorblind(\"Cluster type\") +                                  labs\") +                            theme)             #> Warning in regularize.values): collapsing to#> unique \u2019x\u2019 values                                                     We find that TSSs at annotated promoters are generally highly expressed. Most novel TSSs are expresse d at lower levels, except for some TSSs in 5\u2019-UTRs. Enhancers are expressed at much lower levels than TSSs.Analysing TSS shapes and sequences. A classic analysis of CAGE data is to divide TSSs intoSharp andBroad classes, which show different core promoter regions and different expression patterns across tissues7.CAGEfightR can calculate severalshape statistics that summarizes the shape of a TSS. The Interquartile Range (IQR) can be used to find sharp and broad TSSs. As lowly expressed TSSs cannot show much variation in shape due to their low width and number of tags, we here focused on highly expressed TSSs (average TPM >= 10):# Select highly expressed TSSs                                         highTSSs <- subset >= 10)# Calculate IQR as 10%-90% interval                                    highTSSs <- calcShape                                    #> Splitting by strand...                                              #> Applying function to each cluster...                                #> Preparing output output...                                          We can then plot the bimodal distribution of IQRs. We use a zoom-in panel to highlight the distinction between the two classes:highTSSs %>%                                                                       rowData %>%                                                                    as.data.frame %>%                                                              ggplot(aes(x=IQR)) +                                                           geom_histogram +                       geom_vline +    facet_zoom) +                                                  labs                                        We see most TSSs are either below or above 10 bp IQR (dashed line), so we use this cutoff to classify TSSs into Sharp and Broad:# Divide into groups                                                           rowData(highTSSs)$shape <- ifelse(rowData(highTSSs)$IQR < 10, \"Sharp\", \"Broad\")# Count group sizes                                                            table(rowData(highTSSs)$shape)                                                 #>                                                                             #> Broad Sharp                                                                 #>  9555   812                                                                 BSgenome.Mmusculus.UCSC.mm10 genome package:We can now investigate the core promoters sequences of the two classes of TSSs. We first need to extract the sequences for each TSS: We define this as the TSS peak -40/+10 bp and extract them from using thepromoter_seqs <- highTSSs %>%                    rowRanges %>%                              swapRanges %>%                             promoters %>%    getSeq                           DNAStringSet-object which we can plot as a sequence logo32 via theggseqlogo package33:This returns apromoter_seqs %>%                          as.character %>%                       split(rowData(highTSSs)$shape) %>%     ggseqlogo +    theme_logo +                         themeAs expected, we observe that Sharp TSSs tend to have a stronger TATA-box upstream of the TSS compared to Broad TSSs.Finding candidates for interacting TSSs and enhancers. In addition to simply identifying enhancers, it is also interesting to try infer what genes they might be regulating. CAGE data can itself not provide direct evidence that an enhancer is physically interacting with a TSSs, which would requires specialized chromatin confirmation capture assays such as HiC, 4C, 5C, etc. However, previous studies have shown that TSSs and enhancers that are close to each other and have highly correlated expression are more likely to be interacting. We can therefore use distance and correlation of expression between TSSs and enhancers to identify TSSs-enhancer links as candidates for physical interactions13.CAGEfightR, we first need to indicate the two types of clusters as a factor with two levels:To do this withrowData(RSE)$clusterType <- RSE %>%    rowData %>%                      use_series(\"clusterType\") %>%      as_factor %>%                    fct_relevel(\"TSS\")             We can then calculate all pairwise correlations between TSSs and enhancer within a distance of 50 bp. Here we use the non-parametric Kendall\u2019s tau as a measure of correlation, but other functions for calculating correlation can be supplied :all_links <- RSE %>%                                                            swapRanges %>%                                                              findLinks                                             #> Finding directional links from TSS to Enhancer...                        #> Calculating 41311 pairwise correlations...                               #> Preparing output...                                                      #> # Link summary:                                                          #> Number of links: 41311                                                   #> Summary of pairwise distance:                                            #>    Min. 1st Qu.  Median    Mean 3rd Qu.    Max.                          #>     205    8832   21307   22341   35060   50000                          all_links                                                                   #> GInteractions object with 41311 interactions and 4 metadata columns:     #>              seqnames1   ranges1        seqnames2   ranges2 | orientation#>                  <Rle> <IRanges>            <Rle> <IRanges> | <character>#>       [1]         chr1   6204746 ---         chr1   6226837 |  downstream#>       [2]         chr1   7079251 ---         chr1   7083527 |  downstream#>       [3]         chr1   9535519 ---         chr1   9554735 |  downstream#>       [4]         chr1   9538162 ---         chr1   9554735 |  downstream#>       [5]         chr1  20941781 ---         chr1  20990601 |  downstream#>       ...          ...       ... ...          ...       ... .         ...#>   [41307]  chr9_random    193165 ---  chr9_random    217926 |    upstream#>   [41308]  chr9_random    193165 ---  chr9_random    242951 |    upstream#>   [41309]  chr9_random    223641 ---  chr9_random    217926 |  downstream#>   [41310]  chr9_random    223641 ---  chr9_random    242951 |    upstream#>   [41311] chrUn_random   3714359 --- chrUn_random   3718258 |    upstream#>            distance            estimate             p.value              #>           <integer>           <numeric>           <numeric>              #>       [1]     22090 -0.0603022689155527   0.805433562909099              #>       [2]      4275   0.365994211051474   0.128612838399956              #>       [3]     19215   -0.21320071635561   0.392330339776564              #>       [4]     16572   0.341121146168977    0.17111237306132              #>       [5]     48819    0.14070529413629   0.565460671338501              #>       ...       ...                 ...                 ...              #>   [41307]     24760   0.477084298221423  0.0423302291213607              #>   [41308]     49785   0.180906806746658   0.459929012970529              #>   [41309]      5714 -0.0366987921708787   0.875896057922941              #>   [41310]     19309  -0.261309831967395    0.28579482541369              #>   [41311]      3898  -0.170560573084488   0.493773664508106              #>   -------                                                                #>   regions: 38454 ranges and 8 metadata columns                           #>   seqinfo: 35 sequences (1 circular) from mm9 genome                     GInteractions-object from theInteractionSet package23: For each TSS-enhancer both the distance and orientation (upstream/downstream relative to TSS) is calculated in addition to the correlation estimate and p-value. For now, we are only interested in positive correlations, so we subset and sort the links:The output is a# Subset to only positive correlation       cor_links <- subset# Sort based on correlation                                         cor_links <- cor_links[order]We can then visualize the correlation patterns across a genomic region, here using the most correlated TSS- enhancer link:# Make plotting region                                      plot_region <- cor_links[1] %>%                                 anchors %>%                                                 GRangesList %>%                                           unlist %>%                                                reduce %>%                                add(1000)                                               # Cluster track                                             cluster_track <- RSE %>%                                        subsetByOverlaps(plot_region) %>%                           trackClusters                              #> Setting thick and thin features...                       #> Merging and sorting...                                   #> Preparing track...                                       # Cluster track                                             link_track <- cor_links %>%                                     subsetByOverlaps(plot_region) %>%                           trackLinks                    # Plot at tracks together                                   plotTracks,                                             from = start(plot_region),                                  to=end(plot_region),                                        chromosome = as.character(seqnames(plot_region)))The top track shows the strength of correlations between 3 TSSs around the Atp1b1 gene. The highest correlation is seen between the upstream TSS and the most distal enhancer.Finding stretches of enhancers. Several studies have found that groups or stretches of closely spaced enhancers tend to show different chromatin characteristics and functions compared to singleton enhancers. Such groups of are often referred to as \u201csuper enhancers\u201d or \u201cstretch enhancers\u201d34.CAGEfightR can detect suchenhancer stretches based on CAGE data.CAGEfightR groups nearby enhancers into groups and calculates the average pairwise correlation between them, shown below :# Subset to only enhancersEnhancers <-subset# Find stretchesstretches <-findStretches#> Finding stretches...#> Calculating correlations...#> # Stretch summary:#> Number of stretches: 95#> Total number of clusters inside stretches: 587 / 9943#> Minimum clusters: 5#> Maximum clusters: 15#> Minimum width: 7147#> Maximum width: 92531#> Summary of average pairwise correlations:#>     Min.  1st Qu.   Median     Mean  3rd  Qu.      Max.#> -0.10038 0.01351 0.08107 0.09097 0.16171 0.37105Similarly to TSSs and enhancers, we can also annotate stretches based on their relation with known transcripts:# Annotate                                                             stretches <- assignTxType                    #> Finding hierachical overlaps...                                     #> ### Overlap summary: ###                                            #>       txType count percentage                                       #> 1   promoter    50       52.6                                       #> 2   proximal     0        0.0                                       #> 3    fiveUTR     6        6.3                                       #> 4   threeUTR     5        5.3                                       #> 5        CDS     3        3.2                                       #> 6       exon     2        2.1                                       #> 7     intron    15       15.8                                       #> 8  antisense     0        0.0                                       #> 9 intergenic    14       14.7                                       # Sort by correlation                                                  stretches <- stretches[order]       # Inspect                                                              stretches                                                              #> GRanges object with 95 ranges   and  4 metadata columns:            #>                               seqnames              ranges  strand |#>                                  <Rle>           <IRanges>   <Rle> |#>     chr11:98628005-98647506      chr11   98628005-98647506       * |#>    chr7:139979437-140003112       chr7 139979437-140003112       * |#>     chr15:31261340-31279984      chr15   31261340-31279984       * |#>   chr11:117733009-117752208      chr11 117733009-117752208       * |#>      chr7:97167988-97188451       chr7   97167988-97188451       * |#>                         ...        ...                 ...     ... .#>   chr15:101076561-101093429      chr15 101076561-101093429       * |#>     chr16:91373912-91399202      chr16   91373912-91399202       * |#>    chr7:132619265-132644381       chr7 132619265-132644381       * |#>     chr15:79181690-79208915      chr15   79181690-79208915       * |#>     chr10:94708643-94729408      chr10   94708643-94729408       * |#>                                           revmap nClusters          #>                                    <IntegerList> <integer>          #>     chr11:98628005-98647506   6600,6601,6602,...         6          #>    chr7:139979437-140003112   4220,4221,4222,...         5          #>     chr15:31261340-31279984   7962,7963,7964,...         5          #>   chr11:117733009-117752208   6785,6786,6787,...         6          #>      chr7:97167988-97188451   4022,4023,4024,...         6          #>                         ...                  ...       ...          #>   chr15:101076561-101093429   8320,8321,8322,...         5          #>     chr16:91373912-91399202   8643,8644,8645,...         7          #>    chr7:132619265-132644381   4160,4161,4162,...         5          #>     chr15:79181690-79208915   8144,8145,8146,...         5          #>     chr10:94708643-94729408   5823,5824,5825,...         5          #>                                          aveCor     txType          #>                                       <numeric>   <factor>          #>     chr11:98628005-98647506   0.371052840516797   promoter          #>    chr7:139979437-140003112   0.328630841442886   promoter          #>     chr15:31261340-31279984   0.301603791540209     intron          #>   chr11:117733009-117752208   0.284399425439616   promoter          #>      chr7:97167988-97188451   0.262199740521045   promoter          #>                         ...                 ...        ...          #>   chr15:101076561-101093429 -0.0549688493223916 intergenic          #>     chr16:91373912-91399202 -0.0598361076236999    fiveUTR          #>    chr7:132619265-132644381 -0.0626248504104628   promoter          #>     chr15:79181690-79208915 -0.0981772309926707   promoter          #>     chr10:94708643-94729408  -0.100380656957041     intron          #>   -------                                                           #> seqinfo: 35 sequences (1 circular) from mm9 genome                  GRanges contains the the location, number of enhancers and average correlation for each stretch. Stretches are found in a variety of context, some being intergenic and other spanning various parts of genes. Let us plot one of the top intergenic stretches:The returned# Make plotting region                                         plot_region <- stretches[\"chr17:26666593-26675486\"] + 1000     # Cluster track                                                cluster_track <- RSE %>%                                           subsetByOverlaps(plot_region) %>%                              trackClusters                                 #> Setting thick and thin features...                          #> Merging and sorting...                                      #> Preparing track...                                          # CTSS track                                                   ctss_track <- CTSSs %>%                                            subsetByOverlaps(plot_region) %>%                              trackCTSS(name=\"CTSSs\")                                    #> Splitting pooled signal by strand...                        #> Preparing track...                                          # SE track                                                     stretch_track <- stretches %>%                                     subsetByOverlaps(plot_region) %>%                              AnnotationTrack# Plot at tracks together                                      plotTracks,                                              from = start(plot_region),                                     to=end(plot_region),                                           chromosome = as.character(seqnames(plot_region)))   This stretch is composed of at least 5 enhancers, each of which shows bidirectional transcription.Normalization of expression and EDA. Before performing statistical tests for various measures of Differential Expression (DE), it is important to first conduct a thorough Exploratory Data Analysis (EDA) to identify what factor we need to include in the final model.DESeq220 for normalization and EDA since it offers easy to use functions for performing basic analyses. Other popular tools such asedgeR21 andlimma25 offer similar functionality, as well as more specialized packages for EDA such asEDASeq.Here we will useDESeq2 offers sophisticated normalization and transformation of count data in the form of the variance stabilized transformation: this adds a dynamic pseudo-count to normalized expression values before log transforming to dampen the inherent mean-variance relationship of count data. This is particularly useful for CAGE data, as CAGE can detect even very lowly expressed TSSs and enhancers.First, we fit a \u201cblind\u201d version of the variance-stabilizing transformation, since we do not yet know what design is appropriate for this particular study:# Create DESeq2 object with blank design    dds_blind <- DESeqDataSet# Normalize and log transform               vst_blind <- vst   A very useful first representation is a Principal Components Analysis (PCA) plot summarizing variance across the entire experiment:plotPCAbatch effect. We do not want to mistake this unwanted variation for biological variation when we test for differential expression. To prevent this, we can include the batch information as a factor in the final model. Let first define the batch variable:We observe that PC2 separates the samples according to the experimental group (control vs nano). However, PC1 also separates samples into two groups. This is suggestive of an unwanted yet systematic effect on expression, often referred as a# Extract pca results                                                     pca_res <- plotPCA                   # Define a new variable using PC1                                         batch_var <- ifelse                            # Attach the batch variable as a factor to the experiment                 RSE$Batch <- factor(batch_var)                                            # Show the new design                                                     RSE %>%                                                                       colData %>%                                                             subset) %>%                                        kable(caption = \"Design matrix after adding new batch covariate.\") %>%    kable_styling(latex_options = \"hold_position\")                        sva andRUVSeq can be used to estimate unknown batch effects from the data.An alternative to manually defining the batch variable, tools such asCluster-level differential expression. Following our short EDA above, we are ready to specify the final design for the experiment: We want to take into account both the Class and Batch of samples:# Specify design                                  dds <- DESeqDataSet# Fit DESeq2 model                                dds <- DESeq(dds)                                 #> estimating size factors                        #> estimating dispersions                         #> gene-wise dispersion estimates                 #> mean-dispersion relationship                   #> final dispersion estimates                     #> fitting model and testing                      We can now extract estimated effects (log fold changes) and statistical significance  for the Nanovs-Ctrl comparison, implicitly correcting for the batch effect:# Extract results                                                                  res <- results,                                               alpha=0.05,                                                                        independentFiltering=TRUE,                                                         tidy = TRUE) %>%                                                        bind_cols(as.data.frame(rowData(RSE))) %>%                                         as_tibble                                                                      # Show the top hits                                                                res %>%                                                                                top_n %>%                                                               dplyr::select %>%                                                            kable %>%    kable_styling(latex_options = \"hold_position\")                                 DESeq2 analysis was successful. One such example is an MA-plot :It always a good idea to inspect a few diagnostics plot to make sure theggplot, y=log2FoldChange, color=padj < 0.05)) +    geom_point +                                                 geom_hline +              facet_grid(clusterType~.)                                            We can see that we overall find more differentially expressed TSSs compared to enhancers, which is expectedsince they are also more highly expressed. Many enhancers are filtered away for the final DESeq2 analysis (The \u201cIndependent Filtering\u201d Step), as their expression level is too low to detect any DE: This increases power for detecting DE at higher expression levels.We can tabulate the total number of DE TSSs and enhancers:table(clusterType=rowRanges(RSE)$clusterType, DE=res$padj<0.05)#>            DE                                               #> clusterType FALSE  TRUE                                     #>    TSS      22071  6385                                     #>    Enhancer  3034   199                                     Correcting expression estimates for batch effects. In addition to looking at estimates and significance for each cluster, we might also want to look at individual expression values for some top hits. However, we then need to also correct the expression estimates themselves for batch effects, just like we did for log fold changes and p-values (using the same model of course).35 from thesva package which is suitable for removing simple batch effects from small experiments. For more advanced setups,removeBatchEffect fromlimma can remove arbitrarily complex batch effects. TheRUVSeq package andfsva fromsva can be used to remove unknown batch effects.Here we use ComBatComBat .We again use the variance-stabilizing transformation to prepare the data for# Guided variance stabilizing transformation                     vst_guided <- varianceStabilizingTransformationComBat we need two additional pieces of information: i) A design matrix describing the biological or wanted effects and ii) the known but unwanted batch effect. We first specify the design matrix, and then runComBat:To run# Design matrix of wanted effects                     bio_effects <- model.matrix)# Run ComBat =                                        assay <- ComBat(dat=assay(vst_guided),                                     batch=RSE$Batch, # Unwanted batch                                                         mod=bio_effects)                                      #> Found2batches                                      #> Adjusting for1covariate(s) or covariate level(s)   #> Standardizing Data across genes                    #> Fitting L/S model and finding priors               #> Finding parametric adjustments                     #> Adjusting the Data                                 Let us redo the PCA-plot, to see the global effect of the batch effect correction:# Overwrite assay                        assay(vst_guided) <- assay# Plot as before                         plotPCA             Now Nano and Ctrl are separated along the first principal component (compared to the second principlecomponent before correction).tidyverse code:Then we extract the top 10 DE enhancers using the following# Find top 10 DE enhancers                            top10 <- res %>%                                          filter %>%    group_by(log2FoldChange >= 0) %>%                     top_n) %>%                  pull(row)                                         # Extract expression values in tidy format            tidyEnhancers <- assay %>%         t %>%                                                 as.data.frame %>%                                     rownames_to_column(\"Sample\") %>%                      mutate(Class=RSE$Class) %>%                           gather                           Finally, we can plot the batch-corrected expression profiles of each individual enhancer:ggplot) +             geom_dotplot +               facet_wrap                      #> \u2018stat_bindot\u2018 using \u2018bins = 30\u2018. Pick better value with \u2018binwidth\u2018.Enrichment of DNA-binding motifs. A typical question following identification of differentially expressed TSSs and enhancers, is what TFs might be involved in their regulation. To shed light on this question we can annotate TSSs and enhancers with DNA-binding motifs from the JASPAR database27.First we extract the sequences around TSSs and enhancers. Here we simply define it as +/- 500 bp around TSS peak or enhancer midpoint:cluster_seqs <- RSE %>%    rowRanges %>%          swapRanges %>%       unstrand %>%         add(500) %>%           getSeq     TFBSTools36 package to obtain motifs as Position Frequency Matrices (PFMs) from theJASPAR2016 database:Secondly, we use the# Extract motifs as Position                                        motif_pfms <- getMatrixSet)# Look at the IDs and names of the first few motifs:                head(name(motif_pfms))                                              #> MA0004.1 MA0006.1 MA0029.1 MA0063.1 MA0067.1 MA0078.1            #> \"Arnt\" \"Ahr::Arnt\" \"Mecom\" \"Nkx2-5\" \"Pax2\" \"Sox17\"               motifmatchr package37 to find hits in the sequences:Thirdly, we use the# Find matches                                             motif_hits <- matchMotifs# Matches are returned as a sparse matrix:                 motifMatches(motif_hits)                         #> 5 x 5 sparse Matrix of class \"lgCMatrix\"                #>      MA0004.1 MA0006.1 MA0029.1 MA0063.1 MA0067.1       #>         .        .        .        .        |       #>         .        .        .        .        .       #>         |        .        |        .        .       #>         .        .        .        .        .       #>         .        |        .        |        .       Finally we can do a simple Fisher\u2019s Exact test to see if a motif co-occurs more with DE TSSs and enhancer than we would expect be chance. Here we will look at the FOS::JUN motif (MA0099.2):# 2x2 table for fishers                                     table(FOSJUN = motifMatches(motif_hits),             DE = res$padj < 0.05) %>%                                 print %>%                                                 fisher.test                                           #>        DE                                                #> FOSJUN  FALSE TRUE                                       #>   FALSE 22144 5596                                       #>   TRUE   2961  988                                       #>                                                          #>  Fisher\u2019s Exact Test for Count Data                      #>                                                          #> data:  .                                                 #> p-value = 5.839e-12                                      #> alternative hypothesis: true odds ratio is not equal to 1#> 95 percent confidence interval:                          #>  1.220330 1.427821                                       #> sample estimates:                                        #> odds ratio                                               #>   1.320361                                               A significant odds ratio above 1 indicate that FOS::JUN is a candidate transcription factor  in regulation of the nanotube response. This is not surprising given that FOS::JUN is part of the TNF-alpha inflammatory pathway (see more below).PWMEnrich,rGADEM andmotifcounter implements more advanced statistical methods for calculating enrichment of known motifs.rGADEM,BCRANK andmotifRG can also be used to calculate enrichment of novel motifs, sometimes referred to asmotif discovery.Of course, this is a just a very quick and simple analysis of motif enrichment. One could easily have used different regions around TSSs and enhancers and/or split the enrichment analysis between TSSs and enhancers. Other Bioconductor packages likeGene-level differential expression. While CAGE data is naturally analyzed at the level of clusters (TSSs and enhancers) it is in many cases interesting to also look at gene-level expression estimates. A prime example of this is looking at enrichment of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) terms30 which are only defined at gene-level.CAGEfightR includes functions for annotating clusters with gene models and summarizing expression to gene-level.We can annotate clusters with gene IDs in the same manner as Transcript IDs:RSE <- assignGeneID                          #> Extracting genes...                                             #> Overlapping while taking distance to nearest TSS into account...#> Finding hierachical overlaps...                                 #> ### Overlap Summary: ###                                        #> Features overlapping genes: 81.34 %                             #> Number of unique genes: 13761                                   CAGEfightR to sum counts of TSSs within genes:And then useGSE <- RSE %>%                                            subset(clusterType == \"TSS\") %>%                      quantifyGenesRangedSummarizedExperiment where the ranges are aGRangesList holding the TSSs that were summed within each gene:The result isrowRanges                                                 #> GRangesList object of length 1:                                           #> $100038347                                                                #> GRanges object with 2 ranges and 9 metadata columns:                      #>                            seqnames            ranges strand |            #>                               <Rle>         <IRanges>  <Rle> |            #>   chr7:80884953-80885056;+     chr7 80884953-80885056      + |            #>   chr7:80885120-80885677;+     chr7 80885120-80885677      + |            #>                                     score     thick   support         txID#>                                 <numeric> <IRanges> <integer>  <character>#>   chr7:80884953-80885056;+   11.058474477  80885000         5   uc009hrf.2#>   chr7:80885120-80885677;+ 1162.344739622  80885256        11   uc009hrf.2#>                              txType   balance bidirectionality clusterType#>                            <factor> <numeric>        <numeric>    <factor>#>   chr7:80884953-80885056;+ proximal      <NA>             <NA>         TSS#>   chr7:80885120-80885677;+ promoter      <NA>             <NA>         TSS#>                                 geneID                                    #>                            <character>                                    #>   chr7:80884953-80885056;+   100038347                                    #>   chr7:80885120-80885677;+   100038347                                    #>                                                                           #> -------                                                                   #> seqinfo: 35 sequences (1 circular) from mm9 genome                        org.Mm.eg.db annotation package:The gene IDs in this case is Entrez ID (which is widely used by Bioconductor packages). We can translate these systematic IDs into more human-readable symbols using the# Translate symbols                                        rowData(GSE)$symbol <- mapIds,                                        column=\"SYMBOL\",                                           keytype=\"ENTREZID\")          #> \u2019select\u2019 returned 1:1 mapping between keys and columnslimma makes it easy to perform a subsequent enrichment analysis. Other tools such asDESeq2 (above) oredgeR (see below) could also have been used.Having obtained a gene-level count matrix we can now perform gene-level DE analysis. Here we use limma-voom, sinceNote:limma is a powerful tool for DE analysis of count-based data. However, since it depends on log transforming counts, it is not always suitable for analyzing datasets where features have very low counts. This is usually not a problem for gene-level analysis, but can be a problem for enhancers, which are generally very lowly expressed.DESeq2 analysis, we first build the necessary object and then normalize the expression values:Similarly to the# Create DGElist object                          dge <- DGEList,                     genes=as.data.frame(rowData(GSE)))# Calculate normalization factors                dge <- calcNormFactors(dge)                      Then we apply the voom-transformation to model the mean-variance trend, for which we also need to specify the design matrix (in this case the design must contain both wanted and unwanted effects!). The same design matrix is then used for fitting the gene-wise models:# Design matrix                                          mod <- model.matrix)# Model mean-variance using voom                         v <- voom                               # Fit and shrink DE model                                fit <- lmFit                              eb <- eBayes                           # Summarize the results                                  dt <- decideTests(eb)                                    We can the both report the overall summary of differential gene expression, and look at the first few top hits:# Global summary                                                          dt %>%                                                                        summary %>%                                                               kable %>%    kable_styling(latex_options = \"hold_position\")                        # Inspect top htis                                                 topTable %>%                                     dplyr::select %>%    kable %>%           kable_styling(latex_options = \"hold_position\")                 Enrichment of GO- and KEGG-terms. In addition to looking at individual top genes, we can look at how the differentially expressed genes relate to known databases of gene function to gain insight in what biological processes might be affected in the experiment.limma makes it easy to perform such an enrichment analysis following a DE analysis. As we have gene indexed by Entrez IDs, we can directly usegoana to find enriched GO-terms:goana uses a biased urn-model to estimate enrichment of GO-terms, while taking into account the expression levels of DE genes:# Find enriched GO-terms                                         GO <- goana# Show top hits                                                  topGO %>%                          kable(caption=\"Top enriched or depleted GO-terms.\") %>%          kable_styling(latex_options = \"hold_position\")               And similarly for KEGG terms:# Find enriched KEGG-termsKEGG <-kegga# Show top hitstopKEGG                         %>%knitr::kable(caption=\"Top enriched of depleted KEGG-terms.\")%>%kable_styling(latex_options =\"hold_position\")Both analyses indicate that genes related to the inflammatory response and defense response are upregulated following nanotube exposure. This supports the hypothesis that nanotube induces a response similar to asbestos.pathview package38 to investigate in more detail the genes in a given enriched pathway. For example, we can look at regulation of gene in the TNF- signalling pathway:KEGG-terms represents well defined pathways. We can use the# Visualize a KEGGDE_genes <-Filter(                        function(x) x!=0,                         dt)# This will save a png file to a temporary directorypathview# Show the png filegrid.newpagegrid.raster(png::readPNG(                        \"mmu04668.pathview.png\"))Differential TSS Usage. In the above two analyses we looked at whether an individual TSSs or an individual gene was changing expression between experimental groups. However, we might also want to look at whether a gene show differential TSS usage: whether a gene uses different TSSs under different conditions. This problem is similar to differential splicing in RNA-Seq, but looking at TSSs rather than isoforms26. Here we will use theedgeRdiffSpliceDGE method to find differential TSS usage, although many other packages could have been used, for examplediffSplice fromlimma,DEXSeq,DRIMSeq, etc..diffSpliceDGE tests whether a given TSSs show the same change as other TSSs in the same gene, indicating that TSSs are differentially regulated across the gene. This does however not take into account the relative composition of a given TSSs, e.g. whether a TSS increases from 1%\u20132% of gene output or 25%\u201350%. A useful preprocessing step is therefore to filter out TSSs making only a small contribution to total gene expression before analyses.Intuitively,CAGEfightR to remove TSSs that are not expressed as more than 10% of total gene expression in more than 5 samples (We first remove TSSs not assigned to genes):We use# Filter away lowly expressed                        RSE_filtered <- RSE %>%                                  subset(clusterType == \"TSS\" & !is.na(geneID)) %>%    subsetByComposition                #> Calculating composition...                        #> Subsetting...                                     #> Removed 8001 out of 24500 regions (32.7%)         We can only do differential TSS usage analysis of genes with multiple TSSs. A useful first visualization is therefore to see how many genes use more than one TSS:RSE_filtered %>%                                            rowData %>%                                             as.data.frame %>%                                       as_tibble %>%                                           dplyr::count(geneID) %>%                                ggplot) +                     geom_bar +                                  scale_fill_colorblind(\"Multi-TSS\") +                    labsWhile most genes utilize only a single TSSs, many genes use two or more TSSs.edgeR:Again, we build the necessary R-objects for running# Annotate with symbols like before:                                     rowData(RSE_filtered)$symbol <- mapIds$geneID,                                       column=\"SYMBOL\",                                                         keytype=\"ENTREZID\")               #> \u2019select\u2019 returned 1:1 mapping between keys and columns              # Extract gene info                                                      TSS_info <- RSE_filtered %>%                                                 rowData %>%                                                              subset) %>%                      as.data.frame                                                        # Build DGEList                                                          dge <- DGEList,                                    genes=TSS_info)                                           diffSpliceDGE step:Then we normalize and fit models using the Quasi-likelihood approach, including the# Estimate normalization factors                                 dge <- calcNormFactors(dge)                                      # Estimate dispersion and fit GLMs                               disp <- estimateDisp         QLfit <- glmQLFit               # Apply diffSpliceDGE                                            ds <- diffSpliceDGE#> Total number of exons: 16499                                  #> Total number of genes: 13563                                  #> Number of genes with 1 exon: 11098                            #> Mean number of exons in a gene: 1                             #> Max number of exons in a gene: 5                              Now we can look at differential TSS usage at two-levels: Whether an individual TSS shows differential TSS usage (TSS-level) or whether a gene show differential TSS usage in any way (gene-level). First we can look at individual TSSs :dtu_TSSs <-topSpliceDGEdplyr::select%>%kable%>%kable_styling(                        latex_options =\"hold_position\")The interpretation of log fold changes here is slightly different from before: These log fold changes are relative to the overall log fold change for all TSSs in that gene.Then we can look at results for each gene :dtu_genes <-topSpliceDGEdplyr::select%>%kable%>%kable_styling(latex_options =\"hold_position\")We see that the two lists agree, which is not surprising given that the gene-level results are obtained by aggregating TSS-level p-values across genes.We can look at closer at the TSS usage in on of the top hits: We can visualize the batch-corrected expression (See above) of each TSS in the Fblim1 gene via a heatmap:RSE_filtered %>%                      subset(geneID == \"74202\") %>%     assay(\"ComBat\") %>%               t %>%                             pheatmap(color = magma(100),               cluster_cols = FALSE,             main=\"Fblim1\")       Fblim1 has 3 TSSs, with 2 of them being used in the Ctrl samples, while the Nano samples also uses the chr4:141154044-141154185;- TSS, as also seen in the TSS-level table above. While a heatmap is useful for seeing expression changes, a genome browser view is better to inspect the genomic context of each TSSs:# Define plot area                                                     plot_region <- subset %>%                 rowRanges %>%                                                          reduce(min.gapwidth=1e6) %>%                                           unstrand %>%                                                         add(5e3L)                                                          # Create cluster track                                                 cluster_track <- subsetByOverlaps %>%           trackClusters            #> Setting thick and thin features...                                  #> Merging and sorting...                                              #> Preparing track...                                                  # CTSS tracks for each group                                           ctrl_track <- subset %>%                    calcPooled %>%                                                       subsetByOverlaps(plot_region) %>%                                      trackCTSS(name=\"Ctrl\")                                             #> Warning in calcPooled(.): object already has a column named score in#> rowData: It will be overwritten!                                    #> Splitting pooled signal by strand...                                #> Preparing track...                                                  nano_track <- subset %>%                    calcPooled %>%                                                       subsetByOverlaps(plot_region) %>%                                      trackCTSS(name=\"Nano\")                                             #> Warning in calcPooled(.): object already has a column named score in#> rowData: It will be overwritten!                                    #> Splitting pooled signal by strand...                                #> Preparing track...                                                  # Plot at tracks together                                              plotTracks,                                                      from = start(plot_region),                                             to=end(plot_region),                                                   chromosome = seqnames(plot_region))                         The Fblim1 gene uses two annotated TSSs, but the Nano samples also uses a novel intronic TSS.This workflow is intended as providing an outline of the basic building blocks of CAGE data analysis, going from clustering, to spatial analyses to differential expression. More advanced analyses can be strung together from these basic elements: Finding enhancers linked to DE TSSs, enhancer stretches composed of DE enhancer, comparing DNA binding motif enrichments between DE enhancers and TSSs, etc.40. CAGE can be combined with chromatin confirmation assays such as HiC to find new enhancers that are both co-expressed and physically interacting with TSSs. Many genome-wide association studies are finding that disease-related genetic variants are found in intergenic regions, that are often poorly annotated. The accurate enhancer locations provided by CAGE can greatly aid interpretation of such variants41. The adherence ofCAGEfightR to standard Bioconductor classes facilitates these inter-assay analyses by making it easy to mix-and-match multiple packages developed for different experimental assays.One aspect not covered in this workflow is the utility of CAGE data  in providing accurate TSSs for studying other types of data. For example, having accurate TSSs is highly beneficial in chromatin research, since the location and nucleosome and TSSs are closely relatedThe following software versions were used in this article:R version: R version 3.6.0 (2019-04-26)Bioconductor version: 3.9CAGEfightR version: 1.4.0https://doi.org/10.18129/B9.bioc.CAGEWorkflow42CAGEWorkflow:License: GPL-3https://doi.org/10.18129/B9.bioc.nanotubes24Mouse nanotube CAGE data:License: GPL-3 Thodberg and Sandelin present CAGEfightR, a new Bioconductor package suited for analysis of 5'end oriented datasets, derived from CAGE-seq and similar techniques.\u00a0 Although similar Bioconductor packages exist , the greatest strength of CAGEfightR is unique in its ability to call or predict putative enhancers based on the bidirectional transcription initiation signature, thus filling the gap in the current R-based toolkit for CAGE-like data analysis. In addition, using CAGEfightR, hypotheses of enhancer-promoter interactions based on co-expression levels can be easily set and visualised.The introduction and abstract could state more clearly that CAGE allows TSS mapping of only RNA polymerase II transcripts. Though this is implied through usage of cap-trapping, I would keep in mind that this workflow might be used by general readers not so familiar with TSS-mapping techniques. Considering the advent of technologies that capture RNA polI-RNApolIII transcripts, expected to be much noisier, it would be better to make it as clear as possible. If the authors believe CAGEfightR could be of use on noisier data, from experimental methods based on negative selection (such as TSS-seq), it would be worth testing this and including a few sentences, as this would promote CAGEfightR usage on any TSS mapping technique.I support comparison of existing packages in the form of Table 1;\u00a0however, I would expand this comparison to include unique features that perhaps CAGEfightR does not have - e.g. icetea and TSRchitect support paired-end data, CAGEr has TSS-shifting discovery function and implemented G-correction function to remove mismatching G\u2019s from 5\u2019ends of reads.Common problem with CAGE and CAGE-like data which is obtained through reverse transcription, is the addition of a G, or so called G-bias upstream of the true transcription start site. It would be beneficial for general readers as this is a step-by-step protocol to discuss how to generate BigWig files from fastq files, and how to address the G-bias problem/i.e. remove the mismatching G\u2019s at the 5\u2019end of the reads.The authors prefer to use the term TSS regions or TSSs in place of tag clusters as aggregated CTSSs, and even TSSs as a broader term for CTSS while CTSS is just a CAGE-supported TSS. This becomes very confusing for a general reader, especially page 36: \u201cNow we look at differential TSS usage at two-levels: Whether an individual TSS shows differential TSS usage (TSS-level) or whether a gene show differential TSS usage in any way (gene-level). First we can look at individual TSSs .\u201d I would suggest usage of CTSS for individual CAGE-supported TSSs, tag cluster - for an aggregate of individual CTSSs based on distance based clustering or whatever methodology, and tag cluster can be interchangeably used with promoter where needed.Interquartile range should probably be interquantile range as it spans middle 10-90th percentile of the signal. It would also be beneficial to explain why is it used instead of all signal (more robust measure that excludes outliers and is less sensitive to sequencing depth etc).I am a bit surprised the authors use such harsh filtering step before plotting distributions of IQR , I would assume that the problem is in tag clusters which seem sharp - single bp, and therefore it would perhaps be beneficial to add a more stringent filtering step only to single bp tag clusters to be retained only if highly expressed (>= 5 TPM), while a lower threshold can be applied on broad tag clusters as multiple CTSS within a tag cluster give more certainty that it is not just noise. The package is well-documented, and the step-by-step protocol well written and easy to follow. I only have a few minor comments which could benefit the general reader:I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. In our realistic situations, the EDA approach is quite important. In this sense, I appreciate their demonstration on how to remove batch effects from the expression data between various samples, using ComBat . However, most researchers will not be satisfied with just seeing that the PC1 has become to separate positive and negative groups; it is natural that they would like to confirm if the correction was enough or not; they would also wish to see what the new PC2 as well as the old PC1 represent. Therefore, I recommend the authors to extend Table 2 for characterizing each sample from various features  and to use such features for the interpretation. More discussion and/or additional attempts to clarify the most probable main reason for the initial batch effects would be desirable.Similarly, since the first author does not seem to have been a member of the previous analysis, it is interesting to see the consistency between the two studies. For example, the observation that inflammation-related genes were activated seems to be the same in both analyses. Then, are the genes with differential TSSs likely to explain the phenomenon? How much are the detected enhancers contributing to the differential expression? Do these enhancers (or newly activated TSSs) share any over-represented motifs? From the same reason, I recommend the authors to avoid using (ugly) chromosomal coordinates to represent genes/promoters/enhancers, wherever possible. It would be great if the authors can show that they could perform deeper analyses this time.For the convenience of wider readers, it might be useful to show the way how to obtain BigWig files from rawer data .Similarly, a summary table of used tools (except CAGEfightR), containing their input file information as well as their main purposes might be useful.Also, it might be useful if there is a summary on what CAGEfightR can do/cannot do. For example, is it possible to combine different sources of CAGE data with this workflow?One of my students tried to follow the workflow. At first, she failed to install some of the packages. It was because the version of R she used was R3.5. Thus, this point should be clearly noted. In addition, she reports that to run the code \u201cFit and shrink DE model\u201d, the installation of \u201cstatmod\u201d and \u201cBiasedUrn\u201d was necessary. Perhaps, some additional information on how to setup initial environment would be useful for beginners.As a cookbook, it is desirable that users can find their necessary items more easily .There seems to be some confusion\u00a0on the versions used: As for the mouse genome sequence, (1) both mm9 and mm10 are used. (2) Why didn\u2019t they use the latest version of JASPAR (Jaspar2018)?The manuscript seems to contain many typos. Here are some that we found (there are likely to be more): (1)This\u00a0is\u00a0workflow\u00a0is\u00a0a\u00a0case\u00a0study\u00a0on (2) CAGE dusters (3) can be speed up (4) novel TSSs are expresse d (5) to try infer (6 )this is a just a very quick (7) The returned GRanges contains\u00a0the the location (8) going from clustering, to spatial analyses\u00a0to\u00a0differential expression.In this paper, the authors present a cookbook for analyzing CAGE data mainly through their own Bioconductor package, CAGEfightR, applied to sample data, which were analyzed and published by their group previously. By following the given source codes, readers will be able to learn how they can obtain various kinds of information rather easily. Thus, I feel that this publication will be useful for those who want to learn how to analyze CAGE data quickly. On the other hand, it will not tell us how to solve our deeper problems in research. I know that this is out of the scope of this tutorial but I can\u2019t help but feeling, for example, how the given procedure for reducing batch effects can be justified (see below). Thus, here are some of my suggestions for its further improvement:We confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. There should be a general overview on how the CTSS BigWig files are generated from raw FASTQ files.1Consider using ExperimentHub for the nanotubes package. This provides greater control over which files are downloaded, rather than forcing the user to obtain all files at installation. This is\u00a0especially useful if you have multiple data sets - see, for example, the chipseqDBData package.Explain what a BigWigFileList is, and why it needs to be used instead of having a simple character vector.Consider not having string'ified intervals as the row names in the output of quickTSSs. In some situations, generation of the strings can use more RAM than the actual data itself. It definitely slows down any attempt to 'show'\u00a0the output. I would suggest that this be deferred as late as possible, e.g., until someone needs the strings as row names of a data frame to\u00a0save\u00a0to file.More details are required on how quantification is performed. For example, I assume counts are summed directly from single strands for TSSs. For enhancers, are counts summed from both strands?\u00a0\"As enhancers are the most complicated type, we keep only enhancers if a TSS and enhancer overlaps:\" The complexity of the enhancers doesn't really provide a motivation for only keeping enhancers in cases of overlaps. The better reason is that all enhancers would be detected as two TSSs if the strandedness was ignored; if they do overlap, it would be more appropriate to interpret them as a single enhancer rather than as two distinct TSS events.The Interquartile Range (IQR)... of what? I assume that the range refers to the length of the interval that contains 10 to 90% of a TSS's counts. Incidentally, the IQR is no longer an IQR if it's redefined from 10-90%.The single quotes in the highTSSs call are malformed, which\u00a0prevents copy-pasting.One could consider using a 2-component mixture model to classify elements into sharp/broad in a more automated manner.I presume that the pairwise correlations for the TSS-enhancer interactions are computed across samples for each TSS/enhancer pair. If so, is this done after blocking on the design? Otherwise it is possible to obtain strong positive correlations simply because a TSS and the enhancer happen to respond in the same direction to a given treatment. If there is a genuine physical interaction, it should manifest as correlations within each treatment condition, where stochastic differences in RNA polymerase activity affect both the TSS and its interacting enhancer.There is no correction for multiple testing in the p-values from the links. While I recognise that this is a limitation of the small sample size, it should still be pointed out as a caveat of the analysis.All normalization steps in the DE analyses assume that most of the input features are not differentially expressed between conditions. This is usually not a concern, but if aggressive feature selection is performed, it may become a problem. For example, if one were to perform the DE analysis on superenhancers only, it would give incorrect results in situations where the superenhancer activity increases globally upon treatment.Thodberg and Sandelin describe a comprehensive workflow for the basic analysis of CAGE data. The workflow is simple, well-presented and the code mostly runs without problems. I only have a few minor comments to improve its usefulness for the general reader:I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard."}
+{"text": "Scientific Reports 10.1038/s41598-017-06341-6, published online 27 July 2017Correction to: In this Article, Figure 1B is omitted. The correct Figure\u00a0As a result, the Figure legend,\u201cTen Traumatic brain injury (TBI)-altered microRNAs target approximately 600 pro-survival and/or pro-death genes in dying and surviving hippocampal neurons. In our previous microarray study, we showed that these genes were significantly differentially expressed in dying and surviving neurons 24\u2009h after TBI. Ingenuity pathway analysis miRNA target filter was used to identify predicted gene targets in laser captured dying, Fluoro-Jade-positive (FJ+) and surviving, Fluoro-Jade-negative (FJ\u2212) hippocampal pyramidal neurons\u201d.should read:\u201cTen Traumatic brain injury (TBI)-altered microRNAs target approximately 600 pro-survival and/or pro-death genes in dying and surviving hippocampal pyramidal neurons that were obtained by laser capture microdissection 24\u2009h after TBI. (A) Ingenuity pathway analysis miRNA target filter was used to identify predicted gene targets in dying, Fluoro-Jade-positive (FJ+) and surviving, Fluoro-Jade-negative (FJ\u2212) neurons. These genes were identified in our previous microarray study as significantly differentially expressed in dying and surviving neurons. (B) Differentially expressed miRNA target genes in dying and surviving neurons play essential roles in neuronal function and their misregulation is associated with human disease (see Online Mendelian Inheritance in Man database). The complete, annotated list of differentially expressed miRNA target genes in dying and surviving neurons is shown in Supplementary Table 3\u201d.Additionally, there are typographical errors in the text. In the Results section:\u201cWe found that ten TBI-dysregulated miRNAs targeted, either singly or frequently in combination, about 600 TBI-dysregulated genes  showed that the majority of transcripts are thought to play essential roles in cell function\u201d.should read:\u201cAnalysis of the annotated genes that displayed strikingly disparate expression levels in dying and surviving neurons (Fig."}
+{"text": "Chemotherapy destroys cells indiscriminantly and releases proinflammatory factors into the bloodstream that can adhere to endothelial cells (ECs); resulting in phenotypical changes consistent with \u201caccelerated vascular aging\u201d. This pilot study examined associations between markers of EC integrity, vascular aging, and cognition in 15 female breast cancer survivors 12\u201318 months after chemotherapy (median age: 57 years) and 2 non-cancer controls (58/59 years). EC integrity was evaluated using frequency-dependent electrical impedance (Z4000Hz) and levels of apoptosis (caspase-3/7), inflammation (NFkB activation), and oxidative stress (NRF2 activation) in cultured human endothelial cells (EC) exposed to the subject\u2019s serum. Vascular aging was characterized by low serum insulin growth factor ([IGF1a] <85mg/dL) and laterality in cerebral oxygenation (Lat-FLOX), an in-vivo marker of altered cerebral blood flow (near-infrared spectroscopy). Z4000Hz were higher in cells treated with serum from survivors (520-1100 ohms) than controls (400-450 ohms). Higher Z4000Hz was associated with higher amounts of EC oxidative stress (rNRF2= -.55), inflammation (rNFkB= .43), apoptosis (rcapsase=.76), and Lat-FLOX (r=.39). Higher Z4000Hz (r= -.48) and Lat-FLOX (r= -.66) were associated with lower cognitive function, as measured by the Montreal Cognitive Assessment (MOCA). At lower Z4000Hz, combined Lat-FLOX and low IGF1a characterized persons with cognitive impairment (MOCA < 26). These findings suggest that proinflammatory factors related to cancer and/or its treatment persist for months following active treatment. Cognitive symptoms occur when EC damage results in alterations in cerebral blood flow. With depletion of growth factors, like IGF-1, these symptoms may occur at lower levels of EC damage."}
+{"text": "Low walking ability is highly prevalent with advanced age and associated with a higher risk of major adverse health outcomes. Metabolomics may help better characterize differences among older adults with vastly different walking abilities and provide insight into altered metabolic processes underlying age-related declines in physical functioning. Here, we sought to identify metabolites associated with high versus low walking ability using a nested case-control study of 120 community-dwelling adults ages 79-95  from the Cardiovascular Health Study (CHS) All Stars study. Participants with high versus low walking ability were matched one-to-one on age, gender, race, and fasting time. Using liquid chromatography-mass spectrometry, 569 metabolites were identified in overnight-fasting plasma. High versus low walking ability was defined as the best versus worst tertile of gait speed (\u22650.9 versus <0.7 meters/second) and Walking Ability Index scores (7-9 versus 0-1). Ninety-six metabolites were associated with walking ability extremes , where 24% were triacylglycerols. Triacylglycerols containing mostly polyunsaturated fatty acids  were higher, whereas those containing mostly saturated/monounsaturated fatty acids were lower among those with high versus low walking ability. Arginine and proline metabolism was a top pathway identified. Body mass index partly explained the association between a subset of metabolites and walking ability extremes. These findings may partly reflect pathways implicating modifiable risk factors including excess dietary lipids and lack of physical activity, which contribute to obesity and cause further alterations in metabolic pathways, potentially leading to age-related declines in walking ability in this cohort."}
+{"text": "Dietary, pharmacological and genetic interventions can extend health- and lifespan in diverse mammalian species. DNA methylation has been implicated in mediating the beneficial effects of these interventions; methylation patterns deteriorate during ageing, and this is prevented by lifespan-extending interventions. However, whether these interventions also actively shape the epigenome, and whether such epigenetic reprogramming contributes to improved health at old age, remains underexplored. We analysed published, whole-genome, BS-seq data sets from mouse liver to explore DNA methylation patterns in aged mice in response to three lifespan-extending interventions: dietary restriction (DR), reduced TOR signaling (rapamycin), and reduced growth (Ames dwarf mice). Dwarf mice show enhanced DNA hypermethylation in the body of key genes in lipid biosynthesis, cell proliferation and somatotropic signaling, which strongly correlates with the pattern of transcriptional repression. Remarkably, DR causes a similar hypermethylation in lipid biosynthesis genes, while rapamycin treatment increases methylation signatures in genes coding for growth factor and growth hormone receptors. Shared changes of DNA methylation were restricted to hypermethylated regions, and they were not merely a consequence of slowed ageing, thus suggesting an active mechanism driving their formation. By comparing the overlap in ageing-independent hypermethylated patterns between all three interventions, we identified four regions, which, independent of genetic background or gender, may serve as novel biomarkers for longevity-extending interventions. In summary, we identified gene body hypermethylation as a novel and partly conserved signature of lifespan-extending interventions in mouse, highlighting epigenetic reprogramming as a possible intervention to improve health at old age. Dietary, genetic and pharmacological interventions can extend lifespan in diverse organisms and represent good models for developing therapies against age-related diseases in humans. However, whether these longevity interventions act by slowing down the effects of ageing, or inducing novel phenotypes to cope better with age-related stress, remains unclear. The epigenome is influenced by many factors including diet, drugs and genetic mutations, making it a possible candidate for linking longevity interventions. Here, we conducted a meta-analysis of published mouse liver datasets to profile changes in DNA methylation in response to three lifespan-extending interventions: reduced food intake, the drug rapamycin and a genetic mutation causing dwarfism. In dwarf mice, there was enhanced DNA methylation over specific genes involved in fatty metabolism and growth factor signaling. Reduced food intake and rapamycin treatment shared DNA methylation patterns with dwarf mice, revealing similar influences on the epigenome. Hypermethylated genes were also less active, which may protect dwarf and DR mice against liver steatosis and cancer. In addition, we developed novel DNA methylation biomarkers that could potentially predict longevity-extending interventions. Dietary, genetic and pharmacological interventions can extend health- and lifespan in diverse model organisms whilst delaying the onset of age-related pathologies \u20133. UnderConsistent with its central role in DR-mediated longevity, genetically reduced somatotropic signaling can extend lifespan in mice \u201327. For DNA methylation is an epigenetic modification with a role in regulating gene transcription ,40. MethEpigenetic clocks have recently been developed for mice, and they are remarkably decelerated by DR, rapamycin treatment and reduced growth factor signaling \u201348. In aElovl6, Scd1 and Fasn, independent of genetic background, thereby revealing a robust epigenetic signature of DR. We also re-analyzed WGBS-seq profiles of aged rapamycin-treated and Ames dwarf mice, and found that DNA methylation is specifically remodeled in these interventions as well. Hyper- but not hypo-methylated regions of the genome coincide among different interventions, and are predominantly located in gene bodies. These patterns are induced at young age and do not result from delayed ageing alone, which points to an active mechanism driving their formation. Furthermore, joint methylome profiling identifies a limited set of common hypermethylated regions that could serve as a new DNA methylation-based biomarker for intervention outcome, independent of genetic background and gender.In order to determine if changes in DNA methylation of genes in the lipogenic network are a general feature of DR, we conducted a meta-analysis of published WGBS-seq data for liver derived from two different strains of mice subjected to DR. We found strongly conserved hypermethylation of lipogenic Srebf1-target genes such as IGF-1 and oncogenic downstream targets Egfr and Onecut1. Analysis of published RNA-seq data of DR and Ames dwarf mice further revealed that hypermethylation patterns of gene bodies and RNA transcript profiles were strongly associated, pointing to a potentially causative role of DNA methylation in changes in gene expression in geroprotective interventions.Functionally, Ames dwarf mice shared hypermethylation patterns with rapamycin-treated mice over genes coding for signaling mediators of growth factors and growth hormone, whilst also showing hypermethylation over the same lipogenic Srebf1-target genes as DR-fed mice. In Ames dwarf mice specifically, we found extensive epigenetic silencing of the somatoropic signaling axis, including hypermethylation of We thus found targeted epigenetic reprogramming to be a novel and partly conserved feature of DR, reduced TOR and reduced somatotropic signaling, and characterized how this new epigenotype could causally improve health in old animals.Lifespan-extending interventions such as DR shape the DNA methylome by delaying age-related methylation changes across the genome \u201352. Longad libitum (AL) fed controls [We therefore compared two recently published datasets comprising whole-genome BS-seq data of liver samples ; one frocontrols ,50. UM-Hcontrols . DR incrcontrols  and the controls . The twocontrols ,50. Furtcontrols  , thus overcoming the need for further SNP allele frequency correction. In total, DR induced 1,729 differentially methylated regions (DMRs) in C3B6F1\u2640 and 2,714 DMRs in UM-HET3\u2640 mice , thus confirming a similar epigenetic remodeling independent of genetic background or experimental conditions  when comparing genes instead of individual DMRs  data from blood of DR fed male F1 hybrid mice (B6D2F1\u2642) and DR fed male inbred mice C57BL/6\u2642)  S1A FigS1A Fig. BL/6\u2642  S1Given the robust conservation of DR-related epigenetic reprogramming, we asked whether other longevity interventions also remodelled DNA methylation specifically . We profp < e-16, Fisher\u2019s exact test), strongly indicating that their co-occurrence was not due to chance. In clear contrast, we did not detect any hypomethylated DMRs common to all three interventions and only few hypomethylated DMRs between any two interventions, for which we found no convincing functional association , which represents less than 1.5% of the entire methylome. Of these, DR induced 1,619 DMRs, rapamycin 1,415 and genetic dwarfism 12,619 . Both noociation .p < 0.001, one-sided Fisher\u2019s exact test) but not in rapamycin-treated mice  might reduce the detectability of common methylation patterns and thus repeated the binning and differential methylation analysis with bins covering only 20 CpGs  and 10 CpGs  . ConsistTaken together, reduced growth factor signaling and reduced TOR signaling induce DNA methylation signatures in distinct regions of the genome, pointing to a similar epigenetic remodeling as identified before under DR. In addition, several hundred hyper- but not hypomethylated DMRs are common to at least two interventions, indicating a partly conserved epigenetic signature across interventions, mouse strains and sexes.Following our findings from DR-related hypermethylation of lipid metabolism genes, the overlapping hypermethylation signatures among interventions could suggest a partially shared epigenetic program, acting on specific, functionally connected regions of the genome. In line with our hypothesis, hypermethylated DMRs shared between Ames dwarf and either DR or rapamycin treatment were strongly enriched over gene bodies and open/active chromatin, confirming coordinated methylation increase over euchromatic, coding regions of the genome  for imprAcvr2b [Ltbp1, Ltbp4 [Ghr  and thebp4 [Ghr . Differebp4 [Ghr . GeneticElovl6 and Ghr . Indeed, Ames dwarf mice shared hypermethylation patterns over lipid metabolism genes with DR fed mice , while a and Ghr , S4D Fig and Ghr . In summDR, rapamycin treatment and reduced somatotropic signaling slow down age-related changes of the methylome \u201350,52,67We next determined whether intervention-related methylation changes were already detectable at young age. We analyzed DNA methylation of young DR-treated C3B6F1\u2640 (5 months) and Ames dwarf mice (2 months) in comparison to their respective controls . Our binning approach yielded 1,018,051 bins covering 25.5 million CpGs. Differential methylation analysis detected 1,944 DR- and 5,547 dwarfism-related DMRs at young age , with siElovl6, Scd1 , revealing that the extensive epigenetic reprogramming in response to reduced somatotropic signaling occurs early in life and is maintained life-long  between young and old DR fed mice , includil6, Scd1  and Pnplife-long . DR and Elovl2, a specific epigenetic biomarker predicting interventions that will ameliorate ageing in mice does not exist [Tat gene locus (Wilcoxon rank-sum test) (Wilcoxon rank-sum test) (While reliable DNA methylation markers (\u2018epigenetic clocks\u2019) for murine ageing have been previously developed, including local markers like ot exist \u201348,68. Sne locus . Of thesne locus  making tum test) . We indeum test) .Wilcoxon rank-sum test). The four regions were selected to not overlap with age-related changes in DNA methylation . Consistently, we found 18 hypermethylated dCpGs under DR feeding and 32 dCpGs in Irs1KO mice . One of the four marker regions, however, appeared to be false positive in the WGBS-seq data, as most long-lived animals showed no consistent change at these CpGs (Wilcoxon rank-sum test).In order to verify our marker experimentally, we measured DNA methylation at the marker regions in five DR and five AL fed C3B6F1\u2640 mice (24 months of age) from an independent batch of animals using targeted Bisulfite Amplicon sequencing  and this was even more pronounced when considering only significantly differentially expressed genes  [Gene body hypermethylation under DR has been associated with transcriptional repression of lipogenesis, pointing to a tight coupling between DR-related remodeling of the epigenome and gene expression . We askeed genes . We alsoed genes , suggested genes  Tables. ed genes  Tables. nes Ghr,  and sever, Igf-1  and the  (Hnf-6) \u201378. Thes (Hnf-6) \u201387.Whilst increased DNA methylation in gene bodies is typically correlated with increased expression , recent In summary, our results thus reveal strong epigenetic and transcriptional silencing of the growth hormone signaling axis, which may contribute to delayed occurrence of neoplastic diseases in Ames dwarf and growth hormone signaling deficient mice ,29,30.p < 0.05, Binomial test; Fgfr3, Ras-Mapk and PI3K-AKT pathways [Given the common epigenetic signatures occurring across longevity interventions , we askepathways , was fouFgfr3 is frequently up-regulated in various cancers including hepatocellular carcinoma [Fgfr3 is also repressed in mouse models of genomic instability, which exhibit dwarfism and GH-IGF1-signaling deficiency, thus paralleling our findings in Ames dwarf mice [Fgfr3. Furthermore, in-vitro studies with bladder cancer cell lines confirmed Fgfr3 as a direct activator of lipogenesis via Srebf1 [Fgfr3 in RT112 cells [Fgfr3 in mediating the effects of DR and genetic dwarfism in the liver.As a crucial regulator of cell growth and survival, arcinoma \u201396. Hepaarf mice ,98. Hencarf mice  may invoa Srebf1 \u2013101, whia Srebf1 ,102,103.12 cells  overlappPhysiological consequences of DR including lifespan extension are strongly dependent on genetic background, sex and protocol ,22,104. The net effect of DR on the methylome was highly comparable between strains and studies. Interestingly, the total number of DR-related DMRs in UM-HET3\u2640 mice was about 56% higher compared to C3B6F1\u2640 mice, which correlates with the ~56% stronger improvement in lifespan in the genetically heterogeneous strain . This may hint towards an association between the extent of the epigenetic reprogramming and the improvement in lifespan. However, when comparing which specific regions were affected, approximately 80% of DR-related, hypermethylated DMRs and 95% of hypomethylated DMRs were only detected in one mouse strain/dataset. While these differences may be, in part, due to the genetic background and differing sequencing protocols , there wFasn, Acly, Me1, Elovl6 and Scd1 [Hepatic mRNA expression changes between two commonly housed, DR-fed mouse strains showed a 50% overlap in their response to DR , indicatand Scd1 ,108\u2013112.Our analysis extended the concept of intervention-related DNA methylation changes to both reduced TOR and somatotropic signaling. We also found here that the intervention with the strongest improvement in lifespan (dwarfism) induced the most DMRs, while rapamycin and DR, which have similar effects on lifespan, induced comparable numbers of DMRs. However, the detection of significant methylation changes is dependent on various technical factors such as coverage , and we Gsk3\u03b2) and Raf signaling (Erk1/2) [Dnmt3b) [Hypomethylated DMRs were only shared to a minor extent among interventions, and we found no convincing functional association. Hypomethylated DMRs could thus represent treatment-specific changes. In contrast, intervention-related, hypermethylated DMRs were commonly targeted to gene bodies and partly shared among interventions. Interestingly, downstream mediators of the key longevity pathways, PI3K/Akt  ,114, reg[Dnmt3b) , which m[Dnmt3b) ,117 may Notwithstanding, methylation over four regions robustly increased in response to all three interventions independent of strain and sex, while showing no age-related changes, thus meeting the main requirements for a putative epigenetic marker to directly assess the response to lifespan-extending interventions. As such, we could experimentally confirm the validity of our marker in an independent batch of mice and successfully probe for longevity in Irs1KO mice that were not involved in the marker selection. Albeit weak in effect, methylation at the CpGs measured by targeted BS-AS was overall sensitive enough to detect the anticipated, significant difference. Epigenetic clocks ,46\u201348 anTat gene locus, which has been previously shown to be unaffected by age-related changes in DNA methylation in rat liver, spleen and brain [Tat; intronic CGI of Foxp4) and two at intergenic regions, suggesting that methylation markers are not directly linked to a distinct cellular process [In contrast, concerted hypermethylation over just these four regions was reliably correlated with longevity intervention outcome. None of the clock-CpGs mapped within the four intervention-related DMRs \u201348, unsund brain . The put process ,46\u201348. TOur findings act as a proof-of-principle to demonstrate the general feasibility of a treatment-specific DNA methylation marker. Due to the limited number of available samples, the marker DMRs yield only a binary output . It will be interesting to test the corresponding methylation patterns in lifespan-extending interventions that do not primarily target energy metabolism, e.g. aspirin treatment  or ablatElovl6, Acly and Fasn [Srebp1 and several downstream targets in the liver [Elovl5, Elovl6, Fasn, Gpam, Acly, Acaca, Aacs) [In agreement with common signaling pathways associated with the three lifespan-extending interventions ,19,34\u201337and Fasn ,122,123,and Fasn ,124\u2013126.he liver . Furtherhe liver , which ihe liver ,130 and a, Aacs) ,131\u2013134.a, Aacs) . Hence, a, Aacs) ,136 and a, Aacs) , which iLifr [Fgfr2 [Acvr2b [Ltbp4, Ltbp5 [Ghr) suggests long-term adaptation of the epigenome to altered growth and mTOR signaling, which was even more prevalent in Ames dwarf mice.Pharmacological suppression of mTOR affects cellular sensitivity to growth factors , which aLifr , Fgfr2 [r [Fgfr2 , Acvr2b  [Acvr2b , Ltbp4, 4, Ltbp5  and the Egfr, Lifr, Onecut1) [In Ames dwarf mice specifically, we show for the first time how reduced somatotropic signaling is paralleled by potent hypermethylation and transcriptional repression of the Ghr-Igf1 axis and downstream target genes with key roles in tissue growth and regeneration \u201376. ThesOnecut1)  are alsoOnecut1) ,73,78,79Onecut1) ,30. The Onecut1) , which mThe remarkably strong association between intervention-related shifts in DNA methylation, transcription and phenotype marks a key difference to age-related methylation changes, where epigenome and gene expression changes are generally not correlated ,50,142. in-vitro knockdown of Fgfr3 not only mimicked the DR-like repression of lipogenesis, but also DR-induced up-regulation of transcriptional regulators like Jdp2 [Nfkbia [Arnt [However, gene expression involves an intricate time- and context-specific interplay of epigenetic mechanisms and transcription factors. Genes that show consistently coupled methylation and expression changes in both DR and Ames dwarf mice are therefore strong candidates for further exploration given their robust regulation. For instance, Fgfr3 is an oncogenic mediator of mitogenic signals ,96,147 aike Jdp2 , Nfkbia  [Nfkbia  and Arntia [Arnt . EpigeneThis study provides novel insights into the effects of longevity interventions on DNA methylation and how they may causally contribute to improved health at old age. Dietary restriction (DR), rapamycin treatment and reduced somatotropic signaling remodel DNA methylation partly independent of ageing, converging on defined marker regions predictive of intervention outcome. In addition, DR and rapamycin treatment resemble separate hypermethylation patterns of Ames dwarf mice, affecting lipid metabolism and growth factor signaling genes, respectively. For DR and Ames dwarf mice, we furthermore demonstrate significant association between DNA methylation and gene expression. Therefore, our work establishes hypermethylation signatures as a link between the long-term effects of several longevity models and their transcriptional networks controlling somaotropic signaling and metabolism.The study involving live mice was performed in strict accordance with the recommendations and guidelines of the Federation of the European Laboratory Animal Science Association (FELASA), with all protocols approved by the Landesamt f\u00fcr Natur, Umwelt und Verbraucherschutz, Nordrhein-Westfalen, Germany (reference number: 84\u201302.04.2015.A437). For dissections mice were killed by cervical dislocation.Bisulfite Amplicon sequencing (BS-AS) libraries were prepared from liver tissue of 24 months old female C3B6F1\u2640 mice with the following treatment groups: 5 DR or 5 AL fed mice , 4 homoAn overview of the analyzed datasets and treatment conditions is given in . Raw datFiltering of CpGs and binning was conducted for each of the following analyses separately: a) Old DR treated C3B6F1\u2640 or UM-HET3\u2640 mice including controls  b) old DTat gene locus was visualized by calculating average CpG methylation levels of 500 bp 400 bp overlapping bins to improve resolution.For the example in S2C, the methylation landscape over the Fisher\u2019s exact test with the entire methylome as background. Due to the observed gene body-wide methylation profiles, differentially methylated genes were defined as common when overlapped by at least two DMRs in each intervention . For comparing longevity-related DMRs with age-effects  was performed to determine statistical significance of enrichment. Since most elements showed highly significant enrichment, we log-transformed the adjusted p-values. Ratio of the observed DMR frequency and the average frequency across the genome (\u2018observed/expected\u2019) for individual elements were used to compare enrichments across elements and between DMR sets. This way, we were able compare the strengths of enrichments across elements in the same analysis.Raw datasets were downloaded from the GEO repository under accession ID GSE80672. Raw sequence reads were trimmed using Trim Galore! (v0.4.2). Trimmed sequences were aligned using Bismark  v0.16.3.For the analyses employing WGBS-seq data, we performed functional enrichment of genes overlapped by at least two DMRs and only retained those showing at least \u00b110% average difference. We thereby avoided unclear cases with an equal extent of hyper- and hypomethylation occurring over the same gene. Enrichment analysis was carried out using topGO  and ReacFor the analyses employing RRBS-seq data, we tested each gene for significant enrichment of overlapping dCpGs compared to all detected CpGs overlapping and only retained those with p-values < 0.05 from Fisher\u2019s exact test (after multiple testing correction) and at least \u00b110% average difference.Wilcoxon rank-sum test. The analysis was repeated after manually selecting one representative 500 bp regions for each of the four DMRs.We quantified the methylation for each CpG position individually that mapped within the four hypermethylated DMRs shared between all three longevity interventions but not with age-related hypomethylation . CpGs coWilcoxon rank-sum test.Raw sequencing libraries were de-multiplexed before mapping and methylation extraction was conducted as described for WGBS-seq. De-duplication step was omitted. Data visualization and analysis were performed using SeqMonk and custom RStudio scripts. Data from replicates of the same treatment group were averaged using SeqMonk\u2019s replicate set option. To reduce the effect of coverage differences between samples, only cytosines covered by at least three observations were used for the differential methylation analysis. Differentially methylated cytosines (dCpGs) were identified by pairwise, replicate-sensitive logistic regression tests with subsequent multiple testing correction . Methylation change across CpGs was tested using paired https://github.com/dieterich-lab/CellPlot). To account for tissue-specific expression, we defined all genes passing the independent filtering of Deseq2 [For young and old Ames dwarf and DR-fed C3B6F1\u2640 mice, RNA-seq data derived from liver tissue of the same animals used for WGBS-seq was downloaded from the GEO repository under accession IDs GSE89275 and GSE92486 . Two repf Deseq2  as \u2018exprf Deseq2 . P-valueTo test for correlation between differential methylation and gene expression, we considered only genes overlapped by at least two DMRs. For associations between differential methylation over uiDMRs and expression, we considered only genes with their uiDMRs (0.3\u20138 Kbp downstream of gene start) overlapped by at least one DMR. We averaged methylation differences for multiple DMRs overlapping the same gene (uiDMR) before plotting, and only retained those showing at least \u00b110% average difference. We thereby avoided unclear cases with an equal extent of hyper- and hypomethylation occurring over the same gene (uiDMR). We plotted log2-fold expression changes versus methylation differences and the distribution of genes among the four resulting quadrants. Due to the very few hypomethylated genes common among longevity interventions, we focused on hypermethylated genes for statistical testing. For the group of differentially expressed and hypermethylated genes above the minimum methylation cut-off, we ran a binomial test to probe for a significant trend towards down- or up-regulation. Genes that showed a significant association of hypermethylation and transcriptional repression were analyzed for functional enrichment using topGO .in-vitro knockdown of Fgfr3, we obtained a list of Fgfr3-regulated genes from pre-preprocessed microarray results from [To compare the transcriptional changes induced by DR with lts from . The lislts from . For eacGene annotation used in this study was obtained from the UCSC Genome Browser database . We defiPromoter region: Manually defined region stretching from 5 Kbp upstream and 100 bp downstream of the transcription start site.uiDMR: According to [rding to , uiDMRs CGI: Annotation based on CXXC affinity purification plus deep sequencing (CAP-seq) experiments [eriments  CGIs werChromatin states: Publicly available, pre-processed chromatin annotation in liver tissue based on four histone marks (ENCODE chromHMM segmentation) were obtained from the ENCODE table browser [https://main.genome-browser.bx.psu.edu/cgi-bin/hgTrackUi?g=meryChromHmm7s&db=mm9). browser  and re-m browser . DetailsS1 FigFisher\u2019s exact test).  Edwards-Venn diagrams depicting the overlap of significantly hypo- (E) and hypermethylated (D) genes in liver (see (A) Schematic representation of the data sets analysed and comparisons made. We probed for Dietary Restricted (DR)-related dCpGs in blood of adult B6D2F1\u2642 and C57BL/6\u2642. Pre-processing was conducted in parallel for all experimental groups (B) Number of dCpGs  between each DR cohort and its respective control. Proportion of hypermethylated dCpGs are indicated in %. (C) Venn diagrams depicting the overlap of significantly hypo- and hypermethylated dCpGs in both DR cohorts. Proportions of overlap relative to the C57BL/6\u2642 set are indicated in % Click here for additional data file.S2 Fig(A) Histogram of bin lengths for the comparison in (TIF)Click here for additional data file.S3 FigFisher\u2019s exact test). (B) Enrichment analysis of common hypermethylated 10-CpG-DMRs over common hypermethylated DMRs detected with 50-CpG bins. Bars indicate the ratio of the observed DMR frequency and the average frequency across the genome . (C) Venn diagram depicting the overlap of significantly hypomethylated DMRs under DR, Dwarfism and rapamycin treatment relative to the control groups at old age using bins covering 50, 20 or 10 CpGs .(A) Venn diagram depicting the overlap of significantly hypermethylated DMRs under DR, Dwarfism and rapamycin treatment relative to the control groups at old age using bins covering 50, 20 or 10 CpGs Click here for additional data file.S4 FigFisher\u2019s exact test). (D) Differential methylation landscape of the Elovl6, Egf, Ghr, and Egfr gene loci using 10-CpG bins. Bins are represented as bars with color scale and height indicating methylation differences. Shaded area indicates location of 50-CpG-DMRs for comparison. Arrows indicate gene orientation; merged mRNA structure is depicted below.(A-C) Enrichment analysis of common hypermethylated 10-CpG-DMRs between DR and Dwarfs (n = 6679) and rapamycin treatment and Ames dwarf mice (n = 4355) over genomic elements (A), ENCODE chromatin states (B) and Cistrome binding sites of DNA binding elements (C). Bars indicate the ratio of the observed DMR frequency and the average frequency across the genome Click here for additional data file.S5 FigFunctional enrichment of differentially hyper- and hypomethylated genes in DR-treated mice (A), rapamycin-treated mice (B) and Ames dwarf mice (C) at old age in comparison to respective controls.(TIF)Click here for additional data file.S6 FigFisher\u2019s exact test).(A) Schematic representation of data sets and comparisons made. We analyzed age-related DMRs, comparing old and young control mice for each strain separately. Pre-processing was conducted in parallel for all groups (B) Boxplot representation of global DNA methylation levels in the liver of young and old C3B6F1\u2640, heterozygous Prop1 mutant and UM-HET3\u2640 mice. Strain and sex are indicated above. (C) Number of significantly differentially methylated regions (age-related DMRs)  in response to age in three different mouse strains. Proportion of hypermethylated DMRs are indicated in %. (D) Scatterplot representation of methylation values of each bin in young and old animals compared across strains. Age-related DNA methylation changes are highlighted. Bins that were not differentially regulated (background) are represented in grey. Data density is indicated by color code.  Venn diagram depicting the overlap of significantly age-related hypo- (E) and hypermethylated (F) DMRs across mouse strains. The set of age-related DMRs detected in at least two strains are highlighted in grey Click here for additional data file.S7 FigFisher\u2019s exact test). (B) Schematic representation of data sets and comparisons. We probed for intervention-related DMRs at young age, by comparing long-lived mice to their respective controls. Pre-processing was conducted in parallel for all shown treatment groups. (C) Number of DMRs  between young DR or young Dwarf mice and their respective controls. Proportion of hypermethylated DMRs are indicated in %. (D) Scatterplot comparison of bin-wise differences between Young DR-related DMRs versus changes in young Dwarf mice, respectively. Bins overlapping the Scd1 gene are highlighted in red. Methylation differences under DR were significantly positively associated with differences in Ames dwarf mice (One-sided Fisher\u2019s exact test p < 0.01). Number of bins in each quadrant is indicated in blue. (E) Enrichment analysis of hypermethylated DMRs under young DR or young Dwarf mice over longevity-related DMRs detected at old age. Bars indicate the ratio of the observed DMR frequency and the average frequency across the genome .  Venn diagram depicting the overlap of hypermethylated genes (\u2265 2 DMRs overlapping) under young DR, young Ames dwarf and (F) old DR or (G) old Ames dwarf mice, respectively .  Differential methylation landscape of the Scd1 (H) and Elovl6 (I) gene loci in DR or Ames dwarf mice at young age. Bins are represented as bars with color scale and height indicating methylation differences. Arrows indicate gene orientation; merged mRNA structure is depicted below.(A) Venn diagram depicting the overlap of bins located over hypomethylated age-related DMRs with hypermethylated DMRs common between DR, dwarfism and rapamycin treatment Click here for additional data file.S8 FigWilcoxon rank-sum test).(A) Pictographic representations of chromosome 8 with intervention-related DMRs indicated by colored bars. Highlighted is a DMR common among all three models that was not detected as age-related DMR. (B) The shaded area indicates the hypermethylated DMR common among all three longevity models mapping over the Tat gene locus. For improved resolution, the methylation profile is represented by 500 bp bins overlapping adjacent bins by 400 bp. Arrows indicate gene orientation; merged mRNA structure is depicted below. (C) DNA methylation levels of single cytosines (points) present in four longevity-related, age-independent DMRs in the liver of aged DR (C3B6F1\u2640 and UM-HET3\u2640), Ames Dwarf and Rapamycin treated mice next to their respective controls. Lines represent the methylation change over individual cytosines. Colored boxplots represent methylation levels averaged across all cytosines Click here for additional data file.S9 FigWilcoxon rank-sum test). (B) DNA methylation levels over the same set of cytosines in young and old controls . (C) DNA methylation levels over the same set of cytosines in young Ames dwarf and DR (C3B6F1\u2640) mice next to their respective controls . (D) DNA methylation levels over the same set of cytosines measured by RRBS-seq in blood of adult DR (B6D2F1\u2642) mice next to their respective controls. The dashed box indicates the range of methylation levels that is not covered by RRBS-seq data in blood.(A) DNA methylation levels of single cytosines (points) present in four longevity intervention-related, age-independent 500 bp regions in the liver of aged DR (C3B6F1\u2640 and UM-HET3\u2640), Ames Dwarf and rapamycin-treated mice next to their respective controls. Lines represent the methylation change over individual cytosines. Colored boxplots represent methylation levels averaged across all cytosines Click here for additional data file.S10 Figz-score range). Additionally, replicates of the same treatment group were averaged and provided as additional sample for comparison with individual replicates. Clustering of CpGs dependent on region (rows) and treatment group (columns) are highlighted. White box indicates Region III.  DNA methylation levels of single cytosines  present in (C) four or (D) three longevity-related, age-independent DMRs in the liver of aged DR fed (C3B6F1\u2640) and Irs1-KO mice next to their respective controls. Lines represent the methylation change over individual cytosines. Red lines indicate dCpGs with higher methylation levels in long-lived mice; green lines indicate dCpGs with lower methylation levels. Colored boxplots represent methylation levels averaged across all cytosines .(A) CpG-wise DNA methylation at the four targeted DMRs as measured by BS-AS in exemplary Irs1KO replicate. DNA methylation as measured by WGBS-seq (Dietary restriction) is displayed on top for comparison. Target DMRs and surrounding genes and CGIs are highlighted. Genomic location of the marker regions are listed in the table above (B) Heatmap of unsupervised clustering of CpG-wise methylation changes as measured by BS-AS Click here for additional data file.S11 FigBinomial test p < 0.001). Number of differentially methylated genes in each quadrant is indicated in blue and red, for all genes and differentially expressed genes, respectively. (B) Gene ontology and Reactome enrichment of genes with a negative correlation of gene expression and methylation. Lengths of bars represent negative ln-transformed, adjusted pvalues using Fisher\u2019s exact test. Cells indicate log2-foldchanges (log2FC) between Ames dwarf and controls per gene. (C) Venn diagram depicting the overlap of genes with a negative correlation of gene expression and methylation in young and old Ames Dwarf mice .  Scatterplot of expression differences versus methylation differences of dwarfism-related DMRs mapping uiDMRs at (D) young and (E) old age. Dashed lines indicate DNA methylation cutoff of > \u00b110%. DNA hypermethylation associated significantly with reduced gene expression . Number of differentially methylated genes in each quadrant is indicated in blue and red, for all genes and differentially expressed genes, respectively.(A) Scatterplot of expression differences versus methylation differences of dwarfism-related DMRs at young age. Dashed lines indicate DNA methylation cutoff of > \u00b110%. DNA hypermethylation associated significantly with reduced gene expression ((TIF)Click here for additional data file.S12 FigBinomial test p < 0.05). Number of differentially methylated genes in each quadrant is indicated in blue and red, for all genes and differentially expressed genes, respectively. (B) Gene ontology and Reactome enrichment of genes with a negative correlation of gene expression and methylation. Lengths of bars represent negative ln-transformed, adjusted pvalues using Fisher\u2019s exact test. Cells indicate log2-foldchanges (log2FC) between DR mice and control group per gene.  Venn diagrams depicting the overlap of genes being transcriptionally (C) down- or (D) up-regulated in DR or Ames dwarf mice, respectively. Both down- and up-regulated genes showed a significant overlap between both longevity models . (E) Venn diagram depicting the overlap of genes being transcriptionally down-regulated and hypermethylated in DR and Ames dwarf mice. (F) Differential methylation landscape of the Fgfr3 gene locus in DR, Rapamycin treated and Ames dwarf mice. Bins are represented as bars with color scale and height indicating methylation differences. Arrows indicate gene orientation; merged mRNA structure is depicted below. (G) Fgfr3 mRNA expression by RNA-sequencing in control and Ames Dwarf mice at young and old age, respectively (n = 4 vs 2 and 4 vs 4). (H) Fgfr3 mRNA expression by RNA-sequencing in control and DR mice at young and old age, respectively (n = 3 vs 3 and 3 vs 3).(A) Scatterplot of expression differences versus methylation differences of DR-related DMRs. Dashed lines indicate DNA methylation cutoff of > \u00b110%. DNA hypermethylation associated significantly with reduced gene expression ((TIF)Click here for additional data file.S13 FigFisher\u2019s exact test). (B) Scatterplot of expression differences in livers of DR treated mice versus expression differences in RT112 cells with induced Fgfr3 knockdown. Number of differentially expressed genes in each quadrant is indicated in blue with common expression changes highlighted in red. Both transcriptomes showed significantly common expression signatures . (C) Gene ontology and Reactome enrichment of genes being commonly regulated in DR treated mice and RT112 cells with induced Fgfr3 knockdown. Lengths of bars represent negative ln-transformed, adjusted pvalues using Fisher\u2019s exact test. Cells indicate log2-foldchanges (log2FC) between DR mice and control group per gene.(A) Venn diagram depicting the overlap of genes differentially expressed in livers of DR treated mice and RT112 cells transfected with short-hairpin RNA targeting Fgfr3 Click here for additional data file.S1 Table(XLSX)Click here for additional data file.S2 Table(XLSX)Click here for additional data file.S3 Table(XLSX)Click here for additional data file.S4 Table(XLSX)Click here for additional data file.S5 Table(XLSX)Click here for additional data file.S6 Table(XLSX)Click here for additional data file.S7 Table(XLSX)Click here for additional data file.S8 Table(XLSX)Click here for additional data file.S9 Table(XLSX)Click here for additional data file.S10 Table(XLSX)Click here for additional data file.S11 Table(XLSX)Click here for additional data file.S12 Table(XLSX)Click here for additional data file.S13 Table(XLSX)Click here for additional data file.S14 Table(XLSX)Click here for additional data file.S15 Table(XLSX)Click here for additional data file.S16 Table(XLSX)Click here for additional data file.S17 Table(XLSX)Click here for additional data file.S18 Table(XLSX)Click here for additional data file.S19 Table(XLSX)Click here for additional data file.S20 Table(XLSX)Click here for additional data file.S21 Table(XLSX)Click here for additional data file.S22 Table(XLSX)Click here for additional data file.S23 Table(XLSX)Click here for additional data file."}
+{"text": "Skeletal muscle function declines with aging. Physical activity improves muscle function, but may require upregulation of the hypoxia signalling pathway. In this study, we examine the effect of exercise on muscle function in young and old mice and explore the role of hypoxia pathway in mediating exercise-induced functional improvement. Young (3 months) and old (22-24 months) mice underwent either aerobic exercise training on a treadmill for 8 weeks  or no exercise as a control. Maximum running speed and distance were measured pre- and post-exercise. Following training, there was a significant increase in both maximal speed  and distance (2.5 fold) running in young mice which exercised versus young control (p<0.01). Old mice following exercise training did exhibit any improvement versus the old control group. Notably, protein levels of aryl hydrocarbon receptor nuclear translocator (ARNT), a critical regulator of hypoxia signalling, was 4.7-fold lower in the muscle of old mice after exercise as compared to young (p<0.01). To evaluate further whether loss of hypoxia signaling limits response to exercise, we developed a mouse with an inducible, skeletal muscle specific ARNT knockout (ARNT mKO). ARNT mKO mice exhibited no improvement in either maximal running speed or distance following exercise training. In contrast, littermate controls, with normal ARNT levels, exhibited improvement in both maximal speed and distance running following exercise. Our results suggest that an aging-associated decline ARNT and hypoxia signalling may limit aerobic exercise benefits."}
+{"text": "Management of ticagrelor-associated bleeding is challenging, especially in neurosurgery. Platelet transfusion is inefficient and no antidote is currently available. We report here the first case of recombinant activated factor VII (rFVIIa) use to bypass ticagrelor-induced platelet inhibition. A woman treated with ticagrelor and requiring emergent neurosurgery for an intracranial hematoma received preoperative high-dose platelet transfusion and 60 \u03bcg/kg rFVIIa. Laboratory monitoring demonstrated that platelet transfusion failed to reverse ticagrelor-induced platelet inhibition while rFVIIa improved hemostasis by shortening the thromboelastometric clotting time. Neurosurgery occurred without any bleeding event but the patient presented with a postoperative pulmonary embolism. In conclusion, rFVIIa may decrease ticagrelor-induced bleeding risk but careful assessment of the benefit-risk balance is warranted before using rFVIIa to reverse ticagrelor effects. Ticagrelor is an orally available, direct-acting, selective, and reversibly binding P2Y12receptor antagonists\u2013associated intracranial hemorrhage before neurosurgical procedures.A 58-year-old woman underwent an elective endovascular stent-assisted coiling of a right unruptured middle cerebral artery aneurysm after a 24-hour premedication with dual antiplatelet therapy combining ticagrelor 90\u2009mg twice daily and aspirin 250\u2009mg per day. Aneurysm perforation occurred during coil deployment, inducing intracranial bleeding with intracerebral hematoma, intracranial hypertension, and mass effect, eventually followed with stent thrombosis. Emergent decompressive craniectomy and hematoma removal were needed. Classified as high bleeding risk surgery as all neurosurgical procedures, this procedure required careful preoperative correction of hemostasis, and international guidelines propose to correct platelet function in patients with aspirin- or P2Y11transfused platelets, equivalent to 20 platelet units (PU) (irradiated platelets were oddly provided as such by the blood bank but unrelated to the patient status). The total amount of transfused platelets represents 2- to 2.5-fold the French recommended dose for a 80-kg patient (recommended dose of 0.5 to 0.7\u2009\u00d7\u20091011platelets/10 kg).To reach this aim, platelet transfusion and rFVIIa administration were proposed. High-dose platelet transfusion was performed using two ABO-compatible, irradiated, pooled, random-donor platelet concentrates, stored for 2 days, resulting in 9.9\u2009\u00d7\u20091012receptor antagonists,12receptor inhibition ,12and VASP) was present with respective values below the admitted platelet reactivity thresholds for antithrombotic efficacy.11transfused platelets) increased platelet count with a percentage of platelet recovery approaching 100% but failed to reverse ticagrelor-induced platelet inhibition, as both VASP and VerifyNow-P2Y12values remained below thresholds. rFVIIa had no effect on platelet function but improved hemostasis by shortening the EXTEM clotting time, whereas maximum clot firmness remained unchanged.This observation confirms that platelet transfusion, as already well documented, readily and promptly corrects aspirin effects. On the contrary, high-dose platelet transfusion is inefficient to reverse ticagrelor, as previously reported in a few case reportsIn conclusion, rFVIIa may decrease ticagrelor-induced bleeding risk but careful assessment of the benefit\u2013risk balance is warranted before using rFVIIa to reverse ticagrelor effects."}
+{"text": "This presentation (co-presentation Samus and Sloan) will use combined cross-sectional, baseline data from two intervention studies (n=-642) conducted in Maryland evaluating the impact of dementia care coordination model (MIND at home) to provide a detailed description of common modifiable unmet care needs of family caregivers of community-living persons with dementia (PWD), explore how care needs may differ by the disease stage of the PWD, and presence of racial disparities in care needs. Unmet caregiver needs were identified based on comprehensive in-home assessments using a standardized tool (JHDCNA 2.0) with 6 care domains and 18 items covering caregiver needs. Family caregivers were 77% women; 63 years old (mean); 60% White; and 52% adult children. The most prevalent needs were for education/resources (98%), legal (74%), mental health (44%), and informal support (43%). Needs varied based on dementia severity. African American caregivers (vs. white) had significantly more unmet caregiver needs at baseline (p<.001)."}
+{"text": "Scientific Reports 10.1038/s41598-019-39440-7, published online 18 February 2019Correction to: The original version of this Article contained an error in the Author information.\u201cKai Liu, Xinwei Yang and Jiahe Yang contributed equally.\u201dnow reads:\u201cKai Liu, Jicheng Duan and Hu Liu contributed equally.\u201dThis has now been corrected in the PDF and HTML versions of the paper."}
+{"text": "Curricula to enhance healthcare students\u2019 geriatric training has been lacking. Therefore, we developed AIP, an interprofessional (IP) community-based curriculum, in which IP student teams visit community-dwelling older adults. Using established instruments did not capture personal and professional changes experienced by students. Thus, an additional method using qualitative analyses of students\u2019 six post-visit reflections over 15 weeks was employed to evaluate students \u2018experiential learning. A grounded theory approach was used to describe students\u2019 growth in geriatric proficiencies related to participation in the January-April 2017 AIP program . By program completion, 21 students had submitted 111 reflective essays. An interdisciplinary panel reviewed a sample of reflections and developed an initial coding system, which was then systematically applied to the whole via QSR-NVivo. Seventy-three distinct codes across 111 student essays generated 2515 occurrences. Prevalent themes, revealed by frequency analysis, and themes with remarkable trendlines yielded fifteen central themes. Students became attuned to their client\u2019s life-world (n=185) as demonstrated by four central themes: 1) isolation, loneliness, and depression (n=44); 2) risks of fall (n=19); 3) loss of function/control (n=98); and, 4) importance of socializing in care (n=24). This attunement informed interactional intentionality (n=284), which shaped interactions with their client (n=207). From these authentic encounters, students described learning about 1) myself; 2) current and future practice; 3) team dynamics; and 4) my client as an older person. Systematic analysis of student reflections revealed student growth attributable to AIP. This evaluation approach should be further assessed in geriatric curricula."}
+{"text": "Falls are a major cause of disability nationally are and linked to both fractures and fear of falling. The purpose of this study was to assess the effectiveness of a rural community-based fall prevention program using an academic partnership model with seven physical therapy students rotating through six senior centers. One hundred and fifty-four older adults (Mean age: 76.1+/- 8.5) completed Stepping On at six locations. A mixed-methods design was utilized. Physical therapy students partnered with older adult participants to teach exercises, strategize floor recovery techniques, and identify community safety barriers. A descriptive survey tool assessed demographic profiles, falls efficacy, and program effectiveness among participants. Students participated in a follow-up focus group to discuss perspectives on their role in the fall prevention program. Most participants were female (86.4%), lived alone (50.0%) and taking four or more medications (74%). Thirty-eight participants (24.7%) had fallen over the past year. Eighty-eight (57.1%) subjects noted they had less fear of falling following the community-based intervention; moreover, most subjects (74.7%) reported having an improved plan for floor rise after a fall. Major focus group themes underscored students\u2019 enhanced ability to teach exercise and mobility activities with an increased awareness of interdisciplinary fall prevention. Following a collaborative community-based fall prevention program, seniors have a better understanding of fall causes and plan to seek floor recovery assistance. In turn, student teaching and communication skills are reinforced. Student partnering with seniors promotes fall prevention strategies and affords benefits to both students and participants."}
+{"text": "Correction to: Antimicrob Resist Infect Control (2019) 8:123https://doi.org/10.1186/s13756-019-0577-4a minor editorial typo in the following sentence which has now been corrected:The original article  containe\u2018Social desirability bias might always have occurred, since most people are aware that AMR should require special attention .\u2019"}
+{"text": "Fracture healing follows a strict temporal sequence characterized by an initial inflammatory phase. Perturbation of the inflammatory phase may be responsible for the poorer fracture healing outcomes in older adults. Herein, we examine age-related changes to the macrophage during fracture healing. Macrophages regulate inflammation through pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes. Anti-inflammatory activity is promoted via activation of triggering receptor expressed on myeloid cells 2 (TREM2). Tibia fractures were made in old (24 months) and young (3 months) mice. Immune cells from the fracture callus were analyzed via RNAseq and FACS, and fracture healing was evaluated histologically. Old mice demonstrated significantly delayed fracture healing compared to young (p<0.05). The quantity of infiltrating macrophages into the fracture callus was similar in young and old mice. However, 1222 genes were significantly differentially regulated (FDR<0.1) in callus macrophages from old mice compared to young, and old macrophages demonstrated a more pro-inflammatory phenotype. TREM2 expression was increased in macrophages after fracture in both groups but was significantly less in old mice compared to young via RNAseq and FACS . TREM2-/- mice demonstrated increased pro-inflammatory cytokine expression within the callus with resulting significant delays in fracture healing compared to age-matched controls (p<0.05). Inhibition of macrophage infiltration into the fracture callus significantly improved fracture healing in old mice compared to age-matched controls. Age-related changes to macrophages, including increased pro-inflammatory cytokine expression and dysregulated TREM2 expression, may explain fracture healing deficits observed in older adults. Therapeutically targeting macrophages may improve management of fractures in older adults."}
+{"text": "Genome-scale pooled CRISPR screens are powerful tools for identifying genetic dependencies across varied cellular processes. The vast majority of CRISPR screens reported to date have focused exclusively on the perturbation of protein-coding gene function. However, protein-coding genes comprise <\u20092% of the sequence space in the human genome leaving a substantial portion of the genome uninterrogated. Noncoding regions of the genome harbor important regulatory elements  that influence cellular processes but high-throughput methods for evaluating their essentiality have yet to be established.Here, we describe a CRISPR-based screening approach that facilitates the functional profiling of thousands of noncoding regulatory elements in parallel. We selected the tumor suppressor p53 as a model system and designed a pooled CRISPR library targeting thousands of p53 binding sites throughout the genome. Following transduction into dCas9-KRAB-expressing cells we identified several regulatory elements that influence cell proliferation. Moreover, we uncovered multiple elements that are required for the p53-mediated DNA damage response. Surprisingly, many of these elements are located deep within intergenic regions of the genome that have no prior functional annotations.This work diversifies the applications for pooled CRISPR screens and provides a framework for future functional studies focused on noncoding regulatory elements. The ability to modify genomic DNA using the CRISPR/Cas9 system has rapidly transformed the field of functional genomics \u20134. In adThe majority of CRISPR screens reported to date have focused exclusively on the function of protein-coding genes. In contrast, relatively few reports have described pooled screens that interrogate the function of noncoding regulatory elements. Many of the studies that have utilized pooled screens to characterize regulatory elements have designed dense tiling CRISPR libraries with genomic target sites that are restricted to sequences immediately adjacent to a gene of interest \u201317. IsolThe tumor suppressor p53 is a master regulator of cell fate decisions and a central line of defense against genomic instability \u201324. WhilHere, we use p53 as a model system to evaluate pooled CRISPR screening methods for characterizing the function of noncoding regulatory elements. We designed a pooled CRISPR library targeting p53 binding sites throughout the genome and profile the functional significance of these sites in multiple biological contexts. We demonstrate that pooled CRISPR screens are capable of distinguishing p53-bound regulatory elements that influence cell proliferation and/or cell cycle arrest in response to DNA damage. While some of the regulatory elements we identified are well-characterized p53 targets, many are located within intergenic regions of the genome that lack prior functional annotations. Importantly, orthogonal experimental approaches were able to confirm the functional significance for several of these intergenic regulatory elements.In addition to identifying p53-bound regulatory elements that influence cell proliferation and/or cell cycle arrest in response to DNA damage we explore a variety of practical considerations for the use of pooled CRISPR screens to profile the function of regulatory elements. Most notably, we perform each of our screens using both CRISPR interference (CRISPRi) and CRISPR knockout (CRISPRko) technologies allowing us to directly compare the different screening approaches. Surprisingly, we observed minimal overlap in screening results across technologies and demonstrate that screens performed using CRISPRi more closely recapitulate known biology. Altogether, our findings provide valuable insight into the design of CRISPR-based screening approaches for profiling the function of noncoding regulatory elements.In order to identify an ideal cell-based model system to profile p53 function we took advantage of publicly available data generated through Project Achilles . BrieflyTo identify molecular features associated with cell lines in which p53 knockout resulted in a proliferative advantage we intersected p53 \u2018Enrichment Scores\u2019 with data from the IARC  TP53 database . The IARTo select a cell line for screening p53 function we first narrowed the list of cancer cell lines screened through Project Achilles down to those harboring wildtype p53. We then used data from the IARC TP53 database to further restrict this list to cell lines with no documented mutations in other known tumor suppressors or oncogenes   screens we next generated a 769P-derived cell line expressing Cas9. We stably integrated Cas9 into a population of 769P cells using lentivirus and confirmed Cas9 expression by western blot Fig. c. We theTo calculate changes in sgRNA abundance over the course of the screen we utilized MAGeCK, a computational tool for model-based analysis of pooled CRISPR screens . Analysi2-12CWWG) located within each p53 ChIP-Seq peak  screens we next generated a 769P-derived cell line expressing a nuclease-dead version of Cas9 fused to the KRAB repressive domain (dCas9-KRAB). We stably integrated dCas9-KRAB into a population of 769P cells using lentivirus and confirmed dCas9-KRAB expression by western blot Fig. e. We the). Surprisingly, we identified many p53 binding sites in which CRISPRi-mediated repression resulted in a significant proliferative disadvantage . In contrast, we identified multiple sgRNAs targeting the second p53 consensus motif in Peak 1267 that were significantly enriched in our peak-targeting CRISPRi screen  and their inhibition phenocopied the effect of gene knockout. Surprisingly, some of the regulatory elements identified in our screens were in close proximity to transcription start sites but were not functionally associated with nearby genes. For example, inhibition of Peak 1267 had a significant impact on both cell proliferation and cell cycle arrest in response to DNA damage. Although Peak 1267 is located within 1\u2009kb of the TNFRSF10A transcription start site, knockout of TNFRSF10A had no effect on either process. Despite its proximity to TNFRSF10A, Peak 1267 likely functions as a distal regulatory element for other genes involved in cell proliferation and/or the DNA damage response.Several of the regulatory elements we discovered are located in intergenic regions of the genome that are devoid of any prior functional annotation. For example, Peak 384 is located more than 200\u2009kb away from the nearest annotated gene yet inhibition of this site resulted in a significant reduction in cell proliferation. Among the p53 binding sites that had the greatest impact on cell cycle arrest in response to DNA damage was Peak 685. Interestingly, this peak is located more than 250\u2009kb from the nearest annotated gene. These examples highlight the ability of pooled CRISPR screens to identify functional regulatory elements located deep within intergenic regions the human genome. While we hypothesize that the activity of these intergenic regulatory elements is p53-dependent, we cannot exclude the possibility that they influence cell proliferation and/or cell cycle arrest through a p53-independent mechanism. Regardless, identifying the gene targets of these noncoding regulatory elements will be an exciting area of future research.In the course of our study we evaluated multiple methods for perturbing the function of regulatory elements. More specifically, we performed CRISPRi screens with cells expressing dCas9-KRAB as well as CRISPRko screens with cells expressing Cas9. While pooled CRISPR screens have been performed using dCas9 in the absence of a KRAB domain fusion, we reasoned that the repressive properties of dCas9-KRAB would result in greater impacts on regulatory element function and, in turn, more pronounced cellular phenotypes in our screens. Both CRISPRi and CRISPRko screening methods resulted in the enrichment/depletion of sgRNAs targeting p53 binding sites, although we observed minimal overlap between the different approaches. We identified only one p53 binding site (Peak 1267) targeted by sgRNAs that were enriched using both technologies. Importantly, the sgRNA enrichments/depletions we observed in our peak-targeting CRISPRi screens more closely reflected the results of our gene-targeting CRISPRko screens. We hypothesize that the degenerate nature of the p53 consensus motif allows p53 binding sites to be tolerant of indels that result from DNA cleavage by Cas9 and prevents CRISPRko-based approaches from effectively perturbing their function. Given that many transcription factors bind to degenerate sequence motifs we recommend the use of CRISPRi-based methods when performing pooled CRISPR screens focused on the identification of functional regulatory elements. In contrast, CRISPRko-based approaches that introduce indels would be more appropriate for screens intended to functionally profile the sequences of known regulatory elements at high resolution. Likewise, CRISPR screens performed using dCas9 (without a KRAB domain fusion) could interfere with transcription factor binding and distinguish sites within a regulatory element that are required for activity.With regards to our CRISPR library design, we chose to target all PAM-containing sequences that were proximal to p53 consensus motifs within p53 binding sites when constructing our peak-targeting CRISPR library. While sgRNA design principles have been described for both CRISPRi and CRISPRko approaches, the methods for generating these rules have been based exclusively on the perturbation of protein-coding gene function , 35, 36.In this study we developed screening systems to identify p53-bound regulatory elements that influence cell proliferation and/or cell cycle arrest in response to DNA damage. However, the approaches we describe here can be adapted to profile the function of regulatory elements bound by any transcription factor. Alternatively, these methods can be utilized to interrogate the function of intergenic regions of interest identified in genome-wide association studies (GWAS) or noncoding regions that have been shown to harbor rare genetic variants identified in patient samples. One major challenge associated with each of the aforementioned applications is the development of relevant cell-based model systems in which to perform pooled CRISPR screens.In conclusion, our findings demonstrate that CRISPR-based screening methods can be used to characterize the functional role of noncoding regulatory elements in diverse biological processes. Moreover, our results provide valuable insight into practical considerations for the design and implementation of CRISPR screens focused on noncoding regions of the genome.Human renal adenocarcinoma cells  were cultured in RPMI medium supplemented with 10% Fetal Bovine Serum (Sigma-Aldrich). Cells were cultured with 250\u2009nM doxorubicin (Sigma) for pooled CRISPR screens and validation experiments to induce DNA damage. Cells were tested periodically for mycoplasma contamination and were authenticated by SNP fingerprinting at both the initiation and completion of each CRISPR screen.Lentivirus was produced from vectors encoding Cas9  and dCas9-KRAB  as previously described . For infCell pellets were lysed and protein concentrations were quantified by BCA assay (ThermoFisher). Western blots were performed on protein lysates (60\u2009\u03bcg/well). Primary antibodies used were anti-Cas9  and anti-H3 . Protein was visualized using an IRDye800CW-conjugated secondary antibody .The gene-targeting CRISPR library was designed against 330 protein-coding genes that are predicted targets of p53 . The lib2-12CWWG). All sgRNAs with putative off-target sites within protein-coding genes were excluded from the library. In addition, sgRNAs with more than one potential off-target site within unrelated noncoding regions of the genome were excluded. Cutting frequency determination (CFD) was used to evaluate off-target potential with a CFD\u2009=\u20091 being considered a potential off-target site [The peak-targeting CRISPR library was designed against 2036 previously characterized p53 ChIP-Seq peaks . The libget site .The lentiviral titer for each pooled CRISPR library was determined as previously described . LibraryGenomic DNA was isolated using NucleoSpin Blood XL, Blood L, and Blood columns according to the manufacturer\u2019s protocol (Machery Nagel). Targeted sequencing libraries were generated directly from genomic DNA as previously described . LibrariSequencing reads were translated into read counts by extracting the 20\u2009nt sgRNA sequence from each read followed by alignment to the library reference. For each screen we achieved an average sequencing depth of >\u2009500 aligned reads per sgRNA per replicate. Enrichment/depletion of sgRNAs in each screen was determined with MAGeCK using the alphamedian option to calculate fold changes . Fold chIndividual sgRNAs were cloned into lentiGuide-Puro  and lentivirus was generated as previously described . For infStable CRISPRi cell lines harboring individual sgRNAs were seeded at equal cell numbers and cultured in parallel for 18\u2009days. Every 2\u20133\u2009days cells were collected, counted, and re-seeded at equal cell numbers. All experiments were performed in triplicate.Stable CRISPRi cell lines harboring individual sgRNAs were seeded at equal cell numbers and cultured in the presence or absence of doxorubicin. Cell cycle analysis was performed using the 488 EdU Click Proliferation Kit  in conjunction with propidium iodide staining as per the manufacturer\u2019s guidelines. All experiments were performed in triplicate.Additional file 1: Figure S1. p53 enrichment in pooled CRISPR screens requires wildtype p53. p53 enrichment scores (categorized by p53 mutation status) from pooled CRISPR knockout screens in 350 cancer cell lines. P-values were calculated using the two-tailed unpaired Student\u2019s t-test with equal variances. ***P\u2009<\u20090.001, **P\u2009<\u20090.01.Additional file 2:Figure S2. CRISPR-knockout screen identifies p53-bound regulatory elements that influence cell proliferation. (A) Comparison of log2 fold changes (relative to pDNA) for all sgRNAs between replicates in 769P-Cas9 cells. (B) Volcano plot comparing significance of sgRNA enrichment/depletion and log2 fold change (relative to pDNA) in 769P-Cas9 cells for all sgRNAs in CRISPR library. (C) Visualization of enrichment/depletion in 769P-Cas9 cells for sgRNAs targeting a selected subset of peaks (red) compared to all sgRNAs in CRISPR library (black). (D) Comparison of log2 fold change (relative to pDNA) and distance from nearest annotated TSS for all sgRNAs in CRISPR library. (E) Comparison of log2 fold changes (relative to pDNA) for all sgRNAs between 769P-Cas9 and 769P-dCas9-KRAB screens.Additional file 3:Figure S3. CRISPR screens uncover functional dissociation of p53-bound regulatory element and proximal protein-coding gene. (A) Schematic of p53 motifs and sgRNA targets located in Peak 1267. (ChromHMM track legend: red\u2009=\u2009active promoter) (B) Log2 fold changes (relative to pDNA) in CRISPR screen for sgRNAs targeting TNFRSF10A in 769P-Cas9 cells. (C) Log2 fold changes (relative to pDNA) in CRISPR screen for sgRNAs targeting Peak 1267 in 769P-dCas9-KRAB cells. FDR values were calculated using the Benjamini-Hochberg method.Additional file 4: Figure S4. CRISPR-knockout screen identifies p53-bound regulatory elements that influence cellular response to DNA damage. (A) Comparison of log2 fold changes (relative to pDNA) for all sgRNAs between replicates in 769P-Cas9 cells. (B) Volcano plot comparing significance of sgRNA enrichment/depletion and log2 fold change (relative to pDNA) in 769P-Cas9 cells for all sgRNAs in CRISPR library. (C) Visualization of enrichment/depletion in 769P-Cas9 cells for sgRNAs targeting a selected subset of peaks (red) compared to all sgRNAs in CRISPR library (black). (D) Comparison of log2 fold change (relative to pDNA) and distance from nearest annotated TSS for all sgRNAs in CRISPR library. (E) Comparison of log2 fold changes (relative to pDNA) for all sgRNAs between 769P-Cas9 and 769P-dCas9-KRAB screens.Additional file 5:Figure S5. p53 inhibition influences cellular response to DNA damage. Raw flow cytometry data from cell cycle analysis experiments.Additional file 6:Table S1. Project Achilles \u2013 p53 status and enrichment data.Additional file 7: Table S2. CRISPR library targeting p53-regulated protein-coding genes.Additional file 8:Table S3. CRISPR screen raw read counts (Gene Library/Cas9).Additional file 9:Table S4. Guide-level MAGeCK output (Gene Library/Cas9/Untreated).Additional file 10:Table S5. Gene-level MAGeCK output (Gene Library/Cas9/Untreated).Additional file 11:Table S6. CRISPR library targeting p53 binding sites.Additional file 12:Table S7. CRISPR screen raw read counts (Peak Library/dCas9-KRAB).Additional file 13:Table S8. Guide-level MAGeCK output (Peak Library/dCas9-KRAB/Untreated).Additional file 14: Table S9. Peak-level MAGeCK output (Peak Library/dCas9-KRAB/Untreated).Additional file 15:Table S10. CRISPR screen raw read counts (Peak Library/Cas9).Additional file 16:Table S11. Guide-level MAGeCK output (Peak Library/Cas9/Untreated).Additional file 17: Table S12. Peak-level MAGeCK output (Peak Library/Cas9/Untreated).Additional file 18: Table S13. Guide-level MAGeCK output (Gene Library/Cas9/ Doxorubicin).Additional file 19: Table S14. Gene-level MAGeCK output (Gene Library/Cas9/Doxorubicin).Additional file 20: Table S15. Guide-level MAGeCK output (Peak Library/dCas9-KRAB/ Doxorubicin).Additional file 21:Table S16. Peak-level MAGeCK output (Peak Library/dCas9-KRAB/Doxorubicin)Additional file 22:Table S17. Guide-level MAGeCK output (Peak Library/Cas9/ Doxorubicin).Additional file 23: Table S18. Peak-level MAGeCK output (Peak Library/Cas9/ Doxorubicin).Additional file 24: Table S19. Sequences of sgRNAs used in validation experiments."}
+{"text": "Gp78/autocrine motility factor receptor (Gp78/AMFR) is a cancer-associated endoplasmic reticulum-localized E3 ubiquitin ligase\u00a0and also the cell surface receptor for autocrine motility factor (AMF). The study objective was to determine the association between Gp78/AMFR and AMF endocytosis in thyroid cancer cells.\u00a0Gp78/AMFR expression and AMF internalization were measured in differentiated thyroid cancer (DTC) and anaplastic thyroid cancer (ATC) cell lines and in freshly resected human papillary thyroid cancers (PTC) relative to benign thyroid tissue. Spheroid-like aggregates generated from explants of cancer, goiter, and collateral thyroid tissue were assessed for expression of cancer stem cell markers,\u00a0surface Gp78/AMFR and AMF endocytosis. DTC cell lines showed elevated total and surface Gp78/AMFR and AMF internalization relative to ATC lines. Gp78/AMFR, Oct-4 and Sox-2 protein expression, Gp78/AMFR surface expression and AMF internalization were elevated in PTC-derived aggregates relative to fibroblasts. Elevated levels of Gp78/AMFR expression and AMF internalization in PTC were associated with expression of cancer stem cell markers. Gp78/AMFR expression and AMF uptake are more closely associated with DTC compared to benign thyroid lesions or ATC and with PTC-derived cancer stem-like cells. Thyroid nodules are extremely common in the general population, being palpable in 5% of people and diagnosed by high resolution ultrasound in greater than half of people. Thyroid cancer tends to present as a thyroid nodule and, fortunately, only a small minority of thyroid nodules are eventually diagnosed as being malignant . The steGp78/AMFR internalization of AMF, via a distinct raft-dependent endocytic pathway to the ER, is increased in metastatic cancer cells -11. AMF Antibodies and reagents\u00a0Monoclonal rat IgM antibody against Gp78/AMFR (3F3A) was used in the form of ascites fluid . Alexa-4Cell linesTwo papillary (TCP1 and KTC1), one follicular (FTC133), and three anaplastic  human thyroid cancer cell lines were a kind gift from Dr. Schweppe . Cells were maintained in complete RPMI 1640 containing 10% fetal bovine serum (FBS). To minimize phenotypic drift, all cell lines were passaged two to three times after recovery from frozen stocks before initiating the experiments and maintained in culture for a maximum of 10-12 passages.Human thyroid tissue microarraysHuman tissue microarrays were constructed as previously described . The TMAGp78/AMFR expression was evaluated by immunohistochemistry. Briefly, TMA blocks were cut into 4-um sections using a Leica microtome  and the sections transferred to adhesive-coated slides for immunohistochemical staining. Anti-Gp78/AMFR (3F3A) monoclonal antibody dilutions were validated using cores prepared from thyroid cancer cell pellets  to determine the optimal Gp78/AMFR dilution, and compared to the expression determined by flow cytometry and Western blotting . The TMAHuman thyroid tumour dissociation and labelingSurgical specimens of human thyroid tumors were obtained from the practice of Dr. Sam M. Wiseman, a thyroid surgeon based at St. Paul\u2019s Hospital, Vancouver, British Columbia, Canada. This study was carried out with approval of the Research Ethics Board of the Providence Health Care Research Institute at the University of British Columbia (Ref No. H06-00220). Thyroid specimens were procured immediately after surgical resection. A portion of the tumor tissue was placed into sterile 1.2 ml cryo-vials, snap-frozen in liquid nitrogen and stored at -80\u00b0C. In addition, a portion of the specimen was placed in a sterile tube containing 10 ml of ice cold RPMI, and transported to the lab within one hour after excision. Thyroid tissues were placed into 100-mm plates containing ice-cold PBS and mechanically dissected and enzymatically  digested. Dissociated tissues were filtered through a 150-mm-pore-size nylon mesh to generate a single-cell suspension. Cell suspensions were adjusted to 5x105 cells/mL and processed for Gp78/AMFR surface expression and AMF-FITC uptake by flow cytometry.Isolation of spheroidal cultures from human thyroid tissueFresh PTC, goiter and collateral tissue specimens were subjected to enzymatic digestion  and supernatants, containing the majority of differentiated cells  were removed. Remaining tissue fragments were plated in medium containing 2% FBS and primary \"spheroid-like\" cell aggregates\u00a0collected 5-7 days post culture, transferred to separate wells (12-well plates) containing fresh media (2% FBS) and mechanically dissociated into single cell suspensions to generate \u201csecondary cultures\u201d. Primary aggregates of cells with \u201cspheroid-like\u201d structures were observed 5-7 days post culture and imaged after 14-16 days. Secondary cultures were cloned by limiting dilution.\u00a0Primary fibroblasts were isolated from normal adult resected connective tissues and maintained in culture for the duration of the experiment.Western blottingCell lysates were prepared as previously described and centrifuged for 15 min at 13,000 rpm at 4\u00b0C . Tissue Flow cytometryFlow cytometry of cell surface Gp78/AMFR expression using the anti-Gp78/AMFR monoclonal antibody,\u00a03F3A, and AMF-FITC internalization were performed as previously described . For uptRT-PCRClones derived from spheroidal aggregates obtained from PTC, goiter and collateral tissue specimens were lysed using the PARIS-kit for the extraction of total RNA and proteins following the manufacturer protocol. RT-PCR was performed using total RNA, Superscript III reverse transcriptase  and Oligo (dT)-20mer as described previously . BrieflyStatistical analysisFor TMA analysis the significance of Gp78/AMFR marker expression in DTC, ATC, and benign thyroid lesions, as well as the correlation of clinicopathologic characteristics with the expression of this marker in DTC were assessed with the Pearson \u03c72 or Fisher\u2019s exact test, where appropriate, for categorical variables and Mann-Whitney U test for continuous variables. Gp78/AMFR marker staining pattern for a set of patient matched lymph node metastases were analyzed for correlation with their corresponding primary cancer specimens by Spearman correlation and for significant differences by marginal homogeneity (MH) test. Statistical Package for the Social Sciences (SPSS) statistical software version 16.0  and scripts written in the R programming language  were used for these analyses. P values were corrected for multiple testing using the Benjamini-Hochberg (BH) correction . All staUnless otherwise stated, all values are presented as mean \u00b1 SEM. Statistical significance was evaluated using the Student t-test for paired comparison; P<0.05 was considered significant.Tissue microarray analysis of Gp78/AMFR in human thyroid tumors and clinicopathological correlationsDTC displayed more immunoreactivity than did the benign lesions and the ATCs . Gp78/AMFR showed significantly elevated labeling of DTC relative to either benign or ATC\u00a0as can be seen in Figure Differentiated thyroid cancer cell lines abundantly express Gp78/AMFR and readily internalize AMFWe profiled six human thyroid cancer cell lines: two papillary , one follicular (FTC133), and three anaplastic . These thyroid cell lines have been genetically profiled and their authenticity validated . First, oC and pronase-treated the cells to remove cell surface bound AMF-FITC [To study AMF internalization, we incubated the cells with FITC-conjugated AMF for 30 minutes at 37AMF-FITC . By FACSGp78/AMFR surface expression and AMF-FITC internalization in human thyroid cancerTo determine whether human thyroid cancers can internalize AMF, we assessed Gp78/AMFR surface expression and AMF-FITC uptake in freshly resected primary human thyroid tissues, including five pathologically confirmed PTCs, seven benign thyroid lesions, and 12 normal collateral thyroid tissue specimens. The freshly isolated tissues were mechanically and enzymatically dissociated before analysis by flow cytometry for cell surface Gp78/AMFR expression and AMF-FITC uptake. All PTCs were Gp78/AMFR-positive and demonstrated significantly higher Gp78/AMFR surface expression (P<0.001) compared to non-cancerous thyroid tissues Figure . FurtherGp78/AMFR expression and AMF internalization in potential thyroid cancer stem cells\u00a0Freshly resected PTC, benign thyroid lesions, and collateral normal thyroid tissue specimens were subjected to enzymatic digestion  and tissue fragments were plated in medium containing 2% FBS. Primary \"spheroid-like\" cell aggregates were collected 5-7 days post-culture\u00a0and mechanically dissociated into single cell suspensions to generate \u201csecondary cultures\u201d. Primary aggregates of cells with \u201cspheroid-like\u201d structures were observed 5-7 days post-culture and imaged after 14-16 days  and thyroid stimulating hormone receptor (TsHR) Figure . All colBy Western blot, PTC, goiter and collateral tissue derived clones were found to express Gp78 Figures . Gp78/AMThe current study is the first to comprehensively evaluate Gp78/AMFR expression and AMF internalization in thyroid cancer. A multifaceted analysis of thyroid TMAs, human thyroid cancer cell lines and primary human thyroid cancers has shown that Gp78/AMFR expression and AMF uptake are more closely associated with DTC compared to benign thyroid lesions or ATC. The subpopulation of cells positive for Gp78/AMFR surface expression and AMF internalization increases progressively in collateral thyroid tissue, benign thyroid cancers and papillary thyroid cancers with 20% of the PTC cells positive. This is consistent with increased Gp78 expression in DTC by TMA analysis.Thyroid cancer stem cells have been identified and isolated from human thyroid glands based upon their higher aldehyde dehydrogenase (ALDH) activity , expressGp78/AMFR expression is closely associated with tumor metastasis , 21, 22 A further explanation for this observation may be the dual function of Gp78/AMFR as cell surface AMF receptor and key ER-localized ubiquitin ligase in ERAD. Gp78/AMFR knockout mice show elevated ER stress levels in liver, consistent with the key role of Gp78/AMFR ubiquitin ligase activity in ERAD . At the Gp78/AMFR expression and AMF uptake are more closely associated with DTC compared to benign thyroid lesions or ATC and with PTC-derived cancer stem-like cells. Further study of Gp78/AMFR and AMF uptake by thyroid cancer is warranted and may allow for the development of novel diagnostic and prognostic tools, and therapies, for this common human endocrine cancer type."}
+{"text": "Linum usitatissimum L.) is an important industrial crop that is often cultivated on marginal lands, where salt stress negatively affects yield and quality. High-throughput RNA sequencing (RNA-seq) using the powerful Illumina platform was employed for transcript analysis and gene discovery to reveal flax response mechanisms to salt stress. After cDNA libraries were constructed from flax exposed to water (negative control) or salt (100 mM NaCl) for 12 h, 24 h or 48 h, transcription expression profiles and cDNA sequences representing expressed mRNA were obtained. A total of 431,808,502 clean reads were assembled to form 75,961 unigenes. After ruling out short-length and low-quality sequences, 33,774 differentially expressed unigenes (DEUs) were identified between salt-stressed and unstressed control (C) flax. Of these DEUs, 3669, 8882 and 21,223 unigenes were obtained from flax exposed to salt for 12 h (N1), 24 h (N2) and 48 h (N4), respectively. Gene function classification and pathway assignments of 2842 DEUs were obtained by comparing unigene sequences to information within public data repositories. qRT-PCR of selected DEUs was used to validate flax cDNA libraries generated for various durations of salt exposure. Based on transcriptome sequences, 1777 EST-SSRs were identified of which trinucleotide and dinucleotide repeat microsatellite motifs were most abundant. The flax DEUs and EST-SSRs identified here will serve as a powerful resource to better understand flax response mechanisms to salt exposure for development of more salt-tolerant varieties of flax.Flax ( Linum usitatissimum L.) is an economically important fiber crop, with the flax fiber industry rapidly expanding to meet increasing demand. However, in China flax competes with higher priority food crops, such as grains, that require ever increasing acreage to meet increasing food demands [Worldwide, flax  using bowtie 2 (v2.1.0) (https://sourceforge.net/projects/bowtie-bio/files/bowtie2/2.1.0/) for short reads with default parameter settings (https://omictools.com/rsem-tool) [Illumina paired-end sequencing technology was employed to explore DEUs related to NaCl stress in flax using two biological replicates per time point. A total of 185,457,832 clean reads were generated after removing low quality regions and adapter sequences and sequences were mapped to the flax genome (settings . Only 42Gene expression profiles in response to NaCl stress exposures of 12 h (N1), 24 h (N2) and 48 h (N4) were compared to the no-treatment control (water). DEUs were identified within the set of transcriptome sequences, with 33,774 significant DEUs identified , with values of false discovery rate (FDR) \u2264 0.05 and 2\u00d7 fold change significance cutoffs generated for various treatment time points.At 12 h, 24 h and 48 h of stress exposure, 3669 DEUs (2219 up-regulated and 1450 down-regulated), 8882 DEUs (4865 up-regulated and 4017 down-regulated) and 21,223 DEUs  were significantly differentially regulated in response to NaCl stress exposure, respectively . While dCluster analysis was used to determine expression patterns of DEUs under different experimental conditions. Generally, functions of unknown genes or unknown functions of known genes can be identified by clustering genes with the same or similar expression patterns into classes; genes with similar functions or genes that participate in the same metabolic processes or cell pathways tend to cluster together. DEU dynamic expression patterns for various NaCl stress exposure durations were identified in this study . After hArabidopsis thaliana genome (https://www.arabidopsis.org/). Of 2582 co-expressed unigenes, 2482 (96.13%) displayed significant similarity to known proteins  belong to the Rho-like GTPases from plants (ROP) gene family, which might enhance salt tolerance by increasing root length, improving membrane injury and ion distribution [Interestingly, two salt-tolerant genes (lus10015754 and lus10000310) were obtained here to homologous with Arabidopsis Senescence-Associated Gene29 (SAG29), which was consistent with previous reports [ribution . OverallTo quantitatively assess the reliability of transcriptome data, six candidate DEUs were selected for analysis using real-time reverse transcription quantitative PCR (qRT-PCR) of biological duplicate samples. Consistent with RNA-sequencing analysis results, qRT-PCR showed significant log2-fold expression changes of DEUs among different salt-stress exposure treatments , thus deA total of 1777 EST-SSRs with 2\u20136 bp repeat numbers were identified from sequence data . Among SThe fiber flax variety (Agatha), provided by Heilongjiang Academy of Agricultural Sciences in Harbin, China, provided material for high-throughput RNA-seq. Flaxseeds were placed in cups filled with sterilized vermiculite and maintained at 28 \u00b0C during the day and 22 \u00b0C at night in a growing room on a 16-h light/8-h dark cycle. Plants were irrigated every three days and the humidity in the growth room was maintained at 70%.Three-week-old seedlings were rinsed to remove vermiculite and were placed into tanks filled with 100 mM NaCl solution or water for the control (CK). After seedlings were exposed to NaCl solution or water for 12 h, 24 h or 48 h, whole seedlings were harvested, frozen immediately in liquid nitrogen, then stored at \u221280 \u00b0C until RNA was prepared. Two biological replicates per treatment (each sample containing 10 plants each) were processed in parallel.RNA isolation and cDNA library construction methods have been reported previously .https://www.illumina.com/systems/sequencing-platforms/hiseq-2500.html) to generate paired-end (PE) raw reads, each of ~100 bp in length. Clean reads were generated from raw reads by removal of adaptor sequences, ambiguous \u2018N\u2019 nucleotides (with a ratio of \u2018N\u2019 greater than 10%) and low quality sequences  and were assembled as described by using bowtie2 (2.1.0) software (http://bowtie-bio.sourceforge.net/bowtie2/index.shtml) against a reference genome (ftp://climb.genomics.cn/pub/10.5524/100001_101000/100081/). Only clean, high quality sequence data was used in subsequent analyses.Transcriptome sequencing was performed using the Illumina HiSeq 2500 platform  was selected for use as genetic background, with non-redundant sequences subjected to Pfam (http://pfam.xfam.org/), Gene Ontology (GO) (http://www.geneontology.org/), Eukaryotic Clusters of Orthologous Groups (KOG) (https://www.ncbi.nlm.nih.gov/COG/) and Kyoto Encyclopedia of Genes and Genomes (KEGG) (http://www.genome.jp/kegg/). For gene expression profiling analysis, functional assignments were mapped to GO terms [p values and enrichment factors [For homology-based annotation, the model plant genome of GO terms . Signifi factors .https://www.rdocumentation.org/packages/edgeR/versions/3.14.0) [http://deweylab.github.io/RSEM/; RNA-Seq by Expectation-Maximization) [DEUs were identified based on a negative binomial distribution using the edgeR package (/3.14.0) . Candidaization) . All exphttp://www.r-project.org/) using a distance matrix representing FPKM level profiles of genes across the four sampled time points. The tree produced by the clustering process was split into two branches using the cutree function.Finally, the fold change of FPKM for each sequence was calculated and genes with FPKM fold changes greater or equal to 2 were classified as DEUs. Common DEUs among different time points that exhibited FPKM fold change differences greater than 2 between biological replicates were eliminated. For each gene, normalized FPKM values for each transcript were clustered using the hclust function in R  were selected for analysis of expression levels in flax treated with NaCl solution exposure times of 12 h, 24 h and 48 h using L. ussitatissimum Act1 (GenBank accession no. AY857865) as the internal reference gene. Primer sets were designed from Illumina sequencing data using Primer Premier v6.24 (http://www.premierbiosoft.com/crm/jsp/com/pbi/crm/clientside/ProductList.jsp)  using an ABI 7500 Real-Time PCR System . Data for each experimental sample was corrected for sample loading differences using results of flax Act1 qRT-PCR using the 2\u2212\u0394\u0394Ct method [DEUs identified in transcriptome sequencing analysis were validated using qRT-PCR (quantitative RT-PCR) to further confirm RNA-Seq analysis gene expression results. Six genes (http://archive.gramene.org/db/markers/ssrtool). SSR primer pairs were designed with highest primer scores using Primer-BLAST (https://www.ncbi.nlm.nih.gov/tools/primer-blast/index.cgi?LINK_LOC=BlastHomeAd) with the following standard parameters: target amplicon length of 100\u2013300 bp, annealing temperature variation from 55 to 65 \u00b0C and primer size of 18\u201328 bp.All DEUs identified by transcriptome sequencing were analyzed to identify SSRs with dimer, trimer, tetramer, pentamer and hexamer motifs using SSRIT  and pathways linked to flax response to NaCl exposure were mainly associated with plant hormone signal transduction, photosynthesis-antenna proteins and biosynthesis of amino acids. Number of the genes are homologous to known stress regulators. Transcriptome sequencing results were verified by qRT-PCR. Ultimately, 1777 EST-SSRs based on transcriptome results were identified as important in flax response to NaCl exposure. The results described here thus lay the groundwork for further elucidation of molecular mechanisms of flax stress responses. Ultimately, this information will guide the development of flax varieties that are more tolerant to a wide range of environmental stresses."}
+{"text": "Microbiological investigations confirmed Klebsiella pneumoniae (>106\u00a0cfu/mL) on urine culture whilst two blood cultures were negative. Intravenous fluid resuscitation was successful in restoring hemodynamic stability. Amoxicillin/clavulanic acid (1200mg) was administered and continued for seven days after confirmation on antibiotic sensitivity testing. After ultrasonography confirmed severe right hydronephrosis, a contrasted computed tomography (CT) scan confirmed a horseshoe kidney  with an obstructed right-sided renalmoiety secondary to right pelvi-ureteric junction (PUJ) obstruction (B) and urothelial enhancement suggestive of an infected collecting system. Horseshoe kidneys are the most common congenital renal abnormality with an incidence of 1:400-600. It is commonly asyptomatic and rarely require interventionunless treating complications such as ureteral obstruction (PUJ), urinary tract infections, urolithiasis andWilms Tumour. It is associated with Trisomy 18 and females with Turner syndrome. Our patient underwent a right percutaneous nephrostomy (PCN) and 500 millilitres of infected urine were aspirated. He made a complete recovery at discharge. An interval MAG3 renogram confirmed that both moeities had good and excretion. A pelvi-ureteric junction repair will be performed after 6 weeks.A 21-year-old male presented with a one day history of right flank pain and signs of severe sepsis. The recorded vital signs included a temperature of 39.9\u00b0 Celsius, blood pressure of 95/65 mmHg and heart rate of 165. The laboratory investigations confirmed a raised C-reactive protein (CRP) of 485 mg/l but it was interesting to note thatthe white cell count and creatinine were respectively normal (5.85 x 10"}
+{"text": "Pseudomonas aeruginosa (PaExoY) and the ExoY-like module (VnExoY) found in the MARTX  toxin of Vibrio nigripulchritudo share modest sequence similarity (~38%) but were both recently shown to be activated by actin after their delivery to the eukaryotic host cell. Here, we further characterized the ExoY-like cyclase of V. nigripulchritudo. We show that, in contrast to PaExoY that requires polymerized actin (F-actin) for maximum activation, VnExoY is selectively activated by monomeric actin (G-actin). These two enzymes also display different nucleotide substrate and divalent cation specificities. In vitro in presence of the cation Mg2+, the F-actin activated PaExoY exhibits a promiscuous nucleotidyl cyclase activity with the substrate preference GTP>ATP\u2265UTP>CTP, while the G-actin activated VnExoY shows a strong preference for ATP as substrate, as it is the case for the well-known calmodulin-activated adenylate cyclase toxins from Bordetella pertussis or Bacillus anthracis. These results suggest that the actin-activated nucleotidyl cyclase virulence factors despite sharing a common activator may actually display a greater variability of biological effects in infected cells than initially anticipated.Several bacterial pathogens produce nucleotidyl cyclase toxins to manipulate eukaryotic host cells. Inside host cells they are activated by endogenous cofactors to produce high levels of cyclic nucleotides (cNMPs). The ExoY toxin from  Bordetella pertussis (CyaA) and edema factor from Bacillus anthracis (EF) are strongly activated upon interaction with calmodulin  ATP or [\u03b1-33P] GTP, respectively, PaExoY and indicated amounts of purified actin. cUMP and cCMP synthesis was measured similarly but using \u03b1-32P labeled UTP and CTP substrates. Reaction conditions for VnExoY were similar except that NaCl was replaced by 50 mM KCl when indicated.PaExoY-catalyzed synthesis of cAMP and cGMP synthesis were measured in 50 \u03bcl reactions as described previously  containiMg-ATP-actin was prepared from Ca-ATP-actin for measurements of PaExoY activities as described before .Latrunculin A was purchased from tebu-bio (produced by Focus Biomolecules), added to G-actin in 2-fold access, and incubated for 10 min at room temperature before use in activity assays.S1 Fig(RTF)Click here for additional data file.S2 Fig(DOCX)Click here for additional data file.S3 Fig(RTF)Click here for additional data file.S1 Table(DOCX)Click here for additional data file."}
+{"text": "Aspergillus nidulans.Histone H1 is an evolutionarily conserved linker histone protein that functions in arranging and stabilizing chromatin structure and is frequently fused to a fluorescent protein to track nuclei in live cells. In time-lapse analyses, we observed stochastic exchange of photoactivated Dendra2-histone H1 protein between nuclei within the same cellular compartment. We also observed exchange of histones between genetically distinct nuclei in a heterokaryon derived from fusion of strains carrying histone H1-RFP or H1-GFP. Subsequent analysis of the resulting uninucleate conidia containing both RFP- and GFP-labeled histone H1 proteins showed only parental genotypes, ruling out genetic recombination and diploidization. These data together suggest that the linker histone H1 protein can diffuse between non-daughter nuclei in the filamentous fungus  Histones are members of an ancient family of proteins whose roles have been constantly redefined since their discovery. These proteins were originally thought to function solely in providing structural support for DNA organization and packaging within the nucleus, but recent work has revealed a broad range of intracellular and extracellular functions, including involvement in innate immune response, apoptosis induction, and cellular signaling \u20133. The hAspergillus nidulans. In A. nidulans multiple nuclei undergo \u2018semi-open\u2019 mitosis  within a single cellular compartment . Homokaryotic parental strain LO1699 in heterokaryon fusion containing green nuclei has the genotype . Heterokaryon fusions were generated between the two strains in fully supplemented complete media and all mycelial mats were transferred to selective minimal media. Conidia from heterokaryotic mycelia were harvested and replica-plated onto minimal media supplemented with all combinations of auxotrophic markers from each parental strain, and scored for (+/-) growth. Colonies were visually verified by fluorescence microscopy. Three independent experiments were conducted. N = 50.Marker scoring assay of uninucleate haploid conidia derived from a heterokaryon fusion of histone H1-RFP and histone H1-GFP strains HA344 (Heterokaryon parent # 1) and LO1699 (Heterokaryon Parent #2) respectively. Homokaryotic parental strain HA344 in heterokaryon fusion containing red nuclei has the genotype  software.Heterokaryon fusions of H1-GFP (LO1699) and H1-RFP (HA344) strains were cultured as previously described and allowed to conidiate. Conidia were harvested in ddH20, from excised sections of agar, and plated onto fully supplemented complete media. Two trials containing three biological replicates of 50 colony forming units each were replica-plated onto fully supplemented complete media and minimal media plates supplemented with all combinations of auxotrophic markers from each strain. Two independent trials containing 50 colony forming units each from selected stable diploids, were replica-plated on fully supplemented complete media agar plates and minimal media plates supplemented with all combinations of auxotrophic markers from each strain. Colonies were scored for growth, and verified for fluorescence signal under 100X oil immersion objective lens, using a Zeiss Axioplan microscope.S1 Fig(AVI)Click here for additional data file.S2 Fig(AVI)Click here for additional data file.S3 Fig(AVI)Click here for additional data file.S4 Fig(TIF)Click here for additional data file."}
+{"text": "Halobacillus sp. BBL2006, a moderately halophilic, gram positive bacterium isolated from a sulfidic salt spring in Big Bone Lick State Park, Boone County, Kentucky. The genome of Halobacillus sp. BBL2006 was 3,988,138\u202fbp in length with a GC content of 41.6%. Genome analysis identified 4331 open reading frames including genes for antibiotic resistance and tolerance to heavy metals. The draft genome was deposited at DDBJ/EMBL/GenBank (DNA Databank of Japan/European Molecular Biology Laboratory/Genbank) (JRNX00000000).We present the draft genome sequence of  Specifications tableValue of the data\u2022Halobacillus genomes.These draft genome sequence data add to the growing but still limited list of \u2022Halobacillus isolates are of industrial importance for their production of halotolerant extracellular enzymes.\u2022Halobacillus isolate.These data provide a resource for studying gene structure and function in a salt-spring adapted 1Halobacillus, proposed by Spring et al. in 1996 halobacilli include inhibition of quorum-sensing in gram negative bacteria The genus Halobacillus sp. BBL2006 is a gram positive, moderately halophilic, endospore forming, light orange-yellow, rod shaped bacterium. De novo assembly of 1002 contigs with 84\u00d7 coverage identified a genome size of 3,988,138\u202fbp with a GC content of 41.6%. The NCBI  Prokaryotic Genome Annotation Pipeline Halobacillus genus. A BLAST  query of Genbank using the 16S rRNA gene of BBL2006 identified Halobacillus litoralis (Accession no. NR_029304) Halobacillus trueperi (Accession no. FJ937876) Halobacillus karajensis (Accession no. AJ486874) 2Halobacillus sp. BBL2006 was isolated from a sulfur-enriched salt spring located in Big Bone Lick State Park, in Boone County, KY. BBL2006 genomic DNA was prepared using the Masterpure Gram positive DNA purification Kit (Epicentre) and purified genomic DNA was used for library construction and Illumina sequencing at htSEQ, Seattle, Washington, USA. BBL2006 was chosen for genome sequencing because its phenotypic features are representative of many halobacilli isolated from the Big Bone Lick State Park salt springs."}
+{"text": "Triticum turgidum ssp. carthlicum line Blackbird is a tetraploid relative of durum wheat that offers partial FHB resistance. Resistance QTL were identified for the durum wheat cv. Strongfield \u00d7 Blackbird population on chromosomes 1A, 2A, 2B, 3A, 6A, 6B and 7B in a previous study. The objective of this study was to identify the defense mechanisms underlying the resistance of Blackbird and report candidate regulator defense genes and single nucleotide polymorphism (SNP) markers within these genes for high-resolution mapping of resistance QTL reported for the durum wheat cv. Strongfield/Blackbird population.Fusarium head blight (FHB) resistance in the durum wheat breeding gene pool is rarely reported. P\u2009<\u20090.05) associated with the resistance to FHB spread (Type II FHB resistance) one of which showed significant correlation with both plant height and relative maturity traits. Two gene networks showed subtle differences between Fusarium graminearum-inoculated and mock-inoculated plants, supporting their involvement in constitutive defense. The candidate regulator genes have been implicated in various layers of plant defense including pathogen recognition (mainly Nucleotide-binding Leucine-rich Repeat proteins), signaling pathways including the abscisic acid and mitogen activated protein (MAP) kinase, and downstream defense genes activation including transcription factors , and cell death regulator and cell wall reinforcement genes. The expression of five candidate genes measured by quantitative real-time PCR was correlated with that of RNA-seq, corroborating the technical and analytical accuracy of RNA-sequencing.Gene network analysis identified five networks significantly (Gene network analysis allowed identification of candidate regulator genes and genes associated with constitutive resistance, those that will not be detected using traditional differential expression analysis. This study also shed light on the association of developmental traits with FHB resistance and partially explained the co-localization of FHB resistance with plant height and maturity QTL reported in several previous studies. It also allowed the identification of candidate hub genes within the interval of three previously reported FHB resistance QTL for the Strongfield/Blackbird population and associated SNPs for future high resolution mapping studies. Triticum turgidum L. ssp. durum (Desf.) Husn.) is one of the major cereal food crops grown in the temperate regions of the world. The sustainability of durum wheat production is threatened by the yield and quality losses caused by Fusarium head blight disease (FHB). The dominant causal agent in Canada, Fusarium graminearum Schwabe, produces mycotoxins such as deoxynivalenol (DON) , WTI, PERK9), 2B  and 6B (R1C-3 and Anxa3). It delivered SNPs within most of these candidate genes for future mapping studies. Moving forward, the SNPs within the candidate hub genes will be used for high-resolution mapping of FHB resistance QTL in BB and SF using NILs carrying recombination break points in the FHB resistance QTL interval. SNPs within the candidate genes will also be validated for utilization in breeding programs.The difference between the resistant and susceptible genotypes in deploying defense related transcripts at several layers of plant defense machinery, including recognition, signaling and defense pathway regulation was highlighted in this study. Gene network analysis allowed identification of candidate regulator genes and genes associated with constitutive resistance, those that might be difficult to detect using traditional differential expression analysis. This study also shed light on the association of developmental traits with FHB resistance and partially explained the co-localization of FHB resistance with plant height and maturity QTL reported in several previous studies. It also identified candidate genes within the FHB resistance QTL reported by Sari et al.  on chromAdditional file 1. Hierarchical clustering of gene expression in samples used for weighted gene co-expression network analysis. Genotypes are durum wheat cv. Strongfield (SF), Triticum turgidum ssp. carthlicum line Blackbird (BB) and a resistant (R) and a susceptible (S) doubled haploid line of the SF/BB population. Samples that were inoculated with Fusarium graminearum have \u201c.Fg\u201d suffix. Samples are numbered sequentially to represent the three biological replicates per treatment. Marked in red is an outlier sample excluded from weighted gene co-expression network analysis.Additional file 2. Primer pairs used for quantitative real time PCR of selected candidate hub genes. The candidate hub genes selected encode heat stress transcription factor A-2a (HSFA2A), putative late blight resistance R1C-3 (R1C-3), G-type lectin S-receptor-like serine/threonine-protein kinase SRK (SRK), heat shock cognate 70\u2009kDa protein 2 (HSC-2) and serine/threonine-protein kinase PCRK1 (PCRK1). Expression data were normalized using \u03b1-tubulin as reference gene. Gene-IDs are from International Wheat Genome Sequencing Consortium (IWGSC) RefSeq v1.0 annotations. Genes belonging to various gene co-expression networks (modules) were tested.Additional file 3. Candidate defense genes of the five gene co-expression networks (modules) significantly correlated with Type II FHB resistance.Additional file 4. Genetic variants identified within and in 5\u2032 and 3\u2032 un-translated region around candidate hub genes identified in five gene co-expression networks (modules) significantly correlated with Type II FHB resistance."}
+{"text": "For better characterization an angio-CT was requested. Awell-delimited, 7x4x3cm left atrial homogeneous, slight hyperdense mass was observedalong the lateral portion of the atrial roof (Panel B and C). The patient underwent bothsurgical mass resection and mitral valve replacement with an uneventful recovery. Thepathological analysis showed a multifocal left atrial wall and pericardial fatinfiltration with CD20+, CD5 +, bcl-2+, cyclin D1+, CD10- and CD23- lymphoid cells, inaddition to a left atrial adherent thrombus (Panels D-I). Thesefindings were compatible with lymphocytic lymphoma/chronic lymphocytic leukemia and thepatient remains clinically stable. A 60-year-old Caucasian female with a history of rheumatic mitral stenosis, permanentatrial fibrillation and chronic lymphocytic leukemia was admitted due to decompensatedchronic heart failure. The transthoracic echocardiogram depicted a severe mitralstenosis (anatomic valve area of 0.9 cm1 Despite being mostly clinically silent, cardiac imaging improvementsand availability has led to increased incidental recognition and awareness.Secondary or metastatic tumors are much more common than primary tumors of the heart. Arecent necropsy study revealed that cardiac metastases in patients with leukemia andlymphomas may be present in 25% of patients."}
+{"text": "Background Cognitive stimulation therapy (CST), a 14-session themed groupwork for people with cognitive impairment, shows effectiveness in maintaining cognitive functioning, quality of life and communication. However, its mechanism of optimizing individual cognitive benefits is little known. Engagement, a state of being occupied by meaningful external stimuli, may be an overlooked link. Individual constructive engagement is defined as the verbal or motor individual behavior exhibited for the meaningful purposed activities. Objective To investigate the individual experience of engagement in CST and its effect on cognitive benefits. Methods A total of 108 participants were recruited from 8 community centers, 2 daycare centers and 2 residential care units in Hong Kong. Trained assessors not involved in CST delivery conducted the pre-and-post assessments using Alzheimer\u2019s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Trained raters observed each participant\u2019s engagement under six 5-minute observation windows in total during CST sessions by time sampling using the adapted Myers Institute Engagement Scale. Results Paired t-test shows significant improvement in ADAS-Cog . Individual constructive engagement was exhibited 23.3% of activity time averagely. It correlated with the change in ADAS-Cog positively. Greater individual constructive engagement predicted lower post-intervention ADAS-Cog score , indicating a better cognitive functioning, after controlling baseline ADAS-Cog score  in the multiple linear regression analysis  =121.38, p<.000). Conclusion Engagement is the potential mechanism to maximize individual cognitive benefits. Future studies can investigate contributing factors of engagement to improve intervention effectiveness"}
+{"text": "This data article contains annotation data characterizing Multi Criteria Assessment (MCA) Methods proposed in the agri-food sector by researchers from INRA, Europe's largest agricultural research institute . MCA can be used to assess and compare agricultural and food systems, and support multi-actor decision making and design of innovative systems for crop production, animal production and processing of agricultural products. These data are stored in a public repository managed by INRA . These scientific papers have been extracted from the WOS using two WOS key-words queries (see section These data (954 papers) have been grouped in 1 global Excel file, and split into 13 Excel files corresponding to scientific domains to cover the diversity of the disciplinary approaches and applications developed in INRA . Redundahttps://data.inra.fr/).These data are stored in a INRA institutional data repository powered by Dataverse  has been manually typed MCA (954 papers) or non MCA (3966 papers) by domain experts using a set of positive and negative criteria defining the notion of MCA articles. In the last step, MCA-typed articles have been annotated using 8 characteristics and associated modalities.2.1Two queries have been created to extract articles from the WOS. The first one target articles which refers explicitly to MCA methods. The second one aims papers which propose methods to compare alternatives or directly compare alternatives using several criteria without explicit references to MCA methods.Query 1 (MCA explicit): Field1 AND Field2 AND Field3 with:Field1/* Address INRA */(AD=((France or guad* OR fr* guian* OR kourou OR french* OR Fr pol* OR belg* OR W Ind Assoc St) SAME ((FRENCH INST AGR & FOOD RES* CTR) OR (FRENCH INST AGR* RES*) OR (FRENCH NAT* INST AGR SCI) OR (INCRA) OR (INR4) OR (INRA) OR (INST NACL RECH AGR*) OR (INST NAT* AGR* RES) OR (INST NATL DE LA RECH AGRON) OR (INST NATL RECH A GRONOM) OR (INST NATL RECH AGNON) OR (INST NATL RECH ARGONOM) OR (INST NATL RECH ARON) OR (INST NATL SUPER RECH AGRON) OR (INST* RECH* AGRON*) OR (INST REC* NAT* AGR*) OR (INST SCI RECH AGR*) OR (INST* NAT* REC* AGR*) OR (INST* NAT* RES* AGR*) OR (INT INST AGR* RES*) OR (LINST NAT* REC* AGR*) OR (NAT* INST* AGR* RES*) OR (NAT* AGR* RES) OR (NAT* INST RES* AGR*) OR (NAT* RE* INST AGR*) OR (NRA))))Field2/* Topic */see also .Fig.\u00a01DiDEA OR \"data-envelop* analy*\" OR FisPro OR DMD OR \"Discrete multicriter* decision*\" OR \"Discrete multi-criter* decision*\u201cMCDA OR \"multi-criter* decision-aid*\" OR \"multicriter* decision-aid*\" OR \"multiple criter* decision-aid*\" OR \"multi-criter* decision-analy*\" OR \"multicriter* decision-analy*\" OR \"multiple-criter* decision-analy*\u201c OR MCDM OR \"multi-criter* decision-making\" OR \"multicriter* decision-making\" OR \"multiple criter* decision-making\" OR MODM OR \"multi-objective* decision-making\" OR \"multiple objective* decision-making\" OR MADM OR \"multi-attribute* decision-making\" OR \"multiple attribute* decision-making\" OR MCDS OR \"multi-criter* decision-support\" OR \"multicriter* decision-support\" OR \"multiple criter* decision-support\" OR MCRA OR \"multi-criter* risk-analy*\" OR \"multicriter* risk-analy*\" OR \"multiple criter* risk-analy*\"OR MAUT OR \"multi-attribute* utility-theor*\" OR \u201cmultiple attribute utility theor*\" OR MAVT OR \"multi-attribute* value-theor*\" OR \"multiple attribute* value-theor*\" OR MACBETH OR AHP OR \"analytic* hierarch* process*\" OR Outranking OR ELECTRE* OR PROMETHEE OR MEACROS OR DEXi* OR DEX OR QUALIFLEX OR ORESTE OR EVAMIX OR MELCHIOR OR ARGUS OR Field 3/* Period */year: 2007\u20132017.Query 2 (non MCA explicit): Field1 AND Field2 AND Field3 AND Field4 with:Field1/* Address INRA, same as in Query 1 */Field2/* Topic */evaluat* OR Assess* OR decision OR optim* OR design OR selection*Field3/* Topic */Field 4/* Period */year: 2007\u20132017.2.2A set of positive and negative criteria has been defined and used to classify articles extracted from the WOS in step 1 as MCA or Non-MCA.1.A descriptive study based on a set of variables/indicators not interpreted in terms of comparison of alternative scenarii;2.The design of a phenomena predictive model  except if it is explicitly integrated in a broader approach of multicriteria assessment;3.A mono-objective optimisation study without constraints.The papers have been classified as Non-MCA if they present a study of one of the following types:4.A study of several alternatives based on several criteria/indicators with interpretation , even criterion by criterion;5.A study based on the design of aggregated indicators representing a phenomenon/concept non measurable;6.A multi-objective optimisation study or mono-objective with constraints expressed on criteria;7.A study about methodologies/methods explicitly linked to a MCA approach;8.Strategic/opinion paper about MCA approaches or issues requiring MCA methods;9.A study which identifies a list of criteria taken into account to assess a system/property/concept.The papers have been classified as MCA if they present a study of one of the following types:Classification has been done in two steps. In each scientific domain see , a doubl2.31.Type of study (exclusive: one response only)The MCA articles have been classified according to 8 major characteristics, each of them being divided into several categories. In each Excel file, in the thumbnail \"EMC_YES\", columns A to P provide information about articles results of the bibliographic search. They have been filled automatically. Columns Q to BZ correspond to MCA articles characterization presented below.i)Specific methodological issues, which are not covered by choice ii) e.g., scale change, functional units, uncertainty management; Examples are study on sensitivity of DEXi-based decision tree ii)Development of generic methods: a method that does not propose a given list of criteria but makes it possible to define, choose, organize, aggregate or treat criteria. Examples are ELECTRE iii)Development of methods dedicated to MCA: a method with its given criteria/indicators, its framework to organize and aggregate them. An example is the MASC method iv)Use/Application of method dedicated to MCA: articles applying method, without development, to case studies Applications with no dedicated method: applications using a list of indicators to compare options without a MCA method , even criterion by criterion, see for instance vi)Others: comparison of methods, reviews, position papers, see for instance 2.Purposes (definition of the objectives of the study) \u2013 Multiple choices possible5 categories have been defined:We used the classification of purposes adapted from Lairez et\u00a0al. i)To sensitize/structure actions ii)To deliver new knowledge , e.g., dashboardsiii)To report, e.g., on the achievement of a goal within an action plan , or on the compliance with regulationiv)To identify elements of an option to improve: assessing the strengths and weaknesses of optionsv)To choose, sort out, rank options vi)To access to new market vii)To promote 7 categories:3.Audience \u2013 Multiple choices possibleThe two last categories are targeted when the MCA is oriented towards communication, with or without immediate benefits.i)Scientistsii)Development engineers iii)Farmersiv)Industrials, processors, manufacturersv)private and associate stakeholders vi)public stakeholders 4.Assessed dimensions \u2013 Multiple choices possibleThe targeted audience is the one mentioned (or suggested) in the abstract of the paper and split in 6 categoriesi)Functional and technical performancesii)Economiciii)Environmentaliv)Socialv)Product qualityvi)Human health (ex diet)vii)Animal and plant health and welfareviii)Ecosystem services5.Assessed system/object \u2013 Multiple choices possible8 categoriesi)Plantii)Animaliii)Plant and animaliv)Micro-organismsv)Processingvi)Foodvii)Human organization: socio-economic institutions, farms, industrial sector\u2026viii)Health ix)Natural areas: ecosystem studied as a whole . Examples: rivers, soils, forests, \u2026.x)Other, to be specified6.Spatial scale \u2013 Multiple choices possible10 categoriesi)Individual ii)Collection of individuals, population iii)System (farm/diet/forest/factory/ecosystem)iv)Territory/supply chainv)Nation/World regions (ex EU)vi)Global7.Time scale \u2013 Multiple choices possible 6 categoriesi)Static: instantaneous picture of a system, or a temporal approach ii)Dynamiciii)Scale of a production cycle iv)Scale of the yearv)Several years; long-term8.actors \u2013 Multiple choices possibleContribution of 4 categoriesAn actor is defined as a person consulted for the study (other than the authors), including scientists consulted as experts, to define weights.i)Initial choice of the methodsii)Definition of criteria and indicatorsiii)interpretation of indicators iv)Opinion on aggregation v)Not specifiedvi)Other, to be specifiedvii)Irrelevant (no actor contribution)7 categories"}
+{"text": "P < 0.005), with the strongest enrichment for waist-hip ratio. Of 110 recently described cardiometabolic GWAS loci colocalized with adipose tissue eQTLs, 59 loci had one or more variants overlapping an adipose tissue peak. Annotated variants at the SNX10 waist-hip ratio locus and the ATP2A1-SH2B1 body mass index locus showed allelic differences in regulatory assays. These adipose tissue accessible chromatin regions elucidate genetic variants that may alter adipose tissue function to impact cardiometabolic traits.Identifying the regulatory mechanisms of genome-wide association study (GWAS) loci affecting adipose tissue has been restricted due to limited characterization of adipose transcriptional regulatory elements. We profiled chromatin accessibility in three frozen human subcutaneous adipose tissue needle biopsies and preadipocytes and adipocytes from the Simpson Golabi-Behmel Syndrome (SGBS) cell strain using an assay for transposase-accessible chromatin (ATAC-seq). We identified 68,571 representative accessible chromatin regions (peaks) across adipose tissue samples (FDR < 5%). GWAS loci for eight cardiometabolic traits were enriched in these peaks ( Dysregulation of genes expressed in adipose tissue influences cardiometabolic traits and diseases. Subcutaneous adipose tissue serves as a buffering system for lipid energy balance, particularly fatty acids, participants as previously described.(cellcrusher.com). The tissue powder was resuspended in nuclei isolation buffer . Tubes were rotated at 4\u00b0 for 5 min. The solution was homogenized using a tight homogenizer (Wheaton) for 10 strokes and was centrifuged at 1500 \u00d7 g for 10 min at 4\u00b0. Following removal of the lipid layer and supernatant, the pellet was resuspended in buffer  and centrifuged at 1200 \u00d7 g for 10 min at 4\u00b0. The supernatant was removed and the pellet was used for the transposase reaction as previously described. or did not contain detergent. For tissue sample 2, we generated libraries using \u223c12 mg or \u223c36 mg of tissue and contained detergent. Replicates including detergent and less tissue in library preparation resulted in a greater number of peaks and higher peak similarity between individuals compared to no detergent (Table S11). From these observations, we performed all subsequent analyses with the three detergent-treated replicates. Tissue was pulverized in liquid nitrogen using a Cell Crusher homogenizer (SGBS cells(We obtained previously published adipose ATAC-seq datasets from subcutaneous adipose tissue (ENCODE ENCSR540BML), tissue-dvs. paired-end samples, we merged the mate pair fastq files and trimmed reads to 50 nucleotides for each paired-end ATAC-seq sample and aligned reads from all samples as single-end. We removed sequencing adapters from raw ATAC-seq sequence reads using Tagdust (http://hannonlab.cshl.edu/fastx_toolkit). We aligned filtered reads to the hg19 human genome using bowtie2, and then defined the portion of these peaks that shared at least one base with a replicate peak in two or more replicates as \u2018representative peaks\u2019. The METSIM adipose tissue samples are from different individuals and are not technical replicates. Due to a low number of samples, we used the union of peaks across individuals as representative peaks. Unless otherwise noted, we selected the top 50,000 representative peaks in each group for downstream analyses. For the groups with technical replicates and the single ENCODE adipose tissue sample, we selected the top 50,000 representative peaks with the most significant peak p-values. For METSIM adipose tissue, we ranked the peak p-values in each individual (with 1 being the strongest) and used the average of these ranks to select the top 50,000 representative peaks. This approach reduced the chance that outlier p-values from a single individual would bias peak rank.We generated a total set of accessible chromatin regions by taking the top 50,000 peaks in each group of ATAC-seq samples. For each ATAC-seq sample, we counted the number of non-duplicated nuclear reads overlapping the total set of accessible chromatin regions using featureCounts. with the \u2013create_reference option in the AA-ALIGNER pipeline. The 34 transcription factors included 21 described as adipose core transcription factors by dividing each position in the bound profiles by the corresponding position in the unbound profiles, and then calculated the average TPR across the motifs (mTPR) and the 100 bp flanking regions (fTPR). We considered transcription factor motifs to display an aggregate footprint profile if mTPR was less than fTPR.\u22128 from 11 trait categories from the GWAS catalog (December 2016): type 2 diabetes, insulin, glucose, cardiovascular outcomes, blood pressure traits, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, total cholesterol, body mass index (BMI), and waist-hip ratio adjusted for BMI (WHR). Phenotypes included in trait categories are listed in Table S5. Loci that were associated with multiple traits were assigned to each trait. To remove multiple lead variants for the same association signal, we performed LD clumping using swiss (https://github.com/welchr/swiss) with the 1000G_2014-11_EUR LD reference; variants in moderate LD (2r > 0.2) and within 1 Mb of a variant with a more significant p-value were removed. We used GREGOR to test for enrichment of the resulting GWAS lead variants or their LD proxies  in ATAC-seq peaks relative to control variants. We tested for enrichment in the top 50,000 representative peaks for adipose tissue, SGBS adipocytes, SGBS preadipocytes, and GM12878 lymphoblasts. Enrichment was considered significant if the enrichment p-value was less than the Bonferroni-corrected threshold of 5\u00d710\u22123 (0.05/11 trait groups). To compare enrichment magnitudes between regions and traits, we calculated an enrichment z-score:We tested for enrichment of genetic variants in ATAC-seq peaks using GREGOR, which compares overlap of GWAS variants relative to control variants matched for number of LD proxies, allele frequency, and gene proximity.(2r > 0.8) with the GWAS lead variant at 110 loci  using BEDTools. or duplicate  wells using Lipofectamine 3000 , Lipofectamine 2000 (3T3-L1 preadipocytes and adipocytes) or FUGENE 6 . Firefly luciferase activity of the clones containing the PCR fragments was normalized to Renilla luciferase readings to control for differences in transfection efficiency. We repeated all luciferase transcriptional reporter experiments on independent days and obtained consistent results. Data are reported as fold change in activity relative to an empty pGL4.23 vector. We used two-sided Student\u2019s t-tests to compare luciferase activity.SGBS preadipocyte, 3T3-L1 preadipocyte, SW872 liposarcoma, and THP-1 monocyte cells were maintained and transcriptional reporter luciferase assays were performed as previously described. as previously described. as mismatches. We extraftp://ftp-trace.ncbi.nih.gov/1000genomes/. We downloaded GM12891 SPI1 ChIP-seq alignments  and DNase-seq alignments (ENCFF070BAN) from ENCODE. Allele count pileup files were generated at heterozygous sites with a minimum base quality Phred score of 30 to minimize the impact of sequencing errors using samtools.To confirm allelic imbalance in PU.1 binding and chromatin accessibility at rs7187776 (genomic position chr16:28857645), we analyzed public genotype, SPI1 ChIP-seq, and DNase-seq data for the GM12891 cell line. We obtained genotypes for individual NA12891 from ATAC-seq reads (SGBS preadipocytes and adipocytes) and peaks  can be accessed from GEO: accession number GSE110734.https://doi.org/10.25387/g3.8120933.Supplementary tables and figures are available at FigShare: We generated ATAC-seq open chromatin profiles from three frozen subcutaneous adipose tissue needle biopsy samples (Table S1), two replicates of SGBS preadipocytes, and three replicates of SGBS adipocytes. In the adipose tissue samples, we generated \u223c56-70 million non-duplicated nuclear reads and \u223c36-58 thousand peaks , including 41 motifs enriched in adipose tissue but not lymphoblasts (Table S2). The set of 41 contains motifs for transcription factors known to promote adipogenesis, such as CEBP family members, STAT family members, and PPARG. of frozen clinical subcutaneous adipose tissue samples and SGBS preadipocytes and adipocytes.To evaluate the distribution of ATAC-seq peaks across samples, we examined the accessible chromatin landscape at er assays. AdditioWe compared our adipose tissue and SGBS representative ATAC-seq peaks to existing ATAC-seq datasets from tissue-derived adipocytes,. These tSecond, we compared the distribution of ATAC-seq peaks to Roadmap Epigenomics Consortium chromatin states in adipose nuclei isolated from subcutaneous adipose tissue. We used th most overlap with adipose nuclei enhancers compared to enhancers in other tissue and cell types (Table S3). SGBS preadipocytes showed the most overlap with enhancers in fibroblast cell types, and adipose nuclei ranked 24th among all cell types. As expected, GM12878 lymphoblast peaks showed much less overlap with adipose nuclei enhancers, consistent with the cell type-specific nature of enhancers. in adipose tissue, SGBS adipocyte, and SGBS preadipocyte peaks  in the top 50,000 representative ATAC-seq peaks in adipose tissue, SGBS adipocytes, SGBS preadipocytes, and GM12878 lymphoblasts. Variants at loci for four trait groups  showed significant enrichment (2r > 0.8 with lead GWAS variants). To strengthen annotation at these loci, we overlapped variants at these loci with all representative ATAC-seq peaks rather than the top 50,000 peaks. 147 variants at 59 loci overlapped an adipose tissue peak (Table S7). The loci that had only one variant overlapping an adipose tissue ATAC-seq peak are shown in We next identified cardiometabolic GWAS variants that overlapped candidate regulatory elements defined by ATAC-seq peaks. We focused on ATAC-seq peaks at a subset of 110 cardiometabolic GWAS loci that were colocalized with gene expression quantitative trait loci (eQTLs) in subcutaneous adipose tissue;(SNX10 (encoding sorting nexin 10), was associated with WHR  and CBX3  in adipose tissue.(P = 0.01) in both orientations : 25 reads contained rs7187776-A and 3 reads contained rs7187776-G. rs7187776 is located near a long isoform of SH2B1 (encoding SH2B adaptor protein 1) and is in strong LD (2r > 0.8) with the lead variant associated with BMI . and ATXN2L  in adipose tissue.(2r > 0.8) with the lead GWAS and eQTL variants, and one of five variants that overlapped ATAC-seq peaks at this locus (Table S7). Using EMSA, we observed allele-specific binding of rs7187776-G to purified PU.1 protein and similar binding using nuclear extract from SW872 cells, consistent with the predicted motif  ChIP-seq peak, motif and footprint . In adiped motif . In SGBSAS locus .P < 0.05) in at least one sample (Table S9), 6 of which overlapped variants at GWAS-eQTL loci (Table S10). However, only 40 of 6,692 total GWAS-eQTL variants were heterozygous in at least one adipose tissue sample and were covered by enough ATAC-seq reads for allelic imbalance analysis, suggesting that higher read depth and larger sample sizes that increase the chance of heterozygosity at more eQTL and GWAS loci may enable identification of more disease-associated loci that could mediate their effects on disease through chromatin accessibility.We looked for other examples of allelic imbalance in ATAC-seq reads at heterozygous positions that may indicate altered chromatin accessibility. Only 387 sites showed nominal allelic imbalance . At the TSS for ADIPOQ, we observed adipose tissue and SGBS adipocyte ATAC-seq peaks, and downstream of ADIPOQ, we observed ATAC-seq peaks specific to SGBS preadipocytes. The accessibility pattern of ADIPOQ is consistent with its role in adipocyte differentiation  and others have suggested different functional variants at this locus,(We described two GWAS loci for which ATAC-seq peaks helped prioritize candidate variants. At the In summary, we presented ATAC-seq open chromatin profiles for frozen adipose tissue and cultured preadipocytes and adipocytes. We showed the utility of open chromatin profiles in multiple tissue samples and across cell types within heterogeneous tissue. Together, these data add to the growing understanding of gene regulation in adipose and the complex genetic mechanisms of cardiometabolic traits and diseases."}
+{"text": "Two divergent isolates of turnip yellows virus (TuYV) were identified in pea and rapeseed. The nearly complete genome sequences of the virus isolates share 93.3% nucleotide identity with each other and 89.7% and 92.9% with their closest isolate from South Africa. Two divergent isolates of turnip yellows virus (TuYV) were identified in pea and rapeseed. The nearly complete genome sequences of the virus isolates share 93.3% nucleotide identity with each other and 89.7% and 92.9% with their closest isolate from South Africa. Additionally, a turnip yellows virus-associated RNA was identified. Luteoviridae) (Brassicaceae and Fabaceae families.Turnip yellows virus (TuYV), the non-sugar beet-infecting strain of beet western yellows virus (BWYV), is a polerovirus (family viridae) , 2. TuYVPisum sativum] and oilseed rape [Brassica napus]) displaying yellowing symptoms were collected in Germany . The samples were tested with a triple antibody sandwich enzyme-linked immunosorbent assay (TAS-ELISA) for the presence of luteoviruses/poleroviruses using monoclonal antibodies 5G4 and 6G4 . Four weeks post-aphid inoculation, polerovirus infection of plants was confirmed using TAS-ELISA and reverse transcription-PCR (RT-PCR) with generic polerovirus primers (S2 and AS3) (L39976) and TuYV (GenBank accession number KU198395).Two plant samples . The assembled contigs were used to search the NCBI database using BLASTn. A contig of about 5.6 kb in each sample showed 90.7% and 93.1% nt identities to TuYV (GenBank accession number KU198395). Contig extension using Geneious mapping to the reference tool  resulted in the complete coding sequences and almost-full-genomic sequences for both TuYV isolates; they shared 93.3% nt identity to each other while sharing 89.7% and 92.9%, respectively, to the most closely related isolate, KU198395.For genome sequencing, total RNAs were extracted with the innuPREP RNA minikit , followed by rRNA depletion with the RiboMinus plant kit (Invitrogen). cDNAs were synthesized using ProtoScript II reverse transcriptase (NEB) and random octanucleotide primers, followed by second-strand synthesis with the NEBNext Ultra II nondirectional RNA second-strand synthesis module kit (NEB). The libraries were prepared using a Nextera XT library kit (Illumina) and submitted for high-throughput sequencing (HTS) on the MiSeq version 3 platform (2 \u00d7 301). The raw reads  were analyzed using the Geneious software (11.1.4). The reads were quality trimmed  and size filtered to >99 nucleotides (nt), followed by KU198395.Pairwise comparisons of the amino acid sequences using MUSCLE (3.8.425) showed that some open reading frames (ORFs) are also highly divergent (P0 and P1), whereas others are not (CP and MP)  7). The. The7). KF533709)  from the United Kingdom  under BioProject accession number PRJNA524397 and under BioSample accession numbers SAMN11026350 and SAMN11026351.The complete coding sequences of the two German TuYV isolates and the full sequence of TuYVaRNA can be found in NCBI GenBank under accession numbers"}
+{"text": "N-methyl-D-aspartate receptor (NMDA) dependence and restriction via contact-dependent cellular repulsion with macrophages. These discoveries open the possibility that microglia can migrate outside of their textbook-defined regions in disease states.Microglia are central nervous system (CNS)-resident cells. Their ability to migrate outside of the CNS, however, is not understood. Using time-lapse imaging in an obstetrical brachial plexus injury (OBPI) model, we show that microglia squeeze through the spinal boundary and emigrate to peripheral spinal roots. Although both macrophages and microglia respond, microglia are the debris-clearing cell. Once outside the CNS, microglia re-enter the spinal cord in an altered state. These peripheral nervous system (PNS)-experienced microglia can travel to distal CNS areas from the injury site, including the brain, with debris. This emigration is balanced by two mechanisms\u2014induced emigration via  Microglia are normally assumed to be confined to the central nervous system (CNS), but this study shows show that after spinal root injury, microglia can exit the CNS to clear debris. Upon re-entry, the emigrated microglia are altered and can travel to distal areas such as the brain. Cells are precisely organized in specific anatomical domains to ensure normal functioning of the nervous system. One such cell type, microglia, is usually considered to be confined to the central nervous system (CNS). Using time-lapse imaging to capture microglia as they migrate, we show that their characteristic CNS-residency can be altered after spinal root injury. After such injury, the microglia exit the spinal root to the periphery, where they clear debris at the injury site and then carry that debris back into the CNS. In addition, microglia that leave the CNS after spinal root injury become distinct from those that remain within the CNS. This emigration event of microglia after injury is driven by two mechanisms\u2014dependence on glutamatergic signaling that induces their emigration to the injury and interactions with macrophages that prevent their ectopic exit from the spinal cord. Together, these discoveries raise the possibility that microglia could override their CNS-residency in certain disease contexts. Microglia are the surveying phagocytic cells of the central nervous system (CNS) \u20133. They There is growing evidence that cells can override their domain-specific nature \u201318. CNS-pu1+ cells display stable residency in distinct CNS and PNS domains at 4 days post fertilization (dpf) in zebrafish, a time comparable to when OBPI occurs. We then show that CNS-resident microglia exit their domain to clear PNS debris in these injuries. Despite that both macrophages and microglia respond to these injuries, microglia function as the debris-clearing cell in both the PNS and CNS. This emigration to the PNS alters the microglia as they re-enter the CNS and migrate to distal areas from the injury site, including the brain. We show that the exit of microglia to the PNS is mediated by opposing mechanisms; N-methyl-D-aspartate (NMDA) receptor and glutamate induce emigration, whereas contact-dependent repulsion prevents intrusion. The observation that contact-dependent interactions of microglia with macrophages impact the cells\u2019 anatomical position could provide insight into pathologies of diseases that contain both macrophages and microglia in the same domain [Here, we exploit time-lapse imaging of zebrafish in a laser-induced model of obstetrical brachial plexus injury (OBPI) to dissect the capacity of microglia in the PNS. Spinal root avulsion can occur developmentally during the birth process; OBPI is a complication in an estimated 3 out of every 1,000 births . We firse domain . TogetheTg(ngn1:gfp) zebrafish, which use regulatory sequences of ngn1 to express green fluorescent protein (GFP) in dorsal root ganglia (DRG) neurons [Tg(ngn1:gfp) animals at 4 dpf with anti-Sox10 and anti-GFAP post-avulsion to assess the integrity of the GFAP+ glial limitans and Sox10+ Schwann cells and oligodendrocytes in each injury category immediately following injury ; Tg(sox10:mrfp) animals, which use regulatory sequences of pu1 to express GFP in microglial and macrophages and sox10 to label glial and neuronal cells of sensory and spinal nerves with mRFP [pu1+ cells like PNS macrophages and CNS microglia based on their stable starting location without injury . These movies revealed that the majority of pu1+ cells that colonize the spinal cord at 4 dpf originate from the anterior, potentionally the brain region, which colonizes microglia by 2.5 dpf [pu1+, 4C4, and tmem119, they were also located in the spinal cord proper, distal from the spinal meninges space and the spinal vascular network, and were sensitive to csf1r inhibitors, consistent with their classification as microglia ; Tg(sox10:mrfp) animals. After injury, we imaged z-stacks that spanned the root and spinal cord every 2.5 minutes for 24 hours. Following spinal avulsion and consistent with a microglial injury response, we visualized microglia migrated to the injury site within the first hour following injury ; Tg(sox10:mrfp) animals, created 24-hour movies, identified CNS and PNS GFP+ cells based on their pre-injury location, and then scored mRFP debris within GFP+ cells, a result consistent with clearance of debris from GFP+ cells [+ debris was present in 92% of microglia, whereas mRFP+ debris was present in 8% of macrophages  of the spinal cord on average (Because CNS-resident  average . These m average . This ti average . Based oTg(pu1:gfp);Tg(sox10:mrfp) animals at 4 dpf and observed emigration of microglia to the PNS. Then we created a distal secondary CNS-specific injury. Upon secondary injuries, we observed PNS-primed microglia immediately re-enter the CNS and migrate to the secondary injury site . DAMs transition through a series of stages that include regulation of specific transcription components, changes in physical appearance, and alterations in phagocytic activity . The emiMicroglia and macrophages largely occupy distinct domains. However, during disease states like spinal cord injury, multiple scleroris, and metastatic cancer, these distinct cells can reside in the same domains \u201350. Our Together, our results indicate that microglia function could extend beyond their textbook-defined region. This adds to their already impressive and essential roles in nervous system homeostasis and disease pathogenesis.All animal studies were approved by the University of Notre Dame Institutional Animal Care and Use Committee.csmith67@nd.edu).Reagents are available upon request to Cody J. Smith (Tg(ngn1:gfp) [Tg(sox10:mrfp) [Tg [Tg(gfap:gfp) [Animal studies were approved by the University of Notre Dame IACUC as noted above. Zebrafish strains used for this study were AB, gn1:gfp) , Tg(sox110:mrfp) , Tg(pu1:uas:gfp) , and Tg(fap:gfp) . Pairwisfap:gfp) . Embryoshttps://www.adobe.com/products/illustrator.html, San Jose, CA) and ImageJ  were used to process images. Only brightness and contrast were enhanced for the presented images.Animals were anesthetized with 3-amino-benzoic acid ester (Tricaine), covered in 0.8% low-melting point agarose, and mounted on their right side in glass-bottomed 35 mm Petri dishes . Images Tg(sox10:mrfp);Tg(pu1:gfp) 4-dpf animals were anesthetized using 0.02% 3-aminobenzoic acid ester (Tricaine) in egg water. Fish were then mounted in 0.8% low-melting point agarose solution, arranged laterally on a 10 mm glass coverslip-bottom Petri dish, and placed on the microscope anterior to posterior. Avulsion region of interest was mid-animal and selected upon location of DRG outside the spinal cord. Specific site of laser-induced injury was determined by tracing afferent projections from the DRG into the spinal cord using the z-plane. Projections with greater fluorescence and successful tracing were selected as the site of injury. This area was marked and brought into a focused ablation window. Upon focusing the targeted afferent projection, we moved 1 \u03bcm laterally out of the z-plane and double-clicked on the projection using a 4 \u03bcm cursor tool. All laser parameters used are specific to our confocal microscope. Specific parameters include Laser Power (2), Raster Block Size (1), Double-Click Rectangle Size (8), and Double-Click Repetitions (4).A catalog of all injuries performed was created and analyzed to create three separate categories of injury. Category I injuries are less severe, involving cutting the central projection and little to no surrounding damage. Category II injuries are more severe than involved severance of the central projection and some surrounding damage. Category III injuries are the most severe, involving severance of the central projection, visible damage to the spinal cord, and free-roaming debris. ImageJ was used to measure the length and width of the injury site created. ImageJ was also used to measure the average fluorescence of the injury site before and after the avulsion. These measurements were used to create a range of length, width, and fluorescence to place each avulsion case into a category. These ranges are listed in 20, 0.1% Triton X-100), and acetone for 5 minutes each, then were incubated in \u221230\u00b0C acetone for 10 minutes. Larvae were then washed three times with PBST for 5 minutes and incubated with 5% goat serum in PBST for 1 hour at 25\u00b0C. Then, the larvae were incubated with primary antibody solution for 1 hour at 25\u00b0C, then transferred to \u22124\u00b0C overnight. After three washes with PBST for 30 minutes each and a longer PBST wash for 1 hour, the larvae were incubated with secondary antibody solution for 1 hour at 25\u00b0C, then transferred to \u22124\u00b0C overnight. After three washes with PBST for 1 hour, larvae were stored in 50% glycerol in PBS at 4\u00b0C until imaging. Larvae were mounted, and confocal images were taken using the above protocol for in vivo imaging.The primary antibodies used in the assessment of boundary disruption were anti-Sox10  . Larvae were fixed at 4 dpf using 1 mL fresh fix solution  for 30 minutes. Fixed larvae were then washed twice in 100% methanol for two minutes each and incubated in 100% methanol at (-25\u00b0C) overnight. After one wash of 50% methanol, 30% methanol, and 100% 1\u00d7 PBS for 5 minutes each, the larvae were decapitated using a razor blade. The caudal portion of the animal was then permeabilized with 10 mg/mL proteinase K for 45 minutes at 25\u00b0C. Decapitated larvae were then washed twice in 1\u00d7 PBST  and incubated with 4% PFA at 25\u00b0C for 20 minutes. Fixed larvae were washed twice in 1\u00d7 PBST for 5 minutes each. After 3 washes with 1\u00d7 PBST for 10 minutes each, fixed larvae were incubated with 50% Stellaris Wash Buffer  in 1\u00d7 PBST for 5 minutes. After two 30-minute washes in 100% Stellaris Wash Buffer at 37\u00b0C, fixed larvae were incubated in 1.2 \u03bcL probe mixture and 500 \u03bcL Stellaris Hyb Buffer  at 37\u00b0C overnight. After two washes with 37\u00b0C Stellaris Wash Buffer for 3 minutes each, larvae were washed 4 times for 15 minutes each in 37\u00b0C Stellaris Wash Buffer. Fixed larvae were washed an additional 3 times with 1X PBST at 25\u00b0C for 10 minutes each. Then, larvae were immediately mounted, and confocal images were taken using the above protocol for in vivo imaging.The probe used in the confirmation of microglia in the spinal cord was The chemical reagents used for this study were GW2580 (ApexBio). Stock solutions of 1 \u03bcM, 10 \u03bcM, and 100 \u03bcM were stored at \u221220\u00b0C with concentrations of 1% in DMSO. All embryos were dechorionated at 24 hpf and incubated with 3 mL egg water until desired treatment time. Fish were treated at 3 dpf and 24 hours and 12 hours before imaging at 4 dpf. Control fish were incubated with 1% DMSO in egg water 24 hours and 12 hours before imaging.Tg(sox10:mrfp);Tg(pu1:gfp) 4 dpf animals were anesthetized using 0.02% 3-aminobenzoic acid ester (Tricaine) in egg water. Fish were then mounted in 0.8% low-melting point agarose solution, arranged laterally on a 10 mm glass-coverslip\u2013bottom Petri dish, and placed on the microscope anterior to posterior. Avulsion region of interest was midanimal and selected upon location of DRG outside the spinal cord. Specific site of laser-induced injury was determined by tracing peripheral projections from the DRG into periphery using the z-plane. Projections with greater fluorescence and successful tracing were selected as the site of injury. This area was marked and brought into a focused ablation window. Upon focusing the targeted afferent projection, we moved 1 \u03bcm laterally out of the z-plane and double-clicked on the projection using a 4 \u03bcm cursor tool. All laser parameters used are specific to our confocal microscope. Specific parameters include Laser Power (2), Raster Block Size (1), Double-Click Rectangle Size (8), and Double-Click Repetitions (4).Tg(sox10:mrfp);Tg(pu1:gfp) 4 dpf animals were anesthetized using 0.02% 3-aminobenzoic acid ester (Tricaine) in egg water. Fish were then mounted in 0.8% low-melting point agarose solution, arranged laterally on a 10 mm glass-coverslip\u2013bottom Petri dish, and placed on the microscope anterior to posterior. Avulsion region of interest was midanimal and selected upon location of DRG outside the spinal cord. Specific site of laser-induced injury was determined by selecting a region inside the CNS where several oligodendroctyes, oligodendrocyte progenitor cells, and sox10+ axons were present between two DRGs using the z-plane. This area was marked and brought into a focused ablation window. Upon focusing the targeted deep CNS region, we moved 1 \u03bcm laterally out of the z-plane and double-clicked on a sox10+ region using a 4 \u03bcm cursor tool. All laser parameters used are specific to our confocal microscope. Specific parameters include Laser Power (1), Raster Block Size (1), Double-Click Rectangle Size (4), and Double-Click Repetitions (4).Tg(sox10:mrfp);Tg(pu1:gfp) 4 dpf animals were anesthetized using 0.02% 3-aminobenzoic acid ester (Tricaine) in egg water. Fish were then mounted in 0.8% low-melting point agarose solution, arranged laterally on a 10 mm glass-coverslip\u2013bottom Petri dish, and placed on the microscope anterior to posterior. First, a primary region of interest was selected, and an initial primary avulsion was created following the procedure as previously described in the laser-induced spinal avulsion section, using all the same laser parameters. We observed microglia responding to injury by checking the time lapse of the injury site every 15 minutes. After a microglia emigration event occurred, we immediately moved to a new posterior imaging region that did not overlap with the primary injury site. Then, we created a secondary injury in the CNS caudal to the primary injury site following the laser-avulsion procedure previously described in the CNS-specific injury section using the same laser parameters. We observed PNS-primed microglia response to secondary injury by imaging both the primary and secondary injury sites every 5 minutes for 24 hours.The chemical reagents used for this study were MK-801 and D-AP5 (Tocris). Stock solutions of 25 mM MK-801 and 50 mM D-AP5 were stored at \u221220\u00b0C with concentrations of 1% DMSO . WorkingTg(sox10:mrfp);Tg(pu1:gfp) 4 dpf MK-801 and D-AP5 treated animals were anesthetized using 0.02% 3-aminobenzoic acid ester (Tricaine) in egg water. Fish were then mounted in 0.8% low-melting point agarose solution, arranged laterally on a 10 mm glass-coverslip\u2013bottom Petri dish, and placed on the microscope anterior to posterior. Microglia were identified in the spinal cord by taking confocal z-stack images and rotating each image 90 degrees to verify the cell was inside the CNS. An avulsion of the region of interest was performed following the spinal root avulsion protocol above to elicit microglial response to the injury site. Migration of microglia to the injury post-avulsion was imaged every 5 minutes for 24 hours.The chemical reagents used for this study were MNI-caged-L-glutamate (Tocris). Stock solutions of 50 mM were stored at \u221220\u00b0C with concentrations of 1% DMSO. Working solutions were diluted to 10 \u03bcM. All embryos were dechorionated at 24 hpf and incubated with 3 mL egg water until desired treatment time . Fish weTg(sox10:mrfp);Tg(pu1:gfp) 4 dpf glutamate-treated animals were anesthetized using 0.02% 3-aminobenzoic acid ester (Tricaine) in egg water. Fish were then mounted in 0.8% low-melting point agarose solution, arranged laterally on a 10 mm glass-coverslip\u2013bottom Petri dish, and placed on the microscope anterior to posterior. Microglia were identified in the spinal cord by taking confocal z-stack images and rotating each image 90 degrees to verify the cell was inside the CNS. An avulsion of the region of interest was performed following the spinal root avulsion protocol above to elicit microglial response to the injury site. Migration of microglia to the injury post-avulsion was imaged and directly monitored every 5 minutes by placing markers on the screen during the imaging cycle to track movement. Upon arrival to the injury site, the imaging cycle was stopped to begin the uncaging process. Glutamate uncaging was carried out using UV light on the fluorescent region of the confocal. The specific site of UV exposure was in the same area as the intial avulsion. The region of interest was exposed to the laser line 405 nm for 5 ms to uncage glutamate. Immediately following UV exposure, a time lapse was initiatied to take an image every 2 minutes for the desired imaging window. UV exposure used a 4 \u03bcm cursor tool. All laser parameters used are specific to our confocal microscope.Tg(sox10:mrfp);Tg(pu1:gfp) 4 dpf animals treated with 10 \u03bcM L-glutamate 1 hour pre-avulsion. An avulsion was created in a specific region of interest, and microglial migration was monitored as described above. Upon arrival to the injury site, the imaging cycle was stopped, and \u201cmock\u201d uncaging was performed. Instead of using the 405 nm laser to uncage glutamate, the desired region of interest was exposed to the laser line 561 nm for 5 ms. Following exposure to v561, a time lapse was initiated to take an image every 2 minutes for the desired imaging window.Glutamate uncaging controls (mock injury) were performed using anesthetized Tg(sox10:mrfp);Tg(pu1:gfp) 4 dpf animals were anesthetized using 0.02% 3-aminobenzoic acid ester (Tricaine) in egg water. Fish were then mounted in 0.8% low-melting point agarose solution, arranged laterally on a 10 mm glass-coverslip\u2013bottom Petri dish, and placed on the microscope anterior to posterior. Confocal z-stack images of Tg(sox10:mrfp);Tg(pu1:gfp) 4 dpf animals were taken preinjury. Injuries were then created following the laser-induced injury methods described above to induce both macrophages and microglia to the injury site. Time-lapse images of pu1+ cellular response to injury was monitored every minute for 2 hours. We checked for the presence of pu1+ cells at site of injury every 5 minutes. After 30 to 60 minutes, pu1+ cells arrived to the injury site, and the time lapse was stopped. Macrophages and microglia were confirmed by preimage z-stacks and post\u2013spinal-injury time lapse movies and tracing cells back to their original domains. A confirmed macrophage was chosen and brought into a focused ablation window. Upon focusing the targeted cell, we double-clicked on the center of the cell body using a 4 \u03bcm cursor tool to fire the ablation laser. All laser parameters used are specific to our confocal microscope. Specific parameters include Laser Power (2), Raster Block Size (4), Double-Click Rectangle Size (8), and Double-Click Repetitions (4).https://imagescience.org/meijering/software/mtrackj/, Bethesda, MD). GraphPad Prism software  was used to determine statistical analysis. Full detail of the statistical values can be found in To generate composite z-images for the cell, 3i Slidebook software  was used. Individual z-images were sequentially observed to confirm composite accuracy. All graphically presented data represent the mean of the analyzed data unless otherwise noted. Cell tracking was performed using the MTrackJ plugin for ImageJ  Cells migrated dorsolateral outside of the sox10:mrfp+ range in the spinal cord specifically at the injury site. (2) Cells displayed an hourglass-like morphology that is typical of cells that ectopically migrate from the spinal cord. (3) In visualization of 3D reconstruction of the injury site, the pu1+ cells appeared outside of the sox10+ boundary and curvature of the glial limitans. All migrations that did not definetly meet these criteria were conservatively scored as nonectopic migration. To confirm the ectopic exit, we combined transgenes to label the edge of the spinal cord. As a limit of transgenes and the transient nature of this exiting phenomenon, we combined analysis of Tg(sox10:mrfp); Tg(gfap:gfp) and Tg(sox10:mrfp); Tg(pu1:gfp). We rotated these images 90 degrees to reveal a cross-section of the spinal cord. We then merged the two Tg(sox10:mrfp) channels to align the spinal cord, then merged the two merged images of Tg(sox10:mrfp); Tg(gfap:gfp) versus Tg(sox10:mrfp); Tg(pu1:gfp) to confirm the pu1+ cells that originated from the CNS were clearly outside the normal gfap+ spinal cord glial limitans.To track the ectopic migration of microglia, single cells were tracked using the MTrackJ plugin of ImageJ. The four shape descriptors used to analyze microglia morphology  were measured using ImageJ. ImageJ utilizes the following formulas to calculate each descriptor:pu1+ cells imaged throughout the duration of time lapse imaging were analyzed before and after their arrival to laser-induced avulstion sites. The criteria for debris include that sox10:mrfp+ puncta were free roaming and were picked up by a pu1+ cell in the spinal cord or that sox10:mrfp+ puncta were already present inside a pu1+ cell and migrated with the direction of the pu1+ cell. Colocalization was confirmed by rotating the confocal images at varying time points 90 degrees. If the puncta were inside the pu1+ cells, they were considered debris. The area of the puncta were measured using ImageJ.To track the presence of debris within microglia, single cells were tracked using the MTrackJ plugin of ImageJ. To track the individual paths of macrophage and microglia migration, the MTrackJ plugin on ImageJ was used. The center of each cell body was traced over time, and quantitative data were collected by ImageJ. Resulting x and y coordinates of each cell were overlayed to create migration plots. All distance and time points were calculated by the MTrackJ software and further quantified using Microsoft Excel .The MTrackJ plugin on ImageJ was used for tracing. Initial direction change paths were traced by tracking the location of the center of the cell body. Contact-related directional changes were traced by tracking each cell projection that came into contact with another cell projection. All numerical data were collected by the MTrackJ plugin, and the resulting x and y coordinates of each cell track were used to perform all quantitative analyses.S1 TableValues of total number of cells and animals scored for each figure panel and statistical test used to determine significance.(XLSX)Click here for additional data file.S2 TableValue criteria of injuries created. These criteria determine the overall category of the injury. An injury must meet at least two criteria to be classified as a specific category.(XLSX)Click here for additional data file.S1 FigTg(ngn1:gfp) zebrafish at 4 dpf. Gray box indicates lesion site. (B) Schematic of laser-induced avulsion model involving central and peripheral injury. (C) Quantification of decrease in fluorescent signal along the peripheral sensory DRG projection post-injury in Tg(ngn1:gfp) zebrafish at 4 dpf. Gray box indicates lesion site. (D) Confocal z-projection of Tg(ngn1:gfp) zebrafish at 4 dpf showing peripheral injury post-injury. Note that the lesion is specific to the laser exposure site. Red boxes indicate injury site. Scale bar equals 10 \u03bcm (D). See (A) Quantification of decrease in fluorescent signal along the central sensory DRG projection post-injury in (TIF)Click here for additional data file.S2 FigTg(sox10:mrfp) zebrafish 4 dpf pre- and post-ablation to create category I, II, or III injuries. Qualifications for injury categorization listed in (A) Confocal z-projections of (TIF)Click here for additional data file.S3 FigTg(ngn1:gfp) zebrafish stained with anti-GFAP and anti-Sox10 antibodies comparing the integrity of spinal cord boundary across all injury categories. (B) Orthogonal rotation view of Tg(pu1:gfp);Tg(sox10:mrfp) animals stained with anti-GFAP showing the GFAP+ boundary of the spinal cord after each injury category. Red dashed line indicates absence of GFAP. (C\u2013E) Quantification of the average fluorescence of GFAP present in control vs category I (C), II (D), and III (E) injuries. Red box equals gfap absence. Scale bar equals 10 \u03bcm (A). See (A) Confocal z-stack images taken at 4 dpf in (TIF)Click here for additional data file.S4 FigTg(pu1:gfp);Tg(sox10:mrfp) zebrafish at 4 dpf showing microglia inside the spinal cord and a macrophage outside the spinal cord. Dotted lines indicate spinal cord boundary. (B) Graphical representation of 3D image described in (A). (C) Quantification of average number of pu1+ cells present per 300 \u03bcm region post-treatment with various GW2580 drug concentrations. (D) Quantification of average number of microglia present in the animal upon GW2580 treatments. (E) Quantification of the percentage of animals with no microglia in the spinal cord upon treatment with GW2580. (F) Confocal z-stack images taken from a Tg(pu1:gfp);Tg(sox10:mrfp) animal stained with smFISH tmem119. (G) Images from a 30-minute time-lapse movie starting at 4 dpf in Tg(pu1:gfp);Tg(sox10:mrfp) zebrafish showing that microglia are not associated with vasculature. Arrows indicate microglia. Arrowheads indicate macrophages in vasculature. Dashed lines indicate blood vessels. Scale bar equals 10 \u03bcm . See (A) Rotated orthogonal view image from a 24-hour time-lapse movie using (TIF)Click here for additional data file.S5 FigTg(pu1:gfp);Tg(sox10:mrfp) zebrafish showing microglia responding to injury. (B) Quantification of the average velocity of injury response between microglia and macrophages. (C) Quantification of the average number of microglia or macrophages responding to each injury category. (D) Quantification of the percentage of macrophages and microglia the respond to each injury category. (E) Representative migration plot of three macrophages (grey) and one microglia (blue) displaying response of both cells to injury site. (F) Quantification of individual distances microglia and macrophages traveled from their original location to the injury site. (G) Quantification of percentage of phagocytic cells first to arrive at injury site. Scale bar equals 10 \u03bcm (A). See (A) Images from a 24-hour time-lapse movie starting at 4 dpf in (TIF)Click here for additional data file.S6 Fig(A) Quantification of individual vacuoles per microglia and macrophage. (B) Quantification of individual vacuoles per macrophage before and during injury response. (C) Quantification of average time microglia spend responding to and clearing injury. (D) Quantification of amount of time macrophages spend responding to and clearing injury. See (TIF)Click here for additional data file.S7 FigTg(pu1:gfp);Tg(sox10:mrfp) zebrafish showing microglia exiting the CNS. (B) Orthogonal rotation view of Tg(pu1:gfp);Tg(sox10:mrfp) animals at 4 dpf with microglia present outside of the CNS. Arrows indicate microglia. Arrowheads indicate macrophages. Dashed line indicates spinal cord boundary. (C) Images from a 24-hour time-lapse movie starting at 4 dpf in Tg(pu1:gfp);Tg(sox10:mrfp) zebrafish showing microglia squeeze through the injury site. (D) Tracings of ectopically migrating microglia cells described in (C). (E) Overlayed confocal z-stack images from a Tg(gfap:gfp);Tg(sox10:mrfp) animal and a Tg(pu1:gfp);Tg(sox10:mrfp) animal showing the presence of microglia outside of the glial limitans. (F) Quantification of the distance from the outer z-plane edge of the DRG or microglia cell body to the edge of the spinal cord. (G) Confocal image and (H) traced schematic of an excerpt from a time-lapse movie following injury showing microglia in contact with PNS-located DRG cell bodies. (I) Quantification of the number of microglia per animal that are present in the imaging window that did or did not emigrate to the PNS. (J) Quantification of maximum distance ectopic microglia traveled outside of the sox10+ CNS. (K) Quantification of time microglia spent in PNS five hours post-ablation. (L) Quantification of the average number of oligodendrocytes and microglia that are present in the PNS at the site of avulsion. Scale bar equals 1\u03bcm (C) and 10 \u03bcm . See (A) Images from a 24-hour time-lapse movie starting at 4 dpf in (TIF)Click here for additional data file.S8 FigTg(nbt:dsred) zebrafish 4 dpf pre- and post-distal peripheral ablation. (C) Quantification of the percentage of movies comparing microglia migration to sensory root avulsion, peripheral mixed nerve avulsion, and CNS-specific injury. (D) Quantification of the average number of microglia present in the imaging window compared with those that respond to peripheral mixed nerve injury or CNS-specific injury. (E) Quantification of the average number of macrophages present in the imaging window compared to those that respond to peripheral mixed nerve injury or CNS-specific injury. Scale bar equals 10 \u03bcm (B). See (A) Representative migration plot of two macrophages (green) and one microglia (blue) displaying response of macrophages only to the site of distal peripheral injury. Red box indicates injury site. (B) Confocal z-projection of (TIF)Click here for additional data file.S9 FigTg(pu1:gfp);Tg(sox10:mrfp) zebrafish showing microglia and macrophages in their typical domains pre-injury. Arrows indicate microglia. Arrowheads indicate macrophages.  Migration plots of individual microglia that have migrated to injury site and entered the PNS.  Quantification of distance and time a microglia cell spent inside and outside of the CNS. y-axis numbers > 0 indicate cell\u2019s presence in PNS. y-axis numbers < 0 indicate cell\u2019s presence in CNS. (J) Images from a 24-hour time-lapse movie starting at 4 dpf in Tg(pu1:gfp);Tg(sox10:mrfp) zebrafish showing pre-ectopic PNS migration of microglia. Arrows indicate microglia. Dotted line indicates dorsal edge of spinal cord. (K) Tracing of pre-ectopic microglia in (J). (L) Images from a 24-hour time-lapse movie starting at 4 dpf in Tg(pu1:gfp);Tg(sox10:mrfp) zebrafish showing migration of microglia to PNS. Arrows indicate microglia. Dotted line indicates dorsal edge of spinal cord. (M) Tracing of pre-ectopic microglia in (L). (N) Quantification of debris puncta within microglia collected before migration, during migration, and after migration. (O) Quantification of size of debris puncta within microglia collected before migration, during emigration, and after emigration. Scale bar equals 1 \u03bcm  and 10 \u03bcm (A). See (A) Images from a 24-hour time-lapse movie starting at 4 dpf in (TIF)Click here for additional data file.S10 Fig(A\u2013D) Shape descriptor quantification of the circularity (A), aspect ratio (B), roundness (C), and solidity (D) of microglia in the CNS, leaving the CNS, in PNS, re-entering the CNS, and PNS-primed in the CNS. (E\u2013I) Quantification of the average circularity (E), aspect ratio (F), roundness (G), and solidity (H) of a PNS-primed microglia in the CNS versus a microglia that responded to injury but never left the CNS. (I) Shape descriptor quantification of the circularity of individual microglia in the CNS, in PNS, and PNS-primed in the CNS. (J) Shape descriptor quantification of the solidity of individual microglia in the CNS, in PNS, and PNS-primed in the CNS. (K) Quantification of the total amount of new debris a PNS-primed microglia collected compared to microglia that responded to injury but never left the CNS. (L) Quantification of the amount of primary and secondary projections created across different neuronal domains. (M) Quantification of the total amount of primary and secondary projections a PNS-primed microglia in the CNS versus a microglia that responded to injury but never left the CNS. See (TIF)Click here for additional data file.S11 FigTg(pu1:gfp);Tg(sox10:mrfp) zebrafish representing the entire spinal cord. White boxes coordinate with letter tags represent zones of the animal in which microglia traveled, larger images located below. Yellow box indicates injury site. Note that microglia traveled into brain region shown in (C). (B) Quantification of the percent of the animal surveyed by microglia. (C) Representative quantification of distance microglia traveled throughout the animal anteriorly and posteriorly. Red arrow indicates injury site, origin set to site of injury. (D) Quantification of the average distance each microglia travel throughout the CNS. (E) Quantification of the maximum distance each microglia travel throughout the CNS. (F) Stitched zoning images from a 24-hour time-lapse movie starting at 4 dpf in Tg(pu1:gfp);Tg(sox10:mrfp) zebrafish representing the entire animal and no microglia located within the CNS. Yellow boxes indicate injury site. (G) Images from a 24-hour time-lapse movie starting at 4 dpf in Tg(pu1:gfp);Tg(sox10:mrfp) zebrafish showing macrophage response to injury site. Yellow box indicates injury site. (H) Quantification of the total amount of heterotypic and homotypic cellular contacts. Scale bar equals 1 \u03bcm (bottom A), 10 \u03bcm (G), 100 \u03bcm . See (A) Stitched zoning images from a 24-hour time-lapse movie starting at 4 dpf in (TIF)Click here for additional data file.S12 FigTg(pu1:gfp);Tg(sox10:mrfp) zebrafish showing microglia arriving at the primary injury site, emigrating from the CNS, re-entering the CNS, and then migrating to the secondary injury site. Arrow indicates microglia. Yellow box indicates primary injury site. Blue box indicates secondary injury site. (B) Images from a 24-hour time-lapse movie starting at 4 dpf in Tg(pu1:gfp);Tg(sox10:mrfp) showing primary and secondary projections of PNS-experienced microglia at the secondary injury site. Green arrowheads indicate primary projections. Orange arrowheads indicate secondary projections. (C) Quantification of the average time microglia spent at the secondary injury site. (D) Quantification of the amount of primary and secondary projections PNS-experienced microglia created at the secondary injury site compared to na\u00efve microglia. Scale bar equals 1 \u03bcm (B), 10 \u03bcm (A). See (A) Images from a 24-hour time-lapse movie starting at 4 dpf in (TIF)Click here for additional data file.S13 FigTg(pu1:gfp);Tg(sox10:mrfp) zebrafish comparing DMSO and NMDA inhibitor treated microglia response to the injury site. Arrowheads indicate microglia. (B) Quantification of the percentage of DMSO and NMDA-inhibitor treated animals that had microglia respond to the site of injury. (C) Quantification of the average number of microglia that are present and respond to the injury site. Scale bar equals 10 \u03bcm (A). See (A) Images from a 24-hour time-lapse movie starting at 4 dpf in (TIF)Click here for additional data file.S14 Fig(A-D) Shape descriptor quantification of the circularity (A), aspect ratio (B), roundness (C), and solidity (D) of DMSO compared to NMDA- and glutamate-treated individual microglia before exiting the CNS, in the PNS, and PNS-primed in the CNS. See (TIF)Click here for additional data file.S15 FigTg(pu1:gfp);Tg(sox10:mrfp) zebrafish showing no emigration of microglia to the PNS. Arrowheads indicate microglia. Yellow box indicates site of glutamate uncaging. (H) Quantification of the percentage of uninjured glutamate-treated animals with microglia present near the uncaging site compared to the percentage of microglia that exited the CNS following glutamate uncaging. Scale bar equals 10 \u03bcm (G). See (A) Quantification of the percentage of microglia that exit the CNS within 2 hours post-injury after no glutamate exposure, mock uncaging, and glutamate uncaging. (B) Quantification of the time it takes microglia to respond to injury post-normal injury versus post-glutamate uncaging. (C) Quantification of the distance microglia travel to the injury site post-normal injury versus post-glutamate uncaging. (D) Quantification of the average amount of debris individual microglia collect pre-CNS exit when treated with glutamate. (E) Quantification of the average area of the debris collected by individual microglia pre-CNS exit represented in (D). (F) Quantification of the average amount of debris individual microglia collect while in the PNS when treated with glutamate. (G) Images from a 24-hour time-lapse movie starting at 4 dpf in uninjured glutamate-treated (TIF)Click here for additional data file.S16 FigTg(pu1:gfp);Tg(sox10:mrfp) zebrafish showing microglia experience directional changes. Arrowheads indicate microglia. Red circles indicate previous location of microglia. (B) Quantification of distance traveled pre- and post-contact between two microglia. (C) Quantificaion of distance traveled pre- and post-contact between two macrophages. (D) Quantification of average maximum distance traveled of each cell that experiences a directional change pre- and post-contact with a migrating cell . Scale bar equals 10 \u03bcm (A). Stats summarized in (A) Images from a 24-hour time-lapse movie starting at 4 dpf in (TIF)Click here for additional data file.S17 FigTg(pu1:gfp);Tg(sox10:mrfp) zebrafish showing the ectopic migration of microglia. Dotted line indicates dorsal edge of spinal cord. Yellow box indicates injury site. (B) Quantification of reaching events. y-axis numbers > 0 indicate projection presence in PNS. y-axis numbers < 0 indicate projection presence in CNS. (C) Quantification of microglial projection length in the CNS versus PNS. (D) 3D side view image from a 24-hour time-lapse movie starting at 4 dpf in Tg(pu1:gfp);Tg(sox10:mrfp) zebrafish showing microglial projection reaching into the PNS. (E) Graphical representation of events described in (D). Scale bar equals 1 \u03bcm (A). See (A) Images from a 6-hour time-lapse movie starting at 4 dpf in (TIF)Click here for additional data file.S18 FigTg(pu1:gfp);Tg(sox10:mrfp) zebrafish post-injury showing pU1+ cell responses to injury. (B) Images from a 2-hour time-lapse movie starting at 4 dpf in Tg(pu1:gfp);Tg(sox10:mrfp) zebrafish before and after single-cell macrophage ablation. Arrows indicate microglia. Arrowheads indicate macrophages. Dashed circles indicate ablated macrophages. (C) Images from 24-hour time-lapse movies starting at 4 dpf in Tg(pu1:gfp);Tg(sox10:mrfp) zebrafish post-macrophage ablation showing microglial response to ablation site. Arrows indicate microglia. Dashed circles indicate site of macrophage ablation. (D) Migration plot representing the migration of microglia directly to the site of macrophage ablation. (E) Quantification of the time and distance microglia traveled immediately following macrophage ablation. Red box indicates injury site. y-axis numbers > 0 indicates the PNS. y-axis numbers < 0 indicates the CNS. Scale bar equals 10 \u03bcm (A-C). See (A) Images from a 2-hour time-lapse movie starting at 4 dpf in (TIF)Click here for additional data file.S19 FigTg(pu1:gfp);Tg(sox10:mrfp) zebrafish showing the response of macrophages and microglia to the injury site. Arrows indicate microglia. Arrowheads indicate macrophages. Yellow box indicates injury site. (B) Images from a time-lapse ablation window in Tg(pu1:gfp) zebrafish at 4 dpf showing ablation control and no immediate microglial response. (C) Images from a 2-hour time-lapse movie at 4 dpf in Tg(pu1:gfp);Tg(sox10:mrfp) zebrafish showing no microglial response to the site of control ablation. Arrow indicates microglia. White circle indicates site of macrophage ablation.  Migration plots of microglia not responding to site of control ablations. Red box indicated control ablation site.  Quantification of distance microglia traveled pre- and post-control ablation over time. Red box indicates control ablation site. y-axis > 0 indicates cell\u2019s presence in PNS. y-axis < 0 indicates cell\u2019s presence in CNS. x-axis > 0 indicates after ablation. x-axis < 0 indicates before ablation. Scale bar equals 10 \u03bcm (A-C). See (A) Images from a 30-minute time-lapse movie at 4 dpf in (TIF)Click here for additional data file.S20 FigTg(pu1:gfp);Tg(sox10:mrfp) zebrafish post-injury showing macrophage response to injury in animals without microglia. Stills display how debris puncta were determined. Arrows indicate debris that is cleared. Arrowheads indicate debris that is not cleared. Dashed circles represent cleared debris. Scale bar equals 10 \u03bcm. dpf, days post fertilization.Images from a 24-hour time-lapse movie starting at 4 dpf in (TIF)Click here for additional data file.S21 Fig(A) Model describing the observed nature of macrophages and microglia pre- and post-OBPI. (B) Model describing the glutamate-dependent emigration of microglia compared to unaltered microglia that remain in the CNS. (C) Model describing the factors necessary for the efficiency of microglia emigration after OBPI. CNS, central nervous system; OBPI, obstetrical brachial plexus injury.(TIF)Click here for additional data file.S1 MovieTg(ngn1:gfp) zebrafish showing the successful ablation of the central sensory projection. dpf, days post fertilization.Time-lapse movie starting at 4 dpf in (MOV)Click here for additional data file.S2 MovieTg(pu1:gfp);Tg(sox10:mrfp) showing macrophage and microglia responding to injury. Yellow box indicates injury site. White triangle indicates microglia. Two untracked pu1+ cells at injury are macrophages. Note mRFP+ debris is only present in microglia. Frame rate equals 10 fps. dpf, days post fertilization; fps, frames per second; mRFP, membrane red fluorescent protein.Excerpt from a 24-hour time-lapse movie starting at 4 dpf in (MOV)Click here for additional data file.S3 MovieTg(pu1:gfp);Tg(sox10:mrfp) showing microglia exiting the spinal cord. Two untracked pu1+ cells at injury are macrophages. Yellow box indicates injury site. White triangle indicates microglia. Frame rate equals 10 fps. dpf, days post fertilization; fps, frames per second.Excerpt from a 24-hour time-lapse movie starting at 4 dpf in (MOV)Click here for additional data file.S4 MovieTg(pu1:gfp);Tg(sox10:mrfp) showing microglia surveying the whole animal anterior to posterior. White circle indicates microglia that responded to injury. Yellow box indicates injury site. Frame rate equals 10 fps. dpf, days post fertilization; fps, frames per second.24-hour time-lapse movie starting at 4 dpf in (MOV)Click here for additional data file.S5 MovieTg(pu1:gfp);Tg(sox10:mrfp) animals. Following uncaging, a microglia immediately exits the spinal cord and enters the space where the uncaging occurred and continues to move throughout the PNS. Yellow box indicates site of glutamate uncaging. White triangle indicates microglia. Frame rate equals 1 fps. dpf, days post fertilization; fps, frames per second; PNS, peripheral nervous system.2-hour time-lapse movie starting immediately following a glutamate uncaging event in (MOV)Click here for additional data file.S6 MovieTg(pu1:gfp);Tg(sox10:mrfp) showing microglia attempting to respond to injury. During injury response, the microglia experience several directional changes, producing a \u201czig zag\u201d effect. Yellow box indicates injury site. White triangle indicates microglia. Frame rate equals 10 fps. dpf, days post fertilization; fps, frames per second.Excerpt from a 24-hour time-lapse movie starting at 4 dpf in (MOV)Click here for additional data file.S7 MovieTg(pu1:gfp);Tg(sox10:mrfp) showing an interaction between two microglia. After contact, both cells experience a directional change. Two blue triangles indicate microglia 1 (dark) and microglia 2 (light). Yellow box indicates region of homotypic contact. Frame rate equals 10 fps. dpf, days post fertilization; fps, frames per second.Excerpt from a 24-hour time-lapse movie starting at 4 dpf in (MOV)Click here for additional data file.S8 MovieTg(pu1:gfp);Tg(sox10:mrfp) showing an interaction between a microglia and a macrophage. After contact, the microglia shows a directional change while the macrophage remains stationary. Blue triangle indicates microglia. White triangle indicates macrophage. Yellow box indicates region of heterotypic contact. Frame rate equals 10 fps. dpf, days post fertilization; fps, frames per second.Excerpt from a 24-hour time-lapse movie starting at 4 dpf in (MOV)Click here for additional data file.S9 MovieTg(pu1:gfp);Tg(sox10:mrfp) showing an interaction between two macrophages. After contact, neither cell displays a directional change. Two blue triangles indicate macrophage 1 (dark) and macrophage 2 (light). Yellow box indicates region of homotypic contact. Frame rate equals 10 fps. dpf, days post fertilization; fps, frames per second.Excerpt from a 24-hour time-lapse movie starting at 4 dpf in (MOV)Click here for additional data file.S10 MovieTg(pu1:gfp);Tg(sox10:mrfp) showing microglia exiting the spinal cord. Over time the cell re-enters the spinal cord and creates projections that reach into the PNS. Yellow box indicates injury site. White triangle indicates microglia. White circle traces tip of microglial PNS projections. Frame rate equals 10 fps. dpf, days post fertilization; fps, frames per second; PNS, peripheral nervous system.Excerpt from a 24-hour time-lapse movie starting at 4 dpf in (MOV)Click here for additional data file.S11 MovieTg(pu1:gfp);Tg(sox10:mrfp) showing the single-cell ablation of a macrophage and the microglial response immediately following ablation. Yellow triangle indicates microglia. Red box indicates area of macrophage ablation. Frame rate equals 10 fps. dpf, days post fertilization; fps, frames per second.Time-lapse movie starting at 4 dpf in (MOV)Click here for additional data file.S1 DataAll raw data and statistical values represented in different spreadsheet tabs per figure for (XLSX)Click here for additional data file.S2 DataAll raw data and statistical values represented in different spreadsheet tabs per figure for (XLSX)Click here for additional data file.S3 DataAll raw data and statistical values represented in different spreadsheet tabs per figure for (XLSX)Click here for additional data file.S4 DataAll raw data and statistical values represented in different spreadsheet tabs per figure for (XLSX)Click here for additional data file.S5 DataAll raw data and statistical values represented in different spreadsheet tabs per figure for (XLSX)Click here for additional data file.S6 DataAll raw data and statistical values represented in different spreadsheet tabs per figure for (XLSX)Click here for additional data file.S7 DataAll raw data and statistical values represented in different spreadsheet tabs per figure for (XLSX)Click here for additional data file.S8 DataAll raw data and statistical values represented in different spreadsheet tabs per figure for (XLSX)Click here for additional data file.S9 DataAll raw data and statistical values represented in different spreadsheet tabs per figure for (XLSX)Click here for additional data file.S10 DataAll raw data and statistical values represented in different spreadsheet tabs per figure for (XLSX)Click here for additional data file.S11 DataAll raw data and statistical values represented in different spreadsheet tabs per figure for (XLSX)Click here for additional data file.S12 DataAll raw data and statistical values represented in different spreadsheet tabs per figure for (XLSX)Click here for additional data file.S13 DataAll raw data and statistical values represented in different spreadsheet tabs per figure for (XLSX)Click here for additional data file.S14 DataAll raw data and statistical values represented in different spreadsheet tabs per figure for (XLSX)Click here for additional data file.S15 DataAll raw data and statistical values represented in different spreadsheet tabs per figure for (XLSX)Click here for additional data file.S16 DataAll raw data and statistical values represented in different spreadsheet tabs per figure for (XLSX)Click here for additional data file.S17 DataAll raw data and statistical values represented in different spreadsheet tabs per figure for (XLSX)Click here for additional data file.S18 DataAll raw data and statistical values represented in different spreadsheet tabs per figure for (XLSX)Click here for additional data file.S19 DataAll raw data and statistical values represented in different spreadsheet tabs per figure for (XLSX)Click here for additional data file.S20 DataAll raw data and statistical values represented in different spreadsheet tabs per figure for (XLSX)Click here for additional data file.S21 DataAll raw data and statistical values represented in different spreadsheet tabs per figure for (XLSX)Click here for additional data file.S22 DataAll raw data and statistical values represented in different spreadsheet tabs per figure for (XLSX)Click here for additional data file.S23 DataAll raw data and statistical values represented in different spreadsheet tabs per figure for (XLSX)Click here for additional data file."}
+{"text": "Fermented garlic, often called black garlic, is a traditional food ingredient used in Asian cuisine and possessesvarious health benefits including anti-obesity activity. The anti-obesity effects of fermented garlic might, in part, mightbe mediated through direct actions of its components on adipocytes. To test this hypothesis, we examined whetherfermented garlic extract might stimulate the metabolic activity of human adipose-derived stem cells (ADSCs) in culture.Cell viability measured by 3--2,5-diphenyltetrazolium (MTT) assay exhibited a complex dose-response relationship. The lowest concentration (0.4 mg/ml) reduced cell viability , whereas higher concentrations (0.8 and 1.0 mg/ml) resulted in higher cell viability(P<0.05 as compared to 0.4 mg/ml). However, the extract at concentrations >2 mg/ml markedly decreased cellviability. Higher cell viability observed following treatment with 0.8~1.0 mg/ml might be associated with raised oxygenconsumption. Fluorescent dye-based measurement revealed that the garlic extract at 1.0 mg/ml significantly increasedoxygen consumption. We also detected a significant increase in mRNA expression levels of uncoupling protein-1 (UCP-1). These findings suggest that fermented garlic stimulates the basal metabolic activity of human ADSCs.  As it possessesunique texture and flavor and lacks offensive smells,it has become a popular ingredient not only in Asiancuisines, but for other cooking styles of the world.In addition, black garlic has been shown to producevarious health benefits, some of which may not beseen with fresh product , 2. For Nonshivering thermogenesis accounts at least inpart for alterations in the basal metabolic rate underphysiological conditions. Brown adipose tissues areprimarily responsible for nonshivering thermogenesisin rodents and human infants. Studies conductedduring the last ten years have established that adulthumans also possess active brown adipose tissues -8. FurtKnown in vivo health benefits of black garlicconsumption are likely to influence various organs andcomplex physiological mechanisms. It is also possiblethat black garlic possibly exerts direct beneficialactions on adipocytes. To test this hypothesis, weused human adipose-derived stem cells (ADSCs)and fermented garlic, a type of black garlic that isprepared under sterile and controlled conditions .In thisOrdinary black garlic used for culinary purposesis prepared by fermenting unpeeled garlic usingsupplemented or naturally-occurring microorganisms. The preparing procedure significantly differs from oneregion to another and various microorganisms presentin the producing environment may potentially affect thefinal product. Thus, we used fermented garlic preparedunder conditions with minimized contaminationcaused by environmental microorganisms from HtOLife Co., Ltd. . Thisproduct was prepared by fermentation of peeled andcrushed garlic cloves. Briefly, peeled garlic cloveswere sterilized using ozonized water and crushed intoa paste-like preparation. The garlic paste was thenfermented using the strain, Bacillus subtilis subsp.subtilis KACC91554P, under aerobic conditions.Water-soluble extract was collected by ultrafiltration,and hot air-dried using a spray dryer . The prepared fermented garlicwas tested for various components at Namhae GarlicResearch Institute  toensure the consistency of the preparations .The dried fermented garlic extract was re-dissolvedin water at a final concentration of 100 mg/ml byrigorous vortexing and sonication. Undissolvedmaterials were eliminated by centrifugation, followedby filtration through a cellulose acetate membrane(pore size 0.2-mm). The concentrations of fermentedgarlic mentioned in this paper indicate those measuredbased on the initial dried powder without consideringthe undissolved and eliminated materials.2 atmosphere at 37\u02daC.Human adipose-derived stem cells (ADSCs) werepurchased from Cellular Engineering Technologies. Cells were cultured inDulbecco\u2019s Modified Eagle Medium supplementedwith 10% fetal bovine serum ,50 U/ml penicillin and 50 \u03bcg/ml streptomycin  under 5% COHuman ADSCs were seeded in a 96-well dish at ~5000cells/well. Two days after seeding, cells were treatedwith fermented garlic extract or water for additional2 days. Cell viability was then determined using3-.Human ADSCs were treated with 1.0 mg/ml fermentedgarlic extract or water (1/100 volume) for 2 days. Cellswere then subjected to oxygen consumption assaysaccording to the manufacturer\u2019s protocol. Fluorescencewas monitored every 1.5 minutes over 90 minutes at37\u02daC by a plate reader . A linearportion of blank-collected fluorescent intensity in eachsample was used to estimate the oxygen consumptionrate. Antimycin A, an inhibitor of the electrontransport chain, almost completely eliminated thetime-dependent increase in fluorescent intensity.Total RNAs were isolated from cultured humanADSCs using a phenol-based reagent  and their concentrations were estimatedusing absorbance at 260 nm=40 ng/ml. First-strandcDNAs were synthesized using 0.1 mg total RNA witha mixture of oligo(dT) and random primers . PCR was carried out usingsynthesized cDNA sample (0.1 to 1.0 ml) using primers under thFermented garlic contains various chemicals thatmay influence cellular metabolism in distinct ways.We first used MTT assay which is based on cellularmetabolic activity in terms of reducing MTT. The MTTassay results should represent total cellular metabolicactivity or cell viability in the sample. These assaysare widely used to measure cell proliferation and/orchemical\u2019s toxicity. We treated human ADSCs withfermented garlic extract at various concentrationsfor 2 days and determined cell viability .The celWe wished to further corroborate the possibilitythat fermented garlic extract stimulates the metabolicactivity of ADSCs. Since MTT assays may beassociated with off-target effects, we measured cellularoxygen consumption using a molecular oxygensensitivedye . CellulaUCP-1) mRNA levels; UCP-1is a key protein in proton leak from the mitochondrialinner membrane and physiological heat generationand its coactivator-1\u03b1 (PPARGC1A), master regulatorsof the UCP-1 gene transcription and mitochondrialbiogenesis (PPARG andPPARGC1A mRNA expression. These findings suggestthat fermented garlic induces the browning of humanADSCs.Then we examined whether the observed increase inoxygen consumption is associated with the browningof human ADSCs. We measured mitochondrialuncoupling protein-1 (neration. Low levogenesis . TreatmeUCP-1 mRNA level in cultured human ADSCs.In addition, the extract increased mRNA levels ofPPAR\u03b3 and PGC-1\u03b1 that play pivotal roles in UCP-1expression and mitochondrial biogenesis in adipocytes(Fermented or black garlic has been shown to producevarious health benefits. In particular, intake of blackgarlic reduces body weight and fat masses, andnormalizes physiological and biochemical parametersin animal models of obesity -5. Howevipocytes. Thus, cIt has become evident that cells located in whiteadipose tissues of adult rodents -17 and hFermented or black garlic contains various chemicalcomponents. Unlike fresh garlic, the sulfur-containingalliin and its converted substances with offensive flavorsare much less abundant in fermented products , 2,22."}
+{"text": "In this paper, we obtain some improved exponential approximation inequalities for the functions  W. W1.4). LetandThen we havewhereaandbare the best constants in 8])Letbe the even-indexed Bernoulli numbers, ThenLetbe the even-indexed Bernoulli numbers. Then the following power series expansion:andhold.The following power series expansions can be found in [Letandbe real numbers, and let the power seriesandbe convergent forIfforand ifis strictly increasing (or decreasing) forthen the functionis strictly increasing (or decreasing) onf and g be differentiable on In order to prove Theorem\u00a0Letandbe two real power series converging onandfor all\u00a0k. Suppose that, for certainthe non-constant sequenceis increasing (resp. decreasing) forand decreasing (resp. increasing) forThen the functionis strictly increasing (resp. decreasing) onif and only ifMoreover, ifthen there existssuch that the functionis strictly increasing (resp. decreasing) onand strictly decreasing (resp. increasing) onLetWe now show that (i) We first prove the left-hand side inequality of . Let\\do(ii) Then we prove the right-hand side inequality of . Let\\do(iii) Let(1) Letality of  is compl(2) Letality of  is compl(3) LetLetSinceSoThe results of inequalities in Theorems"}
+{"text": "Proteins of the SNARE  family play a significant role in allvesicular fusion events involved in endocytic and exocytic pathways. These proteins act as molecular machines that assemble into tightfour-helix bundle complex, bridging the opposing membranes into close proximity forming membrane fusion. Almost all SNAREproteins share a 53 amino acid coiled-coil domain, which is mostly linked to the transmembrane domain at the C-terminal end. Despitesignificant variations between SNARE sequences across species, the SNARE mediated membrane fusion is evolutionary conserved inall eukaryotes. It is of interest to compare the functional divergence of SNARE proteins across various eukaryotic groups duringevolution. Here, we report an exhaustive phylogeny of the SNARE proteins retrieved from SNARE database including plants, animals,fungi and protists. The Initial phylogeny segregated SNARE protein sequences into five well-supported clades Qa, Qb, Qc, Qbc and Rreflective of their positions in the four-helix SNARE complex. Further to improve resolution the Qa, Qb, Qc and R family specific treeswere reconstructed, each of these were further segregated into organelle specific clades at first and later diverged into lineage specificsubgroups. This revealed that most of the SNARE orthologs are conserved at subcellular locations or at trafficking pathways acrossvarious species during eukaryotic evolution. The paralogous expansion in SNARE repertoire was observed at metazoans  andplants independently during eukaryotic evolution. However, results also show that the multi-cellular and saprophytic fungi havelimited SNAREs. The evolutionary transition from prokaryotes to multicellulareukaryotes had led to the internal compartmentalization of thecell and emergence of the endomembrane system. The transportof proteins, lipids and other macromolecules between thesecompartments occurs via packaging of vesicles with cargo fromthe donor organelle membrane and its fusion with the targetmembrane. These cargo-laden vesicles have integral membrane proteins termed as v-SNAREs, which form, complex with thecognate t-SNAREs on the target membrane. SNAREs are a familyof small cytoplasmically oriented evolutionarily conservedproteins involved in protein trafficking pathways i.e., traffickingof newly synthesized proteins, turnover of preexisting proteinsand organelle morphogenesis. Functionally these proteins wereclassified into vesicle-associated v-SNAREs and target membraneassociated t-SNAREs. All SNARE proteins are comprised of 53-63amino acid residue long SNARE domain, an extended coil coiledsegment arranged in heptad repeats, which is directly adjacent toa transmembrane domain at the C-terminal end. The SNAREmotifs from complementary sets of SNARE proteins zipper upinto a tight 4-helix bundle complex between opposingmembranes in trans-configuration , 2. ThisQa SNARE family includes almost all known Syntaxins while afew Syntaxins are categorized as Qc SNAREs. Almost allSyntaxins consist of N-terminal regulatory Habc domain linkedto the H3 SNARE domain and end in the transmembranedomain. Most of the Qb SNAREs (except Sec20) and Qc SNAREshave three helix forming N-terminal domains linked to a singleSNARE domain and finally a transmembrane domain at the Cterminalend . LikewisIn addition to evolutionarily conserved SNARE domain, theseproteins harbor specific signatures i.e., K/HDEL retrieval in theER localized SNAREs , NPF motEarly findings had reported an elaborate SNARE repertoire inLast eukaryotic common ancestor (LECA), which remainsconserved throughout the eukaryotic evolution , 3, 13.For this study, 2197 SNARE protein sequences were retrievedfrom more than 200 species of metazoans , plants, fungiand protists listed on the SNARE databasehttp://bioinformatics.mpibpc.mpg.de/ snare/index.jsp afterPERL script written in-house. The dataset include sequences forall five families and subgroups i.e., Qa-504, Qb -424, Qc-570, Qbc-285 and R SNARE subfamily-514.The sequences for each subgroup within the SNARE family werealigned using MAFFT software  and a maPrevious phylogenetic trees of the SNARE family have beenseparately constructed for each of the 20 SNARE subgroupsindependently . The PhyThe Phylogenetic tree reconstructed from Qa SNAREs(Syntaxins) resolved into five organelle specific clades i.e., ERlocalized Syntaxin 18; Golgi localized Syntaxin 5; trans-GolgiNetwork localized Syntaxin 16; Endosome (vacuole) localizedSyntaxin 7 and Plasma membrane localized Syntaxins 1-4 andtheir orthologs .The Endoplasmic Reticulum localized Qa SNARE segregated intometazoan specific Syntaxin 18 and fungi specific Ufe1 subgroups.The Golgi localized Qa SNARE clade segregated into metazoanspecific Syntaxin 5, fungi specific Sed5 and plant specific Syp3.The Trans Golgi Network localized Qa SNARE clade furthersegregated into metazoan specific Syntaxin 16, fungi specific Tlg2and plant specific Syp4. The Endosome (vacuole) localized QaSNARE clade segregated into metazoan specific Syntaxin 7,Syntaxin 13, Syntaxin 20 and fungi specific Pep12 (prevacuolarcompartment) and Vam3 (vacuole) while the plant specific Syp21(prevacuolar compartment) and Syp22 (vacuole) diverged offseparately . InteresThe plasma membrane localized Qa SNARE clade split intometazoan specific Syntaxin 1, 2, 3, 4, Syntaxin 11, 19 and 21; yeastspecific Sso1 and -2; plant specific Syp1 and protist specificSyntaxins. Syntaxin 1 is involved in faster kinetics of exocytosis inneurons  whereas Consistent with existing understanding, our results predict thatthe first round of whole genome duplication led to the expansionof endosomal (vacuole) SNAREs and some secretory SNAREs inhigher eukaryotes while the second genome duplication eventresults in increase in Plasma membrane associated SNAREs. Inmetazoans, the endosomal SNARE Syntaxin 7 duplicated intoSyntaxin 13 and later into Syntaxin 20 . LikewisThe Plasma membrane Syntaxin 1 diverged and evolved into setof secretory Syntaxins in metazoans i.e., Syntaxin 2, 3, 4 andfurther highly deviated paralogs i.e., Syntaxin 11 , SyntaxiThe Phylogenetic tree reconstructed from Qb SNAREs resolvedinto five clades i.e., ER localized Sec20, Golgi localized Membrinand Bos1, trans Golgi Network localized Gos28 and Gos1,Endosome (Vacuole) localized Vti1 and NPSN. Qbc SNAREsconstitute the plasma membrane localized members of thissubfamily and are added for reference .The ER localized Sec20 clade split into metazoan, fungi and plantspecific subgroups. This SNARE protein showed low homologywith other SNAREs and is involved in retrograde transport fromGolgi to ER . LikewisIn metazoans, the endosomal Vti1a and Vti1b are encoded by twoseparate genes; the former localizes to Golgi and TGN whilelatter has a role in early and late endosomal trafficking . BycontThe Phylogenetic tree reconstructed from Qc SNAREs resolvedinto five clusters i.e., ER localized Use1 and Syp7; Golgi localizedBet1, Sft1 and Gs15; Trans Golgi Network localized Syntaxin 6and Syntaxin 10, Endosome localized Syntaxin 8. As mentionedearlier in the Qb subfamily, plasma membrane localization isthrough the specialized Qbc subfamily containing both Qb andQc domains, and is inserted into our analysis as a reference . We noteThe TGN localized Qc SNAREs represent kingdom specificisoforms i.e., metazoan specific Syntaxin 6 and Syntaxin 10SNAREs that arose after gene duplication in metazoans , Tlg1isQbc SNAREs are the only family of SNAREs consisting of dualSNARE motifs connected by a linker region. The Phylogenetictree reconstructed from Qbc SNAREs segregated into SNAP-25,SNAP-23, SNAP-29, SNAP-47, Sec9 and SNAP (Plant). SNAP-23showed homology and clustered along with SNAP-25 whileSNAP-29 and SNAP-47 constituted separate clades. Likewise thefungi paralogs Sec9 and Spo20 clustered together while plantspecific SNAP-33type SNAREs branched off separately . SNAP-25The Phylogenetic tree reconstructed from R-SNAREs segregatedinto four well supported clades based on their localization inrespective organelles i.e., Endoplasmic reticulum localized Sec22;Golgi localized Ykt6; Endosome localized VAMP-7 and Nyv1;vesicle localized Synaptobrevin 1-3, Myobrevin and Snc1/2.TheVAMP-4 clustered together with other vesicle associated RGbrevins while Endobrevin constituted a separate cluster.However, the regulatory R-SNAREs Tomosyn and Amisynsegregated into two separate branches . TheEndLongins i.e., Sec22, Ykt6 and VAMP-7 had been reported inLECA eukaryotic ancestor and are conserved across all theeukaryotes . The EndA comprehensive phylogenetic analysis confirms that the basicSNARE repertoire including twenty SNARE subgroups wasconserved in LECA. Theexpansion of SNARE repertoire in metazoans and plants confersan evolutionary advantage by allowing for provision of moreversatile and orchestrated endosomal and secretory traffickingpathways. However, this expansion cannot be correlated with therise of multi-cellularity as most of the SNAREs remained assingle copy in fungi. Endoplasmic reticulum and Golgi localizedSNAREs are singletons in most eukaryotes and their secretorypathways are preserved . NonetheThe authors have no conflict of interest."}
+{"text": "Financial decision making self-efficacy (FDMSE) is a novel construct that may influence how older adults make financial decisions. Our previous research with a community sample of older adults demonstrated that cognitive functioning and suspected history of financial exploitation were both associated with low FDMSE. We sought to replicate these findings in two clinical samples of older adults: people with mild cognitive impairment (MCI) or probable Alzheimer\u2019s disease (PAD) and current victims of scams or exploitation as determined by a financial coach. Samples were obtained from the Michigan Alzheimer\u2019s Disease Center and a financial coaching intervention study. All participants completed a 4-item FDMSE measure. One-way ANOVAs, t-tests and chi-square tests were conducted to test for group differences with controls on demographics. There was a main effect of cognitive status on FDMSE, F = 8.10, p < .001, which was driven by higher FDMSE in the healthy group (N = 63) than the MCI (N = 76) or PAD (N = 28) groups. Similarly, scam victims (N = 25) had significantly lower FDMSE than non-exploited (N = 25) peers, t(48)=2.33, p < 05. Cognitive impairment and current financial scams are both associated with low FDMSE levels. Low FDMSE may exacerbate cognitive and psychosocial vulnerabilities that contribute to risk for poor financial decisions among older adults. Future interventions to enhance FDMSE may help older adults make better decisions despite changes in thinking abilities or previous negative financial experiences."}
+{"text": "Recent attention to culturally competent care has largely overlooked the needs of older LGB adults. To address this, we conducted a systematic literature review and make recommendations for how the healthcare workforce can reduce sexual-orientation-based disparities. We searched PubMed, PsycINFO & CINAHL for manuscripts 1/1/10-6/19/18 (n=799), deduplicating, dually-screening abstracts (n=80), reviewing full-text articles (n=44), and classifying relevant articles (n=27) into five domains of cultural competency and associated recommendations: 1) Physical environment: display pictures with older same-sex couples and LGB-identified symbols; 2) Education/staffing: expand to include older-specific LGB issues, especially for key conditions  and hire LGB-identified administrative/clinical staff; 3) Inclusive language and communication: review terminology on forms, electronic health records, and used with patients to ensure a broad range of terms  and note older LGB may have more limited understanding/comfort with terminologies ; 4) Patient histories: discuss how factors particular to their sexual orientation  may affect their support networks; 5) Subgroup differences: consider specific health concerns by sexual minority subgroups  and note additional challenges based on characteristics such as race/ethnicity and urbanicity. Cutting across these domains are the ways in which local and national policies affect healthcare access and surrogacy ."}
+{"text": "Stromal cells have been widely used in biomedical research and disease modeling studies in vitro. The most commonly used types of stromal cells are mesenchymal stem cells and fibroblasts. Their cellular phenotypes and differentiation capabilities are quite similar and there are no specific distinction criteria. In order to identify transcriptomic differences between these 2 cell types, we performed next-generation RNA sequencing. Using the global gene expression profile and pathway analysis, we showed that human primary bone marrow mesenchymal stem cells and human primary dermal fibroblasts have different molecular signatures. We also identified critical transcription factors that are differentially expressed between these cells. We then proposed that homeobox genes and some other sequence-specific transcription factors are not only responsible for transcriptional differences, but also discriminate bone marrow mesenchymal stem cells and dermal fibroblasts at the transcriptional level. Stromal cells have been widely used in biomedicalresearch and disease modeling studies in vitro. Oneof the most important types of stromal cells is themesenchymal stem/stromal cell (MSC). MSCs aremultipotent stem cells that originate from mesenchymeand can be isolated from many tissues, but mainly frombone marrow and adipose tissuesAnother type of stromal cell is the dermal fibroblast(DF), which may be obtained easily from skin biopsy ordifferent surgical materials. DFs are mainly responsiblefor extracellular matrix (ECM) synthesis; they are foundin the dermal layer of the skin. Fibroblasts that are derivedfrom this layer are responsible for forming connectivetissue and play a major role in wound healing or repairat injury sitesHuman primary bone marrow mesenchymal stem/stromalcells (BM-MSCs) (Cat. No: PCS-500-012\u2122) and Humanprimary dermal fibroblasts (DFs) (Cat. No: PCS-201-012\u2122)were purchased from American Type Culture Collection. BM-MSCs were obtainedfrom a 24-year-old male Caucasian donor\u2019s bone marrowaspirate (Lot: 63208778) and DFs were obtained from a28-year-old male African\u2013American donor\u2019s abdominalskin (Lot: 63792061). Cells were incubated at 37 \u00b0C, 5%CO2 conditions; passage 3 cells were used, and all sampleswere prepared in triplicate. Culture medium  was changedtwice a week. Aeftr reaching nearly 70%\u201380% confluency,cells were washed with PBS and treated with TRI Reagent\u00aefor RNA isolation . RNA wasisolated according to the manufacturer\u2019s instructions.RNA quality was measured with a Nanodrop\u00ae  spectrophotometerand quantity was measured with a Qubit\u00ae (Thermo FisherScientific) flourometer.For library preparation, a barcoded cDNA library wasfirst generated with a SuperScript VILO cDNA SynthesisKit (Thermo Fisher Scientific) from 10\u00a0 ng of total RNAsample. An Ampliseq Human Gene Expression ChefReady Kit (Thermo Fisher Scientific) was used fortargeted amplification of nearly 20,000 distinct mRNAtargets. Libraries were then generated by an Ion Chefinstrument (Thermo Fisher Scientific), and pooledlibraries were clonally amplified using emulsion PCR onan Ion Torrent OneTouch2 (OT2) instrument (ThermoFisher Scientific). Enrichment was done using an IonOneTouch ES instrument (Thermo Fisher Scientific).The templated libraries were then sequenced on an IonProton semiconductor sequencing system, using an Ion PIHi-Q Sequencing Kit and Ion PI chip v3 (Thermo FisherScientific). All next-generation sequencing experimentswere performed in duplicate.The sequencing data were processed by the Torrent Suiteanalysis pipeline. Raw reads were mapped to the humangenome assembly hg19 AmpliSeq Transcriptome versionby TMAP . The datawere normalized and differentially expressed genes (DEG)were determined with DESeq2. STRING (version 10.5)was used to identify associations between the significantgenes (http://string-db.org/).We found that 419 and 773 genes were upregulated inHuman Primary BM-MSCs and in Human PrimaryDFs, respectively. Volcano plot indicated that these geneexpression changes were statistically significant  in BM-MSCs  homeobox family . Unlike other genes within homeoboxgenes, TALE group members are widely expressed ratherthan cell/tissue-specificThere are also some critical targets, predominantlyexpressed in BM-MSCs, which could be the basis ofgene expression differences between these 2 cell types.According to recent publications, most of the differentiallyexpressed transcription factors have critical roles in stemcell biology. For example, it has been shown that SOXfamily members are responsible for cell fate decisions, andit has also been shown that SOX11, GATA6, and PRDM16have critical roles in MSC self-renewalThis is an example of RNA-sequencing\u2013basedtranscriptomics regarding comparison of different stromalcells. Future studies should focus on stage- and/ordiseasespecific transcriptomic signatures between different typesof stromal cells. By doing this, biological functions andtherapeutic potentials of stromal cells could be identifiedin detail."}
+{"text": "Clostridium estertheticum subsp. laramiense type strain DSM 14864 (ATCC 51254) was isolated from vacuum-packaged refrigerated spoiled beef. This report describes the generation and annotation of the 5.0-Mb draft genome sequence of C. estertheticum subsp. laramiense DSM 14864T. Clostridium estertheticum subsp. laramiense type strain DSM 14864 (ATCC 51254) was isolated from vacuum-packaged refrigerated spoiled beef. This report describes the generation and annotation of the 5.0-Mb draft genome sequence of C. estertheticum subsp. laramiense DSM 14864T. Clostridium estertheticum subsp. laramiense DSM 14864T (ATCC 51254T) is a Gram-positive, spore-forming, slow-growing psychotrophic anaerobe that was originally isolated from vacuum-packaged refrigerated spoiled beef at the University of Wyoming  (Clostridium have been recognized as causative agents of blown pack spoilage (BPS) in vacuum-packed meat products, and DSM 14864T was selected for genome sequencing to examine its role in BPS. Phylogenetic analysis based on 16S rRNA gene sequence data placed DSM 14864T within the Clostridium estertheticum species, being 99% similar to the C. estertheticum type strain DSM 8809 (ATCC 51377)   broth (https://www.bioinformatics.babraham.ac.uk/projects/fastqc/), and the reads were trimmed with Trimmomatic v0.39 (http://www.usadellab.org/cms/?page=trimmomatic) and assembled using the A5-miseq pipeline v20169825, with standard parameters  were predicted, along with 89 tRNA, 26 rRNA, and 243 noncoding RNA (ncRNA) elements using GAMOLA2 (Strain DSM 14864S) broth  and mechT genome is predicted to encode 61 glycoside hydrolase (GH), 34 glycosyltransferase (GT), 6 polysaccharide lyase (PL), 11 carbohydrate esterase (CE), and 20 carbohydrate-binding protein module (CBM) families. Overall, approximately 3% of the DSM 14864T genome (132 coding sequences [CDSs]) is predicted to encode either secreted or intracellular proteins dedicated to carbohydrate and polysaccharide degradation. Interestingly, the enzymatic profiles of DSM 14864T and the well-characterized strain C. estertheticum DSM 8809T (ATCC 51377T) (Carbohydrate-Active enZyme (CAZy)  profilinClostridium estertheticum subsp. laramiense strain DSM 14864T (ATCC 51254T) reported here is a valuable resource for future studies investigating the bacterial genetic mechanisms associated with BPS. In order to improve the phylogenetic resolution of the genus Clostridium and improve our limited knowledge of meat spoilage caused by C. estertheticum, future efforts should focus on the generation of complete genomes across a wider range of Clostridium species.The genome sequence of Clostridium estertheticum subsp. laramiense type strain DSM 14864 (ATCC 51254) were deposited under GenBank accession number WBOE00000000, BioProject number PRJNA574489, and Sequence Read Archive (SRA) accession number SRR10193440.The genome sequence and associated data for"}
+{"text": "Toxicological Sciences:Incorrect images were used for the Control and OTA (80\u03bcg) panels of Citrinin-Generated Reactive Oxygen Species Cause Cell Cycle Arrest Leading to Apoptosis via the Intrinsic Mitochondrial Pathway in Mouse Skin Author list: Rahul Kumar, Premendra D. Dwivedi, Alok Dhawan, Mukul Das, Kausar M. AnsariThe authors apologise for this inadvertent error during figure preparation.The authors provide an updated Due to the time elapsed since experiments were conducted, data underlying S1 Data(ZIP)Click here for additional data file."}
+{"text": "Klebsiella pneumoniae is a Gram-negative bacterium that is a major cause of nosocomial infections worldwide. Here, we present the complete genome sequence of TK421, a clinical bacteremia isolate containing a hypervirulence plasmid carrying tra-associated conjugation machinery genes. Emergence of conjugative hypervirulence plasmids could portend rapid dissemination of hypervirulence among multidrug-resistant K. pneumoniae strains. Klebsiella pneumoniae is a Gram-negative bacterium that is a major cause of nosocomial infections worldwide. Here, we present the complete genome sequence of TK421, a clinical bacteremia isolate containing a hypervirulence plasmid carrying tra-associated conjugation machinery genes. Emergence of conjugative hypervirulence plasmids could portend rapid dissemination of hypervirulence among multidrug-resistant K. pneumoniae strains. Klebsiella pneumoniae is a Gram-negative pathogen that is a major cause of nosocomial infections worldwide (\u2013K. pneumoniae is a commonly multidrug-resistant (MDR) bacterium and a frequent cause of serious infections in immunocompromised patients residing in hospitals and long-term-care facilities (3\u2013K. pneumoniae isolates manifest as invasive community-acquired infections known as hypervirulent K. pneumoniae (hvKP) infections  from a single colony inoculated into lysogeny broth and cultivated at 37\u00b0C overnight with shaking. The SMRTbell template preparation kit v1.0  was used to ligate hairpin adapters required for sequencing sheared genomic DNA. Libraries were sequenced using PacBio P6-C4 chemistry and RS II single-molecule real-time (SMRT) cells 8Pac v3 with 240-min movies on an RS II instrument (Pacific Biosciences). PacBio sequencing yielded 206,462 reads  totaling 2.70\u2009Gb of sequence for an approximate genome coverage of 509-fold. These reads had an N50 value of 22,681 bases and an L50 value of 42,692 bases. Libraries for Illumina sequencing were prepared using the Nextera XT library kit  and sequenced on an Illumina MiSeq instrument with a V3 flow cell to generate paired-end 301-bp reads, yielding 705,712 reads totaling 194\u2009Mb of sequence for an approximate genome coverage of 35-fold. Hybrid assembly and circularization of PacBio and Illumina reads were performed with Unicycler v0.4.8  and aerobactin and salmochelin biosynthesis genes similar to those found on known hypervirulence plasmids  (22tra conjugation machinery genes (traDFGHIS and trbB) . TK421 is closely related to sequence type 34 (ST34) but has two single-nucleotide variants (SNVs) in the elements . The chrK2044) 2225. In adnd trbB) , 27. Plae SSNIH1 . This stSRP227550. The whole-genome hybrid assembly has been deposited at DDBJ/ENA/GenBank under BioProject number PRJNA449090 with accession numbers CP045691 to CP045694 (GCA_009601745).The Illumina and PacBio sequencing reads were deposited in the NCBI Sequence Read Archive (SRA) under accession number"}
+{"text": "Among adults \u2265 age 65, 48% have prediabetes and are eligible to participate in the Medicare-covered Diabetes Prevention Program (DPP). We conducted a six-week pilot study to evaluate the feasibility and acceptability of a telehealth-adapted DPP for Nutrition Services Program (NSP) older adult meal program recipients. We enrolled NSP recipients (n=16) from a New York City senior center. These DPP participants attended weekly interactive DPP webinars and completed questionnaires covering lifestyle, physical activity, quality of life, and food records, and wore physical activity trackers. Retention was 75%; attendance averaged 80%; and weight loss was 2.9% (p=0.001). Our six-week pilot data suggest that a tele-adapted DPP intervention can achieve the Medicare reimbursement goals for attendance and 5% weight loss. We are surveying NSP recipients, who receive home-delivered meals, to evaluate the acceptability and feasibility of conducting a larger scale tele-adapted DPP intervention trial among NSP participants."}
+{"text": "Transcriptome analysis of breast cancer discovered distinct disease subtypes of clinical significance. However, it remains a challenge to define disease biology solely based on gene expression because tumor biology is often the result of protein function. Here, we measured global proteome and transcriptome expression in human breast tumors and adjacent non-cancerous tissue and performed an integrated proteotranscriptomic analysis.We applied a quantitative liquid chromatography/mass spectrometry-based proteome analysis using an untargeted approach and analyzed protein extracts from 65 breast tumors and 53 adjacent non-cancerous tissues. Additional gene expression data from Affymetrix Gene Chip Human Gene ST Arrays were available for 59 tumors and 38 non-cancerous tissues in our study. We then applied an integrated analysis of the proteomic and transcriptomic data to examine relationships between them, disease characteristics, and patient survival. Findings were validated in a second dataset using proteome and transcriptome data from \u201cThe Cancer Genome Atlas\u201d and the Clinical Proteomic Tumor Analysis Consortium.We found that the proteome describes differences between cancerous and non-cancerous tissues that are not revealed by the transcriptome. The proteome, but not the transcriptome, revealed an activation of infection-related signal pathways in basal-like and triple-negative tumors. We also observed that proteins rather than mRNAs are increased in tumors and show that this observation could be related to shortening of the 3\u2032 untranslated region of mRNAs in tumors. The integrated analysis of the two technologies further revealed a global increase in protein-mRNA concordance in tumors. Highly correlated protein-gene pairs were enriched in protein processing and disease metabolic pathways. The increased concordance between transcript and protein levels was additionally associated with aggressive disease, including basal-like/triple-negative tumors, and decreased patient survival. We also uncovered a strong positive association between protein-mRNA concordance and proliferation of tumors. Finally, we observed that protein expression profiles co-segregate with a Myc activation signature and separate breast tumors into two subgroups with different survival outcomes.Our study provides new insights into the relationship between protein and mRNA expression in breast cancer and shows that an integrated analysis of the proteome and transcriptome has the potential of uncovering novel disease characteristics.The online version of this article (10.1186/s13073-018-0602-x) contains supplementary material, which is available to authorized users. Gene expression profiling of breast tumors has led to the landmark discovery of disease subtypes and novel biomarkers for therapy response and disease survival \u20134. HowevBreast cancer patients were recruited between 1993 and 2003, as described previously , 19. SamHomo sapiens database downloaded from the European Bioinformatics Institute website (ftp://ftp.ebi.ac.uk/pub/databases/integr8) using the Proteome Discoverer 2.0 software (Thermo Fisher Scientific) interfaced with the SEQUEST HT algorithm and filtered with percolator to yield peptide identifications at the 1% false discovery rate (FDR) cutoff. We employed the Protein Scorer and Protein FDR Validator nodes to apply an additional 5% protein-level FDR. Up to two missed tryptic cleavage sites and oxidation of methionyl residues were allowed during this database search. The data was searched with a precursor ion tolerance of 1.4\u2009Da and a fragment ion tolerance of 0.5\u2009Da and two levels of grouping were applied, one for peptide grouping and one for protein grouping. We selected the \u201cstrict maximum parsimony principle\u201d option, and only the best ranked peptide-spectrum match (PSM) per spectrum was used for protein identification and grouping. To further reduce false-positive discovery, we considered only those proteins as correctly identified when at least two peptides in a tissue sample uniquely mapped to these proteins. As the last filtering step that was implemented by us, we calculated protein coverage across all samples  of the samples  under the dataset identifier PXD005692. To assess differential protein expression between tissues , we used the Bioconductor package DESeq2 that was shown to perform well in label-free MS proteomics  in tumors , and tumors with the highest concordance scores conferred a significantly increased risk of an early cancer death when compared to tumors with the lowest concordance scores  , as shown by a Cox regression analysis with the proliferation score as covariable Additional file 2:Figure S1. Processing of proteome data. Figure S2. Overlap in identified proteins between our study  and other proteome datasets for breast cancer. Figure S3. Proteome profiles for tumors vs. adjacent non-cancerous tissues and for tumor subtypes. Figure S4. Increased expression of proteins in breast tumors encoded by mRNAs with shortened 3\u2032UTR. Figure S5. KEGG pathways that are significantly enriched for proteins and mRNAs that were differentially expressed between basal-like tumors and adjacent non-cancerous tissue (13 pairs). Figure S6. Robustness of the global protein-mRNA concordance estimates for breast tumors and adjacent non-cancerous tissues. Figure S7. Exclusion of extracellular matrix proteins from the proteome dataset does not significantly alter the protein-mRNA concordance calculations for tumors or non-cancerous tissues. Figure S8. Correlation between tissue protein levels and tumor grade. Figure S9. Correlation between steady-state protein and mRNA abundance (rho) in breast tumors and association with PAM50-defined molecular subtypes using the CPTAC breast cancer proteomics dataset for 77 tumor samples . Figure S10. Non-negative matrix factorization (NMF) clustering of the tumor proteome data. (PDF 2346 kb)Additional file 3:Tables S1. Peptide spectral counts by best ranked UniProt ID for 118 human breast tissues. (XLSX 7681 kb)Additional file 4:Tables S2. Enrichment of differently expressed protein-coding genes in KEGG pathways (tumor vs. adjacent non-cancerous tissue). (XLSX 13 kb)Additional file 5:Tables S3. Patient characteristics. (DOC 52 kb)Additional file 6:Tables S4. Most differentially expressed proteins between LumA, HER2-positive, and TN/basal-like breast cancer subtypes. (XLSX 195 kb)Additional file 7:Tables S5. Significantly differentially expressed proteins between breast tumors and adjacent non-cancerous tissues (n\u2009=\u200952 tissue pairs). (XLSX 636 kb)Additional file 8:Tables S6. Concordance between protein-mRNA pairs in breast tumors and adjacent non-cancerous tissues within six protein abundance categories. (DOC 33 kb)Additional file 9:Tables S7. Proteins (n\u2009=\u2009285) whose abundance in breast tumors correlated with tumor grade. (XLSX 64 kb)Additional file 10:Tables S8. Proliferation score and global protein-mRNA concordance values for 59 breast tumors. (XLSX 15 kb)Additional file 11:Tables S9. Association of protein-mRNA concordance with survival in the tumor proliferation score-adjusted Cox regression analysis. (DOCX 12 kb)Additional file 12:Tables S10. Concordance values (rho) for 5677 protein-mRNA pairs in breast tumors (n\u2009=\u200959). (XLSX 955 kb)"}
+{"text": "Numbers of American children being raised by relatives continue to rise. Over 7.8 million children, representing 10.5% of American children under age 18, lived in a relative-headed home. Of these, 2.5 million have no parent present in their home . Kinship families\u2019 needs are typically complex, needing prompt and sensitive responses. Varied professionals often serve kinship families but the majority report receiving little information or training related to kinship families.  representing varied disciplines in a pre/post-test format to determine change in knowledge and strategies for working with kinship care family members. All respondents were enrolled in graduate courses specifically focused on kinship families. Respondents represented diverse fields including family therapists (n = 9), family service workers (n = 23), teachers (n = 16), school administrators (n = 4), child care providers (n = 2) and health care professionals (n = 7 ). Respondents completed a 17 question pre/post survey. Results demonstrated the majority  had experience with kinship families but most  had received little/no targeted professional training. Post-test results strongly indicated that completing any amount of kinship-related coursework positively impacted professionals\u2019 knowledge, confidence, and readiness to utilize learned strategies in their work with kinship families. Additionally, post-test results of students completing the entire series of classes (9 credits) revealed significantly greater changes, demonstrating the importance of providing comprehensive information to enhance professional practices for working with kinship families."}
+{"text": "Cancer cells become immortalized through telomere maintenance mechanisms, such as telomerase reverse transcriptase (TERT) activation. In addition to maintaining telomere length, TERT activates manifold cell survival signaling pathways. However, telomerase-associated gene signatures in cancer remain elusive.high) and low (TERTlow) cancers using multidimensional data from The Cancer Genome Atlas (TCGA). Multidimensional data were analyzed by propensity score matching weight algorithm. Coexpression networks were constructed by weight gene coexpression network analysis (WGCNA). Random forest classifiers were generated to identify cancer subtypes.We performed a systematic analysis of TERT high  contains supplementary material, which is available to authorized users. Telomeres are the terminal ends of linear chromosomes, and in most eukaryotes, they are composed of a GT-rich DNA repeat sequence (TTAGGG) and capped by telomere-specific binding proteins . TelomerMost cancers activate telomerase to maintain telomere length . TelomerAlthough TERT is actively transcribed in most human normal cells and tissues, TERT transcripts in normal cells are non-functional variants generated by alternative splicing . HoweverA recent systemic analysis of 18,430 samples across 31 cancer types has discovered that approximately 22% of tumors without detectable TERT expression might be absent from the two mechanisms of telomere maintenance . The number of resulting genes ranged from 52 in LGG to 4981 in THCA for DNA methylation and from 102 in KIRP to 5102 in SARC for mRNA expression. When examining the relationship between DNA methylation and mRNA expression, we found that TERThigh or TERTlow-specific DNA methylation was associated with TERThigh or TERTlow-specific downregulated gene expression levels in most cancer types (except for KIRC), suggesting mRNA expression regulation by DNA methylation  are enriched in shared biological processes: mitotic nuclear division/DNA replication and RNA processing ; (B) RNA splicing ; (C) extracellular matrix organization  and (D) angiogenesis/regulation of vasculature development . These results further support the observation that TERT-related signatures are associated with cell cycle and RNA processing.To gain additional system-level understanding of telomerase-associated mRNA expression signatures, we constructed gene coexpression networks using weighted gene coexpression network analysis (WGCNA) for each cancer type. WGCNA identified 38, 63, 76, 70, 52, 101, 47 and 58 coexpression modules in BRCA, KIRC, KIRP, LGG, LIHC, LUAD, SARC and THCA, respectively , indicating the connectivity between cell cycle/mitotic nuclear division and telomere maintenance. Taken together, our transcriptomic analysis results demonstrate a common enriched cell cycle process in TERThigh patients across cancers.We also noticed that genes in the cell cycle/mitotic nuclear division module are highly expressed in TERTP value <\u20092.2e-16, Additional\u00a0file\u00a0In the gene coexpression module network, hub genes with high intramodular connectivity represent a small proportion of nodes with maximal information compared to other nodes . Hub genWe also observed that hub genes in the cell cycle/mitotic nuclear division module vary among cancer types Fig.\u00a0a. For exhigh or TERTlow-specific-expressing miRNAs [FDR\u2009<\u20090.05], ranging from 21 in THCA to 243 in SARC. Assessing the correlation between the first principle component of TERThigh or TERTlow-specific expressing miRNAs and those of their predicted TERThigh or TERTlow-specific downregulated mRNA targets. We observed a significantly negative correlation in 5 cancer types , we found that the expression of the miR-17-92 cluster is TERThigh-specific , we identified 1 TERTlow-specific somatic mutation gene in BRCA, 2 TERTlow-specific and 2 TERThigh-specific somatic mutation genes in LGG, 2 TERTlow-specific and 13 TERThigh-specific genes in LIHC, 34 TERThigh-specific genes in LUAD  identified by GISTIC [high/TERTlow-specific SCNAs with 8 amplification peaks  and 11 deletion peaks  , whereas only 1 amplification peak in SARC and 1 deletion peak in LIHC are TERTlow-specific  targets that were mutated or amplified or 2) targets that were consistently upregulated at least 2-fold in TERTExamining the TERT-associated mutation/SCNA list, we found 8 drug targets with mutations/SCNAs across cancer types Fig.\u00a0a. All tahigh/TERTlow-specific top 20 expressed genes (including TERT) and DNA methylation probes, and the top 5 expressed miRNAs, SNPs and SCNAs. With this classifier, we were able to identify two subtypes (RFcluster1 and RFcluster2) for each cancer type. RFcluster1 showed higher levels of telomerase activity   \u201cglobal markers\u201d, which consist of consensus hub genes of cell cycle/mitosis nuclear division module in WGCNA  Fig. c . Validations in other cancer types and a large cohort of cancer patients are warranted in the future.This study has limitations. We recognize that stratification of patients by cancer stage and TERT promoter mutation has not been conducted. TERT promoter mutations have recently been shown to be major drivers of TERT expression. In our preliminary analysis of LGG, THCA and LIHC patients, we found that the multi-omics signature performs better than the TERT promoter mutation in the classification of TERThigh and TERTlow cancers provides essential insights into telomerase-associated alterations in cancer and opens new avenues for treating cancer.In summary, our report of molecular differences between TERTAdditional file 1:Figure S1. Potential confounders surveyed and balanced. (TIF 2290 kb)Additional file 2:Figure S2. Assessment the robustness of molecular signatures. (TIF 3967 kb)Additional file 3:Table S3. Hub genes of cell cycle/mitotic nuclear division module across eight cancers. (DOCX 102 kb)Additional file 4:Table S1. Number of cancer cases analyzed in this study (DOCX 17 kb)Additional file 5:Figure S3. Regulation of mRNA expression by DNA methylation. (TIF 815 kb)Additional file 6:Figure S4. Coexpression modules in 8 cancers. (TIF 11429 kb)Additional file 7:Figure S5. Preservation of mRNA co-expression modules. (TIF 2988 kb)Additional file 8:Figure S6. Genes in cell cycle/mitotic nuclear division module identified by WGCNA are highly expressed in TERThigh samples across 6 cancers. (TIF 1270 kb)Additional file 9:Table S2. Enrichment of validated telomere maintenance related Genes within the cell cycle/mitotic nuclear division module genes. (DOCX 14 kb)Additional file 10:Figure S7. Association analysis between the cell cycle/mitosis module and telomerase activity. (TIF 1280 kb)Additional file 11:Figure S8. Telomerase activity changes of RAD54L, FOXM1 or NEIL3 knockdown. (TIF 917 kb)Additional file 12:Table S4. Summary of cox regression results. (DOCX 14 kb)"}
+{"text": "Fibronectin (FN) exists in two forms\u2014plasma FN (pFN) and cellular FN (cFN). Although the role of FN in embryonic blood vessel development is well established, its function and the contribution of individual isoforms in early postnatal vascular development are poorly understood. Here, we employed a tamoxifen-dependent cFN inducible knockout (cFN iKO) mouse model to study the consequences of postnatal cFN deletion in smooth muscle cells (SMCs), the major cell type in the vascular wall. Deletion of cFN influences collagen deposition but does not affect life span. Unexpectedly, pFN translocated to the aortic wall in the cFN iKO and in control mice, possibly rescuing the loss of cFN. Postnatal pFN deletion did not show a histological aortic phenotype. Double knockout (dKO) mice lacking both, cFN in SMCs and pFN, resulted in postnatal lethality. These data demonstrate a safeguard role of pFN in vascular stability and the dispensability of the individual FN isoforms in postnatal vascular development. Complete absence of FNs in the dKOs resulted in a disorganized tunica media of the aortic wall. Matrix analysis revealed common and differential roles of the FN isoforms in guiding the assembly/deposition of elastogenic extracellular matrix (ECM) proteins in the aortic wall. In addition, we determined with two cell culture models that that the two FN isoforms acted similarly in supporting matrix formation with a greater contribution from cFN. Together, these data show that pFN exerts a critical role in safeguarding vascular organization and health, and that the two FN isoforms function in an overlapping as well as distinct manner to maintain postnatal vascular matrix integrity. Fibronectin is a protein that exists in vertebrates in two distinct forms: one present in the blood and the other in blood vessel walls. In mammals, fibronectin is important for the development of blood vessels before birth, but whether it is continuously required for blood vessel homeostasis from birth to adulthood is unknown. We present important results from three genetically modified mouse models, which show that at least one form of fibronectin is required for the proper function and integrity of blood vessels during this period. We show that fibronectin can be transferred from the blood into the vessel wall, where it can rescue the integrity of blood vessels in the absence of the vessel form. This represents an important biological mechanism to maintain the health of blood vessels. Our data also highlight the importance of both fibronectin forms in producing and organizing the microenvironment of cells, with a higher contribution from the fibronectin form residing in the blood vessel walls. Together, our findings show that fibronectin from the blood acts as a safeguard to maintain the health of blood vessels, and both fibronectin forms play crucial roles in development and support of the blood vessel microenvironment. Fibronectin (FN) is an abundant and ubiquitously expressed protein in the extracellular matrix (ECM) of various connective tissues as well as in blood of vertebrates ,2. Even FN is broadly expressed in embryos and in adult tissue. It generally regulates a wide spectrum of cellular and matrix related functions that play crucial roles during development, including cell adhesion, migration, growth, differentiation, and tissue repair ,14. The Fn) [Fn in mice also results in embryonic lethality with incomplete penetrance, displaying multiple embryonic cardiovascular defects [The functional relevance of FN in critical physiological and pathological developmental processes is validated by severe defects in mice globally lacking the FN gene (Fn) , includi defects . Althoug defects , it is a defects . It is a defects ,34. pFN  defects . In huma defects , myocard defects , Sturge- defects , and Ehl defects . Altered defects ,41 and i defects . These sThe aim of this study was to elucidate the role of FN isoforms during postnatal vascular development, with a focus on the elastic fiber-rich tunica media. To specifically delete cFN in smooth muscle cells (SMCs), the most prevalent cells in the tunica media, we employed tamoxifen-dependent Cre recombinase under a smooth muscle specific promoter. To discern the role of pFN in vascular development, a liver-specific Cre mouse was used. Our study demonstrates the importance and function of FN isoforms during the development of the aorta in the early postnatal period.It is well documented that FN is crucial in the development of blood vessels during embryogenesis ,43,44. TFn flanked by loxP sites (Fn(fl/fl)) were crossed with an established transgenic mouse line (Sma-Cre-ERT2/+), in which the expression of the tamoxifen-dependent Cre-ERT2 recombinase is under the control of the mouse smooth muscle \u03b1-actin (\u03b1-SMA) promoter. After several breeding rounds, the cFN iKO genotype (Fn(fl/fl); Sma-Cre-ERT2/+) was produced , was confirmed at P8 by a Fn-specific reverse transcriptase polymerase chain reaction (RT-PCR) of RNA isolated from the aortic media of the cFN iKO compared to control mice , a Reporter-Cre mouse strain (R26(fl/fl); Sma-Cre-ERT2/+) was generated ) mice, confirmed an efficient and specific expression of the Cre recombinase in the tunica media, identified by \u03b1-SMA staining  mouse model that allows postnatal, tamoxifen-inducible deletion of cFN in SMC, the major cell type in the aortic media. Mice containing Fn in the tunica media of the cFN iKO mice led to an unexpected increase of collagen deposition at 3 months of age as compared to the control , was injected intraperitoneally daily from P8 to P10 into tamoxifen-treated (P1\u2013P3) control and cFN iKO mice, and mice were sacrificed and analyzed at P11. A strong fluorescent red signal in the ascending as well as in the descending aorta of both the control  and cFN Fn(fl/fl) mice with transgenic mice expressing the Cre recombinase under the control of the albumin promoter (Alb-Cre) active in hepatocytes [Alb-Cre/+ strain has been used successfully by others to generate liver-specific KO mice [Fn(fl/fl); Alb-Cre/+ strain lacks expression of pFN from P3 onwards [To assess if pFN then plays a more important role in maintaining the cellular and matrix integrity of the vasculature, we generated pFN KO mice by crossing the atocytes ,47, the  KO mice ,47,48. T onwards , and theFn(fl/fl); Sma-Cre-ERT2/+; Alb-Cre/+ genotype (Fn(fl/fl); Sma-Cre-ERT2/+; Alb-Cre/+ mice eliminated the possibility of Cre toxicity. These mice had a normal life span and were used as breeders to maintain the mouse colony. Tamoxifen-injected Cre-negative Fn(fl/fl) mice also survived normally, demonstrating the absence of tamoxifen side effects. All other analyses throughout this study were performed on mice dissected immediately after cardiac perfusion to optimally preserve the tissue structure. Immunostaining on dissected dKO aortic wall tissues using a FN antibody that recognizes both isoforms showed a complete absence of pFN and cFN in the media layer, as compared to the control  mice deficient in pFN and cFN with the genotype . These mgenotype . Necropsgenotype , indicatWe further investigated the dKO mice for the consequences of complete FN deficiency on aortic wall development in the early postnatal period. We choose P8 for this analysis, because most dKO mice survive until this time point . To determine cell integrity, we stained aortic cross sections from all four tamoxifen-injected mouse strains with hematoxylin and eosin. SMCs in the aortic walls from dKO mice appeared to be disorganized, as compared to circumferentially aligned cells in the control aortic sections ; Sma-Cre-ERT2/+ mouse aortae were treated with 4-hydroxytamoxifen (4-OH Tamox) for 3 days to induce cFN deletion. As controls, the cells were treated with ethanol . RT-PCR showed an effective deletion of Fn upon treatment with 4-OH Tamox as compared to the EtOH-treated control . Mice were humanely killed by an anesthetic overdose using a ketamine/xylazine/acepromazine cocktail followed by cardiac perfusion.Fn(fl/fl) mice were generated as previously described [Sma-Cre-ERT2/+ mice were a generous gift from Drs. Pierre Chambon and Daniel Metzger and generated as described [Alb-Cre/+ (B6.Cg-Tg(Alb-cre)21Mgn/J; Stock No. 003574) and Rosa26(fl/fl) (B6.129S4-Gt(ROSA)26Sortm1Sor/J; Stock No. 003309) mice were purchased from the Jackson Laboratory. cFN iKO mice (Fn(fl/fl); Sma-Cre-ERT2/+) were generated by crossing Fn(fl/fl) mice with Sma-Cre-ERT2/+ mice following several breeding rounds. pFN KO (Fn(fl/fl); Alb-Cre/+) mice were obtained by crossing Fn(fl/fl) with Alb-Cre/+ mice after several crossings. Generation of double knockout (dKO) (Fn(fl/fl); Sma-Cre-ERT2/+; Alb-Cre/+) mice was achieved by breeding Fn(fl/fl); Sma-Cre-ERT2/+ with Fn(fl/fl); Alb-Cre/+ mice. Several breeding rounds were used to produce Reporter-Cre mice (Rosa26(fl/fl); Sma-Cre-ERT2/+) from Sma-Cre-ERT2/+ and Rosa26(fl/fl) mice.escribed  and wereescribed . Alb-CreFn  in SMCs of cFN iKO and dKO mice, and to induce \u03b2-galactosidase expression in the Reporter-Cre mice, 0.1 mg of tamoxifen (Sigma) was injected intragastrically daily from P1 to P3 using a 2 mg/mL tamoxifen solution in sunflower oil [Fn(fl/fl), pFN KO (Fn(fl/fl);Alb-Cre/+) and Reporter control (Rosa26(fl/fl))).To delete ower oil . The samFn deletion, RT-PCR was performed using total RNA isolated from descending aorta of 8-day-old mice using the Trizol method (Life Technologies). cDNA synthesis was achieved using SuperScript III kit (Invitrogen). A 219 bp Fn-specific PCR product was amplified using Fn-sense 5\u2032-CTGAACCAGCCTACAGATGAC-3\u2032 and antisense 5\u2032-CATTTTCTCCCTGCCGATCC-3\u2032 primers and compared to a 202 bp Gapdh-specific PCR product obtained with Gapdh-sense 5\u2032-GTTGCCATCAACGACCCCTTC-3\u2032 and antisense 5\u2032-ACTCCACGACATACTCAGCAC-3\u2032 primers.To validate Rosa26(fl/fl); Sma-Cre-ERT2/+) and Reporter-control (Rosa26(fl/fl)) mice and were embedded in OCT (Sakura Finetek). Eight micrometer cryosections were stained using an established \u03b2-galactosidase staining protocol [For the analysis of Cre recombinase activity, aortae were harvested from tamoxifen-injected Reporter-Cre , Masson\u2019s trichrome stain (collagen), picrosirius red (collagen), or Hart\u2019s elastin stain using standard procedures. For immunostaining, the sections were treated for antigen retrieval with 10 mM citric acid, 0.05% Tween 20 (pH 6) at 98 \u00b0C, followed by treatment with bacterial type XXIV proteinase . The sections were then incubated with primary antibody . The immunostaining procedure was performed using the Dako Envision+ System-HRP (AEC) staining system (Dako #K4004 and #K4008).For histological and immunohistological staining procedures, mice were humanely killed by an anesthetic overdose using a ketamine/xylazine/acepromazine cocktail. Mice were then cardiac-perfused with 10% neutral-buffered formalin, and aortae were harvested. After an overnight incubation in 10% neutral buffered formalin, the tissues were dehydrated through an increasing EtOH gradient and embedded in paraffin. Four micrometer sections were deparaffinized in CitriSolv (Decon Labs) and rehydrated with decreasing EtOH concentrations in HFor immunofluorescence staining procedures, the aortae were perfused as above but only fixed in formalin for 1\u20132 hours. The tissues were then cryoprotected by incubating in a 30% sucrose solution and then embedded in OCT. Eight micrometer cryosections were cut and hydrated in TBS, and blocked with 2% delipidized bovine serum albumin. Primary antibodies were monoclonal anti-EDA FN , polyclonal rabbit anti-mouse FN , polyclonal rabbit anti-human FBLN-4 , 1:500 dFn(fl/fl)). Human pFN (Millipore #FC010) or 250 kDa amino dextran (Fina Biosolutions #AD 250 \u00d7 100) were covalently coupled to the water-soluble activated fluorophore Oyster-680 N-hydroxysuccinimide ester (Boca Scientific) in 100 mM NaHCO3, 500 mM NaCl, pH 8.4. Oyster-680 emits light at 693 nm, which does not overlap with the known autofluorescence of elastic lamellae in the aorta. Unbound fluorophore was removed by dialysis against the coupling buffer, and the degree of labeling was calculated to be 3\u20134 molecules Oyster-680 per molecule of pFN or dextran. The labeled pFN or dextran was injected in mice intraperitoneally from P8 to P10 (0.13 mg per mouse per day) using an established protocol [pFN and dextran translocation experiments were performed with litters injected with tamoxifen (P1\u2013P3) to generate cFN iKOs and controls ) mice after they were humanely killed. Plasma preparation was performed using EDTA-coated tubes (Sarstedt). Three microliter aliquots of plasma were analyzed by standard western blotting under reducing conditions. The polyclonal rabbit anti-mouse FN antiserum (Millipore #AB2033) was used 1:500 diluted as primary antibody, with the 1:200 diluted Peroxidase-AffiniPure Goat Anti-Rabbit IgG (H+L) (Jackson Laboratories) as secondary antibody.Blood was collected by cardiac puncture from pFN KO and control  were monitored twice every day. Dead pups were found often for dKOs but occasionally we found dead pups from other tamoxifen-injected strains, which were used as controls for the necropsy. Dead pups were fixed in 10% neutral buffered formalin (overnight) and washed twice in phosphate buffered saline to prevent postmortem changes. Necropsy was performed to visualize gross anatomy of the dead pups, with a focus on the aorta and thoracic cavity. Images were recorded using an AmScope dissection microscope (ZM-1TZ2-FOR-GT-10M) equipped with a digital camera. All other analyses throughout this study were performed on mice dissected immediately after cardiac perfusion to optimally preserve the tissue structure and avoid any postmortem changes.For transmission electron microscopic analysis, mice were humanely killed by an anesthetic overdose with a ketamine/xylazine/acepromazine cocktail, followed by cardiac perfusion with 3% glutaraldehyde in 0.1 M sodium cacodylate buffer (pH 7.4) (fixative). The aortae were then harvested and incubated in the fixative overnight. This was followed by a postfixation step with 1% osmium tetraoxide + 1.5% aqueous potassium ferrocyanide. Aortae were then dehydrated with an increasing concentration of acetone, followed by embedding in Epon. Ninety nanometer sections were transferred onto 200 mesh copper TEM grids and counterstained stained using 4% aqueous uranyl acetate and Reynold\u2019s lead before imaging with an FEI Tecnai 12 BioTwin 120 kV transmission electron microscope.Thoracic aortae from all four mouse strains at P8 (post\u2013tamoxifen injection) were extracted by 0.1 N NaOH at 95 \u00b0C for 45 minutes. After centrifugation, the pellets containing insoluble elastin were subjected to hydrolysis and amino acid analysis using a three buffer gradient system and post-column ninhydrin derivatization. The content of elastin cross-links (Isodes and Des) were analyzed in an aliquot of the NaOH-insoluble fraction containing elastin after CF-11 preclearance by amino acid analysis . The amino acid composition of the NaOH-insoluble protein fraction was typical for pure elastin .Gapdh was used as the control gene. Relative quantification of mRNA levels (fold change) was calculated using the 2\u2212\u0394\u0394Ct method. Significance was determined using the two-tailed t test.Descending aortae were harvested from tamoxifen-injected control, dKO, cFN iKO, and pFN KO (littermates) at P8. Total RNA was isolated using the Trizol method (Life Technologies). RNA was reverse transcribed using ProtoScript II First Strand cDNA synthesis kit (New England Biolabs). A QuantStudio 5 Real Time PCR System (Applied Biosystems) was used to perform the quantitative PCR using SYBR Select Master Mix (Applied Biosystems). Specific primers were used for all the genes analyzed. Fn(fl/fl); Sma-Cre-ERT2/+ mice using an established explant-based method [Fn (deleted region as described above). EtOH, the solvent for 4-OH Tamox, was used as a control at a final concentration of 0.02% (same concentration as used for the 4-OH Tamox treatment). For experiments, cells were grown in medium containing fetal bovine serum depleted of pFN by gelatin sepharose chromatography [SMCs were isolated from the tunica media of aortae harvested from d method . Cells wtography . Deletiotography . DOC-solExperiments were designed to mimic the three KO mouse models and the control in cell culture as follows: 4-OH Tamox and EtOH-treated cells were cultured in the presence of 10% mouse plasma prepared from either wild-type or pFN KO mice. The combinations used were: (1) cFN+/pFN+, EtOH-treated cells (cFN present) were grown in medium containing mouse plasma from control mice (pFN present); (2) cFN+/pFN\u2212, EtOH-treated cells (cFN present) were grown in medium containing mouse plasma from pFN KO mice (pFN absent); (3) cFN\u2212/pFN+, 4-OH Tamox-treated cells (cFN absent) were grown in medium containing mouse plasma from control mice (pFN present); and (4) cFN\u2212/pFN\u2212, 4-OH Tamox treated cells (cFN absent) were grown in medium containing mouse plasma from pFN KO mice (pFN absent). After 5 days, cells were fixed with 4% paraformaldehyde and immunofluorescence was performed as described above, additionally with primary LTBP-4 antibody (1:500 diluted) and secondary Cy5 AffiniPure Goat anti-Rabbit IgG (H+L) antibody . No LTBP-4 fibers were observed in this setup. However, when, instead of using mouse plasma, 40 \u03bcg/mL of purified soluble pFN was added to the system, LTBP-4 fibers formed. This could be due to factors present in the mouse plasma, which might affect LTBP-4 assembly.Fn null mouse embryonic stem cells were prepared as described [Fn\u2212/\u2212 embryonic fibroblasts (which do not produce cFN) were grown in pFN-depleted cell culture medium, providing an experimental fibroblast system without pFN and cFN. Affinity chromatography on immobilized gelatin was used to purify human pFN from plasma, as described in detail [Mouse embryonic fibroblasts differentiated from escribed . As for n detail , and cFNn detail . Twelve An epifluorescence microscope  was used to capture all bright field and immunofluorescence images with an AxioCam ICc5 color camera or an Orca Flash 4.0 sCMOS grayscale camera, respectively. Grayscale immunofluorescence images were false colored using the Zen Pro software (Zeiss).Mean pixel intensity analysis of various fluorescent signals  was performed with 8-bit TIFF images using the ImageJ software  on regioFor collagen analysis, picrosirius red stained images of the aorta were obtained through fluorescence microscopy using a Zeiss HQ Texas Red filter set . Mean piPlugins\u2014Skeleton\u2014Skeletonize (2D/3D)\u201d and analyzing the processed image by clicking \u201cAnalyze\u2014Skeleton\u2014Analyze Skeleton (2D/3D)\u201d [Quantification of total fiber lengths and junction number of ECM fibers visualized by immunofluorescence was performed using the ImageJ distribution, Fiji ,84. Colo(2D/3D)\u201d . This prt test was used to determine significance of the difference in protein staining intensities (tissue and cell immunofluorescence) and mRNA levels (qPCR). One-way ANOVA was used to analyze significance for the difference in elastin content and cross-links . Chi-squared test was used to determine the significance of the deviation of mouse strain survival from the Mendelian ratio by comparing the number of observed live mice to that of the expected Mendelian ratio. For all statistical analyses, * denotes p \u2264 0.05, ** denotes p \u2264 0.01, and *** denotes p \u2264 0.001.Two-sample S1 Fig(A\u2013B) Fibrillin-1 immunostaining of cross sections of descending aorta show no change between cFN iKO and control at 8 months (n = 3). (C\u2013D) Hart\u2019s elastin stained cross sections of descending aorta of tamoxifen-injected control and cFN iKO at 8 months. (E\u2013F) Quantification of breaks (E) and forks (F) in the elastic lamellae normalized to the area  of the aortic section analyzed in the cFN iKO and control at 8 months (n = 8\u201310). There was a trend towards more elastin fiber breaks and fewer forks in the cFN iKO, but it did not reach statistical significance. Underlying data are provided in (TIF)Click here for additional data file.S2 Fig(A\u2013B) Hematoxylin and eosin stained cross sections of descending aorta from pFN KO (B) and control (A) mice at P30. Note no difference was observed in the organization of SMCs in the tunica media. (C\u2013D) Masson\u2019s trichrome staining of cross sections of descending aorta from control (C) and pFN KO (D) mice at P30 showed no changes in collagen deposition. (E\u2013F) Immunostaining of cross sections of descending aorta from pFN KO (F) at P30 using fibrillin-1 antibody showed no changes in fibrillin-1 deposition, as compared to the control (E). The lumen is indicated with an asterisk in A\u2013F. pFN KO, plasma fibronectin knockout; SMC, smooth muscle cell.(TIF)Click here for additional data file.S3 FigMore examples of defective elastic lamellae (yellow triangles) and irregular shaped nuclei (red triangles) observed in the cross sections of dKO aorta on analyzing with transmission electron microscopy. Scale bar represents 10 \u03bcm and asterisk (*) denotes aortic lumen. dKO, double knockout.(TIF)Click here for additional data file.S4 Fign = 3). mRNA levels of the proteins analyzed in immunostaining Click here for additional data file.S5 Fign = 3). R indicates reducing conditions, with 20 mM dithiothreitol, and NR represents nonreducing conditions. The arrow indicates FN monomers. FN, fibronectin; vSMC, vascular smooth muscle cell.Immunoblot of FN using DOC-extracted fractions showed complete absence of FN assembly in 4-OH Tamox-treated vSMCs, as compared to the EtOH-treated cells ((TIF)Click here for additional data file.S1 Data(XLSX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file."}
+{"text": "To examine different features in tumorigenicity of various hiPSCs, 10 commonly available hiPSC lines were subjected to in vivo tumorigenicity testing. Transplanted hiPSC lines showed remarkable variation in tumor incidence, formation latency, and volumes. Most of the tumors formed were classified as immature teratomas. However, no signs of malignancies, such as carcinoma and sarcoma, were recognized in the tumors. Characteristics associated tumorigenicity of hiPSCs were investigated with microarray analysis, karyotype analysis, and whole exome sequencing. Gene expression profiling and pathway analysis supported different features of hiPSC lines in tumorigenicity. hiPSC lines showed chromosomal abnormalities in some lines and 61\u201377 variants of cancer-related genes carrying effective nonsynonymous mutations, which were confirmed in the COSMIC databases. In this study, the chromosomal abnormalities and cancer-related gene mutations observed in hiPSC lines did not lead to the malignancy of tumors derived from hiPSCs. Our results suggest that the potential tumorigenicity risk of hCTPs containing residual undifferentiated hiPSCs is dependent on not only amounts of undifferentiated hiPSCs but also features of the cell lines used as raw materials, a finding that should be considered from the perspective of quality of hCTPs used.Human induced pluripotent stem cells (hiPSCs) represent promising raw materials of human cell-based therapeutic products (hCTPs). As undifferentiated hiPSCs exhibit intrinsic tumorigenicity properties that enable them to form teratomas, hCTPs containing residual undifferentiated hiPSCs may cause tumor formation following transplantation. We first established quantitative and sensitive tumorigenicity testing of hiPSCs dissociated into single cells using NOD/Shi-scid IL2R\u03b3 Practically, several clinical trials and studies using hPSC-derived hCTPs have already started to treat spinal cord injuries, age-related macular degeneration, heart failure, and type I diabetes around the world )2. The engraftment was determined according to progressive nodule growth at the injection site. Mice were euthanized and necropsied when tumors grew greater than 10% of their body weight or when a sign of deconditioning was noted according to the categories of Scientists Center for Animal Welfare (SCAW) . Low power view (\u00d7 1.25) of teratoma represents two or three germ layer components . Higher power view (\u00d7 10) shows mesodermal cartilage and endodermal intestinal tract-like duct (B), ectodermal glial tissues, melanocytes and choroid-like tissues (D), ectodermal glial tissues (F), mesodermal smooth muscle and endodermal intestinal tract-like duct (H), ectodermal choroid-like tissues and immature neuroepithelia (J), ectodermal choroid-like tissues and melanocytes (L), ectodermal stratified squamous epithelia and endodermal duct structures (N), ectodermal glial and neural cells and mesodermal blood vessels (P), endodermal duct structures accompanied with intestinal and respiratory epithelium-like cells (R), and mesodermal smooth muscle and endodermal intestinal tract structures (T).NOG mice were subcutaneously injected with 3 \u00d7 10(PDF)Click here for additional data file.S2 FigA set of 16,454 probes on GeneChip Human Genome U133 Plus 2.0 Array was statistically identified with significantly different expression levels among 10 hiPSC lines . Hierarchical clustering analysis was performed using R version 3.5.1 software.(TIFF)Click here for additional data file.S3 FigTranscript expression of OCT3/4 (A), NANOG (B), SOX2 (C), and LIN28A(D) in 10 hiPSC lines is shown with microarray data. Data are represented as mean \u00b1 SD (n = 3).(TIFF)Click here for additional data file."}
+{"text": "CTCF, which we have shown functions as a tumour suppressor gene. While CTCF is essential for embryonic development, little is known of its absolute requirement in somatic cells and the consequences of CTCF haploinsufficiency. We examined the consequences of CTCF depletion in immortalised human and mouse cells using shRNA knockdown and CRISPR/Cas9 genome editing as well as examined the growth and development of heterozygous Ctcf (Ctcf+/\u2212) mice. We also analysed the impact of CTCF haploinsufficiency by examining gene expression changes in CTCF-altered endometrial carcinoma. Knockdown and CRISPR/Cas9-mediated editing of CTCF reduced the cellular growth and colony-forming ability of K562 cells. CTCF knockdown also induced cell cycle arrest and a pro-survival response to apoptotic insult. However, in p53 shRNA-immortalised Ctcf+/\u2212 MEFs we observed the opposite: increased cellular proliferation, colony formation, cell cycle progression, and decreased survival after apoptotic insult compared to wild-type MEFs. CRISPR/Cas9-mediated targeting in Ctcf+/\u2212 MEFs revealed a predominance of in-frame microdeletions in Ctcf in surviving clones, however protein expression could not be ablated. Examination of CTCF mutations in endometrial cancers showed locus-specific alterations in gene expression due to CTCF haploinsufficiency, in concert with downregulation of tumour suppressor genes and upregulation of estrogen-responsive genes. Depletion of CTCF expression imparts a dramatic negative effect on normal cell function. However, CTCF haploinsufficiency can have growth-promoting effects consistent with known cancer hallmarks in the presence of additional genetic hits. Our results confirm the absolute requirement for CTCF expression in somatic cells and provide definitive evidence of CTCF\u2019s role as a haploinsufficient tumour suppressor gene. CTCF genetic alterations in endometrial cancer indicate that gene dysregulation is a likely consequence of CTCF loss, contributing to, but not solely driving cancer growth.CCCTC-binding factor (CTCF) is a conserved transcription factor that performs diverse roles in transcriptional regulation and chromatin architecture. Cancer genome sequencing reveals diverse acquired mutations in  Ctcf null embryos are unable to implant [Ctcf alleles has highlighted the importance of CTCF availability in somatic tissues. Conditional deletion of CTCF in thymocytes can hamper T-cell differentiation and cell cycle progression, but not ablate T cell function [Ctcf in the limb mesenchyme induces extensive apoptosis during limb development highlighting CTCF\u2019s pro-survival role [Ctcf specifically during early mouse brain development, led to PUMA upregulation and subsequent massive apoptosis [Ctcf heterozygous mice, however, are more prone to the formation of spontaneous cancers, as well those induced by radiation and chemical means [CTCF is a conserved multivalent transcription factor with diverse roles in transcriptional regulation and three-dimensional genome organisation such that it has been called the \u2018master weaver\u2019 protein . CTCF is implant . Tissue-function . Conditival role . Similarpoptosis . Of releal means .CTCF links gene regulation to genomic architecture by co-ordinating DNA looping in concert with cohesin ,8,9. WitCTCF mutations have been identified in breast, prostate and Wilms\u2019 tumours [CTCF [CTCF has been classified as a significantly mutated gene owing to its high frequency of mutation and deletion in endometrial cancer [CTCF mutations are detected in 35% of endometrial carcinomas exhibiting microsatellite instability (MSI), and in 20% of MSI-negative tumours [CTCF mutations were identified in 40% of samples including inactivation of specific zinc fingers (ZFs) of CTCF that would lead to altered DNA binding [CTCF genetic alterations have a pro-tumourigenic effect in endometrial cancer by altering cellular polarity and enhancing cell survival [Our previous studies first demonstrated the growth inhibitory effects of CTCF in vitro  and subs tumours  and acut tumours . Howeverrs [CTCF . CTCF hal cancer . CTCF mu tumours . One rep binding . We sincsurvival .CTCF, whether heterozygous deletion, nonsense, frameshift, or even missense ZF mutations, can all result in CTCF haploinsufficiency. In endometrial cancer, CTCF mRNA transcripts expressed from alleles containing nonsense or frameshift mutations are subjected to nonsense-mediated decay [CTCF haploinsufficiency and IGF2 up-regulation in Wilms\u2019 tumours [CTCF haploinsufficiency on CTCF\u2019s tumour suppressor function has not been previously examined.Genetic lesions in ed decay ,32. Somaed decay , indicat tumours . To dateCTCF haploinsufficiency to reveal in detail the impact of heterozygous loss of CTCF in somatic cells, whole mice and human endometrial cancer. Depletion of CTCF expression in K562 erythroleukaemia cells using shRNA knockdown or CRISPR/Cas9-mediated targeting of CTCF decreased cellular proliferation. In vivo, Ctcf heterozygosity negatively impacted the growth and gross development of mice. However, p53 shRNA-immortalised Ctcf+/\u2212 mouse embryonic fibroblasts (MEFs) were functionally distinct from wild-type (WT) MEFs by exhibiting increased cellular growth and other known cancer hallmarks. Importantly, we were unable to generate Ctcf nullizygous MEFs after CRISPR/Cas9 genome editing confirming that CTCF is absolutely essential for somatic cell viability. Finally, we examined curated human endometrial carcinoma genomic data and observed that CTCF haploinsufficiency contributed to the transcriptional dysregulation of specific loci as well as inducing a unique gene signature in human cancers.In this study we assessed several genetic models of p < 0.0001, p < 0.0001, p < 0.0001), and a concomitant reduction of cells in S (p < 0.0001) and G2/M phases  and a decrease in apoptotic (Annexin V-positive) cells  in sh.CTCF K562 cells compared to non dox-treated cells and sh.control cells Ai,ii. CeCTCF haploinsufficiency has not been definitively modelled in vitro. To address this, we used CRISPR/Cas9-directed genome editing to induce genetic lesions in K562 cells  is shown in CTCF allele, we PCR-amplified the edited region in CTCF, cloned the PCR products and then sequenced them. We detected a mixture of CTCF alleles arising in clones including frameshifts induced by deletion or insertions near the protospacer adjacent motif (PAM) site or in-frame deletions leading to microdeletions in the CTCF protein  mice had smaller mean litter sizes than from normal WT x WT mice (Ctcf+/pgkneo mice being born at sub-Mendelian ratios (~28% and ~24% respectively) compared to WT (Ctcf+/+) mice  from a single litter containing 4 Ctcf+/pgkneo and 3 WT pups. These MEFs were immortalised with a retrovirus encoding stable shRNA knockdown of p53 and then analysed by immunoblot for Ctcf protein expression  with a concomitant increase in G2/M phase (p = 0.0043) (Ctcf+/pgkneo MEFs exhibited a decrease in viability and concomitant increase in Annexin V-positive cells compared to WT cells (p = 0.0002 and p = 0.0005 respectively)  D. We nexctively) E. ImmortCtcf in monoallelic hemizygous Ctcf+/pgkneo MEFs to assess the impact of inducing potentially deleterious Ctcf genetic lesions. Four sgRNAs were designed to target the first coding exon (exon 3) of Ctcf, as well as a control sgRNA targeting the Rosa26 locus  dataset from The Cancer Genome Atlas, which exhibits CTCF genetic alterations in 45 out of 232 patient samples (~19%) [CTCF (deep deletion). Many inactivating nonsense and frameshift mutations in CTCF were found in the notionally diploid population  occurred with mutually exclusivity to CTCF mutations  . GISTIC CTCF gene expression was not significantly decreased in CTCF-altered cancers despite the presence of inactivating mutations , and the long arm of chromosome 20  [p = 2.96 \u00d7 10\u221244) [We analysed RNAseq data available for these endometrial cancer samples and showed that utations . We nextutations D. Howeve, and 20 C. Furtheosome 20 D. TP53 ganalysis . To gainhylation E. Closerme 16q22 . Importal cancer ,39, were \u00d7 10\u22126)  as well CTCF was identified as one of nearly 300 haploinsufficient genes in humans based on published literature or a clear association with genetic disease [CTCF  causes intellectual disability in humans; now classified as autosomal dominant mental retardation  [CTCF haploinsufficiency with cancer have yet to be elucidated.Haploinsufficiency arises when only a single functional copy of a gene is inadequate for normal cell function . CTCF wa disease . Herein #615502) ,44,45. T#615502)  and hypeNumerous studies over more than a decade using siRNA or shRNA knockdown of CTCF have only been suggestive of CTCF\u2019s essential role in normal cell function. Typically, such experiments are short term, do not fully ablate CTCF expression and cells remain viable. Similarly, our shRNA knockdown of CTCF in K562 cells showed that cell proliferation and clonogenic capacity was decreased, cell survival after UV insult was increased, and cells underwent growth arrest. Paradoxically, after CTCF knockdown here, and in corroboration of our previous CTCF overexpression study  we obserCTCF heterozygous MCF10A clones generated by CRISPR exhibited similar proliferation rates compared to control, though cells were slower to repair double-stranded DNA breaks [More recently CRISPR/Cas9 mediated genome editing techniques have given tremendous insight into CTCF\u2019s roles in higher-order chromatin organisation. Most studies have focussed on rewiring CTCF-mediated chromatin interactions such as disrupting TAD boundaries  and switA breaks . SilenciA breaks . CTCF in K562 cells and Ctcf hemizygous MEFs. It was clear that despite efficient editing of CTCF alleles in hypotriploid K562 cells, haploinsufficient levels of CTCF protein expression were still maintained in surviving clones. Edited cells exhibited reduced cell proliferation and colony-forming ability consistent with our shRNA knockdown of CTCF in K562 cells. However, in Ctcf hemizygous MEFs that only contain one coding allele of Ctcf, we were unable to completely abolish Ctcf protein expression using CRISPR. Accordingly, in surviving clones we detected a high incidence of in-frame microdeletions in Ctcf. As these microdeletions occur in the intrinsically disordered N-terminus we do not expect them to significantly impact Ctcf function. Induced frameshift deletions were also likely to produce truncated CTCF proteins initiating from alternate in-frame ATG start codons within the N-terminus. These results confirm that CTCF is absolutely required for somatic cell viability and that CTCF cannot be completely inactivated in cells. Interestingly, residual CTCF protein levels can be depleted to minimal amounts in the cell before viability is significantly impacted. Targeted degradation of CTCF in mouse embryonic stem (ES) cells using an auxin-inducible degron system highlighted that endogenous CTCF protein levels could be decreased by up to 99% for at least 2 d duration without a significant impact on cell proliferation or viability [CTCF-null ES cells can progress to the blastocyst stage (E3.5) purely via retention of maternal CTCF mRNA, but exhibit peri-implantation lethality by E4.5\u2013E5.5 [Our strategy was to examine the essentiality of CTCF in somatic cells by CRISPR/Cas9 targeting of iability . Acute diability . CTCF-nuCtcf mice being born at sub-Mendelian rates (24\u201328%) compared to WT littermates, which was previously suggested by a study using mice with a conditionally targeted Ctcf allele, but was not thoroughly quantified or statistically verified [Ctcf hemizygous mice are born at normal Mendelian rates on a mixed C57Bl/6J:129SvJ background [Ctcf genetic deficiency studies in mice. Ctcf heterozygosity also impaired normal mouse weight gain during adult development for up to seven weeks, and which then remained constant in aged male mice. As these mice were fed a normal chow diet, we could not determine whether Ctcf heterozygosity impairs body weight control, metabolism or nutrient signaling pathways. In future studies we will examine glucose and insulin levels in plasma after feeding-fasting cycles, body tissue composition using dual energy X-ray absorption as well as studying the impact of different chow compositions on Ctcf heterozygous mouse development.We have also shown that CTCF has a dose-dependent impact on embryonic development, as even haploinsufficient levels of Ctcf protein affected embryonic development in mice. We observed heterozygous verified . InteresCTCF hemizygous mice are more susceptible than WT mice to spontaneous cancer development, as well as radiation- and chemically-induced cancers [Ctcf+/\u2212 mice compared to WT mice also exhibit increased aggressiveness in terms of invasion, metastatic dissemination and mixed epithelial/mesenchymal differentiation, confirming CTCF as a haploinsufficient tumour suppressor [Ctcf+/\u2212 MEFs support these conclusions. Furthermore, CTCF depletion can increase genomic instability by hindering homologous recombination repair of DNA double-stranded breaks and cause hypersensitivity to DNA damage [Ctcf+/\u2212 MEFs is consistent with impaired DNA repair. These data may explain why CTCF haploinsufficient MEFs in the context of additional genetic hits to p53, exhibited a number of cancer hallmarks.  cancers . Tumoursppressor . Our curA damage . As a reCTCF somatic mutations occurred in POLE ultramutated, MSI hypermutated and copy-number low cancers, whilst copy-number high cancers with a serous-like pathology harboured TP53 mutations [CTCF and TP53 mutations in endometrial cancer. CTCF haploinsufficiency due to CTCF copy loss results in poorer survival outcomes in patients with endometrioid UCEC [CTCF haploinsufficient loss imparts in endometrial cancer via transcriptional regulation. CTCF haploinsufficiency results in differential regulation of genes located at specific loci, particularly on chromosomes 17 and 20, including cytoband 17p13.1 containing the TP53 locus. Whilst this is not reflected in a significant change in TP53 mRNA expression once accounting for the TP53 mutation status of patient samples, genes involved in p53-mediated signal transduction are impacted. Genes involved in DNA methylation were also differentially regulated in CTCF-altered endometrial cancers. Molecular genetic analysis of Ctcf+/\u2212 mice showed DNA methylation instability compared to wild type mice [Ctcf hemizygosity was restricted to specific loci with regions within a 2 kb window surrounding divergent CpGs exhibiting a generalised pattern of DNA hypermethylation [CTCF mutations exhibiting an intellectual disability, specific CTCF sites exhibited DNA hypermethylation [CTCF-altered endometrial cancers. The TCGA UCEC cohort consisting of low- and high-grade endometrioid carcinomas and serous tumours were genetically defined into four categories . The majutations . This waoid UCEC , as welloid UCEC . Our anaype mice . Divergehylation . In humahylation . This epCTCF-altered endometrial cancers is the downregulation of tumour suppressor genes including PIK3CA, CDKN2A, CDH6 and IGF2BP2. The tumour suppressor PIK3CA is ranked fifth after CTCF in the most frequently mutated genes in UCEC [CDKN2A is downregulated in POLE, MSI, and copy-number low cancers compared to high-copy number cancers [IGF2BP2, which was the most down-regulated gene in CTCF-altered endometrial cancer, was identified as a candidate tumour suppressor gene in a pan-cancer screen for homozygously deleted genes [One possible hallmark of  cancers . CDH6, w cancers , has bee cancers . IGF2BP2ed genes . Loss ofed genes .CTCF-altered endometrial cancers is the upregulation of estrogen-responsive genes, which includes KIAA1324, MLPH, MSX2, SPDEF, TFF3 and PIGR. CTCF mutations do not occur in a tumour type-specific manner, but rather they define a subset of hormone-responsive cancers [CTCF haploinsufficient endometrial tumours, FOXA1/ER interactions with chromatin may increase leading to upregulation of estrogen-responsive genes. KIAA1324, which is a positive regulator of the autophagy pathway and may protect cells from cell death, was the most upregulated gene in CTCF-altered endometrial cancer [CTCF-altered cancers, namely SPDEF, TFF3 and PIGR, are also components of these gene signatures, indicating that loss of CTCF could be an important factor determining endometrial cancer progression and pathology.A second hallmark of  cancers . CTCF is cancers ,54. Therl cancer . KIAA132l cancer  and is al cancer ,40. Othev/v), penicillin (100 U/mL) and streptomycin (100 \u03bcg/mL). All human cell lines were authenticated by short tandem repeat profiling . Human erythroid leukaemia (K562) cells were grown in RPM1 1640 medium while human embryonic kidney (HEK293T) and mouse embryonic fibroblast cells were cultured in DMEM. Basal media were supplemented with 10% FCS  FCS/DMEM at 1/100 th of the original volume. Adherent cells (1\u20135 \u00d7 105/well) were seeded in six-well plates before addition of fresh medium containing viral supernatant (~5 \u00d7 105 transducing units) and Polybrene  and \u2018spin-oculated\u2019 for 90 min at 1500 rpm. The supernatant was replaced with medium 12 h post-transduction and fluorescent cells were purified 24 h later by fluorescence activated cell sorting  using a FACS Influx . K562 cells (~5 \u00d7 105/mL) in 1 mL medium with 4 \u03bcg/mL Polybrene were placed in a 5 mL capped FACS tube and transduced with viral supernatant for 90 min by \u2018spin-oculation\u2019. The cells were resuspended and incubated at 37 \u00b0C for 4 h before removal of viral supernatant. For in vitro assays, cells were either plated out immediately or allowed to recover after sorting for 48\u201372 h in medium containing 100 \u03bcg/mL Normocin .Viral supernatants were produced by calcium phosphate transfection of HEK293T cells: with pJK3, pCMVTat and pL-VSV-G packaging plasmids used to produce retroviruses; and pRSV-Rev, pMDLg/p.rre and pMD2.VSV-G used to package lentiviruses. Viral supernatants collected after 24\u201348 h were 0.45 \u03bcM-filtered and snap-frozen or concentrated by ultracentrifugation for 2 h at 20,000 rpm in a SW28 Beckman rotor. Viral supernatant was resuspended on ice in 10% (CTCF and mouse Ctcf (exon 3) were designed using the Zhang lab CRISPR design tool (crispr.mit.edu). SgRNAs targeting the adeno-associated virus integration site 1 (AAVS1) and the Rosa26 locus were used as negative control guides in human and mouse cells respectively. We used lentiviral vectors to co-express a sgRNA with mCherry, as well as a 3XFLAG-tagged Cas9 nuclease 2A-peptide linked to eGFP. Transduced cells were FACS-enriched for eGFP+mCherry+ cells after 48 h from which gDNA was extracted from pools after 6 d for a T7 Endonuclease I assay to detect Cas9-directed DNA cleavage. We also isolated single eGFP+mCherry+ cells by FACS into 96-well plates and expanded them before isolation of genomic DNA and whole cell lysates. Genomic DNA was isolated using the Purelink Genomic DNA Extraction kit (ThermoFisher) and PCR primers were used to amplify across the targeted region . Amplicons were ligated into pGEM-T-Easy  and then transformed into E. coli. Each clonal amplicon was then confirmed using Sanger sequencing in both directions.SgRNAs targeting the first coding exon of human gion see . PCR ampCtcf+/\u2212 mice were obtained on a mixed C57Bl/6:129SvJ background from the Fred Hutchinson Cancer Research Centre  [Ctcf allele replaced with a loxP-flanked cassette containing a pgk promoter and neo gene, designated Ctcf+/pgkneo (Ctcfpgkneo/pgkneo) exhibit embryonic lethality prior to embryo implantation [Ctcf+/pgkneo male mice and C57Bl/6 females and female mice were checked daily for vaginal plugs. At 13.5 dpc, pregnant females were euthanised by CO2 asphyxiation. The uterine horns were removed and the foetuses released whilst immersed in PBS. Each pup was removed from its amniotic sac, decapitated and fetal liver removed. The carcasses were minced with a scalpel and then incubated in trypsin/EDTA solution . The tissue fragments were triturated to break up clumps, and then concentrated using centrifugation to remove trypsin. Fresh trypsin was added to create a homogeneous solution of cellular material. The trypsin was inactivated in excess DMEM medium containing 10% (v/v) FCS and then the centrifugation step repeated. The MEFs were plated in 15 cm plates and allowed to grow for 2\u20133 d until there were sufficient adherent cells for cryopreservation. The remaining MEFs were transduced with MSCVp53.1224 retroviral supernatant for immortalisation. Cells were selected in 50 \u03bcg/mL hygromycin  to enrich for immortalised MEFs and then frozen down after 1\u20132 passages (P2-P3 MEFs). Ctcf+/pgkneo mice and MEFs were genotyped according to primers listed in All animal experiments were performed in accordance with an approved institutional animal ethics protocol from the Royal Prince Alfred Hospital Animal Welfare Committee (SSWAHS #2013/046 approved 5 August 2013). +/pgkneo A. Mice hv/v) Triton X-100, 0.1% (v/v) SDS, 0.5% (w/v) sodium deoxycholate, and EDTA-free protease inhibitor cocktail , prior to separation using denaturing sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Proteins were transferred onto PVDF membranes in a semi-dry transfer apparatus before immunoblotting. Membranes were blocked in PBS/0.1% (v/v) Tween 20 containing 20% (v/v) BlokHen  or PBST containing 0.3% (w/v) BSA, 1% (w/v) polyvinylpyrrolidone and 1% (v/v) PEG (mw 3350). Protein expression was detected using primary antibodies followed by washing and staining with appropriate secondary antibodies conjugated to horseradish peroxidase (HRP). The HRP substrate SuperSignal\u00ae Chemiluminescent Substrate (Pierce) was detected on a Kodak Imagestation 4000R Pro  or BioRad Chemidoc Touch . Blots were stripped with ReBlot Plus  prior to re-probing with protein loading control antibodies. Densitometric analysis of bands from three independent blots was performed using ImageJ .Protein extracts were prepared with cell lysis buffer containing 20 mM Tris-HCl (pH 8), 150 mM NaCl, 1% (5/well in a 12-well plate) were plated in triplicate. The following day, medium was removed from attached cells and replaced with PBS. Plates with lids removed were placed in a Stratalinker UV Crosslinker  and exposed to UVC irradiation  and allowed to recover for 18 h. Cells were harvested and stained with anti-Annexin V-APC  according to the manufacturer\u2019s protocol and with propidium iodide (PI) solution . Cells were analysed on a Fortessa flow cytometer  with analysis performed using FlowJo 9.7.6 software . Cell viability was measured after addition of PI and then analysed by flow cytometry. The viable population represents the Annexin V-PI- cells; the apoptotic population represents the Annexin V+PI\u2212 and Annexin V+PI+ cells combined. Cell proliferation was assessed by 3--2,5-diphenyltetrazolium bromide (MTT) assay . Adherent cells (1000/well) or suspension cells (5000/well) were plated in triplicate in a 96-well plate and proliferation was assessed over 4 d by the addition of MTT at 37 \u00b0C overnight. The reaction was quenched with isopropanol/HCl and absorbance measured at 572 nm using a Polarstar Omega plate reader . The clonogenic capacity of adherent cells was measured by plating 1000 cells/10 cm plate in triplicate and incubating for 8\u201310 d. Cells were washed with PBS, fixed with ice-cold methanol and stained with Giemsa Stain  diluted 1:20 in triple-distilled water before scoring. The clonogenic capacity of K562 cells was measured by plating 5000 cells diluted in Iscove\u2019s Modified Dulbecco Medium  containing 3 mL Methocult GF H4230  onto 35 mm gridded plates in triplicate and incubating for 8\u201310 d. To assess UV-induced apoptosis, cells (1 \u00d7 10v/v) Triton X-100 and RNase-A (200 \u03bcg/mL). Cells were incubated for 15 min in the dark at room temperature and analysed on a Canto-II flow cytometer . Cell cycle analysis was undertaken using FlowJo 9.7.6 cell cycle modelling software  by applying the Dean-Jett-Fox algorithm. For cell cycle analysis by DNA content, cells were washed with PBS prior to fixation in ice-cold 70% ethanol and stored overnight at 4 \u00b0C. Post-fixation, cells were washed twice with PBS to remove all traces of ethanol prior to staining with a solution containing PI (20 \u03bcg/mL), 0.1% (p) and Benjamini-Hochberg adjusted p-values (q). CTCF-altered cancers included those with somatic mutations  and deep deletions (n = 45). Normal CTCF included shallow deletions and non-mutant samples (n = 178). The CTCF-altered gene signature used in subsequent analysis includes all differentially expressed genes (q < 0.05).Gene expression and somatic mutation data from the uterine corpus endometrial carcinoma dataset  was downCTCF using CRISPR the inability to obtain complete ablation of CTCF expression reinforces its requirement. In all cases, cellular fitness in CTCF-targeted cells was compromised leading to surviving cells compensating with reduced CTCF protein expression or truncated CTCF protein variants. Consequently cell proliferation, colony-forming ability and cycling cells were reduced. However, in the presence of additional genetic hits, such as in p53, CTCF haploinsufficient cells exhibited known cancer hallmarks, namely increased proliferation and reduced cell cycle control. In human endometrial cancer datasets, we identified a unique gene signature in CTCF haploinsufficient cancers arising from differential gene expression at specific loci. Downregulation of tumour suppressor genes and upregulation of estrogen-responsive genes may be a molecular feature of CTCF-altered endometrial cancers. Our study clearly demonstrates that CTCF is a haploinsufficient tumour suppressor gene that is essential for somatic cell viability and protects against cancer. As the master of weaver of the genome CTCF plays an essential role in chromatin organisation, the full impact of CTCF haploinsufficiency on three-dimensional chromatin architecture remains to be elucidated.We examined CTCF essentiality and haploinsufficiency in somatic cells and mice using various molecular genetic techniques and models. Despite achieving efficient genome editing of"}
+{"text": "To describe characteristics of choroidal osteomas (CO), using ocular ultrasound, fluorescein angiography, ultra-widefield retinal imaging, ultra-widefield autofluorescence, optical coherence tomography, enhanced-depth-imaging OCT, and OCT angiography (OCT-A).Retrospective, observational case series study. Clinical records from patients with diagnosis of CO who underwent complete imaging evaluation were analyzed.Sixteen eyes from 11 patients were included. Mean patient age was 33.4\u00a0years (range 20\u201361), 72.7% were female, 100% were Hispanic, and 54.5% had unilateral CO. Median visual acuity was 20/150 (range 20/20\u20132000). CO was completely calcified in 25%, partially decalcified in 50%, and decalcified in 25%. Other features included choroidal neovascularization (18.75%), focal choroidal excavation (12.5%), choroidal depression associated to decalcification (18.75%), thinning of outer retina and photoreceptor layers over decalcified tumor (75%). Decreased fluorescence on FAF was observed in decalcified regions while relatively preserved fluorescence was observed in calcified regions.Nowadays, diagnostic tests provide important information about each stage of choroidal osteoma. Progressive decalcification of the tumor might have a common pathogenic role for development of FCE or choroidal depression. OCT-A/FA proved to be valuable tools for detection of CNV in patients with CO. Choroidal osteoma (CO) is a rare benign tumor of the choroid, which is composed of mature bone (trabecular and/or compact) and vascular channels \u20134. Gass CO is typically unilateral (80% of cases) and it usually affects young healthy female patients . It arisOver time, ocular ultrasound (US), fluorescein angiography (FA) and optical coherence tomography (OCT) have been widely used for diagnosis and follow-up of CO. Enhanced depth imaging OCT (EDI-OCT) is a recent addition of OCT, that has been able to reveal the presence of bone lamella, tubular lamella with optically empty center, vascular channels and trabecular bone in patients with CO , 9.In patients with CO, OCT angiography (OCT-A) is a new non-invasive imaging technique that employs motion contrast from blood flow to generate high-resolution angiographic images, in patients with CO has been able to show a dense irregular vascular network in the outer retinal layer (ORL) and choroid capillary layers . On the The aim of this study is to describe the morphology of CO using a multimodal image system.The clinical records of patients with a diagnosis of choroidal osteoma who had undergone multimodal fundus imaging on the retina service at Asociaci\u00f3n para Evitar la Ceguera en M\u00e9xico were reviewed. The diagnosis was based on the presence of a yellow-white to orange-red mass deep to the RPE and bone density on ultrasonography. Institutional review board approval was obtained for this retrospective study.Patient data were extracted from medical records and included age at diagnosis, gender , chief complaint, ocular comorbidities. Ophthalmic features included best-corrected visual acuity (BCVA), tumor laterality , location .Multimodal imaging analysis included ultrasonography (US), fluorescein angiography (FA), ultra-widefield retinal imaging (UWF), ultra-widefield autofluorescence (UWF-FAF), optical coherence tomography (OCT) and OCT angiography (OCT-A).Enhanced depth imaging optical coherence tomography , data included tumor surface configuration (flat or depressed), effects of tumor on overlying retina . One independent physician manually measured osteoma thickness with a caliper function through the epicenter of the tumor.Ultra-wide field color fundus photograph and ultra-widefield fundus autofluorescence  data included tumor location , tumor color , and fundus autofluorescence pattern. Decalcification Calcification  was defined as pale areas within the osteoma, RPE thinning and visibility of underlying choroidal vessels.Fluorescein angiography (FA)  data included presence or absence of CNV. OCT-A images were analyzed in patients in whom FA was performed and correlated with the presence or absence of CNV .There were 16 eyes in 11 patients with choroidal osteoma included in this study. The demographic and clinical characteristics are summarized in Table\u00a0Initial symptoms included blurred vision , metamorphopsia , asymptomatic . Ocular conditions that accompanied the diagnosis of CO were keratoconus (2 patients) and central serous chorioretinopathy (1 patient). Visual acuity was 20/20\u201320/50 in 7 eyes (44%), 20/60\u201320/150 in 2 eyes (12%), 20/200 or worse in 7 eyes (44%). Poor visual acuity (20/200 or worse) was related to foveal photoreceptor loss overlying deossified osteoma (n\u2009=\u20096), subfoveal choroid neovascular membrane (n\u2009=\u20091), keratoconus (n\u2009=\u20091).Five patients (45.5%) had bilateral CO; while the other 54.5% had unilateral CO. The osteoma was completely calcified in 4 eyes (25%), partially decalcified in 8 eyes (50%) and decalcified in 4 eyes (25%). Tumor location was subfoveal in 12 eyes (75%); extrafoveal in 4 eyes (25%).CO showed different FAF patterns, which we classified as normal autofluorescence , predominantly hyper-AF (37.5%) and predominantly hypo-AF (56.25%); decreased fluorescence on FAF was observed in decalcified tumoral regions while relatively preserved fluorescence was observed in calcified regions. Patients with worse visual acuity (\u2264\u200920/200) presented predominantly hypo-AF pattern .OCT data demonstrated a mean central foveal thickness of 265.5\u00a0\u03bcm (range 101\u2013599\u00a0\u03bcm), a mean subfoveal choroidal thickness of 498.17\u00a0\u03bcm (range 288\u2013736), and a mean central tumor thickness of 574.86\u00a0\u03bcm (range 246\u20131084). Patients with decalcified portion of tumor displayed and overlying thinned inner retinal layers in 4 eyes (25%), thinned outer retina with thinned to absent photoreceptor layer in 12 eyes (75%), and overlying RPE hyperplasia in 3 eyes (25%).Seven eyes with clinical suspicion of choroidal CNV were imaged with FA and OCT-A. Leakage of fluorescein dye was present in 2 patients ; OCT-A made evident the location of abnormal vascular network in outer retina and choriocapillaris segmentation. The presence of CNV was excluded in 4 patients using FA & OCT-A.OCT-A analysis showed the following 4 patterns: absence of vascular flow within tumor (6.25%), dark background where decalcification was present (12.5%), vascular network within tumor (25%), and presence of a neovascular membrane (18.75%).Choroidal osteomas may demonstrate decalcification, CNV, retinal pigment epithelium (RPE) alterations and vision loss . PatientChoroidal osteoma is an ossifying tumor involving the choroid, its natural course may include tumor growth, calcification and decalcification; visual acuity depends on choroidal neovascularization and retinal changes associated to decalcification . DuratioIn our series, the mean age at diagnosis was 33\u00a0years and females represented 72.7%, however 45.5% of our patients were bilateral, this patients showed osteomas located in the macular area with extension beyond the vascular arcades and showed RPE alterations due to osteoma decalcification.Patients witth CNV whose medical records had FA and OCT-A also where evaluated, both have good correlation in determining the site of neovascularization.Choroidal excavations observed in this series correlate with previous descriptions made by Jampol et al. and Wakabayashi et al. , 16. TabAlthough several authors have already described clinical and OCT characteristics of CO, to our best knowledge this is the first case series report of multimodal imaging findings of CO in Hispanic patients. Because this is a rare pathology, the number of cases reported in the literature is scarce, and this also constituted a limitation to our study. However, we believe these findings can deepen the information about the behavior of this uncommon tumor."}
+{"text": "PCDH19), which is on the X-chromosome, cause the brain disease Epilepsy in Females with Mental Retardation (EFMR). EFMR is also often associated with autism-like symptoms. In mice and humans, epilepsy occurs only in heterozygous females who have a mixture of PCDH19 wild-type (WT) and mutant cells caused by random X-inactivation; it does not occur in hemizygous PCDH19 mutant males. This unique inheritance pattern strongly suggests the underlying disease mechanism operates via interference between WT and mutant cells rather than being a result of complete loss of PCDH19 functions. Although it remains unclear whether the other symptoms of EFMR also conform to this unique genotype-phenotype relationship, PCDH19 mutant males were recently reported to demonstrate autism-like symptoms. We, therefore, used a Pcdh19 knockout (KO) mouse model to ask whether a complete lack of PCDH19 causes autism-like behaviors. Consistent with the autism observed in EFMR females, we found Pcdh19 heterozygous KO female mice (with mosaic expression of PCDH19) show defects in sociability in the 3-chamber test. Surprisingly, hemizygous Pcdh19 KO male mice (without any PCDH19 expression) exhibit impaired sociability in the 3-chamber test and reduced social interactions in the reciprocal social interaction test. We also observed that, compared to WT mice, mutant mice display more repetitive behaviors, including self-grooming and rearing. These findings indicate that hemizygous Pcdh19 KO male mice show autism-like phenotypes.Mutations in protocadherin 19 ( PCDH19) [PCDH19 mutations, whereas males hemizygous for PCDH19 mutations are unaffected carriers [PCDH19 is X-linked, it is subject to random X-inactivation, producing mosaic expression in heterozygous mutant females [PCDH19 mutations supports the idea that the disease mechanism is related to mosaic expression of PCDH19 [PCDH19 mutation [Epilepsy in Females with Mental Retardation (EFMR) is reportedly caused by mutations  in the X-linked gene protocadherin 19 (PCDH19) \u20134. As thcarriers . Becausef PCDH19 , 7. Thismutation . This unmutation .Pcdh19 heterozygous KO female mice that was well-correlated with seizure-like activities as recorded by electrocorticogram. This result provided the first experimental evidence of cellular interference as a key pathogenic mechanism in EFMR. It is unclear, however, whether autism spectrum disorder (ASD) in EFMR also conforms to both this unusual inheritance pattern and cellular interference mechanism. It is notable that recent human studies identified some males with ASD who have mutations in PCDH19 [PCDH19 mutations may also play a role in producing the symptoms of males with ASD via mechanisms other than cellular interference. In this study, we investigate this possibility using a Pcdh19 KO mouse model.Recently, Pederick et al.  demonstrn PCDH19 , 10, 11,Pcdh19 KO female mice show an abnormal \u201ctiger-striped\u201d pattern of segregation between PCDH19(+) and PCDH19(\u2212) cells in the brain  reporter gene on the X-chromosome where the Pcdh19 gene was deleted  do not show any preference toward exploring a novel mouse (S1) versus a non-social novel object (O) in the 3-chamber test (the sociability test). This suggests heterozygous Pcdh19 KO female mice recapitulate the autism-like symptoms of female EFMR patients. In the social novelty test, in which we measured preference toward a familiar mouse (S1) and a novel mouse (S2), we found the heterozygous Pcdh19 KO mice (XLacZ/X) spend more time exploring the novel mouse (S2)  mice spend significantly more time sniffing a non-social novel object (O) rather than a novel mouse (S1), suggesting abnormal sociality. Both hemizygous males and controls, however, show similar preference towards a novel mouse (S2) in the social novelty test  mice. We found they spend significantly less time interacting with a stranger mouse than WT (X/Y) mice do  mice show increased repetitive behavior\u2014another autism-like phenotype\u2014we monitored their rearing and stereotyped grooming behaviors. We found Pcdh19 XLacZ/Y male mice spend more time rearing and self-grooming  mice show autism-like behaviors.We next examined the male mice to determine whether they also show any social impairment. In the 3-chamber sociability test, we found male Pcdh19 causes autism-like behaviors in male mice, but considering the fact that the abnormal segregation pattern occurs only in the brain of female heterozygous Pcdh19 KO mice [Pcdh19 male KO mice. PCDH19 regulates intracellular binding proteins like NONO and the GABAA receptor alpha subunits [We do not yet know how the complete loss of  KO mice , but notsubunits , 15. Hensubunits . In factPcdh19 mutations are not subject to the same genotype-phenotype relationship observed in epileptic symptoms of EFMR. From this finding, we postulate that both mosaic expression of PCDH19 and PCDH19 insufficiency contribute to the pathogenesis of EFMR. Considering the fact that male patients affected by mosaic PCDH19 mutations also show autism [Pcdh19 deletions will help address the question of whether both mosaic loss and complete loss of PCDH19 result in autism-like behaviors.This is the first report showing, in genetically modified mice, that autism-like behaviors induced by w autism , the indAdditional file 1. Materials and Methods.Additional file 2: Figure S1.Pcdh19 heterozygous KO female mice display autistic-like behaviors in the 3-chamber sociability test."}
+{"text": "Age is the strongest risk factor for AD, and the prevalence of AD among older adults necessitates investigation into preventable risk factors. 25-hydroxyvitamin D [25(OH)D] deficiency is more prevalent in older adults than other age demographics. Research shows a strong correlation between deficient 25(OH)D serum levels (\u226420ng/ml) and AD diagnosis. The association with insufficient (\u226430 ng/ml) levels remains unclear. Older adults (age > 65 yo) of five LTC communities in Texas participated in the cross-sectional study. One-year medical history and demographics were abstracted from medical records using double-blinded data abstraction and entry. Blood draws measured 25(OH)D serum levels. Adjusted logistic regression models examined if insufficient 25(OH)D serum levels (\u226430 ng/ml) are associated with AD diagnosis. Confounders were total daily vitamin D supplementation, BMI, race, gender, age, years in community, and diagnosis of liver and renal disease. Participants  consisted of 63% female and 89% Caucasian. Fifty five percent had insufficient serum 25(OH)D levels , and 20% had diagnosis of AD. 25% had both insufficient serum levels and AD, while 12.6% had adequate serum levels and AD. Those with insufficient 25(OH)D serum levels had elevated odds  of having AD after adjusting for confounders. Insufficient serum 25(OH)D levels (\u226430 ng/ml) are associated with increased diagnoses of AD, indicating the importance of adequate levels among LTC residents."}
+{"text": "Nature Communications 10.1038/ncomms15773, published online 12 June 2017Correction to: This Article contains an error in Fig."}
+{"text": "Influenza virus causes a heterogeneous respiratory infectious disease ranging from self-limiting symptoms to non-resolving pathology in the lungs. Worldwide, seasonal influenza infections claim ~500,000 lives annually. Recent reports describe pathologic pulmonary sequelae that result in remodeling the architecture of lung parenchyma following respiratory infections. These dysfunctional recovery processes that disproportionately impact the elderly have been understudied. Macrophages are involved in tissue remodeling and are critical for survival of severe influenza infection. Here, we found intrinsic deficiency of the nuclear receptor PPAR-\u03b3 in myeloid cells delayed the resolution of pulmonary inflammation following influenza infection. Mice with myeloid cell-specific PPAR-\u03b3 deficiency subsequently presented with increased influenza-induced deposition of pulmonary collagen compared to control mice. This dysfunctional lung remodeling was progressive and sustained for at least 3 months following infection of mice with myeloid PPAR-\u03b3 deficiency. These progressive changes were accompanied by a pro-fibrotic gene signature from lung macrophages and preceded by deficiencies in activation of genes involved with damage repair. Importantly similar aberrant gene expression patterns were also found in a secondary analysis of a study where macrophages were isolated from patients with fibrotic interstitial lung disease. Quite unexpectedly, mice with PPAR-\u03b3 deficient macrophages were more resistant to bleomycin-induced weight loss whereas extracellular matrix deposition was unaffected compared to controls. Therefore PPAR-\u03b3 expression in macrophages may be a pathogen-specific limiter of organ recovery rather than a ubiquitous effector pathway in response to generic damage. Influenza virus infects 5\u201310% of adults and 20\u201330% of children worldwide . A long-Respiratory viruses, including influenza, have indeed been shown to cause abnormal remodeling of lung parenchyma dependent on the severity of infection , 16\u201318. The innate immune system responds to damage- and pathogen-associated molecular patterns (DAMPs and PAMPs) to simultaneously initiate anti-microbial defense, immune-response resolution, and repair mechanisms , 20\u201322. PPAR-\u03b3 is a member of the nuclear hormone receptor superfamily. It is a lipid-sensing nuclear transcription factor with many intracellular ligands, including essential fatty acids and eicosanoids. PPAR-\u03b3 is known to regulate downstream gene expression mediating lipid storage and glucose homeostasis, cell growth, proliferation, and differentiation , 34. OutHere, we demonstrate that myeloid cell PPAR-\u03b3 is important for recovery of influenza- induced injury. Whereas inflammatory and repair responses were largely resolved in wild type (WT) mice 30 days post-infection, they are sustained and delayed in myeloid PPAR-\u03b3 deficient mice. Subsequently, 60 and 90 days post-infection lungs from animals with PPAR-\u03b3 deficient macrophages exhibited a pro-fibrotic gene signature coupled with increased collagen deposition compared to wild type lungs. These findings of pro-fibrosis and pro-inflammatory signatures aligned well with macrophages from pulmonary fibrosis patients, who experience non-resolving progressive lung remodeling. However, mice with the same genetic defect exhibited enhanced recovery from bleomycin induced weight loss, with no effects on collagen deposition during the resolution phase of bleomycin-induced fibrosis. Thus, expression of PPAR-\u03b3 in macrophages limits pathogenic influenza-induced lung remodeling. Our data indicate existing agonists of PPAR-\u03b3 may alter the severity of influenza disease in the elderly that disproportionately experience long-term complications from seasonal flu infections.Ppargfl/fl, were purchased from the Jackson Laboratory and bred in house. Pparg\u0394Lyz2 (PPAR-\u03b3 cKO) mice were generated by crossing Ppargfl/fl (WT) mice with Lyz2-cre mice. All mice housed in a specific pathogen-free environment. For influenza virus infection, influenza A/PR8/34 strain (~200 pfu/mouse) was diluted in FBS-free DMEM media (Corning) on ice and inoculated in ketamine-anesthetized mice through intranasal route as described before , 38Pparg WT mice . To exam WT mice . Since PcKO mice . Howeverrophages . We nextnfection . Striking injury . Since pg injury . Togethe+/ly6G-/CD64+/MerTK+) from WT and myeloid PPAR-\u03b3 deficient mice at day 30 p.i. (isolated from pooled 3\u20134 mice/group/experiment)   , and exarophages . Furthernd Ctgf)  and enhand Timp1 . In accond Timp1 . Thus, lCcl2), growth factor (Pdgfa), and fibrosis-associated gene expression  in macrophages from human IPF patients versus healthy control (Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic lung disease of unknown etiology. The roles of macrophages in IPF development and/or pathogenesis have been increasingly appreciated , 30. How control . The parTo further assess the effect of myeloid deficiency of PPAR-\u03b3 on recovery following influenza infection, we examined lesions and collagen deposition in the lung tissue at 60 days p.i. H&E staining of lung tissue sections revealed sustained inflammation and damage from mice with PPAR-\u03b3 deficient macrophages compared to those of WT lungs that were largely resolved in these regards at 60 days p.i. . At thisTo examine if the PPAR-\u03b3 signaling pathway in macrophages is involved in other damage induced pro-fibrotic responses, we compared the responses induced by intratracheal instillation of bleomycin between wild type and PPAR-\u03b3 cKO mice. In contrast to the enhanced weight loss observed in PPAR-\u03b3 cKO mice following influenza virus infection, we found that myeloid PPAR-\u03b3 deficiency resulted in decreased host morbidity following bleomycin inoculation . These dEmerging evidence has suggested that acute respiratory viral infections can cause chronic disease sequela including fibrotic responses months following the clearance of infectious viruses \u20136. LikewArg1 and Retnla (encodes Relm\u03b1) expression following influenza exposure [Arg1 expression in lung macrophages at 30 days post influenza infection. Thus, it is likely that macrophage PPAR-\u03b3 expression suppresses pulmonary fibrosis independent of M1 or M2 polarization. Indeed, emerging evidence has suggested that a dichotomous stratification of macrophage phenotypes (M1 versus M2) oversimplifies the functional heterogeneity of these highly plastic cells [The roles of macrophage in regulating the development of tissue fibrosis have been well-established. Particularly, alternative-activated macrophages (M2) have been demonstrated to promote fibrosis development in multi-organs including the lungs , 30. PPAexposure . Likely,ic cells , 53, 54.Il1b and Ccl2 expression [Besides the roles of macrophage polarization in fibrosis development, recent data have also suggested important roles of recruited monocyte-derived macrophages in fibrosis development . Monocytpression , suggestpression , 58. ThuInterestingly, the current study is one of multiple reports that has now identified a beneficial role for PPAR-\u03b3 in macrophages following influenza virus infection of mice ,38. ThisBleomycin is a small-molecule used to experimentally induce severe, but reversible fibrosis of the lung parenchyma. Respiratory epithelial cells are susceptible to bleomycin resulting in apoptosis following damage of genomic DNA and ensuing inflammation , 62. AftS1 Fig(TIF)Click here for additional data file."}
+{"text": "OBJECTIVES/SPECIFIC AIMS: We aimed to develop an assay to measure new protein synthesis after Antisense Oligonucleotide treatment, which we hypothesized to be the earliest biochemical identification of RNA-targeting therapy efficacy. METHODS/STUDY POPULATION: We treated 2 transgenic animal models expressing proteins implicated in neurodegenerative disease: human tau protein (hTau) and human superoxide dismutase 1 (hSOD1), with ASO against these mRNA transcripts. Animals received isotope-labeled 13C6-Leucine via drinking water to label newly synthesized proteins. We assayed target protein synthesis and concentration after ASO treatment to determine the earliest identification of ASO target engagement. RESULTS/ANTICIPATED RESULTS: hTau ASO treatment in transgenic mice lowered hTau protein concentration 23 days post-treatment in cortex (95% CI: 0.05%\u201364.0% reduction). In the same tissue, we observed lowering of hTau protein synthesis as early as 13 days (95% CI: 29.4%\u2013123%). In hSOD1 transgenic rats, we observed lowering of 13C6-leucine-labeled hSOD1 in the cerebrospinal fluid 30 days after ASO treatment compared with inactive ASO control (95% CI: 12.0%\u201348.4%). DISCUSSION/SIGNIFICANCE OF IMPACT: In progressive neurodegenerative diseases, it is crucial to develop measurements that identify treatment efficacy early to improve patient outcomes. These data support the use of stable isotope labeling of amino acids to measure new protein synthesis as an early pharmacodynamics measurement for therapies that target RNA and inhibit the translation of proteins."}
+{"text": "Male sex was associated with increased elastin but not fibrillin-1 mRNA expression. Ascending aortas from male and female FBN1mgR/mgR mice significantly differed in the degree of elastin fragmentation . DISCUSSION/SIGNIFICANCE OF IMPACT: Sexual dimorphism of thoracic aortic dilation observed in human TAA patients was recapitulated in the fibirllin-1 hypomorphic mouse model of syndromic thoracic aortic aneurysms. Differences in this mouse model could be explained by the differential expression of extracellular matrix genes.OBJECTIVES/SPECIFIC AIMS: Pre-clinical and clinical observations have noted that increased aortic dilation is associated with male sex. Using an experimental model of severe, syndromic thoracic aortic aneurysms, we quantify aortic dilation and elastin stability in male Versus female mice. METHODS/STUDY POPULATION: Ascending aortas from male and female FBN1mgR/mgR mice and their wild type littermates were assessed every 4 weeks from 6 to 18 weeks of age by ultrasound. Measurements were taken luminal edge to luminal edge in diastole. At termination, aortas were harvested for RT-PCR analysis of extracellular matrix genes. Aortas were serially sectioned and elastin fragmentation was imaged by auto-fluorescence. RESULTS/ANTICIPATED RESULTS: At 12 weeks of age, differences of aortic diameters between male and female FBN1mgR/mgR mice were significantly different (2.24\u00b10.43 vs. 1.57\u00b10.22 mm;"}
+{"text": "Most older adults express the preference to die at home, but the desire for home death may go unfulfilled when the dying process become burdensome. Little is known about the congruence between older adults\u2019 and their caregivers\u2019 desired locations at death. The purpose of this study was to explore how the congruence between caregiver-care recipients desired and actual location at death influenced well-being in bereavement. This exploratory study utilized simultaneous qualitative and quantitative methods. Interviews were conducted with 108 bereaved caregivers about 4 months after the care recipient died while receiving hospice care. Care recipients\u2019 ages ranged from 43-101 (M=79.6); caregivers from 32-88 (M=61.5). Quantitative data included categorical variables about demographics, advance care planning and location at death. The Core Bereavement Items and CDC HRQOL\u201314 \"Healthy Days Measure\" scales were used. Qualitative data involved open-ended questions about the illness trajectory, desired location and perceptions of care at life\u2019s end. Quantitative analysis included comparison of group differences using both Independent Samples t-tests and One-way ANOVA. Of the 92 care recipients who had an advance directive, N=49 (45%) were in the location they desired and for N=49 (45%) there was caregiver/care recipient congruence about location. Caregivers who experienced incongruence reported poorer physical and emotional well-being and higher, more intense bereavement symptoms. Three overarching themes illuminated caregivers\u2019 experiences: (1) Caregiver-recipient congruence; (2) Caregiver-recipient incongruence; (3) Incongruence-influenced bereavement. Results suggest that incongruence between desired and actual location of death affects well-being in bereavement. Implications: Communication about location at death is an essential consideration."}
+{"text": "Salmonella enterica subsp. enterica serovar Typhimurium is one of the most common zoonotic pathogens. Salmonella species reside in a wide variety of hosts, including wild animals. Thus, we report here the genome sequences of 12 monophasic S. Typhimurium strains isolated from healthy wild vultures to gain better insight into their epidemiology and host-pathogen interactions.Monophasic  Salmonella enterica subsp. enterica serovar Typhimurium is one of the most common zoonotic pathogens. Salmonella species reside in a wide variety of hosts, including wild animals. Thus, we report here the genome sequences of 12 monophasic S. Typhimurium strains isolated from healthy wild vultures to gain better insight into their epidemiology and host-pathogen interactions.Monophasic  Salmonella spp. stand out as some of the most common causes of human bacterial food poisoning  fingerprinting patterns similar to those observed in Salmonella strains from pig farms, suggesting that pig farms introduce Salmonella infection into vultures at supplementary feeding stations . DNA libraries were generated using the Illumina Nextera XT library prep kit  and starting from 0.2\u2009ng/\u03bcl of purified gDNA measured by a Qubit double-stranded DNA (dsDNA) high-sensitivity (HS) assay kit . Sample multiplexing was performed using a Nextera XT index kit set C . Libraries were then sequenced using a 2 \u00d7 300-bp paired-end run  on an Illumina MiSeq sequencer.Default parameters were used for all software, unless otherwise specified. The obtained raw sequencing data were quality checked using the PRINSEQ-lite program v0.20.4 , eliminaSalmonella enterica subsp. enterica serovar Typhimurium SL1344 genome (GenBank accession number NC_016810) using the BWA-MEM algorithm (http://bio-bwa.sourceforge.net/). Unmapped reads were filtered out using SAMtools suite v1.8  under the project accession number A5530648 ."}
+{"text": "Home health services has been considered a recommended form of post-discharge management of older patients undergoing surgery. In this study, we examined total 30-day episode payments and 30-day readmission rates for those who were and were not utilizers of home health services following colectomies. We utilized administrative claims data (2012-2017) from the Michigan Value Collaborative across 77 hospitals in Michigan. Post-acute care includes skilled nursing facility, inpatient/outpatient rehabilitation, emergency department visits, home health services, and other outpatient visits. All payments were risk adjusted using generalized linear models using Hierarchical Condition Categories, age, sex, insurance type, and prior 6-month payments. Controlling for selection bias for those utilizing home health services, we performed propensity score matching at a caliper of 0.001 without replacement. We identified 15,531 colectomies with 4,397 (28.3%) utilizing home health services within 30 days. There were 4,197 home health users and non-users with home health users having significantly higher adjusted 30-day episode payments ). While there were only slight differences in adjusted index surgical base payments between home health users  and non-users ), there were substantially larger post-discharge payments for home health users ). Colectomy patients utilizing home health services had a higher readmission rate . Colectomy patients utilizing home health services are more resource intensive in the post-discharge period. Recommendation for home health services increases costs and readmission."}
+{"text": "Antibodies against PD1 have been used to treat progressive multifocal leukoencephalopathy (PML), a rare brain disease caused by JC virus. We used these antibodies (nivolumab) to treat PML in 3 kidney transplant recipients. All died within 8 weeks of diagnosis. Hence, nivolumab did not improve PML outcome after solid organ transplantation. The role of T-cell exhaustion in the development of progressive multifocal leukoencephalopathy (PML), a rare brain disease caused by JC virus, has prompted clinicians to use immune checkpoint inhibitor molecules to treat JC virus\u2013infected patients. Recently, Cortese et al. (https://www.aan.com) consensus, made 5 (range 2\u201317) years after transplantation. We have compiled clinical and radiologic findings for these patients  for severe progressive multifocal leukoencephalopathy; expression of surface T-cell inhibitory molecules in 2 patients after receipt of nivolumab."}
+{"text": "Salmonella enterica subsp. enterica serovar Montevideo strains (CFSAN005645 and FCC0123) and two Salmonella enterica subsp. enterica serovar Senftenberg strains (FSW0104 and CFSAN087304) isolated from pistachios. The genomes were closed using a hybrid assembly method using short- and long-read sequencing technology.Here, we report the genomes of two  Salmonella enterica subsp. enterica serovar Montevideo strains (CFSAN005645 and FCC0123) and two Salmonella enterica subsp. enterica serovar Senftenberg strains (FSW0104 and CFSAN087304) isolated from pistachios. The genomes were closed using a hybrid assembly method using short- and long-read sequencing technology.Here, we report the genomes of two  Salmonella enterica is a Gram-negative bacterium that is responsible for an average of 1.2 million illnesses (https://www.ncbi.nlm.nih.gov/pathogens/) and they were available in the lab. The genomes of these four strains from pistachios were sequenced to create reference strains in the event of future outbreaks. The Salmonella enterica subsp. enterica serovar Senftenberg strains, according to the NCBI pathogen detection site, belong to NCBI single nucleotide polymorphism (SNP) cluster PDS000031739. The Salmonella enterica subsp. enterica serovar Montevideo strains belong to NCBI SNP cluster PDS000032600. These clusters contain numerous isolates from pistachio and environmental samples over a 2- to 5-year timespan. These are all draft genomes with many contigs; therefore, to generate better reference genome sequences for these strains, their genomes were closed using a hybrid assembly method utilizing both short- and long-read sequence technology.These four strains were selected for sequencing because they showed relatedness to each other based on results from the NCBI pathogen detection site  overnight at 37\u00b0C. The genomic DNA was isolated using the Maxwell RSC cultured cells DNA kit  following the manufacturer\u2019s protocols, with the addition of RNase A treatment. The long-read sequencing was performed using a GridION device . The sequencing libraries were prepared using the Rapid Barcoding Sequencing kit SQK-RBK004) following the manufacturer\u2019s protocols. The prepared libraries were sequenced on a FLO-MIN106 (R9.4.1) flowcell for 48 hours. The long reads were base called and demultiplexed using Guppy v3.2.2. All reads below 5,000 base pairs in length were discarded. The short-read sequence data for each strain were previously generated by FDA GenomeTrakr-participating laboratories using a MiSeq instrument with 2 \u00d7 250-bp paired-end chemistry . The short-read sequencing data were downloaded from the NCBI Sequence Read Archive. Each sample was individually analyzed by a previously published method ( followinIn silico multilocus sequence typing (MLST) analyses  (S. Montevideo strains. The S. Senftenberg strains belong to eBG 30, whereas the majority of S. Senftenberg strains are in eBG 55 (The four final assemblies were annotated using the NCBI Prokaryotic Genome Annotation Pipeline and deposited at DDBJ/EMBL/GenBank. The sequencing statistics can be found in analyses  showed tS. enterica strains are listed in The genome sequences of the four"}
+{"text": "Renal osteodystrophy (ROD) represents bone disorders related to chronic kidney disease (CKD) and several bone biomarkers are used clinically to predict ROD in CKD and hemodialysis (HD) patients. Serum albumin associates with inflammation other than nutritional status in these patients. Chronic inflammation is proved to relate with bone loss, however, the influence of hypoalbuminemia on bone biomarkers is still unclear. In this study, we evaluated the pattern of bone biomarker changes and further studied the influence of hypoalbuminemia on these biomarkers. A total of 300 maintenance HD patients were evaluated and 223 HD patients were included in the study. The patients were grouped according to serum parathyroid hormone (PTH) levels . Bone biomarkers and inflammatory markers were measured and their relation with PTH levels was determined. Significantly increased interleukin-6 (IL-6) and lower albumin levels were noted among PTH>600 pg/mL group. Bone turnover markers were significantly higher in PTH >600 pg/mL group (p< 0.05). Hypoalbuminemia significantly increased the fibroblast growth factor-23 (FGF-23) and procollagen type 1N-terminal propeptide (P1NP) in PTH \u2264150 pg/mL, PTH 150-300 pg/mL, PTH 300-600 pg/mL groups, whereas no such relation was noted among PTH> 600 ng/dL group. In conclusion, hypoalbuminemia represents a chronic inflammation which differently relates to bone turnover markers according to serum PTH levels in SHPT patients. Thus, serum albumin measurement should be considered in determining bone disorders among these patients. Chronic kidney disease-mineral bone disorder (CKD-MBD) related renal bone disorder, also known as renal osteodystrophy (ROD), is a clinically unique bone disease of CKD and HD patients and distinct from normal aging-related osteoporosis in the general population. ROD relates with abnormalities of bone turnover, mineralization, volume, linear growth, and strength and results in both bone quantity and bone quality loss Serum intact PTH  has long been regarded as the principal biomarker for assessing the bone turnover in diagnosis and monitoring of ROD However, most bone turnover markers are still not widely used due to lack of definitive sensitivity and/or specificity. Total alkaline phosphatase (ALP), bone-specific alkaline phosphatase (BALP),osteocalcin, and procollagen type 1N-terminal propeptide (P1NP) act as bone formation markers and measure osteoblast function Clinically, chronic inflammation plays an important role in development of osteopenia and osteoporosis. Various studies report an increased risk of osteoporosis and bone loss in various inflammatory conditions including gout, osteomyelitis, rheumatoid arthritis, ankylosing spondylitis, etc However, how the hypoalbuminemia influences the levels of bone turnover markers in HD patients is still unknown. We studied the HD patients and grouped them according to serum PTH levels and different bone turnover biomarkers were measured. Then, we studied the relation between serum albumin and bone turnover markers. Finally, we hope to predict more accurately about the bone turnover status using these biomarkers in HD patients.Table The bone turnover markers were determined according to PTH levels among these patients Table . Serum AA significant negative correlation was noted between IL-6 and serum albumin levels among PTH \u2264150 pg/mL, PTH 300-600 pg/mL and PTH >600 pg/mL groups and no relation or a non-significant positive relation was noted in PTH 150-300 pg/mL groupTable .Relation between serum albumin levels and bone turnover markers was also evaluated among different PTH groups Table . Bone foWe determined the influence of hypoalbuminemia albumin\u22643.5 g/dL) and normoalbuminemia  on the bone formation and resorption markers in different PTH groups  which is recently proved to be related more with oxidative stress other than biological PTH activity instead of measuring non-oxidized PTH A total of 300 patients undergoing maintenance hemodialysis in Cardinal Tien Hospital, Fu-Jen Catholic University and Shuang-Ho Hospital-Taipei Medical University Hemodialysis Unit were included in the study. 23 patients were excluded because they were within 6 months of starting hemodialysis. A further 18 patients treated with parathyroidectomy or calcimimetic agent cinacalcet therapy were excluded. 22 patients had a limited life expectancy due to one, or a combination of terminal malignancy at baseline (n=7), end-stage liver disease (n=4), end-stage cardiac disease (n=8), active infection (n=3) and 14 patients with missing information about starting dates of dialysis were also excluded. A total of 223 patients met our inclusion criteria and included in the study after informed consent.The patients were grouped according to PTH levels  Figure . ClinicaClinical characteristics of the patients, including age, gender and dialysis duration were obtained from medical records. Blood samples were collected into EDTA containing tubes and were processed within 1 h after venipuncture. Samples were subsequently centrifuged for 7 min at 1600 g. Concentrations of plasma calcium, phosphate, albumin, alkaline phosphatase (Alk-P) and other biochemistry parameters were measured by standard laboratory techniques with an automatic chemistry analyser . White blood cells, haemoglobin, and haematocrit were measured by automated hematology analysers XN 9000 .Plasma cytokine IL-6 was determined Human Instant Enzyme-Linked Immunosorbent Assay (ELISA) kit  according to manufacturer's instructions. Serum was also separated to test the bone biomarkers such as wnt 10b, wnt 16, sclerostin (SOST), Dickkopf-related protein 1(DKK-1), Tartrate-resistant acid phosphatase 5b ( TRAP5b), Procollagen 1 N-terminal Propeptide (P1NP) and Fibroblast growth factor 23 (FGF-23) using commercially available ELISAs. .Consistent with the study hypothesis, all analyses were stratified according to PTH. We examined PTH as quartiles: \u2264150, 150-300, 300-600, and >600 pg/mL. The characteristics of different PTH groups were compared using the chi-squared test for categorical variables and Student t test or ANOVA test for continuous variables, and using the Spearman correlation test analysis relation between serum albumin and bone turnover markers. The differences between groups were analyzed with the analysis of covariance (ANCOVA) test after adjusting for age and sex. The mean and standard deviation (SD) of each value were calculated for each group. The SPSS 18.0 statistical package was used for all statistical tests. Results with P < 0.05 were considered statistically significant.Hypoalbuminemia, as a marker of chronic inflammation, differentially influences the bone markers OPG and P1NP in hemodialysis patients among different PTH groups. This might be related with inflammation related bone cells activation independent of PTH actions. Interestingly, this association was not seen in those with severely high PTH levels (PTH>600), which might be due to overwhelming effects of PTH and uremic toxins on bone cells. Future studies need to evaluate the validity of serum albumin in determining bone status among CKD and dialysis patients."}
+{"text": "In 2014, the Advisory Committee on Immunization Practices (ACIP)Streptococcus pneumoniae (pneumococcus) can cause serious illness, including sepsis, meningitis, and pneumonia with bacteremia (invasive) or without bacteremia (noninvasive). Since the early 1980s, PPSV23 has been recommended for persons aged \u22652 years with certain underlying medical conditions, and all adults aged \u226565 years (65 years . In 2014https://www.cdc.gov/vaccines/acip/recs/grade/PCV13-etr.html) the ACIP Pneumococcal Vaccines Work Group reviewed relevant scientific evidence regarding the benefits and harms of PCV13 use among adults aged \u226565 years without an immunocompromising condition, CSF leak, or cochlear implant, in the context of >5 years of pediatric PCV13 use. The Work Group evaluated the quality of evidence for PCV13 efficacy, effectiveness, safety, and population-level impact on pneumococcal-related disease using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach (https://www.cdc.gov/vaccines/acip/recs/grade/PCV13.html).During 2016\u20132019, using the Evidence to Recommendations Framework, , pneumonia . Before the 2014 recommendation, a randomized placebo-controlled Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) conducted in the Netherlands demonstrated 75%  efficacy against PCV13-type IPD and 45% (CI\u00a0=\u00a014%\u201365%) efficacy against noninvasive PCV13-type pneumonia among adults aged \u226565 years (https://www.cdc.gov/vaccines/acip/recs/grade/PCV13.html) demonstrated PCV13 effectiveness against PCV13-type IPD (47%\u201359%) (https://www.cdc.gov/vaccines/acip/recs/grade/PCV13.html). The rates of severe adverse events were similar among participants vaccinated with PCV13 versus placebo or PPSV23 (https://www.cdc.gov/vaccines/acip/recs/grade/PCV13.html). Common reported PCV13-associated adverse reactions included pain, redness, and swelling at the injection site, limitation of movement of the arm in which the injection was given, fatigue, headache, chills, decreased appetite, generalized muscle pain, and joint pain (PCV13 population-level impact (indirect and direct effects) on disease among adults aged \u226565 years. The U.S. pediatric PCV program has been successful in preventing disease among young children through direct protection of vaccinated children as well as in unvaccinated populations through indirect effects . The remaining risk is a function of each individual patient\u2019s risk for exposure to PCV13 serotypes and the influence of underlying medical conditions on the patient\u2019s risk for developing pneumococcal disease if exposure occurs.The following adults aged \u226565 years are potentially at increased risk for exposure to PCV13 serotypes and might attain higher than average benefit from PCV13 vaccination, and providers/practices caring for many patients in these groups may consider regularly offering PCV13 to their patients aged \u226565 years who have not previously received PCV13:Persons residing in nursing homes or other long-term care facilitiesPersons residing in settings with low pediatric PCV13 uptakePersons traveling to settings with no pediatric PCV13 programIncidence of PCV13-type invasive pneumococcal disease and pneumonia increases with increasing age and is higher among persons with chronic heart, lung, or liver disease, diabetes, or alcoholism, and those who smoke cigarettes or who have more than one chronic medical condition.* Ahmed SS, Pondo T, Xing W, et al. Early impact of 13-valent pneumococcal conjugate vaccine use on invasive pneumococcal disease among adults with and without underlying medical conditions\u2014United States. Clin Infect Dis 2019. Epub August 12, 2019.If a decision to administer PCV13 is made, it should be administered before PPSV23 (ACIP continues to recommend PCV13 in series with PPSV23 for adults aged \u226519 years (including those aged \u226565 years) with immunocompromising conditions, CSF leaks, or cochlear implants  (2).PPSV23 for adults aged \u226565 years. ACIP continues to recommend that all adults aged \u226565 years receive 1 dose of PPSV23. A single dose of PPSV23 is recommended for routine use among all adults aged \u226565 years (65 years  (5).CDC will continue to assess the safety, implementation and the impact of shared clinical decision-making regarding administration of PCV13 to adults aged \u226565 years; the indirect effect of pediatric PCV13 vaccination on disease burden among older adults; and the emergence of nonvaccine serotypes, to inform policy decisions for higher valency conjugate vaccines currently in development. ACIP will continue to review relevant data as they become available and update pneumococcal vaccination policy as appropriate.https://vaers.hhs.gov/.Before administering PCV13 or PPSV23, health care providers should consult the relevant package inserts  recommended 13-valent pneumococcal conjugate vaccine (PCV13) in series with 23-valent polysaccharide vaccine (PPSV23) for all adults aged \u226565 years.PCV13 use in children has led to sharp declines in pneumococcal disease among adults and children. Based on a review of accrued evidence ACIP changed the recommendation for PCV13 use in adults.ACIP recommends a routine single dose of PPSV23 for adults aged \u226565 years. Shared clinical decision-making is recommended regarding administration of PCV13 to persons aged \u226565 years who do not have an immunocompromising condition, cerebrospinal fluid leak, or cochlear implant and who have not previously received PCV13. If a decision to administer PCV13 is made, PCV13 should be administered first, followed by PPSV23 at least 1 year later."}
+{"text": "Programs like orthogeriatrics, geriatric cardiology have shown to improve outcomes in hospitalized geriatric patients. Our Geriatrics MICU Co-management program is a quality improvement initiative that instigates a partnership approach with critical care medicine in integrating geriatric assessments and build foundation for interdisciplinary care of critically ill patients. MICU  protocols do not have standard geriatrics assessments integrated in clinical care. An electronic dash-board identifies high risk elderly (HRE) patients admitted at a MICU in a large teaching hospital in Northeast Ohio based on nursing specific screening triggers. A geriatrics co-management team engages in a comprehensive geriatric assessments and care transition. 386 patient were identified using HRE screening triggers in a period of 100 days. 33 % (n=131) were generated as consults for co-management. A pilot review on 131 HRE patients was conducted. 70% (n=93) patients had incident frailty. 93% (n=87) of patients with frailty were diagnosed with incident delirium. 56% (n=74) of patients were newly diagnosed with cognitive impairment. 56 % (N=74) of patients had a medication reduction. An average of 1.23 medication was changed. 85% (n =112) of patients had a warm hand off to the next level of provider on discharge. 90% (n=119) of patients notified improved self-management skills and better understanding of discharge process. The Geri-MICU program demonstrates a patient -centered approach in integrating geriatric assessments for critically ill patients and build foundation of a geriatrics-critical care task force. The program would be a mile stone in optimizing elderly care in critical care units."}
+{"text": "FAP is a post-proline peptidase selectively expressed during tissue remodeling and repair, such as with wound healing, and in the tumor microenvironment by cancer-associated fibroblasts. We targeted FAP function using a novel small molecule inhibitor, UAMC-1110, and mice with germline knockout of FAP and concomitant knock-in of E. coli beta-galactosidase. We depleted CAFs by adoptive transfer of anti-\u03b2gal T cells into the FAP knockout animals. Established syngeneic pancreatic tumors in immune competent mice were targeted with these 3 strategies, followed by focal radiotherapy to the tumor. FAP loss was associated with improved antigen-specific tumor T cell infiltrate and enhanced collagen deposition. However, FAP targeting alone or with tumor-directed radiation did not improve survival even when combined with anti-PD1 therapy. Targeting of CAFs alone or in combination with radiation did not improve survival. We conclude that targeting FAP and CAFs in combination with radiation is capable of enhancing anti-tumor T cell infiltrate and function, but does not result in sufficient tumor clearance to extend survival.Pancreatic ductal adenocarcinoma (PDAC) is characterized by a fibrotic stroma with a poor lymphocyte infiltrate, in part driven by cancer-associated fibroblasts (CAFs). CAFs, which express fibroblast activation protein (FAP), contribute to immune escape via exclusion of anti-tumor CD8 This is consistent with recent data implicating FAP+ CAFs in T cell exclusion, via TGFb signaling, and suppression of T cell proliferation [FAP expression by CAFs has provided a potential therapeutic target in other studies. Prior publications have demonstrated that tumors grown in FAP KO mice demonstrate delayed tumor growth, but enhanced disorganized collagen deposition and p21 signaling via extracellular signal\u2013regulated kinase (ERK) and focal adhesion kinase (FAK). Previouic stroma\u201321. Of nic stroma. Though feration ,40. Otheferation . This isferation . TogetheG12D:Trp53R172H:Pdx-1-Cre (KPC) GEMM [Interpretation of our results must also be taken within the context of our experimental models. We utilized a poorly immunogenic, subcutaneous tumor cell line to model PDAC, Panc02, in order to target a single tumor with radiation. Genetically engineered mouse models (GEMMs) may better recapitulate the mutational landscape of human PDAC, but represent a more challenging model for targeted radiation given that they can develop anywhere within the pancreas, adjacent to nearby critical organs, and require fiducial placement via open laparotomy for radiation targeting. A recent publication using CAR T cells targeting FAP utilized both subcutaneously implanted tumors and tumors arising spontaneously in the KrasPC) GEMM . They obPC) GEMM  suggestiPC) GEMM , while aPC) GEMM . These cPC) GEMM , we founWhile we are the first to examine a selective FAP inhibitor in pre-clinical models of PDAC, our results provide room for improvement. Inhibition of FAP proteolytic activity decreased macrophage infiltrate and genetic knockout of FAP enhanced T cell infiltrate and cytotoxicity. FAP inhibition performed similarly to germline loss of FAP. Further targeting of CAFs, beyond FAP function, combined with radiation did not improve survival over radiation alone suggesting further suppressive pathways are limiting responses. The future success of FAP inhibitors may depend on the endogenous susceptibility of cancer cells to T cell mediated killing.S1 FigPanc02-SIY tumor bearing mice in WT or FAP KO animals, tumors harvested on day 14. a) Immunofluorescent staining for hypoxyprobe (green) and DAPI nuclear stain (blue). b) Quantification of hypoxyprobe positive area relative to DAPI positive area. Panc02-SIY tumor bearing mice in WT or FAP KO animals, tumors harvested on day 14. Panc02 tumor bearing animals in control or UAMC-1110 (UAMC) treated animals alone or following radiation (RT) at day 22 and day 43. c) Immunofluorescent staining for \u03b1SMA (green), CD31 (red), and DAPI nuclear stain (blue). d) Quantification of vessel area by CD31 positive area relative to DAPI positive area. e) Quantification of CAFs by \u03b1SMA positive area relative to DAPI positive area. f) Immunofluorescent staining for vimentin (red), Ki67 (green), and DAPI nuclear satin (blue). g) Quantification of Ki67 positive area relative to DAPI positive area. h) Quantification of vimentin positive area relative to DAPI positive area. i) Immunofluorescent staining for PDGFR\u03b1 (red), cleaved caspase 3 (green), and DAPI nuclear stain (blue). j) Quantification of cleaved caspase 3 positive area relative to DAPI positive area. k) Quantification of PDGFR\u03b1 positive area relative to DAPI positive area. n = 4\u20138 mixed gender mice/group, images representative of group and experiment. NS = not significant, ****p<0.0001.(TIF)Click here for additional data file.S2 FigPanc02-SIY tumor bearing mice in WT (WT) or FAP knockout (FAP KO) animals, randomized to receive 10 Gy x 3 tumor directed radiation (RT) days 14\u201316. Tumors harvested on day 23, homogenized, and evaluated for cytokine levels. n = 4\u20136 mixed gender mice/group. *p<0.05.(TIF)Click here for additional data file.S3 FigMean tumor growth curve. n = 4\u20138 female mice/group.(TIF)Click here for additional data file.S4 Figa) Panc02 or b) Panc02-SIY cells treated with IFN\u03b3 or 20Gy radiation and assessed for PDL1 expression by flow cytometry 24h later.(TIF)Click here for additional data file."}
+{"text": "Tospoviridae family and theOrthotospovirus genus, is a key viral factor thatindirectly modifies vector preference and increases vector performance. NSssuppresses the biosynthesis of plant volatile monoterpenes, which serve asrepellents of the vector western flower thrips . NSs directly interacts with MYC2, the jasmonate (JA)signaling master regulator and its two close homologs MYC3 and MYC4, to disableJA-mediated activation of terpene synthase genes. Thedysfunction of the MYCs subsequently attenuates host defenses, increases theattraction of thrips, and improves thrips fitness. Moreover, MYC2 associatedwith NSs of Tomato zonate spot orthotospovirus, another Euro/Asian-typeorthotospovirus, suggesting that MYC2 is an evolutionarily conserved target ofOrthotospovirus species for suppression of terpene-basedresistance to promote vector performance. These findings elucidate the molecularmechanism through which an orthotospovirus indirectly manipulates vectorbehaviors and therefore facilitates pathogen transmission. Our results provideinsights into the molecular mechanisms by which OrthotospovirusNSs counteracts plant immunity for pathogen transmission.Pandemics of vector-borne human and plant diseases often depend on the behaviorsof their arthropod vectors. Arboviruses, including many bunyaviruses, manipulatevector behavior to accelerate their own transmission to vertebrates, birds,insects, and plants. However, the molecular mechanism underlying thismanipulation remains elusive. Here, we report that the non-structural proteinNSs of Tomato spotted wilt orthotospovirus, a prototype of the Most bunyaviruses are transmitted by arthropod vectors, and some of them canmodify the behaviors of their arthropod vectors to increase transmission tomammals, birds, and plants. NSs is a non-structural bunyavirus protein withmultiple functions that acts as an avirulence determinant and silencingsuppressor. In this study, we identified a new function of NSs as a conservedmanipulator of vector behavior via plant. NSs suppresses jasmonate-mediatedplant immunity against thrips by directly interacting with several homologs ofMYC transcription factors, the core regulators of the jasmonate-signalingpathway. This hijacking by NSs enhances thrips preference and performance.Therefore, our data support the hypothesis that MYC2 is a convergent target thatplant pathogens manipulate to promote their survival in plants. Geminiviridae and Luteoviridae viruses almostuniversally induce preferred settling of the vectors onto infected plants [Potyviridae and Bunyaviridae [Geminiviridae- and Tospoviridae-infectedplants [Potyviridae,Caulimoviridae and Bromoviridae, also canpositively or negatively affect their vectors for efficient virus spread [Arthropod-borne viruses (arboviruses) are virulent causal agents of diseases inhumans, animals, and plants. Vector behaviors have critical ecological andevolutionary consequences for arboviruses, which rely exclusively on their arthropodvectors for dispersal to new hosts. Therefore, it is of evolutionary significancefor an arbovirus to alter its vector\u2019s behavior to facilitate its own transmission.For plant viruses, such influence of vectors by viruses can include plant-mediatedindirect effects or direct manipulation within the vector after acquisition. Amongthe indirect effects, infected plants tend to be more attractive to vectors . For exad plants \u20135, and taviridae \u20139. Moreodplants . For nons spread , 13\u201315.Bunyavirales encompasses nine families of viruses withsingle-stranded negative-sense RNA genomes. As a prototype of the plant-infectedTospoviridae family, Tomato spotted wilt orthotospovirus (TSWV)is transmitted mainly by Frankliniella occidentalis Pergande in a persistent and propagative manner [Bunyavirales [F. occidentalis prefersto settle on TSWV-infected pepper (Capsicum annuum L.) andDatura stramonium plants over noninfected controls [Orthotospovirus and Bunyavirales species isstill unclear, although this plant immunity suppression is thought to occur inTSWV-infected Arabidopsis thaliana [Orthotospovirus NSm protein facilitates the movement of viralribonucleoproteins from cell to cell within the plant host. NSm of TSWV has recentlybeen identified as the avirulence factor recognized by the product of resistancegene Sw-5b from tomato (Solanum lycopersicum L.)[Orthotospovirus functions as a silencing suppressor in bothplants and insects [e manner ,17. Planavirales \u201320. Forcontrols . Howeverthaliana . The bunicum L.). The NSs insects ,24. Thes insects ,26.Many plant species emit herbivore-induced plant volatiles (HIPVs), as an indirectanti-herbivore defense strategy \u201330. HIPVorthotospovirus suppress the JAsignaling pathway in the host plant by directly interacting with MYCs, keyregulators of the JA signaling pathway, to reduce host defense responses againstthrips. Our results establish a molecular mechanism underlying how TSWV attracts andbenefits to its thrips vector by targeting plant MYC proteins.In this study, we showed that TSWV benefits to thrips vector by suppressing aJA-regulated defense pathway of plants against herbivores. We identified the NSsprotein from thrip-borne TSWV as a viral genetic factor induced attraction of itsinsect vector. Various NSs from Frankliniella occidentalis Pergande. We conducted a two-choice assay between infectedand non-infected plants. Pepper (Capsicum annuum L.), a naturalhost of TSWV and an important crop worldwide, was first tested in the tripartitethrip\u2013orthotospovirus\u2013plant interaction. A group of 50 non-viruliferous WFT wasreleased from the center of the two-choice arena between two types of pepperplants. Consistent with previous results from Maris et al. [We first investigated the indirect effect of TSWV infection on the behavioralresponses of the vector s et al. , ~68% ofterpene synthase(TPS) genes in pepper leaves based on our previousfunctional analysis of TPS genes [monoterpenesynthase genes , which are related tomonoterpene synthesis, were upregulated after thrips infestation  treatment, reflecting the same trends as during thrips infestation  (Another model (host) plant for tripartite interaction research, d leaves . Moreovethamiana .Consistestation .JA signestation , weusede (MeJA) .TPS geneexpression, we investigated changes in the emission of plant volatile compoundsafter TSWV infection. Plants have evolved a blend of HIPVs that are emitted inresponse to, and directly repel, herbivores [TPS genes. In addition, there was nosignificant difference in the emissions of the monoterpene D-limonene  in TSWV manipulate vector host choice, we selected three of the fiveviral proteins in TSWV, including a structural protein nucleocapsid protein(Ncp) and two non-structural proteins, NSm and NSs [NSs alone issufficient to attract WFT in peppers.Our data demonstrated that the orthotospovirus TSWV increases the attraction ofinsect vector WFT to its host plant by inhibiting  and NSs . We used and NSs . PVX-GFPArabidopsis cDNA library by yeast two-hybrid analysis andidentified AtMYC2, a key components of the JA signaling pathway [N.benthamiana lines that expressed a nucleus-localizedhistone H2B-red fluorescent protein (H2B-RFP) fusion marker protein. A stronginteraction (represented by fluorescence) was observed in the nucleus  lines were significantlymore attractive to thrips compared to controls  or wild-type Arabidopsis for two weeks. Wecounted the number of new adults and larvae to analyze the effect of NSs on thethrips population. Plants expressing NSs were more suitable forWFT population growth than wild type  wasreported to modify the feeding behavior of mosquito vectors [Rift Valleyfever virus (RVFV) was found to affect mosquito vector morbidityand mortality [Behavioral manipulation has been observed in animal-infecting bunyaviruses formany years. As early as 1980,  vectors . Rift VaNSs is sufficient to control the behavior ofWFT  interactswith MYC2 to subvert plant resistance and to promote vector performance [Begomovirus and Orthotospovirus speciesare persistently transmitted, which tend to induce attraction and promoteperformance of vectors on infected plants for increased transmission efficiency,indicating that viruses with same transmission mechanisms can have commonmanipulation tactics. Interestingly, the silencing suppressor 2b of thenonpersistently transmitted virus Cucumber mosaic virus  also suppresses JA signaling, andmyc234 triple mutant plants were observed to attract theCMV aphid vector [By interrupting MYC-regulated plant defense via NSs,formance . Notablyd vector ,althougd vector . These sToxoplasmagondii, poxviruses (vaccinia and myxoma), andStaphylococcus aureus exploit CCR5 to target and killmammalian immune cells [These similar effects and pathogen manipulation tactics indicate that themechanistic and evolutionary principle for diverse pathogens seems to beconvergent, even in human pathogens. For instance, CCR5, which is the firstdescribed cellular receptor of human immunodeficiency virus (HIV), is necessaryand sufficient for the pathogenesis of many pathogens . The HIVne cells \u201363. WhyIn summary, we have demonstrated that the emission of several monoterpenes isgreatly decreased by the TSWV infection, which in turn promotes WFT preferenceand performance, uncovering a molecular mechanism underpinning the virus-inducedmanipulation through the shared host plant of the WFT vector. This work presentsa mechanism by which a pathogen regulates host-derived olfactory cues for vectorattraction. These results will also help to address similar tripartiteinteraction systems in plants, animals and humans and will allow innovativecontrol methods through interference of vector transmission.Capsicum annuum L.),Nicotiana benthamiana and Arabidopsisthaliana (Col-0) plants were grown in insect-free growth chambersfollowing standard procedures [Arabidopsis myc2-1,tps10-1, and myc234 mutants (Col-0background) were described previously [35S:YFP-NSs transgenic linesNSs-1 and NSs-2 were generated using theAgrobacterium-mediated floral-dip method [Pepper accession Lingfeng  (Thysanoptera: Thripidae) was kindlyprovided by Prof. Youjun Zhang . The thrips were maintained on green bean pods(Phaseolus vulgaris L.) in a climate chamber as describedpreviously [N. benthamiana as described by Mandal etal. [A starting colony of Western flower thrips  or 24 h  after release.For two-choice assays with individual monoterpene, 2 cm \u00d7 2 cm filter papercontaining 40 \u03bcL of a 1:100 (v/v) solution of standard chemical substance fromSigma dissolved in n-hexane or n-hexane alone (as a control) was placed in a16cm-Petri dish. Thrips were released between the two tested samples, and thethrips were counted 5 min after release. The Petri dishes were contained in athrip culture chamber throughout the experiment to maintain consistentenvironmental conditions.The two-choice assays on plants or leaves were performed as described previously,9. PeppeArabidopsis plants grown on solid MS mediumor soil-grown pepper and N. benthamiana plantswere infested with adult thrips for the indicated time period. The thrips weregently removed and the leaf samples collected in liquid nitrogen for furtheranalysis. For the GUS-reporter line expression assays,transgenic Arabidopsis plants were infested with thrips for 24h, followed by GUS activity analysis. The experiment was repeated at least twicewith similar results.Plants were infested with non-viruliferous thrips as described previously . Twenty For volatile analysis on pepper plants, plants were infested with thirty adultsin a nylon mesh cage for 6 h before volatile collection. The volatiles emittedfrom insect\u2010exposed TSWV-infected and control plants were collected with a solidphase microextraction  fiber consisting of100 \u03bcm polydimethylsiloxane (Supelco). Chemical analysis was performed by gaschromatography-mass spectrometry (GC-MS)  coupled with a DB5MScolumn . The SPME fiberwas thermally desorbed in the injector at 250\u00b0C for 1 min. The initial oventemperature was held at 40\u00b0C for 3 min, increased to 240\u00b0C with a gradient of5\u00b0C/min, and maintained at 240\u00b0C for 5 min. The inlet temperature was 250\u00b0C. Thecollection of volatiles for each treatment was repeated 4\u20136 times.N. benthamiana plants were performed asdescribed previously [The collection, isolation, and identification of volatiles fromeviously ,67. PlanNSs, NSm, and Ncp werecloned into the PVX vector pGR208 by using gene-specific primers in CaMV35S promoter. All constructs used for protein expression in plantswere transformed into Agrobacterium tumefaciens strain EHA105.Agrobacterium carrying the binary vectors were infiltratedinto the abaxial sides of pepper and N.benthamiana leaves [For PVX heterologous virus protein expression in pepper, the TSWV virus genesa leaves .Arabidopsis Mate and Plate Library was screened using yeastmating method according to the Matchmaker Gold Yeast Two-Hybrid Systemmanufacturer\u2019s protocol (Clontech). Briefly, full-length NSswas amplified and inserted into the pGBKT7 vector by Gateway recombination, thenthe constructs was transformed into yeast strain Y2HGold and testing forautoactivation by using the Yeastmaker Yeast Transformation System (Clontech).Then the Arabidopsis Mate and Plate Library and BD-NSs yeastclones were mated in YPDA medium. After incubation, isolated destination cloneswere selected from diploid-selection medium (SD/-Leu/-Trp). These primarypositive interactors were secondary screened on medium plates(SD/-Leu/-Trp/-His) and third time screened on medium plates . PCR and BLAST searches were used to obtain sequence informationon corresponding AD- and BD-clones per colony.The The interaction between TSWV NSs and AtMYCs were confirmed according to themanufacturer\u2019s protocol (Clontech). The pGBKT7-NSs and pGAD424-MYCs constructswere co-transformed into yeast strain Y2HGold. Yeast cotransformed with theindicated plasmids was spotted onto synthetic medium (SD-Leu-Trp-His) containing10 mM 3-amino-1,2,4-triazole and 0.04 mg/mL X-\u03b1-gal. The empty vectors pGBKT7(BD) and pGADT7 (AD) were used as negative controls .A.tumefaciens strain EHA105. The recombinant constructs ofA. tumefaciens were infiltrated in 4\u20136week old transgenic N. benthamiana (expressinga nuclear marker-H2B-RFP)[BiFC was performed as described previously . The ind-H2B-RFP) leaves vHis and GST tag fusion proteins were purified using His- and GST-Trap  according to the manufacturer\u2019s instructions . GST-AtMA.tumefaciens carrying the35S:MYC2-Myc or35S:YFP-NSs constructs were infiltratedinto N. benthamiana leaves. About 1g leaftissue was collected and ground to powder in liquid nitrogen. Proteins wereextracted in a cold extraction buffer , one protease inhibitor cocktail/100 mL). Then the protein extracts were incubated with 25 \u03bcLGFP-trap beads for 3 h at 4\u00b0C. After that, the beads were washed three timeswith extraction buffer and resuspended in 2xSDS buffer before used forimmunoblot analysis.Ca-ACT1 andN. benthamiana Nb-EF1\u03b1 were used as theinternal controls  with column DNase treatment. RNA was reverse transcribed usingTransScript One-Step gDNA Removal and cDNA Synthesis SuperMix . Four to six independent biological samples were collected and analyzed.RT-qPCR was performed using SYBR Green Real-Time PCR Master Mix on the CFX 96 system (Bio-Rad). Pepper Arabidopsis plants were grown in soil covered with Parafilm to prevent any thrips from escaping and to facilitate counting.Three-week-old plants were placed in an acryl cylinder chamber (7 cm \u00d7 5 cm) andcovered with a fine mesh. Seven female adults (7\u201314 d after eclosion) wereallowed to infest a single plant for two weeks, and new larvae and adult thripswere counted. Eight plants of each genotype were used per experiment. Theexperiment was repeated at least twice with similar results.The thrip spawning assay was performed as described previously with somemodifications .ArabidoArabidopsis plants expressing theAtMYC2 or AtTPS10promoter:GUS reporter gene were infested with thrips for 24h and incubated in GUS staining buffer  at 37\u00b0C overnight. The stained seedlingswere cleared by washing with 70% ethanol. Untreated plants were used as anegative control. The experiment was repeated at least twice with similarresults.Transgenic t tests or one-way ANOVA; if theANOVA result was significant (P < 0.05), Duncan\u2019s multiple range tests wereused to detect significant differences between groups. Thrip choices betweendifferent treatments were analyzed by nonparametric Wilcoxon matched pairstests. All statistical tests were carried out with GraphPad Prism.Significant differences in gene expression and volatile organic compound levelswere determined by Student\u2019s https://solgenomics.net), TAIR (www.Arabidopsis.org) or GenBank/EMBL underthe following accession numbers: CaMYC2 (CA00g50270), CaMTS1 (CA08g16370),CaMTS2 (CA08g16380), CaMTS3 (CA08g16410), CaMTS4 (CA08g16420), AtMYC2(AT1G32640), AtMYC3 (AT5G46760), AtMYC4 (AT4G17880), AtTPS10 (AT2G24210), TSWVNSs (JF960235.1), TSWV NSm (JF960236.1), and TSWV Ncp (JF960235.1),TZSV(EF552433.1).Sequence data in this study can be found in Sol Genomics Network Relative expression levels of various TPS genes inN. benthamiana after 100 \u03bcM MeJAtreatment for 24h. Values are means + SE, n = 3. **P < 0.01, Student\u2019st-test.(A) Relative expression levels of various (TIF)Click here for additional data file.S2 FigRepresentative extracted ion chromatograms of GC/MS headspace volatilecompounds of peppers. Plants under the same growth condition were infestedwith (pepper-thrips) or without (pepper) thrips for 6 h.(TIF)Click here for additional data file.S3 FigN.benthamiana leaf epidermal cells by agroinfiltration.Bars = 15 \u03bcm.(A) Interaction between TSWV NSs\u2013AtMYC3 and TSWV NSs\u2013AtMYC4 in a yeasttwo-hybrid assay. Yeast cotransformed with the indicated plasmids wasspotted onto synthetic medium (SD-Leu-Trp-His) containing 0.04 mg/mL X-\u03b1-galand 10mM 3-amino-1,2,4-triazole (3-AT). The empty vectors pGBKT7 (BD) andpGADT7 (AD) were used as negative controls. (B) Interaction between TSWVNSs\u2013AtMYC3 and TSWV NSs\u2013AtMYC4 in a BiFC assay. Indicated construsts weretransiently expressed in H2B-RFP transgenic (TIF)Click here for additional data file.S4 FigClustalW was used to construct the phylogenetic tree. It was constructedbased on the amino acid sequences of the NSs protein from 23orthotospoviruses.(TIF)Click here for additional data file.S1 Table(DOCX)Click here for additional data file."}
+{"text": "Correction to: BMC Plant Biol (2018) 18:293https://doi.org/10.1186/s12870-018-1514-zFollowing publication of the original article , a readeOriginal sentence:\u201cSeveral methods have been previously described or proposed for the isolation of male meiocytes [6], such as micromanipulation , capillary collection of meiocytes (CCM) , laser capture microdissection (LCM) in rice , Percoll gradient separation  and isolation of nuclei tagged in specific cell types (INTACT) in Arabidopsis [31].\u201dCorrected sentence:\u201cSeveral methods have been previously described or proposed for the isolation of male meiocytes [6], such as micromanipulation , capillary collection of meiocytes (CCM) , laser capture microdissection (LCM) in rice , Percoll gradient separation  and isolation of nuclei tagged in specific cell types (INTACT) in Arabidopsis [31].\u201d."}
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+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "Dr. Hodes will provide an overview of National Institute on Aging research priorities and funding availability."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The potential scarring effects of long-term youth unemployment and social disengagement have for many years challenged policymakers to develop successful and sustainable interventions."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "Cartesian differential categories are categories equipped with a differential combinator which axiomatizes the directional derivative. Important models of Cartesian differential categories include classical differential calculus of smooth functions and categorical models of the differential"}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "Following publication of the original article  the authOriginal Figure:Correct Figure:"}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "Following publication of the original article (Dilhari et al. The corrected figures are given below."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "This work was partly supported by the Research Council of Norway through its Centers of Excellence funding scheme (grant number 262700)\u2019."}
+{"text": "The Academy of Managed Care Pharmacy (AMCP) and the Foundation forManaged Care Pharmacy (FMCP) gratefully acknowledge the contributionsof many individuals who have devoted substantial time, expertise and commitmentin the preparation of the 3rd revision the AMCP Format for FormularySubmissions."}
+{"text": "Routine use of prolonged intermittent renal replacement therapy (PIRRT) in New Zealand and Canada is long established . Accordi"}
+{"text": "A peer-reviewed journal would not survive without the generous time and insightful comments of the reviewers, whose efforts often go unrecognized. Journal of Negative Results in BioMedicine has been blessed by the support of highly-qualified peer reviewers, and the Editor-in-Chief, Bjorn Olsen, and staff of the journal would like to show their appreciation by thanking the following for their invaluable assistance with review of manuscripts for the journal in Volume 12 (2013). Seena AjitUnited States of AmericaMohammed Al-GayyarEgyptLeonard BieloryUnited States of AmericaLeif BjermerSwedenRollin BrantCanadaChristine ChambersCanadaBradley ChippsUnited States of AmericaAldo ClericoItalyHans Edmund EckelAustriaMichael EisenhutUnited KingdomVera FarahBrazilFran GengoUnited States of AmericaBarbara HeroGermanyMelissa JamersonUnited States of AmericaTimo KoskenkorvaFinlandShozo KusachiJapanWalter LehmacherGermanyMaura MassiminoItalyBryony McNeillAustraliaCathryn MellershUnited KingdomEvelyn Marielle MonninkhofNetherlandsTakashi NagasawaJapanAnja NiehoffGermanyMelanie NoelUnited States of AmericaRobert OlneyUnited States of AmericaIsabel PalmeirimPortugalMichael PolkeyUnited KingdomDavid PriceUnited KingdomTheodore PriceUnited States of AmericaTimothy PrickettNew ZealandDieter ReinhardtCanadaJan RingersNetherlandsTibor RohacsUnited States of AmericaCelena Scheede-BergdahlCanadaFrode SlindeSwedenRoger StuppSwitzerlandEtsuji SuzukiJapanSoshi TakaoJapanJean TchervenkovCanadaDag ThelleSwedenSamuel VergesFranceDongfeng ZhangChina"}
+{"text": "Radiation Oncology would like to thank all our reviewers who have contributed to the journal in Volume 7 (2012).The editor of  Lauren AbreySwitzerlandMario AiroldiItalyIchiro AkagiJapanDavid AllanCanadaFilippo AlongiItalyMichelle Alonso-BasantaUnited States of AmericaDante AmelioItalyRichard AmosUnited States of AmericaFranc AnderluhSloveniaFundagul AndicTurkeyNicolaus AndratschkeGermanyCarmen AresSwitzerlandCynthia AristeiItalyVillers ArnauldFranceJonathan AshmanUnited States of AmericaVasileios AskoxylakisGermanyAvi AssoulineFranceDavid AzriaFranceKoichi AzumaJapanMatthias BacheGermanyKate BakCanadaDavid BallAustraliaVoichita Bar AdUnited States of AmericaIsabelle BarillotFranceThomas BarrUnited States of AmericaBahadir BatarTurkeyGlenn BaumanCanadaMartina BaumannAustriaBrigitta G. 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VerhoeffNetherlandsBhadrasain VIKRAMUnited States of AmericaAsgaut VisteNorwayPeter VoetNetherlandsMichael VogelbaumUnited States of AmericaIvan VogeliusDenmarkDirk VordermarkGermanyJacqueline VukyUnited States of AmericaPhyllis WachsbergerUnited States of AmericaHitoshi WadaJapanMargaret WallingtonAustraliaXiaochun WangUnited States of AmericaDongxu WangUnited States of AmericaUte Warnecke-EberzGermanyDavid WaterhouseAustraliaDamien Charles WeberSwitzerlandGeorge WeinerUnited States of AmericaChristian WeissGermanyGrit WelzelGermanyZhifei WenUnited States of AmericaThomas G. WendtGermanyFrederik WenzGermanyLamberto WidesottItalyJ\u00fcrgen WilbertGermanyFrank WillekeGermanyJacqueline WilliamsUnited States of AmericaElena WilsonUnited KingdomSebastian WinklhoferSwitzerlandJeffrey WongUnited States of AmericaBinbin WuUnited States of AmericaQ. 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+{"text": "Journal of Translational Medicine would like to thank all our reviewers who have contributed to the journal in Volume 11 (2013).The editors of  Katharine AbbaUnited KingdomMario Abbud-FilhoBrazilUssama AbdelUnited States of AmericaAlice Abdel AleemQatarAbhinav AcharyaUnited States of AmericaRaffaele AddeoItalyDaniel AeschlimannUnited KingdomBharat AggarwalUnited States of AmericaDavide AgnelloFranceVincent AgnelloUnited States of AmericaAnurag AgrawalIndiaJing AiChinaPinar AkcakayaSwedenMohammed AkhtarUnited KingdomNehad AlajezSaudi ArabiaSalah-Eddin Al-BatranGermanyRamon AlemanySpainLuis F AlguacilSpainRadica AlicicUnited States of AmericaMalcolm AlisonUnited KingdomHeike AllgayerGermanyFahd Al-MullaKuwaitCestmir AltanerSlovakiaRui Amaral MendesPortugalRobert AmatoUnited States of AmericaShe-Juan AnChinaYi Hua AnChinaHelen AngellFranceMakoto AnrakuJapanAlessandro AntonelliItalyLionel ApetohFranceAndrew AplinUnited States of AmericaMaria Virginia AppleyardUnited KingdomMinoti ApteAustraliaPaolo AreseItalyAtsushi ArugaJapanJunichi AsaumiJapanMaria Libera AsciertoUnited States of AmericaPaolo A. AsciertoItalyVasilios AthyrosGreeceJoanne AttemaAustraliaMichaela AubeleGermanyCharles AuffrayFranceKaren AvrahamIsraelHammadi AyadiTunisiaYasu-Taka AzumaJapanGunnar BaatrupDenmarkHideo BabaJapanMatthias BacheGermanyAtul BagulUnited KingdomLi-Yuan BaiTaiwanYu-Xian BaiChinaMei BakerUnited States of AmericaMichael BallsUnited KingdomAndrea BalsariItalyArun BandyopadhyayIndiaGautam BanerjeeIndiaRathindranath BaralIndiaJonathan BarrattUnited KingdomJirina BartunkovaCzech RepublicVinicius BassanezeBrazilAnalabha BasuIndiaDavide BedognettiUnited States of AmericaMatteo BelloneItalyHelmut BeltraminelliSwitzerlandAndreas BembenekGermanyFabian BenenciaUnited States of AmericaAngela BentivegnaItalyCarmen BerasainSpainMaria Ester BernardoItalyLaia Bernet VegueSpainMichel BernierUnited States of AmericaCyril BerthetFranceFederico BertuzziItalyLevi BeverlyUnited States of AmericaSuk Ho BhangKorea, SouthDwaipayan BharadwajIndiaShephali BhatnagarUnited States of AmericaNisan BhattacharyyaUnited States of AmericaXiu-Wu BianChinaZhaoxiang BianHong KongLuigi BianconeItalyAriane BieblAustriaCatherine BisbalFranceMichael BittnerUnited States of AmericaJames BlanchetteUnited States of AmericaMartin BluthUnited States of AmericaPaul BognerUnited States of AmericaMargherita BonamicoItalyMartin BonaminoBrazilRoumiana BonevaUnited States of AmericaKatherine BordenCanadaLuciana BordinItalyJeffrey BorgiaUnited States of AmericaEmanuela BostjancicSloveniaPavel BouchalCzech RepublicJason BovenkerkUnited States of AmericaJames BowenCanadaKarim BrandtSwitzerlandMichel BraunBelgiumXandra BreakefieldUnited States of AmericaPatrick BrehenyUnited States of AmericaEkua BrenuAustraliaMeredith BriscoUnited States of AmericaRaf BrounsBelgiumLindsay BrownAustraliaNoor Np BuchholzUnited KingdomDaniel BuergyGermanyAbdelbaset BuhmeidaSaudi ArabiaRonald BukowskiUnited States of AmericaKimberly BullockUnited States of AmericaLuigi BuonaguroItalyDennis BurtonUnited States of AmericaLudovico ButiUnited KingdomNiels Henrik BuusDenmarkElif CadirciTurkeyYouqun CaiChinaRodrigo CaladoBrazilAlessandro CannavoUnited States of AmericaMartin CannonUnited States of AmericaYa CaoChinaConcetta CastillettiItalyJustin CatesUnited States of AmericaChristelle CauffiezFranceChristophe CauxFranceCharles CazanaveFranceGiovanna CenacchiItalySimone CenciItalyGediminas CepinskasCanadaLaurence ChanUnited States of AmericaStephanie ChangUnited States of AmericaYu-Sun ChangTaiwanCaroline ChapmanUnited KingdomMark CharikerUnited States of AmericaJaruek CharoensapThailandCaifu ChenUnited States of AmericaChu-Huang ChenUnited States of AmericaChung-Ming ChenTaiwanHonglei ChenChinaHuei-Wen ChenTaiwanJin-Qiang ChenUnited States of AmericaTianxiang ChenChinaXi ChenChinaYidong ChenUnited States of AmericaYih-Sharng ChenTaiwanYong-Peng ChenChinaZhe-Sheng ChenUnited States of AmericaPi-Wan ChengUnited States of AmericaChandramu ChettyUnited States of AmericaHarvinder Singh ChhabraIndiaMaurizio Chiriva-InternatiUnited States of AmericaSridar ChitturUnited States of AmericaBartosz ChmielowskiUnited States of AmericaThinle ChodonUnited States of AmericaKyungmee ChoiKorea, SouthLotfi ChouchaneQatarLouis ChowHong KongI-Min ChuTaiwanGoh Eun ChungKorea, SouthMarcello CiaccioItalyGennaro CilibertoItalyCaterina CintiItalySara CiviniUnited States of AmericaGiovanni CizzaUnited States of AmericaFrancois X ClaretUnited States of AmericaGillian CockerillUnited KingdomMatteo CoenSwitzerlandAlan CohenCanadaPeter CohenUnited States of AmericaBegonya Comin-AnduixUnited States of AmericaGuillaume CounotteNetherlandsLisa CoussensUnited States of AmericaBrendon CoventryAustraliaFrancesca CrobuItalyJianxiu CuiChinaQinghua CuiChinaFulvio D'acquistoUnited KingdomNeetu DahiyaUnited States of AmericaMarc DahlkeGermanyTina DalianisSwedenAshraf DallolSaudi ArabiaDeborah DamonUnited States of AmericaAdrian Daneri-NavarroMexicoAlexandros DaponteGreeceSilvia Darb-EsfahaniGermanyRavi DasuUnited States of AmericaJharna DattaUnited States of AmericaFarshid DayyaniUnited States of AmericaJonathan D'cunhaUnited States of AmericaPiergiuseppe De BerardinisItalyAndrea De MariaItalyValli De ReItalyDominique De SenyBelgiumAyesha De SouzaUnited KingdomNuria Del OlmoSpainLaurie DeleveUnited States of AmericaMario DelgadoSpainLiane DeligdischUnited States of AmericaLF Dell'ossoUnited States of AmericaLucia Gemma DeloguItalySandra DemariaUnited States of AmericaNerina DenaroItalyJing-Yu DengChinaYuan DengChinaSebastien DeshayesFranceAngela Di BaldassarreItalyMassimo Di MaioItalyCatherine DiefenbachUnited States of AmericaMarie-Caroline Dieu-NosjeanFranceXiangwu DingChinaXiaoqiang DingChinaElena DogliottiItalyDonald DollUnited States of AmericaRosario DonatoItalyAlena DondaSwitzerlandHailong DongChinaZizheng DongUnited States of AmericaFrede DonskovDenmarkLeonardo Dos SantosBrazilW. 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Laricchia-RobbioSpainPernille LassenDenmarkNajma LatifUnited KingdomLorenza LazzariItalyManuel LealSpainVirna LeanerSouth AfricaJongho LeeKorea, SouthMong Hong LeeUnited States of AmericaAsada LeelahavanichkulThailandWillem LemsNetherlandsNikoletta LendvaiUnited States of AmericaLaura LentiniItalyGeorg LenzGermanyGregory LesinskiUnited States of AmericaPei-Feng LiChinaJing LiUnited States of AmericaJinjun LiChinaJun LiChinaMin LiUnited States of AmericaRui LiChinaGiovanni Li VoltiItalyHan LiangChinaEvi LianidouGreeceMichael LiebmanUnited States of AmericaYang LifangChinaLiu LijiangChinaJizhen LinUnited States of AmericaKonghua LinJapanSheng-Xiang LinCanadaShi-Ming LinTaiwanYi LinUnited States of AmericaZhao LinUnited States of AmericaLisa LindesmithAfghanistanWenhua LingChinaAlexander LinkGermanyDaniela LisiniItalyChun-Fu LiuChinaDe-Pei LiuChinaHongmin LiuUnited KingdomLei LiuChinaMingyao LiuCanadaQi LiuUnited States of AmericaQi-Fa LiuChinaRan LiuChinaRong LiuChinaWanli LiuChinaYan LiuChinaYu-Ming LiuTaiwanMarkus W. L\u00f6fflerGermanyA. Inkeri LokkiFinlandLucia LopalcoItalyElena LopezSpainJose Antonio Lopez-GuerreroSpainFrazer LoweUnited KingdomBin LuChinaHua LuUnited States of AmericaJiamiao LuUnited States of AmericaPei-Jung LuTaiwanQun LuUnited States of AmericaShixin LuChinaTracy LuckhardtUnited States of AmericaCora LuedersGermanyAlessandro LugliSwitzerlandVivian LuiUnited States of AmericaDavid LumUnited States of AmericaChristina LundSwedenTroy LundUnited States of AmericaMaria LungHong KongPer Johan LuthmanUnited States of AmericaMing-Chieh MaTaiwanStephanie MaHong KongXinliang MaUnited States of AmericaMichael MaesThailandDavide MaggiItalyJared MagnaniUnited States of AmericaMitra Mahdavi-MazdehIranJohn MaherUnited KingdomToivo MaimetsEstoniaArindam MaitraIndiaAjay MakerUnited States of AmericaJames MaloneyUnited States of AmericaKwan ManChinaMario MandalaItalyMasoud ManjiliUnited States of AmericaMaurilio MarcacciItalyArivusudar MarimuthuIndiaJose MarinSpainFrancesco MarincolaUnited States of AmericaDimitra MarioliGreeceAthina MarkouUnited States of AmericaSvetomir MarkovicUnited States of AmericaEva Martinez-BalibreaSpainYoshinori MarunakaJapanGiuseppe MasucciSwedenAnt\u00f3nio MataPortugalSuresh MathivananAustraliaScot MatkovichUnited States of AmericaHisahiro MatsubaraJapanYutaka MatsudaJapanMichael A. MatthayUnited States of AmericaNicola MaureaItalyJoan MaurelSpainHani MawardiUnited States of AmericaRyan MaysUnited States of AmericaJ Philip MccoyUnited States of AmericaBrent MccrightUnited States of AmericaKenneth McgaffinUnited States of AmericaTara McmorrowIrelandRobert MedcalfAustraliaShikhar MehrotraUnited States of AmericaNehal MehtaUnited States of AmericaIgnacio MeleroSpainDavid MelodelimaFranceXianmei MengUnited States of AmericaTiziana MeschiItalyClement MesedaUnited States of AmericaJames MezhirUnited States of AmericaLindsey MilesUnited States of AmericaWilson Miller Jr.CanadaRowan MilnerUnited States of AmericaMaria Chiara MimmiItalyWei-Ping MinCanadaBoris MinevUnited States of AmericaSalvatore MinisolaItalyDavid MinorUnited States of AmericaLaura MitrofanFranceChristopher MizerUnited States of AmericaHiroshi MizunoJapanSimone MocellinItalyRalph MocikatGermanyRajesh MohanrajUnited Arab EmiratesLenny MoiseUnited States of AmericaMyth MokAustraliaJan MolNetherlandsMiguel-Angel Molina-VilaSpainCarlomaurizio MontecuccoItalyAugusto MontezanoUnited KingdomJulia MontgomeryCanadaJan-Renier MoonenNetherlandsRonald MooreCanadaViolaine MoreauFranceDavid MorrisAustraliaPavlos MsaouelUnited States of AmericaHong-Hua MuUnited States of AmericaBrigitte Mueller-HilkeGermanySumanta MukherjeeUnited States of AmericaHans Werner M\u00fcllerGermanyElizabeth MumperUnited States of AmericaSachiko MuraseUnited States of AmericaAntonino MusolinoItalyIoannis MylonasGermanyAlessio NaccaratiItalyCristina NadalSpainSilvio NadalinGermanyJayasree NairUnited States of AmericaNoriaki NakaiJapanNobuhiro NakamotoJapanTetsuya NakatsuraJapanEiichi NakayamaJapanJeong-Seok NamKorea, SouthKaavya NarasimhaluSingaporeUrs NaterGermanyShoji NatsugoeJapanFrank NayaUnited States of AmericaSadaf NazPakistanArmando NegriArgentinaBrad NelsonCanadaWilliam NelsonUnited States of AmericaDirk M. NettelbeckGermanyManish NeupaneUnited States of AmericaDaniel NeureiterAustriaEllen NevenBelgiumBrian NevilleUnited KingdomAkira NifujiJapanJan NilssonSwedenTorbj\u00f6rn NilssonSwedenKatharina NimptschGermanyTao NingChinaPaola NisticoItalyChristopher NiyibiziUnited States of AmericaJoseph NkololaUnited States of AmericaConstance NoguchiUnited States of AmericaSongmi NohKorea, SouthKeith NolopUnited States of AmericaShigeaki NonoyamaJapanGiuseppe Danilo NorataItalyTarcisio NotItalyTakahiro OchiyaJapanMatthias OckerGermanyJos\u00e9-Enrique O'connorSpainNorma O'donovanIrelandPaul OgburnQatarKeiichi OhshimaJapanJeanne OiticicaBrazilSeiichi OkabeJapanHideho OkadaUnited States of AmericaDaniel OliveFranceOluwadayo OluwadaraUnited States of AmericaFrank OndreyUnited States of AmericaAlexander OpotowskyUnited States of AmericaAlexander OpotowskyArubaEster OrlandiItalyPablo Ortega-DeballonFranceBrenna OsborneAustraliaNurhan OzluTurkeyFrederic PadillaFranceDebnath PalIndiaPeter PaleseUnited States of AmericaNicolas PalletFranceGiuseppe PalmieriItalyNicola PalmieriItalyRogelio J Palomino-MoralesSpainMassimo PancioneItalyGopal PandeIndiaHardev PandhaUnited KingdomRungnapa Pankla SranujitThailandConstantinos PantosGreeceAntonio PaoliItalyLaszlo PappUnited KingdomLuther Lalit Kumar Parameswaran GraceSwedenVincenzo ParisiItalyMaura ParkerUnited States of AmericaGiorgio ParmianiItalyGeorge PatrinosGreeceJuan D. Pedrera-ZamoranoSpainYing PengChinaYu-Zhu PengChinaJeroen PenningsNetherlandsKristina PennistonUnited States of AmericaAleth PerdrigerFranceRolando PerezCubaAlessandro PerrellaItalyLars J PetersenDenmarkUlrich PfefferItalyMark PickardUnited KingdomPeter PickkersNetherlandsGabriella PietraItalyMartina PigazziItalyAlessandro PileriItalyAsha PillaiUnited States of AmericaBeena PillaiIndiaShari Pilon-ThomasUnited States of AmericaJef PinxterenBelgiumMaria Pia PistilloItalyMartin PlayfordUnited States of AmericaNicole PohlUnited States of AmericaWaldemar PopikUnited States of AmericaLaura PorrettiItalyGiuseppe PortellaItalyGeorge PotamiasGreeceJacques PouyssegurFranceThomas PovsicUnited States of AmericaSreenivasa PrasadIndiaEnrico ProiettiItalyJoseph ProvostUnited States of AmericaGrzegorz K. PrzybylskiPolandPeiyu PuChinaIgor PuzanovUnited States of AmericaJie QiaoChinaHaibo QiuChinaPeter QuesenberryUnited States of AmericaSamuel RabkinUnited States of AmericaLluigi RacioppiUnited States of AmericaAnne RaimondoUnited KingdomMayur RameshUnited States of AmericaElena RanieriItalyHeikki RantalaFinlandBenedetta RaspiniItalyCyril RauchUnited KingdomPierre-Emmanuel RautouFranceMichael ReedijkCanadaJo-Anna ReemsUnited States of AmericaAbdul RehmanPakistanAndrea RemoItalyJiaqiang RenUnited States of AmericaJia-Qiang RenUnited KingdomPei-Gen RenChinaTao RenChinaXiaoping RenUnited States of AmericaDomenico RendinaItalyYuan R-HTaiwanDomenico RibattiItalyMaria Manuela RiganoItalyRenata RihaUnited KingdomDavid RimmUnited States of AmericaJoseph RissUnited States of AmericaMartin RivasSpainTadeusz RobakPolandJason RobertsUnited States of AmericaLewis RobertsUnited States of AmericaMargo RobertsUnited States of AmericaPaul RobertsUnited States of AmericaAldo RoccaroUnited States of AmericaRafael RochaBrazilAllen RodgersSouth AfricaLuis RodrigoSpainLeonardo RoeverBrazilJoseph RogersUnited States of AmericaRichard RokytaCzech RepublicJana RolffGermanyGuanghua RongChinaShawn RoseUnited States of AmericaRafael RosellSpainMichael RosenblumUnited States of AmericaYvonne RosensteinMexicoReema RoshanIndiaGiulio RossiItalyVioleta RusUnited States of AmericaCatherine RushAustraliaRasna SabharwalUnited States of AmericaNorihisa SaekiJapanP\u00e5l S\u00e6tromNorwayZhi Xin SahnChinaKhashayar SakhaeeUnited States of AmericaSeema SaksenaUnited States of AmericaTakashi SakuJapanAntonio SalgadoPortugalMichael SalmanCanadaLabidi-Galy Sana IntidharFranceLinda SandellUnited States of AmericaWilliam SandersUnited States of AmericaRandeep SanghaCanadaDario SangioloItalyDaniele SantiniItalyLaura SanzSpainZoltan SapiHungaryAnna SaponeItalyDevanand SarkarUnited States of AmericaSeetharama Sastry KonduruQatarNoriyuki SatoJapanYukie Sato-KuwabaraBrazilJohn SayerUnited KingdomChris ScarlettAustraliaFrancesco Paolo SchenaItalyDolores J. SchendelGermanyGabriella SchieraItalyIngolf SchimkeGermanyHenrik SchmidtDenmarkRoland SchmittSwedenJonathan SchneckUnited States of AmericaJoachim SchneiderGermanyReinhard SchneiderLuxembourgStephen SchneiderUnited States of AmericaRalf SchubertGermanyHanneke SchuitemakerNetherlandsGerold SchulerGermanyHildegard M. SchullerUnited States of AmericaJoachim SchultzeGermanyAlbrecht SchwabGermanyAlfredo ScillitaniItalyMichael SeamanUnited States of AmericaWerner SeegerGermanyLudovica SegatItalyKim SeltingUnited States of AmericaPatricia SemedoBrazilNilkantha SenUnited States of AmericaShantanu SenguptaIndiaMukund SeshadriUnited States of AmericaAlex SgambatoItalyRachana ShahUnited States of AmericaAasef ShaikhUnited States of AmericaJingxuan ShanQatarAnil ShankerUnited States of AmericaThomas ShanleyUnited States of AmericaArulkumaran ShanmugamUnited States of AmericaMukut SharmaUnited States of AmericaR ShawUnited KingdomQing-Bai SheUnited States of AmericaFarah SheikhUnited States of AmericaBairong ShenChinaChia-Rui ShenTaiwanLizong ShenChinaXian ShenChinaXizhong ShenChinaWang ShengChinaSung Joon ShinKorea, SouthKen ShinmuraJapanAtsushi ShiozakiJapanAlex ShorttUnited KingdomImad ShureiqiUnited States of AmericaJason SicklickUnited States of AmericaRoswitha SienerGermanyAndre R. SimonUnited KingdomJosko SindikCroatiaPankaj SinghUnited States of AmericaBruno SinnGermanySandhya SitasawadIndiaCristina SkrypnykBahrainRoman SkulecCzech RepublicJohn SleasmanUnited States of AmericaDavid SmadjaFranceEvelien SmitsBelgiumElke SokoyaAustraliaLibing SongChinaLijun SongChinaRichie SoongSingaporeHermona SoreqIsraelFederica SotgiaUnited KingdomClaudio SpadaItalyGiulio C. SpagnoliSwitzerlandPaul SpanNetherlandsBart SpeeNetherlandsClaude SportesUnited States of AmericaDonatella SpottiItalyThilo SprengerGermanyPaul SquiresUnited KingdomGeetha SrikrishnaUnited States of AmericaGiovanni StalloneItalyMaria StamelouGreeceNorbert StefanGermanyUlrike SteinGermanyR. Scott StephensUnited States of AmericaChristian StockGermanyNikolas Hendrik StoeckleinGermanyKatarzyna Stolarz-SkrzypekPolandWalter StorkusUnited States of AmericaDavid StroncekUnited States of AmericaJeppe SturisDenmarkAuguste SturkNetherlandsChangqing SuChinaAnthony SuffrediniUnited States of AmericaKimberly SulivanUnited States of AmericaBaocun SunChinaHongye SunChinaHui-Chuan SunChinaWei SunChinaXueying SunNew ZealandJian SuoChinaAnil SuriIndiaAladar SzalayUnited States of AmericaMario SznolUnited States of AmericaElda TagliabueItalyPierosandro TagliaferriItalyChien-Kuo TaiTaiwanMasafumi TakahashiJapanTakashi TakataJapanNaokazu TakedaJapanEng M TanUnited States of AmericaHao TangChinaJun-Ming TangChinaKai-Fu TangChinaLi TangChinaWei TangJapanHideki TanzawaJapanYongguang TaoChinaSeyed Khosrow TayebatiItalyBin Tean TehItalyMuy-Teck TehUnited KingdomSeagal Teitz-TennenbaumUnited States of AmericaMustafa TekinUnited States of AmericaGrethe TellNorwayMasaki TerabeUnited States of AmericaWolfgang ThaslerGermanyMartin ThelinSwedenGeorge TheodoropoulosGreeceChristoph ThiemermannUnited KingdomLing TianChinaWen-Dong TianChinaHwei-Fang TienTaiwanTakashi TokinoJapanSara TomeiQatarJorge ToroUnited States of AmericaTomomi ToubaiUnited States of AmericaCyril TouboulFranceMarek TreimanDenmarkGiovanni TripepiItalyJakob TroppmairAustriaKwong TsangUnited States of AmericaMasahiko TsujiiJapanMasayuki TsunekiUnited States of AmericaSandra TuyaertsBelgiumLorenzo UccelliniUnited States of AmericaKrishna UdayakumarUnited States of AmericaHirotsugu UemuraJapanMichae UhlinSwedenMF UllahIndiaMasuko Ushio-FukaiUnited States of AmericaDaniel ValleraUnited States of AmericaWillem Jan Marie Van De VenBelgiumPeter Van Der KraanNetherlandsMartine Van GrotelNetherlandsInge Van HoudtNetherlandsFrederik-Jan Van SchootenNetherlandsViggo Van TendelooBelgiumMenno Van ZelmNetherlandsGuido VanhamBelgiumRavi VaratharajaluUnited States of AmericaMarileila Varella-GarciaUnited States of AmericaCatalin VasilescuRomaniaDavid VaudryFranceJuergen VeeckGermanyVaneja VelenikSloveniaPedro L VeraUnited States of AmericaLaura Vera-RamirezSpainSamet VerimTurkeyBhavna VermaUnited States of AmericaFabio VesciniItalyJohn VettoUnited States of AmericaGiuseppe VezzoliItalyFabien VidalFranceFernando Vidal-VanaclochaSpainNatassia VieiraUnited States of AmericaJesus VillarSpainElizabeth VincanAustraliaMaria Luisa ViscianoItalySowmya ViswanathanCanadaMichele VitaccaItalyMassimo VitaleItalyIoannis VoutsadakisCanadaPremkumar Vummidi GiridharUnited States of AmericaNathan WallUnited States of AmericaW WaltherGermanyGang WangUnited States of AmericaGuanghu WangUnited States of AmericaHaibin WangChinaHonglin WangChinaJian WangChinaMong-Heng WangUnited States of AmericaShengdian WangChinaTing WangChinaWei WangChinaXiangdong WangChinaXuejun WangUnited States of AmericaYaohe WangUnited KingdomYingqun WangUnited States of AmericaYouzhen WangChinaYuan WangChinaZhou WangUnited States of AmericaZhu 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AmericaHiroaki YanagimotoJapanAn-Gang YangChinaDawei YangChinaHong YangUnited States of AmericaJianjun YangChinaLily YangUnited States of AmericaQingwu YangChinaZu-Guo YangChinaTakahiro YasuiJapanKosei YasumotoJapanLi YeUnited States of AmericaJim YeungUnited States of AmericaYongping YouChinaShiyu Long Yu LongChinaYongyi YuanChinaAnna ZaczekPolandMaurizio ZanettiUnited States of AmericaPaul ZarogoulidisGreeceFahd ZarroufUnited States of AmericaYekaterina ZaytsevaUnited States of AmericaJiping ZengChinaQingping ZengUnited States of AmericaYi ZengChinaThorsten ZenzGermanyGianpaolo ZerbiniItalyDimitrios ZeugolisIrelandGuo-Jun ZhangChinaLucy ZhangUnited States of AmericaXianglan ZhangKorea, SouthXiao-Shi ZhangChinaXu Dong ZhangAustraliaYu ZhangUnited States of AmericaZengli ZhangChinaZaorui ZhaoUnited States of AmericaGuoping ZhengAustraliaMin ZhengChinaShu ZhengChinaHuijun ZhiUnited KingdomAimin ZhouUnited States of AmericaChuanlong ZhuUnited States of AmericaZhitu ZhuChinaEwa ZiemannPolandAnna Linda ZignegoItalyMassimo ZolloItalyAmina ZoubeidiCanada"}
+{"text": "The editors of BMC Immunology would like to thank all our reviewers who have contributed to the journal in Volume 14 (2013). Jakub AbramsonIsraelJoeri AertsBelgiumNeil AggarwalUnited States of AmericaOmid AkbariUnited States of AmericaRebeca Alonso-AriasSpainSusana AlvarezArgentinaYassine AmraniUnited KingdomAnna AnderssonSwedenAmilcar ArenalBrazilAli AshkarCanadaPaul AshwoodUnited States of AmericaDeshratn AsthanaUnited States of AmericaAthan BailletFranceAnand BalasubramaniUnited States of AmericaAlberto BaldiniItalyTaravat BamdadIranJames BaraniukUnited States of AmericaSurinder BatraUnited States of AmericaElyse BissonnetteCanadaUlrich BlankFranceRussell BlaylockUnited States of AmericaAntje BlumenthalAustraliaMaria Da Gloria Bonecini-AlmeidaBrazilKarina BortoluciBrazilMarcelo BozzaBrazilThorsten BrennerGermanyCharles BrownUnited States of AmericaTodd BruskoUnited States of AmericaPeter BurbeloUnited States of AmericaAnne CaignardFranceMartin CannonUnited States of AmericaMichael CarletonUnited States of AmericaBeatriz CarrenoUnited States of AmericaRobert ChevalierUnited States of AmericaSeok-Goo ChoSouth KoreaGeorge CiancioloUnited States of AmericaStephen CobboldUnited KingdomDavid CousinsUnited KingdomJulio CrodaBrazilMard Da\u00ebronFranceHong DaiUnited States of AmericaGautam DameraUnited States of AmericaJayasri Das SarmaIndiaLuis De La MazaUnited States of AmericaTom DecourseyUnited States of AmericaStephanie Dewitte-OrrCanadaUmberto DianzaniItalyDavid DockrellUnited KingdomTaylor DohertyUnited States of AmericaHarry DolstraNetherlandsJeffrey EbersoleUnited States of AmericaBernd EchtenacherGermanyTatjana EigenbrodGermanyAbdallah ElkhalUnited States of AmericaAnat Erdreich-EpsteinUnited States of AmericaMonica FaccoItalyChiara FenoglioItalyConstantin FeselPortugalBrian FifeUnited States of AmericaCarlos FloresSpainClaudio FozzaItalyAdam Enver FramptonUnited KingdomAlessandra FrancoUnited States of AmericaJianing FuUnited States of AmericaPatricia FulkersonUnited States of AmericaOlivier GarraudFranceParamita GhoshUnited States of AmericaBernhard F GibbsUnited 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MaritsSwedenBen MarslandSwitzerlandMar\u00eda Mart\u00ednez-EsparzaSpainMitsuru MatsumotoJapanAnne Kathrin MausbergGermanyJuan Manuel Mejia-ArangureMexicoTuuli MetsvahtEstoniaDavid MeyaUgandaGerd Meyer Zu H\u00f6rsteGermanyAruna MittalIndiaPhilippe MoingeonFranceMarkus MollSwedenMarcin MoniuszkoPolandLaurence MorelUnited States of AmericaLaura MorfSwitzerlandEiichi MoriiJapanJames MossUnited States of AmericaEric MosselUnited States of AmericaDimitrios MougiakakosGermanyVictoriano MuleroSpainMichael MullerAustraliaDavid MullinsUnited States of AmericaKimihiko NakataniJapanMaki NakayamaUnited States of AmericaAlistair NobleUnited KingdomSusanne NylenSwedenNobuo OkahashiJapanEbru Olgun ErdemirTurkeyConnor O'MearaAustraliaEric OswaldFranceGeorge Pappas-GogosGreeceNikhat ParveenUnited States of AmericaMarina Pasca Di MaglianoUnited States of AmericaDaniel PerryUnited States of AmericaLuca PersaniItalyPaul PfefferUnited KingdomKenneth PollardUnited States of AmericaIlaria PuxedduItalyGovindarajan RajagopalanUnited States of AmericaRoger Keith ReevesUnited States of AmericaAlexandre ReisBrazilEleanor RileyUnited KingdomFabricio Rios-SantosBrazilChiara RomagnaniGermanyLijun RongUnited States of AmericaStefano RossettiUnited States of AmericaAndrew RowleyUnited KingdomNadine RujeniRwandaMat\u00edas S\u00e1enz-CuestaSpainSampa SantraUnited States of AmericaGhanashyam SarikondaUnited States of AmericaMarion ScharpfeneckerNetherlandsStephan SchlickeiserGermanyBianca SchneiderGermanyChristian Sch\u00f6nbachJapanMichael SeamanUnited States of AmericaM\u00e5rten SegelmarkSwedenBoualem SendidFranceYechiel ShaiIsraelTakeshi ShimosatoJapanYehuda ShoenfeldIsraelThomas SissonUnited States of AmericaMonica Fisher SmikleJamaicaVsevolod SmolianovGermanyWenchao SongUnited States of AmericaCate SpeakeUnited States of AmericaLisa SpencerUnited States of AmericaAndreas SpittlerAustriaDeogratius SsemwangaUgandaStephen St JeorUnited States of AmericaSimona StagerCanadaMelanie StumpfUnited States of AmericaChuan SuChinaJie SunUnited States of AmericaKei TakahashiJapanBeatriz Tavares Costa CarvalhoBrazilElma TchilianUnited KingdomAlberto TedeschiItalyWayne ThomasAustraliaWolfgang TillingerAustriaMasanori TohnoJapanGiovanni TononItalyTim TreeUnited KingdomMarten TrendelenburgSwitzerlandMarita Troye-BlombergSwedenAkihito TsubotaJapanSung Hee UmSouth KoreaLuc Van KaerUnited States of AmericaAudard VincentFranceMark WalletUnited States of AmericaDapeng WangUnited States of AmericaClemens WarnkeGermanyClive WasserfallUnited States of AmericaNapoleon WaszkiewiczPolandMarc WatheletUnited States of AmericaWinfried S WelsGermanyThilo WelschGermanyJohnna WesleyUnited States of AmericaGeert WiegertjesNetherlandsHeather WilsonUnited KingdomOla WinqvistSwedenHao WuChinaAini XieUnited States of AmericaZhou XingCanadaMahesh YadavUnited States of AmericaKarina YazdanbakhshUnited States of AmericaLi YeUnited States of AmericaXiaozhou YingChinaSanhong YuUnited States of AmericaYangsheng YuUnited States of AmericaMargit ZeherHungaryAndrea ZelmerUnited KingdomMing ZengUnited States of AmericaJuan Carlos Zuniga-PfluckerCanada"}
+{"text": "Changes in foot and ankle posture are a normal aspect of infant and child development but may also reflect neurological conditions affecting the brain, spinal cord, peripheral nerves or muscles. Development of cavus or planus foot deformities often reflects underlying neurologic disorders and may predate development of more overt neurological signs. This session will concentrate upon signs and symptoms suggestive of occult neurologic problems in children presenting with positional or developmental abnormalities of the lower limbs."}
+{"text": "Radiation Oncology would like to thank all our reviewers who have contributed to the journal in Volume 8 (2013).The editors of  Mehmet Ufuk AbaciogluTurkeyRimpa AchariIndiaDaniel AebersoldSwitzerlandSung Hwan AhnKorea SouthEdwin AirdUnited KingdomFrancesca AlbertiniSwitzerlandValerie AlbrechtGermanyManuel AlgaraSpainBilal Al-NawasGermanyRavi AmaravadiUnited States of AmericaMaurizio AmichettiItalyRichard AmosUnited States of AmericaFundagul AndicTurkeyNicolaus AndratschkeGermanyWilhelm AnsorgeSwitzerlandHidefumi AoyamaJapanCarmen AresSwitzerlandCynthia AristeiItalyMolykutty AryankalayilUnited States of AmericaSabrina AstnerGermanyAlbert AttiaUnited States of AmericaMichele AvanzoItalyBatia AvniIsraelDavid AzriaFranceEishi BabaJapanEmilia BagiellaUnited States of AmericaAmit BahlUnited KingdomKurt BaierGermanyElizabeth BaldiniUnited States of AmericaMary Helen Barcellos-HoffUnited States of AmericaGuido BaroniItalyAlexandra BarrattAustraliaRolf BarthUnited States of AmericaNiels BasslerDenmarkYasser BayoumiSaudi ArabiaStanley BenedictUnited States of AmericaMustafa BenekliTurkeyRene Jean BensadounFranceTanya BerrangCanadaTheocharis BerrisAustriaChristoph BertGermanyS\u00bfAwomir BlamekPolandOliver BlanckGermanyNils BluthgenGermanyFlorian BockAustriaJudit Boda-HeggemannGermanyEdwin BoelkeGermanyTill Tobias B\u00f6hlenAustriaFran\u00e7oise BontempsBelgiumYerko BorgheroChristmas IslandAlberto BossiFranceDirk BottkeGermanyFrank BoudgheneFranceBarton BranstetterUnited States of AmericaPriscilla BrastianosUnited States of AmericaKlaus BratengeierGermanyMichael BremerGermanyCarsten BrinkDenmarkMartin BrownUnited States of AmericaKrzysztof BujkoPolandOmer BurnettUnited States of AmericaEdward ButlerUnited States of AmericaElisabetta CagniItalyFelipe CalvoSpainRaffaella CambriaItalyAntony CarverUnited KingdomJean-Michel CaudrelierCanadaCrister CebergSwedenLaura CellaItalyMustafa CengizTurkeyXiangfei ChaiUnited States of AmericaAnthony ChalmersUnited KingdomMarc ChamberlainUnited States of AmericaMaria ChanUnited States of AmericaAlbert ChangUnited States of AmericaJoe ChangUnited States of AmericaZheng ChangUnited States of AmericaSamuel ChaoUnited States of AmericaNaved ChaudhriGermanyFuxue ChenChinaJosephine ChenUnited States of AmericaRonald ChenUnited States of AmericaYuhchyau ChenUnited States of AmericaYu-Jen ChenTaiwanStephen ChiangUnited States of AmericaEui Kyu ChieKorea SouthNathan ChildressUnited States of AmericaRonny ChinUnited States of AmericaYoungmin ChoiKorea SouthJames ChowCanadaHans ChristiansenGermanyCaroline ChungCanadaHeeteak ChungUnited States of AmericaPeter ChungCanadaPatrizia CiammellaItalySavino CillaItalyAlessandro ClivioSwitzerlandBrian CollinsUnited States of AmericaSean CollinsUnited States of AmericaStephanie E. 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WendtGermanyMaria Werner-WasikUnited States of AmericaDavid WertheimUnited KingdomLukasz WieczorkowskiGermanyRuud WiggenraadNetherlandsHenrik WilmsUnited States of AmericaPaul WilsonUnited States of AmericaOlaf WittGermanyPhilip WongCanadaShiao WooUnited States of AmericaJackson WuCanadaPing XiaUnited States of AmericaFeng XuChinaXiao-Ying XueChinaPoonam YadavUnited States of AmericaDi YanUnited States of AmericaGuanghua YanUnited States of AmericaGary YangUnited States of AmericaRuijie YangChinaXinming YangChinaYong YangUnited States of AmericaZhenzhou YangChinaFang-Fang YinUnited States of AmericaLingshu YinUnited States of AmericaYoshihito YokoyamaJapanShunsuke YonaiJapanSua YooUnited States of AmericaKen YoshidaJapanCedric YuUnited States of AmericaJinming YuChinaSiu Ki YuHong KongYu YuanUnited States of AmericaNing YueUnited States of AmericaAngelika Zabel-Du BoisGermanyNikolaos ZamboglouGermanyVerena ZangenGermanySergei ZavgorodniCanadaMichael ZelefskyUnited States of AmericaCai ZhangChinaHaojian ZhangUnited States of AmericaHong ZhangUnited States of AmericaXiaodong ZhangUnited States of AmericaBoris ZhivotovskySwedenYuan ZhiyongChinaHong ZhouChinaJinyuan ZhouUnited States of AmericaPing-Kun ZhouChinaThomas ZilliSwitzerlandFrank ZimmermannSwitzerlandFaruk ZorluTurkeyDaniel ZwahlenSwitzerland"}
+{"text": "The editors of Molecular Pain would like to thank all the reviewers who have contributed to the journal in Volume 8 (2012). Andrew AhnUnited States of AmericaArmen AkopianUnited States of AmericaHakan AldskogiusSwedenDavid AnderssonUnited KingdomA. Vania ApkarianUnited States of AmericaQassim AzizUnited KingdomAlexandru BabesRomaniaMark BacceiUnited States of AmericaMark BakerUnited KingdomInna BelferUnited States of AmericaCarlos BelmonteSpainKelly BergUnited States of AmericaAndreas BeutlerUnited States of AmericaKnut BiberGermanyFiona BoissonadeUnited KingdomDavid BorsookUnited States of AmericaYves BoucherFranceTim BrennanUnited States of AmericaDavid BrownUnited KingdomPeter CabotAustraliaYu-Qing CaoUnited States of AmericaSusan CarltonUnited States of AmericaMichael CaterinaUnited States of AmericaGuido CavalettiItalyMyeounghoon ChaUnited States of AmericaHee-Jung ChoKorea SouthMacDonald ChristieAustraliaMan-Kyo ChungUnited States of AmericaMark S CooperUnited States of AmericaBarbara CostaItalyTheodore CumminsUnited States of AmericaYi DaiJapanAlexander DaviesKorea SouthBrian DavisUnited States of AmericaLucy DonaldsonUnited KingdomXinzhong DongUnited States of AmericaJonathan DostrovskyCanadaPatrick DoughertyUnited States of AmericaLiam DrewUnited States of AmericaPeter DrummondAustraliaPaul DurhamUnited States of AmericaGreg DussorUnited States of AmericaLars EdvinssonSwedenNobuaki EgashiraJapanNi FanUnited States of AmericaJill FehrenbacherUnited States of AmericaRoger FillingimUnited States of AmericaSue Fleetwood-WalkerUnited KingdomClemens ForsterGermanyKaj FriedSwedenHidemasa FurueJapanLouis GendronCanadaSandrine GerantonUnited KingdomUrs GerberSwitzerlandMichael GoldUnited States of AmericaPeter GoldsteinUnited States of AmericaElena GorodetskyUnited States of AmericaCyril GoudetFrancePeter GraceAustraliaYanping GuUnited States of AmericaKathryn HallUnited States of AmericaLiang HanUnited States of AmericaMenachem HananiIsraelKenneth HargreavesUnited States of AmericaAfton HassettUnited States of AmericaQuinn HoganUnited States of AmericaTomas HokfeltSwedenFiona HolmesUnited KingdomYuuichi HoriJapanHongzhen HuUnited States of AmericaLi-Yen HuangUnited States of AmericaMark HutchinsonAustraliaSun Wook HwangKorea SouthSoichiro IdeJapanHiroshi IkedaJapanJulia InglisAustraliaSeiji ItoJapanAkitoshi ItoJapanKoichi IwataJapanIl-Sung JangKorea SouthMichael JarvisUnited States of AmericaRu-Rong JiUnited States of AmericaElizabeth JosephUnited States of AmericaJames KangUnited States of AmericaFusao KatoJapanBradley KerrCanadaNorikazu KiguchiJapanShiroh KishiokaJapanKohei KogaCanadaToru KonoJapanMichaela KressAustriaTakashi KuriharaJapanMalin LagerstromSwedenC. Justin LeeKorea SouthJon LevineUnited States of AmericaYun-Qing LiChinaJie LiUnited States of AmericaEllen LumpkinUnited States of AmericaZhengLiang MaChinaQiufu MaUnited States of AmericaValerio MagnaghiItalyPatrick MantyhUnited States of AmericaJianren MaoUnited States of AmericaMarco MartinaUnited States of AmericaKoichi MasudaUnited States of AmericaSatoshi MatsuokaJapanDavid McKemyUnited States of AmericaFeng MeiChinaKarl MesslingerGermanyGregory MichaelUnited KingdomVjekoslav MileticUnited States of AmericaErin MilliganUnited States of AmericaMasabumi MinamiJapanJeffrey MogilCanadaYasuo MoriJapanTakayuki NakagawaJapanHiroyuki NakaiUnited States of AmericaTerumasa NakatsukaJapanIan NapierAustraliaJoseph NealeUnited States of AmericaTimothy NessUnited States of AmericaVolker NeugebauerUnited States of AmericaMami NodaJapanKoichi NoguchiJapanHideaki ObataJapanUhtaek OhKorea SouthSeog Bae OhKorea SouthMasahiro OhsawaJapanEnza PalazzoItalyZhizhong PanUnited States of AmericaMichele PapaItalyDaniela ParolaroItalyArdem PatapoutianUnited States of AmericaShane PerrineUnited States of AmericaJeffrey PetruskaUnited States of AmericaOlga PolSpainLouis PremkumarUnited States of AmericaTheodore PriceUnited States of AmericaLi-Ya QiaoUnited States of AmericaKe RenUnited States of AmericaFrank L. RiceUnited States of AmericaMeredith RobbinsUnited States of AmericaEdgar Alfonso Romero-SandovalUnited States of AmericaShivani RuparelUnited States of AmericaAnthony RushSwedenPaola SacerdoteItalyMichael SalterCanadaJana SawynokCanadaMartin SchmelzGermanyPhilippe SeguelaCanadaKenji SeoJapanBarry SessleCanadaHari ShankerSwedenBing ShenChinaShannon ShieldsUnited States of AmericaBai Chuang ShyuTaiwanRobert SikesUnited States of AmericaDonald SimoneUnited States of AmericaClaudia SommerGermanyMartin StebbingAustraliaEmanuel StrehlerUnited States of AmericaSarah SweitzerUnited States of AmericaLauren TaUnited States of AmericaYuan-Xiang TaoUnited States of AmericaIsaura TavaresPortugalAndrew ToddUnited KingdomMakoto TominagaJapanCarole TorsneyUnited KingdomMakoto TsudaJapanHiroshi UedaJapanMagda UlrichNetherlandsMark UrbanUnited States of AmericaYuriy UsachevUnited States of AmericaTodd VanderahUnited States of AmericaPedro VeraUnited States of AmericaYou WanChinaChristopher WatsonUnited States of AmericaFeng WeiUnited States of AmericaFletcher WhiteUnited States of AmericaBeth WinkelsteinUnited States of AmericaJohn WoodUnited KingdomLong-Jun WuUnited States of AmericaDavid WynickUnited KingdomTian-Le XuChinaGuang-Yin XuChinaIpek Yalcin-ChristmannFranceJay YangUnited States of AmericaRobert YezierskiUnited States of AmericaMyung ha YoonKorea SouthHanns Ulrich ZeilhoferSwitzerlandXu ZhangChinaJun-Ming ZhangUnited States of AmericaHailin ZhangChina"}
+{"text": "Journal of Experimental & Clinical Cancer Research would like to thank all our reviewers who have contributed to the journal in Volume 31 (2012).The editor of  Michael AbendGermanyByeong-Cheol AhnKorea SouthSheikh Mohammad Fazle AkbarJapanEiman AleemSwedenPaolo AmerioItalyJie AnUnited States of AmericaVibeke AndersenUnited KingdomHiroyoshi ArigaJapanV Satya Suresh AttiliIndiaGeorges BaffetFranceEnzo BerardescaItalyLothar BergmannGermanyVikas BhardwajUnited States of AmericaGuido BocciItalyLaura BonannoItalyGianluca BossiItalyGeorg BreierGermanyEmilio BriaItalyJan BussinkNetherlandsValentina CaraccioloUnited States of AmericaJason CarrollUnited KingdomPradeep Chaluvally RaghavanUnited States of AmericaYoon Soo ChangKorea SouthZhe ChangUnited States of AmericaShuzhen ChenUnited States of AmericaXian-Ming ChenUnited States of AmericaZihua ChenChinaWen-Fang ChengTaiwanVilai ChentanezThailandChi Hin ChoChinaWilliam CS ChoHong KongYen-Hung ChowTaiwanMara CironeItalyPierFranco ConteItalyAlfredo ContiItalyPierre CordelierFranceGiovanni CorsoItalyPaul CottuFranceBingbing DaiUnited States of AmericaEnrique de AlavaSpainJuan Carlos de VicenteSpainHongxin DengChinaJing-yu DengChinaMarc DenisFranceDanilo Di BonaItalyCherubino Di LorenzoItalySong-Ze DingChinaThomas DittmarGermanyJessica DoningtonUnited States of AmericaGabriella D'OraziItalyWenrui DuanUnited States of AmericaDan DudaUnited States of AmericaMohan EdirisingheUnited KingdomKarin Ekstrom SmedbySwedenFrancesco FaccioloItalyRita FalcioniItalyYue-Zu FanChinaDianchun FangChinaWeiyi FangChinaAmbrogio FassinaItalyFei FeiUnited States of AmericaFalko FendGermanyGlenn FluxUnited KingdomMarco FoliniItalyJing FuUnited States of AmericaJianmin FuChinaToshiyoshi FujiwaraJapanAmy FultonUnited States of AmericaMayuko FurutaJapanRossella GalatiItalyApar Kishor GantiUnited States of AmericaLina GaoUnited States of AmericaQinglei GaoChinaIsabella GashawGermanyMargaret GatesUnited States of AmericaParamita GhoshUnited States of AmericaPatrizio GiacominiItalyConstantinos GiaginisGreeceElena GigliaItalyAnna Gillio-TosItalyAntonio GiordanoItalyGlenda GobeAustraliaZihua GongUnited States of AmericaLaura GramantieriItalyAleksandar GrgicGermanyYan GuChinaAntonino GuerrisiItalyIan GuestUnited States of AmericaJunming GuoChinaCheng GuoChinaJoerg HaierGermanySubrata HaldarUnited States of AmericaInn-Oc HanKorea SouthJitti HanprasertpongThailandLorna HarriesUnited KingdomTakahiro HasebeJapanM. 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+{"text": "Biological Procedures Online has been blessed by the support of highly-qualified peer reviewers, and the Editor-in-Chief, Shulin Li, and staff of the journal would like to show their appreciation by thanking the following for their invaluable assistance with review of manuscripts for the journal in Volume 15 (2013).A peer-reviewed journal would not survive without the generous time and insightful comments of the reviewers, whose efforts often go unrecognized.  Maqusood AhamedSaudi ArabiaJoel BumgardnerUnited States of AmericaWim DHaezeUnited States of AmericaMarxa FigueiredoUnited States of AmericaMichael GeorgeUnited States of AmericaYan GuoUnited States of AmericaRonald JacksonUnited KingdomShisheng LiUnited States of AmericaBolin LiuUnited States of AmericaQI LiuUnited States of AmericaMauro ProvincialiItalyTetsuo ShibuyaJapanDebbal Sidi MohammedAlgeriaTodd StedefordUnited States of AmericaHong-Bo XieAustraliaJianhua YangUnited States of AmericaShaomian YaoUnited States of AmericaLiangfang ZhangUnited States of America"}
+{"text": "Malaria Journal would like to thank the following for their assistance with peer-review of manuscripts for the journal in 2012. Jane AchanUgandaNicole AcheeUnited States of AmericaHans AckermanUnited States of AmericaSelidji Todagbe AgnandjiGabonBartholomew AkanmoriCongoPietro AlanoItalySandra AlbaSwitzerlandAudrey Maud Sandrine AlbertiniSwitzerlandLetusa AlbrechtBrazilMichael AlifrangisDenmarkRichard AllenAustraliaStephen AllenUnited KingdomPaulo AlmeidaPortugalEvelyn Anane-SarpongGhanaRobin AndersAustraliaTim AndersonUnited States of AmericaTakeshi AnnouraNetherlandsNick AnsteyAustraliaPaolo AreseItalyGabriela Ar\u00e9valo Pinz\u00f3nColombiaElizabeth AshleyUnited KingdomPeter AtkinsonUnited States of AmericaJo-An AtkinsonAustraliaSarah AuburnUnited KingdomLorenz Auer-HackenbergAustriaPinarosa AvatoItalyVicky AveryAustraliaGordon AwandareGhanaJohn Kevin BairdIndonesiaDavid BakerUnited KingdomKathryn BarbaraUnited States of AmericaBridget BarberAustraliaKaren BarnesSouth AfricaGuy BarnishUnited KingdomAlyssa BarryAustraliaMaria-Gloria BasanezUnited KingdomLeonardo BascoFranceChristopher Guy BassUnited KingdomQuique BassatSpainImelda BatesUnited KingdomJake BaumAustraliaKatja BeckerGermanyJames BeesonAustraliaCharlotte BehrFranceRon BehrensUnited KingdomJohn BeierUnited States of AmericaEric BeitzGermanyDavid BellSwitzerlandChoukri Ben MamounUnited States of AmericaMark BenedictUnited States of AmericaRamona BenkertUnited States of AmericaAdam BennettUnited States of AmericaFrances BensonUnited KingdomAase BergNorwayElke Bergmann-LeitnerUnited States of AmericaJames BerkleyKenyaKlavs BerzinsSwedenNora BesanskyUnited States of AmericaAjay BhartiUnited States of AmericaAchuyt BhattaraiUnited States of AmericaSimone BiancoUnited States of AmericaAnne-Lise BienvenuFranceBeverley-Ann BiggsAustraliaPeter BillingsleyUnited States of AmericaOliver BillkerUnited KingdomZeno BisoffiItalySukla BiswasIndiaAnders BjorkmanSwedenSimon BlanfordUnited States of AmericaGreg BlatchSouth AfricaMoses BockarieUnited KingdomSteffen BorrmannGermanyEmmanuel BottieauBelgiumOlivier BouchaudFranceCatherine BourgouinFranceTeun BousemaUnited KingdomZbynek BozdechSingaporeBernard BrabinUnited KingdomLoretta BrabinUnited KingdomJohn BradleyUnited KingdomPhilippe BrasseurSenegalCatherine Braun BretonFranceJoel BremanUnited States of AmericaWilliam BriegerUnited States of AmericaOlivier Johan Tavai Bri\u00ebtSwitzerlandCristiana BritoBrazilRachel BronzanUnited States of AmericaBasil BrookeSouth AfricaReto BrunSwitzerlandKwame Ohene BuabengGhanaPierre BuffetFranceGerd BurchardGermanyTom BurkotAustraliaAlice ButterworthAustraliaIb Christian BygbjergDenmarkJens ByskovDenmarkAdriana CalderaroItalyCarlos CampbellUnited States of AmericaErmanno CandolfiFranceJorge Cano-OrtegaUnited KingdomFrancesco CastelliItalyCarlos Eug\u00eanio CavasiniBrazilProsper ChakiTanzaniaSrabasti Jayanti ChakravortyUnited KingdomPascalina Chanda-KapataZambiaDaniel ChandramohanUnited KingdomSandra ChangUnited States of AmericaJacques Derek CharlwoodDenmarkLin ChenUnited States of AmericaQin ChengAustraliaSheleme ChibsaEthiopiaJean-Philippe ChippauxFranceGerardo ChowellUnited States of AmericaPeter ChristensenAustraliaDennis ChristensenDenmarkThomas ChurcherUnited KingdomIan ClarkAustraliaArchie ClementsAustraliaLieselotte CnopsBelgiumJustin CohenUnited States of AmericaJames ColbornUnited States of AmericaWilliam CollinsUnited States of AmericaDavid ConwayUnited KingdomMarc Henri Carl CoosemansBelgiumStanton CopeUnited States of AmericaRoss CoppelAustraliaIsabelle CoppensUnited States of AmericaGiampietro CorradinSwitzerlandPatrick CorranUnited KingdomVladimir CorredorColombiaMichel CotFranceDavid CourtinBeninGraeme CowanUnited KingdomJanet Cox-SinghUnited KingdomPhilip CoyneUnited States of AmericaAlister CraigUnited KingdomJakob Peter CramerGermanyIan CrandallCanadaPedro CravoBrazilPeter CromptonUnited States of AmericaJuan CuadrosSpainLiwang CuiUnited States of AmericaRichard CulletonJapanAlexandre Da SilvaUnited States of AmericaVal\u00e9rie D'acremontSwitzerlandJohanna DailyUnited States of AmericaCyrus DaneshvarUnited KingdomJonathan DarbroAustraliaA. P. DashIndiaClaudia DaubenbergerSwitzerlandTim DavisAustraliaNicholas DayUnited KingdomTania De Koning-WardAustraliaJ. Brian De SouzaUnited KingdomJeremy DebarryUnited States of AmericaKirk DeitschUnited States of AmericaHernando A Del PortilloSpainCharles DelacolletteThailandAlessandra Della TorreItalyPhilippe DeloronFranceDavid DenlingerUnited States of AmericaEvelyn DepoortereBelgiumSilvia Di SantiBrazilGraciela DiapSpainAnelia DietmannAustriaCarlota DobanoSpainArjen M DondorpThailandStefan DongusUnited KingdomMartin DonnellyUnited KingdomDenise DoolanAustraliaChris DrakeleyTanzania & UKJoseph D'silvaUnited States of AmericaJean Pierre DubostFranceRemy DurandFranceHillegonda Maria Dutilh NovaesBrazilJeffrey DvorinUnited States of AmericaPhilip EckhoffUnited States of AmericaGeoffrey EdwardsUnited KingdomTimothy John EganSouth AfricaStephane EgeeFranceStephan EhrhardtUnited States of AmericaDaniel EibachFranceThomas EiseleUnited States of AmericaPaul EmersonUnited States of AmericaChristian EppGermanyEmily ErikssonAustraliaVolker ErmertGermanyAnanias EscalanteUnited States of AmericaRoberto EspositoItalyRick FairhurstUnited States of AmericaThierry FandeurFranceMarit FarenhorstNetherlandsJeremy FarrarViet NamJean-Fran\u00e7ois FaucherFranceGreg FeganKenyaIngrid FelgerSwitzerlandHeather FergusonUnited KingdomDavid FergusonUnited KingdomMarcelo FerreiraBrazilPedro FerreiraJapanMarianne FilletBelgiumUlrike FillingerUnited KingdomLawrence FleckensteinUnited States of AmericaDesmond FoleyUnited States of AmericaAdenilson FonsecaBrazilJeffrey FosterUnited States of AmericaFreya FowkesAustraliaBlandine Franke-FayardNetherlandsJohn FreanSouth AfricaFrederic ArieyFranceMichel FrederichBelgiumMichal FriedUnited States of AmericaFriedrich FrischknechtGermanyGabrielle FrobergSwedenMark FukudaUnited States of AmericaBenoit GamainFranceF. Javier GamoSpainDon GardinerAustraliaSimonetta GattiItalyMichelle GattonAustraliaDeepak GaurIndiaHellen GelbandUnited States of AmericaBlaise GentonSwitzerlandAnnette GerritsenSouth AfricaPeter GethingUnited KingdomJose Pedro GilSwedenPhilippe GilletBelgiumPaul GilsonAustraliaJohn GimnigUnited States of AmericaMichael GingerUnited KingdomHagai GinsburgIsraelDavid GittelmanUnited States of AmericaDean GoldringSouth AfricaIveth Jimena Gonz\u00e1lez Jim\u00e9nezSwitzerlandCatherine GoodmanKenyaRoly GoslingUnited States of AmericaMarimuthu GovindarajanIndiaD. Channe GowdaUnited States of AmericaPatricia GravesAustraliaMichael GreenUnited States of AmericaBryan GreenhouseUnited States of AmericaBrian GreenwoodUnited KingdomPhilippe GrellierFranceJamie GriffinUnited KingdomMartin Peter GrobuschNetherlandsKarin GrossSwitzerlandPhilippe GuerinUnited KingdomLina Andrea Gutierrez BuilesColombiaJulie GutmanUnited States of AmericaStefan HagmannUnited States of AmericaSimon HalesNew ZealandRachel HallettUnited KingdomKatherine HallidayUnited KingdomMary HamelUnited States of AmericaDavidson HamerUnited States of AmericaPenelope HancockUnited KingdomThomas H\u00e4nscheidPortugalLaura HarringtonUnited States of AmericaPaul HarrisonAustraliaJohn HartyUnited States of AmericaEmily HarvilleUnited States of AmericaIan HastingsUnited KingdomSusanna HausmannSwitzerlandMichael HawkesCanadaSimon HayUnited KingdomMichelle HelinskiUnited States of AmericaOlof HellgrenSwedenHenri VialFranceSocrates HerreraColombiaDennis HesselinkNetherlandsManuel W HetzelPapua New GuineaHelena HildenwallSwedenKhumbulani Welcome HlongwanaSouth AfricaMay HoCanadaAry HoffmannAustraliaAnthony HolderUnited KingdomMichael HollingdaleUnited States of AmericaHeinrich HoppeSouth AfricaPeter HorbyViet NamPaul HorrocksUnited KingdomSandrine HouzeFranceNatasha HowardUnited KingdomPaul HowllUnited States of AmericaMichelle HsiangUnited States of AmericaAustin HughesUnited States of AmericaPaul HuntUnited KingdomHilary HurdUnited KingdomLars HviidDenmarkKen IlettAustraliaSeth IrishUnited KingdomJan JacobsBelgiumRichard J\u00e4hnkeGermanyKeith JeromeUnited States of AmericaChandy JohnUnited States of AmericaJacob JohnsonKenyaDavid JollowUnited States of AmericaSomchai JongwutiwesThailandPernille JorgensenLaosIrina Tatiana JovelSwedenJonathan JulianoUnited States of AmericaS. Patrick KachurUnited States of AmericaLinda Kalilani-PhiriMalawiSeitaro KamiyaJapanRajeev KaushikIndiaSatoru KawaiJapanJames KazuraUnited States of AmericaJoseph KeatingUnited States of AmericaLouise Kelly-HopeUnited KingdomRichard KiangUnited States of AmericaAlbert KilianSpainGerry KilleenTanzaniaJung-Ryong KimThailandJean-Marie KindermansFranceKiaran KirkAustraliaDerryck KlarkowskiAustraliaTerry KleinUnited States of AmericaDaniel KlineUnited States of AmericaRobin KobbeGermanyLizette KoekemoerSouth AfricaJacob KoellaUnited KingdomHannah KoenkerUnited States of AmericaConstantianus J.M. KoenraadtNetherlandsCristian KoepfliAustraliaPoul-Erik KofoedDenmarkGilbert Onyango KokwaroKenyaEline KorenrompSwitzerlandBenno KreuelsGermanySanjeev KrishnaUnited KingdomJ\u00fcrgen Kr\u00fcckenGermanyMartin KulldorffUnited States of AmericaDaniel KyabayinzeUgandaSue KyesUnited KingdomDennis KyleUnited States of AmericaMarcus LacerdaBrazilPeter LacknerAustriaDavid LallooUnited KingdomTracey LambUnited States of AmericaAbigail LamikanraUnited KingdomJean LanghorneUnited KingdomMichael LanzerGermanyFrederic LardeuxBoliviaMiriam LauferUnited States of AmericaCatherine LavazecFranceMarc Le BorgneFranceJean-Yves Le HesranUnited KingdomKarin LederAustraliaPeter LeggatAustraliaLeslie LeiserowitzIsraelChristian LengelerSwitzerlandAnnick LengletNetherlandsHoe Nam LeongSingaporeToby LeslieUnited KingdomChae Seung LimKorea SouthKim LindbladeUnited States of AmericaSteve LindsayUnited KingdomBernt LindtjornNorwayTom LittleUnited KingdomFrancesca LittleSouth AfricaMegan LittrellUnited States of AmericaNeil LoboUnited States of AmericaRogelio Lopez-VelezSpainAndrew LoverSingaporeShirley LuckhartUnited States of AmericaLouise LudlowAustraliaJohn Peter Andrea LusinguTanzaniaAdrian LutyFranceSean LynchUnited States of AmericaCharles MaAustraliaMusawenkosi MabasoSouth AfricaVanessa MachaultFranceMargaret MackinnonKenyaAmanda MaestreColombiaPascal MagnussenDenmarkKathryn MaitlandUnited KingdomPawan MalhotraIndiaGustavo MalingerIsraelJessica MalthaBelgiumDenis MalvyFranceSylvie ManguinFranceRon P. 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RiedelGermanyMichelle RiehleUnited States of AmericaMarcus RijkenThailandEleanor RileyUnited KingdomFatima RivasUnited States of AmericaVincent RobertFranceJane RobertsonAustraliaPaul RoepeUnited States of AmericaWilliam RogersUnited States of AmericaStephen RogersonAustraliaChristophe RogierMadagascarPetra RohrbachCanadaRomain GirodFrench GuianaPhilip RosenthalUnited States of AmericaChristian RoussilhonFranceAlexander RoweUnited States of AmericaJose RubioSpainBruce RussellSingaporeTanya RussellTanzaniaElizeus RutebemberwaAngolaLora SabinUnited States of AmericaJohn SacciUnited States of AmericaAnavaj SakuntabhaiFranceAli SalantiDenmarkTobili Sam-YelloweUnited States of AmericaFaruk SarkinfadaNigeriaDemba SarrUnited States of AmericaRobert SauerweinNetherlandsDavid SaundersThailandAllan SchapiraSwitzerlandDavid SchellenbergUnited KingdomPatricia SchlagenhaufSwitzerlandWolfgang Hellmut SchmiedAustriaPetra SchneiderUnited KingdomSteve SchofieldCanadaDirk SchoonbaertBelgiumEvelin SchwarzerItalyK\u00e9zia ScopelBrazilAnna SealeUnited KingdomCarlo SeveriniItalyNaman ShahIndiaDennis ShanksAustraliaY.D. SharmaIndiaSurya Kant SharmaIndiaVinod SharmaIndiaTodd ShearerUnited States of AmericaClive ShiffUnited States of AmericaDelane ShingadiaUnited KingdomAddmore ShonhaiSouth AfricaCarol SibleyUnited States of AmericaBalbir SinghMalaysiaNeeru SinghIndiaAndre SiqueiraBrazilJacek SkarbinskiUnited States of AmericaSuzanne SkevingtonUnited KingdomTina Skinner-AdamsAustraliaOle SkovmandFranceLarry SlutskerUnited States of AmericaJoseph SmithUnited States of AmericaThomas SmithSwitzerlandDavid SmithUnited States of AmericaGeorges SnounouFranceRobert William SnowKenyaAur\u00e9lia SouaresGermanyTobias SpielmannGermanyTrine StaalsoeDenmarkSarah StaedkeUgandaHenry StainesUnited KingdomDanielle StanisicAustraliaMichelle StantonUnited KingdomRebecca StanwaySwitzerlandLaura SteinhardtUnited States of AmericaRichard SteketeeFranceKasia StepniewskaThailandMary StevensonCanadaJonathan StilesUnited States of AmericaJose StouteUnited States of AmericaDaniel StrickmanUnited States of AmericaAngelika SturmAustraliaDavid SullivanUnited States of AmericaCatherine SutcliffeUnited States of AmericaColin SutherlandUnited KingdomTodd SwarthoutFranceJacek SzepietowskiPolandRachida Tahar-BascoFranceKawsar TalaatUnited States of AmericaAmbrose TalisunaKenyaArthur TalmanUnited KingdomDonatella TaramelliItalyGeoff TargettUnited KingdomJoel TarningThailandAndrew TatemUnited KingdomWrj TaylorThailandDiane TaylorUnited States of AmericaTerrie TaylorUnited States of AmericaSteve TaylorUnited States of AmericaAndrew Taylor-RobinsonUnited KingdomFabrizio TediosiSwitzerlandAnnemarie Ter VeenUnited KingdomKevin TettehUnited KingdomSylla ThiamKenyaJoanne ThompsonUnited KingdomAnna ThomsonSwedenJulie ThwingUnited States of AmericaLeann TilleyAustraliaChristian TimmannGermanyAlfred TionoBurkina FasoVincent P.K. TitanjiCameroonGabriella TorciaItalyJean Etienne TouzeFranceHarold TownsonUnited KingdomRichard TrenUnited States of AmericaKatharine TrenholmeAustraliaMarita Troye-BlombergSwedenTakafumi TsuboiJapanCj TuijnNetherlandsV UdhayakumarUnited States of AmericaRachanee UdomsangpetchThailandChairat UthaipibullThailandGlyn ValeZimbabweNeena ValechaIndiaAna M. Valles-MedinaMexicoWim Van BortelBelgiumKatarzyna Van Damme-OstapowiczPolandAnna Maria Van EijkEthiopiaJean-Pierre Van GeertruydenBelgiumAnn Van SchepdaelBelgiumJerome VanderbergUnited States of AmericaVeerle VanlerbergheBelgiumAshley VaughanUnited States of AmericaJefferson VaughanUnited States of AmericaMeera VenkatesanUnited States of AmericaJonathan VennerstromUnited States of AmericaHans VerhoefNetherlandsFederica VerraUnited KingdomJoseph VinetzUnited States of AmericaLorenz Von SeidleinAustraliaJohn VontasGreeceFrancis WafulaKenyaMats WahlgrenSwedenPatrick WalkerUnited KingdomEdward WalkerUnited States of AmericaCatherine WaltonUnited KingdomPing WangUnited States of AmericaDavid WarhurstUnited KingdomNorman WatersUnited States of AmericaMarcia R WeaverUnited States of AmericaJayne WebsterUnited KingdomWalter WeissUnited States of AmericaTimothy WellsSwitzerlandDavid WenkertUnited States of AmericaWalther WernsdorferAustriaBradley WhiteUnited States of AmericaMichael WhiteUnited KingdomNicole WhitehurstUnited States of AmericaChristopher WhittyUnited KingdomKim WilliamsonUnited States of AmericaMark WilsonUnited States of AmericaMichael WilsonUnited States of AmericaErnst A. WimmerGermanyTonia WoodberryAustraliaCharles WoodrowThailandColin WrightUnited KingdomGerhard WunderlichBrazilMichelle WykesAustraliaRajpal Singh YadavSwitzerlandAnjali YadavaUnited States of AmericaStephanie YanowCanadaShunmay YeungUnited KingdomSedigheh ZakeriIranFidel ZavalaUnited States of AmericaHerve ZellerSwedenGuofa ZhouUnited States of AmericaPeter ZimmermanUnited States of AmericaThomas ZollerGermanyDejan ZurovacKenyaJulien ZwangSwitzerland"}
+{"text": "The editors of International Journal of Behavioral Nutrition and Physical Activity would like to thank all our reviewers who have contributed to the journal in Volume 9 (2012). Anna Adachi-MejiaUnited States of AmericaBarbara AinsworthUnited States of AmericaAnnie AndersonUnited KingdomRobert AndrewsUnited KingdomJames AnnesiUnited States of AmericaStephen AntonUnited States of AmericaMarni ArmstrongCanadaLauren ArundellAustraliaAudie AtienzaUnited States of AmericaHannah BadlandAustraliaSurinder BainesAustraliaIsabel BalaguerSpainKylie BallAustraliaTom BaranowskiUnited States of AmericaJacob BarkleyUnited States of AmericaDaheia Barr-AndersonUnited States of AmericaKatherine BauerUnited States of AmericaAdrian BaumanAustraliaMathieu BelangerCanadaElling BereNorwayChristina BergSwedenJerica BergeUnited States of AmericaPatrick BergmanSwedenSveinung BerntsenNorwayKirsten BevelanderNetherlandsJennifer BhallaUnited States of AmericaStuart BiddleUnited KingdomAmanda BirnbaumUnited States of AmericaJackie BlissettUnited KingdomBeth BockUnited States of AmericaFilip BoenBelgiumChristopher BooneUnited States of AmericaJanne Boone-HeinonenUnited States of AmericaLeah BrennanAustraliaRowan BrockmanUnited KingdomHelen BrownAustraliaChristoph BuckGermanyFlavia B\u00fcrgiSwitzerlandDeborah BurnetUnited States of AmericaCarol Byrd-BredbennerUnited States of AmericaRobin CallisterAustraliaAdrian CameronAustraliaJason CaoUnited States of AmericaCristina CaperchioneCanadaGreet CardonBelgiumJordan CarlsonUnited States of AmericaValerie CarsonCanadaAlison CarverAustraliaDarla CastelliUnited States of AmericaNick CavillUnited KingdomCarlos Celis MoralesUnited KingdomFrank ChaloupkaUnited States of AmericaNikos ChatzisarantisSingaporeNigel ChaumetonUnited States of AmericaPalma Chill\u00f3nSpainMai Jeanette Maidy ChinapawNetherlandsLeena ChoiUnited States of AmericaBronwyn ClarkAustraliaVerity ClelandAustraliaNatalie ColabianchiUnited States of AmericaIsobel ContentoUnited States of AmericaTerry ConwayUnited States of AmericaEmma CoombesUnited KingdomKristen CopelandUnited States of AmericaJennifer CopelandCanadaKirsten CorderUnited KingdomNadia CorsiniAustraliaDavid CrawfordAustraliaNoe CrespoUnited States of AmericaScott CrouterUnited States of AmericaRik CrutzenNetherlandsKaren CullenUnited States of AmericaSteven CumminsUnited KingdomPhilippa DallUnited KingdomCatherine DavisUnited States of AmericaKirsten DavisonUnited States of AmericaIlse De BourdeaudhuijBelgiumKatrien De CockerBelgiumStefaan De HenauwBelgiumElske de JongNetherlandsMarleen de MoorNetherlandsNanne de VriesNetherlandsBarbara DennisonUnited States of AmericaCassandra DiepUnited States of AmericaMarsha DowdaUnited States of AmericaClemens DrenowatzGermanyScott DuncanNew ZealandDustin DuncanUnited States of AmericaDavid DunstanAustraliaGenevieve DuntonUnited States of AmericaElizabeth EakinAustraliaRobert EckelUnited States of AmericaMark EdwardsUnited KingdomEric EmersonUnited KingdomLeonard H. EpsteinUnited States of AmericaDale EsligerUnited KingdomCharlotte EvansUnited KingdomKelly EvensonUnited States of AmericaFrank EvesUnited KingdomNicole EzendamNetherlandsStuart FaircloughUnited KingdomMeghan FinchAustraliaKevin FinnUnited States of AmericaMyron FloydUnited States of AmericaAnn ForsythUnited States of AmericaCharlie FosterUnited KingdomSarah FosterAustraliaAnnika FrahsaGermanyPatty FreedsonUnited States of AmericaKim GansUnited States of AmericaRonnesia GaskinsUnited States of AmericaKlaus GebelAustraliaLisa GibbsAustraliaJanneke GiesenNetherlandsGaston GodinCanadaRebecca GolleyAustraliaLora Suzanne GoodellUnited States of AmericaMargaret GrantUnited KingdomCarola GrebitusGermanyMelanie GreenUnited States of AmericaAnders Gr\u00f8ntvedDenmarkJessica Sophia GubbelsNetherlandsJoanne GuthrieUnited States of AmericaLeen HaerensBelgiumEric HallUnited States of AmericaJude HancockUnited KingdomSusan HandyUnited States of AmericaCharlotte HardmanUnited KingdomLisa HarnackUnited States of AmericaFlo HarrisonUnited KingdomEllen HaugNorwaySeverin HaugSwitzerlandMarquis HawkinsUnited States of AmericaEmma HaycraftUnited KingdomGenevieve HealyAustraliaErik HemmingssonSwedenMarike Reinier Catherine HendriksNetherlandsC. Peter HermanCanadaKylie HeskethAustraliaMelanie HingleUnited States of AmericaTrina HinkleyAustraliaTrina HinkleyAustraliaMirja HirvensaloFinlandAnette Hjart\u00e5kerNorwayEric HodgesUnited States of AmericaCaroline HorwathNew ZealandInge HoukesNetherlandsCiska HovingNetherlandsYa Jun HuangHong KongAnne HubletBelgiumSheryl O. HughesUnited States of AmericaAnita Hurtig-WennlofSwedenXanne JanssenAustraliaMajken JensenUnited States of AmericaKaren JetterUnited States of AmericaRachel JonesAustraliaAndy JonesUnited KingdomCarlijn KamphuisNetherlandsAshima KantUnited States of AmericaRuth KippingUnited KingdomAlison KirkUnited KingdomHeather Kitzman-UlrichUnited States of AmericaLinda KnolUnited States of AmericaHarold KohlUnited States of AmericaFerman KonukmanUnited States of AmericaHelena KraemerUnited States of AmericaMagdalena KwasniewskaPolandJouni LahtiFinlandJunilla Kirsten LarsenNetherlandsPatrick W. C. LauHong KongRebecca LawtonUnited KingdomTracey LedouxUnited States of AmericaRebecca LeeUnited States of AmericaAmanda LeeAustraliaIoni LewisAustraliaKaigang LiUnited States of AmericaDjin Gie LiemAustraliaSonia LippkeNetherlandsSam LoganUnited States of AmericaChris LonsdaleAustraliaLobo LouieHong KongAmy Shirong LuUnited States of AmericaDavid LubansAustraliaJulie LumengUnited States of AmericaKyle Macdonald-WallisUnited KingdomDuncan MacfarlaneHong KongRalph MaddisonNew ZealandBernard MaireFranceTomi M\u00e4kinenFinlandDavid MarklandUnited KingdomSimon MarshallUnited States of AmericaBrian C. MartinsonAfghanistanFerence MartonSwedenLouise C. MasseCanadaCharles MatthewsUnited States of AmericaMario MazzocchiItalyNoreen McDonaldUnited States of AmericaKelsey McDonaldUnited States of AmericaSuzanne McGregorUnited KingdomM. Diane McKeeUnited States of AmericaRachael McLeanNew ZealandRobert McMurrayUnited States of AmericaSarah McNaughtonAustraliaJessie MeisNetherlandsRobin MelleckerHong KongJason MendozaUnited States of AmericaDafna MeromAustraliaUrsina MeyerSwitzerlandJulie MidtgaardDenmarkAnn MillardUnited States of AmericaRichard MitchellUnited KingdomLorenzo MonastaItalyGraham MooreUnited KingdomJorge MotaPortugalJean-Claude MoubaracBrazilKerry MummeryCanadaDara Musher-EizenmanUnited States of AmericaIna NehringGermanyGina NettoUnited KingdomDianne Neumark-SztainerUnited States of AmericaCliona Ni MhurchuNew ZealandVirginie NicaiseUnited States of AmericaTheresa NicklasUnited States of AmericaRobert NolandUnited States of AmericaKate NorthstoneUnited KingdomNicole NovakUnited States of AmericaGisela NybergSwedenTeresia O'ConnorUnited States of AmericaTim OldsAustraliaChristine OlsonUnited States of AmericaJean-Michel OppertFranceAngeliki PapadakiUnited KingdomSong-Yi ParkUnited States of AmericaRussell PateUnited States of AmericaHeather PatrickUnited States of AmericaSusan PaxtonAustraliaJamie PearceUnited KingdomGeeske PeetersAustraliaLouisa PeraltaAustraliaGeorge PloubidisUnited KingdomLisa PowellUnited States of AmericaThomas PowerUnited States of AmericaStephanie PrinceCanadaRichard G. PrinsNetherlandsLieke RaaijmakersNetherlandsGail ReganUnited States of AmericaCarry RendersNetherlandsKyung RheeUnited States of AmericaRyan RhodesCanadaKate RidleyAustraliaDeborah RiebeUnited States of AmericaWilliam RileyUnited States of AmericaChris RisselAustraliaChristina RobertoUnited States of AmericaJennifer Robertson-WilsonCanadaEric RobinsonUnited KingdomDori RosenbergUnited States of AmericaNancy RossCanadaJoseph RossiUnited States of AmericaAlex RowlandsUnited KingdomLouise RussellUnited States of AmericaGeert RuttenNetherlandsArja S\u00e4\u00e4kslahtiFinlandBrian SaelensUnited States of AmericaShannon SahlqvistAustraliaJames SallisUnited States of AmericaJo SalmonAustraliaOddrun SamdalNorwayPaul SandersonUnited KingdomTravis SaundersCanadaPeter SchantzSwedenPatrick SchneiderUnited States of AmericaDaniela SchulzNetherlandsSimon SebireUnited KingdomLauren SherarCanadaBrian ShinerUnited States of AmericaNiamh ShorttUnited KingdomMadeleine Sigman-GrantUnited States of AmericaHelen SkouterisAustraliaEline SmitNetherlandsDianna SmithUnited KingdomShawn SomersetAustraliaKendrin SonnevilleUnited States of AmericaJohn SpenceCanadaAlison SpenceAustraliaSeth SpielmanUnited States of AmericaAndrew SpringerUnited States of AmericaJamie StangUnited States of AmericaRebekah SteeleAustraliaJorien StrijkNetherlandsTakemi SugiyamaAustraliaJonas SwartzUnited States of AmericaDeborah TateUnited States of AmericaRachael TaylorNew ZealandSaskia Te VeldeNetherlandsPedro TeixeiraPortugalJennifer TempleUnited States of AmericaGill Ten HoorNetherlandsMegan TeychenneAustraliaCecilie Th\u00f8gersen-NtoumaniUnited KingdomDebbe ThompsonUnited States of AmericaAnne ThorndikeUnited States of AmericaAnna TimperioAustraliaSandar Tin TinNew ZealandAlison TovarUnited States of AmericaStewart TrostUnited States of AmericaStewart TrostAustraliaLarry TuckerUnited States of AmericaGavin TurrellAustraliaL\u00e9onie UijtdewilligenNetherlandsPatricia van AssemaNetherlandsRob van DamSingaporeBart van den BorneNetherlandsDelfien Van DyckBelgiumDave Van KannNetherlandsMireille van PoppelNetherlandsMaartje van StralenNetherlandsCorneel VandelanotteAustraliaElizabeth VandewaterUnited States of AmericaAlison VenturaUnited States of AmericaMaite VerloigneBelgiumVictor VianaPortugalKristin VickersCanadaTommy VisscherNetherlandsEline VlasblomNetherlandsSusan WalkerUnited KingdomMay WangUnited States of AmericaDianne WardUnited States of AmericaJane WardleUnited KingdomTracy WashingtonAustraliaWilma E WaterlanderNew ZealandKathleen WatsonUnited States of AmericaAilsa WelchUnited KingdomGreg WelkUnited States of AmericaJosefine WendelUnited States of AmericaMelicia Whitt-GloverUnited States of AmericaKatrien WijndaeleUnited KingdomGeoffrey WilliamsUnited States of AmericaPhilip Michael WilsonCanadaDonna WilsonCanadaJanet WithallUnited KingdomBente WoldNorwayCatherine WoodsIrelandJohn WrightUnited States of AmericaKiyoshi YamakiUnited States of AmericaDeborah YoungUnited States of AmericaIssa ZakeriUnited States of AmericaCathleen ZickUnited States of America"}
+{"text": "Molecular Cytogenetics would like to thank all our reviewers who have contributed to the journal in volume 5 (2012).The editors of  Joo Wook AhnUnited KingdomMaher AlbitarUnited States of AmericaMichael AlperUnited States of AmericaSevim Balc\u0131TurkeySamarth BhattGermanyMaria Clara BonagliaItalyLukrecija BrecevicCroatiaArthur BrothmanUnited States of AmericaVincenzo CaputoItalyIsabel Maria Marques CarreiraPortugalPatricia Celestino-SoperUnited States of AmericaSau CheungUnited States of AmericaMarcelo CioffiBrazilEdivaldo de OliveiraBrazilMaria DescartesUnited States of AmericaJan DiblikCzech RepublicAndreas DufkeGermanyAmanda FigueiredoBrazilDavid FrancisAustraliaAd Geurts van KesselNetherlandsGuity GhaffariUnited States of AmericaGabriele Gillessen-KaesbachGermanyMassimo GiovannottiItalyEkaterina GornungItalyClaudio GrazianoItalySusan GrossUnited States of AmericaClaudia HaferlachGermanyChristine HarrisonUnited KingdomHenry HengUnited States of AmericaAndreas HoubenGermanyLouanne HudginsUnited States of AmericaIvan IourovRussiaHo-Young KangSouth KoreaNam-Soo KimSouth KoreaElisabeth KleinGermanyNadezda KosyakovaGermanyDieter KotzotAustriaTomasz Ksi\u0105\u017cczykPolandAnna KulpanovichBelarusThomas LiehrGermanyWenjin LiuUnited States of AmericaLuciana LourencoBrazilEmmanouil ManolakosGreeceMarina ManvelyanArmeniaAurelia Meloni-EhrigUnited States of AmericaBj\u00f6rn MentenBelgiumMartina MerkasCroatiaHasmik MkrtchyanArmeniaYi NingUnited States of AmericaFrancesca NovaraItalyEric PasmantFrancePhilippos PatsalisCyprusGreg PetersAustraliaElena RaimondiItalyLaureana RebordinosSpainGabriela RepettoChileNikolai RubtsovRussiaAurora Ruiz-HerreraSpainWarren SangerUnited States of AmericaCatherine SarriGreeceScott SittlerUnited States of AmericaPawel StankiewiczUnited States of AmericaDavid StevensonUnited States of AmericaJonathan StreffordUnited KingdomVladimir TrifonovRussiaKaren VenturaBrazilAmit VermaUnited States of AmericaJoris VermeeschBelgiumAngela Vianna-MorganteBrazilSvetlana VorsanovaRussiaKunbo WangChinaAnja WeiseGermanyXiaojian XuUnited States of AmericaPeng ZhangAustraliaOrsetta ZuffardiItaly"}
+{"text": "Cilia. We greatly appreciate the voluntary contribution made to the journal by all our reviewers.We would like to thank the following experts for their assistance with the peer-review in 2013 for manuscripts submitted to  Jens AndersenDenmarkJose BadanoUruguayAlexandre BenmerahFranceOliver BlacqueIrelandRobert BloodgoodUnited States of AmericaMartin BlumGermanyJason BrownUnited States of AmericaTamara CasparyUnited States of AmericaMark ChilversCanadaSoren ChristensenDenmarkJean CohenFranceDouglas ColeUnited States of AmericaPamela CowinUnited States of AmericaHelen DaweUnited KingdomJames DeaneAustraliaBill DentlerUnited States of AmericaIain DrummondUnited States of AmericaBenedicte DurandFranceRachel GilesNetherlandsEric HaarmanNetherlandsPaul HamelCanadaCourtney HaycraftUnited States of AmericaYuqing HouUnited States of AmericaJinghua HuUnited States of AmericaClaire JacksonUnited KingdomGert JansenNetherlandsKarl LechtreckUnited States of AmericaPaul LefebvreUnited States of AmericaAmanda LeightnerUnited States of AmericaJarema MalickiUnited KingdomJeffrey MartensUnited States of AmericaBrian MitchellUnited States of AmericaDavid MitchellUnited States of AmericaHannah MitchisonUnited KingdomKim G NielsenDenmarkHeymut OmranGermanyGreg PazourUnited States of AmericaLotte PedersenDenmarkElena PugachevaUnited States of AmericaJohn SayerUnited KingdomJonathan ScholeyUnited States of AmericaDiane SlusarskiUnited States of AmericaElizabeth SmithUnited States of AmericaTim StearnsUnited States of AmericaKerry TuckerGermanySue VaughanUnited KingdomChristopher WestlakeUnited States of AmericaMark WineyUnited States of AmericaBradley YoderUnited States of AmericaZhibing ZhangUnited States of America"}
+{"text": "Irish Veterinary Journal editorial team would like to thank the following colleagues who contributed to peer review for the journal in 2013.The  Naveed AkhtarPakistanValeria AlbaneseUnited States of AmericaCharles BaconUnited States of AmericaMarijke BeltmanIrelandJames BreenUnited KingdomBen BrilotUnited KingdomMurray BrownUnited States of AmericaFranz BrulisauerUnited KingdomBryce BuddleNew ZealandSean CallananIrelandJoe CassidyIrelandStephanie CastonUnited States of AmericaPeter ChapmanUnited States of AmericaKarin DarpelUnited KingdomTheo de WaalIrelandMichael DiskinIrelandFiona DoohanIrelandEdward DuboviUnited States of AmericaSeamus FanningIrelandJames GibbonsIrelandJohn GilmoreIrelandEamonn GormleyIrelandJeanne Grad\u00e9BelgiumTerence GrimesIrelandKei HayashiUnited States of AmericaBernhard KaltenboeckUnited States of AmericaNiel KarrowCanadaLauren LacorciaAustraliaDesmond LeadonIrelandIngrid LorenzIrelandKeith MacmillanAustraliaJohn MadiganUnited States of AmericaBryan MarkeyIrelandJohn MeeIrelandPatti MillerUnited States of AmericaStefano NardelliItalyPeter NettletonUnited KingdomErasmus OkineCanadaRonan O\u2019NeillIrelandChris OuraTrinidad and TobagoFelisbina QueirogaPortugalSarah RandolphUnited KingdomCharlotte SandersenBelgiumHorst SchirrmeierGermanyJulie SettlageUnited States of AmericaRobert ShielAustraliaGeorge StewartUnited States of AmericaDavid SuarezUnited States of AmericaDavid Verner-JeffreysUnited KingdomAndrew WallerUnited KingdomKeith WayUnited KingdomPaul WhyteIrelandMike WoodsIreland"}
+{"text": "The Editor of BioMedical Engineering Online would like to thank all the Reviewers who have contributed to the journal in Volume 12 (2013). Vahid AbdollahHong KongMakoto AdachiUnited States of AmericaKerith AginskySouth AfricaBharath Ambale VenkateshUnited States of AmericaKai-Nan AnUnited States of AmericaMaria Rosa AntognazzaItalyPasquale AragonaItalyMina ArvinNetherlandsHiroshi AshikagaUnited States of AmericaOleg AslanidiUnited KingdomRen\u00e9 AttalAustriaUlas BagciUnited States of AmericaJames BaishUnited States of AmericaAlexandre BalbinotBrazilRupak BanerjeeUnited States of AmericaJayme BarbedoBrazilBrandon BartlingUnited States of AmericaDavid BartonUnited KingdomBerna BasarirTurkeyMartin BechGermanyBalazs BenyoHungaryEnrique BerjanoSpainNacim BetrouniFranceLiam BluntUnited KingdomFrank BorgFinlandAndrew BoryorGermanyMarco BottinoUnited States of AmericaStuart BowyerUnited KingdomStefan BraamNetherlandsAndre BrownUnited KingdomChristoph BrueserGermanyJonathan BrumbergUnited States of AmericaHarvey BurdUnited States Minor Outlying IslandsWagner C A PereiraBrazilGiovanni CalcagniniItalyLuca CampanaItalyCristina M.R. CaridadePortugalVincent CaseyIrelandJoshua CashabackCanadaFrancesco CenniItalyBenedetta CesquiItalyHadrien CeyteFranceWallace ChamonBrazilPak-Cheung ChanCanadaJin Ho ChangKorea SouthGeoff ChaseNew ZealandMohd Zulfaezal Che AzeminMalaysiaGuohua ChenChinaHoujin ChenChinaJyh-Cheng ChenTaiwanWeng-Pin ChenTaiwanWufan ChenChinaYanxi ChenChinaZhenglong ChenChinaCongo Tak-Shing ChingTaiwanKyungeun ChoKorea SouthYoung ChoUnited States of AmericaByoung ChoiKorea SouthKwok Wing ChowHong KongBlaine ChristiansenUnited States of AmericaZhang ChunqiuChinaEdward CiaccioUnited States of AmericaGastone CiutiItalyMaureen ClercFranceEthan CohenUnited States of AmericaDamian CraiemArgentinaJoel CramerUnited States of AmericaSaddha CuijpersNetherlandsTien Tuan DaoFranceJoost de JongNetherlandsJunmin DengChinaThomas DesaiveBelgiumThomas DesernGermanyGiovanni Di PinoItalyMarco Di RienzoItalyAlejandro Diaz-SanchezMexicoAnh DinhCanadaMarcelo Do Amaral FerreiraBrazilSebastian DoeltgenAustraliaCyril DonnellyAustraliaElisabetta DonzelliItalyIvan DotsinskyBulgariaThomas DoubletFranceBin DuChinaBin DuanUnited States of AmericaJohn DunlopGermanyMatthieu DuvinageBelgiumAndrzej DziechPolandWilliam EdwardsUnited States of AmericaTurgay EfeGermanyJan EggerGermanyAnders EklundSwedenMiroslawa El FrayPolandIrraivan ElamvazuthiMalaysiaAyman El-BazUnited States of AmericaMohamed-Tarek El-WakadEgyptSauro Emerick SalomoniAustraliaStephen FaircloughUnited KingdomYujiang FanChinaQingling FengChinaJinan FiaidhiCanadaSimonetta FilippiItalyJorge L. FloresMexicoBrian FlynnUnited KingdomHelene FolletFranceHassan FouadEgyptMassimiliano FraldiItalyPiotr FranaszczukUnited States of AmericaLorenzo FranchiItalyYang-Chieh FuUnited States of AmericaWei GaofengChinaMarco Antonio GarciaBrazilMarcos Garcia-FuentesSpainPaolo GargiuloIcelandGunther GerhardtBrazilMatthias GeyerGermanyVijay GoelUnited States of AmericaAlex GolbergIsraelBeat G\u00f6pfertSwitzerlandElliot GreenblattUnited States of AmericaJason GuCanadaEnrique GueradoSpainBerke GurTurkeyDavid GutekunstUnited States of AmericaJosef GuttmannGermanyTaeyiung HaKorea SouthQing HaoUnited States of AmericaShiying HaoUnited States of AmericaAbdelhamid HarabiAlgeriaKamran HassaniIranJan HavlikCzech RepublicHarun Taha HayvaciTurkeyRalph HerkertUnited States of AmericaMasaya HirashimaJapanImo HoeferNetherlandsMarkus HoenickaGermanyDavid HoeyIrelandAles HolobarSloveniaRichard HopkinsUnited States of AmericaMarc HornerUnited States of AmericaTim HowellsSwedenXiao HuUnited States of AmericaHu HuangUnited States of AmericaChangmo HwangKorea SouthErnesto IadanzaItalyNorliza IbrahimMalaysiaNilesh IngleUnited States of AmericaDavid IntCanadaMikhail InyushinUnited States of AmericaLaura LopItalyMuhammad IslamPakistanCinthia ItikiBrazilMarcus J\u00e4gerGermanyIn Gwun JangKorea SouthSabrina Yvonne JauchUnited KingdomMarc JaumainBelgiumMervi JehkonenFinlandMatija JezersekSloveniaEmil JovanovUnited States of AmericaMarianne JuhlerDenmarkMartti JuholaFinlandPiotr KaczmarekPolandJacek KadzielaPolandMalik KahookUnited States of AmericaMaria KallergiGreeceMaarit KangasFinlandDan Stieper KarbingDenmarkYuichi KasaiJapanUlrich KatscherGermanyIra KatzFranceIlda KazaniAlbaniaShawn KellyUnited States of AmericaAndy KerrUnited KingdomDonghyun KimKorea SouthHyunggun KimUnited States of AmericaKyung Chun KimKorea SouthYeonhee KimUnited States of AmericaYoungho KimKorea SouthMalte KirstGermanyChing-Chang KoUnited States of AmericaKranthi KolliUnited States of AmericaGrzegorz KoniecznyPolandRobert KoprowskiPolandAnna KorzynskaPolandYordan KostovUnited States of AmericaBoris KotchoubeyGermanyLevente KovacsHungaryEddy KruegerBrazilElizabeth KrupinskiUnited States of AmericaPrzemyslaw KryczkaJapanJustin LaferrierUnited States of AmericaHsin-Yi LaiTaiwanJonas LantzSwedenDmitry LaptevSwitzerlandKirill LarinUnited States of AmericaMartin LawitzkyGermanySoo Yeol LeeKorea SouthChengwei LeiUnited States of AmericaXu LeiChinaNey LemkeBrazilHaiyun LiChinaHuiqi LiChinaJunbo LiChinaLieber LiTaiwanYu-Shan LiChinaZhi-Yong LiChinaLun-De LiaoSingaporeInger Lillieh\u00f6\u00f6kSwedenShang-Chih LinTaiwanMadalena LiraPortugalHuafeng LiuChinaJiang LiuSingaporeJie LiuChinaWentai LiuUnited States of AmericaYi-Hung LiuTaiwanYiyao LiuChinaXianghong LuanUnited States of AmericaJianwen LuoChinaJianhua MaChinaCalixto MachadoCubaIlia MakedonovCanadaJarmo MalinenFinlandDenis Marcellin-LittleUnited States of AmericaDaniele MarinazzoBelgiumAndrew MartinUnited States of AmericaDaniel MartinUnited KingdomMonika MartiniakovaSlovakiaRichard MathiasUnited States of AmericaEugenio MatteiItalyDennis McFarlandUnited States of AmericaPaolo MelilloItalyLuciano MenegaldoBrazilCarlo MenonCanadaRoberto MerlettiItalyLino MisogutiBrazilChristoph MoenninghoffGermanyIman Mohammad RezazadehUnited States of AmericaKnut M\u00f6llerGermanyJuan C. MorenoSpainRoger MorrellUnited KingdomRobert MotlUnited States of AmericaSayedali MousaviIranMichele MucciniItalyJoung H. MunKorea SouthMarcelo NacifBrazilRoozbeh NaemiUnited KingdomKweon-Ho NamKorea SouthValery NaranjoSpainJonathan NewellUnited States of AmericaMeir NitzanIsraelTianye NiuUnited States of AmericaEmil NovakovFrancePascal Ntsama EloundouCameroonRiccardo NuceraItalyShiro OkaJapanFelipe Orihuela-EspinaMexicoMax Ortiz-CatalanSwedenJulien OsterUnited KingdomPertti PaloUnited KingdomLibor PasaCzech RepublicShamira PereraSingaporeAngkoon PhinyomarkThailandYang-Jun PiChinaKinga PielichowskaPolandMichael Pl\u00f6chlGermanyChristian PuttlitzUnited States of AmericaAike QiaoChinaAnnalisa QuainiUnited States of AmericaTimon RabczukGermanyPawe\u0142 RamosPolandSimon RawlinsonUnited KingdomSabrina RenziItalyMaria Teresa RestivoPortugalFrances RobertsonSouth AfricaJose F RodriguezSpainBaxter RogersUnited States of AmericaSebastien RothFranceDavid RubensteinUnited States of AmericaThorsten RudroffUnited States of AmericaSimo SaarakkalaFinlandRosalind SadleirUnited States of AmericaHassan SaeediIranZahra SafaeepourIranJun SakakibaraJapanSolomon SamuelUnited States of AmericaSaeid SaneiUnited KingdomBernd SaugelGermanyWolfram SchmidtGermanyGert SchoonenbergNetherlandsYoungho SeoUnited States of AmericaToshihiro SeraJapanHassan SerhanUnited States of AmericaIgor SersaSloveniaSuraj ShahCanadaJiaweiShi ChinaAlbert ShihUnited States of AmericaEun Bo ShimKorea SouthMinoru ShinoharaUnited States of AmericaGuofa ShouUnited States of AmericaSudhir ShresthaUnited States of AmericaEmil SidkyUnited States of AmericaTobias SiebertGermanyGunter SiegmundCanadaFernando SilveiraUruguayChrister SinderbyCanadaSitabhra SinhaIndiaGuanbin SongChinaPavel SovkaCzech RepublicPascal SpincemailleUnited States of AmericaFrancesco StaffieriItalyDaniel SteinesUnited States of AmericaBerend StoelNetherlandsAbdulhamit SubasiBosnia and HerzegovinaLei SunHong KongCathryn SundbackUnited States of AmericaTracey SwinglerUnited KingdomEva SwinnenBelgiumHiroki TamuraJapanXiaobo TanUnited States of AmericaDalin TangUnited States of AmericaJoao TavaresPortugalThomas ThueringSwitzerlandLuciana TorresUnited States of AmericaPeppino TropeaItalyKhoa Truang Quang DangVietnamVassiliy TsytsarevUnited States of AmericaAndrea TuraItalyJan TuranSlovakiaGiovanni Jacopo UghiBelgiumCostin UntaroiuUnited States of AmericaMiguel UvaPortugalLiina VahterEstoniaMax ValentinuzziArgentinaLex van VelsenNetherlandsEmir VeledarUnited States of AmericaRiccardo VismaraItalyDung VoUnited States of AmericaAmy Wagoner JohnsonUnited States of AmericaAndrew WalkerSwedenEric WalkerUnited States of AmericaBaikun WanChinaMingxi WanChinaWan Mimi Diyana Wan ZakiMalaysiaGang WangChinaHongsheng WangUnited States of AmericaShengzheng WangChinaShougang WangUnited States of AmericaTao WangUnited States of AmericaVicky WangNew ZealandXintong WangUnited States of AmericaYanzhen WangChinaBeata WeglarzPolandThomas WhiteUnited States of AmericaOliver WiebenUnited States of AmericaSlawomir WilczynskiPolandIvo WolfGermanyQingyu WuChinaShuicai WuChinaYunfeng WuChinaMing XiaoUnited States of AmericaHong-Bo XieAustraliaShane XieNew ZealandLei XingUnited States of AmericaXiao Yun XuUnited KingdomXu XuChinaFraid YaghoubyUnited States of AmericaToshihiko YamasakiJapanCheng-Hong YangTaiwanChia-Yen YangTaiwanJikuang YangSwedenJinzhong YangUnited States of AmericaXiaofeng YeChinaWei YinUnited States of AmericaMasaki YoshidaJapanNingbo YuChinaRad ZderoCanadaZijing ZengUnited States of AmericaWeiqiang ZhangChinaYuting ZhangUnited States of AmericaZhiqiang ZhangUnited KingdomGddr ZhaoChinaHeng ZhaoUnited States of AmericaGuoyan ZhengSwitzerlandJie ZhengUnited States of AmericaYu ZhouUnited States of AmericaPeter ZillaSouth AfricaAdam ZyskUnited States of America"}
+{"text": "Journal of Neurodevelopmental Disorders would like to thank all of our reviewers who have contributed to the journal in volume 4 (2012). High quality and timely reviews are critical to the overall quality of the journal. We are committed to providing a unique and important outlet for scholarship regarding neurodevelopmental disorders and are indebted to the outstanding reviewers who have contributed their time over the last year in helping us to reach this goal.The editors of  Melissa AllenUnited KingdomElizabeth AylwardUnited States of AmericaMargaret BaumanUnited States of AmericaRaphael BernierUnited States of AmericaElina BirminghamCanadaDorothy BishopUnited KingdomSusan BookheimerUnited States of AmericaMarc BrysbaertBelgiumLinda CampbellAustraliaNeva CorriganUnited States of AmericaAna CubilloUnited KingdomGeraldine DawsonUnited States of AmericaSaumitra DebUnited KingdomManny DiCicco-BloomUnited States of AmericaMaria Luz DizonUnited States of AmericaJed ElisonUnited States of AmericaDeborah FidlerUnited States of AmericaCarsten FinkeGermanyChris FrithUnited KingdomSusanna FryerUnited States of AmericaDennis GraysonUnited States of AmericaPaul HagermanUnited States of AmericaFrancesca HappeUnited KingdomTodd HareSwitzerlandJoost JanssenNetherlandsWarren JonesUnited States of AmericaEmily JonesUnited States of AmericaAnnette Karmiloff-SmithUnited KingdomCary KoganCanadaGregor KohlsUnited States of AmericaMeng-Chuan LaiUnited KingdomAmir LevineUnited States of AmericaAlice LinUnited States of AmericaRhiannon LuysterUnited States of AmericaCarla MazefskyUnited States of AmericaJames McPartlandUnited States of AmericaNancy MinshewUnited States of AmericaSandra MooneyUnited States of AmericaJeff MunsonUnited States of AmericaCharles NelsonUnited States of AmericaJoshua NewUnited States of AmericaRichard NowakowskiUnited States of AmericaJohn O'DohertyUnited States of AmericaNoriko OsumiJapanDaniela Plesa SkwererUnited States of AmericaArmin RaznahanUnited States of AmericaAllan ReissUnited States of AmericaLawrence ReynoldsUnited States of AmericaTodd RichardsUnited States of AmericaCary SavageUnited States of AmericaGaia ScerifUnited KingdomStephen SchererCanadaEmily SimonoffUnited KingdomMikle SouthUnited States of AmericaCatherine StoodleyUnited States of AmericaBruce TomblinUnited States of AmericaAnna TuryUnited States of AmericaJaap van PeltNetherlandsKatarina Varn\u00e4sSwedenDavid WalkerAustraliaKarli WatsonUnited States of AmericaZhengang YangChina"}
+{"text": "Scoliosis would like to thank all our reviewers who have contributed to the journal in Volume 7 (2012).The Editor-in-Chief of  Emre AcarogluTurkeyClayton AdamAustraliaBehrooz AkbarniaUnited States of AmericaCarl-Eric AubinCanadaLorenzo AulisaItalyKeith BagnallCanadaSaumyajit BasuIndiaMarie BeausejourCanadaRowan BerkowitzSouth AfricaJosette Bettany-SaltikovUnited KingdomJens Ivar BroxNorwayRichard BurwellUnited KingdomRene Marten CasteleinNetherlandsJack ChengHong KongNachiappan ChockalingamUnited KingdomWinnie ChuChinaPeter DangerfieldUnited KingdomJean Claude De MauroyFranceSabrina DonzelliItalyJean DuboussetFranceFerran EscaladaSpainJeremy FairbankUnited KingdomCharla FischerUnited States of AmericaAzmi HamzaogluTurkeyMartha HawesUnited States of AmericaManabu ItoJapanDonald KatzUnited States of AmericaEustathios KenanidisGreecePatrick KnottUnited States of AmericaTomasz KotwickiPolandVirginie LafageUnited States of AmericaLawrence LenkeUnited States of AmericaKeith LukChinaJean-Marc Mac-ThiongCanadaToru MaruyamaJapanJwalant MehtaUnited KingdomStefano NegriniItalyJoseph O'BrienUnited States of AmericaJames OgilvieUnited States of AmericaAcke OhlinSwedenHarry OpsimosUnited States of AmericaPeter John PapantoniouAustraliaVikas PatelUnited States of AmericaPetros PatiasGreeceNigel PriceUnited States of AmericaGerald QuanAustraliaManuel RigoSpainMichele RomanoItalyJose Miguel Sanchez MarquezSpainAlpaslan SenkoyluTurkeyKonstantinos SoultanisGreeceDavid SpeersUnited States of AmericaLuke StikeleatherUnited States of AmericaPiet van LoonNetherlandsMarian H WadeUnited States of AmericaYan WangChinaHans-Rudolf WeissGermanyAdam WollowickUnited States of AmericaMan-Sang WongHong KongJames WynneUnited States of AmericaFabio ZainaItalyDaniel ZarzyckiPoland"}
+{"text": "Cancer Cell International would like to thank Angela Panther for her continued hard work throughout 2012 in keeping the journal going as our managing editor. We take this opportunity in early 2013 to thank all our reviewers who contributed to the journal in Volume 12 (2012). Last year saw submissions double, which will mean that in 2013 we will certainly have many more articles to publish, and hopefully our Impact Factor will rise above 2.The editor and editorial board of  Monther Al-AlwanSaudi ArabiaMalcolm AlisonUnited KingdomCecilia AnichiniItalyFarrukh AqilUnited States of AmericaRomina Flavia AromandoArgentinaOsama AshourSaudi ArabiaMahfoud AssemUnited States of AmericaMasoud AzodiUnited States of AmericaChristopher BainesUnited States of AmericaElizabeth Balcer-KubiczekUnited States of AmericaAbdulkerim BedirTurkeyJavad BehravanIranHedi Ben MansourTunisiaDanielle BenoitUnited States of AmericaJacqueline BentelAustraliaJuergen BernhagenGermanyJihed BoubakerTunisiaHal BroxmeyerUnited States of AmericaSara ByronUnited States of AmericaGuifang CaoChinaViviana CaputoItalyMichele CaragliaItalyRamin CarbinerUnited KingdomMarcia CarvalhoPortugalMaja CemazarSloveniaHsueh-Wei ChangTaiwanJiwu ChangChinaYing ChangChinaYew Hoong CheahMalaysiaLeila Chekir-GhediraFranceZhou ChengjunChinaChristos ChinopoulosHungaryMaurizio Chiriva InternatiUnited States of AmericaChong-Su ChoKorea SouthWen-Chien ChouTaiwanSalem ChouaibFranceSuebwong ChuthapisithThailandShun-Dong DaiChinaJing-Yu DengChinaMaurizio D'IncalciItalyNicholas DonatoUnited States of AmericaWu Dong-ChengChinaAndrea D\u00f6rnerGermanyRachid DrissiUnited States of AmericaYiannis DrososUnited States of AmericaGangjun DuChinaXiao-Li DuUnited States of AmericaZhenfeng DuanUnited States of AmericaAhmed ElberrySaudi ArabiaHarriet FeilotterCanadaXueping FengChinaMetka FilipicSloveniaRaimundo FreireSpainLiwu FuChinaSidney FuUnited States of AmericaTatsuya FujikawaJapanMayuko FurutaJapanMacoura GadjiCanadaAlexander GasparianUnited States of AmericaRichard GattiUnited States of AmericaPramod GowdaUnited States of AmericaElvira V GrigorievaRussian FederationChandrasekharan GuruvayoorappanIndiaMartin HagedornFrancePing-an HeChinaLei HeUnited States of AmericaMiyake HidaekiJapanAndrew HoffmanUnited States of AmericaMartina HolstSwedenZhou HouxueChinaCH HuangUnited States of AmericaDouglas HurstUnited States of AmericaNikolai IvanovSwitzerlandWeidong JiaChinaKideok JinUnited States of AmericaLee Jong-HwanKorea SouthAnna Margaretha JoubertSouth AfricaBhaskar KallakuryUnited States of AmericaKarl-Henning KallandNorwayTakuro KanekuraJapanDib Junior KaramBrazilVenkat KeshaUnited States of AmericaRaheela KhanUnited KingdomMaryam KhurshidUnited KingdomFumitaka KogaJapanTomonobu KoizumiJapanDimitrios KoutsimpelasGermanyKostyantyn KrysanUnited States of AmericaMuthusamy KunnimalaiyaanUnited States of AmericaAshakumary LakshmikuttyammaUnited States of AmericaFrancois LamoureuxFranceAngel LanasSpainNikki LeeHong KongMathew LeeseUnited KingdomMing LiUnited States of AmericaYangqiu LiChinaTengguo LiUnited States of AmericaLinwei LiChinaZang LinquanChinaVaclav LiskaCzech RepublicDelong LiuUnited States of AmericaJie LiuUnited States of AmericaZhiping LiuUnited States of AmericaMonica LoizzoItalyAnn LouwSouth AfricaHongqi LueGermanyXudong MaChinaPranoti MandrekarUnited States of AmericaRajani MathurIndiaSihem MbarekSpainJale MetindirTurkeyRenata MikolajczakPolandMurielle MimeaultUnited States of AmericaClelia MiraccoItalyJohn MoffatUnited States of AmericaAna Luiza Muccillo-BaischBrazilShamsul MuhamadMalaysiaRita MulherkarIndiaMichael MullerAustraliaSunil NagpalUnited States of AmericaRakesh NaiduMalaysiaSumalee ObchoeiThailandYoshio OhnoJapanTomris OzbenTurkeyJian PanChinaLuis A PardoGermanyAntonio PassaroItalyNives Pecina-SlausCroatiaTanja PejovicUnited States of AmericaOula Penate MedinaGermanyWen-Huang PengTaiwanYmera PignochinoItalyStefania PizzimentiItalyGuillaume PloussardFranceVladimir PushkarevUkraineSaul PuszkinUnited States of AmericaNigel PyneUnited KingdomLi QianChinaNancy Raab-TraubUnited States of AmericaTilman RachnerGermanyCliff RileyJamaicaJ Pablo Rodr\u00edguezChileJesse RomanUnited States of AmericaRozita RosliMalaysiaNorihiko SaitoJapanDaniele SantiniItalyAnna SapinoItalyNoriyoshi SawabataJapanThomas SchlangeSwitzerlandGlen ScholzAustraliaDonald SensUnited States of AmericaBing ShenChinaDaniel Tzu-bi ShihTaiwanBranca SilvaPortugalVladimir StrelnikovRussian FederationJun-Hui SunChinaBela SzendeHungaryClaude SzpirerBelgiumVanja TadicSerbiaKazuaki TakabeUnited States of AmericaOsamu TakaseJapanFeng-Yao TangTaiwanStephan TeglundSwedenJustin TeissieFrancePaul ThelenGermanySuchitra ThongpraditchoteThailandHwei-Fang TienTaiwanQiangsong TongChinaJorg TostFranceJeremy TzengUnited States of AmericaPaola VillaniItalyGuido WabnitzGermanyImen WahabiFranceHeather M WallaceUnited KingdomLuo WangUnited States of AmericaZhiwei WangUnited States of AmericaJian WangNorwayXin Sheng WangChinaWenling WangChinaLing WangChinaGeorg WeberUnited States of AmericaJianjun WeiUnited States of AmericaLi Hui WeiChinaJohanna WeissGermanyPaul WhitingUnited KingdomDennis WijngaartNetherlandsShawn WnekUnited States of AmericaGayle WoloschakUnited States of AmericaXueqiang WuChinaQi XieChinaWilson XuUnited States of AmericaGong YangChinaClement YedjouUnited States of AmericaShijin YinChinaWei YinChinaYusmazura ZakariaMalaysiaZihua ZengUnited States of AmericaSen ZhangChinaGuoyou ZhangAustraliaWei-Guang ZhaoChinaZhen ZhaoUnited States of AmericaQian ZhaoChinaJie ZhengChinaWeide ZhongChinaTim ZimmermannGermany"}
+{"text": "Pediatric Rheumatology would like to thank all our reviewers who have contributed to the journal in Volume 11 (2013).The Editors of  Navid AdibAustraliaAmita AggarwalIndiaRoger AllenAustraliaMariane AmanoBrazilJordi AntonSpainWineke ArmbrustThe NetherlandsTadej AvcinSloveniaEileen BaildamUnited KingdomJennifer BartonUnited States of AmericaRadovan BogdanovicSerbiaMortaza BonyadiIranVictoria BorbaBrazilRiva BrikIsraelPaul BroganUnited KingdomDiane BrownUnited States of AmericaJuergen BrunnerAustriaRuben Burgos-VargasMexicoDavid CabralCanadaAnne Marie CahillUnited States of AmericaLaurent CamousFranceSabrina CavalloCanadaOmkar ChaudharyIndiaNadine ChoueiterUnited States of AmericaRolando CimazItalyTam\u00e1s ConstantinHungaryRandy CronUnited States of AmericaMegan CurranUnited States of AmericaJohn DagleUnited States of AmericaPavla DolezalovaCzech RepublicJean-Charles DoucetCanadaCiaran DuffyCanadaJustine EllisAustraliaFernanda FalciniItalyFrancis FatoyeUnited KingdomPolly FergusonUnited States of AmericaIvan FoeldvariGermanyHelen FosterUnited KingdomDavid FoxUnited States of AmericaMarco GattornoItalyAbraham GedaliaUnited States of AmericaHermann GirschickGermanyRodney GrahameUnited KingdomThomas GriffinUnited States of AmericaAysen Gunel-OzcanTurkeyKathleen HainesUnited States of AmericaKeri HainsworthUnited States of AmericaLiora HarelIsraelTroels HerlinDenmarkAnne HinksUnited KingdomMicha\u00ebl HoferSwitzerlandGerd HorneffGermanyToni HospachGermanyAdam HuberCanadaHaku IizukaJapanRoman JurencakCanadaPentti KallioFinlandAzza Mahmoud KamelEgyptChristian KellenbergerSwitzerlandSusan KimUnited States of AmericaYukiko KimuraUnited States of AmericaMarisa Klein-GitelmanUnited States of AmericaSusan KlepperUnited States of AmericaIsabelle Kone-PautFranceCengiz KorkmazTurkeyKaisu KotaniemiFinlandHelen LachmannUnited KingdomPekka LahdenneFinlandBianca LangCanadaThomas J A LehmanUnited States of AmericaDeborah LevyCanadaCarol LindsleyUnited States of AmericaDaniel LovellUnited States of AmericaSilvia Magni-ManzoniItalyJohn MahanUnited States of AmericaIsabelle MarcCanadaAlberto MartiniItalyLiza MccannUnited KingdomMichael MillerUnited States of AmericaDiana MilojevicUnited States of AmericaKirsten MindenGermanyLakshmi MoorthyUnited States of AmericaMasaaki MoriJapanMary Jo Mulligan-KehoeUnited States of AmericaBahram NamjouUnited States of AmericaRob NickesonUnited States of AmericaEllen NordalNorwaySheila OliveiraBrazilMichael OmbrelloUnited States of AmericaKathleen O\u2019neilUnited States of AmericaKaren OnelUnited States of AmericaOzan OzkayaTurkeyAnjali PatwardhanUnited States of AmericaThomas Klit PedersenDenmarkEvangeline PilleboutFranceOscar PorrasCosta RicaSampath PrahaladUnited States of AmericaBerent PrakkenNetherlandsPierre QuartierFranceEgla RabinovichUnited States of AmericaAthimalaipet RamananUnited KingdomAngelo RavelliItalyJutta RichterGermanyLisa RiderUnited States of AmericaSarah RingoldUnited States of AmericaJohannes RothGermanyRicardo RussoArgentinaHelga SannerNorwayRotraud SaurenmannSwitzerlandLone SchejbelDenmarkChristiaan ScottSouth AfricaAlper SoyluTurkeyAnne Helene SpannowDenmarkJoost SwartNetherlandsYilmaz TabelTurkeyKei TakahashiJapanMelissa TesherUnited States of AmericaAndrea Tesija KunaCroatiaSusan ThompsonUnited States of AmericaKjell TullusUnited KingdomMarinka TwiltCanadaCatrin TzaribachevGermanyYosef UzielIsraelJanjaaap van der NetThe NetherlandsJames W. VarniUnited States of AmericaJelena VojinovicSerbiaLinda Wagner-WeinerUnited States of AmericaCarol WallaceUnited States of AmericaPeter WeiserUnited States of AmericaPatricia WooUnited KingdomNico WulffraatUnited KingdomShumpei YokotaJapanXuan ZhangChinaGaston ZillerueloUnited States of AmericaFrancesco ZulianItaly"}
+{"text": "Cell & Bioscience would like to thank all the reviewers who contributed to the journal in Volume 3 (2013).The editors of  Daniel BuchholzUnited States of AmericaMichael BuszczakUnited States of AmericaLu CaiUnited States of AmericaWeili CaiUnited States of AmericaChia-Hsin ChanUnited States of AmericaWai Yee ChanChinaChia-Hung ChenSingaporeDahua ChenChinaJiandong ChenUnited States of AmericaShu-Hsia ChenUnited States of AmericaWanjun ChenUnited States of AmericaXin ChenUnited States of AmericaYu ChenUnited States of AmericaJocelyn CoteCanadaHongkui DengChinaXiao-Li DuUnited States of AmericaGuoping FanUnited States of AmericaZhaohui FengUnited States of AmericaHuichen FengUnited States of AmericaBurtram FieldingSouth AfricaChuanhai FuHong KongBin GaoUnited States of AmericaChan GaoUnited States of AmericaRui GongChinaNikolai GorbunovUnited States of AmericaXiaoli GuoUnited States of AmericaGeorg HalderBelgiumKieran HarveyAustraliaLiqiang HeUnited States of AmericaShanshan HeUnited States of AmericaAlexander HergovichUnited KingdomWanjin HongSingaporePeggy HsiehUnited States of AmericaChuanshu HuangUnited States of AmericaJing HuangUnited States of AmericaLi-Min HuangTaiwanChien-Fu HungUnited States of AmericaDong-Yan JinHong KongPo-Ling KuoTaiwanMin Gyu LeeUnited States of AmericaAlex LiChinaJun LiChinaQiao LiCanadaShengwen Calvin LiUnited States of AmericaXiaofeng LiUnited States of AmericaHung-Yun LinTaiwanYing-Ju LinTaiwanJunjun LiuUnited States of AmericaWansheng LiuUnited States of AmericaXiang LiuUnited States of AmericaJianfeng LuUnited States of AmericaBingyu MaoChinaYin-Yuan MoUnited States of AmericaPawel MuranskiUnited States of AmericaJian PanUnited States of AmericaXiao PengUnited States of AmericaRobert PiperUnited States of AmericaRytis PrekerisUnited States of AmericaElena Susana RiveraArgentinaLaurent SachsFranceChad SchwartzUnited States of AmericaAshwani SharmaUnited States of AmericaHan-Ming ShenSingaporeYufang ShiChinaJay SinghUnited States of AmericaSteven SperberUnited States of AmericaLishan SuUnited States of AmericaBing SunChinaSai-Wen TangUnited States of AmericaMichael TsangUnited States of AmericaEsther VerheyenCanadaLu WangUnited States of AmericaSophia WangUnited States of AmericaJen-Chywan WangUnited States of AmericaChaochen WangUnited States of AmericaLixin WeiChinaYuehua WeiUnited States of AmericaTao WeitaoUnited States of AmericaJiemin WongChinaPatrick CY WooHong KongSuh-Chin WuTaiwanT-C WuUnited States of AmericaJim XiangCanadaGutian XiaoUnited States of AmericaWei XuUnited States of AmericaHsin-Sheng YangUnited States of AmericaXiaolong YangCanadaYi-Yuan YangTaiwanVenkat YedavalliUnited States of AmericaPaul YenSingaporeYun YenUnited States of AmericaZengqiang YuanChinaDeliang ZhangUnited States of AmericaJiangwei ZhangUnited States of AmericaXiaohui ZhangUnited States of AmericaYanbin ZhangUnited States of AmericaBin ZhaoChinaRichard Y ZhaoUnited States of AmericaZhengyi ZhaoUnited States of AmericaYong-Hui ZhengUnited States of AmericaWeimin ZhongUnited States of America"}
+{"text": "Allergy Asthma & Clinical Immunology would like to thank all of our reviewers who have contributed to the journal in Volume 9 (2013).The editors of  Nils AbergSwedenRitesh AgarwalIndiaReza AlizadehfarCanadaSamuel ArbesUnited States of AmericaNilgun AtakanTurkeyMeghan AzadCanadaClaus BachertBelgiumSami BahnaUnited States of AmericaAnand BalasubramaniUnited States of AmericaBrian BlakleyCanadaCarlos BlancoSpainRobert BoyleUnited KingdomKnut BrockowGermanyJean-Marie BruzzeseUnited States of AmericaAnette BygumDenmarkScott CameronCanadaStuart CarrCanadaJamila ChakirCanadaEdmond ChanCanadaSalvatore ChirumboloItalyDon CockcroftCanadaMitch CohenUnited States of AmericaLinda CoxUnited States of AmericaMaria DalamagaGreeceJohn DeanCanadaDeepak DeshpandeUnited States of AmericaTony DuboisNetherlandsAudrey Dunn GalvinIrelandBernadette EberleinGermanyAarif EifanUnited KingdomRashika El RidiEgyptAnne EllisCanadaAdegoke FaladeNigeriaDaniela FenoglioItalyCharles FrankishCanadaAbdelilah GounniCanadaPaolo GreseleItalyEyal GrunebaumCanadaMichelle HalbrichCanadaKent HayGlassCanadaJonathan HourihaneIrelandNedim InceUnited States of AmericaKomei ItoJapanSushil KabraIndiaRhoda KaganCanadaSandeep KapurCanadaFotini KavadasCanadaPaul Kevin KeithCanadaAtsushi KitaniUnited States of AmericaEster KlaassenNetherlandsRengin KosifTurkeyMitja KosnikSloveniaAstrid KruizingaNetherlandsRajesh KumarUnited States of AmericaDinakantha KumararatneUnited KingdomYing LaiUnited States of AmericaTracy LangkildeUnited States of AmericaS\u00f8ren Thor LarsenDenmarkIan LewkowichUnited States of AmericaPer LidmanCanadaChi-Chen LinTaiwanAllan LinnebergDenmarkJe-Ruei LiuTaiwanScott LorchUnited States of AmericaBruce MazerCanadaLawrence MbuagbawCameroonChristine McCuskerCanadaChris ModyCanadaDumitru MoldovanRomaniaDavid William MooteCanadaThomas MurphyUnited States of AmericaKari NadeauUnited States of AmericaBing NiChinaJean-Francois NicolasFranceAkio NiimiJapanHaruhiko OgawaJapanMitsuhiro OkanoJapanKimihiro OkuboJapanCevdet \u00d6zdemirTurkeyEvy PaulsenDenmarkCesar PicadoSpainThomas Platts- MillsUnited States of AmericaPaul Charles PotterSouth AfricaGregory RexCanadaRachel RobisonUnited States of AmericaMonica Ruiz-GarciaUnited KingdomFranca RusconiItalyJoseph SakshaugGermanyBob SchellenbergCanadaPeter Schmid-GrendelmeierSwitzerlandCarrock SewellUnited KingdomAshok ShahIndiaChristopher ShawCanadaWilliam ShearerUnited States of AmericaMichael ShieldsUnited KingdomFanny Silviu-DanCanadaDonald StarkCanadaHariharan SubramanianUnited States of AmericaMasaya TakemuraJapanSusan TarloCanadaLuis TeranMexicoSimon Francis ThomsenDenmarkEuan ToveyAustraliaPeter VadasCanadaSteven VallesUnited States of AmericaJohannes C van der WoudenNetherlandsTimothy Vander LeekCanadaSusan WasermanCanadaWade WatsonCanadaAnges YadouletonBenin"}
+{"text": "Respiratory Research would like to thank all of our reviewers who have contributed to the journal in Volume 13 (2012).The editors of  Jalal Abu-ShaweeshUnited States of AmericaJohn AdcockUnited KingdomKenneth AdlerUnited States of AmericaIoana AgacheRomaniaAlvar AgustiSpainDorothy AinsworthUnited States of AmericaJohn AlcornUnited States of AmericaNeil AlexisUnited States of AmericaSharilyn AlmodovarUnited States of AmericaSteven AnUnited States of AmericaVikas AnathyUnited States of AmericaWayne AndersonUnited States of AmericaMasaru AndoJapanIgnacio AnsoteguiSpainSabina AntoniuRomaniaKeisuke AoeJapanDavid AronoffUnited States of AmericaKewal AsosinghUnited States of AmericaBaroukh Mautice AssaelItalyEric AustinUnited States of AmericaMalin AxelssonSwedenHoeke BaarsmaNetherlandsGregory BagbyUnited States of AmericaChunxue BaiChinaKatherine BainesAustraliaEls BakkerNetherlandsJohn BalmesUnited States of AmericaPeter BarlowUnited KingdomEric BatemanSouth AfricaSalvatore BattagliaItalyRichard BeasleyNew ZealandMichael BeersUnited States of AmericaJuergen BehrGermanyAbdelmadjid BelkadiUnited States of AmericaMaria BelvisiUnited KingdomYves BerthiaumeCanadaIvan BertoncelloAustraliaUrvashi BhanUnited States of AmericaColin David BingleUnited KingdomAnders BjergSwedenLeif BjermerSwedenThomas BlankenburgGermanyYury BochkovUnited States of AmericaVijay BoggaramUnited States of AmericaMarcel BonayFranceDiana BondermanAustriaFrancesco BonellaGermanyJames BonnerUnited States of AmericaPhilippe BonniaudFranceMichael BorchersUnited States of AmericaSixten BorgSwedenApostolos BossiosSwedenJean BousquetFranceKen BrackeBelgiumFulvio BraidoItalyCaroline BretFranceSteven BrodyUnited States of AmericaCynthia BrownUnited States of AmericaE Sherwood BrownUnited States of AmericaVito BrusascoItalyGuy BrusselleBelgiumPierre-Regis BurgelFranceSergio BurgueteUnited States of AmericaPeter CalverleyUnited KingdomCarlos CamargoUnited States of AmericaGianna CamiciottoliItalyMatthew CampenUnited States of AmericaLuigi CamporotaUnited KingdomVera L CapelozziBrazilGaetano CaramoriItalyTroy CarloUnited States of AmericaChris CarlstenCanadaCiro CasanovaSpainDidier CataldoBelgiumPascal ChanezFrancePeter ChenUnited States of AmericaYin ChenUnited States of AmericaLee-Wei ChenTaiwanChung-Ming ChenTaiwanJianlin ChengUnited States of AmericaDonavan ChengUnited States of AmericaMyung-Haing CHOKorea, SouthLi Ping ChungAustraliaMyoung Ja ChungKorea, SouthLucie ClappUnited KingdomJocelyn ClaudeUnited States of AmericaGregory ConnerUnited States of AmericaMarco ContoliItalyCarlyne CoolUnited States of AmericaGiuseppe M CorboItalyFerry CornelissenNetherlandsJorge Correia-PintoPortugalPeter Alan CoventryUnited KingdomBruno CrestaniFranceTore CurstedtSwedenJeffrey CurtisUnited States of AmericaSalvatore CuzzocreaItalyLaura DadaUnited States of AmericaBhola Kumar DahalGermanySven-Erik Dahl\u00e9nSwedenRavi DasuUnited States of AmericaIan DavisUnited States of AmericaFrancesco De BlasioItalyStijn Piet De LangheUnited States of AmericaRoberto de MarcoItalyNicolas de ProstFranceBart DekkersNetherlandsMarion DelcroixBelgiumPhillip DellingerUnited States of AmericaRolf DembinskiGermanyNavneet DhillonUnited States of AmericaY Peter DiUnited States of AmericaAntonino Di StefanoItalyAlexander DietrichGermanyQuoc Thai DinhGermanyClaudio F DonnerItalyJames DonohueUnited States of AmericaWonder DrakeUnited States of AmericaMarjolein DrentNetherlandsPaul DudasUnited States of AmericaRodney EhrlichSouth AfricaOliver EickelbergGermanyHesham El-ShewyUnited States of AmericaJonas ErikssonSwedenDavid ErleUnited States of AmericaLeo FabbriItalyJames FabisiakUnited States of AmericaAurelie FabreIrelandJoachim FandreyGermanyNeda FarahiUnited KingdomMalgorzata FarnikPolandHeinz FehrenbachGermanyCharles FeldmanSouth AfricaNiki FensNetherlandsLucas FernandezUnited States of AmericaDaniel Clark FilesUnited States of AmericaBernie FischerUnited States of AmericaAnne FitzpatrickUnited States of AmericaPaul ForsytheCanadaJames FrankUnited States of AmericaCharles FrevertUnited States of AmericaAlex FuUnited States of AmericaNobukazu FujimotoJapanJennie GaneUnited KingdomChristine GarciaUnited States of AmericaFrancisco Garc\u00eda-R\u00edoSpainEric GartmanUnited States of AmericaGail GauvreauCanadaMoyar Qing GeUnited States of AmericaThomas GeiserSwitzerlandPierangelo GeppettiItalyMaher GhamloushUnited States of AmericaSaeid GhavamiCanadaYong Song GhoKorea, SouthSudip GhoshUnited KingdomPeter Gerard GibsonAustraliaM Ian GilmourUnited States of AmericaThomas GlaabGermanyConstantinos GlynosBelgiumElena GoncharovaUnited States of AmericaPeter GondrieNetherlandsReinoud GosensNetherlandsKymberly GowdyUnited States of AmericaAndrew GreeningUnited KingdomSilvia GregoriItalyTimm GreulichGermanyCortland GriswoldCanadaMathieu GruetFranceAndreas GuentherGermanyTillie-Louise HackettCanadaAngela HaczkuUnited States of AmericaStig HagstadSwedenAndrew HalaykoCanadaAaron HamvasUnited States of AmericaMeilan HanUnited States of AmericaKeqi HanChinaMasayuki HanaokaJapanTomohiro HandaJapanPhil HansbroAustraliaDavid HansellUnited KingdomKevan HartshornUnited States of AmericaNoboru HattoriJapanGregory HawkinsUnited States of AmericaEnrico HefflerItalyDirk HenrichGermanyPieter HiemstraNetherlandsYuji HigashimotoJapanSandra HodgeAustraliaCory HogaboamUnited States of AmericaAnne HollandAustraliaOlaf HolzGermanyRobert HomerUnited States of AmericaGuochang HuUnited States of AmericaSteven HuangUnited States of AmericaYu-Jing HuangUnited States of AmericaRudolf M. HuberGermanyAlice HuertasFranceDavid HuiHong KongMarc HumbertFranceMachteld HylkemaNetherlandsRobert HyzyUnited States of AmericaMasakazu IchinoseJapanKaori Ihida-StansburyUnited States of AmericaMachiko IkegamiUnited States of AmericaDominique Israel-BietFranceKazuhiro ItoUnited KingdomShingo IwanoJapanTae Jung JangKorea, SouthIlona JaspersUnited States of AmericaMarc JeschkeCanadaAnton JettenUnited States of AmericaSamithamby JeyaseelanUnited States of AmericaZhilong JiangUnited States of AmericaZhi-Cheng JINGChinaMartin JohnsonUnited KingdomPaul JonesUnited KingdomGuy JoosBelgiumAndreas JungSwitzerlandRavi KalhanUnited States of AmericaYoshihide KanaokaUnited States of AmericaMin-Jong KangUnited States of AmericaFerenc KarpatiSwedenAtsushi KatoUnited States of AmericaRuth KatzUnited States of AmericaJoseph KatzUnited States of AmericaSteven KawutUnited States of AmericaKlaus KennGermanyEitan KeremIsraelHuib A M KerstjensNetherlandsKwang KimUnited States of AmericaYoon-Keun KimKorea, SouthDong Soon KimKorea, SouthPaul KingmaUnited States of AmericaJason KirknessUnited States of AmericaAlex KleinJanNetherlandsJoel KlineUnited States of AmericaDarryl KnightCanadaAlan KnoxUnited KingdomBeate KochGermanyAndreas Rembert KoczullaGermanyMelanie K\u00f6nigshoffGermanyStephanie KornGermanyGabor KovacsAustriaKrzysztof KowalPolandMichael KreuterGermanyMarkus KruppGermanyOlga KryskoBelgiumHilmar KuehlGermanyIlko KuljanacCroatiaWolfgang KummerGermanyKen KunisakiUnited States of AmericaHan-Pin KuoTaiwanOm KurmiUnited KingdomEmel KurtTurkeyPaige LacyCanadaDominique Lagadic-GossmannFranceVincent LagenteFranceTimmy LahmUnited States of AmericaVibha LamaUnited States of AmericaKevin LamoteBelgiumIrene LangAustriaPeter LangeDenmarkSophie LanoneFranceAlexander LarcombeAustraliaFran\u00e7ois LaurentFranceWilliam LawsonUnited States of AmericaAili LazaarUnited States of AmericaRomain LazorSwitzerlandAhmed LazrakUnited States of AmericaMaria Cristina LebreNetherlandsDavid LedererUnited States of AmericaYong Chul LeeKorea, SouthPeter LeeUnited KingdomBruce LevyUnited States of AmericaChristiane LexGermanyGang LiuUnited States of AmericaShing-Hwa LiuTaiwanMarek LommatzschGermanyRenaud LouisBelgiumKaizhi LuChinaTracy LuckhardtUnited States of AmericaAmie LundUnited States of AmericaLennart LundbladUnited States of AmericaDaoxin MaChinaHarm MaarsinghNetherlandsRajiv MachadoUnited KingdomRoberto MachadoUnited States of AmericaSerdia MackUnited States of AmericaTania MaesBelgiumHelgo MagnussenGermanyToby MaherUnited KingdomSarah MaherUnited KingdomToby MaherUnited KingdomArnaud MailleuxFranceMario MalerbaItalyPatrick MalliaUnited KingdomDavid ManninoUnited States of AmericaLin MantellUnited States of AmericaFrancois MarchalFranceJames MartinCanadaChristian MartinGermanySadis MatalonUnited States of AmericaThais MauadBrazilRobin McAnultyUnited KingdomChristine McCuskerCanadaEvert MeijerNetherlandsAndrea MelaniItalyBarbro MelgertNetherlandsKeith C MeyerUnited States of AmericaTatiana MichelLuxembourgMarc MiravitllesSpainFirdaus A A Mohamed HoeseinNetherlandsLyn MoirAustraliaPaolo MontuschiItalyJerome MoreauxFrancePeter MorfeldGermanyYasuo MoriJapanDanielle MorseUnited States of AmericaRory MortyGermanyJoachim Mueller-QuernheimGermanyJoaquim MullolSpainJeffrey MunsonUnited States of AmericaJeffrey MyersUnited States of AmericaRobert NaeijeBelgiumYasutaka NakanoJapanPatrick Nana-SinkamUnited States of AmericaViswanathan NatarajanUnited States of AmericaGiuseppe NovelliItalyBenjamin NwosuUnited States of AmericaAnne O\u2019DonnellUnited States of AmericaBenjamin OdryUnited States of AmericaShinichiro OhshimoJapanHorst OlschewskiAustriaJosuel OraItalyPierluigi PaggiaroItalyMikell PaigeUnited States of AmericaRobert PaineUnited States of AmericaLena PalmbergSwedenAnnie PardoMexicoAnand PatelUnited States of AmericaRay Stokes PeeblesUnited States of AmericaRiccardo PellegrinoItalyTonio PeraUnited States of AmericaJesus Perez-GilSpainMichael PetersUnited States of AmericaIrina PetracheUnited States of AmericaAlejandro PezzuloUnited States of AmericaVictor Pinto-PlataUnited States of AmericaMassimo PistolesiItalyCarole PlanesFranceLaurent PlantierFranceDon PoldermansNetherlandsVenerino PolettiItalyJill PooleUnited States of AmericaCeleste PorsbjergDenmarkNicolas PottierFranceY S PrakashUnited States of AmericaAntje PrasseGermanyAlice PrinceUnited States of AmericaMirella ProfitaItalyLuis Puente-MaestuSpainVille PulkkinenFinlandLianqun QiuUnited States of AmericaKurt RackeGermanyMadeleine R\u00e5dingerSwedenIrfan RahmanUnited States of AmericaArjun RamIndiaEve RameryBelgiumSarah RandUnited KingdomLee ReichmanUnited States of AmericaNiels ReinmuthGermanyLuca RicheldiItalyCarlos Robalo CordeiroPortugalGraham RobertsUnited KingdomMac RobinsonUnited States of AmericaRoberto Rodriguez-RoisinSpainDebra RombergerUnited States of AmericaEva R\u00f6nmarkSwedenMary RoseUnited States of AmericaRobbert RottierNetherlandsLewis RubinUnited States of AmericaStephen RuossUnited States of AmericaKristina Rydell-TormanenSwedenBernhard RyffelFranceZeenat SafdarUnited States of AmericaMatthias SalatheUnited States of AmericaDaniel SalernoUnited States of AmericaDedmer SchaafsmaCanadaAndreas SchmidUnited States of AmericaLynn SchnappUnited States of AmericaHildegard M. SchullerUnited States of AmericaMalcolm SearsCanadaSanjay SethiUnited States of AmericaSatish SharmaUnited States of AmericaHuahao ShenChinaYoko ShibataJapanLarissa ShimodaUnited States of AmericaHiroaki ShimokawaJapanVladimir ShirinskyRussian FederationNikos SiafakasGreeceMujgan SidalTurkeyPhilip SilkoffUnited States of AmericaJodie SimpsonAustraliaDave SinghUnited KingdomBaljit SinghCanadaVal\u00e9rie SirouxFranceBrigita SitkauskieneLithuaniaChrysanthi SkevakiGreeceTrude Duelien SkorgeNorwayHortense SlevogtGermanyPeter SlyAustraliaDavid SmithUnited KingdomSaul SoberanesUnited States of AmericaMatteo SofiaItalyPaolo SpagnoloItalyAntonio SpanevelloItalyAnita SpanjerNetherlandsMark SpearsUnited KingdomLissa SpencerAustraliaDomenico SpinaUnited KingdomMichael StalveyUnited States of AmericaBruce StantonUnited States of AmericaCharlie StrangeUnited States of AmericaTakafumi SudaJapanHisatoshi SugiuraJapanMary SundayUnited States of AmericaErna SzikszHungaryRuth Tal-SingerUnited States of AmericaClaudio TantucciItalyDonald TashkinUnited States of AmericaDries TestelmansBelgiumVictor ThannickalUnited States of AmericaDirk TheegartenGermanyNeil ThomsonUnited KingdomDavid ThorntonUnited KingdomPeter TomassenBelgiumKjell Tor\u00e9nSwedenDimitrios ToumpamakisGreeceGerard M TurinoUnited States of AmericaSilvia UlrichSwitzerlandSoban UmarUnited States of AmericaPaul UptonUnited KingdomIsabelle VachierFranceDominique ValeyreFranceThys van der MolenNetherlandsMarco van der ToornNetherlandsFrederik-Jan Van SchootenNetherlandsJeroen VanoirbeekBelgiumRuud VeldhuizenCanadaJohanna VendelinFinlandPer VengeSwedenGiulia VeronesiItalyGiovanni ViegiItalyGary VisnerUnited States of AmericaClaus VogelmeierGermanyRobert VoswinckelGermanyNicolas VuilleumierSwitzerlandElizabeth WagnerUnited States of AmericaBenoit WallaertFrancePatrick WalshIrelandGarry WalshUnited KingdomXiangdong WangChinaGang WangChinaDavid WarburtonUnited States of AmericaGeorge WashkoUnited States of AmericaHenrik WatzGermanyMichael WegmannGermanyAthol WellsUnited KingdomFu-Qiang WenChinaChristine Wenner\u00e5sSwedenThomas WessendorfGermanyCarl WhiteUnited States of AmericaMark WielpuetzGermanyMartin WitzenrathGermanyWill WodzigNetherlandsKeith Keat Huat WongAustraliaPrescott WoodruffUnited States of AmericaWeining XiongChinaIan YangAustraliaIvana YangUnited States of AmericaMordechai YiglaIsraelCuneyt YilmazUnited States of AmericaHamid ZandIranAndrea ZaniniItalyJacques ZimmerLuxembourgJaroslaw ZmijewskiUnited States of AmericaGraeme ZoskyAustralia"}
+{"text": "Retrovirology would like to thank the following for their assistance with peer review of manuscripts for the journal in 2012. Marlen Aasa-ChapmanUnited KingdomIsabella AbbateItalyChristopher AikenUnited States of AmericaLorraine AlbrittonUnited States of AmericaJose AlcamiSpainNeil AlmondUnited KingdomZandrea AmbroseUnited States of AmericaMarie-Line AndreolaFranceNathalie ArhelFranceEric ArtsUnited States of AmericaEugene AsahchopCanadaMasanori BabaJapanEran BacharachIsraelJan BalzariniBelgiumCharles BanghamUnited KingdomNorbert BannertGermanyEric BarklisUnited States of AmericaSt\u00e9phane BasmaciogullariFranceJean-Luc BattiniFranceAli BazarbachiLebanonAnne-Sophie BeignonFranceSerge BenichouFranceMonsef BenkiraneFranceYamina BennasserFranceEdward BergerUnited States of AmericaBen BerkhoutNetherlandsClarisse Berlioz-TorrentFranceNeil BerryUnited KingdomLionel BerthouxCanadaEdouard BetsemFranceJoel BlanksonUnited States of AmericaRonald BontropNetherlandsKathleen Boris-LawrieUnited States of AmericaPersephone BorrowUnited KingdomFadila BouamrUnited States of AmericaCharles BoucherNetherlandsKatarzyna BozekGermanyIneke BraakmanNetherlandsSimon BrackenridgeUnited KingdomAbraham BrassUnited States of AmericaJason BrenchleyUnited States of AmericaBluma BrennerCanadaLaurence BriantFranceMark BrockmanCanadaChristopher BroderUnited States of AmericaJames BrooksCanadaDoryen BubeckUnited KingdomShilpa BuchUnited States of AmericaMichael BukrinskyUnited States of AmericaDonald BurkeUnited States of AmericaDennis BurtonUnited States of AmericaEdward CampbellUnited States of AmericaMary CampbellUnited States of AmericaPaula CannonUnited States of AmericaMary CarringtonUnited States of AmericaCarol CarterUnited States of AmericaChris CaseUnited States of AmericaHannah CastroUnited KingdomFrancesca Ceccherini-SilbersteinItalyShengxi ChenUnited States of AmericaIrvin ChenUnited States of AmericaBenjamin ChenUnited States of AmericaCecilia Cheng-MayerUnited States of AmericaPeter CherepanovUnited KingdomAndrea CimarelliFrancePaul ClaphamUnited States of AmericaJanice ClementsUnited States of AmericaKathleen ClouseUnited States of AmericaAlan CochraneCanadaJohn CoffinUnited States of AmericaEric CohenCanadaPierre CorbeauFranceMarion CornelissenNetherlandsRebecca CravenUnited States of AmericaGael CristofariFranceAtze DasNetherlandsSiddhartha DattaUnited States of AmericaMiles DavenportAustraliaAndrew DaytonUnited States of AmericaAnthony De VicoUnited States of AmericaMichele Di MascioUnited States of AmericaFelipe Diaz-GrifferoUnited States of AmericaDimiter DimitrovUnited States of AmericaRobert DomsUnited States of AmericaMargherita DoriaItalyAlexei DrummondNew ZealandMichel DuponFranceMichael EmermanUnited States of AmericaStephane EmilianiFranceAlan EngelmanUnited States of AmericaOliver FacklerGermanyAriberto FassatiUnited KingdomBenoit FavierFranceMark FederspielUnited States of AmericaJacques FellaySwitzerlandDean FollmannUnited States of AmericaGenoveffa FranchiniUnited States of AmericaPierre FrangeFranceChristophe FraserUnited KingdomEric FreedUnited States of AmericaSebastian FugmannUnited States of AmericaMasahiro FujiiJapanJun-ichi FujisawaJapanDana GabuzdaUnited States of AmericaVitaly GanusovUnited States of AmericaJ. Victor GarciaUnited States of AmericaHenrik GaroffSwedenJeremy GarsonUnited KingdomHiroyuki GatanagaJapanAnne GatignolCanadaGlen GaultonUnited States of AmericaWilliam GelbartUnited States of AmericaAntoine GessainFranceMauro GiaccaItalyNicolas GilbertFrancePaul GoepfertUnited States of AmericaStephen GoffUnited States of AmericaNilu GoonetillekeUnited KingdomRobert J. GorelickUnited States of AmericaPaul GorryAustraliaMatthias GotteCanadaHeinrich GottlingerUnited States of AmericaXavier Gra\u00f1aUnited States of AmericaLuuk GrasNetherlandsPatrick GreenUnited States of AmericaJay GroblerUnited States of AmericaJohn GuatelliUnited States of AmericaLutz GuertlerGermanySamuel GundersonUnited States of AmericaBeatrice HahnUnited States of AmericaNancy HaigwoodUnited States of AmericaWilliam HallIrelandDavid HarrichAustraliaP Richard HarriganCanadaReuben HarrisUnited States of AmericaHideki HasegawaJapanJonathan HeeneyUnited KingdomThierry HeidmannFranceChristopher HellenUnited States of AmericaJoris HemelaarUnited KingdomJoshua HerbeckUnited States of AmericaGeorges HerbeinFranceVanessa HirschUnited States of AmericaPhilip HoggAustraliaThomas HopeUnited States of AmericaLaurent HouzetUnited States of AmericaJames HoxieUnited States of AmericaPeter HraberUnited States of AmericaWei-Shau HuUnited States of AmericaStephen HughesUnited States of AmericaPeter HuntUnited States of AmericaEric HunterUnited States of AmericaHendrik HuthoffUnited KingdomTatsuhiko IgarashiJapanSergey IordanskiyUnited States of AmericaYukihito IshizakaJapanJacques IzopetFranceRichard JennerUnited KingdomHezhao JiCanadaShibo JiangChinaDong-Yan JinHong KongMarc JohnsonUnited States of AmericaPaul JolicoeurCanadaClare JollyUnited KingdomRolf KaiserGermanyGanjam KalpanaUnited States of AmericaAditi KanhereUnited KingdomJonathan KarnUnited States of AmericaFatah KashanchiUnited States of AmericaDavid KatzUnited KingdomBrandon KeeleUnited States of AmericaPaul KellamUnited KingdomStephen KentAustraliaOliver KepplerGermanyRosemary KiernanFranceBaek KimUnited States of AmericaJason KimataUnited States of AmericaFrank KirchhoffGermanyNichole KlattUnited States of AmericaRenate KoenigGermanyWayne KoffUnited States of AmericaDonald KohnUnited States of AmericaNeeltje KootstraNetherlandsYoshio KoyanagiJapanChristine KozakUnited States of AmericaBjorn KuhlUnited States of AmericaPeter KwongUnited States of AmericaBernard LafontUnited States of AmericaNadine LaguetteFranceJean-Marc LanchyUnited States of AmericaNathaniel LandauUnited States of AmericaMichael LaughreaCanadaHa Youn LeeUnited States of AmericaAndrew LeverUnited KingdomLaura LevyUnited States of AmericaSharon LewinAustraliaYuxing LiUnited States of AmericaChen LiangCanadaYi LiuUnited States of AmericaJ. Stephen LodmellUnited States of AmericaJeremy LubanUnited States of AmericaRenaud MahieuxFranceJohnson MakAustraliaFrank MaldarelliUnited States of AmericaMichael MalimUnited KingdomFabrizio MammanoFranceNicolas ManelFranceAnne-Genevieve MarcelinFranceAlessandro MarcelloItalyRichard MarkhamUnited States of AmericaDavid MarkovitzUnited States of AmericaMark MarshUnited KingdomJulio Martin-GarciaUnited States of AmericaJuan Martin-SerranoUnited KingdomBernard MasquelierFranceTetsuro MatanoJapanMasao MatsuokaJapanWendy MauryUnited States of AmericaErnest MaynardUnited States of AmericaMyra McClureUnited KingdomAine McKnightUnited KingdomMark McNallyUnited States of AmericaGregory MelikyanUnited States of AmericaJean-Michel MesnardFranceKarin J. MetznerSwitzerlandMasaaki MiyazawaJapanTakayuki MiyazawaJapanTrine MogensenDenmarkRonald MontelaroUnited States of AmericaJohn MooreUnited States of AmericaLynn MorrisSouth AfricaDonald MosierUnited States of AmericaMarylene MougelFranceAndrew J MoulandCanadaViktor M\u00fcllerHungaryMatteo NegroniFranceStuart NeilUnited KingdomSergei NekhaiUnited States of AmericaYoshiaki NishimuraUnited States of AmericaSebastien NisoleFranceMarc Noguera-JulianSpainPhilip NorrisUnited States of AmericaVlad NovitskyUnited States of AmericaDavid OConnorUnited States of AmericaPaula Ordonez SuarezUnited KingdomMary PacoldUnited States of AmericaLuis A PardoGermanyRoger ParedesSpainVinay PathakUnited States of AmericaWilliam PaxtonNetherlandsMartine PeetersFranceJean-Marie PeloponeseFranceYuri PersidskyUnited States of AmericaBoris Matija PeterlinUnited States of AmericaClaudine PiqueFranceMauro PistelloItalyMassimo PizzatoItalyEric PoeschlaUnited States of AmericaStefan P\u00f6hlmannGermanyGeorgios PollakisNetherlandsYves PommierUnited States of AmericaArt PoonCanadaVinayaka PrasadUnited States of AmericaFlor PujolVenezuelaLynn PulliamUnited States of AmericaMiguel Quinones-MateuUnited States of AmericaAlan ReinUnited States of AmericaAxel RethwilmGermanyAndrew RiceUnited States of AmericaYolande RichardFranceMarjorie Robert-GuroffUnited States of AmericaOlivier RohrFranceMonica RothUnited States of AmericaJean-Pierre RoutyCanadaSarah Rowland-JonesUnited KingdomJonah SachaUnited States of AmericaAli SaibFranceMineki SaitoJapanJun-ichi SakuragiJapanMarco SalemiUnited States of AmericaRogier SandersNetherlandsStefanos SarafianosUnited States of AmericaQuentin SattentauUnited KingdomBassel E SawayaUnited States of AmericaCelia SchifferUnited States of AmericaMichael SchindlerGermanyOlivier SchwartzFranceWalter ScottUnited States of AmericaJamie ScottCanadaOliver John SemmesUnited States of AmericaXiaoying ShenUnited States of AmericaMarc SitbonFranceJacek SkowronskiUnited States of AmericaNicolas Sluis-CremerUnited States of AmericaThomas SmithgallUnited States of AmericaEllen SpargerUnited States of AmericaPaul SpearmanUnited States of AmericaDave SpeijerNetherlandsKlaus StrebelUnited States of AmericaHendrik StreeckUnited States of AmericaMichael SummersUnited States of AmericaWilliam SwitzerUnited States of AmericaChetan TailorCanadaToshikazu TakeshitaJapanYasuhiro TakeuchiUnited KingdomMasafumi TakiguchiJapanAmalio TelentiSwitzerlandAlice TelesnitskyUnited States of AmericaMarkus ThaliUnited States of AmericaKenzo TokunagaJapanGeorgia TomarasUnited States of AmericaGreg TowersUnited KingdomSimon TraversSouth AfricaKlaus \u00dcberlaGermanySusana ValenteUnited States of AmericaTonja van der KuylNetherlandsCarine Van LintBelgiumKoen Van RompayUnited States of AmericaAnne-Mieke VandammeBelgiumLinos VandekerckhoveBelgiumSue vandeWoudeUnited States of AmericaSundararajan VenkatesanUnited States of AmericaBruno VerhasseltBelgiumGabriel WagnerUnited States of AmericaAbdul WaheedUnited States of AmericaMark WainbergCanadaXiaohua WangUnited States of AmericaRobin WeissUnited KingdomKirsten WhiteUnited States of AmericaJames WhitneyUnited States of AmericaBrian WigdahlUnited States of AmericaLucas WillemsBelgiumKenneth WitwerUnited States of AmericaJoseph WongUnited States of AmericaLi WuUnited States of AmericaYuntao WuUnited States of AmericaGutian XiaoUnited States of AmericaHongtao XuCanadaMasahiro YamashitaUnited States of AmericaXiaojian YaoCanadaJunichiro YasunagaJapanAhmad YatimFranceMan Lung YeungHong KongJohn YoungUnited States of AmericaJerome ZackUnited States of AmericaOsvaldo ZagordiSwitzerlandRichard Y ZhaoUnited States of AmericaYong-Hui ZhengUnited States of AmericaZhi-Ming ZhengUnited States of AmericaJoseph ZiegelbauerUnited States of AmericaMichael ZwickUnited States of Americath 2013. This article was seen and approved by him in early January 2013.Dr Kuan-Teh Jeang passed away on January 27"}
+{"text": "Pediatric Rheumatology would like to thank all our reviewers who have contributed to the journal in Volume 10 (2012).The Editors of  Judith AdamsUnited KingdomKazunaga AgematsuJapanAmita AggarwalIndiaJonathan AkikusaAustraliaGraciela AlarconUnited States of AmericaFlorence AllantazUnited States of AmericaGeorgina Marian AllenUnited KingdomMeloni AntonellaJordanTadej AvcinSloveniaNoha AzabEgyptGerard BanezUnited States of AmericaMara BeckerUnited States of AmericaEdward BehrensUnited States of AmericaSusanne BenselerCanadaTimothy BeukelmanUnited States of AmericaJohn BohnsackUnited States of AmericaZulkif BozgeyikTurkeyRiva BrikIsraelMaggie BrombergUnited States of AmericaRuben Burgos-VargasMexicoDavid CabralCanadaHans-Dieter CarlGermanyMagda Carneiro-SampaioBrazilPeter ChiraUnited States of AmericaRolando CimazItalyMark ConnellyUnited States of AmericaRandy CronUnited States of AmericaYanick CrowUnited KingdomMegan CurranUnited States of AmericaBo DingSwedenJie DingChinaDebbie Ehrmann FeldmanCanadaAndrew EichenfieldUnited States of AmericaNahla El SharkawyEgyptMichelle ErnstUnited States of AmericaSubhadra EvansUnited States of AmericaCorona FabriziaItalyFernanda FalciniItalyTzipora Falik-ZaccaiIsraelFlavio FantiniItalyAnders FasthSwedenBrian FeldmanCanadaPolly FergusonUnited States of AmericaNatalya FishUnited States of AmericaBerit Flat\u00f8NorwayIvan FoeldvariGermanyLeng Huat FooMalaysiaAntonella ForlinoItalyHelen FosterUnited KingdomJoost FrenkelNetherlandsAbraham GedaliaUnited States of AmericaStuart GoodmanUnited States of AmericaRakesh K GuptaIndiaKathleen HainesUnited States of AmericaKeri HainsworthUnited States of AmericaLiora HarelIsraelTroels HerlinDenmarkKristin HoughtonCanadaLen HuaUnited States of AmericaZeng HuasongChinaKimme HyrichUnited KingdomOlcay JonesUnited States of AmericaLudmyla KachkoIsraelPhilip KahnUnited States of AmericaJoseph KahwajiUnited States of AmericaGeorge KallioliasUnited States of AmericaSylvia KamphuisNetherlandsOzgur KasapcopurTurkeyRaju KhubchandaniIndiaNa Rae KimSouth KoreaYukiko KimuraUnited States of AmericaMarisa Klein-GitelmanUnited States of AmericaSusan KlepperUnited States of AmericaIchiro KobayashiJapanBianca LangCanadaMario LapecorellaItalyRonald LaxerCanadaMartine Le MerrerFranceThomas J A LehmanUnited States of AmericaCarol LindsleyUnited States of AmericaGustaf LjungmanSwedenDeirdre LoganUnited States of AmericaKathleen LoomesUnited States of AmericaSilvia Magni-ManzoniItalyOuti MakitieFinlandClara MalattiaItalyAlberto MartiniItalyJanet McDonaghUnited KingdomHans-Joachim MentzelGermanyKirsten MindenGermanyCarlomaurizio MontecuccoItalyTerry MooreUnited States of AmericaLakshmi MoorthyUnited States of AmericaZoilo Morel AyalaParaguayTimothy NiewoldUnited States of AmericaPeter NigrovicUnited States of AmericaMegumi OkumuraUnited States of AmericaSheila OliveiraBrazilJo\u00e3o OliveiraUnited States of AmericaKaren OnelUnited States of AmericaIngrid Landgraff \u00d6stlieNorwayHaluk H OztekinTurkeyLauren PachmanUnited States of AmericaMurray PassoUnited States of AmericaAnjali PatwardhanUnited States of AmericaStephen PopperUnited States of AmericaMichael PortmanUnited States of AmericaSampath PrahaladUnited States of AmericaLynn PunaroUnited States of AmericaEgla RabinovichUnited States of AmericaAthimalaipet RamananUnited KingdomAngelo RavelliItalySarah RingoldUnited States of AmericaCarlos RoseUnited States of AmericaKelly Rouster-StevensUnited States of AmericaRicardo RussoArgentinaTomoyuki SaitoJapanRotraud SaurenmannSwitzerlandKen SchiklerUnited States of AmericaQing ShangHong KongDavid SherryUnited States of AmericaSurjit SinghIndiaElisabeth Solau-GervaisFranceSteven SpaldingUnited States of AmericaFrancois SpertiniSwitzerlandMatthew StollUnited States of AmericaJau-Ling SuenTaiwanAndrea Superti-FurgaSwitzerlandJoost SwartNetherlandsYilmaz TabelTurkeyTim TakkenNetherlandsLene TerslevDenmarkAndrea Tesija KunaCroatiaWendy ThomsonUnited KingdomShirley TseCanadaMarinka TwiltCanadaNikolay TzaribachevGermanyJanjaaap van der NetNetherlandsSebastiaan VastertNetherlandsJames VerbskyUnited States of AmericaLinda Wagner-WeinerUnited States of AmericaLucy WedderburnUnited KingdomPatience WhiteUnited States of AmericaChrister WingrenSwedenCarine WoutersBermudaNico WulffraatNetherlandsSwan Sim YeapMalaysiaAndrew ZeftUnited States of AmericaXuan ZhangChinaAristeidis ZibisGreece"}
+{"text": "Journal of Trauma Management and Outcomes and BioMed Central would like to show our appreciation for the following reviewers for their time, hard work and support by reviewing manuscripts for the journal in 2013.The editors of the  Mazhar AbbasIndiaIbrahim AlhabdanSaudi ArabiaAbdulbari BenerQatarAna CarlottiBrazilCharles GerardoUnited States of AmericaMorad HameedCanadaManu MalbrainBelgiumGerrit MatthesGermanyJeffrey IndesUnited States of AmericaLynne MooreCanadaMichael PasqualeUnited States of AmericaJoao Rezende-NetoCanadaUli SchmuckerGermanyVance SohnUnited States of AmericaSandy WidderCanadaHiroshi YatsushigeJapanNiels ZorgerGermany"}
+{"text": "Israel Journal of Health Policy Research would like to thank all reviewers, both external and Editorial Board Members, who have contributed to the journal since its inception, and whose valuable support continues to be essential to the success of the journal.The Editors of  Julia Adler-MilsteinUnited States of AmericaArnon AfekIsraelAkke AlbadaNetherlandsYael ApplbaumIsraelNachman AshIsraelYael AshkenaziIsraelToni AshtonNew ZealandUri AviramIsraelAlexander AviramIsraelOrna Baron-EpelIsraelArie Ben YehudaIsraelJochanan BenbassatIsraelMatthew BendingUnited KingdomNetta BenturIsraelGabi Bin NunIsraelStephen BirchUnited KingdomLinda BirnbaumUnited States of AmericaYair BirnbaumIsraelHaim BittermanIsraelGary BondUnited States of AmericaHeather BoonCanadaJeffrey BorkanUnited States of AmericaShuli Brammli-GreenbergIsraelMayer BrezisIsraelRonit Calderon-MargalitIsraelSilvana CastaldiItalyDavid ChinitzIsraelA Mark ClarfieldIsraelRobert CohenIsraelMarc CohenUnited States of AmericaGregory ConnollyUnited States of AmericaRichard CooperUnited States of AmericaJanet CorriganUnited States of AmericaYehuda DanonIsraelGordon DeFrieseUnited States of AmericaMilka DonchinIsraelRobert DrakeUnited States of AmericaAsher ElhayanyIsraelLinda EmanuelUnited States of AmericaKeren EyalIsraelHenry FalkUnited States of AmericaRoger FeldmanUnited States of AmericaPenny FeldmanUnited States of AmericaEric FinkelsteinSingaporeGary FreedUnited States of AmericaYosef FrostIsraelGuido GiarelliItalyStanton GlantzUnited States of AmericaShimon GlickIsraelMarsha GoldUnited States of AmericaMelissa GoldsteinUnited States of AmericaManfred GreenIsraelDan GreenbergIsraelMichael GrodinUnited States of AmericaItamar GrottoIsraelJonathan HalevyIsraelPinchas HalpernIsraelMartin HatlieUnited States of AmericaMaria M. Hofmarcher-HolzhackerAustriaTuvia HorevIsraelOrit JacobsenIsraelJonathan JavittUnited States of AmericaDeborah JuarezUnited States of AmericaNir KaidarIsraelOfra Kalter-LeiboviciIsraelLital Keinan-BokerIsraelArthur KellermannUnited States of AmericaIlona KickbuschSwitzerlandKristin KieselUnited States of AmericaBarry KinzbrunnerUnited States of AmericaGerald KonradCanadaAnkit KumarFranceAmnon LahadIsraelBruce LandonUnited States of AmericaFleur-Ange LefebvreCanadaMoshe LeshnoIsraelOsnat Levtzion-KorachIsraelHarold LuftUnited States of AmericaNicole LurieUnited States of AmericaWilliam MaasUnited States of AmericaDavid MankutaIsraelIdit MatotIsraelMartin McKeeUnited KingdomPatriek MistiaenNetherlandsShlomo MizrahiIsraelLahad MuliIsraelShlomo Mor-YosefIsraelDenise NaonIsraelNurit NirelIsraelGur OferIsraelAri PaltielIsraelMical PaulIsraelChristopher PearceAustraliaMark PearsonFranceRosalind PlowmanUnited KingdomPhillippa PooleNew ZealandAvi PorathIsraelVardit RavitskyCanadaShmuel ReisIsraelShimon ReisnerIsraelStephen ReschUnited States of AmericaLee ResnickUnited States of AmericaDavid RierIsraelLaura RosenIsraelJoseph RosenblumIsraelLisa RubinIsraelRichard SaltmanUnited States of AmericaAmi SchattnerIsraelHillel SchmidIsraelStephen SchoenbaumUnited States of AmericaJonas Schrey\u00f6ggGermanyRobert SchwartzCanadaWalter SermeusBelgiumJudith ShamianCanadaAmir ShanonIsraelShmuel ShapiraIsraelOren ShavitIsraelTamy ShohatIsraelPesach ShvartzmanIsraelGil SiegalIsraelElisheva SimchenIsraelPierre SingerIsraelSamantha SmithIrelandAlden SolovyIsraelKatherine SwartzUnited States of AmericaYossi TamirIsraelElizabeth TemkinIsraelLawrence TsenUnited States of AmericaTheodore TulchinskyIsraelWynand van de VenNetherlandsDaniel VardyIsraelKim Walsh-ChildersUnited States of AmericaOdette WegwarthGermanyMichael WeingartenIsraelRam WeissIsraelYael YishaiIsraelItzhak ZaidiseIsrael"}
+{"text": "Molecular Cancer last year. All are generous individuals who donated their time to assessing and improving our authors\u2019 submissions. Your combined efforts have been invaluable to the editorial staff in maintaining the continued success of the journal in the Open Access forum.As 2013 commences I would like to take a moment to reflect and recognize the peer reviewers that made the previous year possible. Listed below are those people who reviewed for Molecular Cancer would like to thank all the reviewers who contributed to the journal in Volume 11 (2012) by participating in the review process - taking time out of your busy schedules and even to volunteer - without your critical insights, hard work and support for the journal we wouldn\u2019t be able to do what we do.The editors of  Amir AbdollahiGermanyThomas E. AdrianUnited Arab EmiratesRicardo AguiarUnited States of AmericaSuresh AlahariUnited States of AmericaHeike AllgayerGermanySuresh AmbudkarUnited States of AmericaNancy AminAustraliaPeter AplanUnited States of AmericaWilliam ArthurUnited States of AmericaHassan AshktorabUnited States of AmericaWenlong BaiUnited States of AmericaNicholas BarkerSingaporeBetsy BarnesUnited States of AmericaJohn BasileUnited States of AmericaAlison BauerUnited States of AmericaBoon-Huat BaySingaporeFrancesco BertoliniItalyAndrea BertottiItalyKapil BhallaUnited States of AmericaFeng BiChinaAndrew BiankinAustraliaEric BlairUnited KingdomMassimo BoglioloSpainXandra BreakefieldUnited States of AmericaMassimo BrogginiItalyJacqueline BrombergUnited States of AmericaRobert BrownUnited KingdomMatthias BuckUnited States of AmericaMarie-Annick BuendiaFranceAntony BurgessAustraliaKerry BurnsteinUnited States of AmericaMar\u00eda Calzada Garc\u00edaSpainJennifer CarewUnited States of AmericaStacy Carl-McGrathGermanyAmancio CarneroSpainCatherine CarpenterUnited States of AmericaJason CarrollUnited KingdomLuis Carvajal CarmonaUnited KingdomMarc ChamberlainUnited States of AmericaPaul ChapmanUnited States of AmericaVasyl ChekhunUkraineSrikumar ChellappanUnited States of AmericaWei-Jung ChenTaiwanChangyan ChenUnited States of AmericaRobert ChenUnited States of AmericaBenjamin ChenUnited States of AmericaYuhchyau ChenUnited States of AmericaNikki ChengUnited States of AmericaLiang ChengUnited States of AmericaChun ChengChinaAnnie N.Y. CheungChinaFrancesca D. CiccarelliItalyClemente CilloItalyNicholas ClemonsAustraliaPaolo ComoglioItalyGerolama CondorelliItalySimona CorsoItalyMax CostaUnited States of AmericaDoug CressUnited States of AmericaRichard CummingsUnited States of AmericaMichal DabrowskiPolandYan DaiUnited States of AmericaRoger DalyAustraliaP\u00e1draig D'ArcySwedenPiyali DasguptaUnited States of AmericaRuggero De MariaItalyVeerle De VriendtBelgiumNatasha DeaneUnited States of AmericaThomas DecaensFranceDeepika DhawanUnited States of AmericaMaria Flavia Di RenzoItalyFrancesco Di VirgilioItalySong-Ze DingChinaYu DingUnited States of AmericaBradley DobleCanadaShengli DongUnited States of AmericaMark DraysonUnited KingdomStefan DuensingGermanyVincent DuronioCanadaWolfgang EberhardtGermanySuzanne EcclesUnited KingdomMona Ahmed El-BahrawyUnited KingdomDouglas FallerUnited States of AmericaAmir FathiUnited States of AmericaFrancesco FeoItalyCristiano FerliniUnited States of AmericaJames FinkeUnited States of AmericaWarren FiskusUnited States of AmericaMatilde Y. FolloItalyPhilippe FortFranceElizabeth FranzmannUnited States of AmericaSimon FrickerUnited States of AmericaRobin Fuchs-YoungUnited States of AmericaSimone FuldaGermanyImed GallouziCanadaPaola GasperiniSpainDirk GeertsNetherlandsRobert GemmillUnited States of AmericaNik GeorgopoulosUnited KingdomDavid GewirtzUnited States of AmericaJohn GlodUnited States of AmericaLee GoodglickUnited States of AmericaJeffrey GreenUnited States of AmericaMark GreeneUnited States of AmericaAlex GregorieffCanadaElizabeth GriffithsUnited States of AmericaDonald GullbergNorwayMaolin GuoUnited States of AmericaSanjay GuptaUnited States of AmericaBernard HaendlerGermanyGunnel HalldenUnited KingdomHaiyong HanUnited States of AmericaZhaozhong HanUnited States of AmericaKatherine HannanAustriaYasuaki HarabuchiJapanT. Kendall HardenUnited States of AmericaMalini HarigopalUnited States of AmericaElizabeth HarkerUnited States of AmericaPing-an HeChinaCarola HedbergSwedenDanielle HeidemanNetherlandsJozien HellemanNetherlandsR. Scott HellerDenmarkAn HendrixBelgiumAndreas HerbstGermanyMeenhard HerlynUnited States of AmericaSaw-See HongFranceMiles HouslayUnited KingdomJi Fan HuUnited States of AmericaQihong HuangUnited States of AmericaAmandine HurbinFranceMohamad HusseinUnited States of AmericaYu ImamuraUnited States of AmericaM. Anwar IqbalUnited States of AmericaClaudio IsellaItalySumiya IshigamiJapanToshiyuki IshiwataJapanTae Jung JangKorea, SouthQing JingChinaFrank JonesUnited States of AmericaV. Craig JordanUnited States of AmericaByoung Heon KangKorea, SouthStefan KasperGermanyMasaru KatohJapanSukhwinder KaurUnited States of AmericaYona KeisariIsraelKhandan KeyomarsiUnited States of AmericaRobert KindersUnited States of AmericaRaj KishoreUnited States of AmericaLidija KlampferUnited States of AmericaSteven KnapperUnited KingdomHasan KorkayaUnited States of AmericaNina KorzeniewskiGermanyOliver Kr\u00e4merGermanyGeoffrey KrystalUnited States of AmericaSurinder KumarUnited States of AmericaGopal KunduIndiaRoland KwokUnited States of AmericaLiang-Chuan LaiTaiwanFrancois LamoureuxFranceTed LampidisUnited States of AmericaWallace LangdonAustraliaAlex LangeUnited States of AmericaSilke LassmannGermanyPatrizia LaviaItalyBrian LawUnited States of AmericaCharles LawrieUnited KingdomKeith LeppardUnited KingdomYuanyuan LiUnited States of AmericaYang LiUnited States of AmericaJi-Liang LiUnited KingdomJane LianUnited States of AmericaMassimo LibraItalyJonathan LichtUnited States of AmericaBiaoyang LinUnited States of AmericaJ.Y. LinChinaNoralane LindorUnited States of AmericaPeter LinsleyUnited States of AmericaGaolin LiuChinaMingyao LiuUnited States of AmericaXiao-Li LiuChinaLawrence LoebUnited States of AmericaJoseph LoftusUnited States of AmericaBal LokeshwarUnited States of AmericaShan LuUnited States of AmericaStephanie MaHong KongDavid MacEwanUnited KingdomDaruka MahadevanUnited States of AmericaNupam MahajanUnited States of AmericaSami MalekUnited States of AmericaMarcos MalumbresSpainTheo MantamadiotisAustraliaJohn MariadasonAustraliaAndrea MastroUnited States of AmericaGrant McArthurAustraliaPeter McHughUnited KingdomIain McNeishUnited KingdomEnzo MedicoItalyRalph MeyerUnited States of AmericaCarine MichielsBelgiumThomas MikeskaAustraliaIan MillsUnited KingdomAnirban MitraUnited States of AmericaYin-Yuan MoUnited States of AmericaAnne MonksUnited States of AmericaGareth MorganUnited KingdomJustin MottUnited States of AmericaMarkus MuenzGermanyPamela MunsterUnited States of AmericaMichihiro MutohJapanBurt NaborsUnited States of AmericaFumihiko NakamuraUnited States of AmericaTakuro NakamuraJapanNora NavoneUnited States of AmericaMatthias NeesFinlandShin-ichi NishinaJapanKazuto NishioJapanPaola NisticoItalyRosa NogueraSpainAnja NoheUnited States of AmericaFumio NomuraJapanDouglas NoonanItalyHirohide OhnishiJapanKen OlaussenFrancePatricia OpreskoUnited States of AmericaJon OyerUnited States of AmericaSven P\u00e5hlmanSwedenMoorthy Palanimuthu PonnusamyUnited States of AmericaChinmay PandaIndiaPhilippe PaseroFranceHelen PearsonAustraliaGuang PengUnited States of AmericaShuping PengChinaJose PereaSpainChristos PerisanidisAustriaJeffrey PetersUnited States of AmericaSteffen PetersenPortugalYuri PetersonUnited States of AmericaToby PhesseAustraliaMaria Catherine PietanzaUnited States of AmericaAlbrecht PiiperGermanySmitha PillaiUnited States of AmericaMicheline Piquette-MillerCanadaTerrence PivaAustraliaOsvaldo PodhajcerArgentinaLun-Xiu QinChinaSatyanarayana RachaganiUnited States of AmericaRobert RamsayAustraliaBasabi RanaUnited States of AmericaAnnapoorni RangarajanIndiaAshutosh RaoUnited States of AmericaPeter RevillAustraliaAnna RiegelUnited States of AmericaGail RisbridgerAustraliaSabrina RonenUnited States of AmericaKaren RotherGermanyErik SahaiUnited KingdomRyuichi SakaiJapanDavid SalomonUnited States of AmericaJeffery SampleUnited States of AmericaDavid SantamariaSpainSabine SantucciFranceVittorio SartorelliUnited States of AmericaJeffrey SchellingUnited States of AmericaJens SchittenhelmGermanyJohannes SchmidAustriaThies SchroederUnited States of AmericaHildegard M. SchullerUnited States of AmericaAnna Ivana ScovassiItalyPeter SearleUnited KingdomGregg SemenzaUnited States of AmericaDaniel SepkovicUnited States of AmericaAnnalucia SerafinoItalyGuido SeriniItalyMukund SeshadriUnited States of AmericaYongfeng ShangChinaManisha SharmaAustraliaMalathy ShekharUnited States of AmericaTakashi ShinguUnited States of AmericaYow-Ling ShiueTaiwanNoam ShomronIsraelAlison SinclairUnited KingdomSandeep SinghIndiaPankaj SinghUnited States of AmericaKeiran SmalleyUnited States of AmericaTim SmithUnited KingdomPeter SnijdersNetherlandsClaudio SorioItalyE. Richard StanleyUnited States of AmericaGiorgio StassiItalyGeorgios StathopoulosGreeceHidekazu SuzukiJapanAttila SzantoHungaryAdam SzpechcinskiPolandJames TalmadgeUnited States of AmericaTuomas TammelaUnited States of AmericaTakuji TanakaJapanHiroaki TanakaJapanBor Luen TangSingaporeMaria Angeles Tapia-LalienaGermanySophie Tartare-DeckertFranceKathryn TaylorUnited KingdomChristina ThirlwellUnited KingdomGeraldine ThomasUnited KingdomYanis TolstovGermanyWei-Min TongChinaIvo TouwNetherlandsTatsuya TsurumiJapanAxel UllrichGermanyNeli UlrichGermanyT UpileUnited KingdomAndre van WijnenUnited States of AmericaGabor VarbiroUnited KingdomLyuba VarticovskiUnited States of AmericaLoredana VecchioneBelgiumJulien VignardFrancePeter K VogtUnited States of AmericaHarald von MelchnerGermanyMei WangChinaWeidong WangUnited States of AmericaXiao Qi WangChinaTimothy WangUnited States of AmericaYubao WangUnited States of AmericaKishore WaryUnited States of AmericaGeorg WeberUnited States of AmericaLouis WeinerUnited States of AmericaBernard WeissmanUnited States of AmericaUlrich Friedrich WellnerGermanyAlana WelmUnited States of AmericaMeir WetzlerUnited States of AmericaThomas WexGermanyEdward WhangUnited States of AmericaAdrian WhitehouseUnited KingdomTheresa WhitesideUnited States of AmericaFrank WinklerGermanyYuliang WuCanadaWei WuChinaShunbin XiongUnited States of AmericaLiang XuUnited States of AmericaSanjay YadavIndiaMunekazu YamakuchiUnited States of AmericaJilong YangChinaLiang YouUnited States of AmericaKurt S. ZaenkerGermanyFenghuang ZhanUnited States of AmericaTao ZhangChinaYu ZhangUnited States of AmericaXu Dong ZhangAustraliaRalf ZwackaIrelandWilbert ZwartNetherlands"}
+{"text": "The editors of BMC Neuroscience would like to thank all our reviewers who have contributed to the journal in Volume 13 (2013). Stefanie AbelGermanyRoger AdanNetherlandsFabienne AgasseUnited States of AmericaEspana Agn\u00e8sFranceAlexander AgoulnikUnited States of AmericaTariq AhmedBelgiumZaghloul AhmedUnited States of AmericaZubair AhmedUnited KingdomMichael AkinsUnited States of AmericaHaruhiko AkiyamaJapanNoor AlamUnited States of AmericaRoger AlbinUnited States of AmericaAlessio AlfieriUnited KingdomMark AlkemaUnited States of AmericaShelley AllenUnited KingdomManuel Alvarez DoladoSpainJuli\u00e0 L AmengualSpainMiroslava AnderovaCzech RepublicBalasubramaniam AnnamalaiUnited States of AmericaAndrea AntalGermanyLawrence AppelbaumUnited States of AmericaJuan Carlos ArevaloSpainUbaldo ArmatoItalyWilliam ArmsteadUnited States of AmericaRebecca AshareUnited States of AmericaMariana AstizSpainDenize AtanUnited KingdomColeen AtkinsUnited States of AmericaN. Ahmad AzizNetherlandsSergio BagnatoItalyClaudia BagniBelgiumJoerg BahlmannGermanyTravis BakerCanadaNigel BamfordUnited States of AmericaAndrea BanfiSwitzerlandJianxin BaoUnited States of AmericaClive BateUnited KingdomGiorgio Stefano BattagliaItalyTobias B\u00e4umerGermanySteven L BealerUnited States of AmericaMarie Hoeger BementUnited States of AmericaAlexandra BendixenGermanyPeter BergoldUnited States of AmericaDavid BerronGermanyYasumasa BesshoJapanMatthew BettsGermanyFrederike BeyerGermanyFerdinand BinkofskiGermanyDavid BironUnited States of AmericaBrenda BloodgoodUnited States of AmericaMatteo BolognaItalyUbaldo BonuccelliItalyMei Ying BoonAustraliaStephanie BoothCanadaCesar BorlonganUnited States of AmericaMatthew BoykoIsraelAngela BrennanUnited States of AmericaGregory BrewerUnited States of AmericaHolly BridgeUnited KingdomFilippo BrighinaItalyGuy BrockUnited States of AmericaEmmanuel BrouilletFranceRachel BrownCanadaStefan BrudzynskiCanadaNorbert BruggemannDenmarkSusanne BrummelteCanadaAneta BrzezickaPolandLuigi BubaccoItalyEva C BunkGermanyNico BunzeckGermanyJosh BurkUnited States of AmericaLaura CalzaItalyGabriela CantareroUnited States of AmericaFilippo CaraciItalyCaty CasasSpainNathan CashdollarItalyAndrea Eugenio CavannaUnited KingdomMaximilien ChaumonFranceL. Leon ChenUnited States of AmericaLu ChenUnited States of AmericaMichael ChenUnited States of AmericaSidi ChenUnited States of AmericaIrene ChengTaiwanYu-Chin ChiuUnited States of AmericaEric ChoHong KongVivian CiaramitaroUnited States of AmericaNorberto CoimbraBrazilBoaz CookUnited States of AmericaLaura CornsUnited KingdomValerie CoronasFranceDaniel N. CoxUnited States of AmericaBernard CrespiCanadaAdolfo CuadraUnited States of AmericaCarsten CulmseeGermanyGennady CymbalyukUnited States of AmericaAshraf DahabaAustriaChristina DallaGreeceMark DallasUnited KingdomVladimer DarsaliaSwedenVenkata Ramesh DasariUnited States of AmericaFred DavisUnited States of AmericaAlain de Cheveign\u00e9FranceElvira De LeonibusItalyMaarten De VosGermanyNicole D\u00e9glonSwitzerlandAlberto Del ArcoSpainMaria A. DeliHungaryIgor DelvendahlGermanyThomas DeMarseUnited States of AmericaCatherine DermonGreeceKrishnan DhandapaniUnited States of AmericaRudi D'HoogeBelgiumJames DillmanUnited States of AmericaMaria Jos\u00e9 Di\u00f3genesPortugalUlrich DirnaglGermanyNuria Donamayor AlonsoGermanyVonetta DotsonUnited States of AmericaRobert DowmanUnited States of AmericaCarlos DuartePortugalCelia Duarte CruzPortugalMichael DulasUnited States of AmericaMatthias D\u00fcmpelmannGermanyJohn DuncanUnited KingdomLuc DupuisFrancePatrick DutarFranceAlfred EffenbergGermanyOlga EfimovaRussian FederationHannelore EhrenreichGermanyIngrid EhrlichGermanyPiet EikelenboomNetherlandsAna ElgoyhenArgentinaDan-Mikael EllingsenSwedenEskil Elm\u00e9rSwedenTakeshi EnomotoJapanPeter EnticottAustraliaMichael FalkensteinGermanyZhou FeiChinaDirk FeldmeyerGermanyPedro Fern\u00e1ndez-LlebrezSpainMerari FerrariBrazilDonna FerrieroUnited States of AmericaChase FigleyUnited States of AmericaBonnie FiresteinUnited States of AmericaDan FotiUnited States of AmericaLaura FragoSpainGraham FraserCanadaLluis FuentemillaUnited KingdomInna Gaisler-SalomonIsraelMaria Joao GamaPortugalSubramaniam GaneshIndiaJustine GattAustraliaDavid GazeUnited KingdomEldon GeisertUnited States of AmericaAna GenaroArgentinaAlain GhysenFranceClaire GibsonUnited KingdomCarsten GiessingGermanyStephen GlattUnited States of AmericaSebastian GluthGermanyIlan GobiusAustraliaMartin GoettlichGermanyCarlos G\u00f3mezSpainGuillermo Gonzalez-BurgosUnited States of AmericaPaul GordonUnited States of AmericaDaniel GrafGreeceJorg GrandlUnited States of AmericaWilliam GreenUnited States of AmericaWilliam GriffithUnited States of AmericaLaurent GrocFranceSergiu GroppaGermanyAgn\u00e8s GruartSpainMarcus GrueschowSwitzerlandPaolo GubelliniFranceNicolas GueroutFranceJun GuoChinaKurt HaasCanadaHashem Haghdoost-YazdiIranMatthew HaleAustraliaEdward HallUnited States of AmericaJavad HamiIranKurt HammerschmidtGermanyBill HanssonGermanyMitsuhiro HashimotoJapanSadayuki HashiokaCanadaSilke HaverkampGermanyXiaolong HeVenezuelaYing HeUnited States of AmericaStephan HeermannGermanyMarcus HeldmannGermanyCraig HenriquezUnited States of AmericaDenis HerveFranceJohannes HewigGermanyJohanne HigginsCanadaRachel HillAustraliaKate HimmelmannSwedenArlene HiranoUnited States of AmericaHelena HogbergUnited States of AmericaWugang HouChinaSteven HsiaoUnited States of AmericaBo Hua HuUnited States of AmericaXun HuangChinaYing-Zu HuangTaiwanSandrine HumezFranceFatima HusainUnited States of AmericaRene HusterGermanyAlan HutsonUnited States of AmericaJeffrey IliffUnited States of AmericaNibaldo InestrosaChileMasako IsokawaUnited States of AmericaKoichi IwataJapanCorentin JacquesBelgiumLyn JakemanUnited States of AmericaNatalia JaworskaCanadaGlen JefferyUnited KingdomNick JefferyUnited States of AmericaJaeseung JeongKorea, SouthSuresh JesuthasanSingaporeZhengping JiaCanadaHaitao JiangChinaDianna JohnsonUnited States of AmericaErin Johnson VenkateshUnited States of AmericaJamie JohnstonCanadaWon-Kyu JuUnited States of AmericaNikolai JungGermanyAbigail KalmbachUnited States of AmericaMasahiro KamedaJapanRafal KaminskiBelgiumWessel KarlGermanyDon KatzUnited States of AmericaCharanjit KaurSingaporeHiroshi KawasakiJapanWolfram KawohlSwitzerlandAlex KeeneUnited States of AmericaDavid KellyUnited KingdomMushfiquddin KhanUnited States of AmericaJune Sic KimKorea, SouthYongsung KimUnited States of AmericaAdam KingUnited States of AmericaJochen KluckenGermanyMaria KnikouUnited States of AmericaChristina KnuepfferAustraliaNoriko KoganezawaJapanJari KoistinahoFinlandUlla KoppUnited States of AmericaTomasz KordulaUnited States of AmericaPeter KoulenUnited States of AmericaDimitrios KourtisBelgiumNeil KowallUnited States of AmericaUlrike Kr\u00e4merGermanyLeszek KubinUnited States of AmericaKin-ya KuboJapanStefanie KuertenGermanyIrina KufarevaUnited States of AmericaRon KupersDenmarkKumi KurodaJapanJohn KwokAustraliaCharalambos KyriacouUnited KingdomPeter LacknerAustriaPauline LafenetreFranceBing LangUnited KingdomMark LeDouxUnited States of AmericaChia-lin LeeTaiwanHwee Ling LeeGermanyMichael LeeUnited KingdomSeung-Hwan LeeKorea, SouthJose LemosUnited States of AmericaDamiana LeoItalyChristopher LeonardoUnited States of AmericaNoelle L'EtoileUnited States of AmericaL Stan LeungCanadaJan LewerenzGermanyAndrew LeynesUnited States of AmericaBin LiUnited States of AmericaQingli LiChinaWeiquan LiUnited States of AmericaXin LiUnited States of AmericaYonggang LiUnited States of AmericaShih-Chieh LinUnited States of AmericaDan LindholmFinlandEng-Ang LingSingaporeRalf LinkerGermanyHui-li LiuChinaDoug LobnerUnited States of AmericaMary Kay LoboUnited States of AmericaDavid LodgeUnited KingdomMartin LotzeGermanyAndreas L\u00f6wGermanyDiego Lozano-SoldevillaNetherlandsMei LuUnited States of AmericaThomas LukasUnited States of AmericaWenyu LuoUnited States of AmericaJinglei LvChinaHeidi MullerDenmarkDaqing MaUnited KingdomWeiya MaCanadaWendy MacklinUnited States of AmericaKathy MagnussonUnited States of AmericaMalek MakkiSwitzerlandFrancesca MangialascheSwedenRoger MarekAustraliaValeria MarigoItalyStephen MartinUnited KingdomSergio MartinoiaIsraelValery MatarazzoFranceChantal MathisFranceGregory MatuszekUnited States of AmericaPhilip McGoldrickUnited KingdomChristopher McNorganCanadaMagdalena Mendez-LopezSpainAhmet MenteseTurkeyNicola MercuriItalyPhilipp MergenthalerGermanyCharles MeshulUnited States of AmericaRobert MillerUnited States of AmericaMariarosaria MilosoItalyBerge MinassianCanadaHiroyuki MinoJapanJyoti MishraUnited States of AmericaTsuyoshi MiyakawaJapanToshiyuki MizuiJapanHiren ModiUnited States of AmericaBahram MohammadiGermanyRaffaella MolteniItalyPaola MoralesChileStephan MorattiSpainNadia MoresItalyYasuo MoriJapanAndrea MotheCanadaKhyobeni MozhuiUnited States of AmericaYukitoshi NagaharaJapanShinsuke NakagawaJapanTakayuki NakagawaJapanEsperanza Navarro PardoSpainPhoebe NeoNew ZealandIrene NeunerGermanyZhen NiCanadaNatalia NinkinaUnited KingdomMichael NitscheGermanyMatthias NitschkeGermanyMargaret NiznikiewiczUnited States of AmericaMark ObermannGermanyJohn O'ConnorIrelandSharon ONeillUnited States of AmericaWei-Yi OngSingaporeJuan OrellanaChileBrandi OrmerodUnited States of AmericaRoman OsinskyGermanyYasuomi OuchiJapanHiroshi OueJapanSatu PakarinenFinlandDinesh PalUnited States of AmericaMichele PapaItalyVinay ParikhUnited States of AmericaThomas ParkUnited States of AmericaJuana Maria PasquiniArgentinaJes\u00fas PastorSpainSamirkumar PatelUnited States of AmericaWilliam PearceUnited States of AmericaKeith PennypackerUnited States of AmericaSantiago Perez-LloretFranceMuriel PerronFranceArmando PerrottaItalyRasmus PetersenUnited KingdomLinda PhillipsUnited States of AmericaAndrzej PilcPolandAlberto PisoniItalyKonstanze PlaschkeGermanyMarkus PlonerGermanyUlrich PomperGermanyDouglas PortmanUnited States of AmericaGro PovlsenDenmarkAshley PringleUnited KingdomAndreas ProkopUnited KingdomShuhong QiaoUnited States of AmericaAngelo QuartaroneItalyEugenia RadulescuUnited KingdomChander RamanUnited States of AmericaVickram RamkumarUnited States of AmericaTomi Rantam\u00e4kiFinlandYehoash RaphaelUnited States of AmericaFrank RattayAustriaJohn RedellUnited States of AmericaDamian RefojoGermanyOwen RennertUnited States of AmericaSylvia RichterAustriaLarry RobertsCanadaGeorge robertsonCanadaBorja Rodr\u00edguezSpainAntoni Rodriguez-FornellsSpainBrigitte RoederGermanyArdi RoelofsNetherlandsPatricia RojasMexicoAnne-Sophie RollandUnited States of AmericaMohammad RonaghiUnited States of AmericaMerri RosenUnited States of AmericaSusanna RosiUnited States of AmericaBruno RossionBelgiumPanos RoussosUnited States of AmericaMalgorzata RozanowskaUnited KingdomJascha RuesselerGermanyPhilipp RuhnauItalyRuth RuscheweyhGermanyJane RylettCanadaMariusz SacharczukPolandHarutoshi SakakimaJapanShuzo SakataUnited KingdomKatrin SakreidaGermanyTakeshi SakuraiJapanMaria Victoria S\u00e1nchez-G\u00f3mezSpainUrsula SandauUnited States of AmericaDavid SandersonUnited KingdomTerence SangerUnited States of AmericaPascual SanzSpainLieven SchenkGermanyRoland SchoenherrGermanyMenno SchoonheimNetherlandsDerek SchreihoferUnited States of AmericaMarkus SchubertGermanyDavid SchulzUnited States of AmericaJeremy SeamansCanadaThomas SheaUnited States of AmericaHaroon SheikhCanadaKoji ShibasakiJapanFeng-Shiun ShieTaiwanMarshall ShulerUnited States of AmericaSandy ShultzAustraliaDonald SimoneUnited States of AmericaShiva SinghCanadaIndrani Sinha-HikimUnited States of AmericaDario SiniscalcoItalyJohn SlevinUnited States of AmericaDeanna SmithUnited States of AmericaJanette SmithAustraliaRobert SmithUnited States of AmericaJean-Jacques SoghomonianUnited States of AmericaFarida SohrabjiUnited States of AmericaMaria Angela SortinoItalyMarcia SosthenesBrazilJo\u00e3o SousaPortugalUlla SovioUnited KingdomSarah SpiegelUnited States of AmericaLaure SpieserFranceKartik SreenivasanUnited States of AmericaJames St JohnAustraliaWolfgang SteinGermanyJena SteinleUnited States of AmericaChristian StoppelGermanyJudith StrongUnited States of AmericaJoerg StrotmannGermanyAntonio SuppaItalyMatthew SutherlandUnited States of AmericaMasatoshi SuzukiUnited States of AmericaClive SvendsenUnited States of AmericaAnand SwaroopUnited States of AmericaGregor R. SzycikGermanyAmeer TahaUnited States of AmericaSaeid TaheriUnited States of AmericaHideaki TanakaJapanVictor TapiasUnited States of AmericaSomporn TechangamsuwanThailandAlana M ThackrayUnited KingdomThomas TheilUnited KingdomElizabeth ThomasUnited States of AmericaVeronika ThornsGermanyMichael TobiaGermanyTakuro TojimaJapanLars TongesGermanyMaggie ToplakCanadaPeter TrillenbergGermanyRegina TrollmannGermanyMatt TrudeauUnited States of AmericaNelson Trujillo-BarretoCubaYiu-Kei TsangHong KongKwong-Chung TungTaiwanToos van BeijsterveldtNetherlandsFrank van BelNetherlandsLise van der HaegenBelgiumBart van der WorpNetherlandsMichiel van ElkSwitzerlandArend van GemmertUnited States of AmericaGeerten P. van Nieuw AmerongenNetherlandsCindy van VelthovenNetherlandsAkshya VasudevCanadaAlessandro VercelliItalyKata Orsolya Veres-Ny\u00e9kiHungaryMichael VilligerSwitzerlandScott WaddellUnited KingdomChengzhong WangUnited States of AmericaLing WeiUnited States of AmericaNorbert WeidnerGermanyFletcher WhiteUnited States of AmericaHolger WieseGermanyRoland WiestSwitzerlandKim WilkinsonUnited States of AmericaDaniel WiswedeGermanyGeorge WittenbergUnited States of AmericaMartin WoonUnited States of AmericaLisa WrightCanadaHan-Ping WuTaiwanJian-young WuUnited States of AmericaKit WuUnited KingdomChristopher WyattUnited States of AmericaYang XIangUnited States of AmericaYe XiongUnited States of AmericaBainan XuChinaFuqiang XuChinaShawn XuUnited States of AmericaIpek YalcinFranceKazuhiko YamaguchiJapanNobuhiko YamamotoJapanTakamitsu YamamotoJapanChae Ha YangKorea, SouthHao YangChinaLi YangUnited States of AmericaShaohua YangUnited States of AmericaAnatoliy YashinUnited States of AmericaHiroshi YatsushigeJapanPing YeUnited States of AmericaZheng YeUnited KingdomZheng YeGermanyShin-Young YimKorea, SouthHao-Jun YouChinaZhanyang YuUnited States of AmericaTing YuanChinaBing ZangUnited States of AmericaRichard ZemanUnited States of AmericaKaren ZentgrafGermanyChenggang ZhangChinaJie ZhangUnited States of AmericaJohn ZhangUnited States of AmericaWei ZhangUnited States of AmericaYumin ZhangUnited States of AmericaYun ZhangUnited States of AmericaChunjie ZhaoChinaYanxiang ZhaoHong KongZhangwu ZhaoChinaCui Qing ZhuChinaDong-Ya ZhuChinaLei ZhuUnited States of AmericaJian ZouChina"}
+{"text": "Immunity & Ageing would like to thank the following for their assistance with peer review of manuscripts for the journal in 2012. Arne AkbarUnited KingdomGiorgio AnnoniItalyRichard AspinallUnited KingdomCarmela BalistreriItalyGiovanni BernardiniItalyYang BianUnited States of AmericaMarcia BlackmanUnited States of AmericaAnnemieke BootsNetherlandsLindsay BrownAustraliaGiuseppe CarrubaItalyGiuseppina Colonna-RomanoItalyFrancesco CurcioItalyMarta Di CarloItalyMariani ErminiaItalyDaniela FrascaUnited States of AmericaTamas FulopCanadaJingang GuiUnited States of AmericaYingbo HeUnited States of AmericaPernille HojmanDenmarkRuth HubbardAustraliaDimitris KletsasGreeceAnis LarbiSingaporeFederico LicastroItalyDomenico LioItalyAngela LombardiItalyAnastasios LymperopoulosUnited States of AmericaPhilippa MarrackUnited States of AmericaIlhem MessaoudiUnited States of AmericaEugenio MocchegianiItalyRoberto MonasteroItalyJanko Nikolich-ZugichUnited States of AmericaCarlos OrihuelaUnited States of AmericaRoberto PaganelliItalyAkhilesh PandeyUnited States of AmericaGiuseppe PassarinoItalyAnanda PrasadUnited States of AmericaMauro ProvincialiItalyAnnibale Alessandro PucaItalyNorman RelkinUnited States of AmericaGaia SpinettiItalyLishi SunUnited States of AmericaKathryn TaylorUnited KingdomYuehua WeiUnited States of AmericaRaymond WelshUnited States of AmericaJeffrey WoodsUnited States of AmericaZhen ZhaoUnited States of AmericaXiaofei ZhouUnited States of America"}
+{"text": "Translational Neurodegeneration would like to thank all our reviewers who have contributed to the journal in Volume 1 (2012).The editors of  Clive BallardUnited KingdomLarry BaumHong KongCarsten BuhmannGermanyXiaochun ChenChinaYaomin ChenUnited States of AmericaJianqing DingChinaXiang GaoUnited States of AmericaSerge GauthierCanadaHoward GendelmanUnited States of AmericaGlenda HallidayAustraliaYingbo HeUnited States of AmericaYue HuangAustraliaJianping JiaChinaYing JinChinaSheng-Han KuoUnited States of AmericaDebomoy LahiriUnited States of AmericaRena LiUnited States of AmericaXiao-Jiang LiUnited States of AmericaXiuliang LiangChinaJun LiuChinaWeiguo LiuChinaBill Lei LuUnited States of AmericaDaqing MaUnited KingdomJianfang MaChinaKen MarekUnited States of AmericaFei MiaoChinaJing PanChinaBruce R. RansomUnited States of AmericaHuifang ShangChinaWei ShenUnited States of AmericaJeremy SternUnited KingdomBomin SunChinaEK TanSingaporeYuyan TanChinaBeisha TangChinaJinzhou TianChinaNing WangChinaKai WangChinaXiaochu WangChinaKang WenyanChinaDirk WoitallaGermanyChengbiao WuUnited States of AmericaWeiming XiaUnited States of AmericaXunde (Daniel) XianUnited States of AmericaXianwen ChenChinaMingming XuChinaZuoshang XuUnited States of AmericaMin YeChinaYong ZhangUnited States of AmericaYu ZhangChinaJialin ZhengUnited States of AmericaJian ZhongUnited States of AmericaChunjiu ZhongChristmas IslandXiongwei ZhuUnited States of America"}
+{"text": "We thank all of our reviewers who have contributed to the journal in volume 5 (2013). High quality and timely reviews are critical to the overall quality of the journal. We are committed to providing a unique and important outlet for scholarship regarding neurodevelopmental disorders and are indebted to the outstanding reviewers who have contributed their time over the last year in helping us to reach this goal. Elizabeth AylwardUnited States of AmericaBen A. BarresUnited States of AmericaCarrie BeardenUnited States of AmericaKarl BechterGermanyDorothy BishopUnited KingdomNash BoutrosUnited States of AmericaWilliam BrownUnited States of AmericaMelissa CarterCanadaGuillermo CecchiUnited States of AmericaTony CharmanUnited KingdomNaseem ChoudhuryUnited States of AmericaAndrea ContestabileItalyJacqueline CrawleyUnited States of AmericaLeopold CurfsNetherlandsArnab DattaSingaporePaola DazzanUnited KingdomGabriel DichterUnited States of AmericaManny DiCicco-BloomUnited States of AmericaAnastasia DimitropoulosUnited States of AmericaMagdalena DziembowskaPolandChristine EckerUnited KingdomJed ElisonUnited States of AmericaSusan Ellis WeismerUnited States of AmericaMichela FagioliniUnited States of AmericaJin FanUnited States of AmericaEmily FarranUnited KingdomFaraz FarzinUnited States of AmericaLaura Flores-SarnatCanadaSusan FolsteinUnited States of AmericaTim FoskerUnited KingdomLouise GallagherIrelandMatthew GoodwinUnited States of AmericaBrian HaasUnited States of AmericaPaul HagermanUnited States of AmericaRandi HagermanUnited States of AmericaBrian HallahanIrelandTarik HaydarUnited States of AmericaDavid HesslUnited States of AmericaTony HollandUnited KingdomJamie HorderUnited KingdomPatricia HowlinUnited KingdomKimberly HuberUnited States of AmericaStephan HuijbregtsNetherlandsShafali JesteUnited States of AmericaPeng JinUnited States of AmericaKlaus KesslerUnited KingdomAlexandra KeyUnited States of AmericaBonita Klein-TasmanUnited States of AmericaAmi KlinUnited States of AmericaKami KoldewynUnited KingdomShanna KralovicUnited States of AmericaMeng-Chuan LaiUnited KingdomJasmin LalondeUnited States of AmericaHayley LeonardUnited KingdomAmir LevineUnited States of AmericaOvsanna LeyferUnited States of AmericaMolly LoshUnited States of AmericaEva LothUnited KingdomKristen LyallUnited States of AmericaElena MaestriniItalyMarsha MailickUnited States of AmericaChristian MarshallCanadaMarilee MartensUnited States of AmericaJames McPartlandUnited States of AmericaSuzie MillerAustraliaAnna Victoria MolofskyUnited States of AmericaJeff MunsonUnited States of AmericaMichael MuriasUnited States of AmericaDavid NelsonUnited States of AmericaGiovanni NeriItalyLinda NobleUnited States of AmericaCourtenay NorburyUnited KingdomRichard NowakowskiUnited States of AmericaLindsay ObermanUnited States of AmericaJoachim OertelGermanyJose Luis Olmos SerranoUnited States of AmericaLucy OsborneCanadaJorge PalopUnited States of AmericaKatherine PerdueUnited States of AmericaDavid PickettsCanadaAndrew PieperUnited States of AmericaKaren PierceUnited States of AmericaDaniela Plesa SkwererUnited States of AmericaMelanie PorterAustraliaGudrun RappoldGermanyBrian RashUnited States of AmericaWilburn ReddickUnited States of AmericaSean RedmondUnited States of AmericaAllan ReissUnited States of AmericaMabel RiceUnited States of AmericaTimothy RobertsUnited States of AmericaJacqui RodgersUnited KingdomMiguel \u00c1ngel Romero-Mungu\u00edaMexicoNoah SassonUnited States of AmericaKimberly Scearce-LevieUnited States of AmericaGaia ScerifUnited KingdomSarah SchoenUnited States of AmericaRobert SchultzUnited States of AmericaFrederick ShicUnited States of AmericaBarbara Shinn-CunninghamUnited States of AmericaJeremy SilvermanUnited States of AmericaNancy SnidmanUnited States of AmericaMarjorie SolomonUnited States of AmericaDaniel StahlUnited KingdomCatherine StamoulisUnited States of AmericaJulia StephenUnited States of AmericaHanna StevensUnited States of AmericaYujiao SunUnited States of AmericaElyse SussmanUnited States of AmericaJames SutcliffeUnited States of AmericaPeter SzatmariCanadaMarc J. TasseUnited States of AmericaMark TaylorUnited KingdomErik UllianUnited States of AmericaTherese van AmelsvoortNetherlandsJean-Michel VerdierFranceWillem M.A. VerhoevenNetherlandsAnnick VogelsBelgiumJennifer WagnerUnited States of AmericaLe WangUnited States of AmericaSara WebbUnited States of AmericaRosanna WeksbergCanadaCorrine WeltUnited States of AmericaJeffrey WoodUnited States of AmericaZhengang YangChinaRyan YuenCanadaLonnie ZwaigenbaumCanada"}
+{"text": "Journal of Animal Science and Biotechnology would like to thank all our reviewers who have contributed to the journal in Volume 1 (2012).The editors of  John AndraeUnited States of AmericaFuller BazerUnited States of AmericaGerd BobeUnited States of AmericaEleftherios BonosGreeceMartin BraunschweigSwitzerlandIsabelle Cassar-MalekFranceMingxing ChuChinaJenifer CruickshankUnited States of AmericaCristina CuelloSpainGoutam DasIndiaShelly DruyanIsraelSandra EdwardsUnited KingdomGisela F ErfUnited States of AmericaPeter EricksonUnited States of AmericaWenhai FengChinaBenjamin FriedrichGermanyDaniel GallaherUnited States of AmericaFrancisco Gambon-DezaSpainDorian GarrickUnited States of AmericaRodney GeisertUnited States of AmericaMohamed GhanemEgyptLaura GiojalasArgentinaKevin GlennUnited States of AmericaJoshua GongCanadaRobert GoodbandUnited States of AmericaPawel GorkaPolandKathleen GoughCanadaKristen GovoniUnited States of AmericaAgnieszka GrzegorzewskaPolandWei GuoUnited States of AmericaPSP GuptaIndiaNagaraja HaleagraharaAustraliaKazuyoshi HashizumeJapanJung Min HeoCanadaGary HillUnited States of AmericaAlberto HorcadaSpainYongqing HouChinaWalter HurleyUnited States of AmericaEveline Ibeagha-AwemuCanadaIkhide ImumorinUnited States of AmericaYunliang JiangChinaGreg JohnsonUnited States of AmericaHiroyuki KaiyaJapanDavid KennyIrelandJae Cheol KimAustraliaChanghua LaiChinaCharlotte LauridsenDenmarkHui LiChinaWen-Wen LinTaiwanDasen LiuChinaHaiying LiuChinaWansheng LiuUnited States of AmericaRichard LondravilleUnited States of AmericaCarolina LucciBrazilHailing LuoChinaJuan MariniUnited States of AmericaGerardo Mariscal LandinMexicoDouglas McFarlandUnited States of AmericaKenneth McKeeverUnited States of AmericaJon MeadusCanadaSharat MehtaIndiaJoris MichielsBelgiumSubhash MinochaUnited States of AmericaRonaldo MoratoBrazilPascale MosoniFranceAnita OberbauerUnited States of AmericaJack OdleUnited States of AmericaJie QiaoChinaVelmurugu RavindranNew ZealandRenata Ribeiro AlvarengaBrazilJohanna RochesterUnited States of AmericaAnshan ShanChinaJiuzhou SongUnited States of AmericaDan SteinUnited States of AmericaMichael SturekUnited States of AmericaDongxiao SunChinaQing-Yuan SunChinaLakshmi SunkaraUnited States of AmericaNosratollah Taherpour DariIranAlfredo TeixeiraPortugalThomas ThymannDenmarkStefan ToegelAustriaSwamy TripuraniUnited States of AmericaTrygve VeumUnited States of AmericaAtte von WrightFinlandW WaltherGermanyChunkao WangUnited States of AmericaLi WangChinaAn-Li WangChinaYizhen WangChinaMalcolm WatfordUnited States of AmericaXin WeiUnited States of AmericaPaul WeimerUnited States of AmericaGuoyao WuUnited States of AmericaJingjing XieChinaShouqi XieChinaGao XueChinaHuaxiang YanChinaCaiqiao ZhangChinaQin ZhangChinaFeng-Qi ZhaoUnited States of AmericaShu-Hong ZhaoChinaHuaijun ZhouUnited States of AmericaXiaoqiu ZhouChinaShien zhuChina"}
+{"text": "Infectious Agents & Cancer would like to thank all our reviewers who have contributed to the journal in Volume 7 (2012).The editor of  Clement AdebamowoUnited States of AmericaFrancisco AguayoChileNosheen AhmedPakistanOluyemisi AkinwandeNigeriaDoglio AlainFranceClorinda AnnunziataItalyLuigi AurisicchioItalyAthanase BillisBrazilPatrizia BonelliItalyChristal BowmanUnited States of AmericaSabine BrandtAustriaMichele CaragliaItalyDaniel CarrUnited States of AmericaChiara CattaneoItalyLeonidas ChelisGreeceJianming ChenUnited States of AmericaPaolo ChieffiItalyManola ComarItalyVolker DanielGermanyLaura De MarcoItalyValli De ReItalySilvia de SanjoseSpainRiccardo DolcettiItalyAntonina DoleiItalyGeraldina DominguezUnited States of AmericaRyan DowlingCanadaCharles DzamalalaMalawiSherine ElsawaUnited States of AmericaAtef FahimEgyptHeba FawzyEgyptWeiwei FengChinaSeyed-Mohammad FereshtehnejadIranSilvia FranceschiFranceRenato FrancoItalyIsrael FrancoUnited States of AmericaNancy Gasper-SmithUnited States of AmericaPaolo Giorgi RossiItalyJames GoedertUnited States of AmericaHenri GruffatFranceMohamed HafezEgyptChang HaixinChinaSylvie HermouetFranceMyfanwy HopkinsUnited States of AmericaColin HopperUnited KingdomJohn IdokoNigeriaRS JayshreeIndiaAnbu Karani-AdikesavanUnited States of AmericaCharles KilewoTanzaniaJames KitinyaTanzaniaVijay KumarIndiaEduardo Lazcano-PonceMexicoFeng LiUnited States of AmericaWenjin LiuUnited States of AmericaVicente Madrid-MarinaMexicoRita ManciniItalyMaureen MartinUnited States of AmericaMuhammad Shareef MasoudPakistanTanja Matijevic GlavanCroatiaAlicia McDonaldUnited States of AmericaHashim MissawiSudanSulma MohammedUnited States of AmericaHector Montoya-FuentesMexicoOlivier MoralesFranceDenis MottetBelgiumGeorge MutterUnited States of AmericaAriela NoyUnited States of AmericaLuigi PanicoItalyPatrizia PasanisiItalyDaniela PasqualiItalyAnnacarmen PetrizzoItalyBeatriz PogoUnited States of AmericaMaurizio ProvenzanoSwitzerlandPeter RambauTanzaniaHerv\u00e9 ReychlerBelgiumParamananda SaikiaIndiaLars SandSwedenSreenivasan SasidharanMalaysiaWellerson ScaranoBrazilMichael SelgradGermanyRenat ShaykhievUnited States of AmericaAbdul Moid ShehzadPakistanMisuzu ShimakageJapanLaura SicheroBrazilFreddy SitasAustraliaHeath SkinnerUnited States of AmericaElaine SmithUnited States of AmericaGamil TawadrousEgyptMojtaba TeimooriIranFrederic ThomasFranceAndrea TinelliItalyMaria Lina TorneselloItalyHelen TrottierCanadaGooitzen van DamNetherlandsAldo VenutiItalyMaria Luisa ViscianoItalyGiovanni VitaleItalyElisabete WeiderpassNorwayJianfei XueUnited States of AmericaYibin YangUnited States of AmericaAnna Linda ZignegoItaly"}
+{"text": "Reproductive Health would like to thank all our reviewers who have contributed to the journal in Volume 9 (2012). Peer review is essential to the reliable communication of science and we appreciate the effort and generosity of our reviewers who give their time to furthering the excellence and integrity of the journal.The editor of  Matilda Aberese AkoGhanaSuneth AgampodiSri LankaFrank AndersonUnited States of AmericaRagnar AndersonUnited States of AmericaSamuel AnyaGambiaBerhanemeskel AtsbehaEthiopiaLuis BahamondesBrazilJames BamideleNigeriaBrahima BassaneUnited KingdomEva BazantUnited States of AmericaStan BernsteinUnited States of AmericaNicole BerryCanadaSibhatu BiadgilignEthiopiaMeghan BohrenSwitzerlandEugenia BrageArgentinaGerard BreartFranceMaurice BucaguSwitzerlandPierre BuekensUnited States of AmericaVenkatraman Chandra-MouliSwitzerlandPragti ChhabraIndiaAnne CockcroftSouth AfricaMercedes ColomarUruguayChristine DehlendorfUnited States of AmericaGonul DincTurkeyZehra GolbasiTurkeyRobert GoldenbergUnited States of AmericaArthur GreilUnited States of AmericaDaniel GrossmanUnited States of AmericaRandah HamadehBahrainFrans HelmerhorstNetherlandsJillian HendersonUnited States of AmericaJustus HofmeyrSouth AfricaJaco HomsyUnited States of AmericaMaggie Huff-RousselleFranceLisa HurtUnited KingdomCaio ImaizumiBrazilKirti IyengarIndiaImtiaz JehanPakistanAdriana KaplanSpainTorvid KiserudNorwayJane KnightUnited KingdomSuneeta KrishnanIndiaNicholas KyeiGhanaCatherine KyobutungiKenyaMalinee LaopaiboonThailandMabel LieUnited KingdomJerker LiljestrandCambodiaHui-Sheng LinTaiwanGunilla LindmarkSwedenEnriquito LuUnited States of AmericaAdriana Gomes LuzBrazilRagaa MansourEgyptThubelihle MatholeSouth AfricaMichael MbizvoSwitzerlandSamuel MillsUnited States of AmericaDaya MoodleySouth AfricaAnn MooreUnited States of AmericaAllisyn MoranBangladeshFulata MoyoSwitzerlandTwaha MutyabaUgandaLiem T. NguyenViet NamAdeline NyamathiUnited States of AmericaLemessa OljiraEthiopiaMaria Jos\u00e9 OsisBrazilYutaka OsugaJapanRodolfo PacagnellaBrazilRenato PassiniBrazilAntonino PerinoItalyMary RedmayneNew ZealandRoger RochatUnited States of AmericaArmando Humberto SeucSwitzerlandJai Bhagwan SharmaIndiaJames SilberzweigUnited States of AmericaBibha SimkhadaNepalLucy Smith PaintainUnited KingdomPaul SpiegelSwitzerlandJohn StanbackUnited States of AmericaMary StewartUnited KingdomJohanne SundbyNorwayGeeta SwamyUnited States of AmericaMaria Regina TorloniBrazilAntoinette TshefuCongo, Democratic RepublicThomas van den AkkerNetherlandsJuan C. VazquezCubaRicardo VernonMexicoElisabeth VieiraBrazilKirsten VogelsongUnited States of AmericaDemewoz WoldegebrealEthiopiaTeshome WoldehannaZimbabwePaul YoungUnited States of AmericaNina ZamberlinArgentinaRoger ZerboBurkina Faso"}
+{"text": "Experimental study of neural information processing requires simultaneous sampling of the activity of multiple cells over the network. One of the promising approaches relies on monitoring local field potentials (LFPs) by multi-electrode arrays that can span large brain regions (see Figure"}
+{"text": "Human Genomics would like to thank all our reviewers who have contributed to the journal in volume 7 (2013).The Editors of  Osborne AlmeidaGermanyChristina AquilanteUnited States of AmericaDonald BackosUnited States of AmericaSanjay BhartiUnited States of AmericaJoseph BorgMaltaElspeth BrufordUnited KingdomElizabeth BrydaUnited States of AmericaJohn CarpenterUnited States of AmericaGiorgio CasariItalySebahattin CirakUnited States of AmericaRobin DowellUnited States of AmericaLynnette Robin FergusonNew ZealandAlonso Fernandez-GuastiMexicoAna Teresa FreitasPortugalBaruch FrenkelUnited States of AmericaDexiang GaoUnited States of AmericaParaskevi GoggolidouUnited KingdomJakob GroveDenmarkPei-Ing HwangTaiwanPeilin JiaUnited States of AmericaKalpana KannanUnited States of AmericaKiyoshi KawakamiJapanSok Kean KhooUnited States of AmericaRick KittlesUnited States of AmericaBernd KlausGermanyMichael KnudsenDenmarkChee Seng KuSingaporePoh-San LaiSingaporeJun LiUnited States of AmericaPeng LiUnited States of AmericaJerry LingrelUnited States of AmericaDonna MaglottUnited States of AmericaJose Luis MillanUnited States of AmericaJonathan MudgeUnited KingdomMaria Nastase MannilaSwedenDaniel NebertUnited States of AmericaGeorge PatrinosGreeceSirkku PeltonenFinlandTzu Lip PhangUnited States of AmericaDavid PollockUnited States of AmericaStan PoundsUnited States of AmericaRichard RadcliffeUnited States of AmericaMichael Lee RobinsonUnited States of AmericaJadranka SerticCroatiaImran ShahUnited States of AmericaMark ShriverUnited States of AmericaAlessio SquassinaItalyShivalingappa SwamynathanUnited States of AmericaRonald TrentAustraliaPanagiotis TsonisUnited States of AmericaEvita van den HerikNetherlandsBruce WeirUnited States of AmericaZhi-Hong WenTaiwanCarsten WiufDenmarkYuliang WuCanadaDmitri ZaykinUnited States of AmericaGuojie ZhangChinaVerena ZuberNorway"}
+{"text": "Cilia. Their voluntary participation has led to the launch of a new journal consistently publishing high quality articles and an intelligent peer review process for all our authors.We would like to thank all our reviewers for their contribution to the success of  Wolfgang BaehrUnited States of AmericaAlexandre BenmerahFranceJoseph BesharseUnited States of AmericaDaniel CarrUnited States of AmericaTamara CasparyUnited States of AmericaSoren ChristensenDenmarkDan DohertyUnited States of AmericaJonathan EggenschwilerUnited States of AmericaGuowei FangUnited States of AmericaJacek GaertigUnited States of AmericaRaymond E GoldsteinUnited KingdomUrsula GoodenoughUnited States of AmericaAnna-Katerina HadjantonakisUnited States of AmericaClaire JacksonUnited KingdomDagan JenkinsUnited KingdomJian JiaoChinaHannie KremerNetherlandsTiansen LiUnited States of AmericaKarel LiemUnited States of AmericaBen MargolisUnited States of AmericaJeffrey MartensUnited States of AmericaJohn W McAvoyAustraliaKimberly McDermottUnited States of AmericaHannah MitchisonUnited KingdomNeil MorganUnited KingdomRoland NitschkeGermanyAlbert OngUnited KingdomLotte PedersenDenmarkRuman RahmanUnited KingdomSandra Rovira AmigoSpainPeter SatirUnited States of AmericaPeter SchramlSwitzerlandAmelia ShoemarkUnited KingdomDeepti TrivediUnited States of AmericaJohn WallingfordUnited States of AmericaAngus WannUnited KingdomBradley YoderUnited States of America"}
+{"text": "The Editor-in-Chief would like to thank all the reviewers who contributed to the journal in 2013. Adrian BritschgiSwitzerlandAi-ling TianChinaAjay BommareddyUnited States of AmericaAlberto FerlinItalyAlessia OngaroItalyAlexander DobrovicAustraliaAlfredo De PaulaBrazilAlok MishraUnited States of AmericaAmanda WardUnited States of AmericaAmanda Dixon-McIverNew ZealandAmmad FarooqiPakistanAn\u00e1lia CarmoPortugalAndrea RasolaItalyAndreas VillungerAustriaAnna LitwiniecPolandAnna FriedlGermanyAnthony GavalasGreeceAnthony GavalasGermanyAntoinette HollestelleNetherlandsAntonella CaniniItalyAnwar HossainUnited States of AmericaAras Emre CandaTurkeyAriana BruzzoneArgentinaAshraf Abdel-NaimSaudi ArabiaAxel HegeleGermanyBaoan ChenChinaBasavaraj KotiIndiaBassel El-RayesUnited States of AmericaBen LoosSouth AfricaBenedetta BussolatiItalyBilge SenerTurkeyBin ShanUnited States of AmericaBo CaoUnited States of AmericaBo Guang FanCanadaBonhong MinKorea, SouthBoris ZhivotovskySwedenBoris NegrutskiiUkraineBoudewijn J BraakhuisNetherlandsBruno RobbsBrazilBruno VincenziItalyBulent OzpolatUnited States of AmericaByong Chul YooKorea, SouthCameron BrackenAustraliaCecilia HegardtSwedenCedric RebeFranceChandramu ChettyUnited States of AmericaChin-Cheng SuTaiwanChrister ThomsenSwedenChristian StockGermanyChristiane MaierGermanyDaigo SumiJapanDaisuke EnnishiCanadaDaniel Ramon CioccaArgentinaDaniela GalloItalyDaniele VergaraItalyDarell BignerUnited States of AmericaDavid BuxtonUnited States of AmericaDavid EmletUnited States of AmericaDegang ShiChinaDelia MezzanzanicaItalyDelong LiuUnited States of AmericaDeodutta RoyUnited States of AmericaDick MosserCanadaDihua ShangguanChinaDominique ModrowskiFranceDongjun PengUnited States of AmericaDouglas DemetrickCanadaDouglas HurstUnited States of AmericaDustin DemingUnited States of AmericaElena TakanoAustraliaElena NadezhdinaRussian FederationElif Damla ArisanTurkeyElizabeth GuoChinaEllen HeitzerAustriaElsa Bronze-da-RochaPortugalEmilio GonzalezSpainErhong MengUnited States of AmericaEsra ErdalTurkeyEumorphia KonstantakouGreeceEwa BalcerczakPolandFabio Luis FortiBrazilFan YiChinaFang YanUnited States of AmericaFarah KhanIndiaFederica SotgiaUnited KingdomFiona YullUnited States of AmericaFrancois MartinFranceFrank GrecoUnited States of AmericaFraz AwanPakistanGabriella D'OraziKazakhstanGabriella PagnanItalyGalatea KallergiGreeceGangadhara SareddyUnited States of AmericaGar-Yang ChauTaiwanGeert BultynckBelgiumGeorge CalinUnited States of AmericaGeorgios NteliopoulosUnited KingdomGian Luigi RussoItalyGiulio MetroItalyGloria CalafUnited States of AmericaGrigori RychkovAustraliaGuixing QiuChinaGulgun OktayTurkeyGuochang HuUnited States of AmericaGuoyou ZhangAustraliaHaiteng DengChinaHans-Joachim MuellerGermanyHark KimKorea, SouthHecheng LiChinaHelfrid HocheggerUnited KingdomHong FanChinaHong ChangCanadaHong HeUnited States of AmericaHong YangChinaHong HeAustraliaHong ZhengUnited States of AmericaHongmei NanUnited States of AmericaHong-Sheng ZhangChinaHongwei ZhangChinaHongwei LiChinaHuifang HaoJapanIdo WolfIsraelIndu KohaarUnited States of AmericaIrfan AsanganiUnited States of AmericaIsabel AndujarSpainIsabelle Dhennin-DuthilleFranceIstvan ZupkoHungaryIstvan VermesNetherlandsJames A McCaulUnited KingdomJamie JarboeUnited States of AmericaJean KoffUnited States of AmericaJekaterina ErenpreisaLatviaJenifer ProsperiUnited States of AmericaJessy DeshaneUnited States of AmericaJia XuUnited States of AmericaJiahua ZhuUnited States of AmericaJiajun ShiUnited States of AmericaJing LinUnited States of AmericaJiri VrbaCzech RepublicJoana CarvalhoPortugalJohn PulikkanGermanyJong Bin KimKorea, SouthJong Kuk ParkKorea, SouthJun YaoChinaJun YasudaJapanJun YangUnited States of AmericaJunaid AbdulghaniUnited States of AmericaJune ZouUnited States of AmericaJunming YueUnited States of AmericaJunming GuoChinaJustine RudnerGermanyKajsa PaulssonSwedenKaleeckal HarikumarUnited States of AmericaKameswaran RavichandranUnited States of AmericaKarine BreckpotBelgiumKarl ChaiUnited States of AmericaKatharine IrvineAustraliaKazuhiro KunimasaJapanKeizo TakenagaJapanKen YoungUnited States of AmericaKen-ichi OgawaraJapanKevin SunNew ZealandKonradin MetzeBrazilKotb AbdelmohsenUnited States of AmericaKwadwo Asamoah KusiGhanaLi XiaorongChinaLi CaoUnited States of AmericaLiguang ChenUnited States of AmericaLing WangChinaLiping LiuChinaLisa MurphyIrelandLizong ShenChinaLjubica VucicevicSerbiaLong-Cheng LiUnited States of AmericaLorenzo SempereUnited States of AmericaLuc DirixBelgiumLucia SfondriniItalyLuis GoyaSpainLyuba VarticovskiUnited States of AmericaMagda hagras SaudiArabiaMakoto MakishimaJapanManxiang LiChinaMarco Cerb\u00f3nMexicoMaria Teresa TeresaItalyMarius RaicaRomaniaMartin LiuUnited States of AmericaMartino IntronaItalyMaryna de KockSouth AfricaMassimo DerenziniItalyMassimo AgliettaItalyMassimo ZolloItalyMayuko FurutaJapanMehdi ShafaCanadaMeixia ZhangChinaMeng QingbingChinaMeng-Ru ShenTaiwanMichael ChanTaiwanMichael GranerUnited States of AmericaMichele CaragliaItalyMike FainzilberIranMing YuanUnited KingdomMinghua WuChinaMitsuho OnimaruJapanMohamed Saleh MahmoudCanadaMohit SachdevaUnited States of AmericaMu ZhangUnited States of AmericaMugdha KhaladkarUnited States of AmericaMunirathinam GnanasekarUnited States of AmericaMuriel PriaultFranceMuthusamy KunnimalaiyaanUnited States of AmericaNahum SonenbergCanadaNatalia CeaglioArgentinaNatalija EigelieneFinlandNatarajan AravindanUnited States of AmericaNatasha KyprianouUnited States of AmericaNathalie JohnsonCanadaNavasona KrishnanUnited States of AmericaNayoung KimKorea, SouthNeelu PuriUnited States of AmericaNicholas PavlidisGreeceNicola AcetoUnited States of AmericaNives Pecina-SlausCroatiaNizar MhaidatJordanOla HermansonSwedenOleh StasykUkraineOliver TreeckGermanyOmar MohafezJapanOsamu MiuraJapanPao-Ling TorngTaiwanPaolo AurelloItalyPaolo MartiniUnited States of AmericaPaolo GandelliniItalyParvin MehdipourIranPatricio AllerSpainPaul AgutterUnited KingdomPaul BollykyUnited States of AmericaPavel SoucekCzech RepublicPedro P. Lopez-CasasSpainPeiman LiuUnited States of AmericaPeiyu PuChinaPenka NikolovaUnited KingdomPeriasamy SelvarajUnited States of AmericaPeter SchramlSwitzerlandPeter OlbertGermanyPhyllis WachsbergerUnited States of AmericaPier Giorgio PetroniniItalyPing ZhuChinaPing-an HeChinaPo-Wu GeanTaiwanQian XuChinaQing-Hua MengChinaQingsong ZhuUnited States of AmericaRajakishore MishraUnited States of AmericaRajendra SharmaCanadaRakesh NaiduMalaysiaRamon AlemanySpainRavindresh ChhabraIndiaRik DerynckUnited States of AmericaRishi ChhipaIndiaRobert MilewskiPolandRohit MalikUnited States of AmericaRoland LausterGermanyRomain DebretFranceRoman EliseevUnited States of AmericaRuben PlentzGermanySabine Hombach-KlonischCanadaSalvatore PizzoUnited States of AmericaSamer HakimGermanySander van den DriescheUnited KingdomSandra KarlssonSwedenSarah PriorUnited KingdomSaskia CillessenNetherlandsSen ZhangChinaShaofang WuUnited States of AmericaSheng-mei ZhuChinaShigeki ItoJapanShounanyi YiAustraliaShuyu RenUnited States of AmericaSidney YuHong KongSmadar AvigadIsraelSong YQChinaSreenivasulu ChintalaUnited States of AmericaStefan PuschGermanyStephan ReshkinItalyStephanie VispeFranceSteve ChambersNew ZealandSteven Van LaereBelgiumSudhakar VeerankiUnited States of AmericaSuoqin TangChinaSuresh TikooCanadaSydney MukaratirwaUnited KingdomTadashi KondoJapanTae il KimKorea, SouthTakatsune ShimizuJapanTakeshi MiyamotoJapanTakuya MoriyaJapanTao RenChinaTao LinUnited States of AmericaTaodi LiuChinaTatiana ZybinaRussian FederationTerry MoodyUnited States of AmericaThomas ScheperGermanyTiago RodriguesBrazilTimothy GershonUnited States of AmericaToni IbrahimItalyTonya WalserUnited States of AmericaTsui-Ling ChangTaiwanTsutomu ShimuraJapanUgo TestaItalyUlrich RennerGermanyUlrike SteinGermanyUmberto GalderisiItalyUrmila SantanamUnited States of AmericaUrs LichtenauerGermanyValentina TodorovaUnited States of AmericaValery GrdzelishviliUnited States of AmericaVishal GuptaIndiaVladimir PushkarevUkraineVladimir GogvadzeSwedenW. Keith MiskiminsUnited States of AmericaWanming ZhaoUnited States of AmericaWei DuUnited States of AmericaWei DingChinaWeili CaiUnited States of AmericaWen ZhuangChinaWen Ying WuChinaWendy Hwang-VersluesTaiwanWenjun WangChinaWenling WangChinaWenxi WuChinaWenyue SunUnited States of AmericaWilliam ChoHong KongWolfram MiekischGermanyWu Dong-ChengChinaXiaobin JiaChinaXiaobing HeUnited States of AmericaXiaobo LiUnited States of AmericaXiaochun XuUnited States of AmericaXiaohua JiangHong KongXiaoping MiaoChinaXiaoqing NiuChinaXianoyong ZhengUnited States of AmericaXin-xia TianChinaXiuwu ZhangUnited States of AmericaYajuan SuChinaYan HuangUnited States of AmericaYanfeng QiUnited States of AmericaYang YaoChinaYang-Chang WuTaiwanYangqiu LiChinaYei-Tsung ChenSingaporeYen-Ni TengTaiwanYi ZhangChinaYiannis DrososUnited States of AmericaYing JinChinaYingpeng LiuUnited States of AmericaYmera PignochinoItalyYoji NagashimaJapanYong YangChinaYongwen ChenChinaYoshiki MurakamiJapanYoshio HonmaJapanYu LiuUnited States of AmericaYu JinUnited States of AmericaYunge ZhaoUnited States of AmericaZahid SiddikUnited States of AmericaZeyi ZhengUnited States of AmericaZhaoxiang BianHong KongZhi WangChinaZhi-guang TuChinaZhi-Hong WenTaiwanZhijun DaiChinaZihua ZengUnited States of AmericaZongbing YouUnited States of America"}
+{"text": "Molecular Neurodegeneration would like to thank all the reviewers who have contributed to the journal in Volume 8 (2013).The editors of  Samer Abdul-HayUnited States of AmericaJeffrey AgarUnited States of AmericaAlejandra AlonsoUnited States of AmericaWim AnnaertBelgiumOttavio ArancioUnited States of AmericaJesus AvilaSpainPascale BelenguerFranceJohannes BergerAustriaGal BitanUnited States of AmericaKaj BlennowSwedenDavid BorcheltUnited States of AmericaRalf BraunGermanyMarisa BriniItalySaartje BurgmansNetherlandsJeffrey BurnsUnited States of AmericaRuaidhri CarmodyUnited KingdomAnna CarranoUnited States of AmericaMinerva CarrasquilloUnited States of AmericaEva CarroSpainSally ChappellUnited KingdomFr\u00e9d\u00e9ric CheclerFranceCarlos CruchagaUnited States of AmericaNadia D'AmbrosiItalyPritam DasUnited States of AmericaPeter DaviesUnited States of AmericaTed DawsonUnited States of AmericaBart de StrooperBelgiumRahul DesikanUnited States of AmericaIlse DewachterBelgiumDorothee DormannGermanyPiet EikelenboomNetherlandsSophie ErhardtSwedenSteven EstusUnited States of AmericaAnne FaganUnited States of AmericaNick FoxUnited KingdomPaul FraserCanadaJohn FryerUnited States of AmericaYoshiaki FurukawaJapanFen-Biao GaoUnited States of AmericaLaura GaspariniItalyTania GendronnUnited States of AmericaTony GoldeUnited States of AmericaSue GriffinUnited States of AmericaMariagrazia GrilliItalyChristian HansenSwedenDavid HarrisUnited States of AmericaTakuya HayashiJapanEmmanuel HermansBelgiumDavid HoltzmanUnited States of AmericaJeroen HoozemansNetherlandsBradley HymanUnited States of AmericaHaruhisa InoueJapanJoanna JankowskyUnited States of AmericaAshu JohriUnited States of AmericaJean-Pierre JulienCanadaTakahisa KanekiyoUnited States of AmericaSatyabrata KarCanadaEric KarranUnited KingdomJungsu KimUnited States of AmericaDeniz KirikSwedenRadosveta KoldamovaUnited States of AmericaDora M. KovacsUnited States of AmericaAnil KumarUnited States of AmericaClotilde Lagier-TourenneUnited States of AmericaGary LandrethUnited States of AmericaMinglin LangUnited States of AmericaWeidong LeUnited States of AmericaTony LefebvreFranceEfrat LevyUnited States of AmericaYueming LiUnited States of AmericaFrancesca-Fang LiaoUnited States of AmericaG\u00e9rard LizardFranceWenjie LuoUnited States of AmericaSanford MarkeyUnited States of AmericaLarry MarshUnited States of AmericaEduardo Martinez-MorilloCanadaEliezer MasliahUnited States of AmericaPamela McLeanUnited States of AmericaChristopher MedwayUnited States of AmericaHeather MelroseUnited States of AmericaMichelle MielkeUnited States of AmericaKevin MorganUnited KingdomSandra MulderNetherlandsTomoyuki NishizakiJapanAgneta NordbergSwedenKaren O\u2019MalleyUnited States of AmericaHarry OrrUnited States of AmericaThomas PannickeGermanyRobia PautlerUnited States of AmericaGiuseppa PennettaUnited KingdomRichard PerrinUnited States of AmericaMarina PizziItalyErik PorteliusSwedenLawrence RajendranSwitzerlandG. William RebeckUnited States of AmericaAna Cristina RegoPortugalMarina Romero-RamosDenmarkPaul RosenbergUnited States of AmericaTerrone RosenberryUnited States of AmericaBart RuttenNetherlandsDavid SchafferUnited States of AmericaMichael SendtnerGermanyJie ShenUnited States of AmericaMitsuru ShinoharaUnited States of AmericaOdy SibonNetherlandsSangram SisodiaUnited States of AmericaSolomon SnyderUnited States of AmericaIoannis SotiropoulosPortugalNuno SousaPortugalWolfdieter SpringerUnited States of AmericaHarry SteinbuschNetherlandsGrace StutzmannUnited States of AmericaKeizo SugayaJapanLeon TaiUnited States of AmericaMalu TanseyUnited States of AmericaGopal ThinakaranUnited States of AmericaTaisuke TomitaJapanIan TrounceAustraliaBrigita UrbancUnited States of AmericaChristine Vande VeldeCanadaRobert VassarUnited States of AmericaMarcel VerbeekNetherlandsAaron VoigtGermanyXin WangUnited States of AmericaEdwin WeeberUnited States of AmericaMalin Wennstr\u00f6mSwedenPatrick WeydtGermanyAnthony WhiteAustraliaKristin WildsmithUnited States of AmericaOliver WirthsGermanyBenjamin WolozinUnited States of AmericaZuoshang XuUnited States of AmericaX.William YangUnited States of AmericaPatrick Yu-Wai-ManUnited KingdomDonald ZackUnited States of AmericaYun-wu ZhangChinaHui ZhengUnited States of AmericaXiongwei ZhuUnited States of AmericaBerislav ZlokovicUnited States of America"}
+{"text": "Hepatitis E virus (HEV) is the major aetiological agent of acute viral hepatitis and a member of the Hepeviridae familyA molecular phylogenetic analysis classifies HEV into four major genotypesHEV is spread via the faecal-oral route and transmitted through water or raw food contaminated with faeces12et alIn this issue, Begum"}
+{"text": "World Journal of Emergency Surgery would like to thank all our reviewers who have contributed to the journal in Volume 7 (2012).The Editors of  Ferdinando AgrestaItalyAli AminianIranDarius Deo BalumukaTanzaniaSandro BarniItalyJasneet BhullarUnited States of AmericaWalter BifflUnited States of AmericaSaptarshi BiswasUnited States of AmericaL.D. BrittUnited States of AmericaDesiree BurgerNetherlandsClay Cothren BurlewUnited States of AmericaJill Cherry-BukowiecUnited States of AmericaRaul CoimbraUnited States of AmericaSalomone Di SaverioItalySamer DoughanUnited KingdomAlex EscalonaChileAristomenis K ExadaktylosSwitzerlandAlessandro FancelluItalyTatsuma FukudaJapanRalf Herbert GahrGermanyAthanasios GiannoukasGreeceSanjay GuptaIndiaJohn HolcombUnited States of AmericaRao IvaturyUnited States of AmericaNobuyasu KanoJapanDimos KarangelisUnited KingdomKenji KawamukaiItalyMichael KellyAustraliaFernando KimUnited States of AmericaYoram KlugerIsraelJanusz KowalewskiPolandRifat LatifiUnited States of AmericaPhilipp LenzlingerSwitzerlandCelestino Pio LombardiItalySheikh MuzamilIndiaTakashi NagataJapanMehdi OuaissiFranceGiorgio RossiItalySandeep SainathanUnited States of AmericaBoris SakakushevBulgaria\u00d6zge SenyamanGermanyR. Stephen SmithUnited States of AmericaKorhan TavilogluTurkeyTomislav TrupkovicGermanyGregorio TugnoliItalyGeorge VelmahosUnited States of AmericaSuemoy WallaceUnited States of AmericaImtiaz WaniIndia"}
+{"text": "Journal of Clinical Bioinformatics would like to thank all our reviewers who have contributed to the journal in Volume 2 (2012).The editors of  Avner Bar-HenFranceChristian BaumgartnerAustriaPhei Lang ChangTaiwanLi ChenUnited States of AmericaLuonan ChenChinaYu-Huei ChengTaiwanClaudia dos SantosCanadaAlastair DroopUnited KingdomHariklia EleftherohorinouUnited KingdomEva EnnsUnited States of AmericaMaria ErikssonSwedenRoland FoisnerAustriaRichard GronostajskiUnited States of AmericaXiaowei GuanUnited States of AmericaTao HanUnited States of AmericaMd Rafiul HassanAustraliaDieter HeermannGermanyJohn HuttonUnited States of AmericaKunlin JinUnited States of AmericaAnders JohnsenDenmarkRadha Krishna Murthy KaruturiSingaporeLukas KennerAustriaJu Han KimSouth KoreaPetra KnaupGermanyCharles KooperbergUnited States of AmericaHans KreipeGermanyHane LeeUnited States of AmericaLance LiottaUnited States of AmericaLong LuUnited States of AmericaAvi Ma'ayanUnited States of AmericaLeah MechanicUnited States of AmericaPablo MoscatoAustraliaMichael NetzerAustriaCasey OverbyUnited States of AmericaNitin PatelUnited States of AmericaJeroen PenningsNetherlandsJoshua PlavnickUnited States of AmericaHelmut PopperAustriaCristin PrintNew ZealandJulia SequiSpainAmbuj SinghUnited States of AmericaK. Stephen SuhUnited States of AmericaJuan Antonio VizcainoUnited KingdomXiangdong WangSwedenChristopher WoelkUnited States of AmericaJunming YueUnited States of America"}
+{"text": "Mobile DNA would like to thank all our reviewers who have contributed to the journal in volume 4 (2013).The Editors of  Wenfeng AnUnited States of AmericaIrina ArkhipovaUnited States of AmericaPeter AtkinsonUnited States of AmericaMark BatzerUnited States of AmericaMarlene BelfortUnited States of AmericaJef BoekeUnited States of AmericaStephane BoissinotUnited States of AmericaGuillaume BourqueCanadaAlexandros BousiosGreeceJulio CamareroUnited States of AmericaShawn ChristensenUnited States of AmericaEdward ChuongUnited States of AmericaRichard CordauxFranceJoan CurcioUnited States of AmericaWayne DecaturUnited States of AmericaPrescott DeiningerUnited States of AmericaFred DydaUnited States of AmericaDavid EdgellCanadaJos\u00e9 Eir\u00edn-L\u00f3pezUnited States of AmericaMichael Evgen'evRussiaXiang GaoUnited States of AmericaValer GoteaUnited States of AmericaNigel GrindleyUnited States of AmericaFabien GuidezFranceKyudong HanUnited States of AmericaDustin HancksUnited States of AmericaZsuzsanna IzsvakGermanyNing JiangUnited States of AmericaPatricia JohnsonUnited States of AmericaKoichi KawakamiJapanS\u00e9bastien LeclercqFranceEmmanuelle LeratFranceElgion LoretoBrazilFrancois MichelFranceJohn MoranUnited States of AmericaUlrich MullerUnited States Minor Outlying IslandsAnja NagelGermanyChristian ParisodSwitzerlandSarah SchaackUnited States of AmericaGerald SchumannGermanyPatrick SinnUnited States of AmericaJonathan StaleyUnited States of AmericaJunji TakedaJapanNicolas ToroSpainZhijian (Jake) TuUnited States of AmericaGregory Van DuyneUnited States of AmericaChantal VauryFranceDavid WoodUnited States of AmericaGuojun YangCanadaSteven ZimmerlyCanada"}
+{"text": "Cell & Bioscience would like to thank all the reviewers who contributed to the journal in Volume 2 (2012).The editors of  Christopher AllenUnited States of AmericaJeff BarrowUnited States of AmericaEsteban CelisUnited States of AmericaYonglong ChenChinaTaiping ChenUnited States of AmericaLin-Feng ChenUnited States of AmericaKaifan DaiUnited States of AmericaDonald DeFrancoUnited States of AmericaXiaoli DuUnited States of AmericaXin-Hua FengUnited States of AmericaWeichao GuoUnited States of AmericaYingbo HeUnited States of AmericaXi HeUnited States of AmericaKun HuangUnited States of AmericaHarald HuberGermanyAnders JacobssonSwedenHassan JijakliBelgiumDong-Yan JinHong KongHung-Ying KaoUnited States of AmericaSander KerstenNetherlandsAtif KhanUnited States of AmericaTherese KinsellaIrelandAh-Ng Tony KongUnited States of AmericaAjit KumarUnited States of AmericaNing LeiUnited States of AmericaKangguang LinUnited States of AmericaYusen LiuUnited States of AmericaHui-Wen LoUnited States of AmericaJianfeng LuUnited States of AmericaJIanjie MaUnited States of AmericaVladimir MajerciakUnited States of AmericaFranz OswaldGermanyBala RamaswamiUnited States of AmericaRachel ReinhardGermanyGuangwen RenUnited States of AmericaThomas ScanlanUnited States of AmericaSven SchinnerGermanyChangshun ShaoUnited States of AmericaRajesh SharmaUnited States of AmericaYufang ShiChinaSongtao ShiUnited States of AmericaMichal StachowiakUnited States of AmericaHsin-Hsiung TaiUnited States of AmericaHiroshi TakeshimaJapanTse-Hua TanTaiwanMoon-Shong TangUnited States of AmericaWalter WahliSwitzerlandZhong WangUnited States of AmericaXin Wei WangUnited States of AmericaShiliang WangUnited States of AmericaWeidong WangUnited States of AmericaLuan WenUnited States of AmericaJiemin WongChinaT.-C. WuUnited States of AmericaYuntao WuUnited States of AmericaHui XiaoChinaJing YanUnited States of AmericaYingzi YangUnited States of AmericaPaul YenSingaporeDavid YuUnited States of AmericaYing ZhangUnited States of AmericaXiaoren ZhangChinaBin ZhangUnited States of AmericaZhen ZhangUnited States of AmericaHui ZhaoHong KongZhongming ZhaoUnited States of AmericaZhi-Ming ZhengUnited States of America"}
+{"text": "AIDS Research and Therapy has been blessed by the support of highly qualified peer reviewers and would like to show its appreciation by thanking the following for their assistance with review of manuscripts for the journal in 2012.A peer-reviewed journal would not survive without the generous time and insightful comments of the reviewers whose efforts often go unrecognized.  Upasna AgarwalIndiaKathleen AkgunUnited States of AmericaRamesh AkkinaUnited States of AmericaMehmet Numan AlpTurkeyClaudia AlteriItalyJintanat AnanworanichThailandUsharani AnaparthyIndiaThanomsak AnekthananonThailandSpinello AntinoriItalySasha AppletonUnited KingdomVasilios AthyrosGreeceMelanie BaconUnited States of AmericaGiorgio BarbariniItalyKim BegleyAustraliaEdward BergerUnited States of AmericaLuigi BuonaguroItalyVera Luiza CapelozziBrazilCatherine CherryAustraliaPloenchan ChetchotisakdTimor-LesteJanice ClementsUnited States of AmericaAnali Conesa-BotellaBelgiumLuis CubanoPuerto RicoAntonella D'arminio MonforteItalyAnand DateUnited States of AmericaCynthia DerdeynUnited States of AmericaChris DestacheUnited States of AmericaPere DomingoSvalbard And Jan MayenAndrew EdmondsUnited States of AmericaRoberto EspositoItalyLydia FeinsteinUnited States of AmericaCaroline FosterUnited KingdomJoel GallantUnited States of AmericaJose M GatellSpainPatricia GeorgeUnited States of AmericaNicola GianottiItalyMagnus GisslenSwedenFrances GotchUnited KingdomMichael GottesmanUnited States of AmericaNathan HansenUnited States of AmericaDennis Hartigan-O'connorUnited States of AmericaBernard HirschelSwitzerlandTara HorvathUnited States of AmericaWei HuangUnited States of AmericaRobin HuebnerUnited States of AmericaPatrick Jean-PhilippeUnited States of AmericaAngela KaidaCanadaPeter KamermanSouth AfricaSteve KantersCanadaStephen KerrAustraliaArifa KhanUnited States of AmericaKristina W. KintzigerUnited States of AmericaEugene KroonThailandAdarsh KumarUnited States of AmericaOlivier LambotteFranceJairam LingappaUnited States of AmericaCarmen LogieCanadaEskindir LohaEthiopiaLucia LopalcoItalyVladimir V. LukashovNetherlandsLut LynenBelgiumFrank MaldarelliUnited States of AmericaWeerawat ManosuthiThailandDavid MargolisUnited States of AmericaNorman MarkowitzUnited States of AmericaGary MarksUnited States of AmericaJustin McarthurUnited States of AmericaAna-Claire MeyerUnited States of AmericaPatrick MiailhesFranceJoann MicanUnited States of AmericaEthan MoitraUnited States of AmericaEve MokotoffUnited States of AmericaAndrew MujugiraUgandaRobert L. MurphyUnited States of AmericaSatoshi NagasakaJapanKenrad NelsonUnited States of AmericaNancy NguyenUnited States of AmericaLena Nilsson Sch\u00f6nnessonSwedenAnn O'learyUnited States of AmericaAntonio PachecoBrazilKovit PattanapanyasatThailandVenkateswara PavuluriUnited States of AmericaSantiago Perez CachafeiroSpainMaya PetersenUnited States of AmericaNittaya PhanuphakThailandVinayaka PrasadUnited States of AmericaGarrett PrestageAustraliaPatricia PriceAustraliaLynn RamirezUnited States of AmericaLokinendi RaoUnited States of AmericaPeter RebeiroUnited States of AmericaAndrew RevellUnited KingdomDoug RichmanUnited States of AmericaGiuliano RizzardiniItalyRobert RobeyUnited States of AmericaJessica Robinson-PappUnited States of AmericaMaria RouraSpainBarbara SchmidtGermanyAnjali SharmaUnited States of AmericaGerald SharpUnited States of AmericaMargie SkeerUnited States of AmericaDaniel SkiestUnited States of AmericaGreg SpearUnited States of AmericaStephen SpectorUnited States of AmericaNarasimhachar SrinivasakumarUnited States of AmericaJack StapletonUnited States of AmericaPhyllis TienUnited States of AmericaVivian ToweUnited States of AmericaAvnish TripathiUnited States of AmericaMarius TroseidNorwayDrago TurcinovCroatiaMarc van der ValkNetherlandsMark WainbergCanadaJames WalkupUnited States of AmericaMarie WangUnited States of AmericaJohanna WeissGermanyWilliam WeissUnited States of AmericaSamantha WestropUnited KingdomLori WienerUnited States of AmericaEd WilkinsUnited KingdomPaige WilliamsUnited States of AmericaJeffrey WiluszUnited States of AmericaBenjamin YoungUnited States of America"}
+{"text": "The editors of Clinical Epigenetics would like to thank all our reviewers who have contributed to the journal in volume 4 (2012). Barry IacopettaAustraliaLuciana AlmeidaBrazilKristian AlmstrupDenmarkSanjeev BanerjeeUnited States of AmericaAnthony BenchUnited KingdomAbdulbari BenerQatarJames CloseUnited KingdomJeffrey CraigAustraliaPierre DehanBelgiumDavid Diaz-SanchezUnited States of AmericaChristian DransfeldGermanyThomas EggermannGermanyAlberto FerlinItalyGary FiresteinUnited States of AmericaSimonetta FrisoItalyDaria GrafodatskayaCanadaJoerg GromollGermanyRichard HamelinFranceDana HancockUnited States of AmericaAnja HarderGermanyJaime HartUnited States of AmericaGeorges HerbeinFranceAnelia HorvathUnited States of AmericaCathrine HoyoUnited States of AmericaJian HuangChinaKatsuhide IgarashiKenyaRiadh JemaaTunisiaNagaya KenJapanMatthias LinkeGermanyAugusto LitonjuaUnited States of AmericaAmar MehtaUnited States of AmericaRamzi MohammadUnited States of AmericaIan MorisonNew ZealandVundavalli MurtyUnited States of AmericaAtsushi NatsumeJapanPriscilla NegraesBrazilTakahiro OchiyaJapanShuji OginoUnited States of AmericaAgnieszka pdowskaGermanyIgor PogribnyUnited States of AmericaJan PurruckerGermanyM Ram SairamCanadaYogen SaunthararajahUnited States of AmericaMarkus SchaichGermanyWei ShenUnited States of AmericaBente Talseth-PalmerAustraliaMary Beth TerryUnited States of AmericaHwei-Fang TienTaiwanRobert WrightUnited States of AmericaWeihua ZengUnited States of AmericaYujing ZhangUnited States of AmericaJinying ZhaoUnited States of AmericaJingde ZhuChinaVlatka ZoldosCroatia"}
+{"text": "AIDS Research and Therapy is very grateful for the support of highly qualified peer reviewers and would like to show its appreciation by thanking the following for their assistance with review of manuscripts for the journal in 2013.A peer-reviewed journal would not survive without the generous time and insightful comments of the reviewers whose efforts often go unrecognized.  Ramesh AkkinaUnited States of AmericaJintanat AnanworanichThailandKathryn AnastosUnited States of AmericaLinda AurpibulThailandNatal AyigaSouth AfricaMelanie BaconUnited States of AmericaFirouz\u00e9 Bani SadrFranceLealem BimerewEthiopiaGary BlickUnited States of AmericaLuigi BuonaguroItalyLuciana CardosoBrazilAnn ChahroudiUnited States of AmericaMikhail ChernovJapanPloenchan ChetchotisakdTimor LesteJulio CrodaBrazilShona DalalUgandaRuben DammersNetherlandsChris DestacheUnited States of AmericaStephen DewhurstUnited States of AmericaJoan DugganUnited States of AmericaNicolas DurierThailandAndrew EdmondsUnited States of AmericaStefano FiorucciItalyLuigi FranchiUnited States of AmericaPierre FrangeFranceJoel GallantUnited States of AmericaGloria GarrabouSpainDavide GibelliniItalyPeytavin GillesFranceMagnus GisslenSwedenPhil GonaUnited States of AmericaNeela GoswamiUnited States of AmericaCecile GoujardFranceGiovanni GuaraldiItalyMarguerite GuiguetFranceAnna Dorothee HeemskerkVietnamNatasha HochbergUnited States of AmericaMichael HorbergUnited States of AmericaRobin HuebnerUnited States of AmericaPeter HuntUnited States of AmericaJamaiah IbrahimMalaysiaJoseph KagaayiUgandaGo KanzakiJapanArifa KhanUnited States of AmericaBrian KigoziUgandaAnna KramvisSouth AfricaKenneth LichtensteinUnited States of AmericaShuwen LiuChinaCarol LutzUnited States of AmericaLut LynenBelgiumFrank MaldarelliUnited States of AmericaWilson MandalaMalawiAlexandra MangiliUnited States of AmericaRenato MaseratiItalySheena McCormackUnited KingdomKenneth McIntoshUnited States of AmericaJohn MetcalfeUnited States of AmericaGerd MikusGermanyJean Michel MolinaFrancePatama MonkongdeeThailandDavid MooreCanadaGiulia MorsicaItalyPhilippe MsellatiBurkina FasoEustasius MusengeSouth AfricaCeline NkenfouCameroonAntonio PachecoBrazilWilliam PaxtonNetherlandsRemco PetersSouth AfricaJoao PiedadePortugalVinayaka PrasadUnited States of AmericaWasana PrasitsuebsaiThailandRichard PriceUnited States of AmericaJan PrinsNetherlandsMarie Eve RaguenaudFranceGita RamjeeSouth AfricaPeter RebeiroUnited States of AmericaSteban RiberaSpainElda RighiItalyGreg RobbinsUnited States of AmericaLisa RohanUnited States of AmericaLisa RossUnited States of AmericaStefano RusconiItalyJesus Salazar GonzalezUnited States of AmericaBrigitte SandersUnited States of AmericaNetanya SandlerUnited States of AmericaRengaswamy SankaranarayananFranceKaty Satue`SpainNathaniel SegarenUnited KingdomRobert ShaferUnited States of AmericaGerald SharpUnited States of AmericaBenson SingaKenyaMeghan SiseUnited States of AmericaMark SonderupSouth AfricaAlessandro SoriaItalyVincent SorianoSpainCathia SoulieFranceGreg SpearUnited States of AmericaChristoph SpinnerGermanyMarcel StoeckleSwitzerlandKazuo TanakaJapanVelislava TerzievaBulgariaJim ToddTanzaniaLydie TrautmannUnited States of AmericaReinout van CrevelNetherlandsKoen Van RompayUnited States of AmericaStephane VerguetUnited States of AmericaMichael VinikoorZambiaCarole WallisSouth AfricaJiang WeiminChinaJames WhitneyUnited States of AmericaJeffrey WiluszUnited States of AmericaLauren WongUnited States of AmericaBasia ZabaUnited KingdomClement ZehKenya"}
+{"text": "The editors of Journal of the International Society of Sports Nutrition would like to thank all our reviewers who have contributed to the journal in Volume 10 (2013). The tireless work that all of you have given to us to enhance our journal is highly appreciated. We can\u2019t thank you enough. Michelle AdamsUnited States of AmericaJose AntonioUnited States of AmericaGeorge AphamisCyprusAlan AragonUnited States of AmericaTodd AstorinoUnited States of AmericaMichelle BarrackUnited States of AmericaPedro BastosPortugalJenna BeckerUnited States of AmericaDan BenardotUnited States of AmericaSandeep BhaleUnited States of AmericaWilhelm BlochGermanyLeigh BreenUnited KingdomAurelien BringardSwitzerlandGrant David BrinkworthAustraliaLuke BucciUnited States of AmericaBill CampbellUnited States of AmericaErico CaperutoBrazilAmanda Carlson-PhillipsUnited States of AmericaMichael CarlstonUnited States of AmericaAmelia CarrAustraliaChantal CharoUnited States of AmericaHamdi ChtourouTunisiaAmanda Claassen-SmithersSouth AfricaPablo CostaUnited States Minor Outlying IslandsPaul CribbAustraliaMaria DagliaItalyVincent DalboAustraliaLance DalleckNew ZealandBarbara DaoCanadaBen DascombeAustraliaPatrick DavittUnited States of AmericaJay DawesUnited States of AmericaFelipe DonattoBrazilInna DumovaUnited States of AmericaChristopher DunbarUnited States of AmericaTravis DutkaAustraliaJoan EckersonUnited States of AmericaChris FahsUnited States of AmericaAndrew FoskettNew ZealandDavid FukudaUnited States of AmericaJeffrey GodinUnited States of AmericaJoanna Gromadzka-OstrowskaPolandG. Gregory HaffAustraliaTravis HarveyUnited States of AmericaMarvin HeuerUnited States of AmericaMatthew HigginsUnited KingdomRalf J\u00e4gerUnited States of AmericaJ\u00f8rgen JensenNorwayAndrew JonesUnited KingdomElizabeth JosephUnited States of AmericaDouglas KalmanUnited States of AmericaLynne KammerUnited States of AmericaChad KerksickUnited States of AmericaLiam KilduffUnited KingdomAnil KulkarniUnited States of AmericaPaul La BountyUnited States of AmericaWarren LadigesUnited States of AmericaAntonio LanchaBrazilHubert LeeUnited States of AmericaSukho LeeUnited States of AmericaAnna LepeleyUnited States of AmericaMichael LeverNew ZealandHector LopezUnited States of AmericaLonnie LoweryUnited States of AmericaRyan LoweryUnited States of AmericaShannan LynchUnited States of AmericaIan MacdonaldUnited KingdomMaria Rita Marques de OliveiraBrazilLinda McCargarCanadaAndrew McKuneSouth AfricaGoncalo MendoncaPortugalRicardo Mora-RodriguezSpainCarolina MouraBrazilMichael NelsonUnited States of AmericaGeorg NeumannGermanyLayne NortonUnited States of AmericaMichael OrmsbeeUnited States of AmericaCorey PeacockUnited States of AmericaPeter PeelingAustraliaDungeng PengUnited States of AmericaMike PriceUnited KingdomPeter ResNetherlandsTodd RideoutUnited States of AmericaRobert RobergsAustraliaMichael RobertsUnited States of AmericaJudith RodriguezUnited States of AmericaBrian RoyCanadaEric RyanUnited States of AmericaCraig SaleUnited KingdomSylvia SantosaCanadaTimothy ScheettUnited States of AmericaSteve SchmitzUnited States of AmericaBrad SchoenfeldUnited States of AmericaChristopher ScottUnited States of AmericaRichard SeipUnited States of AmericaPiero SestiliItalyAndrew ShaoUnited States of AmericaJason SieglerAustraliaTobin SilverUnited States of AmericaCarsten SmidtUnited States of AmericaLaura StewartUnited States of AmericaRobert TaklaUnited States of AmericaMinghua TangUnited States of AmericaYuko TanimuraJapanLemuel W TaylorUnited States of AmericaJay UdaniUnited States of AmericaJeff VolekUnited States of AmericaXiao WanChinaBenjamin WaxUnited States of AmericaJoseph WeirUnited States of AmericaShawn WellsUnited States of AmericaLouise WeschlerUnited States of AmericaRob WildmanUnited States of AmericaBoguslaw WilkCanadaMel WilliamsUnited States of AmericaGabriel WilsonUnited States of AmericaGordon ZelloCanadaYang ZhangChinaTim ZiegenfussUnited States of America"}
+{"text": "Respiratory Research would like to thank all of our reviewers who have contributed to the journal in Volume 14 (2013).The editors of  Ian AdcockUnited KingdomMikael AdnerSwedenBernard AguilaniuFranceAlvar AgustiSpainVassilis AidinisGreeceMuhammad Sajid Hamid AkashPakistanNeil AlexisUnited States of AmericaStefano AlibertiItalyJames AllinsonUnited KingdomSteven AnUnited States of AmericaAlessandro AntonelliItalyRaffaele Antonelli-IncalziItalySabina AntoniuRomaniaKjetil AskCanadaSergei AtamasUnited States of AmericaPaul AuerUnited States of AmericaCharles AuffrayFranceMark AvdalovicUnited States of AmericaMalin AxelssonSwedenDavid BadeschUnited States of AmericaMona BafadhelUnited KingdomGregory BagbyUnited States of AmericaEls BakkerNetherlandsVivek BalasubramaniamUnited States of AmericaPeter BalukUnited States of AmericaJoan Albert BarberaSpainEsther BarreiroSpainKonstantinos BartziokasGreeceErik BathoornNetherlandsFrederic BatteuxFranceHasan BayramTurkeyCeline BeamerUnited States of AmericaRichard BeasleyNew ZealandJuergen BehrGermanyChristoph BeisswengerGermanyJohn Kelley BentleyUnited States of AmericaJean-Francois BernaudinFranceIvan BertoncelloAustraliaValerie BesnardFranceVineet BhandariUnited States of AmericaAndras BikovHungaryColin David BingleUnited KingdomJames BirchlerUnited States of AmericaElyse BissonnetteCanadaLucie BlaisCanadaFrancesco BlasiItalyYury BochkovUnited States of AmericaMarcel BonayFranceYnuk BosseCanadaApostolos BossiosSwedenFernando BotelhoUnited States of AmericaGraham BothamleyUnited KingdomArnaud BourdinFranceJane BourkeAustraliaDemosthenes BourosGreeceKen BrackeBelgiumFulvio BraidoItalyCorry-Anke BrandsmaNetherlandsDanny BrazzaleAustraliaSteven BrodyUnited States of AmericaRossa BrughaUnited KingdomVito BrusascoItalyDominique M A BullensBelgiumPierre-Regis BurgelFranceChris BurtinBelgiumDerek ByersUnited States of AmericaPeter CalverleyUnited KingdomCarlos CamargoUnited States of AmericaGianna CamiciottoliItalyLuigi CamporotaUnited KingdomKai-H\u00e5kon CarlsenNorwayJohnny CarsonUnited States of AmericaEdoardo CasigliaItalySuzanne CasselUnited States of AmericaVincent CastranovaUnited States of AmericaDidier CataldoBelgiumMario CazzolaItalyChung-Ming ChenTaiwanYin ChenUnited States of AmericaAnne ChettyUnited States of AmericaMarco ChilosiItalyDong-Sic ChoiSouth KoreaKian Fan ChungUnited KingdomAllan CoatesCanadaHarold CollardUnited States of AmericaGregory ConnerUnited States of AmericaEnrico ConteItalyMarco ContoliItalyPhilip CooperUnited KingdomFerry CornelissenNetherlandsBorja G CosioSpainVincent CottinFranceFrancis CouturaudFranceHarvey CoxsonCanadaBruno CrestaniFranceGerard CurleyIrelandSven-Erik Dahl\u00e9nSwedenKaid DarwicheGermanyWilfried de BackerBelgiumFrans de JonghNetherlandsAl de WeerdNetherlandsBennett DeboisblancUnited States of AmericaMonique DehouxFranceLien DejagerBelgiumStefano Del GiaccoItalyDeepak DeshpandeUnited States of AmericaFabiano Di MarcoItalyAntonino Di StefanoItalyQuoc Thai DinhGermanyRatko DjukanovicUnited KingdomClaudia DoblerAustraliaJames DoddUnited KingdomClaire DoerschukUnited States of AmericaJoanna Domagala-KulawikPolandClaudio F DonnerItalyJames DonohueUnited States of AmericaDavid DoudaCanadaMark DransfieldUnited States of AmericaPaul DudasUnited States of AmericaSteven DuncanUnited States of AmericaBenedicte DurandFranceBalthasar EberleSwitzerlandRonald EcclesUnited KingdomCarsten EhrhardtIrelandStuart ElbornUnited KingdomSouheil El-ChemalyUnited States of AmericaRalph EpaudFranceDavid ErleUnited States of AmericaChristopher EvansUnited States of AmericaLeonardo FabbriItalyAurelie FabreIrelandLucy FaircloughUnited KingdomDavid FairlieAustraliaLaszlo FarkasUnited States of AmericaCarol Feghali-BostwickUnited States of AmericaRenata FerrariBrazilGilbert FerrettiFranceDaniel Clark FilesUnited States of AmericaBernie FischerUnited States of AmericaPaul ForsytheCanadaAllison FryerUnited States of AmericaTrentham FurnessAustraliaMarcelo Gama de AbreuGermanyJennie GaneUnited KingdomRavendra GargCanadaKathy GatelyIrelandAmiq GazdharSwitzerlandMoyar Qing GeUnited States of AmericaArthur GelbUnited States of AmericaSteve GeorasUnited States of AmericaMaher GhamloushUnited States of AmericaTroy GhashghaeiUnited States of AmericaMark GiembyczCanadaStephan GlasserUnited States of AmericaElena GoncharovaUnited States of AmericaReinoud GosensNetherlandsHarry GoskerNetherlandsPhilippe GossetFranceClive GrattanUnited KingdomFlorian GretenGermanyMatthias GrieseGermanyAndreas GroeschelGermanyMathieu GruetFranceOreste GualilloSpainAndreas GuentherGermanyJesus GuineaSpainErich GulbinsGermanySusan GuttentagUnited States of AmericaJosef GuttmannGermanyTillie-Louise HackettCanadaAndrew HalaykoCanadaKeqi HanChinaMeilan HanUnited States of AmericaMasayuki HanaokaJapanPhil HansbroAustraliaJitka Stilund HansenDenmarkCorrine HansonUnited States of AmericaChristof HauckGermanyGregory HawkinsUnited States of AmericaFengtian HeChinaIrene HeijinkNetherlandsMatthias HeldGermanyDirk HenrichGermanyDarryl HillUnited KingdomGeorgios HillasGreeceAri HirvonenFinlandJennifer HoTaiwanSandra HoeglGermanyAndrew HoffmanUnited States of AmericaOlaf HolzGermanyRobert HomerUnited States of AmericaAmjad HoraniUnited States of AmericaTakahiko HoriguchiJapanJay HorvatAustraliaIldiko HorvathHungaryGuochang HuUnited States of AmericaFrancois HuauxBelgiumAlice HuertasFranceWouter HuvenneBelgiumMachteld HylkemaNetherlandsCristoforo IncorvaiaItalySatoru ItoJapanKenji IzuharaJapanDaniel JacksonUnited States of AmericaJeffrey JacobsonUnited States of AmericaThomas JagoeCanadaYong Ju JangSouth KoreaLuke JanssenCanadaAndrew Paul JarmanUnited KingdomTuomas JarttiFinlandIlona JaspersUnited States of AmericaZhilong JiangUnited States of AmericaShengwei JinChinaZhi-Cheng JingChinaMichelle JohnUnited KingdomJill JohnsonUnited KingdomPaul JonesUnited KingdomClaude Jourdan-Le SauxUnited States of AmericaAndreas JungSwitzerlandNoor KalshekerUnited KingdomDavid KampUnited States of AmericaHannu KankaanrantaFinlandTobias KeckGermanyThomas KennedyUnited States of AmericaHuib KerstjensNetherlandsFarrah KheramandUnited States of AmericaYoon-Keun KimSouth KoreaGreg KingAustraliaPascale KippelenUnited KingdomLoes KistemakerNetherlandsYasuo KizawaJapanDarryl KnightAustraliaAlan KnoxUnited KingdomVladimir KoblizekCzech RepublicMartin KolbCanadaJay KollsUnited States of AmericaMasuo KondohJapanMirjam KoolNetherlandsMartina KorfeiGermanyBeata KosmiderUnited States of AmericaKonstantinos KostikasGreeceAnastasia KotanidouGreeceThomas KovesiCanadaFrank KruytNetherlandsVera KrymskayaUnited States of AmericaWolfgang KueblerGermanyKuldeep KumawatNetherlandsPhilipp K\u00fcmpersGermanyLisette KunzNetherlandsMing-Ling KuoTaiwanKatia KvitkoBrazilJeff KwonUnited States of AmericaVincent LagenteFranceFranco LaghiUnited States of AmericaLies LahousseBelgiumIrene LangAustriaSven LarssonSwedenFran\u00e7ois LaurentFranceGeoff LaurentAustraliaWilliam LawsonUnited States of AmericaJohn LayUnited States of AmericaAili LazaarUnited States of AmericaChun Geun LeeUnited States of AmericaJanet LeeUnited States of AmericaKang-Yun LeeTaiwanHakon LefflerSwedenRosa Lemmens-GruberAustriaMichael LevinSouth AfricaBing LiChinaGuiyuan LiChinaTriantafillos LiloglouUnited KingdomShizhang LingUnited States of AmericaDominik LinzGermanyPaulo LisboaUnited KingdomFu-Tong LiuUnited States of AmericaGang LiuChinaJie LiuUnited States of AmericaOlle L\u00f6whagenSwedenMarek LommatzschGermanyLucille LondonUnited States of AmericaM Victorina Lopez VarelaUruguayVictorina Lopez VarelaUruguayRenaud LouisBelgiumStelios LoukidesGreeceJames LoydUnited States of AmericaZi-Qiang LuoChinaHarm MaarsinghNetherlandsRoberto MachadoUnited States of AmericaTania MaesBelgiumArnaud MailleuxFranceNicholas ManzoUnited States of AmericaJian-Hua MaoUnited States of AmericaCrystal MarconettUnited States of AmericaBernard MariFranceThomas MarianiUnited States of AmericaOreste MarroneItalyShuichiro MaruokaJapanJorge MasperoArgentinaKazuo MatsubaraJapanShin MatsuokaJapanHiroto MatsuseJapanGustavo Matute-BelloUnited States of AmericaThais MauadBrazilDonald M. 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Asuncion MejiasUnited States of AmericaAndrea MelaniItalyBarbro MelgertNetherlandsMassimo MiniatiItalyMichael MinnicozziUnited States of AmericaJordan MinovMacedoniaMarc MiravitllesSpainFirdaus A A Mohamed HoeseinNetherlandsLyn MoirAustraliaWinfried M\u00f6llerGermanyPaolo MontuschiItalyJuan MorenoSpainSarah MorganUnited States of AmericaHideaki MoriyamaUnited States of AmericaEdward MorriseyUnited States of AmericaEsmaeil MortazNetherlandsRory MortyGermanyRobert M MrozPolandJoachim M\u00fcller-QuernheimGermanyAnil MukherjeeUnited States of AmericaVeronika M\u00fcllerHungaryJohn T MurchisonUnited KingdomShigeo MuroJapanLynne MurrayUnited KingdomKari NadeauUnited States of AmericaJay NadelUnited States of AmericaRachel NadifFranceRobert NaeijeBelgiumYasutaka NakanoJapanPatrick Nana-SinkamUnited States of AmericaNadia NathanFranceTim NawrotBelgiumThao NguyenUnited States of AmericaLinda NiciUnited States of AmericaKoichi NishimuraUnited KingdomYoshihiro NishimuraJapanMagnus NordSwedenBenjamin NwosuUnited States of AmericaBenjamin OdryUnited States of AmericaToru OgaJapanYoshiharu OhnoJapanBrian OliverAustraliaLiam O'MahonySwitzerlandMichael O'ReillyUnited States of AmericaLarry OstrowskiUnited States of AmericaCaroline OwenUnited States of AmericaAlix Paget-BrownUnited States of AmericaRobert PaineUnited States of AmericaLena PalmbergSwedenKusum PanditUnited States of AmericaAngela Panoskaltsis-MortariUnited States of AmericaGregorino PaoneItalyAndriana PapaioannouGreeceJin-Ah ParkUnited States of AmericaSean ParkerUnited KingdomAnand PatelUnited States of AmericaIan PavordUnited KingdomGirolamo PelaiaItalyRaymond PennUnited States of AmericaTonio PeraUnited States of AmericaJesus Perez-GilSpainRogelio Perez-PadillaMexicoLeif PetersonUnited States of AmericaIrina PetracheUnited States of AmericaAlejandro PezzuloUnited States of AmericaMassimo PifferiItalyVal\u00e9ria Amorim Pires Di LorenzoBrazilFrancesco PistelliItalyFabio PittaBrazilVenerino PolettiItalyMichael PolkeyUnited KingdomJill PooleUnited States of AmericaNicolas PottierFranceSandeep PrabhuUnited States of AmericaY S PrakashUnited States of AmericaJeff PrettoAustraliaDavid PriceUnited KingdomMirella ProfitaItalyGrzegorz PrzybylskiPolandJennifer QuintUnited KingdomAntoine RabbatFranceRoberto RabinovichUnited KingdomThirumalai RamalingamUnited States of AmericaKathryn RamseyAustraliaSarah RandUnited KingdomWinfried RanderathGermanySekhar ReddyUnited States of AmericaJohn ReillyUnited States of AmericaNiki ReynaertNetherlandsPaul ReynoldsUnited States of AmericaFabio RicciardoloItalyGerdt C RiiseSwedenRoberto Rodriguez-RoisinSpainPaola RoglianiItalyJesse RomanUnited States of AmericaDebra RombergerUnited States of AmericaPhilippe RosiasNetherlandsMahmoud RouabhiaCanadaJeremie RouxUnited States of AmericaNikoletta RovinaGreeceLewis RubinUnited States of AmericaClark RussellUnited KingdomErica RuttenNetherlandsSungwoo RyooSouth KoreaRuxana SadikotUnited States of AmericaVenkatesh SampathUnited States of AmericaManuel Sanchez-de-la-TorreSpainPhilip SannesUnited States of AmericaShinji SasadaJapanDedmer SchaafsmaCanadaTom SchabergGermanyBernhard SchlechtaAustriaMartina SchmidtNetherlandsBettina SchockUnited KingdomRichard SchulzGermanyChristian SchumannGermanyStefan SchumannGermanyChris ScottonUnited KingdomAndrea SegretiItalyPetra SeidelSwitzerlandSanjay SethiUnited States of AmericaHuahao ShenChinaYuichiro ShindoJapanJanis ShuteUnited KingdomNikos SiafakasGreeceSalman SiddiquiUnited KingdomRichard SindelarSwedenDave SinghUnited KingdomThomas SissonUnited States of AmericaChrysanthi SkevakiGreeceKristopher SkwarskiUnited KingdomPatricio SmithChileHermelijn SmitsNetherlandsSigrun SmolaGermanyAnita SpanjerNetherlandsMark SpearsUnited KingdomEliot SpindelUnited States of AmericaMartijn SpruitNetherlandsSaranya SridharUnited KingdomBruce StantonUnited States of AmericaKarl StaplesUnited KingdomKatrina SteilingUnited States of AmericaMichael SteinerUnited KingdomRobert StockleyUnited KingdomClare StokesUnited KingdomViranuj SueblinvongUnited States of AmericaMaria SukkarAustraliaYongchang SunChinaNorbert SuttorpGermanyNicola SverzellatiItalyErna SzikszHungaryClifford TaggartUnited KingdomOsamu TaguchiJapanMasao TakataUnited KingdomTsutomu TamadaJapanHui-Leng TanUnited KingdomDale TangUnited States of AmericaJun-Ming TangChinaSuzana Erico TanniBrazilKeith TanswellCanadaLaima Taraseviciene-StewartUnited States of AmericaDonald TashkinUnited States of AmericaChristian TaubeNetherlandsKlaus TenbrockGermanyNeil ThomsonUnited KingdomYing TianUnited States of AmericaRenaud TissierFranceAntoni TorresSpainMaria TsoumakidouGreeceGerard M TurinoUnited States of AmericaEleni TzortzakiGreeceArgyris TzouvelekisGreecePaul UptonUnited KingdomJoost G van den AardwegNetherlandsMaarten van den BergeNetherlandsRene van der MerweUnited KingdomAlbert van der VleitUnited States of AmericaArjan van LaarhovenNetherlandsPieter-Jan van OoijNetherlandsJeroen VanoirbeekBelgiumRuud VeldhuizenCanadaGiovanni ViegiItalyEszter VladarUnited States of AmericaRoss VlahosAustraliaClaus VogelmeierGermanyStephan von GuntenSwitzerlandRobert VoswinckelGermanyGerry WagenaarNetherlandsBenoit WallaertFranceDavid WarburtonUnited States of AmericaPeter WarkAustraliaJenora WatermanUnited States of AmericaHenrik WatzGermanyGuangwei WeiChinaAthol WellsUnited KingdomTobias WelteGermanyFu-Qiang WenChinaSally WenzelUnited States of AmericaSusan WertUnited States of AmericaGunilla Westergren-ThorssonSwedenGuillaume WettsteinFranceEric WhiteUnited States of AmericaJim WhiteUnited States of AmericaJanine WichmannSouth AfricaMark WielpuetzGermanyPeter WijkstraNetherlandsTim WilliamsonUnited States of AmericaDavid WilsonUnited States of AmericaAaron WinklerUnited States of AmericaBrent WinstonCanadaHubert WirtzGermanyKenneth WitwerUnited States of AmericaJeremias WohlschlaegerGermanyEmiel F M WoutersNetherlandsXimei WuChinaDanielle WurzelAustraliaMasao YamaguchiJapanHideyuki YamamotoJapanIan YangAustraliaQi YangUnited States of AmericaXin YaoChinaKazuhiro YasufukuCanadaJunji YodoiJapanAkihito YokoyamaJapanRobert P YoungNew ZealandJason YuanUnited States of AmericaElodie Zana-Ta\u00efebFrancePaul ZarogoulidisGreeceHui ZengChinaHuayan ZhangUnited States of AmericaZe ZhangChinaJinshun ZhaoChinaWeian ZhaoUnited States of AmericaYutong ZhaoUnited States of AmericaDegui ZhiUnited States of America"}
+{"text": "Child and Adolescent Psychiatry and Mental Health would like to thank all of our reviewers who have contributed to the journal in volume 6 (2012).The editors of  Howard AbikoffUnited States of AmericaGwen AdsheadUnited KingdomMarc AllroggenGermanyKim AndersonUnited States of AmericaMuhammad AyubUnited KingdomMelanie BarwickCanadaVincenza BianchiItalyNicoletta BisacchiItalyJeffrey BishopUnited States of AmericaMargarete BoltenSwitzerlandWolfgang BriegelGermanyThomas E BrownUnited States of AmericaBelinda BruwerSouth AfricaRegina BussingUnited States of AmericaMarilyn CampbellAustraliaLuna CentifantiUnited KingdomPatricia ChamberlainUnited States of AmericaAlexander ChapmanCanadaYing-Sheue ChenTaiwanMegan ChesinUnited States of AmericaAnn ChildressUnited States of AmericaMolly Choate SummerUnited States of AmericaMonali ChowdhuryUnited States of AmericaPenny CorkumCanadaSamuele CorteseUnited States of AmericaMichael DavidovitchIsraelDomenico De BerardisItalyMieke DecuyperBelgiumCarmen Desir\u00e9e DirksenNetherlandsKathy DowellUnited States of AmericaKimberly DuMontUnited States of AmericaMichael DunnUnited KingdomTony DurkeeSwedenMayada ElsabbaghCanadaJerome EndrassSwitzerlandTatiana FalconeUnited States of AmericaDineke FeenstraNetherlandsMinne FekkesNetherlandsDavid FergussonNew ZealandReiner FrankGermanyJennifer FreemanUnited States of AmericaMark FriedmanUnited States of AmericaBarbara FriesenUnited States of AmericaSari Fr\u00f6jdFinlandDaniel FungSingaporeAbbe GarciaUnited States of AmericaMorton GernsbacherUnited States of AmericaCatherine GlennUnited States of AmericaMarianne GoodmanUnited States of AmericaJohn GundersonUnited States of AmericaPenelope HaskingAustraliaAnders HelanderSwedenMarisa HilliardUnited States of AmericaMegan HobbsAustraliaSumi HoshikoUnited States of AmericaJennifer HughesUnited States of AmericaStephanie HullmannUnited States of AmericaTonje Lossius HusumNorwayJoost HutsebautNetherlandsNicholas IalongoUnited States of AmericaSusan JackCanadaAstrid JanssensUnited KingdomLisa M JonesUnited States of AmericaMichael KaessGermanyRiittakerttu Kaltiala-HeinoFinlandNestor Damian KapustaAustriaNiranjan KarnikUnited States of AmericaYotaro KatsumataJapanFerdinand KellerGermanyReinhold KilianGermanyHeinz KindlerGermanyDavid J KleinUnited States of AmericaSusanne KnappeGermanyDenis K\u00f6hlerGermanyMaria KovacsUnited States of AmericaKasia KozlowskaAustraliaE Stephanie Krauthamer EwingUnited States of AmericaMaya KrischerGermanyAnne KroegerGermanyCaroline KuoUnited States of AmericaSylvia KwokHong KongMagali LahayeBelgiumBo LarssonNorwayGerd LehmkuhlGermanyUlrike LeissAustriaAdam LewinUnited States of AmericaStephen P LewisCanadaRamon LindauerNetherlandsAstri LundervoldNorwayJenny MacfieUnited States of AmericaAnn MaloneyUnited States of AmericaAbigail MarshUnited States of AmericaGraham MartinAustraliaAndres MartinUnited States of AmericaErin McClureUnited States of AmericaBo MohlDenmarkSuneeta MongaCanadaJennifer MuehlenkampUnited States of AmericaAbraham MukoloUnited States of AmericaWendy NilsenUnited States of AmericaLatha NrughamNorwayBeate OerbeckNorwayPeter O'GormanIrelandSusanne OhmannAustriaGuiomar OliveiraPortugalUkamaka OrucheUnited States of AmericaSonja PerrenSwitzerlandJohn PiacentiniUnited States of AmericaBettina PikoHungaryDominic PlantUnited KingdomPaul L PlenerGermanyChristian PostertGermanyRoslyn PoulosAustraliaColin PritchardUnited KingdomSteven PryjmachukUnited KingdomLamprini PsychogiouUnited KingdomNaren RaoCanadaErin ReutherUnited States of AmericaWolfgang RetzGermanyCarla SabariegoGermanyDaniel SaferUnited States of AmericaMariacarolina SalernoItalyBenno SchimmelmannGermanyRobert SchlackGermanyMarc SchmidSwitzerlandUlrike Margarete Elisabeth SchulzeGermanyNadine SchwartzUnited States of AmericaEmma SciberrasAustraliaStefano SeriUnited KingdomCarla SharpUnited States of AmericaJoel SherrillUnited States of AmericaMargaret SibleyUnited States of AmericaSusan SilvaUnited States of AmericaEllin SimonBelgiumTeesta SomanCanadaLin S\u00f8rensenNorwayCesar SoutulloSpainHans-Christoph SteinhausenDenmarkLisanne StoneNetherlandsEric StorchUnited States of AmericaJeffrey StuewigUnited States of AmericaKevin SullivanUnited States of AmericaCalvin SumnerUnited States of AmericaAnne Mari SundNorwaySharon SungSingaporeLene SymesUnited States of AmericaToshinobu TakedaJapanJessica TearneAustraliaElaine ThompsonUnited States of AmericaUte ThyenGermanyAudrey TluczekUnited States of AmericaLieke van DomburghNetherlandsMartijn van NoordenNetherlandsViolaine VeenNetherlandsRobert VermeirenNetherlandsAlexander von GontardGermanyRebecca VujnovicUnited States of AmericaJan WallanderUnited States of AmericaMichelle WedigUnited States of AmericaOliver WhiteUnited KingdomSilke Wiegand-GrefeGermanyPatricia WilliamsUnited States of AmericaDenise WilsonNew ZealandTuppett YatesUnited States of AmericaCheng-Fang YenTaiwan"}
+{"text": "The editors of Journal of the International Society of Sports Nutrition would like to thank all our reviewers who have contributed to the journal in Volume 9 (2012). Michelle AdamsUnited States of AmericaAjmol AliNew ZealandDawn AndersonUnited States of AmericaHans Joachim AppellGermanyAlan AragonUnited States of AmericaGiannis ArnaoutisGreeceEldon AskewUnited States of AmericaMohammad Ali AzarbayjaniIranNorbert BachlAustriaJenna BeckerUnited States of AmericaSandeep BhaleUnited States of AmericaDouglas BibusUnited States of AmericaFrancois BlachierFranceAndrew BoschSouth AfricaLuiz-Claudio CameronBrazilBill CampbellUnited States of AmericaDarren CandowCanadaAna CastillaUnited States of AmericaEric ClaassenNetherlandsGillian CowenAustraliaKirk CuretonUnited States of AmericaClaudia da LuzBrazilMaeli Dal PaiBrazilLara DugasUnited States of AmericaCharles DumkeUnited States of AmericaInna DumovaUnited States of AmericaChristopher DunbarUnited States of AmericaConrad EarnestUnited KingdomJoan EckersonUnited States of AmericaMohamed ElloumiTunisiaMatt FitzgeraldUnited States of AmericaDonovan FogtUnited States of AmericaEmerson FranchiniBrazilKarl FriedlUnited States of AmericaYukio FujitaJapanMoacir GodoyBrazilMarcela Gonzalez-GrossSpainMike GreenwoodUnited States of AmericaBruno GualanoBrazilMarios HadjicharalambousCyprusMatthew HarberUnited States of AmericaJohn HawleyAustraliaStephen HeinrichsUnited States of AmericaJay HoffmanUnited States of AmericaGeoffrey HudsonUnited States of AmericaMikel IzquierdoSpainPatrick JacobsUnited States of AmericaRalf J\u00e4gerUnited States of AmericaLynne KammerUnited States of AmericaChad KerksickUnited States of AmericaJeong-Su KimUnited States of AmericaMichael KingsleyUnited KingdomPaul La BountyUnited States of AmericaAntonio LanchaBrazilJoan LappeUnited States of AmericaHubert LeeUnited States of AmericaAnna LepeleyUnited States of AmericaShiming LiUnited States of AmericaHector LopezUnited States of AmericaRyan LoweryUnited States of AmericaShannan LynchUnited States of AmericaGerald MangineUnited States of AmericaJames McClungUnited States of AmericaBrendon McDermottUnited States of AmericaAndrew McKuneSouth AfricaAndrea McNeillyUnited KingdomJamie McPheeUnited KingdomVazgen MinasianIranDaniel MoranIsraelElizabeth NagleUnited States of AmericaAnthony NakazawaUnited States of AmericaAngelica NerisUnited States of AmericaLayne NortonUnited States of AmericaMichael OrmsbeeUnited States of AmericaHyon ParkSouth KoreaM\u00e1rio PaschoalBrazilTavis PiattolyUnited States of AmericaNicholas RatamessUnited States of AmericaJohn RathmacherUnited States of AmericaAnthony RicciUnited States of AmericaTania RiveraUnited States of AmericaMichael RobertsUnited States of AmericaScott RobinsonUnited KingdomHamilton RoschelBrazilEdward RyanUnited States of AmericaCraig SaleUnited KingdomStephen SchmitzUnited States of AmericaBrad SchoenfeldUnited States of AmericaChristopher ScottUnited States of AmericaJames ScottUnited States of AmericaRichard SeipUnited States of AmericaPiero SestiliItalyAndrew ShaoUnited States of AmericaTobin SilverUnited States of AmericaDustin SlikvaUnited States of AmericaAbbie SmithUnited States of AmericaJeffrey StoutUnited States of AmericaTetsuya TakamataJapanLemuel W TaylorUnited States of AmericaToni Torres-McGeheeUnited States of AmericaFilomena ValimUnited States of AmericaXuewen WangUnited States of AmericaLouise WeschlerUnited States of AmericaUrban WiklundSwedenColin WilbornUnited States of AmericaDarryn WilloughbyUnited States of AmericaJacob WilsonUnited States of AmericaGabriel WilsonUnited States of AmericaKuan ZhangChinaTim ZiegenfussUnited States of America"}
+{"text": "Annals of General Psychiatry would like to thank all of our reviewers who have contributed to the journal in volume 12 (2013).The editors of  Cengiz AkkayaTurkeyUmberto AlbertItalyTadao ArinamiJapanJean-Michel AzorinFranceChris BaekenBelgiumFilipe BarbosaPortugalAlasdair BarrCanadaMarianne BartonUnited States of AmericaJordana BayerAustraliaEty BerantIsraelFrancesca BrambillaItalyJerome BrunelinFranceTommaso CaiItalyPhilip CandilisUnited States of AmericaAndre CarvalhoBrazilJanet CatovUnited States of AmericaAndrea CavannaUnited KingdomJohn ChapmanUnited States of AmericaHan-Ying ChenTaiwanMark DetweilerUnited States of AmericaCarol DillonArgentinaViktorija Dragojevic-SimicSerbiaTatiana DubayovaSlovakiaSimon DymondUnited KingdomMaria Luisa FigueiraPortugalMichele FornaroItalySoma GanesanCanadaKeming GaoUnited States of AmericaGabor GazdagHungaryMark GeorgeUnited States of AmericaYuri GimelfarbIsraelHans GrabeGermanyNisara GranadoUnited States of AmericaRolf W. Gr\u00e5weNorwayG\u00fclcan G\u00fcle\u00e7TurkeyBarbara HanusaUnited States of AmericaSetsko HanzawaJapanMagnus HaraldssonIcelandEgbert HartstraBelgiumPhilip HarveyUnited States of AmericaKenji HashimotoJapanPia HeppnerUnited States of AmericaHarriet HiscockAustraliaCyril HoschlCzech RepublicShinji IizakaJapanManabu IkedaJapanQin JiangUnited States of AmericaChristopher KearneyUnited States of AmericaBruce KinonUnited States of AmericaTaishiro KishimotoJapanAlexandra KleimanGermanyMichael KoelchGermanyTsuyoshi KondoJapanJyrki KorkeilaFinlandFrank KozelUnited States of AmericaItaru KushimaJapanLawrence T. LamHong KongCynthia LeardMannUnited States of AmericaClaude LeclercCanadaStefan LeuchtGermanyAdam LewinUnited States of AmericaJean-Pierre LindenmayerUnited States of AmericaJuan V. LucianoSpainArja MainioFinlandLouise MarryatUnited KingdomAlmudena MartorellSpainValentin MbekouCanadaRoumen MilevCanadaAli MontazeriIranLindee MorganUnited States of AmericaGunnar MorkenNorwayKai M\u00fcllerGermanyNoeline NakasujjaUgandaMichael Gerhard OdenwaldGermanyTakashi OkadaJapanJo\u00e3o OliveiraBrazilJuhi PandeyUnited States of AmericaAndreas PavalkisCyprusVassilis PavlopoulosGreeceJesus PerezUnited KingdomBernice PescosolidoUnited States of AmericaAntonio PretiItalyJavier QuinteroSpainRajeev RamchandUnited States of AmericaKeith RasmussenUnited States of AmericaHelen RichardsUnited KingdomSoledad RomeroSpainPatricia RosebushCanadaNicolas RuschUnited States of AmericaAnn-Margret RydellSwedenCraig SawchukUnited States of AmericaWilliam SledgeUnited States of AmericaRhonda SmallAustraliaJorgen SundbyNorwayBruce SutorUnited States of AmericaSara TaiUnited KingdomKei-ichiro TakaseJapanCornelia ThielsGermanyM. Inmaculada TorresSpainKarli TreyvaudAustraliaWataru UkaiJapanCarole UpshurUnited States of AmericaBrian van WykSouth AfricaAreti Angeliki VeronikiGreeceSimone VigodCanadaMartin VoracekAustriaMargareta WesterbotnSwedenLeenika WijeratneSri LankaAllison WilliamsUnited States of AmericaJanet WilliamsUnited States of AmericaAndreas WittorfGermanyHeather YardleyUnited States of AmericaNorio Yasui-FurukoriJapanReiji YoshimuraJapan"}
+{"text": "We and the Editorial Board acknowledge and thank all reviewers for their active participation and contribution during 2013. We greatly appreciate their dedication and behind the scenes contribution. It is largely due to their support and expertise that we have been able to publish high-standard manuscripts. We would also like to thank authors for choosing Nutrition & Metabolism and contributing their cherished work. Niyazi AcarFranceMarcia AguilaBrazilSaeed AkhtarKuwaitNayef AlgharaibehJordanDavid AllisonUnited States of AmericaEmma AllottUnited States of AmericaFutwan Al-MohannaSaudi ArabiaJohn AloiaUnited States of AmericaEzequiel AlvarezSpainAnton AmannAustriaTheodore AngelopoulosUnited States of AmericaJose AntonioUnited States of AmericaAlex AregbesolaFinlandVasilios AthyrosGreeceSarah AuharekBrazilSalman AzharUnited States of AmericaThomas BadgerUnited States of AmericaJasmohan BajajUnited States of AmericaAhmed BakillahUnited States of AmericaMichiel BalversNetherlandsTyler BarkerUnited States of AmericaNeal BarnardUnited States of AmericaMasood BazrgarIranElizabeth Bertone-JohnsonUnited States of AmericaH Tanju BeslerTurkeySheng BiUnited States of AmericaXin BiUnited States of AmericaWilliam BlanerUnited States of AmericaKathryn BradburyUnited KingdomGeorge BrayUnited States of AmericaChristopher BreyUnited States of AmericaTom BroderickUnited States of AmericaRuud BuijsMexicoThomas BurkeyUnited States of AmericaL. C. CameronBrazilLuciana CaperutoBrazilLucile CapuronFranceAxel CarlssonSwedenChristian Carp\u00e9n\u00e9FranceSue-Joan ChangTaiwanUbon Cha'onThailandOliver ChenUnited States of AmericaJuei-Tang ChengTaiwanMyung-Sook ChoiKorea SouthMichael ChuaPhilippinesStreamson ChuaUnited States of AmericaKatherine CianfloneCanadaGraeme CloseUnited KingdomKate CollisonSaudi ArabiaPaola Antonia CorsettoItalyPaola CostelliItalyPhilippe CostetUnited States of AmericaSherry DadsetanDenmarkKezhi DaiUnited States of AmericaGM Dallinga-ThieNetherlandsUndurti DasUnited States of AmericaNicholas DavidsonUnited States of AmericaBrenda DavyUnited States of AmericaCarlos De MiguelSpainNicole de WitNetherlandsTam\u00e1s DecsiHungaryYvonne DenkinsUnited States of AmericaWim DeraveBelgiumpskevi DetopoulouGreecePatrick D'HaeseBelgiumMarco Fabr\u00edcio Dias PeixotoBrazilJared DickinsonUnited States of AmericaRyan DilgerUnited States of AmericaHans DreyerUnited States of AmericaAlan DucatmanUnited States of AmericaKlaus EderGermanyAbdalla El-MowafyEgyptMunechika EnjojiJapanMara EpsteinUnited States of AmericaRamon EstruchSpainPeter EuAustraliaChris ExleyUnited KingdomChris FahsUnited States of AmericaGermana FalconeItalyLonghou FangUnited States of AmericaAnthony FardetFranceRichard FeinmanUnited States of AmericaMilagro FerminSpainVictoria FolettaAustraliaBenedicte Fontaine-BissonCanadaFlavio FranciniArgentinaZhengwei FuChinaGotthold G\u00e4belGermanyNicholas GablerUnited States of AmericaAlessandra GamberoBrazilMary C. GannonUnited States of AmericaJavier GisbertSpainJulia GoedeckeSouth AfricaEdward GorhamUnited States of AmericaLouise GrahnemoSwedenAldo GrefhorstNetherlandsSudhiranjan GuptaUnited States of AmericaRobert HackmanUnited States of AmericaTiruneh HailemariamUnited States of AmericaKei HamazakiJapanRobert HarrisUnited States of AmericaEarl HarrisonUnited States of AmericaPeter HavelUnited States of AmericaAlan HayesAustraliaAibin HeUnited States of AmericaHelen Hermana HermsdorffBrazilErnesto HernandezUnited States of AmericaMarvin HeuerUnited States of AmericaMichael HolickUnited States of AmericaJane Hoover-PlowUnited States of AmericaSander Michel HoutenUnited States of AmericaAdela HrubyUnited States of AmericaYong HuUnited States of AmericaM. Mahmood HussainUnited States of AmericaFotios IliadisGreeceHiroyasu InoueJapanJahangir IqbalUnited States of AmericaHelene JacquesCanadaSushil JainUnited States of AmericaYvonne JeanesUnited KingdomEui-Bae JeungKorea SouthBo JiUnited States of AmericaXian-Cheng JiangUnited States of AmericaRavin JugdaohsinghUnited KingdomPierre JulienCanadaAfshan KaleemPakistanDouglas KalmanUnited States of AmericaNishan KalupahanaSri LankaAlvin KamiliAustraliaHideaki KanetoJapanTilakavati KarupaiahMalaysiaHisnaori KatoJapanHisayoshi KawaharaJapanSusanne KeidingDenmarkRoya KelishadiIranDarshan KelleyUnited States of AmericaSander KerstenNetherlandsUlkan KilicTurkeyJung Han KimUnited States of AmericaKyoungKon KimKorea SouthMi-Hyun KimKorea SouthSofia KlingbergSwedenRichard KollmarUnited States of AmericaSuminori KonoJapanHannu KoponenFinlandMark KotowiczAustraliaSandra Kraljevic PavelicCroatiaRichard KreiderUnited States of AmericaNatraj KrishnanUnited States of AmericaAlan KristalUnited States of AmericaHerculina Salome KrugerSouth AfricaTakashi KudoUnited States of AmericaAnil KulkarniUnited States of AmericaChao-Qiang LaiUnited States of AmericaWouter H. LamersNetherlandsAndrew LaneUnited States of AmericaStuart LanhamUnited KingdomMartine LavilleFranceDonald LaymanUnited States of AmericaMi-Kyung LeeKorea SouthMargret LeosdottirSwedenTung Ming LeungUnited States of AmericaDuo LiChinaBernt LindahlSwedenFabio LiraBrazilGeorge LiuChinaJing-Chen LiuChinaYuefei LiuGermanyEulogio J. Llorent-Mart\u00ednezSpainDorothea LoeselGermanyYan-Ru LouFinlandThomas LutzSwitzerlandDavid MaCanadaDenise MafraBrazilSameh MagdeldinJapanAnssi ManninenFinlandRachel Marion-LetellierFranceBrian MartinCanadaSteve McAnultyUnited States of AmericaGethin McBeanIrelandAnn McGintyUnited KingdomRobin McGregorNew ZealandRoger McLeodCanadaRonald MensinkNetherlandsAntti A MeroFinlandJoris MichielsBelgiumCatherine MilteAustraliaBettina MittendorferUnited States of AmericaCarolyn MooreUnited States of AmericaLisa MoranAustraliaAnselmo MoriscotBrazilNaima Moustaid-MoussaUnited States of AmericaJosephia MuindiUnited States of AmericaDavid MullerFranceIsao MurakiUnited States of AmericaMariko MurataJapanAndrew James MurrayUnited KingdomKamatham Akhilender NaiduIndiaHarikumaran Nair NairIndiaAlireza NakhaeeIranForrest NielsenUnited States of AmericaJens NiklasGermanyMichalis NikolaidisGreeceItzhak NissimUnited States of AmericaLuciana NobreBrazilEstela Maria NovakBrazilEverson NunesBrazilHaruhiko OsawaJapanTone-Kari \u00d8stbyeNorwayHenrik OsterGermanyNoriyuki OuchiJapanMototsugu OyaJapanXiaoyue PanUnited States of AmericaAthanasios PapadopoulosGreeceStefan PasiakosUnited States of AmericaDominik PestaUnited States of AmericaAndreas PeterGermanyStuart PhillipsCanadaStephen PhinneyUnited States of AmericaOlivia PhungUnited States of AmericaGustavo Duarte PimentelBrazilW PogozelskiUnited States of AmericaRena PollackUnited States of AmericaGraca PortoPortugalMilton PrabuIndiaJonato PrestesBrazilResia PretoriusSouth AfricaGerald J. Prud'hommeCanadaBolin QinUnited States of AmericaJun QinUnited States of AmericaIan ReidNew ZealandScott ReismanUnited States of AmericaPatrick RensenNetherlandsMarisa RepettoArgentinaGerald RimbachGermanyUlf RiserusSwedenVladimir RitovUnited States of AmericaRoberto RivabeneItalyLee RobertsUnited KingdomHelen RocheIrelandBernardo Rodriguez-IturbeVenezuelaMichael RogersBelgiumSuzanne RogersAustraliaYan RonglinChinaOlav RooyackersSwedenJean-Max RouanetFranceIwona RudkowskaCanadaAlan RyanUnited States of AmericaCraig SaleUnited KingdomHonoo SatakeJapanEdoardo SavarinoItalyAdrienne ScheckUnited States of AmericaJochen Klaus SchubertGermanyMatthew SchubertAustraliaLai-Chu SeeTaiwanAkira SekikawaUnited States of AmericaThomas SeyfriedUnited States of AmericaAbdul Rauf ShakooriPakistanRon ShaoulIsraelSushma SharmaUnited States of AmericaJayant ShenaiUnited States of AmericaVanessa SherkUnited States of AmericaYu ShiUnited States of AmericaJohn L SievenpiperCanadaDavid SilverSingaporeAdrian SleeUnited KingdomDavid SmithUnited KingdomTiina SolakiviFinlandYOONJU SONGKorea SouthJulia SpielmannGermanyRai Ajit SrivastavaUnited States of AmericaWilliam StanleyAustraliaRinke StienstraNetherlandsJeff StoutUnited States of AmericaRyan StreeperUnited States of AmericaShi SunUnited States of AmericaIvan TancevskiAustriaMinghua TangUnited States of AmericaMotohiro TaniJapanLuc TappySwitzerlandCarla TaylorCanadaLemuel W TaylorUnited States of AmericaAndrew TeeUnited KingdomDaniel TeitelbaumUnited States of AmericaAlexander TenenbaumIsraelDiana ThomasUnited States of AmericaJency ThomasAustraliaMichael ThornerUnited States of AmericaUwe TietgeNetherlandsMarijana TodorcevicUnited KingdomRamin TolouianUnited States of AmericaSusan TorresAustraliaJanet TouUnited States of AmericaDonatella TramontanoItalyAngelo TremblayCanadaAntonia TrichopoulouGreeceAntonio ValenciaUnited States of AmericaAngela ValverdeSpainKlaske van NorrenNetherlandsKristin VerbekeBelgiumVictor VictorSpainJeff VolekUnited States of AmericaAndra WaagmeesterNetherlandsYan WangUnited States of AmericaCraig WardenUnited States of AmericaKenchi WatanabeJapanMalcolm WatfordUnited States of AmericaMartin O. WeickertUnited KingdomPeter JM WeijsNetherlandsJoEllen WelshUnited States of AmericaPaul WilliamsUnited States of AmericaDavid WrightCanadaWen-Huey WuTaiwanAngela WyseBrazilGuoliang XiaChinaHariom YadavIndiaKazumasa YamagishiUnited States of AmericaJamey YoungUnited States of AmericaMichael ZemelUnited States of AmericaShuang-Qing ZhangChinaXia ZhangChinaYong ZhuUnited States of America"}
+{"text": "The second author (MV) was incorrectly omitted from the list of authors who \"Conceived and designed the experiments.\""}
+{"text": "We and the Editorial Board acknowledge and thank all reviewers for their active participation and contribution during 2012. We greatly appreciate their dedication and behind the scenes contribution. It is largely due to their support and expertise that we have been able to publish high-standard manuscripts. We would also like to thank authors for choosing Nutrition & Metabolism and contributing their cherished work. Kadega Abdel HameedEgyptMobeen AbdollahiItalyNil\u00fcfer Acar-TekTurkeyKhosrow AdeliCanadaSoumyakanti AdhikariIndiaRobert AdlerUnited States of AmericaKolapo AjuwonUnited States of AmericaMahmood AkhtarUnited KingdomHayder Al-AubaidyAustraliaJaume AlmirallSpainRaj AminUnited States of AmericaElitsa Ananieva-StoyanovaUnited States of AmericaG. Harvey AndersonCanadaRamaroson AndriantsitohainaFranceJoshua AnthonyUnited States of AmericaVasu AppannaCanadaAmbika AshrafUnited States of AmericaArne AstrupDenmarkBela AsztalosUnited States of AmericaLynn Htet Htet AungChinaSalman AzharUnited States of AmericaAlfred AzizCanadaAlexander BachmanovUnited States of AmericaZahra BahadoranIranAhmed BakillahUnited States of AmericaSanjay Kumar BanerjeeIndiaTyler BarkerUnited States of AmericaVicente BarriosSpainElena BartkieneLithuaniaJamie BaumUnited States of AmericaMargaret BaumgartenUnited States of AmericaVic Ben-ezraUnited States of AmericaIna BergheimGermanyShoma BerkemeyerGermanyBodil BjorndalNorwayWilliam BlanerUnited States of AmericaJames BlumenthalUnited States of AmericaGiuseppe BoccuzziItalyAntonio BonettiItalyMaria Halina BorawskaPolandSherazede BouderbalaAlgeriaJeffrey BraultUnited States of AmericaLeigh BreenCanadaDespina BrianaGreeceSamantha BrooksSwedenRoland BuettnerGermanyNicholas BurdNetherlandsCraig BurkhartUnited States of AmericaMario CalommeBelgiumCraig CanapariUnited States of AmericaPatrice D. CaniBelgiumMarly CardosoBrazilJ CarsonUnited States of AmericaSubrata ChakrabartiCanadaEtienne ChalletFranceLoanda CheimBrazilHsiao-Huei ChenCanadaDong ChengUnited States of AmericaStreamson ChuaUnited States of AmericaChristelle ChuaSingaporePeter CliftonAustraliaJeffrey CohnAustraliaKate CollisonSaudi ArabiaRoberto ContiItalyMarcia CooperCanadaGiuseppe CoronaItalyPhilippe CostetFranceSheila CostfordCanadaMagna Cottini F. PassosBrazilMario CozzolinoItalyJim DailyUnited States of AmericaVincent DalboAustraliaBarbara DaoCanadaDominique DardevetFranceMarcus DarrabieUnited States of AmericaNicholas DavidsonUnited States of AmericaRini de CromNetherlandsGiovanni De PergolaItalyAndrea DeierleinUnited States of AmericaYves DeshaiesCanadaMadiha DhibiTunisiaMattia Di NunzioItalyNing DingUnited States of AmericaAlicia DoerflingerUnited States of AmericaSandra Dos SantosUnited States of AmericaDaphna DrorUnited States of AmericaMichael DubickUnited States of AmericaPierre-Henri DucluzeauFranceDavid DyckCanadaMohamed El-FarCanadaYulia ElkinaGermanyAbdalla El-MowafyEgyptFeraye Esen GurselTurkeyJoel FaintuchBrazilJenifer FentonUnited States of AmericaJohn FernstromUnited States of AmericaJudith FlanaganAustraliaElisabet ForsumSwedenJan FrankGermanyLynda FrassettoUnited States of AmericaAsmaa FritahFranceGotthold G\u00e4belGermanyNicholas GablerUnited States of AmericaMary C. GannonUnited States of AmericaPablo M Garcia-RovesSpainMaude GerbaixFranceParamita GhoshUnited States of AmericaVasileios GiaprosGreeceJavier GisbertSpainFernando Gomoll\u00f3n Garc\u00edaSpainJuan GormazChileL\u00e1szl\u00f3 G\u00f3thHungaryRejeanne GougeonCanadaBeau GreerUnited States of AmericaBart GroenNetherlandsKyle HackneyUnited States of AmericaMirko HadzijaCroatiaLena H\u00e5glinSwedenTiruneh HailemariamUnited States of AmericaRuijun HanUnited States of AmericaMarkolf HanefeldGermanyK.V.S. Hari KumarIndiaRobert HarrisUnited States of AmericaFiona HarrisonUnited States of AmericaDavid HautonUnited KingdomDaniel HayesUnited States of AmericaAshley HerdaUnited States of AmericaErnesto HernandezUnited States of AmericaErica HincksonNew ZealandSandra HirschChileZhijun HouChinaG Kees HovinghNetherlandsMiloslav HronekCzech RepublicAdela HrubyUnited States of AmericaOlivier HuckFranceFerenc HusvethHungaryDaniel HwangtUnited States of AmericaShinichi IkushiroJapanJasminka IlichUnited States of AmericaMustapha Umar ImamMalaysiaAkihiro InazuJapanHarvey IndykNew ZealandSheila InnisCanadaJahangir IqbalUnited States of AmericaAshley Simon IzzardUnited KingdomDavid JacobsUnited States of AmericaAbhay JagtapIndiaAmanda Jim\u00e9nezSpainJoby JosekuttyUnited States of AmericaAndrea JosseCanadaKim Kah HwiMalaysiaEnikoe KallayAustriaAmani KallelTunisiaSantosh KatiyarUnited States of AmericaMamdouh KedeesUnited States of AmericaMichael KeenanUnited States of AmericaDarshan KelleyUnited States of AmericaPhilip KerrAustraliaTim KeyUnited KingdomJi Yeon KimSouth KoreaByung-Eun KimUnited States of AmericaKyoung Kon KimSouth KoreaJohn KirwanUnited States of AmericaMitchell KnutsonUnited States of AmericaKaz KobaJapanS EleonoreKoehler NetherlandsSuminori KonoJapanRene KoopmanAustraliaJan KopeckyCzech RepublicZuzana KovacovaCzech RepublicHerculina Salome KrugerSouth AfricaOsman KucukTurkeyUjendra KumarCanadaOran KwonSouth KoreaSteen LarsenDenmarkEnette Larson-MeyerUnited States of AmericaJames LattimerUnited States of AmericaFabienne LaugeretteFranceFulvio LauretaniItalyMartine LavilleFrancePaul LeBlancCanadaMagalie LeducUnited States of AmericaOk-Hwan LeeSouth KoreaLeeCole LegetteUnited States of AmericaTung Ming LeungUnited States of AmericaDefa LiChinaFabio LimaBrazilJulie LinUnited States of AmericaPao-Hwa LinUnited States of AmericaWenhua LingChinaBarbara LingwoodAustraliaJu-Chi LiuTaiwanMargarita Llera-MoyaUnited States of AmericaLiu Lu ShanChinaFiona LynchUnited KingdomZuzana Macek JilkovaFranceMeenalakshmi MariappanUnited States of AmericaDaniel MarksUnited States of AmericaCyrille MaugeaisSwitzerlandGaetan MayerCanadaClaire McEvoyUnited KingdomOwen McGuinnessUnited States of AmericaSyed Musthapa MeeranIndiaRania MekaryUnited States of AmericaEdward MelansonUnited States of AmericaJorge MendozaFranceChristine MetznerGermanyNils MilmanDenmarkParvin MirmiranIranAli MoazzamiSwedenAdam MoeserUnited States of AmericaEl-Jawed MohamedKuwaitSheba Mohan KumarUnited States of AmericaAnselmo MoriscotBrazilMargaret MorrisAustraliaFabio MoscaItalyCarmen MouraBrazilNaima Moustaid-MoussaUnited States of AmericaNaofumi MukaidaJapanManuel Mu\u00f1ozSpainKentaro MurakamiJapanVikkie MustadUnited States of AmericaManar NaderEgyptSyed Nasar-AbbasAustraliaJulie-Anne NazareCanadaTakahiro NemotoJapanMonika Neuhauser-BertholdGermanyAke NilssonSwedenKatharina NimptschUnited States of AmericaWenze NiuUnited States of AmericaEthel NovelliBrazilPatricia NunesNetherlandsRima ObeidGermanyYuichi OishiJapanLawrence OlatunjiNigeriaLuqman OlayakiNigeriaPaulo OliveiraPortugalJohan OlssonSwedenThaddeus PaceUnited States of AmericaLucia PacificoItalyMariona PalouSpainJie PanChinaXiaoyue PanUnited States of AmericaDaniel Paredes-SabjaChileJuyeon ParkSouth KoreaPhani PatraUnited States of AmericaBo PeiUnited States of AmericaMichaela PekarovaCzech RepublicBotond PenkeHungarySandra PetersCanadaStephen PhinneyUnited States of AmericaJingbo PiUnited States of AmericaGustavo Duarte PimentelBrazilCarlos Hermano J. PinheiroBrazilRichard PlanellsFranceGraca PortoPortugalNebojsa PotkonjakSerbiaParinaz PoursafaIranResia PretoriusSouth AfricaSpencer ProctorCanadaJoseph ProhaskaUnited States of AmericaJeanine PrompersNetherlandsPeter PushparajUnited KingdomEoin QuinlivanUnited States of AmericaMizanur RahmanBangladeshNaga RajanIndiaBlake RasmussenUnited States of AmericaSuresh RattanDenmarkRaylene ReimerCanadaRaquel Retana-UgaldeMexicoJames RippeUnited States of AmericaManfredi RizzoItalyDenise RobertsonUnited KingdomJacques RobidouxUnited States of AmericaViviane RochaBrazilEdmond RockFranceOlav RooyackersSwedenJean-Max RouanetFranceJan RozmanGermanyElaine RushNew ZealandLekha SahaIndiaAdolfo SaiardiUnited KingdomRoc\u00edo SalcedaMexicoAbdelbaset SalehEgyptSilvia SavastanoItalySonia G Sayago AyerdiMexicoHerb SchellhornCanadaMary SchoolingHong KongMatthew SchubertUnited States of AmericaMichael ScottUnited States of AmericaFrancisca SerraSpainKartik ShankarUnited States of AmericaPengxiang SheUnited States of AmericaOleg SidorenkovNorwayRakesh SinghUnited States of AmericaBrij SinghUnited States of AmericaSom Nath SinghIndiaKshetrimayum Birla SinghIndiaJon SkorveNorwayAdrian SleeUnited KingdomZeina SoayfaneUnited States of AmericaJames SohUnited States of AmericaRosa Sol\u00e0SpainManjunath SomannavarIndiaRai Ajit SrivastavaUnited States of AmericaKen StarkCanadaChristodoulos StefanadisGreeceChristine StewartUnited States of AmericaKeith StokesUnited KingdomTatsuya SueyoshiUnited States of AmericaPapia SultanaBangladeshMichael SwarbrickAustraliaDaniel TaberUnited States of AmericaMaria TaberneroSpainYoucai TangUnited States of AmericaSimona TeccoItalyDaniel TeitelbaumUnited States of AmericaJohn ThyfaultUnited States of AmericaUwe TietgeNetherlandsAron TroenIsraelChi Tzong CherngTaiwanFelipe Vadillo-OrtegaMexicoMohammadreza VafaIranAngela ValverdeSpainFelix Van der MeerNetherlandsMarta Van LoanUnited States of AmericaYvan VandenplasBelgiumRen\u00e9e Ventura-ClapierFranceAnne-Claire vergnaudUnited KingdomCarla Maria VieiraBrazilNathalie ViguerieFranceJeff VolekUnited States of AmericaChunlin WangChinaXiangbing WangUnited States of AmericaZhao WangUnited States of AmericaFei WangUnited States of AmericaPeter JM WeijsNetherlandsStephen WeinmannUnited States of AmericaEdward WeissUnited States of AmericaAdam Whaley-ConnellUnited States of AmericaJohn WhiteUnited States of AmericaKatrina WilliamsAustraliaPattanee WinichagoonThailandOliver WitardUnited KingdomRichard WoodUnited States of AmericaShunjiang XuChinaYong XuUnited States of AmericaHariom YadavIndiaShigeru YamamotoJapanNaomi YasuiJapanZhong YeUnited States of AmericaJingdong YinChinaChundong YuChinaKyeong Ho YunKorea, SouthKhatijah YusoffMalaysiaLi YuxiuChinaVitali ZagorodnovSingaporeJun ZhangUnited States of AmericaWeili ZhangChinaXia ZhangChinaHang ZhaoUnited States of AmericaShuang-Xia ZhaoChinaDequan ZhouUnited States of AmericaRobert ZoellerUnited States of AmericaAntonio ZorzanoSpain"}
+{"text": "Child and Adolescent Psychiatry and Mental Health would like to thank all of our reviewers who have contributed to the journal in volume 7 (2013).The editors of  Gwen AdsheadUnited KingdomAlka AhujaUnited KingdomKenneth AitkenUnited KingdomCelso ArangoSpainFilip K. ArnbergSwedenPhilippe AubyFranceAgnes AytonUnited KingdomJosephine BarbaroAustraliaClaus BarkmannGermanyChristopher BarryUnited States of AmericaJessica BeattyUnited States of AmericaKatja BeckerGermanyMorton BeiserCanadaMyron BelferUnited States of AmericaFrits BoerNetherlandsMaria Teresa Botello-HarbaumUnited States of AmericaIna BovenschenGermanyHeloisa BrasilBrazilPatricia BrennanUnited States of AmericaPer Hakan BrondboNorwayAnat Brunstein KlomekUnited States of AmericaBrendan BuntingUnited KingdomLarry BurdUnited States of AmericaMarcy BursteinUnited States of AmericaLuna CentifantiUnited KingdomDavid ChambersUnited States of AmericaAlexander ChapmanCanadaDeena ChisolmUnited States of AmericaMolly Choate SummerUnited States of AmericaLucia CiciollaUnited States of AmericaPaula CloutierCanadaJudith CohenUnited States of AmericaDelphine Collin-VezinaCanadaMark ConnollyNetherlandsTrudi CooperAustraliaRobert CourtoisFranceHolger CramerGermanyZuzana Dankulincova VeselskaSlovakiaDeborah DavisUnited States of AmericaWilliam DavissUnited States of AmericaDomenico De BerardisItalyMieke DecuyperBelgiumDenis K\u00f6hlerGermanyJohn DiamondUnited States of AmericaArden DingleUnited States of AmericaRalf W. DittmannGermanyDaphna DollbergIsraelDaniel FatoriBrazilArmando FavazzaUnited States of AmericaDineke FeenstraNetherlandsMinne FekkesNetherlandsMaite FerrinUnited KingdomDavid FinkelhorUnited States of AmericaCarol FitzpatrickIrelandBacy Fleitlich-BilykBrazilPaul FrewenCanadaDaniel FungSingaporeAbbe GarciaUnited States of AmericaKathoiki GeorgiadesCanadaGrant GillettNew ZealandGrazina GintilieneLithuaniaDaniel GormanCanadaTaveeshi GuptaUnited States of AmericaLisa HarrysonSwedenNina HeinrichsGermanyMarisa HilliardUnited States of AmericaChristopher HopwoodUnited States of AmericaStephanie HullmannUnited States of AmericaTina In-AlbonGermanyVanessa JantzerGermanySandra JeeUnited States of AmericaTine K. JensenNorwayMichael KaessGermanyNiranjan KarnikUnited States of AmericaFerdinand KellerGermanySarah KellyUnited States of AmericaStephan KupferschmidSwitzerlandJoshua LangbergUnited States of AmericaKate LangleyUnited KingdomNora LeeUnited States of AmericaAnn LendrumUnited KingdomAdam LewinUnited States of AmericaStephen P. LewisCanadaGarth LippsJamaicaArnold LohausGermanyAudhild L\u00f8hreNorwayKerstin MalmbergSwedenIvo MarxGermanyJon McClellanUnited States of AmericaJohn McMillanNew ZealandLauren Miller-LewisAustraliaSuneeta MongaCanadaMegan MorenoUnited States of AmericaTally MosesUnited States of AmericaBrenda MylesUnited States of AmericaDavid NdeteiKenyaWendy NilsenUnited States of AmericaJessica NoggleUnited States of AmericaLene NyboeDenmarkCarsten ObelDenmarkIngrid Landgraff OestlieNorwayAtte OksanenFinlandThomas OlinoUnited States of AmericaYoon Phaik OoiSingaporeSylvia OswaldGermanySarah ParsonsUnited KingdomJuan PedrazaUnited States of AmericaEva PeneloSpainNoem\u00ed PeredaSpainDominic PlantUnited KingdomPaul L. PlenerGermanyMaria Cristina PorfirioItalyMaj-Britt PosserudNorwayChristian PostertGermanyErica PrentkowskiUnited States of AmericaColin PritchardUnited KingdomNicola ReavleyAustraliaMatthias ReitzleGermanyErin ReutherUnited States of AmericaJoseph ReyAustraliaMichael RobertsonAustraliaThiago RochaBrazilRachel RodgersUnited States of AmericaPaul RohdeUnited States of AmericaMichael SachseGermanyJohn SadlerUnited States of AmericaBj\u00f6rn SalomonssonSwedenCaferi Tayyar SasmazTurkeyIngo Sch\u00e4ferGermanyLeonhard SchilbachGermanySilvia SchneiderGermanyUlrike Margarete Elisabeth SchulzeGermanyDorothy SealsUnited States of AmericaMargaret SibleyUnited States of AmericaInga Dora SigfusdottirIcelandJohan SimonsBelgiumPetros SkapinakisGreeceJohn SmythiesUnited States of AmericaGottfried SpanglerGermanyAnthony SpiritoUnited States of AmericaMarlys StaudtUnited States of AmericaHans-Christoph SteinhausenDenmarkStefan StiegerAustriaLisanne StoneNetherlandsStephen SulzbacherUnited States of AmericaXiang SunUnited KingdomToshinobu TakedaJapanJessica TearneAustraliaJohn TeshimaCanadaUte ThyenGermanyMaggie ToplakCanadaCristiano Tschiedel Belem da SilvaBrazilAdriana Umana-TaylorUnited States of AmericaJulee WaldropUnited States of AmericaJason WashburnUnited States of AmericaAlan WatermanUnited States of AmericaMichelle WedigUnited States of AmericaYifeng WeiCanadaMiranda WolpertUnited KingdomBernardine WooSingaporeSandy WurteleUnited States of AmericaYi ZhengChinaTanja ZimmermannGermanyJulie ZitoUnited States of America"}
+{"text": "The editors of Molecular Neurodegeneration would like to thank all the reviewers who have contributed to the journal in Volume 7 (2012). Samer Abdul-HayUnited States of AmericaHiroyoshi ArigaJapanMarco AtzoriUnited States of AmericaCorinne Augelli-SzafranUnited States of AmericaJianxin BaoUnited States of AmericaAndrew BatemanCanadaChristine BeattieUnited States of AmericaRoland A BenderGermanyJohannes BergerAustriaChristophe BernardFranceGal BitanUnited States of AmericaStephanie BoothCanadaScott T BradyUnited States of AmericaPatrik BrundinSwedenLuigi BubaccoItalyRobert BurkeUnited States of AmericaMark BurnsUnited States of AmericaAshley BushUnited States of AmericaIna CaesarUnited States of AmericaDongming CaiUnited States of AmericaEduardo CastanoArgentinaAnthony WS ChanUnited States of AmericaRaymond Chuen-Chung ChangHong KongSally ChappellUnited KingdomFrederic CheclerFranceJeannie ChenUnited States of AmericaJohn CirritoUnited States of AmericaAbbot ClarkUnited States of AmericaCasey CookUnited States of AmericaMark CooksonUnited States of AmericaCarlos CruchagaUnited States of AmericaEva CzirrUnited States of AmericaLuciano D'AdamioUnited States of AmericaPritam DasUnited States of AmericaTed DawsonUnited States of AmericaBart De StrooperBelgiumMariely DeJesus-HernandezUnited States of AmericaPaula DesplatsUnited States of AmericaMichael DetureUnited States of AmericaMarc DiamondUnited States of AmericaChad DickeyUnited States of AmericaWenzhen DuanUnited States of AmericaMartin DuennwaldUnited States of AmericaNilufer Ertekin-TanerUnited States of AmericaSteven EstusUnited States of AmericaJian FengUnited States of AmericaJohn FryerUnited States of AmericaLi GanUnited States of AmericaTania GendronUnited States of AmericaThomas GillingwaterUnited KingdomTodd GoldeUnited States of AmericaCheng-Xin GongUnited States of AmericaGunnar GourasSwedenTakuya HayashiJapanLawrence HaywardUnited States of AmericaNiels HellingsBelgiumAdel HelmyUnited KingdomPeter Robin HiesingerUnited States of AmericaHyang-Sook HoeUnited States of AmericaElly M HolNetherlandsDavid HoltzmanUnited States of AmericaYong HuangUnited States of AmericaNibaldo InestrosaChileGrazia IsayaUnited States of AmericaDaisuke ItoJapanKurt JellingerAustriaHibiki KawamataUnited States of AmericaRakez KayedUnited States of AmericaMyeong OK KimKorea, SouthJungsu KimUnited States of AmericaAnna KingAustraliaEdward KooUnited States of AmericaMary Jo LaDuUnited States of AmericaBruce LambUnited States of AmericaCorinne LasmezasUnited States of AmericaWeidong LeUnited States of AmericaJiyeon LeeUnited States of AmericaJin-Moo LeeUnited States of AmericaMalcolm LeissringUnited States of AmericaCarla Lema TomeUnited States of AmericaCynthia LemereUnited States of AmericaEfrat LevyUnited States of AmericaYulong LiUnited States of AmericaYueming LiUnited States of AmericaXiao-Jiang LiUnited States of AmericaFrancesca-Fang LiaoUnited States of AmericaCharles LibermanUnited States of AmericaG\u00e9rard LizardFranceSeth LoveUnited KingdomKurt LucinUnited States of AmericaDavid LynchUnited States of AmericaSt\u00e9phane MartinFranceAmelia MarutleSwedenMar\u00eda Paz MarzoloChileEliezer MasliahUnited States of AmericaPamela McLeanUnited States of AmericaHeather MelroseUnited States of AmericaMakoto MichikawaJapanCarol MilliganUnited States of AmericaBrit MollenhauerGermanyKevin MorganUnited KingdomSandra MulderNetherlandsAlysson MuotriUnited States of AmericaNobuki NakanishiUnited States of AmericaRobert NickellsUnited States of AmericaHenrietta NielsenUnited States of AmericaTomoyuki NishizakiJapanRalph A NixonUnited States of AmericaAnders OlsenDenmarkKaren O'MalleyUnited States of AmericaKalipada PahanUnited States of AmericaFrancesc PalauSpainUdai PandeyUnited States of AmericaAnnalisa PastoreUnited KingdomKush PaulUnited States of AmericaRobia PautlerUnited States of AmericaLeonard PetrucelliUnited States of AmericaErik PorteliusSwedenDomenico PraticoUnited States of AmericaMarguerite PriorUnited States of AmericaLawrence RajendranSwitzerlandTomi Rantam\u00e4kiFinlandG William RebeckUnited States of AmericaChristiane Richter-LandsbergGermanyRoberta RigolioItalyJustin RogersUnited States of AmericaTerrone RosenberryUnited States of AmericaOwen RossUnited States of AmericaKumar SambamurtiUnited States of AmericaWiep ScheperNetherlandsClemens ScherzerUnited States of AmericaYong ShenUnited States of AmericaJie ShenUnited States of AmericaMahendra SinghIndiaIoannis SotiropoulosPortugalNuno SousaPortugalNadia StefanovaAustriaJamuna SubramaniamIndiaKeizo SugayaJapanTao SunUnited States of AmericaLeon TaiUnited States of AmericaHaruo TakeshitaJapanDavide TampelliniSwedenZhiqun TanUnited States of AmericaAlexey TerskikhUnited States of AmericaGiuseppina TescoUnited States of AmericaRoberto TestiItalyDietmar ThalGermanyGopal ThinakaranUnited States of AmericaMathias ToftNorwayTaisuke TomitaJapanShichun TuUnited States of AmericaBrigita UrbancUnited States of AmericaLudo Van den BoschBelgiumKlaus Van LeyenUnited States of AmericaRobert VassarUnited States of AmericaMarcel VerbeekNetherlandsYoshinao WadaJapanJochen WalterGermanyBaiping WangUnited States of AmericaXin WangUnited States of AmericaEdwin WeeberUnited States of AmericaAndrew WestUnited States of AmericaChristian WiderSwitzerlandMicha WilhelmusNetherlandsMichael WillemGermanyJuergen WinklerGermanyPhilip WongUnited States of AmericaShaohua XuUnited States of AmericaXuemin XuUnited States of AmericaZuoshang XuUnited States of AmericaShang-Hsun YangTaiwanX William YangUnited States of AmericaIkuru YazawaJapanMidori YenariUnited States of AmericaCelina ZerbinattiUnited States of AmericaHenrik ZetterbergSwedenJianhua ZhangUnited States of AmericaYongjie ZhangUnited States of AmericaYun-wu ZhangChinaZhuohua ZhangChinaHui ZhengUnited States of AmericaXiongwei ZhuUnited States of AmericaHaining ZhuUnited States of America"}
+{"text": "Journal of Ovarian Research would like to thank all of our reviewers who have contributed to the journal in volume 5 (2012).The editors of  David AbbottUnited States of AmericaNermeen Abdel FattahEgyptNuzhat AhmedAustraliaAdriana AlbiniItalyWinfried AmoakuUnited KingdomSatoshi AnaiJapanRitu AnejaUnited States of AmericaSharmila BapatIndiaSusan BellisUnited States of AmericaGiuseppe BenagianoSwitzerlandDeepa BhartiyaIndiaJames Derek BrentonUnited KingdomMolly BrewerUnited States of AmericaLeif BungumSwedenRalf ButzowFinlandKaren ChanHong KongSubhash ChauhanUnited States of AmericaDavid CovellUnited States of AmericaCostantino Di CarloItalyFabio FacchinettiItalyAngela FalboItalyWarren FosterCanadaLuca GianaroliItalyDigant GuptaUnited States of AmericaMatthew HallUnited States of AmericaChi-Chen HongUnited States of AmericaPatricia HoyerUnited States of AmericaHeFeng HuangChinaKaisa HuhtinenFinlandVenkatakrishna JalaUnited States of AmericaKannamannadiar JayaprakasanUnited KingdomSelvendiran KaruppaiyahUnited States of AmericaHidetaka KatabuchiJapanJaehoon KimSouth KoreaTerumi Kohwi-ShigematsuUnited States of AmericaIkuo KonishiJapanPamela KreegerUnited States of AmericaDeepak KumarUnited States of AmericaMiki KushimaJapanAntonio La MarcaItalyGiovanni Battista La SalaItalyHernan LaraChileDjuro MacutSerbiaAntonis MakrigiannakisGreeceMassimo MannoItalyHelen MasonUnited KingdomRichard MooreUnited States of AmericaKenneth NephewUnited States of AmericaCeana NezhatUnited States of AmericaFrancesco OrioItalySandra OrsulicUnited States of AmericaRaoul OrvietoIsraelSiva Kumar PanguluriUnited States of AmericaManish PatankarUnited States of AmericaChun PengCanadaChristine PlogerBrazilMeeta PradhanUnited KingdomEric ProssnitzUnited States of AmericaJie QiaoChinaS\u00e9rgio R SoaresSpainTilman RachnerGermanyMaria Rosaria RaspolliniItalyMariusz RatajczakUnited States of AmericaSuman RiceUnited KingdomJoanne RichardsUnited States of AmericaRajeev SamantUnited States of AmericaDorota SanockaPolandXavier SantamariaSpainJung Ho ShinSouth KoreaMaria ShoshanSwedenMakio ShozuJapanViji ShridharUnited States of AmericaYimin ShuUnited States of AmericaAjay SinghUnited States of AmericaEdgardo SomiglianaItalyPoli Mara SpritzerBrazilOleh StasykUkraineXiao-Feng SunSwedenOya TopalogluTurkeyFabian TrillschGermanySwamy TripuraniUnited States of AmericaToshio TsubotaJapanIrma Virant-KlunSloveniaWeihua WangUnited States of AmericaXuefeng XiaChinaLi YaliChinaPumin ZhangUnited States of AmericaXiaodong ZhouUnited States of America"}
+{"text": "The editors of the Journal of Biological Engineering thank all our reviewers who have contributed to the journal in volume 5 (2011) and volume 6 (2012). Stephen AbedonUnited States of AmericaYagut AllahverdiyevaFinlandJohn AndersonUnited States of AmericaJames BaishUnited States of AmericaRekha BalachandranUnited States of AmericaGeoff BaldwinUnited KingdomIpsita BanerjeeUnited States of AmericaPhilip BarnesUnited States of AmericaCarl BattUnited States of AmericaTravis BayerUnited KingdomDanielle BellmerUnited States of AmericaMatthew BennettUnited States of AmericaLeonidas BlerisUnited States of AmericaNils BluthgenGermanyFrank BosseGermanyPierre-Yves BourguignonGermanyKevin BraeckmansBelgiumGail BrionUnited States of AmericaEric BrouzesUnited States of AmericaSteven BrownUnited States of AmericaDennis BrownUnited States of AmericaA. Malcolm CampbellUnited States of AmericaLisa CasanovaUnited States of AmericaKen ChanHong KongDeepak ChandranUnited States of AmericaChih ChienTaiwanWei-Chun ChinUnited States of AmericaHae Woon ChoiSouth KoreaJin-Woo ChoiUnited States of AmericaPatrick CirinoUnited States of AmericaAndrew CoatesUnited KingdomRory CoffeyIrelandTeodoro C\u00f3rdovaMexicoSophie Demoustier-ChampagneBelgiumDouglas DensmoreUnited States of AmericaPavel DibrovCanadaVera DoroshenkoRussian FederationMary DunlopUnited States of AmericaMark EitemanUnited States of AmericaTom EllisUnited KingdomDrew EndyUnited States of AmericaDaniel EuhusUnited States of AmericaStephen FongUnited States of AmericaPaul FreemontUnited KingdomCinzia FreschiItalySteve FurberUnited KingdomMunia GanguliIndiaMax GarzonUnited States of AmericaEric GaucherUnited States of AmericaR. Christopher GeigerUnited States of AmericaCharles GersbachUnited States of AmericaGeorge GilliesUnited States of AmericaDavid GrahamUnited States of AmericaHaigang GuUnited States of AmericaMark HaidekkerUnited States of AmericaXiaoming HeUnited States of AmericaNathan HillsonUnited States of AmericaChristie HowardUnited States of AmericaShyh-shin HwangTaiwanLorens ImhofGermanyPieter JacobsUnited States of AmericaMichael JewettUnited States of AmericaPhilip JohnsonUnited States of AmericaPatrik Raymond JonesFinlandHan Jong-InSouth KoreaEmil P KartalovUnited States of AmericaRobert KellyUnited States of AmericaJungkyu KimUnited States of AmericaMattheos KoffasUnited States of AmericaWerner JH KoopmanNetherlandsPamela KreegerUnited States of AmericaNatalie KuldellUnited States of AmericaS. C. KunduIndiaSoonjo KwonUnited States of AmericaThomas LandrainFranceHelene LangevinUnited States of AmericaMichelle LaPlacaUnited States of AmericaGaetan LarocheCanadaSang Yup LeeSouth KoreaJames LeeUnited States of AmericaStephen LeeUnited States of AmericaPetros LenasSpainYin LiChinaYanna LiangUnited States of AmericaMarybeth LimaUnited States of AmericaJian LinUnited States of AmericaTom LindstromSwedenAndreas LinningerUnited States of AmericaTim LuUnited States of AmericaToshinari MaedaJapanAbdul MannanPakistanLeidong MaoUnited States of AmericaMario Andrea MarchisioSwitzerlandIan MarisonIrelandJose Luis Martinez-CarrilloMexicoMarty MatlockUnited States of AmericaRoberto MazzoliItalyKara McCloskeyUnited States of AmericaTodd MonroeUnited States of AmericaSuchetana MukhopadhyayUnited States of AmericaChristine MulveyUnited States of AmericaPablo I NikelArgentinaGoutam NistalaUnited States of AmericaVincent NoireauxUnited States of AmericaAngela PannierUnited States of AmericaJin-Byung ParkSouth KoreaDaniel ParkUnited States of AmericaTom PearsonUnited States of AmericaKristala PratherUnited States of AmericaMichael RaghunathSingaporeAnn RajnicekUnited KingdomRamaraja RamasamyUnited States of AmericaBalaji RaoUnited States of AmericaJakob ReiserUnited States of AmericaTom RichardUnited States of AmericaMark RileyUnited States of AmericaPhillip RobertsUnited States of AmericaKenneth RobinsonUnited States of AmericaRoberto RodriguezMexicoJeremy RogersUnited States of AmericaJennifer RossUnited States of AmericaRoger RuanUnited States of AmericaArmenio SantosBrazilFrank SargentUnited KingdomRyan SengerUnited States of AmericaRakesh SharmaIndiaReshma ShettyUnited States of AmericaPamela SilverUnited States of AmericaIstvan SiroHungarySean SleightUnited States of AmericaChinmay SomanUnited States of AmericaHao SongSingaporeOliver SpadiutAustriaFriedrich SriencUnited States of AmericaGene StevensUnited States of AmericaMichael Storrie-LombardiUnited States of AmericaCharles SuhUnited States of AmericaKahp-Yang SuhSouth KoreaLianhong SunUnited States of AmericaDong SunUnited States of AmericaJeffrey TaborUnited States of AmericaMaryam TabrizianCanadaRalf TakorsGermanyTimothy TaylorUnited States of AmericaGlynn TillmanUnited States of AmericaGeorge TsibidisGreeceAndrey TurchinovichGermanySofie Van Den HendeBelgiumBrahm VermaUnited States of AmericaJunwei WangChinaWilfried WeberGermanyLisa WilkenUnited States of AmericaHai YanChinaHabibollah YounesiIranJiajia YuanAustraliaKechun ZhangUnited States of AmericaShusheng ZhangChina"}
+{"text": "Molecular Cytogenetics would like to thank all our reviewers who have contributed to the journal in volume 6 (2013).The Editors of  Dilek AktasTurkeyMara AlmeidaBrazilGilda Alves BrownBrazilBonnet-Garnier Am\u00e9lieFranceNicholas AnagnouGreeceRouben AroutiounianArmeniaEgbert BakkerNetherlandsIstvan BaloghHungaryJohn BarberUnited KingdomLuca BartoliniUnited States of AmericaDenise BatistaUnited States of AmericaDavid BettsIrelandSamarth BhattUnited States of AmericaLukrecija BrecevicCroatiaJoern BullerdiekGermanyJosefa CabreroSpainJuan Pedro CamachoSpainJordi CampsSpainZhong ChenChinaSau CheungUnited States of AmericaMarcelo CioffiBrazilLinda CooleyUnited States of AmericaZunyan DaiUnited States of AmericaJosef DavidssonSwedenEdivaldo de OliveiraBrazilJan DiblikCzech RepublicPeter DuesbergUnited States of AmericaEmel ErgulTurkeySusan ErnstUnited States of AmericaEliana FeldbergBrazilAmanda FigueiredoBrazilManuel Garrido-RamosSpainDavid GenevieveFranceAd Geurts van KesselNetherlandsGabriele Gillessen-KaesbachGermanyRastko GolouhSloveniaUte GrasshoffGermanyFranz GruberNorwayRoberta GuilhermeBrazilOskar HaasAustriaClaudia HaferlachGermanyJulia HentschelGermanyHenrik Hjorth-HansenNorwayGalina HovhannisyanArmeniaIvan IourovRussiaVadym KavsanUkraineElena KirillovaRussiaNadezda KosyakovaGermanyPetr KuglikCzech RepublicLeslie KulikowskiBrazilHuabing LiUnited States of AmericaPeining LiUnited States of AmericaCaroline Mackie OgilvieUnited KingdomChloe MakHong KongFrantisek MarecCzech RepublicDom McMullanUnited KingdomMaria Isabel MelaragnoBrazilClemens MellinkNetherlandsAurelia Meloni-EhrigUnited States of AmericaMartina MerkasCroatiaHasmik MkrtchyanArmeniaWagner MolinaBrazilSantiago MunneUnited States of AmericaVeera Sekaran NadarajanMalaysiaIndrajit NandaGermanyFelix NiggliSwitzerlandYi NingUnited States of AmericaBeata NowakowskaBelgiumNobuhiko OkamotoJapanEttore OlmoItalyMoneeb OthmanGermanyGeorge PatrinosGreeceLorenza PecciariniItalyWilliam QuinnUnited States of AmericaPetr R\u00e1bCzech RepublicLaureana RebordinosSpainHoracio RiveraMexicoElena RossiItalyNikolai RubtsovRussiaAlbert SchinzelSwitzerlandGeorge SeidelUnited States of AmericaYiping ShenUnited States of AmericaFrenny ShethIndiaMarsha SpeevakCanadaPawel StankiewiczUnited States of AmericaKaroly SzuhaiNetherlandsAlan ThornhillUnited KingdomNathan TreffUnited States of AmericaVladimir TrifonovRussiaRaymond TubbsUnited States of AmericaHilde Van EschBelgiumPeter VandenbergheBelgiumFran\u00e7ois VialardFranceSvetlana VorsanovaRussiaYang WangUnited States of AmericaElzbieta Warchalowska-SliwaPolandW. Steven WardUnited States of AmericaJingly WeierUnited States of AmericaUlli WeierUnited States of AmericaAnja WeiseGermanyMarjolein WillemsenNetherlandsJasen WiseUnited States of America"}
+{"text": "Journal of Hematology & Oncology would like to thank all our reviewers who have contributed to the journal in Volume 5 (2012).The editor of  Yasuhito AbeJapanLawrence AfrinUnited States of AmericaHaidar AklBelgiumHaifa Kathrin Al-AliGermanyIna AmarilloUnited States of AmericaBorje AnderssonUnited States of AmericaKelly AndringaUnited States of AmericaEmmanuel AntonarakisUnited States of AmericaThomas AparicioFranceFumio AraiJapanDavid AratenUnited States of AmericaJane ArmstrongUnited KingdomUlrike BacherGermanyOlga BalagueNetherlandsSanjay BansalUnited States of AmericaFrederic BaronBelgiumGiovanni BarosiItalyJohn BarrettUnited States of AmericaSurinder BatraUnited States of AmericaPaul BeckettUnited KingdomTanios Bekaii-SaabUnited States of AmericaAsim F. BelgaumiSaudi ArabiaFrancis BellocFranceFrank BergerGermanyOlivier BernardFranceDidier BouscaryFranceMassimo BrecciaItalyAnsgar Br\u00fcningGermanyAlan BurnettUnited KingdomGianni CazzanigaItalyJan CernyUnited States of AmericaXiu-bao ChangUnited States of AmericaDavid Z ChangUnited States of AmericaNelson ChaoUnited States of AmericaMingyi ChenUnited States of AmericaJen-Shi ChenTaiwanYeu-Chin ChenTaiwanliguang chenUnited States of AmericaJen-Yang ChenTaiwanChong ChenUnited States of AmericaCS ChimChinaBertrand CoiffierFranceEnrique ColadoSpainBrian CurtisUnited States of AmericaZunyan DaiUnited States of AmericaMaria DelioukinaUnited States of AmericaEnrico DerenziniItalyArjan DiepstraNetherlandsJoshua DoloffUnited States of AmericaJia-Hong DongChinaJeanette DoorduijnNetherlandsElias DrakosGreeceMarc EarlUnited States of AmericaThomas EfferthGermanyAvraham EisbruchUnited States of AmericaAndreas EisenreichGermanyEvgeniy EruslanovUnited States of AmericaEmiliano FabianiItalyFranca FagioliItalyHugo FernandezUnited States of AmericaWilliam FiggUnited States of AmericaAlessandro FornariItalyClaudio FozzaItalyHui FuUnited States of AmericaSeiji FukudaJapanMuhammad FurqanUnited States of AmericaApar Kishor GantiUnited States of AmericaJavid GazievItalyUlrich GermingGermanyRomi GhoseUnited States of AmericaSwati GoelUnited States of AmericaGerard GrosveldUnited States of AmericaJian GuanUnited States of AmericaMilena GusellaItalyClaudia HaferlachGermanyAnne M.M.J. HagemeijerBelgiumJean-Luc HarousseauFranceMoustapha HassanSwedenShigetsugu HatakeyamaJapanGeorgia HatzivassiliouUnited States of AmericaGrzegorz HelbigPolandNobuko HijiyaUnited States of AmericaHeather HimburgUnited States of AmericaJessica HochbergUnited States of AmericaAkira HorikoshiJapanKatsuyuki HottaJapanJian HouChinaChung-Tsen HsuehUnited States of AmericaZhenbo HuUnited States of AmericaXi Chun HuChinaRuoqing HuangUnited States of AmericaXuan HuangUnited States of AmericaYao HuangUnited States of AmericaTiangui HuangUnited States of Americaklaudia hunterUnited States of AmericaYasuo ImaiJapanEsma IsenovicUnited States of AmericaMartin J\u00e4derstenSwedenSiegfried JanzUnited States of AmericaElizabeth JefferyUnited States of AmericaDavid JohnsonUnited KingdomEdgar JostGermanyLawrence JungUnited States of AmericaMarketa KalinovaCzech RepublicRotem KarniIsraelFriederike KeatingUnited States of AmericaSantosh KesariUnited States of AmericaWon Seog KimKorea SouthShinya KimuraJapanUlf KleinUnited States of AmericaDong Hoe KooKorea SouthIoannis KotsianidisGreeceRalf KueppersGermanyNaoki KuniiJapanMei-Ling KuoUnited States of AmericaAndrey KuznetsovAustriaYok Lam KwongChinaMichael La QuagliaUnited States of AmericaJatinder LambaUnited States of AmericaGurpreet LambaUnited States of AmericaRichard LarsonUnited States of AmericaTahir LatifUnited States of AmericaUlrich LehmannGermanyCarlos LeonCanadaYangqiu LiChinaLei LiUnited States of AmericaDavid LinchUnited KingdomQi-Fa LiuChinaBei LiuUnited States of AmericaZach liuUnited States of AmericaPaolo LunghiItalyYupo MaUnited States of AmericaNicol MacphersonCanadaIgnazio MajolinoItalyEsther ManorIsraelMaurizio MargaglioneItalyAlberto Maria MartelliItalyGiovanni MartinelliItalyOlivia MartinezUnited States of AmericaMelanie McConnellNew ZealandJason MerkerUnited States of AmericaYutaka MidorikawaJapanJoseph MikhaelUnited States of AmericaPeppino MirabelliItalyRoberto MirandaUnited States of AmericaJun MiyauchiJapanYasushi MiyazakiJapanHiroyuki MomotaJapanPatrick S. MooreUnited States of AmericaMichael MorseUnited States of AmericaToru MotokuraJapanMarek MrazCzech RepublicArend MulderNetherlandsAntonino MusolinoItalyMarta MuzioItalyKyriaki MystakidouGreeceYona NadirIsraelShotaro NakamuraJapanSteffan NawrockiUnited States of AmericaGustav NilsonneSwedenMaria D. OderoSpainShouichi OhgaJapanTakayuki OhguriJapanSeiichi OkabeJapanBarry O'KeefeUnited States of AmericaYasuhiro OkiUnited States of AmericaNicolas OrtonneFranceGiuseppe PalumboItalyPing-Ying PanUnited States of AmericaJen-Jung PanUnited States of AmericaSun ParkKorea SouthIn Hae ParkKorea SouthWendy ParkerAustraliaSteven PavleticUnited States of AmericaMarc PeetersBelgiumAlex PhilchenkovUkrainePier Paolo PiccalugaItalyJosef PrchalUnited States of AmericaChristoph R\u00f6lligGermanyPeter ReimerGermanyRuibao RenUnited States of AmericaThomas RenneSwedenCarmelo RizzariItalyVivek RoyUnited States of AmericaSoya SamUnited States of AmericaBirgitta SanderSwedenRafael Santana DavilaUnited States of AmericaDaniele SantiniItalyMarit SaunesNorwayAkira SawakiJapanPeter SayeskiUnited States of AmericaDevin SchellenbergCanadaHideharu SekineJapanLijian ShaoUnited States of AmericaNima SharifiUnited States of AmericaAubie ShawUnited States of AmericaChangxian ShenUnited States of AmericaAdawiyah Suriza ShuibMalaysiaSaid SifUnited States of AmericaNicola SilvestrisItalySusan SlovinUnited States of AmericaGiedre SmailyteLithuaniaEric SolaryFranceWenru SongUnited States of AmericaMartin SosUnited States of AmericaWolfgang SperrAustriaKeith StewartUnited States of AmericaJan StyczynskiPolandWeijing SunUnited States of AmericaKazutaka SunamiJapanMonalisa SurCanadaJulien TaiebFranceJerome TamburiniFranceAngela TanAustraliaSusan ThorpeUnited KingdomKensei TobinaiJapanMauro TognonItalyTomomi ToubaiUnited States of AmericaAdrian TrifaRomaniaChing-Hwa TsaiTaiwanWilliam TseUnited States of AmericaSaad UsmaniUnited States of AmericaRemco van DoornNetherlandsAmit VermaUnited States of AmericaLuis VillelaMexicoEdmund WallerUnited States of AmericaNaomi WalshIrelandJianxiang WangChinaSa WangUnited States of AmericaHongxia WangChinaJing WangChinaGuoqing WeiChinaJoEllen WelshUnited States of AmericaMeir WetzlerUnited States of AmericaAlice WongHong KongDavid WongUnited States of AmericaNina WorelAustriaKongming WuUnited States of AmericaJie WuUnited States of AmericaYu-Chung WuTaiwanYong-Bing XiangChinaKang XiaonanChinaDazhong XuUnited States of AmericaZhi XuUnited States of AmericaMingjiang XuUnited States of AmericaYutaka YamamotoJapanTakahiro YamauchiJapanMasamitsu YanadaJapanXiaoming YangUnited States of AmericaYibin YangUnited States of AmericaDavid YangUnited States of AmericaXiao-Feng YangUnited States of AmericaYong-Gang YaoChinaJeffrey YeUnited States of AmericaChih-Ching YehTaiwanTzu-Chen YenTaiwanJian YuUnited States of AmericaBo YuanJapanYuan YuanUnited States of AmericaZhao-Chong ZengChinaHongyong ZhangUnited States of AmericaHua ZhangChinaZhen ZhaoUnited States of AmericaZhizhuang Joe ZhaoUnited States of AmericaXianfeng ZhaoUnited States of AmericaXiaoyong ZhengUnited States of AmericaYunli ZhouUnited States of AmericaPing ZhuChinaPier Luigi ZinzaniItalyAxel zur HausenNetherlands"}
+{"text": "International Journal of Pediatric Endocrinology would like to thank all our reviewers who have contributed to the journal in Volume 2013 (2013).The Editors of  Paul Benitez AguirreAustraliaCarolyn BondyUnited States of AmericaRa\u00fal CalzadaMexicoSusan CarlsonUnited States of AmericaAaron CarrelUnited States of AmericaFrancesco ChiarelliItalyPeter ClaytonUnited KingdomLouise CominatoBrazilCathrine ConstantacosUnited States of AmericaLinda DiMeglioUnited States of AmericaErica EugsterUnited States of AmericaCheryl FryarUnited States of AmericaJohn FuquaUnited States of AmericaMichael HallerUnited States of AmericaMelissa HamUnited States of AmericaAdam HittelmanUnited States of AmericaGeorge JehaUnited States of AmericaGudmundur JohannssonSwedenPaul KaplowitzUnited States of AmericaAnna Lauber-BiasonSwitzerlandPeter LeeUnited States of AmericaJohannes LemkeSwitzerlandFrancesco MassartItalyNelly MaurasUnited States of AmericaMark MolitchUnited States of AmericaJohn ParksUnited States of AmericaEdward ReiterUnited States of AmericaRon RosenfeldUnited States of AmericaRobert RosenfieldUnited States of AmericaPaul SaengerUnited States of AmericaDorothy ShulmanUnited States of AmericaJill SimmonsUnited States of AmericaH. Peter SoyerAustraliaPaul ThorntonUnited States of AmericaAmy WisniewskiUnited States of America"}
+{"text": "Annals of General Psychiatry would like to thank all of our reviewers who have contributed to the journal in volume 11 (2012).The editors of  Nobuhito AbeJapanTasnime AkbaralyFranceRamona AlaggiaCanadaUmberto AlbertItalyWilliam ApfeldorfUnited States of AmericaJean-Michel AzorinFranceDaryl BainbridgeCanadaThomas BarnesUnited KingdomRobert BermanUnited States of AmericaCarlo BlancoUnited States of AmericaJulia BoyleUnited KingdomDavid BrentUnited States of AmericaEdson Sherwood BrownUnited States of AmericaLisa BuchyCanadaOscar BuksteinUnited States of AmericaMonika BullingerGermanyRosetta CardoneItalyFranco CavalloItalyKa Fai ChungHong KongYoung-Chul ChungSouth KoreaLars ClemmensenDenmarkCarla CrespoPortugalRudi CrncecAustraliaSerdar DursunCanadaChad EbesutaniUnited States of AmericaMarc-Andreas EdelGermanyDean ElbeCanadaBetina ElfvingDenmarkPeter EnticottAustraliaCarlo FaravelliItalyGiovanni FavaItalyMaria Luisa FigueiraPortugalKishore GaddeUnited States of AmericaBeata Gali\u0144ska-SkokPolandMarta GhisiItalyGeorge GiannakopoulosGreeceMichael GitlinUnited States of AmericaRenee GoodwinUnited States of AmericaDaniela GoursandBrazilPhilip HarveyUnited States of AmericaKotaro HattaJapanNegoro HidekiJapanQin JiangUnited States of AmericaHironobu KatsuyamaJapanIkuko KishidaJapanMichael KoelchGermanyLeena KoivusiltaFinlandDavid LevittUnited States of AmericaMatthias LiechtiSwitzerlandKamala LondonUnited States of AmericaAntonio MaduenoSpainArja MainioFinlandMario MajItalyFerenc MartenyiAustriaAlmudena MartorellSpainValentin MbekouCanadaChristina McCraeUnited States of AmericaMario MendezUnited States of AmericaScott MoellerUnited States of AmericaSomaia MohamedUnited States of AmericaBrent MooreUnited States of AmericaGunnar MorkenNorwayMartin MumenthalerUnited States of AmericaJackob NajmanAustraliaHiroyuki NakamuraJapanTomohiro NakaoJapanUrs NaterGermanyDavid NeubauerUnited States of AmericaTakashi OkadaJapanAndreas PavalkisCyprusVassilis PavlopoulosGreeceJuan D Pedrera-ZamoranoSpainLeah PhillipsCanadaMaurizio PompiliItalyDina PopovicSpainRajeev RamchandUnited States of AmericaSathyanarayana T S RaoIndiaRiju RayBelgiumZoltan RihmerHungaryNicolas RohlederUnited States of AmericaSoledad RomeroSpainJanusz RybakowskiPolandSeija SandbergUnited KingdomJunji SaruwatariJapanSatoshi SasakiJapanPhilip SeemanCanadaKang SimSingaporeRhonda SmallAustraliaCheryl SoHong KongErkki SoiniFinlandJan SorensenDenmarkJustin SpringerUnited States of AmericaMary StewartUnited KingdomYoshihiro TadoriJapanHidehiko TakahashiJapanMichihiro TakahashiJapanTakeshi TeraoJapanAnne ThorupDenmarkAlbina TorresBrazilChi-Chuan WangTaiwanJanet WilliamsUnited States of AmericaLutz WittmannSwitzerlandKlaus W\u00f6lflingGermanyGuohua XiaUnited States of AmericaHakuei YamashitaJapanToshiyuki YasuiJapanDimitrios ZavrasGreece"}
+{"text": "Systematic Reviews has been blessed by the support of highly-qualified peer reviewers, and the Editors-in-Chief, David Moher, Lesley Stewart and Paul Shekelle, and staff of the journal would like to show their appreciation by thanking the following for their invaluable assistance with review of manuscripts for the journal in Volume 2 (2013).A peer-reviewed journal would not survive without the generous time and insightful comments of the reviewers, whose efforts often go unrecognized.  Ahmed Abou-SettaEgyptTony AdesUnited KingdomJesmin AntonyCanadaLuis F AzevedoPortugalEthan BalkUnited States of AmericaJoel BamfordUnited States of AmericaEmmanuelle BelangerCanadaJulia BettsUnited KingdomLaura BonnettUnited KingdomAndrew BoothUnited KingdomKenneth BrownUnited States of AmericaBrad CarlinUnited States of AmericaKathleen CarlsonUnited States of AmericaChris CarswellNew ZealandAnna ChaimaniGreeceStephanie ChangUnited States of AmericaAlexander ClarkCanadaRyan CollerUnited States of AmericaGary CooneyUnited KingdomEsther CorenUnited KingdomMiranda CumpstonAustraliaIsabel De SalisUnited KingdomDeclan DevaneIrelandSanket DhruvaUnited States of AmericaSofia DiasUnited KingdomMarjolein DielemanNetherlandsJanine DretzkeUnited KingdomJo DumvilleUnited KingdomKerry DwanUnited KingdomTarig ElraiyahUnited States of AmericaJonathan EmbersonUnited KingdomZbys FedorowiczBahrainFinola FerryUnited KingdomElizabeth FitzpatrickCanadaAlan FleischerUnited States of AmericaNathan FordSwitzerlandRuth FoxleeUnited KingdomConstance FungUnited States of AmericaRohan GanguliCanadaChantelle GarrittyCanadaLaura GaudetCanadaJean-Francois GehannoFranceMichael GoldsteinUnited States of AmericaJoanne GreenhalghUnited KingdomUlrich GrouvenGermanyShirin HeidariSwitzerlandMorag HeirsUnited KingdomSusanne HempelUnited States of AmericaDavid HowellsAustraliaCarys JonesUnited KingdomKathryn KaiserUnited States of AmericaDevan KansagaraUnited States of AmericaJamie KirkhamUnited KingdomWerner KulpGermanyTom LangUnited States of AmericaDean LanganUnited KingdomToby LassersonUnited KingdomJoseph LauUnited States of AmericaMariska M.G. LeeflangNetherlandsAlexis LlewellynUnited KingdomMargaret MaglioneUnited States of AmericaSabine MaguireUnited KingdomNorman MarksUnited States of AmericaRachel MarshallUnited KingdomHomero MartinezUnited States of AmericaJessie McGowanCanadaNick MeaderUnited KingdomJoerg J. MeerpohlGermanyEdward MillsCanadaJens MinnerupGermanyDavid MoherCanadaDavid MooreUnited KingdomReg MorrisUnited KingdomAndra MorrisonCanadaCynthia MulrowUnited States of AmericaSarah NolanUnited KingdomCharles NormandIrelandSusan L. NorrisUnited States of AmericaMaya O'NeilUnited States of AmericaKaat PeerenboomBelgiumFrank PeinemannGermanyNicola PetrucciItalyMark PetticrewUnited KingdomBob PhillipsUnited KingdomWilfred PigeonUnited States of AmericaShalea PiteauCanadaRobert PlattCanadaMarcel PostNetherlandsMalcolm PriceUnited KingdomDavid RileyUnited States of AmericaMark RodgersUnited KingdomGerta R\u00fcckerGermanyAudrey SaftlasUnited States of AmericaMargaret SampsonCanadaHolger Sch\u00fcnemannUnited States of AmericaRob ScholtenNetherlandsGeorg M. SchuetzGermanyPaul ShekelleUnited States of AmericaJonathan ShepherdUnited KingdomMark SimmondsUnited KingdomBecky SkidmoreCanadaNuno SousaPortugalMai StaffordUnited KingdomJohann SteurerSwitzerlandAdrienne StevensCanadaGavin StewartUnited KingdomXin SunCanadaKarl SweeneyIrelandYemisi TakwoingiUnited KingdomBritta TendalDenmarkDavid ToveyUnited KingdomLyndal TrevenaAustraliaGuy TsafnatAustraliaAlexander TsertsvadzeCanadaWynanda Van EnstNetherlandsArianne VerhagenNetherlandsChristiane VoisinUnited States of AmericaVivian WelchCanadaEmma WelshUnited KingdomShi Wu WenCanadaMarie Elaine WestwoodUnited KingdomDonna WhiteUnited States of AmericaPenny WhitingUnited KingdomSimon WieserSwitzerlandKath WrightUnited KingdomWei-Feng YuChinaBabalwa ZaniSouth AfricaPaula ZieglerUnited States of America"}
+{"text": "Retrovirology would like to sincerely thank the following for giving their time and expertise to review manuscripts for the journal in 2013. Their support for the journal is greatly appreciated. Truus AbbinkUnited KingdomCatherine AdamsonUnited KingdomMarylyn M. AddoUnited States of AmericaPhilippe Vicente AfonsoFranceSunil AhujaUnited States of AmericaChristopher AikenUnited States of AmericaHirofumi AkariJapanJohn AlbinUnited States of AmericaJose AlcamiSpainGhalib AlkhatibUnited States of AmericaNeil AlmondUnited KingdomMarcus AltfeldUnited States of AmericaZandrea AmbroseUnited States of AmericaEmma AndersonUnited KingdomTakashi AngataTaiwanNathalie ArhelFranceJames ArthosUnited States of AmericaEric ArtsUnited States of AmericaEran BacharachIsraelJonathan BallUnited KingdomCharles BanghamUnited KingdomNorbert BannertGermanyMatjaz BarboricFinlandFrancis BarinFranceAndreas BaurGermanyAli BazarbachiLebanonKaren BeemonUnited States of AmericaBrendan BellCanadaSerge BenichouFranceMonsef BenkiraneFranceYamina BennasserFranceBen BerkhoutNetherlandsClarisse Berlioz-TorrentFranceNeil BerryUnited KingdomFrancoise BexBelgiumJames BinleyUnited States of AmericaFabien BlanchetFranceJoel BlanksonUnited States of AmericaJonas BlombergSwedenRobert BlumenthalUnited States of AmericaMorgane BomselFranceKathleen Boris-LawrieUnited States of AmericaPersephone BorrowUnited KingdomFadila BouamrUnited States of AmericaSimon BrackenridgeUnited KingdomMartine BraibantFranceDenys BrandFranceBernard BransonUnited States of AmericaBluma BrennerCanadaMark BrockmanCanadaJames BruceUnited States of AmericaShilpa BuchUnited States of AmericaMichael BukrinskyUnited States of AmericaMary Jo BurkhardUnited States of AmericaJohn BurnettUnited States of AmericaFrederic BushmanUnited States of AmericaPaul U CameronAustraliaEdward CampbellUnited States of AmericaTimothy CardozoUnited States of AmericaJeremy CarltonUnited KingdomWilliam CarrUnited States of AmericaRob CenterAustraliaAnna CeresetoItalyBenjamin ChenUnited States of AmericaBing ChenUnited States of AmericaPeter CherepanovUnited KingdomFrauke ChristBelgiumClaudia CicalaUnited States of AmericaAndrea CimarelliFranceAngela CiuffiSwitzerlandPaul ClaphamUnited States of AmericaJanice ClementsUnited States of AmericaCharles CobbsUnited States of AmericaAlan CochraneCanadaJohn CoffinUnited States of AmericaEric CohenCanadaMyron CohenUnited States of AmericaMark ConnorsUnited States of AmericaRobert CraigieUnited States of AmericaMartin CranageUnited KingdomGael CristofariFranceBryan CullenUnited States of AmericaAtze DasNetherlandsSiddhartha DattaUnited States of AmericaD A DavisUnited States of AmericaPaul de BakkerNetherlandsHugues de RocquignyFranceSteven DeeksUnited States of AmericaJoachim DennerGermanyCynthia DerdeynUnited States of AmericaBenjamin DescoursFranceFrancesca Di NunzioFranceFelipe Diaz-GrifferoUnited States of AmericaGilles DivitaFranceAaron DonahueCanadaTao DongUnited KingdomMargherita DoriaItalyLucy DorrellUnited KingdomIvan D'OrsoUnited States of AmericaDaniel DouekUnited States of AmericaJoseph DoughertyUnited States of AmericaJohn ElderUnited States of AmericaMichael EmermanUnited States of AmericaStephane EmilianiFranceAlan EngelmanUnited States of AmericaJerome EstaquierCanadaEliseo EugeninUnited States of AmericaOliver FacklerGermanyHung FanUnited States of AmericaAriberto FassatiUnited KingdomBenoit FavierFranceEberhard FiebigUnited States of AmericaAdam FletcherUnited KingdomDan FramptonUnited KingdomPierre FrangeFranceEric FreedUnited States of AmericaJun-ichi FujisawaJapanAxel FunNetherlandsHansjakob FurrerSwitzerlandVitaly GanusovUnited States of AmericaFeng GaoUnited States of AmericaGuangxia GaoChinaJ. Victor GarciaUnited States of AmericaGerardo Garcia-LermaUnited States of AmericaJeremy GarsonUnited KingdomAnne GatignolCanadaJonathan GeigerUnited States of AmericaAnna Maria GerettiUnited KingdomDenis GerlierFranceAntoine GessainFranceMauro GiaccaItalyNicolas GilbertFranceM John GillCanadaAmber GillettAustraliaStephen GoffUnited States of AmericaMaureen GoodenowUnited States of AmericaMartin GoodierUnited KingdomRobert J GorelickUnited States of AmericaPaul GorryAustraliaMatthias GotteCanadaHeinrich GottlingerUnited States of AmericaCaroline GoujonUnited KingdomThomas GrambergGermanyJane GreatorexUnited KingdomPatrick GreenUnited States of AmericaDirk GrimmGermanyHarriet GroomUnited KingdomElisabetta GroppelliUnited KingdomJohn GrossUnited States of AmericaJohn GuatelliUnited States of AmericaHuldrych GuenthardSwitzerlandNaveed GulzarCanadaSamuel GundersonUnited States of AmericaJu-Tao GuoUnited States of AmericaRavindra Kumar GuptaUnited KingdomHillel HaimUnited States of AmericaLou HammarskjoldUnited States of AmericaYingshan HanCanadaGordon HarkissUnited KingdomDavid HarrichAustraliaMark HarrisUnited KingdomReuben HarrisUnited States of AmericaRonald HartyUnited States of AmericaAlex HarwigNetherlandsJonathan HeeneyUnited KingdomJoshua HerbeckUnited States of AmericaAndrew HillAustraliaVanessa HirschUnited States of AmericaAmnon HiziIsraelCarol HlelaSouth AfricaAfrica HolguinSpainThomas HopeUnited States of AmericaMargaret HosieUnited KingdomPeter HraberUnited States of AmericaMaite HuarteSpainAmy HulmeUnited States of AmericaEric HunterUnited States of AmericaGero HutterGermanyTatsuhiko IgarashiJapanYukihito IshizakaJapanDmitri IvanovUnited States of AmericaRichard JacksonUnited KingdomMartin Roelsgaard JakobsenDenmarkLeo JamesUnited KingdomKuan-Teh JeangUnited States of AmericaRienk JeeningaNetherlandsRichard JennerUnited KingdomShibo JiangChinaDong-Yan JinHong KongMarc JohnsonUnited States of AmericaClare JollyUnited KingdomAlbert JordanSpainSarah JosephUnited States of AmericaAnjali JoshiUnited States of AmericaDavid KabatUnited States of AmericaTaku KambayashiUnited States of AmericaJonathan KarnUnited States of AmericaFatah KashanchiUnited States of AmericaGeorge KassiotisUnited KingdomDavid KatzensteinUnited States of AmericaDaniel KaufmannCanadaNorihito KawashitaJapanMichael KayUnited States of AmericaMary KearneyUnited States of AmericaAnthony KelleherAustraliaStephen KentAustraliaJulia KenyonUnited KingdomFrank KirchhoffGermanyScott KitchenUnited States of AmericaZachary KlaseUnited States of AmericaP J KlasseUnited States of AmericaRenate KoenigGermanyNeeltje KootstraNetherlandsRoger KouyosSwitzerlandChristine KozakUnited States of AmericaHans-Georg KraeusslichGermanyVictor KramerCanadaMamuka KvaratskheliaUnited States of AmericaMartin R B L\u00f6cheltGermanyAksana LabokhaUnited KingdomNadine LaguetteFrancePhilipp LangGermanyLewis LanierUnited States of AmericaRoger Le GrandFranceChristine Leib-M\u00f6schGermanyJonathan LeisUnited States of AmericaDavid N LevyUnited States of AmericaRonald LevyUnited States of AmericaSharon LewinAustraliaChen LiangCanadaMathias LichterfeldUnited States of AmericaJudy LiebermanUnited States of AmericaFlorian LiegeoisCameroonYing-Ju LinTaiwanMin LuUnited States of AmericaJeremy LubanUnited States of AmericaPaul LuciwUnited States of AmericaVladimir V LukashovNetherlandsPaolo LussoUnited States of AmericaGary MaartensSouth AfricaRenaud MahieuxFranceJohnson MakAustraliaFrank MaldarelliUnited States of AmericaFabrizio MammanoFranceNicolas ManelFranceLouis ManskyUnited States of AmericaLaura ManuelidisUnited States of AmericaAlessandro MarcelloItalyDavid MargolisUnited States of AmericaFlorence Margottin-GoguetFranceDavid MarkovitzUnited States of AmericaSusan MarriottUnited States of AmericaMark MarshUnited KingdomFabiola MartinUnited KingdomCynthia MasisonUnited States of AmericaAntonio MastinoItalyMasao MatsuokaJapanWendy MauryUnited States of AmericaDomenico MavilioItalyMyra McClureUnited KingdomMark McNallyUnited States of AmericaGregory MelikyanUnited States of AmericaZora MelkovaCzech RepublicLuis Menendez-AriasSpainJean-Michel MesnardFranceThibault MespledeCanadaA Dusty MillerUnited States of AmericaMahesh MohanUnited States of AmericaHoi Ping MokUnited KingdomDebasis MondalUnited States of AmericaEugenio MontiniItalyPenny MooreSouth AfricaLynn MorrisSouth AfricaDonald MosierUnited States of AmericaWalther MothesUnited States of AmericaAndrew J MoulandCanadaBarbara MuellerGermanyViktor M\u00fcllerHungaryCarsten M\u00fcnkGermanyDelphine MuriauxFranceEdward L MurphyUnited States of AmericaMatteo NegroniFranceStuart NeilUnited KingdomSergei NekhaiUnited States of AmericaMark NelsonUnited KingdomHironori NishitsujiJapanPhilip NorrisUnited States of AmericaMahdad NoursadeghiUnited KingdomVlad NovitskyUnited States of AmericaJeremy NuttallUnited States of AmericaDavid O\u2019ConnorUnited States of AmericaUna O\u2019DohertyUnited States of AmericaAkihiko OkayamaJapanAkira OnoUnited States of AmericaMarcel OomsUnited States of AmericaDominique OuelletCanadaJulie OverbaughUnited States of AmericaAnnette OxeniusSwitzerlandMirko PaiardiniUnited States of AmericaJean-Christophe PaillartFrancePaul PalumboUnited States of AmericaGianfranco PancinoFranceIvona PandreaUnited States of AmericaDimitrios ParaskevisGreeceVincent ParissiFranceJo-Ann PassmoreSouth AfricaAlexander PasternakNetherlandsVinay PathakUnited States of AmericaWilliam PaxtonNetherlandsFinn Skou PedersenDenmarkMartine PeetersFranceDanielle Perez BercoffLuxembourgLuc\u00eda P\u00e9rez-\u00c1lvarezSpainSallie PermarUnited States of AmericaFred PerrinoUnited States of AmericaBoris Matija PeterlinUnited States of AmericaLouis PickerUnited States of AmericaVincent PiguetUnited KingdomSabine PillerAustraliaAbraham PinterUnited States of AmericaMassimo PizzatoItalyJC PlantierFranceStefan P\u00f6hlmannGermanyGeorgios PollakisNetherlandsLarisa PoluektovaUnited States of AmericaArt PoonCanadaPantelis PoumbouriosAustraliaChristopher PowerCanadaVinayaka PrasadUnited States of AmericaDamian PurcellAustraliaYudong QuanCanadaBharat RamratnamUnited States of AmericaR Keith ReevesUnited States of AmericaJan RehwinkelUnited KingdomAlan ReinUnited States of AmericaAxel RethwilmGermanyAndrew RiceUnited States of AmericaLaura Richert-SpuhlerUnited States of AmericaMarjorie Robert-GuroffUnited States of AmericaHarriet RobinsonUnited States of AmericaMichael RocheAustraliaOlivier RohrFranceMorgane RollandUnited States of AmericaNicola RoseUnited KingdomSusan RossUnited States of AmericaMonica RothUnited States of AmericaKenneth RouxUnited States of AmericaSarah Rowland-JonesUnited KingdomChristopher RowleyUnited States of AmericaWalter RoyalUnited States of AmericaJamil SaadUnited States of AmericaJonah SachaUnited States of AmericaAnthony SadlerAustraliaAsier Saez-CirionFranceManish SagarUnited States of AmericaMineki SaitoJapanKalle SakselaFinlandNitin SaksenaAustraliaJesus Salazar-GonzalezUnited States of AmericaMarco SalemiUnited States of AmericaJohan SandbergSwedenRogier SandersNetherlandsMario SantiagoUnited States of AmericaStefanos SarafianosUnited States of AmericaQuentin SattentauUnited KingdomDaniel SauterGermanyGabriella ScarlattiItalySusan SchaderUnited States of AmericaMichael SchindlerGermanyOlivier SchwartzFranceDaniel Scott-AlgaraFranceNabila SeddikiFranceOliver SemmesUnited States of AmericaBarbara ShacklettUnited States of AmericaRobert ShaferUnited States of AmericaGeorge ShawUnited States of AmericaKeisuke ShindoJapanRobert SilicianoUnited States of AmericaJohn SinclairUnited KingdomJacek SkowronskiUnited States of AmericaRichard David SloanUnited KingdomNicolas Sluis-CremerUnited States of AmericaRedmond SmythFranceMarcelo SoaresBrazilJoseph SparanoUnited States of AmericaPaul SpearmanUnited States of AmericaRoberto SpeckSwitzerlandAnna-Lena SpetzSwedenTzanko StantchevUnited States of AmericaLaura SteelUnited States of AmericaHeribert StoiberAustriaJonathan StoyeUnited KingdomKlaus StrebelUnited States of AmericaPeter SunUnited States of AmericaValentina SvicherItalyRonald SwanstromUnited States of AmericaGilda TachedjianAustraliaAkifumi Takaori-KondoJapanYasuhiro TakeuchiUnited KingdomFr\u00e9d\u00e9ric TangyFranceJamal TaziFranceAmalio TelentiSwitzerlandJohn TiltonUnited States of AmericaBruce TorbettUnited States of AmericaGreg TowersUnited KingdomJozsef TozserHungaryMary-Anne TrabaudFranceMichel J TremblayCanadaAlexandra TrkolaSwitzerlandAthe TsibrisUnited States of AmericaStuart TurvilleAustraliaDerya UnutmazUnited States of AmericaTonja van der KuylNetherlandsCarine Van LintBelgiumKoen Van RompayUnited States of AmericaAnne-Mieke VandammeBermudaGuido VanhamBelgiumBruno VerhasseltBelgiumEric VivierFranceVolker M VogtUnited States of AmericaAnnapurna VyakarnamUnited KingdomStephen WaggonerUnited States of AmericaChin-Tien WangTaiwanJonathan WeberUnited KingdomRobin WeissUnited KingdomSarah WelbournUnited States of AmericaRaymond WelshUnited States of AmericaJames WhitneyUnited States of AmericaBrian WigdahlUnited States of AmericaBrian WillettUnited KingdomBryan WilliamsAustraliaMark WillsUnited KingdomKenneth WitwerUnited States of AmericaJoseph WongUnited States of AmericaLi WuUnited States of AmericaYuntao WuUnited States of AmericaYoshihisa YamanoJordanMasahiro YamashitaUnited States of AmericaMelvyn YapUnited KingdomVenkat YedavalliUnited States of AmericaOsamu YoshieJapanJerome ZackUnited States of AmericaAlessia ZamborliniFranceJohn ZaundersAustraliaSteven ZeichnerUnited States of AmericaRichard Y ZhaoUnited States of AmericaYong-Hui ZhengUnited States of AmericaMichael ZwickUnited States of America"}
+{"text": "Translational Neurodegeneration would like to thank all our reviewers who have contributed to the journal in Volume 2 (2013).The editors of  William BrooksAustraliaHuaibin CaiUnited States of AmericaMeghan CampbellUnited States of AmericaPiu ChanChinaHonglei ChenUnited States of AmericaQi ChengChinaEmilio CiusaniItalyJianqing DingChinaYiru FangChinaSerge GauthierCanadaCheng-Xin GongUnited States of AmericaHaigang GuUnited States of AmericaMarwan HarizUnited KingdomMaria Trinidad HerreroSpainYue HuangAustraliaNancy IpChinaKurt JellingerAustriaZun-JI KeChinaFuzhong LiUnited States of AmericaJun LiuChinaWeiguo LiuChinaXuebin LiuChinaXiao-Guang LuoChinaGuozhao MaChinaJianfang MaChinaKangmu MaUnited States of AmericaJan MarcussonSwedenIan McKeithUnited KingdomM Maral MouradianUnited States of AmericaElizabeth Sajdel-SulkowskaUnited States of AmericaYuan ShenChinaHideto ShinnoJapanFlorindo StellaBrazilBomin SunChinaEK TanSloveniaBeisha TangChinaGang WangChinaHonglin WangChinaJian WangChinaJianzhi WangChinaNing WangChinaFrances WeaverUnited States of AmericaHoward WormanUnited States of AmericaRuey-Meei WuTaiwanZhi-Ying WuChinaKun XiaChinaChen XianwenChinaQin XiaoChinaShifu XiaoChinaTao XieUnited States of AmericaZhongcong XieUnited States of AmericaZhen YanUnited States of AmericaJingya ZhangUnited States of AmericaJialin ZhengUnited States of AmericaJiawei ZhouChinaXiongwei ZhuUnited States of America"}
+{"text": "Journal of Hematology & Oncology would like to thank all our reviewers who have contributed to the journal in Volume 6 (2013).The editors of  Seema AgarwalUnited States of AmericaAkintunde AkinleyeUnited States of AmericaDonatella AldinucciItalyRobert AmatoUnited States of AmericaNingfei AnUnited States of AmericaPeter AndersonUnited States of AmericaRami AqeilanIsraelPhilippe ArnaudFranceFrancis AyukGermanyJeff BarrettUnited States of AmericaSurinder BatraUnited States of AmericaPaul BeaudryCanadaLeonidas BenetatosGreecePaolo BernasconiKazakhstanZwi BernemanBelgiumJaap Jan BoelensNetherlandsAttilio BondanzaItalyElisa BoscoloUnited States of AmericaJoseph BrandweinCanadaAdam BrufskyUnited States of AmericaBrad BryanUnited States of AmericaNicholas BurgisUnited States of AmericaThomas BurmeisterGermanyAlan BurnettUnited KingdomAmanda CashenUnited States of AmericaRichard CathomasSwitzerlandLing CenUnited States of AmericaHong ChangCanadaNan-Shan ChangTaiwanChangyan ChenUnited States of AmericaLiguang ChenUnited States of AmericaLiang ChengUnited States of AmericaAlexander ChiUnited States of AmericaAndy ChienUnited States of AmericaDai ChiharaJapanWilliam ChoHong KongMichael ChoppUnited States of AmericaMagdalena Chrzanowska-WodnickaUnited States of AmericaShih-Sung ChuangTaiwanFabrice CognasseFranceGaetano CorazzelliItalyMei-Zhen CuiUnited States of AmericaNico DantumaSwedenEvandro De AzambujaBelgiumChristophe De RomeufFranceAdriana De SierviArgentinaPaolo DionItalyAngela DispenzieriUnited States of AmericaJixin DongUnited States of AmericaCaigan DuCanadaJames EddyUnited States of AmericaStephan EnsmingerGermanyMehmet Ali ErkurtTurkeyBeth FaimanUnited States of AmericaMarco FalascaUnited KingdomIsabella FaraoniItalyRu FengChinaMichael FlisterUnited States of AmericaAlessandro FornariItalyNathan FowlerUnited States of AmericaMassimo FranchiniItalyArnold FreedmanUnited States of AmericaChristopher FrenchUnited States of AmericaStefan Fr\u00f6hlingGermanyTeruhiko FujiiJapanYutaka FujiwaraJapanSeiji FukudaJapanShirish GadgeelUnited States of AmericaGianluca GaidanoItalyPeter GainesUnited States of AmericaKristen GanjooUnited States of AmericaChristian GeislerDenmarkJean-Pierre GerardFranceLaurence GerardFranceHerve GhesquieresFranceStephane GiraudierFranceStefania GobessiItalyAbhijit GodboleUnited States of AmericaJosee GolayItalySteven GoreUnited States of AmericaAndre GoyUnited States of AmericaRichard GreilAustriaBaiwei GuUnited States of AmericaG\u00f6hring GudrunGermanyAngelo GuerrasioItalyThomas HabermannUnited States of AmericaMichiyuki HakozakiJapanMaria Francisca HamIndonesiaTanja HartmannAustriaRobert HasserjianUnited States of AmericaAiwu HeUnited States of AmericaCharles HemenwayUnited States of AmericaVera HirshCanadaGeorg HopfingerAustriaChung-Tsen HsuehUnited States of AmericaJiong HuChinaHe HuangChinaLiang HuangUnited States of AmericaYujie HuangUnited States of AmericaSara HurvitzUnited States of AmericaShinsuke IidaJapanMartino IntronaItalyFumihiro IshidaJapanYasuo IwadateJapanJun IwashitaJapanElias JabbourUnited States of AmericaTang-Her JaingTaiwanGaetan JegoFranceYuxia JiaUnited States of AmericaEnzi JiangUnited States of AmericaYongping JiangChinaJie JinChinaLiang JinAustraliaQihuang JinUnited States of AmericaGrace KaoUnited States of AmericaSabine Kasimir-BauerGermanyMasaru KatohJapanChul Geun KimKorea, SouthWon Seog KimKorea, SouthHitoshi KiyoiJapanWolfram KlapperGermanyYoung Hyeh KoKorea, SouthMichael KoldehoffGermanyHasan KorkayaUnited States of AmericaAndrei KramerovUnited States of AmericaEric KrautUnited States of AmericaGeoffrey KuUnited States of AmericaKarin KurnikGermanyJunya KurodaJapanMateusz KurzawskiPolandToshihiro KushibikiJapanIntidhar Labidi-GalyUnited States of AmericaGurpreet LambaUnited States of AmericaManuel LemosPortugalJi-Liang LiUnited KingdomTianhong LiChinaYangqiu LiChinaZhong LiChinaSharon LiangUnited States of AmericaEvi LianidouGreeceWolfgang LinkPortugalEva LionBelgiumDelong LiuUnited States of AmericaHong LiuUnited States of AmericaJianguo LiuUnited States of AmericaCristiana Lo NigroItalyIrene Lorand-MetzeBrazilNancy LouisUnited States of AmericaCynthia MaUnited States of AmericaDaoxin MaChinaXiaotu MaUnited States of AmericaAnne-Marie MadecFranceMichael MakrisUnited KingdomElisabet Esteve ManasanchUnited States of AmericaFerdinando MannelloItalyPier Mannuccio MannucciItalyTibiletti Maria GraziaItalyAna MarquesUnited KingdomWilliam MatsuiUnited States of AmericaFabrizio MatteiItalySandra McallisterUnited States of AmericaMichal MegoUnited States of AmericaShu MengUnited States of AmericaAdam MetwalliUnited States of AmericaStefan MeyerUnited KingdomJoseph MikhaelUnited States of AmericaMichele MilellaItalyKen MillsUnited KingdomMark MindenCanadaHans MindermanUnited States of AmericaTony MokHong KongDavid MoleUnited KingdomHiroyuki MomotaJapanTammy MorrishUnited States of AmericaHasan MukhtarUnited 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Stephen SuhUnited States of AmericaAnders SundanNorwayRitsuro SuzukiJapanArthur SytkowskiUnited States of AmericaPhilippe SzankasiUnited States of AmericaShinichiro TakahashiJapanJin TakeuchiJapanDipti TalaulikarAustraliaKeiji TaneseJapanChih-Hsin TangTaiwanMatthias TenbuschGermanyJohn ThompsonUnited States of AmericaKirsty ThomsonUnited KingdomKenneth ToHong KongMariko TomitaJapanNaoto TomitaJapanHai TranUnited States of AmericaMartin TrepelGermanyYang Tsai ShengTaiwanWilliam TseUnited States of AmericaAlessandra TucciItalyTogas TulandiCanadaShinya UchinoJapanHenning UlrichBrazilAntonis ValachisGreeceBen ValdezUnited States of AmericaEric Van Den NesteBelgiumJohan Van KriekenNetherlandsK. David VoducCanadaMaria Teresa VosoItalyDomagoj VucicUnited States of AmericaChristine WalshUnited States of AmericaDazhi WangUnited States of AmericaDonghai WangUnited States of AmericaGang WangChinaKankan WangChinaXin WangChinaYa WangUnited States of AmericaZilong WenHong KongMeir WetzlerUnited States of AmericaAndre WillaschGermanyThian-Sze WongHong KongGang WuChinaDazhong XuUnited States of AmericaQingwen XuUnited States of AmericaTeng XuUnited States of AmericaMotoko YamaguchiJapanYing YanUnited States of AmericaDavid YangUnited States of AmericaYibin YangUnited States of AmericaJean YaredUnited States of AmericaM. James YouUnited States of AmericaKen YoungUnited States of AmericaHerbert YuUnited States of AmericaBo YuanJapanZihua ZengUnited States of AmericaFenghuang ZhanUnited States of AmericaChengcheng ZhangUnited States of AmericaDongwei ZhangUnited States of AmericaHua ZhangChinaJiangwei ZhangUnited States of AmericaJianke ZhangUnited States of AmericaXiaolei ZhangUnited States of AmericaXiaowei ZhangUnited States of AmericaYi ZhangUnited States of AmericaYuxia ZhangUnited States of AmericaQian ZhaoChinaZhizhuang Joe ZhaoUnited States of AmericaXiaoyong ZhengUnited States of AmericaDaohong ZhouUnited States of AmericaZhengping ZhuangUnited States of AmericaMario ZorattiItaly"}
+{"text": "Recent analyses of high resolution nucleosome maps have revealed novel relationships between DNA methylation and localization of nucleosomes ,2. In ouin vitro on the gin vitro  derived"}
+{"text": "Aquatic Biosystems editorial team would like to thank the following colleagues who contributed to peer review for the journal in 2013.The  Javier AlcocerMexicoKartik BaruahBelgiumZenon BatangSaudi ArabiaDonald BehringerUnited States of AmericaPeter CasperGermanyFeng ChenUnited States of AmericaDi\u00f3genes Felix da Silva CostaPortugalDavid GauthierUnited States of AmericaBaban IngoleIndiaLuke IwanowiczUnited States of AmericaJong-Myoung KimKorea, SouthMiroslav MacekMexicoRamon MassanaSpainMaria Rosa MiracleSpainUwe M\u00fcnsterFinlandRufus Kitto MuthunayagamSaudi ArabiaChristopher OttingerUnited States of AmericaWolf PecherUnited States of AmericaDanielle PulsUnited States of AmericaNico SalmasoItalyTerry SnellUnited States of AmericaLuis SotoMexicoEvan StephensAustraliaGabriel StrainUnited States of AmericaSherry TamoneUnited States of AmericaAmandine VasletFranceAndrea Waringer-L\u00f6schenkohlAustriaYik Sung YeongMalaysia"}
+{"text": "Ardipithecus radius\" should instead read \"Ardipithecus ramidus.\"In the second paragraph of the Introduction, \""}
+{"text": "The editors of Journal of Neuroinflammation would like to thank all the reviewers who have contributed to the journal in Volume 9 (2012). 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+{"text": "The third author should be listed under \"Conceived and designed the experiments.\" The correct contribution should read: \"Conceived and designed the experiments: KTRW ALM JFAT\""}
+{"text": "Journal of Animal Science and Biotechnology would like to thank all our reviewers who have contributed to the journal in Volume 4 (2013).The editors of  Andre AarninkNetherlandsHansjoerg AbelGermanyMarieke Abrahamse-BerkeveldNetherlandsMohammad Al-MamunBangladeshOusama AlZahalCanadaWageha AwadAustriaFrancis BarilletFranceMarc BauerUnited States of AmericaFuller BazerUnited States of AmericaDonald BeitzUnited States of AmericaDonagh BerryIrelandShashi BhushanIndiaMario BinelliBrazilDustin BolerUnited States of AmericaPaolo BosiItalyLaura BrownUnited States of AmericaGerardo CajaSpainLaurianne CanarioFranceKathy CarlsteadUnited States of AmericaMargarida CastellSpainG\u00e9rard ChaouatFranceFarid ChematFranceBernadette ChenUnited States of AmericaBeth ClevelandUnited States of AmericaJoe CrenshawUnited States of AmericaMonica Isabella CutrignelliItalyDirk DannenbergerGermanyDavid DaviesUnited KingdomStefaan De SmetBelgiumJared DeckerUnited States of AmericaElizabeth DeLyriaUnited States of AmericaElitsa DimovaFinlandHua DingUnited States of AmericaSami DridiUnited States of AmericaTom DruetBelgiumMike DuganCanadaSamer El-KadiUnited States of AmericaMauricio ElzoUnited States of AmericaChantal FarmerCanadaCatherine FieldCanadaGuo-Hua FongUnited States of AmericaTore FramstadNorwayShaorong GaoChinaMiriam GarciaUnited States of AmericaDorian GarrickUnited States of AmericaRodney GeisertUnited States of AmericaAilian GengChinaJoshua GongCanadaRobert GoodbandUnited States of AmericaRongchao HaoChinaPhilip HarrisNew ZealandBrad HeinsUnited States of AmericaKiichi HirotaUnited KingdomRhonda HoffmanUnited States of AmericaYongqing HouChinaClay IsomUnited States of AmericaBreda Jakovac-StrajnSloveniaPeng JiUnited States of AmericaRunshen JiangChinaJennifer JohnsUnited States of AmericaGreg JohnsonUnited States of AmericaCassandra JonesUnited States of AmericaHenry JorgensenDenmarkKampon KaeoketThailandJuha KantanenFinlandSung Woo KimUnited States of AmericaMaarten KootstraNetherlandsClint KrehbielUnited States of AmericaRami KridliJordanOsman KucukTurkeyWan Sup KwakSouth KoreaChanghua LaiChinaJean-Paul Lall\u00e8sFranceTing LeiUnited States of AmericaApril LeytemUnited States of AmericaChangxi LiCanadaHai LinChinaJan Erik LindbergSwedenYanhong LiuUnited States of AmericaJuan LoorUnited States of AmericaMatthew LucyUnited States of AmericaRobert MaddockUnited States of AmericaHassan MalekinejadNetherlandsMichelle Martinez-MontemayorPuerto RicoFrancesca MartuzziItalyJon MeadusCanadaSam MilletBelgiumPatrick MorelNew ZealandMiquel Moret\u00f3SpainAhmed MoussaAlgeriaSemone MyrieCanadaMark NelsonUnited States of AmericaAnita OberbauerUnited States of AmericaJack OdleUnited States of AmericaGarrett OetzelUnited States of AmericaJernej OgorevcSloveniaOluyinka OlukosiUnited KingdomSuneel OnteruIndiaAmeer PahmUnited States of AmericaVishwanath PatilNorwayRosa Maria PereiraPortugalGeorge PerryUnited States of AmericaJames PettigrewUnited States of AmericaJohn PluskeAustraliaRobert PosseeUnited KingdomGuanghai QiChinaSrujana RayalamUnited States of AmericaAna Isabel RodriguesPortugalAlbert RosenbergerGermanyRick RoushAustraliaZemelak SahleGermanyJaneen Salak-JohnsonUnited States of AmericaJames SartinUnited States of AmericaChwan-Li (Leslie) ShenUnited States of AmericaPaul SiegelUnited States of AmericaSaulo SilvaBrazilFred SilversidesCanadaLeon SpicerUnited States of AmericaHans SteinUnited States of AmericaHui-Min SuTaiwanLakshmi SunkaraUnited States of AmericaSylwester SwiatkiewiczPolandSha TaoUnited States of AmericaAnders ThygesenDenmarkYanan TianUnited States of AmericaMike TokachUnited States of AmericaManoj Kumar TripathiIndiaSwamy TripuraniUnited States of AmericaEleni TsiplakouGreecePedro UrriolaUnited States of AmericaHelena van TolNetherlandsFrancielo VendruscoloBrazilMartin VerstegenNetherlandsMirelle VianaBrazilEnrique ViturroGermanyElizabeth WalkerUnited States of AmericaPer WallgrenSwedenChunkao WangUnited States of AmericaXiaoqiu WangUnited States of AmericaYing WangUnited States of AmericaZurong WangSingaporeMalcolm WatfordUnited States of AmericaJames WellsUnited States of AmericaKevin WellsUnited States of AmericaDe WuChinaJi WuChinaYang XiaojianCanadaJingjing XieChinaWenzhi XueChinaNing YangChinaWenzhu YangCanadaJunhu YaoChinaJingdong YinChinaYulong YinChinaCurtis YoungsUnited States of AmericaWei ZhaiUnited States of AmericaGui-xiang ZhangChinaFeng-Qi ZhaoUnited States of AmericaZhihui ZhaoChinaShien ZhuChinaWei-Yun ZhuChina"}
+{"text": "Implementation Science would like to thank all our reviewers who have contributed to the journal in Volume 7 (2012).The editors of  Charles AbrahamUnited KingdomSara AckermanUnited States of AmericaSusan AdamsUnited States of AmericaMohamed AhmednaQatarBianca AlbersDenmarkMichael AllenCanadaElaine AmellaUnited States of AmericaPeter AndersonSpainLou AtkinsUnited KingdomRoss BailieAustraliaRichard BakerUnited KingdomLuciana BalliniItalyDaynia Elizabeth BallotSouth AfricaClaire BamfordUnited KingdomJonathan BennUnited KingdomFiona BeyerUnited KingdomBarbara BokhourUnited States of AmericaGary BondUnited States of AmericaAndrew BoothUnited KingdomCameo BorntragerUnited States of AmericaAlan BorthwickUnited KingdomMarije BoschAustraliaCandice BowmanUnited States of AmericaGudrun BoysenDenmarkJeffrey BraithwaiteAustraliaJoze BraspenningNetherlandsJamie BrehautCanadaSue BrennanAustraliaMelissa BrouwersCanadaC Hendricks BrownUnited States of AmericaRichard ByngUnited KingdomGuy CafriUnited KingdomJames CaneUnited KingdomTim CareyAustraliaRosemary CaronUnited States of AmericaEnrique Castro-SanchezUnited KingdomCristina CatalloCanadaThane ChambersCanadaEsmita CharaniUnited KingdomFrancine CheaterUnited KingdomKath ChecklandUnited KingdomHelen ChinUnited KingdomSiriporrn ChirawatkulThailandErika Frischknecht ChristensenDenmarkTheopisti ChrysanthakiUnited KingdomAlexander ClarkCanadaSean ClarkeUnited States of AmericaStephanie CohenUnited States of AmericaHeather ColquhounCanadaSimon CoultonUnited KingdomLuis Gabriel CuervoUnited States of AmericaNicky CullumUnited KingdomGavin Daker-WhiteUnited KingdomLaura DamschroderUnited States of AmericaFrank DavidoffUnited States of AmericaMark DavisAustraliaCarl de WetUnited KingdomJames DearingUnited States of AmericaVincent DearyUnited KingdomSophie DesrochesCanadaBrian DixonUnited States of AmericaMary Dixon-WoodsUnited KingdomMaureen DobbinsCanadaDebra DobbsUnited States of AmericaAndrew Don-WauchopeCanadaShannon DorseyUnited States of AmericaColleen DoyleAustraliaPierre DurieuxFranceJudith DysonUnited KingdomMark EbellUnited States of AmericaAndrew EldersUnited KingdomAnn Catrine EldhSwedenMike EnglishKenyaAnna Ess\u00e9nSwedenTracy FinchUnited KingdomGerd FlodgrenUnited KingdomJay FordUnited States of AmericaJill FrancisUnited KingdomAtle FretheimNorwayJeffrey FullerAustraliaAnna GagliardiCanadaNicola GaleUnited KingdomAfschin GandjourGermanyBenjamin GardnerUnited KingdomAnn GarlandUnited States of AmericaMax GeraedtsGermanyRussell GlasgowUnited States of AmericaPaul GlasziouAustraliaLisa GoldAustraliaRalph GonzalesUnited States of AmericaIan GrahamCanadaGonzalo GrandesSpainSarah GriffinUnited States of AmericaI\u00f1aki GutierrezSpainMary HainesAustraliaCarmen HallUnited States of AmericaKara HallUnited States of AmericaJonathan HammondUnited KingdomMargaret HandleyUnited States of AmericaWendy HardemanUnited KingdomKatherine HardingAustraliaClaire HarrisAustraliaMargaret B. HarrisonCanadaGill HarveyUnited KingdomPenelope HaweCanadaLarry HearldUnited States of AmericaRobert HechtUnited States of AmericaAnthony HemmelgarnUnited States of AmericaSusanne HempelUnited States of AmericaJane HendyUnited KingdomAnne HollandAustraliaMargaret Holmes-RovnerUnited States of AmericaDaniel HoltUnited States of AmericaMichelle HoneyNew ZealandMaria HorneUnited KingdomAlison HutchinsonAustraliaSylvia HysongUnited States of AmericaIrene IlottUnited KingdomTheodore IwashynaUnited States of AmericaCatherine JacksonUnited KingdomJesse JacobsUnited States of AmericaKatharina JanusUnited States of AmericaBonnie JenningsUnited States of AmericaPatrick JeurissenNetherlandsPaul JohnsonAustraliaMarie JohnstonUnited KingdomLydia KapiririCanadaElizabeth KendallAustraliaAmy KilbourneUnited States of AmericaGad KilonzoTanzaniaRoman KislovUnited KingdomAlison KitsonUnited KingdomNiina KolehmainenUnited KingdomTiina KortteistoFinlandAnita KothariCanadaSaravana KumarAustraliaRegina KunzSwitzerlandJoseph KwanUnited KingdomYiannis KyratsisUnited KingdomAnna LauUnited States of AmericaMiranda LaurantNetherlandsRebecca LawtonUnited KingdomJennifer LeemanUnited States of AmericaFrance LegareCanadaLaura LevitonUnited States of AmericaCara LewisUnited States of AmericaLinda LiCanadaAndrew LockettUnited KingdomLisa LubomskiUnited States of AmericaPisake LumbiganonThailandRenee LyonsCanadaAnnette MajnemerCanadaRichard MartinUnited States of AmericaGraham MartinUnited KingdomCarl MayUnited KingdomDanielle MazzaAustraliaJohn McAteerUnited KingdomJulie McDonaldAustraliaRosemary McEachanUnited KingdomBradford McFadyenCanadaKatherine McGiltonCanadaLorna McKeeUnited KingdomAnn McKibbonCanadaFiona MillerCanadaStephen MillsThailandDavid MoherCanadaGerard MolloyUnited KingdomGabriel MooreAustraliaDonna MoralejoCanadaJill MorrisonUnited KingdomFelix NaughtonUnited KingdomSkye NewtonAustraliaPer NilsenSwedenWynne NortonUnited States of AmericaSandra NutleyUnited KingdomMathieu OuimetCanadaDeborah ParkerAustraliaJohn ParsonsNew ZealandSalvador Peir\u00f3SpainDavid PilgrimUnited KingdomByron PowellUnited States of AmericaPeter PronovostUnited States of AmericaJoanne ProtheroeUnited KingdomJeff PyneUnited States of AmericaCraig RamsayUnited KingdomGeetha RanmuthugalaAustraliaTim RapleyUnited KingdomArash RashidianIranMelody RhydderchUnited KingdomJaMuir RobinsonUnited States of AmericaHector RodriguezUnited States of AmericaSarah RosenbaumNorwayPatricia RosenbergerUnited States of AmericaLisa RubensteinUnited States of AmericaBruno RushforthUnited KingdomJo Rycroft-MaloneUnited KingdomAnna SallisUnited KingdomShannon ScottCanadaNick SevdalisUnited KingdomRod SheaffUnited KingdomPaul ShekelleUnited States of AmericaSasha ShepperdUnited KingdomNahoko ShindoSwitzerlandStephanie ShortAustraliaJane SilovskyUnited States of AmericaSara SingerUnited States of AmericaFalko F SniehottaUnited KingdomLeif SolbergUnited States of AmericaNelson SooHooUnited States of AmericaNeil SpicerUnited KingdomKatherine StamatakisUnited States of AmericaNicholas SteelUnited KingdomCheryl StetlerUnited States of AmericaKeith StevensonUnited KingdomFrances StillmanUnited States of AmericaTim StokesUnited KingdomSharon StrausCanadaNatalie TaylorUnited KingdomGeorge TeatherCanadaAlan ThomasUnited KingdomEric ThomasUnited States of AmericaEdel TierneyIrelandJonathan TobinUnited States of AmericaChris ToddUnited KingdomLyndal TrevenaAustraliaTari TurnerAustraliaSara TwaddleUnited KingdomTrudy van der WeijdenNetherlandsCharles VincentUnited KingdomIvo VlaevUnited KingdomTara VlasimskyUnited States of AmericaDorothy WadeUnited KingdomAnn WalesUnited KingdomMark WallandAustraliaJohn WalleyUnited KingdomLars WallinSwedenVicky WardUnited KingdomPaul WardAustraliaMargaret Camilla WatsonUnited KingdomBryan WeinerUnited States of AmericaElizabeth WhippleUnited States of AmericaRobin WhitebirdUnited States of AmericaJohn WiggersAustraliaNancy WilczynskiCanadaKaren WillisAustraliaShannon Wiltsey StirmanUnited States of AmericaKath WrightUnited KingdomMarieke ZegersNetherlandsWen ZengMacao"}
+{"text": "The editors of Mobile DNA would like to thank all our reviewers who have contributed to the journal in volume 3 (2012). Peter ArensburgerUnited States of AmericaIrina ArkhipovaUnited States of AmericaFrederick ArnaudFranceJoshua BallerUnited States of AmericaJef BoekeUnited States of AmericaStephane BoissinotUnited States of AmericaGuillaume BourqueSingaporeRichard CalendarUnited States of AmericaJosep CasacubertaSpainRonald ChalmersAfghanistanShawn ChristensenUnited States of AmericaJoan CurcioUnited States of AmericaThomas EikbushUnited States of AmericaAstrid EngelUnited States of AmericaMalcolm FraserUnited States of AmericaAnthony FuranoUnited States of AmericaXiang GaoUnited States of AmericaDavid GarfinkelUnited States of AmericaVera GorbunovaUnited States of AmericaHeidrun GundlachGermanyGraham HatfullUnited States of AmericaZoltan IvicsGermanyI. King JordanUnited States of AmericaI. King JordanUnited States of AmericaRuslan KalendarFinlandHaig KazazianUnited States of AmericaKenji KojimaUnited States of AmericaHoward LatenUnited States of AmericaEmmanuelle LeratFranceJiri MacasCzech RepublicDixie MagerCanadaSandy MartinUnited States of AmericaJens MayerGermanyDidier MazelFranceJohn MoranUnited States of AmericaEllen PrithamUnited States of AmericaDavid RayUnited States of AmericaPhoebe RiceUnited States of AmericaSylvie RimskyFranceAlfredo RuizSpainSuzanne SandmeyerUnited States of AmericaSarah SchaackUnited States of AmericaGerald SchumannGermanyDavid SymerUnited States of AmericaSebastien TempelFranceChristophe TerzianFranceChantal VauryFranceAlexander VershininRussiaJean-Nicolas VolffGermanyDaniel VoytasUnited States of AmericaHolly WichmanUnited States of AmericaDavid WitherspoonUnited States of AmericaJinchuan XingUnited States of AmericaSteven ZimmerlyCanada"}
+{"text": "Reproductive Health would like to extend a sincere thank you to all our valued reviewers listed below who contributed to the journal in Volume 10 (2013). Without the co-operation and collaboration of peer reviewers, these manuscripts would remain static in a submission system with high quality articles unpublished and inaccessible to the public on a global scale. We are very pleased to have a diverse range of reviewers from high, middle and low income countries, contributing to the dissemination of research findings in an open access journal. Please accept our deepest thanks for your knowledge, time and continuing efforts.The editor of  Clara AartsSwedenKarim AbawiSwitzerlandMohammad Jalal Abbasi-ShavaziIranMuhammad Ahmed AbdullahPakistanSileshi AbeyaEthiopiaFarina AbrejoPakistanAsri AdisasmitaIndonesiaMesganaw Fantahun AfeworkEthiopiaSohail AghaUnited States of AmericaMohammed AliAustraliaNiloufer AliPakistanGretchen AntelmanUnited States of AmericaIsabella ArchieUnited KingdomNega AssefaEthiopiaBerhanemeskel AtsbehaEthiopiaTariq AzimEthiopiaSyed Khurram AzmatPakistanFrank BaidenGhanaBabagana BakoNigeriaSibhatu BiadgilignEthiopiaJessica BirdCanadaPaul BlumenthalUnited States of AmericaMaria BortoliniBrazilDoortje BraekenUnited KingdomSally BrownUnited KingdomLynn CallisterUnited States of AmericaClaire CarsonUnited KingdomLidia CasasChileLaura CastlemanUnited States of AmericaChandra-Mouli VenkatramanSwitzerlandCharoenchai ChiamchanyaThailandJohn ClelandUnited KingdomTim ColbournUnited KingdomMercedes ColomarUruguayMark ConnollySwitzerlandGabriela CormickArgentinaDivanise CorreiaBrazilPhyllis Dako-GyekeGhanaJess DavisAustraliaJoshua DavisUnited States of AmericaAdriane DelicioBrazilTh\u00e9r\u00e8se DelvauxBeninDonna DennoUnited States of AmericaKebede DeribeEthiopiaRichard DermanUnited States of AmericaMadhu Dixit DevkotaNepalJohn Ditekemena CongoDemocratic RepublicSom\u00e9 Donmozoun T\u00e9lesphoreBurkina FasoCatherine EgbeSouth AfricaOmaima El GibalyEgyptSebastian EliasonGhanaLaila El-ZeiniEgyptCyril EngmannUnited States of AmericaGedefaw Abeje FekaduEthiopiaHerve FernandezFranceMarcelo FerreiraBrazilJane FisherAustraliaBritt FribergSwedenEnrique GadowArgentinaCynthia GearyUnited States of AmericaTesfay Gebregzabher GebrehiwotEthiopiaTerefe GeliboEthiopiaYoseph GessesseEthiopiaDemian GlujovskyArgentinaAzita GoshtasebiIranRena GreifingerUnited States of AmericaAlexis GuedesBrazilCarlos G\u00fcidaChileYan GuoChinaBernard GuyerUnited States of AmericaGwyn HainsworthUnited States of AmericaJohn HallAustraliaClaudia HansonSwedenMiriam HartmannUnited States of AmericaFariha HaseenBangladeshRobert HenryUnited States of AmericaEllen HodnettCanadaSusie HoffmanUnited States of AmericaJustus HofmeyrSouth AfricaLaili IraniUnited States of AmericaEliana Jimenez-SotoAustraliaNeetu JohnIndiaSarah JohnsonUnited KingdomStan KachnowskiUnited States of AmericaRos KaneUnited KingdomRavneet KaurIndiaMethod KazauraTanzaniaJames KiarieKenyaJoyce KinaroKenyaMarion Koso-ThomasUnited States of AmericaFiona KouyoumdjianCanadaRamesh KumarPakistanYihunie LakewEthiopiaGloria LangatUnited KingdomMalinee LaopaiboonThailandElena LebetkinUnited States of AmericaTippawan LiabsuetrakulThailandFernando Luiz Affonso FonsecaBrazilPisake LumbiganonThailandMercedes Mac MullenArgentinaShawn MalarcherUnited States of AmericaAlice MarchUnited States of AmericaFrancisco MardonesChilePamela MarteyGhanaAnthony MassindeTanzaniaMatthews MathaiSwitzerlandMaureen MayhewCanadaArslan MazharPakistanMichael MbizvoSwitzerlandAnthony MbonyeUgandaAlexandre MegaleBrazilWubegzier MekonnenEthiopiaLegese Alemayehu MekuriaEthiopiaTesfaye MengistuEthiopiaAna Paula Pierre MoraesBrazilRafael MoroniBrazilElise MurowchickUnited States of AmericaDeclare MushiTanzaniaRuta NadisauskieneLithuaniaKatie NewbyUnited KingdomGustavo NigendaMexicoB\u00e9atrice NikiemaCanadaPeter NorrieUnited KingdomAdeline NyamathiUnited States of AmericaAnicet NzabonimpaRwandaFrancis ObareKenyaEkechi OkerekeNigeriaBolajoko O. 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+{"text": "Israel Journal of Health Policy Research would like to thank all reviewers, both external and Editorial Board Members, who have contributed to the journal in 2013, and whose valuable support continues to be essential to the success of the journal.The Editors of  Linda AikenUnited States of AmericaEric AmsterIsraelShai AshkenaziIsraelToni AshtonNew ZealandYaacov BaruchIsraelNetta BenturIsraelYitshal BernerIsraelNina BickellUnited States of AmericaJeffrey BorkanUnited States of AmericaIvy BourgeaultCanadaBarbara BraunUnited States of AmericaMayer BrezisIsraelJenny BrodskyIsraelSusan BuschUnited States of AmericaYeezkel CaineIsraelDavid ChinitzIsraelPaul ClearyUnited States of AmericaRobert CohenJordanAntonia CroninUnited KingdomGordon DeFrieseUnited States of AmericaMilka DonchinIsraelAmy EisensteinUnited States of AmericaAharon FinestoneIsraelGary FreedUnited States of AmericaNurit FriedmanIsraelPaul FroomIsraelStanton GlantzUnited States of AmericaShimon GlickIsraelRosa GofinUnited States of AmericaItamar GrottoIsraelPinchas HalpernIsraelPaul HansenNew ZealandNaomi HausmanIsraelDonna HavensUnited States of AmericaAnthony HeymannIsraelDominic HodgkinUnited States of AmericaGiora KaplanIsraelArthur KellermannUnited States of AmericaAlex KemperUnited States of AmericaSun-Young KimUnited States of AmericaRichard KravitzUnited States of AmericaFleur-Ange LefebvreCanadaMoshe LeshnoIsraelRobert LikeUnited States of AmericaMichelle MacyUnited States of AmericaOrly ManorIsraelGregory MarchildonCanadaRob McNeillNew ZealandDavid MirvisUnited States of AmericaShlomo Mor-YosefIsraelSusan MurrayCanadaYehuda NeumarkIsraelNurit NirelIsraelOra PaltielIsraelKobi PelegIsraelJoseph PliskinIsraelAvi PorathIsraelBasil PorterIsraelShmuel ReisIsraelLinda ResnikUnited States of AmericaShmuel RishponIsraelLaura RosenIsraelAlan RosensteinUnited States of AmericaBrendan SalonerUnited States of AmericaRichard SaltmanUnited States of AmericaJ\u00f6rg SchaaberGermanyGillian SchillerUnited KingdomHarald SchmidtUnited States of AmericaMichael SchoenbaumUnited States of AmericaStephen SchoenbaumUnited States of AmericaChen ShapiraIsraelAmir ShmueliIsraelPierre SingerIsraelDaniel SperlingIsraelKatherine SwartzUnited States of AmericaOrna TalIsraelShlomo VinkerIsraelMichael WeingartenIsraelRachel Wilf MironIsraelJenny WrightUnited KingdomYael YishaiIsraelEyal ZimlichmanIsraelAmitai ZivIsraelJack ZwanzigerUnited States of America"}
+{"text": "The sixth author (AS) was incorrectly omitted from the list of those authors who \"Performed the experiment.\""}
+{"text": "The editors of Conflict and Health would like to thank all our reviewers who have contributed to the journal from Volume 1 (2007) to Volume 7 (2013). Antoine Abu-MusaLebanonHirotsugu AigaJapanGrace AkelloUgandaNazmul AlamUnited States of AmericaSamim Al-DabbaghIraqJoseph AmonUnited States of AmericaAranka AnemaCanadaElizabeth ArokaKenyaLynn Muhimbuura AtuyambeUgandaFrancis BajunirweUgandaSusan BartelsUnited States of AmericaLinda BartlettUnited States of AmericaChristian BautistaPeruJoseph BeckerUnited States of AmericaMarie Theres BennerThailandTheresa BetancourtUnited States of AmericaJoseph BeyeneCanadaCatrien BijleveldNetherlandsOleg BilukhaUnited States of AmericaKarl BlanchetUnited KingdomIlse BlignaultAustraliaFrederick BurkleUnited States of AmericaGerman CasasColombiaMustafa CelikTurkeyPhilip ChanUnited States of AmericaKathryn ChuSouth AfricaAlex CohenUnited KingdomManuela ColombiniUnited KingdomEllen ConnortonUnited States of AmericaAidan CroninIrelandJeremy CunninghamUnited KingdomHenia DakkakUnited States of AmericaKoustuv DalalSwedenStacy De JesusUnited States of AmericaRicardo de la EspriellaColombiaSara De MeyerBelgiumHedwig DeconinckFranceHendrik DierickKenyaShannon DoocyUnited States of AmericaThomas ElbertGermanyTom EllmanSouth AfricaAdel Abdel Aziz El-SayedEgyptKarin S EngstromSwedenAriel EytanSwitzerlandNadine EzardAustraliaHarley FeldbaumUnited States of AmericaNathan FordSouth AfricaRalph FrerichsUnited States of AmericaAleksandra FucicCroatiaRichard GarfieldUnited States of AmericaPeter GichangiKenyaNancy GlassUnited States of AmericaRebecca GraisFranceNatalie GrayAustraliaGregg GreenoughUnited States of AmericaGilles GuerrierFranceEmily HarozUnited States of AmericaPaul HarrellUnited States of AmericaMevludin Hasanovi\u0107Bosnia and HerzegovinaMichael HayesCanadaBritt Hedman Ahlstr\u00f6mSwedenDionisio Jose Herrera GuibertUnited States of AmericaLara HoSwitzerlandJaco HomsyUnited States of AmericaRebecca HornUnited KingdomMazeda HossainUnited KingdomKeng-Yen HuangUnited States of AmericaPeter HughesUnited KingdomRobert HutagalungThailandGeorge JakabUnited States of AmericaJamal JamelIraqGeoffrey JaoUnited States of AmericaPrakash Mohan JeenaSouth AfricaMasamine JimbaJapanKirsten JohnsonCanadaTimothy JohnsonUnited States of AmericaRumi Kato PriceUnited States of AmericaJocelyn KellyUnited States of AmericaErin KennyUnited States of AmericaInes KeygnaertBelgiumAli KhajiIIranBrandon KohrtNepalRyuichi KomatsuSwitzerlandSandra KrauseUnited States of AmericaPhilipp KuwertGermanyChandrakant LahariyaIndiaMarkus A. LandoltSwitzerlandErling LarssonTimor-LesteBee Wah LeeSingaporeThomas LeeUnited States of AmericaToby LeslieUnited KingdomJustin LesslerUnited States of AmericaShai LinnIsraelNatalia LinosUnited States of AmericaAugusto LlosaFranceBarbara Lopes CardozoUnited States of AmericaFrancisco L\u00f3pez-Mu\u00f1ozSpainMassimo Lowicki-ZuccaUgandaKate MackintoshNetherlandsBabu Ram MarasiniNepalMendy MarshUnited States of AmericaPriscilla MartinezUnited States of AmericaMatko MarusicCroatiaTimothy MastroUnited States of AmericaVerena MauchGermanyColin McCordUnited KingdomTherese McGinnUnited States of AmericaThomas McIntyreUnited States of AmericaKenneth MenkhausUnited States of AmericaSteven MilesUnited States of AmericaEdward MillsCanadaSharmistha MishraCanadaMelinda MooreUnited States of AmericaNeo MorojeleSouth AfricaAndres MoyaUnited States of AmericaKatherine MuldoonCanadaLuke MullanyUnited States of AmericaMir Lais MustafaAfghanistanDavid NdeteiKenyaBrett NelsonUnited States of AmericaRichard NeugebauerUnited States of AmericaMarzieh NojomiIranColleen O'ConnellCanadaEmilomo OgbeBelgiumPeter Olupot-OlupotUgandaDonal O'MathunaIrelandChristopher OrachUgandaHermen OrmelNetherlandsEmilio OvugaUgandaFritz ParlUnited States of AmericaBruce ParnellAustraliaPreeti PatelUnited KingdomEnrico PavignaniMozambiqueValerie PercivalCanadaPhuong PhamUnited States of AmericaJonathan PolonskyFranceNatacha ProtopopoffTanzaniaAndrew RasmussenUnited States of AmericaGlen ReevesUnited States of AmericaTony ReidBelgiumChen ReisUnited States of AmericaHugh ReyburnUnited KingdomLes RobertsUnited States of AmericaRoberto RonaUnited KingdomLeonard RubensteinUnited States of AmericaJoseph RujumbaUgandaJohn RussellUnited KingdomNaomi RutenbergUnited States of AmericaTove RymanUnited States of AmericaKhwaja Mir Islam SaeedAfghanistanAlison SchaferAustraliaGita SenIndiaNazar ShabilaIraqHarry ShannonCanadaKate ShannonCanadaDerrick SiloveAustraliaRomesh SilvaUnited States of AmericaSonal SinghUnited States of AmericaKaren SlamaFranceRichard SollomUnited States of AmericaDaya SomasundaramSri LankaEgbert SondorpUnited KingdomIlene SpeizerUnited States of AmericaPaul SpiegelSwitzerlandHakon StenmarkNorwayOrly SternSouth AfricaKatharine StottSouth AfricaAlison StrangUnited KingdomVoravit SuwanvanichkijUnited States of AmericaRaymond SwientonUnited States of AmericaNathan TabackCanadaKate TeelaUnited States of AmericaAra TekianUnited States of AmericaAndrew Thorne-LymanUnited States of AmericaJohn TirmanUnited States of AmericaWietse TolUnited States of AmericaBasia TomczykUnited States of AmericaEls TorreeleUnited States of AmericaLela TsiskarishviliGeorgiaDeborah TurnbullAustraliaMarta ValencianoSpainMichel Van HerpBelgiumMark van OmmerenSwitzerlandAn-Sofie Van ParysBelgiumBeth VannUnited States of AmericaJoanna VeareySouth AfricaPeter VentevogelNetherlandsPatrick VinckUnited States of AmericaUlrike von LersnerGermanyAlexander VuUnited States of AmericaAngelika WahnerUnited States of AmericaJohn WatsonSwitzerlandAnna WhelanAustraliaKumanan WilsonCanadaAndrea WirtzUnited States of AmericaViroj WiwanitkitThailandBente WoldNorwayEvan WoodCanadaBradley WoodruffChinaBernadette WrightAustralia"}
+{"text": "Journal of Translational Medicine would like to thank all our reviewers who have contributed to the journal in Volume 10 (2012).The editor of  Micha\u0142 \u017bmijewskiPolandSonia AbdelhakTunisiaHaitham Abou SalehQatarRaffaele AddeoItalyGail AdlerUnited States of AmericaXabier AgirreSpainAamir AhmadUnited States of AmericaBassil AkraGermanyErdem AktasTurkeySafiye AktasTurkeyIssa Al SalmiOmanAyodele AlaiyaSaudi ArabiaBalbino AlarconSpainAbla Albsoul-YounesJordanMariam AL-MuftahQatarFahd Al-MullaKuwaitCestmir AltanerSlovakiaCristina AlviraUnited States of AmericaYihua AnChinaDaniel AndersonUnited States of AmericaRoland AnderssonSwedenS\u00e9bastien AnguilleBelgiumJavier AnguloSpainEleni AnniUnited States of AmericaStephane AnsieauFranceJedrzej AntosiewiczPolandIchiro AokiJapanJaime AriasSpainM. Simo ArredouaniUnited States of AmericaPaolo A. AsciertoItalyMaria Libera AsciertoUnited States of AmericaEsther AspinallUnited KingdomStephen AtkinUnited KingdomMichaela AubeleGermanyWalter AulitzkyGermanyDorina AvramUnited States of AmericaAlexander AwgulewitschUnited States of AmericaCaner AytekinTurkeyLuciano Cesar AzevedoBrazilN. Ahmad AzizNetherlandsHideo BabaJapanJuan BadimonUnited States of AmericaAbeer BahnassyEgyptXiaowen BaiUnited States of AmericaSasha BakhruUnited States of AmericaAlberto BalbariniItalyMarcelo BaldoUnited States of AmericaMarija BalicAustriaArun BandyopadhyayIndiaProbal BanerjeeUnited States of AmericaMohamed BanniTunisiaRathindranath BaralIndiaDavid BarnettUnited KingdomJonathan BarrattUnited KingdomGuislaine BarriereFranceEsther BastiaannetNetherlandsMarcus BauerGermanyAndrew BauerUnited States of AmericaConstantin BaxevanisGreeceTherese BeckerAustraliaChristian BeckerGermanyNatalia Bednarz-KnollGermanyDavide BedognettiUnited States of AmericaShahinaz BedriQatarCristobal Belda-IniestaSpainMatteo BelloneItalyAndreas BembenekGermanyAhlem Ben Haj AyedTunisiaRotem Ben-HamoIsraelMarc BenhamouFranceTawfeg Ben-OmranQatarMich\u00e8le BergeronCanadaMyriam BernaudinFranceLaia Bernet VegueSpainHarold BernsteinUnited States of AmericaEmanuele BertagliaKazakhstanCyril BerthetFranceBrian BettencourtUnited States of AmericaKaren BiebackGermanyFrancesco BifariItalyMark BighamCanadaRalf Birkenh\u00e4gerGermanyPatrick BistonBelgiumMaria BjorkqvistSwedenBeata BodeSwitzerlandStefan BoehmAustriaFausto BogazziItalyPaul BognerUnited States of AmericaJohannes BoltzeGermanyBruno BonettiItalyFrancesca BonviciniItalyCesar BorlonganUnited States of AmericaFrancesc E. Borr\u00e0sSpainPaolo Boscolo-RizzoItalyDemosthenes BourosGreeceJason BovenkerkUnited States of AmericaOnur BoymanSwitzerlandPeter BraderAustriaValdir BragaBrazilKarim BrandtSwitzerlandAndy BrassUnited KingdomHiltrud BrauchGermanyMichel BraunBelgiumMarco BregniItalyEkua BrenuAustraliaEmilio BriaItalyKristie BridgesUnited States of AmericaMichael BriggsUnited States of AmericaThomas BrinkerUnited States of AmericaCedrik M. BrittenGermanyTom BroderickUnited States of AmericaVincenzo BronteItalyDavid BrownUnited KingdomRobert BrownUnited KingdomLindsay BrownAustraliaRichard BruceUnited States of AmericaBoglarka BrugosHungaryHermann BrustmannAustriaDonald BuchsbaumUnited States of AmericaAlfredo BudillonIsraelKimberly BullockUnited States of AmericaFranco Maria BuonaguroItalyLuigi BuonaguroItalyStefan BurdachGermanyDennis BurtonUnited States of AmericaJames BusselUnited States of AmericaPierre BussonFranceMarcus ButlerCanadaLisa ButterfieldUnited States of AmericaNeslihan CabiogluTurkeyDanielle CamisascaBrazilIrene CantareroSpainMichele CaragliaItalyMichela CarletGermanyPeter CarlssonSwedenAntoine CarpentierFranceRobert CarrUnited States of AmericaWilliam CarsonUnited States of AmericaLorraine CaruccioUnited States of AmericaLuciano CastielloUnited States of AmericaJorge CastilloUnited States of AmericaDiane CathyUnited KingdomAntonino CattaneoItalyCharles CazanaveFranceJonathan CebonAustraliaLaura CerezoSpainRunu ChakravartyIndiaMarc ChamberlainUnited States of AmericaJun Chang DukKorea, SouthBoonsri ChanrachakulThailandAude ChapuisUnited States of AmericaPrabal ChatterjeeUnited KingdomYuh-Ling ChenTaiwanZhe-Sheng ChenUnited States of AmericaWen-Shiang ChenTaiwanYa-Wen ChenTaiwanMiaofen ChenTaiwanKuen-Feng ChenTaiwanGeorge ChenHong KongWenqiang ChenChinaLiang ChengUnited States of AmericaSK CheongMalaysiaJason ChesneyUnited States of AmericaR\u00e9mi CheynierFranceHarvinder Singh ChhabraIndiaMaurizio Chiriva-InternatiUnited States of AmericaWee ChngSingaporeWilliam CS ChoHong KongThinle ChodonUnited States of AmericaMurim ChoiUnited States of AmericaBenjamin ChongUnited States of AmericaJeffrey ChouUnited States of AmericaLotfi ChouchaneQatarSara CiviniUnited States of AmericaGiovanni CizzaUnited States of AmericaJessica ClementUnited States of AmericaMartine ClozelSwitzerlandEverardo CobosUnited States of AmericaDawn CochraneUnited States of AmericaSamuel M. CohenUnited States of AmericaWilliam ColemanUnited States of AmericaRobert ColemanUnited KingdomPablo Conesa-ZamoraSpainRichard ConnollyUnited States of AmericaElena ContiItalyJonathan Cools-LartigueCanadaPierre CordelierFrancePierpaolo CorrealeItalyWinston Costa PereiraIndiaAlain CouvineauFranceTommy J CurryUnited States of AmericaAles CveklUnited States of AmericaGregory CzarnotaCanadaMaria DagliBrazilYang DaiUnited States of AmericaZhong-Min DaiChinaWangde DaiUnited States of AmericaAshraf DallolSaudi ArabiaFelipe Dal-PizzolBrazilRavi DasuUnited States of AmericaNabanita DattaUnited States of AmericaAdil DaudUnited States of AmericaSimon DavisUnited KingdomJonathan D'CunhaUnited States of AmericaAndreia De AlbuquerqueGermanyRob De BoerNetherlandsUgo De GiorgiItalyRenske De JongNetherlandsAndrea De MariaItalyKatleen De PreterBelgiumValli De ReItalyIlaria DecimoItalyMario DelgadoSpainA. Lee DellonUnited States of AmericaSandra DemariaUnited States of AmericaAldona Dembinska-KiecPolandYubin DengChinaJing-Yu DengChinaRajat DeoUnited States of AmericaSebastien DeshayesFranceJoseph DesimoneUnited States of AmericaSusan DeutscherUnited States of AmericaAnimesh DharUnited States of AmericaMaria Di BartolomeoItalyGiuseppe Di LorenzoItalyStefano Di SantoSwitzerlandYinze DiaoChinaValdo Jose Dias Da SilvaBrazilGiorgio DieciItalySusanne DihlmannGermanyIoanna DimopoulouGreeceHong DingQatarMary DisisUnited States of AmericaSoner DoganUnited States of AmericaElena DogliottiItalyAlexander DohnalAustriaAlena DondaSwitzerlandGlenn DorsamUnited States of AmericaXiang DuChinaErin DunbarUnited States of AmericaJeffery DusekUnited States of AmericaRobert EdwardsUnited States of AmericaThomas EfferthGermanyNejat EgilmezUnited States of AmericaBrian EisnerUnited States of AmericaMiquel EkkelenkampNetherlandsHeather EliassenUnited States of AmericaPetrescu EmilRomaniaFelix EngelGermanyMasaru EnomotoJapanMaria EriksdotterSwedenKristina ErikssonSwedenJose EsparzaUnited States of AmericaMarkus EsslerGermanyJames FaixUnited States of AmericaMario FalchiUnited KingdomBuwu FangChinaBingliang FangUnited States of AmericaHaneen FarahIsraelKarim FarhatSaudi ArabiaMark FariesUnited States of AmericaRamon FarreSpainPeter FaschingGermanyHassana FathallahUnited States of AmericaMaria Simonetta Faussone-PellegriniItalyJou FelsbergGermanyJane FergusonUnited States of AmericaDaris FerrariItalySilvano FerriniItalySoldano FerroneUnited States of AmericaNikos FersisGermanyLaszlo FesusHungaryGeorg Martin FiedlerSwitzerlandJonine FigueroaUnited States of AmericaPier Luigi FiorellaItalyMassimo FiorilliItalyPaul FisherUnited States of AmericaFfolliott FisherUnited KingdomTom FlanaganIrelandJane FlintUnited States of AmericaCarlos FloresSpainFranco FolliUnited States of AmericaDominic FongItalyBernard FoxUnited States of AmericaCesari FrancescaItalyRodrigo FrancoUnited States of AmericaRichard FrankUnited States of AmericaKai FuUnited States of AmericaEtsuko FujiiJapanMinoru FukuchiJapanTsuyoshi FukushimaJapanKengo FuruichiJapanTatsuhiko FurukawaJapanMichael GabrielAustriaThomas GajewskiUnited States of AmericaSanjeev GalandeIndiaMaria GalindoSpainMaurizio GalloItalyGiovanni GambaroItalyDashiell GantnerAustraliaGiacomo GaribottoItalyStephen GatelyUnited States of AmericaSebastiano Gattoni-CelliUnited States of AmericaSubhash GautamUnited States of AmericaCarsten GeislerDenmarkCicek Gercel-TaylorUnited States of AmericaThomas GevaertBelgiumAlexander GhanemGermanyShobha GhoshUnited States of AmericaLuca GiacomelliItalyGianluigi GiannelliItalyGeoffrey GibneyUnited States of AmericaM Ian GilmourUnited States of AmericaElisa GiovannettiItalyPaul GissenUnited KingdomGabriella GobbiCanadaSayed GodaUnited KingdomAlessandra GodoyBrazilJacky GoetzFranceDavid GoldfarbUnited States of AmericaEny Maria Goloni BertolloBrazilCarmen GonzalezSpainWalter GotliebCanadaStephen GottschalkUnited States of AmericaMichael GrandnerUnited States of AmericaWilliam B. GrantUnited States of AmericaCatherine Gratas-Rabbia-R\u00e9FranceIris GroeneveldNetherlandsDavid GrossIsraelKenneth GrossmannUnited States of AmericaJin GuChinaJun GuChinaLuigina GuastiItalyGerardo GuiterQatarMaya GulubovaBulgariaJolanta GutkowskaCanadaBalazs Gy\u00f6rffyHungaryMandana Haack-S\u00f8rensenDenmarkJohn HaanenNetherlandsMichael HaaseGermanyTillie-Louise HackettCanadaJoerg HaierGermanyNiels HalamaGermanyHanan HamamySwitzerlandMichal HammelUnited States of AmericaHind Hamzeh-CognasseFranceTakahiko HaraJapanAlexandre HarariSwitzerlandPauline HarperSwedenJohan HartmanSwedenAmanda HarveyUnited KingdomElham HassenTunisiaIlmo HassinenFinlandJames HatcherUnited States of AmericaRobert HawkinsUnited KingdomDouik HayetTunisiaChao HeChinaPing-An HeChinaGrzegorz HelbigPolandRichard HellerUnited States of AmericaPeiman HemattiUnited States of AmericaAkseli HemminkiFinlandKaren HerbstUnited States of AmericaHenry HerceUnited States of AmericaGonzalo HerradonSpainKen HerrmannGermanyHelen HeslopUnited States of AmericaLuke HessonAustraliaMarie-Fran\u00e7oise HeymannFranceSarah HighlanderUnited States of AmericaHarry HillUnited States of AmericaHans H HirschSwitzerlandRobert HoffmanUnited States of AmericaYukihiro HojoJapanBruce HollisUnited States of AmericaUlrika HolmlundSwedenAndrew HoltUnited KingdomDavid HongUnited States of AmericaJin Tae HongKorea, SouthStephen HopkinsUnited KingdomCraig HorbinskiUnited States of AmericaRaymund E. HorchGermanyAkira HoriiJapanHisanori HoriuchiJapanKonstantin-A. 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PanelliUnited States of AmericaKlaus PantelGermanyConstantinos PantosGreeceGianpaolo PapaccioItalyLuis A PardoGermanyJoo-In ParkKorea, SouthJinho ParkKorea, SouthMaura ParkerUnited States of AmericaRobert PassierNetherlandsGregory PastoresUnited States of AmericaGeorge PatrinosNetherlandsAndreas PaulGermanyChrystal Paulos; Ph.D.United States of AmericaValerio PazienzaItalyAndr\u00e9 PelegrinFranceCatherine Pellat-DeceunynckFranceSalley PelsUnited States of AmericaDavid PenetarUnited States of AmericaWen-Huang PengTaiwanJeroen PenningsNetherlandsGeorge PentheroudakisGreeceEduardo Perez-GomezSpainShira PerlUnited States of AmericaAlessandro PerrellaItalyGianluca PerseghinItalyMario PetrettaItalyAnnacarmen PetrizzoItalyBrian PetroffUnited States of AmericaRaffaele PezzilliItalyMichael PiagnerelliBelgiumVincent PialouxFranceGerald PierardBelgiumMario PlebaniItalyNikolaus PlesnilaGermanyClaudia PlottelUnited States of AmericaRyszard PlutaUnited States of AmericaStergios PolyzosGreeceLaurentiu M. 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RestifoUnited States of AmericaSheikh RiazuddinPakistanGiovanni RicevutiItalyJennifer RicherUnited States of AmericaDaniel RicklinUnited States of AmericaRuggero RidolfiItalyClaudia RiedelUnited States of AmericaGregory RielyUnited States of AmericaPeter RiessGermanyGregory RigginsUnited States of AmericaDonata RimoldiSwitzerlandNeil RiordanUnited States of AmericaJon RittenbergerUnited States of AmericaHelen RizosAustraliaClinton RobbinsUnited States of AmericaBruno RobertFranceDavid RobertsonAustraliaAntonio RodriguezSpainJose RojoSpainCristina RomesUnited States of AmericaRafael RosellSpainAnna RosellUnited KingdomFrancesca RossiItalyFran\u00e7ois RossiItalyClaudia RubieGermanyStefan RuhlUnited States of AmericaSteve RussellUnited KingdomMugurel Constantin RusuRomaniaMarianna SabatinoUnited States of AmericaSandra SacreUnited KingdomEvangelista SagnelliItalyRyuichi SakaiJapanKhashayar SakhaeeUnited States of AmericaAntonio SalasSpainGil SallesBrazilAndrea SalmaggiItalyKonstantin SalnikowUnited States of AmericaLobelia SamavatiUnited States of AmericaMarta Sanchez-CarbayoSpainWilliam SandersUnited States of AmericaDario SangioloItalyLaura SanzSpainTakashi SasayamaJapanSeetharama Sastry KonduruQatarNoriyuki SatoJapanAlka SaxenaJapanDolores J. SchendelGermanyErwin SchleicherGermanyMichael SchmidtGermanyIngo Schmidt-WolfGermanyRoland SchmittSwedenRoland SchmitzUnited States of AmericaJonathan SchneckUnited States of AmericaPaul Magnus SchneiderSwitzerlandStephen SchneiderUnited States of AmericaAndreas SchoberAustriaThies SchroederUnited States of AmericaHanneke SchuitemakerNetherlandsPatrick SchulerGermanyGary SchwartzUnited States of AmericaSavino SciasciaItalyJean-Yves ScoazecFranceChristina SelingerAustraliaShantanu SenguptaIndiaM\u00aa Jose SerranoSpainGregor SersaSloveniaSomasekar SeshagiriUnited States of AmericaSana SfarTunisiaDan ShaChinaJames ShamUnited States of AmericaJingxuan ShanQatarDejing ShangChinaAnil ShankerUnited States of AmericaJian-Zhong ShaoChinaOrla SheilsIrelandJiangang ShenHong KongYou-Tang ShenUnited States of AmericaJixin ShiChinaHiroshi ShikuJapanAshish Chandra ShresthaNepalGalina ShurinUnited States of AmericaJason SicklickUnited States of AmericaHarpreet SinghGermanyDoug SippJapanSamuel SoUnited States of AmericaPaul SondelUnited States of AmericaClaudio SpadaItalyGiulio C. SpagnoliSwitzerlandDaniel SpeiserSwitzerlandPasquale SperlonganoItalyGeetha SrikrishnaUnited States of AmericaGiuseppe StabileItalyRumen StefanovBulgariaUlrike SteinGermanyKatarzyna Stolarz-SkrzypekPolandPeter StorzUnited States of AmericaDavid StroncekUnited States of AmericaRalf StummGermanyDan SuChinaJau-Ling SuenTaiwanSeigo SugiyamaJapanClaudio SustmannGermanyHiroshi SuzukiJapanPeter SvecSlovakiaArantxa TaberneroSpainMasami TakeiJapanYuichi TakiguchiJapanGiuseppe TambussiItalyKazuhiro TamuraJapanXiaohua TanChinaBee TanUnited KingdomVivek TanavdeSingaporeYuanjia TangChinaJun-Ming TangChinaPing TangUnited States of AmericaXao TangUnited States of AmericaKai-Fu TangChinaHua TangChinaParisa TaravatiUnited States of AmericaEvangelos TerposGreeceAnnalisa TerranegraItalyArchana ThakurUnited States of AmericaKelly Jean ThomasUnited States of AmericaJohn ThompsonAustraliaPer Thor StratenDenmarkHenrik ThorlaciusSwedenLing TianChinaIngeborg TinhoferGermanyCarlo TocchettiItalyShinsaku TogoJapanRene TolbaGermanySara TomeiQatarMaria Lina TorneselloItalyRosalba TorrisiItalyPaolo ToscoItalyHidenori ToyodaJapanLisbeth TranebjaergDenmarkChristopher TriggleQatarTakeshi TsubataJapanYutaka TsutsumiJapanSandra TuyaertsBelgiumHirotsugu UemuraJapanTakahiro UenishiJapanKenneth UgenUnited States of AmericaMats UlfendahlSwedenAnja UlmerGermanyGudrun Ulrich-MerzenichGermanyNadir UluTurkeyAhmet Tulga UlusTurkeyWalter UrbaUnited States of AmericaIsao UsuiJapanHassan VahidnezhadIranBahareh ValiCanadaHugo Van Den BergUnited KingdomSjoerd H. Van Der BurgNetherlandsJo Van GinderachterBermudaInge Van HoudtNetherlandsKatherine Van LoonUnited States of AmericaLaurens Van MeeterenNetherlandsHein Van PoppelBelgiumIsabelle Van SeuningenFranceGuido VanhamBelgiumMaria Giuliana VannucchiItalyTracy Vargo-GogolaUnited States of AmericaKimberly VarkerUnited States of AmericaDavid VaudryFranceSergia VelhoPortugalVijayalakhsmi VenkatesanIndiaPedro L VeraUnited States of AmericaMarion VermeulenSouth AfricaFabio VesciniItalyJohn VettoUnited States of AmericaNatassia VieiraUnited States of AmericaElizabeth VincanAustraliaMaria Luisa ViscianoItalyDavide VisigalliItalySantiago ViteriSpainLeticia VittoneArgentinaSimona VittoriniItalyK. David VoducCanadaPaul WalkerSwitzerlandSteffen WalterGermanyJasmin WalterSwitzerlandYinsheng WanUnited States of AmericaYaohe WangUnited KingdomYingqun WangUnited States of AmericaJun WangChinaXiangdong WangSwedenMing-Rong WangChinaWei WangChinaWeimin WangChinaXiangdong WangChinaYang WangUnited States of AmericaShengdian WangChinaMong-Heng WangUnited States of AmericaTianyi WangUnited States of AmericaChris WardUnited KingdomMasatoshi WatanabeJapanLouise WatsonUnited KingdomJeffrey WeberUnited States of AmericaLai WeiUnited States of AmericaEllen WeinbergUnited States of AmericaChristoph WeiserAustriaAthol WellsUnited KingdomFrits WijburgNetherlandsMarta WilhelmHungaryChristopher WingardUnited States of AmericaDavid WongUnited States of AmericaAndrea WorschechQatarYaguang XiUnited States of AmericaYunfei XiaChinaZuolin XiangChinaTing XieUnited States of AmericaLu XieChinaLi XingyiChinaBin XiongChinaRuian XUChinaZhenzhong XuUnited States of AmericaNaoki YamamotoJapanHiroki YamaueJapanJun YanUnited States of AmericaBin YangUnited KingdomAn-Gang YangChinaPan-Chyr YangTaiwanPeizeng YangChinaXiao-Feng YangUnited States of AmericaVictoria YeeUnited States of AmericaTe-Huei YehTaiwanSai YendamuriUnited States of AmericaJianming YingChinaLiu YingbinChinaKeiko YoshimotoJapanOsamu YoshinoJapanYongping YouChinaInchan YounKorea, SouthMuhammad Zubair YousafPakistanNasser YousifUnited States of AmericaHans YsselFranceRongjie YuChinaJianda YuanUnited States of AmericaKevin YuenUnited States of AmericaTakashi YugawaJapanAnna ZaczekPolandPaul ZajacSwitzerlandGianpaolo ZerbiniItalyBen ZeskindUnited States of AmericaHenrik ZetterbergSwedenZhongheng ZhangChinaLiping ZhangUnited States of AmericaHongquan ZhangCanadaXu Dong ZhangAustraliaYiqiang ZhangUnited States of AmericaQunzhou ZhangUnited States of AmericaXulong ZhangChinaYan ZhangChinaZiyan ZhaoChinaHong ZhaoChinaJie ZhengChinaRegina ZieglerUnited States of AmericaAnna Linda ZignegoItalyLynn ZijenahZimbabweNiklas ZojerAustriaSteven ZumbrunUnited States of America"}
+{"text": "Journal of the International Society of Sports Nutrition would like to thank all our reviewers who have contributed to the journal from Volume 12 (2015).The editors of  Adriana ColettaUnited States of AmericaAlan AragonUnited States of AmericaAlan WalkerUnited States of AmericaAlexei WongUnited States of AmericaAndrew BarnigerUnited States of AmericaAndrew JagimUnited States of AmericaAndrew JonesUnited KingdomAndrew ShaoUnited States of AmericaAnthony AlmadaUnited States of AmericaAnya EllerbroekUnited States of AmericaBeat KnechtleSwitzerlandBenjamin CarrUnited States of AmericaBenjamin WaxUnited States of AmericaBill CampbellUnited States of AmericaBrad SchoenfeldUnited States of AmericaBruno GualanoBrazilBryan ChungUnited States of AmericaBrynmor BreeseUnited KingdomCatalina CasaruUnited States of AmericaChad KerksickUnited States of AmericaChase HollmerUnited States of AmericaChris HarnishUnited States of AmericaChris LockwoodUnited States of AmericaChristopher MobleyUnited States of AmericaChristopher ScottUnited States of AmericaColin WilbornUnited States of AmericaConrad EarnestUnited States of AmericaDan BenardotUnited States of AmericaDaniel JaffeUnited States of AmericaDarren CandowCanadaDarryn WilloughbyUnited States of AmericaDavid BellarUnited States of AmericaDeclan ConnollyUnited States of AmericaDouglas KalmanUnited States of AmericaEdward WeissUnited States of AmericaElfego GalvanUnited States of AmericaEmma StevensonUnited KingdomEric TrexlerUnited States of AmericaErico CaperutoBrazilEva BlomstrandSwedenFernando NaclerioUnited KingdomGaetano CairoItalyGeoffrey HudsonUnited States of AmericaGlyn HowatsonUnited KingdomHector LopezUnited States of AmericaHubert LeeUnited States of AmericaJames FellAustraliaJason CholewaUnited States of AmericaJean FarupDenmarkJeffrey StoutUnited States of AmericaJenna BeckerUnited States of AmericaJennifer BunnUnited States of AmericaJeremy LoennekeUnited States of AmericaJernej KapusSloveniaJoan EckersonUnited States of AmericaJoel CramerUnited States of AmericaJonathan OliverUnited States of AmericaJordan JoyUnited States of AmericaJose AntonioUnited States of AmericaJoseph PellegrinoUnited States of AmericaJuan del Coso Garrig\u00f3sSpainJulie MinevichUnited States of AmericaKamal PatelCanadaKrista AustinUnited States of AmericaKyle LeversUnited States of AmericaLaurent BannockUnited KingdomLeigh BreenUnited KingdomLemuel TaylorUnited States of AmericaMark FogartyUnited KingdomMark J. TallonUnited KingdomMarvin HeuerUnited States of AmericaMichael RobertsUnited States of AmericaNeil JohannsenUnited States of AmericaNicholas RatamessUnited States of AmericaPablo Sanchez-SoriaCanadaPatrick DavittUnited States of AmericaPatrick JacobsUnited States of AmericaPaul CribbAustraliaPedro TaulerSpainPeter FitschenUnited States of AmericaRafael Longhi Sampaio de BarrosBrazilRalf J\u00e4gerUnited States of AmericaRobert OlekPolandRon MendelUnited States of AmericaRyan LoweryUnited States of AmericaSara CampbellUnited States of AmericaSara HaywardUnited States of AmericaSean CollinsUnited States of AmericaShannan LynchUnited States of AmericaShawn ArentUnited States of AmericaShawn WellsUnited States of AmericaStephanie DillonUnited KingdomStephanie MihalyUnited States of AmericaStephen BaileyUnited KingdomSteve SchmitzUnited States of AmericaSunita PotgieterSouth AfricaSusan KleinerUnited States of AmericaThomas KjeldDenmarkTim ZiegenfussUnited States of AmericaTodd AstorinoUnited States of AmericaTravis HarveyUnited States of AmericaValentina StojceskaUnited KingdomVictor Andrade-SouzaBrazilWill BrinkUnited States of AmericaXanne Janse de JongeAustraliaYang ZhangChina"}
+{"text": "International Journal of Pediatric Endocrinology would like to thank all of our reviewers, both external and Editorial Board Members, who have contributed to the journal in Volume 2014 (2014) and whose valuable support is fundamental to the success of the journal.The Editors of the  Deanna AdkinsUnited States of AmericaCraig AlterUnited States of AmericaJesus ArgenteSpainRichard AuchusUnited States of AmericaAhila AyyavooIndiaBert BachrachUnited States of AmericaAndrew BauerUnited States of AmericaGiorgio BedogniItalySheri BerenbaumAfghanistanPetter BjornstadUnited States of AmericaGianni BonaItalyWalter BonfigGermanyStuart BrinkUnited States of AmericaRa\u00fal CalzadaMexicoDionisios ChrysisGreeceLouise CominatoBrazilMehul DattaniUnited KingdomCatherine DinauerUnited States of AmericaElizabeth EstradaUnited States of AmericaErica EugsterUnited States of AmericaAmy FleischmanUnited States of AmericaGary FrancisUnited States of AmericaMichael FreemarkUnited States of AmericaHeather GilbertsonAustraliaMatti HeroFinlandKhalid HussainUnited KingdomJan IdkowiakUnited KingdomCraig JefferiesNew ZealandGeorge JehaUnited States of AmericaAlexander JorgeBrazilNicholas JospeUnited States of AmericaChirag KapadiaUnited States of AmericaPaul KaplowitzUnited States of AmericaCengiz KaraTurkeyLefkothea KaravitiUnited States of AmericaMimi KimUnited States of AmericaStephen La FranchiUnited States of AmericaAndrew LaneUnited States of AmericaPeter LeeUnited States of AmericaClaudio MaffeisItalyFarid MahmudCanadaThais MannaBrazilNelly MaurasUnited States of AmericaTom MazurUnited States of AmericaAngelika MohnItalyDick MulNetherlandsAnna Nordenstr\u00f6mSwedenJerrold OlshanUnited States of AmericaJennifer OsipoffUnited States of AmericaKenneth RobertsonUnited KingdomMaria Belen Roldan MartinSpainArlan RosenbloomUnited States of AmericaJudith RossUnited States of AmericaPaul SaengerUnited States of AmericaDavid SandbergUnited States of AmericaDorothy ShulmanUnited States of AmericaPeter SimmAustraliaJill SimmonsUnited States of AmericaPhyllis SpeiserUnited States of AmericaDennis StyneUnited States of AmericaSurendra VarmaUnited States of AmericaMaria VogiatziUnited States of AmericaEmily WalvoordUnited States of AmericaBenjamin WheelerNew ZealandAmy WisniewskiUnited States of AmericaJan-Maarten WitNetherlandsJoseph WolfsdorfUnited States of AmericaStefan WudyGermanyTohru YorifujiJapan"}
+{"text": "Conflict and Health would like to thank all our reviewers who have contributed to the journal in Volume 8 (2014).The editors of  Hirotsugu AigaJapanNeil AryaCanadaKarl BlanchetUnited KingdomMarleen BosmansBelgiumMoriah BrierUnited States of AmericaFrederick BurkleUnited States of AmericaAlessandro CassiniSwedenSandro ColomboSpainStephen ComminsUnited States of AmericaSusan CooksonUnited States of AmericaBart CrielBelgiumClaude de Ville de GoyetBelgiumJocelyn DeJongLebanonPamela DeLargyUnited States of AmericaWim DelvaSouth AfricaDelan DevakumarUnited KingdomLesley DoyalUnited KingdomAnbrasi EdwardUnited States of AmericaJack EldonUnited KingdomHelen ElseyUnited KingdomJeroen EnsinkUnited KingdomLarissa FastUnited States of AmericaNathan FordSouth AfricaNoriko FujitaJapanAnanda GalappattiSri LankaRichard GarfieldUnited States of AmericaAsha GeorgeUnited States of AmericaGregg GreenoughUnited States of AmericaAndre GriekspoorSwitzerlandTanya GuentherUnited States of AmericaDebby Guha-SapirBelgiumPeter HillAustraliaLara HoSwitzerlandKeng-Yen HuangUnited States of AmericaMichelle HynesUnited States of AmericaPaul IckxBelgiumSumit KaneNetherlandsUnni Krishnan KarunakaraIndiaStephanie KaydenUnited States of AmericaErin KennyUnited States of AmericaAlbert KilianSpainLouis LillywhiteUnited KingdomInas MahdiUnited States of AmericaSuman MajumdarAustraliaRobert MartenUnited States of AmericaTim MartineauUnited KingdomFarrah MateenUnited States of AmericaVerena MauchGermanyBarbara McPakeUnited KingdomWilliam MossUnited States of AmericaAdrianna MurphyUnited KingdomRobin NandyIndonesiaSonia NavaniUnited States of AmericaColleen O'ConnellCanadaEmilomo OgbeBelgiumDonal O'MathunaIrelandChristopher OrachUgandaKathleen O'ReillyUnited KingdomJennifer PalmerUnited KingdomPreeti PatelUnited KingdomEnrico PavignaniMozambiqueDuncan PedersenCanadaValerie PercivalCanadaCatherine PittUnited KingdomAnita RameshUnited KingdomElizabeth ReedUnited States of AmericaAmelia Reese MastersonUnited States of AmericaKristien RoelensBelgiumSimon RushtonUnited KingdomKhwaja Mir Islam SaeedAfghanistanOuahiba SakaniAlgeriaAbdul Tawab SaljuqiUnited States of AmericaJennifer ScottUnited States of AmericaSimukai ShamuSouth AfricaSudesh Raj SharmaNepalChesmal SiriwardhanaSri LankaJoyce SmithIndonesiaSarah SmithUnited KingdomDaya SomasundaramSri LankaEgbert SondorpUnited KingdomPaul SpiegelSwitzerlandEliana SuarezCanadaMay SudhinarasetUnited States of AmericaNathan TabackCanadaChristine Kirunga TashobyaUgandaAnnemarie ter VeenNetherlandsVianney TricouCentral African RepublicMargaret Usher-PatelUnited KingdomTine Van BortelUnited KingdomWim Van DammeBelgiumEdwin van TeijlingenUnited KingdomPatrick Van de VoordeBelgiumPeter VentevogelNetherlandsLena VerdeliUnited States of AmericaAnna WhelanAustraliaAshley WolfingtonUnited States of America"}
+{"text": "We and the Editorial Board sincerely acknowledge and thank all the reviewers for their active participation and contribution during 2014 (Volume 11). We greatly appreciate their dedication and behind the scenes contribution. It is largely due to their support and expertise that we have been able to publish high standard manuscripts. We would also like to thank authors for choosing Nutrition & Metabolism and contributing their cherished work to this journal. Sarah Abou MerhiUnited States of AmericaNader G. AbrahamUnited States of AmericaCharles AbramsonUnited States of AmericaAbdelaziz AbulelsaadEgyptNihal AhmadUnited States of AmericaKamal AminEgyptRobin AndersonUnited States of AmericaSusan ArthurUnited States of AmericaStella AslibekyanUnited States of AmericaRamy AttiaUnited States of AmericaMaurizio AvernaItalySalman AzharUnited States of AmericaAhmed BakillahUnited States of AmericaMichiel BalversNetherlandsTyler BarkerUnited States of AmericaDarius BatuleviciusLithuaniaJamie BaumUnited States of AmericaJuerg H BeerSwitzerlandElizabeth BeierleUnited States of AmericaDamien BelobrajdicAustraliaMartha BeluryUnited States of AmericaMelissa BentonUnited States of AmericaM'Hamed BentourkiaCanadaElizabeth Bertone-JohnsonUnited States of AmericaDeepak BhatnagarUnited KingdomSheng BiUnited States of AmericaJeffrey BillheimerUnited States of AmericaWilliam BlanerUnited States of AmericaEmanuela BostjancicSloveniaOlivier Bruy\u00e8reBelgiumMartin BurtscherAustriaAndrew ButlerUnited States of AmericaMonika CahovaCzech RepublicEdward CalabreseUnited States of AmericaPhilip CalderUnited KingdomMatthew CannonUnited States of AmericaLuciana CaperutoBrazilAnnalisa CastagnaItalyRolando CeddiaCanadaLisa CegliaUnited States of AmericaGiovanna CenacchiItalyXueying ChenUnited States of AmericaDong ChengUnited States of AmericaMi-La ChoKorea, SouthRobert CokerUnited States of AmericaIan CookSouth AfricaEmmanuel CossonFrancePhilippe CostetUnited States of AmericaGiuseppe CrescenziItalyStephen CunnaneCanadaAlexandre Da SilveiraBrazilDominic D'AgostinoUnited States of AmericaKezhi DaiUnited States of AmericaMark DalyUnited KingdomErick De OliveiraBrazilNicole De WitNetherlandsTam\u00e1s DecsiHungaryHans DegensUnited KingdomChristos DerdemezisGreeceLatha DeviUnited States of AmericaWen-Xing DingUnited States of AmericaMohamed DkhilSaudi ArabiaLharbi DridiCanadaSlavik DushenkovUnited States of AmericaMichael EadesUnited States of AmericaPeter EckCanadaAbdalla El-MowafyEgyptHenk EvertsNetherlandsRichard FeinmanUnited States of AmericaArny FerrandoUnited States of AmericaEduardo FerriolliBrazilYvonne FierzSwitzerlandCarmelo FioreItalyPavel FlachsCzech RepublicJames FleetUnited States of AmericaLeng Huat FooMalaysiaJu Yen FuMalaysiaJose FuentesSpainMary C. GannonUnited States of AmericaMingming GaoUnited States of AmericaDiego Garcia-DiazChileEduardo Garcia-FuentesSpainAmalia GastaldelliItalyAbhisek GhosalUnited States of AmericaBarbara GowerUnited States of AmericaOlaf GriskGermanyRomain HarmanceyUnited States of AmericaRobert HarrisUnited States of AmericaSusan HarrisUnited States of AmericaMorey HaymondUnited States of AmericaGerwin HellerAustriaDarren HenstridgeAustraliaChi-Tang HoUnited States of AmericaConrad HodgkinsonUnited States of AmericaAdenilda Honorio-Fran\u00e7aBrazilMary HonorsUnited States of AmericaPhilip HooperUnited States of AmericaChao-Tien HsuTaiwanYu HuangChinaJuha HulmiFinlandJahangir IqbalUnited States of AmericaEui-Bae JeungKorea, SouthXian-Cheng JiangUnited States of AmericaMirim JinKorea, SouthJulie JurenkaUnited States of AmericaDouglas KalmanUnited States of AmericaKonstantin KandrorUnited States of AmericaTadashi KawaiJapanDaniel KonradSwitzerlandMark KotowiczAustraliaChao-Qiang LaiUnited States of AmericaMarcia LatorracaBrazilDonald LaymanUnited States of AmericaM\u00e9lanie LemireCanadaTung Ming LeungUnited States of AmericaNate LewisUnited States of AmericaKe LiUnited States of AmericaRui LiUnited States of AmericaQiang LiUnited States of AmericaFabio LimaBrazilPao-Hwa LinUnited States of AmericaI-Min LiuTaiwanGeorge LiuChinaKiatlyn LiuUnited States of AmericaAgnieszka LobodaPolandJose Lopez-MirandaSpainEmil LouUnited States of AmericaGuojun LuUnited States of AmericaBing LuanUnited States of AmericaMarco MancaNetherlandsGaowei MaoUnited States of AmericaMaria Raquel Mar\u00e7al NataliBrazilM. Carmen MartinezFranceVera MazurakCanadaBodo MelnikGermanyAli MetwalliSaudi ArabiaChristine MiaskowskiUnited States of AmericaLuca MieleItalyMohammad MinhajuddinUnited States of AmericaBettina MittendorferUnited States of AmericaMahmoud MohammadUnited States of AmericaSrinidi MohanUnited States of AmericaLesley MoiseyCanadaMaria MurholmDenmarkElza MuscelliBrazilThirupathi MuthusamyUnited States of AmericaFernando NaclerioUnited KingdomTakafumu NagatomoJapanJoseph NickelsUnited States of AmericaEstela Maria NovakBrazilToshikatsu OkumuraJapanRytas OstrauskasLithuaniaAlok PachoriUnited States of AmericaXiaoyue PanUnited States of AmericaAthanasios G. PapavassiliouGreeceSandra PeakeAustraliaMichael PearenAustraliaSandra PetersCanadaStephen PhinneyUnited States of AmericaHanno PijlNetherlandsEarl PrinslooSouth AfricaSpencer ProctorCanadaDenis Prud'HommeCanadaRadhakrishna RaoUnited States of AmericaAngela ResendeBrazilJong RhoCanadaDenis RichardCanadaGerald RimbachGermanyRoberto RivabeneItalyCatarina Rodrigues Dos SantosPortugalJean-Max RouanetFranceHelene RundqvistSwedenArkady RutkovskiyNorwayJennifer RyanUnited KingdomFermin Sanchez De MedinaSpainSushma SharmaUnited States of AmericaFareeba SheedfarNetherlandsLaura SheltonUnited States of AmericaSangeetha ShyamMalaysiaAdrian SleeUnited KingdomJames SohUnited States of AmericaEvelien SohlNetherlandsGuisheng SongUnited States of AmericaCarol Souza Da SilvaNetherlandsShanthi SrinivasanUnited States of AmericaAlan SteelUnited KingdomBarbara StrasserAustriaAnne SumnerUnited States of AmericaGuang SunCanadaCenk SuphiogluAustraliaArthur SwislockiUnited States of AmericaToshiaki TamakiJapanDaniel TeitelbaumUnited States of AmericaInge TetensDenmarkMarie ThearleUnited States of AmericaMin TianUnited States of AmericaUwe TietgeNetherlandsAngela TingUnited States of AmericaJanet TouUnited States of AmericaRobbert TouwslagerNetherlandsUlrike TrendelenburgUnited KingdomTsuyoshi TsudukiJapanMariko UeharaJapanAngela ValverdeSpainEvert Van SchothorstNetherlandsVasundara VenkateswaranCanadaAdriana C VidalUnited States of AmericaMeghan WalshUnited States of AmericaWan Zurinah Wan NgahMalaysiaDoug WardUnited KingdomHope WeilerCanadaKlaas WesterterpNetherlandsMargriet Westerterp-PlantengaNetherlandsWanwarang WongcharoenThailandZengying WuUnited States of AmericaMin XiaChinaXunde XianUnited States of AmericaFeifei XiaoUnited States of AmericaYuquan XiongUnited States of AmericaKazumasa YamagishiUnited States of AmericaHua YangChinaKaiping YangCanadaQinglin YangChinaZhong YeUnited States of AmericaMasanori YoshizumiJapanKai YuanUnited States of AmericaFouad ZakhariaUnited States of AmericaXiaodong ZhangUnited States of AmericaJinzhong ZhangUnited States of America"}
+{"text": "International Journal of Pediatric Endocrinology would like to thank all of the reviewers who have contributed to the journal in 2015.The editor of  Alan RogolUnited States of AmericaAlexander JorgeBrazilAlicia RomanoUnited States of AmericaAmanda AckermannUnited States of AmericaAmbika AshrafUnited States of AmericaAndrew DauberUnited States of AmericaAndrew LaneUnited States of AmericaArchana AryaUnited States of AmericaArlan RosenbloomUnited States of AmericaBrenda KohnUnited States of AmericaCraig AlterUnited States of AmericaCraig JefferiesNew ZealandDaina DreimaneUnited States of AmericaDaniel DeSalvoUnited States of AmericaDennis StyneUnited States of AmericaDorothy ShulmanUnited States of AmericaEdward ReiterUnited States of AmericaFlavia ProdamItalyGrace TanninUnited States of AmericaJan IdkowiakUnited KingdomJan-Maarten WitNetherlandsJennifer OsipoffUnited States of AmericaJohn FuquaUnited States of AmericaJonathan WassermanCanadaJoshua MillerUnited States of AmericaKathleen BethinUnited States of AmericaKimberly TafuriUnited States of AmericaLefkothea KaravitiUnited States of AmericaLiuska PesceUnited States of AmericaMaria VogiatziUnited States of AmericaMario RotondiItalyMaya LodishUnited States of AmericaMehul DattaniUnited KingdomMeilan RutterUnited States of AmericaMunier NourCanadaNicholas JospeUnited States of AmericaOlga GuptaUnited States of AmericaPatricia VuguinUnited States of AmericaPaul KaplowitzUnited States of AmericaPaulo Collett-SolbergBrazilPhilip ZeitlerUnited States of AmericaRobert RosenfieldUnited States of AmericaRubina HeptullaUnited States of AmericaSara DiVallUnited States of AmericaSara WatsonUnited States of AmericaScott RivkeesUnited States of AmericaSungdae MoonSouth KoreaSurendra VarmaUnited States of AmericaSusan SchuvalUnited States of AmericaSusanne CabreraUnited States of AmericaTheo SasNetherlandsTracy BekxUnited States of AmericaWalter BonfigGermanyZeynep SiklarTurkey"}
+{"text": "Biotechnology for Biofuels would like to thank all our reviewers who have contributed to the journal in Volume 7 (2014).The editors of  Gabriel AcienSpainDilip AdhikariIndiaWilliam AdneyUnited States of AmericaGeorge AggelisGreeceM. Kalim AkhtarUnited KingdomEva AlbersSwedenJo\u00e3o R.M. AlmeidaBrazilHal AlperUnited States of AmericaJean AlricFranceDiletta AmiItalyDanuta Maria AntosiewiczPolandAna ArabolazaArgentinaPatricia ArmshawIrelandFrances ArnoldUnited States of AmericaVincent ArondelFranceMikko ArvasFinlandShota AtsumiUnited States of AmericaClaudio Avignone-RossaUnited KingdomHyeun-Jong BaeKorea, SouthFengwu BaiChinaJohn BakerUnited States of AmericaScott BakerUnited States of AmericaRobert BakkerNetherlandsVenkatesh BalanUnited States of AmericaPetr BaldrianCzech RepublicMercedes BallesterosSpainNarcisa BandarraPortugalJie BaoChinaBrian BarrUnited States of AmericaAmanda BarryUnited States of AmericaRoberto BassiItalyJacqueline BatleyAustraliaKhorcheska BatyrovaCanadaStefan BauerUnited States of AmericaGregg BeckhamUnited States of AmericaIsabel BeloPortugalJohn BenemannUnited States of AmericaJ. Philipp BenzGermanyBryan BergerUnited States of AmericaNicolas BernetFranceJean-Guy BerrinFranceAlexandre BessonFranceAaron BestUnited States of AmericaMaurizio BettigaSwedenSamarthya BhagiaUnited States of AmericaBalasubramaniyan BharathirajaIndiaPeter BielySlovakiaNatascia BiondiItalyKenneth BischoffUnited States of AmericaAjaya BiswalUnited States of AmericaHans BlaschekUnited States of AmericaWout BoerjanBelgiumRafal Bogel-LukasikPortugalSivia BoladoSpainEckhard BolesGermanyYannick BombleUnited States of AmericaElba BonBrazilNicklas BonanderSwedenAntonio BonomiBrazilMallika BoonmeeThailandIlya BorovokIsraelSuncica BosakCroatiaFederica BrandizziUnited States of AmericaPaola BranduardiItalyNicholas BreretonUnited KingdomOrianna BretschgerUnited States of AmericaGuido BreuerNetherlandsJeff BroadbentUnited States of AmericaSteven BrownUnited States of AmericaHarry BrumerCanadaPhillip BrummUnited States of AmericaTim BuggUnited KingdomVincent BuloneSwedenRenata BuraUnited States of AmericaZeynep Petek CakarTurkeyThomas CanamUnited States of AmericaDanilo A. CanteroSpainCarlos Ariel CardonaColombiaHelene CarrereFranceJulie CarrierUnited States of AmericaSerge CasaregolaFranceEulogio CastroSpainMar\u00eda del Carmen Cer\u00f3n-Garc\u00edaSpainAnuj ChandelBrazilJo-Shu ChangTaiwanJongsoo ChangKorea, SouthAfroditi ChatzifragkouUnited KingdomShuqing ChenChinaHongzhang ChenChinaNing ChenChinaRachel ChenUnited States of AmericaXiaowen ChenUnited States of AmericaKit Ling ChinMalaysiaPaul ChristakopoulosSwedenPanagiotis ChrysanthopoulosAustraliaMarek CieplakPolandAlan CollmerUnited States of AmericaLydia ContrerasUnited States of AmericaQiu CuiChinaJean-Marc DaranNetherlandsAl DarzinsUnited States of AmericaGideon DaviesUnited KingdomMarcos Antonio de Morais JrBrazilPascale de PhilipFranceRonald de VriesNetherlandsSteve DeckerUnited States of AmericaLuis Del RioCanadaMatthew DeLisaUnited States of AmericaMarie DemuezSpainSantino Di BerardinoPortugalBruce DienUnited States of AmericaShi-You DingUnited States of AmericaElio DinuccioItalyDavide DionisiUnited KingdomRichard DixonUnited States of AmericaLucilia DominguesPortugalBryon DonohoeUnited States of AmericaJennifer DunnUnited States of AmericaRobert DunnUnited States of AmericaVincent EijsinkNorwayThomas ElderUnited States of AmericaJames ElkinsUnited States of AmericaStacia EngelUnited States of AmericaMarta Esteban ClaresSpainThaddeus EzejiUnited States of AmericaJinxia FanChinaMing FanCanadaXu FangChinaJianMin fangUnited KingdomPedram FatehiCanadaClaus FelbyDenmarkBruno FernandesPortugalFrancisco Jesus Fernandez MoralesSpainRoberto Fernandez-LafuenteSpainManuel FerrerSpainOliver FiehnUnited States of AmericaOliver FiehnGermanyHenri-Pierre FierobeFranceStephen FongUnited States of AmericaC\u00e9sar FonsecaPortugalLuis FonsecaPortugalMarcus FostonUnited States of AmericaEric FouillandFranceBrian FoxUnited States of AmericaJean Marie FrancoisFranceAnnaliese FranzUnited States of AmericaRuth FreitagGermanyTodd FrenchUnited States of AmericaStephen C. FryUnited KingdomTatsuhito FujimuraJapanEiichiro FukusakiJapanMats GalbeSwedenAnli GengSingaporeFernando GentaBrazilRichard GiannoneUnited States of AmericaThierry GiardinaFranceDonna GibsonUnited States of AmericaNotburga GierlingerAustriaHarry GilbertUnited KingdomFrancisco GirioPortugalRosana GoldbeckBrazilLeonardo GomezUnited KingdomRaquel B. G\u00f3mez-CocaSpainKatsuya GomiJapanPaula GoncalvesPortugalCristina Gonzalez-FernandezSpainUrsula GoodenoughUnited States of AmericaJohann GorgensSouth AfricaSteven GorsichUnited States of AmericaHugo GramajoArgentinaMelinda GriffithsSouth AfricaBernhard GrimmGermanyDominique GrizeauFranceAmy GrundenUnited States of AmericaMichael GuarnieriUnited States of AmericaLuis Tiago GuerraPortugalFabienne GuillonFranceStephane GuillouetFranceGia-Luen GuoTaiwanVijay Kumar GuptaIrelandAna GutierrezSpainYitzhak HadarIsraelPatrick HallenbeckCanadaJason HallettUnited KingdomClaire HalpinUnited KingdomSung Ok HanKorea, SouthPaul HarrisUnited States of AmericaAnnele HatakkaFinlandMingxiong HeChinaLucy HeapUnited KingdomRonald HectorUnited States of AmericaEric HeggUnited States of AmericaJuergen HeinischGermanyKlaas Jan HellingwerfNetherlandsBernard HenrissatFranceMichael HensonUnited States of AmericaIsabelle Herpo\u00ebl-GimbertFranceRobert HettichUnited States of AmericaMark HildebrandUnited States of AmericaSerge HiligsmannBelgiumMaria HingsamerAustriaDavid HodgeUnited States of AmericaSeong Joo HongKorea, SouthSvein Jarle HornNorwayLihua HouChinaBo HuUnited States of AmericaJinguang HuCanadaHong-Ying HuChinaPaul HudsonSwedenPatrick HuntUnited States of AmericaDavid IbarraSpainLonnie IngramUnited States of AmericaHiroyuki InoueJapanMakio IwahashiJapanJavier IzquierdoUnited States of AmericaSebastian JaenickeGermanyNeeraj JainIndiaSarath Chandra JangaUnited States of AmericaChrister JanssonUnited States of AmericaKaemwich JantamaThailandGrzegorz JanuszPolandThomas JeffriesUnited States of AmericaDieter JendrossekGermanyTina JeohUnited States of AmericaMingjie JinUnited States of AmericaYong-Su JinUnited States of AmericaVladimir JiranekAustraliaKatja Salomon JohansenDenmarkSussai John VennisonIndiaWayne JohnstonAustraliaPatrik JonesUnited KingdomHenning JorgensenDenmarkYi-Hsu JuTaiwanUldis KalnenieksLatviaYoichi KamagataJapanKaty KaoUnited States of AmericaLevente KaraffaHungaryDimitar KarakashevDenmarkKaisa KarhumaaSwedenBaljinder KaurIndiaKatariina KemppainenFinlandChristian KennesSpainSung-Koo KimKorea, SouthSeon-Won KimKorea, SouthSylvia KlaubaufSwedenMario KlimacekAustriaKeith KlineUnited States of AmericaPaul KnoxUnited KingdomCaner KocTurkeyKonrad KochGermanyKari KoivurantaFinlandAkihiko KondoJapanYoon-Mo KooKorea, SouthMaarten KootstraNetherlandsRakesh KoppramAustriaKatalin KovacsUnited KingdomKrisztina KovacsSwedenKorn\u00e9l L. Kov\u00e1csHungaryAndrey KovalevskyUnited States of AmericaPreben KrabbenUnited KingdomEmma KreugerSwedenMichael Krogh JensenDenmarkPeter KrothGermanyNathan Kruer-ZerhusenUnited States of AmericaOlaf KruseGermanyMalgorzata KrzywonosPolandChristian P. KubicekAustriaRamesh Chander KuhadIndiaRavindra KumarIndiaLinoj KumarCanadaRajeev KumarUnited States of AmericaSuresh KumarIndiaTa\u00eds Mayumi KuniyoshiBrazilMichael LadischUnited States of AmericaAino-Maija LakaniemiFinlandJerald LalmanCanadaAlicia Lammerts van BuerenNetherlandsLouis LandesmanUnited States of AmericaNuno LapaPortugalMagin LapuertaSpainEdmundo LarenasUnited States of AmericaJohan LarsbrinkNorwayChrister LarssonSwedenLieve LaurensUnited States of AmericaDong-Yup LeeSingaporeKeat Teong LeeMalaysiaEun Yeol LeeKorea, SouthHung LeeCanadaSang Yup LeeKorea, SouthSang Hun LeeUnited States of AmericaSeokhwan LeeKorea, SouthTaek Soon LeeUnited States of AmericaY. Y. LeeUnited States of AmericaGustavo LeiteCanadaGuillaume LetellierFranceFrederick LeungHong KongDavid LevinCanadaOrly LevitanUnited States of AmericaChenlin LiUnited States of AmericaJian-Jun LiChinaShengying LiChinaPengfu LiChinaRobert LiUnited States of AmericaSi-Yu LiTaiwanShizhong LiChinaYan LiAustraliaYantao LiUnited States of AmericaYuanguang LiChinaYonghua Li-BeissonFranceGunnar LidenSwedenCarol Sze Ki LinHong KongSenjie LinUnited States of AmericaPhilipp LinsAustriaDehua liuChinaYan LiuUnited States of AmericaZ. Lewis LiuUnited States of AmericaIrakli LoladzeUnited States of AmericaTeresa Lopes da SilvaPortugalIsabel M. Lopez-LaraMexicoJohn LoveUnited KingdomC\u00e2ndida LucasPortugalRoland LudwigAustriaAndriy LuzhetskyyGermanyLee LyndUnited States of AmericaKesen MaCanadaXiaojun MaChinaWarren MabeeCanadaRobert L. MachAustriaRobert MachAustriaAlasdair MackenzieNorwayRod MackieUnited States of AmericaStefano MacrelliSwedenNirupama MallickIndiaSilvio ManginiItalyPaloma ManzanaresSpainChristos MaraveliasUnited States of AmericaAntoine MargeotFranceIsabel MarquesPortugalPaula MarquesPortugalMark MartenUnited States of AmericaVincent MartinCanadaAlfredo MartinezMexicoAlain MartyFranceEmma MasterCanadaRoberto MazzoliItalyRichard MeilanUnited States of AmericaRodrigo MendesBrazilAngel MeridaSpainAnne S. MeyerDenmarkVera MeyerGermanyYun-gen MiaoChinaRowan A.C. MitchellUnited KingdomEric MoelleringUnited States of AmericaDebra MohnenUnited States of AmericaEmilio Molina GrimaSpainFrederic MonotFranceBeronda MontgomeryUnited States of AmericaStephen MooseUnited States of AmericaEly MoragIsraelJose Moran-MirabalCanadaJos\u00e9 Luis MorenoSpainHaruhide MoriJapanMelanie MormileUnited States of AmericaUffe MortensenDenmarkNathan MosierUnited States of AmericaPatr\u00edcia MouraPortugalSujatha MulpuriIndiaAndrew MunroUnited KingdomKoenraad MuylaertBelgiumNick NagleUnited States of AmericaEndre NagyHungarySatish NairUnited States of AmericaKazunori NakashimaJapanShunichi NakayamaJapanJarunya NarangajavanaThailandNeelakantam NarendranathUnited States of AmericaDonald NatvigUnited States of AmericaJose NeryBrazilWilliam NesUnited States of AmericaHelena NevalainenAustraliaElke NevoigtGermanyJean-Marc NicaudFranceNancy NicholsUnited States of AmericaBernd NidetzkyAustriaCatherine NiuCanadaBeatriz NobrePortugalSue NokesUnited States of AmericaIntawat NookaewSwedenJoakim NorbeckSwedenBirgir NorddahlDenmarkToshihiro ObataGermanyMichael O'DonohueFranceKyeong Keun OhKorea, SouthMin-Kyu OhKorea, SouthPiotr Oleskowicz-PopielPolandJose Miguel OlivaSpainAna Cristina OliveiraPortugalMarina Oliveira de Souza DiasBrazilKim OlofssonDenmarkDaniel OlsonUnited States of AmericaBenny PalmqvistSwedenXuejun PanUnited States of AmericaSeraphim PapanikolaouGreeceE. Terry PapoutsakisUnited States of AmericaPrathap ParameswaranUnited States of AmericaVolkmar PassothSwedenFrancisco I. Javier PastorSpainGilles PeltierFranceJohn PetersUnited States of AmericaLoukas PetridisUnited States of AmericaDimitris PetroutsosFranceRiikka PiispanenFinlandDomenico PirozziItalyJon PittmanUnited KingdomJandora PoliBrazilPhillip PopeNorwayMatthew PosewitzUnited States of AmericaAntje PotthastAustriaRobert PowersUnited States of AmericaRolf PradeUnited States of AmericaKristala PratherUnited States of AmericaJeremy PruvostFranceYuqi QinChinaYinbo QuChinaSathishkumar RamalingamIndiaArthur RagauskasUnited States of AmericaJenni RahikainenFinlandArthur F.J. RamachandriyaNetherlandsKarthikeyan DharmanUnited States of AmericaLuiz RamosBrazilRoberto RanaItalyReza RanjbarNetherlandsAaron RashotteUnited States of AmericaEric RecordFranceGhufran RedzwanMalaysiaJennifer ReedUnited States of AmericaLars RehmannCanadaPeter RichardFinlandHanno RichterUnited States of AmericaDaniel RigdenUnited KingdomBarbara RinconSpainJukka RintalaFinlandIsabel RochaPortugalPaul RoesslerUnited States of AmericaPeter RogersAustraliaManuela RolliniItalyJose RomeroSpainShaunita RoseSouth AfricaAlexander RubanUnited KingdomWattiez RuddyBelgiumAnne RuffingUnited States of AmericaAnas SaadeddinSpainJack SaddlerCanadaDaad SaffariniUnited States of AmericaKazuo SakkaJapanDeanne SammondUnited States of AmericaMats SandgrenSwedenAnders Sandstr\u00f6mSwedenSanjayaUnited States of AmericaFrank SargentUnited KingdomIlona Sarvari HorvathSwedenHisashi SatohJapanLuc SaulnierFranceShigeki SawayamaJapanGary SawersGermanyChristopher ScarlataUnited States of AmericaMichael ScharfUnited States of AmericaHenrik SchellerUnited States of AmericaBettina Schiel-BengelsdorfGermanyJonathan SchillingUnited States of AmericaAndreas SchirmerUnited States of AmericaRobert SchmidtUnited States of AmericaMonika SchmollAustriaAnna Schn\u00fcrerSwedenJohannes ScholtenUnited States of AmericaAugusto SchrankBrazilKathrin SchrickUnited States of AmericaWolfgang SchwarzGermanyAlexander SczyrbaGermanyBernhard SeibothAustriaMichael SeligDenmarkLuis SerranoSpainOsman Ugur SezermanTurkeyA. Joe ShawUnited States of AmericaReshma ShettyUnited States of AmericaHaifeng ShiUnited States of AmericaJian ShiUnited States of AmericaHojae ShimMacaoHyun-Dong ShinUnited States of AmericaVerena SiewersSwedenJean-Claude SigoillotFrancePedro Sim\u00f5esPortugalSteven SingerUnited States of AmericaMunir SkafBrazilKelly SkinnerUnited States of AmericaRaphael SladeUnited KingdomJohn SlatteryUnited KingdomEmily SmithUnited States of AmericaHyohak SongKorea, SouthMorten S\u00f8rlieNorwayAna Maria Souto-MaiorBrazilRiccardo SpacciniItalyRichard SparlingCanadaAlfons StamsNetherlandsEric SteenUnited States of AmericaJonathan StickelUnited States of AmericaGerlind SulzenbacherFranceRun-Cang SunChinaSandhya SwaminathanIndiaEdyta SzewczykUnited States of AmericaEriko TakanoUnited KingdomYue-Qin TangChinaYinjie J. TangUnited States of AmericaSarah TeterUnited States of AmericaJohan TheveleinBelgiumLeya ThomasIndiaChaoguang TianChinaMing TienUnited States of AmericaFolke TjerneldSwedenElia Tomas-PejoSpainGiuseppe TorzilloItalyTina TranAustraliaKaren TrchounianArmeniaArmen TrchounianArmeniaCong TrinhUnited States of AmericaMaobing TuUnited States of AmericaGregory TuckerUnited KingdomWallace TynerUnited States of AmericaCirano UlhoaBrazilDaisuke UmenoJapanBreeanna UrbanowiczUnited States of AmericaJean-Louis UribelarreaFranceMari ValkonenFinlandJohan Van GroenestijnNetherlandsAntonius van MarisNetherlandsJolanda van MunsterUnited KingdomEd van NielSwedenDries VandammeBelgiumHerve VanderschurenSwitzerlandMarco VanoniItalyCristian VarelaAustraliaJoao VarelaPortugalArul Mozhy VarmanUnited States of AmericaAnik\u00f3 V\u00e1rnaiNorwayDimitris VayenasGreeceRafael Vazquez-DuhaltMexicoWim VermaasUnited States of AmericaSimone VincenziItalyJaap VisserNetherlandsHeinrich VolschenkSouth AfricaKeith WaldronUnited KingdomLarry WalkerUnited States of AmericaOla WallbergSwedenDirk WaltherGermanyChengshu WangChinaMichael WangUnited States of AmericaWei WangChinaZhongming WangChinaWeiliang WangChinaXin WangChinaHui WeiUnited States of AmericaPaul WeimerUnited States of AmericaBjorge WesterengNorwayPeter WesthDenmarkJanet WestphelingUnited States of AmericaChristian WilhelmGermanyDavid WilsonUnited States of AmericaGideon WolfaardtCanadaAaron WrightUnited States of AmericaMark WrightUnited States of AmericaJin Chuan WuSingaporeGuojiang WuChinaMo XianChinaEduardo XimenesUnited States of AmericaXin-Hui XingChinaBingqian XuUnited States of AmericaJian XuChinaZeng-Fu XuChinaShihui YangUnited States of AmericaSheng YangChinaHong-Wei YenTaiwanCarl YeomanUnited States of AmericaMinyeong YooFranceHo-Sung YoonKorea, SouthChun YouUnited States of AmericaJiujiang YuUnited States of AmericaJoshua YuanUnited States of AmericaQipeng YuanChinaGuido ZacchiSwedenAn-Ping ZengGermanyMin ZhangUnited States of AmericaXiao ZhangUnited States of AmericaY-H Percival ZhangUnited States of AmericaXiming ZhangChinaGuang ZhaoChinaZongbao ZhaoChinaJizhong ZhouUnited States of AmericaZhi-Gang ZhouChinaZhihua ZhouChinaFrancesco ZimbardiItalyMin-Hua ZongChina"}
+{"text": "Cell & Bioscience would like to thank all the reviewers who contributed to the journal in 2014.The editors of  Sunil AcharyaUnited States of AmericaJordi BarbeSpainVsevolod BelousovRussian FederationBeatrice CardinaliItalyPetr CejkaSwitzerlandPooja ChadhaUnited States of AmericaWai Yee ChanChinaSiew Wee ChanSingaporeVera SF ChanHong KongChuang-Rung ChangTaiwanRaymond Chuen-Chung ChangHong KongYu-sun ChangTaiwanBo-Shiun ChenUnited States of AmericaChaoping ChenUnited States of AmericaYonglong ChenChinaDidi ChenUnited States of AmericaGuoxun ChenUnited States of AmericaPei-Yu ChenUnited States of AmericaRong ChenAustraliaWei-June ChenTaiwanXiaolei ChenUnited States of AmericaYu ChenUnited States of AmericaYa-Hui ChiTaiwanJustin Jang Hann ChuSingaporeMingxing ChuChinaEva CoreyUnited States of AmericaMary DassoUnited States of AmericaLester DavidsSouth AfricaMatthew DeBergeUnited States of AmericaChangwang DengUnited States of AmericaQiurong DingUnited States of AmericaSheng DingUnited States of AmericaJingqi DuanUnited States of AmericaElia DuhUnited States of AmericaQian FengNetherlandsYulong FuUnited States of AmericaAkiyoshi FukamizuJapanQiang GanUnited States of AmericaGuoquan GaoChinaKai GeUnited States of AmericaAi-Di GuUnited States of AmericaPeixuan GuoUnited States of AmericaSanjay GuptaUnited States of AmericaBrett HamblyAustraliaEmma Hamilton-WilliamsAustraliaZhipeng HanChinaLawrence HaywardUnited States of AmericaLiqiang HeUnited States of AmericaYunlong HeUnited States of AmericaShanshan HeUnited States of AmericaYunlong HeUnited States of AmericaVictor HsiaUnited States of AmericaYi-Chiang HsuTaiwanJiancheng HuUnited States of AmericaWenhui HuUnited States of AmericaChuanshu HuangUnited States of AmericaJian HuangChinaMalik HussainAustraliaYoshifumi ItohUnited KingdomZongchao JiaCanadaLili JiangChinaSibo JiangUnited States of AmericaPeng JinUnited States of AmericaShouguang JinUnited States of AmericaHung-Ying KaoUnited States of AmericaJames L. KeckUnited States of AmericaTatsuo KidoUnited States of AmericaHwan Myung KimKoreaChi-Hon LeeUnited States of AmericaTae Jin LeeUnited States of AmericaSy-Jye LeuTaiwanChuan-Yun LiChinaQihan LiChinaChao LiUnited States of AmericaMingtao LiChinaZichong LiUnited States of AmericaQiao LiCanadaShengwen Calvin LiUnited States of AmericaXuhang LiUnited States of AmericaZhongji LiaoUnited States of AmericaAifu LinUnited States of AmericaDing-Yen LinTaiwanXiaowen LiuUnited States of AmericaShan-Lu LiuUnited States of AmericaKiatlyn LiuUnited States of AmericaAmy LoHong KongJianfeng LuUnited States of AmericaZhigang LuUnited States of AmericaVivian LuiHong KongLi MaUnited States of AmericaM. Murali Kannan MaruthamuthuIndiaCraig McLachlanAustraliaDuojiao NiUnited States of AmericaRichard NilesUnited States of AmericaSuman PaulUnited States of AmericaAimin PengUnited States of AmericaXiao PengUnited States of AmericaHarish Nair RamanathanUnited States of AmericaG\u00a0V RaoIndiaUrsula RauchGermanyWilliam RedmondUnited States of AmericaJelena Rnjak-KovacinaAustraliaJean-Marc SabatierFranceMitali Sarkar-TysonUnited KingdomKristina SchmidtUnited States of AmericaDavid SchneiderUnited States of AmericaHuanjie ShaoUnited States of AmericaAshwani SharmaUnited States of AmericaQunxin SheDenmarkC. K. James ShenTaiwanHan-Ming ShenSingaporeJinfeng ShenUnited States of AmericaBing ShenChinaXuan-Zheng ShiUnited States of AmericaYufang ShiChinaSanjeev ShuklaUnited States of AmericaJay SinghUnited States of AmericaWenqiang SongUnited States of AmericaYang SongUnited States of AmericaMarina StanilovaBulgariaYi Henry SunTaiwanKai SunChinaMahima SwamyUnited KingdomDorian SwartsUnited KingdomKatalin SzasziCanadaMing TanUnited States of AmericaYuichiro TanakaUnited States of AmericaSai-Wen TangUnited States of AmericaYanmei TaoChinaChenxi TianUnited States of AmericaMing-Jer TsaiUnited States of AmericaToshikazu UshijimaJapanAlessandro VindigniUnited States of AmericaBing WangUnited States of AmericaHonghe WangUnited States of AmericaRongfu WangUnited States of AmericaShaoying WangUnited States of AmericaTuanlao WangChinaXingsheng WangUnited States of AmericaYi-Ching WangTaiwanYu WangUnited States of AmericaLixin WeiChinaQing WeiUnited States of AmericaTao WeitaoUnited States of AmericaJiemin WongChinaChi-Ming WongHong KongMin WuUnited States of AmericaGutian XiaoUnited States of AmericaPing XieChinaShunbin XiongUnited States of AmericaMingxuan XuUnited States of AmericaLi YeUnited States of AmericaVenkat YedavalliUnited States of AmericaPaul YenSingaporeHao YingChinaKenji YoshidaJapanChundong YuChinaDihua YuUnited States of AmericaHanna YuanTaiwanAnn Marie ZavackiUnited States of AmericaMu-Sheng ZengChinaJiangwei ZhangUnited States of AmericaMingliang ZhangUnited States of AmericaXiang ZhangUnited States of AmericaYanling ZhangUnited States of AmericaGong ZhangChinaLi ZhangChinaZhengmao ZhangUnited States of AmericaRichard Y ZhaoUnited States of AmericaHui ZhaoHong KongZhengyi ZhaoUnited States of AmericaChao ZhengUnited States of AmericaZhi-Ming ZhengUnited States of AmericaWeimin ZhongUnited States of AmericaJun ZhouChinaRongjia ZhouChinaWen ZhouUnited States of AmericaZhou ZhouUnited States of AmericaJun ZhuUnited States of AmericaFangfang ZhuUnited States of AmericaShunyi ZhuChinaWei-Xing ZongUnited States of America"}
+{"text": "World Journal of Emergency Surgery\u2014which received its first Impact Factor in 2013\u2014is extremely grateful for the time, hard work and support of its highly-qualified peer reviewers. The editors of World Journal of Emergency Surgery and BioMed Central would like to show our appreciation by thanking the following people for their assistance reviewing manuscripts for the journal in 2013.The  Ferdinando AgrestaItalyMiklosh BalaIsraelChad BallCanadaZsolt BaloghAustraliaGary BassIrelandChristoph BenckertGermanyCino BendinelliAustraliaJasneet BhullarUnited States of AmericaWalter BifflUnited States of AmericaL.D. BrittUnited States of AmericaClay Cothren BurlewUnited States of AmericaOsvaldo ChiaraItalyIan CivilNew ZealandRaul CoimbraUnited States of AmericaDavid Costa NavarroSpainElias DegiannisSouth AfricaMarci DeLosSantosUnited States of AmericaSalomone Di SaverioItalyHasan EkimTurkeyAlex EscalonaChilePaula FerradaUnited States of AmericaRalf Herbert GahrGermanySanjay GuptaIndiaChien-Sheng HuangTaiwanRao IvaturyUnited States of AmericaGregory JurkovichUnited States of AmericaIgnatius KakandeRwandaJ KashukUnited States of AmericaKenji KawamukaiItalyCuneyt KayaalpTurkeyMichael KellyAustraliaBoris KirshteinIsraelYoram KlugerIsraelM. Margaret KnudsonUnited States of AmericaSungsoo LeeSouth KoreaLuke LeenenNetherlandsI. Michael LeitmanUnited States of AmericaAri LeppaniemiFinlandRonald MaierUnited States of AmericaMark MalangoniUnited States of AmericaGyanendra MallaNepalHaridimos MarkogiannakisGreeceNiels MartinUnited States of AmericaHisashi MatsumotoJapanAndrea MingoliItalyUmberto MorelliFranceSheikh MuzamilIndiaNoel NaidooSouth AfricaMarcus OngSingaporeLars Ivo ParteckeGermanyAbhijeet PatilUnited KingdomMichael RamdassTrinidad and TobagoSandeep SainathanUnited States of AmericaBoris SakakushevBulgariaThomas ScaleaUnited States of AmericaVishalkumar ShelatSingaporeAleksandar SimicSerbiaZoe SmithUnited KingdomPhilip StahelUnited States of AmericaAngela SultanaMaltaWieslaw TarnowskiPolandKorhan TavilogluTurkeyYoshihito UjikeJapanSelman UranuesAustriaGabrielle van RamshorstNetherlandsEttore VulcanoItalyImtiaz WaniIndiaDieter WeberAustralia"}
+{"text": "Journal of Occupational Medicine and Toxicology would like to thank all our reviewers who have contributed to the journal in Volume 9 (2014).The editors of  Peter AngererGermanyKatherine ApplegateUnited States of AmericaMichael BatesUnited States of AmericaOlof BeckSwedenBeate BeermannGermanyAlessandra BinazziItalyElyse BissonnetteCanadaIrina BoeckelmannGermanyRos BramwellUnited KingdomLygia Therese BudnikGermanyMariana ButinofArgentinaLuenda CharlesUnited States of AmericaStephen ChildNew ZealandEmanuela CorsiniItalyVirginia CowenUnited States of AmericaReinhard DammannGermanySabine DariusGermanyMarie de PerioUnited States of AmericaM Teresa del CampoSpainRoland DielGermanyRune DjurhuusNorwayDavid DormanUnited States of AmericaMadeleine DulonGermanyLeslie EasterwoodUnited States of AmericaBernadette EberleinGermanyDidier EboBelgiumPeter Moeller EggertsenDenmarkRosalie ElespuruUnited States of AmericaChristina ErbeGermanyAnnegret FlothowGermanySimon ForstmeierGermanyPriyadarshani GalappatthySri LankaDavid A. GronebergGermanyShamai GrossmanUnited States of AmericaJim GruberCanadaToby HallAustraliaNguyen HangViet NamNoriaki HaradaJapanVolker HarthGermanyJill HarvilchuckUnited States of AmericaArto HautalaFinlandPaul HennebergerUnited States of AmericaMario HermsenSpainJohan HolstNorwayRon HouseCanadaKirsti Husgafvel-PursiainenFinlandLjiljana JanosevicSerbiaKate JonesUnited KingdomDebra KadenUnited States of AmericaBoris KanSwedenNaoto KeichoJapanChandrasekharan Nair KesavachandranIndiaBenedikt KorfSwitzerlandBartosz KoszowskiUnited States of AmericaUlrich KuchGermanyPhilip J. LandriganUnited States of AmericaOlivier LaurentFranceGerald LiCanadaHester LipscombUnited States of AmericaBrian LoweUnited States of AmericaChao LuUnited States of AmericaAlwin LuttmannGermanyStephanie MacNeillUnited KingdomAnne Mette MadsenDenmarkSuzanne MarshUnited States of AmericaBernard MartinUnited States of AmericaLuca MascitelliItalyGiuseppe MastrangeloItalyDenise MatosBrazilGaetane MichaudUnited States of AmericaMarin MladinicCroatiaBente MoenNorwayDiego Moliner-UrdialesSpainAndrew MooreUnited KingdomPeter MorfeldGermanyAlbert NienhausGermanyMatthias NueblingGermanyDaniela OhlendorfGermanyKarin OllingerSwedenChristian OstheimerGermanyCheryl PetersCanadaCeri PhillipsUnited KingdomLisa PompeiiUnited States of AmericaAlexandra Marita PreisserGermanyHeribert RamrothGermanyDavid ReesSouth AfricaSarah RodgersUnited KingdomErwin L RoggenDenmarkChameen SamarawickramaAustraliaRiitta SauniFinlandUlf Martin SchillingSwedenAnnina SchmidUnited KingdomPeter-Ernst SchnabelGermanyAshley SchoenfischUnited States of AmericaPeter William SchofieldAustraliaJohannes SchulzeGermanyAndreas SeidlerGermanyG ShiChinaDennis ShustermanUnited States of AmericaMareike SimonGermanyMaria Fernanda SimonielloArgentinaLidwien SmitNetherlandsRobert TaroneUnited States of AmericaRichard TelfordAustraliaBeatrice ThielmannGermanyFrancesco TomeiItalyJos\u00e9 Torres da CostaPortugalDominique TripodiFranceJukka UittiFinlandVictoria VivilakiGreeceValerie WalkerUnited KingdomEileen M. WankeGermanyHanna WatlingAustraliaHeather WebbUnited States of AmericaSabine WickerGermanyMichael WitcherCanadaRosalind WrightUnited States of AmericaAthanasios XanthopoulosGermanyIl Je YuKorea, SouthAlice ZwerlingUnited States of America"}
+{"text": "Nutrition Journal would like to thank all our reviewers who have contributed to the journal from Volume 14 (2015).The editor of  Abdulla BadawyUnited KingdomAdriana FranzeseItalyAlain KoyamaUnited States of AmericaAlbane MaggioSwitzerlandAlejandro Fern\u00e1ndez MonteroSpainAlexandra JenkinsCanadaAlfredo GeaSpainAli AlkanTurkeyAli MontazeriIranAlison CoatesAustraliaAmanda PattersonAustraliaAmanda WaddellUnited States of AmericaAmedeo LonardoItalyAna Filipa VicenteUnited States of AmericaAna Mar\u00eda Calder\u00f3n de la BarcaMexicoAnand SinghIndiaAnand TamatamIndiaAndre MaltosBrazilAndrea DarlingUnited KingdomAndrew McKuneSouth AfricaAngelo CagnacciItalyAnne-Louise HeathNew ZealandAnthony VillaniAustraliaAnwar-ul-Hassan GilaniEthiopiaArcangelo IannuzziItalyArianna AcetiItalyArun Kumar AggarwalIndiaAsher RosingerUnited States of AmericaAshok TutejaUnited States of AmericaAvula LaxmaiahIndiaBabak HooshmandSwedenBagher LarijaniIranBarbara DaoCanadaBarbara RochaPortugalBarbara TaylorUnited States of AmericaBart KootNetherlandsBeat M\u00fcllerGermanyBee TanUnited KingdomBeng San YeohUnited States of AmericaBenjamin NwosuUnited States of AmericaBenoit ChassaingUnited States of AmericaBernd WeberGermanyBiagio Raffaele Di IorioItalyBin YuChinaBing WanChinaBingjun QianChinaBonnie BeezholdUnited States of AmericaBryan HackfortUnited States of AmericaCaio OliveiraBrazilCarlos Pastor VargasSpainCarol JohnstonUnited States of AmericaCatherine ChanCanadaChesney RichterUnited States of AmericaChris FramptonNew ZealandChris McGloryCanadaChris RaynerAustraliaChristine SommerNorwayChristine von ArnimGermanyChristopher P. MorleyUnited States of AmericaChristopher PapandreouGreeceChristopher SudfeldUnited States of AmericaColin RehmUnited States of AmericaConnie RogersUnited States of AmericaConrad ColeUnited States of AmericaCorrine HansonUnited States of AmericaCreswell EastmanAustraliaDagrun EngesetNorwayDallas DonohoeUnited States of AmericaDavid GarciaUnited States of AmericaDavid JenkinsCanadaDavid SmithUnited KingdomDennis NilsenNorwayDiane MitchelllUnited States of AmericaDick ChanAustraliaDirk AerenhoutsBelgiumDiwakar Bastihalli TukaramraoUnited States of AmericaDouglas KalmanUnited States of AmericaDouglas MacKayUnited States of AmericaEdel Rafael Rodea-MonteroMexicoEduardo De StefaniUruguayEdward LevineUnited States of AmericaEdward RandellCanadaElizabeth PearceUnited States of AmericaEmilie CombetUnited KingdomEmma PattersonSwedenEmmanuel GrelletyFranceEnzo NisoliItalyErick BoyCanadaEsther GranotIsraelEvan CherniackUnited States of AmericaEwa FlorekPolandFelipe PerezUnited States of AmericaFrances Hillier-BrownUnited KingdomFrank GreerUnited States of AmericaGarden TabacchiItalyGerard ClarkeIrelandGerd SchmitzGermanyGerry JagerNetherlandsGilles FeronFranceGilson Teles BoaventuraBrazilGiorgina PiccoliItalyGiovanni de PergolaItalyGiovanni TarantinoItalyGiovanni ViegiItalyGirish KirimanjeswaraUnited States of AmericaGiulia Marcelino MainardiBrazilGiuseppe GrossoItalyGlen LawrenceUnited States of AmericaGrace FarhatUnited KingdomGuglielmo TrovatoItalyH ZittermannGermanyHamed KioumarsiIranHamid Reza BaradaranIranHanen SamoudaLuxembourgHanno PijlNetherlandsHidetaka HamasakiJapanHiromichi KumagaiJapanHiroshi KajiJapanHollie RaynorUnited States of AmericaHoward SessoUnited States of AmericaHui SunUnited States of AmericaI. DanquahGermanyIan NeelandUnited States of AmericaIdoia ZarrazquinSpainIlkka HeinonenNetherlandsImran AzizUnited KingdomIngrid KohlstadtUnited States of AmericaIstvan TelessyHungaryIta LitmanovitzIsraelIvana StrahinicSerbiaJ. UrbanekUnited States of AmericaJ. WangUnited States of AmericaJacque BayNew ZealandJairam VanamalaUnited States of AmericaJan FrankGermanyJean AbedUnited States of AmericaJessy AbrahamIndiaJesus VioqueSpainJin HanRepublic of KoreaJM HeChinaJoAnn LongUnited States of AmericaJo\u00e3o Elias NunesBrazilJohn PettiforSouth AfricaJON TORRES-UNDASpainJonathan LittleCanadaJoshua LambertUnited States of AmericaJulia PotterUnited KingdomJulie LumengUnited States of AmericaJulie SchmidtUnited KingdomJulien CasesFranceJuscelino TovarSwedenK KinugawaJapanKam-Lun Ellis HonHong KongKannan SridharanFijiKarin SchindlerAustriaKarthikeyan SubbiurayanIndiaKatarina B\u00e4lterSwedenKate BowenUnited States of AmericaKatherine KeeneCanadaKatherine Silva-JaramilloEcuadorKazuhiro UenishiJapanKeiko TanakaJapanKeiko WadaJapanKeiron AudainUnited KingdomKeiron AudainZambiaKeng Fai YipMalaysiaKevin FritscheUnited States of AmericaKevin MakiUnited States of AmericaKim Sung-HoonRepublic of KoreaKorry HintzeUnited States of AmericaKotatsu MaruyamaJapanKristina TiainenFinlandL GarneataUnited KingdomLaila HusseinEgyptLaila MeijaLatviaLaura MullaneyIrelandLauri PolariFinlandLeah LipskyUnited States of AmericaLeigh WardAustraliaLeonardo PalombiItalyLeticia Elizondo-MontemayorMexicoLigia MartiniBrazilLingjun ZhuChinaLisa JahnsUnited States of AmericaLiz ApplegateUnited States of AmericaLouise PurtellAustraliaLucienne LaraBrazilLun-Yi ZangUnited States of AmericaLynn RiddellAustraliaLynne McFarlandUnited States of AmericaM RizzoItalyM. BonaccioItalyMakbule Gezmen-KaradagTurkeyManny NoakesAustraliaMaria Alicia Camina MartinSpainMaria Cristina MeriItalyMaria Jose Garcia-MeseguerSpainMaria Jose Romo-PalafoxUnited States of AmericaMaria MoralesSpainMaria Pia VillaItalyMariette GerberFranceMarika MikelsaarEstoniaMario MurciaSpainMarjanne SenekalSouth AfricaMarjorie FreedmanUnited States of AmericaMarleen BaakNetherlandsMarleen van BaakNetherlandsMarta Van LoanUnited States of AmericaMartin Ndegwa MwangiKenyaMartin RootUnited States of AmericaMartine LavilleFranceMary WardUnited KingdomMaryse UmugwanezaSouth AfricaMasakazu TerauchiJapanMasataka ShirakiJapanMat KrauseUnited States of AmericaMatthew CannonUnited States of AmericaMeagan GillespieAustraliaMichael DonaldsonUnited States of AmericaMichael HolickUnited States of AmericaMichael RybakUnited States of AmericaMichael StamosUnited States of AmericaMichelle WienUnited States of AmericaMing LiAustraliaMohamed SaleemIndiaMonica H. CarlsenNorwayMonica MillanSpainMonica SerraUnited States of AmericaMostafa WalyOmanMT RotelliItalyMuraldihar PremkumarUnited States of AmericaMuthalib Asha MurshidaSri LankaMyriam AfeicheSwitzerlandNamson LauAustraliaNaoki IkegayaJapanNasiruddin KhanSaudi ArabiaNatalie ParlettaAustraliaNicolas DarcelFranceNilesh KashikarUnited States of AmericaNivedita NagacharUnited States of AmericaNorman CarvalhoUnited States of AmericaOlivia PhungUnited States of AmericaOlusola SotundeSouth AfricaP PedramCanadaPallavi KawatraUnited States of AmericaPankaj VashiUnited States of AmericaPaola Gauffim CanoArgentinaPaola VitaglioneItalyPascale FritschUnited KingdomPatricia GenaroBrazilPatricia Perez-MatuteSpainPaul JacquesUnited States of AmericaPaula Manuela PereiraUnited States of AmericaPer JeppesenDenmarkPeter CelecSlovakiaPeter HannanUnited States of AmericaPeter KonturekGermanyPhilippa JacksonUnited KingdomPhilippe ChauveauUnited States of AmericaPieter JoosteSouth AfricaPradeep KumarUnited States of AmericaPriscila FassiniBrazilPunam Ohri-VachaspatiUnited States of AmericaQian BingjunChinaR Leon GuerreroGuamRachel BrownNew ZealandRahim AydinTurkeyRajesh KumarIndiaRam\u00f3n Serrano-UrreaSpainRana Abu-DahabJordanRangaiah SashidharamurthyUnited States of AmericaRavi DyavarUnited States of AmericaRichard BrunoUnited States of AmericaRM HafizuUnited States of AmericaRobin TuckerUnited States of AmericaRoger ClemensUnited States of AmericaRok OrelSloveniaRose Ann DiMaria-GhaliliUnited States of AmericaSabine RohrmannSwitzerlandSakae MiyagiJapanSamantha KlingUnited States of AmericaSamuel AlaishUnited States of AmericaSamuel TchumGhanaSandeep PrabhuUnited States of AmericaSandrine P\u00e9neauFranceSanjay MallyaUnited States of AmericaSanne Kellebjerg PoulsenDenmarkSantos Perez-PozoSpainSarah GarnettAustraliaSaverio StrangesUnited KingdomSerenella SalinariItalySergio De MarchiItalySharon ErdrichNew ZealandShervin AssariUnited States of AmericaShetty Ravi DyavarUnited States of AmericaShibig YangChinaShigeru TokiJapanSibylle KranzUnited KingdomSifan ChenGermanySimona BoItalySiwaporn PinkaewSwitzerlandSkye McPhieAustraliaS\u00f8ren GregersenDenmarkS\u00f8ren ToubroDenmarkSt\u00e9phane DubouxSwitzerlandSubbaRao MadhunapantulaIndiaSumangala GokaviUnited States of AmericaSuresh Kumar KarriIndiaSuresh KumarIndiaSusan RaatzUnited States of AmericaTaisun HyunSouth KoreaTakuya YoshidaJapanTamar Ringel-KulkaUnited States of AmericaTamatam AnandIndiaTania JohnCanadaTarig MerghaniSaudi ArabiaTeruo KawadaJapanThiago Bruder-NascimentoBrazilThomas RemerGermanyThomas WoleverCanadaTiange WangUnited States of AmericaTina JafariIranUjjawal GandhiUnited States of AmericaUrsula SchwabFinlandValeria Del BalzoItalyVenkateswarlu ChamchaUnited States of AmericaVeronica MocanuRomaniaVicente LaheraSpainVijay GanjiUnited States of AmericaVishal SinghIndiaVivek NarayanUnited States of AmericaW\u00a0MaUnited States of AmericaWei TangJapanWen LiuUnited States of AmericaWenbo TangUnited States of AmericaWilliam GrantUnited States of AmericaWilliam ManzanaresUruguayWojciech WojciechPolandXu TianChinayasmin asifPakistanYehuda ShoenfeldIsraelYeyi ZhuUnited States of AmericaYiping MaChinaYong ZhuUnited States of AmericaYuan ZhouUnited States of AmericaYujie WangUnited States of AmericaYulong YinChina"}
+{"text": "Journal of Hematology & Oncology would like to thank all our reviewers who have contributed to the journal in Volume 8 (2015).The Editor-in-Chief of  Nacer AbroukUnited States of AmericaAkintunde AkinleyeUnited States of AmericaYoshimitsu AkiyamaJapanUgo AlaItalyA AlousiUnited States of AmericaXiuli AnUnited States of AmericaEphraim Ansa-AddoUnited States of AmericaEmmanuel AntonarakisUnited States of AmericaDorina AvramUnited States of AmericaVeronika BachanovaUnited States of AmericaVeronica BalattiUnited States of AmericaSrinivasa Rao BandiUnited States of AmericaFrederic BaronBelgiumRodolphe BarrangouUnited States of AmericaGiuseppe BassoItalyIoana Berindan-NeagoeRomaniaPaolo BernasconiKazakhstanJin-Song BianSingaporeAndrea BiondiItalyCf BoerkoelCanadaArnold BolomskyAustriaEarle BurgessUnited States of AmericaHong ChangCanadaYing-Jun ChangChinaHuan ChenChinaSuning ChenChinaGuoan ChenUnited States of AmericaM ChenUnited States of AmericaVicky Ping ChenUnited States of AmericaTao ChengChinaHong ChengUnited States of AmericaSeok-Goo ChoSouth KoreaEun Young ChoiKorea, SouthShih-Sung ChuangTaiwanMei-Zhen CuiUnited States of AmericaSilvia DeaglioItalyJiusheng DengUnited States of AmericaFei DuanUnited States of AmericaWilliam DuranteUnited States of AmericaXiucheng FanUnited States of AmericaQipeng FanUnited States of AmericaZhichao FanUnited States of AmericaMark FeinbergUnited States of AmericaMichael FlisterUnited States of AmericaKarlheinz FriedrichGermanyYanfang FuUnited States of AmericaSeiji FukudaJapanClaudia FumarolaItalySara GalimbertiItalyS GallegoSpainGregory GanUnited States of AmericaJoan GilSpainAlois GratwohlUnited States of AmericaCharlotte GrootaertBelgiumAihua GuChinaMing GuanChinaChristina HalseyUnited KingdomLina HanUnited States of AmericaBo HanUnited States of AmericaDonald HarveyUnited States of AmericaLizhi HeUnited States of AmericaYukai HeUnited States of AmericaMark HeaneyUnited States of AmericaCyrus HedvatUnited States of AmericaTom HobmanCanadaJian HouChinaGeorge HsiaoTaiwanWenming HsuUnited States of AmericaChung-Tsen HsuehUnited States of AmericaQinglong HuUnited States of AmericaShimin HuUnited States of AmericaWenwei HuUnited States of AmericaHe HuangChinaXiaojun HuangChinaHuang HuangUnited States of AmericaSuming HuangUnited States of AmericaTiangui HuangUnited States of AmericaTsong-Long HwangTaiwanWilliam HwangSingaporeToshihiko ImamuraJapanBenjamin JacksonUnited States of AmericaGaetan JegoFranceYuxia JiaUnited States of AmericaWei JiangUnited States of AmericaDan JonesUnited States of AmericaCelina JulianoUnited States of AmericaHirokazu KaneganeJapanKhosrow KashfiUnited States of AmericaXiao Yan KeChinaFadi KhasawnehUnited States of AmericaJoseph KhouryUnited States of AmericaEdward KimUnited States of AmericaSeok Jin KimSouth KoreaWon Seog KimSouth KoreaM KitagawaJapanMaria KleppeUnited States of AmericaIlona KovalszkyHungaryDieter KubeGermanyY LaiChinaGurpreet LambaUnited States of AmericaJungwoo LeeUnited States of AmericaMong-Hong LeeUnited States of AmericaRobert LernerUnited States of AmericaChi-Kwong LiHong KongJin LiChinaJi-Liang LiUnited KingdomPeng LiChinaYong LiUnited States of AmericaQiao LiChinaShaoguang LiUnited States of AmericaTianhong LiChinaGuangfu LiUnited States of AmericaShaoguang LiUnited States of AmericaYangqiu LiChinaZhenyu LiUnited States of AmericaZihai LiUnited States of AmericaFelix LichteneggerGermanyEdward LinUnited States of AmericaJianqing LinUnited States of AmericaHongtao LiuUnited States of AmericaJianguo LiuUnited States of AmericaQi-Fa LiuChinaZach LiuUnited States of AmericaSanam LoghaviUnited States of AmericaMin LuChinaHarry LybeckUnited States of AmericaManisha MadkaikarUnited States of AmericaAtsushi ManabeJapanLuigi MarcheselliItalyPhilip MasonUnited States of AmericaRohit MathurUnited States of AmericaSebastien MauryFranceHelmout ModjtahediUnited KingdomS Montes-MorenoSpainHideki MuramatsuJapanHiroshi NakanoJapanHeyu NiCanadaMaria OderoSpainSeiichi OkabeJapanDennis O'malleyUnited States of AmericaThomas PabstSwitzerlandMinggui PanUnited States of AmericaGyorgy PanyiHungarySimrit ParmarUnited States of AmericaLuiz O. PenalvaUnited States of AmericaPiergiorgio PetroniItalySimon PowisUnited KingdomB PsailaUnited KingdomZhenggang RenChinaRuibao RenUnited States of AmericaUwe ReuschGermanyJia RuanUnited States of AmericaKo SatoJapanMartin SauvageauUnited States of AmericaTobias SchattonUnited States of AmericaIg Schmidt-WolfGermanyKaren SeiterUnited States of AmericaLohith ShakaladevanapuraUnited States of AmericaHe ShenUnited States of AmericaYuankai ShiChinaSy ShiehUnited States of AmericaYongqian ShuChinaIrma Rosa SlavutskyArgentinaJ\u00fcrgen SonnemannGermanyCarmen StanganelliArgentinaGp StudzinskiUnited States of AmericaVivek SubbiahUnited States of AmericaMarion SubkleweGermanyM SuenagaJapanHui-Chuan SunChinaDaniel SzeAustraliaAndrew TanSingaporeGuilin TangUnited States of AmericaJianguo TaoUnited States of AmericaJessica ThaxtonUnited States of AmericaErming TianUnited States of AmericaRaoul TibesUnited States of AmericaRamon TiuUnited States of AmericaK TokoyodaGermanyChe-Kai TsaoUnited States of AmericaPanagiotis TsirigotisIsraelJeffrey TynerUnited States of AmericaIkuyo UedaJapanDiamantina VasilatouGreeceAmit VermaUnited States of AmericaMassimiliano VisocchiUnited States of AmericaPhuong VoUnited States of AmericaSinisa VolarevicCroatiaJing WangUnited States of AmericaJiyi WangUnited States of AmericaSa WangUnited States of AmericaQinhong WangUnited States of AmericaWei WangUnited States of AmericaXiaoxiao WangUnited States of AmericaBritta WillUnited States of AmericaPetter WollUnited States of AmericaJustin WongAustraliaJohn WrangleUnited States of AmericaKongming WuChinaShenhong WuUnited States of AmericaYi-Long WuChinaJingjing WuChinaLijun XiaUnited States of AmericaZhijian XiaoChinaYu-Quan XiongChinaBinghe XuChinaDazhong XuUnited States of AmericaRuihua XuChinaOzlem YalcinUnited States of AmericaMasayuki YamamotoJapanShuo YangUnited States of AmericaNaohiro YanoUnited States of AmericaJeffrey YeUnited States of AmericaGo YoshidaJapanScott YoungerUnited States of AmericaEvan YuUnited States of AmericaMin YuUnited States of AmericaJianda YuanUnited States of AmericaZihua ZengUnited States of AmericaHua ZhangChinaLanjing ZhangUnited States of AmericaChengcheng ZhangUnited States of AmericaXi ZhangUnited States of AmericaXu ZhangChinaYue ZhangUnited States of AmericaJing ZhangUnited States of AmericaTi ZhangChinaWei-Li ZhaoChinaGuo-Guang ZhengChinaXiaoyong ZhengUnited States of AmericaHuyong ZhengChinaWenxin ZhengUnited States of AmericaXiaoyong ZhengUnited States of AmericaYong ZhouChinaNiklas ZojerAustria"}
+{"text": "The following information is missing from the Funding section: the Natural Science Fund Project of Anhui Province (1208085MH179)."}
+{"text": "The Editor-in- Chief would like to thank all the reviewers who contributed to the journal in 2014. Junaid AbdulghaniUnited States of AmericaPaul AgutterUnited KingdomJoseph K AgyinUnited States of AmericaGolo AhlenstielAustraliaMohammed AleskandaranyUnited KingdomMikhail AlexeyevUnited States of AmericaHolly AlgoodUnited States of AmericaSameh AliEgyptNicolas AndreFranceRavindran AnkathilIndiaElif Damla ArisanTurkeyRukhsana AslamCanadaKareem AzabUnited States of AmericaRodolphe BarrangouUnited States of AmericaGiuseppina BarreraItalyKevin BennewithCanadaAlfred BereUnited States of AmericaThomas BinderGermanyYaroslav BlumeUkraineLorella BonaccorsiItalyRicardo BorraBrazilConstance BrinckerhoffUnited States of AmericaBarbora BrodskaCzech RepublicElisa CallegariItalyAna Paula CampanelliBrazilAyse G CansevenTurkeyMichele CaragliaItalySilvia CarvalhoPortugalPatrizia CasaliniItalyAwalpreet ChadhaUnited States of AmericaDimple ChakravartyUnited States of AmericaPithi ChanvorachoteThailandEmma ChapmanUnited KingdomLinjin ChenChinaDi ChenUnited States of AmericaStephen ChunUnited States of AmericaCarlos J CiudadSpainLudovica CiuffredaItalyJean ClairambaultFranceRicardo ColettaBrazilDavid ConradCanadaLeah CookUnited States of AmericaRicardo CorreaUnited States of AmericaDaniela Elena CosteaNorwayAlysha CrokerCanadaCem DaneTurkeyKaren DaneUnited States of AmericaJayasri Das SarmaIndiaJharna DattaUnited States of AmericaLester DavidsSouth AfricaMaryna de KockSouth AfricaPaul de SouzaAustraliaPrasenjit DeyUnited States of AmericaIsabelle Dhennin-DuthilleFranceViolante Di DonatoItalyXiaoyan DingChinaRosa DivellaItalyNicole DoudicanUnited States of AmericaYiannis DrososUnited States of AmericaChandradhar DwivediUnited States of AmericaMarzieh EbrahimiIranMartins EkorGhanaSteve ElderUnited States of AmericaAnat Erdreich-EpsteinUnited States of AmericaJekaterina ErenpreisaLatviaShinichi EsakiUnited States of AmericaFei FeiUnited States of AmericaZhou FeiChinaZvi FishelsonIsraelMarco FoliniItalyDimitrios FotiadisGreeceChristian FreiseGermanyKai FuUnited States of AmericaOta FuchsCzech RepublicTeruhiko FujiiJapanMariateresa FulcinitiUnited States of AmericaMayuko FurutaJapanKoraljka Gall TroseljCroatiaMichael GallagherIrelandElena Gallardo Mart\u00ednSpainRosaria GangemiItalyChenxi GaoUnited States of AmericaYong GaoChinaManoj GargSingaporeMaria GazouliGreecePaola GazzanigaItalyPengfei GeChinaR Christopher GeigerUnited States of AmericaEfstathia GiannopoulouGreeceVeronique GirouxUnited States of AmericaNicola GiulianiItalyMunirathinam GnanasekarUnited States of AmericaWolfgang H GoldmannGermanySusumu GoyamaUnited States of AmericaThomas GreitherGermanyKun GuoChinaYige GuoUnited States of AmericaKwon-Soo HaKorea, SouthChristina HacklGermanyJudith HagenbuchnerAustriaJoerg HaierGermanyMu HaoChinaDavid HeinUnited States of AmericaToru HiragaJapanYi-Chiang hsuTaiwanPavla HublarovaCzech RepublicDouglas HurstUnited States of AmericaSudhir IsharwalUnited States of AmericaTom JacksonUnited KingdomRuy JaegerBrazilMorana JaganjacQatarJohn JakupciakUnited States of AmericaTatiana JazedjeBrazilYongfang JiangChinaXiaohua JiangHong KongJonathan JonesUnited States of AmericaShin-ichiro KagamiJapanKazuharu KaiUnited States of AmericaGalatea KallergiGreeceJyotshna KanungoUnited States of AmericaYasumasa KatoJapanEvan KellerUnited States of AmericaSofia KhaitlinaRussian FederationTobias KiesslichAustriaThomas KietzmannFinlandHark KimKorea, SouthYoji KishiJapanRobert KissCanadaJorg KleeffGermanyVera KlotenGermanyLars Oliver KlotzGermanyBurkhard KneitzGermanyJunya KobayashiJapanTakashi KohnoJapanViswa Kalyan KolliIndiaLing-Min KongChinaMaritha KotzeSouth AfricaArpad KovacsHungaryMuthusamy KunnimalaiyaanUnited States of AmericaAjaikumar KunnumakkaraUnited States of AmericaLeoni Kunz-SchughartGermanyElena KurenovaUnited States of AmericaToshihiro KushibikiJapanHiroyuki KuwanoJapanAshakumary LakshmikuttyammaUnited States of AmericaIncilay LayTurkeyFuyang LiUnited States of AmericaXiaoming LiChinaEvi LianidouGreeceCheng-gong LiaoChinaDelong LiuUnited States of AmericaYinkun LiuChinaKaishan LiuChinaYinkun LiuChinaLongshan LiuChinaLawrence LoebUnited States of AmericaEmil LouUnited States of AmericaShixin LuChinaHui-he LuChinaOchiba LukanduKenyaIsabel LuthyArgentinaYoshihiko MaeharaJapanZaynah MaherallyUnited KingdomIlaria MalanchiUnited KingdomGabriella MarucciItalyMasato MatsuokaJapanLoredana MauroItalyJames A McCaulUnited KingdomRheem MedhUnited States of AmericaParvin MehdipourIranAndreas MerdesFranceBonhong MinKorea, SouthToshinari MinamotoJapanKiyoshi MisawaJapanMitsuru MiyachiJapanPetr MlejnekCzech RepublicZengnan MoChinaDavid MoleUnited KingdomEiichi MoriiJapanTaiki MoriyamaJapanDezhi MuChinaPing MuUnited States of AmericaFrancis MussaiUnited States Minor Outlying IslandsShamaladevi NagarajaraoUnited States of AmericaRakesh NaiduMalaysiaShoji NatsugoeJapanTamara Nikuseva-MarticCroatiaHongxiu NingUnited States of AmericaMakoto NodaJapanJoshua ObarUnited States of AmericaNorma O'DonovanIrelandDavid OrnellesUnited States of AmericaIwata OzakiJapanXiufeng pangChinaVassilis PapanikolaouGreecePalak ParekhUnited States of AmericaNicholas PavlidisGreeceNives Pecina-SlausCroatiaJun PengChinaLirong PengUnited States of AmericaQiliu PengChinaGuy PerkinsUnited States of AmericaChristian PetzeltPortugalUlrich PfefferItalyMark PickardUnited KingdomSmitha PillaiUnited States of AmericaPawinee PiyachaturawatThailandStefania PizzimentiItalyDusan PopadicSerbiaGuy PrattUnited KingdomVinesh kumar PuliyappadambaUnited States of AmericaWenbin QianChinaYi QiuUnited States of AmericaXiong-Zhi QuanChinaKomal RamaniUnited States of AmericaStephan ReshkinItalyCarmela RicciardelliAustraliaAlan RichardsonUnited KingdomNicole RiddleUnited States of AmericaChristoph RitterGermanyMaria RizzoItalyAlexander R\u00f6lleGermanyAchmad Chusnu RomdhoniIndonesiaAditi RoyIndiaYe-Chun RuanHong KongClinton RubinUnited States of AmericaHannes SallmonGermanyDario SangioloItalyRonit Satchi-FainaroIsraelMichael SchuligaAustraliaUdo SchumacherGermanyLjiljana SermanCroatiaLi ShenUnited States of AmericaGajanan SherbetUnited KingdomGwo Tarng SheuTaiwanHidenori ShirahaJapanChengchao ShouChinaViji ShridharUnited States of AmericaAndriy SibirnyUkraineStephen SimsCanadaAjay Vikram SinghUnited States of AmericaRonit SionovIsraelOndrej SlabyCzech RepublicCarlos SonnenscheinUnited States of AmericaOleh StasykUkrainePhilipp StawowyGermanyPeter SteinbergerAustriaRostyslav StoikaUkraineSangeetha Sukumari RameshUnited States of AmericaTuangporn SuthiphongchaiThailandLarry SuvaUnited States of AmericaUmesalma SyedIndiaCezary SzczylikPolandBela SzendeHungaryHe TaipingChinaAkimitsu TakagiJapanHiroshi TakemoriJapanLeandro ThiagoBrazilErik (Rik) ThompsonAustraliaMangesh ThoratUnited KingdomQiangsong TongChinaMeng-Feng TsaiTaiwanPo-lin TsengTaiwanMitchell TurkerUnited States of AmericaKin Pong UHong KongRuchan UsluTurkeyPatricia ValerioBrazilTom Vanden BergheBelgiumDaniele VergaraItalyFarhad VesunaUnited States of AmericaJeppe VintherDenmarkTomislav VladusicCroatiaAndr\u00e9 O von BuerenGermanyNathan WallUnited States of AmericaShanshan WanUnited States of AmericaChangxi WangChinaYu-li WangUnited States of AmericaKarl WelteGermanyZhi-Hong WenTaiwanZhenke WenChinaMike-Andrew WesthoffGermanySally WheatleyUnited KingdomTheresa WhitesideUnited States of AmericaSopit WongkhamThailandWilliam WrightUnited States of AmericaYi WuChinaZhe Bao WuChinaNing-shao XiaChinaHongping XiaChinaGuoan XiangChinaGuozhi XiaoUnited States of AmericaJinliang XingChinaLin XuChinaNobuo YaegashiJapanNaoko YamadaJapanMunekazu YamakuchiJapanJu YangChinaJin-Ming YangUnited States of AmericaXiaobo YangChinaZhi-Zhang YangUnited States of AmericaGong YangChinaLin YeUnited KingdomSamantha YeligarUnited States of AmericaVenkat Laxmi YeruvaUnited States of AmericaKen YoungUnited States of AmericaLuyang YuChinaDahai YuChinaWei-dong ZangChinaMariastella ZanniniItalyNeven ZarkovicCroatiaMaria Chiara ZatelliItalyIngeborg ZehbeCanadaZihua ZengUnited States of AmericaBo ZhangChinaJiwang ZhangUnited States of AmericaKejun ZhangChinaSen ZhangChinaShi-Meng ZhangChinaYingshe ZhaoUnited States of AmericaShusen ZhengChinaBinhua ZhouUnited States of AmericaYing ZhuUnited States of AmericaCeniz ZihniUnited Kingdom"}
+{"text": "Human Genomics would like to thank all our reviewers who have contributed to the journal in volume 8 (2014).The Editors of  S\u00fckriye AyterTurkeyEmidio CapriottiUnited States of AmericaThomas ChenUnited States of AmericaShantanu ChowdhuryIndiaMichael ClarkUnited KingdomCarolien de KovelNetherlandsGeorge DedoussisGreeceAlonso Fernandez-GuastiMexicoParaskevi GoggolidouUnited KingdomLeslie Jacqueline GreenbergSouth AfricaLin HouUnited States of AmericaPei-Ing HwangTaiwanBrian JacksonUnited States of AmericaDorothea KasteleijnNetherlandsTheodora KatsilaGreeceRick KittlesUnited States of AmericaBernd KlausGermanyChee Seng KuSingaporePoh-San LaiSingaporeJun LiUnited States of AmericaChristoph LohmannGermanyFrank LovicuAustraliaBrian MeyerSaudi ArabiaJose Luis MillanUnited States of AmericaJonathan MudgeUnited KingdomDaniel NebertUnited States of AmericaMichael NothnagelGermanyGiuseppe NovelliItalyEric PasmantFranceGeorge PatrinosGreeceAndrew PattersonUnited States of AmericaEdward PerkinsUnited States of AmericaMark PetrashUnited States of AmericaRichard RadcliffeUnited States of AmericaMichele RamsaySouth AfricaPeter RobinsonGermanyMichael Lee RobinsonUnited States of AmericaElena SeminaUnited States of AmericaJadranka SerticCroatiaAndrew SharpSwitzerlandClay SmithUnited States of AmericaPoh Seng TanSingaporePanagiotis TsonisUnited States of AmericaCarsten WiufDenmarkMathew WrightUnited KingdomShuhua XuChinaVerena ZuberNorway"}
+{"text": "Child and Adolescent Psychiatry and Mental Health would like to thank all of our reviewers who have contributed to the journal in Volume 9 (2015).The editors of Kenneth J. AitkenUnited KingdomMarc AllroggenGermanyClaire Amstrong-KellyAustraliaAnna-Karin AndershedSwedenMargaret AndoverUnited States of AmericaPhil AshersonUnited KingdomAndrea AsnesUnited StatesOlayinka AtilolaNigeriaMarc AtkinsUnited States of AmericaImke BaetensBelgiumJudit BalazsHungaryPaula BarrettAustraliaLucas BattelBrazilMyron BelferUnited States of AmericaIsabel BoegeGermanyDavid BrentUnited States of AmericaKonrad BresinUnited States of AmericaKatharine-Ann BuckUnited StatesSimona BujoreanuUnited States of AmericaAlison CalearAustraliaGabrielle CampbellAustraliaFranco CavalloItalyHenri ChabrolFranceMegan ChesinUnited States of AmericaChee Hon ChinSingaporeGeorgia ChronakiUnited KingdomJoanna Ting Wai ChuNew ZealandLaurence ClaesBelgiumAntonio ClavennaItalyPaula CloutierCanadaAna CubilloSwitzerlandGraccielle R CunhaBrazil\u00d6rjan Dahlstr\u00f6mSwedenNaomi DavisUnited States of AmericaWilliam DavissUnited States of AmericaMichelle DawsonCanadaDiego De LeoAustraliaSusanne De RooijThe NetherlandsWieke De VenteThe NetherlandsJulia DiehleUnited KingdomJanean Dilworth-BartUnited StatesSarah DoucetteCanadaStefan EcksUnited KingdomSigmund EldevikNorwayPia EnebrinkSwedenEyup Sabri ErcanTurkeySpencer EvansUnited States of AmericaMichelle Evans-ChaseUnited States of AmericaMinne FekkesThe NetherlandsReiner FrankGermanyAndrew FugardUnited KingdomDaniel FungSingaporePenny FurnessUnited KingdomJoy GabrielliUnited States of AmericaAmarendra GandhiBelgiumBernice GarnettUnited States of AmericaChristiane GeyerBrazilCatherine GlennUnited States of AmericaKirstin GothSwitzerlandLaurence GreenhillUnited States of AmericaRebecca GroschwitzGermanyJohannes HaertingGermanyCharlotte HallUnited KingdomBen HanniganUnited KingdomRochelle HansonUnited States of AmericaAntonio HardanUnited StatesPenelope HaskingAustraliaChristopher HautmannGermanyDaniel HayesUnited KingdomNancy HeathCanadaCraig Anne HeflingerUnited States of AmericaHartmut HeinrichGermanyNina HeinrichsGermanySam HimelsteinUnited States of AmericaMaur\u00edcio HoffmannBrazilJacqueline HoranUnited States of AmericaPatricia HowlinUnited KingdomTom HummerUnited States of AmericaJeffrey HuntUnited States of AmericaHiroko IchikawaJapanNazish ImranPakistanDaniza M IvanovicChileAnna-Karin IvertSwedenThomas JansGermanyVanessa JantzerGermanyAbigail JenkinsUnited States of AmericaAnn JohnUnited KingdomUlf JonssonSwedenAndreas JudSwitzerlandJon JureidiniAustraliaMichael KaessGermanyFerdinand KellerGermanyPraveen KhairkarIndiaGlenn KiekensBelgiumChristian KielingBrazilJennifer KiingSingaporeRyan KilmerUnited States of AmericaEvan KleimanUnited States of AmericaE. David KlonskyCanadaMichael KoelchGermanyLiv KosnesUnited KingdomHanna KovshoffUnited KingdomSolvejg KristensenDenmarkAnne K\u00fcnsterGermanyOdilia M. LaceulleThe NetherlandsThao LeUnited States of AmericaStephen P. LewisCanadaSabine LoosGermanyLaura L\u00f3pez-RomeroSpainPaul LysakerUnited StatesAristides Machado-RodriguesPortugalHarriet MacmillanCanadaGisele ManfroBrazilAndres MartinUnited States of AmericaPaul MaruffAustraliaMolly MeersUnited States of AmericaSunil MehtaUnited StatesRichard Meiser-StedmanUnited KingdomYukifumi MondenJapanTa\u00eds MoriyamaBrazilJennifer MuehlenkampUnited States of AmericaIan MuntSingaporeStella MuthuriCanadaMatthew MychailyszynUnited States of AmericaCarl MyersUnited StatesMaaike H. NautaThe NetherlandsTamsin Newlove-DelgadoUnited KingdomJared NgSingaporeDennis NitkowskiGermanyChiara NosartiUnited KingdomBridianne O\u2019deaAustraliaSusanne OhmannAustriaDennis OugrinUnited KingdomSusanna PayneUnited KingdomKatherine PearsUnited StatesFriedemann Pf\u00e4fflinGermanyLue Ping OngSingaporePaul L. PlenerGermanyBeth A. PletcherUnited StatesIrina Elizabeth PoslawskyThe NetherlandsMich\u00e8le PreydeCanadaRavi P. RajkumarIndiaAlessandra RaudinoAustraliaReuben RobbinsUnited States of AmericaCynthia RogersUnited StatesRita RosnerGermanyNeal D. RyanUnited StatesChristina SakaiUnited States of AmericaVedat SarTurkeyIngo Sch\u00e4ferGermanyMichael ScheeringaUnited States of AmericaKlaus SchmeckSwitzerlandMarc SchmidSwitzerlandMichael SchoenbaumUnited States of AmericaFelipe SchuchBrazilAdina SeidenfeldUnited States of AmericaKaushik ShahUnited States of AmericaStephanie ShireUnited States of AmericaFederico SiccaItalyAnna SidorGermanyEllin SimonBelgiumJohan SimonsBelgiumMichael SimonsGermanyApril SmithUnited States of AmericaTristram SmithUnited States of AmericaAnthony SpiritoUnited States of AmericaChristina StadlerSwitzerlandJeremy StewartUnited States of AmericaJoana StraubGermanyMythily SubramaniamSingaporeMichaela SwalesUnited KingdomJames SwansonUnited States of AmericaToshinobu TakedaJapanKanako TakuUnited States of AmericaLil TonmyrCanadaJames TopitzesUnited StatesBrianna TurnerCanadaAlasdair VanceAustraliaMarianne Villab\u00f8NorwayBenedetto VitielloUnited StatesSebastian VollmerGermanyJan WallanderUnited States of AmericaZachary WarrenUnited States of AmericaJason WashburnUnited StatesJames WaxmonskyUnited States of AmericaChang WeiningSingaporeSusan WhiteUnited States of AmericaJanis WhitlockUnited States of AmericaMechthild WolffGermanyAlisa WoodsUnited States of AmericaFrances WymbsUnited States of AmericaMaria ZetterqvistSwedenJulie ZitoUnited States of America"}
+{"text": "Child and Adolescent Psychiatry and Mental Health would like to thank all of our reviewers who have contributed to the journal in volume 8 (2014).The editors of  Marc AllroggenGermanyMartijn ArnsNetherlandsJosephine BarbaroAustraliaClaus BarkmannGreenlandSheri BaumanUnited States of AmericaMichele BaumannLuxembourgMyron BelferUnited States of AmericaVashti BerryUnited KingdomMaria Teresa Botello-HarbaumUnited States of AmericaDavid BuchbinderUnited States of AmericaLarry BurdUnited States of AmericaMarcy BursteinUnited States of AmericaFranco CavalloItalyDavid ChambersUnited States of AmericaYiong Huak ChanSingaporeDeena ChisolmUnited States of AmericaJoanna Ting Wai ChuNew ZealandAntonio ClavennaItalyPaula CloutierCanadaMelissa CortinaUnited KingdomGeorgina CoxAustraliaMichelle DawsonCanadaRafael de Assis da SilvaBrazilArden DingleUnited States of AmericaJoseph DurlakUnited States of AmericaPia EnebrinkSwedenElif ErcanTurkeyPhilip FisherUnited States of AmericaCarol FitzpatrickIrelandBacy Fleitlich-BilykBrazilLila FlemingUnited States of AmericaMarjolein FokkemaNetherlandsDaniel FungSingaporeHolger GevenslebenGermanyLaurence GreenhillUnited States of AmericaJohannes HaertingGermanyCharlotte HanischGermanyLisa HarrysonSwedenNina HeinrichsGermanyPieter J HoekstraNetherlandsEmbry HowellUnited States of AmericaTina In-AlbonGermanySigrid JamesUnited States of AmericaBruce JonasUnited States of AmericaJennifer JordanNew ZealandNiina JunttilaFinlandJon JureidiniAustraliaEsp\u00e9rance KashalaCongo Democratic RepublicFerdinand KellerGermanyDavid KempUnited States of AmericaBonnie KerkerUnited States of AmericaSuzanne KernsUnited States of AmericaPraveen KhairkarIndiaChristian KielingBrazilHyun-Sil KimSouth KoreaBryan KingUnited States of AmericaMichael KohnAustraliaAnne Katrin K\u00fcnsterGermanyNatasha LatzmanUnited States of AmericaElizabeth LetourneauUnited States of AmericaChing-Hua LinTaiwanYu-Ju LinTaiwanArnold LohausGermanyAstri J. LundervoldNorwayAristides Machado-RodriguesPortugalStefania MaggiCanadaRajneesh MahajanUnited States of AmericaAndres MartinUnited States of AmericaTherese MathewsUnited States of AmericaJon McClellanUnited States of AmericaChristopher McDougleUnited States of AmericaJoe McNamaraUnited States of AmericaAnilena MejiaUnited KingdomSusannah MelvilleUnited KingdomEugen MengelGermanyInmaculada Moreno Garc\u00edaSpainTally MosesUnited States of AmericaStella MuthuriCanadaKerstin NeanderSwedenDennis NitkowskiGermanyIngrid Landgraff OestlieNorwayThomas OlinoUnited States of AmericaSusanna PayneUnited KingdomGeraldine PearsonUnited States of AmericaWendy PlanteUnited States of AmericaPaul L. PlenerGermanyGuilherme PolanczykBrazilMaria Cristina PorfirioItalyIrina Elizabeth PoslawskyNetherlandsJonathan PrinceUnited States of AmericaDaniel RadeloffGermanyNicola ReavleyAustraliaRuth ReedUnited KingdomNicole ReillyAustraliaMatthias ReitzleGermanyThiago RochaBrazilPaul RohdeUnited States of AmericaJeanne RyanUnited States of AmericaPer-Anders RydeliusSwedenChristina SakaiUnited States of AmericaGiovanni SalumBrazilMasafumi SanefujiJapanUrsula Sansom-DalyAustraliaCaferi Tayyar SasmazTurkeySusan SawyerAustraliaErin SchoenfelderUnited States of AmericaThomas SchofieldUnited States of AmericaFiona SchulteCanadaDonald SharpeCanadaJordan SibeoniFranceInga Dora SigfusdottirIcelandIlina SinghUnited KingdomPetros SkapinakisGreeceTristram SmithUnited States of AmericaGottfried SpanglerGermanyAnthony SpiritoUnited States of AmericaFabio SticcaSwitzerlandLisanne StoneNetherlandsCarla StoverUnited States of AmericaJames SwansonUnited States of AmericaKatalin SzakszonHungaryToshinobu TakedaJapanSarah TarboxUnited States of AmericaCristiano Tschiedel Belem da SilvaBrazilAina Basilier VaageNorwayMitch van GeelNetherlandsBenedetto VitielloUnited States of AmericaJan WallanderUnited States of AmericaJames WaxmonskyUnited States of AmericaCarl WeemsUnited States of AmericaYifeng WeiCanadaGunda W\u00f6\u00dfnerGermanyPeter ZimmermannGermany"}
+{"text": "The editors of International Journal of Behavioral Nutrition and Physical Activity would like to thank all our reviewers who have contributed to the journal in Volume 11 (2014). Suzanne AbrahamAustraliaAnna Adachi-MejiaUnited States of AmericaEmma AdamsUnited KingdomMinna AittasaloFinlandAnnie AndersonUnited KingdomAndrew J AtkinUnited KingdomSuzanne AudreyUnited KingdomGarry AuldUnited States of AmericaMauricio AvendanoUnited States of AmericaHelena BaertUnited States of AmericaGraham BakerUnited KingdomKatherine BaldockAustraliaAustin BaldwinUnited States of AmericaKylie BallAustraliaTom BaranowskiUnited States of AmericaSally BarberUnited KingdomCristina BarrosoUnited States of AmericaJimikaye BeckUnited States of AmericaRebecca BeekenUnited KingdomMarielle BeenackersNetherlandsChristie BefortUnited States of AmericaElling BereNorwayJerica BergeUnited States of AmericaClaire BernaardsNetherlandsDavid BerriganUnited States of AmericaTanya BerryCanadaKathelijne BessemsNetherlandsHerv\u00e9 BessonUnited KingdomPrachi BhatnagarUnited KingdomStuart BiddleUnited KingdomAmanda BirnbaumUnited States of AmericaMaureen BlackUnited States of AmericaChristine 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+{"text": "Journal of NeuroEngineering and Rehabilitation would like to thank all of our reviewers who have contributed to the journal in volume 12 (2015).The editors of  Peter AdamczykUnited States of AmericaAbidemi Bolu AjiboyeUnited States of AmericaNicholas AndersonUnited States of AmericaTomoko AokiJapanPhilippe ArchambaultCanadaLuca ArdigoItalyPanagiotis ArtemiadisUnited States of AmericaMusa AuduUnited States of AmericaLouis AwadUnited States of AmericaRichard BakerUnited KingdomBel\u00e9n BallesterSpainRobert BarryUnited States of AmericaDorothy Barth\u00e9lemyCanadaKilian BaurSwitzerlandScott BeardsleyUnited States of AmericaRobin Bekrater-BodmannGermanyJuan-Manuel Belda-LoisSpainLeah BentCanadaSergi Berm\u00fadez I BadiaPortugalStuart Binder-MacleodUnited States of AmericaAmy BlankUnited States of AmericaFlorian BodranghienBelgiumMarco BonizzatoSwitzerlandDavid BortonUnited States of AmericaDennis BourbeauUnited States of AmericaJocelyn BowdenAustraliaMark BowdenUnited States of AmericaElena BrownUnited States of AmericaStephen BrownCanadaCynthia BrownUnited States of AmericaSzofia BullainUnited States of AmericaRocco CalabroItalyCarmen Capo-LugoUnited States of AmericaStephanie CareyUnited States of AmericaIlaria CarpinellaItalyAmanda CartyIrelandMaura CasadioItalyMargherita CastronovoGermanyMarco CempiniItalyMassimo CenciariniGermanyAndrea CereattiItalyBenedetta CesquiItalyGuohong ChaiChinaDar-Zen ChenTaiwanMaoqi ChenChinaLorenzo ChiariItalyYounggeun ChoiSouth KoreaCipriani ChristianItalyAnita ChristieUnited States of AmericaImre CikajloSloveniaSteve CollinsUnited States of AmericaRoberto ColomboItalyJos\u00e9 Contreras-VidalUnited States of AmericaLouise CorbenAustraliaMartina CosciaSwitzerlandMichael CraryUnited States of AmericaRobert CreathUnited States of AmericaDustin CrouchUnited States of AmericaWilliam CusackUnited States of AmericaGislins DagnelieUnited States of AmericaFrederic DanionFranceKoel DasIndiaEling D de BruinSwitzerlandCarlos Alberto de Lima Braga Lopes CordeiroPortugalCristiano de MarchisItalyStefano de RossiUnited KingdomDalia de SantisItalyJesse DeanUnited States of AmericaFrederik DeconinckBelgiumAntonio del AmaSpainSilvia Del-DinUnited KingdomUgo Della CroceItalyCharmaine DemanueleUnited States of AmericaNandini DeshpandeCanadaRonald DeumensBelgiumVolker DietzSwitzerlandDan DingUnited States of AmericaCatherine Disselhorst-KlugGermanyAn DoUnited States of AmericaAntoinette DomingoUnited States of AmericaNick DonaldsonUnited KingdomStrahinja DosenGermanyRaffy DotanCanadaEdward DoughertyUnited States of AmericaMarcos DuarteBrazilSean DukelowCanadaAyelet DunskyIsraelWilliam DurfeeUnited States of AmericaGammon EarhartUnited States of AmericaReggie EdgertonUnited States of AmericaDebbie EspyUnited States of AmericaTimothy ExellUnited KingdomDeborah FallaGermanySusan FasoliUnited States of AmericaWilliam FilerUnited States of AmericaJames FinleyUnited States of AmericaLee FisherUnited States of AmericaKevin 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+{"text": "The editors of BMC Pharmacology and Toxicology would like to thank all ourreviewers who have contributed to the journal in Volume 14 (2013). 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TournierFranceLuigi UccioliItalyMikko Uusi-OukariFinlandEric VanderploegUnited States of AmericaRick VegaUnited States of AmericaElisabetta Verderio EdwardsUnited KingdomAndreas VilhelmssonSwedenChris VulpeUnited States of AmericaCheryl WatsonUnited States of AmericaBj\u00f6rn WettermarkSwedenZhigang XieUnited States of AmericaFadi XuUnited States of AmericaJialin XuUnited States of AmericaHsin-Sheng YangUnited States of AmericaZhiyong YangUnited States of AmericaTzung-Hai YenTaiwanUlrich ZachariaeUnited KingdomMing ZhanUnited States of AmericaJianli ZhangChinaLiming ZhouChinaFrans ZitmanNetherlandsClaudia ZwingmannCanadaThe pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/2050-6511/15/33/prepub"}
+{"text": "The editors of BMC Neuroscience would like to thank all our reviewers who have contributed to the journal in Volume 15 (2014). Paula AgostinhoPortugalSaif Ahmad SaudiArabiaLudwig AignerAustriaMichael AkinsUnited States of AmericaHakan AldskogiusSwedenJohn AllenUnited States of AmericaSilvana AllodiBrazilJuli\u00e0 L AmengualSpainMiroslava AnderovaCzech RepublicBalasubramaniam AnnamalaiUnited States of AmericaSaema AnsarSwedenUbaldo ArmatoItalyMariana AstizSpainIlknur AyUnited States of AmericaTravis BakerCanadaVeera Venkata Ratnam BandaruUnited States of AmericaRina BandopadhyayUnited KingdomAndrew BankstonUnited States of AmericaJianxin BaoUnited States of AmericaGuido BarchiesiItalyAnirban BasuIndiaNadhim BayattiUnited KingdomRichard BazinetUnited States of AmericaM. 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+{"text": "BMC Evolutionary Biology would like to thank all our reviewers who have contributed to the journal in Volume 14 (2014).The editors of  Matthew AardemaUnited States of AmericaFederico AbascalSpainAmir AbbasiPakistanPatrick AbbotUnited States of AmericaPelayo AcevedoSpainCristina AcostaArgentinaIrina Adonina RussianFederationKwaku Aduse-PokuUnited KingdomIngi AgnarssonUnited States of AmericaSebastian Aguilar Pierl\u00e9United States of AmericaMineaki AizawaJapanM.Mar AlbaSpainFernando AldaSpainPaulo AmaralUnited KingdomGuruprasad AnandaUnited States of AmericaBarbara J AndersonNew ZealandMarkus AnkenbrandGermanyTomohiro ArakiJapanDan ArdiaUnited States of AmericaRoberto ArganoItalyTatiana Arias GarzonHong KongStephane Aris-BrosouCanadaSophie Arnaud-HaondFranceBirgit Arnholdt-SchmittPortugalNatasha AroraSwitzerlandPaula ArribasSpainNils ArrigoSwitzerlandJairo ArroyaveUnited States of AmericaMarina AscunceUnited States of AmericaRaquel AssisUnited States of AmericaShreyas AthavaleUnited States of AmericaDenis AugotFranceStuart AuldUnited KingdomJanelle AyresUnited States of AmericaMounawer BadriTunisiaMumtaz BaigIndiaStuart BairdFranceAllan BakerCanadaChristopher BalakrishnanUnited States of AmericaDaniel BaldassarreUnited States of AmericaJanneke BalkUnited KingdomDavid BaltrusUnited States of AmericaMarta BarluengaSpainCraig BarrettUnited States of AmericaSeth BarribeauSwitzerlandAakash BasuUnited States of AmericaAndrew BatemanCanadaFabia Ursula BattistuzziUnited States of AmericaDavid BaumUnited States of AmericaDenis BaurainBelgiumJeremy BeaulieuUnited States of AmericaLutz BecksGermanyJasminca Behrmann-GodelGermanySusanta BehuraUnited States of AmericaEric BeitzGermanyAlbano Beja-PereiraPortugalPatr\u00edcia BeldadePortugalAlexa BelyUnited States of AmericaJohn BenzieIrelandFernanda BeredBrazilStewart BerlocherUnited States of AmericaGiorgio BertorelleItalyStephanie BertrandFranceTimothy BestorUnited States of AmericaKaspar BienefeldGermanyJean-Christophe BilleterNetherlandsOlaf Bininda-EmondsGermanyMichael BlackNew ZealandJohn BlazierUnited States of AmericaChristoph BleidornGermanyPaulette BloomerSouth AfricaLeigh BoardmanSouth AfricaJulien BobeFranceLadislav BocakCzech RepublicDavid BogumilGermanyKirsten BohnUnited States of AmericaAureliano BombarelyUnited States of AmericaMichael BonkowskiGermanyCamille BonneaudUnited KingdomSung Min BooSouth KoreaCarlos Andr\u00e9s BoteroUnited States of AmericaJennifer Botha-BrinkSouth AfricaJean BoubliUnited KingdomMarylene BouletCanadaLouis BoumansNorwayLaura BoykinUnited States of AmericaRobert BradleyUnited States of AmericaHans BreeuwerNetherlandsAmanda BretmanUnited KingdomJory BrinkerhoffUnited States of AmericaJanice Britton-DavidianFranceLuciano BrocchieriUnited States of AmericaJohn BrookfieldUnited KingdomDavid BryantNew ZealandJosef BryjaCzech RepublicMike BuckleyUnited KingdomMartin BurdAustraliaJohn BurkaCanadaGeraldine ButlerIrelandNicholas ButterfieldUnited KingdomNadia BystriakovaUnited KingdomAna CaicedoUnited States of AmericaFrancesc CalafellSpainCarla CaloItalyLahcen CampbellIrelandSimona CandianiItalyJun CaoChinaCristian CapelliUnited KingdomTim CaroUnited States of AmericaMartin CarrUnited KingdomBryan CarstensUnited States of AmericaJerome CasasFranceAntonio CastroSpainIsa CavacoSwedenStephen CaversUnited KingdomStephane ChaillouFranceYingguang Frank ChanGermanyBelinda ChangCanadaYa-Ting ChaoTaiwanMichel ChapuisatSwitzerlandThierry ChardotFranceGyaneshwer ChaubeyEstoniaAlan ChengUnited States of AmericaChangde ChengUnited States of AmericaTzen-Yuh ChiangTaiwanAlberto CivettaCanadaMarcus ClaussSwitzerlandMartin CoetzeeSouth AfricaDavid CollarUnited States of AmericaH\u00e9l\u00e8ne CollinUnited KingdomGavin ConantUnited States of AmericaMarty CondonUnited States of AmericaTim ConnallonUnited States of AmericaJohn ConranAustraliaSofia ConsuegraUnited KingdomDavid CookeUnited KingdomArielle CooleyUnited States of AmericaAlan CooperAustraliaSteven CooperAustraliaVaughn CooperUnited States of AmericaMiguel CoronaUnited States of AmericaAndrea CosacovArgentinaSheena CotterUnited KingdomFPD CotterillSouth AfricaMarie-Agnes CoutellecFranceRobert CowieUnited States of AmericaCymon John CoxPortugalPhilip CoxUnited KingdomBrian CrotherUnited States of AmericaJose CuestaSpainChristopher CullisUnited States of AmericaCameron CurrieUnited States of AmericaRute Da FonsecaPortugalAnn Daly UnitedKingdomKavitha DamalUnited States of AmericaJakob DamgaardDenmarkIgor DanilovRussian FederationPatrick DanleyUnited States of AmericaLiliana DavalosUnited States of AmericaCharles DavisUnited States of AmericaJerrold DavisUnited States of AmericaJill De JongUnited States of AmericaA. 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LaugenFinlandJustin LawrenceUnited States of AmericaEster L\u00e1zaroSpainArnaud Le RouzicFranceEllouise LeadbeaterUnited KingdomLarry LeamyUnited States of AmericaPei-Fen LeeTaiwanMichael LeeAustraliaCheng-Ruei LeeAustriaLuc LegalFranceBen LehnerSpainJussi LehtonenAustraliaTuomas LeinonenFinlandFrederik LeliaertBelgiumTobias LenzGermanyHannes LerpGermanyFay-Wei LiUnited States of AmericaQing-Jun LiChinaXiwen LiChinaYang LiUnited States of AmericaJessica LiberlesUnited States of AmericaDavid LiberlesUnited States of AmericaEva LiebauGermanyBurton LimCanadaDoro LindtkeUnited States of AmericaCharles LinkemUnited States of AmericaSimone LinzGermanyThomas LisneyCanadaAmy LittUnited States of AmericaTom LittleUnited KingdomCheng LiuChinaPeter LockhartNew ZealandCarla Jo Logan-YoungUnited States of AmericaKevin LoopeUnited States of AmericaXavier LopezSpainPhilippe LopezFranceJordi L\u00f3pez-PujolSpainCarlos Lopez-VaamondeFranceStefan L\u00f6ttersGermanyStephen LougheedCanadaJeffrey LozierUnited States of AmericaAndrea LuchettiItalySulan LuoChinaStefan LupoldUnited States of AmericaAndrew MacCollUnited KingdomGonzalo Machado-SchiaffinoGermanyD Luke MahlerUnited States of AmericaRafael MaiaUnited States of AmericaIrina Maljkovic BerryUnited States of AmericaRichard MallyNorwaySteven ManchesterUnited States of AmericaMollie ManierUnited States of AmericaPatrick MardulynBelgiumDouglas MarkleUnited States of AmericaPeter MarkoUnited States of AmericaTherese MarkowUnited States of AmericaWilliam MartinGermanyGuillaume MartinFranceJulien MartinezUnited KingdomJesus Martinez-PadillaSpainJohn P MaslyUnited States of AmericaNicholas MasonUnited States of AmericaDaniel MaticzkaGermanyYu MatsuuraJapanMike MaxwellUnited States of AmericaGerald MayrGermanyKaren D McCoyFranceMichael McGowenUnited KingdomJoel McManusUnited States of AmericaMark McPeekUnited States of AmericaJulie MeachenUnited States of AmericaRichard H MeadowUnited States of AmericaRaul MedinaUnited States of AmericaJonathan MeeCanadaRita MehtaUnited States of AmericaCarlo MeloroUnited KingdomVincent MerckxNetherlandsJoachim MergeayBelgiumSami MerilaitaFinlandFlorian Mermillod-BlondinFranceMargarita MetallinouUnited States of AmericaNeil MetcalfeUnited KingdomKaren MeusemannGermanyAxel MeyerGermanyJustin MeyerUnited States of AmericaWolfgang MeyerhofGermanyTheodore MeyersUnited States of AmericaLeithen M'GonigleUnited States of AmericaAndy MichelUnited States of AmericaAlexander MikheyevJapanAlessandro MinelliItalyRakesh MishraIndiaMichael MiyamotoUnited States of AmericaGaurav MogheUnited States of AmericaVera Moiseenkova-BellUnited States of AmericaBabak MomeniUnited States of AmericaAntonio Jose MonforteSpainPhilippe MongetFranceStefano MontanariAustraliaFrancisco MonteroSpainMichael MoodyUnited States of AmericaPaul MorrisUnited States of AmericaEdward MorrowUnited KingdomAlan MosesCanadaAdnan MoussalliAustraliaUlrich MullerUnited States of AmericaTobias M\u00fcllerGermanyJohn MulleyUnited KingdomMartha MunozAustraliaShona MurphyUnited KingdomWilliam MurphyUnited States of AmericaBrent MurrayCanadaNavdeep MuttiUnited States of AmericaSatoshi NamekawaUnited States of AmericaLeanne NashUnited States of AmericaNicolas NavarroFranceAndre NelFranceRafik NemeGermanySterling NesbittUnited States of AmericaJulienne NgUnited States of AmericaChris NiceUnited States of AmericaCaroline NieberdingBelgiumClaus NielsenDenmarkChen NiuUnited States of AmericaDaniel NobleAustraliaMohamed NoorUnited States of AmericaRobert NuddsUnited KingdomJuan N\u00fa\u00f1ez-Farf\u00e1nMexicoSuat OezbekGermanyHiroyuki OgataFranceDario Ojeda AlayonCanadaBrian OliverUnited States of America\u00c5ke OlsonSwedenCarrie Olson-ManningUnited States of AmericaDenise O'MearaIrelandJuan OpazoChileClaudia Patricia Ornelas-GarciaMexicoPablo Orozco-TerwengelUnited KingdomGuillermo OrtiUnited States of AmericaLars OstergaardUnited KingdomNorman Owen-SmithSouth AfricaAnnalise PaabyUnited States of AmericaMark PagelUnited KingdomMaria PalaUnited KingdomFerran PaleroFranceAndrei PapkouGermanyHanu PappuUnited States of AmericaChristine ParentUnited States of AmericaMargot ParisFranceDaesik ParkSouth KoreaKevin ParsonsUnited KingdomMark ParthunUnited States of AmericaGiuseppe PassarinoItalyBruce PattersonUnited States of AmericaJames L. PattonUnited States of AmericaJoana Paup\u00e9rioPortugalJames PeaseUnited States of AmericaKatia PellegrinoBrazilCarlos PenaFinlandOsnat PennUnited States of AmericaDeepak PentalIndiaAlan PepperUnited States of AmericaJohn PepperUnited States of AmericaLuisa PereiraPortugalGuy PerriereFranceGeorge PerryUnited States of AmericaXavier PicoSpainMarcio PieBrazilWilliam PielUnited States of AmericaDavide PisaniUnited KingdomMiroslav PlohlCroatiaGrant PogsonUnited States of AmericaGianluca PolgarBruneiJohn PoolUnited States of AmericaAnthony PooleNew ZealandEmmanuelle PorcherFranceDaniele PorrettaItalyCalvin PorterUnited States of AmericaMegan PorterUnited States of AmericaDaniel PortikUnited States of AmericaJaime PottiSpainJan Yde PoulsenNorwayChristine PourcelFranceThomas PowellUnited States of AmericaPeter PrentisAustraliaJill PrestonUnited States of AmericaChristopher PrevitiGermanyJonathan PriceUnited States of AmericaTom PriceUnited KingdomElizabeth PringleUnited States of AmericaKathleen PrudicUnited States of AmericaJasna PuizinaCroatiaBenoit PujolFranceChristian RabelingUnited States of AmericaUte RadespielGermanyJacek RadwanPolandRahul RaghavanUnited States of AmericaSteven RammGermanyPedro RangePortugalVincent RanwezFranceDavid RayUnited States of AmericaSuvendra RayIndiaSushma ReddyUnited States of AmericaRosemary RedfieldCanadaAlexandre Reis PercequilloBrazilDavid L. RemingtonUnited States of AmericaJana RepkovaCzech RepublicDirk RepsilberSwedenPaula Reyes-HerreraItaly\u00c2ngela RibeiroPortugalOldrich RicanCzech RepublicStefan RichterGermanyFabio RindiItalyChristian RobertFranceTerence J RobinsonSouth AfricaAlfred RocaUnited States of AmericaLuiz RochaUnited States of AmericaNicolas RodrigueCanadaIgor RogozinUnited States of AmericaAna RojasSpainAntonis RokasUnited States of AmericaJonathan RollandFranceDavid RollinsonUnited KingdomSophie RommelGermanyHoward RosenbaumUnited States of AmericaAndrew RossUnited KingdomOmar Rota-StabelliItalyCandy RoweUnited KingdomKevin RoweAustraliaJulio RozasSpainDaniel RozenNetherlandsNimrod RubinsteinUnited States of AmericaJasmin RuchGermanyManuel RuediSwitzerlandEduardo Ruiz-SanchezMexicoAnna RunemarkSwedenAnthony RussellCanadaDanilo RussoItalyAssieh SaadatpourUnited States of AmericaCarlos SaavedraSpainKeiko SakakibaraJapanDaniele SalviPortugalLeah SambergUnited States of AmericaAlvaro San MillanUnited KingdomEmilia SantosFranceFrancisco SantosPortugalMauro SantosSpainAlexandra S\u00e1-PintoPortugalMichael SavageauUnited States of AmericaHanno SchaeferGermanyHelmut SchaschlAustriaChristian Schl\u00f6ttererAustriaJames SchnableUnited States of AmericaChristian Sch\u00f6nbachJapanFrederick SchramUnited States of AmericaHannes SchulerUnited States of AmericaPeter SchusterAustriaSchraga SchwartzUnited States of AmericaErich SchwarzUnited States of AmericaRoland SchwarzUnited KingdomMatthew ScotchUnited States of AmericaCatherine SearleUnited States of AmericaLaure SegurelUnited States of AmericaRyan SeipkeUnited KingdomJae Young SeongSouth KoreaIrem SepilUnited KingdomOtto Sepp\u00e4l\u00e4SwitzerlandRobert SeyfarthUnited States of AmericaAaron ShaferSwedenEugene ShakhnovichUnited States of AmericaA. Jonathan ShawUnited States of AmericaAndrew ShedlockUnited States of AmericaLara ShepherdNew ZealandTakahito ShikanoFinlandMahmood ShivjiUnited States of AmericaJohn ShueyUnited States of AmericaDustin SiegelUnited States of AmericaJulia SigwartUnited KingdomRalph SimonGermanyLuca SineoItalyTiratha Raj SinghIndiaJon SlateUnited KingdomAdam SmithUnited States of AmericaGavin SmithSingaporeJames SobelUnited States of AmericaJordi SolanaGermanyEmanuela SolanoItalyJuan Jose SolerSpainJingyuan SongChinaIgnacio Mar\u00eda SotoArgentinaJulien SoubrierAustraliaDieter SpitellerGermanyPeter F StadlerGermanyTanja StadlerSwitzerlandKlara StefflovaUnited States of AmericaSandra SteigerGermanyRike StelkensUnited KingdomCaitlin SternUnited States of AmericaJohn W. StillerUnited States of AmericaTanja StrandSwedenPatrick StrutzenbergerGermanyBing SuChinaHans-Dieter SuesUnited States of AmericaShan SunChinaPaul SunnucksAustraliaHitoshi SuzukiJapanLuc SweversGreeceAlfred SzmidtJapanYasuoki TakamiJapanNobuto TakeuchiJapanNaoko TakezakiJapanShohei TakunoJapanGerard TalaveraUnited States of AmericaKristiina TambetsEstoniaSithichoke TangphatsornruangThailandPedro TarrosoPortugalScott TaylorUnited States of AmericaJohn TaylorCanadaAshley TeufelUnited States of AmericaAnne ThielschGermanyMichael ThomUnited KingdomDaniel ThomasNetherlandsPaul ThomasUnited States of AmericaMaria Tereza Thom\u00e9BrazilDacheng TianChinaNicholas TipperyUnited States of AmericaTakayuki TohgeGermanyKoji TojoJapanHaiyan TongFranceJo\u00e3o Filipe ToniniUnited States of AmericaArne TraulsenGermanyTom TregenzaUnited KingdomLudwig TriestBelgiumStephen TrumboUnited States of AmericaJames TurnerUnited KingdomXavier TuronSpainAlex TwyfordUnited States of AmericaHildegard UeckerAustriaJeremy UllmannAustraliaNathan UphamUnited States of AmericaLawrence UricchioUnited States of AmericaMario Vallejo-MarinUnited KingdomInes Van BocxlaerBelgiumAlexander van der GeerNetherlandsArie van der MeijdenPortugalJoost van HeerwaardenNetherlandsSimon van NoortSouth AfricaBettine van VuurenSouth AfricaJohn VandenberghUnited States of AmericaGreg VanlerbergheCanadaSandra VargaFinlandParis VeltsosUnited KingdomMiguel VencesGermanyFrederic VeyrunesFranceLinda VigilantGermanyMark VineyUnited KingdomEmma VitikainenUnited KingdomThomas Von RintelenGermanyChristoph VorburgerSwitzerlandNiklas WahlbergFinlandLutz WalterGermanyHongjian WanChinaQi WangChinaHurng-Yi WangTaiwanSteve WangUnited States of AmericaWen WangChinaErik WapstraAustraliaAndrew WargoUnited States of AmericaRachel WarnockUnited States of AmericaPaul WassarmanUnited States of AmericaPhillip WattsFinlandBonnie WebsterUnited KingdomSonja WedmannGermanyMich\u00e8le WegmannSwitzerlandShu-Jun WeiChinaJanuary WeinerGermanyDavid WeisrockUnited States of AmericaSteven WeissAustriaMathias WernetUnited States of AmericaSarah WerningUnited States of AmericaLinda Wessel-BeaverPuerto RicoJen WhiteUnited States of AmericaJames WhitfieldUnited States of AmericaMartin WiemersGermanyJohn WiensUnited States of AmericaStuart WigbyUnited KingdomShawn WilderAustraliaClaus WilkeUnited States of AmericaEske WillerslevDenmarkChristopher WillettUnited States of AmericaThomas WilliamsUnited States of AmericaTony WilsonUnited States of AmericaRachel WiltshireUnited States of AmericaManuela WinklerAustriaMichael WiserUnited States of AmericaChristian WoehleGermanyGuinevere WoganUnited States of AmericaDiana WolfUnited States of AmericaMatthias WolfGermanyYuri WolfUnited States of AmericaRebecca WoodAustraliaApril WrightUnited States of AmericaRaquel XavierPortugalXuhua XiaCanadaFuliang XieChinaToshihiro YamadaJapanMarna Yandeau-NelsonUnited States of AmericaJin-Quan YangChinaJianrong YangUnited States of AmericaKeisuke YoshidaJapanHon-Tsen YuTaiwanBisong YueChinaLorenzo ZaneItalyEinat Zchori-FeinIsraelMiriam ZelditchUnited States of AmericaAimin ZhangChinaDe-Xing ZhangChinaYuan-Ming ZhangChinaYanjun ZhangChinaChiyu ZhangChinaMingli ZhangChinaHuabin ZhaoChinaLi ZhaoUnited States of AmericaYahui ZhaoChinaQing ZhouUnited States of AmericaRenchao ZhouChinaShunyi ZhuChinaAlbert ZlotnikUnited States of America"}
+{"text": "Maternal Health, Neonatology, and Perinatology would like to thank all of the reviewers who have contributed to the journal in Volume 1 (2015).The editor of  Alexandria HillUnited States of AmericaAlireza ShamshirazUnited States of AmericaAnup KatheriaUnited States of AmericaAshley WilliamsUnited States of AmericaCarlos BlancoIrelandChristina HerreraUnited States of AmericaDavid HutchonUnited KingdomDevaraj SambalingamUnited States of AmericaDon McCurninUnited States of AmericaElizabeth McClureUnited States of AmericaHeike RabeUnited KingdomJayashree RamasethuUnited States of AmericaJonathan SametUnited States of AmericaJorge TolosaUnited States of AmericaKelli BarbourUnited States of AmericaMalissa ParisiUnited States of AmericaMartin KeszlerUnited States of AmericaMatthew LaughonUnited States of AmericaNithi FernandesUnited States of AmericaPayam ValiUnited States of AmericaPraveen ChandrasekharanUnited States of AmericaRobert SilverUnited States of AmericaRodriguez ChristinaUnited States of AmericaRoland HentschelGermanyRosemary HigginsUnited States of AmericaRuth GrunauCanadaSatyan LakshminrusimhaUnited States of AmericaStuart HooperAustraliaVikramaditya DumpaUnited States of AmericaVinay SharmaUnited States of AmericaWare BranchUnited States of AmericaWilliam ZornUnited States of AmericaYawei ZhangUnited States of America"}
+{"text": "Journal of the International Society of Sports Nutrition would like to thank all our reviewers who have contributed to the journal from Volume 11 (2014).The editors of  Michelle AdamsUnited States of AmericaJose AntonioUnited States of AmericaAlan AragonUnited States of AmericaLuis AragonCosta RicaShawn ArentUnited States of AmericaSainath BabuUnited States of AmericaAudrey BaguetBelgiumDerek BallUnited KingdomLaurent BannockUnited KingdomMatthew BarnesNew ZealandKatherine BealsUnited States of AmericaDan BenardotUnited States of AmericaSandeep BhaleUnited States of AmericaScarlett BlandonUnited States of AmericaAmanda BonikowskeUnited States of AmericaAurelien BringardSwitzerlandWill BrinkUnited States of AmericaErik BustilloUnited States of AmericaBill CampbellUnited States of AmericaSara CampbellUnited States of AmericaErico CaperutoBrazilMichael CarlstonUnited States of AmericaAndres CarrilloUnited States of AmericaShuping ChenTaiwanAmanda Claassen-SmithersSouth AfricaMatthew CocksUnited KingdomAdriana ColettaUnited States of AmericaScott CongerUnited States of AmericaJoel CramerUnited States of AmericaBen DascombeAustraliaInna DumovaUnited States of AmericaConrad EarnestUnited States of AmericaJoan EckersonUnited States of AmericaAnya EllerbroekUnited States of AmericaMark FariesUnited States of AmericaAnthony FisherUnited KingdomAndreas FlourisGreeceMark FogartyUnited KingdomElfego GalvanUnited States of AmericaJeffrey GodinUnited States of AmericaJoanna Gromadzka-OstrowskaPolandBruno GualanoBrazilDaniel GwartneyUnited States of AmericaMichael HartmanUnited States of AmericaPhillip HarveyUnited States of AmericaTravis HarveyUnited States of AmericaJudith HaudumAustriaJaramillo Londo\u00f1o Hilda NorhaColombiaGlyn HowatsonUnited KingdomGeoffrey HudsonUnited States of AmericaPatrick JacobsUnited States of AmericaRalf J\u00e4gerUnited States of AmericaAndrew JagimUnited States of AmericaXanne Janse De JongeAustraliaDouglas KalmanUnited States of AmericaBettina KarstenUnited KingdomKristina KendallUnited States of AmericaWesley KephartUnited States of AmericaChad KerksickUnited States of AmericaArie KiesNetherlandsAndrea KirkUnited States of AmericaSusan KleinerUnited States of AmericaBeat KnechtleSwitzerlandRichard KreiderUnited States of AmericaJamie KrzykowskiUnited States of AmericaPaul La BountyUnited States of AmericaAnna LepeleyUnited States of AmericaKyle LeversUnited States of AmericaVivienne LewisUnited States of AmericaChris LockwoodUnited States of AmericaHector LopezUnited States of AmericaLonnie LoweryUnited States of AmericaRyan LoweryUnited States of AmericaJames LugoUnited States of AmericaShannan LynchUnited States of AmericaAndrew MckuneSouth AfricaRon MendelUnited States of AmericaAntti A MeroFinlandChristopher MobleyUnited States of AmericaJordan MoonUnited States of AmericaTaro MurakamiJapanMichael NelsonUnited States of AmericaGeorg NeumannGermanyJonathan OliverUnited States of AmericaCheong Hwa OoiMalaysiaMichael OrmsbeeUnited States of AmericaHidenori OtaniJapanCorey PeacockUnited States of AmericaSunita PotgieterSouth AfricaJonato PrestesBrazilMartin PurpuraUnited States of AmericaChristoph RaschkaGermanyNicholas RatamessUnited States of AmericaJohn RathmacherUnited States of AmericaMichael RobertsUnited States of AmericaVanessa Rodrigues VilelaBrazilF.Nese SahinTurkeySteve SchmitzUnited States of AmericaBrad SchoenfeldUnited States of AmericaNeil SchwarzUnited States of AmericaJohn SeifertUnited States of AmericaPiero SestiliItalyAndrew ShaoUnited States of AmericaTobin SilverUnited States of AmericaAbbie Smith-RyanUnited States of AmericaJeffrey StoutUnited States of AmericaMark J. TallonUnited KingdomMinghua TangUnited States of AmericaLemuel W TaylorUnited States of AmericaLisa Te MorengaNew ZealandNicholas TillerUnited KingdomJulio TirapeguiBrazilGianluca TognonSwedenMarie-Berengere TroadecFranceBenjamin WaxUnited States of AmericaShawn WellsUnited States of AmericaDarryn WilloughbyUnited States of AmericaJacob WilsonUnited States of AmericaAbdelmoneim YounisUnited States of AmericaYang ZhangChinaHassane ZouhalFrance"}
+{"text": "Microbiome in 2014. We hope that you all will continue to support the journal as a reviewer or, better yet, as a contributing author.We are deeply grateful to all of the names listed below, who reviewed manuscripts submitted to  Kjersti AagaardUnited States of AmericaKatherine AmatoUnited States of AmericaFlorent AnglyAustraliaManimozhiyan ArumugamDenmarkHarsh BaisUnited States of AmericaAlbert BarberanUnited States of AmericaClara BelzerNetherlandsJennifer BiddleUnited States of AmericaDebby BogaertNetherlandsHomer BousheyUnited States of AmericaAndreas BruneGermanyFrederic BushmanUnited States of AmericaKaty CaliffUnited States of AmericaIan CarrollUnited States of AmericaFrank ChervenakUnited States of AmericaErika ClaudUnited States of AmericaMaria Carmen ColladoSpainPierre CornelisBelgiumMinucci DariaItalySuzanne DevkotaUnited States of AmericaRobert DyerUnited States of AmericaNajwa El-NachefUnited States of AmericaJohn Erb-DownwardUnited States of AmericaJames FosterUnited States of AmericaW. Florian FrickeGermanyKei FujimuraUnited States of AmericaPawel GajerUnited States of AmericaJack GilbertUnited States of AmericaSteven GillUnited States of AmericaGreg GloorCanadaMichael GorinUnited States of AmericaAnn GriffenUnited States of AmericaBrian HaasUnited States of AmericaYiping HanUnited States of AmericaRobert HettichUnited States of AmericaMarkus HiltySwitzerlandLucas HoffmanUnited States of AmericaDeborah HoganUnited States of AmericaIan HolmesUnited States of AmericaYuichi HongohJapanMichael ImelfortAustraliaIan JefferyIrelandChristian JobinUnited States of AmericaHannah JonesUnited KingdomJohn KellyUnited States of AmericaMogens KilianDenmarkClaudia KniefGermanySergey KonstantinovNetherlandsOmry KorenUnited States of AmericaPurnima KumarUnited States of AmericaVladimir LazarevicSwitzerlandFrancois LebretonUnited States of AmericaCharles LeeNew ZealandKatherine LemonUnited States of AmericaCatherine LeyUnited States of AmericaHuilin LiUnited States of AmericaMark LilesUnited States of AmericaJohn LiPumaUnited States of AmericaNathan LoAustraliaRamiro LogaresSpainNicholas LomanUnited KingdomPetra LouisUnited KingdomSusan LynchUnited States of AmericaBing MaUnited States of AmericaVolker MaiUnited States of AmericaJulian MarchesiUnited KingdomJulia MarescaUnited States of AmericaDavid H. MartinUnited States of AmericaRocio MartinNetherlandsEmmanuel F. MongodinUnited States of AmericaMichael MorowitzUnited States of AmericaArdythe MorrowUnited States of AmericaTanya MurphyUnited States of AmericaKenneth NickersonUnited States of AmericaDennis S. NielsenDenmarkWilliam NiermanUnited States of AmericaOrla O'SullivanIrelandGeorge O'TooleUnited States of AmericaJohn ParkinsonCanadaRembert PieperUnited States of AmericaJose Miguel PoncianoUnited States of AmericaThomas RatteiAustriaJohn RawlsUnited States of AmericaMary ReganUnited States of AmericaJuan Miguel RodriguezSpainGail RosenUnited States of AmericaBernard RousseauUnited States of AmericaSusannah SalterUnited KingdomKaren SchwarzbergUnited States of AmericaCynthia SearsUnited States of AmericaJulia SegreUnited States of AmericaThomas SharptonUnited States of AmericaJason StajichUnited States of AmericaYijun SunUnited States of AmericaEric TriplettUnited States of AmericaSilvia TurroniItalyChris van der GastUnited KingdomChristian von MeringSwitzerlandWilliam WadeUnited KingdomAlan WalkerUnited KingdomJens WalterCanadaHung WinnUnited States of AmericaDongying WuUnited States of AmericaYanbao YuUnited States of AmericaEgija ZauraNetherlands"}
+{"text": "Molecular Brain would like to thank all our reviewers who have contributed to the journal in Volume 8 (2015).The editors of  Marisela AgudeloUnited States of AmericaYoshiki ArakawaJapanValeria AvdoshinaUnited States of AmericaNagi AyadUnited States of AmericaKasum AzimUnited States of AmericaTudor C BadeaUnited States of AmericaDaehyun BaekRepublic of KoreaAngel BarcoSpainArnab BarikUnited States of AmericaMark BearUnited States of AmericaOren BecherUnited States of AmericaGuoqiang BiChinaHaruhiko BitoJapanVadim BolshakovUnited States of AmericaVictor BorrellSpainDenis BurdakovUnited KingdomTimothy BusseyUnited KingdomMarco CanossaUnited States of AmericaMian CaoChinaL CaoUnited States of AmericaShuwen CaoUnited States of AmericaFrancesco CardonaItalyMartine CattarelliFranceSebastiano CavallaroItalySunghoe ChangRepublic of KoreaBrian ChenCanadaGong ChenUnited States of AmericaXuanmao ChenUnited States of AmericaYoujun ChenUnited States of AmericaZheyu ChenChinaKei ChoUnited KingdomDh ChoRepublic of KoreaYoungshik ChoeRepublic of KoreaSoo Young ChoiRepublic of KoreaKimberly ChristianUnited States of AmericaSteven ClarkeUnited States of AmericaDaniel CohenFranceGraham CollingridgeUnited KingdomJaqueline CrawleyUnited States of AmericaWim CrusioFranceFernando De CastroSpainJessica DeslauriersCanadaYuqiang DingChinaTr DoeppnerGermanyBo DuanUnited States of AmericaSebastian DworkinAustraliaMarina EmborgUnited States of AmericaJose Antonio EstebanSpainCinthia FarinaItalyAndr\u00e9 FischerGermanyPatrick FisherDenmarkMasayo FujitaJapanMasaki FukataJapanTomoyuki FuruyashikiJapanPeter GassGermanyAnamitra GhoshUnited States of AmericaPeter GieseUnited KingdomChristian Johannes GloecknerGermanyKerui GongUnited States of AmericaJohannes GraeffSwazilandKamalesh GuliakIndiaCamilla GustafsenDenmarkHideo HagiharaJapanJin-Hee HanCanadaKihoon HanRepublic of KoreaYoung-Goo HanUnited States of AmericaDaniela HartlGermanyYasunori HayashiJapanYasunori HayashiUnited States of AmericaYiping HeUnited States of AmericaKarl HerrupChinaHajime HiraseJapanXiu-Ti HuUnited States of AmericaAndrew HuangTaiwan, Republic of ChinaEunmi HurRepublic of KoreaJeong-Jin HwangRepublic of KoreaSun Wook HwangRepublic of KoreaSu-Kyeong HwangRepublic of KoreaKazutaka IkedaJapanMasashi IkedaJapanMasai IshiiJapanAnthony IslesUnited KingdomShigeyoshi ItoharaJapanTakuji IwasatoJapanDeok-Jin JangRepublic of KoreaRu-Rong JiUnited States of AmericaZhengping JiaCanadaSeonmi JoRepublic of KoreaFrancois JouretBelgiumYong-Keun JungRepublic of KoreaBong-Kiun KaangRepublic of KoreaWataru KakegawaJapanRoger KammUnited States of AmericaFusao KatoJapanSatoshi KidaJapanEun-Kyoung KimRepublic of KoreaHyong Kyu KimRepublic of KoreaJanghwan KimRepublic of KoreaJaesang KimRepublic of KoreaEunjoon KimRepublic of KoreaSang Jeong KimRepublic of KoreaByung Gon KimRepublic of KoreaJin KimRepublic of KoreaJung-Woong KimRepublic of KoreaHye-Sun KimRepublic of KoreaSang Jeong KimRepublic of KoreaHyoung KimUnited States of AmericaYang-Hee KimRepublic of KoreaJanine KirbyUnited KingdomEric KlannUnited States of AmericaShira KnafoSpainJaewon KoRepublic of KoreaKohei KogaCanadaSchichi KoizumiJapanJa Wook KooRepublic of KoreaHisatsugu KoshimizuJapanChandra KothapalliUnited States of AmericaKiyoshi KurataJapanMiguel LafargaSpainCatherine LawrenceUnited KingdomKyungmin LeeRepublic of KoreaJae-Hyung LeeRepublic of KoreaJin-A LeeRepublic of KoreaSung Joong LeeRepublic of KoreaYong-Seok LeeRepublic of KoreaJeong Ho LeeRepublic of KoreaSeungbok LeeRepublic of KoreaSeung-Hee LeeRepublic of KoreaJaekwang LeeRepublic of KoreaJong Eun LeeRepublic of KoreaSeungkyu LeeUnited States of AmericaSeung-Jae LeeRepublic of KoreaYong-Seok LeeRepublic of KoreaWeidong LiChinaMinghua LiUnited States of AmericaShihua LiUnited States of AmericaHe LiUnited States of AmericaXiao-Jiang LiUnited States of AmericaF LiaoUnited States of AmericaChae Seok LimRepublic of KoreaFang LiuCanadaJose Lopez-AtalayaSpainDaniel LubelskiUnited States of AmericaKatarzyna LukasiukPolandZhenzhong MaUnited States of AmericaD MaUnited States of AmericaToshiya ManabeJapanIsabel MartinezUnited States of AmericaFernando Martinez-GarciaSpainAngeles Martin-RequeroSpainMiho MatsumataJapanThomas MchughJapanBritt MellstromSpainKarine MerienneFranceValerie MezgerFranceTsuyoshi MiyakawaJapanElek MolnarUnited KingdomInhee Mook-JungRepublic of KoreaFlavio MoroniItalyKirsten M\u00fcller-VahlGermanyKarim NaderCanadaMaria Da Gra\u00e7a Naffah-MazzacorattiBrazilShin NakagawaJapanYasushi NakagawaUnited States of AmericaKazutoshi NakazawaUnited States of AmericaJose R. NaranjoSpainFerdinando NicolettiItalyMarta NietoSpainTomoyuki NishizakiJapanWendy NobleUnited KingdomAlexi NottUnited States of AmericaYoung J. OhRepublic of KoreaSeog Bae OhRepublic of KoreaMasuo OhnoUnited States of AmericaToshihisa OhtsukaJapanHideyuki OkanoJapanTakaaki OzawaJapanHyungju ParkRepublic of KoreaH.R. ParriUnited KingdomStephane PeineauUnited KingdomJan PlockSwitzerlandAndrew PoulosUnited States of AmericaShuang QiuChinaYong RaoCanadaKimberlei RichardsonUnited States of AmericaCl RoulstonAustraliaMichael RowanIrelandHoon RyuUnited States of AmericaKatherine SadleirUnited States of AmericaMasanori SakaguchiJapanCarlo SalaItalyAnupama SathyamurthyUnited States of AmericaMako SatoJapanShailendra SaxenaIndiaJe Hoon SeoRepublic of KoreaWongi SeolRepublic of KoreaChengyong ShenChinaSanbing ShenIrelandHirotaka ShojiJapanBai Chuang ShyuTaiwan, Republic of ChinaJong-Woo SohnRepublic of KoreaJuan SongUnited States of AmericaTinna StevnsnerDenmarkVolko StraubUnited KingdomYongchao SuUnited States of AmericaByung-Chang SuhRepublic of KoreaCheuk-Kwan SunTaiwan, Republic of ChinaDandan SunUnited States of AmericaChao TaiUnited States of AmericaKeizo TakaoJapanKenkichi TakaseJapanTomohiko TakeiJapanXiangshi TanChinaZhi-Yong TanUnited States of AmericaZhibin TanUnited States of AmericaKoichi TanakaJapanYanmei TaoChinaAhmad TariqUnited States of AmericaAyumu TashiroSingaporeKathryn ToddCanadaHiroshi TokumitsuJapanIkuo TooyamaJapanHiroki ToyodaJapanRicha TripathiUnited KingdomHiroshi TsudaCanadaMakoto TsudaJapanShusaku UchidaJapanYoichi UetaUnited States of AmericaJuzoh UmemoriFinlandAtsuhiko UnoJapanLuis M. ValorSpainManlio VinciguerraUnited KingdomNoah WaltonUnited States of AmericaChao WangUnited States of AmericaTzu-Hao WangTaiwan, Republic of ChinaYing WangUnited States of AmericaXiaoming WangUnited States of AmericaYong-Ting WangChinaYuan WangChinaAyako WatabeJapanSumiko WatanabeJapanZhexing WenUnited States of AmericaAlbert WongCanadaLong-Jun WuUnited States of AmericaZhigang XiongUnited States of AmericaJunyu XuChinaKoji YamanakaJapanJun YanCanadaRiqiang YanUnited States of AmericaYuchio YanagawaJapanZhengang YangChinaMark YeomanUnited KingdomSeung-Yong YoonRepublic of KoreaZili YouChinaSeong-Woon YuRepublic of KoreaXiang YuChinaGerald W ZamponiCanadaScott ZeitlinUnited States of AmericaXiaohui ZhangChinaMing-Gao ZhaoChinaChunjie ZhaoChinaYu ZhouChinaFeng-Quan ZhouUnited States of AmericaJiawei ZhouChinaYang ZhouUnited States of AmericaMin ZhuoCanada"}
+{"text": "We thank all of the reviewers who have contributed to the journal in volume 7 (2015). High quality and timely reviews are critical to the overall quality of the journal. We are committed to providing a unique and important outlet for scholarship regarding neurodevelopmental disorders and are indebted to the outstanding reviewers who have contributed their time over the last year in helping us to reach this goal. Ted AbelUnited States of AmericaKevin AntshelUnited States of AmericaSimon Baron-CohenUnited KingdomCarrie BeardenUnited States of AmericaNan Bernstein RatnerUnited States of AmericaThomas BourgeronFranceRandal CarpenterUnited States of AmericaTony CharmanUnited KingdomKatarzyna ChawarskaUnited States of AmericaRina CianfaglioneUnited KingdomClaire ColesUnited States of AmericaJohn ColomboUnited States of AmericaJohn ConstantinoUnited States of AmericaCheryl CorcoranUnited States of AmericaJacqueline CrawleyUnited States of AmericaJulie DanielsUnited States of AmericaPetrus de VriesSouth AfricaWilliam DeBassioUnited States of AmericaAdele DimianUnited States of AmericaAnastasia DimitropoulosUnited States of AmericaIlan DinsteinIsraelDennis DraynaUnited States of AmericaInge-Marie EigstiUnited States of AmericaJed ElisonUnited States of AmericaSusan FajaUnited States of AmericaReinhold FeldmannGermanySusanna FryerUnited States of AmericaOscar GershanikArgentinaSimon GregoryUnited States of AmericaAmanda Hampton WrayUnited States of AmericaPamela HeatonUnited KingdomMelissa HinesUnited KingdomLisa M JacolaUnited States of AmericaAnna JansenBelgiumChris JarroldUnited KingdomLoydie Jerome-MajewskaCanadaShafali JesteUnited States of AmericaTracy JirikowicUnited States of AmericaEmily JonesUnited KingdomRobert JosephUnited States of AmericaMatthew JudsonUnited States of AmericaAnnette Karmiloff-SmithUnited KingdomWendy KatesUnited States of AmericaBrandon KeehnUnited States of AmericaKelly KingUnited States of AmericaBonita Klein-TasmanUnited States of AmericaAmi KlinUnited States of AmericaRebecca KnickmeyerUnited States of AmericaAlexander KolevzonUnited States of AmericaBarry KosofskyUnited States of AmericaRebecca LandaUnited States of AmericaJanine LaSalleUnited States of AmericaCatherine LebelCanadaEva LothUnited KingdomRebecca LucasUnited KingdomBryan LuikartUnited States of AmericaSuzanne MacariUnited States of AmericaMarsha MailickUnited States of AmericaChristian MarshallCanadaKlara MartonUnited States of AmericaJoe McCleeryUnited States of AmericaJennifer MillerUnited States of AmericaEric MorrowUnited States of AmericaMatt MosconiUnited States of AmericaJeff MunsonUnited States of AmericaMichael MuriasUnited States of AmericaClodagh MurphyUnited KingdomCharles NelsonUnited States of AmericaRowena NgUnited States of AmericaSusan NittrouerUnited States of AmericaCourtenay NorburyUnited KingdomChristine NordahlUnited States of AmericaLindsay ObermanUnited States of AmericaLucy OsborneCanadaNoriko OsumiJapanOpal OusleyUnited States of AmericaDavid PerrettUnited KingdomSarika PetersUnited States of AmericaDaniela Plesa SkwererUnited States of AmericaElizabeth PowellUnited States of AmericaNatalie PrideAustraliaZhenghan QiUnited States of AmericaAndrea QuinteroUnited States of AmericaPeter RabinsUnited States of AmericaArmin RaznahanUnited States of AmericaAvi ReichenbergUnited States of AmericaLeslie RescorlaUnited States of AmericaElisabeth RoofUnited States of AmericaJoanne RovetCanadaDaniela RubinUnited States of AmericaMustafa SahinUnited States of AmericaMark SandsUnited States of AmericaMichael SchmeisserGermanyElliott SherrUnited States of AmericaFrederick ShicUnited States of AmericaLinmarie SikichUnited States of AmericaTony SimonUnited States of AmericaMikle SouthUnited States of AmericaSarah SpenceUnited States of AmericaDimitri StavropoulosCanadaKyle SteinmanUnited States of AmericaAndre StrydomUnited KingdomJohn SweeneyUnited States of AmericaYukari TakaraeUnited States of AmericaKristiina TammimiesSwedenRaffaella TancrediItalyAmanda TarulloUnited States of AmericaMarc TasseUnited States of AmericaLucina Q UddinUnited States of AmericaAndrea VaagsCanadaTherese van AmelsvoortNetherlandsGiacomo VivantiUnited States of AmericaSam WassUnited KingdomJason WolffUnited States of AmericaKate WoodcockUnited KingdomGregory YoungUnited States of AmericaRichard ZieglerUnited States of America"}
+{"text": "Journal of NeuroEngineering and Rehabilitation would like to thank all of our reviewers who have contributed to the journal in volume 11 (2014).The editors of  Daijiro AbeJapanU. Rajendra AcharyaSingaporeDiane E. AdamoUnited States of AmericaSergei AdamovichUnited States of AmericaAllan AdkinCanadaValentina AgostiniItalyZaghloul AhmedUnited States of AmericaMark AlbertUnited States of AmericaJoan F. AlonsoSpainFarshid AmirabdollahianUnited KingdomPhilippe ArchambaultCanadaJ. Hans ArendzenNetherlandsJohn ArkwrightAustraliaPanagiotis ArtemiadisUnited States of AmericaAlexander AruinUnited States of AmericaOskar AszmannAustriaMusa AuduUnited States of AmericaLouis AwadUnited States of AmericaAli BahramisharifNetherlandsAlberto BaldiniItalySubhasis BanerjiSingaporeRobert John BarryAustraliaDorothy Barth\u00e9lemyCanadaGabor BartonUnited KingdomRezaul BeggAustraliaNikunj BhagatUnited States of AmericaTanvi BhattUnited States of AmericaDaniele BibboItalySandra BillingerUnited States of AmericaMartin BilodeauCanadaStuart Binder-MacleodUnited States of AmericaAndreanne BlanchetteCanadaAmy BlankUnited States of AmericaFlorian BodranghienBelgiumRichard BohannonUnited States of AmericaMatthieu BoisgontierBelgiumFrank BorgFinlandJ\u00f6rgen BorgSwedenDennis BourbeauUnited States of AmericaMark BowdenUnited States of AmericaJohn-Stuart BrittainUnited KingdomCynthia BrownUnited States of AmericaDustin BrueningUnited States of AmericaMichelle BurackUnited States of AmericaEtienne BurdetUnited KingdomMonica CameiraoPortugalFilippo CamerotaItalyLeonardo CappelloItalyStephanie CareyUnited States of AmericaTom CarlsonUnited KingdomStephen CarpUnited States of AmericaHelder CarvalhoPortugalMargherita CastronovoGermanyBrian CaulfieldIrelandMassimo CenciariniGermanyRosa H. M. ChanHong KongShuo-Hsiu ChangUnited States of AmericaYao-Jen ChangTaiwanXiang ChenChinaF\u00e9lix Ch\u00e9nierCanadaCarmelo ChisariItalyVeronica CimolinItalyPietro CipressoItalyEdward (Ted) ClancyUnited States of AmericaRoss ClarkAustraliaSue CobbUnited KingdomSteve CollinsUnited States of AmericaSilvia ConfortoItalyElaine CorbettAustraliaPatrick CostiganCanadaElaine CoulterUnited KingdomPatrick CragoUnited States of AmericaFrederic CrevecoeurCanadaDustin CrouchUnited States of AmericaXingran CuiUnited States of AmericaArmin CurtSwitzerlandMarco D'AlonzoItalyCarmen D'AnnaItalyPaulo de FreitasBrazilRay de LeonUnited States of AmericaAna de los Reyes Guzm\u00e1nSpainHelios de RosarioSpainJesse DeanUnited States of AmericaPhilippe DedieuFranceUgo Della CroceItalyThibault DeschampsFranceNandini DeshpandeCanadaJudith DeutschUnited States of AmericaMichael DevlinCanadaNuno DiasPortugalDan DingUnited States of AmericaAn DoUnited States of AmericaChristian DohleGermanyTakehiko DoiJapanStrahinja DosenGermanyJennifer DunnNew ZealandLucy DunneUnited States of AmericaAssaf DvorkinUnited States of AmericaGerold EbenbichlerAustriaGail EskesCanadaDebbie EspyUnited States of AmericaAlberto EsquenaziUnited States of AmericaAlfonso FasanoCanadaPhilippe FaureFranceXin FengUnited States of AmericaJing FengUnited States of AmericaSimona FerranteItalyGiancarlo FerrignoItalyDaniel FerrisUnited States of AmericaPeter FeysBelgiumFanny FicucielloItalyHillel FinestoneCanadaJames FinleyUnited States of AmericaLee FisherUnited States of AmericaKevin FiteUnited States of AmericaBertine FleerkotteNetherlandsRobert FlintUnited States of AmericaGerard FluetUnited States of AmericaStephen FoldesUnited States of AmericaKenneth FongHong KongEmily FoxUnited States of AmericaJason FriedmanIsraelGail FrostCanadaDavid GabrielCanadaAlejandro Galan-MercantSpainSujay GalenUnited States of AmericaPhilippe GallienFranceBrook GalnaUnited KingdomFan GaoUnited States of AmericaNicolas Garcia AracilSpainLaura GastaldiItalyLynne GauthierUnited States of AmericaXinling GengChinaAlireza GharabaghiGermanyGiuseppina GiniItalyLeonardo GizziGermanyManuel Gonz\u00e1lez-S\u00e1nchezSpainKeith GordonUnited States of AmericaAlena GrabowskiUnited States of AmericaRobert GreggUnited States of AmericaPhilip GreweGermanyMichael GreyUnited KingdomGiuliana GrimaldiBelgiumEleni GrimpampiItalyEmmanuel GuigonFranceEtienne GuillaudFranceLan-Yuen GuoTaiwanMichael HahnUnited States of AmericaCourtney HallUnited States of AmericaGyu Cheol HanSouth KoreaNoor HanifUnited KingdomAndrew HansenUnited States of AmericaOrla HardimanIrelandLevi HargroveUnited States of AmericaChris HassUnited States of AmericaChristopher HassonUnited States of AmericaAnna HattonAustraliaMalcolm HawkenUnited KingdomDaniel HeitzmannGermanyTrent HerdaUnited States of AmericaStefan HesseGermanyShivayogi HiremathUnited States of AmericaAles HolobarSloveniaTiago HoriCanadaElizabeth Hsiao-WeckslerUnited States of AmericaRu-Lan HsiehTaiwanJwu-Sheng HuTaiwanYong HuHong KongHsiu-Chen HuangTaiwanHe (Helen) HuangUnited States of AmericaChristopher HurtUnited States of AmericaIng-Shiou HwangTaiwanTrienke IJmkerNetherlandsMarco IosaItalyMd. Anamul IslamMalaysiaMark IsonUnited States of AmericaNathanael Jarrass\u00e9FranceSteve JaxUnited States of AmericaArun JayaramanUnited States of AmericaJean-Yves JennyFijiWinnie JensenDenmarkNing JiangGermanyReva JohnsonUnited States of AmericaAlon KalronIsraelDerek KamperUnited States of AmericaGuiyeom KangIrelandShigehisa KawakamiJapanStephen KellyUnited KingdomTrisha KesarUnited States of AmericaRami KhushabaAustraliaKevin KilgoreUnited States of AmericaGyoung-Mo KimSouth KoreaSohee KimSouth KoreaKristof KippUnited States of AmericaRachel KizonyIsraelVerena Klamroth-MarganskaSwitzerlandBert KleineNetherlandsRudolf KlemettiFinlandMarco KnaflitzItalyMaria KnikouUnited States of AmericaToshiki KobayashiUnited States of AmericaSilvia Erika KoberAustriaDylan KobsarCanadaRodger KramUnited States of AmericaSharon KramerAustraliaHermano Igo KrebsUnited States of AmericaCarmen KrewerGermanyHollis KrugUnited States of AmericaTodd KuikenUnited States of AmericaDinesh KumarAustraliaJason KutchUnited States of AmericaLaurel KuxhausUnited States of AmericaRuben KuznieckyUnited States of AmericaPeter KyberdCanadaJoris LambrechtUnited States of AmericaClaudine LamothNetherlandsBeom Chan LeeUnited States of AmericaHyunglae LeeUnited States of AmericaSang Wook LeeUnited States of AmericaYun-Ju LeeUnited States of AmericaYafi LevanonIsraelMindy LevinCanadaBeth LewandowskiUnited States of AmericaSandra LewisUnited KingdomJan LexellSwedenGuanglin LiChinaKaren LiCanadaKe LiChinaLi LiUnited States of AmericaMeiling LiChinaQingguo LiCanadaJoachim LiepertGermanyFang LinUnited States of AmericaJonathan LinCanadaSuh-Jen LinUnited States of AmericaPavel LindbergFranceSimon LittleUnited KingdomBeth LopourUnited States of AmericaStephen LordAustraliaRichard LoveringUnited States of AmericaMadeleine LoweryIrelandMarilyn MacKay-LyonsCanadaAndreas MaierGermanyMargaret MakHong KongPhilippe MalcolmBelgiumMartina ManciniUnited States of AmericaBrad ManorUnited States of AmericaMario MantoBelgiumMarin ManuelFranceRobin MarcusUnited States of AmericaSusan MarionUnited States of AmericaAlain MartinFranceJoel MartinUnited States of AmericaRoshan Joy MartisSingaporeSarah MasonUnited KingdomGiulia MatroneItalyAlessandro MauroItalyClaudia Mazz\u00e0ItalySuzanne McDonoughUnited KingdomBradford McFadyenCanadaPaul McGeochUnited States of AmericaKevin McGillUnited States of AmericaLinda McLeanCanadaRanjana MehtaUnited States of AmericaSabato MelloneItalyWilliam MembergUnited States of AmericaRochelle MendoncaUnited States of AmericaThomas MergnerGermanyAnat MirelmanIsraelSambit MohapatraUnited States of AmericaFilippo MolinariItalyMarco MolinariItalyLuis MontesanoSpainJ. Leon Morales-QuezadaUnited States of AmericaJuan C. MorenoSpainSteven MorrisonUnited States of AmericaWinfred MuggeNetherlandsGernot M\u00fcller-PutzAustriaSandro Mussa-IvaldiUnited States of AmericaKristin MusselmanCanadaPratik MuthaIndiaJiro NakanoJapanDominic NathanUnited States of AmericaTobias NefSwitzerlandFrancesco NegroGermanyElizabeth NightingaleAustraliaDomen NovakSwitzerlandToru OgataJapanShinya OgayaJapanLauro OjedaUnited States of AmericaTaher OmariAustraliaKenneth OttenbacherUnited States of AmericaKerstin PalombaroUnited States of AmericaEnrica PapiUnited KingdomMatthew ParkesUnited KingdomIlaria PasciutoItalyBen PatrittiAustraliaCarolynn PattenUnited States of AmericaKara PattersonCanadaLorna PaulUnited KingdomAlessandra PedrocchiItalyJoel PerrySpainAngel PeterchevUnited States of AmericaMark PetersonUnited States of AmericaDaniel PetersonUnited States of AmericaGert PfurtschellerAustriaElena PirogovaAustraliaMark PitkinUnited States of AmericaDejan PopovicSerbiaMira PopovicSerbiaSigal PortnoyIsraelMartin PoschAustriaGerdienke B. PrangeNetherlandsRachel ProffittUnited States of AmericaAlessio PulizzottoItalyKai QianUnited States of AmericaRobrecht RaedtBelgiumDanny RaffertyUnited KingdomFabian RastSwitzerlandRafael RayaSpainJeffrey ReinboltUnited States of AmericaOlivier Remy-NerisFranceDaniel RenjewskiSwitzerlandChristopher RheaUnited States of AmericaSarah RidgeUnited States of AmericaLaura RocchiItalyEduardo RoconSpainEric RombokasUnited States of AmericaNoah RosenblattUnited States of AmericaDiana Ruiz BuenoSpainRuediger RuppGermanyDavid RussUnited States of AmericaManning SabatierUnited States of AmericaHooshang SaberiIranBrian SandroffUnited States of AmericaAmirehsan Sarabadani TafreshiSwitzerlandMakoto SasakiJapanKatherine SaulUnited States of AmericaZimi SawachaItalyLumy SawakiUnited States of AmericaAndrew SawersUnited States of AmericaGregory SawickiUnited States of AmericaEdward SazonovUnited States of AmericaSydney SchaeferUnited States of AmericaPhilip SchatzUnited States of AmericaErik SchemeCanadaSheila Schindler-IvensUnited States of AmericaMaurizio SchmidItalyPeter SchneiderGermanyAlfred SchoutenNetherlandsStylianos ScordilisUnited States of AmericaStephen ScottCanadaThomas SeelGermanyAva SegalUnited States of AmericaErvin SejdicUnited States of AmericaMasaki SekineJapanJon SensingerCanadaNa Jin SeoUnited States of AmericaGiacomo SeveriniUnited States of AmericaLudy ShihUnited States of AmericaPete ShullChinaKathryn SibleyCanadaAnn SimonUnited States of AmericaMikhail SimonovItalyTarkeshwar SinghUnited States of AmericaSue Ann SistoUnited States of AmericaManoj SivanUnited KingdomLauren SmithUnited States of AmericaMarco Soares dos SantosPortugalJacob SosnoffUnited States of AmericaPatrick SpartoUnited States of AmericaShmuel SpringerIsraelDaniel StashukCanadaDespina StavrinosUnited States of AmericaJoel SteinUnited States of AmericaJill StewartUnited States of AmericaIan StokesUnited States of AmericaOliver StollerSwitzerlandJake StreepeyUnited States of AmericaFong-Chin SuTaiwanSandeep SubramanianCanadaTomohiko TakeiJapanAndrew TanUnited States of AmericaNitish ThakorUnited States of AmericaMichael ThautUnited States of AmericaAlessandro TognettiItalyCraig TokunoCanadaDiego TorricelliSpainYannick Tousignant-LaflammeCanadaDiana TrojanielloItalyRandy TrumbowerUnited States of AmericaInna TsirlinCanadaCarole TuckerUnited States of AmericaAndrea TurollaItalyAilie TurtonUnited KingdomEdwin van AsseldonkNetherlandsHerman van der KooijNetherlandsBram van DunAustraliaRichard van EmmerikUnited States of AmericaNatalie VanicekUnited KingdomGiovanni VecchiatoItalyBeatrix VereijkenNorwayPaul F.M.J. VerschureSpainBruce VolpeUnited States of AmericaTim WagnerUnited States of AmericaErik WalbeehmNetherlandsConrad WallUnited States of AmericaJinsung WangUnited States of AmericaYijun WangUnited States of AmericaWilliam WarrenUnited States of AmericaKathleen WatsonUnited States of AmericaSeng Kwee WeeSingaporeJoseph WeirUnited States of AmericaAner WeissIsraelJill WhitallUnited States of AmericaMaura WhittakerCanadaJason WingertUnited States of AmericaHartwig WoldagGermanyShun-Chi WuTaiwanMing WuUnited States of AmericaJianhui WuChinaMax WuehrGermanySophie Marie WurthSwitzerlandHongbo XieAustraliaFeng XuChinaZhongliang YangChinaJun YaoUnited States of AmericaAaron YoungUnited States of AmericaNuray YozbatiranUnited States of AmericaBing YuUnited States of AmericaKarl ZabjekCanadaVladimir ZatsiorskyUnited States of AmericaKarl ZelikUnited States of AmericaErika Zemkov\u00e1SlovakiaJoseph ZeniUnited States of AmericaMingming ZhangNew ZealandQin ZhangChinaXu ZhangChinaYingchun ZhangUnited States of AmericaJun-Tian ZhangCanada"}
+{"text": "Clinical Epigenetics would like to thank all our reviewers who have contributed to the journal in Volume 7 (2015).The editors of  Hany Abdel-HafizUnited States of AmericaCharbel Abi KhalilUnited States of AmericaNita AhujaUnited States of AmericaNeil AlexisUnited States of AmericaElizabeth AlgarAustraliaMarkus AlmenSwedenKristian AlmstrupDenmarkLucia AltucciItalyConcetta AmbrosinoItalyOle AmmerpohlGermanyCindy AndersonUnited States of AmericaTakahiro ArimaJapanPaola ArimondoFranceHideo BabaJapanFrancesc BalaguerSpainAlfonso BaldiItalyAjay BansalUnited States of AmericaLudovic BaraultItalyRomain Barr\u00e8sDenmarkMarisa BartolomeiUnited States of AmericaSubit BaruaUnited States of AmericaChristopher BellUnited KingdomJordana BellUnited KinhdomRosaria BenedettiItalyMark BettingtonAustraliaAndr\u00e1s BikovHungaryGiovanni BlandinoItalyChristoph BockGermanyLinda BooijCanadaYvonne B\u00f6ttcherGermanySophie BouchatBelgiumPierre BougneresFranceMariana BraitUnited States of AmericaElizabeth BraithwaiteUnited KingdomLutz BreitlingGermanyKarin BrobergSwedenHannah BrownAustraliaRobert BrownUnited KingdomMichael BucklandAustraliaStefan BurdachGermanyHeather BurrisUnited States of AmericaChristian BuschGermanyPaul CairnsUnited States of AmericaDaniele CalistriItalyMonica CappettaUruguayMichele CaragliaItalyJason CarlyonUnited States of AmericaAndr\u00e9 CarvalhoUnited States of AmericaBiman ChakrabortyUnited KingdomMichael ChanTaiwanBrian ChenUnited States of AmericaXiangmei ChenChinaYW ChenUnited States of AmericaTravers ChingUnited States of AmericaBrock ChristensenUnited States of AmericaMaximilian ChristopeitGermanySteven ClarkeUnited States of AmericaTine Dalsgaard ClausenDenmarkSarah Cohen-WoodsAustriaWilliam ColemanUnited States of AmericaPablo Conesa-ZamoraSpainElizabeth ConradtUnited States of AmericaMariarosaria ConteItalyFabio CoppedeItalySabrina CorbettaItalyRene CorteseUnited States of AmericaIvan CostaGermanyBruno CostaPortugalChristos CoutifarisUnited States of AmericaJeffrey CraigAustraliaMarion CremerGermanyTeresa Cunha-OliveiraPortugalEdward CurryUnited KingdomIngrid DahlmanSwedenRoderick DashwoodUnited States of AmericaDario De BiaseItalySimone de JongUnited KingdomVanessa de Mello LaaksonenFinlandSusanne de RooijNetherlandsLissette Delgado CruzataUnited States of AmericaFloriana Della RagioneItalyEmma DempsterUnited KingdomChristine DistecheUnited States of AmericaHester DoyleUnited States of AmericaZhenzong DuChinaChristophe DupontFranceGerda EggerAustriaThomas EggermannGermanyRachel EigesItalyMattias EkstedtSwedenMagdeldin ElgizouliGermanyLena EliassonSwedenElliot EpnerUnited States of AmericaTodd EversonUnited States of AmericaMary Jo FacklerUnited States of AmericaSanja A FarkasSwedenRobert FeilFranceJanine FelixNetherlandsWeiwei FengChinaLeonides FernandezSpainEduardo Fernandez-RebolloGermanyJames FlanaganUnited KingdomMichael FleischhackerGermanyKirsty FlowerUnited KingdomRoger FooUnited KingdomKaren ForbesUnited KingdomDelphine FradinFranceGianluigi FranciItalyDiha FreijeUnited States of AmericaSimonetta FrisoItalyMattia FrontiniUnited KingdomRebecca FryUnited States of AmericaTing FuUnited States of AmericaTohru FujiwaraJapanAtsushi FukudaJapanTamas FulopCanadaJochen GaedckeGermanyThilo GambichlerGermanyYuzhen GaoChinaRegina GarciaSpainLana GarmireUnited States of AmericaFrancine Garrett-BakelmanUnited States of AmericaNiklas GebauerGermanyMaurizio GenuardiItalyPhilippe GeorgelUnited States of AmericaClarissa GerhauserGermanyUgur GezerTurkeyElisa GiovannettiItalyMarcus GomesBrazilZhiyun GongChinaMaria Gonzalez CaoSpainMichael GordonUnited KingdomSteven GrayIrelandBenjamin GreenUnited States of AmericaJoerg GromollGermanyElin GrundbergCanadaRafael Guerrero-PrestonUnited States of AmericaSonia GuilSpainShicheng GuoUnited States of AmericaJan HaasGermanyMichael HaffnerUnited States of AmericaPaul HaggartyUnited KingdomJohn HalsallUnited KingdomToshio HamataniJapanQin HanChinaEilis HannonUnited KingdomSara HarlidUnited States of AmericaAlexander HaslbergerAustriaNaoko HattoriJapanShunmin HeChinaChristopher HeeschenUnited KingdomRui HenriquePortugalGeorges HerbeinFranceEric HervouetFranceKinjal HewUnited States of AmericaHolger HeynSpainToshinori HinoueUnited States of AmericaHitoshi HiuraJapanMarie-France HivertCanadaTrang HoangCanadaStefan HoldenriederDenmarkNina HollandUnited States of AmericaShin-ichi HorikeJAPANSteve HorvathUnited States of AmericaJ-Fan HuUnited States of AmericaYuhui HuangUnited States of AmericaT HuangChinaPaula HylandUnited KingdomVito IacobazziItalyTakuya ImamuraJapanMiho IshidaUnited KingdomKhaled IsmailUnited KingdomBenjamin JacksonUnited KingdomBram JanssenBelgiumMagdalene JawaharAustraliaPaul JedlickaUnited States of AmericaJaroslav JelinekUnited States of AmericaAlbert JeltschGermanyCarmen JeronimoPortugalVictor JinUnited States of AmericaIan JohnsonUnited KingdomRicky JohnstoneAustraliaTakako I JonesUnited States of AmericaPeter JonesUnited States of AmericaJihoon JooAustraliaKerstin JunkerGermanyJennifer KalishUnited States of AmericaZachary KaminskyUnited States of AmericaGyeong Hoon KangSouth KoreaMaya KappilUnited States of AmericaPawel KarpinskiPolandJyotdeep KaurIndiaRichard KellyUnited KingdomKarl KelseyUnited States of AmericaAmy KenterUnited States of AmericaJoomyeong KimUnited States of AmericaYoung-Joon KimSouth KoreaM KimuraJapanAmanda KirkhamUnited KingdomDevin KoestlerUnited States of AmericaDieuwertje KokNetherlandsKlaas KokNetherlandsYutaka KondoJapanGabor L KovacsHungaryRenu KowluruUnited States of AmericaTheo F. J. KrausGermanySmriti KrishnaAustraliaXiong KuangnanUnited States of AmericaAgn\u00e9 Kulyt\u00e9SwedenAmit KumarFranceRobert KumstaGermanyAlina KurylowiczPolandMatthew A. KutnyUnited States of AmericaBernard Kwabi-AddoUnited States of AmericaViviane LabrieCanadaHung-Cheng LaiTaiwanRosa LapalombellaUnited States of AmericaJanine LaSalleUnited States of AmericaMartin LaussSwedenBarbara LeggettAustraliaUlrich LehmannGermanyAngela LekUnited States of AmericaRichard LemmersNetherlandsDavid LeslieUnited KingdomCorina LesseurFranceSiu-wai LeungMacaoWilliam LewisUnited States of AmericaSymen LigthartNetherlandsCharlotte LingSwedenAlexander LinkGermanyRanlu LiuUnited States of AmericaMo-Fang LiuChinaAdana A LlanosUnited States of AmericaGeover LoboIndiaColin LogieNetherlandsQianjin LuChinaXiangfeng LuUnited States of AmericaAmaia LujambioUnited States of AmericaKatie LunnonUnited KingdomRobert LyleNorwayHeidi LyngNorwayDonia Macartney-CoxsonNew ZealandJennifer MaccaniUnited States of AmericaDeborah MackayUnited KingdomLuca MagnaniUnited KingdomEamonn MaherUnited KingdomN. MahmudUnited States of AmericaMellissa MannCanadaAntonio MaraverFranceJuliana MaricatoUnited States of AmericaRiccardo MarioniUnited KingdomCarmen MarsitUnited States of AmericaJohn MartensNetherlandsDaniel Martinez-ArguellesCanadaDavid MartinoAustraliaAthena MatakidouUnited KingdomGiuseppe MatulloItalyRobert McKnightUnited StatesAllan McraeAustraliaRichard MeehanUnited KingdomGunther MeinlschmidtSwitzerlandL.J. MelchersNetherlandsBodo MelnikGermanyMaite MendiorozSpainGerlinde MetzCanadaAlexander MichelsUnited States of AmericaDaniel MillerUnited States of AmericaSheikh MimiUnited KingdomSvetlana MinakhinaUnited States of AmericaRaghavendra MirmiraUnited States of AmericaPeter MolloyAustraliaSantiago Montes MorenoSpainGudrun MooreUnited KingdomMonika MorakDenmarkEva MoralesSpainValeria MottaItalySofia Mov\u00e9rare-SkrticSwedenAnna MurrayUnited KingdomAdele MurrellUnited KingdomAlessio NaccaratiItalyKari NadeauUnited States of AmericaBalint NagyHungaryKazuhiko NakabayashiJapanJavad NazarianUnited States of AmericaMihai NiculescuUnited States of AmericaEmma NilssonSwedenJonas NilssonSwedenStephen NimerUnited States of AmericaShuji NomotoJapanBoris NovakovicAustraliaAndreas NusslerGermanyShuji OginoUnited States of AmericaGabriel OhCanadaJun OhganeJapanJoyce OhmUnited States of AmericaCarla OliveiraPortugalFabiola OlivieriItalyMiina OllikainenFinlandFrancisco OrtegaSpainSasha ParetsUnited States of AmericaPaola ParrellaItalyMarcelina ParrizasSpainArpad V. PataiHungaryVeeresh K PatilUnited KingdomSamir PatraIndiaSofia PavanelloItalyKevin PearsonUnited States of AmericaMattia PelizzolaItalyPaivi Peltom\u00e4kiFinlandPaola PeregoItalyMarcello PersicoItalyRobert PhilibertUnited States of AmericaJ. Richard PilsnerUnited StatesHugo PinheiroPortugalCarlos PirolaArgentinaFlemming PociotDenmarkDirk PrawittGermanyJulian PuppeGermanyYang QinChinaLyudmila RachekUnited States of AmericaStacey RaimondiUnited States of AmericaEmma RaitoharjuFinlandAgnieszka Raw\u0142uszko-WieczorekPolandYasser RiazalhosseiniCanadaRasmus Ribel-MadsenDenmarkChristopher RickettsUnited States of AmericaWendy RobinsonCanadaAna RoblesUnited States of AmericaEuan RodgerNew ZealandSilvia RogattoBrazilTina R\u00f6nnSwedenChristophe RostyAustraliaPeter RotweinUnited States of AmericaCarlos roviraSwedenJoanne RyanAustraliaSonia SaadAustraliaRichard safferyAustraliaGilles SalbertFranceDonato SantovitoItalyCarmen SapienzaUnited States of AmericaShun SatoJapanBeat Sch\u00e4ferSwitzerlandLeonard SchalkwykUnited KingdomWolfgang SchulzGermanyStuart ScottUnited States of AmericaJurgen SerthGermanyKarolina SetyowatiSingaporeJing ShenUnited States of AmericaBoris Arkadievich ShenderovRussiaRachna ShroffUnited States of AmericaRoderick SliekerNetherlandsHarold SniederNetherlandsYuhu SongChinaKarina Dalsgaard S\u00f8rensenDenmarkR\u00e9gine Steegers-TheunissenNetherlandsRenske SteenbergenNetherlandsOlafur StefanssonIcelandClare StirzakerAustraliaMichael P StoneUnited States of AmericaSusan R SturgeonUnited States of AmericaIsao SuetakeJapanHiroko SugawaraJapanKarsten SuhreFranceSaraswati SukumarUnited States of AmericaDeqiang SunUnited States of AmericaYan SunUnited States of AmericaCecilie SvanesNorwayAtsushi TajimaJapanRie TakahashiUnited States of AmericaRajeev TaliyanIndiaQihua TanDenmarkSatoshi TanakaJapanKristen TaylorUnited States of AmericaMathewos TessemaUnited States of AmericaVincent ThijsBelgiumStefania TommasiItalyMarcio Alberto TorsoniBrazilJorg TostFranceEric ToussirotFranceFabiola TrainaBrazilPhilipp TropbergerUnited States of AmericaJiajie TuChinaRossella TuplerUnited States of AmericaGustavo TureckiCanadaBryan TurnerUnited KingdomSantiago Uribe-LewisUnited KingdomToshikazu UshijimaJapanValentina VairaItalySusan Van dijkAustraliaHoang Van TongGermanyDonata VercelliUnited States of AmericaMukesh VermaUnited States of AmericaSarah VoisinSwedenPaul VranaUnited States of AmericaJun WadaJapanGraham WallaceUnited KingdomJin WangChinaJiucun WangChinaGaofeng WangUnited States of AmericaJu WangUnited States of AmericaXiaoling WangUnited States of AmericaZhanwei WangUnited States of AmericaRobert WaterlandUnited States of AmericaEugene WeeAustraliaMarco WeinbergSouth AfricaRosanna WeksbergCanadaAntje WeselerNetherlandsGunnar WestinSwedenStefan WiemannGermanyStefan WillemsNetherlandsOla WinqvistSwedenBea WismanNetherlandsJustin WongAustraliaChun-Ming WongHong KongKY WongHong KongC WoodmanUnited States of AmericaMaria J. WorshamUnited States of AmericaWenji YanChinaRongxi YangGermanyIvana YangUnited States of AmericaXiaofei YuUnited States of AmericaJian YuChinaYouwei YueChinaNadia ZaffaroniItalyAdam ZawadaGermanyAmer ZeidanUnited States of AmericaZhi-Gang ZhangChinaRongxin ZhangChinaYuqi ZhaoUnited States of AmericaWei-Guo ZhuChinaInti ZlobecSwitzerland"}
+{"text": "Retrovirology would like to sincerely thank the following for giving their time and expertise to review manuscripts for the journal in 2014. Their support for the journal is greatly appreciated. Ana AbecasisPortugalPhilippe AfonsoFranceDaniel AguiarBrazilChristopher AikenUnited States of AmericaJan AlbertSwedenJose AlcamiSpainGhalib AlkhatibUnited States of AmericaNeil AlmondUnited KingdomZandrea AmbroseUnited States of AmericaEmma AndersonUnited KingdomValgerdur AndresdottirIndiaAdam ArkinUnited States of AmericaJohn ArmourUnited KingdomElmostafa BahraouiFranceNorbert BannertGermanyFrancis BarinFranceEric BarklisUnited States of AmericaSt\u00e9phane BasmaciogullariFranceAndreas BaurGermanyRupert BealeUnited KingdomBruno BeaumelleFranceRobert BelshawUnited KingdomSerge BenichouFranceYamina BennasserFranceSteven BensingerUnited States of AmericaClarisse Berlioz-TorrentFranceNeil BerryUnited KingdomLionel BerthouxCanadaDorothee BienzleCanadaFabien BlanchetFranceJulia BlancoSpainJonas BlombergSwedenWilly BogersNetherlandsMorgane BomselFranceKathleen Boris-LawrieUnited States of AmericaPedro BorregoPortugalFadila BouamrUnited States of AmericaPaul BoyerUnited States of AmericaChristian BranderSpainAbraham BrassUnited States of AmericaJason BrenchleyUnited States of AmericaBluma BrennerCanadaMark BrockmanCanadaKristina BrolidenSwedenJames BruceUnited States of AmericaMichael BukrinskyUnited States of AmericaDennis BurtonUnited States of AmericaFlorence BuseyneFrancePaul U CameronAustraliaEdward CampbellUnited States of AmericaCarol CarterUnited States of AmericaNicoletta CasartelliFranceFrancesca Ceccherini-SilbersteinItalyShan CenChinaRob CenterAustraliaTheresa L ChangUnited States of AmericaNathalie ChazalFranceLinda ChelicoCanadaBing ChenUnited States of AmericaBenjamin ChenUnited States of AmericaIrvin ChenUnited States of AmericaCecilia Cheng-MayerUnited States of AmericaPeter CherepanovUnited KingdomFrancesca ChiodiSwedenNicolas ChomontUnited States of AmericaFrauke ChristBelgiumTomas CihlarUnited States of AmericaAndrea CimarelliFranceAngela CiuffiSwitzerlandPaul ClaphamUnited States of AmericaFrancois ClavelFranceMario ClericiItalyAlan CochraneCanadaJohn CoffinUnited States of AmericaEric CohenCanadaRonald CollmanUnited States of AmericaRafael Contreras-GalindoUnited States of AmericaPierre CorbeauFranceBarbara CoulsonAustraliaRobert CraigieUnited States of AmericaAlexandra CribierFranceSuzanne CroweAustraliaNathan CumminsUnited States of AmericaAnthony CunninghamAustraliaAtze DasNetherlandsSiddhartha DattaUnited States of AmericaMiles DavenportAustraliaRob de BoerNetherlandsHugues de RocquignyFranceThushan de SilvaUnited KingdomGregg DeanUnited States of AmericaZeger DebyserBelgiumNathalie Dejucq-RainsfordFranceGregory Del PreteUnited States of AmericaJoachim DennerGermanyPaul DentonDenmarkCynthia DerdeynUnited States of AmericaDiane DescampsFranceBenjamin DescoursFranceJeffrey DeStefanoUnited States of AmericaFelipe Diaz-GrifferoUnited States of AmericaKatie DooresUnited KingdomVictoria D'SouzaUnited States of AmericaDiako EbrahimiAustraliaDirk EgginkNetherlandsMaryam EhteshamiUnited States of AmericaMichael EmermanUnited States of AmericaStephane EmilianiFranceAlan EngelmanUnited States of AmericaLe Rouzic ErwannFranceJose EsteSpainOliver FacklerGermanyHung FanUnited States of AmericaNuno FariaUnited KingdomAriberto FassatiUnited KingdomMaurizio FedericoItalyJacques FellaySwitzerlandAndr\u00e9s FinziCanadaDonald ForthalUnited States of AmericaPhilippe Foss\u00e9FranceAlan FrankelUnited States of AmericaEric FreedUnited States of AmericaSimon FrostUnited KingdomJun-ichi FujisawaJapanAxel FunUnited KingdomSusanne GabrielssonSwedenYonatan GanorFranceMichael GantierAustraliaFeng GaoUnited States of AmericaVictor J GarciaUnited States of AmericaGerardo Garcia-LermaUnited States of AmericaAnne GatignolCanadaHoward GendelmanUnited States of AmericaAnna Maria GerettiUnited KingdomMatthias GeyerGermanyMauro GiaccaItalyRobert GiffordUnited KingdomPaul GoepfertUnited States of AmericaStephen GoffUnited States of AmericaMaureen GoodenowUnited States of AmericaJohn GoodierUnited States of AmericaNilu GoonetillekeUnited States of AmericaMiroslaw GornyUnited States of AmericaPaul GorryAustraliaHeinrich GottlingerUnited States of AmericaDuane GrandgenettUnited States of AmericaLachlan GrayAustraliaPatrick GreenUnited States of AmericaHarriet GroomUnited KingdomJohn GuatelliUnited States of AmericaHillel HaimUnited States of AmericaLou HammarskjoldUnited States of AmericaDavid HarrichAustraliaRichard HarriganCanadaReuben HarrisUnited States of AmericaAlex HarwigNetherlandsTheodora HatziioannouUnited States of AmericaJohnny HeUnited States of AmericaSonya HeathUnited States of AmericaJonathan HeeneyUnited KingdomJiri HejnarCzech RepublicGeorges HerbeinFranceAnn HessellUnited States of AmericaVanessa HirschUnited States of AmericaCarol HlelaSouth AfricaJ. Robert HoggUnited States of AmericaMargaret HosieUnited KingdomAgnes Hotz-WagenblattGermanySelwyn Joseph HurwitzUnited States of AmericaHendrik HuthoffUnited KingdomJun-ichiro InoueJapanFumitoshi IshinoJapanAstrid IversenUnited KingdomYasumasa IwataniJapanNuria Izquierdo-UserosSpainPooja JainUnited States of AmericaMartin Roelsgaard JakobsenDenmarkWilliam JamesUnited KingdomMarianne JanssonSwedenAnthony JaworowskiAustraliaDarlix Jean LucFranceRienk JeeningaNetherlandsShibo JiangChinaDong-Yan JinHong KongGary JohanningUnited States of AmericaMina JohnAustraliaMarc JohnsonUnited States of AmericaClare JollyUnited KingdomSarah JosephUnited States of AmericaGeorgette KanmogneUnited States of AmericaJohn KappesUnited States of AmericaJonathan KarnUnited States of AmericaFatah KashanchiUnited States of AmericaAris KatzourakisUnited KingdomRuian KeUnited States of AmericaBrandon KeeleUnited States of AmericaStephen KentAustraliaJulia KenyonUnited KingdomArifa KhanUnited States of AmericaRosemary KiernanFranceFrank KirchhoffGermanyAndrea KirmaierUnited States of AmericaP.J. KlasseUnited States of AmericaNichole KlattUnited States of AmericaThomas KlimkaitSwitzerlandRenate KoenigGermanyMadhavi KolliUnited States of AmericaJan KonvalinkaCzech RepublicGerrit KoopmanNetherlandsDusan KordisSloveniaYoshio KoyanagiJapanChristine KozakUnited States of AmericaMarit KramskiAustraliaIsaac KraussUnited States of AmericaOlaf KutschUnited States of AmericaMamuka KvaratskheliaUnited States of AmericaJesse KwiekUnited States of AmericaAksana LabokhaUnited KingdomBernard LafontUnited States of AmericaNadine LaguetteFranceNathaniel LandauUnited States of AmericaAlan LandayUnited States of AmericaMarie LarssonSwedenStuart Le GriceUnited States of AmericaKelly LeeUnited States of AmericaEdwin LeeansyahSwedenAndrew Leigh BrownUnited KingdomThomas LeitnerUnited States of AmericaAlice LenUnited KingdomJack LenzUnited States of AmericaJeanette LeusenNetherlandsSharon LewinAustraliaChen LiangCanadaMathias LichterfeldUnited States of AmericaJaisri LingappaUnited States of AmericaMaxine LinialUnited States of AmericaManuel LlanoUnited States of AmericaJ. Stephen LodmellUnited States of AmericaMartin R. B. 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AmericaHarriet RobinsonUnited States of AmericaMichael RocheAustraliaOlivier RohrFranceNikolaus RomaniAustriaSusan RossUnited States of AmericaEdina RostaUnited KingdomKenneth RouxUnited States of AmericaIoulia RouzinaUnited States of AmericaSarah Rowland-JonesUnited KingdomWalter RoyalUnited States of AmericaRuth RuprechtUnited States of AmericaAkihide RyoJapanIvan SadowskiCanadaAsier Saez-CirionFranceManish SagarUnited States of AmericaMineki SaitoJapanJun-ichi SakuragiJapanHiroaki SakuraiJapanMarco SalemiUnited States of AmericaRogier SandersNetherlandsMario SantiagoUnited States of AmericaNuno SantosPortugalSarah SassonAustraliaQuentin SattentauUnited KingdomAndrea SavarinoItalyBassel E SawayaUnited States of AmericaTorsten SchallerGermanyMichael SchindlerGermanyEric SchirmerUnited KingdomTimothy SchlubAustraliaJean-Claude SchmitLuxembourgDominique ScholsBelgiumOlivier SchwartzFranceRobin ShattockUnited KingdomAnn SheehyUnited States of AmericaRobert SilicianoUnited States of AmericaViviana SimonUnited States of AmericaRichard David SloanUnited KingdomNicolas Sluis-CremerUnited States of AmericaEllen SpargerUnited States of AmericaPaul SpearmanUnited States of AmericaRoberto SpeckSwitzerlandMario StevensonUnited States of AmericaCarol StockingGermanyJonathan StoyeUnited KingdomKlaus StrebelUnited States of AmericaHendrik StreeckUnited States of AmericaJustine SunshineUnited States of AmericaShinya SuzuJapanValentina SvicherItalyMichael SwansonUnited States of AmericaYasuhiro TakeuchiUnited KingdomMasafumi TakiguchiJapanJun Jie TanMalaysiaJamal TaziFrancePhilip TedburyUnited States of AmericaAmalio TelentiUnited States of AmericaEmiliano Tesoro-CruzMexicoGeorgia TomarasUnited States of AmericaSodsai TovanabutraUnited States of AmericaSimon TraversSouth AfricaAlexandra TrkolaSwitzerlandAthe TsibrisUnited States of AmericaMudit TyagiUnited States of AmericaKlaus \u00dcberlaGermanyTonja van der KuylNetherlandsMarit van GilsNetherlandsCarine Van LintBelgiumKoen Van RompayUnited States of AmericaAnne-Mieke VandammeBermudaBruno VerhasseltBelgiumTheo VerripsNetherlandsBeata G VertessyHungaryPornpun VivithanapornThailandVolker M VogtUnited States of AmericaThomas VollbrechtUnited States of AmericaToshiki WatanabeJapanIrene WeberUnited States of AmericaLeor WeinbergerUnited States of AmericaCarol WeissUnited States of AmericaRobin WeissUnited KingdomSarah WelbournUnited States of AmericaLucas WillemsBelgiumSam WilsonUnited KingdomCheryl WinklerUnited States of AmericaLi WuUnited States of AmericaYuntao WuUnited States of AmericaYoshihisa YamanoJordanAhmad YatimFranceVenkat YedavalliUnited States of AmericaXiao-Fang YuUnited States of AmericaKarina YusimUnited States of AmericaJerome ZackUnited States of AmericaSteven ZeichnerUnited States of AmericaRichard Y ZhaoUnited States of AmericaYong-Hui ZhengUnited States of America"}
+{"text": "Chiropractic & Manual Therapies would like to thank all our reviewers who have contributed to the journal in Volume 22 (2014).The editors of  Ellen AartunDenmarkLyndon Amorin-WoodsAustraliaAnnette BishopUnited KingdomFelicity BishopUnited KingdomKate BolamSwedenJennifer BoltonUnited KingdomRod BonelloUnited States of AmericaMarcelo BotelhoBrazilJonathan BranneyUnited KingdomAlan BreenUnited KingdomAndr\u00e9 Bussi\u00e8resCanadaDavid ByfieldUnited KingdomJerrilyn CambronUnited States of AmericaMelainie CameronAustraliaCarol CancelliereCanadaJ. David CassidyDenmarkJohn CerfUnited States of AmericaThomas ChristUnited States of AmericaChad CookUnited States of AmericaJeffrey CooleyAustraliaColin CrawfordAustraliaLee DaffinAustraliaLaura DaviesUnited KingdomKatie de LucaAustraliaAlasdair DempseyAustraliaMartin DescarreauxCanadaJames DeVochtUnited States of AmericaAron DownieAustraliaAdrian EstermanAustraliaRoni EvansUnited States of AmericaRandy FerranceUnited States of AmericaElisa FluessUnited KingdomJohn GlastonburyAustraliaWilliam GrantUnited States of AmericaMitchell HaasUnited States of AmericaMark HancockAustraliaJan HartvigsenDenmarkCheryl HawkUnited States of AmericaStephen HealeyUnited States of AmericaLise HestbaekDenmarkAlison HoggAustraliaEric HurwitzUnited States of AmericaTue Secher JensenDenmarkAsbjorn JokstadNorwayGwendolen JullAustraliaShane KoppenhaverUnited States of AmericaDana LawrenceUnited States of AmericaC.M. Janine LeachUnited KingdomCharlotte Leboeuf-YdeDenmarkChris MaherAustraliaJo-Anne MaireAustraliaBarbara MansholtUnited States of AmericaAmanda MeyerAustraliaSilvano MiorCanadaTimothy MirtzUnited States of AmericaTom MolyneuxAustraliaDonald MurphyUnited States of AmericaDavid NewellUnited KingdomMandy NielsenAustraliaNicholas PalmieriUnited States of AmericaGregory Parkin-SmithAustraliaLuke ParkitnyUnited States of AmericaPatrick PartingtonUnited KingdomSteven PassmoreCanadaStephen PerleUnited States of AmericaCynthia PetersonSwitzerlandErik PoulsenDenmarkAlexander RuheGermanyRuth SandefurUnited States of AmericaMichael SchneiderUnited States of AmericaWilliam SheltonUnited States of AmericaMaureen SimmondsUnited States of AmericaJ Keith SimpsonAustraliaNorman StomskiAustraliaJohn TrianoCanadaArianne VerhagenNetherlandsHoward VernonCanadaBruce WalkerAustraliaMark WebsterUnited KingdomNiels WedderkoppDenmarkJan-Falco WilbrandGermanyJessica WongCanadaKenneth YoungAustraliaMartin YoungUnited Kingdom"}
+{"text": "International Breastfeeding Journal would like to thank all our reviewers who have contributed to the journal in Volume 9 (2014).The editor of  Clara AartsSwedenOjo AgunbiadeSouth AfricaJames AkreSwitzerlandAlex AndersonUnited States of AmericaPhilip AndersonUnited States of AmericaAnnette Noble BeasleyNew ZealandGenevieve BeckerIrelandFetene Berhanu BelihuAustraliaPamela BerensUnited States of AmericaColin BinnsAustraliaNancy BrentUnited States of AmericaWendy BrodribbAustraliaAmy BrownUnited KingdomMiranda BuckAustraliaSusan BurgerUnited States of AmericaMarsha Campbell-YeoCanadaMa del Carmen CasanovasSwitzerlandCaroline ChantryUnited States of AmericaElise ChapinItalyDonna ChapmanUnited States of AmericaEllen ChetwyndUnited States of AmericaLumbwe CholaSouth AfricaAnna CoutsoudisSouth AfricaMeabh CullinaneAustraliaMarina CuttiniItalyMary-Ann DaveyAustraliaEmily de JagerAustraliaTanya DohertySouth AfricaSusan DonathAustraliaTherese DowswellUnited KingdomGudina EgataEthiopiaMegan Elliott-RudderAustraliaMargaret FloodAustraliaDella ForsterAustraliaKevin FrickUnited States of AmericaJudith GaltryNew ZealandAda GarciaUnited KingdomMichel GarenneFranceCamila GiuglianiBrazilKarleen GribbleAustraliaLuke GrzeskowiakAustraliaRukhsana HaiderBangladeshKarin HammarbergAustraliaDebra HectorAustraliaCaroline HomerAustraliaBernardo HortaBrazilKathryn HoukUnited States of AmericaRuss HoveyUnited States of AmericaJenny IngramUnited KingdomBriana JegierUnited States of AmericaKate JollyUnited KingdomVishnu KhanalNepalHanne KronborgDenmarkLinda KvistSwedenMiriam LabbokUnited States of AmericaLaura LambertiUnited States of AmericaRebecca LanderUnited States of AmericaHa LeAustraliaCheryl LoveladyUnited States of AmericaNyovani MadiseUnited KingdomCynthia MannionCanadaSusana MatiasUnited States of AmericaEllen McIntyreAustraliaHelen McLachlanAustraliaMaureen MinchinAustraliaElizabeth MooreUnited States of AmericaAnita MoorheadAustraliaPamela MorrisonUnited KingdomMelinda MunosUnited States of AmericaJudith MyersAustraliaNathan NickelCanadaTinuade OgunlesiNigeriaFunmilola OlaOlorunNigeriaGillian OpieAustraliaCarmen Pall\u00e1sSpainTaran\u00e9 ProbstGermanyPhyllis RippeyoungCanadaNikki RogersUnited States of AmericaNigel RollinsSouth AfricaHeather RoweAustraliaKath RyanAustraliaSina SafayiUnited States of AmericaJane ScottAustraliaSonia SemenicCanadaTouran ShafieiAustraliaJames SheltonUnited States of AmericaLing ShiUnited States of AmericaRhonda SmallAustraliaZaharah SulaimanMalaysiaKristin SvenssonSwedenKenzo TakahashiJapanKeiko TanakaJapanDavid TappinUnited KingdomGill ThomsonUnited KingdomBarbara Wilson-ClayUnited States of AmericaJane YellandAustraliaSera YoungUnited States of AmericaIrena Zakarija-GrkovicCroatia"}
+{"text": "Patient Safety in Surgery would like to thank all of our reviewers who have contributed to the journal in Volume 9 (2015).The editors of  Shay BessUnited States of AmericaEvalina BurgerUnited States of AmericaNathan ButlerUnited States of AmericaTed ClarkeUnited States of AmericaMichael DaytonUnited States of AmericaJoan FiguerasSpainJoerg FrankeGermanyBeat GloorSwitzerlandAndrew GroseUnited States of AmericaDieter HahnloserSwitzerlandMark HakeUnited States of AmericaEric Mark HammerbergUnited States of AmericaChristoph-E. HeydeGermanyMarkus Huber-LangGermanyKyros IpaktchiUnited States of AmericaJeffry KashukUnited States of AmericaFernando KimUnited States of AmericaPhilipp LenzlingerSwitzerlandCyril MauffreyUnited States of AmericaWilson MolinaUnited States of AmericaLeslie NessUnited States of AmericaGiuseppe NigriItalyLena NilssonSwedenYohan RobinsonSwedenMarius ScarlatFranceBeth SchulteUnited States of AmericaDavid SeligsonUnited States of AmericaTodd VanderheidenUnited States of AmericaMichael VictoroffUnited States of AmericaSebastian WeckbachUnited States of AmericaHeather YoungUnited States of AmericaGeorge YoungsonUnited KingdomNavid ZiranUnited States of AMerica"}
+{"text": "Nutrition Journal would like to thank all our reviewers who have contributed to the journal from Volume 13 (2014).The editor of  Jean AbedUnited States of AmericaArianna AcetiItalyDirk AerenhoutsBelgiumHaleama Al SabbahUnited Arab EmiratesUte AlexyGermanyBettaieb AliFranceGjumrakch AlievUnited States of AmericaAlessandro AntonelliItalyJose AntonioUnited States of AmericaGeorgios AntonoglouFinlandHidekazu AraiJapanTrevor ArcherSwedenShervin AssariUnited States of AmericaHans-J\u00f6rg AssionGermanyDeniz AtalayerUnited States of AmericaDagfinn AuneUnited KingdomFazli AwanPakistanMax Oscar BachmannUnited KingdomInkyung BaikKorea, SouthPat BairdUnited States of AmericaWilliam BakerUnited States of AmericaRiccardo BarbagalloItalyNeal BarnardUnited States of AmericaJoshua BarzilayUnited States of AmericaNadia BastideFranceJamie BaumUnited States of AmericaJacquie BayNew ZealandAdrianne BendichUnited States of AmericaJudit BeneHungaryJean-Jacques BenolielFranceRolf Kristian BergeNorwayJoline BeulensNetherlandsIlana BezerraBrazilDiane BirtUnited States of AmericaSimona BoItalyPawel BogdanskiPolandCeline BonnetFranceIngvar BosaeusSwedenRachel BrownNew ZealandThiago Bruder-NascimentoBrazilRichard BrunoUnited States of AmericaMy BuiUnited States of AmericaVictoria BunikRussian FederationMona CalvoUnited States of AmericaMar\u00eda Alicia Camina Mart\u00ednSpainT Colin CampbellUnited States of AmericaMonica H. CarlsenNorwayMaria Annunziata CarluccioItalyTimothy CarrUnited States of AmericaSusana CasalPortugalDick ChanAustraliaRonna ChanUnited States of AmericaSybil CharriereFranceBenoit ChassaingUnited States of AmericaVisith ChavasitThailandWayman CheathamUnited States of AmericaGuo-Chong ChenChinaOliver ChenUnited States of AmericaYu-Han ChiuUnited States of AmericaKai-Chow ChoiHong KongJason CholewaUnited States of AmericaEfterpi ChristakiGreeceOck K. ChunUnited States of AmericaGaudichon ClaireFranceMiriam CleggUnited KingdomRoger ClemensUnited States of AmericaRaquel CoelhoBrazilScott CollierUnited States of AmericaClare CollinsAustraliaEmilie CombetUnited KingdomKevin ComerfordUnited States of AmericaHelen CoulthardUnited KingdomMaria CovasSpainDaniel CrabtreeUnited KingdomLeslie Cunningham-SaboUnited States of AmericaJustyna Czech-KowalskaPolandRiccardo Dalle GraveItalyDominique DardevetFranceUndurti DasUnited States of AmericaSrinivasa Raju DatlaUnited States of AmericaLuc DauchetFranceBrenda DavyUnited States of AmericaWillem De KeyzerBelgiumAndrea De SilvaAustraliaRafael DeminiceBrazilElizabeth DennisUnited States of AmericaPeter DeriemaekerBelgiumLaura DeromaItalyJonathan DevriesUnited States of AmericaRam DickmanIsraelJames DinicolantonioUnited States of AmericaGustav DobosGermanyLorenzo M DoniniItalyFiona Doolan-NobleNew ZealandVicky DrapeauCanadaPin-Der DuhTaiwanLeticia Elizondo-MontemayorMexicoSean FairIrelandFrida F\u00e5kSwedenIoannis FatourosGreeceSally FergusonAustraliaBrigite FerreiraPortugalRobyn FlipseUnited States of AmericaEwa FlorekPolandMaria Jo\u00e3o FonsecaPortugalMael\u00e1n Fontes VillalbaSpainAdrian FrankeUnited States of AmericaXueyan FuUnited States of AmericaEllen FungUnited States of AmericaUjjawal GandhiUnited States of AmericaVijay GanjiUnited States of AmericaParveen GargUnited States of AmericaGenevieve GariepyCanadaGlen GibsonUnited KingdomDenise GiganteBrazilIan GivensUnited KingdomColleen GobertCanadaRobert GoldbergUnited States of AmericaAdele GreenAustraliaFrank GreenwayUnited States of AmericaFrank GreerUnited States of AmericaEttore GriffoItalyCarley GrimesAustraliaJolanta GromadzinskaPolandGiuseppe GrossoItalyPilar Guallar-Castill\u00f3nSpainCraig GundersenUnited States of AmericaVanessa HaCanadaPeter HannanUnited States of AmericaJoanna HarasymPolandAbdelmonem HassanQatarWei HeUnited States of AmericaAnne-Louise HeathNew ZealandJean-Luc HeebSwitzerlandKevin HeffernanUnited States of AmericaVenkatesh HegdeUnited States of AmericaNazisa HejaziMalaysiaHelen Hermana HermsdorffBrazilTeri L. HernandezUnited States of AmericaAlyson HillUnited KingdomMasao HirayamaJapanTadakazu HisamatsuJapanJonathan HodgsonAustraliaJustus HofmeyrSouth AfricaTrygve HolmoyNorwayAstrid HorstmanNetherlandsMichael HourdakisGreeceMelanie HowesUnited KingdomGuowei HuangChinaXianju HuangChinaFatma HuffmanUnited States of AmericaTommaso IannittiUnited KingdomSabine Ibr\u00fcggerDenmarkFumiaki ImamuraUnited KingdomConcetta IraceItalyFatima IsaUnited KingdomMamoru IsemuraJapanMasanori IwaseJapanSandra JacobsonUnited States of AmericaTina JafariIranGreta JakobsdottirSwedenAnthony Paul JamesAustraliaWasantha JayawardeneUnited States of AmericaMaria Elena JefferdsUnited States of AmericaYou-Jin JeonKorea, SouthInken JobseGermanyElizabeth JohnsonUnited States of AmericaCarol JohnstonUnited States of AmericaMargalida JoySpainJordi JulvezSpainAndriana KalioraGreecePaul KalliokoskiSwedenMasao KanekiUnited States of AmericaPaige KaplanUnited States of AmericaMaria KapsokefalouGreeceTeruo KawadaJapanSarah KehoeUnited KingdomChad KerksickUnited States of AmericaAmina KhambaliaAustraliaOlga KhavjouUnited States of AmericaGeok Lin KhorMalaysiaJong Yeol KimKorea, SouthStanislaw KlekPolandKazuki KobayashiJapanMallory KoeningsUnited States of AmericaJohn KoetheUnited States of AmericaRene KoopmanAustraliaBart KootNetherlandsArkadiusz KozubekPolandRichard KreiderUnited States of AmericaHanne KronborgDenmarkAnna Kucharska-NewtonUnited States of AmericaRemko KuipersNetherlandsHiromichi KumagaiJapanTeru KumagiJapanBenoit LamarcheCanadaLinda LandiniItalyLies LangoucheBelgiumJohn LasekanUnited States of AmericaMartine LavilleFranceChrystalleni LazarouGreeceMarcelo LealBrazilNaruemon LeelayuwatThailandAngela LeungUnited States of AmericaShengxu LiUnited States of AmericaLi-Chan LinTaiwanYK LinTaiwanBengt LindholmSwedenDavid LinebackUnited States of AmericaJonathan LittleCanadaKeith LividiniUnited States of AmericaAdrian LoprestiAustraliaAlice LuceyIrelandClaudia Luevano-ContrerasUnited States of AmericaNatalie LuscombeAustraliaIrja LutsarEstoniaRuth MacdonaldUnited States of AmericaLesley Macdonald-WicksAustraliaAmanda MacfarlaneCanadaSubbarao MadhunapantulaIndiaMelinda MaggardUnited States of AmericaChandana MaitraAustraliaKevin MakiUnited States of AmericaGrace MarquisCanadaBernadette MarriottUnited States of AmericaJennifer Martin-BiggersUnited States of AmericaElisabet Mauri ObradorsSpainElba MaurizSpainMark MccartyUnited States of AmericaMegan MccroryUnited States of AmericaRobert MccueUnited States of AmericaCameron McdonaldAustraliaLynne McfarlandUnited States of AmericaGael MearnsNew ZealandAndreas MichalsenGermanyWalter A MihatschGermanyIvon MilderNetherlandsIrina MilisavSloveniaMarcos MinicucciBrazilAnoop MisraIndiaTha\u00eds MoreiraBrazilUmberto MorelliFranceHidekazu MoriyaJapanJean-Claude MoubaracBrazilJane MuirAustraliaKenneth MukamalUnited States of AmericaMatthew MuldoonUnited States of AmericaIan MurrayUnited KingdomKazufumi NakamuraJapanYoshio NakataJapanJolly NankundaUgandaFlavio NerviChileClaudia NettoBrazilDavid C. NiemanUnited States of AmericaPriyanka NigamIndiaKatharina NimptschUnited States of AmericaGavin NortonSouth AfricaPaulina NowickaSwedenBennett NwangumaNigeriaSarah NyanteUnited States of AmericaCaio OliveiraBrazilJot Hui OoiUnited States of AmericaMaretha OppermanSouth AfricaErin O'ReillyCanadaMichael OrmsbeeUnited States of AmericaErika OtaJapanRei OtsukaJapanHsiao-Liang PaiUnited States of AmericaLachlan PalmerAustraliaAntonio PaoliItalyIsabelle PapetFranceEunyoung ParkUnited States of AmericaSohyun ParkUnited States of AmericaNatalie ParlettaAustraliaTimo PartonenFinlandAmanda PattersonAustraliaElizabeth Jo\u00e3o PavinBrazilNath\u00e9rcia PercegoniBrazilRosangela PereiraBrazilMiroslav PetrCzech RepublicRegina PhillipsUnited States of AmericaOlivia PhungUnited States of AmericaGrant PierceCanadaNuno PimentaPortugalEvangelos PolychronopoulosGreeceShideh PouriaUnited KingdomJoe ProiettoAustraliaBo QinUnited States of AmericaLi-Qiang QinChinaSusan RaatzUnited States of AmericaSusan RacetteUnited States of AmericaRetnagowri RajandramMalaysiaRita RamanUnited States of AmericaDan RamdathCanadaHeather RasmussenUnited States of AmericaNorman RatcliffeUnited KingdomHollie RaynorUnited States of AmericaAsnat RazielIsraelAnne RentfroUnited States of AmericaMarcelo RibeiroBrazilNico RizzoUnited States of AmericaLindsay RobinsonCanadaRosalia Rodriguez-RodriguezSpainJoshua RoffmanUnited States of AmericaNipa RojroongwasinkulThailandMartin RootUnited States of AmericaFilippo RossiItalyAnne-Fran\u00e7oise RousseauBelgiumKevin RowleyAustraliaFrank SacksUnited States of AmericaGulhan SamurTurkeyFrancisco J S\u00e1nchez-MunizSpainShridhar SatheUnited States of AmericaGiovanni ScapagniniItalyJeffery SchauCanadaSusan SchembreUnited States of AmericaBarbara SchneemanUnited States of AmericaSt\u00e9phane SchneiderFranceGina Segovia-SiapcoUnited States of AmericaR. Andew ShanelyUnited States of AmericaNick ShawAustraliaSangeetha ShyamMalaysiaVishal SinghIndiaSheila SkeaffNew ZealandHelen SkouterisAustraliaAnn Skulas-RayUnited States of AmericaInez Slamet-LoedinPhilippinesJoanne SlavinUnited States of AmericaDavid SmithUnited KingdomDavid SmithUnited KingdomKylie SmithAustraliaNoel W. SolononsGuatemalaElys\u00e9e SomasseBelgiumMarijn SpeeckaertBelgiumSally StablerUnited States of AmericaKimon StamatelopoulosGreeceZeno StangaSwitzerlandCatherine StantonIrelandBlanka StiburkovaCzech RepublicManfred StommelUnited States of AmericaJavier StosicArgentinaJeff StoutUnited States of AmericaSaverio StrangesUnited KingdomNis StrideDenmarkJean-Marc TadieFranceMarkus TakkunenFinlandKiyoshi TanakaJapanLinda TapsellAustraliaPaul TerryUnited States of AmericaAnastasios TheodorouCyprusFrank ThiesUnited KingdomTinku ThomasIndiaGeorge ThomsonUnited KingdomGianluca TognonSwedenHirofumi TomiyamaJapanDuong TranUnited States of AmericaChin-Hsiao TsengTaiwanKoichi TsuneyamaJapanTao-Hsin TungTaiwanGiovanna TurconiItalyJairam VanamalaUnited States of AmericaKrista VaradyUnited States of AmericaJuliana VazBrazilAlfonso Vidal CasariegoSpainMatam Vijay-KumarUnited States of AmericaRamon VilallongaSpainHeather VincentUnited States of AmericaNishant VisavadiyaUnited States of AmericaStella VolpeUnited States of AmericaLidia WadolowskaPolandDan WaitzbergBrazilYujie WangUnited States of AmericaXuewen WangUnited States of AmericaMary WardUnited KingdomTamar WeenenNetherlandsMartin O. WeickertUnited KingdomFriede WenholdSouth AfricaJay WhelanUnited States of AmericaStephney WhillierAustraliaAnne WijtzesNetherlandsJacob WilsonUnited States of AmericaSemon WuTaiwanAndrzej WykretowiczPolandWenzhong XiaoUnited States of AmericaWanghong XuChinaWeili XuSwedenSho-Ichi YamagishiJapanYong YangUnited States of AmericaBeng San YeohUnited States of AmericaYusuf YilmazTurkeyIan YoungUnited KingdomDanxia YuUnited States of AmericaKeun-Sang YumKorea, SouthRaul Zamora-RosSpainBaoshun ZhangChinaJian ZhangChinaKun ZhuAustraliaZongjian ZhuUnited States of AmericaAngela ZivkovicUnited States of AmericaClaire ZizzaUnited States of America"}
+{"text": "We thank all of our reviewers who have contributed to the journal in volume 6 (2014). High quality and timely reviews are critical to the overall quality of the journal. We are committed to providing a unique and important outlet for scholarship regarding neurodevelopmental disorders and are indebted to the outstanding reviewers who have contributed their time over the last year in helping us to reach this goal. Brett AbrahamsUnited States of AmericaJane AdamsUnited States of AmericaMaria ArvioFinlandTorsten BaldewegUnited KingdomSimon Baron-CohenUnited KingdomBen A. BarresUnited States of AmericaRenata BartesaghiItalyAyelet Ben-SasonIsraelRaphael BernierUnited States of AmericaNan Bernstein RatnerUnited States of AmericaCatalina BetancurFranceDorothy BishopUnited KingdomSomer BishopUnited States of AmericaSven BolteSwedenMaria Clara BonagliaItalyOliver BraddickUnited KingdomWilliam BrownUnited States of AmericaGeorge CaponeUnited States of AmericaMelissa CarterCanadaLeslie CarverUnited States of AmericaCarissa CascioUnited States of AmericaTony CharmanUnited KingdomAbhijit ChaudhuriUnited KingdomJohn ColomboUnited States of AmericaAndrea ContestabileItalyGina Conti-RamsdenUnited KingdomMichael CorballisNew ZealandMichael CraigUnited KingdomSteve DagerUnited States of AmericaKim DaltonUnited States of AmericaJulie DanielsUnited States of AmericaGabriel DichterUnited States of AmericaDagmara DimitriouUnited KingdomMagdalena DziembowskaPolandInge-Marie EigstiUnited States of AmericaChrista EinspielerAustriaPeggy EisUnited States of AmericaJed ElisonUnited States of AmericaSusan FajaUnited States of AmericaEmily FarranUnited KingdomDeborah FidlerUnited States of AmericaSusan FolsteinUnited States of AmericaTim FoskerUnited KingdomNathan FoxUnited States of AmericaNouchine HadjikhaniUnited States of AmericaEveline HagebeukNetherlandsBrian HallahanIrelandElizabeth HeadUnited States of AmericaPatricia HowlinUnited KingdomEric HuangUnited States of AmericaYadong HuangUnited States of AmericaLisa M. JacolaUnited States of AmericaShafali JesteUnited States of AmericaMichael V. JohnstonUnited States of AmericaRobert JosephUnited States of AmericaRajesh KanaUnited States of AmericaKatherine KarlsgodtUnited States of AmericaWalter KaufmannUnited States of AmericaKelly KingUnited States of AmericaBonita Klein-TasmanUnited States of AmericaKami KoldewynUnited KingdomNikolaos KozeisGreeceSilvia LanfranchiItalyHayley LeonardUnited KingdomApril LevinUnited States of AmericaOvsanna LeyferUnited States of AmericaMolly LoshUnited States of AmericaEva LothUnited KingdomBeth MalowUnited States of AmericaChristian MarshallCanadaPeter MarshallUnited States of AmericaKarla McGregorUnited States of AmericaCarolyn MervisUnited States of AmericaPaul MoesUnited States of AmericaAnna Victoria MolofskyUnited States of AmericaEric MorrowUnited States of AmericaMatt MosconiUnited States of AmericaKazuhiko NakabayashiJapanMasato NakafukuUnited States of AmericaGiovanni NeriItalyNora NewcombeUnited States of AmericaCraig NewschafferUnited States of AmericaRowena NgUnited States of AmericaRob NicolsonCanadaJose Luis Olmos-SerranoUnited States of AmericaLucy OsborneCanadaOpal OusleyUnited States of AmericaTyler PerrachioneUnited States of AmericaIsaac PessahUnited States of AmericaKaren PierceUnited States of AmericaElena PlanteUnited States of AmericaDaniela Plesa-SkwererUnited States of AmericaMelanie PorterAustraliaJohn R. Pruett JrUnited States of AmericaZhenghan QiUnited States of AmericaMichael RafiiUnited States of AmericaSusan RavizzaUnited States of AmericaKeith RaynerUnited States of AmericaFrancesco RiaItalyMabel RiceUnited States of AmericaJane RobertsUnited States of AmericaTimothy RobertsUnited States of AmericaRandal RossUnited States of AmericaJoanne RovetCanadaFabio SambataroItalyCarolyn SchanenUnited States of AmericaStephen SchererCanadaSuzy ScherfUnited States of AmericaMichael SchlundUnited States of AmericaSarah SchoenUnited States of AmericaRobert SchultzUnited States of AmericaElsa ShapiroUnited States of AmericaFrederick ShicUnited States of AmericaTony SimonUnited States of AmericaKarun SinghCanadaLiz SmithUnited KingdomJesse SnedekerUnited States of AmericaMikle SouthUnited States of AmericaSarah SpenceUnited States of AmericaDaniel StahlUnited KingdomCatherine StamoulisUnited States of AmericaJulia StephenUnited States of AmericaCourtney StevensUnited States of AmericaYujiao SunUnited States of AmericaJohn SweeneyUnited States of AmericaFrank SymonsUnited States of AmericaNicole TartagliaUnited States of AmericaMichel Thiebaut de SchottenUnited KingdomBrent Vander WykUnited States of AmericaStefano VicariItalyGiacomo VivantiAustraliaJennifer WagnerUnited States of AmericaSeth WarschauskyUnited States of AmericaSara WebbUnited States of AmericaCorrine WeltUnited States of AmericaAndrew WhitehouseAustraliaKate WoodcockUnited KingdomTimothy YuUnited States of AmericaRyan YuenCanada"}
+{"text": "Journal of Animal Science and Biotechnology would like to thank all our reviewers who have contributed to the journal in Volume 5 (2014).The editors of  Tomas J AcostaJapanDavid AdelsonAustraliaJuliana AlmeidaUnited States of AmericaJill AndersonUnited States of AmericaRobin AndersonUnited States of AmericaCheryl AshworthUnited KingdomJean-Denis BaillyFranceFuller BazerUnited States of AmericaDenise BeaulieuCanadaJohn BernardUnited States of AmericaDonagh BerryIrelandMario BinelliBrazilJohn BlackAustraliaJoaquim BrufauSpainLuigi CalamariItalyAna Calderon de la BarcaMexicoAnthony CapucoUnited States of AmericaEduardo CasasUnited States of AmericaYou-Tzung ChenTaiwanLee I. ChibaUnited States of AmericaMingan ChoctAustraliaYoungsok ChoiSouth KoreaIain ClarkeAustraliaGiuseppe ConteItalyG Andres ContrerasUnited States of AmericaJoe CrenshawUnited States of AmericaThomas CrenshawUnited States of AmericaDirk DannenbergerGermanyTeresa DavisUnited States of AmericaLaura De MartinoItalyChristian DiotFranceJames DrackleyUnited States of AmericaCaroline EozenouFranceKay FaabergUnited States of AmericaCatherine FieldCanadaJeffrey FirkinsUnited States of AmericaCarolyn FitzsimmonsCanadaJorge FloresUnited States of AmericaWilliam FlowersUnited States of AmericaStephen FordUnited States of AmericaNiamh FordeIrelandMichel A FortierCanadaAbigail FowdenUnited KingdomGeorge FoxcroftCanadaAnita FranczakPolandRick FunstonUnited States of AmericaShaorong GaoChinaDorian GarrickUnited States of AmericaJo\u00ebl GautronFranceRodney GeisertUnited States of AmericaIlias GiannenasGreeceSylvie Giger-ReverdinFranceGuillermo GiovambattistaArgentinaRobert GoodbandUnited States of AmericaAlison GosbyAustraliaHeather GreenleeUnited States of AmericaVeronika HalasHungaryJoshua HareUnited States of AmericaKenton HartUnited KingdomZhixiong HeCanadaJung Min HeoSouth KoreaJill HineyUnited States of AmericaAsraf HossainIndiaKazuhiko ImakawaJapanRobert IvarieUnited States of AmericaEui-Bae JeungSouth KoreaPeng JiUnited States of AmericaLi JiangChinaChen JilanChinaGreg JohnsonUnited States of AmericaHakhyun KaSouth KoreaMonika KaczmarekPolandFiliz KaradasTurkeyLevent KeskintepeUnited States of AmericaTarek KhalifaGreeceMahesh KhatriUnited States of AmericaBeob KimSouth KoreaInho KimSouth KoreaSung Woo KimUnited States of AmericaTerry KlopfensteinUnited States of AmericaMarlon KnightsUnited States of AmericaEsther KokNetherlandsXingen LeiUnited States of AmericaCrystal LevesqueUnited States of AmericaYan LiUnited States of AmericaChangxi LiCanadaFenge LiChinaMing LiUnited States of AmericaWen LiUnited States of AmericaYanhong LiuUnited States of AmericaJian-Xin LiuChinaLi LiuChinaTing LuUnited States of AmericaRobert LucitoUnited States of AmericaRod MackieUnited States of AmericaKasey Maddock CarlinUnited States of AmericaIsabelle MansuySwitzerlandMilan MarounekCzech RepublicMatthew McCabeIrelandPhillip MillerUnited States of AmericaByungrok MinUnited States of AmericaJ. Ernest MintonUnited States of AmericaKamal MjounUnited States of AmericaNoura Mohamed SalihSudanQinghua NieChinaAkbar NikkhahIranMartin NyachotiCanadaJack OdleUnited States of AmericaHakan OeztuerkTurkeyPadraig O\u2019KielyIrelandGunilla OlivecronaSwedenChristopher O'NeillAustraliaTroy OttUnited States of AmericaThomas OvertonUnited States of AmericaFred OwensUnited States of AmericaDonald PalmquistUnited States of AmericaVolkmar PassothSwedenJohn PatienceUnited States of AmericaAmlan PatraIndiaZoran PavlovicSerbiaOlli PeltoniemiFinlandRosa Maria PereiraPortugalChristiane PfarrerGermanyThonart PhilippeBelgiumKarina PierceIrelandRolf PradeUnited States of AmericaKaty ProudfootUnited States of AmericaGerardo Quiroz-Rocha,MexicoLawrence ReynoldsUnited States of AmericaXavier RollinBelgiumSina SafayiUnited States of AmericaOlivier SandraFranceAndrew SchallyUnited States of AmericaLeonardo A SechiItalyAnshan ShanChinaZhentao Sheng,United States of AmericaMathieu SilberbergFranceRoberto SilvaBrazilPanagiotis SimitzisGreeceRaj Kumar SinghIndiaDariusz J. SkarzynskiPolandStephen SmithUnited States of AmericaTamas SomfaiJapanChad StahlUnited States of AmericaAgata StanekPolandKim StanfordCanadaHans SteinUnited States of AmericaAijun SunUnited States of AmericaLakshmi SunkaraUnited States of AmericaSylwester SwiatkiewiczPolandKiyoshi TajimaJapanFuyuhiko TamanoiUnited States of AmericaSha TaoUnited States of AmericaNarasaraju TeluguakulaUnited States of AmericaRobert ThalerUnited States of AmericaLeo TimmsUnited States of AmericaMia TorchettiUnited States of AmericaYutaka UyenoJapanChristof Van PouckeBelgiumTrygve VeumUnited States of AmericaKimberly VonnahmeUnited States of AmericaShuichi WadaJapanJacqueline WallaceUnited KingdomJohn WallaceUnited KingdomYing WangUnited States of AmericaXin WangUnited States of AmericaXiaoqiu WangUnited States of AmericaKevin WannerUnited States of AmericaMalcolm WatfordUnited States of AmericaThomas WestUnited States of AmericaNiki WhitleyUnited States of AmericaGu XianhongChinaSumei YanChinaNing YangChinaWenzhu YangCanadaMing YangCanadaJingdong YinChinaYulong YinChinaPeiqiang YuCanadaLidan ZhaoUnited States of AmericaLech ZwierzchowskiPoland"}
+{"text": "Journal of Ovarian Research would like to thank all of our reviewers who have contributed to the journal in Volume 8 (2015).The editors of  Elham AbbasiIranNuzhat AhmedAustraliaJuan Luis AlcazarSpainM\u0160 Alebi\u0107CroatiaGiovanni AlettiItalySimon AlfredCanadaAdolfo AllegraItalyCarlo AlviggiItalyMark AndersonUnited KingdomRitu AnejaUnited States of AmericaStefano AngioniItalyFernando AnschauBrazilAmita AttleeUnited Arab EmiratesXiaochun BaiChinaJay BaltzCanadaSharmila BapatIndiaGiovanni Battista La SalaItalyGeorge R. BeckUnited States of AmericaSusan BellisUnited States of AmericaDeepa BhartiyaIndiaP BhideUnited KingdomGiuseppe BifulcoItalyGiorgio BoganiItalyPeter BolsBelgiumChinmoy BoseIndiaMarcus BosenbergBrazilTheodore BrownCanadaAriana BruzzoneArgentinaDavid BuxtonUnited States of AmericaYihua CaiUnited States of AmericaShelley CargillUnited KingdomJvan CasarinItalyLivio CasariniItalySophie Catteau-JonardFranceJuliana CelestinoBrazilRachel ChanHong KongRachel ChanUnited KingdomShuo ChenChinaZi-Jiang ChenChinaRi-Cheng ChianCanadaIndrajit ChowdhuryUnited States of AmericaGreg ChristmanUnited States of AmericaAnita Chudecka-GlazPolandHugh ClarkeCanadaFabrice CognasseFranceBarbara ComettiSwitzerlandPamela ConstantinouUnited States of AmericaRoberta CoronaBelgiumGiovanni CoticchioItalyAndrea CuppUnited States of AmericaMarek CybulskiPolandChendil DamodaranUnited States of AmericaGennaro DanieleItalyTrinath DasUnited States of AmericaJohn S. DavisUnited States of AmericaGaetano De FeoItalyDanny N. DhanasekaranUnited States of AmericaMartin Wanda A DorsettAmerican SamoaJoelle DupontFranceHusamettin EkiciTurkeyDorraya El-AshryUnited States of AmericaEvelin EliaArgentinaSebastien ElisFranceAkmal El-MaznyEgyptYoussef Abo ElwanEgyptKevin EngUnited States of AmericaSvend EngelholmDenmarkTze Kiong ErTaiwanMike FainzilberIranAngela FalboItalyFrancesco FanfaniItalyWarren FosterCanadaWouter FroymanBelgiumFiona FurlongUnited KingdomDirk GeertsNetherlandsAncuta Gheorghisan-GalateanuRomaniaFabio GhezziItalySalvatore GizzoItalyNorbert GleicherUnited States of AmericaStefano GreggiItalyUmran GulecTurkeyToshiyuki HataJapanYuka HattoriJapanIoannis HatzipetrosHungaryOsamu HiraikeJapanRashidi Batool HosseinIranAriel HourvitzIsraelBunpei IshizukaJapanCiro IsidoroItalyAkira IwaseJapanPooja JagmohanSingaporeAnders JakobsenDenmarkLina JiaChinaSangita JindalUnited States of AmericaErica JohnsonUnited States of AmericaMasanori KanemuraJapanSujata KarIndiaAdam KarpfUnited States of AmericaSelvendiran KaruppaiyahUnited States of AmericaJohn KastelicCanadaShlomit KenigsbergCanadaA KhruninRussian FederationKi Hyung KimSouth KoreaWon Ho KimSouth KoreaTadashi KimuraJapanFolgueira Maria Aparecida A KoikeBrazilB KotowiczUnited States of AmericaDiane KrauseUnited States of AmericaSzyllo KrzysztofPolandMagdalena KuciaUnited States of AmericaMiki KushimaJapanAntonio La MarcaItalyKevin LamHong KongT N Vuong Lan VietnamFlorian LangGermanyMaria LaszczynskaPolandTien LeCanadaIssam LebbiTunisiaKeren LevanonIsraelMarie-Claude LeveilleCanadaJulang LiCanadaMonica LipayBrazilFeng-Yuan LiuTaiwanPeishu LiuChinaJoshua LoganUnited States of AmericaEmil LouUnited States of AmericaZhen LuUnited States of AmericaEmilio LuciaItalyJinfeng MaChinaMohammed MalikUnited States of AmericaVincenzo Dario MandatoItalyMarc MansourCanadaClaudia MarchettiItalyArtur MayerhoferGermanyRajiv McCoyUnited States of AmericaRyan MengChinaJanusz MenkiszakPolandFakhroddin MesbahIranAnne-Marie Mes-MassonCanadaIoannis MessinisGreeceMiller-DonaldUnited States of AmericaE MiralpeixSpainGillian MitchellAustraliaBen MolAustraliaMonica MontopoliItalyBarb MorenoMexicoDaria MoriniItalyGiovanni MorroneItalyP. B. MullanUnited KingdomCarine MunautBelgiumGiovanna MuscogiuriItalyErcan Cihangir MutluTurkeyMani NassirGermanyKaei NasuJapanKazem NejatiIranCeana NezhatUnited States of AmericaErnest NgHong KongAlessia NicoliItalyWarren NothnickUnited States of AmericaKiyoshi OkadaJapanRenato OliveiraBrazilAki OrideJapanFrancesco OrioItalyMakoto OrisakaJapanRaoul OrvietoIsraelYutaka OsugaJapanJohannes OttAustriaEmre Goksan PabuccuTurkeyGeorge PadosGreeceStefano PalombaItalyRenato PasqualiItalyManish PatankarUnited States of AmericaBibbin PaulUnited States of AmericaMichael PearlUnited States of AmericaEmanuele PelosiUnited States of AmericaChun PengCanadaMerviel PhilippeFranceMoorthy Palanimuthu PonnusamyUnited States of AmericaLuis Qui\u00f1onesChileChristina RasmussenDenmarkMariusz RatajczakUnited States of AmericaSuman RiceUnited KingdomCarmen RomeroChileCarlo Maria RotellaItalyDebarshi RoyUnited States of AmericaRosaria RuggeriItalyM Ram SairamCanadaAmany SalamaEgyptMauricio SalcedoMexicoBO SalehIraqSanada SakikoJapanJindal SangitaUnited States of AmericaCarol SartoriusUnited States of AmericaWlodzimierz SawickiPolandEm SchmelzUnited States of AmericaMatthew SchultzUnited States of AmericaKok-Min SeowTaiwanMasayuki ShimadaJapanTadahiro ShojiJapanYimin ShuUnited States of AmericaSanthi SilambananIndiaAjay SinghUnited States of AmericaRajesh SinghUnited States of AmericaRajiv SinglaIndiaMarc-Andre SirardCanadaMichelle KY SiuHong KongSteven C SmithSwazilandVinayak SmithAustraliaJohan SmitzBelgiumRakesh SrivastavaUnited States of AmericaSherri StewartUnited States of AmericaNorihiro SuginoJapanToru SugiyamaJapanSuman SumanUnited States of AmericaPierosandro TagliaferriItalyToshifumi TakahashiJapanFuminori TaniguchiJapanVasilios TanosvCyprusHakan TimurTurkeyAlison TingUnited States of AmericaAntoine TorreFranceFilippo Maria UbaldiItalyStefano UccellaItalyGuido Valente ValenteItalyBruno van HerendaelBelgiumEngelina van HoutenNetherlandsBarbara VanderhydenCanadaLukas VrbaUnited States of AmericaQi WangUnited States of AmericaRobert WeinbergUnited States of AmericaStephanie B WheelerAustriaMarie Louise WissingDenmarkJerzy WydmanskiPolandYang XiaokuiChinaKai XueChinaTakashi YazawaJapanBulent O YildizTurkeyYoshihito YokoyamaJapanEr Leong YongSingaporeJian ZhangChinaYue ZhaoChinaChun ZhouUnited States of AmericaR.S. ZimmermanUnited States of AmericaSurekha ZingadeIndiaFulvio ZulloItalyEnrico ZupiItaly"}
+{"text": "Molecular Cytogenetics would like to thank all our reviewers who have contributed to the journal in volume 7 (2014).The Editors of  Lauri AaltonenFinlandDilek AktasTurkeyEyad AlhouraniSyriaDaniela AlosiDenmarkGilda AlvesBrazilBonnet-Garnier Am\u00e9lieFranceRouben AroutiounianArmeniaLiming BaoUnited States of AmericaJohn BarberUnited KingdomDenise BatistaUnited States of AmericaElena BenaventeSpainSoledad BerriosChileThomas BetteckenGermanyDavid BettsIrelandSamarth BhattUnited States of AmericaJoan BlancoSpainMaria Clara BonagliaItalyFatih BoyarUnited States of AmericaLukrecija BrecevicCroatiaHelene BruyereCanadaThe-Hung BuiSwedenMonica BullejosSpainJoern BullerdiekGermanyJ Peter BurbachNetherlandsIsabel Maria Marques CarreiraPortugalArunrat ChaveerachThailandSau CheungUnited States of AmericaRichard ChoyHong KongMarcelo CioffiBrazilCarlos Cordova-FletesMexicoNicholas CrossUnited KingdomPatricia CrotwellUnited States of AmericaMarta CzakoHungaryZunyan DaiUnited States of AmericaPaola Dal CinUnited States of AmericaMarc De BraekeleerFranceEdivaldo de OliveiraBrazilIgnacio del CastilloSpainMarie Dell'AquilaUnited States of AmericaMartine Doco-FenzyFranceYassamine DoubajMoroccoRegen DrouinCanadaPeter DuesbergUnited States of AmericaJean-Michel DupontFranceEmel ErgulTurkeyYao-Shan FanUnited States of AmericaJelena FilipovicSerbiaMichael FranckiAustraliaRita GenesioItalyMary Ann GeorgeCanadaIoannis GeorgiouGreeceAd Geurts van KesselNetherlandsRoberto GiordaItalySanthosh GirirajanUnited States of AmericaJohn GrahamUnited States of AmericaAhmed HamidDenmarkKaren HarrisonCanadaNyla HeeremaUnited States of AmericaSimone HeidemannGermanyJulia HentschelGermanyJennelle HodgeUnited States of AmericaAndreas HoubenGermanyColleen Jackson-CookUnited States of AmericaFan JinChinaVaidehi JobanputraUnited States of AmericaSteve KargasUnited States of AmericaMichael KharasUnited States of AmericaTjitske KleefstraNetherlandsElena KolomietzCanadaYahui KongUnited States of AmericaDal-Hoe KooUnited States of AmericaGy\u00f6rgy Kosztol\u00e1nyiHungaryDieter KotzotAustriaAlma KuechlerGermanyJ\u00fcrgen KunzGermanyIngo KurthGermanyEdward LammerUnited States of AmericaLidia LarizzaItalySonja LevanatCroatiaMarilyn LiUnited States of AmericaPeining LiUnited States of AmericaCaroline Mackie OgilvieUnited KingdomKamlesh MadanNetherlandsPamela MaginiItalyMarina ManvelyanArmeniaJian-Hua MaoUnited States of AmericaLucia MartelliBrazilLudmila MatyakhinaUnited States of AmericaAriadni MavrouGreeceElizabeth McCreadyCanadaCristina MecucciItalyMaria Isabel MelaragnoBrazilClemens MellinkNetherlandsJoana MeloPortugalMartina MerkasCroatiaKonstantin MillerGermanyAnna-Maja MolinSwedenMarta Molnar-LangHungaryKristin MrasekGermanyElisabeth NachevaUnited KingdomAbdelhafid NatiqMoroccoYi NingUnited States of AmericaJunQi NiuChinaBeata NowakowskaBelgiumMaria Oliver-BonetSpainMoneeb OthmanYemenGeorge PatrinosGreeceGreg PetersAustraliaMichael PetersenDenmarkRuthann PfauUnited States of AmericaQingwei QiChinaZhongxia QiUnited States of AmericaPetr R\u00e1bCzech RepublicGopakumar RadhakrishnanIndiaAleksandar RajkovicUnited States of AmericaTerje RaudseppUnited States of AmericaPierre RayFranceHoracio RiveraMexicoLaura RodriguezSpainMarta Rodriguez de AlbaSpainCaroline Rooryck-ThamboFranceNikolai RubtsovRussian FederationJuliana SaUnited States of AmericaAntonio SanchezSpainHeather SandersUnited States of AmericaAlbert SchinzelSwitzerlandClaire SchwabUnited KingdomMarco SeriItalyFrenny ShethIndiaHarsh ShethUnited KingdomPhotini SinnisUnited States of AmericaCarolina SismaniCyprusDominique SmeetsNetherlandsYoung Bae SohnSouth KoreaJeremy SquireBrazilPawel StankiewiczUnited States of AmericaJoshua StevensUnited States of AmericaMichael TalkowskiUnited States of AmericaJan Traeger-SynodinosGreeceVladimir TrifonovRussian FederationMars van't VeerUnited KingdomRoberta VanniItalyJoris VermeeschBelgiumT\u00e1rsis VieiraBrazilOlaya VillaSpainEmanuela VolpiUnited KingdomEls VoorhoeveNetherlandsSvetlana VorsanovaRussian FederationAbdulsamad WafaSyriaMeaghan WallAustraliaKui WangChinaJingly WeierUnited States of AmericaHeinz-Ulrich WeierUnited States of AmericaAnja WeiseGermanyDaynna WolffUnited States of AmericaZhengfeng XuChinaFengtang YangUnited KingdomMingjun ZhangUnited States of AmericaYing ZouUnited States of America"}
+{"text": "Experimental studies have shown that neurons at an intermediate stage of the primate ventral visual pathway encode the conformation and spatial relations of facial features , while nA hierarchical neural network model of the primate\u2019s ventral visual pathway is trained by presenting many randomly generated faces to the hierarchical competitive neural network while a local learning rule modifies the strengths of the synaptic connections between successive layers  Figure . After t"}
+{"text": "Table S4mRNA relative expression levels of heat shock proteins in ileal tissue of pigs born to control or antibiotics-treated sows and slaughtered at different ages .(DOCX)Click here for additional data file."}
+{"text": "Respiratory Research would like to thank all of our reviewers who have contributed to the journal in Volume 15 (2014).The editors of  Ritesh AgarwalIndiaAnurag AgrawalIndiaAlvar AgustiSpainAkira AkasawaJapanJohn AlcornUnited States of AmericaStefano AlibertiItalyCatarina AlmqvistSwedenNamasivayam AmbalavananUnited States of AmericaYassine AmraniUnited KingdomTobias AnkermannGermanyDavid AnnUnited States of AmericaSabina AntoniuRomaniaHirokazu ArakawaJapanElias AwjiUnited States of AmericaMona BafadhelUnited KingdomChunxue BaiChinaJoan A. BarberaSpainEsther BarreiroSpainEric BatemanSouth AfricaFrederic BatteuxFranceNatalie BauerUnited States of AmericaHasan BayramTurkeyRichard BeasleyNew ZealandFrederic BecqFranceKai Michael BeehGermanyChristoph BeisswengerGermanyKylie BelchamberUnited KingdomSalvador BelloSpainSaverio BellusciGermanyClaudia BenjamimBrazilValerie BesnardFranceTomoko BetsuyakuJapanSurya BhattUnited States of AmericaAndrea BiancoItalyKimberly BigelowUnited States of AmericaCharlotte BillingtonUnited KingdomMark Andrew BirrellUnited KingdomNatalia BogatchevaUnited States of AmericaCharlotte BoltonUnited KingdomJessica BonUnited States of AmericaMarcel BonayFranceJames BonnerUnited States of AmericaMaria BonsignoreItalySerhat BorTurkeyMichael BorchersUnited States of AmericaLee Anthony BorthwickUnited KingdomYnuk BosseCanadaJoshua BoyceUnited States of AmericaKen BrackeBelgiumThomas BrandUnited KingdomJohn BrehmUnited States of AmericaJames BridgesUnited States of AmericaVolker BrinkmannGermanyMairi BrittanUnited KingdomPierre-Regis BurgelFranceChris BurtinBelgiumRa\u00fal Cabrera-RubioSpainPeter CalverleyUnited KingdomGianna CamiciottoliItalyGiorgio Walter CanonicaItalyAndre CantinCanadaGaetano CaramoriItalyCiro CasanovaSpainPeter CastaldiUnited States of AmericaJames ChalmersUnited KingdomTa-Chien ChanTaiwanStephen ChanUnited States of AmericaDivay ChandraUnited States of AmericaPascal ChanezFranceNan-Shan ChangTaiwanKenneth ChapmanCanadaPing ChenChinaAlfredo ChettaItalyWen Chin ChiangSingaporeNan ChiangUnited States of AmericaHideki ChibaJapanMarco ChilosiItalyDoo Hyun ChungSouth KoreaKian Fan ChungUnited KingdomJuliana Cini PerryBrazilAntonio ClavennaItalyDavid CollieUnited KingdomMarco ContoliItalyAlexandru CorlateanuMoldovaGiuseppe CornagliaItalyMassimo CorradiItalyAlessandro CortiItalyJulio CortijoSpainSoraia CostaBrazilHarvey CoxsonCanadaBruno CrestaniFranceGerard CurleyCanadaRonald DahlDenmarkJordi de BatlleFranceJavier de Miguel D\u00edezSpainMonique DehouxFranceBart DekkersNetherlandsStefano Del GiaccoItalyMarion DelcroixBelgiumHimanshu DesaiUnited States of AmericaFabiano di MarcoItalyQuoc Thai DinhGermanyMiguel DivoUnited States of AmericaRatko DjukanovicUnited KingdomCristian DogaruSwitzerlandLouise DonnellyUnited KingdomJames DonohueUnited States of AmericaDavid DoudaUnited States of AmericaJo DouglassAustraliaMark DransfieldUnited States of AmericaNickolai DulinUnited States of AmericaDaniel DusserFranceCarsten EhrhardtIrelandMarinos EliaUnited KingdomCharles EmalaUnited States of AmericaPierre ErnstCanadaSantiago EwigGermanyLeonardo FabbriItalyLeo FabbriItalyAurelie FabreIrelandJeremy FalkUnited States of AmericaRosa FanerSpainHarrison FarberUnited States of AmericaLaszlo FarkasUnited States of AmericaBernie FischerUnited States of AmericaRachel FoongAustraliaEvangelia FoukaGreeceFrits FranssenNetherlandsElaine FuertesGermanyTrentham FurnessAustraliaJudith Garcia-AymerichSpainMarian Garcia-Nu\u00f1ezSpainAmiq GazdharSwitzerlandMoyar Qing GeUnited States of AmericaArthur GelbUnited States of AmericaPatrick GeraghtyUnited States of AmericaPeter GibsonAustraliaStephan GlasserUnited States of AmericaRainer GloecklGermanyJohn GodleskiUnited States of AmericaFelicia GohAustraliaNeil GoldenbergCanadaNira GoldsteinUnited States of AmericaMarcin GolecPolandLudwig GortnerGermanyReinoud GosensNetherlandsHarry GoskerNetherlandsChristopher GossUnited States of AmericaAbdelilah GounniCanadaLidwien Graat-VerboomNetherlandsCatherine GreeneIrelandChristoph GriessingerGermanyJochen GrommesGermanyJohan GrootenBelgiumChristophe GuignabertFranceErich GulbinsGermanySudhiranjan GuptaUnited States of AmericaRobert GuzyUnited States of AmericaAngela HaczkuUnited States of AmericaJames HagoodUnited States of AmericaKathleen HaleyUnited States of AmericaDavid HallUnited States of AmericaIan HallUnited KingdomAlf HamannGermanyMeilan HanUnited States of AmericaPhil HansbroAustraliaCorrine HansonUnited States of AmericaLouise HeckerUnited States of AmericaMatt HegewaldUnited States of AmericaIrene HeijinkNetherlandsMy HelmsUnited States of AmericaMarc HershensonUnited States of AmericaPieter HiemstraNetherlandsYuji HigashimotoJapanBlanca HimesUnited States of AmericaToyohiro HiraiJapanAnne HollandAustraliaRaewyn HopkinsNew ZealandVegard HovlandNorwayReuben HowdenUnited States of AmericaBiao HuUnited States of AmericaFrancois HuauxBelgiumAlice HuertasFranceWouter HuvenneBelgiumMachteld HylkemaNetherlandsTomomi IchikawaJapanMasakazu IchinoseJapanStephane IllianoFranceHiromasa InoueJapanSatoru ItoJapanKathryn IveyUnited States of AmericaBogdan JakielaPolandTania Janaudis-FerreiraCanadaSam JanesUnited KingdomAn Soo JangSouth KoreaMatthew JankowichUnited States of AmericaAnan JarabJordanGisli JenkinsUnited KingdomPrescilla Vera JeurinkNetherlandsSamithamby JeyaseelanUnited States of AmericaKylie JohnstonAustraliaPaul JonesUnited KingdomPavol JoppaSlovakiaJoseph JudeUnited States of AmericaWolfgang JungraithmayrSwitzerlandEleanor KableAustraliaRalf KaiserGermanySuresh KalathilUnited States of AmericaRavi KalhanUnited States of AmericaNoor KalshekerUnited KingdomRichard KannerUnited States of AmericaKhalil KarimiCanadaHarry Karmouty-QuintanaUnited States of AmericaMaya KartaUnited States of AmericaHideki KatsuraJapanPrabha KcUnited States of AmericaAchsah KeeganUnited States of AmericaAlexandra Kathrin KiemerGermanyVictor KimUnited States of AmericaPaul KingmaUnited States of AmericaGregory KinneyUnited States of AmericaUday KishoreUnited KingdomAlex KleinJanNetherlandsDaren KnoellUnited States of AmericaAkira KoaraiJapanTakashi KohnoJapanJay KollsUnited States of AmericaStephanie KornGermanyLaura KothUnited States of AmericaAngela KoutsokeraSwitzerlandMatthew KowgierCanadaSusanne Krauss-EtschmannGermanyJames KreindlerUnited States of AmericaRamaswamy KrishnanUnited States of AmericaStefan Kr\u00fcgerGermanyVera KrymskayaUnited States of AmericaKuldeep KumawatNetherlandsMaciej KupczykPolandIchiro KuwahiraJapanMatthew LammiUnited States of AmericaLarry LandsCanadaIrene LangAustriaGee W LauUnited States of AmericaFederico LavoriniItalyAili LazaarUnited States of AmericaJae Cheol LeeSouth KoreaPetra LeidingerGermanyAndrew LeitchUnited KingdomArne LeitteGermanySteve LeuTaiwanJulia Ley-ZaporozhanGermanyNing LiUnited States of AmericaChristian Lino CardenasUnited States of AmericaHuiping LiuUnited States of AmericaJie LiuUnited States of AmericaLucille LondonUnited States of AmericaJose Luis Lopez-CamposSpainMatthew LozaUnited States of AmericaFabrizio LuppiItalyBarbara LuteyUnited States of AmericaKelvin MacDonaldUnited States of AmericaRoberto MachadoUnited States of AmericaTania MaesBelgiumPiero MaestrelliItalyAntoine MagnanFranceSarah MaherUnited KingdomArnaud MailleuxFranceSusan MajkaUnited States of AmericaPatrick MalliaUnited KingdomG. B. 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+{"text": "The following information is missing from the Funding section: This study was co-financed by Fundo Europeu de Desenvolvimento Regional (FEDER) through the Programa Operacional Factores de Competitividade (COMPETE) Program."}
+{"text": "Pediatric Rheumatology would like to thank all our reviewers who have contributed to the journal in Volume 13 (2015).The Editors of  Rabheh Abdul AzizUnited States of AmericaAlexa AdamsUnited KingdomAmita AggarwalIndiaHaluk AkinTurkeyDaniel AlbertUnited States of AmericaJordi AntonSpainMonica ArduraUnited States of AmericaWineke ArmbrustNetherlandsTadej AvcinSloveniaSevcan BakkalogluTurkeyMichael BeresfordUnited KingdomPeter BerlitGermanyPeter BlierUnited States of AmericaJohn BohnsackUnited States of AmericaRiva BrikIsraelPaul BroganUnited KingdomJuergen BrunnerAustriaRuben Burgos-VargasMexicoJon BurnhamUnited States of AmericaDaniela CabibiItalyAhmet Okay CaglayanTurkeyScott CannaUnited States of AmericaRuy CarrascoUnited States of AmericaJeffrey ChaitowAustraliaMercedes ChanCanadaPeter ChiraUnited States of AmericaRolando CimazItalyRandy CronUnited States of AmericaRub\u00e9n Jos\u00e9 CutticaArgentinaRuben CutticaSpainJaime De InocencioSpainFatma DedeogluUnited States of AmericaPavla DolezalovaCzech RepublicKyla DriestUnited States of AmericaAnne EberhardUnited States of AmericaBarbara EberhardUnited States of AmericaDespina EleftheriouUnited KingdomRaoul EngelbertNetherlandsFernanda FalciniItalyAnders FasthSwedenGuido FillerCanadaIvan FoeldvariGermanyEmily FoxUnited States of AmericaCaroline GaleottiFranceAbraham GedaliaUnited States of AmericaHermann GirschickGermanyThomas Brent GrahamUnited States of AmericaThomas GriffinUnited States of AmericaBrandt GrohUnited States of AmericaAlexei GromUnited States of AmericaJaime GuzmanCanadaKathleen HainesUnited States of AmericaNajia Hajjaj-HassouniMoroccoAkiko Hamaoka-OkamotoJapanLiora HarelIsraelShunji HasegawaJapanPhilip HashkesIsraelLauren HendersonUnited States of AmericaAimee HershUnited States of AmericaGloria HigginsUnited States of AmericaKerry HitosAustraliaMark HoeltzelUnited States of AmericaMicha\u00ebl HoferSwitzerlandMatthew HollanderUnited States of AmericaDaniel HortonUnited States of AmericaKristin HoughtonCanadaAdam HuberCanadaReagan HuntUnited States of AmericaMaria IbarraUnited States of AmericaPaul JensenUnited States of AmericaPeter JunkerDenmarkLeonard KabanUnited States of AmericaSylvia KamphuisNetherlandsSusan KimUnited States of AmericaYukiko KimuraUnited States of AmericaSusan KlepperUnited States of AmericaAndrea KnightUnited States of AmericaGeorg KojdaGermanyRebecca KunderUnited States of AmericaBianca LangCanadaRonald LaxerCanadaCarol LindsleyUnited States of AmericaMindy LoUnited States of AmericaDaniel LovellUnited States of AmericaKaren MarzanUnited States of AmericaF MayoufSaudi ArabiaDeborah McCurdyUnited States of AmericaJanet McDonaghUnited KingdomJay MehtaUnited States of AmericaMichael MillerUnited States of AmericaChi Chiu MokHong KongTerry MooreUnited States of AmericaAsha MoudgilUnited States of AmericaKabita NandaUnited States of AmericaRob NickesonUnited States of AmericaEdward OberleUnited States of AmericaSheila OliveiraBrazilKathleen O'NeilUnited States of AmericaKaren OnelUnited States of AmericaMurray PassoUnited States of AmericaPeri Hickman PepmuellerUnited States of AmericaSampath PrahaladUnited States of AmericaEgla RabinovichUnited States of AmericaAthimalaipet RamananUnited KingdomAngelo RavelliItalyAndreas ReiffUnited States of AmericaSarah RingoldUnited States of AmericaAngela RobinsonUnited States of AmericaTova RonisUnited States of AmericaRicardo RussoArgentinaLatasha RuthUnited States of AmericaMarite RyggNorwayRotraud SaurenmannSwitzerlandTore SaxneSwedenKen SchiklerUnited States of AmericaKara Murphy SchmidtUnited States of AmericaYehuda SchoenfeldIsraelL SchwartzUnited States of AmericaSusan ShenoiUnited States of AmericaStanford ShulmanUnited States of AmericaSoumitri SilUnited States of AmericaAnne StevensUnited States of AmericaMatthew StollUnited States of AmericaGrant SyversonUnited States of AmericaMelissa TesherUnited States of AmericaTracy TingUnited States of AmericaNatasa ToplakSloveniaKathryn TorokUnited States of AmericaLori TuckerCanadaYosef UzielIsraelJanjaaap van der NetNetherlandsMarielle van GijnNetherlandsRichard VeheUnited States of AmericaJelena VojinovicSerbiaLinda Wagner-WeinerUnited States of AmericaCarol WallaceUnited States of AmericaPamela WeissUnited States of AmericaHelmut WittkowskiGermanyNico WulffraatNetherlandsCagri Yildirim TorunerUnited States of AmericaLawrence ZemelUnited States of AmericaDan ZhaoUnited States of AmericaVincent ZimmerGermany"}
+{"text": "Upon publication of the original article (Mallam and Bhushana Rao"}
+{"text": "Emerging Themes in Epidemiology would like to thank all our reviewers who have contributed to the journal in Volume 11 (2014).The editor of  Cornelia AdlhochSwedenNeal AlexanderUnited KingdomWladimir AlonsoUnited States of AmericaBen ArmstrongUnited KingdomKari AuranenFinlandJulie BalenUnited KingdomLarry BeesonUnited States of AmericaM. Hanna BosNetherlandsLaura BrownUnited States of AmericaAnne BuchananUnited States of AmericaNicole CarnegieUnited States of AmericaYan CheChinaCynthia CheeSingaporeStuart ClarkeUnited KingdomElizabeth CostenbaderUnited States of AmericaDouglas Curran-EverettUnited States of AmericaOlaf DekkersNetherlandsFrank DudbridgeUnited KingdomConrad FernandezCanadaLea FortunatoUnited KingdomWilliam GrayUnited KingdomDiane GrossUnited States of AmericaAndrew HaywardUnited KingdomDonald HendersonUnited States of AmericaWilliam JohnsonUnited KingdomAmalia KarahaliosAustraliaMishal KhanPakistanCarl KoppeschaarNetherlandsMarleen Kraaij - DirkzwagerNetherlandsKarl KuschnerUnited States of AmericaVincenzo LaganiGreeceHeidi LarsonUnited KingdomAndrew LoverUnited States of AmericaJoelle MakUnited KingdomSamuel MandaSouth AfricaPunam MangtaniUnited KingdomPatricia MechaelUnited States of AmericaZiad MemishSaudi ArabiaDaniela PaolottiItalyDaniel PayneUnited States of AmericaNeil PearceUnited KingdomWirichada PongtavornpinyoThailandCharles PooleUnited States of AmericaNaghma RehanPakistanCristina Rodriguez SanchezSpainDaniel RothCanadaJalil SafaeiCanadaM A Yushuf SharkerBangladeshJet SmitNetherlandsEva Steliarova-FoucherFranceJan StochlUnited KingdomAndrew TaiAustraliaClare TantonUnited KingdomLaurie TomlinsonUnited KingdomPierre TraissacFranceArianne B van Gageldonk-LafeberNetherlandsSukumar VellakkalUnited KingdomDamja VukcevicAustraliaClarice WatersSingaporeRoger WatsonUnited KingdomElizabeth WebbUnited KingdomDouglas WeedUnited States of AmericaHelen WeissUnited KingdomLaura WoodsUnited KingdomChen-Yi WuTaiwanYan ZhengUnited States of America"}
+{"text": "Mobile DNA would like to thank all our reviewers who have contributed to the journal in volume 5 (2014).The Editors of  Wenfeng AnUnited States of AmericaIrina ArkhipovaUnited States of AmericaPeter AtkinsonUnited States of AmericaDaniel BarbashUnited States of AmericaMarlene BelfortUnited States of AmericaGuillaume BourqueCanadaFrederic BrunetFranceKathleen BurnsUnited States of AmericaPierre CapyFranceRichard CawthonUnited States of AmericaWayne DecaturUnited States of AmericaPrescott DeiningerUnited States of AmericaKeith DerbyshireUnited States of AmericaDavid EdgellCanadaAnthony FuranoUnited States of AmericaJose Luis Garcia-PerezSpainClement GilbertFranceValer GoteaUnited States of AmericaNing JiangUnited States of AmericaI. King JordanUnited States of AmericaAurelie KapustaUnited States of AmericaHaig KazazianUnited States of AmericaDusan KordisSloveniaZev KronenbergUnited States of AmericaAshwini KucknoorUnited States of AmericaEmmanuelle LeratFranceElgion LoretoBrazilHarmit MalikUnited States of AmericaColin MaloneUnited States of AmericaFrancois MichelFranceOlivier PanaudFranceJoseph PetersUnited States of AmericaRamesh PillaiFranceEllen PrithamUnited States of AmericaDavid RayUnited States of AmericaFrancois SabotFranceGerald SchumannGermanyHaruhiko SiomiJapanJainy ThomasUnited States of AmericaChantal VauryFranceCristina VieiraFranceThomas WickerSwitzerlandDavid WitherspoonUnited States of AmericaSteven ZimmerlyCanada"}
+{"text": "Implementation Science would like to thank all our reviewers and editors who have contributed to the journal in Volume 9 (2014).The editors of  ReviewersEivind AakhusNorwayMichele AbendsternUnited KingdomPurva AbhyankarUnited KingdomSarah AldersonUnited KingdomLisa AraiUnited KingdomStephanie ArcherUnited KingdomRebecca ArmstrongAustraliaMelissa ArmstrongUnited States of AmericaDavid AronUnited States of AmericaKelly AschbrennerUnited States of AmericaThanos AthanasiouUnited KingdomLou AtkinsUnited KingdomRoss BailieAustraliaDavid BakerUnited States of AmericaLuciana BalliniItalyMelanie BarwickCanadaMark BayleyCanadaSteven BelenkoUnited States of AmericaDerek BellUnited KingdomSara BennettUnited States of AmericaGuillermo BernalUnited States of AmericaJoanne BeswickUnited States of AmericaFiona BeyerUnited KingdomChristian BlickemUnited KingdomGary BondUnited States of AmericaDebbie BonettiUnited KingdomAndrew BoothUnited KingdomMarije BoschAustraliaXavier Bosch-CapblanchSwitzerlandPeter BowerUnited KingdomJennifer BoykoCanadaDaniel BradfordUnited States of AmericaJeffrey BraithwaiteAustraliaPaula BrauerCanadaJamie BrehautCanadaCarinne BrodyUnited States of AmericaHelen BrooksUnited KingdomC Hendricks BrownUnited States of AmericaAngela BuchholzGermanyHelen BurchettUnited KingdomJako BurgersNetherlandsAndr\u00e9 Bussi\u00e8resCanadaPhyllis ButowAustraliaBernard CandasCanadaMartin CartwrightUnited KingdomTrudie ChalderUnited KingdomCatherine ChamberlainAustraliaDuncan ChambersUnited KingdomJohn ChatwinUnited KingdomElaine ChenUnited States of AmericaSudeh Cheraghi-SohiUnited KingdomTimothy R. 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+{"text": "The compaction of chromatin fibers regulates the accessibility of embedded DNA, highly associated with transcriptional activities"}
+{"text": "World Journal of Emergency Surgery would like to thank all our reviewers who have contributed to the journal in volume 10 (2015).The editors of  Fikri Abu-ZidanUnited Arab EmiratesFerdinando AgrestaItalyJamir ArlikarIndiaErman AytacTurkeyMiklosh BalaIsraelCino BendinelliAustraliaJasneet BhullarUnited States of AmericaWalter BifflUnited States of AmericaLuigi BonavinaItalyClay Cothren BurlewUnited States of AmericaFabio CampanileItalyOsvaldo ChiaraItalyMircea ChiricaFranceIan CivilNew ZealandFederico CoccoliniItalyRaul CoimbraUnited States of AmericaLidia DalfinoItalyJames DavisUnited States of AmericaMarc De MoyaUnited States of AmericaNicola de'AngelisFranceMarc deMoyaUnited States of AmericaSalomone Di SaverioItalyJose DiazUnited States of AmericaPaul EustaceIrelandEriberto FarinellaItalyPaula FerradaUnited States of AmericaAndreas FetteGermanyGustavo FragaBrazilRalf Herbert GahrGermanySanjay GuptaIndiaDaithi HeffernanUnited States of AmericaRao IvaturyUnited States of AmericaJeffry KashukIsraelRadwan KassirFranceKenji KawamukaiItalyMichael KellyAustraliaPeter KimUnited States of AmericaFernando KimUnited States of AmericaBoris KirshteinIsraelYoram KlugerIsraelRosemary KozarUnited States of AmericaRifat LatifiUnited States of AmericaI. Michael LeitmanUnited States of AmericaAri LeppaniemiFinlandLawrence LottenbergUnited States of AmericaRonald MaierUnited States of AmericaMark MalangoniUnited States of AmericaIngo MarziGermanyOner MentesTurkeyDavid MuckartSouth AfricaPradeep NavsariaSouth AfricaVinesh PadayachySouth AfricaAbhijeet PatilUnited KingdomEdoardo PicettiItalyStefano RauseiItalyJoao Rezende-NetoCanadaSandro RizoliCanadaGiorgio RossiItalyBoris SakakushevBulgariaMassimo SartelliItalyThomas ScaleaUnited States of AmericaHelmut Segovia LohseParaguayPablo SerranoCanadaMohd SheikhUnited States of AmericaKjetil SoreideNorwayPhilip StahelUnited KingdomAngela SultanaMaltaPeep TalvingEstoniaGia TomadzeGeorgiaGregorio TugnoliItalyGeorge VelmahosUnited States of AmericaImtiaz WaniIndiaDieter WeberAustralia"}
+{"text": "The authors inadvertently omitted a phosphate group from the chemical structure of Inositol phosphorylceramide (IPC) in"}
+{"text": "Microbiome would like to thank all our reviewers who have contributed to the journal in 2015.The editors of  Rachel AdamsUnited States of AmericaEmma Allen-VercoeCanadaKatherine AmatoUnited States of AmericaFlorent AnglyAustraliaClaire ArrietaCanadaManimozhiyan ArumugamDenmarkGuy BaeleBelgiumMartin Iain BahlDenmarkDavid BaltrusUnited States of AmericaKenneth BarfodDenmarkChristine BassisUnited States of AmericaKirsten BenkendorffAustraliaGabriele BergAustriaDavid BerryAustriaKyle BibbyUnited States of AmericaKristi BiswasNew ZealandCinnamon BlossUnited States of AmericaBlaise BolesUnited States of AmericaRobert BrittonUnited States of AmericaBrandon BrooksUnited States of AmericaDries BuddingNetherlandsTsute ChenUnited States of AmericaNicholas ChiaUnited States of AmericaDavid CoilUnited States of AmericaMaria Carmen ColladoSpainWilliam CooksonUnited KingdomEmily CopeUnited States of AmericaMichael CoxUnited KingdomKeith CrandallUnited States of AmericaLeah CuthbertsonUnited KingdomKaren DannemillerUnited States of AmericaRobert DicksonUnited States of AmericaSharon DonovanUnited States of AmericaSylvia DuncanUnited KingdomJuliana DurackUnited States of AmericaRobert DyerUnited States of AmericaJoanne EmersonUnited States of AmericaDanilo ErcoliniItalyPatricia FabianUnited States of AmericaJennifer FettweisUnited States of AmericaRoberto FloresUnited States of AmericaAnthony FodorUnited States of AmericaLarry ForneyUnited States of AmericaKristoffer ForslundGermanyJames FosterUnited States of AmericaBetsy FoxmanUnited States of AmericaPilar FrancinoSpainFlorian FrickeGermanyValerie Gaboriau-RothiauFrancePawel GajerUnited States of AmericaAndrew GenneryUnited KingdomSommer GentryUnited States of AmericaPhilippe GerardFranceAndre GessnerGermanySean GibbonsUnited States of AmericaJack GilbertUnited States of AmericaElizabeth M. 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+{"text": "Journal of Eating Disorders editorial team would like to thank all reviewers who have contributed to the journal in 2014.The  Karina AllenAustraliaJon ArcelusUnited KingdomRachel Bachner-MelmanIsraelBryony BamfordUnited KingdomCaroline BraetBelgiumCynthia BulikUnited States of AmericaSusan ByrneAustraliaTerry CarneyAustraliaLouis CharlandCanadaAngelica ClaudinoBrazilCarolyn CostinUnited States of AmericaRoss CrosbyUnited States of AmericaScott CrowUnited States of AmericaLisa DawsonAustraliaPhillippa DiedrichsUnited KingdomMurray DrummondAustraliaPravin DullurAustraliaKamryn EddyUnited States of AmericaSarah FogartyAustraliaAndrea GoldschmidtUnited States of AmericaScott GriffithsAustraliaSusan HartAustraliaPhillipa HayAustraliaNatasha HepworthAustraliaGabriella HerucAustraliaHans W. HoekNetherlandsDavid JimersonUnited States of AmericaAllison KellyCanadaJanet LatnerUnited States of AmericaSau Fong LeungHong KongKatharine LoebUnited States of AmericaSarah MaguireAustraliaBarbara Mangweth-MatzekAustriaJeffrey MossUnited States of AmericaRichard NewtonAustraliaGreta NoordenbosNetherlandsKenneth NunnAustraliaSusan PaxtonAustraliaJanette PerzAustraliaKathleen PikeUnited States of AmericaKevin PileAustraliaJanet PolivyCanadaCecile Rausch HerscoviciArgentinaDeborah Lynn ReasNorwayPaul RhodesAustraliaLina RicciardelliAustraliaAmanda SalisAustraliaUlrike SchmidtUnited KingdomUlrich SchweigerGermanyLucy SerpellUnited KingdomPratap SharanIndiaAmy SlaterUnited KingdomFrederique SminkNetherlandsDaniel SteinIsraelLois SurgenorNew ZealandAmy TalbotAustraliaMarika TiggemannAustraliaStephen TouyzAustraliaEva TrujilloMexicoFrederique Van den EyndeCanadaEric van FurthNetherlandsBetteke van NoortGermanyTracey WadeAustraliaCortney WarrenUnited States of AmericaHunna WatsonAustraliaLucene WisniewskiUnited States of AmericaBlake WoodsideCanada"}
+{"text": "Biology Direct would like to thank all the reviewers who have contributed to the journal in Volume 9 (2014).The editors of  Anthony AlmudevarUnited States of AmericaVivek AnantharamanUnited States of AmericaMiguel A Andrade-NavarroGermanyDavid ArdellUnited States of AmericaManju BansalIndiaEric BaptesteFranceJuergen BrosiusGermanyAlexander Maxwell BurroughsUnited States of AmericaOliviero CarugoAustriaDragos CretoiuRomaniaThomas DandekarGermanyValerian DoljaUnited States of AmericaMikhail DozmorovUnited States of AmericaFrank EisenhaberSingaporeXiangdong FangChinaAlistair ForrestJapanPatrick ForterreFranceToni GabaldonSpainMichael GalperinUnited States of AmericaNicolas GaltierFranceZolt\u00e1n G\u00e1sp\u00e1riHungaryRachel GersteinUnited States of AmericaMichael GilchristUnited States of AmericaUri GophnaIsraelDan GraurUnited States of AmericaNeil GreenspanUnited States of AmericaNick GrishinUnited States of AmericaMichael GromihaIndiaYuriy GusevUnited States of AmericaBalazs Gy\u00f6rffyHungaryDaniel HaftUnited States of AmericaWayne HancockUnited States of AmericaLeonid HaninUnited States of AmericaMartijn HuynenNetherlandsOllivier HyrienUnited States of AmericaLakshminarayan IyerUnited States of AmericaChristine JacobFranceEtienne JolyFranceI. King JordanUnited States of AmericaMarek KimmelUnited States of AmericaLev KlebanovCzech RepublicRob KnightUnited States of AmericaFyodor KondrashovSpainEugene KooninUnited States of AmericaD. P. KreilAustriaYang KuangUnited States of AmericaVladimir KuznetsovSingaporeDoron LancetIsraelNick LaneUnited KingdomQing Kay LiUnited States of AmericaHan LiangUnited States of AmericaAlexander LobkovskyUnited States of AmericaPurificacion Lopez-GarciaFranceKira MakarovaUnited States of AmericaWilliam MartinGermanySergei MaslovUnited States of AmericaJames McInerneyIrelandArmen MulkidjanianGermanyRobert MurphyUnited States of AmericaSandor PongorItalyAnthony PooleNew ZealandVladimir PoroikovRussian FederationShyam PrabhakarSingaporeMark RaganAustraliaNathalie ReuterNorwayIsidore RigoutsosUnited States of AmericaIgor RogozinUnited States of AmericaInaki Ruiz-TrilloSpainAndrey RzhetskyUnited States of AmericaPaul SchimmelUnited States of AmericaAlexander SchleifferAustriaChristian Sch\u00f6nbachJapanJeremy SelengutUnited States of AmericaFedor SeverinRussian FederationGeorge V. (Yura) ShpakovskiRussian FederationNeil SmalheiserUnited States of AmericaBerend SnelNetherlandsNarayanaswamy SrinivasanIndiaGiovanni StracquadanioUnited States of AmericaManabu SugaiJapanShamil SunyaevUnited States of AmericaNektarios TavernarakisGreeceLutz WalterGermanyChristine WellsAustraliaClaus WilkeUnited States of AmericaLimsoon WongSingaporeSoojin YiUnited States of AmericaJun YuChinaWeixiong ZhangUnited States of AmericaHong ZhouUnited States of AmericaIgor ZhulinUnited States of AmericaPiotr ZielenkiewiczPoland"}
+{"text": "International Journal of Health Geographics would like to thank all our reviewers who have contributed to the journal in Volume 13 (2014).The editor of  Philip AbdelMalikCanadaBahadir AktugFranceJose Luis AlfonsoSpainDonald AllanAustraliaPhilippe ApparicioCanadaMariana ArcayaUnited States of AmericaRenato AssuncaoBrazilM. Eric BenbowUnited States of AmericaDavid BerriganUnited States of AmericaJohn BethlehemNetherlandsNevzat BeyazitTurkeyLing BianUnited States of AmericaJanne Boone-HeinonenUnited States of AmericaFrancis BoscoeBouvet IslandThomas BurgoineUnited KingdomMattia CalzolariItalyAnibal Eduardo CarbajoArgentinaMari\u00e2ngela CarneiroBrazilTa-Chien ChanTaiwanYang ChengChinaAndrew ClarkCanadaJustin CohenUnited States of AmericaMichelle Colacicco-MayhughUnited States of AmericaRoxanne ConnellyUnited KingdomRobert CornerAustraliaRobert CromleyUnited States of AmericaAndrew CurtisUnited States of AmericaJacqueline CurtisUnited States of AmericaPeter DambachGermanyLorinne du ToitAustraliaMitch J DuncanAustraliaGenevieve DuntonUnited States of AmericaBenoit DurandFranceKhaled El EmamCanadaChellafe EnsoyBelgiumLuis E. EscobarUnited States of AmericaDaniel ExeterNew ZealandElisabeth Fichet-CalvetGermanyRohan FisherAustraliaEdward FitzgeraldUnited States of AmericaRobin FlowerdewUnited KingdomDesmond FoleyUnited States of AmericaRalph FrerichsUnited States of AmericaDavid FrostSouth AfricaClaire FullerUnited KingdomJavier Garcia-PerezSpainRamy GhaliEgyptDaniel GoldbergUnited States of AmericaGordon GongUnited States of AmericaPaul GoodmanUnited KingdomTrish GorelyUnited KingdomEstella GraghtyUnited States of AmericaJohn GriecoUnited States of AmericaTony GrubesicUnited States of AmericaAline GuttmannFranceMichael HagenlocherAustriaKristen HamptonUnited States of AmericaAnna HansellUnited KingdomFlo HarrisonUnited KingdomJoseph HendersonUnited States of AmericaKevin HenryUnited States of AmericaHans-Werner HenseGermanyZhiyong HuUnited States of AmericaZhuojie HuangUnited States of AmericaAnke HussNetherlandsEzzeldin IbrahimSaudi ArabiaMonica JacksonUnited States of AmericaBryan JamesUnited States of AmericaAndy JonesUnited KingdomMalia JonesUnited States of AmericaStephen JonesUnited States of AmericaJessica Jones-SmithUnited States of AmericaGreg KearneyUnited States of AmericaBrian KellyUnited KingdomCheryl KellyUnited States of AmericaLouise Kelly-HopeUnited KingdomJacqueline KerrUnited States of AmericaYan KestensCanadaStefan KienbergerAustriaGerry KilleenTanzaniaDiane KingUnited States of AmericaKatherine KingUnited States of AmericaCharlotte Demant KlinkerDenmarkTom KochCanadaDaniela KollerGermanySari KovatsUnited KingdomThomas KrafftNetherlandsMartin KulldorffUnited States of AmericaMei-Po KwanUnited States of AmericaDuncan LeeUnited KingdomJae Seung LeeKorea, SouthMichael LevyUnited States of AmericaAngela LieseUnited States of AmericaGina LovasiUnited States of AmericaStephen MatthewsUnited States of AmericaSoumya MazumdarAustraliaRobert McCannNetherlandsMatthew McGrailAustraliaJulie M\u00e9lineFranceGiulia MelisItalyAmy MorrisonPeruStephen MungaKenyaSarah-Anne MunozUnited KingdomKevin MwendaUnited States of AmericaKathryn NeckermanUnited States of AmericaRobin NesbittGermanyCory NeudorfCanadaJohn NuckolsUnited States of AmericaIsabel OliverUnited KingdomDermot O'ReillyUnited KingdomNicolas OreskovicUnited States of AmericaCosimo PalagianoItalyAmber PearsonNew ZealandMaurizio PisatiItalyRichard G. 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Salinas-PerezSpainMatthew SaltzmanUnited States of AmericaJasper SchipperijnDenmarkJ\u00fcrgen SchweikartGermanyJoseph SharkeyUnited States of AmericaWeiqun ShuChinaChantel SloanUnited States of AmericaJohn SnelgroveCanadaJeffrey StanawayUnited States of AmericaAurelia StefaniFrench GuianaRebecca SteinbachUnited KingdomTim StinearAustraliaSamaah SullivanUnited States of AmericaGuibo SunHong KongOlivier TelleFranceUsa ThisyakornThailandLukar ThorntonAustraliaJie TianUnited States of AmericaNathan TorbickUnited States of AmericaJelle Van CauwenbergBelgiumMarie-Claire van der WesthuizenSouth AfricaVeerle Van HolleBelgiumEdwin van WijngaardenUnited States of AmericaSophie VanwambekeBelgiumTeeradache ViangteeravatUnited States of AmericaJean-Francois VielFranceKaren VillanuevaAustraliaEloy VisoSpainJohn VululeKenyaJeremy WalkerUnited KingdomYvonne WalzGermanyFahui WangUnited States of AmericaSamuel WanjiCameroonBenedict WheelerUnited KingdomDavid WheelerUnited States of AmericaJulianne WilliamsUnited KingdomRuifu YangChinaHuanming YangChinaShinya YasumotoJapanNikolaos William YiannakouliasCanadaCaroline ZeimesBelgiumShannon ZenkUnited States of AmericaDale ZimmermanUnited States of America"}
+{"text": "Israel Journal of Health Policy Research would like to thank all reviewers, both external and Editorial Board Members, who have contributed to the journal in 2014, and whose valuable support continues to be essential to the success of the journal.The Editors of  David AbramsUnited States of AmericaLinda H AikenUnited States of AmericaMoty AmarIsraelGilhar AmosIsraelNachman AshIsraelIgor BarashIsraelOrna Baron-EpelIsraelIlana BelmakerIsraelNetta BenturIsraelBobbie BerkowitzUnited States of AmericaGabi Bin NunIsraelSue BognerUnited States of AmericaMalke BorowIsraelShuli Brammli-GreenbergIsraelMayer BrezisIsraelTimothy BrownUnited States of AmericaYeezkel CaineIsraelRonit Calderon-MargalitIsraelMichael ChaitonCanadaDavid ChinitzIsraelGabriel ChodickIsraelJeannie CimiottiUnited States of AmericaDaniel CohenIsraelMarc CohenUnited Arab EmiratesRobert CohenJordanNihaya DaoudIsraelAad de RooNetherlandsGordon DeFrieseUnited States of AmericaMarion DevauxFranceFrancois DionneCanadaMilka DonchinIsraelAvi DorUnited States of AmericaIsrael DoronIsraelErin DuPreeUnited States of AmericaEldad ElnekaveIsraelRuth EndacottUnited KingdomRonit EndeveltIsraelPaula Feder-BubisIsraelRoger FeldmanUnited States of AmericaAharon FinestoneIsraelShira FischerUnited States of AmericaSaralee GlasserIsraelShimon GlickIsraelMichael GordonCanadaDan GreenbergIsraelAlexander GrinshpoonIsraelRaz GrossIsraelItamar GrottoIsraelDror GubermanIsraelZiona HaklaiIsraelJonathan HalevyIsraelPinchas HalpernIsraelPaul HansenNew ZealandNaomi HausmanIsraelDavid HepnerUnited States of AmericaAndreas HoeftGermanyTuvia HorevIsraelJonathan HuppertIsraelDena JaffeIsraelMarcia JavittUnited States of AmericaJonathan JavittIsraelPatrick JeurissenNetherlandsNir KaidarIsraelOrit Karnieli-MillerIsraelVladimir KhanassovCanadaShmuel KlangIsraelEileen LakeUnited States of AmericaBruce LandonUnited States of AmericaLu\u00eds Lap\u00e3oPortugalLeonard LeiboviciIsraelGila LeiterUnited States of AmericaMoshe LeshnoIsraelHagai LevineIsraelOsnat Levtzion-KorachIsraelNoah Lewin-EpsteinIsraelRobert LikeUnited States of AmericaOrly ManorIsraelMartin McKeeUnited KingdomJacob MenczelIsraelTal MorginstinIsraelShlomo Mor-YosefIsraelGuy MundlakIsraelYaron MushkatIsraelLeanne Nanttais-SmithUnited States of AmericaYehuda NeumarkIsraelLiebermann NickyIsraelNurit NirelIsraelCharles NormandIrelandOra PaltielIsraelElyse ParkUnited States of AmericaL Gregory PawlsonUnited States of AmericaJoseph PliskinIsraelAvi PorathIsraelNosaiba RayanIsraelBrian ReichmanIsraelShmuel RishponIsraelDavid RoeIsraelAlvin RothUnited States of AmericaSiegal SadetzkiIsraelRichard SaltmanUnited States of AmericaJ\u00f6rg SchaaberGermanyStephen SchoenbaumUnited States of AmericaMichal SchusterIsraelEfrat ShadmiIsraelSigal Shafran -TikvaIsraelCarmel ShalevIsraelVarda ShalevIsraelSegev ShaniIsraelNathan ShapiroUnited States of AmericaYaniv ShererIsraelAmir ShmueliIsraelJudith ShuvalIsraelPierre SingerIsraelShepherd Roee SingerIsraelVarda SoskolneIsraelRuth StalnikowiczIsraelAvraham SteinbergIsraelTzipi StraussIsraelOrly TorenIsraelLori Uscher-PinesUnited States of AmericaWynand van de VenNetherlandsBaruch VelanIsraelShlomo VinkerIsraelCharles WeissmanIsraelRachel Wilf MironIsraelRaphael WittenbergUnited KingdomPnina ZadkaIsrael"}
+{"text": "Pathological changes in the maxillary sinus mucosae of patients with recurrent odontogenic maxillary sinusitis.This article titled \u201cPathological changes in the maxillary sinus mucosae of patients with recurrent odontogenic maxillary sinusitisShaukat Ali JawaidChief EditorPakistan Journal of Medical SciencesKarachi - Pakistan."}
+{"text": "Molecular Cancer would like to thank all the reviewers who contributed to the journal in Volume 13 (2014) by participating in the review process.The editors of The online version of this article (doi:10.1186/s12943-015-0308-2) contains supplementary material, which is available to authorized users. 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HoebenNetherlandsAndrea Hoelbl-KovacicAustriaAlexander HoelleinGermanyDavid HongUnited States of AmericaLiu HongChinaWanjin HongSingaporePeter HordijkNetherlandsWeihong HouUnited States of AmericaGillian HowellUnited States of AmericaSarah HowieUnited KingdomGuochang HuangUnited States of AmericaTony HuangUnited States of AmericaRobert HuebertUnited States of AmericaKam HuiSingaporeJoseph HumtsoeUnited States of AmericaKeun HurKorea SouthDouglas HurstUnited States of AmericaAntoni HurtadoNorwayR. 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States of AmericaSuresh MathivananAustraliaYasunobu MatsudaJordanIsao MatsuuraTaiwanMichelle MatterUnited States of AmericaRobert MattsUnited States of AmericaMassimiliano MazzoneBelgiumDennis McCanceUnited KingdomJohn McDonaldUnited States of AmericaKerrie McDonaldAustraliaDeclan McKennaUnited KingdomIain McNeishUnited KingdomBarbara MelendezSpainZhiqiang MengChinaLaura MercataliItalyJean-Louis MERLINFranceMarkus MetzlerGermanyAntimo MigliaccioItalyMatthew MillerUnited States of AmericaIan MillsNorwayTom MilneUnited KingdomToshinari MinamotoJapanNikica MiseGermanyAkira MiyajimaJapanSuzanne MiyamotoUnited States of AmericaYin-Yuan MoUnited States of AmericaBeverly MockUnited States of AmericaFaustino MollinedoSpainHugo MonteiroBrazilRodolfo MontironiItalyRichard MooreUnited States of AmericaHari Narayana MoorthyPortugalMark MorganUnited KingdomPat MorinUnited States of AmericaSharon Celeste MorleyUnited States of AmericaLaura MoroItalyDavid MorrisAustraliaFranck MortreuxFranceJustin MottUnited States of AmericaMirna Mourtada-MaarabouniUnited KingdomCaroline Moyret-LalleFranceLina MuUnited States of AmericaNaofumi MukaidaJapanHasan MukhtarUnited States of AmericaJames MullinUnited States of AmericaTeresita Munoz-AntoniaUnited States of AmericaJordi Muntan\u00e9SpainSatoshi MurataJapanSatu MustjokiFinlandJoe MymrykCanadaKarthikeyan MythreyeUnited States of AmericaErnest NadalUnited States of AmericaAlo NagIndiaSonia NajjarUnited States of AmericaHiroyasu NakanoJapanIchiro NakanoUnited States of AmericaHarikrishna NakshatriUnited States of AmericaKalyan NannuruUnited States of AmericaChristian NanoffAustriaHonami NaoraUnited States of AmericaAziza NassarUnited States of AmericaSathish kumar NatarajanUnited States of AmericaDirk M. NettelbeckGermanyJochen NeuhausGermanyDaniel NeureiterAustriaThu NguyenUnited States of AmericaBing NiChinaChristophe NicotUnited States of AmericaDouglas NoonanItalySusan NozellUnited States of AmericaGreg OakleyUnited States of AmericaEva ObermayrAustriaJosiah OchiengUnited States of AmericaTakahiro OchiyaJapanYoshinao OdaJapanKarin OechsleGermanyYukio OkanoJapanBarry O'KeefeUnited States of AmericaDenise O'KeefeUnited States of AmericaSoriani OlivierFranceGhislain OpdenakkerBelgiumV\u00e9ronique Orian-RousseauGermanyFrancisco Jos\u00e9 OrtegaSpainMajid OsmanSwedenLindsey OudijkNetherlandsJaya PadmanabhanUnited States of AmericaJihye PaikUnited States of AmericaJos\u00e9 PalaciosSpainTanapat PalagaThailandMoorthy Palanimuthu PonnusamyUnited States of AmericaSwati Palit DebUnited States of AmericaJoanna Pancewicz-WojtkiewiczPolandAtanasio PandiellaSpainCarlos PanizoSpainBenedict PanizzaAustraliaRenate Panzer-Gr\u00fcmayerAustriaMayra PaolilloItalyAnthony PapenfussAustraliaLuis A 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AmericaDeepa SampathUnited States of AmericaOltea SampetreanJapanDavid SantamariaSpainGiorgio SantoniItalyMassimo SantoroItalyTakashi SasayamaJapanFuminori SatiJapanShoko SatoJapanYuichiro SatoJapanNicholas SaundersAustraliaStefania ScalaItalyInga-Marie SchaeferGermanyLiliana SchaeferGermanyZachary SchaferUnited States of AmericaDaniela SchillingGermanyJohannes SchmidAustriaLaura SchmidtUnited States of AmericaGuenter SchneiderGermanySallie SchneiderUnited States of AmericaJohannes SchulteGermanyGregg SemenzaUnited States of AmericaShantibushan SenapatiIndiaPeter SenterUnited States of AmericaParthasarathy SeshacharyuluUnited States of AmericaClaudio SetteItalyMark ShackletonAustraliaKenneth ShainUnited States of AmericaAyesha Shajahan-HaqUnited States of AmericaRajesh SharanIndiaNima SharifiUnited States of AmericaDipali SharmaUnited States of AmericaHongbing ShenChinaLalita Shevde-SamantUnited States of AmericaHubing ShiUnited States of AmericaJian ShiUnited States of AmericaLei 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SpagnoliSwitzerlandRiccardo SpizzoItalySanjay K. SrivastavaUnited States of AmericaPeter StacpooleUnited States of AmericaOlle StalSwedenDaniel StarczynowskiUnited States of AmericaSandra SteffensGermanyUlrike SteinGermanyCarsten StephanGermanyUrsula StochajCanadaChristian StockGermanyDeborah StrokaSwitzerlandThorsten St\u00fchmerGermanyDwayne StupackUnited States of AmericaSaraswati SukumarUnited States of AmericaYan SunChinaLuyang sunChinaRobyn SutherlandAustraliaHiromu SuzukiJapanYoshihiro Suzuki-KarasakiJapanMikael SvenssonSwedenElda TagliabueItalyChiaki TakahashiJapanFuyuhiko TamanoiUnited States of AmericaPoh Seng TanSingaporeShinji TanakaJapanReshma TanejaSingaporeFaqing TangChinaTakanobu TaniguchiJapanHou-Quan TaoChinaMaria Angels Tapia-LalienaGermanyElisa TassanoItalyAda Maria TataItalyHussein TawbiUnited States of AmericaCormac TaylorIrelandKathryn TaylorUnited KingdomLuba TchertanovFrancePeter ten DijkeNetherlandsVinay TergaonkarSingaporeLuigi TerraccianoSwitzerlandStephane TerryFranceGeorge ThalmannSwitzerlandChristoforos ThomasUnited States of AmericaChenxi TianUnited States of AmericaRandal TibbettsUnited States of AmericaGregory TietjenUnited States of AmericaIngeborg TinhoferGermanyVerena Maria TischlerSwitzerlandDean TolanUnited States of AmericaIvan TopisirovicCanadaNobuyuki ToshikuniJapanSophie ToyaUnited States of AmericaMarianna TrakalaSpainMark TrifiroCanadaTudorita TumbarUnited States of AmericaMusaffe TunaUnited States of AmericaMasuko Ushio-FukaiUnited States of AmericaKatsuhiro UzawaJapanRemco van DoornNetherlandsMatthew Vander HeidenUnited States of AmericaPetr VanharaCzech RepublicFranz VargaAustriaSudhir VarmaUnited States of AmericaEdo VellengaNetherlandsPasquale VerdeItalyGyorgy VerebHungaryLars VereeckeBelgiumSuresh Kumar VermaUnited States of AmericaAlejandro VillagraUnited States of AmericaCarlo ViscoItalyRebecca VoltanItalyPeter VranaUnited States of AmericaPaul WadeUnited States of AmericaPat WadsworthUnited States of AmericaBridget WagnerUnited States of AmericaMatthew 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AmericaYadi WuUnited States of AmericaGuo XiaoboChinaKe XuChinaLiang XuUnited States of AmericaQilin XuUnited States of AmericaNagendra YadavaUnited States of AmericaNobuo YaegashiJapanRyuji YamaguchiJapanMunekazu YamakuchiJapanSoichiro YamamuraUnited States of AmericaMin YanUnited States of AmericaBurton YangCanadaJin-Ming YangUnited States of AmericaRuey-Bing YangTaiwanYong YangChinaYanan YangUnited States of AmericaHua YangChinaMing YangChinaYoung YangKorea SouthZeng-jie YangUnited States of AmericaJason YapUnited KingdomChueh-Chuan YenTaiwanVenkat Laxmi YeruvaUnited States of AmericaJunji YodoiJapanTakehiko YokoboriJapanTakashi YokotaJapanYukio YonedaJapanYoung YooKorea SouthGo YoshidaJapanKosuke YoshiharaJapanLiang YouUnited States of AmericaLawrence YoungUnited KingdomShi-cang YuChinaXiaozhong YuUnited States of AmericaZhang YuChinaZhong YunUnited States of AmericaPeter ZageUnited States of AmericaStefan ZahlerGermanyRoza ZakanyHungaryGerard ZambettiUnited States of AmericaHamid ZandIranMengwei ZangUnited States of AmericaGiorgio ZauliItalyJean-Claude ZenklusenUnited States of AmericaAnn ZeunerItalyJose ZevallosUnited States of AmericaDong-Er ZhangUnited States of AmericaJian-Ting ZhangUnited States of AmericaWei ZhangSingaporeWei ZhangUnited States of AmericaXu Dong ZhangAustraliaXiaohong ZhangUnited States of AmericaLingqiang ZhangChinaLin ZhangUnited States of AmericaWei ZhangChinaYongsheng ZhangChinaJianhua ZhangUnited States of AmericaZhiyong ZhangUnited States of AmericaChen ZhaoUnited States of AmericaLingyu ZhaoChinaZhihe ZhaoChinaJun-Nian ZhengChinaSuting ZhengUnited States of AmericaWenxin ZhengUnited States of AmericaMinghao ZhongUnited States of AmericaWeide ZhongChinaXiaomin ZhongChinaChunyan ZhouChinaJianwei ZhouChinaBinhua ZhouUnited States of AmericaYu-Dong ZhouUnited KingdomYi-Hong ZhouUnited States of AmericaYunli ZhouUnited States of AmericaQinbo ZhouUnited States of AmericaChangQi ZhuCanadaJay-Jiguang ZhuUnited States of AmericaWei-Guo ZhuChinaZhengping ZhuangUnited States of AmericaInti ZlobecSwitzerlandMassimo ZolloItalyWei-Xing ZongUnited States of America"}
+{"text": "The Editors of Theoretical Biology and Medical Modelling would like to thank all the Reviewers who have contributed to the journal in Volume 11 (2014). Paul AgutterUnited KingdomGary AnUnited States of AmericaAndrea ApolloniUnited KingdomNicolas BacaerFranceBo BaldetorpSwedenAmy BauerUnited States of AmericaDeepak BharkhadaUnited States of AmericaDonald BuerkUnited States of AmericaTed CarmichaelUnited States of AmericaNilay ChakrabortyUnited States of AmericaXiao ChangUnited States of AmericaHamidreza ChitsazUnited States of AmericaThanat ChookajornThailandGerardo ChowellUnited States of AmericaChaeshin ChuKorea, SouthJean ClairambaultFranceVittoria ColizzaFranceGiuseppe CollocaItalyMichel CostaBrazilGheorghe CraciunUnited States of AmericaDamian CraiemArgentinaMarc Antoine CustaudFrancePetr DanecekUnited KingdomKiranmoy DasUnited States of AmericaBo DingUnited States of AmericaYueping DongJapanIlaria DorigattiUnited KingdomMichael EdererGermanyKeisuke EjimaJapanGloria ElliottUnited States of AmericaHeiko EnderlingUnited States of AmericaIvo FoppaUnited States of AmericaHolly FreedmanCanadaMarc GarbeyUnited States of AmericaStephen GrandUnited States of AmericaXueying GuanUnited States of AmericaMohammed GueddaFranceShakti GuptaUnited States of AmericaKonstantin GurevichRussian FederationRobert G HahnSwedenUlrich HartmannGermanySereina HerzogAustriaAtsushi HijikataJapanYoshito HirataJapanSharon HoriUnited States of AmericaTingjun HouChinaTao HuangChinaMarcos IntagliettaUnited States of AmericaShuji IshiharaJapanCharles William JeffordSwitzerlandMilan JokanovicSerbiaAntonio JureticCroatiaIrina KarevaUnited States of AmericaRuian KeUnited States of AmericaClaude KrummenacherUnited States of AmericaOlga KrylovaCanadaChris LearyUnited States of AmericaMarie-Paule LefrancFranceHuan LeiUnited States of AmericaXuejin LiUnited States of AmericaZhengfei LuUnited States of AmericaFeilim Mac GabhannUnited States of AmericaDann MalletAustraliaNatalia Mantilla-BeniersMexicoPeter MazurUnited States of AmericaJames McCawAustraliaAttila MisetaHungaryTakashi MiuraJapanKenji MizumotoJapanShinji NakaokaJapanSatyaprakash NayakUnited States of AmericaHiroshi NishiuraJapanAe Nim PaeKorea, SouthKlot PatanarapeelertThailandMaria Angeles PerezSpainMarco PettiniFranceArkady PikovskyGermanyDavid ReganAustraliaXianwen RenChinaEdward RietmanUnited States of AmericaJean Rodolphe RocheFranceWagner Rodrigo WeinertBrazilLibin RongUnited States of AmericaKamlesh SahuCanadaMahdi SanatiUnited States of AmericaJean SandersUnited States of AmericaFumitoshi SatoJapanNick SavillUnited KingdomDaniel SchmidtAustraliaJan SchmoranzerGermanyJim SlatteryUnited KingdomGerhard SmekalAustriaSilvia SodduItalyWilliam SpillmanUnited States of AmericaAndreas SteingoetterSwitzerlandKaoru SugimuraJapanAkos SveiczerHungaryMichael TakazaIrelandJijun TangUnited States of AmericaDaniel TartakovskyUnited States of AmericaYu TengUnited States of AmericaDavid ThomasUnited States of AmericaTianhai TianAustraliaJack TuszynskiCanadaGert VerpootenBelgiumBOUARIFI WalidMoroccoGuanyu WangUnited States of AmericaZhilin WangChinaYaqun WangUnited States of AmericaTarynn WittenUnited States of AmericaSong WuUnited States of AmericaJianhong WuCanadaSi WuChinaDan XueChinaNaji YebariMoroccoYao YuUnited States of AmericaYongyuth YuthavongThailandTao ZhangChinaNi ZhaoUnited States of America"}
+{"text": "Human Genomics would like to thank all our reviewers who have contributed to the journal in volume 9 (2015).The Editors of  Luisa AzevedoPortugalChad BrockerUnited States of AmericaGeorgia CharkoftakiUnited States of AmericaZissis ChroneosUnited States of AmericaStephen CurryUnited States of AmericaDaniela Del GaudioUnited States of AmericaAndrew DewanUnited States of AmericaLynnette Robin FergusonNew ZealandKristofer FritzUnited States of AmericaChristos HatzisUnited States of AmericaXiu HuangUnited States of AmericaParaskevas IatropoulosItalyChee Seng KuSingaporePoh San LaiSingaporeTukiet LamUnited States of AmericaJun LiUnited States of AmericaBeata LipskaPolandXiaochuan LiuUnited States of AmericaJirong LongUnited States of AmericaQianyi MaUnited States of AmericaBrian MeyerSaudi ArabiaAndrew MonteUnited States of AmericaDaniel NebertUnited States of AmericaMichael NothnagelGermanyA. Bilge OzelUnited States of AmericaEric PasmantFranceGeorge PatrinosGreeceTzu Lip PhangUnited States of AmericaMichele RamsaySouth AfricaJuergen ReichardtEcuadorDaniela SaggioroItalyRobert ScheinmanUnited States of AmericaJadranka SerticCroatiaDavid SinclairUnited States of AmericaSurendra SinghUnited States of AmericaSumio SuganoJapanPeter TaschnerNetherlandsEleni TomazouAustriaJeffrey TownsendUnited States of AmericaPanagiotis A. TsonisUnited States of AmericaArgyrios TzouvelekisUnited States of AmericaNong Van HaiVietnamAthanassios VasilopoulosUnited States of AmericaAlkis VatopoulosGreeceCarsten WiufDenmarkTongbin WuUnited States of AmericaZheng XiaUnited States of AmericaFan XiuchengUnited States of AmericaShuhua XuChinaXiaoqing YuUnited States of AmericaYawei ZhangUnited States of AmericaGuojie ZhangChinaHongyu ZhaoUnited States of AmericaYong ZhuUnited States of America"}
+{"text": "The editors of Journal of Ovarian Research would like to thank all of our reviewers who have contributed to the journal in volume 6 (2013). Ronit AbirIsraelPedro Aci\u00e9nSpainRaffaele AddeoItalyLaurie AillesCanadaAyman Al-HendyUnited States of AmericaAdolfo AllegraItalyCarlo AlviggiItalyStavroula BakaGreeceShisan BaoAustraliaSharmila BapatIndiaAnimesh BaruaUnited States of AmericaSusan BellisUnited States of AmericaSinan BerkmanTurkeyDeepa BhartiyaIndiaMariusz BidzinskiPolandZachariah BobbyIndiaFernando Bonilla-MusolesSpainChinmoy BoseIndiaAndrew BradfordUnited States of AmericaPedro Caballero-CampoUnited States of AmericaValentina CasciniItalyNeeraj ChawlaIndiaRi-Cheng ChianCanadaNam Hoon ChoSouth KoreaFabrice CognasseFranceDenise ConnollyUnited States of AmericaShantanu DeshpandeIndiaLaura Diaz CuetoMexicoJacques DonnezBelgiumToshiaki EndoJapanJeong Min EomSouth KoreaAngela FalboItalyDavid FederBrazilLingda FengChinaGabriella FerrandinaItalyChristina FotopoulouUnited KingdomJohn FruehaufUnited States of AmericaNorbert GleicherUnited States of AmericaVictor GomelCanadaAngelique GoverdeNetherlandsJedrzejewski GrzegorzPolandIlknur GumusTurkeyTayfun GungorTurkeyHua GuoUnited States of AmericaDigant GuptaUnited States of AmericaMicah HillUnited States of AmericaRoy HomburgIsraelHeFeng HuangChinaKaisa HuhtinenFinlandKrishna JagarlamudiUnited States of AmericaVenkatakrishna JalaUnited States of AmericaKannamannadiar JayaprakasanUnited KingdomZe-Xu JiaoUnited States of AmericaJoshua JohnsonUnited States of AmericaZheng JunchChinaEvanthia KandarakisGreeceSelvendiran KaruppaiyahUnited States of AmericaHidetaka KatabuchiJapanNadeem KhanUnited States of AmericaTae Jin KimSouth KoreaYun Hwan KimSouth KoreaJunpei KimuraJapanEndre Kiss-TothUnited KingdomCarolyn KlingeUnited States of AmericaGulengul K\u00f6kenTurkeyIkuo KonishiJapanPamela KreegerUnited States of AmericaLydia KrieglArubaKuang-Tai KuoTaiwanMertihan KurdogluTurkeyHiroaki KuriharaJapanRobert J. KurmanUnited States of AmericaAntonio La MarcaItalyGiovanni Battista La SalaItalyJoseph LauUnited States of AmericaDavid LeeUnited States of AmericaJung Hun LeeSouth KoreaMarie-Claude LeveilleCanadaChang-Zhong LiChinaElaine LinUnited States of AmericaGen-Min LinTaiwanShanling LiuChinaFelicity LoseAustraliaEmilio LuciaItalyFernando Luiz Affonso FonsecaBrazilMohammad MalikUnited States of AmericaVincenzo Dario MandatoItalySantos Ma\u00f1esSpainUdo R. MarkertGermanyMaurie MarkmanUnited States of AmericaJohn MartignettiUnited States of AmericaAxel MethnerGermanyTakashi MinegishiJapanBruce MurphyCanadaDaniela MurtasItalyToyofumi NakaJapanKenneth NephewUnited States of AmericaCeana NezhatUnited States of AmericaPaul NguewaSpainGabriela M Oprea-IliesUnited States of AmericaFrancesco OrioItalyMakoto OrisakaJapanRaoul OrvietoIsraelShoji OuraJapanNuri OzturkUnited States of AmericaGiuseppina PadovaItalyLynn ParkerUnited States of AmericaDivya PatelUnited States of AmericaSushmita PathyIndiaGilberto Paz FilhoAustraliaTanja PejovicUnited States of AmericaChun PengCanadaTerhi PiltonenFinlandVito PistoiaItalyRicardo PommerChileRenaud PrudentFranceTilman RachnerGermanyMariusz RatajczakUnited States of AmericaMojtaba Rezazadeh ValojerdiIranTyvin A RichAmerican SamoaRodney RocconiUnited States of AmericaPeter RoseUnited States of AmericaRosaria RuggeriItalyNobuyuki SakuraiJapanBerna SeckinTurkeyEllora SenIndiaKok-Min SeowTaiwanFrancesco SestiItalyJohn Henry ShepherdUnited KingdomYuan-Wei ShihTaiwanMasayuki ShimadaJapanYimin ShuUnited States of AmericaArti ShuklaUnited States of AmericaElvio SilvaUnited States of AmericaAjay SinghUnited States of AmericaRajesh SinghUnited States of AmericaShailesh SinghUnited States of AmericaJohan SmitzBelgiumJanusz SolskiPolandHeidi SowterUnited KingdomClare StevinsonUnited KingdomColin StewartAustraliaNorihiro SuginoJapanYing SunUnited KingdomSuchinda TaepongsoratThailandPierosandro TagliaferriItalyRussell TaichmanUnited States of AmericaShailendra TamaskarIndiaHiroshi TamuraJapanDun-Xian TanUnited States of AmericaPremal ThakerUnited States of AmericaHoward H TingAustraliaFabian TrillschGermanyToshio TsubotaJapanAnne Van LangendoncktBelgiumJeffery VancemUnited KingdomBarbara VanderhydenCanadaDe Leo VincenzoItalyIrma Virant-KlunSloveniaRadu VladareanuRomaniaYinsheng WanUnited States of AmericaHe WangChinaHongmei WangChinaLiwei WangChinaWeihua WangUnited States of AmericaGerburg WulfUnited States of AmericaLei XiUnited States of AmericaXuefeng XiaUnited States of AmericaAli YavuzcanTurkeyHui YuChinaAlain ZeimetAustriaPumin ZhangUnited States of AmericaYe ZhangUnited States of AmericaChengquan ZhaoUnited States of AmericaLingjun ZhaoUnited States of AmericaMin ZhaoChinaZhi-Qing ZhaoUnited States of AmericaXiaodong ZhouUnited States of AmericaShien ZhuChinaStephanie C. ZiehrAustriaAnca ZimmermannGermanySurekha ZingdeIndiaFulvio ZulloItaly"}
+{"text": "Patient Safety in Surgery would like to thank all ourreviewers who have contributed to the journal in Volume 7 (2013).The Editors of  Mohamad AllafUnited States of AmericaRodrigo BanegasUnited States of AmericaArne BernerGermanyShay BessUnited States of AmericaJon BravermanUnited States of AmericaJonathan BravmanUnited States of AmericaEvalina BurgerUnited States of AmericaFranco CavaliereItalyTed ClarkeUnited States of AmericaChristoph EingartnerGermanyMats EkelundSwedenFederica FaggianUnited KingdomJohannes FaklerGermanyJoan FiguerasSpainMichael FlierlUnited States of AmericaMichael FrinkGermanyBeat GloorSwitzerlandDieter HahnloserSwitzerlandDavid HakUnited States of AmericaAmy HalversonUnited States of AmericaEric Mark HammerbergUnited States of AmericaKirk HoganUnited States of AmericaKyros IpaktchiUnited States of AmericaThilo JohnGermanyReto KaderliSwitzerlandEnes KanlicUnited States of AmericaJeffry KashukUnited States of AmericaStephen KatesUnited States of AmericaFernando KimUnited States of AmericaSenat KrasniciGermanyPhilipp LenzlingerSwitzerlandShalin MaheshwariIndiaLucas McCormackArgentinaTimothy MooreUnited States of AmericaJohn MukhopadhayaIndiaMatthias M\u00fcnzbergGermanyFrank MuscaraAustraliaGiuseppe NigriItalyLena NilssonSwedenHans OesternGermanyDipen ParekhUnited States of AmericaMarco PenalonzoGuatemalaJean-Claude RoujeauFranceEllen SarconeUnited States of AmericaDaniel ScheideggerSwitzerlandHagen SchmalGermanySamuel SmithUnited States of AmericaWade SmithUnited States of AmericaMartin StockmannGermanyRobert StovallUnited States of AmericaChun-Hao TsaiTaiwanTodd VanderHeidenUnited States of AmericaMichael VictoroffUnited States of AmericaCharles VincentUnited KingdomSebastian WeckbachUnited States of AmericaClement M.L. WernerSwitzerlandKathryn WitzemanUnited States of AmericaHeather YoungUnited States of AmericaGeorge YoungsonUnited Kingdom"}
+{"text": "Allergy, Asthma & Clinical Immunology would like to thank all of our reviewers who have contributed to the journal in Volume 10 (2014).The editors of  Rohan AmeratungaNew ZealandFrancesco AnnunziatoItalyMeghan AzadCanadaAllan BeckerCanadaStephen BetschelCanadaPatrizia BonadonnaItalyRobert BoyleUnited KingdomJohn BrannanAustraliaArnon BroidesIsraelHelen Annaruth BroughUnited KingdomGianfranco CalogiuriItalyMarilia CascalhoUnited States of AmericaZave ChadCanadaEdmond ChanCanadaTesfahun ChanieEthiopiaAnca Mirela ChiriacFranceAntonella CanferoniUnited States of AmericaDon CockcroftCanadaMichele ColumboUnited States of AmericaRobert CowieCanadaLinda CoxUnited States of AmericaTimothy CraigUnited States of AmericaAnahit DemirchyanArmeniaPascal DemolyFranceGabriele Di LorenzoItalyTony DuboisNetherlandsAudrey DunnGalvinIrelandAnne EllisCanadaMarion EspeliFranceBerrylin FergusonUnited States of AmericaJavier FernandezSpainKristian FilionCanadaCharles FrankishCanadaAnastasios GermenisGreeceRomain GherardiFrancePaul GreenbergerUnited States of AmericaMichelle HalbrichCanadaAgnes HamzaouiTunisiaKyla HildebrandCanadaTomomitsu HirotaJapanFriedrich HorakBahamasKomei ItoJapanRajashri Shuba IyengarUnited States of AmericaRobert JacobsUnited States of AmericaJudith S JacobsonUnited States of AmericaRhoda KaganCanadaSandeep KapurCanadaFotini KavadasCanadaPaul Kevin KeithCanadaHarold KimCanadaJiro KitauraJapanMarek KowalskiPolandRajesh KumarUnited States of AmericaJerold LastUnited States of AmericaIan LewkowichUnited States of AmericaPer LidmanCanadaPhil LiebermanUnited States of AmericaHilary LonghurstUnited KingdomScott LorchUnited States of AmericaKristian MacdonaldCanadaFlemming MadsenDenmarkSoheila MalekiUnited States of AmericaDavid MartinoAustraliaPaolo MatricardiItalyOsamu MatsunoJapanMarcus MaurerGermanyBruce MazerCanadaChristine McCuskerCanadaTreasure McGuireAustraliaPaul Michel MertesFranceDavid William MooteCanadaRalph M\u00f6sgesGermanyBing NiChinaAnna NoppSwedenKimihiro OkuboJapanJohn OppenheimerUnited States of AmericaCevdet \u00d6zdemirTurkeyCarmine ParianteUnited KingdomJonathan ParsonsUnited States of AmericaNiraj PatelUnited States of AmericaJaclyn QuirtCanadaAvner ReshefIsraelMercedes RinconUnited States of AmericaRachel RobisonUnited States of AmericaMonica Ruiz-GarciaUnited KingdomTakashi SaitoJapanRobert SchellenbergCanadaRalph ShapiroUnited States of AmericaPeter SmallCanadaDiana StafforiniUnited States of AmericaDonald StarkCanadaRuey SuCanadaGordon SussmanCanadaSusan TarloCanadaPeter VadasCanadaCynthia VisnessUnited States of AmericaGiovanna VitalitiItalyHarissios VliagoftisCanadaBrandie WalkerCanadaKong-Sang WanTaiwanMeng-Ting WangTaiwanSusan WasermanCanadaWade WatsonCanadaKatharine WoessnerUnited States of America"}
+{"text": "Journal of Hematology & Oncology would like to thank all our reviewers who have contributed to the journal in Volume 7 (2014).The editors of  Akintunde AkinleyeUnited States of AmericaRamon AlemanySpainVeerajalandhar AllareddyUnited States of AmericaLyndal AndersonAustraliaPeter AndersonUnited States of AmericaShunya ArariJapanDiego ArenasMexicoTomohiro AsaiJapanMichele BaccaraniItalyJonathan BackSwitzerlandElisabetta BaldiItalyFrederic BaronBelgiumDavid BartlettUnited States of AmericaAmer BeitinjanehUnited States of AmericaLeonidas BenetatosGreeceJackie BoultwoodUnited KingdomM Mitzi BrentaniBrazilHal BroxmeyerUnited States of AmericaDavide CalebiroGermanyDan CanaaniIsraelDaniel CatovskyUnited KingdomAngela ChanCanadaHong ChangCanadaAndy ChaseUnited KingdomGuoan ChenUnited States of AmericaMichelle Y.Q. ChenChinaYi-Bin ChenUnited States of AmericaSreenivasulu ChintalaUnited States of AmericaWilliam CS ChoHong KongDavid ChuiUnited States of AmericaMonika Cs\u00f3kaHungaryZoran CuligAustriaNico DantumaSwedenNaval DaverUnited States of AmericaGuido DavidBelgiumMarc De BraekeleerFranceSilvia DeaglioItalyJiusheng DengUnited States of AmericaHusheng DingUnited States of AmericaKenneth DorshkindUnited States of AmericaSinisa DovatUnited States of AmericaMadeleine DuvicUnited States of AmericaBrian DymockSingaporeAgnieszka Dzikiewicz-KrawczykPolandAndreas EisenreichGermanyMonica ElseUnited KingdomMonika EngelhardtGermanyFerry ALM EskensNetherlandsLucia FarinaItalyJay FoxUnited States of AmericaOta FuchsCzech RepublicHiroshi FukamachiJapanMuhammad FurqanUnited States of AmericaShou-Jiang GaoUnited States of AmericaEnrico GarattiniItalyValter GatteiItalyChristian GisselbrechtFranceDamjan GlavacSloveniaAlvaro GonzalezSpainFinn GreyUnited KingdomManuel GrezGermanyJohn GribbenUnited KingdomAihua GuChinaChunhua GuoUnited States of AmericaHans HaeckerUnited States of AmericaJames HagmanUnited States of AmericaHideo HarigaeJapanClaire HarrisonUnited KingdomDongmei HeChinaJeff HolstAustraliaMichael HsiaoTaiwanChung-Tsen HsuehUnited States of AmericaHe HuangChinaXiaojun HuangChinaSuming HuangUnited States of AmericaKam HUISingaporeJung-Jyh HungTaiwanMotoshi IchikawaJapanShinsuke IidaJapanMichael IttmannUnited States of AmericaTomoo IwakumaUnited States of AmericaYongping JiangUnited States of AmericaZhong JiangUnited States of AmericaZhenyu JuChinaHsueh-Fen JuanTaiwanTamar Juven-GershonIsraelDieter KabelitzGermanyBin KangUnited States of AmericaLyndal KearneyUnited KingdomSophia KhaldoyanidiUnited States of AmericaEvgeny KlyuchnikovGermanySergej KonoplevUnited States of AmericaGopal KunduIndiaAnn LaCasceUnited States of AmericaStephen LangabeerIrelandAlessandro LavianoItalyHillard LazarusUnited States of AmericaJohn LednickyUnited States of AmericaClaudia LengerkeSwitzerlandSirpa Lepp\u00e4FinlandVera LevinaUnited States of AmericaChengang LIUnited States of AmericaQiang LiUnited States of AmericaShaoguang LiUnited States of AmericaYangqiu LiChinaPatrick LinUnited States of AmericaKe LiuUnited States of AmericaWenyu LiuUnited States of AmericaJun LiuUnited States of AmericaPengyuan LiuUnited States of AmericaLuca Lo NigroItalyOlli LohiFinlandXiaolin LuoUnited States of AmericaNigel MackmanUnited States of AmericaDaichi MaedaJapanSaradhi MallampatiUnited States of AmericaSridhar ManiUnited States of AmericaFrancesco MannelliItalyJohn MascarenhasUnited States of AmericaKunio MatsumotoJapanHiromichi MatsushitaJapanAnna Rita MigliaccioUnited States of AmericaKen MillsUnited KingdomChang-Ki MinSouth KoreaZdravko MitrovicCroatiaYohei MiyagiJapanHelmout ModjtahediUnited KingdomL. Rhoda MolifeUnited KingdomAndrei MorozBrazilAlison MoskowitzUnited States of AmericaWalid MouradCanadaMarek MrazCzech RepublicHasan MukhtarUnited States of AmericaMarta MuzioItalyHideaki NakajimaJapanRyotaro NakamuraUnited States of AmericaDavid NaorIsraelJavier NavalSpainJiri NeuzilAustraliaSiok Bian NgSingaporeFrancesco NovelliItalySeiichi OkabeJapanLucy OsborneCanadaThomas PabstSwitzerlandChong-xian PanUnited States of AmericaSamir ParekhUnited States of AmericaJino ParkUnited States of AmericaWilliam ParkerUnited States of AmericaLouis PelusUnited States of AmericaArchibald PerkinsUnited States of AmericaIver PetersenGermanyJan Peveling-OberhagGermanyLinda PilarskiCanadaCharalampos PontikoglouGreeceLouise PurtonAustraliaRaju PusapatiUnited States of AmericaKaren RabinUnited States of AmericaJohn RadfordUnited KingdomJoseph RagazCanadaVK RajasekharUnited States of AmericaPavan Mahendra RavellaUnited States of AmericaRuibao RenUnited States of AmericaHugh ReyburnSpainAdam RichUnited States of AmericaIngo RingshausenUnited KingdomMarthe Rizk-RabinFranceMaria RizzoItalyPierre RohrlichFranceLuisa RomaoPortugalEmanuela RosatiItalyStefan Rose-JohnGermanyPatricia RousselleFranceJeffrey RubnitzUnited States of AmericaAhmad SafaUnited States of AmericaKuniaki SaitoJapanRalph SalloumUnited States of AmericaBrenda SandmaierUnited States of AmericaBipin SavaniUnited States of AmericaPeter SayeskiUnited States of AmericaTobias SchattonUnited States of AmericaUdo SchumacherGermanyHeidi SchwarzenbachGermanyKaren SeiterUnited States of AmericaCarmine SelleriItalyXiaojin ShaUnited States of AmericaBin ShanUnited States of AmericaMala ShanmugamUnited States of AmericaYukari ShirasugiJapanYongqian ShuChinaMitchell SmithUnited States of AmericaWenru SongUnited States of AmericaMichael SpinellaUnited States of AmericaEva SzegezdiIrelandShinichiro TakahashiJapanFumi Takahashi-YanagaJapanKazuhiro TamuraJapanCorrado TarellaItalyPierfrancesco TassoneItalyUgo TestaItalyKensei TobinaiJapanSanne ToninoNetherlandsJorg TostFranceIvo TouwNetherlandsMounir TrimecheTunisiaVolodymyr TryndyakUnited States of AmericaWilliam TseUnited States of AmericaDavid TulasneFranceJeffrey TynerUnited States of AmericaSusumu UchiyamaJapanAnke van den BergNetherlandsRosa VisoneItalyLydia VisserNetherlandsDonghai WangUnited States of AmericaKankan WangChinaQinhong WangUnited States of AmericaYu WangUnited States of AmericaErik WiemerNetherlandsJustin WongAustraliaBas WoutersNetherlandsKongming WuChinaJennifer WuUnited States of AmericaYan WuUnited States of AmericaDazhong XuUnited States of AmericaHui XuUnited States of AmericaMingjiang XuUnited States of AmericaXiang-Xi XuUnited States of AmericaZhen XUUnited States of AmericaXiao-Feng YangUnited States of AmericaJilong YangChinaSherry YangUnited States of AmericaB. Hilda YeUnited States of AmericaGo YoshidaJapanM. James YouUnited States of AmericaNadia ZaffaroniItalyApostolos ZaravinosSwedenAli ZarrinUnited States of AmericaHaiyan ZhaiUnited States of AmericaQing ZhangChinaSuping ZhangUnited States of AmericaHua ZhangChinaMingjun ZhangUnited States of AmericaDekuang ZhaoUnited States of AmericaMeng ZhaoUnited States of AmericaXiaohong ZhaoUnited States of AmericaXiaohong ZhengUnited States of AmericaMinghao ZhongUnited States of AmericaLiang ZhouUnited States of AmericaYong ZhouChinaPier Luigi ZinzaniItalyVassilis ZoumpourlisGreece"}
+{"text": "The Editors of Patient Safety in Surgery would like to thank all our reviewers who have contributed to the journal in Volume 8 (2014). Negar AhmadiCanadaEmma-Louise AvelingUnited KingdomFernando BaldyBrazilRodrigo BanegasUnited States of AmericaWilliam BerryUnited States of AmericaShay BessUnited States of AmericaWalter L. BifflUnited States of AmericaFrank BodeGermanyNathan ButlerUnited States of AmericaMark ChandlerUnited States of AmericaQi ChenUnited States of AmericaTed ClarkeUnited States of AmericaMuhammad Muzzammil EdhiPakistanVincent EustermanUnited States of AmericaJohannes FaklerGermanyJoan FiguerasSpainIngo FissGermanyMichael FlierlUnited States of AmericaCharles FoxUnited States of AmericaBeat GloorSwitzerlandDieter HahnloserSwitzerlandEric Mark HammerbergUnited States of AmericaJiandong HaoUnited States of AmericaMarkus Huber-LangGermanyKyros IpaktchiUnited States of AmericaRatna JohariIndiaJeffrey JohnsonUnited States of AmericaJeffry KashukUnited States of AmericaSebastian KatscherGermanyFernando KimUnited States of AmericaKodi KojimaBrazilChristian K. LacknerGermanySusan LadleyUnited States of AmericaPhilipp LenzlingerSwitzerlandShalin MaheshwariIndiaMatthias MajetschakUnited States of AmericaCyril MauffreyUnited States of AmericaHoward MillerUnited States of AmericaWilson MolinaUnited States of AmericaPhilipp MommsenGermanyJohn MukhopadhayaIndiaKenneth NeppleUnited States of AmericaJustin NewmanUnited States of AmericaGiuseppe NigriItalyLena NilssonSwedenAndrew RobsonUnited KingdomJames RuskinUnited States of AmericaStefan SauerlandGermanySamuel SmithUnited States of AmericaWade SmithUnited States of AmericaOlaf SuessGermanyPeter TeschendorfGermanyPer TrobischGermanyTodd VanderHeidenUnited States of AmericaMichael VictoroffUnited States of AmericaRobert WaltzUnited States of AmericaSebastian WeckbachUnited States of AmericaAllison WilliamsUnited States of AmericaHeather YoungUnited States of AmericaBruce ZiranUnited States of America"}
+{"text": "The editors of Neural Development would like to thank all the reviewers who have contributed to the journal in Volume 9 (2014). Clare BakerUnited KingdomLaure Bally-CuifFranceLinda BarlowUnited States of AmericaMartin BastmeyerGermanyRenata BastoFranceDavid BersonUnited States of AmericaFlorence BesseFrancePaola BovolentaSpainRobert BradleyUnited States of AmericaJean-Fran\u00e7ois BrunetFranceNoel BuckleyUnited KingdomFlorencia CavodeassiSpainFrederic CharronCanadaAlain ChedotalFranceMatthew ColonneseUnited States of AmericaHelen CooperAustraliaMichael CrairUnited States of AmericaIgor B DawidUnited States of AmericaLuca Della SantinaItalyClaude DesplanUnited States of AmericaRichard DorskyUnited States of AmericaWolfgang DrieverGermanyJudith S EisenUnited States of AmericaHeithem El-HodiriUnited States of AmericaKazuo EmotoJapanJohan EricsonSwedenJames FawcettUnited KingdomDonna FeketeUnited States of AmericaMarla FellerUnited States of AmericaMonica FolgueiraUnited KingdomTroy GhashghaeiUnited States of AmericaTom GlaserUnited States of AmericaCayetano GonzalezSpainRay GuilleryUnited KingdomVolker HartensteinUnited States of AmericaSamer HattarUnited States of AmericaEloisa HerreraSpainSimon HippenmeyerAustriaChristine HoltUnited KingdomAndrew HubermanUnited States of AmericaSuresh JesuthasanSingaporeRyoichiro KageyamaJapanHiroyuki KamiguchiJapanRaymond KellerUnited States of AmericaTim KennedyCanadaEunjoon KimKorea, SouthChristian KlaembtGermanyRuediger KleinGermanyAlex KolodkinUnited States of AmericaLawrence KromerUnited States of AmericaRonald K\u00fchnleinGermanyGuofa LiuUnited States of AmericaHernan Lopez-SchierGermanyLiqun LuoUnited States of AmericaGiuseppe LupoItalyDavid LyonsUnited KingdomDavid MillerUnited States of AmericaWilliam MoodyUnited States of AmericaDonald Francis NewgreenAustraliaLaurent NguyenBelgiumShigeo OkabeJapanHitoshi OkamotoJapanSuzanne ParadisUnited States of AmericaJuha PartanenFinlandGang PengChinaMuriel PerronFranceAndreas ProkopUnited KingdomPamela RaymondUnited States of AmericaSylvie RetauxFranceAnne RidleyUnited KingdomCarol SchuurmansCanadaNenad SestanUnited States of AmericaJane C SowdenUnited KingdomEsther StoeckliSwitzerlandGuy TearUnited KingdomKristin Tessmar-RaibleAustriaAndrew TomlinsonUnited States of AmericaEric TurnerUnited States of AmericaDavid Van VactorUnited States of AmericaFan WangUnited States of AmericaStephen WilsonUnited KingdomXiang YuChinaKai ZinnUnited States of AmericaKaren ZitoUnited States of AmericaMichael ZuberUnited States of America"}
+{"text": "The authors retract this article  followinThe online version of this article contains the full text of the retracted article as electronic supplementary material (Additional file"}
+{"text": "International Journal of Behavioral Nutrition and Physical Activity would like to thank all our reviewers who have contributed to the journal in Volume 12 (2015).The editors of  Adam WalshAustraliaAdrian CameronAustraliaAdrian DavisUnited KingdomAileen GrantUnited KingdomAlison CarverAustraliaAlison MillerUnited States of AmericaAlison VennAustraliaAllison WattsUnited States of AmericaAmanda BirnbaumUnited States of AmericaAmanda LeeAustraliaAmanda PattersonAustraliaAmanda StaianoUnited States of AmericaAmber VaughnUnited States of AmericaAmy McphersonCanadaAna BaylinUnited States of AmericaAnders Gr\u00f8ntvedDenmarkAndreas HoltermannDenmarkAndrew J AtkinUnited KingdomAndrew SpringerUnited States of AmericaAndy JonesUnited KingdomAngela DoninUnited KingdomAngeliki PapadakiUnited KingdomAnita Hurtig-WennlofSwedenAnne LoyenNetherlandsAnnemarie KosterNetherlandsAnnie AndersonUnited KingdomAnouk MiddelweerdNetherlandsAnthony OkelyAustraliaApril CarconeUnited States of AmericaApril Idalski CarconeUnited States of AmericaAsa TornbergSwedenAshley GearhardtUnited States of AmericaAstrid EtmanNetherlandsAustin BaldwinUnited States of AmericaBarbara AinsworthUnited States of AmericaBarbara FieseUnited States of AmericaBenedicte DeforcheBelgiumBenjamin GardnerUnited KingdomBente WoldNorwayBirgit Wallmann-SperlichGermanyBongers PeggyNetherlandsBrandon IrwinUnited States of AmericaBridget KellyAustraliaBronwyn ClarkAustraliaCallie BrownUnited States of AmericaCarlos MonterioBrazilCarol Byrd-BredbennerUnited States of AmericaCarol MaherAustraliaCatherine ChanCanadaCatherine DraperSouth AfricaCatherine PacquetAustraliaCatherine RussellAustraliaCatherine WoodsIrelandCatrine Tudor-LockeUnited States of AmericaCharlie FosterUnited KingdomChris RisselAustraliaChristine BlakeUnited States of AmericaChristine FeketeSwitzerlandCindy GrayUnited KingdomCiska HovingNetherlandsClaire BernaardsNetherlandsClaudia VadeboncoeurUnited KingdomColin GreavesUnited KingdomColin RehmUnited States of AmericaCorneel VandelanotteAustraliaDafna MeromAustraliaDan BornsteinUnited States of AmericaDana Lee OlstadAustraliaDane Van DomelenUnited States of AmericaDaniel AggioUnited KingdomDavid BerriganUnited States of AmericaDavid CavalloUnited States of AmericaDavid CrawfordAustraliaDavid DzewaltowskiUnited States of AmericaDavid LubansAustraliaDavid McminnUnited KingdomDebbe ThompsonUnited States of AmericaDebbie Ann LohMalaysiaDeborah KerrAustraliaDeirdre HarringtonUnited KingdomDelfien Van DyckBelgiumDiane EhlersUnited States of AmericaDiane JacksonUnited KingdomDianne WardUnited States of AmericaDori RosenbergUnited States of AmericaDorota ZarnowieckiAustraliaDorus GeversNetherlandsDuncan MacfarlaneHong KongEdward CoffieldUnited States of AmericaElin JohanssonSwedenElissa JelalianUnited States of AmericaElizabeth EakinAustraliaElling BereNorwayEmily KotheAustraliaEmma BoylandUnited KingdomEmma CoombesUnited KingdomEmma FosterUnited KingdomEmma LeaAustraliaEmma ThomasUnited KingdomEnrique Garcia BengoecheaCanadaEric SticeUnited States of AmericaEric WickelUnited States of AmericaErica HincksonNew ZealandErica JamesAustraliaErica L. 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HartmanUnited States of AmericaMarjolein VisserNetherlandsMarjorie FreedmanUnited States of AmericaMark HamerUnited KingdomMarla ReicksUnited States of AmericaMatthew BumanUnited States of AmericaMeg brueningUnited States of AmericaMegan JarmanCanadaMegan RolloAustraliaMegan TeychenneAustraliaMegan TeychenneAustraliaMeizi HeUnited States of AmericaMelanie HingleUnited States of AmericaMelanie HingleUnited States of AmericaMelanie HingleUnited States of AmericaMelinda HutchessonAustraliaMelissa HorningUnited States of AmericaMelvyn HillsdonUnited KingdomMelvyn HillsdonUnited KingdomMelvyn HillsdonUnited KingdomMelvyn HillsdonUnited KingdomMelvyn HillsdonUnited KingdomMinKyoung SongUnited States of AmericaMinna AittasaloFinlandMinna AittasaloFinlandMitch J DuncanAustraliaMoira DeanUnited KingdomNana AnokyeUnited KingdomNanna LienNorwayNanna LienNorwayNanna LienNorwayNanna LienNorwayNanna LienNorwayNatalie PearsonUnited KingdomNatalie PearsonUnited KingdomNatalie PearsonUnited KingdomNatalie PearsonUnited KingdomNicholas GilsonAustraliaNicola Diane RidgersAustraliaNicola RidgersAustraliaNicola RidgersAustraliaNicole LarsonUnited States of AmericaNiko KacirotiUnited States of AmericaNiko KacirotiUnited States of AmericaNiko KacirotiUnited States of AmericaNiko KacirotiUnited States of AmericaNiko KacirotiUnited States of AmericaNiko KacirotiUnited States of AmericaNoe CrespoUnited States of America\u00d6rjan EkblomSweden\u00d6rjan EkblomSwedenPatricia HagemanUnited States of AmericaPatricia HagemanUnited States of AmericaPatricia HagemanUnited States of AmericaPatrick BergmanSwedenPatti-Jean NaylorCanadaPatti-Jean NaylorCanadaPaul FuglestadUnited States of AmericaPaul GardinerAustraliaPaul KellyUnited KingdomPaul LoprinziUnited States of AmericaPauliina HusuFinlandPaulina NowickaSwedenPauline JansenNetherlandsPedro TeixeiraPortugalPedro TeixeiraPortugalPedro TeixeiraPortugalPeter HannanUnited States of AmericaPeter HannanUnited States of AmericaPeter KatzmarzykUnited States of AmericaPhilip BakerAustraliaPhilip TropedUnited States of AmericaPrachi BhatnagarUnited KingdomRachel PecheyUnited KingdomRalph MaddisonNew ZealandRalph MaddisonNew ZealandRalph MaddisonNew ZealandRalph MaddisonNew ZealandRebecca GolleyAustraliaRebecca LeechAustraliaRebecca LeechAustraliaRebecca LeechAustraliaRebecca WyseAustraliaRichard G. PrinsNetherlandsRichard G. PrinsNetherlandsRichard G. PrinsNetherlandsRichard LaroucheCanadaRichard MitchellUnited KingdomRichard RosenkranzUnited States of AmericaRichard RosenkranzUnited States of AmericaRichard RosenkranzUnited States of AmericaRichard RosenkranzUnited States of AmericaRichard TroianoUnited States of AmericaRobert W. JefferyUnited States of AmericaRobert W. JefferyUnited States of AmericaRobert W. JefferyUnited States of AmericaRobert W. JefferyUnited States of AmericaRobin CallisterAustraliaRobin CallisterAustraliaRobin MelleckerHong KongRonald PlotnikoffAustraliaRonald PlotnikoffAustraliaRonald PlotnikoffAustraliaRuth HunterUnited KingdomRuth KippingUnited KingdomRuth MabryOmanRuth MabryOmanRuth MabryOmanRuth MabryOmanRyan RhodesCanadaRyan RhodesCanadaSally Akarolo-AnthonyUnited States of AmericaSally MackayNew ZealandSandar Tin TinNew ZealandSandar Tin TinNew ZealandSandra MandicNew ZealandSandy SlaterUnited States of AmericaSandy SlaterUnited States of AmericaSanford DeVoeCanadaSanne GerardsNetherlandsSanne GerardsNetherlandsSarah Kozey KeadleUnited States of AmericaSarah McnaughtonAustraliaSarah McNaughtonAustraliaScott DuncanNew ZealandScott DuncanNew ZealandScott DuncanNew ZealandScott DuncanNew ZealandScott DuncanNew ZealandScott DuncanNew ZealandScott DuncanNew ZealandScott DuncanNew ZealandSebastien ChastinUnited KingdomSebastien ChastinUnited KingdomShayla HolubUnited States of AmericaShayla HolubUnited States of AmericaSheryl HughesUnited States of AmericaShigeru InoueJapanShigeru InoueJapanShigeru InoueJapanShufa DuUnited States of AmericaShufa DuUnited States of AmericaShufa DuUnited States of AmericaShufa DuUnited States of AmericaShufa DuUnited States of AmericaShufa DuUnited States of AmericaShufa DuUnited States of AmericaShufa DuUnited States of AmericaShufa DuUnited States of AmericaShufa DuUnited States of AmericaShufa DuUnited States of AmericaSibylle KranzUnited KingdomSibylle KranzUnited KingdomSimon SebireUnited KingdomSimon SebireUnited KingdomSimon SebireUnited KingdomSimone DohleGermanySimone DohleGermanySimone DohleGermanySimone DohleGermanySimone PettigrewAustraliaSonja KahlmeierSwitzerlandStef KremersNetherlandsStef KremersNetherlandsStefanie VandevijvereNew ZealandStefanie VandevijvereNew ZealandStephanie ChambersUnited KingdomStephanie SchoeppeAustraliaStephanie SchoeppeAustraliaStephenie LemonUnited States of AmericaSteve HerrmannUnited States of AmericaStuart BiddleAustraliaStuart BiddleAustraliaStuart BiddleAustraliaStuart BiddleAustraliaStuart BiddleAustraliaStuart BiddleAustraliaStuart BiddleAustraliaStuart BiddleAustraliaStuart BiddleAustraliaStuart BiddleAustraliaStuart FaircloughUnited KingdomSusan CarnellUnited States of AmericaSusan CarnellUnited States of AmericaSusan CarnellUnited States of AmericaSusan HandyUnited States of AmericaSusan PaxtonAustraliaSusan SladeAustraliaSusan SladeAustraliaSuzanna ForwoodUnited KingdomSuzanne Domel BaxterUnited States of AmericaSuzanne Domel BaxterUnited States of AmericaSylvia TitzeAustriaSylvia TitzeAustriaSylvia TitzeAustriaSylvia TitzeAustriaTamara BucherAustraliaTamara BucherAustraliaTamara BucherAustraliaTamara BucherAustraliaTamara BucherAustraliaTanya BerryCanadaTeatske AltenburgNetherlandsTeresia O'ConnorUnited States of AmericaTeresia O'ConnorUnited States of AmericaThomas PowerUnited States of AmericaThomas PowerUnited States of AmericaThomas PowerUnited States of AmericaThomas PowerUnited States of AmericaThomas PowerUnited States of AmericaTiago BarreiraUnited States of AmericaTom BaranowskiUnited States of AmericaTom BaranowskiUnited States of AmericaTom BaranowskiUnited States of AmericaTom BaranowskiUnited States of AmericaTom BaranowskiUnited States of AmericaTracy Kolbe-AlexanderAustraliaTracy RichmondUnited States of AmericaTrina HinkleyAustraliaTrinidad QuizanMexicoTuija TammelinFinlandTzu-An ChenUnited States of AmericaVera StormGermanyVictor VianaPortugalVirginia QuickUnited States of AmericaWendy Van LippeveldeBelgiumWendy Van LippeveldeBelgiumWendy Van LippeveldeBelgiumWim GrootenSwedenxiaoli chenUnited States of AmericaYang LiuFinlandYang LiuFinlandYoungwon KimUnited KingdomZan GaoUnited States of AmericaZan GaoUnited States of AmericaZewditu DemissieUnited States of America"}
+{"text": "Neural Development would like to thank all the reviewers who have contributed to the journal in Volume 10 (2015).The editors of  Richard AdamsUnited KingdomChristine AurichAustriaClare BakerUnited KingdomAnthony BarnesUnited States of AmericaMarie-Laure BaudetItalyEric BellefroidBelgiumOlivia Bermingham-McdonoghUnited States of AmericaFlorence BesseFranceHolger BielenUnited KingdomSandra BlaessGermanyPaola BovolentaSpainAndrea BrandUnited KingdomSusan BrockerhoffUnited States of AmericaJean-Francois BrunetFranceFlorencia CavodeassiSpainChieh ChangUnited States of AmericaZhe ChenUnited States of AmericaAjay ChitnisUnited States of AmericaHollis ClineUnited States of AmericaHelen CooperAustraliaDavid CopenhagenUnited States of AmericaRobin DavisUnited States of AmericaChristopher DeppmannUnited States of AmericaChris DoeUnited States of AmericaRichard DorskyUnited States of AmericaKazuo EmotoJapanEdward GinigerUnited States of AmericaTom GlaserUnited States of AmericaPhillip Gordon-WeeksUnited KingdomYukiko GotohJapanElizabeth Ann GroveUnited States of AmericaFrancois GuillemotUnited KingdomKurt HaasCanadaMark HankinsUnited KingdomYi-Ping HsuehTaiwan, Republic of ChinaLilia IakouchevaUnited States of AmericaHiroyuki KamiguchiJapanKarl KandlerUnited States of AmericaArtur KaniaCanadaTim KennedyCanadaDaniel KerschensteinerUnited States of AmericaLawrence KromerUnited States of AmericaRaj LadherIndiaCheng-Yu LeeUnited States of AmericaJames LiUnited States of AmericaRick LiveseyUnited KingdomHernan Lopez-SchierGermanyXiaowei LuUnited States of AmericaErik LundquistUnited States of AmericaLe MaUnited States of AmericaRyan MacdonaldUnited KingdomJeremy NathansUnited States of AmericaKevin ParkUnited States of AmericaMuriel PerronFranceStephen PriceUnited KingdomJonathan RaperUnited States of AmericaAnne RidleyUnited KingdomJean-Yves RoignantGermanyDavid RowitchUnited States of AmericaDietmar SchmuckerBelgiumCarol SchuurmansCanadaJerry SilverUnited States of AmericaPatrice SmithUnited KingdomDavid SoleckiUnited States of AmericaFlorentina SotoUnited States of AmericaKristin Tessmar-RaibleAustriaDavid Van VactorUnited States of AmericaWei WeiUnited States of AmericaDonna WhitlonUnited States of AmericaHynek WichterleUnited States of AmericaMiles WilkinsonUnited States of AmericaKevin WrightUnited States of AmericaFengwei YuSingaporeChun-Li ZhangUnited States of AmericaKai ZinnUnited States of America"}
+{"text": "Reproductive Health would like to extend a sincere thank you to all our valued reviewers listed below who contributed to the journal in Volume 11 (2014). The journal has grown 63% in submissions and 43% in publications compared to 2013 and therefore the co-operation and dedicated time of peer reviewers is increasingly essential in order to move these manuscripts through the submission system so high quality research does not remain static and unpublished. We are very pleased to have a diverse range of reviewers from high, middle and low income countries, contributing to the dissemination of research findings in an open access journal. Please accept our sincerest and deepest thanks for your knowledge, time and continuing efforts.The editors of  Aniekan AbasiattaiNigeriaShelly Natasha AbdoolPanamaSileshi Garoma AbeyaEthiopiaSuniti AcharyaNepalIshag AdamSudanSusan AdamchakUnited States of AmericaRichard AdanuGhanaRamesh AdhikariNepalSohail AghaUnited States of AmericaTahera AhmedBangladeshAdetoun AkinwusiNigeriaNazmul AlamCanadaHesham Al-InanyEgyptAvni AminSwitzerlandIrene Andia-BiraroUgandaAugustine AnkomahGhanaBao-Yi AnnTaiwanMudassir AnwarMalaysiaLaura ArbourCanadaAntenah AsefaEthiopiaHussen Mekonnen AsfawEthiopiaIan AskewKenyaShervin AssariUnited States of AmericaBerhanemeskel AtsbehaEthiopiaJos\u00e9 AyresBrazilStella BabalolaUnited States of AmericaRebecca BaileyUnited States of AmericaRobert BaileyUnited States of AmericaAriel BardachArgentinaAlka BaruaIndiaAngela M BayerUnited States of AmericaFatemeh BazarganipourIranRachel BeanlandUnited KingdomMrutyunjaya BelladIndiaRegina BenevidesUnited States of AmericaPeter BjerregaardDenmarkAlemayehu BogaleEthiopiaStephan BrennerGermanyIracema MP CalderonBrazilChristopher CarrollUnited KingdomJanet CatovUnited States of AmericaFrancesca CavallaroUnited KingdomVenkatraman Chandra-MouliSwitzerlandCollins ChansaZambiaSubidita ChaterjeeIndiaDafang ChenChinaAmsale CherieEthiopiaZ. Mike ChirenjeZimbabweTim ColbournUnited KingdomSelby ConradUnited States of AmericaDeborah ConstantSouth AfricaDiane CooperSouth AfricaDivanise CorreiaBrazilVanessa DaltonUnited States of AmericaEugene Kofuor Maafo DartehGhanaAnindita DasguptaUnited States of AmericaDaniel DatikoEthiopiaNancy DayUnited States of AmericaCaroline de CostaAustraliaKorrie de KoningNetherlandsGurmesa Tura DebelewEthiopiaPeter DecatBelgiumKebede DeribeEthiopiaClaudia Diaz OlavarrietaMexicoNagasa DidaEthiopiaMartha DirnfeldIsraelMai DoUnited States of AmericaAmol DongreIndiaMelba D'SouzaOmanPutu DuffCanadaJill DurocherUnited States of AmericaShahul EbrahimUnited States of AmericaAnke EhrhardtUnited States of AmericaOmaima El-GibalyEgyptCherrie Lynn EvansUnited States of AmericaAlexandre Faisal-CuryBrazilCristina FaludiRomaniaWael FayekEgyptXing Lin FengChinaSonia Fernandez-BalbuenaSpainTamara FettersUnited States of AmericaSarah Finocchario KesslerUnited States of AmericaVirginia FonnerUnited States of AmericaEdward FottrellUnited KingdomTine GammeltoftDenmarkKaberi GayenBangladeshAbebaw GebeyehuEthiopiaSamson GebremedhinEthiopiaKasiye GemechuEthiopiaLindsey GottschalkUnited States of AmericaDana GreesonUnited States of AmericaSorina Grisaru-GranovskyIsraelNermin G\u00fcrhanTurkeyEshetu GurmuEthiopiaJuan Pablo GutierrezMexicoRandi HagermanUnited States of AmericaDemewoz HaileEthiopiaTsegazeab HailuEthiopiaKarin HammarbergAustraliaKarin HannesBelgiumJane HarriesSouth AfricaEmily HarvilleUnited States of AmericaLisa HirschhornUnited States of AmericaSarah Jane HolcombeUnited States of AmericaCaroline HomerAustraliaAndrea HoopesUnited States of AmericaSennen HountonUnited States of AmericaJustine HsuSwitzerlandLawrence IkamariKenyaChimaraoke IzugbaraNigeriaMeenakshi JainIndiaVictoria JenningsUnited States of AmericaMarianne JohanssonSwedenNiels J\u00f8rgensenDenmarkAllen KabagenyiUgandaHumayun KabirBangladeshFatch Welcome KalemboChinaGizat Molla KassieSwazilandLeila KatzBrazilDan KayeUgandaMethod KazauraTanzaniaCarl KendallUnited States of AmericaAmna KhanPakistanTahir KhanMalaysiaCharles KiggunduUgandaMary KinneySouth AfricaKerri KissellUnited States of AmericaKim KleinNetherlandsMarion Koso-ThomasUnited States of AmericaChen-I KuanTaiwanLucy KululangaMalawiKelly KuoUnited States of AmericaBetty KwagalaUgandaAmos LaarGhanaMalinee LaopaiboonThailandDennis LaryeaGhanaMaria LealBrazilElena LebetkinUnited States of AmericaJami LeichliterUnited States of AmericaKelly L'EngleUnited States of AmericaChristine LeynsBelgiumWilson LiambilaKenyaYang Chu LinTaiwanNancy LiuUnited States of AmericaAlejandra Lopez G\u00f3mezUruguayIsabelle LorraineUnited KingdomMona LoutfyCanadaKizito LubanoKenyaFernando Luiz Affonso FonsecaBrazilRebecka LundgrenUnited States of AmericaCourtney LynchUnited States of AmericaPatricia MachawiraSouth AfricaMoke MagomaTanzaniaJennifer MalinowskiUnited States of AmericaMats MalqvistSwedenJacob R.S. MalungoZambiaDonald MarazzoUnited States of AmericaRoberto MarciItalyMelisa Mart\u00ednez \u00c1lvarezUnited KingdomWellington MartinsBrazilAnthony MassindeTanzaniaRooyen MavenyengwaNamibiaMichael MbizvoSwitzerlandElizabeth McClureUnited States of AmericaSarah McDonaldCanadaTamara MelnikBrazilTesfaye MengistuEthiopiaPhilippe MervielFranceVildan MevsimTurkeyKim MillerUnited States of AmericaSamuel MillsUnited States of AmericaAbdurahman MohammedEthiopiaLamiya MohiyiddeenUnited KingdomBen MolAfghanistanAllisyn MoranUnited States of AmericaMahmood MorshediUnited States of AmericaEduardo MottaBrazilCheryl MoyerUnited States of AmericaElias MpofuAustraliaProjestine MuganyiziTanzaniaPeter MukasaUgandaSunni MumfordUnited States of AmericaEunice MuthengiKenyaSandra Nakic RadosCroatiaPriya NandaIndiaAhmed NasrEgyptMercy NassaliBangladeshErnest NgHong KongStella Maris NicolauBrazilDabere NigatuEthiopiaFrancis ObareKenyaZeliha \u00d6cekTurkeyJon OyvindNorwayKanayo OgujiubaNigeriaEkechi OkerekeNigeriaPius OkongUgandaSamuel OlowookereNigeriaAlfred OsotiKenyaEasmon OtupiriGhanaCarter OwenUnited States of AmericaOzlem OzdegirmenciTurkeyAllison PackUnited States of AmericaKatalin PappHungaryJohn ParkUnited States of AmericaSheila PatelUnited States of AmericaMandira PaulSwedenJoana PauletaPortugalErin PearsonUnited States of AmericaBrennan PetersonUnited States of AmericaKaren PhillipsCanadaCarrie PurcellUnited KingdomAnisur RahmanBangladeshSalima RahmanBangladeshSunanda RayZimbabweKrishna RegmiUnited KingdomOlivia RemesCanadaJennifer RequejoUnited States of AmericaNarjis RizviPakistanHelen RockliffUnited KingdomNicolette RomanSouth AfricaLori RossCanadaSarah SaleemPakistanA Sathiya SusumanSouth AfricaRebecca SchlaffUnited States of AmericaAbdulbasit SeidEthiopiaSalaam SemaanUnited States of AmericaAgumasie SemahegnEthiopiaArgentina ServinUnited States of AmericaBat Zion ShacharUnited States of AmericaIqbal ShahSwitzerlandBabar Tasneem ShaikhPakistanGerald ShambiraZimbabweLing ShiUnited States of AmericaOluwafolahan SholeyeNigeriaBinjwala ShresthaNepalEstelle Monique SidzeKenyaCharalambos SiristatidisGreeceDragan SoldoCroatiaAndrea Solnes MiltenburgNetherlandsIlene SpeizerUnited States of AmericaJoar SvanemyrSwitzerlandMonica TarceaRomaniaDessalegn TessoEthiopiaNarbada ThapaNepalTizta TilahunEthiopiaFarhan TirmiziPakistanMaria Regina ToloiBrazilMaria Regina TorloniBrazilCheryl VamosUnited States of AmericaCarolina VieiraBrazilJohn VincePapua New GuineaFernando VolpeBrazilJennifer WagmanUnited States of AmericaBobby WebsterUnited States of AmericaMary Nell WegnerUnited States of AmericaMaxine WhittakerAustraliaMandika WijeyaratneSri LankaErin WolffUnited States of AmericaKapil YadavIndiaHakan YaraliTurkeyEngida YismaEthiopiaMezgebu YitayalEthiopiaJun YoshinagaJapanShehla ZaidiPakistanSanjay ZodpeyIndia"}
+{"text": "In the closing plenary lecture, Prof Peter Horby describes the challenges of conducting clinical trials in emergency settings."}
+{"text": "Journal of Ovarian Research would like to thank all of our reviewers who have contributed to the journal in Volume 7 (2014).The editors of  Abban-Mete G\u00fclcinTurkeyAlviggi CarloItalyAmorim ChristianiBelgiumAngioli RobertoItalyAnschau FernandoBrazilArcher GaryUnited States of AmericaArgenta PeterUnited States of AmericaArisan Elif DamlaTurkeyAydin YusufTurkeyBaka StavroulaGreeceBao ShisanAustraliaBarbolina MariaUnited States of AmericaBarua AnimeshUnited States of AmericaBashiri AsherIsraelBast RobertUnited States of AmericaBellis SusanUnited States of AmericaBermudez YiraUnited States of AmericaBevilacqua EstelaBrazilBhartiya DeepaIndiaBidzinski MariuszPolandBosenberg MarcusBrazilBranchini GiseleBrazilBukovsky AntoninCzech RepublicB\u00fcldt GeorgGermanyBuxton DavidUnited States of AmericaCannon MarkUnited States of AmericaCao CongChinaCapodanno FrancescoItalyCatteau-Jonard SophieFranceCecconi SandraItalyCedar Marcelle I.United States of AmericaCheema BirinderAustraliaChen ShuoChinaChen Mei-jouTaiwanChian Ri-ChengCanadaChristenson LaneUnited States of AmericaChristman GregoryUnited States of AmericaChudecka-Glaz AnitaPolandCognasse FabriceFranceConstantinou PamelaUnited States of AmericaCorleta HelenaBrazilCosar EmineTurkeyDahan MichaelCanadaDane BanuTurkeyDavis John S.United States of AmericaDe Leo VincenzoItalyDiFeo AnalisaUnited States of AmericaDonnez JacquesBelgiumDorsett Martin Wanda AAmerican SamoaDowns StephenUnited States of AmericaDursun PolatTurkeyEckstein NielsGermanyEmoto MakotoJapanEr Tze KiongTaiwanErcan Cihangir MutluTurkeyEvans AcoIrelandFainzilber MikeIranFalbo AngelaItalyFeng LingdaChinaFerrari RenataBrazilFiorillo LuciaItalyFolgueira Maria Aparecida A KoikeBrazilFoster WarrenCanadaFurlong FionaUnited KingdomGarcia AngelSpainGarcia KaraUnited States of AmericaGeller MelissaUnited States of AmericaGenazzani AlessandroItalyGeorgopoulos NeoklisGreeceGhezzi FabioItalyGoel PoonamIndiaGokce CumaliTurkeyGomez RaulSpainGrabowski AndrzejPolandGu JianrenChinaGuedes AlexisBrazilGungor TayfunTurkeyGuo HuaUnited States of AmericaGupta DigantUnited States of AmericaHan GenchengChinaHashizume KazuyoshiJapanHawkridge AdamUnited States of AmericaHayashi MasahiroUnited States of AmericaHiraike OsamuJapanHohenstein PeterUnited KingdomHomburg RoyIsraelHovatta OutiSwedenHsu Ming-ITaiwanHua JinlianChinaHuang HeFengChinaHuhtinen KaisaFinlandHumaidan PeterDenmarkHuntsman DavidCanadaIavazzo ChristosGreeceIrving-Rodgers HelenAustraliaIsidoro CiroItalyJana BarbaraPolandJiang ZhongliChinaJiao Ze-XuUnited States of AmericaJindal SangitaUnited States of AmericaJohnson JoshuaUnited States of AmericaKakar ShamUnited States of AmericaKantara CarlaUnited States of AmericaKar SujataIndiaKarpf AdamUnited States of AmericaKaruppaiyah SelvendiranUnited States of AmericaKatabuchi HidetakaJapanKatiyar SantoshUnited States of AmericaKenigsberg ShlomitCanadaKim Won HoSouth KoreaKim Yun HwanSouth KoreaKim Tae JoongSouth KoreaKiss-Toth EndreUnited KingdomKnapp PawelPolandKobayashi HiroshiJapanKoumarianou AnnaGreeceKrause DianeUnited States of AmericaKreeger PamelaUnited States of AmericaKrzysztof SzylloPolandKucukgoz Gulec UmranTurkeyKumaramanickavel GovindasamyIndiaKurihara HiroakiJapanKushnir VitalyUnited States of AmericaKyritsis AthanassiosGreeceLa Sala Giovanni BattistaItalyLe TienCanadaLeader ArthurCanadaLedger WilliamAustraliaLee Keun HoSouth KoreaLevy TallyIsraelLi XuelianChinaLim CarolUnited States of AmericaLipay MonicaBrazilLiu PingChinaMa JinfengChinaMachado Santelli Glaucia MBrazilMaggio da Fonseca AngelaBrazilMahner SvenGermanyMandato Vincenzo DarioItalyMandel (molinas) NilTurkeyMariani LucianoItalyMarkman MaurieUnited States of AmericaMarkowska JaninaPolandMasters SethAustraliaMateizel IleanaBelgiumMatos Maria HelenaBrazilMayer BarbaraGermanyMeng RyanChinaMes-Masson Anne-MarieCanadaMessinis IoannisGreeceMinegishi TakashiJapanMitchell GillianAustraliaMiyano TakashiJapanMoncef BenkhalifaFranceMoreno BarbItalyMorgante GiuseppeItalyMurphy BruceCanadaMuscogiuri GiovannaItalyNakamura YasuhikoJapanNam Joo-HyunSouth KoreaNassir ManiGermanyNg ErnestHong KongNicoli AlessiaItalyNilsson EricUnited States of AmericaOhmichi MasahideJapanOkada KiyoshiJapanOprea-Ilies Gabriela MUnited States of AmericaOrio FrancescoItalyOrisaka MakotoJapanOrvieto RaoulIsraelOsuga YutakaJapan\u00d6zt\u00fcrk Turhan Nilg\u00fcnTurkeyPados GeorgeGreecePalanimuthu Ponnusamy MoorthyUnited States of AmericaPalmer JuliaUnited KingdomPalomba StefanoItalyPatankar ManishUnited States of AmericaPatel DivyaUnited States of AmericaPathy SushmitaIndiaPaz Filho GilbertoAustraliaPearl MichaelUnited States of AmericaPejovic TanjaUnited States of AmericaPelosi EmanueleUnited States of AmericaPeng ChunCanadaPenzes PeterUnited States of AmericaPiltonen TerhiFinlandPocard MarcFrancePorpora Maria GraziaItalyPoveda AndresSpainRasekh Jahromi AtharIranRatajczak MariuszUnited States of AmericaReiter RusselUnited States of AmericaRichard FrancoisCanadaRichards JoAnneUnited States of AmericaRivkin SaulUnited States of AmericaRobert ClaudeCanadaRodgers RayAustraliaRodriguez Ana BeatrizSpainRose PeterUnited States of AmericaRoy DebarshiUnited States of AmericaRueda BoUnited States of AmericaRuggeri RosariaItalySairam M RamCanadaSakumoto RyosukeJapanSalih SanaUnited States of AmericaSalvetti NataliaArgentinaSamant RajeevUnited States of AmericaSanada SakikoJapanSaraga-Babic MirnaCroatiaSawicki WlodzimierzPolandSayki Arslan MuyesserTurkeyScalici JenniferUnited States of AmericaSchattman GlennUnited States of AmericaSchouten PhilipNetherlandsSchultz MatthewUnited States of AmericaSellappan SelvarajuIndiaSeow Kok-MinTaiwanShimada MasayukiJapanShoji TadahiroJapanShu YiminUnited States of AmericaSilambanan SanthiIndiaSingh AjayUnited States of AmericaSingh ShaileshUnited States of AmericaSmith PeterNew ZealandSmith Steven CSwazilandSmitz JohanBelgiumSongsasen NucharinUnited States of AmericaSonoda KenzoJapanSowter HeidiUnited KingdomSpeicher DavidUnited States of AmericaSrivastava RakeshUnited States of AmericaSuganuma NobuhikoJapanSugino NorihiroJapanSugiyama ToruJapanSui GuangchaoUnited States of AmericaSun Qing-YuanChinaSun YingUnited KingdomTagliaferri PierosandroItalyTanos VasiliosCyprusTelleria CarlosUnited States of AmericaTeruyoshi SaitoJapanTsai Eing-MeiTaiwanTsang BenjaminCanadaTukiendorf AndrzejPolandT\u00fcttelmann FrankGermanyUccella StefanoItalyVaclavikova RadkaCzech RepublicVanderhyden BarbaraCanadaVincenzo De LeoItalyVirant-Klun IrmaSloveniaWang JunjieChinaWang QiCanadaWang QiUnited States of AmericaWheeler Stephanie BAustriaWiest JonathanUnited States of AmericaWojakowski WojciechPolandWong AliceHong KongWong P CSingaporeXue KaiChinaYavuzcan AliTurkeyYazbek JosephUnited KingdomYokoyama YoshihitoJapanYoshida JunjiJapanYoshino KiyoshiJapanZeillinger RobertAustriaZeimet AlainAustriaZhang XiaUnited States of AmericaZullo FulvioItaly"}
+{"text": "Journal of Neuroinflammation would like to thank all our reviewers who have contributed to the journal in Volume 12 (2015).The editors of  Lailla AbdullahUnited States of AmericaRosella AbetiUnited KingdomYousef Abu-AmerUnited States of AmericaDong AhnRepublic of KoreaSaba A\u00efdFranceYousef Al-AbedUnited States of AmericaPhilipp AlbrechtGermanyJessy AlexanderUnited States of AmericaLena Al-HarthiUnited States of AmericaArtino AllenUnited States of AmericaJoshua AllenUnited States of AmericaLydia AlvarezSpainDiana AmanteaItalyFumimasa AmayaJapanWinfried AmoakuUnited KingdomAileen AndersonLebanonAnuska Andjelkovic ZochowskaUnited States of AmericaZane AndrewsAustraliaJuan AnguitaSpainDaniel AnthonyUnited KingdomIchio AokiJapanRevital ArichaIsraelKiyoshi AriizumiUnited States of AmericaRegina ArmstrongUnited States of AmericaRand AskalanCanadaSt\u00e9phane AuvinFranceHafidi AzizFranceAna BaamondeSpainAdam BachstetterUnited States of AmericaRyan BachtellUnited States of AmericaVeerle BaekelandtBelgiumFulvio BaggiItalyDavid BakerUnited KingdomSilvia BalossoItalyGiorgos BamiasGreeceBanani BanerjeeUnited States of AmericaWilliam BanksUnited States of AmericaSteven BargerUnited States of AmericaAnne Baron-Van EvercoorenFranceRuth BarrientosUnited States of AmericaAnirban BasuIndiaJan BauerAustriaIngo BechmannGermanyAndreas BeinekeGermanyJean-Pierre BellierJapanKendra BenceUnited States of AmericaJeffrey BennettUnited States of AmericaThomas BergerAustriaCornelia BergmannUnited States of AmericaKristen BernardUnited States of AmericaSonia Berrih-AkninFranceSonja BestUnited States of AmericaKnut BiberGermanyRoger BickUnited States of AmericaPaula BickfordUnited States of AmericaHelle Bielefeldt-OhmannAustraliaStacy BilboUnited States of AmericaSilvia BistiItalyGregory BixUnited States of AmericaGregory BixUnited States of AmericaKlas BlomgrenSwedenMathew Blurton-JonesUnited States of AmericaJuan BolanosSpainKathryn BollingerUnited States of AmericaJessica BoltonUnited States of AmericaBruno BonazFranceKarin BorgesAustraliaCesar BorlonganUnited States of AmericaKenneth BostUnited States of AmericaCharles BradberryUnited States of AmericaMonika BradlAustriaLars-Ove BrandenburgGermanyDavid BraunUnited States of AmericaAmy BrewsterUnited States of AmericaKris BrickmanUnited States of AmericaCelia BrosnanUnited States of AmericaBrad BroughtonAustraliaJonathan BrouilletteCanadaGuy BrownUnited KingdomJoan BrownUnited States of AmericaWolfgang Br\u00fcckGermanyLuigi BubaccoItalyMarion BuckwalterUnited States of AmericaBruce BunnellUnited States of AmericaIrina BurdUnited States of AmericaTa ButterickUnited States of AmericaKimberly ByrnesUnited States of AmericaHuaibin CaiUnited States of AmericaLilian Calderon-GarciduenasUnited States of AmericaPatrick CaldersBelgiumRuth CaldwellUnited States of AmericaSean CallananIrelandArezoo CampbellUnited States of AmericaMatthew CampbellIrelandEduardo Candelario-JalilUnited States of AmericaLing CaoUnited States of AmericaJeffrey CapadonaUnited States of AmericaDaniel CarrUnited States of AmericaRichard CarrGermanyMonica CarsonUnited States of AmericaAnna CartaItalyIgnazio CastagliuoloItalyBogdan CatalinGermanyPaola CavalcanteItalyParamita ChakrabartyUnited States of AmericaSaikat ChakrabortyUnited States of AmericaAngel ChamorroSpainAndrew ChanGermanyAlexandre ChanSingaporeGusharan ChanaAustraliaChristiane Charriaut-MarlangueFranceAbhijit ChaudhuriUnited KingdomMaxim CheeranUnited States of AmericaSylvain ChemtobCanadaChu ChenUnited States of AmericaSzu-Fu ChenTaiwan Republic of ChinaChun-Jung ChenTaiwan Republic of ChinaZhihong ChenUnited States of AmericaJonathan CherryUnited States of AmericaGlyn ChidlowAustraliaIsaac ChiuUnited States of AmericaSunghee ChoUnited States of AmericaSang-Ho ChoiUnited States of AmericaMichael ChoppUnited States of AmericaKon ChuRepublic of KoreaJ. ClarkUnited States of AmericaDiego ClementeSpainManola ComarItalyColin CombsUnited States of AmericaPhillippe CorciaFrancePeter CrackAustraliaDavid CribbsUnited States of AmericaAnne CrossUnited States of AmericaE CudabackUnited States of AmericaColm CunninghamIrelandRiccardo CuppiniItalyDaniela CurtiItalyKrzysztof CzajaUnited States of AmericaEndre CzeiterHungaryCleide Da SilvaUnited States of AmericaHaibin DaiChinaRussell DaleAustraliaRobert DantzerUnited States of AmericaKunjan DaveUnited States of AmericaTerry DavidsonUnited States of AmericaRandall DavisUnited States of AmericaAlejandro De DenicolaArgentinaPierre De GraanNetherlandsJoris De ManBelgiumRoc\u00edo M. De PablosSpainTara De SilvaUnited States of AmericaTerrence DeakUnited States of AmericaRashid DeaneUnited States of AmericaGregory DekabanCanadaSharon DemorrowUnited States of AmericaGerald V. DenisUnited States of AmericaCandan DepboyluGermanyMatthew DerrickUnited States of AmericaRonald DeumensBelgiumKumlesh DevIrelandCarlie DevriesNetherlandsCourtney DevriesUnited States of AmericaCameron DezfulianUnited States of AmericaBarbara Di BenedettoGermanyBetty DiamondUnited States of AmericaExuperio Diez-TejedorSpainChristine D. DijkstraNetherlandsCharles DinarelloUnited States of AmericaKelley DineleyUnited States of AmericaYuchuan DingUnited States of AmericaRosario DonatoItalyCatherine DostertLuxembourgPatrick DoughertyUnited States of AmericaSarah DoyleIrelandAlex DreganUnited KingdomPaul DrewUnited States of AmericaKirk DrueyUnited States of AmericaRonald DumanUnited States of AmericaAaron DumontUnited States of AmericaAlexander EastonCanadaDavid EdwardsUnited States of AmericaArik EisenkraftIsraelJoseph El KhouryUnited States of AmericaNajira El-HageUnited States of AmericaLl EliasBrazilMichal ElovitzUnited States of AmericaAzza El-RemessyUnited States of AmericaMitsuhiro EnomotoJapanAdviye ErgulUnited States of AmericaMichelle EricksonUnited States of AmericaAna EsquifinoSpainElsa FabbrettiSloveniaSarah FalkDenmarkBrian FallonUnited States of AmericaChen-Ming FanUnited States of AmericaCinthia FarinaItalyKrysten FarjoUnited States of AmericaGeraldine FavraisFranceDouglas FeinsteinUnited States of AmericaRobert FelderUnited States of AmericaVicente FelipoSpainHua FengChinaPatricia FernandezPanamaJavier Fernandez-RuizSpainElisabeth FernellSwedenDonna FerrieroUnited States of AmericaBernd FiebichGermanyStefano FiorucciItalyMark FisherUnited States of AmericaLoretta Flanagan-CatoUnited States of AmericaMary Ann FletcherUnited States of AmericaWillem-Jan FokkinkNetherlandsLaura FonkenUnited States of AmericaG ForloniItalyCarola ForsterGermanyThomas C. FosterUnited States of AmericaFornai FrancescoItalyJoseph FrancisUnited States of AmericaMartin FraschCanadaSally FrautschyUnited States of AmericaGregory FreundUnited States of AmericaManuel FrieseGermanyJohn FryerUnited States of AmericaWen-Mei FuTaiwan Republic of ChinaDietmar FuchsAustriaKen-Ichiro FukuchiUnited States of AmericaRoberto FurlanItalyPrasad GabbitaUnited States of AmericaBhakta Prasad GaireRepublic of KoreaRob GalinskyNew ZealandLucio GamaUnited States of AmericaMe GambuzzaItalyOlgo GaraschuckGermanyLidia Garcia-BonillaUnited States of AmericaBorja Garc\u00eda-BuenoSpainD Garcia-OvejeroSpainGwenn GardenUnited States of AmericaPeter GarredDenmarkPeter GaskillUnited States of AmericaJulie GavardFranceHarris GelbardUnited States of AmericaJohn GenselUnited States of AmericaSteve M GentlemanUnited KingdomIgal GeryUnited States of AmericaSimantini GhoshUnited States of AmericaOthman GhribiUnited States of AmericaFrancesca GilliUnited States of AmericaPietro GiustiItalyJonathan GodboutUnited States of AmericaNorbert GoebelsGermanyBeryl GokUnited States of AmericaRalf GoldGermanyYona GoldshmitIsraelDiego Gomez-NicolaUnited KingdomMichael GoodmanUnited States of AmericaNicolai GorbunovUnited States of AmericaCarmen GottfriedBrazilPeter GraceUnited States of AmericaPeter GraceUnited States of AmericaManuel GraeberAustraliaElizabeth GrayUnited KingdomKim GreenUnited States of AmericaPaul GreenUnited States of AmericaKim GreenUnited States of AmericaElisa GreggioItalyDiane GriffinUnited States of AmericaChristian GrimmSwitzerlandWolfgang GrisoldAustriaFloris GroenendaalNetherlandsAntje GroscheGermanyRoss GruberUnited States of AmericaAlexandra GrubmanAustraliaFranz GrusGermanyJean-Charles Gu\u00e9ryFranceAlistair GunnNew ZealandRainer HaberbergerAustraliaAbigail HackamUnited States of AmericaMarc HaltermanUnited States of AmericaKhalid HanafyUnited States of AmericaAndrew HarkinIrelandAshley HarmsUnited States of AmericaMarni Harris-WhiteUnited States of AmericaHigashida HaruhiroJapanDavid HasanUnited States of AmericaTomoki HashimotoUnited States of AmericaJohnny HeUnited States of AmericaShuhan HeUnited States of AmericaJohnny HeUnited States of AmericaRaimund HelbokAustriaMichael HenekaGermanyMichael HennessyUnited States of AmericaKenneth HensleyUnited States of AmericaMarina HernandesUnited States of AmericaPaco HersonUnited States of AmericaDavid HessUnited States of AmericaJames HewettUnited States of AmericaSandra HewettUnited States of AmericaHubertus HimmerichGermanyRabea HinkelGermanyHolly HinsonUnited States of AmericaYoshitaka HirookaJapanSilke HirschGermanyRoger HoSingaporeShelley HooksUnited States of AmericaDouglas HooperUnited States of AmericaKathryn HoppertonCanadaMotohiro HoriuchiJapanCharles HoweUnited States of AmericaChristine HsiehUnited States of AmericaHuijuan HuUnited States of AmericaXiaoming HuUnited States of AmericaRui HuangChinaChristian HumpelAustriaFumito IchinoseUnited States of AmericaO IgweUnited States of AmericaHiroko Ikeshima-KataokaJapanJeffrey IliffUnited States of AmericaAtsuko InoueJapanDavid IraniUnited States of AmericaTakayuki ItohUnited States of AmericaJason IvanusicAustraliaKoichi IwataJapanJoel JackobssonSwedenSanjay JainUnited States of AmericaTatjana JakobsUnited States of AmericaKrzysztof JaneczkoPolandGlen JefferyUnited KingdomHui-Rong JiangUnited KingdomMeiyan JiangUnited States of AmericaErik JohnsonUnited States of AmericaJohn JohnsonUnited States of AmericaAaron JohnsonUnited States of AmericaNicole JonesAustraliaIlona Joniec-MaciejakPolandChung JuRepublic of KoreaRobert KahoudUnited States of AmericaRyuji KajiJapanShuji KanekoJapanScott KanoskiUnited States of AmericaA. KanthasamyUnited States of AmericaWilliam KarpusUnited States of AmericaToshihiko KatafuchiJapanYasufumi KataokaUnited States of AmericaHiroshi KatsukiJapanAnu KauppinenFinlandSyed KazimUnited States of AmericaRichard KeepUnited States of AmericaSamia KhouryLebanonMahmoud KiaeiUnited States of AmericaAnton KichevUnited KingdomHo Jin KimRepublic of KoreaJung-Ae KimRepublic of KoreaHyoung-Chun KimRepublic of KoreaMyeung Ju KimRepublic of KoreaNicholas KingAustraliaT KiyotaUnited States of AmericaChristoph KleinschnitzGermanyIngo KleiterGermanyFiras KobeissyUnited States of AmericaJae Young KohRepublic of KoreaHideo KohnoJapanRon KooijmanBelgiumJuerfen KopitzGermanyThomas KornGermanyS. KorteNetherlandsEl\u00f6d K\u00f6rtvelyGermanyRobert KraftGermanyChia-Yi KuanUnited States of AmericaMarkus KuehnUnited States of AmericaStefanie KuertenGermanyPatrick KueryGermanyDonald KuhnUnited States of AmericaStephanie KullmannGermanyAnil KumarUnited States of AmericaJinn-Rung KuoTaiwan Republic of ChinaJacek KurzepaPolandKatarzyna KwiatkowskaPolandAnne La FlammeNew ZealandJose L Labandeira-GarciaSpainSteve LacroixCanadaMary Jo. LaduUnited States of AmericaPhilip LandfieldUnited States of AmericaGary LandrethUnited States of AmericaThomas LaneUnited States of AmericaThomas LangmannGermanyMj LavoieUnited States of AmericaCatherine LawrenceUnited KingdomDavid LawrenceUnited States of AmericaMarcus LawsonUnited States of AmericaEric LazarteguesUnited States of AmericaEric LazartiguesUnited States of AmericaJohn LeeAustraliaSung Joong LeeRepublic of KoreaSung Joong LeeRepublic of KoreaSunhee LeeUnited States of AmericaSunhee LeeUnited States of AmericaChristian Lefebvre D'hellencourtFranceDonald LehmannUnited KingdomHelmar LehmannGermanyMichael LehmannUnited States of AmericaEmily LeibovitchUnited States of AmericaGuilhian LeipnitzBrazilMarcel LeistGermanyVincent LelievreFranceLisa LeonUnited States of AmericaChristina LeslieUnited States of AmericaMichael LevyUnited States of AmericaPatrick LewisUnited KingdomFrank LeypoldtGermanyDidier LeysFranceCai LiUnited States of AmericaJ LiUnited States of AmericaJunfa LiChinaJian LiangUnited States of AmericaDaniel LieblUnited States of AmericaFabian LiechtiSwitzerlandJihyeon LimUnited States of AmericaCharles L. LimoliUnited States of AmericaRaija LindbergSwitzerlandDan LindholmFinlandEng-Ang LingSingaporeRalf LinkerGermanyGregory LiouUnited States of AmericaRob LisakUnited States of AmericaLucia LisiItalyFudong LiuUnited States of AmericaLixin LiuCanadaNk LiuUnited States of AmericaJialing LiuUnited States of AmericaYawei LiuDenmarkYutong LiuUnited States of AmericaJordi LlopSpainSarah Elisabeth LloydUnited KingdomEng LoUnited States of AmericaDavid LoaneUnited States of AmericaDavid LoefflerUnited States of AmericaJames LokensgardUnited States of AmericaRuben Lopez-ValesSpainLisa LoramUnited States of AmericaSeth LoveUnited KingdomQingxian LuUnited States of AmericaRu-Band LuTaiwan Republic of ChinaPaul LucassenNetherlandsRalph LucusGermanyJan LuenemannSwitzerlandJia LuoUnited States of AmericaSarah LutzUnited States of AmericaMarina LynchIrelandDaqing MaUnited KingdomQingyi MaChinaHalina MachelskaGermanyAndrew MacleanUnited States of AmericaAkiko MaedaUnited States of AmericaSanjay MaggirwarUnited States of AmericaKathleen Maguire-ZeissUnited States of AmericaPamela MaherUnited States of AmericaSabatino MaioneItalyMarzia MalcangioUnited KingdomAnne-Marie MalfaitUnited States of AmericaCarina MallardSwedenFrederic ManfredssonUnited States of AmericaSanthakumar ManicassamyUnited States of AmericaMark MapstoneUnited States of AmericaYannick MarchalantUnited States of AmericaNicola MarchiUnited States of AmericaCarmela MarinoItalyDaniel MarksUnited States of AmericaPaola MarmiroliItalyIan MarriottUnited States of AmericaThomas MartinUnited States of AmericaJ Martinez-GonzalezSpainRicardo Martinez-ZamudioFranceRudolf MartiniGermany\u00c1ngeles Mart\u00edn-RequeroSpainEliezer MasliahUnited States of AmericaIara Massias-ReasonBrazilClayton MathewsUnited States of AmericaKaspar MatiasekGermanyF MatsudaJapanCarlow MatuteSpainAnne Kathrin MausbergGermanyChristian MawrinGermanyAudrey MazaratiUnited States of AmericaMervyn MazeUnited States of AmericaSimon McarthurUnited KingdomLouise McculloughUnited States of AmericaRobert MccuskerUnited States of AmericaBraden McfarlandUnited States of AmericaJames McginnisUnited States of AmericaDeclan MckernanIrelandGordon MearesUnited States of AmericaStephane Melik ParsadaniantzFranceRichard MellanbyUnited KingdomTil MengeGermanyDoron MerklerGermanyAxel MethnerGermanyJeffrey MeyerCanadaGerd Meyer Zu HorsteGermanyGeert MeyfroidtBelgiumJens MikkelsenDenmarkDjordje MiljkovicSerbia And MontenegroC MillerUnited States of AmericaDonald MillerCanadaDennis MillerUnited States of AmericaRobert MillerUnited States of AmericaRichard MillerUnited States of AmericaRachel MillerUnited States of AmericaRichard MilnerUnited States of AmericaLuisa MinghettiItalyYasushi MiuraJapanTakuro MiyazakiJapanEhsan Moazen ZadehIslamic Republic Of IranAlon MonsonegoIsraelJoan MontanerSpainDarren MooreUnited States of AmericaJames MorganUnited KingdomDave MorganUnited States of AmericaKouichi MoritaJapanMelissa MossUnited States of AmericaBruno MourvillierFranceElliott MufsonUnited States of AmericaAngelika M\u00fchlebnerNetherlandsRob MullinsUnited States of AmericaBenjamin MurdockUnited States of AmericaErland NagelhusNorwayIstvan NagyUnited KingdomMatthias NahrendorfUnited States of AmericaRanuka NairIndiaKunihiro NakaiJapanHideaki NakajimaJapanMike NamakaCanadaRoland NauGermanyChristian NausCanadaLucia NegriItalyAndrew NeilsonUnited States of AmericaVivek NerurkarUnited States of AmericaEric NgUnited States of AmericaMichael NicholsUnited States of AmericaRobert NickellsUnited States of AmericaRobert NitschGermanyChristopher NorrisUnited States of AmericaKelly NudelmanUnited States of AmericaM. Kerry O'banionUnited States of AmericaBirgit ObermeierUnited States of AmericaJason O'connorUnited States of AmericaJanis O'donnellUnited States of AmericaHalina OffnerUnited States of AmericaToru OgataJapanU OhUnited States of AmericaAndreas OhlmannGermanyK OhnoJapanToshio OhshimaJapanJohanna OjalaFinlandTatsusada OkunoJapanJohn OlschowkaUnited States of AmericaJulie OlsonUnited States of AmericaBenjamin OndruschkaGermanyHiroaki OoboshiJapanLisa OpanashukUnited States of AmericaGregory OrdwayUnited States of AmericaMichael OsthoffSwitzerlandTrevor OwensDenmarkYoko OzawaJapanRosana PaganoBrazilGuylene PageFranceKalipada PahanUnited States of AmericaMaria PanaroItalyAlberto PaneraiItalyFrancesco ParmeggianiItalyRimma ParnovaRussian FederationGuilio M. PasinettiUnited States of AmericaCesare PatroneSwedenGesine PaulSwedenPrasit PavasantThailandKrystyna PawlakPolandMarcela PeknaSwedenRosalia PellitteriItalyLuis PenalvaUnited States of AmericaYu-Ping PengChinaKeith PennypackerUnited States of AmericaLiyanage PereraUnited States of AmericaKarin PetersonUnited States of AmericaA Petit-PaitelFranceAshley PetroneUnited States of AmericaMary PetzkeUnited States of AmericaMario PhilippUnited States of AmericaJoanna PhillipsUnited States of AmericaIrene PichlerItalyChristian PikeUnited States of AmericaKelly PikeCanadaSudheesh Pilakka KanthikeelUnited States of AmericaPaulo PiresUnited States of AmericaAnna PlanasSpainPatrizia PontissoItalyDean PountneyAustraliaDavid PowellUnited States of AmericaElizabeth PowellUnited States of AmericaChristopher PowerCanadaDomenico PraticoUnited States of AmericaDarwin ProckopUnited States of AmericaBarbara PrzewlockaPolandChaim PuttermanUnited States of AmericaZenaide QuezadoUnited States of AmericaRichard QuiggUnited States of AmericaAndre Quincozes-SantosBrazilP RakoczyAustraliaGlenn RallUnited States of AmericaM. RamanathanIndiaMatt RamerUnited States of AmericaAna RamirezSpainG. RebeckUnited States of AmericaRaymond ReganUnited States of AmericaWilliam RegenoldUnited States of AmericaTheo ReinGermanyMarkus ReindlAustriaTonia RexUnited States of AmericaSusanna RicciItalyGianfranco RisuleoItalyFatima RiveraUnited States of AmericaPhillip RiveraUnited States of AmericaRobert RoachUnited States of AmericaMayela RodriguezMexicoMoses RodriguezUnited States of AmericaMary-Louise RogersAustraliaGu Seob RohRepublic of KoreaTroy RohnUnited States of AmericaJulian RomeroSpainLorenzo Romero-RamirezSpainM Romero-RamosDenmarkChristopher RoseCanadaAnna RosellSpainThad RosenbergerUnited States of AmericaSusanna RosiUnited States of AmericaKharah RossUnited States of AmericaJoachim RothGermanySteven RothUnited States of AmericaGuido RubboliDenmarkMarc RuitenbergAustraliaChristoph RummelGermanyKlemens RuprechtGermanyHorea RusUnited States of AmericaKarsten RuscherSwedenJong RyuRepublic of KoreaDaniel SabanUnited States of AmericaRoger SabbadiniUnited States of AmericaAhmad SalehiUnited States of AmericaSamina SalimUnited States of AmericaPaul SalvaterraUnited States of AmericaTarek SamadUnited States of AmericaVanesa Sanchez-GuajardoDenmarkJuergen SandkuehlerAustriaLauren SansingUnited States of AmericaAbel SantamariaMexicoAna SantiagoPortugalMichael SantilloUnited States of AmericaThomas SantoroUnited States of AmericaRebecca SappingtonUnited States of AmericaManuel SarasaSpainSohobhan SarkarCanadaHarvey SarnatCanadaNorman SaundersAustraliaJosep SauraSpainValentina SavchenkoUnited States of AmericaCristoforo ScavoneBrazilEliana ScemesUnited States of AmericaTanja SchlerethGermanyJ\u00fcrgen Schneider- SchauliesGermanyHerbert SchwarzSingaporeGuillaume SebireCanadaJose SegoviaMexicoFatima SehbaUnited States of AmericaMiho SekiguchiJapanDana SelleyUnited States of AmericaBridgette SempleAustraliaMrudang ShahUnited States of AmericaZahoor A. ShahUnited States of AmericaLee ShapiroUnited States of AmericaHari SharmaSwedenHayley ShawnCanadaKazim SheikhUnited States of AmericaJiangang ShenChinaJohn SheridanUnited States of AmericaT ShinRepublic of KoreaSeiji ShiodaJapanEsther ShohamiIsraelVeronica ShubayevUnited States of AmericaRafael SimoSpainRoger SimonUnited States of AmericaDario SiniscalcoItalyLuigi SironiItalyStephen SkaperItalyThomas SkripuletzGermanyAnn SmithUnited States of AmericaJessica SnowdenUnited States of AmericaTomas SobrinoSpainBetty SolivenUnited States of AmericaVolkan SolmazTurkeyClaudia SommerGermanyYoshifumi SonobeJapanLinda SorkinUnited States of AmericaLydia SorokinGermanyRosa SorrentinoItalyLirlandia SousaBrazilPeter SpaethSwitzerlandJames St JohnAustraliaPhilip StahelUnited States of AmericaMartin StangelGermanyLarry SteinmanUnited States of AmericaMark StettnerGermanyJonathan StilesUnited States of AmericaJonathan StoneAustraliaT StoneUnited KingdomBarbara StonestreetUnited States of AmericaWolfgang J. StreitUnited States of AmericaTatyana StrekalovaNetherlandsStephen StromSwedenHyeon-Sook SuhUnited States of AmericaHyeon-Sook SuhUnited States of AmericaKyoungho SukRepublic of KoreaGrace SunUnited States of AmericaStevens SusanUnited States of AmericaTobias SuterSwitzerlandRaymond SwansonUnited States of AmericaFabian SzepanowskiGermanyPatricia SzotUnited States of AmericaBj\u00f6rn TackenbergGermanyKanda TakashiJapanShao-Jun TangUnited States of AmericaMalu TanseyUnited States of AmericaMaki TateyamaJapanJuliet TaylorAustraliaElena TchougounovaSwedenIrmgard TegederGermanyPeter TeismannUnited KingdomAndrea TennerUnited States of AmericaNiccolo TerrandoUnited States of AmericaCharlotte TeunissenNetherlandsDietmar ThalGermanyPraveen ThumbikatUnited States of AmericaLeonardo TonelliUnited States of AmericaLars TongesGermanyTerrence TownUnited States of AmericaCorinna TrebstGermanyMarie-Eve TremblayCanadaJames TsaiUnited States of AmericaKuen-Jer TsaiTaiwan Republic of ChinaStyliani TsirkaUnited States of AmericaAlexander TsiskaridzeGeorgiaErdem TuzunTurkeyNeetu TyagiUnited States of AmericaSuresh TyagiUnited States of AmericaKenneth TylerUnited States of AmericaWilliam TyorUnited States of AmericaMarta Valcarcel-AresUnited States of AmericaLuc VallieresCanadaBart Van BerckelNetherlandsAnne-Marie Van DamNetherlandsLinda Van EldikUnited States of AmericaBarbara Van LeeuwenNetherlandsE. 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+{"text": "Clinical Epigenetics would like to thank all our reviewers who have contributed to the journal in volume 6 (2014).The Editors of  Antonella AgodiItalyNita AhujaUnited States of AmericaHasan AksitTurkeyAnna AlisiItalyLucia AltucciItalyDenise AndiaBrazilSergi ArandaSpainAmy AuAustraliaShairaz BakshCanadaAnna-Maria BarciszewskaPolandRosaria BenedettiItalyMaria BerdascoSpainDavid BernardFranceBhavana BhatnagarUnited States of AmericaKarol BomsztykUnited States of AmericaCarrie BretonUnited States of AmericaRobert BrownUnited KingdomBethany Buck-KoehntopUnited States of AmericaHyang-Min ByunUnited States of AmericaBernard CallusAustraliaGabriel CapellaSpainMartin CarrollUnited States of AmericaPaolo CasaliUnited States of AmericaPo-Yuan ChangTaiwanIsabelle CheminFranceJing ChenUnited States of AmericaWantao ChenChinaYangchao ChenHong KongYuen Yee ChengAustraliaNan-Haw ChowTaiwanBrock ChristensenUnited States of AmericaJeffrey CraigAustraliaMagali CucchiariniGermanyHengmi CuiUnited States of AmericaRoderick DashwoodUnited States of AmericaJessica de GreefUnited States of AmericaGeorge DedoussisGreeceFloriana Della RagioneItalyCarmela Dell'aversanaItalyEmma DempsterUnited KingdomPaula DesplatsUnited States of AmericaStella DrachevaUnited States of AmericaJulie DumonceauxFranceThomas EggermannGermanyMattias EkstedtSwedenTomas Ekstr\u00f6mSwedenOsman El-MaarriGermanyJesus EspadaSpainMario Fdez. FragaSpainAlexey FedulovUnited States of AmericaRebecca FryUnited States of AmericaHiroshi FurukawaJapanPhilippe GeorgelUnited States of AmericaSantosh GhoshUnited States of AmericaMarcus GomesBrazilZhiyun GongChinaSteven GrayIrelandDavid GuerreroSpainSonia GuilSpainSanjay GuptaUnited States of AmericaQin HanChinaAlexander HaslbergerAustriaMartin HasselblattGermanyDanielle HeidemanNetherlandsLuke HessonAustraliaKinjal HewUnited States of AmericaYu-Mei HsuehTaiwanHailiang HuangUnited States of AmericaYun HuangUnited States of AmericaMazhar IqbalPakistanJean-Pierre IssaUnited States of AmericaNikolai IvanovSwitzerlandVincent JaddoeNetherlandsJaroslav JelinekUnited States of AmericaCarmen JeronimoPortugalYideng JiangChinaGuanghui JinChinaRicky JohnstoneAustraliaSuh-Hang JuoTaiwanClaudia KappenUnited States of AmericaAtsushi KasaiJapanWahab KhanCanadaSeong Who KimSouth KoreaMark KirschbaumUnited States of AmericaGaspar KitangeUnited States of AmericaYutaka KondoJapanIgor KoturbashUnited States of AmericaJose Miguel Laffita MesaCubaJanine LaSalleUnited States of AmericaElena LesmaItalyEric Letouz\u00e9FranceBin LiChinaHsin-Pai LiTaiwanJonathan LichtUnited States of AmericaCharlotte LingSwedenYi-Wen LiuTaiwanQianjin LuChinaDeborah MackayUnited KingdomLuca MagnaniUnited KingdomPhilip MarsdenCanadaDeborah MarshAustraliaCarmen MarsitUnited States of AmericaDaniel Martinez-ArguellesCanadaMaria MatarazzoItalyHisahiro MatsubaraJapanRichard MeehanUnited KingdomAlexander MichelsUnited States of AmericaMontserrat MilaSpainDaniel MillerUnited States of AmericaMonica MiozzoItalyPradyumna MishraIndiaRichard MomparlerCanadaEva MoralesSpainMo MotamediUnited States of AmericaPamela MunsterUnited States of AmericaMartinet NadineFranceKazuhiko NakabayashiJapanKazuaki NakamuraJapanRajeswari NarayanappaIndiaRuta NavakauskieneLithuaniaClara NerviItalyTorbj\u00f6rn NilssonSwedenHoutan NoushmehrBrazilMargarete OdenthalGermanyShuji OginoUnited States of AmericaSam OhUnited States of AmericaRieko OhkiJapanJoyce OhmUnited States of AmericaJaroslaw PaluszczakPolandVassilios PapadopoulosCanadaArpad PataiHungaryMattia PelizzolaItalyPalsamy PeriyasamyUnited States of AmericaMarcello PersicoItalyW. Jeffrey PettyUnited States of AmericaCarmen PheifferSouth AfricaRuth PidsleyUnited KingdomChristoph PlassGermanyTorsten PloschNetherlandsJacek PolosakPolandDeepa RastogiUnited States of AmericaNoel RaynalCanadaStella Marie Reamon-BuettnerGermanyAndrea RiccioItalyTina R\u00f6nnSwedenRossella RotaItalyMarianne RotsNetherlandsLisa RussellUnited KingdomRichard SafferyAustraliaYan SandersUnited States of AmericaCarmen SapienzaUnited States of AmericaPrimo Sch\u00e4rSwitzerlandCarlo SelmiUnited States of AmericaAlexander SemmlerSwitzerlandHuidong ShiUnited States of AmericaDavid SimarAustraliaRoderick SliekerNetherlandsAlicia SmithUnited States of AmericaTamar SoferUnited States of AmericaTijana StankovicSerbiaRenske SteenbergenNetherlandsMichael SteinerNew ZealandDavid StewartCanadaCong SunAustraliaYuan SunUnited States of AmericaHua TangChinaKai-Fu TangChinaWan Yee TangUnited States of AmericaAndrew TeschendorffChinaMathewos TessemaUnited States of AmericaKulbhushan TikooIndiaYasushi TohJapanTrygve TollefsbolUnited States of AmericaStefania TommasiItalyJ\u00e9r\u00f4me TorrisaniFranceRossella TuplerUnited States of AmericaToshikazu UshijimaJapanFatima Valdes MoraAustraliaNicholas VenthamUnited KingdomMukesh VermaIndiaPaolo VineisUnited KingdomSarah VoisinSwedenWolfgang WagnerGermanyThomas WilhelmUnited KingdomMaria WingUnited States of AmericaBea WismanNetherlandsOlaf WittGermanyYu Mi WooSouth KoreaTongjing XingChinaJin-Chen YangUnited States of AmericaQiwei YangUnited States of AmericaNadia ZaffaroniItalyKai ZhangChinaYan ZhengUnited States of AmericaVlatka ZoldosCroatia"}
+{"text": "Journal of Experimental & Clinical Cancer Research wouldlike to thank all our reviewers who have contributed to the journal in Volume 32(2013).The editor of  Michael AbendGermanyAaron AdamsonUnited States of AmericaKhalil AhmedUnited States of AmericaYoshimitsu AkiyamaJapanEiman AleemSwedenCinzia AntognelliItalyVincenzo ArenaItalyLeon BachAustraliaJean-Paul BaharyCanadaXuhui BaoUnited States of AmericaCarlton BarnettUnited States of AmericaLuisa BegnozziItalySonja BerndtUnited States of AmericaGiovanni BlandinoItalyGianluca BossiItalyChristian BronnerFranceRosaria BufalinoItalyDengfeng CaoChinaNing CaoUnited States of AmericaMichele CaragliaItalyGaetano CaramoriItalyVioleta CardenalSpainAlice CarrierFrancePaola CassoniItalyChiara CastelliItalyPradeep Chaluvally RaghavanUnited States of AmericaMario Chammas, Jr.BrazilChawnshang ChangUnited States of AmericaTammy ChangUnited States of AmericaHui-Ju Ch'angTaiwanGang ChenUnited States of AmericaLin-Feng ChenUnited States of AmericaShih-Shun ChenTaiwanShuda ChenChinaWantao ChenChinaLiang ChengUnited States of AmericaYung Hyun ChoiKorea, SouthDavid ChungAustraliaMara CironeItalyMartin ClynesIrelandFlaminia ColuzziItalyKim CreekUnited States of AmericaZiyou CuiUnited States of AmericaMaria Czyzyk-KrzeskaUnited States of AmericaBingbing DaiUnited States of AmericaAlan Dal PraSwitzerlandSidsel Damkj\u00e6rDenmarkTrina DasUnited States of AmericaPaolo De FabritiisItalyMarina De ResendeBrazilKathleen DeckerCanadaDomenico DeliaItalyChrist\u00e8le Desbois-MouthonFranceBenjamin DescoursFranceXiangwu DingChinaRuslan DmitrievRussian FederationHongdo DoAustraliaChiara DobrinjaItalyJessica DoningtonUnited States of AmericaHarry DrabkinUnited States of AmericaJinwei DuUnited States of AmericaXiao-Li DuUnited States of AmericaEwald DumontNetherlandsKonstantinos EconomopoulosUnited States of AmericaJulien EdelineFranceSusumu EguchiJapanIorio Eugenio LuigiItalyAlessandra FabiItalyXiaolong FanChinaHuaqiang FangUnited States of AmericaFrancesca FaniniItalyEmanuela Felley-BoscoSwitzerlandGen-Sheng FengUnited States of AmericaZizhen FengUnited States of AmericaAvelino FragaPortugalJean-Noel FreundFranceDoriana FruciItalyJianfei FuChinaSidney FuUnited States of AmericaAmy FultonUnited States of AmericaNozomu FuseJapanFeng GaoUnited States of AmericaLina GaoUnited States of AmericaAnna Gasperi-CampaniItalyGiovanni GaudinoUnited States of AmericaJing-Shu GengChinaAntonio GiordanoItalyCarlo GiordanoItalyDavid GisselssonSwedenMunirathinam GnanasekarUnited States of AmericaMaria Gonzalez CaoSpainPhilip GruppusoUnited States of AmericaAnna GruszkaPolandJian GuanUnited States of AmericaSezgin G\u00fcnesTurkeyJiangfeng GuoChinaJunming GuoChinaKun GuoChinaLinlang GuoChinaQifeng GuoChinaSonal GuptaUnited States of AmericaJeung-Whan HanKorea, SouthJianxun HanCanadaDavid HangauerUnited States of AmericaSwei Sunny HannChinaHuifang HaoJapanNoboru HaraJapanBass HassanUnited KingdomEtsuro HatanoJapanBiao HeUnited States of AmericaYoshihiko HirohashiJapanGerald HoeflerAustriaRobert HoffmanUnited States of AmericaJeff HollyUnited KingdomMichael HorsmanDenmarkYingwei HuChinaWei-Chien HuangTaiwanXiaojun HuangChinaYan HuangUnited States of AmericaFazlul HuqAustraliaDaisuke IizukaJapanShiro ItagakiJapanChunyan JiChinaXinguo JiangUnited States of AmericaRenjie JinUnited States of AmericaChunsheng KangChinaShailender KanwarUnited States of AmericaSid KarUnited States of AmericaW. Martin KastUnited States of AmericaNancy KemenyUnited States of AmericaDong-Wan KimKorea, SouthJee Hyun KimKorea, SouthDominique KoensgenGermanyLingling KongChinaManousos KonstadoulakisGreeceKaoru KusamaJapanJandee LeeKorea, SouthSang Joon LeeKorea, SouthWei LeiUnited States of AmericaCarlo LeonettiItalyKaren LeroyFranceChung-Pin LiTaiwanJi-Liang LiUnited KingdomKai LiChinaMin LiUnited States of AmericaQin LiUnited States of AmericaRui LiChinaXiaoli LiUnited States of AmericaXiuling LiUnited States of AmericaYu-Chih LiangTaiwanZhiyong LiangChinaRongxia LiaoChinaWeng LihongChinaJen-Kou LinTaiwanYiwei LinUnited States of AmericaHubert LincetFranceHui LingUnited States of AmericaTian LiuUnited States of AmericaXi LiuUnited States of AmericaYan LiuUnited States of AmericaYinkun LiuChinaYong LiuUnited States of AmericaZhihua LiuChinaWen Lian LoTaiwanPei-Jung LuTaiwanYong LuUnited States of AmericaRobert LucitoUnited States of AmericaPaolo MacchiariniSwedenPeter MalfertheinerGermanyMalgorzata Malodobra-MazurPolandRichard MaraisUnited KingdomJodi MaranchieUnited States of AmericaOrnella MarelliItalyKazumasa MatsumotoJapanFekicity Eb MayUnited KingdomSoeren Torge MeesGermanyErhong MengUnited States of AmericaMichele MenottaItalyLeonardo A. Meza-ZepedaNorwayPaolo MiccoliItalyMartin MichaelisUnited KingdomShuji MikamiJapanRuben MolinaSpainRichard MooreUnited States of AmericaFabiola MorettiItalyMarcella MottoleseItalySusan MougUnited KingdomKen-Ichi MukaishoJapanShigeki NagamachiJapanBinoj NairUnited States of AmericaTohru NakanishiJapanJoo-Hyun NamKorea, SouthPatrick NasarreUnited States of AmericaReiki NishimuraJapanShyam NyatiUnited States of AmericaElena OdintsovaUnited KingdomSae-Ock OhKorea, SouthMasayuki OhtsukaJapanMasaaki OkaJapanHirotaka OsadaJapanMarco PaggiItalyClaudia PalenaUnited States of AmericaJianji PanChinaLingya PanChinaJae Myung ParkKorea, SouthHeba PashaEgyptBo PengChinaCheng PengUnited States of AmericaMarzia PennatiItalyLars J PetersenDenmarkCathie PflegerUnited States of AmericaAda PiepoliItalyAlla PiirsooEstoniaNicola PimpinelliItalyCarme Pi\u00f1olSpainRobert PirkerAustriaElena PiskounovaUnited States of AmericaGeorge PlataniotisUnited KingdomMarta PokrywczynskaPolandZhi Rong QianJapanGuixing QiuChinaXiaofei QiuChinaOsvaldo RampadoItalyCarlo RealeItalyLuigi RicciardielloItalyMario RoselliItalyAntonio RussoItalyKristina RysevaiteLithuaniaErica SalvatiItalyRosario SanguedolceItalyDaniele SantiniItalyAnna SapinoItalyIngo Schmidt-WolfGermanyWolfgang SchulzGermanyAli ShamseddineLebanonBal Krishan SharmaIndiaHiroaki ShibaJapanYusuke ShiozawaUnited States of AmericaWu ShixiuChinaAnuraag ShrivastavCanadaZheng Shui-ErChinaBhuminder SinghUnited States of AmericaPreet Paul SinghUnited States of AmericaDoris SiwakUnited States of AmericaMaja SmerdelDenmarkSilvia SodduItalyHai SongUnited States of AmericaEnrico SpugniniItalyEdmond SterpinBelgiumCarol StockingGermanySubbaya SubramanianUnited States of AmericaYuan SunUnited States of AmericaDeepa TaggarsheUnited KingdomKohji TakaraJapanWayne TamUnited States of AmericaManish TandonUnited States of AmericaKeiji TanimotoJapanJianguo TaoUnited States of AmericaRong-Hua TaoUnited States of AmericaLucio TentoriItalyXing-Song TianChinaXinxia TianChinaDanai TiwawechThailandMarcos Tobias-MachadoBrazilMaria Lauda TomasiItalyGian Paolo ToniniItalyNobuyuki ToshikuniJapanGiancarlo TronconeItalyShaw-Jenq TsaiTaiwanShuiping TuChinaShahab UddinSaudi ArabiaMaciej UgorskiPolandKatsuhiro UzawaJapanAntonis ValachisGreeceKenneth Van GolenUnited States of AmericaLaura Vargas-RoigArgentinaAldo VenutiItalyGiovanni VitaleItalyDemitrios VyniosGreeceChristine WalshUnited States of AmericaShaogui WanUnited States of AmericaCongjun WangChinaLei WangUnited States of AmericaLinda WangSingaporePing WangUnited States of AmericaQiuyan WangUnited States of AmericaXiaoming WangChinaYadong WangChinaYan WangUnited States of AmericaYingqun WangUnited States of AmericaYucai WangUnited States of AmericaNaoki WatanabeJapanMiranda WeenAustraliaHaiming WeiChinaJun WeiUnited States of AmericaJames WellsAustraliaVictor Chun-Lam WongUnited States of AmericaSopit WongkhamThailandJonathan WrightUnited States of AmericaShaofang WuUnited States of AmericaZhengrong WuChinaHarry XiaUnited States of AmericaQinghua XiaChinaJunjie XiaoChinaZhi-Qiang XiaoChinaZuoxiang XiaoUnited States of AmericaKe XuChinaLi XuUnited States of AmericaQilin XuUnited States of AmericaXiaochun XuUnited States of AmericaNaoko YamadaJapanLibo YanUnited States of AmericaEric YangUnited States of AmericaGong YangChinaLeixiang YangUnited States of AmericaYibin YangUnited States of AmericaYinmo YangChinaZhengduo YangUnited States of AmericaJun YaoChinaJun YasudaJapanHuquan YinUnited States of AmericaQi YinUnited States of AmericaHiroaki YokomoriJapanMee Sup YoonUnited States of AmericaKouichi YoshinariJapanTomokazu YoshizakiJapanGuang-Yan YuChinaDong YuanUnited States of AmericaZhong YunUnited States of AmericaPeng ZaimeiChinaKostas ZarogoulidisGreeceMaria Chiara ZatelliItalyAbdel-Rahman ZekriEgyptHaibo ZhangUnited States of AmericaHongyu ZhangChinaJiangwei ZhangUnited States of AmericaMingzhi ZhangChinaQunzhou ZhangUnited States of AmericaShiwu ZhangChinaYanling ZhangUnited States of AmericaYou-Qing ZhangUnited States of AmericaZhenwei ZhangUnited States of AmericaYuhai ZhaoUnited States of AmericaLei ZhengUnited States of AmericaXiuyi ZhiChinaBing ZhouUnited States of AmericaJianwei ZhouChinaZhongren ZhouUnited States of AmericaXiaofeng ZhuChinaXiaolin ZhuUnited States of AmericaChristoph ZielinskiAustriaWainer ZoliItalyYang ZongUnited States of AmericaAshraf ZytoonEgypt"}
+{"text": "In the original published version of the above article contained missing information. The equal contribution of the authors Yusef Moulla and Ines Gockel information should have been presented as follows:\u201cYusef Moulla and Ines Gockel contributed equally as last authors of this article.\u201dThe original article has been corrected."}
+{"text": "Following publication of the original article , the autGuangzhou health care collaborative innovation major special project (201704020218)."}
+{"text": "The correct reference is: Initiative for Vaccine Research. WHO guide for standardization of economic evaluations of immunization programmes [Internet]. WHO; 2019 [cited 2021 Jan 15]. Available from:"}
+{"text": "In Response: We appreciate the insightful comments from Azman et al. on use of licensed hepatitis E virus (HEV) vaccine  for outbreak control regardless of virus genotype  recommendation, the National Immunization Technical Advisory Groups of Sudan convened an emergency meeting to discuss the feasibility of deploying HEV vaccine. After considering the WHO position paper about the use of HEV vaccine ("}
+{"text": "Following the publication of the original article  the authThe correct Fig."}
+{"text": "In Li et al. (2022),\u201cWe deeply appreciated the kindly gift of all the myricetin derivatives from Professor Wei Xue of Guizhou University.\u201dThe updated acknowledgment section is given below:"}
+{"text": "Computational Intelligence and Neuroscience has retracted the article titled \u201cTargeting Inhibition of Notch1 Signaling Pathway on the Study of Human Gastric Cancer Stem Cells with Chemosensitization [Following an investigation conducted by the Hindawi Research Integrity team , signifi"}
+{"text": "The corrected author listing (first/last) names is shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "We also acknowledge the Department of Health and Social Care Antimicrobial Research Capital Funding Award (reference NIHR200638)."}
+{"text": "Authors\u2019 affiliations and their roles in the supervisory activities of the Fukushima Health Management Survey as of fiscal year 2022 (in square brackets)* Affiliation 1 denotes the main affiliation"}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "Following publication of the original article (Archibald and Allott The original article (Archibald and Allott"}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The author wants to correct the values of the 95% confidence interval of the standardized mortality ratio (SMR) in"}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientificvalidity of this paper, hence has issued an expression of concern to notify readerswhilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientificvalidity of this paper, hence has issued an expression of concern to notify readerswhilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "Ankylosing spinal disease (ASD) is a common clinical entity 1]. The main etiologies of ASD are diffuse idiopathic skeletal hyperostosis (DISH), ankylosing spondylitis and postoperative spinal fusion after removal of instrumentation. Because of the rigidity of the spine patients with ASD are prone to fractures even with minor trauma and unstable fracture patterns (distraction fractures and involvement of the posterior column) are common . The mai. NonetheNone declared."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "Following the publication of the original article  the authThe correct Fig."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The authors inadvertently presented duplicate sperm images for XY and XESxrbO mouse testes of The journal and the authors apologise for an error in the above titled article published in this journal (vol 144, pp The correct"}
+{"text": "Dear EditorA recent population preference for treatment of uncomplicated appendicitis reported half would prefer antibiotics to surgery and that most would accept 31 per cent risk of recurrenceThe authors reported that 20 per cent of patients will require open surgery"}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "Following publication of the original article , the autAffiliation 1 and 3 should also include: Affiliated Hospital of Zunyi Medical UniversityAffiliation 2 indicated Zunyi Medical University Hospital while it should instead read: Affiliated Hospital of Zunyi Medical UniversityThe affiliations have been updated in the correction article and the original article  has been"}
+{"text": "Following publication of the original article , the autThe incorrect author names reads:Nasel ChristianPoetsch AngelinaBrunner CorneliaMoser EwaldThe correct author names should read:Christian NaselAngelina PoetschCornelia BrunnerEwald MoserThe author group has been updated above and the original article  has been"}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The above article  publisheThe correct department name is Department of Emergency Medicine and Indiana CTSI Translational Research Development Program."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientificvalidity of this paper, hence has issued an expression of concern to notify readerswhilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "This session provides insights into how the pandemic challenged the capabilities and ingenuity of the Older Americans Act (OAA) programs and the aging network. Speakers will include key aging network stakeholders, who will discuss the overnight evolution of programs serving often isolated older adults."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "This session provides insights into how the pandemic challenged the capabilities and ingenuity of the Older Americans Act (OAA) programs and the aging network. Speakers will include key aging network stakeholders, who will discuss the overnight evolution of programs serving often isolated older adults."}
+{"text": "Following publication of the original article (Ebrahimi et al. The correct tables are given below."}
+{"text": "After publication of the original article , an erroThe sentence currently reads: Third parking checking will remain constrained without public health support and exemptions that recognize the challenges of drug checking within prohibition and substance use stigma.The sentence should read: Third party checking will remain constrained without public health support and exemptions that recognize the challenges of drug checking within prohibition and substance use stigma.The original article has been corrected."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates."}
+{"text": "Little is known about the accumulative impacts of neighbourhood physical environments on depression among older adults. Based on a cohort study of 2,081 older adults in Hong Kong, this study examined longitudinal relationships between neighbourhood physical environments and depressive symptoms among older adults and the moderating effects of the slope of terrain and individual functional ability using latent growth curve modelling. Results indicated that the availability of community centres and passive leisure facilities reduced depressive symptoms over time. The protective effects of residential surrounding greenness on depressive symptoms among older adults differed by the slope of terrain. Longitudinal associations between neighbourhood physical environments and depressive symptoms varied between older adults with and without functional limitations. Identifying environmental barriers and applying targeted residential environment interventions are essential."}
+{"text": "To the Editor:While I appreciate the effort of Blades et al in conducting the valuable research for \"Rural Community Knowledge of Stroke Warning Signs and Risk Factors\" , I belie"}
+{"text": "A prospective study of 232 patients with primary invasive breast cancer  and histologically confirmed axillary node status was carried out to assess the prognostic significance of several readily available clinical and pathological characteristics. In addition to the recognised utility of tumour size and axillary lymph node status, the presence or absence of cohesive clumps of malignant cells in peritumoral vascular spaces (both lymphatic and blood vessels) was found to be prognostically important."}
+{"text": "Erick Turner appropriately points out the high levels of rigor applied during regulatory authorities' review of clinical trial data . However"}
+{"text": "We present a previously unreported series of five cases of acute angle closure glaucoma associated with watching the Australia soap opera \"Neighbours\". Two cases were bilateral and associated with watching two episodes of \"Neighbours\" on the same day. The pathogenesis, and possible role of watching soap operas in the causation of primary angle closure glaucoma is discussed."}
+{"text": "This article briefly describes the biological pathways involved in the development of RCC and the results of clinical trials using targeted therapy in metastatic RCC.Renal cell carcinoma (RCC) is a highly vascular tumor in which a growing understanding of disease biology has been translated into clinically active systemic therapies. The most clinically developed targeted therapies in advanced RCC are those that target the vascular endothelial growth factor (VEGF) ligand or receptor (VEGFR) and therapy directed against the mammalian target of rapamycin (mTOR). Sutent and sorafenib are orally available inhibitors of the VEGFR and platelet derived growth factor receptor (PDGFR). Temsirolimus is an mTOR inhibitor that leads to G"}
+{"text": "Addiction Science & Clinical Practice would like to thank all reviewers who have contributed to the journal in Volume 9 (2014).The editor of  Marc AuriacombeFrancePreben BendtsenSwedenNicolas BertholetSwitzerlandRandall BrownUnited States of AmericaSpencer BujarskiUnited States of AmericaDebbie ChengUnited States of AmericaJan CopelandAustraliaJohn CunninghamAustraliaItai DanovitchUnited States of AmericaCarol Dawson-RoseUnited States of AmericaWilliam DeJongUnited States of AmericaMichelle DrapkinUnited States of AmericaQuyen Epstein-NgoUnited States of AmericaLoretta FinneganUnited States of AmericaNiamh FitzgeraldUnited KingdomJacques GaumeSwitzerlandStuart GitlowUnited States of AmericaTraci GreenUnited States of AmericaKevin HaggertyUnited States of AmericaJan KamphuisNetherlandsRobert KempainenUnited States of AmericaMegan LimAustraliaJan LindsayUnited States of AmericaKarsten LunzeUnited States of AmericaJim McCambridgeUnited KingdomAnna McDaniUnited States of AmericaJennifer MerrillUnited States of AmericaNicola MetrebianUnited KingdomJane MetrikUnited States of AmericaKaren MiottoUnited States of AmericaWillscott NauglerUnited States of AmericaJosiah RichUnited States of AmericaRutherfoord RoseUnited States of AmericaAndrew SaxonUnited States of AmericaGM SchippersNetherlandsJ.D. SmithUnited States of AmericaCindy ThomasUnited States of AmericaSteven ZeliadtUnited States of America"}
+{"text": "The title of this article contains a typo and should read as follows: \"Recurrent Biliary Obstruction Secondary to Portal Biliopathy and the Role of Cholangioscopy: A Case Report.\"The letter \"n\" was erroneously removed from \"Cholangioscopy\" prior to publication. The Cureus editorial team offers its sincere apologies for this error."}
+{"text": "The following information is missing from the Funding section: Partial funding also through Model of Infectious Disease Agent Study National Institution of General Medical Sciences U54GM111274."}
+{"text": "There is an error in the funding statement. The number of the National Institutes of Health grant \"GM074942\" should instead be \"GM094585\"."}
+{"text": "S19 FileHere we report and discuss a number of auxiliary results supporting the main findings of the principal paper and assess the robustness of our calculations.(PDF)Click here for additional data file."}
+{"text": "Fertility Research and Practice would like to thank all of our reviewers who have contributed to the journal in Volume 1 (2015).The editors of  Aaron StyerUnited States of AmericaAlexander QuassUnited States of AmericaAmanda StephensUnited States of AmericaAmber CooperUnited States of AmericaBorut KovacicSloveniaDaniel KaserUnited States of AmericaDivya ShahUnited States of AmericaElizabeth StewartUnited States of AmericaErma DrobnisUnited States of AmericaGordon BatesUnited States of AmericaHelene BernsteinUnited States of AmericaKathy Sharpe-TimmsUnited States of AmericaLeslie FarlandUnited States of AmericaQuaker HarmonUnited States of AmericaRandi GoldmanUnited States of AmericaRonit MachtingerIsraelSacha KriegUnited States of AmericaSanjeeva ReddyIndiaSerene SroujiUnited States of AmericaShruthi MahalingaiahUnited States of AmericaTakeshi NagamatsuJapanTony PropstUnited States of AmericaWendy KuohungUnited States of AmericaXinna ChenChina"}
+{"text": "Despite the introduction of stents for large bowel obstruction, many patients still require an emergency laparotomy."}
+{"text": "The previously observed impairment of macrophage activity can then be explained at a subcellular level.Alveolar macrophages have recently been postulated as being involved in the aetiology of adult respiratory distress syndrome (ARDS). To evaluate their role, basal cyclic AMP levels and responsiveness of adenylyl cyclase alveolar macrophages were determined at four intermediate stages of developing respiratory distress in piglets using a protocol with repeated lung lavage. Examination of alveolar cells recovered from the subsequent lavages reveals an influx of granulocytes (neutrophils and eosinophils) within 1 h of two intensive lung lavages. During the developing respiratory distress the basal cyclic AMPlevel of alveolar macrophages increases and adenylyl cyclase responsiveness to prostaglandin E"}
+{"text": "The tissues and organs of multicellular eukaryotes are frequently observed tocomprise complex three-dimensional interspersions of different cell types. It isa reasonable assumption that different global patterns of gene expression arefound within these different cell types. This review outlines general experimentalstrategies designed to characterize these global gene expression patterns, based ona combination of methods of transgenic fluorescent protein (FP) expression andtargeting, of flow cytometry and sorting and of high-throughput gene expressionanalysis."}
+{"text": "This case report describes arthroscopic findings of the effect on articular distraction ofankle joint by means of external fixator for the patient with chondrolysis. Arthroscopyshowed fibrocartilage tissue lying between the talus and tibia to protect damaged articularsurfaces although apparent repair of surface cartilage failed to find."}
+{"text": "This brief meeting review summarizes the recommendations of NSF and NPGI fundedbioinformaticians concerning the future requirements for plant bioinformatics systems anddatabases."}
+{"text": "The presence or absence of intestinal metaplasia of the stomach was determined in 272 patients by direct vision biopsy of standardized intragastric sites using fiberoptic gastroscopy. Analysis of ABO blood groupings and Rhesus factor failed to reveal an association with metaplasia."}
+{"text": "Prevention of preterm birth and subsequent newborn immaturity is a primary goal of obstetrical care worldwide. Accumulated evidence shows that 1) as many as 25\u201350% of preterm births are caused by common genital tract infections and subsequent maternal/fetal inflammatory responses; 2) microbial and maternal host factors  play roles in preterm labor and preterm premature rupture of membranes (pPROM); 3) integrated aspects of maternal and fetal host responses  play increasingly understood roles in premature activation of parturition; and 4) identification and systemic treatment of common genitourinary infections, most importantly bacterial vaginosis (BV), reduce the risks of preterm delivery and PROM."}
+{"text": "Subjects/Discussion. Two cases of clinical and radiological response of recurrent mixed Mullerian tumours following treatment with either nasal (Buserilin) or intramuscular (Goserilin) GnRH analogues are reported and a short review of the evidence to support this treatment option presented."}
+{"text": "The incidence of tumours ectopically producing the human chorionic gonadotrophins was studied in patients with breast cancer. Specific radioimmunoassay of subunits of HCG was utilized. Nine out of 65 patients with carcinoma of breast showed the presence of circulating HCG. Patients with other pathological conditions of breast tissue did not show any evidence of circulating HCG."}
+{"text": "The total number of peripheral blood B lymphocytes was increased in the melanoma patients (1048/mmThe expression of excess IgD bearing lymphocytes in these melanoma patients may reflect a derepression of oncofoetal type."}
+{"text": "A brief account is given of two types of rare soft tissue sarcoma of uncertain histogenesis. The danger of mistaking the epitheloid sarcoma for a benign lesion is emphasized."}
+{"text": "The etiology of adenoma of the ampulla of Vater isnot well understood. Previous authors reported theassociation of this neoplasm with polycystic kidneydisease of two fraternal sisters. They concluded thatthese two conditions were somehow related. Wedescribe a case of ampullary adenoma associatedwith polycystic kidney disease. This presentationraises again the question of a possible link betweenthese two diseases."}
+{"text": "Sileneae\" [The published version of the article entitled \"Phylogenetic analysis of mitochondrial substitution rate variation in the angiosperm tribe ileneae\"  containe"}
+{"text": "Few data exist about perceptions regarding the etiology of foodborne illness. Among public health staff throughout Tennessee, the three pathogens most commonly believed to cause foodborne illness in the United States actually account for only 12% of disease. Fewer than 3% of respondents correctly identified the leading cause of foodborne illness."}
+{"text": "The fourth sentence of the last paragraph of the Results section was incorrect. The correct sentence is: Compared to the lowest estimated figure of 521 needing treatment (assuming conservative initiation criteria in place during the period of study), these figures suggest approximately half of infants requiring HAART had initiated treatment."}
+{"text": "Whereas sarcoma cell cultures obtained through meticulous efforts aimed at the elimination of allnon-malignant cells of the tumor's original microenvironment consist of subpopulations of tumor cells growing exclusivelywith the support of their own autocrine growth loops .Human sarcoma cell populations maintained in culture reflect to the native tumor cells better if the culture retains thosenonmalignant cells that comprised the tumor's microenvironment"}
+{"text": "Duodenal injury following blunt abdominal trauma is uncommon. The severity of injury can vary froman intramural haematoma to a duodenal rupture with associated transection of the pancreatic duct. Acase of duodenal rupture with avulsion of the ampulla of Vater is presented and discussed."}
+{"text": "A case of a primary carcinoid tumor of the common bile duct is presented. Diagnostic and therapeutic uncertainties of this extremely rare cause of jaundice are discussed."}
+{"text": "This paper gives a brief survey of the use of algebraic rewriting systems for modellingand simulating various biological processes, particularly at the cellular level."}
+{"text": "The authors also acknowledge support for this work from National Institutes of Health grant AI48489."}
+{"text": "Impact of electronic acute kidney injury (AKI) alerts with automated nephrologist consultation on detection and severity of AKI: a quality improvement study."}
+{"text": "This session will focus on recent advances in understanding how biological aging impacts neurological function and risk of developing age-related neurodegenerative diseases."}
+{"text": "The following information is missing from the Funding statement: The authors acknowledge Fondazione Cassa di Risparmio di Pistoia e Pescia for funding the contribution of S Simeone and MP Rambaldi."}
+{"text": "Women\u2019s Midlife Health would like to thank all of the reviewers who have contributed to the journal in Volume 1 (2015).The editor of  Annemarie KosterNetherlandsCarrie Karvonen-GutierrezUnited States of AmericaCassandra SzoekeAustraliaElsa StrotmeyerUnited States of AmericaGail GreendaleUnited States of AmericaGary VenoliniUnited States of AmericaGeena AthappillyUnited States of AmericaGlinda CooperUnited States of AmericaGloria BachmannUnited States of AmericaJanis MillerUnited States of AmericaJodi FlawsUnited States of AmericaJohn RandolphUnited States of AmericaJosefina RomagueraPuerto RicoJoyce BrombergerUnited States of AmericaL. Elaine WaetjenUnited States of AmericaLorraine DennersteinAustraliaMartha GoetschUnited States of AmericaMary SammelUnited States of AmericaMichelle WarrenUnited States of AmericaMorgana Mongraw-ChaffinUnited States of AmericaNancy PhillipsUnited States of AmericaNancy WoodsUnited States of AmericaSiob\u00e1n HarlowUnited States of America"}
+{"text": "Following publication of the original article (Guo et al."}
+{"text": "At the request of the authors and editors, the article titled \u201cOverexpression of NTRK1 Promotes Differentiation of Neural Stem Cells into Cholinergic Neurons\u201d [The corresponding author apologizes to the readers and editors of BioMed Research International."}
+{"text": "Following publication of the original article , the autJim DimitroulakisIncorrect author name upon publication:Jim DimitroulakosThe correct author name:"}
+{"text": "The human genome dominated science news last week. Both Science and Nature lead this week with articles about the simultaneous publication of the human genome sequence by the private company Celera Genomics and the publicly funded Human Genome Project (HGP)."}
+{"text": "The following information is missing from the Funding section: MB received funding from the National Alopecia Areata Foundation (USA) and Associazione Mediterranea Alopecia Areata ."}
+{"text": "Transcatheter aortic valve replacement (TAVR) has changed the landscape of interventional cardiology and is now the treatment of choice for patients with severe aortic stenosis and elevated surgical risk . TAVR wa"}
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+{"text": "Bugeranus carunculatus) has been decoded by next-generation sequencing and genome assembly. The assembled mitogenome, consisting of 16,679\u2009bp, has unique 14 protein-coding genes (PCGs), 22 transfer RNAs and 2 ribosomal RNAs genes. The complete mitogenome provides essential and important DNA molecular data for further phylogenetic and evolutionary analysis for wattled crane phylogeny.In this study, the complete mitogenome sequence of wattled crane ( Bugeranus carunculatus) is a large bird found in Africa, which populations are widely distributed in the southern Africa region, particularly in Angola, Botswana, Democratic Republic of Congo, Malawi, Mozambique, Namibia, Zambia and South Africa. Globally, wattled crane is listed as vulnerable and endangered species, under the International Union of Conservation for Nature (IUCN) Red Data List  were collected from Beijing Zoo in Beijing, China. The specimens were kept in the laboratory at \u221280\u2009\u00b0C, total genomic DNA was extracted using a DNA extract kit following the previously reports , 22 transfer RNA genes and two ribosomal RNA genes, all details were listed in GeneBank (MH041486) and shown in Struthio camelus, Grus japonensis, Grus Americana, Grus grus, Grus monacha, Grus nigricollis, Grus carunculatus, Anthropoides paradiseus, Grus vipio, Grus rubicunda, Grus Antigone, Grus Canadensis and Grus leucogeranus. We used MEGA6 to produce the phylogenetic tree based on the maximum-likelihood method (To further validate the new sequences, we used all of mitochondrial genome sequences published in GeneBank of other crane species to construct the phylogenetic tree. These species were as follows: d method . The phy"}
+{"text": "Mycosporine-like amino acids (MAAs), maximally absorbed in the wavelength region of 310\u2013360 nm, are widely distributed in algae, phytoplankton and microorganisms, as a class of possible multi-functional compounds. In this work, based on the Web of Science, Springer, Google Scholar, and China national knowledge infrastructure (CNKI), we have summarized and analyzed the studies related to MAAs in marine macroalgae over the past 30 years (1990\u20132019), mainly focused on MAAs distribution, contents, and types. It was confirmed that 572 species marine macroalgae contained MAAs, namely in 45 species of Chlorophytes, 41 species of Phaeophytes, and 486 species of Rhodophytes, and they respectively belonged to 28 orders. On this basis, we established an open online database to quickly retrieve MAAs in 501 species of marine macroalgae. Furthermore, research concerning MAAs in marine macroalgae were analyzed using CiteSpace. It could easily be seen that the preparation and purification of MAAs in marine macroalgae have not been intensively studied during the past 10 years, and therefore it is necessary to strengthen the research in the preparation and purification of MAA purified standards from marine macroalgae in the future. We agreed that this process is not only interesting, but important due to the potential use of MAAs as food and cosmetics, as well as within the medicine industry.  MAAs (mycosporine-like amino acids) are natural compounds with low molecular weight and exist in diverse aquatic organisms, from algae ,4,5,6,7 MAAs have maxima absorption ranging between 310 and 360 nm . They coAcrosiphonia arcta [Boodlea composite [Prasiola crispa ssp. antarctica [Prasiola crispa [Ecklonia radiata [Halopteris scoparia [Hydroclathrus clathratus [Laminaria saccharina [Ahnfeltiopsis devoniensis [Apophlaea lyallii [Bangia atropurpurea [Chondrus crispus [Gracilaria chilensis [Iridaea sp. [Palmaria palmata [Porphyra umbilicalis [Bangia atropurpurea [Calliarthron tuberculosum [Catenella repens [Gelidium lingulatum [Gloiopeltis furcate [Palmaria palmata [Pyropia plicata [Solieria chordalis [MAAs were found in marine organisms in the 1960s . Howeveria arcta , Boodleaomposite , Prasioltarctica , Prasiola crispa  and othea crispa ,5,7 in C radiata , Haloptescoparia , Hydroclccharina , and othccharina ,5,7; manoniensis , Apophla lyallii , Bangia purpurea , Chondru crispus , Gracilahilensis , Iridaeadaea sp. , Palmari palmata , Porphyrilicalis ,46. Frompurpurea , Calliarrculosum , Catenela repens , Gelidiungulatum , Gloiope furcate , Palmari palmata , Pyropia plicata , Solierihordalis  and othehordalis ,56,57,58http://210.28.32.218/MAAs/). Marine macroalgae as marine primary productivity have developed complex and unique metabolic pathways. Therefore, they have been become the target of exploiting natural bioactive components. To date, MAAs in more than 500 marine macroalgae have been reported. However, unfortunately, the summary and generalization about these researches were lacked. This made it very difficult to provide relevant information on MAAs of marine macroalgae. Therefore, this paper will provide an overview of MAAs in marine macroalgae since 1990 and focus on the contents and types of MAAs, and their distribution in marine macroalgae. The two databases related MAAs in marine macroalgae have been showed ,59. AlthCiteSpace was a software used in scientific literature to identify and display new trends of scientific development . FinallyIn our survey that summarized of more than 660 species, 572 species of marine macroalgae contained MAAs, found namely in 45 species in Chlorophyta, 41 species in Phaeophyta, and 486 species in Rhodophyta , and theThe research efforts made pertaining to MAAs in marine macroalgae have drawn signifficant attention since 1990. The contents and composition of MAAs in marine macroalgae were important in developing MAAs. Therefore, the summary and analysis of total MAAs contents and MAAs composition in marine macroalgae have been conducted according to different orders in this paper .Prasiola crispa ssp. antarctica [Prasiola crispa collected from South Shetlands [MAAs have been found in 45 species of the green algae in Chlorophyta ,35,64. Ahetlands  and KongChorda tomentosa [Desmarestia menziesii [Dictyota bartayresii [Dictyosiphon foeniculaceus [Pilayella littoralis [Ecklonia radiata [Halopteris scoparia [Hydroclathrus clathratus [Sargassum oligocystum [The brown algae 41 species) in Phaeophyta also were confirmed to contain MAAs 1 species,32,37,38tayresii , Dictyosathratus  and Sarggocystum , the totActinotrichia fragilis [Asparagopsis taxiformi [Galaxaura oblongata [Gelidium corneum [Georgiella confluens [Rhodymenia spp. Belonging to order Rhodymeniales had a surprisingly high MAAs contents  [http://210.28.32.218/MAAs/) built by our team, which we will explain in detail later. A total of 486 MAA-containing strains of macroalgal Rhodophytes were detected. In order to present these reports from 1990 to 2019 more clearly, they are shown in two maps in fragilis , Asparagaxiformi , Galaxaublongata , Gelidiu corneum , and Geoonfluens , etc. [3onfluens ,69, and mg/g DW) . This isFrom 1990 to 2019, the survey found that MAAs in marine macroalgae mainly focus on macroalgal Rhodophytes , therefoBoodlea composita [Chaetomorpha aerea [Codium fragile [Enteromorpha intestinalis [Halimeda polentia [Rhizoclonium tortuosum [Spongomorpha spinescens [Ulva lactuca [Agarum cribosum [Alaria esculenta [Ascophyllum nodosum [Chorda filum [Drsmarestia aculeata [Elachista fucicola [Fucus vesiculosis [Laminaria saccharina [Laminariocolas tomentosoides [Sargassum fluitans [Alaria esculenta [Elachista fucicola [Fucus vesiculosis [Laminaria saccharina [Laminariocolas tomentosoides [Acanthophora specifera [Chondrus crispus [Corallina officinalis [Cystoclonium purpureum [Lomentaria orcadensis [Mastocarpus stellata [Phycodrys rubens [Porphyra umbilicalis [Actinotrichia fragilis [Ahnfeltiopsis devoniensis [Amphiroa rigida [Asparagopsis armata [Bangia atropurpurea [Apophlaea lyallii [Palmaria palmata [Acanthophora specifera [Bangia atropurpurea [Caloglossa apomeiotica [Porphyra dioica [Bostrychia radicans [Ceramium nodulosum [Catenella impudica [Curdiea racovitzae [Gracilaria domingensis [Gymnogongrus griffithsiae [Mastocarpus stellatus [In omposita , Chaetomha aerea , Codium  fragile , Enteromstinalis , Halimedpolentia , Rhizoclortuosum , Spongominescens , and Ulv lactuca  is more cribosum , Alaria sculenta , Ascophy nodosum , Chorda da filum , Drsmareaculeata , Elachisfucicola , Fucus viculosis , Laminarccharina , Laminartosoides , and Sarfluitans , this prsculenta , Elachisfucicola , Fucus viculosis , Laminarccharina , and Lamtosoides . In Rhodpecifera , Chondru crispus , Coralliicinalis , Cystoclurpureum , Lomentacadensis , Mastocastellata , Phycodrs rubens , Porphyrilicalis , and othilicalis ,76,77,78fragilis , Ahnfeltoniensis , Amphiroa rigida , Asparags armata , and Banpurpurea , etc. [1purpurea ,85,86,87 lyallii  and Palm palmata , the pro palmata ,5,73, Ph palmata ,73 speci palmata ,39,88,89purpurea , Calogloa dioica , Bostrycradicans , Ceramiuodulosum , Catenelimpudica , Curdieacovitzae , Gracilaingensis , Gymnogofithsiae , and Mastellatus , etc. [3tellatus ,92,93. Stictosiphonia tangatensi [Chondrus crispus, which in culture esposured to green or blue light radiation, exhibited asterina-330, palythene, palythinol and shinorine that were lack of MAAs in the field sample. Similary phenomenons also occurred in other seaweeds, such as Bostrychia radicans [Caloglossa stipitata [Chondrus crispus [Kallymenia antarctica [Mazzaella laminarioides [Neuroglossum ligulatum [Palmaria decipiens [Plocamium cartilagineum [Porphyra columbina [Porphyra endiviifolium [In addition, it is worth mentioning that the difference of the total MAAs or MAA value between cultivated marine macroalgae and field material existed from same collection location. For exsample, cultured ngatensi  exhibitengatensi . Chondruradicans ,40, Calotipitata ,49, Chon crispus ,72, Kallarioides , Neuroglolumbina ,43, and The specific parameters of 10 types of MAAs in marine macroalgae, such as structure, extinction coefficient, retention time and maximum absorption wavelength, have been showed in In order to clearly present the distribution of specific MAA in each marine macroalgae, based on the literature information from the Web of Science, Springer, Google Scholar, and CNKI, http://210.28.32.218/MAAs/) of MAAs in marine macroalgae over the past nearly 30 years utilizing data information from the Web of Science, Springer, Google Scholar and CNKI. In this database, more detailed information in relation to algal MAAs, such as the total contents of MAAs, content of specific MAA, type of MAAs, origin of marine macroalgae, and/or composition of specific MAA in MAAs, was listed. This was the comprehensive summary database of MAAs in marine macroalgae at home and abroad, and it was open and free. In order for the scientists in the field to have a more comprehensive and clearer understanding of MAAs in marine macroalgae, it was necessary to establish a corresponding database. Therefore, our project team established a database  in Chlorophyta, the brown algae 37 species) in Phaeophyta, and the red algae 45 species) in Rhodophyta were confirmed to have no detectable MAAs concentrations , such as7 species plumosa , Odontha5 species dentate . MAAs were an important class of bioactive secondary metabolites in marine macroalgae ,68, theiMAAs were multi-functional compounds, namely included UV-photoprotective activity , antioxiIn fact, the extraction of MAAs in marine macroalgae has been involved in many studies which were mainly concentrated on the distribution ,95,114, Bostrychia scorpioides [Catenella repens [Chondrus crispus [Palmaria palmata [Porphyra dioica [Porphyra haitanensis [Rhodymenia pseudopalmata [Bangia atropurpurea [Eucheuma [Gracilaria changii [Porphyra vietnamensis [Porphyra yezoensis [Rhodymenia pseudopalmata [Agarophyton chilense [Ahnfeltiopsis devoniensis [Bostrychia scorpioides [Champia novae-zelandiae [Chlamydomonas hedlyei [Chondracanthus chamissoi [Chondrus crispus [Gelidium corneum [Gelidium lingulatum [Gracilaria changii [Gracilaria cornea [Mastocarpus stellatus [Palmaria decipiens [Palmaria palmata [Porphyra dioica [Porphyra rosengurttii [Porphyra sp. [Porphyra tenera [Porphyra yezoensis [Pyropia leucosticte [Pyropia plicata [etc., that were often used as standards for identification and quantification of MAAs, also have been researched. The extraction process of MAAs in Eucheuma [Gloiopeltis furcata [Gracilaria chilensis [Porphyra sp., [Porphyra haitanensis [Porphyra yezoensis [Until now, there were few studies on the isolation, purification, and preparation of MAAs in marine macroalgae. Six novel mycosporine-like amino acids, bostrychines A\u2013F, were obtained from rpioides . A new Ma repens . MAAs in crispus , Palmari palmata , Porphyra dioica , Porphyrtanensis  and Rhodopalmata  have beepurpurea , EucheumEucheuma , Gracila changii , Porphyrnamensis , Porphyrezoensis , and Rhoopalmata  has beenchilense , Ahnfeltoniensis ,129, Bosrpioides ,77, Chamelandiae , Chlamyd hedlyei , Chondrahamissoi , Chondru crispus ,57, Geli corneum ,129, Gelngulatum , Gracila changii ,130, Graa cornea , Mastocatellatus ,77, Palmecipiens , Palmari palmata , Porphyrngurttii ,119, Porhyra sp. ,131, Pora tenera ,132, Porezoensis ,128, Pyrcosticte  and Pyro plicata , such asEucheuma ,133, Glo furcata , Gracilahilensis , Porphyryra sp., ,135, Porezoensis  has beenUtilizing data obtained from the Web of Science, Springer, Google Scholar, and CNKI, the reliable material sources of this systematic manuscript paper were obtained from literature published during the last thirty years. Further, to provide more explicit knowledge, the development tendency of the studies about MAAs in marine macroalgae has been analyzed by using CiteSpace (4.0) . Corresphttp://210.28.32.218/MAAs/), which was built by our team. A great deal of reports which were collected from the Web of Science, Springer, Google Scholar, and CNKI were built for this database. In this work, total MAAs content and/or specific MAA concentration in each marine macroalgae species was not clearly listed, however, they were obtained using an online database  in them. Five MAAs, namely shinorine, porphyra-334, palythine, asterina-330, and palythinol were the most common in Rhodophytes, followed by mycosporine-glycine, palythene, and usujirene. Among them, seven MAAs, including asterina-330, mycosporine-glycine, palythene, palythinol, porphyra-334, palythine, and shinorine, were found in Chlorophytes and Phaeophytes. In addition, so far, aplysiapalythine A, aplysiapaly thine B, catenelline, prasiolin and bostrychines A\u2013F only have been found in Rhodophytes. According to different orders of marine macroalgae, the total MAAs contents in 12 species macroalgal Chlorophytes, 8 species macroalgal Phaeophytes and 323 species macroalgal Rhodophytes were pointed out in this work. Meanwhile, we detailed the structure, extinction coefficient, retention time, and maximum absorption wavelength of 10 common MAAs. http://210.28.32.218/MAAs/) for MAAs in 501 species of marine macroalgae was established on datas metioned above to quickly retrieve information related to MAAs in marine macroalgae since 1990. In this database, the source (field/culture) and collection site of marine macroalgae, total MAAs content, MAA type and/or content have been listed. Further, an open online database (Finally, the studies about MAAs in marine macroalgae were analyzed using CiteSpace considering the past 10 years, and the result demonstrated that the purification and preparation of MAA purified standards from marine macroalgae constitute a domain worthy to be penetratingly explored in future studies. In order to gain better knowledge about the current states and progress of MAAs in marine macroalgae, more reports have to be collected regarding MAAs from other sources of data. Overall, based on data from the last 30 years, our work provided more a comprehensive reference and fast inquiry about MAAs in marine macroalgae for relevant researchers."}
+{"text": "Currently, most commercial recombinant technologies rely on host systems. However, each host has their own benefits and drawbacks, depending on the target products. Prokaryote host is lack of post-transcriptional and post-translational mechanisms, making them unsuitable for eukaryotic productions like phytochemicals. Even there are other eukaryote hosts , but those hosts have some limitations, such as low yield, high cost, time consuming, virus contamination, and so on. Thus, flexible platforms and efficient methods that can produced phytochemicals are required. The use of heterotrophic microalgae as a host system is interesting because it possibly overcome those obstacles. This paper presents a comprehensive review of heterotrophic microalgal expression host including advantages of heterotrophic microalgae as a host, genetic engineering of microalgae, genetic transformation of microalgae, microalgal engineering for phytochemicals production, challenges of microalgal hosts, key market trends, and future view. Finally, this review might be a directions of the alternative microalgae host for high-value phytochemicals production in the next few years. Generally, phytochemicals were classified into six major categories based on their chemical structures and characteristics  . Even thEukaryotic algae, especially green microalgae, share evolutionary ancestry with land plants . They hoNormally, microalgae are considered photoautotrophic organisms, whereas heterotrophic cultivation, which can use external carbon sources under dark conditions, has also been used to obtain high value products. Heterotrophs have many advantages compared to autotrophs, such as growing on a larger scale, having more FDA-approved standards and protocols for industrial fermenters, and ability to grow in higher cell density, among others . Green mMicroalgae are also known as single-cell algae that have a vital role in the food chain. Interestingly, microalgae can produce other nutrients that are also found in higher plants, including synthesizing lipids, fatty acids, proteins, nucleic acids, carbohydrates, fibers, starches, vitamins, and antioxidants . UnicellRecently, attention has been drawn to microalgae as simple models for a sustainable source of high-value compounds, ranging from therapeutic proteins to biofuels . ApparenEscherichia coli is not always the easiest hosts for this process ((1) Compared with traditional used host, prokaryotic hosts are the most commonly used platforms. Due to post-translational modification and protein localization are important for the production of phytocompounds or eukaryotic substances, whereas, prokaryotic  process . However process . Hence,  process . Moreove process . The com(2) Compared to plant cultivation and synthesized phytochemicals, microalgae are easily scalable in fermenters or bioreactors compared to plant cultivation because they can be constructed on any land type or industrial site . This shChlamydomonas and tobacco are alike, as both proteins synthesis machinery in chloroplast is highly conserved. (3) Compared to transgenic plant, microalgae share evolutionary ancestry with land plants. That means genetic manipulation techniques might be easily adapted to microalgae, such as codon optimization, intron addition, expression methods, and vectors . For tra2 and light as inorganic carbon and energy sources, whereas heterotrophs use organic carbon as a source of carbon and energy  Compared among microalgae cultivation, heterotrophic microalgae have more benefits, such as cheaper nutrients, low cost of instruments, and easy to operate and maintain. They can be adapted to a large scale with no cell density and less-stress concerns in only a few weeks . Autotrod energy . Severalproducts . Althougproducts . For bioproducts . Moreovenditions . In partnditions . In addinditions . From onnditions . The carnditions . While, nditions . Thus, cChlorella vulgaris  is normally used as a food additive, feed for animals, and diet supplements. Moreover, Arthrospira platensis , which has high protein and nutrient contents, is consumed as food and feed ((5) In medicine, where production for humans is regulated under strict safety aspects , there aand feed . Therefo(6) When considering the environmental impact of host systems, there are three main indicators, namely less greenhouse gas emissions, low water supply, and efficiency of land use. Heterotrophic microalgae offer these three main criteria. A study found that whole algae protein has a lower water footprint than beef and whey but more protein per hectare than other sources . Moreove2. In the heterotrophic status of Chlorella sorokiniana, high aeration increased cell growth, fatty acid yield, and unsaturated dienoic and trienoic fatty acids; conversely, this decreased cell lipid content  and less-complexity with only 99 genes. Although chloroplast transformation is also feasible for plenty of plant species, such as tobacco, tomato, and petunia, there are still fundamental challenges and less achievement reports than those for nuclear transformation  mediated transformation, particle bombardment, and Agrobacterium-mediated transformation . The cel enzymes . The mos enzymes . This tr enzymes . Thus, cCommon strategies have been considered, including increasing transcription levels by choosing strong promoters with appropriate enhancers and leader sequences, the improvement of translation via codon usage optimization, control of transgene copy number, gene product targeting by using signal peptide, and host genome position .C. reinhardtii . Promoters are a crucial factor for gene expression and have a significant transcriptional regulation effect. There are different types of optional promoters. In general, high gene expression is positively correlated with a strong promoter. Some native promoters, including heat shock protein 70A (HSP70A), Rubisco small submit (RBCS2), or photosystem I protein D (psaD), are used in nhardtii . Moreoveer genes . Thus, ter genes . Accordiromoters . Thus, fromoters .Reporter genes that encode easily recognizable proteins are useful for studying transformation efficiency, protein localization, and stability of transgenes. While selectable markers are proteins for helping the selection of positive transformants by being resistant to antibiotics , herbicides , or having a function as a metabolic mutant  . AlthougP. tricoronutum (diatom) because diatom is sensitivity and slow growth, even though they have less-complex genetic data.Codon optimization is also important to consider because it significantly affects translation efficiency and protein expression levels. Codon bias from tRNA abundance can be quite different not only for various species genomes but for various organelles. The length of vector construction can lead to false positive transformants in microalgal hosts. The efficiency of positive transformants can range from 2\u201350% depending on the construct . MicroalChlamydomonas, but these cannot be applied for all microalgae. Until now, non-model microalgae were still a challenge because of the lack of development in tools and strategies , mammalian cells (0. 55\u201380 mg/L), and insect cells (80\u2013300 mg/L). Fortunately, rapid growth of Chlorella might gain higher yield . Some organizations, such as European Food Safety Authority (EFSA)rganisms . For insTremendous breakthroughs in the new discovery of novel expression platforms for producing biopharmaceuticals or phytochemicals are needed. Heterotrophic microalgae are a sustainable and scalable host for recombinant technology. Microalgae share many attributes with higher plants, such as glycosylation patterns and having low risk of contamination by viruses or prions. Unlike higher plants, the closed-system of heterotrophs in fermenters is attractive because of safety aspects for biopharmaceutical products, cost-effectiveness, well-controlled environment, fast growth, and high yield on a large scale, suggesting the use of these organisms as alternative biotechnology. Thus, the genetic tools and design concepts of heterotrophic microalgae should be developed for increasing the number of known microalgae species under heterotrophic conditions.Chlorella sp., Dunaliella salina, and Haematococcus pluvialis, may provide opportunities for reducing costs and scaling-up; moreover, these promising hosts will help to expand the various applications for recombinant microalgae-based production. Apparently, expanding basic or applied research for the use of autotrophic and heterotrophic microalgae is necessary.Microalgae cultivation is well known to be the most profitable business in biotechnological industry since it has less waste. Additionally, the development of other GRAS species that have been grown commercially, such as The challenges to meet the economic demand are multifaceted, including quantities, qualities, and cost-effectiveness. Improving yield and product quality in some microalgal hosts remain to be addressed. A small number of microalgal hosts are approaching commercialization as the demand for therapeutics and other production is continually growing. These still remain some limitations for being microalgal host, such as difficult engineering due to the lack of a high-efficiency genetic toolbox , less-available molecular specific toolkits, short-term stability genetic system, and less efficient manipulation outside laboratory. To counter these limitations of phytocompounds using microalgal host, the basal study of molecular elements, such as identification and cloning of promoters, enhancers, and terminator should be studied up more. The innovation and toolkits for microalgae are also need to be specifically improved. Using industrial or agricultural waste contained with less microbial load should be adapted to medium for sustainability and saving cost for industrial scale. Indeed, fundamental knowledge and research are also necessary, making more research on various cultivation conditions a good option within the next few years.Many plant chemicals that are of pharmaceutical interest are waiting to be produced by the benefits of genetic engineering of microbial synthesis on an industrial scale. In terms of sustainability, combined with economic, environmental, and short life cycle benefits, hetero- and autotrophic microalgae may reach this goal.SJ: conceptualization, writing\u2013original draft preparation, writing-reviewing, editing, and investigation\u2013data collection. CP: conceptualization, writing\u2013original draft preparation, writing\u2013reviewing, editing, and supervision. Both authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Hyphantria cunea appear incorrectly throughout the article. The correct gene names are HcunOBPs, HcunPBPs, HcunCSPs, HcunORs, HcunGRs, HcunIRs and HcunSNMPs. Please see the original abbreviations and the corrected abbreviations here.The prefixes of all abbreviated names of genes related to"}
+{"text": "The author liast has ben updated from Jie Geng, Yitong Cai, Yali Zhao, Zheyuan Wang, Mancai Wang, and Zhihong Wei to Jie Geng, Yali Zhao, Zheyuan Wang, Mancai Wang, and Zhihong Wei in the published version.This article, \u201cDressing interventions to heal pressure ulcers: A protocol for an overview of systematic reviews and meta-analysis\u201d,"}
+{"text": "Differential impacts of the COVID-19 pandemic have brought deeply rooted inequities to the forefront, where increasing evidence has shown that racialized immigrant and migrant (im/migrant) populations face a disproportionate burden of COVID-19. Im/migrant communities may be worst affected by lockdowns and restrictive measures, face less opportunity to physically distance or stay home sick within \u2018essential\u2019 jobs, and experience severe barriers to healthcare. Insufficient attention to experiences of racialized im/migrants in current pandemic responses globally highlights an urgent need to more fulsomely address unmet health needs through an anti-racist, equity-oriented lens. This commentary aims to highlight the need for public health and clinical training, research, and policy to thoughtfully prioritize im/migrant health equity during and beyond the COVID-19 pandemic.Global pandemic responses have neglected im/migrants by continuing to ignore or insufficiently address inequities, exacerbating COVID transmission, xenophobia, and occupational injustice. Deaths, illness, stress, and other negative outcomes of the overlapping epidemics of COVID-19 and structural racism disproportionately borne by racialized im/migrants suggest the urgent need for action. As evidence mounts about how im/migrants have been left behind in times of crises, we need enhanced focus on health equity within COVID-19 research and interventions, including research that examines and pursues structural interventions necessary to mitigate these impacts, and that identifies patterns and harms of xenophobic policy, structural racism, and white supremacy in shaping im/migrant health outcomes. We must also strengthen anti-racist and equity-oriented curriculum within health education, and ensure sufficient attention to the needs of im/migrant communities within public health, clinical, and research training.The COVID-19 pandemic has exacerbated and rendered more visible the deeply rooted health and social inequities faced by racialized im/migrants across diverse settings. We argue for a greater emphasis on equity-focused and anti-racist im/migrant health research, interventions, and training. Policymakers and practitioners must ensure that healthcare policies and practices do not exacerbate inequities, and instead meaningfully address unmet needs of communities, including racialized im/migrants. Ethical and respectful community engagement, commitment and collaboration with global, national, and local communities, policymakers, academics, and educators, as well as accountability across sectors, is critical. The COVID-19 pandemic has swept the globe, but its differential impacts among racialized and marginalized immigrant populations have brought deeply rooted inequities to the forefront. Racialization continues to ensure that the identities of immigrants within social structures and institutions are defined by their race, leading to severe inequities among immigrants of colour\u00a0, 3. We uGlobal pandemic responses have neglected im/migrants by continuing to ignore or at best, insufficiently address inequities, exacerbating COVID transmission, xenophobia, racism, and occupational injustice\u00a0. XenophoThese inequities manifest across diverse settings. Despite portrayals of Canada as a setting of universal healthcare and inclusion, racialized immigrants with and without status face stark health and social inequities prior to and during COVID-19, including racial profiling by police, inabilities to meet basic needs, and barriers to healthcare\u00a0. Im/migrAs evidence mounts about how racialized immigrants have been left behind in times of crises, there is a need to sharpen public health decision-making and evidence with intentional considerations of equity and social justice. Alongside crucially needed biomedical work including COVID-19 testing and vaccine development, there is a need to address deep inequities being produced and exacerbated by the COVID-19 pandemic by examining and pursuing structural interventions that are necessary to mitigate these impacts\u00a0. In the Finally, there is a need to strengthen anti-racist and equity-oriented curriculum within health education, and ensure sufficient attention to the needs of im/migrant communities within public health, clinical, and research training. This includes addressing the severe structural challenges faced by international students across settings during the pandemic;\u00a0 during CThe COVID-19 pandemic has exacerbated and rendered more visible the deeply rooted health and social inequities faced by racialized im/migrants across diverse settings. In this commentary, we argue for a greater emphasis on equity-focused and anti-racist im/migrant health research, interventions, and training. Policymakers and practitioners have a responsibility to ensure that healthcare policies and practices do not exacerbate inequities, and instead meaningfully address unmet needs of communities, including racialized im/migrants. Ethical and respectful community engagement is critical for achieving this. To fulsomely advance equity-focused research and interventions, deep commitment and collaboration with global, national, and local communities, policymakers, academics, and educators, as well as accountability across sectors, is needed."}
+{"text": "Agastache Gronovius, Hyptis Jacquin, Lavandula L., Lepechinia Willdenow, Mentha L., Melissa L., Ocimum L., Origanum L., Perilla L., Perovskia Kar., Phlomis L., Rosmarinus L., Salvia L., Satureja L., Teucrium L., Thymus L., Zataria Boissier, and Zhumeria Rech. Along with acute toxicity, the sublethal effects were illustrated such as repellency, antifeedant activity, and adverse effects on the protein, lipid, and carbohydrate contents, and on the esterase and glutathione S-transferase enzymes. Chemical profiles of the introduced essential oils and the pesticidal effects of their main components have also been documented including terpenes  and aliphatic phenylpropanoid. Consequently, the essential oils of the Lamiaceae plant family and their main components, especially monoterpenoid ones with several bioeffects and multiple modes of action against different groups of damaging insects and mites, are considered to be safe, available, and efficient alternatives to the harmful synthetic pesticides.On the basis of the side effects of detrimental synthetic chemicals, introducing healthy, available, and effective bioagents for pest management is critical. Due to this circumstance, several studies have been conducted that evaluate the pesticidal potency of plant-derived essential oils. This review presents the pesticidal efficiency of essential oils isolated from different genera of the Lamiaceae family including  Synthetic chemicals such as carbamates, pyrethroids, organochlorines, and organophosphates have played a principal role in the plant protection strategies against agroindustrial and medicinal arthropod pests within the past and present century. However, there are public concerns all over the world about the negative side effects of detrimental chemicals such as residues on food and in drinking water, acute or chronic toxicity to humans and other non-target organisms, outbreaks of secondary pests by abolishing their natural enemies, and the emergence of pest resistance ,2,3. AccIn recent years, the utilization of biopesticides in pest management has been progressing. Three categories of biopesticides have been identified by the United State Environmental Protection Agency as follows: biochemical biopesticides such as botanical pesticides and other natural compounds, plant-incorporated protectants such as transgenic Bt toxin, and biocontrol organisms such as microbial fungi and parasitoid wasps . Plants Although the susceptibility of many detrimental insects and mites to the essential oils extracted from different plant families has been documented, there are considerably many more reports on the high pesticidal potential of diverse species in the Lamiaceae family ,15,16. TPlant essential oils, which are the principal reason for the odors of aromatic plants, are complex mixtures of terpenic , aromatic, and aliphatic components with about 24 to 48 h half-lives, and are non-persistent in the environment ,17. The Essential oils exhibit a wide spectrum of pesticidal activities from lethal to sublethal effects against a wide range of insects and mites ,24,28. PThe Lamiaceae or mint family with a wide distribution in different natural ecosystems comprises 236 genera and about 6000 species . These aAgastache, Hyptis, Lavandula, Lepechinia, Mentha, Melissa, Ocimum, Origanum, Perilla, Perovskia, Phlomis, Rosmarinus, Salvia, Satureja, Teucrium, Thymus, Zataria, and Zhumeria have great potential in pest management strategies. According to Lavandula, Mentha, Ocimum, Origanum, Satureja, and Thymus species are among the most promising plants in detrimental pest management [The search in large scientific databases including Scopus, Web of Science, PubMed, and Google Scholar displayed that Plant genera of the family Lamiaceae including nagement ,45,46,47Agastache foeniculum (Pursh) Kuntze, Lavandula angustifolia Miller, Lavandula hybrida Briq., Lavandula luisieri (Rozeira) Rozeira, Mentha microphylla C. Kock, Mentha spicata L., Perovskia atriplicifolia Benth., Rosmarinus officinalis L., Salvia apiana Jepson, Salvia multicaulis Vahl., Salvia pratensis L., and Satureja hortensis L. essential oils. In contrast, some others were found as main components in the unique species. Sclareol, for instance, was reported as a major component only in the Salvia sclarea L. essential oil , mono- (two units), sesqui- (three units), di- (four units), ses- (five units), tri- (six units), tetra- (8 units), and polyterpenes (n units) [Terpenes which are large and diverse natural hydrocarbons are commonly classified according to the number of isoprene units Cn units) . Althougn units) ,87. In gn units)  possess Sitophilus zeamais Motschulsky (Coleoptera: Curculionidae) [Salvia leriifolia Benth (Lamiaceae) showed the highest insecticidal activity as fumigant and contact agents against adults of C. maculatus, S. oryzae, and T. castaneum [C. maculatus [T. castaneum adults. Terpinen-4-ol and \u03b1-terpinene as cyclic terpenes had the most fumigant toxicity followed by menthone, \u03c1-cymene, \u03b1-pinene, and eugenol [Cimex lectularius L.) and it was found that cyclic monoterpenoids thymol and carvacrol had much more fumigant toxicity than bicyclic monoterpenoids camphor and 1,8-cineole, cyclic monoterpene limonene, bicyclic monoterpene \u03b1-pinene, and phenylpropanes cinnamaldehdye, citronellic acid, eugenol and methyl eugenol [ionidae) . The ketionidae) . The essastaneum . It was aculatus . In anot eugenol . In cont eugenol . Consequ eugenol .S. hortensis, Mentha pulegium L., Mentha viridis L., R. officinalis, and Z. multiflora was demonstrated against Tetranychus turkestani Ugarov and Nikolskii (Acari: Tetranychidae) [R. officinalis essential oil were toxic against Tetranychus urticae Koch. (Acari: Tetranychidae) on bean and tomato plants. However, a synergistic effect among the active and inactive constituents was observed when they were mixed with each other [Apart from insecticidal activity, the acaricidal efficacy of essential oils extracted from some Lamiaceae species have also been reported. The acaricidal effects of the essential oils of ychidae) . Some ofch other . Mentha piperita L. (Lamiaceae) was found to be an effective larvicidal agent against the housefly, Musca domestica (L.) (Diptera: Muscidae) [M. piperita had higher larvicidal pupicidal than M. citrata Ehrh oil in contact and fumigant applications against M. domestica [M. piperita which had the most promising larvicidal against Anopheles stephensi Liston and Aedes aegypti L. (Diptera: Anophelinae) among 25 tested plant essential oils [M. piperita essential oil with a high quantity of bioactive monoterpenes were also reported on the M. domestica and An. stephensi larvae [Culex quinquefasciatus Say were assessed and it was demonstrated that carvacrol and thymol as cyclic monoterpenoids were the most toxic against larvae among all tested components [Since larva is the damaging stage of insects, evaluating the larvicidal effect of essential oils is of great importance. For example, the larvicidal potential of essential oils of different Lamiaceae species has been reported in literature studies. The oil of uscidae) . The essomestica . Similarial oils . The lari larvae . In othemponents .M. piperita and M. citrata showed effective repellency against M. domestica populations [Salvia dorisiana Standl, S. longifolia Nutt, and S. sclarea were reported against Aedes albopictus (Diptera:Culicidae) [Ephestia kuehniella (Zeller)  and Plodia interpunctella (H\u00fcbner)  were also significantly repelled by Thymus daenensis Celak essential oil [M. pulegium caused high repellent activity against the adults of T. castaneum and Lasioderma serricorne (F.) (Coleoptera: Anobiidae) [M. piperita essential oil on M. domestica has been reported which was higher than Eucalyptus globulus Labill and Citrus sinensis (L.) Osbeck essential oils [Most of the Lamiaceae essential oils also have high repellent activity toward insects. For example, the essential oils of ulations . The replicidae) . Ephestitial oil . The essobiidae) . Furtherial oils .The mechanism of action of Lamiaceae essential oils and their components on pests is not completely recognized but, based on their diverse lethal and sublethal effects, it is obvious that these natural agents affect in different ways. The difference in the pesticidal potential of these agents could also be related to differences in their structures. For example, the higher toxicity of oxygenated monoterpenes as compared with the non-oxygenated ones could be due to the different structures of these components. Furthermore, according to recent findings, different physiological and behavioral modes of action of essential oils and their components have been reported. For example, inhibition of adenosine triphosphatases (ATPases), acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) ,96, and The overuse of synthetic chemicals in pest management programs has caused several side effects, such as contamination of drinking water; residues on food; acute or chronic negative effects on mammals and non-target organism including bird, bees, parasitoids, and predators; and the development of pest resistance. Due to this circumstance, researchers have focused on the application of plant-derived essential oils from different plant genera and families in recent years. Although the pesticidal properties of essential oils extracted from different species of Apiaceae, Lamiaceae, Myrtaceae, Rutaceae, Verbenaceae, and Zingiberaceae families have been recognized, the present review focused on the Lamiaceae species based on their availability and diversity. Along with these advantages, plant essential oils generally are nontoxic to mammals and other vertebrates. Furthermore, based on their multiple modes of action, development of pests\u2019 resistance against them is very low. Consequently, the Lamiaceae plant essential oils and their components with a wide range of lethal and sublethal effects against different damaging insects and mites in the field, greenhouse and storage conditions, have great potential in pests\u2019 management strategies and are considered to be safe, available, and eco-friendly alternatives to the synthetic chemicals. Indeed, the most important issue to be considered for the application of essential oils is their rapid degradation under the influence of air and light, which could be overcome by encapsulation or controlled release techniques. Briefly, the essential oils and their components, as core materials, are protected from adverse environmental factors in these techniques. Emulsifying the essential oils and components through adjuvants is another solution to improve pesticidal efficiency. However, their direct and indirect effects on the other non-target organisms such as honeybees and natural biocontrol agents and the economic aspects must be assessed before commercialization."}
+{"text": "Bacillus alone produces a majority of diverse lipopeptides. Lipopeptides are low molecular weight compounds which havemultiple industrial roles apart from being usedas biosurfactants and antimicrobials. In plant protection, lipopeptides have wide prospects owing totheirpore-forming ability in pathogens, siderophore activity, biofilm inhibition, and dislodging activity, preventing colonization bypathogens, antiviral activity, etc. Microbes with lipopeptides that haveall these actions are good biocontrol agents. Exploring these antimicrobial compounds could widen the vistasof biological pest control for existing and emerging plant pathogens. The broader diversity and strong antimicrobial behavior of lipopeptides could be a boon for dealing withcomplex pathosystems and controlling diseases of greater economic importance. Understanding which and how these compounds modulate the synthesis and production of defense-related biomolecules in the plants is a key question\u2014the answer of whichneeds in-depth investigation. The present reviewprovides a comprehensive picture of important lipopeptides produced by plant microbiome, their isolation, characterization, mechanisms of disease control, behavior against phytopathogens to understand different aspects of antagonism, and potential prospects for future explorations as antimicrobial agents. Understanding and exploring the antimicrobial lipopeptides from bacteria and fungi could also open upan entire new arena of biopesticides for effective control of devastating plant diseases. Microorganisms area treasure in terms of theproduction of various bioactive compounds which are being explored in different arenas of applied sciences. In agriculture, microbes and their bioactive compounds are being utilized in growth promotion and health promotion withnutrient fortification and its acquisition. Exhaustive explorations are unraveling the vast diversity of microbialcompounds with their potential usage in solving multiferous problems incrop production. Lipopeptides are one of such microbial compounds which havestrong antimicrobial properties against different plant pathogens. These compounds are reported to be produced by bacteria, cyanobacteria, fungi, and few other microorganisms; however, genus  Bacillus genus whichis considered one of the most important bioactive compound factories [Crop plants are damaged every year by phytopathogens, leading to enormous economic losses to farmers across the world. Currently, themost effective available control measure for plant diseasesthroughchemical pesticideshasresulted intoxic effectsonnon-target organismsandas these compounds arenon-biodegradable in nature, this has become a matter of serious concern for contemporary environmentalists. Since chemical control is not sustainable and is almost certain to cause environmental pollution ,2,3, difactories . Plant dactories ,10. Micractories .Bacillus and Pseudomonas spp. [via a multi-enzyme biosynthesis pathway [Bacillus groups and are mainly composed of a hydrophilic amino acid (7\u201310 amino acids) linked with a hydrophobic fatty acid tail. Aneurinifactin is a group of lipopeptide reported from marine bacterium Aneurinibacillus aneurinilyticus isolated from the Gulf of Mannar [Due to the enormous variation in the chemical structures, lower toxicity to non-targets, biodegradability, and effectiveness to be functional under extreme environmental conditions such as high pH, extreme temperature, salinity, drought, metal stress, etc., these bio-surfactants qualifythe parameters set for asuitable green and eco-friendly alternative as compared to their synthetic counterparts for managing phytopathogens and reduce crop losses therefrom. Duetothese properties, they have gained much attension in applied sectors ranging from pharmaceutical, cosmetics, agriculture, oil recovery, and food industriestothe activities related to environmental remediation ,14,15,16nas spp. ,18. In g pathway . Surfactf Mannar . Moreovef Mannar , surfactf Mannar , sophorof Mannar , rhamnolf Mannar , trehalof Mannar , and manf Mannar  exhibitef Mannar . Surfactf Mannar ,18,22. viz. the perception of bacterial elicitor, systemic signal transduction, and, finally, defense gene expression in the host system [Pseudomonas fluorescens SS101 elicit ISR-reactions in tomatoeschallenged with Phytophthora infestans.These cyclic lipopeptides produced by different microorganisms retain antiviral, antifungal, antibacterial, biofilm-forming, and plant resistance-inducing activities. Several reports indicate that these small molecular weight lipopeptides facilitate root colonization in many plants ,10,15,16t system ,9,10. Hot system ,32. Untit system ,34,35, vt system , iron-ret system ,38,39, at system ,41,42,43t system . Tran ett system  reportedSimilarly, members of the surfactins and fengycins families also act as elicitors of ISR by supplementing and eliciting the host resistance potential . MembersBacillus [Lipopeptides are chiefly synthesized by microorganisms belongingto bacterial genus Bacillus  by multiBacillus  grew theBacillus ,53,54. TBacillus . Lipopeptide producing genes are well characterized and studies on specific lipopeptides can be done with great efficiency by a PCR based approach using specific primer pairs ,57. SomeBacillus spp., including B. subtilis, B. amyloliquefaciens, B. licheniformis, B. globigii, B. pumilus, B. cereus, B. megatarium, and B. thurigiensis [Lipopeptides are a group of microbial surfactants such as surfactin, lichenycin, iturin, and fengycin . From prigiensis ,72,73,74Bacillus spp. is low molecular weight lipopeptide iturin. Iturin have antimicrobial potential against plant pathogens [The antifungal cyclic lipopeptide produced by athogens . The bioathogens . Iturin athogens . Bacillus spp. [Bacillus subtilis, it has been proven to be cidal to the bacterial phytopathogen, Pseudomonas syringae pv. tomato in Arabidopsis [Pseudomonas syringae, Xanthomonas axonopodis, Sclerotinia sclerotium, Botrytis cinerea, Colletotrichum gloeosporioides, and also activated ISR [Surfactins showed high antifungal and antibacterial activities and constitute one of the major classes of antibiotic lipopeptides produced by lus spp. ,78. It ibidopsis . In the bidopsis . A changbidopsis . The amibidopsis . Surfactbidopsis ,83. In bated ISR ,85. Bacillus and Paenibacillus. They have antifungal activity and affect filamentous fungi [Fengycins are a family of lipopeptides produced by members of genera us fungi , the mosus fungi ,88. ThisPseudomonas fluorescens. There are of two major types\u2014Pseudofactin I and Pseudofactin II. This class has got a huge therapeutic usage, especially Pseudofactin II, which has got antiadhesive properties [These are a class of lipopeptides produced by operties . Itsgreaoperties . Pseudomonas fluorescens and have antibacterial and antifungal activity. The specific feature of viscosins is itshigh surface-activeness, which can inhibit the migration of cancer cells. In the case of Pseudomonas, viscosins increase the efficiency of plant roots and also have protective roles for germinating seedlings against plant pathogens [Viscosins are also obtained from athogens . Staphylococcus, Streptococcus, Pneumococcus, Clostridium, and Enterococcus. The source microorganism for the production of daptomycin is actinobacterium Streptomyces roseosporus [Daptomycins are a newer class of lipopeptide antibiotics approved by the US FDA and are effective against Gram-positive bacterial infections . Structueosporus . It inhieosporus . Rhizoctonia solani causing damping-off [Pseudomonas spp. [Poaeamides are known fortheir diverse capability like swarming, biofilm formation, and regulation of attachment-detachment to plant roots, etc., apart from antifungal activity against plant pathogens like ping-off ,93. It inas spp.  and has Bacillus species produce antimicrobial compounds known as lipopeptides and several strains of B. subtilis and B. amyloliquefaciens are reported to produce lipopeptides. Gong et al. [Bacillus and phyto-pathogens are related to the presence of cyclic lipopeptide genes. However, natural Bacillus strains play an important role in the production of different concentrations of each lipopeptide and thus are crucial for their interaction with plant as well as biofilm formation interaction with plants and the production of biofilms [in vitro and in planta conditions [Bacillus pumilus strain HY1 hasshown strong biocontrol activity against harmful aflatoxin producing fungi A. flavus and A. parasiticus suppress the fungal species Aspergillus flavus and A. parasiticus, which areproducers of potentially harmful aflatoxins. There are a few key mechanisms discussed in this section by which lipopeptides show antimicrobial activities  by acting on plasma membrane [Pseudomonas syringae pv. syringae derived cyclic lipodepsipeptides, Syringopeptin, and Syringomycin also exhibited ion channel formation and lytic against plant and human cells due to their membrane-permeabilizing properties [Fusarium sp. Verticillium and Halosarpheia, acts as an ionophore which first gets incorporated in the cell membrane and leads to the intracellular ion leakage and cation specific pores formation. This may establish the basis of the mechanism of actionof enniatin as a antimicrobial, anthelmintic, anticancer, and enzyme inhibiting agent [Studies using scanning electron and optical microscopy revealed that membrane . Pseudomoperties ,166,167.ng agent .Pseudomonas fluorescens lipopeptides putisovin I and II are reported to suppress the biofilm formation and breakdown of existing biofilm [Agrobacterium tumefaciens biofilm by a mixture of lipopeptides produced by Bacillus amyloliquifaciens. The mixture maybe able to inhibit tumor formation upon pathogen adhesion on a tomato stem. In this experiment, the formation of new biofilm was also inhibited and the old ones dislodged. In agriculture, antiadhesive properties of various lipopeptides biosurfactants may also be used to reduce the attachment of phytopathogens on the plant surface and thus, their colonization efficiency, which is very crucial for the development of various plant diseases.Disruption of the integrity and permeability of biological membranes due to thepore and ion channels forming ability of lipopeptide surfactants has been established as the most important mode or mechanism of their action for explaining their applications as antibacterial, antifungal, antitumor, and hemolytic agents in the agriculture, biomedical, pharmaceutical, and therapeutic sectors. Moreover, the synergistic effect of various lipopeptides  showed antiadhesive activity, resulting in the reduction of colonization and stimulating biofilm dispersion of pathogenic bacteriadue to their amphiphilic surfactant like property . The bio biofilm . Abdalla biofilm  reportedviz. Halomonas, Marinobacter, Ochrobactrum, Synechococcus, and Vibrio [Variovorax boronicumulans BAM-48, a plant-associated terrestrial bacterium wasalso found to produce variochelins [Iron is an essential nutrient that is required for normal functioning of important physiological processes including biological nitrogen fixation, transportation of oxygen, methane production, and DNA biosynthesis . Microbed Vibrio ,177,178.ochelins . These sochelins ,180. Somochelins . These mochelins ,184,185.ochelins . Herbaspirillum seropedicae Z67 (class Betaproteobacterium), a N2 fixing and growth promoting endophyte, inhabiting many important crop has been reported to secrete a class of amphiphillic lipopeptidal siderophore called serobactins [Moreover, obactins ,189,190.obactins . The lipBacillus spp. strains are known to induce defense responses in plants, but knowledge about the molecular determinants of the Bacillus mediated ISR is very limited [Bacillus subtilis strain 168 (poor producer) elevated the ISR potential of derivatives in tomato and bean plants. Moreover, increase in the activity of the main enzymes of the lipoxygenase pathway were observed in resistant plants when challenged with lipopeptide overproducers. They also hypothesized that surfactins and fengycins should have a distinct mechanism for ISR-induction in plants. Some beneficial bacteria indirectly protect plants from disease-causing microbes through the stimulation of inducible defense mechanisms which are systemic in nature and called ISR, which are effective in the management of several plant diseases . Lipopep limited ,192. Ong limited  showed tB.\u2009subtilis [Magnaporthe oryzae due to H2O2-mediated defense responses sensitized by ISR responses elicited by semi-purified surfactin lipopeptides in perennial ryegrass [Pseudomonas-derived cyclic lipopeptide orfamide was shown to act as an ISR elicitor, triggering early defense events and inducing expression of defence related genes without causing cell death in rice against the brown spot disease fungus Cochliobolus miyabeanus [Bacillus sp. has been utilized in protecting maize and horse-bean fungal pathogens. Gond et al. [Surfactin and fengycin caused ISR induction in the plants against phytopathogenic fungi, but showed varying responses in different plant cell types . Now, itsubtilis . The binsubtilis . Enhanceryegrass . The Pseyabeanus . Endophyd et al.  reportedCropdestruction by existing and emerging phytopathogens is an important issue of contemporary agriculture that needs to be addressed properly to optimize gains from this age-old enterprise. As the population continues to build up, losses due to plant diseases are emerging as a threat to global food security. Plant diseases affect agricultural produce not only quantitatively, but also qualitatively, hence affecting the gains from marketable produce at two distinct levels. Not only this, but food safety is also a concern that is related to microbial infestation of agricultural produce . Many ofMicrobial agents for biological control are being explored extensively in different crops against an array of pathogens as they exhibit a wider range of antimicrobial activities. Some microbial agents directly act upon the pathogens by millions of antimicrobial compounds, nutrient quenching, competition for space, etc. Whereas, others interact with plants with long-distance signaling by eliciting defense responses using microbe-associated molecular patterns and their compounds or priming plants without making any direct interaction to the pathogen in question. These beneficial microbes modulate the growth condition of the surrounding region so that the pathogen could not thrive and develop in numbers to cause economically significant damage to plants. via hyperparasitism and antibiosis in direct interaction. This involves multiple mechanisms and compounds generated through highly regulated cascades. To use these antimicrobial metabolites for the control of pathogens on the field requires a stringent and exhaustive registration process to avoid any non-target effects on the other constituents of the environment. In this aspect, currently, risks associated with antagonistic microbial metabolites are often assessed similar to that of single-molecule fungicides. Since the nature of the compound and mode of actions are different, thisrequires a re-thinking of data requirements for the registration of microbial agents as biopecticides. Endless research data indicated the enormous antimicrobial capabilities of the genus Bacillus, Pseudomonas, and Trichoderma. These three genera are considered as factories for the production of biologically active molecules which are potent growth inhibitors of phytopathogens. Lipopeptides, a subclass of antimicrobial peptides, arenow emerging as an attractive alternative for the development of new peptide-based biopesticides [Bacillus lipopeptides, surfactins, iturins, and fengycins, along with other new groups of antimicrobial lipopetides are being explored for their effectiveness against a wide range of phytopathogens including bacteria, fungi, and viruses [Bacillus species has numbers of antagonizing attributes against plant pathogens including the production of lipopeptides, enzymes, and plant growth promotion. Hazarika et al. [Antagonistic microbes control the pathogens sticides ,200. The viruses . Shafi e viruses  advocatea et al.  studied Acremonium, Aspergillus, Alternaria, Metarhizium, Beauveria, Fusarium, Penicillium, etc. They exhibit cytotoxic, antimicrobial, antiviral, insecticidal, antitumoral, and enzyme-inhibitory activities which could be potential weapon against plant pathogens of economic importance [Apart from bacterial lipopetides, fungi-derived lipopeptide antibiotics are also gaining importance. These lipopetides have four categories: cyclic depsipeptides, peptaibiotics, non-depsipeptide cyclic lipopeptides, and non-peptaibiotic linear lipopeptides ,204. Theportance . Fungi dThis could open an entire new arena of biopesticides since the whole of society is concerned about green chemicals. These biodegradable biosurfactants could be environmentally-friendly with low toxicity andalternatives to highly toxic synthetic chemical pesticides . The imp"}
+{"text": "Telomeres are specialized genomic elements located at the ends of chromosomes that protect protein-encoding DNA from progressive loss during cellular replication. Telomeres shorten with age; therefore, telomere dysfunction is of particular relevance for understanding age-related disease mechanisms. Telomere disorders produce multisystem degenerative organ dysfunction that largely resembles aging phenotypes, including pulmonary fibrosis (PF), emphysema, cirrhosis, bone marry dysfunction, immunosenescence, and premature hair graying. The degree of telomere shortening influences age of disease onset, involved organs, and disease severity. Notably, the most common manifestation of telomere biology disorders is PF. Subsequently, PF is a model for translating telomere biology into clinical practice. I will discuss the genetics of telomere dysfunction and the clinical manifestations that overlap with age-related phenotypes, focusing on PF. Next, I will discuss how short leukocyte telomere length is an informative prognostic, and potentially theragnostic, biomarker in patients with a range of PF subtypes."}
+{"text": "Palatal myoclonus can be primary or secondary. In primary palatal myoclonus, no obvious structural brain lesions can be found within the triangle of Guillain and Mollaret. Common causes of secondary myoclonus include stroke, demyelination, infections, trauma, and neurodegeneration. Palatal myoclonus can be primary or secondary. In primary palatal myoclonus, no obvious structural brain lesions can be found within the triangle of Guillain and Mollaret. Common causes of secondary myoclonus include stroke, demyelination, infections, trauma, and neurodegeneration. A 49\u2010year\u2010old woman with remote history of pulmonary sarcoidosis presented with gait and speech problems. Neurological examination showed dysarthria, left upper and lower extremity dysmetria, truncal ataxia, and perioral myokymia. Magnetic resonance imaging of the brain revealed a hyperintense lesion within the right cerebellar peduncle extending up into the pons on fluid\u2010attenuated inversion recovery sequence demonstrating enhancement, affecting the Guillain and Mollaret triangle Figure .Three months later, the patient developed palatal myoclonus (see Video Palatal myoclonus can be primary or secondary. In primary palatal myoclonus, no obvious structural brain lesions can be found within the triangle of Guillain and Mollaret.None declared.ABM: involved in conception and design, acquisition of data, analysis and interpretation of data, drafting the article, revising it critically for important intellectual content, and final approval of the version to be published. DD: contributed to conception, design, data collection, and interpretation of data.\u00a0Click here for additional data file."}
+{"text": "Dental clinics are at high risk of the coronavirus disease (COVID-19) and cross-infection dueto the use of instruments that produce aerosols, droplets of secretions, saliva, and blood.These can cause transmission between dental practitioners and patients. Large droplets couldpotentially cause the viral transmission to subjects nearby, whereas smaller droplets can besuspended in the air for some time. Other than spreading from an infected person, there is arisk of being exposed to asymptomatic undiagnosed patients. It is essential for a dentalclinic to ensure hand-hygiene, personal-protective equipment, and caution inaerosol-generating procedures ; the desIn any dental clinic, it is imperative to separate two areas: treatment and nontreatmentzones. Patients are in direct contact in the treatment zone, where different procedures takeplace, including impression taking and radiography. Nontreatment zones include waiting areas,reception, lavatory, breakrooms, and office space . The treThe COVID-19 is caused by SARS-CoV-2 virus, and depending on materials, it remains active oninanimate objects from 2 hours to 9 days . AerosolIt may be recommended that copper \u201cshould\u201d be used for frequently touched surfaces like doorhandles, countertops, and interior cladding material. Copper floor, paint, roof, or wallinstallation might purify surrounding air, continuously reducing dependence on an airpurifier. The use of air conditioners in warm climate is mandatory, where copper alloy airvents or air conditioning ducts might help purify circulating air while cooling it. Sinks andfaucets should be designed for minimal hand contact. Foot pedal or arm-operated faucets shouldbe introduced with auto-dispensing soap stations, and paper towels should be used instead ofcloth towels . To avoiIt may be recommended that copper \u201cshould\u201d be used for frequently touched surfaceslike door handles, countertops, and interior cladding material. Copper floor, paint,roof, or wall installation might purify surrounding air, continuously reducingdependence on an air purifierSamia Naz Isha, BDS (Dentistry), MPH , MSc Research Associate, Department of Public Health Sciences, Centre for InjuryPrevention and Research (CIPRB), Dhaka, BangladeshAshfi Ahmad, BSc (Architecture), MSc (Eco-cities)Part-time Lecturer, Department of Architecture, North South University, Dhaka,BangladeshRussell Kabir, BDS (Dentistry), MSc , MSc (Research Methods), PhD Senior Lecturer in Research Methods, School of Allied Health, Faculty of Health,Education, Medicine and Social Care, Anglia Ruskin University, Chelmsford, UKEhsanul Hoque Apu, BDS (Dentistry), MSc , PhD (Cancer Medicine)Postdoctoral Research Associate and Faculty, Department of Biomedical Engineering,Michigan State University, East Lansing, MI, USA"}
+{"text": "A 53-year-old man presented with a 4-month history of painful lesions on the inner side of his left thigh with drainage of purulent secretion. His past medical history included gouty arthritis and chronic use of corticosteroids for eight years. On physical examination, he had ulcers with high, well-defined edges, covered with necrotic and purulent material on the inner side of the left thigh, resembling pyoderma gangrenosum . Histopa,Cutaneous cryptococcosis is a rare disease characterized by varied lesion morphology, including umbilicated papules, plaques, nodules, pustules, granulomas, abscesses or ulcerations"}
+{"text": "Having a sense of purpose directs behaviors, hence, purpose in life (PIL) can be a useful indicator/moderator of healthy mental and physical behaviors and outcomes. As such, purpose in life, particularly in lower income older adults, might encourage meaningful engagement in activities and life that lead to positive health. Thirty-nine residents  of affordable housing for older adults in Wilmington, NC and State College, PA were surveyed on demographics, mental health, well-being , health behaviors, and their perceptions on immediate housing and the community resources. Findings suggest that for higher educated, younger and Black older adults, PIL moderates or protects against negative mental outcomes (p<.05). For higher educated older adults, PIL moderates or encourages positive perception of job opportunities in the community (p<.05) and healthier behaviors (p<.05). More research is needed to understand how environment interacts with PIL to promote healthy behaviors and outcomes."}
+{"text": "Fibrotic conditions account for over 30% of deaths around the world . PatholoThe major producers of ECM are fibroblasts, which are tissue-resident stromal cells of mesenchymal origin. Activated fibroblasts synthesize and secrete ECM macromolecules, growth factors, cytokines, and chemokines, migrate, adhere to, contract, and remodel connective tissue, and transdifferentiate into contractile myofibroblasts . There iThis thematic series focuses on updated topics on mechanisms regulating tissue fibrosis and their potential application to novel therapeutic strategies. Since mechanisms underlying pathologic fibrosis are not the same across the organ systems, this series features pathologic fibrosis in the skin, kidney, and heart, which are relevant to human intractable diseases. I hope that these review articles would offer novel insights into tissue fibrosis and contribute to development of novel therapeutic to this devastating condition."}
+{"text": "Answering calls for deeper consideration of the relationship between moral panicsand emergent media systems, this exploratory article assesses the effects ofsocial media \u2013 web-based venues that enable and encourage the production andexchange of user-generated content. Contra claims of their empowering anddeflationary consequences, it finds that, on balance, recent technologicaltransformations unleash and intensify collective alarm. Whether generating fearabout social change, sharpening social distance, or offering new opportunitiesfor vilifying outsiders, distorting communications, manipulating public opinion,and mobilizing embittered individuals, digital platforms and communicationsconstitute significant targets, facilitators, and instruments of panicproduction. The conceptual implications of these findings are considered. Popularized in Cohen\u2019s study of youthful hooliganism in post-war Britain, \u2018moral panic\u2019constitutes a keyword in social-scientific studies of crime, deviance, and control.Referring to episodes where folk devils \u2013 moral outlaws and \u2018visible reminders of whatwe should not be\u2019 : 2 \u2013 areWhile the concept\u2019s influence endures, seismic shifts in media space \u2013 the rise of socialmedia and digital platforms \u2013 broaden access to information and are transforming theproduction of public knowledge. Given panics\u2019 status as struggles over the boundaries oforder, truth, and normality, such developments \u2018pose some of the most interestingcontemporary questions for moral panic theory\u2019 : 4. ReflWhen viewed from the standpoint of the present, both perspectives contain significantomissions. One the one hand, eliding socio-technical changes promotes a static,universal model that smooths out complexity and encourages intellectual inertia.Conversely, critiques of Cohen\u2019s framework neglect its continued relevance and areincommensurate with contemporary realities. Evinced in an upsurge of authoritarianpopulism that hinges on the scapegoating of despised others, affluent societies appearwracked by unremitting fear and resentment , conditiReflecting such concerns, this article surveys social media\u2019s effects on the issues andclaims-making patterns that propel moral panics. It argues that, whether generatinganxiety about social change, sharpening social distance, or offering new opportunitiesfor vilifying outsiders, distorting communications, manipulating public opinion, andmobilizing embittered individuals, digital platforms and communications constitutesignificant targets, facilitators, and instruments of panic production. Accentuatingsuch dynamics is not intended to dismiss received perspectives but to invigorate them,promoting more holistic consideration of the implications of new media. To be sure, ahandful of works have provided commentary on or case studies of social media and cognatetechnologies  to distort online conversations andmobilize receptive users. An exemplary case of digitally mediated crusadesappeared during the 2016 American election as dedicated members of the\u2018alt-right\u2019, as well as digital mercenaries employed by the InternetResearch Agency (IRA), a Russia-backed \u2018troll farm\u2019, devoted considerableenergy and resources to shaping political communication and behaviour.Central to their efforts was the creation, sharing, liking and promotion ofmisinformation and provocative discourse about contentious socioculturalissues, including race relations, gun control, abortion, Islamophobia andmen\u2019s rights .8 Armed  anxiety .9 Reflecting a\u2018politics of substitution\u2019 , an infectious respiratory disease of zoonoticorigin. Following its emergence in Wuhan, China in January 2020, widespreadscapegoating and fear-mongering erupted across social media. In relation tothe former, the virus was racialized, with numerous messages linking it tothe ostensibly exotic dietary practices and unsanitary behaviour of Chinesepopulations, with representations depicting them as folk devils anddangerous, impure others .9 Reflecitution\u2019 , such clitution\u2019 . By contitution\u2019 . Asthisitution\u2019 , digitalitution\u2019 .vox populi , activities , and associations  are continuously scrutinized for commercial,legal and political purposes . Once hamessages .Accompanying geodemographic criteria, algorithms can identify and calculateexpressive energies and subjective orientations \u2013 moods, sensibilities, andemotions. With advances in machine learning and sentiment analysis, digitalcommunications can be analysed to map meaning structures, and discernpersonality traits on scales previously unimaginable . Forexa12 Practices ofdataveillance are also recursive, as feedback in the form of engagementpatterns is reflexively monitored to elaborate correlations and deepenknowledge of users  voices into conspicuous claimants .13 They content\u2019 : 1 not ocontent\u2019  but alsocontent\u2019 . Finallycontent\u2019 .14Beyond advancing understanding of the media\u2013moral panic relationship, an importanttask in its own right, by initiating dialogue between theoretical expectations andempirical instances, the preceding analysis promotes conceptual refinement andrenewal. Specifically, accounting for social media\u2019s effects on panic productionilluminates significant mutations surrounding the interactants, functions andcommunicative patterns that define contemporary crusades. First, as many-to-manysystems of communication, social media promote novel patterns of participation,offering ordinary persons a greater role, facilitating spontaneous outbursts drivenby multitudes and introducing automated, machine-led campaigns. Additionally, inenabling new techniques of media manipulation, digital platforms contribute to theweaponization of panics. While conventional wisdom suggests that panics representdomestic affairs, oriented towards mobilizing support, acquiring power and status ormanufacturing consent, the case of Russia and information warfare suggests thatnormative conflict may be exogenously engineered to provoke significant social andpsychological disruption. Finally, in place of uniform messages and mass appeal, thecombination of data-mining and behavioural profiling unleashes claims-makingtechniques that are inhabited and hyper-targeted.Drawing attention to these features exposes significant transformations and bolstersthe versatility and explanatory capacity of Cohen\u2019s paradigm. Thus, mirroring otherrecent interventions , by accoAs an account of reaction and social problems construction, moral panic theory hastraditionally emphasized the mass media\u2019s role in sculpting collective knowledge,arbitrating between the real and represented, and generating significant discrepancybetween risk and response. This article suggests that, while the legacy presscontinues to play a significant role, with the ubiquity of digital platforms andtechnologies, the emergence and spread of panics is being reconstituted. Inparticular, scholars can further refine and expand the concept\u2019s range and impact byengaging with social media\u2019s diverse and far-reaching effects on the contours ofcollective alarm. While it is admittedly premature to predict what new attributesmedia systems will assume, and there is too much contingency to suggest that futuredevelopments will follow an inexorable path, it is hoped that, by takingtechnological change into account, the idea of moral panic will continue toinfluence understandings of how fear and transgression are mobilized for variedpurposes."}
+{"text": "Aging brings increased impact of infectious disease in terms of hospitalization, morbidity, and mortality. This increased susceptibility to infection results from immunosenescence, age-related changes in the immune system, anatomic and functional changes, and environmental exposure to infections. Adults age 65 and over are at increased risk of pertussis, shingles, influenza and pneumococcal disease, and evidence-based recommendations for vaccination are protect older adults against these diseases. Underlying medical conditions including end stage renal disease, chronic lung, heart and liver disease, diabetes and immunocompromised place adults age 65 and over at increased risk of infectious diseases, therefore evidence-based vaccine recommendations in older adults with additional risk factors are in place to protect against varicella, hepatitis A and B, meningococcal meningitidis and Haemophilus influenzae type b. Investigational vaccines are developed to protect against infectious diseases causing significant morbidity and mortality in older adults, for example, respiratory syncytial virus, to further promote healthy aging. Part of a symposium sponsored by the Health Behavior Change Interest Group."}
+{"text": "Poor nutritional status leads to postoperative complications, infections, poor healing, and increased mortality, creating a high-risk situation for older adults undergoing surgery. Psychosocial and environmental factors, including socioeconomic disadvantage, disability, social isolation and depression, are known precipitators of nutritional risk. However, these potentially modifiable concerns are rarely taken into consideration preoperatively. In 736 older Veterans preparing for surgery, we found 42% reported it was hard/somewhat hard to pay for basic needs, 6% reported sometimes/often times not having enough to eat, 24% reported living along, 47% reported needing assistance with 1 or more IADLs, and 42% reported a history of depression. Findings from older, Veterans, illustrate the prevalence of psychosocial and environmental risk factors prior to surgery. Best practices for identifying these factors, the importance of an interprofessional team for intervening, and specific resources that can be utilized throughout the perioperative period to improve outcomes will be presented."}
+{"text": "Being able to drive safely ensures older adults\u2019 transportation mobility and independence. It is also a key element for social participation and to achieve productive aging. However, when accounting for driving exposure, crash risk and crashed-related deaths increase for older drivers aged 70 years and plus. By analyzing data from NHATS, this study aimed to assess factors that might affect driving frequency . I examined whether productive aging activities , perceived importance of social participation, mental wellbeing, physical capacity, cognition, sensory function, and community environment were either positively or negatively related to driving frequency. Age, gender, race, household size, marital status, and self-rated health were controlled for in this study. Results from ordinal regression showed that higher driving frequency was observed among older adults who reported that they worked for pay, provided care, visited friends and family, and went out for enjoyment. Higher driving frequency was also related to a higher perception of social participation importance. Inability to walk six blocks, lower scores on delayed word recall, and poorer vision were associated with lower driving frequency. Lower driving frequency was also found among women, married couples, and people with worth health and advanced age (80 years and older). These results suggest that higher driving frequency is associated with active social engagement and participation. New vehicle technologies or alternative transportation services and programs could be implemented to ensure safety, mobility, and social participation."}
+{"text": "Regardless of the cause of the superficial siderosis (SS) disease, which is bleeding, the source of bleeding cannot be found in some cases.In this article, we report two cases with idiopathic SS. Case 1 presented with bilateral hearing loss, cognitive impairment, sleep disturbances, and tremors. Case 2 presented with sensory neural hearing loss, ataxia, and spastic paraparesis. In both cases, brain MRI indicated evidence of SS. CT myelogram and SPECT with labeled RBC couldn\u2019t help finding the source of occult bleeding.SS is a rare central nervous system disease caused by the deposition of hemosiderin in the brain and spinal cord, which results in the progression of neurological deficits. The cause of this hemorrhage is often subarachnoid haemorrhage, intracranial surgery, carcinoma, arteriovenous malformation, nerve root avulsion, and dural abnormality. The condition progresses slowly and, by the time diagnosis is confirmed, the damage is often irreversible. In our cases, brain MRI clarified the definitive diagnosis, but we could not find the source of bleeding. SS should be considered in cases with ataxia and hearing loss, even if no source of bleeding is found. Superficial siderosis (SS) is an extremely rare central nervous system (CNS) condition in which hemosiderin (a product of the breakdown of blood) is deposited in the leptomeninges, subpial layer, ependymal surface, and other parts of the CNS and results in progressive neurological dysfunction . SS affeGiven the unspecific sensorineural, neurological, and cerebrovascular findings associated with SS combined with its low population prevalence, the condition can often be misdiagnosed or entirely missed. In this paper, we describe diagnostic and treatment considerations in two patients with SS.A sixty-two-year-old man presented to our neurology clinic with complete bilateral hearing loss, which began at the age of thirty-five. Twelve years ago, he started feeling unsteadiness in his lower limb, especially in the left one, which was slowly progressive, and now although he could still stand, he suffered from gait imbalance and could not walk without help. The patient was referred to the local county hospital, but the treatment was unsuccessful. Gradually the symptoms worsened, and when the patient presented at our clinic, he could not walk and do daily livings independently. He also experienced cognitive impairment, sleep disturbances, tremors, and difficulty in swallowing since two years ago. He had no past medical history. He did not have a history of falling or accidents. He declined to undergo any severe headache or brain / spinal surgery. He had a negative family history. The general physical examination was normal. Neurological examination revealed bilateral hearing loss (air conduction > bone conduction), reduced muscle force of the lower limbs, bilateral Babinski sign, bilateral pain and temperature loss below T3, weak finger to nose test, poor heel shin test, and moderate dysdiadochokinesia. He had abnormal mental status with memory impairment, and reflexes were increased. Mini-mental state examination (MMSE) score was 21 . Laboratory analysis findings, including blood tests, urine tests, liver function tests, renal function tests, blood electrolytes, coagulation, thyroid function tests, folic acid, B12, ferritin, etc, were all within the normal range. He underwent brain MRI (1.5\u2009T), which indicated low signal rim coating the surface of the brain and brain stem, particularly the cerebellum, with obvious signal void intensity in susceptibility weighted imaging (SWI) sequences , bilateral Babinski sign, dysarthria spastic quadriparesis, and limb ataxia. There was no sensory problem. His mental state was normal, with no cognitive impairment. The MMSE score was 28. Laboratory analysis, including blood tests, urine tests, liver function tests, renal function tests, blood electrolytes, coagulation, thyroid function tests, folic acid, B12, ferritin, etc, were all within the normal range. He underwent brain MRI, which indicated low signal intensity coating the surface of the brain and spinal cord and atrophy of cerebellar vermis  examination through xanthochromia, elevated presence of RBCs, high iron and ferritin concentrations, and elevated levels of the proteins Tau, beta-amyloid (Ab42), and glial fibrillary acidic protein (GFAP), but in most of the cases CSF is normal . CT scanSS is a progressive neurological condition that must be identified early in order to be successfully treated. Studies have indicated that the first presentation usually appears after at least 6 months of subarachnoid hemorrhage from injury in 97% of cases , 20. WheIn conclusion, SS is a rare CNS disorder caused by hemosiderin deposition in the leptomeninges, subpial layer, ependymal surface and can result in neurological dysfunction and progressive, irreversible signs and symptoms. Here, we presented two cases of SS with severe symptoms that were misdiagnosed. To prevent potential misdiagnoses, we recommend that SS should be considered as a clinical diagnosis for patients, particularly those on anticoagulation and with or without a history of brain damage or accident, which have bilateral sensorineural hearing loss and gait ataxia."}
+{"text": "Objectives: As an inevitable part of daily life, solitude has both positive and negative consequences which are moderated by one\u2019s motivation for solitude. Self-determined motivation correlates with few psychological risks, whereas other-determined motivation correlates with higher risks . However, little is known about the antecedents of different motivations for solitude. The purpose of this study is to investigate the antecedents of motivation for solitude in a sample with younger, middle-aged, and older adults. Methods: We recruited 468 participants from Amazon Mechanical Turk and Introduction to Psychology class . Preference and motivation for solitude were measured with the Preference for Solitude Scale and Motivation for Solitude Scale-Short Form. Age, sex, marital status, education level, living arrangement, instrumental activities of daily living (IADLs), civic engagement, social contact frequency, introversion, and empathy were measured as antecedents. Results: People with older age, higher empathy for fictional characters, lower personal distress, higher introversion, and females tended to have higher general preference for solitude. People with higher empathy for fictional characters tended to have higher self-determined motivation. People with higher empathy for fictional characters, lower empathic concern, higher personal distress, higher IADLs, and higher introversion were more likely to have higher other-determined motivation. Discussion: A person with an introverted personality, functional limitation, more negative empathic reactions towards others are likely to have maladaptive motivation for solitude and may need intervention. Future research should further investigate other antecedents for self-determined motivation."}
+{"text": "Plant endophytic fungi spend all or part of their lives inside host tissues without causing disease symptoms. They can colonize the plant to protect against predators, pathogens and abiotic stresses generated by drought, salinity, high concentrations of heavy metals, UV radiation and temperature fluctuations. They can also promote plant growth through the biosynthesis of phytohormones and nutrient acquisition. In recent years, the study of endophytic fungi for biological control of plant diseases and pests has been intensified to try to reduce the ecological and public health impacts due the use of chemicals and the emergence of fungicide resistance. In this review, we examine 185 patents related to endophytic fungi (from January 1988 to December 2019) and discuss their applicability for abiotic stress tolerance and growth promotion of plants, as agents for biocontrol of herbivores and plant pathogens and bio- and phytoremediation applications. An endophytic fungus is any organism inhabiting plant organs that, at certain point in its lifetime, can colonize tissues without causing apparent harm . EndophyMoreover, interaction between fungi and their hosts drives changes in the host metabolism, altering the response to environmental stress and predator attack. Additionally, this interaction leads to the production of secondary metabolites by both the fungi and the host, which further enhance the capability to respond to the environment ,5,6,7.The use of endophytic fungi for environmental applications such as growth promotion, relief of abiotic stress, biocontrol of pest and plant pathogens and bio/phytoremediation has gained important attention in recent years due to the concern about global climate change and contamination in soils and natural sources that increases stress in crops, limiting and reducing the production ,9,10,11.The highlighted topics in each of the patents, cited here, could inspire other researchers to take their investigation to the next level and contribute to overcome, in a more efficient way, some of the principal challenges of humanity today.\u00ae and Google Patents databases. The search was initially conducted in Scifinder\u00ae using the terms \u201cendophytic fungi\u201d and \u201cpatents\u201d covering the period from 1988 to 2019. 12,315 references were found. After removing duplicates (those describing the same patent/endophyte), we selected those related to the aim of this review, resulting in 185 documents. The patents covered in this study are described in five tables below. The present review was conducted mainly through searches in the ScifinderThe description and analysis of patents was divided, considering the main objective of each one, into four sections; those associated to:  abiotic The principal abiotic stress factors in plants include drought, salinity, high heavy metal concentrations, UV radiation and temperature fluctuations . AbioticAcremonium, Alternaria, Aspergillus, Chaetomium, Fusarium, Penicillium, and others  root and seed development; (b) nutrient uptake or absorption; (c) photosynthesis promotion; (d) growth of biomass; (e) increase chlorophyll content; and (f) abiotic stress resistance. Numerous genera have been used for such purposes, including d others . A specinticosus , Salvia iorrhiza , Rumex gii Turcz , Acacia  confusa , Coix layma-jobi , Cynanchcuminata , Huperzi serrata , Anoectoxburghii , Arnebiaebia sp. , Saussururea sp. , Rhizomaletillae , Salvia iorrhiza ,27, and ptus sp. ,29,30. Aptus sp. ,35,36,37etifolia ,39,40,41etifolia ,43,44,45 montana ,49,50,51bium sp. ,53,54, tbium sp. ,56,57,58 superba ,60,61, B striata ,63, and ilum sp. .Crop plant diseases represent a major threat in agriculture . The numAcremonium have been described to control Verticillium wilt [Listronotus bonariensis) [Bipolaris oryzae, Colletotrichum falcatum, Colletotrichum gloeosporioides, Corynespora cassiicola, Corynespora sp., Drechslera sp., Fusarium oxysporum, Gloeosporium musarum, and Magnaporthe grisea [Alternaria can control the growth of different pathogens such as Rhizoctonia solani, Fusarium oxysporum, Botrytis cinerea, Phytophthora capsici, Pseudomonas aeruginosa, Proteus hauseri, and Plasmopara viticola [Aspergillus have been applied to limit the growth of nematodes in soil [Sclerotinia sclerotiorum, Rhizoctonia solani, and Thanatephorus cucumeris [Chaetomium have been reported to enhance plant disease resistance in Anoectochilus roxburghii cultivation [Erwinia causing soft rot and Ralstonia solanacearum causing bacterial wilt [Exserohilum turcicum, Coniothyrium diplodiella, and Rhizopus stolonifer [Fusarium can prevent and treat black spot and fungal diseases in Panax notoginseng [Fusarium oxysporum, Cytospora mandshurica, Colletotrichum gloeosporioides, Venturia pyrina, and Fusarium graminearum) [Neotyphodium can decrease the mildewing rate of Elymus sibiricus seeds at the germination stage [Penicillium can restrain the effects of Panax notoginseng anthracnose, root rot [Alternaria panax [Sclerotinia rot of colza and tobacco blackleg [Rhexocercosporidium can control the fungal pathogens Colletotrichum gloeosporioides, Fusarium solani, and Alternaria panax Whetzel on Panax notoginseng [Several patents describe the biocontrol of herbivores and plant pathogens using endophytic fungi . Speciesium wilt ; Argentiriensis) ; plant de grisea ; and to e grisea . Speciesviticola ,114,115. in soil ; the plaucumeris ,117,118;ucumeris . Severaltivation , to conttivation ,121,122,ial wilt , to inhiial wilt , in the ial wilt , and in olonifer . Speciesoginseng ,128, coninearum) , and coninearum) ,131 and inearum) . Specieson stage  and impron stage ,135. Speroot rot ,137,138,ia panax ; controlia panax ,141 and ia panax ; and preblackleg . Speciesoginseng ,144,145.Beauveria, Cladosporium, Metarhizium, Muscodor, Trichoderma, and others have also been described in patents to control pests or different plant diseases  in water and soil [Species of and soil ,202. Addand soil .Neotyphodium uncinatum to induce insect resistant and drought tolerance in plants [Phoma sp. can improve salt stress resistance, promote the growth and increase biomass in crop plants such as wheat and rice [Clonostachys rosea promotes plant growth, stress resistance and reduces dependency on chemical pesticides [Fusarium sp. stimulates plant growth and reduces heavy metal absorption in tobacco [Rhizoctonia sp. fosters plant growth and stress resistance in Anoectochilus roxburghii [A small number of patents comprised more than one possible application ; this isn plants ; Phoma sand rice ; Clonoststicides ,207; Fus tobacco , and Rhixburghii .We found two patents, whose applications implicated the use a plural number of fungi (genus/species); one of them claims the capability to increase biomass and promote biotic and abiotic stress resistance in cereal crops , the othAlternaria, Aspergillus, Chaetomium, Fusarium, Penicillium and Muscodor.In the present review, we highlight a wide number of endophytic fungi that have been patented for developing processes, methodologies, or new techniques in applications that include but are not restricted to (a) alternatives to overcome biotic and abiotic stress and to reduce the use of chemicals associated with environmental toxicity in agricultural practices, (b) the degradation of harmful compounds, and (c) improvement in the ability of plants to remove contaminants from soil, water, and air. Abiotic stress tolerance and growth promotion of plants, and biocontrol of herbivores and plant pathogens, were the most patentable applications of endophytic fungi with 88 and 90 patents, respectively; concerning bio- and phytoremediation, 7 patents were recorded for the period 1988\u20132019 . The mosStudies of endophytic fungi ecology have allowed the understanding of the multiple interactions they develop with their host, other endophytes, as well with herbivores and pathogens that put the host under abiotic stress. Nonetheless, it is evident that one individual or group of endophytes can be used for mitigation stresses from different origins. Due to the concerns about global climate change and its implications in food security, there are an increased interest to develop applications for the use of endophytic fungi in abiotic stress tolerance and growth promotion of important food crops , as wellConsidering the abundance of endophytic fungi under study, the development of patentable applications like those reviewed here, and other applications still unexplored like fungal pigments , has becThe use of endophytic fungi to improve the nutrients absorption in plants can change the optimum usage of organic and inorganic fertilizers . The cap2 absorption by plants, degradation and biotransformation of waste, enhance food production without altering its quality or those that provided drought resistance/nutrient absorption capability to plant species related to human or animal feeding could be areas of significance to develop new applications and patents. The investigations applied in these fields are forwarded by the advance in the techniques used for the characterization of endophytic fungi and also by the technological advances in analytical techniques for carrying out studies of chemical processes at the cellular level.The use of endophytic fungi on remediation of contaminated ecosystems is an interesting prospect for further studies. Fungi that could increase the capacity of CO"}
+{"text": "Guest editors introduce the special section of Journal of Biomedical Optics Volume 25, Issue 3, entitled \u201cBiomedical Imaging and Sensing II,\u201d a collection of papers related to the topics of the conference \u201cBiomedical Imaging and Sensing Conference 2019\u201d (BISC\u201919), which was held in April 2019, in Yokohama, Japan. This conference provides an international forum for reporting recent progress in imaging and sensing technologies in the fields of biology and medicine, as well as related areas.This In biomedical optics and photonics, optical tools are employed for the understanding and treatment of diseases, from the cellular level to macroscopic applications. At the cellular level, highly precise laser applications allow the manipulation, operation, or stimulation of cells, even in living organisms or animals. Optical microscopy has been revolutionized by increased understanding of the different markers and their switching behavior. Marker-free microscopy technologies, like CARS (coherent anti-Stokes Raman scattering), SHG- (second-harmonic-generation) or THG- (third-harmonic-generation) microscopy, optical coherence tomography (OCT), and DHM , are spreading into multiple biological and clinical imaging applications. OCT is continuously broadening its clinical applicability by becoming even higher resolution, higher speed, and more compact. In the broader field of optics and photonics, biomedical imaging and sensing are the most quickly progressing and expanding areas. Techniques developed in these areas could greatly advance physical, engineering, and biological knowledge, as well as optics and photonics technology.This conference includes basic research at the cellular level through clinical applications of various optical technologies. Topics covered include medical and biological imaging instrumentation and techniques, advanced microscopy, advanced endoscopy, super resolution, computational imaging, adaptive optics, structured illumination, OCT, digital holography, quantitative phase imaging, diffuse spectroscopy and tomography, photoacoustic imaging, multimodal imaging and sensing, optical biopsy, multispectral imaging and sensing, spectroscopic imaging and sensing, scattering imaging, fluorescence imaging, molecular imaging, terahertz sensing, imaging and sensing techniques for biomedicine, optical fibers and sensors for biomedicine, and multimodal optical diagnostic systems. Recently, computational imaging such as light field imaging, digital holography, and compressive sensing is expected to open new imaging techniques to improve image quality, obtain multimodal physical parameters, and apply the weak light condition using a photon-counting device.This special section includes interesting articles on OCT endoscopy, multimodal digital holographic imaging, computational fluorescence 3D imaging, and laser speckle contrast imaging for medical applications. We believe that this special section on biomedical imaging and sensing will serve to advance biomedical imaging and sensing techniques."}
+{"text": "A 13-year-old boy presented with a long history of swallowing difficulty, regurgitation, and reflux with vomiting. He had undergone multiple surgeries for reflux and achalasia. He had history of alacrimia from early childhood. There was a history of recurrent syncopal episodes. He had severe wasting, and was undernourished with diffuse hyperpigmentation. On examination, he had postural hypotension, microcephaly, long philtrum with thin upper lip and atrophic tongue . Neurolo1 Patients with Allgrove syndrome can present with varied neurological manifestations such as autonomic neuropathy, sensorimotor axonal neuropathy, amyotrophy, optic atrophy, intellectual disability, seizures, and cranial nerve involvement.2 Early diagnosis and timely replacement of steroids can allow normal growth and development in pediatric patients.The presence of amyotrophy  and autonomic neuropathy with alacrimia, achalasia, and adrenal insufficiency clinched the diagnosis in this case, Allgrove syndrome or 5A Syndrome. Allgrove syndrome, typically known as triple A syndrome, consists of a triad of achalasia cardia, alacrima, and adrenal hypoplasia. It was first reported by Allgrove et al. in 1978."}
+{"text": "Arabidopsis. The combined analysis of data from stress markers on different levels together with image data are important for understanding the impact of salt stress on plants.Plant growth and development is adversely affected by different kind of stresses. One of the major abiotic stresses, salinity, causes complex changes in plants by influencing the interactions of genes. The modulated genetic regulation perturbs metabolic balance, which may alter plant\u2019s physiology and eventually causing yield losses. To improve agricultural output, researchers have concentrated on identification, characterization and selection of salt tolerant varieties and genotypes, although, most of these varieties are less adopted for commercial production. Nowadays, phenotyping plants through Machine learning (deep learning) approaches that analyze the images of plant leaves to predict biotic and abiotic damage on plant leaves have increased. Here, we review salinity stress related markers on molecular, physiological and morphological levels for crops such as maize, rice, ryegrass, tomato, salicornia, wheat and model plant,  Growth and development of plants are affected by various stresses. Salinity is one of the major abiotic stress which adversely affects the overall growth and yield of crops ,2,3. It To improve productivity in salt-affected soils, selection and adoption of plant varieties with high salt tolerance has always been a preferred choice ,11. ThisThe advent of information technology (IT), especially different smart data analysis techniques which are being applied in other fields, are also directed towards the improvement of agriculture. These used techniques are known as machine learning\u2014a subset of artificial intelligence. Machine learning algorithms build a model based on data samples, called \u201ctraining data,\u201d developed in order to make predictions or decisions without being explicitly programmed to do so . Deep leArabidopsis, wheat, maize, rice and rye grass, the decrease of total plant biomass was observed at 100\u2013150 mM NaCl levels, while in tomato and sunflower, the weight decreased on 50 mM NaCl application  content and/or ratio of K+/Na+ are also frequently used  in Arabidopsis, wheat, rice and maize [Measurement of Nan plants . Measuretly used . In addit uptake . Increasnd maize ,32,68,78Arabidopsis decreases upon treatment with 100 mM NaCl  ,141 see. The cellicornia ,147,148.licornia ,133,134.licornia ,19. Theslicornia . These cTranscriptomic and proteomic studies reveal that stress triggers the transcript and proteome changes in plants . From trNAC, NAP, WRKY 53, WRKY 25, SAG12, GDH  See . Also, sG12, GDH . MeasureThe molecular markers for evaluation of stresses are rarely used in research for trees and other non-model plants compared with the morphological and physiological measurements, which are less expensive and easy to conduct. However, it might be possible to generate molecular markers for less/rarely studied plants based on homologues of stress related genes that were studied well in other model or important crop plants .Arabidopsis and tomato are more sensitive, whereas others such as wheat, rice, rye grass and so forth are less sensitive  and tolerant  plants side-by-side in a smart greenhouse could reliably predict the ability of the examined plant to tolerate the extent of salt stress. For example, if the plant being studied suffers similar to tomato or Arabidopsis while salicornia growth remains unaffected, the salinity level in the soil is likely to in the range of 100\u2013300 mM NaCl  and tolerant  plants, for their identification and prediction of salinity stress in plant (Generally, all these high-throughput phenotyping technologies are based on the analysis of different type of images such as RGB imaging, near-infrared imaging, infrared thermal imaging and fluorescence imaging ,201,202.in plant . Additioin plant  with GFPContinuous expansion of soil salinization area is inversely proportional to crop yield and this poses a challenge to global food security. To improve plant adaptability and performance to such condition, different areas such as plant stress physiology, molecular biology, genetic engineering, biotechnology are being exploited. Machine learning approaches are promising in developing smart greenhouse, by phenotyping plants and controlling the environmental growth parameters. Developing such controlled growth room conditions require not only equipped imaging technologies but also important physiological, oxidative and molecular data. Morphological markers in plants such as root or shoot growth, germination, flowering time indicate obvious signs of stress but also the appearance of senescence symptoms under salinity stress is an important sign\u2014which appear early in older leaves after salt application. From physiological parameters, the chlorophyll content, RWC, electrolyte leakage, stomatal conductance, water potential, proline, glycine betaine changes in plants are commonly detected under NaCl stress. These physiological changes manifest themselves before the molecular markers. ROS and ROS-related-enzyme changes are also early recognizable markers for stress. Molecular and oxidative stress maybe useful in early detection of salinity stress impact. Still, each stress marker, either morphological, physiological, oxidative or molecular changes in plants, have their own limitation. An integrated approach and usage of different sensors for specific areas of the plant such as old leaves would increase the sensitivity in detection of salinity stress in plants. However, this integration of morphological, physiological, molecular and deep learning parameters requires concerted studies."}
+{"text": "Tomatoes are consumed worldwide as fresh vegetables because of their high contents of essential nutrients and antioxidant-rich phytochemicals. Tomatoes contain minerals, vitamins, proteins, essential amino acids , monounsaturated fatty acids (linoleic and linolenic acids), carotenoids (lycopene and \u03b2-carotenoids) and phytosterols . Lycopene is the main dietary carotenoid in tomato and tomato-based food products and lycopene consumption by humans has been reported to protect against cancer, cardiovascular diseases, cognitive function and osteoporosis. Among the phenolic compounds present in tomato, quercetin, kaempferol, naringenin, caffeic acid and lutein are the most common. Many of these compounds have antioxidant activities and are effective in protecting the human body against various oxidative stress-related diseases. Dietary tomatoes increase the body\u2019s level of antioxidants, trapping reactive oxygen species and reducing oxidative damage to important biomolecules such as membrane lipids, enzymatic proteins and DNA, thereby ameliorating oxidative stress. We reviewed the nutritional and phytochemical compositions of tomatoes. In addition, the impacts of the constituents on human health, particularly in ameliorating some degenerative diseases, are also discussed. Solanum lycopersicum L.), which are frequently included in the Mediterranean diet and are widely consumed as vegetables, play an important role in nutrition because of their well-established health benefits [Tomatoes .Proximate analysis is one of the first approaches for food characterization, particularly for the identification of nutrients in any food products. Generally, water, ash, protein, lipid, carbohydrate, sugar and reducing sugar contents, as well as pH, energy and acidity are the key proximate compositions of a food sample . For insProteins, which are macromolecules present in food, are important for cellular structure and biological functions. Protein analysis is crucial for nutritional labeling, as well as in describing the biological activities and functional properties of food products ,34,35. LCarbohydrate analysis is also important as a major (more than 70%) energy source. Carbohydrate analysis yields nutritional information, standard of identity, water holding capacity, flavors, desirable textures, and stability of food products ,38. In aMinerals are naturally occurring inorganic solid substances. They are essential for a variety of bodily functions, including the regulation of metabolic pathways, formation of vital organs, maintenance of bodily physiological functions, regulation of pH balance, fluid balance, blood pressure, nerve transmission, muscle contraction and energy production ,54,55,56From a nutritional perspective, tomato is a good source of minerals and other elements ,44. In tThe accurate and precise analysis of vitamin content is important for a standard balanced diet because low or excessive amounts of vitamins can contribute to disease conditions by hampering normal cell growth . TomatoeTomato contains many different types of fatty acids . Among tAmino acids are the building blocks of proteins that conduct important bodily functions, including the maintenance of cellular structure, transport and storage of nutrients, wound healing, and repair of damaged tissues . A totalTomato contains various types of carotenoids and is rich in lycopene and \u03b2-carotenoids . CarotenSterols are mainly found in plants, animals, and microorganisms. Plant sterols, also known as phytosterols, commonly occur as a mixture of \u03b2-sitosterol, campesterol and stigmasterol. Phytosterols play important roles in human health. Phytosterols block cholesterol absorption sites in the human intestine and reduce cholesterol absorption, leading to a reduction in low-density lipoprotein cholesterol (LDL-C) and prevention of CVD . ResearcAntioxidants are biomolecules that (1) prevent the oxidation of other molecules by inhibiting the initiation and elongation of the oxidizing chain reaction of ROS and (2) by inhibiting the proliferation of cells, free radical scavenging, the modulation of enzymatic activity via chelation of metallic ions and signal transduction pathways . AntioxiTomatoes are consumed worldwide in various forms, either raw or processed and provide a significant amount of important antioxidants ,105 inclPhenolic compounds present in tomato are considered as the primary antioxidant based on their ability to donate hydrogen atoms to reactive free radicals . CarotenThe health benefits of tomatoes mainly associated with its rich supply of nutrients and secondary metabolites, including vitamins, minerals, essential fatty acids, carotenoids, antioxidants, and other bioactive compounds. In addition to its high amounts of vitamins A, C, E, K and B-complex ,37, tomaLycopene is a natural antioxidant that can help combat different types of cancer, including prostate, breast, lung, stomach, colorectal, oral, esophageal, pancreatic, bladder, cervical and ovarian cancers ,17. AbunThe consumption of carotenoid-rich tomato has been reported to protect against vitamin A deficiency disorders and other chronic diseases including light-induced eye damage, the development of cataracts and age-related macular degeneration . In factOxidative stress is the main contributor to the development of chronic diseases in humans. ROS, including superoxide anion radicals, hydroxyl radicals and hydrogen peroxide, are highly reactive oxidant molecules that are endogenously induced by regular metabolic activity in the body, diet, and secondary lifestyle activities ,128. TheIn summary, the health benefits of tomato are associated with its rich supply of nutrients to the body, such as minerals, vitamins, proteins, essential amino acids, fatty acids, and other antioxidants. The consumption of tomato is associated with the relief of cancer, diabetes, CVDs, eye disease and constipation, with blood pressure reduction, improved blood circulation, improved body fluid balance, cholesterol reduction, detoxification of toxins, reduction in inflammation, prevention of premature aging and improvement of digestive function .Generally, CVD is a category of disease that affects the blood vessels and the heart . Common phox or neutrophil cytosol factor 1 and therefore reduces the levels of superoxide anion (O2\u2212), as mediated by nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase), ultimately preventing endothelial dysfunction in hypertension [Quercetin is a potential chelator of metal ions, constraining xanthine oxidase while reducing lipid peroxidation and scavenging free radicals, which ultimately help to reduce the risk of CVD ,145. Furrtension .Caffeic acid, which can increase the plasma level of vitamin E, scavenge free radicals, and reduce oxidative stress, demonstrates its effectiveness in MI ,152. It Lutein reduces carotid artery intima-media thickness, especially in patients with subclinical atherosclerosis . MoreoveVanillic acid reduces hypertension and infarct size in I/R, improves ventricular function and shows antioxidant mechanisms that can confer some cardioprotective effect ,162,163.On the other hand, chrysin has an anti-atherogenic activity and can ameliorate MI by activating peroxisome proliferator-activated receptor gamma (PPAR-\u0263) and inhibiting oxidative stress as well as inflammation, mediated by the advance glycation end product ,171. CatSome bioactive compounds present in tomato are effective in diabetes . For insQuercetin stimulates glucose uptake by regulating mitogen-activated protein kinase (MAPK) insulin-dependent mechanisms, improving renal function, inhibiting the overexpression of transforming growth factor beta 1 (TGF-\u03b21) and connective tissue growth factor (CTGF), hindering polyol accumulation as well as blocking aldose reductase, and thus reducing joint pain, irritation, and numbness, which are common symptoms observed in diabetes . QuercetOn the other hand, kaempferol minimizes \u03b1-glucosidase activity, increases antioxidant activity, reduces lipid peroxidation level, protects \u03b2 cell function and improves insulin sensitivity of the periphery, therefore exhibiting antidiabetic properties ,190,191.Naringenin, which has the potential to diminish nephropathy and improve endothelial complications along with lipid and glucose metabolisms in diabetes, shows antifibrotic, anti-oxidative and anti-inflammatory activities ,195. IntCaffeic acid has been reported to confer some anti-inflammatory and antiglycemic activities in diabetic kidney disease . ChlorogIn pregnant women affected by gestational diabetes, lutein intake has been reported to reduce neonatal oxidative stress during birth . MoreoveVanillic acid reduces blood pressure, plasma glucose and insulin by activating antioxidants, thereby reducing oxidative stress . FerulicCinnamic acid and some of its derivatives have the potential to be applied in the treatment of diabetes because of their many useful properties including (1) increased glucose uptake, adiponectin secretion, insulin secretion and hepatic glycolysis; (2) improved functionality of pancreatic \u03b2 cells; (3) reduced adipogenesis; (4) improved hepatic gluconeogenesis, protein glycation, insulin fibrillation and intestinal glucose absorption and (5) decreased activity of certain enzymes, including \u03b1-glucosidase, dipeptidyl peptidase-4, pancreatic \u03b1-amylase and protein tyrosine phosphatase 1B .Sinapic acid improves hyperglycemia and maximizes glucose utilization by regulating the signals of phospholipase C (PLC) and protein kinase C (PKC) in diabetes . CatechiEpicatechin, another important constituent of tomato, reduces insulin resistance, increases insulin sensitivity, and reduces oxidative stress . It alsoMany recent studies have suggested that regular intake of fruits and vegetables that are high in antioxidants prevents the progression of cancer cells ,225. TheMany epidemiological studies have suggested that dietary intake of tomato can ameliorate cancer ,70. In fLycopene, a major carotenoid present in tomato, has antioxidant properties and can prevent prostate cancer by blocking ROS generation, scavenging free radicals, and protecting both cell membrane and DNA from oxidative damage ,17,241. 21, Bax and caspase-3, and thus preventing the expression of the cell cycle regulator cdc2/cdk-1, cyclin B1, phosphorylated pRB and apoptosis markers Bcl-2 and Bcl-XL [Quercetin confers both antioxidant and anticancer properties that prevent the proliferation of prostate cancer cells by increasing the levels of pd Bcl-XL . In anotd Bcl-XL . Quercetd Bcl-XL . Luteolid Bcl-XL . Apigenid Bcl-XL .The nutritional composition of tomato depends on the maturation of fruits, ripening time, geographical location, tomato variety, freshness and whether they are tomato-based food products. The nutritional composition will also differ depending on the conditions of sample preparation, collection, and tomato parts. Nevertheless, to date, there are limited data on the nutritional contents of tomato peel and pulp for a good comparison to be made. Therefore, in this review, only the nutritional composition of fresh matured tomatoes is discussed. Further study needs to investigate the bioactive compounds present and investigate their impact on human health.Additionally, although some research works have been published on tomato processing by-products containing many bioactive nutrients including lycopene, beta-carotene, amino acids, proteins, lipids, and dietary fibers ,250, theTomatoes are vegetables/fruits that contain significant amounts of dietary nutrients, including dietary fiber, reducing sugars, vitamins, minerals, protein, essential fatty acids, phytosterols and carotenoids. The nutritive elements play an important role in bodily function and are beneficial in ameliorating chronic diseases. Tomatoes are also rich with health promoting bioactive phytochemicals, such as phenolic compounds including lycopene, quercetin, kaempferol, naringenin, caffeic acid and lutein. The bioactive constituents show antioxidant, antiproliferative, antidiabetic, anti-inflammatory, and other health-promoting activities, indicating the vast potential of tomato in preventing and/or ameliorating several chronic degenerative diseases. Lycopene and \u03b2-carotene are two main active ingredients in tomato that have strong antioxidant properties, which are linked with many health benefits, including cancer and heart diseases. They also participate in preventing the development of cataracts. Additionally, the water content and dietary fibers help the body in terms of hydration, bowel movements, reducing constipation, improving obesity through weight loss, and preventing colon cancer. All immune stimulating activities of tomatoes make them active ingredients for the development of functional foods. Thus, tomato is an excellent source of dietary nutrients and is useful in disease prevention."}
+{"text": "Dear Editor:The letter by Dr. WermelingerIn terms of innovative methods for vector control involving interaction betweenmosquitoes and bacteria, greater advances have been made in controlling dengue thanmalaria due to the differing biology of the respective vectors.Anopheles genus, which is in contrast to what hasbeen observed in some Aedes species that are susceptible toWolbachia. This susceptibility, along with the fact that colonizedmosquitoes are refractory to dengue virus infection, represents an exciting potentialnew form of biocontrol for arboviral diseases, including dengue. Strains ofWolbachia, deliberately introduced into Ae.aegypti mosquitoes, have been shown a capacity to spread in highfrequencies within mosquito populations in release trials, and mosquitoes infected withthese strains have shown markedly reduced vector competence,,Anopheles, it is possible that secondary symbionts may havebecome recently more susceptible to anophelines and are, therefore, not obligatePlasmodiumPrevious studies on the anopheline microbiome indicate that there is no natural obligateendosymbiont in the Wolbachia in Ae. aegyptisince Wolbachia also blocks other circulating arboviruses such asChikungunya and Zika viruses,Anopheles, only Plasmodiumparasites are transmitted, making it difficult to plan joint control strategiesinvolving other diseases.Wermelinger\u2019s letter also highlights the need to consider methodological principles thatshould guide control interventions, with an emphasis on integrated vector management.This appears possible using Ae. aegypti is an extremely anthropophilic mosquito, frequently foundin urban areas, that lives in or around households or other buildings frequented bypeople, such as businesses and schools. An. darlingi, the mostimportant vector of malaria in Brazil, is the most frequent anopheline found withinhuman housing. This mosquito is particularly aggressive towards humans, usuallyattacking people inside their homes in the early evening. Ae. aegyptimosquitoes prefer to breed in areas such as stagnantwater and in artificial containers such as flower vases, uncovered barrels, buckets, anddiscarded tires, whereas An. darlingi use natural and artificial waterbodies, such as ponds, riverbanks, puddles, and water-logged fields, preferablyinvolving clean water comprising organic matter, aquatic vegetation, and shade.Therefore, anophelines are much more exposed to other environmental bacteria that couldcompete with Wolbachia. In addition, malaria also occurs in rural,riverine, and indigenous areas, where the maintenance of engineered vector populationsmay only last for short periods of time. Wolbachia method into three Brazilian cities, Campo Grande (MS),Belo Horizonte (MG), and Petrolina (PE)All these factors are likely to help explain studies indicating the usefulness ofartificially manipulated microbiome mosquitoes in relation to dengue fever and theabsence of similar field studies concerning malaria. Recently, the Brazilian Ministry ofHealth, in partnership with Fiocruz\u2019s World Mosquito Program-Brazil, as part of acampaign against dengue, Zika, Chikungunya, and yellow fever, announced the expansion ofthe Bacillusthuringiensis and B. sphaericus. Even for the availablestrains, information concerning their action in the field is scarce in the Amazonia,Bacillus thuringiensis OR Bacillus sphaericus andAedes OR dengue retrieved 676 publications, whereas using the termsBacillus thuringiensis OR Bacillus sphaericus andAnopheles OR malaria identified 384 publications.Currently, promising entomopathogens remain restricted to Wolbachia-like microorganisms), and breeding sitemanagement with bioinsecticides should be considered. However, apart from theunpublished experiences of individual malaria control programmers and unlike thesituation with dengue, there is a lack of robust evidence supporting the efficacy ofspecific tools for malaria control and elimination through employing vector controlmeasures.To reduce malaria transmission, a successful programmer needs to focus on severalaspects, including early diagnosis, use of effective antimalarial drugs, and vectorcontrol"}
+{"text": "We report the case of a 56-year-old male patient, who over two decades, sequentially presented with a combination of clinical manifestations. These included thrombotic thrombocytopenic purpura (TTP), right leg deep vein thrombosis (DVT), and eventually constitutional symptoms, arthralgia, diffuse lymphadenopathy, pancytopenia, skin rash, pericarditis, and glomerulonephritis. Serologic tests and renal pathology uncovered a diagnosis of systemic lupus erythematosus (SLE), and immunosuppressive therapy was initiated. Soon after, the patient developed striking cytomegalovirus (CMV) viremia, requiring prolonged antiviral therapy and reduction of immunosuppression. Finally, an acute embolic stroke complicated the disease course. Prompt interventions allowed an excellent clinical outcome. Systemic lupus erythematosus (SLE) is the prototypical systemic autoimmune disease, characterized by a wide spectrum of clinical manifestations, often exhibiting a relapsing-remitting course . As treaA 56-year-old male presented to the emergency department with a 2-month history of extreme weakness, fatigue, and anorexia. His past medical record was remarkable for a previous event of thrombotic thrombocytopenic purpura (TTP) 20 years earlier. He was then treated with plasmapheresis, aspirin, and corticosteroids, with complete recovery. 18 months thereafter, he was diagnosed with an unprovoked right leg deep vein thrombosis (DVT), for which no etiology was found. Noticeably, antiphospholipid antibodies (APLAs) were negative.Similar constitutional symptoms had plagued the patient before. Several years prior to his current presentation, he was admitted for weakness and weight loss (30\u2009kg over a few months). He then underwent a thorough investigation, including blood tests, whole-body computed tomography (CT), and positron emission tomography/CT (PET/CT). Diffuse hypermetabolic lymphadenopathy, involving axillary, abdominal, and retroperitoneal lymph nodes (LNs), was seen. Excisional biopsy of a pelvic LN (PN) and bone marrow (BM) biopsy were performed, both being unremarkable. Immune serologies sent at that time showed only a weakly positive antinuclear antibody (ANA). The differential diagnosis comprised a systemic infection, an indolent neoplastic process, and autoimmune lymphoproliferative syndrome (ALPS). None of these entities was proven however, leaving the patient undiagnosed despite regular follow-up. Thereafter, he spontaneously recovered, enjoying several uneventful years.+ and CD8+). Blood cultures and broad bacterial and viral serologies were negative. The patient's urinalysis was significant for hematuria and proteinuria, and urine microscopy revealed red blood cell (RBC) casts, along with dysmorphic RBCs. 24-hour urine collection demonstrated nephrotic range proteinuria (3.9\u2009g/d).Upon the patient's current admission, physical examination revealed mild bilateral leg edema and numerous lichen-like skin lesions see . RecurreDuring this time, the patient's clinical condition was one of the ongoing weakness, fatigue, and dyspnea. He also suffered from pleuritic chest pain and progressive, asymmetric leg edema. Further work-up directed at these complaints showed an extensive right leg DVT, elevated cardiac enzymes, and new-onset atrial fibrillation (AF). In addition, a small pericardial effusion was found on transesophageal echocardiography (TTE). Therapy with enoxaparin was started for his DVT and AF, and broad-spectrum antibiotic coverage was instituted for a suspected bacterial infection. Pericarditis was added to this ever-growing list of diagnoses.Results of ANA and anti-double-stranded deoxyribonucleic acid (anti-dsDNA) antibody were reported at this stage, both being strongly positive, along with low complement levels see . NotablyPseudomonas aeroguinosa, and therapy with ciprofloxacin was started. Besides, mycophenolate mofetil and prednisone doses were reduced in an attempt to minimize immunosuppression, and intravenous ganciclovir therapy was initiated. The lack of clear signs of end-organ involvement has made it difficult to define the required duration of ganciclovir treatment, and the CMV viremia was monitored instead. Following the gradual elimination of viremia, antiviral therapy was stopped. Diligent wound care, compression stockings, and antibiotic treatment allowed stepwise healing of the ulcer.Less than one month after discharge, the patient was readmitted due to a painful right calf ulcer, productive cough, and general weakness. Thorough work-up revealed significant cytomegalovirus (CMV) viremia , with no signs of visceral involvement upon bronchoscopy, sigmoidoscopy, and ophthalmologic evaluation. The leg ulcer was attributed to postphlebitic syndrome, and biopsy of the ulcer was noncontributory. Cultures from both the ulcer and bronchoalveolar lavage fluid grew Three months later, the patient was again admitted for sudden-onset dysarthria and right-sided hemiparesis. Brain CT angiography showed left middle cerebral artery branch obstruction, consistent with an embolic etiology. An emergent thrombectomy was performed. TTE, transesophageal echocardiography (TEE), and carotid Doppler studies revealed no embolic source. Aspirin and high-dose statin were added, and the patient continued apixaban. Gradually, he was able to regain excellent functional capacity.As of today, one year after his index presentation, the patient is well and suffers no residual neurologic deficits. His most recent labs, including blood counts, chemistry panels, complement levels, and urinalysis, are unremarkable. His proteinuria has declined to 170\u2009mg/d, and CMV titers in blood are undetectable.Our patient was eventually diagnosed with SLE. Over 20 years, he presented with an assembly of disease manifestations, including hematologic, musculoskeletal, dermatologic, cardiac, and renal phenomena. Initially experiencing events of TTP and DVT, he went on to develop, over many years and in a relapsing-remitting manner, constitutional symptoms, arthralgia, lymphadenopathy, pancytopenia, skin lesions, pericarditis, and glomerulonephritis. Past immune serologies showed only a weakly positive ANA, with normal complement levels. The absence of classic lupus manifestations in the past obscured the diagnosis, and it was not until significant visceral involvement occurred many years thereafter, that the correct conclusions were drawn. In these days of extensive testing and follow-up, \u201cthe great pretender,\u201d lupus, appears to present a lesser diagnostic dilemma than in the past. Atypical manifestations, combined with spontaneous disease remissions, may nonetheless obfuscate the clinical picture.Constitutional symptoms, including fatigue, anorexia, fever, and weight loss, are commonly seen in patients with SLE. Fatigue is a frequent, sometimes disabling, disease symptom. Its etiology is multifactorial and includes chronic inflammation, cytokine dysregulation, side effect of medications, comorbidities, and hormonal imbalances . Fever o3 and usually necessitates aggressive therapy [SLE is known to have myriad hematologic manifestations, many of which appeared in our case. Lymphadenopathy is a common, often unappreciated feature. LNs are usually soft and nontender and may fluctuate in size with disease exacerbations. Biopsy usually shows reactive hyperplasia . 50% of  therapy . While T therapy . Thrombo therapy . Immunol therapy .Regarding cardiac involvement, SLE can affect any layer of the heart. Pericardial effusion secondary to pericarditis is the most common manifestation . ValvulaSkin disease is a well-characterized feature of lupus. Chronic cutaneous lupus includes a lupus-lichen overlap entity . In the Renal involvement remains one of the most devastating manifestations of SLE, with increased morbidity and mortality. Despite advances in management, 10% of the patients still progress to renal insufficiency and end-stage renal disease .Complications of immunosuppression are also represented in our case. CMV viremia dominated the clinical picture, necessitating reduction of immunosuppression and institution of prolonged intravenous antiviral therapy. The heavy immunosuppressive regimens used in systemic autoimmune diseases are known to predispose to opportunistic infections. These remain the most frequent cause of hospitalization, morbidity, and mortality in SLE patients. More than half of the infections are viral, the most common being herpes zoster . No guidWe believe our case is educational in several aspects. First, the patient showed a remarkable mixture of systemic manifestations see , varying"}
+{"text": "Bunyavirales order was established by the International Committee on Taxonomy of Viruses (ICTV) to incorporate the increasing number of related viruses across 13 viral families. While diverse, four of the families  contain known human pathogens and share a similar tri-segmented, negative-sense RNA genomic organization. In addition to the nucleoprotein and envelope glycoproteins encoded by the small and medium segments, respectively, many of the viruses in these families also encode for non-structural (NS) NSs and NSm proteins. The NSs of Phenuiviridae is the most extensively studied as a host interferon antagonist, functioning through a variety of mechanisms seen throughout the other three families. In addition, functions impacting cellular apoptosis, chromatin organization, and transcriptional activities, to name a few, are possessed by NSs across the families. Peribunyaviridae, Nairoviridae, and Phenuiviridae also encode an NSm, although less extensively studied than NSs, that has roles in antagonizing immune responses, promoting viral assembly and infectivity, and even maintenance of infection in host mosquito vectors. Overall, the similar and divergent roles of NS proteins of these human pathogenic Bunyavirales are of particular interest in understanding disease progression, viral pathogenesis, and developing strategies for interventions and treatments.In 2016, the  Bunyaviridae family . Ea. EaPerib NSs ORF , and the NSs ORF . The maipe I IFN . IFN indpe I IFN . MDA5 anpe I IFN ,31. NSs pe I IFN . In BUNVpe I IFN . This cope I IFN . LACV NSaviruses . BUNV NSaviruses . These dOrthobunyaviruses possess alternative methods for blocking type I IFN. Despite not having an NSs protein, Tacauima virus (TCMV), inhibits type I IFN . Th. Th48]. avirales , has an avirales . Howeveravirales  and likeavirales . GP38, eavirales . In the avirales ,59. Thisavirales ,60. Sequavirales .\u2212/\u2212) mice infected with rCCHFV lacking NSm succumbed to severe and lethal disease, albeit at a delay , is, is11], oprotein . RVFV NSsquitoes ,151, thesquitoes  and whersquitoes . Double squitoes . Furthersquitoes . Interessquitoes . The prosquitoes ,153,154,squitoes , integrasquitoes , and regsquitoes . Furthersquitoes . Howeversquitoes . Lastly,h larger . Inducinh larger . As PTV h larger , but theh larger . OverallBunyavirales and its 13 families, it is interesting to note the human pathogen-containing families have conserved NS protein functions, including interferon antagonism (NSs), interference with host cell apoptosis (NSs), supporting viral replication (NSs/NSm), and facilitating infection (NSm)  . These con (NSm) . While t viruses , showingBunyavirales order. The significant attenuation of many viruses engineered to lack an NSs and the diversity in interactions between viral NSs and host proteins present a variety of therapeutic strategies and targets to limit severe disease caused by these viruses. NSm, although divergent across Bunyavirales, has some conserved function in viral infectivity and interference in host immunity. As the NSm is not as well understood as NSs, further research may show new and exciting functions, lending to overall Bunyavirales knowledge and informing development of future interventions. Cumulatively, despite wide diversity in geographic range, susceptible hosts, vector species, human disease, and genomic organization, the general conservation of NS proteins across the Bunyavirales order indicates these are important viral proteins that may mediate the severity of human morbidity and mortality caused by these viruses.However, further research is needed to fully determine the role of NS proteins in viral pathogenesis across the"}
+{"text": "While cerebral lesions are common in Fabry disease (FD), spinal lesions have not been described, and their presence was suggested to be indicative of multiple sclerosis. Here, we present a FD patient with histopathological confirmed spinal ischemic stroke.A patient with genetically and biochemically diagnosed FD and characteristic manifestations  presented with paraplegia, loss of all sensory modalities below Th9, and loss of bowel and bladder function. While cranial MRI was inconspicuous, spinal MRI showed a T2 hyperintense, non-contrast-enhancing lesion of the thoracic spinal cord. Lumbar puncture revealed mild pleocytosis, increased total protein and lactate levels, decreased glucose ratio, and negative oligoclonal bands. Rheumatic, neoplastic, and infectious disorders were excluded. The patient received intravenous and intrathecal methylprednisolone, plasmapheresis, intravenous immunoglobulins, and cyclophosphamide without clinical improvement. A biopsy of the thoracic lesion was performed. A histopathological examination revealed necrotic tissue consistent with spinal cord ischemia. Diagnostic work-up for stroke etiology clarification was not conspicuous. Two years onward, the patient suffered from a pontine infarction and a transient ischemic attack.The current case highlights the possible occurrence of spinal ischemic lesions in FD. Thus, the diagnosis of FD should not be prematurely discarded in the presence of spinal lesions. Fabry disease (FD) is a rare, multiorgan, life-threatening, X-linked inherited lysosomal storage disorder with central and peripheral nervous system involvement, including cerebral micro- and macroangiopathy and neuropathic pain , 2.Cerebral MRI mainly shows a variable degree of non-specific distributed T2-weighted and fluid-attenuated inversion recovery (FLAIR) hyperintense white matter lesions (WMLs). Ischemic strokes frequently occur before diagnosis, and there is an inconstant appearance of dilative arteriopathy in the vertebrobasilar system .FD is commonly misdiagnosed as multiple sclerosis (MS) because patients with either disease may present with sensory symptoms, pain, cognitive impairment, and WMLs. Although microangiopathic cerebral lesions are common, spinal lesions are not described in FD. Thus, some authors suggest that the\u00a0absence of spinal lesions should prompt clinicians to revise\u00a0an initial diagnosis of MS to FD . Here, wA 24-year-old male Caucasian was first diagnosed with FD in June 2010. FD was genetically and biochemically confirmed , chromosome Xq22, exon 2 (IVS2+1G>T); The patient\u2019s mother with genetically and biochemically confirmed FD also suffered from acroparesthesia triggered by physical stress and exogenous heat. She is also treated with agalsidase.In February 2016, the patient presented to our clinic with a complete spinal cord syndrome with paraplegia, loss of all sensory modalities below Th9, and loss of bowel and bladder function. The symptoms developed within one day.Cranial MRI during hospitalization was unrevealing. Spinal MRI demonstrated a pronounced T2 hyperintense lesion of the thoracic spinal cord that did not enhance after gadolinium administration Table 1.18F-FDG-PET/CT to exclude malignancies revealed no clarifying results. Repeated lumbar puncture showed persisting elevated total protein levels  but no more pleocytosis and still negative oligoclonal bands. The patient received another eight cycles of plasmapheresis, which did not lead to clinical improvement. Finally, a biopsy of the thoracic lesion was performed by hemilaminectomy for further clarification. The histological examination revealed necrotic tissue consistent with previous spinal cord ischemia , eight cycles of plasmapheresis, intrathecal methylprednisolone (120 mg), and\u00a0five times intravenous immunoglobulins \u00a0were administered. Immunosuppressive therapy with cyclophosphamide was initiated. Due to a lack of improvement, the patient had a diagnostic re-evaluation one month later. Spinal MRI demonstrated unchanged findings, and whole-body WMLs are early and frequent findings in FD. Thus, FD was suggested as a model disease for cerebral microangiopathy . CerebraOur case is the first report of spinal ischemic stroke in a patient with Fabry-typical clinical manifestations and a classical mutation, highlighting the possible occurrence of spinal ischemic manifestations in FD. However, because FD patients are not regularly subjected to spinal MRI, spinal lesions might be underestimated in FD .Spinal cord infarctions and infarctions in the posterior circulation are predominantly of cardio-embolic origin. Extensive stroke work-up, including long-term ECG and transesophageal echocardiography, was inconspicuous. Although we could not detect any suspicious cardiac findings indicating a potential cardio-embolic mechanism , this mechanism appears likely in our case. Reviewing the literature, FD patients with cardiac involvement often have brain infarctions with embolic pattern. In summary, our patient experienced two infarctions, probably caused by recurrent cardiac emboli.The CSF findings in our patient are in line with previous reports, describing an \u201caseptic meningitis\u201d or \u201cchronic meningitis\u201d with mild to moderate pleocytosis and elevated total protein levels suggestive of a disturbed blood-cerebrospinal fluid barrier . The addIn conclusion, ischemic lesions of the spinal cord can occur in patients with FD and need to be investigated. The diagnosis of FD should not be prematurely excluded in the presence of spinal lesions. Most importantly, since appropriate disease-modifying therapies are available for both diseases, the ability to distinguish FD from MS remains essential. Therefore, we suggest deleting the red flag for the presence/absence of spinal lesions in the differential diagnosis between MS and FD.Since initially a diagnosis could not be established, I felt very helpless at that time. In the end, I hope that physicians all over the world have learned something from reading my case.Fabry disease was biochemically diagnosed seven years before occurrence of the complete spinal cord syndrome. Infectious disorders were excluded as possible causes in serum and CSF. The antibody screening in serum was negative.The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.JK, FG, and TD conceived the study and defined the concept. JK, FG, TD, HW, EB, CP, MH, SM, and ML collected and interpreted the data. JK wrote the initial draft of the manuscript. All authors contributed to the article and approved the submitted version. All authors agreed to be accountable for all aspects of the work by ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.JK: received honoraria for lecturing from Biogen, Novartis, Genzyme, Merck, Mylan, and Teva and financial research support from Sanofi Genzyme and Novartis. EB: received research grants and speaker honoraria from Sanofi Genzyme, Shire/Takeda, and Amicus Therapeutics. ML: received speaker honoraria from Amicus Therapeutics, Sanofi Genzyme, and Shire/Takeda and advisory board honoraria from Sanofi Genzyme. HW: received compensation for serving on Scientific Advisory Boards/Steering Committees for Bayer Healthcare, Biogen Idec, Sanofi Genzyme, Merck Serono, and Novartis. He has received speaker honoraria and travel support from Bayer Vital GmbH, Bayer Schering AG, Biogen, CSL Behring, EMD Serono, Fresenius Medical Care, Genzyme, Merck Serono, Omniamed, Novartis, and Sanofi Aventis. He has received compensation as a consultant from Biogen Idec, Merck Serono, Novartis, Roche, and Sanofi-Genzyme. HW also received research support from Bayer Healthcare, Bayer Vital, Biogen Idec, Merck Serono, Novartis, Sanofi Genzyme, Sanofi US, and Teva. SM: received honoraria for lecturing and travel expenses for attending meetings from Almirall, Amicus Therapeutics Germany, Bayer Health Care, Biogen, Celgene, Diamed, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, Roche, Sanofi-Aventis, Chugai Pharma, QuintilesIMS, and Teva. His research is funded by the German Ministry for Education and Research (BMBF), Deutsche Forschungsgemeinschaft (DFG), Else Kr\u00f6ner Fresenius Foundation, German Academic Exchange Service, Hertie Foundation, Interdisciplinary Center for Clinical Studies (IZKF) Muenster, German Foundation Neurology, and by Almirall, Amicus Therapeutics Germany, Biogen, Diamed, Fresenius Medical Care, Genzyme, Merck Serono, Novartis, ONO Pharma, Roche, and Teva. TD: received honoraria and travel expenses from Genzyme, Shire, Bristol-Myers Squibb, Boehringer-Ingelheim Pharma, Sanofi Aventis, Wisai, Novartis, Bayer Vital, Merz Pharma, Actelion, and Lundbeck for serving as a speaker and consultant. He received research support from Genzyme, Shire, and Actelion and grants from Novartis and Merz Pharma for conducting dementia studies.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Coral microbiomes are critical to holobiont health and functioning, but the stability of host\u2013microbial interactions is fragile, easily shifting from eubiosis to dysbiosis. The heat-induced breakdown of the symbiosis between the host and its dinoflagellate algae , is one of the most devastating outcomes for reef ecosystems. Yet, bleaching tolerance has been observed in some coral species. This review provides an overview of the holobiont\u2019s diversity, explores coral thermal tolerance in relation to their associated microorganisms, discusses the hypothesis of adaptive dysbiosis as a mechanism of environmental adaptation, mentions potential solutions to mitigate bleaching, and suggests new research avenues. More specifically, we define coral bleaching as the succession of three holobiont stages, where the microbiota can (i) maintain essential functions for holobiont homeostasis during stress and/or (ii) act as a buffer to mitigate bleaching by favoring the recruitment of thermally tolerant Symbiodiniaceae species (adaptive dysbiosis), and where (iii) environmental stressors exceed the buffering capacity of both microbial and dinoflagellate partners leading to coral death. Coral reefs are one of the most biologically diverse and economically important marine ecosystems on the planet. Often called the rainforest of the sea due to their outstanding biodiversity, coral reefs only cover less than 0.1% of the ocean seafloor ,3. CoralThe stability of the holobiont is fragile. Holobionts can transition from eubiosis  to dysbiosis  as, for instance, environmental conditions deteriorate. The health of the holobiont depends on many biotic  and abiotic  factorsSince the first description in the 1980s , increasThe coral holobiont comprises the cnidarian host and all its associated microscopic organisms that functionally interact with one another via several metabolic pathways, further contributing to the physiology and health of the holobiont. The coral holobiont can be separated into three main components: (i) the cnidarian host, (ii) the Symbiodiniaceae algae, and (iii) the microbiota .Since their first appearance around 425 million years ago, scleractinian corals have radiated into more than 1500 species , about 9As in other invertebrates, an innate immune system allows corals to maintain homeostasis. Invertebrates lack an adaptive immune system , but theCorals can reproduce through both sexually and asexually  ,85. CoraThe reproduction mode influences the early establishment of the microbial consortium in corals. The Symbiodiniaceae endosymbiont transmission is generally horizontal in broadcast spawners, and vertical and mixed in brooders ,94,95. H3\u2212) to the algal symbionts [2\u2212) produced by the polyps, which also promotes the dissociation of carbonic acid (H2CO3) from the water column and allows calcium carbonate (CaCO3) to precipitate. Thus, this photosymbiosis also powers light-enhanced calcification and the rapid growth of corals [Zooxanthellae are crucial components of the coral holobiont. The endosymbiotic dinoflagellates, from the family Symbiodiniaceae  are phoymbionts , while tf corals ,105,106,f corals .Symbiodinium [Symbiodinium, Breviolum, Cladocopium, Durusdinium, Effrenium, Fugacium, and Gerakladium  [Symbiodinium, Breviolum, Cladocopium, and Durusdinium, while the genera Fugacium and Gerakladium are only occasional scleractinian associates [Symbiodinium, Breviolum, and Durusdinium species are more suited for light regimes associated with shallow habitats [Durusdinium species being the most thermally tolerant [Cladocopium species are considered depth-generalists, although populations of shallow habitats can exhibit greater assemblage diversity compared to deeper habitats at some reef locations [Based on the phylogenetic disparity in the Internal Transcribed Spacer 2 (ITS2) sequence, these dinoflagellate algae were initially distinguished into nine phylogenetic clades (nominated A to I) within the genus iodinium ,108,109.ctively) . Among tsociates ,111. Corsociates ,112,113.sociates  and Carisociates , while vsociates ,116. Forhabitats ,118, wittolerant ,119. On ocations .A possible determinant of host-specificity and environmentally induced variations in Symbiodiniaceae composition is the mode of symbiont acquisition. The Symbiodiniaceae algae can be passed on to the offspring vertically  ,121,122.In scleractinian corals, the microbiota encompasses a wide range of microbial organisms, including archaea, bacteria, eukaryotes , and viruses ,22,129, The heritability of such phenotypic traits can result partially from vertical transmission of the microbiota, i.e., when the host passes on a sample of its microbes to the offspring . This veOverall, the coral host represents a great diversity of microhabitats , each sheltering a specific set of microbes ,32,142. Endozoicomonas, Vibrio, and Serratia genera are the most represented [Orbicella faveolata and Porites lutea are involved in nutrient cycling , featuring genes for carbon fixation  and degradation [P. lutea [Bacterial symbionts are key players supporting the functioning and health of corals and reef ecosystems . Corals resented , with baresented . These bresented , oxygen resented ,165 and resented , controlresented ,167,168,resented ,170, andresented ,130. Forradation ,132. Int4+) [3\u2212) reduces photosynthetic health [2) for photosynthesis, which can ultimately increase Symbiodiniaceae abundance, promote photosynthetic health, and enhance coral health [Endozoicomonas symbionts of the bacterial family Hahellaceae also play a significant role in nutrient acquisition and cycling of organic compounds because of their ability to metabolize dimethylsulfoniopropionate (DMSP) [When the availability of nitrogen decreases in the environment, bacteria can supply the host with organic nitrogen. The microbiota harbors nitrifying  and denitrifying (reduces nitrites and nitrates into dinitrogen) bacterial species that transform nitrogen-related waste produced by the host into non-toxic compounds ,27. By r4+) . The amm4+) , while tc health . The occl health ,172. Becl health ,174. Dial health . Endozoie (DMSP) , a molece (DMSP) . Some coe (DMSP) .Another key role of the microbiota is to provide protection against pathogens via diverse mechanisms, including competitive exclusion, antibiotic production, inhibition of quorum sensing, and secondary metabolite production ,177. TheEndozoicomonas species, has been observed [Vibrio species [Vibrio spp. (about 0 to 30% of the relative abundance) in corals experiencing heat-induced bleaching, while their abundances return to normal in resilient corals . Although this study suggests that Vibrio spp. might be specifically linked to coral bleaching, current knowledge makes it impossible to disentangle whether their presence, increase in abundance, and virulence in thermally stressed corals is a consequence of bleaching [Although heat-induced bleaching is triggered by the breakdown of the symbiosis between corals and their dinoflagellate symbionts, bleaching is sometimes accompanied by changes in the coral-associated bacterial community composition, ranging from mutualistic species to commensalistic, and parasitic ,57,184. observed . On the  species ,186,187, species . Bourne leaching  or playsleaching .Viruses are found in both tissue and mucus layers, where they hold diverse essential functions in the coral holobiont, including bacterial population maintenance, protection against pathogens, nutrient cycling, and horizontal gene transfer ,191. As Dominated by bacteriophages , the virV. coralliilyticus) [Rising temperature can also increase virulence by expressing genes causing dysbiosis  . Consequlyticus) , and thePocillopora damicornis [The microbiota also includes many other microbes such as archaea, protists, and fungi. However, much less attention has been paid to these microbial members and to their role in coral bleaching. Archaea are very common in marine environments. The archaeal groups Euryarchaeota and Thaumarcheota can associate with corals , with thmicornis .Ostreobium microalgae  [Ostreobium can potentially provide an alternative source of energy to the coral host during bleaching via the transfer of photosynthates [Acropora hyacinthus comprised a high diversity of basidiomycetes and ascomycetes species [Although there is growing interest in the endolithic communities, their functional role within the coral holobiont and bleaching responses remains poorly understood. The skeleton of many coral species is often dominated by the filamentous rophyta)  that seerophyta) . Despiterophyta) ,208,209,ynthates ,210. Altynthates . Yet, th species . Fungi p species , stress  species , and bio species .Since the partnership with microbial symbionts serves a wide range of beneficial functions within the coral holobiont, functional activity of microbes may mitigate or even prevent bleaching responses by supporting the internal equilibrium between the host and Symbiodiniaceae, and by maintaining stable rates of photosynthesis ,166,172.As of today, the role of coral-associated microorganisms in bleaching remains poorly understood, although changes in bacterial community composition are frequently associated with coral bleaching ,186,217.(1)Adaptive dysbiosis without Symbiodiniaceae community restructuring;(2)Adaptive dysbiosis with Symbiodiniaceae community restructuring with or without transient bleaching;(3)Maladaptive/traumatic dysbiosis with irreversible loss of Symbiodiniaceae and invasion of opportunistic microbes leading to holobiont death.The adaptive dysbiosis hypothesis (ADH) stands on the principle that the microbiota confers resistance and resilience to its host via functional redundancy (reviewed in ), and isWhen corals are exposed to thermal stress (among others), major changes in microbiome composition occur, often associated with different bleaching states, but without inferring a causative link between the two ,142. TheAmong these mechanisms, the increase in cyanobacteria and plastid ratio within microbial communities under stress has been identified as a potential mechanism to compensate for reduced photosynthetic activity linked to a lower abundance of Symbiodiniaceae cells , while aPorites species and up to 100% in Montipora capitata [The intake of new microbial symbionts is not always mandatory to maintain functional homeostasis. The microbiota can activate a natural defense mechanism against invading pathogens during coral dysbiosis. For instance, commensal bacteria are known to produce antibiotics and other metabolites involved in the enzyme inhibition  ,238. Uticapitata , while hcapitata .Coral holobionts living in variable environments can express some level of metagenomic plasticity since they are forced to modify their physiological activity and/or their microbial composition frequently ,242. ComFirst introduced by Buddemeier and Fautin , this hoDurusdinium species are considered thermo-tolerant, these better adapted Symbiodiniaceae can minimize coral bleaching and increase host survival under thermal stress [Cladocopium. Although some Durusdinium species can potentially confer greater thermal tolerance, associating with this genus might represent a trade-off for corals, as for example they support slower coral growth compared to Cladocopium species [Durusdinium, can replace other, less resistant species during bleaching to help the coral survive before returning to its beneficial association with its original partner. Durusdinium species might therefore act as transitional helpers rather than permanent partners.Because some l stress ,251,252, species ,254. Cor species , suggestThe transition between two Symbiodiniaceae genera is costly in terms of energy, often resulting in a reduced number of symbionts for photosynthesis ,257. BecOstreobium sp. contribute to the dissolution of the calcium carbonate structure of dead corals, thus enhancing erosion by ocean acidification [In cases of abrupt or prolonged elevated temperature, the microbiome can no longer maintain resistance against invading opportunistic pathogens  and an irreversible breakdown in the holobiont equilibrium takes place, where the dinoflagellate symbiont loss is permanent . Followification .P. damicornis have proven to be useful in lessening the effects of bleaching through the addition of a consortium of native putatively beneficial microorganisms for corals (pBMCs), including five Pseudoalteromonas sp., a Halomonas taeanensis and a Cobetia marina-related species strains [Coral reefs are undergoing rapid decline globally as human activities have led to a gradual increase in sea temperature that surpasses the physiological tolerance of corals and their associated microorganisms. We are currently witnessing the most prolonged global coral die-off to date, mostly due to coral bleaching (from 2014 onwards) . In 1998 strains . Such mi strains . Because strains ,269.Despite the potential for harnessing the benefits of coral microbiomes, their manipulations are not enough to overcome the impact of human-induced climate change and other threats  on coral reef ecosystems. Other local/small scale actions must be taken, in combination with climate action, to protect and restore these diverse and productive ecosystems. Ecological restoration, creation of marine protected areas, strict monitoring of physicochemical parameters, and international collaboration sharing data on corals are only a few examples that would help in mitigating the current and unprecedented coral decline ,271,272."}
+{"text": "Based on the data from National Social Life, Health and Aging Project, Wave 3, this study examined two research questions: what is the role of race in predicting cognitive status? and what are predictors of cognitive status between white and black older adults? Cognitive status was assessed using the 18-item survey-adapted Montreal Cognitive Assessment. Using the ecological framework, correlates of cognitive status were conceptualized in three levels of environments: micro- , meso- , and macro-environments (community characteristics). Hierarchical regressions analyses were employed. Findings indicated that 83% of the sample  were whites and the mean age was 72.95. Bivariate analyses suggested significant racial differences in cognitive status, marital status, income, education, health, social relationship, and community characteristics. Additive and interactive models showed that race had an independent effect as well as joint effects with the three levels of environments in explaining cognitive status. Parallel regression analyses for each racial group were undertaken and models were significant (P < .0001). In two separate models, common predictors for better cognition included being younger, more educated, fewer IADL impairments, and less depression. For older whites, unique correlates for better cognition were being female, higher income, sense of control in life, safer community, and neighbor relations. The only unique correlate for older blacks to have better cognition was community cohesion. Results provided insights on racial differences in cognition experienced among community-dwelling older Americans, and emphasized the need for social programs that promote race-sensitive, age-friendly communities to protect against cognitive decline."}
+{"text": "Following the publication of the original article  we were The correct author names are shown here below:Rosaria Talarico, Sara Cannizzo, Valentina Lorenzoni, Diana Marinello, Ilaria Palla, Salvatore Pirri, Simone Ticciati, Leopoldo Trieste, Isotta Triulzi, Enrique Terol, Anna Bucher and Giuseppe Turchetti.The author names have been corrected in the author list of this Correction and updated in the original article."}
+{"text": "Dear Editor,Cote et al. (2020) conductCreed et al.  conductRegarding the mechanism of the association, the flavanols are the most important compound of tea polyphenols that predominantly include catechins, such as epicatechin, epicatechin gallate, epigallocatechin, epigallocatechin gallate, and catechin. Among them, Le et al. (2018) reporteThe author declares no conflict of interest."}
+{"text": "Following publication of the original article , the autDepartment of Clinical Immunology, Wroclaw Medical University, Wroclaw, Poland.The corrected affiliation list is reflected in this Correction."}
+{"text": "Brain metastasis, one of the common complications of lung cancer, is an important cause of death in patients with advanced cancer, despite progress in treatment strategies. Lung cancers with positive driver genes have higher incidence and risk of brain metastases, suggesting that driver events associated with these genes might be biomarkers to detect and prevent disease progression. Common lung cancer driver genes mainly encode receptor tyrosine kinases (RTKs), which are important internal signal molecules that interact with external signals. RTKs and their downstream signal pathways are crucial for tumor cell survival, invasion, and colonization in the brain. In addition, new tumor driver genes, which also encode important molecules closely related to the RTK signaling pathway, have been found to be closely related to the brain metastases of lung cancer. In this article, we reviewed the relationship between lung cancer driver genes and brain metastasis, and summarized the mechanism of driver gene-associated pathways in brain metastasis. By understanding the molecular characteristics during brain metastasis, we can better stratify lung cancer patients and alert those at high risk of brain metastasis, which helps to promote individual therapy for lung cancer. In 2003EGFR and ALK) can benefit from targeted therapy. Progress has also been achieved in research on rare mutations such as ERBB2, MET, RET, ROS1, and PIK3CA, and new inhibitors targeting the products of these genes are under development , PI3K/protein kinase B (AKT) pathways were associated with an increased risk of brain metastasis in NSCLC patients , 68. RecEGFR, ERBB2, MET, RET, ALK, and ROS1, all encoding genes for receptor tyrosine kinases (RTKs). Abnormal RTKs activation in tumors mainly includes acquired mutations, genome amplification, chromosome rearrangement, and autocrine activation, which lead to the imbalance of RTK signals and promote cell proliferation, metabolism, cytoskeleton remodeling, cell migration, and anti-apoptosis effects  . Tyrosineceptors . Interfeeceptors \u201385. Mohrl models . In addith NSCLC . MoleculMutations introduced during primary tumor cell growth can result in clonal heterogeneity. Vogelstein put forward four types of genetic heterogeneity in tumors: intratumoral, intermetastatic, intrametastatic, and interpatient . IntratuDuring the process of brain metastasis, abnormal genes drive tumor cells to escape normal regulatory mechanisms and change the microenvironment of lung cancer tumors through various signals, which continues to enhance tumor invasiveness, induce epithelial-mesenchymal transition (EMT) and accelerate vascular invasion . MetastaEGFR, ERBB2, TGFbR2, MET, RAS, RAF, PIK3CA, and PTEN genes, can proliferate under limiting nutrient concentrations , which produce IL-6 after engulfing particles released by tumor cells , 107. TAvia EMT  and zinc finger E-box binding homeobox 1 (ZEB1) protein , and grow autonomously in brain tissue through tumor-specific signaling pathways. Tumor cells interact with microglia and affect angiogenesis and survival through activation of STAT3 pathway in microglia . In multin vitro . Activatin vitro . In braiin vitro . UnfortuKAS or EGFR mutation to colonize the brain  ligand 2, recruitment of myeloid cells, promotion of cell proliferation, and reduced apoptosis, which further enhances the growth of tumor cells in metastatic sites .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Alterations in myelin, the protective and insulating sheath surrounding axons, affect brain function, as is evident in demyelinating diseases where the loss of myelin leads to cognitive and motor dysfunction. Recent evidence suggests that changes in myelination, including both hyper- and hypo-myelination, may also play a role in numerous neurological and psychiatric diseases. Protecting myelin and promoting remyelination is thus crucial for a wide range of disorders. Oligodendrocytes (OLs) are the cells that generate myelin, and oligodendrogenesis, the creation of new OLs, continues throughout life and is necessary for myelin plasticity and remyelination. Understanding the regulation of oligodendrogenesis and myelin plasticity within disease contexts is, therefore, critical for the development of novel therapeutic targets. In our companion manuscript, we review literature demonstrating that multiple hormone classes are involved in the regulation of oligodendrogenesis under physiological conditions. The majority of hormones enhance oligodendrogenesis, increasing oligodendrocyte precursor cell differentiation and inducing maturation and myelin production in OLs. Thus, hormonal treatments present a promising route to promote remyelination. Here, we review the literature on hormonal regulation of oligodendrogenesis within the context of disorders. We focus on steroid hormones, including glucocorticoids and sex hormones, peptide hormones such as insulin-like growth factor 1, and thyroid hormones. For each hormone, we describe whether they aid in OL survival, differentiation, or remyelination, and we discuss their mechanisms of action, if known. Several of these hormones have yielded promising results in both animal models and in human conditions; however, a better understanding of hormonal effects, interactions, and their mechanisms will ultimately lead to more targeted therapeutics for myelin repair. Many neurological disorders are characterized by changes in myelin, the protective and insulating sheath surrounding axons. Such disorders include psychiatric disorders, Alzheimer\u2019s Disease (AD), and demyelinating disorders, conditions in which myelin is damaged and ultimately lost ,2,3,4. IOligodendrocytes (OLs) are the glial cells in the CNS that generate the myelin sheath. Once matured, these cells may have a dramatically limited capacity for creating new myelin ,13,14. IThe mechanisms underlying the process of remyelination can be investigated in animal models that replicate some aspects of human pathologies. The most commonly used animal model for MS is experimental autoimmune encephalomyelitis (EAE), which involves the induction of an immune response to myelin antigens. This leads to the progressive loss of myelin, as well as cognitive and motor deficits ,28. In aOligodendrogenesis is regulated by numerous endogenous factors, including many different hormones . In facIn this review, we will explore how hormonal factors affect oligodendrogenesis within disease contexts. The accompanying review introduces the hormones discussed and explores the hormonal regulation of oligodendrogenesis under physiological conditions . As in oSteroids are hydrophobic molecules synthesized from cholesterol that have important actions within the CNS, including regulation of oligodendrogenesis . For thiGCs are one of the primary stress hormones. This family includes endogenous cortisol (the primary GC for humans), corticosterone (the primary GC for rodents), and synthetic hormones such as dexamethasone (Dex). Like many steroid hormones, GCs enhance oligodendrogenesis in vitro and in vivo, specifically by enhancing differentiation of neural stem cells (NSCs) and OPCs, via activation of glucocorticoid receptors (GRs) ,40, and Levels of circulating GC hormones can be increased by stress, injury, and disease, and although prolonged or high levels of GCs may be harmful, acute increases in GCs may in fact be beneficial. For example, methylprednisolone (MP), a synthetic GR agonist, often given to spinal cord patients within a few hours of injury, protects against OL cell death following SCI in mice; specifically, MP treatment after SCI increases the number of mature OLs at the site of injury eight days later . This prOL apoptosis, often induced by inflammation, is important in MS as well as other demyelinating disorders ,47,48. IDespite this evidence for prevention of OL loss, there is conflicting evidence of whether GCs can enhance remyelination in an injury or disease context. While GCs such as Dex and MP accelerate OPC differentiation in culture, GCs impair remyelination in the corpus callosum in vivo in cuprizone-treated mice . Thus, wUnderstanding how GCs affect oligodendrogenesis has important broader implications not only for demyelinating disorders but also for human disorders characterized by alterations in the hypothalamic\u2013pituitary\u2013adrenal axis and changes in cortisol, including PTSD and depression ,55. InteBox 1Many neuropsychiatric disorders are characterized by alterations in myelin, both in white matter and grey matter regions ,25,60. WSex hormones, including the estrogens, progestogens, and androgens, all modulate oligodendrogenesis and myelogenesis, as we describe in our companion review ,73,74. IEstrogens, the major family of female sex hormones, are produced primarily by the ovaries. The most potent estrogen, 17-\u03b2 estradiol (E2), has many physiological functions for both male and female animals, including regulation of oligodendrogenesis . BroadlyEstrogen treatments may have protective and rehabilitative properties for OLs, with important implications for demyelinating disorders. Indeed, estrogen treatments improve clinical outcomes for MS patients and are now ready for phase three clinical trials ,82,83. IIn addition to ER-mediated effects, estrogens may aid remyelination, in part, via interactions with other hormones. For example, in cuprizone-induced demyelination models, E2 induces production of IGF-1 by astrocytes, which in turn promotes OL proliferation and differentiation . In addiEstrogen replacement therapy may also play a role in protecting middle-aged women from adverse effects following menopause, including myelin abnormalities and impaired cognition ,96,97. MThe steroid hormone progesterone is commonly known for its role in the maintenance of pregnancy, yet it also has a wide range of functions in the body and throughout the CNS, including effects on oligodendrogenesis . ProgestProgesterone has a significant impact on remyelination . ProgesIn SCI models, chronic treatments with progesterone enhance OPC proliferation, differentiation, and remyelination following injury ,106,107.Similar to findings in SCI models, progesterone has protective and pro-remyelinating effects in LPC, cuprizone, and other toxin-induced demyelination models ,110,111.In the rodent EAE model, progesterone may improve remyelination through beneficial influences on inflammation, specifically by reducing inflammatory cell infiltration, proinflammatory cytokine levels, and numbers of reactive microglia ,114,115.While progesterone has primarily been studied in the context of SCI and demyelinating disorders, it also has beneficial effects for other disorders associated with myelin loss, such as AD and stroke ,118,119.Androgens are a class of steroid hormones that includes testosterone , dihydrotestosterone , and several weakly acting hormones . AndrogeStudies reporting androgen-induced OL cell death under physiological conditions are somewhat at odds with several studies, demonstrating a protective effect of testosterone in demyelinating disorders. Indeed, early studies suggested that in mouse EAE models, castration induces clinical relapses and a greater influx of activated T-cells into the CNS, suggesting that male gonadal hormones are protective . MoreoveNestin-Cre mice). Furthermore, this myelin-rescuing effect can be mimicked in vitro in cerebellar slice culture; applying testosterone or DHT following LPC-induced demyelination restores myelination, an effect that is blocked by an AR antagonist. Together, these data suggest AR signaling has a direct role in CNS remyelination [Androgens can also enhance remyelination following toxin-induced demyelination. For example, 12 weeks of cuprizone administration results in long-lasting loss of OLs and myelin in the corpus callosum of both castrated male and ovariectomized female mice; however, administering testosterone for six weeks following cuprizone withdrawal increases the number of OPCs and restores mature OL numbers and MBP expression in both sexes, suggesting that testosterone enhances OPC recruitment, differentiation, and remyelination . This relination . Similarlination . Specifilination . It was lination . OverallAlthough the mechanism of action remains somewhat unclear, the ability of androgens to protect against demyelination and enhance remyelination may ultimately have implications for disorders such as MS. Reports suggest that women are more susceptible to MS than men ; howeverIn this section, we discuss the role of amino acid-derived hormones and their receptors in oligodendrogenesis and myelin repair. These hormones can be genetically encoded chains of two or more amino acids (peptides) or enzymatically altered compounds derived from single amino acids (amines and THs). As we describe in our companion review, many of these hormones act to enhance OPC proliferation and/or OL survival through common signaling pathways .IGF-1 is a peptide that broadly contributes to cell growth, proliferation, differentiation, and survival. IGF-1 exerts its effects in part by binding the IGF-1 receptor (IGF1R), which is expressed in all CNS cell types, including OLs ,139,140.IGF-1 exerts protective effects in several animal models of myelin damage. In alignment with the anti-apoptotic effects of IGF-1 under physiological conditions, administering IGF-1 or constitutively overexpressing IGF-1 prevents OL apoptosis and/or myelin loss induced by a host of demyelinating conditions, including cuprizone treatment, LPC treatment, undernourishment, and ischemia ,144,145.IGF-1 has also been targeted as a potential treatment for demyelinating disorders such as MS. Interestingly, constitutive loss of IGF1R impairs OPC survival, proliferation, and subsequent OL remyelination after cuprizone-induced demyelination , again sInsulin is a metabolic hormone that classically regulates glucose homeostasis but also acts within the CNS in both an endocrine and paracrine fashion . InsulinDespite insulin\u2019s ability to promote OL survival, treatment with insulin appears to be ineffective in demyelinating disorders. In both young and aged EAE rats, chronic treatment with IGF-1, but not insulin, ameliorates clinical severity scores . Given tInsulin\u2019s effects on oligodendrogenesis may have implications for disorders characterized by significant disruptions in insulin signaling, such as type 1 and type 2 diabetes. Indeed, peripheral demyelination is a common diabetes-induced complication, and insulin signaling may contribute to myelin production in Schwann cells ,158,159.Prolactin is a peptide that promotes lactation and regulates diverse functions, including oligodendrogenesis . While cProlactin has garnered interest for its therapeutic potential in demyelinating disorders such as MS. This interest began with early observations that female MS patients show fewer relapses during the third trimester of pregnancy when prolactin and sex hormone levels are high . InteresWhile these results are promising, prolactin has known pro-inflammatory effects that could complicate its use as a treatment in disorders such as MS and antagonize its remyelination benefits . In factMelatonin is an indolamine neurohormone produced primarily by the pineal gland and, to a lesser extent, locally within the brain that regulates circadian rhythms and exhibits anti-inflammatory actions ,179,180.Few studies have examined the molecular effects of melatonin on oligodendrogenesis under physiological conditions; however, several have examined melatonin\u2019s protective effects under demyelinating conditions. Such conditions include ischemia ,183, strMany of the studies noted here also investigated the effects of melatonin on inflammation. Consistent with melatonin\u2019s anti-inflammatory properties, melatonin treatment decreases pro-inflammatory cytokine levels in cuprizone-induced demyelination, EAE, and ischemia ,186,189.Interestingly, melatonin may exert pro-apoptotic effects on cancerous tissues, including oligodendrogliomas ,191,192.In sum, melatonin may be a promising candidate for the prevention of demyelination and the amelioration of disease severity; however, the mechanism of melatonin action remains unclear. Melatonin consistently attenuates myelin loss and reduces levels of pro-inflammatory cytokines and microglial reactivity; however, no study has demonstrated a causal link between these two parallel effects.THs are tyrosine-based hormones that act on almost every cell type in the body to regulate CNS development, including oligodendrogenesis. ,200,201.It has long been known that TH deficiency, in both humans and other animals, leads to impairments in myelin during development ,212,213 In EAE models, TH again aids in remyelination ,224,225.Broadly, hormonal actions on oligodendrogenesis represent an underexplored therapeutic avenue for myelin repair. Yet, as we have noted throughout this review, there are many unanswered questions. For example, while many studies have shown that hormones have neuroprotective and pro-remyelination effects in animal models of white matter damage, their mechanisms of action remain largely unclear. Understanding these mechanisms will be crucial for designing therapeutics that target specifically oligodendrogenesis and remyelination and minimize off-target effects in the CNS. In addition, many of these hormones both improve myelin loss and reduce inflammation. Thus, it remains to be determined if hormones act directly on the OL lineage to enhance remyelination or indirectly through interactions with the immune system and other factors.In addition, few studies have addressed the complex interactions amongst the hormones themselves. For example, estradiol induces upregulation of PRs, and treatments with both estrogens and progesterone combined were more effective in restoring myelination ,93,94. IFurther, we have little understanding of how hormones might affect oligodendrogenesis and myelin repair based on age. Indeed, the actions of several of the hormones discussed here change over the course of development and adulthood . Thus, tHormones across many classes exert protective and remyelinating effects on disorders characterized by myelin loss . Many of"}
+{"text": "The continuous population increase of older adults with metabolic diseases may contribute to increased prevalence of sarcopenia and obesity and requires advocacy of optimal nutrition treatments to combat their deleterious outcomes. Sarcopenic obesity, characterized by age-induced skeletal-muscle atrophy and increased adiposity, may accelerate functional decline and increase the risk of disability and mortality. In this review, we explore the influence of dietary protein on the gut microbiome and its impact on sarcopenia and obesity. Given the associations between red meat proteins and altered gut microbiota, a combination of plant and animal-based proteins are deemed favorable for gut microbiota eubiosis and muscle-protein synthesis. Additionally, high-protein diets with elevated essential amino-acid concentrations, alongside increased dietary fiber intake, may promote gut microbiota eubiosis, given the metabolic effects derived from short-chain fatty-acid and branched-chain fatty-acid production. In conclusion, a greater abundance of specific gut bacteria associated with increased satiation, protein synthesis, and overall metabolic health may be driven by protein and fiber consumption. This could counteract the development of sarcopenia and obesity and, therefore, represent a novel approach for dietary recommendations based on the gut microbiota profile. However, more human trials utilizing advanced metabolomic techniques to investigate the microbiome and its relationship with macronutrient intake, especially protein, are warranted. By 2050, the worldwide population of those aged over 65 years is projected to increase by approximately 10%, reaching 2.1 billion . In aginulations . In the ulations , whereas980\u20132013 .Gut microbiota dysbiosis is linked to age-related systemic inflammation, leading to impaired muscle function and increased proinflammatory cytokines, which are associated with higher risk of obesity . Gut micIn this review, we discuss how dietary protein may influence the gut microbiota ecosystem and its potential role in sarcopenia and obesity. We further aim to provide perspectives on novel future dietary recommendations, focusing primarily on the potential anabolic-induced effects that emerge from elevated protein and fiber consumption.Sarcopenia is accompanied by a greater incidence of comorbidities, including type 2 diabetes and obesity ,27,28, wPorphytomonas, Prevotella), Firmicutes , Proteobacteria with minor groups of Actinobacteria (Bifidobacterium), Acidobacteria, Fusobacteria, and Verrumicrobia [Lactobacillus, Veillonella) and Proteobacteria (Helicobacter) are dominant in the proximal gut, whereas Firmicutes (Lachnospiraceae) and Bacteroidetes are observed in the colon [The human gut is colonized by numerous microorganisms , which are considered a contributor to a range of physiological functions, such as strengthening the gut integrity , regulatmicrobia . Firmicuhe colon ,50. The Faecalibacterium prausnitzii and Bifidobacterium infantis may result in the production of the anti-inflammatory cytokine interleukin-10 and regulate T cell activation against the pathogen-stimulated NF-\u03baB inflammatory pathway [Due to the antimicrobial effects of gastric and bile-acid secretion, a relatively low number of microbiota are present in the stomach and the proximal small intestine . The com pathway . Other s pathway . Further pathway , as well pathway . Alterat pathway . A catal pathway ,59,60, a pathway .Bifidobacterium, Lactobacillus, Akkermansia, Fecalibacterium, Eubacterium, Roseburia, Ruminococcus, and Blautia species are considered beneficial for metabolic health in the elderly [Lactobacillus-species restoration reduced muscle atrophy, which is also correlated with a decrease in various proinflammatory cytokines [Clostridium, Enterobacter, Enterococcus, and Ruminococcus are associated with altered energy balance and greater risk of obesity [The gut microbiota has a substantial impact on the regulation of metabolic processes, including nutrient and amino-acid metabolism ,63. Alte elderly ,84. For ytokines . On the  obesity . Multipl obesity ,86. Howe obesity . Most st obesity .Bifidobacterium and Lactobacillus may promote more efficient nutrient absorption and amino-acid synthesis, whereas low microbial diversity is associated with excess nutrient uptake and storage and increased Firmicutes to Bacteroidetes ratio [Bifidobacterium levels are detected during aging, which is linked to increased circulating levels of lipopolysaccharide (LPS). Elevated levels of the endotoxin LPS are marked in obese and diabetic individuals, leading to gut microbiota dysbiosis, skeletal-muscle-insulin resistance and increased gut permeability [Bifidobacterium) to influence the development of sarcopenic obesity through decreased glucose tolerance in the skeletal muscle [Moreover, alterations in gut microbiota composition are observed more commonly in people over the age of 65 compared to younger adults ,90. Highes ratio ,92. A gres ratio ,94. Inteeability ,97,98,99eability ,101. Thil muscle ,103,104.l muscle ,108,109.l muscle . Therefol muscle ,112. Howl muscle ,114.Protein is the dominant macronutrient in weight-loss strategies combatting sarcopenic obesity, given its appetite-suppressive effects  and anabMost protein is digested and absorbed efficiently in the small intestine by pancreatic enzymes and peptidases used by enterocytes, although approximately 10% of proteins that pass through the small intestine may not be completely digested . Going tMultiple human and animal studies have linked increased branched-chain amino acids (BCAAs) with insulin resistance and type 2 diabetes in obese groups ,152,153.Bifidobacterium, Roseburia, Ruminococcus bromii, Lactobacillus, and Roseburia content [Bacteroides, Alistipes, Bilophila, and Clostridium perfrigens, found primarily in animal proteins [Bacteroidetes, Bifidobacterium, and decreased serum LPS levels compared to meat, dairy, and casein-protein consumption have been associated with soy-protein intake [Bifidobacteria and Lactobacilli, which are linked to decreased diet-induced obesity and improved insulin sensitivity have been further supported by soy-protein consumption [Lactobacillus and Bifidobacterium levels, and reduced Firmicutes have been reported following soybean, mungbean, and buckwheat proteins [Bacteroides fragilis and Clostridium perfingens, increased acetate production, and greater Lactobacillus and Bifidobacterium diversity [Lactobacillus and Bifidobacteria species have been associated with increased muscle strength, weight loss, and reduced obesogenic environments in humans and rodents [Lactobacillus and Bifidobacteria, as reported in rodent studies [Lactobacillus abundance has been demonstrated from white-meat-protein consumption, while supplementation of Lactobacillus plantarum has resulted in increased muscle mass in mice [It is suggested that protein sources and amino-acid balance may influence gut microbial diversity. For instance, plant proteins are associated with greater  content , as oppoproteins ,162. A gn intake ,164. Fursumption ,166,167.proteins ,169. In iversity ,171,172. rodents ,175,176. studies ,178,179. in mice ,181. ExaHelicobacter) have been found in mice supplemented with seafood protein, which is characterized by increased taurine levels [Bifidobacterium, Lactobacillus, and SCFA production have been observed by high pea-protein intake, which suppresses the secretion of inflammatory cytokines, IL-6 and TNF-\u03b1, and improves interleukin-10 (IL-10) expression and glucose homeostasis [Bacteroides and Fusobacterium and lower levels of Lactobacillus and Roseburia, which are also linked with lower anti-inflammatory responses and increased incidence of type 2 diabetes [Roseburia, Bifidobacterium longum, and Blautia and increased Bacteroidetes species compared to the control group receiving maltodextrin [Prevotellaceae family compared to the lower-functionality older-adult donors [Lactobacillus [Bifidobacterium and Lactobacillus species for their regulatory effects on the microbiome, bone, and muscle health, which are crucial against frailty phenotypes in older individuals [Clostridium bartlettii, Eubacterium hallii, and Bacteroides [Bifidobacterium and Akkermansia [Furthermore, greater SCFA content and reduced Proteobacteria  consumption  during cRoseburia and Anaerostipes were lower than the probiotic added groups and no changes were seen regarding Eubacterium and Ruminococcus, possibly due to the higher fiber intake of the plant-based products. Accordingly, a synbiotic-used probiotic component expressed increased Bifidobacterium and Lactobacillus during a weight-loss program containing a high-protein/low carbohydrate diet compared to the placebo group, indicating the potential requirement of probiotic supplementation for improved microbial richness [Roseburia and Eubacterium rectale, displaying a dose\u2013response relationship, as carbohydrate intake was decreasing [Eubacterium rectale and Bifidobacteria have been observed during weight-loss strategies in overweight and obese individuals in which further resistant-starch-carbohydrates reductions were common [Furthermore, the influence of protein fermentation in the gut is primarily regulated by substrate utilization and transit time. It is suggested that the ratio of carbohydrates and protein consumed impacts the protein utilized by the microbiome. Following a 2-week high-protein diet (1.5\u20132.2 g/kg/day) in older women, microbial composition remained unaltered in the absence of added probiotic formulation . The suprichness . Moreovecreasing ,238,239.e common ,241.Bacteroides and Dorea and reduced Faecalibacterium species have also been reported in elite race walkers following a 2.2 g/kg/day diet containing <50 g carbohydrates, although their training and body composition status are confounding factors [Roseburia genera, Faecalibacterium, and Clostridium XIVa, as well as increased Firmicutes, have been confirmed by high-protein consumption as opposed to moderate protein intakes [Altered microbial composition by increased  factors . In anim intakes ,244. TheOverall, complex carbohydrate availability may lower protein fermentation, leading to a greater number of nitrogenous substrates intended to promote muscle anabolism. Therefore, recommendations on the ratio and source of dietary protein  and carbThe above sections illustrate the necessity of evaluating appropriate dietary components with the inclusion of both animal and plant-based food sources to optimize certain levels of gut microbiota species within high-protein diets. Regulating the quantity and source of food products may serve as a critical component for the control of protein and carbohydrate-fermenting bacteria, which could greatly influence various metabolic pathways. Given that different high-protein foods contain a varied micro- and macronutrient profile with notable distinctions among legumes, dairy, red and white meat, the microbial environment responsible for benefits and drawbacks in sarcopenic obesity cannot be accredited to a specific protein origin.Consequently, the amount and source of protein combined with other lifestyle factors need to be defined in regards to microbial diversity, which further supports a personalized overall macronutrient approach considering individual variation in microbial composition. Gender, ethnicity, medical history, medication use, physical activity, genetics, local environment, and diet may all contribute significantly to different microbiota composition in older adults. Designing novel dietary patterns by examining these factors carefully in relation to specific microbial species may lead to a reduced incidence of obesity and improvements in skeletal-muscle-insulin sensitivity, as well as counteract sarcopenia and obesity during weight loss interventions using high-protein and fiber-rich diets. Therefore, biomarkers identifying dietary protein\u2019s digestive capacity could aid older groups in monitoring their optimal daily protein intake and would minimise inappropriate amino acids reaching the colon and provide greater caloric availability for increased consumption of other vital macronutrients, such as dietary fiber, to optimize gut microbial eubiosis. Furthermore, fortification of plant-based products with essential amino acids and the addition of host-protective bacteria in high-protein animal products  could provide optimal MPS synthesis and microbial diversity. However, the overall quality of foods and supplements, alongside their protein content should also be evaluated considering the gut microbial changes that may occur throughout food processing. Moreover, the lack of long-term experimental human trials, more effective gene-sequencing methods for bacterial identification, and microbial exploration in several organs of the gastrointestinal tract present challenges in predicting the appropriate timing during which microbiome testing should be performed to identify microbiome changes occurring over time. At present, more human studies investigating the microbiome of sarcopenic obese groups are warranted. Focusing on the establishment and promotion of novel dietary protein and fiber RDAs, and aiming for greater BCFA and SCFA abundance, respectively, could provide various metabolic benefits in sarcopenic and obese individuals before we move towards a more personalized dietary approach through advanced microbiome metabolomic techniques."}
+{"text": "N-oxide (TMAO), short-chain fatty acids, and bile acid metabolites (amino acid breakdown products) with CVD. Human blood platelets are a critical contributor to the hemostatic process. Besides, these blood cells play a crucial role in developing atherosclerosis and, finally, contribute to cardiac events. Since the TMAO, and other metabolites of the gut microbiota, are asociated with platelet hyperactivity, lipid disorders, and oxidative stress, the diet-gut microbiota interactions have become an important research area in the cardiovascular field. The gut microbiota and their metabolites may be targeted for the therapeutic benefit of CVD from a clinical perspective. This review\u2019s main aim is to highlight the complex interactions between microbiota, their metabolites, and several CVD risk factors.Emerging data have demonstrated a strong association between the gut microbiota and the development of cardiovascular disease (CVD) risk factors such as atherosclerosis, inflammation, obesity, insulin resistance, platelet hyperactivity, and plasma lipid abnormalities. Several studies in humans and animal models have demonstrated an association between gut microbial metabolites such as trimethylamine- Cardiovascular disease (CVD) is the single biggest contributor to global mortality . CVD encWithin the human body reside trillions of different microbes, collectively referred to as the human microbiota. The largest microbe population is found in the gut, containing 100 trillion microbes of at least 1000 different bacterial species. Sufficient data indicates that the gut microbiome regulates numerous physiological functions, immune system, cardiovascular system, intestinal function, and absorption and metabolism of nutrients and their metabolites. Several studies have implicated gut dysbiosis in CVD pathology, including atherosclerosis, hypertension, platelet hyperactivity, abnormal lipid metabolism, and vascular dysfunction . Gut dysEmerging evidence suggests that targeting the gut microbiota and their metabolites can be an effective strategy in the treatment and prevention of CVD ,10,11. NThis review describes the current evidence linking gut microbiota and their metabolites with various CVD risk factors.The atherosclerosis process involves fibrosis of the intima, the formation of fatty plaque, the proliferation of smooth muscle cells, migration of monocytes and T lymphocytes, hyperactive platelets, and cholesterol accumulation . EmerginInflammation plays a major role in many diseases, including atherosclerosis ,16,17. AAkkermansia muciniphila exert protective effects against atherosclerosis by improving gut barrier functions [Roseburia and Eubacterium, while Collinsella was higher in CVD patients than in healthy individuals [The gut barrier\u2019s integrity is essential for maintaining the host\u2019s health and preventing inflammation and atherosclerosis processes. Intestinal permeability is impaired by the reduced expression of tight junction proteins such as zonula occludens-1, claudin-1, occludin, and creating an imbalance between intestinal epithelial cell death and regeneration ,20. Akkeunctions . Gut metividuals . The metividuals , even thividuals . The intividuals . When thividuals .Impaired gut barrier integrity induced by gut dysbiosis is a significant risk factor for chronic inflammation observed in several diseases, including atherosclerosis: the microbial component, lipopolysaccharide, is one of the PAMPs involved in the development of CVD. The association between lipopolysaccharide and CVD risk was first observed in 1999, determined by the endotoxin levels in patients , and, laDysbiosis increases the intestinal permeability by suppressing tight junction proteins, allowing the translocation of lipopolysaccharide into the circulation ,30. Gut Metagenomic sequencing has showed that patients with atherosclerosis had enrichment of genes that encoded peptidoglycan synthesis . The preFurthermore, in an extensive study involving 4012 patients with stable coronary artery disease, the administration of azithromycin showed no effect on cardiac event risk . HoweverGut microbial metabolites such as methylamines, polyamines, short-chain fatty acids (SCFAs), trimethylamine (TMA), and secondary bile acids play important roles in the host\u2019s physiology and in the development of CVD ,42. SCFABacteroidetes, Firmicutes, Actinobacteria, Proteobacteria, and Verrucomicrobia [Bacteroidetes and Firmicutes account for more than 90% of the total bacterial species [There is now sufficient evidence that gut microbiota participates in intestinal, cardiovascular health and immune function. The human gut microbiome has predominantly five phyla: microbia . In the  species . The gut species . They arThe gut microbiota metabolizes dietary phosphatidylcholine or l-carnitine into TMA . TMA is TMAO affects platelet activity, lipid metabolism, obesity, insulin resistance, vascular tone, and diabetes, thus stimulating the atherosclerosis processmethanobacteriales that reside in the human gut. The methanogenic bacteria have been shown to deplete both TMA and TMAO [Bacteroidetes-to-Firmicutes ratio and the growth of Bacteroides, Lactobacillus, and Bifidobacterium [The use of both prebiotics and probiotics in combination or alone impacts gut microbiota composition. Prebiotics including galacto-oligosaccharides, fructo-oligosaccharides, inulin, etc., stimulate the growth of beneficial microflora, while probiotics have specific beneficial bacterial strains. These interventions can help modulate bacteria to transform precursors into TMA and increase bacteria\u2019s ability to deplete it, or can help modulate bacteria devoid of the genes responsible for converting carnitine or choline to TMA. A majority of bacteria belong to the and TMAO ,53. Resvacterium ,55. ThesTMAO is associated with obesity, insulin resistance, and renal disease . A link A high choline diet caused increased TMAO levels and atherosclerosis in animal studies. TMAO mediates, at least in part, the established link between red meat consumption and CVD risk. Therefore, the low blood levels of TMAO as a result of fruits and vegetable intake may account for their cardioprotective effects. Work is ongoing to find novel therapeutic approaches that decrease plasma TMAO levels. The available data indicate modulation of the gut microbial TMAO generating pathway that attenuates atherosclerosis and platelet hyperactivity and in vivo thrombosis potential in animal models; however, the effective treatment modality has yet to be established. Lifestyle modification, including exercise, diet, functional foods, and changing microbiota, could be useful for lowering TMAO levels .TMAO exacerbates the vascular wall\u2019s inflammatory reactions, induces ROS production, and prevents cholesterol reverse transport . TMAO mo\u2212/\u2212 mice. The CD36, steroid receptor RNA activator 1 (SR-A1), and 2 macrophage scavenger receptors were measured. The levels of CD36 and SR-A1 in the macrophages of TMAO-treated mice were increased compared with controls, and antibiotic intervention reduced foam cell formation by decreasing TMA production [The role of TMAO in atherosclerosis was investigated using a dietary choline supplement in ApoEoduction . No sign\u2212/\u2212 mice [TMAO also promotes atherosclerosis by suppressing reverse cholesterol transport and altering cholesterol transporters\u2019 activity in macrophages . Besides\u2212/\u2212 mice ,66,73,74TMAO accelerates atherosclerosis by several mechanisms such as promoting cholesterol influx, inhibiting cholesterol efflux, blocking the bile acid pathway, and causing hyperactivity platelets. TMAO also upregulated the expression of vascular cell adhesion molecule-1 (VCAM-1) and activated protein kinase C (PKC) and NF\u03baB. TMAO thus stimulates atherosclerosis via endothelial cell dysfunction and increases the adhesion of monocytes . These f\u2212/\u2212 ) mice, but its status was inversely correlated with aortic lesion size [TMAO may be regarded as an independent risk factor for CVD. However, inconsistent results were also observed, especially in broad population observations ,80. Cholion size . Severalion size ,83. HoweAnother gut microbiota-derived metabolite, bile acid, is involved in various metabolic diseases . Bile acMethanobrevibacter smithii, Clostridium, Enterococcus [Bile acids can accelerate atherosclerosis development through bile-salt hydrolase activity and bile acid receptors ,89. Bilerococcus ,91. Bactrococcus .\u2212/\u2212 and ApoE\u2212/\u2212) mice [TGR5, the G protein-coupled receptor, is an important bile acid receptor of the host that mediates the systemic effects of bile acids . TGR5 ca/\u2212) mice .The microbiota-derived secondary bile acids play essential roles in atherosclerosis development by modulating various bile acid receptors such as FXR, PXR, TGR5, and VDR, and S1PR2. Favorable modulation of bile acid metabolism by targeting microbiota may also prevent the atherosclerosis process .Firmicutes/Bacteroidetes [Hypertension is considered the most preventable risk factor for CVD, and successful hypertension prevention and treatment are key to reducing the risk of CVD . Convincroidetes .Firmicutes/Bacteroidetes [Generally, blood pressure is regulated by the amplitude of vasoconstriction and vasodilation of blood vessels . In sponroidetes . Infusioroidetes . The gutStreptococcus spp., Prevotella spp., Bifidobacterium spp., Clostridium pp., A. muciniphila, etc. [Bacteroides spp., Salmonella spp., Dialister spp., Veillonella spp., Roseburiainulinivorans, Coprococcus catus, Blautia obeum. [Lachnospiraceae, Ruminococcaceae, and Acidaminococcaceae families mainly produce butyric acid in the gut [Bacteroides acidifaciens, which was shown to play a beneficial role in hypertension in a mice model [SCFAs such as acetate, propionate, and butyrate play crucial roles in maintaining the gut microbiome\u2019s homeostasis and host immunity ,107,108.la, etc. , whereasa obeum. . Lachnos the gut . The hig the gut . Supplemce model .The role of various G-protein-coupled receptors (GPRs) in hypertension was reviewed . The gutDysbiosis can promote oxidation of LDL to oxLDL ,120. ThuSCFAs, short-chain fatty acids; GPRs, G-protein-coupled receptors; Olfr78, olfactory receptor 78; NO, nitric oxide; OxLDL, oxidized low-density lipoprotein; ETA, endothelin receptor A. For details, please see the text.Platelets have various functions in physiology. Apart from hemostasis, platelets are involved in several cardiovascular processes, such as atherosclerosis, immune system, inflammation, interaction with other cells, and cardiac events ,126,127.The platelet membrane microparticles have multiple functions and contribute to thrombus and foam cell formation; they are involved in atherosclerotic processes, blood vessel activation, and inflammation. Thus, inhibiting platelet activation/aggregation can protect against CVD development that affects millions of people worldwide. Though aspirin is still the major anti-platelet therapy, it does not benefit all, as evidenced by the phenomenon of aspirin resistance and unwanted side effects. Therefore, aspirin is not recommended for use in the primary prevention of CVD.Atherosclerosis is a continuous process promoted by several risk factors, including hypertension, hyperlipidemia, cigarette smoking, diabetes mellitus, dyslipidemia, and platelet hyperactivity. Platelet hyperactivity is a major clinical feature observed in hypertension, diabetes mellitus, obesity, and several other metabolic and vascular diseases ,130. SufHuman blood platelets become hyperactive in diabetes mellitus, hyperlipidemia, high fat diet, sedentary lifestyle, etc. The gut microbial metabolite, TMAO, also induces hyperactivity in blood platelets. Hyperactive platelets contribute to atherosclerosis development by different mechanisms. Besides, hyperactive platelets are involved in penultimate thrombotic events. 2+ [Platelet-derived CD40L release pro-inflammatory cytokines from vascular cells in the atheroma to stabilize platelet-rich thrombin and inhibit the re-endothelization of damaged vessels. When activated, platelets release different growth factors such as platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF), membrane particles, and cytokines that participate in atherosclerosis development by promoting vascular smooth muscle cell proliferation . Platele2+ . Further2+ . Platele2+ release from intracellular stores, contributing to increased risk of CVD and plaque formation [2+ release from internal stores, leading to platelet activation. In several animal models, acute elevation of circulating TMAO by infusion was shown to enhance in vivo thrombosis potential [Besides these above pathological conditions, the gut metabolite TMAO also activates circulating blood platelets by elevating Caormation . TMAO protential . In humaotential  and alteotential .\u00ae), as this significantly inhibited platelet aggregation both in vivo and ex vivo [\u00ae. Fruitflow\u00ae is a functional product approved by the European Food Safety Authority (EFSA) [\u00ae can serve as a safe anti-platelet prophylactic treatment for those at high risk or as an alternative to pharmacological compounds with side effects g [\u00ae may be useful in the primary prevention of CVD. Proteomic studies have shown that the tomato-derived compounds in Fruitflow\u00ae  affect platelet proteins with platelet structure, platelet coagulation, platelet membrane trafficking, platelet secretion, redox system proteins, and HSP70s [Therefore, the maintenance of regular platelet activity is critical to maintaining hemostasis. The most predominant anti-platelet agent, aspirin, has a number of severe side effects, making it unsuitable for the primary prevention of CVD. Moreover, aspirin-treated platelets do not have the potential to be involved in other physiological functions, apart from aggregation, in their lifetime. The use of anti-platelet drugs is not recommended as a primary preventive measure. Therefore, it is imperative to find alternative and safe anti-platelet agents to tame hyperactive platelets to reduce the risk of CVD development. Reducing platelet hyperactivity by TMAO may have a significant impact on atherosclerosis and thrombotic complications. Thus, a different approach to suppressing platelet function is needed. However, as of yet only a limited number of food-derived compounds have been investigated in depth for their anti-platelet effects clinically. High intakes of fruit and vegetables and moderate intake of marine fish can lower platelet hyperactivity to some extent ,139. The ex vivo ,141,142.ffects g . The accEmerging data suggest a strong relationship between microbiota-derived compounds and an increased risk of CVD. Therefore, it is important to investigate further the roles of diets, microbial production of TMAO and SCFAs, and their cellular signaling to determine their effects on cardiovascular physiology. The relationship between platelet hyperactivity and CVD is now established. Given the growing concern over CVD due to platelet hyperactivity as observed in obesity, abnormal lipid metabolism, sedentary lifestyle, insulin resistance, TMAO and many others, a new therapy of probiotics and prebiotics may constitute a suitable primary prevention regime without overly reducing the nutritionally important intake of precursors of TMA, such as choline, betaine, and L-carnitine. Although several drugs are available to treat CVD, it is currently the leading cause of death worldwide.Sufficient convincing data have emerged on the relationship between gut dysbiosis and CVD. However, further work is required for the establishment of gut microbiota-targeted therapy for CVD. Since various experimental and clinical data on the mechanisms of gut microbiota mediated-development of CVD are available, there is a strong possibility of finding new approaches to treat or prevent CVD. SCFAs and some types of bile acids, or reducing the microbial metabolite, TMA, can be modulated by diets, prebiotics, and probiotics and with specific TMA inhibitors. The gut microbial composition may also be favorably modified with probiotics, prebiotics, and natural components. To this end, well-designed large-scale clinical studies are required to validate the preclinical and other small-sized human trials data. The currently available data allows us to target the gut microbiota and its metabolites to understand CVD mechanisms and develop novel preventative or therapeutic regimes."}
+{"text": "Background: Polyneuropathies (PNP) are a broad field of diseases affecting millions of people. While the symptoms presented are mostly similar, underlying causes are abundant. Thus, early identification of treatable causes is often difficult. Besides clinical data and basic laboratory findings, nerve conduction studies are crucial for etiological classification, yet limited. Besides Magnetic Resonance Imaging (MRI), high-resolution nerve ultrasound (HRUS) has become a noninvasive, fast, economic and available tool to help distinguish different types of nerve alterations in neuropathies. Methods: We aim to describe typical ultrasound findings in PNP and patterns of morphological changes in hereditary, immune-mediated, diabetic, metabolic and neurodegenerative PNP. Literature research was performed in PubMed using the terms \u2018nerve ultrasound\u2019, neuromuscular ultrasound, high-resolution nerve ultrasound, peripheral nerves, nerve enlargement, demyelinating, hereditary, polyneuropathies, hypertrophy\u2019. Results: Plenty of studies over the past 20 years investigated the value of nerve ultrasound in different neuropathies. Next to nerve enlargement, patterns of nerve enlargement, echointensity, vascularization and elastography have been evaluated for diagnostic terms. Furthermore, different scores have been developed to distinguish different etiologies of PNP. Conclusions: Where morphological alterations of the nerves reflect underlying pathologies, early nerve ultrasound might enable a timely start of available treatment and also facilitate follow up of therapy success. Polyneuropathies are among the most frequent neurological disorders and cause significant morbidity and use of resources. Finding the cause of neuropathic deficits still remains a challenge in daily clinical routine. Although technical tools have improved and nerve conduction studies, skin and nerve biopsy, next generation sequencing, cerebrospinal fluid (CSF) analysis or antibody testing are established methods, the cause of PNP remains unclear in up to one third of patients. Imaging tools such as MRI of the roots and nerves could contribute to the diagnosis of immune-mediated neuropathies, hereditary transthyretin (TTR) associated systemic amyloidosis and others in the recent past ,2,3. HowSeveral aspects can be visualized and measured by ultrasound ,7. BeforSo far, reference data for CSA in adults and children older than two years for most of the larger peripheral nerves have been published by many groups ,23,24,252) is feasible. We recommend a structured analysis of cervical roots (C5 and C6), vagus, median, ulnar and radial nerve, tibial, fibular and sural nerve and its measurement at predefined measurement points [Another important point is to establish a scanning protocol, which includes the nerve and its measure points. Several analyzing protocols have been published so far ,24,25,27t points . In caseThe most intriguing nerve enlargement can be found in patients with Charcot Marie Tooth (CMT) type 1 (CMT1) neuropathies, particularly type A ,36,37,38In addition, the number of reported patients with a genetically confirmed neuropathy and a superimposed nerve inflammation increases rapidly . In 1982In contrast to demyelinating CMT1 types, in axonal CMT forms, CMT2, almost no nerve enlargement occurs. Merely, some fascicles can be enlarged, but CSA is broadly documented within reference ranges ,34,36. ORemarkably, the underlying genetic defect and not nerve conduction study (NCS) results  seems to determine the nerve morphology in CMT, considering that in neurofilament light polypeptide gene (NEFL) or myelin protein zero (MPZ) associated CMT1 or CMT2 similar ultrasound aspects are observed .Finally, hereditary neuropathy with liability to pressure palsies (HNPP), mostly due to peripheral myelin protein 22 (PMP22) deletion, has a pathognomonic pattern of nerve enlargement at entrapment sites  with normal nerve segment in between. Entrapment ratios  are enlarged , which enables differentiation to other inherited and demyelinating neuropathies ,48,49,50ATTR is a systemic disorder leading to amyloid fibril deposition with cardiac dysfunction, carpal tunnel syndrome and severe autonomic and sensorimotor polyneuropathy . MeanwhiIn contrast to ATTR, little is known about acquired amyloidosis. One case with amyloid light-chain (AL) amyloidosis is described with severe course and significant nerve enlargement suggesting a correlation between amyloid deposits in the nerves and mentioned enlargement; however, further studies are required .The role of imaging tools in CIDP, like MR neurography and HRUS, has been widely analyzed ,68,69,70Three distinct classes of nerve enlargement have been described ,12: ClasOnly few data are available concerning imaging of paranodopathies, but the pattern seems to be similar to that seen in typical CIDP, probably more often affecting cranial nerves ,79.Only few reports concerning patients with Lewis-Sumner Syndrome (LSS) or multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) are available ,84,85,86In patients with monoclonal gammopathy of undetermined significance (MGUS) and polyneuropathy, we have to differentiate several subtypes of neuropathies . This isSo far, less is known about POEMS  patients, who exhibit demyelinating NCS with uniform pattern and, as described so far, enlarged CSA especially in entrapment sites or slightly enlarged nerves as compared to healthy controls ,97. ThisAnother immune-mediated neuropathy affecting several pure motor nerves in one or more limbs with mostly asymmetric onset is the multifocal motor neuropathy  infection have been described ,110,111.The Miller Fisher syndrome (MFS), presenting with ataxia, areflexia and ophthalmoplegia, is a variant of GBS with antiGQ1b IgG antibodies, often presenting as an overlap syndrome with MFS and GBS symptoms , also shAlthough DN are a large and important part of all neuropathies worldwide, literature concerning ultrasound in this entity is not rich. Some authors suggest that DN does not cause nerve enlargement, particularly the classical distal-symmetric axonal type ,121. HowUntil now, ultrasound patterns for axonal neuropathies have mostly been described as for subgroups of large cohorts, not differentiating between toxic, metabolic, idiopathic or inherited axonal neuropathies ,129,130.Another entity of neuropathies, which has recently been more and more diagnosed and though is not entirely understood, is the small fiber neuropathy (SFN). SFN often presents with neuropathic pain and numbness while revealing normal NCS. The use of nerve ultrasound in SFN is currently under investigation.Neoplastic affection of the peripheral nerve system (PNS) in lymphoma is a rare manifestation called neurolymphomatosis  and arisGraft versus host disease (GvHD) after allogenic marrow transplantation mostly affects the skin and the gastrointestinal system. However, neuromuscular involvement can be an issue . If the Growing data are available concerning rare storage diseases, for example metachromatic leucodystrophies, adrenoleucodystrophies, xantochromatosis or glucocerebrosidosis ,146,147.Next to muscle ultrasound in motor neuron diseases such as ALS, nerve ultrasound can contribute important information concerning the nervous system ,148,149.In general, demyelinating neuropathies regularly show nerve enlargement, whereas axonal ones do not ,129,130.Our colleagues from Bochum University Hospital developed the Bochum Ultrasound Score (BUS), which enables differentiation between GBS and CIDP in the early disease course ,153. MorA for peripheral sensorimotor nerves, UPS B for roots C5 and 6 and vagus nerve and UPS C for sensory nerves. Additionally, it includes further evaluation of homogeneity of nerve enlargement [A further established score is the ultrasound pattern sum score (UPSS) ,87,138, Next to the UPSS or BUS, Padua et al. described several echointensity classes in immune-mediated neuropathies , which pA summary of BUS and UPSS is shown in Although many aspects concerning the value of nerve ultrasound are still missing in the diagnosis of PNP, its use for several neuropathies has been widely proven. It might help to reduce the high number of unknown etiologies and thus support practitioners to target their diagnostic steps. Still, before performing ultrasound, profound knowledge of ultrasound technique, anatomy of the musculoskeletal and nervous system as well as its distinct pathologies is essential ,7. Thus,Examiners using ultrasound must bear in mind the limitations of nerve ultrasound. Most of the studies are single center based and thus sensitivities and specificities must be interpreted with care. Further, many distinct scoring tools have been used, which influenced the sensitivity and specificity significantly. To get profound values, multicentric studies including several neuropathy types are mandatory in the future. Normal data might depend on ethnicity, weight, height, and sex ,18,19,20Therefore, ultrasound should be included as a basic tool in every neurophysiology department as it adds important information."}
+{"text": "Cellular senescence is a complex cell fate, often induced by stress or damage, that can be beneficial or deleterious, depending on the physiological context and age of the organism. A prominent feature of senescent cells is a multi-faceted senescence-associated secretory phenotype (SASP), which includes growth factors, cytokine and chemokines, growth factors, proteases, bioactive lipids and metabolites. Senescent cells increase with age in most, if not all, mammalian tissues. Through the use of transgenic mouse models, senescent cells are now known to causally drive numerous age-related pathologies, largely through the SASP. Eliminating senescent cells, genetically or through the use of senolytic/senomorphic agents, can improve the health span, at least in mice, and hold promise for extension to humans in the near future."}
+{"text": "Atholus Thomson, 1859, Hemisaprinus Kryzhanovskij, 1976, Hister Linnaeus, 1758, Hypocacculus Bickhardt, 1914, Margarinotus Marseul, 1853, Saprinus Erichson, 1834, Tribalus Erichson, 1834, and Xenonychus Wollaston, 1864 were recorded. Specimens were sampled mainly with pitfall traps baited with ephemeral materials like pig dung, decayed fish, and pig carcasses. Several species were collected by sifting soil detritus, sand cascading, and other specialized techniques. Six newly recorded species for the Lebanese fauna are the necrophilous Histersepulchralis Erichson, 1834, Hemisaprinussubvirescens , Saprinus (Saprinus) externus , Saprinus (Saprinus) figuratus Marseul, 1855, and Saprinus (Saprinus) niger  all associated with rotting fish and dung, and the psammophilous Xenonychustridens . With the exception of Histersepulchralis, all these taxa belong to the Saprininae subfamily. A most likely undescribed species of Tribalus   has also been collected in detritus at wet places near rivers in Lebanon. Because of the complexity of the genus Tribalus, with possible numerous new species present in the circum-Mediterranean area, the Lebanese species is not described herein, pending a revision of the genus. This study advocates further research aimed at improving taxonomic and ecological knowledge of this coleopteran family in Lebanon. The number of Histeridae species currently known from Lebanon stands at 41; a key to all species including images is included.The occurrence of histerids in Lebanon has received little specific attention. Hence, an aim to enrich the knowledge of this coleopteran family through a survey across different Lebanese regions in this work. Seventeen species belonging to the genera  Coleoptera is the largest hexapodan order with ca. 400,000 described species worldwide, which comprise 40% of all described insect species  contain 4260 species and 400 genera, grouped in nine subfamilies  metallescens  have only recently been recorded for the fauna of the country , one species belonging to otherwise oriental genus Notodoma Lacordaire, 1854 (Exosternini), two species of Platylister Lewis, 1892, and one species of Platysoma Leach, 1817 (Platysomatini) , Margarinotus (Ptomister) brunneus , and Margarinotus (Grammostethus) ruficornis  were recently newly recorded for the Lebanese fauna  is recorded from the country. Two species of Onthophilus Leach, 1817 are known from Lebanon within Onthophilinae.Within the omatini) . Atholusse fauna . Within Tribalinae has hitherto been recorded from Lebanon, but it was recorded from a geographically close country, Cyprus . Thus, the occurrence of Tribalus in Lebanon is to be expected.No representative of the subfamily Histeridae in different Lebanese regions relating to their colonization of ephemeral resources (carrion and dung). We likewise comment on Histeridae that were collected during field trips that are not necessarily associated to the ephemeral resources. A checklist of species, as well as key to all Lebanese Histeridae  are provided.This study is aimed to investigate the diversity of the Atholus, Margarinotus, and Hypocacculus were recorded from sampling pitfall traps baited by pig carcasses.The majority of specimens were collected in pitfall traps (28 cm height and 16 cm width) baited with rotting fish and pig dung. Specimens were collected after one week of placing the pitfall trap in each locality. The localities and their coordinates are mentioned in Table Saprinus species can be usually recognized through the examination of the anterior tarsal setae, which are expanded and lamellate, whereas they are unexpanded and pointed in female. Often the males possess a longitudinal depression on the metaventrite and occasionally also a single or two tiny tubercles on the apical metaventral margin. Male genitalia were first macerated in 10% KOH solution for ca. 3 hours, cleared in 80% ethanol, macerated in lactic acid with fuchsine, incubated at 60 \u00b0C for another 30 min, subsequently cleared in 80 % ethanol, and then observed in \u03b1-terpineol in a small dish. Digital photographs of male genitalia were taken by a Nikon 4500 Coolpix camera and edited in Adobe Photoshop CS5. Genitalia drawings based on the photographs or direct observations were produced with the aid of Hakuba klv7000 light box. Habitus photographs were taken by F. Slamka . Specimens were measured with an ocular micrometer. Higher taxa in our paper are arranged according to Histeridae in the Middle East is extrapolated from General observations and dissections were carried out using stereomicroscope Nikon SMZ1500. Without genital extraction, males of The maps of species distribution were made using Google maps and Microsoft Visual Studio Code (Version 1.37).Histeridae species of Lebanon are provided.List of species recorded from Lebanon; their distribution in the Middle East and biology are mentioned. The list records are based on the Palaearctic catalogue  and on oDistribution. The subfamily contains five tribes and is distributed worldwide Figure 18Distribution in the Middle East. Cyprus, Lebanon, Syria, Turkey .Abraeomorphus Reitter, 1886Distribution. Oriental, Australasian, and Palearctic regions Figure 17Distribution in the Middle East. Lebanon  sp.Figures 120Distribution.Tribalus contains 65 described species divided into two subgenera and is considered a species-rich genus . We collected 20 specimens of an unidentified species of Tribalus from under stones and tree bark, respectively, in wet areas near rivers of Baissour (8 specimens) and Rechmaya (12 specimens).Distribution. Worldwide  simeani  and Platysoma (Cylister) cornix Marseul, 1861 have yet been recorded from Lebanon. On the other hand, likewise subcortical species Platysoma (Platysoma) compressum  and P. (P.) inexpectatum Lackner, 2004 have been recorded from neighboring Syria; their occurrence in Lebanon therefore cannot be ruled out. As mentioned in the introduction, a single member of the otherwise oriental genus Notodoma Lacordaire, 1854, N.lewisi Reitter, 1910 has been recorded from Lebanon; this species is otherwise also known from Turkey Figures 121Distribution in the Middle East. Iran, Israel, Saudi Arabia, Syria, Turkey Figure 10Distribution in the Middle East. Cyprus, Iran, Iraq, Israel, Jordan, Lebanon, Syria, Turkey  and Eudiplisterplanulus  were found under plant remains, under stones, under dry excrements, especially in arid places and semi-deserts  present in dung  brunneus Figures 126Distribution in the Middle East. Iran, Israel, Turkey (M. (P.) brunneus is reported from the following Lebanese localities: Fanar, Kfeir, Mimes, Naas, Nabaa Al Safa  brunneus was collected from carrion during spring in Fanar (50 specimens) and Naas (181 specimens). It was also collected during the same season from rotting fish-baited pitfall traps in Kfeir (1 specimen), Mimes (1 specimen), and Nabaa Al Safa (6 specimens). A very common and widespread species in Lebanon. carrion , and has carrion  as well  carrion . In LebaMargarinotus (Grammostethus) ruficornis Figures 121Distribution in the Middle East. Israel, Jordan, Syria and Turkey ; it has likewise been known to occur on excrement (M. (G.) ruficornis was collected from carrion during spring in Fanar.xcrement . In our Platylister Lewis, 1892Distribution. Genus Platylister contains three subgenera and is distributed predominantly across Afrotropical, Oriental, and Australasian regions, with two species recorded also from circum-mediterranean area  subcortical insects ( insects .Platylister (Popinus) simeani Figure 7Distribution in the Middle East. Lebanon, Turkey, United Arab Emirates  (abaceae) .Platysoma Leach, 1817Distribution.Platysoma contains three subgenera and is spread across the whole world, albeit only a single species is known from South America  cornix Marseul, 1861Figure 8Distribution in the Middle East. Cyprus, Israel, Lebanon, Syria, Turkey  and filter feed on the liquid coating of fresh dung; some are known to prey on Diptera that develop on rotting fungi. Their mouthparts bear modified setae that seem to strain particles from liquid .Onthophilusstriatusinconditus Reichardt, 1941Figure 2Distribution in the Middle East. Cyprus, Israel, Jordan, Lebanon, Syria, Turkey Figure 20Distribution in the Middle East. Iran, Iraq, Israel, Lebanon, Syria, Turkey Figure 21Distribution in the Middle East. Lebanon, Syria, Turkey .Chalcionellusaemulus Figure 19Distribution in the Middle East. Iran, Israel, Jordan, Lebanon, Turkey .Gnathoncus Jacquelin du Val, 1857Distribution. Predominantly Holarctic in distribution; a single species is known from tropical Africa  marginally enters also the Oriental region Figures 126Distribution in the Middle East. Cyprus, Iran, Iraq, Israel, Jordan, Syria, Turkey  metallescens Figures 126Distribution in the Middle East. Cyprus, Israel, Iran, Iraq, Oman, Saudi Arabia, Syria  praecox Figure 24Distribution in the Middle East. Cyprus, Iran, Israel, Lebanon, Oman, Saudi Arabia, Syria, Turkey, United Arab Emirates, Yemen  praecox is a psammo-halobiotic species, which frequents coastal dunes near the roots of halophilous plants and can be attracted to animal carcasses  baudii Figure 26Distribution in the Middle East. Cyprus, Israel, Lebanon, Syria  aegialius Reitter, 1884Distribution in the Middle East. Iran, Lebanon, Syria, Turkey  calatravensis Fuente, 1899Figures 126Distribution in the Middle East. Iran, Israel, Oman, Saudi Arabia, Turkey  forests in Spain (in Spain . We repoSaprinus (Saprinus) chalcites Figures 126Distribution in the Middle East. Cyprus, Iran, Iraq, Israel, Jordan, Kuwait, Oman, Saudi Arabia, Syria, Turkey, Yemen  externus Figures 126Distribution in the Middle East. Iran, Jordan, Syria, Turkey  externus is an infrequent taxon in Lebanon. According to al areas . SaprinuSaprinus (Saprinus) figuratus Marseul, 1855Figures 126Distribution in the Middle East. Israel, Jordan, Oman, Saudi Arabia, Syria  figuratus occurs on carrion, with restriction to the meso-mediterranean holm oak forests on basic soils  godet Figures 126Distribution in the Middle East. Turkey, Saudi Arabia (i Arabia . Alreadyi Arabia . We herei Arabia .Biology. Occurs on carcasses (arcasses . In LebaSaprinus (Saprinus) niger Figures 126Distribution in the Middle East. Iran, Iraq, Israel, Jordan, Syria, Turkey  robustus Kr\u00e1sa, 1944Figures 126Distribution in the Middle East. Cyprus, Iran, Israel, Jordan, Lebanon, Syria, Turkey  robustus inhabits dung and carrion alike  strigil Marseul, 1855Figures 126Distribution in the Middle East. Cyprus, Iran, Iraq, Israel, Oman, Saudi Arabia, Syria, Yemen  strigil was encountered on carrion ( carrion . We collSaprinus (Saprinus) subnitescens Bickhardt, 1909Figures 126Distribution in the Middle East. Cyprus, Iran, Iraq, Israel, Lebanon, Syria, Turkey  subnitescens is a predator without an obvious habitat preference; it has been found on carrion  tenuistriussparsutus Solsky, 1876Figures 126Distribution in the Middle East. Iran, Iraq, Israel, Syria, Turkey (S. (S.) tenuistriussparsutus is a frequent taxon in the Eastern Mediterranean area. Already known from Lebanon  is distributed from the Cape Verde Archipelago and Canary Islands in the west through the Sahara Belt along the Mediterranean coast to the Arabian Peninsula in the east. Xenonychusaralocaspius Kryzhanovskij, 1976 is found around the Caspian and Aral Seas, and further inland in the middle Asian countries of Kazakhstan, Uzbekistan and Turkmenistan, while Xenonychussomaliensis  is, so far, known exclusively from Somalia Figures 125Distribution in the Middle East. Cyprus, Israel, Oman, Saudi Arabia, Syria, Turkey, United Arab Emirates . According to Spathochuscoyei, which has been recorded from the neighboring countries and we strongly suspect it might also occur in Lebanon. If a histerid specimen from Lebanon cannot be identified using our key, we advocate using the monograph of the USSR fauna by We should like to stress that our key contains only species recorded from the territory of Lebanon, with a single exception of This checklist is based on Histeridae in Lebanon as 41 species are currently known from Lebanon. In addition to the knowledge of Saprinus of forensic relevance  subnitescens was the most abundant species on pig carrion (Saprinus (S.) strigil was common on decomposing pig carcasses (Saprinus (S.) chalcites, Saprinus (S.) godet, Saprinus (S.) robustus, Saprinus (S.) tenuistriussparsutus were also attracted to dung, decomposing fish and to carrion (g plants . Many spg plants . Saprinu carrion . In our arcasses . It was  carrion .Saprinus (S.) caerulescens was only attracted to mammalian carrion and it was absent from other baits (rotting fish and dung). This is in accordance with T. Lackner\u2019s personal observation that this species is common on large carcasses. However, Margarinotus spp. are varied in habits (Margarinotus likewise shows preference to cold and humid forest floor (n habits . In our st floor . The latst floor .Atholusduodecimstriatusduodecimstriatus was collected from carrion only during summer. Unlike the findings of Hypocacculus (H.) metallescens was rare and collected during summer from carrion and absent from other decomposing matter, dung, and sand dunes, which it is normally associated with  figuratus was found only on fish carcasses and not on pig ones. In a similar Mediterranean climate, in Spain, this species was found to be rare and restricted to mesomediterranean holm oak forests (Saprinus (S.) niger was also collected only from fish carcasses and not from other carrion. In Spain, it was found also on squid carcasses, which are effective for collecting carrion insects and species inventories resemble those from pig studies (Saprinus (S.) externus is uncommon in Turkey and that carrion is not its primary habitat. Also, According to arcasses . In our  forests . Unlike  studies . Al-TunsTribalus s. str. of the genus Tribalus is a species-rich group mostly occurring in Africa with smaller number of species found in the Palaearctic and Oriental regions  capensis  shows preference to dung that has lost much of its moisture and that Tribalus (T.) cavernicola Lewis, 1908 occurs in cave entrances. Those two species of Tribalus are not found in the Palaearctic region  praecox is a psammo-halobiotic species (Xenonychustridens on a sandy beach in Tyre (Lebanon). It is important to study the entomofauna associated with carcasses on the seashore or those buried in sand, which could help in estimating the minimum postmortem interval (PMImin). For instance, in 2018 a murdered woman was found covered with sand in Sidon Rmeileh beach-Lebanon  ruficornis, Platysoma (Cylister) cornix, and Platylister (Popinus) simeani are often associated with decaying plant matter and/or bark of trees like pine , pitfall traps, etc. should be also used in the future. Seasonal sampling and replicates are needed to show the peak activity, seasonality, and habitat preferences of members of this family.This is considered the first faunistic study of the"}
+{"text": "Dengue infection may manifest as dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS). The World Health Organization (WHO) came up with the term \"expanded dengue syndrome\" (EDS) to designate cases which do not fall into either DHF or DSS, with unusual manifestations in other organs such as the cardiovascular system, the nervous system, the kidneys, the gut, and the hematological system, which\u00a0have been increasingly reported and called EDS. Furthermore, EDS is becoming widespread globally with unusual features and increased severity. There are increasing reports of under-recognized and infrequent manifestations with severe organ involvement. This review gives knowledge of expanded dengue syndrome which helps to catch the diagnosis of dengue early, particularly during the ongoing epidemics and escaping from further series of unnecessary investigations. Dengue is caused by a vector-borne arbovirus of the flavivirus family. It is transmitted by the female mosquitoes Aedes aegypti, Aedes\u00a0albopictus, Aedes scutellaris, and Aedes polynesiensis. Dengue virus is an arbovirus disease-causing 390 million dengue infections per year, of which 96 million manifests clinically in nearly 129 countries around the world [Dengue is an acute and self-limited disease characterized by fever, headache, retro-orbital pain, myalgia, nausea, vomiting, skin rash, leukopenia, and thrombocytopenia associated with or without plasma leakage . FurtherWe performed a PubMed\u00ae\u00a0and a Google Scholar search for all papers published in the English language using the keyword of expanded dengue syndrome and atypical manifestations of DF. All abstracts were read independently by the authors. Observational studies, case series, and\u00a0fifteen case reports of patients with a confirmed diagnosis of dengue were screened for inclusion. In all included reports, laboratory diagnosis of dengue was considered essential by any of the established diagnostic tests such as positive dengue immunoglobulin M (IgM) antibody by the enzyme-linked immunosorbent assay (ELISA), or positive dengue NS1 antigen, or positive dengue polymerase chain reaction (PCR). We excluded reports where co-infection with other diseases was present. This review gives knowledge of EDS, which helps to clinch the diagnosis of dengue early, particularly during ongoing epidemics, escaping from further series of investigations.Unusual manifestationsDF is characterized by abrupt onset of fever, often accompanied by a severe headache and pain behind the eyes, muscle pain, joint pains, nausea, vomiting, abdominal pain, and loss of appetite. Two distinct clinical entities, DHF and DSS, have been associated with poorer outcomes. Though, regardless of the dogged grouping of dengue into DF, DHF, and DSS, the overlap between the different manifestations could be observed. End organ damage, such as liver, kidney, heart, brain, and bone marrow involvement, has been mostly reported in severe dengue with plasma leakage, or bleeding, which may confuse the clinicians whether this end-organ damage is part of dengue shock or EDS.EDS is a term announced by the WHO in 2011 to cover the uncommon expressions of dengue involving severe damage to the liver, kidneys, bone marrow, heart, or brain . They maPathogenesis of severe dengue feverThere have been several recent advances in understanding the pathogenesis of dengue; however, the precise mechanisms remain to be fully delineated.\u00a0All four dengue virus serotypes (SE) have related to the spectrum of disease. However, certain genotypes of dengue virus (SE 2 and 3) have been shown to be more virulent and cause massive dengue epidemics . Dengue The typical of dengue cases are mild to moderate in severity; however, severe cases are mostly related to two recognized pathophysiologic trademarks, which are called plasma leakage and bleeding; it causes shock and death. Even though the underlying mechanisms for a severe form of dengue have not been fully explained, but the sturdy association of severe dengue with different serotypes and an immune-mediated reaction has been assumed. In severe dengue, both T-cell mediated and antibody-dependent mechanisms have been implicated . It has Neurological manifestationsThe spectrum of neurological complications has been reported in DF, which are ranging from encephalopathy, encephalitis, acute disseminated encephalomyelitis (ADEM), neuromyelitis-optica (NMO), optic neuritis, myelitis, encephalopathy, Guillain-Barr\u00e9 syndrome (GBS) to dengue associated stroke. The pathogenesis of neurological indices is associated with direct invasion of the central nervous system by the dengue virus, autoimmune reactions, and metabolic alterations . Even thGastrointestinal manifestationsElevation of liver transaminases was greater in patients with DHF compared to DF, and aspartate transaminase (AST) levels were higher than alanine aminotransferase (ALT) levels. It is assumed that the latter may be a result of myositis . AlthougRenal manifestationsDengue has been related to various forms of renal involvement. These include electrolyte imbalance, acute kidney injury (AKI), proteinuria, glomerulonephritis, alanine aminotransferase (IgA) nephropathy, hemolytic uremic syndrome, and acute tubular necrosis . The incCardiac manifestationsA diversity of cardiac manifestations has been reported in dengue infection. Cardiac involvement of varying degrees has been described ranging from arrhythmias to myocardial depression, pericarditis, and myocarditis . The preRespiratory manifestationsThe spectrum of pulmonary involvement can occur in DF, ranging from pleural effusion, pneumonitis, non-cardiogenic pulmonary edema to hemoptysis . In DF, Hematological manifestationsThe foremost blood abnormalities are hematocrit, lymphocytosis, basophilia, monocytosis, thrombocytopenia, and atypical lymphocytosis. Disseminated intravascular coagulopathy (DIC), hemophagocytic lymphohistiocytosis (HLH), cytopenias, lymphadenopathy, hepatomegaly, and splenomegaly have been reported in dengue fever -34. FurtDengue infection may manifest as an asymptomatic DF, DHF, and DSS. The WHO presented the term \"expanded dengue syndrome\" to designate cases that do not fall into either dengue shock syndrome or dengue hemorrhagic fever. The most common are cardiac and neurological manifestations\u00a0and dengue encephalitis is a significant cause of the fatal outcome. The sensible knowledge about EDS helps to establish the diagnosis and prompt the appropriate treatment for dengue with unusual manifestations. Clinicians must be mindful of these unusual features so that they can suspect dengue early, especially during ongoing epidemics."}
+{"text": "Chitin and its derivative chitosan are popular constituents in wound-treatment technologies due to their nanoscale fibrous morphology and attractive biomedical properties that accelerate healing and reduce scarring. These abundant natural polymers found in arthropod exoskeletons and fungal cell walls affect almost every phase of the healing process, acting as hemostatic and antibacterial agents that also support cell proliferation and attachment. However, key differences exist in the structure, properties, processing, and associated polymers of fungal and arthropod chitin, affecting their respective application to wound treatment. High purity crustacean-derived chitin and chitosan have been widely investigated for wound-treatment applications, with research incorporating chemically modified chitosan derivatives and advanced nanocomposite dressings utilizing biocompatible additives, such as natural polysaccharides, mineral clays, and metal nanoparticles used to achieve excellent mechanical and biomedical properties. Conversely, fungi-derived chitin is covalently decorated with \u03b2-glucan and has received less research interest despite its mass production potential, simple extraction process, variations in chitin and associated polymer content, and the established healing properties of fungal exopolysaccharides. This review investigates the proven biomedical properties of both fungal- and crustacean-derived chitin and chitosan, their healing mechanisms, and their potential to advance modern wound-treatment methods through further research and practical application. N-acetylglucosamine, and its derivative chitosan are among the most popular nanofibers used in wound-dressing research [Accidents or diseases resulting in skin damage are a commonplace occurrence in everyday life, making wound dressings a critical element of modern healthcare . Wound dresearch . Naturalresearch . Both chresearch ,3. HowevChitin is one of the most abundant organic polymers on Earth, constituting the structural component of arthropod exoskeletons, mollusk radula, cephalopod endoskeletons, fungal cell walls, and fish and lissamphibian scales . The larBoth crustacean and fungal chitin have a similar molecular structure to cellulose, which is the structural component of the primary cell wall of all green plants, algae, and oomycetes. The main difference between cellulose and chitin is the replacement of the C2 hydroxyl group of cellulose with an acetamide group, which can be deacetylated to obtain chitosan . Two majHowever, key differences exist between crustacean and fungal chitin. Crustacean chitin normally has minimal residual protein and binds with sclerotized proteins and minerals, whereas fungal chitin is associated with other polysaccharides, such as glucan, which can occur in quantities exceeding the chitin content itself . CrossliThe extraction processes for fungal and crustacean chitin are similar , with boFungal chitin sources are generally easily homogenized using a kitchen blender , while tChitosan can be generated from both fungal and crustacean chitin in a simple deacetylation process, whereby the acetyl group of chitin\u2019s acetamide group is cleaved off under strong alkaline conditions , typicalWound healing is a complex biological process comprising four stages: hemostasis, inflammation, proliferation, and remodeling  Figure . These sThe hemostasis phase starts immediately upon injury occurrence and is intended to stop hemorrhage by forming a fibrin clot  Figure , a step Once the hemorrhage has been stopped, the degranulating fibrin clot and surrounding tissue cells trigger the next stages of healing by releasing cytokines and growth factors, which attract cells to the wound site . ChitosaMacrophages, which consume PMNs , become Fibroblasts, which lay a new skin fundament in the wound, are also a key cell type for wound healing. They produce the extracellular cell matrix , the strThe effects of molecular weight and degree of deacetylation on the wound-healing potential of chitin and chitosan have also been studied, albeit to a lesser extent. An in vivo study on incisions in rats investigated the effect of chitin , chitosan , and their oligomers and monomers on wound break strength and collagenase activity . The resThe molecular weights of the chitin and chitosan used in these studies falls in the low-molecular-weight range, as both chitin and chitosan can have molecular weights >1000 kDa . HoweverIt is however clear that chitosan with a higher degree of deacetylation exhibits higher biological activity than that with a lower degree of deacetylation ,76. The Phycomycetes mucor, Penicillium notatum, and Aspergillus niger on rat wounds to confirm the healing properties of glucosamine (polymer units of chitosan), which was thought to be responsible for the healing potential of the cartilage material historically used in wound treatment [P. mucor associated with the highest skin tensile strengths  and N-acetylglucosamine (~40%), and creating a weavable skin substitute called Sacchachitin , schizophyllan from S. commune (split gill), zymosan from S. cereviase (baker\u2019s yeast), pleuran from P. ostreatus (oyster), and ganoderan from G. lucidum (reishii), have also been extensively studied due to the human immune system\u2019s ability to recognize them, promoting immune stimulation, antibacterial, antitumor, anticancer, and antioxidant properties [More recently, with the rise of research interest into the wound-treatment potential of purer crustacean chitin derivatives, academic interest in the medical applications of fungal material has shifted to the investigation of fungal exopolysaccharides (EPS). EPS are not components of the fungal intercellular matrix or cell wall, where chitin is typically found, but rather occur on the cell surface or in the extracellular matrix . Compareoperties ,93,94,95operties  and receoperties ,100,101,operties  and noveMost research concerning the application of crustacean-derived chitin and chitosan in wound dressings focuses on either chemical modification (derivatization) or material engineering practices, such as hybridization or incorporation of chitin or chitosan into nanocomposites, to address the physical, biomedical, or mechanical shortcomings of each respective polymer. Derivatization often deals with improving the solubility of chitin and chitosan , which tO-carboxymethyl chitosan, N-carboxymethyl chitosan, N,O-carboxymethyl chitosan, and N,N-dicarboxymethyl chitosan [Carboxymethylation of chitin and chitosan is commonly regarded as one of the most useful derivatizations. Through the addition of the carboxymethyl group to chitin or chitosan, an anionic functional group (carboxyl) is introduced. This addition makes chitin or chitosan more hydrophilic and improves solubility, both in water and some organic solvents . Carboxychitosan  , which has improved solubility in water over a wide pH range  and exhibits improved antibacterial properties, against both Gram-negative and Gram-positive bacteria [Notably, carboxymethylated chitin or chitosan can be further functionalized through the introduction of additional substituents to the backbone of the chitin or chitosan structure or the carboxyl group of the carboxymethyl. Some examples of further functionalization include the addition of acrylic groups, like 2-hydroxy-3-methacryloyloxypropylate, to the backbone, resulting in a tissue adhesive utilizable in wound-closure applications . Ethylenbacteria . Furtherbacteria .3)3+, with the increased charge generating a higher polar character in chitin or chitosan and enhancing solubility in polar solvents, like water and some organic solvents. The leading hypothesis regarding the improved antibacterial properties of these derivatives is that increases in cationic groups result in interaction with the negative surface of bacteria, which inhibits bacterial growth [N-quaternization, as the amine group simply needs to be methylated, resulting in N,N,N-trimethylchitosan (TMC), which exhibits improved solubility and antibacterial properties. However, the unintended methylation of the OH-groups of chitosan can also accrue under the classical synthesis route, which may reduce the solubility of the product. Such potential methylation has led to the creation of O-methylation free TMC synthesis procedures [Quaternization is another popular chitin- and chitosan-derivatization process, which converts a tertiary amine to a quaternary ammonium compound, enhancing solubility in water and organic solvents, as well as increasing antibacterial activity ,116,117.l growth ,119. Varl growth ,121. Howl growth . ConversThe mechanical properties of chitosan-based wound dressings are also sometimes the focus of derivatizations utilizing crosslinking. Despite the unsuitability of polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP) hydrogels themselves as wound-dressing materials due to their insufficient elasticity and limited hydrophilicity , they arMany other derivatizations of chitin and chitosan are also possible, including sulfonation, which leads to properties resembling heparin, a blood thinner , and phoRecent advances in chitin- and chitosan-based wound dressings include polymer, mineral, and metal additives, rather than utilizing pure chitin or chitosan. These additives are typically included to improve the mechanical properties, such as tensile strength and modulus, and biomedical properties, such as antibacterial and antifungal activity of the dressings . HoweverBiocompatible additives include natural polysaccharides, such as cellulose, and mineral clays, such as the aluminum phyllosilicate clays bentonite and halloysite. These additives are primarily used as reinforcements to improve the mechanical properties of wound dressings , which iMinerals, such the aluminum phyllosilicate clays bentonite and halloysite, can alternatively provide increases in tensile strength ,145, whi2) nanoparticles were incorporated into chitosan-based wound dressings, to enhance antibacterial activity [2, behave similarly, interacting with water or hydroxide ions to form hydroxyl radicals, which can be reduced to superoxide. These radicals then degrade active components governing normal bacterial morphological and physiological function, providing an antibacterial effect [However, while many additives are included in wound dressings as reinforcement, others serve purely to enhance the antibacterial properties of the dressing. Metal nanoparticles are popular additives to chitosan-based wound dressings due to their ability to alter the metabolic activity of bacteria they encounter, crossing the bacterial membrane and affecting the shape and function of the cell membrane ,152 Fig. The preactivity ,158,159.l effect . Similarl effect ,161.\u00ae, Beschitin\u00ae W, Bexident\u00ae Post, Celox\u00ae, Chitohem\u00ae, HemCon\u00ae, Medisorb\u00ae R, Surgi shield\u00ae, and SEQUA\u00ae San Chitosan, in addition to custom-prepared treatments, have prompted several human clinical trials of chitin and chitosan for wound-healing applications. These studies predominantly focus on chitosan and chitosan derivatives for use as wound dressings, gels, powders, films, membranes, and even mouthwash for oral, nasal, ear, and skin applications, in addition to treatment of ulcers and serious hemorrhages , postoperative and tooth extraction wounds. Chitosan mouthwash (0.5%) reduced aphthous stomatitis pain and ulcer size, exhibiting comparable performance to Triamcinolone, a corticosteroid product . Similar the ear .Chitin and its chitosan derivative have experienced significant research interest for wound-dressing applications since the 1970s due to their ability to accelerate healing and reduce scarring. While chitin historically received academic attention due to its biomedical properties, its deacetylated derivative chitosan has been the focus of more recent scientific research due to its superior healing properties. These beneficial properties of chitin and chitosan include nontoxicity, biocompatibility, biodegradability, and antimicrobial activity and are achieved through numerous mechanisms, such as hemostatic activity and support in cellular proliferation and attachment. Crustacean-derived chitosan has been widely investigated and used in wound-healing research due to its high yields and purity, with significant advances in wound dressings incorporating chemically modified chitosan derivatives to improve solubility and antimicrobial activity. Chitosan blends incorporating biocompatible additives, such as natural polysaccharides, synthetic polymers, mineral clays, and metal nanoparticles, have also been utilized to generate advanced wound dressings with excellent mechanical and biomedical properties. Fungi, on the other hand, have received significantly less scientific interest due to their lower chitin content. Moreover, the chitin present in fungi is covalently linked to \u03b2-glucan. However, the mass production potential and simple extraction processes associated with fungal chitin, coupled with variations in the chitin content of fungal species, recent advances in fungal materials technologies, and the discovery of healing properties in fungal exopolysaccharides suggest that further investigation of the healing potential of fungal polysaccharide constituents is warranted. With proven biomedical properties, both fungi- and crustacean-derived chitin and chitosan constitute powerful natural medicinal agents, with the potential to advance modern medicine and wound treatment through further research and practical application."}
+{"text": "Systemic lupus erythematosus (SLE) is a complex autoimmune disorder involving a dysregulated immune response which ultimately leads to multiple organ failure. Several immunological and cellular checkpoints are available as drug targets. However, the available chemosynthetic drugs such as non-steroidal anti-inflammatory drugs and corticosteroids provide limited therapy with extreme toxicities. Moreover, the disease heterogeneity in SLE is very difficult to manage by a single drug component. Hence, it is imperative to utilize the holistic capabilities of natural plant products as immunomodulators and intracellular signaling regulators, thereby providing an auxiliary option of treatment. Additionally, the herbal drugs also serve as symptomatic relief providers, thereby serving as a prophylactic remedy in case of cerebrovascular, hepatic, nephropathological, hematological, cardiopulmonary, mucocutaneous and musculoskeletal manifestations of SLE. The present review attempts to showcase the current state of knowledge regarding the utility of plant-derived phyto-metabolites with their probable mechanistic roles in treating SLE, by means of targeting the signaling cascade, proinflammatory cytokine production and B\u2013T cell co-stimulation. It is hoped that further preclinical and clinical studies will be embarked upon in order to understand the underlying therapeutic and mechanistic aspects of these medicinal herbs. Systemic lupus erythromatosus (SLE) is a chronic, incapacitating autoimmune disorder with an unusual trend of latency and relapses, mainly afflicting women of Asian, African or American ethnicities . The unpTREX1, KLK1 and KLK3 [The main etiological factors responsible for causing SLE primarily include genetic factors  ,5,6. Theand KLK3 ,8,9.Certain epigenetic changes such as post-translation modification of histones and DNA methylation often induce susceptibility to SLE. External factors such as ultraviolet rays, demethylating drugs  and viral infection (Epstein\u2013Barr virus) often trigger the possibility of occurrence of SLE . MoreoveAll these etiological factors lead to certain immune dysfunctionalities , thereby causing the immune system to attack its own cells and destroy multiple organ systems including the cardiovascular, mucocutaneous, cerebrovascular and pulmonary systems, etc., ultimately leading to SLE . CharactMost of the clinical manifestations of the disease are associated with certain pathophysiological cascades, particularly involving the hyperactivation of the immune response and abnormality in the immune regulation system. Proinflammatory cytokines, namely IL6, IL10, IL12, IL17, IL21 and IL23, are produced in excess as mediated by rho associated protein kinase (ROCK); transcription factors, namely STAT3 and CREM\u03b1; nuclear factor NF\u03baB and NFAT, thereby leading to the co-stimulation of B and T cells, ultimately causing the excessive production of autoantibodies. Furthermore, transcription and nuclear factors, such as CREB, NF\u03baB and NFAT also lead to the production of BCL6 which downregulates the production of immunoregulatory cytokines, i.e., IL2 ,16,17,18This disease follows an erratic course of latency and recurrence, thereby making its prognosis and diagnosis difficult . CurrentThe primary remedial regimes for SLE include corticosteroidal drugs, non-steroidal anti-inflammatory drugs (NSAIDs) and antimalarial drugs. These remedies are not absolute but are the only available option for curbing this disease and its related symptoms. Corticosteroids are frequently used to suppress the acute, inflammatory condition of SLE. They are prescribed in either high or low doses for treating severe to long-term manifestations. Unfortunately, a significant proportion of patients still depend on corticosteroids for months to a lifetime. Such dependency on steroids has become a grave clinical problem, wherein any attempt to reduce or discontinue the dose of corticosteroids further aggravates the complications . MoreoveBesides, nonsteroidal anti-inflammatory drugs (NSAIDs) are universally prescribed to relieve arthralgia, inflammation, serositis and fever in SLE patients . NSAIDs Furthermore, most of the patients with SLE are advised to administer antimalarial drugs (hydroxychloroquine and chloroquine) as auxiliary treatment regimens ,52. The BAFF), which can be downregulated by employing anti-BAFF antibodies [It is noteworthy that the monoclonal antibody biologic, rituximab, has been investigated for its efficacy against SLE as it induces B cell depletion, thereby controlling the overproduction of autoantibodies . Moreovetibodies . A number of plant-derived phytoconstituents are known to exert immunosuppressive effects and hence can be used for the management of autoimmune disorders such as SLE. Phytocompounds belonging to diverse categories as alkaloids (berbamine), lectin (tomato lectin), flavonoids (quercetin), phenolic glycosides (curcumin), terpenoids (azadirachtin) and saponins (ginsenoside) have been found to reduce inflammatory cytokines and intracellular signaling, thereby exerting anti-inflammatory and immunoregulatory effects ,35. MoreAcacia farnesiana, Allium sativum, Andrographis paniculata, Angelica glauca, Arundo donax, Camellia sinensis, Commelina benghalensis, Coriandrum sativum, Costus speciosus, Curcuma longa, Cymbopogon citratus, Dracocephalum rupestre, Malus domestica, Morinda citrifolia, Ocimum gratissimum, Paeonia lactiflora, Picrorhiza scrophulariiflora, Salvia miltiorrhiza and Uncaria tomentosa, etc. These plants contain one or more phytoconstituents that exhibit an exclusive antioxidant or anti-inflammatory activity. These phytoconstituents may also act as modulators of cytokine production and B\u2013T cell co-stimulation, thereby eliminating the chances of the formation of autoantibodies and hyperactivation of the immune response in the case of SLE [Phytocompounds have emerged as safer immunomodulatory therapeutics and have been used since time immemorial. These phytoconstituents serve as immunoregulatory drug candidates by means of either downregulating the functions of immune cells or by controlling the production of inflammatory cytokines, thereby maintaining immune homeostasis . The maie of SLE ,59,60,61Curcuma longa (active phytoconstituent: curcumin) which is known to inactivate the transcription of TLR2 and NF\u03baB, both of which are involved in preparing the plasmacytoid dendritic cell for presenting the autoantigens, thereby leading to the production of autoantibodies. Additionally, curcumin is also known to inhibit the expression of STAT3 and hence, downstream activation of proinflammatory cytokines, namely IL17 and BCL6, can be prevented [Tripterygium wilfordii contains a diterpenoid epoxide, namely triptolide which is known to inhibit the transcription of IL-17 and STAT3 [Berberis aristata, is known to downregulate the expression of STAT3, and also inhibits the production of interferons that induce apoptotic cascade in SLE [Andrographis paniculata, Argyrolobium roseum, Artemisia vestita, Bupleurum falcatum, Campylotropis hirtella, Clerodendron trichotomum, Dracocephalum kotschyi, Periploca sepium and Salvia mirzayanii, have also been found to exhibit similar roles as intracellular signaling regulators and hence may possess probable utility as natural remedies for SLE [Certain natural plant products are known to exhibit a strong anti-inflammatory activity by means of regulating the expression of various signaling protein kinases and cell cycle proteins which are involved in the transcription of inflammatory cytokines and autoantibodies. One such example is revented ,41. In ond STAT3 ,39. Simie in SLE . Several for SLE ,62,63,64Conventional medicines for treating SLE include the use of corticosteroids, antimalarial drugs and non-steroidal anti-inflammatory drugs (NSAIDS). However, these treatment regimens offer contingent results that may vary with changing patient profiles. Moreover, all these chemotherapeutic moieties are unsafe for continued use as they may induce organ toxicities ,45,51. UMucuna pruriens), papaverine (Papaver somniferum), pseudoephedrine (Ephedra sinica), pyrocatechol , pyrogallol (Anogeissus latifolia), theophylline (Camellia sinensis), tyramine (Crataegus laevigata) and yohimbine (Catharanthus roseus), are known to exhibit symptomatic relief in cases of cardiovascular manifestations. Natural compounds such as tocopherol, arecoline, baicalin, ginkgolide, glabridin, naringenin, quercetin, rosmarinic acid, tangeretin and puerarin particularly, serve as cerebroprotective and neurostimulating remedies. Cynocobalamin and folacin  serve as hematopoietic and hepatoprotective remedies. Similarly, Ephedra antisyphilitica, Alchemilla arvensis, Bixa orellana, Cimicifuga racemosa, Helianthus annuus, Ledum palustre, Piper longum, etc., serve as remedies for managing renal and pulmonary afflictions. Most specifically, the maculopapular manifestation in the form of butterfly shaped cutaneous rashes can be treated with the aid of herbal drugs such as Achyranthes aspera, Allium cepa, Allium sativum, Aloe vera, Azadirachta indica, Bauhinia variegata, Beta vulgaris, Calendula officinalis, Camellia sinensis, Curcuma longa, Lawsonia inermis, Lycopersicon esculentum, Momordica charantia, Rosmarinus officinalis and Thymus vulgaris [The primary clinical manifestations of SLE are cardiovascular, cerebrovascular, hematopoietic, hepatic, mucocutaneous, musculoskeletal, pulmonary and renal afflictions. Phytoconstituents, namely bufotenine  nitric oxide synthase (iNOS) and COX-2 inhibitors; (ii) autoantibody production inhibitors; (iii) lymphocyte proliferation inhibitors; (iv) NF\u03baB and NFAT-mediated signaling inhibitors; (v) STAT3, CREM\u03b1 and Rho-associated protein kinase (ROCK) inhibitors; (vi) pro-inflammatory cytokine production regulators; and (vii) symptomatic relief providers. Some of the natural plant products also provide manifold therapeutic benefits as they act upon more than one of the molecular targets of SLE. One such example is l ulcers .Andrographis paniculata, Camellia sinensis, Coriandrum sativum and Curcuma longa serve as immunomodulatory as well as anti-inflammatory herbs, wherein they probably act via reducing the levels of iNOS, COX-2, PGE2, TNF-alpha, IL-6 and IL-12. Hence, these herbs may aid in suppressing inflammation by inhibiting the proliferation of pro-inflammation cytokines, as well as impeding the activation of NF\u03baB signaling [Furthermore, ignaling ,36,38,41Berberis aristata and Morinda citrifolia serve as specific signaling regulators for downregulating the expression of STAT3, RAF1 and mTOR. Hence, both these herbals may serve as promising sources of lead drug molecules targeting SLE [It is noteworthy that certain phyto-molecules such as alizarin, asperuloside, chrysophanol, digoxin and berbamine isolated from ting SLE ,42.These suggested herbal drug candidates are devoid of any potential toxicity or adverse drug reactions, as evident from their previously published toxicological profiles . HencefoAllium sativum, Angelica glauca, Camellia sinensis and Curcuma longa may serve to cater manifold benefits as they can aid in both preventing the occurrence of SLE by acting as immunomodulators and managing the consequences of SLE by providing symptomatic relief. These suggested phyto-metabolites act via regulating a specific molecular target and hence can serve as probable drug candidates for developing a suitable pharmacophore. Undoubtedly, more research must be performed to evaluate the mechanistic roles and clinical benefits of these natural plant products before engaging them as the alternative treatment armamentarium of SLE.Systemic lupus erythromatosus is a prevalent autoimmune disorder with life threatening consequences. It causes widespread cutaneous as well as systemic inflammation, thereby leading to multiple organ damage. There is still a dearth of absolute treatment regimens for the appropriate management of this disease, wherein the available synthetic chemotherapeutic drugs possess multiple toxicities. As a consequence, one must utilize the alternative therapeutic modalities in the form of natural plant products as these phytoconstituents have negligible toxicities, if any, and are endowed with holistic therapeutic activities. These phytoconstituents may serve as immunoregulatory moieties, intracellular signaling regulators and symptomatic relief providers. Certain herbals like"}
+{"text": "Acne fulminans (AF) is a rare and highly inflammatory severe form of acne most commonly seen in adolescent males. Unlike acne vulgaris, AF presents with associated systemic manifestations including, but not limited to, malaise, myalgia, arthralgia, fever, anorexia, and weight loss. It is often an extremely painful condition of sudden onset and can occur years after mild or moderate acne vulgaris. While the inciting agent for this condition has been postulated to be an explosive hypersensitivity reaction to the bacterium Propionobacterium acnes, increased androgens, namely testosterone, have also been reported to play a role in the pathogenesis of this disease process. Additionally, environmental triggers such as air pollution and exposure to halogenated hydrocarbons during occupational activities in enclosed, high temperature settings have been identified as possible etiologies or exacerbating factors. AF is primarily a clinical diagnosis. Isotretinoin, in combination with systemic steroids, are generally the treatments of choice for this disease entity. A Caucasian male in his early 40\u2019s presented to the authors\u2019 clinic with a chief complaint of painful acneiform nodules, cysts, papules, pustules, and abscesses on his back, chest, neck, shoulders, upper arms, and thighs for several months. This case report demonstrates a refractory case of AF with significant clinical improvement after six weeks of topical treatment with subcutaneous adalimumab in combination with oral doxycycline. This case provides evidence supporting the role of Adalimumab in the treatment of AF in addition to the other inflammatory conditions currently FDA approved for treatment with this tumor-necrosis factor (TNF) alpha inhibitor. These conditions include plaque psoriasis, Crohn\u2019s disease, hidradenitis suppurativa, psoriatic arthritis, and rheumatoid arthritis. Acne fulminans (AF) is a rare, highly inflammatory and severe form of acne presenting with an eruption of painful nodules, pustules, and hemorrhagic ulcerations in association with systemic manifestations such as fever, arthralgia, myalgia, hepatosplenomegaly, leukocytosis, anemia, and increased inflammatory lab markers including TNF-alpha.AF is primarily a clinical diagnosis and treatment is often challenging at best. To date, combination therapy with isotretinoin and systemic corticosteroids have been the treatments of choice.A Caucasian male in his early 40\u2019s presented to the authors\u2019 Dermatology clinic with a chief complaint of painful acneiform nodules, cysts, papules, pustules, and abscesses on his back, chest, neck, shoulders, upper arms, and thighs for several months. He reported a history of mild acne throughout his adolescence and early adulthood prior to this eruption. His associated symptoms included tenderness, swelling, pain, and drainage in the areas affected by these acneiform papulonodules and abscesses, most notably on the back, chest, and shoulders.He reported constitutional symptoms of arthritis and occasional fevers but denied chills, night sweats, myalgia, malaise, and weight loss. He had failed previous treatment with multiple oral and topical antibiotics over a course of approximately one year, isotretinoin therapy for roughly six months, and phototherapy, oral/intralesional steroids, and incision/drainage. Each of these treatments had been delivered on an as-needed basis.On examination, this patient demonstrated widespread erythematous  and inflamed acneiform nodules, cysts, papules, pustules, and abscesses on his back, chest, neck, shoulders, upper arms, and thighs.  Several cysts were fluctuant  and tender with active serosanguineous  drainage. On further exam, he had widespread ill-defined hyperpigmented patches. The worst areas of involvement included the trunk, namely the back.This man was diagnosed with AF and started on a treatment regimen of topical and oral medications including topical clindamycin and Tretinoin, once weekly phototherapy, Oral medications included Doxycycline 100 mg twice daily, isotretinoin, and oral and intralesional steroids, all with minimal improvement after a total of 12 months.Due to his limited multi-therapy success, and after appropriate preliminary laboratory evaluation, he was started on the following subsequent regimen: continuation of Doxycycline and initiation of self-administered subcutaneous injections with 40 mg of adalimumab every two weeks. After only six weeks of treatment on this new regimen, he exhibited a significant reduction in inflammatory nodules, cysts, papules, pustules, and abscesses. AF is a rare and severe form of inflammatory acne characterized by the abrupt onset of painful nodules, pustules, and hemorrhagic ulcerations in association with systemic manifestations including fever, arthralgia, myalgia, hepatosplenomegaly, leukocytosis, anemia, and increased inflammatory lab markers such as TNF-alpha levels.Propionobacterium acnes, increased androgens, namely testosterone, and environmental triggers such as air pollution and exposure to halogenated hydrocarbons in occupational high temperature settings which promote occlusion and excess sweating.Additionally, osteolytic bone lesions  may be detected, most commonly involving the clavicle and sternum.Although various options have been described, the treatment of AF remains a challenge for clinicians. The current recommendations suggest a combination treatment with systemic oral prednisolone and oral isotretinoin.Conventional treatments with oral antibiotics, topical corticosteroids, and nonsteroidal anti-inflammatory drugs have been used without significant improvement or sustained remissions.Since the mid-1990s to early 2000s, a more complete understanding of immunology and advances in biologic drug development has popularized the use of TNF-alpha inhibitor therapy. Adalimumab is a recombinant human monoclonal antibody that binds to TNF-alpha thereby halting the progression of the cytokine driven inflammatory cascade. Recent reports of TNF-alpha inhibitor therapy for severe inflammatory acne postulate their use and efficacy in patients with AF and provide the impetus for the use of subcutaneous adalimumab in our patient with refractory AF.Early reports of TNF-alpha inhibitor use to control AF lesions involved patients with SAPHO syndrome  who had failed conventional treatments.It has been well established that patients with SAPHO syndrome have elevated levels of TNF-alpha from purified neutrophils as well as in bone biopsies analyzed with in situ hybridization and immunohistochemistry.Recently, TNF-alpha inhibitors adalimumab, etanercept, and infliximab have been used to treat resistant AC, a variant of severe inflammatory acne and part of the follicular occlusion tetrad . Two case reports describe patients responding to adalimumab monotherapy after failing conventional treatments for recalcitrant AC.Additionally, one patient with AC of the face, neck, and trunk responded to treatment with etanercept demonstrating complete resolution of acneiform lesions at 24 weeks.The results published in the recent literature support the mechanism and role of TNF-alpha inhibitors in the treatment of recalcitrant inflammatory acne. Our case report further supports these results and provides additional evidence for a role of TNF-alpha inhibitors in the treatment of such resistant inflammatory disorders including AF. While the evidence appears promising, current recommendations for treatment of AF remains a combination of oral isotretinoin and systemic steroids.Further research in this area is needed to elucidate the efficacy and most appropriate use of TNF-alpha inhibitors in the setting of inflammatory acne, particularly cases that have failed the current standard of care.The authors declare no conflict of interest."}
+{"text": "In \u201cReal-Time Forecasting of the COVID-19 Outbreak in Chinese Provinces: Machine Learning Approach Using Novel Digital Data and Estimates From Mechanistic Models\u201d :e20285) the authors noted three errors.The order of authors in the original article was listed as:Canelle Poirier, Dianbo Liu, Leonardo Clemente, Xiyu Ding, Matteo Chinazzi, Jessica Davis, Alessandro Vespignani, Mauricio SantillanaThe correct order of authors is:Dianbo Liu, Leonardo Clemente, Canelle Poirier, Xiyu Ding, Matteo Chinazzi, Jessica Davis, Alessandro Vespignani, Mauricio SantillanaAs well, degree information for authors Leonardo Clemente, Xiyu Ding, and Jessica Davis was listed incorrectly as \"MD\" in the original article. The correct degree for Leonardo Clemente and Xiyu Ding is \"MSc\"; the correct degree for Jessica Davis is \"BSc\".The correction will appear in the online version of the paper on the JMIR Publications website on September 22, 2020, together with the publication of this correction notice. Because this was made after submission to PubMed, PubMed Central, and other full-text repositories, the corrected article has also been resubmitted to those repositories."}
+{"text": "The dataset presented here supports the research paper entitled \u201cA calculator to quantify cover crop effects on soil health and productivity\u201d. Soil health  is a concept that describes soil as a living system to sustain plants, animals, and human. Soil physical, chemical, and biological properties, along with their interactions, are required to quantify soil health. The use of cover crops in agricultural rotations may enhance soil health, yet there has been little progress in understanding how external factors such as climate, soil type, and agronomic practices affect soil and cash crop responses. In response, this dataset compiles measurements from 281 studies and provides an analysis of field-measured changes in 38 soil health indicators due to cover crop usage. Environmental and background indicators were also compiled to assess how climatic and management practices affect soil and cash crop responses to cover crops, with specific categories including climate type , soil texture , cover crop type , and cash crop type . An unbalanced analysis of variation was used to determine the hierarchy of most to least important factors that affected responsiveness of each soil health indicator. Based on the hierarchy structure, a soil health calculator was then developed to quantify the response of 13 parameters \u2013 erosion, runoff, weed suppression, soil aggregate stability, leaching, infiltration, microbial biomass carbon, soil bulk density, soil organic carbon, soil nitrogen, microbial biomass nitrogen, cash crop yield, and saturated hydraulic conductivity \u2013 to cover crops. The presented data in the calculator report the mean change in parameter values based on all combinations of climate, soil texture, cover crop type, and cash crop type. All RR values for a given indicator were assembled. To ensure normality, RR distributions were resampled (with replacement) 1000 times via bootstrapping  to test for significant differences in RR values in 38 soil health indicators, examining the data as grouped by Koppen climate type . As the final step, these data were used to develop a web-based soil health calculator  for each parameter. Climate was set as the highest level, while the remaining three factors were ordered from lowest to highest p-values in the unbalanced ANOVA. This analysis was applied to calculate mean RR for all combinations of climate type, soil texture, cash crop type, and cover crop type, specifically focusing on 13 key soil health indicators: cash crop yield, bulk density, soil organic carbon, soil nitrogen, soil aggregation, soil infiltration, soil saturated conductivity, soil erosion, surface runoff, leaching, weed pressures, soil microbial carbon, and soil microbial nitrogen (lculator , with th"}
+{"text": "This individual symposium abstract will focus on the epidemiology of suicide in older adults, with particular focus on risk factors, changing demographics, and population shifts with the baby-boomers aging. Epidemiologically, older men aged 75 and older have a suicide rate of 39.7 deaths per 100,000 in 2017, compared to the general population of 14.0 deaths per 100,000. Risk factors for suicide in older adults include functional disability, multiple chronic physical conditions, and social isolation. In addition, older adults often face stressors such as relationship issues, life crises (loss of spouse), and social factors . Limited mobility, physical and mental health conditions, and lack of social support can affect healthcare access and utilization. Many older adults do not routinely seek behavioral health treatment, with reported under-detection of mental health conditions such as depression, substance use disorders, and suicidal ideation."}
+{"text": "Scurvy is a disease caused by vitamin C deficiency, historically associated with long sea voyages, periods of famine and war. Currently, it is often misdiagnosed and underreported, as physicians tend to consider it a disease of the past.We present the case of a 79-year-old female who was admitted to the Emergency Department complaining of pruritus. The patient lived alone and in poor hygiene conditions. Diet was scarce. One week before admission she was in contact with flea-ridden stray dogs. Sometime later she noted several fleas and multiple pruritic small papules, crusts, and excoriations on her torso, limbs, palms, soles, and scalp. Physical examination showed the patient to be pale, emaciated, and poorly groomed. Laboratory analysis showed microcytic anemia. Flea bites were treated with oral antihistamines and prednisolone. Follow-up one month later\u00a0showed weight gain and partial resolution of skin lesions. However, multiple small ecchymosis on both lower and upper limbs, and occasional perifollicular petechias on her lower extremities, were noted. Additional workup showed undetectable serum vitamin C levels. A diagnosis of scurvy was made. The patient was treated with 1000 mg per day of oral vitamin C for one month leading to complete recovery.We present this case to remind that early recognition of vitamin C deficiency and appropriate supplementation are essential in patients with scurvy. Physicians should be aware of classic signs, symptoms, and social factors associated with this forgotten disease. Individual health conditions and outcomes are shaped by biological, as well as social, environmental, cultural, political, and economic factors. These include access not only to quality housing, healthcare, education, work conditions, but also to environmental quality, sanitation availability, safety, and food .Scurvy is a disease caused by vitamin C deficiency, historically associated with long sea voyages, periods of famine and war . During At-risk populations include low-income patients (poor access to groceries), adults living alone , patients with psychiatric or behavioural disorders,\u00a0cancer, inflammatory bowel disease, peptic disease, or gastroesophageal reflux. Poor or absent dentition, bizarre dietary beliefs, nutritional ignorance, diet fads, and taste preferences further challenge regular consumption of fruit and vegetables. The most common behavioural disorder associated with scurvy is alcoholism ,8.Scurvy is frequently misdiagnosed and underreported, misleading physicians to consider it a disease of the past. We present the case of a malnourished 79-year-old patient with scurvy, and a summary of the pathophysiology and therapeutic options.A 79-year-old female was admitted to a Portuguese Emergency Department (ED) due to complaints of pruritus. She had a previous history of arterial hypertension and alcoholism, though she was abstinent for more than 40 years. Regular medication was amlodipine 5mg once a day. No allergies, tobacco, toxins, drug exposure, or other medical history were known. The patient lived alone in a suburban apartment, with extremely poor conditions of insulation and hygiene. She had contact with stray dogs and cats. Income was insufficient and irregular.\u00a0As the patient was edentulous, her diet consisted of liquid dairy products and sugary processed foods, and was irregular due to frequent income shortage.One week before admission she had contact with presumably flea-infected stray dogs. A few hours later she noted multiple pruritic small papules on her torso, limbs, palms, soles, and scalp. Distribution did not follow any specific pattern. Multiple crusts and excoriations soon developed due to scratching. As the pruritus became unbearable, she was admitted to the ED.On admission, she complained of generalized pruritus and hunger. Detailed medical history was negative for any other symptoms, namely fever, asthenia, dyspnoea, bleeding, melena, dysphagia, nausea, vomit, diarrhoea, obstipation, arthralgia, thoracic or abdominal pain, on admission or on the previous days. On physical examination the patient was pale, emaciated, and poorly groomed. Reported weight was 32 Kg for a height of 158 cm (body mass index (BMI) of\u00a012.8). Besides the small erythematous papules, crusts, and excoriations previously described, several fleas were identified.\u00a0She otherwise appeared comfortable. Blood pressure (BP) and heart rate (HR) were stable (BP: 143/67 mmHg and HR: 92 bpm), peripheral oxygenation saturation\u00a0100% and she was afebrile. No other abnormalities were noted.9/L). Serum iron concentration was low (iron: 10 \u00b5/dL) and total iron-binding capacity was elevated . Serum ferritin, folic acid, vitamin B12, bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and gamma-glutamyl transferase were normal and no other abnormalities were detected. In the ED she was showered, new clothes were given, and she was fed. Oral antihistamines and 20mg of oral prednisolone were prescribed with marked improvement from the pruritus. Hospital discharge was possible, on next day, after ensuring safe housing conditions with a sensible family member. Oral iron supplements were prescribed, and a complete diet rich in iron was recommended.Laboratory analysis revealed microcytic anemia  and leucocytosis . She had gained 1 Kg BMI: 13.2) and most of the papules, crusts, and excoriations had disappeared. Nevertheless, multiple small ecchymosis on both lower and upper limbs .Vitamin C is a simple water-soluble sugar-like molecule present in most fruits and vegetables. Most animals can derive it from glucose via various enzyme systems. Humans, other primates, and guinea pigs are some of the few animal species that are unable to do so, and, therefore, must absorb it through dietary intake. The recommended daily allowance (RDA) of vitamin C ranges from 75 mg per day for women to 90 mg per day for men, though during lactation and other inflammatory states the RDA is increased up to 100 mg per day. A single orange contains approximately 50 mg of vitamin C and as little as 6 to 10 mg of vitamin C per day is enough to prevent clinical scurvy [Vitamin C acts as an essential cofactor for the two enzymes required for collagen synthesis. It also acts as an antioxidant, reducing reactive free radical and oxygen species in oxidative states. Other actions include promotion of iron absorption, biosynthesis of carnitine, hormones , and neurotransmitters (conversion of dopamine to norepinephrine), and metabolism of cholesterol and tyrosine. The most frequent clinical manifestations are consequences of impaired collagen synthesis, which leads to tissue and capillary fragility, tissue haemorrhage, delayed wound healing, scar dehiscence, dystrophic hair lesions, and bone fragility. Early manifestations usually appear in areas subjected to higher hydrostatic pressure, such as buttocks and lower limbs, but can be present in almost any organ .Skin and integumentary system manifestations include perifollicular haemorrhage, petechiae, ecchymoses, palpable purpure, and oedema. Perifollicular haemorrhage, with corkscrew hair deformity due to follicular hyperkeratosis is virtually pathognomonic of scurvy. Oral complications are frequent and include gingival hypertrophy, chronic inflammation, intramucosal vascular fragility leading to oedema and microhaemorrhage. This, combined with poor oral hygiene and alveolar bone absorption, leads to tooth decay and loss. Rheumatological manifestations include arthralgias, usually due to hemarthrosis and subperiosteal haemorrhages. Myalgias are common and thought to be due to the reduced production of carnitine. Ocular complications include conjunctival haemorrhages, fundus changes of flame-shaped haemorrhages and cotton-wool spots. Papilledema and optic nerve atrophy can develop if bleeding locates in the retrobulbar space and optic nerve sheaths. Other associated symptoms are asthenia, depression, anorexia, sicca symptoms\u00a0and peripheral neuropathy .Constitutional symptoms may be secondary to anemia, which accompanies scurvy in up to 75% of patients. Anemia in vitamin C deficiency is multifactorial. Hemorrhage may lead to normochromic-normocytic anemia with elevated reticulocyte count and erythrocyte hyperplasia in bone marrow samples. Decreased inhibition of folate excretion by vitamin C and concomitant decreased folate ingestion  and some patients can\u00a0also present with to macrocytic anemia.\u00a0Hemolysis is usual, though the exact mechanism is unknown. Iron deficiency due to decreased iron absorption leads to microcytic anemia in other patients. Chest pain, hypotension, dyspnoea, cyanosis, ST-segment elevation, and first-degree heart block have all been described, and have been also associated to heart failure, pulmonary hypertension, hemopericardium, impaired catecholamine synthesis and weakened vasomotor response ,12.The differential diagnosis of scurvy is broad and includes haematological abnormalities, medication side effects, infections, ulcerative gingivitis, vascular disorders, other vitamin deficiencies and trauma. Common misdiagnoses include vasculitis, blood dyscrasias, and ulcerative gingivitis, making high suspicion and clinical recognition central to avoid unnecessary complementary exams and inappropriate treatments .Diagnosis of scurvy is clinical, based on dietary history, clinical features, and resolution of signs after vitamin C supplementation. Serum levels of vitamin C below 0.2 mg/dL suggest scurvy and are useful to confirm atypical cases. At these concentrations, fatigue is invariably present, and other symptoms and signs will appear soon after . NeverthTreatment is based on appropriate dietary adjustments and vitamin C supplementation. Consumption of five servings of fruit and vegetables a day will not only exceed the RDA for vitamin C, but it also has the benefit of treating other common concomitant vitamin deficiencies that may be present. Dose and duration of vitamin C supplementation should be individualized, and recommendations vary . Oral viAcute treatment of scurvy supplementation carries an excellent prognosis even in severe disease. Except for lost teeth, no permanent sequalae are known. Symptoms usually resolve in one to five days, most physical findings in one to two weeks, normal hair growth resumes in four weeks, and complete recovery usually occurs before three months of treatment ,10.Bartonella henselae, Rickettsia typhi, Rickettsia felis, and Yersinia pestis), treatment must include eradication of fleas both in the patient and in domestic reservoirs [In our patient, a concomitant flea infestation masqueraded scurvy manifestations. Fleabites are characterized by sudden-onset multiple pruritic papules with haemorrhagic crusts appearing in exposed areas of skin. Some patients present severe hypersensitivity reactions resembling urticaria, and persistent infestations with fleas can lead to papular urticaria and psychological distress. Symptomatic fleabites are usually treated with oral antihistamines and topical corticosteroids. As important vectors for infectious diseases (servoirs .Clinical manifestations of scurvy are time-dependent and proportional to the body's vitamin C deficit. Both mild cases, presenting subtle and nonspecific symptoms such as fatigue and myalgia, as well as severe cases, presenting haemorrhagic and cardiovascular complications, are often misdiagnosed. Direct sequalae from scurvy after appropriate treatment are mainly related to tooth loss, as treatment is extremely safe and effective even in advanced disease. Therefore, severe adverse outcomes are usually associated with complications related to delayed diagnosis, and to unnecessary or inappropriate tests, treatments, or procedures. Classic signs and symptoms should be straightforwardly recognized by physicians and vitamin C supplementation immediately started in suspicious cases. Laboratory confirmation is not essential for diagnosis, though it is useful in patients with atypical or mild signs.\u00a0Though early recognition of vitamin C deficiency and supplementation is essential, scurvy arises from the sum of biological and social factors, hence addressing both is fundamental for a favourable outcome."}
+{"text": "Human skin has remarkable features such as self-healing ability, flexibility, stretchability, high sensitivity and tactile sensing capability. It senses pressure, humidity, temperature and other multifaceted interactions with the surrounding environment. The imitation of human skin sensing properties via electronic systems is one of the frontrunner research topics in prosthetics, robotics, human-machine interfaces, artificial intelligence, virtual reality, haptics, biomedical instrumentation and healthcare, to name but a few.Electronic skins or artificial skins are devices that aim to assimilate and/or mimic the versatility and richness of the human sense of touch via advanced materials and technologies. Generally, electronic skins encompass embedded electronic systems which integrate tactile sensing arrays, signal acquisition, data processing and decoding. Tactile sensors sense diversity of properties via direct physical contact , e.g., vibration, humidity, softness, texture, shape, surface recognition, temperature, shear and normal forces. Tactile sensors are dispersed sensors that translate mechanical and physical variables and pain stimuli into electrical signals. They are based on a wide range of technologies and materials, e.g., capacitive, piezoresistive, optical, inductive, magnetic and strain gauges. Artificial tactile sensing allows the detection, measurement and conversion of tactile information acquired from physical interaction with objects. In the last two decades, the development of tactile sensors has shown impressive advances in sensor materials, design and fabrication, transduction techniques, capability and integration; however, tactile sensors are still limited by a set of constraints related to flexibility, conformability, stretchability, complexity and by real-time implementation of information decoding and processing. The Special Issue collects eight published papers, tackling the fabrication, integration and implementation of tactile sensing in some of the abovementioned applications such as haptics, robotics, human-computer interaction and artificial intelligence, modeling, decoding and processing of tactile information using machine learning techniques. Particularly, Wang et al. presented a flexible tactile sensor array 3x3) with surface texture recognition method for human-robotic interactions. They developed and tested a novel method based on Fine Element Modeling and phase delay to investigate the usability of the proposed flexible array for slippage and grooved surface discrimination when slipping over an object . Choi etx3 with sI would like to take the opportunity to give my genuine thanks to all the authors for submitting such valuable scientific contributions to this Special Issue. Furthermore, my sincere undisputed thanks to all the reviewers for dedicating time and effort to revising the various manuscripts."}
+{"text": "Thrombomodulin (TM), which is predominantly expressed on the endothelium, plays an important role in maintaining vascular homeostasis by regulating the coagulation system. Intravascular injury and inflammation are complicated physiological processes that are induced by injured endothelium-mediated pro-coagulant signaling, necrotic endothelial- and blood cell-derived damage-associated molecular patterns (DAMPs), and DAMP-mediated inflammation. During the hypercoagulable state after endothelial injury, TM is released into the intravascular space by proteolytic cleavage of the endothelium component. Recombinant TM (rTM) is clinically applied to patients with disseminated intravascular coagulation, resulting in protection from tissue injury. Recent studies have revealed that rTM functions as an inflammatory regulator beyond hemostasis through various molecular mechanisms. More specifically, rTM neutralizes DAMPs, including histones and high mobility group box 1 (HMGB1), suppresses excessive activation of the complement system, physiologically protects the endothelium, and influences both innate and acquired immunity. Neutrophil extracellular traps (NETs) promote immunothrombosis by orchestrating platelets to enclose infectious invaders as part of the innate immune system, but excessive immunothrombosis can cause intravascular injury. However, rTM can directly and indirectly regulate NET formation. Furthermore, rTM interacts with mediators of acquired immunity to resolve vascular inflammation. So far, rTM has shown good efficacy in suppressing inflammation in various experimental models, including thrombotic microangiopathy, sterile inflammatory disorders, autoimmune diseases, and sepsis. Thus, rTM has the potential to become a novel tool to regulate intravascular injury via pleiotropic effects. Endothelial cells coordinate vascular homeostasis, including vessel permeability, provision of a lining surface, and coagulation system regulation. To prevent unnecessary clotting, the endothelium expresses anti-coagulant factors, such as tissue factor pathway inhibitor and thrombomodulin (TM), and regulators of platelet activation, such as nitric oxide, prostacyclin, and ADPase, at steady state. When traumatic vascular injury occurs, platelet aggregation and the activated blood coagulation system invoke a thrombus to prevent blood loss. Moreover, damaged endothelium reduces the expression of anti-coagulant and platelet molecules, and releases pro-coagulant factors via the activation of nuclear factor-kappa B (NF-\u03baB) signaling, consequently enhancing thrombus formation. Meanwhile, during non-traumatic intravascular injury, including disseminated intravascular coagulation (DIC), atherosclerosis, and thrombotic microangiopathy , the endTHBD gene, and it is expressed on endothelium, immune cells , vascular smooth muscle cells, keratinocytes, and lung alveolar epithelial cells  inhibiting leukocyte-mediated intravascular injury, (2) neutralizing DAMPs, including high mobility group box 1 (HMGB1) protein and histones, (3) binding to bacteria-derived components, and (4) suppressing the complement system. (1) Transgenic mice with a genetically deleted TMD1 domain showed increased mortality in endotoxin-induced sepsis, together with the finding that adhesion molecule expression and neutrophil infiltration were increased in TMD1-deficient endothelium . Ex vivoadhesion . Furtheradhesion  showed tadhesion . The latadhesion , 18. TM adhesion , 20. (3)adhesion . (4) TM adhesion . Abnormaadhesion . Furtheradhesion , contribVarious stimuli induce NETs through their own NETs-signaling mechanisms. However, regardless of the type of trigger, the NETs resulting from it could become major sources of DAMPs, and act as initiators of immunothrombosis in the face of intravascular injury , 26. ThuOf note, rTM containing all the extracellular domains acts not only as an anti-coagulant, but also displays anti-inflammatory properties, hence contributing to the resolution of various diseases .Sepsis involves multi-organ dysfunction with systemic inflammatory processes, immune dysregulation, coagulopathy, and other physiological responses. Among these processes, NETs and necrotic cell-derived DAMPs directly injure the endothelium and contribute to the development of immunothrombosis through the activation of platelets, coagulation systems, and recruitment of neutrophils , 89, 90.IRI occurs in response to the physiological processes that accompany tissue ischemia with inadequate oxygen supply. This is followed by reperfusion that drives regulated necrosis and subsequent inflammatory responses, leading not only to local organ damage, but also to remote organ injury in the form of necroinflammation , 92. In Escherichia coli (O157:H7) induces HUS by producing Shiga toxins, which bind to endothelial cells in the kidney and brain, triggering them to undergo cell death by inhibiting protein synthesis and inducing the secretion of Von Willebrand factor multimers, which leads to endothelial injury and microthrombi (E. coli (STEC)-HUS -HUS . FurtherTEC)-HUS .2-induced abdominal aortic aneurysm model, rTM  treatmetodomain . In vitrutophagy , 100. ThIn previous sections, the anti-inflammatory effects of rTM against intravascular injury were mainly described. In autoimmune diseases, including Goodpasture's syndrome  and autoSeveral studies have reported the serum TM level to examine its role in various diseases. Sepsis , ischemipost-hoc subgroup analysis stratified by the persistence of abnormal coagulation showed a tendency to decrease mortality (In randomized, double-blind clinical trials, in which patients with DIC associated with hematologic malignancy or infection were treated with rTM or heparin, rTM improved DIC, and alleviated hemorrhagic complications compared with heparin . Althougortality . Meanwhiortality . Moreoveortality . A retroortality .TMA is associated with high mortality regardless of the underlying disease, including HUS, TTP, transplant complications, and drug side effects. In a case series of three patients with HUS, rTM ameliorated clinical outcomes with improvements reflected in reduced platelet counts and excessive complement activation . FurtherAE-IPF is a lethal condition associated with endothelial damage and abnormalities of the coagulation system , 117. HMIn vitro and animal studies indicate that rTM possesses the direct immunomodulatory effects in innate and acquired immunity independently of anti-coagulant effect (Although the efficacy of rTM has not been clinically shown in autoimmune disease and inflammatory disorder, several experimental data represent the potential to overcome these diseases. t effect , 15. Bast effect , rTM is t effect , 41 is 1Immunothrombosis during intravascular injury leads to organ damage and further intravascular injury via cellular and molecular signaling, including excessive inflammation, coagulation, and cell activation. rTM regulates the immunothrombosis to terminate inflammation/coagulation, neutralize DAMPs, and affect immunity. The administration of rTM has the potential to become a novel therapeutic strategy for various diseases associated with immunothrombosis-mediated intravascular injury.KW-K and DN conducted the literature research and reviewed all articles. AI and TA edited the article. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Autoimmune adverse events are the most relevant risks of alemtuzumab therapy. We present a patient with relapsing-remitting multiple sclerosis, who developed adult-onset Still\u2019s disease (AOSD) following alemtuzumab treatment.The patient suffered from sore throat, swallowing difficulties, high spiking quotidian fever, generalized skin rash, arthritis, and myalgia 2 months after the second course of alemtuzumab. Laboratory tests revealed elevated acute-phase reactants, anemia, neutrophilic leukocytosis, and thrombocytosis. Serum calprotectin, interleukin-2, and interleukin-6 levels were strongly increased. Autoimmune, rheumatic, neoplastic, infectious, and granulomatous disorders were excluded. The NLRP1 and NLRP3 gene test, which was performed under the presumption of a cryopyrin-associated autoinflammatory syndrome, was negative. Based on the Yamaguchi and Fautrel criteria, and supported by the histological findings from a skin biopsy of the rash, the diagnosis of AOSD was established. Therapy with the anti-IL-1 agent (anakinra) led to a significant improvement of symptoms and blood parameters. However, anakinra had to be converted to rituximab due to generalized drug eruption. Following therapy with rituximab, the patient has fully recovered.The current case highlights AOSD as another rare and potentially life-threatening secondary autoinflammatory/autoimmune event following alemtuzumab treatment. The use of alemtuzumab as therapy for active relapsing-remitting multiple sclerosis was recently restricted due to safety concerns. The potential development of secondary autoimmunity represents the most relevant risk of this therapy . In the Adult-onset Still\u2019s disease is a rare, multigenic, clinically highly variable, multi-systemic inflammatory disease of unknown etiology, and pathogenesis usually affecting young adults. It is typically characterized by high spiking fever, arthralgia or arthritis, and transient maculopapular salmon-pink evanescent skin rash. Other manifestations are sore throat or pharyngitis, dynophagia, myalgia or myositis, generalized lymphadenopathy, hepatosplenomegaly, serositis, and cardiopulmonary or kidney involvement , 6. CommA 26-year-old, previously completely healthy, female Caucasian was first diagnosed with relapsing-remitting multiple sclerosis in August 2016. Family history of neurological and autoimmune diseases was negative. Due to high clinical disease activity (three relapses in 2016), she received two courses of alemtuzumab (10/2016 and 10/2017) as first-line therapy. Urticaria after the first course of alemtuzumab had to be treated with antihistamines. In February 2017, the patient suffered from varicella-zoster virus-induced left ophthalmic zoster , which w) and antihistamines, the rash improved only temporarily. However, the patient developed arthritis and myalgia. She was referred to her local clinic of neurology, rheumatology, and dermatology.The patient further suffered from high spiking quotidian fever of up to 40 degrees occurring in the evenings, and a generalized itching, evanescent maculopapular, salmon-pink skin rash  that accFigures 1D,ERepeated dermatological examinations  were not indicative. She developed anemia, neutrophilic leukocytosis, and thrombocytosis, and showed elevated acute-phase reactants  includin) and subsequent oral prednisolone with slow dose tapering, symptoms improved, and inflammatory blood parameters decreased. When trying to reduce oral prednisolone, the symptoms came back, and inflammatory blood parameters and platelets immediately increased , initiated in April 2018, led to a significant improvement of symptoms and blood parameters . Besidesd spleen .,), and initiation of rituximab therapy .The current case highlights AOSD as another potentially life-threatening secondary autoinflammatory/autoimmune event following alemtuzumab treatment. Thorough clinical follow-up and early intense interdisciplinary communication and intervention are necessary in suspicious cases after treatment with alemtuzumab.While treatment with corticosteroids caused only a short-term improvement, initiation of rituximab therapy induced long-lasting remission. Now, i am feeling fine again, but these 4 months were the worst experiences of my life. I do not want anyone to go through what I had to. In the end I hope that physicians all over the world have learned something from reading my case.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Written informed consent to publish the present case details  was obtained from the patient. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.JK, SM, and VS conceived the study and defined the concept. JK, TK-O, H-JL, PS, DF, SM, and VS collected and interpreted the data. JK wrote the initial draft of the manuscript. TK-O prepared the histopathological images. JK, TK-O, H-JL, PS, DF, SM, and VS critically discussed the data, revised the manuscript for intellectual content, and approved the version to be published. All authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.JK received honoraria for lecturing from Biogen, Novartis, Genzyme, Merck, Mylan, and Teva, and financial research support from Sanofi Genzyme and Novartis. TK-O, H-JL, and PS declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. DF received honoraria for lecturing and travel expenses for attending meetings from Chugai-Roche, Novartis, and SOBI, and financial research support from Novartis, Pfizer, and SOBI. SM received honoraria for lecturing and travel expenses for attending meetings from Almirall, Amicus Therapeutics Germany, Bayer Health Care, Biogen, Celgene, Diamed, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, Roche, Sanofi-Aventis, Chugai Pharma, QuintilesIMS, and Teva. His research is funded by the German Ministry for Education and Research (BMBF), Deutsche Forschungsgemeinschaft (DFG), Else Kr\u00f6ner Fresenius Foundation, German Academic Exchange Service, Hertie Foundation, Interdisciplinary Center for Clinical Studies (IZKF) M\u00fcnster, German Foundation Neurology, and by Almirall, Amicus Therapeutics Germany, Biogen, Diamed, Fresenius Medical Care, Genzyme, Merck Serono, Novartis, ONO Pharma, Roche, and Teva. VS received honoraria for serving on Scientific Advisory Boards, lecturing and travel expenses for attending meetings from Novartis, Biogen, Merck Serono, Sanofi Genzyme, Roche, and Teva."}
+{"text": "Purpose: The incidence and the clinical presentation of neurological manifestations of coronavirus disease-2019 (COVID-19) remain unclear. No data regarding the use of neuromonitoring tools in this group of patients are available.Methods: This is a retrospective study of prospectively collected data. The primary aim was to assess the incidence and the type of neurological complications in critically ill COVID-19 patients and their effect on survival as well as on hospital and intensive care unit (ICU) length of stay. The secondary aim was to describe cerebral hemodynamic changes detected by noninvasive neuromonitoring modalities such as transcranial Doppler, optic nerve sheath diameter (ONSD), and automated pupillometry.Results: Ninety-four patients with COVID-19 admitted to an ICU from February 28 to June 30, 2020, were included in this study. Fifty-three patients underwent noninvasive neuromonitoring. Neurological complications were detected in 50% of patients, with delirium as the most common manifestation. Patients with neurological complications, compared to those without, had longer hospital  and ICU  stay. The duration of mechanical ventilation was independently associated with the risk of developing neurological complications . Patients with increased intracranial pressure measured by ONSD  had longer ICU stay.Conclusions: Neurological complications are common in critically ill patients with COVID-19 receiving invasive mechanical ventilation and are associated with prolonged ICU length of stay. Multimodal noninvasive neuromonitoring systems are useful tools for the early detection of variations in cerebrovascular parameters in COVID-19. Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) , is primCoronaviruses may pass to the central nervous system by different routes , 8, inclA recent systematic review of 37 articles revealed that 20% of COVID-19 patients present with headache, 60% with anosmia/ageusia, 25% with myalgia/myositis, 8.8% with encephalopathy, 2.8% with ischemic stroke, and 0.45% with intracerebral hemorrhage . Other nNoninvasive neuromonitoring systems are widely used in neurointensive care settings for patients with primary cerebral damage; more recently, they are also being employed in critically ill patients in general as useful tools to detect neurological complications , 23. In The primary aim of our study was to describe the type and the frequency of neurological complications in a cohort of critically ill patients with COVID-19 receiving invasive mechanical ventilation in an intensive care unit (ICU) and the effects of these complications on outcome. As a secondary aim, we sought to assess changes in cerebral hemodynamics, their effects on outcome, and their role as potential predictors of neurological complications in a subgroup of patients who underwent noninvasive neuromonitoring .This is a single-center, retrospective, observational study of prospectively collected data. The study was carried out during the COVID-19 pandemic, from February 28 through June 30, 2020, at the ICU of the San Martino Policlinico Hospital (SMPH) IRCCS for Oncology and Neurosciences, Genoa, Italy. The SMPH is the main hospital serving both the metropolitan area of Genoa  and the wider Liguria Region . The usual ICU capacity is 52 adult beds, increased to 74 during the peak of the SARS-CoV-2 outbreak in Italy. The study protocol followed good clinical practice principles in compliance with the Declaration of Helsinki, and the Ethics Committee of Liguria, Italy (registry number 163/2020), approved the study and waived the informed consent for participation because of the retrospective nature of the study.Patients aged \u226518 years, confirmed positive for SARS-CoV-2 infection by reverse transcriptase-polymerase chain reaction (RT-PCR) of nasopharyngeal swab specimens at the moment of ICU admission, and who were critically ill, requiring invasive mechanical ventilation, were eligible for inclusion. Patients who were not neurologically evaluable due to deep sedation for life-threatening respiratory failure were excluded.2), sequential organ failure assessment score (2), moderate/severe liver disease (defined as compensated/decompensated liver cirrhosis) (2)  were collected from daily test results throughout each patient's ICU stay. At the time of ICU and hospital discharge, data on ICU length of stay (ICU-LOS) (days), overall hospital LOS (days), duration of mechanical ventilation (days), neurological complications (type and number), and mortality were collected.The following data were collected from the patients' electronic records at the time of ICU admission: age in years, gender, body mass index  , and can2O, pressure control or pressure support in cmH2O, respiratory rate in breaths per minute, tidal volume in mL, and fraction of inspired oxygen (FiO2)], arterial blood gas values , vital signs , sedation (including type of sedative), analgesia , and neuromuscular blockade. The neurological complications and scales used for outcome measures are defined in the The following data were collected from patients who underwent noninvasive neuromonitoring during the day of assessment and throughout their ICU stay: ventilatory parameters . As dess 5\u20136 mm ; this su2, which can cause cerebral vasodilatation . Thus, neuromonitoring data are neither complete nor available for all patients. Second, TCD, ONSD, and automated pupillometer measurements were intermittent and were obtained at different stages of the patients' ICU stays. Continuous, daily, standardized monitoring would have provided more accurate data on the behavior of cerebrovascular hemodynamics in this population. Because of the critical demands of the pandemic, we were unable to obtain multiple neuromonitoring measurements to reduce intra- and inter-observer variability among the operators. However, our team consists of a group of specialized physicians with ample experience in the use of noninvasive monitoring. Third, we did not use other methods\u2014such as neuroimaging or lumbar puncture\u2014to confirm the findings of intracranial hypertension. Fourth, the relatively small sample size of our study, which depended on the number of COVID-19 patients admitted to our ICU and was thus beyond our control, limits the strength of our conclusions and results. Fourth, since this is not an interventional study, the sedation and analgesia protocols were not standardized but rather were based on the clinical needs of the patients, which may have had an impact on FV, ONSD, and automated pupillometer-derived values. Fifth, in this study population, ICP was only moderately elevated due to factors not related to intracranial pathologies, which might explain why the neurological complications did not lead to life-threatening complications.Neurological complications, particularly delirium, are common in COVID-19 patients and are associated with longer hospital and ICU stay. The duration of mechanical ventilation is strongly associated with the development of neurological complications. Noninvasive neuromonitoring during ICU stay may be helpful to detect cerebrovascular alterations earlier. Further studies, including a larger number of patients, may provide new insights on the role of noninvasive neuromonitoring in non-COVID-19 patients admitted to ICU for different pathologies.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Ethics Committee of Liguria, Italy (registry number 163/2020). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.DB and CR conceived the study, designed the study, acquired data, interpreted the data, and drafted the manuscript. GS analyzed and interpreted the data, critically revised the manuscript, and gave final approval. KC, FI, and MBL contributed to the acquisition of data, critical revision of the manuscript, and final approval. FT, LB, DG, AV, MBT, PR, NP, and IB contributed to the critical revision of the manuscript and final approval. PP helped with the study design, interpretation of the data, critical revision of the manuscript, and final approval. All authors contributed to the article and approved the submitted version.Chiara Berri, Anesthesia and Intensive Care, San Martino Policlinico Hospital, IRCCS for Oncology and Neurosciences, Genoa, Italy; Serena Cavalcoli, Anesthesia and Intensive Care, San Martino Policlinico Hospital, IRCCS for Oncology and Neurosciences, Genoa, Italy, Department of Surgical Sciences and Integrated Diagnostic (DISC), University of Genoa, Genoa, Italy; Elena Ciaravolo, Anesthesia and Intensive Care, San Martino Policlinico Hospital, IRCCS for Oncology and Neurosciences, Genoa, Italy, Department of Surgical Sciences and Integrated Diagnostic (DISC), University of Genoa, Genoa, Italy; Marcus Ferretti, Anesthesia and Intensive Care, San Martino Policlinico Hospital, IRCCS for Oncology and Neurosciences, Genoa, Italy; Maurizio Loconte, Anesthesia and Intensive Care, San Martino Policlinico Hospital, IRCCS for Oncology and Neurosciences, Genoa, Italy; Marco Sottano, Anesthesia and Intensive Care, San Martino Policlinico Hospital, IRCCS for Oncology and Neurosciences, Genoa, Italy, Department of Surgical Sciences and Integrated Diagnostic (DISC), University of Genoa, Genoa, Italy; Stefano Nogas, Anesthesia and Intensive Care, San Martino Policlinico Hospital, IRCCS for Oncology and Neurosciences, Genoa, Italy, Department of Surgical Sciences and Integrated Diagnostic (DISC), University of Genoa, Genoa, Italy; Paolo Frisoni, Anesthesia and Intensive Care, San Martino Policlinico Hospital, IRCCS for Oncology and Neurosciences, Genoa, Italy; Pasquale Anania, Department of Neurology, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, (DINOGMI), University of Genoa, Genoa, Italy; Pietro Fiaschi, Department of Neurology, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, (DINOGMI), University of Genoa, Genoa, Italy, Department of Neurosurgery, San Martino Policlinico Hospital, IRCCS for Oncology and Neurosciences, Genoa, Italy; Alessandro Prior Department of Neurology, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, (DINOGMI), University of Genoa, Genoa, Italy; Alessandro Bertuccio, Neurosurgical Unit, Surgical Department, Azienda Ospedaliera SS. Antonio e Biagio e Cesare Arrigo, Alessandria, Italy; Angelo Schenone, Department of Neurosurgery, San Martino Policlinico Hospital, IRCCS for Oncology and Neurosciences, Genoa, Italy; Gianluigi Zona, Department of Neurology, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, (DINOGMI), University of Genoa, Italy, Department of Neurosurgery, San Martino Policlinico Hospital, IRCCS for Oncology and Neurosciences, Genoa, Italy; Angelo Gratarola, Anesthesia and Intensive Care, San Martino Policlinico Hospital, IRCCS for Oncology and Neurosciences, Genoa, Italy; Flavio Villani, Division of Clinical Neurophysiology and Epilepsy Center, San Martino Policlinico Hospital, IRCCS for Oncology and Neurosciences, Genoa, Italy.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Improving health and lives of people is undoubtedly one of the prime goals of healthcare organizations, policy-makers, and leaders around the world. The need of ageing, disability, long-term care, and palliative care in our current society pose formidable challenges for disease burden and healthcare systems that must be addressed . In ordeIn this special issue, we aim to provide new insights on research data analytics and applications of wearable devices/sensors in healthcare by covering wide range of related topics. This issue represents the latest research that spans across 19 countries, 37 institutions and is covered by a total of 28 articles. To make better understanding of the research articles, we have arranged them in an order to show various covered aspects in this field, such as technology integration research, prediction systems, rehabilitation studies, prototype systems, community health studies, detection systems, ergonomics studies, technology acceptance studies, monitoring systems, warning systems, sports studies, clinical systems, feasibility studies, parameters measurement systems, design studies, location based systems, tracking systems, observational studies, risk assessment studies, activity recognition systems, impact measurement systems and systematic review. In order to provide a basic overview, we will go through and provide brief summary of all the articles of wearable devices/sensors covered in this issue one by one. Bayo-Monton et al.  provided"}
+{"text": "Large trials have shown that sodium glucose co-transporter-2 (SGLT2) inhibitors reduce the risk of adverse kidney and cardiovascular outcomes in patients with heart failure or chronic kidney disease, or with type 2 diabetes and high risk of atherosclerotic cardiovascular disease. None of the trials recruiting patients with and without diabetes were designed to assess outcomes separately in patients without diabetes.We did a systematic review and meta-analysis of SGLT2 inhibitor trials. We searched the MEDLINE and Embase databases for trials published from database inception to Sept 5, 2022. SGLT2 inhibitor trials that were double-blind, placebo-controlled, performed in adults (age \u226518 years), large (\u2265500 participants per group), and at least 6 months in duration were included. Summary-level data used for analysis were extracted from published reports or provided by trial investigators, and inverse-variance-weighted meta-analyses were conducted to estimate treatment effects. The main efficacy outcomes were kidney disease progression , acute kidney injury, and a composite of cardiovascular death or hospitalisation for heart failure. Other outcomes were death from cardiovascular and non-cardiovascular disease considered separately, and the main safety outcomes were ketoacidosis and lower limb amputation. This study is registered with PROSPERO, CRD42022351618.2). Compared with placebo, allocation to an SGLT2 inhibitor reduced the risk of kidney disease progression by 37%  with similar RRs in patients with and without diabetes. In the four chronic kidney disease trials, RRs were similar irrespective of primary kidney diagnosis. SGLT2 inhibitors reduced the risk of acute kidney injury by 23%  and the risk of cardiovascular death or hospitalisation for heart failure by 23% , again with similar effects in those with and without diabetes. SGLT2 inhibitors also reduced the risk of cardiovascular death  but did not significantly reduce the risk of non-cardiovascular death . For these mortality outcomes, RRs were similar in patients with and without diabetes. For all outcomes, results were broadly similar irrespective of trial mean baseline eGFR. Based on estimates of absolute effects, the absolute benefits of SGLT2 inhibition outweighed any serious hazards of ketoacidosis or amputation.We identified 13 trials involving 90\u2009413 participants. After exclusion of four participants with uncertain diabetes status, we analysed 90\u2009409 participants (74\u2009804 [82\u00b77%] participants with diabetes [>99% with type 2 diabetes] and 15\u2009605 [17\u00b73%] without diabetes; trial-level mean baseline eGFR range 37\u201385 mL/min per 1\u00b773 mIn addition to the established cardiovascular benefits of SGLT2 inhibitors, the randomised data support their use for modifying risk of kidney disease progression and acute kidney injury, not only in patients with type 2 diabetes at high cardiovascular risk, but also in patients with chronic kidney disease or heart failure irrespective of diabetes status, primary kidney disease, or kidney function.UK Medical Research Council and Kidney Research UK. Large placebo-controlled trials have shown that sodium glucose co-transporter-2 (SGLT2) inhibitors reduce the risk of cardiovascular disease, and particularly hospitalisation for heart failure, in patients with type 2 diabetes at high risk of atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease. There is good evidence to support the use of SGLT2 inhibitors as a foundational therapy to prevent cardiovascular death or hospitalisation for heart failure in patients with heart failure, irrespective of ejection fraction or history of previous diabetes.11Evidence before this studyIn our previous systematic review and meta-analysis reported in 2021, we systematically searched MEDLINE and Embase from inception to Aug 28, 2021, for large double-blind placebo-controlled sodium glucose co-transporter-2 (SGLT2) inhibitor trials. We identified 11 large trials with low risk of bias conducted in three at-risk populations . Overall, SGLT2 inhibitors reduced the risk of kidney disease progression and the composite of cardiovascular death or hospitalisation for heart failure, both by about a quarter. Relative risks were markedly consistent across the different patient groups. However, data were limited in patients without diabetes who were eligible for inclusion . Estimates of the effects of SGLT2 inhibitors on kidney disease progression in patients without diabetes were based on around 100 events from the chronic kidney disease trial and around 100 events from the heart failure trials. This limits the quality of evidence for making clinical practice recommendations. The influence of diabetes on the effects of SGLT2 inhibitors on acute kidney injury, cardiovascular and non-cardiovascular mortality, and safety outcomes was also not explored in the previous meta-analysis.Added value of this studyThe majority of people with chronic kidney disease do not have diabetes, and thus more information about SGLT2 inhibitors in this patient group has particular public health importance. Since 2021, two placebo-controlled SGLT2 inhibitor trials (EMPA-KIDNEY and DELIVER) have studied a large number of people without diabetes. EMPA-KIDNEY recruited 6609 patients with chronic kidney disease including 3569 patients without diabetes, and DELIVER recruited 6263 patients with heart failure with mildly reduced or preserved (>40%) ejection fraction including 3109 patients without diabetes. By incorporating data from these trials and standardising outcome definitions, the current updated meta-analysis shows that in the studied patients with chronic kidney disease or heart failure (in whom chronic kidney disease was common), SGLT2 inhibitors safely reduced the risk of kidney disease progression by 37%  and of acute kidney injury by 23% , compared with placebo, with similar reductions in patients with and without diabetes. Apparent benefits on kidney disease progression were also similar across the range of studied kidney function, and appeared unmodified by primary kidney diagnosis.Implications of all the available evidenceThis meta-analysis provides high-quality evidence to support guideline recommendations for the use of SGLT2 inhibitors as a foundational therapy to reduce the risk of kidney disease progression and acute kidney injury not only in patients with type 2 diabetes at high cardiovascular risk, but also in patients who have chronic kidney disease or heart failure, irrespective of diabetes status, primary kidney diagnosis, or level of kidney function.2),2), including 3569 (54\u00b70%) without diabetes.Two recent placebo-controlled SGLT2 inhibitor trials have provided important new information on the effects of SGLT2 inhibitors on kidney disease progression and other outcomes in patients without diabetes. DELIVER randomly assigned 6263 patients with stable heart failure and an ejection fraction of greater than 40%, including 3109 (49\u00b76%) patients without diabetes  with discrepancies resolved by consensus discussion . For tri2 or <10 mL/min per 1\u00b773 m2) or death from kidney failure  from randomisation, end-stage kidney disease , a sustained low eGFR ; and other kidney disease or diagnosis or unknown combined.Analyses were done separately in patients with and without diabetes at baseline . When possible, diabetes-specific (or primary kidney diagnosis-specific) effects of treatment were obtained from Cox models reported in trial publications. When these effects were unavailable , log rel2 tests for heterogeneity were used to assess whether treatment effects differed between those with and without diabetes at recruitment, by trial population  and by primary kidney diagnosis. Heterogeneity was also assessed post hoc for the lower limb amputation outcome, comparing CANVAS with the other 12 trials combined. In forest plots, trials were ordered by their mean baseline eGFR values and effect modification by kidney function was assessed by a standard \u03c72 test for trend across the set of ordered results. Heterogeneity and trend p values were interpreted in the context of the multiple exploratory hypotheses being tested and the absence of individual participant-level data. For trials reporting median eGFR and its IQR, mean and SD values were estimated.Tests of between-study heterogeneity were conducted in our previous meta-analysis published in 2021, which established that effects were generally similar across its included trials (excluding DELIVER and EMPA-KIDNEY).Rates of outcome events were presented per 1000 patient-years. For the outcomes of kidney disease progression, acute kidney injury, cardiovascular death or hospitalisation for heart failure, ketoacidosis, and lower limb amputation, absolute benefits and harms of SGLT2 inhibitors versus placebo per 1000 patient-years were estimated by diabetes status and patient group. Absolute effects were estimated by applying the diabetes status-specific RRs, or their 95% CIs, to the corresponding mean event rates in the placebo arms (first event only). As in our previous report,All analyses were performed in SAS (version 9.4) and R (version 3.6.2). Our outline protocol was registered in PROSPERO on Aug 5, 2022 (CRD42022351618).The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.Our literature searches identified 15 large trials . Two lar2 in the type 2 diabetes and high atherosclerotic cardiovascular disease risk trials, 51\u201366 mL/min per 1\u00b773 m2 in the heart failure trials, and 37\u201356 mL/min per 1\u00b773 m2 in the chronic kidney disease trials. Median follow-up was longest for the type 2 diabetes and high atherosclerotic cardiovascular disease risk trials (2\u00b74\u20134\u00b72 years), intermediate for the chronic kidney disease trials (1\u00b73\u20132\u00b76 years), and shortest for the heart failure trials (0\u00b78\u20132\u00b72 years).Four trials included 42\u2009568 patients with type 2 diabetes and high risk of atherosclerotic cardiovascular disease; five trials included 21\u2009947 patients with heart failure ; and four trials included 25\u2009898 patients with chronic kidney disease . Thus across all trials, allocation to an SGLT2 inhibitor was associated with a 15% increase in the risk of lower limb amputation . Compared with patients with diabetes, the baseline absolute risk of lower limb amputation was markedly lower among patients without diabetes. The RRs for amputations did not appear to vary depending on mean baseline eGFR . In all the trial populations studied to date, the absolute benefits of SGLT2 inhibition considerably outweighed any serious hazards.Large placebo-controlled trials of SGLT2 inhibitors have assessed patients with type 2 diabetes, chronic kidney disease, and heart failure, but no previous trial has been specifically powered to assess kidney or cardiovascular effects in patients without diabetes. Our key objective was to perform a collaborative meta-analysis incorporating all of the available evidence from all large SGLT2 inhibitor trials in populations with chronic kidney disease, heart failure, and type 2 diabetes at high cardiovascular risk, to compare the effects of SGLT2 inhibitors on the risk of kidney disease progression, acute kidney injury, and other key outcomes in patients with and without diabetes. Our analyses included information from around 90\u2009000 trial participants, including about 16\u2009000 people without diabetes. We defined kidney disease progression on the basis of a sustained decrease in eGFR (\u226550%) from randomisation, a need to start maintenance dialysis or receive a kidney transplant, sustained low eGFR, or death from kidney failure. Our results showed that SGLT2 inhibitors reduce the risk of kidney disease progression by 37% and acute kidney injury by 23%, with similar effects in patients with and without diabetes. Patients with a wide range of kidney function have been studied in the reported trials, and despite attenuation of the effects of SGLT2 inhibitors on glycosuria with lower kidney function,The outcome of a sustained decrease in eGFR \u226550%) from randomisation has been widely used to explore effects on kidney disease progression in subanalyses of the DAPA-CKD trial.% from ra2. A total of 489 kidney disease progression outcomes accrued in those with an eGFR less than 30 mL/min per 1\u00b773 m2 in those two trials.2 (based on grade B levels of evidence),2 or 30 mL/min per 1\u00b773 m2.2 with continued use below this level. Several hundred participants in the chronic kidney disease trials had an eGFR below 20 mL/min per 1\u00b773 m2 at randomisation or during follow-up , providing indirect evidence to support initiation of SGLT2 inhibitors in selected patients with an eGFR less than 20 mL/min per 1\u00b773 m2.Based on the average risk in different trial populations, we estimated that for every 1000 patients with chronic kidney disease treated for one year with an SGLT2 inhibitor, 11 first kidney disease progression events would be prevented in patients with diabetes, and 15 would be prevented in patients without diabetes. In these patients, such treatment also appeared to result in an estimated four to five fewer acute kidney injury events in patients with and without diabetes. Individual trials have shown that kidney benefits translate into important reductions in the need for dialysis or kidney transplantation,NCT05374291), and data are insufficient to assess the effects on kidney and cardiovascular clinical outcomes for patients with other kidney diagnoses excluded from the chronic kidney disease trials  and for patients with type 1 diabetes  from around 90\u2009000 people recruited into 13 relevant SGLT2 inhibitor clinical trials. The inclusion of new EMPA-KIDNEY and DELIVER data has more than doubled the number of outcomes previously available for kidney disease progression in patients without diabetes.diabetes .44, 60 FIn conclusion, our meta-analysis of the available large placebo-controlled SGLT2 inhibitor trials has shown that in the studied populations, SGLT2 inhibitors safely reduce the risk of kidney disease progression, acute kidney injury, cardiovascular death, and hospitalisation for heart failure in patients with chronic kidney disease or heart failure, irrespective of diabetes status. The proportional benefits were similar in patients with and without diabetes and appeared to be evident across the wide range of kidney function studied. In the trials of patients with chronic kidney disease, we also found that the proportional benefits on kidney disease progression were similar across the range of primary kidney diagnoses studied. The data from these large trials therefore support a central role for SGLT2 inhibitors as a disease-modifying therapy for chronic kidney disease, irrespective of diabetes status, primary kidney diagnosis, or level of kidney function.will.herrington@ndph.ox.ac.ukCorrespondence to: Assoc Prof William Herrington, Medical Research Council Population Health Research Unit at the University of Oxford, Nuffield Department of Population Health, Oxford OX3 7LF, UK All analysed summary data were extracted from published sources that are publicly available or were requested from individual trials (and are provided in the presented tables and figures). For the purpose of open access, the authors have applied a Creative Commons Attribution (CC BY) licence to any Author-Accepted Manuscript version arising.NS, RH, KJM, AJR, SYAN, DZ, PJ, DP, MJL, CB, JRE, and WGH report institutional grant funding from Boehringer Ingelheim and Eli Lilly for the EMPA-KIDNEY trial. NS additionally reports institutional grant funding from Novo Nordisk. RH additionally reports institutional grant funding from Novartis; and trial drug supply from Roche and Regeneron. CB additionally reports grant funding from the UK Medical Research Council, the UK National Institute for Health and Care Research Health Technology Assessment, and Health Data Research UK; and advisory roles for Merck, the National Institute for Health and Care Research Health Technology Assessment, the British Heart Foundation, and the European Society of Cardiology. WGH additionally reports funding from the UK Medical Research Council\u2013Kidney Research UK Professor David Kerr Clinician Scientist Award. BLN reports consultancy fees and honorarium paid to his institution by AstraZeneca, Bayer, Boehringer Ingelheim, Cambridge Healthcare Research, American Diabetes Association, Renal Society of Australasia and Janssen; and advisory board membership (fees paid to institution) with AstraZeneca, Bayer, and Boehringer Ingelheim. SJH and MB are full-time employees of Boehringer Ingelheim International. SDA reports institutional grant funding from Vifor Int and Abbott Vascular; consultancy or advisory board fees from CVRx, Amgen, Respicardia, Novo Nordisk, Brahms, Novartis, Sanofi, and Cordio; and additional leadership or advisory board roles with Vifor Int, Bayer, Boehringer Ingelheim, Servier, Abbott Vascular, Impulse Dynamics, AstraZeneca, Bioventrix, Janssen, Cardior, V-Wave, Cardiac Dimensions, and Occlutech. JB reports consultancy fees and honorarium from Abbott, Adrenomed, Amgen, Applied Therapeutics, Array, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, G3 Pharma, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Roche, Sequana Medical, and Vifor. DZIC reports institutional grant funding from Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca, CSL-Behring, and Novo Nordisk; and consultancy fees and honorarium from Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi-Tanabe, AbbVie, Janssen, Bayer, Prometic, Bristol Myers Squibb, Maze, Gilead, CSL-Behring, Otsuka, Novartis, Youngene, Lexicon, and Novo Nordisk. JBG reports institutional grant funding from Boehringer Ingelheim-Lilly, Merck, Roche, and Sanofi and Lexicon; and consultancy fees from Boehringer Ingelheim-Lilly, Bayer, AstraZeneca, Sanofi and Lexicon, Hawthorne Effect and Omada, Pfizer, Valo, Anji, Vertex, and Novo Nordisk. C-CL is an employee of Merck Sharp & Dohme (a subsidiary of Merck & Co) and owns stock and/or stock options in Merck & Co. FRMcC reports grant funding from NIDDK, Satellite Healthcare, Advanced Medical, and Fifth Eye; and consultancy fees from GlaxoSmithKline, Advanced Medical, and Zydus Therapeutics. DKMcG reports consultancy fees from Merck & Co, Applied Therapeutics, Metavant, Sanofi, Afimmune, Lilly USA, Boehringer Ingelheim, Novo Nordisk, Bayer, GlaxoSmithKline, Lexicon, Altimmune, and Esperion; and other honorarium from Kirkland & Ellis, Pfizer, GlaxoSmithKline, Janssen, Afimmune, Sanofi, Boehringer Ingelheim, Merck & Co, AstraZeneca, Novo Nordisk, Esperion, and Lilly USA. JJVMcM reports institutional grant funding from AstraZeneca; consultancy fees from Abbott, Alkem Metabolics, Eris Lifesciences, Hikma, Lupin, Sun Pharmaceuticals, Heart.Org (Medscape Cardiology), ProAdWise Communications, Radcliffe Cardiology, Servier, and The Corpus; and fees paid to his institution for other advisory roles by Cytokinetics, Amgen, AstraZeneca, Theracos, Ionis Pharmaceuticals, DalCor, Cardurion, Novartis, GlaxoSmithKline, Bayer, KBP Biosciences, Boehringer Ingelheim, and Bristol Myers Squibb. MP reports personal fees from AbbVie, Actavis, Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Imara, Lilly, Moderna, Novartis, Reata, Relypsa, and Salamandra. VP reports consultancy fees, honorarium, or advisory roles supported by AbbVie, Bayer, Boehringer Ingelheim, Chinook, GlaxoSmithKline, Janssen, Pfizer, AstraZeneca, Baxter, Eli Lilly, Gilead, Merck, Mitsubishi Tanabe, Mundipharma, Novartis, Novo Nordisk, Otsuka, Retrophin, Roche, Sanofi, Servier, and Vitae. MSS reports institutional grant funding from Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Daiichi-Sankyo, Eisai, Intarcia, Ionis, Medicines Company, MedImmune, Merck, Novartis, Pfizer, and Quark Pharmaceuticals; and consultancy fees from Althera, Amgen, Anthos Therapeutics, AstraZeneca, Beren Therapeutics, Bristol Myers Squibb, and DalCor. SDS reports institutional grant funding from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, the National Heart, Lung, and Blood Institute , Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; and consultancy fees from Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Puretech Health. MV reports grant funding or advisory board fees from Amgen, AstraZeneca, American Regent, Baxter HealthCare, Bayer, Boehringer Ingelheim, Cytokinetics, Pharmacosmos, Relypsa, Novartis, Roche Diagnostics, Lexicon Pharmaceuticals, Galmed, Occlutech, Impulse Dynamics, Sanofi, and Tricog Health; speaker fees from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics; and actively participates on clinical trial committees for studies sponsored by Galmed, Novartis, Bayer, Occlutech, and Impulse Dynamics. CW reports institutional grant funding from Boehringer Ingelheim; and consultancy fees and honorarium from Boehringer Ingelheim, AstraZeneca, Merck Sharp & Dohme, and Bayer. SDW reports institutional grant funding from Abbott, Amgen, Anthos Therapeutics, ARCA Biopharma, AstraZeneca, Bayer HealthCare Pharmaceuticals, Daiichi-Sankyo, Eisai, Intarcia, Ionis Pharmaceuticals, Janssen Research and Development, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals, Roche, Siemens Healthcare Diagnostics, Softcell Medical, The Medicines Company, and Zora Biosciences; and consultancy fees from AstraZeneca, Boston Clinical Research Institute, Icon Clinical, and Novo Nordisk. FZ reports consultancy fees from Amgen, Applied therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cardior, Cereno Scientific, CEVA, Cellprothera, CVRx, Novartis, Novo Nordisk, Servier, Merck, Bristol Myers Squibb; and honorarium or other personal fees from Boehringer Ingelheim, Merck, Bayer, Vifor, Fresenius, Roche Diagnostics, Hogan and Lovells, and Acceleron. HJLH reports grant funding from AstraZeneca, Boehringer Ingelheim, Janssen, and Novo Nordisk; consultancy fees from AstraZeneca, AbbVie, Bayer, Boehringer Ingelheim, CSL Behring, Chinook, Dimerix, Eli Lilly, Gilead, Goldfinch Bio, Merck, Novartis, Novo Nordisk, Janssen, and Travere Therapeutics; and other payment or honorarium from AstraZeneca, Novo Nordisk, and Eli Lilly. MJL additionally reports institutional grant funding from Novartis and Janssen; and trial drug supply from Roche and Regeneron."}
+{"text": "For more than thirty years, methods and theories from evolutionary biology, phylogenetics, population genetics and molecular biology have been used by conservation biologists to better understand threats to endangered species due to anthropogenic changes. Commonly described as Conservation Genetics, the scope of research has included investigating effects of habitat fragmentation and over-harvesting on small populations, barriers to natural gene flow, uncertainty about units of conservation due to unresolved taxonomies and cryptic species, illegal and commercial trade in wildlife, and molecular ecology of threatened populations and species .Genes on \u201cConservation Genetics and Genomics\u201d features 14 original research articles harnessing the data collection and analytical approaches of population genomics, phylogenomics, and metagenomics to address questions of conservation concern. Traditional approaches using neutral genetic markers now take advantage of vastly expanded data sets of single nucleotide polymorphisms (SNPs) discovered in a variety of ways, including using restriction site-associated DNA sequencing (RAD Seq) and reference genome mining [Advances in genomic tools, along with demonstration of their applicability to non-invasive sampling approaches often necessary for at-risk species, have greatly expanded the purview and value of this field of study . This spe mining . Whole-ge mining ,6. Likewe mining ,8. In ote mining . Expandee mining ,11,12. Ie mining ,14,15. Ie mining . As exti"}
+{"text": "Francisella tularensis, human immunodeficiency virus-1 (HIV-1),Toxoplasma gondii, Variola virus, andYersinia pestis. Results confirm that heptapeptide overlap is high between pathogens andHomo sapiens, but not between pathogens and primates. Data are discussed in light of the possible genetic bases that differently model primate phenomes, thus possibly underlying the zero/low level of molecular mimicry between infectious agents and primates. Notably, this study might help address preclinical vaccine tests that currently utilize primates as animal models, since autoimmune cross-reactions and the consequent adverse events cannot occurin absentiaof shared sequences.Recently, it was found that proteomes from poliovirus, measles virus, dengue virus, and severe acute respiratory syndrome-related Coronavirus 2 (SARS-CoV-2) have high molecular mimicry at the heptapeptide level with the human proteome, while heptapeptide commonality is minimal or absent with proteomes from nonhuman primates, that is, gorilla, chimpanzee, and rhesus macaque. To acquire more data on the issue, analyses here have been expanded to Ebola virus, Beginning in 2000, a high, unexpected level of molecular mimicry between microbial and human proteins has been repeatedly documented; accordingly, the consequent potential cross-reactivity following infections or active immunizations has been highlighted.As a matter of fact, pathogen-derived immunoreactive epitopes are mostly composed of peptide sequences present in human proteins,par excellence,namely, rhesus macaque (Macaca mulatta), which is a nonhuman primate phylogenetically close to humans.However, as recently underlined,primum movensof autoimmune pathologies via cross-reactivity, then different levels of peptide sharing with pathogens should characterize the proteomes of humans and primates.De facto, comparative amino acid (aa) sequence analyses documented that poliovirus, measles virus, dengue virus, and SARS-CoV-2 share peptide sequences almost exclusively with the human and murine proteomes, but not with primate proteomes.in absentiaof molecular mimicry.Therefore, it was hypothesized that if the peptide sharing between pathogens and humans is theYersinia pestisIn this research frame, the present study expands comparative sequence analyses to additional pathogens that, although thoroughly investigated, still remain without safe and efficacious therapies, for example,http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi): membrane protein/O-antigen protein fromFrancisella tularensis, 409 aa (177416); apical membrane antigen 1-like protein fromToxoplasma gondii, 651 aa (432359); surface antigen S from variola virus, 354 aa (587200); virulence-associated V antigen fromYersinia pestis, 326 aa (632); proteome from Ebola virus, 5494 aa (128952); proteome from HIV-1, 3134 aa (11676).Molecular mimicry analyses were conducted by using heptapeptides as immunobiological units. The analyzed pathogen proteins/proteomes are as follows (with NCBI TaxId in parentheses and further details atwww.uniprot.org/proteomes).Homo sapiens(9606); gorilla,Gorilla gorilla gorilla(9595); chimpanzee,Pan troglodytes(9598); and rhesus macaque,Macaca mulatta(9544). In addition, proteomes from the following mammalian organisms were analyzed as controls: cow,Bos taurus(9913); dog,Canis lupus familiaris(9615); cat,Felis catus(9685); rabbit,Oryctolagus cuniculus(9986); mouse,Mus musculus(10090); rat,Rattus norvegicus(10116); pig,Sus scrofa(9823); and bat,Pteropus alecto(9402).The primary aa sequences of the pathogen proteins/proteomes were dissected into heptapeptides offset by one residue, that is, MIRAYEQ, IRAYEQN, RAYEQNP, and so on. Then, each pathogen heptapeptide was analyzed for occurrences within mammalian reference proteomes, that is, proteomes that have been selected because they cover well-studied model organisms and other organisms of interest for biomedical research and phylogeny F. tularensis,T, gondii, variola virus, andY. pestis, respectively, and two pathogen proteomes, namely, Ebola virus proteome, and HIV-1 proteome for heptapeptide sharing with the mammalian proteomes described under Methods. The heptapeptide sharing is quantitatively reported inWe analyzed four protein antigens derived frommn/N, wheremis the number of heptapeptides present in the first protein,nis the number of heptapeptides present in the second protein, and N is 20mandn<< N, the probability of sharing only one heptapeptide is 0.00000000078125, that is infinitesimal.As a preliminary observation, it is noteworthy, as already underscored elsewhere,Then,On the whole, the data exposed into say that efficacy trials of HIV vaccines and microbicides have, to date, been disappointing is something of an understatement.\u201d Today, in 2020, Thomas' observation is still valid and the promised effective vaccine that had to cure HIV has not yet been found,Thus,Recently, it was shown that heptapeptides from poliovirus, measles virus, dengue virus, and SARS-CoV-2 occur in the human proteome, but not in proteomes from primates and domestic animals.F. tularensis,T. gondii, variola virus,Y. pestis, Ebola virus, and HIV-1, and the human proteome. Such high molecular mimicry is practically absent when proteomes from primates, domestic animals, and cattle are analyzed. Hence, this study might explain not only the wave of autoimmune diseases that are increasingly burdening the human population worldwide,The present study confirms such previous dataAlso, it has to be considered that the present data underestimate the cross-reactivity potential by two orders of magnitude. Indeed, if one considers that a minimal immune determinant corresponds to five aa residues,In light of these additional caveats and of the consequent higher cross-reactivity risk, it appears to be mandatory to investigate the molecular mechanisms that underlie the different extents of molecular mimicry between pathogens and mammals. Possible objects of investigation might be, for example, alterations of gene transcription/translation potentially involved in the different shaping of human and primate genomes/phenomes.In this regard, studies by Puente et alIn addition, segmental duplications in the genome and transposable elements are important sources of genetic/phenetic differences between humans and primates. Segmental duplications are blocks of highly homologous duplicated sequences that define hotspots of chromosomal rearrangement and act as mediators of normal variation as well as genomic diseases.In sum, it is not surprising that primates are not good models for many major human diseases/conditionsFinally, as a conclusive note, it appears pertinent to recall the basic concept first stated in 2000"}
+{"text": "Dear Editor:Emergency response in a natural disaster causing evacuation, transportation, and mass gathering in the affected areas may contrast prevention strategies in the COVID-19 pandemic, including physical distancing and home isolation. We haveAs seen in the early cases of COVID-19 potentially associated with the seafood market where seafood, bats, marmots, and snakes were available, the food system has challenges for bioactive ingredients, food safety and security, and sustainability. The traThe Asia-Pacific region is vulnerable to natural disasters partially due to climate change, seismic activities, and human development. After t"}
+{"text": "Simia Nanodes Lichtenstein, 1791 is a senior synonym of Simia Moloch Audebert, 1797, otherwise regarded as the oldest binomen applicable to the Javan gibbon. However, since Simia Nanodes failed to enter common usage, these names are subject to a reversal of precedence as defined by Article 23.9 of the International Code of Zoological Nomenclature. Simia Moloch Audebert, 1797 must be maintained as a nomen protectum, resulting in Hylobates moloch  staying the valid name of the species. Simia Nanodes Lichtenstein, 1791 is declared a nomen oblitum. In compliance with this, I provide a complete scientific synonymy of the Javan gibbon and comment on its early research history.Over the course of their long research history, a plethora of scientific names have been applied to the different species of apes (Hominoidea). Although numerous authors, past and present, have attempted to reconstruct hominoid nomenclatural history in detail, it appears that parts of it, mostly concerning the lesser apes or gibbons, still remain overlooked. Here I show that The online version of this article (10.1007/s10329-020-00822-5) contains supplementary material, which is available to authorized users. The history of primate research and nomenclature is the subject of ongoing scientific discussion, with that of apes (Hominoidea) being of particular concern. In the case of great apes (Hominidae) this interest continues to regularly spawn new monographs , the white-handed or lar gibbon), the first small ape known to science , and was released by the publishing house of Benjamin Gottlob Hoffmann. Therein, Lichtenstein , he doubted that they knew about the existence of the Javanese species. Nowadays, it is assumed that ancient Western authors did not have any notion of gibbons in general (Groves The first author who referenced the rockhaus\u00a0), several Groves .Simia Nanodes:Lichtenstein  added thEcaudis, natibus calvis, brachiis longitudine corporis, capite obovato, facie nigra triangulari, serie pilorum ex albo cinereorum circumdata. Simia Nanodes he provided:Still, he pointed at the possibility that Javan and lar gibbon might at some point be identified as representatives of one morphologically variable species. The description was not accompanied by an illustration. As a locality for Habitat in India, praefertim in Java. .wouwou\u201d and \u201cwauwau\u201d (the latter being the Germanized spelling of the former) are non-scientific terms referring to this species and cites a German translation ).Lichtenstein was a philologist interested in the conceptional history of primatology rather than a zoologist , which could be the reason why his naming of the Javan gibbon remained undetected by the contemporary authorities on primates. It was, however, cited and in parts commented on by several German-speaking authors, most noteworthy Ludwig ,\u00a0who incUnaffected by the reversal of precedence, the name-bearing type of the Javan gibbon remains a mounted specimen preserved at the Mus\u00e9um National d\u2019Histoire Naturelle in Paris . It wasHylobates moloch  as well as Javan gibbons into H. moloch, the taxonomic histories of which had long been intertwined .Simia Leucisca Schreber, Pit.[Pithecus] cinereus: Latreille, Simia hirsuta Forster, mentioned in Sonnerat, Nomen nudum. ? Pithecus leuciscus: Geoffroy Saint-Hilaire, S.[Satyrus] Leuciscus: Oken, Hylobates leuciscus: Kuhl, Hylobates leuciscus Matschie, Hylobates muelleri abbotti).Cheiron Leuciscus: Burnett, 1829:307. New name combination.H.[Hybolates] Leusiscus Geoffroy Saint-Hilaire, Hylobates leuciscus Kuhl, H.[Hylobates] leucurus Gray, Hylobates leuciscus Kuhl, Hylobates javanicus Matschie, Hylobates lar leuciscus: Pocock, Hylobates cinereus cinereus: Kloss, Hylobates moloch: Frechkop, Hylobates moloch moloch: Chasen, Hylobates lar moloch: Sody, Hylobates lar pongoalsoni Sody, H. moloch pongoalsoni) .Supplementary file1 (DOCX 15 kb)Below is the link to the electronic supplementary material."}
+{"text": "Alphaherpesvirinae and Gammaherpesvirinae subfamilies. To date, gammaherpesviruses have not been reported in the central nervous system of odontocetes.Herpesvirus infections in cetaceans have always been attributed to the Stenella coeruleoalba) occurred in Cantabria (Spain) on 18th May 2019. Tissue samples were collected and tested for herpesvirus using nested polymerase chain reaction (PCR), and for cetacean morbillivirus using reverse transcription-PCR. Cetacean morbillivirus was not detected in any of the animals, while gammaherpesvirus was detected in nine male and one female dolphins. Three of these males were coinfected by alphaherpesviruses. Alphaherpesvirus sequences were detected in the cerebrum, spinal cord and tracheobronchial lymph node, while gammaherpesvirus sequences were detected in the cerebrum, cerebellum, spinal cord, pharyngeal tonsils, mesenteric lymph node, tracheobronchial lymph node, lung, skin and penile mucosa. Macroscopic and histopathological post-mortem examinations did not unveil the potential cause of the mass stranding event or any evidence of severe infectious disease in the dolphins. The only observed lesions that may be associated with herpesvirus were three cases of balanitis and one penile papilloma.A mass stranding of 14 striped dolphins (To the authors\u2019 knowledge, this is the first report of gammaherpesvirus infection in the central nervous system of odontocete cetaceans. This raises new questions for future studies about how gammaherpesviruses reach the central nervous system and how infection manifests clinically. Herpesviruses contain a linear, double-stranded DNA genome 125\u2013290 kpb) within an icosahedral capsid, surrounded by a protein matrix tegument and a lipid bilayer with membrane-associated proteins 5\u2013290 kpb.Herpesviridae family, which consists of three subfamilies: Alpha-, Beta-, and Gammaherpesvirinae [Alpha- and/or Gammaherpesvirinae have been identified in eight cetacean families: Delphinidae, Kogiidae, Ziphiidae, Physeteridae, Monodontidae, Phocoenidae, Iniidae (odontocetes), and Balaenopteridae (mysticetes) [Herpesvirus belongs to the svirinae . Herpesvsvirinae . So far,ticetes) \u201311. Cetaticetes) .Herpesvirus infections in cetaceans have been associated with pathological processes such as systemic infections , 13, 14,Alpha- and Gammaherpesvirinae were identified in 11 striped dolphins  in a mass stranding of 14 dolphins in Cantabria (Spain). Using molecular techniques, gammaherpesvirus were detected in ten dolphins , and in four of them  the central nervous system was infected. Alphaherperpesvirus were also detected in four striped dolphins . To our knowledge, this study is the first to detect gammaherpesvirus in the central nervous system of odontocetes.In this study, different strains of On 18th May 2019, 14 striped dolphins were found stranded in Oyambre Beach, Cantabria, Spain . Ten dolphins were found dead, three died during the rescue intervention, and one was euthanized by veterinary staff for humanitarian reasons. The dolphin carcasses were kept refrigerated for up to four days until necropsies could be performed. Detailed necropsies of all animals were carried out as described , 29.Dorsoventral pectoral x-rays were taken in left flipper of all individuals using a conventional veterinary x-ray equipment  and 70kVp and 6.4mAs exposition setting following Barratclough et al. 2019 . PhysiolAnisakis spp.)   and balanitis was reported also in three animals . However, the most common lesion observed during the necropsies was moderate to severe congestion of the cerebrum and cerebellum  Fig.\u00a0a, and heDuring the necropsies, the following tissues were sampled: skin, blubber, muscle, rete mirabile, pharyngeal tonsils, thyroid, thymus, lymph nodes , lung, heart, stomach, intestine, liver, pancreas, spleen, adrenal gland, kidney, urinary bladder, ovary/testicle, uterus, penis, mammary gland, cerebrum, cerebellum, and spinal cord. From one of the pregnant females umbilical cord and placenta samples were also collected and from both amniotic fluid and foetus blood. Two sets of tissue samples were collected from each dolphin: the first set was preserved in 10% neutral buffered formalin and used for conventional histopathology, while the second set was stored at \u2212\u200980\u00a0\u00b0C and used for virology analysis.The histopathological findings are summarized in Table\u00a0Toxoplasma spp. were not observed in any of the animals. Tissue sections from most animals showed minimal inflammation, which was not associated with visible infectious agents or notable tissue damage.Minimal lymphoplasmacytic nonspecific encephalitis was observed in nine animals, while mild lymphoplasmacytic and histiocytic meningitis was detected in one dolphin Fig.\u00a0f and g. Most lymphoid organs were reactive Fig.\u00a0h, and thDuring the virology analysis, tissue samples were evaluated for the presence of herpesvirus and cetacean morbillivirus (CeMV). Standard precautions were taken during all laboratory procedures in order to avoid cross-contamination of samples. All samples were diluted 1:10 with phosphate-buffered saline (PBS) and homogenized using stainless steel 4.8-mm beads . DNA from the homogenates was extracted using the High Pure Template Preparation Kit , and total RNA was extracted using the High Pure Viral Nucleic Acid Kit (Roche Diagnostics), based on the manufacturer\u2019s instructions.Phocoena phocoena) cerebrum. The agarose bands were purified using the QIAquick\u00ae Gel Extraction Kit , and 212-bp amplicons were sequenced completely by Sanger sequencing. The results of the molecular analysis and the herpesvirus sequence accession numbers are provided in Table\u00a0A molecular diagnosis of the herpesvirus was carried out based on a previously described pan-herpesvirus nested PCR targeting the DNApol gene . This asDNA sequencing confirmed the presence of herpesvirus in 11 of the 14 striped dolphins (78.57%). Eight novel sequences were identified and deposited in GenBank under accession numbers MN698989 , MN698992 , MN698995 , MN699002 , MN699008 , MN699009  and MT770740 . Sequences with accession numbers MN698990 , MN698991 , MN698993 , MN698994 , MN698996 , MN698997 , MN698998 , MN698999 , MN69900 , MN699001 , MN699003 , MN699004 , MN699005  and MN699006  were identical to MN698995. Sequence with accession number MN699007  was identical to the previously described sequence KJ156332 of a herpesvirus from a striped dolphin from Canary Islands [The herpesvirus nucleotide and deduced amino acid sequences were analyzed phylogenetically using the maximum likelihood method in MEGA X software  Figs.\u00a033 and 4. Alphaherpesvirinae subfamily, while sequences MN698989, MN698990, MN698991, MN698992, MN698993, MN698994, MN698995, MN698996, MN698997, MN698998, MN698999, MN699000, MN699001, MN699002, MN699003, MN699004, MN699005, MN699006, MT770740, MT770741, MT770742, MT770743, MT770744, MT770745, MT770746, MT770747, MT770748, MT770749, MT770750 and MT770751 belong to the Gammaherpesvirinae subfamily  from Florida, USA (AY757301) [Stenella frontalis) from Sao Francisco do Sul, Brazil (MF999155) [Grampus griseus) from a striped dolphin from the Valencian Community coast, Spain (KP995683) (unpublished) .The phylogenetic analysis revealed that sequences MN699007, MN699008, MN699009 and MT770752 belong to the F999155)  (nucleotRNA extracted from tissues targeted by CeMV were assayed for the virus using a reverse transcription-PCR method that targets the fusion protein gene and is based on the Universal Probe Library platform . These tAdditionally, DNA extracts from four skin lesions were tested for Poxvirus by conventional PCR . UltrapuHistopathology and PCR were used to assess the effect of herpesvirus infections on 14 striped dolphins from the Cantabrian Sea stranded on a beach in Cantabria, Spain. Several cetacean mass stranding causes have been proposed, and include: receding tides, navigational errors, geomagnetic disturbances, disturbance of echolocation, following prey inshore, escaping from predators, disease in one or more individuals in a social group, algal toxins or meteorological events . The cauGammaherpesvirus has been associated with skin and genital lesions in cetaceans , 18\u201321. However, some neurotropism has also been suggested in human gammaherpesviruses \u201350. ThusAnother aspect to consider was the lack of lesions caused or potentially associated with a herpesviral infection apart from the three cases of balanitis. Tissue reaction and inflammation associated with the presence of the virus could help elucidate the route or the pathologic relevance of the infection. The minimal lymphoplasmacytic inflammation within the central nervous system in nine of the animals was nonspecific, and could not be associated with any specific agent, and it was not severe enough to trigger clinical manifestations. Findings thus support the hypothesis that virus was causing subclinical infection at the least, at the time of death.Alphaherpesvirinae and Gammaherpesvirinae, have been detected in skin and genitals from cetaceans [Both subfamilies, etaceans , 18\u201325, etaceans . To our etaceans , 48 and etaceans  suggesti"}
+{"text": "Ingestion of toxic alcohols other than ethanol  can cause life-threatening complications including altered level of consciousness, respiratory depression, and organ damage from metabolites. Many hospitals lack the ability to specifically analyze these compounds using gas chromatography, gas chromatography/mass spectrometry, or by enzymatic assays for ethylene glycol. Consequently, the presence of these compounds in blood is often ascertained indirectly by laboratory testing for acid-base status, osmolal gap, and anion gap. In the related research article, we analyzed 260 samples originating from 158 unique patients that had osmolal gap and specific testing for toxic alcohols performed on serum/plasma at an academic medical center central clinical laboratory. The data in this article provide the patient demographic, osmolal gap , ethanol concentration by enzymatic assay, specific testing for toxic alcohols  and acetone, anion gap, clinical history, antidotal treatment, and estimated timing of ingestion. The analyzed data is provided in the supplementary tables included in this article. Bias plots of osmolal gap estimations are included in a figure. The dataset reported is related to the research article entitled \u201cCorrelation of Osmolal Gap with Measured Concentrations of Acetone, Ethylene Glycol, Isopropanol, Methanol, and Propylene Glycol in Patients at an Academic Medical Center\u201d [1]. \u2022The osmolal gap estimated from measured concentrations of toxic alcohols tends to underestimate the traditional osmolal gap.\u2022Elevated anion gaps are common in patients ingesting ethylene glycol, isopropanol, and methanol.\u2022Activated charcoal administration was a common cause of propylene glycol detected in serum/plasma. Many cl2Serum/plasma blood urea nitrogen, electrolytes, ethanol by enzymatic assay, and ethylene glycol by enzymatic assay were determined on Roche Diagnostics chemistry analyzers. Serum/plasma osmolality was determined on an osmometer by freezing point depression. Specific analysis of acetone, ethanol, ethylene glycol, isopropanol, methanol, and propylene glycol was achieved using GC, with a lower limit of quantitation of 10 mg/dL. Enzymatic assay analysis for ethylene glycol was available in the hospital clinical laboratory starting in October 2010 ,12. Epic"}
+{"text": "In \u201cIncorporating Breast Cancer Recurrence Events Into Population-Based Cancer Registries Using Medical Claims: Cohort Study\" :e18143) the authors noted two errors.The metadata erroneously listed only Teresa A'mar and Ruth Etzioni as having contributed equally; this has been corrected to reflect that Teresa A'mar, Jessica Chubak, and Ruth Etzioni contributed equally.In addition, Jessica Chubak's affiliation was originally listed as:Washington Health Research Institute, Kaiser Permanente, Seattle, WA, United StatesThis affiliation has been corrected to:Kaiser Permanente Washington Health Research Institute, Seattle, WA, United StatesThe correction will appear in the online version of the paper on the JMIR website on September 24, 2020, toegether with the publication of this correction notice. Because this was made after submission to PubMed, PubMed Central, and other full-text repositories, the corrected article has also been submitted to those repositories."}
+{"text": "An estimated 49,000 women and children who lived in the Islamic State are being held in the Al-Hol refugee camp in Syria. Several countries have repatriated some of these women and children, though most have thus far refused to do so. Many countries are asking whether it is possible to successfully rehabilitate and reintegrate this group and how the evidence base could inform their approach.The overall objective of this paper is to inform the rehabilitation and reintegration of child returnees from the Islamic State by rapidly reviewing the evidence on children exposed to trauma and adversity.A rapid review was conducted to identify pertinent evidence regarding outcomes, risk and protective factors, and interventions and to build a framework that could guide policies and practices. Prior work in the areas of refugee children, war-impacted children, child criminal gang members, child victims of maltreatment, and child victims of sex trafficking was reviewed. Evidence was collected and analyzed from 31 prior reviews and studies.The Rehabilitation and Reintegration Intervention Framework (RRIF) incorporates five levels  and identifies five primary goals: 1) promoting individual mental health and well-being; 2) promoting family support; 3) promoting educational success; 4) promoting community support; and 5) improving structural conditions and protecting public safety. Implementing this framework requires public-private partnership with extensive civil society involvement.Rehabilitation and reintegration programs should be based on the evidence of prior work with children exposed to trauma and adversity. RRIF defines a multi-level approach that encompasses promoting individual mental health and well-being, family support, educational success, community support, structural conditions, and public safety. Further multi-disciplinary research is needed to develop evidence in several identified areas concerning child health and developmental problems, family custody, faith and religiosity, and violent extremism assessment and prevention. The Islamic State (IS) terrorist organization orchestrated a calculated recruitment strategy that drew nearly 30,000 men and women from countries all over the world . Many of2In the Syrian Al-Hol refugee camp, there are nearly 49,000 children who have been refused by their home communities and confined to abysmal conditions . Many coThus far, a relatively small number of children and mothers have been repatriated to their countries. The United States has accepted only about a dozen returnees . KazakhsThere is a shortage of international good practices and frameworks to guide rehabilitation and reintegration of child returnees . As a reExisting literature in the clinical, community, and social sciences has examined children and their families who have been impacted by a number of different traumatic and adverse situations. These include: refugee children, war-impacted children, child criminal gang members, child victims of maltreatment, and child victims of sex trafficking. None of these other groups are exactly the same as the children who are returning from the IS, but nonetheless there are important similarities, as described below.outcomes ; risk factors ; protective factors (multi-level characteristics that reduce a risk factor\u2019s adverse impact); and evidence-based practices .In reviewing the literature, we first identified how the research articles typically define the following key components: The overall objective of this paper is to inform the rehabilitation and reintegration of child returnees from the Islamic State by rapidly reviewing the evidence on children exposed to trauma and adversity.We conducted a rapid review of the literature on refugee children, war-impacted children, child soldiers, child criminal gang members, child victims of maltreatment, and child victims of sex trafficking. These six areas were chosen because each area had adequate scientific literature and because children\u2019s exposure to trauma and adversity in each area overlapped significantly with that of child returnees from the IS, as represented in Table Rapid reviews are a way of gathering evidence to inform policy and program decision making by streamlining the methods of a systematic literature review . CompareIn order to assess the relevant literature, PubMed and EBSCO were searched for English-language articles using the following keywords in various combinations: refugees, war-impacted, child soldiers, terrorism, criminal gangs, maltreatment, sex trafficking, risk factors, protective factors, and research. The reference sections of these articles were also examined to identify additional relevant articles. Given the first author\u2019s extensive prior work on this topic, files from past searches were examined and relevant articles included. The authors acknowledge that despite extensive literature searches, some relevant articles may have been omitted. A total of 73 articles or chapters were reviewed for possible inclusion, of which a total of 31 were chosen, including 14 reviews.From a preliminary review of the entire database of articles, we first identified three key questions that could apply to each of the above groups: 1) How are positive outcomes defined? 2) What are the multi-level  risk and protective factors associated with positive outcomes? 3) What evidence-based, best, or emerging practices are being used? Further, a comprehensive table and summary narratives were developed to answer each of these questions in each of the five areas of literature reviewed.In order to build the framework, lists of potentially modifiable outcomes, risk and protective factors, and practices were grouped into the following five levels of goals: 1) promoting individual mental health and well-being; 2) promoting family support; 3) promoting educational success; 4) promoting community support; and 5) improving structural conditions and protecting public safety. The findings were further refined into an overall framework called the Rehabilitation and Reintegration Intervention Framework (RRIF), which identified the risk and protective factors at each of the five levels, associated levers of community resilience, and policy and program priorities.The results of the rapid review are summarized in Table Positive outcomes for refugee children were defined as an absence of psychological difficulties and adverse mental health outcomes.The studies identified eleven risk factors for refugee children at multiple levels (as indicated in parentheses): exposure to violence, chronic illness, behavioral issues, developmental disorders, strenuous immigration policies, housing issues, and acculturative stress such as language barriers ; family conflict and trauma, family separation, and poor parental health (family level); stigmatization and discrimination, including bullying and racism, and high crime rates (community level) 101113141516.131415We identified ten protective factors for refugee children that could similarly be organized by socio-ecological levels: positive self-esteem, social flexibility, forgiveness, perception of self-control, perception of retributive justice and spirituality/religiosity ; family cohesion and adaptability, strong parental health, and higher household socioeconomic status (family level); strong social support networks, community acceptance, education, presence of religious leaders, and safe environments (community level) 101113141516.131415Helpful clinical, educational, and community-based interventions were identified as follows, with attention to the socio-ecological levels at which an intervention is delivered: cognitive behavior therapy (CBT), narrative exposure therapy (NET), testimony psychotherapy, psycho-educational group therapy, eye movement desensitization and reprocessing therapy, creative therapy ; family therapy, parent-child focused therapy (family level); school sensitization, robust anti-bullying policies (school level); cultural and spiritual celebrations and programs, and community sensitization (community level); and housing, training, and employment programs  12131516.121315War-impacted children included child soldiers and other children impacted by warfare and extremism in their countries. For example, one study focused on children in Afghanistan exposed to extremism and prolonged conflict  and anotPositive outcomes for war-impacted children were an absence of psychopathy, symptom reduction, and increased prosocial behaviors.We identified thirteen risk factors for war-impacted children at multiple levels: chronic exposure to violence, vengefulness, presence of a physical or mental disability ; economic hardship, maltreatment, family separation (family level); stigmatization and humiliation, lack of work for mothers and other adult family members, acculturation stressors, overcrowding, inequitable access to facilities, and the lack of environmental safety (community level) 1820212223.202122We identified sixteen protective factors for war-impacted children at multiple levels: sense of humor, empathy, positive self-esteem, social intelligence, temperament, and optimism ; a safe home environment, strong family roles and values, unity, and family acceptance and support (family level); social support, education, community acceptance/awareness, institutional support, political participation, and religious and cultural affiliations (community level) 18192022232425.222324Helpful intervention strategies included CBT, NET, trauma group psychotherapy, dance and movement therapy ; parent-child interaction therapy (family level); teacher sensitization and trauma-informed education (school); community resilience and sensitization, anti-discrimination campaigns, medical care and health worker sensitization (community level) 181921222324.212223While this rapid review is concerned with children, the literature on criminal gang members includes both children and adults. Positive outcomes for former gang members were desistance from gang-related activities and increased prosocial behavior. For example, Gormally analyzed the factors that promoted desistance from youth gang behaviors in Glasgow, such as maturation .We identified six risk factors for former criminal gang members at multiple levels: commitment to delinquent peers, fear of gang retaliation, lack of education and employment ; family disorganization and discord including child maltreatment (family level); stigmatization, lack of access to quality education and employment (community level) 28293031.282930We identified nine protective factors for former criminal gang members at multiple levels: maturation, disillusionment ; healthy family relationships and responsibilities (family level); access to education, meaningful employment, resettlement, spirituality/religiosity, strong network of support and encouragement (community level) 2729303132.293031Helpful intervention strategies included psychosocial treatment, peer mentoring, community and criminal justice-supported desistance, resettlement, education, training, and employment programs 293132. H2931Positive outcomes for child victims of maltreatment were an absence of psychopathy, increased social functioning, and fewer long-term negative outcomes.We identified eight risk factors for child victims of maltreatment at multiple levels: substance abuse and earlier instances of maltreatment ; parental rejection and economic hardship (family level); stigmatization, discrimination, lack of access to care, community violence, poor education, and social isolation (community level) 34353637.343536We identified seventeen protective factors for child victims of maltreatment at multiple levels: externalizing blame, emotional intelligence, and life satisfaction ; consistent parental employment, less unilateral parent decision-making, family cohesion, positive parenting practices, emotional attachment to a family member, and high SES (family level); access to care and social services, perceived social support, strong friendships, mentors outside the family, school attendance and safety, positive school experiences, adequate housing, spirituality/religiosity, and participation in leisure activities (community level) 3335363738.353637Helpful intervention strategies included trauma-focused CBT, educational engagement, health promotion initiatives, and resilience programming that espouses a broad network of support to facilitate interpersonal trust 3438. For34Positive outcomes for sex trafficking victims were a recovery from trauma and improved health outcomes.We identified eleven risk factors for sex trafficking victims at multiple levels: substance abuse, shame, dissociation and detachment, attachment to traffickers, and early separation from caregivers ; conflictual family relationships and family punishments (family level); stigmatization, discrimination, social isolation, forced involvement in the criminal justice process, and poverty (community level) 4041. For40We identified ten protective factors for sex trafficking victims at multiple levels: personal growth and strong identity ; strong family relationships (family level); community support, structure, and safety, employment and financial stability, adequate housing, education, spirituality/religiosity, and cultural identity (community level) 4041. Abu40Helpful intervention strategies include trauma-focused CBT, individual counseling, group trauma therapy, rights-based care, creative therapies, language, and culturally appropriate services, and medical care ; housing, job training, employment, public awareness campaigns, and legislation (community level) 394041. F3940Based upon the evidence from the 31 prior reviews and studies, and also informed by our field experience with in several countries rehabilitation and reintegration programs, we built the Rehabilitation and Reintegration Intervention Framework (RRIF). It consists of five distinct levels  promoting individual mental health and well-being; 2) promoting family support; 3) promoting educational success; 4) promoting community support; and 5) improving structural conditions and protecting public safety. Note: the proportionality of this figure is not intended to convey that the larger, lower levels of the model are more important.Then, we sorted the risk and protective factors identified through the review into those five levels Figure  below. RThen, we drew upon the evidence-based practices from the review to determine the overall policy goals for each level. These goals optimize risk and protective factors so as to achieve the best outcomes for child returnees Figure  below. Ilevers of community resilience [Finally, the RRIF also identifies how each of the goals corresponds to the known silience   health and developmental problems in children due, for example, to illness, injury, or malnutrition 4345; 2) 43454648424550Rehabilitation and reintegration programs should be based on evidence of prior work with children exposed to trauma and adversity. RRIF defines a multi-level approach that encompasses promoting individual mental health and well-being, family support, educational success, community support, structural conditions and public safety.The new framework can be compared to existing models of working with war-impacted communities, such as the IASC Guidelines or the WHO Service Organization Pyramid 53. Thesewellness, access, family resilience, education, partnership, engagement, equity, and safety. To facilitate buy-in and sustainability, this approach should also consider encompassing other threats, risks, and resources that the community identifies. In addition, exclusively focusing new services and supports on child returnees while neglecting other children\u2019s needs could unintentionally create resentment and fuel stigma.Rehabilitation and reintegration programs should encompass building resilience to violent extremism through activities that enhance the levers of The framework developed through this rapid review can only be implemented through public-private partnership with intensive civil society involvement and multidisciplinary collaboration. Notably, the security-focused goal requires the leadership of security agencies but should also involve community policing approaches and the active, appropriate participation of civil society partners such as learning how to do violence risk assessments. This implies that security and civil society organizations and practitioners need to find additional ways to share information, cooperate, and collaborate. To successfully implement community-based programs that provide multilevel and multidimensional support to child returnees will require multiple actors from multiple sectors working collaboratively.It is worth noting that most research included as the basis for this review was conducted in the U.S. or other high-income countries in the West. As such, issues of relevancy and adaptability will be important to consider when developing programming for returnees to low- and middle-income countries with diverse sociocultural contexts.In many countries, especially low- and middle-income countries, efforts are needed to build the capacity of leadership and practitioners in government and civil society. Areas of need include locally focused training on: 1) trauma-informed mental health care; 2) developmental assessment and support; 3) specialized educational programs for children with educational difficulties or special needs; 4) violence extremism risk assessment and prevention; and 5) building community and family resilience.Further research is needed to support rehabilitation and reintegration programs involving child returnees from the IS. That research should embody a rigorous longitudinal design to investigate the process and impact of rehabilitation and reintegration activities. It is especially important to build evidence in the gaps outlined above concerning health and developmental problems, family custody, faith and religion, and violent extremism assessment and prevention. To do so will require multidisciplinary research collaborations, combining clinical, community, security, and social sciences expertise."}
+{"text": "The first two authors, Seid Legesse and Tefera Alemu, should be noted as contributing equally to this work.The third, fourth, and fifth authors, Mulugeta Tassew, Birtukan Shiferaw, and Semagn Amare, should be noted as having also contributed equally to this work."}
+{"text": "Recently, the development of nanotechnology has bloomed in numerous industries. In this regard, graphene, a two-dimensional carbon nanomaterial, has been extensively researched, due to its high academic interests and commercial potential. Due to its unique structure and outstanding material properties, the research on graphene has enabled substantial progress in the development of electronics devices, thermoelectric appliances, optical devices, sensors, and energy harvesting applications. In addition, the mechanical properties, such as young modulus 1TPa), intrinsic strength (130 GPa), high stiffness, and fracture strain, make graphene a promising candidate for industries like nanocomposite coatings, paints, and bioapplications TPa, intr. This spGraphene shows numerous novel and inimitable physical properties, such as the anomalous quantum hall effect, the ambipolar electric field effect, Klein tunneling, and ballistic transport, due to its exclusive crystal and electronic structure. However, the band gap characteristics of graphene limits its applications and commercial interests. The properties of graphene can be tuned by altering its nanostructure in terms of boundary configuration, structural defects, chemical doping, and the formation of heterogeneous structures to meet the demands of the electronic, photo thermal, thermoelectric and photoelectric fields . High enThe special issue is completed with review papers ,3,8,9, w\u201cElectronic and Thermal Properties of Graphene\u201d compiles a series of original research articles and recent review papers to provide depth information on the development of graphene based next generation devices. We hope that this special issue will provide an interesting insight into the latest perspectives in this rapidly evolving industry.In summary, this special issue of nanomaterials entitled"}
+{"text": "Environmental health in subway stations, a typical type of urban underground space, is becoming increasingly important. Ventilation is the principal measure for optimizing the complex physical environment in a subway station. This paper narratively reviews the environmental and health effects of subway ventilation and discusses the relevant engineering, environmental, and medical aspects in combination. Ventilation exerts a notable dual effect on environmental health in a subway station. On the one hand, ventilation controls temperature, humidity, and indoor air quality to ensure human comfort and health. On the other hand, ventilation also carries the potential risks of spreading air pollutants or fire smoke through the complex wind environment as well as produces continuous noise. Assessment and management of health risks associated with subway ventilation is essential to attain a healthy subway environment. This, however, requires exposure, threshold data, and thereby necessitates more research into long-term effects, and toxicity as well as epidemiological studies. Additionally, more research is needed to further examine the design and maintenance of ventilation systems. An understanding of the pathogenic mechanisms and aerodynamic characteristics of various pollutants can help formulate ventilation strategies to reduce pollutant concentrations. Moreover, current comprehensive underground space development affords a possibility for creating flexible spaces that optimize ventilation efficiency, acoustic comfort, and space perception. Subways, a typical type of urban underground space (UUS), are the most commonly used mode of public transportation, and are gradually becoming an indispensable component of large cities. With rapid urban development, transit-oriented developments (TODs) and are gradually becoming a new urban model ,2,3,4. SSafety and environmental health in subways has become increasingly important and attracted attention from numerous researchers in recent decades. However, the lack of long-term-effect research and limited detection technology may lead to the neglect of the environmental health effects of subways. Health effects and pathogenesis are complex due to interactions of risk factors, such as additive, synergistic, or cumulative reactions . TherefoA subway space is usually isolated from the atmospheric environment, and its hermetic nature may lead to heat and moisture accumulation. Various sources of pollution can result in the accumulation, breeding, and transmission of harmful substances. Additionally, complex ambient airflows referred to as \u201csubway climate\u201d, affects the dispersion of air pollutants, fire smoke, and biological or chemical agents ,20,21. TWhat environmental factors are affected by ventilation systems in subway stations?How do these environmental factors affect human health?How can ventilation improve environmental health in subway stations?In this paper, we have attempted to answer three crucial questions: Because of the wide range of environmental and health effects, it was not feasible to conduct a single systematic review. This narrative review used the following search terms \u201cunderground space\u201d, \u201csubsurface space\u201d, \u201csubway\u201d, \u201cmetro\u201d, \u201ctube\u201d, \u201cunderground railway\u201d, together with \u201chealth\u201d, \u201cwell-being\u201d, \u201chealth impact\u201d, \u201chealth effect\u201d, \u201chealth risk\u201d, \u201chealth implication\u201d, \u201cexposure assessment\u201d, and as well as \u201cventilation\u201d, \u201cfiltration\u201d, \u201cpurification\u201d, \u201cwind environment\u201d, \u201cairflow\u201d, \u201cair quality\u201d, \u201csick building syndrome (SBS)\u201d, and \u201cbuilding-related illness (BRI)\u201d. The search literature databases include PubMed, Medline (Ovid), Science Direct, Scopus, Google Scholar, and through websites including the Associated Research Centers for the Urban Underground Space (ACUUS), the World Health Organization (WHO), and various government websites including construction, environment, and health ministries since 1980 to 2019. As this was not a systematic but narrative review, no formal validity/quality, risk of bias assessments were done, and no exclusion criteria were applied. Through literature retrieval and analysis, the review framework expanded to other effects not previously considered, like \u201cfire evacuation\u201d and \u201cnoise.\u201d There has been a limited review of the health effects due to poor ventilation for both aboveground or underground buildings. Sepp\u00e4nen and Fisk reviewed human responses to ventilation on aboveground buildings but mainly focused on epidemiological statistics of responses and diseases . SundellThe structure of this paper is based on the above aspects and results. In Due to the limited connection with the atmospheric environment, natural ventilation is not only unable to meet the strict subway ventilation requirements but also disrupts indoor airflow. Mechanical ventilation is a reliable measure for optimizing the thermal environment and IAQ. A subway ventilation system is composed of multiple systems that cooperate and coordinate with each other, including heating, ventilating, and air conditioning (HVAC) systems and platform screen doors (PSDs). Intelligent ventilation systems are capable of adjusting their mode of operation based on external and internal conditions and thereby ensure a comfortable, healthy, thermal environment and IAQ in subway stations. The failure of a subway ventilation system to adjust the physical environment in a timely and effective manner will incur a number of health effects, which will be discussed in the following sections.The thermal environment in subways significantly affects human comfort and health, as well as related environmental factors such as IAQ, airflow, and sound transmission. The water vapor condensation, humidity radiation, and indoor air pollution lead to high temperature and humidity in a subway environment. Exposure to heat and cold has extensive effects on almost every body system, including the cardiovascular, digestive, endocrine, immune, skin, muscular, nervous, reproductive, respiratory, skeletal, urinary, and auditory systems ,31,32.Any impairment of thermoregulation may increase the risks of heat-related diseases . The theOn the contrary, a subway environment is not too cold, because it has good thermal stability and various heat sources. Nevertheless, improper ventilation may cause a cold environment or alternate heat and cold. The human body is more sensitive to cold stimuli than to warm . On the 2 concentrations increased to 12,000 ppm at an RH of 85% [Humidity directly affects passengers\u2019 environmental perception and exerts potential risks to human health. On the one hand, high humidity can cause discomfort, especially when the relative humidity (RH) is above 70% ,48. SignH of 85% . FurtherH of 85% ,52,53,54H of 85% ,56. On tH of 85% ,59,60,61H of 85%  and incrH of 85% . BecauseH of 85% ,63.On the contrary, low humidity affects perceived air quality (PAQ), sensory irritations, work performance, and virus survival . The perHVAC systems can effectively adjust the thermal environment of subway stations. However, identifying environmental indices that ensure human health remains a challenge. Evaluation standards for thermal environment include three categories, of survival, comfort, and efficiency. There are several evaluation indices such as teq , ET (effective temperature), ET*, SET* (standard effective temperature), HIS (heat stress index), WBGT (wet bulb globe temperature index), and PMV (predicted mean vote). The PMV-PPD (predicted percentage dissatisfied) evaluation system, included in ISO  7730 . In the Rational designs of entrances and shafts can prevent outdoor rain, moisture, and cold air from entering subway stations. To be more specific, first, entrances and shafts should be kept away from underground water, streets, and close to urban air corridors and wind directions, so that air pollutants or heat can be removed quickly from aboveground surroundings. Next, roof, barricade, air curtain, and green wall can prevent rainwater and cold wind from entering the station. Then, increasing length, section, and area of entrance channel, and installing an HVAC system obviously buffer inside and outside temperature differences. Finally, plane shapes of entrance channels, such as linear, broken linear, or L-shaped, can be designed according to the demand of using piston wind. Additionally, controlling water seepage and accumulation in tunnels reduces the sources of humidity and air pollutants. Similarly, controlling the water sourced from station toilets, cleaning rooms, and equipment improves the thermal conditions and IAQ. Furthermore, the condensate water of the air-conditioning system is still a problem, which produces mold and other microbes. Conventional air-conditioning systems share a cold source and simultaneously cools and dehumidifies the air to remove heat and moisture. Because of the temperature difference between cooling (below the air) and dehumidification (below the dew point), conventional systems increase energy waste and condensate water, because they can only accurately control one parameter of temperature or humidity and hence, cause an uncomfortable sensation of \u201ctoo cold\u201d or \u201cstuffy\u201d. Temperature and humidity independent control systems can address this problem and adjust flexibly for different subway zones ,78. In t2, NO2, and O3. Instead of establishing a logic for health risk control, these reviews focused on certain aspects of health effects. This paper clarifies a path of air pollutants from generation to impact to reduction. Sources and compositions are the basis of controlling pollutant generations and studying their toxicities. Although relevant studies aboveground have certain reference significances, studies specialized in subway pollutants are more conducive to formulate environmental indices for risk control.Confined subway spaces tend to accumulate air pollutants generated from indoor or outdoor ,80,81,82PMs are the most concerned research object of air pollutants in subways. Subway PMs\u2019 sources are from both outdoor and indoor: (1) aboveground atmosphere and surrounding environment, and (2) underground tunnels, stations, facilities, and passengers. The compositions and characteristics of subway PMs are mainly determined by indoor sources, including mechanical wear, material degradation, tunnel dust, and human activities like cleaning. Wheel and brake pads, steel rails, and power supply materials give the particles a peculiarly metalliferous character. Subway PM concentrations are directly affected by frequency of train, commuter influx, ventilation system, surrounding air, soil resuspension, construction year, station depth, and other pollutant concentrations ,108,109.PMs of different sizes can reach different human organs and exert specific health effects . SmallerStudies on pathological and toxicological responses of the human body provide a quantitative basis. Nevertheless, research on cell damage and the health effects of specific physical properties or chemical compositions of subway particles are still insufficient ,149. InhSubway environments expose passengers to a high level of VOCs, particularly during rush-hours. Subways account for 10%\u201320% of daily VOC exposure . The lonSubway VOCs have complex sources of indoor emissions and outdoor infiltrations ,179,180.VOCs affect the human body through inhalation, ingestion, and dermal sorption ,186. ExpBioaerosols refer to aerosols containing biological particles, such as bacteria, fungi, viruses, and parasite eggs, and have infectivity, pathogenicity, and allergenicity. Subways are high-risk places for microbial growth and propagation due to various sources, thermal environment, limited ventilation, and crowded population ,191,192.Sources and compositions of microbes are affected by various factors such as humans, soil, water, outdoor air, location, depth, and building materials ,201,202.Bioaerosol concentrations have strong time dependence and condition dependence. On the one hand, bioaerosol emissions during peak hours are much higher than those during off-peak hours ,204,208,Pathogenic mechanisms of microbes are similar even in different environments. Crowded passengers increase microbial sources and deteriorate physical environments in subways. Increases in indoor temperature, humidity, and carbon dioxide indirectly promote microbial growth. Besides, crowded environments enhance antibiotic resistance and pathogen transmissions ,197. The2, NO2, and other air compositions rapidly accumulate in subway stations and carriages due to confined spaces, huge populations, and various sources. CO usually remains at a relatively low level because fossil fuels and smoking are prohibited [2, its concentrations closely correlate with passenger numbers. When CO2 concentration exceeds 1000 ppm, occupants may complain about headaches, nose and throat ailments, tiredness, lack of concentration, and fatigue [Other air compositions in subways also exert potential risks on passengers. CO, COohibited , but CO ohibited . When it fatigue ,217,218. fatigue ,221,222.In short, mitigation measures for IAQ aim at reducing pollutant concentrations and can be summarized into three aspects: (1) preventing external infiltration, (2) limiting internal sources, and (3) eliminating or diluting pollutants.2, and VOCs, (3) photocatalysts to VOCs and microbes, (4) negative ion to PMs, bacteria, and fungi, (5) ultraviolet to bacteria and fungi, and (6) plasma to PMs, VOCs, bacteria, and viruses [Firstly, air exchanges with ambient atmosphere may bring harmful substances into subways such as PMs, VOCs, microbes, allergens, moisture, and waste heat. Hence, aboveground ventilation shafts and entrances should be designed away from pollution sources. Furthermore, efficient filtrations are essential to prevent pollutant infiltrations. Filtration systems affect not only fresh air quality but also heat exchange rates of subway ventilation . On the  viruses ,231,232. viruses .Secondly, various internal sources are more challenging in confined subways. Pollutants from passengers are difficult to control, and toilets, cleaning rooms, dustbins, and facilities are inevitable subway operations. Hence, mitigations mainly depend on controlling pollutant transmissions and cleaner materials. On the one hand, early ventilation designs depend on simple fresh air systems and winds driven by thermal pressure and train motion that bring polluted airflows from tunnels to whole stations. Hence, unreasonable ventilations become a source of exposure, which is discussed in detail in the next chapter. Zonal controls, air curtains, and PSDs have been installed to prevent polluted airflows from flowing into passenger zones. On the other hand, preventing emissions of harmful substances can radically reduce environmental risks. Applying liquid dust suppressants to new ballasts, prohibiting diesel-powered trains or facilities, building along a straight, horizontal trajectory, designing a variable longitudinal profile railway, and slowing trains at sharp curves and high gradients may minimize wears of rail, wheels, and brakes, and then reduce metallic PM emissions. Besides, developments of materials that emit fewer and less toxic particles are a positive way forward ,235,236.Thirdly, although adsorption and sterilization devices can gradually eliminate some pollutants, they cannot meet the instantaneous huge demand in the subway which accommodates a large number of passengers. Hence, exhausting or diluting air pollutants through sufficient air exchanges and flexible ventilation strategies dominates IAQ controls of subways. Displacement ventilations are efficient air exchange means widely used to reduce indoor pollutants. They supply fresh air at very low-velocity levels at or near the floor level and then rise, driven by thermal stratifications, to bring pollutants to the surface, which allows pollutants to leave breathing areas and be removed more easily . MeanwhiWhile optimizing the physical environment, a subway ventilation system also carries potential health risks that cannot be overlooked, such as transmission of air pollutants and generation of uncomfortable draft sensations. A subway is a whole network with its own climatic conditions, which significantly affect the ambient airflow and pollutant transmission. Air pollutants can originate from a myriad of sources, including the external atmosphere, underground tunnels, cleaning chemicals, and equipment, and may spread throughout subway stations. To adjust the complex wind environment, flexible design and efficient operation of comprehensive mechanical ventilation and environmental control systems are required. However, ventilation systems that are in continuous operation and under heavy loads are more prone to pollution by PMs and microbes. The hygiene of ventilation systems is always a problem. It has been found that indoor microbe pollution is closely associated with poor ventilation system hygiene. Several mitigation measures have been proposed, including regular cleaning of baffle plates and filters, the use of cooling systems, and, particularly, strictly controlling temperature and humidity in subway stations ,238,239.Wind environments in subways are affected by mechanical ventilation, outside winds, buoyancy-driven airflows, train-induced winds (piston winds), or a combination of the above factors. The airflows that spread air pollutants from one space to another may cause IAQ problems in multiple indoor areas. Airflows from various pollutant sources inside and outside subways all bring air pollutants into subway stations. Airflows generated by passengers and trains cause resuspensions of settled pollutants . These aUnlike aboveground office and residential buildings, subways only have several ventilation vents or station exits with limited sizes for air exchanges. High ventilation rates and frequent facility utilizations require ventilation systems to keep their cleanliness and efficiency to ensure abundant clean air entering subways. Furthermore, some recent energy-saving studies propose to utilize piston winds through train movement ,243,244 Fire evacuation is another serious potential risk associated with subway ventilations. Ventilations and smoke exhausts should not only exhaust smoke efficiently but also ensure the separation of humans and smoke because fire smokes have high temperatures and immediate risks to humans. On the one hand, fire smokes include several toxic gases, especially CO. CO can quickly cause dyspnea and poisoning symptoms. A high-density smoke also reduces the visibility of evacuees ,247,248.Firstly, \u201csubway climatology\u201d was defined by Pflitsch in the late 1990s, which referred to natural airflows caused by temperature differences between subways and outer atmospheres. Because temperatures inside subways are generally higher than those outside from the late summer to winter, penetrating cold airs and rising warm airs at subway openings to external atmospheres drive natural airflow in tunnels. Therefore, such climates significantly affect dispersions of airborne substances ,253. ForSecondly, piston winds affect human health through IAQ, thermal comfort, and draft sensation. Piston winds are generated by vehicle motion and blow through whole stations. Piston winds force a large number of air pollutants or cold air into subway stations because their speeds significantly exceed the design values of ventilation systems . Hence, Thirdly, without mechanical ventilation and piston wind, stack effects dominate airflows to move towards stairwells, elevator shafts, and ventilation shafts, and may spread fire smokes throughout subway stations. Preliminary designs of subway spaces and environmental controls decide the performance of stack effects. Under the same condition, areas and locations of shafts usually predominate airflows, and areas are more dominant than locations . FurtherMitigations of wind environments in subways are comprehensive systems, which require coordinated operations of multiple systems. Firstly, zonal control is the most feasible for complex thermal and wind environments in subways. Especially at transfer stations or multilevel stations, zonal control can meet various ventilation requirements to maintain a consistent indoor environment. Secondly, using and limiting piston winds are difficult problems to maintain environmental health in subways. Thirdly, air supplies closely correlate with draft sensations and ventilation efficiencies, which are common problems in subways. Fourthly, mechanical smoke exhaust should ensure safe evacuations of passengers in emergency situations such as fire or a biological attack. Lastly, dynamic ventilation systems can adjust ventilation strategies to stable subway environments and energy conservations through computer technology and real-time monitoring. Corresponding mitigation measures of the above five aspects are analyzed in detail below.Firstly, zonal environmental controls and personalized ventilation systems can limit the spread of air pollutants to a certain extent and maintain a unified comfort level. In general, there are three zones in subways: station hall, platform, and tunnel. Each area is composed of multiple functional areas or rooms. In terms of health risk, platforms almost isolate from the outside atmosphere and are the most complex subway zones, which are directly affected by polluted airs from station halls and tunnels. Platforms gather numerous passengers and intractable pollution sources like toilets, cleaning rooms, and machine rooms ,215. IncSecondly, air curtains and PSDs are major devices to control piston winds. On the one hand, air curtains can effectively control unsteady airflows to improve ventilation efficiencies, ensure comfortable draft sensations, and reduce energy consumptions ,255,275.Thirdly, velocities, temperatures, and locations of air supplies directly affect environmental health and human health. The vertical temperature gradient presents a significant variation in subway stations . Deep anFourthly, mechanical exhaust systems can ensure passengers\u2019 safety in case of fires or biochemical attacks. On the one hand, due to the flexibility and reliability, hybrid exhaust systems are more suitable for subway environments. Integrated utilization of mechanical and natural ventilation effectively inhibit fire smoke dispersions and decrease toxic substance concentrations . Smoke eLastly, subway IAQs significantly change in real-time due to various time-dependent factors such as subway schedules, passenger loads, and outdoor climates. . For quiNoise generated by ventilation systems constitutes a limited part of subway noise but lasts the longest. Long-term exposure to environmental noise can have a number of health effects ,310. TheNoises have adverse effects on psychological, biological, immunological, and endocrine systems . BecauseReduction measures for subway noise can be classified into four categories: source mitigations of tracks, such as braking mechanisms, ventilation machines , sound iSubways have gradually become the most used UUS for urban residents on a daily basis. Therefore, it is important to pay attention to exposure risks associated with subway microenvironments and establish their control standards, evaluation systems, and mitigation toolbox . HoweverThrough a narrative literature review, a distinguishing feature of subway ventilation was uncovered in this study, that is, subway ventilation exerts a dual effect, as both a mitigation measure and a source of exposure. The accumulation of heat, moisture, and air pollutants inside a subway station dictates the health level of its environment in normal time. Deterioration of the thermal environment can cause adverse responses in almost every body system, and then increase disease incidence. Temperature and humidity also exert indirect health effects by affecting other environmental factors such as PAQ, microbial pollution, and pressure difference. When it comes to IAQ in subways, PMs, VOCs, and bioaerosols are sources of exposure of the most concern. Metallic PM and the resulting oxidation potentials are viewed as representative risks that affect environmental health in subways and have been extensively analyzed through pathological studies and simulations. Health risks of VOCs, which are carcinogenic and genetically toxic, may be underestimated due to their complex sources, delayed effects, and insufficient toxicity studies. Humid environments and ventilation systems provide conditions for the growth and spread of microbes and bioaerosols. These problems can be addressed using efficient ventilation. However, ventilation is a double-edged sword, due to the lack of a source of totally clean air in subways. First, natural airflows caused by pressure difference and piston wind may bring polluted air or fire smoke throughout the subway station and thereby worsen IAQ. Then, the humid condition, huge load, continuous operation, and fixed installation all render it difficult to maintain a clean ventilation system. Moreover, high-speed air supply causes uncomfortable draft sensations that may affect passengers\u2019 integumentary, respiratory, and cardiovascular systems. Finally, noise will be amplified in the closed subway space. Continuous noise generated by ventilation systems should be minimized. Overall, ventilation exerts not only direct effects on human health and comfort but also indirect effects by affecting other environmental factors. Notwithstanding, ventilation is an indispensable measure for controlling the indoor environment in a subway station. Hence, it requires a more comprehensive design, flexible adjustment, and continuous maintenance.Further research is required to study some problems related to environmental health in subways. In terms of medicine and epidemiology, the exposure threshold, disability-adjusted life year (DALY), acceptable daily intake (ADI), and other indices are controversial on some risks. The correlations and differences between experiments in vitro and in vivo complicate the formulation of these indices. It is, therefore, necessary to take into consideration whether there are environmental influences or interactions between pathogenic factors when studying pathogenic mechanisms and exposure thresholds. Long-term epidemiological surveys may be more reliable than toxicity tests. Furthermore, life cycle impact assessment models require further improvement to comprehensively assess the health effects and not only use physicochemical and toxicological properties but also other relevant parameters combined with environmental characteristics, such as the USEtox method . More spBased on reliable exposure thresholds and maximum acceptable concentrations, environmental health indices can be used to control health risks more effectively. A number of countries and organizations have published health-based environmental control guidelines or standards, as shown in Ventilation not only significantly affects the thermal and humid environment in a subway station but also plays a vital role in air pollutant transmission and air pollutant-related infection. On the one hand, integrated and intelligent ventilation systems can improve IAQ and conserve energy in subway stations ,243,244.Another potential problem is various interactions between different ventilation strategies. On the one hand, ventilation measures described in the previous paragraph inevitably result in an inconsistent environment in a subway station characterized by variable conditions  as well as dirty \u201cdead zone\u201d and uncomfortable draft sensations. Therefore, subway ventilations need comprehensive design and flexible adjustment through real-time monitoring, demand forecasting, timely feedback, and other dynamic ventilation strategies. On the other hand, synergistic or inhibitory interactions exist in different ventilation strategies, which echoes the dual effect of subway ventilation. Large air volume can effectively discharge air pollutants and improve IAQ, but also reduce efficiencies of cooling or heating systems, affecting the thermal comfort of passengers. Meanwhile, the ventilation strategy of using piston wind to exhaust heat can cause draft sensations, especially in narrow spaces, and cause the spread of air pollutants to whole stations. Among these interactions, a significant problem is some defects of ventilation paths and space design in traditional subway stations. Therefore, it is necessary to emphasize the impact of space design on environmental health in subway stations. Arguably, a rational space design is the basis for efficient ventilation. Adverse effects of unreasonable subway spaces are hardly compensated by traditional ventilation-based design patterns of environmental control systems. Compared with ventilation systems, spatial connection and airflow movement dominate the spreading of airflow movement and thermal comfort in subway stations, which is a basic problem more or less neglected by previous studies and engineering design. Meanwhile, spatial acoustic design, to a certain extent, affects subway noise control. The subway environment is significantly affected by its interior space factors, including shape, size, material, connection and separation of spaces, and the number, location, and size of vertical shafts, stairs, and exits. In architectural and interior design, there are often some spaces or components that block smoke movement and exhaustion . For exaThis study clarifies the complex relationship between ventilation and human health in subway stations from the perspectives of pathology, epidemiology, engineering, and built environment. Recommend exposure thresholds or values from medical and epidemiological studies that offer a basis for health risk assessment and environmental control are discussed. Health risk assessments of subways should further integrate specific toxicology research of subway pollutants, long-term epidemiological data, and environmental characteristics of subways. Based on these data, engineering measures can be implemented to effectively improve environmental health in subway stations. In short, ventilation exerts a notable dual effect on environmental health in subway stations. Ventilation, on the one hand, is a dispensable measure for optimizing the physical environment in a subway station and, on the other hand, can potentially negatively affect its wind and acoustic environment. Wind environments are more complex in subway stations than in aboveground buildings due to various pollution sources, limited ventilation inlets/outlets, and strong background airflows caused by piston wind and subway climate. Ventilation systems in subway stations not only should introduce clean, fresh air and dilute and/or discharge air pollutants, but also should be controlled zonally and adjusted in real-time. It is necessary to simulate and analyze the effects of variable airflow combined with the aerodynamic behavior of various air pollutants. Additionally, space optimization, as the basis of efficient ventilation, has not received enough attention in the past due to limited construction technologies and immature professional cooperation. Unreasonable space connections and ventilation paths may cause a series of adverse effects and contradictions, which are hardly compensated by ventilation systems and devices. In the traditional design pattern of a subway environment, space precedes ventilation, and ventilation remedies space, which should be replaced by a more comprehensive design pattern. The coupling relationship between space and ventilation should be considered at an early stage, and the organization strategy of internal and external airflow should be determined according to regional climate and environmental conditions."}
+{"text": "Despite increasing attention to the social determinants of health in recent decades, globally there is an unprecedented burden from non-communicable diseases (NCDs). Recently, the corporate and commercial conditions associated with these, commercial determinants of health (CDoH), have also begun to receive attention. This research aims to articulate the CDoH as described in the literature, summarize substantive findings, and assess strengths and limitations of current literature.Systematic review of formal  and grey literature . Searching identified 125 texts for full-text review, with 33 included for final review. Data extracted were analyzed thematically.The dynamics constituting CDoH include broad facilitators such as globalization of trade, corporate structures, and regulatory systems, articulation of social and economic power, neoliberal and capitalist ideologies; additional elements include corporate activities such as marketing, corporate political activities, corporate social responsibility, extensive supply chains, harmful products and production, and issues of accessibility. These contribute significantly to worsened global health outcomes.Literature describing effects of macro conditions and corporate activities on health could usefully utilize CDoH terminology. Facilitation via revised, consistent and operational definition of CDoH would assist. Social, political, commercial and economic structures and relations of CDoH are under-theorized. Systematic approaches to identifying, describing, and disrupting these are required to improve global health. Recently, research addressing social determinants of health (SDoH), following formative work by Marmot and colleagues , has focNCDs are often termed \u2018lifestyle diseases\u2019 given their origins in behaviors including diet, physical inactivity, alcohol use, and tobacco use , 5. HoweArticulate how CDoH, and the prevention or minimization of harm associated with these, have been described in the literature;Summarize substantive findings from identified research; and,Assess the strengths and limitations of identified literature.Despite increasing references to CDoH in the literature, to date, no systematic synthesis of the CDoH literature base has been produced. This review seeks to address this and distil the current CDoH evidence base. This systematic review aims to:The working CDoH definition guiding initial stages of this review was that proposed by Kickbusch, Allen and Franz: \u201cstrategies and approaches used by the private sector to promote products and choices that are detrimental to health\u201d .This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement . No protOriginal studies, reviews, commentaries, editorials, discussion papers, books and book chapters, reports, web articles and resources from government and non-government organizations, and conceptual works were included, where they met inclusion criteria. Other works such as newspaper and online news articles, presentations or speeches, and social media posts were excluded. Data could be qualitative, quantitative, or mixed-method.Papers naming CDoH directly, and/or describing similar concepts such as \u2018corporate determinants\u2019 or corporations and associated practices as social determinants of disease, ill-health, or NCDs were included. Whilst there is an expanse of literature that could be categorized as CDoH, including literature that does not name the CDoH or associated terms explicitly, this review sought a narrower framing to focus in literature self-identified as pertaining to CDoH.The search strategy was fivefold and developed with the assistance of two specialist librarians. First, Medline (Ovid), EMBASE (Ovid), Scopus, and Global Health databases were searched. Second, grey literature databases, including Community Guides (CDC), National Institute for Health and Care Excellence, Centre for Reviews Dissemination (University of York), and Health Evidence (Canada) were searched. Third, further grey literature searching was conducted using Google Advanced Searches consistent with systematic grey literature searching approaches described elsewhere , 22. FouAn iterative approach and preliminary search testing indicated appropriate search terms. A keyword search was adopted to capture the relevant CDoH literature .mp AND (determinant*.mp) AND .mp). Databases were searched 15 May 2018, and all results were exported, duplicates removed, and screened using EndNote X8 software. Grey literature searches were conducted in June 2018, with results screened online, and relevant full-texts imported to EndNote. Consistent with previous studies the first 100 results for web searches were screened . CitatioTitles and abstracts were screened for all search results. Where abstracts were not available, executive summaries and/or tables of contents were used. Literature was excluded where it: was not published in English; included data and/or findings relating to non-humans; presented modelling, clinical and/or laboratory findings without examining underlying determinants; or, presented descriptive findings from population-level disease or risk behavior surveillance and/or public health or health promotion interventions without examining underlying determinants. We included literature that provided a definition and/or description of CDoH, either naming these directly, or describing these indirectly as underlying determinants of health and/or disease as described previously.Following screening, full texts were retrieved, with literature excluded where full texts were unavailable. Full texts were independently reviewed by two reviewers, and tabulated by one reviewer. Discrepancies were resolved via consultation between reviewers. Literature failing to meet inclusion criteria was excluded. Data extracted included author(s), date, title, publisher/source, type of publication, type of evidence provided, underpinning theories and/or frameworks used to frame analysis, and CDoH terms used . Two organizational web articles, a book chapter, a conference paper, a magazine editorial, a United Nations (UN) meeting report, a World Health Organization (WHO) report, and an organizational policy statement were included  only twEight texts framed analysis through theory and/or frameworks. Two included theoretical descriptions of power. Hastings  used de Kickbusch et al.  presenten\u2009=\u200919) texts provided no definition. Three prominent definitions were identified.No widely accepted CDoH definition was apparent. Most  , CSR, extensive and highly integrated supply chains, products and production detrimental to health, and the accessibility of such products.Marketing and advertising of unhealthy commodities were widely described as harming health , 31, 37 Corporations reportedly continue to spend significantly on marketing , 16, allComprehensive regulation was described as the only strategy likely to effectively reduce the effects associated with marketing , 27, 40.CPA was described variously. Lobbying was regarded as a prominent barrier to healthy public policy, and often used to oppose policies beneficial to public health at the expense of corporate profits , 39, 42.Litigation, or threatening litigation, was another tactic described as being used against governments seeking to implement policies that might reduce industry profits , 33, 42.Arguments about infringements of personal choice and freedom of speech , 34, 40 Other CPAs described included lucrative \u2018revolving door\u2019 arrangements shuffling individuals between government and commercial sectors, and political donations. Further, participation in government agencies, commissions, committees, and partnerships, pressures on international trade arrangements, and illegal activities were also discussed , 38, 39.CSR is reportedly used to deflect attention from questionable practices, \u2018whitewash tarnished reputations\u2019 , 26, 35,Product formulation and production processes reportedly have significant impacts on health , 31, 36.The extensive and highly integrated supply chains of modern companies were seen as amplifying influence globally , 40, 43.To achieve elevated profits, corporations may externalize costs  to avoid capturing the true aggregate \u2018cost\u2019 of their products , 34, 43.Downstream consequences of CDoH were consistently described as premature death and disability associated with NCDs and chronic diseases including \u2018industrial epidemics\u2019 and \u2018profit driven\u2019 epidemics , 37, 40.Harms to population health were described as outcomes of \u2018toxic\u2019 environments. Kickbusch et al.  argued tThese environments were said to lead to malnutrition, stunting, overweight, obesity, and diabetes within the same populations . EmerginConsequences for physical environments and planetary health associated production and trade included land clearing, lost biodiversity, air pollution, respiratory and cardiovascular diseases, and labor practices including child labor and inadequate maternity protections , and polCDoH literature most often referenced the food industry. However, the tobacco and alcohol industries were also frequently described. Pharmaceutical, automotive, firearms, mining and gambling industries were discussed to a lesser extent (see Table\u00a0Tobacco industry discussions often referenced the WHO Framework Convention on Tobacco Control (FCTC), comparing it with other industries. Kickbusch  emphasizAuthors described a \u2018hierarchy\u2019 of harmful industries, where tobacco is portrayed as the \u2018worst\u2019 industry, whilst others were \u2018not as bad\u2019. Kickbusch  and IrelSome argued that practitioners should view tobacco, alcohol and processed food industries as equivalents, noting unfavorable outcomes associated with alcohol and obesity as \u201coften in a magnitude comparable to that of tobacco\u201d and health-related costs as similar and \u201cperhaps highest for obesity, rather than for tobacco\u201d .\u201cWHO\u2019s institutional commitment to preventing and managing conflicts of interest with industry is unambiguous, but the scope of the challenge in relation to commercial determinants of NCDs may be impossible to govern\u201d.Thus, WHO\u2019s financial insecurity may be seen as possibly encouraging some forms of industry engagement, despite their stance on tobacco.Others highlighted the distinction between industries within WHO. Buse et al.  assert tAuthors appraised existing efforts to address CDoH as inadequate. Buse et al.  noted \u201cWThe need for collaboration beyond single health issues , 18, 31 Whilst much of the rights discussion focused on corporate legal and commercial rights, including trade, intellectual property, freedom of speech, and limited liability rights, some supported a reorientation towards human rights and social justice in order to achieve sustainable population health and wellbeing , 36, 43.CDoH are described as underpinning many global health challenges. The CDoH literature ties together macro-level conditions such as economic and political systems, globalization, trade, power dynamics, corporate structures including rights and responsibilities, and regulatory and accountability approaches, with lower-level activities, structures and relations of corporations and related industry groups. However, much of this literature lacks specificity.No CDoH definition has been consistently applied in the literature. Many authors fail to provide any definition, seemingly assuming some implicit understanding of CDoH. The apparent discord between three definitions identified, whereby West and Marteau  emphasizFurther, the CDoH term is not consistently applied. Some texts refer to corporations as elements of SDoH , 25 or dMany activities, such as marketing , 48, 49,Whilst CDoH outcomes are mostly described as harms, Millar  proposedThis review documents the macro-level conditions, relations, structures and activities, and consequences constituting CDoH as described in the CDoH literature. That is, literature self-identified as describing CDoH and associated concepts. Given the nascent nature of the CDoH literature, this review provides a timely synthesis of the current state of understanding.Some limitations apply to this review. The narrow searching frame may have meant that some literature pertaining to peripheral CDoH concepts may not have been captured in this review. Further, the working definition adopted for initial planning may present a potential limitation .Reviewed literature was limited to that published in English only. As such, perspectives from high-income countries frame much of the literature. However, material reviewed also discusses implications for low- and middle-income countries, including understanding and concern for the flow of commercial influences into these countries , 34, 38.There are some inherent limitations to grey literature searching given the volume of results and the \u2018filter bubble\u2019, generated by search engines that tailor results to individual search histories and preferences. However, the inclusion of grey literature allowed for a more comprehensive review.CDoH present an emerging, yet relatively underdeveloped, area of academic interest and concern. There is limited capacity to synthesize substantive findings, as these are not yet developed in the CDoH-specific literature. So far, the literature has largely focused on describing, rather than addressing, harm. As such, approaches to preventing the harms associated with CDoH are largely hypothetical, with some important exclusions including tobacco control efforts. It is anticipated that the literature base will continue to expand over coming years, with future work beginning to explore this further in the context of CDoH specifically.The CDoH field is of increasing social and public health relevance. Whilst the literature base is in its infancy, it has begun to illustrate the multiple elements constituting CDoH, groups most affected, and resulting diminished population health outcomes. Overall, there is a need for greater specificity in the CDoH literature. As there is no widely accepted CDoH definition in use, evolution of this may be pertinent. Further, CDoH language should be more widely adopted to describe corporate influences on health and mechanisms reinforcing these globally, to better recognize these as significant contributors to global disease. In order to reduce NCDs and improve population wellbeing globally, systematic approaches to identifying, describing, and where necessary disrupting the complex conditions constituting CDoH are needed.Additional file 1. Search strategies. Complete commercial determinants of health search strategies from database and grey literature searches."}
+{"text": "There exist significant race disparities in the prevalence of dementia, with black persons with dementia (PWD) showing higher co-morbidity and more frequent hospitalizations, yet little is known how clinical presentations compare. This study compared physical function, delirium, depressive symptoms, and behavioral and psychological symptoms of distress (BPSD) in black and white PWDs when hospitalized. A multivariate analysis of covariance showed that, controlling for age, gender, cognitive status, and comorbidities, black PWD had more delirium  as compared to white PWDs . Additionally, black PWD had more depressive symptoms  as compared to white PWD , and less improvement in functional status admission to discharge  as compared to white PWD . There were no differences in BPSD. Continued research examining factors influencing differences in race cohorts is warranted."}
+{"text": "The global emergence of zoonotic viruses, including poxviruses, poses one of the greatest threats to human and animal health. Forty years after the eradication of smallpox, emerging zoonotic orthopoxviruses, such as monkeypox, cowpox, and vaccinia viruses continue to infect humans as well as wild and domestic animals. Currently, the geographical distribution of poxviruses in a broad range of hosts worldwide raises concerns regarding the possibility of outbreaks or viral dissemination to new geographical regions. Here, we review the global host ranges and current epidemiological understanding of zoonotic orthopoxviruses while focusing on orthopoxviruses with epidemic potential, including monkeypox, cowpox, and vaccinia viruses. Zoonotic diseases, defined as diseases or infections that are naturally transmissible from vertebrate animals to humans, represent a significant threat to global health . Among tPoxviridae family is divided into two subfamilies, namely: Chordopoxvirinae, which infect vertebrates, and Entomopoxvirinae (A\u2013C), which infect invertebrates. The Chordopoxvirinae subfamily is further divided into 18 genera , distinguishable by their serological reactions [Poxviruses are of great veterinary and human importance and infect numerous vertebrate and invertebrate animals, including humans. The eactions ,7.Poxviridae comprises large, brick-shaped or ovoid enveloped viruses containing a linear, double-stranded DNA genome approximately 200 kilobase pairs in length [Variola virus (VARV), the causative agent of smallpox. Before its remarkable eradication in 1980, VARV represented a centuries-old threat to humans worldwide and killed approximately 300\u2013500 million people during the 20th century [The family n length ,8. Poxvi century ,11. Alth century ,13.Orthopoxvirus is the most important and well-characterized poxvirus genus, mainly due to its impact on human and animal health [Orthopoxviruses are remarkable for their wide host spectrum, ranging from humans to domestic and wild animals . Orthopol health ,8. Here,Orthopoxvirus species, according to different regions of the world . Orthopoxvirus infections have been demonstrated in animals belonging to different orders, using different methods . The occurrence of some zoonotic orthopoxviruses has already been confirmed  in some geographical regions  in South America, Europe, Asia, and the Middle East; brown: monkeypox virus in Africa and North America; orange: cowpox virus in Europe and Asia).The image shows the range of animal hosts (represented by orders) that have been demonstrated to be naturally infected by some Orthopoxvirus genus comprises VARV, VACV, CPXV, MPXV, camelpox virus, Akhmeta virus, and other species with zoonotic potential. All orthopoxviruses share significant DNA sequence similarity and are immunologically cross-reactive and cross-protective. Infection with any orthopoxvirus is considered to generate protection against exposure or re- exposure to any other member of the genus [The he genus ,15. Orthhe genus ,17,18,19he genus . Regardihe genus .The evolution of generalists pathogens requires the successful crossing of host transmission barriers . These iDespite the eradication of smallpox, the possibility of its re-emergence or the emergence of other orthopoxviruses in human and animal populations is a relevant global health issue. As smallpox vaccination is no longer mandatory, most of the world\u2019s population that is under 40 years of age lacks immunity against orthopoxviruses ,25. ThisMacaca fascicularis) arriving in Copenhagen, Denmark, from Singapore [Monkeypox virus isolates are subdivided into two clades, namely, the West African and the Congo Basin clades, based on genetic and phenotypic (virulence) differences . Notablyingapore . Despiteingapore .Mus musculus), rabbits (Oryctolagus cuniculus), hamsters, woodchucks (Marmota monax), jerboas (Jaculus sp.), and porcupines (Atherurus africanus) (Myrmecophaga tridactyla), black-tailed prairie dogs (Cynomys ludovicianus), southern opossums , short-tailed opossums (Monodelphis domestica), African hedgehogs (Atelerix sp.), and several non-human primate species. Additionally, serological surveys have implicated several African rodents, including giant pouched rats (Cricetomys spp.), African dormices (Graphiurus spp.), rope squirrels (Funisciurus spp.), and sun squirrels (Heliosciurus spp.) as primary orthopoxvirus hosts in Africa [Further insights into the range of taxa susceptible to MPXV infection were obtained by laboratory studies and field surveys. MPXV infections have been reported in a broad range of rodents, such as mice (ricanus) . Similarn Africa ,62,63.Macaca fascicularis), sooty mangabeys (Cercocebus atys), orangutans (Pongo pygmaeus), and chimpanzees (Pan troglodytes) can be infected with MPXV. Among New World non-human primates [Callithrix jacchus) was shown to be susceptible to MPXV infection through intravenous inoculation [Among Old World non-human primates, cynomolgus monkeys . Human infection was associated with direct contact with ill pet prairie dogs that were kept near to infected exotic animals imported from Ghana, West Africa . This epAlthough humans are also accidental hosts , MPXV beAlarmingly, several outbreaks of monkeypox in humans have been reported in African regions in the last decade. In 2010, two confirmed and eight suspected cases were described in the Republic of Congo related to the migration of refugees, regional inter-ethnic conflicts, or autochthonous cases. No deaths were reported among the confirmed cases, although one individual with suspected infection died . In the Some African regions have continuously reported human cases of MPXV infection in recent years (2017 to 2020), including the Central African Republican (27 confirmed cases and two deaths) ,92, NigeFunisciurus anerythrus), Zaire, in 1985 [Cercocebus atys), C\u00f4te d\u2019Ivoire, in 2012 [The natural source of MPXV and its maintenance cycle in nature remains unknown as the virus has only been isolated twice in nature : once from the rope squirrel , are known to be the primary CPXV reservoirs in nature [Edward Jenner was the first to document CPXV infection after observing local lesions on the teats of cows, which he called \u201csmallpox . There wsmallpox . Howeversmallpox  increasesmallpox ,111,112,smallpox ,116,117,smallpox , rodentssmallpox ,124,125,smallpox ,127, rhismallpox ,114,128,smallpox , okapis smallpox , horses smallpox , anteatesmallpox , stone msmallpox , bearcatsmallpox , and farsmallpox ,135  and wood mice (Apodemus sylvaticus), while in Turkmenistan and Russia CPXV was isolated in the laboratory as well as in wild rodents [Vulpes vulpes) in Western Europe being possibly related to CPXV infection, halthough red foxes are also known to be susceptible to ectromelia virus [CPXV is currently mostly found in Europe and northern and central Asia where cases of infections in rodents, cats, and humans continue to be reported. In Great Britain, CPXV is endemic in rodents such as bank voles  that are kept as pets [The infection of pet rats and domestic cats by CPXV brings a higher risk of exposure to humans in the domestic environment, but rural or wild areas may be important as the source of infection . Cowpox  as pets ,38,121.  as pets ,121. TheVaccinia virus, the prototype species of the Orthopoxvirus genus, is best known as the live attenuated virus used worldwide by the WHO in the smallpox vaccine [Although VACV is the most extensively studied orthopoxvirus, its origin remains unknown . Vaccini vaccine ,147,148. vaccine ,149. Dur vaccine ,151. For vaccine ,153,154. vaccine ,53,155.Bubalus bubalis), but also cows and humans [In India, BPXV was first described in 1934, and was responsible for infections that mainly affected domestic buffaloes  was proposed to be a molecular marker that can separate Br-VACVs into two distinct clades (group 1 and group 2) [Since the detection of VACV in rural areas in Southeast Brazil, in 1999, several Brazilian-VACV (Br-VACV) isolates have been identified in the country  ,174,175.group 2) ,177,178.group 2) ,187,188.group 2) ,190. TheSapajus apella and Alouatta caraya) [Didelphis aurita, Didelphis albiventris, and, Nasua nasua) [Euphractus sexcintus) [Didelphis sp. and Caluromys philander) [Molossus rufus and Eumops perotis) [Oligoryzomys nigripes, Oligoryzomys flavescens, Sooretamys angouya, Calomys sp., Akodon sp., Necromys lasiurus, Necromys squamipes, Trinomys setosu, Cerradomys subflavus, Mus musculus, Rattus rattus, and Hydrochoerus hydrochaeris) [Initially, VACV outbreaks were described as affecting dairy cattle and humans in rural environments. Consequently, the epidemiology of bovine vaccine in Brazil is associated with economic losses resulting from compromised milking herds ,191,192. caraya) ; procynoa nasua) ,194; cinxcintus) ; marsupiilander) ,194; batperotis) ; and wilchaeris) ,195,196.chaeris) ,197,198,chaeris) ,182,195,chaeris) , cats [1chaeris) , and micchaeris)  (Table 2Although direct VACV transmission between wild and domestic animals and between wild animals and humans has not been documented to date, these possibilities cannot be excluded. Several studies have indicated that cattle have a role as amplifiers in the bovine vaccinia cycle and have also demonstrated that VACV excretion in feces may favor viral transmission and its maintenance in the environment ,200,201.Although VACV is known to have a broad range of hosts, many aspects of its natural history remain unknown. Bovine vaccinia is mainly caused by contact with infected cattle and is associated with economic losses to the dairy industry in Asia and South America ,53,148; The history of poxviruses and orthopoxviruses has frequently been related to human cultural behavior. The establishment of agricultural settlements is considered one of the factors that favored the emergence of smallpox approximately 10,000 years ago. Orthopoxviruses continue to emerge and re-emerge due to the increasing proximity of humans to wild and rural habitats. Following smallpox eradication, the global scenario is marked by a vast na\u00efve human population and the wide circulation of different orthopoxviruses. These facts raise concerns on the possible epidemic potential of these viruses in animals and humans. In fact, zoonotic orthopoxviruses already represent an important issue for animal health and economics. An example is the case of VACV and BPXV that have been associated with significant economic losses resulting from dairy cattle and livestock infection in several Asian and South American countries ,191,192.Currently, MPXV is mostly observed in Africa; CPXV in Europe and Asia; BPXV in Asia and the Middle East; and VACV in South America ,168,205.Because orthopoxviruses such as VACV, CPXV, and MPXV have genetic and phenotypic traits that allow them to possess a variety of mammals hosts , one canOrthopoxvirus outbreaks are usually related to populations living in rural areas or small villages. However, factors such as a high population density, increased urbanization, agriculture activities, deforestation, approximation to wild habitats, and inter-continental travel of people from endemic to pox-free regions may introduce poxviruses into different zones including urban environments ,206. A pThe epidemic potential of a virus is related to several factors, including geographical distribution, route of transmission, pathogenicity, and host range, among others. The epidemic potential may be lower for orthopoxviruses than for other RNA viruses or viruses transmitted by airway routes. Nevertheless, orthopoxviruses are remarkable regarding their transmission and dissemination among several hosts and environments. Wild and domestic animals could act as intermediate hosts for the emergence or re-emergence of orthopoxviruses in the human population. For instance, CPXV is transmitted from wild to domestic animals and then to humans, MPXV can be transmitted directly from wild animals to humans, and VACV is transmitted from domestic animals to humans ,104,144.The cessation of routine vaccination against smallpox decades ago has resulted in a large contingent of people that are susceptible to orthopoxvirus infections, which have high morbidity rates. Moreover, in immunosuppressed individuals, exposure to orthopoxvirus infection can result in severe forms of the disease, or even death . To date"}
+{"text": "Gut microbiota and its metabolites such as short chain fatty acids (SCFA), lipopolysaccharides (LPS), and trimethylamine-N-oxide (TMAO) impact cardiovascular health. In this review, we discuss how gut microbiota and gut metabolites can affect hypertension and atherosclerosis. Hypertensive patients were shown to have lower alpha diversity, lower abundance of SCFA-producing microbiota, and higher abundance of gram-negative bacteria, which are a source of LPS. Animal studies point towards a direct role for SCFAs in blood pressure regulation and show that LPS has pro-inflammatory effects. Translocation of LPS into the systemic circulation is a consequence of increased gut permeability. Atherosclerosis, a multifactorial disease, is influenced by the gut microbiota through multiple pathways. Many studies have focused on the pro-atherogenic role of TMAO, however, it is not clear if this is a causal factor. In addition, gut microbiota play a key role in bile acid metabolism and some interventions targeting bile acid receptors tend to decrease atherosclerosis. Concluding, gut microbiota affect hypertension and atherosclerosis through many pathways, providing a wide range of potential therapeutic targets. Challenges ahead include translation of findings and mechanisms to humans and development of therapeutic interventions that target cardiovascular risk by modulation of gut microbes and metabolites. Cardiovascular diseases, including atherosclerosis and hypertension, are public health care priorities of the World Health Organization (WHO) . CardiovLow-grade chronic inflammation contributes to the development of both atherosclerosis and hypertension ,15,16,17Hypertension is the most important modifiable risk factor for cardiovascular disease . AlthougSeveral animal studies have reported compositional differences in the gut microbiota of animal models for hypertension, including Dahl-sensitive rats, spontaneous hypertensive rats, angiotensin-II induced hypertensive rats, and deoxycorticosterone acetate (DOCA)-salt mice, when compared to wild-type animals ,26,27,28Klebsiella, Parabacteroides, Desulfovibrio, and Prevotella were associated with higher blood pressure. Gram-negative bacteria are a source of lipopolysaccharides (LPS), also known as endotoxins, that are pro-inflammatory. In contrast, SCFA-producing bacteria, including Ruminococcaceae, Roseburia, and Faecalibacterium spp. were less abundant in hypertensive compared to normotensive patients [In humans, several cross-sectional studies have assessed associations between gut microbiota composition and blood pressure or hypertension  27,29,3,35,36,37patients ,34,35,37Lachnospiraceae, Ruminococcus, and Parasutterella spp. and decrease in Lactobacillus and Oscillibacter [Lactobacillus abundance has been associated with salt sensitivity in hypertension, since supplementation of Lactobacillus spp. in a mice model has been shown to attenuate salt-sensitive hypertension, presumably by modulation of Th17-cells [Lactobacillus was confirmed by several other animal models [Lactobacillus spp. was only reported by one of the cross-sectional studies in hypertensive subjects in Lactobacillus spp. [Dietary salt intake affects both the incidence of hypertension as well as gut microbiota composition. Higher salt intake has been associated with a shift in microbiota composition in several animal models, including an increase in libacter ,39,40. Ll models ,42,43,44lus spp. .In summary, animal studies suggest a causal link between gut microbiota composition and blood pressure regulation. Cross-sectional studies in human subjects show specific differences in microbiota composition between hypertensive subjects and controls, including lower SCFA-producing bacteria and higher Gram-negative species. These differences point to a role for SCFAs and LPS in hypertension, although the direction of this association is unclear.Ruminococcaceae and Lachnospiraceae, but also bacteria such as Anaerobutyricum hallii and Anaerostipes spp. Acetate and propionate are mainly produced by Bifidobacterium spp. and mucin-degrading bacteria such as Akkermansia muciniphila [SCFAs, including acetate, propionate, and butyrate, are produced by specific gut microbes by fermentation of otherwise indigestible dietary fibers . Fecal ainiphila . Most ofiniphila ,51. As aHuman studies on the role of SCFAs in blood pressure regulation are rather scarce. Intriguingly, fecal SCFA concentrations in humans have been associated with higher blood pressure , while SIn animal models, SCFAs were associated with both higher and lower blood pressure, which might be explained by the differential effects of SCFA receptors . SeveralIn addition, SCFAs, in particular butyrate, have anti-inflammatory effects that are presumed to be mediated by inhibition of histone deacetylase (HDAC) ,61. ButySCFAs have also been suggested to be implicated in gut\u2013brain communication. Vagal afferents express receptors that can sense SCFAs, which provides another pathway for the blood pressure modulating effects of SCFAs . Animal Vibrio cholerae appear to exploit this physiological pathway by excreting zona occludens toxin, a zonulin homologue that has similar effects [Gut microbiota can also affect gut permeability and therefore influence the extent to which metabolites and endotoxins are absorbed . The bar effects .Animal models suggest that gut permeability is higher in the hypertensive state. Hypertensive rats had lower levels of mRNA of gap junction proteins, indicating higher gut permeability, which was restored after fecal microbiota transplantation from controls . In a siA consequence of higher gut permeability is increased translocation of certain metabolites and endotoxins in the portal and systemic circulation, which could cause further amplification of gut permeability . Lipopoln = 8) group of human subjects that showed a significant decrease in systolic and diastolic blood pressure after administration of LPS. Moreover, in this study, LPS increased brain microglial activation on positron emission tomography (PET)-scans [LPS is known to induce systemic inflammation and has been shown to have both metabolic and cardiovascular effects. In mice, infusion of LPS to 2- to 3-fold higher plasma levels resulted in higher glucose and insulin levels and weight gain comparable to mice on a 4-week high-fat diet . LPS-admT)-scans . SummariIncreased sympathetic activation is considered one of the causal factors in the development of hypertension, and can already be observed in early stages . The symGut\u2013brain communication could stimulate sympathetic activation and therefore play a role in the hypertension pathogenesis. The gut is innervated by the autonomic nervous system that signals physiological conditions such as acidity, osmolarity, and pain . IntrinsElevated sympathetic drive shifts bone marrow hemopoietic stem cells to a pro-inflammatory state, and the release of these immune cells contributes to further hypertension development ,93. An aAtherosclerosis is a multifactorial process, with lipid metabolism, inflammation, vascular ageing, and blood pressure as key players. Atherosclerosis is closely related to arterial stiffness, which is caused by a loss of elastic fibers and thickening of arteriole walls. Arterial stiffness tends to increase with age and results in a less compliant arterial system and higher pulse wave velocity. The resulting increased shear stress has an aggravating effect on the formation of subsequent atherosclerotic plaques ,95. In tStreptococcus, Pseudomonas, Klebsiella, Veillonella spp., and Chlamydia pneumoniae [An atherosclerotic plaque was shown to be a microbial environment on itself, containing microbes such as eumoniae ,99,100. eumoniae ,102. It eumoniae ,104. Inteumoniae ,106. Theeumoniae .Collinsella genus, Enterobacteriaceae, Streptococcaceae, and Klebsiella spp., and lower abundance of SCFA-producing bacteria Eubacterium, Roseburia, and Ruminococcaceae spp. in the gut microbiota of patients with symptomatic atherosclerosis compared to healthy controls [Ruminococcaceae spp. in middle aged women in the TwinUK cohort [-/- mice had 29% larger plaque sizes than controls [In humans, cross-sectional studies showed that higher abundance of the controls ,109,110.K cohort . Hence, controls . AlternaClostridia and Enterobacteriaceae, in the degradation of nutrients such as carnitine, choline, and lecithin, that can be found in dietary products including meat and eggs [The role of trimethylamine (TMA) and TMAO in the development of atherosclerosis is an extensively researched topic. The role of gut microbiota in TMAO production is illustrated by and eggs . After aand eggs . Plasma and eggs . In addiand eggs . TMAO isand eggs .Several mechanisms for the role of TMAO in atherosclerosis have been proposed, including the effects TMAO has on inflammation, cholesterol metabolism, and thrombosis. TMAO was shown to increase the production of pro-inflammatory cytokines such as TNF-alpha and IL-1B, and decrease anti-inflammatory cytokines such as IL-10 . In addiAdministration of TMAO indeed promoted atherosclerosis in several mouse models ,121. HowNevertheless, a causal effect of TMAO on atherosclerosis has not yet been proven. An elegant way to assess causality is Mendelian randomization, using genetic variants known to modify the exposure to examine the effect on disease . In thisBile acid metabolism is dependent on microbial modifications in the gut  and this\u2212/\u2212 mice [TGR5 is expressed in a variety of tissues, including liver, gall bladder, intestines, kidneys, pancreas, muscle, and adipose tissue, but can also be found on leukocytes, macrophages, and endothelial cells . A TGR5 \u2212/\u2212 mice ,143. Tra\u2212/\u2212 mice . TGR5 ag\u2212/\u2212 mice .Atherogenic mice models with FXR knock-out showed conflicting findings, with both increased and decreased atherosclerosis ,147,148.Dual agents that target both TGR5 and FXR might have more therapeutic potential. Animal studies on the effect of dual agonists reported beneficial effects on metabolic syndrome, NASH, cholangiopathy, progression of diabetic nephropathy, and atherosclerosis ,156,157.The changes in gut microbiota composition and gut metabolites discussed in this review could all be potential therapeutic targets in the treatment of atherosclerosis and hypertension. The most direct ways of altering gut microbiota composition are oral supplementation of specific microbial strains and fecal microbiota transplantation (FMT).Bifidobacterium, Enterococcus, and Lactobacillus were suggested to have a variety of health benefits including anti-inflammatory and beneficial metabolic effects [Bifidobacterium, Lactobacillus, and SCFA-producing Anaerobutyricum soehngenii species had modest blood pressure lowering effects in humans [Probiotics containing SCFA-producing microbes including  effects . In addin humans ,159. Hown humans . Therefon humans .Probiotic efficacy is both disease-specific and strain-specific , underliAlternatively, FMT could be used to optimize microbiota composition in individuals at risk for cardiovascular disease. FMT has been shown to be efficacious with limited adverse effects . HoweverTo date, only one FMT trial targeted cardiovascular risk by transplantation from lean vegan donors to meat-consuming subjects with metabolic syndrome in order to lower TMAO levels . DespiteBifidobacterium and Lactobacillus. Diet also has a substantial influence on gut microbiota composition. Dietary interventions such as the DASH and the Mediterranean diet were shown to lower cardiovascular risk [Prebiotics and dietary interventions target gut microbiota composition indirectly. Prebiotics selectively stimulate specific microbes in the colon. Prebiotics are often fibers, although not all fibers are prebiotics . Prebiotlar risk ,171. HowIn summary, multiple interventions could target gut microbiota composition and its associated metabolites, ranging from targeted approaches to more accessible but non-specific interventions. However, translation of findings from animal studies to humans is needed, preferably by prospective cohort studies using metagenomic sequencing that can also assess microbiome functionality. In addition, adjusting for confounders when assessing associations between microbiota and cardiovascular disease is vital, since microbiota composition is shaped by a combination of lifestyle factors, health conditions, and medication use.The pathways by which gut microbiota affect hypertension and atherosclerosis are diverse and often interact, as shown in"}
+{"text": "Plant cells are frequently challenged with a wide range of adverse environmental conditions that restrict plant growth and limit the productivity of agricultural crops. Rapid development of nanotechnology and unsystematic discharge of metal containing nanoparticles (NPs) into the environment pose a serious threat to the ecological receptors including plants. Engineered nanoparticles are synthesized by physical, chemical, biological, or hybrid methods. In addition, volcanic eruption, mechanical grinding of earthquake-generating faults in Earth\u2019s crust, ocean spray, and ultrafine cosmic dust are the natural source of NPs in the atmosphere. Untying the nature of plant interactions with NPs is fundamental for assessing their uptake and distribution, as well as evaluating phytotoxicity. Modern mass spectrometry-based proteomic techniques allow precise identification of low abundant proteins, protein\u2013protein interactions, and in-depth analyses of cellular signaling networks. The present review highlights current understanding of plant responses to NPs exploiting high-throughput proteomics techniques. Synthesis of NPs, their morphophysiological effects on crops, and applications of proteomic techniques, are discussed in details to comprehend the underlying mechanism of NPs stress acclimation. Rapid advancement in nanotechnology has taken the food industry to a new height . NanoparArabidopsis thaliana by nZVI-mediated OH radical-induced cell wall loosening. Conversely, iron\u2013ion/NPs did not affect physiological parameters in lettuce plant [Among metal based NPs, iron NPs are widely used in environmental remediation, biomedical, diagnostic field, and drug delivery because of their unique properties, such as excellent biodegradability, low cytotoxicity, and ability to attach with multiple targeted ligands or antibodies ,13. Few ce plant . Similarce plant . Howeverce plant . Hence, ce plant . Techniqce plant , transcrce plant , and proce plant  have beece plant . These hce plant . Althougce plant , informaThe high-throughput techniques used in proteomics focus on revealing structure and conformation of proteins, protein\u2212protein, and protein\u2212ligand interactions. Proteomics offer several advantages over the genome or transcriptome-based technologies as it directly deals with the functional molecules rather than DNA or mRNA . Gel-basThe size, concentration, and stability of NPs primarily determine their effects on plants . The chaThese methods are being used for the synthesis of various economically important NPs, such as silver, copper, iron, titanium, and others. The method of tube furnace was used for the synthesis of spherical silver NPs ; while lThe chemical reduction using a variety of organic/inorganic reducing agents, electrochemical techniques, physicochemical reduction, and radiolysis is a well-accepted approach for the synthesis of NPs . The proMorganella [Litchi chinensis [Eucalyptus macrocarpa [Rhazya stricta [Elaeagnus angustifolia, saffron, Ziziphus jujube [Albizia lebbeck bioactive compounds in the stabilization of zincoxide NPs were confirmed through various techniques and revealed irregular spherical morphology [Ricinus communis [Aloe vera also synthesized highly stable and spherical zinc oxide NPs [Ocimum sanctum leaf [Cassia alata flower [Capparis zelynica leaf [Syzygium aromaticum solution [In biological and green methods, living organisms, such as bacteria, viruses, and plants, are used as capping and reducing agents. The crystal lattice structure of synthesized copper NPs was achieved through rganella . Silver hinensis , Eucalypcrocarpa , and Rha stricta . Iron NPs jujube , grape ts jujube , and gres jujube . The invrphology ; while ccommunis . Leaf exxide NPs . Copper tum leaf , Cassia a flower , Cappariica leaf , and Syzsolution . StudiesThe most advanced interdisciplinary tool with the larger potential in agriculture for increased crop productivity is the nanotechnology in which NPs with varying size, concentration, and surface charge influenced the growth and development of diverse plant species . A varieArabidopsis thaliana [Solanum lycopersicum [Allium cepa [Cucurbita pepo [The impact of NPs depends on the type of plant species used. The aqueous suspension of aluminum oxide NPs improved the root growth of radish  but reduthaliana  and restthaliana . The aquthaliana  and carrthaliana , but enhthaliana , wheat [thaliana , and spithaliana ,75,76,77persicum , Allium ium cepa , and wheium cepa , while rita pepo , rice [7ita pepo , and letita pepo . These sVigna radiata [The carbon nanotubes, copper-oxide NPs, and titanium-dioxide NPs increased resistance to fungal infection by altering the level of endogenous hormones . The dir radiata . The hyd radiata ; while i radiata . Changes radiata  and impr radiata , respect radiata ; while c radiata . The flo radiata ; while e radiata . Silver  radiata  and ceri radiata  improved radiata , titaniu radiata , and cop radiata  treatmenVarious modes of applications determine the effects of NPs on growth and productivity of plants. Direct application of aluminum oxide NPs improved root length of wheat ; while rWith the advancements in mass spectrometry, proteomics has become a powerful technology for the identification and characterization of stress-induced proteins. Detailed proteome analysis of plant organelles generates comprehensive information about the intrinsic mechanisms of plant stress responses towards NPs. Proteomic analyses of various crops exposed to different NPs are summarized in Chlamydomonas [Escherichia coli [Bacillus thuringiensis [Eruca sativa, proteins associated with the endoplasmic reticulum and vacuole were differentially modulated under silver NPs exposure [Silver NPs are considered as a promising antibacterial agent due to their strong biocidal effect against microorganisms . These Nydomonas , Escherihia coli , and Bacngiensis . Currentngiensis . Proteinngiensis . In wheangiensis . Silver ngiensis . Large nngiensis . Silver ngiensis . Proteinngiensis . In Erucexposure . These fAluminum oxide NPs are mostly used in military and commercial products . ExtensiAmong the various metal-based NPs, copper NPs are by far the most well studied NPs whose toxicity has been tested in wide range of crops. They have wide applications in electronics, air/liquid filtration, ceramics, wood preservation, bioactive coatings, and films/textiles . At the Similar to copper NPs, iron NPs have extensive industrial, commercial, and biomedical applications . BecauseChlamydomonas reinhardtii were accessed by monitoring the changes in the physiology and cyto-ultrastructure [One of the most commonly used nanomaterials in agriculture and the energy sector is titanium dioxide NPs . They hatructure . AuthorsIn addition, various NPs are being extensively utilized to improve the growth and productivity of crop plants. However, application of zinc oxide NPs had marked effects on soybean seedling growth, rigidity of roots, and root cell viability . Gel-freAll of these studies indicate that NPs have the potential to modulate plant metabolic processes, and impact of NPs could be either positive or negative, depending on the plant species and type of nanoparticles used, their size, composition, concentration, and physical/chemical properties.2+ ions are only taken up by the roots [The phytotoxicity of NPs largely depends on the particle size, concentration and chemistry of NPs, in addition to the chemical milieu of the subcellular sites at which the NPs are deposited . Plants,he roots . Only a 2O2) is decayed by the metal ions leading to the formation of more toxic ROS, namely hydroxyl radical (\u2022OH) and hydroxyl anion (OH\u2212). Elevated ROS generation was documented in leaves of soybean exposed to zinc oxide NPs and silver NPs [Once NPs enter the root cells, these ultrafine particles upon dissolution discharge metal ions that interact with the functional groups of proteins (carboxyl and sulfhydryl groups) causing altered protein activity. The released redox-active metal ions could trigger reactive oxygen species (ROS) generation through the Fenton and Haber\u2013Weiss reactions . In theslver NPs  as well lver NPs . These Nlver NPs .Cellular compartments with extremely high oxidizing metabolic activity or with an intense rate of electron flow, such as mitochondria, chloroplasts, and peroxisomes, constitute a major source of ROS production in plants . Investi\u2022OH) is known to be the most reactive, capable of stealing hydrogen atom from a methylene (-CH2-) group present in polyunsaturated fatty acid side chain of membrane lipids and, thus, initiates lipid peroxidation [\u2022OH is derived from H2O2 as a consequence of one electron reduction, H2O2 scavenging peroxides play essential roles in protecting lipid membranes from NPs mediated oxidative stress. Among ROS, a recent study revealed down regulation of ascorbate peroxidase (APX1) in zinc oxide NPs challenged maize leaves with concomitant increased malondialdehyde (MDA) level, an indicative of oxidative stress induced damage to the lipid membrane [Moreover, NPs exposure often leads to disruption of cellular redox homeostasis and cause cell membrane damage through lipid peroxidation ,106,108.xidation . Since, membrane  and SyriApart from enzymatic component of ascorbate-glutathione cycle, plants have evolved a second line of defense to cope with the NPs induced oxidative stress. The thioredoxin (Trx) family protein is one of them, engage in mitigating oxidative damages by providing reducing power to reductases, detoxifying lipid hydroperoxides or repairing oxidized proteins. They also act as regulators of scavenging mechanisms and key components of signaling pathways in the plant antioxidant network . In addiNanotechnology has gained tremendous momentum in recent times because of the wide applications of NPs in agriculture, cosmetic industry, cellular imaging, medical diagnosis, biosensing, drug delivery, and cancer therapy. Nevertheless, unintended release of such commercially manufactured nanomaterials into the environment has raised global concern. Hence, considerable attention is now being paid to the methods and strategies of NPs synthesis, plant-nanomaterials interactions, and their environmental fate. As compared to traditional physical and chemical processes, green synthesis of NPs using microorganisms and plants is an environment-friendly, cost effective, safe, biocompatible, green alternative approach for large scale production of NPs. Morphophysiological as well as proteomic studies on NPs-induced phytotoxicity reveal that particle size, concentration, and chemistry of NPs, as well as the type of plant species used, are the key factors determining the type and magnitude of the cellular responses. However, more initiatives must be taken to find out whether the metal-based NPs exert phytotoxicity exclusively due to their high surface area and nanoscale size or due to the released metal ions. Moreover, there is a need for more comprehensive omics approach integrating genomics, transcriptomics, proteomics, and metabolomics, so that the impact of the applied NPs on plants can be assessed well in time."}
+{"text": "Acinetobacter baumanniii, vancomycin resistant Enterococcus, methicillin resistance Staphylococcus aureus, and Pseudomonas aeruginosa, as well as other WHO priority pathogens, are becoming extremely difficult to treat. In 2017, the EU adopted the \u201cOne Health\u201d approach to combat antibiotic resistance in animal and human medicine and to prevent the transmission of zoonotic disease. As the current therapeutic agents become increasingly inadequate, there is a dire need to establish novel methods of treatment under this One Health Framework. Bacteriophages (phages), viruses infecting bacterial species, demonstrate clear antimicrobial activity against an array of resistant species, with high levels of specificity and potency. Bacteriophages play key roles in bacterial evolution and are essential components of all ecosystems, including the human microbiome. Factors such are their specificity, potency, biocompatibility, and bactericidal activity make them desirable options as therapeutics. Issues remain, however, relating to their large-scale production, formulation, stability, and bacterial resistance, limiting their implementation globally. Phages used in therapy must be virulent, purified, and well characterized before administration. Clinical studies are warranted to assess the in vivo pharmacokinetics and pharmacodynamic characteristics of phages to fully establish their therapeutic potential.Antimicrobial resistance necessitates action to reduce and eliminate infectious disease, ensure animal and human health, and combat emerging diseases. Species such as  Klebsiella pneumoniae, Escherichia. coli, Acinetobacter baumannii, and Pseudomonas aeruginosa; and Gram-positive methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), and Streptococcus pneumoniae are frequently associated with high morbidity rates due to limited treatment options [Candida albicans, Candida krusei, Candida auris, Aspergillus fumigatus, and Cryptococcus neoformans [Candida auris is an emerging MDR nosocomial pathogen associated with high mortality [Archaea to stimulate gastrointestinal and metabolic diseases, such as colorectal cancer, inflammatory bowel disease, irritable bowel syndrome, constipation, and obesity in humans [Antimicrobial resistance (AMR) and multidrug resistance (MDR) are increasing issues globally, as more microbial species  gain resistance to currently available therapeutic options. As such, issues increasingly arise relating to prolonged infectious disease, increased mortality, biosecurity issues, animal health, and foodborne disease outbreaks. Indeed, the issue is so great that different classifications have been established for MDR species, where extensively drug-resistant (XDR) species are only susceptible to 2 antimicrobial drug categories and pan-drug-resistant (PDR) species are resistant to all antimicrobial drug categories  currentl options . Fungal  options . Fungal oformans . Candidaortality . At presn humans . HoweverAt present, there is a global drive to identify, develop, and manufacture novel antimicrobial agents for use in fighting this AMR pandemic . Novel aThe significant increase in human populations, domestic animal populations, and food-producing animal populations; the global decline in wild animal populations; and widespread environmental damage has promoted the occurrence of emerging and re-emerging diseases. Environmental changes, agricultural intensification, climate change, and the destruction of wildlife habitats are also factors promoting the emergence of zoonotic diseases , which tE. coli, K. pneumoniae, MRSA, C. difficile, VRE, P. aeruginosa, and Salmonella sp., amongst others. These species are frequently associated with therapeutic failures, increased risk of complications, deteriorating pathological conditions, and mortality [Antimicrobial therapeutics have been one of the most beneficial medical discoveries to date. The synthetic and semi-synthetic production of these natural antibacterial compounds has provided an effective means of controlling infectious disease for decades. Unfortunately, antibiotic resistance is also a natural survival mechanism for assaulted species, which has been proliferated by anthropogenic use in human and veterinary applications. Antibiotic use is predominant in two areas\u2014in human medicine and in food-producing animals for growth promotion and prophylaxis . Resistaortality . Furtherortality . One heaortality . Howeverortality . ControlE. coli isolated from poultry, dairy, and pig farming, with resistance genes to tetracycline, quinolones, aminoglycosides, vancomycin, and \u03b2-lactams also detected in animal species [Salmonella and Campylobacter is considered is a major concern in food-producing animals, where resistance to fluoroquinolones or third-generation cephalosporins represents a major risk [Salmonella and E. coli infections in humans [Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are the leading cause of nosocomial infections globally [E. coli, K. pneumoniae, and A. baumannii strains from humans, livestock, and contaminated food indicate livestock as a source of these clinically relevant bacteria. A. baumannii strains have been isolated from animals, including poultry, livestock, horses, and domestic animals, and are mainly associated with outbreaks in veterinary clinics or hospitals [Zoonotic diseases negatively impact society by reducing the quantity and value of the produce from livestock, decreasing trade and productivity, and increasing financial expenditure on disease control and treatment and environmental pollution with AMR and ARGs. In food production, for example, excessive use of antibiotic therapy has been correlated with AMR  species . Resistajor risk , as bothn humans . Sulfonan humans . The Worglobally . The isoospitals . The majospitals  of the hPseudomonas and Acinetobacter), which are prevalent in food-producing animals, slaughterhouse wastewater, and surrounding environments. The emergence of ESBL-producing or fluoroquinolone-resistant Enterobacteriaceae in healthcare settings and in the poultry production chain is one example of MDR pathogens of zoonotic nature [Enterococcus species [The emergence of AMR ESKAPE bacteria is associated with the inappropriate use of antibiotics, followed by distribution into the environment and transfer to animals and humans . ESKAPE c nature . The use species . An exte species . Alterat species , and sys species .Myoviridae, Siphoviridae, and Podoviridae [One health calls for interdisciplinary research into combating the issue of AMR and encourages the development of novel treatment options to reduce or replace antibiotic agents in human and animal medicine. Certainly, one area showing potential is the use of phages to combat bacterial infectious disease. Such phages are viral species that specifically infect bacteria by injecting their genetic material into the host bacterial cell. They are ubiquitous in aquatic and terrestrial ecosystems and in the microbiome of animal species. In humans, phages are present on body surfaces, such as skin, oral cavity, lungs, intestines, and the urinary tract, where they act as a natural predator to the bacterial microbiome . Commensoviridae ,61. The oviridae . As withoviridae .E. coli phages MS2 and Q\u03b2  , and eveYersinia ,64,77. TYersinia . Phage tent care . The inv evident . Similarcultures .E. coli cells more so than the unmodified T7 phages [Salmonella ser. Typhimurium, Pseudomonas aeruginosa, and Acinetobacter baumannii [The Eliava Institute in Georgia has reported a significant improvement in patients treated with staphylococcal phages. Indeed, staphylococcal phages have been used to successfully treat infections where antibiotics have failed; for example, diabetic patients suffering with MRSA-infected foot ulcerations were healed with phage therapy when amputation was the only alternative option . The mod7 phages . Additioaumannii . Such stBacteriophages offer numerous advantages over conventional antibiotics for treating infectious disease. Specifically, these advantages include bacterial specificity, potency, limited immune response in the host, self-propagation while also being self-limiting, single administration, and being amenable to bioengineering, giving them undeniable potential as the way forward in combatting AMR. Phage specificity for host bacterial species is a major advantage  once theSuccessful phage therapy is dependent on the pharmacodynamic and pharmacokinetic properties of the phage in vivo . Phage kListeria monocytogenes, Salmonella species, and E. coli 0157:H7 [Listeria monocytogenes and Salmonella enterica, respectively, and are currently generally recognized as safe (GRAS) for use in the food industry [Pseudomonas and Aeromonas infections in aquaculture, as intensive fish farming is prone to bacterial disease outbreaks. Phage therapy has been investigated to control Salmonella in chickens and pigs, as well as avian pathogenic E. coli (causative agent of colibacillosis) and Campylobacter in poultry, with varying degrees of success [Clostridium perfringens, the causative agent of necrotic enteritis in poultry [E. coli [Phages represent a major problem for the dairy industry  in relation to fermentation procedures where they are present within the bacterial starter culture, causing cell death during the process. The industry relies on practical approaches to control phages, including modified factory design, increased sanitation, adequate ventilation, improved starter medium, and culture rotation . Phages  0157:H7 . ListShiindustry . Proteon success . Intraly poultry . Bacteri[E. coli .A. baumannii infection in mice demonstrated 2.3-fold increased survival in the treated vs. untreated group [A. baumannii prophages effective against clinical MDR isolates capable of curing fatal infectious disease in mice has also been characterized [P. aeruginosa hemorrhagic pneumonia in a mink model, A. baumannii- and Klebsiella pneumoniae-induced pneumonia in mice, and fatal E. coli respiratory infection in chickens [E. coli, Enterococcus, Pseudomonas, and Streptococcus), Staphylococcus aureus, however, is associated with chronic, contagious infections that are difficult to treat [E. coli isolates showed a 3- to 5-log decrease in E. coli in raw milk [Brucella, Chlamydia, or Mycobacteria infections [Mycobacterium avium subspecies paratuberculosis (MAP) is the causative agent of paratuberculosis or Johne\u2019s disease (JD) in cattle, a chronic granulomatous wasting gastroenteritis that closely resembles Crohn\u2019s disease (CD) in humans [Studies investigating the efficacy of phage therapy against ed group . A novelcterized . Inhaledchickens . The conto treat . Furtherraw milk . Studiesraw milk  and VRE raw milk . Phage tfections . Mycobacn humans . MAP is n humans  and CD in humans .E. coli (STEC), Vibrio cholerae, and E. coli 0157:H7 carrying the Shiga toxin are associated with hemolytic uremic syndrome [Corynebacterium diphtheriae and Clostridium botulinum [Salmonella, Clostridium, Streptococcus, Staphylococcus, and Bacillus. Approximately 75% of Streptococcus pyogenes isolates contain one or more prophages, many of which have the potential to perform transduction [E. coli strains, resulting in multiple antimicrobial resistances [blaTEM (\u03b2lactams), qnrS (fluoroquinolones), ermB (macrolides), sulI (sulphonamides), and tetW (tetracyclines) were identified in the virome of activated sludge and environmental water samples [Temperate phages conducting a lysogenic cycle can insert phage genomes coding for toxins and other critical virulence factors into their bacterial host, increasing the bacterial pathogenesis to humans. This lysogenic conversion is necessary to ensure the survival of the bacteria and the virus in nature , as virusyndrome . Additiosyndrome . Phages otulinum . The trasduction . This tristances . Additio samples . Phages  samples . Stress  samples .Fungal dermal and invasive infections are increasing globally, with many species demonstrating antifungal resistance. Indeed, current antifungal therapeutics have other issues, such as severe toxicity to mammalian cells relating to hepatotoxicity and nephrotoxicity. Alternative, effective, safe antifungal agents are also needed to combat the increasing number of fungal species identified as causative agents of disease. Moreover, the zoonotic nature of respiratory and dermal fungal pathogens is common knowledge, where neglected fungal disease represents a serious threat to human and animal health. Immunocompromised patients are particularly at risk of increased morbidity and mortality from fungal infectious disease. As such, zoonotic fungal infections must also be considered under One Health in food-producing and companion animals. Indeed, emerging fungal infections are often neglected diseases, such as Paracoccidioidomycosis, Adiaspiromycosis, and lobomycosis, where zoonosis is often undetermined. Implementing the One Health approach is vital for preventing the emergence and re-emergence of such fungal diseases.P. aeruginosa may negatively impact fungal growth in Aspergillus fumigatus and C. albicans [C. albicans is one of the most prominent nosocomial fungal infections globally and is associated with high mortality rates. Mycoviruses (viruses that selectively infect fungi) are phages of fungal species and have been identified for the major taxonomic classes of the fungi. The majority of these characterized mycoviruses have dsRNA genomes and are grouped into five families: Partitiviridae, Totiviridae, Chrysoviridae, Reoviridae, and Hypoviridae [Ustilago maydis [Saccharomyces cerevisiae, Hanseniaspora uvarum, and Zygosaccharomyces bailii. Furthermore, the toxin isolated from Z. bailii, referred to as zygocin, kills C. albicans, C. glabrata, and C. tropicalis yeast cells [Z. bailii shows promise as an antifungal agent due to its broad-spectrum activity against a range of pathogenic and non-pathogenic zoonotic yeasts and filamentous fungi [Some studies suggest that certain phages produced by albicans , zoonotioviridae . As witho maydis , secreteo maydis . Toxin-pst cells  and appest cells . This anus fungi .Escherichia coli, Salmonella, Campylobacter, Pseudomonas aeruginosa, Klebsiella pneumoniae, Staphylococcus aureus, Streptococcus pyogenes, and Listeria monocytogenes. Bacteriophages may also offer a means of controlling emerging and re-emerging pathogens, where 75% of emerging infectious disease are zoonotic according to the CDC. Key advantages include bacterial strain specificity and potency, with limited immune reactions induced in the patient. Indeed, phages are currently used as delivery vehicles for protein pharmaceutical ingredients and DNA vaccines. The phages\u2019 self-propagation in vivo and their self-limiting nature following the clearance of the bacterial host also makes them attractive for combating infectious disease. As antimicrobial agents, however, their pharmacokinetics and pharmacodynamics need to be fully elucidated to maximize treatment options. Additionally, the evolution of bacterial resistance to phages must be understood if they are to be implemented therapeutically. While issues such as formulation, stability, and specificity must be overcome, initial studies indicate that phages have great potential for antimicrobial therapy in both human and animal medicines, thereby contributing to One Health. Antimicrobial phage therapy may be the way forward in combatting infectious disease and multidrug resistance.As microbial species become increasingly drug resistant, there is a dire need to find alternative therapy options for mitigating and controlling infectious diseases to protect human and animal health. Antibiotic-resistant zoonotic pathogens in the food chain and the re-emergence of zoonotic pathogens are global public health issues. The current antibiotic crisis necessitates the development of alternative strategies to fight drug-resistant bacterial species. Bacteriophages have been implemented in veterinary applications for decades, but their use in human medicine is limited and still requires clinical research. Studies have shown phage application in successfully treating zoonotic pathogens, including"}
+{"text": "Conventional recommendations for dietary intervention have been generally based on population groups divided by gender and age. However, it is well known that diversities in lifestyle, culture, social status, and genetic variants affect responses to nutritional intervention. Therefore, the concept of precision nutrition has been advocated. Precision nutrition refers to individual nutritional regimens designed to treat or prevent various diseases. To plan precision nutrition, the interplay between metabolic, genetic, social, and environmental factors must be considered . PrecisiNutrients focused on the relationships between precision nutrition and the microbiome [A recent review published in crobiome . The autcrobiome ,3. Furthcrobiome . They alcrobiome . Glut5 and Ketohexokinase [-/- mice [Following their review, we can understand that metagenomics is a useful tool to facilitate precise nutrition, but there remain problems involved in the interpretation of metagenomics data. While the enterotype concept is attractive for its ability to predict biomarkers of responsiveness to dietary intervention, there is the possibility that factors other than population, age and diet groups, such as genetic variation and medication, underlie the enterotypes. For example, carbohydrate response element binding protein (ChREBP) regulates intestinal glucose and fructose absorption via gene transcription of xokinase , thereby-/- mice . We prev-/- mice , while m-/- mice . Falony -/- mice ,7. Impor-/- mice . In cont-/- mice ,10. We s"}
+{"text": "The first and second authors are incorrectly listed as having contributed equally to this work. The correct byline is: Xia Liu, James Blackar Mawolo, Xiaohua Du, Yingjie Zhou, Haifang Wang, Fayang Liu, Zhiqing He, Haqi Astika Marela."}
+{"text": "Betel quid, traditionally prepared with areca nut, betel leaf, and slaked lime, has been consumed for thousands of years, mainly in the form of chewing. Originally used for cultural, medicinal, and ceremonial purposes mainly in South Asian countries, its use has recently spread across the globe due to its psychoactive, euphoric, and aphrodisiac properties. Now it is widely used as a social lubricant and source of financial profit. Unfortunately, the profit motive has led to high rates of habitual consumption with eventual conversion to addiction among young girls and boys. Moreover, the worrisome practice of including tobacco in quid preparations has grown, particularly among pregnant women. Major health concerns include increased rates of malignancy, oral pathology, and cardiovascular, hepatic, fertility, metabolic, and neuropsychiatric disorders. Metabolic disorders and insulin resistance disease states such as type 2 diabetes, obesity, and metabolic syndrome contribute to cognitive decline and neurodegeneration. Mechanistically, the constituents of areca nut/betel quid are metabolized to N-nitroso compounds, i.e., nitrosamines, which are carcinogenic at high doses and cause insulin resistance following chronic low-level exposures. From an epidemiological perspective, the rising tide of insulin resistance diseases including obesity, diabetes, and dementias that now disproportionately burden poor countries has been propagated by rapid commercialization and enhanced access to betel quid. Public health measures are needed to impose socially and ethically responsible barriers to yet another cause of global health disparity. Epidemiological trends reflecting progressively increased prevalence rates of insulin resistance diseases including diabetes mellitus, non-alcoholic fatty liver disease, and Alzheimer\u2019s disease (AD)-type dementia in Asian (primarily Southern and South Eastern) countries are not readily explained since, until relatively recent times, they have been spared of preservative-laden highly processed Western foods and attendant morbid obesity . On the This article was generated by a systematic review of primary and summary historical, social, economic, demographic, chemical, epidemiological, and clinical literature pertaining to areca nut/betel quid uses and consumption from 1919 to 2019. English language databases searched included PubMed, Google Scholar, Scopus, and government reports. Keywords and pairings included: areca nut or betel quid with consumption; exposure; youth; cultural practices; women; tobacco; metabolic; insulin; central nervous system; smoking; nitrosamine; diabetes; cognitive impairment; nicotine; arecoline; Asia; economics; preparation; metabolism; addiction; health; school age. Exclusion terms were as follows: malignancy; experimental animal model; signal transduction; aging; immunology; molecular biology; modern medicinal use; and genetics. Unfortunately, due to socioeconomic limitations and lack of adequate resources, most of the primary data were generated by observational, retrospective, and cross-sectional designs in selected regions or countries. However, to optimize robustness of this review, emphasis was placed on reproducible large-scale studies.Areca catechu tree, and for centuries it has been consumed by chewing, particularly in preparations known as \u201cbetel quid\u201d. Betel quid preparation and chewing can be dated back to 10,000 BCE [Areca nut is the fruit of the ,000 BCE ,5. Descr,000 BCE ,7, and M,000 BCE . However,000 BCE , or the ,000 BCE ,10.Areca catechu palm tree requires little care, has a lifespan of 60 to 100 years, and can produce up to 800 areca nuts per year. After removing its outer hard shell, the ripe or unripe areca nut can be chewed raw, boiled, sun-dried, benzoin-smoked, or salted and dried [Piper betle plant (vine). All ingredients needed to prepare betel quid can be cultivated or readily obtained in Thailand, India, Bangladesh, China, the Pacific Islands, Taiwan, and Vietnam [The earliest and simplest preparations of betel quid required just three ingredients: crushed areca nut, slaked lime, and a betel leaf. The nd dried ,11,12. S Vietnam .Betel quid is prepared by first folding the betel leaf into a small pocket that can secure the other ingredients through several cycles of chewing and spitting. Crushed areca nut is mixed with slated lime as a paste and inserted into the betel leaf pocket . Chewinghttp://www.fao.org/faostat/en/#rankings/countries_by_commodity. http://www.fao.org/faostat/en/#data). Although all age groups were affected, the greatest impact of increased areca nut availability/production was in youths from socially and economically disadvantaged populations [Over 600 million people worldwide regularly consume betel quid, making it the 4th most commonly used or abused psychoactive stimulant ,16 afterulations .Due to its euphoric, psychoactive, and aphrodisiac effects, the practice of using betel quid at social gatherings and religious ceremonies and for wedding gifts has persisted for centuries to the present time ,18. BeteArecoline has been shown to transiently modulate cognitive functions by improving focus, arousal, and learning ,25 due tThe substitution of tobacco for betel leaves in quid preparations contributes to dependence and addiction . Case\u2013coAreca catechu palm trees were cultivated to meet individual and community needs [Areca catechu palm tree farming to be converted into a cash crop. Data from the Food and Agriculture Organization revealed substantial growth in areca nut production and profits led by India, followed by Indonesia, China, Myanmar, and Bangladesh [Areca catechu, and millions throughout India are economically dependent upon the areca nut industry for subsistence [Historically, ty needs , but ovengladesh   and . For example, in Taiwan, betel nut girls run up to cars at drive-through services and allow their breasts to be fondled while handing over a packet of betel quid. For higher fees, the so-called betel nut beauties or binlang girls, attired in revealing clothes jump into the cars to perform oral sex. This type of marketing greatly expanded the industry in urban, suburban, and rural areas of Taiwan.Sex is an important factor driving betel quid consumption  (MW = 151.397), the dominant psychoactive component in areca nut, has 3 hydrogen bond acceptor sites enabling it to form two main metabolites: arecoline-N-Oxide via N-oxidation, and arecaidine via carboxylesterase-mediated hydrolyzation [7H11NO2) (MW = 141.17) also has 3 main hydrogen bond acceptor sites as well as 1 hydrogen bond donor site. Guvacine (MW = 127.14 Da) is a secondary amino compound that acts as an alpha\u2013beta unsaturated nicotinic carboxylic acid. Guvacoline (C7H11NO2) (MW = 141.17) is a derivative of guvacine and a beta-amino acid ester.Both areca nut and tobacco have short- and long-term effects on the body. The four main alkaloids present in areca nut are, arecoline, which comprises approximately 1% of the nut\u2019s dry mass ; arecaidlyzation . ArecaidThe short-term psychoactive effects of arecoline in areca nut and nicotine in tobacco, promote their habitual use, dependency, and eventual addiction due to their excitatory actions on the parasympathetic nervous system. The other major alkaloids in areca nut are arecaidine, guvacoline, and guvacine . ArecoliArecoline constitutes between 1% and 1.4% of the dry mass of areca nut . FollowiAlthough the full spectrum of arecoline-derived nitrosamines and their downstream effects on the body are not known, the International Agency for Research on Cancer has classified areca nut as a Group 1 carcinogen . AccordiAlthough tobacco contains several alkaloids including nicotine, nornicotine, anabasine, anatabine, and myosmine, only nicotine, which comprises between 1% and 2% of the dry mass of unburned tobacco is responsible for its addictive properties . NicotinNicotine is rapidly metabolized by cytochrome P450 (CYP) in the liver, lung, kidney, nasal mucosa, and brain . OxidatiLimited research suggests that the addition of tobacco to betel quid exacerbates the adverse health effects of either exposure alone. For example, chewers of areca nut with tobacco had higher levels of C-reactive protein, a marker of systemic inflammation compared with subjects who chewed only areca nut . The sevFor centuries, the prevalence rates of obesity, type 2 diabetes mellitus, metabolic syndrome, and dementia were low in Southeast Asian populations. However, increased areca nut consumption has been associated with glucose intolerance or type 2 diabetes in both mice and humans ,145,146.Insulin resistance in type 2 diabetes and obesity is a critical factor driving cognitive decline, especially in verbal memory, learning, and mental speed, suggesting that chronic areca nut consumption also could be associated with cognitive impairment ,152,153.Arecoline-associated cellular and tissue injury and disease patterns largely correspond with its chemical and metabolite distributions. Toxic effects of arecoline metabolites have been detected in bone marrow cells, lymphocytes, neuronal cells, hepatocytes, myoblasts, and endothelial cells . In someFurthermore, there is evidence that apart from its direct effects, toxic metabolites of arecoline may have critical roles as mediators of cellular injury. Importantly, the generation of toxic metabolites may be driven by the inclusion of lime and nitrites in the betel quid preparations. Correspondingly, treatment of areca nut with lime increased the rate of arecoline hydrolysis to arecaidine . In addiMastication of betel quid causes areca nut to be saturated with saliva and exposed to major salivary enzymes including amylases, lipases, and proteases, and an array of minor salivary enzymes such as cholinesterases. Arecoline metabolism in the oral cavity is partly achieved through the actions of amylase and cholinesterase, which function optimally at pHs ranging from 6.7 to 7.4. Increased salivary enzyme metabolism of arecoline could potentially limit the quantities that enter the gastrointestinal tract and systemic circulation and exert end-organ damage. Since various food substances can stimulate the secretion of saliva and salivary enzymes and also influence the pH of saliva, we hypothesize that dietary manipulation could potentially be used to reduce partial oral metabolism of arecoline and the attendant local accumulation of toxic metabolites that cause oral and esophageal cancers. We hypothesize that inefficient partial metabolism by salivary enzymes poses a greater health risk than bypassing the process to permit more complete metabolism in the liver. For example, leafy green spinach has a basic pH and is highly rich in nitrate . The higGrapefruit, although highly acidic (pH 3), only transiently decreases the pH of saliva because soon after its ingestion, sodium bicarbonate is secreted by the salivary glands, increasing pH and diminishing enzymatic activity . BlueberThis article reviews the historical, cultural, social, and economic perspectives on the growing global consumption of betel quid. Due to increased availability of processed and preserved betel quid, combined with commercialization, particularly in relation to sex and promise of \u201cfeel good states of mind,\u201d exposures have shifted to highly vulnerable populations, particularly school-age boys and girls, pregnant women, and the poor. Unfortunately, a major side effect of habitual usage is addiction. Growing evidence indicates that toxic components of areca nut used to prepare quid promote a range of metabolic diseases including diabetes and metabolic syndrome, i.e., insulin resistance. These effects can be exacerbated by the popular addition of tobacco to the preparations. The authors hypothesize that nitrosamines present in areca nut and tobacco mediate these significant adverse health effects which, based on demographic trends, are now disproportionately impacting young vulnerable populations from poor nations. Although more research is needed, natural dietary interventions could aid in reducing the long-term toxic-metabolic effects of quid.Despite significant health concerns related to addiction and chronic diseases and significant adverse impact from fetal through late adolescent and early adult development and maturation, policies to govern production, distribution, and sales of areca nut and betel quid have remained stagnant. Obstacles to progress include heavy lobbying from industry representatives together with the scarcity of objective, quantitative, and evidence-based clinical and experimental data showing detrimental effects of early life exposures to areca nut/betel quid, either alone or combined with tobacco."}
+{"text": "Journal of Educational Evaluation for Health Professions (JEEHP):This year has brought us some good news for the First, JEEHP was accepted for inclusion in Scopus by Scopus Content Selection and Advisory Board (CSAB) . AlthougSecond, JEEHP was included in Korea Citation Index (KCI) in April this year, an abstract and reference database maintained by the National Research Foundation of Korea (NRF), which is certainly a prestigious achievement because NRF had not allowed online-only journal without regular frequency to be included in KCI thus far. It had only allowed Scopus, SCIE (Science Citation Index Expanded), SSCI , or A&HCI (Arts and Humanities Citation index)-indexed journals to be included in KCI even if the journal has no frequency. JEEHP is believed to be the first scholarly journal in Korea published as online-only without regular frequency since 2006 [New technology was adopted by the JEEHP this year: (1) review process counter from October 16; (2) country map of authors in each year with a table of content and editorial board members from December 9; (3) country flag of the authors and the editorial board members from December 9; and (4) distribution of countries of the authors in metrics from December 9. Among these, review process counter can be a good incentive to submitting authors. Authors want decisions on their manuscripts as soon as possible, and currently the median value of the period to the first decision is 16 days . CountriJournal performance can be presented based on the bibliometric indexes including total citations and an impact factor. Twelve countries of the authors of 41 articles published this year are presented in The fate of manuscripts submitted to this journal up to December 27, 2019 is summarized in It is anticipated that the enactment of immediate open access publication without embargo period for articles will soon be supported by the US federal funding agencies including National Science Foundation and National Institute of Health ,4. It maI am deeply indebted to following reviewers. Without their tremendous help, I couldn\u2019t have edited and published the journal so beautifully:Abdolghani Abdollahimohammad, Neeka Akhavan, Malhotra Anita, Marcela Andrea Ant\u00fanez-Riveros, Colin Block, Raul Alfredo Borracci, Megan Brown, Su-Jin Chae, Lucia Chehade, A Ra Cho, Kyunghee Chun, Cheol-Woon Chung, Derek Clewley, Fabrizio Consorti, Mariana D'amico, Saeideh Daryazadeh, Olivos David, Upreet Dhaliwal, Ilse Erich, Christian Ezeala, Min Huang, Karen Huhn, Yera Hur, Geum-Hee Jeong, Williams Joy, Im Jung Jun, Taehoon Kang, Chien Kevin, Ahmed Khalifa Khalif, Kyung Won Kim, Seock-Ho kim, Young Min Kim, Ju-Yeun Lee, Young Hwan Lee, Eun Young Lim, Paula Kay Martin, argetto-Fernandez Miguel, Kyung-A Nam, Younjae Oh, Robin Parish, Bhina Patria, Rano Mal Piryani, Agarwal Ramesh, Marcus Roll, Dong Gi Seo, Jihyun Seo, Ravi Shankar, Eunah Shin, Mohan Sunkad, Chloe Thabet, Gideon Victor, Yanhua Yi, and Hon Yuen.Voluntary work of audio recording of the abstract when authors were not available, was done by Tom Huh, a student with a major in Biology, Korea University, Seoul, Korea.I am very happy to have published 41 articles this year, including 30 research articles, 2 reviews, 3 brief reports, 1 technical report, 3 editorials, 1 educational/faculty development materials, and 1 announcement. Next year is the year of \u201cwhite rat\u201d according to the sexagenary cycle. Rats stand for multi-parity, diligence, and abundance of riches in Korean culture. I hope the journal to also prosper in receiving an adequate number of interesting and practical manuscripts for medical health educators. I will be more than happy if the contents of this journal are adopted by many experts in medical health educational fields worldwide."}
+{"text": "Liquid biopsy or the sampling of bodily fluids, mostly blood, has been intensely investigated and developed for clinical utility in medicine, especially oncology . Analysi\u00ae for capturing and enumerating CTCs, and conventional methods for the isolation of exosomes using Western blotting and enzyme linked immunosorbent assay (ELISA). Analysis of the genetic contents in the liquid biopsied biomarkers by advanced techniques of polymerase chain reactions (PCR) and next-generation technology is described. The clinical utility of liquid biopsy in colorectal, breast, hepatocellular, gastric, and lung carcinomas is discussed. By enabling the detection of genetic alterations in the tumors, liquid biopsy-based biomarkers may be utilized for predicting tumor response to treatment, monitoring anti-tumor response during therapy, and determining prognosis. In this article , Mathai While pancreatic cancer (PC) is relatively uncommon, its mortality rate has remained the highest among all malignant diseases . PC is fAs demonstrated in a number of studies, CTCs, ctDNA, and extracellular vesicles (including exosomes and microvesicles) have been detected in patients with PC ,9,10. AnAccumulating evidence indicates the clinical utility of liquid biopsy for potential biomarkers in patients with malignant diseases . The com"}
+{"text": "Cleidion javanicum, Tinospora crispa, Litsea cubeba, Aesculus assamica, Tadehagi triquetrum, Senna alata, Tithonia diversifolia, Embelia sessiliflora, and Combretum indicum were the most commonly used in treatments of infectious diseases. We suggest that these plant species should be the first to be pharmacologically tested for possible development of medicines, and the remaining species registered should subsequently undergo testing.Pharmacology has developed many drugs to treat infections, but many people, especially in developing countries, cannot afford to purchase them, and still depend on traditional knowledge and local medicinal plants to fight off infections. In addition, numerous microbes have developed resistance to the pharmaceutical drugs developed to fight them, and for many, such as Covid-19, effective drugs remain to be found. Ethnomedicinal knowledge is useful, not only for local people as a source of medicine for primary health care, but also for new pharmacological discoveries. This study aimed to identify the plants that the Karen, the largest hill-tribe ethnic minority in northern and western Thailand, use for treatments of infectious diseases. We present a meta-analysis of data from 16 ethnobotanical studies of 25 Karen villages with the aim of understanding traditional knowledge and treatments and point to potential plants for further pharmacological development. The Karen used 127 plant species from 59 plant families to treat infections and infectious diseases. The Cultural Important Index (CI) showed that the Leguminosae, Euphorbiaceae, Asteraceae, Lauraceae, Apocynaceae, Menispermaceae, and Lamiaceae were the most commonly used families. As for species,  Escherichia coli O104: H4 and nontyphoidal Salmonella, are also severe and sometimes fatal [Infectious diseases have troubled humans through history and killed many all over the world, especially when the diseases were new- and re-emerging. In the 16th century, smallpox and Cocoliztli devasted large numbers of people in Mexico . Over thes fatal .Staphylococcus aureus [From an evolutionary perspective, we now face serious health problems caused by antibiotic-resistant strains of for example s aureus . It is es aureus . Nowadays aureus . Most trOpium was known as a medicine for millennia. The world\u2019s oldest clay tablet was made using this plant by the Sumerians and it was used for pain relief [Quinine is another example of a high impact drug, which was until recently the most potent medicine used to treat malaria [artemisinin, the WHO is no longer recommending quinine as a first-line to treat malaria, and it should be used only when artemisinin is unavailable, due to quinine\u2019s undesirable side effects [Artemisia annua L. emerged as an outstanding inhibitor of parasitic growth, and the enriched extract turned out to be non-toxic. The active ingredient, artemisinin, was identified [Many modern pharmaceuticals were derived from plant sources and metabolic scaffolds, and a significant number were developed based on ethnobotanical knowledge . In clasn relief . Today dn relief . Quinine malaria . Quinine malaria . However effects . Artemisentified  and is nentified ,10, the entified . These eThailand is botanically very rich ,13 and aIn the 16 references, that covered 25 Karen villages, we found 185 reports of plants, which included 127 species in 59 plant families, used to treat infectious diseases. Most reports mentioned uses for treatments of protozoal (23%), bacterial (20%), helminth worm (19%), and viral (16%) infections. There were also 16 reports of uses for fungal infection, and nine reports for small animal infestation . Seven pCleidion javanicum and Tinospora crispa had the highest total CI values. Cleidion javanicum was used to treat bacterial, protozoal, and viral infections, whereas T. crispa was used to treat bacterial, helminth worm, protozoal, and unidentified infection types. Litsea cubeba was another plant with high CI value for treatments of infectious diseases. The Karen used this species to treat bacterial, fungal, protozoal, and viral infections. Three species were used to treat four infection types, namely Litsea cubeba , Tinospora crispa , Rotheca serrata . Six species were used to treat three infection types\u2014Cleidion javanicum , Aristolochia tagala , Acacia caesia , Cajanus cajan , Acacia concinna , and Scoparia dulcis . Nine species were used to treat two infection types, and the remaining species were used to treat a single infection type  [When compared by their cultural importance, as expressed in the CI index, lue (UV) .Andrographis paniculata [Tadehagi triquetrum, Scoparia dulcis, Rotheca serrata, Melicope glomerata, Cleidion javanicum, Chromolaena odorata, and Alstonia scholaris  used for protozoal infections and 28 species (22%) for helminth worm infection , which includes almost all post graduate student theses, scientific articles, and scientific reports from all higher educational institutions in Thailand. Repeated data were removed by screening data from journal articles that repeated student\u2019s theses. Reports that did not use ethnobotanical methods for their studies, and reports that did not provide scientific plant names were also excluded. All scientific plant names were updated following The Plant List website (www.theplantlist.org), which is now merged into the World Flora Online website (http://www.worldfloraonline.org/). All plant uses for treatments of the category infections/infestations in the Economic Botany Data Collection Standard (EBDCS) [Data were collected from published data in Thai university libraries, Thai online journals, online databases , and the database of the Thai Library Integrated System ( (EBDCS)  were incTo rank the plants according to how important they were to the Karen for treating infectious diseases we calculated the Cultural Importance Index (CI)  as:CI = lue (UV) , which ilue (UV) . Becauselue (UV) , which rCleidion javanicum, Tinospora crispa, Litsea cubeba, Aesculus assamica, Tadehagi triquetrum, Senna alata, Tithonia diversifolia, Embelia sessiliflora, and Combretum indicum were the most commonly used. We recommend that these could be candidates for pharmacological research in discoveries of modern medicines for treatments of infectious diseases.We identified medicinal plants used by the Karen for treatments of infectious diseases from 25 Karen villages in northern and western Thailand. We found 127 species in 59 families, which so far is the largest list of anti-infectious plants assembled for the Karen ethnic group. Among the families, Leguminosae, Euphorbiaceae, Asteraceae, Lauraceae, Apocynaceae, Menispermaceae, and Lamiaceae were the most commonly used. Among the species,"}
+{"text": "Self-neglect, the most frequently reported allegation to Adult Protective Services (APS), involves profoundly harmful behaviors often due to functional or cognitive limitations, health problems, and insufficient resources that result in older adults insufficiently meeting their basic needs. Outcomes include high risk of illness, hospitalization and readmission, hospice and nursing home use, early mortality, and placement under surrogate decision-making authority of either well-intended or opportunistic others. APS staff are charged with assessing self-neglect and intervening to reduce client danger. A nationwide APS survey revealed program policies, procedures, resources, and needs affecting the client welfare. For example, 92% of APS programs have provisions for seeking guardianship for self-neglecting individuals, in 25% of programs staff serve as court-appointed guardians, and a wide variety of tools are used within APS programs to assess clients\u2019 mental capacity. Key study findings, implications, and recommendations will be presented."}
+{"text": "The polymeric composite material with desirable features can be gained by selecting suitable biopolymers with selected additives to get polymer-filler interaction. Several parameters can be modified according to the design requirements, such as chemical structure, degradation kinetics, and biopolymer composites\u2019 mechanical properties. The interfacial interactions between the biopolymer and the nanofiller have substantial control over biopolymer composites\u2019 mechanical characteristics. This review focuses on different applications of biopolymeric composites in controlled drug release, tissue engineering, and wound healing with considerable properties. The biopolymeric composite materials are required with advanced and multifunctional properties in the biomedical field and regenerative medicines with a complete analysis of routine biomaterials with enhanced biomedical engineering characteristics. Several studies in the literature on tissue engineering, drug delivery, and wound dressing have been mentioned. These results need to be reviewed for possible development and analysis, which makes an essential study. Recently, biopolymers have attained enormous attention with perspective multifunctional and high-performance biocomposites having a low environmental impact with unique properties like, abundantly available, renewable, eco-friendly, and lightweight. Biopolymeric composites should substitute synthetic materials in optics, biochemistry, and biomedical engineering with versatile applications, and investment and research on these materials increase significantly. Biopolymers and biodegradable synthetic polymers have attracted researchers\u2019 enormous attention in recent years ,2. Such Furthermore, the oil resources are limited and costly, thus adding to the recycling problems. Biopolymeric composite materials will potentially resolve the environmental sustainability-pollution conflicts and will decrease fossil fuel dependency ,5. Thus,(i)Biopolymers: Types of polymers obtained from biological resources, such as living organisms and plants. These are also known as biological macromolecules, biological polymers, or biopolymers.(ii)Derived biopolymers are polymers that are chemically modified, and their monomers are derived from biopolymers as a starting material like polysaccharides, polypeptides, and other biopolymers.Production of durable, stronger, and lightweight multifunctional biopolymeric materials is desired for biomedical applications. However, developing or choosing approaches to meet the architectural design challenges requires a compromise between visions and objectives, usually conflicting in novel biomaterials ,7. It caThe polymers obtained from living resources or biological origin, including plants, animals, or microorganisms, and their system biology processes are called natural polymers. Carbohydrates, i.e., arabinoxylan, chitosan and starch, proteins, e.g., gelatin and keratin, and polyhydroxyalkanoates (PHAs) such as poly-(3-hydroxybutyrate) [P(3HB)], are all known as biopolymers . BiopolyNonetheless, physical, chemical, and biological action can turn them into useful multifunctional materials for several purposeful applications . The cheChitosan is a well-known compound from the carbohydrate polysaccharide family. It has gained popularity due to bio-sustainability, biodegradability, and compatibility in various fields. It is easily produced from marine sources  and can be used in different biopolymeric composite materials . Among tPolymeric composites come from a wide range of sources, from common synthetic materials (petroleum-based) including polystyrene to natural biopolymers like cellulose, proteins, and microbial polyesters, which are important for biological structure and function ,19. A brCategory 1: Polymers extracted or separated from biomass, such as starch, cellulose, arabinoxylan, and keratin.Category 2: Polymers obtained from standard chemical processing using renewable biopolymer originated monomers such as polylactic acid (PLA), cellulose acetate (CA), etc., are produced through the fermentation of carbohydrate feedstock.Category 3: Polymers acquired from microorganisms processing, e.g., mainly PHAs, but bacterial cellulose is under development.A composite is a generally recognized material composed of one to several different materials or polymers with a marked difference in chemical or physical properties. Composites are used to produce customized properties through enhancing or imparting certain features that cannot be demonstrated by particular homogeneous substances. When polymeric composites contain specific biological phases, they are defined as bio-composites ,21,22. BThe biopolymers like arabinoxylan, chitosan, guar gum, and xyloglucan have potential benefits over synthetic polymers. These provide a fundamental variety of alternatives in biomedical science for efficient polymeric biomaterials and composite materials. Polysaccharides are potential candidates to give multi-functional, biocompatible, mechanically stable, sustainable, and biodegradable materials. Henceforth, they are emerging as ideal candidates for synthesizing novel composite materials, offering therapeutic efficacy and controlled drug release pertinent for several biomedical applications, and wound remedial and tissue engineering . The polComposites based on polysaccharides, including arabinoxylan, chitosan, and xyloglucan have exhibited an innovative potential as carriers to deliver therapeutic agents, including genes, biomolecules, and biological drugs, as shown in Controlled drug delivery aims to administer therapeutic agents at a steady speed and maintain the effective therapeutic window at the targeted site, usually in blood. It offers economic and desirable therapeutic results that decrease or remove dose-related adverse side effects and toxicity complications and increase patient recovery and comfort. It is believed that the most desirable drug features from biomaterial systems are controlled degradation and sustainable release after accumulation at the targeted site . This coThe targeted drug delivery system usually needs to activate the cellular sites for a controlled release of therapeutic payloads. Accordingly, a customized drug delivery approach needs to optimize precursors\u2019 synthesis or functionalization, composite manufacturing conditions, and drug encapsulation strategy to fit well with the desired release kinetics ,40. HencTissue engineering involves the synthesis of biomaterial scaffolds to treat or regenerate defective tissue, as illustrated in Tissue engineering was, therefore classified into two types:Bone tissue engineering.Skin tissue engineering.Bone tissue engineering (BTE) is a capable technique that aims at 3D bone scaffolding, containing viable cells and bioactive molecules . BTE focBones constitute the basis of our physical locomotion.Bones support our load-bearing skeleton and our internal organs with safety.The bones retain the necessary biological elements for hematopoiesis.The bones adsorb highly toxic metals due to a porous matrix.Bones retain vital electrolytes homeostasis by storing calcium and phosphate ions.The bone undergoes a continuous resorption and reconstruction process that undergoes the exchange of chemicals and structural remodelling due to internal intermediaries and external mechanical standards. Bone was historically and most accurately named the ultimate intelligent material because of its scarce regenerative adaptability. Functional bone tissue engineering includes the fusion of the newly healed bone with the adjacent host bone and, most significantly, the native bone functions ,53,54. TVarious engineering methodologies could include adequate extracellular matrix molecules or adherent ligands that stimulate stem cells and mediate earlier to regenerate bone tissues. Bone tissue engineering should be aimed at fabricating scaffolds to promote angiogenesis that incorporates growth factors and has the porous structure needed for vascular growth ,61. TissSubsequently, bone tissue therapies in hospitals need a more definitive strategy, such as using in-vitro scaffold regeneration machines to restore bone functions in vivo. 3D printing or additive manufacturing (AM) has been frequently used in different industries, including construction, design and development, biomechanical, and tissue engineering ,65. The Nonetheless, poly(lactic) acid (PLA) is among the synthetic polymers used primarily for 3D scaffold printing . It is nThe skin is considered one of the most sensitive organs due to its multi-functional roles, such as acting as a protecting enclosure for internal organs\u2019 safety, regulating the body\u2019s temperature, and acting as a sense organ ,94. NormThe outmost waterproof layer is the epidermis, which acts as a defensive barricade against pathogens and foreign materials, and plays a critical role in body temperature and humidity regulation ,96. KeraAutologous keratinocytes are formed and grown in interconnected layers of the epithelium, and these are substituted for those with large skin deficiencies. Approximately, after more than 140 replications, we can isolate clonogenic keratinocytes or holoclones from the skin and gradually increase culture. In many studies related to tissue engineering, polymeric materials have multifunctional properties to support stem-cell growth and differentiation. These studies have been proved multifunctional properties of polymeric material to grow stem cells based on their abilities to regenerate various skin lines ,115. TheWounds are an irregular skin puncture, breakage, or deformity of the skin due to thermal/physical damage or chronic disease . DependiThe physiological regeneration of wounds includes coordinated cooperation between different biological systems. It comprises a cascade of regulated activities to heal a wound completely. Hysteresis and blood clotting begins as a lesion, occurs in any part of the body, and the main objective of such processes is to prevent instant exsanguinations. This lesion is also a secondary long-term target and a matrix for adhesion to invading cells ,133. HomMany biopolymers, including fibrous proteins and various polysaccharides, are commonly engaged in wound care and treatment. These biocompatible, biodegradable polymeric matrixes maintain an atmosphere analogous to the extracellular environment and speed up the usually slow wound healing process ,139,140.Hydrogels were utilized in biomedical research and clinical applications, including tissue engineering, regenerative medicine, cancer treatment, infectious diseases, controlled drug delivery, and peptide delivery ,184. TheA better understanding of the sequential, structural, and functional characteristics of natural polymers plays a substantial role in designing and synthesizing multifunctional polymeric materials. These advanced artificial biomaterials have abilities of self-assembly and stimuli response under certain conditions to promote cell interaction and proliferation ,197,198.Recent developments in genetic engineering have promised the design and synthesis of advanced biomaterials based on artificial proteins. These biomaterials have unique performance compared to their native counterparts, such as enhancing the self-assembly into the fibrous structures ,206. DifThis review article aims to address the possible biopolymers, biocomposite materials, and potential applications in drug release, tissue engineering, wound healing, and advanced functional biomaterial. Previously, petroleum-based synthetic polymers were considered the best biomaterials in tissue engineering and regenerative medicines. Still, due to depletion in resources, biodegradability, eco-friendly and environmental sustainability make scientists and research to replace them with other biopolymers. The biopolymers are the best substitutes for synthetic polymers obtained from petroleum with considerable renewable, biodegradable, environmental, and eco-friendly properties. The biopolymers don\u2019t support mechanical properties like high tensile strength, impact strength, flexural strength, thermal stability, etc. However, their ceramic composites display sufficient mechanical strength to support load-bearing applications. Still, further attention, developments, and improvements are necessary. The traditional blending techniques have been adopted to tailor the microstructural properties of biocomposite by adding reinforcements. Sometimes, their structural properties are also enhanced by blending them with synthetic polymers . Different fillers have been recently introduced into the biopolymers to prepare highly functional composites for the biomedical industry.Study in this field has grown dramatically in recent decades, which has been confirmed by the resulting rise in the number of newly published materials. In many industries, including packaging, vehicles, building, electronics, and most significantly, biopolymer composites find countless daily applications in medicine. The widely used biochemical recipes for biopolymer composites synthesis include injecting, extrusion, and in situ synthesis. The introduction of graphene and its derivatives as fillers into biopolymers strengthened their mechanical properties to obtain desired biomaterials, such as tensile, effect, flexural, and other structural properties. The metallic nanoparticles also have played a vital role as fillers to synthesize biocomposite to enable several opportunities to explore their innovative properties in medical applications. Mechanical behavior and poor dispersion are the major problems that limit the use of biopolymers to synthesize biocomposites. The fillers form agglomerates with a biopolymer matrix, resulting in poor interfacial bonding resulting in poor mechanical properties with poor structural uniformity. Such composites result in many other odd parameters, including high-temperature sensitivity, moisture sensitivity, low impact strength, and shelf life, etc. Future directions lead towards new biomaterial to address the stated factors and fit well with the economic viability, recycling processes and being eco-friendly."}
+{"text": "As health indicators such as life expectancy have improved for many older adults, some older adults experience a disproportionate amount of preventable disease, death, and disability. The causes of health disparities among older adults are multidimensional in that disparities are due to multiple, interacting factors such as socioeconomic status, disability status, geographic location, and race/ethnicity. Achieving health equity in late-life requires innovative strategies to address interconnected environmental, sociocultural, behavioral and biological factors that impede opportunities to achieve optimal health and quality of life. This symposium will present state-of-the-art innovations and strategies employed among socially disadvantaged racial, ethnic, and other population groups, and communities. We will discuss innovations in the workforce enhancements with older adult peer support specialists and community health workers, community engagement techniques in program design, and digital solutions aimed at addressing multiple dimensions of health in older adults."}
+{"text": "Mitochondrial dysfunction plays a central role in the formation of neuroinflammation and oxidative stress, which are important factors contributing to the development of brain disease. Ample evidence suggests mitochondria are a promising target for neuroprotection. Recently, methods targeting mitochondria have been considered as potential approaches for treatment of brain disease through the inhibition of inflammation and oxidative injury. This review will discuss two widely studied approaches for the improvement of brain mitochondrial respiration, methylene blue (MB) and photobiomodulation (PBM). MB is a widely studied drug with potential beneficial effects in animal models of brain disease, as well as limited human studies. Similarly, PBM is a non-invasive treatment that promotes energy production and reduces both oxidative stress and inflammation, and has garnered increasing attention in recent years. MB and PBM have similar beneficial effects on mitochondrial function, oxidative damage, inflammation, and subsequent behavioral symptoms. However, the mechanisms underlying the energy enhancing, antioxidant, and anti-inflammatory effects of MB and PBM differ. This review will focus on mitochondrial dysfunction in several different brain diseases and the pathological improvements following MB and PBM treatment. There are several common causal factors for brain disorders, including oxidative stress, inflammation, transcriptional alterations, and excitotoxicity. Mitochondrial dysfunction plays a central role in the induction of these factors which lead to neurological disorders . As a reMitochondria are organelles found in eukayotic cells and are characterized by a double membrane structure . In euka2+ imbalance, dysfunctional electron transport, impaired mitochondrial trafficking, altered mitochondrial dynamics, and defective mitophagy, are involved in various brain diseases  . T. T295]. In pathological states, the increased mitochondrial membrane potential mediated by PBM is able to lower ROS production , 295. As2+ overload, aberrant mitophagy, altered mitochondrial dynamics, impaired mitochondrial trafficking, and subsequent neuroinflammation (Fig. MB and PBM are two promising therapeutic approaches for brain disorders. Both MB and PBM target mitochondria, although their underlying mechanisms differ Table . The stuion Fig. , of whic"}
+{"text": "Antenatal care (ANC) aims of monitoring wellbeing of mother and foetus during pregnancy. We validate a set of indicators aimed of measuring the quality of ANC of women on low-risk, uncomplicated pregnancy through their relationship with maternal and neonatal outcomes. We conducted a population-based cohort study including 122,563 deliveries that occurred between 2015 and 2017 in the Lombardy Region, Italy. Promptness and appropriateness of number and timing of gynaecological visits, ultrasounds and laboratory tests were evaluated. We assessed several maternal and neonatal outcomes. Log-binomial regression models were used to estimate prevalence ratio (PR), and corresponding 95% confidence interval (95% CI), for the exposure\u2192outcome association. Compared with women who adhered with recommendations, those who were no adherent had a significant higher prevalence of maternal intensive care units admission , low Apgar score , and low birth weight . Benefits for mothers and newborn are expected from improving adherence to guidelines-driven recommendations regarding antenatal care even for low-risk, uncomplicated pregnancies. Antenatal care (ANC) aims to monitor and improve the wellbeing of the mother and foetus, detect complications, prepare for birth, and promote healthy behaviours ,2. ModerFor example, ANC standards have been recently updated by the World Health Organization , and nowA system for assessing integrated care pathways for specific conditions, including pregnancy, is being developed by a national group of experts under the Italian Health Ministry: the monitoring and assessing diagnostic-therapeutic paths (MAP) working group . Taking All Italian citizens have equal access to health care services as part of the National Health Service (NHS). A system of Healthcare Utilization (HCU) databases allows each Italian region to manage NHS. HCU data concern a variety of information about services supplied to NHS beneficiaries , including diagnosis at discharge and inpatient services provided from public or private hospitals, outpatient drug prescriptions, specialist visits, and diagnostic exams. In addition, a database reporting the Certificates of Delivery Assistance , providing detailed information on the mother\u2019s socioeconomic traits, as well as medical information on pregnancy, childbirth, and child presentation at delivery, is consistently managed in all Italian regions. As a unique personal identification code is used for all databases within each region, their record linkage allows searching out the complete care pathway of beneficiaries of NHS. In order to preserve privacy, identification codes are automatically converted into anonymous codes, and the inverse process is prevented by deletion of the conversion table. Details of healthcare utilization databases in the field of mental health have been reported elsewhere ,14,15,16Specific diagnostic and therapeutic codes used for the current study are given in Data used for the present study were retrieved from the HCU databases of Lombardy, a region of Italy that accounts for about 16% (more than ten millions) of its population. Childbirths occurred from female residents in Lombardy during the period 1 January 2015 to 31 December 2017  were selected from the CeDAP database. Women who became beneficiaries of the regional NHS from less than two years before the last menstrual period (LMP) were excluded, to allow investigating their previous history. Exclusion was extended to women with signs suggestive of intermediate/high-risk, complicated pregnancy, the latter being qualified according to three time-related criteria: (i) the entire reproductive history ; (ii) two years before LMP ; and (iii) current pregnancy . The remaining women, who we considered at low-risk, i.e., those expected to experience an uncomplicated pregnancy, were included in the study cohort. Selected maternal traits of the study cohort including age at delivery, nationality, marital status, education, employment and parity, were considered.In accordance with the National System for physiological pregnancy guidelines, recommendations regarded promptness and appropriateness of number and timing of ANC, including gynaecological visits, ultrasounds, and laboratory tests . ApproprOther than for each individual recommendation, the cumulative number of recommendations was calculated. A score of increasing adherence was developed by categorizing each cohort woman, according to whether she complied with none or almost none (0 or 1), just some (2), almost all (3), or all (4) of the recommendations during pregnancy.Both maternal and neonatal adverse outcomes, expected to be worse among women who did not adhere with recommendations, were considered. Maternal outcomes included those that occurred during delivery  and/or in the following seven days , and/or in the following 42 days . Women who did not have vaginal birth  were excluded from the cohort for calculating the proportion of women who experienced third and fourth degree perineal tears.Neonatal outcomes included low Apgar scores at five minutes , low birth weight , and late preterm birth . The expanded cohort, including women with gestational age ranging from the 34th to the 42nd week, was considered for calculating the proportion of women who experienced late preterm birth. Information on maternal and neonatal outcomes were retrieved from the CeDAP and the inpatient service database, where appropriate.Descriptive, univariate methods were used for measuring prevalence of women who were adherent with recommendations, and of maternal and neonatal outcomes.Log-binomial regression models were fitted to estimate the prevalence ratio (PR), and corresponding 95% confidence interval (95% CI), measuring the association between exposure to no-adherence with a given recommendation and the risk of a maternal or neonatal outcome. The model that included one recommendation at a time as the only covariate, as well as the model that included other maternal features  were fitted, and the corresponding estimates were respectively denoted (unadjusted and adjusted ones). In addition, an overall log-binomial regression model was built by considering the association between the score of increasing adherence and the risk of each maternal or neonatal outcome while adjusting for the above-mentioned baseline data.p-values were reported based on 2-sided tests and p < 0.05 was considered statistically significant.Several tools were used for measuring the associations of interest. First, as we aimed to test the association between four recommendations and eight outcomes , we reasoned on the high probability of generating false positive associations simply by chance . For this reason, we accounted for multiple comparisons correction by using the false discovery rate (FDR) proposed by Benjamini and Hochberg . All p-vSecond, we realized that low exposure prevalence was expected to occur in our cohort . For this reason, a cautious approach was adopted by excluding from the calculations exposure\u2013outcome pairs for which our sample size was not sufficient to appreciate a 2.0 minimum detectable PR, with a 0.80 power .Third, data on maternal characteristics were sometimes missing. Restricting analyses to the subset of women with all of the data observed would have resulted in a significant loss of information and possibly biased estimations. For this reason, we decided to generate appropriate values of missing data for those women with missing covariates. With this aim, the iterative procedure known as fully conditional specification (FCS) was used .Fourth, as the adherence with recommendations, as well as the considered outcomes, are likely affected by relevant characters not recorded in healthcare databases such as ours, residual confounding should be taken into account. With this aim, the high-dimensional propensity score (HDPS) stratification design was adopted to account for residual confounders . ExposurFifth, women who had shorter pregnancy duration  had less time to experience appropriate care . Since this may lead to misclassified immortal person-time , we did Finally, the robust estimator, which took into account correlations in women with multiple pregnancies during the study period, did not substantially modify the estimates; correlation structures were omitted from analyses.Among the 233,239 deliveries that occurred in Lombardy from 2015 to 2017, 27,886 (12%) were excluded because the mother was an NHS beneficiary for less than two years before the last menstrual period (LMP); others 82,790 (40.3%) had signs suggestive of intermediate/high-risk, complicated pregnancies, detected from the entire reproductive history (1121), from investigations limited to two years before LMP  or from the current pregnancy . The remaining 122,563 mother\u2013newborn pairs were included in the study cohort .Finally, a trend towards increasing prevalence of neonatal outcome  with decreasing number of complied recommendations was observed . ConversAccording to the very stringent criteria set up by our MAP group for post-hoc definition of low-risk, uncomplicated pregnancies, around 60% of the pregnancies observed in the Italian region of Lombardy, should have been candidates for \u201croutine\u201d ANC. The complementary figure that about 40% of pregnancies should be considered at intermediate/high-risk, a percentage enormously higher than expected 6\u201333% ,24,25, mIn our cohort of pregnancies classified at low-risk for complications where a low prevalence of adverse outcomes had been consequently manifested, a high proportion of women (about 88%) adhered with all of the recommendations established by guidelines. The new important finding, however, is that lack of adherence to recommendations on gynaecologic visits, ultrasounds, and laboratory tests, and was associated with several maternal and neonatal adverse outcomes. The strength of these associations was not trivial since maternal outcome prevalence observed among no-adherent women was from 20% (gynaecologic visit promptness and pregnancy-related complications) to 210% (gynaecologic visit appropriateness and intensive care unit transferring) higher than those observed among adherent women. Analogously, risk excess of adverse neonatal outcomes (in particular low-Apgar score) was observed for women who did no adhere to recommendations on appropriateness of gynaecologic visits (60%) and ultrasounds (110%). It should be emphasized that, among the 28 investigated associations, none suggested a protective action of the non-adherence to recommendations. In addition, we found that, beyond each individual recommendation, the cumulative number of complied recommendations predicted neonatal adverse outcome\u2014that is, the higher the value, the better the protective action on Apgar score and birth weight. Among the possible explanations for this finding, the more reasonable the risk of adverse neonatal outcome might be reduced, even in low-risk, uncomplicated pregnancies by structured care, of which regular control might be a proxy. Anyhow, under the point of view of public heath, these findings taken together are very important for reaching a consensus on how to measure and compare the quality of ANC in low-risk, uncomplicated pregnancies, developing process improvements, and reducing practice heterogeneity.One explanation of our results is that non-adherence with recommendations may be a surrogate of uncontrolled factors linked with overall health-seeking behaviour, which accompany, but are different from, a better adherence. For example, women more adherent might be more compliant with healthy lifestyle advice , and might have healthier anthropometric features . It should be emphasized, however, that such unmeasured factors are expected to be intermediate outcomes of better adherence. That is, women who regularly attend gynaecological/obstetric outpatient clinics, receive advice for healthier behaviour, so that these factors should mediate the action of adherence on the considered outcomes, rather than confound its effect ,31,32,33Our study has strengths and limitations. It is a very large investigation reporting real-world evidence on the association between adherence with recommended ANC in low-risk, uncomplicated pregnancy, and maternal and neonatal adverse outcomes, a field which, according to our best knowledge, has never been investigated. On the other hand, random and systematic uncertainty of observational evaluations, especially in the setting of ANC, should be carefully considered. As far as random uncertainty is concerned, despite avoiding underpowered exposure\u2013outcome associations, weak associations  likely had escaped. In addition, despite the Benjamini and Hochberg method allowed accounting for multiple testing, a power loss must to put in the bill . As far In our large cohort of women experiencing low-risk, uncomplicated pregnancy, the lack of adherence with recommendations established by guidelines  was associated with several maternal and neonatal adverse outcomes. This suggests that maternal and infant health might be improved even in low-risk, uncomplicated pregnancies by structured care, of which regular control, by using \u201cadministrative data\u201d from Italian NHS databases, might be a proxy. On the policymaker point of view, tight control through regular clinical examinations must consider the cornerstones of national guidance, national audits, and quality improvement incentive schemes.\u201cMonitoring and assessing care pathways (MAP)\u201d working group Italian Ministry of Health, Dept of Health Planning: Silvia ARC\u00c0, Donata BELLENTANI, Velia BRUNO, Simona CARBONE, Carla CECCOLINI, Angela DE FEO, Lucia LISPI, Rosanna MARINIELLO, Maurizio MASULLO, Federica MEDICI, Paola PISANTI, Modesta VISCA, Rinaldo ZANINI; Dept of health prevention: Teresa DI FIANDRA, Natalia MAGLIOCCHETTI, Giovanna ROMANOUniversity of Milano-Bicocca, Laboratory of Healthcare Research & Pharmacoepidemiology: Anna CANTARUTTI, Giovanni CORRAO, Pietro PUGNI, Federico READepartment of Epidemiology Lazio Region: Marina DAVOLI, Mirko DI MARTINO, Adele LALLOAosta Valley Region: Patrizia VITTORI, Giuliana VuillerminCampania Region: Alfonso Bernardo, Anna FuscianteEmilia Romagna Region: Laura BELOTTI, Rossana DE PALMA, Enza DI FELICEFriuli Venezia Giulia Region: Roberta CHIANDETTI, Elena CLAGNAN, Stefania DEL ZOTTO, Andrea DI LENARDA, Aldo MARIOTTO, Marisa PREZZA, Loris ZANIERLazio Region: Marina DAVOLI, Danilo FUSCO, Mirko DI MARTINO, Adele LALLO, Chiara MARINACCILombardy Region: Antonio LORA, Luca MERLINOMarche Region: Liana SPAZZAFUMO, Simone PIZZIMolise Region: Maria SIMIELE, Giuseppe MASSAROPuglia Region: Ettore ATTOLINI, Vito LEPORE, Vito PETRAROLOSicily Region: Giovanni DE LUCA, Giovanna FANTACI, Sebastiano POLLINA ADDARIO, Salvatore SCONDOTTOTuscany Region: Francesco BELLOMO, Mario BRAGA, Valeria DI FABRIZIO, Silvia FORNI, Paolo FRANCESCONI, Francesco PROFILIVeneto Region: Francesco AVOSSA, Matteo CORRADIN, Silvia VIGNAResearch and Health Foundation : Letizia DONDI, Nello MARTINI, Antonella PEDRINI, Carlo PICCINNINational Agency for Regional Health Services: Mimma COSENTINO, Maria Grazia MARVULLIANMCO  Study Center: Aldo MAGGIONIPolytechnic University of Marche (coordinator): Andrea BUCCI, Flavia CARLE, Marianxhela DAJKO"}
+{"text": "Light is a key factor that affects phytochemical synthesis and accumulation in plants. Due to limitations of the environment or cultivated land, there is an urgent need to develop indoor cultivation systems to obtain higher yields with increased phytochemical concentrations using convenient light sources. Light-emitting diodes (LEDs) have several advantages, including consumption of lesser power, longer half-life, higher efficacy, and wider variation in the spectral wavelength than traditional light sources; therefore, these devices are preferred for in vitro culture and indoor plant growth. Moreover, LED irradiation of seedlings enhances plant biomass, nutrient and secondary metabolite levels, and antioxidant properties. Specifically, red and blue LED irradiation exerts strong effects on photosynthesis, stomatal functioning, phototropism, photomorphogenesis, and photosynthetic pigment levels. Additionally, ex vitro plantlet development and acclimatization can be enhanced by regulating the spectral properties of LEDs. Applying an appropriate LED spectral wavelength significantly increases antioxidant enzyme activity in plants, thereby enhancing the cell defense system and providing protection from oxidative damage. Since different plant species respond differently to lighting in the cultivation environment, it is necessary to evaluate specific wavebands before large-scale LED application for controlled in vitro plant growth. This review focuses on the most recent advances and applications of LEDs for in vitro culture organogenesis. The mechanisms underlying the production of different phytochemicals, including phenolics, flavonoids, carotenoids, anthocyanins, and antioxidant enzymes, have also been discussed. Among the different environmental factors, light is the most important factor that affects plant gene expression, enzyme activity, growth, development, and nutritional composition ,2,3. RecLight is a primary factor that affects plant development, physiology, and cellular differentiation . EnvironCunninghamia lanceolata and Nadeem et al. [Ocimum basilicum under LED irradiation. Plant growth, development, and metabolite production are strongly affected by the light spectrum of the LEDs. A previous study suggested that the blue light spectrum was involved in morphogenesis, phototropism, the leaf photosynthetic process, and stomatal opening [Plants perceive light through photoreceptors, such as red light-sensitive phytochromes, blue light-sensitive phototropins, and cryptochromes, which regulate several specific physiological responses, including organogenesis and metabolite synthesis ,29. The m et al.  in Ocimu opening . Red LEDThe present review highlights the variation in in vitro organogenesis and somatic embryogenesis among different plant species grown under LED irradiation. Additionally, this review elucidates the effects of LED irradiation on secondary metabolite accumulation and antioxidant properties of plants. Finally, the effects of LED irradiation on the expression of genes related to the production of phenolic acids, flavonoids, carotenoids, and chlorophyll have been discussed.Carpesium triste Maxim [C. triste [Cynoglossum officinale grown under dark conditions showed increased CAT activity, whereas those grown under blue and white light conditions showed reduced CAT activity [2O2 [Curculigo orchioides grown under combined red and blue LED irradiation [Prunus avium and strawberries grown under blue LED irradiation. In similar studies, enhanced SOD and CAT activities were observed during adventitious shoot formation in Gladiolus hybridus [Albizia adorratissima [2O2 dismutation [Light is an important factor that affects several biochemical pathways in plants during their growth and development. Antioxidant compounds, such as phenolic acids, vitamins, anthocyanins, carotenoids, and \u03b1-tocopherol, are widely affected by the duration of light exposure and spectral wavelength of light sources ,38,39. Ste Maxim . Increas. triste , wheat [. triste , pea [44. triste   Spreng [C. orchioides cultured under red LED irradiation. Similarly, enhanced POD activity was observed in C. orchioides irradiated with blue LEDs [In several instances, increased bioactive compound production observed in plant species grown in vitro could be maintained under irradiation with different LEDs ,133,134.i Carol\u2019 , and myradiation . Irradianieri L.  and Plec) Spreng . Increas) Spreng  observedlue LEDs . Additiolue LEDs ,140,141,Tocopherols, synthesized through the isopropenoid pathway, are associated with the antioxidant properties of green plants . These pFtPSY, FtLCYB, FtCHXB, FtCHXE, FtLCYe, and FtZEP genes, which are associated with carotenoid biosynthesis, following white LED irradiation [CitPSY, CitZDS, CitPDS, and CitLCY, in citrus species, indicating a differential stimulatory role of LED irradiation in the regulatory mechanism of carotenoid biosynthesis in plants.Carotenoids, including \u03b2-carotene and lutein, are present in most green plants and green algae and are associated with light harvesting and the transfer of energy to the reaction center of photosystems ,150. Theadiation . In a siadiation  observedCyclocarya paliurus grown under blue LED irradiation [p-coumaric acid and epicatechin levels were observed in wheat sprouts grown under blue LED irradiation [Anoectochilus roxburghii, further resulting in increased flavonoid accumulation [Flavonoids are widely distributed phytochemicals found in plants and are involved in multiple mechanisms, including protection against pathogens and ultraviolet (UV) radiation, flower coloration, and male fertility ,159,160.adiation . Park etadiation  reportedadiation . IrradiaCamellia sinensis (L.) O. Kuntze \u2018Zhonghuang 3\u2032 grown under blue LED irradiation [MD-MYB10 and MdUFGT genes, which are related to anthocyanin biosynthesis [V1MYBA1-2, VIMYBA2, and VvUFGT, was increased with the enhancement in anthocyanin accumulation in grape berries irradiated with blue LEDs [Anthocyanins are soluble flavonoids that are widely distributed in plants and are associated with seed dispersal, pollination, stress resistance, and flower coloration. They are widely used in the food industry for coloring purposes . Additioadiation . These radiation . Accordiynthesis . Moreoveynthesis . In anotlue LEDs .Brassica microgreens, respectively. A similar trend was also observed in lettuce leaves [p-hydrobenzoic acid, and gentisic acid levels in Pachyrhizus erosus grown under red LED irradiation. An increased concentration of p-coumaric acid was observed in P. erosus grown under blue LED irradiation. The accumulation of phenolic compounds, such as p-coumaric, gallic, ferulic, and hydroxybenzoic acids, was increased in wheat sprouts irradiated with blue LEDs [Phenolic compounds are ubiquitous in most higher plants and are associated with plant defense systems against abiotic and biotic factors, including UV radiation, high temperature, excess light, pathogen attack, and wounding ,171. Phee leaves ,173. Blue leaves . Other se leaves , indicate leaves ,174,175.lue LEDs . Severallue LEDs .TaPA1, TAPA2, TaC4H, TaCHI, TaCHS, and TaF3H genes; these genes are involved in phenolic compound synthesis through the phenylpropanoid biosynthesis pathway [Cyclocarya paliurus irradiated with blue LEDs [Irradiation with blue LEDs triggered increased phenolic compound accumulation and phenolic compound biosynthesis-related gene expression ,74,77. I pathway . The higlue LEDs .In this review, we aimed to provide updates on the innovative use of LEDs in improving nutritional quality of plants grown in vitro and in vivo. Moreover, in the present review, we summarized the expression patterns of various genes related to phytochemical biosynthesis in response to different LED spectral wavelengths. It is important to identify the appropriate light quality and intensity to increase the quantity and quality of important phytochemicals associated with nutrition and human health. It can be concluded from this overview of research that the flexibility of LED irradiation allows the enhancement of nutritional levels of vegetables and phytochemical contents of plant species. Moreover, irradiation with LED combinations at different ratios and combination of LEDs with normal light (FL) sources can enhance phytochemical content, biomass, and nutritional quality of vegetables and medicinal plants. However, detailed studies on the association between LEDs and their phytochemical accumulation-promoting effects as well as the underlying physiological and molecular mechanisms are required. We observed that different plant species respond differentially to various LED spectral wavelengths. Therefore, further research is required to understand the application of LEDs for the successful growth and mass propagation of plants."}
+{"text": "AbstractINBO). It contains more than 94,000 sampling events (site counts), covering over 710,000 species observations (and zero counts when there is no associated occurrence) and 36 million individual birds for the period 1991\u20132016. The dataset includes information on 167 different species in nearly 1,100 wetland sites. The aim of these bird counts is to gather information on the size, distribution, and long-term trends of wintering waterbird populations in Flanders. These data are also used to assess the importance of individual sites for waterbirds, using quantitative criteria. Furthermore, the waterbird counts contribute to international monitoring programs, such as the International Waterbird Census  and fulfil some of the objectives of the European Bird Directive, the Ramsar Convention, and the Agreement on the Conservation of African-Eurasian Migratory Waterbirds (AEWA). Here the dataset is published as a standardized Darwin Core Archive and includes for each event: a stable event ID, date and location of observation and a short description of the sampling protocol, effort and conditions (in the event core), supplemented with specific information for each occurrence: a stable occurrence ID, the scientific name and higher classification of the observed species, the number of recorded individuals, and a reference to the observer of the record (in the occurrence extension). Issues with the dataset can be reported at https://github.com/inbo/data-publication/issues.\"Watervogels \u2013 Wintering waterbirds in Flanders, Belgium\" is a sampling event dataset published by the Research Institute for Nature and Forest  locations and counts from before 1991.https://creativecommons.org/publicdomain/zero/1.0/). We would appreciate it if you follow the INBO norms for data use (https://www.inbo.be/en/norms-data-use) when using the data. If you have any questions regarding this dataset, do not hesitate to contact us via the contact information provided in the metadata or via opendata@inbo.be.We have released this dataset to the public domain under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication ( AEWA). These results are also used for informed decision-making by conservation bodies, planners and developers, and contribute to the sustainable use and management of wetlands and their dependent waterbirds.Counting waterbirds has a long tradition in Flanders, going back to the 1960s. The aim of this long-running monitoring scheme is to gather reliable information on the numbers, trends, and distribution of these species during their winter and migration period. This project provides data for international treaties and conventions such as the European Union (EU) Birds and Habitats Directives, the Ramsar Convention on Wetlands, and the Agreement on the Conservation of African-Eurasian Migratory Waterbirds (INBO (http://watervogels.be). This site is only available in Dutch and a login is required. Since 2012, data gathered in the application are available as open data on GBIF. There is a three-year latency between the moment of recording and the moment of data publication, due to quality control and specific agreements with the regional coordinators. The counts are organized with the assistance of Natuurpunt, a regional nature conservation organization. The database is managed by the INBO and is the source for this dataset.Counts and additional information can be recorded through the waterbirds web application, developed by AEWA and thus does not only include species that belong to the order Anseriformes, but all species which are ecologically dependent on wetlands for at least part of their annual cycle. The dataset includes 167 species  belonging to the following species groups: divers, grebes, cormorants, herons, storks, spoonbills, swans, geese, ducks, coots, rails, cranes, waders, gulls, and terns. Non-native species that have been introduced or escaped are also included. The top five of most observed species, collectively representing one third of the dataset, are Anasplatyrhynchos, Fulicaatra, Gallinulachloropus, Ardeacinerea, and Phalacrocoraxcarbo. The 30 most frequently counted  taxa are shown in Figure The term waterbirds is used as defined in the Chloephagamelanoptera which is not listed by Euring.For all 183 taxa, the Dutch vernacular name is indicated in vernacularName. To allow interoperability with other databases, the Euring code is added in taxonID for all taxa, except for Kingdom: Animalia Phylum: Chordata (chordates)Class: Aves (birds)Families: Alcidae (auks), Anatidae , Ardeidae (herons), Charadriidae , Ciconiidae (storks), Gaviidae (divers), Gruidae (cranes), Haematopodidae (oystercatchers), Laridae (gulls), Pelecanidae (pelicans), Phalacrocoracidae (cormorants), Phoenicopteridae (flamingos), Podicipedidae (grebes), Rallidae (rails), Recurvirostridae (avocets & stilts), Scolopacidae (sandpipers), Stercorariidae (skuas), Threskiornithidae (ibises & spoonbills)Species: Actitishypoleucos, Aixsponsa, Aixgalericulata, Allealle, Alopochenaegyptiaca, Anasformosa, Anaspenelope, Anascarolinensis, Anascrecca, Anasbahamensis, Anasundulata, Anasacuta, Anasplatyrhynchos, Anascyanoptera, Anasamericana, Anasplatyrhynchos, Anasdiscors, Anassibilatrix, Anaspoecilorhyncha, Anasstrepera, Anascapensis, Anasfalcate, Anasrubripes, Anasquerquedula, Anasclypeata, Anasflavirostris, Anasversicolor, Anseranser, Anseralbifrons, Anserfabalis, Anseralbifrons, Anseranser, Ansercygnoides, Anserindicus, Ansererythropus, Anserfabalis, Anserbrachyrhynchus, Anserfabalis, Ardeaalba, Ardeapurpurea, Ardeacinerea, Arenariainterpres, Aythyamarila, Aythyanyroca, Aythyafuligula, Aythyacollaris, Aythyavalisineria, Aythyaferina, Aythyaaffinis, Botaurusstellaris, Brantabernicla, Brantasandvicensis, Brantaleucopsis, Brantacanadensis, Brantahutchinsii, Brantabernicla, Brantabernicla, Brantaruficollis, Bubulcusibis, Bucephalaalbeola, Bucephalaclangula, Cairinamoschata, Calidrismaritima, Calidrisferruginea, Calidristemminckii, Calidrisalba, Calidrisalpine, Calidrisminuta, Calidrismelanotos, Calidriscanutus, Callonettaleucophrys, Cepphusgrylle, Charadriusmorinellus, Charadriusalexandrinus, Charadriushiaticula, Charadriusdubius, Chencaerulescens, Chencanagica, Chenrossii, Chenonettajubata, Chlidoniashybrida, Chlidoniasniger, Chloephagapicta, Chloephagamelanoptera, Chroicocephalusridibundus, Ciconiaciconia, Clangulahyemalis, Crexcrex, Cygnusatratus, Cygnusolor, Cygnuscygnus, Cygnuscolumbianus, Dendrocygnaautumnalis, Dendrocygnabicolor, Egrettagarzetta, Eudocimusalbus, Fulicaatra, Gallinagogallinago, Gallinulachloropus, Gaviaarctica, Gaviastellata, Gaviaimmer, Grusgrus, Haematopusostralegus, Himantopushimantopus, Ichthyaetusmelanocephalus, Ixobrychusminutus, Larushyperboreus, Larusfuscus, Larusdelawarensis, Larusmichahellis, Larusargentatus, Larusmarinus, Larusglaucoides, Laruscanus, Laruscachinnans, Larusminutus, Limosalapponica, Limosalimosa, Lophodytescucullatus, Lymnocryptesminimus, Marmaronettaangustirostris, Melanittanigra, Melanittafusca, Mergellusalbellus, Mergusserrator, Mergusmerganser, Nettarufina, Numeniusarquata, Numeniusphaeopus, Nycticoraxnycticorax, Oxyuraleucocephala, Oxyurajamaicensis, Pelecanusrufescens, Pelecanusonocrotalus, Phalacrocoraxaristotelis, Phalacrocoraxcarbo, Phalaropuslobatus, Phalaropusfulicarius, Philomachuspugnax, Phoeniconaiasminor, Phoenicopterusruber, Platalealeucorodia, Plegadisfalcinellus, Pluvialisfulva, Pluvialisapricaria, Pluvialissquatarola, Podicepsnigricollis, Podicepscristatus, Podicepsauritus, Podicepsgrisegena, Porzanaporzana, Rallusaquaticus, Recurvirostraavosetta, Rissatridactyla, Scolopaxrusticola, Somateriamollissima, Stercorariusparasiticus, Stercorariuspomarinus, Stercorariusskua, Sternaparadisaea, Sternahirundo, Sternulaalbifrons, Tachybaptusruficollis, Tadornacana, Tadornaferruginea, Tadornatadorna, Thalasseussandvicensis, Threskiornisaethiopicus, Tringaochropus, Tringaerythropus, Tringatotanus, Tringaglareola, Tringanebularia, Uriaaalge, Vanellusgregarius, Vanellusvanellus, Xemasabini.The birds were counted at 1,189 predefined locations . The network divides Flanders, Belgium into 24 regions, each of them with a local coordinator. The fieldwork is mainly done by skilled volunteer birdwatchers, often working together within local bird clubs. The NGO Natuurpunt (http://natuurpunt.be) supports the majority of these bird clubs and volunteers, and thereby delivers an important contribution to the waterbird project. A number of large and important wetland areas are counted by INBO staff .The bird counts are organized as a regional network \"Waterbird counts Flanders\" coordinated by the Research Institute for Nature and Forest , covering all kinds of wetland habitats in Flanders, such as lakes, ponds, reservoirs, and rivers. They also include agricultural areas, often holding large numbers of waterbirds (such as wintering geese). Although the project aims for a (nearly) complete coverage of all areas hosting substantial numbers of waterbirds, this is difficult to achieve and the number of counted sites varies between months and years.To allow reliable comparisons between years and between areas, the counts are aimed for maximum standardization. Every winter, birds are counted in six monthly censuses from October to March, on the weekend the closest to the 15During counts, numbers of all waterbird species are recorded. This includes divers, grebes, cormorants, herons and allies, swans, geese, ducks, coots and rails. Waders and gulls  have been added to the species list in 1999. Counts of coastal waders are, however, available since 1992.http://watervogels.inbo.be, volunteers can enter their count and additional data directly into a central database.Through the watervogels web application, https://tinyurl.com/t5tdt6v. The geographic coordinates for the occurrences represent the centroid of the locality.The counts are done at predefined locations, called waterVogelTelgebied. The name of each waterVogelTelgebied is indicated in locality, while its ID is indicated in locationID. The polygon shape for most of these localities can be found at INBO staff. The count method  is indicated in samplingProtocol, while the achieved effort and the completeness of the survey  is indicated in samplingEffort. In dynamicProperties, we provide the sample conditions in JSON format:Within the borders of these areas, present waterbird species are counted as completely as possible. Clearly visible areas are often counted from one point with a telescope. Large and less visible areas are usually traversed on foot, by bicycle or by car. A special case are the monthly counts on the Zeeschelde which are performed from boats by th of the month. In large areas with a high probability of local movements, observers are asked to pay special attention to count more or less simultaneously, preferably with multiple observers. Birds are counted during daytime, while specific high tide counts are organized for typical coastal waders (gathering on specific high tide roosts). The Zeeschelde on the contrary, is mainly counted at low tide due to better visibility of the birds. For some species that are dispersed widely during the day, simultaneous counts on the roost sites are a better alternative for gathering information on their population size. Each winter, supplementary counts are organized for Great Cormorant (since 2003), gulls and Eurasian Curlew. These roost counts are however not included in this database.To reduce the likelihood of birds being double counted or missed, the counts are synchronized as much as possible. Counts are organized on the weekend closest to the 15Keep in mind that covering of the sites differs between months and years. Calculations of trends and population sizes therefore have to deal with missing values.Quality control descriptionINBO waterbird expert. If, during the analysis of the data, outliers are found, these records will also be removed from the database.All published records are validated. The initial validation is done manually by the These are the steps for entering data into the centralized database:1. Indicate date, start time, and end time .2. Indicate observer (recordedBy).3. Indicate specific count area . The area has a unique ID (locationID) and is linked higher geography (continent & countryCode). Together with the time information, this constitutes a count, which has a unique ID as well (eventID).4. Indicate count method (samplingProtocol) and achieved effort (samplingEffort).5. Indicate the count conditions, such as samplingConditions, samplingCoverage, snow, ice, and waterLevel .6. For each observed waterbird species (scientificName), indicate the estimated number of birds .For publication, the data is further processed:1. Each record gets a GUID, based on the ID assigned by the database (occurrenceID).https://tinyurl.com/t5tdt6v).2. The locationID is cross referenced with the geospatial information for the localities  and Dutch vernacular name (vernacularName).4. Dataset metadata information is added  as well the rights holder (rightsHolder), the license (rights) and data use norms (accessRights).http://rs.tdwg.org/dwc/terms/) in the dataset are: occurrenceID, type, language, license, rightsHolder, accessRights, datasetID, institutionCode, datasetName, dynamicProperties, basisOfRecord, recordedBy, individualCount, eventID, samplingProtocol, samplingEffort, eventDate, locationID, continent, countryCode, locality, decimalLatitude, decimalLongitude, geodeticDatum, georeferenceRemarks, taxonID, scientificName, kingdom, phylum, class, taxonRank, scientificNameAuthorship, vernacularName, and nomenclaturalCode.The Darwin Core terms .The data are standardized to Darwin Core  with a c Toolkit  instanceThe data are organized as a sampling event resource, with an event core containing 94,163 records and 1 occurrence extension containing 717,006 records.INBO IPT archives the data and thus serves as the data repository. The data and resource metadata are available for download in the downloads section. The versions table lists other versions of the resource that have been made publicly available and allows tracking changes made to the resource over time.The The following information is not included in this dataset and available upon request: roost site counts, counts from historical (inactive) locations.DatasetProject titleWaterbird counts FlandersFundingThis monitoring project receives funding from the Flemish Government.The Waterbirds application is developed with financial support from the EU (LIFE14 IPE BE 002 Belgian Nature Integrated Project)Content providersMany volunteers from Natuurpunt."}
+{"text": "Coats disease is a sporadic, retinal vascular abnormality, causing blindness. Several interventional methods, including laser photocoagulation, have been proposed; however, the use of intravitreal dexamethasone in refractory Coats disease is not well described.A 38-year-old man presented with a painless reduction in visual acuity in his right eye, commencing 15 days prior to initial assessment.Clinical manifestations and multimodal imaging indicated Coats disease.Retinal laser photocoagulation was performed in the nonperfused areas, 15 months later, the exudative retinal detachment, and macular edema remained, the patient was then treated with an intravitreal slow-release dexamethasone implant.The exudative retinal detachment and macular edema had resolved, and the BCVA had also improved.Dexamethasone intravitreal implantation was effective in treating refractory Coats disease. Several complications of Coats disease, such as exudative retinal detachment, macular edema, and neovascular glaucoma, have been reported. Previously described treatments, include retinal laser photocoagulation, intravitreal injection of triamcinolone acetonide or anti-vascular endothelial growth factor (VEGF); however, several consequences of these modalities have also been reported.454 Here we reported a refractory case of adult-onset Coats disease, treated with an intravitreal implant, releasing dexamethasone, following ineffective laser photocoagulation therapy.Coats disease, first described by George Coats in 1908, is a sporadic, retinal vascular abnormality, characterized by telangiectasia and exudate accumulation.2A 38-year-old man presented with a painless reduction in visual acuity in his right eye, commencing 15 days prior to initial assessment. His medical and ophthalmic history were unremarkable. The best-corrected visual acuity (BCVA) in the right eye was 20/30, and 20/20 in the left eye, the anterior segments were clear, and the intraocular pressure was normal in both eyes. Fundus examination revealed scattered exudate in the macula of the right eye . After 2 months, the exudative retinal detachment and macular edema had resolved Fig. A, and th3 The etiology of the disease is unclear, and the prognosis remains poor. Currently, no guidelines exist for treating Coats disease, although, several interventional methods have been proposed, including laser photocoagulation, anti-VEGF therapy, surgery, and intravitreal injection of triamcinolone acetonide.67867Coats disease is a retinal disorder characterized by retinal telangiectasia, leading to exudate accumulation, exudative retinal detachment, macular edema, and/or secondary glaucoma. However, exudative retinal detachment may remain unresolved, due to the presence of subretinal fluid. Therefore, close observation is required in order to detect the possible recurrence of subretinal detachment. In this case, retinal laser photocoagulation was performed to treat the nonperfused areas. Declining exudation and peripheral retinal scars were observed at the 15-month follow-up, but the exudative retinal detachment and macular edema remained, leading us to consider it a refractory case.Retinal laser photocoagulation can destroy the affected retinal blood vessels, particularly the telangiectasias and aneurysms. The immediate shrinkage of the proliferative membrane, and the improvement of secondary tractional retinal detachment has also been seen, following bevacizumab injection. Intravitreal triamcinolone acetonide can also be used to promote absorption of the subretinal fluid and exudate, however, this has also been associated with elevated intraocular pressure, cataract, and endophthalmitis.Alleviation of macular edema and exudation, with complete resolution of exudative retinal detachment, has been shown with intravitreal anti-VEGF therapy. The resolution of fibrosis and traction favors the treatment of telangiectasia and exudative retinal detachment by retinal laser photocoagulation and/or cryotherapy.In clinically advanced cases of Coats disease, surgical interventions may alleviate the significant epiretinal traction caused by the preretinal membranes or proliferative vitreoretinopathy. Vitrectomy can eliminate the VEGF-containing vitreous; however, it may result in iatrogenic retinal breaks. The effects of anti-VEGF drugs only last 1 month; hence, monthly intravitreal injections are required, potentially increasing patient discomfort and the risk of infection. The effects of Ozurdex persist for up to 6 months, meaning Ozurdex is a safe and more convenient treatment option than the anti-VEGF drugs. In this study, treatment with Ozurdex resolved retinal detachment and macular edema, improved visual acuity to 20/30, and normalized intraocular pressure, with no further recurrence noted during the 4-month follow-up period.Ozurdex is a biodegradable, sustained-release dexamethasone delivery system, used to treat macular edema secondary to diabetic retinopathy or age-related macular degeneration; however, few cases describing the therapeutic effects of Ozurdex in refractory Coats disease have been reported. Saatci et al demonstrated that Ozurdex implantation contributed to favorable anatomical and visual outcomes in patients with Coats disease.In conclusion, Coats disease is a sporadic, retinal vascular abnormality, associated with several serious complications. The use of an intravitreal dexamethasone implant has been shown to be an effective method for treating the complications in refractory Coats patients. Further studies involving more cases and longer follow-up periods are required in order to better understand the efficacy and safety of therapy with Ozurdex.Investigation: Bangtao YaoProject administration: Yuhua DingSupervision: Xiaogui Zhao, Hao YuWriting \u2013 original draft: Bangtao Yao, Xiaogui Zhao, Yuhua DingWriting \u2013 review & editing: Gang Liu, Xiuying WangAll authors read and approved the final manuscript."}
+{"text": "The outcomes of Radical prostatectomy (RP), regardless of the surgical approach, play an important role on patients' quality of life, mainly due its impact on urinary and sexual function. These outcomes are dependent on multiple factors including patient's anatomy, age, comorbidities, tumor staging, surgeon's experience, nerve sparing approach among others \u20135. SeverPerineal prostatectomy (RPP) was the first and oldest surgical technique described for prostate cancer treatment, progressively replaced by retropubic prostatectomy (RRP) after the introduction and standardization of the nerve-sparing technique by Walsh , 13. As"}
+{"text": "Pain and symptom management is critical in ensuring quality of life for chronically or seriously ill older adults. However, while pain management and palliative care have steadily expanded in recent years, many underserved populations, such as rural older adults, experience barriers in accessing such specialty services, particularly due to transportation issues. The purpose of this systematic review is to examine the specific types of transportation-related barriers experienced by rural older adults in accessing pain and palliative care. Studies were searched through the following 10 databases: Abstracts in Social Gerontology, Academic Search Premier, CINAHL, MEDLINE, PsycINFO, SocINDEX with Full Text, Cochrane Database of Systematic Reviews, Nursing & Allied Health Database, Sociological Abstracts, and PubMED. Studies were chosen for initial review if they were written in English, full-text, included older adults in sample, and examined pain/palliative care/hospice, rural areas, and transportation. A total of 174 abstracts were initially screened, 15 articles received full-text reviews and eight met the inclusion criteria. Findings of the eight studies identified transportation-related issues as major access barrier to pain and palliative care among rural older adults: specifically, lack of public transportation; lack of special needs/wheelchair accessible vehicles; lack of reliable drivers; high cost of transportation services; poor road conditions; and remoteness to the closest pain and palliative care service providers. Results suggest that rural older adults have unique transportation needs due to the urban-centric location of pain and palliative care services. Implications for practice, policy and research with older adults are discussed."}
+{"text": "In this Special Issue, redox/nitrosative signaling has been considered in several aspects of cardiosciences and oncology, namely cardioncology. In particular, the authors focused on the role of physiologic levels of radicals, reactive oxygen species (ROS), and reactive nitrogen species (RNS). Besides considering the modulation of several physiological mechanisms and functions, the authors stressed that ROS/RNS can be involved in a plethora of pathological conditions. Indeed, ROS/RNS may lead to several diseases, such as cancer, neurodegenerative disease, lung disease, cardiovascular diseases, and ischemia/reperfusion injury. In an elegant review of this issue by Mailloux , the fun"}
+{"text": "In \u201cSelf-Administered Behavioral Skills\u2013Based At-Home Virtual Reality Therapy for Chronic Low Back Pain: Protocol for a Randomized Controlled Trial\u201d :e25291), the authors noted five author names missing middle initials.In the originally published paper, the list of authors appeared as follows:Laura Garcia, Beth Darnall, Parthasarathy Krishnamurthy, Ian Mackey, Josh Sackman, Robert Louis, Todd Maddox, Brandon BirckheadThe list has been corrected as follows:Laura M Garcia, Beth D Darnall, Parthasarathy Krishnamurthy, Ian G Mackey, Josh Sackman, Robert G Louis, Todd Maddox, Brandon J BirckheadThe correction will appear in the online version of the paper on the JMIR Publications website on February 12, 2021, together with the publication of this correction notice. Because this was made after submission to PubMed, PubMed Central, and other full-text repositories, the corrected article has also been resubmitted to those repositories."}
+{"text": "Diversity is observed in the wave of global aging because it is a complex biological process exhibiting individual variability. To assess aging physiologically, markers for biological aging are required in addition to the calendar age. From a metabolic perspective, the aging hypothesis includes the mitochondrial hypothesis and the calorie restriction (CR) hypothesis. In experimental models, several compounds or metabolites exert similar lifespan-extending effects, like CR. However, little is known about whether these metabolic modulations are applicable to human longevity, as human aging is greatly affected by a variety of factors, including lifestyle, genetic or epigenetic factors, exposure to stress, diet, and social environment. A comprehensive analysis of the human blood metabolome captures complex changes with individual differences. Moreover, a non-targeted analysis of the whole blood metabolome discloses unexpected aspects of human biology. By using such approaches, markers for aging or aging-relevant conditions were identified. This information should prove valuable for future diagnosis or clinical interventions in diseases relevant to aging. Currently, Japan is the only country in the world with a societal aging rate (% of population over 65 years old) exceeding 30%  . DurWhen calorie intake is reduced by 20\u201330%, lifespan is extended by 20% or more in many model organisms, such as mice, flies, fish, spiders, etc. ,14. CaloInterestingly, metabolites modulating these signaling pathways are effective both for extension of organismal lifespan in experimental models and for treatment of human diseases of aging: Resveratrol (activator of sirtuins) against obesity, rapamycin (inhibitor for Tor kinase) as an anti-cancer drug or immunosuppressor, and metformin (activator for AMPK) in diabetic therapy ,24,25,26Caenorhabditis and Drosophila are extended by partial inactivation of mitochondrial functions, such as mitochondrial SOD, mitochondrial complex protein, and mitochondrial ribosomal proteins , wh, wh56], First, among 15 frailty markers, seven compounds that decreased in frailty are associated with antioxidative defense: Acetyl-carnosine, ergothioneine (ET), S-methyl-ET, trimethyl-histidine, OA, 2-ketobutyrate, and urate . TrimethInterestingly, metabolites affected in frailty largely overlap with metabolites that decrease during aging  and compounds that increase during fasting , indicating an intriguing metabolic link between frailty and human aging. Various antioxidative metabolites are conspicuously included among frailty and aging markers, suggesting that one of the key stressors to which frail elderly are vulnerable is oxidative stress. In this context, increased oxidative defense during fasting may effectively moderate aging or aging-relevant disorders.+, decreased in elderly, activates Sirtuin, while citrulline, accumulated in elderly, stimulates TOR kinase; 3-HB inhibits histone deacetylases, followed by FOXO activation. Thus, metabolites might affect aging or aging-related diseases by modulating signal modules [Diversity of aging has a significant impact not only on clinical and basic research, but also on national economies, and facilitates structural changes in entire societies. The answer to the fundamental question, \u201cWhat is aging?\u201d is not yet fully known. Accumulating evidence suggests that defining \u201caging\u201d only on the basis of chronological age does not explain the entire situation. Interestingly, some of the metabolites described in this review are known to interact with the signal molecules . NAD+, d modules ,103,104."}
+{"text": "Mora, an automated tool for generating invariants of probabilistic programs. Inputs to Mora are so-called Prob-solvable\u00a0loops, that is probabilistic programs with polynomial assignments over random variables and parametrized distributions. Combining methods from symbolic computation and statistics, Mora computes invariant properties over higher-order moments of loop variables, expressing, for example, statistical properties, such as expected values and variances, over the value distribution of loop variables.We introduce"}
+{"text": "Copulatory or pelvic thrusting dyskinesia is a subtype of tardive dyskinesia (TD) which is caused by exposure to dopamine blocking agents.A man exhibiting rhythmic, stereotypical pelvic thrusting movements.Recognition of copulatory dyskinesia as a distinctive iatrogenic disorder helps prevent unnecessary investigations and guides the implementation of corrective strategies. Tardive dyskinesia (TD) is an iatrogenic movement disorder resulting from exposure to neuroleptics, also known as dopamine-receptor blocking agents (DRBAs). The disorder is characterized by repetitive, stereotypic movements involving various body regions including mouth, tongue, face, trunk and extremities. Unlike most iatrogenic disorders, in most patients the abnormal movements may persist or worsen after discontinuation of the offending agent . We docuA 71-year-old man with history of depression was treated with aripiprazole. After 9 months of treatment, slow gait, hypomimia and hypophonia prompted a switch to brexpiprazole, which modestly attenuated the parkinsonism but within a few months elicited slight pelvic movements without alleviating his parkinsonism. Brexpiprazole was discontinued after 3\u20134 months and within weeks of discontinuation there was nearly complete resolution of the parkinsonian features but the rhythmic pelvic movements, which he could only transiently suppress, became troublesome  receptor encephalitis, in which there is variability of amplitude, frequency, and topographical distribution. Brexpiprazole, a third-generation antipsychotic, is a partial agonist at 5-HTBesides copulatory dyskinesia, neuroleptic exposure can also yield other axial dyskinesias, including respiratory dyskinesia and Belly dancer\u2019s dyskinesia. Respiratory dyskinesia manifests as irregular breathing, tachypnea and abnormal chest movements due to involvement of respiratory muscles . Belly dA single-center (not yet replicated) retrospective study suggested that copulatory dyskinesia may more commonly be a complication of the antiemetic metoclopramide . While t1Drs. Sharma & Gupta report no disclosures. Dr. Espay has received grant support from the NIH and the Michael J Fox Foundation; personal compensation as a consultant/scientific advisory board member for Abbvie, Neuroderm, Neurocrine, Amneal, Acadia, Acorda, Kyowa Kirin, Sunovion, Lundbeck, and USWorldMeds; publishing royalties from Lippincott Williams & Wilkins, Cambridge University Press, and Springer; and honoraria from USWorldMeds, Acadia, and Sunovion."}
+{"text": "Granulomatous slack skin (GSS) is a very rare subtype of mycosis fungoides (MF), with fewer than 50 cases already reported. It is 1 of the 3 variants of MF, along with folliculotropic MF and pagetoid reticulosis . There is a male predominance and an onset usually during adulthood.A 74-year-old man presented with a 4-year history of a lesion on his right axilla. During these years the patient had received various diagnoses, including intertrigo, dermatitis, and inverse psoriasis. Based on his experience, minimal remission was observed only with the use of a medium-potency topical steroid, but the lesion relapsed after treatment discontinuation. Clinical examination revealed a well-circumscribed erythematous plaque, consisting of pendulous, wrinkled, lax skin, unilaterally affecting the axillary fold . DermoscGSS is clinically characterized by slow, progressive development of large areas of asymptomatic, pendulous, lax skin in the major skin folds, with a predilection for axillae and groins. Clinically, differential diagnosis includes acquired cutis laxa, anetoderma, as well as other dermatoses involving the skin folds . To our The histological analysis reveals a dense, diffuse dermal infiltrate of atypical, irregular, convoluted lymphocytes  that may extend to the subcutaneous tissue, together with diffuse, multinucleated giant cells and histiocytes that display prominent elastophagocytosis and lymphophagocytosis. The granulomatous infiltrate is correlated with simultaneous loss of elastic fibers. Molecular analysis reveals a monoclonal rearrangement of the T cell receptor genes. The diagnosis of GSS, as in our case, is based on the typical clinical and histological features .The disease follows an indolent course, with an excellent prognosis. The reported 5-year survival rate is almost 100%. However, since there is an association with other lymphoid neoplasias (mainly with Hodgkin lymphoma), lifelong monitoring is recommended .There is no standard of care for GSS. Common therapeutic strategies are PUVA, local or total skin electron beam radiotherapy, nitrogen mustard, interferons, corticosteroids, retinoids, azathioprine, methotrexate, or chemoimmunotherapy . Surgica"}
+{"text": "To understand the prevalence of daily injury-related risk behaviors among secondary technical vocational school students, and to provide scientific proof and effective guidance for further injury intervention.A cluster sampling method was used to conduct a questionnaire survey of all grade one and grade two students in a secondary technical vocational school in Jiangsu Province in April 2018, to understand the current status of injury-related risk behaviors.Secondary technical vocational school students traffic risk behaviors, bullying and violence experience, sports risk behaviors, unsafe animal contact, were highly prevalent. The following behaviors occurred more than 25%: running a red light, not using the crosswalk, playing electronic equipment while crossing the road, not using a helmet, not wearing a seat-belt, not using reflective equipment at night, no preparation activities before sports, no protective measures during exercise, playing with stray cats, etc.Injury-related risk behaviors among secondary technical vocational school students were highly prevalent. The intervention of such risk behaviors should aim at characteristics of the population and their behaviors, take full advantage of families, schools, communities and other resources to solve intervention obstacles and promote correct behavior recognized as social norms, and create safe environment and atmosphere of families, schools, communities, and the whole society.Secondary technical vocational school, Injury, Risk behavior"}
+{"text": "Case Report. The patient is a 49-year-old male with KSS, diagnosed clinically upon the core features, namely, onset before the age 20 of years, pigmentary retinopathy, and ophthalmoparesis, and the complementary features, namely, elevated CSF protein, cardiac conduction defects, and cerebellar ataxia. The patient presented also with other previously described features, such as diabetes, short stature, white matter lesions, hypoacusis, migraine, hepatopathy, steatosis hepatis, hypocorticism (hyponatremia), and cataract. Unusual features the patient presented with were congenital anisocoria, severe caries, liver cysts, pituitary enlargement, desquamation of hands and feet, bone chondroma, aortic ectasia, dermoidal cyst, and sinusoidal polyposis. The course was untypical since most of the core phenotypic features developed not earlier than in adulthood.  To describe unusual course and unusual phenotypic features in an adult patient with Kearns\u2013Sayre syndrome (KSS).  KSS is a multisystem disease, but the number of tissues affected is higher than so far anticipated. KSS should be considered even if core features develop not earlier than in adulthood and if unusual features accompany the presentation. Kearns\u2013Sayre syndrome (KSS) is a mitochondrial disorder (MID) most frequently due to a single mtDNA deletion and rarely due to mtDNA point mutations , 2. The The patient is a 49-year-old male, with height 161\u2009cm, weight 85\u2009kg, and a history of preterm birth at gestational week 34 from nonconsanguineous parents, congenital anisocoria, developmental delay, hypoacusis, and tetra-ataxia . During At age of 30 years, left anterior hemiblock and right bundle-branch-block were recorded. Since age 35, recurrent mild elevation of creatine-kinase (CK) was noted. Aldolase and myoglobin were also elevated. Since age 35, recurrent electrolyte disturbances  and hyperuricemia developed. At age 36, he experienced a first episode of disorientation, impaired cognition, bradyphrenia, and secessus urinae. Clinical exam revealed bilateral ophthalmoparesis and dysarthria. Magnetic resonance imaging (MRI) showed subcortical hyperintensities in a nonvascular distribution, which were hyperintens on diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) . NeuropsThe family history was positive for hypotonia (mother), diabetes , carcinoma (father), and stroke (father). Neurological exam at age 49, revealed short stature, microcephaly, facial dysmorphism, myopathic face, ophthalmoparesis, pupils nonreactive to light, anisocoria , divergence of bulbs, ophthalmoparesis , bilateral ptosis (right\u2009>\u2009left), reduced corneal reflexes, hypoacusis requiring bilateral hearing devices, dysarthria, dropped head, weakness for right elbow extension and flexion, reduced tendon reflexes on the upper limbs, ataxia and brady-dysdiadochokinesia on the upper limbs, marked wasting of the thighs, ataxia on the lower limbs, truncal ataxia, and ataxic stance, and gait. Gnome calves bilaterally, which were described at age 38 were no longer present. The last medication included indapamide, furosemide/spironolactone, simvastatin, NaCl, KCl, coenzyme-Q (60\u2009mg/d), and vitamin-D.The presented patient is interesting in several aspects. Though clinical manifestations of KSS developed already in early infancy and childhood, the majority of the typical phenotypic features  and hepatopathy were recognised not earlier than in adulthood. Possibly, the typical features of KSS required for establishing the diagnosis , 2 were Another interesting point is the phenotype. Though the patient fulfilled the diagnostic criteria for KSS, he additionally presented with a plethora of manifestations, of which some have been reported earlier in KSS. In addition to the features required for diagnosing KSS, the patient presented with the known features of diabetes , hypocorConcerning the recurrent deteriorations of the phenotype during infections or spontaneously, it cannot be excluded that these conditions were in fact seizures or stroke-like episodes (SLEs), which remained unrecognized and recovered spontaneously. At least 4 of these episodes were documented. An argument for SLEs is that MRI at the first episode at age 36 showed subcortical T2-hyperintensities, which were also hyperintense on DWI and ADC and not confined to a vascular territory, suggesting a vasogenic edema. Whether arterial hypertension should be regarded as a manifestation of the MID is questionable but there are indications from Chinese studies that arterial hypertension can be in fact a phenotypic feature of an MID [Limitations of the study were that the diagnosis was not confirmed by genetic investigations, that the mother was not investigated for the presence of a MID, and that no biochemical investigations of the muscle homogenate were carried out.In conclusion, this case shows that KSS is indeed a multisystem disease affecting all types of tissues and that the phenotypic presentation may be broader than so far anticipated."}
+{"text": "Several cannulation sites alternative to the ascending aorta, such as femoral, right axillary, carotid, innominate artery, and, less commonly, apical sites, have been proposed. Cannulation of the right subclavian artery, through sternotomy, is one possible means of establishing cardiopulmonary bypass, hence avoiding a second surgical incision. In our experience, cardiopulmonary bypass flow was adequate and circulatory arrest with antegrade cerebral perfusion was successfully performed in all cases. There was no in-hospital mortality. When cannulation of the ascending aorta is not advisable, such as in cases of Type-A aortic dissection, alternatives including femoral, right axillary, carotid, and, less commonly, apex of the left ventricle have been proposed.Cannulation of the femoral vessels carries risk of poor perfusion and retrograde thrombotic embolism.Twenty consecutive patients with Type A aortic dissection received cannulation of the right subclavian artery, directly through percutaneous cannula placement or using a dacron graft, after sternotomy, before pericardial incision . Blood Nowadays the subclavian artery is our preferred site for cannulation when dissection involves the innominate artery, thus avoiding the complications of a second surgical incision. Dissection is still the bigger issue, but the subclavian artery usually is not involved in the dissection process, although is generally more fragile than the femoral artery and cannulation can therefore be traumatic."}
+{"text": "The classical senses  play a key role in social function by allowing interaction and communication. We assessed whether sensory impairment across all 5 modalities  was associated with social function in older adults. Sensory function was measured in 3,005 home-dwelling older U.S. adults at baseline in the National Social Life, Health, and Aging Project and GSI, a validated measure, was calculated. Social network size and kin composition, number of close friends, and social engagement were assessed at baseline and 5- and 10-year follow-up. Ordinal logistic regression and mixed effects ordinal logistic regression analyzed cross-sectional and longitudinal relationships respectively, controlling for demographics, physical/mental health, disability, and cognitive function (at baseline). Adults with worse GSI had smaller networks , fewer close friends  and lower engagement  at baseline, relationships that persisted at 5 and 10 year follow-up. Men, older people, African-Americans, and those with less education, fewer assets, poor mental health, worse cognitive function, and more disability had worse GSI. Men and those with fewer assets, worse cognitive function, and less education had smaller networks and lower engagement. African-American and Hispanic individuals had smaller networks and fewer close friends, but more engagement. Older respondents also had more engagement. In summary, GSI independently predicts smaller social networks, fewer close friends, and lower social engagement over time, suggesting that sensory decline results in decreased social function. Thus, rehabilitating multisensory impairment may be a strategy to enhance social function as people age."}
+{"text": "Age-related neurodegeneration associated with Alzheimer\u2019s (AD) disease begins in middle age, well before the onset of symptoms. Therefore, translational models to identify modifiable risk factors in middle-age are needed to understand etiology and identify therapeutic targets. Vervet monkeys (Chlorocebus aethiops sabaeus), like humans, naturally develop several risk factors for AD with age, including obesity, prediabetes, and hypertension. Furthermore, older vervets exhibit accumulation of amyloid and tauopathies, decreased brain volumes, and physical declines in gait speed, suggesting that these NHPs may be useful models of early AD-like neuropathology. Currently, we are investigating the extent to which cognitive and physical decline co-occur in 20 elder  and 10 middle-aged (mean age=11 years) females through assessments of physical performance, executive function, social cognition, and short-term memory. These measures are part of a larger study to integrate physical, social, and cognitive function with measures of body composition, metabolic profiles, CSF, blood, neuroimages, and neuropathology. While tests of social cognition and short-term memory are ongoing, assessments of executive function indicate that performance declines with age . Furthermore, animals that exhibit slower gait speed also perform poorly on the executive function task . These preliminary results suggest that accelerated aging co-occurs in multiple systems in vervets. This study will enable examination of temporal relationships between physical and cognitive declines. Ultimately, this comprehensive, integrative whole-body approach will help clarify the mechanisms underlying divergent aging trajectories and inspire interventions that promote multi-system healthy aging."}
+{"text": "Growing and purchasing demand for organic fresh produce is increasing rapidly. Consumers are aware of health, environmental safety, pesticide harmfulness, nutrients, bioactive compounds, and safe food. Many research works are available on organic and conventional fresh produce. As organic fresh produce growing and purchasing demand is increasing, it has become necessary to review the recent trends in quality, safety, and consumer preferences of organic and conventional fresh food products. A few reports have been compiled on organic and conventional fresh produce. Researchers have started working on organic and conventional fresh produce with the help of modern technology to improve nutritional and functional quality, safety, and consumer preferences. Nutritional and functional quality, safety, and consumer preferences depend on cultivation techniques, treatment, crop cultivar, and appearance of products. Therefore, it is necessary to compile the literature on organic and conventional fresh produce based on quality, safety, and consumer preferences. Organic and conventional fruit, vegetable, and cereal quality, safety, and preferences are becoming an issue for producers and consumers considered in the literature. Consumers demand quality and safety of fresh produce. Fresh produce quality reflects on taste, color, nutritional value, and microbial safety ,2.As it is grown in an organic manner, there undoubtedly are no synthetic pesticides and fertilizers, which can be harmful to human health. While synthetic pesticides are not authorized in many countries for organic farming, growers use manure and compost as organic fertilizer ,4. GrowiThe conventional system typically uses synthetic pesticides and fertilizers, which can be harmful to human health if growers use them improperly ,6. For tIt is very difficult to compare organic and conventional foods. A valid comparison requires the same cultivar, proximity of the farms, similar growing media, same climate conditions, and a similar growing system. In this review paper, we tried to compare organic and conventional fresh produce according to quality, safety, and consumer preferences. Moreover, we focused on fresh produce growing materials in the organic and conventional systems. This article highlighted an overview of the recent works on organic and conventional fruit, vegetable, and cereal production systems, product quality, product safety, and consumer preferences.Organic fresh produce markets are the fastest-growing in agriculture. In the year 2018, the organic food revenue in the USA was 40.56 billion euros, followed by Germany (10.91 billion euros) and France (9.14 billion euros), China (8.09 billion euros), Italy (3.48 billion euros), Canada (3.12 billion euros), Switzerland (2.66 billion euros), UK (2.54 billion euros), Sweden (2.30 billion euros) and Spain (1.90 billion euros) . The groSafe consumption depends on personal and economic factors, sociocultural factors, and marketing factors . These aFresh and sustainable consumption, extrinsic attributes, health, sensory appeal, weight concern, and social status are used to consider organic food products. Furthermore, consumer motives, preferences, and attitudes can vary depending on the product category. Consumers are willing to pay additional 0.18 euro/kg organic apples in Italy , whereasFirmness is an essential parameter for fresh produce. Conventional kiwifruits showed higher firmness than organic ones  Table 1Table 1. Moreover, smaller fruits showed higher firmness than bigger ones ,22. AlthLess ripe fruits have enriched titratable acidity, for example, cherry tomato fruits, because during the ripening time, acid converts to sugar ,6,17,26.Mineral concentration is an important factor for conventional cultivation. Faba beans showed the lowest Ca content among the crops  Table 3Table 3 aConventional strawberry fruits showed higher P, K, Ca, Mg, B, and Zn content than the organic ones . More coSensory qualities of organic and conventional fresh produce may differ across crops and the findings are inconsistent  Table 4Table 4. The organic lettuce maintained excellent sensorial characteristics as they developed a higher carbon dioxide concentration compared with the conventionally grown ones. Visual quality and shelf life are essential parameters for consumers because they influence the choice, selection, and purchase intentions. The quality of fruit depends on visual characteristics (size and color) ,40, postThe color of organically and conventionally produced fruits and vegetables differs significantly. Color is directly associated with consumer acceptability. Poor color development leads to loss of the fresh produce\u2019s market value . Among sOrganic fresh produce demand is increasing . We needThe quality of fresh produce grown using organic and conventional methods is shown in In this section, soluble solids, sugar content, dry matter content, and dietary fiber are discussed. Increase and decrease in nutritional quality may depend on growing conditions and environmental factors.The soluble solids content is an important parameter for consumer preferences. A higher soluble solids content is often associated with better taste . The seaOrganic pears, blackcurrants, beetroots, celery, kiwifruits, and tomatoes showed higher sugar content compared with the conventionally grown ones ,28,29 T. OrganicOrganic melons, tomatoes, potatoes, beets, and watermelons showed increased dry matter  and convDry matter content increases the flesh product of organic lettuce and, as a result, produce shows less decay and decomposition with increased storage life . Yu et aTalinum triangulare and pumpkins contained more dietary fiber than the conventionally grown ones [Conventional plums, grapes, and wheat performed better in total dietary fiber and soluble fiber than the organic ones ,55 Tabl. In insoown ones ,57. The own ones . In the own ones . Secondaown ones . The conown ones .In this section, the content of total phenolic acids, vitamin C, \u03b2-carotene, anthocyanin, flavonoids, lycopene, and antioxidants of organically and conventionally grownn fresh produce was discussed.Phenolic acids are antioxidants and secondary metabolites that have a functional role against cardiovascular diseases, neurological diseases, and cancer. Phenolic content variation mainly depends on the cultivar, growing condition, and treatment. For instance, Feteasca regal\u0103, Muscat Ottone, Napoca, Chasselas dor\u00e9, and Muscat Hamburg cultivars of organic grapefruit skin showed higher polyphenol content than Aromat de Ia\u015fi, Traminer Roz, Riesling Italian, and Timpuriu de Cluj cultivars of conventional grapefruit skin . Some reOrganic broccoli, blueberries, grapefruits, peppers, plums, potatoes, strawberries, and tomatoes are rich in phenolic compounds ,43,44,45Vitamin C is an antioxidant and it has an influential role in scurvy. It is effective against microorganisms. Organic strawberries, beetroots, and lettuce showed higher vitamin C content than the conventionally grown ones ,4,41 Ta. OrganicAccording to Barrett et al. , higher Carotenoids are natural pigments that are contained in fruits and vegetables. Carotenoids have a functional role as an anti-cancer, anti-oxidation, eyesight, osteoporosis, and skin aging prevention agent. Organic peppers and tomatoes exhibited higher \u03b2-carotene content than the conventionally grown ones ,48,52 T. Some reIn contrast, the level of carotenoids is often lower in organic passion fruit compared with the conventionally grown ones . IncreasAnthocyanin is a bioactive compound, which is found in colored fruits. Anthocyanin is a plant pigment, which is synthesized in epidermal layers. Organically cultured strawberries exhibited higher anthocyanin content than the conventionally grown ones ,41 Tabl; this maIn the case of blueberries, there is no specific trend. Some cultivars showed high, and some showed low anthocyanin content. For instance, cultivar \u201cPowder blue\u201d showed high anthocyanin content in the organic system and cultivars \u201cClimax\u201d and \u201cWoodward\u201d showed high anthocyanin content in the conventional cultivation system . So, botLevels of the flavonoid content were more increased in conventional apples, beetroots, and cabbages than in the organic ones ,27,51 T. HoweverGrapefruit flavanone content was described by Chebrolu et al.  during hLycopene is contained in ripening fruits with light-red to red colors. For instance, red cherry tomatoes showed higher lycopene content compared with the light-red ones ,6,26. OrAntioxidant activity in organic strawberries, pears, carrots, blackcurrants, beetroots, eggplants, peppers, spinach, plums, and celery was higher than in the conventionally grown ones ,64,74,76It was further discovered that organic vegetables showed higher antioxidant content due to lower N availability . ConventE. coli, mycotoxins, and parasites because of the limitation of pesticides  in organic farming. It is necessary to find the proper interval between applying manure and harvesting fresh produce to minimize the risk of microbial contamination . Fungal toxins are also a threat to human health. For example, in the storage period, bacterial and fungal incidence can increase in cherry tomato fruits and leafy vegetables due to internal functional activity resulting from quality deterioration [Microbial contamination risk may increase in organic farming due to ioration ,26. Bourioration  mentioneioration . Organicioration . Fruits ioration .Nitrates are naturally present in plant products and are considered a matter of concern for health due to their easy conversion to nitrites and their reactivity . NitriteThe ban on toxic chemicals like fungicides, insecticides, and herbicides in organic agriculture ensures the protection of workers\u2019 health. Organic foods of plant origin did not contain any pesticide residues . OrganicAspergillus group produces aflatoxins, mainly, Aspergillus flavus produces aflatoxin B1 and B2 and A. parasiticus produces aflatoxins B1, B2, G1, and G2 [1.Aflatoxins occur in nut trees, dried fruits, cereals, and coffee . They ha, and G2 . OrganicThis paper discusses consumer preference, quality, and safety of organic and conventional fresh produce. The studies evaluated included information on consumer perception, physicochemical quality, sensory quality, nutritional quality, bioactive compounds, and food safety. Most of the differences detected between organic and conventional fresh produce could be strongly linked to differences in crops, fertilizers, environment, and pest management. According to the literature reviewed, consumers have a higher perception of organic fresh produce than of the conventional produce and are willing to pay additional money. They prefer organic fresh produce, which is free from synthetic fertilizers, fungicides, insecticides, and herbicides. Physicochemical quality, mainly, firmness was high in organic apples, strawberries, kiwifruits, and sweet peppers. Conventionally grown celery, lettuce, tomatoes, and sweet peppers contained high levels of organic acids. Organic growing methods adversely affect sensory properties because they depend on the fertilizer type, not climate, soil, or other factors. Conventionally grown grapes, sweet peppers showed abundant dietary fiber, whereas in organically grown fruits, the increased soluble solids (apples and beetroots) and sugar content (beetroots) depends on growing conditions. Organic fresh produce has high phenolic content. This may happen due to the endogenous phenolic-enriching plant defense mechanisms in the absence of synthetic fertilizers and pesticides commonly used in the conventional growing system ,87. The"}
+{"text": "Canadians aged 65 and older compromised 79% of the individuals who chose a medically assisted death between January 1 \u2013 October 31, 2018. Despite public approval for MAID, and positive professional reception, few practitioners are participating in MAID care and the underlying factors influencing this require exploration. What are the factors considered by practitioners when contemplating MAID participation? Interpretive Description guided a qualitative, exploratory project. Data included semi-structured interviews with 35 practitioners who currently did not participate in MAID, interviewer field notes and reflective content. Data was analyzed through open coding, a constant comparative approach and thematic analysis. Participants are contemplating numerous endogenous and exogenous factors in determining care participation. The endogenous factors included philosophy of care, MAID/faith/spirituality congruence, the conceptualization of duty, comfort with death and previous life experiences. Within these factors, participants described knowing if MAID participation was, or was not, possible through a process of self-reconciliation. Those who thought MAID care participation may be possible, but yet were not participating, intentionally contemplated numerous exogenous factors including risk, time and practice factors, patient, family and community considerations, system structures, and visibility. Non-participation in MAID care is important to understand to support the self-determination of older adults who may consider MAID. Contemplating involvement in MAID care is complex with both numerous factors influencing practitioner choice. Practitioners require care options, safe passage, respect, model of care clarity, removal of practice barriers, open conversations, enhanced education opportunities and time to facilitate safe, supportive work environments and client care."}
+{"text": "Several international cohorts of older adults share past experiences of welfare-related adversity. In Ireland, reports of childhood maltreatment, neglect, and abuse within institutional welfare settings included a harsh regime, childhood labour, and physical and sexual assault. Preliminary research with these Irish survivors revealed a high prevalence of psychological disorders in adulthood. A pathological perspective of aging is often applied to such older adults, due to the long-term health consequences associated with childhood trauma. However, little is known about later life resilience or resilience mechanisms in this population. Therefore, using conceptual models of resilience, this qualitative study aimed to investigate factors associated with resilience in older adult survivors of childhood institutional abuse. Participants were 17 Irish older adults, 50-77 years of age, with experiences of childhood abuse in institutional care settings. Semi-structured interviews were conducted, lasting 60-120 minutes. Transcribed interviews were analysed using the Framework Analysis method. Nine themes were derived from the data, including core, internal, and external resilience factors: Individual characteristics, personality characteristics, support systems, goal attainment, adaptive belief systems, processing, influential events and experiences, recognition and collective identity, and access to services. Results suggest that resilience can be understood not only as an inherent trait, but also as a learnable set of behaviours, thoughts, and attitudes, which can be supported by external resources in an older adults\u2019 environment. The identification of personal and contextual factors underpinning resilience in older adults with trauma experiences may help foster a more positive, strengths-based approach to aging in psychological research and practice."}
+{"text": "PURPOSE: This study examines psychosocial risk factors associated with hospitalization among community-dwelling older adults in the United States. METHODS: Using two waves of the National Health and Aging Trends Study from 2011 and 2015, we conducted descriptive and multivariate analyses of individual-level data from a nationally representative sample of 8,003 Medicare beneficiaries ages 65 and older. Associations between hospitalization and risk factors including social isolation, depression, and anxiety were assessed. Covariates included gender, race/ethnicity, age, region, insurance type, falls, and comorbidities. RESULTS: Overall, about 20.9% of older adults reported a hospitalization within the past year and 22.2% were socially isolated. The odds of hospitalization were higher for socially isolated adults , for depressed adults , and for individuals with anxiety . Individuals living in the Western region had lower odds of hospitalization , whereas men , those requiring assistance with activities of daily living , and those having one  or more  chronic health conditions had higher odds of hospitalization. CONCLUSION: Social isolation, depression, and anxiety represent significant psychosocial risk factors for hospitalization among community-dwelling older adults in the United States. Efforts to reduce health care costs and improve health outcomes for older adults should explore ways to strengthen social integration and improve mental health."}
+{"text": "As married couples aging together, their health behaviors and outcomes could be shaped by both one\u2019s own and the spouse\u2019s characteristics. Using dyadic datasets, speakers in this symposium explored the interdependence nature of marital relations by identifying the mechanisms of how shared resources or strains affect spouses\u2019 physical and mental health outcomes among married couples. Wang, Kim, and Burr identified distinct types of personality configurations among older couples using the Health and Retirement Study, and examined how personality compatibilities could buffer negative effects of adverse life events on older couples\u2019 mental health. Using data from the National Social Life, Health, and Aging Project, Proulx, Skoblow, and Han further investigated the associations between marital quality and mental health among caregiving dyads, with a special focus on a comparison of different caregiving groups . From a physical health perspective, Wilson and Novak presented the dynamic behind relationship quality, joint health behaviors, health problems, health satisfaction, and health similarity between spouses. Finally, Kim, Jang, Park, and Chiriboga focused on couple contexts for acculturation among older Korean immigrants in the U.S., and examined how each spousal acculturation level affects healthcare utilization and difficulties in health service use. Focusing on married couples, this symposium showcases the interplay of family experiences, health behaviors, and relational dynamics of both spouses in shaping their health, and highlights the benefits of dyadic approaches. Speakers and our discussant, Dr. Karen Lyons, will discuss implications for social program design and future research."}
+{"text": "A 56-year-old man receiving rituximab who had months of neurologic symptoms was found to have Jamestown Canyon virus in cerebrospinal fluid by clinical metagenomic sequencing. The patient died, and postmortem examination revealed extensive neuropathologic abnormalities. Deep sequencing enabled detailed characterization of viral genomes from the cerebrospinal fluid, cerebellum, and cerebral cortex. Jamestown Canyon orthobunyavirus (JCV) is a negative-sense RNA virus in the California serogroup. Its tripartite genome comprises small (nucleocapsid), medium (glycoprotein), and large (polymerase) segments. JCV is distributed throughout the United States and Canada and has been isolated from multiple mammals and mosquitoes . Cranial nerve, tone, strength, sensory, and reflex examinations were normal. Gait was wide-based and slow without ataxia or parkinsonism. Magnetic resonance imaging of the brain showed mild ventriculomegaly attributed to atrophy but was otherwise unremarkable, without contrast enhancement, cortical diffusion restriction, mass lesions, hemorrhage, or infarction . ElectroA CSF sample collected in April 2018 underwent clinical metagenomic next-generation sequencing (mNGS) testing at the University of California\u2013San Francisco  Figure 1The patient was treated with intravenous immunoglobulin , followed by a 2-week course of favipiravir, an experimental inhibitor of viral RNA polymerase, without improvement. His mental status deteriorated to a comatose state. He was transitioned to comfort care and died in June 2018, \u22481 year after suspected symptom onset.At autopsy, the unfixed brain weighed 1,240 g and appeared grossly normal, with no masses, hemorrhage, infarctions, or herniation. Histologic abnormalities were most prominent in the cerebral cortex , cerebellum, and hippocampus; milder changes in basal ganglia, thalamus, and brainstem were observed, including severe loss of neurons, diffuse microgliosis with microglial nodules and neuronophagia, and perivascular and parenchymal chronic inflammation . LeptomeComplete or near-complete JCV genomes were recovered from premortem CSF and postmortem cerebellum and cortex tissue  . PhylogeWe describe an unusual fatal case of chronic JCV encephalitis in a patient who was being treated with rituximab. In contrast to this case, previously described patients with JCV have had acute illness, and JCV infection is rarely fatal (The lack of distinguishing clinical, radiographic, and pathologic features of JCV underscores the diagnostic utility of clinical mNGS (In addition to diagnosis, mNGS also provides valuable information about pathogen genomics. We report the unique assembly of a JCV genome from human clinical samples, an important advance in the study of JVC pathogenesis, virus evolution, and differences between the enzootic transmission cycle and human infection (Although treatment options for JCV infection are largely unexplored, response to antiviral drugs probably depends on initiating treatment early in the disease course and reaching therapeutic levels in the CSF before extensive neuronal loss. Thus, broad-spectrum molecular assays such as mNGS could potentially lead to earlier treatment with improved outcomes (Additional information about a fatal case of chronic Jamestown Canyon virus encephalitis diagnosed by metagenomic sequencing in a patient receiving rituximab."}
+{"text": "Heart failure is one of the most important reasons for hospitalization among elderly individuals and is associated with significant mortality and morbidity. Epidemiological studies require the establishment of high-quality databases. Several datasets that primarily involve heart failure populations have been established in Western countries and have generated many high-quality studies. However, no such dataset is available from China. Due to differences in genetic background and healthcare systems between China and Western countries, the establishment of a heart failure database for the Chinese population is urgently needed. We performed a retrospective single-center observational study to collect data regarding the characteristics of heart failure patients in China by integrating electronic healthcare records and follow-up outcome data. The study collected information for a total of 2,008 patients with heart failure, containing 166 attributes. Machine-accessible metadata file describing the reported data: 10.6084/m9.figshare.13064054 By using mathematical prediction models, heart failure is estimated to affect 8 million people over the age of 182. Heart failure is one of the most important reasons for hospitalization among elderly individuals and is also associated with significant mortality and morbidity. It has been reported that the mortality ranges from 20% to 60% one year after hospitalization for acute HF6, depending on comorbidities and coexisting medical conditions. Many cohort studies have been carried out for epidemiological investigations of hospitalized patients with HF. For instance, the Cleveland Heart Disease dataset, which contains 75 variables for 303 patients, is mainly used for practising machine learning algorithms7. The Nationwide Inpatient Sample (NIS) is a publicly available database from the Healthcare Utilization Project (HCUP) that is supported by the Agency for Healthcare Research and Quality. This dataset contains many patients with heart diseases, but the variables/attributes included in this dataset are not specifically designed for HF10. The Medical Information Mart for Intensive Care (MIMIC) database contains data associated with >60,000 distinct hospital admissions to critical care units between 2001 and 2012. Many of the patients have a HF diagnosis, and thus MIMIC is a good resource for testing research hypotheses related to critically ill HF patients11. However, these studies are either designed with attributes that are limited in number or not specific for HF. In other words, data collection was dictated by expert knowledge, and only variables deemed important were entered into the data collection form. The determination of feature variable inclusion/exclusion is largely driven by expertise and previous studies. Such a dataset can be used only to address a limited number of clinical questions. For example, the ESC-Heart Failure Association (HFA) EURObservational Research Programme (EORP) generated a large dataset that contained specifically HF patients, and a large amount of data that are routinely collected during clinical practice were abandoned. To the best of our knowledge, this is the largest HF dataset in the world, including 337 cardiology centres from 33 ESC Member countries12. In essence, many trivial attributes may work together to influence the clinical outcome. Thus, a dataset including all aspects of individual patient-level data can help disentangle complex relationships among attributes. In the era of big data, the electronic healthcare records are able to produce a large amount of data related to a given HF patient. These multiparameter relational databases may or may not be related to a given research question. Different studies and analyses require different variables. Making such a publicly available dataset can help to encourage data reuse, thereby promoting more medical knowledge discovery.Heart failure (HF) affects over 6 million people in the United States, with an estimated incidence of 21 per 1000 people in the elderly peopleOur study aimed to establish a HF database based on electronic healthcare records. Data on subsequent hospital admissions and mortality were obtained at mandatory follow\u2010up visits at 28 days, 3 months and 6 months . The study was a retrospective study enrolling hospitalized patients with heart failure from December 2016 to June 2019. Patients were enrolled from Zigong Fourth People\u2019s Hospital. Data were extracted from electronic healthcare records. However, this is a single-centre dataset, covering only Chinese patients. Findings with these data alone may not have convincing generalizability. Researchers may combine this dataset with other heart failure cohort data for a larger-scale study.The study was conducted at Zigong Fourth People\u2019s Hospital, Sichuan, China from December 2016 to June 2019, and was approved by the ethics committee of Zigong Fourth People\u2019s Hospital . Informed consent was waived due to the retrospective design of the study. The study complies with the Declaration of Helsinki.13:The presence of symptoms and/or signs of HF. Typical symptoms include breathlessness, orthopnoea, paroxymal nocturnal dyspnea, reduced exercise tolerance, fatigue, tiredness, increased time to recover after exercise and ankle swelling. Typical signs include elevated jugular venous pressure, hepatojugular reflux, third heart sound  and laterally displaced apical impulse.Elevated levels of BNPs (BNP >35\u2009pg/mL and/or NT\u2010proBNP >125\u2009pg/mL)Objective evidence of other cardiac functional and structural alterations underlying HF.In case of uncertainty, a stress test or invasively measured elevated LV filling pressure may be needed to confirm the diagnosis.Electronic healthcare records of consecutive patients with a diagnosis of HF were reviewed. We included all types of heart failure including acute HF, chronic HF, left HF, right HF, or a mixture of all. Heart failure was defined according to the European Society of Cardiology (ESC) criteriaPatients who had a diagnosis of heart failure on hospital admission were enrolled in our study. The diagnosis was recorded with ICD- 9 in the EHR Table\u00a0.Table 1IData collected for the dataset included three broad categories: demographic data, baseline clinical characteristics, comorbidities, laboratory findings, drugs and outcomes. Demographic data were entered manually into the EMR system by the nurses on admission if a patient first visited our hospital. Otherwise, demographic data could be automatically extracted from previous visits. Some missing or error data were checked if they were identified by the nurses. To ensure the accuracy and consistency of data entry, a drop-down list was used for some variables in our EMR system, such as sex, department of admission and occupation. Laboratory tests and drugs were electronically entered by physicians and/or lab workers. Data in the EMR were extracted by SQL query to establish the current database. The accuracy of the SQL query was then checked manually by randomly selecting 50 patients. Many data items were recorded in Chinese in the electronic healthcare record database, thus the largest challenge is the language barrier. All the lab test items, examinations, drug names and diagnoses were recorded in Chinese in the electronic healthcare record database. To address this problem, all Chinese terms were translated to English by the principal investigators .The demographic data were obtained from the first sheet of the medical records and included age, sex, height, body weight, admission ward, type of admission (emergency vs. nonemergency), occupation, discharge department, admission date, visit times, and marital status.Baseline clinical characteristics were measured on the day of hospital admission and included body temperature, pulse, respiration rate, systolic blood pressure, diastolic blood pressure, mean arterial blood pressure, weight, height, body mass index (BMI), type of heart failure, New York Heart Association (NYHA) cardiac function, Killip Grade , and Glasgow Coma Scale (GCS) score. Echocardiographic findings included left ventricular ejection fraction (LVEF), left ventricular end diastolic diameter, mitral valve peak E wave velocity (m/s), mitral valve peak A wave velocity (m/s), E/A, tricuspid valve regurgitation velocity, and tricuspid valve regurgitation pressure.14. A minority of patients were not coded as having a diagnosis of \u201ccongestive heart failure\u201d in the comorbidity list because they did not have a past history of congestive heart failure on admission. They were diagnosed with HF for the first time in the index hospitalization. The comorbidities were taken from the admission notes.Comorbidities included a medical history of myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, dementia, chronic obstructive pulmonary disease (COPD), connective tissue disease, peptic ulcer disease, diabetes, moderate-to-severe chronic kidney disease, hemiplegia, leukaemia, malignant lymphoma, solid tumour, liver disease and AIDS. The Charlson Comorbidity Index (CCI) was calculated by summing all comorbidity points described aboveLaboratory findings were obtained from day one of hospital admission, including serum creatinine, urea, uric acid, glomerular filtration rate, cystatin, white blood cell count, monocyte ratio, monocyte count, red blood cell count, coefficient of variation of red blood cell distribution width, standard deviation of red blood cell distribution width, mean corpuscular volume, haematocrit, lymphocyte count, mean haemoglobin volume, mean haemoglobin concentration, mean platelet volume, basophil ratio, basophil count, eosinophil ratio, eosinophil count, haemoglobin, platelet, platelet distribution width, platelet haematocrit, neutrophil ratio, neutrophil count, D-dimer, international normalized ratio, activated partial thromboplastin time, thrombin time, prothrombin activity, prothrombin time ratio, fibrinogen, high sensitivity troponin, myoglobin, carbon dioxide binding capacity, calcium, potassium, chloride, sodium, inorganic phosphorus, serum magnesium, creatine kinase isoenzyme to creatine kinase, hydroxybutyrate dehydrogenase to lactate dehydrogenase, hydroxybutyrate dehydrogenase, glutamic oxaloacetic transaminase, creatine kinase, creatine kinase isoenzyme, lactate dehydrogenase, brain natriuretic peptide, high sensitivity protein, nucleotidase, fucosidase, albumin, albumin/globulin ratio, cholinesterase, glutamyltranspeptidase, glutamic pyruvic transaminase, glutamic oxaliplatin, indirect bilirubin, alkaline phosphatase, globulin, direct bilirubin, total bilirubin, total bile acid, total protein, erythrocyte sedimentation rate, cholesterol, low-density lipoprotein cholesterol, triglyceride, high-density lipoprotein cholesterol, homocysteine, apolipoprotein A, apolipoprotein B, lipoprotein, pH, standard residual base, standard bicarbonate, partial pressure of carbon dioxide, total carbon dioxide, methemoglobin, haematocrit blood gas, reduced haemoglobin, potassium ion, chloride ion, sodium ion, glucose blood gas, lactate, measured residual base, measured bicarbonate, carboxyhemoglobin, body temperature blood gas, oxygen saturation, partial oxygen pressure, oxyhemoglobin, anion gap, free calcium, and total haemoglobin.Primary drug categories included in our dataset were diuretics, inotropes, and vasodilators. The diuretics included furosemide, torasemide and spironolactone. Inotropes included deslanoside, dobutamine, digoxin, isoprenaline and milrinone. Vasodilators included isosorbide mononitrate and nitroglycerin.DestinationDischarge\u201d was recorded after hospital discharge, and the variable \u201coutcome.during.hospitalization\u201d was recorded after the decision to discharge was made.Outcome variables included discharge date of the index hospital, vital status at hospital discharge, death within 28 days, readmission within 28 days, death within 3 months, readmission within 3 months, death within 6 months, readmission within 6 months, time to death , time to readmission , return to emergency department within 6 months, and time to visit emergency department within 6 months. The variable \u201c15. Missing values are indicated with blanks. Detailed information on variable specifications is included in a variable description file.The study generated a single dataset, that contained information on 166 attributes of 2008 hospitalized patients from December 2016 to June 2019. The dataset is available at PhysioNet (10.13026/8a9e-w734)The present study was a retrospective design. Information on eligible patients was collected at Zigong Fourth People\u2019s Hospital. First, the required data were exported from the electronic healthcare database with the assistance of the information technology technician. The exported data were then checked by expert emergency and critical care physicians; if outliers in each variable and contradictions within data were detected, data were validated by another investigator. The outliers and contradictions were judged by expert emergency and critical care physicians. Data on subsequent hospital admissions and mortality were obtained at mandatory follow\u2010up visit at 28 days, 3 months and 6 months .Data were finalized and fully anonymized on June 8, 2020.The overall mortality rate at hospital discharge was 1% 14/2008). A total of 212 patients were discharged to unknown places , 1344 patients were discharged home (67%) and 438 patients were discharged to healthcare facilities (22%). Most patients were admitted to the department of cardiology , followed by the general ward , others  and the ICU . There was also a significant difference between emergency and nonemergency patients (Online-only Table\u00a0008. A to"}
+{"text": "Osseointegrated dental implants are a revolutionary tool in the armament of reconstructive dentistry, employed to replace missing teeth and restore masticatory, occlusal, and esthetic functions. Like natural teeth, the orally exposed part of dental implants offers a pristine nonshedding surface for salivary pellicle-mediated microbial adhesion and biofilm formation. In early colonization stages, these bacterial communities closely resemble those of healthy periodontal sites, with lower diversity. Because the peri-implant tissues are more susceptible to endogenous oral infections, understanding of the ecological triggers that underpin the microbial pathogenesis of peri-implantitis is central to developing improved prevention, diagnosis, and therapeutic strategies. The advent of next-generation sequencing (NGS) technologies, notably applied to 16S ribosomal RNA gene amplicons, has enabled the comprehensive taxonomic characterization of peri-implant bacterial communities in health and disease, revealing a differentially abundant microbiota between these 2 states, or with periodontitis. With that, the peri-implant niche is highlighted as a distinct ecosystem that shapes its individual resident microbial community. Shifts from health to disease include an increase in diversity and a gradual depletion of commensals, along with an enrichment of classical and emerging periodontal pathogens. Metatranscriptomic profiling revealed similarities in the virulence characteristics of microbial communities from peri-implantitis and periodontitis, nonetheless with some distinctive pathways and interbacterial networks. Deeper functional assessment of the physiology and virulence of the well-characterized microbial communities of the peri-implant niche will elucidate further the etiopathogenic mechanisms and drivers of the disease. Along with the advent of dental implants as a reconstructive treatment option in dentistry, peri-implant infections have emerged as a by-product of this advancement in bioengineering. Peri-implant infections are categorized as either peri-implant mucositis, if the induced inflammation is limited to peri-implant soft tissues, or peri-implantitis, if the inflammation extends to the underlying bone, further causing osteolysis. Diagnostic criteria for peri-implant infections primarily rely on clinical and radiographic examinations. Accordingly, the clinical sign of bleeding on probing (BOP) is central to detecting peri-implant inflammation in the form of mucositis. The diagnosis of peri-implantitis is commensurate with radiographic changes in crestal bone levels, particularly characterized by a symmetrical \u201csaucer-shaped\u201d bone defect around the implant. The latest case definitions for peri-implant mucositis include BOP or suppuration but no radiographic crestal bone loss beyond the initial remodeling. Peri-implantitis also includes further bone loss and increased probing pocket depth (PPD), compared to previous examinations . OverallManufactured primarily out of titanium, dental implants consist of an endosseous rough-surfaced part that promotes osseointegration and a transmucosal smooth-surfaced part exposed to the intraoral environment. Since they are expected to compensate for the absence of natural teeth and their physiological functions, there is also a tendency to perceive peri-implant infections as pathologies analogous to gingivitis and periodontitis of natural teeth. Nonetheless, fundamental histological and immunophysiological differences with natural teeth render dental implants more susceptible to endogenous oral infections . First, Tannerella, Prevotella, Fretibacterium, or Treponema spp., that further correlated with a regional increase in proinflammatory cytokines , in contrast to inefficient osseointegration due to contamination during insertion (early failure) or compromised bone regeneration/reosseointegration during the surgical reconstructive phase of its treatment.Whereas the patient\u2019s systemic conditions or genetic susceptibility may also increase the odds for the development of peri-implant infections , the perThe implant surface structure and abutment interface may affect microbial colonization and disease progression , whereasPorphyromonas gingivalis, Tannerella forsythia, Treponema denticola, and also other species from Treponema groups I to III and Synergistetes cluster A were typically associated with peri-implantitis , that is, high-throughput DNA sequencing technologies, has become the method of choice for the taxonomic and functional characterization of the oral microbiota. NGS methods have led to a quantum leap in the number of sequence reads generated, thereby greatly improving coverage depth of analyses. Application of NGS has found unquestionable relevance for the study of oral ecosystems that encompass over 700 bacterial species, among which about 30% remained as yet uncultivated . To dateBurkholderia, Anaerovorax, Anaerococcus, Aerofilium, and Exiguobacterium, appeared unique to the peri-implant niche. The predominant genera in the peri-implant microbiota were Butyrivibrio, Campylobacter, Eubacterium, Prevotella, Selenomonas, Streptococcus, Actinomyces, Leptotrichia, Propionibacterium, Peptococcus, Lactococcus, and Treponema. Peri-implantitis sites were associated with lower levels of Prevotella and Leptotrichia and higher levels of Actinomyces, Peptococcus, Campylobacter, nonmutans Streptococcus, Butyrivibrio, and mutans Streptococcus than healthy peri-implant sites. In a subsequent study, the same group refined their approach to examine peri-implant and periodontal microbiotas from adjacent sites (Staphylococcus pettenkoferi and Staphylococcus hominis) at significantly higher abundances in peri-implantitis than periodontitis microbial communities. Interestingly, 85% of individuals shared less than 8% of abundant species between pairs of adjacent peri-implant and periodontal sites.nt sites . ConsistPrevotella nigrescens presenting at significantly higher abundance in peri-implantitis, whereas Peptostreptococcaceae sp. and Desulfomicrobium orale were significantly higher in periodontitis. An as-yet-uncultivated Treponema sp. HMT-257 was uniquely associated with the severity of peri-implantitis, correlating markedly with radiographic bone loss, PPD, and suppuration.Distinct bacterial communities between peri-implantitis and periodontitis have also been observed in another 16S rRNA-based study , with PrP. gingivalis, T. forsythia, and Prevotella intermedia. The microbiota from peri-implantitis also harbored differentially abundant communities, compared to earlier clinical stages, with a marked enrichment of several members of the Eubacterium spp.In an effort to better understand the progressive shifts that occur within microbial communities during the establishment of a peri-implant infection, Bacteroidetes, Spirochetes, and Synergistetes, whereas Actinobacteria prevailed at healthy sites. At lower taxonomic levels, acknowledged periodontal pathogens, such as P. gingivalis, T. forsythia, and T. denticola were more abundant in peri-implantitis sites, along with some less well-characterized taxa, including Peptostreptococcaceae, Desulfobulbus, Treponema maltophilum, Eubacterium saphenum, Filifactor alocis, Freitbacterium fastidiosum, and Fretibacterium HMT 360. In contrast, Veillonella dispar, Rothia dentocariosa, and Streptococcus sanguinis displayed significantly higher abundances at healthy sites.Whereas these described studies relied on 454 pyrosequencing (Roche), the technology was gradually discontinued from 2013, superseded by the Illumina platforms . DespiteVibrio, Campylobacter, and Granulicatella were observed in health, whereas Acinetobacter, Micrococcus, and Moraxella were enriched in peri-implantitis  rather than submucosal biofilms also identified differentially abundant bacterial communities between peri-implant health and disease. Increased abundances of genera lantitis .Filifactor, Mogibacterium, Propionibacterium, Acinetobacter, Staphylococcus, Paludibacter, and Bradyrhizobium. It is known that Filifactor is commonly associated with chronic periodontal lesions . As examples, the choice of the variable regions to sequence may introduce biases, as not all regions display comparable ability to distinguish between taxa, and taxonomic resolution is limited to the species level . AlthougAlthough few studies have investigated the transcriptome of human cells during the course of peri-implant infections , to the Leptotrichia spp. and Eubacterium spp. appear to be differentially abundant in peri-implant health and peri-implantitis, respectively, whereas Fusobacterium spp. and Veillonella spp. comprise part of their shared core microbiome (The advent of NGS approaches to characterize the peri-implant microbiota has drastically improved our appreciation of the diversity and ecology of the bacterial communities. Peri-implant sites are distinct ecological niches, characterized by lower diversities than periodontal niches, yet harboring a differently abundant microbiota in both health and disease. These community surveys further indicated that health and disease situations were associated with compositional shifts within communities rather than the presence of specific pathogenic taxa. As examples, crobiome .Functional and virulence differences between strains of the same species, expressed as altered transcriptional profiles, may directly potentiate the pathogenicity of the entire community. This latter field is unexplored in the context of peri-implant infections and is worth researching more extensively. It is now high-time that researching the microbiology of peri-implantitis and its differences with periodontitis serves more than the scientific curiosity of their comparative etiologies. Rather, efforts invested in deciphering the ecological triggers of functional pathogenicity might prove more beneficial to build improved strategies for risk assessment, prevention, diagnosis, or supportive therapy when required. Since metatranscriptomic pathways specific to peri-implantitis have been identified , could RTreponema species may be impaired by the administration of a specific oxidoreductase inhibitor (On the treatment side, could we preferentially target and block functional or metabolic pathways crucial to those taxa identified as differentially abundant in peri-implantitis or even at the earlier stage of peri-implant mucositis? Recent preliminary data in this direction indicate that growth, motility, and complement resistance in several oral nhibitor  or that nhibitor . DespiteG.N. Belibasakis, D. Manoil, contributed to conception, design, data acquisition, and interpretation, drafted and critically revised the manuscript. Both authors gave final approval and agree to be accountable for all aspects of the work."}
+{"text": "Background: As an erratic human behavior, panic buying is an understudied research area. Although panic buying has been reported in the past, it has not been studied systematically in Bangladesh.Aim: This study aimed to explore the characteristics of panic buying episodes in Bangladesh in comparison to current concepts.Methods: A retrospective and explorative search were done using the search engine Google on November 6, 2020, with the search term \u201cpanic buying in Bangladesh.\u201d All the available news reports published in the English language were extracted. A thorough content analysis was done focusing on the study objectives.Results: From the initial search, a total of 30 reports were extracted. However, six reports were not included based upon the exclusion criteria, resulting in an analysis of 24 reports. Five panic buying episodes were identified, discussing the precipitating events, responsible factors, goods acquired through panic buying, and prevention measures. Flood, curfew, COVID-19, and export ban were found to be precipitating events. Media reports frequently mentioned prevention strategies, expert opinion, supply chain status, rationing, and government action. The reported goods that were panic bought were items necessary for daily living such as rice, oil, spices, and safety products such as hand sanitizer and masks.Conclusion: The study revealed preliminary findings on panic buying in Bangladesh; however, they are aligned with the current concept of it. Further empirical studies are warranted to see the geographical variation, precise factors, and to test the culturally appropriate controlling measures. Panic buying (PB) is an erratic human behavior that has been noticed in at least 93 countries all over the world during the COVID-19 pandemic , 3. FuelA previous study also postulated a causative model of PB mentioning that any adverse precipitating event usually stimulates this behavior . As per PB has many negative effects such as disruption of supply chains, artificial commodity shortages, and stoke price rise. Furthermore, large crowds and queues appearing in retail spaces and stores could result in further clusters. Some prevention strategies have been proposed such as responsible media reporting, kinship promotion, rationing, assurance from the authority, some psychological measures to prevent the episodes , 7.Given this scenario, there is a need for further research into the precipitating factors of PB, evaluating the responsible factors, and possible mitigating strategies. Country specific research on PB is limited though, and it is crucial to consider prevention strategies. Against this background, we conducted the present analysis to assess the characteristics of panic buying episodes in Bangladesh, a populous country in South-East Asia. In particular, we aimed to evaluate precipitating events, responsible factors, goods of panic buying, and control strategies. Driven by previous research methods in PB, we used media reports to identify articles related to PB for analysis. The goal was to provide country-specific data that may inform management and prevention strategies to control PB.A retrospective and explorative search were done in Google on November 6, 2020, with the search term \u201cpanic buying in Bangladesh.\u201d All the available news reports published in the English language were extracted. A thorough content analysis was done focusing on the study objectives. A method of three previous similar studies was followed to extract the reports, analyze the contents, identify the panic buying goods, assess the media reports, trace the responsible factors, and mention the controlling strategies , 4, 6. TThe inclusion criteria for this analysis include reports from any report discussing panic buying from the media covering news, blogs, personal views, opinions that were published in English. Vernacular (Bangla) reports were not considered due to a lack of specification of the exact Bangla word for \u201cpanic buying.\u201dSocial media posts, scholarly articles, duplications, and news of the panic buying behaviors of Bangladeshis living outside Bangladesh were excluded from the study. Social media posts were excluded because they are supposed to be more emotionally charged and are very often biased. We excluded scholarly articles because we aimed to assess primary observations reported in the media. Various types of scholarly articles with various objectives would dislocate the research focus. Moreover, conformity bias, group-thinking, and herd behavior may be considered as potential sources of biases in social media posts .We used the Microsoft Excel spreadsheet 2019 version for data coding. As a preliminary explorative study detail, statistical analysis was not performed.The study was conducted in compliance with the declaration of Helsinki (1964). As we analyzed publicly available media reports, no formal ethical approval was obtained.From the initial extraction, a total of 30 reports were retrieved. However, six reports were dropped after considering the exclusion criteria, resulting in the analysis of 24 reports . From thFrom the reports, flood, curfew, COVID-19, and export bans  were fouSeveral attributing factors were identified from the reports such as rumor of danger (flood), curfew, policy ban, uncertainty, the anticipation of an impending lockdown, increased demand, anticipation of price hike, and anticipation of short supply .The reported goods are necessary for daily living such as rice, sugar, salt, onion, pulse, potatoes, spices, masks, sanitizers, toilet paper, flour, lentil, pulse, oil, milk powder, chicken, fish, beef, egg, garlic, ginger, biscuits, baby diaper, mosquito coils, soaps, hygiene products, noodles, drugs , and pulse oximeter .Media reports frequently mentioned prevention strategies, expert opinion, supply chain status, rationing, and government action. Raising awareness, selling goods at a lower price by the government, formulation of the special monitoring team, punishment to maleficent sellers, dissemination of stock status to the general people, assurance of stocks, import from alternative sources, reduced use of goods (onion), rationing while selling from the super shops, publishing circulars in newspapers to raise awareness, and a reduction of import duty were the controlling measures identified by the analysis.Panic buying is an under-researched area even though it is common behavior during emergencies. This study aimed to identify the characteristics of panic buying episodes in Bangladesh in comparison to current concepts. We checked 24 published news reports  to identFrom the available evidence, we established that PB usually starts with an adverse stimulus, and people usually buy necessary goods in response to several psychological reactions \u20134. MediaThe first episode happened in 1998 where a flood acted as a precipitating event. During this event rice, wheat, sugar, salt, onion, pulse, potatoes, and spices were brought, and assurance of adequate stocks was disseminated . The fouThe study revealed primitive characteristics of panic buying episodes, where it starts with adverse stimuli, have an extra buying of necessary goods, resulting in disruption of supply chains supporting the existing causative model of PB proposed by Arafat et al. . The praThis is the first systematic assessment of panic buying in Bangladesh and reveals preliminary explorative findings that could help to formulate prevention strategies in future.Data were extracted from media reports which are not of scientific quality. The sample size was small. Data extraction and the search were done by a single person (first author). No structured instrument was used to extract the data. Only English language reports were studied.The study revealed preliminary findings of panic buying in Bangladesh. However, they are aligned with the current concept of panic buying. Further empirical studies are warranted to explore geographical variation, demographics , consumption behavior, precise factors, and to test culturally appropriate control measures.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The study was conducted complying with the declaration of Helsinki (1964). As we analyzed the publicly available media reports, no formal ethical approval was obtained.SA contributed to the concept, design, data analysis, and writing. All authors contributed to manuscript writing, revision, read, and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Article title: Risk factors and outcomes of cardiovascular disease readmission within the first year after dialysis in peritoneal dialysis patientsAuthors: Jianbo Li, Naya Huang, Zhong Zhong, Dan Wang, Zhen Ai, Lanping Jiang and Fengxian HuangJournal:Renal FailureCitation details: Vol. 43, Number 1, pages 159\u2013167DOI:10.1080/0886022X.2020.1866009When the above article was published online, the authors were listed as: Jianbo Li, Naya Huang, Zhong Zhong, Pema Joe, Dan Wang, Zhen Ai, Lisha Wu, Lanping Jiang and Fengxian Huang. However, since publication Pema Joe and Lisha Wu have requested to be removed from the author list because although they helped with the preliminary work related to this study, they do not meet the authorship criteria for the full research represented in this article. This has been agreed with and approved by all the other authors of this article.The updated author list is now:Jianbo Li, Naya Huang, Zhong Zhong, Dan Wang, Zhen Ai, Lanping Jiang and Fengxian HuangThe affiliation c has been removed as the remaining authors was not affiliated with Linzhi People\u2019s Hospital.The online version has been corrected."}
+{"text": "Overall, a huge variety of structures is found, indicating that chemodiversity correlates to the amazing biodiversity of this fascinating group of molluscs.Heterobranch molluscs are rich in natural products. As other marine organisms, these gastropods are still quite unexplored, but they provide a stunning arsenal of compounds with interesting activities. Among their natural products, terpenoids are particularly abundant and diverse, including monoterpenoids, sesquiterpenoids, diterpenoids, sesterterpenoids, triterpenoids, tetraterpenoids, and steroids. This review evaluates the different kinds of terpenoids found in heterobranchs and reports on their bioactivity. It includes more than 330 metabolites isolated from ca. 70 species of heterobranchs. The monoterpenoids reported may be linear or monocyclic, while sesquiterpenoids may include linear, monocyclic, bicyclic, or tricyclic molecules. Diterpenoids in heterobranchs may include linear, monocyclic, bicyclic, tricyclic, or tetracyclic compounds. Sesterterpenoids, instead, are linear, bicyclic, or tetracyclic. Triterpenoids, tetraterpenoids, and steroids are not as abundant as the previously mentioned types. Within heterobranch molluscs, no terpenoids have been described in this period in tylodinoideans, cephalaspideans, or pteropods, and most terpenoids have been found in nudibranchs, anaspideans, and sacoglossans, with very few compounds in pleurobranchoideans and pulmonates. Monoterpenoids are present mostly in anaspidea, and less abundant in sacoglossa. Nudibranchs are especially rich in sesquiterpenes, which are also present in anaspidea, and in less numbers in sacoglossa and pulmonata. Diterpenoids are also very abundant in nudibranchs, present also in anaspidea, and scarce in pleurobranchoidea, sacoglossa, and pulmonata. Sesterterpenoids are only found in nudibranchia, while triterpenoids, carotenoids, and steroids are only reported for nudibranchia, pleurobranchoidea, and anaspidea. Many of these compounds are obtained from their diet, while others are biotransformed, or  Marine organisms produce a wide variety of natural products, often unique and critical for their survival and ecological performance ,2,3,4. AThe methodology for extracting natural compounds from organisms includes diverse techniques that are usually expensive and time-consuming ,14. Somede novo biosynthesized. Among these chemicals, terpenoids are widely present.Within marine organisms, molluscs are one of the most abundant and chemically rich invertebrate groups, possessing high amounts of terpenoids ,15,16. Hde novo biosynthesized, but also alkaloids and other compounds , si, siElysiAplysia parvula accumulates several brominated and chlorinated compounds from the red alga Plocamium costatum in New Zealand. Among them, costatone (7)  and B  (50 = 19\u201396 \u03bcg/mL) , w, wDendrobins A\u2013N . Moreoved esters , allocat species . D. denis mantle . The phyAtlantic . De novo pathway ,118,119.censin A , located species . Doriops. pharpa , while ePhyllidiella pustulosa, where compounds are obtained from the demosponge Acanthella cavernosa . F. FPhyllinge diet .Cadlina laevis and C. pellucida present laevidiene (27)  , w, wGoniob viscera .Thuridilla hopei, a beautifully colored species, contains the three diterpenoids thuridillins A\u2013C (40)   176] an anThuridA\u2013C (40) \u2014suggesteA\u2013C (40)  177]. T. TThuridnuissima , also coplendens . Thuridi serenus . The cone Udotea ,180,181.Phyllidiella pustulosa from China is one monocyclic isocyanide diterpenoid ..Aplysia Trimusculus does not possess the typical propionates common in this group, instead it possesses a single type of labdane diterpenoids, some of them similar to those of the pleurobranchoid Pleurobranchaea meckelii ,216Doris1\u20139 (68)  is de noecursors ,218,219.pecimens . Similarty acids ,221,222.ulations ,224. Theycerides , and thiycerides ,226,227.Phyllodesmium briarieum, P. longicirrum and P. magnum possess several diterpenes along with some sesquiterpenes, possibly obtained from their octocoral prey , s, sCharcoeterrent .Hypselodoris capensis, which presents the 22-deoxy-23-hydroxymethyl-variabilin, together with the abovementioned compounds, obtained from its suggested prey demosponges Fasciospongia sp. and Dysidea sp. , i, iAplysi kurodai . In addi kurodai . Mucus sve gland . Syphonota geographica, a Mediterranean-invasive sea hare, presents two degraded sterols, aplykurodinone-1 and -2 (88)  , in the ipulacea . Syphonode novo biosynthesized by the molluscs. Bacterial origin has been suggested for several types of compounds in heterobranchs [Heterobranch molluscs are rich in natural products; however, only a small proportion has been studied so far. As reported here, their terpenoids are particularly abundant and diverse; they include monoterpenoids, sesquiterpenoids, diterpenoids, sesterterpenoids, triterpenoids, tetraterpenoids, and steroids. This review discusses more than 330 metabolites isolated from ca. 70 species of heterobranch molluscs. The monoterpenoids reported here may be linear or monocyclic, while sesquiterpenoids may include linear, monocyclic, bicyclic, or tricyclic molecules. Diterpenoids may include linear, monocyclic, bicyclic, tricyclic, or tetracyclic compounds. Sesterterpenoids, instead, are linear, bicyclic, or tetracyclic. Triterpenoids, tetraterpenoids, and steroids are not as abundant as the previously mentioned types. Remarkably, no terpenoids have been described in this period in tylodinoideans, cephalaspideans, or pteropods; and most terpenoids have been found in nudibranchs, anaspideans, and sacoglossans, with very few compounds in pleurobranchoideans and pulmonates. Many of these compounds found in heterobranchs are obtained from their diet, while others are biotransformed, or obranchs . Howeverde novo biosynthesized. Some compounds are present as glyceryl esters, such as verrucosins. De novo biosynthesis has been demonstrated in a few cases, as well as the putative symbiotic origin of some metabolites [Monoterpenoids are present mostly in anaspidea and are less abundant in sacoglossa. Nudibranchs are especially rich in sesquiterpenes, which are also present in anaspidea, and in less numbers in sacoglossa and pulmonata. Diterpenoids are also abundant in nudibranchs, present also in anaspidea, and scarce in pleurobranchoidea, sacoglossa, and pulmonata. Sesterterpenoids are only found in nudibranchia, while triterpenoids, carotenoids, and steroids are only reported for a few nudibranchia, pleurobranchoidea, and anaspidea. Anaspidea include many halogenated and non-halogenated terpenoids, mostly from diet. Nudibranchs possess many sesquiterpenoids and diterpenoids, mostly from diet, but also abolites ,15, probThe ecological role of these compounds includes many examples of feeding deterrence against sympatric predators, mostly fish and crabs, as well as toxicity. However, many assays are still conducted with species that do not live in the same habitat as the heterobranchs, and thus the ecological significance of many compounds continues to be further examined. The low numbers of reliable field experimental data available is evident. The pharmacological potential of heterobranch terpenoids is clear from the examples reported above\u2014from cytotoxicity to antiplasmodial activity, antituberculosis, antifouling, antifungal, antibacterial, antitumoral, and apoptosis inducers.Overall, a huge variety of terpenoid structures is found in heterobranchs, indicating that chemodiversity correlates to the biodiversity of this amazing group of molluscs. The potential to vastly increase the number and diversity of known natural products in heterobranchs, as well as their bioactivity, is open to further research. The search for effective and efficient methods of integral and/or selective extraction of terpenoids from heterobranchs, in particular, deserves more attention, since environmentally friendly practices are needed. How global change will affect biodiversity, and thus chemodiversity, in heterobranch molluscs remains to be further investigated, hopefully before both species and molecules disappear."}
+{"text": "Herbal medicine use has grown considerably worldwide among pregnant women, and is particularly widespread in sub-Saharan Africa. However, herbal medicines used across sub-Saharan Africa are associated with important research gaps and a lack of regulatory framework. This is particularly problematic, as herbal medicine use during pregnancy raises several concerns attributed to the herbal ingredient itself, conventional drug-herbal medicine interactions, and contamination or adulteration of herbal remedies. Moreover, several local herbal remedies used by sub-Saharan African pregnant women have never been botanically identified. In this review, an overview of the practice of herbal medicine, including the regulations, challenges and overall safety, is provided. Then, we discuss the prevalence of herbal medicine use during pregnancy across different sub-Saharan African countries, as well as the indications, adverse outcomes, and effectiveness of the most commonly used herbal medicines during pregnancy in that region. Pregnancy is characterized by significant physiological changes resulting in various symptoms, such as nausea, vomiting, heartburn, and constipation. These ailments often cause pregnant women to resort to self-medication including the use of herbal medicines . ConsequPrevious research has shown that herbal medicine use during pregnancy is quite common across sub-Saharan Africa . HoweverAccording to the World Health Organization, there are several challenges associated with the herbal medicine practice .The diversity of herbal remedies and their uses between different countries makes scientifically evaluating and regulating them very challenging . Hence, Moringa oleifera Lam., a commonly used medicinal plant with multiple health benefits, when given together or following a long period of ingestion of Moringa oleifera Lam. In the presence of Moringa oleifera Lam., the peak plasma concentration of amodiaquine decreased by up to 40%, as well as its area under the plasma concentration-time curve which decreased by approximately 11%, leading to a significantly delayed absorption of amodiaquine , Vaccinium oxycoccus L./Vaccinium macrocarpon Aiton L. (cranberry), Valeriana officinalis L. , Rubus idaeus L. (raspberry leaf), Matricaria chamomilla L. (chamomile), and Mentha piperita L. (peppermint) , Allium sativum L. (garlic), Cucurbita pepo L. (pumpkin), Gymnanthemum amygdalinum (Delile) Sch.Bip.  (bitter leaf), Ricinus communis L. (castor oil), Garcinia kola Heckel (bitter kola), Ocimum lamiifolium Hochst. ex Benth. (basil or Dama Kesse in Amharic), Azadirachta indica A. Juss (neem), Ruta chalepensis L. , and Aloe vera (L.) Burm.f. (Aloe vera)  . The Afrpermint) . This sppermint) . The mosoe vera) . Table 2Several cross-sectional studies have shown that ginger is commonly used by pregnant women across sub-Saharan Africa for nausea and vomiting during pregnancy . A systeGarlic is characterized by diverse therapeutic properties, including anti-hypertensive, anti- inflammatory, anti-oxidant, anti-bacterial, hypocholesteremic, and anti-cancer properties . In a raCucurbita, could exert anti-oxidant effects by elevating glutathione peroxidase and superoxide dismutase activity as well as reducing serum levels of malondialdehyde , highlighting the oxytocic properties of this medicinal plant . Castor traction . With retraction . Neverthtraction .Bitter kola is a flowering plant found mostly in the tropical rain forest region of Central and West Africa. Although bitter kola is mostly used among pregnant women to treat nausea and vomiting , reporteDama Kesse is a versatile aromatic genus that is particularly popular in Ethiopia, with anti-malarial, antipyretic, anti-oxidant, anti-spasmodic, and anti-bacterial properties . DespiteNeem is a fast-growing tree that is a member of the Meliaceae family. It is characterized by a broad spectrum of activity including anti-inflammatory, antipyretic, analgesic, cardiovascular, hypoglycemic, diuretic, immunomodulatory, dermatological, anti-bacterial, anti-fungal, anti-ulcer, anti-tumor, and anti-malarial effects. Although its exact mechanism in the prevention of pathogenesis is not entirely understood, the therapeutic activity of neem is thought to result from the synergistic/additive effects of its various bioactive compounds such as azadirachtin, nimbolinin, nimbin, nimbidin, nimbidol, sodium nimbinate, gedunin, salannin, and quercetin . DespiteTena Adam is a shrubby plant that is cultivated in the highlands of Ethiopia. Similarly to Dama Kesse, it is poorly studied with no clinical trial data available. However, the administration of an aqueous infusion of Tena Adam during organogenic period in pregnant mice led to increased flow and decreased vascular resistance in the placenta bed, as well as fetal thymic involution . Thus, TAloe vera is perhaps one of the most widely used herbal remedies for topical skin conditions. Aloe vera extracts improve skin moisture by a humectant mechanism, and prevent skin ulcers as they contain mucopolysaccharides, amino acids, zinc, and water (Aloe vera is associated with infrequent adverse events (Aloe vera whole leaf extract has shown clear evidence of carcinogenic activity in rats, and was classified by the International Agency for Research on Cancer as a possible human carcinogen (Aloe vera because its cathartic property might result in stimulating uterine contractions, thereby increasing the risk for premature labor or miscarriage (nd water . Althouge events , orally rcinogen . In addicarriage .Sub-Saharan Africa is home to an extensive and diverse medicinal plant life. Consequently, the use of herbal medicines is widespread in that region. Despite this, the study of herbal medicine use during pregnancy which is related to maternal health, a public health priority in many sub-Saharan African countries, remains limited . CurrentA low disclosure rate of herbal medicine use to health care providers has also been identified in the present review. This suggests that collaborative communication by health care providers is important, as it may mitigate against the potential dangers of herbal medicine use during pregnancy and of uncoordinated concurrent herbal and conventional medicine use. Finally, given that traditional and sociocultural influence may play a role in herbal medicine use during pregnancy, there is a need to better understand the reasons and facilitators of herbal medicine use in pregnant women from sub-Saharan Africa.MH drafted the manuscript. LH revised the manuscript.This work was funded by the Centre for International Health, University of Bergen, Norway.MH is a Partner 4 Health employee.The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Stimuli or insults during critical developmental transitions induce alterations in progeny anatomy, physiology, and metabolism that may be transient, sometimes reversible, but often durable, which defines programming. Glucolipotoxicity is the combined, synergistic, deleterious effect of simultaneously elevated glucose (chronic hyperglycemia) and saturated fatty acids (derived from high-fat diet overconsumption and subsequent metabolism) that are harmful to organs, micro-organs, and cells. Glucolipotoxicity induces beta cell death, dysfunction, and failure through endoplasmic reticulum and oxidative stress and inflammation. In beta cells, the misfolding of pro/insulin proteins beyond the cellular threshold triggers the unfolded protein response and endoplasmic reticulum stress. Consequentially there is incomplete and inadequate pro/insulin biosynthesis and impaired insulin secretion. Cellular stress triggers cellular inflammation, where immune cells migrate to, infiltrate, and amplify in beta cells, leading to beta cell inflammation. Endoplasmic reticulum stress reciprocally induces beta cell inflammation, whereas beta cell inflammation can self-activate and further exacerbate its inflammation. These metabolic sequelae reflect the vicious cycle of beta cell stress and inflammation in the pathophysiology of diabetes. Beta cells are dynamic and respond to fluctuating demands for insulin. Inflammation contributes to the pathogenesis and is an underlying mechanism of several metabolic diseases. Developmental programming (hereafter programming) through a nutritional insult, such as maintenance on a high-fat diet (HFD) during fetal and early neonatal life, alters growth and developmental trajectories at the organ , micro-organ , and cellular  levels that trigger the pathogenesis of metabolic diseases. In beta cells, high-fat programming  induces beta cell hypoplasia and hypotrophy  that diminishes beta cell function  evident by impaired glucose-stimulated insulin secretion (GSIS) resulting in insufficient insulin release that results in and exacerbates hyperglycemia, as demonstrated in neonatal, weanling, and adult progeny ,6,7,8,9.Macrophages are integral for inducing islet inflammation. In diabetes, intra-islet macrophage hyperplasia is the primary source of intra-islet proinflammatory cytokines . ProinflProgramming refers to a stimulus or insult during critical developmental transitions that induces alterations in offspring anatomy, physiology, and metabolism that may be transient or durable, and sometimes reversible. Nutrition, through a HFD, is one way to initiate programming. Pregnant HFD-fed C57/BL6J mice were obese with increased adiposity but not overtly diabetic . HoweverIn non-obese diabetic mice exposed to hyperglycemia in utero, the protective compensatory factor in response to islet stress, regenerating islet-derived protein 3 gamma (Reg3g), was decreased with a high fold change ,20 that Obesity is associated with immune cell hyperplasia ,26,27,28This snapshot of the influence of programming through a HFD, hyperglycemia, and maternal obesity  reveals the metabolic derangements that programming confers to progeny, e.g., hepatic steatosis, inflammation , insulin resistance, glucose intolerance, oxidative stress, and diminished islet and beta cell viability and function.Glucolipotoxicity is the combined deleterious consequences of elevated chronic glucose and saturated fatty acids  concentrations on specific organs , and micro-organs  and cells  . GlucoliHowever, during high-fat programming, glucolipotoxic effects can manifest earlier, given the particularly vulnerable life stage that the progeny are exposed to the insult. Hence, glucolipotoxicity induces derangements in beta cell structure and function, thereby inducing beta cell dysfunction; insulin resistance often follows as a consequence but can also contribute to beta cell dysfunction, and with progression to beta cell failure, diabetes ultimately manifests.Beta cells initiate insulin transcription for pro/insulin biosynthesis and insulin exocytosis to restore glucose homeostasis, typically after ingesting a meal. Whereas glucose stimulates insulin transcription, pre-mRNA splicing and mRNA stability, proinsulin translation, maturation (to insulin) and insulin secretion, lipotoxicity and glucolipotoxicity impair several of these steps  and are Glucotoxicity is a key regulator of beta cells, whereas lipotoxicity and glucolipotoxicity were recently suggested to be less clinically relevant . ElevatePerpetual hyperglycemia and chronic saturated fatty acid exposure present as glucolipotoxicity, which contributes to islet and beta cell stress (endoplasmic reticulum (ER) and oxidative stress) and inflammation. Hyperglycemia and hyperlipidemia are traits of obesity and diabetes, and in diabetes, chronically high circulating NEFA concentrations, particularly saturated fatty acids, mediate a progressive decline in beta cell function leading to death, dysfunction  and fail2K, an anion) and peroxynitrite (ONOOK) production by beta cell mitochondria and drives NOS2 expression, which leads to nitric oxide (NO) production and induces ER and oxidative stress [In murine and human islets and beta cells, palmitate has been extensively used for the induction of ER and oxidative stress ,52,53,54e stress . Palmitae stress ,57 with e stress  and inite stress .N-terminal kinase (JNK) activation; all lead to inflammation [In isolated islets, the adverse effects of NEFA on GSIS are most profound with long-chain saturated fatty acids, e.g., palmitic acid . Palmitiammation ,59. In hammation . These eammation ,60. Howeammation . In muriammation . This esammation ,63, whicammation ,65,66, aammation ,63. GlucGlucolipotoxicity links beta cell stress to inflammation. Glucolipotoxicity alters mitochondrial function by impairing electron transport chain activity, which leads to increased reactive oxygen species (ROS) generation which, in turn, induces inflammation in beta cells and peripheral organs . MitochoCellular stress induced by ER and oxidative stress are integral to islet and beta cell inflammation, death, dysfunction, and failure. Beta cells are highly specialized for insulin biosynthesis, with pro/insulin accounting for 30\u201350% of total protein in beta cells . ER streBeta cells often encounter ER overload due to increased metabolic demand, e.g., due to rapid and increased insulin biosynthesis and secretion in response to hyperglycemia  to maintThe highly metabolically active beta cells are susceptible to oxidative stress due to low levels of some antioxidants, e.g., glutathione peroxidase (GPx) and catalase ,76. Howe2K and the hydroxyl radical (OH); non-radicals, e.g., hydrogen peroxide (H2O2); or anions, e.g., ONOOK [In beta cells, ROS and RNS include free radicals, e.g., NO, O., ONOOK ,77,78. O., ONOOK .The close association of oxidative and ER stress is evident as oxidative stress induces protein misfolding through the disruption of the ER redox state and disulphide bond formation, and protein misfolding prompts ROS production . The detSeveral mechanisms induce ER and oxidative stress that lead to beta cell inflammation, i.e., inflamed beta cells, and beta cell death, that then activates islet-resident cells, e.g., macrophages entwined with B, T, endothelial and dendritic cells, and myofibroblasts, concomitant with an increase in leukocyte recruitment ,83,84. TIn beta cells, IL1\u03b2 (and other proinflammatory cytokines) induces ER stress and UPR activation, and promotes NF\u03baB-dependent inducible nitric oxide synthase (iNOS) expression and NO production . CytokinThe islet cell production of proinflammatory mediators results in ER stress, oxidative stress, mitochondrial dysfunction, and islet cell dysfunction. Overnutrition results in obesity and increased adipose tissue mass, and with perpetual nutritional glucose and saturated fatty acid overload, leads to ER stress. In humans, beta cell dedifferentiation in response to chronic overnutrition may be reversible within the first decade of diabetes . Weight Beta cell dysfunction initially presents in prediabetes  through their hypersecretion of insulin in response to elevated glucose concentrations. In obesity, hyperinsulinemia occurs due to the hypersecretion of insulin and compensatory response to insulin resistance . In adolIn obesity and diabetes, there is an increase in circulating NEFA and ectopic fat accumulation in organs . In human islets treated with palmitate, there was increased islet triglyceride content concomitant with impaired function . With chVarious programming insults such as fetal and lactational exposure to a high saturated fat diet, hyperglycemia or obesity , can initiate glucolipotoxicity . PostnatIn overextended beta cells, glucolipotoxicity contributes to pro/insulin (and other) protein misfolding and accumulation in the ER lumen, resulting in ER overload which activates the UPR leading to ER stress . FurtherGlucolipotoxicity induces beta cell stress with the increase in the UPR leading to ER and oxidative stress leading to increased beta cell inflammation . FurtherExacerbating obesity, adipose tissue insulin resistance and chronic overnutrition further prompt excess beta cell production of proinflammatory mediators. In pre-existing diabetes, islet and beta cell inflammation will exacerbate the disease and lead to further morbidities. ER stress induces and is induced by beta cell inflammation, whereas beta cell inflammation can self-activate and exacerbate beta cell inflammation. This reflects the vicious cycle of beta cell stress and inflammation in the pathophysiology of diabetes.Programming, glucolipotoxicity, and the interactions of ER and oxidative stress in the pathogenesis and maintenance of disease require further unraveling and supporting evidence from clinical studies. Nutritionally and metabolically overloaded beta cells become stressed and inflamed with worsening outcomes for metabolic disease. Beta cell stress and inflammation require further investigation into adaptive mechanisms that evolve to mitigate cellular stress and inflammation, to identify strategies and targets for preserving beta cell physiology."}
+{"text": "Bacillus subtilis sigma factor SigB of RNA polymerase (RNAP) specifically expressed during germination and outgrowth. SigB is critical for the cell\u2019s response to general stress but is also expressed during spore germination and outgrowth, and this specific regulon is not known. This approach allowed us to (i) define a subset of the known SigB regulon controlled by SigB specifically during spore germination and outgrowth, (ii) identify the influence of the promoter sequence binding motif organization on the expression of the SigB-regulated genes, and (iii) suggest additional sigma factors co-controlling other SigB-dependent genes. Experiments then validated promoter sequence characteristics necessary for direct RNAP\u2013SigB binding. In summary, this work documents the potential of computational approaches to unravel new information even for a well-studied system; moreover, the study specifically identifies the subset of the SigB regulon, which is activated during germination and outgrowth.The exponential increase in the number of conducted studies combined with the development of sequencing methods have led to an enormous accumulation of partially processed experimental data in the past two decades. Here, we present an approach using literature-mined data complemented with gene expression kinetic modeling and promoter sequence analysis. This approach allowed us to identify the regulon of  Advances and limitations of network inference methods were reviewed by UTP.Multiple round transcription reactions were carried out in 10 \u03bcL reaction volumes with 60 nM E. coli RNAP and the templates were DNA fragments of the hcr gene and plasmid pLK1 [All transcription experiments were performed at 37 \u00b0C. Transcription was induced by adding reconstituted RNAP holoenzyme and allowed to proceed for 15 min. Transcriptions were stopped with equal volumes (10 \u03bcL) of formamide stop solution ). To generate molecular size RNA marker, we used the same conditions. The only differences were the usage of mid pLK1 . These tIn this paragraph, we discuss the use of the expression profile of SigB to identify genes that could be, from the kinetic point of view, controlled by SigB. This was achieved by modelling of their expression profiles using Equations (1) and (3). Those genes for which the model well fitted their expression profiles were identified as potentially controlled by SigB.http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE6865) that contained expression profiles of 4008 genes measured at 14 time points , the pre-processing excluded 1349 genes with low expression, and 135 genes with constant rate of expression. Of the remaining 2524 genes, another 327 genes with profiles that had been at least once modelled with the random expression profiles were removed .Out of the 411 genes , 260 were reported to be controlled exclusively by SigB  were modeled and the ability of the model to fit the experimental data was assessed . For 17 genes , the best fit was obtained when SigB and SigA acted together. In summary, the modeling confirmed 148 (36%) genes that were during germination and outgrowth controlled by SigB alone (94) or with a possible participation of other regulators (54).Modeling results are summarized in gabD, katX, rsbU, V, W, X, yfhE, F, yxjI, yugU) or by SigB together with one or more reported regulators. No model could be found for six genes . Generally, in all remaining cases, two regulators were always sufficient to model the target gene expression profile equally well as if more regulators were employed.Finally, we found that of the 46 genes reported as controlled by three or more regulators, 11 were equally well modeled by SigB alone  of the known SigB-dependent genes with their expression kinetics analysis.We took all genes of the documented SigB regulon  and we sIn total, 95% of type 1 genes possessed the \u221235 motif, 78% the \u221210 motif, and 73% of these genes contained both motifs. Similarly, 97% of type 2 genes had the \u221235 motif and 66% the \u221210 motif; 63% contained both motifs. To the contrary, only 53% of type 3 genes had the \u221210 motif and only 40% of them had both. Importantly, the distance between the binding motifs was more consistent for type 1 and 2 genes where the mean distance was around 15 bp, while for the excluded genes, the mean distance was 18 bp. The largest deviations were observed for the genes for which the kinetic modeling did not find any regulator, or those that were excluded for low expression or flat expression profile (type 3). Therefore, this analysis clearly specified genes whose binding site composition determines that they could be regulated by SigB only and those that require during germination and outgrowth additional/different regulators.B. subtilis RNAP and DNA fragments containing the promoter regions. Altogether, 16 promoter regions were selected. For the full list, see pgcA and yqhY, for which the model was fitted with the negative value of the parameter w, suggesting inverse correlation with the profile of SigB.Finally, we performed in vitro transcriptions in a defined cell-free system for selected genes with different organization of SigB-binding motifs in the promoter region. The genes were selected according to the motif organization and the shape of its gene expression profile see . We usedyqhY gene was selected for its inversely correlated profile with the expression profile of SigB. The SigB binding motif was present and the promoter was active in vitro . The phenomenon of inversely correlated profiles was also observed for some other genes . aag, aldY, atpC, bmrU, clpC, copB, cpgA, csbB, csbC, csbD, csbX, csoR, ctc, ctsR, cypC, dps, galK, galT, gspA, gtaB, katE, katX, malS, mcsA, mcsB, menC, mgsR, nagBA, nhaX, ohrB, opuD, opuE, pgcA, phoH, pth, radA, rbfA, rnr, rpe, rpmEB, rsbRD, rsbV, rsbW, rsbX, rsoA, sigB, tmk, truB, trxA, ung, yaaI, ybyB, ycbP, ycdF, ycdG, yczO, ydaC, ydaD, ydaE, ydaG, ydaJ, ydaK, ydaL, ydaM, ydaN, ydaP, ydaS, ydaT, ydbD, ydfO, ydjJ, yerD, yetO, yfhD, yfhF, yfhK, yfhO, yfkM, yflA, yflD, yflT, yhcM, yhdF, yhdN, yhxD, yjgB, yjgC, yjgD, yjlB, yjzE, ykgA, ykzN, ylxP, ymaE, yocB, yocK, yojJ, yorA, yoxB, yoxC, ypuD, yqbM, yqgC, yqhB, yqhY, yqjF, yqxL, yrhK, yrvD, ysnF, ytaB, ytxG, ytxH, ytxJ, yugU, yuzH, yvaA, yvaG, yvaK, yvbG, yvgN, yvgO, yvrE, yvyD, yvyI, ywiE, ywjC, ywkB, ywlB, ywmE, ywmF, ywsB, ywtG, ywzA, yxaB, yxbG, yxkA, yxkO, yxnA, yxxB, yxzF, yybO, yycD, yyzG, yyzH; the full list of the genes and their operons is given in tabular form in the n = 106), and the second largest group belonged to a category \u201cmembrane proteins\u201d with 27 genes (18%). The remaining genes of the reported SigB regulon may be expressed under different conditions, require additional factors, or are controlled by different sigma factors or cofactors  were expressed and controlled by SigB during normal growth conditions; most of them coded for stress and/or membrane proteins. The remaining genes of the reported SigB regulon may be expressed under different conditions, are controlled by different sigma factors or in combination with them (mainly SigA), or they require additional factor or cofactors for their expression. The analysis also showed the importance of the organization of the promoter binding sequence, especially the spacing of \u221235 and \u221210 elements for promoter recognition by the RNAP\u2013SigB holoenzyme. Consistently, experimentally confirmed class III promoters, which have not been assigned to SigB-dependent regulation by the other analyses presented here , failed to be recognized by the RNAP\u2013SigB holoenzyme in our study. The presented approach shows that in order to identify the regulon active during a specific biological process or specific conditions, the static information  is not sufficient and other additional source of information is necessary to employ. It also shows that the vast amount of data accumulated in literature and databases can be effectively used to discover new relations even in already well studied systems. The presented approach is general enough to be applied to other systems for which sufficient amounts of data are available.In this study, using a combined approach of static and dynamic information analyses, we defined the SigB regulon in"}
+{"text": "Shifting historical, political, and social times have impacted transgender older adults in experiences and development. Examining how gender identities interact with life events within a historical context elucidates differences by generations and gender. Using a transgender subsample (n=205) from the National Health, Aging, and Sexuality/Gender Study , (logistic) weighted regressions with sociodemographic adjustment were performed to examine generational differences and gender interaction in key life experiences in identity, work, kin, bias, community, and health/well-being. Silenced , than Pride , Generation disclosed identity later, is less visible, more likely retired and veteran, more likely for lifetime opposite-sex marriage and divorce. Significant gender interactions exist in community engagement, kin relationships, and physical health. Despite small sample size, Invisible Generation  has unique differences. Findings show complexity of generational differences among transgender older adults, understanding of what helps better serve them as they age with their accumulated life experiences."}
+{"text": "Over the past few decades, many pathogenic bacteria have become resistant to existing antibiotics, which has become a threat to infectious disease control worldwide. Hence, there has been an extensive search for new, efficient, and alternative sources of antimicrobial agents to combat multidrug-resistant pathogenic microorganisms. Numerous studies have reported the potential of both essential oils and metal/metal oxide nanocomposites with broad spectra of bioactivities including antioxidant, anticancer, and antimicrobial attributes. However, only monometallic nanoparticles combined with essential oils have been reported on so far with limited data. Bi- and tri-metallic nanoparticles have attracted immense attention because of their diverse sizes, shapes, high surface-to-volume ratios, activities, physical and chemical stability, and greater degree of selectivity. Combination therapy is currently blooming and represents a potential area that requires greater attention and is worthy of future investigations. This review summarizes the synergistic effects of essential oils with other antimicrobial combinations such as mono-, bi-, and tri-metallic nanocomposites. Thus, the various aspects of this comprehensive review may prove useful in the development of new and alternative therapeutics against antibiotic resistant pathogens in the future.  Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae, ceftazidime-resistant Klebsiella pneumonia and Escherichia coli, and Pseudomonas aeruginosa resistant to fluoroquinolones [Bacillus cereus, E. coli, Listeria monocytogenes, Salmonella enteritidis, and S. aureus present a major threat to public health and safety [Infectious diseases and foodborne illnesses are the leading cause of severe health problems worldwide and can even lead to death. Antibiotics and other antimicrobial agents are the major strategies used to combat pathogenic bacteria in human medicine . Howeverinolones . In addid safety . Owing td safety . Traditid safety . The preEssential oils (EOs) are natural mixtures of volatile secondary metabolites extracted from different parts of plants, such as the flowers, buds, seeds, leaves, twigs, bark, herbs, wood, fruits, and roots . EOs mayEOs contain various components which have been screened for their antimicrobial activities. Among these, terpenes\u2014such as carvacrol, geraniol, menthol, and thymol\u2014have higher antimicrobial properties. Compared to the individual components, the whole or multicomponent EOs appear to have greater antibacterial activity. However, each single chemical component in EOs plays an important role, such as in the density, fragrance, color, texture, cell penetration ability, fixation on cell walls, and bioavailability. Therefore, it is assumed that the other molecules present in EOs regulate the function of the main components to enhance synergistic effects . Thus, tNanotechnology has proved to be a powerful tool for solving various biomedical and technological problems using its predefined structures. This field provides the power of transforming the structures of atoms or molecules into desired geometry and properties. It has both health and environmental applications, which includes effective drug delivery, cancer treatment, food packaging, harvesting solar energy, and water purification, and reduces the use of industrial chemicals, thereby making the environment healthier and safer . Over thThis review highlights the most recent literature on EOs, with special focus on mono, bi-and tri-metallic NPs, along with their antimicrobial potential. We have discussed the extraction methods, chemical composition, antimicrobial effects of EOs, nano-encapsulation of EOs, and their synergistic effects on infection resistant pathogens. Potential effects and antimicrobial activities of mono-, bi-, and tri-metallic NPs will also be discussed. Additionally, the future prospects of the synergistic effects of EOs and bi- and tri-metallic NPs have also been discussed herein. Some important and widely used medicinal plants act as antimicrobial activities are depicted in 2 extraction, hydrodistillation, steam distillation, dry distillation, mechanical cold pressing, microwave-assisted extraction, supercritical fluid extraction, simultaneous distillation extraction, vacuum distillation, solid-phase microextraction, direct thermal desorption, dynamic headspace, static headspace, and high-concentration capacity headspace sampling [EOs can be extracted from different parts of plants using several methods with appropriate solvents and techniques. Based on the characteristics of different plant materials, some specific extraction techniques are used for extracting the volatile fraction from aromatic plants. The techniques include solvent extraction, solvent flavor evaporation, Soxhlet extraction, maceration, COsampling ,31. The sampling ,33,34,35sampling ,37. EOs sampling .Modern methods such as supercritical fluid extraction and microwave-assisted extraction were achieved at the laboratory scale, but they are intuitively difficult to expect a reliable scale-up. Solvent extraction is one of the most convenient and frequently used method to extract bioactive compounds from plant materials. Solvent extraction method is a simple and efficient method used to separate a compound into its components based on the solubility of the components when it is mixed with a solvent. It is important to choose a good solvent since a residue of the solvent could be present in the final product due to its polarity, viscosity, and vapor pressure. High solvent requirement, long extraction period, and unsatisfactory reproducibility are some few disadvantages of this method ,40.Hydrodistillation is a simple and traditional method for extracting EOs from plant samples and is further classified into the subcategories of water distillation, steam distillation, and direct steam distillation . In thisSoxhlet extraction is a common conventional method that involves solid\u2013liquid contact for extracting several compounds. This extraction method uses chemical solvents to extract oils; the solvent is heated in a distillation flask and the resulting vapor is condensed. The condensed solvent from the condenser flows into the thimble that contains the sample. When the solution reaches an overflow, a siphon pulls the solution in the thimble back into the distillation flask, thus carrying dissolved solute into the bulk liquid ,43. This2 as an ideal solvent. This technique requires low pressure, moderate temperature, and CO2 as solvent for a wide variety of applications such as EO and metal cation extraction. CO2 is non-toxic, non-explosive, noncorrosive, readily available, safe, inexpensive, and easily eliminated from the extract [Maceration is the simplest process of extraction; the whole or coarsely powdered sample is mixed with solvent and left to macerate for a known period with frequent agitations at room temperature. After maceration, the sample mixture is pressed and filtered through an appropriate filter . Cold pr extract ,45.2 emissions [Ultrasound-assisted extraction provides a cutting edge with higher yields, superior quality, clean process, and less energy. Sonication process was carried out as a solvent- or water-based method to penetrate into the plant cells via bubble implosion generated by ultrasonic cavitation . The bubmissions ,49. In tmissions . Infusiomissions . Some di5H8)n through the mevalonic acid pathway, which occurs in the cytoplasm of the cell [The chemical composition of EOs are attributed to various factors, e.g., plant species, climatic conditions, soil type, temperature, humidity, ecotype, phenophase, photoperiod, irradiance, genotype, harvesting seasons, age of leaves, agronomic conditions, geographic region, and extraction process ,61,62. Ethe cell . Based othe cell . Sesquitthe cell ,66.Some different kinds of organic compounds\u2014such as sterols , alkaloiE. coli, S. aureus, P. aeruginosa, Enterococcus spp., Salmonella spp., and coagulase-negative Staphylococcus, and are included in the category of community and hospital acquired pathogens, which affects public health [At present, many new antimicrobial agents or antibiotics have been developed from various sources for treating different microbial pathogens. However, the increased use of antibiotics has resulted in the emergence of multidrug resistance bacteria, which has led to the severity of diseases caused by bacterial pathogens. Some of the main multidrug resistance bacteria are c health .Natural resources like plant extracts widely used as medicinal plants with high antimicrobial activities against human pathogens . EOs andThe minimum inhibitory concentration (MIC) is the lowest concentration of antimicrobial agent that completely inhibits growth of the organism in micro-dilution wells or tubes as detected by the unaided eye . HoweverE. coli and S. aureus [Dipterocarpus gracilis inhibited the growth of P. mirabilis and B. cereus by infecting cytoplasmic membrane. The differences in antimicrobial activity of EOs may be associated with the chemical constituents, geographical location, seasons, and extraction methods [The various bioactive components present in different EOs play an individual role; for instance, the EOs of cinnamon and black pepper damaged the cell membrane and decreased the metabolic activity of . aureus ,86. Simi methods . Some imZanthoxylum alatum, Ammodaucus leucotrichus, Marrubium globosum, Citrus sinensis and Citrus latifolia, Lawsonia inermis, Thymus fontanesii, Artemisia herba-alba and Rosmarinus officinalis, Syzygium aromaticum L., Origanum vulgare L., Mentha spicata L., and Eremanthus erythropappus M showed promising antioxidant activity [Free radicals play an important role in origin of life and biological evolution, leaving beneficial effects on the organisms and involved in many biochemical activities of cells such as signal transduction, gene transcription, and regulation. The human body produces oxygen free radicals and other reactive oxygen species (ROS) as byproducts through several physiological and biochemical processes. However, over production of free radicals can cause oxidative damage to biomolecules leading to many chronic diseases such as cancer, cardiovascular, diabetics, chronic inflammation, and atherosclerosis in humans. Therefore, much attention has been focused on the use of antioxidants to inhibit lipid peroxidation due to free radicals by using synthetics or natural antioxidants. Synthetic antioxidants such as butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) are suspected to be harmful to human health. On the other hand, natural products present in medicinal plants like EOs shows significant antioxidants performance from different plant source. The EOs obtained from activity ,136,137.Over the past decades, several mono-, bi- and tri-metallic NPs have drawn significant attention due to their catalytic, optical, and magnetic properties in a wide array of fields such as catalysis, medical, imaging, remote sensing, environmental, and energy applications. As the name suggests, monometallic NPs are composed of only a single metal , whereas, bi- and tri-metallic NPs are composed of two and three different metals , respectively. Bi- and tri-metallic NPs have tunable and better properties due to the addition of a second and third metal of the nanoparticle combination, and can improve catalytic activity and selectivity when compared to monometallic NPs . The catThe properties of bimetallic NPs include electronic, catalytic, thermal, size, and shape, which may differ from those of the monometallic NPs. In tri-metallic NPs, the addition of a third metal modifies the electronic structure, reduces the lattice, and increases the charge shift, catalytic performance, and selectivity when compared to monometallic and bimetallic NPs ,140. TheBi- and tri-metallic NPs contain a few tens to several thousand of atoms, which are excellent catalysts, with improved selectivity and efficiency due to their highly active surfaces, and act as green catalysts by recyclability . Multi-mBacterial resistance has become a severe problem due to the substantial application of antibiotics preferred for the treatment of infectious disease without proper medical indications. In order to solve this problem, the use of alternative antibacterial agents to treat infectious diseases have attracted great interest, due to their heat resistance, sustainability, and improved stability under harsh processing conditions. Due to their smaller dimensions and large surface area to volume ratios, metallic NPs provide strong, targeted, and extended antimicrobial interaction with bacteria and biofilms at smaller doses. In the last few decades, new and novel antimicrobial agents\u2014such as metallic NPs and macromolecules\u2014have been found to be the most effective agents to combat pathogenic bacteria. 2O3), iron oxide (Fe3O4), titanium dioxide (TiO2), copper oxide (CuO), zinc oxide (ZnO), cobalt oxide (Co3O4), manganese oxide (Mn2O3), magnesium oxide (MgO), indium oxide (In2O3), silicon dioxide (SiO2), nickel oxide (Ni2O3), zirconium dioxide (ZrO2), and chromium oxide (Cr2O3) have also shown potential antimicrobial activities , gold (Au), gallium (Ga), copper (Cu), zinc (Zn), iron (Fe), and palladium (Pd) have potential antimicrobial activities. Metal oxide NPs like aluminum oxide  and water (liquid), in which one is dispersed in the other with the help of a surfactant that stabilizes emulsions. Surfactants are required to formulate nanoemulsions and decrease the size of the droplet and increment the inflexibility and quality of interfacial layer. The combination of Span 20 with Tween 40 was seen to be sophisticated by delivering ideal mineral oil emulsions. For instance, the clove, cinnamon, and thyme oil nanoemulsions which were formulated with nonionic surfactants (Spans and Tweens) were having droplet size less than 100nm. Nanoemulsions are a promising nanocarrier widely used in drug delivery, which helps in improving biodistribution of drugs and minimizing toxicity. To protect EOs from extrinsic and intrinsic factors such as pH, temperature, water, humidity, activity, storage environment, and enzymatic degradation, some different delivery systems have been used as carriers including chitosan cyclodextrin, alginate, albumin, globulin, maltodextrin, and starch. Among the many nanocarriers, naturally occurring polymers such as chitosan and alginate are widely used in the biomedical and pharmaceutical fields as emulsions. S. aureus, L. monocytogenes, Shigella dysenteriae, and E. coli as nanoemulsion [S. aureus as nanoemulsion [Schinus molle with chitosan against Aspergillus parasiticus as nanoprecipitation [Zataria multiflora with lipid phase (glyceryl monostearat) and precirol against Aspergillus ochraceus, Aspergillus niger, Aspergillus flavus, Alternaria solani, Rhizoctonia solani, and Rhizopus stolonifer as solid-lipid nanoparticles [Gaultheria procumbens with chitosan-cinnamic acid microgel against A. flavus as microencapsulation [Thymus capitatus with sodium dodecyl sulfate against E. coli and B. subtilis as nanoencapsulation [E. coli and S. aureus as nanocomposites [Siparuna guianensis with chitosan against larvicide Aedes aegypti as nanoencapsulation [Many studies in academia and industry have continued to enhance the physical stability of EOs by encapsulating them into nanocarrriers. Recently, nanoemulsions were achieved by using low concentrations of EOs, pectin, and surfactants with the help of pseudo-ternary diagrams . Similaremulsion . Soybeanemulsion , Schinuspitation , Zatariaarticles . In addisulation , Thymus sulation , cardamomposites , and Sipsulation .Nanotechnology emerged significantly in pharmaceutical industry up to a considerable extent. Nanoparticles is a combined name for any colloidal carrier like nanospheres and nanocapsules. EOs can be enhanced by encapsulating with several nanomaterials such as polymeric NPs, liposomes, solid lipid NPs and nano-emulsions which consists of inner liquid core surrounded by an outer polymeric membrane called nanocapsule. Nanocapsules possess a polymeric membrane with a liquid nucleus, in which the active compounds of EOs is confined to a cavity . SimilarThe constituents of EOs along with bi- and tri-metallic NPs with their diverse sizes, shapes, high surface-to-volume ratios, physical and chemical stability, and degree of selectivity can unlock the cell membrane channels, thus opening the passage of EOs/multimetallic to reach their target sites. These metal NPs or nanoemulsions/nanoencapsulations enclosing EOs can be adhered via electrostatic, hydrogen bonding, and covalent interactions to produce antimicrobial packaging systems. Once NPs adhere to cell walls, they directly effects toxicity due to larger concentration of NPs release more ions and distributed in the environment surrounding the bacterial cell wall. The larger concentration of generated ions disrupt cell membrane and ROS production and further helps to penetrate the cells . When NPTorreya grandis aril EOs and studied their antibacterial properties against S. aureus found stronger antibacterial activities than chitosan NPs alone [Kelussia odoratissima and Teucrium polium investigated their enhanced effect against multidrug-resistant bacteria [Cymbopogon martinii EOs shows efficient and enhanced antifungal and antimycotoxin activities against Fusarium graminearum [E. coli, MRSA, S. enteric, and B. subtilis [Nigella sativa EO coated with gold nanoparticles effectively controlled the growth and biofilm formation of S. aureus [S. aureus, L. monocytogenes, E. coli, and S. Typhimurium [There are two possible ways to combat multidrug resistant pathogens along with EOs either by nano-encapsulation method or combination with bi- and tri-metallic NPs with EOs. Recently, Wu et al., prepared chitosan NPs embedded with Ps alone . Synergibacteria . Chitosaminearum . Similarsubtilis  and Nige. aureus . Whereashimurium .The development of resistance to different antimicrobial agents by bacteria, fungi, viruses, and parasites is a great challenge to the effective treatment of infectious diseases, and hence there is a need for more intensive, new, and novel antimicrobials. Some plant extracts and EOs have been used as medicine for the treatment of infectious diseases traditionally. However, these plant-based medicines are not effective for severe systemic infections due to the absence of clinically applicable pharmaceutical forms. Subsequently, many antibiotics have been developed as synthetic antimicrobial agents, but these drugs are complicated by their high toxicity, low tolerability, and ineffectiveness against new emerging microbes. One probable way to enhance the range and scope of current antimicrobial therapy is the use of a combination of antimicrobials. A. niger, P. chrysogenum, A. flavus, and A. parasiticus when compared to the antimicrobial activity of a single EO. Similarly, in a study conducted by Knezevic et al. [Eucalyptus camaldulensis with conventional antibiotics such as gentamycin, ciprofloxacin, and polymyxin B showed synergistic antibacterial effect against Acinetobacter baumannii.The combination of antimicrobial agents such as essential/volatile oils, plant extract/EOs, plant extracts/antibiotics, EOs/EOs, EOs/antibiotics, plant extract/plant extract, EOs/monometallic NPs, and phytochemical/antibiotics  has confc et al. , it was Origanum vulgare EO resulted in synergistic antimicrobial activities against E. coli, A. baumannii, and S. aureus. Similarly, hydroxyapatite NPs with peppermint EO against S. aureus, E. faecium, E. coli, P. aeruginosa, and C. parapsilosis [P. pyogenes and S. aureus [Siparuna guianensis EO with chitosan NPs against A. aegypti [S. aureus, L. monocytogenes, E. coli, and S. typhimurium [E. coli and S. aureus [Very few researchers have studied the synergistic antimicrobial effects of metal and metal oxide NPs  along with EOs and conventional antibiotics ,200. Scapsilosis , olive E. aureus , Siparun aegypti  showed ehimurium , cinnamo. aureus  also hadEOs have great potential for the promotion of health and preventing and treating infectious diseases. However, EOs have some drawbacks due to their low solubility, stability, and high volatility in medicinal applications. Hence, the encapsulation of EOs increases their solubility and stability, and maintains controlled release, which makes them more bioavailable; protects them from air, humidity, light; and lead to volatilization, increasing their biological activities. To date, there are limited studies on synergistic antimicrobial effects of metal and metal oxide NPs along with EOs. Bi-and tri-metallic NPs have recently attracted more attention because of their unique catalytic, optical, electronic, and magnetic properties , and theBi- and tri-metallic NPs are formed by the combination of two or more different metals or materials into a single system, and they exhibit special properties which are not observed in the case of the monometallic forms . MoreoveThe present study acknowledged more findings on in vitro studies of EOs, and nanoencapsulation of EOs, however, more efforts are required to conduct studies on the synergistic effects of bi- and tri-metallic NPs along with different EOs. Tuning into different size, shape, and/or surface chemistry of NPs allows their functionalities to be more enhanced for better applications. Furthermore, the use of multi-component nanoparticles like bi- and tri-metallic NPs comprised of three or more metals have also intervened as hybrid materials that can upgrade optical and magnetic properties. However, the inertness of these materials with respect to the environment, health, and safety concerns must be considered due to their potential hazards and toxicity. Thus, EOs along with mono, bi-, and tri-metallic NPs might be a prospective source of alternative antimicrobial agents, and may play an important synergistic role in the discovery of new drugs for the treatment of a wide range of pathogenic infections in the near future. Finally, we will continue to see creative advances in the synthesis of these unique dual-component and multi-component nanomaterials and their antimicrobial activities along with EOs individually or in combinations.The increasing number of clinical complications related to multidrug resistant microorganisms has inspired researchers to focus their interest on alternative antimicrobial agents, which are an appropriate solution to treating infections that are more serious to human health. There are several types of EOs, which have individual components with diverse bioactivities including antimicrobial potential. However, EOs have certain limitations, including low solubility and stability, and currently they have reduced clinical applications owing to the development of resistance. Nanotechnology is expected to have a significant impact on the therapeutics of antimicrobial agents at the nanoscale level to develop nanomedicines. As the size of a particle decreases, the specific surface area, reactivity, and bioavailability increases, allowing greater interaction with the surrounding environment that enhances the antimicrobial effects. Indeed, nanoparticles are able to solve the major inconvenience of EO components by increasing the chemical stability in the presence of moisture, air, light, and high temperatures, factors which can lead to the rapid evaporation and to the degradation of the active components. Encapsulation simultaneously increases the antimicrobial potency of EOs by controlled or sustained release and facilitating close interaction with the microorganisms.Metal and metal oxide NPs like Ag, Au, Ga, FeO, ZnO, TiO, MgO, and CuO act as promising antimicrobial agents. Bi-metallic or multimetallic nanostructures such as hybrid, core\u2013shell, or alloy structures like FePd, AuPd, CuPd, PtPd, AuFeAg, and FeAgPt enhance antimicrobial activities and catalytic performance. For this reason, it is necessary to find an alternative method to combat multidrug resistance pathogens by using EO encapsulation with suitable metal or metal oxide NPs or combination of EOs with different bi- and tri-metallic NPs. The present study revealed more information on the extraction methods, chemical composition, nano-encapsulation, and antimicrobial activities of EOs and antimicrobial potential of some metal and metal oxide NPs. The future biotechnological perspective to stabilize EOs using nanostructured materials might establish a valuable prerequisite for obtaining functionalized materials with modified surface, inhibitory effects and ability to adhere on the microorganisms for targeting and/or controlled release. However, more research is required to explore the mechanism of individual essential oil components along with bi- and tri-metallic NPs with an initiation in systematically conduct experiments on the synergistic mechanisms among different components. Therefore, new or alternative strategies for EOs with bi- and tri-metallic NPs and synergistic studies can provide an interesting platform in the future to combat multidrug resistance pathogens with greater activity. In addition, it is necessary to control the toxicity, risk assessment, and safety aspects, and to avoid the passage of such nanomaterials into the human body."}
+{"text": "The purpose of this article is to describe dependence and withdrawal phenomena related to CNS drugs discontinuation and to clarify issues related to the evaluation of clinical drug withdrawal and rebound as they relate to safety in new drug development. The article presents current understanding and definitions of drug dependence and withdrawal which are also relevant and important features of addiction, though not the same. Addiction, called substance use disorder in DSM-5, affects an individual\u2019s brain and behaviour, represents uncontrollable drug abuse and inability to stop taking a drug regardless of the harm it causes. Characteristic withdrawal syndromes following abrupt discontinuation of CNS-active drugs from numerous drug classes are described. These include drugs both scheduled and non-scheduled in the Controlled Substances Act, which categorizes drugs in five schedules based on their relative abuse potentials and dependence liabilities and for regulatory purposes. Schedules 1 and 2 contain drugs identified as those with the highest abuse potential and strictest regulations. Less recognized aspects of drug withdrawal, such as rebound and protracted withdrawal syndromes for several drug classes are also addressed. Part I presents relevant definitions and describes clinical withdrawal and dependence phenomena. Part II reviews known withdrawal syndromes for the different drug classes, Part III describes rebound and Part IV describes protracted withdrawal syndromes. To our knowledge, this is the first compilation of withdrawal syndromes for CNS drugs. Part V provides details of evaluation of dependence and withdrawal in the clinical trials for CNS drugs, which includes general design recommendations, and several tools, such as withdrawal questionnaires and multiple scales that are helpful in the systematic evaluation of withdrawal. The limitations of different aspects of this method of dependence and withdrawal evaluation are also discussed. This manuscript introduces the concepts of dependence, withdrawal and rebound for CNS-active drugs and provides a comprehensive review of multiple currently known withdrawal syndromes for scheduled and non-scheduled drugs. The manuscript also describes details of evaluation of dependence and withdrawal in clinical trials for drugs that are being developed.  In the United States, the significance of drug dependence, especially as it relates to addiction, came to the foreground and captured public attention only in recent decades, following epidemics of drug abuse, dependence and addiction, sweeping the country, resulting in staggering numbers of deaths. Most cases are related not only to opioid drugs, but also to benzodiazepines (BZ), stimulants and street drugs, including heroin, highly potent fentanyl and its analogues, cathinone-like hallucinogens and dissociative substances, and stimulants similar in action to cocaine and methamphetamine  physical dependence is a state of adaptation that is manifested by a drug class-specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, reducing blood level of the drug and/or administration of an antagonist; (ii) psychological dependence is a subjective sense of need for a specific psychoactive substance, either for its positive effects or to avoid negative effects associated with its abstinence; and (iii) one category of psychoactive substance use disorder in previous editions of the Diagnostic and Statistical Manual of Mental Disorders, but not in the DSM-5, published in 2013.Addiction is characterized by inability to consistently abstain, impairment in behavioural control, craving, diminished recognition of significant problems with one\u2019s behaviours and interpersonal relationships, and a dysfunctional emotional response. Like other chronic diseases, addiction often involves cycles of relapse and remission. Without treatment or engagement in recovery activities, addiction is progressive and can result in disability or premature death.Tolerance\u2014a state of adaptation in which exposure to a drug over time results in diminution of one or more of the drug\u2019s physiologic effects.Withdrawal syndrome\u2014the onset of a predictable constellation of signs and symptoms following the abrupt discontinuation of, or rapid reduction in, the dose of a psychoactive substance.These definitions are important for distinguishing between dependence and addiction or substance use disorder.However, for drugs, in particular CNS active, which are being developed and evaluated by FDA, we will be using another definition, more appropriate for this function, namely, part (i) of the dependence definition cited by the American Society of Addiction Medicine (ASAM). The recent ASAM definitions of dependence, addiction, tolerance and withdrawal gained support by the American Academy of Pain Medicine and the American Pain Society in 2001, and have since then been updated : Newly emerging signs and symptoms which occur almost immediately after abrupt drug discontinuation or sometimes even after the dose decrease. These symptoms are related to the disruption of neuroregulatory changes (neuroadaptation) established during drug administration.Rebound: Recurrence of symptoms of the treated disorder in patients, more severe than before the treatment.Protracted withdrawal syndrome: Usually appears long past the timeframe of acute withdrawal symptoms, may last for weeks and months, and sometimes may present as a newly emerging disorder.Relapse. Return of signs and symptoms of the disease after a remission due to natural causes or termination of treatment; it occurs as a phenomenon in the natural history of the disorder. Relapse is not an aspect of dependence; however, it is mentioned here because it occurs during the timeframe of acute withdrawal and needs to be differentiated from the withdrawal.Symptoms of delayed drug toxicity: May be over-imposed on acute withdrawal symptoms and sometimes are difficult to differentiate from them.We present here withdrawal-related phenomena which can be identified for many different drug groups; this list is based largely on a description of clinical aspects of withdrawal emerging after discontinuation of selective serotonin reuptake inhibitors SSRIs; . These wSeveral studies were performed to evaluate the influence of various factors on the development of dependence. A general consensus is that: (i) timing and rate of exposure(s); (ii) dose; and (iii) drug potency, critically impact the formation of dependence, where with a longer timeframe of use, higher dose and higher drug potency, the likelihood of dependence formation increases , Adjective Rating Scale for Withdrawal (ARSW) and Visual Analogue Scale (VAS). The results showed that gender difference examined with COWS was small (effect size = 0.12), also no statistically significant gender-related differences in withdrawal symptoms were revealed with the ARSW or VAS. Subjective craving as measured with VAS was significantly higher in women than men.However, further research studies with humans, males and females, are needed to investigate sex and gender variables that influence the various conditions affected by opioids, including treating pain, occurrence of adverse events and development of addiction  seem to develop somewhat different withdrawal symptoms than do younger people after BZ discontinuation. These include emergence of confusion and disorientation, sometimes with hallucinations in older people instead of anxiety, insomnia and perceptual changes noted in younger people . Also, iSome investigators consider that withdrawal symptoms last only for a maximum of five half-lives of the drug, which is obviously incorrect, although it is not clear where this statement originated as we did not find the source. For example, heroin half-life is 2-6\u2009min, but duration of the withdrawal syndrome is approximately 4\u201310\u2009days see , althougBecause few drug groups discussed in this manuscript namely opioids, stimulants and BZ are also involved in addictive disorders alternative concepts of dependence and withdrawal are presented a, b.Addiction is depicted as a compulsive disorder with excessive drug intake and loss of control over intake, with decreases in reward neurotransmission and activation of brain stress systems. Addiction is a disorder that involves elements of both impulsivity and compulsivity in which impulsivity predominates at the early stages of addiction (preoccupation and anticipation) whereas compulsivity dominates at the final stages of withdrawal and negative affect.The key brain structures involved in these processes are ventral striatum with neurotransmitters dopamine and opioid peptides and extended amygdala with corticotropin-releasing factor, norepinephrine and dynorphin. In fact, it is proposed that all main drugs of abuse act through the central nucleus of the amygdala producing increases in reward thresholds, anxiety-like responses and extracellular levels of corticotropin-releasing factor. Specifically, during development of dependence and withdrawal brain antireward systems are recruited and include corticotropin-releasing factor, norepinephrine and dynorphin which produce aversive states such as dysphoria and stress. The components of acute drug withdrawal include decrease of activity of the mesocorticolimbic dopaminergic system and decreased activity in the nucleus accumbens/amygdala mediated by opioid peptides, GABA and glutamate.Dependence and withdrawal are results of neuroadaptation that occur during drug treatment.Dependence and withdrawal are not equated with drug addiction although may coexist.The shortest known time to acquire dependence occurs with opioid drugs where 2\u20133 weeks or longer exposure at the therapeutic dose may produce dependence and upon drug discontinuation or exposure to antagonist  also an acute withdrawal syndrome.New withdrawal symptoms include the symptoms that first appeared during the drug discontinuation or dose decrease and are not related to symptoms of the patient\u2019s original illness.Different classes of CNS drugs have some common withdrawal symptoms, as well as some specific to the drug class withdrawal symptoms.New withdrawal symptoms which are common to many CNS drugs include: nausea, anxiety, headaches, decreased concentration, irritability, agitation, tremor, sleep disturbances, dysphoria and depression.\u2022\u2003Lacrimation, rhinorrhoea and sneezing for opioids\u2022\u2003Electric-shock sensations, confusion and myoclonus for SSRIs.Some new withdrawal symptoms may be characteristic of a specific CNS drug class:The new withdrawal symptoms are usually transient and reversible.Major complications of abrupt withdrawal may occur, such as seizures and psychoses in cases of BZ withdrawal , seizureThe onset of withdrawal symptoms depends on the duration of action; usually, short-acting drugs have an early peak of onset.Drugs with higher potency and short/intermediate half-life have greater risks for formation of drug dependence and withdrawal symptoms.There are well-known withdrawal syndromes in different classes of scheduled and unscheduled drugs. These are described in detail below, along with symptoms and time course of withdrawal syndrome.OpioidsBenzodiazepinesZ-Drugs BarbituratesStimulants Testosterone and androgenic anabolic steroidsKetamineCannabisWithdrawal syndromes for unscheduled drug classes apply to:Antidepressants: SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs)Tricyclic antidepressantsAntipsychoticsAnti-Parkinsonian drugsMonoamine oxidase inhibitorsGabapentinNicotine/tobaccoCorticosteroidsStatinsAspirinWithdrawal syndromes for scheduled drug classes apply to:The first descriptions of opioid withdrawal are those by For long-acting opioid (methadone) withdrawal starts after 36\u201348\u2009h after the last dose, and may last 3\u20136\u2009weeks .The withdrawal symptoms of oxycodone products include restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia and mydriasis, also other symptoms may develop such as irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhoea, increased blood pressure, respiratory rate and heart rate .Neurological adverse events such as anxiety, agitation, grimacing, insomnia, increased muscle tone, abnormal tremors and choreoathetoid movements.Gastrointestinal symptoms included vomiting, diarrhoea and poor appetite.Autonomic signs included tachypnoea, tachycardia, fever, sweating and hypertension  is unusual in that the withdrawal symptoms are related to the maternal opioid intake but then manifest in the newborn. The clinical presentation of NAS includes signs of neurological excitability such as tremors, hyperirritability, increased wakefulness, excessive high-pitched crying, increased muscle tone, hyperactive deep tendon reflexes, exaggerated Moro reflex, seizures, frequent yawning and sneezing, and also symptoms of gastrointestinal dysfunction such as poor feeding, unco-ordinated and constant sucking, hyperphagia, vomiting, diarrhoea and dehydration. Onset varies with the opioid pharmacology, in case of maternal use of heroin NAS may start 24\u2009h of birth, whereas in case of withdrawal from methadone NAS usually starts around 24\u201372\u2009h of age . Adverse events reported within 48\u2009h of drug discontinuation included fatigue, nausea, flushing, lightheadedness, uncontrolled crying, emesis, stomach cramps, panic attack, nervousness, abdominal discomfort, hyperventilation, shallow breathing, angry feelings, cramping muscles and restlessness  and labeAlso, withdrawal symptoms after discontinuation of zopiclone were reported, and included cravings, rebound insomnia, anxiety or panic attacks, weakness, palpitations, tachycardia, tremor and withdrawal seizures. These symptoms were mainly seen in subjects using supratherapeutic doses; rebound insomnia and rebound anxiety were also noted .Abrupt discontinuation of a barbiturate after prolonged use or abuse can result in a withdrawal syndrome which is sometimes life-threatening. Withdrawal symptoms include weakness, tremor, muscle twitches, agitation, anxiety, anorexia, nausea, vomiting, weight loss, disorientation in time and place, agitation, tremulousness, insomnia, delusions, visual and auditory hallucinations, postural hypotension and high fever. The most serious adverse events of withdrawal are delirium, generalized convulsions and cardiovascular collapse that may lead to death; however, severe withdrawal occurs mainly after dependence on short- or intermediate-acting barbiturates such as pentobarbital, secobarbital, amobarbital or butalbital .Also, neonatal withdrawal syndrome associated with barbiturates has been identified.Infants born to mothers physically dependent on barbiturates may develop dependence and subsequently experience withdrawal. The withdrawal may manifest within the first few days of life and symptoms include excessive crying, hyperphagia, vomiting, diarrhoea, tremors, irritability, hyperacusis, vasomotor instability, sweating, restlessness, sleeplessness, increased tone and sometimes seizures  and labeWithdrawal from stimulants such as amphetamine (including dexamphetamine and methamphetamine), MDMA (ecstasy) and cocaine usually occurs in three phases , Withdrawal from stimulant drugs is generally not medically dangerous; however, depressive symptoms with suicidal ideation or behaviour may occur and are generally the most serious problems seen during the stimulant withdrawal .Ketamine is known for the formation of severe psychological dependence and significant, rapidly developing tolerance  acute withdrawal symptoms that typically begin within 24\u2009h of discontinuing ketamine use and last approximately 3 days; symptoms include shaking, fatigue, insomnia, rage, depression, hallucinations, delusions, tremors, nausea and rapid breathing; (ii) withdrawal symptoms that may persist for 2 weeks, but begin to decrease; and (iii) after approximately 2 weeks, most withdrawal symptoms usually stabilize.The withdrawal syndrome after a chronic intake of supratherapeutic doses of testosterone and androgenic anabolic steroids can last for weeks or months and is characterized by depressed mood, major depression, suicidality, fatigue, craving, headache, muscle and joint pain, anorexia, anxiety, restlessness, irritability, insomnia or hypersomnia, decreased libido, hypogonadotropic hypogonadism and suppression of the hypothalamic\u2013pituitary\u2013testicular (HPT) axis .Withdrawal symptoms of cannabis include irritability, anger, aggression, decreased appetite, weight loss, nervousness, anxiety, restlessness, sleep difficulties including insomnia and strange or disturbing dreams, abdominal pain, shakiness, tremors, fever and headache. Less common symptoms include chills, depressed mood and sweating .Withdrawal symptoms usually start within the first 1\u20134\u2009days of abstinence, peak within the first week, and then resolve within 2\u20133\u2009weeks of drug discontinuation  setting.Some more frequently used SSRIs include: fluoxetine, fluvoxamine, paroxetine, citalopram and sertraline. Some more frequently used SNRIs include: venlafaxine, desvenlafaxine and duloxetine.The SSRIs and SNRIs withdrawal syndrome is characterized by the following symptoms, general: headaches, flu-like symptoms, tachycardia; gastrointestinal: nausea, vomiting, diarrhoea, anorexia; sleep-related: vivid dreams, nightmares, insomnia or hypersomnia; neuropsychiatric: anxiety, depression, suicidality, hypomania, agitation, dysphoria, aggression, hallucinations, de-realization and depersonalization, decreased concentration, dizziness, ataxia, electric-shock sensations (\u2018brain-zaps\u2019), confusion and myoclonus . The indOf note, there is a tendency in the scientific literature to call SSRIs and SNRIs withdrawal syndrome a \u2018discontinuation syndrome\u2019, which in our opinion is both scientifically incorrect and misleading, as it may suggest an absence of the withdrawal syndrome. A comment by In addition, neonatal withdrawal syndrome associated with SSRIs has been identified. It includes respiratory distress, cyanosis, seizures, feeding difficulty, vomiting, hypoglycaemia, hypotonia or hypertonia, hyperreflexia, tremor, jitteriness, irritability, pulmonary hypertension; and with paroxetine use, necrotizing enterocolitis  gastrointestinal and general somatic distress with occasional anxiety and agitation, also nausea, vomiting, diarrhoea, abdominal pain and anorexia; (ii) sleep disturbances, such as initial and middle insomnia, vivid dreams and nightmares; (iii) parkinsonism including bradykinesia, cogwheel rigidity, tremor or akathisia; and (iv) paradoxical mania. Sometimes withdrawal syndrome presents as a \u2018flu-like\u2019 syndrome; which in addition to gastrointestinal symptoms, also includes diaphoresis, dizziness, chills, malaise, fatigue, myalgia and headache; also suicidality and delirium may occur .This is an uncommon, but potentially fatal complication  in Parkinson\u2019s disease patients who were withdrawn from long-term treatment with dopamine agonists due to the development of impulse control disorders. The syndrome presents as a constellation of neuropsychiatric and autonomic symptoms: depression, anxiety, agoraphobia, fatigue, dysphoria, irritability, agitation, pain, sleep disturbances, diaphoresis, orthostatic hypotension and drug cravings.The nicotine withdrawal syndrome includes subsets of somatic components, cognitive, and affective components; the somatic signs include bradycardia, constipation, increased appetite and weight gain; affective symptoms include depressed mood and anhedonia, anxiety, irritability, frustration, dysphoria, emotional lability, anger, other symptoms are restlessness, insomnia, fatigue, somnolence, difficulty concentrating, sweating, confusion and craving. Tobacco/nicotine withdrawal usually begins within 24\u201372\u2009h of stopping or decreasing tobacco use, peaks at 2\u20133\u2009days after abstinence, and lasts 2\u20134\u2009weeks  taper at the end of treatment; (ii) after abrupt drug discontinuation immediate substitute with the drug with similar mechanism of action or reinstitute the discontinued drug, if possible, and taper much slower; (iii) treat symptomatically the dangerous or unpleasant symptoms such as seizures, psychosis, depression, headaches, vomiting, diarrhoea  and natalizumab. The abrupt withdrawal of these drugs produces severe, sometimes life-threatening or fatal rebound in multiple sclerosis patients, accompanied by drastic increases in new lesions or enhancing lesions seen on MRI , persistent post-withdrawal syndrome, and prolonged withdrawal syndrome, describes a set of persistent impairments that occur after withdrawal from some drug classes, such as BZ, opioids, antipsychotics and antidepressants. Symptoms of protracted withdrawal frequently appear later, well past the expected timeframe for acute withdrawal, last longer, and sometimes are irreversible. Because many names are used to describe protracted withdrawal symptoms, which makes identification confusing at times, we present a list of all known to date names of this syndrome, compiled by the Substance Abuse and Mental Health Services Administration .Protracted withdrawal syndrome is not only characteristic of drugs of abuse but also was described for non-scheduled drug classes, such as SSRIs and antipsychotics. In this study, we present some known examples of post-acute withdrawal syndromes.Protracted withdrawal symptoms related to opioid withdrawal include: opioid cravings, memory problems, inability to think clearly, fatigue, anxiety, depression, dysphoria, irritability, sleep disturbances, insomnia, palpitations, restlessness, periodic diarrhoea and hypomania , paraesthesia, formication, tinnitus and irritable bowel syndrome, and there is a characteristic fluctuation of symptoms that may wax and wane . GeneralProtracted withdrawal sometimes called the extinction phase is characterized by symptoms such as fluctuations in mood and energy levels, irritability, restlessness, anxiety, agitation, fatigue, lacking energy and anhedonia, cravings and disturbed sleep and this phase may last for weeks to months .Protracted withdrawal symptoms include: tardive insomnia, major depression, bipolar disorder, panic disorder, agitation, anxiety disorders and panic attacks, emotional lability, mood swings, irritability, aggression, impaired concentration, impaired memory and pathological gambling. These disorders can last for several months to years when the previous drug treatment is not restarted .Main protracted withdrawal symptoms for antipsychotics include tardive dyskinesia and supersensitivity psychosis (Protracted withdrawal is a relatively less known aspect of dependence and withdrawal; however, its duration and severity affect the ability of subjects to terminate therapeutic drugs and drugs of abuse and addiction.Protracted withdrawal may represent very slowly reversible or permanent pathological changes in the neurocircuitry.Evaluation of dependence, withdrawal and rebound for new drugs being developed is of great importance, as it provides information related to potential drug scheduling and safe use. The evaluation provides critically important safety information for patients and physicians, especially in cases when the drug must be abruptly withdrawn due to serious, life-threatening adverse events.It is probably important to note here that for regulatory purposes an animal dependence study is not an alternative to a human dependence evaluation. It is only a first step, one which is important for gathering information about potentially serious adverse events of withdrawal, such as convulsions.The recommended design of a clinical dependence study contains consideration of the following components: population, design, statistical considerations, dose, pharmacodynamic and pharmacokinetic assessments, evaluation of rebound, adverse events collection and analysis. All listed technical details and considerations are available as the Major issues in the evaluation of dependence and withdrawal involve the definitions and nomenclature currently used. Both can possibly contribute to misunderstanding and confusion. This particularly affects different authors\u2019 naming conventions for acute withdrawal syndrome, and even more so, for protracted withdrawal syndrome.In general, the authors consider the nomenclature of withdrawal syndrome and the time course of withdrawal phenomena, presented by It is important to note that some drugs and drug classes were not mentioned in this short review. This does not necessarily mean that these drugs do not produce a withdrawal syndrome, it may simply mean that withdrawal has never been evaluated and described.As discussed above, the evaluation of dependence and withdrawal is critically important for CNS-active drugs, which are likely to be scheduled. However, the withdrawal evaluation is also important for non-scheduled CNS-active drugs, mainly for safety reasons. Except for a few drug groups comprising highly addictive drugs, such as opioids, BZ and stimulants; and non-scheduled drugs such as SSRIs, there is relatively little knowledge of different aspects of the withdrawal phenomena for most currently used drugs. But even for these drug classes mentioned above, product labels often do not always reflect all current information available in the scientific literature and fail to provide adequate warnings for patients and physicians.The evaluation of dependence and withdrawal for drugs in paediatric population is very important and should be also addressed in the future. The current available data are more than sparse and only available for some opioid and BZ drugs and some stimulants. Also, the sex differences in the withdrawal symptomatology should be further explored as the data for many scheduled and unscheduled drug is not available.This is the authors\u2019 hope that future drug development will incorporate many of the methods described in this review as the knowledge of the withdrawal symptoms is critical for patients\u2019 safety. Also, equally important is incorporating knowledge on withdrawal and dependence in the drug labels.fcz025_Supplementary_DataClick here for additional data file."}
+{"text": "Cereals are one of staple foods in human diet, mainly consumed as refined grains. Nonetheless, epidemiological data indicate that whole grain (WG) intake is inversely related to risk of type 2 diabetes, cardiovascular disease, and several cancer types, as well as to all-cause mortality. Particularly responsive to WG positive action is the gastrointestinal tract, daily exposed to bioactive food components. Herein, we shall provide an up-to-date overview on relationship between WG intake and prevention of gastrointestinal tumors, with a particular focus on colorectal, stomach, and esophagus cancers. Unlike refined counterparts, WG consumption is inversely associated with risk of these gastrointestinal cancers, most consistently with the risk of colorectal tumor. Some WG effects may be mediated by beneficial constituents (such as fiber and polyphenols) that are reduced/lost during milling process. Beside health-promoting action, WGs are still under-consumed in most countries; therefore, World Health Organization and other public/private stakeholders should cooperate to implement WG consumption in the whole population, in order to reach nutritionally effective intakes. Poaceae family, are grasses producing edible grains . Usually, the term also includes grains from non-herbaceous plants, known as pseudocereals , which have a composition similar to \u201creal\u201d grains [Cereals, plant species belonging to the \u201d grains ,2,3.Rice, maize, and wheat are the most common farmed cereals with a production of 2646 million tons in 2018\u20132019 [Scientific interest in health properties of WGs began in the late 1970s, when the surgeon Denis Parsons Burkitt, noting the difference in disease incidence in rural Africa and the UK, brought together data coming from several disciplines and launched the dietary fiber hypothesis; he and other researchers, indeed, noted that a diet highly refined and lacking WG foods might be involved in several diseases, including coronary heart disease, obesity, diabetes, dental caries, as well as in some cancer types, such as gastric and colon tumors . Since tEach country or organization uses different WG definitions that are constantly updated ,28,29. TStarchy endosperm, germ, and bran are the three principal fractions in cereal kernels . EndospeDuring milling process of refined flours, bran and germ are removed (and used for food and non-food applications) ,34; as a2), Kristensen and co-workers [2) subjects [As above mentioned, compared to refined counterparts, WG are associated with benefits for human health . Among m-workers  reportedsubjects . Accordisubjects . Besidessubjects ,12,13,14N-oxide) in urine samples [An important role in chronic diseases seems to be played by gut microbiota, whose composition is influenced not only by genetics and age, but also by diet . A stron samples . As MD r samples ,45,46, i samples .In this context, it should be underlined that, unlike RG eaters, WG consumers generally follow health and diet recommendations and ingest few, if any, non-recommended, indulgent foods. For this reason, studies on WG intake must take into account all confounders, in order to remove potential bias from data.Fiber and polyphenols (or phenolic compounds) are the main dietary bioactive compounds studied for prevention of chronic diseases; they have different chemical structures, physical and biological properties, and ability to activate distinct metabolic pathways ,49.The definition of dietary fiber is constantly evolving and, although AACC has proposed that it is: \u201cthe remnants of the edible part of plants or analogous carbohydrates that are resistant to digestion and absorption in the human small intestine, with complete or partial fermentation in the large intestine\u201d , the morIn WG, dietary fiber primarily derives from the outer portion of cereal kernel  and mainly consists of non-starch polysaccharides, distinguished by fermentability to SCFAs, solubility in water, viscosity, and cation exchange capacity ,53. CellPolyphenols, secondary metabolites found in plant tissues, are heterogeneous compounds, possessing one or more aromatic rings with one or more hydroxyl groups. Polyphenols can be subdivided into (i) phenolic acids, (ii) flavonoids, (iii) stilbenes, and (iv) lignans ,64; theyp-cumaric, vanillic, siryngic, gallic, and caffeic acids are the most common phenolic acids of grains  in different gastrointestinal organs. To the best of our knowledge, no epidemiological studies about WG intake and risk of gallbladder and bile duct carcinomas have been published, while only one study demonstrated inverse association between WG  intake and risk of hepatocellular carcinoma, the predominant histological form of primary liver cancer . As emerSimilarly, literature data on association between unrefined grains and oral cavity and oropharynx cancers are scarce, not updated and just based on few case-control and cohort studies. Some investigations highlighted that WG intake was favorably related to risk of upper aerodigestive tract cancers ,93,94,95Based on this evidence, we focused on colorectal, gastric, and esophageal tumors, the most diagnosed and severe gastrointestinal cancers, for which investigations are more extensive and continuously updated.In 2020, 1.9 million of individuals were diagnosed for colorectal cancer, the second mostly incident cancer and the third leading cause of cancer death worldwide. It has slightly higher incidence in males  than females  ; althougDepending on location , colorectal cancer varies in terms of etiology and sensitivity to specific risk factors ,105. OnlIn this context, WGs represent protective factors, as high intakes have been associated with significant decrease of cancer risk . In a 14The American Institute for Cancer Research and the World Cancer Research Fund stated that eating at least 90 g/day WG reduces colorectal cancer risk, mainly due to its high fiber content . Among mp-coumaric acids modulate S and G2/M phase transitions, respectively [Concerning phenolic compounds, these phytochemicals exert anti-cancer activities in colon-cancer cells, mainly by inducing cell-cycle arrest and apoptosis. Just an example, ferulic and ectively ; the twoectively , and relectively ,128. Likectively ,130,131.ectively ,134,135.ectively ,137,138.In order to overcome challenges in polyphenol delivery to target tissues, recent studies have attempted to find novel strategies for improving bioavailability and anti-tumor efficacy of these phytochemicals. For example, the novel stable ferulic derivative tributyltin(IV) ferulate has been designed and found to potently exert anti-tumor activity; this synthetic compound, indeed, triggers autophagic cell death through generation of reactive oxygen species and endoplasmic reticulum stress in colon cancer cells . SimilarGastric cancer is the fourth cause of tumor-related deaths. Incidence  is higher in males  than females ; 75.3% of cases occur in Asia, followed by Europe (12.5%) and Latin America and Caribbean (6.2%) .Helicobacter pylori infection, while cardiac gastric cancer is also related to other risk factors, including esophageal reflux, Barrett\u2019s esophagus, and obesity [Generally, gastric cancer is classified into non-cardiac gastric cancer, originating from distal regions of stomach, and cardiac gastric cancer, arising near the esophageal-gastric junction ; both fo obesity ,148,149.H. pylori infection [Among factors affecting cancer onset, dietary habits play an important role ,151,152:nfection , whereasnfection ,155. A pnfection . Severalnfection ,162,163.To date, no conclusions on the role of fiber in WG/gastric cancer association can be drawn since available investigations are somehow misleading and difficult to interpret. Except for the cohort Iowa Women\u2019s Health Study (demonstrating strong protective effects of WG fiber against stomach cancer) , almost H. pylori proliferation, as well as invasion and metastasis of cancer cells [2+ homeostasis [p-coumaric acid exerts antitumor effects by regulating hsa-miR-30a-5p, hsa-miR-125a-5p, and hsa-miR-7-5p [Among polyphenols, gallic acid has been shown to inhibit er cells . Similarer cells  demonstreostasis , feruliceostasis , and apieostasis ,168. LasmiR-7-5p ,171,172.According to Globocan 2020, 508,585 cancer victims  were affected by esophageal cancer, the sixth cause of cancer deaths . IncidenEsophageal tumors are distinguished into esophageal squamous cell carcinomas, affecting upper layer cells lining esophagus, and adenocarcinomas, arising in glandular cells located between the esophagus\u2013stomach junction ,174; esoHigher frequency of WG food consumption may be accounted among indicators of reduced risk of esophageal cancer . In a smAdditionally, polyphenols could be beneficial in esophageal cancer, thanks to their antioxidant activity, ability to improve esophageal reflux-related inflammation, and modulation of cell proliferation and survival ,190. GalCancer onset, progression, and outcome are strictly dependent on interaction among genetic, metabolic, and environmental factors. Remarkably, besides some unhealthy habits , consumption of harmful foodstuff and nutrients increases cancer risk; coherently, healthy dietary behaviors, which involve consumption of healthy foods  and nutrients , are worldwide recognized as a valid strategy for primary cancer prevention. Scientific organizations of several countries encourage WG intake in maintaining health and reducing risk of chronic diseases, such as type 2 diabetes, cardiovascular disease, and cancer ,196,197.Herein, we focused on inverse relationship between WGs, whose consumption is increasingly recommended, and gastrointestinal cancer onset and outcomes. What emerged is that WGs, unlike refined counterparts, consistently protect against gastrointestinal cancer, especially colorectal type; such differences can mainly be ascribed to reduction (or loss) of beneficial nutrients and phytochemicals during milling process. WG is indeed a complex food matrix containing different bioactive compounds, which synergistically act in chronic disease prevention. It is therefore difficult to identify which constituent is responsible for protection; for this reason, attention should be shifted not to single compounds, but instead to WG food matrix. For example, some WG positive effects essentially depends on fiber, but fiber varies from grain to grain and is present in other food items  that are equally consumed by high WG users. Thereby, although both fiber and WGs have healthy benefits, they are not interchangeable and consumers should pay particular attention to high-fiber products, sometimes containing bran or other added fiber without actually having much, if any, WG.Noteworthily, WG consumers are more likely to consume less sugar, alcohol, fat, red meat, and indulgent foods, while consuming more fruits, vegetables, and fish; moreover, they have high education and socioeconomic status, as well as healthy lifestyle . For this reason, most of studies investigated WG effects after accurate statistical adjustments for all of these possible confounders, thus removing potential bias from data and providing authentic and real relationship between WG intake and gastrointestinal cancer. Nonetheless, several elements point out that we are far from a solid, scientific-based knowledge for developing individualized WG-based regimens to prevent and manage cancer. WG consumption, indeed, reduces risk of digestive tract tumors with significant heterogeneity because of additional confounding factors, including differences in (i) type, duration, quality, and sample size of investigations; (ii) methods of collecting WG intake (food-frequency questionnaires vs. more quantitative questionnaires); (iii) type of WG foods; (iv) racial and ethnic demographic groups displaying different nutritional habits.Despite all these limitations, beneficial effects of WGs cannot be denied, and therefore programs aimed at increasing WG consumption should be implemented through a broad partnership involving both public (Government authorities) and private (industries) stakeholders. Several barriers to WG consumption should, indeed, be removed by effective strategies: (i) univocal, quantitative, and international recommendations; (ii) nutritional education programs; (iii) improvement of sensory characteristics and increase of variety of WG foods ; (iv) better identification of WG-containing products; (v) reduction of purchase costs."}
+{"text": "We designed a cohort study to describe characteristics and outcomes of patients with coronavirus disease (COVID-19) admitted to the intensive care unit (ICU) in the largest public hospital in Sao Paulo, Brazil, as Latin America becomes the epicenter of the pandemic.This is the protocol for a study being conducted at an academic hospital in Brazil with 300 adult ICU beds dedicated to COVID-19 patients. We will include adult patients admitted to the ICU with suspected or confirmed COVID-19 during the study period. The main outcome is ICU survival at 28 days. Data will be collected prospectively and retrospectively by trained investigators from the hospital\u2019s electronic medical records, using an electronic data capture tool. We will collect data on demographics, comorbidities, severity of disease, and laboratorial test results at admission. Information on the need for advanced life support and ventilator parameters will be collected during ICU stay. Patients will be followed up for 28 days in the ICU and 60 days in the hospital. We will plot Kaplan-Meier curves to estimate ICU and hospital survival and perform survival analysis using the Cox proportional hazards model to identify the main risk factors for mortality. ClinicalTrials.gov: NCT04378582.We expect to include a large sample of patients with COVID-19 admitted to the ICU and to be able to provide data on admission characteristics, use of advanced life support, ICU survival at 28 days, and hospital survival at 60 days.This study will provide epidemiological data about critically ill patients with COVID-19 in Brazil, which could inform health policy and resource allocation in low- and middle-income countries. In December 2019, an outbreak of severe acute respiratory syndrome (SARS) attributed to a new coronavirus, namely, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), was identified in the Wuhan region of China . The disth , and the study was registered in a public database . The requirement for informed consent was waived because of the observational nature of the study.From March 13 to April 16, 200 previously functioning ICU beds were converted into COVID-19-dedicated ICU beds. In the following 45 days, operating rooms and several hospital wards were repurposed to accommodate 100 additional COVID-19-ICU beds. Physicians, nurses, and respiratory therapists were hired to constitute new ICU teams dedicated to patients occupying these additional beds. New staff were trained and distributed within experienced ICU teams.The study is observational, and patient care was carried out following institutional protocols developed specifically for COVID-19 patients. The protocol recommends routine use of deep venous thrombosis prophylaxis and systemic antibiotics if bacterial coinfection is suspected. Specific drugs for treating SARS-CoV-2 were not recommended but could be administered at the discretion of the attending physician. The study also included specific protocols for the ventilatory management of respiratory failure and for sedation management throughout ICU stay. Other critical care standards were not changed during the pandemic.We will include all consecutive adult patients with suspected or confirmed COVID-19 admitted to the ICUs between March 30 and June 30, 2020 with an expected ICU stay longer than 24 hours . The onlThe main outcome is ICU survival at 28 days. Secondary outcomes include duration of mechanical ventilation, need for rescue therapies for severe hypoxemia, need for renal replacement therapy, ICU complications, and hospital survival at 60 days.Data will be collected prospectively from study approval (May 6) to August 30, 2020 and retrospectively from March 30 to May 5, 2020. Trained data collectors will retrieve patient information from the hospital electronic medical records, and at the bedside . Study dQuality control measures will include the use of REDCap-based structured data collection forms, training data collectors to ensure data completeness and consistency, and data management processes within the platform to deal with missing data, outliers, and data collection mistakes.We will report study results in accordance to recommended guidelines for reporting observational studies, the Strengthening The Reporting of Observational Studies in Epidemiology (STROBE) , and theA sample size of 300 patients was initially anticipated. As the epidemic in Sao Paulo grew fast, the hospital included new ICU beds, and we revised the anticipated sample size to 500 patients. Given that the study carries no risks for participants and that the requirement for informed consent was waived by the IRB, we intend to collect data on all patients with COVID-19 admitted to the ICUs during the study period, a sample possibly larger than the anticipated sample size. Such a large sample would suffice to allow identification of predictors of survival.a priori as clinically relevant  or median (interquartile range), as appropriate. All hypothesis tests will be two-tailed, with a significance level of 0.05, and they will be performed using the R software . We will build Kaplan-Meier curves to estimate 28-days survival. ICU survival will be defined as the time interval between ICU admission and patient death from any cause or ICU discharge. Time will be censored at 28 days for patients who are still alive. Hospital survival will be defined as the time interval between ICU admission and patient death from any cause or hospital discharge. Patients discharged home will be considered alive at day 28. We will perform survival analysis using the Cox proportional hazards model censored at 28 days to identify the main risk factors for ICU survival beyond expected associations, such as age, comorbidity burden, and severity of disease at ICU admission. Variables identified relevant  and addivs. previously functioning ICUs) are some of the system-level characteristics that highlight the importance of this study to assess overall survival of COVID-19 patients in LMICs.Our study will report characteristics and outcomes of all patients admitted to the ICU at the largest academic hospital in Brazil during the peak of the pandemic of COVID-19 in Sao Paulo. The hospital developed a preparedness plan that included grouping COVID-19 patients in a building dedicated exclusively for the care of these patients, creation of surge ICUs to increase ICU bed capacity, and hiring additional healthcare professionals to work exclusively in the COVID-19 ICUs. The actions were coordinated by a crisis committee composed of critical care specialists, pulmonologists, infectious disease specialists, nurses, respiratory specialists, pharmacists, engineers, and administrators, among others, who met daily to make shared decisions. Such an effort helped prevent shortage of personal protective equipment and important medications, facilitated the development of institutional protocols for patient care and infection control, and contributed to a rational distribution of limited resources with potential impact on patient outcomes . The resWe will also be able to assess resource utilization beyond mechanical ventilation, such as renal replacement therapy and ICU length of stay, to characterize the burden of this surge of severe respiratory failure patients to our hospital and healthcare system. In the main manuscript, both characterization of the cohort and the risk factors for increased mortality will be assessed and compared to the current literature. Our main benchmark for ICU and hospital survival is the result published regularly by the Intensive Care National Audit & Research Centre (ICNARC), that is, 35%-45% hospital mortality among patients receiving mechanical ventilation , which rIn addition, the study will provide answers to many ancillary research questions:Rate of use and success rate of non-invasive ventilation and high-flow nasal cannula use to treat respiratory failure and of commonly used strategies for refractory respiratory failure, including inhaled nitric oxide, prone positioning, and ECMO.Prediction models of hospital mortality specific for COVID-19.Characterization of subgroups of interest, such as oncologic and transplant patients.System-level research questions to compare outcomes and processes of care in \u201csurge\u201d ICUs and previously functioning ICUs, which would allow planning for future surges in critical care capacity.In conclusion, we will be able to describe the characteristics and outcomes of a large sample of critically ill patients with COVID-19 admitted to a dedicated hospital in a LMIC, which could inform health policy and resource allocation and allow for many exploratory research questions to be answered.Adriana Hirota, Alberto Kendy Kanasiro, Alessandra Crescenzi, Amanda Coelho Fernandes, Anna Miethke-Morais; Arthur Petrillo Bellintani, Artur Ribeiro Canasiro, B\u00e1rbara Vieira Carneiro, Beatriz Keiko Zanbon, Bernardo Pinheiro De Senna Nogueira Batista, Bianca Ruiz Nicolao, Bruno Adler Maccagnan Pinheiro Besen, Bruno Biselli, Bruno Rocha De Macedo, Caio Machado Gomes De Toledo, Carlos Eduardo Pompilio, Carlos Roberto Ribeiro De Carvalho, Caroline Gomes Mol, Cassio Stipanich, Caue Gasparotto Bueno, Cibele Garzillo, Clarice Tanaka, Daniel Neves Forte, Daniel Joelsons, Daniele Robira, Eduardo Leite Vieira Costa, Elson Mendes Da Silva J\u00fanior, Fabiane Aliotti Regalio, Gabriela Cardoso Segura, Gustavo Brasil Marcelino, Giulia Sefrin Louro, Yeh-Li Ho, Isabela Argollo Ferreira, Jeison de Oliveira Gois, Joao Manoel Da Silva Junior, Jose Otto Reusing Junior, Julia Fray Ribeiro, Juliana Carvalho Ferreira, Karine Vusberg Galleti, Katia Regina Silva, Larissa Padrao Isensee, Larissa dos Santos Oliveira, Leandro Utino Taniguchi, Leila Suemi Letaif, L\u00edgia Trombetta Lima, Lucas Yongsoo Park, Lucas Chaves Netto, Luciana Cassimiro Nobrega, Luciana Haddad, Ludhmila Hajjar, Luiz Marcelo Malbouisson, Manuela Cristina Adsuara Pandolfi, Marcelo Park, Maria Jos\u00e9 Carvalho Carmona, Maria Castilho Prandini H De Andrade, Mariana Moreira Santos, Matheus Pereira Bateloche, Mayra Akimi Suiama, Mayron Faria de Oliveira, Mayson Laercio Sousa, Michelle Louvaes, Natassja Huemer, Pedro Mendes, Paulo Ricardo Gessolo Lins, Pedro Gaspar Dos Santos, Pedro Ferreira Paiva Moreira, Renata Mello Guazzelli, Renato Batista Dos Reis, Renato Daltro De Oliveira, Roberta Muriel Longo Roepke, Rodolpho Augusto De Moura Pedro, Rodrigo Kondo, Samia Zahi Rached, Sergio Roberto Silveira Da Fonseca, Thais Sousa Borges, Thalissa Ferreira, Vilson Cobello Junior, Vivian Vieira Ten\u00f3rio Sales, Willaby Serafim Cassa Ferreira. All investigators are from Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, SP, BR.Ferreira JC, Besen BAP, Malbouisson LMS, Taniguchi LU, Ho YL, Mendes PV, Carmona MJC, and Carvalho CRR were responsible for the study concept and design. Ferreira JC, Besen BAP, Taniguchi LU, Mendes PV, Costa ELV, Park M, Daltro R, Roepke RML, Silva Jr JM and EPICCov site investigators were responsible for the acquisition, analysis, or interpretation of data. Ferreira JC, Besen BAP, Malbouisson LMS, Taniguchi LU, Ho YL, Mendes PV, Costa ELV, Park M, Daltro R, Roepke RML and Silva Jr JM were responsible for the manuscript drafting. Ferreira JC, Besen BAP, Malbouisson LMS, Taniguchi LU, Ho YL, Mendes PV, Costa ELV, Park M, Daltro R, Roepke RML, Silva Jr JM, Carmona MJC, Carvalho CRR and EPICCov site investigators were responsible for the critical revision of the manuscript for important intellectual content. Besen BAP, Costa ELV and Park M were responsible for the statistical analysis. Ferreira JC, Besen BAP, Ho YL and Malbouisson LMS were responsible for the study supervision."}
+{"text": "Mus musculus, Rattus norvegicus, and Rattus rattus were found to be the most common. Fleas were the most reported ectoparasites (87 articles), followed by mites (53), ticks (44), and lice (25). Xenopsylla cheopis, Polyplax spinulosa, Ornithonyssus bacoti, and Hyalomma rhipicephaloides were the most commonly described fleas, lice, mites, and ticks, respectively. Based on the reviewed articles, the median flea, louse, mite, and tick indices were highest in Israel (4.15), Egypt (1.39), Egypt (1.27), and Saudi Arabia (1.17), respectively. Quantitative meta-analysis, using a random-effects model, determined the overall pooled flea prevalence in the Middle East as 40% , ranging between 13%  in Iran and 59%  in Israel. The overall pooled louse prevalence was found to be 30% , ranging between 25% in Iran  and 38% in Egypt . In the case of mites, the pooled prevalence in this region was 33% , where the country-specific prevalence estimates were 30% in Iran  and 32% in Egypt . For ticks, the overall prevalence was found to be 25% , ranging from 16% in Iran  to 42% in Egypt . The control of rodent ectoparasites should be considered to reduce their adverse effects. Using the One Health strategy, rodent control, and precisely control of the most common rodent species, i.e., Mus musculus, Rattus norvegicus, and Rattus rattus, should be considered to control the rodent-borne ectoparasites in this region.Rodents carry many ectoparasites, such as ticks, lice, fleas, and mites, which have potential public health importance. Middle Eastern countries are hotspots for many emerging and re-emerging infectious diseases, such as plague, leishmaniasis, Crimean Congo hemorrhagic fever, and Q fever, due to their ecological, socioeconomic, and political diversity. Rodent ectoparasites can act as vectors for many of these pathogens. Knowledge of rodent ectoparasites is of prime importance in controlling rodent ectoparasite-borne zoonotic diseases in this region. The current systematic review and meta-analysis performs a comprehensive synthesis of the available knowledge, providing an evidence-based overview of the ectoparasites detected on rodents in Middle Eastern countries. Following a systematic search in Pubmed, Scopus, and Web of Science, a total of 113 published articles on rodent ectoparasites were studied and analyzed. A total of 87 rodent species were documented, from which  Crimean-Congo hemorrhagic fever virus (CCHFV), Coxiella, Rickettsia and Hymenolepis . On. On25]. Systematic searches on PubMed, Scopus, and Web of Science were performed by 16 October 2020. The search covered every original research article published in English containing field information on rodent ectoparasites in the Middle Eastern countries without any restrictions on publication dates. Following a previous systematic review , the keyhttps://rayyan.qcri.org/) for title and abstract screening. If any article\u2019s title and abstract were ambiguous in terms of relevance to our study, it was subjected to full-text analysis. At first, EndNote X9  was used to identify and exclude duplicate studies. Imported citations were then transferred to Rayyan , ectoparasite-specific data , and the associating factors for ectoparasite abundance on rodents . The taxSE = SQRT(p(1 \u2212 p)/n), where p is the reported prevalence, and n is its sample size. The Inconsistency Index (I2) was used to assess the degree of heterogeneity among studies, as it is known to be less influenced by the number of included studies. According to the country and rodent species, subgroup meta-analyses were performed to investigate possible explanations of significant heterogeneity (I2 > 75%). However, each subgroup had to be represented by at least three studies to be included for analysis. The results of all meta-analyses were illustrated in forest plots. Finally, funnel plots were generated and visually-examined to assess the possibility of publication bias.The extracted data were organized and stored in Microsoft Excel  spreadsheets. The initial descriptive analysis of the included studies was conducted using the same application. Ectoparasite indices were calculated for each of the four types of ectoparasites  by dividing the total numbers detected for the specific ectoparasite by the total number of sampled rodents . CentralThe literature search resulted in 113 articles  publisheMus musculus , Rattus norvegicus (48%), and Rattus rattus (19%) were found to be the most common and widely-distributed rodents. Moreover, Acomys cahirinus, Acomys dimidiatus, Apodemus mystacinus, Apodemus sylvaticus, Cricetulus migratorius, Gerbillus nanus, Jaculus jaculus, Meriones crassus, Meriones libycus, and Meriones tristrami were reported from at least three countries of the Middle East, and can be considered as widely-distributed rodents in this region.The 113 studies examined at least 26,003 rodents from 87 rodent species belonging to seven families . Among tBased on the reviewed articles, the Boxplots  summarizXenopsylla cheopis, Echidnophaga gallinacea, and Xenopsylla cleopatrae . The most frequently reported species of fleas were Xenopsylla cheopis (41 reports), Leptopsylla segnis (22), and Ctenocephalides felis (19). Fifteen species of fleas were reported from at least three countries, such as Echidnophaga murina, Leptopsylla segnis, Leptopsylla taschenbergi, Nosopsyllus fasciatus, Nosopsyllus iranus, Parapulex chephrenis, Pulex irritans, Stenoponia tripectinata, Xenopsylla astia, Xenopsylla cheopis, Xenopsylla cleopatrae, Xenopsylla conformis, Xenopsylla nubica, and Xenopsylla ramesis.Based on the records of 82 articles with rodent fleas, a total of 67,057 fleas were examined, which were from 104 flea species , of whicI2 = 100%, p < 0.00001), ranging between 13%  in Iran and 59%  in Israel , Rattus norvegicus  and Rattus rattus   .Polyplax spinulosa represented 88.79% of the total lice, and was reported by 25 articles from Egypt, Iran, Kuwait, Palestine and Saudi Arabia. The 39 articles studied a collective 31,543 lice on rodents, and detected 28 species of lice in the Middle Eastern rodents . HoweverI2 = 100%, p < 0.00001), ranging between 25% in Iran  and 38% in Egypt  , and 53% in Rattus rattus   . Moreove = 100%) .Laelaps nuttalli (29%), Ornithonyssus bacoti (34%), and Radfordia ensifera (10%). However, Echinolaelaps echidninus, Eulaelaps stabularis, Haemolaelaps glasgowi, Laelaps nuttalli, and Ornithonyssus bacoti were reported from at least three countries of the Middle East, whereas Ornithonyssus bacoti and Laelaps nuttalli were the highest reported mites . The review detected 134 species  of mitesI2 = 100%, p < 0.00001) (I2 = 99%) and Egypt   to 56% in Rattus rattus   . Country = 100%) . The pre = 100%) . Hyalomma rhipicephaloides and Ixodes eldaricus, respectively. Three species of ticks were reported from more than three countries, such as Ixodes spp., Rhipicephalus sanguineus, and Rhipicephalus turanicus. The reviewed studies identified 2897 ticks from at least 27 species , of whicI2 = 100%, p < 0.00001) (I2 = 74%) to 42% in Egypt  , to 24% in Mus musculus   , ranging = 100%) . The tic2 = 91%) . Our study reviewed the published literature on rodent ectoparasites in the Middle Eastern countries to provide a comprehensive overview of rodent ectoparasites in this region. Most of the studies were from Iran, Egypt, and Israel (82 out of 113). A previous history of rodent-borne disease epidemics, such as plague, leishmaniasis, and murine typhus, may be behind the increased interest in rodent-related pathogens by researchers in these countries . EctoparRhipicephalus sanguineus, is abundant on stray dogs in Jordan [Rhipicephalus sanguineus and Xenopsylla astia were identified on domestic cats in UAE [Although there were no rodent ectoparasite reports from Bahrain, Iraq, Jordan, Oman, Syria, and UAE in our systematic review, there are rodent-related ectoparasites reported in some of these countries from non-rodent hosts. The brown dog tick, n Jordan . Rhipices in UAE . This ins in UAE , suggestAllactaga sp., Apodemus witherbyi, Dryomys nitedula, Gerbillus nanus, Jaculus blanfordi, Meriones crassus, Meriones libycus, Meriones persicus, Microtus socialis, Mus musculus, Nesokia indica, Rattus norvegicus, Rattus rattus, Rhombomys opimus, Tatera indica [Acomys cahirinus, Acomys russatus, Dipodillus dasyurus, Eliomys quercinus, Gerbillus andersoni, Gerbillus gerbillus, Gerbillus pyramidium, Jaculus jaculus, Jaculus orientalis, Meriones crassus, Meriones sacramenti, Meriones tristrami, Mus musculus, Psammomys obesus, Rattus norvegicus, Rattus rattus, Sekeetamys calurus [The present review listed a total of 87 species of rodents that occur in the Middle Eastern region. In Iran, 79 species of rodents have been described, of which 15 are considered common, i.e., a indica ,141. Sev calurus . All theRadfordia musculi, Radfordia musculinus, Radfordia affinis, and Radfordia ensifera are mainly found in laboratory rodents [Dermanyssus gallinae and Ornithonyssus sylviarum are poultry mites [Macrocheles spp. Tryophagus sp. and Zygoribatula sp., which are known as non-parasitic mites [Ornithodoros sp., which can parasitize humans, rodents, livestock, and poultry [Some of the rodent ectoparasites addressed in this review have high public and animal health importance. Similar to their impact on humans and other animals, they can also cause certain diseases in the host rodents. Nevertheless, the ectoparasites identified in this review are not always rodent-specific. The host specificity of ectoparasites generally falls within one of three broad categories: (i) ectoparasites specific to rodents, which do not, or only accidentally, infest other mammals (including humans) and birds; (ii) ectoparasites specific to other species that accidentally attack rodents; or (iii) ectoparasites with a broad host range. Rodent fur mites  rodents ,144,145.ry mites ,148,149.ry mites ,151. Somry mites ,98,121, ic mites ,153,154. poultry ,156. Ctenocephalides canis and Ctenocephalides felis, which can infest dogs, cats, rodents, and humans. These fleas carry multiple zoonotic pathogens, such as Bartonella, Rickettsia felis, Dipylidium caninum, and Yersinia pestis, which can be transmitted at the humans\u2013animal interface [Xenopsylla cheopis is an essential vector of Bartonellosis, plague, and murine typhus [Ornithonyssus bacoti can transmit numerous pathogens such as Rickettsia typhi (murine typhus), Coxiella burnetti (Q-fever), and Trypanosoma cruzi (Chagas\u2019 disease) [Ornithonyssus sylviarum can bite humans and cause allergic reactions [Ornithodoros sp. has been described to carry Alkhurma hemorrhagic fever virus in Saudi Arabia [Borrelia sp. in Egypt [Rhipicephalus spp. were also found to carry genomes of CCHFV in Iran [Coxiella, Francisella, Rickettsia, Babesia, and Theileria in Turkey [Cheyletus sp., cause allergy in humans [Dermanyssus gallinae and Dermanyssus americanus can cause dermatitis in humans [There is considerable public health importance attributed to ectoparasites with a broad host range, mainly if this includes humans, such as nterface ,159,160.e typhus . The trodisease) . The noreactions . Ornithoi Arabia ; Borreliin Egypt ,166,167,in Egypt ,169, Isrin Egypt ,171, Jorin Egypt , Palestiin Egypt ; and CCHin Egypt . Rhipice in Iran  and Saud in Iran , and Coxn Turkey . Moreoven humans . Infestan humans ,176.Mus musculus, Rattus norvegicus, and Rattus rattus. These rodents have been identified as the most common and extensively-distributed rodent species in the Middle Eastern countries by a previous study [However, meticulously-designed and well-implemented control programs against rodent ectoparasites are of the utmost importance to regional health authorities to control rodent ectoparasite-borne zoonotic diseases effectively. A useful approach would be to limit the spread of rodents themselves. Many of the reviewed articles in this study ,34,40 stus study , and theus study ,177, witRodent ectoparasites, including rodent fleas, lice, mites, and ticks, in Middle Eastern countries, including Cyprus, Egypt, Iran, Israel, Kuwait, Lebanon, Palestine, Qatar, KSA, Turkey, and Yemen, have been reported. In total, 104 flea species, 28 louse species, 134 mite species, and 27 tick species have been detected on 87 rodent species in these countries. Some rodent ectoparasites have substantial public health importance as they are known to carry a broad spectrum of zoonotic pathogens. Besides the One Health approach for rodent control, some other factors such as rodent abundance, season of the year, and trapping location should be considered during the rodent ectoparasite control program. Our systematic review reveals knowledge gaps on rodent ectoparasites in this region, suggesting that it is essential to conduct countrywide in-depth studies on rodent ectoparasites and their public health importance. As the threats of zoonotic diseases increase, including rodent-borne diseases, it is crucial to expand all efforts from all angles to mitigate these threats."}
+{"text": "Mimopsorientalis Kraepelin, 1903 is a monotypic species of Mimopidae endemic to China. The species is known only from a single specimen, the holotype. Little is known about its biology, habitat associations, or phylogenetic relationships. It was rediscovered on Qinling Mountain in Shaanxi and Henan provinces, China, 117 years after its last record. Detailed descriptions and colour photographs of living specimens are provided along with its ecology, updated conservation notes, and data on sexual dimorphism. A genetic analysis  was conducted to assess the phylogenetic relationships among Mimopidae, Cryptopidae, Scolopendridae, Scolopocryptopidae, and Plutoniumidae. The results support classifying Mimopidae as a valid family. Mimops Kraepelin, 1903 is one of the least-known genera of scolopendromorph centipedes. The type species, Mimopsorientalis Kraepelin, 1903, described from a single specimen from Shaanxi Province, China, has a single white ocellus on each side of the cephalic plate. Since the original description, the exact type locality of this species has been unknown, and no additional findings of M.orientalis have been reported. The genus Mimops was initially placed in the Cryptopidae and subsequently redescribed by M.orientalis, establishing a new monotypic family, Mimopidae Lewis, 2006.M.orientalis, the unsexed holotype specimen, did not allow Mimops. Because M.orientalis possesses characteristics from the families Plutoniumidae, Cryptopidae, Scolopocryptopidae, and Scolopendridae , the taxonomic status of Mimopidae is still confusing, as are the phylogenetic relationships among Mimopidae, Cryptopidae, Scolopendridae, Scolopocryptopidae, and Plutoniumidae.However, the only material of M.orientalis was collected at the edge of Qinling Mountain. It is a region that has only few previous surveys for centipedes but has been highlighted as one of 16 biodiversity hotspots .The studied individuals of The taxonomic characteristics of the specimens were observed under an Olympus SZ16 stereomicroscope. Multifocus montage images were produced using Helicon Focus 6.7.1 software from a series of source images taken by a Canon 50D digital camera attached to the stereomicroscope. Terminology applied to the external anatomy follows All newly collected centipede specimens were stored in 75% ethanol. Legs 15 and 17 of the newly collected specimens were removed and stored in 100% ethanol for DNA extraction.mtDNA), the encoded parts of the COI and 16S ribosomal RNA genes, and a fragment of 28S nuclear ribosomal RNA were amplified according to previously literature . Two fragments of mitochondrial DNA . The best-fit substitution models and partitioning strategies were inferred for these three datasets using ModelFinder .Shaanxi, China. Perhaps referring to Xi\u2019an, Shaanxi, China.Mimopsorientalis specimens were collected near a river in the Taiping National Forest Park, Hu county, Shaanxi, China , and another M.orientalis were collected in 2019 from Funiushan National Nature Reserve, Luanchuan, Henan, China. Mimopsorientalis (n = 8). CMMI 20190714001, adult, under a stone near a river, Longyuwan National Forest Park, Luanchuan, Henan, China,  collected by Mengxuan Shi, on 14 Jul. 2019. CMMI 20190908001, adult male, under a stone near a ditch, Taiping National Forest Park, Hu county, Shaanxi, China , collected by Chao Jiang, on 08 Sept. 2019. CMMI 20190908002, juvenile, under a stone in some brushwood, Taiping National Forest Park, Hu county, Shaanxi, China , collected by Chao Jiang, on 08 Sept. 2019. CMMI 20190908003 and CMMI 20190908004, juvenile, under stones in grass halfway up a steep hill, Taiping National Forest Park, Hu county, Shaanxi, China , collected by Chao Jiang, on 08 Sept 2019. CMMI 20190908005, adult, under a trash bin near the road, Taiping National Forest Park, Hu county, Shaanxi, China , collected by Chao Jiang, on 08 Sept. 2019. CMMI 20190908006, subadult, under a stone near the collection site of specimen CMMI 20190908005, collected by Chao Jiang, on 08 Sept. 2019. CMMI 20190908007, juvenile, under a stone of brushwood, Taiping National Forest Park, Hu county, Shaanxi, China , collected by Chao Jiang, on 08 Sept 2019.Seven Plutoniumidae: Theatopschuanensis Di et al., 2010, CMMI 20190405013, Tianzishan National Reserve, Zhangjiajie, Hunan province, China. CMMI 20190606004, Wen county, Longnan, Gansu province, China.Cryptopidae: Cryptops sp., CMMI 20190413007, Longjin road, Huoshan county, Liu\u2019an, Anhui province, China.Scolopendridae: Scolopendramutilans L. Koch, CMMI 20190331001, Qianfodong National Forest Park, Duodao distinct, Jinmen, Hubei province, China. CMMI 20190702006, Xiangshan, Dinghai distinct, Zhoushan, Zhejiang province, China.Scolopocryptopidae: Scolopocryptopsnigrimaculatus Song, Song & Zhu, 2004, CMMI 20181207002, Jinxi hotel, West Lake, Hangzhou, Zhejiang province, China.M.orientalis occurs on Qinling Mountain (Shaanxi and Henan provinces) and inhabits forests near rivers above 500\u20131200 m elevation , always in forest edges near a river and under microhabitat refuges . Two adult specimens were hiding under stones coated with moss, and another adult was encountered under some garbage containing rainwater. Most juveniles were encountered under small stones in bushes or moving over leaf litter in a fragmented patch of Liquidambarformosana Hance. Natural vegetation in the surrounding areas is deciduous forest, composed mainly of Juglansregia L., Cotinuscoggygria Scop., and L.formosana Hance. Vegetative cover was ornamented by Urtica spp., Viola spp., Cyperusiria L., and Oplismenusundulatifolius (Arduino) Beauv  or 6 and 7  had sparse hair; articles 8\u201318 were densely hirsute.Adult length 42\u201356 mm. Cephalic plate smooth, about as long as it is wide, very finely punctate with the posterior margin overlying tergite 1. Cephalic plate lacks paramedian sulci in adults (two sulci in juvenile). A pale area instead of lateral ocelli at the base of each antenna , and artTooth plates are short but wide, ridged and have approximately 25 ridges on each side and a prominent seta behind the anterior margin Fig. . ForcipuTergite 1 with anterior transverse (ring) sulcus Fig. . TergiteAll legs with two-segmented tarsi. Two tibial spurs on legs 1\u201318, 19 with one, 20 without. Legs 1\u201320 each with two tarsal spurs Fig. . Legs 1\u2013Tergite 21 with small spines and a narrow posterior median depression Fig. . SternitGenital segments well developed, reaching the distance between the posterior margin of sternite 21 and the distal part of the coxopleural process. In males, sternite of genital segment 1 round, with short setae ventrally, genital segment 2 round and convex, also with short setae ventrally. Penis columnar, with long setae dorsally. Gonopod present in males with seven or eight long setae Fig. . Anal vaAlthough this species was found from two localities separated by 400 km, there is not yet enough information about the distribution, abundance, or threats to this species, and so further surveys are needed; we consider it Data Deficient for now (IUCN 2020).M.orientalis. The complete matrix included sequences from 44 centipede species , Craterostigmustasmanianus (Craterostigmomorpha), Lithobiusforficatus (Lithobiomorpha), and Bothriogastersignata (Geophilomorpha) were selected as outgroups to assess the phylogenetic of M.orientalis as well as Mimopidae.We obtained 887 bp sequences of COI, 537 bp of 16S and 992 bp of 28S of BI) and maximum likelihood (ML) analyses yielded trees based on the combined alignments of COI + 16S + 28S, which demonstrated essentially consistent topologies. All Scolopendromorpha species used in this study could be considered as two main clades, the ocellate scolopendromorphs and the blind scolopendromorphs, both well supported in the ML tree. Mimopidae was positioned as sister group to the other families of blind scolopendromorphs. However, Bayesian inference analyses identified Scolopendromorpha species as belonging to three clades, the ocellate scolopendromorphs, the blind scolopendromorphs sensu Pocock, 1896 , and the monophyletic family Mimopidae with quite strong support (PP 0.94). Both methods obtained from the molecular data place Scolopendridae as a monophyletic family, comprising two subfamilies, Scolopendrinae and Otostigminae. Likewise, Scolopocryptopidae comprises two subfamilies, Scolopocryptopinae and Newportiinae. Cryptopidae, and Scolopocryptopidae are sister groups together with Plutoniumidae in the molecular analysis.The results of the phylogenetic analysis are presented in Figures Mimops has been controversial for many years. Attems (1930) divided scolopendromorphs into blind scolopendromorphs and ocellate scolopendromorphs, the latter containing only a single family, Scolopendridae, whereas the former includes three eye-less scolopendromorph families , hence, the name blind clade. The genus Mimops was first classified into the subfamily Cryptopinae of the family Cryptopidae by Attems (1930) and then removed from Cryptopinae in a cladistic analysis by Mimops to the Scolopendridae, and subsequently Mimopidae. Most recently, Mimops as an ocellate scolopendromorph in the monotypic family Mimopidae. A critical controversy focused on the presence or absence of ocelli in M.orientalis. Attems (1930) and Schileyko treated the \u201cAugenfleck\u201d not as a real eye and placed the species in the blind clade, whereas Lewis, Shelley, and Edgecombe considered it as a single ocellus. With careful inspection, we found that M.orientalis has two round pale areas, rather than ocelli, at the base of the antenna. The pale area of M.orientalis is identical to that of Theatopschuanensis of the family Plutoniumidae, but absent in Scolopocryptopidae . Three recently described scolopendrid centipedes, CormocephalussagmusC.pyropygusC.deltaCormocephalus Newport, 1844 which otherwise presents four ocelli. Mimops also shares many scolopendrid-like characteristics, but distinct differences from Tonkinodentus and Cormocephalus imply that eye loss may have occurred several times in the evolution of Scolopendromorpha.The taxonomic position of dae Figs . HoweverMimopsorientalis also possesses several unusual characteristics among Plutoniumidae, Cryptopidae, Scolopocryptopidae, and Scolopendridae. It shares many characteristics with scolopendrid centipedes, including a smooth cephalic plate without setae or spines, several glabrous basal antennal articles, the presence of sternite and tergite paramedian sutures, the presence of spines on the prefemora of the ultimate legs, and an anterior transverse sulcus on tergite 1. These characteristics render it similar to Scolopendra species, particularly many New World varieties. However, M.orientalis lacks lateral ocelli and instead possesses a pale area, which is only present in plutoniumids, and the spines on the ultimate legs are very small, which is similar to some Trigonocryptops species, e.g., Cryptops (Trigonocryptops) camoowealensis Edgecombe, 2006. This renders the taxonomic position of Mimops puzzling.Mimopidae as a valid family based on both morphological and molecular data. We also place Mimops as the basal taxa of scolopendromorphs for the following reasons: 1) M.orientalis is resolved as monophyletic both in maximum likelihood and Bayesian inference analyses under all parameter sets that were explored; 2) the ocelli of Mimops are regressed and have left two pale areas, whereas the outgroups Lithobiomorpha, Scutigeromorpha, and Craterostigmomorpha all have ocelli (or a compound eye with ommatidia in the case of Scutigeromorpha), indicating that ocelli may be a plesiomorphic characteristic; 3) Mimops bears 21 trunk segments, whereas 21 to 23 segments is an unreversed apomorphy of Scolopocryptopidae; 4) the long and acute spines on the forcipular trochanteroprefemoras of Mimops may be a primitive characteristic of trochanteroprefemur process; and 5) the small homologous spines on the ultimate legs, coxopleural process and ultimate sternites seem to be an intermediate state between setae and spines. However, although BI and ML analyses both support the validity of Mimopidae, the precise position of Mimops is not delimited due to the unresolved trichotomy in BI tree. Further research based on complete mitochondrial genome or transcriptomic data may help to clarify phylogenetic relationships among Mimopidae and other families.In this study, we confirmed"}
+{"text": "Anserine folliculosis is a rare dermatological entity presenting with multiple closely grouped follicular-oriented papules on the chin, neck, and jaw. It is difficult to clinically differentiate it from other folliculocentric keratotic disorders like keratosis pilaris, lichen nitidus, follicular mucinosis, and folliculotropic mycosis fungoides (FMF). Dermoscopy can provide an essential clue in the diagnosis of anserine folliculosis and differentiate it from other known entities.Here, we present 3 cases with rough lesions on the chin or jaw of varying duration . HistoryAnserine folliculosis mostly presents in a younger age group with follicular papules on the chin, neck, or jaw and has a sandpaper or goose skin-like feeling on touch. The patients usually give a history of friction or trauma, which has been considered a possible etiologic factor. However, it is not found in all cases. The presence of atopy has been linked to the incidence of anserine folliculosis. Dermoscopic signs have not been elucidated to date. Histopathological features include epidermis with hyperkeratosis, hypergranulosis, the focal presence or increase of the stratum lucidum, rudimentary follicles, and dilatation of follicular openings with retention of keratotic material . HyperkeLichen nitidus presents as multiple, tiny, discrete, shiny papules in clusters over the flexor aspect of upper extremities, genitalia, and anterior trunk . DermoscKeratosis pilaris presents as keratotic follicular plugs with or without perifollicular erythema over the extensor aspect of forearms, thighs, trunk, buttocks, and face . DermoscPrimary follicular mucinosis presents as one or several pink plaques, often composed of grouped follicular papules. Dermoscopy features are dilated follicular ostia with follicular plugs of amorphous material. FMF presents as follicle-based patches, plaques, infiltrated plaques, tumors, and prurigo nodularis-like lesions, as well as keratosis pilaris-like lesions and acneiform lesions mostly on the head and neck region. Dermoscopy shows dilation of follicular openings with partial destruction of hair follicles, orange-pink perifollicular clods, yellowish background, white/pigmented halos, white clods/structureless areas or short fine vessels, or a combination of these. These features were not seen in our cases.Keratotic papules on the chin are a diagnostic challenge. Anserine folliculosis is a rare entity that presents with similarities to follicular-oriented conditions. Dermoscopy can aid in the diagnosis of this condition."}
+{"text": "Dear Editor,Necrotic xanthogranuloma (NX) is a non-Langerhans histiocytosis, initially described in 1980,A 73-year-old man, attended the dermatology outpatient clinic, with yellowish lesions on the trunk that had benn present fortwo years. On physical examination, he showed infiltrated annular plates with clear centers and erythematous borders on the thorax and abdomen, and asymptomatic lower limbs . One of NX has cutaneous findings, predominantly yellowish plaques in the periorbital area, trunk, and extremities, most often associated with paraproteinemia, and can coexist with systemic involvement of multiple organs, such as the heart, respiratory system, spleen, kidneys, liver, skeletal muscle, and central nervous system.The association between NX and hematological disorders is well documented, with an increased risk of hematological diseases, malignancies, and lymphoproliferative disorders.Other changes that may accompany NX are neutropenia, hypocomplementemia, cryoglobulinemia, or hyperlipidemia. Associated diseases include multiple myeloma, chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, asthma, and Quincke's edema.The differential diagnoses for NX include lipoid necrobiosis, juvenile xanthogranuloma, annular granuloma, foreign body granuloma, subcutaneous rheumatoid nodules, xanthomas , amyloidosis, and Erdheim\u2013Chester disease.In histopathology, NX shows typical areas of necrobiosis surrounded by granulomas composed of giant Touton cells, foamy histiocytes, and giant foreign-type giant cells, as well as lymphocytes, compromising the entire dermis.In the pathogenesis of NX, it is suggested that serum immunoglobulins bind to lipids, depositing in the skin, which would provoke a foreign body reaction. Another hypothesis is that paraprotein would bind the Fc portion of IgG by activating a secondary proliferation of macrophages. It has also been proposed that the paraprotein in NX has the functional characteristics of a lipoprotein that can bind to histiocyte lipoprotein receptors and induce granuloma formation.Treatment options include immunomodulatory drugs, immunosuppressive agents, corticosteroids, alkylating agents, plasmapheresis, and radiotherapy.None declared.Isaura Azevedo Fasciani: composition of the manuscript.Neusa Yuriko Sakai Valente: statistical analysis, approval of the final version of the manuscript; participation in the design of the study; critical review of the literature.Maria Claudia Alves Luce: conception and planning of the study.Priscila Kakizaki: approval of the final version of the manuscript; participation in the design of the study; critical review of the manuscript.None declared."}
+{"text": "Helicobacter pylori and Malassezia, among others). The oncobiomes from long- and short-term survivors of pancreatic adenocarcinoma are different and transplantation of the microbiome from long-term survivors into animal models of pancreatic adenocarcinoma prolongs survival. The oncobiome in pancreatic adenocarcinoma modulates the inflammatory processes that drive carcinogenesis. In this review, we point out that bacterial metabolites  also have a role in the microbiome-driven pathogenesis of pancreatic adenocarcinoma. Finally, we show that bacterial metabolism and the bacterial metabolome is largely dysregulated in pancreatic adenocarcinoma. The pathogenic role of additional metabolites and metabolic pathways will be identified in the near future, widening the scope of this therapeutically and diagnostically exploitable pathogenic pathway in pancreatic adenocarcinoma.Pancreatic adenocarcinoma is one of the most lethal cancers in both men and women, with a median five-year survival of around 5%. Therefore, pancreatic adenocarcinoma represents an unmet medical need. Neoplastic diseases, such as pancreatic adenocarcinoma, often are associated with microbiome dysbiosis, termed oncobiosis. In pancreatic adenocarcinoma, the oral, duodenal, ductal, and fecal microbiome become dysbiotic. Furthermore, the pancreas frequently becomes colonized (by  Pancreatic adenocarcinoma stems from the exocrine glands and ducts of the pancreas and usually appears in the head of the pancreas 2/3 of cases). Pancreatic adenocarcinoma is the fourth most prevalent cancer with the highest mortality in both men and women . Worldwi of casesCurative surgical treatment can only be achieved in 15\u201320% of patients with pancreatic adenocarcinoma, due to the spreading of the disease around blood vessels, rendering patients inoperable. Neoadjuvant therapy can reduce tumor size and enable surgical excision. The chemotherapy regimen to combat pancreatic adenocarcinoma includes nucleoside analogs , antimetabolites (5-fluorouracil), topoisomerase inhibitors (irinotecan), taxanes -paclitaxel), and platinum compounds  ). ChemotKRAS were identified in approximately 80% of pancreatic adenocarcinoma cases [BRCA1, TP53, and a set of other DNA repair factors [Environmental risk factors for pancreatic adenocarcinoma include smoking, alcoholism, chronic or recurrent pancreatitis, obesity, and diabetes mellitus . Geneticma cases . Recent  factors .The microbiome shows characteristic changes in neoplastic diseases; the transformed microbiome, a characteristic of neoplasia, is termed the oncobiome ,16,17,18Hanahan and Weinberg ,32 coineSustained inflammation and the consequent oxidative stress can lead to DNA damage and genomic instability, which are risk factors for accumulating mutations and, subsequently, for carcinogenic transformation ,37,38. AThe oncobiome usually has a different immunogenic character than the normal microbiome (eubiome), as oncobiosis alters the immune system . The tolSeveral studies have shown that oncobiotic transformation supports cellular proliferation, invasion, and metastasis ,23,24,25What are the elementary steps behind these processes? Bacterial metabolites modulate the redox balance of cancer cells ,34, as wWhat can cause oncobiotic transformation or, in general, changes to the microbiome? Among the factors inducing oncobiosis, lifestyle plays a key role, including activities such as smoking , diet, oHelicobacter pylori colonization was associated with pancreatitis [The relationship between the microbiome and pancreatic adenocarcinoma was first suggested by the discovery that reatitis . This wareatitis , gut [64reatitis ,65,66, areatitis ,67 microreatitis , and panEnterobacter, Enterococcus, and E. coli bactibilia [Kras\u2212/\u2212Tp53\u2212/\u2212 model), the food microbiome can also invade the pancreas [According to our current understanding, elements of the oral, gastric, and intestinal microbiome can drive inflammation, which is a risk factor for carcinogenesis in the pancreas. In brief, the oral, gastric, and duodenal flora can colonize the common duct, the bile duct, and the pancreatic duct and, finally, the pancreas itself, as shown in a series of animal and human studies ,78,79,80ctibilia ,92,93,94ctibilia . In a mupancreas . The patpancreas . Similarpancreas , while bpancreas  or ampicpancreas ) were prpancreas . Furtherpancreas ,91.The main findings concerning the oncobiome in pancreatic adenocarcinoma are summarized in Porphyromonas gingivalis increased in pancreatic adenocarcinoma [Helicobacter pylori [Enterobacter, Enterococcus [Fusobacteria [E. coli [Fusobacteria count in tumors was higher compared to the healthy, untransformed tissues [Malassezia, also increased in pancreatic adenocarcinoma patients [Some bacterial species showed a strong association with pancreatic adenocarcinoma. In the oral microbiome, arcinoma ,85,101. r pylori ,69,70, Erococcus ,90,92,93bacteria ,94,102, [E. coli ,93 were patients . The orapatients . In factpatients , poor orpatients , or recuPrevotella, Hallella, and Enterobacter [Pancreatic bacterial invasion predominantly induces persistent inflammation. Both the innate and adaptive immunity participate in recognizing pancreatic bacteria and orchestrating the subsequent inflammatory reaction ,40. The robacter ) increasrobacter . TLR actrobacter .Besides the direct immunogenicity of the microbiome, an endocrine-like function was also described in several cancers ,106,107 The gut microbiome harbors a large number of species with an immense and diverse metabolism. Bacterial metabolites or components of bacteria can enter the systemic circulation of the host and be transferred to distant sites where the metabolites can exert hormone-like effects ,30,108. Enterobacteriaceae  and Borrelia burgdorferi [Short chain fatty acids (SCFAs), namely acetate, propionate, butyrate, and lactate, are derived from non-digestible carbohydrates by bacterial saccharolytic fermentation ,110. Thegdorferi ,114,115.gdorferi .Bacteroidetes primarily produce acetate and propionate, while Firmicutes chiefly produce butyrate [Akkermansia muciniphila has a pivotal role in propionate synthesis through the degradation of mucin [Lachnospiraceae, Ruminococcus obeum, and Roseburia inulinivorans produce propionate through the degradation of deoxy sugars , while Bacteroidetes and Negativicutes use hexoses to produce propionate [Phascolarctobacterium spp., Dialister spp., Veillonella spp., Salmonella spp., Megasphaera elsdenii, and Coprococcus catus [Lactobacillus spp., Bifidobacterium spp., Akkermansia muciniphila, Bacteroides spp., Prevotella spp., Ruminococcus spp., and Streptococcus spp [Odoribacter, Anaeotruncus, Faecalibacterium prausnitzii,Eubacterium rectale, Roseburia faecis, Clostridium leptum, Coprococcus eutactus, Faecalibacterium prausnitzii, Eubacterium rectale, Anaerostipes caccae, Eubacterium hallii, and an unnamed cultured species SS2/1 [SCFA production is common among bacteria. butyrate . Akkermaof mucin . Lachnosopionate . Other pus catus ,121. Aceccus spp . The bules SS2/1 ,123. TheThe human serum reference concentrations of SCFAs fall into the range of 10\u2013100 \u00b5M ,135,136.Acetate can ameliorate pancreatitis and its sequels, and, hence, protect against a risk factor of pancreatic adenocarcinoma . AcetateChenodeoxycholic acid (CDCA) and cholic acid (CA) are primary bile acids, which are mainly synthesized in the liver; however, extrahepatic tissues  can contribute to this synthesis . PrimaryBacteroides fragilis, Bacteroides vulgatus, Listeria monocytogenes, Clostridium, Lactobacillus, and Bifidobacterium possess bile salt hydrolases [Firmicutes , Bacteroides, and Escherichia, while dehydroxylation is linked to Clostridia and Eubacteria [The primary-to-secondary bile acid conversion is linked to the gut microbiome. Primarily, colonic bacteria are responsible for bile acid conversion; nevertheless, upper segments of the gastrointestinal tract may also play a role in bile acid transformation. Deconjugation takes place first, followed by oxidation, dehydroxylation, and epimerization. Deconjugation is catalyzed by bile salt hydrolases. drolases ,128,129.bacteria ,126,128.bacteria .Takeda G Protein-Coupled Receptor 5/G-protein-coupled bile acid receptor (TGR5), constitutive androstane receptor (CAR), vitamin D receptor (VDR), and pregnane X receptor (PXR). These receptors are nuclear receptors, except for TGR5. Through these receptors, bile acids impact on immune responses, gastrointestinal mucosal barrier function, gestation [Bile acids have multiple receptors, including farnesoid-X-receptor (FXR), liver-X receptor (LXR), estation , carcinoestation ,34, and estation ,159.Enterococci are considered bile acid resistant bacteria, which may explain the reports showing increased abundance of this bacteria in pancreatic adenocarcinoma [Bile acid homeostasis is largely hampered in cancer and metabolic diseases . Originaarcinoma ,90,93.Bile acid levels were reported to increase in pancreatic adenocarcinoma. A study comprised of 15 patients with pancreatic cancer and 15 patients with benign disease showed increasing trends in all bile acid species detected in pancreatic cancer patients. Increases in unconjugated bile acid levels in pancreatic adenocarcinoma patients were significant and surprisingly large (26 fold) .Most bile acids have a carcinogenic role in pancreatic adenocarcinoma. Bile acids modulate risk factors for pancreatic adenocarcinoma; bile acids impact pancreatitis and bile acid efflux disorders, type II diabetes, obesity, and hyperlipidemia. Furthermore, bile acids reduce susceptibility to apoptosis, induce inflammatory mediators, and may perturb membranes and cellular movement (reviewed in ). GallstExpression levels for VDR , FXR 19, and PXRPolyamine metabolism is dysregulated in pancreatic adenocarcinoma . The funE. coli, Enterococcus faecalis, Staphylococcus aureus, Haemophilus influenzae, Neisseria flava, Pseudomonas aeruginosa, Campylobacter jejuni, Yersinia pestis, Vibrio cholerae, Bacteroides dorei, Bacteroides thetaiotaomicron, Bacteroides fragilis, Bacillus subtilis, and Proteus mirabilis were shown to produce, accumulate, or need/use polyamines [Enzymes of the polyamine pathway had been identified in numerous species. However, the functional characterization of polyamine biosynthesis is limited to a few species . E. colilyamines ,130,131.Shigella flexneri, Shigella sonnei, Escherichia coli, and Streptococcus possess enzymes for cadaverine biosynthesis [E. coli [Cadaverine is a decarboxylation product of lysine and the bacterial enzymes LdcC and CadA are responsible for cadaverine biosynthesis ,203. Botynthesis . Putresc[E. coli . Polyami[E. coli .A metabolomic and metatranscriptomic study of the fecal microbiome from a murine pancreatic adenocarcinoma model  showed tLipopolysaccharides, lypoglycans, or endotoxins are components of the bacterial outer membrane in Gram-negative bacteria ,205. AltPrevotella, Hallella, and Enterobacter) increases [In pancreatic adenocarcinoma-associated oncobiosis, the proportion of LPS producing bacteria Clostridium sporogenes and Ruminococcus gnavus possess enzymes for tryptophan decarboxylation [The decarboxylation of tryptophan yields tryptamine. xylation .(2)Tryptophanase deaminates tryptophan to indole pyruvic acid, which is then metabolized to indole. Indole can be further oxidized and the subsequent conjugation of sulphate yields indican. Tryptophanase, denoted as TnaA, can be found in the tryptophanase operon . Tryptop(3)Lactobacillus, Clostridium, and Bacteroides [Indole pyruvic acid can be decarboxylated to indole acetaldehyde. Indole acetaldehyde can be converted to tryptophol or indole acetic acid. Indole acetic acid can be decarboxylated to yield skatole or conjugated with glutamine to yield indole acetic acid-glutamine. The main genera for this pathway are teroides .(4)The reduction of indole pyruvic acid yields indole lactate, the dehydration of which yields indole acrylic acid. This compound can be reduced to indole propionic acid. Indole propionic acid can be further converted by human enzymes.Tryptophan is an amino acid with a very complex and intricate metabolism, in which bacterial metabolism plays a major role. A considerable portion of tryptophan, 4\u20136%, is metabolized by bacteria to yield indol derivatives . In germLactobacillus reuteri and inhibit the growth of pathogenic bacteria [Lactobacillus utilizes tryptophan as an energy source [Tryptophan-derivatives (indoles) are ligands for the aryl hydrocarbon receptor (AHR) and can also bind to the PXR receptor ,215,216.bacteria ,220,221.y source .Although direct data are missing for the effects of indole-derivatives in pancreatic adenocarcinoma, the invasive behavior of pancreatic adenocarcinoma cells can be modulated through the selective AHR modulators, Omeprazole and Tranilast . FurtherTo date, two studies reported in silico reconstruction of metabolic pathways of the microbiome in pancreatic adenocarcinoma. These data identify bacterial metabolites that potentially influence pancreatic adenocarcinoma cells or carcinogenesis itself, thus, we review these data and provide a list in Mendez and colleagues  reportedThe second study was a prospective study of 85 pancreatic adenocarcinoma patients and 57 matched healthy controls in which the fecal microbiome was assessed . A decreAs we noted earlier, certain studies assessing the oncobiome in pancreatic adenocarcinoma came to the conclusion that the composition of the oral ,88,223, Most studies mentioned above had low patient numbers (tens of patients to a few hundred) and, therefore, did not reach the level of statistical significance. When already existing shotgun sequencing data of tumor DNA was assessed for the presence of bacterial DNA detected statistically , counts As the detection of pancreatic adenocarcinoma is difficult at early (curable) stages, early detection through detecting oncobiotic transformation has clear advantages for patients. The choice of antibiotics used for premedication before surgical excision of pancreatic adenocarcinoma can also be based on the composition of the pancreatic microbiome .Oncobiosis in pancreatic adenocarcinoma is a complex process, involving multiple microbiome compartments, including the oral, gastric, duodenal, ductal, pancreatic, and fecal compartments. The bacterial colonization of the pancreas drives inflammation and probably facilitates the initiation and progression of the disease to determine the aggressiveness of the disease. Furthermore, there seems to be a large set of bacterial metabolites released into the circulation or tumor microenvironment that has direct effects on the behavior of pancreatic adenocarcinoma cells .The involvement of bacterial metabolites is just coming of age in the microbiome field. In other cancers, the involvement of the microbiome has gained ground quickly and holds promise for new treatment modalities ,225. StuEstablishing the causative role of oncobiosis in pancreatic adenocarcinoma will facilitate the assessment of how antibiotics, probiotics, or prebiotics may modulate the behavior of the disease in analogy to other diseases and studies ,227,228."}
+{"text": "Xu et\u00a0al.), basal angiosperms , monocot , basal eudicot , core eudicot , Lamiids  and Campanulids , etc. These research findings provide rich compound and pharmacological activity data for further exploration on pharmacophylogeny, facilitating the analysis of distribution patterns of various medicinal compounds and pharmacological activities on the phylogenetic tree ; many alkaloids of these sub-groups are solely found in different species complex of Aconitum. Morphologically, Paeoniaceae was thought to be close to Ranunculaceae , while some phenolics and flavonoids such as antioxidants kaempferol and quercitrin are ubiquitously found in numerous taxonomic groups . Both Verbenaceae and Lamiaceae belong to the order Lamiales, but the former is closer to Martyniaceae , possibly due to the actions of flavonoids, steroids, prenol lipids and macrolides, etc., whereas many Ajuga species (Lamiaceae) are employed in Traditional Chinese Medicine (TCM) for relieving cough, reducing sputum, and arresting bleeding .Pharmacophylogeny suggests that curative plants of the related taxonomic groups are more likely to possess the analogous chemical profiles/efficacies, which is supported by the cross-cultural patterns  and ethnlkaloids , and areculaceae , but molculaceae . Phytochyniaceae , while tJuniperus is rich in diterpenes, triterpenes, phenolic acids, flavonoids and lignans , which could be responsible for its anti-inflammatory, antioxidant, antiviral, antibacterial, hypotensive, anticancer, antidiabetic, and neuroprotective properties. Juniperus is closer to Cupressus, and it is expected that they share some bioactive phytometabolites, which warrants further studies. In the coming years, pharmacophylogeny and pharmacophylogenomics could be more powerful in mining natural products, refining ethnopharmacology understandings, therefore promoting the sustainable conservation and utilization of longstanding/natural pharmaceutical resources.Currently, pharmacophylogeny is very useful in expanding medicinal plant resources , authentAjuga based on the whole chloroplast (cp) genome sequences . The Lamiaceae genus Ajuga has around 40-50 species, and 18 are distributed in China , Polygonatum cyrtonema and P. sibiricum , Paeonia ostii  and many Lamiaceae species. The active components of TCM and natural medicine are not limited to specialized metabolites  plants , e.g., Cabolites . Many cuHu et\u00a0al.). Given that some closely related species may exhibit similar behavioral/defense traits , integrating ecological and evolutionary factors helps to gain a more comprehensive understanding of phytochemical changes in changing environments. Pharmacophylogeny successfully guides the development of novel curative taxa (In summary, according to pharmacophylogeny, taxa in sister phylogeny groups have closely related genetic features ; they arive taxa , while cD-CH: Conceptualization, Writing \u2013 original draft. Y-XW: Formal Analysis, Writing \u2013 original draft. C-NH: Writing \u2013 review & editing. RS: Writing \u2013 review & editing."}
+{"text": "Objectives: High-touch surface (HTS) cleaning is critical to prevent healthcare-associated infections. However, HTS definitions and cleaning frequency vary across guidelines. We conducted a scoping review of published guidelines on HTS definitions and recommended cleaning frequency in inpatient wards. Methods: We searched national and societal guidelines on Google and PubMed using the following search terms: . We compared the guidelines\u2019 HTS definitions, recommended cleaning frequency, and supporting evidence. Results: In total, 9 environmental cleaning guidelines were included: Centers for Disease Control and Prevention (CDC 2020); Asia Pacific Society of Infection Control (APSIC 2013); International Society for Infectious Diseases (ISID 2018); Joint Commission Resources (JCR 2018); National Health Service, United Kingdom (NHSUK 2021); Public Health Agency, Northern Ireland (PHANI 2016); Public Health Ontario, Canada (PHOC 2018); National Health and Medical Research Council, Australia (NHMRC 2019); Ministry of Health, Singapore (MOH 2013). These 6 guidelines identified 31 types of HTS: bed rails and frames [mentioned by 6 of 6 guidelines]; call bells, doorknobs and handles (5 of 6 guidelines); bedside tables and handles, light switches, overbed and tray tables, and sinks and faucet handles (4 of 6 guidelines); chairs and chair arms, edges of privacy curtains, IV infusion pumps and poles, keyboards, medical equipment, monitoring equipment, and telephones (3 of 6 guidelines); assist bars, counters, elevator buttons, toilet seats and flushes, transport equipment, and wall areas around the toilet (2 of 6 guidelines); and bedpan cleaners, beds, blankets, commodes/bedpans, dispensers, documents, mattresses, monitors, mouse, pillows, and touch screens (1 of 6 guidelines). The JCR, NHMRC, NHSUK guidelines did not define HTSs. The 6 guidelines recommended at least daily cleaning for HTSs, but ISID, JCR, and NHSUK guidelines did not mention HTS cleaning frequency. The CDC guidelines further specified at least once daily cleaning for inpatient wards and private toilets and twice daily for public or shared toilets. None of the guidelines cited any references for HTS cleaning frequency recommendations. Conclusions: There is no uniformity in HTS definitions among 6 guidelines, and the recommended HTS cleaning frequency in these guidelines was not supported by published evidence. Studies exploring optimal cleaning frequency of HTSs are needed."}
+{"text": "Precision and organization govern the cell cycle, ensuring normal proliferation. However, some cells may undergo abnormal cell divisions (neosis) or variations of mitotic cycles (endopolyploidy). Consequently, the formation of polyploid giant cancer cells (PGCCs), critical for tumor survival, resistance, and immortalization, can occur. Newly formed cells end up accessing numerous multicellular and unicellular programs that enable metastasis, drug resistance, tumor recurrence, and self-renewal or diverse clone formation. An integrative literature review was carried out, searching articles in several sites, including: PUBMED, NCBI-PMC, and Google Academic, published in English, indexed in referenced databases and without a publication time filter, but prioritizing articles from the last 3 years, to answer the following questions: (i) \u201cWhat is the current knowledge about polyploidy in tumors?\u201d; (ii) \u201cWhat are the applications of computational studies for the understanding of cancer polyploidy?\u201d; and (iii) \u201cHow do PGCCs contribute to tumorigenesis?\u201d The cell cycle is a series of events that occur to accurately replicate genetic material and cellular contents into daughter cells. This regulation is precisely monitored and controlled . NeverthPolyploidy, a cell that has three or more chromosomal sets , in cancFei et al. , GlassmaRecent data demonstrated that PGCCs may form from oncogenic and therapeutic stress, generating reprogrammed cancer cells  and beinBharadwaj et al. , MirzayaNumerous studies have begun to use high throughput approaches through multiple techniques, including next generation sequencing (NGS), multi-omics, and phylostratigraphy, among others. Additionally, this review seeks to integrate theories, show different hypotheses, emphasize the need for multidisciplinary and collaborative approaches, demonstrate possible therapeutic options, and highlight the impact of ploidy on different stages of carcinogenesis. Our goal is to discuss the following questions: (i) \u201cWhat is the current knowledge about polyploidy in tumors?\u201d; (ii) \u201cWhat are the applications of computational studies for the understanding of cancer polyploidy?\u201d; and (iii) \u201cHow do PGCCs contribute to tumorigenesis?\u201dCell cycle deregulation and/or failures in mitosis can lead to polyploidy, the upregulation of genes that positively impact the cell cycle progression, and cytostatic genes downregulation ,28 in phPolyploid cells are vulnerable during meiosis due to chromosome pairing difficulties and genomic instability ; this caPGCCs have been observed for at least 180 years in diverse cancer types ,37,38,39PGCCs are a special subpopulation of tumor cells containing a large cytoplasm and multiple nuclei , undergoStress factors such as chemotherapy, antimitotic drugs, radiotherapy, hypoxia, or a deficient microenvironment may induce PGCCs formation  by meansThere is a correlation between endoreplication cell cycles and the amount of DNA replication mistakes, followed by complete dedifferentiation. In parallel, cell division stagnation reflects the degree of tumor malignancy . As a reGenotoxic agents used in cancer therapy are associated with the induction of cell stress, ploidy, and cell size variation; these can lead to the generation of 3D structures similar to a blastocyst ,45. ThesPGCCs can rejuvenate by way of amitotic division, generating cancer stem cells like blastomeres, that may transdifferentiate into different lineages, while the mother cell retains undifferentiated cancer properties .The diversity of PGCCs functions suggests polyploidy as an evolutionary source of tissue regeneration and plasticity, being explored by cancer cells to promote survival  and streThe Warburg effect is the utilization of aerobic glycolysis for ATP synthesis, despite having abundant oxygen available. PGCCs probably use a Warburg effect similar to the embryo in state of pre-implantation by means of glucose repression of oxidative phosphorylation, as seen in the yeast Crabtree effect. The occurrence of polyploidy or aneuploidy in PGCCs ends up passing through gene losses that could alter the relative amount of enzymes favoring glycolysis, and, consequently, investing in rapid cell division ,52.The functionalities developed by the PGCCs also influence tumor resistance and recurrence; these are still big challenges for modern therapies, especially because they can produce stem cells able to repopulate the tumor microenvironment .Thus, polyploid tumor cells can be used as a molecular model for better understanding fundamental evolutive paradigms ,55; evolTumor evolution is a process by which tumor cells change across time, acquiring advantageous characteristics for their survival and perpetuation, surviving immune attack, drug treatments, and diverse anti-proliferative signals ,58. Key PGCCs also share features of the Mendel and McClintock models , showingIn parallel to this mechanism of ploidy regulation, numerous other processes are shared by PGCCs, including endoreplication (endocycle and endomitosis), cell fusion, cytokinesis failure, cell cannibalism (entosis), emperipolesis, reductive mitosis, budding, fragmentation, nucleophagy, and sporulation , leading to a quite unlimited potential for PGCCs to resist extinction and achieve immortalization ,62, as sVladimir Niculescu has also highlighted the potential of \u201cpre-existing PGCCs\u201d (before response to therapies) that can turn into multinucleated genome repair structures (MGRNs) and, subsequently, originate PGCCs ,63,64.Liu  suggestsExperimental studies with tumor cell lines suggest that targeted PGCCs therapies in cancer may be more efficient than conventional therapies. Even under similar stresses, PGCCs may exhibit tumor specific features and responses, which are shown below according to tumor type:Lin et al.  showed tLopez-S\u00e1nchez et al. , Zhang eQu et al.  and Liu Tagal and Roth  and GlasWhite-Gilbertson et al. ,80, workZhang et al. , Lv et aZhang, Mercado-Uribe, and Liu , Fei et Ultimately, the primary purposes of tumor polyploidization are to activate survival and aggressiveness (metastasis).Autophagy seems to be involved in the generation of PGCCs, since autophagy inhibitors before chemotherapy decreases the formation of PGCCs . This prSenescence and PGCCs have been related through comparative transcriptome studies, revealing the altered expression of meiotic cell cycle genes, spermatogenesis, and EMT ,88. SeneCellular damage triggered by genotoxic stress induces senescence which, under the influence of senescence-associated secretory phenotype (SASP) and immune response evasion, facilitates reversible polyploidy through mitotic slippage, circumventing mitotic catastrophe and terminal senescence, followed by endoreplication and damage repair; this, in turn, directs new polyploid tumor cells to generate aneuploid offspring ,50. Ther2 and traditional cancer treatments for PGCCs induction [Histological, physiological, and morphological PGCCs studies used (i) CoClnduction ,91; (ii)nduction ,93;  database, Yan et al.  analyzedIn addition, Wang et al.  investigAnother comparative study using bioinformatics for transcriptome analysis of polyploid versus diploid cells from normal mammalian tissues highlighted a potential downregulation of circadian clock genes by c-Myc (a cell cycle regulator), whereas polyploidization correlated with deletion of bivalent genes responsible for circadian rhythm regulation .Structural variants (SVs) are crucial to understanding cancer polyploidy. Kosugi et al.  evaluateIn addition to such basic research applications, computing linked to tumor polyploidy also highlights new paths for clinical studies and strengthened by the advancement of high-throughput technology integration. Among the main computational approaches, machine learning algorithms stand out , showinghttps://clinicaltrials.gov (accessed on 15 February 2023), only two studies were found for the terms \u201ccancer\u201d and \u201cpolyploidy\u201d. The distribution of clinical trials around the globe demonstrated a study recruiting patients (USA) and another already completed (Germany), confirming that research on PGCCs needs to be further developed worldwide.In a search on polyploidy clinical trials around the world at the website Although there are still obstacles to the implementation of computational PGCC analyses in clinical practice, some tools demonstrate new trends towards faster and more personalized diagnoses and treatments . In addiMultiple analyses, including multi-omics, comparative phylostratigraphy, mathematical modeling, and others, will provide a better understanding of cell subtype and state. The computational era has provided simulation tools to better understand cell-to-cell interactions in normal and altered cell cycles, relying on specific and detailed cell cycle models, with the aim of understanding the dynamics of tumor formation and the potential outcomes associated with polyploidy . Such inAs highlighted in this review, advances in computing permeate artificial intelligence approaches, machine learning algorithms , personaApplications of systems biology, computational biology, and bioinformatics, as shown by the studies in Research with artificial intelligence will embody the personalization of prevention, diagnosis, and therapy ,166. NewIn addition, machine learning will provide new answers for studies in oncology and tumor polyploidy , and will further extend its sophisticated approaches with studies in microrobotics for cell manipulation ,169, ploComputational tools provide ideal support for understanding self-organization in face of cellular chaos, linked to the complex genomic functioning of the polyploid cells ,173. SinPolyploidization in tumors runs through multiple mechanisms phylogenetically shared between unicellular and multicellular organisms, resulting in evolutionary advantages for the tumor, thus reverberating an intrinsic complexity that is highly difficult to access through isolated studies. Thus, the need for integrated and multidisciplinary approaches capable of elucidating polyploidy in tumors becomes clear. Computational biology, bioinformatics, NGS, single-cell analysis, multi-omics studies, and systems biology reveal a growing and promising potential in the understanding of polyploidization as well as its innovative potentials to create personalized, comprehensive, and multifactorial therapies in cancer treatment."}
+{"text": "Simple liver cysts are common, and usually benign and asymptomatic, requiring little to no treatment. Liver cysts with biliary communication, however, are rare and require effective treatment to avoid recurrence.A 70-year-old woman with breast cancer visited our hospital for treatment. Physical examination revealed abdominal distension and bilateral lower leg edema.Abdominal contrast-enhanced computed tomography revealed a giant liver cyst, inducing inferior vena cava compression that was causing her edema.Percutaneous transhepatic cyst drainage was performed. Since the bilirubin level in the drained fluid was high, the patient was diagnosed with a liver cyst with biliary communication. After the procedure, her symptoms improved and the cyst decreased in size. However, the drainage volume did not decrease after approximately 2 weeks. Sclerotherapy with minocycline was ineffective. Thus, endoscopic retrograde cholangiopancreatography was performed, and an endoscopic nasobiliary drainage tube was inserted. The percutaneous drainage tube was clamped, and the cyst showed increase in size. Therefore, endoscopic ultrasound-guided cyst drainage, which is less invasive than surgery, was performed.The cyst tended to decrease in size even after the percutaneous drainage tube had been removed. At 3years follow-up, the cyst has almost disappeared.Endoscopic ultrasound-guided drainage can treat liver cyst with biliary communication. However, liver cysts with biliary communication are rare, and in some cases, patients are symptomatic. Trauma, percutaneous drainage, or infection of the cysts can cause communication between the liver cysts and the bile duct. Symptomatic treatment is necessary for abdominal pain, jaundice, and other complications of infection. The most commonly performed interventions are percutaneous drainage, sclerotherapy with minocycline, and endoscopic transduodenal papillary drainage. Surgical treatment may be considered for cases that fail to improve after initial intervention.3, high C-reactive protein level of 1.08 mg/dL, and a low albumin level of 2.3 mg/dL. Abdominal contrast-enhanced computed tomography (CT) revealed a large cyst in the liver and significant ascites fluid accumulation , a normal white blood cell count of 5200/mmion Fig. . Althoug-7 it has been associated with a high recurrence rate.,9 Sclerotherapy with ethanol or minocycline hydrochloride is indicated for cases that do not improve with percutaneous drainage. However, the recurrence rate of liver cysts following percutaneous drainage is high, regardless of additional sclerotherapy, and some patients eventually require surgical treatment.,8Simple liver cysts are typically detected as an incidental finding on abdominal imaging. Most of these cysts are benign, present asymptomatically, and require no treatment. For symptomatic patients, various treatments, including percutaneous drainage, cystojejunostomy, deroofing or excision of the cyst, partial liver resection, and endoscopic drainage are indicated. Although percutaneous drainage is the most common treatment for liver cysts, In our case, ERCP and endoscopic nasobiliary drainage tube placement was performed, but proved ineffective. Surgical treatment was then performed. Deroofing of the cyst is the standard treatment for cases of solitary cysts or polycystic liver diseases without malignancy or biliary communication because of its simplicity, effectiveness, and low morbidity rate.-13 Previous reports have discussed the usefulness of laparoscopic deroofing for liver cysts with biliary communication. However, it proved to be inappropriate for cases with biliary communication because the bile ducts would need to be treated to prevent postoperative bile leakage, with treatment of the bile ducts possibly leading to hepatic resection.,14,15 In this case, since early breast cancer treatment was preferred, minimally invasive EUS-guided drainage was performed.ERCP has been reported to be an effective treatment option for liver cysts with biliary communication that were unresponsive to percutaneous drainage.,16 However, there have been no reports describing EUS-guided drainage of a liver cyst with biliary communication, such as in our case. In most cases involving EUS-guided drainage of liver lesions, the puncture route was through the stomach, and plastic or metal stents were used. In other cases, nasal drainage tubes were used (Table ,33 In our case, no serious adverse events occurred. There have been few reports of complications, including death after EUS-guided drainage due to bleeding. Although safe and effective, the procedure is technique sensitive, and should be performed by a skilled endoscopist.There have been some reports on the drainage of liver lesions, liver cysts without biliary communication, liver abscesses, and bilomas. The long-term efficacy and safety of EUS-guided drainage for simple or infected liver cysts has also been reported.,16,34 In our case, sclerotherapy using minocycline was ineffective. Therefore, EUS-guided ethanol injection was not performed. More than 3 years have passed since the end of treatment, with no recurrence or complications.Another reported treatment, involving EUS for liver cysts, is EUS-guided ethanol injection, which is effective and less invasive for simple liver cysts. However, ethanol injection therapy is not recommended for liver cysts with biliary communication.In conclusion, EUS-guided cyst drainage is an effective, minimally invasive treatment for liver cysts with biliary communication that were unresponsive to conventional treatments, such as percutaneous drainage, sclerotherapy, and endoscopic transpapillary drainage.th Japan Gastroenterological Endoscopy Society Kanto Chapter meeting held at Tokyo Medical University Hospital on December 4 and 5, 2021.This paper is based on the oral presentation at the 113Conceptualization: Kento Shionoya, Kazuya Koizumi.Data curation: Kento Shionoya.Investigation: Kento Shionoya, Kazuya Koizumi, Sakue Masuda, Yuma Suno, Jun Kawachi, Karen Kimura, Makomo Makazu, Jun Kubota, Takashi Nishino, Chihiro Sumida, Junichi Tasaki, Chikamasa Ichita, Akiko Sasaki, Hiroki Hadano, Makoto Kako.Supervision: Kazuya Koizumi.Writing - original draft: Kento Shionoya.Writing - review & editing: Kazuya Koizumi."}
+{"text": "Malaria, a highly perilous infectious disease, impacted approximately 230 million individuals globally in 2019. Mosquitoes, vectors of over 10% of worldwide diseases, pose a significant public health menace. The pressing need for novel antimalarial drugs arises due to the imminent threat faced by nearly 40% of the global population and the escalating resistance of parasites to current treatments. This study comprehensively addresses prevalent parasitic and viral illnesses transmitted by mosquitoes, leading to the annual symptomatic infections of 400 million individuals, placing 100 million at constant risk of contracting these diseases. Extensive investigations underscore the pivotal role of traditional plants as rich sources for pioneering pharmaceuticals. The latter half of this century witnessed the ascent of bioactive compounds within traditional medicine, laying the foundation for modern therapeutic breakthroughs. Herbal medicine, notably influential in underdeveloped or developing nations, remains an essential healthcare resource. Traditional Indian medical systems such as Ayurveda, Siddha, and Unani, with a history of successful outcomes, highlight the potential of these methodologies. Current scrutiny of Indian medicinal herbs reveals their promise as cutting-edge drug reservoirs. The propensity of plant-derived compounds to interact with biological receptors positions them as prime candidates for drug development. Yet, a comprehensive perspective is crucial. While this study underscores the promise of plant-based compounds as therapeutic agents against malaria and dengue fever, acknowledging the intricate complexities of drug development and the challenges therein are imperative. The journey from traditional remedies to contemporary medical applications is multifaceted and warrants prudent consideration. This research aspires to offer invaluable insights into the management of malaria and dengue fever. By unveiling plant-based compounds with potential antimalarial and antiviral properties, this study aims to contribute to disease control. In pursuit of this goal, a thorough understanding of the mechanistic foundations of traditional antimalarial and antidengue plants opens doors to novel therapeutic avenues. Mosquitoes, those seemingly innocuous insects, hold the dubious distinction of being humanity's most formidable adversaries in the realm of public health. These tiny vectors, belonging to the Diptera Culicidae family, are the harbingers of a multitude of diseases that strike with devastating impact. Among their cargo are notorious maladies such as dengue, yellow fever, chikungunya, encephalitis, West Nile virus, and Zika virus. These infectious scourges have morphed into substantial threats, especially in equatorial regions, wreaking havoc not only on human lives but also on economies. Annually, more than 700,000 lives succumb to the relentless onslaught of vector-borne illnesses \u20133.In the face of these mosquito-transmitted diseases, the absence of effective vaccines and specific antiviral medications leaves a void eagerly waiting to be filled. Herein lays the promise of natural compounds. With their anticipated minimal side effects, widespread availability, and potential efficacy, natural compounds emerge as beacons of hope, particularly for economically challenged nations . Numerou\u03b1) [In in vitro tests involving THP-1 cells treated with papaya leaf extract (PLE), the antiviral activity was evident, leading to a notable reduction in viral load and an increase in the expression of type I interferon (IFN-\u03b1) . Through\u03b1) , 7. The \u03b1) , 8.As we grapple with the emergence of drug-resistant Plasmodium strains, the battle against malaria has taken on even greater urgency. Over the past two decades, research into alternative antimalarial strategies has gained momentum. Novel therapeutic targets for both treatment and prevention are becoming increasingly vital in our fight against this relentless adversary. Medicinal herbs, with their repository of natural products, have been foundational in traditional medicine for centuries. Indian systems of medicine, such as Ayurveda, Siddha, and Unani, boast a rich history of utilizing these natural products. These systems, which have evolved into well-organized and regulated practices, have significantly contributed to antimalarial medications, yielding compounds such as quinines, triterpenes, lapinone, quassinoids, and artemisinin . The stuAedes aegypti, a prominent vector, thrives in and around polluted environments, often taking refuge amidst man-made refuse and exclusively seeking human blood [A. aegypti and A. albopictus. These vectors, in addition to transmitting dengue, also serve as carriers for the Zika virus and are associated with other diseases such as chikungunya and yellow fever. Dengue fever casts its ominous shadow primarily over tropical regions, with varying degrees of risk dictated by factors such as rainfall, temperature, and unchecked urban expansion. The severity of the virus, manifested as dengue haemorrhagic fever (DHF), has made dengue a significant cause of suffering and death among both children and adults in several Asian and Latin American nations [an blood . In the an blood . The pri nations . The den nations , 8.Plasmodium vivax, Plasmodium falciparum, Plasmodium malariae, and Plasmodium ovale. Each year, this disease claims the lives of over 400,000 individuals and afflicts an estimated 219 million people worldwide. Tragically, the majority of fatalities involve children under the age of five [Plasmodium vivax and Plasmodium falciparum [P. falciparum stands out as the most ominous, capable of causing severe infections that, if left untreated, can escalate into the deadliest form of the disease [Malaria, a potentially life-threatening malady, is inflicted by an array of parasites, including lciparum . Within Against this backdrop, this study aims to delve into the rich repository of medicinal plants used in the treatment of malaria and dengue fever in humans. The exploration of plant-based compounds with antimalarial and antiviral properties holds immense promise, paving the way for novel therapeutics in the fight against these formidable diseases.In recent decades, the global prevalence of dengue fever has surged, with alarming statistics painting a grim picture. Current estimates suggest that approximately 390 million dengue infections occur each year, spanning a wide range from 284 to 528 million, with around 96 million cases exhibiting varying degrees of clinical symptoms . ShockinIt is worth noting that before 1970, dengue outbreaks were confined to just nine countries. However, since 2010, this insidious disease has spread its tendrils to over a hundred countries within the WHO region. The reported cases have ballooned, escalating from 2.2 million in 2010 to a staggering estimated 3.2 million in 2015  , South-East Asia (6%), and the Eastern Mediterranean (3%) [The specter of malaria continues to cast a long shadow over public health, with numbers that demand attention. Back in 1990, approximately 75 million Indians stood at high risk of contracting malaria, while another 240 million lived under moderate risk, and a staggering 500 million had a relatively low risk . This foThe past few years have witnessed an extraordinary surge in the utilization of traditional and complementary medicine on a global scale. These therapies have not only found their place in the hearts of communities but have also made profound inroads into modern healthcare systems. The statistics paint a vivid picture: nearly 80% of Africa's population now relies on traditional medicine as their primary healthcare . In ChinThe trend is not limited to specific regions; it is a global phenomenon. Approximately 48% of individuals in Australia, 70% in Canada, 80% in Germany, 42% in the United States, 39% in Belgium, and a striking 76% in France have reported using traditional or complementary medicine at least once , 19. In But what lies at the heart of this resurgence of interest in traditional medicine? It is not merely a return to ancient practices; it is a testament to the growing recognition of the holistic benefits these therapies offer. The increasing use of traditional medicine has transformed healthcare systems, offering a holistic approach that addresses not only physical ailments but also mental and spiritual well-being \u201319. In aThe Indian system of medicine (ISM) boasts an impressive arsenal of approximately 25,000 effective plant-based formulations. These remedies have long been the trusted choice of rural and ethnic communities in India, and their popularity is steadily growing among the general population. The demand for these medicinal plant materials is substantial, with an estimated yearly requirement exceeding 2,000 tonnes. In this vast landscape, over 1,500 herbal products are available as dietary supplements or traditional ethnic treatments, and many are marketed commercially [Amid this flourishing industry, about 960 species of medicinal plants actively participate in commerce, with 178 of these species having an annual consumption exceeding 100 metric tonnes. The economic significance of this sector is profound, with approximately INR 80\u201390 billion traded within the AYUSH  sector domestically and an additional INR 110 billion exported from India in the form of medicinal plants and allied items. Although there was a slight decrease in exports in the financial year 2013-2014 compared to the previous year, INR 24,741.2 crores worth of goods were exported in 2012-2013. Remarkably, the AYUSH items constituted 0.36% of India's overall commerce in 2013-2014. Against the backdrop of this expansive growth, it is noteworthy that the global herbal trade is projected to reach an astonishing $7 trillion in sales worldwide by the year 2050 .Asparagus adscends has many medicinally significant compounds that date back to ancient times, including vasicine and vasicinone, derived from Adhatoda vasica, Homoharringtonine, obtained from Cephalotaxus, morphine, and Camptothecin, discovered in Camptotheca acuminate, Bacosoids, extracted from Bacopa monnieri, Codeine, derived from Papaver somniferum, Tylophorine, found in Tylophora indica, Sarsasapogenin, Asparanin A, and Asparanin B, and isolated from Asparagus adscendens. Likely, some of the findings [Acacia catechu, Trigonelline is found in Trigonella foenumgraecum, Shatavarin, obtained from Asparagus racemosus, Glycyrrhizin, extracted from Glycyrrhiza glabra, Atropine, found in Atropa belladonna, cocaine, derived from Erythroxylum coca, Tinosporic acid, discovered in Tinospora cordifolia, Sophoradin, obtained from Sophora subprostrata, Aloin, derived from Aloe vera, Quinine, derived from Cinchona spp., Protodioscin, discovered in Tribulu sterrestris, Aegelin, and marmelosin, isolated from Aeglemarmelos, Withanolides, obtained from Withania somnifera, Plumbagin, found in Plumbago indica, Arjunolic acid, derived from Terminalia arjuna, Jatamansone, found in Nardostachys jatamansi, Quassinoids, obtained from Ailanthus spp., Asiaticoside, found in Centella asiatica, Boeravinones, discovered in Boerhavia diffusa, Curcumin, extracted from Curcuma longa, Forskolin, extracted from Coleus forskohlii, Paclitaxel, extracted from Taxus baccata and Taxus brevifolia, Gingerols, found in Zingiber officinale, Emetine, derived from Cephaelis ipecacuanha, Digoxin and digitoxin isolated from Digitalis lantana, Dysobinin, obtained from Dysoxylum binectariferum, Psoralen, extracted from Psoralea corylifolia, Nimbidin, found in Azadirachta indica, Berberine, derived from Berberis aristate, Allicin, obtained from Allium sativum, Podophyllin, derived from Podophyllum emodi, Pilocarpine, derived from Pilocarpus jaborandi, Vinblastine and vincristine, extracted from Catharanthus roseus, and Diosgenin, found in Dioscorea spp. and many more [It is becoming more popular to conduct drug discovery studies using botanicals traditionally employed in various Indian healing traditions. As a result of employing natural substances as a starting point, several new medications have been found. Such a study relied heavily on investigations both in India and overseas. findings \u201325 are sany more , 25. MorAccording to World Health Organization (WHO) information from December 2008, certain African and Asian countries heavily rely on the use of conventional treatment as their main healthcare system due to its economic limitations and geographic restrictions . NaturalEuphorbia hirta and Uvaria chamae are used to treat dengue disease in the Philippines by rural residents [E. hirta leaves may cure the viral disease and prevent the fever from advancing into severe stages, but no scientific investigations have shown its efficacy [E. hirta and papaya leaf extract are combined to make E. hirta, which is employed as an antibiotic for treating fever. In addition to killing the germs that produce fever, E. Hirta and Aloe vera extracts help stop bleeding. Psidium guava leaves have also been reported to raise platelets, thereby reducing the risk of blood clots [The folk remedy esidents . Practitefficacy . In certod clots , 44. Guaod clots , 45. Accod clots , 47. DurNaphthoquinone lapichol, a natural substance, was also shown to be the active component in tree rind used to cure malaria [Artemisia annua, was originally identified in 1971, it contained the compound artemisinin. These long-acting, totally synthetic compounds derived from a unique endoperoxide group are now under clinical development [To comprehend the origins of antimalarial chemotherapy, it is essential to delve into the historical background of herbal medicines. Antimalarial chemotherapy was first made possible by the discovery of Quinine, a natural compound extracted from the bark of the Cinchona tree and subsequently refined in 1820 . To manu malaria . It was  malaria . When thelopment  and may Phyllanthus emblica, Phyllanthus acidus, and Leucas aspera leaf ethyl acetate and methanolic extracts showed potential antiplasmodial action against CQ-sensitive (3D7) and CQ-resistant (D2) strains of P. falciparum, according to the research [Murraya koenigii and showed potential activity against P. falciparum (3D7) and in vivo mice infected with P. berghei (NK65) strains [Toddalia asiatica's root leaves, bark, and fruits in ethyl and methanol demonstrated effective antimalarial activity against P. falciparumCQ-sensitive (D6) and CQ-resistant (W2) strains [Aegle marmelos, Lantana camara, Leucas aspera, Momordica charantia, Phyllanthus amarus, and Piper nigrum extract showed the highest activity against CQ-sensitive 3D7 and CQ-resistant INDO strains of P. falciparum [Dicoma tomentosa, has good in vitro antiplasmodial activity against P. falciparum strains CQ-sensitive and CQ-resistant (3D7 and W2), respectively. Good antiplasmodial activity against the CQ-resistant (2/K1) strain of P. falciparum was found in the methanol extracts of the leaves and stems of Chrozophora oblongifolia, Ficus ingens, Plectranthus barbatus, and Lavandula dentate [More than a few nations in Africa, the Americas, and Asia have long relied on botanicals to cure malaria . There iresearch . The pro strains . Extract strains . Aegle mlciparum . It was  dentate .Anopheles stephensi mosquitoes transmit P. falciparum, which causes chikungunya, dengue, malaria, yellow fever, Zika fever, Japanese encephalitis, and lymphatic filariasis among other awful illnesses, to humans [Artimisia nilagirica leaf filtrate-based biological silver nanoparticle manufacturing might be a viable green larvicidal option for the control of mosquitoes throughout the development phases of the malaria vector A. stephensi and the dengue vector Aedes anaxyrus [A. stephensi larvae and pupae were killed by both the Ulva lactuca extract and the green-synthesized AgNP, both of which were examined [A. stephensi mosquitoes, which cause malaria, as well as their larvicidal efficacy against A. stephensi larvae [Suaeda maritima-synthesized AgNP demonstrated larvicidal and pupicidal effects against the dengue vector Aedes aegypti [Sargassum wightii extract and ZnO NP exhibited larvicidal and pupicidal toxicity against the malaria vector Aedes stephensi. As of 2018, Nalini et al. [Cleistanthus collinus and Strychnos nuxvomica plant leaf extracts which were used to create metallic silver nanohybrids (AgNPs) against chikungunya, dengue, and Zika vectors. According to Murugan et al. [Belosynapsis kewensis leaf extracts. Bhuvaneswari et al. [Culex quinquefaciatus was studied via the production of silver nanoparticles from aqueous leaf extracts of Leucas aspera and Hyptis suaveolens, respectively, and their ability to reduce C. quinquefaciatus to silver nanoparticles [Annona squamosa contain isoamyl acetate, which has larvicidal properties against mosquitoes that transmit dengue fever (Aegypti) and filariasis (C. quinquefaciatus). [Artemisia vulgaris might be used to make gold nanoparticles [A. aegypti, an old Indian medicinal plant called Pedalium murex was used to produce silver nanoparticles [o humans . Many aro humans . This eno humans  . , 118. Enarticles , 120. Agarticles , 121. InNatural products continue to serve as an abundant and untapped reservoir of chemical diversity, offering potential as a primary origin for the emergence of new therapeutic agents to address various health conditions, including infectious disorders. New approaches to combating dengue and malaria might result from accepting and validating traditional medicinal methods and hunting for plant-derived medications. So, the hunt for innovative and, if possible, low-cost medications must continue. Dengue and malaria parasites, which are becoming harder to treat because of resistance to currently available treatments, must be eradicated via the development of safe and economical drugs. The customary use of many plants and their preparations in various areas of India for dengue and malaria has been documented. Indian researchers employed a comprehensive approach, including clinical trials and in vivo and in vitro studies, to scientifically validate emerging herbal alternatives to examine their effectiveness against dengue viruses and malarial parasites. Dengue and malaria-fighting plants have received very few such scientific validations in India. Only a few herbs and extracts have been professionally researched and shown to be effective. For antidengue and antimalarial effectiveness and safety to be confirmed, more local herbal formulations need to be sought after, documented, and scientifically validated. This will help us better understand how these formulations work. If the appropriate steps of product creation, validation, and value addition are followed, herbal formulations already used by communities and healers could potentially offer alternative and supplementary therapies."}
+{"text": "An estimated 85% of research resources are wasted worldwide, while there is growing demand for context-based evidence-informed health policymaking. In low- and middle-income countries (LMICs), research uptake for health policymaking and practice is even lower, while little is known about the barriers to the translation of health evidence to policy and local implementation. We aimed to compile the current evidence on barriers to uptake of research in health policy and practice in LMICs using scoping review.The scoping review followed the Preferred Reporting Items for Systematic Review and Meta-Analyses-extension for Scoping Reviews (PRISMA-ScR) and the Arksey and O'Malley framework. Both published evidence and grey literature on research uptake were systematically searched from major databases , Global Health (Ovid)) and direct Google Scholar. Literature exploring barriers to uptake of research evidence in health policy and practice in LMICs were included and their key findings were synthesized using thematic areas to address the review question.A total of 4291 publications were retrieved in the initial search, of which 142 were included meeting the eligibility criteria. Overall, research uptake for policymaking and practice in LMICs was very low. The challenges to research uptake were related to lack of understanding of the local contexts, low political priority, poor stakeholder engagement and partnership, resource and capacity constraints, low system response for accountability and lack of communication and dissemination platforms.Important barriers to research uptake, mainly limited contextual understanding and low participation of key stakeholders and ownership, have been identified. Understanding the local research and policy context and participatory evidence production and dissemination may promote research uptake for policy and practice. Institutions that bridge the chasm between knowledge formation, evidence synthesis and translation may play critical role in the translation process.The online version contains supplementary material available at 10.1186/s12961-023-01084-5. Globally, an estimated 85% of research resources are wasted due to errors, exaggeration and inefficiency , 2. ContAbout 42% of research resource waste is avoidable through simple and inexpensive intervention . HoweverAbout 40\u201390% of research published from trials is not replicable \u201317, and Research evidence is vital for policymaking, and the role of researchers in translating research evidence into policymaking is crucial . Power rWhat is the available evidence on barriers to uptake of research for policymaking in LMICs?What are the challenges to research uptake for policymaking process in LMICs?What recommendations might strengthen evidence uptake for policymaking in LMICs?The scoping review followed the Preferred Reporting Items for Systematic Review and Meta-Analyses-extension for Scoping Reviews (PRISMA-ScR) \u201333 and tRelevant publications on research uptake for policymaking were identified from major databases , Global Health (Ovid), and direct search of Google Scholar and other sources, including sharing of high-quality evidence via email from authors and senior researchers. Only publications since 2000 were considered due to the growing interest in evidence-informed policy making over the last two decades . LiteratDocuments written in EnglishPublished and relevant grey literature on evidence uptake to policy strategiesEvidence related to research uptake challenges and opportunities in LMICs. The LMICs were selected based on the World Bank\u2019s country classification .Editorials, commentaries, fact sheets, conference abstracts and case-studies.Publications were retrieved from selected databases, recorded using citation manager (EndNote), and duplicates were removed. Two authors (AS & EG) independently screened the title and abstracts of retrieved publications against the eligibility criteria, and based on review questions. Further appraisal assessed the methodological quality and findings before any article was included into the scoping review. Any disagreement between the two independent reviewers was resolved through consensus. If consensus was not reached, two of the senior authors (AF & TM) made a final decision based on the predetermined eligibility criteria. The screening and selection process of the scoping review was guided by the PRISMA flow diagram  Fig.\u00a01)1).Fig. 1Basic descriptions of the included studies, including authors, date, aim of the article, type of study, key findings and recommendation for action, were abstracted and recorded in a Microsoft Word table The challenges of research uptake for policymaking are presented thematically. Eight main themes emerged: understanding context, stakeholder engagement and partnership, building trust and ownership, research capacity, resource constraints and misuse of resources, platform for evidence production and translation, investment in research infrastructure development, and research uptake framework and accountability Fig.\u00a0. ThematiWe found over 30 papers on the importance of understanding the research uptake context , 145. ThPolitical dimension: Mapping the political dimensions and policy demand [y demand , 135\u2013138y demand , 147, poy demand , 130, any demand , 91, 131y demand , 135\u2013137y demand , 138 incy demand , lack ofy demand , 140, wey demand , 143\u2013145y demand , 147. Siy demand , bureaucy demand , leadersy demand , 105, aly demand , and noty demand , 150 arePriority setting: Priority setting [ setting , 29\u2013156  setting , 156 and setting , 153, an setting \u2013154, 156 setting , 156, an setting , 106. Pr setting , 146 mus setting , 153. Ne setting , 115, sc setting , 158 and setting , 155 are setting , 115. St setting , 159. Po setting .Leadership: Willingness and/or commitment of political leaders influence health research translation in LMICs [. Evidence-informed health policymaking relies on good leadership [in LMICs , 163. Evadership , 157, leadership , 163, deadership , 71. Lacadership , 81, pooadership , 121, anadership , 139 areadership  will heladership , 160. Laadership , 49, 125Engagement of key stakeholders is a crucial strategy in translation of evidence to policy , 159\u2013166Concerns about the quality of evidence have limited research uptake for policymaking , 156\u2013158Limited research capacity is a major challenge to research uptake for policymaking in LMICs , 162\u2013165The lack of skill that researchers have in research and translation , 146, anResource constraints are a major barrier to uptake of research for policy and practice in LMICs. , 165. UnResearch uptake for health policy and practice requires an enabling platform for research priority setting and dissemination of findings , 163, caResearch infrastructure development , 164, in. In addition, addressing bottle necks related to legal frameworks, policy, and system responses are critical to guide evidence use for policy [Developing a testable evidence uptake framework , 163 thar policy , 139. Enr policy , 139 is r policy , 113. Thr policy , 155, otr policy , 90, 155r policy , 88, 155We have identified several pieces of evidence that forward key recommendations , 160. WeEvidence-to-policy platform: Establishing knowledge translation platforms [latforms , 151, stlatforms , 81, andlatforms , 155 arelatforms , 157, anlatforms , 149 areRecognize context: Understanding political dimension and contexts [contexts , 160 andcontexts , 131 placontexts , addresscontexts , and idecontexts  are alsocontexts .Collaboration and stakeholders engagements: Engagement of stakeholders is a critical step in establishing strong multisectoral collaborations and partnerships and has a key role in improving evidence uptake for policymaking [cymaking , 162. Stcymaking , 112, focymaking , 153, stcymaking , 122, incymaking , 157, ancymaking  are robucymaking , 101, ancymaking , 164. Stcymaking , 158.Advocacy and ownership: Building a sense of ownership through co-production of evidence [evidence \u2013159, 164evidence  are esseevidence , 152, glevidence , 120 andevidence , 91, 120evidence , 76, 87 evidence , 163, stevidence , 159, anevidence , 92, 155evidence .Invest in research: Investments in research infrastructure to strengthen and sustain institutional research capacity [capacity , 158 wilcapacity , mobilizcapacity , 91, 130capacity , supportcapacity , 87, 138capacity , are sugcapacity  and engacapacity , 147 maycapacity , 163 is capacity , 130, stcapacity , and undcapacity . Establicapacity , 157, crcapacity , 158, anEndogenous capacity building: establishing a contextual model for capacity development will help to drive evidence uptake for policymaking [cymaking , 163. Recymaking , 164 andcymaking , 83 playcymaking , 157 is Considerable amount of evidence relevant to translation of evidence into policymaking in LMICs was identified. We found that the common barriers to research uptake are lack of understanding political dimension, low government priority, poor engagement of stakeholders, low investment in research, capacity and resource constraints, lack of ownership and trust in domestic research products, lack of a guiding research uptake framework, and lack of platform to bridge the research uptake gap in LMICs. Mapping to identify the most common forms of research use involves the direct application of research to policymaking and practice , and priWe have identified common barriers limiting research uptake for health policymaking in low resource setting. Enhancing capacity for evidence-informed policy improves priority setting, filtration and amplification of evidence for policy-making and practice . InstituWe identified key recommendations to improve research uptake for health policymaking in LMICs. Establishing evidence translation platforms, improving health policy research literacy and understanding the political dimension and context \u2013174 are Research uptake for health policymaking requires strategies to contextualize and balance global and local health research findings, to understand the complexity of producing high-quality research  and to aStakeholder involvement will improve policy-maker confidence , 66, resThis scoping review has mainly focused on the translation of research evidence into policy. Evidence-informed practice was considered to be a manifestation of uptake; however, the evidence-to-policymaking process is far greater than evidence-informed practice or implementation.This scoping review identified challenges to evidence uptake and possible strategies through which this might be strengthened. A range of studies were identified, including primary studies, trials, and syntheses. Mapping the availability of quality evidence and recognizing challenges to evidence translation will enhance policymaking and practice. Dedicated centers or platforms appear likely to facilitate evidence uptake in real settings. Stakeholders in the research production and translation ecosystem should use pragmatic approaches to assess the political context and priorities, enhance collaboration, invest in research infrastructure development and adapt contextual pathways for evidence uptake. These finding will guide the focus of a Unit for Health Evidence and Policy (UHEP) which is being established to serve as a platform for evidence translation in Ethiopia and beyond. Establishing a platform to bridge the gap between researchers and policy makers is crucial to utilize available evidence for health policymaking and practice.We found substantial evidence on challenges to health research uptake for policymaking and practice in LMICs. Understanding of the national and international context and priorities, involving key stakeholders, resource and establishing a coordinating platform to facilitate capacity building, quality evidence production, communication and a framework for accountability are crucial to facilitate evidence uptake for policymaking. Barriers to poor evidence uptake for health policymaking have to be addressed through investing in research capacity building, partnership and stakeholder participation, co-mobilize resources, building trust and ownership on evidence production. This must be guided by a well-grounded theory of change framework to address barriers in LMICs. A platform for interaction and capacity building of key actors, including politicians, policy makers, academics, public health researchers and medical practitioners is essential to improve insight and establish a network for evidence sharing in LMICs.Additional file1. Completed- Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) Checklist.Additional file 2.\u00a0Literature search strategies.Additional file 3. Data charting."}
+{"text": "Flowers have played a significant role in society, focusing on their aesthetic value rather than their food potential. This study\u2019s goal was to look into flowering plants for everything from health benefits to other possible applications. This review presents detailed information on 119 species of flowers with agri-food and health relevance. Data were collected on their family, species, common name, commonly used plant part, bioremediation applications, main chemical compounds, medicinal and gastronomic uses, and concentration of bioactive compounds such as carotenoids and phenolic compounds. In this respect, 87% of the floral species studied contain some toxic compounds, sometimes making them inedible, but specific molecules from these species have been used in medicine. Seventy-six percent can be consumed in low doses by infusion. In addition, 97% of the species studied are reported to have medicinal uses (32% immune system), and 63% could be used in the bioremediation of contaminated environments. Significantly, more than 50% of the species were only analysed for total concentrations of carotenoids and phenolic compounds, indicating a significant gap in identifying specific molecules of these bioactive compounds. These potential sources of bioactive compounds could transform the health and nutraceutical industries, offering innovative approaches to combat oxidative stress and promote optimal well-being. Since time immemorial, flowers have played a fundamental role in society. They are appreciated for their beauty and used for ornamental purposes in various spaces, whether in pots, gardens, landscaping, or as cut flower arrangements in containers. Grown specifically for their striking appearance, distinctive foliage, and delicate fragrance, ornamental plants add charm and distinction to any environment. Their presence goes beyond mere aesthetics, as throughout history, flowers have been symbols of emotion, used in celebrations, expressions of love, condolences, and religious rituals, and providing benefits for emotional well-being and mental health .In recent years, the market for edible flowers has experienced remarkable growth. This phenomenon can be attributed to several reasons, including the increasing availability of information on their nutritional value and bioactive potential ,3. In adFlowers are used in gastronomy for their pigments , which improve the appearance of dishes , and forThis review aimed to collect relevant information on ornamental plant flowers with potential health promotion as botanicals, foods, or other uses, following sustainability principles and the circular economy. Plants from fifty families are covered, including Asteraceae, Lamiaceae, Fabaceae, and Malvaceae, as well as plants with edible flowers from the families Asteraceae, Apiaceae, Brassicaceae, Oleacaceae, Malvaceae, and Ranunculaceae. Therefore, Chamomilla recutita L.), whose dried flowers have been used since ancient times to treat menstrual disorders, insomnia, ulcers, haemorrhoids, and other ailments [Cannabis sativa L.), known for its soothing and anticonvulsant properties, has been used therapeutically in many cultures. This plant was even included in the British and later American pharmacopoeia but was eliminated in the 20th century because of concerns about the risk of abuse and intoxication [Achillea millefolium L., Arnica montana L., Bellis perennis L., Calendula officinalis L., Chamaemelum nobile (L.) All., Helichrysum stoechas (L.) Moench, and Taraxacum officinale L.) have been traditionally used in folk medicine for various therapeutic purposes [The use of flowers in food and medicine has a long history dating back to antiquity. The earliest records of these uses date back to 4000 BC in Mesopotamian and Egyptian cultures . An emblailments . Similarxication . Similarpurposes .Around 180 plant species belonging to 97 families have been reported as producing edible flowers . The useNowadays, thanks mainly to globalisation, the use of flowers in gastronomy is growing steadily . The incThanks to the undoubted increase in demand for edible flowers, there is a growing body of research on how to extend their shelf life and improve their overall quality by enhancing post-harvest treatments ,448,449.Several new food preservation technologies have been investigated to increase the shelf life of edible flowers. Among them are high hydrostatic pressure (HHP), irradiation, ultraviolet, ionising radiation, and new packaging alternatives ,4. On thEchium vulgare L.). Other examples of flowers that are not eaten whole include tulips (Tulipa spp.) and chrysanthemums (Chrysanthemum) , daisies (Bellis perennis L.) and garden nasturtium (Tropaeolum majus L.) (only the flower buds), and pumpkins (Cucurbita spp.) (only the tiny and undeveloped fruits with flowers) [Edible flowers are mainly used fresh as decoration or a garnish for some meals, such as salads or light curry, adding colour and fragrance. In addition, they are also used for other culinary purposes, such as ingredients in bread, pancakes, sauces, jellies, syrups, vinegar, honey, oils, soups, infusions, flower-scented sugars, candied flowers, cheeses, ice cream, crisps, juices, rice, cakes, butter, pasta, wine, and flavoured liqueurs. Edible flowers can even be consumed dried, in ice cubes in cocktails, directly as vegetables, or in stir-fried dishes ,4,12,454flowers) . InformaUsing flowers as food is not exclusively for aesthetic reasons; the nutritional contribution should also be considered. Flowers provide important elements for nutrition and health. Some flowers contain proteins, fats, carbohydrates, vitamins A, B, C, and E, mineral elements, and bioactives . The conThe presence of compounds with nutritional interest differs across floral structures. Pollen has high concentrations of proteins, amino acids, carbohydrates, and lipids, among other nutrients. Nevertheless, the amount of pollen in the flower is very small, and in addition, it has a flat taste without individual characteristics. Nectar, which typically has a sweet taste, contains a balanced mixture of sugars , amino acids (mainly prolin), proteins, inorganic ions, lipids, organic acids, alkaloids, etc. Lastly, the petals and the rest of the flower may also be significant sources of vitamins, minerals, and bioactive compounds ,444.Although before 2000, studies on edible flowers focused mainly on their nutrients, recent research has revealed the importance of studying compounds with bioactive properties. Phenolic compounds  and carotenoids are among the main bioactive compounds. The concentration of carotenoids and phenolic compounds in plants is detailed in Renealmia alpinia (Rottb.) Maas [These compounds usually account for their colour, either directly or indirectly through copigmentation ,6,447. Ib.) Maas .Both phenolic compounds and carotenoids have been attracting a great deal of interest in recent decades about their possible health-promoting biological actions , hence tPhytosterols (\u03b2-sitosterol), alkaloids, lignans, neolignanes, coumarins, and bisabolol oxides A and B are other phytochemicals distributed in edible flowers. However, these compounds are usually present in smaller concentrations ,447.Among the beneficial actions attributed to various flowers are antioxidants, anti-inflammatory, anti-carcinogenic, anti-obesity, hepatoprotective, neuroprotective, gastroprotective, antidiarrheal, anti-infective, antitumor, antispasmodic, analgesic, and astringent, among others ,12,465 . HoweverCosmos sulphureus Cav.), coral vine (Antigonon leptopus Hook. & Arn.), lesser bougainvillea (Bougainvillea glabra Choisy), jasmine, honeysuckle rose, cassia fistula, chives, calendula, and pomegranate [Some studies indicate that certain edible flowers can exhibit anti-carcinogenic activity against liver, colon, brain, skin, bladder, prostate, or breast cancers ,12,444. egranate ,467.Several flowers may exhibit anti-inflammatory activity. Examples are Roselle, Hangzhou white chrysanthemum, wild chrysanthemum, honeysuckle, and daylily. Antiobesity effects have been observed in flowers such as Roselle, magnolia, and waterlily. According to the literature, other beneficial effects that can be derived from the consumption of flowers include neuroprotective, visceral injury prevention, anti-diabetic, and antimicrobial effects, among others ,444,468.Hibiscus rosa-sinensis L., Chrysanthemum spp., Dahlia coccinea Cav., and Citrullus lanatus (Thunb.) Matsum. & Nakai, could protect against diseases linked to obesity , neurological (Alzheimer and Parkinson) [Others, such as rkinson)  and liverkinson) .Tagetes erecta L.), can act as a filter that protects the macula from blue light and oxidative damage. Thus, various studies have suggested that they could reduce the risk of ocular pathologies, especially age-related macular degeneration [Finally, the carotenoids lutein and zeaxanthin, present in high concentrations in the petals of the tagete flowers (neration . These cneration . InformaErythrina species (4.9 and 6.3 trypsin inhibitors/mg sample) caused by alkaloids by cooking the flowers and eliminating the cooking water [Although there is a wide variety of edible flowers, care must be taken since some flowers are poisonous or contain antinutrients. In any case, it is essential to consider that there are some techniques that people have learned over the years to eliminate or diminish antinutrients and toxic compounds. For example, people reduce the toxicity of flowers from ng water .Adonis aestivalis L.), which contains cardioactive steroids resembling digitalis, or Chrysanthemum (Chrysanthemum species), which contains sesquiterpene lactones [Amaranthus hybridus (500.0 mg Pb/kg plant) and Medicago sativa L. (720.0 mg Pb/kg plant), species used for phytoremediation processes  [Regarding the possible effects of the toxic flowers, these can vary from minor effects on the skin  to death when ingested. The toxicity of plants is mainly due to compounds such as alkaloids, tannins, alcohols, phytotoxins, glycosides, resins, nitrites, photosensitising substances, and calcium oxalates. Toxic compounds may be present in plants naturally or due to environmental pollution , living agents, or diseases . Examplelactones . Informalutants) . On the lutants) .Rosa usually contain high levels of tannins, such as gallotannins and ellagitannins. The flowers of Woodfordia fruticosa Salisb. (0.2 g/100 g DW) and Ensete superbum (Roxb.) Cheesman (0.003 g/100 g DW) also have tannins [E. superbum (0.1 g/100 g DW), decreases the bioavailability of some minerals and proteins, but its content can be reduced by processing [Parkia biglobosa, usually consumed in Nigeria; E. superbum (0.03 g/100 g DW); and Woodfordia fruticosa (0.06 g/100 g DW) [A. xalapensis [A. salmiana and Y. filifera [Antinutrients are substances that have a negative impact on our nutrition by preventing the absorption or assimilation of a nutrient or inactivating its effect . Some an tannins ,473 Phyt00 g DW) . Lectinslapensis . Saponinfilifera . In any filifera . InformaFlowers can become alternative sources of health-promoting dietary sources and sustainably contribute to food security, as suggested in an insightful review that addresses important topics of the 17 goals of the United Nations to transform our world included in the 2030 Agenda for Sustainable Development . The agrTaking advantage of biodiversity  is very important in this scenario. Biodiversity for food and agriculture is a subset that contributes directly and indirectly to agri-food. It encompasses \u201cdomesticated plants and animals raised in crop, livestock, forest, and aquaculture systems; harvested forest and aquatic species; wild relatives of domesticated species; other wild species harvested for food and other products; and what is known as \u2018associated biodiversity\u2019, the wide range of organisms that live in and around food and agricultural production systems, sustaining them and contributing to their production. Agriculture is considered here to include crop and livestock production, forestry, fisheries, and aquaculture. The importance of biodiversity in this context is at different levels, as many untapped edible species are very nutritious, are adapted to diverse edaphoclimatic conditions, and provide important ecosystem services . FlowersFood production is estimated to account for ~40% of land and 70% of freshwater use, which are precious and increasingly scarce resources. Therefore, contamination of soil and water is an important problem. More specifically, the elevated presence of heavy metals, other minerals, or organic pollutants in soils used for food production is an important environmental problem, a great threat to life on earth, and poses health risks when they enter the food chain. Being non-biodegradable, heavy metals accumulate in the environment and enter the food chain. This is undesirable from environmental and health standpoints, as some heavy metals are carcinogenic, mutagenic, teratogenic, and endocrine disruptors, while others cause neurological and behavioural changes. Naturally present or derived from anthropogenic sources, such metals can be reduced using physical and chemical approaches. However, these are costly and laborious and can lead to disturbances in physicochemical and microbial soil characteristics. Phytoremediation is gaining importance due to its public acceptance, efficiency, cost-effectiveness, and eco-friendliness. It can also reduce organic pollutants such as polynuclear aromatic hydrocarbons, polychlorinated biphenyls, and pesticides .Tagetes erecta, Calendula officinalis, and Chrysanthemum indicum) have been reported to tolerate heavy metal soil pollution [It uses green plants and associated microbes to minimise the toxic effects of potential contaminants in the environment. There are several ways to remediate. Phytostabilisation or phytoimmobilisation refers to the decrease in the mobility or/and bioavailability of a metal, which impairs its leaching to water or its entry into the food chain. Once uptaken by roots, a specific heavy metal may either be phytoimmobilised there or translocated to aerial parts. Phytovolatilisation involves the conversion of the metal into a volatile form and its release into the atmosphere through stomata. This technique is primarily helpful for Hg, although the volatilised metal can eventually return to the soil through precipitation. Phytodegradation is the degradation of organic pollutants by plants with the help of enzymes. Rhizodegradation refers to the breakdown of organic contaminants in the soil by microorganisms in the rhizosphere. Phytodesalination refers to the use of halophytic plants for the removal of salts from salt-affected soils to enable them to support normal plant growth ,479. Plaollution .Phytoextraction is considered the most important phytoremediation approach and can be more suitable for commercial applications. Ideally, plants selected for phytoextraction should be widely distributed, easy to cultivate, rapidly grow, produce important amounts of biomass, and be poly-harvest. About metals, they should be hyperaccumulators of heavy metals, translocate them from root to shoot, and tolerate their toxic effects well. Additionally, plants should be resistant to biotic stresses, well adapted to edaphoclimatic conditions, and not attractive to herbivores to avoid the entry of heavy metals into the food chain. Although promising, phytoremediation has yet to be widely used at a large scale due to limitations of diverse nature . New approaches are being evaluated, including assistance with chelators, biochar, bacteria, fungi, microbes, and transgenic plants ,480.Plant biomass enriched with phytoextracted heavy metals can be incinerated for energy and ash recovery. The latter can be considered bio-ore and be further processed for extracting heavy metals, a process called phytomining ,480.Phytoremediation has also been proven to be cost-effective and technically feasible in the remediation of heavy metal pollution in water quality issues, including wastewater treatment ,480. ReuAs can be seen in Although the uptake of heavy metals and other pollutants could sometimes affect the use of flowers for human consumption , others are feasible, including pot plants, cut flowers, essential oils, perfumes, air freshener production, metal phytomining, and feedstock in silk production .Kigelia africana flowers have also been studied as possible materials for the functional colouration of textile materials, with promising results in terms of fastness, colour strength, antibacterial, antioxidant, and UV-protection properties [The replacement of synthetic dyes with more natural alternatives in textiles is gaining acceptance to reduce the negative environmental impacts and toxicity associated with the latter. Besides, some natural extracts can exhibit properties , which can be interesting for developing functional fabrics with added value. The application of natural dyes in the textile industry is gaining popularity due to the increasing awareness of the environmental, ecological, and pollution caused by synthetic dyes. Different conditions of pH, temperature, salt, time, chemical levels, and biomordants have been tested for the dying of wool with rose flowers. As a result, different colour hues were obtained, some with good colour strength. . Kigeliaoperties .Waste jasmine flowers have recently been tested to produce bioethanol mediated by immobilised yeasts. Pretreatments that included alkalinisation, heating, and enzymatic hydrolysis were evaluated to favour the accessibility of the carbohydrate fraction, and response surface methodology was applied to assess the interactions of different variables to better understand the bioethanol yield .Saffron purple petals have been evaluated as a possible environmental-friendly additive for bentonite-based drilling fluids, and significant enhanced rheological, filtration, and corrosion protection properties were observed.Drilling fluids are circulated in boreholes to help perform an efficient drilling operation with minimal damage to prospective formations .Porous carbon nanosheets have been obtained from the carbonisation of a paper flower. The materials exhibited interesting properties for their potential use in energy storage and dye removal .Tagetes erecta, whose flowers are commercially exploited both for their exquisite ornamental beauty and for their remarkable lutein content, a valuable carotenoids widely used in industry as a dye and as a key component of health-promoting dietary supplements. In a similar context, the flowers of Renealmia alpinia have emerged as botanical gems, standing out as rich sources of provitamin A carotenoids such as \u03b1- and \u03b2-carotene [Flowers have played a fundamental role in human culture over the centuries, finding value in both their aesthetic appeal and their nutritional and therapeutic properties. A vivid example of this duality is theprized carotene ,366. Thicarotene . HoweverHowever, they can also be used for other purposes at different points in their life cycles, including as phytoremediators , dying a-How bioavailable are health-promoting compounds from flowers? And how do post-harvest, industrial, or culinary treatments affect such bioavailability? Can ingesting large amounts of flowers significantly raise plasma and tissue levels of health-promoting compounds?-Can post-harvest, industrial, or culinary treatments make potentially toxic flowers edible? Can biorefinery approaches be used to obtain added-value products from potentially toxic flowers?-What plants can be used for phytoremediation and to provide health-promoting rich flowers without posing health risks due to excessive accumulation of pollutants in edible parts?-What amount of floral waste is necessary for its alternative circular use to be economically viable? How can smaller amounts of waste be used alternatively?-What floral species can be used to cultivate areas with harsh edaphoclimatic conditions and/or enrich biodiversity by attracting pollinators?Some questions remain, such as:"}
+{"text": "PNAS Nexus, Volume 2, Issue 1, January 2023, pgac309, https://doi.org/10.1093/pnasnexus/pgac309This is a correction to: Kartik Shankar, Sumera A Ali, Meghan L Ruebel, Saleem Jessani, Sarah J Borengasser, Stephanie P Gilley, Puujee Jambal, Deaunabah N Yazza, Nicholas Weaver, Jennifer F Kemp, Jamie L Westcott, Audrey E Hendricks, Sarah Saleem, Robert L Goldenberg, K Michael Hambidge, Nancy F Krebs, Maternal nutritional status modifies heat-associated growth restriction in women with chronic malnutrition, PNAS Nexus, it was discovered that this paper was missing a statement acknowledging compliance with the PNAS Nexus Human and Animal Participants and Clinical Trials policy:During a retroactive audit conducted by Written informed consent was obtained from all participants prior to enrollment into the study. All study procedures and protocols were approved by the Colorado Multiple Institutional Review Board, University of Colorado, and the local and/or national ethics committees for each of the sites , and the Data Coordinating Center . The study was registered with clinicaltrials.gov (NCT01883193). Additionally, a federally constituted Data Monitoring Committee reviewed the study progress for safety, trial progress, data completion, supplement compliance, and protocol violations twice yearly. All study procedures are also described in detail in a previous publication describing the study protocol  and in Hambidge KM et al., 2019 Cited as ref 42; describing the primary outcomes of the trial.This error has been corrected in the original article."}
+{"text": "The development of Enhanced Recovery After Surgery (ERAS) has brought about substantial transformations in perioperative care, substituting conventional methods with a patient-centric, evidence-based strategy. ERAS protocol adopts a holistic approach to patient care, which includes all stages preceding, during, and following the operation. These programs prioritize patient-specific therapies that are tailored to their specific requirements. Nutritional assessment and enhancement, patient education, minimally invasive procedures, and multimodal pain management are all fundamental components of ERAS. ERAS provides a multitude of advantages, including diminished postoperative complications, abbreviated hospital stays, heightened patient satisfaction, and healthcare cost reductions. This article examines the foundational tenets of ERAS, their incorporation into the field of general surgery, their suitability for diverse surgical specialties, the obstacles faced during implementation, and possible directions for further investigation, such as the integration of digital health technologies, personalized patient care, and the long-term viability of ERAS protocols. The implementation of Enhanced Recovery after Surgery (ERAS) has significantly transformed perioperative care by introducing a patient-centric, evidence-based approach that has previously been unheard of. Historically, standard surgical procedures entailed extended bed rest, protracted fasting, and bowel preparation preceding the procedure. These measures resulted in complications, prolonged hospital stays, and increased healthcare expenditures. Since the late 1990s, ERAS protocols have become increasingly well-known, placing significant emphasis on the cooperative endeavors of a multidisciplinary group including dietitians, surgeons, anesthesiologists, and nurses. The principal aim of this collaborative endeavor is to enhance the quality of surgical care as a whole, including the preoperative, intraoperative, and postoperative stages, by emphasizing individualized treatment plans that address the specific requirements of each patient .,21.20,21Furthermore, variations within ERAS protocols are essential to accommodate the diverse demands of different surgical specialties and procedures. While the fundamental principles, including early mobilization, optimized nutrition, and individualized pain management, remain consistent, specific elements are tailored to suit each surgical context's unique requirements. This customization is especially pronounced in orthopedics, gynecology, urology, and cardiothoracic surgery. For example, urological surgery emphasizes early catheter removal, while orthopedic procedures prioritize rapid ambulation and specialized pain control, particularly in joint replacement surgeries ,23.Additionally, patient selection and individualization are pivotal aspects of ERAS. These protocols acknowledge that not all patients are ideal candidates and that a personalized approach is essential. Criteria for patient selection may encompass factors such as age, comorbidities, and psychosocial support, optimizing care based on each patient's unique needs. On the other hand, conventional healthcare may employ a standardized approach, disregarding the unique variances in patients' health conditions and social contexts. As a result, ERAS demonstrates a dedication to patient selection and individualization, which contributes to the provision of customized treatment. This approach eventually improves patient outcomes and enhances surgical experience .Future directions and research gapsIn the dynamic realm of ERAS, numerous nascent patterns are poised to influence the trajectory of surgical care in the foreseeable future. It is essential to highlight that patient-centered treatment is anticipated to be prioritized, specifically catering to each individual's unique preferences, values, and objectives. The implementation of personalization inside the ERAS framework has the potential to enhance patient satisfaction and engagement. Moreover, the adoption of digital health solutions, telemedicine, and wearable gadgets for remote monitoring and follow-up is becoming increasingly prominent. Real-time data gathering and communication can enhance the overall postoperative recovery experience. The concept of prehabilitation, which involves preparing patients physically and mentally before surgery, is likely to become a more integral part of ERAS, allowing patients to optimize their health and resilience for improved outcomes. Tailoring nutritional interventions based on a patient's genetic makeup, known as nutrigenomics, presents a promising avenue for enhancing postoperative recovery. Understanding how genetic predispositions influence nutritional needs can be a future direction. Furthermore, sustainability is emerging as a relevant consideration in ERAS, emphasizing adopting environmentally friendly practices, such as reducing single-use plastics and optimizing resource utilization, in alignment with broader sustainability goals ,26.In the realm of ERAS, several areas demand further research to advance our understanding and refine the implementation of these protocols. One such area pertains to the assessment of long-term outcomes. While numerous studies have focused on short-term results, investigating how ERAS impacts patients' quality of life, long-term complications, and disease-free survival in cancer patients is critical for a comprehensive understanding. Evaluating the cost-effectiveness of ERAS programs is another crucial avenue for research. This should encompass immediate healthcare costs, broader economic implications, and societal benefits. Research into the most effective strategies for implementing ERAS across diverse healthcare settings and surgical specialties is needed to overcome barriers and devise practical solutions. Additionally, optimizing pain management within ERAS, including exploring non-pharmacological interventions, is vital to reduce reliance on opioids and enhance patient comfort. A focus on the patient experience within ERAS offers valuable insights into tailoring care to individual needs and preferences, thus enhancing overall satisfaction and compliance.ERAS represents a transformative paradigm shift in perioperative care, offering a holistic and evidence-based approach to enhance patient outcomes and expedite postoperative recovery. By focusing on individualized care, multidisciplinary collaboration, and innovative strategies, ERAS has consistently shown its capacity to reduce complications, hospital stays, and healthcare costs while improving patient satisfaction and quality of life. Future research must explore long-term outcomes, cost-effectiveness, implementation strategies, pain management optimization, and patient experience to overcome challenges and refine ERAS implementation. As ERAS continues to evolve, patient-centered care, digital health integration, and sustainability practices are expected to shape the future of surgical care, ensuring that ERAS remains at the forefront of perioperative medicine."}
+{"text": "Considering the unique advantages of the quantum size, volume, surface, and macroscopical quantum tunnel effects, nanomaterials have been paid increasing attention for various applications in environmental, medical, biological, and chemical analyses in recent decades. Recently, nanomaterial-based electrochemical sensors and biosensors have been widely focused on, due to their outstanding properties in terms of conductivity, selectivity, and biocompatibility, as well as their cost-effectiveness ,2. In thIn this Special Issue, titled \u201cRecent Advances in Functional Nanomaterials for Electrochemical Sensors and Biosensors\u201d, eight contributions, including six original research papers and two review papers, were collected to showcase the recent advances in various functional nanomaterials for electrochemical sensors and biosensors.In one review, Soto and Orozco give a comprehensive review on recent advances in the applications of hybrid nanobioengineered nanomaterials in ultrasensitive electrochemical biosensors, mainly based on novel organic\u2013inorganic hybrids with enhanced electrophysicochemical properties, including some recently engineered organic\u2013inorganic metallic, silicon, carbonaceous, and polymeric nanomaterials . The limIn another review, Amen et al. present an overview of metal-oxide semiconductor field effect transistor biosensors for point-of-care testing devices . VariousWang et al. developed a simple strategy to prepare a biofilm reactor sensor for the determination of biochemical oxygen demand . In theiLi et al. constructed an ultrasensitive electrochemical biosensor for glypican-3 detection using the hemin-reduced graphene oxide-palladium nanoparticles and nanozyme-enhanced silver nanoparticles deposition signal amplification strategy . In theiWang et al. synthesized bismuth nanoparticles decorated with one-dimensional honeycomb-like carbon nanofibers for the sensitive determination of nitrite . In thei2+ quenching luminescence of functionalized carbon quantum dots [Zhang et al. synthesized porphyrin-functionalized carbon quantum dots through electrostatic interaction by a simple mixing method, which was used as a novel luminescent nanocomposite for the sensitive detection of copper ions in the Cutum dots . The conWang et al. developed a novel electrochemical sensor by electrodepositing polyglycine/reduced graphene oxide on a glassy carbon electrode for the simultaneously selective and sensitive determination of xanthine and hypoxanthine . By takiHuang et al. established a rapid detection method for rutin in food using nitrogen-doped carbon quantum dots as the fluorescent probe . In theiIn conclusion, this Special Issue aims to provide an overview of recent progress in applications of functional nanomaterials in electrochemical sensors and biosensors. As discussed above, various functional nanomaterials  have been synthesized and applied in constructing different electrochemical sensors and biosensors in the fields of environmental, biochemical, and pharmaceutical analyses. In fact, many techniques have been developed to synthesize functional nanomaterials to improve the sensitivity, biocompatibility, stability, and repeatability of electrochemical sensors and biosensors, including solvent-thermal, hydro-thermal, chemical vapor deposition, electrodeposition, and electrospinning methods. Despite some barriers and challenges, we believe that more functional nanomaterials with controllable and adjustable morphologies, structures, and properties will be designed, synthesized, and applied in fabricating electrochemical sensors and biosensors."}
+{"text": "Acute intermittent porphyria (AIP) is a rare genetic disorder that affects porphyrin metabolism in the blood. The disease causes defects in specific enzymes in the body, which in turn leads to the accumulation of porphyrin metabolites. Patients may experience abdominal pain, neurological symptoms, muscle pain, and nausea, but it does not directly cause pancreatitis.The patient is a young woman, 23 years old, who was admitted to our hospital with intermittent abdominal pain for 2 days, the pain was not fixed, episodic, with no obvious trigger, and 1 day before admission, the patient started to experience nausea and vomiting, with gastric contents as the vomitus, and similar symptoms had occurred many times in the past. Blood amylase 600 U/L, blood sodium 120.6 mmol/L, blood routine, and coagulation function results were normal; abdominal CT showed pancreatic swelling with unclear surrounding fat interstitial, acute pancreatitis was considered. The patient\u2019s urine was dark red, and the results of the qualitative urine porphyrin test were positive.AIP complicated with acute pancreatitis.Relief of symptoms, control of pain, correction of electrolyte disturbances, and high-carbohydrate therapy.The patient was discharged with complete symptomatic relief after 10 days of high-carbohydrate therapy.AIP complicated with acute pancreatitis is very rare. Treatment of AIPs aims to control acute attacks and prevent potential triggers. Porphyrins are chemicals produced in the body that are involved in oxygen transport by combining with iron ions in the blood to form hemoglobin. There are 2 main types of porphyria: acute and chronic. Acute porphyria are abnormalities in porphyrin metabolism due to defects in specific enzymes in the body; the most common type is acute intermittent porphyria (AIP).,4 Attacks of the disease are associated with abdominal pain, vomiting, and neurological symptoms, and may be misdiagnosed as other acute abdominal conditions. In severe cases, the disease may lead to damage to the heart, nervous system, and other organs, and may even be life-threatening. In this article, we report a rare case of AIP complicated with acute pancreatitis and analyze relevant literature.Porphyria are a group of inherited diseases caused by a disorder of porphyrin metabolism in the body.A 23-year-old woman presented to our hospital with intermittent abdominal pain for 2 days. The pain was not specific to any location and occurred in paroxysms without an obvious trigger. One day before admission, the patient began experiencing nausea and vomiting, with vomitus consisting of gastric contents. Similar symptoms had occurred in the past, but the patient denied any history of special diseases. On physical examination at admission, the patient showed mild tenderness throughout the abdomen without rebound tenderness or other positive signs. Laboratory tests revealed elevated serum amylase levels (600 U/L) and hyponatremia (serum sodium level of 120.6 mmol/L). Blood routine examination and coagulation function were normal. Abdominal CT revealed pancreatic edema and unclear surrounding fat interspaces, indicative of acute pancreatitis.The patient was diagnosed with acute pancreatitis and hyponatremia. Treatment included inhibition of pancreatic secretion, fasting, gastrointestinal decompression, intravenous nutrition, sodium supplementation , and analgesia. However, the abdominal pain did not significantly improve, although the nausea and vomiting subsided somewhat. reexamination showed a decrease in serum amylase to 200 U/L and an increase in serum sodium to 122.6 mmol/L. It was also observed that the patient\u2019s urine was dark red in color  and received opioid analgesics for pain management. Blood amylase levels were monitored and remained normal during treatment. After 10 days of high-carbohydrate therapy, the patient\u2019s symptoms completely resolved, and she was discharged from the hospital. In addition to AIP, there are 3 other genetic porphyrias that share a similar clinical presentation and are collectively referred to as acute hepatic porphyrias. These include delta-aminolevulinic acid dehydratase deficiency porphyria, hereditary coproporphyria, and variegate porphyria. Among these subtypes, AIP is the most common.AIP is a rare autosomal dominant genetic disease caused by a deficiency of the third enzyme in heme biosynthesis, hydroxymethylbilane synthase (HMBS), leading to the accumulation of the porphyrin precursors delta-aminolevulinic acid (ALA), and porphobilinogen (PBG). The toxic effects of these porphyrin precursors can result in a range of symptoms, with abdominal pain as the predominant feature, accompanied by various neurological and psychiatric manifestations. In young women, hormonal fluctuations and weight loss are identified as the primary triggers according to several studies.AIP is a rare autosomal dominant genetic disease characterized by recurrent acute onset. AIP attacks can be triggered by various factors such as surgery, certain medications, radiation exposure, pregnancy, menstruation, infection, and fasting. Acute abdominal pain is the most common and earliest symptom of AIP, with over 95% of Chinese patients presenting with this symptom.,10 AIP-induced abdominal pain is typically severe, persistent, and diffuse, accompanied by constipation, bloating, nausea, vomiting, and occasionally intestinal obstruction. Neurological and psychiatric abnormalities are also hallmark features of AIP acute attacks. These can be classified as central nervous system symptoms, peripheral nervous system symptoms, autonomic nervous system symptoms, and psychiatric symptoms. Central nervous system symptoms can manifest as seizures, altered consciousness, limb paralysis, respiratory failure, and coma. Peripheral nervous system symptoms often involve motor neuropathy and sometimes sensory abnormalities. Autonomic nervous system symptoms can cause hypertension, tachycardia, sweating, electrolyte imbalances, and hyponatremia. The mechanism of tachycardia may be related to sympathetic overactivity and increased catecholamine levels, while hyponatremia may result from hypothalamic impairment, abnormal antidiuretic hormone secretion, vomiting, inadequate sodium intake, and increased renal sodium excretion. Psychiatric symptoms can include emotional lability, depression, and anxiety, and a few patients may experience auditory or sensory hallucinations.The clinical features of AIP primarily include abdominal pain, neurological dysfunction, and psychiatric abnormalities.,13 Early diagnosis and standardized treatment are crucial for improving long-term prognosis. The diagnosis of AIP mainly relies on clinical manifestations and enzyme assays, with significant increases in urine ALA and PBG during acute attacks. Genetic testing is the gold standard for AIP diagnosis, but it is not yet widely available in most medical institutions, and the testing process is time-consuming, making timely diagnosis challenging. During acute attacks, patients\u2019 urine is often red or dark red due to the presence of large amounts of porphobilinogen, which turns into a characteristic burgundy color after exposure to sunlight, providing an important diagnostic clue.AIP is often accompanied by liver dysfunction, significantly increasing the risk of cirrhosis, liver cell carcinoma, and kidney failure.,15 High-carbohydrate therapy is the primary treatment for acute AIP attacks. Increased carbohydrate intake can interfere with ALAS1 transcription and inhibit the accumulation of related products in the body, thereby improving symptoms. Glucose can also stimulate insulin secretion, directly inhibiting ALAS1 expression.,18 In the acute phase of AIP attacks, a high-carbohydrate diet (300\u2013500\u2009g/d) is recommended. Heme is currently the only effective drug for AIP treatment. Heme not only downregulates ALAS1 transcription through negative feedback but also reduces hepatic ALAS1 levels by interfering with mRNA stability or blocking mature enzymes from entering the mitochondria. However, this drug is expensive, and its availability is limited in China due to the difficulty in diagnosing AIP. Therefore, it is not suitable as an experimental treatment for highly suspected patients. For acute pain caused by AIP, nonsteroidal anti-inflammatory drugs and opioids are effective, but their oral efficacy is poor. Gene therapy is currently the main research direction and hot topic in AIP treatment, mainly including gene supplementation therapy and gene silencing therapy. The former involves introducing wild-type HMBSmRNA into liver cells to increase PBGD protein levels significantly, while the latter involves introducing specific small interfering RNA (siRNA) into liver cells to silence ALAS1 mRNA, reducing ALA and PBG production.,21 Givosiran is a representative drug that has been studied in clinical trials and can rapidly and continuously reduce ALAS1 mRNA levels, decrease heme precursor levels, and reduce the incidence of acute attacks, with good clinical prospects.In terms of treatment, timely removal of trigger factors and symptomatic treatment are vital for controlling AIP attacks and improving prognosis. According to some studies, the use of ovarian function suppression drugs to block menstruation can effectively prevent AIP attacks in young women. Therefore, caution should be exercised when using high-carbohydrate therapy to avoid secondary damage to pancreatic function. Some studies have reported that some patients were diagnosed with AIP after negative exploratory surgery, indicating that clinicians should be aware of the possibility of AIP acute attacks when dealing with patients whose primary symptoms are acute abdominal pain, while also considering surgical indications.In this case, the patient presented with symptoms of acute pancreatitis, and relevant characteristics of the case met the diagnostic criteria for acute pancreatitis. Similar cases with AIP as the underlying cause are rare in China. AIP has complex and diverse clinical manifestations and lacks specificity, leading to high misdiagnosis and missed diagnosis rates of up to 70%.Conceptualization: Cheng Jiao, Wei Liu, Jin-Hui Chen, Jun Guo, Yi-Ming Qiao.Data curation: Wei Liu, Jun Guo, Yi-Ming Qiao.Funding acquisition: Cheng Jiao, Wei Liu, Jun Guo, Yi-Ming Qiao.Methodology: Cheng Jiao, Wei Liu, Jun Guo, Yi-Ming Qiao.Project administration: Cheng Jiao.Resources: Cheng Jiao, Wei Liu, Jin-Hui Chen, Jun Guo, Yi-Ming Qiao.Software: Cheng Jiao.Supervision: Cheng Jiao, Wei Liu, Jun Guo.Validation: Cheng Jiao, Jin-Hui Chen, Yi-Ming Qiao.Writing \u2013 original draft: Cheng Jiao.Writing \u2013review & editing: Wei Liu."}
+{"text": "This narrative review delves into the potential of artificial intelligence (AI) in predicting, stratifying risk, and personalizing treatment planning for congenital heart disease (CHD). CHD is a complex condition that affects individuals across various age groups. The review highlights the challenges in predicting risks, planning treatments, and prognosticating long-term outcomes due to CHD's multifaceted nature, limited data, ethical concerns, and individual variabilities. AI, with its ability to analyze extensive data sets, presents a promising solution. The review emphasizes the need for larger, diverse datasets, the integration of various data sources, and the analysis of longitudinal data. Prospective validation in real-world clinical settings, interpretability, and the importance of human clinical expertise are also underscored. The ethical considerations surrounding privacy, consent, bias, monitoring, and human oversight are examined. AI's implications include improved patient outcomes, cost-effectiveness, and real-time decision support. The review aims to provide a comprehensive understanding of AI's potential for revolutionizing CHD management and highlights the significance of collaboration and transparency to address challenges and limitations. Congenital heart disease (CHD) is a complex condition affecting various age groups, with up to 4 to 5/1,000 live births affected by its diverse structural abnormalities .The capacity of AI to analyze extensive datasets, recognize patterns, and generate insights has immense implications for CHD management. It excels in predicting CHD occurrence and progression, enabling early interventions and preventive measures. The technology aids in risk stratification by factoring in patient-specific variables, facilitating personalized monitoring, and targeting interventions ,4. AI opFurthermore, this narrative review delves into the application of AI in crafting personalized treatment strategies for CHD patients. By assessing individual patient traits, therapeutic responses, and treatment outcomes, AI aids in formulating tailored and evidence-based plans. It also discusses the potential of AI in optimizing surgical procedures, drug selection, and exploring novel therapies . UltimatPrediction of CHDs\u00a0AI is increasingly proving transformative across various sectors, including healthcare, particularly in the realm of diagnosing and managing CHDs. The potential applications of AI encompass a range of critical functions in the early detection and prognosis of CHD. These tasks include image acquisition, optimization, automated measurements, outlier detection, diagnostic classification, and outcome prediction . The conThe integration of AI and machine learning (ML) has significantly improved the visualization of cardiac defects. By processing data and identifying patterns, AI algorithms can enhance the accuracy of fetal heart pictures and assist in evaluating cardiac form and function. This is particularly relevant given the challenges posed by factors like rapid fetal heartbeat, small heart size, and limited access to the fetus. The applications of AI in pediatric cardiology are multifaceted and extend to clinical examination, image processing, fetal cardiology, risk assessment, precision cardiology, and treatment planning. Machine learning algorithms have shown promise in diagnosing both critical and non-critical CHDs . In receOne notable achievement is the combination of human-performed ultrasound (US) and machine analysis, leading to a remarkable 95% detection rate of CHDs in a test sample . This suAI algorithms come in various forms, including deep learning (DL), a subset of ML that employs artificial neural networks for complex tasks such as object recognition and speech analysis . The appRisk stratification of CHDsThe potential benefits of AI extend to various domains of healthcare, including adult CHD. Developing and using risk scores based on AI predictions can enhance patient care by guiding appropriate follow-up frequencies, treatment escalations, and referrals for procedures or transplantation . The impIn the field of pediatric cardiology, AI-based algorithms play a vital role in clinical assessment, diagnosis, procedure planning, and intervention management . These aSeveral AI models, including Multilayer Perceptron, Random Forest, Extra Trees, Stochastic Gradient Boosting, Ada Boost Classification, and Bag Decision Trees, have demonstrated success in the medical literature ,20. ThesPersonalized treatment for CHDsAI is transforming the field of CHD by enabling precision medicine through the analysis of large datasets from these patients. This approach holds the potential to revolutionize diagnosis, treatment planning, and interventions for individual patients. The ability of AI to amalgamate diverse layers of medical data, including clinical records, imaging data, environmental factors, and social influences, offers personalized analytics that can improve patient outcomes. Precision medicine AI in precision medicine for CHD is revolutionizing diagnosis and treatment by leveraging vast datasets to provide personalized care. The integration of AI into CHD management is reshaping the landscape of healthcare, offering the potential for more accurate diagnoses, tailored treatment strategies, and improved patient outcomes.At the core of AI's impact is its ability to process large amounts of data from CHD patients, including clinical information, environmental factors, imaging data, and social influences. This wealth of data serves as the foundation for developing predictive models that can guide individualized treatment plans. For instance, serum metabolite panels and DNA methylation are being explored as tools for CHD screening, showcasing the potential of AI in identifying unique biomarkers for early detection ,22. DigiThe potential of AI is evident in studies that utilize deep learning algorithms to diagnose, predict prognosis, and direct therapy for adult patients with CHD. With impressive accuracy rates, these algorithms analyze vast medical records to provide insights into diagnosis, disease complexity, and disease progression . Diller AI techniques are employed in multiple facets of personalized treatment planning for CHD patients. AI techniques like reinforcement learning, supervised learning, and unsupervised learning are used to analyze extensive datasets, uncover patterns, and generate predictive models . These mAI algorithms utilize patient-specific variables to develop risk prediction models. These models calculate probabilities of complications, disease progression, and treatment outcomes, guiding individualized treatment plans based on unique risk profiles . AI-poweAI-driven decision support systems offer several advantages for CHD treatment. The ability of AI to analyze extensive patient data enhances the accuracy and precision of diagnosis and treatment recommendations. AI algorithms consider various factors to provide personalized treatment strategies that consider anatomical variations, comorbidities, and patient preferences. Decision support systems rely on evidence-based medicine and the latest clinical recommendations, ensuring patients receive the most current and effective treatments . These sEthical considerations and challengesThe utilization of AI in the prediction, risk stratification, and personalized treatment planning for CHD introduces a range of ethical considerations. These considerations encompass aspects like privacy, informed consent, bias, ongoing monitoring, and the role of human judgment. The application of AI, particularly in cardiovascular medicine, raises concerns about patient data privacy and security . ProtectAlgorithmic bias is a significant concern, as AI systems trained on biased datasets can lead to biased predictions and recommendations . EnsurinEffective AI model training relies on comprehensive and diverse datasets. However, data availability can be limited, particularly for rare CHD conditions. Insufficient data can hinder the development of accurate AI algorithms and affect their performance and applicability . Some AIAddressing these challenges requires collaborative efforts among researchers, healthcare professionals, policymakers, and regulatory authorities. To fully harness the potential of AI in CHD treatment planning, the development of interpretable AI algorithms, the improvement of data quality and diversity, and comprehensive real-world validations are essential steps forward. By navigating these ethical considerations and limitations, AI has the potential to revolutionize the management of congenital heart diseases and enhance patient outcomes.Future directions and implicationsThe application of AI in the realm of CHDs holds great potential for enhancing prediction, risk assessment, and personalized treatment planning. However, several key challenges must be addressed to fully leverage AI's capabilities and ensure its seamless integration into clinical practice.One notable challenge is the need for larger and more diverse datasets . The effA critical aspect that demands attention is the dynamic nature of CHD and the need for longitudinal analysis. CHD patients undergo various interventions, and their condition evolves. AI models should be designed to analyze longitudinal data, offering insights into disease progression, treatment effectiveness, and long-term outcomes. By adapting to these changes and continuously learning from new data, AI can provide real-time predictions and recommendations, aiding clinicians in making informed decisions . ProspecThe integration of AI into clinical practice has profound implications. First, it can lead to improved patient outcomes by enabling early intervention, risk stratification, and tailored treatment planning. This, in turn, can reduce complications and enhance the quality of life for CHD patients . AdditioIn conclusion, the use of AI in CHD offers transformative possibilities for patient care, but overcoming challenges related to data, dynamic modeling, and validation is crucial. By embracing collaborations, diversifying data sources, and ensuring transparency, the full potential of AI can be harnessed, resulting in improved patient outcomes, efficient resource allocation, and personalized treatment approaches.In the rapidly evolving landscape of healthcare, the convergence of AI and CHD management holds great promise. This comprehensive narrative review underscores the potential of AI to transform prediction, risk stratification, and personalized treatment planning for CHD. The intricate nature of CHD, coupled with limited data and ethical considerations, necessitates innovative solutions. The ability of AI to analyze vast datasets, identify patterns, and generate insights offers a path forward. The review emphasizes the critical importance of collaboration, diverse datasets, and longitudinal analysis to overcome challenges and unlock AI's full potential. While AI offers groundbreaking opportunities, ethical considerations surrounding privacy, bias, transparency, and the role of human judgment cannot be overlooked. This intersection of AI and CHD management demands a delicate balance, where AI serves as a tool to complement clinical expertise. As the healthcare landscape continues to evolve, AI's role in CHD management will undoubtedly expand. By navigating challenges, harnessing collaborative efforts, and ensuring ethical adherence, the consolidation of AI and CHD management holds the promise to revolutionize care, enhance patient outcomes, and create a future where precision medicine becomes a reality for all individuals affected by congenital heart diseases."}
+{"text": "Influenza A viruses (IAV) are a prevalent respiratory pathogen that can cause seasonal flu and global pandemics, posing a significant global public health threat. Emerging research suggests that IAV infections may disrupt the balance of gut microbiota, while gut dysbiosis can affect disease progression in IAV patients. Therefore, restoring gut microbiota balance may represent a promising therapeutic target for IAV infections. Traditional Chinese medicine, with its ability to regulate gut microbiota, offers significant potential in preventing and treating IAV. This article provides a comprehensive review of the relationship between IAV and gut microbiota, highlighting the impact of gut microbiota on IAV infections. It also explores the mechanisms and role of traditional Chinese medicine in regulating gut microbiota for the prevention and treatment of IAV, presenting novel research avenues for traditional Chinese medicine-based IAV treatments. Influenza A viruses  are a frequent respiratory pathogen that can cause seasonal flu and global pandemics, with clinical symptoms that include fever, cough, chills, and sweating . SeasonaAspergillus and Penicillium, and enrichment of Candida. The study also found a correlation between Aspergillus-induced increase in C-reactive protein levels and mycobiota-induced decrease in calcitonin levels, leading to clinical symptoms [Mounting evidence suggests that the intestinal microbiota of patients with IAV undergoes significant changes. Notably, one study revealed that the intestinal microbial community of H1N1 patients exhibited reduced diversity and relative abundance of beneficial microbes compared to those of healthy controls . Similarsymptoms . Overallrod-shaped bacteria, lactobacilli, Prevotella, clostridia, and Veillonella while reducing the relative abundance of Bacteroides and Ruminococcus in the gut of mice with asthma-like airway inflammation. This results in higher production of acetic, propionic, butyric, isobutyric, valeric, isovaleric, and hexanoic acids, reduced eosinophil cells in bronchoalveolar lavage fluid , as well as decreased serum Immunoglobulin E , Interleukin-6 , Tumor Necrosis Factor \u03b1 , and Interleukin-1\u03b2  levels [bifidobacteria, clostridia, and rod-shaped bacteria can transform them into more active ginsenoside compounds [Traditional Chinese Medicine  has a long history of use in China for treating respiratory diseases and recent research has demonstrated its effectiveness in treating the 2019 novel coronavirus, SARS coronavirus, MERS coronavirus, H7N9 avian influenza virus, and H1N1 influenza virus \u201316. Rese14 known bacteria [Firmicutes, Bacteroidetes, Proteobacteria, Verrumicribia, Actinobacteria, Cyanobacteria, among others. The gut microbiota plays a vital role in maintaining intestinal mucosal integrity, regulating immune and nervous systems, synthesizing nutrients and metabolites, and defending against harmful pathogens [segmented filamentous bacteria  had increased susceptibility to lung inflammation and higher mortality rates than mice colonized with SFB. However, after colonization with SFB, even in SFB-lacking mice, the Th17 immune response increased, and levels of IL-22 in BALF, as well as the number of T cell receptor \u03b2  cells and neutrophils, increased, indicating that gut microbiota can modulate the lung immune response and alleviate severe lung infections.The human microbiota is a complex microbial system that coexists with humans, and the microbiota residing in the gut is composed of approximately 10bacteria , includiathogens \u201324. Reseathogens , 26. Conathogens \u201329. In cathogens . Furtherathogens  showed tphylum Bacteroidetes and a decrease in the number of bacteria in the phylum Firmicutes. Likewise, another study revealed that influenza infection alters the gut microbiota, promoting the consumption of gut-specific anaerobic bacteria and the enrichment of Bacillus deformis, leading to gut dysbiosis [Helicobacteraceae and Clostridiaceae, leading to decreased protein synthesis of short-chain fatty acids and affecting the functionality of the gut microbiota [Bacteroides, Parabacteroides, and Alistipes, while negative correlations were observed between the changes in CC chemokine ligand 3 , CC chemokine ligand 5 , and the abundance of Prevotella and Butyrivibrio. Additionally, the abundance of Proteus was found to be directly proportional to the weight changes in infected mice [There is an established relationship between IAV infection and the gut microbiota. IAV infection can alter the composition and metabolites of the gut microbiota, leading to changes in gut barrier function and immune responses. This can result in secondary respiratory infections and impact disease prognosis. A study conducted by Groves et al.  demonstrysbiosis . Furthercrobiota . Converscrobiota . Positivted mice . Furtherted mice . Valentited mice  found thRadix Scutellariae, Forsythia Fructus, and Flos Lonicerae. It possesses the functions of dispelling wind, clearing heat, and detoxification. Animal experiments have demonstrated its potential in reducing the lung index of H1N1-infected mice, downregulating the expression of inflammatory factors, and inhibiting the release of IFN-\u03b2 in bronchoalveolar lavage fluid (BALF). Additionally, it significantly improves the survival rate and extends the lifespan of infected mice [Artemisia annua L., Lonicerae japonica Thunb., Schizonepeta tenuifolia (Benth.) Briq., Mentha haplocalyx Briq., Chrysanthemum indicum L., Isatidis tinctorial L., Forsythia suspensa (Thunb.) Vahl., Commelina communis L., Peucedanum praeruptorum Dunn, and Glycine max (L.) Merr)have demonstrated broad-spectrum anti-influenza virus activity in vitro and significant protective effects against lethal influenza virus infection in mice, improving their survival rate, disease symptoms, blood parameters, lung index, and pulmonary pathological changes [Bovis Calculus Atifactus, Rhei Radix et Rhizoma, Caprae Hircus Cornu, Gypsum Fibrosum, Scutellariae Radix, Fritillariae Ussuriensis Bulbus, Chloriti Lapis, and Glycyrrhizae Radix et Rhizoma. It possesses the effects of clearing heat and detoxification, eliminating phlegm, and relieving cough. Research has shown that it can alleviate the imbalance of intestinal flora caused by H1N1 infection in mice by regulating the content of lactobacillus, thus reducing pulmonary inflammation and edema in influenza-infected mice [Ephedra sinica Stapf, Prunus armeniaca L., Lycopodiella cernua (L.) Pic. Serm., Scutellaria baicalensis Georgi, Bombyx batryticatus, Reynoutria japonica Houtt., Scleromitrion diffusum (Willd.)R.J. Wang, Houttuynia cordata Thunb., Trichosanthes kirilowii Maxim, Platycodon grandiflorus (Jacq.) A.DC.,Forsythia suspensa (Thunb.) Vahl, and Glycyrrhiza glabra L., has been found to have the effect of clearing the lungs and relieving asthma. Experimental studies have shown that it can alleviate lung damage, improve survival rate, and reduce lung viral load in mice infected with influenza. Furthermore, studies have revealed that Qingfei drink can enhance the relative abundance of fecal bacteria, such as Enterococcus, Ruminococcus, Lactobacillus, and Prevotella, in infected mice. It also alleviates the reduction in the abundance of Escherichia coli, Proteus, Acinetobacter, and Bacteroides [pathogenic Proteus mirabilis, and cytokine secretion. This has a synergistic effect in reducing lung and intestinal injuries while significantly improving intestinal mucosal barrier function [Modern pharmacological research has demonstrated that traditional Chinese medicine has numerous advantages due to its multi-component and multi-target efficacy, enabling it to effectively improve clinical symptoms such as fever, cough, and respiratory failure caused by viral infections, and reduce pathological changes . For exated mice . Additio changes . Furtherted mice . Similarteroides . Intervefunction .To summarize, TCM has a significant therapeutic effect on H1N1 influenza virus infection, with its mechanism of action being closely related to the regulation of intestinal flora.Gypsum Fibrosum, Radix et Rhizoma Rhei, Percarpium Trichosanthis Kirlowiis, and Semen Pruni Armeniacae. It has the functions of clearing heat and phlegm from the lungs, purging heat from the intestines. Animal experiments have shown that XBCQ can significantly improve the survival rate of mice infected with IAV and alleviate lung and intestinal damage in mice. The mechanism of action is related to the reduction in the relative abundance of Enterobacteriaceae and Bacteroidaceae and the increase in the relative abundance of Firmicutes and Lachnospiraceae [Lactobacillaceae and Bifidobacteriaceae in the gut microbiota [roasted Atractylodes macrocephala, Ephedra sinica, Agastache rugosa, Sophora flavescens, Eupatorium fortunei, Belamcanda chinensis, Physalis angulata, and Glycyrrhiza uralensis. It possesses the functions of dampness elimination, spleen invigoration, heat clearance, and detoxification) to mice infected with influenza can reduce mortality, alleviate weight loss, lower lung virus titers, and alleviate lung pathological injury. CMHD has also been found to decrease the levels of IL-1\u03b2 and TNF-\u03b1 while increasing the levels of IL-10, superoxide dismutase, and glutathione peroxidase. The underlying mechanism may involve CMHD\u2019s ability to regulate the abundance of certain gut microbes, including Bifidobacterium, Clostridium, Bacteroides, and Prevotella, in mice. Similarly, polysaccharides found in fish-mint have been found to reduce mucus production and regulate gut microbiota composition in mice infected with influenza, resulting in decreased expression of hypoxia-inducible factors and reduced levels of Toll-like receptors and IL-1\u03b2, and increased production of Interleukin-10  [Forsythiae Fructus, Lonicerae Japonicae Flos, Ephedrae Herba, Armeniacae Semen Amarum, Gypsum Fibrosum, Isatidis Radix, Asteris Radix et Rhizoma, Houttuyniae Herba, Pogostemonis Herba, Rhei Radix et Rhizoma, Rhodiola Crenulata, Menthae Haplocalycis Herba and Glycyrrhizae Radix. It possesses the functions of clearing away heat and toxins, promoting lung function, and experimental studies have demonstrated that it can reduce virus load in the lungs of influenza-infected mice. Additionally, it can alleviate weight loss and prolong survival time in infected mice, mitigate damage to lung and intestinal mucosa barriers, reverse the decrease in alpha diversity of gut microbiota, and significantly increase the abundance of Bacteroidetes and Muribaculaceae. The mechanism of action is related to LHQW\u2019s ability to restore gut microbiota homeostasis, repair intestinal mucosa, and regulate the TLR4/NF-\u03baB signaling pathway in the lungs [The stability and composition of the gut microbiota are closely linked to the prognosis of influenza A virus infection. It has been demonstrated that alterations in the gut microbiota post-infection can impact host immune responses, heighten susceptibility to recurring infections, and aid pathogen growth - all of which can ultimately contribute to exacerbating lung inflammation and worsening disease . Studiespiraceae . Likewiscrobiota . Furthercrobiota  has demo, IL-10) . Additiohe lungs . In summPogostemon cablin Benth., Chrysanthemum morifolium Ramat., Forsythia suspensa Vahl, Isatis indigotica Fort., Isatis tinctoria L., Rehmannia glutinosa Libosch., Cortex Lycii, Cynanchum atratum Bge., Mentha canadensis Linnaeus, and Gypsum Fibrosuum), a cold granule for children, can relieve weight loss in H1N1-infected mice, reduce the levels of inflammatory cytokines such as IL-6 and IL-1\u03b2, decrease lung index and pathological damage, protect the intestinal barrier by maintaining the number of colon goblet cells, and reduce the expression of interleukin 17\u00a0A  in colon tissue [The dysfunction of the intestinal mucosal barrier function after infection with the influenza A virus is closely related to the severity of the infection. Studies have shown that the intestinal mucosal barrier is constructed by intestinal epithelial cells, which secrete various immune factors and transmit bacterial antigens, playing an important role in maintaining the symbiotic relationship between the intestinal flora and the host , and actn tissue . Likewisn tissue  found th+ CD4+ T cells, which are effector cells derived from the lung, are recruited to the small intestine where they secrete Interferon-\u03b3. This leads to an imbalance in the gut microbiota that promotes Th17 cell polarization in the small intestine. Ultimately, this results in IL-17\u00a0A secretion, which mediates immune damage [Scutellariae Radix, Coptidis Rhizoma, Puerariae Lobatae Radix, and Glycyrrhizae Radix et Rhizoma, exhibits the effects of relieving muscle tension, clearing heat, and stopping diarrhea. Studies have shown that the treatment with GQD can increase Akkermansia_muciniphila, Desulfovibrio_C21_c20, and Lactobacillus_salivarius in the intestines of mice infected with influenza A virus, while reducing Escherichia coli. This leads to a decrease in the mortality rate and improved lung inflammation in influenza-infected mice. Furthermore, the combination of GQD with fecal microbiota transplantation can suppress the inflammatory differentiation of CD4\u2009+\u2009T cells and exhibit systemic protection. These findings suggest that GQD can influence systemic immunity by modulating the gut microbiota [Astragalus membranaceus, Saposhnikovia divaricata, Angelica dahurica, Ardisia crenata, Magnolia biondii, Prunus armeniaca, Lepidium apetalum and Glycyrrhiza uralensis. Liu et al. [Ralstonia and Blautia in the lung microbiota. FTF has been found to significantly elevate the levels of sIgA and SCFAs in lung and intestinal tissues, indicating its ability to regulate the composition and structure of the lung and gut microbiota, as well as the levels of sIgA in the lung and gut. Moreover, a correlation analysis between the gut microbiota and sIgA in rats revealed a negative correlation between g__Lactobacillus and gut mucosal sIgA, suggesting that g__Lactobacillus may inhibit intestinal mucosal immunity. Xuanfei Baidu decoction has been found to regulate gut microbiota diversity and positively correlate with the changes in Bacteroides, Escherichia-Shigella, Eubacterium nodatum, Turicibacter, and Clostridium sensu stricto 1, which are associated with TNF-a levels. Additionally, Xuanlung Baidu decoction can reconstruct gut immunity by down-regulating the Th1/Th2 ratio [Christensenella, and increasing the levels of Kurthia, Citrobacter, and Klebsiella. Moreover, it can modulate the Th17/Treg balance in the spleen of mice and down-regulate serum TNF-\u03b1 and IL-17\u00a0A levels [The gut microbiota plays a critical role in regulating the severity of IAV infection by modulating host immunity . Studiese damage . Numeroucrobiota . The Feiu et al.  have shoh2 ratio . Rosin aA levels . FinallyA levels . These fAkkermansia, Allobaculum, Anaerovorax, coriobacteriaceae_uc-002, Lachnoclostridium, ruminantium_group, tanbacteria, and Mur ibaculacea in rat intestines, thereby maintaining the stable production of SCFAs in the intestines, maintaining intestinal homeostasis, and reducing inflammatory reactions [Angelica sinensis, Paeonia lactiflora, Bupleurum chinense, Poria cocos, Atractylodes macrocephala, and Glycyrrhiza uralensis, possesses the effect of soothing the liver and invigorating the spleen. Animal experiments have shown that Xiaoyaosan can reduce the abundance of bacteria that produce short-chain fatty acids (SCFAs), leading to a decrease in SCFA levels and a subsequent reduction in the release of inflammatory factors [Ephedra sinica Stapf, Gypsum, Bupleurum Chinense DC, Scutellaria baicalensis Georgi, Artemisia carvifolia Buch. - Ham. ex Roxb., Atractylodes lancea (Thunb.), Pogostemon cablin (Blanco) Benth., Verbena officinalis L. and Glycyrrhiza uralensis Fisch) has a significant regulatory effect on T and B lymphocytes and reduces the expression of various pro-inflammatory cytokines, which is instrumental in alleviating influenza A virus infection. The metabolomics and 16\u00a0S studies revealed that its mechanism of action is linked to the regulation of intestinal citrate and amino acids metabolism, stability of intestinal flora, and enrichment of beneficial bacteria in the intestine [The changes in intestinal metabolites are closely linked to the development of disease following infection with influenza A virus. The study conducted by Becattini et al.  reveals eactions . Xiaoyao factors . It has ntestine . In summTCM has been utilized clinically for over a thousand years, and recent studies have demonstrated its efficacy in reducing lung inflammation and improving clinical symptoms, shortening treatment duration, and promoting recovery in IAV patients. Current challenges in IAV treatment focus on preventing complications and reducing the number of critical cases. Research indicates that the gut microbiota plays a vital role in IAV infection; IAV-infected patients often experience gut dysbiosis and impaired gut barrier function, making them susceptible to secondary bacterial infections that worsen the disease. Conversely, the gut microbiota can also regulate the immune response systemically and locally, significantly impacting patient prognosis. Therefore, regulating and restoring gut microbiota balance is crucial in treating and preventing IAV infection. TCM positively impacts the prognosis of IAV patients by regulating the gut microbiota\u2019s composition, function, gut mucosal barrier, metabolites, immune, and inflammatory response. However, the specific correspondence between components and microbial communities in this regulatory role is currently lacking in research. Furthermore, due to the multitude of components in traditional Chinese medicine, it is not yet clear whether these components directly regulate the gut microbiota in concert or indirectly regulate them through metabolites. Future studies using high-throughput sequencing techniques such as 16\u00a0S rRNA gene sequencing, metagenomics, and metabolomics in IAV disease models and traditional Chinese medicine intervention are needed to identify advantageous microbial communities, their metabolites, and metabolic pathways. Additionally, further experiments involving microbial transplantation using advantageous strains will help elucidate the specific pharmacological and molecular mechanisms by which traditional Chinese medicine regulates the gut microbiota.We firmly believe that with the advancement of scientific technology, research on TCM and the gut microbiota has been gradually deepening. Although the specific mechanisms underlying their interaction are intricate, there is hope for a clearer understanding in the future. We look forward to TCM\u2019s continued advantages in regulating the gut microbiota and demonstrating even more remarkable outcomes. In conclusion, the use of TCM in modulating the gut microbiota for the prevention and treatment of IAV holds significant research significance as a novel therapeutic direction."}
+{"text": "Microbial compost plays a crucial role in improving soil health, soil fertility, and plant biomass. These biofertilizers, based on microorganisms, offer numerous benefits such as enhanced nutrient acquisition , production of hydrogen cyanide (HCN), and control of pathogens through induced systematic resistance. Additionally, they promote the production of phytohormones, siderophore, vitamins, protective enzymes, and antibiotics, further contributing to soil sustainability and optimal agricultural productivity. The escalating generation of organic waste from farm operations poses significant threats to the environment and soil fertility. Simultaneously, the excessive utilization of chemical fertilizers to achieve high crop yields results in detrimental impacts on soil structure and fertility. To address these challenges, a sustainable agriculture system that ensures enhanced soil fertility and minimal ecological impact is imperative. Microbial composts, developed by incorporating characterized plant-growth-promoting bacteria or fungal strains into compost derived from agricultural waste, offer a promising solution. These biofertilizers, with selected microbial strains capable of thriving in compost, offer an eco-friendly, cost-effective, and sustainable alternative for agricultural practices. In this review article, we explore the potential of microbial composts as a viable strategy for improving plant growth and environmental safety. By harnessing the benefits of microorganisms in compost, we can pave the way for sustainable agriculture and foster a healthier relationship between soil, plants, and the environment. In recent years, global food security has been increasingly threatened by the combination of population increase and the scarcity of limited arable land worldwide ,2. ConseProduction of nutrient-rich compost from agricultural waste has been emerging as an alternative way of disposal . A dark Composting is the process in which organic materials like food scraps, leaves, twigs, lawn clippings, wood waste, and other organic matter are decayed by the soil microorganisms under controlled ambiance ,19. To cThis review examines the feasibility and advantages of producing microbial compost-based biofertilizers using agricultural feedstock enriched with decomposing phytobeneficial microorganisms. Compost serves as an ideal carrier material for potential plant-beneficial microorganisms, presenting a possible alternative to chemical fertilizers. The application of microbial compost in fertilization holds immense promise for bolstering soil sustainability and elevating overall plant productivity. Additionally, we explore the factors influencing the microbial composting process and highlight the future prospects of adopting microbial compost-based biofertilizers.Agricultural productivity is decreasing continuously due to nutrient deficiency in the soils and the growth of obnoxious weeds and pests . ConversAzotobacter spp., Escherichia coli, Pseudomonas spp., and Bacillus spp., and arbuscular mycorrhizal fungi (AMF), such as Glomus versiforme, Aspergillus awamori, Glomus macrocarpum, and Sclerocystis coremioides, are often exploited in broad spectrum biofertilizers without causing any negative chemical influence on the soils [Rhizobium, Azotobacter, and vesicular arbuscular mycorrhiza (VAM) as biofertilizer enhanced the straw and grain yield when applied to wheat plants along with rock phosphate as a phosphate source [Thiobacillus thioxidans, Bacillus subtilis, and Saccharomyces sp. was found capable of converting micronutrients into soluble forms such as Mn, Zn, Fe, etc., and making them available to plants [Trichoderma spp. are also known to improve the tolerance of plants to biotic and abiotic stresses by producing enzymes that can detoxify harmful chemicals and by increasing the production of stress-response proteins in the plant [Trichoderma harzianum inoculation improved tomato plants\u2019 tolerance to chilling stress by enhancing physiological, biochemical, and molecular responses [Biofertilizers utilize beneficial microorganisms to optimize plant growth by increasing nutrient supply, effectively enhancing overall nutrient availability, and promoting healthier and more robust plant development ,35. Genehe soils ,39,40. Me source . Similaro plants . Trichodhe plant . For exaesponses . The bioesponses . Hence, Overall, the utilization of biofertilizers has been in practice for a considerable period due to their eco-friendly nature and superior cost-efficiency compared with chemical fertilizers. The biofertilizers can also be used to convert complex organic materials into simple compounds, followed by a change in the color and texture of the soil ,46. TheyAgricultural waste is now emerging as a compelling and cost-effective resource that can provide organic matter and essential plant nutrients to the soil, effectively supporting crop production . HoweverAzotobacter spp., Pseudomonas spp., Escherichia coli, and Bacillus spp., and some AMF, such as Aspergillus awamori, Glomus macrocarpum, and Sclerocystis coremioides, were found to be involved in the decomposition process [The process of controlled decomposition of organic material like agricultural residues is known as composting . A compo process ,63. Thes process ,65. Comp process . A schem2), and nitrogen [2, but the process of anaerobic respiration is less energy-efficient and it utilizes chemical species like sulfate, carbon dioxide, nitrates, sulfur, and oxidized metal ions. Hence, to suppress the development of anaerobic conditions, artificial aerobic conditions should be introduced in the compost pile through pulling or pushing the air [The compost feedstock is often rich in organic compounds that are rich in components like carbon (C), hydrogen (H), oxygen . The members of filamentous fungi that drive the composting process mainly belong to the genus Aspergillus and have a low population density  [The composting process can be characterized as the biodegradation of organic waste into useful products under controlled ambiance. These products are applied to the soil, and they effectively enhance the physico-chemical properties of the soil ,73. The 8 CFU/g) .Xanthomonas, Agrobacterium, Streptomyces, Alcaligenes, Cellulomonas, Arthrobacter, Amorpho sporangium, Bacillus, Pseudomonas sp., Azotobacter, Actinoplanes, Rhizobium, Erwinia, Bradyrhizobium, Enterobacter, Rhizophagus irregularis, and Glomus intraradices [2 to ammonia [Ectorhizospheric strains and Endosymbiotic rhizobia have been defined as efficient phosphate solubilizers [Pseudomonas, Bacillus, Enterobacter, and Rhizobium genera [Bradyrhizobium, Pseudomonas, Rhizobium, Agrobacterium, Klebsiella, Enterobacter, Azotobacter, and Bacillus, are best known for their phytohormones production potential. These microbe-oriented phytohormones have an effective role in plant growth stimulation.A group of specific microorganisms which positively influences plant growth are PGPR and AMF ,74. A nuaradices . Generalaradices . Nitroge ammonia . Some mibilizers . The mosm genera ,78. SimiBurkholderia sp., Bacillus mucilaginosus, Ferrooxidans sp., Paenibacillus sp., Pseudomonas sp., Bacillus edaphicus, and Acidothiobacillus sp., are PGPR that solubilize potassium-bearing minerals, thereby releasing the potassium in the form that is available for plants [The ability of PGPR to solubilize potassium rock by secreting organic acids has also been investigated. A number of bacterial strains, including r plants . TherefoEnriching compost with nutrients, beneficial bacteria, and AMF is a key strategy for improving its nutritional value and enhancing its positive effects on plant growth . By estaThe number of global agricultural products is rising steadily despite the global decrease in cultivated land area, due to the increased demand to produce food to feed an increasing population ,138. TheCereal residues encompass the materials remaining in croplands after crop harvest, comprising stems, leaves, straw, and seedpods. Additionally, process residues like husk, roots, bagasse, and seeds are the by-products remaining after the processing of cereal crops . The harAbout 70% of the world\u2019s agricultural land and 26% of the world\u2019s total land area is comprised of grasslands ,147. In Fruits and vegetables are essential natural sources of minerals, dietary fibers, and vitamins in both developing and developed countries. The fruit and vegetable production is continuously improving in many developing countries in, for example, South America and Asia . The larAnimal manure and slurry cause environmental pollution due to the improper recycling of them . The comMicroorganisms are an integral part of soil nutrient cycling in soil\u2013plant\u2013microbe systems. Plant growth and development is facilitated by the soil microbial community in several different ways . General2), because the plants are unable to use the atmospheric molecular nitrogen (N2) directly [3\u2212 and NH4+ as well as low-molecular-weight dissolved organic nitrogen (DON), especially amino acids. Plants cannot utilize the atmospheric dinitrogen (N2) unless some diazotrophic microorganisms reduce it to more usable form like ammonia (NH3) [2 to NH3. BNF provides more than 2 \u00d7 1013 g nitrogen annually throughout the world. Symbiotic fixation adds about 80% of this amount, while the remaining is contributed by either free-living or associative nitrogen-fixing systems [Glomus macrocarpum, Glomus hoi, and Glomus mosseae [Pseudomonas spp., Alcaligenes spp., Azotobacter spp., Azospirillum spp., Enterobacter spp., Arthrobacter spp., Acinetobacter spp., Bacillus spp., Bradyrhizobium japonicum, Serratia (Brady) rhizobium spp., and Burkholderia spp. [Gordonia exhibits nitrogenase reductase activity and was found to be involved in the nitrogen metabolic reaction of compost [Nitrogen (N) is an essential plant nutrient. Significant energy is needed to break the triple bonds between the two N-atoms of atmospheric molecular nitrogen  . In biol systems ,209. Bac mosseae ,83,84 anria spp. ,211. Com compost . Thus, aB. megatheriumand, Enterobacter, Erwinia, O. anthropi TRS-2, and Pseudomonas striata [Enterobacter, Serratia, Azotobacter, Beijerinckia, Bacillus, Pseudomonas, Burkholderia, Microbacterium, Erwinia, Rhizobium, and Flavobacterium are amongst the most important bacterial genera that have been reported to solubilize phosphate [Phosphorus (P) is the second most crucial nutrient for plant growth, and its scarcity can severely limit crop production to a critical level . To addr striata . Such bahosphate . Rivera-hosphate . These mhosphate ,217.Paenibacillus sp., Pseudomonas sp., Bacillus edaphicus, Acidothiobacillus sp., Burkholderia sp., Bacillus mucilaginosus, and Ferrooxidans sp., have been reported to release potassium in an accessible form by solubilizing potassium-bearing minerals in soils [Aspergillus terreus and Aspergillus niger have demonstrated the capability to solubilize potassium and produce acids by utilizing feldspar and potassium aluminum silicate as insoluble K sources [Bacillus sp. UBFBa4 and UBFBa7) improves the growth of wheat by increasing the uptake of K. The compost generally caused an increase in the population density of K-mobilizers, which convert the insoluble K into plant-useable forms by lowering the pH through organic acid production [Potassium (K) is an essential macronutrient and is required for plant growth. The concentration of soluble potassium is usually low in soil because more than 90 percent of the potassium exists in the form of silicate minerals and insoluble rock. Potassium deficiency is also one of the major constraints for an optimal crop production ,219. Thein soils . Similar sources . Hence, oduction .Bacillus sp., Gluconacetobacter diazotrophicus, fluorescent pseudomonads, and Pennisetum have been reported to increase Zn solubility in soil [Beauveria caledonica, Hymenoscyphus ericae, and Oidiodendron maius have been found to be Zn solubilizers [Zinc (Zn) is an important nutrient required by the plant tissues in small amounts for growth and gene regulation . Increas in soil ,97,98,99bilizers ,95. Compbilizers .Azospirillum, Enterobacter, Pseudomonas, Bacillus, Azotobacter, Paecilomyces formosus, Asprgillus fumigatus, and Fusarium proliferatum. Amongst the phytohormones, indole-3-acitic acid (IAA) plays a significant role in the growth and division of cells and increases the growth of lateral roots in plants [Plant growth hormones are organic compounds utilized by plants as messengers to interact with and respond to their environment . These hn plants ,228,230.n plants ,232. Varn plants .Azospirillum, is distinguished in terms of its production of a significant concentration of IAA to stimulate plant growth [IAA has a role in organogenesis, gene regulation, cell division, cell elongation, and cell expansion ,235. It t growth . Active t growth . For exat growth . It has t growth . Both co2+) form of iron is oxidized and converted into ferric (Fe3+), which is a relatively more stable form [Pseudomonas fluorescens, Rhodococcus, Acinetobacte, Pseudomonas putida, Aspergillus fumigatus, Glomus etunicatum, Glomus mossae, Trichoderma spp., and Aspergillus niger, have been reported to harbor the potential for production of siderophores [Siderophores are low-molecular-weight substances which have chelation properties and are primarily produced and employed by microorganisms to fulfil the nutritional requirements for iron . Sideropble form ,245. Wheble form . After trophores ,107,108.rophores . The approphores . The comBacillus drentensis, Azotobacter vinelandii, Enterobacter cloacae, Rhizobium sp., Agrobacterium sp., and Xanthomonas sp. [Exopolysaccharides (EPSs) are biodegradable polymers usually with a high molecular weight. Various bacteria, algae, and plants have been reported to produce these extrapolymeric substances . EPSs plonas sp. . The comRhizobium, Aeromonas, Alcaligenes, etc., have been reported to harbor the potential for HCN production in the rhizospheric soil and plant root nodules [Pseudomonas in the rhizosphere was found to hinder the primary growth of roots in Arabidopsis because of the suppression of an auxin-responsive gene [Hydrogen cyanide (HCN) is a poisonous chemical which is produced by the soil microbes and has a low molecular weight and antifungal properties . HCN is  nodules . Many st nodules ,255. Howive gene . The useArabidopsis thaliana was found to be managed by soil microbes using their 1-amino-cyclopropane-1-carboxylic acid (ACC) deaminase, which stops ACC from acting in ethylene biosynthesis pathways [Azospirillum, Enterobacter, Bacillus, Achromobacter, Rhizobium, Pseudomonas, and Gigaspora rosea, have the potential to produce ACC deaminase, an enzyme responsible for the cleavage of ACC into ammonia and \u03b1-ketobutyrate [Brassicacompestris through inoculation with three bacillus spp.  carrying ACC deaminase activity. In another study, the shoot dry biomass was enhanced in Brassica napus after the inoculation with Pseudomonas asplenii harboring the ACC deaminase gene [Plants require a suitable quantity of ethylene for their growth and development. However, its high concentration can influence the plant cellular processes and can hinder growth . The levpathways . Some PGbutyrate ,116,117.ase gene . Therefoase gene . Plants ase gene .Bacillus spp. and Pseudomonas are the most examined rhizobacteria that activate ISR [Trichoderma virens, Pseudomonas, and Bacillus spp., have been used to induce systemic resistance in plants [Many non-pathogenic rhizobacteria and beneficial fungi have the ability to overcome diseases by producing a defense mechanism known as \u201cInduced Systemic Resistance\u201d (ISR) . ISR is vate ISR ,264. Then plants ,121,265.Glomus aggregatum, Glomus viscosum, Azospirillum brasilense, Rhizobium leguminosarum, Azotobacter vinelandii, Azospirillum spp., Bacillus subtilis, Sinorhizobium meliloti, Rhizobium etli, Mesorhizobium loti, and Pseudomonas fluorescens [Microbes that produce vitamins are widespread in the rhizosphere. Vitamins are either obtained from root exudates or synthesized from rhizospheric bacteria and fungi ,267. In orescens ,123,124.orescens . The micBurkholderia, Staphylococcus, Enterobacter, Bacillus, Pseudomonas and Serratia, Aspergillus niger, and Glomus spp. [Pseudomonas, Bacillus, and Serratia can provide numerous extracellular lytic enzymes including b-1, 3 glucanases, chitinases, cellulases, laminarinase, and proteases [Plant microorganisms possess the capacity to produce certain proteins that promote and enhance plant development and growth. Root symbionts, such as ectomycorrhizal fungi and other rhizosphere microorganisms, play a vital role in facilitating these processes . The enzmus spp. ,255. In mus spp. . Pseudomroteases . ProtectP. fluorescens BL915 strains produce the pyrrolnitrin that can stop the destruction of Rhizoctonia solani during the damping off of the cotton plant [Pseudomonads can synthesize the 2,4-Dthat, which is a very active and extensively studied antibiotic, and can cause damage to the membrane of Pythium spp. [Pseudomonads produce the phenazine exhibiting redox activity, through which it can suppress the pathogens of plants such as Gaeumannomyces graminis and F. oxysporum [Bacillus spp.  are very effective against Gram-negative and Gram-positive bacteria, and against many other pathogenic fungi as well [Pseudomonas, Bacillus, and Azotobacter exhibited a broad-spectrum antifungal activity on Muller\u2013Hinton medium against different fungal pathogens such as Aspergillus, Fusarium, and Rhizoctonia bataticola [The most significant antagonistic activity for combating phytopathogens is the generation of diverse antibiotics by microbes . Severalon plant . Pseudomium spp. . Moreovexysporum . The ant as well . In anottaticola . CompostPseudomonas fluorescens, Bacillus mojavensis, and Trichoderma sp. have been reported to produce different types of VOCs [Bacillus subtilis and Bacillus amyloliquefaciens produce 2,3-butanediol and acetoin, which play a significant role in promoting plant growth [Soil microorganisms generate different types of metabolites during their metabolic activities . The pro of VOCs ,132,133.t growth . Other pt growth . VOCs cat growth . On the t growth . Anothert growth . MoreoveThe composting process is influenced by several parameters that need to be monitored throughout to ensure the production of high-quality compost. The mechanism of composting is affected by various physico-chemical characteristics of the agricultural feedstocks, including porosity, temperature, oxygen levels, C/N ratio, pH value, proper aeration, and moisture content ,156,282.Temperature is a key factor which significantly affects the growth and activity of the functional microbial communities in the composting of organic mass (OM). The OM transformation into compost takes place between thermophilic and mesophilic environments. The thermophilic conditions trigger the decomposition of organic waste. The catabolic activities of aerobes help in establishing the ambiance favorable for the decomposition process by shooting up the temperature to 65\u201370 \u00b0C within a few days ,284. HasThe carbon and nitrogen (C/N) ratio has a major impact on organic waste decomposition during composting. Every organism has a fixed C/N ratio at tissue level. This ratio has a crucial role in deciding the pathway for microbe-mediated decomposition of OM. Carbon serves as an energy source for microorganisms, and hence, it is the basic structural unit of life, whereas nitrogen is an important constituent of proteins, nucleic acids, and other cellular components . Hence, The chemical profile of the raw material is very important in the composting process. The low-end product recovery is achieved using organic-content-depleted biomass . TherefoAs the biochemical transformation is facilitated by aerobes, proper aeration is needed to ensure oxygen availability. Proper aeration is linked with the periodic turning of the feedstock piles . TurningMoisture level is another important factor for the bioconversion process. The optimal range of moisture content is 50 to 55% for organic waste composting . The preIn conclusion, as the agricultural industry faces challenges posed by escalating production costs and a growing global population, it is evident that a paradigm shift is needed in the fertilizer sector. The era of the green revolution, once dominated by chemical fertilizers, is gradually fading due to their exorbitant costs and environmental implications. In response to these concerns, the exploration of alternative technologies, such as compost and rhizospheric microorganisms, for sustainable agricultural practices has gained momentum, offering a profitable and eco-friendly solution. Globally, extensive research has been undertaken to investigate the potential of bacterial, cyanobacterial, and fungal biofertilizers for various crops. The application of these biofertilizers has demonstrated positive effects on soil fertility and crop yields in arable lands. Beyond improving nutrient availability, these microorganisms contribute to plant growth through the production of beneficial plant hormones, induction of stress resistance, and biocontrol of plant pathogens. While their performance may vary under different field conditions, the use of microbial fertilizers is anticipated to surge in the foreseeable future due to their economic and ecological benefits.Looking ahead, the technology of microbial fertilizers can be further enhanced by incorporating sustainable materials as carriers. Utilizing compost as a carrier material, given its sustainability and inherent fertilizing properties, has the potential to elevate biofertilizer technology to the next level. Moreover, in-depth research is required to identify compatible microbial strains capable of thriving in compost and demonstrating optimal physiological performance therein. The application of genome engineering holds potential as a tool for developing superior microbial strains, further advancing the efficacy of biofertilizers. The concept of compost-based biofertilizers represents a novel approach, fostering a unique setting for plant\u2013microbe interactions by harnessing the combined effects of compost and characterized microbial strains. Compost, when combined with a microbial consortium, offers an alternative nutrient source for agricultural plants, while also exhibiting antagonistic effects against soil-borne phytopathogens and inducing tolerance against biotic and abiotic stresses. Furthermore, compost-based biofertilizers not only positively impact soil fertility, but also uphold their safety for use, owing to their eco-friendly nature. Overall, the continuous exploration and development of compost-based biofertilizers, alongside advancements in microbial strain selection and genome engineering, promise to revolutionize modern agriculture, making it more sustainable, economically viable, and environmentally responsible. Embracing these innovations will pave the way for a greener, more productive, and resilient agricultural future."}
+{"text": "Plant-based diets, both vegan and vegetarian, which emphasize grains, vegetables, fruits, legumes, nuts, and seeds are increasingly popular for health as well as financial, ethical, and religious reasons. The medical literature clearly demonstrates that whole food plant-based diets can be both nutritionally sufficient and medically beneficial. However, any person on an intentionally restrictive, but poorly-designed diet may predispose themselves to clinically-relevant nutritional deficiencies. For persons on a poorly-designed plant-based diet, deficiencies are possible in both macronutrients  and micronutrients . Practitioner evaluation of symptomatic patients on a plant-based diet requires special consideration of seven key nutrient concerns for plant-based diets. This article translates these concerns into seven practical questions that all practitioners can introduce into their patient assessments and clinical reasoning. Ideally, persons on plant-based diets should be able to answer these seven questions. Each serves as a heuristic prompt for both clinician and patient attentiveness to a complete diet. As such, these seven questions support increased patient nutrition knowledge and practitioner capacity to counsel, refer, and appropriately focus clinical resources. In recent decades, both practitioners and patients have grown in awareness of the potentially life-saving importance of shifting to a plant-based diet ,2. SeverThe definition of a plant-based diet itself is the subject of some confusion in the medical literature. A recent review documented that the majority of plant-based dietary intervention studies completely proscribed animal products. However, more than 30% of trials included dairy products and 20% were semi-vegetarian .In the 12-million-member Kaiser-Permanente health plan (United States), the patient-directed Plant-Based Eating Guidebook see  describeIdeally, people on a plant-based diet will follow a well-planned diet that provides all the necessary nutrients and energy for health. Realistically, however, a well-designed plant-based diet may not be well-implemented . A plantNumerous reflexive factors guide dietary choices and require mindful attention. These include culture, upbringing, and comfort with cooking, access, convenience, cost, as well as available time or energy. Additionally, plant-based diets can include highly-processed foods that increase health risk including refined grains, fried foods, and added sugar that increase nutritional inadequacy and health risk .A healthy plant-based diet may be further complicated by additional restrictions, such as gluten-free diets or diets that minimize ingestion of lectins, corn, histamine, tyramine, methionine, oxalates, salicylates, nickel, mold, or FODMAPs. Even more nutritional challenges are found in patients with hypochlorhydria ; food inFurthermore, pregnancy, breastfeeding, childhood/adolescence, intense physical work, or athletic training represent additional challenges for a healthy diet. Based upon decades of clinical experience, innumerable common patient scenarios exist where the nutritional adequacy of a plant-based diet needs to be considered in the clinical assessment of symptomatic patients. To the extent that nutrition is important for health, the differential diagnosis for all patients with many common, non-specific symptoms, including fatigue, depression, anxiety, insomnia, dizziness, cognitive complaints, as well as chronic pain includes the possibility of one or more dietary nutrient deficiencies ,27. AsceJust as with any other prescribed intervention, the monitoring and reassessment of a prescribed plant-based diet is medically indicated. However, patients may also embark on a plant-based diet with neither a prescription nor sufficient guidance. They may add other dietary restrictions or be unaware of increased risks with prescribed medications. Ironically, this means that well-intentioned, but poorly-designed or poorly-implemented diets for better health may actually promote nutritional deficiencies.For all these reasons, practitioners now need the capacity to assess quickly if their patient is following a well-planned, plant-based diet. This is especially true for the patient with symptoms presenting for diagnosis. Yet, numerous studies have documented that physicians may lack both the knowledge and the confidence to address nutritional concerns ,32,33,34Additionally, a recent review of the food-based dietary guidelines for 100 countries found that most countries do not provide information to their citizens that cover the broad spectrum of plant-based diets . To addrSeven nutrients require special consideration. For patients on any form of a plant-based diet presenting for assessment of new symptoms or worsened chronic symptoms, physicians need to consider their intake of vitamin B12, iron, essential fatty acids, calcium, vitamin D, zinc, and protein. To rapidly screen in primary or subspecialty care, we identified the following seven questions as practical guides that can empower physicians to both consider nutritional status in their clinical reasoning and appropriately utilize clinical resources.Dietary vitamin B12 for humans is only produced by the microbial and archaea kingdoms. This vitamin is readily found in dairy, eggs, meat, and fish as animals can concentrate this nutrient and feedlot animals are often supplemented.Persons on a plant-based diet without vitamin B12 supplementation, as well as elderly or pregnant persons, are more susceptible to B12 deficiency . Plant-bUnfortified plant-based diets do not contain bioactive vitamin B12 . Vitamin B12 is the most common vitamin deficiency in the vegan diet .People on plant-based diets require vitamin B12 supplementation. The only reliable plant-based sources are processed foods fortified with vitamin B12. Examples include fortified plant milks, breakfast cereals, soy products, and nutritional yeasts. Fermented soy products , shiitake mushrooms, algae, and unfortified nutritional yeast contain inactive analogues of vitamin B12 can contribute to vitamin B12 intake, but are not considered reliable sources ,39. The Vitamin B12 is the necessary co-factor for only two enzymatic reactions in human physiology ,44,45,46Neurotransmitter metabolism ;Estrogen metabolism ;Histamine clearance (histamine intolerance);Phosphatidylcholine production ;Creatine and carnitine production ;Myelin production ;DNA synthesis.The first enzyme, methionine synthase, is crucial in the methylation cycle. Insufficient B12 in the methylcobalamin form results in elevated homocysteine and impairment of all methylation-dependent processes including ,47:NeuroThe second enzyme, L-methylmalonyl-coA mutase, is the last enzyme needed for fatty acids and amino acids to enter the Kreb\u2019s cycle (via succinyl CoA rather than acetyl CoA). Insufficient B12 in the adenosylcobalamin form results in elevated methylmalonic acid ,48,49.For women of childbearing age, B12 status is important for both maternal health as well as minimizing neural tube defect risk in the child . In infaHelicobacter pylori infection, gastric bypass, intestinal bacteria overgrowth, and malabsorption disorders. Iatrogenic risk factors for low vitamin B12 absorption include use of proton pump inhibitors or metformin  .Patients who adopt a plant-based diet and health professionals who guide them must ensure the adequate intake of total protein in addition to the sufficient intake of the nine essential amino acids.All protein in the diet and all proteins in muscle, bone and brain are made from amino acids. Twenty amino acids exist and nine of these amino acids are termed essential. This means that they must be eaten as they cannot be made by the body. All 20 amino acids can be found in a plant-based diet. However, plants provide a less optimal balance and amino acid distribution compared to animal foods ,195. PerPlant-based foods that contain all nine of the essential amino acids in themselves are infrequent. These include buckwheat, chia seeds, original Ezekiel bread, nutritional yeast, and quinoa. Daily meals should include mixed combinations of proteins to ensure the completeness of amino acid intakes. Common examples of complementary proteins include beans and brown rice, roasted vegetables and lentils, or different colored vegetables in a soup/stew with miso/lentils/beans and a whole grain. Protein digestibility of cereals, legumes, nuts, and seeds may be improved by soaking, sprouting, cooking, and, especially, pressure cooking ,198. CurIndividuals on a plant-based diet are able to consume adequate protein. However, even persons on a relatively high-protein plant-based diet can be at risk for low intake of three essential amino acids, i.e., lysine, methionine and tryptophan ,199. HisMany plant-based foods can be great protein sources, but they vary considerably in their protein content as well as their amino acid content. Red flags for symptomatic patients are plant-based diets that are low in total protein; or that consist of a low intake of legumes, grains, seeds, or nuts. For example, one cup of quinoa contains 8 g of protein, whereas one cup of cooked lentils contains 18 g. However, unlike the complete amino acid profile for quinoa, lentils have very little of the essential amino acids\u2019 methionine and tryptophan. They are also low in the amino acid cysteine. Thus, a diet containing predominantly lentils may be high protein and still be incomplete. Similarly, diets with high intakes of powdered plant-proteins may be incomplete. For example, commercially-available powdered pea and soy proteins have very low methionine content ,202,203.Diets with too few legumes, such as low lectin diets, may mean an insufficient intake of lysine. Significant lysine deficiency can exist despite a diet rich in fruits and vegetables, nuts and seeds, as well as corn, wheat, and brown rice . Lysine Likewise, plant-based diets low in grains, such as gluten-free diets, but still rich in legumes, may be low in methionine. Commonly eaten foods low in methionine are asparagus, beets, broccoli, cabbage, carrots, cauliflower, celery, kale, pea, soy, spinach, squash, sweet potatoes, seaweed, turnips, and zucchini. Plant-based diets are best balanced with the inclusion of grains rich in methionine: wheat, wheat germ, millet, barley, rice including brown rice, corn, kamut, oats, rye, sorghum, teff, triticale, and quinoa. Of these, only millet, rice, corn, sorghum, teff, and quinoa are gluten-free. Oats, depending upon processing, may be gluten-free.Methionine sufficiency is essential for growth, healthy hair, skin, and nails. Methionine sufficiency is required for selenium and zinc absorption, as well as T-cell proliferation and differentiation. Additionally, methionine is essential for methylation, an important factor in the prevention of both neural tube defects and osteoporosis ,207. Of Tryptophan deficiency can occur in diets low in total protein or with low intake of seeds, , nuts, legumes, and grains. Concentration of this essential amino acid in proteins is most often significantly lower than for other amino acids. For example, plant-based diets rich in foods, such as lentils, avocados, broccoli, eggplant, spinach, and tomatoes, may be low in tryptophan ,210.Tryptophan is the essential amino-acid necessary for growth, as well as the production of serotonin, melatonin, and vitamin B3 . Tryptophan deficiencies can present as mood disorders, fatigue, insomnia, or disordered eating. Vitamin B3 deficiencies can present with headaches and dizziness, as well as changes in skin, mood, energy, cognition, and digestive system function .  creatine , 2) carnitine , and 3) taurine . These conditionally essential nutrients, under normal conditions, can be produced by the body in amounts sufficient to meet physiological requirements. However, pathophysiological stress and/or restricted dietary intake of key amino acids can impair their production and increase the risk of multiple medical concerns.Creatine supplies energy to both the muscle and brain to meet suddenly increased energy demands. Plant-based diets are inherently low in creatine, a principal component of both muscle and brain. Supplementation may be important. For persons with a genetic impairment of creatine production, creatine supplementation reverses cognitive and neurodevelopmental defects . SimilarCarnitine status is clinically relevant as it is crucial for mitochondrial function and cellular energy production. Persons consuming a plant-based diet under increased physical stress, including pregnancy or dialysis, are at increased risk of hypocarnitinemia ,216. CarDefective fatty acid oxidation can present as fatigue, non-alcoholic fatty liver disease, fat accumulation, or hypoglycemia ,219,220.Taurine is one of the most important amino acids in high energy tissues, including the brain, retina, and muscles. Plant-based diets do not contain taurine . AnalysiTaurine is critical for neurological development and neurodegenerative protection. In the eye, taurine provides critical antioxidant protection for the retina, lens, vitreous, cornea, iris, and ciliary body. This includes critical photoreceptor and retinal pigment epithelium antioxidant protection ,225.Taurine supports bile flow and cholesterol conjugation. It affects blood pressure regulation, mitochondrial function, and electron transport chain activity ,225. TauConsequences of inadequate taurine intake or production include magnesium wasting, cardiomyopathy and arrhythmias, renal dysfunction, pancreatic beta cell dysfunction, plus numerous neurological and vision disorders including loss of retinal photoreceptors. Additional concerns with insufficiency include infertility, still births, and neonatal developmental problems ,225.The RDA for dietary protein intake is set at 0.8 g/kg of body weight . Free-liThe value of dietary protein depends not only on amino acid composition, but factors such as the protein digestibility corrected amino acid score (PDCAAS) ,228. PDCAdditionally, protein digestion and absorption are adversely affected by the numerous causes of hypochlorhydria, including aging, medications, and gastric bypass/banding. Furthermore, the phytic acid and trypsin inhibitors found in many plants may impact protein digestibility. Humans may lack adequate phytate-degrading enzymes in the digestive tract and the body may require increased dietary protein in order to compensate. Phytic acid is found in cereals, legumes, seeds, and nuts. Trypsin inhibitors are found in common beans, chickpeas, lentils, peas, broad beans, peanuts, and soybeans. Phytic acid and trypsin inhibitors may be reduced by soaking and cooking these foods ,233. TheAssessment of specific amino acid distributions in the diet and of total protein intake is primarily based upon patient self-report. In children, height and weight should be measured at each clinical visit. Symptomatic patients for any reason will likely benefit from the screening for blood urea nitrogen, creatinine, total protein, and albumin found in commonly ordered metabolic profiles.Intentional plant-based diets provide numerous health benefits. Yet, if poorly informed, combined with restrictive diets, or combined with certain prescription medications, they can drive or worsen physical symptoms. Furthermore, well-informed practitioner attention is required with the special situations of pregnancy, breastfeeding, childhood/adolescence, intense physical work, athletic training, and concomitant medical conditions. As with all medical interventions, physicians must be aware of the benefits, risks, and potential concerns following from prescribed plant-based diets. In addition, with more patients self-initiating plant-based diets, all practitioners need the capacity to question, assess, test, counsel, and appropriately refer for nutritional concerns. The seven questions identified here provide a framework for the rational consideration of several nutritional factors that may underlie a symptomatic patient\u2019s presentation. They can be incorporated into pre-visit questionnaires or into visits.One limitation in this review is the exclusion of questions regarding dietary sources of riboflavin (vitamin B2), choline, iodine, and selenium or other nutritional deficiencies. These remain important medical concerns, but represent emerging areas of clinical interest with limited research data for persons on plant-based diets. Likewise, further scientific study is required to understand the value of plant ferritin as a source of iron and endogenous cobalamin synthesis as a source of vitamin B12. Moreover, not addressed above is the potential for iatrogenic vitamin K deficiency for persons on a plant-based diet prescribed vitamin K antagonists  for anti-coagulation with venous thromboembolism, atrial fibrillation, and prosthetic heart valves. In the past, physicians have ordered patients to not consume vitamin-K-rich foods, such as green leafy vegetables ,236. HowHealth professional competence increasingly requires a working knowledge of clinical nutrition. This review, and the seven questions identified here, support clinician capacity to include nutritional concerns into the differential diagnosis for any given presenting patient concern. The underlying hypothesis is that clinician consideration of potential nutritional insufficiencies will guide both appropriate diagnoses and cost-effective treatments. For further guidance, laboratory tests are found in"}
+{"text": "Soil fauna plays a crucial role in contributing to litter breakdown, accelerating the decomposition rate and enhancing the biogeochemical cycle in terrestrial ecosystems. Comprehending the specific fauna role of functional species in litter decomposition is challenging due to their vast numbers and diversity. Climate and litter quality are widely acknowledged as dominant drives of litter decomposition across large spatial scales. However, the pattern of climate and litter quality modulates the effect of soil fauna on litter decomposition remains largely unexplored. To address this gap, we conducted an extensive analysis using data from 81 studies to investigate how climate and litter traits affects soil fauna in the decomposition.The paper describes fauna body size, climate zones , ecosystem types , soil types , decomposed duration , litter initial traits, average annual temperature and precipitation. The litter traits encompass various parameters such as concentrations of carbon, nitrogen, phosphorus, potassium, lignin, cellulose, total phenol, condensed tannin, hydrolysable tannin and other nutrient traits. These comprehensive datasets provide valuable insights into the role of soil fauna on the decomposition at global scale. Furthermore, the data will give researchers keys to assess how climate, litter quality and soil fauna interact to determine decomposition rates. As a multifunctional heritage of plants, litter drives biogeochemical cycles and provides habitat and food resources for soil organisms , 2. Its Climate and litter quality as pivotal factors that influence litter decomposition , which cData were collected from the Web of Science and the Chinese National Knowledge Infrastructure (CNKI) databases before 2022. We synthesized studies that the contribution of soil fauna on litter the decomposition in Web of Science using document search formula: TS=(decomposition* or breakdown* or processing* or decay*) and (litter* or leaf* or foliar*or trait*) and . In the China National Knowledge Infrastructure (CNKI), we used keywords such as (\u2018decomposition\u2019 or \u2018decay\u2019) and (\u2018leaf\u2019 or \u2018litter\u2019) and  and (\u2018litterbag\u2019). This search yielded a total of 1400 references.k in field litterbags experiment with different soil fauna; (ii) experiments must incorporate two data categories (soil fauna being both excluded and present treatments); (iii) soil fauna being both excluded and included must possess available data on mean, sample size or replicate, and standard deviation (SD) or standard error (SE); (iv) the published article must have at least one of the following 37 variables: litter properties of mass loss, decomposing k, mass remaining, concentrations of carbon, nitrogen, phosphorus, potassium, sodium, calcium, magnesium, manganese, lignin, cellulose, hemicellulose, total phenol, condensed tannins, hydrolysable tannins, leaf thickness, leaf toughness; fauna properties of specific diversity (Simpson\u2019s diversity index and Shannon\u2013Wiener diversity index), species evenness (Pielou\u2019s evenness index), species richness , individual density, number of fauna groups; soil quality parameters including soil moisture, soil temperature, pH, soil bulk density, soil total nitrogen, soil total phosphorus, soil organic carbon, soil calcium, soil microbial biomass, soil microbial biomass carbon, soil microbial biomass nitrogen, amount of litter, fine root biomass. In total, the database covered papers published on 81 studies performed at 75 separate sites .Several criteria were used to minimise potential publication bias: (i) studies had to quantitatively compare litter mass loss, or remaining mass, or calculate the decomposing constant (i) The climate types in this database were categorized as tropical, subtropical, and temperate zone. Tibetan Plateau belongs to the temperate zone, it may have a different climate from other temperate zones due to its elevated altitude, strong radiation and low temperature. Hence, it is advisable to consider segregating the Tibetan Plateau from the temperate zone in future research. (ii) The vegetation types in this study collected data from four distinct ecosystems: forest, grassland, wetland and farmland, but did not collect experimental data on ecosystem transition zone. The relationship between soil fauna and litter decomposition in ecological ecotones maybe differ from a single ecosystem. (iii) The methodology employed for positioning litter bag was not accurately recorded in this database, such as lay flat on the ground, the height above the ground, and the depth of burial into the ground, which may affect the experimental results."}
+{"text": "Biological particles, along with inorganic gaseous and particulate pollutants, constitute an ever-present component of the atmosphere and surfaces. Among these particles are fungal species colonizing almost all ecosystems, including the human body. Although inoffensive to most people, fungi can be responsible for several health problems, such as allergic fungal diseases and fungal infections. Worldwide fungal disease incidence is increasing, with new emerging fungal diseases appearing yearly. Reasons for this increase are the expansion of life expectancy, the number of immunocompromised patients , the number of uncontrolled underlying conditions , and the misusage of medication . Managing fungal diseases is challenging; only four classes of antifungal drugs are available, resistance to these drugs is increasing, and no vaccines have been approved. The present work reviews the implications of fungal particles in human health from allergic diseases  to infections . Topics such as the etiological agent, risk factors, clinical manifestations, diagnosis, and treatment will be revised to improve the knowledge of this growing health concern. Biological particles, along with inorganic gaseous and particulate pollutants, constitute an ever-present component of the atmosphere and surfaces. Among these bioparticles are fungal spores and hyphae ,2 that cFungal spores rarely exceed 20 \u00b5m in diameter, ranging from 3 to 8 \u00b5m . SmallerThe following sections will address the several clinical manifestations associated with exposure to fungal spores. The first section describes diseases related to the host\u2019s adverse immune responses, while the second includes illnesses related to direct infection of the host by fungal pathogens.Exposure to fungal particles  is associated with several allergic diseases, such as allergic bronchopulmonary aspergillosis , severe asthma with fungal sensitization , and allergic fungal rhinosinusitis  .Alternaria spp. and Cladosporium spp.) that present airborne concentrations overlapping seasonal disease symptoms of acute allergic exacerbations. The second group includes an allergic response to thermotolerant filamentous fungal genera  that not only act as aeroallergens but can also germinate in the airway, colonizing the lung and leading to a persistent allergenic stimulus that damages lung tissue .,47.AsperThe initial treatment of patients with SAFS should be similar to that of patients with severe asthma: asthma education; treatment optimization ; non-pharmacological interventions ; comorbidities treatment and non-biologic add-on therapy  . NeverthThunderstorm asthma can be defined as the increase in acute asthma exacerbations after thunderstorms affecting individuals close to each other and the associated storm front . Some paAlternaria spp., Cladosporium spp., Diatrypaceae, Didymella exitialis, Phaeospaeria nigrans, and Sporobolomyces spp.) 192].Diagnosis relies on medical and travel history, symptom records, physical examinations, lab tests , and imaging tests  .Acacia nubica, Nigella sativa, Boswellia papyrifera, Melaleuca alternifolia, Moringa oleifera, Zingiber officinalis, Piper nigrum, Eugenia caryophillus, and Cinnamomum verum, have been suggested, with positive effects on the treatment of this disease [Eumycetoma treatment includes the use of oral antifungal medication . Nevertheless, more complex and incontrollable cases may require surgery and amputation ,192,193. disease .Like Eumycetoma, chromoblastomycosis is endemic in tropical and sub-tropical regions between 30\u00b0 North and 30\u00b0 South .Fonsecaea pedrosoi, F. monophora, F. nubica, F. pugnacius, Cladophialophora carrionii, C. yegresii, C. samoensis, Phialophora verrucosa, Rhinocladiella aquaspersa, R. tropicalis, R. similis, and Cyphellophora ludoviensis. As common characteristics, all these species present low pathogenicity and are saprophytes from the soil, plants, and decomposing organic matter [The most common etiological agents are c matter ,196. MosRisk factors include age (50\u201360 years), gender , underlying medical conditions (secondary immunodeficiencies and poor nutrition), and environmental exposure . This disease is considered an occupational disease, highly prevalent among farm laborers, loggers, and vendors of farm products in endemic regions.Transmission occurs when the fungal spores in the soil, plants, and decomposing matter, enter the human body (mainly lower members) through wounds or other minor skin injuries.Chromoblastomycosis presents with the formation of nodules or papules with centrifugal growth\u2014moriform bodies\u2014at the infection site. The initial lesion remains stable for several months or years and evolves into metastatic lesions  at other anatomic sites .The diagnosis is based on medical and travel history, symptom records, physical examinations, and lab tests  ,197.2 laser, and photodynamic therapy [The treatment includes oral antifungal medication , surgery (to remove lesions), cryosurgery (liquid nitrogen), thermotherapy , CO therapy ,197.Aspergillus species are an ever-present component of the airborne microflora from indoor and outdoor environments continuously inhaled by humans. These conidia present reduced dimensions (2.5 to 3.5 \u03bcm in diameter). They are coated by a hydrophobic layer that helps them to evade the filtration in the nose and enter the respiratory airways. In healthy individuals, conidia are effectively trapped by the mucociliary clearance mechanisms, inactivated, and eliminated. However, if conidia reach the alveoli, several immunological cellular defenses are activated to clear these particles. In immunodeficient patients, the conidia can evade this defense mechanism clearance from the respiratory tract. As such, conidia that reach deeper regions of the respiratory tract germinate and establish fungal masses inside the lungs [Conidia from he lungs .Aspergillosis is a group of illnesses dependent on host factors and their immunologic response. Noninvasive forms include allergic bronchopulmonary aspergillosis  and alleA. fumigatus. However, other non-fumigatus Aspergillus species also contribute to the disease outset; among these are: A. niger, A. terreus, A. nidulans, and A. oryzae , the existence of underlying medical conditions  ,200,201.Aspergillus conidia can enter the human body through other tissues, such as the skin, central nervous system, eyes, and nails, disseminating throughout the body [The main route of infection is through the respiratory tract by spore inhalation. Nonetheless, the body . No persAspergillus hyphae, cellular debris, and mucus. Since the fungus colonizes a preexisting cavity in the lung parenchyma, it is considered a noninvasive form of chronic pulmonary aspergillosis. The global burden of aspergilloma is nearly 1.2 million, corresponding to the higher incidence and prevalence rates in lower-income countries in Africa, the western Pacific, and Southeast Asia. Although fungal balls mainly develop in the lung, they can also be found in other organs, such as nasal sinuses, the heart, and the brain [An aspergilloma is a fungus ball formed by a mixture of he brain .Invasive pulmonary aspergillosis (IPA) is a severe infection with rapid dissemination from the lungs to the brain, heart, kidneys, or skin . It is tThe main clinical manifestations include arthralgia, cephalalgia, chills and fever, chest pain, dry cough, cough with hemoptysis, wheezing, dyspnea, eye symptoms, skin lesions, fatigue, and weight loss ,202.Aspergillus antigen, detection of IgG and IgM antibodies against Aspergillus, culture, and molecular identification from biopsy, blood, sputum, tracheal aspirate, and broncho-alveolar lavage), and imaging tests  [Early diagnosis is essential for a favorable prognosis. It includes a detailed medical history, symptoms description, physical examinations, lab tests  .Candida spp.) and deep-seated infection  [Candidiasis, a general medical term, includes cutaneous and mucosal infections  and invayelitis) ,206, whiCandida spp. cause invasive candidiasis. Among them, C. albicans is the most common etiological agent. However, an increasing number of infections can be attributed to non-albicans Candida species, such as C. glabrata, C. auris, C. parapsilosis, C. tropicalis, and C. krusei [More than 15 . krusei . Neverth. krusei .Candida from the gastrointestinal tract to the bloodstream or contamination/colonization of an intravenous catheter. Deep-seated candidiasis results from the non-hematogenous introduction of Candida species into sterile sites, mainly the abdominal cavity, following gastrointestinal tract disruption or via an infected peritoneal catheter [Candidemia is associated with the translocation of commensal catheter . Invasivcatheter . Risk facatheter .Invasive candidiasis does not present specific clinical signs or symptoms, including abdominal pain, cephalalgia, chills, fatigue, fever, light sensitivity, low blood pressure, memory loss, mental confusion, myalgia, skin rash, vision changes, and weakness .Candida antigens and anti-Candida antibodies, molecular identification, culture from biopsy and blood) [The early diagnosis of invasive candidiasis is challenging and essential to effectively managing the disease . The diad blood) ,210.Cryptococcus spp., has become a significant infection in both immunocompromised and immunocompetent hosts, frequently associated with significant mortality rates  [Cryptococcosis, an invasive disease caused by the yeastlike fungus untries) ,212.Cryptococcus gattii/Cryptococcus neoformans species complexes . No person-to-person transmission has been reported . The priIn cases of meningitis, symptoms include cephalalgia, cervicalgia, mental confusion, nausea and vomiting, and sensitivity to light. In the case of pulmonary disease, symptoms include fever, chills, cough, malaise, sleep hyperhidrosis, dyspnea, weight loss, and hemoptysis .Diagnosis is achieved through medical history, symptoms records, physical examinations, lab tests , and imaging tests  ,215,218.Blastomyces spp. \u2014a dimorphic pathogen , hemoptysis, fatigue, anorexia, and weight loss .B. dermatitidis may present as pulmonary or extrapulmonary disseminated disease.As with most endemic mycoses, symptom severity and disease course depend on exposure extent (inoculum size) and the immune status of the exposed individual. Based mainly on blastomycosis outbreak studies, the symptomatic disease occurs in less than half of infected individuals. Clinical illness caused by A classic form of blastomycosis is chronic cutaneous involvement that is almost always the result of hematogenous dissemination from the lung, in most instances without evident pulmonary lesions or systemic symptoms. Pulmonary blastomycosis may be asymptomatic or present as a mild flulike illness. More severe infection resembles bacterial pneumonia with acute onset, high fever, lobar infiltrates, and cough. Progression to fulminant adult respiratory distress syndrome with high fever, diffuse infiltrates, and respiratory failure may occur. A more subacute or chronic respiratory form of blastomycosis may resemble tuberculosis or lung cancer, with the radiographic presentation of pulmonary mass lesions or fibronodular infiltrates.Clinical suspicion is essential for diagnosis, and delays can be avoided based on laboratory testing.B. dermatitidis antigen detection, and molecular identification from tracheal aspirates, sputum, bronchoalveolar lavage, bone, blood, cerebrospinal fluid (CSF), prostatic tissue, urine), and imagological tests (X-ray) [Diagnosis requires a detailed medical and travel history, symptoms record, physical examinations, lab tests  ,225.Coccidioides immitis and C. posadasii from soils, is a group of fungal infections of the Western hemisphere and is endemic to areas with reduced rainfall levels, occurring between the latitudes 40\u00b0 north and 40\u00b0 south [Coccidioidomycosis , caused by 0\u00b0 south ,227,228 0\u00b0 south .The transmission route is established by inhaling arthroconidia that become airborne due to natural  and anthropogenic events . Although no person-to-person transmission has been established, sporadic cases of transmission by transplanted organs  and neonatal transmission  have been reported . The mosMost of patients (60%) with coccidioidomycosis remain asymptomatic. One-third of the patients develop a pulmonary illness; in 0.5\u20132% of cases, the infection disseminates to other body locations . The most common symptoms include arthralgia, cephalalgia, chest pain, chills, cough, hemoptysis, dyspnea, fatigue, fever, myalgia, lung nodules, rashes, sleep hyperhidrosis, and weight loss .Coccidioides antigens, molecular identification, culture from biopsy and blood) [Diagnosis includes detailed medical history, symptoms records, physical examinations, and lab tests  ,229.Histoplasma capsulatum, is a global disease endemic to regions distributed through the six inhabited continents , and imaging tests (X-ray or CT scan) [Accurate diagnosis is challenging and limited in countries where histoplasmosis is highly endemic. Diagnostic steps include a medical history, symptoms, physical examinations, lab tests  ,233.Histoplasmosis can be cured without medication in most patients. However, treatment is recommended in immunocompromised patients and those with progressive disseminated or acute pulmonary disease .Emergomyces [E. pasteurianus, E. africanus, E. canadensis, E. orientalis, and E. europaeus [Emergomycosis, a recently emerged systemic fungal infection, is caused by the novel dimorphic fungus species rgomyces . The cauuropaeus ,236,237 Infection occurs through inhaling airborne conidia released from saprophytic mycelia in soil. In the human body, conidia are converted into yeast-like cells that replicate and disseminate to other body parts  . Risk faCutaneous manifestations include umbilicated papules, nodules, ulcers, verrucous lesions, crusted hyperkeratotic plaques, and erythema. Respiratory manifestations include epistaxis, nasal congestion, oroantral fistula, pneumonia, and lobar atelectasis. Hematological manifestations include anemia and thrombocytopenia. Central nervous system manifestations include changes in mental status, headache, seizure, ataxia, vision changes, and behavioral changes. Gastrointestinal manifestations are associated with changes in different enzymes. Genital manifestations include the appearance of endocervical masses .Diagnosis relies on medical history, symptoms records, physical examinations, and lab tests  .So far, no treatment guidelines are available. Therefore, current therapeutic approaches are based on those applied to similar disseminated fungal diseases .Paracoccidioides americana, P. restrepiensis, P. venezuelensis, and P. lutzii [Paracoccidioidomycosis , an endemic fungal disease from Latin American countries, presents a greater prevalence in Central and South America ,239. The. lutzii ,240,241 Transmission routes include the inhalation of airborne fungal conidia or the entry of spores through minor traumas. No person-to-person transmission . The risParacoccidioidomycosis symptoms resemble numerous other infections  and noninfectious diseases  and include cough, dyspnea, fatigue, fever, hepatosplenomegaly, lesions in the mouth and throat, lymphadenitis, weight loss .Diagnosis includes elaborating a medical and travel history, symptom reports, physical examinations, lab tests , and imaging tests (MRI) ,243.T. marneffei , is a life-threatening mycosis caused by the fungus arneffei . This diThe main transmission route of infection occurs by spore inhalation. Another route is established when fungal spores live in the soil and plants and enter the body through wounds or other minor skin injuries . The priThe symptoms of infection are agitation, anemia, confusion, depressed consciousness, dyspnea, fatigue, fever, hepatosplenomegaly, lymphadenopathy, respiratory and gastrointestinal abnormalities, skin lesions , and weight loss .Diagnosis includes a medical and travel history, symptoms records, physical examinations, and lab tests  .Fusarium spp., is a disseminated fungal disease  or disseminated diseases  [Fusariosis, caused by  disease . Fungus ariosis) .Fusarium species present a worldwide distribution, with several species complexes associated with disease onset. Among the most relevant are F. solani (40\u201360% of cases), F. oxysporum (nearly 20% of cases), F. fujikuroi, F. moniliforme, F. incarnatum-equiseti, F. clamydosporum, F. dimerum, F. sambucinum, F. concolor, and F. lateritium [teritium ,250.Transmission occurs when fungal spores in the soil and plants enter the body through wounds or other minor skin injuries. The main risk factors are secondary immunodeficiencies  ,249.Symptoms inlcude fever, myalgia, pneumonia, skin lesions, superficial infection in the feet with lymphangitis, and toxaemic appearance .Diagnosis includes the medical history, symptoms record, physical examinations, and lab tests  ,252.Aspergillus spp., Acremonium spp., Basidiomycota, Beauvaria spp., Chaetoconidium spp., Chrysosporium spp., Fusarium spp., Microascus spp., Paecilomyces spp., Penicillium spp., Pseudallescheria spp., Scedosporium spp., Schizophyllum spp., Scopulariopsis spp., and Trichoderma spp. , underlying medical conditions , trauma, burns, surgery, and the use of a central venous catheter ,254.The most significant hyalohyphomycosis symptoms include anemia, arthralgia, cellulitis, encephalitis, mental confusion, cough, endophthalmitis, fever, hepatosplenomegaly, keratitis, lymphadenopathy, onychomycosis, osteomyelitis, peripheral edema, peritonitis, pneumonia, renal failure, sinusitis, and weight loss ,254.Diagnosis is performed by elaborating a medical history, symptoms record, physical examinations, and lab tests  ,254.L. prolificans (previously known as Scedosporium prolificans)    I,J. DepeThis fungus has been isolated from several environmental sources  from different locations with dry climates . Two main routes of entry in the human have been described: inhalation of airborne conidia and traumatic inoculation of conidial cells from contaminated environmental sources. Risk factors for lomentosporiosis development include medication , underlying medical conditions , surgery, and trauma. Behavioral aspects such as intravenous drug use can facilitate disease development .Cutaneous infection signs include numerous erythematous nonpruritic skin nodules with or without a necrotic center. Respiratory infection symptoms are cough, dyspnea, fever, and pleuritic chest pain. Cardiac infection presents with fever and embolic phenomena. Central nervous system involvement includes meningitis, meningoencephalitis, and brain abscess formation. Eye infection includes endophthalmitis, kerato-scleritis, and kerato-uveitis. Moreover, other clinical manifestations, such as mycotic aneurysms, external otitis, sinusitis, peritonitis, onychomycosis, and esophagitis, have been previously linked to lomentosporiosis ,256.Diagnosis includes elaborating a medical history, symptoms record, physical examinations, and lab tests  ,257.Apophysomyces (A. variabilis), Cunninghamella (C. bertholletiae), Lichtheimia , Mucor (M. circinelloides), Rhizopus , Rhizomucor (R. pusillus), and Saksenaea (S. vasiformis) [Mucormycosis (previously known as zygomycosis) is an angio-invasive fungal infection initiated by the fungi belonging to the order Mucorales. This disease is associated with high morbidity and mortality rates. The species most frequently isolated from patients are iformis) ,259 , underlying medical conditions . Behavioral aspects include injectable drugs and chronic alcoholism .Mucormycosis mild infections involve the cutaneous tissue. More severe and disseminated forms can affect several organs, such as the brain, lungs, gastrointestinal tract, kidney, bones, heart, ear, parotid gland, uterus, urinary bladder, and lymph nodes. Therefore, a wide range of signs and symptoms can be associated with this disease. Among them are abdominal pain, cephalalgia, chest pain, mental status changes, coma, cough, dyspnea, fever, nausea and vomiting, gastrointestinal bleeding, lesions on the nasal bridge or palate, nasal or sinus congestion, and unilateral facial edema .Diagnosis comprises medical history, symptom record, physical examinations, lab tests , and imaging tests (CT scan) .Alternaria, Aureobasidium, Biatriospora, Bipolaris, Chaetomium, Cladophialophora, Corynespora, Curvularia, Exophiala, Exserohilum, Fonsecaea, Microsphaeropsis, Phialemonium, and Ramichloridium [Phaeohyphomycosis includes several diseases caused by opportunistic \u201cdematiaceous\u201d or \u201cmelanized\u201d fungi, distinguished by the presence of melanin in their cell walls, considered a virulence factor in these organisms. These fungi belong to the genera loridium ,262  .Pneumocystis pneumonia (PCP) , is caused by P. jirovecii  and with underlying medical conditions  ,265.As with many other fungal diseases, PCP symptoms are nonspecific and include chest pain, chills, nonproductive cough, dyspnea, hypoxemia, respiratory failure, fatigue, and fever. The lungs are the primary site of infection. Nevertheless, rare cases of extrapulmonary PCP have been reported in humans, including the eyes, ears, lymph nodes, liver, spleen, and bone marrow. Systemic dissemination has also been documented .The diagnostic steps include elaborating a medical history, symptoms record, physical examinations, lab tests , and imageology tests (X-ray) ,266,267.Sporothrix spp. . Although rare, infection by inhalation of aerosolized fungal propagules has also been reported. Over the last few years, the epidemic of sporotrichosis outbreaks in domestic animals (zoonosis) in Asia and South America demonstrated that the disease could also be disseminated when humans have close contact with animals . No person-to-person transmission has been reported ,270,271.Symptoms include arthralgia, cephalalgia, chest pain, cough, dyspnea, fever, mental confusion, seizures, skin nodules, and weight loss .Diagnosis includes the elaboration of a detailed medical and travel history, symptoms record, physical examinations, lab tests , and imagological tests (X-ray) .Treatments for these severe systemic fungal infections include systemic azole agents , echinocandins , antimetabolites (flucytosine) or polyene therapy . In most severe cases, a combination of antifungal agents is considered to seek synergy.Some of these fungi are inherently non-susceptible to standard antifungal therapy, alternative antifungal agents, and surgical management may be required. Furthermore, it is crucial to reverse the underlying impairment of host defenses.Alternaria spp., Cladosporium spp., Epicoccum spp.), warmer temperatures at higher latitudes will contribute to the colonization of new geographical locations, increasing the distribution of otherwise endemic fungal pathogens. On the other hand, the increase in rainfall and relative humidity levels associated with floods and hurricanes will favor the increase in concentrations of wet weather spores .Some predictions can be made concerning the evolution of the trends of fungal diseases in the decades ahead . ClimateThe number of patients at risk is continuously increasing. Among these patients are those with HIV/AIDS and those subjected to chemotherapy or immunosuppression therapies, mainly in low-income countries with limited health resources . The numDespite all efforts, no vaccines or immune therapies for fungal diseases are available. The development of these products, their commercialization and distribution would reduce the number of fungal diseases worldwide.A. fumigatus and Fusarium spp. [Another matter of concern is the increasing number of antifungal resistances. So far, four main drug classes  are available. Resistance to azoles, driven by the over-usage of fungicides for agricultural and veterinary purposes that later spread to human pathogens by several mechanisms , has already been reported in several fungal human pathogens, such as ium spp. . It is eium spp. . The incAlthough with different concentrations, fungal spores are an ever-present component of indoor and outdoor environments. These airborne particles can cause several human diseases ranging from mild allergic diseases  to severe disseminated infections (mainly associated with immunocompromised patients).More than thirty fungal genera have been identified as producing allergens so far . These aAround sixty fungal genera are responsible for the onset of fungal infections . The main risk factors associated with the development of these diseases are underlying medical conditions mainly associated with a secondary immunodeficiency such as diabetes mellitus, the use of medication , together with environmental exposure associated with either healthcare facilities, work, or leisure activities. Routes of transmission include inhalation, the entry of fungal spores through skin injuries, ingesting contaminated food products, nosocomial infections, and person-to-person transmission. The main clinical manifestations include respiratory  and central nervous system symptoms . Currently, only four drug classes  are used in therapeutics.More profound knowledge of the diversity of fungal diseases will increase the awareness of these diseases, and the control of associated risk factors, improving its diagnosis and treatment."}
+{"text": "Colorectal cancer, ranking among the most prevalent causes of cancer-related mortality, is an escalating global health concern. The incidence and mortality of colorectal cancer are expected to surge substantially by 2030, posing a significant public health challenge. This article provides a comprehensive overview of rectal cancer, encompassing its epidemiology, anatomical intricacies, pathophysiology, clinical presentation, and diagnosis. The tumor-node-metastasis (TNM) classification system for rectal cancer is detailed, offering crucial insights for staging and treatment decisions. Various treatment modalities are discussed, including surgical approaches, systemic therapies, radiation therapy, and local therapies for metastases. Recent advances in robotic surgery and innovative radiation technologies are explored. Furthermore, prevention strategies are elucidated, focusing on lifestyle modifications and pharmacological interventions that may mitigate the risk of colorectal cancer. The article underscores the importance of understanding rectal cancer for healthcare professionals and patients, enabling informed decision-making and enhanced management of this disease. Prognostic factors are outlined, with survival rates and the prognosis of rectal cancer contingent on several influential elements, highlighting the multifaceted nature of this condition. In conclusion, accurate diagnosis, diverse treatment options, and prevention strategies, including advances like robotic surgery, influence rectal cancer outcomes. A comprehensive overview empowers healthcare professionals and patients to make informed decisions for improved disease management and prognosis. Colorectal cancer, as per Global Cancer Statistics (GLOBOCAN) data, ranks as one of the most prevalent and fatal malignant diseases globally. It stands as the third leading cause of cancer-related mortality and the fourth most commonly diagnosed malignant condition, with its incidence steadily increasing . The gloAnatomy of the rectumThe rectum is a vital anatomical element within the gastrointestinal tract, commencing at the sacral promontory as a seamless extension of the sigmoid colon. Its external longitudinal muscular layer is a result of the merging of the taenia coli. This gastrointestinal segment exhibits a length spanning from 12 to 15 centimeters, extending from the rectosigmoid junction to the dentate line in the anal canal. The anatomical trajectory of the rectum is marked by two anterior-posterior curvatures, initially following the concavity of the sacrum at the sacral flexure and subsequently bending with an anterior convexity at the anorectal flexure  and appears to be associated with a more positive prognosis, whereas signet-ring cell carcinomas are linked with a less favorable outlook. .The objective of this article is to provide a comprehensive overview of rectal cancer, covering its epidemiology and risk factors, anatomy, pathophysiology, clinical presentation, diagnosis, tumor-node-metastasis (TNM) classification, treatment modalities including surgery, systemic therapy, and local therapies for metastases, and recent advances in the field. It also discusses prevention strategies and the factors influencing the prognosis of rectal cancer patients. This article aims to offer a thorough understanding of rectal cancer for healthcare professionals and patients, facilitating informed decision-making and improved management of the disease.Epidemiology and risk factorsTo effectively address the prevention and management of colorectal cancer, it is paramount to comprehensively understand the associated risk factors. These factors can be categorized into various groups. Gender and race play pivotal roles, with men having a higher risk and often experiencing more unfavorable prognoses than their female counterparts. Notably, non-Hispanic Black individuals exhibit a higher incidence rate compared to other racial groups. Socioeconomic determinants also exert a substantial influence on risk, as individuals with low socioeconomic status face elevated risks due to limited access to healthcare, unhealthy lifestyle habits, and dietary factors. An intricate grasp of these risk factors is indispensable for the prevention, early detection, and effective management of colorectal cancer. Additionally, lifestyle choices play a pivotal role in shaping colorectal cancer risk. Dietary preferences, such as high consumption of red and processed meats and low intake of dietary fiber, fruits, and vegetables, are unequivocally associated with an increased risk. Conversely, adequate intake of calcium, vitamin D, and dairy products may confer a protective effect. The risk is further exacerbated by factors such as overweight and obesity, physical inactivity, and a sedentary lifestyle. Moreover, the consumption of tobacco and alcohol, particularly in excessive quantities, stands as a well-established risk factor -9.Family and personal medical history are substantial contributors to risk. A family history of colorectal cancer, particularly in first-degree relatives, significantly elevates the individual's risk. Hereditary non-polyposis colorectal cancer (HNPCC), also known as Lynch syndrome, and familial adenomatous polyposis (FAP) substantially augment the risk. A personal history of cancer further compounds the risk. Inflammatory bowel diseases, particularly Crohn's disease and ulcerative colitis, are associated with an increased risk, particularly in cases of longer disease duration and greater severity. Colon polyps, particularly adenomatous polyps, possess the potential to progress into malignancy, and approximately 95% of colorectal cancers originate from such polyps. The risk associated with colon polyps escalates with factors like polyp size, degree of dysplasia, and age. It is essential to underscore that alterations in gut microbiota have been implicated in the development of colorectal cancer, engaging diverse mechanisms, including DNA damage and inflammation. Age is a prominent factor, with risk increasing significantly with advancing age, and the majority of cases occurring in individuals over the age of 50. Nevertheless, it is noteworthy that recent trends indicate a rising incidence of colorectal cancer among young adults ..1].The prognosis of rectal cancer is influenced by several key factors, including the cancer's stage, tumor size, lymph node involvement, presence of metastasis, histologic grade, molecular and genetic markers, the patient's overall health, response to treatment, completeness of surgery, the expertise of the treatment team, and the emergence of novel therapies such as immunotherapy and targeted treatments. More favorable prognoses are associated with earlier stages, smaller tumors, absence of lymph node involvement, and successful surgical removal of the tumor .A new tIn conclusion, rectal cancer is a global health concern with increasing incidence rates and specific risk factors, including gender, race, lifestyle choices, and family history. Accurate diagnosis through colonoscopy, biopsy, and imaging is essential. Treatment options include surgery, systemic therapies , and radiation therapy. Local therapies for metastases are vital, while recent advances in robotic surgery improve outcomes. Prevention involves lifestyle changes and certain medications. The prognosis depends on various factors, with a 5-year survival rate of around 67%. This comprehensive overview aids healthcare professionals and patients in informed decision-making for more effective disease management."}
+{"text": "Although the rates of response to first-line pharmacological treatments (serotonin reuptake inhibitors \u2013 SRIs) are generally twice that of placebo, only 40-60% of patients respond sufficiently or are able to tolerate traditional first-line pharmacotherapy. Augmentation with dopamine antagonist medications is associated with the strongest evidence, yet dopamine antagonists benefit only a minority of those who try them and carry elevated risks of adverse effects. Based on evolving pathophysiologic models of OCD, a variety of agents targeting serotonin, dopamine, norepinephrine, glutamate, and anti-inflammatory pathways have been explored as alternative or adjunctive therapies for treatment-resistant OCD and have at least preliminary evidence of efficacy. Similarly, approximately 50% of patients do not respond optimally to first psychotherapeutic treatments including cognitive behavioural therapy (CBT) and exposure and response prevention (ERP), even when combined with pharmacotherapy. The psychotherapy outcome literature is heterogeneous and very few psychological strategies have been developed specifically to treat treatment resistant OCD. However, a recent systematic review concluded that CBT improved treatment response in individuals with pharmacotherapy resistance. This presentation will present an update on the pharmacological and psychotherapeutic treatment of refractory OCD including novel strategies such as the use of psychedelics.M. Van Ameringen Grant / Research support from: Elvium, CIHR,Hamilton Academic Health Sciences Organization, Consultant of: Abbvie, Bausch Health, Boehringer Ingelheim, Elvium, Jazz, Vistagen, Speakers bureau of: Abbvie, Elvium (Purdue), Lundbeck, Otsuka, Sunovion, and Takeda"}
+{"text": "Journal of Managed Care + Specialty Pharmacy (JMCP) is to advance science, expertise, and evidence-based decision making to improve patient health through access to high-quality, cost-effective medications and other therapies. We adopted this mission statement in 2020, which coincided with the 25th anniversary of the journal and is aligned with AMCP\u2019s mission.The mission of the JMCP editorial team extends the following guiding principles for the journal. These principles can be applied to several functions, such as editorial prioritization, policy setting, strategic planning, and stakeholder engagement.We favored brevity in the crafting of our mission statement, yet we recognize the importance of elucidating and elaborating on the concepts within. Therefore, in support of our mission statement, the JMCP\u2019s mission is to advance science, expertise, and evidence-based decision making to improve patient health through access to high-quality, cost-effective medications and other therapies.As the premier journal in managed care pharmacy thought leadership and research, we:Publish scientific research, real-world evidence, commentary, and practice guidance that is actionable in managed care pharmacy practiceFoster the exchange of ideas across health care decision makers, policymakers, managed care pharmacy practitioners, specialty pharmacy practitioners, academicians, drug developers, and patientsExplore current and emerging trends in managed care and specialty pharmacyInfluence policy by informing the managed care pharmacy community, government, media, and others concerned with access to high-quality, cost-effective therapiesEmbrace broad ethical, legal, social, and public health frameworksPromote managed care pharmacy\u2019s role in addressing racial and social inequities in medication useMaintain policies that foster the highest standards of research ethics and integrity by investigators who publish in our journalAdhere to the highest standards of publication ethics, peer review, and editorial independenceLaura E Happe, PharmD, MPHEditor-in-ChiefUniversity of FloridaDonald G Klepser, PhD, MBAAssociate EditorUniversity of Nebraska Medical CenterCarrie McAdam-Marx, BSPharm, MS, PhDSection EditorUniversity of Nebraska Medical CenterMelissa S McCart, PharmD, MSAssociate EditorXcendaKaren L Rascati, PhDAssociate EditorUniversity of Texas College of PharmacyMichael T Rupp, BSPharm, PhDSection EditorMidwestern UniversitySara Carruth, PharmDAstraZenecaBonnie Greenwood, BCPS, PharmDEAB ChairCommonwealth Medicine, University of Massachusetts Medical SchoolGene Reeder, PhDUniversity of South CarolinaPrabashni Reddy, BSPharmPartners Healthcare"}
+{"text": "Frontotemporal dementia (FTD) is the second most common type of dementia seen between 45-65 years of age and affects the frontal and/or temporal lobes. FTD is clinically characterized by progressively the change in behavior, personality, and language dysfunctions.Clinical features of FTD include restlessness, disinhibition, apathy, blunted affect, avolition, social withdrawal, impulsiveness, and loss of executive function. Most patients with FTD act as socially inappropriate behaviors, not talking much, compulsive-like acts, poor insight, and psychiatric features including hallucinations and paranoid delusions. According to symptoms, the diagnosis of FTD may be confused with depression, mania, or schizophrenia.In this case report, we wanted to draw attention that FTD should be considered in the differential diagnosis of late-onset psychosis.A 53-year-old female, married, uneducated, and not having children patient has applied to our clinic with complaints, that started a year ago, about social withdrawal, activity, decreased sense of purpose, neglecting personal hygiene, not eating well, and acting inappropriately and impulsively.The patient reported that she was walking out of the house for hours, having profanity speeches, and forgetfulness.She was admitted to the psychiatry hospital a year ago and discharged with a diagnosis of bipolar disorder.Brain MRI showed atrophy of frontal and anterior temporal structures bilaterally. PET scan demonstrated left frontal, parietal, and temporal hypo perfusion of the brain.In our clinical observation, she had apathy, inappropriate jokes, lack of eye contact, flat affect, lack of gesturing when communicating, unable to respond to questions, and visual hallucinations.Due to the similarity of the clinical resemblance of BPAD and FTD, the diagnosis of FTD can be confusing. In this case, amnesia and sudden onset of the symptoms with rapid destruction may help the diagnosis of FTD.Psychosis symptoms in our clinical observation also suggested the diagnosis of psychosis. However, its atypical course and early-onset psychosis symptoms brought us closer to organic pathology. Investigations of structural and functional brain imaging may help support the diagnosis.Image:Image 2:Psychiatric symptoms in FTD may cause misdiagnosis. Organic pathologies should be kept in mind, especially in late and sudden onset symptoms.None Declared"}
+{"text": "Background: A mechanistic understanding of the effects of dietary treatment in irritable bowel syndrome (IBS) is lacking. Our aim was therefore to investigate how fermentable oligo- di-, monosaccharides, and polyols (FODMAPs) and gluten affected gut microbiota and circulating metabolite profiles, as well as to investigate potential links between gut microbiota, metabolites, and IBS symptoms. Methods: We used data from a double-blind, randomized, crossover study with week-long provocations of FODMAPs, gluten, and placebo in participants with IBS. To study the effects of the provocations on fecal microbiota, fecal and plasma short-chain fatty acids, the untargeted plasma metabolome, and IBS symptoms, we used Random Forest, linear mixed model and Spearman correlation analysis. Results: FODMAPs increased fecal saccharolytic bacteria, plasma phenolic-derived metabolites, 3-indolepropionate, and decreased isobutyrate and bile acids. Gluten decreased fecal isovalerate and altered carnitine derivatives, CoA, and fatty acids in plasma. For FODMAPs, modest correlations were observed between microbiota and phenolic-derived metabolites and 3-indolepropionate, previously associated with improved metabolic health, and reduced inflammation. Correlations between molecular data and IBS symptoms were weak. Conclusions: FODMAPs, but not gluten, altered microbiota composition and correlated with phenolic-derived metabolites and 3-indolepropionate, with only weak associations with IBS symptoms. Thus, the minor effect of FODMAPs on IBS symptoms must be weighed against the effect on microbiota and metabolites related to positive health factors. Bifidobacterium  sequences per sample. After filtering and bioinformatic processing corresponding, values were 106062 [14907 (20236)] sequences. No intervention effect was found on gut microbiota diversity measured by richness, Shannon\u2019s diversity index, Simpson\u2019s index or inverse Simpson\u2019s index . UnsuperAnaerostipes, Bifidobacterium, Faecalibacterium, Fusicatenibacter, Agathobacter, Paraprevotella, and Oxalobacter increased after the FODMAP intervention compared to the placebo  torques, Lachnospiraceae NK4A136, Lachnospiraceae NA, Hungatella, Eisenbergiella, Negativibacillus, Coprostanoligenes group NA, and Flavinofractor decreased , Roseburia, Lachnoclostridium, and an unknown Lachnospiraceae genus r \u2264 0.25, p < 0.05). However, those genera were not affected by FODMAP intake. None of the correlations remained statistically significant after adjustment for multiple testing.Among the bacterial genera that increased after the FODMAP intervention compared to the placebo, p = 0.02). Isovalerate in feces was reduced after gluten compared to the placebo . Top selected variables of interest included Anaerostipes, Bifidobacterium, 3-indolepropionate (IPA), phenyl sulphates and as yet unidentified metabolites  correlated negatively with valerate, isovalerate, isobutyrate, succinate, acetate, butyrate, and propionate in feces , while Flavinofractor, Eisenbergiella, an unknown Christensenellaceae genus and Peptococcus correlated negatively. Blautia, Anaerostipes, Fusicatenibacter, Butyriccoccus, Roseburia, Erysipelotrichaceae UCG-003, the Lachnospiraceae ND3007_group, an unknown Lachnospiraceae genus, and Turicibacter correlated positively with IPA, an unknown quionoline/indole compound, and an unidentified feature, whereas Flavinofractor, an unknown Christensenellaceae genus, and an unknown Coprostanotigenes genus correlated negatively. Marvinbryantia, Negativibacillus, Turicibacter, Eisenbergiella, an unknown Christensenellaceae genus, and an unknown Coprostanotigenes genus, Oxalobacter, Peptococcus, and Hungatella correlated positively, whereas the (Ruminoccocus)_grauveauii_group, Faecalibacterium, Agathobacter, Blautia, Anaerostipes, Fusicatenibacter, Butyricicoccus, Anaerovoracaceae Family_XII_UCG-001, Paraprevotella, and the Lachnospiraceae NK4A136_group correlated negatively with unknown phenyl sulphates and a quinoline/indole derivate  torques was reduced after the FODMAP intervention. This genus has been associated with increased gut permeability and inflammation [Flavinofractor by FODMAPs in this study is in line with a previously reported reduction in relation to plant foods [Flavinofractor was not associated with IBS symptoms in this study. The mechanistic role of Flavinofractor in relation to health, both in subjects with and without IBS, remains unclear [The fact that  results ,68,69,70 results . Roseburn intake . Similar FODMAPs . In line FODMAPs , (Ruminoammation ,75,76,77nt foods . Moreovent foods ,80, and nt foods , Flavino unclear , and reqPrevious studies with low and high intake of FODMAPs have only had a minor or even a lack of effect on SCFAs in feces ,15,16. IBifidobacterium correlated weakly with pain linked to bowel emptying, although it had previously not been related to IBS symptoms [symptoms ,12,14. Osymptoms , IBS beisymptoms  with higsymptoms , and thesymptoms . In addisymptoms .Agathobacter increased with FODMAPs and correlated most strongly with phenolic derivates, which to our knowledge has not previously been reported. Interestingly, similar to our study, the Bifidobacterium and Fusicatenibacter species were reported to correlate with 3-3-hydroxyphenylpropionate and 3-hydroxyhippurate in an online atlas of human plasma microbial-derived metabolites [It was previously shown that the conversion of polyphenols to intermediate metabolites, such as 3-3-hydroxyphenylpropionate and 3-hydroxyhippurate, depends on gut microbiota ,88,89. Iabolites . HoweverAnaerostipes and Fusicatenibacter have previously been associated with IPA [Oxalobacter correlated with the group of phenyl sulfates and unidentified features affected by FODMAP intake. Identification of these features and their interplay with gut microbiota needs to be further studied.Several genera that increased after FODMAP intake correlated with IPA and a quinoline/indole derivative in plasma. Among these genera, with IPA . It is kwith IPA . Moreovewith IPA . Howeverwith IPA . Only OxIt is well known that carbohydrates are preferred substrates for gut microbiota fermentation, whereas protein fermentation normally occurs when carbohydrates are depleted . Even thConcerning SCFAs, the reduced level of isovalerate in plasma after the gluten intervention was surprising: isovalerate is a branched-chain fatty acid, and if anything, increased levels from protein breakdown would be expected . InteresThis trial has several limitations. The intervention periods were of relatively short duration, and the effects on the microbiota and metabolites could have been more pronounced with longer durations. However, the intervention periods were decided on to enhance participation for the primary endpoint of investigating IBS symptoms and the microbiota investigation was exploratory. Regardless, the effect after one week of intervention are still of high interest. Similarly, the one-week washouts might not have been sufficient to eliminate carry-over. However, analysis of the sequence order did not show any indications of systematic differences. We therefore assume that one week of washout was sufficient. Furthermore, a hydrogen breath test was not used, which would have given a direct measure of fermentation. The use of sucrose as a placebo can be questioned, due to reported sucrase-isomaltase deficiency in IBS . HoweverA particular strength of this study was the double-blind study design, which reduced the risk of bias, combined with a large sample size and a three-way placebo-controlled cross-over design, which should limit the contribution of individual variability to treatment effects. Another strength is the elimination-exposure character of the study, making the molecular responses specific to the exposures, not confounded by the treatment effect. Furthermore, the joint analysis of gut microbiota and metabolites added knowledge about the physiological effect of FODMAP intake, both regarding gut microbiota composition and functionality, which may be of relevance to health, although more research is needed.Agathobacter, Anaerostipes, Fucicatenibacter, and Bifidobacterium correlated with increased plasma concentrations of phenolic-derived metabolites and 3-indolepropionate. The weak correlations of FODMAP-related gut microbiota and metabolites with IBS symptoms indicate that responses to the interventions had limited impact on symptoms. Consequently, the minor effect of FODMAPs on IBS symptoms must be weighed against beneficial health effects. However, since the interventions were of short duration, the results should be interpreted with caution and long-term randomized controlled trials are highly warranted.Our combined gut microbiota- and metabolite-centered approach showed that the intake of FODMAP, but not gluten, over one week altered the gut microbiota composition, which correlated with metabolites positively associated with health. Specifically, the genera"}
+{"text": "Datura stramonium) exposure within a family in the United States. In this narrative, a pregnant 36-year-old Asian woman and her family unknowingly ingested homemade soup infused with Jimson weed leaves. This led to symptoms such as vomiting, dry mouth, blurred vision, flushed skin, breathing difficulties, and hallucinations. While the woman and her daughter quickly recovered, the husband's severe hallucinations required intensive care. The episode underscores the vital importance of accurate plant identification, particularly in homegrown produce. Recognizing and understanding anticholinergic poisoning symptoms becomes crucial for timely diagnosis and intervention, preventing such occurrences. This case serves as a poignant reminder of the potential risks concealed within our everyday environments.This case report reveals a rare incident of unintended Jimson weed ( Datura stramonium), belonging to the Solanaceae family, is renowned for its abundance of tropane alkaloids, encompassing scopolamine, hyoscyamine, and atropine .In contemporary times, Jimson weed poisoning predominantly occurs among adolescents seeking its hallucinogenic effects. In 1998, the American Association of Poison Control Centers documented 152 cases, though the true prevalence is likely higher . The antThe characteristic symptoms of anticholinergic toxicity, including mydriasis, dry skin, hallucinations, heightened agitation, urinary retention, and tachycardia, can be summarized as \"blind as a bat, dry as a bone, red as a beet, mad as a hatter, and hot as a hare.\"Effectively managing Jimson weed poisoning involves critical steps, beginning with initial assessment, symptom recognition, toxin elimination, providing supportive care, and vigilant monitoring. Maintaining open airways, proper breathing, and optimal circulation is vital. In cases of compromised airways, interventions such as intubation and mechanical ventilation may be necessary. A thorough evaluation, along with a detailed medical history, can provide valuable diagnostic clues, especially when Jimson weed poisoning symptoms are not immediately evident. Swiftly recognizing symptoms such as dry mouth, blurred vision, hallucinations, and altered mental status supports early intervention.To rule out concurrent drug use, toxicology screening is a valuable tool, although it may not always detect pure anticholinergic toxins. Activated charcoal can minimize toxin absorption, and consideration of gastric lavage for removing plant material remains relevant. Inducing emesis is an option for conscious patients. While most cases resolve with vigilant observation, cautious administration of physostigmine, an acetylcholinesterase inhibitor, can counter anticholinergic effects. However, its use carries risks and should be reserved for targeted situations . In addiIn conclusion, the harmful effects of Jimson weed exposure can be attributed to its potent anticholinergic agents. Swift recognition, competent supportive care, and sustained monitoring are imperative to ensure patient well-being.In summary, Jimson weed poisoning presents with characteristic anticholinergic symptoms, often resolving through supportive care and observation. Swift recognition is key, even though severe cases are infrequent. The profound ingestion of Jimson weed can lead to severe complications, possibly even fatal. Therefore, we should emphasize the necessity of vigilance. Physostigmine stands out as a pivotal treatment for critical instances, while benzodiazepines effectively manage agitation. Furthermore, proactive counseling becomes paramount, particularly during the summer and early fall seasons. This educational effort aims to raise awareness about potential risks, urging individuals to exercise caution when cultivating backyard vegetables. This underscores the importance of informed decision-making regarding consumption, thus fostering a culture of safety and mindfulness. Ultimately, being conscientious about what we grow and consume is an essential step toward a safer and more informed approach to plant-based interactions in our daily lives."}
+{"text": "Staphylococcus aureus is the leading cause of death due to bacterial blood stream infection. Female sex was a risk factor for mortality in S. aureus bacteremia (SAB) in some studies, but not in others. The aim of this systematic review and meta-analysis was to determine whether female sex is associated with mortality in SAB.The key question for this systematic review and meta-analysis was as follows: For patients with SAB, is female sex at birth associated with increased mortality? MEDLINE, Embase, and Web of Science were searched from inception to October 31, 2022. We included studies that met all the following conditions: 1) randomized or observational studies evaluating adults with SAB, 2) \u2265200 patients, 3) reported mortality at or before 90-days following SAB, and 4) reported mortality stratified by sex . Exclusion criteria included studies on specific subpopulations , studies that included SAB patients as a subgroup (e.g. patients with bacteremia by any microorganism), and studies using the same cohort as another study included in this review. Both unadjusted and adjusted mortality data, stratified by sex, were extracted.From 5117 studies, 87 were included in the final analysis . Study and patient characteristics are summarized in Table 1. Unadjusted mortality data was available from 80 studies  and revealed a small but significant increased mortality in females compared to males . Adjusted mortality data that accounted for additional patient characteristics and treatment variables were available from 31 studies , and revealed a similar increased mortality in females relative to males . No clear evidence of publication bias was encountered. Sensitivity analysis showed that exclusion of any single study did not influence overall results.Females with SAB have higher mortality than males in both unadjusted and adjusted analyses. Whether this increased mortality is based on biological sex differences rather than social factors has yet to be clarified.Stacey Maskarinec, MD, PHD, National Institutes of Health: Grant/Research Support Vance G. Fowler, MD, MHS, Amphliphi Biosciences, Integrated Biotherapeutics; C3J, Armata, Valanbio; Akagera, Aridis, Roche, Astra Zeneca: Advisor/Consultant|Genentech, Regeneron, Deep Blue, Basilea, Janssen;: Grant/Research Support|Infectious Diseases Society of America: Honoraria|MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck; Medical Biosurfaces; Locus; Affinergy; Contrafect; Karius;: Grant/Research Support|Novartis, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., MedImmune, Bayer, Basilea, Affinergy, Janssen, Contrafect, Regeneron, Destiny,: Advisor/Consultant|Sepsis diagnostic: Patent pending|UpToDate: Royalties|Valanbio and ArcBio: Stock Options Joshua T. Thaden, MD, PhD, Resonantia Diagnostics, Inc: Advisor/Consultant"}
+{"text": "Exposure to phytotoxins that are present in imported ornamental or native plants is an important cause of animal disease. Factors such as animal behaviors , climate change, and an increase in the global market for household and ornamental plants led to the appearance of new, previously unreported plant poisonings in Europe. This has resulted in an increase in the incidence of rarely reported intoxications. This review presents some of the emerging and well-established plant species that are responsible for poisoning episodes in companion animals and livestock in Europe. The main plant species are described, and the mechanism of action of the primary active agents and their clinical effects are presented. Data reflecting the real incidence of emerging poisoning cases from plant toxins are scarce to nonexistent in most European countries due to a lack of a centralized reporting/poison control system. The diversity of plant species and phytotoxins, as well as the emerging nature of certain plant poisonings, warrant a continuous update of knowledge by veterinarians and animal owners. The taxonomy and active agents present in these plants should be communicated to ensure awareness of the risks these toxins pose for domestic animals. Poisonings by phytotoxins, such as alkaloids, glycosides, oxalates, proteins, and others ,2, exertThe toxicological effects depend not only on the characteristics of the plant, but may also be influenced by its growth stage, the amount ingested, and, at times, the part of the plant ingested .Both livestock and companion animals are affected by plant poisoning ,5,6,7,8.Most of the poisoning cases involving dogs and cats are accidental  and are Although dogs are most frequently involved in poisoning cases, cats appear to be more susceptible to plant toxins , and youLarge animal plant poisoning rarely occurs; it usually happens if no other feed is available or when hay or silage are contaminated ,10. AmonA recent analysis of European literature  reportedRecent studies revealed a new epidemiological trend of plant toxicoses mainly related to the current global trade in ornamental plants . These nThe present review aimed to update current knowledge regarding plant poisonings, emerging and not, in Europe, with a focus on describing the main plant species involved , their aAllium cepa (onion) and Allium sativum (garlic) belong to the Amaryllidaceae family. They are pungent aromatic herbs that sprout from bulbs, and their leaves are basal and long with sheathing bases. Their flowers are in umbels and the fruits are three-lobed loculicidal capsules [capsules  (pp. 753Allium species include Allium porrum (leek) and Allium schoenoprasum (chive). Allium case reports in dogs and cats are frequently reviewed [Onion is a biennial or perennial plant, frequently harvested in its first growing season, while garlic is a perennial plant that is usually grown as an annual crop. Other important potentially toxic reviewed . Fresh, reviewed ,33 ylcysteine sulfoxides. Traumatic destruction of the plant tissues will allow for the enzymatic conversion of sulfoxides to less stable compounds, which are further converted into an array of sulfides, disulfides, trisulfides, and thiosulfonates by nonenzymatic reactions [Allium species can form highly reactive oxidants. Unsaturated 1-propylene is the most important hemolytic agent. The hemolytic effect occurs when the level of oxidants in red blood cells is high enough to overwhelm the capacity of their antioxidant metabolic pathways [The active compounds of these plants are disulfides and thiosulfates, especially n-propyl disulfide   with tubular casts, and splenic hematopoietic foci may also be observed   reported the case of a 2-year-old, 2.5 kg male Yorkshire terrier, who displayed anorexia, weakness, depressed mentation, and vomiting after ingesting a meal with meat and onion. Hemolytic anemia and dark-colored urine (hemoglobinuria) were detected at the hematological examination and urinalysis. The dog fully recovered following treatment .In Spain, Guitart et al. (2008) reported Heinz body anemia in two dogs after the ingestion of Catalan spring onions. In both cases, severe Heinz body anemia and the presence of eccentrocytes in new methylene-blue-stained blood smears were noted. Both animals fully recovered following rigorous therapy .Allium ampeloprasum) consumption in a South American coati at the London Zoo in the United Kingdom. Leeks were introduced into the animal diet for 2\u20135 days prior to the initial presentation. Supportive care, along with a blood transfusion, resulted in the immediate improvement of the clinical signs [Jayson et al. (2018) reported a case of Heinz body hemolytic anemia associated with leek  is a weed of notoriety and an ornamental plant from the Verbenaceae family [e family ,52. It ie family ,53,54  are reported. Usually, the gallbladder is enlarged and edema of the wall is evident microscopically [The pathological change routinely observed in affected animals is the congestion of the gastrointestinal mucosa due to the irritating effect of opically   and steroidal saponins. The active compounds are found in the aqueous extract of the plant material ,61. The Hemerocallis (daylilies) are also nephrotoxic to cats and will induce similar clinical signs as Lilium spp. [Different species of ium spp.   and clinical signs were mostly limited to gastrointestinal signs  [The lethal dose of hydrogen cyanide ranges from 2 to 2.5 mg/kg body weight for most species , and acuiarrhea) .Persea americana) is an evergreen tree in the laurel family (Lauraceae family). The tree is approximately 30 m tall with slightly furrowed brown bark [Avocado , peaches, cherries, apricots, plums, and nectarines [These compounds are present in several ctarines .In the gastrointestinal tract, following the hydrolysis of cyanogenic glycosides, hydrogen cyanide is formed . HydrogeMost dogs and cats that consume plants containing cyanogenic glycosides exhibit gastrointestinal symptoms, including vomiting, diarrhea, and abdominal pain. Depending on the extent of exposure, there is also a chance of constipation and gastrointestinal obstruction. Particular signs of cherry laurel poisoning include trembling, shaking, high excitability, convulsions, difficulty breathing, cardiac arrhythmias, frothing at the mouth, and profuse drooling .There are numerous case reports detailing goat intoxication. All cases reported acute clinical signs, including weakness, depressed mentation, hypersalivation, seizure-like activity, mouth breathing, dyspnea, and lateral recumbency. The diagnoses were made postmortem following the finding of large quantities of cherry laurel leaves in the rumen ,29. LessPrunus lauracerasus poisoning in a goat was recently reported by the Milan Poison Control Centre [A fatal case of l Centre .Sorghum spp. (Poaceae family) are among the most widely used pastures for animals and cereals for humans. Sorghum spp. play a significant economic role in the production of grain, hay, silage, and forage. It is the fifth most important cereal grown for forage, grain, and biofuel [ biofuel . Neverth biofuel ,85 (pp. Sorghum plants are represented by cyanogenic glycosides, but they are also nitrate accumulators [The major active compounds of mulators  (pp. 888mulators . For examulators . Soil haSorghum plants is dhurrin, which is a chemical that is non-toxic when unaltered, but following metabolism, is converted into hydrogen cyanide via a two-step enzymatic hydrolysis [All animals are susceptible to this type of intoxication, but the ability of ruminal microflora to rapidly hydrolyze cyanogenic glycosides makes ruminants particularly at risk of cyanide intoxication . All sordrolysis . The HCNdrolysis .After the ingestion of the plant, the HCN is released in the rumen, absorbed into the bloodstream, and transported to the tissues. In the cytochrome oxidase system, cyanide ions and ferric irons interact to block the electron transport chain. HCN does not inhibit hemoglobin from carrying oxygen, but blocks the utilization of oxygen from hemoglobin, resulting in cellular anoxia and rapid death ,89,90.An animal poisoned with cyanide exhibits acute clinical signs of tachypnea, tachycardia, gasping, muscle twitching or anxiety, trembling, foaming from the mouth, cyanosis, and spasms or convulsions; death results from respiratory paralysis ,91. TherSorghum plants high in cyanogenic glycosides. The excessive accumulation of cyanogenic glycosides was attributed to excessive drought during the summer months [In August 2022 in northwestern Italy, more than 50 cows died after consuming young r months .Spathiphyllum spp., or peace lily, are tropical plants and members of the Aracae family. They are evergreen perennial plants with large, dark green, glossy leaves [y leaves  (pp. 131The active compounds of this plant are insoluble calcium oxalate crystals that are aggregated in raphides in special cells called idioblasts  (pp. 131Airway obstruction and even death are possible, but life-threatening problems are rare ,95 (pp. The eyes can also be affected, as contact with plant juice can induce conjunctivitis ,96 (pp. Zantedeschia aethiopica, or calla lily, from the Araceae family is native to Southern Africa and used as cut flowers or ornamental plants [l plants . The call plants . The stel plants ,32.Toxicosis from calla lily is reported in dogs and cats, who seem particularly susceptible ,6,8,15, Clinical signs manifest within 2 h post-exposure and include oral hyperemia and edema, hypersalivation, anorexia, depressed mentation, and other gastrointestinal signs, such as emesis, diarrhea, and abdominal pain; dermal exposure can cause dermatitis [Aucuba japonica, Cyclamen spp., Dieffenbachia spp., Dracaena marginata, Euphorbia pulcherrima, Ficus benjamina, and Rhododendron spp. [Other ornamental plants involved in pet poisoning episodes in recent years in Europe are ron spp. .Adenium obesum, Aglaonema commutatum, Clivia minata, Codiaeum variegatum, Convallaria majalis, Crocus vernus, Epipremnum aureum, Fatsia japonica, Ficus spp., Hippeastrum x hortorum, Hyacinthus orientalis, Kalanchoe spp., Lonicera spp., Monstera deliciosa, Muscari armeniacum, Nerium oleander, Philodendron spp., Sansevieria trifasciata, Schefflera arboricola, Senecio rowleyanus, Syngonium podophyllum, and Taxus baccata [Other potentially poisonous plants for companion animals are  baccata ,100.Plants are frequently involved in animal poisoning in Europe ,8. In re"}
+{"text": "On 3 February 2023, a train derailed in the village of East Palestine, Ohio, home to approximately 4700 residents. Approximately 1.1 million pounds of vinyl chloride, a toxic flammable gas, was released and quickly became volatile . The accThe inhalation of certain irritant gases, such as chlorine, at sufficiently high acute doses can cause bronchiolitis obliterans, a rare disease involving concentric bronchiolar fibrosis in a few months . Small aMoreover, toxic chemical disasters pose a high risk of psychological trauma for nearby residents. A wide spectrum of psychological distress, including the acute onset of psychiatric disorders and the exacerbation of existing psychological and psychiatric conditions, has been seen at accident sites . Hence, Therefore, health assessments should include a comprehensive evaluation of the residents\u2019 medical records, as well as the collection of data on any health effects experienced by the surrounding community regarding cancer, COPD, cardiovascular diseases, mental health, etc. Third-party scientific opinions are warranted to calm down the panic among the community and should acknowledge uncertainty and inform the public about what is known and unknown . Any mis"}
+{"text": "PNAS Nexus, Volume 2, Issue 6, June 2023, pgad163, https://doi.org/10.1093/pnasnexus/pgad163This is a correction to: Gustav Markkula, Yi-Shin Lin, Aravinda Ramakrishnan Srinivasan, Jac Billington, Matteo Leonetti, Amir Hossein Kalantari, Yue Yang, Yee Mun Lee, Ruth Madigan, Natasha Merat, Explaining human interactions on the road by large-scale integration of computational psychological theory, PNAS Nexus, it was discovered that this paper was missing a statement acknowledging compliance with the PNAS Nexus Human and Animal Participants and Clinical Trials policy:During a retroactive audit conducted by Informed consent was obtained from all participants prior to their participation.This error has been corrected in the original article."}
+{"text": "Both preclinical and clinicalstudies have demonstrated the effectiveness of microbiota manipulationin the treatment of IBD and neurodegenerative diseases.6 In particular, increasing attention has been paid to oral probiotictherapies for treating or curing colitis. Tablets, capsules, and powdersof typical probiotic strains, such as Bifidobacteria and Lactobacilli that have long been used in theclinic, are available on the market; however, traditional formulationsof such probiotics show poor stability and low bioavailability, thuslimiting their therapeutic effects.Over 2000 years ago, the Greekphysician Hippocrates of Kos, lauded as the father of western medicine,proclaimed that \u201cAll disease begins in the gut\u201d. Thegut microbiome exerts pivotal roles in health and diseases, by regulatingcritical biological processes in metabolism, inflammation, and immunity.Dysbiosis of the gut microbiota is involved in the pathogenesis ofnumerous diseases, such as obesity, diabetes, inflammatory bowel disease(IBD), liver diseases, respiratory diseases, cardiovascular diseases,autism, anxiety, schizophrenia, Parkinson\u2019s disease, Alzheimer\u2019sdisease, infectious diseases, and cancers.in vivo efficacies. However, therapeuticbenefits of probiotic therapies remain to be improved, with respectto clinical translation. In this issue of ACS Central Science, Zhang, Liu, Shi, and co-workers rationally designed and constructeda multifunctional calcium tungstate microgel (CTM)-based system fororal probiotic delivery.1 CTM was formulatedby the Ca2+-mediated cross-linking of sodium alginate andsodium tungstate in aqueous solution, giving rise to calcium tungstate(CaWO4) nanoparticle-loaded alginate microgels , a highly expressedprotein at colitis sites, due to strong interactions between CP andCa2+. Released tungsten can inhibit the growth of Enterobacteriaceae by attenuating Enterobacteriaceae-dependent molybdenum enzyme activity. Since the growth of probioticsis independent of molybdenum enzymes, tungsten has no significanteffects on probiotics loaded in CTM. Consequently, CTM can selectivelysuppress the growth of Enterobacteriaceae in colitis,thus disrupting the ecological niche occupied by pathogenic bacteriaand promoting probiotic colonization. Using Bacillus coagulans (BC) as a candidate probiotic, the authors demonstrated that orallydelivered BC-containing CTM  effectively inhibited theproliferation of harmful bacteria, facilitated probiotic colonization,and restored gut microbiota homeostasis in mice with dextran sulfatesodium (DSS)-induced colitis , common lung diseases (such as asthma and chronicobstructive pulmonary disease), neurological disorders , and vaginal diseases,considering the presence of the microbiota in other tissues such asthe oral cavity, respiratory tract, and vagina as well as the well-recognizedgut\u2013liver, gut\u2013lung, and gut\u2013brain axes.11As for the limitations of this study, only one mouse model of colitisand one probiotic were used. Future translation studies should validatethe proposed strategy in other animal models of colitis and usingdifferent probiotic strains. In addition, gut microbiota-derived metabolites,such as trimethylamine/trimethylamine-"}
+{"text": "With the continuous development and integration of molecular biology and forensic science, non-coding RNAs (ncRNAs), especially ncRNAs with regulatory functions such as microRNA, long non-coding RNA, and circular RNA, have recently been actively explored by forensic scholars. In this study, we review the literature on these ncRNAs in various fields of forensic science, including postmortem interval determination, wound age estimation, forensic age assessment, cause of death analysis, and body fluid identification, aiming to evaluate the current research and provide a perspective for future applications."}
+{"text": "Bouveret syndrome is a rare condition where a gallstone obstructs the gastric outlet. This report discusses its diagnosis, management, and the need for further research. Prompt recognition is crucial to prevent complications. CT scan with oral contrast aids in diagnosis. Treatment options include conservative measures, endoscopy, or surgery. A multidisciplinary approach is essential for successful management. More research is needed to understand this condition fully. Bouveret syndrome, an exceptionally rare and unusual form of gallstone ileus, accounts for less than 1% of mechanical intestinal obstructions. Named after its first describer, L\u00e9on Bouveret, in 1896, this condition involves the migration of a large gallstone into the duodenum or pylorus, leading to gastric outlet obstruction. Despite its historical recognition, only a few hundred cases have been reported, underscoring its rarity and diagnostic complexities [The pathogenesis of Bouveret syndrome unfolds in a sequence of events. In patients with cholelithiasis, a gallstone is believed to erode through the gallbladder wall, creating a cholecystoduodenal fistula. Subsequently, the gallstone may pass through the fistula and lodge in the duodenum or pylorus, causing gastric outlet obstruction. The impacted stone acts as a mechanical barrier, obstructing the passage of food and gastric contents .The clinical presentation of Bouveret syndrome is variable and non-specific, posing diagnostic challenges. Patients often manifest symptoms resembling gastric outlet obstruction, such as abdominal pain, nausea, vomiting, early satiety, and weight loss. These symptoms can mimic other common causes of obstruction, such as peptic ulcer disease or malignancy. Consequently, diagnosing Bouveret syndrome necessitates a high index of suspicion, especially in patients with a known history of cholelithiasis .This case report contributes to the limited literature on Bouveret syndrome, elucidating its clinical presentation, diagnostic intricacies, and management strategies. By augmenting our comprehension of this rare gastrointestinal disease, healthcare professionals can refine their diagnostic acumen, facilitate early intervention, and optimize patient outcomes. Collaborative research efforts are needed to expand the literature and establish evidence-based guidelines for Bouveret syndrome management.A 68-year-old male presented at the emergency department with worsening abdominal pain, nausea, vomiting, and inability to eat for five days. The pain was constant and centered in the epigastric region, intensifying after meals. He had no fever, melena, or hematemesis. The patient had a medical history of hypertension, hyperlipidemia, and cholelithiasis, but had not experienced biliary colic before.During the physical examination, the patient seemed uncomfortable and slightly distressed. His vital signs were normal, with a blood pressure of 128/78 mmHg, a heart rate of 88 beats per minute, a respiratory rate of 16 breaths per minute, and an oxygen saturation of 98% on room air. The abdominal examination showed moderate distention with visible peristaltic waves, tenderness in the epigastric region upon palpation, and hypoactive bowel sounds. There were no signs of peritonitis, such as guarding or rebound tenderness.Initial laboratory tests including complete blood count, liver function tests, and serum amylase levels were within normal ranges except for white cell count, which was mildly raised. The electrolyte panel showed no abnormalities. The complete blood workup results are provided in Table The patient was promptly admitted for further investigations due to clinical presentation and imaging findings, and a CT scan with oral contrast was performed. The CT scan revealed a 3 cm gallstone lodged in the duodenal bulb, causing gastric outlet obstruction Figure . MoreoveBouveret syndrome was diagnosed based on the clinical symptoms and imaging results. A multidisciplinary team, including general surgery, gastroenterology, and interventional radiology, collaborated on the management plan. The patient and his family were informed about the various treatment options, including their risks, benefits, and potential complications.Despite attempting conservative management, the patient's symptoms did not improve, and gastric decompression showed no progress over 48 hours. Given the gallstone's large size and impacted location, endoscopic retrieval was considered high-risk, leading to the decision for surgical intervention. Following informed consent, the patient underwent an exploratory laparotomy.The surgical intervention necessitated a midline incision for an in-depth exploration of the abdominal cavity. Upon investigation, a gallstone, measuring approximately 3 cm in diameter, was discovered impacted in the duodenal bulb, confirming its role in the gastric outlet obstruction. A meticulously executed gastrotomy facilitated the gallstone's extraction, with rigorous care to prevent any spillage or contamination. Simultaneously, a cholecystoduodenal fistula was detected and repaired with an omental patch. The gastrotomy site was then securely closed using interrupted sutures. To preclude the recurrence of Bouveret syndrome, a concurrent cholecystectomy was carried out. The patient subsequently had an uneventful recovery, showing symptom resolution and no postoperative complications.Post surgery, the patient was closely monitored in the surgical intensive care unit. Nasogastric decompression was maintained to ensure proper gastric decompression. Intravenous fluid resuscitation, electrolyte correction, and antibiotic therapy were continued. Over time, the patient's symptoms improved, with abdominal pain, nausea, and vomiting resolving. Oral intake was gradually reintroduced, starting with clear liquids and progressing to a regular diet as tolerated.The patient's recovery after surgery was smooth, without any surgical site infection, wound dehiscence, or complications. Throughout the hospital stay, the patient remained hemodynamically stable. On the sixth postoperative day, the nasogastric tube was removed, and the patient continued to tolerate a regular diet without signs of recurrent gastric outlet obstruction. Follow-up imaging, including abdominal X-ray and CT scan, showed no residual stones or complications.The patient was discharged on the seventh postoperative day with appropriate postoperative care instructions and a referral for outpatient follow-up. During follow-ups, the patient was thoroughly assessed with no remarkable or adverse findings noted. Additionally, potential complications related to the fistula repair, such as anastomotic leakage, wound infection, and bowel obstruction, were evaluated, but no significant abnormalities were identified. The patient reported a complete resolution of symptoms and expressed satisfaction with the surgical intervention.\u00a0Bouveret syndrome is a rare and complex clinical condition characterized by gastric outlet obstruction resulting from a gallstone lodged in the duodenum or pylorus. Its diagnosis presents a challenge due to the non-specific clinical presentation, often resembling other common causes of gastric outlet obstruction.\u00a0Effectively managing Bouveret syndrome requires a multidisciplinary approach, involving general surgery, gastroenterology, and interventional radiology. Treatment options encompass conservative measures, endoscopic techniques, and surgical intervention, with the chosen approach depending on patient stability, gallstone size and location, and the presence of associated complications . Prompt Imaging studies play a pivotal role in confirming the diagnosis of Bouveret syndrome. Abdominal radiography may reveal gastric dilatation with air-fluid levels, suggesting an obstructive pattern. However, the definitive diagnostic tool is a CT scan with oral contrast, providing detailed visualization of the impacted gallstone and its precise location within the duodenum or pylorus. The CT scan also aids in evaluating associated complications, such as gallstone-related perforation or inflammation .In our case, the patient exhibited typical symptoms of gastric outlet obstruction, including abdominal pain, nausea, vomiting, and intolerance to oral intake. Abdominal radiography showed pronounced gastric dilatation with air-fluid levels, raising suspicion of gastric outlet obstruction. CT scan confirmed the diagnosis by revealing a large gallstone lodged in the duodenal bulb, causing significant luminal narrowing and gastric outlet obstruction.Conservative management, including nasogastric decompression, fluid resuscitation, electrolyte correction, and antibiotics, may be attempted in stable patients without evidence of peritonitis. The aim of this approach is to alleviate gastric distention, correct electrolyte imbalances, and facilitate the spontaneous passage of the gallstone. However, it should be noted that conservative management may not be efficacious in cases involving large or impacted stones, as observed in our patient, necessitating further intervention to address persistent symptoms.Endoscopic techniques such as endoscopic lithotripsy, mechanical lithotripsy, or laser lithotripsy have proven successful as minimally invasive approaches for gallstone retrieval in selected cases of Bouveret syndrome. Nonetheless, the feasibility and success rate of endoscopic interventions rely on factors such as stone size, location, and the expertise of the endoscopist. In our case, endoscopic retrieval was considered high risk due to the large size and impacted location of the gallstone, leading to the decision for surgical intervention .Surgical intervention remains the definitive treatment for Bouveret syndrome, particularly when dealing with large or impacted gallstones. The surgical procedure typically involves an exploratory laparotomy, identification of the impacted stone, and extraction through a gastrotomy or duodenotomy. Primarily, closure of the defect is performed to minimize the risk of postoperative complications, such as bleeding or leakage. Concurrent cholecystectomy is often carried out to prevent recurrence, given the frequent association of cholecystoduodenal fistulae with Bouveret syndrome .The prognosis of Bouveret syndrome depends on several factors, including the patient's overall health status, the presence of associated complications, and the promptness of intervention. Delayed diagnosis and treatment can lead to significant morbidity and mortality, such as gastric necrosis, perforation, or sepsis. Therefore, early recognition and intervention are crucial in achieving favorable outcomes .Considering the rarity of Bouveret syndrome, limited literature exists regarding its optimal management strategies. Thus, the choice of treatment should be individualized based on the patient's clinical condition, gallstone size and location, and the expertise of the medical team. Further research, including case reports and collaborative studies, is necessary to build up the literature and establish evidence-based guidelines for the management of Bouveret syndrome.Bouveret syndrome is a rare gastrointestinal condition with symptoms of gastric outlet obstruction. Early recognition, accurate diagnosis, and prompt intervention are crucial for successful management. CT scan with oral contrast aids in diagnosis. Treatment options include conservative measures, endoscopy, or surgery, with the latter being definitive for large or impacted stones. Timely intervention and a multidisciplinary approach are essential for positive outcomes. More research and case reports are needed for optimal management."}
+{"text": "Heavy metals are the metal compounds found in earth\u2019s crust and have densities higher than that of water. Common heavy metals include the lead, arsenic, mercury, cadmium, copper, manganese, chromium, nickel, and aluminum. Their environmental levels are consistently rising above the permissible limits and they are highly toxic as enter living systems via inhalation, ingestion, or inoculation. Prolonged exposures cause the disruption of metabolism, altered gene and/or protein expression, and dysregulated metabolite profiles. Metabolomics is a state of the art analytical tool widely used for pathomolecular inv22estigations, biomarkers, drug discovery and validation of biotransformation pathways in the fields of biomedicine, nutrition, agriculture, and industry. Here, we overview studies using metabolomics as a dynamic tool to decipher the mechanisms of metabolic impairment related to heavy metal toxicities caused by the environmental or experimental exposures in different living systems. These investigations highlight the key role of metabolomics in identifying perturbations in pathways of lipid and amino acid metabolism, with a critical role of oxidative stress in metabolic impairment. We present the conclusions with future perspectives on metabolomics applications in meeting emerging needs. The profiling of metabolome is known as metabonomics or metabolomics, which is a branch of \u201comics\u201d science including genomics, proteomics, transcriptomics, inomics, phenomics, and metabolomics . MetabonMetabolomics is located at the bottom of the \u201comics\u201d cascade and relates to both the downstream output of the genome and the upstream input of the environment and may, therefore, answers queries that might not be answered using other branches of \u201comics\u201d science . WhereasThe metals found in earth\u2019s crust with density higher than that of water are called heavy metals . Humans Such heavy metals include the lead , arsenic (As), mercury (Hg), cadmium (Cd), copper (Cu), manganese , chromium (Cr), nickel (Ni), and aluminum (Al); all of which are highly toxic when inhaled, ingested, or experimentally inoculated in living systems. Following entry into the body, these heavy metals damage the cellular organelles and inhibit biochemical and metabolic pathways to impair physiological functions of the organs. The heavy metals have specific mechanisms of toxicity in the living systems and most cause oxidative stress which leads to an excessive accumulation of highly toxic reactive oxygen species (ROS) and free radical-associated damage to the critical organs, tissues, cells, and macromolecules . ROS can irreversibly damage the major organs like liver, kidney, brain, heart, lung, as well as the reproductive and immune systems. Heavy metals can also cause gene mutations, carcinogenesis, skin irritation, cell damage, and cell death. The metabolism of carbohydrates, lipids, and amino acids is also affected by heavy metals. Prolonged exposures to heavy metals cause altered gene and protein expression as well as disruption of metabolism and metabolites. The damages caused by heavy metals can become life threatening and irreversible . The majTypically, a biospecimen such as an organ, tissue biopsy, or cultured cells from an organism is metabolically quenched using nitrogen gas. To prepare a biospecimen containing thousands of metabolites, the sample is homogenized by an electric homogenizer to obtain the liquid mixture of the sample. Since the tissue extraction process is somewhat complex, it is rather more convenient to collect the biofluids such as cell culture supernatants, sweat, breast milk, bile, feces, cerebrospinal fluid, urine, saliva, and blood. Certain metabolites can be found in both blood and urine samples, while others may be more specific to each sample type. In contrast, saliva samples generally contain a limited number of metabolites compared to blood and urine. The selection of the appropriate sample for metabolomics studies is of utmost importance, as it significantly influences the outcomes. Therefore, it is essential to handle, store, and process the samples under specific conditions to ensure the accuracy and reliability of the results. Any deviation from these specified conditions can impact the identification of metabolites and their associated pathways. Once the sample is prepared, it can be injected into one or more analytical instruments such as gas chromatography/mass spectrometry (GC-MS), NMR, liquid chromatography/mass spectrometry (LC-MS), capillary electrophoresis/mass spectrometry (CE-MS), or ion mobility spectrometer/mass spectrometer (IMS-MS) systems.in vitro models  as well as using small cohorts might contribute as potential sources of bias and data variability. Furthermore, the preliminary metabolomics data obtained must be further validated, for which, putative biomarkers that have been identified using metabolomics must be accurately and precisely assessed in larger study cohorts. Special consideration should also be given to the data stored in databases and biobanks which, in case of heavy metal toxicometabolomics, still need to be further expanded and improved. A complete workflow of metabolomics is illustrated in Overall, to develop better workflows in heavy metal toxicity assessments using metabolomics, it is imperative to increase the reproducibility and translatability of toxicometabolomics data through the standardized approach or procedures based on appropriate selection of experimental design, optimal sample collection, storage, extraction and preparation, correct choice of analytical instruments/platform and proper data analysis, all of which can considerably affect the obtained results. Since the optimal and simultaneous extraction, detection, and quantification of all metabolites is unlikely while using a single method, use of multiple analytical platforms enhances the metabolite coverage. To date, NMR and MS are the commonest approaches used to generate metabolomics data . It shou3 , neurological issues, and cancers of the lung, liver, bladder and skin . RegardiPb is used in several industries, agriculture, and home items. Common toxicities occur via inhalation and ingestion. It induces expression of free radicals and increased ROS lead to changes in lipid metabolism, DNA damage, and dysregulated gene expression, also interrupting the heme pathway to cause anemia . A Pb to2+ in metallothionein, they can interfere with free radical scavenging and lead to oxidative damage (Cd and chlorpyrifos (CPF) are the environmental contaminants and exposures occur via inhalation (tobacco smoking) and ingestion (dietary sources), resulting in acute and chronic intoxications. These can bind with cysteine, glutamate, histidine, and aspartate, causing iron deficiency and neurotoxicity. By replacing Zne damage . Regardie damage . Cd, CPFe damage . Metabole damage .Cr is found in the industrial environment such as metallurgy, electroplating, chemicals, paints, pigments, tanning, wood, pulp, and paper production. Cr toxicity causes dysfunction of antioxidant enzymes such as catalase, peroxidase, and cytochrome oxidase, leading to ROS overexpression and oxidative stress which damages the DNA/RNA, lipids, and proteins .2+ homeostasis, and the accumulation of neurotoxic molecules including aspartate, glutamate, and serotonin which may lead to malfunctioning of nerves, brain, kidneys, and muscles  is highly neurotoxic and causes free radical formation, lipid peroxidation, damage to the ribosomes, endoplasmic reticulum (ER) and mitochondria, disruption of mitochondrial membrane potential (\u0394\u03a8m) and Ca muscles . A toxic muscles .2+ ions is critical to cellular Cu homeostasis. Increased Cu levels lead to oxidative stress through Fenton reactions, DNA damage, reduced cell proliferation, and metabolic disruption  as well as certain non-radical species (peroxynitrite ONOO\u2212 and hydrogen peroxide H2O2) and mitochondrial dysfunction , and glutathione peroxidase (GPx), resulting in generation of highly reactive free radicals or ROS (superoxide Ofunction . The imbfunction . These cfunction  and mitofunction , dysregufunction , cell cyfunction . Heavy mfunction , downregfunction , DNA metfunction , other efunction , and hisfunction .Heavy metals also have deleterious effects on kidneys and are responsible for tubular proteinuria, renal glycosuria, aminoaciduria, glucosuria, phosphaturia, and Fanconi-like syndrome . Nephrot2+ signaling (Chronic heavy metal exposures can lead to hyperpigmentation , hyperkeignaling , thromboignaling , suppresignaling  and overignaling , and incignaling .Overall, oxidative stress from exposure to heavy metals leads to ROS-associated metabolic reprogramming, cellular and/or organelle dysfunction, as well as perturbations of critical pathways related to carbohydrate, protein, and lipid metabolism . Heavy mCompared with other relatively more established \u201comics\u201d, such as transcriptomics, we have just begun to realize the robustness and enormous potentials of metabolomics as a state of the art technique to investigate heavy metal toxicities at the cellular, tissue, and organismal levels. Metabolomics provides unique perspectives on cytotoxicity-induced changes in metabolic profiles and functions. Herein, we have reviewed the studies that investigated toxicity effects of heavy metals or derivatives such as Pb, As, Cd, Cr, Hg/MeHg, Ni, PFOS, Cu/CuO NPs, and Al, using metabolomics of blood, plasma, serum, urine, toenails, brain samples of humans and animals as well as cell lines. Heavy metals cause impairment of antioxidant defense, resulting in excessive accumulation of highly reactive free radicals or ROS which emerge as key players in pathophysiology of heavy metal toxicity. Apart from causing damage to the ER and mitochondria, ROS irreversibly damage the cellular biological macromolecules including nucleic acids, proteins, and lipids. ROS-induced genotoxic changes such as abstraction or addition of bases, strand breaks in DNA sugar-phosphate backbone, and other DNA lesions may lead to cancer development. While, protein and lipid per/oxidation metabolites give rise to multiple toxicities including molecular, cell and organ damage, altered transcriptional and translational regulation, reproductive and developmental disorders, and neurological, dermatological, hepatic, renal, pulmonary, cardiovascular, hematologic, and immunological morbidities. Metabolomics yields the unique information about key metabolic changes affecting morbid processes in a wide variety of living systems by identifying, quantifying, and characterizing small metabolites with high precision. Metabolic fingerprinting and footprinting help decipher metabolites that derange homeostasis, metabolism, physiology, and immune functioning in the body.Nonetheless, there are some challenges involved that need to be pointed out. First, while using untargeted or knowledge-discovery approach, it might be difficult to pinpoint which metabolic pathways play a key role as this type of investigations aim to measure as many metabolites as possible, given that this information provides basis of hypothesis building for future work. It is encouraging to see that better tools are becoming available for enrichment analyses and network constructions which enhances capabilities for data interpretation. Second, metabolomics might be laborious and expensive, given the chemical diversity of metabolome and rapid turnover of metabolites, both of which affect reproducibility of data generated. Third, in order for metabolomics data to be more meaningful, data integration with other systems biology approaches like transcriptomics and proteomics might be required for temporal comparison. From broader perspectives, metabolomics is a dynamic tool for cutting edge research in healthcare, pharmaceutics, food sciences, agriculture, and chemical industries. Metabolomics is guiding decision making for drug safety and biomarker discovery. In the near future, individualized metabolomics will most likely be mainstay for human health and environment monitoring and emerge as a lead analytical tool for molecular diagnostics, drug phenotyping, customized therapeutics, and much more."}
+{"text": "The last decade has seen an exponential increase in therapeutic options for rare hematologic diseases. The latter encompass benign conditions, including congenital anemias, autoimmune cytopenias, bone marrow failure syndromes , and rare hemostatic disorders, as well as neoplastic ones  ,3,4,5,6.Regarding congenital disorders, Bou-Fakhredin and colleagues  lead us Switching to acquired autoimmune forms, Mingot-Castellano and colleagues  recapituIn the field of hemostatic disorders, Gualtierotti et al.  provide cKIT gene.Finally, Scium\u00e8 and colleagues  face theOverall, the novel therapies discussed in this Special Issue are at different phases of development  and will likely be positioned at different disease stages or in specific settings soon. Along with efficacy, which may vary according to disease phenotype, new toxicities are emerging and novel specific monitoring and preventive strategies will have to be developed. Finally, each novel drug poses a challenge to the treating physician, who will have to individualize treatment by choosing the best therapy for the best patient."}
+{"text": "Scientific Reports 10.1038/srep26051, published online 17 May 2016Retraction of: Editors have retracted this Article.After publication of this paper concerns about ethical oversight of this study were brought to the attention of the Editors. The Authors were not able to provide documentation of appropriate approval from an ethics committee in either Niger or Senegal, where the participants in this study were based.Catherine Robert agrees with this retraction. Matthieu Million, Jean-Christophe Lagier, Souleymane Brah, Cheikh Sokhna, Philippe Parola, and Didier Raoult disagree with this retraction. Caroline Michelle and Bernard Henrissat did not explicitly state whether they agree with this retraction. Maryam Tidjani Alou, Saber Khelaifia, Dipankar Bachar, Niokhor Dione, Perrine Hugon, Vincent Lombard, Fabrice Armougom, Julien Fromonot, Alexandre Fabre, and R\u00e9gis Guieu did not respond to correspondence from the Editors about this retraction. The Editors were not able to confirm current contact details for Aldiouma Diallo."}
+{"text": "Biostimulant application can be considered an effective, practical, and sustainable nutritional crop supplementation and may lessen the environmental problems related to excessive fertilization. Biostimulants provide beneficial properties to plants by increasing plant metabolism, which promotes crop yield and improves the quality of crops; protecting plants against environmental stresses such as water shortage, soil salinization, and exposure to sub-optimal growth temperatures; and promoting plant growth via higher nutrient uptake. Other important benefits include promoting soil enzymatic and microbial activities, changing the architecture of roots, increasing the solubility and mobility of micronutrients, and enhancing the fertility of the soil, predominantly by nurturing the development of complementary soil microbes. Biostimulants are classified as microbial, such as arbuscular mycorrhizae fungi (AMF), plant-growth-promoting rhizobacteria (PGPR), non-pathogenic fungi, protozoa, and nematodes, or non-microbial, such as seaweed extract, phosphite, humic acid, other inorganic salts, chitin and chitosan derivatives, protein hydrolysates and free amino acids, and complex organic materials. Arbuscular mycorrhizal fungi are among the most prominent microbial biostimulants and have an important role in cultivating better, healthier, and more functional foods in sustainable agriculture. AMF assist plant nutrient and water acquisition; enhance plant stress tolerance against salinity, drought, and heavy metals; and reduce soil erosion. AMF are proven to be a sustainable and environmentally friendly source of crop supplements. The current manuscript gives many examples of the potential of biostimulants for the production of different crops. However, further studies are needed to better understand the effectiveness of different biostimulants in sustainable agriculture. The review focuses on how AMF application can overcome nutrient limitations typical of organic systems by improving nutrient availability, uptake, and assimilation, consequently reducing the gap between organic and conventional yields. The aim of this literature review is to survey the impacts of AMF by presenting case studies and successful paradigms in different crops as well as introducing the main mechanisms of action of the different biostimulant products. N-containing compounds, botanicals, seaweed extracts, chitosan and other related biopolymers, beneficial bacteria and fungi, and inorganic compounds are the major categories of plant biostimulants. Modern crop production has to cope with abiotic and biotic stressors such as soil and irrigation water salinity, extreme and untimely weather phenomena, water limitations, infections from pathogens, and pests, which severely influence crop performance and the quality of the final products [Mucor rouxii, Penicillium chrysogenum, Aspergillus niger, Lactarius vellereus), insects , and mollusks . Crustacean shells are the most notable chitin source, and chitin recovery involves three steps consisting of demineralization, deproteination, and the elimination of pigments and lipids [Lactobacillus sp., Bacillus sp., Pseudomonas sp., Serrati marcescens, etc., are the most significant strains applied in chitin and chitosan production [Biostimulant application is known as an eco-friendly and novel farming practice and is relevant to two otherwise contrasting concepts, namely crop sustainability and intensification . Biostimproducts ,4,5. Theproducts ,4,5,6. Bproducts ,8. Howevproducts . Differed lipids ,11,12. Moduction . Ecklonia maxima extracts, and indole-3-butyric acid on seedlings of mustard greens grown in soils from goldmines boosted phytoremediation activities through the accumulation of heavy metals [Azotobacter spp., Rhizobium spp., and Azospirillum spp., as well as different mycorrhizal fungi [Glomerales, Paraglomerales, Archaeosporales, and Diversisporales, have been recognized in this sub-phylum, which contains 25 genera [Biostimulants containing organic substances, humic acids, amino acids, algae extracts, and carbon and boron increased plant growth, yield, and shelf life of onion bulbs , and they metals . Foliar y metals , while ry metals ,19. In iy metals ,21. Biosy metals , which cy metals ,24,25. Tal fungi ,27  Trainer\u00ae increased the yield of tobacco by 5.5% and 6.7%, respectively, in comparison with untreated plants. Bozhinova [Glycine max under drought stress [Gigaspora decipiens and Glomus mosseae can boost the chlorophyll content and growth of Triticum aestivum, and Rhizophagus intraradices can improve levels of Mg, Zn, Cu, and F in grains of Triticum durum [Rhizophagus intraradices can increase N, P, and K uptake in Zea mays [Funneliformis geosporus BEG11 can increase water use efficiency in Fragaria ananassa [Glomus deserticola can improve the level of proline and the number of leaves in Antirrhinum majus [Gigaspora gregaria can increase mineral levels and decrease the level of proline in Vigna subterranea [Paraglomus occultum can increase the rate of water absorption and the length of the hypha in Poncirus trifoliata [Rhizophagus irregularis can increase the conductivity of stomata and dry matter of shoot in Digitaria eriantha [Glomus species can improve the osmotic potential adjustment in Ipomoea batatas [Saccharum arundinaceum [Rhizophagus irregularis can increase the fresh weight of shoots and roots and the number of leaves of Solanum lycopersicum [Claroideoglomus etunicatum can increase the conductivity of stomata and the level of soluble sugars in Aleurites moluccanus [Claroideoglomus etunicatum can boost the dry mass of shoots and roots as well as the conductivity of stomata in Aeluropus littoralis [Rhizophagus irregularis and Funneliformis mosseae can increase photochemical reactions, decrease the damage in the membrane, and activate the antioxidant defense system in Solanum melongena [Rhizophagus irregularis can improve the plant photosynthetic efficiency of Solanum lycopersicum under heat stress [Rhizoglomus irregulare and Funnerliformis mosseae can significantly influence the growth, productivity, and nutraceutical and nutritional quality of tomato cultivars, as AMF increase the biosynthesis and nutrient uptake of notable molecules involved in cellular pH and oxidative stress [Acaulospora laevis, Acaulospora scrobiculata, Gigaspora gigantea, Entrophospora colombiana, Glomus manihotis, and Scutellospora heterogama) and a mixture of AMF  recultured with Chloris gayana increased survival, improved tolerance against stress, and boosted the nutritional status, relative water content, photosynthetic rate, and the contents of P, N, Mg, and Fe in Vitis vinifera cv. Pusa Navrang [Rhizophagus irregularis, Pseudomonas fluorescens, and Funneliformis mosseae application lead to an increase in APX and GPX enzyme activities, an enhancement of plant growth parameters, the alleviation of water deficit damage, a decrease in H2O2 and lipid peroxidation, and an improvement of drought tolerance in Cupressus arizonica Green [Glomus mosseae, Rhizobium leguminosarum, and Arthrobacter protophormiae induced a decrease in proline content and lipid peroxidation, an improvement of plant weight, an enhancement of nutrient uptake, an increase in pigment content, and the alleviation of salt stress of Pisum sativum under salt stress [Acaulospora sp., Claroideoglomus etunicatum, Rhizobium sp., and Burkholderia sp. led to an improvement in the absorption of chemical fertilizers and an increase in the wood yield of Schizolobium parahyba var. amazonicum under salt stress [Bacillus megaterium, Rhizophagus irregularis, and Frateuria aurantia induced an enhancement of nutrient uptake responses, an improvement of low-mobility nutrient uptake such as Zn and Ca, an enhancement of total microbial biomass and microbial metabolism, an increase in plant growth, and an increase in gluten quality of Triticum aestivum L. under salt stress [Various notable protective mechanisms in the utilization of microbial biostimulants under different stresses are osmolite production, phytohormone level modulation, increased antioxidant activity, and secretion of extracellular polymeric substances (EPS) under water stress such as flooding and drought ,130,131;ozhinova  also nott stress . Under dum durum ,146. UndZea mays ; Funneliananassa ; Glomus um majus ; and Gigterranea . Amid waifoliata ; Rhizopheriantha ; and Glo batatas  and incrdinaceum . Under spersicum , Claroidluccanus , and Clattoralis . Under celongena . Rhizopht stress . AMF cone stress . Six sin Navrang . Rhizophca Green . The utit stress . The appt stress . Bacillut stress . Miceli t stress  reportedPenicillium sp., Phoma glomerata, Glomus intraradices, Exophiala sp., and Paecilomyces formosus may lead to greater soil exploration by roots or fungal hyphae with meaningful improved root conductivity [There are two types of mechanisms of action of microbial biostimulants. For direct mechanisms, it has been reported that microbes are active in the synthesis of components that can boost the adsorption of nutrients, while indirect mechanisms refer to siderophore production, zinc solubilization, phosphorus solubilization, indole acetic acid biosynthesis, antioxidant enzyme production, ammonia and hydrogen cyanide production, biological nitrogen fixation, and phytohormone production ,167. Micuctivity ,190.Mucoromycota and subphylum Glomeromycotina. AMF are available in our natural environment and are helpful in several ways; they play an important role in increasing plant nutrition acquisition, improving plant tolerance and resistance to stresses, and increasing soil fertility and structure, and have several beneficial applications in agriculture [AMF, favorable microorganisms extensively distributed in nature, can establish a symbiotic relationship with most terrestrial herbs. AMF belong to 11 families, 25 genera, and nearly 250 species . Arbuscuiculture ,199,200.iculture ,202,203.iculture . Malus robusta) by adjusting the expression levels of genes associated with these pathways. GO and KEGG pathway analysis showed that gene expression changes in different critical gene families, such as auxin response , TCA cycles , phosphate transporters , and Ca2+ signal transduction pathways , showing that apple stimulates the expression of genes related to auxin synthesis, organic acid secretion, and calcium transporters and channels, thus promoting the growth of apple root and improving the secretion of organic acids, which may lead to an increase in calcium effectiveness in soil [Rhizobium and AMF inoculation were investigated on the growth and yield of Lablab purpureus, Vigna unguiculata, and Mucuna pruriens, and in comparison to single inoculation and uninoculated forages, the dual inoculation with AMF and Rhizobia improved the growth and biomass yield of forage legumes, and dual inoculation could be an optimal alternative in attempts to decrease the overreliance of chemical fertilizers on forage production [AMF promoted the utilization and accumulation of Ca in apple rootstock ( in soil . Uptake  in soil . The com in soil . The impoduction . The eff2O2), and senescence-associated genes (SAGs) to decrease heat stress in perennial ryegrass [LpASMT1, LpTDC1, LpCOMT1, LpTDC2, and LpASMT3), the abscisic acid (ABA) catabolic gene, the CTK biosynthesis genes, the GA biosynthesis genes, and the associated signal transduction response transcription factors (TFs) (type-B ARRs) showed increased levels, whereas the expression of the GA to ABA exerted decreased levels after MT application and AMF inoculation in heat-stressed plants [When AMF are inoculated in a plant, they increase the plant\u2019s tolerance against different stresses such as heavy metals, drought, and high temperatures. AMF form spores and hyphae in the rhizosphere, while inside the root tissues, they shape arbuscular, vesicles, and hyphae to improve the accessibility of plant roots to large soil surface areas by hyphal network knowledge with roots of plants, therefore increasing growth in the plant . AMF synryegrass . AMF inod plants . AMF cand plants . Hc.AKR, Hc.GH3.1, and Hc.PHR1, thus playing an important role in enhancing kenaf\u2019s Cd tolerance [AMF increased the plant height, root weight, root length, and stem weight of lettuce, and the functional composition profiles showed that several functions were increased, including cell motility and environmental adaptation, and AMF had a significant influence on the lettuce endophytic bacterial network community and structure function . AMF witolerance . Iris pseudacorus) and suppressed Cr translocation from roots to shoots, which showed that the interaction between plants and AMF could significantly improve the immobilization of high Cr concentrations in semi-aquatic habitats [Medicago sativa to need water during a drought event, which worsens soil water deficit and thus may increase interspecific water competition between Medicago sativa and Broussonetia papyrifera. The results of one experiment revealed that in the roots of tomato plants colonized by AMF, there was a meaningful mutual relationship between the insects feeding on the plant and the fungal species  [Micro-proton-induced X-ray emission was utilized to determine element localization and indicated that AMF improved the nutrient uptake by wetland plants (habitats . AMF inoranicus) . Glomus spp.) play a role in upregulating plant growth and nutrition status in Fe-ore tailings in technosols of host plants like sorghum, providing the basis for the involvement of AM fungi in the eco-engineered pedogenesis of iron ore tailings [Anadenanthera colubrina (Vell.) Brenan, seedlings had more saponins and flavanols and showed significant antioxidant activity when inoculated with AMF  [Iris tectorum and reduced the constituents of Cr in soils; furthermore, it can boost the abundance of functional genes related to nutrient cycling  in rhizosphere microbial communities, increase the abundance of functional genes associated with heavy metal resistance and transporters in the rhizosphere microbial community, and increase the complexity and stability of the rhizosphere microbial community [Glomus versiforme (Gv) symbiosis significantly increased P uptake, plant growth, and photosynthesis in upland rice, and Gv inoculation decreased the expression of Nramp5, thus reducing Cd absorption, transfer, and accumulation in upland rice and enhancing the activities of catalase (CAT) and peroxide (POD) in Gv-inoculated upland rice [Glomeraceae and Paraglomeraceae are the dominant fungi affecting the available P content. Expanding Glomeraceae and Paraglomeraceae and applying them to Eucalyptus plantations may increase soil P availability, and the structure of the AMF community may be a sensitive indicator of the quality of soil-available P in Eucalyptus plantations [AM fungi (tailings . In the longula) ,221. AMFommunity . AMF redommunity . It has and rice . Glomerantations . AMF redntations . Glomus sp. and Paraglomus sp. boosted the biomass of plants and promoted root growth under replanting conditions, and it can also induce the activity of chitinase and \u03b2-1,3-glucanase and increase the resistance of apple rootstock by upregulating root reactive oxygen species levels and the antioxidant system under replanting conditions [Ligustrum vicaryi plants, and the mediation of Ca2+, Zn2+, N, Mg2+, and soluble protein components could be the basic mechanism underlying salt tolerance in mycorrhizal plants [Funneliformis mosseae inoculation under water stress, and AMF plants showed higher scavenging activity of hydroxyl radical and superoxide (O2\u2212) by root flavonoid extracts under water stress, together with lower levels of O2\u2212 and hydrogen peroxide and the degree of membrane lipid peroxidation in comparison with non-AMF plants, as well as increased flavonoid synthesis of trifoliate orange for reducing oxidative damage under water stress [Claroideoglomus etunicatum and Rhizophagus clarus promoted the accumulation of nitrogen in the aerial part of cowpea cultivars, and plants inoculated with C. etunicatum had similar or superior responses to plants fertilized with NPK or P [Glomus intraradices had maximum wheat yield and growth, which mechanically resulted from a higher rhizosphere colonization level, photosynthetic rate, and water use efficiency under drought stress [Inoculation with indigenous AMF such as nditions . It is sl plants . AMF andl plants . Activitr stress . The sinNPK or P . Wheat it stress . Piriformospora indica relatively replaced AMF in citrus plants [Melissa officinalis L.), and notably contributed to high essential oil yield [Rubus idaeus L.) [Tamarindus indica by increasing the contents of chlorophyll and carotenoids [Trichoderma, are capable of controlling the pathogens Xylella fastidiosa and Pseudomonas savastanoi via the production and release of secondary metabolites; they are also effective against Oomycetes sp. and Colletotrichum sp. [3 (Gibberellic acid) and AMF (Rhizophagus irregularis) decreased growth impairment under salinity conditions by upregulating the hormonal balance of plants. The utilization of AMF was able to increase the productivity of sweet basil (Ocimum basilicum) plants under salinity conditions, and mycorrhizal inoculation significantly promoted water use efficiency and chlorophyll content under salinity stress [+ and Cl\u2212 content and improved the relative water content (RWC), the total fresh and dry weight, and the photosynthetic activity of olive plants [Mangifera indica L.) root stocks reacted to AMF inoculation in the nursery and also in the field with improved nutrient uptake, plant growth, and yield [Fungal inoculations partly improved fruit quality and mineral element components, depending on the fungi species, while the cultured mycorrhiza-like fungus s plants . Inoculail yield . The mixil yield . AMF inoaeus L.) , while totenoids . Differechum sp. . The comy stress . AMF fory stress . Furthere plants . Mango  system. Hashem et al. [Ocimum basilicum plants from salinity stress by promoting water use efficiency, and increased chlorophyll synthesis and mineral uptake. Other examples of modes of action of AMF include the increased antioxidant activity and the accumulation of osmolytes [+ and K+. The recent findings in omics science have also helped show that microbial biostimulants\u2019 application involves great alterations in secondary and primary metabolites such as amino acids, phenolic acids, lipids, and tricarboxylic acid (TCA) intermediates, as well as alterations in protective mechanisms against stress that involve redox homeostasis, the stabilization of cell membranes, osmoregulation, the production of energy via amino acid degradation, and the increased expression of stress-related genes [Rouphael et al.  concludem et al.  reportedm et al.  reportedsmolytes , the adjsmolytes ,247, andsmolytes ,249. Regsmolytes  concludeed genes ,251. Qiued genes  reporteded genes  found thLippia alba (Mill.) N.E.Br. [2O emissions from legume systems by increasing P acquisition for biological N2 fixation, suggesting that AMF benefit crop production for higher yield and fewer N2O emissions in legume systems. The AMF Gigaspora margarita KKU-BH-01 can effectively increase the growth and aid eucalyptus seedlings to survive leaf blight disease (Cylindrocladium quinqueseptatum), as AMF induced plant chitinase and \u03b2-1,3-glucanase enzymes, resulting in improved disease resistance in plants [Glomus etunicatum strains were more effective than the Glomus lamellosum strain, and mycorrhizal oregano plants had higher dry weight than mycorrhizal mint plants [Ipomoea aquatica Forsk.) growth and reduced the accumulation of Ni but not Cd. Glomus mosseae and Glomus deserticola increased shoot length, dry weight, chlorophyll quantity, and total N, P, and K components in Eucalyptus globulus shoots [The application of humic substances and AMF treatment led to a reduction in carvone content compared to treatment with humic substances alone, and it was suggested that AMF inoculation combined with a high P rate promoted essential oil content, whereas AMF inoculation combined with a high P rate and humic substance addition decreased the carvone content in  N.E.Br. . AMF can N.E.Br. . It has  N.E.Br. . Wang et N.E.Br.  showed tn plants . Mycorrht plants . Lam andt plants  reporteds shoots . Gheisars shoots  concludeFusarium root rot under greenhouse conditions; additionally, essential oils (EOs) from mycorrhizal lemongrass frequently inhibited Fusarium Solani Fs4 development, notably more than the non-inoculated counterpart [Rhizophagus irregularis and Funneliformis mosseae, phosphorous components in the leaves of tomato plants were increased under both watering regimes, and even under limited watering conditions, Ca, K, Zn, Mg, and Mn were increased to levels similar to those of non-stressed plants [Miscanthus plants in phytoremediation and growing them in Zn-deficient soils. AMF improved plant growth under toxic trace element (TE) stress. The function of AMF in regulating heavy metal transport is concentration-dependent, and the transport direction of Cd and Zn in plants regulated by AMF changes with TE. AMF increased the absorption of Zn by growth dilution and Cd by biological enrichment, and the interaction between Cd and Zn was affected by AMF and other components [AMF inoculation changed the biochemical procedures of lemongrass with a subsequent effect on growth and increased the suppression of nterpart . AMF cannterpart . The mosnterpart ,392. In nterpart . The synnterpart . In the d plants . AMF incd plants . Sarkar d plants  reportedmponents . Funneliformis mosseae in pepper can promote the dry mass production photosynthesis rate under Cu stress [Glomus versiforme and Rhizophagus intraradices can increase P nutrition and antioxidant activity of Lotus japonica under Cd stress [Rhizophagus intraradices can accumulate Cr in roots and decrease its translocation towards shoots of Brachiaria mutica under Cr stress, Rhizophagus irregularis may immobilize Cu and Pb in soil for the cultivation of willows [Rhizophagus intraradices can regulate As transporter in root epidermis cells and decrease its uptake in pea seedlings [Claroideoglomus and Rhizophagus spp. can decrease Cd accumulation in wheat grains [Funneliformis mosseae is a famous mycorrhiza among different AMF species for its symbiosis with the roots of various plant species, and it may facilitate the exchange of nutrients via the expansion of roots through the outer membrane of the mycelia and by boosting root development [Rhizophagus irregularis reducing soil nutrient deficiencies of P and Zn in Medicago truncatula by increasing MtZIP5 and MtPT4 gene induction [Rhizophagus irregularis boosting root absorption area and soil P availability in maize, Rhizophagus irregularis modifying the ZIP transporter response in barley and boosting grain Zn bioavailability [Funneliformis mosseae promoting the uptake of nutrients such as Mn, Mg, Zn, Fe, Ca, S, N, P, and K in cucumber [Rhizophagus irregularis stimulating MtZIP6 gene expression and boosting the root absorption area in Medicago truncatula [Rhizoctonia solani or Rhizoctonia root rot disease, namely improved plant growth, increased plant nutrition, cytoplasmic granulation, improved cell wall thickening, and the accumulation of some antimicrobial components such as defense-related enzymes and phenolic substances [2 assimilation, namely malic enzyme and ribulose-1,5-bisphosphate carboxylase; and boosted the expression of S-adenosylmethionine synthase. Under salinity stress, glomus mosseae can increase total proline and phenol content, leaf area, and root and shoot dry weights and lengths in Triticum aestivum [Funneliformis mosseae can increase nutrient uptake, the photosynthetic rate, and the stand establishment rate of Cucumis sativus [Rhizobium irregularis and Funneliformis mosseae can increase plant biomass and decrease oxidative burst by strengthening the antioxidant enzymatic activities of Cajanus cajan [Glomus intraradices can improve both nutrient use efficiency and increase the defense response against herbivorous insects (Spodoptera litura) in blackgram. AMF symbiosis reduces temperature stress in host plants by improving the osmotic adjustment [Mycorrhizal fungi respond to metal contamination in different ways. u stress , Glomus d stress , Rhizoph willows , Rhizopheedlings , and Clat grains . Funnelielopment . Some ofnduction , Rhizophlability , Funnelicucumber , and Rhiuncatula . Variousbstances . Li et abstances  reportedaestivum ; Funneli sativus ; and Rhius cajan . Yu et aus cajan  reportedus cajan  observedjustment , increasjustment , increasjustment , improvijustment ,419. Farjustment  reportedGlomus margarita, Glomus versiforme, Rhizobium irregular, Rhizobium clarus, and Funneliformis mosseae [Pseudomonas putida can increase iron uptake in rice, and Pseudomonas fluorescens can improve grain yield, plant height, and biomass in rice, sweet potato, and rapeseed [Streptomyces strain shows positive effects on the plant growth of tomato and rice [Azospirillum brasilense Sp245, and Aeromonas spp. increased the root area of rice [Comamonas acidovorans and Bacillus subtilis have significantly improved plant growth and increased cytokinin constituents in shoots and roots [Bacillus licheniformis application increased fresh weight, enhanced cell division, and raised the chlorophyll content in cucumber [Azospirillum lipoferum improved the root hair density of maize seedlings [Azospirillum lipoferum increased tolerance to salinity stress in wheat [Pseudomonas putida application led to increased shoot and root biomass and water content of white clover [Alternaria sp. stimulated drought tolerance in wheat [Azoarcus sp. increased plant nitrogen nutrition and root growth and reduced nutrient deficiency in wheat [Azorhizobium sp. boosted plant nitrogen nutrition and root growth and alleviated nutrient deficiency [Rhizobium meliloti improved plant growth, nitrogen use efficiency, and the quality of pods of peanuts [Rhizobium leguminosarum boosted growth and yield performance under drought stress in soybean seedlings [Azotobacter chroococcum and Azotobacter vinelandii increase root and shoot length, chlorophyll content, and root and leaf number [Bacillus halotolerans, Pseudomonas frederiksbergensis RG2, and Enterobacter hormaechei increased germination, growth, and yield; induced better drought resistance; and improved uptake of P, N, and Zn [Rhizoglomus irregulare Aoufous consortium enhanced growth traits and physiological characteristics that have functions in the absorption of N and P content, increased protein and sugar content, reduced MDA and H2O2, alleviated soil pH, and increased the electrical conductivity, organic matter, and total organic carbon of date palm under drought conditions [Glomus spp. increased root fresh weigh, root length, shoot height, shoot fresh weight, and germination index and improved the root basal diameter, dry biomass, and seedling length of date palm under heavy metal stress conditions [Bacillus subtilis and AMF regarding nitrate, nitrate reductase, and nitrogenase properties and the components of phenols, lipids, fiber, and osmoprotectants such as proline, betaine, and glycine [Culture-dependent approaches have allowed the isolation of various bacteria taxa from the mycorrhizosphere of  mosseae ,422,423.rapeseed ,425,426.and rice ,428. Imp of rice . Comamonnd roots ,431. Baccucumber , and Azoeedlings . Azospirin wheat , and Psee clover . The utiin wheat ,437. It in wheat , and Azoficiency . Rhizobi peanuts ,440, andeedlings . Azotobaf number . Applica, and Zn . Rhizoglnditions . Glomus nditions . AMF alsnditions ,447; for glycine . Zamljen glycine  reported glycine  conclude glycine ,462,463.Biostimulants are sustainable and eco-friendly products that may promote metabolic and enzymatic processes in plants to enhance their yield, productivity, and crop quality and increase resistance to abiotic stresses. Biostimulants contain substances or products containing special formulations, natural components, or microorganisms that can naturally improve plant growth. The most important categories of biostimulants are humic and fulvic acid, fungi, bacteria, amino-acid-containing products, hormone-containing products, etc. Biostimulants are not only considered important alternatives to mineral fertilizers, but are also distinguished in organic farming systems under sustainable crop production management. Increased shoot and root growth, better root growth potential, improved resistance to stressors, and reduced nitrogen fertilizer inputs are some of the most noteworthy effects of biostimulant application in sustainable agriculture systems. Rhizophagus (formerly known as Glomus) intraradices and Funneliformis (formerly known as Glomus) mosseae. AMF make a positive contribution to growth, yield, stress tolerance, pathogen protection, and the maintenance of agricultural ecosystem sustainability. The increased activities of secondary metabolite production and antioxidant defense system enzymes related to plant defense have been extensively reported in mycorrhizal plants. Arbuscular mycorrhizal fungi are widespread root colonization fungi associated with the roots of higher plants. The current multiplication methods of mycorrhizal species under root organ culture (ROC) have become efficient alternatives for the cultivation of specific secondary metabolite compounds. Several kinds of studies have shown that AMF lead to significant changes in the quality and quantity of secondary metabolites that originate from medicinal and aromatic plants of economic interest. AMF can only be grown in the presence of host plants and are extensively used in agriculture and horticulture, especially In conclusion, AMF play a key role in plant nutrition and performance due to their capacity to improve plant mineral uptake. AMF, like other microbial biostimulants, can increase the sustainability of agricultural and horticultural production systems as well as improve the quality and quantity of food for the ever-growing world population. Moreover, studying the molecular mechanisms behind the observed activities will help to reveal the physiological and plant metabolism pathways involved in these processes and provide farmers with tailor-made products suitable for various conditions. However, further studies are needed to improve the reproducibility of the positive effects and to standardize the production processes from the lab to an industrial scale. This review article concludes that inoculation with specific arbuscular mycorrhizal fungi can increase the concentration of secondary metabolites in plants. However, future studies are needed to increase the reproducibility of the positive impacts, and more in-depth research is needed to identify the influence of interactions between AMF and biostimulants for promoting plants\u2019 physiological characteristics."}
+{"text": "Platynosomum illiciens, a trematode parasite known for its intricate life cycle, predominantly infests the liver, gallbladder, and bile ducts of domestic cats. In this study, we examined feline fecal samples from a cat sanctuary in Metropolitan Rio de Janeiro, Brazil, aiming to determine whether, even in such environments, cats retain their atavistic hunting habits, as evidenced by the presence of P. illiciens in fecal samples. The infection diagnosis utilized centrifugal sedimentation in the formalin-ethyl acetate test. Out of 72 fecal samples collected from various cats, four tested positive for P. illiciens eggs. This study serves as a reminder that even in environments where they are well-fed, cats exhibit predatory behavior, engaging in hunting and consuming prey, thus exposing themselves to parasites. It emphasizes the importance of veterinarians and cat caretakers being cognizant of the widespread presence of P. illiciens in Brazil and considering it in the differential diagnosis for cats presenting with liver or gallbladder issues. In conclusion, our findings underscore that the ancestral instinct for hunting and predation, preserved in domestic cats, persists despite fulfilling their nutritional needs. Platynosomum illiciens predominantly targets the liver, gallbladder, and bile ducts of its final hosts, leading to the shedding of eggs into the environment. Cats become infected when they hunt and ingest an infected paratenic hosts, such as snails or lizards   .P. illiciens is widely recognized in Brazil for causing subclinical infections. Clinical manifestations, when present, typically manifest as hepatic and biliary pathology (The parasite athology . While pathology , comprehP. illiciens infection, indicating that they can supplement their diet by hunting, potentially leading to infection with this parasite, and yet appear asymptomatic. Veterinarians and cat caretakers should be vigilant, recognizing the widespread presence of P. illiciens in Brazil and acknowledge that cats, despite provisions, may engage in hunting (P. illiciens as a differential diagnosis. The intermittent shedding of the parasite\u2019s eggs with feces necessitates specialized coproparasitological tests for accurate detection (This study, focusing on well-cared for cats in a sanctuary, reveals that even in such environments, where nutritional needs are met, cats engage in hunting and consuming prey. This behavior exposes them to  hunting . Clinicietection .Our findings underscore that the atavistic instinct preserved in domestic cats persists, unaffected by the fulfillment of their nutritional needs."}
+{"text": "Dear Editor,1. It is colliding with traditional clinical practice models, as researchers increasingly explore its integration into medicine. Timely summarization and reflection on current research are essential to effectively address future changes in this field.Chat Generative Pre-trained Transformer (ChatGPT), an artificial intelligence (AI) language model, goes beyond its apparent capabilities of natural language processing and conversational interactionA bibliometric study was conducted employing CiteSpace software to analyze published articles pertaining to ChatGPT. The primary objective of this study was to discern research hotspots and emerging trends, with the intention of furnishing healthcare professionals with pertinent references and guidance. We searched the Web of Science Core Collection with \u2018ChatGPT\u2019 as the keyword from its inception until June 2023. A total of 557 studies were included after removing duplicates and irrelevant articles, comprising 338 original articles, 37 review articles, and 192 correspondences and editorials. These studies originated from 65 countries or regions and formed interconnected author groups  to generate tailored treatment recommendations and predict individual responses. Seamless integration into existing clinical workflows and electronic health record (EHR) systems is essential for ChatGPT\u2019s effective use. This enables efficient real-time clinical decision support and documentation. Future research should explore integrating ChatGPT into EHR systems for intelligent data extraction, summarization, and analysis, supporting clinical research, healthcare quality improvement, and evidence-based medicine.The integration of ChatGPT into clinical practice is promising. Incorporating ChatGPT into monitoring systems provides surgeons with timely alerts, risk assessments, and predictive analytics, aiding early intervention and adverse event prevention3. It can assist medical students as a self-learning tool, simulate clinical scenarios, and contribute as a virtual team member. Physicians can consult ChatGPT for up-to-date medical research, treatment guidelines, and clinical practices, advancing their continuing education. Additionally, ChatGPT can educate patients by addressing inquiries, providing health education, aiding in treatment decisions, facilitating patient triage, conducting preliminary assessments, offering remote guidance for home care, and ultimately empowering patients to understand their conditions and actively participate in their treatment.The possibility of ChatGPT in medical education is being exploredChatGPT enhances the efficiency of medical research by facilitating literature reviews and knowledge organization. It assists researchers in staying updated on the latest advancements and research trends in specific fields. Additionally, ChatGPT enables the analysis of extensive medical data, such as clinical trial results, case reports, and medical imaging, for data interpretation, pattern recognition, and correlation analysis. This drives progress in medical research and ultimately improves patient outcomes.4. Ethical review boards should strengthen their evaluation and supervision of ChatGPT research and applications. Moreover, enhancing the transparency and interpretability of ChatGPT\u2019s algorithms is necessary, given its complex deep learning model.The clinical application of ChatGPT poses potential risks and challenges, considering the inclusion of sensitive patient data. Therefore, its use in medical decision-making must comply with ethical guidelines and legal regulations. Healthcare professionals and researchers should define ChatGPT\u2019s role and limitations in medical practice, ensuring patient informed consent and confidentialityIn conclusion, the collision between ChatGPT and traditional medicine is highly significant, with the potential to improve healthcare quality, patient outcomes, and advance medical education and research. However, it also poses challenges and risks that necessitate careful consideration in its utilization.Not applicable.None.Z.T.: conceptualization, data acquisition, and writing; Q.H.: statistical analysis, creation of figures, and writing; S.F.: review, editing, and supervision.The authors declare that they no conflicts of interest.None.All authors.Data are available from the corresponding author if the justification for the requirement is justified."}
+{"text": "While literature is inconclusive about whether midwives themselves want to be more autonomous6, a WHO report confirmed that midwives worldwide seek more professional autonomy7. Here, we delve into the diverse dimensions of Belgian midwives\u2019 professional autonomy. Through this exploration, we illuminate persistent knowledge gaps. As we traverse this domain, we extend an invitation to the global maternity care community, urging reflection on the interplay between autonomy, aspiration, and external influences. This journey is dedicated to advancing empowerment for midwives worldwide.In the ever-evolving landscape of healthcare professions, the importance of professional autonomy has been widely recognized, with positive impacts on job satisfaction, sense of belonging, and subjective well-being8. The authors chose to explore Belgian midwives\u2019 professional autonomy, as the status of their professional autonomy was undisclosed while insights from stakeholders are lacking. This research could have a positive impact on the professionalization of midwifery, not only in Belgium but also in other countries facing similar challenges.The phenomenon of midwifery autonomy is complex, intertwined with contextual influences, societal perceptions, policy frameworks, and educational paradigms. A study exploring the state of professionalization of midwifery in Europe recommended more in-depth studies on midwives\u2019 autonomy and maternity care culture in individual countriesTo gain a comprehensive understanding of Belgian midwives\u2019 professional autonomy across all regions and professional domains, five studies were conducted:9;Our journey commenced with an analysis of relevant policy and academic texts, underpinned by Greenwood\u2019s sociological criteria for a profession. As such, the state of the professionalization of midwifery in Belgium was described. We identified documented challenges spanning societal, structural, and professional domains. Recommendations to advance the midwifery profession involve increasing public awareness, implementing comprehensive midwifery practices, and enhancing professional autonomy through collaborative endeavors among midwifery organizations, women\u2019s groups, maternity care professionals, and policy-makers10. We established a communal definition of midwifery autonomy in Belgium, comprising 15 components related to midwives\u2019 work content, professionalism and relationship with others;The forging of a consensus definition of \u2018midwifery autonomy\u2019, using a modified Delhi study with 27 content experts, was an ambitious stride, fostering a deeper grasp of this concept11;Through meticulous inquiry, a subsequent descriptive observational study among 312 midwives revealed nuanced perceptions from midwives. Amidst this diverse tapestry of perspectives, notable disparities emerged between hospital-based and primary care midwives, as well as across various regions. Furthermore, the study echoed midwives\u2019 desire for heightened professional autonomy, coupled with a strong wish for societal recognition and respect in the realm of maternity care. Yet, a complex interplay emerged \u2013 the intricate interposition of perceived autonomy and latent fears of liability12; andAdditionally, through heterogeneous virtual focus group interviews (n=3), using a qualitative approach, maternity care stakeholders (n=27) views on midwives\u2019 professional autonomy were identified. Stakeholders, including health professionals, policy advisors, hospital managers and service-users emphasized vital prerequisites for professional autonomy, including education, continuous professional development, competence, experience, and collaboration. Furthermore, stakeholders stressed the emergence of an integrated maternity collaborative framework and advocated for stringent regulations to uphold care quality and fortify midwives\u2019 autonomyFinally, through homogeneous in-person focus group interviews (n=3), using a qualitative approach, the experiences and understanding of midwifery autonomy among final-year midwifery students was explored. Students emphasized the need for supportive learning environments, collaborative practice and continuous professional development to promote midwifery autonomy. In students\u2019 views, cultivating safe and supportive learning environments, may contribute to midwives\u2019 professional autonomy, ultimately improving maternal and new-born health.13. With these insights in hand, a clear call for action emerged, urging a focus on recognized authority, to prevent midwives from being undervalued, underutilized, and underpaid. Aligning regulation and education with the International Confederation of Midwives\u2019 standards, promotes midwives\u2019 professional autonomy worldwide14. Additionally, strengthening professional leadership in midwifery, from local to international levels, is essential. This entails developing leadership within the midwifery profession and forging partnerships across political, societal, and inter-professional domains. Such efforts are key to enhancing midwifery autonomy and elevating its global influence15.Our research illuminated barriers compromising the autonomy of Belgian midwives, categorized them through the lens of Greenwoods\u2019 professionalism criteriaRecommendations to enhance midwives\u2019 professional autonomy encompass prioritizing midwife-led continuity of care, fostering interprofessional collaboration, tailoring continuous professional development, increasing public awareness, and advocating for policy changes. The trajectory to empowerment necessitates a metamorphosis, cultivating environments where autonomy flourishes. Our research provided valuable insights in how to promote midwives\u2019 professional autonomy. Nevertheless, it is important to acknowledge certain limitations in this study, including the inherent subjectivity in our interpretations and the potential challenge of generalizing findings beyond Belgium.We extend an open invitation to engage, initiate dialogue, and foster alliances across borders and maternity care disciplines. As we unite to embrace professional autonomy, recognition, and collaborative excellence, the journey that was embarked upon by Belgian midwives resonates as an embodiment of empowerment, shaping the trajectory of midwifery, not only within Belgium but also on the global stage."}
+{"text": "Pancreatic cancer (PCa) is a highly aggressive and deadly form of cancer with a low five-year survival rate. This paper explores the role of pharmacologic anthropology in understanding and addressing health disparities related to PCa. Pharmacologic anthropology examines how cultural, social, economic, and behavioral factors affect the use and effectiveness of pharmaceutical treatments. In the context of PCa, it helps us understand why different population groups experience disparities in PCa outcomes. By adopting this interdisciplinary approach, researchers, healthcare providers, and policymakers can better understand the complex dynamics of PCa health disparities. This understanding can lead to culturally sensitive interventions, improved communication between patients and providers, increased community engagement, and policies that enhance access to quality care for all PCa patients.Pancreatic cancer (PCa) remains a formidable global health challenge, with high mortality rates and limited treatment options. While advancements in pharmacology have led to improved outcomes for various cancers, PCa continues to exhibit significant health disparities, disproportionately affecting certain populations. This paper explores the intersection of pharmacology and anthropology in understanding the health disparities associated with PCa. By considering the socio-cultural, economic, and behavioral factors that influence the development, diagnosis, treatment, and outcomes of PCa, pharmacologic anthropology provides a comprehensive framework to address these disparities and improve patient care. Pancreatic cancer (PCa) is one of the most aggressive and lethal forms of cancer, with a five-year survival rate below 12% ,4,5,6. TPharmacologic anthropology is an interdisciplinary field that explores the dynamic relationship between pharmacology (the study of drugs and their effects on the body) and anthropology (the study of human societies and cultures) . It focuPCa is characterized by its aggressive nature, late-stage diagnosis, limited treatment options, and poor survival rates ,9. HowevPharmacologic anthropology, as applied to PCa, seeks to understand the multifaceted nature of these health disparities. It recognizes that the development, diagnosis, treatment, and outcomes of PCa are influenced not only by biological factors but also by socio-cultural contexts and individual behaviors. By adopting an anthropological lens, this field acknowledges that healthcare practices, beliefs, and systems are embedded within specific cultural and social contexts and are influenced by factors such as race, ethnicity, socioeconomic status, and gender.The scope of pharmacologic anthropology in the context of cancer in general and PCa specifically is broad and encompasses several aspects such as cultural and behavioral factors, socioeconomic factors, access to healthcare and treatment disparities, as well as genetic and biological factors. It investigates the impact of cultural norms and traditions on treatment-seeking behaviors , patientBy embracing these principles, researchers, healthcare providers, and policymakers can gain a more comprehensive understanding of the complex dynamics surrounding PCa health disparities. This interdisciplinary approach helps to identify and address the root causes of these disparities, inform culturally sensitive interventions, enhance patient-provider communication, promote community engagement, and advocate for policies that improve access to quality care for all individuals affected by PCa.PCa provides a compelling context to explore the interplay between pharmacology and anthropology. Understanding this interplay is crucial for comprehending the multifaceted factors that influence the development, treatment, and outcomes of PCa within diverse populations. Pharmacology, as the study of drugs and their effects, plays a central role in PCa treatment. It encompasses the discovery, development, and utilization of pharmaceutical interventions such as chemotherapy, targeted therapies, immunotherapies, and supportive medications. By analyzing the social and cultural contexts in which pharmaceutical interventions are utilized, anthropology sheds light on the complex interactions between individuals, communities, and healthcare systems.The interplay between pharmacology and anthropology in the context of PCa can be observed in several ways: cultural perceptions and beliefs, treatment decision-making, socioeconomic disparities, patient-provider interactions, and health systems and policies. Anthropological healthcare research explores how cultural beliefs and perceptions regarding illness, cancer, and pharmaceutical interventions influence the acceptance and utilization of specific treatments for PCa ,33. UndeBy recognizing the interplay between pharmacology and anthropology, researchers, healthcare providers, and policymakers can develop a comprehensive understanding of the complex factors influencing PCa outcomes. This interdisciplinary approach allows for the development of patient-centered interventions, tailored healthcare strategies, and policies that address health disparities, enhance treatment efficacy, and improve the overall well-being of individuals affected by PCa.Socioeconomic factors play a significant role in the occurrence, diagnosis, treatment, and outcomes of PCa, contributing to health disparities observed in different populations ,46,47,48Lower income levels and limited educational attainment have been associated with an increased risk of PCa. However, the data would indicate that the estimated number of new cases of pancreatic cancer in low-income countries and individuals is often lower than in higher-income countries and individuals . SocioecLack of health insurance or inadequate coverage is a significant socioeconomic factor contributing to PCa health disparities. Individuals without insurance or with limited coverage may delay seeking medical care, receive less comprehensive diagnostic evaluations, experience delays in treatment initiation, or have limited access to innovative therapies. Insurance status significantly influences the quality and timeliness of PCa care .Geographic disparities play a role in PCa outcomes. Rural and underserved areas often have limited healthcare infrastructure, including oncology centers and specialized medical professionals ,53. LimiCertain occupations and occupational exposures have been associated with an increased risk of PCa. Occupational factors, such as exposure to carcinogens like asbestos, pesticides, or heavy metals, can contribute to the development of PCa ,56,57. FSocioeconomic disparities in health literacy and knowledge about PCa can influence individuals\u2019 ability to understand and navigate the healthcare system effectively ,62,63. LAddressing socioeconomic factors in PCa health disparities requires a multi-faceted approach that includes improving access to healthcare, enhancing health education and awareness, supporting the socioeconomically disadvantaged, strengthening occupational health and safety, and enhancing health literacy. Efforts should focus on increasing access to affordable healthcare services, including cancer screenings, diagnostic tests, and specialized treatment centers. Expanding health insurance coverage, particularly for vulnerable populations, can reduce financial barriers and ensure timely access to necessary care. Implementing targeted health education campaigns can improve awareness about PCa risk factors, symptoms, and the importance of early detection . CulturaCultural and behavioral factors significantly contribute to health disparities in PCa, shaping individuals\u2019 beliefs, attitudes, and behaviors related to prevention, diagnosis, treatment-seeking, and adherence ,66. UndeAddressing cultural and behavioral factors in PCa health disparities requires culturally sensitive strategies. These strategies may include culturally tailored education and outreach, community engagement, patient navigation and support, healthcare provider cultural competence, or a multidisciplinary collaboration ,81,82. DAccess to healthcare and treatment disparities significantly contribute to PCa health disparities . These dAddressing access to healthcare and treatment disparities in PCa requires comprehensive strategies. Policy initiatives focused on expanding healthcare coverage, improving insurance affordability, and reducing barriers to access can help mitigate disparities. Advocacy efforts can raise awareness about PCa health disparities and push for policy changes that promote equity in access to care . CommuniGenetic and biological factors play a significant role in PCa health disparities, contributing to variations in disease incidence, prognosis, and response to treatment among different population groups ,96. UndeUnderstanding the genetic and biological factors contributing to PCa health disparities can inform strategies to address these disparities. Implementing genetic testing and counseling programs can help identify individuals at increased genetic risk for PCa, particularly those from high-risk ethnic groups or those with a family history. Offering targeted screening and preventive measures to individuals with identified genetic mutations can reduce disparities in PCa incidence and mortality ,108,109.As has already been articulated, pancreatic cancer is known for its aggressive nature and high mortality rates . It has One of the primary barriers to adequate pancreatic cancer screening among individuals with familial risk factors is their socioeconomic status . It has Racial and ethnic disparities also play a part in the underutilization of pancreatic cancer screening among individuals with familial risk factors . In the Healthcare provider disparities are another aspect of the problem . Not allIn order to address pancreatic cancer screening disparities among individuals with familial risk factors, a multifaceted approach is needed. Public health campaigns and educational programs ,128 shouPharmacologic anthropology explores the intersection between culture, society, and medicine, focusing on how local knowledge and practices influence health, healing, and the use of medications . In the To leverage the insights gained from understanding local knowledge and practices, several strategies can be implemented. Conducting community-based research allows for the inclusion of local knowledge and perspectives in PCa studies ,82. EngaCultural beliefs and perceptions play a significant role in shaping individuals\u2019 understanding of the disease, influencing health-seeking behaviors, treatment decisions, and medication adherence. By assessing and understanding these cultural beliefs, healthcare providers and researchers can develop culturally sensitive approaches to PCa prevention, treatment, and support, thereby addressing health disparities. Qualitative research methods, such as interviews, focus groups, and ethnographic observations, can be employed to explore cultural beliefs and perceptions related to PCa. These methods allow researchers to engage with individuals and communities, gaining insights into their perspectives, experiences, and cultural frameworks regarding the disease ,159. By By assessing cultural beliefs and perceptions related to PCa, pharmacologic anthropology provides valuable insights for addressing health disparities. Findings from cultural assessments can inform the development of culturally sensitive educational materials and awareness campaigns ,156. ThePharmacologic anthropology emphasizes the importance of community engagement and health education in addressing PCa disparities. By actively involving communities in the development and implementation of interventions and by providing culturally appropriate health education, healthcare providers can empower individuals and communities to make informed decisions about PCa prevention, treatment, and support. Community-Based Participatory Research (CBPR) involves collaborating with community members, organizations, and stakeholders in all phases of the research process. Engaging the community as equal partners fosters mutual learning, builds trust, and ensures that interventions are grounded in the community\u2019s needs, values, and cultural contexts. This approach promotes community ownership and the sustainability of interventions ,172,173.Pharmacologic anthropology recognizes the importance of addressing structural and systemic barriers in order to reduce PCa disparities. These barriers can disproportionately affect certain populations, including marginalized communities, low-income individuals, and racial/ethnic minorities. By understanding and addressing these barriers, healthcare providers and policymakers can work towards creating a more equitable healthcare system for PCa prevention, diagnosis, treatment, and support. Structural barriers, such as lack of health insurance, limited healthcare facilities, transportation challenges, and long waiting times, can hinder access to timely and quality healthcare services . EffortsPharmacologic anthropology recognizes the importance of enhancing patient-provider communication in the context of PCa care. Effective communication is vital for building trust, promoting shared decision-making, ensuring patient understanding, and addressing the unique cultural and social factors that influence patients\u2019 experiences and perspectives. Here are some ways in which pharmacologic anthropology can contribute to enhancing patient-provider communication. Healthcare providers should be aware of and respect patients\u2019 cultural beliefs, values, and practices ,186. By While PCa remains a challenging disease with significant health disparities, several successful interventions have been implemented to address these disparities . Here arCBPR is a collaborative research approach that involves the active engagement of community members, organizations, and researchers in all stages of this research process. CBPR has been successfully employed in PCa research, contributing to improved understanding of the disease, addressing health disparities, and developing effective interventions. Here are a few case studies and best practices showcasing the impact of CBPR in PCa. The Detroit Urban Research Center (DURC) is a partnership between community organizations, academic institutions, and researchers aimed at addressing health disparities in Detroit, including PCa. Through CBPR, the DURC engaged community members in the design and implementation of studies, community outreach programs, and policy advocacy efforts ,204. ThiEngaging community members from the outset: Involving community members in this research design, implementation, and dissemination phases ensures that research is responsive to community needs and priorities.Building trusting relationships: Establishing trust between researchers and community partners is crucial for successful CBPR. Transparent communication, mutual respect, and recognition of the expertise and contributions of all stakeholders help foster trust and collaboration.Incorporating cultural competence: Recognizing and addressing cultural factors that influence health beliefs, practices, and access to care is essential. Cultural competence training for researchers and incorporating cultural perspectives into research protocols ensure that interventions are culturally appropriate.Sharing power and resources: CBPR requires equitable power sharing and resource distribution among community partners and researchers. Meaningful involvement of community members in decision-making processes, capacity building, and resource allocation fosters a sense of ownership and sustainability.Capacity building: CBPR should include capacity-building efforts to enhance this research skills and knowledge of community members. This empowers community partners to actively contribute to the research process, strengthen their own advocacy efforts, and sustain interventions beyond this research project.Best practices in CBPR for PCa research include:CBPR in PCa research has demonstrated its effectiveness in addressing health disparities, promoting community engagement, and developing interventions that are responsive to community needs. By leveraging the expertise of both researchers and community members, CBPR will contribute to more equitable and impactful approaches to PCa prevention, treatment, and support.Culturally sensitive interventions are critical in addressing PCa disparities and ensuring that healthcare approaches are tailored to the cultural beliefs, values, and practices of diverse populations. Here we describe some case studies and best practices that highlight the importance of culturally sensitive interventions in PCa:Project ECHO  is a telehealth-based collaborative model that has been used at Rutgers Cancer Institute of New Jersey, MD Anderson Cancer Center, the National Institutes of Health, Indiana University at Purdue, and others to improve PCa care in underserved communities. Through this program, specialists connect with primary care providers and community health workers via videoconferencing to deliver training, mentorship, and support. Culturally sensitive approaches are incorporated by considering the unique cultural perspectives, health beliefs, and social determinants of health within each community. By leveraging local knowledge and understanding cultural contexts, Project ECHO promotes better communication and enhances the delivery of culturally sensitive care.Native patient navigation programs have been implemented to improve access to PCa care among Indigenous communities. These programs employ patient navigators who are embedded within the community and possess cultural competency. Navigators provide support, education, and assistance in navigating the healthcare system, addressing cultural barriers, and promoting adherence to treatment. By understanding and respecting cultural practices, traditions, and beliefs, patient navigators can build trust and foster effective communication, resulting in improved outcomes for Native patients with PCa ,213,214.Faith-based organizations have played a significant role in implementing culturally sensitive interventions for PCa. For example, partnerships between healthcare providers and faith-based organizations have facilitated community outreach, education, and support programs ,217,218.Developing culturally tailored educational materials is essential to effectively communicating information about PCa prevention, risk factors, and early detection. This includes using appropriate language, visuals, and examples that resonate with the target population ,220. ForCommunity health workers (CHWs) have been instrumental in delivering culturally sensitive interventions for PCa. CHWs are members of the community who have a deep understanding of cultural norms, beliefs, and healthcare challenges. They provide education, support, and navigation services within their communities, bridging the gap between healthcare providers and community members ,222,223.Engage community members and stakeholders from the target population in the intervention planning, design, and implementation process.Conduct a thorough assessment of the cultural beliefs, values, practices, and health disparities prevalent within the community.Collaborate with community leaders, cultural organizations, and faith-based institutions to leverage existing resources and networks.Train healthcare providers and researchers in cultural competence to enhance their understanding of diverse populations and improve patient-provider communication.Provide language-appropriate and culturally relevant educational materials, ensuring they are easily understandable and accessible to the target population.Incorporate cultural traditions, rituals, and preferences into interventions to enhance engagement and acceptance.Evaluate and adapt interventions based on community feedback and outcomes to ensure ongoing cultural relevance and effectiveness.Best practices for culturally sensitive interventions in PCa include:By embracing culturally sensitive interventions, healthcare providers and researchers can improve access to care, enhance communication, and reduce disparities in PCa outcomes among diverse populations.Patient advocacy and empowerment play a crucial role in addressing PCa disparities by ensuring that patients have a voice, are actively involved in their care decisions, and have access to the resources and support they need. Here are some case studies and best practices that highlight the importance of patient advocacy and empowerment in PCa:PanCAN is a patient advocacy organization dedicated to improving the lives of individuals affected by PCa. They provide resources, support, and advocacy opportunities for patients and their families. PanCAN has been successful in raising awareness about PCa, advocating for increased research funding, and promoting policies that improve access to quality care. Through their advocacy efforts, they empower patients and their families to become informed advocates for themselves and others.Support groups for PCa patients and caregivers provide a platform for sharing experiences, knowledge, and emotional support. These groups empower patients by fostering a sense of community, reducing isolation, and providing opportunities to learn from others who have faced similar challenges. Support groups often collaborate with healthcare providers to ensure that patients receive accurate information and access to resources, enhancing patient empowerment ,224.Shared decision-making involves healthcare providers and patients working together to make informed treatment decisions based on the patient\u2019s values, preferences, and available evidence ,226. In Providing comprehensive and understandable health education materials empowers patients to actively engage in their care. Educational resources should cover various aspects of PCa, including treatment options, potential side effects, symptom management, and survivorship ,228,229.Empowering patients does not end with treatment completion. Survivorship programs for PCa patients focus on addressing physical, emotional, and psychosocial needs after treatment. These programs offer resources, support, and survivorship care plans to empower patients to manage their long-term health, cope with potential side effects, and promote overall well-being ,222. SurPatient navigation programs assist patients in navigating the healthcare system, coordinating care, and accessing necessary resources. Patient navigators act as advocates, providing support, guidance, and information throughout the cancer journey. By empowering patients with knowledge and assistance, patient navigation programs help overcome barriers to care, improve health outcomes, and enhance patient empowerment ,152.Online communities and forums provide a platform for patients and caregivers to connect, share information, and seek support ,152. TheFacilitating open and honest communication between patients and healthcare providers ensures that patients are active participants in their care.Encouraging patients to ask questions, seek second opinions, and actively engage in treatment decision-making.Providing clear and accessible information about treatment options, clinical trials, and supportive care services.Collaborating with patient advocacy organizations to connect patients with resources, support groups, and educational materials.Promoting patient education and health literacy to enhance patients\u2019 understanding of their diagnosis, treatment, and self-care.Advocating for policies that improve access to affordable healthcare, clinical trials, and supportive services for PCa patients.Recognizing and respecting patients\u2019 cultural, religious, and personal values when developing care plans and support services.Best practices for patient advocacy and empowerment in PCa include:By prioritizing patient advocacy and empowerment in PCa care, healthcare providers, researchers, and patient advocacy organizations can create a supportive environment that empowers patients to actively participate in their care decisions, access resources, and advocate for their needs. This comprehensive approach improves patient outcomes and contributes to reducing disparities in PCa.PCa continues to pose significant health disparities, necessitating a multi-disciplinary approach to improve outcomes and reduce disparities. Collaborations among various disciplines, including healthcare providers, researchers, public health professionals, community organizations, and policymakers, are vital for addressing PCa health disparities. Future directions and challenges in this area are numerous. Advancements in precision medicine hold promise for improving PCa outcomes. Collaborations between researchers, oncologists, and geneticists can further identify and validate biomarkers associated with PCa risk, prognosis, and response to treatment ,231,232.Challenges in multi-disciplinary collaborations include communication and coordination, resource allocation, institutional and cultural barriers, and sustainability. Effective collaboration requires clear communication and coordination among diverse stakeholders. Overcoming language barriers, varying expertise, and organizational structures can be challenging. Establishing effective communication channels and platforms for sharing information and fostering collaboration is crucial. Collaboration often necessitates the allocation of resources, including funding, staff, and infrastructure. Securing and distributing resources equitably among collaborating entities can be challenging. Ensuring adequate resources for research, intervention implementation, and sustainability is critical for successful multi-disciplinary collaborations. Different disciplines may have varying approaches, priorities, and institutional cultures. Overcoming disciplinary silos and bridging these gaps require mutual understanding, respect, and a willingness to work collaboratively. Building relationships and fostering a culture of collaboration among stakeholders can help address these barriers. Maintaining long-term collaborations and sustaining interventions beyond research projects can be challenging. Developing strategies for sustainability, including securing funding, training, and capacity-building, and establishing partnerships with community organizations, are essential for the long-term success of multi-disciplinary collaborations. In conclusion, multi-disciplinary collaborations are crucial for addressing PCa health disparities. Future directions involve precision medicine, health system innovations, community engagement, policy advocacy, and data integration. Overcoming challenges related to communication, resource allocation, institutional barriers, and sustainability is essential for successful collaborations. By working together, stakeholders can develop comprehensive strategies, implement effective interventions, and reduce PCa disparities, ultimately improving outcomes for all populations.Precision medicine, which involves tailoring medical treatments to individual patients based on their unique characteristics, holds significant potential for improving PCa outcomes and reducing health disparities. Future directions and challenges related to precision medicine and personalized care in addressing PCa health disparities remain in their infancy. Advancements in genomic profiling have identified specific genetic mutations and alterations that drive PCa ,241. ColPolicy changes and a focus on health equity are crucial for addressing PCa health disparities. Future directions involve advocating for increased research funding specifically allocated to PCa, with a focus on understanding the causes, risk factors, and mechanisms underlying the disease. Collaborations between researchers, patient advocacy groups, and policymakers can influence funding priorities and ensure that PCa research receives adequate support. Increased research funding can lead to advancements in early detection, treatment options, and targeted therapies. Policy changes should aim to improve access to and utilization of screening methods for PCa, particularly among high-risk populations. Collaboration between policymakers, healthcare providers, and professional societies can result in guidelines that promote regular screening for individuals with known risk factors, such as a family history of PCa or specific genetic mutations. Increasing awareness of early warning signs and symptoms can also aid in early detection efforts. Policy changes should focus on improving access to high-quality care for all individuals diagnosed with PCa. This includes ensuring that healthcare facilities and providers in underserved areas have the resources and expertise necessary to diagnose and treat PCa effectively. Cooperation between policymakers, healthcare systems, and community organizations can identify barriers to access and develop strategies to overcome them, such as expanding healthcare coverage, improving transportation options, and implementing telemedicine services. Policy changes should address health insurance disparities that contribute to unequal access to PCa care. Synergy between policymakers, insurers, and patient advocacy groups can promote reforms that provide comprehensive coverage for screening, diagnostic tests, treatment options, and supportive care services. Efforts should focus on reducing financial barriers, such as high out-of-pocket costs and pre-existing condition exclusions, to ensure equitable access to necessary care. Policy changes should emphasize the importance of culturally competent care in addressing PCa disparities. Partnerships between policymakers, healthcare providers, and community organizations can support initiatives that promote diversity and inclusion in the healthcare workforce, ensure language access to services, and address cultural barriers to care. Policies should encourage the development of educational programs that enhance healthcare providers\u2019 cultural competence, enabling them to deliver personalized care that respects patients\u2019 values, beliefs, and preferences. Policy changes should prioritize health literacy initiatives and patient education programs to improve understanding of PCa prevention, early detection, treatment options, and survivorship. Collaboration between policymakers, healthcare providers, and patient advocacy groups can develop and implement policies that promote clear and accessible health information, including educational materials, digital resources, and community-based workshops. Efforts should focus on reaching diverse populations, considering language, literacy levels, and cultural considerations. Addressing PCa disparities requires addressing the social determinants of health that contribute to unequal outcomes. Policy changes should target broader factors such as socioeconomic status, education, employment, and housing, which impact access to healthcare and influence health behaviors. Synergy between policymakers, public health experts, and community organizations can promote policies that address social determinants of health, ultimately leading to improved health equity.Challenges in implementing policy changes and promoting health equity include overcoming political obstacles and garnering support for policy changes. This will require strong advocacy efforts. Collaboration between patient advocacy groups, researchers, healthcare providers, and policymakers is essential to driving policy changes that prioritize PCa disparities and health equity. Comprehensive data collection and surveillance systems are needed to monitor PCa disparities and evaluate the impact of policy changes. Collaboration between researchers, healthcare systems, and policymakers can facilitate the development of robust data infrastructure and standardized reporting mechanisms to track disparities over time and inform policy decisions. Addressing PCa disparities requires collaboration across sectors, including healthcare, public health, education, and social services. Collaboration between stakeholders from different sectors can be challenging due to differing priorities, structures, and funding streams. Efforts should be made to foster cross-sector collaborations, share resources, and align goals to promote health equity. Policy changes should be accompanied by rigorous evaluation to assess their effectiveness in reducing PCa disparities. Partnerships between researchers, policymakers, and healthcare providers are necessary to establish evaluation frameworks, measure outcomes, and hold stakeholders accountable for achieving health equity goals. In conclusion, policy changes and a focus on health equity are vital for addressing PCa health disparities. Future directions involve increasing research funding, promoting screening and early detection, enhancing access to quality care, addressing health insurance disparities, promoting culturally competent care, improving health literacy, and addressing social determinants of health. Overcoming challenges and fostering collaboration among stakeholders are essential for implementing effective policies and achieving health equity in PCa care.Technological innovations have the potential to play a significant role in addressing PCa health disparities by improving access to information, diagnosis, treatment, and supportive care. Future directions and challenges related to technological innovations and access in addressing PCa health disparities should be prioritized and tackled head-on. Telemedicine and virtual care technologies can enhance access to specialized healthcare services for individuals in underserved areas ,254.Collaboration between healthcare providers, technology developers, and policymakers can facilitate the implementation of telemedicine platforms that enable remote consultations, follow-up care, and multidisciplinary tumor boards . HoweverCollaborations between technology developers, healthcare providers, and researchers can lead to the development of mobile health applications (apps) that empower individuals to track symptoms, manage medications, access educational resources, and connect with support networks ,257. TheSynergy between researchers, data scientists, and healthcare providers can harness the power of artificial intelligence (AI) and data analytics to improve PCa outcomes. AI algorithms can assist in early detection, risk prediction, treatment planning, and response monitoring ,259. HowCollaborations between healthcare systems, technology developers, and policymakers can promote the establishment of health information exchange networks . These nWearable devices, such as smartwatches and fitness trackers, can enable continuous monitoring of vital signs, physical activity, and symptom progression. Collaboration between technology developers, researchers, and healthcare providers can leverage these devices to provide real-time data for early detection, personalized treatment monitoring, and patient self-management. Challenges include ensuring accuracy, reliability, and affordability of wearable devices, as well as addressing disparities in access to and utilization of these technologies ,262.Technological innovations can exacerbate health disparities if individuals lack digital literacy skills or face barriers to accessing technology. Collaboration between healthcare providers, community organizations, and policymakers is needed to bridge the digital divide by providing digital literacy training, ensuring affordability and availability of internet access, and tailoring technological solutions to diverse populations\u2019 needs and preferences.Policy changes and collaborations between policymakers, researchers, and technology developers are necessary to establish guidelines and regulations that ensure the ethical use of technology in PCa care. This includes addressing issues of privacy, security, informed consent, and transparency in data collection and utilization.Addressing challenges related to technological innovations and access requires collaboration among stakeholders, including healthcare providers, technology developers, researchers, policymakers, and patient advocacy groups. Efforts should focus on promoting equity in technology development and implementation, addressing barriers to access, and ensuring that technological innovations are culturally sensitive, user-friendly, and effective across diverse populations. In conclusion, technological innovations have the potential to improve access and outcomes in PCa care. Future directions involve leveraging telemedicine, mobile health apps, AI, health information exchange, wearable devices, and remote monitoring . HoweverIn conclusion, this manuscript underscores the multifaceted nature of pancreatic cancer health disparities and the critical need for a comprehensive approach to address this pressing issue. The evidence and arguments presented throughout this work emphasize the intricate interplay of factors contributing to these health disparities, while pharmacologic anthropology provides a lens through which we can better understand and address them.One of the pivotal facets of this issue lies in the genetic and biological factors influencing pancreatic cancer incidence and outcomes. Deepening our understanding of the genetic predispositions and molecular pathways associated with this disease is essential for developing targeted interventions and therapies that can reduce disparities in diagnosis, treatment outcomes, and even earlier detection.Access to healthcare and treatment remains a central concern in addressing pancreatic cancer health disparities. Disparities in healthcare access, particularly in underserved communities, can significantly hinder early diagnosis and timely intervention. Efforts must be made to improve access to specialized care, ensure equitable resource allocation, and promote the availability of state-of-the-art treatments for all individuals affected by pancreatic cancer.Socioeconomic factors play a pivotal role in perpetuating these disparities. Income inequality, education disparities, and economic instability can pose significant barriers to accessing healthcare services and adhering to treatment plans. Addressing the social determinants of health, such as employment opportunities and education, is crucial to reducing the burden of pancreatic cancer on marginalized populations and even the military.Furthermore, enhanced patient-provider communications are essential to bridging the gap in healthcare disparities. Effective communication, rooted in cultural competence and empathy, fosters trust, shared decision-making, and treatment adherence. Healthcare providers must prioritize open and respectful dialogues with their patients, ensuring that information is accessible, comprehensible, and tailored to individual needs.Comprehensive Genetic and Biological Research: Invest in robust research initiatives that delve into the genetic and biological underpinnings of pancreatic cancer, aiming to identify risk factors, biomarkers, and therapeutic targets that can lead to more equitable treatment outcomes.Equitable Access and Enhanced Communication: Advocate for policies and interventions that ensure equitable access to healthcare and treatment, while also emphasizing the importance of enhanced patient-provider communications, cultural competence, and shared decision-making in reducing disparities.In light of these considerations, it is evident that addressing pancreatic cancer health disparities necessitates a multi-pronged approach. By integrating the insights of pharmacologic anthropology, we can develop strategies that account for the cultural, social, and biological factors at play. To strategically address these disparities, two key actions emerge:In conclusion, this manuscript underscores the urgency of addressing pancreatic cancer health disparities and offers a pathway forward through the integration of pharmacologic anthropology principles. By taking concrete steps to advance genetic and biological research, improve access to care, address socioeconomic determinants, and enhance patient-provider communications, we can move closer to the goal of achieving health equity for all individuals affected by pancreatic cancer."}
+{"text": "The School of Life Sciences at the Jawaharlal Nehru University in New Delhi, India held an International Symposium on Mitochondria, Cell Death and Human Diseases on February 18\u201319, 2023. The meeting provided a highly interactive forum for scientific discussion, cultural exchange, and collaborations between international scientists working in diverse areas of mitochondrial biology, cell death, and cancer. The two-day symposium attracted more than 180 delegates that included leading international scientists, early career researchers in India, as well as postdoctoral fellows and students. Several of the students, postdoctoral fellows, and junior faculty presented platform talks and had a chance to showcase the depth and emerging progress in biomedical research in India. The meeting will be instrumental for planning future congresses and symposium throughout India, not only to focus on mitochondrial biology, cell death and cancer but to foster continued ferment and collaborations in the biological sciences throughout India. The symposium was organized by Prof. Rana P Singh, School of Life Sciences, Jawaharlal Nehru University (JNU), and Cancer Research and Care Academy, New Delhi, India; Prof. Raymond B. Birge, Rutgers School of Biomedical and Health Sciences, USA; and Prof. Dhyan Chandra, Roswell Park Comprehensive Cancer Center, USA. The 2-day symposium provided an interactive platform for brainstorming current updates in the areas of mitochondria, cell death, and human diseases as well as highlighted major advances in biomedical research in many disciplines in india. The meeting was instrumental in fostering interactions between students, emerging scholars, and established leaders in mitochondrial and cell death biology. The meeting also cultivated international collaborations among established scientists in India and abroad. More than 40 senior scientists from India and USA participated in the meeting. The program included two keynote talks, five plenary talks, fifteen talks by senior scientists, and selected six talks by young faculty and five talks by young Ph.D. research scholars for the award categories. Moreover, 45 poster presentations were included on various disciplines focusing on mitochondria, cell death, and cancer in relation to human diseases. The symposium witnessed the participation of more than 180 delegates.The International Symposium on Mitochondria, Cell Death and Human Diseases (Major themes encompass (a) mitochondrial dynamics including fission and fusion, dysfunction, and cell death, (b) role of mitochondria in cancer, (c) mitochondria in translational research, (d) mitochondria in stem cell and regeneration, (e) role of mitochondria in aging, (f) mitochondria in metabolism, inflammation, and immunity, (g) recent advances in mitochondrial research (h) mitochondrial communication, (i) mitochondria in neurological diseases and (j) cancer therapeutics.th February with an inaugural ceremony addressed by the convenor of the symposium Prof. Rana P. Singh, School of Life Sciences and Special Center for Systems Medicine JNU, New Delhi, India. The opening ceremony had a special welcome from the co-chairs Prof. Supriya Chakraborty, Dean, School of Life Sciences, JNU, New Delhi, India; Prof. R.N.K. Bamezai, Former Professor and Dean, School of Life Sciences, JNU; Prof. Dhyan Chandra, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA; Prof. Raymond B. Birge, Rutgers School of Biomedical and Health Sciences, Newark, New Jersey, USA; Prof. S. C. Garkoti, and Rector, JNU, New Delhi, India. The special vote of thanks was delivered by Prof. Paulraj Rajamani, School of Environmental Sciences, JNU, New Delhi, India.The symposium began on 18Scientific sessions highlighted basic and translational research focused on mitochondrial and cell death biology as well as on therapeutic vulnerabilities in cancer and other human diseases. The first session began with the keynote lecture by Prof. Marcus E. Peter, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA. He summarized the current advances on the role of death induced by survival gene elimination (DISE)/6mer seed toxicity in cancer and neurodegenerative diseases. Prof. Raymond B. Birge, Rutgers School of Biomedical and Health Sciences, Newark, New Jersey, discussed on how phosphatidylserine exposure, stress, and cell death causes immune regulation in cancer. Prof. Dhyan Chandra, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA elaborated the importance of mitochondrial unfolded protein response in prostate cancer followed by a talk by Prof. Pankaj K. Singh, the University of Oklahoma College of Medicine, Oklahoma, USA on the role of mitochondrial metabolism and its therapeutic vulnerability in cancer. Prof. K. Thangaraj, Centre for DNA Fingerprinting and Diagnostics (CDFD) Hyderabad, Telangana, India emphasized on the dual genetic origin of neuromuscular disorders.The second session started with a discussion on mitochondrial biology and genome. Prof. Sanjay V. Malhotra Knight Cancer Institute, Oregon Health & Science University, Portland, USA talked about targeting Guanylate Binding Protein 1 (GBP1) regulated modulation of proteasomal machinery for cancer treatment. Prof. Benu Brata Das from the Indian Association for the Cultivation of Science Kolkata, India emphasized on trapped protein-DNA covalent complexes in the mitochondria and their role in human diseases. Dr. Subhrajit Saha University of Kansas Medical Center Kansas City, Kansas, USA discussed mitochondrial biology of radiation and other anti-cancer treatment. Prof. K. Satyamoorthy, Department of Cell and Molecular Biology, School of Life Sciences, MAHE, Manipal, India, gave an overview on relevance of mitochondrial RNA:DNA hybrids during senescence in breast cancer cells. Dr. Swasti Raychaudhuri, CSIR- Centre for Cellular and Molecular Biology Hyderabad, Telangana, India, provided the importance of the inner mitochondrial membrane microenvironment on the evolution of respiratory complexes.Several excellent talks highlighted current updates on mitochondrial bioenergetics, metabolism and communications on the second day of the meeting. Dr. Dhanasekaran Shanmugam, CSIR National Chemical Laboratory, Pune, discussed the role of mitochondrial metabolism in malaria parasites resistance followed by presentation on electron transfer activity of the mitochondrial outer membrane protein mito-NEET from Prof. Huangen Ding, Lousiana State University. Prof. Yidong Bai summarized current updates on the importance on mitochondrial dysfunction in tumorigenesis. Dr. Piya Ghose elaborated the mitochondria and endoplasmic reticulum communications in compartmentalized cell elimination. Mitochondial imaging and therapeutics aspects were discussed by Drs. Sudipta Basu and Lokendra Kumar Sharma. Mitochondrial DNA mutations in COVID-19 disease severity and mutation profile and function in neurodegenerative mitochondriopathy-LHON were introduced by Drs. Yamini Singh and P. Sundaresan, respectively. Mitochondrial targeted imaging and toxicity due to chemical threat exposure were also discussed by Drs. Samit Guha and Neera Tewari-Singh, respectively. Second keynote speaker, Dr. Jerry Chipuk, Icahn School of Medicine at Mount Sinai, New York, USA, highlighted on mitochondrial contributions to cancer: causes, consequences, and coincidence. Dr. Chipuk also discussed about the importance of shape and size of mitochondria with respect to various pathological conditions.A final panel discussion session was led by Rana P Singh and Dhyan Chandra where panelists  and other scientists made the meeting much more interactive and aware about the challenges and opportunities for targeting mitochondria and cell death in cancer control and management. Overall, the symposium provided a platform to share, analyze, and gain knowledge about recent research by interacting with eminent speakers and delegates as well as symposium emphasized on advances in mitochondrial biology and therapeutics in cancer and other human diseases. The meeting was concluded by award ceremony for junior faculty and young investigators. All in all, the meeting showcased the emerging growth in biomedical sciences in India, and provided a rewarding cultural and scientific exchange for all."}
+{"text": "The literature is full of studies reporting environmental and health issues related to using traditional pesticides in food production and storage. Fortunately, alternatives have arisen in the last few decades, showing that organic agriculture is possible and economically feasible. And in this scenario, fungi may be helpful. In the natural environment, when associated with plants, these microorganisms offer plant-growth-promoting molecules, facilitate plant nutrient uptake, and antagonize phytopathogens. It is true that fungi can also be phytopathogenic, but even they can benefit agriculture in some way\u2014since pathogenicity is species-specific, these fungi are shown to be useful against weeds (as bioherbicides). Finally, plant-associated yeasts and molds are natural biofactories, and the metabolites they produce while dwelling in leaves, flowers, roots, or the rhizosphere have the potential to be employed in different industrial activities. By addressing all these subjects, this manuscript comprehensively reviews the biotechnological uses of plant-associated fungi and, in addition, aims to sensitize academics, researchers, and investors to new alternatives for healthier and more environmentally friendly production processes. Molds and yeasts occupy different spaces in ecosystems, from the soil to the atmosphere, participating in important ecological relationships such as nutrient cycling . In manyDuring this terrestrial-environment colonization process, plants adapted both morphologically and genetically, starting to present receptors capable of identifying molecular patterns of mutualistic fungi and pathogens, such as Microbe- and Pathogen-Associated Molecular Patterns  . ComplemUsually, when we think about the association of fungi with plants, we remember the damage caused to crops by invading fungi, which accounts for about 10 to 20% of crop losses and causes about 100 to 200 billion dollars a year in damage . HoweverIn endophytis, the fungus lives in the host tissue, producing compounds that can promote plant tolerance to stress. Furthermore, endophytic fungi can inhibit pathogens and pests through their VOCs, enzymes, and bioactive compounds ,11,12. IMoreover, plant-associated fungi have been investigated for different biotechnological purposes. Although some species are widely studied and applied in different industrial sectors, many new non-conventional molds and yeasts have shown biotechnological potential as well. In such cases, applications are vast for food, pharmaceutical, or fuel companies ,10,16.Through a biochemical and ecological look at fungus-plant interaction, this article presents the compounds involved in mutualistic relationships, whether in promoting plant growth, pest control, or pathogenic interaction with the plant. Finally, the biotechnological importance of prospecting fungi associated with plants for commercial applications is discussed here. As a clarifying note, herein we are considering molds or filamentous fungi as pluricellular microorganisms of the Kingdom Fungi with hyphal and mycelial growth and yeasts as unicellular fungi that grow as individual cells or form pseudohyphae. Another important definition: we considered volatile compounds to be those low-molecular-weight solids or liquids that easily reach the gas phase at atmospheric pressure and room temperature.In many cases, mutualistic interaction with fungi is vital for plants. This is the case with mycorrhizal fungi, for instance. However, analyses of plant-associated molds and yeasts reveal many more benefits for both parts and for food production. Fungi may produce metabolites associated with promoting plant growth. These molecules can function as hormones, macro- and micronutrients, organic acids, siderophores, lytic enzymes, and/or volatile compounds, exerting direct or indirect action on plant growth ,18,19,20Pseudozyma aphidis is recognized for its production of siderophores. Likewise, the species Metschnikowia pulcherrima, Papiliotrema flavecens, and Rhodotorula glutinis are efficient in assimilating iron in ferric form from the surrounding substrate, even under metal-limiting conditions. Similarly, Candida pimensis, Candida apicola, and Dothideomycetes sp. have already been shown to be able to increase zinc availability in plants [As part of yeast secretomes, siderophores have a metallic affinity for iron and zinc. The chelation of these micronutrients promotes their adsorption in the liquid fraction of the soil and, consequently, the growth of plants. The species n plants ,20,21. Lachancea thermotolerans. The ability of yeasts to increase the bioavailability of nutrients is linked to the secretion of acids, enzymes, and chelators [Rhodotorula mucilaginosa, Clavispora lusitaniae, Suhomyces prunicola, and Kurtzmaniella quercitrusa [In addition to the chelation of metal ions, yeasts can also contribute to the solubilization of phosphate, which is usually poorly available to plants despite being necessary for their growth. Millan et al. , when ishelators ,23,24. Ircitrusa .Drosera indica, the yeasts Hannaella coprosmaensis, Aureobasidium pullulans, and Pseudozyma aphidis increased the number of lateral roots by inhibiting fungal pathogens and by producing the phytohormone indole-3-acetic acid (IAA) [Drosera spatulata), the yeast Sporidiobolus ruineniae, thanks to the production of IAA, increased primary root formation, stem length, chlorophyll content, and the number of lateral roots and leaves [Kazachstania rupicola and Rhodosporidium diabovatum, which were isolated from the water of a bromeliad tank. When this filtrate was applied to bromeliads, a higher photosynthetic rate, and greater plant growth were observed [Isolated from the leaf surface of id (IAA) . IAA actid (IAA) ,27 and rid (IAA) . Furtherid (IAA) . Also isd leaves . IAA wasobserved . Similarobserved .Pichia kudriavzevii and Issatchenkia terricola isolated from grape, pomegranate, tomato, and black grass seeds were reported to produce, besides siderophores and IAA, hydrogen cyanide (a volatile organic compound associated with aromas from plants) and auxin [Solicoccozyma sp., C. lusitaniae, R. glutinis, and Naganishia sp. are also efficient producers of auxins. When inoculated into the plant Arabidopsis thaliana, they induced the expression of auxin-responsive genes. Inoculation of auxin-producing yeasts in maize plants improved height, fresh mass, and root length [The yeasts nd auxin . Auxin ind auxin . The yeat length .Meyerozyma stand out as ammonia producers, which serves as a probable communication signal between colonies [Millan et al.  demonstrcolonies . At the colonies . Meyerozyma guilliermondii and Pichia dianae isolated from grapes provided an increase in shoot and root weight, the formation of long root hairs, and better branching. These yeasts also increased the chlorophyll content of the leaves [R. mucilaginosa and Cystobasidium sloffiae promoted plant growth and seed germination in a bioassay using brown mustard (Brassica juncea). The yeasts e leaves . In the e leaves , yeasts Fusarium oxysporum, which is responsible for plant diseases that lead to reduced growth, colonizes phytoenvironments and can settle inside the seeds. The yeasts Candida orthopsilosis and R. mucilaginosa managed to inhibit the growth of this fungus and thus reduce the mycotoxin zearalenone produced by it within wheat plants. In wheat roots and ears infected with F. oxysporum, inhibition of zearalenone was complete when treated with both yeasts [By protecting plants from pathogens, yeasts can also contribute to plant growth. The fungus h yeasts . Candida tropicalis and the bacterium Rhizobium sp., when inoculated together, promoted greater nodulation and absorption of nutrients by the plants, which showed increased growth. Candida tropicalis enhances nodulation through its unique metabolites, such as indole compounds, tryptophan, phenolic compounds, and \u03b1-D-galactopyranoside [Yeasts can also associate with other microorganisms to promote plant growth. Isolated from the bean roots, the yeast ranoside .Trichoderma, Penicillium, and Aspergillus have been extensively investigated for their ability to promote plant growth. These fungi can colonize and interact with plant roots in several ways, including nutrient absorption enhancement, phytohormone synthesis, and the induction of systemic resistance and abiotic stress tolerance. As biological control agents, they protect plants by competing for resources and space while producing antibiotics and hydrolytic enzymes that hinder the growth of phytopathogens. These fungi have found utility in various crops, including tomatoes, corn, beans, soybeans, and lettuce. An additional benefit of these fungi is their ubiquitous presence and widespread distribution in soil [Fungi possess exceptional metabolic abilities, which have led to the development of several biotechnological compounds that have significantly impacted the fields of medicine and different industry sectors. These compounds encompass a wide range of products, such as vitamins, plasma substitutes, anticancer agents, healing accelerators, enzymes, proteins, polysaccharides, and organic acids ,38,39. P in soil ,41,42.Trichoderma atroviride and Arabidopsis thaliana was studied using Petri plates with co-cultivation of this plant and the endophytic fungus [T. atroviridae can induce lateral root proliferation and enhance biomass production. Besides, it was identified that sucrose biosynthesis is induced after Trichoderma cultivation. It is suggested that this induction occurs because of the volatiles produced by the fungus, which act through transporters like SUC2 and SWEET to trigger root growth [Trichoderma spp. may be due to several factors, including their ability to acidify the rhizosphere, solubilize nutrients, and produce secondary metabolites such as blends of volatile substances [Trichoderma include lactones, ketones, alcohols, mono- and sesquiterpenes, esters, and aldehydes\u2014compounds produced through various metabolic pathways [The relationship between c fungus . Due to t growth . Indeed,bstances . Some VOpathways .Cadophora, Leptodontidium, Phialophora, and Phialocephala, isolated from roots of poplar trees from metal-polluted sites, demonstrated that root and shoot growth promotion is plant- and strain-dependent, with Phialophora and Leptodontidium strains having a higher potential for improved plant growth. The release of VOCs was related to six strains, but the production of auxins was associated with all of them. Cadophora and Leptodontidium strains demonstrated the ability to grow and produce VOCs even at high concentrations of several metals, which suggests that endophytes present significant potential to promote sustainable production of bioenergy crops in the phytomanagement of sites with metals [A study with strains of dark septate endophytes (DSEs), h metals .Sophora flavescens , Turbat et al. [Alternaria sorghi and Penicillium commune were able to produce IAA. The authors compared the direct application of plant hormones to bean crops with the application of fungi and, interestingly, observed that cultures inoculated with fungi outperformed those treated with exogenous hormones in characteristics such as increased biomass and carbohydrate and protein content.In a more general sense, given the broad host specificity exhibited by these fungi, they could potentially serve as plant growth-promoting agents in horticulture and agriculture. When analyzing the plant-growth-promoting activity of 15 strains of endophytic fungi isolated from t et al.  verifiedt et al. . Similart et al.  also fouEpichloe bromicola contributes to the tolerance of wild barley (Hordeum brevisubulatum) to this stress, increasing germination and seed growth capacity [Trichoderma parareesei also increased the productivity of canola plants under dry and salinity conditions [Pinus tabulaeformis after inoculation with fungi of the genus Phoma. Likewise, a positive effect was found under water stress following the inoculation of barley plants with the symbiont Piriformospora indica. Analysis of the plant proteome after P. indica inoculation showed an increase in proteins involved in energy metabolism, including photosynthesis, as well as in proteins involved in redox metabolism\u2014mechanisms possibly related to barley\u2019s tolerance to water stress [Exophiala pisciphila associated with the root of Zea mays generated a significant tolerance of the plant to Cadmium, leading to a decrease in phytotoxicity of the metal and an increase in maize growth [In addition to acting directly on the growth of some plant crops, fungi can also act positively through indirect mechanisms, such as increasing tolerance to abiotic stresses, mainly salinity and drought, and resistance to soils with heavy metals. For example, under conditions of high salinity, studies show that the endophytic fungus capacity ,52. The nditions . Under dnditions  also repr stress . Other br stress  and soile growth .Microorganisms colonize all parts of plants, from roots to shoots, including fruits. Some fungi remarkably establish a parasitic relationship with plants; however, it is also verified that the phytopathogens themselves can suffer the parasitism of another microorganism, which is called hyperparasitism . In thisMetschnikowia pulcherrima, for example, has already been identified as a potential parasite of the deteriorating fungus Cladosporium cladosporioides [Pseudozyma aphidis antagonizes phytopathogenic fungi of the genus Phyllactinia (powdery mildew), acting directly on their conidia via parasitism. Yeast causes conidial atrophy, collapse, and eventually the cleavage and death of powdery mildew. Dimorphic growth of the yeast P. aphidis was reported, which forms hyphae that grow around the conidia of Phyllactinia sp. and on its surface, using them as a source of nutrients [Pseudozyma  showed antagonistic activity against the phytopathogenic bacteria Xanthomonas axonopodi, protecting pepper seedlings [The literature demonstrates that some yeasts manage to reduce the radial growth of pathogenic molds. orioides . Similarutrients . Intereseedlings . Botrytis cinerea, found on grapes (Vitis vinifera), is antagonized by the yeast Metschnikowia pulcherrima, which is also commonly found on fruits such as grapes and apples. This yeast produces pulcherrimine [M. pulcherrima have already demonstrated chitinase activity [The fungus errimine , a chemierrimine . In conterrimine ,67,68. Factivity . This enactivity .Naganishia antarctica, Aureobasidium pullulans, Cryptococcus terrestris, and Filobasidium oeirense also proved to be potential biocontrol agents against the pathogenic fungi B. cinerea, Monilinia laxa, Penicillium expansum, and Geotrichum candidum [The endophytic yeasts candidum . In the candidum . This enWickerhamomyces anomalus isolated from grapes and other plants demonstrated strong antagonist activity against the molds B. cinerea, Magnaporthe oryzae, and Roesleria subterranea. In the secretome of this yeast, lytic enzymes with \u03b2-glucosidase, protease, amylase, and cellulase activity were identified [Wickerhamomyces anomalus has also demonstrated its glucanase activity against the fungi B. cinerea and P. expansum on apples, Penicillium digitatum on oranges, and Colletotrichum gloeosporioides on papaya [B. cinerea by the yeast W. anomalus [Similarly, strains of entified . Wickerhn papaya . In anotanomalus . Thus, tanomalus .The control of parasites based mostly on chemical pesticides may cause problems like residues found in plants, fruits, and vegetables, besides serious environmental impacts . For plaDuponchelia fovealis, a European pepper moth that becomes a pest to some plants, was studied using fungal isolates from strawberry leaves [D. fovealis and induced the highest mortality rates in its larvae. The root-knot nematode Meloidogyne incognita is a pest that interferes with the cultivation of sacha inchi (Plukenetia volubilis L.). Some fungi isolated from this species were explored as biocontrol agents against damage caused by M. incognita [Trichoderma and Clonostachys significantly reduced the number of galls induced by the nematode, besides allowing better root development in these plants. The control of y leaves . A totalncognita . CompareTrichoderma is, in most cases, associated with its capability to produce secondary metabolites like pyrones, gliovirin, gliotoxin, and polyketides [Ralstonia solanacearum, a severe bacterial pathogen of tomato plants, had its growth strongly inhibited by Trichoderma pseudoharzianum and Trichoderma asperelloides [Trichoderma, which interfered with the cell morphology of R. solanacearum through rupture of cell walls, leakage of cell contents, and disintegration of the cell membrane. The potential antibacterial activity attributed to the genus yketides . For inselloides . This efAcremonium sp. Ld-03 was isolated from the plant species Lilium davidii and demonstrated the capability of inhibiting the phytopathogenic fungi Fusarium fujikuroi, B. cinerea, and F. oxysporum. The inhibitory zones respectively observed were 33 mm (43%), 22 mm (56%), 30 mm (78%), and 30 mm (20%), with metabolites obtained from the ethyl acetate fraction [Acremonium can act as a promoter of plant growth by increasing the production of the plant hormone IAA. Likewise, Chowdhary and Kaushik [Acremonium MPHSS-2.1 and MPM-2.1 against B. cinerea, F. oxysporum, and Rhizoctonia solani.fraction . In addifraction  showed t Kaushik  evaluateTrichoderma, a genus first described by Persoon in 1974, has been known for its biocontrol activities since 1932, as reported by Weindling [Hypocreaceae family and can be found in various environments, particularly those with decomposing organic matter [Trichoderma species can colonize plant roots and engage in a beneficial exchange of compounds, which offers protection against multiple phytopathogens [T. virens is known to produce trichodermamides, while T. koningii synthesizes koningins, which are compounds that possess antimicrobial and antifungal activity against plants [Trichoderma. These enzymes exhibit antifungal properties, highlighting the potential of Trichoderma spp. as an effective biocontrol agent against fungal infections [Trichoderma atroviride is a filamentous fungus commonly found in soil, especially in temperate regions. It exhibits optimal growth at a temperature of 25 \u00b0C and produces thin, hyaline colonies with inconspicuous aerial hyphae. After a period of 2 to 7 days, this fungus develops gray to dark green conidia [eindling . This gec matter . Trichodathogens . For exat plants ,105. Thefections . Trichod conidia  and show conidia .Trichoderma harzianum against the phytopathogenic fungi Rhizoctonia solani and Pythium aphanidermatum has been reported. Inocula with T. harzianum reduced the severity of rhizome rot and leaf blight in turmeric, diseases related to the so-called pathogens [Trichoderma also demonstrate antagonistic activities against nematodes and insects by different mechanisms: T. harzianum induced metabolic changes in tomato plants that attracted the parasitic wasp Aphidius ervi, which, in turn, neutralized the attack of the aphid Macrosiphum euphorbiae [T. atroviride not only induced systemic resistance in tomato plants against the nematode Meloidogyne javanica, but also the progeny of these plants inoculated with T. atroviride inherited this resistance [The biocontrol activity of athogens . In addiphorbiae . Also insistance .Clonostachys rosea has been extensively researched as a biocontrol agent against many pathogenic fungi, such as Alternaria dauci, Alternaria radicina, Botrytis cinerea, Botrytis aclada, and Helminthosporium solani [C. rosea has also been linked to the biocontrol of some nematodes and insects [C. Rosea, studies of functional genetics and transcriptomic analyses with this fungus found some genes that seem to be important for mycoparasitism and biocontrol activity, such as those that encode proteins involved in the biosynthesis of secondary metabolites, enzymes that degrade pathogen cell walls, enzymes involved in complex carbohydrate metabolism, and membrane transporters related to drug resistance [Fusarium graminearum, a frequent pathogen in various crops such as maize, wheat, and beans [The filamentous fungus m solani ,112,113. insects ,115. Regsistance . In addind beans .Despite the several examples above of mutualistic interactions, yeasts and molds may also be harmful to plants. In this regard, fungi can lead to critical losses in food production. However, from another point of view, this pathogenicity may be used to promote crops in some circumstances. This is the case with yeasts and molds that have been tested against weeds (as bioherbicides).Fusarium and Aspergillus genera, can even produce toxins, posing a risk to human health when the infected plant is consumed [By threatening plant health, phytopathogenic fungi cause severe damage to world agricultural production ,119. Manconsumed . Plants consumed , and theconsumed ,123,124.Biotrophic pathogens, which do not lead to plant death and derive nutrients from living tissues, generally have a lower gene content for cell wall-degrading enzymes in their genome. In this way, damage to the host is more subtle, avoiding plant defense responses that can be triggered by the release of cell wall fragments ,126. On Cryptococcus neoformans also secretes cellulases, pectinases, laccases, and hemicellulases that degrade the cell wall of plant cells and provide their invasive behavior [S. cerevisiae. Actually, this phytohormone tends to prevent the proliferation of fungal cells, but in doing so, it ends up stimulating the morphological transition of the yeast [Like many filamentous fungi, the yeast behavior . On the behavior ,129. It he yeast . Additiohe yeast . Diseases caused by fungi, however, have long been addressed in the literature. Considering the focus of this work is mainly on the positive relationships for agriculture, the next section discusses how this pathogenicity can benefit crops against weeds. It is worth noting, though, that the use of fungi as bioherbicides has only been shown to be feasible because their antagonistic profile is species-specific.Weeds are a significant problem for food production, and their management is paramount for current agriculture. Thus, seeking herbicides that are less harmful to the environment and that provide effective control of weeds is highly desirable. And this can be achieved by bioprospecting microorganisms for the production of phytotoxic metabolites .As stated before, endophytic fungi live within plant tissues without causing apparent damage to the host plant. However, they can produce bioactive compounds (which include volatile and non-volatile secondary metabolites) with phytotoxic properties, which can be exploited in agriculture for weed control ,133. LucFungi can inhibit weeds\u2019 growth by delaying nutrient absorption and preventing the synthesis of photosynthetic pigments and plant-growth hormones. Consequently, the production of reactive oxygen species and hormones mediated by plant stress increases. Some metabolites can cause disease, necrosis, and chlorosis, thereby inhibiting weed seed germination and growth ,134 Fig.Alternaria, Botrytis, Colletotrichum, Fusarium, Helminthosporium, and Phoma [Colletotrichum coccodes, for example, was tested as a bioherbicide against the nightshade plant (Solanum ptycanthum), a troublesome weed in part because of its tolerance and resistance to certain conventional herbicides [Phoma show herbicidal activity against weeds, such as Asparagus sp., Tricyrtis maculado, Beta vulgaris, Chenopodium album, Cirsium arvense, and Sonchus arvensis, and this activity regards the several phytotoxic secondary metabolites produced by the fungus [Phytopathogenic fungi are mainly among the genera nd Phoma . The funrbicides . Severale fungus .Mycoleptodiscus indicus UFSM-54 was tested on Cucumis sativus, Conyza sp., and Sorghum bicolor. The metabolites produced by the fungus impaired germination, initial growth, and the development of leaves in the three plant species. Interestingly, the metabolites obtained from M. indicus UFSM-54 were not toxic to rhizosphere-associated earthworms (Eisenia andrei). Souza et al. [C. sativus. The most effective strain was sequenced and identified as belonging to the genus Diaporthe, previously reported as a bioherbicide producer [In the study by Portela et al. , the phya et al.  selectedproducer ,139.Papiliotrema laurentii, Meyerozyma caribbica, and Rhodotorula mucilaginosa isolated from insects and an Antarctic lagoon, for example, are capable of secreting these enzymes [Despite a few studies using yeasts as bioherbicides, there is some evidence of their potential to inhibit weed growth. Yeasts carrying enzymes such as lipases, cellulases, xylanases, pectinases, proteases, and peroxidases are capable of degrading the polysaccharides of weeds\u2019 cell walls ,141. Spe enzymes ,142. Mor enzymes . In thisSince they are sessile living beings, plants have evolved by establishing a series of strategies to connect to the environment around them and survive adverse conditions. This includes a network of interactions with microorganisms that comprise the so-called plant microbiome . These mSporormiella intermedia increased the absorption of minerals when inoculated in the clover Trifolium subterraneum, while the fungus Mucor hiemalis increased the absorption of potassium and strontium in the grass Poa pratensis, demonstrating the potential of these fungi to improve the nutritional value of these forages [Plant-dwelling fungi have been linked to benefits for the plant, particularly in directly promoting plant growth and nutrient uptake . Because forages .Trichoderma already make up bioformulations used to control fungal pathogens, mainly those that affect the root systems of crops. Among the species, the main ones employed are T. atroviride, T. hamatum, T. harzianum, and T. viride [The present review also addressed the role of fungi as biocontrol agents, eliminating or reducing the presence of pathogens. For this biocontrol action to occur, some mechanisms have been identified, such as competition between beneficial fungi and pathogens for nutrients and space, the secretion of volatile organic compounds by beneficial fungi, the production of lytic enzymes, mycoparasitism, and the induction of systemic resistance in the plant ,147. In . viride ,148,149.Pseudozyma, which colonize many parts of plants, have been shown to be able to secrete a number of industrially useful products, such as lipases, glycolipids, and esterases [S. cerevisiae, W. anomalus, M. pulcherrima, and A. pullulans are known to be efficient against the phytopathogens B. cinerea, Colletotrichum acutatum, P. expansum, P. digitatum, and Penicillium italicum [Leucosporidium scottii, which produced VOCs that inhibited apple rot fungi [P. expansum, B. cinerea, Alternaria alternata, Alternaria tenuissima, and Alternaria arborescens [Last but not least, more than just being directly employed in crops (either as plant-growth-promoting or biocontrol agents), plant-associated fungi might show other biotechnological properties. For instance, yeasts of the genus sterases . Moreoveitalicum ,151. Theot fungi , and theorescens . Among torescens ,46,60,61Fungi can also serve as biofactories. Some terpenoids from plant essential oils are recognized as bioherbicides. However, to be produced on a large scale and meet the demand for agricultural production, they would need large areas of cultivation and tons of biomass to generate the necessary amount ,153,154.In nature, fungi and plants establish complex and dynamic ecological relationships. This interaction between the two biological kingdoms can benefit the plant, as the presence of some fungi can help with plant growth, pest control, increased nutrient absorption, or even plant resistance to different growth stresses. Through a better understanding of the biochemical bases of this mutualistic relationship, several molecules have already been discovered, such as phytohormones, vitamins, antibiotics, organic acids, siderophores, lytic enzymes, phenolic compounds, and volatile compounds, which play a key role in the benefits provided by fungi. In this sense, bioprospecting fungi that inhabit plants is a great starting point for developing fungal formulations that act as bioinoculants or in the biocontrol of pests, representing an emerging biochemical and biotechnological area. On the other hand, the fungus-plant interaction can be phytopathogenic, and many fungal diseases in plants are already well-known and studied. However, as the phytopathogenic profile of fungi is species-specific, this pathogenicity can benefit crops by using these fungi or their metabolites as bioherbicides against weeds\u2014a broad biotechnological field still little explored. Finally, the metabolites resulting from the fungus-plant interaction represent a valuable source of biocompounds with applications in the health, cosmetics, pharmaceutical, and food industries.Thus, there is a wide biotechnological area being discovered from the interaction between fungi and plants, and that can not only be applied to the improvement and defense of plant cultures. Many compounds arising from this interaction may also represent new molecules of interest to the food, cosmetics, and drug industries ,144. Ind"}
+{"text": "Cardiovascular diseases (CVDs) remain a leading cause of morbidity and mortality worldwide. Lifestyle modifications have gained increasing recognition as key interventions in preventing and managing CVDs. This narrative review aims to provide a thorough assessment of the impact of lifestyle modifications on cardiovascular health. The review encompasses various aspects, including diet, physical activity, smoking cessation, stress management, and weight management. Additionally, the review explores the underlying mechanisms by which lifestyle modifications influence cardiovascular health and highlights the evidence from clinical trials, observational studies, and meta-analyses. The findings of this review emphasize the importance of lifestyle modifications in reducing the risk factors associated with CVDs and improving cardiovascular outcomes. Cardiovascular diseases (CVDs) pose a significant global burden in terms of morbidity, mortality, and economic impact. CVDs are highly prevalent worldwide . AccordiLifestyle modifications serve as crucial preventive measures for CVDs. Risk factors associated with CVDs are modifiable\u00a0and can be influenced through lifestyle modifications. Lifestyle modifications, such as adopting a healthy diet, engaging in regular physical activity, quitting smoking, managing stress, and maintaining a healthy weight, directly target these risk factors. By addressing modifiable risk factors, individuals can significantly reduce their risk of developing CVDs . LifestyImpact of diet on cardiovascular healthRole of a Heart-Healthy Diet in Reducing Cardiovascular RiskA heart-healthy diet plays a critical role in reducing cardiovascular risk. A heart-healthy diet helps lower levels of low-density lipoprotein (LDL). High LDL is a major risk factor for the development of atherosclerosis. By reducing dietary intake of saturated and trans fats, a heart-healthy diet can help maintain optimal cholesterol levels and prevent the formation of plaque . A heartMaintaining a healthy weight is essential for reducing cardiovascular risk. A heart-healthy diet focuses on nutrient-dense foods that are lower in calories, unhealthy fats, and added sugars. It emphasizes portion control and encourages the consumption of lean proteins, fiber-rich foods, and healthy fats. Such dietary patterns, combined with regular physical activity, promote weight management and help prevent obesity, a significant risk factor for CVDs . The lonReview of Evidence Supporting the Mediterranean Diet, DASH Diet, and Other Dietary PatternsThe Mediterranean diet and the DASH\u00a0diet are two well-studied dietary patterns that have demonstrated significant benefits for cardiovascular health. Here is a summary of the evidence supporting these diets, as well as other dietary patterns.Mediterranean diet: The Mediterranean diet refers to a dietary pattern inspired by the traditional eating habits of people living in Mediterranean regions, such as Greece, Italy, and Spain. It is characterized by an abundance of plant-based foods, including fruits, vegetables, whole grains, legumes, nuts, and seeds. Olive oil is the primary source of fat in this diet. Moderate consumption of fish and poultry is encouraged, with red meat being consumed in smaller quantities. The PREDIMED study (Prevenci\u00f3n con Dieta Mediterr\u00e1nea) found that individuals who followed a Mediterranean diet supplemented with extra-virgin olive oil or mixed nuts had a 30% reduction in the risk of cardiovascular events compared to a control group following a low-fat diet . Meta-anDASH diet: The DASH\u00a0diet, which emphasizes fruits, vegetables, whole grains, low-fat dairy products, lean proteins, and limited sodium intake, has been extensively studied for its impact on blood pressure. The original DASH trial demonstrated that individuals following the DASH diet experienced significant reductions in blood pressure, particularly among those with hypertension\u00a0. SubsequPlant-based diets: Plant-based diets, such as vegetarian and vegan diets, have been associated with a lower risk of CVDs. A systematic review and meta-analysis showed that vegetarian and vegan diets are associated with lower blood pressure levels, improved lipid profiles, reduced body weight, and lower risk of ischemic heart disease compared to non-vegetarian diets . The EPIDietary approaches: The American Heart Association (AHA) has recommended dietary approaches for cardiovascular health, including the combination of a heart-healthy diet (such as the Mediterranean or DASH diet) with reduced sodium intake, limited added sugars, and avoidance of trans fats. The AHA's \"Life's Simple 7\" guidelines, which include diet, physical activity, smoking cessation, weight management, blood pressure control, cholesterol management, and glucose control, have been associated with a significantly reduced risk of CVDs . It is wEffect of Specific Nutrients on Cardiovascular OutcomesSpecific nutrients play a significant role in cardiovascular outcomes. Omega-3 fatty acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) found in fatty fish, have been associated with a reduced risk of cardiovascular events. They have shown benefits in reducing triglyceride levels, lowering blood pressure, improving endothelial function, and reducing inflammation . The AHAAntioxidants, such as vitamins C and E, beta-carotene, and polyphenols, have been associated with cardiovascular benefits. They help reduce oxidative stress and inflammation, which are involved in the development of CVDs . Foods rThe lifestyle changes which shall impact cardiovascular health are depicted in Figure Physical activity and cardiovascular healthRelationship Between Physical Activity and Cardiovascular Risk ReductionPhysical activity plays a crucial role in reducing cardiovascular risk. Regular physical activity helps lower blood pressure, which is a major risk factor for CVDs. Engaging in aerobic exercises, such as brisk walking, jogging, cycling, or swimming, can lead to a decrease in both systolic and diastolic blood pressure. It improves the efficiency of the heart and blood vessels, reducing the strain on the cardiovascular system\u00a0. PhysicaRegular physical activity contributes to weight management and helps maintain a healthy body weight. Obesity is a significant risk factor for CVDs, and losing excess weight or preventing weight gain through physical activity reduces the risk of developing cardiovascular conditions such as heart disease, stroke, and type 2 diabetes . PhysicaChronic inflammation is involved in the development and progression of CVDs. Regular physical activity has anti-inflammatory effects, reducing levels of inflammatory markers in the body. By reducing inflammation, physical activity helps protect the blood vessels and lowers the risk of cardiovascular events . PhysicaIt is important to note that the beneficial effects of physical activity on cardiovascular health are dose-dependent, meaning that higher levels of activity often lead to greater risk reduction. The AHA recommends at least 150 minutes of moderate-intensity aerobic exercise or 75 minutes of vigorous-intensity aerobic exercise per week, along with muscle-strengthening activities at least two days a week, for optimal cardiovascular health\u00a0.Effects of Aerobic Exercise, Resistance Training, and Combined Training on Cardiovascular OutcomesAerobic exercise, resistance training, and combined training (a combination of aerobic and resistance exercises) each have distinct effects on cardiovascular outcomes. Aerobic exercise, also known as cardiovascular or endurance exercise, includes activities that increase the heart rate and promote cardiovascular fitness. Regular aerobic exercise improves cardiovascular health by strengthening the heart muscle, increasing the heart's efficiency, and enhancing blood flow throughout the body. Benefits of aerobic exercise include a reduction in resting heart rate, improved oxygen uptake, increased cardiac output, and improved blood vessel function. Aerobic exercise has been associated with a lower risk of developing CVDs, such as coronary heart disease, stroke, and heart failure. It increases the levels of HDL cholesterol and reduces total cholesterol, LDL cholesterol, and triglycerides. Aerobic exercise also helps control blood pressure, reduces inflammation, improves insulin sensitivity, and promotes weight management .Resistance training, also known as strength or weight training, involves using resistance or weights to strengthen muscles.\u00a0While resistance training primarily focuses on muscular strength and endurance, it also has cardiovascular benefits. Resistance training can improve cardiovascular health by reducing resting blood pressure, increasing HDL cholesterol levels, and improving insulin sensitivity. It enhances overall body composition by increasing muscle mass and reducing body fat, which contributes to improved cardiovascular risk factors. Resistance training can have a positive impact on arterial stiffness, a measure of blood vessel health, and improve endothelial function. Combining resistance training with aerobic exercise has been found to have additive effects on cardiovascular outcomes, providing a comprehensive approach to cardiovascular health\u00a0.Combined training refers to the integration of both aerobic exercise and resistance training into a single exercise program. This approach provides the benefits of both aerobic and resistance exercises, leading to improved cardiovascular health and overall fitness. Combined training has been shown to be effective in reducing blood pressure, improving lipid profiles, and enhancing insulin sensitivity. It can lead to greater improvements in body composition, including increased muscle mass and decreased body fat, compared to either aerobic or resistance training alone. Combined training is particularly beneficial for individuals aiming to achieve overall cardiovascular fitness, maintain a healthy weight, and manage multiple cardiovascular risk factors\u00a0.Recommended Exercise Guidelines for Cardiovascular HealthThe AHA\u00a0provides exercise guidelines for cardiovascular health .Aerobic exercise: Adults should aim for at least 150 minutes of moderate-intensity aerobic exercise or 75 minutes of vigorous-intensity aerobic exercise per week. Moderate-intensity aerobic activities include brisk walking, cycling at a moderate pace, swimming, or dancing. Vigorous-intensity activities include running, cycling at a high speed, aerobic dancing, or playing sports like soccer or basketball. These aerobic exercises can be performed in bouts of 10 minutes or more throughout the week. For additional health benefits, adults can increase the aerobic exercise duration to 300 minutes of moderate-intensity or 150 minutes of vigorous-intensity per week .Resistance training: Adults should include strength training exercises at least two days per week. Focus on exercises that target major muscle groups, including the legs, hips, back, abdomen, chest, shoulders, and arms. Perform a variety of exercises using body weight, resistance bands, free weights, or weight machines. Aim for eight to 12 repetitions of each exercise, gradually increasing the resistance over time\u00a0.Flexibility and balance exercises: Include flexibility exercises at least two to three days per week, focusing on major muscle-tendon groups. Stretching exercises, yoga, or Pilates can help improve flexibility. For older adults at risk of falls, balance exercises should be incorporated into the routine. Examples include standing on one foot, walking heel-to-toe, or tai chi\u00a0.Sedentary behavior: Reduce sedentary behavior and aim to minimize the amount of time spent sitting. Incorporate breaks from sitting by standing or walking for a few minutes every hour\u00a0.Smoking cessation and cardiovascular healthSmoking is a well-established risk factor for CVDs, and the harmful effects of smoking on the cardiovascular system are mediated through various mechanisms such as endothelial dysfunction, inflammation, oxidative stress, lipid abnormalities, platelet activation, thrombosis, increased blood pressure, coronary spasm, and impaired cardiac function. It is worth noting that the harmful effects of smoking on the cardiovascular system are not limited to active smokers. Second-hand smoke exposure  also poses risks to cardiovascular health\u00a0. QuittinApproaches and Interventions for Smoking CessationThere are several approaches and interventions available to support individuals in their journey toward\u00a0smoking cessation, such as behavioral counseling, medications, combination therapy, motivational interviews, mobile apps and online programs, support groups, mindfulness and stress reduction techniques, and tailored interventions based on specific circumstances. Quitting smoking is a highly individual process, and different strategies may work better for different people. Combining multiple approaches, staying motivated, and persisting in the face of challenges can greatly increase the chances of successful smoking cessation .Stress management and cardiovascular healthChronic stress plays a significant role in the development and progression of CVDs by activation of the sympathetic nervous system, leading to a state of chronic inflammation in the body, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, changes in blood clotting and platelet function, and unhealthy coping behaviors. It impacts sleep\u00a0and contributes to psychological factors such as depression, anxiety, and social isolation. It is important to note that chronic stress does not act in isolation, and its impact on cardiovascular health can interact with other risk factors, such as smoking, obesity, and genetics, amplifying the overall risk. Effective stress management techniques, such as regular exercise, relaxation techniques , social support, and seeking professional help when needed, can help mitigate the detrimental effects of chronic stress on cardiovascular health\u00a0.There are several techniques for stress reduction that have been shown to have positive effects on cardiovascular outcomes, such as relaxation techniques, regular physical exercise, building and maintaining strong social connections and support networks, cognitive-behavioral therapy (CBT), mindfulness-based stress reduction (MBSR), biofeedback techniques that involve using electronic devices to monitor physiological signals, such as heart rate, blood pressure, or muscle tension, and providing real-time feedback. It is important to note that the effectiveness of these techniques may vary among individuals, and it may be beneficial to explore a combination of approaches to find what works best for each person .Clinical evidence and recommendationsThere is a wealth of evidence from clinical trials, observational studies, and meta-analyses supporting the positive impact of lifestyle modifications on various aspects of health, including cardiovascular health. Diabetes Prevention Program (DPP), a landmark clinical trial, demonstrated that lifestyle interventions, including diet modification and increased physical activity, were effective in reducing the incidence of type 2 diabetes in high-risk individuals . DASH-SoCurrent guidelines and recommendations for lifestyle modifications in cardiovascular healthThe American Heart Association (AHA) GuidelinesDiet: The AHA recommends a heart-healthy diet that emphasizes fruits, vegetables, whole grains, lean proteins, and low-fat dairy products. It encourages limiting saturated and trans fats, sodium, and added sugars.Physical activity: The AHA recommends at least 150 minutes of moderate-intensity aerobic activity or 75 minutes of vigorous-intensity aerobic activity per week, along with muscle-strengthening activities at least two days per week.Smoking cessation: The AHA strongly advises against smoking and supports comprehensive smoking cessation programs .The European Society of Cardiology (ESC) GuidelinesLifestyle modifications: The ESC guidelines emphasize lifestyle modifications as the foundation for CVD\u00a0prevention. These include a healthy diet, regular physical activity, smoking cessation, and weight management.Dietary patterns: The ESC recommends the Mediterranean diet as an optimal dietary pattern for cardiovascular health due to its emphasis on fruits, vegetables, whole grains, legumes, fish, and olive oil.Physical activity: The ESC recommends at least 150 minutes of moderate-intensity aerobic exercise or 75 minutes of vigorous-intensity aerobic exercise per week, along with muscle-strengthening activities .The World Health Organization (WHO) RecommendationsDiet: The WHO recommends a balanced diet that includes a variety of fruits, vegetables, whole grains, lean proteins, and healthy fats. It advises reducing the intake of free sugars, salt, and saturated and trans fats.Physical activity: The WHO recommends at least 150 minutes of moderate-intensity aerobic activity or 75 minutes of vigorous-intensity aerobic activity per week, along with muscle-strengthening activities.Tobacco control: The WHO advocates for comprehensive tobacco control policies, including tobacco taxes, smoke-free environments, and cessation support .Lifestyle modifications have a profound impact on cardiovascular health. Implementing healthy habits, such as regular physical activity, a balanced diet, smoking cessation, stress management, and adequate sleep, can significantly reduce the risk of CVDs and improve overall cardiovascular well-being. This review underscores the need for a comprehensive approach to lifestyle modifications. Combining multiple healthy habits yields synergistic effects on cardiovascular health. Adoption of these lifestyle modifications should be sustained over the long term to maximize their benefits. While the evidence presented in this review is compelling, it is essential to acknowledge that individual factors, such as genetics and underlying medical conditions, can influence the effectiveness of lifestyle modifications on cardiovascular health. Therefore, personalized approaches, tailored to each individual's unique circumstances, are warranted."}
+{"text": "Working memory (WM) is the cognitive system necessary for the temporary storage and manipulation of information during complex tasks like reasoning, comprehension, and learning  with VR for facial palsy and consciousness disorders rehabilitation, demonstrating improved outcomes (Qidwai et al., Research on BCI-VR in WM training and evaluation is still in its early stages, and a few recent studies have preliminarily investigated its effectiveness. One study adopted a quantitative approach, utilizing EEG signals and game performance data to assess cognitive levels (Wan et al., For the future direction of WMT, the combination of BCI and VR technology, which can provide immersive training environments to attract the subjects to focus on training, and collect EEG signals in real-time for cognitive training evaluation, is a promising option for conducting effective WMT. In WM training, more interaction ways, such as gestures or utilizing EEG signals, can replace the manual operation in traditional digital games to control virtual characters in VR games, thus enhancing the training experience and improving the effectiveness of WMT. In addition, in WM evaluation, in terms of EEG signal analysis, multiple feature extraction methods can be used for feature coupling analysis, thus further verifying the analysis from multiple perspectives. Moreover, for WM evaluation, relying solely on EEG signals and behavioral data may not provide a comprehensive assessment. Subsequently, NIRS, fMRI, and various physiological signals such as eye movement and electrocardiogram signals, can be fused to evaluate the WMT effect from multiple perspectives. Furthermore, for the BCI-VR system, it is important to further improve its software and hardware integration to make the device more portable and low-cost, and to make WM training and evaluation more efficient and accurate.In conclusion, this study analyzed the current research status of WM training and evaluation, and emphasizing challenges and future directions related to BCI-VR technology. The integration of novel VR technology into WMT, known for its immersive environment and natural interaction, has gained prominence in cognitive training research. Additionally, the real-time visualization of neural changes through EEG signals positions BCI as a valuable tool for quantitatively and objectively assessing the effects of WMT. In consequence, our opinion is that the BCI-VR technology combined with EEG signal analysis is of great potential in WM training and evaluation, and can effectively help improve individual cognitive capabilities and performance. Currently, research in BCI-VR-based WMT is mainly in the experimental phase, but with technological advancements, it will hold substantial potential to benefit diverse populations across education, healthcare, mental health, aging, and sports domains, bearing significant socioeconomic value.DD: Funding acquisition, Writing\u2014original draft. ZW: Writing\u2014original draft, Investigation. YZ: Investigation, Writing\u2014original draft. XW: Investigation, Writing\u2014original draft. DW: Funding acquisition, Methodology, Supervision, Writing\u2014review and editing."}
+{"text": "Diagnosing Eosinophilic esophagitis (EoE) has been challenging as the clinical presentation is often indeterminate as symptoms resemble GERD, achalasia, Celiac, Crohns, Hypereosinophilic syndrome, Eosinophilic GI disease, and drug hypersensitivity. Eosinophilic esophagitis (EoE) is a chronic immune-mediated inflammatory disorder characterized by eosinophilic infiltration of the esophagus strongly correlated with chronic seasonal allergies, atopy, asthma, and asthma eczemas in children and adults having male preponderance. It has a prevalence of approximately 34.4/100 000 worldwide. A Case report is presented below with clinical, pathological, and endoscopic findings of (EoE).A 34-year-old Male with a childhood history of Bronchial asthma was referred from Gastroenterology with a presumed diagnosis of GERD, unresponsive to 8 weeks of Pantoprazole 40mg BID to the Allergy and Immunology department for further evaluation for complaints of generalized pruritus since two days, persistent dysphagia and upper abdominal discomfort since three months exacerbated by egg meals and relieves by avoidance of it. Persistent dysphagia was more to solids with dull epigastric pain. The patient denied a history of urticarial rashes, flushing, vomiting, itching/redness of eyes, cough, chest pain tightness, chest tightness, and dyspnoea. The patient was compliant with Albuterol MDI , has no recent exacerbations, and regularly follows up in the asthma clinic. His Blood investigations were unremarkable, and the skin prick test was negative for common allergens. The upper GI endoscopy showed stacked oesophageal rings, linear furrows, and proximal and distal sections of the biopsy showed mucosal eosinophilic infiltration (>15 Eosinophils HPF) and eosinophil micro-abscesses. A diagnosis of Eosinophilic esophagitis was made. The patient was prescribed Topical Fluticasone  and Esomeprazole 40mg once daily for eight weeks with dietary modifications. Symptoms improved, and subsequently, the patient was started with maintenance therapy Budesonide (0.5mg twice daily).Misdiagnosis of EoE as GERD leads to prolonged PPI treatment with no improvement. A definitive diagnosis of EoE should be strongly considered after correlating allergic history, clinical symptoms, and positive investigatory findings, which can result in better disease and treatment outcomes."}
+{"text": "Chronic diseases, such as cardiovascular diseases, diabetes, cancer, and chronic respiratory diseases, are leading causes of morbidity and mortality worldwide . AccordiCurrently, the Global Leadership Initiative on Malnutrition (GLIM) guidelines  emphasizThis editorial aims to provide a concise summary of the tools available for nutritional assessment in patients with chronic diseases, illuminate the unique challenges faced by clinicians and researchers in this area, and offer insights into the promising future directions in the field of nutritional assessment.Various tools and methods are available for nutritional assessment, each with its strengths and limitations. These tools include dietary surveys, anthropometric measurements, nutritional assessment questionnaires, biochemical markers, and medical devices such as dual-energy X-ray absorptiometry (DXA) and bioelectrical impedance analysis (BIA).Dietary surveys serve as important tools for assessing nutritional status. These surveys involve collecting comprehensive information about an individual\u2019s dietary habits, food choices, portion sizes, and meal patterns. Through careful analysis, dietary surveys can provide valuable insights into macronutrient and micronutrient intake, as well as dietary patterns that may contribute to, or mitigate, chronic disease risk. Commonly used surveys include 24-h dietary recalls, food frequency questionnaires, and food diaries [Anthropometric measurements involve assessing physical characteristics, such as body weight, height, BMI, waist circumference, and skinfold thickness. These measurements are simple but very useful, as unintentional weight loss and reduced BMI remain the phenotypic criteria of GLIM-defined malnutrition . Many questionnaires are available for assessing nutritional status. For example, the Subjective Global Assessment (SGA) was originally used in surgical patients to diagnose protein\u2013calorie malnutrition but is now widely utilized in other conditions, such as in patients with HIV , cancer Additionally, the Mini Nutritional Assessment (MNA) was developed to provide a single, rapid assessment of malnutrition risk in geriatric populations in hospitals, outpatient clinics, and nursing homes .Other questionnaires, such as the Malnutrition Screening Tool (MST) , MalnutrBiomarkers may offer objective data on a patient\u2019s nutritional status. Common biomarkers include serum albumin, prealbumin, hemoglobin, and various vitamins and minerals . These mIncorporating DXA and BIA into the toolkit for nutritional assessment enhances the precision and depth of the evaluation. These techniques provide valuable insights into body composition, allowing healthcare providers to tailor interventions more effectively to address the specific nutritional needs and challenges of each patient.In this Special Issue, two papers focus on the implementation of BIA among patients with chronic diseases. In a prospective study, Sk\u00f3rka and colleagues  reportedOne of the foremost challenges in nutritional assessment lies in addressing disease-specific considerations. Each chronic disease presents unique nutritional requirements and challenges . For exaGeriatric patients often present with multiple chronic conditions, a phenomenon known as multimorbidity . This coNutritional needs and preferences can vary significantly among patients, even among those with the same chronic disease. Factors such as age, gender, genetics, cultural background, socioeconomic status, and individual dietary habits all contribute to this variability. For instance, dietary preferences may be influenced by cultural traditions or religious beliefs, leading to variations in food choices and meal preparation methods. This diversity underscores the need for healthcare providers to adopt a patient-centered approach, taking into account the individual\u2019s unique circumstances and preferences when designing nutritional interventions.Resource limitations pose a significant challenge to comprehensive nutritional assessment and intervention, particularly in healthcare settings with constraints on budget and personnel . Time reAdvances in genomics and metabolomics hold significant promise for the development of personalized nutritional plans . By analThe advent of digital health technologies, including mobile applications, wearable devices, and telehealth platforms, presents new opportunities for real-time nutritional assessment and support. These tools enable individuals to monitor their dietary intake, track changes in nutritional status, and receive personalized feedback and recommendations from healthcare providers. For example, a smartphone app that records food intake and provides instant nutritional analysis can empower patients to make informed dietary choices and adhere to prescribed nutritional plans . MoreoveThe complexity of managing chronic diseases necessitates a multidisciplinary approach toward care. Collaboration between healthcare professionals, including dietitians, nurses, physicians, pharmacists, physical therapists, and occupational therapists, can facilitate comprehensive and holistic nutritional assessments and care. Interdisciplinary teams can address the diverse and evolving needs of patients with chronic diseases effectively. To address the unique challenges of nutritional assessment in the context of chronic diseases, healthcare professionals must receive specialized education and training. This education should encompass not only the basics of nutritional assessment but also disease-specific considerations, communication strategies, cultural competence, and the integration of emerging technologies. An informed and skilled workforce is essential for delivering high-quality nutritional care to patients with chronic diseases, promoting evidence-based practice, and advancing the field of clinical nutrition.In conclusion, nutritional assessment in patients with chronic diseases is a complex and multifaceted endeavor that requires a nuanced and patient-centered approach. The increasing prevalence of chronic diseases underscores the importance of addressing the unique challenges associated with nutritional assessment and management. Researchers, clinicians, policymakers, and educators should collaborate to develop and implement innovative tools and strategies that optimize nutritional care, improve health outcomes, and enhance the quality of life for individuals living with chronic diseases."}
+{"text": "The skin shows the physiological condition of the body\u2019s organs and systems that prevent infections and physical damage. Throughout the ages, in folk medicine, phytotherapy was considered a primary form of treatment in all countries, including Kazakhstan, due to the abundance and availability of plant-based remedies. This paper discusses several medicinal plants that are traditionally used in the treatment of skin diseases in the Republic of Kazakhstan. The chemical composition of these plants was analyzed, with a particular focus on the biologically active basic compounds responsible for their therapeutic efficiency in treating skin ailments. According to the eminent scientist, philosopher, and physician Avicenna, \u201ca doctor has three tools: the word, the plant, the knife\u201d. The plant kingdom is recognized as the humanity\u2019s earliest and the most ancient healing source, which people employed to treat and prevent illnesses. Tracing back through history, the most ancient documented proof of plants\u2019 utilization in medicine dates back to a Sumerian clay slab discovered in Nagpur about 5000 years ago. This artifact included a compilation of twelve medicinal recipes that involved over 250 diverse plant species. Sumerian healers prepared powders and therapeutic infusions from plant roots and stems. Pears and figs also possessed healing properties. Additionally, they utilized dried and ground young shoots of willow and plum trees, and pine and fir trees as components in compresses and poultices. Powders from animal and mineral sources were often mixed with ones extracted from dried and crushed plants. Notably, in addition to water, wine and beer were used as solvents. Thus, at least 80 centuries ago, people employed the most simple medicinal plant-based preparations for treatment .Regarding Kazakh folk medicine, it has not yet been fully researched. The traditional medicine of the Kazakh people covers not only the mere treatment of ailments but also rests on robust theoretical knowledge. Oteiboydak Tleukabyluly (1388\u20131478), a distinguished Kazakh healer who lived in the 15th century, wrote the ethnographic and medical book \u201cMedical Narrative\u201d between the years 1466 and 1473 with az-Zhanibek Khan\u2019s order who held Oteiboydak Tleukabyluly in high esteem as a healer. Oteiboydak Tleukabyluly wrote in his book about the secrets of the healing art. This medical encyclopedia delineates the functions of various organs of the human body and provides a catalogue of the primary diseases associated with them. Furthermore, it includes a meticulous description of the methods used in traditional medicine at present, such as setting bones, listening to the pulse, and incantations. Through practical experimentation and experimentation conducted in the steppe laboratory, the healer formulated a total of 1108 different medicinal compounds, of which 858 were derived from medicinal plants, 318 were extracted from animal organs, and roughly 60 were sourced from metals. The moniker \u201cTeacher without a teacher\u201d was bestowed on Oteiboydak Tleukabyluly who created methods for treating 1050 different diseases .At present, phytotherapy is widely practiced all over the world. According to the World Health Organization\u2019s (WHO) global review of national policies concerning traditional, complementary, and alternative medicine, as well as the regulation of herbal medicines, there is an evident growth in the European and Asian market for herbal medicines .Kazakhstan accounts for a natural flora of over 6000 plant species . The exaThis study mainly discusses the plant phytochemical composition. The main components responsible for their therapeutic effects in treating dermatitis, atopic dermatitis, and eczema were analyzed.Achillea millefolium L., commonly known as common yarrow, belongs to the Asteraceae family (Asteraceae Dumort.). The plant was referred to as \u201cvenus eyelashes\u201d during the Middle Ages due to its the feathery appearance of its leaves, while the whole plant was known as \u201csoldier\u2019s grass\u201d for its use in treating wounds. There are over 100 different species of Achillea millefolium L., which are found in various regions worldwide, including North America, Europe, Asia, Australia, New Zealand, and the Middle East [dle East ,6,7,8. Tdle East .A. millefolium are essential oils and phenolic compounds, monoterpenes, sesquiterpenes, lactones [The main components of lactones , amino alactones . The comlactones ,14,15,16lactones .A. millefolium can be attributed to the presence of sesquiterpene lactones in its essential oil. The quantity of essential oil produced by the plant is largely dependent on the growth stage. During the early stage of growth, the content of essential oil is 0.13%, which rises to 0.34% in the process of flowering [The bitter taste of lowering ,16.In traditional medicine, yarrow has been employed to alleviate a variety of ailments including respiratory diseases (such as asthma and bronchitis), dyspepsia, skin inflammation, and headaches. The aerial part of the plant, including the leaves, stems, and inflorescences, is typically collected during the flowering phase for its usage as medicinal raw material. Yarrow is often administered as infusions, extracts, and potions to treat bleeding, flatulence, and gastrointestinal diseases ,11,18.A. millefolium possesses various therapeutic properties such as disinfectant, anti-inflammatory, antispasmodic, anthelmintic, antibacterial, antioxidant, and antimicrobial effects [ effects . Additio effects , while t effects .Yarrow has long been utilized in traditional medicine as an efficient remedy for various skin ailments, including acne, eczema, neurodermatitis, and urticaria. Moreover, yarrow is incorporated into medicinal preparations for vasculitis. It is administered orally to prevent the recurrence of eczema ,22,23.The wound-healing and anti-inflammatory effect of yarrow is due to the content of chamazulene  (12.34%)A. millefolium. Thus, the effect of the water\u2013alcohol extract of Achillea millefolium (HEAML) on the proliferation and stimulation of the human skin fibroblast growth (HSF-PI-16) was studied. The extract selectively inhibited the proliferation of HSF-PI-16 cells at higher concentrations (>20.0 mg/mL) and were stimulated at lower concentrations (<20.0 mg/mL). After treating the HSF-PI-16 medium for 72 h with the extract, a significantly increased proliferation rate and stimulation in the scratch analysis was noted [Achillea millefolium L. significantly reduces the expression of proinflammatory cytokines in mouse macrophage cells treated with lipopolysaccharide [The results of the study  explain as noted . The actccharide .Acorus calamus L.  marsh is a perennial plant containing aromatic compounds and is widespread in Central Asia, India, and the Himalayas. Although its distribution has significantly diminished in Europe, it remains a common plant in the northern marshy regions with a temperate climate [ climate . It is fCalamus marsh is rich in various chemical compounds, including bitter glycoside acorin, essential oil (which contains proazulene), gum, resins, ascorbic acid, tannins, starch, and mucus. The dried rhizome of Calamus marsh consists of yellow aromatic volatile oils comprising of small amounts of sesquiterpenes and their alcohols; and choline, flavone, acoradin, galangin, acolamon, and isocolamon. Furthermore, it contains cineol, limonene, terpineol, azulene, eugenol, camphene, cadinene, ethanol, galangin, magnesium, zinc, terpenes, menthol, and camphor .Calamus root is considered in traditional medicine to be a therapeutic agent for a range of ailments, such as arthritis, neuralgia, diarrhea, dyspepsia, and hair loss ,29.The plant has been found to possess potent antioxidant, anti-inflammatory, antiulcer, antimicrobial, and wound-healing properties. It is employed in dermatology to cure pyoderma, acne vulgaris, alopecia, and eczema ,31,32. T\u03b2-Azarone is known to contribute to the body\u2019s natural defense against ultraviolet rays, but it has also been found to have carcinogenic properties and induce liver tumors. Calamus marsh, which includes varying amounts of \u03b2-azarone depending on the variety, has traditionally been used in Asian medicine for its anti-inflammatory properties, which can help alleviate skin itching, swelling, and redness. Meanwhile, European varieties of Calamus marsh are known to contain sesquiterpenoids, which possess psychoactive properties and display beneficial medicinal effects ,34,35.Embelina ribes) is useful in curing eczema and other skin diseases [Calamus rhizomes have been found to be very useful as a topical agent in skin-related problems. The rhizomes are used in the form of powder, balms, enemas, and pills and also in ghee preparations. A tub bath in the decoction of vacha, kustha (Savccera lappa) and vidanga , and sesquiterpenes. Moreover, the plant contains vanillin glucoside, iron, minerals, and significant quantities of silica. Among the phenolic compounds found in the plant are p-hydroxybenzoic, vanillic, and p-coumaric acids, as well as chlorogenic acid, p-hydroxycinnamic acids, and p-hydroxycinnamic acid esters. The rhizomes consist of polysaccharides, glycosides such as quercetin and luteolin, phenolic glucosides, fatty acids, and amino acids  ,40. FurtAgropyron repens L. was used in folk medicine as a sedative diuretic to relieve pain and spasms in the urinary tract, and as a sedative and tonic. The traditional medicinal use of Agropyron repens L. in urolithiasis has been scientifically proved, with confirmed pharmacological effects including hypoglycemic, hypolipidemic, anti-inflammatory, and antidiabetic effects, as well as effects on motility and benefits in urinary tract infections [fections ,41,42,43The presence of flavonoids, alkaloids, and coumarin in the composition of this plant evidences its potential activity in the treatment of skin diseases, such as inflammatory skin diseases, atopic dermatitis, and acne . Thus, iArtemisia absinthium L., a plant species commonly known as wormwood, is widely distributed in Asia, the Middle East, Europe, and North Africa. It grows everywhere in Kazakhstan [zakhstan ,47,48.A. absinthium is a plant species that possesses various biologically active compounds. The grass of this plant is utilized as a source material for oil production. The oil mainly consists of thujone esters, \u03b1- and \u03b2-thujone, camphene, \u03b1-cadinene, guaiazulene, (Z)-epoxycymene, (E)-sabinyl acetate, (Z)-chrysanthenyl acetate, as well as bitter sesquiterpenoid lactones, azulene group compounds, and tannins [A. absinthium extract is dependent on the type of solvent utilized in the extraction process. The alcoholic extract, in particular, has a considerably higher concentration of flavonoids, phenols, and tannins in comparison to the aqueous and chloroform extracts [ tannins . Moreove tannins . The comextracts .A. absinthium has been used in traditional medicine to cure a wide range of ailments, particularly parasitic diseases and digestive disorders, as well as fever reduction [A. absinthium tincture is highly esteemed as a tonic and digestive aid. In a published paper [For many years, eduction . The leaed paper , the wored paper .A. absinthium demonstrates various biological activities, including but not limited to antibacterial, anti-inflammatory, hepatoprotective, antidepressant, antispasmodic, and antipyretic effects [ effects ,54. More effects ,55.A. absinthium has been shown to expedite wound healing, diminish inflammation, and exhibit antimicrobial and wound-healing properties. This effect is due to the significant content of oxygenated components in the oil, such as camphor  activity. In addition, the oil contains chamazulene  (10.35%), which contributes to the manifestation of antioxidant/anti-radical activity ,57.Bidens tripartita L. is widely distributed in the European part of the CIS, Transcaucasia, Siberia, Central Asia (excluding Turkmenistan), and the southern region of the Far East. Its range also extends to North Africa and North America [ America . In KazaB. tripartita is a plant that is rich in various biologically active compounds, including essential oil, chlorophylls, flavonoids, cinnamic acid derivatives, tannins with a high polyphenol fraction content, polysaccharides, carotenoids, ascorbic acid, coumarins, chalcones, and minerals such as Zn, Sr, Se, and Mn. Flavonoids found in the plant include luteolin, butein, sulphuretin, sulphurein, cynaroside, auron, (+)-catechin, (\u2212)-epicatechin, rutin, myricetin, 7-hydroxyflavone, esculetin, and umbelliferone, among others [g others ,63,64,65B. tripartita have been utilized for a considerable time period in combination with baths for the treatment of scrofula, rickets, exudative diathesis, and various pustular skin diseases such as acne and boils, as well as for the management of gout, arthritis, and articular rheumatism. They are also recommended for improving appetite and digestion, and for the treatment of liver and spleen disorders, colds, bronchitis, and diabetes mellitus [In traditional medicine, the water infusion and decoction of mellitus ,67.B. tripartita exhibit a range of therapeutic effects, including anti-inflammatory, hemostatic, antiseptic, sedative, and wound-healing properties, lower blood pressure, and increase the amplitude of heart contractions [B. tripartita have also been proved [B. tripartita manifests antioxidant activity against cancer cells and has the ability to inhibit key enzymes, such as \u03b1-amylase and \u03b1-glucosidase. In addition, according to evidence, the herb has antidiabetic activity, as well as antihyperglycemic and antioxidant effects [Preparations derived from ractions ,69. The n proved ,71. The  effects .The broad pharmacological effects of the plant are attributed to its abundant content of various biologically active substances. Manganese ions in the plant\u2019s enzyme systems are believed to influence hematopoiesis, blood coagulation, endocrine gland activity, liver cell function, and blood vessel and bile duct tone, and may prevent intravascular thrombus formation and enhance antimicrobial properties of the plants ,69. FlavB. tripartita is used in the treatment of many skin diseases: psoriasis, seborrhea, urticaria, diathesis, acne, pimples, wounds, and ulcers, as well as small cracks. The beneficial effects on the skin can be attributed to the presence of tannins. Tannins also help to get rid of increased sweating of the armpits and legs. Thus, B. tripartita is employed for making baths, lotions, and wipes to treat microbial eczema of the feet, epidermophytosis [B. tripartita (from 10\u201330 g of herbs) is added to the bath [The extract of phytosis ,66,67,73phytosis ,69. Durithe bath .B. tripartita, which was used to cure contact allergic dermatitis experimentally caused in guinea pigs by 2,4-dinitrochlorobenzene. The study results showed that 5% ointment had the greatest therapeutic effect compared to the antihistamines Psilo-Balsam and glucocorticoid ointment Celestoderm. At the same time, the rate of reduction in the severity of skin manifestations (Ind) was the highest compared to other studied groups\u201437.9%.Khatamov et al.  developeCapsella bursa-pastoris L. is a wild plant with significant nutritional value that is suitable for human consumption. This plant is widely distributed across many countries, including Cyprus, Europe, Saudi Arabia, Turkey, Pakistan, India, Iraq, Iran, China, Azerbaijan, and other Asian countries [ountries . It is aC. bursa-pastoris contains a variety of chemical components including flavonoids, polypeptides, choline, acetylcholine, histamine, tyramine, fatty acids, sterols, organic acids, amino acids, sulforaphane, vitamins [vitamins , and varvitamins ,78,79,80vitamins .C. bursa-pastoris has been used for centuries in China and Japan as a hemostatic, diuretic, and antipyretic agent [C. bursa-pastoris plant [In traditional medicine, ic agent . The plaic agent . The entis plant .Based on the literature, raw plant extracts and certain phytocomponents have been reported to exhibit various pharmacological effects, such as anti-inflammatory, antispasmodic, antimicrobial, hepatoprotective, cardiovascular, anticancer, sedative, and antioxidant effects ,84,85,86C. bursa-pastoris exhibits potent antioxidant activity attributed to its flavonoid compounds, namely quercetin, chrysoeriol, kaempferol, and isorhamnetin. In vitro studies have shown that its extracts possess antioxidant activity that prevents the development of various free radicals such as DPPH radicals, peroxyl radicals, hydroxyl radicals, and hydrogen peroxide [peroxide . Additioperoxide . Furtherperoxide .C. bursa-pastoris exhibits an excellent efficiency in the treatment of eczema in dermatology [C. bursa-pastoris have been registered and recommended by the German Institute for Pharmaceuticals and Medicines for the additional treatment of skin diseases and wounds [matology . Moreoved wounds . Fumaratd wounds .Chelidonium majus L., a plant species commonly known as greater celandine, is widely distributed across Asia, North America, and northwestern Africa [n Africa .C. majus is known to contain a high concentration of isoquinoline alkaloids, with levels ranging from 0.27 to 2.25% in the aerial parts and 3\u20134% in the root. Over 70 compounds have been identified, including various alkaloids , flavonoids , saponins, vitamins (such as vitamin A and C), mineral elements, a small amount of phytosterols (such as \u03b1-spinasterol and ergosterol), and aromatic and aliphatic acids  and their derivatives. Additionally, celandine consists of polysaccharides, alcohols , choline, tyramine, histamine, and saponosides. It should be noted that a previous study provided the formulas of all organic components [The plant mponents . The conmponents ,96,97.C. majus has a long history of traditional use in Europe, Asia, and Africa to treat various ailments, including those affecting the liver and bile ducts, as well as to cure skin conditions such as warts, calluses, and eczema. Additionally, the plant has been used to treat stomach ulcers, tuberculosis, skin rashes, and oral infections. In traditional Chinese medicine and homeopathy, C. majus is used to alleviate congestion, pain, swelling, and jaundice [jaundice ,98.C. majus. Additionally, the plant has demonstrated immunomodulatory, lipid-lowering, and radioprotective properties [C. majus has been found to contain biologically active secondary metabolites with significant inhibitory effects that prevent Alzheimer\u2019s disease [Celandine extracts have been found to possess a broad spectrum of pharmacological activities including anti-inflammatory, antimicrobial, anticancer, antioxidant, hepatoprotective, natriuretic, and antidiuretic effects, corroborating some of the traditional medicinal uses of operties ,95,98,99 disease .The milky juice of the celandine is rich in alkaloids among which the predominant one is chelidonine a. StudieCichorium intybus L., a perennial herbaceous plant belonging to the Asteraceae family, is known by various common names such as roadside grass, blue flower, roadside cornflower, bride of the sun, and sun grass. Its recognizable feature is the inflorescences-baskets that exclusively comprise reed blue flowers. However, the said baskets only open during early morning hours or in cloudy weather. The term \u201cchicory\u201d is derived from the Latin word, meaning \u201centering the fields.\u201d Due to its therapeutic properties, this plant has earned the followings names: \u201cking root,\u201d \u201cgolden root,\u201d and \u201ccure for a hundred diseases\u201d [iseases\u201d .C. intybus exhibits a wide geographical distribution encompassing Northern and Central Europe, Siberia, Turkey, Afghanistan, Northern and Central China, South America, South Africa, Ethiopia, Madagascar, India, Australia, and New Zealand. This herbaceous plant is capable of growing in the territories of the Commonwealth of Independent States, except the Far North region [h region .C. intybus contain 56\u201365% inulin (in terms of dry matter), the maximum accumulation of which is observed in autumn. Intibin glycoside gives specific bitterness to chicory roots. Proteins, sugars, pectin, and sesquiterpene lactones were also found in the roots, as well as guayanolides: cycriosides B and C, sonchuside C, tannins and resinous substances, choline, carotene, vitamins B, B2, PP and C, from mineral elements\u2014sodium, potassium, calcium, manganese, and phosphorus, iron. Chicory roots contain taraxasterol, phenolic acids  [C. intybus, chicory glycoside was found, in the seeds: inulin and protocatechin aldehyde [The roots of c acids) ,102. In aldehyde ,104, prealdehyde ,106. Alialdehyde .C. intybus L. are extensively employed in traditional medicine, such as in Chinese and Mongolian practices, as an agent for modulating the immune system, promoting bile secretion, protecting the liver, and reducing blood glucose levels. The plant is documented in the Chinese Pharmacopoeia and is utilized in the formulation of homeopathic remedies in Germany. The extract of chicory herb is a constituent of the LIV-52 complex preparation from India [The aerial and subterranean portions of om India .C. intybus exhibits antiseptic and astringent properties and produces choleretic and diuretic effects. It positively influences the nervous and cardiovascular systems. Additionally, its infusion has been employed for normalizing heart rhythm. According to the literature, preparations derived from C. intybus are efficient in treating various diseases connected with the gallbladder, liver, kidneys, and urinary system. Additionally, chicory preparations have been shown to exhibit potential therapeutic benefits in managing obesity, liver diseases, atherosclerosis, hypoacid gastritis, tachycardia, arrhythmia, and nephritis. The milky juice of the plant contains bitter substances that have been found to stimulate peristalsis of the gastrointestinal tract, increase the secretion of gastric and intestinal juice, and promote regular bowel movements and appetite. According to the published literature, C. intybus has been found to possess a notable therapeutic effect in curing and preventing diabetes mellitus and in preventing it (antidiabetic effect). This effect is attributed to the presence of inulin, a natural sugar substitute that eliminates toxins and non-nutrient substances from the body. Preparations based on C. intybus exhibit diverse pharmacological activities, including anti-inflammatory, antioxidant, antiviral, choleretic, diuretic, hepatoprotective, and antibacterial effects, making them beneficial in treating colitis, gastritis, and enteritis. Decoctions of C. intybus roots have been reported to be effective in the treatment of helminthic invasion, anemia, malaria, scurvy, eczema, and tumors of the spleen [C. intybus L. may modulate immune responses [C. intybus flowers have been found to possess antiseptic, anti-inflammatory, moisturizing, and nourishing properties, which are beneficial in treating inflammation of the skin and eyes [e spleen ,110,111.esponses . Infusioand eyes .C. intybus L. is commonly applied externally  for the treatment of various skin diseases, including but not limited to eczema, urticaria, psoriasis, seboroid dermatitis, neurodermatitis, atopic dermatitis, vitiligo, acne, and furunculosis. Additionally, the herb is known for its efficiency in the care of dry skin [A decoction of dry skin ,107.C. intybus extract has been clinically tested on volunteers as a skin UV-protecting means. The analysis results of the microrelief control area applied with sodium lauryl sulfate and causing skin damage showed there was a significant increase in roughness after 28 days of the study, while in the areas where sodium lauryl sulfate was applied on the plant extract, the roughness of the skin did not undergo any significant changes, which indicates the plant\u2019s protective properties [operties .Equisetum arvense L., a herbaceous plant belonging to the Equisetaceae family, is widely distributed in North America, Europe, and Asia, including the territory of Kazakhstan [zakhstan ,114.E. arvense contains more than 210 natural compounds distributed in various organs. These compounds include alkaloids, carbohydrates, proteins and amino acids, phytosterols, saponins, sterols, ascorbic acid, silicic acid, phenolic compounds, and their glycosides, tannins, flavonoids , triterpenoids, volatile oils, and other bioactive substances [bstances ,116.E. arvense, a plant species from the Equisetaceae family, has been utilized in traditional medicine for its therapeutic properties. Its applications include the treatment of tuberculosis, and renal and bladder catarrh, as well as a hemostatic agent during excessive menstruation, nasal, pulmonary, and gastric bleeding, among others [g others .E. arvense has demonstrated various biological activities including antioxidant [E. arvense has been traditionally used for its analgesic effects on rheumatism and frostbite, as well as its anti-inflammatory properties, which can improve blood circulation. This plant has been employed as a bath agent for skin diseases and incorporated into cosmetic products as a rejuvenating, moisturizing, anti-wrinkle, anti-acne, antiperspirant, and conditioning agent [The water\u2013alcohol extract of ioxidant , anti-inioxidant . Studiesioxidant , as wellioxidant , neuro- ioxidant ,123. Addng agent .Equisetum arvense L. is recognized for its high content of silicon, a compound that is associated with promoting skin health. Silicon maintains skin firmness and elasticity, while its mild exfoliating properties allow the elimination of dead skin cells and enhancing of skin texture [ texture ,126.E. arvense has been attributed to the presence of flavonoids such as quercetin , , inflammatory enzyme (COX-2), and transcription factor (NF-kB). In addition, quercetin promotes increased growth factors (VEGF and TGF-\u03b21) as well as anti-inflammatory cytokines (IL-10) and antioxidant defenses . This compound also has an antifibrotic effect on second-target wounds, increasing the expression of \u03b1intergrin  and beta acids (lupulones). The essential oils contain myrcene, linalool, and geraniol, which are the most important aromatic compounds. Additionally, lupulin contains polyphenols, such as quercetin  extracts to evaluate biological activity against acne vulgaris [Propionibacterium acnes, Staphylococcus epidermidis, Staphylococcus aureus, Kocuria rhizophila, and Staphylococcus pyogenes, were selected as the main acne-causing bacteria. Hop extracts xanthohumol , proteins, amino acids, as well as vitamins E, C, \u03b2-carotene, and essential minerals such as potassium, calcium, magnesium, sulfur, and phosphorus . MoreoveJuglans regia L. includes a cumulative 40 metabolites classified under megastigmane, tetralone, phenylpropanoid, neolignan, and juglone glycosides [The chemical composition of walnut leaves is characterized by the presence of various biologically active components, including trace amounts of iodine, \u03b1- and \u03b2-hydrojuglone, polyphenols, tannins, glycosides, flavonoids, terpenoids, vitamin C, carotene, vitamin B1, essential oils, and tannins ,191,192.ycosides .Juglans regia L. are utilized to cure several ailments such as diabetes, infectious diseases, and periodontal disease [In traditional medicine, diverse components of  disease . Further disease ,197. Not disease . Additio disease .Juglans regia L. are traditionally used to alleviate skin inflammation and excessive sweating of the hands and feet. Moreover, they are recommended for the treatment of acne, warts, eczema, and psoriasis due to the presence of flavonoids, specifically quercetin derivatives, and tannins [J. regia contributes to its antioxidant effect, which promotes the repair of damaged skin and strengthens the epidermal layer [The leaves of  tannins ,201,202.al layer .Matricaria chamomilla L. is a globally distributed, well known medicinal plant [al plant ,205.M. chamomilla contains numerous biologically active compounds, including flavonoids (such as apigenin and luteolin) and their glycosides, as well as coumarins (including gerniarin and umbelliferone) [iferone) . The essiferone) ,207,208.M. chamomilla has been widely employed in traditional medicine for treating a variety of ailments, including infections, neuropsychiatric disorders, respiratory tract, gastrointestinal, and liver diseases. Furthermore, the plant possesses sedative, antispasmodic, antiseptic, and antiemetic properties [operties .M. chamomilla encompass a diverse array of medical conditions, including inflammatory conditions, bacterial infections, and lesions of the skin and mucous membranes such as those found in the oral cavity, gastrointestinal tract, and respiratory tract. Additionally, the plant has been employed as a remedy for spasms and ulcers of the gastrointestinal tract, insomnia, and nervous breakdown [Therapeutic indications for reakdown ,213,214.reakdown  and wounreakdown , and actreakdown .M. chamomilla is regarded as a viable alternative due to a high content of bioactive secondary metabolites that can be used for the treatment of diverse skin problems, such as wounds, abscesses, and skin diseases. The plant\u2019s therapeutic efficiency in treating skin diseases is attributed to the presence of quercetin  contained combinations of Matricaria with other plant species, including those belonging to the genus Calendula, Salviae, Eucalyptus, Urtica, and Aloe vera. On the other hand, four patents (20.00%) reported the development of bioproducts containing only species classified as chamomile, two (10.00%) with M. parthenium, and two (10.00%), M. chamomilla. Based on the information of these extracts, externally applied pharmaceutical remedies such as creams, ointments, lotions, solutions, textile dressing, and banding were developed. Capsules, granules, and alcohol dye have been developed for oral use. Regarding the skin disease treated, the selected inventions claim to treat wounds and burns, erythema and rosacea, eczema and dyshidrosis, and spots and hyperpigmentation of the skin by UV radiation. Skin peeling and damaged stratum corneum, dermatitis, hemorrhagic incision, excoriations, hand-foot syndrome, psoriasis, and acne were also mentioned.Dos Santos et al.  presenteOnonis spinosa L. is widely distributed in Africa, Asia, and Europe. It is found in countries such as Algeria, Libya, Morocco, Tunisia, Afghanistan, Iran, Iraq, Palestine, Jordan, Lebanon, Syria, Turkey, Armenia, Azerbaijan, India, Denmark, Norway, Sweden, Great Britain, Austria, Belgium, Czechoslovakia, Germany, Hungary, the Netherlands, Poland, Switzerland, Estonia, Lithuania, Moldova, the European part of the Russian Federation, Albania, Bulgaria, Greece, Italy, Romania, France, Portugal, and Spain [nd Spain .O. spinosa contains a large amount of isoflavonoids, pterocarpans, and dihydroisoflavonoids, including formononetin, calicosin, pseudobaptigenin, medicarpin, maakiain, onogenin, and sativanon, with metabolites present in the form of glucosides, glucoside malonates, glucoside acetates, and free aglycones [The root of glycones ,223.O. spinosa were utilized in folk medicine for their antitussive, laxative, and diuretic properties. Infusions of the plant were employed to treat dropsy, urinary tract infections, inflammation, and rheumatism, while external applications were used to promote wound healing and alleviate skin conditions such as eczema. In Iraq, the roots were valued for their diuretic, blood purifying, laxative, and expectorant qualities [The roots, leaves, and flowers of ualities .O. spinosa has demonstrated resistance to various Candida species [Additionally, ash derived from burned samples of  species .O. spinosa exhibits noteworthy hepatoprotective and antitumor properties [Pharmacological investigations have demonstrated that operties , and mayoperties .O. spinosa has been utilized in dermatology for its efficiency in treating skin ailments such as dermatitis (eczema) and pruritus. It also possesses wound-healing properties beneficial in the treatment of burns [of burns .Ononis spinosa extract and glycerin have been clinically tested for facial laxity and wrinkles. The particular focus was made on immediate and delayed effects. Thirty-nine women used the product daily for an eight-week treatment period. Clinical assessment by experts and a new 2D imaging method (measuring the effect of an upper eyelid lift) were made at different time periods. The results showed an immediate and significant improvement in sagging and wrinkle parameters seven hours after the first application, in addition to significant long-term improvement. The lifting effect calculated from 2D images was 1.08 mm immediately after application and 1.80 mm after an eight-week treatment period. Ononis spinosa root extract inhibited hyaluronidases; Hyal-1 inhibition was a promising remedy for improving wound healing, tissue regeneration, and inducing diuresis. Two non-polar fractions of the roots of Ononis spinosa were the most active, causing inhibition of Hyal-1 by 86 \u00b1 3% and 96 \u00b1 13% at a concentration of 1 mg/mL, respectively. Chemical analysis revealed three main components, which were identified as onogenin, sativanon, and medikarpine. The percentages of inhibition for concentrations of 250 \u03bcM of these compounds were 25.3 \u00b1 18, 61, 20 \u00b1 20.6, and 22.4 \u00b1 16, respectively. The IC50 of sativanone was determined to be 151 \u00b5M. Hot water and hydroalcoholic extracts of the Ononis spinosa root showed a moderate inhibitory effect on hyaluronidase-1  , while dichloromethane extract had an inhibitory effect  with IC50 190 \u00b5g/mL [90 \u00b5g/mL .Onopordum acanthium L. is a widely distributed species of plants found across Africa (Algeria), Asia , throughout Europe, Australia, New Zealand, and North and South America  [Uruguay) ,228.O. acanthium is a plant species that contains various phytochemical compounds, including saponins, alkaloids, sesquiterpene lactones, flavonoids, triterpenes, sterols, nitrogen-containing compounds, phenolic acids, coumarins, inulin, soluble sugars, proteins, and oils [O. acanthium, while the roots were found to contain sesquiterpene lactones and polyacetylenes [and oils . The fatand oils ,230. Addetylenes .O. acanthium, including its powder, juice, and decoction of the aerial part, were utilized as diuretics. This plant is known to stimulate the central nervous system and has demonstrated cardiotonic and hemostatic properties. Infusions of the leaves and inflorescences have also been employed to reduce swelling of various etiologies [In traditional medicine, various preparations of iologies . Furtheriologies ,233. Theiologies . Additioiologies , as wellEriodictyol a and queO. acanthium resistant to A431 culture  was examined by the authors of [The antitumor activity of extracts obtained from a combination of flowers and fruits, leaves, and roots of thors of . AqueousOnopordum acanthium L., among them 4\u03b2,14-dihydro-3-dehydrozaluzanin C  is a plant species that is indigenous to Europe and Asia [Parsnip  and octyl hexanoate (6.68%) as its major constituents. Remarkably, this essential oil exhibited significant antioxidant and antimicrobial activity [Pastinaca sativa. These vitamins eliminate and neutralize the free radicals responsible for body diseases (chronic diseases) and premature aging [The dried seeds of activity . A largere aging .Recent studies in dermatology have shown the effects of furanocoumarins on the skin. Heraclenol a and oxyPlantago major L. (plantain) is a well-known and widely used medicinal plant. The genus Plantago L. comprises approximately 300 diverse species that flourish in temperate areas all over the world, including 16 plant species that occur in Kazakhstan [P. major is comparatively scarce and is primarily found along riverbanks and in intensely irrigated crops.zakhstan ,262. In Plantain is a botanical specimen that contains diverse chemical constituents, including carbohydrates, lipids, allantoin, essential and non-essential amino acids, caffeic acid derivatives, flavonoids including baicalein, scutellarein, luteolin, baicalin, apigenin, among others; phenolcarboxylic acids and their derivatives; iridoid glycosides such as aucubin, catalpol, and aukubozid; terpenoids; and alicyclic compounds such as loliolid. Furthermore, the leaves of plantain exhibit a significant concentration of phenols and their derivatives such as ferulic acid and tyrosol, tannins, and vitamin K. The seeds of plantain contain organic acids such as succinic acid, mucus, iridoids such as aucubin, sterols such as \u03b2-sitosterol, stigmasterol, campesterol, saponins, alkaloids, tannins, flavonoids such as isoquercitrin, and fatty oil. These findings have been reported in numerous sources ,265,266.For centuries plantain had been considered to possess therapeutic properties. Various parts of the plant, including mature seeds, leaves, and juice, were used for medicinal purposes. Plantain leaves were employed in the treatment of numerous diseases, including digestive, reproductive, and circulatory ailments, as well as inflammatory skin disorders  and urogThe mucus, enzymes, and phytoncides present in psyllium provide an enveloping and mucolytic effect that restores the protective function of the ciliated epithelium in the respiratory tract, leading to increased secretion of bronchial mucus and liquefaction of sputum for easy expectoration. It is noted in  that plaP. major is used in various types of wound and skin diseases: deep wound, purulent wound, chronic and progressive wound, malignant wound, fire burn, erysipelas, progressive blister, pruritus, irritating urticarial, and fistula. The treatment is carried out by sprinkling the plant powder on the wound or by using a bandage covered by Plantago major together with salt or without it. It is also used for head and face skin ulcers in the same manner [P. major components that have shown inhibitory effects on cyclooxygenase (COX-2)-catalyzed prostaglandin production. Luteolin (one of the flavonoids) also has the ability to suppress leukocyte migration and inhibit mast cell degranulation, which all together can be considered as anti-urticaria treatment strategies [e manner . This ple manner . Ursolicrategies  Polysaccrategies ,276,277.Ribes nigrum L. is a diminutive perennial shrub indigenous to Central Europe and North Asia that has been widely cultivated globally, including in the United States [d States . Furtherd States .Fresh blackcurrant fruits are known to contain a diverse range of functional and biologically active compounds, including soluble sugars, flavonoids, organic acids, vitamins, polyamino acids, macro- and microelements, and unsaturated fatty acids ,281. AddRibes nigrum, both in fresh and dried form, have been traditionally used as a multivitamin and general tonic for hypovitaminosis and beriberi, as well as for enhancing the immune system. In folk medicine, the leaves of Ribes nigrum have been used for treating various conditions, including kidney stones, gout, cystitis, urethritis, osteochondrosis, rheumatism, muscle and joint pain, exudative diathesis, eczema, and furunculosis [Ribes nigrum is used in homeopathy [Ribes nigrum extract, rich in anthocyanins, were indicated. Extracts containing more than 20% anthocyanins were found to exhibit antioxidant, anti-inflammatory, and phytoestrogenic activity, anti-postprandial hyperglycemic and antidiabetic effects, and cardioprotective effects. Furthermore, the anthocyanin-rich fraction of black currant peel extract has been found to exhibit a strong cytotoxic effect on human liver cancer cells, and to have a positive effect on vision and eye health.The fruits, leaves, and shoots of nculosis . Additiomeopathy . In a stmeopathy , a wide Ribes nigrum may be helpful in treating various skin diseases, such as atopic dermatitis, psoriasis, and acne, owing to its higher anthocyanin content [In the field of dermatology, blackcurrant leaves have been utilized for treating skin lesions resulting from atopic dermatitis and allergic itchy dermatoses , while leaves and fruits have been used for curing psoriasis, scleroderma, lichen planus, vasculitis, and acne vulgaris ,287. Rib content . The ant content . Vitamin content .Ribes nigrum) on immunomodulation in laboratory mice. The introduction of CAPS was found out to improve the symptoms of atopic dermatitis by inhibiting the migration of mast cells into the skin of the epidermis. CAPS administration was also found to suppress immunoglobulin (IgE) overproduction and induce transcription of the IFN-\u03b3 gene in the spleen.The authors of  studied R. glabrifolia, R. laxa Retz., R. Acicularis Lindl., R. majalis Herrm. (R. cinnamomea L.), and R. pimpinellifolia L. (R. spinosissima L.) [Rose hips have considerable economic importance and are widespread garden plants in Europe, Asia, North America, and the Middle East. The distribution of wild roses in different regions of Kazakhstan is heterogenous. In particular, a greater range of species diversity has been observed in forest and forest-steppe zones . There isima L.) .R. canina are highly valued by the food and pharmaceutical industries due to their rich content of biologically and physiologically active compounds. These include a wide range of vitamins , flavonoids, carotenes, carbohydrates (mono- and oligosaccharides), organic acids , polyunsaturated fatty acids, trace elements, and others [The fruits of d others ,294. Thed others . Dog rosd others .Rosa canina L.) is incorporated into compositions and complexes for the treatment of inflammatory diseases, including but not limited to rheumatoid arthritis, reactive arthritis, osteoarthritis, and other types of arthritis. It is also helpful in upper respiratory tract infections and psoriasis. Its other application includes the prevention of oxidative stress in the oral cavity. The unique phytochemical composition of rose hips is of huge interest because it can be considered a promising source for making functional foods, natural medicines, and cosmo-nutraceuticals. Presently, rose hips are employed as a constituent in probiotic products [Rose hips have a well-established history in traditional medicine as a preventative and treatment remedy for colds and other infections, as well as a diuretic and therapy for various inflammatory disorders. In modern medical practice, dog rose , lipids , steroidal sapogenins , and pigments (such as lycopene and lycoxanthin) [S. dulcamara has been found to contain steroidal alkaloids, including solanine (xanthin) . Notablysolanine  in immatS. dulcamara stems have traditionally been employed in folk medicine as a narcotic agent and as a remedy for conditions such as rheumatism, migraine, and severe inflammation [ammation .S. dulcamara demonstrates significant anti-inflammatory and antioxidant activity [S. dulcamara is reputed to possess a variety of therapeutic properties, including antimicrobial, analgesic, hepatoprotective, immunomodulatory, antitumor, and neurogenetic effects [S. dulcamara is particularly rich in alkaloids, which contribute to its antibacterial activity against Streptococcus pyogenes, Staphylococcus epidermidis, and S. aureus.An ethyl acetate extract obtained from the ripe fruits of activity . Moreove effects , as well effects , antihyp effects , antibac effects ,306, and effects . The aerS. dulcamara is a known remedy for the treatment of skin diseases and warts [S. dulcamara possess remarkable antioxidant activity, as they are capable of absorbing free radicals. Due to their beneficial properties, saponins are often utilized in cosmetology, where they improve the rheological and foaming properties of body-washing products and reduce the risk of skin irritation [S. dulcamara are attributed to the presence of various phenolic compounds, flavonoids, anthocyanins, and carotenoids such as lycophyll , 10 amides, 16 saponins, 14 steroid alkaloids, 6 lignans, and 15 other compounds [Through non-targeted LC/MS analysis, 83 metabolites have been identified in ompounds . NotablyS. dulcamara, unripe fruits contained a higher concentration of \u03b3-solamarin, \u03b1-solazonin, \u03b1-solanine, abutiloside H, and solanandaine compared to ripe fruits. Moreover, methanol fruit extracts were found to exhibit significant potential in eliminating DPPH and hydroxyl radicals. Interestingly, the ability of methanol extracts to remove DPPH was found to be tissue-specific, with the outer tissue (skin) of the bittersweet fruits showing a higher antioxidant activity than the inner tissues (pulp and seeds), possibly due to the higher phenol content in the peel [According to the investigations of the metabolites present in the peel .Sorbus aucuparia L., a botanical species known for its nutritional and medicinal beneficial properties, is considered a valuable source of edible fruits. This plant is characterized by its ability to survive in cold and harsh environments, and is widely distributed in various regions of Northern Europe, the Caucasus, the Middle East, and East Asia [ast Asia ,315,316.Sorbi fructus, commonly known as Rowan fruits, serve as essential medicinal resources. The berries are harvested during their complete maturation phase, from August to September, before the advent of frost. During collection, it is advisable to exercise caution and avoid damaging the branches. The stalks of harvested raw materials are cut, and then these materials are subjected to a drying process in well-ventilated rooms or dryers, employing a temperature range of 60\u201380 \u00b0C .This fruit, popularly referred to as a \u201csuperfruit,\u201d contains a diverse array of phytochemicals, comprising phenolic acids: neochlorogenic and chlorogenic acids (see above), flavonoids, proanthocyanidins, iridoids, coumarins, hydrolysable tannins, carotenoids, and anthocyanins, as well as vitamins  ,318,319.S. aucuparia have been utilized in traditional medicine to alleviate ailments related to cardiovascular and digestive systems. In addition to their medicinal applications, these fruits can be eaten raw or utilized in the production of jams, syrups, and as flavoring agents in alcoholic and non-alcoholic beverages, including beer and wine [Throughout history, the fruits of and wine .S. aucuparia have demonstrated antioxidant [The fruit extracts derived from ioxidant  and antiioxidant . The antioxidant , and antioxidant ,324 withioxidant  reportedWithin the field of dermatology, Rowan berries are a valuable multivitamin raw material for the treatment of allergic diseases and other skin problems due to their wound-healing properties .Sorbic and parasorbic acids, present in the fruits of mountain ash, have an antimicrobial and antifungal effect. Based on the fruits of mountain ash, an ointment is prepared that has anti-inflammatory and wound-healing properties .Symphytum officinale L., commonly known as comfrey, is distributed across the humid meadow and lakeside regions of Asia, Europe, and America, as supported by reference [eference . Its occeference .Comfrey contains various chemical compounds including phenolic compounds, flavonoids, fatty acids, polysaccharides, purine derivatives, and triterpenes ,331,332.In terms of ethnopharmacology, preparations made from the roots, leaves, or entire aerial parts of comfrey have been traditionally used since ancient times to treat various internal ailments such as respiratory, gastrointestinal, and genitourinary disorders, as well as external conditions such as bruises and tumors, through the administration of tinctures, infusions, decoctions, compresses, and ointments ,334.Symphytum officinale. The plant has been reported to possess anti-inflammatory, anti-apoptotic, antitumor, neuroprotective, and antioxidant properties [The literature indicates the potential therapeutic effects of operties . Furtheroperties .Allantoin  and rosmAllantoin  has beenComfrey also contains caffeic acid  and chloPolyphenolic compounds present in hydroalcoholic extracts were shown to possess antioxidant and free radical scavenging properties, preventing the release of reactive species responsible for the oxidative stress and tissue damage in burns .Comfrey also contains tannins and pyrrolizidine alkaloids, which contribute to its anti-inflammatory and wound-healing effects ,343.Tanacetum vulgare L. is a well-known medicinal plant that is distributed across Northern Europe, North America, Russia, China, North Korea, Kazakhstan, and Japan [nd Japan ,345.T. vulgare is rich in phenolic acids, flavonoids, and their derivatives [ivatives . The plaivatives .T. vulgare flowers are commonly used to prepare tea with various therapeutic effects such as antihelminthic, carminative, antispasmodic, abdominal organ stimulant, tonic, menstruation stimulant, antidiabetic, diuretic, and antihypertensive properties [T. vulgare is also utilized in the production of balms, cosmetics, dyes, insecticides, drugs, and preservatives [T. vulgare-based preparations have been used for the treatment of several illnesses including hysteria, migraine, neuralgia, rheumatism, renal failure, and fever [T. vulgare.In the traditional medicine of southeastern Serbia, operties ,349. Aparvatives . Furthernd fever . The samT. vulgare, including sesquiterpene lactones, volatile oils, flavonoids, and phenolic acids, have been found to possess antioxidant, anticancer, anti-inflammatory, and antiulcer properties [The bioactive components of operties .T. vulgare are responsible for its anti-inflammatory and antiallergic effects, making it a potential remedy for treating skin diseases such as atopic dermatitis, eczema, and psoriasis [Taraxasterol a, luteolsoriasis ,351,352.Inulin and chlorogenic acid d , and anemia. These therapeutic effects are attributed to the various phytochemical compounds present in dandelion, including sesquiterpene lactones, triterpene compounds, flavonoids, fatty acids, and vitamins and minerals such as vitamins A, C, D, E, and B, inositol, lecithin, and minerals such as iron, magnesium, sodium, calcium, silicon, copper, phosphorus, zinc, and manganese [According to the traditional medicine specialists\u2019 evidence it has the tonic and diuretic properties of anganese ,369,370.Taraxacum officinale has been found to contain taraxasterol , which causes dandruff in dogs [A study of  in dogs .Vaccinium myrtillus L. is a plant species that is predominantly found in forested areas in Northern Europe and North America [ America , as well America . Its dis America .V. myrtillus are a rich source of bioactive compounds such as phenolic acids (chlorogenic acid being the most common), flavonoids (isoquercetin), and resveratrol in the leaf extract [The fruits of  extract ,396. In  extract ,398. Mor extract .V. myrtillus flowers are utilized as ointments to treat a lot of skin-related diseases, including but not limited to ulcers, eczema, burns, bruises, rashes, varicose veins, and acne [According to traditional medicinal practices, and acne . Moreoveand acne .Blueberries are regarded as a valuable source of antioxidants, which explains their utilization in treating numerous ailments  linked to an increased oxidative stress ,397,400.Blueberry leaves have been found to possess hypoglycemic effects, attributed to the presence of myrtillin glycoside, which acts similarly to insulin and regulates pancreatic function. Dried blueberries are known for their astringent properties, while fresh blueberries are known to have carminative, anti-inflammatory, diuretic, hemostatic, antibiotic, and vitamin properties, and can regulate metabolism and digestive activity. In traditional medicine, blueberries have been used to treat various ailments such as bile duct and bladder stones, coughs, scurvy, and pulmonary tuberculosis. They have also been used to treat gastroenterocolitis and diarrhea, particularly in children. Due to their high content of vitamin C, blueberries have been used for scurvy treatment and external application to cure stomatitis and pharyngitis, which are accompanied by oral cavity wounds and ulcers ,402.The high antioxidant potential of blueberry seed oil, which contains chlorogenic acid d, isoqueV. myrtillus species is represented by various groups of phenolic compounds, which are known to be effective exogenous factors of antioxidant protection [The component composition of otection . Currentotection .In the case of skin diseases, long-lasting wounds, and ulcers, infusions made of fruits or leaves in the form of perfumes are applied externally.Viscum album L., commonly known as white mistletoe, is an evergreen hemiparasitic plant that grows widely in the Caucasus, Europe, and western and southern Asia [ern Asia ,407.Various chemical components have been identified in mistletoe through chemical studies, including viscotoxins (a mixture of amino acids), phenylpropanes, lignans, flavonoids, amines , \u03b1-viscol (\u03b2-amirin), \u03b2-viscol (lupeol), polysaccharides, lectins, fatty acids , alcohols , resinous substances, and mineral salts ,410,411.Viscum album L. has a rich ethnopharmacological history, with traditional uses including the treatment of various ailments such as epilepsy, anxiety, hypertension, internal bleeding, atherosclerosis, inflammation, and headaches. Additionally, it has been used as an antidote in some cultures [cultures ,414.Viscum album L. exhibits antioxidant [Mistletoe-based preparations possess hypotensive and analgesic effects. For instance, a tincture of fresh mistletoe leaves, found in the \u201cAkofit\u201d preparation, is utilized to treat acute radiculitis . The vasioxidant , antitumioxidant , antivirioxidant ,419,420.ioxidant ,422.Studies have shown that methanol extract significantly reduces the pigmentation of primary human melanocytes. In addition, reporter promoter analysis showed that the methanol extract inhibits the transcription of microphthalmia-associated transcription factor, melanophilin, tyrosinase protein-2, and tyrosinase genes in melanoma cells .Viscum album L. extract was found to significantly inhibit the expression of monocyte chemoattractant protein 1 (MCP-1). These results imply that Viscum album L. extract, as well as its active components, viscumneoside III and viscumneoside V, can regulate the production of MCP-1 and may have the ability to reduce skin toxicity induced by erlotinib by altering the activity of macrophages, without interfering with the anticancer effect of the drug [The presence of viscumneoside III and viscumneoside V in the drug .V. album extract was administered in combination with doxorubicin, it exhibited a synergistic effect, enhancing the antitumor impact on Ehrlich tumor cells [Research of an alcoholic extract of mistletoe has indicated its efficiency in treating skin cancer. The extract is assumed to boost immune mechanisms, which in turn restrain the proliferation of cancerous cells. Additionally, when or cells . Mistletor cells .In this review, we systematically summarized 30 plants of the flora of Kazakhstan, which were used traditionally for the treatment of skin diseases. As shown by analysis of the scientific literature, in Kazakhstan, these plants have been insufficiently studied to identify the pharmacological activity in the treatment of skin diseases. Earlier works ,428 descWhile conducting a literature search, we paid attention to the phytochemical composition of plants, especially to those secondary metabolites that condition the pharmacological effect in the treatment of skin diseases. Mechanisms of action of these biologically active compounds are described for some plants.The Matricaria recutita, Plantago major, Chelidonium majus, Achillea millefolium, and Bidens tripartita have good potential and are used as therapeutic agents both separately and as part of phytopreparation. The high pharmacological effect is due, in most cases, to the content in plants of flavonoids , phenolic acids , tannins, and other BAS, which synergize the pharmacological action, and the pharmacological action of plant extracts is quite broad, including wound healing, antioxidant, anti-inflammatory, antimicrobial, and anticarcinogenic effects. In turn, it should be noted that there are several plant species that have been little studied for pharmacological activity in the treatment of skin diseases . These plants can be the subject of future studies, which may add to the arsenal of phytopreparations for the treatment of dermatitis, eczema, psoriasis, lichen, and other skin inflammatory processes.As we know and according to the literature data, plants In our work, we conducted a literature search, which allowed us to conclude that the medicinal plants of the flora of the Republic of Kazakhstan are rich in medicinal plants, which are widely used in medicine to create dosage forms and preparations. Most of these plants have a complex of biologically active substances that give them high biological activity. Many plants are essential for the treatment of a wide range of ailments, including skin conditions, and can be used as natural alternative medicines. In general, our results confirm the importance and value of medicinal plants of the flora of Kazakhstan for scientific and medical research."}
+{"text": "Therapeutics comprising of nucleotide entities is very broad class, covers nucleotide analogs, oligonucleotides and nucleic acid-based based therapeutic. Nucleotide/nucleoside-based drugs are already very well explored, with clinically approved candidates as antiviral, anti-cancer, anti-bacterial and anti-rheumatoid etc . OligonuCurrently, 15 oligonucleotides therapeutics are approved for treatment of various rare diseases in the United States, in which four are approved against Duchenne muscular dystrophy. Particularly, in March 2020, approval of viltolarsen attracted attention of researchers worldwide towards oligonucleotides therapeutics .Nucleic acid-based therapies comprising of long polynucleotides target the diseases at the genetic level, and aiming to modulate gene expression, correct genetic mutations, or interfere with disease-causing processes . DiscoveResearchers are striving continue to explore the translational potential of oligonucleotides, while addressing various associated challenges like specificity, delivery, off-target effects, and undesirable pharmacokinetic profile. Numerous trials are underway, exploring their suitable route of administration, targeted delivery, optimized formulations, and long-term therapeutic effects. The translation of oligonucleotide could provide solution of various diseases in terms of precision medicine, which can treat diseases at molecular level .Under the current Research Topic, five review and one research, total six studies are published. First study covers the potential of oligonucleotide therapeutics (OT) emphasising on patient customization, while second review discussed on intranasal delivery of nucleic acid-based therapeutics, targeting the CNS disorders. Next two review focus on Parkinson\u2019s disease, one cover nasal delivery of nucleic acid-based therapeutics and while another discussed miRNA and antisense oligonucleotide. Fifth review study emphasized on nano-siRNA based approaches in treatment of cancer, while research study illustrated the immunostimulatory responses of RES-010, an antimiR-22 oligonucleotide on mononuclear cells.Thakur et al. highlights the past and present of OTs, emphasizing on the ongoing efforts to develop them as future therapeutics. Study specially highlighted their potential against the targets, which are undruggable for the conventional drugs. Overview of OTs, especially antisense RNAs, microRNAs, small interfering RNAs, and aptamers, being explored for the treatment of neurodegenerative disorders, cancer, and orphan diseases etc., is provided in the study. Key safety aspects of OTs like persistent gene silencing, off-target related toxicities, immuno-stimulatory responses, Renal accumulation, thrombocytopenia, and coagulation inhibition etc., are pointed in the study. Study discussed oligonucleotide instability, delivery-related issues, briefly provide overview of delivery vector. Strategies adopted to overcome the challenges faced with oligonucleotide delivery are summarized, including advanced drug carrier systems.Study by Shah et al., summarized the potential of nucleic acid-based therapeutics (NBTs) in treating various diseases like cardiovascular, inflammatory, neurological, hereditary disorders, cancer, and infectious diseases. Delivering NBTs to the target sites poses several challenges, study covers such challenges like stability, target specificity, biodistribution, and suitability of administration via non-invasive routes. Study illustrated nasal delivery an alternative non-invasiveness route for NBTs, with several advantages like sustained delivery potential, improved patient compliance, and ability to bypass the blood-brain barrier. Study also covered the recent approaches being undertaking like chemical modifications, delivery technologies, and nanoplatforms to troubleshoot delivery challenges.Study by Pandey and Singh briefly discussed pathophysiology of Parkinson\u2019s Disease (PD), and illustrated accumulation of \u03b1-synuclein aggregates, known as Lewy bodies as hallmark pathology of disease. Elaborating the nucleic acid therapeutics, including antisense oligonucleotides, microRNA, and gene therapy against PD, review study stated their potential role in modulating genetic dysregulation and downregulating \u03b1-synuclein expression. Superiority and associated challenges of NBTs, related to target specificity, stability, toxicity, and pharmacokinetics are also covered in this study. Although, studies support positive outcome of gene therapy approaches in PD by restoring function and ameliorating symptoms, however, further research and more clinical trials are required to validate their efficacy and safety in PD patients.Suvarna et al. focuses on recent advances in oligonucleotides based therapeutics against the Parkinson\u2019s disease, particularly by targeting alpha-synuclein protein. Study provided an overview of alpha-synuclein, aggregation mechanism, and its significant role in neuronal dysfunction and death, particularly in Parkinson\u2019s disease. Study covers recent advances in oligonucleotide chemistry, leading to the development of potential alpha-synuclein targeting molecules. Study discussed ASOs, suppressing the expression of the SNCA, gene responsible for alpha-synuclein production, preventing neurodegeneration. MiRNA inhibitors have shown potential in downregulating dysfunctional miRNAs involved in Parkinson\u2019s disease. Study discussed associated challenges with ASOs and miRNA-based therapeutics as well as undergoing research to address the challenges, particularly chemical modifications approach to enhance target specificity, stability, and reduce off-target effects is well illustrated.Review study by Goyal et al. discussed various perspective of SiRNA-based therapies against cancer, starting from introduction, mechanistic aspects, safety, selectivity, and associated challenges in translating them into clinical setting. Review also discussed on the combination of siRNA with chemotherapeutic drug delivery systems for the treatment of cancer and provided an overview of several nanocarrier formulations for siRNA delivery which are currently being explored. Study reviewed scope of chemical modifications of siRNAs, and its effect on their therapeutic efficacy and stability. Study advocated simultaneous targeting of multiples genes with combination of siRNAs and chemotherapy to achieve better therapeutic outcome. SiRNA nanoparticle delivery relies on the EPR effect, but exclusive selectivity on silencing siRNA target genes in tumor tissues needs to be assessed. The development of effective delivery mechanisms and evaluation of safety and effectiveness in clinical trials are suggested as deciding factors for the advancement of siRNA-based therapies.Study by Panella et al. was an extension of work on RES-010, a chemically modified antisense oligonucleotides (ASOs). Research study briefly provide background of MicroRNA, with special emphasis on MicroRNA-22 (miR-22), later is documented crucial in maintaining lipid and energy balance, and promising target for addressing NAFLD and obesity. In this study, impact of RES-010 was evaluated for immune responses on peripheral blood mononuclear cells (PBMCs) of human origin. PBMCs obtained from six healthy volunteers were treated with various concentrations of RES-010, subsequently, levels of proinflammatory cytokines were assessed. Study evaluated T-cell activation  and cell viability after exposure to RES-010. Findings of the study indicated that RES-010 did not elicit significant immunostimulatory responses in human PBMCs in vitro compared to control conditions, consequently, suggested its low proinflammatory potential.Research study reported by Recent trends and spotlight on nucleotide-based drugs: novel targets, their design, delivery, and clinical potential, discussed various studies published on nucleic acids-based therapeutics, especially oligonucleotides category. Published articles highlights intriguing potential of oligonucleotides therapeutics against Parkinson, Cancer, and other physiological disorders. Published studies covered the molecular pathways, targets, therapeutic potential, development status, associated challenges, and future perspectives of oligonucleotides therapeutics.In conclusion, Research Topic, entitled"}
+{"text": "Bone is an important tissue which is a structural body component, carrying out the roles of mechanical stress response and organ/tissue protection. In addition, bone, as an integral organ, not only regulates bone metabolism and regulates the hematopoietic niche, but also acts as an endocrine organ to control some metabolic processes that are independent of bone metabolism.Bone homeostasis is regulated and maintained by the remodeling cycle of osteoblastic bone formation and osteoclastic bone resorption ,2. When Regarding bone metabolism, several mechanisms and pathways, such as the wingless-type (WNT)/beta-catenin, bone morphogenetic protein (BMP) 2 or parathyroid hormone (PTH) signaling pathways, have been thoroughly studied over the last few decades. Among numerous regulatory factors in bone metabolism, mechanical stress is recognized as a critically important factor in bone-associated cell differentiation/growth and their functions, including those of osteoblasts, osteoclasts and osteocytes ,6,7. RecConversely, a recent report clearly indicates that physiologic mechanical stress directly causes osteoblast differentiation and increased bone formation without a mechanism involving the Wnt/beta-catenin signaling pathway connecting osteocytes and osteoblasts as mentioned above . SomemurAttention has been attracted by recent findings that the nicotinamide adenine dinucleotide (NAD)-dependent deacetylase Sirt-1 regulates many metabolic functions, such as inflammatory response, apoptosis, cell cycle, DNA repair, genome stability, mitochondrial function, cellular energy metabolism (adenosine triphosphate production) and cell responses to extrinsic stresses, including mechanical stress ,21,22,23In particular, several factors and proteins are linked to the regulatory mechanisms of bone development and growth, as well as bone regeneration and degeneration ,28,29,30"}
+{"text": "In this 2nd volume of \u201cNeuroendocrine Research in Health and Disease\u201d, we collected papers of neuroendocrine research in the following themes.Li et al. presented that individuals with obsessive-compulsive disorder have biomarkers like docosapentaenoic acid and 5-hydroxytryptophan, which help obsessive-compulsive disorder identification and prediction of sertraline treatment outcome, respectively.Mental health and behaviors are closely associated with balanced actions of hormones that are under the control of neuroendocrine activity . The study on this rare sweating disease provides novel pathological mechanism underlying the \u201cdiabetes insipidus\u201d and its optimal therapy.Many endocrine diseases can be treated with hormones. Hormone replacement therapy (HRT) in aged women has a long history to improve menopausal symptoms while many other health issues like Alzheimer's dementia . This review provides medical workers a new strategy dealing with COVID-19 and other infectious diseases.Many studies have revealed that neuropeptides have antimicrobial properties (Aresti Sanz and El Aidy, As a whole, neuroendocrine research provides novel view of neuroendocrine regulation of social and non-social behaviors, cognition and a variety of body functions by hormonal actions via endocrine, autocrine, paracrine and intracrine routes. Thus, they play dominant roles in shaping normal life activity. By contrast, abnormal expression and malfunction of these neuropeptides underlie many diseases including but not limited to stress, hyperthyroidism, infertility, hypertension, hyponatremia, obesity, diabetes mellitus, breastfeeding failure, intellectual disability, psychiatric disorders, metabolic disorders as well as increased susceptibility to tumors and infectious diseases.Future directions in neuroendocrine studies may include analyzing functions and regulation of classical neuropeptides and hormones, identifying and characterizing novel neuropeptides, exploring cellular and molecular mechanisms underlying neuropeptide actions, constructing the integration center for instinctive behaviors, establishing microbe-gut-brain axis. Certainly, application of modern biomedical techniques such as magnetic resonance imaging (Chen et al., Y-FW: Conceptualization, Resources, Validation, Writing\u2014first draft and editing. KK: Conceptualization, Resources, Validation, Writing\u2014review and editing. XC: Conceptualization, Resources, Validation, Writing\u2014review and editing. LS: Conceptualization, Resources, Validation, Writing\u2014review and editing."}
+{"text": "The psychological burden of the COVID-19 pandemic can have a lasting impact on the emotional well-being of healthcare workers (HCWs). Healthcare professionals working during the pandemic experienced increased occupational stress due to the high risk of contracting the virus, work overload, significantly increased working hours and overlapping job responsibilitiesThe study aimed to assess the dynamics of mental health and coping and to analyze how HCWs\u2019 emotional responses to a pandemic at the beginning of the pandemic and at the two-year follow-up. This study compared the results of examination of emotional response of HCWs in 2020 and 2022. The relationships between stress and alexithymia, emotional processing, and negative / positive affect in healthcare professionals were analyzed.All respondents of the study were hospital or ambulatory healthcare professionals. Overall, 285 subjects were examined in 2020 while 252 subjects were examined in 2022. Respondents completed several questionnaires such as e.g., the Toronto Alexithymia Scale-20, the Perceived Stress Scale (PSS-10), the Emotional Processing Scale (EPS), and the Positive and Negative Affect Scale (PANAS).Significant increased scores were observed forthe following parameters: alexithymia, identifying feelings, verbalizing feelings, operative thinking style, emotional processing, suppression, signs of unprocessed emotion, controllability of emotions, avoidance of emotional triggers, impoverished emotional experience, surrogate activities, denial, substance use, self-blame, stress, negative mood, somatic disorders, concern, dysfunction, depression, anxiety state and trait.The results were significantly lower for planning, using instrumental support, positive reframing, acceptance, religion, using emotional support, venting and positive mood.Statistically significant differences could not be found for acceptance, active coping, humor and behavioral disengagementResearch indicates that exposure to the pandemic a pandemic is associated with greater severity of a range of symptoms in HCWs. Two years of the pandemic may have led to psychological impairment. HCWs are more likely to use coping focused on emotional freezing, suppression, avoidance and / or an increase in negative emotions. Clinical observations indicate that caring for others does not correlate with appropriate self-careNone Declared"}
+{"text": "Chikungunya fever (CHIK) is a neglected tropical disease associated with chronic arthritis. CHIK is usually a self-limiting condition; however, extra-articular manifestations present as atypical illness in a minority of patients. These atypical features may mimic other conditions and potentially distract physicians from the true diagnosis. This review analyzes the evidence of many unusual extra-articular manifestations reported in cases of CHIK. Depending on the affected system, these unusual manifestations include encephalitis, myocarditis, acute interstitial nephritis, cutaneous manifestations, acute anterior uveitis, abdominal pain, and depression. In addition, coinfections and comorbidities may cause atypical illness and obscure the diagnosis. Further studies are required to clarify the pathophysiology and natural history of CHIK, as it remains a burdening condition. Exploring its atypical symptoms may be the missing scientific piece of this puzzle.  There are three distinct clades: the West African, Asian, and East/Central/South African (ECSA) genotypes. Most patients develop prominent symptoms of arthritisWhen faced with atypical symptoms, diagnosing CHIK is more challenging. Given that CHIK is a severely neglected tropical disease, few studies have adequately characterized these atypical casesIn this narrative review, we outline the current knowledge regarding the atypical, often severe, extra-articular presentations of CHIK infection, providing valuable insights into its pathophysiology, clinical picture, and management. Additionally, we discuss the prognoses of these manifestations and highlight the challenges and perspectives in managing possible sequelae. Although CHIKV is not typically considered a neurotropic virus, sporadic cases of nervous system involvement have been reported since the 1960s,-The frequency of nervous system involvement in patients with CHIK ranges from 7 to 33 %. The most frequently observed complication is encephalitis, followed by myelitis, encephalomyelitis, Guillain-Barr\u00e9 syndrome, acute disseminated encephalomyelitis, optic neuropathy, and neuroretinitis. Less frequently reported complications include seizures, sensorineural hearing loss, stroke, cerebellitis, meningism, cranial nerve palsy, carpal tunnel syndrome, ophthalmoplegia, and disorientation,,Previous studies have documented that children are more susceptible to neurological disease than adultsCoinfection with other arboviruses, such as Zika and dengue viruses, is associated with more severe neurological disease, necessitating intensive care support and prolonged hospitalization. Additionally, cerebrovascular disease is three times more common in patients with dual infections than in those with mono-infectionTreatment of CHIK neurological disease is typically symptomatic. The prognosis is variable, although most patients with neurological disease recover without sequelae. During CHIK infection, multiple organ systems can be simultaneously involved with neurological disease; therefore, a multidisciplinary approach is critical,Cardiovascular manifestations are one of the most common extra-articular features of CHIK infection, affecting up to 54.2% of the infected patients--The protean cardiovascular manifestations of CHIK include pericarditis, cardiac tamponade, hypotension, shock, Raynaud\u2019s phenomenon, arrhythmias, cardiac murmurs, myocarditis, dilated cardiomyopathy, congestive insufficiency, and heart failure. Approximately 22% of fatal CHIK cases are caused by cardiovascular diseases, with heart failure being the most common. The most commonly reported abnormality in the electrocardiograms of patients with CHIK is the inversion of T waves in leads DII, III, aVF, V5-V6, and elevation of the ST segment,,,As with other arboviral infections, the optimal management of cardiovascular complications in patients with CHIK remains uncertain. The sporadic nature of cardiac CHIK cases limits these studies. Some unanswered questions include the lack of data on whether different CHIK viral strains affect cardiac susceptibility. From a treatment perspective, similar to other forms of viral myocarditis, the role of corticosteroids remains uncertain. The most crucial steps in management involve early monitoring and rapid intervention to prevent sequelae-CHIKV infection causes milder laboratory abnormalities compared to infection. While mild thrombocytopenia may occur, severe cases are rare, with platelet levels usually above 100,000/\u00b5l. Lymphopenia is the most common abnormality, observed in approximately 80% of patients. Hemorrhagic complications are rare in CHIKV infectionRenal complications have been reported in 21%-45% of CHIK cases and are more common among severely ill patients. Most of these patients have renal comorbidities, particularly chronic kidney disease, which contributes to high mortality rate,Acute interstitial nephritis and tubular injury were the most common renal findings,,Kidney transplant recipients with CHIKV infection have a similar prognosis and clinical course as the general population. Although transitory graft dysfunction has been previously reported, it is usually mild and reversibleThe treatment of renal complications is symptomatic. In more severe cases, intensive care and monitoring of renal function may be imperativeThe most prevalent skin finding in CHIK infection is morbilliform exanthem, which is usually observed between the third and fifth days of febrile acute illness. It commonly starts in the upper limbs, spares the face, is self-limiting, and associated with mild pruritus. Immune complex deposition in the dermal capillaries is believed to be the pathophysiological mechanism underlying these cutaneous manifestations of CHIK. This type III hypersensitivity reaction may be observed in approximately 40-50% of cases,Soon after the eruptions resolve, post-inflammatory hypermelanosis may occur, which is particularly common in dark-skinned individuals. Case reports have observed this skin condition in the nose, whereas some refer to this finding as a \u201cCHIK sign.\u201d The outer ear and limbs may also have been affected. Hypermelanosis can present as flagellated, freckle-simile, or discrete macules-,Exacerbation of preexisting dermatological conditions has also been reported in patients with CHIK. Erythroderma and psoriasis are the most common skin comorbidities that worsen during early febrile illness. Cheilitis, skin and mouth ulcers, crusted lesions, vesiculobullous lesions (frequently observed in children and neonates), skin peeling, xerosis, papules, erythema nodosum, and vasculitis-like lesions have also been reportedNail disorders in CHIK occur as red or black lunulae, periungual ulcers, and/or subungual hemorrhage. Periungual desquamation, and diffuse and longitudinal melanonychia have also described-Treatment of CHIK skin manifestations commonly relies on antibiotics  and corticosteroids. Although most skin lesions resolve spontaneously, some heal with significant scarring. Drug choices are inconsistent between studies, and there is limited evidence on the efficacy of these strategies, given the self-limiting character of skin findings,,Ocular manifestations of CHIK infection include nonspecific conjunctival conditions, retinitis, and occasional exudative retinal detachment,,During the acute phase of the disease, retro-orbital pain and photophobia without visual changes are the most prevalent ocular symptoms. Throughout the illness, patients may report decreased visual acuity, which is a symptom that causes most patients to seek ophthalmological evaluation. Unilateral or bilateral uveitis, ocular hypertension, retinal edema, and retinal hemorrhage may cause decreased visual acuity, and more rarely, inflammatory foveal lesions and macular ischemiaThe treatment for uveitis generally involves the use of corticosteroids. A favorable response may require 10-12 weeks. The best response is obtained when the diagnosis is promptly made and treatment is immediately initiated,Gastrointestinal symptoms, especially abdominal pain and nausea, have been reported in up to 66% of patientsConclusive information on gastrointestinal symptoms in CHIK remains unattainable because of the low number of publications on the subject and differences in the populations studied and the prevalent strains. There is no consensus regarding the treatment of the gastrointestinal manifestations of CHIK. -In some patients with neurological involvement, there may be psychiatric symptoms such as confusion, delirium, disorientation, and even psychosis.Depression in acute CHIK affects up to half of the patients. Younger patients and those with severe arthritis and gastrointestinal symptoms are more likely to self-report depression.In acute CHIKV infections, elevated levels of cytokines, including IL-6, are associated with stress susceptibility along with social factors that contribute to post-CHIKV depression. Notably, IL-6, IL-1RA, IL-12, TNF-\u03b1, IFN-\u03b3, IL-10, IL-1\u03b2, and IL-8/CXCL8 exhibit increased levels in both acute and chronic CHIKV cases, as well as in depression. This suggests the potential of concurrent immunomodulatory interventions targeting these cytokines in comprehensive clinical assessments to mitigate the impact of CHIKV and depressive disorders..Manic episodes are treated with antipsychotics such as olanzapine,Although rare, respiratory manifestations can occur in CHIK patients. CHIKV can infect the lungs and the CHIKV antigen has been isolated from post-mortem biopsies. An intense type I inflammatory response to the virus can lead to acute respiratory distress syndrome (ARDS)Management of respiratory manifestations is mostly supportive. Noninvasive ventilation may be used successfully in ARDSAlthough CHIK infection is usually self-limiting, extra-articular involvement with atypical symptoms may present diagnostic challenges, delay diagnosis, and negatively affect disease outcomes. According to the affected system, the main extra-articular manifestations include encephalitis, myocarditis, acute interstitial nephritis, maculopapular rash, acute anterior uveitis, abdominal pain, and depression. Co-infections, comorbidities, advanced age, pregnancy, and newborns are significant risk factors for unusual and more severe manifestations. The pathogenesis, clinical features, and management of extra-articular CHIK infections remain unclear. Understanding the pathogenic mechanisms underlying CHIK could also be applicable to other rheumatological and autoimmune diseases, given the role of inflammation and cytokines. An improved understanding of the clinical features of extra-articular manifestations could lead to timely recognition of CHIK, reducing the incidence of its potential complications and long-term sequelae, which represent a high burden to patients. Potential treatments for this neglected tropical disease should be developed and made available in the endemic regions. Such treatments must consider the socioeconomic factors that impact the disease toll. Public health policies in settings where CHIK is prevalent must consider the priorities and values of individuals and their cultural beliefs in order to reduce inequalities, achieve better access to care, and improve the overall quality of life."}
+{"text": "Multifocal bone pain in a pediatric patient prompts a broad differential diagnosis, which should include chronic recurrent multifocal osteomyelitis (CRMO), particularly when the patient has a personal or family history of autoimmune diseases or chronic inflammatory disorders. CRMO is a difficult diagnosis, as several similar disorders must be ruled out first, and it requires extensive verification based on clinical, radiological, and pathological criteria. It often mimics other medical diagnoses, including Langerhans cell histiocytosis and infectious osteomyelitis. Maintaining a high index of suspicion for CRMO is important to minimize unnecessary medical testing, optimize pain control, and preserve physical function. We present the case of a nine-year-old female who presented with multifocal bone pain and was diagnosed with CRMO. Chronic recurrent multifocal osteomyelitis (CRMO) is a rare inflammatory bone disease that primarily occurs in children and adolescents. From 1972 to 2011, more than 200 cases have been reported worldwide . PreviouCRMO remains a difficult diagnosis, for which similar diseases must first be ruled out via clinical, radiological, and pathological criteria, with outlined major and minor criteria . The mosCRMO is a radiographically diverse entity, ranging from lesions characteristic of bone lysis, sclerosis, or bone collapse ,9. SclerTreatment modalities have evolved substantially within the last two decades as more historical data regarding this rare disease has become available. Nonsteroidal anti-inflammatory agents (NSAIDS) remain the most common first-line treatment, but a combination of tumor necrosis factor inhibitors and disease-modifying anti-rheumatic drug therapies has become increasingly popular . There hA previously healthy nine-year-old female with a past medical history significant for celiac disease and intermittent headaches presented to the ED with complaints of fevers, fatigue, and joint pain in her right hip, right knee, right wrist, and left ankle. Her symptoms began two weeks prior with a fever, chills, cough, diarrhea, and sore throat. Since they began immediately after her mother\u2019s COVID infection, PCR testing was performed, which showed that the patient was COVID-negative. Her respiratory and gastrointestinal symptoms resolved within two weeks of their onset, but she continued to have intermittent fevers as high as 38.9 \u00b0C. The pain waxed and waned, causing nighttime awakenings that significantly affected her daily activities. Just prior to the ED presentation, she was prescribed a five-day course of prednisone with the suspicion of reactive arthritis after her recent gastrointestinal illness from her primary physician. Initially, pain and fever improved, only to return upon completion of the steroid course, prompting the ED evaluation. On presentation, her pain was rated as moderate, and though she still remained mobile, she was unable to ambulate normally. Acetaminophen provided only minor relief from her symptoms. There was no erythema overlying the joints and no rash, but there was mild edema and tenderness of the left ankle. The patient and parent denied recent trauma, night sweats, weight loss, emesis, diarrhea, abdominal pain, cough, congestion, rhinorrhea, sore throat, difficulty breathing, easy bruising, bleeding, or petechiae. After three weeks of symptoms, X-rays of her right wrist and both knees revealed multiple lytic lesions Figures -3.Due to persistent fevers and her inability to ambulate as the pain progressed, she was admitted for additional workup and management. The differential diagnosis included systemic juvenile idiopathic arthritis, systemic lupus erythematosus, Ewing sarcoma, osteosarcoma, Langerhans cell histiocytosis (LCH), osteomyelitis, Brodie\u2019s abscess, CRMO, septic arthritis, and post-strep reactive arthritis. Post-strep-reactive arthritis was included due to a positive strep test two to three months prior to presenting to the ED. Diagnostic lab work included a complete blood count, a complete metabolic panel, C-reactive protein levels, an autoimmune profile , mycoplasma titers, prothrombin, a prothrombin time test, an INR, and blood cultures. All of these were unremarkable. Her sedimentation rate was elevated at 34 mm/hour (reference range: 3-13 mm/hour). Immunoglobulin A was elevated at 229 (reference range 47-221 mg/dL), and immunoglobulin E was negative at <60 IU/mL (reference range <60 IU/mL). A PET scan revealed metabolically active lesions in the right proximal tibia, left distal tibia, left distal femur, right distal radius, sacrum (S5), and right acetabulum (Figure Two different bone biopsies showed foamy histiocytes and mixed inflammatory cells. Cultures performed using the biopsied bone were negative. Once tests and cultures were complete, she was diagnosed with CRMO. Her pain was controlled with NSAIDS, acetaminophen, and short-acting oral opioids. The patient was managed by pediatric rheumatology as an outpatient and started on oral steroids and bisphosphonates. The patient\u2019s pain was difficult to control but has since improved with the addition of adalimumab. In addition to medical management, she was referred to physical therapy, which significantly improved her ambulatory function, though at six months post-diagnosis, she had still not returned to her baseline activity level.CRMO is a disease that often mimics other medical conditions, including LCH, osteomyelitis, Ewing\u2019s sarcoma, metastatic neuroblastoma, and hematolymphoid malignancy. In particular, CRMO closely resembles, both clinically and radiologically, infectious osteomyelitis and LCH. It can be a challenge to differentiate CRMO from infectious osteomyelitis based on clinical and laboratory findings, but children with bacterial osteomyelitis will frequently present with local inflammatory signs and possible abscesses . Those dLCH can occur at any age but is most commonly seen between the ages of one and four, with a slight male predominance . LCH hasOnce CRMO is accurately diagnosed, emphasis is placed on pain management and improving the patient\u2019s physical function. Consultation with pediatric rheumatology, physical medicine, and rehabilitation can also help manage these patients. First-line pharmacological therapy for pain control includes NSAIDs, followed by oral corticosteroids. NSAIDS can help with both pain and the prevention of bone damage . Second-CRMO is a rare inflammatory bone condition that must be considered in pediatric patients presenting with multifocal bone pain. Because CRMO is difficult to diagnose, it is imperative that patients with bone pain undergo a comprehensive workup to rule out other causes, such as infection, malignancy, and Langerhans cell histiocytosis. A biopsy may be considered to aid in narrowing the differential. Treatment for CRMO includes pain management, supportive care, and an early referral to appropriate specialists. The appropriate workup and timely diagnosis of patients with CRMO are essential steps in improving the patient\u2019s quality of life and preventing joint destruction and functional loss."}
+{"text": "The survival of a species depends on its ability to reproduce . It has Puberty is the stage when fertility is achieved and maintained throughout all subsequent stages of life. This process is initiated by the pulsatile secretion of the gonadotropin-releasing hormone (GnRH) from the hypothalamus ,5. GnRH Factors such as genetic predispositions, under or overnutrition, and exposure to environmental endocrine disruptors can influence the timing of puberty and affect the integrity of the hypothalamic\u2013pituitary\u2013gonadal axis, which is essential for preserving fertility at all stages of life ,5. PatieAdolescence and young adulthood are critical stages when lifestyle factors such as weight, smoking, alcohol, caffeine consumption, diet, exercise, psychological stress, and environmental and occupational exposures can impact fertility in both sexes ,7,8. For example, obesity and being underweight are associated with gonad dysfunction and infertility, while certain vitamins  and food groups (including high-fat diets) have an important impact on reproductive health by influencing semen quality and ovulation ,11,12,13Additionally, excessive exercise can affect body energy balance and hypothalamic function, negatively impacting the reproductive system ,5. Finally, unhealthy lifestyle and environmental exposures can have transgenerational effects on endocrine disruptors in reproductive tissues, not only through oocytes, but also through sperm , demonstUnderstanding the impacts of environmental, nutritional, and lifestyle factors in regulating the reproductive system is essential for maintaining gonadal function, preserving fertility and protecting overall wellbeing. Preventative strategies that modify lifestyle factors can be useful in enhancing reproductive health and maximizing fertility outcomes, starting from childhood."}
+{"text": "As a bone and cartilage disease, osteoporosis, resulting from an imbalance in remodeling between bone formation and resorption, has become a major global public concern, often resulting in fracture and seriously impacting activities of daily living . EvidencDuan et al., they summarized KTTCM\u2019s ability to regulate estrogen expression, promote osteoblasts, inhibit osteoclasts, and restrain adipogenesis, as well as related molecular mechanisms including but not limited to osteoprotegerin (OPG)/receptor activator of nuclear factor kappa B (RANK)/RANK ligand (RANKL), bone morphogenetic protein (BMP)/suppressor of mothers against decapentaplegic (Smad), mitogen-activated protein kinases (MAPKs), and wingless/integrated (Wnt) signaling pathways. Furthermore, Jiao et al. reviewed the mechanisms by which kidney-tonifying Chinese herbs prevent osteoclastogenesis, emphasizing their immune effect.Based on the TCM theory that \u201ckidney governs bone,\u201d kidneys can be a target for the treatment of bone diseases using \u201ckidney-tonifying Chinese herbs\u201d and \u201ckidney-tonifying TCM (KTTCM).\u201d In a review paper by Wu and Liu summarized what is known about genistein in the treatment of bone and cartilage diseases, including intervertebral discs, osteoporosis, osteoarthritis, and rheumatoid arthritis. The involved molecular pathways were also discussed in each section to provide in-depth insights for future treatment. Ultimately, the authors also discussed clinical perspectives and limitations, such as low water solubility and the poor bioavailability of genistein, which need to be further investigated to improve genistein\u2019s curative effect.Genistein, a polyphenolic isoflavone, is found in varying dietary vegetables, such as soy beans and leguminous plants; it exhibits biological effects, such as anti-cancer, anti-inflammation, anti-oxidation, and bone/cartilage protection. The similarity in structure to estrogen provides genistein with estrogen-like activity in defending against osteoporosis and osteoarthritis. Lin et al. reviewed the effect of natural alkaloids on mesenchymal stem cells, osteoblasts, osteoclasts, and related signaling pathways; their evidence supported the beneficial effects of alkaloids in promoting osteoblast proliferation and inhibiting osteoclast formation. Current efforts indicate that alkaloids could be a novel solution for the treatment of osteoporosis.Natural alkaloids, a class of naturally occurring organic nitrogen-carrying bases, have diverse and crucial physiological effects on humans; this class includes strychnine, morphine, quinine, ephedrine, and nicotine. Additional evidence shows that alkaloids play a role in bone and cartilage diseases. Salvia miltiorrhiza Bge, and Salvia przewalskii Maxim, have been widely used to treat some diseases, such as liver diseases  pathway.Dehydromiltirone (DHT), a diterpenoid quinone originating in TCM, diseases . Using tIn conclusion, TCM and its effective compounds show great promise for drug development. Potentially, natural compounds, such as genistein and DHT, may become alternative candidates for the treatment of bone and cartilage diseases. However, some important Research Topics need to be addressed. For example, the pharmacokinetic profiles of these botanicals still need to be elucidated and clinical trials should be undertaken. In addition, the underlying molecular mechanisms of natural compounds in treating bone and cartilage diseases may be complex due to their multi-target and multi-pathway characteristics. The interaction of natural compounds with the gut microbiome may also complicate pharmacological activity."}
+{"text": "Fungi play many roles in different ecosystems. The precise identification of fungi is important in different aspects. Historically, they were identified based on morphological characteristics, but technological advancements such as polymerase chain reaction (PCR) and DNA sequencing now enable more accurate identification and taxonomy, and higher-level classifications. However, some species, referred to as \u201cdark taxa\u201d, lack distinct physical features that makes their identification challenging. High-throughput sequencing and metagenomics of environmental samples provide a solution to identifying new lineages of fungi. This paper discusses different approaches to taxonomy, including PCR amplification and sequencing of rDNA, multi-loci phylogenetic analyses, and the importance of various omics  techniques for understanding fungal applications. The use of proteomics, transcriptomics, metatranscriptomics, metabolomics, and interactomics provides a comprehensive understanding of fungi. These advanced technologies are critical for expanding the knowledge of the Kingdom of Fungi, including its impact on food safety and security, edible mushrooms foodomics, fungal secondary metabolites, mycotoxin-producing fungi, and biomedical and therapeutic applications, including antifungal drugs and drug resistance, and fungal omics data for novel drug development. The paper also highlights the importance of exploring fungi from extreme environments and understudied areas to identify novel lineages in the fungal dark taxa. Fungi comprise diverse taxa that are abundant in various environments. They have crucial ecological roles as decomposers, mutualists, and disease-causing agents ,2,3. TaxAspergillus and Penicillium. Moreover, many species lack visible distinguishing physical characteristics such as fruiting bodies  or conidiophores 51], thist genera ,51.Unculturable taxa represent a significant portion of the Kingdom Fungi, potentially representing missing lineages that can be analyzed from ecological samples using HTS. In addition, HTS technologies are proving valuable in analyzing DNA from older herbarium specimens that lack DNA sequences from the PCR/Sanger sequencing approach .Fungi are used as cell factories to produce antibiotics, enzymes, and other compounds for diverse industrial uses ,54. The Candida albicans biofilm formation and drug resistance   ,178,179.Plants and microorganisms are the main sources of natural metabolites. The cultivation of fungi is not affected by seasonal or geographical variations like plant crops, and fungi can be genetically engineered for increased metabolite production. The advantages of fungi over plants also include high growth rates, small space requirements, and the ability to be cultivated in inexpensive media with high biomass concentrations . DespiteA. niger and A. oryzae, proteases from A. oryzae, pectic enzymes from various Aspergillus species, galactosidase from Mortierella vinaceae, lactase from A. oryzae and A. niger, and invertase from Saccharomyces species [Aspergillus oryzae is used for fermenting traditional Japanese foods like sake, shoyu, miso, and vinegar. Fungi also produce important vitamins used in the food industry, such as vitamin B2 (riboflavin), which is synthesized by Candida guilliermondii, Debaryomyces subglobosus, and Ashbya gossypii [Mortierella alpiney has the capability to synthesize longer polyunsaturated fatty acids [Lentinula edodes, Ganoderma lucidum, Tremella mesnterica, Hericium erinaceus, Sclerotinia sclerotiorum, Cordyceps sinensis, and Trametes versicolor are responsible for their popularity [Fusarium venenatum has been used as a food-grade protein source with a texture similar to meat that can be frozen, canned, and dried. Mycoproteins are versatile and can be combined with different food items such as biscuits, soups, and fortified drinks. Analyzing the genetic makeup and nutritional value of these alternative food sources can be achieved through a combination of genomics, proteomics, and metabolomics [It is essential to explore alternative food sources, including alternative protein sources, as a means of reducing food security risks. Fungal enzymes have a crucial role in the food industry, as demonstrated by the use of amylases from  species ,183,184.gossypii . Mortierty acids . The nutpularity . Since 1bolomics .Pseudogymnoascus destructans, which can cause catastrophic epidemics in bats and a concomitant increase in crop-destroying insects in fields [Aspergillus and Penicillium are common mycotoxin-producing fungi that can contaminate food products [Fungi are a major cause of damage to cereal production worldwide, affecting major crops such as wheat, maize, and rice. Therefore, the detection of fungi and their metabolites is important in the food industry to ensure food security ,189. Funn fields . Mycotoxn fields . Aspergiproducts . Mycotoxproducts ,158,190.Alternaria, Fusarium, and Claviceps, which have the highest toxigenic potential [Aspergillus responsible for Aculeacin A, B, C, D, E, F, and G; Aflatoxin B; Aflatrem; and Ochratoxin; (b) Penicillium responsible for Citrinin, Amauromine, Agroclavine, and Patulin; (c) Claviceps responsible for Aflatrem, Chanoclavine I, Ergochromes, Ergobutine, Ergobutyrine, and Ergobine; and (d) Fusarium responsible for Deoxynivalenol, Fumonisins, Trichothecenes, and Zearalenone [Rhizoctonia solani, Botrytis cinerea, Ustilago maydis, Sclerotinia sclerotiorum, Magnaporthe oryzae, and Fusarium graminearum have revealed mechanisms of fungal infection and plant defense [The metabolomic approach has been successful in detecting various types of mycotoxins produced by different fungal species, including otential . These motential ,158,191.ralenone . Metabol defense . The int defense ,193. Bes defense . In addi defense ,195, not defense .Aspergillus flavus produces aflatoxin, a major contaminant of several crops including groundnut and maize. Transcriptomic and proteomics approaches have been used to identify genes and proteins associated with resistance to aflatoxin contamination in groundnut and maize, leading to understanding the host defense mechanism that includes pathogenesis and antioxidant-related genes involved in the suppression of aflatoxin biosynthesis or its detoxification [Vitis vinifera) to resist a fungal pathogen (Septoria tritici) [Fungal omics approaches such as transcriptomics and proteomics are important for the development of biomarkers and biosensors of mycotoxin-producing fungi . Aspergification . The stutritici) .Magnaporthe oryzae and the powdery mildew pathogen Podosphaera xanthii [The knowledge of candidate biomarkers of resistance to fungal pathogens obtained from omics approaches has spurred efforts to create pathogen-resistant transgenic crop varieties with modifications of resistance-associated genes. For example, transgenic finger millet crops have been developed with enhanced gene expression to combat fungal blast disease and improve yield . The gen xanthii .Lacticaseibacillus rhamnosus and L. paracasei can delay spoilage and increase the shelf life of dairy products. Metabolomics can identify the key compounds that are essential for antifungal activity. This approach has been successfully applied against Penicillium commune and Mucor racemosus, resulting in the development of new protective strains [Geotrichum candidum and Penicillium camemberti in the cheese ripening process [Among food industries, the dairy industry is the most impacted by fungi. Spoilage of dairy products by molds poses a major food safety challenge. To control molds, antifungal lactobacilli species like  strains . Additio process . The use process ,195.Penicillium spp., Botrytis cinerea, Alternaria alternata, Monilinia spp., Trichothecium roseum, Fusarium spp., and Colletotrichum spp. are responsible for the majority of postharvest losses [Postharvest losses of food affect quality, nutrition, seed viability, and market value . The glot losses .Fusarium proliferatum in the infection process of banana peel were identified by comparative proteomics [Monilinia fructicola were identified by sequence analyses and gene expression studies [B. cinerea mutants identified genes encoding the cell-wall-degrading enzymes cellobiohydrolase and xylanase to be essential for virulence [Understanding the infection process mechanism of fungal pathogens is crucial for mitigation of post-harvest diseases. Phytotoxic metabolites, secreted proteins, and small RNAs of fungal pathogens contribute to the infection process. At the early stage of infection, necrotrophic pathogenic fungi kill host cells and develop necrotic areas for successful colonization . Proteinoteomics , and cel studies . Furtherirulence .B. cinerea were observed by NoxR gene knockout [B. cinerea produces sRNAs that hijack the host RNA interference machinery and selectively silence host plant immune genes [Pdos2, PdSlt2, and PdMpkB in the signal transduction pathway were shown to regulate the pathogenicity of Penicillium digitatum [Fusarium graminearum [When a pathogenic fungus attacks a plant, reactive oxygen species (ROS) accumulate around the infection site as part of the plant defense mechanism . ROS derknockout . In addiknockout . The patne genes . In addiigitatum , and traminearum .Despite advances in diagnostic and treatment methods, the incidence of invasive fungal infections in humans is rising rapidly. Since 2020, disruptions in public health measures owing to the COVID-19 pandemic have led to a rise in invasive fungal infections, with Aspergillosis, mucormycosis, and candidaemia being common fungal infections with fatal consequences. In response to this threat, the World Health Organization (WHO) released the fungal pathogens priority list (FPPL) in October 2022. This list includes 19 fungi that pose the highest health risk and is the first global effort to prioritize fungal diseases based on research and development (R&D) needs and public health implications .Aspergillus fumigatus, Cryptococcus neoformans, Candida auris, and Candida albicans. The high-priority group includes Nakaseomyces glabrata (=Candida glabrata), Histoplasma spp., eumycetoma causative agents, Mucorales, Fusarium spp., Candida tropicalis, and C. parapsilosis. The medium-priority group includes Scedosporium spp., Lomentospora prolificans, Coccidioides spp., Pichia kudriavzeveii (=Candida krusei), Cryptococcus gattii, Talaromyces marneffei, Pneumocystis jirovecii, and Paracoccidioides spp. The aim of the WHO FPPL is to prioritize research and policy measures to improve global responses to fungal infections and antifungal resistance [The WHO FPPL has categorized 19 fungal pathogens into three priority groups based on their public health implications and R&D needs . The prisistance . Currentsistance ,219,220.Candida and Cryptococcus species [Due to the conservation of essential eukaryotic genes between fungi and humans, there are a limited number of targets for developing safe and effective antifungal drugs ,221. Mos species . Azoles  species .Streptomyces comprises polyene-producing taxa, which have broad-spectrum activity against various fungal species. These drugs work by binding to ergosterol in the fungal cell membrane, leading to the development of transmembrane holes, depolarization of the membrane, and ultimately, cell death. Echinocandins are cyclic lipopeptides with a semisynthetic acyl lipid side chain. Caspofungin, micafungin, and anidulafungin are examples of echinocandins that inhibit -D-glucan synthase, a crucial component of fungal cell walls that is not present in humans. The lack of -D-glucan production in fungi leads to osmotic instability and eventual cell death [The ll death ,222,223.The surge in the number of fungal infections has led to a rise in research for new antifungal treatments. Although current commercially available antifungal drugs primarily aim at the cell wall and plasma membrane, alternative targets have been identified. Recent studies have concentrated on identifying new drugs targeting fungal virulence factors .Candida are associated with reduced ergosterol levels in the fungal membrane and resistance to azoles and polyenes [Antifungal drug resistance has become a concern due to the limited number of available options to treat the increasing number of opportunistic fungal infections. Azole resistance is primarily attributed to overexpression of the ERG11 drug target gene  and multpolyenes ,232. In polyenes ,234.In the past two decades, mycology research has been transformed by the use of mass-spectrometry-based proteomics, which allows for the measurement of protein synthesis, posttranslational modifications, alternative protein isoforms, and interaction networks. A number of studies on fungal omics data are available, and we recommend that readers consult them for a comprehensive understanding of the utility of fungal omics data ,237,238.Multidrug resistance is often linked to the increased expression of pleiotropic drug resistance (PDR) efflux pumps belonging to the ABC transporter superfamily . PDRs haWhen pathogens infect hosts, they face various stresses such as heat shock and oxidative stress, and their survival relies on their ability to respond to these external conditions at the molecular level. The stress response in the context of host\u2013pathogen interactions has recently been identified as an important and innovative mechanism for developing antimicrobial agents . HoweverEnterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) responsible for the majority of nosocomial infections [The Hsp100 protein family includes promising targets for developing novel antimicrobial inhibitors. Hsp100 chaperones, which rely on ATP, are essential for the survival of lower eukaryotes, plants, and bacteria (where they are referred to as ClpB) under stress conditions. In microbial cells that experience stress, Hsp100s play a role in exclusively disentangling misfolded proteins. Unlike other heat-shock protein families, Hsp100s are not present in animals or humans ,244,245.fections . In yeasfections ,247.Recently, Zokiewski and colleagues have proposed that inhibitors of AAA + ATPases, distantly related to Hsp100, may act as prototype scaffolds for developing Hsp100-selective ligands . AlthougThis article highlights the importance of omics technologies in identifying the impact of fungi on different ecosystems and their multifaceted roles, which can be beneficial or detrimental. The limitations of the traditional method of identifying fungal species based on morphological traits are discussed, and advanced technologies such as PCR and DNA sequencing are presented as more accurate classification and identification tools. HTS and metagenomics of environmental samples are also highlighted as solutions to identify novel lineages in the Kingdom of Fungi. The analysis of protein-coding genes and whole genomes (phylogenomics) is revolutionizing our understanding of phylogenetic relationships and fungal taxonomy. The applications of metabolomics proteomics, transcriptomics, and metatranscriptomics are important for a comprehensive understanding of fungal metabolism. Advanced omics technologies are crucial in identifying and classifying diverse fungal species and broadening the understanding of fungi, which has significant implications for food safety and security, edible mushrooms, fungal secondary metabolites, and biomedical and therapeutic applications. Despite their benefits, individual omics technologies have certain limitations. For example, genomics can only provide information about metabolic potential, whereas transcriptomics and proteomics are often characterized by poor reproducibility ,250,251.The future prospects of fungal omics are promising, with advancements in sequencing technologies, the integration of multiomics data, computational analysis, and bioinformatics tools. These developments will enable comprehensive exploration of fungal genomes and functional elements, leading to the discovery of novel species, pathways, and bioactive compounds. Fungal omics will continue to contribute to bioremediation, industrial biotechnology, agriculture, and medicine, while also providing insights into fungal\u2013host interactions and personalized approaches for disease management. Continued collaboration, technological advancements, and interdisciplinary research will drive further advancements in fungal omics, paving the way for new discoveries and applications."}
+{"text": "Heart failure and diabetes mellitus are 2 common and closely intertwined chronic conditions that often coexist in individuals. The relationship between heart failure and diabetes is bidirectional, meaning that each condition can influence the development and progression of the other. Understanding this complex interplay is crucial for optimizing the management and outcomes of patients with these comorbidities. This review comprehensively analyzed the literature to examine the bidirectional relationship between heart failure and diabetes. We searched various electronic databases and included studies that explored the pathophysiological mechanisms, epidemiology, clinical implications, and therapeutic considerations associated with this relationship. The bidirectional relationship between heart failure and diabetes is multifactorial and involves several interconnected mechanisms. Diabetes is a recognized risk factor for heart failure, increasing the risk of its development and accelerating its progression. On the other hand, heart failure can contribute to the development of insulin resistance and worsen glycemic control in patients with diabetes. Shared risk factors, such as obesity, hypertension, and dyslipidemia, contribute to development of both conditions. Additionally, hyperglycemia, insulin resistance, chronic inflammation, oxidative stress, and mitochondrial dysfunction play significant roles in the pathogenesis of heart failure in individuals with diabetes. The bidirectional relationship between heart failure and diabetes has important clinical implications. Patients with heart failure and diabetes have worse outcomes, including higher hospitalization rates, morbidity, and mortality, than those without diabetes. Optimal management strategies should target both conditions simultaneously, focusing on lifestyle modifications, pharmacotherapy, glycemic control, and cardiovascular risk reduction. What makes the relationship between HF and diabetes particularly noteworthy is its bidirectional nature, wherein each condition influences the development and progression of the other. Understanding the intricate interplay between HF and diabetes is crucial for optimizing patient management and improving outcomes in individuals with these comorbidities.Heart failure (HF) and diabetes mellitus are prevalent chronic conditions with substantial global burdens. Both states significantly impact morbidity, mortality, and healthcare costs. It is well-established that diabetes is a significant risk factor for the development of cardiovascular diseases, including HF. Several population-based studies have consistently demonstrated that diabetes increases the risk of HF by 2- to 5-fold.,4 The underlying mechanisms linking diabetes and HF involve complex pathophysiological processes, including insulin resistance, endothelial dysfunction, inflammation, and oxidative stress.Diabetes mellitus, characterized by chronic hyperglycemia, affects approximately 9.3% of the global population.On the other hand, HF can also contribute to the development and worsening of glucose metabolism abnormalities, leading to the onset of diabetes or the deterioration of glycemic control in individuals with preexisting diabetes. This bidirectional relationship is influenced by shared risk factors such as obesity, hypertension, and dyslipidemia, as well as systemic inflammation and neurohormonal activation.Given the bidirectional nature of the relationship between HF and diabetes, it becomes essential to recognize and address both conditions simultaneously to achieve optimal outcomes. Integrated care models involving multidisciplinary teams, including cardiologists, endocrinologists, and primary care physicians, are essential for comprehensive management strategies for individuals with HF and diabetes.This review aims to analyze the bidirectional relationship between HF and diabetes comprehensively. Examining the existing literature will explore the pathophysiological mechanisms, epidemiology, clinical implications, and therapeutic considerations associated with this complex relationship.To examine the pathophysiological mechanisms underlying the bidirectional relationship between HF and diabetes mellitus.To assess the epidemiological characteristics and prevalence of the coexistence of HF and diabetes.To explore the clinical implications of the bidirectional relationship, including the impact on morbidity, mortality, and healthcare utilization.Identify the therapeutic considerations and management strategies for individuals with HF and diabetes.To highlight the importance of integrated care models involving multidisciplinary teams in optimizing outcomes for patients with HF and diabetes.To identify gaps in current knowledge and areas for future research regarding the bidirectional relationship between HF and diabetes.This review comprehensively analyzed the literature to examine the bidirectional relationship between HF and diabetes mellitus. The methodology involved a systematic search of electronic databases, including PubMed, MEDLINE, and Google Scholar, using relevant keywords such as \u201cHF,\u201d \u201cdiabetes mellitus,\u201d \u201cbidirectional relationship,\u201d and variations thereof. The search covered a time range from the databases\u2019 inception to the knowledge cutoff of September 2021.The inclusion criteria for the selection of studies included the following:Studies published in peer-reviewed journals.Studies that investigated the bidirectional relationship between HF and diabetes.Studies that examined the pathophysiological mechanisms, epidemiology, clinical implications, and therapeutic considerations associated with the relationship.Studies published in English.The initial search yielded many articles, and duplicates were removed. The remaining articles were screened based on their titles and abstracts for relevance to the research topic. Full-text articles were then retrieved for further evaluation.The selected articles were critically reviewed and synthesized to extract relevant information about the study objectives. Data on pathophysiological mechanisms, epidemiology, clinical implications, and therapeutic considerations were extracted and analyzed. Key findings and trends were identified and organized under appropriate subheadings.The study limitations include potential publication bias and the exclusion of non-English articles, which may have resulted in the omission of relevant studies. However, efforts were made to include a wide range of studies to provide a comprehensive analysis of the bidirectional relationship between HF and diabetes.The findings and discussions presented in this review are based on the analysis and synthesis of the selected literature. The conclusions drawn are derived from the collective evidence available in the literature. They should be interpreted in the context of the study limitations and existing knowledge in the field.The bidirectional relationship between HF and diabetes mellitus has significant implications for the epidemiology of both conditions. The coexistence of HF and diabetes is common and has been extensively studied. Moreover, diabetes increases the risk of incident HF by 2- to 5-fold.,6 The risk appears higher in individuals with type 2 diabetes than those with type 1 diabetes. The relationship between diabetes and HF is observed across different populations and ethnicities.Epidemiological studies consistently demonstrate that diabetes is a significant risk factor for the development of HF. The prevalence of HF is significantly higher in individuals with diabetes compared to those without diabetes. It has been estimated that approximately 30% to 40% of patients with HF have concurrent diabetes. The presence of HF increases the risk of developing diabetes, and this risk is further amplified in patients with reduced ejection fraction and advanced HF. The mechanisms underlying the development of diabetes in HF patients involve factors such as insulin resistance, impaired glucose metabolism, and neurohormonal dysregulation.Conversely, HF can also contribute to the development and worsening of diabetes. Studies have shown that the prevalence of diabetes is higher among patients with HF compared to the general population. These risk factors contribute to the development and progression of HF and diabetes, establishing a bidirectional relationship between the 2.Shared risk factors play a crucial role in the epidemiology of HF and diabetes. Obesity, hypertension, dyslipidemia, and a sedentary lifestyle are common risk factors for both conditions.The epidemiology of HF and diabetes has important implications for healthcare utilization and outcomes. The coexistence of HF and diabetes is associated with worse results, including increased hospitalization rates, morbidity, and mortality. Patients with HF and diabetes have higher healthcare costs and require more intensive management strategies than those without diabetes.In conclusion, the bidirectional relationship between HF and diabetes significantly impacts their epidemiology. Diabetes is a significant risk factor for the development of HF, while HF increases the risk of developing and worsening diabetes. Shared risk factors contribute to the coexistence of these conditions. Understanding the epidemiological aspects of HF and diabetes is crucial for effective management and prevention strategies.The bidirectional relationship between HF and diabetes mellitus is complex and involves an intricate interplay between the molecular, cellular, and systemic conditions. Several pathophysiological mechanisms contribute to the development and progression of HF and diabetes, and understanding these mechanisms is crucial for comprehending their bidirectional association. The pathophysiology of the HF-diabetes relationship can be described as follows:Insulin resistance, a hallmark of type 2 diabetes, is a central component of the pathophysiology linking HF and diabetes. In insulin resistance, tissues such as skeletal muscle, adipose tissue, and the liver exhibit reduced responsiveness to insulin, leading to impaired glucose uptake and utilization. Hyperglycemia ensues due to reduced glucose uptake in peripheral tissues and increased hepatic glucose production. Insulin resistance is common in both conditions and is influenced by shared risk factors, including obesity, sedentary lifestyle, and systemic inflammation.HF and diabetes are characterized by dysregulation of neurohormonal pathways, particularly the sympathetic nervous system and the renin-angiotensin-aldosterone system. In HF, reduced cardiac output and impaired tissue perfusion trigger compensatory mechanisms, leading to sympathetic activation and increased catecholamine release. Chronic sympathetic stimulation contributes to insulin resistance and hyperglycemia in diabetes. Similarly, in diabetes, hyperglycemia and insulin resistance may stimulate sympathetic activity, exacerbating cardiovascular dysfunction and contributing to the development of HF.,18Both HF and diabetes are associated with increased oxidative stress and systemic inflammation. Chronic inflammation and oxidative stress play a critical role in the pathogenesis of insulin resistance, impaired endothelial function, and vascular damage. In HF, oxidative stress contributes to myocardial dysfunction, fibrosis, and adverse remodeling, while in diabetes, it promotes endothelial dysfunction, atherosclerosis, and microvascular complications. Shared inflammatory pathways may contribute to the cross-talk between HF and diabetes.Endothelial dysfunction, characterized by impaired nitric oxide bioavailability and increased endothelin-1 production, is a crucial factor in the pathogenesis of both HF and diabetes. Endothelial dysfunction contributes to vascular stiffness, impaired vasodilation, and microvascular abnormalities, leading to systemic and coronary microcirculation impairments. In HF, endothelial dysfunction may contribute to impaired cardiac contractility and coronary perfusion, while in diabetes, it contributes to atherosclerosis and diabetic cardiomyopathy. These lipid-related mechanisms may contribute to the development of diabetic cardiomyopathy and the progression of HF.In diabetes, excessive circulating free fatty acids and triglycerides contribute to myocardial lipotoxicity and steatosis, impairing myocardial energetics and contractile dysfunction. Myocardial steatosis may promote cardiomyocyte apoptosis and fibrosis. In HF, elevated free fatty acids exacerbate myocardial lipotoxicity and oxidative stress, leading to further myocardial dysfunction and remodeling.Diabetic cardiomyopathy represents a unique form characterized by myocardial dysfunction in the absence of coronary artery disease or hypertension. The underlying pathophysiology involves a combination of myocardial fibrosis, impaired calcium handling, altered energetics, and inflammatory processes. Diabetic cardiomyopathy may predispose individuals to the development of HF.,18Microvascular dysfunction is a shared pathophysiological mechanism in both HF and diabetes. In diabetes, impaired microvascular circulation contributes to diabetic nephropathy, retinopathy, and neuropathy. Similarly, microvascular dysfunction in HF may lead to impaired organ perfusion, renal dysfunction, and tissue hypoxia.HF and diabetes share several risk factors, such as obesity, hypertension, dyslipidemia, and a sedentary lifestyle. These risk factors contribute to insulin resistance, endothelial dysfunction, inflammation, and oxidative stress, linking the pathophysiological processes of both conditions.,16\u201318The bidirectional relationship between HF and diabetes involves a complex interplay of shared risk factors, pathophysiological mechanisms, and molecular processes. The pathophysiology of this relationship highlights the importance of early detection, integrated management strategies, and targeted therapeutic approaches to address the comorbidities and improve outcomes in individuals affected by HF and diabetes.Diagnosing and managing the bidirectional relationship between HF and diabetes mellitus require a comprehensive evaluation, including laboratory investigations. Several laboratory abnormalities are associated with both conditions and are crucial in their diagnosis and monitoring. In patients with HF, diabetes, or both conditions, monitoring Glycosylated hemoglobin levels can help assess glycemic control and guide treatment strategies to improve outcomes.Diabetes is characterized by hyperglycemia, and the measurement of glycemic control is essential in diagnosing and managing the condition. Glycosylated hemoglobin levels indicate long-term glucose control, reflecting the average blood glucose levels over the past few months.In HF, cardiac biomarkers such as B-type natriuretic peptide and N-terminal pro-B-type natriuretic peptide are essential diagnostic tools. These biomarkers are elevated in response to cardiac stress and correlate with the severity of HF. In patients with diabetes and HF, assessing cardiac biomarkers can aid in diagnosing HF, monitoring disease progression, and guiding treatment decisions.Dyslipidemia is a common risk factor for HF and diabetes. Measuring the lipid profile, including total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides, is crucial in identifying lipid abnormalities and addressing cardiovascular risk factors in patients with both conditions.Both HF and diabetes can lead to kidney dysfunction. Monitoring kidney function through blood tests, such as serum creatinine and estimated glomerular filtration rate, is essential to assess renal health and identify any deterioration in kidney function, which may impact treatment decisions and outcomes.Electrolyte imbalances, particularly hypokalemia, and hyponatremia, are common in HF and may also occur in some diabetic patients. Regularly monitoring electrolyte levels is necessary to guide treatment and prevent complications related to imbalances.Chronic inflammation plays a role in the pathophysiology of both HF and diabetes. Measurement of inflammatory markers, such as C-reactive protein and pro-inflammatory cytokines , can provide insights into the inflammatory state and guide treatment strategies targeting inflammation.Echocardiography is a valuable imaging tool to assess cardiac structure and function in HF and diabetes patients. It provides information on left ventricular function, ejection fraction, and any structural abnormalities, aiding in the diagnosis and management of HF and assessing its impact on patients with diabetes.Diagnosing the bidirectional relationship between HF and diabetes requires a comprehensive evaluation integrating clinical assessment, laboratory abnormalities, and imaging findings. A multidisciplinary approach involving cardiologists, endocrinologists, and other specialists is crucial for accurate diagnosis, appropriate management, and individualized treatment plans.Managing the bidirectional relationship between HF and diabetes mellitus requires a comprehensive and multidisciplinary approach. The primary goals of management include controlling blood glucose levels, optimizing cardiac function, preventing complications, and improving the overall quality of life. Table  The New York Heart Association (NYHA) functional classification is the most commonly used classification system, categorizing HF into 4 classes. Although the NYHA classification may not directly relate to the bidirectional relationship between HF and diabetes, it plays a crucial role in the comprehensive evaluation and management of HF patients, including those with diabetes. The management approach may vary depending on the class of HF. Here is an overview of the NYHA classification for managing HF:The classification for managing HF is typically based on the severity of symptoms and the degree of functional impairment. The management goal for Class I HF is to prevent disease progression and optimize cardiovascular health through lifestyle modifications, risk factor management, and appropriate monitoring.Patients with Class I HF have no limitations or symptoms of HF during ordinary physical activity. They do not experience shortness of breath, fatigue, or palpitations unless they exercise strenuously. The management goal for Class II HF is to relieve symptoms, improve exercise tolerance, and prevent hospitalization. It typically involves lifestyle modifications, medication therapy , and patient education on self-care management.Patients with Class II HF have mild limitations and symptoms of HF during ordinary physical activity. They may experience fatigue, shortness of breath, or palpitations with moderate exertion. The management goal for Class III HF is to stabilize symptoms, improve quality of life, and reduce the risk of hospitalization. Treatment strategies often include lifestyle modifications, optimized medication therapy, cardiac rehabilitation, and close monitoring.Patients with Class III HF have marked limitations and symptoms of HF during less-than-ordinary physical activity. They may experience fatigue, shortness of breath, or palpitations with minimal exertion. The management goal for Class IV HF is to alleviate symptoms, improve comfort, and prevent further deterioration. Treatment approaches may include advanced therapies such as heart transplantation, mechanical circulatory support, palliative care, and symptom management.Patients with Class IV HF have severe limitations and symptoms of HF at rest or with any physical activity. They may experience severe fatigue, shortness of breath, or palpitations even at rest.It important to note that the management of HF is individualized based on the patient specific clinical profile, comorbidities, and response to treatment. Regular follow-up visits, monitoring of symptoms and disease markers, and adjustments in management plans are necessary to optimize outcomes and improve the patient overall well-being. Here are some key points regarding the prognosis:The prognosis of patients with the bidirectional relationship between HF and diabetes mellitus can be influenced by various factors, including the severity of HF, the degree of glycemic control, comorbidities, and adherence to treatment regimens. Combining these conditions leads to a higher cardiovascular disease burden and worse outcomes than each condition alone.The presence of both HF and diabetes significantly increases the risk of cardiovascular events, such as myocardial infarction, stroke, and cardiovascular mortality.Poorly controlled diabetes can contribute to the development and progression of HF by causing structural and functional changes in the heart. This can lead to reduced cardiac function, increased risk of HF exacerbations, and poorer prognosis.,36HF and diabetes are associated with an increased risk of complications. Patients with this bidirectional relationship may be more prone to microvascular complications  and macrovascular complications , which can further impact prognosis.Comorbidities, such as hypertension, obesity, and chronic kidney disease, can complicate the management of HF and diabetes and contribute to a worse prognosis. Close monitoring and management of these comorbidities are crucial for improving outcomes. Similarly, achieving and maintaining reasonable glycemic control through lifestyle modifications and appropriate use of antihyperglycemic medications can help mitigate complications and improve outcomes.The prognosis can be influenced by the response to treatment. Optimal management of HF with guideline-directed medical therapy, including medications targeting neurohormonal pathways, device therapy , and lifestyle modifications, can improve symptoms, reduce hospitalizations, and prolong survival.Adherence to treatment regimens, including medication adherence, dietary modifications, regular physical activity, and self-monitoring of blood glucose levels, plays a crucial role in determining the prognosis. Patient education, support, and involvement in shared decision-making are essential to promote adherence and improve outcomes.It is important to note that prognosis can vary widely among individuals, and individualized assessment and management are necessary. Regular follow-up, monitoring of symptoms and disease markers, and collaboration between healthcare providers and patients are vital for optimizing prognosis in this population.The bidirectional relationship between HF and diabetes mellitus can increase the risk of complications. These complications can significantly impact the quality of life, increase healthcare utilization, and worsen outcomes. Here are some critical complications associated with this relationship:Myocardial infarction: Patients with HF and diabetes have a higher risk of experiencing a heart attack due to the combined effects of underlying coronary artery disease, atherosclerosis, and impaired cardiac function.Stroke: The presence of diabetes and HF increases the risk of ischemic and hemorrhagic strokes, often attributed to the vascular complications associated with diabetes and the potential for embolic events in HF patients with atrial fibrillation.Peripheral artery disease: Diabetes and HF can contribute to the development of peripheral artery disease, characterized by reduced blood flow to the extremities, resulting in symptoms such as leg pain, non-healing wounds, and increased risk of limb amputation.Diabetic nephropathy: Diabetes is a leading cause of chronic kidney disease, and the combination of diabetes and HF further increases the risk of developing diabetic nephropathy, leading to progressive loss of renal function.Fluid and electrolyte imbalance: HF can cause fluid retention, leading to volume overload and edema, which can further strain the kidneys and impair renal function.Diabetic ketoacidosis: In individuals with uncontrolled diabetes, the development of HF can complicate glycemic control and increase the risk of diabetic ketoacidosis, a life-threatening metabolic emergency characterized by elevated ketone levels and acidosis.Hypoglycemia: Some antihyperglycemic medications used in managing diabetes can increase the risk of hypoglycemia, which can be particularly problematic in patients with HF due to the impact on cardiac function and symptoms.Pulmonary edema: HF can lead to fluid accumulation in the lungs, resulting in pulmonary edema and respiratory distress. This can be further exacerbated by comorbidities such as chronic obstructive pulmonary disease or sleep apnea.Symptom burden: The combination of HF and diabetes can result in a significant symptom burden, including fatigue, dyspnea, exercise intolerance, polyuria, and polydipsia, impacting daily activities and quality of life.Depression and anxiety: The chronic nature of HF and diabetes, along with the associated complications and lifestyle modifications, can contribute to depression and anxiety disorders, further affecting overall well-being.Early recognition and proactive management of these complications are essential to prevent disease progression, improve outcomes, and enhance the overall quality of life for individuals with the bidirectional relationship between HF and diabetes.The bidirectional relationship between HF and diabetes mellitus poses significant challenges in clinical management. The coexistence of these 2 conditions amplifies the risk of complications, worsens prognosis, and increases healthcare utilization. Understanding this relationship pathophysiological mechanisms, shared risk factors, and clinical implications is crucial for effective management.Evidence-based management strategies for HF and diabetes involve a multidisciplinary approach that includes lifestyle modifications, pharmacological interventions, and targeted monitoring. Optimization of glycemic control, blood pressure, and lipid levels, along with guideline-directed medical therapies for HF, plays a pivotal role in improving outcomes.Emerging therapies, such as sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists, have shown promising results in reducing cardiovascular events, hospitalizations, and mortality in patients with HF and diabetes. These agents offer additional benefits beyond glycemic control, including favorable effects on cardiovascular and renal outcomes.Collaboration between cardiologists, endocrinologists, primary care physicians, and other healthcare providers is essential for a comprehensive and individualized approach to managing the bidirectional relationship between HF and diabetes. Regular monitoring, patient education, and adherence to treatment plans are crucial to optimize outcomes and improve the overall quality of life for affected individuals.Future research should focus on identifying novel therapeutic targets, refining risk stratification tools, and exploring personalized management strategies tailored to the unique needs of patients with HF and diabetes. Healthcare providers can significantly reduce this challenging clinical scenario morbidity, mortality, and healthcare burden by addressing the complex interplay between these 2 conditions.Conceptualization: Chukwuka Elendu, Dependable C. Amaechi, Tochi C. Elendu, Manizha Ashna, Jennifer Ross-Comptis, Sandra O. Ansong, Akinbayo A. Akintunde, Chigozirim M. Agu-ben.Data curation: Chukwuka Elendu, Dependable C. Amaechi, Tochi C. Elendu, Clinton A. Olawuni, Erica I. Pius.Formal analysis: Chukwuka Elendu, Dependable C. Amaechi, Tochi C. Elendu.Investigation: Chukwuka Elendu, Dependable C. Amaechi, Tochi C. Elendu.Methodology: Chukwuka Elendu, Dependable C. Amaechi, Tochi C. Elendu, Sandra O. Ansong, Emmanuel O. Egbunu, Geraldine C. Okafor, Onyekachukwu R. Ekwem.Project administration: Chukwuka Elendu, Dependable C. Amaechi, Tochi C. Elendu.Resources: Chukwuka Elendu, Dependable C. Amaechi, Tochi C. Elendu.Software: Chukwuka Elendu, Dependable C. Amaechi, Tochi C. Elendu.Supervision: Chukwuka Elendu, Dependable C. Amaechi, Tochi C. Elendu, Manizha Ashna.Validation: Chukwuka Elendu, Dependable C. Amaechi, Tochi C. Elendu.Visualization: Chukwuka Elendu, Dependable C. Amaechi, Tochi C. Elendu, Manizha Ashna, Jennifer Ross-Comptis, Akinbayo A. Akintunde, Boluwatife A. Oyedele, Mercy O. Asekhauno, Brandon Carl Monika Pouekoua.Writing \u2013 original draft: Chukwuka Elendu, Dependable C. Amaechi, Tochi C. Elendu, Manizha Ashna, Jennifer Ross-Comptis, Mercy O. Asekhauno.Writing \u2013 review & editing: Chukwuka Elendu, Dependable C. Amaechi, Tochi C. Elendu, Sandra O. Ansong, Emmanuel O. Egbunu, Klein A. Jingwa, Akinbayo A. Akintunde, Chidinma M. Ogah, Melissa O. Edeko, Ayodeji V. Ibitoye, Mojetoluwa O. Ogunseye, Chisom E. Alakwe-Ojimba, Eunice K. Omeludike, Chibuike A. Oguine, Rechner N. Afuh, Mercy O. Asekhauno, John A. Ladele, Chinonso B. Okoro, Brandon Carl Monika Pouekoua, Joseph S. Adenikinju, Chigozirim M. Agu-ben, Ooreofe Aborisade."}
+{"text": "The rodent behavioural examination techniques are used to assess various psychological, neurological models and neurotoxicity studies. Therefore, it isof interest to document the various behavioural assessment methods used in rodent model to study the motor, sensory, cognitive functions and emotionalbehaviour. This field has placed a growing emphasis on variouscommonly used species, recognizing the significance of animals' motor, cognitive, and social activities.  Despitef tests. The grouf tests. Weight, f tests..Behavioural assessment is a critical parameter in neurotoxicity studies, drug development, and neurological and psychological model screening. A widerange of tests are available for assessing motor, sensory, cognitive, and emotional states in rodents. The choice of tests should align with the study'snature and be carried out with adherence to ethical animal handling practices. To minimize bias during analysis, video recordings of behavioral sessions arerecommended."}
+{"text": "Sports performance is a multifaceted phenomenon influenced by the interactions of various factors, including sports immunometabolism, training load, and nutrition (Lima et al., The articles within this Research Topic address diverse aspects of sports immunometabolism, training load, and nutrition, providing insights into their effects on sports performance and psychological wellbeing. Spanning a range of disciplines, including exercise physiology, nutritional science, psychology, and sports medicine, these studies collectively examine the comprehensive interplay of these factors. By investigating these relationships, the research presented offers valuable knowledge on how athletes can enhance their performance and maintain optimal mental health.Immunometabolism, the study of the metabolic processes underlying immune system function, is a rapidly evolving field with significant implications for sports performance. Several articles in this Research Topic explore the intricate relationship between immune system functioning, energy metabolism, and athletic performance Suzuki, . These sTraining load, encompassing the volume, intensity, and duration of physical training, is crucial in determining sports performance outcomes. The articles in this Research Topic investigate various aspects of training load, including its quantification, periodization, and impact on physiological adaptations and performance outcomes. By analyzing the intricate relationship between training load and performance, these studies offer evidence-based strategies for optimizing training programs, preventing overtraining, and maximizing athletic potential. They emphasize the importance of individualized training approaches that consider age, gender, and sport-specific demands.Proper nutrition serves as a fundamental pillar of sports performance. The articles within this Research Topic examine the impact of nutrition on various aspects of athletic performance and psychological wellbeing. Researchers investigate the roles of macronutrients, micronutrients, hydration, and supplementation in optimizing sports performance. Their findings provide valuable insights into the specific nutritional requirements of athletes, emphasizing the need for individualized approaches tailored to their unique physiological and performance needs. Additionally, these studies explore the effects of nutrition on cognitive function, mood, and mental health, highlighting the bidirectional relationship between nutrition and psychological wellbeing (Bustamante-Sanchez et al., The articles presented in this Research Topic contribute to our understanding of the complex interactions among sports immunometabolism, training load, and nutrition about sports performance and psychological behavior of athletes. By bridging the gaps between multiple disciplines, these studies pave the way for evidence-based interventions and strategies that can enhance athletic performance, prevent injuries, and promote the overall wellbeing of athletes. We are confident that this collection of articles will serve as a valuable resource for researchers, coaches, and practitioners in the field, ultimately benefiting athletes of all levels and disciplines.HN: Project administration, Writing\u2014original draft, Writing\u2014review and editing. JC: Writing\u2014original draft, Writing\u2014review and editing. KS: Writing\u2014original draft, Writing\u2014review and editing."}
+{"text": "Abrupt visual impairment constitutes a medical urgency, necessitating an interdisciplinary diagnostic and therapeutic approach owing to the broad spectrum of potential etiologies, thereby engaging numerous medical specialties.A 21-year-old Mixed White and Asian female patient, with medical history of nonsteroidal antiinflammatory drug-exacerbated respiratory disease necessitating previous sinus surgery, reported sudden monocular vision loss. Unremarkable ophthalmological examination of the fellow eye and hematological parameters, save for a slight elevation in lymphocytes and eosinophils, were observed. Imaging studies indicated recurrence of bilateral chronic rhinosinusitis with nasal polyps and a mucocele in the left sphenoid sinus, accompanied by bony structural deficits. Emergency revision sinus surgery, guided by navigation, was promptly performed. The patient received treatment with methylprednisolone, ceftriaxone, cyanocobalamin, pyridoxine, thiamine, and acetylsalicylic acid. During the hospital stay, she developed steroid-induced glaucoma, which was subsequently managed successfully. Negative microbiological swabs, along with pathohistological evidence of increased tissue eosinophilia and the patient\u2019s clinical history, led to the diagnosis of toxic retrobulbar neuritis secondary to recurrent nonsteroidal antiinflammatory drug-exacerbated respiratory disease-associated chronic rhinosinusitis of the left sphenoid sinus.In cases of acute unilateral vision loss, optic neuritis is a highly probable differential diagnosis and may be induced by pathologies of the paranasal sinuses. Nonsteroidal antiinflammatory drug-exacerbated respiratory disease, a subtype of chronic rhinosinusitis, is associated with type 2 inflammation, which is increasingly recognized for its role in the pathogenesis of bronchial asthma, eosinophilic esophagitis, and atopic eczema. Clinicians should consider chronic rhinosinusitis as a potential differential diagnosis in unilateral visual loss and be cognizant of the rising significance of type 2 inflammations, which are relevant to a variety of diseases. Optic neuritis, a primary differential diagnosis for acute monocular vision loss, bifurcates into two subtypes : typicalChronic rhinosinusitis (CRS), a potential etiology of atypical optic neuritis, is an inflammatory condition of the nasal passages and paranasal sinuses, with a prevalence of 4.5\u201312% in North America and Europe. Manifesting through persistent symptoms such as nasal congestion, rhinorrhea, olfactory dysfunction, facial pain, or headache for over 12\u00a0weeks, CRS is further classified by the presence or absence of nasal polyposis , and continuation of existing medications. On the third day post surgery, intraocular pressure increased , suggesting a steroid response. Administration of methylprednisolone was halted, and the pressure was promptly reduced with acetazolamide, intraocular dorzolamide, and apraclonidine to 29\u00a0mmHg.Emergency revision sinus surgery was conducted with decompression of the optic nerve Fig.\u00a0. PostsurHistopathological analysis indicated chronic sinusitis, polyp presence, and elevated tissue eosinophilia, pointing to a type 2 inflammatory endotype consistent with an allergic or NERD etiopathogenesis. There was no evidence of malignancy or infection, aligning with the negative microbiological results.Twelve weeks post discharge, the patient\u2019s left-eye visual acuity improved to 20/50 (Snellen), intraocular pressures were normal, and the anterior segment examination was regular. Ophthalmoscopy Fig.\u00a0A confirmBartonella infection), tumor infiltration, metabolic deficiency, toxic damage, and neuronal ischemia also need to be considered.The presented case deals with unilateral sudden vision loss, symptomatic of optic neuritis. Typically, optic neuritis manifests unilaterally, frequently in association with multiple sclerosis, resulting in progressive axonal damage and demyelination. Atypical optic neuritis, on the other hand, arises from diverse underlying conditions such as temporal arteritis, Devic syndrome, sarcoidosis, lupus erythematosus, chronic relapsing inflammatory optic neuropathy, and Leber\u2019s hereditary optic neuropathy. Post-vaccine reactions and para- or postinfectious states  was selected as the appropriate imaging modality . In conjThe therapeutic approach for CRSwNP encompasses regular applications of intranasal glucocorticoids, large-volume nasal rinsing, and, for severe cases, oral corticoids and sinus surgery . AdditioDiagnosing and managing optic neuritis demands an interdisciplinary approach. In this patient\u2019s case, her NERD history and increased tissue eosinophilia guided the diagnosis. Effective treatment of CRS entails consistent and early therapy to enhance patient quality of life and avert severe complications. Appreciation of type 2 inflammations and emerging therapies such as dupilumab is crucial. However, acute complications call for immediate surgical interventions to alleviate nerve trauma and toxicity, mitigating progressive or irreversible deficits."}
+{"text": "Folliculosebaceous cystic hamartoma is a cutaneous malformation composed of a cystic folliculosebaceous structure associated with mesenchymal elements, generally consisting of fibrous stroma, adipocytes and small vascular channels. We report the case of a 55-year-old female patient with a cutaneous nodule of the right nasal wing. Microscopically, the lesion showed a dilated hair follicle with multiple sebaceous glands, surrounded by a mesenchymal component composed of fibromyxoid stroma, spindle cells, mature-appearing adipocytes and collagen bundles, resembling spindle cell lipoma, associated with an additional neural component, consisting of small nerve bundles. In folliculosebaceous cystic hamartoma, the association of spindle cell lipomatous and neural components has not previously reported. Folliculosebaceous cystic hamartoma is a cutaneous lesion, originally described in 1991 by Kimura et al., who described five cases of a distinct pilosebaceous malformation, proposing a set of specific diagnostic criteria . More thFolliculosebaceous cystic hamartoma is, probably, an underdiagnosed lesion, because of the lack of specific clinical features ,4. CliniHistopathologically, folliculosebaceous cystic hamartoma appears as a complex lesion composed of epithelial, follicular and sebaceous, and mesenchymal tissues. The tumor shows a cystically dilated hair follicle with multiple radiating sebaceous glands, associated with a mesenchymal component, generally consisting of abundant fibrous stroma, small venules and a variable proportion of mature adipose tissue ,4,5,6,7.We report a case of folliculosebaceous cystic hamartoma showing the association of two additional rare mesenchymal features: a spindle cell lipomatous component, mimicking spindle cell lipoma, and a neural component, consisting of short nerve bundles embedded in the lesional stroma.A 55-year-old female patient presented a 10 \u00d7 9 mm non-pigmented, slowly enlarging, cutaneous nodule of the right wing of the nose. The lesion, previously treated by diathermo-coagulation, was removed by simple excision, with a provisional clinical diagnosis of intradermal nevus or fibrous papule. The patient has had no complications or recurrence. The specimen, measuring 12 \u00d7 9 \u00d7 7 mm, was fixed in 10% buffered formalin and entirely embedded in paraffin. The tissue sections were stained with hematoxylin-eosin for histologic examination; some sections were histochemically stained with Alcian blue. Additional tissue sections were immunohistochemically studied for CD34, S-100 protein, factor XIIIa, SMA (smooth muscle actin), and Ki67.Histopathological examination showed a dilated follicular structure, located in the dermis and extending to the upper portion of the subcutaneous fat; from this, multiple enlarged sebaceous lobules extended to the adjacent and underlying dermis A. This fAlthough lacking a characteristic clinical appearance, folliculosebaceous cystic hamartoma shows distinct histologic features. The basic parameters for the histopathologic diagnosis, originally stated by Kimura et al., were: (I) an infundibular cystic structure with connected sebaceous glands; (II) a compact fibroplasia around the epithelial component; (III) mesenchymal changes around the fibroepithelial structure, including fibrillary bundles of collagen, adipocytes, and an increased number of small venules; (IV) clefts between the fibroepithelial structure and the surrounding stroma and at the periphery between the altered stroma and the adjacent compressed fibrous tissue; (V) confinement of the process primarily to the dermis, but with a possible subcutaneous extension . A high Folliculosebaceous cystic hamartoma may also resemble trichofolliculoma and has been also considered a late stage of this benign neoplasm ; howeverhamartanein , refers to a malformation, consisting of abnormally arranged mature normal tissues, in an organ composed of identical tissues and cellular elements [The term \u201chamartoma\u201d, derived from the Greek verb elements . Therefoelements ,4,5,6,7.nevus lipomatosus superficialis with a folliculosebaceous cystic hamartoma [nevus lipomatosus superficialis having a folliculosebaceous component [In some lesions, showing the characteristic histologic epithelial features of folliculosebaceous cystic hamartoma, a conspicuous amount of mature fat tissue has been reported ,15,16. Iamartoma ,15 or, aMore rarely, folliculosebaceous cystic hamartoma also shows other elements, composed of other tissues and cells normally present in the skin, although arranged in abnormal structures. Such additional components include small superficial sebaceous lobules directly connected to the overlying epidermis, without associated pilar structures , immaturIn the reported case, the epithelial component of the lesion was represented by an enlarged, dilated follicular structure with irregular sebaceous lobules. As expected, the mesenchymal component showed a dense fibrous stroma, numerous small and medium-caliber vascular structures and clusters of mature adipocytes. However, in addition to these classic features, in the stroma surrounding the pilosebaceous structure, a certain number of short neural bundles were seen. Moreover, in its deep portion, the lesion displayed a stromal mucinous Alcian blue-positive component, composed of normal adipocytes associated with spindle elongated cells with single elongated nuclei and collagen bundles, resembling spindle cell lipoma. As in some previous reported cases ,18, clefIn folliculosebaceous cystic hamartoma, the occurrence of these two latter features seems to be rare. A neural component has been reported in only two previous cases. In 1993, Donati and Balus described a case of a 32-year-old woman with a pedunculated skin-colored nodule on the antitragus of her right ear, histologically showing small nerve branches . In 1997Spindle cell lipoma is a soft tissue benign tumor, described by Enzinger and Harvey in 1975. Histologically, the lesion may display various patterns. The classic form consists of a mixture of mature fat and spindle cells, showing elongated nuclei and cytoplasmic processes. These cells appear embedded in a mucoid matrix and are often mixed with characteristic birefringent collagen bundles .A lipomatous component, showing a close resemblance to spindle cell lipoma, has been recently reported in two cases. In 2015, Nguyen, Skupsky and Cassarino reported a case of a 24-year-old man presenting a nasal papule, histologically showing a cystic follicular structure with multiple irregular sebaceous lobules, associated with a dermal mesenchymal component, consisting of mature adipocytes, fibromyxoid stroma, prominent collection of mucin, CD34+ spindle cells, and ropey collagen bundles, mimicking spindle cell lipoma . More reIn our case, the lipomatous spindle cell component appeared very similar to that observed in these case, although collagen bundles were shorter and thicker. Interestingly, a similar stromal component, composed of spindle cells, adipose tissue and prominent collagen bundles, resembling spindle cell lipoma, has been recently reported in cases of spindle cell predominant trichodiscomas , includeIn conclusion, we reported a rare case of folliculosebaceous cystic hamartoma showing the association of a spindle cell lipomatous component with an neural component. To our knowledge, such an association has not been previously reported."}
+{"text": "Terrestrial civilization is currently below the entry level I. Particularly advanced civilizations, which are above the highest level,may engineer interstellar travel and could move their planets across interstellar distances. Communication among civilizations has always been of keen interest. In termsof ability to communicate among advanced civilizations, neutrinos may be used for galactic and inter-galactic communication, in addition to or instead of usingelectromagnetic radiation. Thus, at this juncture, deliberation and debate are essential to proceed with development of civilization and communication.Communications among civilizations may include self-descriptive bioinformation because pathogen dynamics exist in their astrobiology and astrovirology, which couldbecome pathogenic upon actual contact. This information is of mutual benefit, if reciprocated. However, in contrast, the strategic counter-scenario of self-hiddencivilizations is also discussed. Civilizations, including extra-terrestrial civilizations have been divided and stratified into three levels, using a wide non-linearlogarithmic scale. The levels are based on their energy expenditures: level 1 is at 4x10 Neutrino research provides an unparalleled window into fundamental particle cosmology. They have several characteristics that are under study, many of which extendbeyond the Standard Model of particle physics. The primary effect they exhibit that has puzzled the field is that they have mass, which is not predicted within theStandard Model. A few neutrinos properties include the following. Cognate with the three negatively charged leptons (electron (e), muon (m), and tau (t)), neutrinososcillate among three uncharged flavors . Neutrinos have very low energy and mass compared with the other elementary particles,and neutrinos have life-times akin to cosmological timescales -3. PasacSeveral thousand years of recorded history have brimmed with speculations of extraterrestrial life and ETI. However, there have been no detections confirmed in accordwith scientific methods. Nevertheless, in 1964, Kardashev hypothesized a type of organization of extraterrestrial civilizations, according to their estimated energyconsumption. Kardashev designated three stratification levels and thus placed the search for extraterrestrials on a more scientific and technology-based footing, usingmeasurables including energetics, technology, astronomy, and astrophysics. Sagan constructed an equation that allowed calculation of Kardashev intermediate echelons amongthe three levels. Remarkably, estimation of the energy utilization of current terrestrial technology placed our current development below Stage I in Kardashev'sstratification system. Using these constraints, it will take an additional 327 years for human civilization to reach Stage I. -17 UsinThe possible influence of neutrino dynamics on planetary astrobiology/exobiology is a recent addition to origin of life research. In point, neutrino chirality andflavor may influence molecular chirality selection and discriminatory mechanisms during the origin and development of life. Such processes could occur, depending on theproximity of neutrino sources, such as their suns, other stars, neutron stars, dwarfs, supernovae, pulsars, quasars, and blazars. Whether neutrino dynamics influenced theterrestrial origin of life in any respect is under investigation. ,24 DurinAnalysis of several diverse research fields syndicate global consequences that were previously unanticipated by each alone. Jointly and individually, the sundry arenasmentioned in this article have bearings on human health, safety, communication, technological development, and survival. Prior cultures and civilizations analyzed suchcomplications with some degree of histo-riographic accuracy. In 411 BCE, in Athens, Thucydides published one of the earliest history books, 'The History of the PeloponnesianWars'. He discussed the problems faced by prosperous city-states becoming victims to aggressive predatory city-states. Consequently, Thucydides advocated concealment as astrategy to avoid predation and annihilation. However, about 2,393 years later, Sagan and colleagues were less pessimistic about such situations, with respect to ETI andterrestrial civilizations. Based on the Drake-Sagan equation and possible rates of ETI civilization galactic diffusion theory, probability scenarios were calculated amongETIs at differing relative times. It may be inferred that consequently, an inferior ETI civilization would have negligible sway on the contact outcome and would be utterlyat the mercy of the more developed superior ETI civilization. Similarly, terrestrial civilization would likely be dominated by ETI civilizations that happened upon oursolar system and the Earth ,26. NeveIn conclusion, undoubtedly, far-reaching impacts on terrestrial civilization will occur, if we continue attempts to communicate with extraterrestrial ETI civilizations,which could result in contact. The outcomes portend being illogical games of dice. The gamut of connection scenarios includes neutrino and EM communications and dependson fields embracing particle physics, astrophysics, astrobiology, astro-virology, and artificial intelligence. We may add that revelatory civilizations could providecrucial bioinformation in their communications, which would be important in any possible actual interactions. From a Bioinformation point of view, contacts would then notbe proceeding completely blindly, but nonetheless would remain dicey at best ,30."}
+{"text": "JPGN Reports, a joint publication by the North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society of Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). JPGN Reports will be a popular venue for publication, especially for case reports and clinical studies related to pediatric gastroenterology, hepatology, and nutrition.We are pleased to announce a new online, peer-reviewed, open access journal, JPGN Reports aims to publish novel case reports, images and videos, original articles, clinical trials protocols, review articles, short communications, letters to the editor, selected meeting proceedings, editorials, and commentaries on all aspects of clinical and translational research, educational, and public health issues in the area of pediatric gastroenterology, hepatology, and nutrition. JPGN Reports also welcomes novel exploratory hypothesis-generating research, qualitative and quantitative epidemiologic research, studies of novel mechanisms and methodologies including public health interventions, hypothesis-generating small studies, methods papers, and translational research applicable for pediatric pathogenesis and physiology in health and disease.JPGN Reports directly to the website: https://www.editorialmanager.com/jpgnreports/default.aspx.We welcome your submissions to our new journal. Manuscripts may be submitted to"}
+{"text": "Lice, bed bugs, ticks, leeches, and other tiny blood-sucking crawling creatures are regarded as nasty vampires, causing itches, eliciting disgusting feeling, vectoring human and animal diseases, and thereby bringing about medical, health, hygienic and mental problems in human societies Lehane, . BesidesMicrobial Associates of Blood-Sucking Arthropods and Other Animals: Relevance to Their Physiology, Ecology and Evolution\u201d is aimed to provide a forum for new findings emerging in this research field. In total, nine articles and two reviews are compiled, which showcase the microbial associates of a diverse array of blood-feeding invertebrates including lice (Insecta: Psocodea), tsetse flies (Insecta: Diptera), fleas (Insecta: Siphonaptera), ticks (Arachnida: Ixodida) and mites (Arachnida: Mesostigmata) from the terrestrial ecosystem, and Elthusa and Nerocila (Crustacea: Isopoda), Lernanthropus (Crustacea: Copepoda) and fish leeches (Hirudinea: Piscicolidae) from the marine ecosystem.Owing to recent development of high-throughput DNA sequencing technologies, our knowledge of the microbiomes associated with these blood-sucking invertebrates, which must be connected to their unique feeding habit and physiology, has been growing rapidly. Hence, this Research Topic \u201cNishide, Oguchi, et al., investigated the endosymbiotic microbiota of the boar louse Haematopinus apri, identified a primary endosymbiont clade associated with the boar, swine and cattle lice, and designated it as \u201cCandidatus Haematopinicola symbiotica\u201d. \u0158\u00edhov\u00e1 et al. screened and assembled the metagenomic data of the chipmunk lice Neohaematopinus spp. and identified a genome-reduced endosymbiont designated as \u201cCandidatus Lightella neohaematopini\u201d. Do\u00f1a et al. surveyed the microbiota associated with the seal louse Echinophthirius horridus, which uncovered diverse bacterial associates but failed to identify principal symbiotic bacteria. These reports highlight the dynamic evolutionary trajectories of the louse-microbe endosymbiotic associations entailing multiple and independent gains and losses.Sucking lice (Psocodea: Anoplura) live on vertebrate blood as the sole food source throughout their life cycle  are obligatory blood feeders distributed in sub-Saharan Africa, where they vector devastating human and animal pathogens Krafsur, . Tsetse s Aksoy, . In the Yersinia pestis and other pathogens  are obligatory blood feeders of mammals and birds as adults, and notorious for vectoring Rickettsia, Coxiella and other pathogens causing human and animal diseases  are obligatory blood feeders of terrestrial vertebrates including mammals, birds, reptiles and amphibians  is a blood sucking avian ectoparasite that often causes significant economic damage on poultry production , riboflavin (= vitamin B2) and pyridoxine (= vitamin B6). By contrast, Nishide, Sugimoto, et al., reported that, from 144 samples of D. gallinae collected from 18 poultry farms in Japan, Bartonella, Cardinium, Wolbachia and Tsukamurella were detected as major bacterial components, but Rickettsiella was not detected at all. These reports uncovered strikingly different microbiota across European and Japanese populations of D. gallinae. At present, whether Rickettsiella is the vitamin-provisioning primary symbiont of D. gallinae or not is elusive and to be established in future studies.The poultry red mite Goffredi et al. reported the microbiomes of marine obligatory blood feeders that have been little investigated previously: fish ectoparasitic isopods Elthusa vulgaris and Nerocila californica (Isopoda: Cymothoidae); a fish ectoparasitic copepod Lernanthropus latis (Copepoda: Lernanthropidae); and fish leeches Pterobdella occidentalis, Ostreobdella californiana, and Branchellion lobata (Hirudinea: Piscicolidae). Interestingly, all the marine blood suckers exhibited peculiar gut microbiomes characterized by relatively low diversity dominated by Vibrio species.Finally, as the highlight of this Research Topic, In conclusion, the Research Topic presents an impressive overview of the current research coverage on the diversity of microbial symbioses among blood-sucking arthropods and other invertebrates. These reports significantly broaden our knowledge as to what types of microbiomes are associated with the obligatory blood feeders, and highlight the untouched research fields represented by, for example, marine obligatory blood feeders and their biological and functional aspects, as promising targets for future studies. It has been widely accepted that symbiotic interactions with microorganisms are essential for the ecology of insects, ticks, leeches and other invertebrates with obligatory blood feeding habit. Diverse bacterial lineages have independently evolved functional interactions with the obligatory blood feeders, but, notably, all converge to an analogous biochemical feature of vitamin provisioning.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
+{"text": "Intimately tied to SIRT1 pathways are mammalian forkhead transcription factors (FoxOs) which can modulate cardiac disease to reduce oxidative stress, repair microcirculation disturbances, and reduce atherogenesis through pathways of autophagy, apoptosis, and ferroptosis. AMP activated protein kinase (AMPK) also is critical among these pathways for the oversight of cardiac cellular metabolism, insulin sensitivity, mitochondrial function, inflammation, and the susceptibility to viral infections such as severe acute respiratory syndrome coronavirus that can impact cardiovascular disease. Yet, the relationship among these pathways is both intricate and complex and requires detailed insight to successfully translate these pathways into clinical care for cardiovascular disorders.As a significant non-communicable disease, cardiovascular disease is the leading cause of death for both men and women, comprises almost twenty percent of deaths in most racial and ethnic groups, can affect greater than twenty-five million individuals worldwide over the age of twenty, and impacts global economies with far-reaching financial challenges. Multiple factors can affect the onset of cardiovascular disease that include high serum cholesterol levels, elevated blood pressure, tobacco consumption and secondhand smoke exposure, poor nutrition, physical inactivity, obesity, and concurrent diabetes mellitus. Yet, addressing any of these factors cannot completely eliminate the onset or progression of cardiovascular disorders. Novel strategies are necessary to target underlying cardiovascular disease mechanisms. The silent mating type information regulation 2 homolog 1 Non-communicable diseases (NCDs) affect an increasing portion of the global population with at least fifteen million of these individuals ranging in age between thirty and sixty-nine years , influenza and pneumonia, kidney disease, and suicide . CardioClosely tied to the increasing prevalence of NCDs and cardiovascular disease are the effects of the aging process  (SIRT1), mammalian forkhead transcription factors (FoxOs), and AMP activated protein kinase (AMPK) (Table 1+), cell senescence and lifespan, reactive oxygen species exposure, stem cell survival, mitochondrial injury, trophic factor protection, infectious agent injury, and programmed cell death pathways of apoptosis, autophagy, and ferroptosis.Multiple factors can lead to the onset of cardiovascular disease. Focusing upon adults who are male or female, age sixty and over, or non-Hispanic black, or of lower income who are at high risk may reduce the onset and progression of cardiovascular disease  Table 1. Intimat (Saccharomyces cerevisiae) (SIRT1) plays a significant role during the onset and progression of cardiovascular disease  is used as a substrate for SIRT1  . The coal., 2005, 2022). T). T+ proese, 2021). Yet ifong, 2014). This iese, 2020). Circadese, 2020; Birnie ese, 2020; Felten ese, 2020; Hardelaese, 2020; Hsu et ese, 2020; Huang eese, 2020; Kalam eese, 2020; Klionskese, 2020; Lathe aese, 2020; Luo et ese, 2020; Maiese,ese, 2020, 2020, 20, 20+ proese, 2020; Olejnicese, 2020; Xu et aese, 2020). In relese, 2020). + can lead to the production of nicotinamide. Yet, feedback mechanisms exist and nicotinamide can block SIRT1 activity by intercepting an ADP-ribosyl-enzyme-acetyl peptide intermediate with the regeneration of NAD+ . Physioal., 2003). As a ral., 2003). Howeveal., 2008).+ replenishment is believed to foster cardiac and vascular health . Enhancese, 2008, 2015). O). O+ preal., 2023). With tal., 202374]; Gov; Gov+ pral., 2023; Hu et aal., 2023; Maiese,al., 2023, 2023[15al., 2023; Maiese al., 2023; Senousyal., 2023; Sergio al., 2023; Yang etal., 2023). EPO leal., 2023), fosteral., 2023; Hou et al., 2023). EPO isal., 2023) and decal., 2023; Maiese al., 2023; Zhao etal., 2023).Caenorhabditis elegans, Drosophila melanogaster, and mammals. FoxO proteins are homologous to the transcription factor DAuer Formation-16 (DAF-16) in the worm Caenorhabditis elegans that can oversee metabolic insulin signaling, cell survival, cell cycle regulation, and lifespan extension . FoxO pal., 1997; Maiese al., 1997), cerebral., 1997), and glal., 1997). FoxOs al., 1997; Peng etal., 1997; Zeng etal., 1997), ubiquial., 1997), and acal., 1997; Ren et al., 1997; Shati aal., 1997). Forkheal., 1997, 2020[18al., 1997) such thal., 1997; Sanphuial., 1997; Wang etal., 1997). Akt alal., 1997; Farhan al., 1997; Ren et al., 1997; Shati aal., 1997). Intereal., 1997). In a number of scenarios, the inhibition of FoxO activity can be beneficial for cell survival and the prevention of apoptotic pathways , a member of the mechanistic target of rapamycin (mTOR) pathway , FoxO1, and FoxO3a  or by ual., 2008). The SIal., 2008; Herranzal., 2008). Throughout the world, cardiovascular disease is the leading cause of death for both women and men to the extent that an individual expires every thirty-three seconds as a result of heart disease in just the US alone. Healthcare costs for cardiovascular disease can be greater than $ 555 billion US dollars and are expected to exceed $ 1.1 trillion US dollars by the year 2025. Cardiovascular disease is affected by the increased lifespan of the global population that also leads to cellular pathways that mediate progressive cellular oxidative stress, the shortening of TLs, and the inception of cell senescence. The onset of cardiovascular disease has additional risks that involve age sixty and over, lower income, high serum cholesterol levels, elevated blood pressure, tobacco consumption and secondhand smoke exposure, poor nutrition, physical inactivity, obesity, and the existence of DM. Although treatment of disorders such as DM can lessen the risk of developing cardiovascular disease, cardiac disease may continue to progress and the risk of additional complications may develop, such as the loss of organ mass. These considerations for the development of novel and effective treatments for cardiovascular disease call for innovative strategies that involve SIRT1, FoxOs, and AMPK.+ pathways and increase cardiomyoblast survival, improve stem cell development, assist with endothelial cell function, reduce coronary artery disease, limit cell senescence, and prevent cardiac injury during DM. SIRT1 also promotes necessary circadian rhythm pathways during obesity and treatment with metformin, mediates growth factor protection with EPO, and leads to the production of nicotinamide to maintain mitochondrial function. Yet, feedback pathways are necessary between SIRT1 and nicotinamide to effectively foster anti-inflammatory pathways. SIRT1, a histone deacetylase that can impact DNA transcription, can oversee metabolic homeostasis through NADPathways of SIRT1 are also closely tied to FoxO activity. SIRT1 activation can oversee FoxO cardiac activity to limit oxidative stress, reduce DM complications, repair microcirculation disturbances, improve left ventricular remodeling, and activate senescence mesenchymal stem cells through telomerase activity. Feedback pathways exist for SIRT1 and FoxOs such that forkhead transcription can be altered and that FoxOs can increase SIRT1 expression. This intimate relationship is vital since under some scenarios, the increased activity of FoxOs rather than inhibition of FoxO activity can promote cell survival during cardiotoxicity and ferroptosis through the activation of autophagy pathways. With other circumstances, FoxOs and SIRT1 can function in a synergistic manner to increase cell survival and block mitochondrial dysfunction during oxidative stress. The pathways of SIRT1 and FoxOs are also complemented by the mTOR pathway AMPK. AMPK through autophagy activation can modulate infections with COVID-19, reduce endothelial dysfunction, increase lifespan, improve insulin sensitivity, and assist nicotinamide to maintain mitochondrial function. Furthermore, AMPK can function through the application of metformin to block cardiac apoptosis during DM, reduce cardiac infarct size, and limit cellular senescence. SIRT1 also is vital in the AMPK pathway to not only oversee AMPK activity, but also for AMPK to increase SIRT1 activation to limit cardiomyopathy, cell injury, and mitochondrial dysfunction.+, cell senescence and lifespan, mitochondrial injury, trophic factor protection, infectious agent injury, and programmed cell death pathways that include apoptosis, autophagy, and ferroptosis. However, the relationship among these pathways is highly complex with the existence of multiple feedback systems that will require a continued focus on new insights to safely and effectively target these innovative mechanisms for current and future clinical translation in the treatment of cardiovascular disease.The cellular pathways of SIRT1, FoxOs, and AMPK offer highly novel considerations to address the onset and development of cardiovascular disease. These pathways are significant in the ability to modulate cellular oxidative stress, metabolic pathways with NADThis research was supported by the following grants to Kenneth Maiese: American Diabetes Association, American Heart Association, NIH NIEHS, NIH NIA, NIH NINDS, and NIH ARRA.The author declares no conflict of interest."}
+{"text": "Digital twin technology is revolutionizing healthcare systems by leveraging real-time data integration, advanced analytics, and virtual simulations to enhance patient care, enable predictive analytics, optimize clinical operations, and facilitate training and simulation. With the ability to gather and analyze a wealth of patient data from various sources, digital twins can offer personalized treatment plans based on individual characteristics, medical history, and real-time physiological data. Predictive analytics and preventive interventions are made possible by machine learning algorithms, allowing for early detection of health risks and proactive interventions. Digital twins can optimize clinical operations by analyzing workflows and resource allocation, leading to streamlined processes and improved patient care. Moreover, digital twins can provide a safe and realistic environment for healthcare professionals to enhance their skills and practice complex procedures. The implementation of digital twin technology in healthcare has the potential to significantly improve patient outcomes, enhance patient safety, and drive innovation in the healthcare industry. Digital twin technology is emerging as a transformative force in healthcare systems, revolutionizing the way patient care is delivered. By leveraging real-time data integration, advanced analytics, and virtual simulations, digital twins offer enhanced patient care, predictive analytics, optimization of clinical operations, and training and simulation opportunities .In terms of enhanced patient care, digital twins enable healthcare providers to gather and analyze a wealth of patient data from various sources, including electronic health records (EHRs), wearables, and medical devices . This hoPredictive analytics and preventive interventions are facilitated through digital twin technology by analyzing patient data and employing machine learning algorithms. Digital twins can predict disease progression, identify high-risk individuals, and recommend preventive measures. This proactive approach improves patient safety, long-term outcomes, and resource allocation within healthcare systems . Thus, dPubMed Medline Web of Science, Google Scholar, Scopus databases were used for the research, with only articles in English language, using the following terms: \u201cDigital twin\u201d, \u201cDigital health\u201d and \u201cHealthcare\u201d. Articles included in this review were both, original research, reviews, viewpoints, and opinions articles. Literature was searched from inception to 2023.In recent times, the notion of digital twin has garnered escalating attention from both researchers and engineers. As research in the field of digital twin advances, conducted by both industry and academia, the distinctions between digital twin and other related concepts have begun to fade. Initially, the scope of digital twin encompassed physical and virtual products along with their interconnections . This coSubsequently, digital twin was redefined as a digital replication of living or non-living physical entities, ushering in applications in areas like health and well-being . FunctioBroadly, the technologies essential for digital twin can be categorized into two groups: one involves a data-driven statistical model, while the other integrates multi-scale knowledge and data into a mechanical model , 11. TheThe impact of digital twin is profoundly reshaping industries and has been embraced by major corporations to heighten efficiency and identify issues. This transformative technology is also finding its way into the healthcare sector. Within this context, digital twin can treat patients as virtualized standalone assets applicable to diverse healthcare scenarios . This poWithin the realm of healthcare, a digital twin embodies a virtual replica of a tangible entity or process, such as a patient, their anatomical structure, or the setting of a hospital. At present, digital twins in healthcare are designed to dynamically mirror various data sources, including EHRs, disease registries, \u201c-omics\u201d data , as well as physical indicators, demographic information, and lifestyle data pertaining to an individual's progression over time , 13. TheDigital twin technology has the potential to significantly enhance patient care by leveraging real-time data integration, advanced analytics, and personalized insights . These tHealthcare professionals could receive support from digital twins in achieving precise and timely diagnoses . By analThe integration of digital twins with real-time data from wearable devices, remote monitoring systems, and IoT devices enables the ongoing monitoring of patients . By moniDigital twins empower patients to actively participate in their own care . By provThese tools can leverage predictive analytics and machine learning algorithms to forecast disease progression and treatment outcomes . By analThrough secure sharing of patient data across diverse healthcare providers and settings, digital twins can streamline the continuity of care seamlessly . This enDigital twin technology, with its ability to integrate real-time data and advanced analytics, holds great potential for predictive analytics and preventive interventions in healthcare. By leveraging patient data, machine learning algorithms, and predictive modeling, digital twins can identify potential health risks, predict disease progression, and enable proactive interventions .Integrating and analyzing an extensive range of patient data, including medical history, lifestyle factors, genetic information, and real-time physiological data, fosters a comprehensive view of individual health . By applDigital twins can simulate disease progression based on patient data and historical trends . By analRisk stratification can be supported by digital twins, as they categorize patients into varying risk groups according to their health data and predictive models . By idenDigital twins can enable proactive interventions and preventive care by alerting healthcare providers to potential health risks in real-time . ThroughPopulation health management can be enhanced by digital twins, which analyze collective data from large populations. Employing predictive analytics on this data enables healthcare systems to recognize health trends, risk factors, and disease prevalence patterns at the population level. Digital twins enable healthcare providers to design targeted interventions and preventive strategies at a population level, such as public health campaigns, vaccination programs, or community-based interventions. This population health approach aims to prevent the onset of diseases, improve health outcomes, and reduce the overall burden on the healthcare system , 36.Digital twin technology offers significant potential for optimizing clinical operations within healthcare systems. By creating virtual replicas of physical systems and integrating real-time data, digital twins enable healthcare providers to analyze and streamline workflows, enhance resource allocation, and improve operational efficiency .Offering a holistic perspective of the clinical workflow, digital twins enable healthcare providers to assess and enhance processes. Through the integration of data from diverse sources like electronic health records (EHRs), medical devices, and administrative systems, digital twins pinpoint bottlenecks, inefficiencies, and areas with potential for improvement , 15. ThiContributing to resource allocation optimization within healthcare systems, digital twins offer insights into patient volumes, demand patterns, and resource utilization by analyzing patient data, historical trends, and real-time information . This enBy predictive analytics and machine learning algorithms, digital twins could aid in operational decision-making. They analyze data from various sources, encompassing patient flow, staffing levels, and equipment usage, enabling them to anticipate future operational scenarios . This enIntegrating seamlessly with real-time data from IoT devices, wearables, and medical sensors, digital twins enable continuous monitoring of clinical operations. Through the monitoring of key performance indicators, patient flow, and operational metrics, digital twins can swiftly identify deviations from anticipated norms and initiate alerts , 39. ThiDigital twins can support quality improvement initiatives and enhance patient safety within clinical operations . By analEnabling collaboration and communication among various departments and healthcare professionals, digital twins establish a shared virtual platform. This platform permits real-time data sharing, facilitates collaboration on patient care plans, and streamlines communication processes , 41. By Digital twins can support continuous monitoring and iterative improvement of clinical operations . By contDigital twin technology can offer valuable opportunities for training and simulation in the healthcare sector . By creaHealthcare professionals, notably surgeons, can use digital twins to rehearse and enhance their surgical skills in a simulated environment . By replA platform for healthcare professionals to simulate various medical procedures can be provided by digital twins . From inThus, these tools could be particularly valuable for training healthcare professionals in emergency response situations . By simuThe simulation of intricate clinical cases, providing healthcare professionals with the opportunity to refine and augment their clinical decision-making abilities can be supported by digital twins . By incoBy furnishing a shared virtual platform, digital twins facilitate interprofessional collaboration and communication among healthcare professionals from diverse disciplines, enabling them to collaborate effectively . ThroughA platform for continuous professional development for healthcare professionals can be offered by digital twins' use. By providing access to virtual training modules, case studies, and simulation scenarios, digital twins enable healthcare professionals to stay updated with the latest advancements, learn new techniques, and acquire specialized skills. This self-paced learning and continuous training enhance professional development, promote lifelong learning, and ensure healthcare professionals are well-prepared to deliver high-quality care.Digital twins can also serve as a valuable tool for research and innovation in healthcare . ResearcIn conclusion, digital twin technology holds immense promise for revolutionizing healthcare systems and enhancing patient care. By integrating real-time data, advanced analytics, and virtual simulations, digital twins offer personalized treatment plans, predictive analytics, optimized clinical operations, and immersive training opportunities. The use of digital twins empowers healthcare professionals to make accurate diagnoses, monitor patients in real-time, and intervene proactively to prevent adverse events. It also enables patients to actively participate in their own care and promotes collaborative decision-making between patients and healthcare providers. Moreover, digital twins optimize resource allocation, streamline workflows, and improve operational efficiency within healthcare systems. The potential of digital twin technology in healthcare is vast, and its implementation has the potential to significantly improve patient outcomes, enhance patient safety, and drive innovation in the healthcare industry. However, its successful implementation requires addressing challenges related to data privacy, interoperability, data quality, ethics, resource intensity, integration with workflows, validation, education, scalability, and cultural shifts. As these challenges are navigated, digital twin technology could revolutionize healthcare systems, leading to improved patient outcomes, more efficient operations, and a higher quality of care."}
+{"text": "ST-Segment Elevation Myocardial Infarction (STEMI) is a life-threatening medical emergency characterized by complete coronary artery occlusion, leading to myocardial ischemia and subsequent necrosis. Over the years, STEMI has remained a significant cause of morbidity and mortality worldwide, necessitating a comprehensive understanding of its pathophysiology, accurate diagnostic strategies, and effective treatment approaches.This review article aims to thoroughly analyze the current knowledge surrounding STEMI, emphasizing key aspects crucial for optimizing patient outcomes. Firstly, the pathophysiology of STEMI will be explored, elucidating the sequence of events from coronary artery plaque rupture to thrombus formation and occlusion. This section will also cover the underlying risk factors contributing to STEMI development, including atherosclerosis, hypertension, and diabetes.Secondly, the diagnostic modalities for STEMI will be critically evaluated. Traditional electrocardiography remains the cornerstone of STEMI diagnosis. Still, advancements in imaging techniques such as cardiac magnetic resonance imaging and coronary angiography have enhanced accuracy and allow for better risk stratification.Furthermore, the review will delve into the latest treatment approaches for STEMI. Prompt reperfusion therapy through primary percutaneous coronary intervention or thrombolytic therapy is essential in restoring blood flow and salvaging the jeopardized myocardium. The role of adjunctive medical treatment, including antiplatelet agents, beta-blockers, and statins, will also be discussed in post-STEMI management. STEMI is a significant cause of worldwide morbidity and mortality, necessitating a thorough understanding of its pathophysiology, diagnosis, and management.The motivation for this comprehensive review of ST-Segment Elevation Myocardial Infarction (STEMI) stems from the critical importance of this cardiovascular emergency in contemporary medicine. While individual studies and guidelines exist, there is a need for more total reviews that bring together the latest research findings and evidence-based recommendations. The objectives of this proposed work are as follows:One of the primary research gaps this review seeks to address is the need for a comprehensive and up-to-date synthesis of the existing literature and guidelines related to STEMI.This includes a detailed examination of how the incidence and prevalence of STEMI vary across different populations and regions, considering demographic and lifestyle factors.We aim to explore the intricate mechanisms behind the development of STEMI, focusing on atherosclerotic plaque rupture, thrombus formation, and myocardial ischemia.We will delve into the various diagnostic modalities, including electrocardiography (ECG), cardiac biomarkers, and imaging techniques, highlighting their roles and limitations.This encompasses a detailed analysis of primary percutaneous coronary intervention (PCI), thrombolytic therapy, adjunctive medical therapies, and their impact on patient outcomes.We will provide insights into the recommendations by reputable organizations like the American Heart Association (AHA) and the European Society of Cardiology (ESC) to guide healthcare professionals in the optimal care of STEMI patients.This includes examining mortality rates, complications, and factors influencing long-term outcomes.We will emphasize the importance of post-STEMI care in reducing the risk of recurrent cardiovascular events and improving patients\u2019 overall quality of life.This section discusses relevant studies that have contributed to STEMI research, specifically focusing on imaging and predictive modeling advancements. the authors investigated the value of 3-dimensional strain parameters in predicting left ventricular remodeling after STEMI. Their work provides valuable insights into assessing post-STEMI cardiac remodeling, an essential aspect of patient outcomes. By incorporating advanced imaging techniques and strain analysis, Xu et al demonstrated the potential of these parameters as predictors of remodeling. We recognize the significance of their findings in the context of our review, as they shed light on the evolving landscape of post-STEMI assessment.In the study conducted by Xu et al (2017), delves into the application of deep learning analysis in coronary computed tomography angiography (CCTA) imaging for the assessment of patients with coronary artery stenosis. While our review primarily focuses on the clinical aspects of STEMI management, we acknowledge the growing importance of advanced imaging techniques in diagnosing and assessing coronary artery disease. Han et al work exemplifies integrating cutting-edge technology, such as deep learning, into cardiovascular imaging, highlighting its potential to enhance diagnostic accuracy and patient care.The study by Han et al (2020)Incorporating these studies into our review broadens the scope of our discussion, encompassing not only the clinical aspects of STEMI but also the technological advancements that contribute to improved patient care. While our primary focus remains on the comprehensive understanding of STEMI, we recognize the value of these related works in showcasing the multidisciplinary nature of research in this field.By acknowledging these studies, we aim to provide a well-rounded perspective on the evolving landscape of STEMI research, where clinical insights and technological innovations intersect to enhance patient outcomes and the quality of care.A comprehensive literature review was conducted to achieve the objectives of this study. The study design involved searching and analyzing relevant scientific publications, peer-reviewed journal articles, clinical practice guidelines, and academic books about STEMI. The literature search was performed from reputable databases, including PubMed, MEDLINE, Google Scholar, and Cochrane Library. The search encompassed articles published from inception until the study\u2019s data collection phase in September 2021.The data collection process involved using specific search terms, including \u201cST-Segment Elevation Myocardial Infarction,\u201d \u201cSTEMI pathophysiology,\u201d \u201cSTEMI diagnosis,\u201d \u201cSTEMI treatment,\u201d \u201cpercutaneous coronary intervention,\u201d \u201cthrombolytic therapy,\u201d and \u201cmedical therapy for STEMI.\u201d Additionally, relevant MeSH terms were incorporated to enhance the comprehensiveness of the search.Articles were included if they met the following criteria: Published in English; Peer-reviewed; Focused on the pathophysiology, diagnosis, or treatment of STEMI, and; Contained information contributing to the study\u2019s objectives. Studies not meeting these criteria were excluded from the analysis.The identified articles were evaluated thoroughly, including abstract and full-text screening, by 2 independent reviewers to ensure consistency and accuracy. Relevant data, such as pathophysiological mechanisms of STEMI, diagnostic strategies, treatment modalities, and outcomes, were extracted from the selected articles. Data from the literature were synthesized and organized based on the predetermined subheadings in the study.The literature search yielded 387 articles relevant to the study objectives. After applying the inclusion and exclusion criteria, 81 articles were selected for comprehensive analysis. The data extracted from these articles provided a comprehensive overview of the pathophysiology, diagnostic strategies, and treatment approaches for ST-Segment Elevation Myocardial Infarction.The findings from the literature review were discussed in detail, addressing each objective of the study. Pathophysiological mechanisms leading to STEMI were explored, highlighting the critical role of atherosclerosis and plaque rupture. Diagnostic strategies were evaluated for accuracy and clinical utility, including ECG, cardiac magnetic resonance imaging (MRI), and coronary angiography. The current treatment approaches, including reperfusion and adjunctive medical therapy, were critically analyzed for their efficacy and potential benefits in managing STEMI patients. The comprehensive literature review provided valuable insights into the pathophysiology, diagnostic strategies, and treatment approaches for ST-Segment Elevation Myocardial Infarction. The study highlighted the importance of prompt recognition, accurate diagnosis, and appropriate management in improving patient outcomes. By addressing the objectives of this study, the findings aim to contribute to the existing knowledge on STEMI and serve as a valuable resource for healthcare professionals involved in the care of STEMI patients. STEMI is typically diagnosed based on electrocardiographic changes, specifically ST-segment elevation, in conjunction with clinical symptoms and cardiac biomarker elevations, such as troponin.STEMI is a severe acute coronary syndrome characterized by complete or near-complete coronary artery occlusion, resulting in prolonged myocardial ischemia and subsequent necrosis of the affected heart muscle.STEMI is a significant public health concern worldwide, accounting for a substantial portion of cardiovascular-related morbidity and mortality. The incidence of STEMI varies across different regions and populations and is influenced by various factors, including age, sex, lifestyle, and access to healthcare. In Europe, the overall incidence of STEMI varies among countries, with rates ranging from 80 to 370 cases per 100,000 person-years. Similarly, there is considerable heterogeneity in STEMI incidence in Asia, with reported rates ranging from 33 to 138 cases per 100,000 person-years.According to global estimates, the incidence of STEMI has shown variability across countries, with higher rates reported in high-income regions. In the United States, approximately 965,000 cases of STEMI are reported annually.Age is a significant determinant of STEMI risk, with incidence rates increasing with advancing age. Elderly individuals, particularly those over 65, have a higher prevalence of comorbidities, including atherosclerotic disease, hypertension, and diabetes, contributing to increased STEMI susceptibility.Sex differences also exist in STEMI epidemiology. Men are generally at a higher risk of developing STEMI than premenopausal women. However, the risk for women increases after menopause, narrowing the gender gap.Furthermore, socioeconomic factors, lifestyle choices, and access to healthcare services influence STEMI prevalence and outcomes. Lower socioeconomic status, unhealthy dietary habits, smoking, physical inactivity, and limited access to timely medical care have been associated with an increased risk of STEMI.In conclusion, ST-Segment Elevation Myocardial Infarction is a severe and life-threatening cardiovascular condition that significantly burdens global health systems. Understanding its epidemiology and risk factors is crucial for implementing effective preventive strategies and improving the management and outcomes of STEMI patients.The pathophysiology of STEMI is characterized by a complex interplay of atherosclerotic plaque formation, plaque rupture, and subsequent thrombus formation, leading to acute coronary artery occlusion and myocardial ischemia.The process of STEMI begins with the development of atherosclerosis, a chronic inflammatory condition characterized by the deposition of lipids, cholesterol, and cellular debris within the intimal layer of the coronary arteries. Over time, these deposits, known as atherosclerotic plaques, grow and lead to the narrowing of the arterial lumen, reducing blood flow to the heart muscle. The rupture exposes the thrombogenic contents of the plaque to the circulating blood, leading to platelet activation and the formation of a thrombus at the site of the lesion.Vulnerable plaques, characterized by a thin fibrous cap covering a lipid-rich core, are prone to rupture under various triggers, such as increased shear stress, inflammation, and the release of pro-thrombotic substances.The thrombus, composed of platelets and fibrin, rapidly propagates within the coronary artery, resulting in partial or complete occlusion of the vessel. This sudden reduction in blood flow to the downstream myocardial territory leads to acute myocardial ischemia.The affected region of the heart muscle undergoes ischemic injury, with a decrease in oxygen and nutrient supply. As a result, the cardiomyocytes become hypoxic, and their ability to generate energy through aerobic metabolism is impaired. Without prompt reperfusion, the ischemic myocardium progresses to irreversible cell death (infarction).The ischemic insult triggers an inflammatory response involving the release of cytokines and chemokines, leading to the recruitment of immune cells, such as neutrophils and macrophages. These cells exacerbate tissue injury and promote additional plaque instability.The timely restoration of blood flow, such as through reperfusion therapy, is crucial to salvage the ischemic myocardium. However, reperfusion can also trigger further damage, known as reperfusion injury, characterized by oxidative stress, calcium overload, and inflammation.Following the acute phase, the surviving myocardium undergoes a remodeling process involving changes in structure, composition, and function. This process can lead to adverse ventricular remodeling, impairing cardiac function and increasing the risk of heart failure and arrhythmias.In conclusion, the pathophysiology of ST-Segment Elevation Myocardial Infarction involves the progressive development of atherosclerosis, vulnerable plaque rupture, and thrombus formation, ultimately leading to acute coronary artery occlusion and myocardial ischemia. Timely recognition and intervention are essential to mitigate the detrimental effects of STEMI and prevent long-term complications.STEMI diagnosis involves a combination of clinical evaluation, ECG, and advanced imaging modalities. Early and accurate diagnosis is crucial for prompt initiation of reperfusion therapy and improved patient outcomes.The initial step in diagnosing STEMI involves a thorough clinical assessment, which includes a detailed medical history, physical examination, and evaluation of presenting symptoms. Common symptoms of STEMI include chest pain or discomfort, shortness of breath, diaphoresis, and radiation of pain to the left arm, neck, or jaw. The presence and severity of risk factors such as smoking, hypertension, diabetes, and hyperlipidemia should be assessed. Prompt acquisition and interpretation of ECG findings are essential for early recognition and immediate initiation of reperfusion therapy.ECG remains the cornerstone of STEMI diagnosis. It provides real-time information about the heart\u2019s electrical activity and identifies characteristic changes associated with myocardial ischemia. In STEMI, the ECG typically shows ST-segment elevation of at least 1\u2009mm (0.1 mV) in 2 contiguous leads, accompanied by T-wave inversion or development of pathological Q waves in the corresponding leads.Measuring cardiac biomarkers, such as troponin and creatine kinase-MB, is crucial in STEMI diagnosis. Troponin is highly sensitive and specific for myocardial injury and is usually detectable within a few hours of symptom onset. Elevated levels of troponin in the blood, compatible clinical symptoms, and ECG changes confirm the diagnosis of STEMI.Echocardiography: Transthoracic echocardiography is valuable in assessing regional wall motion abnormalities, left ventricular function, and the presence of complications, such as mechanical complications or acute mitral regurgitation.Cardiac MRI: Cardiac MRI provides high-resolution heart images and allows for accurate assessment of myocardial viability, infarct size, and microvascular obstruction, aiding in risk stratification, and prognosis prediction.Coronary angiography: Coronary angiography is considered the gold standard for visualizing coronary artery anatomy and identifying the site and severity of coronary artery occlusion in STEMI patients. It is essential for guiding subsequent reperfusion therapies, such as primary PCI.Risk stratification is essential in STEMI patients to identify those at higher risk of adverse outcomes. Clinical risk scores, such as the Global Registry of Acute Coronary Events score, can assist in estimating the short-term and long-term mortality risk, aiding in decision-making regarding treatment strategies and the level of care required.In conclusion, a comprehensive diagnostic approach is essential for timely and accurate ST-Segment Elevation Myocardial Infarction diagnosis. Clinical evaluation, ECG, and cardiac biomarkers play vital roles in the initial assessment, while advanced imaging modalities, such as echocardiography, cardiac MRI, and coronary angiography, provide valuable information for risk stratification and treatment planning.STEMI management has evolved significantly over the years, focusing on prompt reperfusion therapy and adjunctive medical treatments to reduce myocardial damage and improve clinical outcomes.Primary PCI: Primary PCI is the preferred reperfusion strategy for STEMI patients when it can be performed promptly by an experienced team. This intervention involves the mechanical removal of the thrombus and restoration of blood flow by placing a stent in the occluded coronary artery. Primary PCI has demonstrated superior outcomes compared to thrombolytic therapy in terms of reduced mortality rates and lower risk of reinfarction.Thrombolytic therapy: In cases where primary PCI is not readily available or significant delays in performing the procedure, thrombolytic therapy may be considered an alternative reperfusion strategy. Thrombolytic agents, such as tissue plasminogen activator or reteplase, can dissolve the coronary artery thrombus and restore blood flow. However, primary PCI is preferred if performed promptly due to its better outcomes.Dual antiplatelet therapy: All STEMI patients undergoing reperfusion therapy receive dual antiplatelet therapy, typically consisting of aspirin and a P2Y12 receptor inhibitor . Dual antiplatelet therapy reduces the risk of recurrent thrombotic events and stent thrombosis.Anticoagulation: Intravenous unfractionated heparin or low-molecular-weight heparin is administered to STEMI patients to prevent clot formation and extension during reperfusion therapy. It is often used in combination with antiplatelet therapy.Beta-blockers: Beta-blockers, such as metoprolol and carvedilol, are recommended in the acute phase of STEMI to reduce heart rate, blood pressure, and myocardial oxygen demand. They help in stabilizing the infarcted myocardium and preventing arrhythmias.Angiotensin-converting enzyme (ACE) Inhibitors and angiotensin receptor blockers (ARBs): These medications are prescribed in the early phase of STEMI to reduce ventricular remodeling, improve cardiac function, and prevent heart failure development.Statins: Early initiation of statin therapy is recommended in STEMI patients to reduce cholesterol levels and decrease the risk of recurrent cardiovascular events.Cardiac rehabilitation is an integral part of the management of STEMI patients. It involves a structured program that includes exercise training, education on heart-healthy lifestyle modifications, and psychosocial support. Cardiac rehabilitation has been shown to improve functional capacity, quality of life, and long-term outcomes in STEMI patients.In conclusion, the current treatment approaches for ST-Segment Elevation Myocardial Infarction focus on timely reperfusion therapy, using primary PCI as the preferred method whenever feasible. Adjunctive medical therapies reduce myocardial damage and improve patient outcomes, including dual antiplatelet therapy, anticoagulants, beta-blockers, ACE inhibitors or ARBs, and statins. Cardiac rehabilitation also plays a significant role in optimizing recovery and long-term management.Several reputable organizations have developed guidelines for managing STEMI. These guidelines provide evidence-based recommendations for the timely and effective diagnosis and treatment of STEMI patients. For patients who cannot undergo PCI within the recommended time frame, fibrinolytic therapy is an alternative if initiated within 30 minutes of hospital arrival. The guidelines also stress the importance of dual antiplatelet therapy, beta-blockers, ACE inhibitors or ARBs, and statins in managing STEMI patients.The AHA/ACC guidelines provide comprehensive recommendations for managing STEMI, emphasizing the importance of timely reperfusion and adjunctive medical therapies. These guidelines highlight the role of primary PCI as the preferred reperfusion strategy when feasible, with a door-to-balloon time of 90 minutes or less for STEMI patients eligible for primary PCI. The guidelines also guide the use of antiplatelet therapy, anticoagulation, beta-blockers, ACE inhibitors or ARBs, and statins in STEMI patients. Moreover, the ESC guidelines stress the significance of cardiac rehabilitation and secondary prevention measures in improving long-term outcomes and reducing recurrent cardiovascular events.The ESC guidelines provide evidence-based recommendations for managing acute myocardial infarction, including STEMI. The guidelines emphasize the importance of rapid diagnosis and immediate reperfusion therapy, with a recommended door-to-balloon time of 90 minutes or less for primary PCI.The guidelines provided by the AHA, the ACC, and the ESC serve as valuable resources for healthcare professionals involved in the care of STEMI patients. These evidence-based recommendations underscore the critical importance of timely reperfusion therapy, optimal medical management, and cardiac rehabilitation in improving patient outcomes and reducing the burden of STEMI on global public health.The prognosis of STEMI is influenced by several factors, including the extent of myocardial damage, the presence of complications, the effectiveness of reperfusion therapy, and the presence of comorbidities. Early and effective treatment and adherence to secondary prevention measures can significantly impact patient outcomes.STEMI is a severe and life-threatening condition; it can lead to substantial morbidity and mortality without prompt intervention. The mortality rate in STEMI patients varies depending on age, comorbidities, and the time to reperfusion therapy. Advances in reperfusion strategies and optimal medical management have improved survival rates. With timely reperfusion therapy, including primary PCI, mortality rates have decreased significantly.Complications following STEMI, such as heart failure, ventricular arrhythmias, cardiogenic shock, and mechanical complications , can significantly impact prognosis. The early identification and management of these complications are crucial in improving patient outcomes.The extent of myocardial damage in STEMI can lead to impaired left ventricular function. Left ventricular ejection fraction is an essential prognostic marker, with lower left ventricular ejection fraction values associated with a higher risk of adverse outcomes, including heart failure and mortality.STEMI patients are at an increased risk of experiencing recurrent cardiovascular events, such as myocardial infarction, stroke, or unstable angina. Secondary prevention measures, including adherence to medication regimens and lifestyle modifications, are essential in reducing the risk of recurrent events.Participation in cardiac rehabilitation programs has improved functional capacity and quality of life and reduced mortality in STEMI patients. Regular exercise, education on risk factor modification, and psychosocial support contribute to better long-term outcomes.In conclusion, the prognosis of ST-Segment Elevation Myocardial Infarction is influenced by various factors, including myocardial damage, complications, and the effectiveness of reperfusion therapy. Early and effective treatment and adherence to secondary prevention measures can significantly impact patient outcomes and improve long-term prognosis.STEMI represents a critical and life-threatening cardiovascular emergency that demands immediate attention and optimal management. The condition arises from the sudden occlusion of a coronary artery due to atherosclerotic plaque rupture and subsequent thrombus formation, leading to acute myocardial ischemia and necrosis. Prompt recognition and intervention are paramount to salvaging the ischemic myocardium and reducing morbidity and mortality.Advances in reperfusion strategies, such as primary PCI, have revolutionized the treatment of STEMI patients, significantly improving survival rates and reducing long-term complications. The administration of adjunctive medical therapies, including dual antiplatelet therapy, anticoagulation, beta-blockers, ACE inhibitors or ARBs, and statins, further enhances outcomes and reduces the risk of recurrent events. The guidelines provided by renowned organizations, such as the AHA and the ESC, serve as invaluable resources, offering evidence-based recommendations to healthcare professionals involved in the care of STEMI patients.Despite significant advancements in diagnosis and management, STEMI remains a considerable global health concern. Its epidemiology and risk factors vary across different regions and populations, with age, sex, lifestyle, and access to healthcare playing critical roles. Furthermore, the prognosis of STEMI patients is influenced by factors such as the extent of myocardial damage, complications, left ventricular function, and adherence to secondary prevention measures.Early recognition and effective reperfusion therapy implementation, comprehensive medical management, and cardiac rehabilitation are essential to optimize patient outcomes. Furthermore, addressing risk factors, promoting healthy lifestyle choices, and ensuring timely access to medical care can significantly contribute to reducing the burden of STEMI on global health systems.In pursuing better patient outcomes, research and innovation continue to drive improvements in the diagnosis, treatment, and management of STEMI. The evolving landscape of cardiovascular medicine offers hope for further advancements, with the ultimate goal of reducing the incidence, morbidity, and mortality associated with ST-Segment Elevation Myocardial Infarction.Conceptualization: Chukwuka Elendu, Dependable C. Amaechi, Tochi C. Elendu, Chisom E. Alakwe-Ojimba, Otite L. Akpovona, Yuliana Paola Oros Sucari, Kanishk Dang.Data curation: Chukwuka Elendu, Dependable C. Amaechi, Tochi C. Elendu, Kanishk Dang.Formal analysis: Chukwuka Elendu, Dependable C. Amaechi, Tochi C. Elendu.Funding acquisition: Chukwuka Elendu.Investigation: Chukwuka Elendu, Dependable C. Amaechi, Tochi C. Elendu, Eunice K. Omeludike.Methodology: Chukwuka Elendu, Dependable C. Amaechi, Tochi C. Elendu, Chisom E. Alakwe-Ojimba, Yuliana Paola Oros Sucari.Project administration: Chukwuka Elendu, Dependable C. Amaechi, Tochi C. Elendu, Babajide Obidigbo, Kanishk Dang.Resources: Chukwuka Elendu, Dependable C. Amaechi, Tochi C. Elendu, Babajide Obidigbo.Software: Chukwuka Elendu, Dependable C. Amaechi, Tochi C. Elendu, Sehajmeet Kaur Saggi, Chinedu P. Chinedu.Supervision: Chukwuka Elendu, Dependable C. Amaechi, Tochi C. Elendu, Yuliana Paola Oros Sucari, Chinedu P. Chinedu.Validation: Chukwuka Elendu, Dependable C. Amaechi, Tochi C. Elendu.Visualization: Chukwuka Elendu, Dependable C. Amaechi, Tochi C. Elendu, Sehajmeet Kaur Saggi, Kanishk Dang.Writing \u2013 original draft: Chukwuka Elendu, Dependable C. Amaechi, Tochi C. Elendu, Yuliana Paola Oros Sucari, Sehajmeet Kaur Saggi.Writing \u2013 review & editing: Chukwuka Elendu, Dependable C. Amaechi, Tochi C. Elendu, Eunice K. Omeludike, Otite L. Akpovona, Yuliana Paola Oros Sucari, Sehajmeet Kaur Saggi, Kanishk Dang."}
+{"text": "Heat shock proteins (HSPs) encompass both extrinsic chaperones and stress proteins. These proteins, with molecular weights ranging from 14 to 120 kDa, are conserved across all living organisms and are expressed in response to stress. The upregulation of specific genes triggers the synthesis of HSPs, facilitated by the interaction between heat shock factors and gene promoter regions. Notably, HSPs function as chaperones or helper molecules in various cellular processes involving lipids and proteins, and their upregulation is not limited to heat-induced stress but also occurs in response to anoxia, acidosis, hypoxia, toxins, ischemia, protein breakdown, and microbial infection. HSPs play a vital role in regulating protein synthesis in cells. They assist in the folding and assembly of other cellular proteins, primarily through HSP families such as HSP70 and HSP90. Additionally, the process of the folding, translocation, and aggregation of proteins is governed by the dynamic partitioning facilitated by HSPs throughout the cell. Beyond their involvement in protein metabolism, HSPs also exert a significant influence on apoptosis, the immune system, and various characteristics of inflammation. The immunity of aquatic organisms, including shrimp, fish, and shellfish, relies heavily on the development of inflammation, as well as non-specific and specific immune responses to viral and bacterial infections. Recent advancements in aquatic research have demonstrated that the HSP levels in populations of fish, shrimp, and shellfish can be increased through non-traumatic means such as water or oral administration of HSP stimulants, exogenous HSPs, and heat induction. These methods have proven useful in reducing physical stress and trauma, while also facilitating sustainable husbandry practices such as vaccination and transportation, thereby offering health benefits. Hence, the present review discusses the importance of HSPs in different tissues in aquatic organisms , and their expression levels during pathogen invasion; this gives new insights into the significance of HSPs in invertebrates. Due to the poikilothermic nature of aquatic animals, minor changes in the environment might lead to stress in fish. Fish are often exposed to various environmental stressors, such as pathogens, toxic gases, trauma, temperature fluctuations, and hypoxia. These factors, often referred to as stressors or stress factors, hold significant importance in determining the sequence of events that unfolds after encountering adverse consequences such as microbial infections, toxic exposure, traumatic injury, radiation, or nutritional deficiencies . AccordiResearch on the general adaptation syndrome in fish has primarily focused on hormonal and nervous responses. The role of the hypothalamic\u2013pituitary internal axis in the GAS in fish has been extensively reviewed by Sumpter 1997) . The imp . The imThe impact of temperature on organisms is well recognized, as it can influence their physiology ,12,13, bCrassostrea hongkongensis [Eriocheir sinensis [Scylla paramamosain [Portunus trituberculatus, HSP60, HSP70, and HSP90 showed either downregulated or upregulated expression profiles when exposed to low salinity (4 ppt) [Osmotic stress is a prevalent environmental factor that affects aquatic organisms. Osmoregulation, which is vital in maintaining osmotic homeostasis, plays a crucial role in response to this type of stress. The influence of stressors such as temperature or salinity on organisms has been studied extensively ,25. Thesongensis  and Eriosinensis ,29 undermamosain . In the  (4 ppt) . These fParacyclopina nana [Ultraviolet (UV) radiation, an abiotic factor, can have detrimental effects on organisms, both directly and indirectly. Direct exposure to UV radiation can lead to changes in protein synthesis and DNA due to the absorption of high-energy photons. Indirectly, UV radiation can generate reactive oxygen species that cause damage to proteins, nucleic acids, and lipids ,33,34. TPortunus trituberculatus [Heavy metals pose a significant problem as a cause of pollution in water, soil, and plants. They enter water sources through seepage from household or industrial waste, resulting in serious risks to aquatic ecosystems and aquaculture animals. In laboratory studies focusing on crustaceans, the impact of heavy metals on gene expression changes has been extensively examined. Commonly tested heavy metals include copper (Cu), silver (Ag), zinc (Zn), lead (Pb), manganese (Mn), arsenic (As), and cadmium (Cd) ,37,38. Hrculatus . This tyrculatus  and heatrculatus ,38. Heatrculatus ,37,38.Endocrine disruptor chemicals (EDCs) are compounds that imitate natural hormones, inhibiting their activity or altering their normal regulatory function within the immune, nervous, and endocrine systems . These c2O2), among others. They accumulate in aquatic and/or terrestrial environments through the release of household and/or industrial waste. Research studies have demonstrated that these toxicants can have harmful effects on crustaceans [Skeletonema marinoi) that produced strong oxylipins for only two days led to the significant downregulation of heat shock proteins (HSP40 and HSP70) in the copepod Calanus helgolandicus. Diatom oxylipins are known to induce the generation of free radicals, including reactive oxygen species, which can cause oxidative stress and cellular damage. Furthermore, nitrite is considered one of the most prevalent pollutants in aquaculture due to its numerous integrated effects. A study on shrimp demonstrated that oxidative stress was one of the mechanisms of nitrite toxicity [Apart from the previously mentioned primary chemicals, there exist a significant number of other toxic substances in the habitats of aquatic organisms. These toxicants include hydrocarbons, diatom toxins, emamectin benzoate, nitrite, and prooxidant chemical hydrogen peroxide  initially occurred in o stress . Since to stress ,56. In ao stress ,58. Physo stress ,60. In to stress . Furthero stress .Crustacean aquaculture plays a significant role in the economies of several countries worldwide. However, the expansion and intensification of aquaculture farms have led to the emergence of various new diseases in commercially cultivated species. Disease outbreaks caused by viruses, bacteria, and environmental stressors pose a serious threat to the global crustacean aquaculture industry, resulting in substantial economic losses. Unlike vertebrates, invertebrates lack true adaptive immunity and have developed defense systems that respond to physiological and environmental stresses ,63. DuriVibrio, chitinoclastic bacteria, Aeromonas, Spiroplasma, Rickettsia-like organisms, Chlamydia-like organisms, Rhodobacteriales-like organisms, white spot syndrome virus (WSSV), yellow head virus (YHV), infectious myonecrosis virus (IMNV), Enterocytozoon hepatopenaei (EHP) microsporidian parasites, and covert mortality nodavirus (CMNV), have been identified as causes of disease in crustaceans [Vibrio species, found in various marine and freshwater crustaceans, are widespread worldwide. Vibrio infections commonly result in bacteremia and shell diseases [Vibrio parahaemolyticus infection caused acute hepatopancreatic necrosis disease (AHPND) and led to significant mortality in a penaeid shrimp aquaculture [Rickettsia-like organisms, Chlamydia-like organisms, spiroplasma, and Rhodobacteriales-like organisms, have caused severe stress or fatal diseases in crustaceans. Efforts have been made by numerous researchers to find effective methods to control bacterial diseases. Recent studies have shown that synbiotics can induce penaeid shrimp immunity and promote the growth of aquatic animals [spiroplasma disease [Shellfish diseases are prevalent and frequently observed in various commercially exploited crustacean species. Currently, a range of pathogens, including staceans . Vibrio diseases . For insaculture . Chitinoaculture  or septiaculture . Infecti animals . Oxytetr disease . Several disease , have be disease . Additio disease .Danio rerio), rainbow trout (Oncorhynchus mykiss), and gilthead seabream (Sparus aurata), in response to stressors [The presence of heat shock proteins (HSPs) in fish has been extensively documented, emphasizing their importance in responding to stress and safeguarding cellular integrity. HSPs are a group of highly conserved proteins that serve as molecular chaperones, aiding in the folding, assembly, and breakdown of other proteins. Fish exhibit increased HSP production when exposed to various stressors, such as elevated temperatures, exposure to heavy metals, oxidative stress, and infection by pathogens. Numerous studies have observed the heightened expression of HSPs in different fish species, including zebrafish  during development (The expression of heat shock proteins (HSPs) is associated with important developmental processes in various species, including gametogenesis, embryogenesis, and metamorphosis. In marine invertebrates with a biphasic life cycle, where pelagic larvae undergo settlement and metamorphosis, research has revealed interesting findings. For instance, studies on Eastern oyster elopment . HSP70, elopment . These pDrosophila busckii, Ritossa was the first to note that heat and the metabolic uncoupler dinitrophenol caused a distinctive pattern of puffing in the salivary gland chromosomes [Drosophila cells in response to stressors such as heat shock was made in 1974 [A group of conserved polypeptides collectively known as heat shock proteins (HSPs) are rapidly increased in synthesis by insects in response to high temperatures and a variety of chemical and physical stimuli. Hspshave molecular-weight-based names, such as Hsp10, Hsp40, Hsp60, Hsp70, Hsp90, and Hsp100. Small Hsps (sHsp) are a subclass of Hsps that play a role in the folding and unfolding of other proteins . In the omosomes . This di in 1974 . There i in 1974 ,172.T. bryosalmonae, a parasite, faces the challenge of overcoming the robust immune responses mounted by both brown trout and rainbow trout [T. bryosalmonae, including protein structure and function. Moreover, HSPs found in several parasites, such as T. cruzi [Ceratonova shasta, Myxobolus cerebralis, and Sphaerospora molnari from the intestine and abdominal cavity (ascitic fluid) of rainbow trout expressed HSP70 when exposed to oxidative stress [Heat shock proteins (HSPs) are expressed by parasites as a response to various stimuli, such as heat and oxidative stress. These HSPs provide parasites with resistance to these harsh conditions, which is crucial for their survival. The genes associated with protein refolding, including HSP60, HSP70, and HSP80 family members, express these heat shock proteins. Apart from their role in protein refolding, HSPs also show significant involvement in other processes, such as maintaining protein balance and stability. They have the ability to bind to abnormal forms of proteins and facilitate their folding into their natural conformations. ow trout . This chT. cruzi  and SchiT. cruzi , have bee stress .The heat shock protein family, such as HSP70, are primarily studied for disease control purposes, but other members, such as small heat shock proteins (sHSPs), including HSP60 and HSP90, alongside HSP40/co-chaperone, have shown potential in treating pathogen infections. sHSPs act as oligomeric platforms, binding structurally perturbed proteins without requiring ATP, thereby preventing their irreversible denaturation under cellular stress. HSP90, HSP70, and HSP60 are stress-induced and provide protection against irreversible protein denaturation. However, their primary function involves binding and folding newly synthesized proteins through allosteric rearrangement, which is driven by ATP, although the mechanisms of action and the molecular structure differ among the chaperone families. In cooperation, these HSPs form intracellular networks with accessory proteins and other co-chaperones. sHSP monomers are a group of conserved \u03b1-crystallin domains flanked by carboxyl- and amino-terminal sequences and assemble into oligomers. The \u03b1-crystallin domain facilitates monomer dimerization and substrate binding, with the efficiency depending on the terminal region. During stress, sHSP oligomers may undergo structural rearrangement or disassemble, which promotes substrate protein interactions and increases surface hydrophobicity. Upon stress resolution, proteins released from sHSPs have the ability to spontaneously refold with the assistance of HSP70, which is an ATP-dependent HSP . The keyL. vannamei) and Scrippsiella trochoidea, various HSP genes  are significantly induced under acute thermal stress, highlighting their sensitivity to temperature fluctuations. Shrimp HSPs are also highly expressed in response to pathogen infections, as demonstrated by the upregulation of LvHsp60 in the gills, hemocytes, and hepatopancreas after challenge with Gram-negative or Gram-positive bacteria. Furthermore, the use of plant-based polyphenolic compounds such as phloroglucinol and carvacrol has been shown to result in the induction of HSP70 and protection against bacterial infection in brine shrimp and freshwater prawns [In aquatic organisms, such as the white shrimp  and result in serious losses in aquaculture  203,204204. In aOur understanding of the chaperone system of HSPs and its significance in farmed aquatic organisms is still limited, but progress is being made in medical and veterinary research. There have been rapid advances in comprehending the fundamental aspects of HSP genes and the effects of their products and their regulation on cell maintenance, as well as cell signaling, inflammation, and the immune response. This knowledge has been applied to various veterinary and human clinical situations, and promising results have been obtained during the initial development of HSP vaccines derived from pathogens. These advancements indicate the potential value of HSPs in numerous areas of aquatic science. Further exploration of the HSP chaperone system and its applications could have significant implications for the health and wellbeing of farmed aquatic animals, providing opportunities for advancements in aquaculture practices, disease prevention, and overall aquatic ecosystem management."}
+{"text": "Lactobacillus and Bifidobacterium), prebiotics , synbiotics, postbiotics , dairy products, spices , fruits, vegetables, medicinal herbs, and so on, could exert protective effects against mental disorders by enhancing beneficial gut microbiota while suppressing harmful ones. In this paper, the mental disorder-associated gut microbiota are summarized. In addition, the protective effects of dietary components on mental health through targeting the gut microbiota are discussed. This paper can be helpful to develop some dietary natural products into pharmaceuticals and functional foods to prevent and treat mental disorders.The number of individuals experiencing mental disorders  has significantly risen in recent years. Therefore, it is essential to seek prevention and treatment strategies for mental disorders. Several gut microbiota, especially Firmicutes and Bacteroidetes, are demonstrated to affect mental health through microbiota\u2013gut\u2013brain axis, and the gut microbiota dysbiosis can be related to mental disorders, such as anxiety, depression, and other mental disorders. On the other hand, dietary components, including probiotics (e.g.,  Bacteroides uniformis, Roseburia inulinivorans, Eubacterium rectale, and Faecalibacterium prausnitzii exerted a positive effect on the maintenance of mental health by producing short-chain fatty acids (SCFAs) and regulating amino acid, taurine, and cortisol metabolism pathways [Mental health is one of the United Nations\u2019 Sustainable Development Goals, and mental disorders mainly include anxiety, depression, bipolar disorder, autism spectrum disorder (ASD), schizophrenia, and eating disorders . In 2019pathways . Additiopathways ,19. Therpathways . Therefopathways ,23,24,25pathways ,26,27. Fpathways . Anotherpathways .In this narrative review, we conducted a comprehensive search of Web of Science Core Collection and PubMed databases, gathered relevant high-quality literature published within the past five years, and retrieved the keywords of anxiety, depression, bipolar disorder, autism spectrum disorder, schizophrenia, mental disorder, mental health, gut microbiota, probiotics, prebiotics, postbiotics, dairy product, spice, fruit, vegetable, medicinal herb, and natural product. In this review paper, the relationships between gut microbiota and mental disorders are first summarized, followed by a discussion of the impacts of natural dietary products on mental health by regulating the gut microbiome, emphasizing the underlying mechanisms. This review paper could be helpful for people to make informed choices regarding natural dietary products for the prevention and management of mental disorders, and it may also promote the development of natural dietary products by the industry as pharmaceuticals and functional foods to maintain mental health. The composition of gut microbiota is complex; some microorganisms may protect mental health, while others may be related to the onset and development of mental disorders. In the following part, the association of gut microbiota with certain mental disorders is summarized below, and more detailed information can be found in Prevotella was increased, while the Firmicutes/Bacteroidetes ratio and the abundance of Faecalibacterium spp. were significantly reduced in individuals with social exclusion [Firmicutes spp. and microbiota that produce SCFAs, but more Fusobacteria and Bacteroidetes [Prevotella_9 and Lachnospira, as well as immunoglobulin proteins, but had an increase in the abundances of Lactobacillales, Sellimonas, Streptococcus, and Enterococcus [Firmicutes [Anxiety is among the most common mental disorders . It is ixclusion . Moreovexclusion . Additioroidetes . In addirococcus . Moreoverococcus . Anotherrmicutes .Firmicutes, but higher Bacteroidetes and Fusobacteria. At the genus level, several gut microbiota genera were positively correlated with anxiety, such as Prevotella, Lactobacillales, Sellimonas, Streptococcus, and Enterococcus, while some gut microbiota genera were inversely correlated with anxiety, suggesting that targeting these gut microbiomes could be a promising approach for preventing anxiety. At present, most studies focus on the genus level of anxiety-related gut microbiota. In the future, more research should highlight the species level of gut microbiota, considering that different species in the same genera could exert different functions, or even the opposite functions, on anxiety.In brief, patients/mice with anxiety showed dramatically decreased microbial richness and diversity. At the phylum level, anxiety patients/mice usually had lower Dialister and Coprococcus spp. were decreased in patients with depression [Prevotella, Klebsiella, Streptococcus and Clostridium XI, but lower levels of Bacteroidetes [Helicobacter pylori (H. pylori) infection could induce a pathological state of gastrointestinal flora. For instance, a cross-sectional study including 5558 Chinese people found a significantly higher risk of depressive symptoms in women infected with H. pylori, but not in men [H. pylori and cancer [Klebsiella aerogenes) compared to healthy controls [Dialister sp., which could modulate the immune and metabolic activity of the host.Depression is considered a major public health problem . Depresspression . Furtherroidetes . Moreovet in men . This cod cancer . In addicontrols . Furthercontrols . Anothercontrols . Anothercontrols . AdditioPrevotella, Klebsiella, and Clostridium, showed a positive relationship with depression. Moreover, gut microbiota dysbiosis might be a crucial factor in the pathogenesis of depression via influencing the protein expression in tissues related to the gut\u2013brain axis. Although the specific gut microbiota of people with depression varied from study to study, all these discoveries showed that gut microbiota composition significantly changed in depressive individuals and indicated that gut microbiota might be a novel target for the prevention and management of depression. Similar to the anxiety mentioned above, most of the studies about gut microbiota related to depression have been mainly at the genus level in recent years. More research studies should be conducted at the species level to further investigate the connection between gut microbiota and depression, since the effects of different species of gut microbiota in the same genera on depression could be different or opposite. In a word, gut microbiota in individuals/animals with depression were found to differ in composition and abundance from those in healthy controls. At the family level, certain gut microbiota were positively correlated with depression, such as Paraprevotella, but some others were negatively associated with depression, such as Streptococcaceae and Gemella. At the genus level, several gut microbiota genera, such as Clostridiaceae and Collinsella [Flavonifractor was associated with bipolar disorder (odds ratio (OR), 2.9; 95% CI, 1.6\u20135.2) [Faecalibacterium significantly decreased in bipolar disorder patients [Bifidobacterium (phylum Actinobacteria) or Lactobacillus bacterial counts between the two groups of 39 bipolar disorder patients and 58 healthy individuals [Bipolar disorder is a chronic and incapacitating illness that often reoccurs, leading to cognitive and functional impairment . Severallinsella . Additio1.6\u20135.2) . Anotherpatients . Moreovepatients . Howeverividuals . The disClostridiaceae, Collinsella, and the phyla of Actinobacteria and Coriobacteria, but lower abundances of Faecalibacterium and Ruminococcaceae. Further large-scale population studies are required in the future to investigate the impact of various gut microbiota on bipolar disorder, and the participants should be more representative, such as more races from different countries with different gender as well as age. In general, bipolar disorder patients had higher abundances of Clostridium bolteae than their unaffected family members [Clostridium paraputri, Clostridium bolteae, and Clostridium perfringens were found in the feces of Egyptian ASD children. In addition, Clostridium diffiicile and Clostridium clostridiioforme were only found in ASD children, while Clostridium tertium was only found in normal children [Actinobacteria, Proteobacteria, as well as Bacilli [Fmrl KO mice with autistic-like behaviors had a reduced population of Akkermansia muciniphila, accompanied with increased levels of TNF-\u03b1 and Iba1 [Faecalibacterium and Agathobacter. These bacterial strains were positively linked to the levels of 3-hydroxybutyric acid and melatonin, but negatively correlated with the level of serotonin [ASD is a heterogeneous neurodevelopmental disorder . Researc members . Anotherchildren . Moreove Bacilli . Additioand Iba1 . Furthererotonin . Clostridium diffiicile and Clostridium clostridiioforme. Moreover, certain gut microbiota were increased in ASD patients/animals, such as Actinobacteria, Proteobacteria, and Bacilli, whereas some were decreased, such as Akkermansia muciniphila, Faecalibacterium and Agathobacter. In the future, more studies about the association between gut microbiota and ASD need to be conducted to find out more beneficial or harmful gut microbiota, which could be targeted for the management of ASD.Overall, several species of gut microbiota were only found in ASD patients, such as Schizophrenia affects 1% of the world\u2019s population, and patients with schizophrenia may exhibit positive symptoms like hallucinations and disorganized speech, negative symptoms like an absence of interest and motivation, and cognitive deficits like impaired executive functions and memory . Haemophilus [Haemophilus abundance and negative symptoms of schizophrenia [Ruminococcus and Roseburia, as well as an increased abundance of Veillonella [Lachnospiraceae [Lactobacillus fermentum and Enterococcus faecium [Proteobacteria, but lower abundances of Faecalibacterium and Lachnospiraceae [Succinivibrio was positively correlated with the severity of schizophrenia symptoms, while the abundance of Corynebacterium was negatively related to the negative symptoms [Mounting evidence indicated that schizophrenia was associated with gut microbiota dysbiosis. For instance, a case-control study showed that gut microbiome dysbiosis was found in schizophrenia patients . A crossmophilus . Howeverophrenia . The disllonella . Anotherpiraceae . Additio faecium . Anotherpiraceae . In addisymptoms . Additiosymptoms .Lactobacillus fermentum, Enterococcus faecium, and Alkaliphilus oremlandii, could be only found in patients with schizophrenia. Some gut microbiota were positively correlated to the severity of schizophrenia, such as Lachnospiraceae, Veillonella, Collinsella, Lactobacillus, Succinivibrio, and Corynebacterium, whereas some were negatively correlated with schizophrenia, such as Coprococcus, Ruminococcus, Roseburia, Adlercreutzia, Anaerostipes, and Faecalibacterium. Furthermore, the gut microbiota could affect neurochemistry and neurologic function through modulating the metabolism of enteric and central nervous system function-related molecules, such as GABA. A supplement of beneficial gut microbiota, which were absent in patients with schizophrenia, might be useful for the treatment of schizophrenia. Alternatively, the reduction in harmful gut microbiota, which were only found in patients with schizophrenia, could be another therapeutic strategy via the administration of medicine or functional foods. Collectively, some special gut bacteria, such as Eubacterium hallii and Bacteroides eggerthii were correlated to the reappearance of post-traumatic stress symptoms in frontline healthcare workers during the COVID-19 pandemic [Mitsuokella, Odoribacter, Catenibacterium, and Olsenella [Fusicatenibacter saccharivorans [Agathobacter, Anaerostipes, and Lachnospiraceae, as well as the plasma level of TNF-\u03b1 [In addition to the mental disorders mentioned above, many other mental disorders are linked to the gut microbiota, such as anorexia nervosa, PTSD, and attention-deficit/hyperactivity disorder (ADHD). For example, it was reported that patients with anorexia nervosa had a reduction in Bacteroidetes and gut microbiota dysbiosis, contributing to anorexia nervosa-specific pathologies . Anotherpandemic . Anotherlsenella . A studyrivorans . Additioof TNF-\u03b1 . Anotherof TNF-\u03b1 .In short, some gut microbiota were associated with some mental disorders, such as anxiety, depression, bipolar disorder, ASD, schizophrenia, anorexia nervosa, PTSD, and ADHD , which cMany dietary components have been shown to exert protective effects against mental disorders through regulating gut microbiota, such as probiotics, prebiotics, postbiotics, fruits, vegetables, and spices, which are discussed below and are shown in Lactobacillus, could prevent and manage several mental disorders by modulating the gut microbiota. For instance, a study showed that Lactobacillus murine (L. murine) and L. reuteri could increase GABA content in the hippocampus and alleviate depression-like behaviors in Dcf1 knockout mice [L. rhamnosus zz-1 alleviated depression-like behaviors in mice induced by chronic unpredictable mild stress (CUMS) improved hypothalamic\u2013pituitary\u2013adrenal (HPA) axis hyperactivity, and increased monoamine neurotransmitters, brain-derived neurotrophic factor (BDNF), and tyrosine kinase receptor B (TrkB) through regulation of gut microbiota, such as recovering the relative abundances of Lachnospiraceae NK4A136, Bacteroides as well as Muribaculum [Pediococcus acidilactici CCFM6432 could alleviate anxiety-like behaviors caused by stress through inhibiting the over-proliferation of Escherichia shigella and promoting Bifidobacterium growth in C57BL/6 mice [Akkermansia muciniphila reduced depressive-like behavior in mice through reversing gut microbial abnormalities [Enterococcus faecalis strain EC-12 reduced anxiety-like behavior and enhanced Butyricicoccus and Enterococcus in mice [L. rhamnosus HN001 significantly decreased the depression and anxiety scores of women in the postpartum period [L. rhamnosus Probio-M9 enhanced the psychological and physiological qualities of life in stressed adults through increasing the relative abundances of certain species of gut microbiota [Probiotics have become a hotspot in the research fields of foods, nutrition, biology, and medicine, and can be used to prevent and manage several diseases, such as constipation, obesity, and cardiovascular disease. As mentioned above, several mental disorders were associated with abnormalities in gut microbiota. An increasing number of studies have revealed that probiotics, particularly the genus out mice . Moreoveibaculum . AdditioL/6 mice . Moreovemalities . In addi in mice . A studym period . Anothercrobiota . Lactobacillus reuteri NK33 and Bifidobacterium adolescentis NK98 improved mental health and sleep through modulating gut microbiota [Ruminococcus gauvreauii and Coprococcus 3 [Actinobacteria, Cyanobacteria, and S24-7_unclassified were decreased in the gut of stress mice, while multi-strains of probiotics recovered these changes as well as reduced depressive-like behaviors in mice [The multi-strain probiotic formulation could also exert preventive and therapeutic effects on mental disorders. A study based on 156 adults with subclinical symptoms of mental disorders showed that the mixture of crobiota . Anothercoccus 3 . Moreove in mice . Lactobacillus, Bifidobacterium, Pediococcus acidilactici CCFM6432, and Akkermansia muciniphila, showed significant preventive and therapeutic effects on several mental disorders, such as anxiety and depression. They influenced neurotransmitter metabolism, improved HPA axis hyperactivity, and increased the expression of BDNF and TrkB through modulating gut microbiota. Furthermore, multi-strain probiotic formulations might have more efficient actions on mental health protection compared with a single probiotic strain. It is also important to consider the interactions between different bacteria and their metabolites when exploring multi-strain probiotics formulations. The beneficial effects of more probiotics on different mental disorders (not only anxiety and depression) should be investigated by high-quality clinical trials in the future. In short, probiotics, such as The studies indicated that prebiotics and postbiotics could also be potential for the prevention and management of mental disorders, such as anxiety, depression, ASD, and schizophrenia ,113,114.Bifidobacterium in the 4-week intervention of 64 late adolescent females [\u00ae galactooligosaccharide (B-GOS\u00ae) prebiotic dramatically increased Lachnospiraceae and enhanced anti-social behavior in 30 autistic children [Bifidobacterium in a study based on 20 depression patients in Japan [Lactobacillus and Bifidobacterium [It was reported that dietary fibers could improve the relationship between gut microbiota and the central nervous system in schizophrenia patients through regulating gut microbiota . A doubl females . Anotherchildren . Howeverin Japan . The disacterium . Additioacterium . A study showed that SCFAs could ameliorate high fructose-induced depressive-like behaviors in mice by improving hippocampal neurogenesis decline and blood\u2013brain barrier damage . It was \u00ae and alpha-lactalbumin) as well as postbiotics (such as SCFAs) exerted protective effects on mental health, especially in combinative administration. Moreover, prebiotics could be a potential agent to alleviate the side effects of antipsychotics. In the future, the effects of more prebiotics and postbiotics on different mental disorders should be studied. Because synbiotics could exert the synergistic or additive effects of probiotics and prebiotics, more attention should be paid to the effects of synbiotics on mental disorders. In addition, because postbiotics are considered to be safer and more stable than probiotics, their effects on mental disorders should also be highlighted. Furthermore, more large-scale clinical trials are necessary to prove the influences of prebiotics and postbiotics on mental disorders, including health benefits as well as side effects.In a word, prebiotics , but decreased harmful bacteria  in the gut, and ultimately alleviated constipation and potentially depressive symptoms [Lactobacillus spp. in juvenile rats, which was positively correlated with changes in serotonin (5-HT)1A and 5-HT2C mRNA expression [Lactiplantibacillus plantarum ST-III-fermented milk improved the autistic-like behaviors in male ASD mice through modulating specific gut microbes, such as increasing the relative abundance of family Lachnospiraceae and genus Kineothrix [Dipteryx alata Vog.) and goat whey modulated gut microbiota  improved memory and relieved anxiety in elderly rats [Lactobacillus by 235%, decreased Phascolarctobacterium by 25% in gut microbiota, and improved hippocampal function [Dairy products are important components of both traditional and modern diets, and have a variety of health benefits. A double-blinded RCT based on 82 depressive patients with constipation found that the intervention of a fermented dairy beverage containing symptoms . Anotherpression . It was neothrix . In addirly rats . Moreovefunction . Howeverfunction . This diTo sum up, dairy products and their bioactive components showed neuroprotective effects via modulation of gut microbiota . Since fCurcuma longa), shows various biological activities [Capsicum annuum L.), alleviated lipopolysaccharide-induced depressive-like behaviors and reduced levels of 5-HT and TNF-\u03b1 by enhancing the relative abundances of certain gut microbiota, such as Ruminococcus and Prevotella [Zanthoxylum bungeanum may have a significant impact in alleviating and mitigating symptoms of depression via restoring the chronic unpredictable stress-induced gut microbiota dysbiosis, such as increasing Bacteroidales_S24-7_group, Lactobacillaceae, and Prevotellaceae, and decreasing Lachnospiraceae [Spices have a long history of being used as both food flavorings and traditional medicine, which possess many bioactive functions, such as anti-inflammatory, antibacterial, antifungal, and anticancer activities ,120. Mortivities ,122. It tivities . In addievotella . Furtherpiraceae .Zanthoxylum bungeanum, curcumin, and capsaicin) showed protective effects against anxiety and depression via regulating gut microbiota  enhanced memory and attention via regulating gut microbiota. The study further found that Cereboost\u00ae could increase levels of certain SCFAs in the intestinal tract through increasing the abundances of Akkermansia muciniphila and Lactobacillus by an in vitro model [Ginkgo biloba leaves could reduce stress-induced depression through reversing gut dysbiosis [Lycium barbarum polysaccharide during pregnancy could reduce the emotional injury of offspring caused by prenatal chronic stress through modulating the intestinal microbiota, such as enhancing the diversity of gut microbiota [Many other natural products also played vital roles in the prevention and management of mental disorders through the regulation of gut microbiota, such as fruits, vegetables, and medicinal herbs. A study showed that a higher intake of fruits and vegetables was positively correlated with better mental health based on 5845 Australian adults . Anothererium_uc . Additioro model . Anotherysbiosis . Moreovecrobiota . Additiocrobiota .Camellia sinensis, such as green tea and black tea) and tea-like beverages  should be given increased attention, because they are popular beverages with many bioactivities and beneficial effects.In a word, several fruits, vegetables, and medicinal herbs could alleviate the severity of mental disorders and enhance mental health via modulating the gut microbiota . In the Lactobacillus and Bifidobacterium), prebiotics , synbiotics, postbiotics , dairy products, spices , fruits, vegetables, and medicinal herbs could prevent and manage the mental disorders by modulating intestinal microbiota, including increasing beneficial gut microbiota and reducing harmful gut microbiota. Therefore, the supplement of dietary components mentioned above could be potential prevention and treatment strategies for mental disorders, except pharmacotherapy and psychotherapy. In addition, when the results from animal experiments are extrapolated to human beings, the differences between animals and humans should be considered. In the future, a greater number of experimental studies and high-quality large-sample clinical trials are required to explore the effects of more dietary components on mental disorders through the microbiota\u2013gut\u2013brain axis, and synbiotics and postbiotics need highlighting. Meanwhile, further elucidation and investigation of the underlying mechanisms of action is imperative. This paper is helpful for the public to choose natural dietary products to maintain mental health, and for natural dietary products to be developed into pharmaceuticals and functional foods for the prevention and treatment of several mental disorders.The gut microbiota and its metabolites could play an important role in mental health through the microbiota\u2013gut\u2013brain axis. The composition and abundance of gut microbiota, especially Firmicutes and Bacteroidetes, were associated with several mental disorders, such as anxiety, depression, bipolar disorder, ASD, and schizophrenia. At present, most studies about gut microbiota with mental disorders focused on the genus level, and more studies on gut microbiota should be carried out at the species level in the future, because the different species in the same genera could have different effects (even the opposite function) on mental disorders. Furthermore, due to the potential significant differences in the composition of the gut microbiome among individuals, it is crucial to accurately identify the changes of featured microbes that occur in each individual with mental disorders, which is important for personalized treatment of mental disorders through targeting gut microbiota. The epidemiological, experimental, and clinical studies have revealed that many kinds of probiotics (particularly"}
+{"text": "Pets (mostly domestic dogs and cats) play an important role in the daily lives of humans and their health has attracted growing attention from pet owners. The intestinal microbiota, a complex microbial community with barrier-protective, nutritional, metabolic, and immunological functions, is integral to host health. Dysbiosis has been related to a variety of diseases in humans and animals. Probiotics have been used in functional foods and dietary supplements to modulate intestinal microbiota and promote host health, which has been introduced in pet dogs and cats in recent years. Various canine- and feline-derived probiotic strains have been isolated and characterized. The administration of probiotics has shown positive effects on the gut health and can alleviate some intestinal diseases and disorders in dogs and cats, although the underlying mechanisms are largely unresolved. In this review, we summarize the current knowledge on the benefits of probiotics and discuss their possible mechanisms in dogs and cats in order to provide new insights for the further development and application of probiotics in pets. With the advancement of society and improvement in people\u2019s quality of life, an increasing number of households are raising pets or companion animalsthat are dominated by domestic dogs and cats. According to a report by the American Pet Products Association, 70% of American households owned pets by 2021 ,4. It isThe microbiota in the gastrointestinal tract (GIT) comprises a complex community of microorganisms, including bacteria, fungi, archaea, protists, and viruses . The GITLactobacillus, Bifidobacterium, Enterococcus, and Saccharomyces are commonly used probiotics in functional foods and dietary supplements [The use of probiotics is a promising approach for manipulating the gut microbiota to promote host health ,21,22,23plements ,24,27.Probiotics have been introduced to companion animals in recent years, and current evidence suggests the benefits of probiotics in health promotion and disease prevention in dogs and cats, although related research is not thorough relative to that in humans and livestock species ,28,29. HAdvancements in high-throughput microbiome techniques such as 16S rRNA gene sequencing, metagenomics, metatranscriptomics, metabolomics, culturomic, and multi-omics make it possible to decipher the composition and function of the microbiota, discover microbiota-associated biomarkers, and reveal host\u2212microbiota interactions ,31,32. A4\u2013105 CFU/g, 105\u2013109 CFU/g, 109\u20131011 CFU/g, and 108\u20131011 CFU/g, respectively [Helicobacter and Lactobacillus [Lactobacillus, Bifidobacterium, Enterococcus, Streptococcus, and Pediococcus are dominant in canine feces [Faecalibacterium and Blautia) or lactic acid bacteria  with probiotic properties [Prevotella and Bacteroides in the phylum Bacteroidetes were abundant in dog feces. Fusobacterium is associated with health and is, thus, a potential therapeutic target [Fusobacterium, Prevotella 9 (a sub cluster of the Prevotellaceae family), and Bacteroides are the core intestinal microbiota in both dogs and cats [Bifidobacterium spp. and lactic acid-producing bacteria have been identified in canine feces [Lactobacillus is widespread in the canine and feline intestines and can be the origin of probiotics [The canine and feline GIT microbiota remain largely unexplored. Available data suggest that the composition of the GIT microbiota is generally similar between dogs and cats ,35 Tabl. Microbiectively . In healbacillus ,36. Firmbacillus ,28,36,37bacillus ,36. At tne feces ,39. Moreoperties . Prevotec target . Similarand cats . Many Bine feces . Lactobaobiotics ,42.Enterococcus, Fusobacterium, and Megamonas were higher in the feces of dogs, while multiple genera, including Bifidobacterium, Faecalibacterium, Carnobacterium, Adlercreutzia, Alistipes, Collinsella, Coprococcus, Desulfovibrio, Oscillospira, Parabacteroides, Peptococcus, Peptostreptococcus, Ruminococcus, Slackia, and Sutterella, were more abundant in cats [Bifidobacterium in the guts of cats [Despite similarities between the canine and feline intestinal microbiota, differences have been observed between the two species. The diversity of fecal microbiota has been reported to be higher in cats ,43. A st of cats . Dogs an of cats . Domesti of cats . The difAn intact intestinal microbiota is essential for maintaining host homeostasis, whereas dysbiosis in the gut microbiota can be linked to a variety of diseases and disorders, such as IBD, diarrhea, obesity, autoimmune diseases, and cancers in humans ,17. CurrFusobacterium and Faecalibacterium praunitzii), and overgrowth of Clostridium perfringens have been observed in dogs with chronic enteropathy [Ruminococcaceae, Blautia, Faecalibacterium, and Turicibacter have been observed in acute and chronic enteropathy in dogs [Bifidobacterium but increased Escherichia coli have been reported in cats with IBD [Enterococcus hirae, a dominant species of Enterococcus in the small intestinal mucosa of healthy shelter kittens, was found to be negatively associated with enteritis in kittens and was confirmed to have probiotic properties [Altered gut microbiota structures and/or metabolite profiles were observed in dogs and cats with intestinal inflammation ,45,46,47eropathy ,18. Redu in dogs . Decreaswith IBD . The diswith IBD ,49. The operties ,51.Lactobacillus acidophilus, Lacticaseibacillus casei, Lactobacillus delbrueckii subsp. bulgaricus, Lacticaseibacillus rhamnosus, Lactiplantibacillus plantarum, and Limosilactobacillus reuteri), Bifidobacterium , and Saccharomyces (Saccharomyces boulardii and Saccharomyces cerevisiae), which have been used as probiotics for a long time with validated safety and efficacy [Akkermansia muciniphila, Faecalibacterium prausnitzii, Prevotella copri, Bacteroides spp., Anaerobutyricum hallii, Parabacteroides goldsteinii, Roseburia, and Propionibacterium are potentially next-generation probiotics [Probiotics are live microorganisms with beneficial effects on host health when administered in adequate amounts, as defined by the International Scientific Association for Probiotics and Prebiotics . Probiotefficacy ,24,27. Aobiotics ,53,54.Lactobacillus and Bifidobacterium genera do not produce butyrate per se, but can cross-feed other commensals to produce butyrate and increase levels of SCFAs, which have multifaceted and important physiological activities [L. casei, L. paracasei, L. plantarum, B. breve, A. muciniphila, Bacteroides thetaiotaomicron, and E. coli Nissle 1917, stimulate the production of host-derived HDPs in humans and animals [Probiotics have been shown to promote health in many diseases, including IBD, diarrhea, colorectal cancer, allergy, type 2 diabetes, and atopic dermatitis, with strain-specific activity ,24,55. Ptivities ,57. More animals ,59,60,61 animals . With an animals ,63.Lactobacillus, Bifidobacterium, A. muciniphila, and SCFAs stimulate the expression, production, and secretion of mucins [The integrity of the intestinal epithelial layer is integral to intestinal homeostasis as the first physical barrier against the external environment and is largely maintained by the mucus layer and tight junctions linking adjacent epithelial cells ,64,65. If mucins .Streptococcus thermophiles and Lactobacillus spp., can produce \u03b2-galactosidase and bile salt hydrolase, which are involved in lactose digestion and bile acid metabolism, respectively [Moreover, probiotics modulate immune functions by stimulating T-cell differentiation, regulating pro- and anti-inflammatory cytokine profiles, and inducing sIgA production ,55,67. Fectively . Althougectively .Lactobacillus, Bifidobacterium, and Enterococcus [Probiotics derived from dogs, cats, and other species have been evaluated in healthy animals and those with intestinal diseases in the form of monostrain or multistrain. The most commonly studied probiotics in dogs and cats are rococcus ,47,69. Irococcus ,28. The rococcus ,71,72.Lactobacillus strains from healthy dogs and revealed their antagonistic activities against Campylobacter in vitro [L. plantarum strain RW1 isolated from canine feces displayed tolerance to low pH and bile salts, good adhesion to intestinal epithelial cells, and anti-inflammatory activity induced by Salmonella infection [Ligilactobacillus animalis, identified as the dominant lactic acid bacterium in canine feces, showed various inhibitory effects against enteropathogens [Lactobacillus and Enterococcus) and characterized their probiotic properties in vitro [Enterococcus faecalis and Enterococcus faecium exhibited better adhesion to the intestinal mucosa of dogs than chicken-derived strains of the same species [L. acidophilus strain showed a higher adhesive ability to canine colonic mucus than strains derived from pigs and humans [Multiple canine-derived bacterial strains with probiotic properties were isolated and identified. A recent study isolated dozens of in vitro . L. plannfection . Ligilacathogens . Other sin vitro ,80,81,82in vitro ,28. For  species . Similard humans ,85.L. reuteri ZJF036 altered the fecal microbiota composition with increased relative abundances of Lactobacillus, but decreased relative abundances of Turicibacter and Blautia in healthy beagle dogs [S. cerevisiae yeast increased the abundance of Turicibacter, decreased the abundance of E. coli, increased fecal butyrate, and shifted the microbial functional gene profile in healthy adult beagle dogs [Lactiplantibacillus paraplantarum L-ZS9 changed the intestinal microbial diversity, composition, and metabolism in dogs [\u00ae had decreased fecal C. perfringens and increased fecal Bifidobacterium and Lactobacillus [Studies have indicated that the use of probiotics improves intestinal microbiota composition and changes microbial functions in healthy dogs by adopting 16S rRNA gene sequencing, metagenomics and metabolomics ,87 Tabl. Dietarygle dogs . Feedinggle dogs . The adm in dogs . Healthybacillus . Metabolbacillus ,71. Feedbacillus . Multistbacillus ,92.S. cerevisiae yeast decreased the fecal pH and concentrations of total biogenic amines and ammonia [Bacillus subtilis and Bacillus licheniformis improved the fecal score, reduced nitrogen fermentation products in feces, and reduced fecal odor in dogs [Weissella cibaria JW15 decreased fecal ammonia emission in dogs [Moreover, studies have suggested improved fecal quality and reduced nitrogen fermentation through probiotic treatments in dogs ,93,94. F ammonia . Dietary in dogs ,88,89,94 in dogs .\u00ae alleviated the signs of canine colonic dysmotility [Limosilactobacillus fermentum, L. rhamnosus, and L. plantarum isolated from dogs decreased the frequency of diarrhea in dogs administered with non-steroidal anti-inflammatory drugs [Lactobacillus and Bifidobacterium strains increased fecal microbiota diversity, improved microbiota structure, and regulated microbial functional pathways in dogs with diarrhea [L. rhamnosus MP01 or L. plantarum MP02 isolated from canine milk prevented gastrointestinal infections in puppies [Probiotics confer health benefits in dogs with various intestinal disorders . Studiesmotility . A lactiry drugs . Feedingdiarrhea . Dietary puppies . Oral ad puppies . A probi puppies .Bifidobacterium and other lactic acid-producing bacteria, which are largely detected in the feces of healthy cats, are potential sources for the selection of probiotics [L. plantarum, L. rhamnosus, L. acidophilus and B. adolescentis isolated from various biotopes of healthy cats showed in vitro probiotic properties such as adhesive activity and antimicrobial activity against causative agents of surgical infection in cats [L. reuteri, L. fermentum), E. faecium and Pediococcus pentosaceus from the feces of dogs and cats, although in vivo confirmation of safety and effectiveness is needed for further use [Bacteroides sp. CACC 737 isolated from feline feces has potential probiotic properties, as revealed by functional genome analysis [E. hirae isolated from a healthy kitten decreased the diarrhea rate but did not influence the growth or composition of major bacterial phyla [obiotics . A recen in cats . Anotherther use . Bacteroanalysis . Freeze-al phyla .L. acidophilus CECT 4529 in the diet improved fecal quality and decreased fecal coliform counts in healthy adult cats [S. boulardii and Pediococcus acidilactici increased the production of butyric acid and total SCFAs, reduced concentrations of inflammatory markers myeloperoxidase and calprotectin, and improved the activity of antioxidant enzymes superoxide dismutase and glutathione in the feces of healthy short-haired cats [E. faecium SF68 decreased the diarrhea rate in shelter cats but did not affect the diarrhea rate of shelter dogs [L. acidophilus DSM13241 increased the numbers of Lactobacillus and L. acidophilus and decreased the numbers of Clostridium spp. and E. faecalis in the feces of healthy adult cats [The administration of probiotics promoted the intestinal health of healthy dogs . Supplemult cats . Multistred cats . Interesred cats . Feedingter dogs . Dietaryult cats .Bacillus licheniformis-fermented products relieved diarrhea, enriched bacteria belonging to Clostridium cluster XIVa, and reduced C. perfringens in the feces of cats with chronic diarrhea [Lactobacillus and Streptococcus in cats with chronic constipation and idiopathic megacolon [E. faecium strain SF68 improved the fecal quality in cats treated with amoxicillin\u2212clavulanate, which can cause vomiting or diarrhea [Positive effects of probiotics have also been noted in cats with intestinal disorders . Oral addiarrhea . A pilotegacolon . Feedingdiarrhea . Although diverse aspects of probiotics have been elucidated, not all activities have been confirmed for every probiotic strain. There are inherent differences between probiotic strains, and the efficacy of probiotics can be influenced by many factors such as species, disease conditions, age, and sex ,102,107.Probiotics exert health-promoting effects via direct interaction with the host cells and resident microbiota, or indirectly via microbial metabolites. The intestine hosts the largest and the most complex microbial community. More precise and accurate measurements of microbiota composition and further characterization of microbial functions in the intestine would expand the range and accelerate the selection of probiotics for use in cats and dogs . AlthougL. fermentum in dogs [It is worth noting that the microbiota can be influenced by many factors, such as species, age, sex, breed, diet, surgery, and antibiotic interventions ,110,111. in dogs . WhetherAlthough several mechanisms of action of probiotics have been proposed, not all have been verified in dogs and cats, warranting more comprehensive measurements and analysis in further research. Moreover, probiotic activities can be heterogeneous and strain-specific; therefore, a precise mechanistic investigation is needed.Lactobacillus, Bifidobacterium, A. muciniphila, and F. prausnitzii are sensitive to stressful conditions such as heat, oxygen, pH, enzymes, and bile salts, which compromise their efficacy during processing, storage, distribution, and passage through the GIT [Stability is one of the concerns in the application of probiotics. Probiotics such as  the GIT . Encapsu the GIT ,112. Emu the GIT . Each ap the GIT ,114. Fur the GIT . Researc the GIT . FurtherMaintaining the intestinal health of dogs and cats is becoming increasingly important as pet owners pay more attention to the health of their pets. The utilization of probiotics is an effective strategy to enhance the health of dogs and cats. The administration of probiotics can improve the balance of the intestinal microbiota, suppress inflammation, enhance immune function, and alleviate intestinal disorders in dogs and cats. Various bacterial strains derived from dogs and cats have shown probiotic properties in vitro, but their health benefits need to be confirmed in vivo. Moreover, the mechanisms of action of probiotics need to be further elucidated. Finer characterization of the intestinal microbiota of dogs and cats under different health conditions may facilitate the discovery of novel probiotics for use in pets."}
+{"text": "This literature review delves into the transformative potential of artificial intelligence (AI) in the field of surgery, exploring its evolution, applications, and technological advancements. AI, with its ability to mimic human intelligence, presents a paradigm shift in surgical practices. The review critically analyzes a broad range of research, encompassing machine learning, deep learning, natural language processing, and their diverse applications in preoperative planning, surgical simulation, intraoperative guidance, and postoperative analysis. Ethical, legal, and regulatory considerations, as well as challenges and future directions, are also explored. The study underscores AI's ability to revolutionize surgical visualization and its role in shaping the future of healthcare. As artificial intelligence (AI) continues to evolve, its role in medicine is expected to become increasingly prominent. The ongoing collaboration between clinicians, data scientists, and technologists promises to unlock new frontiers in healthcare. The transformative potential of AI in surgery represents not only a testament to the progress made in the field but also a glimpse into the future of healthcare, where advanced technologies work hand in hand with medical expertise to deliver superior patient care .Artificial intelligence (AI) has a profound history of influencing various medical disciplines. Its origins can be traced back to the mid-20th century when pioneers in computer science conceived the idea of machines capable of emulating human cognitive functions. This audacious vision gave birth to the field of AI, initiating decades of dedicated research and inventive exploration [In the early stages, AI was largely an academic pursuit, with researchers exploring the fundamental concepts of machine learning and pattern recognition. As computing power grew, so did the capabilities of AI systems. In the 1970s and 1980s, AI began to find its place in the medical domain, albeit in more rudimentary forms. Early applications focused on rule-based systems designed to assist with diagnostic decision-making. These systems were limited by the complexity of medical data and the computational resources available at the time .However, as computing technology advanced, so did the potential of AI in medicine. The advent of expert systems in the 1980s marked a significant milestone. These systems, designed to emulate human expertise in specific domains, found applications in fields like radiology and pathology. They provided valuable decision support to healthcare professionals, aiding in the interpretation of medical images and diagnostic data ,5.The 1990s witnessed further progress with the emergence of machine learning algorithms that could adapt and improve over time. This was a pivotal moment for AI in medicine, as it enabled systems to learn from large volumes of medical data, uncovering intricate patterns and relationships. These advancements paved the way for more sophisticated applications, including natural language processing for analyzing clinical notes and text-based medical literature ,7.In recent years, the convergence of big data, advanced algorithms, and powerful computing resources has propelled AI to the forefront of healthcare innovation. Today, AI is poised to revolutionize surgical practices across various specialties. The integration of AI into surgical workflows holds the promise of significantly enhancing patient care and outcomes. By leveraging AI's capabilities, surgeons can achieve higher levels of diagnostic accuracy, optimize treatment strategies, and execute procedures with unprecedented precision .This article aims to explore the integration of artificial intelligence (AI) in surgery, focusing on its applications, advancements, and potential to enhance surgical procedures and improve patient outcomes. The objective is to provide insights into various AI types, their relevance in surgical practice, and their role in reshaping the future of surgical procedures. Through a synthesis of existing research and scholarly works, the article aims to contribute to a comprehensive understanding of AI's transformative potential in surgery.The integration of artificial intelligence (AI) into the field of surgery holds substantial significance Figure . SurgeonAI has become increasingly integral in various surgical specialties, revolutionizing approaches to patient care and outcomes. This article delves into the current applications of AI across different surgical disciplines, showcasing its potential to refine diagnostic accuracy, treatment strategies, and overall surgical precision .The field of surgical technology and AI is divided into three key areas: preoperative planning, intraoperative guidance, and surgical robotics. Preoperative planning focuses on the requirements of accuracy, automation, privacy, and speed in preparing for surgery. However, it faces challenges related to multi-modal input, patient diversity, complicated symptoms, and less informative diagnostic data. Sub-areas within preoperative planning include classification, detection, segmentation, and registration. Intraoperative guidance demands real-time precision and high-resolution data but encounters difficulties in limited and low-resolution input, tissue deformation, and environmental variance. Sub-areas of intraoperative guidance encompass 3D shape instantiation, endoscopic navigation, tissue feature tracking, and augmented reality. Surgical robotics, with requirements for precision, robustness, real-time performance, and safety, deals with challenges related to accurate kinematics and dynamics modeling, perception of the dynamic environment, and high autonomy. Sub-areas in surgical robotics include robotic perception, localisation and mapping, system modelling and control, and human-robot interaction ,12  for early detection and risk assessment. AI-based algorithms assist in predicting patient prognosis, guiding treatment decisions, and identifying potential drug targets. Additionally, AI contributes to the reduction of interval cancers by improving the detection of flat or small polyps. At a population level, AI helps assess the risk of colorectal cancer, enabling more efficient screening strategies and resource allocation .AI-driven systems offer significant benefits in polyp detection, enhancing sensitivity in CRC screening and reducing the rate of missed post-colonoscopy CRC cases, especially for right-sided, flat, or small polyps. Furthermore, AI models contribute to polyp characterization, aiding in distinguishing neoplastic lesions from non-neoplastic mimickers and providing insights into submucosal invasion depth. Various imaging techniques, including magnification endoscopy, endocytoscopy, confocal laser endomicroscopy, magnifying chromoendoscopy, autofluorescence endoscopy, and white light endoscopy, can be combined with AI to improve the precision of polyp characterization. Additionally, AI plays a role in treatment strategies by assisting in robotic-assisted surgery and chemotherapy, offering more efficient and minimally invasive surgical options, as well as personalized drug treatments for CRC patients. Lastly, AI contributes to the field of precision oncology, helping identify genetic biomarkers, drug interactions, and potential therapeutic targets, thus tailoring treatment approaches to individual CRC patients more effectively ,15.Similar to colorectal surgeries, upper gastrointestinal surgeries also benefit from AI technologies, particularly in the diagnosis and treatment of conditions such as esophageal cancer. AI algorithms can analyze endoscopic images and help detect abnormalities or early-stage malignancies, enabling timely interventions. Additionally, AI systems play a role in surgical planning, ensuring optimal approaches to resection and minimizing complications. In hepatobiliary surgery, AI aids in liver disease diagnosis, predicting patient outcomes, and optimizing liver resections. Machine learning models analyze liver imaging data to determine tumor margins and guide surgeons during the resection process. These AI-driven insights lead to better surgical outcomes and postoperative patient care -18.In the field of neurosurgery, AI is employed in image-guided surgery, assisting surgeons in navigating through intricate brain structures with higher precision. Machine learning algorithms help in real-time tumor segmentation, aiding surgeons in the removal of brain tumors while minimizing damage to healthy tissues. Additionally, AI-powered diagnostic tools can enhance the detection of neurological disorders, such as strokes, by rapidly analyzing medical imaging data ,20.In the realm of orthopedic surgery, AI plays a pivotal role in customizing treatment plans. AI algorithms assist in predicting patient outcomes after joint replacements, allowing for personalized care. Furthermore, robotic surgical systems are increasingly utilized in orthopedics, enhancing the precision of procedures like joint arthroplasty. These systems offer real-time feedback to surgeons, helping them make more informed decisions before and during surgery .In the field of cardiology, AI applications have brought about significant advancements in the diagnosis and treatment of heart-related conditions. Machine learning models can analyze cardiac images, such as echocardiograms and angiograms, to detect anomalies and assess heart function. AI-powered monitoring devices can continuously track patients' cardiac health and provide early warning signs, leading to improved management of heart conditions. Moreover, during cardiac surgeries, AI-driven robotic systems aid surgeons in performing complex procedures with a high degree of accuracy, reducing the risk of complications ,23.The use of robotic-assisted keyhole surgery in gynaecology has expanded due to technical advancements, offering benefits like improved depth perception, reduced tremor, increased precision, faster learning curve, and enhanced surgeon comfort compared to traditional keyhole and open surgeries. Robotic-assisted surgery improves performance without increasing operating time, minimizes blood loss and complications, and reduces the need for open surgery. Surgeons using robots experience fewer musculoskeletal issues, making it a safer and more effective option for complex gynaecological procedures, especially for patients with high BMI or respiratory problems. This innovation has decreased the need for open surgeries, lowering the risk of conversions, impacting cost-effectiveness considerations .The rapid strides in robotics including Davinci, AI robots and nanorobotics Figure  and theiAlongside all the benefits of AI, the adoption of artificial intelligence (AI) in healthcare brings forth several concerns and negative impacts. These include challenges related to data collection, as healthcare data is often siloed and access is limited, posing obstacles to effective AI development. Data privacy and security are significant concerns, with the potential for breaches of sensitive patient information. Bias in AI algorithms, overfitting, and data quality issues can lead to distorted or unfair outcomes, exacerbating healthcare disparities. The \"black-box\" nature of many AI systems presents transparency and accountability challenges. Ethical concerns revolve around responsibility and standards for AI decision-making, while job displacement fears among healthcare professionals persist. Addressing these concerns requires improved data sharing, security measures, bias mitigation strategies, transparency, ethical frameworks, and empirical validation of AI applications .This overview underscores the promising applications of AI across various surgical specialties. It is important to acknowledge that the field is continuously evolving, and further research and technological advances will expand the scope and impact of AI in surgery.Artificial intelligence has emerged as a pivotal force in surgery, promising to enhance patient outcomes and transform traditional surgical approaches. The review has highlighted the significant impact of AI in various surgical domains, spanning from preoperative planning to postoperative analysis. Machine learning and deep learning algorithms, coupled with natural language processing, showcase immense potential in predicting surgical outcomes, aiding decision-making, and improving surgical education. Additionally, AI's integration into surgical visualization through advanced technologies like virtual reality and three-dimensional (3D) printing offers unparalleled opportunities for surgical training and planning. However, challenges such as generalizability, cost-effectiveness, and ethical considerations remain, necessitating continued research and collaboration to maximize the benefits of AI in surgical practice. Overall, the evolution and application of AI in surgery hold the promise of reshaping the landscape of healthcare, ushering in a new era of precision, efficiency, and superior patient care."}
+{"text": "This puts a weighty financialburden on individuals and families, as well as on healthcare systems and governments.Thirdly, cancer and its treatment drastically impact patients\u2019 quality of life. Treatmentssuch as chemotherapy, radiation therapy, and surgery cause physical and emotional side effects that are debilitating andlong-lasting. Fourthly, not all cancer types are preventable. Many cases are connected tolifestyle factors, for example, smoking, alcohol consumption, poor diet, and so on. Finally, cancer research is a chief focus of public healthefforts around the world. Advances in cancer diagnosis, drug treatment, and diseaseprevention lead to better survival rates, but there is much research to be studied about itspathology and treatment.Cancer is a significant crisis worldwide. Firstly, cancer is one of the leading sources ofdeath worldwide. According to World Health Organization, cancer caused estimated 9.6 milliondeaths in 2018. Secondly, its treatment is costly, diagnosis, prediction, survival rate estimation, treatment, and control measures are still the foremost challenges in the recentdecade. With the development of biomedical imaging, inspection, and health managementtechnologies, medical big data (MBD), such as biomedical images, omics, and clinical electronic medical records, are accumulating rapidly. How can we usethis MBD to build better health records and more accurate prediction models to help diseasediagnose and treat cancer better? In the past decade, the rapid development of machinelearning (ML) methods has provided many successful cases to answer this fundamentalquestion.Cancer screening, decision trees, random forests, support vector machines, neural networks, k-means clustering, principal component analysis, na\u00efve Bayes, gradient boosting, and so on. However, ML methods suffer several shortcomings. Traditional ML modelscannot predict outcomes with a high level of accuracy due to a lack of complexity in theirunderlying algorithms. Scalability is another shortcoming. The number of input variables intraditional ML methods is often limited, making it difficult to build systems that arerobust and scalable.Commonly used ML methods for cancer analysis include linear regression, logistic regression, has been the hottest ML method for cancer analysis nowadays. The reasons are 5aspects. (i) DL can handle large and complex datasets with many variables, which isessential for massive amounts of genomic and clinical data. (ii) DL can detect patterns andidentify correlations in cancer data that might not be visible to the human eye. (iii) DLcan help predict how individual patients will respond to different treatments based on theirgenetic profile, medical history, and other factors. (iv) DL models can be trained on large cancer datasets, such as mammograms or 3-dimensional computed tomography scans, to detect early signs of cancer that areinvisible to the human eye. (v) DL can predict the effectiveness of new cancer drugs and identify potential drug targets based on genetic and other data.Recently, deep learning (DL) long short-term memory networks, capsule networks, and so on. There are many other variants of DL algorithms andcombinations of these algorithms for various applications of cancer analysis.Some top DL algorithms include convolutional neural networks, recurrent neural networks,autoencoders, generative adversarial networks, and data isolation.Although ML and DL have shown great potential in helping cancer screening, diagnosis,prognosis, and treatment, many significant data-related problems still hinder theapplication of ML and DL in cancer analysis. These problems include excessive noise, labeleddata deficiency, heterogeneous data, unbalanced data, multisource domain data,Interpretability and validation are 2 other issues. Most ML and DL models are oftenreferred to as black boxes because it is difficult to interpret how they arrive at theirpredictions. In cancer analysis, interpretability is crucial to understanding how the ML andDL models arrive at their decisions and gaining insights into the disease's biologicalmechanism. Meanwhile, ML and DL models can suffer from overfitting, where the model learnsto perform well on the training data but performs poorly on new, unseen data. Valuing ML andDL models in cancer analysis is challenging when the data is limited or biased. methods, data representation learning methods, and novel efficient ML and DL models.To better apply ML and DL models to cancer analysis, it is important to develop novel data preprocessing"}
+{"text": "The World Health Organization is leading initiatives to drive public understanding of antibiotics and antimicrobial resistance. It is important to assess levels of understanding across countries and age groups.Observational, questionnaire-based study across 12 countries  explored respondent experience of respiratory illnesses and symptoms, antibiotic use, and attitudes to and perceptions of antibiotics. Respondents aged 18\u201364 years who had experienced and treated respiratory symptoms  in the past 6 months were included.Of the 12,000 eligible adults (18\u201364 years) who completed the questionnaire, 6000 were from countries in Asia, Latin America, the Middle East, or Africa and 1816 were aged 25\u201334 years. Sixty-five percent of all respondents thought that they were quite knowledgeable about how antibiotics work on respiratory symptoms. However, answers to further questions indicated substantial misunderstanding. For example, several respondents believed that antibiotics kill viruses (65%), are effective for sore throat (73%), and relieve pain (65%). Typically, 25\u201334-year-olds had a lower understanding . Almost half (48%) of all respondents felt they do not have enough knowledge on how to treat respiratory symptoms without antibiotics, which was similar in 25\u201334-year-olds (49%). Overall, 40% would feel anxious about being treated for respiratory symptoms without antibiotics; in 25\u201334-year-olds this response ranged from 33% (South Africa) to 55% (Thailand). There were misconceptions around when antibiotics should be stopped. For example, 40% of all respondents thought that you should stop taking antibiotics as quickly as possible; in 25\u201334-year-olds this response ranged from 29% (South Africa) to 52% (Philippines and Thailand).Although variable, there are still concerning misbeliefs surrounding antibiotic use for the management of respiratory illnesses, especially in the younger population. Different channels of communication may be required to increase health literacy on the appropriate use of antibiotics in the younger population.Sabiha Essack, B. Pharm, M. Pharm, PhD, Reckitt Benckiser Healthcare International Ltd, UK: Chairperson of the Global Respiratory Infection Partnership, supported by unrestricted educational grant from Reckitt Benckiser Healthcare Ltd|Reckitt Benckiser Healthcare International Ltd, UK: Member of the Global Hygiene Council, supported by unrestricted educational grant from Reckitt Benckiser Healthcare Ltd Sergio Caretta-Barradas, MD, Reckitt Benckiser Healthcare International Ltd, UK: Member of the Global Respiratory Infection Partnership, supported by unrestricted educational grant from Reckitt Benckiser Healthcare Ltd Antonio Pignatari, MD, Reckitt Benckiser Healthcare International Ltd, UK: Member of the Global Respiratory Infection Partnership, supported by unrestricted educational grant from Reckitt Benckiser Healthcare Ltd Khalid Eljaaly, PharmD, MS, BCPS, BCIDP, FCCP, Reckitt Benckiser Healthcare International Ltd, UK: Member of the Global Respiratory Infection Partnership, supported by unrestricted educational grant from Reckitt Benckiser Healthcare Ltd Wirat Tongrod, PharmD, MBA, PhD, Reckitt Benckiser Healthcare International Ltd, UK: Member of the Global Respiratory Infection Partnership, supported by unrestricted educational grant from Reckitt Benckiser Healthcare Ltd Adrian shephard, BSc, Reckitt Benckiser Healthcare International Ltd, UK: Employee Alike van der Velden, PhD, Reckitt Benckiser Healthcare International Ltd, UK: Member of the Global Respiratory Infection Partnership, supported by unrestricted educational grant from Reckitt Benckiser Healthcare Ltd"}
+{"text": "Chronic respiratory diseases (CRDs) are a leading cause of death and hospitalisation in low- and middle-income countries (LMICs) , with chThe teach-the-teacher (TtT) model is an educational approach adapted from the International Primary Care Respiratory Group (IPCRG) that aims to build sustainable local capacity in teaching and health care delivery . It invoThe success of the TtT programme depends on identifying the appropriate target population. With this in mind, the learning needs of the population were assessed, competencies mapped, and relevant groups prioritised. These groups included rehabilitation physicians, respiratory physicians, primary care physicians, staff nurses, therapists, medical social workers, pharmacists, and dieticians. The head of service and target population were identified as key in ensuring teaching was cascaded.The TtT workshop taught participants how to create clear learning objectives appropriate for their diverse learning contexts through interactive lectures. The specific, measurable, achievable, relevant, and time-bound (SMART) was used to define realistic targets , while tWorkshop participants learned how to create a teaching programme or content by identifying the components of learning outcomes such as knowledge, skills, or attitude, which should align with the learning objectives. They were explained the fundamental ideas of teaching approaches such as physical lectures, hands-on workshops, working with small groups, distance learning, and webinars, and coached on how to design instructional content and identify teaching approaches during the workshop.Effective engagement and good presentation delivery require proper selection of teaching methods and resources. Passive teaching methods have lower learning retention rates compared to participation teaching methods . ParticiDuring the TtT workshop, participants were introduced to various types of assessments and taught how to distinguish between objective and subjective assessments. They learned how to plan and evaluate a project and its impact, with the goal of determining mastery of critical skills and knowledge and evaluating the program\u2019s effectiveness over time. To enhance interaction and brainstorming, they were divided into groups, where they discussed practical and theoretical evaluation methods, including direct observation during clinical practice, logbooks, practical assessments, multiple-choice questions, and theoretical quizzes.The success of a presentation heavily relies on the presenter's skill and ability to reach the audience . The SENThe lack of a systematic PR programme in Malaysia requires the development of a tailored PR model that will work in a particular setting. Interactive lectures and group discussions were conducted to teach participants how to develop a PR programme in their facilities; they were presented with various PR models used globally, such as inpatient PR, outpatient PR, home PR, and community PR, and they agreed on the model that would work best for their facility. A team of medical professionals, including physicians, nurses, therapists, social workers, counsellors, pharmacists, dieticians, and palliative care, is required to establish a PR programme. The participants discussed the target population for PR, including individuals with CRD post-COVID-19, interstitial lung disease, COPD, bronchiectasis, and post-lung surgery. Inpatient PR could take place in the respiratory ward, while outpatient PR could be held in the rehabilitation department therapy area. Resources such as educational materials, a resistive band, a QR code for an exercise video, and an incentive spirometer are necessary. The programme should include COPD education, coping strategies, energy conservation, activities of daily living (ADL) retraining, assistive devices, pharmacological optimisation, nutrition, smoking cessation, self-management, end-of-life discussion, and assessments. The programme should also include St George's Respiratory Questionnaire (SGRQ-C), a quality of life (QOL) questionnaire, and an exercise component-breathing exercises, resistance exercise, endurance training, and a home exercise programme. Assessments should include the two-minute walking test (2MWT) for inpatients and the six-minute walking test (6MWT) and spirometry for outpatients. The programme should use the Donabedian framework to evaluate care quality, with a multidisciplinary team involved in general exercise, functional activities, psycho-social therapies, education, and specific actions tailored to patients' priorities and goals. Comprehensive assessments would include various tests and questionnaires. The participants plan to establish a PR programme in their facility soon, and policymakers' involvement is crucial to advance PR uptake in the country. To achieve this, they suggest introducing the programme at the hospital level, encouraging early referrals, utilising pre-existing PR services, incorporating clinical practice guidelines, providing more teaching programmes, and involving primary care physicians in health clinics to develop a community PR programme.Following the training, HCPs engaged in conversations regarding potential challenges they may encounter when initiating a PR programme at their respective facilities, including Malaysia (The workshop was originally intended to include a visit to the country's top PR facilities, but due to the rapid spread of the Omicron strain of COVID-19, it adopted a virtual format and the site visit was cancelled. This visit was expected to provide participants with a better understanding of the components of a well-structured PR programme. However, the virtual format allowed HCPs from remote locations to participate without travel restrictions.In Malaysia, the development of a well-structured PR programme remains a challenge, which could be resolved through a TtT programme, which could train more HCPs to become teachers and expand PR services across the country. The workshop participants identified potential challenges in the development of PR and proposed solutions to overcome them. By addressing these concerns, HCPs could efficiently create and implement PR programmes at their facilities."}
+{"text": "Over the past few decades, life expectancy has been increasing in several countries. However, this positive trend is accompanied by a rise in the occurrence of inflammatory and degenerative diseases, including neurodegenerative conditions, autoimmune diseases, metabolic disorders, and cancers.Within this context, regenerative medicine emerges as an interdisciplinary field that integrates two essential areas: research and clinical practice, aiming to promote the regeneration and restoration of tissues and organs and additionally restore their physiological conditions. Specifically, regenerative medicine is based on an understanding of the mechanistic pathways that drive cellular and tissue regeneration, along with exogenous and endogenous factors. This knowledge is used to develop new therapeutic options for regenerating or restoring the functions of tissues and organs damaged by various conditions .Tissue engineering has developed with an increased impact on medical procedures, involving last-generation biomaterials, newly discovered stem cell lines, and biologically active substances , to aid the physiological processes leading to tissue repair. Over the years, researched have developed various types of scaffolds aiming to increase their biomimetic ability; scaffold functionalization has been obtained with different degrees of porosity , biodegradability, biocompatibility, mechanical properties, and physical behavior.Currently, novel biomaterials are designed for long-term contact with biological tissues, and they can simultaneously act as supportive and bioactive scaffolds ,2,3. TheMSCs can be sourced from various tissues and organs, including bone marrow, adipose tissue, the periosteum, umbilical cord, placenta, trabecular bone, skeletal muscle, and oral cavity . Oral-deThe main types of oral MSCs include dental pulp stem cells (DPSCs), stem cells from human exfoliated deciduous teeth (SHEDs), periodontal ligament stem cells (PDLSCs), dental follicle stem cells (DFSCs), apical papilla stem cells (SCAPs), gingival stem cells (GMSCs), and human periapical cyst stem cells (hPCy-MSCs) .Interestingly, human periodontal ligament stem cells (hPDLSCs) not only possess wide-ranging differentiation capabilities but also exhibit immunosuppressive effects . SpecifiFurthermore, the concept of obtaining MSCs from \u201cbiological waste\u201d has gained significant attention in the scientific community. This concept has been translated into the isolation of MSCs from inflamed human dental cysts (hPCy-MSCs); numerous studies have demonstrated the great clinical potential of hPCy-MSCs, particularly in bone regeneration and in the production of organoids, such as the midbrain-like organoids mimicking the deficit in dopaminergic neurons involved in neurodegenerative disorders including Parkinson\u2019s disease (PD) .Dentin-derived MSCs, originating from the neural crest, exhibit notable neuro-regenerative potential, making them attractive for the treatment of neurodegenerative disorders. These cells express neuronal markers under basal conditions, such as nestin, beta-3-tubulin, receptors for neurotrophins, and neurofilaments ,11.Several research groups are actively involved in the field of structural and functional regeneration of bone and dental tissue, which represents an intriguing and extensively debated topic in medicine. Beyond dentistry, oral MSCs have been combined with innovative biotechnologies in the fields of bone regeneration. In fact, bone defects arising from trauma, disease, surgery, or congenital malformations pose significant global health challenges ,13. In tMSC-based therapy for bone and cartilage repair  currentlExtensive research conducted in both preclinical and clinical settings has provided valuable insight into the crucial role played by mesenchymal stem cells (MSCs) in maintaining tissue homeostasis. MSCs have demonstrated immense potential in tissue engineering and regenerative medicine. Oral MSCs have the further and unique characteristics, being easily obtainable from several sources with interesting differentiating behaviors, thus making them promising candidates for a wide range of clinical applications.Looking to the future, ongoing investigations will play a critical role in overcoming the existing limitations of regenerative medicine. Advancements in our understanding of the precise mechanisms through which oral MSCs exert their overall therapeutic effects will pave the way for the development of innovative strategies. Additionally, through exploring the potential of oral MSCs in combination with other biotechnologies, these cells will contribute significantly to the development of personalized regenerative therapies."}
+{"text": "Cancer is amenable to low-cost treatments, given that it has a significant metabolic component, which can be affected through diet and lifestyle change at minimal cost. The Warburg hypothesis states that cancer cells have an altered cell metabolism towards anaerobic glycolysis. Given this metabolic reprogramming in cancer cells, it is possible to target cancers metabolically by depriving them of glucose. In addition to dietary and lifestyle modifications which work on tumors metabolically, there are a panoply of nutritional supplements and repurposed drugs associated with cancer prevention and better treatment outcomes. These interventions and their evidentiary basis are covered in the latter half of this review to guide future cancer treatment. Warburg\u2019s hypothesis for cancer progression is that cancer cells undergo a two-step transformation. First, there is irreversible failure of respiration, and secondly, the cell survives by fermentation energy. Fermentation energy is far less efficient than aerobic glycolysis, producing only 2 ATP for a glucose molecule as opposed to 38 via aerobic glycolysis .Cancerous cells shunt a majority of glucose through the anaerobic pathway , and canTo test the validity of the metabolic theory of cancer, nuclear transplantation experiments were performed . These eUntil recently, the Warburg hypothesis had not received much attention for its treatment implications for cancer. Case reports on the ketogenic diet for treatment in cancer were published in the 1990s . AdherenMetabolic approaches work systemically , as oppoThere are multiple interventions that one can apply, each of which affects a less conducive environment for cancer growth. Therapeutic combinations that stress the cancer through multiple pathways can prevent cancer progression, encouraging reversal and remission. Typically, therapeutic combinations are studied either in isolation or in combination with a few other (often complementary) therapeutic interventions.Cancer fitness is a multidimensional landscape, and combinations of interventions can be selected to reduce tumor fitness while maintaining the fitness of normal cells. Metabolic reprogramming in cancer cells opens a significant number of therapeutic modalities. Not only does dietary ketosis proportionately disfavor cancer cells from an energy availability standpoint, but it also deprives the cancer cell of the vital building blocks for cell replication , and ketThe metabolic shift to glycolysis is also useful for the tumor microenvironment prior to angiogenesis, which is a hypoxic condition . The rapBeyond anaerobic glycolysis , other metabolic shifts occur in cancer cells. In a 2016 review, authors Pavlova and Thompson identified six metabolic hallmarks: (1) deregulated uptake of glucose and amino acids, (2) use of opportunistic modes of nutrient acquisition, (3) use of glycolysis/TCA cycle intermediates for biosynthesis and NADPH production, (4) increased demand for nitrogen, (5) alterations in metabolite driven gene regulation, and (6) metabolic interactions with the microenvironment . That isThe metabolic paradigm of cancer research is still novel and requires much more fervent investigation. However, it demonstrates great therapeutic promise, both in terms of mechanistic understanding and clinical data .Several existing and investigational anticancer agents act on metabolic pathways. Dichloroacetate, for example, inhibits pyruvate dehydrogenase kinase, in turn increasing pyruvate flux into the mitochondria. This promotes glucose oxidation, as opposed to glycolysis , which iMetabolic approaches also demonstrate potential in the adjunctive setting, when combined with other approaches. Combining chemotherapy with a ketogenic diet can enhance the effect of chemotherapy ,31,32. AThe interventions covered in this review are summarized in Additionally, non-recommended interventions with a lower evidentiary basis for their efficacy are included in A carbohydrate-restricted diet, specifically a ketogenic diet, high in saturated fat and Omega-3 fatty acids, is suggested for various health benefits, including its potential role in cancer management . The dieTo flatten the blood glucose curve, various interventions are recommended, including eating foods in the right order , skipping breakfast, avoiding snacking, and incorporating vinegar or fiber tablets before consuming starchy or sweet foods . EstabliOverall, these dietary and lifestyle recommendations aim to support health and potentially impact cancer management positively by optimizing blood glucose levels, promoting a favorable microbiome, and ensuring a balanced intake of fats and oils.Restricting carbohydrates induces the body to adopt ketosis as its glucose fuel source is restricted and it must necessarily meet energy demands through another mechanism. This mechanism is ketosis, with which it is difficult to meet the metabolic demands of cancers, as these cells have damage to the cellular respiration pathways and ferment glucose preferentially. Ketones also have antitumor effects ,18,20. TCarbohydrate restriction upregulates ketone production in the liver, either in a state of fasting or a ketogenic diet . Cancer The state of ketosis can also positively impact the immune targeting of cancer cells . ReducinMultiple trials have been performed in the last decade showing the clinical benefit of ketogenic diets in the treatment of cancer, showing an antitumor effect in the high majority of trials .It typically takes two weeks to adjust to the state of ketosis when stating a ketogenic diet . KetogenIndividuals with the following conditions should not embark on the ketogenic diet : primaryIt is recommended to start at a higher level of carbohydrates and taper down gradually . Before These resources are useful, as adherence is often an issue , though For this reason, we recommend the tools of a continuous glucose monitor and ketone test strips, as the latter can demonstrate ketogenic diet adherence by testing \u03b2-hydroxybutyrate (BHB) levels , which cRecommendations for ketogenic diets are provided in the existing literature ,285,286,Lifestyle modification is crucial for reducing the risk of death from cancer and improving quality of life. This includes exercise, a healthy diet, and stress reduction ,291. PatThe Combined Aerobic and Resistance Exercise (CARE) Trial demonstrated that a combined dose of 50\u201360 min of aerobic and resistance exercise performed three times weekly led to better patient-reported outcomes and health-related quality of life compared to performing aerobic exercise alone during breast cancer chemotherapy . Meta-anPsychosocial stress is associated with a higher incidence of cancer and poorer survival in cancer patients . To reduAdequate and high-quality sleep is crucial for neural development, learning, memory, and cardiovascular and metabolic regulation . DisruptThis review summarizes the most promising repurposed drugs for treating cancer, including their mechanism of action, clinical efficacy (if available), and dosing considerations, including safety. These are summarized in For evidence, we include first meta-analyses of clinical trials. If these are not available, we then include individual clinical trials. If these are not available, we include case series, and then case studies. If human studies are not available, we rely on preclinical evidence. https://www.pharmacychecker.com/ (accessed on 11 September 2023).The prices of the different compounds have been compiled in Vitamin D is synthesized in the human skin through the influence of UV B radiation and is then converted into the active form, 1,25-dihydroxyvitamin D3 , in the kidney ,318,319.Vitamin D plays a critical role in various physiological pathways, including energy metabolism, immunity, and cellular growth . It has Vitamin D exhibits diverse antineoplastic activity through various pathways. It binds to the vitamin D receptor and induces differentiation and apoptosis; it also inhibits cancer stem cells, proliferation, angiogenesis, and metastatic potential . It promMultiple studies indicate that a significant proportion of cancer patients are vitamin D-deficient (level < 20 ng/mL) and that higher plasma 25-hydroxyvitamin D levels are associated with improved survival in colorectal, breast, gastric, and lymphoma cancer patients ,344,345.Vitamin D supplementation is likely beneficial for most types of cancers, especially breast, colorectal, gastric, esophageal, lung, and prostate cancer, lymphomas, and melanoma. Due to the severe vitamin D deficiency observed in most cancer patients, a high loading dose of vitamin D is recommended, followed by dose titration aiming for a level of >50 ng/mL (target 55\u201390 ng/mL). Some types of cancer may require higher levels, up to 150 ng/mL, to halt growth and metastasis. Daily doses of 20,000 to 50,000 IU/day are suggested until the desired vitamin D level is reached. It is important to monitor vitamin D levels to ensure appropriate maintenance dosing, and daily dosing of vitamin D3 is preferred over large intermittent bolus dosing. Vitamin K2 (menaquinone (MK4/MK7)) and magnesium are recommended in conjunction with high vitamin D doses (>8000 IU/day). Measuring parathyroid levels and calcium levels can help titrate the vitamin D dose according to the Coimbra Protocol ,65.Melatonin, a lipophilic molecule synthesized by the pineal gland with a circadian pattern, exhibits elevated levels at night and contributes to homeostatic metabolic rhythms and disease protection . It actsLow melatonin levels have been associated with cancer development, and various studies have shown reduced melatonin levels in cancer patients compared to healthy individuals of the same age . Disruptp < 0.001). Improved effects were found for complete response, partial response, and stable disease. In trials combining melatonin with chemotherapy, adjuvant melatonin decreased 1-year mortality .In addition to case studies ,367, theMelatonin may be active in several cancers including cancers of the breast, ovary, pancreas, liver, kidney, mouth, stomach, colon/rectum, brain, lung, prostate, head and neck, and various leukemias and sarcomas ,67. ProvThe biochemical impact of green tea on cancer is multifarious, as green tea is a combination of many bioactive compounds. Of particular interest are catechins, of which epigallocatechin gallate (EGCG) is the most abundant . Green tNumerous experimental models and epidemiological data support the anticancer effects of green tea catechins (GTCs). A meta-analysis showed an inverse association between tea catechin intake and various cancers , and anoGreen tea catechins are recommended to be taken at a dose of 500\u20131000 mg/day during or after a meal to minimize the risk of liver toxicity . The US Metformin exhibits anticancer activity through direct effects on cancer cells , includiMeta-analyses and observational studies have shown that metformin plays a significant role in the primary prevention of cancer, reducing overall cancer incidence ,390. It Metformin shows a broad spectrum of anticancer activity and may be beneficial in preventing various malignancies, including breast, pancreatic, gastric, colorectal, endometrial, prostate, non-small-cell lung cancer (NSCLC), and bladder cancers ,398,399.Curcumin, popularly called \u201ccurry powder\u201d or turmeric, is a polyphenol extracted from Curcuma longa. Curcumin has antioxidant, anti-inflammatory, antimicrobial, antiviral, and anticancer properties .Curcumin, a bioactive compound found in turmeric, exhibits a wide range of anticancer effects by targeting multiple cell signaling pathways in cancer cells . It inteThe clinical use of curcumin for its broad anticancer activities has been limited by its poor bioavailability, attributed to low absorption, extensive biotransformation, and rapid elimination . VariousCurcumin (turmeric) may be beneficial for various types of cancers, including colorectal, lung, pancreatic, breast, prostate, chronic myeloid leukemia, liver, gastric, brain tumors, ovarian, skin, head and neck, lymphoma, esophageal cancer, and myeloma ,415,416.Mebendazole (MBZ), originally developed to treat parasitic worms, disrupts cellular microtubule formation in abnormal cancer cells, inhibiting tumor progression factors such as tubulin polymerization, angiogenesis, pro-survival pathways, matrix metalloproteinases, and drug resistance proteins ,422. It Clinical studies on the use of benzimidazoles in cancer are limited to a few case reports ,93 and aMebendazole has demonstrated potential benefits in a wide range of cancers, including NSCLC, adrenocortical, colorectal, chemo-resistant melanoma, glioblastoma multiforme, colon, leukemia, osteosarcoma/soft tissue sarcoma, acute myeloid sarcoma, breast , kidney, and ovarian carcinoma ,422,426.Polyunsaturated fatty acids (PUFA), including alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), have been extensively studied for their therapeutic effects against various human diseases, including cardiovascular and neurodegenerative diseases, and cancer . These sOmega-3 fatty acids (omega-3 FAs) have been proposed to exhibit four main antineoplastic activities: modulation of cyclooxygenase (COX) activity, alteration of membrane dynamics and cell surface receptor function, increased cellular oxidative stress, and the production of novel anti-inflammatory lipid mediators such as resolvins, protectins, and maresins ,429. OmeClinical studies have shown promising results regarding the beneficial effects of omega-3 fatty acids (omega-3 FAs) in reducing the risk of developing cancer and improving outcomes in cancer patients. Prospective randomized controlled trials (RCTs) and cohort studies have demonstrated that the intake of omega-3 FAs is associated with a reduced risk of breast cancer, colorectal neoplasia, and prostate cancer-related death ,435,436.Omega-3 fatty acids may be beneficial in breast cancer, colorectal cancer, leukemia, gastric cancer, pancreatic cancer, esophageal cancer, prostate cancer, lung cancer, and head and neck cancer when taken at a dose of 2\u20134 g daily, but caution should be exercised in patients on anticoagulants due to the potential risk of bleeding .Berberine exhibits multiple anticancer mechanisms, including reducing cancer cell growth, preventing metastasis, and inducing apoptosis . It may While there are limited clinical data on the benefits of berberine, a randomized, double-blind study demonstrated that berberine in a dose of 300 mg twice daily significantly reduced the risk of recurrent colorectal adenomas following polypectomy .Berberine demonstrates anticancer effects in various cancer types, including breast, lung, gastric, liver, colorectal, ovarian, cervical, and prostate . A suggeStatins exert direct anticancer effects by inhibiting the cholesterol-producing enzyme HMG CoA, leading to reduced availability of cholesterol needed for cell membrane formation in rapidly proliferating tumors ,451. ThiClinical studies have consistently shown that lipophilic statins, such as simvastatin, reduce the incidence and mortality of various cancers, including prostate, breast, colorectal, hepatocellular, and lung ,116. StaStudies have used 40 mg 2x/day as a dosage for atorvastatin . An alteDisulfiram (DSF) inhibits aldehyde dehydrogenase, leading to acetaldehyde accumulation and unpleasant effects when alcohol is consumed, making it an anti-alcoholism drug; however, it has been repurposed as a potent cancer treatment, showing anti-tumor effects in preclinical studies and recent success in treating seven types of cancer in humans .Disulfiram (DSF) exhibits multiple anticancer pathways, including inhibition of NF-kB signaling, proteasome activity, and ALDH, induction of ER stress and autophagy, and targeting of cancer stem cells . DSF\u2019s cIn a double-blind trial with breast cancer patients, treatment with sodium ditiocarb (diethyldithiocarbamate) significantly improved overall survival (81% vs. 55%) and disease-free survival (76% vs. 55%) compared to the placebo group . A phaseDSF may be beneficial in treating breast, lung, pancreatic, prostate, liver, and ovarian cancer, as well as acute myeloid leukemia, glioblastoma, and melanoma, with a particular role in glioblastoma patients ,454. TheCimetidine, commonly used to treat ulcers and gastroesophageal reflux disease, exhibits multiple anti-tumor effects , includip = 0.02), and higher relative survival rates were observed in the cimetidine-treated patients at 1 year (45% vs. 28%) [The clinical benefits of cimetidine in cancer patients are not extensively studied, with most research focusing on post-operative colorectal surgery patients . Howevervs. 28%) .Cimetidine may be beneficial in patients with colorectal cancer, melanoma, gastric cancer, pancreatic cancer, ovarian carcinoma, prostate cancer, Kaposi\u2019s Sarcoma, salivary gland tumors, renal cell carcinoma, breast cancer, glioblastoma, and bladder cancer . The staViscum album L.) is commonly used in continental Europe as an adjunctive treatment for cancer patients, with mistletoe extracts administered subcutaneously or intravenously to reduce disease- and treatment-related symptoms and improve quality of life [The European white-berry mistletoe  and may have a favorable effect on survival in cancer patients  when used as an adjunct to conventional treatments [Over 50 prospective studies, including more than 30 randomized controlled trials (RCTs), have investigated the role of mistletoe in cancer patients, showing benefits in terms of improved quality of life, performance index, symptom scales, and reduced adverse effects of chemotherapy . A Cochreatments . A phaseeatments .Mistletoe has shown benefits in improving the quality of life in patients with various types of cancers, including breast, bladder, gynecological , colorectal, gastric, pancreatic, glioma, head and neck, lung, melanoma, and osteosarcoma. However, as mistletoe is administered parenterally (subcutaneously or intravenously), it requires supervision by an integrative oncologist as part of a personalized treatment protocol .Withania somnifera, WS), historically employed in Mediterranean and Ayurvedic medicine, functions as both a functional food and medicinal plant with potential anticancer attributes [Ashwagandha  and stress levels (p = 0.005) compared to placebo [In the context of cancer, Ashwagandha has been primarily investigated through experimental models, with limited clinical data on its efficacy. Biswell et al. conducted an open-label prospective nonrandomized trial involving breast cancer patients, administering a combination of chemotherapy and Ashwagandha or chemotherapy alone. The study group receiving Withania somnifera root extract exhibited significantly lower fatigue levels and improved quality of life scores. Although the 24-month overall survival rates were higher in the study group (72%) compared to the control group (56%), the difference was not statistically significant . Apart f placebo . AlthougAshwagandha may be effective against cancers such as breast, colon, lung, prostate, glioblastoma multiforme, melanoma, and blood cancers ,472. AshSelective phosphodiesterase 5 inhibitors, including sildenafil, tadalafil, and vardenafil, are widely used in the treatment of erectile dysfunction and pulmonary arterial hypertension . These dPDE5 inhibitors, such as sildenafil and tadalafil, have shown promising anticancer effects in various types of cancers . These iSeveral studies have demonstrated the potential anticancer benefits of PDE5 inhibitors. A large study involving 192,661 patients showed that PDE5 inhibitor use was associated with a reduced risk of developing colon cancer, and in men with benign colorectal neoplasms, it was associated with a lower risk of colorectal cancer . ClinicaPhosphodiesterase 5 inhibitors, such as sildenafil and tadalafil, may be beneficial for the treatment of prostate, breast, hepatocellular, colorectal, lung, and head and neck cancers, glioblastoma, and leukemias . The recItraconazole, a well-established antifungal agent inhibiting lanosterol 14\u03b1-demethylase, has demonstrated potential as an anticancer agent through mechanisms unrelated to its antifungal effects.Its anticancer activity involves the reversal of P-glycoprotein-mediated chemoresistance, modulation of the Hedgehog, mTOR, and Wnt/\u03b2-catenin pathways, angiogenesis and lymphangiogenesis inhibition, and potential interference with cancer-stromal interactions . MechaniItraconazole demonstrates potential anticancer efficacy either as a single agent or in combination therapy based on preclinical and clinical data ,498,499.Itraconazole in a dose of 400\u2013600 mg/day is recommended. Itraconazole is a conventional antifungal drug that has received FDA approval and has an excellent safety record . HoweverAdjunctive therapies demonstrate some potential for use in the treatment of cancer. These are summarized in \u00ae system, utilizing transdermally transmitted 100\u2013400 kHz AC electric fields through orthogonal transducer arrays to disrupt mitosis [Tumor treating fields (TTF) are non-invasive alternating electric fields administered via the Optune mitosis ,503. Thi mitosis . Althoug mitosis . In GBM, mitosis . The Nat mitosis ,506. ComPhotodynamic therapy (PDT) involves tissue destruction through visible light when combined with a photosensitizer and oxygen . When exHypoxia is a critical hallmark of solid tumors, associated with enhanced cell survival, angiogenesis, glycolytic metabolism, and metastasis . Hyperba"}
+{"text": "Suicide in older people is a critical public and mental health issue which requires attention, given that the ageing population is increasing.Multiple factors, including biological, psychological, and social stressors increase suicidal susceptibility. Unfortunately, elderly are more susceptible to these, such as psychiatric disturbances, physical comorbidities, prior suicide-related behaviours, lack of social support, grief, and increased difficulty in problem-solvingIn order to review the risk and protective factors, assessment and prevention of suicide in older adults.Bibliographic research through PubMed and Web of Science.Older people can be subdivided into three age groups (from \u201cyoung old\u201d at 65 years old to \u201coldest old\u201d after 85 years of age), with suicide being more prevalent in the oldest-old, and overall in men above 75 years old.Previous psychiatric background, suicidal attempts, substance abuse, poor physical health or disability, family psychiatric history, low social support or isolation, and finantial stress most frequently predispose to suicidal ideation, suicide attempts or death by suicide in this community.Besides this, ageing relates to a tendency to cognitive impairment, which affects coping mechanisms, leading to deficits in reasoning and decision-making under stressful circumstances during depressive episodes. This can mediate suicidal ideation and associates to greater lethality methods. Geriatric suicidal attempters have been shown to have greater degrees of cortical and subcortical cerebral areas, including the frontal, parietal and temporal regions, as well as significant loss of volume in the dorsomedial prefrontal cortex, insula, midbrain, cerebellum, lentiform nucleus and putamen. Abnormalities in these regions can impair executive and cognitive function, attention, problem solving and ultimately be responsible for suicidal behaviour.On the other hand, there are suicide protective elements such as physical and cognitive fitness, quality of life and life satisfaction, marital status, religiousness and social support. A prompt identification of modifiable risk factors and strengthening the protective ones by health professionals can reduce this prospect.Suicidal ideation in older people is a multifactorial public health concern given the very high frequency of completed suicides in this population. Therefore, it is urgent to review and further research to build more effective suicide prevention strategies.None Declared"}
+{"text": "In craniofacial research and routine dental clinical procedures, multifunctional materials with antimicrobial properties are in constant demand. Ionic liquids (ILs) are one such multifunctional intelligent material. Over the last three decades, ILs have been explored for different biomedical applications due to their unique physical and chemical properties, high task specificity, and sustainability. Their stable physical and chemical characteristics and extremely low vapor pressure make them suitable for various applications. Their unique properties, such as density, viscosity, and hydrophilicity/hydrophobicity, may provide higher performance as a potential dental material. ILs have functionalities for optimizing dental implants, infiltrate materials, oral hygiene maintenance products, and restorative materials. They also serve as sensors for dental chairside usage to detect oral cancer, periodontal lesions, breath-based sobriety, and dental hard tissue defects. With further optimization, ILs might also make vital contributions to craniofacial regeneration, oral hygiene maintenance, oral disease prevention, and antimicrobial materials. This review explores the different advantages and properties of ILs as possible dental material. The first ionic liquid (IL), ethylammonium nitrate, was reported in 1914 by Paul Walden  reportedILs have drawn attention due to their attractive properties, including low vapor pressure, high chemical and thermal stability, wide electrochemical window, nonflammability, and the ability to dissolve various organic and inorganic materials. The properties of ILs, such as density, viscosity, and hydrophilicity/hydrophobicity, can be modified by judicious selection of cations and anions, by fine-tuning the lengths of the cation alkyl chain, or by the covalent tethering of task-specific functionalities to one or both of the constituent ions ,7,8,9,10The unique properties of ILs make them particularly promising candidates as environmentally benign or \u201cgreen\u201d alternatives to organic solvents for chemical synthesis , catalysAlthough few reviews have explained the potentiality of ILs in biomedical applications, none have discussed the potential role of ILs in dentistry and craniofacial sciences in details. This comprehensive review is a pioneering study in dentistry and craniofacial engineering, exploring the different functionalities and applications of ILs in this field.According to the Centers for Disease Control and Prevention (CDC) of the United States (U.S.) ,22, moreCell membranes, both plasma membranes or internal membranes are made of glycerophospholipids: a glycerol, phosphate group, and two fatty acid chains. Glycerol is a three-carbon poly alcohol that acts as the connector and attaches the phosphate polar (hydrophilic) head group and two nonpolar, hydrophobic hydrocarbon fatty acid tails . The difDue to the surface charge (phosphate head group) of the lipid bi-layer, the cationic moiety of the ILs adsorbed on the lipid membrane interacts with the transdermal protein and disorganizes the bi-layer with the penetration of its long alkyl chain, which ultimately changes the regular properties of a cell membrane ,28,29. TPseudomonas aeruginosa, Escherichia coli, and Staphylococcus aureus [Antimicrobial properties can be enhanced by increasing the alkyl chain length. In a recent study, replacing an alkyl group with a phenolic group and increasing the other alkyl chain length of an imidazolium-based IL exhibited minimal inhibitory concentrations (MICs) < 7.81 \u00b5M against s aureus . ILs becs aureus ,31. Polys aureus .A series of experimental and computational studies ,39,40,41The long-term stability of proteins is essential in terms of dealing with proteins. Generally, proteins are folded to avoid loss due to aggregation. Instead of aqueous buffers, ILs help prevent aggregation and reverse aggregation or refolding (only 3% loss) for many cycles ,54,55. CAccording to the American Academy of Implant Dentistry (AAID) and the American College of Prosthodontists, approximately 36 million U.S. citizens have lost all their teeth, and 120 million are missing at least one. These numbers are expected to grow over the next two decades. People can lose their teeth irrespective of age to numerous causes, including decay, gum disease, injury, accident, cancer, etc. Loss of a single tooth worsens overall oral health by weakening the jawbone. Dental implants are the most common treatment for dental loss. An implant consists of three components: an implant post, a cylindrical screw-shaped device anchored into the mandibular bone that provides necessary support for a dental prosthesis (crown), and an abutment that connects dentures to dental posts . Endo-osA successful dental implant is associated with the osseointegration of surrounding soft and bone tissues with the dental implant surface ,61,62,63Non-cavitated carious lesions near dental surfaces are a prevalent dental disease . To protDesigning highly active antimicrobial surfaces or coatings is a significant challenge for public health. Resins are inert methacrylate monomers, such as triethylene glycol dimethacrylate (TEGDMA) and bisphenol A-glycidyl methacrylate (Bis-GMA), that lack antimicrobial activity. Hence, efforts are being made to endow resin infiltrates with antimicrobial properties. Cuppini et al. developed microcapsules loaded with 2.5wt%, 5wt%, or 10wt% ionic liquid as resin infiltrates  Figure .Escherichia coli (E. coli) and found potent biofilm inhibition of ~92%. Importantly, imidazolium ionic liquids can replace carcinogenic bisphenol A. Recently, an RTIL (BMIMTFSI) was successfully used as an antibacterial experimental orthodontic adhesive against Streptococcus mutans [Microcapsule-loaded RTILs show excellent antibacterial properties without changing other physicochemical properties or eliciting cytotoxicity (cell viability > 90%). In recent studies ,80, thres mutans  and resis mutans .Nanoparticles, especially silver (AgNP), zinc oxide, titanium dioxide nanoparticles, quaternary ammonium, and cationic nanoparticles, have been incorporated into resin as antibacterial agents, showing promising results ,83,84. EEfforts have been made to develop IL-based oral hygiene products, such as dental toothpaste and mouthwash/mouth rinse. Madhusudan et al. proposed an oral care composition for removing or reducing plaque comprising an IL formulated with choline salicylate and tris-(2-hydroxyethyl) methylammonium methylsulfate. They developed 74 prototype formulations; in vivo experimental results suggested several formulations might provide clinical efficacy to disrupt, dissolve, and remove bacterial plaque. The function of ionic liquid-based oral care compositions will also prevent different gingivitis and oral cavity diseases, such as dental caries, calculus, erosion, periodontitis, halitosis, and even salivary gland disorders, including xerostomia/dry mouth .In clinics, dental cement selection is vital in achieving successful restoration and significantly increases the duration of teeth restoration . KajimotResearchers have shown that interleukin-6 (IL-6) promotes tumor growth by causing DNA methylation changes, which can lead to changes in the oral cancer cell gene expression . Higher In the future, oral health care could utilize ionic liquids (ILs) as a strategy for early oral cancer diagnosis. IL with menthol can be used to mass-screen patients for early oral cancer diagnosis. The IL\u2019s chemical structure can affect the menthol release rate . ComplexA common condition in many oral diseases, such as gingivitis, is inflammation. Microorganisms cause an inflammatory immune response mediated by changes in the vascular network and the exudation of gingival crevicular fluid (GCF), which contains inflammatory and plasma cells, ultimately resulting in tissue death. Gingivitis is the primary cause of bleeding gums that allows plaque to accumulate at the gum line. Tartar will form if plaque is left untreated. This results in bleeding as well as periodontitis, a severe form of gum and jawbone disease . FunctioThe most prevalent cause of cracked tooth syndrome is chewing on hard foods, which causes an incomplete tooth fracture. This is the third most frequent cause of tooth loss , with noDrinking too much alcohol can result in overdose, car accidents, intoxication of athletes/pilots, etc. According to studies, the blood and saliva alcohol levels are consistent . A driveA person\u2019s oral cavity contains more than 70 different species of bacteria. Although most are harmless, some bacteria are dangerous and can lead to dental problems, including tooth decay and gum disease . Oral heIonic liquids (ILs) have long been considered environmentally friendly and ecologically benign solvents. Nevertheless, concerns have recently arisen regarding their potential toxicity to human health and environmental impact, necessitating a thorough investigation. ILs are engineered to possess low volatility and stability, which, unfortunately, reduces their biodegradability . The toxEscherichia coli, Staphylococcus aureus, Bacillus subtilis, Pseudomonas flurescens, and Saccharomyces cerevisiae, reinforcing the trend that higher alkyl chain lengths are associated with greater toxicity [Notably, ILs featuring choline-based components exhibit lower toxicity than the commonly used imidazolium, pyridinium, and pyrrolidinium variants ,114,115.toxicity ,119. HowWith proper optimization, ILs can be incorporated into drug formulations to avoid the development of cancer treatment resistance. Adequate knowledge of the toxicity will provide vital information for anti-cancer drug development, as apoptosis-related drug resistance is challenging for different cancer types. Additionally, there is an interest in identifying other means of inducing cytotoxicity . This inRoom temperature ionic liquids (RTILs) have high potential in advanced tissue engineering applications, including craniofacial engineering and dental procedures. They can be easily incorporated with self-healing materials , magnetoMost cell types respond to electrical stimuli, which control the healing and regeneration of skin wounds, spinal cord injury, bone fractures, and neural growth . The comOral hygiene maintenance is critical for a healthy oral cavity and lifestyle. However, unfortunately, due to musculoskeletal disorders such as osteoarthritis, rheumatoid arthritis, and other conditions, many elders find it challenging to maintain good oral hygiene . Also, tWith advanced 3D bioprinting techniques, there are enormous opportunities for combining various amounts of ILs in toothpaste/mouthwash compositions to enhance the protective environment within the oral cavities. Hayashi et al. recently explored a technique enabling ILs to formulate fluoridated toothpaste. They reported preparing a new class of hybrid ILs, called \u201cfluoride ion-encapsulated germoxane cages\u201d, containing a fluoride ion inside .Breath-based sensors could be another area for future bench-side applications of ILs in clinical dentistry. There is evidence that the presence of chronic disease and cancer alters cellular metabolic processes, and these alterations are recorded in the released volatile organic compound (VOC) compositions of cancer cells. We have shown the potential of using VOC sensors as a biomedical engineering approach for oral cancer detection. Due to their multifunctional nature, ILs could be used for such breath-based early detection systems .Like any healthcare facility, dental clinics pose a risk of spreading coronavirus disease (COVID-19) via cross-infection among patients, dentists, and community members. In clinical dental settings, the instruments produce aerosols, droplets of saliva, secretions, saliva, and blood, which can rapidly transmit viruses between dental practitioners, assistants, and patients and their attendants ,136. DueA denture appliance resides in the oral cavity and is highly prone to microbial growth, bacterial biofilm formation, and contamination. Many antimicrobial agents are commonly used for denture preparation, such as titanium dioxide, methacrylic acid monomers, silica, and MPDB/12-methacryloyloxy dodecylpyridinium bromide. Due to their multifunctional properties and antimicrobial nature, RTILs can be incorporated as routine agents to fabricate anti-viral dentures .Further studies are required to accurately assess the toxicity at the cellular and molecular levels. Experiments should be conducted utilizing flat two-dimensional (2D) cultures and more advanced three-dimensional (3D) in vitro models  with cells embedded in extracellular matrices, such as rat tail-derived collagen type 1 and mice sarcoma tissue-derived basement membrane mimicking matrices ,138. AftIonic liquids (ILs) have a unique multifunctional property that might allow researchers to explore the potentiality of remote sensing and controlling cellular growth in the craniofacial region. ILs are antimicrobial and easy to characterize, enhancing the functionality of dental cement, 3D bioprinting, and implants with sensing capabilities. However, further in vitro and in vivo studies are required to evaluate the cytotoxicity of ILs and optimized their formulations."}
+{"text": "Castration of male animals is intended to produce high-enhance quality of animal meat, prevent unpleasant taste, reduce aggressive behavior, and manage overbreeding. Over the years, Tranditional methods of mechanical and surgical castration have been employed over the years, but they fall short of meeting animal welfare requirements due to the associated risk of infection, pain, and stress. Immunocastration, specifically Gonadotropin-releasing hormone (GnRH)-immunocastration, targeting the hypothalamic\u2013pituitary-testis (HPT) axis, has emerged as an animal-friendly alternative to surgical castration, effectively addressing these issues. This review seeks to systematically summarize the principles, development, current applications and challenges of GnRH-immunocastration, offering insights into its role in promoting animal welfare. While c2.Currently, various techniques for castrating male animals exist, including chemical castration, Bloodless castration, surgical castration, and immunocastration . Unlike 3.Immunocastration primarily targets reproductive hormones within the HPT axis , disrupt4.Physiological doses of GnRH can significantly increases LH levels and slight increase FSH levels in plasma, reaching the gonads via the pituitary portal circulation, This stimulated the synthesis and secretion of gonadal steroid hormones, promoting gonadal development, gamete production, and the occurrence and maintenance of secondary sexual characteristics. GnRH immunocastration induces a lot of GnRH-antibodies that neutralize endogenous GnRH, and the production of the antibody is a sustained biological effect. As a result, GnRH immunocastration consistently inhibit testicular or ovarian endocrine function, reducing hormone levels and reproductive activity, and associated odors, primarily skatole and androstenone . Immuniz5.Immunocastration is not limited to pork production but is also employed in other livestock animals as an alternative to surgical castration. Its key advantage lies in eliminating pain, wound infection risks, and potential losses associated with castration . Now, se6.Immunocastration, often administered using the GnRH vaccine, has undergone extensive investigation in male mammals and birds  43, 57\u2013. Outcome6.1.In mammals, the majority of research on GnRH-immunocastration has focused on male animals, and spermatogenesis is inhibited after GnRH immunization. For example, immunizing male animals such as boars, bulls, stallions, rams, bucks, and rats with GnRH vaccine leads to the suppression of testicular, epididymal, and vas deferens development. This results in reduced sperm concentration in the testicles with low viability, constriction of the seminiferous tubules, and inhibition of spermatogonia and spermatoblast production in the deep epithelium , 64\u201368.At present, GnRH immunocastration is the most widely used in boars. Androstenone is a male hormone that is formed in the cells of the Leydig and has a urine-like odor . SkatoleMeat quality is increasingly valued by consumers, so male livestock are castrated in production to improve meat quality. Currently, a large number of studies have focused on the improvement of meat quality through immunocastration. GnRH immunocastration reduces the accumulation of taint compounds in adipose tissue and improves meat quality and carcass characteristics in male mammals . However6.2.The utilization and assessment of immunocastration vaccines in pigs has been extensively reported , 48, 75.7.Immunocastration currently faces challenges related to immunization failure. These challenges include significant variations in individual responses among immunized animals, insensitivity to antigens in some individuals, failure to elicit an immune response, or a shorter duration of immune effect. This shorter duration leads to an increase in testosterone concentration during the recovery period compared to the previous phase, resulting in a gradual return of sexual behavior. Multiple vaccinations are necessary to counter this effect, which in turn escalates costs. Moreover, there are associated disadvantages for farmers, including increased expenses for purchasing produce and labor management, the risk of accidental self-injection by farm workers, and uncertainty regarding consumer attitudes toward meat from pharmacologically castrated animals. However, it\u2019s important to note that immunocastration offers several advantages, such as reducing animal stress, lowering the risk of infections and complications associated with surgical castration, significantly improving animal welfare, and being relatively straightforward to implement in production settings. Therefore, immunocastration may remain a safe alternative to surgical castration in the future.In the future development of commercial castration vaccines, particularly GnRH immunocastration vaccines for male animals, there should be an exploration of the construction of immunogens, immune dosages, immune strategies, and timing. Attention should be directed toward enhancing the effectiveness and prolonging the duration of immune response for these vaccines. Currently, research on GnRH vaccines primarily focuses on chemical synthesis of polypeptides, dual conjugate vaccines, DNA vaccines, tandem conjugate vaccines, among others. However, these approaches have their limitations. Considering the existing challenges with GnRH gene vaccines, it\u2019s worth considering research and development of GnRH gene engineering vaccines and GnRH recombinant adenovirus vaccines in the future. In summary, the future focus of immunocastration vaccine development will revolve around creating products with sustained immunogenicity, easy production, and stable effects. These advancements could hold the key to the future of immunocastration vaccines.CW: drafting the manuscript. YZ and CY: provision of study materials. MZ: conceptualization and supervision. All authors contributed to the article and approved the submitted version."}
+{"text": "The aim of this review article is to appraise the design and functionality of above-knee prosthetic legs. So far, various transfemoral prosthetic legs are found to offer a stable gait to amputees but are limited to laboratories. The commercially available prosthetic legs are not reliable and comfortable enough to satisfy amputees. There is a dire need for creating a powered prosthetic knee joint that could address amputees\u2019 requirements. To pinpoint the gap in transfemoral prosthetic legs, prosthetic knee unit model designs, control frameworks, kinematics, and gait evaluations are concentrated. Ambulation exercises, ground-level walking, running, and slope walking are considered to help identify research gaps and areas where existing prostheses can be ameliorated. The results show that above-knee amputees can more effectively manage their issues with the aid of an active prosthesis, capable of reliable gait. To accomplish the necessary control, closed loop controllers and volitional control are integral parts. Future studies should consider designing a transfemoral electromechanical prosthesis based on electromyographic (EMG) signals to better predict the amputee\u2019s intent and control in accordance with that intent. The emergence of rehabilitation has enabled amputees to regain their mobility by using various types of prostheses. Transfemoral amputees have their legs amputated between the hip and knee, at the level of thigh muscles ,2. ActivStandards for a microprocessor-based prosthetic knee were developed by Ottobock C-leg. While carrying a burden, it maintains body movements and prevents falls ,13,14. BThe increased risk of tripping with transfemoral prostheses is another problem. Tripping incidents are common among people using transfemoral prostheses. De facto, transfemoral prostheses increase step width while improving gait symmetry and energy efficiency. To reduce the step width, a specific strategy must be designed ,19. The Numerous prostheses have been created that successfully offer full kinematics and kinetics for walking on level ground and climbing stairs . HoweverThe main goal of this systematic review is to offer a critical evaluation of the functions of the knee prosthetic units already in use, as well as an assessment of their levels of mobility, ranges of motion, degrees of freedom, dependability, confidence level, independence, and overall standard of living for amputees. Second, their flaws or deficiencies are evaluated as well, including the risk of falling, ease of mobility and use, design, gait, and kinematics. This systematic evaluation also examines how closely or how differently these transfemoral prostheses functioned naturally compared to a knee joint.In this study, Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed .There were several transfemoral prostheses used, with a focus on the role of the knee unit in gait biomechanics. Transtibial prosthesis-related studies, osseointegrated prosthesis, and those that ignored gait biomechanics were disregarded. The outcomes included mobility, running, supporting body weight, preventing falls, weight, durability, cosmesis (appearance), comfort, wear-and-tear, and pain ,27. The Duplicates were removed and titles and abstracts were screened at level 1, and entire texts were screened at level 2, using Covidence and Endnote ,30. If tThe search template for MEDLINE was created using rehabilitation-related terms and keywords including transfemoral amputation, gait analysis, knee kinematics, and prosthetic knee unit design. The same method was then applied to other databases.Data was extracted, and its accuracy was then evaluated. Author, year, region, study group, level of amputation, kind of prosthesis, degrees of freedom, range of motion, research methodology, outcome measures, and key findings were obtained.Using the Cochrane \u201crisk of bias\u201d technique, the risk of bias in studies was independently evaluated . PRISMA n = 286), at level 1 we examined 1086 citations. 30 publications were found after two screening steps were completed at level 2: one involved titles and abstracts and the second involved entire articles , named I-knee, was developed with non-microprocessor-controlled prosthetic knees (NMPKs), for its efficiency at different walking speeds . The comVarious mechanical and electromechanical prostheses have been developed so far, which work to fulfill requirements regarding biomechanical parameters. However, few are commercially available, mostly are under research in laboratories ,34,38,39Various research studies have been carried out on transfemoral prosthesis, which meet biomechanical parameters to different extent, as represented in After ground level walk, next goal for researchers is the stairs ambulation. Tran et al.  devised Various prostheses offering ramp walk have been the focus of researchers yet require realization for commercial availability. Azimi et al.\u2019s  researchGait patterns for various terrains, with various walking speeds and switching over have been investigated by researchers. Andrysek et al.  appraiseNormally different types of materials are used for manufacturing prosthetic knees for transfemoral amputees, including aluminum, titanium, biomaterials like fiber reinforced composites, glass fiber composites etc. ,61,62. TIn the systematic review, we screened various transfemoral prostheses addressing different biomechanical parameters for movement, to find a research gap. Firstly, this review found multiple aspects, covered in different research articles. For instance, microprocessor-based and non-microprocessor-based prosthesis, gait analysis, kinematics, prosthesis designs, types of ambulation activities, control strategies, volitional control, etc. A comparison of microprocessor-based prosthetics with non-microprocessor-based prostheses proved that microprocessor-based prostheses were more efficient and intelligent, to ensure controlled movement of the knee joint for a stable walk ,37. HoweMost of the researchers have preferably worked on stairs ascending and descending and offered required biomechanics, however, could not address intent recognition to adjust to stair height, cadence, etc. ,44,45. STo provide desired control, active prostheses require closed-loop systems with particularly designed controller(s). Some controller-based studies validate their prosthesis efficiency for stable gait in just simulation . HoweverResearch work for transfemoral prosthetic knee joint led to the point that volitional control and surface recognition are interlinked, as the variation in the surface would make amputees make accordingly decisions ,57,58,59For the manufacturing of prostheses, material selection is very crucial. Various factors are considered for material selection, out of which strength, stiffness, and cost are among the most important ones ,62. OwinThis systematic review has analyzed current state-of-the-art research on different types of design and biomechanical features of transfemoral prostheses. The reviewed articles present evidence for our hypothesis that active prostheses have much more pronounced results as compared to the passive ones regarding the kinetics and kinematics of the prosthetic knee joint. The articles based on gait analysis and biomechanical parameters have shown the reliance on closed-loop control systems along with power sources. Likely trained amputees show vigorous amelioration in results as compared to untrained amputees. Hence, amputees require appropriate training time prior to using prostheses, either for testing or personal usage.Researchers in the field of transfemoral prosthesis are recently focusing on electromechanical design and control of powered prostheses; however, there are still many areas that need to be emphasized. Firstly, modern controlled prostheses designed for stable walking are still limited to research and experimental work and are not yet commercially available owing to their higher cost. Most prostheses are limited to model frameworks, real-time testing is missing, or their experimentation is performed just on healthy subjects in a virtual environment. A control system for a prosthetic knee unit requires work to ensure a comfortable, stable, and free-of-fall walk, with real-time testing with transfemoral amputees. More realistic results would be obtained when experiments were conducted on large groups of varied participants and on amputees.Regarding different ambulation activities, various researchers have focused on ground-level walking and stair ambulation with ameliorated performance. The challenge is to focus on the kinematics and gait analysis of the transfemoral prosthesis for ramp walking to ensure the required symmetrical gait pattern, knee joint angle, torque, power output, and impedance control without causing load on the hip and other healthy limbs. This would require controlled speed for ascending and descending, particularly to prevent falling during descent.Adaptation to various locomotion modes, gait phases, and uneven surfaces is dependent on anticipation methods, and EMG plays an elementary role in this requirement. Since EMG provides intent recognition to transition between ambulation modes and complete control to walk over different types of surfaces with different speeds and gait cycles. However, active EMG-based transfemoral prostheses are still a challenge for researchers and need attention."}
+{"text": "In \u201cRacial/Ethnic Disparity in Association Between Fetal Alcohol Syndrome and Alcohol Intake During Pregnancy: Multisite Retrospective Cohort Study\u201d  the authors noted one error.The authorship was previously published as:Sarah Soyeon Oh, SangMin Kim, Bada Kang, Jewel Park, Seung Hee Lee, Eun-Cheol Park, Ichiro KawachiAnd will be changed to read as follows:Sarah Soyeon Oh, Bada Kang, Jewel Park, SangMin Kim, Eun-Cheol Park, Seung Hee Lee, Ichiro KawachiThe correction will appear in the online version of the paper on the JMIR Publications website on April 28, 2023 together with the publication of this correction notice. Because this was made after submission to PubMed, PubMed Central, and other full-text repositories, the corrected article has also been resubmitted to those repositories."}
+{"text": "Pathogens, especially invasive species, have caused significant global ecological, economic, and social losses in forests. Plant disease research has traditionally focused on direct interactions between plants and pathogens in an appropriate environment. However, recent research indicates that the microbiome can interact with the plant host and pathogens to modulate plant resistance or pathogen pathogenicity, thereby altering the outcome of plant\u2013pathogen interactions. Thus, this presents new opportunities for studying the microbial management of forest diseases. Compared to parallel studies on human and crop microbiomes, research into the forest tree microbiome and its critical role in forest disease progression has lagged. The rapid development of microbiome sequencing and analysis technologies has resulted in the rapid accumulation of a large body of evidence regarding the association between forest microbiomes and diseases. These data will aid the development of innovative, effective, and environmentally sustainable methods for the microbial management of forest diseases. Herein, we summarize the most recent findings on the dynamic structure and composition of forest tree microbiomes in belowground and aboveground plant tissues , as well as their pleiotropic impact on plant immunity and pathogen pathogenicity, highlighting representative examples of biological control agents used to modulate relevant tree microbiomes. Lastly, we discuss the potential application of forest tree microbiomes in disease control as well as their future prospects and challenges. Ophiostoma ulmi and O. novo-ulmi) [Phytophthora cinnamomi and Phytophthora cambivora) [Cryphonectria parasitica) [Phytophthora ramorum) [Bursaphelenchus xylophilus) [Hymenoscyphus fraxineus), and laurel wilt (Raffaelea lauricola) [Forests offer numerous services to humans, including climate regulation, water supply and regulation, and biodiverse habitats. Nevertheless, the current state of global forest resources does not bode well for their conservation . Apart fvo-ulmi) , Phytophmbivora) , chestnuasitica) , sudden ramorum) , pine wiophilus) , ash dieuricola) . These duricola) ,9,10,11,Plant microbiomes exist widely in the rhizosphere, in the phyllosphere, and inside plants. Microbiome-wide association studies (MWAS) have been widely used to investigate the links between the altered microbiome and the development of human diseases, including but not restricted to rheumatoid arthritis, liver cirrhosis, type 2 diabetes, obesity, and colorectal cancer . Due to Strengthening our ability to prevent and control forest diseases and protecting the healthy production of forest trees are major issues facing the development of the forest industry . Trees pIn the natural environment, WP\u2013microbiome interactions  occur inside (such as in the leaf endosphere and root endosphere) and on WP surfaces (such as in the rhizosphere and phyllosphere) ,28 Figu. The aboP. cinnamomi is an extremely damaging and prevalent soil-borne pathogen that infects several woody plant hosts, such as eucalyptus, oaks, chestnuts, and pines [Ralstonia solanacearum causes bacterial wilt in eucalyptus [Ceratocystis sp. causes damping off in many forestry species, including Acacia spp., Eucalyptus spp., and Quercus spp. [Verticillium dahliae, which is a classical soil-borne disease that presents a threat to olive trees [Compared to herbaceous and cereal plants, the rhizosphere zone of woody plants is larger, contains more microorganisms, has increased variety, and is more active. When certain microorganisms expand and reproduce in large numbers, they have the potential to cause root diseases in forest trees. For example, nd pines . Ralstoncalyptus  and fig calyptus . Ceratoccus spp. ,36. Vascve trees , smoke tve trees , and manve trees .Bacillus and Pseudomonas, fungi: Trichoderma and yeast, and actinomycetes: Streptomyces) to inhibit pathogen growth and reproduction by competing with pathogens for rhizosphere nutrition and niches, or by secreting siderophile elements, hydrolytic enzymes, volatile organic compounds, and antibiotics, thereby indirectly promoting plant growth [Pseudomonas fluorescens strain PICF7 has been applied to olive trees to induce host resistance to Verticillium wilts caused by the pathogen V. dahliae [Approximately 2\u20135% of rhizosphere microorganisms mainly form two types of symbioses, arbuscular mycorrhiza (AM) and ectomycorrhiza (ECM), with forest roots, which have a significant impact on promoting plant growth and reducing plant diseases ,41,42,43t growth ,44. For  dahliae ,46. Some dahliae .Arabidopsis roots, selectively signals and, in a dose-dependent manner, recruits the beneficial rhizobacterium Bacillus subtilis, resulting in a stronger immune response to Pseudomonas syringae pathovar tomato (Pst). Salicylic acid (SA), a defense phytohormone secreted in the Arabidopsis root zone, has been reported by Lebeis et al. [B. subtilis N11 and promotes biofilm formation [Triadica sebifera) release flavonoids that can help AM fungal spores germinate and colonize. These flavonoids may also have an effect on soil microbes and other soil processes [Trees can change the composition of rhizosphere microbiota by secreting bioactive exudates  into the region of the rhizosphere ,49,50,51s et al.  to modulormation . The roorocesses .N-acyl-homoserine lactone-driven quorum-sensing (QS) signaling molecules are produced by PGPRs, which are responsible for promoting plant growth [Since the types and concentrations of root exudates vary among different plant species and among different natural populations within the same plant species, and there are different plant growth stages, nutritional statuses, and stress exposures ,58,59, tt growth  and indut growth . Microbit growth ,66,67.The interactions between plants and the rhizosphere microbiome can generate a strong selective pressure that shapes the rate and pattern of microbial evolution and eventually affects the rhizosphere microbiome\u2019s composition . In respIn comparison to annual and/or herbaceous plants, perennial woody plants can establish long-term associations with their associated microbiome. For most crops used in previous studies, short growth periods limit the stability of the rhizosphere microbiome. Therefore, their role in plant resistance is readily disrupted by environmental factors ,73. As a2 [The phyllosphere  accounts for a substantially larger proportion of a terrestrial plant than the root system. Leaves, with a global leaf envelope estimated to be about one billion km2 , represe2  and are 2 , followe2  and bact2  , poplar, and other tree leaves [The colonization source of the phyllosphere remains somewhat uncertain. Recent research indicates that soil is the ultimate source of phylloplane microorganisms . At the thaliana ,86,87,88thaliana . Bacterithaliana , but thethaliana ,91. Izhathaliana  identifit growth . In chart growth  showed te leaves ,96,97,98Tamarix trees  cultivated in the same geographical location possessed strikingly similar bacterial communities, suggesting that the major determinant of the composition of phyllosphere bacterial communities was geographical location, not plant species. In a later study, sampling of leaves from T. aphylla trees growing across the Sonoran Desert in the southwestern United States provided additional evidence of the main impact of geographic distances on phyllosphere bacterial communities [Pinus ponderosa exhibited remarkable similarity among them. Additionally, leaves collected from 56 distinct tree species originating from the same geographical location contained bacterial populations unique to each plant species [Usually, soil types and properties, the climate, genetic characteristics of plants (genotype and phenotype), geographical location, and attack by pathogens, among other factors, are drivers that contribute to the assembly of phyllosphere bacterial communities ,100,101.munities . However species . In a st species  also indAlternaria, Fusarium, Cladosporium, Penicillium, Mucor, Colletotrichum, Acremonium, and Aspergillus [Quercus macrocarpa) leaves [Fagus sylvatica) leaves, fungal community assembly is determined by host genetics [Populus balsamifera) [The fungal microbiota of the phyllosphere consists of two dominant groups: yeast and filamentous fungi . On healergillus ,106,107.ergillus ,109. At ) leaves . On beecgenetics . Similaramifera) ,112. In amifera) ,116,117.Arabidopsis mfec mutant and cad1 mutant displayed leaf damage (chlorosis and/or necrosis phenotypes) and simultaneously caused marked changes in the endophytic phyllosphere microbiota of A. thaliana, including an overall increased bacterial population size, decreased community diversity, and a shift from a Firmicutes-rich community to a Proteobacteria-rich community. To the best of our knowledge, this is the first report regarding the genetic regulation of microbiome assembly in the phyllosphere and its consequential impact on plant health. However, significant knowledge gaps still exist about this aspect.The leaf surface creates stressful and unstable conditions, including deficiency in nutrient supplies, harmful ultraviolet (UV) radiation, oxidative stress, low water content, fluctuating temperature throughout the day, and biotic stress. Phyllosphere-associated microbes, regardless of whether they are commensal, beneficial, or detrimental microorganisms, employ distinct fitness strategies (tolerance or avoidance strategies) to deal with this combination of stresses for successful colonization . For exaPst, which is the causal agent of bacterial speck. Furthermore, the degree of protection was determined by the initial dose of the microbiota administered. Similarly, considerable changes in leaf-associated fungal and bacterial communities were noted upon Huanglongbing (HLB) infection in citrus [Quercus robur) [Erysiphe alphitoides, suggesting that some of these taxonomic units potentially conferred protection upon the oak phyllosphere by inhibiting E. alphitoides, thereby reducing the incidence of powdery mildew. More recently, Li, Zhu, Zhang, Xu, Wang, Wang, and Li [Sphingomonas spp.) and newly recruited microbes  compared to those of uninfected leaves by the melanose pathogen D. citri. Further, Sphingomonas spp. exhibited promising results in protecting the citrus phyllosphere against disease invasion through its ability to compete for iron. Overall, the roles played by phyllosphere microbiomes in conferring resistance against pathogen invasion and their contribution to plant health have only recently gained attention and provided a significant opportunity to develop microbiome-based tools for disease prevention or prediction.Plants can utilize the \u201ccry for help\u201d strategy whereby they selectively recruit beneficial microbes from the surrounding environment to assist in combating pathogen stress ,124,125.n citrus  and upons robur) , respect, and Li  reportedPoaceae Barnhart and Brassicaceae Burnett plants compared to forest plants. Endophytes secrete specialized metabolites or bioactive compounds that help keep plants away from pathogens by means of antagonism, mycoparasitism, and induction of plant defense responses. For example, endophytic bacteria produce defensive enzymes  [Endophytes that colonize within plants can confer ecological advantages to the host plants and improve plant fitness,  . Endophyoxidase) ,134 and oxidase) , and secoxidase) ,138,139 Colletotrichum tropicale induces the expression of hundreds of host defense-related genes in Theobroma cacao, leading to enhanced plant immunity [Phoma medicaginis, which causes alfalfa leaf spots, is resisted by arbuscular mycorrhizal fungus through the activation of defense activities, including JA, SA, peroxidase, and polyphenol oxidase [Endophytes may promote the induction of defense-related genes and confer pathogen resistance . For insimmunity . Moreove oxidase . Pathoge oxidase . The end oxidase ,76.Fusarium culmorum, Rhizoctonia solani, Pythium ultimum, and Gaemannomyces graminis var. tritici) as well as promoting plant growth [Diaporthe maritima, which exhibited antifungal activity against Microbotryum violaceum and B. subtilis [Pinus strobus (eastern white pine) were found to produce potently antifungal compounds, as reported by Sumarah et al. [Lophodermium nitens was accountable for suppressing the growth of the pine pathogen Cronartium ribicola [Relatively few studies have been conducted on the utilization of biocontrol endophytes for the purpose of managing forest pests and diseases. Most of the available studies have largely focused on identifying beneficial endophytes that antagonize pathogens and structurally characterizing their metabolic antimicrobial compounds ,144. Fort growth ,146. Exasubtilis . In addih et al. . Furtherribicola . Other bribicola . Thus, tPlants make good use of two types of immune receptors that are located on the cell surface and inside of cells which can recognize invasive microorganisms  and activate protective immune responses in plants. However, when pathogens infect host plants, they secrete effectors into the host cells or extracellular space to interfere with host physiological activities to facilitate their infection or colonization. Cell surface immune receptors, also known as \u201cpattern-recognition receptors (PRRs)\u201d, comprise mainly single transmembrane receptor-like kinases and receptor-like proteins that detect pathogen-associated molecular patterns (PAMPs), such as bacterial flagellins, bacterial elongation factors, fungal chitin polysaccharides, fungal xylanases, and endogenous elicitors. The immunity triggered by PRRs is known as pattern-triggered immunity (PTI). Intracellular immune receptors are mainly a class of receptor proteins containing nucleotide-binding and nucleotide-binding leucine-rich repeat receptors, which recognize cytoplasmic effector proteins to elicit effector-triggered immunity.In addition to pathogens, some plant symbiotic microbes also possess microbe-associated molecular patterns (MAMPs) that can stimulate the innate immune response , which is similar to PTI . When syCandidatus Liberibacter asiaticus, associated with HLB, drastically altered the composition of citrus microbiome communities across the disease spectrum [Increasing evidence indicates that under pathogen stress, the composition of the plant microbiome changes, leading to plants actively recruiting beneficial or protective microbes  to aid pspectrum . Moreovespectrum . The plaPantoea agglomerans, a Gram-negative bacterium, exhibits antibiosis activity that limits the growth of Erwinia amylovora, which is the causative agent of fire blight disease on apple and pear trees [Bacillus sp. strains secrete lipopeptides , polyketides, surfactants, and VOCs, among others, to directly kill or suppress pathogen growth, thereby improving the natural soil resistance against pathogens [Bacillus bacteria can also eliminate pathogens by interfering with pathogen QS signaling [Sclerotinia sclerotiorum, Fusarium oxysporum, and Rhizoctonia solani through mechanisms of parasitism [Pathogen-infected plants can recruit and enrich beneficial microbial communities to directly antagonize infecting pathogens via a variety of methods, such as the \u201ccry for help\u201d strategy. Specific mechanisms include competing with pathogens for ecological niches and nutrients, secretion of antagonistic compounds , parasitism and predation, and inhibition of pathogen signaling systems, among others . For exaar trees ,158. Bacathogens ,161,162.ignaling . Beneficrasitism ,165,166.Hyaloperonospora arabidopsidis leads to the promotion of three bacterial species  in the rhizosphere of Arabidopsis plants, conferring a soil-mediated legacy that provides enhanced resistance against this pathogen [The plant microbiome can act indirectly by priming plant immunity  to inhibit pathogen invasion and protect the under- and aboveground parts from encroachment . For exapathogen . A set opathogen ,168,169.Compared to annual crops like wheat, potatoes, or herbaceous plants, tree generations can persist for decades. Therefore, strategies to control tree diseases need to be effective over many years, not just during a specific growing season . In planIn recent years, the potential for BCAs has been realized as a crucial part of integrated pest management. The present study builds upon the advancements of omics approaches, synthetic communities, and microbial network inference to construct beneficial microbial consortiums with the potential to support broad and persistent plant protection. Such strategies are also increasingly being adopted in planted forests, despite the fact that just a few instances of success are known. Importantly, the adaptation of endophytes to plant interior tissues and their persistence within plants for long periods of time make endophytes potentially promising as biocontrol agents for chronic woody plant diseases . In factBacillus velezensis Bs006 and Trichoderma virens GI006 was found to be more efficient against infection by Fusarium wilt in cape gooseberry than individual strains [Trichoderma harzianum CBF2 and Pseudomonas aeruginosa DRB1conferred more consistent protection against Fusarium wilt in banana than individual community members [In several cases in the management of soil-borne crop diseases, various BCA consortia comprising two or more microbial strains appear to possess enhanced biocontrol activity compared to single-strain BCAs ,174,175. strains . A bacte members . The int members . ConsequHyphomicrobium spp. is capable of associating with methanotrophs, therefore establishing a microbial association in the rhizosphere. This association enables Hyphomicrobium spp. to eliminate methanol, thereby preventing methanotrophs from proliferating in the rhizosphere [A large number of microbe\u2212microbe interactions have been documented to have a positive impact on facilitating rhizosphere colonization by beneficial microorganisms through boosting biofilm formation, microbial proliferation, migration within the microbiome, and interaction with plant roots. For examples, a five-species biocontrol community was found to lead to a higher formation of biofilm compared to single strains, both in vitro and in vivo, thus stimulating host root colonization . Hyphomizosphere . The synzosphere ,62, indiMulti-strain BCAs have been found to provide enhanced suppressive efficacy against pathogen growth compared to single-strain BCAs. This can be attributed to the beneficial effects of inter- and/or intra-domain interactions within multi-strain BCAs, including the increased capability to utilize resources ,183,184 In addition to the above positive features in controlling diseases via the application of multi-strain BCAs, inducing elevated plant defense against plant pathogens through biocontrol consortia has been described in many studies. This is mainly directed by activating a number of distinctive metabolic and signaling pathways in order to combat a given disease ,187,188.\u00ae, which has been used for around 30 years to prevent elm trees from being infected by the blue stain fungus O. novo-ulmi, which is known to cause Dutch elm disease [Because of the inherent characteristics of trees  and pathogens , the implementation of biological control strategies in trees and woody plants presents difficulties, limitations, and challenges. For instance, the occurrence of a tree disease can extend over successive growing seasons, not just during a specific growing season, which can impact the effectiveness of biocontrol strategies. As a result, the implementation of BCAs for disease control in trees and woody plants has been comparatively less extensive than their use in annual crops and herbaceous species. Despite this, there are many cases where biocontrol applications have been successfully used to improve forest plantation health and have even facilitated the emergence of commercial biocontrol products. One example is Dutch Trig disease . In orde"}
+{"text": "Developing new, ecologically healthy feed has always been the focus of sustainable animal husbandry development and has been a research hotspot in academic circles. Currently, the bio-feed industry is developing rapidly and efficiently. The resources of feed raw materials are constantly being enriched and expanded, strain screening research is gradually deepening, production technologies such as enzyme preparations and bacterial preparations are continuously being optimized and upgraded, and the number of professional livestock personnel is constantly increasing. The development of bio-feed has broad application prospects. However, there are increasing problems facing biological feed. Therefore, this paper summarizes the classification, function, application, and existing issues of biological feed in livestock and poultry production to provide a reference for subsequent related research and applications.Biological feed is a feed product developed through bioengineering technologies such as fermentation engineering, enzyme engineering, protein engineering, and genetic engineering. It possesses functional characteristics of high nutritional value and good palatability that can improve feed utilization, replace antibiotics, enhance the health level of livestock and poultry, improve the quality of livestock products, and promote a better breeding environment. A comprehensive review is provided on the types of biological feed, their mechanism of action, fermenting strains, fermenting raw material resources, and their current status in animal production to facilitate in-depth research and development of applications. Developing new, ecologically healthy feed has always been the focus of sustainable animal husbandry development, and has been a research hotspot in academic circles . BiologiSaccharomyces cerevisiae boulardii (SCB) can reduce diarrhea and promote growth rates in pig and broiler production [S. cerevisiae on health and performance in young calves [Probiotics are bacteria that help maintain the natural balance of microorganisms in the gut and have beneficial health effects for humans and animals. Studies on non-ruminant animals have shown that the probiotic oduction ,4,6. Cong calves . Supplemg calves . Howeverg calves . Similarg calves . For exag calves  found thg calves ,13. SincBeef has the advantages of high protein, low fat, more phospholipids, less cholesterol, delicate and soft muscle fibers, and a unique flavor. With the improvement of people\u2019s living standards and changes in dietary habits, beef consumption has continued to rise steadily, presenting exceptional opportunities for the development of beef production. This paper provides a comprehensive review of the various types, mechanisms of action, and fermentation cultures utilized in bio-fermented feed. The utilization status of fermentation raw material resources in animal production is discussed, which offers a scientific basis for enhancing beef cattle meat quality and practical guidance for beef cattle production.The standard of \u201cBiological Feed Product Classification\u201d categorizes biological feed products into fermented feed, enzymatic hydrolysate feed, bacterial enzyme synergistic feed and biological feed additives. Based on distinct characteristics and production processes, the biological feeds are further classified into 4 main categories, 10 subcategories, 17 sub-subcategories, 50 sub-sub-subcategories, and 112 product categories [According to the characteristics of the strain, it is mainly divided into oxygen consumption fermentation, anaerobic fermentation, and facultative anaerobic fermentation. The classification is illustrated below in Enzymatic hydrolysis feed has been extensively used in livestock and poultry breeding, with the process parameters and treatment efficacy of pre-digestion of enzymatic feed having been duly validated. The levels of inorganic phosphorus, acid detergent, and reducing sugar serve as crucial indicators that reflect the pre-digestion efficacy of enzyme-based feed in vitro . OptimizIn recent years, research findings have demonstrated that the co-treatment of bacterial enzymes yields superior results compared to the individual actions of bacteria and enzymes; the classification is illustrated below in Bioengineering technology has been applied to develop a range of feed additives that can enhance feed utilization efficiency, improve animal health, and boost production performance. These additives include microbial feed additives, enzyme preparations, and oligosaccharides ,15. The Biological feed can enhance palatability, reduce anti-nutritional factors, optimize nutrient utilization, facilitate the efficient use of agricultural and agricultural by-products, minimize reliance on pharmaceutical additives such as antibiotics, and ultimately improve livestock and poultry production performance ,25,26. TIt is found that after feed fermentation, the number of beneficial microorganisms in feed can be effectively increased so that more beneficial microorganisms can enter the intestines of livestock and poultry to form a competitive advantage and quickly colonize and become dominant flora. For instance, lactic acid bacteria can effectively lower the intestinal pH by producing significant amounts of lactic acid and acetic acid. This promotes the growth of intestinal villi, expands the absorption area of the small intestine, and strengthens the intestinal barrier through competitive inhibition and production of adhesion substances. Additionally, it restricts the adhesion and proliferation of pathogenic bacteria on intestinal mucosal epithelial cells, thereby reducing harmful bacterial populations in the intestines and maintaining a balanced microbial environment, as well as decreasing the incidence of diarrhea in livestock and poultry ,28. As nAlthough the effect of probiotics on gut microbial composition has been extensively studied in swine and poultry , it is sFecalibacterium is recognized as a prominent butyrate producer, and the presence of butyrate has been shown to potentially enhance the integrity of the intestinal epithelial barrier [Fecalibacterium spp. In fecal specimens from neonatal calves was linked to increased weight gain and reduced incidence of diarrhea in preweaning dairy calves [Fecalibacterium spp. Was observed to be reduced in canines suffering from acute diarrhea [Lactobacillus has been demonstrated to reduce the incidence of diarrhea in calves [E. coli and Shiga toxin-producing E. coli [Lactobacillus and a decrease in E. coli could help ensure normal growth performance of calves even when they experience diarrhea [ barrier . A greaty calves , while tdiarrhea . On the diarrhea . Lactoban calves , while E E. coli , which cdiarrhea .After fermentation, feed can produce a variety of unsaturated fatty acids and aromatic compounds that impart unique flavors and enhance palatability. This leads to a significant increase in feed intake among livestock and poultry. Additionally, biological feed generates proteases, amylases, cellulases, phytases, water-soluble vitamins, amino acids, and various growth-promoting factors upon metabolism within the digestive system of animals. These components promote optimal growth and development in livestock and poultry ,46,47. MS. cerevisiae as a probiotic supplement in ruminant feed has been shown to enhance the growth performance and feed efficiency of fattening calves [Saccharomyces cerevisiae (SCB) on the growth performance, health status, and fecal microorganisms of Holstein calves aged 6 \u00b1 3 days. However, supplementation with yeast (10 \u00d7 109 cfu/d) did not improve the average daily gain, final weight, dry matter intake (DMI), and other performance indicators. On a positive note, it did decrease the incidence of diarrhea in calves. Lee et al. [9 cfu/d) in the diet resulted in a significant increase in DMI and water intake under thermoneutral conditions, while concurrently reducing the incidence of diarrhea. Crossland et al. [Yeast is widely distributed in nature, with a fast reproduction rate, short growth cycle, and strong metabolism. This includes tropical candida, prion-producing candida, brewer\u2019s yeast, red yeast, among others. Yeast is a rich source of B vitamins, proteins, amino acids and other nutrients that can effectively enhance the nutritional value of animal feed, improve its digestibility and utilization by livestock and poultry, boost their immune system function and suppress the growth of harmful microorganisms ,52,53. Tg calves . Villot g calves  demonstre et al.  demonstrd et al. ,58 also In the field of biological feed, the majority of previous research has primarily focused on exploring the application of diverse strains of lactic acid bacteria ,59. LactMold is a broad term encompassing filamentous fungi, and mold fermentation yields functional enzyme fungi with a wider range of enzymes than bacteria, including cellulase, protease, phytase, among others. Approximately 90% of the enzyme preparations listed in the Feed Additives Catalogue are derived from mold sources. However, mycotoxins produced by molds pose serious threats to feed quality and livestock safety; examples include zearalenone, vomitoxin, aflatoxin B1 ,61,62.Bacillus, including Bacillus cereus, Bacillus subtilis, Bacillus macrosporidus, and Bacillus licheniformis, is present in the intestines of animals. It can tolerate gastric acid and has strong resistance to feed processing engineering. Additionally, it exhibits high stability and possesses high levels of protease, amylase, and lipase activities. Furthermore, it can degrade some complex compounds found in plant feed [Bacillus strains, such as Bacillus licheniformis and Bacillus subtilis, are commonly used in the feed industry due to their ability to effectively increase soluble protein content while reducing sugar levels, amino acid concentrations, and cellulose degradation rates [ant feed ,64. Bacion rates .Bacillus species are not typically indigenous to the gastrointestinal tract. Nevertheless, it has been reported that the oral administration of adequate amounts of Bacillus subtilis can favorably modulate the microflora balance in the gastrointestinal tract and enhance animal performance [B. subtilis possesses remarkable immunostimulatory properties [Bacillus subtilis in the diet of calves resulted in increased dry matter intake, digestibility, final weight gain, and feed conversion efficiency. Additionally, there was an increase in total volatile fatty acids and ammonia nitrogen concentration within the rumen while protozoal populations were reduced. Blood levels of total protein, albumin, triglycerides, aspartate aminotransferase and glutamic-pyruvic aminotransferase were also significantly elevated along with lower levels of urea and creatinine.formance ,66. Moreoperties  and may operties ,68. Varioperties . Khaziahoperties  also ackoperties  demonstrBacillus subtilis (DSM 28343), Bampidis et al. [The enzyme preparations belong to a group of proteins possessing biocatalytic capabilities that can be derived from animals, plants, and microorganisms. They include single enzyme preparations  and complex enzyme preparations (which are mixtures of multiple single enzyme preparations) . Enzyme s et al.  concludeThe application of biological feed in ruminants primarily helps the rumen establish a dominant flora, regulates rumen function and microflora, promotes rumen metabolism, increases antioxidant capacity and immunity ,58, and Stressful environmental factors, such as warmer temperatures and high humidity, can cause heat stress in calves. Exposure to heat stress results in poor growth performance due to reduced feed intake ,78, impaOne of the most common outcomes of reduced feed intake and lowered physiological responses in calves is poor growth. Without adequate nutrition, young animals are unable to develop properly and may suffer from stunted growth or malnourishment.Another serious consequence is the outbreak of calf diarrhea. This condition can be caused by a variety of factors, including changes in diet or stress on the animal\u2019s digestive system. However, when combined with reduced feed intake and weakened immunity, it becomes much more likely to occur\u2014leading to dehydration, weight loss, and potentially fatal complications.In extreme cases where these conditions go untreated or unaddressed for too long, death may unfortunately become an outcome. It is crucial that farmers take steps to ensure their livestock receive proper nutrition and care at all times in order to prevent these negative outcomes from occurring.Saccharomyces cerevisiae CNCM I-1077 (2 \u00d7 1010 cfu/g) to grain, the intake and growth rate of immature animals can be significantly enhanced prior to weaning [Saccharomyces boulardii (SB) CNCM I-1079 (2 \u00d7 1010 cfu/g) into milk replacer fails to enhance the dry matter intake or promote growth in immature calves [E. coli O55:B5) exhibit an elevation in body temperature [By supplementing 0.5 g of a product containing  weaning . Howevere calves . Intrigue calves , withoute calves ,83,84. Cperature . Meanwhiperature  and acutperature . HoweverPrevious studies have demonstrated that the supplementation of SCB did not result in any growth or performance improvement in calves, both during the pre-weaning period  and postRoughage, though containing relatively minor nutrients other than neutral detergent fiber and being poorly palatable, is an indispensable component of ruminant feed. By means of microbial fermentation technology, the nutritional characteristics of roughage can be effectively improved , and canBiological feed has the ability to regulate the microflora of ruminant rumen, boost immunity and antioxidant capacity, optimize growth performance, and enhance meat quality.The swift advancement of biological feed holds immense significance in mitigating the dearth of feed resources. The development of biological feed enhances the nutritional value of fodder, curbs resource wastage and environmental pollution, and facilitates cost-effective breeding with high returns, thereby presenting vast prospects for growth."}
+{"text": "Bosma arhinia microphthalmia syndrome (BAMS) is a rare condition,\u00a0with about\u00a0100 cases identified worldwide. It is characterized by nasal and ophthalmic abnormalities, as well as disturbances in puberty and sexual development. The cardinal sign is arhinia, though some cases have partial aplasia of the external nose. In addition, several reports have revealed abnormal brain structure, including changes to the olfactory bulbs.\u00a0This case describes a 29-year-old female who has suffered from BAMS since birth. On presentation, she was noted to have congenital arhinia, bilateral microphthalmia, vision loss, mouth-breathing, an unclear speaking voice, a high arched or cleft palate, and a hypoplastic maxilla. Her paranasal sinuses were ossified and underdeveloped. This syndrome occurs rarely, both within Vietnam and worldwide. It is characterized by four major features: arrhinia, complete absence of the paranasal sinuses, eye defects, and absent sexual maturation. This case report describes the presentation of the disorder to improve otolaryngologists\u2019 understanding of BAMS. Criteria for diagnosis consist of arhinia, midface hypoplasia (with a hypoplastic maxilla), hypogonadotropic hypogonadism, and normal intellectual abilities. Additional important findings are microphthalmia with or without coloboma, anosmia, maxillary hypoplasia, a high-arched palate, and absence of paranasal sinuses and olfactory bulbs. Bosma arhinia microphthalmia syndrome (BAMS) was first described in 1981 . There hA 29-year-old female presented to Cho Ray Hospital,\u00a0Ho Chi Minh City, Vietnam, for arhinia, which was noted immediately at birth and remained underdeveloped. Past medical and family history were unremarkable. Examination revealed bilateral microphthalmia, 8/10 visual acuity in both eyes, and complete anosmia. Breathing was possible only through her mouth. She also had an unclear speaking voice, a short soft palate, and an undeveloped upper jaw . Subsequently, gonadotropin, which controls the production of reproductive hormones, is also affected. The decreased levels of gonadotropin may explain the hypoplasia of these patients\u2019 genital organs .It should be noted, however, that some patients with SMCHD1 mutations have presented with arrhinia, but not the other characteristics associated with BAMS, or with only mild nasal defects. Researchers, therefore, suspect that other genetic factors may play a role in producing these symptom. However, this area has not been studied in depth.ManagementBAMS may not be too difficult to diagnose because of the arhinia feature. Therefore, its early recognition and diagnosis is critical. To date, disease management remains unspecific and mainly involves full investigation of nasal, ophthalmic, ocular, cardiac, and reproductive defects, followed by appropriate surgical intervention. Particularly in female patients, genital organs should be examined and treated for any abnormality to improve reproductive capacity. Patients should also be provided with necessary vitamins to prevent osteoporosis. Careful follow-up and management of associated abnormalities is essential, depending on the severity of their presentation. Structural defects may be reconstructed using plastic surgery once patients reach adulthood .BAMS is a rare disease, with very few cases identified worldwide. It has many different types of damage to various organs. Criteria for diagnosis consists of arhinia, midface hypoplasia (with a hypoplastic maxilla), hypogonadotropic hypogonadism, and normal intellectual abilities. Additional important findings are microphthalmia with or without coloboma, anosmia, maxillary hypoplasia, a high-arched palate, and absence of paranasal sinuses and olfactory bulbs. Therefore, we introduced a typical case to enable clinicians to recognize and approach it comprehensively without being confused in diagnosis and approach of the damage to the patient."}
+{"text": "Reversible cerebral vasoconstriction syndrome (RCVS) typically manifests as a sudden, severe thunderclap headache due to narrowing of the cerebral arteries. Symptoms usually resolve within three months. An imbalance in cerebral vascular tone, an abnormal endothelial function, and a decreased autoregulation of cerebral blood flow are thought to be involved in the pathogenesis of RCVS. However, the precise origin of this condition is not yet fully understood. Symptoms of Raynaud\u2019s phenomenon (RP) include vasospasm of arterioles of the digits. The pathophysiology of RP includes interactions between the endothelium, smooth muscle, and autonomic and sensory neurons that innervate arteries to help maintain vasomotor homeostasis. RP may occur before the clinical manifestation of a rheumatic condition. RCVS is rare in patients with autoimmune rheumatic disease. We describe a 54-year-old female who had a history of Raynaud\u2019s phenomenon affecting her fingers and toes since the age of 12 years. The patient was diagnosed with RCVS in 2012. She described RCVS precipitants, including the regular use of cannabis, cocaine, and amphetamine and tobacco smoking. In 2021, she presented with oral ulcers, intermittent swallowing difficulties, and Raynaud\u2019s phenomenon. Clinical examination revealed early sclerodactyly, and abnormal nail-fold capillaroscopy showed multiple giant capillaries, dilated capillary loops, and areas of capillary hemorrhage with capillary drop-out. The investigation revealed positive ANA, strongly positive SRP antibodies, and Ro60 antibodies. Our case report indicates that there may be a correlation between RCVS and Raynaud\u2019s phenomenon, and a potential connection between RCVS and autoimmune rheumatic diseases. Hence, physicians must be aware of the red flags and subtle differences in neurological abnormalities, such as headaches, in patients with autoimmune rheumatic diseases who have an inactive clinical status to improve patient care and outcomes. Reversible cerebral vasoconstriction syndrome (RCVS) is a rare disease characterized by severe acute thunderclap headaches associated with cerebral artery constriction  that spontaneously reverses in 12 weeks and can occur at any age. RCVS may occur spontaneously; however, in many cases, a secondary factor can contribute, such as vasoactive medications or postpartum status ,4,5. MauA 54-year-old female patient presented with a history of autism, Asperger\u2019s syndrome, attention deficit hyperactivity disorder, complex post-traumatic stress disorder, and Raynaud\u2019s phenomenon affecting her fingers and toes since she was 12 years old. She developed psoriasis at 10 years of age. She had undergone silicone breast implants 20 years ago. In 2012, she presented with severe thunderclap headaches and was diagnosed by neurologists with reversible cerebral vasoconstriction syndrome.In 2021, she developed fatigue, oral ulcers, Raynaud\u2019s phenomenon, difficulty swallowing, intermittent blurred vision, poor handwriting, nausea, difficulty walking, and depression. There was no history of digital, oral, or genital ulcers, miscarriages, or thrombosis. She reported regular cannabis and tobacco use and alcohol consumption. She had been a cocaine and amphetamine user in the past. She had a family history of Raynaud\u2019s phenomenon. On examination, she had normal blood pressure, early sclerodactyly, faint livedo reticularis on her lower limbs, minor lymphadenopathy in the neck and axillae, an ejection systolic murmur, and an early diastolic murmur in accordance with the aortic valve lesion on the echocardiogram. Chest, abdomen, neurology, and musculoskeletal examinations were normal. The investigation showed positive antinuclear antibody (ANA) of 1:80, positive anti-signal recognition particle (SRP) antibodies, positive Ro/SS-A (Ro60) antibodies, negative anti-double stranded DNA (anti-dsDNA), antineutrophil cytoplasmic antibodies (ANCA), rheumatoid factor, and antiphospholipid antibodies, normal complement, normal CK level, troponin, brain natriuretic peptide (BNP), and inflammatory markers, and negative urinalysis. The urine screening was positive for cannabis and negative for cocaine.Nail-fold capillaroscopy was abnormal with multiple giant capillaries and dilated capillary loops, and many areas of capillary hemorrhage with some capillary drop-out were evident .There may be an association between RCVS and Raynaud\u2019s phenomenon in patients with systemic autoimmune disorders . SecondaWe report a patient who was initially diagnosed with reversible cerebral vasoconstriction syndrome but ultimately exhibited clinical, serological, and capillaroscopic evidence for an underlying autoimmune rheumatic disorder. Our case report suggests that there may be an association between RCVS and Raynaud\u2019s phenomenon, and a possible link between RCVS and autoimmune rheumatic diseases. The use of nail-fold capillaroscopy is crucial for prognostication and for avoiding serious consequences. RCVS diagnosis in patients with autoimmune rheumatic disease is a key point that prompts rapid treatment and prognosis. Hence, physicians must be aware of the red flags and subtle differences in neurological abnormalities, such as headaches, in patients with autoimmune rheumatic diseases who have an inactive clinical status to improve patient care and outcomes."}
+{"text": "Older adults with schizophrenia often have multiple chronic conditions, or multimorbidity, yet most prior research has focused on single medical conditions.To characterize multimorbidity patterns and utilization among older adults with schizophrenia to understand how multimorbidity affects this population and their clinical service needs.This retrospective cohort study included veterans aged 50 years and older with schizophrenia and followed their comorbid diagnoses and utilization  from 2012 to 2019. Comorbid diagnoses included myocardial infarction, congestive heart failure, stroke, chronic obstructive pulmonary disease (COPD), cancer, dementia, traumatic brain injury, hepatitis C, osteoarthritis, renal disease, chronic pain, sleep disorder, depression, dysthymia, posttraumatic stress disorder (PTSD), general anxiety disorder, alcohol use disorder, other substance use disorder, and tobacco use disorder. Latent class analysis was used to identify latent profiles of psychiatric and medical comorbidity. Chi-square and F-tests were used to assess differences in demographics, comorbidities, and utilization across the latent classes.The cohort included 82,495 adults with schizophrenia. Three distinct multimorbidity classes were identified: Minimal Comorbidity (67.0% of the cohort), High Comorbidity (17.6%) and Substance Use Disorders and Related Conditions (SUDRC) (15.4%). The Minimal Comorbidity class had <10% prevalence of all comorbid diagnoses. The High Comorbidity class had >20% prevalence of congestive heart failure, COPD, dementia, renal disease, sleep disorder, and depression. The SUDRC class had >70% prevalence of alcohol and drug use disorders and >20% prevalence of COPD, hepatitis C, depression, and PTSD. Although the High Comorbidity class had the highest rates of chronic medical conditions, the SUDRC class had the highest rates of emergency and inpatient medical care and emergency, inpatient, and outpatient mental health care utilization. Comparing across classes, all p-values were <.001 for utilization.Older adults with schizophrenia are a heterogeneous group with distinct multimorbidity classes and different patterns of utilization. Those with high prevalence of substance use disorders had the highest rates of emergency and inpatient medical and overall mental health care utilization. Tailoring integrated care services to target specific clinical needs could improve outcomes for this population.None Declared"}
+{"text": "Molecular probes, specialized tools or substances meticulously designed to bind to specific molecules or biomarkers within cells, tissues, or biological samples, play a pivotal role in various domains such as biomedical research, diagnostics, and medical treatments . They arThis editorial features a study by Zheng et al., highlighting the potential of molecular subtyping in guiding diagnosis and personalized treatment decisions for esophageal squamous cell carcinoma (ESCC). This study identified two distinct molecular subtypes of ESCC, S1 and S2, and linked them to the tumor microenvironment, distinct immune pathways, and clinical outcomes . Ye et aIn this Special Issue, we have explored the evolving role of advanced molecular probes. These specialized tools have become increasingly precise and sensitive, aiding in the detection and manipulation of specific molecules within cells and tissues. The articles cover various diseases, highlighting how molecular probes are reshaping diagnosis, treatment, and therapeutic possibilities. Collaborations between scientists, healthcare experts, and technologists promise to drive continued progress in this field, offering new avenues for disease management and improved patient outcomes."}
+{"text": "Acute and transitory psychotic disorders comprise a polymorphous picture such as Leonhard\u2019s cycloid psychoses, which alternate episodes of affective symptoms such as psychosis between two poles .To describe a case report of a 20-year-old man, in outpatient psychiatric follow-up, after debuting at age 18 with a severe depressive episode of endogenomorphic characteristics without psychotic symptoms, with subsequent complete remission. Two years after clinical stability, he required prolonged hospitalization due to polymorphous psychotic syndrome of abrupt onset in a context of previous continuous use of cannabis and cocaine. Suspicion towards parents, bizarre behaviors, rushing desires, unmotivated laughter, fixed gaze, bewilderment, anguish with a feeling of imminent death, alternates with euphoria and senseless purchases.We present the case report of this patient with a mental examination of conscious, scattered attention with marked distractibility, confusion and experiences of strangeness, memory gaps, subjective sensation of well-being with tachypsychia, which fluctuates with thymic oscillations and alternates with episodes of marked indefinite anguish, intense anxiety with delusional fear of the death of him or his family. Little systematized ideas of reference and prejudice based on intuitions or delusional occurrences in their environment. Megalomaniac and religious-messianic ideation. No sensory perception disturbances. Disintegrated course of thought, with frequent illogical associations, ambivalence of thought, affectivity and psychomotricity. Motor restlessness and behavioral disorganization. Global insomnia. Judgment of reality and superior functions diminished. No auto/heteroaggressiveness.Various psychoactive drugs were tested for two months, obtaining a response only with valproic acid 1500mg, pregabalin 450mg and olanzapine 15mg, presenting slow improvement in a situation of absence of consumption, with a predominance of symptomatic polymorphism, decreasing fluctuation between episodes of expansiveness and psychotic anguish, remitting disorganization and motility alterations, persisting poor awareness of the disease and cognitive complaints. He was referred for follow-up at the mental health center where his gradual recovery continued.A differential diagnosis of polymorphous psychosis is proposed, compatible with a cycloid psychosis of the anxiety-happiness type with marked affective symptoms, precipitated by substance use.Cycloid anxiety-happiness psychosis stands out for intense and fluctuating anxiety, oscillating with feelings of happiness, ecstasy, and placidity, mystical-religious delusions, and preoccupation with death, which may comprise a different psychotic debut.None Declared"}
+{"text": "Insects are a significant source of food for millions of people worldwide. Since ancient times, insects in medicine have been contributing to the treatment of diseases in humans and animals. Compared to conventional animal farming, the production of insects for food and feed generates significantly less greenhouse gas emissions and uses considerably less land. Edible insects provide many ecosystem services, including pollination, environmental health monitoring, and the decomposition of organic waste materials. Some wild edible insects are pests of cash crops. Thus, harvesting and consuming edible insect pests as food and utilizing them for therapeutic purposes could be a significant progress in the biological control of insect pests. Our review discusses the contribution of edible insects to food and nutritional security. It highlights therapeutic uses of insects and recommends ways to ensure a sustainable insect diet. We stress that the design and implementation of guidelines for producing, harvesting, processing, and consuming edible insects must be prioritized to ensure safe and sustainable use. The global population is rising exponentially, and so is the societal difficulty of meeting nutritional needs, which drives up the worldwide demand for meat . As a reEdible insects can solve many environmental and health issues, including climate change, hunger, and environmental degradation caused by agro-industrial production . The groOryctes monoceros (Olivier), Asiatic rhinoceros beetles Oryctes rhinoceros (Linnaeus), and African palm weevil Rhychophorus phoenicis (L.) attack and kill economically important crops, such as palms, banana, and pineapple  affected the growth of Lactobacillus and Bifidobacterium by improving short-chain fatty acid production and viability in nutritive stress conditions  exhibited lower levels of thrombin, plasminogen activator inhibitor, and factor Xa after exposure to indole alkaloids derived from Protaetia brevitaris seulensis (Kolbe) (Gryllus bimaculatus (De Geer), Oxya chinensis sinuosa (Mishchenko), and Protaetia brevitaris seulensis reduced intracellular lipid accumulation and triacylglycerol in liver hepatocellular carcinoma (HepG2) (Bombyx mori (L.)  . The eth (HepG2) . Lipid aori (L.) . Again, trophils .Danio rerio (F. Hamilton) fed with Hermetia illucens (L.) showed a significant increase in growth rate (Allomyrina dichotoma (L.) administered to septic C57BL/6 mice increased their survival rate , 64% of the world\u2019s NH4 emissions, water pollution, and biodiversity loss  were lower than pigs and far lower than cattle (Protaetia brevitarsis seulensis production (15.93 kgCO2eq) was lower than the conventional meat sources, such as chicken (18\u201336 kgCO2eq), pork (21\u201353 kgCO2eq), and beef (75\u2013170 kgCO2eq)  . FurtherkgCO2eq) . Using tkgCO2eq) . Also, tEdible insects provide direct and indirect ecosystem services like cultural, provision, maintenance, and regulation as per the definition by the Millennium Ecosystem Services . One of Agrius convolvuli (L.), a Hawk moth, is a critical papaya pollinator in Kenya and Southeast Asia , Alphitobius diaperinus (Panzer), H. illucens, Gryllodes sigillatus , Gryllus assimilisit (Fabr.), T. molitor (L.), A. domesticus (L.)  . Due to cus (L.) . If otheA recent study showed how insects create socioeconomic changes, mitigate societal challenges, create healthier food, and reduce animal waste production and consumption . In ThaiSchistocerca gregaria (Forssk\u00e5l), L. migratoria, Locusta napardalina , Zonocerus variegatus (L.) and Nomadacris septemfasciata (Audinet-Serville)  and S. exempta can destroy entire crops by feeding on the early stages of the maize plant. The larvae of the pest are consumed in Zambia  . Oryctess to die . The lars to die . The falInsects as food and feed have recently attracted tremendous attention due to their high-quality nutrient contents, ability to upcycle low-grade organic substrates into high-quality insect biomass, and reduction in environmental footprint . DespiteA. domesticus and G. assimilis and compared populations associated with the surface and whole body of crickets to uncover potentially beneficial and pathogenic microorganisms. Findings from the study support the use of probiotics composed of microorganisms already present in the human digestive system  larvae which are a potential source of food-safety-related microbes , 116. Inop yield . Thus, p species , 118. KuEcthyma contagiosum (Poxviridae), which causes ecthyma in sheep and goats and humans exposed to disease-infected animals , especially SDGs 6, 12\u201315 . ProvidiFarming insects for food and feed has recently received considerable attention as a sustainable alternative to conventional food production models, providing food for humans and animals with minimal environmental footprint  97). To. To97). Among several factors considered in assessing environmental impact is methane release, which results from the fermentation of Methano-bacteriaceae in the gut, food conversion, and reproduction rate, all typical in beef cattle, poultry, and pigs. This far, cockroaches, termites, and beetles are known to release methane, and less so for other edible insects. For instance, the yellow mealworm is not known to produce methane and thus retains a low global warming potential relative to other livestock products . GreenhoZ. variegatus) as an aquafeed. In their analysis, Quang Tran et al.  keeps declining in South Africa and Zimbabwe due to increased commercialization and overexploitation (Over-exploitation of insects significantly contributes to the decline of many edible insect species, threatening wild insects . Usuallyoitation . The glooitation . During oitation . A declioitation .Nosema spp. and Gregarine spp., which cause severe losses to bee colonies worldwide, are the common parasites of Locusts. Acheta domesticus harbors Nosema spp., Gregarine spp., and Steinernema spp. (A. domesticus are often consumed in powdery form or protein extracts, the insect can also be consumed directly (Using insects as food and feed has a long history since ancient times and continues to provide food for millions of people worldwide. Edible insects contain essential nutrients, such as carbohydrates, proteins, vitamins, and minerals, which have antimicrobial properties. Apart from these benefits, edible insects require a smaller space for production than livestock, which need more extensive land to produce the same amount of energy. Edible insects provide many ecosystem services, such as decomposition, pollination, reduction of food waste and support of food chain or web, and monitoring of environmental health. Utilizing insects as food and feed, we can alter beef, fish, and poultry consumption and the life cycle assessment, thereby reducing greenhouse gas emissions, ammonia emissions, and carbon footprints. Several activities associated with edible insect production and marking generate jobs, and income, thereby ensuring poverty reduction and zero hunger, especially in developing countries. Edible insects can potentially improve our global food security significantly, but they also have several challenges that need addressing. Some wild edible insects harbour pathogens of plants, animals, and humans. For instance, migratory locusts are consumed by amphibians, reptiles, and humans, mainly in parts of Africa and Asia. ema spp. . Though directly , 137. Redirectly . SpecifiOFA: Study \u2013 conceived and designed, writing \u2013 original draft, and review and editing. JO-O, KA, AKD, BOB, SKD, KDN, and SYC: writing \u2013 original draft, review and editing. SAS: review and editing. All authors contributed to proofreading of the final version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Haliangium, Acidicaldus, Reyranella, Acidobacterium, Aquicella, and Granulicella, and the key changed characteristic microbial metabolic pathways were ko00072, ko00473, ko00750, ko01055, ko00521, and ko02040. Furthermore, the results found that pruning promoted Haliangium, Acidicaldus, and Reyranella abundances, ko00072, ko00473, and ko00750, respectively, microbial metabolic pathways in tea trees rhizosphere soil, and reduced Acidobacterium, Granulicella, and Aquicella abundance, ko01055, ko00521, and ko02040, respectively, microbial metabolic pathways, thereby increasing the activities of soil catalase, acid phosphatase, and sucrase, improving soil organic matter decomposition efficiency and available phosphorus content, and promoting tea yield, but not synthesis and accumulation of quality-related compounds in tea leaves. This study provides an important theoretical reference for the management of agronomic measures in tea plantations.Pruning is an important agronomic measure in tea plantation management. This study analyzed the effects of pruning on tea tree growth, tea quality, rhizosphere soil physicochemical indexes, microbial communities, and metabolic pathways. The results showed that pruning was beneficial for promoting tea tree growth and increasing tea yield, but not for the synthesis and accumulation of quality-related compounds in tea leaves. After pruning, organic matter, available phosphorus content and catalase, acid phosphatase, and sucrase activities in rhizosphere soil were significantly higher than those in unpruned tea trees, while total phosphorus, total potassium, and available nitrogen content were significantly lower than those in unpruned tea trees. The results of microbial community analysis of tea rhizosphere soil showed that the key changed characteristic microorganisms after pruning were Pruning is an important agronomic measure in tea cultivation and management. We found that pruning was beneficial to increase tea yield, but it would reduce tea quality, especially the content of polyphenols, theanine, flavonoids, and free amino acids in tea leaves was reduced. The reason for this phenomenon was that pruning promotes the enrichment of special functional microorganisms and the enhancement of special metabolic pathways in the soil, leading to changes in the nutrient cycle in the soil. Soil microorganisms, especially bacteria, are important contributors to the biogeochemical nutrient  cycle , 2. CompIn China, tea trees are a very important cash crop and require a lot of manual management intervention during cultivation to improve the yield and quality of tea leaves, such as fertilization, weeding, pest control, pruning, etc. \u201310. WhAccordingly, this study was conducted to analyze the effects of pruning on tea tree growth, tea quality, rhizosphere soil physicochemical indexes, microbial communities, and metabolic pathways, using Shuixian, a major tea tree cultivar cultivated in Wuyi Mountain, as the research object; at the same time, key microorganisms and microbial metabolic pathways in rhizosphere soil were screened for major changes after tea tree pruning and further analyzed about tea tree growth and tea quality. This study provides an important theoretical basis for the management of agronomic measures in tea plantations.Pruning is an important agronomic measure in the cultivation and management of tea trees, which helps tea trees grow more lateral branches and thus increase tea yield . In thisPruning is an abiotic stress for tea trees themselves, and in order to adapt to environmental changes, tea trees can modify the rhizosphere microecological environment by regulating the type or amount of root secretions, thus safeguarding their growth , 19. In R2Y value of the fit goodness and Q2 value for predictability of the OPLS-DA model reached a significant level (P < 0.005), and the model had a good fit degree and high reliability. Secondly, the OPLS-DA scoring chart showed that SP and SC were clearly differentiated in different areas  involving 211 genera of microorganisms were detected in the rhizosphere soil of tea trees. Secondly, the overall abundance of microorganisms in rhizosphere soil did not change significantly after pruning tea trees (SP) compared to unpruned tea trees (SC) . The resnt areas . The S-pnt areas  that a tthan 73% .R2Y value for goodness of fit and Q2 value for predictability of the OPLS-DA model reached a significant level (P < 0.005), indicating a good fit degree and high reliability of the model. Secondly, the OPLS-DA scoring chart showed that SP and SC were clearly distinguished in different areas  metabolic pathways in tea rhizosphere soil, and the results showed that soil microorganisms were involved in 163 metabolic pathways, among which the overall abundance of microorganisms in 163 metabolic pathways in tea rhizosphere soil did not change significantly after pruning (SP) compared to unpruned tea tree (SC) . The resnt areas . The S-pnt areas  that a tnt areas .Based on the above analysis, this study further selected growth indexes, quality indexes, soil physicochemical indexes, soil enzymes, characteristic microorganisms, and metabolic pathways that changed significantly after pruning for correlation matrix analysis. The results showed  that groHaliangium, Acidicaldus, Reyranella, Nitrospira, Sphingomonas, Gaiella, Blastochloris, Rhodoplanes, Sphingopyxis, Frankia, Phaselicystis, Pedomicrobium, and Flavitalea, of which the top three microbial populations were Haliangium, Acidicaldus, and Reyranella. Secondly, there were eight genera of characteristic microorganisms that affected tea quality indexes , soil total phosphorus, total potassium, and available nitrogen, such as Acidobacterium, Granulicella, Aquicella, Pedosphaera, Inquilinus, Coxiella, Bacillus, and Sporosarcina, of which the top three microbial populations were Acidobacterium, Granulicella, and Aquicella. Phosphorus has been reported to be beneficial in promoting the growth of plant lateral branches, improving plant photosynthesis and plant yield, but not in plant phenols and flavonoids synthesis , ko00473 , ko00750 (vitamin B6 metabolism), ko01055 (biosynthesis of vancomycin group antibiotics), ko00521 (streptomycin biosynthesis), and ko02040 (flagellar assembly). The results of microbial function and interaction showed that pruning was beneficial to increase the richness of specific microorganisms in rhizosphere soil, to enhance the nutrient absorption capacity of tea trees, and to promote their growth. Secondly, pruning was conducive to increasing the abundance of Haliangium, Acidicaldus, and Reyranella in tea rhizosphere soil, decreasing the abundance of Acidobacterium, Granulicella, and Aquicella, thus increasing the abundance of microbial metabolic pathways of ko00072, ko00473, and ko00750, and decreasing that of ko01055, ko00521, and ko02040, improving catalase, acid phosphatase, and sucrase activities, and the decomposition efficiency of organic matter and available phosphorus in the soil, promoting tea yield, but not the synthesis and accumulation of quality-related compounds in tea leaves, especially tea polyphenols, theanine, flavonoids, and free amino acids. This study provides an important reference for the management of agronomic measures in tea plantations.Pruning is an important agronomic measure in tea cultivation and management. In this study, the effects of pruning on tea tree growth, tea quality, rhizosphere soil physicochemical index, and microbial community were analyzed. The results showed that pruning was beneficial to promoting tea tree growth and increasing tea yield, but not to the synthesis and accumulation of tea polyphenols, theanine, flavonoids, and free amino acids in tea leaves. Secondly, pruning increased the content of organic matter and available phosphorus, and enhanced catalase, acid phosphatase, and sucrase activities in rhizosphere soil, but reduced the content of total phosphorus, total potassium, and available nitrogen. This indicated that the application of nitrogen fertilizer and potash fertilizer should be increased after pruning, and the application of P should be reasonably controlled. The results of microbial community analysis of tea rhizosphere soil showed that the key changed characteristic microorganisms after pruning were The experimental site was located at Foguoyan  in Wuyi Mountain Scenic Spot, Fujian Province, China, with an altitude of 280 m, annual rainfall of 160.5 mm, and annual mean temperature of 25\u00b0C. The total area of the experimental tea plantation was 0.9 ha, and the tea plantation was planted with \u201cShuixian,\u201d which was 20 years old. During the experiment, the tea plantation was divided into six areas, each area being about 0.15 ha, and the tea trees in three areas were pruned in August 2021 (SP), while the tea trees in the other three areas were left unpruned as controls (SC), that is, three replicates per treatment. The specific pruning method was to cut off 3\u20135 cm of the green leaf layer of the tea tree canopy , and theIn October 2021, the tea plantation was fertilized with 500 kg/ha of compound fertilizer (N:P:K = 21:8:16), and other management measures of tea plantations were the same except for pruning. In May 2022, tea tree growth indexes were determined, while tea tree leaves were collected for quality indexes\u2019 determination. The basic conditions of the tea plantation during the experiment were shown in Table S3. Tea leaves were sampled by randomly selecting 10 tea plants treated with SP or SC, respectively, and collecting the inverted second leaves (first mature leaves) of tea plants uniformly and mixing them for a replication sample. The tea leaves collected were immediately stored in liquid nitrogen for transcriptome analysis and quality indicator determination. The rhizosphere soil of tea trees was collected to determine soil physicochemical index, soil enzyme activity, and soil microbial community diversity with three replicates per sample. The rhizosphere soil of tea trees was sampled by removing fallen leaves from the surface, gently digging out the tea tree, removing the root system, and shaking off the soil attached to the root surface. Each soil was then divided into two parts. One part of the soil samples was stored at \u221280\u00b0C for the analysis of soil microbes and soil enzymes, and the other part was air-dried for physicochemical properties\u2019 analysis.2 of tea plantations in each region, picking them according to traditional tea picking standards, and then converting them into tea yield per hectare.In May 2022, tea tree growth indexes mainly determined the leaf area, hundred bud weight, chlorophyll content, and yield of tea trees after pruning and unpruned treatment . Leaf arThe quality indexes of tea leaves were mainly determined by water extract, tea polyphenols, theanine, caffeine, free amino acids, soluble sugars, and flavonoids, with three replicates per sample. Among them, the determination method of tea water extract refers to the national standard of the People\u2019s Republic of China GB/T 8305-2013 , the detThe rhizosphere soil of the tea tree was dried naturally, crushed, sieved through a 2-mm mesh sieve, and sampled according to the four-part method. The pH value, total nitrogen, total phosphorus, total potassium, available nitrogen, available phosphorus, available potassium, and organic matter content of the soil were determined according to the method of experimental manual of \u201cMethods of soil agricultural chemical analysis\u201d . Each saThe soil enzymes measured in this study mainly include urease, sucrase, polyphenol oxidase, catalase, and acid phosphatase. The determination methods all refer to the experimental manual of \u201cSoil and environmental microbiology research method . A briefACTCCTACGGGAGGCAGCAG) and 806R (GGACTACHVGGGTWTCTAAT). The PCR products of each sample were subjected to deep sequencing using the Miseq platform at Allwegene Biotechnology Co., Ltd. .The soil DNA extraction method and 16S rDNA amplification were performed as previously described . The hypPurified amplicons representing bacterial 16S rDNA gene sequence reads were performed using Illumina Analysis Pipeline Version 2.6. To minimize the impact of random sequencing errors, we screened and removed raw data for low-quality scores (\u226420), sequences shorter than 200 bp, and sequences that did not exactly match primers and barcode tags. The purified sequences were clustered into OTUs with 97% similarity to SILVA v128 reference set at a minimum support threshold of 70%. The Ribosomal Database Project classifier tool was used to classify all sequences into different taxonomic groups.Excel 2017 software was used to calculate the mean value and variance of the data. Rstudio 3.3 software was used to make cloud and rain maps, principal component maps, bubble maps, volcanic maps, OPLS-DA simulation, correlation matrix, and redundancy analysis."}
+{"text": "Environmental vinyl chloride (VC) exposure may result in serious acute and chronic dermatological conditions. Because existing literature largely focuses on exposures in occupational settings, a gap persists in our understanding of the medical consequences of large-scale chemical spills.This study aims to examine the potential dermatological manifestations of VC exposure in the context of industrial spills and other environmental disasters and to highlight the public health and justice implications of such releases.In this narrative review, relevant evidence-based, peer-reviewed scientific sources, gray literature, and media reports were identified via searches of search PubMed and Google using predetermined keyword search terms related to VC, VC spills and releases, train derailment, cutaneous disease, public health, and vulnerable and marginalized populations.Contact dermatitis and frostbite may arise acutely, highlighting the importance of swift decontamination. Long-term manifestations from chronic VC exposure due to persistence in environmental reservoirs include Raynaud disease, sclerodermatous skin changes, acro-osteolysis, and cutaneous malignancies. The clinical severity of cutaneous manifestations is influenced by individual susceptibility as well as duration, intensity, and route of exposure. Additionally, chemical releases of VC more frequently impact Communities of Color and those of lower socioeconomic status, resulting in greater rates of exposure-related disease.With environmental release events of hazardous chemicals becoming increasingly common and because the skin has increased contact with environmental toxins relative to other organs, an urgent need exists for a greater understanding of the overall short- and long-term health impacts of large-scale, toxic exposures, underscoring the need for ongoing clinical vigilance. Dermatologists and public health officials should also aim to better understand the ways in which the disproportionate impacts of hazardous chemical exposures on lower-income and minority populations may exacerbate existing health disparities. Herein, we describe the health implications of toxic releases with particular consideration paid to marginalized and vulnerable populations. In addition to legal and regulatory frameworks, we advocate for improved public health measures, to not only mitigate the risk of environmental catastrophes in the future, but also ensure timely and effective responses to them. In a now well-publicized event, a Norfolk Southern Railway train hauling 149 cars, 20 of which were tanker cars containing hazardous industrial chemicals, derailed in East Palestine, Ohio, in the evening hours of February 3, 2023 [VC is a manmade organochloride used in the production of plastics composed of polyvinyl chloride (PVC). Occupational, environmental, and accidental exposure to VC is associated with a range of health effects spanning multiple organ systems . AlthougVC is transported as a liquefied gas under vapor pressure. Given its flammability, exposure to intense heat may result in container explosion, greatly magnifying dispersal during transportation and industrial accidents. Historically, VC exposure occurred among factory workers in direct contact with the chemical during PVC manufacturing. However, community exposures secondary to intentional industrial releases and accidental spills have occurred for decades and are well-reported  Table 1Table 1. To characterize the cutaneous effects associated with VC exposure, especially those resulting from industrial releases and accidental spills, a narrative review was conducted using a comprehensive approach to identify relevant evidence-based, peer-reviewed scientific sources, gray literature, and media reports. Searches were performed in reputable databases such as PubMed and Google, using predetermined keyword search terms related to VC, spills and releases, train derailment, cutaneous disease, public health, and vulnerable and marginalized populations. We recognize this nonsystematic approach has inherent limitations of content selection, such as the potential for subjectivity and bias , but givProduction of VC began in the 1930s. Currently, 99% of VC is used to manufacture PVC, of which 7.2 million metric tons were produced in 2019 in the United States . The larUnder the Toxics Release Inventory (TRI) Program, the Environmental Protection Agency (EPA) tracks toxic chemicals that pose a threat to human health and the environment, including VC ,19. ManuWhile VC should volatilize to the atmosphere, its water solubility may allow leaching through soil and into groundwater prior to evaporation . As a reA particularly noteworthy example is the Axiall Chemical Plant in Westlake, Louisiana, which reportedly stores 100 million pounds of VC and has a long history of industrial accidents, fires, and major environmental violations . EPA surBeyond EPA-tracked and regulated toxic releases, uncontrolled or illegally released hazardous substances as a result of acute chemical incidents also pose a significant public health threat. According to the last report by the National Toxic Substance Incidents Program, 14,175 acute chemical incidents, including VC releases, were documented in the United States in 2013 with 64% associated with fixed facility releases and 36% attributed to transportation-related releases . VolatilThe full magnitude of health impacts resulting from the recent VC spill in Ohio may not be realized for years to come. However, acute health concerns have already emerged. For example, many residents have anecdotally noted skin \u201crashes\u201d in the aftermath of the spill . Acute dMost existing reports focus on chronic occupational exposure and predate 1995. Accordingly, the medical literature appears to have an incomplete understanding of the impacts of acute and persistent environmental VC exposure following toxic environmental release events. As such, health care providers may struggle to identify and treat the immediate and long-term effects of VC exposures, suggesting that further studies are needed to fully elucidate the health risks posed by VC in these situations. Despite existing limitations, evidence suggests that VC exposure causes short- and long-term skin-related manifestations, which we describe in detail herein ,28.Cutaneous exposure to VC may cause contact dermatitis, while rapid evaporative cooling of liquid VC on the skin may result in frostbite with erythema, blistering, and desquamation . IndividVC exposure may lead to the development of vinyl chloride disease, which is characterized by the triad of Raynaud symptoms, sclerodermatous skin changes, and lytic bone lesions known as AOL . VariablThe scleroderma-like changes observed in VC exposure are characterized by unique clinical features that help in distinguishing this entity from primary systemic sclerosis (SS). Namely, the cutaneous lesions in VC-associated disease primarily affect the dorsal hands and forearms and present as papules, nodules, and plaques with associated pruritus and hyperhidrosis. Additionally, coarsening of the skin on the forehead and cheeks may occur, whereas microstomia, matted telangiectasias, and calcinosis\u2014classic features of limited cutaneous SS\u2014are generally absent. Clubbing and fingertip shortening accompanied by lytic lesions in the distal phalanges, the key features of AOL, typify VC-associated scleroderma rather than the more common distal tufting observed in SS ,30. VC-iRaynaud syndrome, a dominant sign resulting from VC exposure, may be severe and accompanied by trophic changes and digital ulceration. Progressive bone resorption and deformity of the distal phalanges in AOL may damage underlying vasculature, causing secondary skin and nail changes, including clubbing and nail dystrophy . In one Additionally, evidence suggests that VC exposures alter immunologic function and may lead to the observed autoimmune presentations observed clinically. Prior studies in VC-exposed workers and animal models dating back decades demonstrate a range of responses, including B-cell proliferation, hypergammaglobulinemia, oxidative stress, elevated complement levels, and production of proinflammatory cytokines  . InteresHowever, studies suggest that VC-induced Raynaud disease may, in part, be triggered by immune complex deposition. A study examining 22 patients with a history of VC exposure, who subsequently developed Raynaud disease, detected cryoglobulins in 81% of sera samples with cryoglobulinemia occurring, in part, due to hyperactivation of humoral responses following the exposure . DisturbTissue fibrosis within the liver, skin, lungs, and kidneys is a well-reported consequence of VC toxicity, but the pathomechanisms responsible for inducing cutaneous fibrosis remain poorly understood. Studies of VC-associated hepatic, renal, and pulmonary fibrosis demonstrate upregulation of plasminogen activator inhibitor-1, transforming growth factor-\u03b2, platelet-derived growth factor, vascular endothelial growth factor, and connective tissue growth factor -37. Sincras and p53, which are implicated in cutaneous carcinogenesis [The carcinogenicity of VC was established in the 1960s . Evidencogenesis -42. Geneogenesis .Additionally, cutaneous stigmata of chronic hepatic injury, including spider angiomas, palmar erythema, xanthelasma, jaundice, and pigmentary changes may occur, as well as thrombocytopenic purpura as a consequence of portal hypertension-induced splenomegaly and platelet sequestration . One repWhen assessing dermatological effects, the volume of VC released into the environment along with the duration, intensity, and route of exposure  must be considered. Variability in individual susceptibility to VC toxicity based on overall medical status and underlying genetic predisposition should dually be considered. For example, those with preexisting atopy, autoimmunity, vascular injury, or polymorphisms that increase VC-induced carcinogenic mutations may be at increased risk of cutaneous disease . FinallyTo minimize the risk of long-term health issues, prompt medical evaluation is crucial in cases of VC exposure. Dermatologists, public health experts, and frontline health workers play a critical role in identifying and treating exposure-related skin conditions as well as detecting individuals at risk of internal sequelae. Following acute exposure, the priority is decontamination by removing saturated clothing and cleansing exposed skin and hair with soap and water to halt further exposure. Notably, children are more susceptible to skin absorption than adults due to a higher surface area to body weight ratio . FrostbiBecause VC persists in environmental reservoirs for years, clinicians should remain alert to long-term manifestations arising from chronic exposure. The Occupational Health and Safety Administration  recommenWith limited treatment options for VC-related exposure, prevention is paramount. Public health officials play an integral role in preventing and mitigating chemical exposure\u2013related health conditions through regulatory oversight and health policy implementation. While the precise cause of the Ohio derailment remains under investigation, decades of divestment in government spending for maintenance of infrastructure, including transportation networks, coupled with industry participation in the EPA\u2019s peer review process for scientific assessments in which disease thresholds and exposure limits to toxic substances are established, widespread environmental deregulation, and successful lobbying against broad definitions for high-hazard flammable trains and implementation of electronically controlled pneumatic brakes on trains transporting hazardous materials contribute collectively to the likelihood of future disasters ,47,48. MWith respect to health equity, dermatologists, public health professionals, and primary care providers should recognize that hazardous chemical exposures exacerbate existing health disparities among marginalized populations. In the United States, most railroads traverse neighborhoods of lower socioeconomic status and racially divide cities, while fenceline communities in industrial zones are predominantly Black ,51. In EThe 2023 Ohio train derailment has renewed the spotlight on the health consequences arising from chemical exposures following environmental releases. Because most existing literature on VC is decades old and focuses primarily on occupational exposure, accurately assessing potential risks to public health associated with chemical spills, including identification and treatment of exposure-related dermatological conditions, is challenging for health professionals. Despite these limitations, evidence suggests acute dermatological manifestations may include contact dermatitis and frostbite. Notable subacute-to-chronic manifestations include Raynaud disease, acral sclerodermatous changes, AOL, skin cancer, and cutaneous stigmata of liver disease. In addition to individual susceptibility, factors that may influence severity include duration, intensity, and route of exposure.We advocate for the consideration of viable alternatives to plastic products requiring the use of VC in their production. Examples of such alternatives include glass, ceramics, and linoleum. European nations have implemented restrictions and outright bans on VC use, signaling growing recognition of the importance of risk reduction associated with this hazardous chemical . Further"}
+{"text": "The affiliation for the fifth author is incorrect. Tahir Yusuf Noorani is not affiliated with #2 but with #3: Conservative Dentistry Unit, School of Dental Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kota Bharu 16150, Kelantan, Malaysia."}
+{"text": "Internationalisation of medical education encompasses the integration of global dimensions and intercultural experiences into medical practices. This process is planned to prepare globally conscious, culturally competent medical workforce that can efficiently address international health challenges. This article describes the impact of internationalisation of medical education on students, teachers and patients. International health crises, such as SARS, Ebola virus, or COVID-19 pandemic, affected human health, societies and health care provides at different levels. Such crises show the significance of effective global collaboration and communication in education, biomedical research, and patient care. To tackle international health emergencies, culturally competent and highly skilled medical professionals\u2019 leadership, efficient international communication, rapid global health response, and collaborations on medical science and biotechnology research at international level are needed .The internationalisation of medical education (IoME) plays a key role in equipping healthcare professionals with prerequisite global skills and mindsets to carry out cross-border transformative work in practice , 2.The concept of IoME encompasses systematic, intentional, and evidence-based activities planned to enable students to achieve learning outcomes by participating in high-quality learning opportunities . Thus, IAdditionally, the integration of IoME is possible at curriculum, faculty, and student level \u2014 based on the three-dimensional model approach: The traditional model covers a local curriculum, local student, and local teacher; the international medical graduate (IMG) is described by a local curriculum, local teacher, and international student; and the global or translational model comprises an international curriculum, international teacher, and international student .IoME extends beyond reformations in the medical curriculum and can involve a wide range of stakeholders and attributes such as institutions, faculty, students, and government .IoME has brought numerous experiences such as curriculum expansion, cross-culture exposure, global collaboration and institutional partnership . IoME esIn the past few years, the importance of IoME has been increased significantly as medical institutions aim to produce globally competent and empathic graduates who are capable to practice medicine in miscellaneous cultural settings , 7, 8.International global collaboration and institutional partnerships can also build a huge global medical community. To tackle global health crises, the efficient use of social media and modern technology led by institutional partnerships will be important in near future. Therefore, current technology should be further expanded and incorporated in the medical school curriculum. International institutional partnerships seem to be a mutual practice of IoME but have a great variation in impact and strength . LiteratIoME implementation requires multiple players at different levels including medical educators, medical professional, administration, government, students, and faculty . A signiStudents are primary stakeholders of IoME and may perform various activities in the context of IoME such as attending lectures (\u201cIoME at home\u201d), networking and peer-to-peer connections, gaining intercultural experiences in clinical practices, inbound mobility involving international student employment, and outbound mobility exercises .IoME provides an important platform for students to develop general competencies, such as problem solving, appreciation, collaboration, professionalism, tolerance, empathy, and personal development; leadership skills by participating in extracurricular activities to train themselves in ownership of projects, managerial abilities, and independence; and basic science experience by participation on summer internship programs conducted in basic science laboratories .Institutional partnership also plays an important role in facilitation of peer connections between faculty and students. Advanced technology, like videoconferencing, also connects students from home to international community of students, professionals, or researchers .Finally, IoME can significantly contribute to patient care explicitly or implicitly by facilitating the access to healthcare system, supporting patient-centered care, and promoting culture competence. The IoME comprises for example acquiring knowledge, and comprehending differences in global healthcare education, healthcare delivery services, health laws, heath ethics, and health economics, and establishing global peer networks. IoME further aims to equip prospective physicians with expertise in international competencies, teamwork, and leadership to prepare them best for their future tasks Accordingly, IoME provides knowledge and raises awareness about existing international cultural, economic, social, and ethical disparities in healthcare systems and patients and strengthens effective communication, collaborations, understandings, and feelings of belongingness to a global medical community .Nowadays, the IoME can notably contribute to emerging healthcare globalisation and optimise the healthcare worldwide. IoME is playing a key role in integrating international, cross-culture, or global aspects into medical education to promote healthcare quality. This program is particularly designed to enable including researchers, faculty members, students, patients, physicians, institutions, and government to efficiently serve medical community globally.Articles on the mentioned or other effects of internationalisation on medical education, are welcome for the Collection \u201cInternationalisation of Medical Education.\u201d"}
+{"text": "Positive psychology aims to understand how people can better their lives, and ultimately, flourish. Since Martin Seligman spearheaded this movement, focusing on the positives in life rather than focusing on the negatives, substantial research has been conducted. This research indicates that positive psychological resources, including resilience, self-efficacy, optimism, hope, self-efficacy, and self-esteem, can assist individuals in developing their personal capabilities. These capabilities are associated with higher levels of physical, psychological, social, and behavioral wellbeing , acute leukemia , and COVID , as well as those living with HIV (Orth and Van Wyk) and schizophrenia . Additionally, it includes studies on populations facing stress, such as general populations (Burke and Dunne), empty nesters , and employees . Furthermore, the Research Topic addresses health providers, including family doctors , health professionals  nurses , and emergency physicians . It also encompasses studies on various student populations, including college students , university students , and nursing students .The findings derived from the current Research Topic align closely with the aims outlined this topic:This call for submissions on Ma, Wan et al.). Additionally, the pillars of Lifestyle medicine serve as predictors of psychological flourishing (Burke and Dunne), while resilience mediates mental health literacy and positive coping styles .1) They demonstrate how the construct of positive psychology mitigates negative consequences for patients and family coping with disease burden. For instance, post-traumatic growth is positively correlated with social support , as well as individual and organizational resilience acting as predictor of job performance . Furthermore, psychological capital serve as a predictor of anxiety and depression , and gratitude mediates distributive justice and organizational citizenship behaviors .2) They also illustrate how the construct of positive psychology mitigates the negative consequences for healthcare workers experiencing job-related stress. This includes the mediating effect of culture on positive leadership and quality of work and life . Additionally, learning motivation and target positioning on emotion regulation and happiness , while resilience and positive coping style affect the relationship between maladaptive perfectionism and academic procrastination .3) The findings demonstrate how positive psychology helps to mitigate the negative consequences of learning stress. This encompasses emotion regulation and positive psychological capital as predictors of depression, with stress beliefs and core self-evaluations of procrastination mediating these effects , online expressive writing for reducing psychological distress , WeChat-based self-compassion training to enhance the treatment adherence , and a nurse-manager dualistic intervention program to alleviate burnout .4) They also explore the efficacy, effectiveness and implementation of positive psychology-based intervention for patients or healthcare workers to promote resiliency. This includes cognitive intervention intervention for improving quality of life (Orth and Van Wyk). These findings hold significant potential for advancing future theoretical and empirical studies in this field.5) Finally, the findings contribute to the development of culturally sensitive and contextually innovative theories and instruments. Notably, they aid in the conceptualizing of mental wellness among adolescents living with HIV (However, several limitations should be emphasized here. First, a majority of the articles employed an observational cross-sectional design, primarily focusing on examining mediation or moderation effects. Consequently, the full potential of positive constructs in enhancing long-term adaptation outcomes under stress remains incompletely elucidated (Lam et al., AW: Writing \u2013 original draft, Writing \u2013 review & editing. FH: Writing \u2013 review & editing. YG: Writing \u2013 review & editing. FL: Writing \u2013 review & editing. YS: Writing \u2013 review & editing."}
+{"text": "The gut\u2013brain axis (GBA) is a complex bidirectional communication network connecting the gut and brain. It involves neural, immune, and endocrine communication pathways between the gastrointestinal (GI) tract and the central nervous system (CNS). Perturbations of the GBA have been reported in many neurodegenerative disorders (NDDs), such as Alzheimer\u2019s disease (AD), Parkinson\u2019s disease (PD), and amyotrophic lateral sclerosis (ALS), among others, suggesting a possible role in disease pathogenesis. The gut microbiota is a pivotal component of the GBA, and alterations in its composition, known as gut dysbiosis, have been associated with GBA dysfunction and neurodegeneration. The gut microbiota might influence the homeostasis of the CNS by modulating the immune system and, more directly, regulating the production of molecules and metabolites that influence the nervous and endocrine systems, making it a potential therapeutic target. Preclinical trials manipulating microbial composition through dietary intervention, probiotic and prebiotic supplementation, and fecal microbial transplantation (FMT) have provided promising outcomes. However, its clear mechanism is not well understood, and the results are not always consistent. Here, we provide an overview of the major components and communication pathways of the GBA, as well as therapeutic approaches targeting the GBA to ameliorate NDDs. In recent years, there has been a notable surge in interest surrounding the gut\u2013brain axis (GBA) due to its increasingly recognized role in the regulation of health and the development of diseases, as well as its potential as a therapeutic target ,2. A groThe gut\u2013brain axis (GBA) represents the bidirectional communication between gut microbiota and the brain. This intricate communication involves the coordinated interaction of the nervous system, immune system, and endocrine system . It playThe gut microbiota refers to a dynamic community of microorganisms that inhabit the GI tract of animals, including humans. It primarily consists of bacteria, along with fungi, archaea, parasites, and viruses to a lesser extent . These mFirmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria), along with two minor phyla (Fusobacteria and Verrucomicrobia), with Firmicutes and Bacteroidetes representing approximately 90% of the gut microbiota [The human gut microbiota comprises four major phyla , obesity, and dementia [The gut microbiota is closely related to human well-being, involving immune response, digestive function, metabolism as well as neurological signaling transmission . Studiesrvention . Elevatedementia ,24,25.The autonomic nervous system (ANS), encompassing the sympathetic (SNS) and parasympathetic nervous systems (PNS), forms a neural network comprising neurons widely distributed throughout the central and peripheral regions. It regulates involuntary bodily functions such as heartbeat, breathing, and digestion ,27. The yptophan . These nThe vagus nerve is a pivotal component of the PNS, deriving its name from the Latin word meaning \u201cwandering\u201d. It consists of 80% afferent and 20% efferent neurons, which tonically transmit crucial information from visceral organs such as the GI, cardiovascular, and respiratory systems to the CNS  and furnish feedback to the viscera . Substantial evidence supports the essential roles of vagal nerve pathways in the regulation of appetite, stress responses, inflammation, and cognitive reactions .Vagal afferents establish three distinct categories of connections within the ENS: intraganglionic laminar terminals and intramuscular arrays , both enGut-related signals from vagal afferents travel to the nucleus tractus solitarius (NTS) in the brainstem . This inThe vagus nerve plays a pivotal role in promoting neurogenic and neurotrophic signaling pathways. In fact, animal studies have demonstrated that the disruption of the vagus nerve reduced neurogenesis  and actiThe enteric nervous system (ENS), a significant component of the ANS, is situated within the GI tract and constitutes a complex mesh of 200 to 600 million neurons facilitating the control of gut functions, including motor activity, secretion, absorption, and immune defense, playing a pivotal role in maintaining gut homeostasis and interacting with the microbiota and host systems . The ENSThe gut microbiota significantly influences ENS development and function through the activation of pattern recognition receptors (PRRs) such as toll-like receptors TLR-2 and TLR-4, which recognize microbial lipopolysaccharide (LPS), peptidoglycan, and viral RNA. Studies in TLR-deficient mice have demonstrated changes in ENS functions, including reduced stool output, water content, and gut motility ,47. GermThe hypothalamic\u2013pituitary\u2013adrenal (HPA) axis is considered an essential neuroendocrine pathway integral to GBA communication, orchestrating physiological adaptation to stress. During stress, the hypothalamus initiates the synthesis and secretion of corticotropin-releasing hormone (CRH), which serves as the primary regulatory factor for the HPA axis. CRH subsequently traverses to the anterior pituitary gland, where it binds to its corticotropin receptor, thereby inducing the release of adrenocorticotropic hormone (ACTH) into the systemic circulation. ACTH stimulates the adrenal gland to synthesize and secrete glucocorticoids (cortisol in humans and corticosterone in rodents), serving as downstream effectors of the HPA axis. These glucocorticoids regulate physiological alterations through ubiquitously disseminated intracellular receptors to meet metabolic, physical, and psychological demands under stress. Nevertheless, both excessive and insufficient activation of the HPA axis leads to psychophysiological disorders ,53.Specifically, appropriate levels of glucocorticoids are essential for proper neurodevelopment, and cognitive processes such as learning and memory . ExperimNeurotransmitters mediate intercellular signal transduction across diverse neuronal types and glial cells, influencing learning, memory, emotion, and movement. Neurotransmitters can be categorized into excitatory neurotransmitters, such as glutamate, acetylcholine, norepinephrine, and dopamine, as well as inhibitory neurotransmitters, such as GABA, glycine, and serotonin . Their sEscherichia is known to produce norepinephrine [Bacillus can biosynthesize norepinephrine and dopamine, both catecholamines that regulate emotion, cognition, and gut motility. Staphylococcus inhabited in the human gut also has been reported to express staphylococcal aromatic amino acid decarboxylase, able to convert precursor L-3,4-dihydroxy-phenylalanine (L-DOPA) into dopamine [Lactobacillus spp. [Escherichia spp. [Clostridia, have been linked to the promotion of serotonin biosynthesis by enhancing the gene expression of tryptophan hydroxylase 1, the rate-limiting enzyme for serotonin synthesis [staphylococci can use amino acid decarboxylase to decarboxylate the precursor 5-hydroxytryptophan into serotonin [E. coli and Morganella morganii are some of the bacteria known to produce biogenic amines like histamine [Bacillus subtilis, Lactobacillus plantarum, E. coli, and Staphylococcus aureus [Interestingly, emerging evidence underscores that certain members of the microbiota are capable of producing enzymes or metabolites that facilitate the synthesis of neurotransmitters or their precursors, thereby influencing brain function ,61. Thisnephrine , and Bacdopamine . Lactobalus spp.  and Eschhia spp.  have beehia spp. . Interesynthesis , and cererotonin . E. coliistamine , which iistamine . Its dysistamine  and can s aureus ,72. Reses aureus ,74. ThesThe immune system plays a crucial role in distinguishing between \u201charmful\u201d and \u201charmless\u201d signals and orchestrating appropriate responses, especially in the GI tract, where the immune system constantly interacts with microorganisms through innate and adaptive immunity . EnterocNotable immune receptors include PRRs such as TLRs, which specifically identify microorganism-associated molecular patterns (MAMPs). Examples of these patterns include LPS and polysaccharide A for Gram-negative bacteria and peptidoglycan for Gram-positive bacteria ,76. ThisL. rhamnosus and L. helveticus [Gut microbiota depletion induced by antibiotic treatment or GF mice exhibit systemic and CNS immune system responses ,80. The icroglia , which cicroglia . A studylveticus . Thus, pEnteroendocrine cells (EECs) are distributed widely throughout the GI tract, comprising only 1% of the epithelial cell population within this milieu. Nonetheless, they collectively form the body\u2019s largest endocrine organ and wield pivotal regulatory effects on bidirectional communication between the gut and the brain ,85. CurrEECs primarily exhibit an open-type cell morphology, characterized by a bottleneck shape with an apical membrane in direct interaction with the lumen and a basolateral membrane in proximity to blood vessels and innervating neurons . EECs exWhile more than 20 gut peptides have been identified within the GI tract, most of these play a central role in modulating energy and glucose homeostasis . SeveralThe BBB is a dynamic interface that separates the CNS from the systemic circulation, maintaining brain homeostasis. Functioning as a selective barrier, it allows essential nutrients, oxygen, and waste products to pass while preventing the entry of toxins, pathogens, and harmful molecules. The disruption of the BBB integrity is implicated in the pathology and progression of NDDs. The BBB is structurally organized by endothelial cells lining cerebral microvessels, along with tight junction proteins, pericytes, basement membranes, and glial cells.Endothelial cells in the CNS possess unique properties with low rates of transcytosis, higher numbers of mitochondria, a reduced expression of leukocyte adhesion molecules, and an elevated expression of various transporters and enzymes . These fPostmortem and MRI imaging analysis have confirmed the impairment of the BBB in AD patients . InteresThe intestinal barrier serves as a semipermeable surface responsible for the intricate selective functions of the gut. It facilitates the absorption of essential nutrients and immune surveillance while concurrently restricting the transport of pathogenic molecules and microorganisms. Both structural and molecular components of the barrier interplay in a dynamic manner to fulfill the complex task and maintain intestinal integrity and immune homeostasis .Structurally, the intestinal barrier is primarily composed of the outer mucus layer, a continuous monolayer formed by the epithelial cells, and the inner lamina propria carrying the adaptive and innate immune systems . The outAny damage to the structure and composition of the intestinal barrier may dramatically affect its functionality. A dysfunction of the intestinal barrier has been linked to a range of human diseases, including GI tract diseases such as irritable bowel syndrome , as wellBacteroides and Firmicutes, and an increase in pathogenic bacteria such as Prevotellaceae and Enterobacteriaceae. This imbalance can have negative effects on the host\u2019s health, including metabolic disorders, endogenous intoxication, systemic inflammation, and reduced essential metabolites [Gut dysbiosis refers to an imbalance in the gut microbiota, characterized by a decrease in microbial richness, abundance, and the loss of beneficial bacteria such as abolites .Dysbiosis can stem from a multitude of factors, encompassing an imbalanced dietary regimen predominantly composed of refined constituents, inadequate dietary fiber incorporation, elevated alcohol consumption, exposure to exogenous substances and contaminants, the administration of pharmaceutical agents including antibiotics, persistent psychological stress, sleep deprivation, bacterial or viral infections, as well as various medical conditions such as metabolic disorders notably T2D, and NDDs .Roseburia species show promise as a PD marker [Enterobacteriaceae may predict poststroke cognitive impairment [Several potential biomarkers of dysbiosis have been employed in disease diagnosis. When combined with clinical and other biomarkers, microbiome-based biomarkers can improve the precision of disease classification . NotablyD marker . Microbipairment .Recent studies have shown that gut microbiota dysbiosis can lead to an increased permeability of both the intestinal barrier and the BBB , along wThe neurodegeneration process caused by gut dysbiosis is highly complex, with various physiological changes being interrelated see . Specifiammation . Chronicammation . These cFurthermore, the decreased presence of beneficial gut microbiota due to dysbiosis results in impaired microbial metabolism of neuroactive substances  ,119. Contathione . This retathione .Salmonella enterica and E. coli, and is involved in antigen presentation and lymphocyte development. The disruption of autophagy in the gut can exacerbate gut dysbiosis. In turn, gut dysbiosis can lead to chronic inflammation and oxidative stress, impairing autophagic clearance processes in both the gut and the brain. Gut dysbiosis also contributes to fibril formation. In PD, Emerging research highlights a bidirectional link between gut microbiota and autophagy . Autophacrobiota . Since t-amyloid .Prevotellaceae species and an increase in Enterobacteriaceae abundance in the feces of PD patients [Prevotellaceae play a role in producing mucin and SCFAs through dietary fiber fermentation. This reduction could increase gut permeability, allowing endotoxins to enter the bloodstream, and potentially encouraging Enterobacteriaceae has been positively correlated with the severity of postural instability and gait issues. An increase in Enterobacteriaceae raises serum LPS, triggers systemic inflammation, disrupts the BBB, and contributes to Ralstonia, Proteobacteria, and Enterococcaceae, along with reduced levels of anti-inflammatory butyrate-producing bacteria including Faecalibacterium, Coprococcus, Roseburia, and Blautia in PD patients\u2019 mucosa and stool samples [Escherichia/Shigella spp. and decreased levels of anti-inflammatory bacteria such as Eubacterium rectale spp. in the fecal microbiome [Interestingly, numerous studies have revealed changes in the microbiome associated with specific NDDs. For example, one study reported a decrease in patients . Prevoteia nigra . Another samples . Similarcrobiome . CollectThe link between gut dysbiosis and NDDs suggests that dietary interventions targeting gut dysbiosis could be a promising strategy for treating symptoms and slowing down the neuroinflammatory and degenerative processes in NDDs. To establish eubiosis and promote overall gut health, complementary nutritional interventions aimed at modulating gut microbiota composition and associated metabolites could complement existing therapeutic approaches. These interventions include various dietary plans, prebiotics, probiotics, synbiotics, and fecal microbiota transplantation (FMT) , which hDiet can affect gut microbiota composition, which plays a critical role in maintaining host homeostasis. The Mediterranean diet (MD) emphasizes fruits, vegetables, legumes, and cereals and is considered a healthy dietary receipt. One trial found that adherence to the MD slowed the progression of AD by 1.5 to 3.5 years, and beneficial effects of the MD may be mediated through changes in gut microbiota and its anti-inflammatory characteristics .A high consumption of plant-based foods consistent with the MD diets modulates the gut flora, increasing SCFAs in feces and decreasing trimethylamine N-oxide (TMAO) in urine . SupplemPolyphenols, rich in fruits and vegetables, exhibit diverse physiological roles, can regulate ROS to prevent oxidative stress, modulate the autophagy pathway to reduce apoptosis, affect gut microbiota composition to improve the integrity of the intestinal barrier, and repair gut inflammation . In animes (NFT) . In a raes (NFT) .High-sugar, high-fat diets, and alcohol consumption all have detrimental effects on NDDs. However, various dietary components, such as polyunsaturated fatty acids, antioxidants like blueberry polyphenols, curcumin, sulforaphane, resveratrol, and salvionic acid, as well as caloric restriction, are beneficial for health . This suLactobacilli and Bifidobacteria, and inhibiting pathogenic bacteria [Prebiotics are defined as indigestible dietary components in the upper part of the human GI tract but are selectively utilized by beneficial gut microbes in the large bowel, thereby promoting host health . Accordibacteria . The pribacteria .RS has been shown to maintain bacterial abundance and improve lipid metabolism and intestinal function . Recentleostasis .Bifidobacterium, Lactobacillus, Bacillus, Streptococcus, and Enterococcus [Probiotics refer to live nonpathogenic microorganisms that confer health benefits when consumed in adequate amounts. Some of the most commonly used probiotics include rococcus ,146. Sturococcus ; they strococcus .Lactic acid bacteria and Bifidobacteria, named SLAB51, strategically modulated gut microbiota composition, increasing Bifidobacterium spp., and decreasing Campylobacterales, with an increased production of SCFAs and neuroprotective gut peptide hormones, which contribute to reducing ALactobacillus acidophilus, Lactobacillus casei, Bifidobacterium bifidum, and Lactobacillus fermentum. Supplementation with these probiotics improved patients\u2019 cognitive performance and metabolic parameters, such as insulin sensitivity and serum triglyceride levels [Lactobacillus paracasei K71 prevented age-dependent cognitive impairment, with the proposed mechanism involving the upregulation of BDNF levels in the hippocampus [Lactobacillus, Bifidobacterium, Typhimurium, and Eosinophilus, was found to ameliorate age-related BBB and intestinal barrier disturbances. It also reduced plasma and brain LPS and proinflammatory markers such as IL-6 and TNF-A probiotic formulation of el of AD ,150. Akbe levels . Long-tepocampus . Probiotce model .Synbiotics are defined as specialized formulations of prebiotics and probiotics in which the prebiotics selectively promote the growth and metabolic activity of probiotics, enhance their viability and benefits, positively affect the host\u2019s microbiota composition, and increase the abundance of beneficial microbes in the GI tract, thereby potentially conferring health benefits on the host . The comLacticaseibacillus rhamnosus GG promoted their respective neuroprotection against PD. Specifically, the administration of polymannuronic acid or Lacticaseibacillus rhamnosus GG alone or in combination for 5 weeks prevented the loss of dopaminergic neurons, improved movement, activity, muscle strength, and increased the expression of the tyrosine hydroxylase gene/protein in the midbrain and striatum of PD mice. Remarkably, the synbiotic showed significantly superior neuroprotective effects [Lactobacillus plantarum NCIMB 8826, Lactobacillus fermentum NCIMB 5221, and Bifidobacteria longum spp. infantis NCIMB 702255\u2014along with a polyphenol-rich prebiotic, acted through the GBA to enhance survivability and improve motility, reduce AA novel symbiotic comprising prebiotic polymannuronic acid and probiotic  effects . Anotherla model . A randola model .Fecal microbiota transplantation (FMT) aims to restore a healthy gut microbiome and enhance gut microbiota diversity and function by transferring prescreened donor feces into the patients\u2019 GI tract. Many studies have focused on the potential of FMT in the treatment of inflammatory bowel disease, metabolic disorders, and NDDs ,159,160.In APP/PS1 transgenic mice, Harach et al. found that 16S rRNA sequencing of conventionally raised APP/PS1 mice showed significant gut microbiota alterations compared to wild-type mice. In contrast, GF APP transgenic mice had significantly lower levels of A did not .The frequent transfer and transplantation of fecal microbiota from wild-type mice to ADLPent mice . Additioent mice .The availability of well-organized stool banks and various routes of administration, including capsules, enemas, or colonoscopies, offers opportunities to harness FMT as a potentially convenient and effective therapy for the treatment of NDDs. However, FMT treatment poses significant unique, and complex challenges for clinicians and regulators, including poorly defined mechanisms of action, stool availability, donor selection, adverse effects, and a relative lack of long-term follow-up data . A recenContinuous advancements in the field of microbiome research are bringing us closer to unraveling the intricate connections between gut microbiota and their symbiotic relationship with humans. In the future, a comprehensive understanding of the impact of the microbiome on NDDs such as AD and PD will significantly contribute to their prevention, treatment, and management.It is intriguing that apparently, simple daily dietary interventions may hold substantial therapeutic potential. The development of functional foods containing prebiotics and probiotics seems to have profound implications. Furthermore, as our understanding of the gut microbiota deepens, innovative strategies for noninvasive prognostic indicators and predictive biomarkers for various NDDs and their outcomes can be developed. For instance, using fecal DNA sequencing to quantify the richness of microbial communities and assess the ratio of \u201cbeneficial\u201d to \u201charmful\u201d bacteria may offer valuable insights. Ultimately, the uniqueness of individual microbiomes and targeted improvements in individual gut microbiota health will drive advances in personalized medicine."}
+{"text": "Glycyrrhiza glabra and established EGFR inhibitors have been screened againstthe EGFR catalytic site. The compounds LTS0058805, LTS0114552, LTS0128805, LTS0174203, LTS0007447, and LTS0164690 exhibited bindingenergies to the EGFR that were comparable to those of established EGFR inhibitors. Further, these hit compounds were observed tointeract with critical residues of the EGFR, suggesting their potential as inhibitors of the receptor. In addition, these hits possessgood drug-like properties and merit further exploration for their potential application in cancer management.Overexpression of the epidermal growth factor receptor (EGFR) has been shown to be a critical factor in tumor development and cancerprogression. Although established EGFR inhibitors have been effective in the treatment of cancer, they are associated with several sideeffects. As a result, there is an urgent need to develop novel EGFR inhibitors that can effectively target the receptor while causingno adverse side effects. Here, the bioactive compounds of  Glycyrrhiza glabra (G. glabra) that could potentially serve as EGFR inhibitors incancer treatment is located on the surface of epithelial cells and pertains to the family of tyrosinekinase receptors. It is activated by various endogenous ligands, including epidermal growth factor (EGF), which initiates signalingpathways to resume stable cellular functions . Under ntreatment.Using the ChEMBL database (https://www.ebi.ac.uk/chembl/), 15 known EGFR inhibitors were obtained in \"sdf\" format. Then, DiscoveryStudio (DS) was used to minimize and convert them to pdbqt file types. ChEMBL is a database of biologically active molecules withdrug-like properties that are manually curated. The active compounds of G. glabra were extracted from the LOTUS database, one of The 3D structure of the EGFR was obtained from the Protein Data Bank. Several crystal structures of EGFR have been reported thatcapture distinct snapshots of the protein's conformation and are co-crystallized with various inhibitors. This research utilized 1M17,which is a co-crystallized EGFR tyrosine kinase domain with the 4-anilinoquinazoline inhibitor erlotinib.The PyRx program's built-in AutoDock VINA was utilized to conduct virtual screening (VS) of active compounds from G. glabra andknown inhibitors of EGFR, against the active site of a prepared target protein, EGFR . TheselThe pharmacokinetics, efficacy, and safety profiles of these selected hits were predicted using the DataWarrior tool.EGFR overexpression has been shown to play a critical role in tumorigenesis and cancer progression ;thus, tThe compounds LTS0058805, LTS0114552, LTS0128805, LTS0174203, LTS0007447, and LTS0164690 were selected for in-depth interactionanalysis. LTS0174203 interacted with Glu738, Thr766, Met742, Leu764, Ile720, Val702, Leu820, Ala719, Pro770, Gly772, Leu694, Leu768,Met769, Thr830, Gln767, Asp831, Lys721, and Phe832 residues of EGFR ; while MThe interaction analysis of established inhibitors showed that Lys721, Glu738, Asp831, Gly833, Asp813, Asn818, Arg817, Gly772,Cys773, Tyr777, Asp776, Leu694, Pro770, Met769, Leu768, Gln767, Ala719, Leu820, Val702, and Phe699 residues are important in bindingwith EGFR . InteresClinical medicine research is paying more attention to the utilization of natural ingredients and medicinal plants as cancertreatments . One of The binding characteristics of selected G. glabra bioactive compounds  concerning EGFR, have been thoroughly documented and merit further exploration for their potentialapplication in cancer management."}
+{"text": "This review focuses on electroencephalogram (EEG) acquisition and feedback technology and its core elements, including the composition and principles of the acquisition devices, a wide range of applications, and commonly used EEG signal classification algorithms. First, we describe the construction of EEG acquisition and feedback devices encompassing EEG electrodes, signal processing, and control and feedback systems, which collaborate to measure faint EEG signals from the scalp, convert them into interpretable data, and accomplish practical applications using control feedback systems. Subsequently, we examine the diverse applications of EEG acquisition and feedback across various domains. In the medical field, EEG signals are employed for epilepsy diagnosis, brain injury monitoring, and sleep disorder research. EEG acquisition has revealed associations between brain functionality, cognition, and emotions, providing essential insights for psychologists and neuroscientists. Brain\u2013computer interface technology utilizes EEG signals for human\u2013computer interaction, driving innovation in the medical, engineering, and rehabilitation domains. Finally, we introduce commonly used EEG signal classification algorithms. These classification tasks can identify different cognitive states, emotional states, brain disorders, and brain\u2013computer interface control and promote further development and application of EEG technology. In conclusion, EEG acquisition technology can deepen the understanding of EEG signals while simultaneously promoting developments across multiple domains, such as medicine, science, and engineering. The brain is the most advanced part of the nervous system and possesses immensely powerful functions and complex structures. Electroencephalogram (EEG) is a significant bioelectric signal produced by neural activity that reflects the physiological processes of neurons in the brain and contains a wealth of brain activity information ,2. The sEEG acquisition and feedback devices can transform brainwave signals acquired from the brain into command signals that can be understood by computers or other external devices , enablinWith the advancement of neuroscience, computer technology, and signal processing, EEG acquisition technology has undergone extensive research and application over the past few decades ,15. For Generally, research on EEG acquisition and feedback technology has reached a relatively mature stage, with various research institutions and companies applying it extensively in the medical, military, entertainment, and other fields. There are many comprehensive research studies related to EEG acquisition and feedback devices. For instance, J. Wang et al. have explored the latest classifications and future development directions of flexible electrodes to facilitate the advancement of EEG electrode technology . In the The following article will systematically investigate the application and development of EEG acquisition technology in four main sections: \u201cEEG acquisition devices serve as a data source for various EEG applications and studies. As a precision testing instrument, it must ensure user safety while maintaining high accuracy and a high common-mode rejection ratio (CMRR) of the system. Additionally, efforts have been made to minimize the power consumption, size, and cost of the system ,21. A coThe components of the EEG acquisition system include EEG electrodes, preprocessing circuits, analog-to-digital converters (ADC), and EEG signal control and feedback ,24,25,26In the fields of medicine, neuroscience, psychology, and various brain signal research domains, Ag/AgCl electrodes are widely regarded as one of the most commonly used EEG electrodes due to their excellent signal-to-noise ratio, reliability, stable signal quality, and cost-effectiveness. They serve as the standard against which the performance of other electrode types is often compared. However, Ag/AgCl electrodes require the use of conductive gel, and the electrode preparation and application processes can be complex and time-consuming . TherefoAs shown in Compared to invasive brain EEG electrodes, the fabrication process for micro-needle and finger-like non-invasive EEG electrodes is relatively straightforward. For instance, using 3D printing technology, the electrode models are initially designed with 3D modeling software. Subsequently, the generated files are loaded into a 3D printer, which uses an insulating flexible polymer to create the electrode\u2019s structure. Finally, a layer of conductive metal is deposited on the flexible electrode surface to complete the EEG electrode production . Using pAs shown in For invasive EEG electrodes, due to the need to ensure both signal quality and the safety of electrode penetration into the human body, the electrode fabrication process has higher requirements. The production of thin-film invasive EEG electrodes mainly involves preparing a flexible substrate (such as polyester film like PET or polyimide film like PI), coating with conductive materials , drying, electrode patterning, adding additional layers, encapsulation, connection and wiring, testing, calibration, and finally packaging ,41,42. TIn conclusion, brain electrodes play a crucial role in EEG data acquisition systems, significantly influencing the quality of recorded brain signals. Therefore, the development of comfortable and convenient wearable brain electrodes that can establish effective contact with the skin or organ tissues is a pressing issue. With the advancement of various flexible fabrication techniques, such as the assembly of complex 3D structures, it is anticipated that the current challenges associated with brain electrodes will be effectively addressed ,48,49,50In EEG signal acquisition, the ADC is the core component responsible for converting analog voltage signals into digital form. The ADC performance significantly affects the quality and accuracy of EEG signals .First, ADC resolution is a crucial factor affecting the EEG signal acquisition quality . A higheIn summary, ADC plays a crucial role in EEG acquisition devices. To obtain high-quality EEG signals, factors such as ADC resolution, sampling rate, noise, power-supply noise, reference electrodes, power consumption, and size must be considered ,58,59,60During the recording of EEG signals, various noise and artifacts can interfere with the signals, posing significant challenges for signal analysis and processing. Hence, prior to EEG signal recording, preprocessing circuits are typically employed to enhance the signal quality and accuracy by reducing noise and artifacts. Preprocessing circuits generally comprise several main modules, including amplifiers, filters, and reference electrodes. Amplifiers are responsible for increasing the amplitude of EEG signals, making them easier to record . FiltersThe design of preprocessing circuits must consider multiple factors, such as the signal frequency range, amplification gain, and reference electrode type ,67,68. DIn conclusion, the preprocessing circuits play a crucial role in EEG signal acquisition. They reduce interference from noise and artifacts, enhancing signal quality and accuracy. The design of preprocessing circuits should be flexibly chosen according to specific requirements to meet the diverse needs of different types of EEG experiments.In an EEG system, the processor circuit is a core component that enables real-time processing and analysis of raw signals obtained from the EEG acquisition device, laying the foundation for subsequent data-processing and research. Commonly used processor circuits include a field-programmable gate array (FPGA), digital signal processors (DSP), and central processing unit (CPU) .An FPGA processor circuit is preferred because of its high speed, flexibility, and reconfigurability. It can execute various digital signal processing tasks at the hardware circuit level, including digital filtering, spectral analysis, waveform analysis, and time-frequency analysis . AdditioIn conclusion, the processor circuit plays a crucial role in EEG signal acquisition and processing. Different types of processor circuits have their own advantages and limitations, and their selection should be based on actual requirements and application scenarios.After acquiring the EEG signals, online preprocessing is performed, including eyeblink artifact removal, feature extraction, and pattern classification. Subsequently, the classification results are sent via serial communication to a motion control module based on the DSP TMS32 chip. This module is responsible for controlling specific mechanisms to initiate motion and achieve real-time control of the mechanism through EEG signals. Finally, feedback from the participant, such as pressure, vibration, and temperature signals, is utilized to assess the motion structure status, enabling closed-loop control ,79,80,81The integration of EEG acquisition systems with control feedback systems has immense potential in various applications. This technology can be useful in the medical field, such as offering EEG-based biofeedback therapy to individuals with impaired self-regulation and treating neurological disorders . MoreoveScientists have classified brainwave signals into different types based on their frequency fluctuations. These waves, in descending order of frequency, are beta, alpha, theta, and delta waves, as shown in In the field of movement assistance, EEG data collection plays a significant role in aiding patients with movement disorders or disabilities in rehabilitation training and accomplishing activities of daily living ,100,101,EEG classification algorithms are designed to analyze and categorize EEG data based on specific patterns or features. These algorithms are crucial for understanding and interpreting the brain\u2019s electrical activity ,104,105.In the classification of EEG signals, support vector machine (SVM) is employed to identify different brain states or events by extracting features from EEG signals and training models. SVM aims to find the optimal decision boundary that maximizes the margin between different categories. It enhances classification performance through suitable feature extraction, data preprocessing, and cross-validation. SVM plays a crucial role in applications such as neuroscience research and brain\u2013computer interfaces. As shown in In the classification of EEG signals, the application principles of artificial neural networks (ANNs) encompass several steps, including data preprocessing, feature extraction, the construction of an appropriate neural network architecture, learning mapping relationships from training data, evaluating performance using validation data, and ultimately applying the trained model to classify brain states or events in new data. This approach effectively extracts valuable information from EEG signals, contributing to applications in fields such as neuroscience research and brain\u2013computer interfaces. As shown in Random forests (RF) is a powerful ensemble learning algorithm widely applied in the classification of EEG signals. This method begins by extracting features from EEG signal data and then constructs multiple decision trees. These decision trees are combined through a voting mechanism to identify different brain states or events. Each decision tree is built based on random samples and features using a bootstrap sampling approach, thereby enhancing model diversity and robustness. Through the voting mechanism, random forests effectively handle complex EEG signal data, improve classification accuracy, and play a crucial role in fields such as neuroscience research, brain\u2013computer interfaces, and clinical applications, while also exhibiting strong generalization capabilities. As shown in The k-nearest neighbors algorithm (k-NN) is employed in the classification of EEG signals by measuring the distances between test data points and the nearest neighbors in the training dataset. The class of a test data point is then determined through a majority voting decision. Key steps in this method include data preprocessing, feature extraction, the selection of an appropriate k-value, distance metrics, classification decisions, and performance evaluation. While k-NN is simple and easy to understand, it performs well in applications with small datasets and high interpretability requirements. It can be used for EEG signal classification to identify different brain states or events. As shown in These algorithms have been widely applied across various research and application scenarios, and have achieved notable success. The selection of the most suitable algorithm depends on the specific dataset and task requirements. For smaller datasets and simpler classification tasks, traditional machine learning algorithms such as SVM and RF are often sufficient ,116,117.Electroencephalography (EEG) data collection technology has evolved significantly, redefining our understanding of the intricate dynamics of the human brain. This technology involves capturing electrical activity produced by neurons using electrodes placed on the scalp. Over time, EEG data collection has transcended conventional neurological research, finding applications across diverse domains and paving the way for transformative advancements. Recent years have witnessed remarkable advances in EEG data collection systems to enhance the precision, efficiency, and practicality of brain research. Innovations in electrode design, signal processing methodologies, and integration with complementary technologies have substantially improved the quality and reliability of acquired data ,38,41. HThe future of EEG data collection is promising and multifaceted. Its applications extend beyond traditional research, spanning healthcare, brain\u2013computer interfaces (BCIs), cognitive augmentation, and neuropsychological assessments. The fusion of EEG with artificial intelligence, machine learning, and advanced data analytics is poised to reveal novel dimensions of brain function, leading to more precise diagnostics and tailored interventions for neurological disorders ,112,113.In summary, EEG data collection technology has reshaped neuroscience and several other fields, empowering researchers to delve into the enigmatic realm of the human mind. As advancements continue and diverse fields converge, the horizon for EEG technology appears rich with possibilities and promising deeper insights into the complexities of cerebral function."}
+{"text": "Curcuma longa L.), a plant used for centuries as an anti-inflammatory, are attributed to its polyphenolic curcuminoids, where curcumin predominates. Although \u201ccurcumin\u201d supplements are a top-selling botanical with promising pre-clinical effects, questions remain regarding biological activity in humans. To address this, a scoping review was conducted to assess human clinical trials reporting oral curcumin effects on disease outcomes. Eight databases were searched using established guidelines, yielding 389 citations  that met inclusion criteria. Half focused on obesity-associated metabolic disorders (29%) or musculoskeletal disorders (17%), where inflammation is a key driver, and beneficial effects on clinical outcomes and/or biomarkers were reported for most citations (75%) in studies that were primarily double-blind, randomized, and placebo-controlled trials . Citations for the next most studied disease categories , were far fewer in number and yielded mixed results depending on study quality and condition studied. Although additional research is needed, including systematic evaluation of diverse curcumin formulations and doses in larger D-RCT studies, the preponderance of current evidence for several highly studied diseases , which are also clinically common, are suggestive of clinical benefits.Medicinal properties of turmeric ( Curcuma longa L., a tropical plant native to India and southeast Asia, has been used for centuries as a spice, dye, and medicine  ,211,212,studies] ,215,216,studies] ,219,220,studies] ,222,223,studies] , or traustudies] ), more tstudies] ,237,238 studies] ,247,248.studies] ,237,238 studies] ,244,246.studies] ,246.H. pylori infections [Clinical trials examining curcumin effects on gastrointestinal (GI) disorders ,286,287,fections ,260,261.fections  while nofections . With thfections , subsequfections ,274,275.fections ,263. Citfections ,357,358.Cancer clinical trial citations were the fifth largest category ,320,321,Among the less commonly studied disorders Other, , cardiovCurcuma longa L.) medicinally for thousands of years, primarily for the treatment of inflammatory conditions, as documented by historical medical texts and archeological evidence. While continuous medicinal use for such an extended time period is supportive of the likelihood that curcumin can yield biological effects in humans, this scoping review of curcumin clinical trial outcomes was undertaken to assess scientific evidence querying this postulate, both with respect to diseases treated and biological processes targeted. After a comprehensive search of eight databases for publications, abstracts, and clinicaltrials.gov citations from 1900 to 2020, strong scientific evidence emerged from clinical trials, which primarily (70%) utilized gold standard D-RCT designs, indicating that curcumin can impact disease conditions in humans. Evidence was strongest for highly studied diseases where inflammation, which remains an important etiologic contributor for over 50% of deaths worldwide [Humans have used curcumin-containing turmeric , while particularly relevant due to their commercial availability to consumers  with trends over time suggesting that this topic is not a strong focus of current interest. This contrasts with current usage patterns, however, as, for example, 16% of breast cancer survivors in a recent large epidemiologic study reported concurrent curcumin use during chemotherapy despite an absence of data supporting efficacy, or, perhaps even more importantly, safety when used in this context . The serSecular trends uncovered by this scoping review also yielded interesting findings suggestive of a maturation in certain fields of study. This was most notable for curcumin clinical trials evaluating cognition and memory, where two early negative D-RCTs evaluating non-bioenhanced curcumin in Alzheimer\u2019s disease (AD) populations ,248 wereOne limitation of this scoping review is the lack of inclusion of 2021\u20132022 citations due to pandemic-related delays in data analysis after identification of citations. However, this circumstance allows for comparison of results from this scoping review with those of a systematic review of curcumin clinical trials completed in 2020 , which pLastly, it is important to note that few clinical trials analyzed in this scoping review examined dose-dependent effects of a single agent, comparative effects of disparate products, and/or provided pharmacokinetic data to facilitate cross-comparison across studies. Thus, best practices for clinical curcumin use, even in conditions where the preponderance of existing evidence supported benefits, remain uncertain and would benefit from the conduct of additional well-funded and carefully designed studies, informed by over three decades of curcumin clinical trial results, as summarized here.In conclusion, based on the results of this scoping review, curcumin does appear to have biological activity in humans, with significant evidence that curcumin may have medicinal benefits in the treatment of certain inflammatory and/or obesity-related conditions that are common contributors to higher mortality, morbidity, and loss of productivity in the workforce.A literature review was conducted using recommended five-step scoping review guidelines ,27: (1) All identified records were exported to the management software EndNote Version X9 , which was used to document and delete duplicate records and pre-screen out animal studies and publications unavailable in English (CLH). Two independent reviewers  screened the titles and abstracts of all remaining articles for relevance to the topic. Disagreements were resolved by consensus and consultation with the senior author (JLF). The remaining titles and abstracts were then rescreened for relevance, only retaining citations for clinical trials testing oral formulations with study designs allowing for assessment of curcuminoid products as a sole variable (curcuminoid products containing piperine to enhance curcumin bioavailability were retained). Citations reporting different outcomes from a single study were retained, while citations lacking trial data  or referencing duplicate data from a single study were excluded.All included citations were categorized according to general organ system and further subdivided into disease categories (JFL). All citations for a given organ system were read in their entirety by a single reviewer . The following data were extracted and collated from the selected publications: year of publication, disease and population studied, study design, study size and duration, product type and dose, and disease outcomes assessed . Collated data for a given organ system and/or disease were then summarized for report here . Limited statistical analyses, consistent with the design and purpose of this scoping review, were conducted using Prism software ."}
+{"text": "The term \u201cOsmotic Demyelination Syndrome\u201d (ODS) is synonymous with central pontine myelinolysis (CPM), denoting a condition characterised by brain damage, particularly affecting the white matter tracts of the pontine region. This damage arises due to the rapid correction of metabolic imbalances, primarily cases of hyponatremia. Noteworthy triggers encompass severe burns, liver transplantations, anorexia nervosa, hyperemesis gravidarum, and hyperglycaemia, all linked to the development of CPM. Clinical manifestations encompass a spectrum of signs and symptoms, including dysphagia, dysarthria, spastic quadriparesis, pseudobulbar paralysis, ataxia, lethargy, tremors, disorientation, catatonia, and, in severe instances, locked-in syndrome and coma. A recent case involving a 45-year-old woman illustrates these complexities. Upon admission to the Medicine Intensive Care Unit, she presented with symptoms indicative of diminished responsiveness and bilateral weakness in the upper and lower limbs. Of significance, the patient had a pre-existing medical history of hyperthyroidism. Extensive diagnostic investigations were undertaken, revealing compelling evidence of profound hyponatremia through blood analyses. Furthermore, magnetic resonance imaging (MRI) was performed, unveiling conspicuous areas of abnormal hyperintensity located in the central pons, intriguingly accompanied by spared peripheral regions. These radiological findings align with the characteristic pattern associated with osmotic demyelination syndrome, illuminating the underlying pathology. The following magnetic resonance imaging (MRI) images displaying different indicators observed in osmotic demyelination syndrome ."}
+{"text": "Oryza sativa L.) in Brazil were sequenced. They ranged in size from 3,695,387\u2009bp to 5,682,101\u2009bp, encompassing genes of saprophytic ability and stress tolerance. Genome taxonomy enabled their classification as Priestia megaterium, Bacillus altitudinis, and three putative new species of Pseudomonas, Lysinibacillus, and Agrobacterium.The genomes of five elite strains identified as growth promoters of lowland rice ( Oryza sativa L.) is an important crop for food security and human nutrition in Brazil and is included in the daily diet of most of the population; the main production comes from the lowlands in the southern region (Rice (n region . The usen region . A strain region . Five prn region . Using tThe strains were grown in tryptic soy broth (TSB) at 28\u00b0C for 24 to 48\u2009h, and then total DNA was extracted using the DNeasy blood and tissue kit (Qiagen). Libraries were constructed using the Nextera XT kit, and the genomes were sequenced on the NextSeq 1000 instrument (Illumina) at Embrapa Soybean . The paired-end reads were assembled using the A5 MiSeq pipeline version 20140604 , and theThe genome sizes ranged from 3,695,387 to 5,682,101\u2009bp, with coverages of at least 255-fold. Between 3,706 and 5,811 coding sequences enriched in genes involved in iron, nitrogen, sulfur, phosphorus, amino acid, vitamin, and cofactor metabolism and several genes related to stress response were identified in all genomes in the PGAP analysis. These genes are indicative of saprophytic ability and tolerance to environmental stresses. More information about the assemblies is provided in Priestia megaterium. Strain CNPSo 3703 shared ANI and dDDH values above 98% and 83%, respectively, with two Bacillus species; however, as Bacillus aerius is no longer recognized as a species (Bacillus altitudinis. The other three strains are putative new species belonging to the genera Pseudomonas, Lysinibacillus, and Agrobacterium (Complete 16S rRNA gene sequence comparisons were carried out with species of each genus to select the closest species, defined as sharing \u226598.7% similarity  and digi species , strain acterium .These results highlight the high diversity of plant growth-promoting elite bacterial strains identified in the Brazilian lowlands cropped to rice. Proper genomic identification will allow their use as microbial inoculants for rice, bringing economic and environmental benefits.PRJNA933527. The BioSample, GenBank, and Sequence Read Archive accession numbers are, respectively, SAMN33238823, JAQZSI000000000, and SRR23468783 for CNPSo 3701; SAMN33271202, JARBGV000000000, and SRR23489148 for CNPSo 3703; SAMN33271204, JAQZSD000000000, and SRR23456433 for CNPSo 3705; SAMN33271201, JAQZSE000000000, and SRR23456434 for CNPSo 3706; and SAMN33271203, JAQZSF000000000, and SRR23456515 for CNPSo 3708.The genomic data and reads were deposited at DDBJ/ENA/GenBank under BioProject accession number"}
+{"text": "Given the various ocular manifestations of limbal stem cell insufficiency, an awareness of the genetic, acquired, and immunological causes and associated additional treatments of limbal stem cell deficiency (LSCD) is essential for providers. We performed a comprehensive review of the literature on the various etiologies and specific therapies for LSCD. The resources utilized in this review included Medline (PubMed), Embase, and Google Scholar. All English-language articles and case reports published from November 1986 through to October 2022 were reviewed in this study. There were collectively 99 articles on these topics. No other exclusion criteria were applied. Depending on the etiology, ocular manifestations of limbal stem cell deficiency range from dry eye syndrome and redness to more severe outcomes, including corneal ulceration, ocular surface failure, and vision loss. Identifying the source of damage for LSCD is critical in the treatment process, given that therapy may extend beyond the scope of the standard protocol, including artificial tears, refractive surgery, and allogeneic stem cell transplants. This comprehensive review of the literature demonstrates the various genetic, acquired, and immunological causes of LSCD and the spectrum of supplemental therapies available. Ocular homeostasis is maintained by several processes involving the eye\u2019s structural layers, cell populations, and immunoregulatory responses. These processes involve the corneal stromal stem cells (CSSCs) and limbal epithelial stem cells (LESCs), each of which contributes to the regeneration of the corneal stromal layer and corneal surface, respectively . DisruptThe cornea can be separated into five distinct layers: corneal epithelial layer, Bowman\u2019s membrane, corneal stroma layer, Descemet\u2019s membrane, and corneal endothelium, from superficial to deep . The limA deficiency of limbal epithelial stem cells occurs in two ways: first, as limbal stem cell aplasia secondary to destruction via chemical burns, contact lens use, Stevens\u2013Johnson syndrome (SJS), microbial keratitis, multiple surgeries or procedures; and second, insufficient stromal support, or an \u201cabnormal microenvironment\u201d, causing the decreased function of the limbal epithelial crypts . The latThe current literature on LSCD shows that the leading cause is ocular surface burns . Global Presentation of LSCD differs according to the etiology, and symptoms are often due to poor epithelial healing, resulting in decreased vision, pain from epithelial breakdown, foreign body sensation, conjunctival redness, and tearing ,16. EarlDiagnostic tools for LSCD include patient history, impression cytology for the presence of goblet cells on the cornea, in vivo laser scanning confocal microscopy (IVCM) of the limbus, anterior segment optical coherence tomography (AS-OCT) to measure the epithelial thickness and assess corneal vasculature, and direct histological staining (H&E and Papanicolaou staining) to assess the morphology of the epithelium ,16. The Management of LSCD primarily follows a stepwise approach, focused on addressing the standard presentations seen in the disease and employing less invasive strategies first. Treatment starts with the discontinuation or limitation of the offending agent ; next is the administration of corticosteroids for ocular surface inflammation, and thereafter, support to the residual limbal stem cells is offered via preservative-free lubricants and amniotic membrane transplants, and in severe cases, the restoration of stem cell reserves via a limbal stem cell transplant and penetrating keratoplasty is attempted . LSC traGenetic etiologies of LSCD include aniridia or aniridic keratopathy, ectrodactyly\u2013ectodermal dysplasia\u2013clefting syndrome (EEC), keratitis\u2013ichthyosis\u2013deafness (KID) syndrome, xeroderma pigmentosum, keratitis, and dyskeratosis congenita. The mechanism of injury and management associated with each genetic cause of LSCD is referenced in LSCD from aniridic keratopathy is characterized by insufficient PAX6 protein expression, leading to severe congenital and corneal epithelial dysfunction and subsequent LSC deficiency. The PAX6 protein is a transcription factor expressed in embryonic ocular tissues and is involved in the regulation of corneal epithelial cell differentiation . EvidencA variant of aniridia, hereditary keratitis is an autosomal-dominant disorder often diagnosed in childhood by recurrent stromal keratitis and vascularization of the anterior cornea . It is aEctrodactyly\u2013ectodermal dysplasia\u2013clefting syndrome (EEC) is an autosomal-dominant condition characterized by mutations in the p63 gene, belonging to a protein family transcriptionally responsible for the stem cell differentiation and embryogenesis in stratified epithelia . The ocuKeratitis\u2013ichthyosis\u2013deafness (KID) syndrome is an autosomal-dominant condition resulting from mutations in the GJB2 gene encoding for connexin 26, a gap junction protein found in the epithelium of the inner ear and cornea . KID synXeroderma pigmentosum is an autosomal recessive condition characterized by cutaneous pigmentary abnormalities and neurological and systemic manifestations. Ocular defects in this condition include neovascularization, keratitis, and ocular surface neoplasia ,36. CommThe genetic etiology of LSCD, dyskeratosis congenita, also known as Zinsser\u2013Cole\u2013Engman syndrome, is a rare hereditary disease distinguished by a triad of reticulate hyperpigmentation, nail dystrophy, and leukoplakia . In dyskAcquired etiologies of LSCD include ocular surface disease, contact lens-induced injury or trauma-induced , atopic and vernal keratoconjunctivitis, and bullous keratopathy. Ocular surface diseases, dry eye syndrome (DES), and meibomian gland dysfunction (MGD) are major causes of LSCD, given their effects on ocular surface health. DES is a loss in tear film homeostasis following a disruption to the components of tears: mucin, lipids, or aqueous constituents, resulting in an ocular surface unfit to protect against environmental insult . The cliOne of the most common but easily missed etiologies of LSCD is contact lens-induced LSCD (CL-LSCD). CL-LSCD is distinguished by its whorl-like epitheliopathy (opaque) extending from the superior limbus of the cornea and neovascularization, frequently diagnosed with a fluorescein stain and cobalt blue filter ,49. The Injury to the ocular surface via chemical or thermal burns, radiation, or ocular surgery is a serious and vision-threatening cause of LSCD. Chemical and thermal burns to the ocular surface, classified under chemical insults, are the leading cause of LSCD  and prodDamage to the ocular surface from radiation therapy utilized in treating many systemic cancers has been documented to reduce the functioning of LSCs . FujishiThe destruction of the limbus and deficiency of limbal epithelial stem cells may be due to ocular surgical procedures, including the excision of limbal and conjunctival tumors, trabeculectomy, and pterygium surgery . This foAtopic and vernal keratoconjunctivitis are allergic conjunctival diseases characterized by ocular edema, thickening of the eyelid, corneal scarring and neovascularization, and tear film instability . Atopic Bullous keratopathy (BK) is defined by a reduction in corneal endothelial cells (CEC), resulting in corneal thickening, haziness, and a subsequent loss of vision . BK can Immunological etiologies of LSCD include medication toxicity, severe infection , Stevens\u2013Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), mucous membrane pemphigoid, pterygium and pterygium excision, and rosacea. The mechanism of injury and management associated with each immunological cause of LSCD are summarized in Medication toxicity from Mitomycin C, 5-fluorouracil, and systemic chemotherapy with hydroxycarbamide have been proposed as causes of LSCD. Knowledge of these adverse reactions may be useful to ophthalmologists with patients at risk for limbal stem cell insufficiency in generating treatment plans. Sauder et al. discuss the link between LSCD and medication toxicity in an interventional case series following subconjunctival injections of Mitomycin C for the surgical treatment of glaucoma. The study documented corneal thinning and scleral melting in 43% of the patients following the injection, suggesting LSCD as a complication of subconjunctival Mitomycin C . SimilarSevere infection of the ocular surface and LSCD have been linked in numerous reports within the literature. Of those reports, herpes simplex keratitis and herpes zoster ophthalmicus, microbial keratitis, and trachoma were the most referenced infections to cause limbal stem cell insufficiency. Herpes simplex virus type 1 keratitis (HSK) is an infectious disease characterized by epithelial keratitis, which may progress to corneal opacification, corneal scarring, neovascularization, and loss of vision . HSV\u2019s cStevens\u2013Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe medication-induced inflammatory reactions of the skin and mucosa in the eyes, mouth, and genitals . SJS andOcular mucous membrane pemphigoid (OcMMP) is an immunological condition of the conjunctiva, wherein blisters form between the conjunctival epithelium and sub-epithelium and where significant scarring of the conjunctiva develops. OcMMP damages mucous membranes by IgA, IgG, and C3 deposition . As the A pterygium is an ocular surface lesion postulated to derive from UV-exposed limbal stem cells. These lesions often invade tissues between the Bowman\u2019s membrane and corneal epithelium and lead to epithelial proliferation, goblet cell hyperplasia, stromal plaques, inflammation, and Bowman\u2019s membrane dissolution . The patAs discussed in the literature, physical injury to the stroma, as seen in ocular burns, SJS/TEN, OcMMP, contact lens wear, and severe infections to the ocular surface, results in the destruction of limbal stem cells and the disruption of the limbal niche, termed secondary LSCD. Ocular rosacea, a chronic inflammatory disease, is characterized by inflammation of the ocular surface, blepharitis, tear film instability, conjunctivitis and, in the most severe cases, corneal neovascularization and vision loss . CornealFor patients with hematologic malignancies and diseases, a hematopoietic stem cell transplantation (HSCT) has curative potential. One of the major complications of a HSCT is graft vs. host disease (GVHD), which occurs due to a donor T-cell response against the host tissues, most commonly, minor histocompatibility antigens . Ocular Ocular surface squamous neoplasia (OSSN) is a term that includes the following spectrum of conditions: conjunctival intraepithelial neoplasia, corneal intraepithelial neoplasia, and squamous cell carcinoma of the conjunctiva. OSSN is an extremely rare disease, with only 17\u201320 per million new diagnoses each year . SymptomLimbal epithelial stem cells are a complex component of the ocular surface, vulnerable to a multitude of cellular processes and environmental insults. Upon diagnosis of LSCD, the source of damage is key to providing the appropriate plan of treatment, given the nature of damage that each etiology ensues. Injury via genetic causes, such as aniridic keratopathy, keratitis, EEC, KID syndrome, xeroderma pigmentosum, and dyskeratosis congenita, convey the following treatments in addition to the standard protocol: limbal stem cell transplantation, penetrating keratoplasty, supportive care to residual LSCs and the ocular surface, lubrication and anti-inflammatory agents, and a UV exposure protocol, respectively. Injury via acquired causes, including DES and MGD, contact lens-induced, trauma-induced , atopic and vernal keratoconjunctivitis, and bullous keratopathy indicate the following supplemental treatments: DES topical medications, MGD expression and probing, topical steroids and surgical/refractive procedures, autologous platelet-rich-plasma, antihistamine therapies, and penetrating/endothelial keratoplasty, respectively. Lastly, injury via the immunological processes include medication toxicity, severe infections, SJS/TEN, OcMMP, pterygium-induced, rosacea, GVHD-induced, and OSSN-associated LSCD suggest the following therapies in addition to the standard: amniotic membrane transplantation and anti-inflammatory therapy, antibiotics and antiviral medications, systemic corticosteroids and immunoglobulins, ocular surface disease therapies, limbal stem cell and conjunctival transplantations, autologous serum eye drops, allogenic LSC transplantations from the same bone marrow donor, and neoplastic excision with autologous/allogenic LSC transplantations, respectively.The following resources were used to search the peer-reviewed literature: Medline (PubMed), Embase, and Google Scholar. The keywords used in the search included: limbal stem cells, LSCD, cornea, cornea stromal layer, genetics of limbal stem cells, aniridic keratopathy, keratitis, ectrodactyly-ectodermal-dysplasia-clefting syndrome, keratitis-ichthyosis-deafness syndrome, xeroderma pigmentosum, dyskeratosis congenita, dry eye syndrome, meibomian gland dysfunction, contact lens limbal deficiency, ocular burn limbal deficiency, radiation limbal stem cells, trabeculectomy, pterygium surgery, atopic/vernal keratoconjunctivitis, bullous keratopathy, mitomycin c limbal stem cell, herpes limbal stem cell, microbial keratitis, trachoma, Stevens-Johnson syndrome, toxic epidermal necrolysis, pemphigoid, rosacea, graft vs. host disease limbal stem cell, and squamous cell conjunctival carcinoma limbal stem cell. All English-language articles and case reports published from November 1986 through to October 2022 were reviewed in this study. There were collectively 93 articles on these topics."}
+{"text": "Iodinated contrast agents are extensively employed in clinical settings, with allergic reactions and renal impairment being the most prevalent adverse events. Contrast-induced encephalopathy (CIE) can present with heterogeneous clinical features, making diagnosis challenging. Prior studies on CIE have primarily documented rapid recovery within several days. However, this paper describes a case of CIE in a patient whose clinical symptoms took 3 months to fully abate.A female patient, aged 54 years, received drug-coated balloon therapy for stenosis in a branch of the anterior descending coronary artery. Unfortunately, the patient developed CIE, which initially manifested as visual disturbances and subsequently progressed to gastrointestinal and limb movement issues, as well as an altered mental status, all of which occurred within a 24-hour period during hospitalization.The patient was diagnosed with CIE after cerebral hemorrhage, and cerebral edema was ruled out based on the history of contrast medium administration and radiographic exams.Dexamethasone (10\u2009mg/d), mannitol (100\u2009mL/d), betahistine (500\u2009mL), trazodone (25\u2009mg), and hydration supplementation were given to treat CIE-related symptoms. Aspirin and clopidogrel were administered for the management of the cardiovascular ailment. The neurologist prescribed neurotrophic agents, namely, cytarabine and methylcobalamin, based on the cerebral magnetic resonance imaging findings. Despite the treatment, the patient\u2019s ocular symptoms, including blurry vision, diplopia, and impaired intraocular retraction, persisted. Furthermore, the patient\u2019s mental state was altered, and she continued to exhibit a depressive state during her 1-month follow-up visit.CIE is a comparatively infrequent ailment, and its prompt identification and management are of paramount importance. Although the treatments for CIE are primarily symptomatic, it is crucial to acknowledge that the symptoms may not always subside quickly within a short duration. In conjunction with pharmacotherapy, counseling should be offered to address patients\u2019 mental health. The employment of drug-coated balloons (DCBs) as interventional treatment for coronary artery disease is rapidly expanding.,3 Numerous registry studies have reported cerebrovascular complication rates of 0.30% to 0.40% for percutaneous coronary intervention therapy and 0.05% to 0.11% for coronary angiography. Several studies have indicated that patients who undergo iodine contrast injections have an incidence of CIE of nearly 0.38%. CIE typically follows a benign course, and many patients exhibit recovery within a few days of its onset; however, it is relatively uncommon for the recuperation to span over weeks or months. The present case study highlights a CIE instance in which the duration of recovery was notably protracted.Contrast-induced encephalopathy (CIE) is an abrupt, transient neurological dysfunction that arises from the intracerebral perfusion of contrast agents.The patient, a 54-year-old female, presented to the hospital with chest pain. She had no prior history of food or drug allergies, long-term medication use, hypertension, diabetes mellitus, coronary artery disease, or any other chronic ailments. The patient\u2019s blood pressure was 134/83\u2009mm Hg, her weight was 60\u2009kg, her heart rate and pulse were both 75 beats per minute, and a physical examination revealed no obvious abnormalities. An electrocardiogram obtained from another hospital depicted a sinus rhythm, premature atrial beats, and ST-T alterations. The patient underwent pertinent laboratory examinations and was initially diagnosed with coronary artery disease, unstable angina, arrhythmia, and premature atrial beats. The patient\u2019s laboratory results indicated elevated levels of triglycerides, total cholesterol, low-density lipoprotein cholesterol, and high-sensitivity troponin I . All other tests, such as those for liver and kidney function, produced normal results. Cardiac ultrasonography demonstrated a dilated ascending aorta, a left ventricular ejection fraction of 62%, a small amount of tricuspid regurgitation, and diminished left ventricular diastolic function. The chest CT scan revealed mild emphysema, modest pleural thickening, coronary artery calcification foci, chronic inflammation, and small lung lesions. Based on the results of the coronary angiography, the patient was found to have mild stenosis (30%) in the mid-left anterior descending coronary, severe stenosis (90\u201395%) in the mid-D1, mild stenosis (20%) in the left circumflex artery, and moderate stenosis (40\u201350%) in the mid-right coronary artery, with a TIMI class III antegrade flow , trazodone (25\u2009mg), betahistine (500\u2009mg), and intravenous fluids were administered. Upon undergoing cranial magnetic resonance imaging (MRI), the patient was diagnosed with fresh infarct foci in the right parietal cortex and cerebral bridge, multiple brain foci of ischemic degeneration, and alterations compatible with mild cerebral atherosclerosis Fig. . At thatFollowing the treatment, the patient\u2019s psychological condition ameliorated, allowing her to stand; however, she was still unable to ambulate, and her gastrointestinal manifestations subsided on the second day after the operation. As the days passed, the patient\u2019s previously mentioned symptoms gradually improved, and she was ultimately discharged from the hospital. Nevertheless, at the time of discharge, the patient still presented with diplopia, blurry vision, and reduced physical vigor.One month after the patient\u2019s discharge, we conducted a follow-up and observed that in addition to the decreased physical strength, there was also a noticeable slowing of her thought processes. The patient appeared less responsive and communicative, exhibited reluctance toward social interactions, and displayed a pessimistic attitude. Furthermore, she continued to experience diplopia and blurred vision in her left eye, and the motor function of the eye had not yet returned to normal.After the patient\u2019s discharge from the hospital, it took her 3 months to fully recover. During this period, she was diagnosed with high eye pressure in her right eye at the local county hospital. It is worth noting that the patient was also struggling with psychological depression at this time. However, with constant reassurance and care from her doctor, her mood gradually improved, and she returned to her normal state by the fifth month.,8Identifying CIE in a timely manner is a formidable task due to the dearth of diagnostic criteria. CIE is an infrequent occurrence in clinical settings, and it is typically witnessed subsequent to interventions or surgeries on the cardiac and cerebral vasculature. The origin of CIE is largely ascribed to its heightened viscosity, osmolarity, and direct neurotoxicity, which can result in aberrant blood\u2013brain barrier functionality, an imbalance in cerebrospinal fluid electrolytes, cerebrovascular spasms, and direct neural cell damage. Etiological factors, contrast agent type, dosage, surgical timing, patient age, hypertension, hyperlipidemia, hyperglycemia, and a history of cerebrovascular lesions are among the various risk factors for CIE. Nonionic iodine contrast agents are preferred due to their low incidence of adverse reactions. In this particular case, the patient was administered the nonionic contrast agent iodixanol, which is deemed safer because it does not cause renal harm and has an osmotic pressure that approximates human plasma. Although the patient did not exhibit any of the aforementioned risk factors, a cerebral infarction was detected via cranial MRI. We postulated that the underlying cause was the contrast agent\u2019s high viscosity, which impeded blood flow in the cerebral arteries and resulted in neurotoxicity.Based on their physicochemical structure, iodine contrast agents that are employed in clinical settings are presently categorized into the following groups: ionic monomers, for example, such as pantethine; ionic dimers, such as iodic acid; nonionic monomers, such as iodophoresol and iodofol; and nonionic dimers, such as iodixanol.\u201313 In addition to memory loss, dysarthria, cortical blindness, fever, dizziness, and headache, CIE can also present with a range of clinical manifestations. These may include gastrointestinal symptoms, such as nausea, vomiting, and abdominal distention; psychiatric symptoms, such as confusion, delirium, and loss of consciousness; and neurological impairments, such as limb movement disorders, optic nerve and motoneural dysfunction, memory loss, and even cardiopulmonary arrest.\u201315Additionally, CIE can manifest differently in individuals, and there have been cases in which patients developed CIE despite receiving a minute amount of contrast agent or undergoing intravenous contrast-enhanced CT scans. Indeed, there have been instances of CIE where the symptoms and imaging findings do not correlate or where there are no imaging characteristics present at all.,18Clinical professionals may encounter challenges in diagnosing or differentiating certain symptoms of CIE, as they can be easily mistaken for those of primary cerebrovascular lesions. Brain ischemia or cerebral hemorrhage are 2 potential imaging findings in CIE patients. To distinguish between cerebral ischemia and CIE, it has been suggested that the apparent diffusion coefficient (ADC) be employed. ADC measures the signal intensity of diffusion-weighted imaging images in cranial MRI. In patients with CIE, there is no abnormal intensity, while in patients with acute ischemic stroke and cytotoxic edema, a decrease in water diffusion in the infarcted tissue results in a decrease in ADC.The patient in question developed the aforementioned symptoms following DCB treatment, and CIE was diagnosed through a combination of these symptoms and diffusion-weighted imaging images from a cranial MRI. The main approach to treating CIE is symptomatic, which involves adequate hydration to aid in the discharge of the contrast agent, the use of glucocorticoids to reduce neurotoxic effects, with dexamethasone being the most commonly used medication, maintaining water-electrolyte balance, providing anti-epileptic medications in the case of epilepsy, and administering calcium antagonists if vasospasm occurs. After treatment, this patient experienced a rapid remission of numerous symptoms. reported a patient with CIE who required 19 days to recover after undergoing cerebral angiography. The case report by Leong et al reported a patient who developed CIE after undergoing intracranial aneurysm coiling, and 1 year later, the patient still suffered from chronic left-sided limb spasticity and was diagnosed with irreversible CIE. Among the CIE cases they analyzed, the median duration for neurological function recovery was 2.5 days. Despite receiving prompt therapy, the patient\u2019s ocular problems took a slow and gradual recovery course and were ultimately resolved after a period of 3 months.In our view, the purpose of this case report is to raise awareness about the variable prognosis of CIE. It should be noted that not all CIE symptoms improve rapidly with treatment, particularly those related to nervous system damage, including visual disturbances, diplopia, and oculomotor dysfunction, which may be caused by optic and oculomotor nerve injury. Although most patients with CIE have a self-limited course and recover within 72 hours without sequelae, Qiu et alIn addition to attending to the physical manifestations of the disease, it is crucial to pay close attention to the psychological well-being of patients. Psychological distress and despondency can exacerbate symptoms and delay recovery. During follow-up, we observed that the patient\u2019s psychological distress post-CIE onset was due to social comparison, as she had acquaintances who underwent similar coronary procedures without encountering CIE, which made her fear that she would never fully recover. An all-encompassing approach to the management of CIE should address both the physical and psychological aspects of the disease to ensure optimal outcomes for patients.CIE manifests in a plethora of ways, thereby rendering diagnosis and differentiation arduous. Symptomatic convalescence may be prolonged, and CIE can manifest in coronary DCB procedures, as ascertained from this patient\u2019s case. Clinicians, in addition to expeditiously identifying and treating CIE, must provide patients with psychotherapeutic intervention to buttress their psychological welfare, which fosters their recuperation.Conceptualization: Lixin Liu, Xueying Chen.Data curation: Kaiyuan Kong, Anyong Chen, Guoliang Yang, Ronghua Gao, Shaohui Zhang.Formal analysis: Kaiyuan Kong, Anyong Chen, Guoliang Yang, Ronghua Gao, Shaohui Zhang, Lixin Liu.Funding acquisition: Xueying Chen.Investigation: Kaiyuan Kong, Anyong Chen, Guoliang Yang, Ronghua Gao, Shaohui Zhang, Lixin Liu, Xueying Chen.Project administration: Ronghua Gao, Shaohui Zhang, Lixin Liu, Xueying Chen.Writing \u2013 original draft: Kaiyuan Kong.Writing \u2013 review & editing: Anyong Chen, Guoliang Yang, Ronghua Gao, Shaohui Zhang, Lixin Liu, Xueying Chen."}
+{"text": "Brachycephalic dogs are affected by respiratory disorders related to abnormal anatomic conformation that can significantly affect their general health and quality of life. In this review, we address dermatological disorders in these breeds which are less recognized, but can also considerably impact welfare.Malassezia dermatitis, and otitis externa/media. In addition, the frequently neglected but often lifelong dermatological problems of brachycephalic dogs are an important consideration when discussing genetic and medical conditions affecting the welfare of those dogs. Here we review the current state of knowledge concerning dermatological problems in brachycephalic dogs and combine it with clinical experience in the management of these challenging disorders.Brachycephalic dogs are not only affected by brachycephalic obstructive airway syndrome (BOAS), but are also frequently referred to veterinary dermatologists for skin conditions, with English bulldogs and pugs particularly over-represented. Some skin diseases, such as skin fold dermatitis, are directly associated with the abnormal anatomic conformation of brachycephalic dogs, while for others, such as atopic dermatitis and viral pigmented plaques, there is an underlying genetic basis or a general predisposition. Anatomic alterations associated with brachycephaly, leading to fold formation of the skin and stenosis of the ear canal, together with primary immunodeficiencies described in some breeds, favor the development of pyoderma,  Brachycephalic dogs are very popular due to cultural and social influences, as well as their \u201cbabyface\u201d appearance and personality traits that favor bonding and companionship with their owners ,2. OwnerThe prevalence of dermatological abnormalities in brachycephalic dogs ranges from 10% to almost 30%, depending on breed and geographic origin ,7. GenetMany of these skin conditions may become chronic and difficult to treat, as well as causing pain and pruritus, leading to abnormal behavior and thus negatively impacting quality of life ,12. In this evidence-based narrative review, we overview the dermatological diseases encountered in brachycephalic breeds of dogs, including; (i) disorders directly associated with brachycephaly that are likely to be improved if measures to prevent extreme brachycephaly are implemented, as well as (ii) disorders that are not directly linked to brachycephalic conformation. The electronic database \u201cWeb of Science\u201d was searched using key words including \u201cdog\u201d, \u201cbrachycephaly/brachycephalic\u201d, \u201cwelfare\u201d, \u201cgenetics\u201d, \u201cpredisposition\u201d, \u201cskin diseases\u201d, \u201cdermatologic/dermatological\u201d, as well as individual dog breeds  and individual diseases identified during the initial search . Selected articles were critically appraised and compared before the incorporation of relevant information in this review.There is no definitive list of brachycephalic breeds because no uniform measure is used. Some authors use the cephalic index (CI), the ratio of the width of the skull compared with its length, while others use the craniofacial ratio or craniofacial angle . In addiSkin fold dermatitis, or intertrigo, is a major problem in brachycephalic breeds, especially in British bulldogs, French bulldogs, Pugs, Pekingese, Boston Terriers, and Shar Peis ,97,98,99Reduced air circulation and increased temperature, humidity, and debris within skin folds, together with intermittent friction and trauma, lead to commensal overgrowth and toxin production, followed by inflammation, maceration, and infection ,115. AffInvolved areas can be pruritic and painful. Since the changes take place between skin folds, disease may not be noticed by owners ,14,115. Otitis externa (OE), inflammation of the ear canal and often the outer ear, is more prevalent in brachycephalic dogs, especially British bulldogs, Pugs, and Boxers, than in non-brachycephalic dogs ,59,60,69Clinical signs of OE include abnormal scratching of the pinnae, excoriations, head shaking, otic discharge, malodour, swelling, pain, formation of \u201chot-spots\u201d (moist dermatitis), and othematoma  14,119],11914,11Treatment of OE typically includes a combination of topical ear drops, an ear cleaner, and, if not contra-indicated, an anti-inflammatory dose of oral glucocorticoids to reduce the stenosis, pruritus, and pain ,121. It This congenital and multifactorial inherited abnormality was first recognized and reported in Cavalier King Charles Spaniels (CKCS), with up to 95% of individuals being affected ,37,38,39Magnetic resonance imaging (MRI) is the modality of choice to diagnose Chiari-like malformations, but computed tomography (CT) may also be used .Medical treatment with non-steroidal inflammatory inhibitors, glucocorticoids, opioids, and anticonvulsants  helps to relieve pain, while omeprazole, acetazolamide, and methazolamide may be prescribed to reduce the formation of cerebrospinal fluid ,131. AltPrimary secretory otitis media, a sterile effusion of the middle ear, is mainly described in CKCS but also in other brachycephalic breeds such as Boxers and Boston Terriers ,46,136. Affected dogs present with head and neck pain, spontaneous vocalization, abnormal neck carriage, fatigue, aural pruritus, neurological signs , or reduced hearing, but may also be asymptomatic ,45.Diagnostic work-up includes video otoscopy , myringotomy , and MRI or CT ,136. ForMyringotomy of the pars tensa of the tympanic membrane with subsequent flushing of the bulla, systemic antibiotics, topical ear drops, and a short course of systemic anti-inflammatory glucocorticoids are common treatment steps ,45,46. AMalassezia dermatitis/overgrowth, pododermatitis, and otitis externa are common sequela ,10414,10Brachycephalic breeds are predisposed to skin cyst formation and nail overgrowth, the latter especially in British bulldogs and Pugs ,59,60. BDermatological disorders are common among brachycephalic breeds. While some are a direct consequence of the anatomic abnormalities that have been selected for over generations of breeding, others are not linked to brachycephaly but highlight the consequences of small gene pool diversity within dog breeds. As breeding programs are modified to select for less extreme brachycephalic confirmation, the prevalence and expression of unrelated genetic disorders need to be carefully monitored to prevent their unwitting selection.Brachycephalic dogs are not only adversely affected by their airway problems, chronic hypoxia, hypertension, sleep disorders, ophthalmologic, dental, and gastrointestinal problems, but also by lifelong dermatological dilemmas, which are often challenging to treat and negatively affect their quality of life. These are enough arguments to suggest that revised breed standards for those dogs are desperately needed."}
+{"text": "Dear Editor,,Nursing care planning is a critical and daily task in managing and treating patients with cancer. It involves the systematic nursing assessment, diagnosis, planning, interventions, and evaluation of care plans tailored to the unique needs of patients with cancer.To illustrate the application of LLMs in oncology nursing care planning, let us consider the hypothetical case of a 55-year-old female patient, Mrs. Jones, who was recently diagnosed with stage II breast cancer . Upon diSkepticism towards artificial intelligence (AI) in healthcare stems from transparency issues, data privacy concerns, job displacement fears, and ethical quandaries.To summarize, harnessing LLMs like GPT-4 in oncology nursing care planning holds significant promise for improving the quality of care for cancer patients. This technology plays an important role in predicting silent trends in the given patient's data. Through enhanced decision-making, patient education, and care coordination, these models can lead to more personalized, proactive, and collaborative approaches, ultimately contributing to better patient outcomes."}
+{"text": "Alnus glutinosa (L.) Gaertn.) is a tree species native to Ireland and Europe with high economic and ecological importance. The presence of Alder has many benefits including the ability to adapt to multiple climate types, as well as aiding in ecosystem restoration due to its colonization capabilities within disturbed soils. However, Alder is susceptible to infection of the root rot pathogen Phytophthora alni, amongst other pathogens associated with this tree species. P. alni has become an issue within the forestry sector as it continues to spread across Europe, infecting Alder plantations, thus affecting their growth and survival and altering ecosystem dynamics. Beneficial microbiota and biocontrol agents play a crucial role in maintaining the health and resilience of plants. Studies have shown that beneficial microbes promote plant growth as well as aid in the protection against pathogens and abiotic stress. Understanding the interactions between A. glutinosa and its microbiota, both beneficial and pathogenic, is essential for developing integrated management strategies to mitigate the impact of P. alni and maintain the health of Alder trees. This review is focused on collating the relevant literature associated with Alder, current threats to the species, what is known about its microbial composition, and Common Alder\u2013microbe interactions that have been observed worldwide to date. It also summarizes the beneficial fungi, bacteria, and biocontrol agents, underpinning genetic mechanisms and secondary metabolites identified within the forestry sector in relation to the Alder tree species. In addition, biocontrol mechanisms and microbiome-assisted breeding as well as gaps within research that require further attention are discussed.Common Alder ( Alnus glutinosa (L.) Gaertn) [Alnus belongs to the family Betulaceae, the birch clade [Alnus species worldwide, including shrubs and trees, with A. glutinosa being the primary native species within Europe [A. cordata), Grey Alder (A. incana), Red Alder (A. rubra), White Alder (A. rhombifolia), Japanese Alder (A. japonica), and American Green Alder (A. viridis) [A. glutinosa has been found on a broad range of sites; however, it favours wet, riverine, and fertile areas with high humidity [Over the last two decades, there has been an elevated interest regarding the significance of native tree species, such as Common Alder ( Gaertn) , also knch clade . Alder ich clade . In addich clade ,4. This ch clade . There an Europe ,7. Whileviridis) ,5. Alderviridis) . This reviridis) . A. gluthumidity ,10. Prefhumidity . This sphumidity . Alder hhumidity ,13,14.Historically, Alder was considered to generate an inferior class of wood with low economic value . A blackFrankia [Alder tends to have an extensive rooting system and forms large nitrogen-fixing root nodules via symbiosis with nitrogen-fixing filamentous bacteria, such as the genus Frankia . Thus, tFrankia ,21. OtheFrankia ,5. AlderFrankia . Alder pFrankia ,22. For Frankia .A. glutinosa, coupled with the worldwide distribution of this species has substantially increased its importance and promising utilisation [A. glutinosa are being cultivated within commercial forests in order to generate trees to produce timber [Its porous wood has various uses for carpentry, building, furniture production, biomass production, instrument manufacturing, cabinetry, dyes, and manufacturing charcoal ,5,16. Itlisation . As a ree timber ,16. As pe timber .Alnus-associated beneficial microbes could provide an ecological, environmentally sustainable solution to the biological control of Phytophthora infection. Therefore, to gain a better understanding of the beneficial and pathogenic microbiota associated with A. glutinosa, this review reports the known microbiome of Alder, pathogenic threats of Alder, as well as any biological solutions available to date for the control of these pathogenic threats.There are numerous existing threats to Alder cultivation, some of which are abiotic such as drought ,27, whilMicroorganisms are extremely diverse and plentiful within the environment. The type and abundance of microbial communities that exist within an organism are influenced by the environmental conditions surrounding plant communities as well as soil type, indicating the presence of selective communities associated with different plant species. Forest trees exist in close association with a diverse range of microbial organisms that play a crucial role in maintaining tree health, nutrient conditions, and ecosystem functions. This association can be mutualistic, parasitic, or symbiotic. Combined, these microbial communities associated with the tree are known as its microbiome. The composition of the microbial community can vary due to a range of factors including climate, edaphic conditions, anthropogenic activities, silviculture management practices, and various other events and stressors . OrganicTree roots and rhizospheric soil tend to have a particular and plentiful microbial community due to the occurrence of nutrient and mineral exchange between the soil microbiota and tree-component microbiota present in root tissues, ectomycorrhizal fungal roots, arbuscular mycorrhiza roots, and fungal mycelia . These rP. cinnamomi, a root rot pathogen of avocados and reported that sporangia production was reduced when cellulase enzymes were present, indicating that cellulase enzymes may have the ability to decelerate the spread of P. cinnamomi within avocado sites [Betulaceae family and identified beneficial microbes including Actinobacteria genera  [Rhizobium) [Bacillus isolates  [Pseudomonas) [Arthrobacter, Azospirillum, Azorhizobium, Burkholderia, Flavobacterium, Mesorhizob, and Methylobacterium [Plant growth-promoting rhizobacteria (PGPR) play a significant role in the forest ecosystem by releasing numerous regulatory molecules, aiding the growth and development of forest trees . Deciduodo sites . Pectinado sites . Other mdo sites . In addido sites . Some PGtomyces) ,48,49,50izobium) , Bacilluisporus) ,53,54, adomonas) . Other kacterium . With thAlnus species have a tendency to form stable long-term biological interactions with mycorrhizae, including ectomycorrhizal fungi and/or arbuscular mycorrhizal fungi [Paxillus involutus OW-5, promoted growth and increased tolerance in saline soils [Betulaceae family include arbuscular mycorrhizal fungi (Gigaspora rosea), ectomycorrhizal fungi , endophytic fungi , DSE , and ericoid fungi (Oidiodendron) [Alternaria, Chaetomium, Penicillum, Phoma, Serendipita, and Trichoderma [Trichoderma, Penicillum, and Aspergillus are the most studied within agriculture as they can promote crop growth and act as eco-friendly biological control agents to promote resistance/tolerance to biotic stresses [The inoculation of plants with plant growth-promoting fungi (PGPF) has demonstrated many health benefits including enhanced seed germination, seed vigour, root morphogenesis, pathogenic suppression, the reduction of (a)biotic stressors, as well as an improved process of photosynthesis and mineralization . The rooal fungi . This syal fungi . For exane soils . Culturane soils ,60. Fungne soils ,61. Fungdendron) ,63,64,65choderma . There hstresses . These fA. glutinosa. Much of the information that is available focuses on the microbial communities present within Alnus roots and their associated rhizosphere. These studies particularly focus on soil salinity [Frankia alni), Acidobacteria (Granulicella), Alphaproteobacteria , Bacteroidetes , Betaproteobacteria, Firmicutes (Bacillus licheniformis and Bacillus pumilus), Gammaproteobacteria, Pseudomonadota , and Thermoleophilia [Cryptosporiopsis), Basidiomycota , Ectomycorrhizal fungi , Glomeromycota (Gigaspora rosea), and Zygomycota (Rhizocyphus) [Alnus species. With the economic and environmental importance of Alder coupled with its pathogenic threat, research regarding the root and rhizospheric microbiomes may potentially grow in the future.To date, there have been few studies regarding microbes associated with salinity , inoculasalinity , colonissalinity , plant gsalinity , antagonsalinity , as wellsalinity . Alder-aeophilia ,53,65,73ocyphus) ,60,65,74A. glutinosa female catkins and found high levels of methanol extracts, ellagic acid, and ethyl acetate indicating their potential use as natural antioxidants [A. glutinosa growing in saline soil. Three fungal species were isolated from A. glutinosa catkins, which were Amanita muscaria, Paxillus involutus, and Gymnopus. Seedlings were later inoculated with each fungus to determine their effects against salt stress. It was observed that P. involutus aided in promoting the growth of seedlings and showed a degree of salt tolerance [A. glutinosa leaf tinctures to be used as wound-healing gels. It was determined that this gel had the ability to regenerate and heal wounds due to the presence of flavonoids, tannins, and phenolic acid [Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa, and Candida albicans [Alternaria alternata, A. raphani, Aspergillus niger, Cladosporium cladosporioides, Epicoccum purpurascens, Fusarium oxysporum, Gliocladium roseum, Mucor hiemalis, and Pestalotiopsis sp. [Very little is known about the leaf, bark, and catkin microbiomes of Alder trees. A greater focus has been placed on analysing the chemical and biological components, as well as the secondary metabolites present in the bark, leaf, and fruit due to the medicinal value of these components ,40,41. Soxidants . Thiem eolerance . There hlic acid . Leaf exalbicans . Concernpsis sp. . A greatTaphrina alni, is a causal agent of Alder tongue galls on female catkins and has been identified throughout Europe. These galls are known as Alder tongues, as they are green-red elongated structures (depending on the season) [Septoria alnifolia has been known to form leaf spots, stem cankers, and stem breakage on Alder trees [Melampsoridium hiratsukanum, causing yellow\u2013brown spotting on Alder leaves, followed by early leaf fall, crown thinning, and/or death, has been identified [Mycopappus alni tends to cause brown blotches on leaves and defoliation of Alder trees [Erwinia alni, has been found to cause bark cankers and bleeding and eventually kill off branches and/or the tree as a whole if the infection is severe [Pseudomonas syringae has been reported to cause leaf necrosis and the dieback of Common Alder [Agelastica alni, has been identified in Europe causing damage and defoliation of Common Alder [Monsoma pulveratum [Eriocampa ovata [Hernichroa crocea, and Cimbex conatus [Fenusa dohrnii, was identified as a pest of Alder that causes damage [Phytophthora.There are several pests and microbial pathogens associated with Alder. For example, Alder yellows phytoplasma disease  has been identified within numerous European countries, which causes stunted growth, yellowing of leaves, reduction of leave size and amount, as well as dieback and/or death ,80,81,82 season) . The funer trees . Furtherentified . The funer trees . The bacs severe . The bacon Alder . With reon Alder . Severallveratum , Eriocampa ovata , Hernich conatus . A leaf s damage . There is damage . McVean s damage , howeverPhytophthora, meaning \u2018plant destroyer\u2019, has been associated with the dieback and decline of Alder across Europe [Phytophthora, with more species unnamed/unidentified and likely to be discovered [Phytophthora chlamydospores, hyphae, oospores, sporangium, and more frequently zoospores. Flagellated Phytophthora zoospores have a similar morphology to filamentous fungi but mainly have diploid hyphae and a cell wall comprising cellulose and/or \u03b2-glucans [Phytophthora show phylogenetic similarities to algae and diatoms due to the structural composition of zoospores as well as the release of similar sexual antheridia  and oogonia  [Phytophthora are soil-borne water moulds that have a strong dependency on water and humidity; therefore, the zoospores typically disperse and spread throughout water systems, eventually infecting tree roots [Phytophthora species. Zoospores swim through water within wet soils where they have the ability to form cysts on susceptible tree roots and bark near the root collar [The species s Europe . There ascovered . The patscovered . Infecti-glucans . Phytoph ,98. Phytee roots ,99. In tee roots ,100. Oost collar ,100. Inft collar .Phytophthora alni, and after three weeks, oogonia, oospore, sporangium, antheridium, and mycelium were found at different stages of the reproductive cycle throughout the plant tissues [P. alni hyphae has the ability to grow from Alder roots into the bark via secondary growth, travelling throughout the tree and infecting the cambium layer and adjacent phloem and xylem by continuously reproducing [P. alni infects Alder bark via lenticels and/or bark wounds and spreads via secondary growth throughout the plant tissues by medullary rays into the bark xylem [P. alni directly infects Alder leaves and catkins; however, infection of the roots and bark has damaging effects on all compartments of the tree.Nave et al. (2021) inoculated Alder roots with  tissues . P. alniroducing . P. alnirk xylem . When thP. alni has been a major issue within many countries and has continued to spread worldwide today, causing a range of damage to the Alnus species, which is believed to have emerged due to hybridisation within Europe [P. alni are P. uniformis (diploid) and P. multiformis (haploid), with the ploidy level showing that P. alni contains half of each parental genome; therefore P. alni is a triploid homoploid-type taxon [P. alni is due to clonal dispersion, since several mitochondrial haplotype variations have been observed, which may imply that multiple sexual hybridisation incidents generated a hybrid from several clones [P. alni ssp. lat. was formally named by Brasier et al. (2004) and is now divided into three subspecies: P. alni ssp. alni, P. alni ssp. uniformis, and P. alni ssp. multiformis, considering different variants and hybrids amongst the species, with P. alni ssp. alni being the most aggressive one [P. alni species complex was later renamed by Husson et al. (2015) to P. \u00d7 alni, P. \u00d7 multiformis, and P. uniformis [P. alni ssp. uniformis has been identified in North America to date [P. alni complex species include dieback of branches, crown thinning, bleeding bark, dark spotting on stems, stunted leaf growth, premature leaf abscission, leaf yellowing, root rot, necrotic lesions on Alder bark, an excessive number of catkins on the species due to stress, and/or death [Since the 1990s, n Europe ,106,107.pe taxon ,109  found that P. plurivora caused a high mortality rate within inoculated Alder seedlings, indicating that this species is pathogenic to Alder seedlings [P. \u00d7 alni, P. \u00d7 multiformis, and P. uniformis, and it was observed that the pathogen caused foliar necrosis, indicating that the roots and root collar may not be the only source of pathogen inoculum [Jung et al. (2018) conducted a thorough review of forestry diseases causing decline and suggested that other  decline ,115,116. species . In Ukra dieback . TkaczykSlovakia . Bregantd Poland . Furthereedlings . Haque ainoculum .A. glutinosa has many antioxidant, anti-inflammatory, antitumour, and inhibition properties due to the presence of anthraquinones, betulinic acid, diarylheptanoids, flavonoids, phenols, terpenes, tannins, steroids, and saponins; thus, these substances have the potential as BCAs within forestry [Enterobacter aerogenes against the pathogen P. lateralis, which tends to affect tree roots within soil and water, causing root rot disease of Lawson cypress trees [Acacia extensa, A. stenoptera, A. alata, and A. pulchella against the root rot disease caused by P. cinnamomi, to observe that these genera have the potential to provide protection to susceptible species [Alnus species being under threat from the harmful effects of Phytophthora, such studies could potentially aid in determining the association between P. alni and the Alnus species and thus determining potential BCAs to prevent infections.Biocontrol agents tend to be any beneficial organism, including PGPR and PGPF, which have the ability to provide biological control against harmful pathogenic disease, as well as assisting in acquiring nutrients and amplifying resistive traits within a plant species . Furtherforestry ,18,122. forestry ,124. Thiss trees . D\u2019Souza species . With thHymenoscyphus fraxineus, a study performed on the microbial community associated with ash tree leaves (Fraxinus excelsior) discovered elevated amounts of isolates within the genera Luteimonas, Aureimonas, Pseudomonas, Bacillus, and Paenibacillus present within tolerant trees, which potentially inhibit the invasion and spread of ash dieback disease (H. fraxineus) by direct competition or inducing systemic resistance, as well as the potential production of antagonistic metabolites and/or antifungal compounds [Aureimonas altamirensis had the ability to reduce H. fraxineus infections by niche exclusion and inducing mechanisms such as exopolysaccharides production and protein secretion [Streptomyces have proven to be a prime choice as BCAs since these are readily available in nature and have the capacity to control pathogenic infections [daidzein was produced by the bacterial genus Streptomyces and isolated it from a root of A. nepalensis alongside the Streptomyces bacterium, which may have potential antioxidant, anti-inflammatory, and anticancer effects [Streptomyces can produce the enzyme chitinase, which has been shown to have antagonistic effects against fungi due to the ability to degrade chitin present in the cell walls of fungi as well as reduce spore germination [Several bacterial strains could potentially provide BCAs against emerging tree pathogens . For exaompounds ,129. Simecretion . The plafections ,132,133. effects ,135. Themination .Pseudomonas strain [Biocontrol modes of action can be direct (interaction between pathogens and BCAs) or indirect biotic stressors) . Direct s strain . In thiss strain . Genes as strain . Mitogens strain . TGA tras strain . In addis strain .Fusarium pathogens, which have been found within soils, causing root rot [Bacillus subtilis, isolated from the rhizosphere roots of black pepper, has potential as a bio-agent for Fusarium antagonism [Sclerostagonospora sp., Setomelanomma holmii, Epicoccum nigrum, Boeremia exigua, and Fusarium sp. against the dieback-causing fungus, H. fraxineus, and it was observed that these endophytes are potential BCAs [Hypoxylon rubiginosum on H. fraxineus, and it was determined that this endophyte has potential as a BCA due to the production of metabolites that are toxic to the pathogen [Chitinase has been used in agriculture during crop cultivation for disease management, improved growth, and greater yields . Kumar eroot rot ,145. IAAroot rot . Trinh etagonism . Fungal tagonism . For exaial BCAs . Haleckepathogen ,148. ThiPseudomonas, Bacillus, and Trichoderma [Pseudomonas (P. pudida 06909) was used as a biocontrol agent against Phytophthora root rot within citrus orchids [P. chlororaphis has antagonistic effects against the cacao rot pathogen Ph. Palmivora [Bacillus amyloliquefaciens isolated from ginseng rhizosphere induced systemic resistance to Ph. cactorum [Trichoderma virens, Trichoderma harzianum, Trichoderma asperellum, and Trichoderma spirale isolated from cocoa show antagonistic effects against Ph. Palmivora [Trichoderma saturnisporum also showed antagonistic effects against the Phytophthora spp. [Trichoderma spp. against R. solani including secondary metabolite genes, siderophores genes, signalling molecular genes, cell wall degradation enzymatic genes, and plant growth regulatory genes [Trichoderma for biocontrol against R. solani [Trichoderma has the ability to generate chitinase, which can minimise the survival of R. solani through the activation of the expression of chitinase genes [Phytophthora pathogens [Pseudomonas fluorescence isolated from the flowering vine saw greenbrier, which showed antagonistic effects against P. parasitica, P. cinnamomi and P. palmivora, as well as Burkholderia spp. isolated from the herb huperzine showing the ability to inhibit the growth of P. capsici. The isolate Acinebacter calcoaceticus from soybeans showed antagonistic effects against P. sojae. An isolate from a tomato plant (Bacillus cereus) helped to reduce the infection severity of P. capsici associated with cacao trees. Several strains of bacteria isolated from cucurbits including Bacillus, Cronobacer, Enterobacteriaceae, Lactococcus, Pantoea, and Pediococus showed antagonistic activity against P. capsici using various biocontrol mechanisms. Some fungal examples include species of Trichoderma, Pestalotiopsis, and Fusarium which were isolated from cacao trees and illustrated antagonism against P. palmivora. The fungus Muscodor crispans was isolated from a pineapple plant and showed inhibition properties against P. cinnamomi and P. palmivora. Hernando Jos\u00e9 et al. (2021) discuss numerous other bacterial and fungal strains that showed biocontrol activities and mechanisms against P. capsici, P. infestans, P. citricola, P. cactorum, and P. pini [Phytophthora species, but there are minimal studies regarding P. alni.The most commonly used biocontrol agents belong to the genera choderma . For exa orchids , P. chloalmivora , and Baccactorum . In addialmivora , and Triora spp. ,153. Abbry genes . Further. solani . Moreovese genes . Hernandathogens . Some ba P. pini . It is eA. glutinosa resistance to P. alni [P. alni using in vitro and in planta analysis with a cyclolipopeptide (CLP)-producing Pseudomonas veronii metabolite (PAZ1) [In recent studies, a greater focus has been placed on ways to detect and diagnose tree diseases, understand the interactions between trees and pathogens, develop disease-resistant trees, and ultimately optimise soil and tree microbiomes to improve plant health and behaviour ,158,159. P. alni . These i P. alni . Zaspel e (PAZ1) . It was P. lateralis, Sitka spruce and white pine weevil resistance, Loblolly pine and fusiform rust resistance, Pinus radiata and Dothistroma pini resistance, Koa and koa wilt resistance, American beech and beech bark disease resistance, and Dutch elm disease [A. glutinosa to P. alni; however, this project appears to be complete since 2018 [Alnus genus coupled with identifying species-specific biocontrol agents to minimise the infection of the pathogen P. alni will greatly aid in the protection of the Alnus species.In order to aid the protection and integrity of forestry, natural genetic resistance breeding programmes of several species against biotic stressors have been studied . Example disease ,162,163. disease ,164. Sin disease . The Insnce 2018 . A greatR. solani due to the presence of several species of Proteobacteria, Firmicutes, and Actinobacteria, which play a role in disease suppression. Santhanam et al. (2015) showed that synthetic root-associated microbiota transplants using a mixture of native bacterial isolates  were effective at reducing the wilt disease of tobacco Nicotiana attenuate and that they increased crop resilience [Enterobacter hormaechei and Brevundimonas naejangsanensis, to enhance the productivity of inoculated chickpeas seeds, and it was observed that the consortium increased plant-growth attributes, yields, nutritional content, levels of IAA, siderophore, ammonia, phosphate solubilisation, and potassium solubilisation, as well as antagonistic activity against Fusarium sp. due to successful manipulation of the plant microbiome [Pseudomonas strains isolated from the medicinal plant M\u0101nuka, and it was determined that the bacterial strains aided the pathogenic resistance of P. syringae, indicating that microbe transfer can be successful in reducing disease severity [The practice of microbiome engineering has been applied recently to enhance human well-being, agricultural efficiency and combat challenges of bioremediation and contamination within the environment ,170. Thisilience . Mukherjcrobiome . Wicaksoseverity . There iPhytophthora alni. Other Phytophthora species may also contribute to Alder decline, as well as other pests and pathogens to a lesser extent. Understanding the beneficial and pathogenic microbiota associated with Alder is crucial for developing biological solutions to control these threats. Forest trees have many relationships with a wide variety of microbial organisms, which are essential for tree health, nutrient conditions, and ecosystem functionality. Beneficial microbiota, such as PGPR/F, are present in the tree\u2019s endosphere, phyllosphere, and rhizosphere, providing benefits such as nutrient fixation, hormone production, pathogen suppression, and improved plant growth. Research associated with the microbiota of Alnus species is limited and mainly focuses on the root and rhizosphere soil. Bacterial phyla such as Actinobacteria, Acidobacteria, Proteobacteria, Bacteroidetes, and Firmicutes, as well as fungal phyla including Ascomycota, Basidiomycota, Ectomycorrhizal fungi, Glomeromycota, and Zygomycota, have been identified in association with the roots and rhizosphere of Alder trees.The Common Alder plays a significant ecological role and has many commercial uses; however, the native species is under threat of decline due to the known causal agent P. alni. Biocontrol agents have the ability to induce mechanisms to suppress pathogenic infections by direct attack on the pathogen, competition for resources, and indirectly due to a systemic stress response resulting in improved defence and resistance. The identification of species-specific biocontrol agents will aid in the protection of Alder trees from this disease threat. Also, the application of PGPR and PGPF to Alder affected by this disease could potentially pave the way to control its spread. The identification of biocontrol agents which can persist in sufficiently large populations within the microbial communities associated with Alder, and are capable of effectively expressing their biocontrol genes, is a very promising approach to minimise the severity and spread of devastating diseases of Alder and other important tree species. Another current knowledge gap that exists within this sector includes a detailed understanding of the systemic Alder microbiome and its seasonal and geographical dynamics. It is important to understand the different varieties and species of Alder as well as the type of microbes present in tolerant versus susceptible genotypes that can be exploited to improve the health of future Alder stands. Furthermore, having the ability to identify effective Phytophthora BCAs that can systematically colonise the tree and persist for long periods of time will aid the long-term survival of Alder to (a)biotic stressors. However, greater knowledge is required to identify effective methods of BCA inoculation of new and existing Alder stands, as well as what positive/negative effects these BCAs have on non-target microbial species within Alder stands.Although, there is limited information available on the microbial communities in other parts of Alder trees, such as the leaves, bark, and catkins. Further research is needed to explore the microbial communities within different compartments of Alder trees and their potential interactions. Understanding the core microbiome of Alder and its functional roles will help improve our knowledge of Alder tree health, growth, and tolerance to (a)biotic stressors. Additionally, exploring the use of plant growth-promoting microbes in the forestry sector may result in beneficial applications for sustainable tree production and protection against pathogens. A greater global focus is needed regarding the breeding of microbe-optimised Alder trees that have a degree of resistance to infection caused by"}
+{"text": "Connexins (Cxs) form gap junctions through homotypic/heterotypic oligomerization. Cxs are initially synthesized in the endoplasmic reticulum, then assembled as hexamers in the Golgi apparatus before being integrated into the cell membrane as hemichannels. These hemichannels remain closed until they combine to create gap junctions, directly connecting neighboring cells. Changes in the intracellular or extracellular environment are believed to trigger the opening of hemichannels, creating a passage between the inside and outside of the cell. The size of the channel pore depends on the Cx isoform and cellular context-specific effects such as posttranslational modifications. Hemichannels allow various bioactive molecules, under ~1 kDa, to move in and out of the host cell in the direction of the electrochemical gradient. In this review, we explore the fundamental roles of Cxs and their clinical implications in various neurological dysfunctions, including hereditary diseases, ischemic brain disorders, degenerative conditions, demyelinating disorders, and psychiatric illnesses. The influence of Cxs on the pathomechanisms of different neurological disorders varies depending on the circumstances. Hemichannels are hypothesized to contribute to proinflammatory effects by releasing ATP, adenosine, glutamate, and other bioactive molecules, leading to neuroglial inflammation. Modulating Cxs\u2019 hemichannels has emerged as a promising therapeutic approach. Gap junctions, assembled from connexins (Cxs), are crucial for direct cell-to-cell communication . The expMultiple sclerosis (MS) is a demyelinating disease that affects the central nervous system (CNS). It has profound implications on the intricate CNS landscape. MS lesions involve a complex interplay between infiltrating inflammatory cells, demyelinated neurons, and activated glial cells. Within this environment, activated microglial cells clear cellular debris, and activated astroglial cells encircle the lesion site . Notably+ buffering, H+/Ca2+ regulation, neurotransmitter uptake , the control of cerebral blood flow, water transport, oxidant neutralization, and glucose transport  imbalance and astrocyte activation, which might harm astroglia survival and affect astrocyte-to-neuron support, making neurons more vulnerable to inflammation and subsequent immune challenges. [Ca2+] imbalances from these channels can harm astroglia survival and neuron support, making neurons more vulnerable to inflammation and subsequent immune challenges. Maternal inflammation can also trigger excitotoxicity through these channels, further harming neurons. Understanding hemichannels and pannexons in maternal inflammation-induced brain problems is vital for developing pharmacological therapies for affected offspring.In postmortem brains of autism spectrum disorder (ASD) patients, Cx43 expression is increased in the superior frontal cortex. This increase in Cx43 also indicates a relationship between glial inflammation and ASD mechanisms . RecentlBrain metastasis from various cancers is a major cause of illness and death, often resistant to chemotherapy. Chen et al. explore the role of astroglia, the most abundant brain cells, in promoting brain metastasis. Breast and lung cancer cells express protocadherin 7 (PCDH7), facilitating the formation of gap junctions between cancer cells and astroglia using Cx43. This connection allows the transfer of cyclic guanosine monophosphate\u2013adenosine monophosphate (cGAMP), a second messenger, to astroglia, triggering the STING pathway and the release of inflammatory cytokines. These cytokines, acting as paracrine signals, activate pathways in metastatic cells, promoting tumor growth and drug resistance. Meclofenamate and tonabersat, drugs modulating gap junctions, disrupt this signaling loop, offering a potential treatment for established brain metastasis . RegardiIn this review, we focus on the discovery, basic research, translational research, and clinical implications related to gap junctions and hemichannels, including Cxs and pannexins. Given the widespread presence of Cx/pannexin-expressing cells throughout the body, disturbances in homeostatic functions, whether congenital or acquired, can lead to various disorders. Open hemichannels release bioactive small molecules like ATP, adenosine, glutamate, and more, thereby activating neighboring cells and promoting inflammation. Consequently, hemichannel blockers are emerging as promising drug candidates.Gap junctions within the CNS are crucial structures, enabling intercellular communication through Cx proteins. They go beyond mere structural components and play intricate roles in the pathogenesis of various neurological disorders. To understand their profound impact, we must delve into the complex web of cellular interactions within the CNS. Neurons and glial cells, including astroglia and oligodendrocytes, create an interconnected network through gap junctions, facilitating the rapid exchange of ions, metabolites, and signaling molecules. However, disruptions in this network can lead to severe CNS disorders, including epilepsy, multiple sclerosis, Alzheimer\u2019s disease, autism spectrum disorders, ischemic brain lesions, demyelinating disorders, and more. Understanding gap junctions\u2019 multifaceted role in these conditions is crucial for modern neuroscience. One promising avenue of research involves selectively modulating gap junction and hemichannel activity to develop novel drugs. Scientists aim to restore normal cell communication and inhibit excessive signaling, potentially revolutionizing the treatment of CNS disorders.In conclusion, Cxs form complex communication channels in the CNS. Their study offers hope for innovative therapies and improved outcomes for those with CNS disorders."}
+{"text": "Gestational diabetes mellitus (GDM) is an intractable issue that negatively impacts the quality of pregnancy. The incidence of GDM is on the rise, becoming a major health burden for both mothers and children. However, the specific etiology and pathophysiology of GDM remain unknown. Recently, the importance of gut microbiota and related metabolic molecules has gained prominence. Studies have indicated that women with GDM have significantly distinct gut microbiota and gut metabolites than healthy pregnant women. Given that the metabolic pathways of gut flora and related metabolites have a substantial impact on inflammation, insulin signaling, glucose, and lipid metabolism, and so on, gut microbiota or its metabolites, such as short-chain fatty acids, may play a significant role in both pathogenesis and progression of GDM. Whereas the role of intestinal flora during pregnancy is still in its infancy, this review aims to summarize the effects and mechanisms of gut microbiota and related metabolic molecules involved in GDM, thus providing potential intervention targets. Gestational diabetes mellitus (GDM) is the most common metabolic complication of pregnancy, affecting up to 25.5% of pregnant women ,2. It isUntil now, the specific etiology and pathophysiology of GDM are still unknown. Profound hormonal, metabolic, and immunological changes that occur during pregnancy may be important contributors to GDM . The firThe 16S sequencing method, metabolomics, and next-generation sequencing (NGS) platforms all assist us in better comprehending the relationship between gut microecology and diseases . The samFirmicutes and Bacteroidetes are the most abundant forms of bacteria in gut flora, followed by Actinomycetes and Proteobacteria . To prepFaecalibacterium and Eubacterium were identified to be over-represented in the first trimester [Akkermansia, Bifidobacterium, and Firmicutes, were hypothesized to be increased in the third trimester, and proinflammatory bacteria Proteobacteria and Actinobacteria were also augmented [Most studies agreed that the abundance of gut bacteria associated with energy storage promotion and inflammatory states might increase during pregnancy. Butyrate-producing bacteria such as rimester . At the ugmented ,28,29. Sugmented . Moreoveugmented ,25. Fecaugmented  and inteugmented ,32.Pregnant women with GDM are characterized by higher IR and glucose intolerance during pregnancy as compared to healthy pregnant women . PreviouEmerging studies have concentrated on alterations of intestinal flora and related metabolites during GDM. Most studies have revealed that women with GDM had significant differences in beta diversity  and lower alpha diversity (the number of species present in the given community) ,37,38,39Ruminococcaceae family was significantly augmented during early pregnancy in women who later progressed to GDM compared to those without developing GDM [Ruminococcaceae family abundance was related to impaired glucose homeostasis, probably via boosting inflammatory state and consequent impairment of insulin metabolism [Eisenbergiella, Tyzzerella 4, and Lachnospiraceae NK4A136 were enriched in the GDM group compared to controls who were matched with age, gestational age, and sample collection date [Eisenbergiella and Tyzzerella 4 were positively correlated with fasting blood glucose levels [Lachnospiraceae spp., and Rothia were considerably reduced, whereas Enterobacteriaceae, Ruminococcaceae spp., and Veillonellaceae were augmented in GDM women. Furthermore, Hu et al. affirmed the predictive power of microbial alterations; they demonstrated that the abundance of Staphylococcus relative to Clostridium, Coriobacteriaceae, and Roseburia was positively correlated with fasting blood glucose and postprandial glucose level [Changes appear in early pregnancy. A case-control study with 75 overweight participants that thoroughly removed any confounding factors discovered that the relative abundance of the ping GDM . Greatertabolism ,45. It rion date . They ale levels . Functioe levels . In a nese level .P. distasonis, Klebsiella variicola, and Catenibacterium mitsuokai, which were positively associated with maternal glucose levels, were revealed to be elevated during the second trimester in women with GDM compared to women without GDM. In comparison, the levels of beneficial butyrate-producing bacteria, including Alistipess spp., Bifidobacterium spp., Eubacterium spp., and Methanobrevibacter smithii, were lowered [Bifidobacterium spp., Eubacterium spp., were depleted while Corynebacterium spp., Lactobacillus spp., and Blautia hydrogenotrophica were enriched in GDM patients [Blautia and Eubacterium hallii group, with a reduction in the richness of Faecalibacterium in GDM patients who failed to control glycemic [Ruminococcus bromii, Clostridium colinum, and Streptococcus infantis were significantly associated with the GDM samples. Moreover, S. infantis were positively associated with blood glucose levels after adjusting for body mass index (BMI) [Bacteroides caccae, Bacteroides massiliensis, and Bacteroides thetaiotaomicron, with a lower abundance of Bacteroides vulgatus, Eubacterium eligens, Lactobacillus rogosae, and Prevotella copri were detected in women with GDM [Bacteroides and Lachnoclostridium were more abundant, but Ruminococcaceae UCG-002, Ruminococcaceae UCG-005, Clostridium sensu stricto 1, and Streptococcus were reduced in the GDM group. Further, Paraprevotella, Roseburia, Faecalibacterium, and Ruminococcaceae_UCG-002 were significantly negatively correlated with glucose. Ruminococcaceae_UCG-002 was significantly negatively correlated with hemoglobin A1c. Bacteroides were significantly positively correlated with glucose, while Sutterella, Oscillibacter, and Bifidobacterium were significantly positively correlated with glucagon-like peptide-1 [Gut microbiota dysbiosis in women with GDM also occurs during the second trimester. Pathobionts, such as  lowered . Moreove lowered . Chen etpatients . Ye and glycemic . It was glycemic . Simultaglycemic . Wei et ex (BMI) . A crosswith GDM . Accordiwith GDM . Liang eeptide-1 .Akkermansia genus was enhanced in women with GDM [Faecalibacterium was found to decrease substantially [Collinsella, Desulfovibrio, and Rothia at the genus level were more abundant in GDM women [Akkermansia were associated with decreased insulin sensitivity, while Christensenella OTUs were associated with greater fasting plasma glucose concentration in GDM women [Ruminococcus and Prevotella were increased, while Bacteroides, Eubacterium, and Firmicutes were reduced in women with GDM during the third trimester [Haemophilus abundances were found in women with GDM compared to weight-matched controls [Firmicutes, and a lower proportion of Bacteroides than healthy controls [Coprococcus and Streptococcus levels, and suppressed interbacterial interactions, which may potentially serve as early biomarkers for GDM [During the third trimester, the with GDM , while tantially . AccordiDM women . After aDM women . CrusellDM women . Accordirimester ,52. In acontrols . Howevercontrols . Dynamic for GDM  , and a decrease in bacteria with probiotics properties [In a nutshell, despite many studies focusing on gut microbiota in GDM, the findings are inconclusive. Disparities in these findings can be attributed to sample size, geographical location, study design, and participant selection criteria  . Moreoveoperties ,47,50,54Currently, research into the underlying mechanisms involving GDM and gut microbiota dysbiosis is at the preliminary stage. Many studies have reported that changes in gut microecology were associated with decreased insulin sensitivity, higher plasma glucose concentration, and greater BMI in GDM women. These changes appear to begin in early pregnancy and last for several months after delivery, negatively affecting intestinal function.Akkermancia muciniphila, butyrate-producing bacteria, including Roseburia and Faecalibacterium prauznitzii, were reduced [Studies also indicated that pregnant women with GDM tend to have a significantly higher pre-pregnancy BMI than women without GDM ,43. Over reduced ,58,59. A reduced ,64,65,66 reduced .GDM is usually accompanied by hyperglycemia and IR. Human metagenome-wide association studies in patients with type 2 diabetes demonstrated highly significant correlations between hyperglycemia and IR and specific intestinal bacteria, bacterial genes, and associated metabolic pathways . HyperglHypotheses have been put forward that changes in microecology may be related to GDM by affecting intestinal barrier function, glucose metabolism disorder, energy accumulation, and other ways.Prevotella and Akkermansia levels are reported to be elevated in women with GDM. They are mucin-degrading pathobionts, which can increase mucin oligosaccharide degradation beyond the normal limit, leading to gut barrier dysfunction and leaky gut [Zonulin, which is released by the liver and gut epithelial cells, is a physiological tight junction modulator and a potential predictor of gastrointestinal permeability ,79. Receeaky gut ,82. Addieaky gut ,35. Elhaeaky gut . TherefoPrevotella, Haemophilus, and Desulfovibrio in both mid and late pregnancy [+Ser307 (IRS-1+Ser307), resulting in suppression of phosphatidylinositol 3-kinase (PI3-K) and protein kinase BSer473 (AktSer473). This procedure will impair insulin signaling and reduce glucose uptake in peripheral tissues, resulting in hyperglycemia in GDM women [The other feature of gut microbiota dysbiosis in women with GDM is the elevated level of gram-negative bacteria, including regnancy ,38,42,52regnancy ,52. Elevregnancy . Elevateregnancy ,79. Furtregnancy ,72,73. TDM women ,72,73 , amino acids, and so on. Metabolomics analysis has revealed that these metabolites were significantly altered in women with GDM, especially SCFAs.SCFAs are derived from microbiota-accessible carbohydrates (MACs) fermented in the colon from dietary fibers and resistant starch fermentation ,85. TheyFaecalibacterium, Roseburia, and Bifidobacterium, produce butyrate, whereas Bacteroidetes produce acetate and propionate [As mentioned above, the amount and types of SCFAs are largely determined by the number of SCFA-producing bacteria. The Firmicutes phylum, particularly opionate . The majopionate ,99.Faecalibacterium, Bifidobacterium, Ruminococcus, Roseburia, Coprococcus, Akkermansia, Phascolarctobacterium, and Eubacterium were deficient in women with GDM and were inversely correlated with glucose tolerance [Phascolarctobacterium, Faecalibacterium, and Bacteroidetes also occur in women with GDM, which lead to excessive butyrate, isobutyrate, isovalerate, acetic and propionic production [Alterations in the abundance of SCFA-producing bacteria have been reported in women with GDM. The compositions of SCFA-producing genus olerance ,48,51,53olerance ,100. Inaolerance ,48. Simuolerance ,48. At tolerance . On the oduction ,101. Excoduction . Additiooduction ,102. BotAkkermansia, Bifidobacterium, and Firmicutes, were augmented during the third trimester in healthy pregnant women. However, bacterium levels appeared to be lower in the second trimester [Akkermansia levels were higher in the third trimester in women with GDM [Bacteroidetes was reported to be elevated in GDM women and was positively correlated with blood glucose. Bacteroidetes is considered a gram-negative bacterium that can produce a proinflammatory marker\u2014LPS [Apart from the effect of SCFA on energy storage, changes in the gut microbiota of women with GDM may also have a direct impact on energy storage. It was reported that bacteria associated with energy storage promotion, such as rimester ,36,47, wwith GDM ,51. Hencwith GDM ,62,86. Orker\u2014LPS . It may rker\u2014LPS ,38,103.Clostridium, Fusobacterium, and Eubacterium were decreased in GDM women compared to healthy pregnant women [Moreover, aromatic amino acids (AAA)-degrading bacteria such as nt women ,37. Thatnt women . Since Ant women . This nent women . HoweverAs GDM has become a major health burden for both mothers and children, it is critical to propose effective prevention and treatment strategies. Nonetheless, pregnancy is a unique time, and treatment must take the safety of the fetus into account. In the United States, insulin is currently the first-line agent recommended for the treatment of GDM, whereas metformin and glyburide are not because they can cross the placenta to the fetus and cause neonatal hypoglycemia . Hence, Collinsella (a genus closely linked to higher blood glucose) and Sutterella (a Proteobacteria linked to inflammatory status), and higher serum zonulin levels [Lifestyle behavior change, including dietary restriction and exercise, is the first line of GDM management , which an levels ,113,114.n levels .Roseburia hominis, which raises butyrate concentrations in both humans and mice [Exercise, on the other hand, has been shown to strengthen gut health by increasing microbiome diversity and balancing beneficial and pathogenic bacterial communities ,116,117.and mice . It can and mice .Lactobacillus salivarius UCC118 [Probiotics and prebiotics are live microorganisms that benefit the host when administered in adequate amounts . As prevs UCC118 . Differes UCC118 ,124. Thes UCC118 .The scope of this review is limited because research into the gut and GDM is still in its early stages. Moreover, the results may be affected by the different study designs and participant selection criteria . We believe it is necessary to further investigate the changes in intestinal flora before the occurrence of hyperglycemia in GDM to provide new approaches for GDM prevention.Although the abnormalities of the intestinal tract may not be the initial factor of GDM, it has been considered to participate in the pathological process of GDM greatly. Women with GDM have significantly distinct gut microbiota and gut metabolites than healthy pregnant women. In turn, the alerted gut microecology and related metabolites substantially impact intestinal barrier function, inflammation, insulin signaling, glucose metabolism, lipid metabolism, and energy accumulation, playing a significant role in both the pathogenesis and progression of GDM. Dietary restrictions, exercise, and probiotics (prebiotics), which can reverse the altered gut microbiota and metabolites, may help alleviate symptoms of GDM."}
+{"text": "The development of triboelectric nanogenerators (TENGs) over time has resulted in considerable improvements to the efficiency, effectiveness, and sensitivity of self-powered sensing. Triboelectric nanogenerators have low restriction and high sensitivity while also having high efficiency. The vast majority of previous research has found that accidents on the road can be attributed to road conditions. For instance, extreme weather conditions, such as heavy winds or rain, can reduce the safety of the roads, while excessive temperatures might make it unpleasant to be behind the wheel. Air pollution also has a negative impact on visibility while driving. As a result, sensing road surroundings is the most important technical system that is used to evaluate a vehicle and make decisions. This paper discusses both monitoring driving behavior and self-powered sensors influenced by triboelectric nanogenerators (TENGs). It also considers energy harvesting and sustainability in smart road environments such as bridges, tunnels, and highways. Furthermore, the information gathered in this study can help readers enhance their knowledge concerning the advantages of employing these technologies for innovative uses of their powers. Triboelectric nanogenerator (TENG) technology was first presented in 2012, and since then, it has become one of the most significant technological advances in the world of energy collection . The TENTriboelectric nanogenerators, more often known as TENGs, are an innovative type of energy generator that was publicly shown for the first time in 2012 ,75,76,77A TENG generates alternating current as a result of its reciprocating action. The contact separation mode of a TENG is depicted in Many sensing technologies have been created due to the rapid growth of structural health monitoring systems ,87,88,89Triboelectric nanogenerators can be the source of power for the health monitoring of bridges , polytetrafluoroethylene (PTFE), polyvinylidene fluoride (PVDF), and their composites. Conductive materials: indium tin oxide (ITO), graphene, carbon nanotubes (CNTs), and silver nanowires. Substrate materials: flexible and durable materials such as polyimide, polyethylene terephthalate (PET), or polyethylene naphthalate (PEN). Encapsulation materials: to protect the TENG-based sensor from environmental factors, materials like epoxy resins or silicone elastomers are commonly used.Self-powered sensor based on triboelectric nanogenerators for tunnels: Similar to bridge applications, polymeric materials  and conductive materials  are frequently used. Special attention is given to materials with high durability and resistance to moisture, dust, and harsh underground conditions.Self-powered sensor based on triboelectric nanogenerators for highways: Materials used in highway applications are typically selected for their robustness, flexibility, and resistance to weathering. Flexible polymers, such as PDMS, PTFE, and PVDF, are commonly employed due to their resilience and ability to withstand external forces. Conductive materials, including ITO, graphene, CNTs, and silver nanowires, are used to ensure efficient charge transfer and conductivity.Smart infrastructure to harvest energy from roads: Materials used for energy harvesting systems integrated into roads should possess high piezoelectric or triboelectric properties. Piezoelectric materials: lead zirconate titanate (PZT), zinc oxide (ZnO), polyvinylidene fluoride (PVDF), and its copolymers. Triboelectric materials: PDMS, PTFE, PVDF, and their composites, as well as materials with high triboelectric coefficients, like polyamide or polyethylene.Self-powered vehicle sensors based on triboelectric nanogenerators for road intelligent systems: Similar to bridge and highway applications, flexible polymers  and conductive materials  are commonly used. Additionally, pressure-sensitive materials, such as pressure-sensitive films or elastomers, are employed to capture vehicle-related parameters.Smart pedestrian crossing system based on triboelectric nanogenerators: Materials used in smart pedestrian crossing systems require good triboelectric properties and mechanical resilience. PDMS, PTFE, PVDF, and their composites are commonly used for the triboelectric layers. For the structural components, flexible and durable materials like PET, PEN, or elastomers are employed.Self-powered sensors based on triboelectric nanogenerators (TENGs) offer promising opportunities for transportation applications, including bridges, tunnels, highways, smart infrastructure, road intelligent systems, smart pedestrian crossing systems, and monitoring driving behaviors. The selection of appropriate materials is crucial for optimizing the performance and efficiency of TENG-based sensors in each application. Here, we discuss the different materials commonly employed in these specific scenarios:In addition to intelligent automobiles, intelligent roads are also a significant component. Finally, there are several materials, designs, and structures that hold promise for further exploration and development.Materials: Researchers should continue to investigate advanced materials with enhanced triboelectric properties and mechanical resilience. This includes exploring new polymeric materials, such as polymethylpentene (PMP), thermoplastic polyurethane (TPU), or composites with improved performance. Additionally, the exploration of novel conductive materials like carbon-based nanomaterials, metal oxides, or conducting polymers can contribute to higher charge transfer efficiency.Designs: The design of TENGs for intelligent transportation infrastructure should focus on maximizing energy conversion efficiency and system integration. Novel design approaches, such as multilayered structures, hierarchical structures, or patterned surface modifications, can enhance the overall performance of TENGs. Exploring innovative electrode designs, such as microstructured surfaces or three-dimensional architectures, can also improve energy harvesting capabilities.Structures: Researchers should explore adaptable and scalable TENG structures to accommodate various transportation infrastructure applications. Developing flexible and conformable TENGs that can be easily integrated into different surfaces, such as bridges, highways, and tunnels, is crucial. Additionally, investigating self-powered sensing systems with distributed TENGs to enable large-scale monitoring and data collection would be beneficial.According to self-powered sensors based on triboelectric nanogenerators (TENGs) with attractive characteristics of high sensitivity, low limitation, and high efficiency, TENGs have recently been researched and have significantly benefited self-powered sensing. The TENG is anticipated to contribute significantly to the construction of smart roads, which will benefit the entire road system, including bridges, tunnels, and freeways. A number of the applications, including energy harvesting, self-powered sensing, and self-adaptation, have eventually been developed and come into use as the process has continued. The information in this article will be useful for industrialists associated with transportation engineering, including bridges, highways, and tunnels who work on self-powered sensors, energy harvesting, and sustainability. In the present study, the application of self-powered sensors based on triboelectric nanogenerators (TENGs) in intelligent road environments was described along with the monitoring of driving behavior. An overview of triboelectric nanogenerators for intelligent road environments was also presented."}
+{"text": "The ocean covers 71% of the surface of our planet and comprises a diverse variety of biological resources\u2014a combination of marine animals, marine plants, and marine microorganisms that have economic value for human beings. Some of them can be used directly as food, and others may be developed into high-value healthy food, marine drugs, or novel materials.https://www.un.org/en/global-issues/population). The global food supply will face a significant challenge. Seafood plays an important role in the global food supply system. In 2020, global production of marine animals and marine algae was estimated at 112 million tonnes and ~34 million tonnes (wet weight), respectively, as reported by the Food and Agriculture Organization of the United Nations (FAO) [The world\u2019s population reached 8 billion people and will reach 9.7 billion in 2050  (https:/Currently, an increasing number of people are concerned about the nutritional and healthy benefits of food, rather than only being a source of energy. Marine biological resources contain a large number of bioactive molecules that are beneficial to human health. The development and application of novel technologies for extracting nutrients and bioactive ingredients from marine biological resources will produce a diversity of high-value nutritional food, healthy food, special medical food, cosmetic products, medical materials, and marine drugs. Therefore, high-value utilization of marine biological resources can also benefit human health and the global blue economy.Marine biological resources include various seafood, seafood processing by-products, and inedible marine microbial resources. Seafood, such as marine fish, marine shrimp, marine crab, scallops, oysters, squid, jellyfish, sea cucumber, sea urchin, kelp, wakame, sargassum, and seaweeds, etc., contains several proteins, enzymes, peptides, polysaccharides, omega-3 long-chain polyunsaturated fatty acids, astaxanthin, taurine, saponin, vitamins, etc. . HoweverAlthough seafood contains many nutrients and bioactive substances, it may not be completely absorbed and fully display its functions in our body without further processing. The deep-processing of seafood is an application of advanced processing technologies, including supercritical fluid extraction technology, microencapsulation technology, ultra-micro pulverization technology, membrane separation technology, enzyme technology, fermentation technology, etc., for the production of a diversity of high-value healthy food, functional food, and special medical food.Engraulis ringens, shrimp Antarctic krill, seaweed Ulva prolifera, and jellyfish. However, those marine animals and plants are also rich in plenty of bioactive molecules, which can be used as raw materials to produce high-value products such as fish peptides, surimi, shrimp oil with omega-3, EPA, and DHA, chitin/chitosan/chitooligosaccharide, jellyfish peptides, etc. [Seafood processing by-products are usually discarded as garbage or made into low-value animal feed or fertilizer, which may also cause environmental pollution and marine biological resource waste. Seafood processing by-products still contain many bioactive components, such as residual proteins, collagen in fish skin, chitin in the shells of shrimp and crab, chondroitin sulfate in fish cartilage, enzymes in animal visceral organs, fucoidan in algae waste, minerals in the shells of scallops and oysters, etc. . These aes, etc. .Although marine microorganisms cannot be directly used as food for humans, they contain many kinds of special enzymes as a result of the harsh living conditions with high salinity, extensive pH, a wide temperature range, and high pressure. Marine-derived enzymes such as chitinase, chitosanase, alginate lyase, agarase, carrageenase, \u03b1-amylase, xylanase, lipases, proteases, and collagenases can specifically recognize and degrade substrates into low-molecular-weight and highly active oligosaccharides, monosaccharides, peptides, or lipids, which can be applied to food, healthcare, cosmetics, agriculture, and the pharmaceutical industry ,7.At present, our understanding, development, and utilization of marine biological resources are still very limited and face many challenges. We believe that with the progress of scientific research and the development of new biotechnologies, the high-value utilization of marine biological resources will further benefit human health and life in the future.This Special Issue aims to publish high-quality articles on the high-value utilization of marine biological resources from a wide range of aspects, including deep-processing of seafood, high-value utilization of seafood processing by-products and low-value seafood, and the identification and characterization of enzymes from marine organisms for potential application in the food industry to produce food materials or additives such as chitosan, carrageenan, and gelatin."}
+{"text": "Since the creation of the glucose enzyme sensor in the early 1960s by Clark and Lyons . BiodeviImportant analytical bioinformation can continuously be accessed in real time for biomedical, nutritional, therapeutic, healthcare, wellness, and disease-management applications with a new generation of advanced biosensors. The biosensing can be conducted with small molecules, including dopamine and uric acid serving as bioindicators of vital physiological functions in the complex matrix, helped by electrochemical techniques ,5. The cRelevant biochemical markers in breath have been associated with many diseases, including cystic fibrosis, diabetes, heart failure, and lung cancer , making"}
+{"text": "Patients with complicated wound care, rashes, desquamating skin disorders and necrotizing soft tissue infections are often transferred to burn centers due to the multi-disciplinary expertise in wound care despite the pathophysiology of burn injury being different. Our objective was to critically evaluate outcomes of patients admitted to our institution with skin disorders to patients with burn injury.Patients were identified using Institutional Burn Center registry, and linked to the clinical and administrative data. All adult patients admitted between January 1, 2012 and June 30, 2022 were eligible for inclusion. Demographics, length of stay (LOS), and mortality were evaluated. Bivariate logistic regression and inverse probability of treatment weighting (IPTW) was performed, and significance was accepted as p< 0.05.We included 9,821 patients in the study, of whom 805 (8.2%) were admitted with skin disorders. These patients were more likely to be older, Black, of female sex, have longer ICU stays, be on mechanical ventilation, and have complications, p< 0.001. Unadjusted estimates show that patients with skin disorders had 3.84 higher odds of mortality compared to patients admitted for burn injury. However, after adjusting for age, involved body surface area, sex, race, intensive care unit days, mechanical ventilation, inhalation injury, and complications using IPTW, patients with skin disorders twice higher odds of mortality.Patients with skin disorders have increased morbidity and mortality compared to burn injured patients even when controlling for age, involved body surface area, sex, race, intensive care unit days, mechanical ventilation, inhalation injury, and complications when admitted to our burn unit. Further study is warranted to investigate and mitigate these outcome disparities in this patient population.This study may demonstrate that all skin conditions are not the same, and may warrant different specialties to improve and optimize outcomes."}
+{"text": "Essential oils are a mixture of natural aromatic volatile oils extracted from plants. The use of essential oils is ancient, and has prevailed in different cultures around the world, such as those of the Egyptians, Greeks, Persians, and Chinese. Today, essential oils are used in traditional and complimentary medicines, aromatherapy, massage therapies, cosmetics, perfumes and food industries. The screening effect of essential oils has been studied worldwide. They demonstrate a range of biological activities, such as antiparasitic, antifungal, antibacterial, antiviral, antioxidant, anti-inflammatory, anticancer, antiaging, and neuroprotective properties. In this scoping review, we provide a 10-year updated comprehensive assessment of volatile oils and their effects on the nervous system. MEDLINE, Scopus, and Google Scholar were systematically and strategically searched for original studies investigating these effects from 2012 to 2022. Approximately seventy studies were selected as included studies. Among these studies, several outcomes were reported, including antistress, antianxiety, analgesic, cognitive, and autonomic effects. Some essential oils showed developmental benefits, with the potential to induce neurite outgrowth. The neurotransmitter receptor level can also be modified by essential oil application. Physiological and pathophysiological outcome measures were reported. For physiological outcomes, arousal, cognitive performance, circadian eating behavior, emotional modulation, consumer acceptance, preferences, and willingness to buy were investigated. For pathophysiological conditions, pain, depression, anxiety, stress, sleep disorder, mental fatigue, agitated behavior, and quality of life were measured. In conclusion, essential oils showed promising effects on the nervous system, which can be further applied to their use in functional foods, drinks, and alternative therapy. Essential oils (EOs) are the naturally aromatic oily liquids produced by plants, which are responsible for their essence or odor. EOs are found in great quantities in plant oil sacs or oil glands. EOs can be extracted from different parts of plants, including their leaves, barks, flowers, buds, seeds, and peels. As EOs are a concentrated hydrophobic mixture of hydrocarbon volatile compounds that easily evaporate at room temperatures, they are also known as volatile oils. Thus, inhalation via the olfactory system is a common method of use. During the extraction, most volatiles oil are commonly and easily isolated through steam- or hydro-distillation methods. However, for the oils produced from the rind of fruits such as those in the citrus family, the cold-pressed or expressed oils extraction method is usually used. A solvent extraction method is also used for some plant materials that cannot tolerate heat (in steam) or be subjected to cold-pressing, such as the rose, neroli, tuberose, jasmine, and oak . In mostCitrus spp., which includes essential oils such as orange, bergamot, grapefruit, and lemon (24.4%). Rosemary essential oil was the third choice after the lavender oil and Citrus spp. oil (5.51%). Mint, rose, cedar wood, geranium, lemon grass, chamomile, cinnamon, and others were also used, though in smaller amounts. The routes of administration used in the included studies including inhaled, oral, topical, massage, injection, and immersion. Inhalation was the most popular route of administration at approximately 58.57%. There was a wide range of study populations and age groups, as reported in According to the included studies, the effects of essential oils on the nervous system have been widely studied in every region around the world. Several types of essential oils were used in the included studies. In this scoping review, we included both animal and human studies to comprehensively understand the possible mechanisms to outcome measures in humans. The PubMed database showed more specific results than others; however, Scopus and Google Scholar showed more sensitivity than PubMed . Based oJuniperus phoenicea gum extract, Copaifera officinalis  resin, Aniba rosaeodora (Rosewood) wood oil, Juniperus virginiana oil, grapefruit oil, and petitgrain revealed autonomic nervous system (ANS) activity modification via the inhalation route. A massage with lavender and geranium oils also affected the ANS by reducing heart rate and blood pressure after the massage. In the opposite of alertness, lavender improved objective sleep quality. For another type of alertness and arousal, peppermint, rosemary, grapefruit, and cinnamon oils improved vigilance using a vigilance test. In response to olfactory stimuli, the cortisol level and salivary chromogranin A were affected by lavender, bergamot, yuzu, Juniperus phoenicea gum extract, Copaifera officinalis resin, Aniba rosaeodora wood oil, Juniperus virginiana oil, and grapefruit essential oil.Several levels of physiological hierarchy were investigated . At the Juniperus phoenicea gum extract, Copaifera officinalis resin, Aniba rosaeodora wood oil, Juniperus virginiana oil, Origanum majorana, Citrus sinensis, and petitgrain. At the uppermost levels, cognitive functions and behaviors were finally affected by essential oils. Rosemary essential oil improved cognition using a computerized cognitive task. Spearmint and peppermint essential oils modulated performance during a demanding cognitive task and reduced mental fatigue during a prolonged cognitive task. Petitgrain essential oil could improve performance in the workplace when added to an aroma diffuser in the work room. Oregano and rosemary essential oils increased consumer acceptability and willingness to buy food products. Among the positive results, there were also negative results. Lavender could not modulate stress and ANS responses in patients with coronary bypass surgery, which only affected systolic blood pressure. Koteless and Babulka also showed negative effects of rosemary, lavender, and eucalyptus oils on adult volunteers.In addition to the objective measure of stress hormones, these oils also affected subjective emotional measurements. Interestingly, most essential oil use decreased stress and negative emotions with the reduction in stress hormones and parasympathetic stimulation. Anxiolytic effects were reported in lavender, Melissa officinalis  showed an analgesic effect, which can be observed in mice, rats, neonatal, premature babies, and women with dysmenorrhea. Lavender, bergamot, geranium, mountain pepper, chamomile, Juniperus phoenicea gum extract, Copaifera officinalis resin, Aniba rosaeodora wood oil, Juniperus virginiana oil, and Citrus spp. oil showed anxiolytic activity in several types of populations. Other interesting outcomes in different groups of patients were reported as described in Depression was the most studied clinical manifestation related to the effect of essential oils. Lavender, chamomile, bergamot, sweet orange, anise, geranium, and mountain pepper reduced depression in the elderly, postpartum women, restless patients, breast cancer patients, irritable bowel syndrome patients, mixed anxiety and depressive disorder, and residents in a long-term care unit. Analgesic and anxiolytic effects were the second most attractive topics. Lavender, bergamot, and Acori Tatarinowii Rhizoma showed a synergistic effect with the nerve growth factor in pheochromocytoma PC12 cells potentiating neurite outgrowth in an essential oil co-treatment group. Menthol could increase the circadian eating behavior in animal research. The treatment of alpha (\u03b1)- and beta (\u03b2)-pinene could reduce the nitrite level in the hippocampus and lower dopamine and norepinephrine levels in the striatum, resulting in seizure intensity reduction. Ocimum gratissimum essential oil showed anesthetic properties and reduced stress in Nile tilapia during transport. Coriander oil and linalool showed a sedative effect, reducing stress-related behaviors in chicks in a manner similar to the effects of diazepam. Lavender, peppermint, rosemary, grapefruit, bergamot, and yuzu could modulate autonomic nervous system function, resulting in changes in cardiovascular parameters and cortisol release. Citronellol showed a nociceptive effect of orofacial pain via the retrosplenial cortex and periaqueductal gray activations. Bergamot oil also reduced the central sensitization-phase-related pain and agitation behaviors in a mouse model. Peppermint essential oil reduced mental fatigue and prolonged cognitive tasks with acetylcholinesterase inhibitory and gamma-aminobutyric acid A receptor stimulating properties. Geraniol oil also improved learning and memory impairment related to aging.Lavender was one of the essential oils that was completely researched in terms of its safety and mechanisms in humans . From thIn this scoping review, we updated the effects of essential oils on the nervous system for this decade in terms of physiological and pathophysiological conditions. The number of studies on essential oils is increasing year by year, and more mechanisms are being revealed. The PubMed search strategy showed more specific research compared with Scopus and Google Scholar. However, a number of studies were found in the Scopus and Google Scholar databases. In this review, we intended to provide a comprehensive view of this issue. Therefore, we included both animal and human research to completely explain the beneficial properties and related mechanisms. We did not perform risk of bias in this systematic scoping review. Most of the excluded studies were not related to nervous system function and were written in other languages. The population covered in this review is broad, as reported in It is not only the olfactory system that plays a role in this intervention; the direct effect of odorant compounds also takes part in the central nervous system . The intRegarding the null results in children with burns, breast reconstruction patients, and open-heart surgery patients, there are several explanations in these cases ,39,50. VPreferred reporting items for systematic reviews and meta-analyses extension for scoping reviews were used as guidelines during the preparation of this scoping review. The scoping review intended to update the comprehensive evidence to answer the following question: \u201cWhat are the effects of essential oils on the nervous system?\u201dTo completely answer the question, we set up a strategic search concerning sensitivity and specificity to identify literature related to the nervous system. Three electronic databases\u2014PubMed, Scopus, and Google Scholar\u2014were used in this study, which was conducted by two independent reviewers (AS and PK) on 5 October 2022. A search strategy for PubMed was created using a combination of MeSH terms and Boolean operators \u201cAND\u201d, \u201cOR\u201d:  OR ) AND (((((((((Nervous System[MeSH Terms]) OR (nervous system*[Title/Abstract])) OR (cognition[MeSH Terms])) OR (consciousnesses[MeSH Terms])) OR ) OR ) OR (behavior[MeSH Terms])) OR (behavior*[Title/Abstract])) OR (executive function[MeSH Terms])) filters: from 2012 to 2022. For other databases, the searching strategy was partially modified. Articles published from January 2012 onward were included in the acquisition process. Included studies were further screened, and a manual search was performed to discover any missing data. Endnote 20  LLC under license) was used as an imported and managing software.Duplicated studies were filtered using Endnote. Two reviewers (AS and PK) independently screened the titles and abstracts of all studies and subjected them to the inclusion and exclusion criteria. For the inclusion criteria, original articles written in English and describing animal and human studies were selected for every age group and health condition. For the exclusion criteria, articles published in other languages and including no outcome of the nervous system were excluded. Then, the full texts were downloaded and evaluated. Any disagreements during the selection processes were resolved via discussion and consensus between the two writing reviewers.The data extraction process was performed by two writing reviewers (AS and PK). A standardized data extraction form including the author, year, study design, type of essential oils, route of administration, population, outcome measure methodology, and outcome was extracted using Microsoft Excel software. Any disagreements during the selection processes were resolved via discussion and consensus between the two writing reviewers. Tables listing the essential oils and outcomes were created to conclude the selected studies.Essential oils showed beneficial effects on the nervous system in both animal and human research via the olfactory system and its chemical properties, impacting physiology and pathophysiology."}
+{"text": "A large body of evidence from old stimulation and lesion studies on the hypothalamus in animals and humans demonstrates that this subcortical area significantly affects socioemotional behavior ,2,3,4; mNotwithstanding these findings on the important hypothalamic role in mediating socioemotional responses, this brain region was, for a long time, mainly considered a relay station, passing signals among the amygdala, basal forebrain, and mesencephalic structures to support behavioral, autonomic, and endocrine components of higher-level controlled emotional responses. Furthermore, until recently a rather limited number of investigations explored, in humans, the direct involvement of the hypothalamus during socioemotional responses. In addition, functional neuroimaging studies often undervalued or neglected the hypothalamic contribution to social cognition and behavior.Building on this evidence, this Special Issue, titled \u201cHypothalamus, Neuropeptides and Socioemotional Behavior\u201d, attempted to collect novel scientific reports highlighting the central role of the hypothalamus in socioemotional behavior from different neurobiological perspectives and methodologies in both healthy and clinical human populations, and in animals. The studies hosted in this Special Issue, including neuroimaging or neurochemical investigations, indeed provided some additional insights into the relevance of the hypothalamus and its associated neuropeptides in modulating socioaffective responses.For instance, considering the well-known modulatory role of oxytocin in social interactions, including social comparisons and intergroup competition, the research of Kim and colleagues  examinedLinking OXT and parental behavior, Cataldo and colleagues  aimed toAiming to explore potential group differences in endogenous OXT concentrations between individuals with autism spectrum disorder, ASD, and neurotypical (NT) controls, Moerkerke and colleagues  conducteIn addition to the well-established relationship between oxytocin and social behavior, phoenixin, a novel peptide that has been associated with reproductive functions in both the hypothalamus and pituitary , has recIn relation to hypothalamic nuclei, Carollo and colleagues  reviewedFinally, Caria and Dall\u2019\u00d2  providedOn the basis of the observed heterogeneity of hypothalamus-mediated socioemotional responses, I propose that the hypothalamus and its associated peptides might play an extended functional role in species survival and preservation, ranging from exploratory and approaching behaviors, promoting social interactions, to aggressive and avoidance responses, protecting and defending established social bonds. I have recently postulated  that theFurthermore, according to an allostatic perspective ,39,40, tFuture research exploiting ultra-high-resolution neuroimaging methodologies and advanced methods for measuring neurochemicals and neuropetides is required to better comprehend the complex neurophysiological regulation and neuropeptidergic signaling orchestrated by the hypothalamus during human socioemotional interactions. Moreover, a multimodal integrated approach, linking genetic, or other risk factors for socioemotional disorders, to neurophysiological, neurochemical, or behavioral mechanisms, will also help to clarify the exact role of this brain region in mediating maladaptive interpersonal behaviors observed in several neuropsychiatric disorders with severe socioaffective impairments such as autism, schizophrenia, and antisocial personality disorder."}
+{"text": "Crop breeding is one of the main approaches to increase crop yield and improve crop quality. However, the breeding process faces challenges such as complex data, difficulties in data acquisition, and low prediction accuracy, resulting in low breeding efficiency and long cycle. Deep learning-based crop breeding is a strategy that applies deep learning techniques to improve and optimize the breeding process, leading to accelerated crop improvement, enhanced breeding efficiency, and the development of higher-yielding, more adaptive, and disease-resistant varieties for agricultural production. This perspective briefly discusses the mechanisms, key applications, and impact of deep learning in crop breeding. We also highlight the current challenges associated with this topic and provide insights into its future application prospects. Crop quality has always been a focal point in human cultivation, and crop breeding, as a primary approach to increasing crop yield and improving crop quality, is one of the oldest agricultural activities, equivalent to human civilization . EmerginDuring the entire history of crop breeding technology, it has roughly gone through three major stages, and it is now advancing towards the fourth stage. The first stage is conventional breeding (Breeding 1.0), which mainly relies on visual observation of crop phenotypes and subjective selection of crops that meet predetermined requirements. Generally, wild species are gradually domesticated into cultivated varieties with improved qualities through multiple rounds of artificial selection . HoweverWith the push of large-scale datasets, powerful computing capabilities, and algorithmic improvements, deep learning has made breakthrough progress in multiple fields . Deep leDeep learning-empowered breeding is a method that applies deep learning techniques to improve and optimize the breeding process. It utilizes deep learning models to analyze and process agricultural and genetic data, in order to predict and optimize the agricultural characteristics and genetic traits of crops . Deep leDeep learning solves complex problems by processing large-scale data. Currently, images remain the main data format for phenotypic selection in crop breeding . The appDeep learning-empowered breeding is built upon important identified genes, integrating multiomics, next-generation biotechnologies, and novel information technologies such as artificial intelligence and big data. The identification of important genes using genetics and transgenic methods forms the foundation of deep learning-based breeding. New technologies, including multiomics, artificial intelligence, and big data, expedite the breeding process through plant phenotypic analysis and high-throughput phenotyping platforms, facilitate the evaluation of plant materials, discovery of specific genes, and accelerated breeding . Integrain vivo transcription factor binding sites -DNA binding , and deeng sites . In summng sites , chromatng sites , DNA conng sites , DNA metng sites , gene exng sites , and RNAng sites . Additiong sites  and enhang sites . Not surng sites . InteresThere is a close relationship between the function and structure of proteins. The function of a protein is determined by its tertiary structure, which can be revealed through comprehensive analysis of various protein characteristics. To extract important amino acid features from primary peptide sequences, DeepNovo  was deveDespite the presence of numerous genetic variations in natural populations, it is possible to train deep learning models on a small subset of these variations to predict the effects across the entire spectrum of mutations . For insArabidopsis thaliana, offering new insights for improving crop drought resistance  for the publication of any identifiable images or data included in this article.XW: Formal Analysis, Software, Visualization, Writing \u2013 original draft. HZ: Formal Analysis, Software, Visualization, Writing \u2013 original draft. LL: Visualization, Writing \u2013 original draft. YH: Visualization, Writing \u2013 original draft. HL: Conceptualization, Methodology, Supervision, Visualization, Writing \u2013 original draft. YQ: Conceptualization, Funding acquisition, Project administration, Resources, Supervision, Writing \u2013 review & editing."}
+{"text": "Plant fibers possess high strength, high fracture toughness and elasticity, and have proven useful because of their diversity, versatility, renewability, and sustainability. For biomedical applications, these natural fibers have been used as reinforcement for biocomposites to infer these hybrid biomaterials mechanical characteristics, such as stiffness, strength, and durability. The reinforced hybrid composites have been tested in structural and semi-structural biodevices for potential applications in orthopedics, prosthesis, tissue engineering, and wound dressings. This review introduces plant fibers, their properties and factors impacting them, in addition to their applications. Then, it discusses different methodologies used to prepare hybrid composites based on these widespread, renewable fibers and the unique properties that the obtained biomaterials possess. It also examines several examples of hybrid composites and their biomedical applications. Finally, the findings are summed up and some thoughts for future developments are provided. Overall, the focus of the present review lies in analyzing the design, requirements, and performance, and future developments of hybrid composites based on plant fibers. Fiber-reinforced composites have been gradually developed over the past few decades to provide them unique characteristics and properties . Plant fThe extraction process of plant fibers involves several steps that start with harvesting the plant material. Fibers are then separated from the non-cellulosic material using a method such as retting or pulping. Extraction is conducted through either chemical or mechanical methods. First, it breaks down the pectin, lignin, and hemicellulose that bind the fibers. Once separated, fibers are cleaned to remove any impurities and, subsequently, dried. Specific methods in the extraction process vary depending on the source and intended use of the fibers. Common sources of plant fibers include seeds and fruit , bast and leaves , straw , and wood  ,11,12 F.Plant fibers are attractive for many industrial applications requiring unique mechanical properties owing to their special features, such as low cost, low density, flexibility, tensile strength, elasticity, rigidity, non-toxicity, and biodegradability ,14,15. LIncorporating plant fibers into various applications can reduce the industrial reliance on landfills and elicit the development of the circular economy. The UNEP DTU Partnership and United Nations Environment Programme reported that, in the study titled Reducing Consumer Food Waste Using Green and Digital Technologies, around 931 million tons of food waste, including plant waste  are being discarded each year . ConsequAncient civilizations, such as the Egyptians, Greeks, and Romans, used natural composites made of straw, mud, and animal dung to build structures, such as houses and walls . These eComposites are made up of two phases that fulfill specific functions. The first is a strong discontinuous phase called the reinforcement material; it is embedded in a secondary, more ductile, and less complex continuous phase called the matrix . MatriceOverall, composite materials have shown great promise in the field of biomedical applications due to their unique combinations of properties that cannot be achieved with traditional materials. Carbon fiber-reinforced polymer (CFRP) composites, for instance, are used for prosthetic limbs and orthopedic implants because of their lightweight nature and strength . NaturalCurrently, there is a pressing need for a new generation of composites that can combine both synthetic and natural materials, with the ultimate goal of creating entirely environmentally friendly materials . VegetabNatural fibers used in medicine can be extracted from inexpensive and natural resources, such as bast fibers , seed fibers , leaf fibers , grass fibers (bamboo) and straw fibers  . CertainAccording to Karimah et al., other factors, such as storage period and condition, can affect fiber qualities; thus, those elements should be monitored efficiently . SimilarPlant-based natural fibers can be used for biomedical applications based on their composition, sustainable potential, and biological function . UsuallyVarious synthetic fibers are extensively used in the biomedical field due to their mechanical properties and versatility . HoweverFundamentally, the physical and chemical composition of raw material play an important role in the final mechanical properties of natural fibers . These aThe main components of plant fibers are sugar-based polymers, such as cellulose, which is incorporated into a matrix containing hemicellulose, lignin, and pectin see . Cellulo2, H2O, hydrocarbons, methane, and biomass through chemical and biological reactions [Plant fibers are characterized by their ability to absorb water because they have a high percentage of cellulose, which is a hydrophilic molecule. Therefore, the high cellulose content is reflected in the increased water absorption. This property is considered a valuable advantage over synthetic fibers, which are hydrophobic ,91. Anoteactions . Table 3As discussed above , the divGrewia optiva fibers and determined the percentage to be 30% of the fiber loading to obtain optimal properties, such as tensile, flexural, and compressive strength [Composites are composed of at least two different materials, separated by interphases, to obtain better properties . The constrength . Similarstrength . Likewisstrength .Biocomposites are prepared using several manufacturing methods, such as injection molding, vacuum infusion, compression molding, resin transfer molding (RTM), hand layup, and direct extrusion ,91,107. 2) using the injection molding method to be applied in bone implants [The injection molding method is used mostly for the mass production of composites . This primplants .In the RTM process, reinforcing fibers are placed in a mold cavity that is clamped and closed . SubsequManufacturing by compression molding is based on the production of compounds that have thermoplastic characteristics and are of light molecular weight . First, The hand layup is the oldest fabrication method used and consists of the manual manufacture of mold layers and the subsequent application of a resin matrix . The comDirect extrusion is the most common method for creating products with a constant cross-section . This meFlax, jute, hemp, sisal, bamboo and kenaf are widely used in biocomposites . SpinifeCellulosic/lignin fibers exert lower immunogenicity than their glass/synthetic counterparts, making, therefore, these natural fibers suitable for various biomedical applications, such as drug delivery ,73, tissRanganathan et al. screened the effect of viscose fiber content on the mechanical properties of several composites containing given amounts of polypropylene (PP), maleated PP , and jute, and manufactured via direct long fiber thermoplastic extrusion and compression molding . Their rTo date, only a small portion of the existing natural fibers has been explored for potential uses in composites for structural and non-structural applications in the biomedical field ,138. HowMost investigations on plant fiber composites use epoxy resins due to their mechanical, electrical, and chemical properties. While plant fibers increase flexibility and tensile strength, adding graphene improves the resins\u2019 shear strength . As addiInvestigations have focused on developing novel drug delivery systems to release pharmaceuticals more effectively and safely into the body . In addiEscherichia coli and Bacillus subtilis, accelerating the wound-healing process. Hence, natural fiber-based composites, combined with specific biomolecules, create the opportunity for biomedical applications, such as in drug delivery, antibiotic activity, and wound healing.For instance, Macha et al. conducted an in vitro study on hand-woven cotton fabric/polylactic acid (PLA) composites and found that these composites are promising for the delivery of amoxicillin, which is an antibiotic widely used to stop bacteria growth and treat certain bacterial infections . AnotherCurrent natural fiber-reinforced polymer composites are extensively studied to determine the feasibility of their application in orthopedics . NaturalComposites reinforced with natural fibers have been reported as a potential material for prosthetics, in addition to those with an underlying biopolymer matrix . For insThese studies demonstrate that certain combinations of natural fibers and polymers can significantly improve the mechanical properties of composite materials. Therefore, natural fibers can be a promising and more sustainable alternative to conventional materials used in the manufacturing of prostheses and orthopedic devices.Natural fiber composites can be used for biomedical applications for bone and tissue repair and reconstruction . Natural2, ZnO, CuS, and TiO2 into polymer matrices [2 nanocoatings on ginger lily fibers using DC reactive magnetron sputtering. The research provides valuable insights into the morphological, mechanical, optical, and photocatalytic properties of the TiO2-coated fibers, opening up possibilities for their utilization in various fields, including textiles and composites in the medical area [By integrating nanotechnology with natural plant fibers, researchers have sought to enhance their biomedical properties and expand their applications in the healthcare domain. Several studies have improved engineered biocomposites\u2019 mechanical and tribological properties with inorganic nanoparticles such as ZrOmatrices . The advcal area .The fabrication of nanofibers starting from natural plant polymers, such as cellulose, chitosan, and silk relies on various techniques, such as electrospinning or self-assembly methods . These nMoreover, incorporating nanoparticles, such as silver, gold, or magnetic nanoparticles, into natural plant fiber matrices has shown great potential in imparting antibacterial, antimicrobial, or magnetic properties to the resulting nanocomposites . These hPlant fibers present various issues related to inadequate interfacial adhesion, high levels of moisture absorption, poor wettability, poor fire resistance, and low impact strength and durability . As a reIn biomedical applications, it is necessary to consider factors such as bioaccumulation, biodegradation, excretion, and the effect of enzymes, hormones, and the immune response on the fibers. Lignin, for example, possesses excellent antioxidant, antimicrobial, and optical properties, making it suitable for biomedical applications, although some challenges are yet to be overcome . TypicalMany industries rely on developing composites to obtain novel, environmentally friendly materials with tunable properties for the target application. Natural fibers, mainly made of cellulose, have been widely studied as a critical component of composites. These fibers provide the composite with unique properties, such as enhanced mechanical resilience, flexibility, biocompatibility, and antimicrobial effects. In addition, they are highly hydrophilic, biocompatible, and biodegradable, and exhibit low immunogenicity. Most often, they should be combined or hybridized with other natural or glass/synthetic fibers to achieve good mechanical properties. In biomedicine, biocomposites have received particular attention since natural fibers can enhance the composite immune acceptance and improve the cell viability, as evidenced by in vitro studies for various potential biomedical applications, including prostheses, drug delivery technologies, wound healing, and scaffolds for tissue engineering.Some parameters, such as the source of the natural fiber, cellulose content, extraction, and preparation methods, affect the final properties of the biocomposites. Additionally, the preparation method should be carefully chosen depending on the desired definitive characteristics. Manufacturing processes can damage the biocomposites if humidity, pressure, and synthesis temperature are not meticulously controlled. Consequently, investigating manufacturing techniques is a crucial step in the development of composites to enhance or decrease their tensile, flexural, and impact strength towards, ultimately, their translation from the lab bench to commercial products. Finally, nanomaterials, carbon-based materials and bioactive compounds should be considered for future investigations to face the encountered challenges and limitations of hybrid composites based on natural fibers."}
+{"text": "Brassica napus L., is a major oilseed crop that has various uses in the food, feed, and industrial sectors. It is one of the most widely produced and consumed oilseeds in the world because of its high oil content and favorable fatty acid composition. Canola grains and their derived products, such as canola oil, meal, flour, and bakery products, have a high potential for food applications as they offer various nutritional and functional benefits. However, they are affected by various factors during the production cycle, post-harvest processing, and storage. These factors may compromise their quality and quantity by affecting their chemical composition, physical properties, functional characteristics, and sensory attributes. Therefore, it is important to optimize the production and processing methods of canola grains and their derived products to ensure their safety, stability, and suitability for different food applications. This literature review provides a comprehensive overview of how these factors affect the quality of canola grains and their derived products. The review also suggests future research needs and challenges for enhancing canola quality and its utilization in food.Canola,  Brassica napus L., native to Asia and the Mediterranean, is one of the most important oilseed crops in the world, with a wide range of applications in food, feed, and industrial sectors [\u22121) content [B. napus were Canada, China, and India, representing roughly 60% of global production and harvested area [Canola or oilseed rape,  sectors . Canadia content  and name content . From 20ted area . Variousted area . These cted area .The most important component of canola seeds is oil, which accounts for 40\u201350% of the seed weight, depending on the cultivar ,9. The oIn addition to the oil, canola meal, and flour, the by-products of oil extraction contain residual oil and protein that can be used for animal and human nutrition. Canola meal contains up to 50% protein, determined on a dry weight basis  and a 1. The amiCanola flour can be used as a human food ingredient, especially for bakery products. It can enhance the nutritional value, antioxidant capacity, and dietary fiber content of grain-based foods, as well as improve their flavor, texture, and shelf-life ,23,24. HCanola grain quality depends on various factors, such as genotype, environment, harvesting, storage, and processing ,25,26. TThis literature review aims to cover the critical factors affecting the quality of canola grains and their implications for grain-based foods. The objectives are to: (i) summarize the current knowledge on the quality characteristics and evaluation of canola grains, oil, and meal; (ii) review the effects of genotypic, environmental, agronomic, and post-harvest factors on canola quality; (iii) discuss the applications and markets for canola oil, meal, flour, and bakery products; and (iv) identify the knowledge gaps and research needs for improving canola seed quality and their implications for grain-based foods.The quality of canola grains is a crucial factor that affects their market value and usability for various purposes. Many factors can affect the quality of canola grains, including genetic factors, environmental factors, agronomic practices, and post-harvest factors . Figure Genetic Diversity and Population Structure of Canola GermplasmB. napus lines from different regions using 84 simple sequence repeat (SSR) markers. They found that genetic diversity varied among regions, with Europe having the highest and Australia and Canada having the lowest, and the lines were divided into two subpopulations based on growth habits. This study suggested that the lines with unique alleles could be useful for breeding programs. In another study, the allelic diversity of 72 B. napus genotypes covering contemporary germplasms in Australia and China, as well as samples from India, Europe, and Canada, was described using 55 polymorphic SSR markers spanning the complete B. napus genome [B. napus genotypes. Chinese genotypes, particularly those in the China-1 group, have inherited unique alleles from interspecific crossing, primarily with B. rapa, whereas the China-2 group shares several alleles with Australian genotypes. Other researchers analyzed the genetic diversity and population structure of feral rapeseeds by genotyping 537 individuals in Japan using 30 microsatellite markers [The genetic diversity and population structure of the canola germplasm reflect its origin, history, adaptation, and improvement. Several studies have assessed the genetic diversity and population structure of canola at global or regional scales using molecular markers. For example, Gyawali et al.  studied s genome . Hierarc markers . The ferGenetic Architecture and Molecular Mechanisms of Quality Traits in CanolaDifferent canola varieties exhibit variations in oil, protein, chlorophyll, GSLs, fatty acids, seed size and weight, and other traits that influence the quality of canola grains and their derived products ,33. ThesB. napus and identified loci and candidate genes that can be utilized in molecular breeding strategies to increase SOC in this important seed crop. That study identified 1713 candidate genes in the 26 QTLs confidence interval. To narrow down the focus, differentially expressed genes (DEGs) were identified between high- and low-SOC accessions, leading to the identification of 21 candidate genes related to SOC. Another study collected 204 accessions and recombinant inbred lines (RILs) from a natural population for genome-wide association analysis (GWAS) and QTL mapping [Oil content is one of the most important quality traits in canola, as it determines the yield and quality of canola oil. It is highly heritable and varies from 30% to 50% among canola varieties . Several mapping . Based oFatty acid composition is another important quality trait in canola, as it affects the nutritional and industrial properties of the oil. Canola oil contains mainly unsaturated fatty acids, such as oleic acid (C18:1), linoleic acid (C18:2), and linolenic acid (C18:3), which have beneficial effects on human health . HoweverB. napus accessions for phenotypic variations in seed fatty acid content and composition at four US locations over multiple years. They observed highly heritable variations for total oil content, nine fatty acid compounds, and fourteen derivative traits. A GWAS detected 53 SNPs significantly associated with one or more of the twenty-four fatty acid seed traits, implicating the genetic role of twelve candidate genes, including four with two homologs each from the acyl-lipid pathway. Whole-genome prediction showed moderately high predictive abilities (70% of traits with abilities > 0.70), suggesting that these traits are highly amenable to genomic selection.Protein content is another important quality trait in canola, as it determines the value and quality of canola meals for animal feed. Protein content is moderately heritable and varies from 17 to 26% among canola varieties . SeveralGlucosinolates are sulfur-containing compounds that have anti-nutritional effects on animals and humans, such as reducing iodine uptake, impairing thyroid function, and causing goiter . TherefoB. napus, it\u2019s important to increase leaf GSL content while keeping seed content low. Liu et al. [B. napus.Recently, a GWAS of six GSL metabolites was conducted in rapeseed, including three aliphatic GSLs , one aromatic GSL (m157 gluconasturtiin), and two indole GSLs (m165 indolylmethyl GSL and m172 4-hydroxyglucobrassicin) . There wu et al.  found a Agronomic traits in canola, including yield potential, disease resistance, herbicide tolerance, and shatter resistance, are complex and influenced by both genetics and environmental factors, such as drought and plant density . Recent B. napus growth and yield. Significant relationships have been identified for twelve traits at two densities, and transcriptome analysis demonstrated gene-regulatory responses to simulated shade. Candidate genes were identified within canola QTLs, and their effects on density responses in Arabidopsis lines were investigated. Within canola QTLs, candidate genes were identified, and their impacts on density responses in Arabidopsis lines were studied. TCP1 gene supports growth regardless of density, but HY5 especially enhances biomass and yield at high density. PIN genes accelerate blooming time in a density-dependent manner, whereas FT, HY5, and TCP1 act in a density-independent manner. Combining agronomic field experiments with genetic and transcriptomic approaches can improve crop productivity.Menendez et al.  used 152During the crop cycle, the quality of canola grains is significantly influenced by weather conditions such as air temperature, rainfall, relative humidity, and photoperiod, especially during the flowering and seed-filling stages ,63. TempPrecipitation and soil moisture availability are crucial factors for canola production because water stress can impact canola grain yield and quality by influencing various physiological processes, including photosynthesis, respiration, transpiration, nutrient uptake, and metabolism . DroughtB. napus seeds, which can be harmful to human health [Soil nutrients, particularly nitrogen (N), phosphorus (P), potassium (K), and sulfur (S), are essential for canola growth and grain quality ,74. Adeqn health . TherefoB. napus are flea beetles, cutworms, diamondback moths, cabbage seedpod weevils, root maggots, Sclerotinia stem rot, blackleg, clubroot, and Alternaria black spot [Pests and diseases can affect the quality of canola grain by causing physical damage, nutrient loss, toxin accumulation, hormonal imbalance in plants, and reduced yield ,81. In aack spot ,83. HoweAgronomic practices, including seed selection, sowing date, plant density, fertilization, irrigation, disease and pest control, and harvesting, influence canola grain quality ,84,85,86The sowing date of canola affects the exposure of the crop to different weather conditions during its growth cycle, which may have an impact on grain yield and quality . Canola Irrigation can affect the soil moisture status and water stress level of canola plants, which can influence the physiological processes and biochemical reactions of canola grains ,96. Espe\u22121 (19.4%) on average from 2010 to 2015. Furthermore, nitrogen saving was observed when the pea plant was included in the rotation. Another study showed that green manure in B. napus rotation increased grain yield and nutrient uptake, while co-application of farmyard manure, compost, and chemical fertilizers increased grain yield and oil yield [Crop rotation with different families of plants may help in breaking disease cycles and improving soil fertility . Seed yiil yield .Weed control is essential for optimizing canola quality, as weeds can compete with canola for resources, reduce crop yield and quality, and increase dockage and green seed levels . Timely Effective pest management strategies, including the use of resistant cultivars, crop rotation, and timely application of pesticides, can help minimize the damage caused by pests and diseases while maintaining high-quality canola grains ,107. On Harvesting, Drying, Storage and TransportationThe quality of canola grains is influenced by post-harvest factors such as harvesting, drying, storage, and transportation. These factors can affect the physical and chemical properties and stability of canola grains and their derived products and can impact the nutritional and functional properties of the oil . There aHarvesting too early or too late can affect the potential of canola seeds to develop secondary dormancy, which is a mechanism of seedbank persistence that can cause volunteer weed problems in subsequent crops. Secondary dormancy is influenced by both genetic and environmental factors in the mother plant. Canola seeds had a lower potential for secondary dormancy at early development but a higher potential at full maturity . TherefoDrying is the process of reducing the moisture content of canola grains to a safe level for storage and processing. Drying methods include natural drying and artificial drying. Natural drying is the process of allowing the grains to dry naturally by air circulation in bins or silos. Artificial drying is the process of applying heat and forced air to the grains in dryers. Drying methods can affect the quality of canola grains by influencing the moisture content, oil content, FFA content, GSL content, chlorophyll content, and germination capacity . Grain wCleaning and grading are essential post-harvest processes that remove impurities and separate canola grains according to size and density. Proper cleaning and grading can improve the quality of canola grains by reducing impurities and improving the uniformity of the grains. However, improper cleaning and grading can damage the grains and reduce their quality . Canola Post-harvest management, including storage and processing, plays a crucial role in maintaining canola grain quality . Proper Quality Assessment Methods and StandardsQuality assessment methods and standards for canola grains include various physical, chemical, and biological methods to evaluate the quality attributes such as moisture, test weight, oil content, protein content, fatty acid composition, GSL content, impurities, seed contaminants, and genetic purity . These mThe quality of canola grain is affected by several factors that occur during post-harvest processing and storage, including drying methods, storage conditions, milling methods, extraction methods, and refining methods . Grain qFactors Affecting Canola Oil ExtractionHigh-quality canola grains are essential for producing high-quality canola oil with a desirable fatty acid profile, low levels of impurities, and good oxidative stability . HoweverMoisture content is an important factor that affects oil extraction efficiency. It influences the physical and chemical properties of both the seeds and the oil, such as density, viscosity, solubility, and stability . DiffereThe extraction method is another factor that influences oil extraction efficiency. The choice of the canola oil extraction method depends on several factors, such as oil yield, oil quality, energy consumption, capital cost, regulatory constraints, and environmental impact . There aFactors Affecting Canola Oil RefiningCanola oil needs to undergo several refining processes to improve its quality and stability before it can be used for human consumption or industrial applications. These processes include degumming, neutralization, bleaching, and deodorization. Crude oil quality affects the refining requirements and performance by influencing the amount and type of impurities present in the oil, such as phospholipids, pigments, FFAs, peroxides, and volatile compounds . The quaDegumming is the first step in canola oil refining and aims to remove phospholipids and other impurities from crude oil. Phospholipids are undesirable in the oil because they can cause emulsification, foaming, and darkening during subsequent refining steps . DegummiNeutralization is the second step of canola oil refining and aims to remove FFAs from the oil. FFAs are undesirable in the oil because they can cause rancidity, off-flavors, and a reduced smoke point . NeutralBleaching is the third step in canola oil refining and aims to remove color pigments and other impurities from the oil. Color pigments are undesirable in the oil because they can affect its appearance and stability . BleachiDeodorization is the final step of canola oil refining, which aims to remove odorous compounds from the oil. Odorous compounds are undesirable in the oil because they can affect its flavor and shelf life . DeodoriRefining conditions affect the quality and quantity of canola oil by influencing the extent and rate of impurity removal during degumming, bleaching, and deodorization processes . Some reThe quality and nutritional value of canola meal can vary depending on several factors . These fDesolventized flakes are heated during toasting to lower moisture content and enhance flavor and meal stability . The quaAnti-nutritional factors are compounds that can interfere with the digestion and absorption of nutrients in animals. Canola meal contains several anti-nutritional factors, such as GSLs, phytic acid, and tannins . GSLs arFactors Affecting Flour ProductionThe production of canola flour from canola bran involves milling and sieving. Milling is a process that reduces the particle size and distribution of canola bran by using roller mills or hammer mills. Sieving is a process that separates fine particles from coarse particles using sieves or classifiers. The choice of production method depends on several factors, such as flour quality, product specifications, energy consumption, capital cost, and environmental impact . MillingParticle size is one of the factors that affect the functional properties of canola flour. Particle size refers to the diameter of the canola flour particles, which can range from fine to coarse. Particle size can influence the water absorption capacity, oil absorption capacity, and pasting properties of canola flour . Water aMoisture content is another factor that affects the shelf life and stability of canola flour. Moisture content refers to the amount of water present in canola flour, which can vary depending on the drying conditions and storage conditions. Moisture content can affect the microbial growth, lipid oxidation, and enzymatic activity of canola flour . MicrobiBran temperature is another factor that affects the milling and sieving efficiency of canola flour. Bran temperature refers to the temperature of canola bran during milling and sieving, which can vary depending on the heating conditions and ambient conditions. Bran temperature can affect the physical and chemical properties of canola bran, such as hardness, elasticity, brittleness, and solubility . These pFactors Affecting Bakery ProductsThe use of canola oil, meal, or flour in bakery products involves several steps, such as mixing, kneading, proofing, baking, and cooling. The choice of bakery product formulation and processing method depends on several factors, such as product quality, product specifications, consumer preferences, cost, and availability . Canola Ingredient composition affects the quality and quantity of bakery products by influencing the proportion and balance of different components in the bakery product, such as flour, fat, sugar, water, eggs, leavening agents, and additives . This coIngredient interaction affects the compatibility and synergy of different components in the bakery product, such as flour-fat, flour-water, flour-protein, flour-starch, flour-sugar, fat-water, fat-protein, fat-starch, fat-sugar, water-protein, water-starch, water-sugar, protein-starch, protein-sugar, and starch-sugar interactions ,166. TheStorage conditions also have an impact on the physical and chemical changes that occur during different stages of bakery product storage, such as packaging, transportation, and distribution ,168,169.Canola quality is affected by various factors, such as genetic variation, environmental conditions, agronomic practices, harvesting methods, storage conditions, and processing techniques. Therefore, there is a need for continuous research and innovation to improve canola quality and meet the changing demands of consumers and industries. Some of the future research needs and challenges for improving canola quality and its implications for grain-based foods are discussed below.Improving oil quality: One of the main objectives of canola breeding is to improve the oil quality by increasing the content of desirable fatty acids and reducing the content of undesirable ones. For example, increasing the oleic acid content can improve the oxidative stability and shelf life of canola oil, while reducing the linolenic acid content can reduce the need for hydrogenation and trans-fat formation. Moreover, increasing the content of omega-3 fatty acids can increase the nutritional value and health benefits of canola oil . HoweverImproving protein quality: Another objective of canola breeding is to improve protein quality by increasing the digestibility, enhancing the amino acid profile, and reducing anti-nutritional factors such as GSLs. Improving protein quality can increase the value and utilization of canola meals for animal feed and human food applications. For example, canola meals can be used as a protein ingredient in grain-based foods such as breads, cakes, cookies, noodles, pasta, and snacks. However, improving protein quality also faces some challenges, such as maintaining or improving oil content and quality, overcoming genetic limitations and trade-offs, developing novel processing methods to enhance protein functionality and palatability, and ensuring food safety and regulatory compliance.Improving chlorophyll content: Chlorophyll is a pigment that gives canola seeds their green color. It is an undesirable component in canola oil because it reduces its clarity and stability, increases its refining cost, and affects its sensory properties. Therefore, reducing chlorophyll content is another goal of canola breeding and processing. The chlorophyll content is influenced by genetic factors as well as environmental factors such as temperature, moisture stress, frost damage, insect damage, disease infection, premature harvest, and delayed swathing. Therefore, there is a need for developing cultivars with low chlorophyll content or high chlorophyll degradation capacity under various conditions. Moreover, there is a need to develop novel methods to reduce chlorophyll content during post-harvest and processing stages, such as using enzymes and antioxidants.Improving end-use quality: Canola oil and meal can be used for various end-use applications, such as food, feed, fuel, and industrial products. However, different end-use applications may have different quality requirements and specifications. Therefore, there is a need to improve the end-use quality of canola products by optimizing the processing conditions, modifying the functional properties, enhancing the sensory attributes, and ensuring safety and quality standards. For example, canola oil can be used for frying, baking, salad dressing, margarine, shortening, and biodiesel production. However, each of these applications may require different oil characteristics, such as smoke point, oxidative stability, flavor, color, viscosity, and fatty acid composition. Similarly, canola meals can be used for making bread, cakes, cookies, noodles, pasta, snacks, and animal feed. However, each of these applications may require different meal characteristics, such as protein content and quality, water absorption capacity, oil binding capacity, emulsifying properties, gelation properties, and flavor.Improving canola processing: The United Nations\u2019 sustainable development goals require the oilseed processing industry to use solvent extraction processes that are safe and eco-friendly. This poses a challenge, as the industry needs to find and optimize alternative and greener solvents that can process oilseeds without compromising the oil quality . FurtherThe quality of canola grains and their derived products, such as canola oil, meal, flour, and bakery products, is influenced by a myriad of factors throughout their production, post-harvest processing, and storage. These factors can impact the chemical composition, physical properties, functional characteristics, and sensory attributes of canola grains and their products, which in turn affect their suitability for various food applications. This literature review has delineated the major factors affecting canola quality, including genetic factors, agronomic practices, environmental conditions, post-harvest processing techniques, and storage conditions. It has also highlighted the importance of optimizing these factors to ensure the safety, stability, and nutritive value of canola grains and their derived products. Future research should focus on the development of improved canola varieties with enhanced quality traits and better resistance to biotic and abiotic stresses and the assessment of the environmental, economic, and social impacts of canola production and consumption. Additionally, the optimization of agronomic practices, post-harvest processing methods, and storage conditions is crucial in maintaining the quality of canola grains and their products. Innovative technologies and processing techniques should be explored to minimize the impact of detrimental factors on canola quality while preserving its favorable nutritional and functional properties. Canola production must also adapt to the changes in terms of climatic, agricultural, economic, and regulatory conditions that affect the industry. This requires further research and discussion on the adaptation levers that can be put forward in the future. A multidisciplinary approach involving scientists, researchers, industry professionals, and policymakers is essential in order to develop sustainable, efficient, and innovative solutions that will contribute to the improvement of canola grain quality and the overall success of the canola industry. By addressing these challenges and maximizing the potential of canola grains and their derived products, we can contribute to the development of healthier and more sustainable food systems that will benefit consumers, producers, and the environment."}
+{"text": "Screening processes to identify patients who have chronic kidney disease (CKD) early in the disease allow time to manage its comorbidities and complications effectively and aggressively. The Kidney Early Evaluation Program (KEEP), sponsored by the National Kidney Foundation (NKF), is a free screening program that targets people who have diabetes, hypertension, and parents, grandparents, or siblings with diabetes, hypertension, or CKD.To (1) introduce KEEP and its objectives and (2) review population data and progress with goals to date.The KEEP goals are to raise awareness of CKD, especially in high-risk patients, provide free testing, and encourage dialogue between patients and their physicians, leading to a treatment plan. Of the 55,000 patients who have been screened through KEEP, approximately 13,000 (29%), or nearly 1 in 3 patients, have been identified as having CKD. Once a patient has been diagnosed with CKD, clinicians must address risk factors such as diabetes, hypertension, and kidney-specific diseases  that contribute to the process of renal decline. The NKF through the Kidney Disease Outcomes Quality Initiative has assembled a series of guidelines addressing dialysis adequacy, vascular access, anemia, nutrition, CKD, bone and mineral metabolism, dyslipidemia, hypertension, cardiovascular disease, and diabetes.CKD is quite common but often unrecognized and undertreated, even though rigorous guidelines for diagnosis and care have been developed. Ten areas have been identified as important for optimal care of the CKD patient. Each of these areas should be addressed and closely monitored in this population: hypertension, anemia, glucose control, lipid control, smoking cessation, aspirin prophylaxis and use of a beta-blocker post-myocardial infarction, use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, diet, exercise, and weight control."}
+{"text": "Small-livestock products, such as poultry and rabbit meats, are essential to global animal food production. Poultry and rabbit production has recently experienced many challenges, including climate change, disease spread, and antibiotic misuse. Bee products have emerged as promising natural alternatives to antibiotics due to their nutritional and therapeutic properties. This review aims to present an overview of the possible advantages of using different bee products, separately or combined, in poultry and rabbit farms. The results indicate that bee products can positively affect poultry and rabbit\u2019s physiological traits, production, reproduction, health/immunity, and product quality. Therefore, bee products have great potential as a safe and effective addition to poultry and rabbit production.Poultry and rabbit production are important and rapidly growing agricultural subsectors, particularly in several developing countries. To ensure the sustainability of poultry and rabbit production, realistic poultry and rabbit farming practices must be improved. Apitherapy is a traditional alternative medicine that involves the prevention and treatment of some diseases with several bee products including propolis, royal jelly, pollen, and venom. More feeding investigations on the numerous benefits of bee products for poultry and rabbits are crucial to be addressed. Poultry and rabbit production has recently experienced numerous challenges, including climate change, disease spread, and antibiotic misuse. Improving animal welfare, health, and production is a top priority for all livestock farms, as is supplying consumers with safe and healthy products. Therefore, this review aims to collect and investigate recent relevant literature on the use of bee products, as feed additives, drinking water supplements, and injections, for poultry and rabbits to improve animal health and production. From the current findings, bee products can improve the growth and immunological performance of small-livestock animals, such as poultry and rabbits, by activating digestive enzymes, maintaining microbial balance, and promoting vitamin synthesis. Therefore, bee products could be a promising natural alternative to growth promoters, reproductive stimulants, and immunological enhancers in poultry and rabbit farms to provide safe and healthy products for humans. Small-livestock farming, such as poultry and rabbits, is an important component of food production, helping to meet the expanding global need for protein-rich foods. Consumers have expressed considerable interest in enhancing animal welfare and product quality. In several developed countries, they have also become interested in functional, healthy, and organic foods . HoweverApis mellifera L. produced materials, including honey and venom, for the treatment of various diseases. Bee products not only provide essential nutrients, but also have medicinal properties [in ovo technique, as a recent aspect of poultry farming [Apitherapy is a subspecialty of complementary medicine that involves using operties ,4  is a natural bio-product rich in resins, phenolic acids, and flavonoids, besides containing active enzymes, minerals, and vitamins, which have significant antioxidant and antimicrobial activities ,50,51,523) and corticosterone), and cholesterol concentrations, is a good indicator of animal health and production because blood biochemical trait concentrations are related to several productive traits and immunological health performance [Hassan et al.  reportedformance ,55,56,57formance  revealedformance  indicateformance . It can formance . Accordiformance , propoliformance  found thformance .Salmonella spp. and Escherichia coli in the cecum of treated rabbits [On the other hand, adding propolis to rabbit diets, at the level of 250\u2013500 mg/kg of diet, lowered the colonization of  rabbits . Thus, t rabbits . Similar rabbits  reportedRumex crispus, Potentilla anserina, and Polygonum aviculare) [El-Sherbiny  showed ticulare) .Bee pollen grains  are the cells of the male reproductive spore of flowers collected and combined with special enzymes and natural substances derived from bee salivary gland secretion ,69. It pBee pollen, according to , can incBee pollen administered to broilers\u2019 basal diet at a rate of 20 g/kg diet resulted in a 15.5% increase in average daily gain compared to the control group . This in3 and IGF-1 levels in the plasma without any negative effect on carcass quality. Moreover, bee pollen and propolis combination positively increased rabbits\u2019 body weight, besides decreasing blood cholesterol level, and aspartate aminotransferase/alanine aminotransferase ratio [According to , the incse ratio . Zeedan se ratio  noted thse ratio ; thus, ise ratio  revealedRoyal jelly is a prominent bee product that is extensively utilized as a natural nourishment for humans and animals due to its high content of essential nutrients. It is high in vitamins B and C, folic acid, and phenolic acids. It is also a good source of minerals. It has various important biological functions in living beings, such as serving as an antioxidant agent, growth promoter, and immunostimulant . Royal jHoneybee venom  is a complex biogenic mixture that is produced in the venom gland of honeybees and has several pharmaceutical and medical properties ,88,89. IBee venom supplementation in drinking water (1 mg/L) had a substantial effect on broiler performance, including body weight, feed intake, and antioxidative capacity, especially during the early stages of life . In the On the other hand, bee venom can be a safe naturalistic growth promoter, antioxidant, immune stimulant, and anti-inflammatory replacement for synthetic chemical drugs in rabbit farms, as injecting 0.3 mg bee venom/rabbit twice weekly improved rabbit productive performance and welfare considerably ,98. Acco2 that have been found in bee venom have a strong immunoregulatory function, thus bee venom could be effective for several immune diseases [Bee venom can also be an effective and safe alternative for use in rabbit farms instead of artificial synthetic reproductive enhancers that can impair consumer health ,47. It cdiseases ,101.Based on the current results, using bee products, such as propolis, bee pollen, royal jelly, and bee venom, either in the diet, drinking water, or by injection, has many benefits to poultry and rabbits. It is a practical approach that can be applied to poultry and rabbit farms, especially in thermally temperate and subtropical regions. Due to their nutritional and pharmaceutical-beneficial properties, bee products have been proven to improve several physiological, reproductive, antioxidative and immunological responses, along with increasing animal productivity. This makes bee product treatment appealing as a natural promising growth promoter, reproductive stimulant, and immunity enhancer in poultry and rabbits, besides enriching the produced meat with vital bioactive substances. However, more studies and investigations are needed to ensure the safe doses and limits of using these products."}
+{"text": "Plant roots host numerous microorganisms around and inside their roots, forming a community known as the root microbiome. An increasing bulk of research is underlining the influences root-associated microbial communities can have on plant health and development. However, knowledge on how plant roots and their associated microbes interact to bring about crop growth and yield is limited. Here, we presented (i) the communication strategies between plant roots and root-associated microbes and (ii) the applications of plant root-associated microbes in enhancing plant growth and yield. This review has been divided into three main sections: communications between root microbiome and plant root; the mechanism employed by root-associated microbes; and the chemical communication mechanisms between plants and microbes and their application in plant growth and yield. Understanding how plant root and root-associated microbes communicate is vital in designing ecofriendly strategies for targeted disease suppression and improved plant growth that will help in sustainable agriculture. Ensuring that plants become healthy and productive entails keeping plants under surveillance around the roots to recognize disease-causing microbes and similarly exploit the services of beneficial microorganisms in nutrient acquisition, stress mitigation, and growth promotion. The orthodox methods of attaining improved agricultural output are not environmentally sustainable. For instance, the superfluous and prolonged application of artificial agrochemicals results in soil nutrients depletion and water pollution as well as environmental degradation . If nothPlant microbiome nexuses could provide a prospect to develop schemes for sustainable agricultural practices . Plants Understanding the concept and relevance of the root microbiome to plant health will improve our insight into the colossal power of these tiny giants in ecosystem function. In recent years, research has focused on the composition and the structure of root microorganisms . However+ efflux, CO2 from cell respiration, mucilage, intact root border cells, and proteins . Th. Th31]. n plants ,34,35,36n plants ,38,39.Alongside different rhizodeposits produced in the rhizosphere, different hormones are also produced that aid plant-microbe communication cascades . These hIn the past, microbial ecologists used to face big challenges in investigating multifaceted microbial societies. However, today the tide has changed thanks to methodological advances like the high throughput deoxyribonucleic acid sequencing machinery that provides comprehensive information on the composition and structure of microbial groups ,46,47. WPseudomonas chlororaphis O6 produced 2R, 3R-butanediol in the presence of jasmonic acid, ethylene, and salicylic acid signaling pathways, increasing the tolerance to drought in Arabidopsis thaliana by increasing the proportion of closed stomata. Another study revealed that under salt stress conditions, Pseudomonas simiae strain AU produced volatile organic compounds that provided salt tolerance in soybean plants by decreasing sodium ion and increasing the amount of potassium and phosphorus content [Pseudomonas simiae strain AU [Arthrobacter agilis UMCV2 increased iron obtainability in Medicago truncatula. This became possible due to (i) the dimethylhexadecylamine released by Arthrobacter agilis UMCV2 stimulating acidification in the root biome. (ii) This then promoted proton extrusion under an iron deficit. (iii) Finally, it led to an increase in ferric reductase activity. Fungal colonization primes the chemical protection development in plants by increasing the levels of fatty acid derivatives, alkaloids, terpenoids, and phenylpropanoid polyamine conjugates in plants; these compounds are emitted to prevent pests [Microorganisms use processes like enzymes release, induction of systemic resistance in host plants, antibiosis, and rhizospheric competence to stimulate plant-microbe communications, and these processes originated from chemical signaling . Distinc content . Their itrain AU . Some chtrain AU . del Cartrain AU  reportednt pests ,62. The nt pests ,64.Bacillaceae, Enterobacteriaceae, and Pseudomonadaceae isolated from the Araucaria angustifolia root were tremendous plant growth-promoting bacteria. Some of these bacterial strains are P-solubilizing microbes that help the crops tolerate drought, salt, and extreme temperature conditions through the production of numerous phytohormones, antioxidants, and exopolysaccharides; the production of 1-aminocyclopropane-1-carboxylate deaminase; the enrichment of nutrient uptake; the production of many volatile compounds; and the initiation of the buildup of osmolytes. They also help in the regulation of stress-responsive genes [Glomus mosseae and Bradyrhizobium japonicum in drought-stressed soybean plants resulted in increased leghemoglobin content, acetylene reductase activity, and protein content by 25%, 112%, and 15%, respectively, compared with well-watered soybean plants and plants colonized by Bradyrhizobium alone.Crops are often exposed to physical stresses such as soil salinization, submergence, extreme temperatures, nutrient imbalances, and drought, to mention a few . The facve genes ,69. Undeve genes  found thve genes  showed t+ and confine Na+ inflow into the roots. They produced volatile organic compounds (VOCs) during stress conditions so that VOCs can activate high-affinity K+ transporter (HKT1) reduction in roots and stimulate HKT1 in shoots, thereby restraining Na+ entrance into roots and easing shoot-to-root Na+ retransmission. The K+/Na+ ratio is increased by arbuscular mycorrhizal fungi by immensely improving Ca2+ and K+ absorption and eluding the movement of toxic Na+ under salty conditions. Furthermore, for effective water assimilation in saline-strained plants, roots\u2019 closely associated microbes control the processes of genes encrypting the plasma membrane integral proteins to aquaporin activity [Pseudomonas and Rhizobium at the seedling stage of maize. Their findings showed that under sodium chloride conditions alone, a harmful effect on maize growth and development was observed. Furthermore, improved sodium chloride tolerance of maize upon co-inoculation with Pseudomonas and Rhizobium is linked with reduced electrolyte leakage, increased proline production, and conservation of leaf water contents. The improvement of nutrient uptake to boost plant survival under salt conditions is another mechanism employed by root-associated microbes. For instance, the introduction of Bacillus aquimaris to wheat plants resulted in a substantial rise in phosphorus, nitrogen, and potassium in wheat leaves (Upadhyay and Singh 2015). The root-associated microbe can also aid plants in withstanding high- or low-temperature conditions, either by increasing or decreasing anthocyanin, proline, and sugar contents. Barka et al., [Burkholderia phytofirmans strain PsJN increased physiological activity and grapevine growth through a substantial increase in proline, starch deposition, carbohydrates, and phenol contents compared with the control.Root-associated microbes also use other strategies to retain ion homeostasis in plants facing salt stress. For instance, bacterial exopolysaccharides fix Naactivity ,73,74. Bactivity  induced  et al.,  reportedStreptomyces, Pantoea, Citrobacter, Azospirillum, Bacillus, Herbaspirillum, Achromobacter, Gluconacetobacter, Burkholderia, Chryseobacterium, Bacillus, Klebsiella, Azotobacter, and Pantoea, have been reported to enhance plant development and growth via the uptake of micronutrients and stimulate the development of plant roots [Azoarcus, Herbaspirillum, Acetobacter, and diazotrophicus, have been reported to be active in nitrogen fixation. Some diazotrophic endophytic microbial communities, such as Bacillus, Gammaproteobacteria, and Actinobacteria, have been largely reported as atmospheric nitrogen fixers in rice [Burkholderiales, form root nodules with legumes, which convert atmospheric nitrogen into ammonia, which is readily available to the plant, while the plant, in return, produces carbon compounds [Brevibacillus, Kineococcus, Microbacterium, Rhizobium, Burkholderia, Nocardia, Bacillus, Rhodococcus, Methylobacterium, Mesorhizobium, and Paenibacillus associated with Eucalyptus plant have been reported to be involved in the fixing of nitrogen [Most micronutrients and macronutrients important for plant growth are available in the soil in insoluble forms. Plants devise several mechanisms for the acquisition of these nutrients in the soil. The plant root microbiome enhances the uptake of major micronutrients by mineralizing or solubilizing them and ensuring their bioavailability through acidification ,86, secrnt roots ,92,93,94nt roots . Root en in rice ,96,97. Rompounds ,99. Somenitrogen ,100. A sGlomeromycota, Basidiomycota, Ascomycota, and Zygomycota, are capable of secreting inhibitory compounds, some of which are terpenoids, polyketones, phenols, chlorinated compound, alkaloids, peptides, steroids, and flavonoids, which aid the protection of plants from insects, pathogens, and herbivores [Streptomyces spp. secretes many antimicrobial compounds such as indolo-sesquiterpene antimicrobial compounds, munumbicins, coronamycin, and kakadumycins [Xylella fastidiosa (a pathogen responsible for chlorosis in citrus trees) via siderophore production [Rhizoctonia solani, which commonly attacks sugar beet [Gammaproteobacteria have also successfully inhibited the disease via non-ribosomal peptide synthesis (NRPS) [Streptomyces, Bacillus, Paenibacillus, and Rhizobium in the root microbial community of cucumber was cultivated and monitored in suppressive soil [Insects and pathogens attack plants and retard their yield, growth, and health. However, plant root microbiomes have been reported to be a reservoir of many bioactive metabolites that can protect and enhance plant resistance against attacks from pathogens and pests . Phyllosrbivores . Actinomdumycins ,122,123.oduction . Rhizobigar beet , while Gs (NRPS) . A high ive soil . A summaIt is evident that plant-microbe signaling cascades are essential regulators of plant development and growth, and these signal molecules can alter the morphology and physiology of the host plant. Plants develop complex interactions and communicate with various microbes in their rhizosphere through different signals that affect plant growth and modulate the plant-specific core root microbiome. These signals, secreted by micro- and macro-symbionts, can enhance root development, increase nutrient and water uptake, and promote tolerance to biotic and abiotic stresses. As a result of the roles that plant growth-promoting organisms played in improving plant growth and yield, the role of plant-microbe signals in sustainable agriculture and the recovery of marginal lands cannot be overemphasized. It is, therefore, important to focus future research on the understanding of intra- and inter-communication that can lead to the identification of more signal molecules and similarly improve plant growth and development. There is a need to develop efficient technologies for isolating and identifying signal compounds useful for sustainable development."}
+{"text": "Microbes hold immense potential, based on the fact that they are widely acknowledged for their role in mitigating the detrimental impacts of chemical fertilizers and pesticides, which were extensively employed during the Green Revolution era. The consequence of this extensive use has been the degradation of agricultural land, soil health and fertility deterioration, and a decline in crop quality. Despite the existence of environmentally friendly and sustainable alternatives, microbial bioinoculants encounter numerous challenges in real-world agricultural settings. These challenges include harsh environmental conditions like unfavorable soil pH, temperature extremes, and nutrient imbalances, as well as stiff competition with native microbial species and host plant specificity. Moreover, obstacles spanning from large-scale production to commercialization persist. Therefore, substantial efforts are underway to identify superior solutions that can foster a sustainable and eco-conscious agricultural system. In this context, attention has shifted towards the utilization of cell-free microbial exudates as opposed to traditional microbial inoculants. Microbial exudates refer to the diverse array of cellular metabolites secreted by microbial cells. These metabolites enclose a wide range of chemical compounds, including sugars, organic acids, amino acids, peptides, siderophores, volatiles, and more. The composition and function of these compounds in exudates can vary considerably, depending on the specific microbial strains and prevailing environmental conditions. Remarkably, they possess the capability to modulate and influence various plant physiological processes, thereby inducing tolerance to both biotic and abiotic stresses. Furthermore, these exudates facilitate plant growth and aid in the remediation of environmental pollutants such as chemicals and heavy metals in agroecosystems. Much like live microbes, when applied, these exudates actively participate in the phyllosphere and rhizosphere, engaging in continuous interactions with plants and plant-associated microbes. Consequently, they play a pivotal role in reshaping the microbiome. The biostimulant properties exhibited by these exudates position them as promising biological components for fostering cleaner and more sustainable agricultural systems. The ecology of the phytosphere is highly complex, where continuous interactions between plants and microbes are evident. This interplay can either benefit each other through various mechanisms, such as nutrient exchange, the induction of metabolic pathways/processes, and the secretion of various exudates or metabolites, or harm each other through disease initiation, a reduction in plant growth, and the modification of the microbiome. Microbe\u2013microbe interactions further shape the microbiome structure, including both beneficial and harmful microbes. These multi-trophic interactions create a unique chemical niche around the plant, determining the fate of phytospheric health and, ultimately, maintaining ecological balance in agroecosystems. Unfortunately, the introduction of xenobiotic compounds  into agroecosystems in the form of pesticides, herbicides, and fertilizers has resulted in soil degradation and environmental deterioration.Exploring and harnessing beneficial microbes is an emerging option forsolving this problem. These beneficial microbes include plant-growth-promoting rhizobacteria (PGPRs), plant-growth-promoting fungi (PGPFs), endophytes, biocontrol agents, mycorrhiza, algae, etc. They play multifunctional roles in direct and indirect plant growth and development, as well as promotion. Directly, they can interfere with other microbes through hyperparasitism, predation, and ecological competition. Indirectly, they can secrete various biologically active compounds such as sugars , enzymesRhizobium sp., Mycorrhiza sp., Azotobacter sp., and Azospirillum sp., and a microbial plant biostimulant can consist of these micro-organisms or their consortia. Such strict regulation could hinder and prohibit the use of novel beneficial microbes, as well as the formulation of their products in the market. Nevertheless, the European Biostimulant Industry Council (EBIC) has directed its focus to redefine its regulatory and safety requirement on the EU market and update the CMC-7 list in the new regulation [A promising solution to address these challenges may arise from the rhizosphere, where plants and microbes exist as interacting entities, producing an array of diverse chemical compounds that play a crucial role in plant growth and development. Over 20,000 compounds produced by microbes can influence plants\u2019 behavior, combat biotic and abiotic stress, and promote normal growth and development. Such compounds, collectively known as \u201cbiostimulants,\u201d of microbial origin are included under the European Union (EU) regulation 2019/1009 as fertilizing products, providing they function to stimulate plant nutrition processes independent of products\u2019 nutrient content and improve characteristics such as nutrient use efficiency, tolerance to stress, quality traits, or nutrient availability in soil, plants, or the rhizosphere . In thisgulation  to encouCurrently, cell-free microbial exudates show great potential in various fields of agriculture, from stimulating plant growth and defense to the bioremediation of harmful pesticides and heavy metals. Due to their low environmental impact, these exudates can be preferred over fertilizers and pesticides, making them viable components for sustainable agricultural systems. However, since the precise definition of microbial exudates remains uncertain, this review aims to encompass and classify the diverse nature of compounds secreted or exudated by microbes, which can be referred to as microbial exudates. The review primarily focuses on the role of microbial exudates as biostimulants, and their function in plant growth, health promotion, plant protection, and the alleviation of abiotic stress. Additionally, the strategies or mechanisms involved in the cell-free microbial exudate-mediated remediation of heavy metals and the degradation of xenobiotic compounds are illustrated, along with their impact on the plant microbiome.Microbes release a variety of exudates into the rhizosphere, where the term \u201cexudates\u201d refers to compounds released through exudation, secretion, or both. These compounds are diverse, with the majority being organic, inorganic, or chemical in nature. They include metabolites like hormones, organic acids, amino acids, exopolysaccharides, siderophores, hydrogen cyanide (HCN), and volatile organic compounds(VOCs) . Microbe+6), cobalt (Co+2), manganese (Mn+2), and nickel (Ni+2), and facilitate their transportation within the plant cell through membrane receptor molecules [+2), zinc (Zn+2), cadmium (Cd+2), uranium (U+6), plutonium (Pu+4), thorium (Th+4), and Ni+2, altering their toxicity [Siderophores are low molecular weight organic compounds synthesized by numerous bacterial and fungal species under iron (Fe)-deficient environments. They are structurally and chemically diverse molecules with different iron-chelation capacities. Plants growing under iron-stressed conditions utilize siderophores produced by rhizospheric microbes surrounding the root zone to meet their iron demand. These siderophores have been reported to enhance biochemical and physiological processes in plants under drought conditions , saline olecules . Sideroptoxicity . Consequtoxicity . Based o3+complex when secreted. Various beneficial plant-associated bacterial species produce this type of siderophore, such as 2,3-dihydroxybenzoylglycine (Bacillus subtilis) [Azospirillum brasilense), 2,3-dihydroxybenzoic acid (Azospirillumlipoferum) [Azotobacter vinelandii) [Rhizobium radiobactor) [Rhizobium leguminosarum) [Bacillus subtilis is reported to enhance seed germination and plant growth in Coriandrum sativum [These siderophores contain mono- or dihydroxybenzoic acid moieties engaged in the chelation of ferric iron via hydroxyl groups, forming a hexadentate octahedral siderophore\u2013Feubtilis) , spirilopoferum) , aminochelandii) , Agrobacobactor) , and 2,3nosarum) . For exa sativum . Under d sativum .3+) ions via a carbonyl group. They are produced by bacterial and fungal species and form stable and strong hexadentate octahedral complexes with Fe3+. Examples include Vicibactin (Rhizobium leguminosarum bv. viciae), Ferrichrome (Ustilago ferrigona), Desferridoxamine B (Streptomyces griseus), and ferribactin (Pseudomonas fluorescens). Hydroxamate produced by Bacillus subtilis MF497446 and Pseudomonas korensis MG209738 significantly increased polyphenol oxidase, catalase, and peroxidase activities in maize, along with boosting the plant chlorophyll and carotenoid content, leading to improved crop yield [These siderophores are mostly derivatives of hydroxamic acids, with hexadentate ligands involved in the chelation of ferric (Feop yield .Sinorhizobium meliloti (Rhizobactin) [Rhizopus microspores (Rhizoferrin) and other mucorals [Pseudomonas sp.) and hydroxymate and phenol catechol functional groups. Pyoverdine-like and Pyochelin-like siderophores produced by Pantoea eucalypti M91 under alkaline conditions were reported to promote morphological and biochemical changes in the lotus plant and induce improved photosynthesis and iron translocation [Carboxylate siderophores are derivatives of citric acids, containing hydroxyl and carboxyl groups as proton donors for iron acquisition. They are produced by bacteria like obactin)  and fungmucorals . Mixed-llocation .Exopolysaccharides (EPSs) are extracellular sugar molecules produced by various microbes, including bacteria, cyanobacteria, marine microalgae, and marine micro-organisms . They arBacillus subtilis TP7 and Marinobacter lipolyticus SM19 restricted the uptake of Na+ by wheat. The binding and biofilm formation property of EPSs favor soil aggregation, stability, and the retention of the water layer around root cells, improving cell adhesion in plants growing under salt stress [Pseudomonas chlororaphis A20 and Bacillus proteolyticus A27) on the cell count, polysaccharide content, and invertase activity in the soil. They reported an increase in the cell biomass, polysaccharide content (by 158\u2013174%), invertase activity (153\u2013198%), and the ratio of water-stable soil macroaggregates and water-stable macro-aggregates in soil compared to the un-inoculated control, possibly due to the production of specific EPSs . Furthermore, EPSs have been reported to slow down the evaporation process, increasing water availability in plants [B. subtilis strain UD1022 reduced the hydraulic conductivity and accumulative evaporation in treated soil by altering/modifying water\u2019s physiochemical properties (viscosity and surface tension), soil matrix structure, and pore space connectivity. This provides more time for plants to make necessary metabolic adjustments during drought stress. Benard et al. [B. subtilis strain NCIB 3610, where EPSs produced by the strain reduced evaporative drying and water loss from the soil by reducing the soil hydraulic conductivity and capillary forces, enabling the retention of a water layer below the dry soil.For example, Atouei et al.  reportedt stress ,46 and dt stress ,48. Chent stress  demonstrn plants . EPSs prd et al.  reportedPhytohormones like auxin, gibberellin, cytokinin, and ethylene are exogenously produced by diverse microbes, including rhizospheric, epiphytic, symbiotic, and pathogenic fungi and bacteria. These phytohormones act as mediators for communication between plant hosts and microbes and serve as natural growth promoters for plants. Indole acetic acid (IAA) belongs to indole derivatives and is produced by many rhizospheric and epiphytic bacteria, as well as methylobacteria. Its biosynthesis in micro-organisms is associated with tryptophan metabolism and is formed via indole-3-pyruvic acid, indole-3-acetic aldehyde, and indole-3-acetamide formation. In plants, IAA binds to amino acids, sugars, or proteins and is stored in an inactive form; it is released when required. Gibberellins, on the other hand, are complex molecules of tetra-carbocyclic diterpenes consisting of isoprene residues that form four rings . The best-studied GAs are GA3, GA7, GA1, and GA4, and several other gibberellins are characterized based on characteristic biological activity. GAs in plants are required for stem elongation, cell division, the activation of amylolytic enzymes, and membrane stabilization. Another phytohormone, cytokinin, is produced by some microbes, such as rhizobacteria, streptomycetes, methylotrophic and methanotrophic bacteria, and PGPR strains, and includes adenine derivatives. These microbes synthesize zeatin, kinetin, iso-pentenyl-adenine, and some other cytokinin derivatives. Cytokinin regulates a wide range of physiological responses in plants, such as the activation of cellular RNA/protein synthesis, the inhibition of quiescence, the regulation of chloroplast formation, and the stabilization of the photosynthetic apparatus under adverse environmental stress. Additionally, certain bacteria and fungi can produce ethylene, which is biosynthesized via methionine metabolism. Phytohormones produced by microbes thus work as regulators for numerous physiological processes in both plants and microbes, can serve as a nutrient source, and have antimicrobial properties, as well as have a direct influence on microbial communities. Microbial auxins are reported to enhance root growth and root hair formation. Their capacity to sustain plant growth under abiotic stress or nutrient deficiency can be attributed to their role in altering root development and architecture . Further2, CO2, N2, NH3, SO2, SO3, H2S, O2, NO2\u2212, and HCN) or organic molecules that are small (<300 Da) C-based molecules. Classification has also been performed based on their molecular features, such as ring moieties, the number of C-atoms, and substituent groups [Microbial VOCs are a group of compounds emitted by microbes, such as bacteria and fungi, under diverse ecosystems. Chemically, microbial VOCs comprise heterogeneous molecular classes such as alcohols, ketones, thioalcohols, hydrocarbons, aldehydes, thioesters, cyclohexane, phenols, and benzene derivatives ,54,55,56t groups . Microbit groups . Microbit groups .Pantoea sp. on the roots of poplar, and its concentration was positively correlated with biofilm formation [Pseudomonas and Bacillus, as well as the phosphorus concentration of rhizospheric soils [Distinguishing between microbial exudates and plant root exudates is challenging in an actual plant\u2013microbe interacting set-up, as both are interrelated and collegial. Many researchers use the term \u201cexudates\u201d for compounds released by roots and associated microbes . Exudateormation . Oxalic ic soils . Organicic soils .Microbial biostimulants are essential for promoting plant growth and stress resistance. However, the emphasis has recently changed to employing cell-free microbial exudates as biostimulants to tackle the problems of shelf life of microbial cells and spores. To find secondary metabolites in microbial exudates, new methods have been devised . The chaBefore beginning these analyses, microbes are grown in liquid broth media, followed by refrigerated centrifugation, collection of the supernatant, vigorous shaking, and separation using a separating funnel. This procedure extracts microbial exudates using ethyl acetate, ethanol, or methanol. In order to discover new secondary metabolites as biostimulants, the resulting fraction is further separated and gathered for a biological assay and biochemical investigation .Separate fractions can be dried and dissolved in sterilized distilled water or methanol. A methylthiazolyldiphenyl-tetrazolium bromide (MTT)-based assay in microtitre plates can be used to determine the optimal dose for increasing the germination percentage without having any phytotoxic effects . The fraAs foliar sprays for dipping roots prior to transplanting or for irrigating seedlings placed in sterilized soil, the stated water and organic fractions can be utilized. The impact on seedling biomass accumulation, root shape, shoot biomass index, yield, and nutritional status can be evaluated ,79. The The specified doses of biostimulants can be evaluated through hydroponics and field trials, followed by field crop phenotyping through drone imaging . To asseDifferent analytical methods, including thin layer chromatography (TLC), gas chromatography coupled with mass spectrometry (GC-MS), liquid chromatography coupled with mass spectrometry (LC-MS), high-performance liquid chromatography (HPLC), column chromatography (CC), and high-resolution mass spectrometry (HRMS), etc. can be used to examine the fractions that have positive effects on plant growth and stress resilience ,84,85,86If the microbe\u2019s entire genome sequence is available, or once it has been generated, tools like the antiSMASH and KEGG pathway analyser can be used to undertake genome annotation and secondary metabolite gene cluster analyses ,89.This E. coli for low-cost commercial production, which is crucial for agricultural crop productivity and stress resilience [The molecular identification of genes associated with biostimulant production in microbes is essential for their further exploitation. The medium can be modified to increase the production of the desired metabolite once it has been identified as a biostimulant in the microbial exudate. Alternatively, mutants can be generated to increase the metabolite\u2019s production. Genes responsible for metabolite synthesis can be engineered and introduced into silience .Biostimulants encompass natural, synthetic, or formulated products of biological origin that can modify or regulate plant physiological processes, ultimately improving plant health and growth. The majority of biostimulants are of microbial origin and consist of secretions, extracts, or exudates from various microbes, including bacteria (endosymbiotic and plant-growth-promoting bacteria), fungi , and algae. Endophytic microbes produce metabolites with diverse biological activities, such as alkaloids, polypeptides, polyketides, and terpenoids, which hold significant importance in various fields, particularly agriculture. Antimicrobial compounds and phytohormones released by endophytes play a crucial role in enhancing biotic stress tolerance and promoting plant development and growth. These microbial exudates function through direct and indirect mechanisms, facilitating plant growth promotion and regulating plant defense against biotic and abiotic stress ,105. WhiAspergillus niger, Trichoderma harzianum, and Penicillium citrinum promote shoot and root length in chickpeas [Bacillus pumilus and Pseudomonas pseudolcaligenes stimulate rice growth and yield [Microbial exudates can promote and stimulate crop growth and development through various mechanisms, such as the solubilization of insoluble minerals, production of organic acids, antimicrobial metabolites/lytic enzymes, or regulation of growth-regulating genes . These mhickpeas . Microbihickpeas . For insnd yield . Algal eIn addition to promoting plant health, microbial exudates induce or stimulate the plant defense system against diverse biotic and abiotic stresses through modifications in physiological, biochemical, and biological properties .Fusarium sp., Sclerotinia sp., Rhizoctonia sp., Alternaria sp., Pythium sp., and Phytophthora sp. [Bacillus firmus (I-1582) arereported to be effective against various plant parasitic nematodes [Brevibacillus laterosporus (UNISS 18) is reported to secrete certain enzymes like chitinase , bacillolysin (Bl18), collagenase-like protease (prtC), and insecticidal toxin (mtx) capable of targeting wide range of Dipterans, Coleopterans, Lepidopterans, and nematodes [Fusarium sp. VOCs produced by P. fluorescens ZX, mainly organic acids and sulfur compounds, significantly inhibiting the conidial germination and mycelial growth of Penicillium italicum, and reducing blue mold decay on postharvest citrus [Microbial exudates contain several active compounds, such as hormones, exopolysaccharides, and volatiles, capable of inducing plant defense against various pathogens . These chora sp. ,167,168.ematodes ,170. Simematodes ,172,173.ematodes  reportedt citrus ,176.Lactobacillus planetarium elicit defense gene expression in tomatoes, increasing the catalytic activity of intracellular defense enzymes, such as PAL, PO, and polyphenoloxidase, and regulating the generation of reactive oxygen species (ROS) through catalase, superoxide dismutase, and hydrogen peroxide production [Pseudomonas fluorescence LPK2 and Sinorhizobium fredii KCC5 induces the synthesis of chitinase and \u03b2-1, 3-glucanase in plant hosts, suppressing Fusarium wilt caused by F. udum and F. oxysporum [P. fluorescence LBUM223 negatively regulates the txtA gene (virulence and pathogenicity gene) expression of Streptomyces sp. and thaxtomin A production, resulting in the inhibition of Streptomyces spin potato infection [Azospirillum brasilense strain V5 and V6 increases the expression level of defense genes like pathogenesis-related (PR) proteins and oxidative-stress-responsive genes in maize plants, enhancing plant growth [Fusarium sp. [Trichoderma virens enhances the symbiotic relationship between plants and microbes and elicits the plant\u2019s defense response to pathogens and parasites [Exopolysaccharides produced by oduction . The exoxysporum . Phenazinfection . Along wt growth ,181. Furrium sp. ,183,184.arasites .Under the European Green Deal policy, the \u2018From Farm to Fork\u2019 strategy aims to reduce the use of pesticides by 50% till 2030 to narrow down chemical interventions in agriculture. To address the policy\u2019s target of a climate-friendly approach, this strategy will encourage the adoption of alternative pest and disease management practices and pave the way for microbial-based active compounds and products. Such microbes can be explored for use as plant protection products (PPPs).Pseudomonas aeruginosa and Pseudomonas putida influence the chromium bioavailability, solubility, and transport or sorption behavior in subsurface systems [Bacillus amyloliquefaciens FZB42 are reported to protect plants by enhancing the biofilm stability in Arabidopsis thaliana [3+, Al3+, Cu2+, Eu3+, and Pb2+ [Azotobacter chroococcum help in alleviating heavy metal stress in maize [Agrobacterium radiobacter were effective in removing 54% of arsenic from polluted sites [P. citronellolis strain SLP6 H is reported to enhance the chlorophyll content, production of antioxidant enzymes, and plant growth in Helianthus annuus by producing the Hydroxamate siderophore [B. aryabhattai MS3 in rice boosted crop production by 60% and 43% under non-saline and saline (200mM NaCl) conditions, respectively [The potential of microbial biostimulants to reprogram plant defense systems against abiotic stresses like heavy metal toxicity, osmotic stress, and heat stress is still not fully recognized. However, the remarkable ability of microbial biostimulants, such as exopolysaccharides, siderophores, and other compounds, to enhance abiotic stress tolerance in plants makes them a suitable choice for mitigating the adverse effects of climate change on crop physiology . Extrace systems ,187. Undthaliana ,189. Thiand Pb2+ ,190,191.in maize . Similared sites . Under serophore . The appIn this context, the exploration and utilization of plant-growth-promoting rhizobacteria (PGPRs) present a promising avenue. Some PGPRs alleviate drought stress in plants by producing certain VOCs, 1-aminocyclopropane-1-carboxylate (ACC) dismutase, EPSs, phytohormones, antioxidants, etc. The ACC-deaminase enzyme produced by PGPR strains can degrade ACC produced during environmental stress conditions, thereby reducing ethylene levels in the soil and improving plant health during drought . Exopoly+ under salt stress. Proline can also act as a chemical chaperone to stabilize proteins [B. subtilis from its precursor glycine betaine choline by GbsB, GbsA, and GbsB enzymes [+ ions or reduce Na+ ions in shoots [Glomus sp., has been reported to have soil aggregating properties that improve the soil composition and provide drought tolerance [Plants colonized with rhizobacteria can uptake proline produced by their bacterial partners with minimal or no modification . This prproteins , and it  enzymes . Under h enzymes . Addition shoots ,204. Gloolerance . In suchXenobiotic compounds are manmade or chemical compounds introduced into the environment through industries, fossil fuel spills, mining activities, and agriculture, releasing excessive amounts of fertilizers, pesticides, and herbicides. These xenobiotics exhibit long-term persistence and slow degradation, leading to deleterious effects on the environment, soil, plants, and living organisms. Once they enter the food chain, they bioaccumulate, exerting carcinogenic, mutagenic, and toxic effects on organisms at higher trophic levels. Moreover, they alter the physio-chemical properties of the soil, microbial activity, and diversity, leading to ecotoxicological effects . In planKoribacter, Acidomicrobium, Bradyrhizobium, and Burkholderia revealed the abundance of phosphodiesterase-encoding genes, potentially capable of degrading organophosphorus compounds. These genera of bacteria were found in soil contaminated with pesticides [Trichoderma hamatum FBL 587 reported the upregulation of about 1706 genes involved in DDT degradation. Various DDT-metabolizing enzymes like epoxide hydrolases, glycosyl and glutathione-transferases, and FAD-dependent mono-oxygenases were also upregulated [Bacillus amyloliquefaciens YP6 was illustrated through transcriptome analysis, revealing the upregulation of oxidase, NADPH-cytochrome P450 reductase, and hydrolase genes for the oxidation, dealkylation, and hydrolysis of phoxim [The hazardous impact of xenobiotics necessitates immediate degradation methods. Although physical and chemical degradation methods like adsorption, electrolysis, filtration, coagulation, ozonation, and chemical precipitation are available, their stringent, complicated, and high-cost methodologies, as well as toxic by-products, are major drawbacks for their application in xenobiotic degradation ,210. Altsticides . Similaregulated . The degf phoxim . MicrobiMicrobial exudates enclose an array of molecules, including sugars, organic acids, hormones, secondary metabolites, polymers (mucilage), proteins, peptides, volatiles, and more . While tIt can be presumed that chemically similar compounds are secreted by a group of microbes and their relatives that belong to the same taxonomic clade. Sometimes, these chemical exudates have either beneficial or harmful effects on other microbial populations. They may be used as metabolic substrates and growth regulators, or act as toxic, antagonistic compounds, and signaling molecules, ultimately altering the microenvironment and influencing the population of surrounding organisms. The composition and functioning of microbial exudates play a key role in shaping the plant microbiome .Bacillus sp., Pseudomonas sp., and Streptomyces sp.) and other rhizospheric microbiota involved in the N-cycle, sugar degradation, and organic acid production.Most microbial exudates consist of a substantial amount of carbon-containing compounds such as sugars, organic acids, and amino acids. These molecules are often utilized as the preferred carbon source by some microbes. For instance, beneficial rhizospheric bacteria prefer sugars and polymers like chitin, chitosan, glucan, glucosamine, etc., which they metabolize into organic acids like acetic acid, citric acid, formic acid, glycolic acid, lactic acid, malonic acid, oxalic acid, succinic acid, and more . The subOrganic acids are another significant component of microbial exudates involved in restructuring the microbial community. They are associated with the mineralization process, and specific groups of microbes are engaged in different stages of the mineralization cycle. The exogenous application of organic acids supports the colonization of specific microbial groups and decreases species richness by lowering diversity indices, resulting in continuous changes in the microbiological community structure. For example, lactic acid favors the proliferation of members of the family Bacillaceae and Micrococcaceae, supporting biodegradation and enhancing soil fertility, leading to rapid changes in the microbiota composition. However, once the lactic acid is degraded, the previous microbial species return to the niche, while specific members of certain distinctive families like Pseudomonadaceae and Rhizobiaceae remain constantly present. Similar phenomena are also evident in citric acid, which favors the growth of members of the Clostridiaceae family, along with the presence of Pseudomonadaceae family members. Likewise, oxalic acid induces long-term changes in the bacterial community composition, with the dominance of members of Burkholderiaceae accompanied by plant-growth-promoting rhizobacteria . In thisLactuca sativa L.) and also promotes the population of entomopathogenic fungi (Beauveria sp. and Metarhizium sp.) to suppress fungi and nematode infestation [Enterobacter sp., Pantoea sp., etc. [Peptides and amino acids present in microbial exudates can also serve as nutritional sources of both carbon and nitrogen for the plant-associated microbiome. These molecules are generated through the proteolysis of complex proteinaceous compounds in the environment or as cellular efflux from microbial cells. Phylospheric and rhizospheric microbes can use these amino acids as organic nitrogen for their growth and proliferation. For instance, the exogenous application of L-\u03b1-amino-acid-based biostimulants containing biologically active free amino acids enhances the population of Actinobacteria in the rhizospheric soil of lettuce  act as signal molecules that trigger quorum sensing (QS) mechanisms in plant-associated microbes, including beneficial and pathogenic species. QS is crucial for cellular communication within microbial groups or between groups, necessary for biofilm formation and gene activation for microbial function. The exogenous application of N-AHLs can change the alpha and beta diversity of the rhizospheric microbial population, as evident in udomonas , thus plRhizobium etli [Azospirillum brasilense [Streptomyces sp. [Likewise, hormones are another crucial chemical compound found in cell-free microbial exudates, produced abundantly in the cultural filtrates of many plant-associated microbes. They act as \u2018messengers\u2019 or signaling compounds involved in many biological processes of plants, as well as microbes present in the phyllosphere and rhizosphere. Apart from supporting cellular and physiological processes in plants, they act as signaling compounds  and a nuium etli  and Azosasilense , inducesyces sp. , and actyces sp.  and chemyces sp. . In thisFlaveria robusta with sucrose + amino acids and sucrose alone enhances microbial diversity in its phyllosphere zone and niche partitioning between two bacteria, namely, Pantoea sp. and Pseudomonas sp., through cross-feeding interactions [3+, Ca2+, Na2+, K2+, etc. They also help in the release of phosphates from insoluble phosphate compounds to make them available for the plant and associated microbes [The microbial ecology of the plant rhizosphere is very complex and is presented in terms of the diversity and composition of microbial taxa within it. Within a plant rhizospheric ecology, different microbial groups form small niches for their specific properties and metabolic activities . The exuractions . This comicrobes , thus chP. syringae [The utilization of microbial biostimulants in crop production is comparatively a new approach and is still lagging due to a lack of awareness regarding their potential. The strategy has gained prominence only in the past decades. The diverse nature and chemical composition of microbial active compounds have widened their utilization in various fields. However, several constraints need to be addressed before we commercialize any of the microbial exudates as biostimulants or bio-agents. The genetic basis of interaction between these biostimulants and plants is not fully explored, and the actual mechanism and mode of action of these biostimulants remain unclear. The diversity in microbial strains and their bioactive compounds makes it difficult to compare the effect of their application and evaluate the results. The relation between microbial biostimulants and how they alter or modify plant physiology is complex, and the lack of research illustrating the role and relevance of these molecules involved in the biostimulation process or their molecular mechanism involved in the bio-stimulatory action is a drawback for further research. The application of these metabolites has shown positive results in plant growth and development, protection against phytopathogenic microbes and abiotic stress, or mitigation of metal toxicity, especially in the invitro condition. However, replicating the same results at the field level is a bottleneck due to difficulties in producing suitable formulations for modern agriculture and also due to the failure of some exudates to be effective at a large scale. For instance, the field application of 3-pentanol and 2-butanol (VOCs) showed limited control over syringae . AnotherThe interaction between plant systems and microbes dates back to ancient times, resulting in an intricate relationship that can be beneficial, detrimental, or neutral. While numerous microbes are phytopathogenic, a good share of beneficial microbes interacts with the plant, positively influencing crop development. Microbes produce a diverse array of bioactive compounds/metabolites, allowing them to form an intricate relationship with the plant system. Various metabolites and exudates are released in the process, which can alter or modify plant physiology to improve its growth, development, and resilience against biotic and abiotic stress. Exudates secreted or released by microbes, such as phytohormones, exopolysaccharides, and VOCs, are mainly secondary metabolites of diverse chemical nature and composition, which play diverse roles in crop improvement and can be effective biostimulants. The need to minimize the use of chemical fertilizers and pesticides is imperative if sustainability, soil fertility conservation, and ecological balance are to be restored. The potential role of microbes and their exudates can prove to be essential components as bio-agents, bioremediators, or biostimulants in regenerative agriculture or organic farming systems.Despite realizing the potential of microbes to some extent, there is a fundamental lack of investment in and implementation of their role in the agriculture sector. Thus, optimizing cultivation conditions, biochemically characterizing microbial biostimulants, conducting extensive research on their mode of action and mechanism, and determining the dose and concentration of the compounds and their effective formulation are necessary for developing microbial exudates as biostimulants at the commercial level. It is essential to qualitatively and quantitatively identify compounds secreted by microbes and explore their transcriptomics, metabolomics, and proteomics to characterize their biosynthetic pathways and maximize their utilization as potential biostimulants. Addressing these challenges and constraints will pave the way for realizing the full potential of microbial exudates as an essential component of sustainable and eco-friendly agriculture systems."}
+{"text": "This perspective piece focuses on and analyzes several lesbians, gays, bisexuals, and transgender (LGBT) individuals' rights and their limitations in the Association of Southeast Asian Nations (ASEAN) region, including the limited recognition of self-determined gender identity, limited legal provisions for LGBT marriage, inadequate anti-discrimination policies, and the criminalization of homosexuality. These inadequacies in LGBT rights may stem from colonial, religious, and cultural factors. Moreover, these limited LGBT rights and their societal repercussions may contribute to the minority stress of LGBT individuals, leading to their higher rates of mental health problems. Thus, there may be a need to uphold, recognize, and protect LGBT rights as the region pursue equitable mental health. Toward this pursuit, the region may possibly benefit from culturally adapting gender-affirming practices, increasing their social support, opposing the practice of conversion therapy, and decriminalizing homosexuality. It may also be necessary to explore, analyze, and study the intersection of LGBT identity and mental health, especially longitudinal and interventional studies. The Association of Southeast Asian Nations (ASEAN) comprises ten member states, including Brunei Darussalam, Cambodia, Indonesia, Lao PDR, Malaysia, Myanmar, Philippines, Singapore, Thailand, and Vietnam. The ASEAN is also a region with diverse cultures, traditions, and policies  individuals as distal stressors, which are the \u201cexternal, objective stressful events and conditions Meyer, \u201d. As conThis perspective piece reviews the legislation for several LGBT rights, their limitations, and their possible implications for mental health in the ASEAN region. While LGBT rights have been examined using various theoretical and methodological approaches and frameworks  .\u201d Richardson  identifiThis limited gender identity recognition may contribute to minority stress, leading to heightened rates of mental disorders among LGBT individuals in the region (Tan and Saw, In general, LGBT individuals in the region may benefit from gender identity affirmation. In addition, the region can also culturally adapt other countries' gender-affirming guidance to fit their context. For instance, US gender-affirming practices such as gender-specific group therapy can be adapted to the Philippines by implementing this therapy among its closely-bonded peer groups called \u201cbakadahan\u201d (Alibudbud, Like gender affirmation, marriage may also offer protection against poor mental health (Wight et al., This limited marriage equality may be attributed to social and legal impediments. For instance, the Philippines' Family Code, similar to Thailand, states that marriage is between a \u201cman\u201d and a \u201cwoman\u201d (UNDP and USAID, Freedom from discrimination is an inherent right accorded to individuals. The sexual citizenship framework identifies protection from SOGIE-based discrimination as a possibly fundamental sexual right of LGBT individuals (Richardson, These negative societal attitudes and norms toward LGBT individuals are influenced by traditional religious values, especially in Malaysia, Indonesia, the Philippines, and Brunei (Manalastas et al., In recent years, there have been steps toward decreasing these stressors. Thailand and some Philippine localities have policies that protect from sexuality and gender-based discrimination Kwatra, . HoweverSince discrimination may be detrimental to LGBT mental health, anti-discrimination policies may need to be strengthened Meyer, . FurtherThe participation and enjoyment of sexual acts and autonomy over one's body were important aspects of sexual rights based on conduct-based discourses (Richardson, While these penalties are rarely enforced, they may perpetuate the societal stigma against LGBT individuals in the region Kwatra, . In addiRecently, there has been a movement in the region toward ending the criminalization of homosexuality. For example, in 2022, LGBT individuals in Singapore celebrated their government's move to abolish the colonial-era 377A law, which criminalizes sex between men (Alibudbud, This perspective piece identified several LGBT rights in the ASEAN region following the sexual citizenship framework of Richardson , includiThe original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.RA had substantial contributions to the design, drafting, revision, acquisition, interpretation, and final approval of the data and work."}
+{"text": "The purpose of this study was to further monitor the in vitro activity of eravacycline against Staphylococcus aureus , Enterococcus spp.  and Streptococcus spp.Eravacycline is a fully synthetic, fluorocycline approved for the treatment of complicated intra-abdominal infections (cIAI) in patients \u226518 years of age in Europe, Singapore, Hong Kong, mainland China, the US, and the UK. Previous surveillance studies of eravacycline have demonstrated potent A total of 1,557 clinical isolates were collected worldwide during 2021 from multiple infection sources, including bodily fluids, gastrointestinal, genitourinary, and respiratory. Of the 1,557 isolates, 316, 649, and 592 were from Asia/Pacific, Europe, and North America, respectively. Minimum inhibitory concentrations (MICs) were determined by CLSI broth microdilution. For comparative purposes, antibiotic susceptibility for eravacycline and tigecycline was determined with both FDA and EUCAST breakpoints, where available.Summary MIC data for eravacycline and tigecycline, as a selected comparator, are shown in the Table. Susceptibility to eravacycline in all Gram-positive pathogens was greater than 90% for most species/phenotypes though was notably higher when EUCAST breakpoints were applied to the analysis.Eravacycline demonstrated sustained high susceptibility rates against clinically important Gram-positive pathogens, including resistant isolates. Importantly, no CLSI breakpoint exists to date for eravacycline, though the use of EUCAST breakpoints showed higher susceptibilities compared with the use of FDA breakpoints. Harmonization of clinical breakpoints for eravacycline would be desirable.Stephen Hawser, PhD, Allecra: study funding|Innoviva Specialty Therapeutics, Inc.: Honoraria|Roche: Honoraria|Roche: This project has been funded by BARDA (HHSO100201600038C). Nimmi Kothari, PhD, Allecra: Allecra (study funding)|Innoviva Specialty Therapeutics, Inc.: Honoraria|Roche: Honoraria|Roche: This project has been funded by BARDA (HHSO100201600038C). Federica Monti, PhD, Allecra: Study funded|Innoviva Specialty Therapeutics, Inc.: Honoraria Tony Hodges, MD, La Jolla Pharmaceutical Company: Employee|La Jolla Pharmaceutical Company: Stocks/Bonds Kristie Zappas, PhD, La Jolla Pharmaceutical Company: employee|La Jolla Pharmaceutical Company: Stocks/Bonds"}
+{"text": "Over the past two decades, Sub-Saharan Africa (SSA) has faced multiple public health emergencies . A publiThe region has also seen a rise in zoonotic pathogen outbreaks caused by monkeypox and Ebola viruses. From 2012 to 2022, zoonotic disease outbreaks in SSA rose 63% compared to 2001\u20132011. From 2001 to 2022, 33% of PHEs were zoonotic disease outbreaks . In thisIn this section, we unpack challenges faced during previous outbreaks grouped into individual, health system, and community-level challenges.Poor socioeconomic status (SES), stigma, low-risk perception, limited access to healthcare, and cultural beliefs contribute to emerging infectious disease outbreaks in SSA . About 3Poor SES is linked to low health literacy, limiting infection prevention and control knowledge. Reduced awareness leads to fewer immunizations and delayed treatment, possibly contributing to emerging infectious disease spread . Some peUnderinvestment in health , conflicPoor disease surveillance has been attributed to a lack of experienced HCWs, heavy workloads, and low HCW motivation. The lack of PPE and isolation rooms complicates infection control, resulting in patient-to-HCW cross-infections . Low labPeople unlawfully cross SSA's porous borders . WithoutThere were also some notable strengths, which we stratified into individual-level, health system-level, and community-level strengths.In 2018, SSA had 44% mobile phone penetration . Cell phSeveral SSA nations have had an emerging infectious disease outbreak, therefore they have response strategies for PHEs. HCWs with prior experience in handling emerging infectious disease outbreaks are valuable in managing ongoing emerging infectious disease outbreaks . As partDuring the EVD and COVID-19 epidemics, SSA nations cooperated to improve disease testing . The majDuring COVID-19, SSA increased genomic surveillance, and South Africa and Botswana detected the Beta and Omicron variants. Transparency in reporting revealed SSA countries were ready to collaborate to control emerging infectious diseases . DespitePast PHEs in Africa resulted in structures for future emerging infectious disease outbreaks . Re-engaFrom the challenges and strengths experienced during the previous and current emerging infectious disease outbreaks, we came up with recommendations on how SSA might better prepare for future emerging infectious disease outbreaks.SSA's low SES worsens conflict and disease outbreaks. SSA countries should come up with plans to raise their populations' SES. Strategies include increasing industrialization, maximizing agricultural potential, and integrating regional markets . ImproveWe advocate improving access to education and initiating health education in preschool to increase health literacy. With more health knowledge, the population's risk perception may rise, leading to more vaccinations and healthcare utilization .The health system recommendations include the implementation and strengthening of the One Health approach, strengthening health systems, and improving disease surveillance.SSA countries should strengthen the One Health Approach. One Health Approach addresses zoonoses where people, animals, and the environment intersect. It aims to create interdisciplinary, cross-sectoral, and cross-regional collaboration to predict emerging infectious disease outbreaks . DomestiSub-Saharan Africa should enhance its health systems to handle future emerging infectious disease outbreaks. Workforce, service delivery, health information systems, access to essential medicines, health financing, and leadership and governance should be reinforced. These initiatives should be localized , 38\u201341. Laboratories' capacity needs to be improved to be able to identify a variety of pathogens. Furthermore, it is important to create laboratory networks that link national, regional, and research reference laboratories . More HCSSA countries must upgrade their information, communication, and technology (ICT) infrastructure to gather and send patient health data. By reducing data volume and automating data collection, validation, and analysis, ICT can reduce errors. Local health management information systems (HMIS) should be integrated with national HMIS, and data should be used at every level of the healthcare system to enable ICT uptake and use. Data should be aggregated and summarized to offer summary indicators for planning and resource allocation . The natBig data and artificial intelligence (AI) can transform emerging infectious disease surveillance and response by improving the current traditional systems and strengthening outbreak detection and response . DigitalSSA countries should inform local populations about emerging infectious diseases using billboards, mainstream media, and social media platforms in their native languages . Social SSA has had multiple PHEs in the past two decades, most of them emerging infectious disease outbreaks. Emerging infectious disease outbreaks were caused by microorganism adaptation and alteration due to climatic and environmental changes, shifting habitats, and increased human susceptibility to infection due to immunosuppression, undernourishment, and poor vaccination. The bulk of emerging infectious disease outbreaks was caused by zoonotic pathogens, and their rise has been related to urbanization, a fast-expanding population, increased demand for animal food, and invasion of natural habitats. When managing and containing the emerging infectious disease outbreaks, the countries in the region encountered several challenges at the individual, health system, and community levels. Furthermore, the management and control of these outbreaks also revealed several strengths the region has. Based on these challenges and strengths, we suggest that the region implement and strengthen the One Health approach, improve the socioeconomic status of the population, strengthen its health systems, improve disease surveillance, and involve and educate communities about emerging infectious diseases.EM and MM: conceptualization and writing original draft. PM: writing original draft. TD: conceptualization, supervision, and writing review and editing. IC and GM: writing review and editing. All authors contributed to the article and approved the submitted version."}
+{"text": "To evaluate the association between gestational weight gain (GWG) and adverse neonatal outcomes in women who conceived using assisted reproductive technology (ART).The National Vital Statistics System (NVSS) 2019\u20132021 provided data for this retrospective cohort study. Adverse neonatal outcomes included premature birth, small for gestational age (SGA), large for gestational age (LGA), macrosomia, low birth weight (LBW), and other abnormal conditions. Any adverse outcome was defined as at least one of the above six outcomes. Multivariate logistic regression analysis was employed to evaluate the associations between GWG and different outcomes, after adjusting for confounding factors. These associations were further assessed in subgroups of maternal age at delivery, paternal age at delivery, preconception body mass index (BMI), gestational age, maternal race, parity, gestational diabetes, and gestational hypertension.P<0.001] and excessive GWG  had significantly greater risks of any adverse outcome than those with sufficient GWG. In contrast to sufficient GWG, insufficient GWG was associated with significantly elevated risks of premature birth , SGA , LBW , and other abnormal conditions , and excessive GWG was associated with significantly lower risks of premature birth , SGA , LBW , and other abnormal conditions . Infants born to women with insufficient GWG had significantly decreased risks of LGA  and macrosomia , and infants born to women with excessive GWG had significantly increased risks of LGA  and macrosomia .Totally 108201 women were included, with 22282 in the insufficient GWG group, 38034 in the sufficient GWG group, and 47885 in the excessive GWG group. Women with insufficient GWG [odds ratios (OR) = 1.11, 95%CI: 1.07\u20131.16, Insufficient GWG and excessive GWG were associated with increased risks of any adverse outcome than sufficient GWG in women who conceived with ART, indicating the applicability of recommended GWG by the Institute of Medicine (IOM) in this population. With the increasing prevalence of infertility and the postponement of childbearing time worldwide, the application of assisted reproductive technology (ART) is gradually increasing , 2, whicGestational weight gain (GWG) is a potentially modifiable factor in adverse pregnancy outcomes . GWG is This study intended to evaluate the association between GWG and adverse neonatal outcomes in women who conceived using ART, considering preconception BMI and using the data from the National Vital Statistics System (NVSS) database, in order to assess the applicability of the GWG recommended by the IOM in this population. The association was further assessed in subgroups of maternal age at delivery, paternal age at delivery, preconception BMI, gestational age, maternal race, parity, gestational diabetes, and gestational hypertension.The NVSS 2019\u20132021 provided data for this retrospective cohort study. The NVSS database collects nationwide data on births, deaths, marriages, and other events in 50 states, New York City, District of Columbia, and 5 territories  of the United States . Since t2 was considered as underweight, BMI of 18.5\u201324.9 kg/m2 as normal weight, BMI of 25.0\u201329.9 kg/m2 as overweight, and BMI \u2265 30.0 kg/m2 as obese, of which 30.0\u201334.9 kg/m2 was regarded as obesity class I, 35.0\u201339.9 kg/m2 as obesity class II, and \u2265 40 kg/m2 as obesity class III. For GWG classification, when preconception BMI < 18.5 kg/m2 (underweight), 12.5\u201318.0 kg was regarded as sufficient GWG; when preconception BMI was 18.5\u201324.9 kg/m2 , 11.5\u201316.0 kg was regarded as sufficient GWG; when preconception BMI was 25.0\u201329.9 kg/m2 (overweight), 7.0\u201311.5 kg was regarded as sufficient GWG; when preconception BMI \u2265 30.0 kg/m2 (obese), 5.0\u20139.0 kg was regarded as sufficient GWG. The weight gain below sufficient GWG was deemed as insufficient weight. The weight gain above sufficient GWG was considered as excessive weight . Premature birth was defined as birth at gestational age < 37 weeks. SGA was defined as a birth weight below the 10th percentile. LGA was defined as a birth weight above the 90th percentile. Macrosomia was defined as a birth weight > 4000 g. LBW was defined as a birth weight < 2500 g. Any adverse outcome was defined as at least one of the above six outcomes.The following clinical data were collected: gestational age (weeks), maternal age at delivery (years), maternal race , maternal education level , paternal age at delivery, paternal education level , paternal race , marital status , parity , smoking before pregnancy, smoking during pregnancy, start time of prenatal care (months), prenatal care visit (times), pre-gestational diabetes, gestational diabetes, pre-gestational hypertension, gestational hypertension, hypertension eclampsia, fever, previous premature birth, previous cesarean delivery.1, Q3)], and the rank sum test was applied for intergroup comparisons. Categorical data were shown as the number of cases and the composition ratio [n (%)], and intergroup comparisons were subject to the Chi-square test. Missing values were deleted, and sensitivity analysis was performed for data before and after deletion of missing values , and the t test was used for comparisons among groups. Continuous data with skewed distribution described with median and quartile [M .In total, 125732 women aged \u226518 years and with singleton pregnancy resulting from ART were included from the NVSS 2019\u20132021. After excluding women without 24\u201342 weeks of gestational age (n = 7364), and with missing information on GWG (n = 2260), preconception BMI (n = 196), neonatal outcomes (n = 32), paternal age (n = 5816), smoking during pregnancy (n = 228), start time of prenatal care (n = 1182), prenatal care visit (n = 440), and fever (n = 13), 108201 women were eligible for this study. The flow chart of study population selection is illustrated in The overall incidence of any adverse outcome showed a U-shaped trend as GWG increased. The relationship between any adverse outcome and GWG and the relationship between any adverse outcome and average GWG per gestational age had a similar trend. When GWG was within a reasonable range, the incidence of adverse neonatal outcomes may be the lowest . Then anP<0.05), and insufficient GWG was associated with a significantly increased risk of other abnormal conditions (P<0.001)  .P<0.001) and excessive GWG  were associated with significantly higher risks of any adverse outcome. Compared with the sufficient GWG group, the insufficient GWG group had significantly increased risks of delivering premature infants , SGA infants , LBW infants , and infants with other abnormal conditions , and the excessive GWG group had significantly decreased risks of delivering premature infants , SGA infants , and LBW infants . In contrast to sufficient GWG, insufficient GWG was associated with significantly lower risks of LGA  and macrosomia , and excessive GWG was associated with significantly greater risks of LGA  and macrosomia   .P<0.001) and excessive  GWG groups was significantly higher than that in the sufficient GWG group. Compared with sufficient GWG, insufficient GWG was associated with significantly elevated risks of preterm birth , SGA , LBW , and other abnormal conditions , while excessive GWG was associated with significantly reduced risks of preterm birth , SGA , and LBW . Women with insufficient GWG had significantly lower risks of delivering LGA infants  and macrosomia , and those with excessive GWG showed significantly greater risks of delivering LGA infants  and macrosomia  than women with sufficient GWG  and excessive GWG  had significantly greater risks of any adverse outcome than those with sufficient GWG. In contrast to sufficient GWG, insufficient GWG was associated with significantly elevated risks of premature birth , SGA , LBW , and other abnormal conditions , and excessive GWG was associated with significantly lower risks of premature birth , SGA , LBW , and other abnormal conditions . Infants born to women with insufficient GWG had significantly decreased risks of LGA  and macrosomia , and infants born to women with excessive GWG had significantly increased risks of LGA  and macrosomia  , women with insufficient GWG  .For both women \u2264 35 years and women > 35 years, insufficient GWG and excessive GWG were associated with significantly greater risks of any adverse outcome than sufficient GWG. Among both women \u2264 35 years and women > 35 years, insufficient GWG was associated with significantly increased risks of premature birth, SGA, LBW, and other abnormal conditions, and significantly reduced risks of LGA and macrosomia; excessive GWG was associated with significantly lower risks of premature birth, SGA, LBW, and other abnormal conditions, and significantly higher risks of LGA and macrosomia .Regarding paternal age \u2264 35 years, insufficient GWG was associated with significantly elevated risks of any adverse outcome, premature birth, SGA, LBW, and other abnormal conditions, and significantly reduced risks of LGA and macrosomia; excessive GWG was associated with significantly higher risks of any adverse outcome, LGA, and macrosomia, and significantly lower risks of premature birth, SGA and LBW. For paternal age > 35 years, insufficient GWG was associated with significantly increased risks of any adverse outcome, premature birth, SGA, LBW, and other abnormal conditions, and significantly decreased risks of LGA and macrosomia; excessive GWG was associated with significantly greater risks of any adverse outcome, LGA, and macrosomia, and significantly lower risks of premature birth, SGA, LBW, and other abnormal conditions .For underweight women before pregnancy, insufficient GWG was associated with significantly increased risks of premature birth, excessive GWG was associated with significantly higher risks of any adverse outcome, LBW, and other abnormal conditions. For normal weight women before pregnancy, insufficient GWG was associated with greater risks of any adverse outcome, premature birth, SGA, LBW, and other abnormal conditions; excessive GWG was associated with significantly increased any adverse outcome, LGA, and macrosomia. For overweight women before pregnancy, insufficient GWG was associated with significantly increased risks of any adverse outcome, premature birth, SGA, and other abnormal conditions; excessive GWG was associated with a significantly lower risk of premature birth, and significantly higher risks of LGA and macrosomia. For obese women before pregnancy, insufficient GWG was associated with significantly elevated risks of premature birth, LBW, and other abnormal conditions, and significantly decreased risks of LGA and macrosomia; excessive GWG was associated with significantly lower risks of premature birth, SGA, LBW, and other abnormal conditions, and significantly higher risks of LGA and macrosomia .Concerning women with gestational age <37 weeks, insufficient GWG was associated with a significantly lower risk of LGA, and significantly increased risks of SGA, LBW, and other abnormal conditions; excessive GWG was associated with a significantly elevated risk of LGA, and significantly reduced risks of LBW and other abnormal conditions. For women with gestational age of 37 weeks and above and less than 40 weeks, insufficient GWG was associated with a significantly reduced risk of LGA, and significantly increased risks of SGA, LBW, and other abnormal conditions; excessive GWG was associated with significantly higher risks of LGA and macrosomia. For women with gestational age \u226540 weeks, insufficient GWG was associated with significantly reduced risks of LGA and macrosomia, and significantly higher risks of SGA and LBW; excessive GWG was associated with significantly increased risks of any adverse outcome, LGA, and macrosomia, and a significantly lower risk of SGA .As regards White women, insufficient GWG was associated with significantly greater risks of any adverse outcome, premature birth, SGA, LBW, and other abnormal conditions, and significantly lower risks of LGA and macrosomia; excessive GWG was associated with significantly elevated risks of any adverse outcome, LGA, and macrosomia, and significantly decreased risks of premature birth, SGA, LBW, and other abnormal conditions. For Black women, insufficient GWG was associated with a significantly higher risk of premature birth; excessive GWG was associated with significantly greater risks of LGA and macrosomia, and a significantly lower risk of SGA. For Asian women, insufficient GWG was associated with significantly elevated risks of any adverse outcome, premature birth, SGA, LBW, and other abnormal conditions, and a significantly reduced risk of LGA and macrosomia; excessive GWG was associated with significantly lower risks of premature birth and SGA, and significantly higher risks of LGA and macrosomia .For multiparas, insufficient GWG was associated with significantly higher risks of premature birth, SGA, LBW, and other abnormal conditions, and significantly lower risks of LGA and macrosomia; excessive GWG was associated with significantly greater risks of any adverse outcome, LGA, and macrosomia, and significantly reduced risks of premature birth, SGA and other abnormal conditions. For nulliparas, insufficient GWG was associated with significantly increased risks of any adverse outcome, premature birth, SGA, LBW, and other abnormal conditions, and significantly decreased risks of LGA and macrosomia; excessive GWG was associated with significantly elevated risks of any adverse outcome, premature birth, LGA, and macrosomia, and significantly reduced risks of SGA, LBW, and other abnormal conditions .In women without diabetes, insufficient GWG was associated with significantly greater risks of any adverse outcome, premature birth, SGA, LBW, and other abnormal conditions, and significantly lower risks of LGA and macrosomia; excessive GWG was associated with significantly elevated risks of any adverse outcome, premature birth, LGA, and macrosomia, and significantly reduced risks of SGA, LBW and other abnormal conditions. Among women with diabetes, insufficient GWG was associated with significantly higher risks of any adverse outcome, premature birth, SGA, LBW, and other abnormal conditions, and significantly lower risks of LGA and macrosomia; excessive GWG was associated with significantly increased risks of any adverse outcome, LGA, and macrosomia, and significantly decreased risks of SGA .For women without gestational hypertension, insufficient GWG was associated with significantly higher risks of any adverse outcome, premature birth, SGA, LBW, and other abnormal conditions, and significantly lower risks of LGA and macrosomia; excessive GWG was associated with significantly increased risks of any adverse outcome, LGA, and macrosomia, and significantly reduced risks of premature birth, SGA, LBW and other abnormal conditions. For women with gestational hypertension, insufficient GWG was associated with significantly elevated risks of premature birth, SGA and other abnormal conditions, and significantly decreased risks of LGA and macrosomia; excessive GWG was associated with significantly greater risks of LGA and macrosomia, and significantly lower risks of premature birth, SGA and other abnormal conditions .This study took preconception BMI into account and explored the association between GWG and adverse neonatal outcomes in women who conceived with ART for the first time. With the data on 108201 women from the NVSS, we found that insufficient GWG and excessive GWG were associated with significantly higher risks of any adverse outcome than sufficient GWG, indicating the applicability of the GWG recommended by the IOM in this population. Specifically, compared with sufficient GWG, insufficient GWG was associated with significantly elevated risks of premature birth, SGA, LBW, and other abnormal conditions; excessive GWG was associated with significantly increased risks of LGA and macrosomia. These findings may serve as a reference for weight management of women conceiving via ART to prevent or lower the risk of adverse neonatal outcomes.According to a systematic review and meta-analysis, insufficient GWG was associated with greater risks of preterm birth and SGA; excessive GWG was associated with higher risks of LGA and macrosomia . Eick etWith respect to specific neonatal outcomes, insufficient GWG was associated with elevated risks of premature birth, SGA, LBW, and other abnormal conditions; excessive GWG was associated with increased risks of LGA and macrosomia in contrast to sufficient GWG. For potential mechanisms, GWG is regarded as a sign of many physiological processes, including metabolism and body composition, and may indicate nutritional status . InsuffiThis study further evaluated the association between GWG and adverse neonatal outcomes among ART conceptions in terms of maternal age at delivery, paternal age at delivery, preconception BMI, gestational age, maternal race, parity, gestational diabetes, and gestational hypertension. For women \u2264 35 years and > 35 years, the associations of insufficient and excessive GWG with all adverse neonatal outcomes were consistent, which suggested that maternal age at delivery did not significantly affect these associations. As regards paternal age at delivery, excessive GWG was associated with a significantly lower risk of other abnormal conditions when paternal age was over 35 years, while no significant was found for paternal age \u2264 35 years, which necessitates more evidence to assess the effect of paternal age on these abnormal conditions. On the other hand, the research by Basso et al.  and Ni e2, sufficient GWG is 12.5\u201318.0 kg; for preconception BMI of 18.5\u201324.9 kg/m2, sufficient GWG is 11.5\u201316.0 kg; for preconception BMI of 25.0\u201329.9 kg/m2, sufficient GWG is 7.0\u201311.5 kg; for preconception BMI \u2265 30.0 kg/m2, sufficient GWG is 5.0\u20139.0 kg. Clinicians could provide prenatal counseling for women who conceived via ART to maintain an appropriate weight during pregnancy, and thus manage the risk of adverse neonatal outcomes. Lifestyle interventions, such as having a healthy balanced diet and exercising properly, can help women using ART achieve the recommended GWG. Knowledge about the association between GWG and adverse neonatal outcomes and feasible interventions should also be popularized among this population. Some limitations should be noted when interpreting our findings. First, it is difficult to obtain and adjust for other possible confounders during pregnancy due to the limitation of the NVSS, such as dietary patterns and interventions for pregnancy complications. Second, this study paid attention to singleton pregnancy with 24\u201342 weeks of gestation, which may not be applicable to multiple pregnancy and newborns outside 24\u201342 weeks of gestational age. Third, the NVSS were an American database, and our research may have limited generalizability in other populations.The present study utilized a large nationally representative sample from the NVSS, and first evaluated the association between GWG and adverse neonatal outcomes in women conceiving with ART and applicability of the recommended GWG by the IOM in these women. In view of our findings, emphasis should be given on the importance of sufficient GWG for different preconception BMI. For women with preconception BMI < 18.5 kg/mInsufficient GWG and excessive GWG were associated with increased risks of any adverse outcome than sufficient GWG in women who conceived with ART, indicating the applicability of the GWG recommended by the IOM in this population. These women should maintain an appropriate weight during pregnancy to manage the risk of adverse neonatal outcomes. More studies are needed to confirm our findings.S1 TableBMI, body mass index; GWG, gestational weight gain; LGA, large for gestational age; SGA, small for gestational age; LBW, low birth weight; M, Median; Q1, 1st quartile; Q3, 3st quartile.(DOCX)Click here for additional data file.S2 TableOR, odds ratio; CI, confidence interval Ref, reference.(DOCX)Click here for additional data file."}
+{"text": "HighlightsSimian Haemorrhagic Fever Virus (SHFV) poses a great threat to African primates by causing fatal haemorrhagic fever.Researchers have reported CD163, as an intracellular receptor for SHFV.Replication competency of SHFV in human monocytes further increases the concern.Dear Editor,The global population is witnessing the emergence of infectious zoonotic diseases due to altered environmental homeostasis by humans at the peak of evolution. Remarkably, primitive microbes mutate and adapt according to the need or turmoil. Anthropogenic activities, such as civilisation, industrialisation, and deforestation, have brought humans and wild animals in close proximity, resulting in the spillover of new pathogens. Diseases like Influenza, Ebola, Marburg, Zika, Boca, SARS-CoV (severe acute respiratory syndrome coronavirus), MERS-CoV (Middle East respiratory syndrome coronavirus), Lassa, Nipah, and Hendra, originating in response to natural infringement, have spread globally. Additionally, many pathogens are on the verge of spillover to humans after a long and continuous adaptation process, owing to continuous contact with human cells followed by a series of mutations. Many distinctive pathogens circulate among domestic and wild animals worldwide without causing symptoms. An increasing number of unique pathogens, like animal viruses, have jumped to humans and wreaked havoc on naive immune systems by unravelling, gaining access to cells, multiplying, and escaping the body\u2019s defence mechanisms. The Simian Haemorrhagic Fever Virus (SHFV), endemic in monkeys and some African primates, poses a great risk of spillover in the near future.Arteriviridae, first isolated in 1964 from rhesus macaques. Arteriviruses include equine arteritis virus, porcine reproductive and respiratory syndrome virus, SHFV, lactate dehydrogenase-elevating virus, and wobbly possum disease virus, and their hosts include horses, pigs, possums, nonhuman primates, and rodents. Various African nonhuman primates, such as patas monkeys, vervets, Guinea baboons, and olive baboons, have been implicated as potential carriersSHFV is a single-stranded, positive-sense RNA virus within the family SHFV poses a great threat to African primates by causing fatal haemorrhagic fevers and jumping species barriers. Interestingly, researchers have reported CD163 as an intracellular receptor for SHFV, which serves as a rare mode of virus entry shared with other haemorrhagic fever viruses such as Ebola virus and Lassa virushttps://www.news-medical.net/news/20220930/Obscure-family-of-viruses-already-endemic-in-African-monkeys-poised-for-spillover-to-humans.aspx). These findings suggest that it is necessary to monitor SHFV to avoid another possible pandemic.Remarkably, profound similarities have been reported in SHFVs and simian viruses responsible for the human immunodeficiency virus (HIV) pandemic. Like HIV and simian immunodeficiency virus (SIV), SHFV has also been reported to successfully evade human cells by disabling protective immune mechanisms, thus taking long-term hold in the body (Although SHFV infections have not been reported in humans, studies on simian arteriviruses must be prioritised by global health communities, considering its spillover potential. High arterivirus viral loads have been reported in asymptomatic African monkeys, which frequently interact with human populations. HIV has been reported to originate from SIVs in African nonhuman primates and jumped to humans during the early 1900s. It caused fatalities in humans in the 1980s in the United States, but no serological tests or treatments were available. Thus, although jumping the species barrier in SHFV is uncertain, more animal viruses are likely to spread to humans. As humans are immunologically naive to SHFV, the development of serological tests for serosurveillance of high-risk populations in close contact with animal carriers is needed. Moreover, raising awareness and continuously monitoring viruses with zoonotic potential is critical for the rapid containment of possible future spillovers.Globalisation, human settlements in forests, and increased international travel have enabled the rapid spread of pathogens than ever before. Historically, it took years or even decades for diseases to spread between countries and continents, allowing many previously unexplored regions of the world to remain disease-free; for example the Black Death happened over 150 years before Columbus\u2019s first expedition to the Americas, leaving these continents largely unaffected. Based on the \u2018One Health\u2019 perspective and experiences from past epidemics and pandemics, drivers of spillover events can be impeded by strategic planningNot applicable.Not applicable.None.All the authors substantially contributed to this work.There are no conflicts of interest.Not commissioned, externally peer-reviewed."}
+{"text": "Dear Editor,.Wunderlich syndrome (WS) is an uncommon but potentially life-threatening entity andconsists of spontaneous renal or perirenal hemorrhageth postoperative day he was discharged. The pathological examination ofthe surgical specimen confirmed acquired cystic kidney disease (ACKD) and identifiedbleeding in some of the cysts, through the lacerated renal capsule and into theperirenal adipose tissue. There was no evidence of neoplastic disease.We report a case of a 56-year-old man with a history of end-stage renal disease due toAPOL1-mediated kidney disease on maintenance hemodialysis who was referred to theemergency department with left flank pain, hypotension, nausea, and vomiting of suddenonset during his routine hemodialysis session. He denied other complaints and was not onantiplatelet or anticoagulant drugs. Computed tomography (CT) angiography was performed,revealing 7-centimeter-long kidneys with several cystic lesions, as well as a subacuteleft kidney hematoma that extended into the perirenal space and pelvic cavity, with noevidence of active bleeding . The pat. Although cyst hemorrhage is a frequent complication in autosomal dominantpolycystic kidney disease (ADPKD), WS is uncommon both in ADPKD and ACKD. In patients on hemodialysis, it appears to result from a combination of factors,namely platelet dysfunction, oral anticoagulant medications, and heparinization of theextracorporeal circuit \u2013 nonetheless, WS may be associated solely with cyst or tumor development,without any other predisposing factors. The diagnosis must be confirmed radiologically, ideally by contrast-enhanced CT. Management may be conservative  or interventional . The first option entails the need for close initial surveillance (in order tointervene in case of deterioration) and subsequent radiological follow-up . While stable patients with benign conditions may be treated conservatively,angiographic embolization might be attempted when active bleeding is detected, andnephrectomy is preferred in the presence of instability or high likelihood ofmalignancy. Ultimately, the most appropriate treatment should be chosen on an individualbasis, depending on clinical stability, evidence of active hemorrhage, suspected cause,and risk/benefit ratio of the available alternatives.WS may present with the classic Lenk\u2019s triad, characterized by acute flank pain, palpablemass, and hypotension; nevertheless, atypical presentations are more frequent. Potentialunderlying etiologies can be varied, and include mostly neoplasms, but also vasculardisease, cyst rupture, coagulopathy, or infectionR. Birne reports the following: employed by Diaverum; research funding from Gilead,Bayer, and Boehringer; member in advisory board of Bayer and Boehringer; and memberof the speakers bureau of AstraZeneca, Bayer, Boehringer, MSD and Bial. M. Roxoreports the following: employed by Fresenius Medical Care."}
+{"text": "Emerging literature suggests that childhood trauma may influence facial emotion perception (FEP), with the potential to negatively bias both emotion perception and reactions to emotion-related inputs. Negative emotion perception biases are associated with a range of psychiatric and behavioral problems, potentially due or as a result of difficult social interactions. Unfortunately, there is a poor understanding of whether observed negative biases are related to childhood trauma history, depression history, or processes common to  both experiences.n\u2009=\u200941) and without psychiatric histories . Accuracy of emotion categorization and negative bias errors during FEP and brain activation were each measured during exposure to fearful, angry, happy, sad, and neutral faces. We examined participant behavioral and neural responses in relation to total reported severity of childhood abuse and neglect .The present cross-sectional study examines the relation between FEP and neural activation during FEP with retrospectively reported childhood trauma in young adult participants with remitted major depressive disorder  positively correlated with trauma scores when participants viewed faces that they correctly categorized as angry, fearful, sad, and happy.Identifying the neural mechanisms by which childhood trauma and MDD may change facial emotion perception could inform targeted prevention efforts for MDD or related interpersonal difficulties. It is also unclear whether individuals\u2019 histories are associated with unique neural patterns of responding during exposure to positive, negative, and neutral facial expressions. Of note, active symptoms of depression may obscure trait-based measurements of these cognitive processes . Prior positive rather than negative relation between activation within the MFG and childhood trauma. This opposite pattern may be due to the current sample\u2019s lack of active mood symptoms, such that both blunted DLPFC activation and increased amygdala activation during FEP occurs only during an episode, with associated cognitive burden or loss of functioning. On the other hand, positive relations between activation in MFG and childhood trauma during accurate facial expression perception may demonstrate adaptive compensation or suppression of amygdala activation to emotionally salient stimuli. Indeed, Brice\u00f1o et al.  and individual differences effects that can be ascribed to processes other than excessive childhood trauma exposure or trait-based effects of MDD \u201365. Anoto et al.  found tho et al. \u201370, thero et al. \u201370.correctly categorized the emotion of a facial expression, it is possible that interesting activation patterns related to childhood trauma may also present in the instances where participants incorrectly categorized a face. There was a surprising and interesting relationship where happy faces were more likely to be incorrectly labeled as angry in individuals with higher CTQ scores. Future studies could pursue this with longer versions of the test so that there would be enough errors to reliably model the BOLD signal for errors of different emotions.While neural results demonstrate group differences in brain activation and trauma histories on trials when participants both neutral facial expression trials and at rest  for FEP studies. Researchers often assume that neutral and rest block conditions capture \u201cnormative\u201d activity that would be unrelated to trauma or disease. Many scientists use such designs to establish a baseline against which emotion evocation or FEP conditions can be compared to cancel out unrelated neural activation noise. Our results demonstrated that patterns of neural activation varied systematically with CTQ scores in  at rest . As such at rest ]. FutureAlthough this study design has several strengths, including investigation of childhood trauma in young adults while early in the course of recurrent MDD processes, limitations should be considered. First, we used a retrospective measure of childhood trauma, which may be influenced by environmental factors, symptoms, and poor recall, and therefore potentially limited in their validity , 73, altChildhood trauma is a multifaceted developmental experience. Researchers should continue to study distal effects of trauma on social emotional processing in order to hone prevention efforts and better elucidate risk for interpersonal difficulties and adverse health outcomes, including risk for MDD. The present study provides evidence that childhood trauma is related to emotion processing, categorization, and biased recognition accuracy as well as differing patterns of neural activation while engaged in emotion processing and categorization. Furthermore, some of these effects differed by individuals\u2019 experiences of prior episodes of depression. Additional research is needed to extrapolate potential long-term influences that different types of trauma may have on emotion processing in adulthood, and how these processes may vary across persons with different mental health diagnoses.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by University of Michigan (UM) and the University of Illinois at Chicago (UIC). The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any identifiable images or data included in this article.AR, KB, LJ, JS, KR, and SL: conceptualization. AR, KB, and SL: data curation. AR, KB, LJ, JS, and SL: formal analysis and writing \u2013 original draft. AR, EK, and SL: funding acquisition. AR, KS, LG, LK, and SL: investigation. AR, LG, LK, KR, MS, EK, SC, and SL: methodology. KB, KS, LG, LK, and SL: project administration. KR and SL: resources and software. KB, LG, LK, and SL: supervision. KB, MS, EK, SC, and SL: validation. KB, LJ, and SL: visualization. AR, KB, LJ, KS, LG, LK, JS, KR, MS, EK, SC, and SL: writing \u2013 review and editing. All authors contributed to the article and approved the submitted version."}
+{"text": "Data integration workflows for multiomics data take many forms across academia and industry. Efforts with limited resources often encountered in academia can easily fall short of data integration best practices for processing and combining high-content imaging, proteomics, metabolomics, and other omics data. We present Phenonaut, a Python software package designed to address the data workflow needs of migration, control, integration, and auditability in the application of literature and proprietary techniques for data source and structure agnostic workflow creation.https://github.com/CarragherLab/phenonaut, Documentation: https://carragherlab.github.io/phenonaut, PyPI package: https://pypi.org/project/phenonaut/.Source code:  We present Phenonaut, a Python package for the analysis of multiomic biological data in a compliant and reproducible manner. With a focus on multiparametric multiomic data, Phenonaut differentiates itself from other available software packages, such as BIOVIA Dassault Syst\u00e8mes\u2019 Pipeline Pilot, KNIME (\u00ae, Pycytominer (As academic drug discovery efforts further embrace multiparametric assay technologies and multiomic dataset generation , the mant, KNIME , Core Liytominer , SCANPY ytominer , and Snaytominer , all of Written in Python, Phenonaut is a pip-installable package for data integration and workflow generation. Users do not have to be proficient in the Python programming language, as Phenonaut implements a workflow mode using simple YAML files. See With continued use, development, promotion, and community engagement, we anticipate the implementation of further novel and established literature techniques integrated into Phenonaut, as well as inviting community contributions via email or GitHub pull requests. We envision Phenonaut becoming a gold standard workflow integration tool for multiparametric multiomics data within the fields of phenotypic screening, biomarker discovery, and beyond.btad143_Supplementary_DataClick here for additional data file."}
+{"text": "JMIR Aging commits to supporting the community of patients and families, clinicians, and scientists to improve the efficiency, equity, and effectiveness of older adult care through the dissemination of cutting-edge evidence.Entering a new digital era where novel devices and emerging technologies, including artificial intelligence, are playing an incredible role with significant impact on health and health care delivery,  One in every six people in the world will be aged 60 years or over in 2030, totaling 2.1 billion by 2050 , augmentThough the rise of technological and data science innovations brings promises, it also poses challenges. For example, many older adults, due to the lack of familiarity with technology, digital literacy, access to technological tools, or access to internet services, are negatively affected by the digital divide ,12. DigiJMIR Aging strives to serve as a platform to support information-sharing and communications about older adults\u2019 health and health care among clinicians, patients, caregivers, researchers, and policy makers. Our mission is to promote the use of technological innovations and data science to inform and improve health care services and health outcomes for older adults. Our focus includes digital health; emerging technologies; health informatics applications; patient education; and preventative care, clinical care, home care, and self-management support for older adults. JMIR Aging also covers aging-focused big data analytics using data from electronic health record systems, health insurance databases, federal reimbursement databases , and other large data sets.As an open-access journal, JMIR Aging has published 254 articles on various topics, such as the use of remote monitoring and artificial intelligence or robotic-driven systems [JMIR Aging has been indexed in PubMed, PubMed Central, DOAJ, Scopus, and the Emerging Sources Citation Index (Clarivate), and it is expected to receive an influential impact factor in 2023.Founded in 2018,  systems , telehea systems , and fal systems . JMIR AgJMIR Aging commits to supporting the community of patients and families, clinicians, and scientists to improve the efficiency, equity, and effectiveness of older adult care through the dissemination of cutting-edge evidence.Entering a new digital era where novel devices and emerging technologies, including artificial intelligence, are playing an incredible role with significant impact on health and health care delivery,"}
+{"text": "NUMB has been initially identified as a critical cell fate determinant that modulates cell differentiation via asymmetrical partitioning during mitosis, including tumor cells. However, it remains absent that a systematic assessment of the mechanisms underlying NUMB and its homologous protein NUMBLIKE (NUMBL) involvement in cancer. This study aimed to investigate the prognostic significance for NUMB and NUMBL in pan-cancer. In this study, using the online databases TIMER2.0, gene expression profiling interactive analysis, cBioPortal, the University of ALabama at Birmingham CANcer data analysis Portal, SearchTool for the Retrieval of Interacting Genes/Proteins, and R software, we focused on the relevance between NUMB/NUMBL and oncogenesis, progression, mutation, phosphorylation, function and prognosis. This study demonstrated that abnormal expression of NUMB and NUMBL were found to be significantly associated with clinicopathologic stages and the prognosis of survival. Besides, genetic alternations of NUMB and NUMBL focused on uterine corpus endometrial carcinoma, and higher genetic mutations of NUMBL were correlated with more prolonged overall survival and disease-free survival in different cancers. Moreover, S438 locus of NUMB peptide fragment was frequently phosphorylated in 4 cancer types and relevant to its phosphorylation sites. Furthermore, endocytosis processing and neurogenesis regulation were involved in the functional mechanisms of NUMB and NUMBL separately. Additionally, the pathway enrichment suggested that NUMB was implicated in Hippo, Neurotrophin, Thyroid hormone, and FoxO pathways, while MAPK, Hippo, Rap1, mTOR, and Notch pathways were related to the functions of NUMBL. This study highlights the predictive roles of NUMB and NUMBL in pan-cancer, suggesting NUMB and NUMBL might be served as potential biomarkers for diagnosis and prognosis in various malignant tumors. Despite the consistent exertion and process executed in oncological research, such as surgery, radiotherapy, and chemotherapy, numerous tumors still remain incurable due to the lack of efficient therapeutic targets. Hence, it is imperative to identify robust prognostic biomarkers and provide optimal curative molecular targets for the devastating tumors. Owing to the tumor heterogeneity, it is necessary to conduct a pan-cancer expression analysis, which has been extensively used to shed more light on the common clinical features, heterogeneities, and prognostic survival of various human malignancies. Recently, pan-cancer analysis, presented by the cancer genome atlas (TCGA) and relevant online databases, provides the evaluation of different human cancer tissues at epigenomic, genomic, proteomic and transcriptomic levels. It is employed to distinguish specific functional genes and signaling pathways, contributing to a compositive and thorough understanding of human malignant tumors.Malignant cancers, on account of high incidence of relapse and poor prognosis, are one of the leading causes of death worldwide.\u201311 In mammals neurogenesis, NUMBL primarily has redundant functions with NUMB. However, NUMB, identified initially as the cell fate determinant, shows asymmetric distribution in cells, yet, NUMBL exhibits to be symmetrically distributed in cytoplasm. In addition, NUMB is widely expressed during morphogenesis, whereas NUMBL is more restrictive to the central nervous system development. Accumulating evidence verifies that NUMB/NUMBL play critical roles in oncogenesis, tumor progression, and tumor metastasis.NUMB and its mammalian homolog NUMBLIKE (NUMBL) belong to an evolutionarily conserved family of proteins, implicated in a variety range of important cellular processes, including cell fate determination, cell adhesion, cell migration, protein endocytosis and ubiquitination.\u201319 The tumor suppressor function of NUMB is mainly involved in Notch signaling pathway inhibition, p53 stabilization, or Wnt signaling pathway stimulation, accompanied by the regulation mechanisms of epithelial\u2013mesenchymal transition.,20\u201322 Additionally, an increasing number of micro-RNAs also enhance oncogenicity by antagonizing NUMB, such as miR-31, miR-146, miR-543, miR-335, and miR-9.,16,23,24 In contrast, experimental evidence indicates that NUMB has acted as an oncogenic modulator in hepatocellular carcinoma and lung adenocarcinoma and squamous cell carcinoma, by promoting cell proliferation, migration, and invasion, meanwhile.,26 Therefore, it is still lacking that a systematic understanding of the biological roles and clinical significance of the NUMB protein in neoplasia of diversiform cancers.To date, it remains controversial whether NUMB is characterized as a tumor suppressor gene or an oncogene. For one thing, downregulation of NUMB displays in several types of tumors, including breast, colorectal, oral, endometrial and lung cancer. Analogously, NUMBL deficiency, with no changes of NUMB expression, leads to increment in tumorigenic properties with a worse prognosis, based on NUMBL repressing the Notch pathway in breast, lung and colorectal tumors. On the contrary, another report has obtained that NUMBL also maintain multiple nodes of metastatic progression by persisting of cancer-initiating cells in advanced lung cancer. Consequently, studies undertaken so far provide conflicting evidence concerning the role of NUMBL in tumor progression. More importantly, it is of the utmost importance to investigate the similarity and divergence in function of NUMB and NUMBL regarding their pivotal roles in regulating tumorigenic progression and correlative molecular mechanisms.Previous researches have established that the overexpression of NUMBL inhibits, while the elimination of NUMBL triggers the migration and invasion of glioma cells.Herein, a comprehensive pan-cancer analysis was systematically conducted, for the first time, that the relationship between NUMB/NUMBL and patient clinicopathological characteristics by using datasets, consisting of TIMER, Gene expression profiling interactive analysis (GEPIA), cBioPortal, the University of ALabama at Birmingham CANcer data analysis Portal (UALCAN), SearchTool for the Retrieval of Interacting Genes/Proteins (STRING), and R software. Then the links between NUMB/NUMBL and tumor pathogenesis were further explored, containing differential gene expression, pathological features, prognostic survival, genetic mutation, protein phosphorylation, and relative cellular pathway. Consequently, these results furnish novel expectations into the functional roles of NUMB/NUMBL in diversified human malignancies, emphasizing the potential molecular mechanisms of NUMB/NUMBL in the tumorigenicity and clinical prognosis in different cancers.The study has been approved by the Institutional Animal Care and Use Committee of Hebei University of Chinese Medicine (No. DWLL2020063). And the data retrieved from the online datasets could be confirmed that all written informed consent had already been obtained.https://cistrome.shinyapps.io/timer) provides user-friendly analytic modules for dynamic analysis and visualization of a wide-spectrum of factors for systematical analysis of immune infiltrates across diverse cancer types, including gene expression, clinical outcomes, somatic mutations, and somatic copy number alterations. NUMB and NUMBL are selected to input via \u201cGene_module\u201d and generated boxplots to visualize the expression difference of NUMB/NUMBL between tumor and normal tissues for the different tumor subtypes of the TCGA project.TIMER: Tumor Immune Estimation Resource (http://gepia.cancer-pku.cn) is a web-based analytical server for unleashing the RNA sequencing expression data of 9736 tumors and 8587 normal samples from the big genomic data in TCGA and genotype-tissue expression datasets, using a standard processing pipeline. In this study, customizable differential gene expression was performed to assess comparison between various cancers and normal samples, pathological stage analysis, survival prognosis and correlation analysis provided by GEPIA. The threshold was selected as the default value.The GEPIA database  is a comprehensive open-access resource, providing customized data storage for exploring, visualizing, and analyzing multidimensional cancer genomics data. Based on TCGA dataset, genetic mutations in NUMB/NUMBL and their associations with overall survival (OS) and disease-free survival (DFS) of patients were obtained from cBioPortal.The cBioPortal for Cancer Genomics  provides level 3 RNA-seq and clinical data from 31 cancer types from TCGA database, estimating the effect of potential gene expression level and clinicopathologic features. In this study, UALCAN was utilized to analyze phosphorylation of NUMB/NUMBL between normal tissue and primary tissues of selected tumors.The UALCAN dataset (https://string-db.org/) is an online database of protein\u2013protein interaction (PPI) information analysis, achieving a comprehensive and objective global network presented with a unique set of computational predictions. A PPI network analysis was applied to collect and integrate associations of NUMB/NUMBL and their potential co-expressed genes through STRING.STRING  and Kyoto encyclopedia of genes and genomes (KEGG) enriched pathways were finally performed with the \u201cggplot2\u201d and \u201cCluster Profiler\u201d R packages to extract the canonical bioprocesses. The data for biological process (BP), cellular component (CC), and molecular function (MF) were visualized as dotplots by using the dotplot function. The R language software Rstudio (Version 4.2.0) was utilized in this analysis. Two-tailed NUMB/NUMBL expressions in multiple tumor and normal tissue types of TCGA, mRNA expressions were analyzed by TIMER2 approach. As shown in Figure NUMB was significantly declined relative to the corresponding normal controls in bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), colon adenocarcinoma (COAD), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), prostate adenocarcinoma (PRAD), rectum adenocarcinoma (READ), skin cutaneous melanoma, thyroid carcinoma (THCA), and uterine corpus endometrial carcinoma (UCEC). In contrast, the expression of NUMB was observably elevated in cholangiocarcinoma (CHOL), esophageal carcinoma (ESCA), head and neck squamous cell carcinoma (HNSC), liver hepatocellular carcinoma (LIHC), and stomach adenocarcinoma (STAD), compared to normal controls.To elucidate the significance of NUMB was explored by GEPIA. In lymphoid neoplasm diffuse large B-cell lymphoma (DLBC), ovarian serous cystadenocarcinoma (OV), thymoma (THYM), and uterine carcinosarcoma (UCS), the expression of NUMB was lower than counterpart controls. In comparison, the expression level was higher than normal controls in acute myeloid leukemia (LAML) and pancreatic adenocarcinoma (PAAD)  Fig. C.NUMBL remarkably down-regulated in adrenocortical carcinoma (ACC), BLCA, BRCA, COAD, cervical squamous cell carcinoma and endocervical adenocarcinoma, glioblastoma, kidney chromophobe (KICH), LAML, brain low grade glioma (LGG), OV, PRAD, READ, testicular germ cell tumor (TGCT), THCA, UCS, and UCEC. Furthermore, significant up-regulation of NUMBL was also found in CHOL, ESCA, HNSC, kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), LIHC, LUAD, LUSC, THYM, PAAD, and pheochromocytoma and paraganglioma  and NUMBL (14%) appeared for patients with UCEC (Fig. Epigenetic alternations play an essential role in early tumor malignancies.d NUMBL 1% appeareFurthermore, the relationship of genetic alternation in NUMB/NUMBL with OS and DFS of UCEC patients were analyzed by cBioPortal dataset. Results observed from the Kaplan\u2013Meier plot and log-rank test revealed that the genetic mutation of NUMB had no significant relation to OS and DFS, whereas altered NUMBL correlated to lower OS and DFS of UCEC patients Fig. D and E. In order to explore the association between protein phosphorylation and oncogenicity, the differences in NUMB/NUMBL phosphorylation levels between primary tumor tissues and normal tissues were compared. Utilizing the UALCAN database, 6 categories of tumors, including LUAD, OV, KIRC, BRCA, COAD, and UCEC, were analyzed.As shown in Figure NUMB/NUMBL in oncogenesis and metastasis, NUMB- or NUMBL-related proteins were screened via STRING website. Based on the STRING instrument, the integrated network constructed by totally 50 NUMB- or NUMBL-interacted proteins supported by experimental evidence, separately (Fig. NUMB- or NUMBL were gathered respectively.To further investigate the molecular mechanisms of ely Fig. A and E. EPS15, ITCH, MPP5, and PLEKHA7 for NUMB and LLGL1, NOTCH1, NOTCH2, NOTCH3, and NOTCH5 for NUMBL. Then the scatter diagrams showed that the NUMB expression level was positively correlated with EPS15, ITCH, MPP5, and PLEKHA7, while the NUMBL expression level was also positively correlated with LLGL1, NOTCH1, NOTCH2, and NOTCH3 (Fig. NUMB or NUMBL and their above targeting genes in the majority of detailed cancers (Fig. An intersection analysis of the above 2 gene clusters indicated 4 overlapped members severally Fig. B and F, CH3 Fig. C and G. ers Fig. D and H.After analyzing the correlated genes of NUMB/NUMBL in differing tumors from TCGA, the potential functions and pathways of NUMB/NUMBL and their associated genes were further predicted by GO and KEGG annotation. GO enrichment analysis represented the underlying functional roles of target host genes on the basis of 3 aspects, including BPs, CCs, and MFs.As shown in Figure KEGG annotation can illuminate the pathways relevant to the functions of NUMB/NUMBL alterations and the frequently overlapping genes. In KEGG analysis, apart from multiple kinds of cancer, a number of signaling pathways, including Hippo, Neurotrophin, Thyroid hormone, and FoxO pathways, were associated with the functions of NUMB mutations Fig. G. MoreovEmerging publications have reported functional links between NUMB/NUMBL and clinicopathologic features in many types of cancers. Although the roles of NUMB/NUMBL in the tumorigenesis and prognosis of several cancers have been partially confirmed, further systematical analysis, especially pan-cancer analysis, of NUMB/NUMBL has yet to be elucidated. The present study, thus, is the first time to comprehensively examine the NUMB/NUMBL in a total of 33 categories of tumors based on the data of TCGA database and the molecular characteristics of relative gene expression, survival prognosis, genetic mutation, protein phosphorylation, and related signaling pathways.\u201340 Firstly, NUMB has been regarded as a tumor suppressor by means of regulating several critical signaling pathways, including Notch, p53, Wnt, and Hedgehog.,21,41,42 Moreover, prior studies have noted the essential role of NUMB in modulating epithelial\u2013mesenchymal transition process, which is defined as inappropriately exploited during carcinogenesis, inducing the oncogenic transformation of cancer cells, making them prone to oncogenesis, migration, and invasion.,44 What is more, being a characterized cell fate determinant during morphogenesis, NUMB also appears to control division mode in cancer stem cells, resulting in inhibition of their invasiveness and clonal and sphere formation capabilities. However, an increasing number of reports have uncovered that NUMB also acts as an oncogene in correlates with cell proliferation and poor prognosis in hepatocellular carcinoma patients. Interestingly, in lung cancer, how NUMB performs the function depends on the subtypes of tumors. As mentioned in the literature, high expression of NUMB was correlated with favorable prognosis in patients with lung adenocarcinoma rather than squamous cell carcinoma. Taken together, considering the complexity of NUMB, it should be dialectically elaborate the underlying mechanisms of NUMB functioning in tumorigenesis.Recent studies have revealed diminished expression of NUMB in majority tumors, and the absence of NUMB has been involved in promoting tumor growth, invasion, metastasis, and cell stemness.NUMB exhibits in 14 of 33 total cancers, consisting of BLCA, BRCA, COAD, DLBC, LUAD, LUSC, OV, PRAD, READ, skin cutaneous melanoma, THCA, THYM, UCEC, and UCS. Inversely, bioinformatic analysis also indicated significantly increased expression of NUMB in a few types of cancer, including CHOL, ESCA, HNSC, LAML, LIHC, PAAD, and STAD. Additionally, GEPIA data also reveals the considerable differences between pathological stages and NUMB mRNA expression in ACC, BLCA, COAD, DLBC, and TGCT, suggesting that NUMB may play several roles depending on distinct cell types and specific stages of development. Importantly, in most cancers, the upshot supports the idea that elevated NUMB expression predicts poorer patient prognosis. Only in KIRC, does lower NUMB expression correlate with poorer patient prognosis. Notably, an additional key finding in this study, by using cBioPortal dataset, is that the genetic alternation of NUMB performs an indispensable role in multiple cancer types, especially in UCEC. Further, we found frequent protein phosphorylation loci of NUMB in LUAD, OV, KIRC, BRCA, COAD, and UCEC, by utilizing UALCAN online tool, indicating the possible controlling sites of NUMB. Foremost, via STRING and GEPIA, co-expression genes of NUMB are collected to conduct NUMB-related partners, containing EPS15, ITCH, MPP5, and PLEKHA7. Based on collective overlapping genes, GO and KEGG enrichment clearly confirm that Hippo, Neurotrophin, Thyroid hormone, and FoxO pathways are closely interrelated to NUMB alternations. While, being distinguished from subsistent pathways, such as p53, Notch, Wnt, and Hedgehog, we have concluded novel signaling pathways underlying the molecular mechanisms of NUMB in tumor initiation, progression, and metastasis.The evidence from this study implies that NUMB can have both tumor promoting and inhibiting capacities and those opposite impacts of NUMB might rely on tumor types. Through relative mRNA expression analysis via TIMER2 and GEPIA databases, our findings point that down-regulated expression of NUMBL between tumor and normal tissues shows that dysregulation of NUMBL emerges in 27 of 33 tumor types of TCGA data library, more extensive than NUMB. Similarly, NUMBL also acts as both tumor suppressor and activator in various types of malignancies. Concerning the different stages of cancer patients, NUMBL relative expression exhibits remarkably variations in ACC, BLCA, COAD, DLBC, HNBC, KICH, KIRC, KIRP, LUAD, READ, STAD, TGCT, and THCA. Whereas the relevance between NUMB mRNA expression and pathological stages only presents in 5 tumor species. Dramatically, the increased NUMBL expression consistently predicts a poorer prognosis in both OS and DFS, which has imparities from NUMB. Furthermore, epigenetics mutation frequency of NUMBL is higher than NUMB among different cancers, and altered NUMBL, rather than NUMB, associated to lower OS and DFS of UCEC patients. Additionally, protein phosphorylation analysis demonstrates that the occurrence of NUMBL phosphorylation is less frequent than NUMB and the amount of phosphorylation loci of NUMBL is less than NUMB. Apparently, it has been investigated that overlapping genes of NUMBL, consisting of LLGL1, NOTCH1, NOTCH2, and NOTCH3, indicate the intimate interrelation between NUMBL and Notch signaling pathway. Notably, KEGG enrichment observation reveals the underlying mechanisms of NUMBL are implicated in MAPK, Hippo, Rap1, mTOR, Notch, ErbB, and Hedgehog pathways.Compared to NUMB, less is known about the expression and role of NUMBL in most types of cancer until now. Unexpectedly, the analysis of expression level of In accordance with our results, a pan-cancer analysis systematically investigates the role and function and relevant molecular mechanisms of NUMB and NUMBL in majority types of cancer, and discusses the similarities and divergences between these 2 homologous proteins. The pivotal finding is that the discrepancies of effects between NUMB and NUMBL on the signaling pathways. A possible explanation for this might be correlated to the alternative splicing of NUMB in tumors. It has been reported that NUMB has 4 splicing isoforms, while public databases may not take the alternative splicing into account, although they are robust tools to gain available data.,36 lung, colon, prostate,,18 liver, and pancreatic cancers. Although we tried our best to make this research results accurate and reliable, the present study still has several limitations. Firstly, the sample size of some rare cancer types was limited, which may have led to erroneous results or ambiguous conclusions. Secondly, the current research mainly focused on bioinformatics analysis, and the prediction results need to be verified by further in vivo and in vitro experiments, such as real-time fluorescence quantitative polymerase chain reaction, western blot, and immunocytochemistry should be performed to understand specific functions of NUMB and NUMBL in carcinogenesis.In summary, the results above anticipate that both NUMB and NUMBL may have values as promising biomarkers in detective and therapeutic measures of human malignancies. To date, the ultimate mechanisms of NUMB and NUMBL mediating cancer processes concentrate on breast,We thank all authors who contributed valuable methods and data and made them public.Conceptualization: Yue Zhang, Hongxia Yang, Aiying Li.Data curation: Yue Zhang.Formal analysis: Weizhe Liu.Investigation: Yunfeng Li.Methodology: Qiuhang Song, Dingyan Zhou.Project administration: Juanjuan Zhang.Resources: Hongxia Yang, Aiying Li.Software: Yue Zhang.Writing \u2013 original draft: Yue Zhang."}
+{"text": "Patients with systemic lupus erythematosus (SLE) have cognitive dysfunctions as a neuropsychiatric manifestation, associated with disabling symptoms. However, the presence of other medical or psychiatric comorbidities can delay or lead to a misdiagnose.To present a case of a patient with diagnostic difficulty in the face of multiple medical and neurocognitive comorbidities.Description of a case report.19-year-old female, Mexican, unemployed, with incomplete high school, with medical history of preterm birth by cesarean at 30 weeks due to placenta previa, history of early puberty, 4 years evolution of focal epilepsy, 1 year evolution of hypothyroidism and mild depression.She began her symptoms 4 years ago, characterized by an abrupt onset of memory disturbances, decreased concentration, poor academic performance, infantile behavior, need for affection, alternated with irritability periods, verbal and physical aggression, repetitive and erratic behavior. She went to multiple specialists with different therapeutic approaches without clinical improvement. In 2020, she was referred to our service for evaluation, evidenciating a mild depressive episode and psychotherapeutic treatment was started.Mental and neurological examination without alterations, normal vital signs, at physical examination: malar rash, oral ulcers, alopecia. Labs: increased erythrocyte sedimentation rate, normocytic anemia, leukopenia, rest normal. An electroencephalogram was requested, without alterations. Simple brain MRI was performed .Psychological (figure 2) and Neuropsychological tests (table 1) were performed, showing alterations in memory recall and inhibitory control.Due to the symptoms presented by the patient, SLE was suspected, and rheumatology evaluation was requested, integrating a diagnosis of incomplete SLE, and started treatment. The patient presented symptomatic improvement in cognitive symptoms and systemic signs. Likewise, a genetic evaluation was requested, without meeting the criteria for a genetic syndrome. The patient continues with symptomatic improvement and multidisciplinary treatment.Image:Image 2:Neurocognitive alterations are one of the most frequent manifestations of neurolupus, although its diagnosis and treatment may be delayed in the absence of clinical suspicion, mainly in multi-comorbid patients.In the case, the patient presented multiple diseases that can explain a picture of neurocognitive impairment, such as epilepsy, depression, hypothyroidism. However, in these cases, a multidisciplinary approach is imperative, requiring to rule out the different causes of the patient\u2019s symptoms.None Declared"}
+{"text": "Reflective case discussion (RCD) is a reflective activity conducted by nurses, midwives, and other healthcare workers to enhance their skills, critical thinking, and knowledge. This systematic review follows the PRISMA Guideline checklist and includes articles from various databases, such as Scopus, PubMed, ProQuest, and ScienceDirect. The quality assessment of each article was performed using the Critical Appraisal Skills Program (CASP). During the initial database search, we retrieved 997 articles from Scopus, 700 articles from ProQuest, 357,554 articles from PubMed, and 1,526 articles from ScienceDirect. The search was conducted using relevant keywords, including \"reflective case discussion,\" \"nursing,\" \"critical thinking,\" \"skills,\" and \"knowledge.\" Following the inclusion and exclusion criteria, eight relevant articles were identified, excluding duplicate studies, limited to full papers, open access, conducted in a hospital setting, and written in English. The findings demonstrate that RCD effectively enhances nurses' skills, critical thinking, and knowledge, contributing to their professionalism in patient care. RCD also proved beneficial in preventing repetitive mistakes and promoting teamwork among nurses. Thus, RCD should be embraced as a valuable form of Continuing Professional Development (CPD) and integrated into nurses' ongoing learning processes. Reflective practice is an ongoing effort to develop the professional development and knowledge advancement of nurses worldwide , 2. It hThe British Association of Sport and Exercise Sciences describes the reflective practice as allowing nurses to reflect on ideas and experiences as a team with group methods fostering relational approaches . In otheReflective practice, mainly conducted through reflective case discussions (RCD), is related to the professional attitude in delivering nursing care . It encoThis systematic review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Guideline (PRISMA) 2020 checklist . We usedIn the PubMed database, the search was conducted using the keywords \"case reflection discussion\" [Mesh] and \"nursing\" [Mesh], resulting in 434 articles. Additionally, the keywords \"critical thinking, skill, knowledge\" [Mesh] and \"nursing\" were used, yielding 10,768 articles. Furthermore, a search using the ScienceDirect database with the first keyword \"case reflection discussion\" or \"reflective practice and nursing\" identified 12,981 articles. Using the second keyword, \"critical thinking, skill, knowledge, and nursing,\" 17,052 articles were found. When these two keywords were combined, 4,281 articles were identified. Filtering the articles for the last 10 years resulted in 1,526 research articles.An article search using the ProQuest database with the keywords \"reflective practice\" and nursing\" found 31,709 articles. The second keyword, \"critical thinking, skill, knowledge, and nursing,\" found 818,212 articles. If the first and second keywords were combined, 791,532 articles were obtained. After applying filters for full-text availability, open access, being in the English language, and published within the last 10 years, approximately 700 articles remained. Lastly, a search using the Scopus database with the keywords \"reflective OR reflection AND nursing AND critical thinking AND professional\" identified 997 articles.The initial search resulted in a number of titles from different databases. However, only 8 final articles were found eligible and used as references in this systematic review after undergoing a rigorous selection procedure based on inclusion and exclusion criteria and applying additional filters such as removing duplicate publications .et al. [The study by Ardian et al.  demonstret al. [Another study  stated tet al.  found thet al. , 30 suppet al. -23.Nurses' ability to think critically is crucial for delivering effective patient care. Various approaches, such as simulations, case studies, reflection, and RCD, have been employed to enhance nurses' critical thinking skills. Many studies focus on RCD, for instance, Ardian's research which adopts the Graham Gibss Cycle technique to measure critical thinking dimensions in the form of thinking engagement, cognitive maturity, and innovativeness . The finSkills in providing nursing care to patients are needed, especially when collaborating with other health workers. Koopmans argues that skilled nurses contribute to the client's quality of life, job satisfaction, and quality of care provided  and haveet al. [Providing optimal healthcare services is closely linked to employing trained and knowledgeable personnel within hospitals . This iset al. , indicatet al. , supportet al. . The refet al. . This fiet al. -41.Some of the limitations of this review include the restriction to papers published in the English language and the focus on articles conducted in clinical settings. These limitations should be acknowledged as they may influence the generalizability and scope of the findings.The findings of this review underscore the significance of reflective practice in enhancing the professionalism of nurses in hospital settings. Reflective Case Discussion (RCD) serves as a valuable tool for discussing and refining Standard Operating Procedures (SOPs). It not only contributes to improved teamwork and mutual respect among nurses but also provides a platform for sharing experiences and minimizing the occurrence of repeated mistakes."}
+{"text": "In this case, the patient, who was scheduled for surgery, unexpectedly showed axillary lymph node metastasis on a preoperative 18F-FDG PET scan, which was subsequently confirmed via histological examination. Although such cases are exceptionally rare, this accurate diagnosis prompted a modification of the treatment plan, leading to a positive therapeutic response.Distant metastasis of cholangiocarcinoma is most commonly diagnosed in the liver; however, it can also be found in the lungs, distant lymph nodes, bones, and brain. Distant lymph node metastasis outside the abdominal region without concurrent abdominal metastasis is exceedingly rare in extrahepatic cholangiocarcinoma. Herein, we present interesting"}
+{"text": "Melghat Plant databank (MPdb) is the first attempt to review all the past floristic documents and medicinal plants and digitizethe Melghat Flora. This curated database contains compiled information about 1028 plants from 139 plant families and 537 genera.Curated medicinal plant information gathered 660 medicinal species records from 128 plant families and 421 genera in MPdb for MelghatFlora. Each plant record is reviewed, scrutinizes, and recorded. More than 9000 records for medicinal uses for nearly 140 diseases,reported phytochemicals, and published cross references. MPdb will serve as a valuable information resource for students, researchers,and aboriginal communities to explore Melghat Flora for better-applied prospects in herbal drug research. In the current worldwide scenario, herbal remedies, products, and supplements have shown tremendously increasing demand andacceptance over the past four decades. Medicinal plants play vital roles in disease prevention; thus, their promotion with consciousefforts towards recognizing, identifying, and scrutinizing the ethnobotanical data for their medicinal uses. MelghatPre-defined criteria  were conThe Melghat Plant Databank (MPdb) has been developed in HTML, CSS, MySQL, and PHP. While the webpages were designed in HTML and CSS,the backend database was built in MySQL, and for the server-side pre-processing, PHP was used. AJAX scripting was utilized to improveauto-search and auto-suggest user search queries.The MPdb is a user-friendly online free web database , wherein the user can search plant records by \"BotanicalName\", \"Common Name\", or \"Family\". Search results facilitate the user to select the entry of interest from displayed records, and theuser can further explore the respective record. The total number of plants and medicinal plants were categorized (Table 1- see PDF)into eight categories per their habitat. Users can select their respective categories as well. Each MPdb record consists of thedatabank id, botanical name, synonyms, common names, category, family, classification, location, and current status, plant description,medicinal uses, reported phytochemicals, and published cross references. The MPdb database also provides an interactive dashboard available at http://mpdb.co.in/dashboard/. It summarizes the data withcriteria of the plant family, category, genus, medicinal, and non-medicinal record count information about the MPdb databank. Thisdashboard has been developed using Google Data Studio.With the above previews, our future objectives for MPdb are to review and update the phytochemical for complete Melghat Flora, withphysiochemical information, structural information, druggability information, and bioactivities for possible phytochemicals. Further,we also have plans to include ethnobotanical information for possible diseasesand plant parts used by ethnic communities with validcross-published references for the same.Melghat Plant Databank (MPdb) is a user-friendly online web database that records 1028 plant species from 139 families and 537genera; among them, 660 species have medicinal values used for more than 140 different diseases. MPdb records also provide information(Table 2 - see PDF), as per IUCN RED LIST  species"}
+{"text": "Biomimetic delivery systems (BDSs), inspired by the intricate designs of biological systems, have emerged as a groundbreaking paradigm in nanomedicine, offering unparalleled advantages in therapeutic delivery. These systems, encompassing platforms such as liposomes, protein-based nanoparticles, extracellular vesicles, and polysaccharides, are lauded for their targeted delivery, minimized side effects, and enhanced therapeutic outcomes. However, the translation of BDSs from research settings to clinical applications is fraught with challenges, including reproducibility concerns, physiological stability, and rigorous efficacy and safety evaluations. Furthermore, the innovative nature of BDSs demands the reevaluation and evolution of existing regulatory and ethical frameworks. This review provides an overview of BDSs and delves into the multifaceted translational challenges and present emerging solutions, underscored by real-world case studies. Emphasizing the potential of BDSs to redefine healthcare, we advocate for sustained interdisciplinary collaboration and research. As our understanding of biological systems deepens, the future of BDSs in clinical translation appears promising, with a focus on personalized medicine and refined patient-specific delivery systems. Biomimetic delivery systems (BDSs), defined by their ability to mimic biological systems, hold significant promise in the realm of biomedicine and nanomedicine. They leverage the principles of nature, emulating the structural or functional attributes of biological systems to enhance drug delivery capabilities ,2,3. BDSThe theoretical bedrock of biomimetic delivery systems (BDSs) is fundamentally rooted in the principles of self-assembly, molecular recognition, and biocompatibility ,2,3. SelThese advancements have catalyzed previously unattainable therapeutic opportunities, including targeted cancer therapies , gene edThis review elucidates the translational challenges prevalent in the field, focusing on their intricate aspects and contemplating potential resolutions . Given tIn the rapidly evolving landscape of drug delivery, BDSs stand out as a beacon of innovation, drawing inspiration from biological structures and processes to optimize therapeutic delivery. By mimicking nature, BDSs aim to overcome the myriad challenges associated with traditional drug delivery, ranging from off-target effects to limited bioavailability . BDSs spLiposomes are spherical vesicles composed of phospholipid bilayers that can encapsulate a wide variety of therapeutic agents. Their biocompatibility arises from their resemblance to biological membranes, making them a preferred choice for drug delivery . DespiteProtein-based NPs, encompassing albumin NPs, protein-based nanocages, VLPs, and NDs, offer a versatile toolkit for enhancing drug delivery, each with distinct advantages and shared challenges. Albumin NPs utilize human serum albumin, which has a natural propensity to bind to various substances, thereby facilitating the transport of a wide range of molecules . The bioSilk fibroin (SF) and gelatin (GA) epitomize the contrasting paradigms within BDSs, each with inherent strengths and challenges. SF is distinguished by its robust mechanical properties and sustained release potential, making it a quintessential candidate for structurally demanding applications such as in bone tissue engineering and targeted cancer therapies ,70,71. NEVs and CMDNs represent two innovative approaches in the realm of biomimetic drug delivery, each leveraging the innate properties of cellular components. EVs, owing to their natural origin, can transport a wide variety of biomolecules and have the ability to cross biological barriers with a low risk of immune response, positioning them as promising vectors for regenerative medicine and targeted cancer therapies ,75,76. NPolysaccharides, a diverse group of biopolymers, including alginate, chitosan, hyaluronic acid, and dextran, play a pivotal role in the landscape of therapeutic delivery due to their inherent biocompatibility and tailored biodegradability ,83. AlgiDespite these advantages, the application of polysaccharides is not devoid of challenges; their susceptibility to rapid degradation in vivo may limit their utility, and potential immunogenicity cannot be entirely discounted. Moreover, the batch-to-batch variability and the complexity of producing highly purified, well-characterized polysaccharides can impact the reproducibility and scalability of pharmaceutical products. Hence, while polysaccharides offer considerable benefits for drug delivery, their clinical application requires meticulous optimization to ensure efficacy, safety, and manufacturability.In the realm of biomimetic delivery systems, different biomimetic materials and structures have been explored for their potential advantages in the delivery of therapeutic agents. Each of these systems brings unique complexities and challenges in terms of their production and ensuring their reproducibility , which i\u00ae/Caelyx\u00ae and AmBisome\u00ae [Liposomes, vesicular structures composed of lipid bilayers, are valuable carriers for various drugs, improving their pharmacokinetics, biodistribution, and therapeutic index, exemplified by clinically approved liposomal drugs such as DoxilmBisome\u00ae . HowevermBisome\u00ae . Size anmBisome\u00ae ,93,94,95mBisome\u00ae ,97,98. FmBisome\u00ae . HowevermBisome\u00ae . In silimBisome\u00ae ,101. WhiThe exploration of endogenous proteins such as albumin in drug delivery is growing due to their biocompatibility and enhanced pharmacokinetics. However, the translation of albumin-based carriers is intricate due to challenges in modification and resultant variability . The comFerritin-based PNPs show promise for personalized medicine due to their encapsulation abilities but face translation challenges stemming from the complexity and reproducibility of assembly ,125,126.Virus-like particles (VLPs) use the infectious properties of viruses for therapeutic delivery, relying on complex recombinant DNA technology , and facNanodiscs (NDs), stabilized by membrane scaffold proteins (MSPs), are discoidal structures apt for studying membrane proteins and delivering bioactive agents due to their biomimetic nature ,30. HoweSilk fibroin (SF) and gelatin (GA) have been extensively researched for their potential in biomimetic delivery systems, owing to their biocompatibility and adjustable degradation rates, essential for in vivo nanoparticle application, especially in drug delivery ,74,162. Extracellular vesicles (EVs) are notable for their potential in targeted therapeutic delivery and have gained prominence in biomedical research due to their capacity to transfer cellular information. However, their clinical transition is impeded by challenges related to their production, heterogeneity, scalability, and stability ,179. EVsCell membrane-derived nanocarriers (CMDNs), particularly from erythrocytes, present a promising frontier in targeted therapeutic delivery due to their biological stealth characteristics ,26,27. NPolysaccharides such as alginate, chitosan, hyaluronic acid (HA), and dextran are prominent in nanoparticle synthesis due to their biocompatibility and safety . HoweverThe quest for the stability and longevity of BDSs in physiological conditions is a complex journey marked by numerous challenges . These sLiposomes are inherently unstable due to the susceptibility of phospholipids to oxidation and hydrolysis, affecting their structural integrity and function ,215. OxiAlbumin-based BDSs, revered for their biocompatibility and molecule-binding potential, encounter numerous challenges in clinical transition due to their interactions with various bodily substances, leading to aggregation and premature therapeutic release ,110,226.Protein-based nanocages, led by ferritin, are a breakthrough in theranostic devices. They promise innovative drug delivery systems based on biomimetic principles. However, the journey to clinical use presents challenges, including structural disruption in varying in vivo environments, which might trigger unintended drug release . These nVLPs are renowned for their precise control, defined structures, and adjustable immunogenicity, marking them as ideal candidates for targeted delivery platforms. However, their stability is compromised in demanding physiological environments due to factors such as pH fluctuations and the presence of proteases, causing potential premature therapeutic release and impacting targeting capabilities ,248,249.NDs serve as versatile drug delivery platforms but are hampered by challenges stemming from their amphiphilic lipid nature, causing instability in size, shape, and functional efficacy. Factors including temperature, pH, and ionic strength can induce lipid phase transitions and nanodisc aggregation, potentially causing premature drug release and reducing therapeutic efficacy ,260. TheFibroin and gelatin, due to their biocompatibility and biodegradability, are widely used in biomimetic delivery systems but face challenges related to stability and longevity under physiological conditions ,266. TheEVs exhibit promising capabilities for targeted therapies due to their unique biological functionality but face substantial challenges in maintaining stability and longevity ,281,282.In biomimetic delivery, CMDNs, particularly those derived from red blood cells (RBCs), display significant stability and longevity challenges and can trigger immune responses leading to premature clearance due to alterations during the extraction and modification processes . The monPolysaccharide-based carriers such as alginate, chitosan, hyaluronic acid, and dextran exhibit unique stability issues. Alginate and chitosan are notable for their biocompatibility and biodegradability but are susceptible to instability due to their hydrophilic nature, resulting in vulnerability to environmental factors such as pH and ionic strength ,298. CheThe efficacy and safety of therapeutic agents, especially BDSs that emulate natural biological entities, are fundamental to their clinical utility. These BDSs are anticipated to provide efficacy comparable or superior to existing treatments with a satisfactory safety profile, but their clinical translation encounters substantial challenges such as unpredictable in vivo behavior, potential off-target effects, and unexpected immune responses . ComprehLiposome-based BDSs, noted for their ability to encapsulate diverse agents, promise enhanced drug solubility and targeted delivery . However\u00ae and AmBisome\u00ae, highlights the innovation in therapeutic delivery. Doxil\u00ae, a paradigmatic FDA-approved nanodrug, utilized adaptive trial designs for dynamic dose adjustments, balancing efficacy with safety and showcasing the importance of real-time data-based refinements [\u00ae distinguished itself with a meticulous comparative approach in clinical trials, revealing its superior therapeutic index in antifungal treatments [\u00ae and AmBisome\u00ae, informs and refines subsequent clinical trials and therapeutic guidelines. The clinical success of liposomal technologies underscores the essential role of innovative trial designs, adaptability, and ongoing evaluation in advancing liposomal therapeutics from experimental to established clinical treatments.The clinical translation of liposomal technologies, exemplified by pioneering formulations such as Doxilinements . AmBisomeatments ,310. Theeatments ,312. Thieatments ,314. ThiPNPs, encompassing a diverse set of biomaterials such as Albumin nanoparticles, protein-based nanocages (exemplified by ferritin), VLPs, NDs, fibroin, and gelatin, are advancing to the forefront of drug delivery research due to their inherent biocompatibility, biodegradability, and potential for precision-targeted therapeutic delivery. For Albumin nanoparticles, despite being synthesized from endogenous proteins, the inherent risk lies in the potential elicitation of immunogenic reactions, stemming from slight alterations or impurities during the nanoparticle formation process ; moreoveEVs and CMDNs, including exosomes, microvesicles, and apoptotic bodies, are prominent for their therapeutic delivery potential due to their biocompatibility and capability for targeted delivery, offering advantages over synthetic carriers. Nevertheless, integrating them into clinical paradigms requires rigorous evaluation of therapeutic efficacy and safety ,321. AchPolysaccharide-based BDSs are renowned for their biocompatibility, biodegradability, and functional modification capacities, making them prominent in drug delivery research ,211,300.A holistic assessment of polysaccharide-based BDSs necessitates a transition from traditional to more innovative, flexible clinical trial designs, with adaptive designs becoming pivotal for modifications including dose titrations based on interim analyses, addressing biomimetics\u2019 unpredictability ,327,328.In conclusion, while each biomimetic delivery system carries unique opportunities, they all share common challenges in terms of their in vivo behavior, safety, and efficacy profiles. To enable their clinical translation, a comprehensive understanding of these challenges and the development of strategies to address them is crucial. This should include extensive preclinical and clinical evaluation of their pharmacokinetics, pharmacodynamics, and potential for inducing immunogenicity. The successful resolution of these challenges will unlock the therapeutic potential of these biomimetic delivery systems, improving patient outcomes across a range of diseases and conditions.The clinical implementation journey of BDSs encompasses intricate regulatory necessities and significant ethical considerations, often aligning with advanced therapy medicinal products (ATMPs) or nanomedicines, requiring specialized regulatory pathways ,338. TheLiposomes require intricate characterization due to their diverse properties, raising regulatory and informed consent complexities , and theThe emerging BDSs epitomize the integration of nature\u2019s complex designs with human technological developments and have brought to the forefront an urgent necessity for advanced regulatory and ethical frameworks tailored to their nuances . HistoriBDSs have emerged as a transformative frontier in nanomedicine, promising unparalleled advantages in drug delivery and therapeutic modalities. These systems, rooted in the principles of self-assembly, molecular recognition, and biocompatibility, encompass a variety of platforms such as liposomes , PNPs 3,341,342,The future holds substantial promise for the clinical translation of BDSs as advancements in understanding biological systems continue to refine the design and capabilities of BDSs. Anticipated innovations, emerging from interdisciplinary collaborations among biologists, chemists, engineers, and clinicians, will likely be more refined, efficient, and personalized, aligning with individual patient profiles for optimized outcomes. The evolving familiarity of global regulatory bodies with BDSs anticipates the establishment of more streamlined guidelines, expediting clinical translation. Initial challenges and learnings in clinical translation will be instrumental in refining subsequent iterations of BDSs for enhanced clinical application. In essence, BDSs, merging nature\u2019s design with human ingenuity, have immense potential in revolutionizing drug delivery, and despite existing challenges, the commitment of the scientific community and ongoing technological and regulatory advancements underline a future replete with potential."}
+{"text": "Quercetin is a flavonoid present in apples, onions, tea, red wines, and berries, and it has shown different beneficial effects, such as providing cardiovascular protection, possessing anti-inflammatory properties, and demonstrating anticancer activity, among others. These diseases are related to oxidizing molecules such as ROS because these species react and induce the oxidation of cellular biomolecules, such as proteins, lipids, DNA, or carbohydrates, which alters cellular homeostasis. Regarding lipids, the oxidation of these molecules induces lipid hydroperoxides which, if not decreased, particularly by GPX4, produce highly reactive aldehydes such as 4HNE and MDA. These oxidative conditions induce ferroptosis, a type of cell death associated with oxidation that differs from other types of cell death, such as apoptosis, necrosis, or autophagy. The induction of ferroptosis is desired in some diseases, such as cancer, but in others, such as cardiovascular diseases, this type of cell death is not wanted. The possible effects of quercetin associated with reducing or inducing ferroptosis have not been reviewed. Thus, this review focuses on the ability of quercetin to produce ferroptosis in diseases such as cancer as a treatment option and, conversely, on its role in deactivating ferroptosis to alleviate diseases such as cardiovascular diseases. Plants synthesize and accumulate a plethora of natural products such as alkaloids, flavonoids, and terpenoids. These compounds serve as messengers in different cell signaling pathways, e.g., as signals for nitrogen-fixing bacteria; they are also protective agents since they act as shields against ultraviolet light, attractants for pollination and oviposition, and even antimicrobial/antiviral agents . FlavonoFerroptosis was described by Dixon et al. , who fouFang et al.  showed tNon-alcoholic fatty liver disease (NAFLD) is related to hepatic steatosis, a cell condition characterized by excess triglyceride accumulation stored as lipid droplets in the cytosol of hepatocytes, which may develop into nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma . NAFLD aAcrylamide (ACR), produced in carbohydrate-rich foods during thermal processing, can also generate hepatotoxicity. During this hepatotoxicity, ACR elevates the levels of alanine transaminase (ALT), aspartate aminotransferase (AST), ROS, lipid peroxidation, and ferroptosis, which are alleviated via quercetin. Huang et al.  demonstrParkinson\u2019s disease (PD) is a progressive neurodegenerative disorder of nigrostriatal dopaminergic (DA) neurons; until now, a disease without a cure, where treatments can only help alleviate symptoms. Therefore, it is urgent to develop effective drugs for treating PD. Since PD is related to oxidative stress and damage induced via lipid peroxidation, causing cell death, such as ferroptosis of DA neurons, compounds such as quercetin can alleviate OS, preventing the development of ferroptosis and PD or stopping the progression of the disease. Jiang et al.  demonstrEpilepsy is a neurological disorder where classical antiepileptic drugs induce drug toxicity and cognitive function impairment, which makes it essential to develop novel therapies to solve this issue. It has been suggested that the activation of Nrf2 could reduce ferroptosis cell death, representing a potential therapy for seizures. Quercetin, as a natural polyphenol that activates Nrf2, could avoid ferroptosis, alleviate seizure-induced neuron death, and preserve cognitive function. Xie et al.  found thSpinal cord injury (SCI) produces impaired mobility, sensory, and autonomic dysfunctions. Oligodendrocyte progenitor cells (OPCs) differentiate into mature oligodendrocytes, and remyelinate damaged axons. The loss of OPCs results in poor SCI recovery, so inhibiting OPC loss is challenging to overcome. It has been shown that quercetin prevents the ferroptosis of OPCs by downregulating the inhibitor of DNA binding 2 (Id2)/transferrin pathway. In this work, the authors demonstrated that erastin increases OPCs cell iron concentration, ROS generation, and prostaglandin-endoperoxide synthase 2 (PTGS2) protein levels, decreasing cell viability, GSH, and GPX4 protein levels. However, quercetin increases cell viability, GSH, and GPX4 levels, ameliorating iron concentration, ROS production, and PTGS2 levels. Moreover, erastin also induces shrunken mitochondria, increased membrane density, and decreased mitochondrial cristae, alleviated with quercetin treatment. These effects induced quercetin to reduce axonal and myelin loss caused by erastin treatment . Interes2O2). H2O2 treatment induces ROS production, reducing BMSC viability and osteogenic key proteins such as runt-related transcription factor 2 (RUNX2), alkaline phosphatase (ALP), and osteopontin (OPN) /Protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway. Thus, quercetin inhibited ferroptosis and the dephosphorylation levels of PI3K, AKT, and mTOR, maintaining the viability and the osteoblastic differentiation of BMSCs upon H2O2 stimulation . Ly. Ly14]. Quercetin also works as an inducer of ferroptosis oppositely, as mentioned in the first part of this review, this double edge of quercetin\u2019s mechanism of action warns us about its use, highlighting the search for the therapeutic concentration of this compound. Finding this window for quercetin treatment in each disease will provide us with a powerful tool for using quercetin as a potential anticancer compound or alleviating illnesses associated with the liver, pancreas, kidney, central nervous system injury, or inflammation. It also provided information on whether this concentration could be toxic to other healthy cells, which warrants further investigation. We present in Quercetin has several pharmacological effects as a form of anti-cancer and cardiovascular protection due to its chelating, antioxidant, and anti-inflammatory properties. Moreover, quercetin has been shown to inhibit ferroptosis and improve renal damage, type 2 diabetes, inflammation, and the liver of mice fed a high-fat diet. Therefore, quercetin has the potential as a broad therapeutic compound and could be helpful to treat ferroptosis in many diseases where it is desired to prevent this death or induce ferroptosis cell death in conditions such as cancer. However, the potential application of quercetin in treating these diseases still needs further investigation since the possible toxic effect that this component could have on patients must be ruled out."}
+{"text": "For most countries it is currently unknown to what degree concentrations of psychotropic drugs in surface water exceed environmental threshold concentrations (ETCs) [MOU1] for ecosystems and what risk mitigation could be applied. ETCs are defined as per-compound threshold concentrations above which detrimental effects on reproduction, growth, and mortality of aquatic organisms cannot be excludeTo quantify levels of antidepressants, antipsychotics, mood stabilizers, and benzodiazepines in surface water, investigate their sources and assess whether these levels exceed ETCs.Cross-sectional analysis of measured and modeled data. Environmental levels were compared to ETCs to evaluate their risks for the aquatic environment. Finally, sources of psychotropic drugs were investigated.All available Dutch water monitoring data from all regional and national monitoring campaigns of 2019, the last year before the COVID-19 pandemic.Concentrations of aripiprazole, carbamazepine and its metabolites, clozapine, diazepam, (es)citalopram, fluoxetine, haloperidol, nortriptyline, olanzapine, oxazepam, temazepam, quetiapine, sertraline, valproic acid, and venlafaxine.The main outcomes were measured and modeled concentrations of the aforementioned agents in surface water. As a secondary outcome, where possible, average risk quotients (RQs) were calculated by dividing the measured or modeled concentrations by the ETC. An RQ > 1 was interpreted as a risk to the environment.Psychotropic drug samples  showed the highest average concentrations for oxazepam  and carbamazepine , with individual measurements exceeding ETCs. For other drugs, measured concentrations did not reach the detection limit citalopram, quetiapine, and venlafaxine) or did not exceed the ETC (fluoxetine). Furthermore, households contributed most to psychotropics in surface water. Finally, psychotropics were cleared less efficiently from a wastewater treatment plant than other medications.Psychotropic drugs are present in surface water, are primarily emitted by households, and may put organisms at risk. We signal a need to reduce concentrations of several psychotropic agents in the environment. Our findings set the stage for policies and research aimed at curtailing emissions of psychotropic drugs into the environment and highlight a need for responsible prescribing and waste measures.None Declared"}
+{"text": "There is an update to the authorship. We recognize the invaluable participation of Dr Caroline Junqueira and her students, Guiherme Castro and Camila Barbosa, who helped us in performing the experiments and providing important insights during the beginning of the project. I apologize for the inconvenience of not including their names in the first version of the manuscript.With the inclusion, the order of the authorship will be as follows:Greg\u00f3rio Guilherme Almeida, Pedro Augusto Carvalho Costa, Ma\u00edsa da Silva Araujo, Gabriela Ribeiro Gomes, Camila Raquel Rodrigues Barbosa, Alex Fiorini Carvalho, Maria Marta Figueiredo, Guilherme Castro, Dhelio Batista Pereira, Mauro Shugiro Tada, Jansen Fernandes de Medeiros, Irene da Silva Soares, Luzia Helena Carvalho, Flora Satiko Kano, Marcia Caldas de Castro, Joseph Michael Vinetz, Douglas Taylor Golenbock, Caroline Junqueira, Lis Ribeiro do Valle Antonelli, and Ricardo Tostes Gazzinelli."}
+{"text": "Chromosomal instability (CIN) is a prevalent characteristic of solid tumours and haematological malignancies. CIN results in an increased frequency of chromosome mis-segregation events, thus yielding numerical and structural copy number alterations, a state also known as aneuploidy. CIN is associated with increased chances of tumour recurrence, metastasis, and acquisition of resistance to therapeutic interventions, and this is a dismal prognosis. In this review, we delve into the interplay between CIN and cancer, with a focus on its impact on the tumour microenvironment\u2014a driving force behind metastasis. We discuss the potential therapeutic avenues that have resulted from these insights and underscore their crucial role in shaping innovative strategies for cancer treatment. Chromosomal instability (CIN), a process driving genomic alterations , promoteCIN in cancer cells is caused by various, often co-occurring factors, each yielding unique CIN signatures ,13. For While novel cancer therapies have significantly improved survival rates and quality of life in patients with various malignancies, therapy resistance is one of the most important factors affecting overall patient survival ,20. The + tumours.In this review, we will discuss the relationship between CIN, metastasis, and the TME, and highlight recent work that might provide new directions for therapeutic interventions of CINAs CIN drives karyotype heterogeneity, it contributes significantly to tumour evolution and adaptation ,24. WhilWhile the effects that CIN has on the TME will likely influence the efficacy of metastatic seeding, CIN also has effects that more directly promote metastatic potential ,8. GenetOne pathway that has increasingly been associated with CIN, the TME, and metastasis is the cGAS-STING pathway. In the next section, we will explain this relationship in more detail. Under normal conditions, DNA is strictly confined to the nucleus. This prevents DNA from being recognised by the cyclic GMP-AMP synthase (cGAS), which will activate the cGAS-STING signalling pathway, ultimately mounting an innate immune response ,34,35. cVarious genes, including KIF2B/C, PICH, MASTL, PRC1, APOBEC3A, and CCAT2 lncRNA, have been shown to modulate tumour immunity through their interactions with the cGAS-STING pathway ,41,42,43+ cancers were found to circumvent immune surveillance through the amplification of oncogenes, which yielded inhibition of the cGAS-STING pathway and reduced production of type I IFN [+ cancers quickly adapt by alleviating the immune-activating IFN signalling to prevent immune clearance. Therefore, new therapies that reactivate immune recognition of CIN+ cancer cells are urgently needed. In addition to activating cGAS-STING signalling, CIN also triggers type I interferon (IFN) signalling, a cornerstone of the antiviral defence and tumour immune surveillance . Intrigupe I IFN ,8. Additpe I IFN ,45. TherEpithelial-mesenchymal transition (EMT) is a dynamic cellular process orchestrated by EMT-activating transcription factors (EMT-TFs) like SNAIL, TWIST, and ZEB families, leading epithelial cells to acquire mesenchymal traits ,47,48. EWhile CIN can promote EMT, EMT inducers like Twist1 might also induce genomic instability, for instance as shown for colorectal cancer ,53. SimiCollectively, these findings underscore the relationship between EMT and CIN in promoting metastasis. Although we do not yet fully understand this relationship, assessing markers for EMT in combination with inference or quantification of intratumour karyotype heterogeneity as a proxy of ongoing CIN might help predict treatment stratification and outcome ,57 also. CIN and aneuploidy often result in a deregulation of metabolic signalling, thereby disrupting metabolic homeostasis ,61,62,63How does CIN lead to this altered cellular metabolism? One important factor is that the resulting aneuploidy will affect copy numbers of metabolic enzymes and thus alter the expression of these genes, resulting in imbalances in various metabolic pathways ,71. AddiIn conclusion, metabolic rewiring and CIN go hand in hand to drive cancer development, therapy resistance, and metastasis also see . TherefoThe tumour microenvironment (TME) is a complex environment in which tumour cells originate and reside . It compCIN-induced mitotic errors lead to a series of changes that reshape the TME, including shifts in the composition of immune cells, reorganisation of the extracellular matrix, alterations in extracellular vesicle communication, changes in angiogenic factors, and shifts in communication between tumour and stromal cells ,4,82,83.+ tumours recruiting a tumour-suppressive immune landscape and late tumours circumventing this [The tumour microenvironment is composed of diverse cellular components, including T cells, B cells, macrophages, and cancer-associated fibroblasts (CAFs) . The celing this ,92. + cancer cells may yield a more tumour-suppressive environment, which in turn will contribute to the dysfunction of CD8 T cells [Indeed, CIN as well as the resulting aneuploidy have been associated with significantly altered immune landscapes in the TME ,86,87,93 T cells ,94. Fina T cells ,95,96.Besides immune cells, cancer-associated fibroblasts (CAFs) also contribute to an immunosuppressive TME through exosome and growth factor secretion, thus promoting tumour growth and metastasis . While CCollectively, these observations indicate that the degree of CIN significantly impacts the composition of immune cell populations within the TME, thereby establishing a nexus between CIN, immune cell infiltration, and their collective impact on the complex landscape of tumourigenesis ,90. As sIn addition to cellular elements, CIN might also influence the composition of non-cellular components of the TME . These nThe extracellular matrix (ECM) is primarily produced by cancer-associated fibroblasts (CAFs) and plays an essential role in driving tumour growth and metastasis ,102,103.Gene expression profiling of colorectal cancer samples revealed that high aneuploidy scores and microsatellite instability (MSI) correlate with increased expression of the POSTN gene (periostin), a factor known to remodel the extracellular matrix (ECM) . FurtherVice versa, rigidity of the tumour microenvironment can also facilitate further chromosomal breaks within cancer cells to progress tumour progression ,105. For+ cancer cells on the ECM [Taken together, these observations underscore the importance of understanding the effects of CIN the ECM ,104. As Extracellular vesicles (EVs) are released by various cell types and act as carriers for RNA, DNA, and proteins, enabling bidirectional communication between cancer cells and the TME to modify signalling cues in recipient cells ,107. TumPrior work has revealed many important interactions between CIN and EVs ,112,113.+ cancers [+ cancers.What content within the EVs can explain their effect on the TME? Functional characterization of tumour EVs has revealed a three-miRNA signature that might serve as an indicator for genomic instability in breast cancer . As EVs  cancers . While mIn summary, CIN plays a crucial role in promoting metastasis by affecting both the cellular and non-cellular components of the TME . CIN is Developing better therapeutic strategies that exploit the effects of CIN in cancer is expected to advance cancer treatment. In this section, we review various approaches to target specific mechanisms influenced by CIN, including immune modulation, metabolic reprogramming, or targeting the extracellular matrix or STING pathway. + cancers across cancer types [+ cancer cells circumvent this before this concept can be translated into tangible clinical benefits.The inflammatory response that results from CIN activates the immune system, and this likely explains why highly aneuploid cancers circumvent immune recognition, leading to immune-depleted TMEs ,86,87,93er types ,8,31,116+ cancer cells might provide a powerful means to impair proliferation of these cells [+ cancer cells, for instance, through modulation of lactate levels [CIN has major effects on the metabolism of cancer cells, which contributes to their aggressive behaviour . Therefose cells . Severale levels ,117,118.e levels ,117,118.STING is another factor that links CIN, innate immunity, and the cellular metabolism ,119. RecWhile more work is required, jointly this work suggests that CIN leads to metabolic and immune-related vulnerabilities that can be exploited in cancer therapy also see .+ cancers [+ cells [+ cancer cells, restraining tumour growth and underscoring its potential to treat cancers that display high-grade aneuploidy and substantial intratumoural karyotype heterogeneity [+ cancer cells via the deregulation of microtubule-kinetochore interactions [Manipulating CIN rates might provide another powerful strategy to selectively treat CIN cancers ,122. Inc cancers ,124,125.[+ cells . Similarogeneity . Further+ cancer cells can be selectively targeted. While promising first steps have been made, a further systematic exploration of synthetic lethal interactions instigated by CIN is required to fully exploit the potential of this approach. In conclusion, the strategic manipulation of CIN phenotypes in cancer presents another potential avenue for targeted cancer therapy also see . By targ+ cancers in therapy [+ cancers, mitigating CIN in these cancer cells [Mitigating CIN phenotypes by targeting the ECM might provide another strategy to exploit unique features of CIN therapy ,105. To  therapy ,129. Oneer cells . These findings underscore that ECM-targeted strategies might have the potential to manipulate aneuploidy landscapes and the consequences of these across cancers also see . Therefo+ cancers [As discussed earlier, CIN promotes metastasis, and STING is a proposed mediator of this effect ,8. Activ cancers . Indeed, cancers ,8,130.+ cancer cell survival and metastasis [The experimental evidence that STING is activated by CIN, in combination with its role in modulating the TME to promote metastasis, underscores the clinical potential of modulating STING activity in cancer. Further work is required to determine when STING should be inhibited to block its tumour-promoting effects, such as driving CINtastasis , or actitastasis . + cancers, exploiting CIN-dependent metabolic vulnerabilities, manipulating CIN rates, modulating of the ECM, and exploiting the multifaceted role of STING signalling all emerge as promising strategies to battle CIN+ cancers (Altogether, these findings highlight the various effects that CIN has on the immune landscape of cancers. Manipulating the immune composition of the TME of CIN cancers . However+ cells. CIN+ cancer cells appear to circumvent this immune recognition through various mechanisms. Our growing understanding of this inflammatory response and mechanisms of immune suppression within the TME provide novel opportunities for therapeutic intervention, including immune modulation to reactivate the immune response and clear CIN+ cancer cells, or inhibition of the CIN-induced inflammatory response to kill CIN+ cancer cells. While the translation to the clinic of these approaches still requires further work, they might provide important next steps towards innovative therapies that target CIN+ cancers more effectively with fewer side effects.In this review, we have explored the effects that CIN can have on the TME locally and at distant sites. As CIN discriminates cancer cells from non-cancer cells, targeting CIN provides an attractive target for selective cancer therapy. CIN results in an accumulation of aneuploid cells with various karyotypes, thus promoting cancer cell evolution. As a genome-shaping factor, CIN is associated with tumour recurrence, metastasis, and treatment resistance. Simultaneously, CIN promotes inflammatory phenotypes in cancer cells as a result of chronic cGAS-STING pathway activation, which ultimately leads to mobilization of immune cells to clear CIN"}
+{"text": "Pheochromocytomas and paragangliomas are catecholamine-secreting tumors that originate from chromaffin cells of the adrenal medulla and autonomic neural ganglia, respectively. Patients with pheochromocytomas and paragangliomas typically present with paroxysmal headache, sweating, tachycardia, and hypertension. Although most pheochromocytoma cases are sporadic, many of the cases occur as part of a genetic disorder. Here, we report the case of a 14-year-old male patient who presented with hypertension. Laboratory tests showed elevated levels of serum and urinary catecholamines, metanephrines, and chromogranin. Abdominal ultrasound and computed tomography studies revealed bilateral solid adrenal masses and an isolated splenic mass. Further assessment identified an underlying Von Hippel-Lindau syndrome. The patient was initially treated medically and later surgically. This case highlights the importance of always considering pheochromocytomas and paragangliomas as rare differentials of secondary hypertension, especially in the presence of episodic headaches, sweating, and tachycardia. Furthermore, screening for underlying genetic disorders, such as in our case, should be considered in cases of bilateral tumors, onset at a young age, and presence of extra-adrenal tumors. Catecholamine-secreting tumors are uncommon causes of hypertension . GeneralPatients with pheochromocytomas and paragangliomas can be asymptomatic or present with variable non-specific symptoms depending on the location and size of the tumor; hence, they are often referred to as the \u201cgreat mimickers\u201d . If presCompared to adults, pediatric patients with pheochromocytomas are more likely to have an underlying genetic or familial disease, bilateral adrenal tumors, multiple tumors, and extra-adrenal tumors . For insVHL syndrome is an autosomal dominant familial neoplastic syndrome caused by genetic aberrations of the tumor suppressor gene VHL. According to the genotype and phenotype, VHL is classified into two types: type 1 which occurs due to truncating or missense mutations and type 2 which occurs due to missense mutation . AdditioHere, we report the case of a 14-year-old male patient who presented with hypertension due to pheochromocytoma. Further assessment revealed an underlying VHL genetic disorder.\u00a0This case reiterates the need for screening for pheochromocytomas in cases of hypertension in young patients with episodic symptoms of sweating and headaches. Moreover, this case emphasizes the need to perform genetic testing in cases of bilateral tumors and those occurring at a younger age.A 14-year-old boy with no underlying chronic illnesses presented to our tertiary care center with a six-month history of severe headaches and vomiting. The headaches were frontal, throbbing in nature, paroxysmal, progressive, and worsened over the last two weeks before the presentation. The patient had no other symptoms such as dizziness, loss of consciousness, neurological deficits, visual impairment, chest pain, dyspnea, or fever. His family history included a history of essential hypertension in both parents and otherwise healthy siblings.The patient\u2019s physical assessment revealed an elevated blood pressure (195/130 mmHg) consistent with bilateral readings. Cardiovascular, neurological, thyroid, and renal examinations were normal. Additionally, electrocardiography was normal. Initial laboratory investigations including complete blood count, renal function, troponin, electrolytes, and urine analysis were normal  with subsequent blood pressure readings ranging between 140/90 mmHg and 170/100 mmHg.Further investigations to assess secondary causes of hypertension were conducted. These investigations included thyroid stimulating hormone, aldosterone, renin, random cortisol, aldosterone renin ratio, serum and urinary catecholamines, and metanephrine levels. Hormonal assays revealed elevated levels of serum and urinary catecholamines, metanephrines, and chromogranin Table .In view of the elevated renin and catecholamines, an abdominal and renal ultrasound study was conducted to assess the adrenal glands, renal arteries, and kidneys. Ultrasonography showed bilateral solid adrenal masses and the abdominal CT revealed bilateral 42 x 34 mm and 43 x 27 mm adrenal masses that were lobulated with central hypodensities and exophytic enhancement. In addition to that, another 22 x 21 mm mass was found in the left subphrenic space . Genetic testing was positive for VHL syndrome. Thus, screening for the patient\u2019s family members was done.Here, we presented a rare case of pheochromocytoma and paraganglioma due to underlying VHL syndrome. Our patient presented with typical symptoms of paroxysmal hypertension and headaches. The differential diagnoses of recurrent spells of palpitations, headaches, hypertension, and sweating include pheochromocytoma, hyperthyroidism, hyperadrenergic spells, hypoglycemia, postural orthostatic tachycardia syndrome, mast cell disease, and carcinoid syndrome . Our casThe diagnostic work-up of pheochromocytomas and paragangliomas includes biochemical hormonal detection of excess catecholamine secretion, imaging studies to locate and stage the tumor, and genetic testing. Additional tests might be needed to detect syndromic features if the diagnosis of a genetic syndrome is confirmed. The initial biochemical testing should include plasma-free metanephrines or urinary fractionated metanephrine levels  [The biochemical assessment should be followed by imaging studies to localize and stage the tumors. CT scan is the recommended imaging modality as it provides better spatial resolution than magnetic resonance imaging (MRI) . In addiGenetic testing should also be considered in all cases of pheochromocytomas and paragangliomas; particularly, in pediatric patients, patients with bilateral or extra-adrenal tumors, and those with known genetic disorders . Around A multidisciplinary approach that considers patient characteristics like age, physical status, underlying comorbidities, tumor features such as primary tumor site, presence of metastasis or tumor growth rate, and genetic profile is needed to manage pheochromocytomas and paragangliomas . SurgicaFollow-up visits to assess the clinical and biochemical response to treatment are recommended. The follow-up visit should include an assessment of blood pressure, catecholamine biomarkers, imaging studies, and screening for associated cancers such as renal and brain tumors and retina screening if a genetic disorder is confirmed . Our patPheochromocytomas and paragangliomas are rare causes of secondary hypertension but should be suspected in certain circumstances, such as in our case. These include the presence of episodic headaches, sweating, tachycardia, and hypertension. Screening for underlying genetic disorders and genetic counselling should be considered in cases of bilateral tumors, pediatric patients, and extra-adrenal tumors. Surgical resection is the mainstay treatment, and regular follow-up is crucial to identify recurrence or missed lesions."}
+{"text": "As aging societies in the western world face a growing prevalence of vascular cognitive impairment and Alzheimer\u2019s disease (AD), understanding their underlying causes and associated risk factors becomes increasingly critical. A salient concern in the western dietary context is the high consumption of methionine-rich foods such as red meat. The present review delves into the impact of this methionine-heavy diet and the resultant hyperhomocysteinemia on accelerated cerebrovascular and brain aging, emphasizing their potential roles in cognitive impairment. Through a comprehensive exploration of existing evidence, a link between high methionine intake and hyperhomocysteinemia and oxidative stress, mitochondrial dysfunction, inflammation, and accelerated epigenetic aging is drawn. Moreover, the microvascular determinants of cognitive deterioration, including endothelial dysfunction, reduced cerebral blood flow, microvascular rarefaction, impaired neurovascular coupling, and blood\u2013brain barrier (BBB) disruption, are explored. The mechanisms by which excessive methionine consumption and hyperhomocysteinemia might drive cerebromicrovascular and brain aging processes are elucidated. By presenting an intricate understanding of the relationships among methionine-rich diets, hyperhomocysteinemia, cerebrovascular and brain aging, and cognitive impairment, avenues for future research and potential therapeutic interventions are suggested. The Western world is undergoing a profound demographic shift, with an increasingly aging population ,2,3. ThiEpidemiological studies have shed light on the prevalence and impact of cognitive decline and dementia across the aging populations of the developed world ,11,12,13Significant progress has been made in elucidating the cellular and molecular mechanisms underlying cerebrovascular and brain aging, as well as age-related pathologies affecting the central nervous system ,58,59,60Among dietary factors of interest, high methionine intake has been implicated as a potential contributor to unhealthy cerebrovascular and brain aging ,80,81,82Preclinical studies utilizing laboratory animals have provided valuable insights into the effects of high-methionine diets and hyperhomocysteinemia on cardiovascular, cerebrovascular, and brain aging ,93,94,95In light of these observations, this review aims to comprehensively examine the available evidence regarding the role of a methionine-rich diet in unhealthy cerebrovascular and brain aging, with a specific focus on its implications for cognitive impairment. By evaluating epidemiological data, preclinical studies, and the molecular mechanisms involved, we aim to provide a deeper understanding of the impact of high methionine consumption on cerebrovascular health, brain aging, and cognitive function. By examining the impact of a methionine-rich diet on cognitive decline and age-related pathologies, we aim to shed light on the importance of healthy dietary choices in supporting optimal brain health and mitigating the risk of cognitive impairment and dementia in aging populations. Understanding the impact of high methionine consumption on cerebrovascular and brain aging is essential for developing targeted dietary interventions to promote healthy aging and maintain cognitive function throughout the aging process.Methionine can be obtained through dietary sources. Certain foods are particularly high in methionine and can contribute to a methionine-rich diet. Foods that are known to be rich sources of methionine include red meat , fish , and dairy products , and some plant-based foods .Red meat consumption in particular has been a topic of increasing interest in the context of aging and age-related diseases . Access Methionine metabolism is a complex and highly regulated process that begins when methionine is taken up from food sources during digestion. Once ingested, methionine is absorbed into the bloodstream and transported to various tissues throughout the body. In the liver, the major site of methionine metabolism, methionine can undergo two main pathways. Through the transmethylation pathway, methionine is converted into SAM through a reaction catalyzed by the enzyme methionine adenosyltransferase. SAM is a universal methyl donor involved in various methylation reactions. It donates methyl groups to molecules such as DNA, histones, proteins, and neurotransmitters, playing a crucial role in epigenetic regulation, protein synthesis, and neurotransmitter metabolism. Excess SAM can be converted back to methionine through the methionine cycle.Under normal conditions, a smaller portion of methionine is metabolized through the transsulfuration pathway. Here, methionine is converted into homocysteine, a process that requires the enzyme cystathionine beta-synthase (CBS). Subsequently, homocysteine is converted into cysteine, another important sulfur-containing amino acid. Normal methionine-homocysteine metabolism involves a tightly regulated series of biochemical reactions, including the remethylation pathway, that maintains the balance of these two sulfur-containing amino acids in the body. Folate and vitamin B12 are essential cofactors for the remethylation of homocysteine back to methionine. In this process, homocysteine is converted to methionine through the actions of methionine synthase, a vitamin B12-dependent enzyme. Folate donates a methyl group to homocysteine, which is transferred by methionine synthase, along with a methyl group from 5-methyltetrahydrofolate (the active form of folate), to produce methionine. Vitamin B6 is required for the transsulfuration pathway, where homocysteine is converted into cysteine through a series of reactions involving the enzyme cystathionine gamma-lyase (CGL). This well-coordinated system ensures that the levels of methionine and homocysteine are tightly regulated. Proper methionine-homocysteine metabolism is vital for various cellular processes, including protein synthesis, epigenetic regulation, neurotransmitter metabolism, and maintaining redox balance. Disruptions in this finely balanced metabolism, arising from deficiencies in the necessary vitamins, genetic mutations impacting the enzymes involved, or an excess intake of methionine, can lead to a condition known as hyperhomocysteinemia. This condition is associated with an elevated risk of various health issues, including cardiovascular and cerebrovascular diseases, neurodegenerative disorders, and other related health complications (as detailed below). Hyperhomocysteinemia is a condition characterized by elevated levels of homocysteine, a sulfur-containing amino acid derived from methionine metabolism ,138,139.In addition to high methionine intake, hyperhomocysteinemia itself can affect various organ systems. Elevated homocysteine levels have been associated with an increased risk of cardiovascular diseases, including atherosclerosis, arterial thrombosis, and stroke ,145,146.The mechanisms of aging represent a complex interplay of cellular processes that lead to the gradual decline of physiological functions and an increased susceptibility to age-related diseases. In recent years, research has shed light on the potential impact of dietary factors in general and methionine intake in particular on the aging process ,111,112.Conversely, evidence delineates a pleiotropic relationship between methionine intake and health outcomes. Methionine restriction\u2014though potentially beneficial\u2014can engender adverse effects including the onset of hair greying , atherosIn this section, we explore some of the key mechanisms through which high methionine consumption can accelerate the aging process. From its role in increased oxidative stress, DNA damage, and induction of mitochondrial dysfunction to epigenetic modifications and altered protein homeostasis, we delve into the intricate pathways that link high methionine intake to the accelerated aging phenotype. Understanding these mechanisms is crucial for devising strategies to mitigate the adverse effects of a methionine-rich diet and potentially promote healthier aging outcomes.Oxidative stress is a hallmark of aging and is implicated in the pathogenesis of various age-related diseases. Importantly, high methionine intake has been associated with increased cellular oxidative stress ,152,153.There is strong evidence that high methionine intake and hyperhomocysteinemia increase mitochondrial ROS production, whereas dietary methionine restriction attenuates mitochondrial oxidative stress ,110. MitHigh methionine intake and/or hyperhomocysteinemia have also been shown to up-regulate major cellular oxidant systems, including NAD(P)H oxidases ,93,94,95Both mitochondrial ROS generation and the activity and expression of cellular NAD(P)H oxidases are regulated by humoral factors ,169,170 Chronic low-grade inflammation, often referred to as inflammaging, is associated with accelerated aging and age-related cardiovascular, cerebrovascular, and brain diseases ,193,194.Epigenetic modifications, including DNA methylation, histone modifications, and non-coding RNA expression, play a crucial role in regulating gene expression patterns, cellular function, genomic stability, cellular identity, and organismal aging ,216,217.Increased oxidative stress leads to DNA damage accumulation in aged cells . High meCellular senescence is a cellular stress response, characterized by a state of irreversible growth arrest in which cells lose their ability to divide and proliferate, even in the presence of stimuli that would typically promote cell division. This state is often accompanied by distinct changes in cell morphology and function. Cellular senescence can be triggered by a variety of stressors, including DNA damage, telomere shortening, and exposure to oxidative stress. Senescent cells remain metabolically active but play a role in aging biology by secreting pro-inflammatory molecules and other factors that can influence tissue function and contribute to the pathogenesis of age-related diseases ,242,243.Importantly, cellular senescence has emerged as a pivotal player in the biology of cerebrovascular and brain aging, with profound implications for brain health ,46,244. In the context of cerebrovascular and neurovascular aging, senescence of endothelial cells, pericytes, astrocytes, and paravascular microglia contributes to endothelial dysfunction, neurovascular dysfunction, blood brain barrier dysfunction, and genesis of cerebral microhemorrhages. These changes can lead to diminished cerebral blood flow, impairing nutrient and oxygen delivery to the aging brain, disruption of neuronal networks, and neuroinflammation. Furthermore, senescent cells within the cerebral circulation can disrupt neurovascular coupling, affecting the brain\u2019s ability to respond to changing metabolic demands . This, iRemarkably, a high-methionine diet has been implicated in the induction of cellular senescence ,255,256.Protein homeostasis, or proteostasis, is a critical cellular process responsible for maintaining the proper folding, function, and degradation of proteins, which is essential for maintaining cellular function and preventing protein aggregation, a hallmark of aging and neurodegenerative diseases ,263,264.The brain\u2019s elevated metabolic requirements are sustained by an intricate microcirculatory network, estimated to encompass approximately 600 km in length within the human body. This cerebral microcirculation serves as a vital conduit, ensuring the precise distribution of essential resources such as oxygen, glucose, and other nutrients to neural tissues. Additionally, it actively participates in the removal of metabolic waste products, maintains the ionic balance crucial for neuronal function, orchestrates the formation and integrity of the blood\u2013brain barrier (BBB), and governs the transport of diverse substances across this barrier. Thus, the health of the microvasculature assumes a pivotal role in preserving normal cognitive and neuronal functions ,275,276.Both hyperhomocysteinemia and increased methionine intake are associated with atherosclerotic vascular diseases, including stroke ,286,287.Endothelial cells play a crucial role in maintaining vascular homeostasis. Endothelium-dependent, NO-mediated dilation of cerebral microvessels plays a crucial role both in maintaining cerebral blood flow ,296 and With aging, endothelial dysfunction occurs, characterized by impaired endothelium-dependent vasodilation, increased oxidative stress, and inflammation ,305,306.Earlier research has indicated that consumption of a methionine-rich diet and an increase in plasma homocysteine levels can impair endothelium-mediated vasodilation in humans ,315,316,Microvascular rarefaction refers to a reduction in the density and branching of small blood vessels, impairing microcirculation and nutrient exchange in the brain. Aging is associated with microvascular rarefaction, which can compromise cerebral perfusion and contribute to cognitive decline ,320,321.The blood\u2013brain barrier (BBB) regulates the exchange of substances between the blood and the brain, maintaining brain homeostasis ,273,274.A significant outcome of BBB disruption is the leakage of plasma components, including IgG, thrombin, and fibrinogen, into the brain parenchyma . This heSynaptic plasticity, the ability of synapses to strengthen or weaken over time in response to changes in their activity, is fundamental to learning and memory processes. High methionine intake and hyperhomocysteinemia have been shown to impact synaptic plasticity by disrupting key molecular signaling pathways involved in synaptic function ,353,354.Neurodegenerative diseases, characterized by the progressive loss of structure and function of neurons, represent a burgeoning global health concern ,358. ConPreclinical studies have shown that a methionine-rich diet and hyperhomocysteinemia can induce neurodegenerative disease-like changes, including protein aggregation and neuroinflammation. Clinical evidence has also suggested associations between high methionine intake or hyperhomocysteinemia, imaging biomarkers of accelerated aging of the central nervous system ,360, andFunctional connectivity refers to the temporal correlation of neural activity between different brain regions, which reflects the coordination and integration of neural networks. Disruptions in functional connectivity with aging  have beeIn summary, the relationship between elevated methionine intake, hyperhomocysteinemia, and the aging processes affecting cerebrovascular and brain health stands as a pivotal area of investigation in understanding age-related cognitive decline. This review has shed light on the multifaceted pathways through which these dietary and metabolic factors accelerate aging mechanisms within the cerebrovascular system and brain, ultimately contributing to cognitive impairment. From the initiation of oxidative stress and mitochondrial dysfunction to the induction of chronic inflammation and accelerated epigenetic aging, high methionine consumption and hyperhomocysteinemia set forth a cascade of detrimental effects.The body of evidence available underscores the pivotal role played by microvascular health in the context of age-related cognitive impairment, offering illuminating insights into how factors such as endothelial dysfunction, reduced cerebral blood flow, microvascular rarefaction, compromised neurovascular coupling, and blood\u2013brain barrier disruption collectively contribute to the complex landscape of cognitive decline. Importantly, it should be noted that these factors are modifiable through dietary interventions and lifestyle adjustments, providing promising avenues for the preservation of cognitive function and the promotion of healthy brain aging. The profound impact on synaptic function and neuronal health further underscores the extensive consequences of these dietary factors.Looking forward, further research should delve deeper into the intricate molecular mechanisms underpinning the relationship between methionine-rich diets, hyperhomocysteinemia, and cerebrovascular and brain aging. It is imperative to investigate the dose-response relationship between methionine intake and cerebrovascular/brain aging to establish optimal intake thresholds. Additionally, efforts should focus on elucidating the molecular mechanisms through which high methionine intake affects microvascular dysfunction, synaptic function, and neuronal health. Exploring the interactions between methionine metabolism and other dietary factors in modulating cerebrovascular health and brain aging will be crucial in gaining a comprehensive understanding of these processes. Investigations into potential interventions to mitigate the detrimental effects of high methionine intake on cerebrovascular health and brain aging are warranted. Strategies targeting these mechanisms, such as dietary modifications, supplementation, or pharmacological interventions, should be further explored in preclinical and clinical settings.To optimize cerebrovascular and brain health and counteract the adverse effects of a methionine-rich diet, several dietary recommendations and potential therapeutic strategies can be considered ,398,399."}
+{"text": "The machine learning algorithms used were extreme gradient boosting, light-gradient boosting machine, multilayer perceptron, logistic regression, and balanced random forest (BRF). The prediction abilities of the machine learning models were assessed using the area under the receiver operating characteristic curve, feature importance, and average precisions of precision-recall curve, precision, recall, f1 score, and accuracy. PPE occurred in 3584 (1.6%) and 1896 (5.4%) patients in the training and test sets, respectively. The BRF model exhibited the best performance . However, its precision and f1 score metrics were not good. The five major features included arterial line monitoring, American Society of Anesthesiologists physical status, urine output, age, and Foley catheter status. Machine learning models  could predict PPE risk and improve clinical decision-making, thereby enhancing postoperative management.Postoperative pulmonary edema (PPE) is a well-known postoperative complication. We hypothesized that a machine learning model could predict PPE risk using pre- and intraoperative data, thereby improving postoperative management. This retrospective study analyzed the medical records of patients aged > 18 years who underwent surgery between January 2011 and November 2021 at five South Korean hospitals. Data from four hospitals ( Postoperative pulmonary edema (PPE) is a well-known complication with multiple possible causes . PreexisIt is often difficult to determine the cause of PPE during its early stages, particularly in patients with overlapping etiologies ,6,7. TheAdvances in computing have enhanced several key areas of clinical research; artificial-intelligence-based methods may have additional applications. Machine learning (ML) systems are widely used in clinical research to analyze big data. Compared to traditional scoring systems, ML models perform better when predicting various clinical conditions ,12,13. TThis retrospective cohort study protocol was approved by the Clinical Research Ethics Committee of Chuncheon Sacred Heart Hospital, Hallym University. The need for informed consent was waived because of the retrospective study design. The medical records of patients treated between 1 January 2011 and 15 November 2021 were obtained from the clinical data warehouses of five hospitals affiliated with Hallym University Medical Center. The hospitals were located in Seoul , Gyeonggi Province , and Gangwon Province .A clinical data warehouse is a database of medical records, prescriptions, and test results, which can be used to identify patients based on prescriptions, examinations, and diagnostic data. The timing and results of investigations, drug administration, transfusions, and other information were extracted in an unstructured text format. The requested data were provided in a de-identified format, but the data of specific patients could be extracted using a key.The study included adult patients aged > 18 years who did not exhibit preoperative pulmonary edema. The exclusion criteria and outlier data were missing. Pulmonary edema was diagnosed by radiologists on the basis of chest radiographs. Patients were presumed not to have PPE if they lacked perioperative respiratory symptoms and did not undergo chest radiography.2O use, anesthesia time (min), surgery time (min), intraoperative blood and fluid administration, intraoperative urine output, and estimated blood loss; the statuses of arterial line monitoring, central venous pressure monitoring, Foley catheter, Levin tube, and patient-controlled analgesia; the administration of intraoperative packed red blood cells, frozen fresh plasma, platelets (concentration and cryoprecipitate), rocuronium, vecuronium, atracurium, cisatracurium, succinylcholine, pyridostigmine, neostigmine, sugammadex, fentanyl, alfentanil, sufentanil, remifentanil, and pethidine; blood urea nitrogen level, creatinine level, glomerular filtration rate, prothrombin time, activated partial thromboplastin time, and platelet count; the levels of sodium, potassium, uric acid, protein, and albumin; and the statuses of robotic surgery, laparoscopic surgery, heart surgery, abdominal surgery, breast surgery, ear surgery, endocrine surgery, eye surgery, head and neck surgery, musculoskeletal surgery, neurosurgery, obstetric and gynecological surgery, spine surgery, thoracic surgery, transplant surgery, urogenital surgery, vascular surgery, and skin and soft tissue surgery.The dataset involved the following 98 perioperative variables: age, male sex, and order of surgery; the statuses of preoperative atelectasis, preoperative effusion, preoperative pneumothorax, preoperative pneumonia, preoperative pulmonary thromboembolism, and preoperative acute respiratory distress; body mass index; the statuses of congestive heart failure, cardiac arrhythmia, valvular diseases, pulmonary circulation disorders, peripheral vascular disorders, hypertension (uncomplicated vs. complicated), paralysis, other neurological disorders, chronic pulmonary diseases, diabetes (uncomplicated vs. complicated), hypothyroidism, renal failure, liver diseases, peptic ulcer diseases (excluding bleeding), acquired immune deficiency syndrome/human immunodeficiency virus, lymphoma, metastatic cancer, solid tumors (without metastasis), and rheumatoid arthritis/collagen vascular diseases; alcohol consumption, current smoking status, smoking frequency (packs), smoking duration (years), emergency status, American Society of Anesthesiologists physical status of >2, use of general anesthesia, maintenance anesthetics administered, NThe dataset was divided into training and test sets. The training set included data from Kangnam Sacred Heart Hospital, Hangang Sacred Heart Hospital, Hallym University Sacred Heart Hospital, and Dongtan Sacred Heart Hospital. The test set included data from Chuncheon Sacred Heart Hospital. The training set was used for model learning, whereas the test set was used to evaluate model performance. Both datasets were standardized using min.\u2013max. scaling based on the training set.The study used supervised learning, which is an ML paradigm for data consisting of labeled examples . Five ML algorithms were used: random forest, light-gradient boosting machine, extreme-gradient boosting machine, multilayer perceptron, and logistic regression ,22,23,24The dataset was imbalanced and may have caused low model performance. Therefore, we used the synthetic minority oversampling technique for all algorithms except random forest . After tAn additional carved dataset was used to modify the prediction model based on the large and complex dataset. This dataset was learned and validated using the best prediction algorithm from the original data. First, the test dataset was reduced by under-sampling using the Tomek\u2019s link method to validate our best model . Second,Six metrics were calculated for model performance. The primary metric was the area under the receiver operating characteristic curve. The average precisions of precision-recall curve, best threshold, precision, recall and f1 score, and accuracy were calculated. Google Colab  was used to calculate model metrics.p-values of < 0.05 were considered statistically significant.Descriptive analysis was performed to compare the characteristics of patients with and without PPE. Categorical variables were presented as numbers (%) and compared using the chi-squared test. Continuous variables were presented as medians (interquartile ranges) and compared using the Mann\u2013Whitney U test. n = 26,593) and outlier (n = 4) data, and 4480 preoperative PPE patients, a total of 256,899 patients were included in the analysis. PPE occurred in 5480 (2.8%) patients. The training and test sets included 221,908 and 34,991 patients, respectively. PPE occurred in 3584 (2.1%) and 1896 (7.4%) patients in the training and test sets, respectively . The performances of the remaining models are summarized in The evaluation of feature importance in the BRF model revealed that arterial line monitoring was the most important feature. Ten major features in the BRF model are shown in After under-sampling of the test dataset, PPE patients were 1896 and No-PPE patients were 32,621. In the simplified prediction model, the included features were as follows: arterial monitoring, American Society of Anesthesiologists physical status, age, urine output, intraoperative fluid, estimated blood loss, foley catheter, anesthesia time, albumin, glomerular filtration rate, central venous pressure monitoring, operation time, prothrombin time, blood urea nitrogen, protein, creatinine, prothrombin time-international normalized ratio, platelet, body mass index, and intraoperative packed red blood cell. Validation results are summarized in We used ML to develop models for the prediction of PPE. Model training using data from 221,908 patients was followed by model testing using data from 34,991 patients. Five algorithms were used to develop the models, whereas six metrics were used to evaluate their performances. BRF exhibited the best performance in terms of area under the receiver operating characteristic curve, recall, and accuracy. However, no model had a good precision or f1 score.Numerous studies have developed ML models to predict postoperative pulmonary complications. Peng et al. developed and validated a deep-neural-network model based on combined natural language data and structured data to predict pulmonary complications in geriatric patients . Xue et PPE has various causes, several of which can occur simultaneously. PPE may be cardiogenic or noncardiogenic, but it is difficult to distinguish between these etiologies because of their similar clinical features. In patients with acute myocardial infarction, cardiogenic pulmonary edema may be complicated by noncardiogenic edema related to the aspiration of gastric contents, syncope, or cardiac arrest. Conversely, in patients with severe trauma or infections accompanied by noncardiogenic pulmonary edema, fluid resuscitation may cause pulmonary edema through volume overload and increased pulmonary vascular hydrostatic pressure ,6,31. ThThe present study investigated the important features of the best model for the prediction of PPE risk. Ten major PPE risk factors were included, primarily those related to fluid and hydrostatic pressure rather than the other causes of PPE. This means that the PPE prediction model could mainly predict cardiogenic and hydrostatic pulmonary edema. However, the evidence is not conclusive because the etiologies of PPE in this study were not known.The most important feature was arterial line monitoring, which is required in patients who need continuous blood pressure monitoring or multiple blood sampling during surgery . ArteriaTo the best of our knowledge, our model is the first to predict PPE risk, and its performance was better than the previous PPE models. However, the present study had some limitations. First, the overall performance of the model was good, but its precision and f1 scores were low, even for the best threshold. Because recall (sensitivity) was good, the proportion of false positives may be high, presumably because of the low proportion of patients with pulmonary edema in the overall dataset. Thus, our model interpreted the normal state as PPE in many cases. There were similar results in the validation with the under-sampling dataset. Second, our model requires many features to predict PPE, which reduces its practicality. Although the performance was not significantly worse in the model with twenty features, this limitation of the model could not be resolved. A prediction model based on fewer features while maintaining the performance may be needed in the future. To resolve the first two limitations, additional datasets should be acquired and learned, or features with better predictive values should be selected. Third, our model could not distinguish between cardiogenic and noncardiogenic PPE. Additional studies are needed to develop models that can distinguish between the two PPE types and predict the risk of each type.In conclusion, we developed an ML model that could predict PPE risk in patients undergoing surgery. The model was superior to previously reported prediction models for postoperative pulmonary complications. Our ML model may improve clinical decision-making, thereby enhancing postoperative management. However, further improvements are needed to reduce the false positive rate and enhance the practical usefulness."}
+{"text": "Conductive hydrogels have gained significant attention for their extensive applications in healthcare monitoring, wearable sensors, electronic devices, soft robotics, energy storage, and human\u2013machine interfaces. To address the limitations of conductive hydrogels, researchers are focused on enhancing properties such as sensitivity, mechanical strength, electrical performance at low temperatures, stability, antibacterial properties, and conductivity. Composite materials, including nanoparticles, nanowires, polymers, and ionic liquids, are incorporated to improve the conductivity and mechanical strength. Biocompatibility and biosafety are emphasized for safe integration with biological tissues. Conductive hydrogels exhibit unique properties such as stretchability, self-healing, wet adhesion, anti-freezing, transparency, UV-shielding, and adjustable mechanical properties, making them suitable for specific applications. Researchers aim to develop multifunctional hydrogels with antibacterial characteristics, self-healing capabilities, transparency, UV-shielding, gas-sensing, and strain-sensitivity. Flexible conductive hydrogels have attracted significant attention due to their unique combination of mechanical flexibility, electrical conductivity, and biocompatibility, making them highly promising for a wide range of applications in healthcare monitoring, human\u2013machine interfaces, soft robots, and wearable devices ,2,3,4. UOne key aspect of the structure\u2013property correlation in flexible conductive hydrogels revolves around the molecular design and synthesis of the hydrogel matrix ,2,3,4. SThe incorporation of ionic liquid segmental polyelectrolytes and conductive materials has been found to enhance the electrical conductivity of hydrogels ,4,12. ThFurthermore, the mechanical properties of flexible conductive hydrogels are essential for their applications in wearable devices and soft robotics ,4,15. ReThe interaction between the hydrogel matrix and the surrounding environment is another critical aspect of the structure\u2013property correlation ,20,21. PIntegrating responsive elements into flexible conductive hydrogels enhances their functionality in sensing and human\u2013machine interaction applications ,25,26. SThe double-network structure has been highlighted for its ability to enhance the mechanical properties of hydrogels. Incorporating interpenetrating polymer networks and crosslinking agents has been shown to improve stretchability, toughness, and tensile strength . MoreoveThe electrical conductivity of conductive hydrogels is vital for their integration into electronic devices and sensors. Achieving stable electrical properties and high ionic conductivity is essential ,32. IncoBiocompatibility is a critical factor when considering the application of flexible conductive hydrogels in healthcare and wearable electronic devices. Hydrogels need to be compatible with biological systems and exhibit low cytotoxicity. Incorporating biocompatible materials enhances the biocompatibility of hydrogels ,33.Flexible conductive hydrogels find applications in various sensing and monitoring devices, including strain sensors, temperature sensors, and physiological signal monitoring. The properties of hydrogels significantly influence the sensitivity, linearity, response time, and durability of these sensors ,34.To achieve multifunctionality, conductive hydrogels often incorporate stimuli-responsive materials. For instance, thermoresponsive hydrogels can undergo reversible volume changes in response to temperature variations, enabling them to detect human motion and respond to environmental temperature changes .Composite structures, such as graphene nanocomposites, have been explored to improve the mechanical and electrical properties of conductive hydrogels . The addSelf-healing properties have also gained significant attention in the development of flexible conductive hydrogels. These hydrogels possess the remarkable ability to autonomously repair mechanical damage, leading to a prolonged lifespan and improved durability .In summary, the properties of flexible conductive hydrogels, including the mechanical properties, electrical conductivity, environmental stability, biocompatibility, and sensing capabilities, can be improved through various strategies. These advancements open up possibilities for their widespread applications in areas such as soft robotics, wearable electronics, biomedical devices, and sensor technologies. Ongoing research in this field continues to push the boundaries, unlocking new possibilities for the practical implementation of flexible conductive hydrogels.Strain-sensitive conductive hydrogels have emerged as promising materials for the development of wearable sensors due to their unique properties, such as stretchability, flexibility, biocompatibility, and conductivity. These hydrogels enable the detection and monitoring of various human body movements, making them valuable in healthcare monitoring, biomechanics, and other applications. In this section, we will discuss several studies that highlight the advances in strain-sensitive conductive hydrogels and their applications in wearable sensors.3+)  dimethyl-(3-sulfopropyl) (PSBMA), MXene nanosheets, and glycerol. This organohydrogel exhibited high fracture strength, stretchability, toughness, adhesion to diverse substrates, fatigue resistance, and stability under extreme temperatures. A sensor based on this organohydrogel demonstrated the ability to monitor joint motions and changes in facial expressions, highlighting its potential for wearable sensors in various environments .Another study focused on an adhesive, self-healing, and antibacterial conductive hydrogel prepared using dopamine methacrylate (DMA), methacrylatoethyl trimethyl ammonium chloride (DMC), and acrylic acid (AA). This hydrogel exhibited strong adhesion to various materials, good antibacterial properties, excellent self-healing properties, ductility, biocompatibility, and conductivity. These characteristics make the hydrogel suitable for applications in electronic skin and wearable devices for monitoring physiological activities .E. coli bacteria (Another conductive hydrogel composed of cationic micelles prepared with copolymerization of hydrophilic monomer acrylamide (AM) and hydrophobic (Hb) monomer stearyl methacrylate C18 crosslinked in the polyacrylamide (PAM) network P(AM-Hb/CM) showed antibacterial activity against bacteria  along wi2 sensing. These hydrogels demonstrated high sensitivity, a short response and recovery time, a low limit of detection, and high selectivity, stability, and conductivity. The incorporation of calcium chloride (CaCl2) via salt-infiltration improved the gas-sensing performance with higher sensitivity and a lower limit of detection. The salt-infiltrated hydrogel has potential for wearable electronics with gas-sensing capabilities in both anaerobic and aerobic environments . Th. Th73]. A multistimulus-responsive and multifunctional hydrogel system, composed of carboxymethyl cellulose and poly acrylic-acrylamide, demonstrates excellent elasticity, flexibility, and stable conductivity . This hyAnother multifunctional conductive hydrogel, comprising a polyacrylamide/chitosan hybrid network, exhibits exceptional flexibility, puncture resistance, and self-healing capability . With itA hybrid hydrogel system composed of poly(N-isopropylacrylamide), poly, sodium tetraborate decahydrate, and poly(sodium acrylate) enables the simultaneous monitoring of touch points and temperature . This syResearchers have developed a highly stretchable, self-healing, and electro-conductive hydrogel with a hierarchically triple-network structure . This hyA multifunctional conductive polymer hydrogel, incorporating multiple hydrogen-bonding 2-ureido-4[1-11]-pyrimidinone (UPy) groups as crosslinking points, demonstrates high conductivity, excellent stretchability, injectability, and rapid self-healing capability . This hyTo develop wearable thermoelectric-energy-harvesting fibers, researchers have produced a highly conductive p-type PEDOT:PSS fiber through a gelation process . A post-A strategy for fabricating flexible, anti-fatigue, and conductive cotton fabrics involves a hierarchical coating structure comprising an l-cysteine binder, silver nanoparticles (Ag NPs), and a conductive hydrogel coating . This coLastly, a highly sensitive, low-cost, wearable pressure sensor based on conductive single-walled carbon nanotube/alginate hydrogel spheres has been developed . This seIn conclusion, functional conductive hydrogels with remarkable properties and functionalities have gained significant attention in recent years. These hydrogels find applications in a wide range of fields, including wearable technology, healthcare monitoring, soft robotics, artificial intelligence, and biomimetic prostheses. The studies mentioned above represent significant advancements in the development and application of functional conductive hydrogels, contributing to the progress of these fields and opening new avenues for innovation and improved functionality. The field of strain-sensitive and conductive hydrogels has experienced significant advancements with the development of novel materials and approaches ,20,22,37Conductive hydrogels for wearable sensors have made notable progress in the development of various materials and approaches ,38,40,48Sustainable methods for preparing conductive hydrogels have been developed, contributing to the production of flexible and durable materials for wearable electronic devices ,45,49,80The development of conductive hydrogels with self-healing properties, antibacterial properties, and incorporating various additives has significant implications for flexible electronic devices, healthcare monitoring, biomaterials, soft robotics, gas-sensing technologies, and human\u2013machine interfaces ,43,46,51Conductive hydrogels for wearable human\u2013machine interfaces and sensors offer solutions for stable electrode\u2013skin interfaces, painless signal acquisition, pressure sensing, self-healing, adhesiveness, motion detection, strain sensing, stretchability, ionic conductivity, and high sensitivity ,81,82,83The integration of conductive hydrogels with thermoresponsive hydrogels, the development of composite hydrogels, and the utilization of nanomaterials in flexible electronics offer flexibility, high sensitivity, mechanical strength, electrical conductivity, self-healing, self-adhesiveness, and responsiveness to multiple stimuli ,58,84,85High-sensitivity strain and pressure hydrogel sensors, nature-inspired glycogen-based hydrogels, super-stretchable and recoverable hydrogel-based sensors, intelligent zwitterionic hydrogel-based bionic e-skin, and other functional conductive hydrogels offer remarkable properties and functionalities ,69,70,71In conclusion, the utilization of conductive hydrogel polymers involves several strategies and considerations. The combination of conductive polymers with other materials, the enhancement of mechanical properties, the incorporation of multiple components, crosslinking and interpenetrating networks, the utilization of nanocomposites, advanced manufacturing techniques, integration with electronic components, and biomedical applications are key aspects to consider in the design and development of conductive hydrogels. These strategies aim to improve conductivity, mechanical strength, flexibility, self-healing ability, and other desirable properties required for specific applications.However, there are also challenges that need to be addressed. One of the challenges is achieving a balance between conductivity and mechanical properties, as increasing conductivity may compromise the mechanical integrity of the hydrogel. Additionally, the stability of the conductive polymers and their interaction with other components need to be carefully evaluated to ensure long-term performance. Furthermore, the scalability and cost-effectiveness of the fabrication processes are important considerations for large-scale production and commercialization of conductive hydrogels.Despite these challenges, conductive hydrogels hold great potential for a wide range of applications. They offer advantages such as biocompatibility, antibacterial activity, transparency, and biodegradability, making them suitable for wearable sensors, biomedical devices, antibacterial materials, and tissue adhesives. Conductive hydrogels also demonstrate high sensitivity, stability, and low detection limits, enabling their use in sensing and biosensing applications."}
+{"text": "Although on the one hand polymers are arousing increasing interest due to their remarkable properties in terms of lightness, cost-effectiveness, easy processing, and mechanical resistance, on the other hand, they still present several restrictions in practical applications ,2. These"}
+{"text": "HighlightsThe recent rise in antimicrobial resistance has increased the burden of infectious diseases caused by bacteria, parasites, and viruses. The development of immunotherapy provides new treatment options in the fight against infectious diseases.host-directed treatment options are now becoming viable adjuncts to standard antimicrobial treatment, despite having some toxicities such as dermatologic, gastrointestinal, thyroid, pituitary, neurologic, renal, ocular, cardiovascular, and hematologic toxicit.Improving the management of infectious diseases requires the development and use of immunological therapy. Some of our suggestions for using immune treatment to lessen the impact of viral diseases include. Increased vaccine production and supply should be emphasized.Dear Editor,Respivax, have been tested. Clinical data has shown it to be a prospective treatment for respiratory infections in complex treatment in some immunodeficiency states such as AIDSStaphylococcus aureus and Pseudomonas aeruginosain vitro to be effective against S. aureus, Staphylococcus epidermidis, and Streptococcus pneumoniaePlasmodium falciparum is RTS,S/ASO1, which contains a virus-like particle \u2013 the terminal domain of P. falciparum circumsporozoite protein combined with hepatitis B virus surface antigen being formulated with potent liposomal adjuvant system ASO1. Although the vaccine has proven efficacy against clinical malaria in phase III trials, protection is partial as subsequent declines ensue with time. Immunotherapy is linked to the following toxicities: dermatologic, gastrointestinal, hepatitis, thyroid, pituitary, neurological, renal, ocular, cardiovascular, and hematological toxicities. In the antimicrobial resistance era, immunotherapy is important to fight against emerging infectious diseases. Some of our suggestions for using immune treatment to lessen the impact of viral diseases include. Increased vaccine production and supply should be emphasized. Vaccination is essential in improving immunity against infectious diseases such as polio, measles, and pneumoniaCoronavirus disease 2019 (COVID-19) has opened opportunities for immunotherapy as an effective option in treating emerging diseases. Immunotherapy act against pathogens and infected host cells by manipulating immune system components to target and eradicate them. Immunotherapy has been mostly associated with cancer treatment but initiatives are made to curative different diseases such as malaria, zika virus, HIV, tuberculosis, and COVID-19Not applicable.Not applicable.O.U. contributed in the conceptualization, project administration, writing \u2212 review and designing. All authors were involved in the writing of manuscript, data collection and assembly, and final approval of manuscript.The authors declare that they have no financial conflict of interest with regard to the content of this report.Not applicable.Abubakar Nazir."}
+{"text": "Sarcoidosis is an inflammatory and granulomatous disease of uncertain etiology that can impact various organ systems and exhibits diverse clinical presentations, which adds to the complexity of disease diagnosis and management. Pathologically, it is distinguished by the presence of noncaseating granulomas within the affected organ system. In this case report, we describe a 34-year-old Caucasian female patient with isolated\u00a0splenic and possible hepatic involvement of sarcoidosis, presenting with severe abdominal pain. The absence of the typical pulmonary, cutaneous, or joint involvement posed challenges in achieving a definitive diagnosis and determining the appropriate management. Imaging studies revealed hepatic and splenic hypodensities, necessitating consideration of various differential diagnoses, including lymphoproliferative disorders, immunological disorders, environmental particle exposure, infectious causes, neoplasms, and drug reactions. The severity of symptoms in this case required hospital admission for pain and nausea control, biopsy, and eventual splenectomy with pathology that confirmed the diagnosis of splenic sarcoidosis. Sarcoidosis, a multisystem inflammatory disease, was initially identified and named over a century ago. In 1878, Sir Jonathan Hutchinson first described the condition of sarcoidosis . While iThis article was previously presented as an abstract at the 2023 WV Society of Hospital Medicine Abstract Competition in May 2023.Cytomegalovirus, Human immunodeficiency virus, Epstein-Barr virus, hepatitis panel, acid-fast bacilli, Bartonella, Chlamydia trachomatis, Chlamydia psittaci,\u00a0Treponema pallidum, enteric bacteria profile, Lyme disease, Coxiella, Cryptococcus, Histoplasma capsulatum,\u00a0Blastomyces dermatitidis, ova and parasites, and Toxoplasma gondii. Additionally, an autoimmune workup was conducted, involving testing for systemic lupus erythematosus, mixed connective tissue diseases, Sjogren's syndrome, scleroderma, polymyositis, alpha-1 antitrypsin, and ceruloplasmin. The comprehensive workup yielded unremarkable results, except for an elevated C-reactive protein level of 4.2 mg/dL (reference range <0.9 mg/dL). Additional imaging studies, including CT of the chest and CT of the head, did not reveal any significant findings. The patient received symptomatic management and was referred to a tertiary care facility for further workup, which was also unrevealing. Despite extensive workup and symptomatic management, she continued to have persistent abdominal pain.\u00a0She was then admitted to the hospital, where a repeat liver biopsy was performed via endoscopic ultrasound, this was inconclusive with some rare noncaseating granulomas. Universal PCR analysis was repeated, and the results were negative for fungal DNA or mycobacterium DNA. Sarcoidosis was suspected, prompting initial treatment with a prednisone taper. However, the patient did not tolerate the steroids, due to significant anxiety, agitation, and other adverse side effects.\u00a0Although antibiotics were tried based on infectious disease recommendations, no definitive diagnosis had been made at that time, and this failed to provide relief for the patient.\u00a0Consequently, the patient opted for splenectomy, and the subsequent pathology report confirmed the suspected diagnosis of sarcoidosis . Contrast-enhanced abdominal and pelvic computed tomography (CT) displayed multiple low-attenuation lesions in the liver and spleen Figure . A liverDue to its intricate characteristics, the potential for multiorgan involvement, and the absence of pathognomonic features, sarcoidosis is primarily considered a diagnosis of exclusion. The diverse range of clinical presentations associated with sarcoidosis can present challenges in both diagnosing and managing the disease. While sarcoidosis was suspected\u00a0in this case, the involvement of splenic and hepatic lesions with an inconclusive biopsy necessitated a comprehensive differential diagnosis, encompassing lymphoproliferative disorders, immunological disorders, environmental particles exposure, infectious causes, neoplasms, and drug reactions . ExtrapuIsolated splenic sarcoidosis represents a rare manifestation of sarcoidosis, which poses challenges in terms of diagnosis due to the absence of a definitive diagnostic test. Instead, the diagnosis relies on the presence of clinical and radiographic manifestations consistent with sarcoidosis, exclusion of other diseases, and histopathologic identification of noncaseating granulomas. The treatment of sarcoidosis often involves the administration of steroids; however, in this specific instance, the patient exhibited poor tolerance, thereby requiring alternative therapeutic approaches. Improving care for patients with sarcoidosis often requires multidisciplinary teams working together to understand the unique patient presentation and affected organ system, to maximize the diagnosis and treatment for the safety and quality of life of the patient."}
+{"text": "IntroductionRecognizing the concerns posed by spine injuries within homes, stemming from falls, interactions with furnishings, and daily activities, it is imperative to consider preventive strategies. Our analysis of spine injuries utilizing the National Electronic Injury Surveillance System (NEISS) data sheds light on falls, furnishings, age-specific risks, recreation, technology, and socioeconomic disparities as contributing elements, accentuating the need for targeted interventions. This\u00a0study aims to provide insights into the prevalence of spine injuries in different household locations, associated products, age groups, and gender, thus informing injury prevention strategies for safer living environments.MethodsThis is a retrospective, cross-sectional study utilizing data between 2013 to 2022 from the National Electronic Injury Surveillance System database. Specific household product codes and demographic data, such as age and gender, were analyzed. Statistical analysis in R  involved descriptive statistics and multivariate logistic regressions.ResultsIn analyzing 44,267 spine injuries, the study revealed location-specific variations in spine injuries within households. Living rooms and bedrooms had the highest injury rates at 34.17% and 21.65%, respectively. Significant differences in injury rates between males and females across various home locations. Females accounted for 51.78% of injuries in the living room and 59.99% in the bedroom. In the kitchen, females experienced 53.21% of injuries, while males accounted for 46.79% of cases. Notably, overall spine injuries exhibited a significant difference between males and females, with females having a higher total likelihood of injuries . Regarding age,\u00a0individuals between 51-60 years were most vulnerable to spine injuries, accounting for 17.98% of total cases. Notably, the age group of 61-70 years exhibited a substantial proportion of injuries at 17.12%, while the age group of 71-80 years accounted for 14.39%. The age group of 41-50 years also displayed a notable injury rate of 14.12%. The youngest age group, 0-10 years, demonstrated the lowest percentage of injuries at 4.79%. This age-based analysis provides valuable insights into the distribution of spine injuries across different demographic segments.Regarding age, individuals between 51-60 years were most vulnerable to spine injuries, comprising 17.98% of total cases. Age groups of 41-50 and 61-70 years also showed substantial proportions of injuries, accounting for 14.12% and 17.12%, respectively. The youngest age group, 0-10, exhibited the lowest percentage of injuries at 4.79%.ConclusionThe study focuses on the occurrence of spinal injuries in common sites of injury in the household, such as the living room, bedroom, kitchen, and stairs. There is increased prevalence amongst females and increased risk vulnerability amongst people 51 to 60 years of age. Our research emphasizes the necessity of implementing specific injury prevention measures tailored to different demographic groups within their home setting. This approach should involve collaborative decision-making with patients while prioritizing patient education to create a safer living environment and reduce the likelihood of spine injuries. Spinal injuries that occur within the confines of one's own home pose a serious threat to public health and lead to considerable levels of injury and healthcare expenses, with costs per patient exceeding one million US dollars . A highlNumerous inquiries have shed light on the importance of comprehending the underlying factors that contribute to these injuries. For instance, a certain study discovered that slipping, tripping, stumbling, and tumbling down from structures like buildings, stairs, and steps are the primary culprits behind spinal injuries caused by falls in residential areas. Furthermore, this examination showed that individuals aged 61 years or more are particularly prone to experiencing falls on the same level, which subsequently result in severe functional spinal injuries at the cervical and thoracic levels. This underscores the imperative need for targeted fall prevention approaches specifically designed for the elderly population ,6,9.\u00a0Items in the home environment are significant factors contributing to spine injuries ,10. ItemThe rise of recreational activities and sports in the household environment has also created unique events leading to spine injuries . TrampolIn addition, the social determinants of health play a role in the burden of home-related spine injuries. Individuals from lower-income households experience higher rates of such injuries, which emphasizes the need for injury prevention strategies tailored specifically for these populations ,18,19. WSpine injuries that occur in homes are a matter of great concern when it comes to public health. Our study, which relies on the NEISS database, presents a thorough examination shedding light on the epidemiology, risk factors, and preventive measures connected to these injuries. Having knowledge about these contributing factors is crucial for creating interventions with specific goals in mind, encouraging safety practices, and ultimately reducing the occurrence of spine injuries within residential environments.A cross-sectional design examined total spine injuries occurring within households across different age groups over ten years from 2013 to 2022. The primary data source for this investigation was the National Electronic Injury Surveillance System (NEISS) database, which has been previously utilized in several published studies . This daOur study's initiation involved an initial count of 48,263 entries, specifically focused on spine injuries. We systematically excluded entries that were missing an associated product code. To ensure a contemporary analysis, we focused on data from the previous decade. Within this timeframe, we gathered spine injury data from each year, culminating in an analysis sample of N=44,267. Our database search encompassed diagnoses related to spine injuries categorized under the body part code \"spine\" from 2013 to 2022. Our research team then meticulously selected relevant product codes linked to various household environments, including \"kitchen,\" \"living room,\" \"bedroom,\" \"stairs,\" \"outdoor,\" and \"other,\" for further investigation.In the \u201ckitchen\u201d category, items such as toasters, ice crushers, ice cream makers, coffee makers, electric blenders, electric frying pans, electric can openers, electric waffle irons, bread-making machines, and kitchen gadgets were included in the analysis. The \u201cliving room\u201d category included items such as sofas, couches, tables, entertainment centers, TV stands, recliners, armchairs, media consoles, coffee tables, end tables, picture frames, mirrors, floor lamps, table lamps, wall art, magazine racks, and decorative items. The \u201cbedroom\u201d category included items such as mattresses, bedding, bedspreads, throws, bunk beds, toddler beds, bed rails, bedside tables, dressers, wardrobes, full-length mirrors, jewelry boxes, alarm clocks, pillows, and decorative cushions. The \u201cstairs\u201d category included items included stair gates, staircases, stair treads, balusters, newel posts, stair risers, stair stringers, stair nosing, stair handrail brackets, stair carpet pads, stair mats, stair carpet or runners, stair slide or play accessories, stair gates for child safety, and stair railing kits. The \u201coutdoor\u201d category included items such as garden tools, barbecue grills, garden tractors, snow blowers, patio furniture, outdoor kitchen equipment, treehouses, garden furniture, outdoor umbrellas, outdoor heaters, garden sprayers, outdoor lighting, outdoor storage, outdoor decor, outdoor water features, outdoor pet houses, outdoor power tools, outdoor sports equipment, outdoor safety equipment, outdoor insect traps, and outdoor surveillance cameras. The \u201cother\u201d category included items such as decorative items, clocks, curtains, blinds, shades, curtains, indoor safety equipment, indoor plants, indoor exercise equipment, indoor games, indoor decorative lighting, indoor storage solutions, indoor sports equipment, indoor entertainment systems, indoor water features, indoor games, and various home-related products such as first aid kits, emergency kits, home office furniture and equipment, laundry appliances, and home automation devices. This approach allowed diverse analysis to occur across different living spaces, providing valuable insights into spine injuries localized to specific environments in the home.\u00a0For each spine injury, the age group and gender of the individual were extracted and analyzed to provide demographic associations in the prevalence of spine injuries per prior literature -23. The Descriptive statistics were employed to analyze and present the patterns and trends associated with spine injuries and home location, sex, and age group. Similar to prior studies, sex patterns were examined using multivariate logistic regression and were adjusted for age in the analysis ,24-27. ATable Table In the living room, females showcased a slightly higher probability of spine injuries than males , though this outcome did not achieve statistical significance. However, notable distinctions emerged in the bedroom , stairs , and other spaces , where females exhibited increased likelihoods of injuries in comparison to males. No statistically significant differences were observed in the kitchen and outdoor(yard/patio) areas. Spine injuries across all locations demonstrated a noteworthy difference between males and females , underscoring the increased probability of spine injuries among females.Table To visually represent these findings, the graph in Figure This study provides a comprehensive investigation into spinal injuries that occur in residential settings, with a particular emphasis on various factors including location, gender, and age groups. By delving further into these aspects of analysis, it is uncovered that living rooms witness the highest occurrence of such injuries, making up 34.17% of the total reported cases (Table Furthermore, it becomes evident that females constitute a significant proportion of the documented cases while varying degrees of injury rates are observed across different areas within households based on gender-specific patterns. Furthermore, age emerges as a crucial determining factor; individuals between the ages of 51-60 years experience the highest percentage of injuries irrespective of their location within homes Table . ConversFigure Furthermore, when examining gender-specific patterns, it is evident that females report more instances of spine injuries than males. There are variations regarding where these injuries occur based on gender, suggesting potential risks tied to specific sections of households designed for each gender. For instance, females experience significantly higher odds of injury in other undesignated areas outside, bedrooms, and stairs when compared to males Table . This coThe prevalence of injuries reveals that age plays a pivotal role, with the highest occurrence among individuals aged 51-60. This highlights the importance of addressing age-related vulnerability when creating preventative strategies. Although younger age groups, particularly children aged 0-10, experience fewer injuries, this can be attributed to increased vigilance and safety measures implemented for them at home. However, the diverse injury rates across different age brackets provide valuable insights for designing interventions and safety guidelines specific to each age group. Additionally, it is crucial to consider age-specific susceptibility when implementing preventive measures. Older individuals within the 51-70 range appear to face higher risk and thus necessitate interventions tailored precisely according to their unique safety needs ,5,29. NeAdditionally, adopting a multidisciplinary approach becomes imperative to risk stratify accurately as well as assess and manage adults living within community settings.\u00a0Improving environments free of poor lighting, lack of a grab rail, and unsafe climbing on chairs and ladders while addressing underlying functional impairment reduces the risk of falls in older adults. Patient education, physiotherapy referral, and encouraging patient involvement in addressing risk factors, capacity, and behaviors for falls have been effective interventions, as well ,14,29,30With regards to the youngest age group, encompassing individuals aged 0 to 10 years old, even though the rates of injury are lower, it is imperative that efforts in prevention be focused on creating a safe environment and enhancing supervision. This will help in decreasing the likelihood of spine injuries.\u00a0Recognizing the limitations of this study is vital, including its dependence on information obtained from hospital emergency departments. These departments may not accurately document all cases of spinal injuries occurring in homes, potentially skewing the results. Moreover, it's important to note that the NEISS database lacks comprehensive data on the specific mechanisms and circumstances surrounding these injuries. This missing information hinders a thorough comprehension of the pathophysiology underlying spinal injury occurrences.This research presents valuable insights into the frequency of spinal injuries in residential settings. Additionally, it introduces options for adopting evidence-based approaches like motivational interviewing, home repairs, patient education, and shared decision-making to establish safer living spaces and ultimately reduce the chances of spinal injuries. To further alleviate the prevalence and impact of spinal injuries at home, future research should explore other risk factors and potential interventions ,10.This study provides valuable insights into spine injuries in households, focusing on home locations, sex, and age groups. The living room, bedroom, kitchen, and stairs are common injury sites, warranting targeted preventive measures. Females experience more cases, and injury rates vary among home locations. Age-specific vulnerability is evident, with the 51-60 age group at highest risk. Tailored interventions for specific areas and demographics are crucial for a safer living environment. Our findings suggest that evidence-based strategies such as motivational interviewing, patient education, home repair, and shared decision-making would reduce spine injuries in household environments."}
+{"text": "Continuous cropping (CC) is a common practice in agriculture, and usually causes serious economic losses due to soil degeneration, decreased crop yield and quality, and increased disease incidence, especially in medicinal plants. Continuous cropping obstacles (CCOs) are mainly due to changes in soil microbial communities, nutrient availability, and allelopathic effects. Recently, progressive studies have illustrated the molecular mechanisms of CCOs, and valid strategies to overcome them. Transcriptomic and metabolomics analyses revealed that identified DEGs (differently expressed genes) and metabolites involved in the response to CCOs are involved in various biological processes, including photosynthesis, carbon metabolism, secondary metabolite biosynthesis, and bioactive compounds. Soil improvement is an effective strategy to overcome this problem. Soil amendments can improve the microbial community by increasing the abundance of beneficial microorganisms, soil fertility, and nutrient availability. In this review, we sum up the recent status of the research on CCOs in medicinal plants, the combination of transcriptomic and metabolomics studies, and related control strategies, including uses of soil amendments, crop rotation, and intercropping. Finally, we propose future research trends for understanding CCOs, and strategies to overcome these obstacles and promote sustainable agriculture practices in medicinal plants. Fagopyrum tataricum, yield declined up to 6.36% in the first year, 24.85% in the second year, 78.62% in the third year, and 83.10% in the fourth year of CC, which caused severe economic losses. The availability of nutrients, soluble proteins, soil enzyme activities, total chlorophyll contents, and the number of actinomycetes in leaves gradually decrease during CC ,9,10FagoRehmannia glutinosa L. plants suffering from CCOs had small leaves, losses in root ATPase activity, slow growth rates, and decreased root activity [Fusarium oxysporum by reducing the abundances of Bacillus, Rhizobacteria, and Pseudomonas, all of which promote plant development [In summary, by inhibiting plant defense enzymes, CCOs upset the equilibrium of the relative oxygen species (ROS) metabolism, allowing ROS to build up in overabundance, ultimately resulting in membrane lipid peroxidation. There were notable differences in levels of degraded aromatic compounds, microbiome activity, chitin degradation, nitrogen fixation, and atrazine metabolism. Soil degradation and the microbial inhabitants\u2019 edifice imbalance were the primary causes of CCOs . Transcractivity . Negativactivity ,15. CC selopment ,17. It ielopment . Farmerselopment ,20. Howeelopment . DiffereIn this review, we have outlined the problem of CC in medicinal plants. In order to develop medicinal plant resources more wisely, we also identified the current issues and proposed some appropriate remedies. Identifying the response of various medicinal plant species and CC on genome-wide transcriptome profiles, the structure and composition of soil microbial communities, candidate genes, and pathways related to CC response, intercropping, soil amendments, crop rotation, and understanding related molecular mechanisms are the goals of this study. In order to cope with CC soil, comprehensive procedures are now being used, including physical, chemical, and agronomic measures; positive results have been obtained in reducing the impact of continuous cropping challenges. Finally, potential research directions for the future are also discussed.We conducted a systematic review of Google Scholar, Web of Science, and Pub-Med/continuous cropping and medicinal plants libraries using varied keywords: \u201cmedicinal plants\u201d, \u201ccontinuous cropping obstacles\u201d, \u201cmicrobial community\u201d, \u201cmolecular mechanisms\u201d, \u201ctranscriptomic analysis\u201d, \u201cmetabolomics study\u201d, \u201cgene regulation\u201d, \u201ccontrol strategies\u201d, \u201csoil amendments\u201d, \u201ccrop rotation\u201d, and \u201cintercropping\u201d, in numerous amalgamations. We evaluated the facts from research articles as well as review articles to create a systematic review of continuous cropping obstacles in medicinal plants within recent publications. This study identified 178 advanced articles for inclusion .The results and discussion were analyzed and arranged according to the principal relationships: \u201ccauses of continuous cropping obstacles\u201d, \u201cmolecular mechanisms in continuous cropping obstacles\u201d, and \u201cmedicinal plants and control strategies\u201d, with a special emphasis on transcriptomic and metabolomics studies. Finally, we recommended future study directions regarding control strategies in the field of continuous cropping in medicinal plants.CCOs are often caused by a mix of abiotic and biotic conditions, containing decreasing soil physicochemical properties, plant autotoxicity, and changes in the composition and diversity of microbial communities . MicrobiRalstonia) bacteria, which causes an epidemic of bacterial wilt disease [CCOs are created and reduced by the soil microbial community due to their strong connection with the absorption of the plant\u2019s nutrients, infectious diseases, and the immune system . During  disease . The soi disease . When an disease . In cont disease . Several disease ,52. Pres disease .The main factors and markers of soil\u2019s strength are its carbon contents and organic matter, which are necessary for the fertility, quality, functionality, and sustainability of soil . The gro+4-N) reduced organic matter mineralization (gross ammonification declined from 13% to 21%), limiting the nitrogen cycle and altering soil fertility [One important sign of soil fertility and the health of agroecosystems is soil carbon and nitrogen mineralization . Soil stertility . Furtherertility . Meanwhiertility . Unfertiertility . Mineralertility . Becauseertility . Furtherertility . To foreNitrogen-rich fertilizer usage, the intensity of tillage, and the breakdown of the crop residues  are primarily responsible for the decline in soil pH in the CC system . The avaThe following soil physiochemical characteristics  are not exhaustive. Numerous soil physicochemical characteristics, including pH and concentrations of vital micronutrients and macronutrients, might be impacted by CC . Soil pHBurkholderia and Spingomonas) and diseases that affect agriculture [Fusarium oxysporum development at low doses, but reduced it at high doses [Phytolacca americana [Autotoxicity, a specific kind of allelopathy, is a phenomenon wherein the same plant\u2019s development and growth are prevented by allelochemicals . The priiculture . Ferulicgh doses . A high mericana .P. ternata seedling development in CCOs is significantly inhibited by substances like chlorogenic acid, vanillin, benzofuran, vanillic acid, syringic acid, ferulic acid, protocatechuic acid, gallic acid, syringaldehyde, etc. As a result, these substances are regarded as primary allelochemicals and autotoxins of P. ternata [Changes in soil pH have a significant impact on the composition of the soil microbial community, which might cause problems for ongoing crop growth . Numerou ternata . Under C ternata . Soil mi ternata . In addi ternata . Current ternata . TherefoPanax ginseng) plant\u2019s transcriptional response to benzoic acid (Autotoxin), a soil root exudate compound that is continually farmed [Pogostemon cablin) plant has demonstrated how CC changed the protein expression involved in the metabolism of amino acids, energy, and carbohydrates [Codonopsis tangshen plant [C. tangshen plant, the downregulated genes in leaves are psaA, psbA and the psbW [Transcriptomic analysis is a cutting-edge biologic discipline which utilizes high throughput, high resolution, and sensitive methods to analyze both model and non-model entities. Transcriptomic studies can assist researchers in assessing medicinal plants\u2019 controlling mechanisms and functional genes to improve cultivation systems and breeding methods in CC . Additioy farmed . Recentlhydrates . The 762en plant . Additiothe psbW . The genthe psbW . DifferePinellia ternata) reacts to treatment with phenolic acids in CCO. The transcriptome showed that phenolic acid treatment elevated the DEGs associated with cell wall deterioration and ROS metabolism. Moreover, the levels of the critical metabolites were lowered due to downregulated DEGs in the pathways for phenylpropanoid production and metabolism of sucrose and starch  [Metabolomics is employed in a wide range of studies to examine the adaptations and regulations occurring within complex systems, influenced by both internal and external factors . In metage (SMB) . Polyamige (SMB) .Panax quinquefolius, 3, 4-dihydroxybenzoic, lignoceric, salicylic, palmitic, azelaic, heptadecanoic, cerotinic, benzoic, and oleic acid levels were significantly increased, while phytol, D-Talose, N-Acetyl-D-galactosamine, and mannose were significantly decreased [Continuous cropping has been demonstrated in studies to alter plants\u2019 metabolites and to decrease the amount of key therapeutic medicinal plant components . Patchouecreased . This medh rice mutant with overexpression of osa-miR171c demonstrated a substantial decrease in salt tolerance throughout the germination and seedling stages [R. glutinosa, miRNAs were probably responsible for continuous cropping challenges [Salvia miltiorrhiza, containing one particular miRNA that reacted due to CC [The challenges caused by CC are a complicated kind of stress that seriously impedes a viable increase in resources for pharmaceutical plants. The majority of plant life activities, including development and growth, metabolism, stress response, and hormone signaling are regulated by miRNAs . Under dg stages . In respg stages . In receg stages . Worldwig stages . Wild meg stages . As a reallenges . A totalue to CC . Accordiue to CC . The funue to CC .Pogostemon cablin) plant [Genomic studies in CC reveal the expressions of both mRNA and miRNA data of the root mechanism of the patchouli (n) plant . Forty-sn) plant . DiffereBrassica species) with soil amendments [P. notoginseng plant quality, production, and N, P, and K upturns [Citrullus lanatus [Arachis hypogaea CC, after twenty years, organic fertilizer application increases the yield of the grains, reduces major diseases, including Ralstonia , and improves the rhizobacteria [Fusarium wilt, enhanced plant growth, resistance against stress, soil hydraulic and physical properties, microbial activities, root activity, SOD and POD activity, MDA contents, CAT, and plant photosynthesis [Soil amendment is an effective substitute; chemical fumigation is an ecologically harmful alternative method for controlling soil-borne diseases, and also improves the soil\u2019s physicochemical properties and the microbiota ,134. Thiendments . Chlorop upturns . The add upturns . To sati lanatus . In Aracbacteria . Bio-orgynthesis ,145. In ynthesis . Crude cynthesis ,148.Glomus hoi either favorably, like Firmicutes, or negatively, like Bacteroidetes and Actinobacteria [Pseudomonas and Bacillus , plant inter-cropping, choosing resistant cultivars, and biological management are only a few strategies for overcoming the drawbacks of CC ,159. CR oginseng . Cucumbeacterium . Making Fusarium wilt [A. lancea decreased the accretion of autotoxic compounds in CC soil, improved the invertase and urease activity of the soil, inhibited the fungal population, and stimulated the bacterial community. In particular, the G-bacteria biomass intensely increased, and this was able to lessen the buildup of phenolic allelochemicals in the bulk soil and rhizosphere [Intercropping is the synchronized planting of two or more crops in the same field. In addition to facilitating the growth of medicinal plants, a rational intercropping system can increase yield and quality, while also increasing space utilization efficiency amongst species . Therefoium wilt . Intercrzosphere . CCOs inObstacles to continuous cropping are now a significant factor impacting crop output and quality. Their negative effects include a decline in the fundamental chemical and physical characteristics of soil, modifications to microbial community structure, the buildup of autotoxins, weakened plant development, and an escalation of pests and diseases. In conclusion, CCOs in medicinal plants can be alleviated by using soil amendments to improve the microbial community and soil fertility. Transcriptomic and metabolomics studies provide insights into the molecular mechanisms involved in plant responses to CCO, which can guide the progress of new strategies to overcome these obstacles and improve medicinal plant production. Overall, a multi-pronged approach that incorporates soil amendments, crop rotation, and intercropping, along with a deeper understanding of plant\u2013microbe relations and stress responses, may help us to overcome the obstacles associated with continuous cropping of medicinal plants.Further study is required to recognize the most effective soil amendments and their application rates for different medicinal plant species and growing conditions. To mitigate these effects, farmers and researchers may need to implement strategies, such as crop rotation, intercropping, and soil amendments to maintain soil fertility and promote healthy plant growth, so that they can develop sustainable cropping practices to minimize these effects. By improving soil health, farmers can maintain high crop yields and ensure the viable production of medicinal plants."}
+{"text": "Fetal biliary lithiasis is a benign condition characterized by the presence of gallstones in the gallbladder of a developing fetus. It is typically detected incidentally during a routine obstetric echography. The incidence of this condition varies from 0.03% to 2.3%. In most cases, fetal cholelithiasis resolves spontaneously and has an excellent prognosis. However, there are certain risk factors that may contribute to its development. Maternal factors that increase the risk of fetal cholelithiasis include placental abruption, elevated estrogen levels, narcotic use, diabetes, enteral nutrition, and specific medications, such as ceftriaxone, furosemide, and prostaglandin E2. Fetal factors that can contribute to the condition include Rhesus or ABO blood group incompatibility, congenital anomalies affecting the cardiovascular, gastrointestinal, or urinary systems, twin pregnancies with the fetal demise of one twin, genetic anomalies such as trisomy 21, chromosomal aberrations, cystic fibrosis, growth restriction, oligohydramnios, hepatitis, or idiopathic causes. Usually, the gallstones spontaneously resolve before or after birth without requiring specific treatment. However, in rare instances, complications can arise, such as the formation of biliary sludge, inflammation of the gallbladder (cholecystitis), or obstruction of the bile ducts. If complications occur or if the gallstones persist after birth, further evaluation and management may be necessary. Treatment options can include medication, minimally invasive procedures, or, in severe cases, surgical removal of the gallbladder."}
+{"text": "Hypertension is common during pregnancy . In manyAll pregnant women with hypertension need to be tested for proteinuria and related parameters for preeclampsia-related end-organ dysfunction. These parameters include the presence of thrombocytopenia, renal insufficiency, elevated liver transaminases, pulmonary edema, and recent cerebral or visual symptoms. Those who have negative proteinuria and do not have significant evidence of end-organ dysfunction upon follow-up can be classified as having gestational hypertension. For these patients, only sufficient control of blood pressure is adequate .Pregnant women with new hypertension who are tested positive for significant proteinuria or end-organ dysfunction upon follow-up are considered to have preeclampsia . For theAt the initial prenatal visits, patients should be evaluated for relevant risk factors such as past history of preeclampsia, proteinuria, chronic hypertension, chronic kidney disease, or autoimmune conditions such as APS and SLE . PreeclaSome pregnant patients with preeclampsia present with hemolysis, elevated liver enzymes, and low platelets, or the HELLP syndrome . HELLP sA better understanding of preeclampsia and HELLP syndrome is needed for timely detection, accurate diagnosis, and proper management of this life-threatening condition ,3,4. At"}
+{"text": "Neurovascular orofacial pain (NVOP) is a relatively rare type of facial pain syndrome that shares similarities with migraine, orofacial migraine, and trigeminal autonomic cephalalgias (TACs). NVOP is characterized by pain in the orofacial region. Diagnosing NVOP can be particularly challenging. Recently, it was included as a recognized diagnosis in the latest classification of orofacial pain\u2014ICOP . In this editorial, we explore the symptoms, causes, diagnosis, and treatment of NVOP ,3,4.Symptoms:NVOP typically presents as episodic, unilateral or bilateral pain or discomfort in the orofacial region. The pain is often described as a dull ache, pressure, or throbbing and may migrate between teeth. Additional symptoms can include sensitivity to light, sound, or odors; nausea; vomiting; visual disturbances; and numbness or tingling of the face, mouth, or tongue ,6.Causes:The exact cause of NVOP is unknown, but it is thought to be related to neurovascular mechanisms that contribute to other types of migraines. These mechanisms involve changes in the blood vessels and nerves in the brain, resulting in inflammation, blood vessel dilation, and activation of pain pathways. NVOP can be triggered by various factors such as stress, hormonal changes, certain foods, weather or altitude changes, and physical exertion .Diagnosis:Diagnosing NVOP can be challenging due to its resemblance to other dental and facial pain disorders such as acute pulpitis, trigeminal neuralgia ,8, or teTreatment:The NVOP treatment approach usually involves a combination of lifestyle modifications, medications, and nonpharmacological therapies. Lifestyle modifications may include avoiding triggers, maintaining regular sleep patterns, and employing stress-reduction techniques such as meditation or yoga. Naturally, success depends on individuals\u2019 expectations and coping strategies . MedicatIn conclusion, neurovascular orofacial pain or NVOP is a relatively rare type of facial pain syndrome that shares similarities with other facial pain disorders, including migraines. NVOP is characterized by episodic pain or discomfort in the orofacial region, which may migrate between the teeth. Treatment typically involves lifestyle modifications, medications, and nonpharmacological therapies. If you experience symptoms of NVOP, medical attention must be sought to exclude other potential causes and receive appropriate treatment."}
+{"text": "The incidence of psychological disorders in patients with cancer is very high (30\u201360%), with approximately 29\u201343% fulfilling the diagnostic criteria for psychiatric disorders. The most commonly encountered mental problems encompass depressive symptoms associated with mixed anxiety and adjustment disorder or depressive mood or major depression.The aim of this research is to highlight the characteristics of psychiatric manifestations in patients with cancer and to analyse the risk factors that influence the occurrence of these psychiatric manifestations.\u0391 bibliographical review was performed using the PubMED platform. All relevant articles were found using the keywords: cancer, psychiatric manifestations, risk factors.Sleep problems, irritability, tendency to cry easily, sadness, and pain were among the leading symptoms at baseline. Women reported sleep problems, tendency to cry easily, irritability, pre-occupation with the illness, and sadness as the first five most frequent issues, and men reported sleep problems, irritability, pain , sadness, and tendency to cry easily as the most frequent problems.Significant risk factors that increased the mood disorders were recurrence, presence of secondary cancer, other chronic medical illnesses, history of psychiatric disorder, low income level, poor social support, and being single or divorced.None Declared"}
+{"text": "Lactococcus lactis, Lactobacillus helveticus, Pseudoalteromonas nigrifaciens, Streptococcus thermophiles, and Lactobacillus acetotolerans were retrieved from the shotgun sequencing representing the dominant taxa in the studied fermented foods. Additionally, 33 genes that cause antimicrobial resistance (ARGs) against ten different antibiotic classes were detected. Metabolic pathways were abundant in the studied metagenomes, such as amino acid metabolism, carbohydrate metabolism, cofactors, and vitamin biosynthesis. Metagenomic evaluation of Arabian fermented foods, including the identification of probiotics, pathogenic bacteria, and ARGs, illustrates the importance of microbiological analysis in evaluating their health effects.This study uncovered microbial communities and evaluated the microbiological safety of traditional fermented foods consumed in the Arab region. Samples of dairy and non-dairy fermented foods\u2014mish, jibneh, zabadi, and pickles\u2014were collected from local markets in Saudi Arabia. Using the MiSeq system, samples were sequenced using 16S amplicons and shotgun metagenomics. Alpha and beta diversity indicated inter- and intra-variation in the studied fermented foods\u2019 bacterial communities. In the case of mish, the replicates were clustered. Twenty-one genera were found to be significantly different (FDR < 0.05) in abundance in pairwise comparison of fermented foods. Five high-quality, metagenome-assembled genomes (MAGs) of  Saudi Arabia occupies most of the Arabian Peninsula, and most of its population descended from nomadic tribes who historically lived throughout the region. Saudi Arabian society has rapidly shifted from nomadic to urban life in the last fifty years. Despite the modern advancements that have come with this transformation, many people continue to raise goat, sheep, and camel herds. Their daily meals consist of fermented milk products such as laban, mish, cheese, and yogurt, as well as non-dairy, traditional vegetable pickles ,2. AlthoLactobacillus delbrueckii and Streptococcus thermophilus, but may also harbor harmful pathogens, including Salmonella, Listeria monocytogenes, and Staphylococcus aureus  were collected aseptically in sterilized containers. The samples were kept in an icebox during transportation and then stored at a temperature of \u221280 \u00b0C in the laboratory.g. The top fatty layer and supernatant were discarded, and the pellet was used for DNA extraction with the beads-beating method of DNeasy PowerSoil Pro Kit . The beads-beating method is efficient at extracting DNA from a wide variety of microorganisms, and the selected kit also removes PCR inhibitors. DNA extraction from pickle samples was performed following the removal of the vegetable debris using cheesecloth as described previously , bacterial secretion system [PATH:ko03070], and phosphotransferase system [PATH:ko02060] in the studied metagenomes . The cardamX gene for an inner membrane protein involved in bile resistance, and mdtABCD (multidrug resistance protein) were found in mish. The enzymes involved in horizontal gene transfer, including integrase, DNA primase, and phage lysin, were detected in all the fermented foods metagenomes.Relative to pickle, a higher abundance of genes responsible for the glycine, serine, and threonine [PATH:ko00260], arginine and proline [PATH:ko00330], cysteine and methionine [PATH:ko00270], lysine biosynthesis [PATH:ko00300], histidine [PATH:ko00340], phenylalanine, tyrosine and tryptophan biosynthesis [PATH:ko00400], and valine, leucine and isoleucine biosynthesis [PATH:ko00290] were detected in the dairy fermented food samples . HoweverMarinomonas genus from Gammaproteobacteria and Lactococcus and Leuconostoc from Firmicutes were predominantly found in mish samples. These genera were found in lower abundance in most of the other fermented foods that were examined. Limited studies have evaluated the microbiology of mish, and the available culture analysis reported Staphylococcus aureus, psychotropic bacteria, yeast, and lactobacilli from mish samples mainly conducted in Sudan [E. coli, S. aureus, Streptococcus spp., and Salmonella spp. in a study of characterizing microbial hazards associated with mish and other fermented milk [In this study, a combinatorial sequencing approach of 16S amplicon sequencing and shotgun sequencing was employed to study the microbial diversity and the functional potential of the traditional Arabian fermented milk foods and non-dairy fermented foods commonly consumed in the Arabian Peninsula. We identified microbial diversity, probiotics, and variations in relatively dominant bacterial taxa in the studied fermented foods metagenomes. Consistent with previous studies for fermented foods, Firmicutes, Proteobacteria, Bacteroidetes, and Actinobacteria were commonly found in the studied samples ,34,35. Tin Sudan ,37. Abdated milk .Streptococcus and Lactobacillus were found in relatively high abundance in zabadi and jibneh samples. However, genera of Bacillus, Calothrix, Weissella, and Lactobacillus were abundantly found in pickle samples indicates variation in bacterial community composition among different fermented food types as observed in previous studies and could be linked to the fermented foods substrates, production recipes, environment influence, and manufacturing conditions [Bacillus, Lactobacillus, Clostridium, and Streptococcus were the most prevalent taxa in pickles, and our findings were consistent with the studies from fermented soybeans and vegetables [Lactococcus lactis and Lactobacillus helveticus from jibneh, Streptococcus thermophiles from zabadi, and Lactobacillus acetotolerans were identified from the pickle sample. However, Pseudoalteromonas nigrifaciens genome was retrieved from mish along with Lactococcus species. The source of Pseudoalteromonas nigrifaciens in mish sample is not known, but a previous study by Kothe et al. retrieved P. nigrifaciens from the cheese sample using a metagenomic approach [Taxa of nditions ,6,7. A rnditions . Bacillugetables ,41. Overapproach . FurtherStreptococcus thermophilus and Lactococcus lactis were identified in dairy fermented foods, mainly in zabadi (59.1%) and jibneh (59.7%), respectively. Streptococcus thermophiles and Lactococcus lactis are the prominent probiotics in the dairy industry and possess health beneficial immunomodulatory ability [Lactobacilli strains were also reported in traditional Polish vegetable fermented food [n = 11) followed by in mish (n = 8) samples. The safety of food is a major concern for consumers. Several PORPB were found in the studied samples, mainly in mish (n = 23) metagenome, but the relative abundance of those clinically important pathogenic bacteria was less than 0.1% as previously reported [Vibrio parahaemolyticus (0.06%) and Clostridium botulinum (0.01%) were detected in pickle metagenome. Similarly, an increased number of ARGs were found in mish (26 ARGs) metagenome conferring resistance to lincosamide, tetracycline, pleuromutilin, aminoglycoside, glycopeptide, and beta-lactam antibiotics. Genes causing glycopeptide, beta-lactam antibiotic, and multidrug resistance were also found in the jibneh and zabadi metagenomes. ARGs have been found in fermented vegetables and dairy products at varying levels, reducing the effectiveness of clinically important antibiotics such as aminoglycosides, fluoroquinolones, beta-lactams, tetracycline, lincosamides, fosfomycin, nitrofurans, nitroimidazoles, phenicols, macrolides, and rifamycin [The probiotic species reported in dairy fermented foods were different relative to the beneficial taxa of non-dairy fermented food, probably due to the nature of food substrates. In this study, the enhanced level of  ability ,44,45. Tted food ; in linemish n = 3 metagenibneh 59.%, respecticus 0.0% and Cloifamycin ,48. As aifamycin .Lactobacilli species in dairy and non-dairy fermented foods and encoding the genes for vitamin biosynthesis, fermentation, and secondary metabolites production [Propionibacterium freudenreichii, Bifidobacteria, and Lactobacilli in the gut that could synthesize most of the water-soluble vitamins, including biotin, cobalamin, riboflavin, folates, pyridoxine and thiamine, thus able to fulfill the requirement of the vitamins for the host [Humans fail to synthesize several metabolites, including SCFAs and vitamins, whereas an exogenous supply is needed for the overall development ,50,51. Moduction ,7,53. Vioduction . Moreovethe host ,55,56. Sthe host . Cofactothe host . OverallMarinomonas, Lactococcus, and Leuconostoc were predominantly identified in mish samples, whereas their presence was relatively less pronounced in most other studied fermented food samples. Streptococcus and Lactobacillus were found in relatively high abundance within zabadi and jibneh samples. The mish metagenome exhibited an increased number of ARGs and pathogenic bacteria; however, these were in minor relative abundance. Furthermore, the outcomes of this study suggest that Arabian fermented foods serve as significant sources of probiotic bacteria, fostering carbohydrate and amino acid metabolism, as well as vitamin biosynthesis. Presently, the overall risk to human health stemming from the consumption of these foods is assessed to be low. Nevertheless, responsible production practices and ongoing research are imperative to oversee the safety, nutritional advantages, and potential implications for public health associated with these fermented foods.This study provided an integrated analysis of dairy and non-dairy fermented foods in the Arabian Peninsula, linking microbial diversity and functional gene content. Noticeably distinct bacterial diversity was observed among dominant taxa at lower taxonomic levels in traditional fermented milk mish, when compared to other dairy and pickle samples. Genera such as"}
+{"text": "Discovering habitable exoplanets and exomoons increases the possibility of detecting extraterrestrial life. A bilateral approach,using neutrino and electromagnetic (EM) radiation technologies, can be used to simultaneously characterize star types that generallyhave exoplanets and exomoons. This includes cool main-sequence, sub-giant, and red-giant stars. Additionally, supernovae, black holes,and neutron and dwarf stars, will be included to widen the investigation, since they sometimes have companions, including stars andplanets. Currently, space exploration is advancing beyond the solar system and proliferating into deep space. For this expansion,sophisticated artificial intelligence (AI) is required and being developed for self-coordination and interactive regulation of thevarious exploratory vehicles and telescopes. ,4,5,6 Future stellar system research could synchronously utilize detectors for neutrinos and EM Each of these methodologies detects different target properties. These properties include physical and chemical properties, evolution,and origin of target host star systems and their habitable exoplanets and exomoons. Favorable conditions and signatures of life may bedetected. Incidental to the discovery and possible existence of astrobiology, astrovirology, and astromicrobiology elsewhere in theuniverse, detection of extra-terrestrial intelligence (ETI) may be possible. ,8,9,10Over the millenia, the possible existence of life elsewhere in the universe has been of central and enigmatic concern. However, theuniverse is more habitable than previously considered. As of February 22nd, 2023, 6,176 candidate exoplanets were detected, 5,272 wereconfirmed, and 63 habitable exoplanets were identified. This is a remarkable achievement, and further endeavors and discoveries areforthcoming. Concomitant uses of the two technologies, neutrinos and EM, improve reliability of the endeavor. Using both study windowspromotes consistent production of confirmatory and reliable data. In this respect, usage of prospective study designs produces resultswith greater statistical significance, compared to serendipitous studies that were not prospectively designed. ,9,10,11EM radiation is the primary means of asterometric exploration and communication. EM signals may be perturbed by interstellar andintergalactic distance and occlusion. The use of neutrinos complements such studies as neutrinos also emanate from distant targets.Neutrinos have a high penetrance, which allows them to traverse inter-galactic distances. Neutrinos from stellar sources (e.g. supernovae)reach the Earth prior to photons from the same sources, due to the high penetrance of neutrinos. However, neutrino studies are still atan early stage of development compared to EM studies and are being optimized for asterometric analysis. Using the two methodologies inparallel increases the sensitivity and probability of producing signatures related to astrobiology and ETI detection. This has additionalsignificance for scenarios under which humans may actually encounter exobiologies, exovirologies, and exomicrobiologies. Various safetyand survival issues ensue that have been previously discussed. ,12,13Problems in the use of neutrinos include issues of the current huge sizes of transmitter and receiver apparatus, costs, detectionefficiency, specificity, lack of focal point source definition, and improving understanding of target dynamics. The development andevolution of AI to control machines for expansion into deep space is ongoing. A long-range time scale is projected as factories andassembly sites must be constructed on the Moon or Mars, and in inter-planetary space in the Solar system, if resources permit. Additionaldifficulties include improving engineering focused directional long-distance beams, sensitivity, resolution, and signal purity oftransmitted and received neutrinos. Signal sensitivity and specificity of source locations are also problems. Clearly, miniaturizationof these machines will facilitate development. ,15,16Frank Drake, Carl Sagan, William Newman, Freeman Dyson, Arthur Clark, and colleagues developed signposts of technological civilizationdevelopment. They deduced 20th century technological development as a relatively early stage of space exploration. Thus, now in the21st century, radiotelescope satellite programs are increasing the sophistication and complexity of space exploration. EM spacetelescope observatories include Hubble, Kepler, Fermi gamma, Spitzer, Dark Universe, and recently, Transiting Exoplanet SurveySatellite (TESS) Asteroseismic Science Consortium (TASC) space telescope. Neutrino detectors include Super-Kamiokande, Borexino,Antares, Sudbury Neutrino observatory, Daya Bay Reactor Neutrino Experiment, Germanium detector array, Kamioka Liquid ScintillationAntineutrino detector, KM3NET, Cherenkov detector, Gallex, Katrin, Scintillator, Dumand Project, and Ino Peak Project Theni.,19,20Neutrino research is used in many fields including asterometrics, astronomy, astrophysics, and cosmology. Neutrino sources includethe Sun, other stars, supernovae, neutron stars, blackholes, cosmic rays, particle accelerators, nuclear reactors, as well asneutrinos from the early universe and big bang. Thus, there is an intense neutrino crisscrossing background, which also includes atemporal dimension of their production since the Big Bang. Neutrinos interact very weakly with matter; however, their detection isgreatly enhanced by their huge numbers. Neutrinos undergo flavor oscillations among electron-, mu-, and tau-neutrino states. Inparticular, neutrino profiles are designed to characterize various star types and their evolution and their association with habitableexoplanets and exomoons. Corollary to these studies, their use is pertinent to detection of ETI. Very large neutrino detectors anddetection technologies include the use of Cerenkov radiation, liquid scintillation, iron calorimeter, and liquid Argon. Neutrinodetectors are found in many countries including the USA, Canada, Italy, France, Japan, Russia, India, South Korea, China, as well asin the Mediterranean Sea and beneath Antarctica. ,2121,22Since 1977, Pasachoff, Saenz, and colleagues proposed the use of neutrinos in communications. This has been accomplished withterrestrial communications and could be used for long-distance interstellar and intergalactic messaging. These considerations are mademore complex as neutrino properties are incomplete and not fully understood. For example, neutrino analyses indicate neutrinos havemass, in contradiction to the Standard Model of particle physics, and that consequently, they undergo flavor oscillations as do quarks.Moreover, do neutrinos obey Pauli exclusion statistics, Fermi statisticsm or Bose-Einstein condensate statistics? Are light neutrinoscomponents of Dark Matter? Are neutrinos Dirac or Majorana? Is there a double beta decay model where A\u00e1 A' + 2 anti-neutrinos + 2electrons?  Such fundamental research questions must be solved, prior to commencing reliable detection ofneutrino communications from prospective candidate ETIs, as well as improving human technology development. ,25,26Neutrino and EM detection systems are best used synchronously and prospectively to detect and analyze stars and their habitableexoplanets and exomoons. This is taking place during space exploration development and expansion. Development of advanced AI-controlledcommunications and signaling among space probes will be helpful and obligatory. ,24,26"}
+{"text": "Polycystic ovary syndrome (PCOS) is an endocrine systemic disorder with a prevalence of between 5% and 20% that commonly affects childbearing-aged women ,2,3. PriDue to syndrome heterogeneity, PCOS women generally exhibit not only gynecologic manifestations, but also different metabolic and endocrine impairments, including insulin resistance (IR). Furthermore, PCOS often involves more morbidities such as psychiatric disorders, obstructive sleep apnea, disordered eating, sexual and thyroid dysfunctions, acne, alopecia, and hirsutism, impairing quality of life.This broad and varied set of clinical dysregulations needs to be carefully examined because they commonly lead to an increased risk of cardiovascular diseases (CVDs), type 2 diabetes mellitus (T2DM), metabolic syndrome (MetS), nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD), atherosclerosis, obesity, autoimmune diseases, infertility, endometrial carcinoma, and adverse pregnancy outcomes .PCOS is a complex polygenic and multifactorial syndrome, whose development can be influenced by individual predispositions, precise clinical sub-phenotyping, age, BMI, epigenetic, and environmental factors. However, PCOS etiopathogenesis still remains unclear; the relative signaling pathways and molecular mechanisms need to be largely investigated, focusing on possible interactions between genetic and environmental factors.The Special Issue described herein offers a wide overview of the current knowledge on the progression of PCOS from present clinical evidence to future perspectives across a whole series of research articles, papers, and reviews primarily focused on the evaluation of the involved molecular mechanisms and signaling pathways and aimed to find innovative counteracting therapies.Among PCOS\u2019s remarkable manifestations, endocrine imbalance and related risk factors have been extensively researched via clinical, in vivo, or in vitro studies.In the systematic review by Glintborg et al. , evidencFurthermore, Glintborg et al.  conducteRelated to the PCOS endocrine imbalance are also gonadotropin dysfunctions , all of which potentially compete with pathogenesis. Therefore, Gargus et al.  mimickedOn the other hand, Abdul Hamid et al.  explore Regarding androgenic dysfunctions, a concept paper by Gleicher et al.  reclassiPCOS metabolic anomalies are demonstrated to be related to incorrect element metabolism. A clinical study by Szczuko et al.  examinedAlthough little is known about molecular mechanisms and signaling pathways involved in PCOS pathogenesis , severalYAP1 gene among PCOS adolescents compared to healthy cases, evaluating any possible correlation with PCOS clinical manifestations. Indeed, it has been observed that the YAP1 gene plays a key role in PCOS pathogenesis and relative metabolic diseases.Genome-wide association studies (GWAS) have found several genetic loci associated with PCOS and its clinical features. Lidaka et al.  investigAlternatively, Scarf\u00f2 et al.  reviewedIn summary, this Special Issue tries to understand PCOS pathophysiology via the study of molecular and epigenetic mechanisms, individuate potential diagnostic markers and therapeutic targets, improve syndrome management, and encourage non-pharmacological strategies."}
+{"text": "Agri-food systems (AFS) encompass the entirety of activities and components that develop the inter-connectedness in agriculture and food value chain. This comprehensive system encompasses a variety of elements, including technological research and development, input and production processes, agricultural product storage and distribution, processing and packaging, and the various stages of retail, wholesale, catering, and consumption. Moreover, it encompasses critical natural resources like water and soil essential for agricultural and food production, as well as the policies, mechanisms, and cultural traditions associated with agriculture and food. Within this framework, farmers, and stakeholders involved in these related activities, including agricultural institutions and organizations, play a significant role. Additionally, the outcomes of these agricultural and food system activities extend to socio-economic, nutritional, health, and environmental aspects. The Agri-food system's vast scope is pivotal in ensuring food security, enhancing nutritional wellbeing, and fostering human prosperity . It not Food security exists when all people, at all times, have physical and economic access to sufficient, safe and nutritious food that meets their dietary needs and food preferences for an active and healthy life\u201d  in organic agriculture, promoting soil fertility and crop productivity. AMF is becoming indispensable in nature-friendly, organic agriculture, contributing to sustainable practices.Mauricio-Sandoval et al. explore the impact of Mangifera indica and Myrciaria dubia on ice cream. These fruits enrich ice cream with phytochemicals, improving antioxidant potential and sensory appeal while maintaining health benefits.Wang et al. investigate the factors influencing the green supply chain resilience of agricultural products, emphasizing standardization, normalization, and collaboration among stakeholders, facilitated by government policies, and subsidies.Garc\u00eda-Ram\u00f3n et al. discusses the influence of Peruvian Andean grain flours on sliced bread. Enrichment with these grains affects dough properties, texture, color, and nutritional content, offering the potential to develop healthier, higher-quality bread.Agri-food Innovations in the quest for Food and Environmental Security\u201d presents a comprehensive Research Topic of original research, reviews, and systematic reviews that encompass various facets of recent advancements in the field. It is our hope that scholars will recognize the diverse nature of the challenges and be motivated to explore new avenues of study, thereby contributing to the development of Agri-food systems (AFS) that are both food and environmentally secure. Such efforts align with the Sustainable Development Goals and play a crucial role in enhancing production, nutrition, environmental sustainability, and overall quality of life. The imperative for global transformation toward more effective, inclusive, resilient, and sustainable AFS is widely acknowledged. Agricultural innovations are instrumental in achieving nutritional security on a global scale and aligning with sustainable climate objectives. All the facts and concepts have also been duly verifies by the contributing authors as Verma et al., George and Ray, Mauricio-Sandoval et al., Wang et al., and Garc\u00eda-Ram\u00f3n et al.. Collaborative efforts involving technology companies, government entities, and farmers are driving solutions within the agri-food industry. Initiatives like innovation clubs are further bolstering the sustainability, resilience, and efficiency of AFS. Recognizing the need for accelerated and redirected transformation, we envision several scenarios for the future of our world's food system. The least desirable path would involve the continuation of practices detrimental to our farms and water resources. Conversely, we can embark on a transformative journey by embracing sustainable practices that benefit both us and our planet. To achieve this, it has been crucial to acknowledge the shortcomings and inefficiencies of the current food system. Our primary objectives should encompass alleviating food insecurity and crises, enhancing agricultural practices, reducing food loss and waste, and taking significant steps toward mitigating climate change. In doing so, we can work toward constructing a new, improved global food system capable of nourishing every hungry individual worldwide.The Research Topic entitled \u201cMT: Conceptualization, Formal analysis, Project administration, Validation, Writing\u2014original draft, Writing\u2014review & editing. MP: Data curation, Supervision, Writing\u2014review & editing. HH: Validation, Visualization, Writing\u2014original draft."}
+{"text": "Schizophrenia, a severe mental illness affecting about 1% of the population, manifests during young adulthood, leading to abnormal mental function and behavior. Its multifactorial etiology involves genetic factors, experiences of adversity, infection, and gene\u2013environment interactions. Emerging research indicates that maternal infection or stress during pregnancy may also increase schizophrenia risk in offspring. Recent research on the gut\u2013brain axis highlights the gut microbiome\u2019s potential influence on central nervous system (CNS) function and mental health, including schizophrenia. The gut microbiota, located in the digestive system, has a significant role to play in human physiology, affecting immune system development, vitamin synthesis, and protection against pathogenic bacteria. Disruptions to the gut microbiota, caused by diet, medication use, environmental pollutants, and stress, may lead to imbalances with far-reaching effects on CNS function and mental health. Of interest are short-chain fatty acids (SCFAs), metabolic byproducts produced by gut microbes during fermentation. SCFAs can cross the blood\u2013brain barrier, influencing CNS activity, including microglia and cytokine modulation. The dysregulation of neurotransmitters produced by gut microbes may contribute to CNS disorders, including schizophrenia. This review explores the potential relationship between SCFAs, the gut microbiome, and schizophrenia. Our aim is to deepen the understanding of the gut\u2013brain axis in schizophrenia and to elucidate its implications for future research and therapeutic approaches. Schizophrenia is a severe psychiatric condition that results in a combination of hallucinations, delusions, and profoundly chaotic cognitive processes and behavior . SchizopOver the past few decades, the relationship between the gut, microbiota, and the brain has been a subject of significant attention. Extensive experimental evidence highlights the substantial influence that the microbiota can have on both gut and brain functions ,11. CommThe gut microbiota, a diverse community of microorganisms residing in the gastrointestinal tract, plays a crucial role in human physiology and pathology, affecting various biological functions like the maturation of the immune system, the synthesis of essential vitamins, and protection against pathogenic bacteria ,15,16. DEspecially noteworthy within the context of schizophrenia are short-chain fatty acids (SCFAs), which are metabolic byproducts produced by gut microbes during the fermentation process ,24,25. SThe objective of this review is to investigate and elucidate the possible connection involving SCFAs, the gut microbiome, and schizophrenia. By synthesizing the existing literature on this topic, our goal is to deepen our comprehension of the gut\u2013brain axis in schizophrenia and its implications for future research and therapeutic strategies.Schizophrenia impacts approximately 1% of the population, usually manifesting during early adulthood, and persisting throughout an individual\u2019s life, with a higher risk observed in males ,37. PosiSchizophrenia is closely correlated with genetic factors, particularly involving specific chromosomal regions such as 22q11\u201313, 6p, 13q, 8p, and 1q21\u201322, which have been linked to its pathogenesis . Even thToxoplasma gondii alters behavior and affects the functioning of neurotransmitters, while in humans, Toxoplasma gondii infection is associated with symptoms similar to those observed in patients with schizophrenia [Toxoplasma gondii infection induces the production of various cytokines by microglia, astrocytes, and neurons [Toxoplasma gondii, schizophrenia has also been linked to other infections like Chlamydophila psittaci, Chlamydophila pneumoniae, Human Herpesvirus 2, Borna Disease Virus, and Human Endogenous Retrovirus W. [Toxoplasma gondii infection affected the gut microbiome of mice [Indeed, exposure to infectious pathogens and inflammatory stimuli profoundly impacts the brain and behavior . For insophrenia . Notablyophrenia . Toxopla neurons . Additio neurons . Apart fvirus W. . Notably of mice , highlig of mice .Schizophrenia is associated with deficits in neural connectivity, that are associated with multiple brain development processes, such as myelination, synaptic pruning, and the development of inhibitory neural networks. Synaptic pruning is a critical process during brain development in which connections between neurons, known as synapses, are modified and optimized. Myelination involves the formation of a protective layer called myelin around nerve fibers or axons. Additionally, the physiological maturation of inhibitory neural networks is essential for proper brain function ,59,60. D2+, Na+, K+, and Cl\u2212 ions [Neurotransmitters are naturally occurring chemicals that facilitate communication between neurons throughout the body and play a vital role in regulating various physiological processes . They arCl\u2212 ions .Dopamine is a neurotransmitter involved in regulating motor functions, sensory perception, and reward signaling in the mammalian brain . In patiNorepinephrine, produced in the locus coeruleus, plays a role in various functions in the CNS, including arousal, attention, motivation, reward, learning, and memory regulation ,71. Dysrd-serine/glycine and glutamate. They are controlled by astrocytes and are crucial for synaptic plasticity, learning, and memory. The glutamate hypothesis suggests that a deficiency in NMDA glutamate receptors may lead to symptoms of schizophrenia [Glutamate, an excitatory neurotransmitter, has a vital function in facilitating nervous system plasticity and is capable of causing cell death through a process called \u201cexcitotoxicity\u201d. It also plays a significant role in memory storage . The enzophrenia ,75,76,77ophrenia . Furtherophrenia . Additioophrenia , and EAAophrenia .Moreover, excess serotonin induced by stress in the anterior cingulate cortex and the dorsolateral prefrontal cortex is associated with schizophrenia . SerotonHistamine is a neurotransmitter that plays a significant role in immune response, inflammation, wakefulness, appetite control, and cognition, and it is involved in various CNS disorders, including schizophrenia ,83. The GABA is an inhibitory neurotransmitter, and aside from schizophrenia, conditions such as anxiety and mood disorders are linked to reduced GABA levels . PostmorThe autonomic nervous system (ANS) has a vital role in controlling the homeostasis of various bodily functions, including heart rate, respiratory rate, and digestive function. Studies have indicated that ANS function is slower in patients with schizophrenia compared to healthy individuals . AdditioSchizophrenia is linked to compromised immune system functioning, and individuals with schizophrenia have displayed abnormal cytokine levels . CytokinAstrocytes and microglia have the ability to promote inflammation or reduce it, depending on the type of injury or damage they encounter . After aAstrocytes, as CNS tissue cells, have a vital role in the development of neural circuits and synaptic activity ,111. In Microglia, another type of CNS tissue cell, also play a critical role in CNS diseases . MicroglIn neuropsychiatric disorders, exposure to traumatic experiences during adolescence in offspring with prenatal experiences can increase vulnerability to stress and raise the risk of neuropsychiatric disorders . Active Neurotrophic factors, comprising neurotrophins and neuropeptides, are protein molecules released to control the viability, growth, and normal activities of neurons in both the central and peripheral nervous systems. They have a pivotal function in normal neural activity and are also implicated in responses to trauma, ischemia, and neuroinflammatory reactions . Among tFirmicutes, which include species like Lactobacillus, Clostridium, and Enterococcus, as well as Bacteroidetes, encompassing species like Bacteroides. In addition, smaller quantities of Actinobacteria (including Bifidobacteria), Proteobacteria (such as Escherichia coli), Fusobacteria, Verrucomicrobia, and Cyanobacteria are also present [14 bacteria reside in the human gut, exceeding the number of human cells by a factor of 10 and possessing more than 100 times the amount of genomic content compared to human genomic DNA [The microbiota resides in various regions of the body, including the skin, conjunctiva, oral cavity, airway, vagina, and gastrointestinal tract . Among t present ,139,140.omic DNA .The gut microbiota has a crucial function in human physiology and disease, aiding in the formation of gastric mucus and promoting enzymatic activity within the mucous lining to support the digestive system . Some baMicrobiota are already present in the placenta, amniotic fluid, and umbilical cord, indicating that microbial colonization begins even before birth ,18,19. HE. coli and Clostridium innocuum, while showing a positive correlation with beneficial anaerobic bacteria like F. prausnitzii and Agathobaculum butyriciproducens [Alistipes, Bilophila, and Bacteroides). Additionally, the genes within these bacteria responsible for encoding microbial bile salt hydrolase, a key enzyme for secondary bile acid production, show notably increased activity when included in an animal-based diet [Biophila wadsworthia, a member of the Desulfovibrionaceae family known for triggering acute inflammation through taurine respiration, resulting in the production of hydrogen sulfide. Conversely, when mice were fed unsaturated fats, such as polyunsaturated fats, there was a notable increase in the abundance of beneficial bacteria like Lactobacillus, known for its probiotic properties, and Akkermansia muciniphila, a species thriving in nutrient-rich environments [The process of gut microbiota colonization undergoes changes based on variations in diet or health conditions . In otheroducens . On the sed diet . Substansed diet . Interesronments . A high-ronments . Furtherronments . The admronments . The gutronments . This imronments . Disruptronments . Moreoveronments . A studyronments .The gut microbiota play a vital role in regulating brain function and behavior through the \u201cmicrobiota-gut-brain\u201d (MGB) axis  Figure . The intThe ANS governs involuntary physiological functions such as heart rate, blood pressure, respiration, and digestion. It comprises the sympathetic nervous system (SNS), parasympathetic nervous system (PNS), and ENS . ActivatIntestinal epithelial cells (IEC) create a physical barrier separating the intestinal lumen from immune cells, and they fulfill diverse immunological roles. They generate and respond to different cytokines, as well as express molecules that interact with lymphocytes, and have pattern-recognition receptors in their composition . StudiesBifidobacterium bifidum, Bifidobacterium infantis, and Bifidobacterium breve. Propionate undergoes three distinct conversions by bacteria. Certain types of bacteria, like Prevotella and Veillonella, are responsible for converting it into a specific compound called succinic acid. The acrylate pathway is utilized by certain bacterial groups, such as Coprococcus, while the propanediol-dependent metabolic pathway is utilized by bacteria like Roseburia inulinivorans and Blautia species. Butyrate is produced by bacteria from the Lachnospiraceae and Ruminococcaceae families [The gut microbiota interacts with the CNS not only to regulate food digestion, immune function, and enteroendocrine signal transmission but also through the production of various metabolites, including substances like bile acids, SCFAs, glutamate, norepinephrine, dopamine, GABA, serotonin, and histamine . Among tfamilies . These Sfamilies .Butyric acid, one of the SCFAs, especially exerts notable influences on the generation of various factors, including BDNF, which promotes the synthesis of neurotransmitters in the CNS through the VN . AdditioSCFAs have been associated with several mental disorders. For example, patients with neuropathy show decreased levels of serotonin, GABA, and dopamine, as well as reduced levels of butyrate, propionate, and acetate . AdditioThe gut microbiota has a significant role to play in producing and consuming SCFAs and mammalian neurotransmitters, influencing both the CNS and the ENS . HoweverStreptococcus vestibularis, an oral bacterium, into mice, it led to the development of schizophrenia-like behavior [Faecalibacterium, Roseburia, and Butyricicoccus, which play a role in butyrate production, and the aforementioned increased cytokines, while showing a positive correlation with the decreased cytokines mentioned earlier [N-methyl-d-aspartate (NMDA) and brain-derived neurotrophic factor (BDNF)/glial-cell derived neurotrophic factor (GDNF) receptors, which regulate brain plasticity, in schizophrenia patients [Bacteroides, Bifidobacterium, Faecalibacterium, Blautia, Collinsella, and Eubacterium_coprostanoligenes decreased. Furthermore, the ScZ-Ag group showed significantly lower levels of acetic acid, propanoic acid, butyric acid, isobutyric acid, isovaleric acid, and isohexanoic acid in their stool compared to the NScZ-Ag group [When comparing the metabolic processes involving glucose and lipids of SCFA-producing bacteria and gut microbiota in schizophrenia patients to healthy individuals, SCFA-producing bacteria were less abundant, and the gut microbiota showed abnormal glucose and lipid metabolism . In the behavior . Out of  earlier . The chapatients ,192. Whepatients . Glutamapatients . Notablypatients ,196, andAg group . MoreoveAg group . Among tAg group ,199. In Ag group . In patiAg group .In this review, our primary objective was to explore and shed light on the potential relationship between schizophrenia, the gut microbiota, the gut\u2013brain axis, and SCFAs. We investigated whether SCFA, a metabolite produced by the gut microbiota, might be associated with schizophrenia. Our findings suggest that SCFAs can traverse the blood\u2013brain barrier (BBB) and influence CNS activity, including the modulation of microglia activity and cytokine production. Specifically, butyrate appears to impact epigenetic processes, leading to increased histone acetylation.It is essential to note that there has been limited research into how the gut microbiota influences mental health, particularly in the context of schizophrenia. Most studies have lacked large-scale human clinical trials, and the considerable variability in gut microbiota composition and SCFA production among individuals makes it challenging to establish a clear association with schizophrenia. Additionally, the precise mechanism through which SCFA influences schizophrenia remains unclear, necessitating further research before considering therapeutic applications.Despite these limitations, our findings hold promise for potential future developments. As the realm of research on the gut\u2013brain axis and its impact on mental health continues to grow, these studies may serve as potential indicators for identifying and predicting of schizophrenia. Additionally, additional progress in this field could result in the creation of innovative treatment approaches that target the gut microbiota for the management of schizophrenia.In conclusion, while our review highlights the potential link between SCFA, the gut microbiota, and schizophrenia, it is crucial to acknowledge the current limitations and the need for further research. As the scientific community delves deeper into this field, an improved comprehension of the gut\u2013brain axis in schizophrenia could offer valuable insights into diagnosis, treatment, and patient outcomes."}
+{"text": "Natural products, especially plants and phytochemicals, show potential as radioprotective agents against radiation damage during cancer radiotherapy. They exhibit radioprotective effects through mechanisms such as free-radical scavenging, inhibition of inflammation, promotion of DNA damage repair, and inhibition of cell death pathways. Polyphenols, polysaccharides, alkaloids, and saponins from natural sources have radioprotective activity. However, clinical translation of these natural radioprotective agents is limited by issues such as low bioavailability, poor solubility, and high cost. Structural modification of natural compounds can improve their radioprotective efficacy and reduce toxic side effects.Radiotherapy is an important cancer treatment. However, in addition to killing tumor cells, radiotherapy causes damage to the surrounding cells and is toxic to normal tissues. Therefore, an effective radioprotective agent that prevents the deleterious effects of ionizing radiation is required. Numerous synthetic substances have been shown to have clear radioprotective effects. However, most of these have not been translated for use in clinical applications due to their high toxicity and side effects. Many medicinal plants have been shown to exhibit various biological activities, including antioxidant, anti-inflammatory, and anticancer activities. In recent years, new agents obtained from natural products have been investigated by radioprotection researchers, due to their abundance of sources, high efficiency, and low toxicity. In this review, we summarize the mechanisms underlying the radioprotective effects of natural products, including ROS scavenging, promotion of DNA damage repair, anti-inflammatory effects, and the inhibition of cell death signaling pathways. In addition, we systematically review natural products with radioprotective properties, including polyphenols, polysaccharides, alkaloids, and saponins. Specifically, we discuss the polyphenols apigenin, genistein, epigallocatechin gallate, quercetin, resveratrol, and curcumin; the polysaccharides astragalus, schisandra, and Hohenbuehelia serotina; the saponins ginsenosides and acanthopanax senticosus; and the alkaloids matrine, ligustrazine, and \u03b2-carboline. However, further optimization through structural modification, improved extraction and purification methods, and clinical trials are needed before clinical translation. With a deeper understanding of the radioprotective mechanisms involved and the development of high-throughput screening methods, natural products could become promising novel radioprotective agents. Th. Th95]. Flavonoids, which are low-molecular-weight polyphenolic compounds classified into six groups\u2014isoflavonoids, flavanones, flavanols, flavonols, flavones, and anthocyanidins\u2014share a common chemical structure characterized by two benzene rings . PolypheApigenin , a natural plant flavonoid, is abundant in medicinal plants, fruits, and vegetables, including Chinese cabbage, bell peppers, guava, garlic, celery, parsley, and chamomile ,100. TheGenistein , a soy isoflavone, has been shown to play a role in radioprotection ,108. TheEpigallocatechin-gallate (EGCG) is the main component of green tea and has anti-inflammatory, antioxidant, anticancer, antiaging, antiarthritic, and neuroprotective effects ,121. EGCQuercetin  is a flavonoid found in a wide variety of plants, including berries, onions, shallots, apples, and tea . Past stAnthocyanins are a subgroup of flavonoids widely found in colored fruits and vegetables, such as blueberries, raspberries, purple kale, and purple potatoes , and thep53. Hesperidin is a naturally occurring flavanone glycoside that is mainly used as an antioxidant [Silibinin is a natural flavonoid that exerts anticancer activity in vitro and in vivo . Severalioxidant . Studiesioxidant ,153. Furioxidant . In addiioxidant ,156, baiioxidant ,158,159,ioxidant ,161,162,ioxidant ,164, andioxidant ,165 haveCurcuma longa, grapes, berries, peanuts, and other plant sources [Resveratrol  is a natural polyphenol that was discovered in 1939 and is derived from  sources . Studies sources ,167. Car sources  first re sources  found th sources  found th sources . However sources . Therefo sources .Curcumin -hepta-1,6-diene-3,5-dione), a well-known bioactive polyphenolic compound, is the major active component of turmeric . CurcumiCapsicum annuum) had good X-ray radioprotective activity in lymphocytes, effectively scavenging free radicals and reducing radiation-induced oxidative damage, and were not cytotoxic to human lymphocytes at all concentrations tested. Furthermore, studies have found that coniferyl aldehyde can reduce the radiation-induced genotoxicity and protect DNA from radiation damage [Gallic acid  is a phenolic compound found in various plants, such as green tea, grapes, and strawberries . Nair etn damage .Polysaccharides are chains of more than 20 glycosyl groups formed by many monosaccharide molecules linked by glycosidic bonds . NaturalPolysaccharides, naturally occurring in various plant organs such as flowers, roots, leaves, and fruits, have been found to exhibit a broad spectrum of biological activities in consumer organisms, including immunomodulatory, antioxidative, and antitumor activities. Plant polysaccharides have drawn increasing attention because of their biodegradability, sustainability, low processing costs, and low toxicity.Astragalus propinquus is one of the most popular traditional medicinal herbs due to its diverse pharmacological activities, including antitumor, antiviral, antibacterial, and immune-promoting activities. Astragalus polysaccharides are polysaccharides from Astragalus propinquus isolated by extraction, separation, and purification. Liu et al. [Astragalus polysaccharides against 60Co-\u03b3 radiation by using a Balb/c mouse model. It was shown that Astragalus polysaccharides significantly reduced the levels of alanine transaminase, aspartate transaminase, and lactose dehydrogenase in mice, and high doses of Astragalus polysaccharides also alleviated the ionizing radiation-induced liver and lung injury. In another study, Astragalus polysaccharides, at concentrations of several hundred \u00b5g/mL, were found to reduce the UVA-induced intracellular ROS production and mitochondrial membrane potential; thus, protecting the human keratinocyte cell line from UVA-induced damage [u et al.  investigd damage . HoweverSchisandra polysaccharide could prevent damage to the immune system by protecting immunoglobulins and inhibiting lymphocyte apoptosis, ultimately reducing the side effects caused by radiation therapy, which suggested that Schisandra polysaccharide may serve as a potential novel radioprotective agent. Acetylated mannan in aloe protected irradiated mice by regulating the immune system and stimulating the proliferation of hematopoietic cells [Rheum tanguticum polysaccharide (RTP) could significantly reduce apoptosis and inflammatory factors by regulating Nrf2 and its downstream protein HO-1; thereby, significantly alleviating radiation-induced intestinal injury. Wang et al. [Hohenbuehelia serotina polysaccharides could effectively increase the activity of SOD and CAT in splenocytes and decrease the MDA content in splenocytes by mediating the endoplasmic reticulum apoptosis pathway, ultimately achieving radioprotective effects. Chen et al. [Sambucus nigra substrate polysaccharide (SNAAP) could increase gluconeogenesis and glycogen synthesis in 60Co-\u03b3-irradiated mice and restore radiation-induced disorders of glucose metabolism by regulating stress-activated protein kinase (JNK) pathways in the liver and pancreatic duodenal homologous box factor-1 (PDX-1) and glucose transporter protein-2 (GLUT-2) in the pancreas. In conclusion, while several polysaccharides, including Schisandra polysaccharide and Rheum tanguticum polysaccharide, have shown potential in radioprotection, the determination of safe and effective concentrations for clinical use is a critical factor that needs further exploration.Zhao et al.  found thic cells . Zhang eic cells  found thg et al.  found thn et al.  showed tAngelica sinensis polysaccharide was found to exert radioprotective effects by increasing thymic and splenic indices and increasing the number of red and white blood cells in the peripheral blood [Angelica sinensis polysaccharide was also related to increasing the antioxidant capacity of cells and reducing the DNA damage. Malyarenko et al. [aloe polysaccharide [Mesona blume polysaccharide [Heliantnus tuberosus L. polysaccharide, Laminaria japonica polysaccharide, Alga polysaccharide, Haberlea rhodopensis polysaccharide, purple sweet potato polysaccharide, soybean meal polysaccharide, pectin polysaccharide, Panax ginseng polysaccharide, and Tinospora cordifolia root polysaccharide, have demonstrated radioprotective effects.al blood . Furthero et al. ,194 founccharide , Mesona ccharide , cereal ccharide , Heliant137Cs-\u03b3-ray radiation (4.0 Gy) injury model and treated the mice with siphon worm polysaccharide (SNP). SNP led to an increase in DNA and a decrease in the micronucleus rate in bone marrow cells, with a significant increase in antioxidant capacity and bone marrow damage protection. Moreover, a study found that chondroitin sulfate A derived from animals could increase the DNA content of mouse bone marrow after radiation therapy [Animal polysaccharides mainly include glycosaminoglycans and chitosan, which have antioxidant, anti-inflammatory, antibacterial, antiultraviolet, and other biological activities and may, thus, be used in drug development and in the biomedical field. Among the functional groups, the presence of uronic acid and sulfuric acid groups is closely related to the radioprotection of animal polysaccharides. For example, Li Na et al.  construc therapy .Lactobacillus polysaccharides could improve the survival rate of zebrafish after radiation exposure, reduce the number of dead cells in the body, and decrease the production of ROS and nitric oxide in zebrafish; thus, demonstrating good radioprotective and antioxidant activities. Li et al. [Hohenbuehelia serotina could effectively increase the amount of bone marrow DNA, significantly inhibit the expression of Bax protein, and promote the expression of the Bcl-2 protein, which in turn inhibited the release of cytochrome c and promoted the expression of Caspase-3; thereby, blocking the mitochondrial apoptosis pathway in mouse spleen cells; this indicates that neutral polysaccharides have radioprotective effects.Polysaccharides derived from microorganisms are among the main types of polysaccharides, and several microbial polysaccharides have been found to have significant radioprotective effects. Lee et al.  found thi et al.  found thSophora flavescens that has been demonstrated to attenuate the side effects of chemotherapy and radiotherapy by regulating and enhancing immune function in patients with cancer and synergizing with the therapeutic effects of chemotherapy and radiotherapy [Alkaloids are a class of organic compounds containing nitrogen with base-like properties, complex ring structures, and remarkable biological activities, including antitumor, anti-inflammatory, radioprotective, and other effects. Matrine is an alkaloid isolated from otherapy . Ligustrotherapy  found thotherapy . Sverdlootherapy  found thOriganum, contain saponins, which have been shown to have expectorant, antitussive, antibacterial, anticancer, and antioxidant activities, in addition to enhancing DNA repair. Ginsenosides are the main active components in ginseng, and they have strong antioxidant and radioprotective effects. Kim et al. [Acanthopanax senticosus (Siberian ginseng) saponins at concentrations of 1.25 mg/100 mL\u20135 mg/100 mL protect neurons from free radical damage by scavenging oxygen free radicals, strengthening the cell membrane, and preventing oxidative stress [Saponins are a class of glycosides based on triterpenes or spirosteroids that are not only found in vascular plants but also occur in small amounts in marine plants. Many herbs, such as ginseng and m et al.  found thm et al.  found the stress . Pokeweee stress . Gymnemae stress . Kim et e stress  found thIn addition to the polysaccharides, polyphenols, and saponins mentioned above, many other compounds in natural products have also demonstrated radioprotective effects . For exaAlthough preclinical studies have demonstrated the radioprotective effects of natural compounds, their clinical translation has been limited. Overall, there are many limitations in developing these natural compounds into drugs that could be used in the clinic, such as low bioavailability, water insolubility, excretion time from the body, and the high cost of extraction and isolation. First, one of the critical limitations hindering the clinical translation of natural products as radioprotective agents is the issue of effective concentrations. In many preclinical studies, natural compounds have demonstrated substantial radioprotective effects. However, these are often observed at concentrations of several hundred \u00b5g/mL, which may not be achievable or safe in a clinical setting ,33. For The development of radioprotective agents is imperative in cancer radiotherapy. Although many synthetic drugs have shown effective protection against radiation, their practical application is limited due to their high toxicity. Several plants and phytochemicals have been shown to be effective in radioprotection during radiotherapy, as they exhibit both radioprotective and anticancer properties. Compared with traditional chemically synthesized drugs, drugs derived from natural sources have the advantages of high activity, high selectivity, and low toxic side effects, and have broad developmental prospects as radioprotective drugs. However, most of this research is only at the stage of in vitro or in vivo experimentation, and few products have been used in clinical applications. To develop these phytochemicals into clinically effective drugs, the biological characteristics of these natural products with radioprotective effects and the mechanisms of their radioprotection must be studied in depth. Furthermore, relevant in vivo trials should be accelerated to assess the toxicity and pharmacokinetics of the drugs in preparation for clinical trials. Moreover, most of the recent studies include single-component antiradiation drugs, and we hope that researchers build on what has been found and exploit the characteristics of each compound to screen for low toxicity, effective compound radiation protection agents. In conclusion, the use of plant-based radioprotectors as an adjunct to radiotherapy is effective and safe, and they may serve as potential candidates for radioprotection soon."}
+{"text": "Perception of the environment is an essential skill for robotic applications that interact with their surroundings. Alongside perception often comes the ability to recognize objects, people, or dynamic situations. This skill is of paramount importance in many use cases, from industrial to social robotics. Robots that can accurately perceive and understand their environment are critical for tasks like manufacturing, delivery, healthcare, and assisting humans in homes or public spaces. Object recognition enables robots to identify items, tools, and obstacles in their vicinity. This allows industrial robots to select the right parts or manipulators, logistics robots to handle packages, and autonomous vehicles to avoid collisions. Activity recognition allows robots to interpret human motions and behavior. This facilitates safe and intuitive collaboration in shared workspaces. It also permits service robots to determine user intents and respond appropriately. Person recognition provides robots the means to identify individuals. This capability supports applications like personalized assistance, healthcare monitoring, and security surveillance. Altogether, these skills comprise the fundamental building blocks for robots to operate adaptively in the real world.Sensors seeks to explore new research proposals on this increasingly important topic. The fifteen accepted papers in this issue cover human\u2013robot collaboration [This Special Issue \u201cRecognition Robotics\u201d of boration , person boration ,3, humanboration ,5, visuaboration , cooperaboration , semantiboration ,9, objecboration , multi-oboration , robot pboration , embeddeboration , activitboration , and robboration . These wIn , Yal\u00e7inkIn , Casao eThe authors of  propose In , B\u0142a\u017cejoIn , MarquesIn , MarchioThe authors of  propose In , PinkoviLee et al. introduce in  an \u201cExtrThe authors of  present Paper  proposesIn the research presented by Ryka\u0142a et al. , a path-The authors of  provide In , StrazdaThe authors of  review tIn summary, the fifteen papers in this Special Issue on \u201cRecognition Robotics\u201d demonstrate the tremendous progress being made in enabling robots to effectively perceive, understand, plan, and interact in the real world. However, significant challenges remain before these innovative techniques can be reliably deployed in unconstrained environments. Testing novel algorithms in controlled simulations or lab settings with simplified assumptions can be deceptively promising, because applying recognition capabilities on physical robotic platforms in complex dynamic scenarios reveals many subtleties. Interactive testing is critical to expose limitations around uncertainty, variability, and computational constraints. Moving innovations out of the lab or controlled scenarios requires addressing edge cases and graceful failure modes, and therefore there is still substantial effort needed to robustly handle the diversity and unpredictability of the real world. Nevertheless, the field continues steadily on an exciting path towards enabling robot assistants and coworkers that can perceive, learn, reason, and collaborate at a human level. These capabilities will lead to transformative applications, and the works presented in this Special Issue provide an inspiring snapshot of the road ahead."}
+{"text": "The intricate microenvironment at the wound site, coupled with the multi-phase nature of the healing process, pose significant challenges to the development of wound repair treatments. In recent years, applying the distinctive benefits of hydrogels to the development of wound repair strategies has yielded some promising results. Multifunctional hydrogels, by meeting the different requirements of wound healing stages, have greatly improved the healing effectiveness of chronic wounds, offering immense potential in wound repair applications. This review summarized the recent research and applications of multifunctional hydrogels in wound repair. The focus was placed on the research progress of diverse multifunctional hydrogels, and their mechanisms of action at different stages of wound repair were discussed in detail. Through a comprehensive analysis, we found that multifunctional hydrogels play an indispensable role in the process of wound repair by providing a moist environment, controlling inflammation, promoting angiogenesis, and effectively preventing infection. However, further implementation of multifunctional hydrogel-based therapeutic strategies also faces various challenges, such as the contradiction between the complexity of multifunctionality and the simplicity required for clinical translation and application. In the future, we should work to address these challenges, further optimize the design and preparation of multifunctional hydrogels, enhance their effectiveness in wound repair, and promote their widespread application in clinical practice. The skin, a crucial organ that envelops the body\u2019s surface and directly interacts with the external surroundings, serves multiple functions, including sensing external stimuli, maintaining body temperature, and safeguarding the body against external harm. Damage to its structural integrity and function can lead to diverse forms of wounds. Research indicated that the process of skin wound repair is recognized as a dynamic and intricate journey, encompassing four consecutive stages, primarily categorized as hemostasis, inflammation, proliferation, and tissue remodeling ,2,3,4. ICommon wound treatment strategies include ultrasound , electroThis review focused on the recent research and advancements in utilizing multifunctional hydrogels for wound repair . FirstlyHydrogels are large polymer molecules composed of a network of crosslinked polymer chains . The phyThe preparation method of hydrogels is a crucial factor that determines their physicochemical properties and applications. Researchers have developed various advanced functional hydrogels by applying different preparation methods to meet the different requirements of wound healing at different stages. With the pursuit of precision therapy, the development of more advanced hydrogels has attracted considerable attention. Different types of skin wounds have different shapes  and clinical manifestations , and the ideal hydrogel wound dressing should have the functions of rapidly forming an anti-infective barrier, promoting rapid blood coagulation, absorbing wound exudate, blocking nerve endings to reduce pain, and providing nutrients to promote tissue regeneration, etc. To meet these varying requirements for wound repair, researchers have developed various functional types of hydrogels, and the common ones include injectable, smart-response, conductive, and shape-memory.+) dressing by grafting DNA subunits, comprising cytosine (C)-rich strands and an fractalkine aptamer (FKNa), and it demonstrates remarkable suitability and significant potential for clinical translation in promoting and accelerating the healing of a methicillin-resistant staphylococcus aureus (MRSA)-infected wound , rendering them exceptionally promising for various wound repair applications. Injectable hydrogels can be categorized into two distinct types based on their gelation state and injection behavior: in situ gel-forming and shear-thinning hydrogels ,35. Amoned wound .2, etc.) that encounter the wound\u2019s surface and physiological factors  within the wound. Based on this, researchers have developed a series of responsive hydrogels in recent years, including physically responsive hydrogels responding to physical signals  [Responsive hydrogels are novel smart biomaterials capable of undergoing polymer chain conformational transitions or network changes under external environmental stimuli , resulting in a series of specific responses, such as significant volume contraction/expansion, color change, and phase transition, making them injectable and self-healing with other properties . These cd, etc.) ,44,45,46d, etc.) ,48,49,50d, etc.) ,52,53, ad, etc.) ,55. For d, etc.)  utilizedd, etc.)    prepared4 S m\u22121 and exhibited rapid and effective self-healing properties. Guo et al. [3+. These hydrogels exhibited excellent electrical conductivity, self-healing capabilities, and photothermal antibacterial properties, thereby significantly enhancing the process of wound healing.Electrical stimulation expedites wound healing processes across all stages by engaging in multiple ways ,60. It ro et al.  proposedo et al.  successfo et al.  successfo et al.  construc700). Mano et al. [Shape memory hydrogels (SMHs) can retain a temporary shape and restore their initial shape under specific stimuli, displaying a shape memory capability ,77. Theyo et al.  reportedo et al.  presenteo et al.  reportedCombining the sequential stages of wound healing and their distinctive characteristics, hydrogel-based wound repair strategies often focus on antimicrobial, anti-inflammatory, antioxidant, pro-vascularization, and a combination of multiple therapeutic approaches to promote rapid wound healing, as shown in +, Cu2+, etc.), cationic polymers (quaternized chitosan), biomimetic nano-enzymes (MoS2), antimicrobial peptides, etc. [S. aureus stands as the primary pathogen responsible for skin infections, and the presence and dissemination of MRSA have presented a significant hurdle in treating wound infections due to its formidable drug resistance and potent virulence. Moreover, the excessive production of reactive ROS at the site of skin wounds exacerbates inflammation, resulting in delayed healing and extensive scarring. Drawing from this information, Lu et al. [MRSA, whether in planktonic form or within biofilm structures. In vivo, this hydrogel effectively promoted the healing of MRSA-infected whole skin defects by impeding quorum sensing (QS), eradicating bacteria, and suppressing inflammation, ultimately promoting the healing process, and this study provided new insights into scarless healing of methicillin-resistant S. aureus-infected skin wounds  and hyaluronic acid (HA) grafting onto microneedle (MN) patches and introduced amine-modified mesoporous silica nanoparticles (AP-MSN) into the substrate, resulting in PFG/M microneedle patches. The experimental results showed that the microneedle patch combined chemical dynamic therapy (CDT), photothermal therapy (PTT), and tip-Fe/PDA@GOx@HA-induced M2 macrophage polarization, exhibiting excellent antimicrobial and immunomodulatory properties. This innovative development holds great promise as a potential clinical candidate for the treatment of infected wounds.The occurrence of bacterial infections during wound healing presents an unavoidable and urgent challenge. Regrettably, the improper utilization of antibiotics has resulted in the emergence of multidrug-resistant bacteria, thereby exacerbating the already formidable challenges associated with antimicrobial therapy for wound treatment. Addressing the medical bottleneck of achieving efficient antimicrobial efficacy while effectively promoting the wound healing process remains a paramount challenge that necessitates the collective efforts of researchers. There are many kinds of antimicrobial materials, including antibiotics, metal ions  nanoparticles and manganese oxide  nanoparticles and carbon nanomaterials), etc. These materials, compared to natural antioxidants, maintain high stability in more complex disease environments [3+), and phosphoric acid-functionalized polycitric acid as the raw materials. SGPA has good injectability, self-healing properties, and controlled biodegradability. In addition, it exhibits favorable cytocompatibility and hemocompatibility while also enhancing the migration of endothelial cells. Moreover, the SGPA hydrogel demonstrated notable hemostatic efficacy in an in vivo liver hemorrhage model. In the complete skin wound model, the SGPA hydrogel demonstrated significant effectiveness in promoting wound healing by reducing the expression of inflammatory factors and stimulating angiogenesis in the peri-wound area. Xie et al. [xCy , which exhibits certain ROS scavenging abilities and can play a pro-infectious wound healing role through resistance to E. coli, S. aureus infection, antioxidant, and macrophage polarization modulation properties.During the second stage of wound healing, known as inflammation, immune cells secrete various inflammatory mediators such as cytokines, chemokines, adhesion molecules, etc., to combat bacterial or viral infections and eliminate factors causing physical damage. However, at the same time, oxygen consumption increases, and the accumulation of reactive ROS generated by the \u201crespiratory burst\u201d can lead to DNA damage and apoptosis, further exacerbating inflammation and affecting wound healing. Appropriate inflammation is essential in wound repair, and therefore the regulation of inflammation is important for wound repair. Antioxidants can aid in capturing and neutralizing free radicals, thus eliminating their damaging substances to the organism . The incronments . Incorporonments ,116,117.ronments  preparede et al.  develope3+) in the hydrogel served as a photothermal conversion agent, converting light energy into gentle heat at an 808 nm excitation wavelength. The incorporation of iron ions in the hydrogel significantly facilitated the expression of genes related to blood vessel growth, such as bFGF, bFGFR, and HIF-1. The mild thermal effect additionally induced the expression of VEGF. The upregulation of these angiogenesis-related genes promoted vascular formation at the wound site.Blood vessels are involved in the transportation of oxygen and other nutrients required for wound healing; therefore, neovascularization is essential for the healing of wounds, and it can be argued that the timely development of blood vessels in the early stages is inherently linked to the rate of wound healing . Over thE. coli and S. aureus, and avoid secondary fixation of dressings. Furthermore, the hydrogel\u2019s dual functionality, stemming from its photothermal characteristics and enzyme-like activity, effectively eliminated bacterial infections, mitigated oxidative stress, enhanced the wound microenvironment, and facilitated the process of wound healing.Wound healing is a complex process that can be impacted by diseases or infections in diverse ways, such as changes in inflammatory responses, altered ROS signaling, and more. Treating wound repair by addressing a single factor is insufficient. In recent years, researchers have developed a variety of combination therapies to address the challenges of wound healing. Wen et al.  designedThe process of wound healing is intricate and time-consuming, significantly impacting the quality of life of countless individuals worldwide. Recently, significant progress has been made in the research of various multifunctional hydrogels, which also show great potential and application in wound repair. We reviewed the therapeutic strategies of multifunctional hydrogels in different stages of wound repair, such as antimicrobial, anti-inflammatory, antioxidant, pro-angiogenic, and a combination of multiple strategies, which provide strong support for wound healing. In addition, multifunctional hydrogels have been combined with other advanced fabrication technologies, such as 3D printing, for personalized wound repair strategies ,129. DesHowever, we must also face the challenges faced by multifunctional hydrogels in practical applications, including how to rationally design and combine the functionality and therapeutic strategies of hydrogels, how to prepare hydrogels on a large scale and effectively preserve them, and how to design and screen them more efficiently with the help of artificial intelligence. In addition, patients are not only pursuing the filling of simple defects in the treatment of wounds, but they also have the demand for full functional recovery and aesthetics, and there remains ample opportunity for the further development of therapeutic strategies based on multifunctional hydrogels in the prevention and treatment of scarring, regeneration of hair follicles, and improvement of pigmentation abnormality. It is worth noting that achieving multifunctionality of hydrogels typically involves complex designs of hydrogels, which is contradictory to the simplicity required for clinical translational applications. Therefore, to further enhance the efficacy and clinical application of multifunctional hydrogels in wound repair, we need to actively explore advanced preparation techniques, expand wider application areas, and strengthen the integration of clinical practice and scientific research. Last but not least, multifunctional hydrogels used for wound repair must possess superior safety, biocompatibility, and non-immunogenicity for their clinical application. This ensures that the hydrogel, when in contact with human tissues, does not cause any harmful side effects, including allergies, tissue necrosis, inflammation, or excessive immune system reactions. Therefore, strict control over the selection of raw materials, preparation processes, and quality assurance is necessary to guarantee the effectiveness and safety of hydrogel in clinical use. Overall, the research and application of multifunctional hydrogels in wound repair will bring important innovations and advances to the medical field and substantially improve the health and quality of life of patients."}
+{"text": "Despite its rarity, symptomatic micronutrient deficiency remains a public health problem. Scurvy is the differential diagnosis for bleeding disorders and hematological and rheumatological diseases, especially in patients with eating disorders. However, it is unrelated to autism spectrum disorders or other neurodevelopmental disorders. A previously healthy 10-year-old boy living in S\u00e3o Paulo, Brazil, had a history of significant food selectivity unrelated to autism spectrum disorder, resulting in symptomatic ascorbic acid deficiency (scurvy). This resulted in pain and purpuric lesions on the lower limbs, gingival edema, bleeding during tooth brushing, asthenia, weakness, malaise, and sadness. Therefore, dietary anamnesis is important for routine monitoring of child growth and development. This process helps prevent nutritional deficiencies, facilitates early diagnosis of eating disorders, and enables multidisciplinary follow-up for these patients. Scurvy is a nutritional disorder caused by an ascorbic acid deficiency. It was historically notorious among sailors but is a rare occurrence today. High-risk groups for scurvy in the modern world include people prone to malnutrition, psychiatric illnesses, eating disorders, limited food access, and malabsorptive states.The presenting patient had extreme dietary selectivity and presented with an eating disorder characterized by components of both anorexia nervosa and Avoidant Restrictive Food Intake Disorder (ARFID). These conditions were influenced by his socioeconomic status, which contributed to vitamin deficiency and the development of scurvy.A previously healthy 10-year-old boy was admitted to the emergency department due to a one-week history of pain and purpuric lesions on the lower limbs and symptoms of gingival edema and bleeding during tooth brushing. In addition, he complained of asthenia, weakness, malaise, and sadness. The child lived with his mother and three adult brothers in S\u00e3o Paulo, Brazil. The patient was in good general condition at admission, conscious, pale, eupneic, and afebrile. He had swollen and inflamed gums  and symmThe first hypothesis during hospitalization for clinical evaluation was IgA vasculitis (Henoch-Sch\u00f6nlein purpura). An eating disorder was evident due to a current dietary intake of only rice, beans, and cookies. Approximately three years before hospital admission, the patient began exhibiting food selectivity that progressively worsened in 2020, with a reported weight loss of 25kg between March and June 2021.The pediatric, nutrition, and psychiatry teams evaluated the patient. Considering the recent weight loss, food selectivity, and concern with weight gain and body appearance, the teams identified the risk of nutritional deficiencies, ARFID, and anorexia nervosa. Based on the presented clinical symptoms and the patient's dietary history, the initial treatment approach focused on addressing the patient's ascorbic acid deficiency (scurvy).Laboratory tests revealed normal values for blood count, coagulation, renal function, electrolytes, liver function, bilirubin, total protein, albumin, iron, transferrin, folic acid, blood glucose, glycated hemoglobin, vitamin D, vitamin B12, total cholesterol and fractions, triglycerides, and thyroid hormones. Ascorbic acid levels were not measured at our hospital.Coagulopathy and other nutritional deficiencies were excluded before initiating treatment for scurvy with ascorbic acid  until the symptoms improved. Patient referrals included nutrition services, children's psychiatric centers, and community health centers.Seven days after hospital discharge and regular use of ascorbic acid, the patient showed improved diet acceptance, better mood, and the absence of asthenia, lower limb pain, and gingival lesions. There was also a significant regression of purpuric lesions on the lower limbs, confirming the diagnosis of ascorbic acid deficiency.Secretaria Municipal da Sa\u00fade .This case study was approved by the Ethics Committee of Despite its rarity, symptomatic micronutrient deficiency remains a major public health concern. Even though micronutrients are required in small amounts, their deficiency can have detrimental effects on health if not managed effectively. Deficiency of ascorbic acid-a water-soluble vitamin-causes scurvy, characterized by gingivitis, abnormal wound healing, arthralgia, asthenia, and skin manifestations such as purpura.Iron, iodine, folate, vitamin A, and zinc were the most common micronutrient deficiencies.Although less frequent in pediatric patients, researchers have reported ascorbic acid deficiencies in children with more restrictive diets. These patients often include children with intellectual disability, autism spectrum disorder (ASD), major eating disorders, or those living in poverty; also affected are children with iron overload due to medical conditions, such as sickle cell anemia.,5 The patient in our case study similarly exhibited extreme dietary selectivity and presented with a combination of anorexia nervosa and ARFID components due to his socioeconomic status. These factors contributed to vitamin deficiency and the development of scurvy.Childhood eating disorders can be triggered by various psychiatric or eating disorders such as ASD, anorexia nervosa, and ARFID, among others. These diagnoses are based on the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), which categorizes eating disorders based on observed symptoms.,7 Diagnostic criteria for anorexia nervosa include significant fear of gaining weight or becoming fat, or persistent behaviors that prevent weight gain despite being underweight; restriction of energy intake that leads to low body weight relative to the patient's age, sex, developmental trajectory, and physical health; distorted perception of body weight and shape; the undue influence of weight and shape on self-esteem; or denial of the medical severity of low body weight.Studies suggest that the pathogenesis of anorexia nervosa can include genetic and environmental factors, as well as changes in brain structure and function. While early onset anorexia nervosa and ARFID share common food restrictions, the underlying reasons for restrictions differ. In ARFID, the restriction may be influenced by factors such as the sensory characteristics of food, fear of the consequences of ingestion, or lack of interest in eating, whereas in early onset anorexia nervosa, the restriction stems from the fear of gaining weight.Avoidant Restrictive Food Intake Disorder is an eating disorder characterized by a persistent failure to meet nutritional or energy needs, which can manifest as clinically significant weight loss or, in children, poor growth or failure to achieve the expected weight gain. Individuals with ARFID may depend on enteral feeding or nutritional supplements, experience significant nutritional deficiencies, and face marked interference with psychosocial functioning. The human body does not produce ascorbic acid; therefore, it is an essential dietary micronutrient. The preliminary stages of ascorbic acid deficiency generate nonspecific symptoms, such as irritability, myalgia, arthralgia, weight loss, weakness, malaise, and lethargy. More advanced stages result in connective tissue defects, which can weaken the capillaries with subsequent hemorrhaging, bone damage, and impaired growth in children.Cutaneous manifestations include follicular hyperkeratosis and perifollicular hemorrhage. Initially, petechiae appear flat and sparse but become confluent, leading to palpable purpura. The purpuric lesions observed in the patient suggest systemic vasculitis, with IgA vasculitis as the primary differential diagnosis. The oral manifestations included swelling, purplish and friable gums, spontaneous bleeding after minor trauma, eventual tooth loss, and secondary bacterial infection.Ascorbic acid participates in fatty acid transport, collagen synthesis, neurotransmitter synthesis, prostaglandin metabolism, and nitric oxide synthesis.,10Edema, weakness, and fracture of long bones may occur in addition to intramuscular and subperiosteal hemorrhages. The most common radiographic findings are osteopenia and sclerosis. In infants, musculoskeletal impairments begin with irritability, pain during movement, and delayed growth. This measurement was not available at our hospital; therefore, the scurvy diagnosis, in this case, was based on the clinical presentation, dietary history, and rapid remission of manifestations after diagnostic and therapeutic intervention with ascorbic acid replacement.Scruvy manifests when the body's pool of ascorbic acid  falls below 300mg.One limitation of our study is the absence of a laboratory methodology for ascorbic acid dosing, which prevented us from confirming the micronutrient deficiency. However, we collected various other laboratory test results that were within the normal range; our patient improved with our nutritional recommendations, which supported our diagnosis of ascorbic acid deficiency.Despite the low prevalence of ascorbic acid deficiency, it remains a differential diagnosis for bleeding disorders and hematologic and rheumatologic diseases, particularly in patients with associated eating disorders. However, it is unrelated to autism spectrum disorder or other neurodevelopmental disorders.In this case, diagnostic suspicion arose based on the clinical presentation and the patient's history of food selectivity, which was confirmed after diagnostic and therapeutic tests. Dietary anamnesis is important for the routine monitoring of child growth and development. It helps in the prevention of nutritional deficiencies, early diagnosis of eating disorders, and ensures comprehensive multidisciplinary follow-up for these patients."}
+{"text": "Maintaining brain health is crucial, and it can be achieved through the increasing physical activity, preventing metabolic syndrome, preserving mental health, and improving sleep quality. Physical activity encompasses a wide range of exercises, from walking to intense sports, which contribute to cerebral blood flow, a healthy sympathetic system, and cellular brain regeneration. Neglecting physical activity can lead to various neurological diseases, affecting around one billion people worldwide. The abandonment of prevention at different levels worsens the situation, including negligence of key factors, lack of preventive programs, and inadequate health care systems.2The brain is a complex organ responsible for various functions, including somatic motor and sensory control, perception, memory, learning, and emotions. To maintain optimal brain health, it is essential to focus on physical activity, prevention of metabolic syndrome, preservation of mental health, and improvement of sleep quality. There are seven key factors that contribute to brain health, including maintaining sufficient cerebral blood flow, an active sympathetic system, brain generation at the cellular level, a strong immune system, proper oxygen saturation, angiogenesis for delivering oxygen and nutrients, and hormonal balance.By following these preventive measures, it is possible to reduce the risk of neurological diseases such as ischemic stroke, hypoxic ischemia encephalopathy, neurodegenerative diseases, brain infections, psychiatric disorders, and cognitive decline caused by stress hormones. Neglecting physical activity and preventive measures can lead to a rise in neurological diseases worldwide, as reported by the WHO.Physical activity directly influences brain health through various mechanisms, including improving cardiovascular fitness, enhancing cerebral circulation, stimulating neurotrophic factors like brain derived neurotrophic factor (BDNF) for neuron protection and neurogenesis, and increasing dopamine production, which impacts movement, memory, pleasure, and satisfaction. By understanding the significance of physical activity interventions, we can explore their role in preventing neurological diseases effectively Figure\u00a0.33.1Pathomechanisms that lead to neurological diseases involves environmental, behavioral, genetic as well as lifestyles related factors. Among many we can state decreased neuroplasticity, oxidative stress, protein misfolding and neuroinflammation. Not only Physical activity can have a favorable impact on various disorders but also can mitigate inflammation, enhance antioxidant defenses and encourage the development of neuroprotective proteins.Physical activity has different positive effects on the brain and nervous system. Physical activity works by preventing neurodegeneration and improves synaptic connections and neuronal regeneration. It can improve memory and reduce anxiety or depression Additionally, it can improve cognitive abilities, aid in memory and concentration improvement, and lift mood and mental well\u2010being As a result, physical exercise can lower your risk of cognitive decline and dementia. Stroke, AD, and PD risk may be elevated by a lifestyle lacking enough exercise training. Aerobic exercise improved cognitive function in older persons.3.2Brain insulin signaling can both prevent and correct abnormalities in BDNF transport, which are necessary for neuronal survival and the maintenance of vital brain functions. Diabetes, obesity, cardiovascular disease, hypertension, and all have links to insulin dysregulation. Learning and memory problems aberrant brain insulin signaling pathways are related to different neurodegenerative disorders.3.3The human brain adapts to changing demands by altering its functional and structural properties (\u201cneuroplasticity\u201d) which results in learning and acquiring skills activity improves cognitive functions such as attention, memory, executive functions  have been explained."}
+{"text": "Sakshi Painuli: Conceptualization; data curation; formal analysis; software; validation; visualization; writing\u2014original draft; writing\u2014review and editing. Prabhakar Semwal: Formal analysis; investigation; supervision; validation; visualization; writing\u2014original draft; writing\u2014review and editing. Rohit Sharma: Data curation; supervision; validation; visualization; writing\u2014review and editing. Shopnil Akash: Validation; visualization; writing\u2014review and editing.The authors declare no conflict of interest.Dear Editor,1As the world struggles to recover from the recent COVID pandemic, antimicrobial resistance (AMR) is proving to be a new threat to human health, food security, and economic development. According to the World Health Organization (WHO), multidrug\u2010resistant pathogens/superbugs are considered a serious threat to health, worldwide. The Interagency Coordinating Group on AMR has estimated that by 2050, the mortality rate due to AMR may increase, with an estimated annual death rate of approximately 10 million people. The term multidrug resistant pathogens refers to those bacteria, viruses, fungi, or parasites that become resistant to the standard treatment and no longer respond to the treatment due to inappropriate use of antimicrobial drugs, consumption of unhygienic food, poor sanitary conditions, inappropriate infection prevention, and so forth.Acinetobacter baumannii (carbapenem resistant), Pseudomonas aeruginosa (carbapenem resistant), Enterobacteriaceae (carbapenem resistant), and Extended\u2010spectrum beta\u2010lactamases producing bacteria as priority 1 pathogens; Neisseria gonorrhoeae , Enterococcus faecium (vancomycin resistant), nontyphoidal Salmonella (fluoroquinolones resistant), Staphylococcus aureus (methicillin and vancomycin resistant), Helicobacter pylori (clarithromycin resistant), and Campylobacter spp. (fluoroquinolone resistant) as priority 2 pathogens; and Haemophilus influenzae (ampicillin resistant), Shigella species (fluoroquinolones resistant) and Streptococcus pneumoniae (penicillin resistant) as priority 3 pathogens . Along with them, Klebsiella pneumoniae , Escherichia coli , and Mycobacterium tuberculosis , showed the highest resistant rates. Infections caused by fungal growth are treated with antifungal drugs such as Deoxyribonucleic and Ribonucleic acid synthesis inhibitors (flucytosine), azole derivatives , 1,3\u2010\u03b2\u2010glucan synthase inhibitors (echinocandins), and polyene macrolides (amphotericin B), although fungal strains like Trichosporon beigelii, Aspergillus spp., Cryptococcus neoformans, Candida spp., Scopulariopsis spp., and so forth, have gained resistance against these drugs.Toxoplasma gondiischi, and Trichomonas vaginalis have developed resistance against drugs like amphotericin B, artemisinin, miltefosine, paromomycin, chloroquine, and pyrimethamine.Usually, superbugs or multidrug resistance developed by natural phenomenon, however the morbidity rate increases in immunodeficient conditions, like diabetes, severe burn patients, HIV infection, COVID infection, organ transplant recipients, and so forth. According to a list published by WHO several types of bacteria are rapidly developing resistance to antibiotics and these bacteria have been categorized into three priority groups including Candida glabrata and other fungi. Another report suggests that the fungal strain Aspergillus fumigatus worsened the condition of patients suffering from acute COVID infection.Candida auris.The COVID\u201019 pandemic, which spread uncontrollably in different parts of the world, has reported up to 532 million positive cases, including over 6 million deaths worldwide, till June 2022.Zingiber officinale have shown antibacterial properties against 18 resistant pathogens.Z. officinale showed significant activity against Salmonella enterica serovar typhimurium.Vernonia auriculifera Hiern have shown activity against E. coli, Enterobacter aerogenes, K. pneumoniae, P. aeruginosa and S. aureus.S. aureus.Limonia acidissima have shown activity against K. pneumonia' Shigella, Streptococus, staphylococcus and S. paratyphi.Aloe vera also showed the antimicrobial activity against S. aureus, E. coli, P. pseudomonas, A. baumannii strains.Although several new techniques and approaches including bio\u2010nanotechnology approaches, antimicrobial polymeric biomaterials products, combinational drug approaches, and so forth, have been developed in recent years to combat various AMR.Over time, there has been a sharp reduction in the emergence and approval of new antimicrobials. Dalbavancin, oritavancin, meropenem and vaborbactam, eravacycline, pretomanid, cefiderocol, plazomicin, delafloxacin and tedizolid are some of the recently approved antibiotics.Presently, many drugs and vaccines for these resistant pathogens are under clinical trial, which are likely to be available in the upcoming years, but in the meanwhile with the help of some control and preventive measures, we can reduce the number of active cases of multidrug resistant pathogens. These preventive measures include proper hygiene practices, like appropriate sanitation and protective measures must be taken to avoid human to human transmission of resistant strains. Antimicrobial drugs should be prescribed judiciously and unnecessary length of treatment and use of broad\u2010spectrum antimicrobial drugs should also be avoided. The awareness of both the physician and the patient regarding extensive and inappropriate use of antimicrobial drugs can suppress the rise of AMR strains. Both developing and developed countries must follow certain rules and regulations to prevent wasteful drug marketing. The use of drugs against highly resistant microbial strains in feed for animals like chicken, pig, fish and so forth, should be investigated, as they can directly develop resistant strains in humans. One should consume good and healthy food which has high nutrient and vitamin content to boost immunity naturally.In conclusion, as we know that the development of new and effective drugs, vaccines, and therapies against multiple drug resistant pathogens is in the pipeline. In the last few years, we have also seen the deadly consequences of COVID, from which we should take lessons and prepare ourselves for the upcoming threat of superbugs. The combinational drug approaches, nano\u2010particles based formulations, antimicrobial polymeric biomaterial products, new vaccine technology and so forth, can be good alternatives to treat multidrug resistant pathogens. Additionally, preventive measures, consuming good and healthy food which has high nutrient and vitamin content can help in combating against AMR."}
+{"text": "Background: Lumican (LUM), a proteoglycan of the extracellular matrix, has been reported to be involved in the regulation of immune escape processes, but the data supporting this phenomenon are not sufficient. In this study, we aimed to explore the links among LUM expression, survival, tumor microenvironment (TME), and immunotherapy in 33 cancer types.Methods: Data from several databases, such as UCSC Xena, GTEx, UALCAN, HPA, GEPIA2, TISIDB, PrognoScan, TIMER2, and GEO, as well as published studies, were used to determine the relationship between LUM expression and clinical features, TME, heterogeneity, and tumor stemness.Results: The expression of LUM was statistically different in most tumors versus normal tissues, both at the RNA and protein expression levels. High expression of LUM was typically associated with a poor prognosis in tumors. Additionally, immune scores, six immune cells, four immunosuppressive cells, cancer-associated fibroblasts (CAFs)-associated and immunosuppressive factors, tumor mutation burden (TMB), microsatellite instability (MSI), DNAss, and RNAss were all significantly associated with LUM. Among them, LUM expression displayed a significant positive correlation with CAFs and their factors, and exhibited immunosuppressive effects in six independent immunotherapy cohorts.Conclusion: Multi-omics analysis suggests that LUM may have been a prognostic marker, contributed to immunosuppression in the TME, and decreased the effectiveness of immune checkpoint inhibitors. The tumor microenvironment (TME), as the environment for tumor cell survival and material basis for influencing tumor development, is mainly composed of non-tumor cells , vascular endothelial cells), extracellular matrix (ECM), and various cytokines . The extBiologically, LUM inhibits or enhances cancer cell growth, differentiation, migration or metastasis by regulating growth receptors and signaling pathways . In gastIn conclusion, LUM has different roles in different tumors, and this heterogeneity seriously affects our overall understanding of LUM, so this study performed a pan-cancer analysis of LUM to explore the overall trend of LUM. In the study, we comprehensively analyzed the expressions and prognostic significance of LUM and explored the relationship between LUM with major TME components and immunotherapy to reveal its regulatory mechanisms in 33 tumors. Our findings elucidate on the significance of LUM in cancer therapy.https://xenabrowser.net/datapages/). Full names and abbreviations for the 33 cancers are listed in https://www.gtexportal.org/). To assess the relationship between LUM expressions and the efficacy of immune checkpoint inhibitor therapy, we searched for relevant study cohorts involving immune checkpoint inhibitor therapy for which complete clinical and gene expression information had been published. IMvigor210, a very classical research project, is a cohort study of the biological phenotype of patients with metastatic uroepithelial cancer treated with anti-PD-L1 drugs (Atezolizumab) (https://www.ncbi.nlm.nih.gov/geo/).The FPKM value of gene expressions, somatic mutation data, and clinicopathological information for 33 human cancers were downloaded from UCSC Xena (lizumab) . The GSEhttp://gepia2.cancer-pku.cn) and TISIDB (http://cis.hku.hk/TISIDB) databases were used to investigate the relationship between LUM expression and the stage of the pan-cancer. The CPTAC database in the UALCAN portal website  was used to investigate differences in LUM protein expressions between normal and tumor tissues (https://www.proteinatlas.org).We extracted the gene expression data from the TCGA and GTEx databases separately using a perl script, and used the limma package and its normalizeBetweenArrays algorithm to merge and normalize the gene expression data from the two databases. The Wilcoxon rank sum test was used to evaluate the difference in LUM expression between a tumor group and a normal group, as well as among different stages of tumor groups. The GEPIA2  were visualized. Through the \u201cView 3D Structure\u201d of the \u201cMutations\u201d module, the most frequent mutation sites of LUM were displayed in the 3D schematic diagram of the protein structure of LUM.Subsequently, genetic alterations of LUM in the TCGA pan-cancer atlas cohort of cBioPortal (http://dna00.bio.kyutech.ac.jp/PrognoScan/index.html) was used to assess the relationship between LUM expression and patient survival outcomes, and meta-analysis was used to further confirm the association between LUM expression and breast cancer survival.Data for survival time of cancer patients downloaded from UCSC Xena website included Overall Survival (OS), Disease Free Survival (DFS), Progression Free Survival (PFS), and Disease-Specific Survival (DSS). Patients with different tumour types were classified into high and low LUM expression groups based on median LUM expression values. Using \u201csurvival\u201d and \u201csurvminer\u201d packages in R, univariate Cox regression and Kaplan-Meier (KM) analyses were performed to determine the correlation between LUM and four survival indicators in 33 cancers. Next, we designed a forest map using \u201cForestPlot\u201d in R software and Adobe Photoshop 2021 software. The PrognoScan database  was used to analyze correlations between LUM expressions and 6 immune cell types  and 4 kinds of immunosuppressive cells, including CAFs, regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and M2 subtype of tumor-associated macrophages (M2-TAMs). Since the Timer2 website records many algorithms on immune cells, which are not conducive for visualization of the immune infiltrating landscape, results of the TIMER algorithm were visualized using \u201creshape2\u201d and \u201cRColorBrewer\u201d R packages.Then, the TIMER2 website  and microsatellite instability (MSI) imply a good efficacy of immune checkpoint inhibitors. The TMB values were calculated from somatic mutation data from 33 cancers based on Perl scripts, while the MSI data were obtained from previous studies . FinallyWhat\u2019s more, we obtained tumor stemness scores from previous studies for all TCGA tumor types , includiLastly, gene set enrichment analysis (GSEA) was performed to divide the samples into two groups based on LUM expression levels and retrieve statistically different pathways between the two groups from the subset based on c2.cp.kegg.v7.4.symbols.gmt.http://bioinfo.life.hust.edu.cn/GSCA/#/drug). Thirty of the most sensitive drugs were identified. Positive correlations meant that the LUM gene was drug resistant. Then, we verified the correlations between LUM transcriptome levels and chemotherapeutic responses in patients with OV, colorectal cancer, GBM and breast cancer on ROC Plotter Server (http://www.rocplot.org/site/index).Associations between drugs and LUM expressions in the GDSC database were determined using the GSCA website (http://tide.dfci.harvard.edu/).To elucidate on the prognostic significance of LUM after immunotherapy, the three retrieved immunotherapeutic studies were assigned into response and non-response groups, respectively. The response group had patients who achieved a complete response (CR) or partial response (PR) after immunotherapy, while the non-response group had patients with progressive disease (PD) or stable disease (SD). Differences in LUM expressions between non-response and response groups were determined by the Wilcoxon test. Finally, to investigate the cause of LUM-mediated immunotherapeutic insensitivity, correlations between LUM expressions and survival risk and cytotoxic T lymphocytes (CTL) in different cohorts with immunotherapy were queried in the \u201cQuery Gene\u201d module of the TIDE website  was associated with prognosis closely, where LUM was a risk factor in GBM, OV, colorectal cancer, BLCA, LGG, glioma, and KIRC , and LUMWe evaluated stromal and immune scores for 33 cancers using the ESTIMATE algorithm and analyzed the correlations between these two scores and LUM. LUM levels were significantly positively correlated with immune scores in 8 tumor types, including BLCA, COAD, CHOL, GBM, PAAD, PCPG, PRAD, and THCA, and stromal scores in 28 tumor types, including BLCA, BRCA, CHOL, CESC, COAD, ESCA, GBM, HNSC, KIRP, KICH, KIRC, LIHC, LUAD, LUSC, LGG, MESO, OV, PCPG, PRAD, PAAD, READ, SARC, STAD, SKCM, TGCT, THCA, UCS, and UCEC .Then, we used the TIMER2 database to assess the association between LUM and tumor immune cells. We also assessed the relationship between infiltrations of 4 immunosuppressive cells and LUM expressions. LUM expressions were positively correlated with CAFs, derived by various algorithms in almost all tumors. Although correlations between LUM and M2-TAMs/Tregs were not completely consistent in different algorithms, LUM expressions were positively correlated with M2-TAMs in BLCA, BRCA, COAD, CESC, ESCA, KIRC, LIHC, LUAD, LUSC, LGG, PCPG, PRAD, PAAD, READ, STAD, and TGCT, and Tregs in BLCA, BRCA, COAD, LUAD, LUSC, PAAD, PCPG, PRAD, STAD, THCA, THYM, UCS, and UVM. Expressions of LUM in a large proportion of tumors, including BLCA, BRCA, COAD, LUAD, LUSC, PAAD, PCPG, PRAD, STAD, THCA, THYM, UCS, and UVM were inversely associated with the degree of MDSCs levels . Figure Next, correlations between LUM expressions and TMB/MSI were evaluated by a radar map to predict immunotherapeutic efficacies. Expressions of LUM were negatively correlated with TMB of STAD, SKCM, PCPG, PAAD, LUAD, LUSC, LIHC, KIRP, KIRC, GBM, CHOL, CESC, and BRCA, but positively correlated with TMB of THYM, OV, LGG, and LAML . ExpressDNAss reflects epigenetic characteristics and RNAss reflects gene expression. The higher these two tumor stem cell indices, the more deficient the immune cell infiltration in the tumor microenvironment and the lower the PD-L1 expression . The finp-value were displayed -7-Oxozeaenol, 17-AAG, docetaxel, GSK269962A, midostaurin, pazopanib, RDEA119, as well as SB216763 and decreased activities of 5-Fluorouracil, AICAR, AT-751g, CUDC-101, EKU-569, GSK690693, I-BET-762, ispinesib mesylate, KIN001-102, LAQ824, methotrexate, NPK76-II-72-1, navitoclax, PHA-793887, PIK-93, SNX-2112, TAK-715, THZ-2-102-1, TPCA-1, tubastain A, WZ3105, and ZSTK474 in various cancer cell lines .The impact of LUM on chemotherapeutic responses in different tumor cohorts was also determined. It was found that OV patients with elevated LUM levels were not sensitive to chemotherapy, while breast cancer, colorectal cancer and GBM patients with elevated LUM levels had greater chemotherapeutic benefits, relative to those with low expressions .The relationships between LUM expressions and immunotherapeutic responses were validated by three independent cohorts . There wTo investigate the reasons for poor immunotherapeutic effects in patients with high LUM expressions, a LUM gene query was conducted on the TIDE website. In bladder cancer, GBM and melanoma, relations between LUM and prognosis and the relation between LUM and CTL were inconsistent . The higLUM is involved in tumorigenesis and progression, including cell transformation, hyperplasia, adhesion and invasion . In mostLUM expressions have been reported to be higher in metastatic gastric, colon, and renal clear cancers, relative to non-metastatic groups. Moreover, by inhibiting FOXO3 and weakening its binding with the LUM promoter, LUM expressions are suppressed, leading to reduced migration of neuroblastoma cells . Our difWith regards to growth and metastasis, LUM plays a dual regulatory role in several cancer types, however, the specific mechanisms have yet to be established . The posin vivo. Therefore, we postulate that the LUM protein is mostly produced by CAFs and may be one of the causes of disease deterioration in tumor patients.In this study, eight tumor types showed good associations between LUM expressions and immune scores. Stromal cells are an essential part of TME and have important functions in cancer biology. LUM expressions were positively associated with stromal scores in most tumors. The eight cancer types that were positively correlated with immune scores exhibited good overall positive correlations with infiltration levels of six immune cell types. Assessment of the association between LUM expressions and four immunosuppressive cells in 33 human cancers revealed that LUM expressions were positively correlated with CAFs in almost all tumors. To our knowledge, tumors usually present as connective tissue hyperplasia that increases deposition and cross binding of ECM proteins, with CAFs, as the main ECM producers, being the dominant cell type. In a previous study, gastric cancer cells co-cultured with LUM knockout CAFs exhibited significantly reduced proliferation and metastasis Additionally, we investigated the association between LUM and two immunotherapeutic biomarkers. TMB and MSI, measured by comprehensive genomic profiling, are reliable predictors of immunotherapeutic responses . PatientTo inform the clinical applications of LUM, we evaluated the correlations between LUM with chemotherapy and immunotherapy. In various cancer cell lines, elevated LUM expressions were associated with decreased sensitivity to AICAR (an AMPK activator). Autophagy is a type of protective cellular response to chemotherapies . LUM supWe have observed a trend that patients with high LUM levels tend to be more insensitive to immunotherapy. In addition, we found that three cohorts of bladder cancer, glioblastoma, and melanoma with low LUM expressions had higher survival outcomes after ICB treatment, confirming the importance of low LUM levels in immunotherapy. Surprisingly, elevated levels of LUM expressions in these queues were positively associated with CTL. CTLs are important in elimination of malignant cells. However, CTL-mediated tumor killing exhibit a long-lasting clinical efficacy in extremely few cancer patients . The smain vivo and in vitro experiments.Our findings imply that LUM is a potential prognostic factor for cancers. Its expression is significantly associated with TME, therapeutic responses, and pathogenesis. Among them, LUM was positively correlated with CAFs, and high expression of LUM showed poor efficacy in the immunotherapy cohort, further confirming the involvement of lumican in immunosuppression. Identifying high-risk patients through LUM and formulating personalized treatment plans will hopefully improve their prognosis. The results in this study should be verified via"}
+{"text": "Sarcopenic obesity, which refers to concurrent sarcopenia and obesity, is characterized by decreased muscle mass, strength, and performance along with abnormally excessive fat mass. Sarcopenic obesity has received considerable attention as a major health threat in older people. However, it has recently become a health problem in the general population. Sarcopenic obesity is a major risk factor for metabolic syndrome and other complications such as osteoarthritis, osteoporosis, liver disease, lung disease, renal disease, mental disease and functional disability. The pathogenesis of sarcopenic obesity is multifactorial and complicated, and it is caused by insulin resistance, inflammation, hormonal changes, decreased physical activity, poor diet and aging. Oxidative stress is a core mechanism underlying sarcopenic obesity. Some evidence indicates a protective role of antioxidant flavonoids in sarcopenic obesity, although the precise mechanisms remain unclear. This review summarizes the general characteristics and pathophysiology of sarcopenic obesity and focuses on the role of oxidative stress in sarcopenic obesity. The potential benefits of flavonoids in sarcopenic obesity have also been discussed. Obesity epidemics and aging are two major health concerns in developed countries. Over the last decade, obesity has become a worldwide pandemic . CoupledSarcopenic obesity can lead to various health problems such as metabolic syndrome, functional disability, osteoarthritis, osteoporosis, lung disease, renal disease, and depression ,13,14,15Recently, there has been increasing interest in the therapeutic use of flavonoids for sarcopenic obesity. Flavonoids are bioactive molecules present in many plants including fruits, vegetables, grains, and spices. They provide a diverse range of health benefits including antioxidant, anti-inflammatory, anti-viral, anti-diabetic, anti-cancer, cardioprotective, and neuroprotective properties . There iA rational consideration of sarcopenia and obesity is required to diagnose and treat sarcopenic obesity. Sarcopenia is characterized by the loss of skeletal muscle mass, strength, and physical function, which can lead to physical disability, lower quality of life, and a higher mortality rate ,24,25. ASarcopenia is a known risk factor for various health issues, including chronic disease progression, physical disability, falls, osteoporosis, and postoperative complications (both infections and noninfectious complications) ,32,33,342 in adults indicates obesity. However, it is recommended to use a lower BMI cut-off point for defining obesity (\u226525 kg/m2) in the Asian population, due to a higher risk of obesity-related diseases such as diabetes [Obesity is defined as abnormal or excessive fat accumulation that may be a health hazard . Accordidiabetes . Waist cdiabetes . Waist cdiabetes ,40,41. Rdiabetes . The obesity epidemic is increasing worldwide . The obeSarcopenia commonly occurs with aging and is often accompanied a relative or absolute increase in adiposity. However, it can strike anyone with obesity, regardless of age. Obesity can independently cause sarcopenia, because underlying factors contributing to obesity such as inflammation, insulin resistance, and oxidative stress can adversely affect sarcopenia . MeanwhiObesity and sarcopenia have common pathophysiological characteristics, including insulin resistance, inflammation (increased secretion of pro-inflammatory markers and decreased anti-inflammatory markers), hormonal changes , lack of physical activity, and oxidative stress ,17,18,19Oxidative stress is a critical factor that links sarcopenic obesity with related comorbidities . It is aMitochondrial dysfunction can increase ROS production  because The removal of dysfunctional mitochondria via mitophagy (a selective form of autophagy) is critical for maintaining the redox balance and muscle health. A lack of capacity of muscles to effectively remove dysfunctional mitochondria can contribute to excessive ROS formation and a consequent decrease in mitochondrial quantity and quality, which can lead to the development of muscle fiber atrophy in sarcopenia . Muscle Oxidative stress associated with obesity can also trigger disturbances in mitochondrial function, resulting in increased ROS production. Although white adipose tissue (WAT) is not a mitochondria-rich tissue, mitochondria in WAT have a critical role in maintaining metabolic homeostasis, including adipogenesis, lipogenesis, lipolysis, and adipokine production ,72. ObesThe protein kinase A (PKA)/liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) signaling pathway plays essential roles in improving mitochondrial dysfunction and inhibiting oxidative stress ,77. PKA The ER performs many functions, particularly in protein synthesis and folding. The excessive formation of unfolded or misfolded proteins in the ER can lead to ER stress . As redoER stress is commonly observed in obese subjects and in genetically modified or high-energy diet-induced obese animals ,80,81. CER stress is also an important contributor to sarcopenia development. Skeletal muscle contains the ER, which plays a critical role in the regulation of calcium storage and protein homeostasis. ER stress is increased in the skeletal muscles of both aged people and rodents ,88,89,90The balance between the anabolic and catabolic pathways is important for maintaining muscle mass. Oxidative stress causes muscle wasting by activating the catabolic pathways and inhibiting the anabolic pathway . In skeletal muscle, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway is one of the major anabolic pathways controlling protein synthesis ,95. The The PI3K/Akt/mTOR pathway is activated by several upstream triggers, such as insulin-like growth factor 1 (IGF-1), insulin, and physical activity, all of which are associated with obesity or aging ,102. CirThe loss of skeletal muscle occurs in a state of protein degradation that exceeds its synthesis. In skeletal muscle, protein degradation is mainly mediated by two catabolic pathways: the ubiquitin\u2013proteasome pathway and the autophagic/lysosomal pathway. The ubiquitin\u2013proteasome pathway is crucial for protein degradation in striped muscles . FoxO acMultiple triggers including oxidative stress and inflammatory cytokines affect protein degradation. Oxidative stress-induced atrophy is associated with the up-regulation of FoxO1 and MuRF1 expression in muscle cells, whereas treatment with ascorbic acid, an antioxidant, counteracts oxidative stress-induced atrophy by down-regulating FoxO1, MuRF1, and atrogin-1 expression . ROS alsSatellite cells, also known as muscle stem cells, are the primary source for muscle re-generation. It is critical for muscle fiber maintenance, repair, and remodeling . Age-relConsiderable evidence suggests that excess ROS and diminished antioxidant capacity can impair muscle regeneration, primarily by affecting satellite cell homeostasis ,136. An Myogenic regulatory factors  play a critical role in controlling the myogenesis via satellite cells. The expression of myogenic regulatory factors is up-regulated during myogenesis and influences the activation and differentiation of stem cells . By contFlavonoids are among the most abundant phenolic compounds in edible plants . More thApigenin  is a flavone that is plentiful in edible plants such as parsley, celery, celeriac, oranges, and chamomile . There iIn addition, apigenin exerts a protective effect against sarcopenia. In lipopolysaccharide (LPS)-treated mouse skeletal muscle cells, it decreases the expression of the atrophic genes atrogin-1 and MAFbx . This anAnother flavone luteolin , commonly occurring in edible plants such as celery, parsley, and broccoli , has a pQuercetin  is a flavonol abundantly present in various vegetables and fruits . It can The protective effects of quercetin on obesity-induced skeletal muscle atrophy have also been demonstrated in vivo ,190. In Its anti-atrophic effects have been observed in other animal models ,183,184.Dihydromyricetin, also known as ampelopsin, is a flavonol present in medicinal herbs, vegetables, and fruits, including grapes and berries . It has In addition, Zhou et al.  reportedEpigallocatechin gallate (EGCG) is a flavanol abundantly present in tea, especially green tea, and is also present in small amounts in other plant foods, such as apples, carobs, berries, and avocados ,213. It The existing evidence indicates the beneficial effect of EGCG in alleviating sarcopenia. In aged rats, EGCG increases the recovery of muscle mass and function after disuse by de-creasing apoptotic signaling and increasing satellite proliferation . TakahasEpicatechin, another flavanol found in green tea, also hinders aging-associated skeletal muscle degeneration and enhances physical activity in mice . Similar5,7-dimethoxyflavone, a flavone found in Kaempferia parviflora, also exerts protective effects on sarcopenia and obesity ,248. SupGlabridin, an isoflavan found in licorice, prevents glucocorticoid-induced muscle atrophy in vivo and in vitro . FurtherHesperetin, a major flavanone abundant in citrus fruits, such as lemons and oranges, decreases body weight and fat mass in HFD-induced obese mice . It alsoAnother citrus flavanone, naringenin, reportedly protects against HFD-induced adiposity and inflammation in ovariectomized mice . MoreoveOther flavonoids, such as daidzein (isoflavone), genistein (isoflavone), baicalin (fla-vone), sinensetin (flavone), icaritin (flavonol), isobavachalcone , and panduratin A , have the potential to attenuate obesity and sarcopenia ,271,272.Sarcopenic obesity has become a global epidemic affecting all generations, including the elderly. In addition to age-related diseases, multiorgan dysfunction and multiple mechanisms are implicated in the development of sarcopenic obesity. The development and progression of sarcopenic obesity are related to oxidative stress, inflammation, insulin resistance, hormonal changes, and behavioral problems. Accumulating evidence suggests that flavonoids may be effective in preventing and treating sarcopenic obesity, owing to their ability to control oxidative stress, inflammation, insulin resistance, mitochondrial dysfunction, anabolic and catabolic pathways, and satellite cells . FlavonoHowever, the underlying mechanisms of action remain obscure, and limited human clinical trials have investigated the effectiveness of flavonoids in sarcopenic obesity. Therefore, further studies are required to assess the potential impact and mechanism of flavonoid-mediated prevention of sarcopenic obesity. In addition, advancing the understanding of sarcopenic obesity may contribute to the emergence of novel therapies to prevent associated comorbidities, such as cardiometabolic diseases."}
+{"text": "Cardiovascular Research, 2022, cvac110, https://doi.org/10.1093/cvr/cvac110This is an erratum to: Carla Carnovale, Cristiana Perrotta, Sara Baldelli, Dario Cattaneo, Cristina Montrasio, Silvia S Barbieri, Giulio Pompilio, Chiara Vantaggiato, Emilio Clementi, Marco Pozzi, Antihypertensive drugs and brain function: mechanisms underlying therapeutically beneficial and harmful neuropsychiatric effects, In the originally published online version of this manuscript Table 2 was published as plain text without colour markers. This information was correct in the PDF version and so only the online version has been updated. The publisher apologizes to the authors and readers for any confusion caused.This error in the online version has now been corrected."}
+{"text": "Nature has always been a precious source of bioactive molecules which are used for the treatment of various diseases . NaturalThe application of natural products in the field of chemotherapy and chemoprevention is a valuable research topic, leading to the extensive use of plant-derived compounds as potent antitumor molecules . In addiNatural products effectively inhibit cell proliferation, regulate the cell cycle, and interfere with several tumorigenic signaling pathways ,11. The Currently, many plant-based antitumor drugs are in clinical use, such as taxanes, vinblastine, vincristine, and podophyllotoxin analogues. The combined use of phytochemicals like resveratrol, curcumin, and thymoquinone with other antitumor agents has shown significant success in preclinical studies, allowing enhanced efficacy and mitigation of side effects ,18. EmerIn this Topic, 30 original articles and 3 reviews have been collected, with a particular focus on the isolation of bioactive compounds from natural sources, the mechanisms of action of anticancer compounds at the cellular level, and the application of active molecules against a panel of solid and hematological cancers, including melanoma, breast, lung, colorectal, prostate, bladder, and gastric cancer. Most of the analyzed compounds were from natural sources, whereas some semi-synthetic derivatives were also identified and discussed.Viscum album var. coloratum, Drimia Maritima, Trichosanthes, Lupinus albus, Bryopsis plumosa, Elephantus scaber L., Paejangsan, Coix Seed, Lupinus albus, Ocimum sanctum Linn., Euphorbia fischeriana, Moldavian dragonhead, Streptomyces ardesiacus, Cichorium intybus, and Trichosanthes.The most recent findings on the effects of extracts and their constituents in treating various cancers are discussed. Most works focus on the effect of water or ethanolic extracts from natural plants or fungi, such as The extracts and the isolated components have proven effective against breast, colorectal, lung, bladder, myeloma, and prostate cancer through several mechanisms, including decreased tumor cell viability, modulation of cytokines, secretion of chemokines, modulation of ROS, reduction of specific MMP subtypes, apoptosis, cell cycle inhibition, or by downregulating MAPK."}
+{"text": "Social media, leveraging Web 2.0 technologies, plays a vital role in healthcare, medical education, and research by fostering collaboration and enabling research dissemination. Healthcare professionals use these platforms to improve public health literacy, but concerns about misinformation and content accuracy persist. In 2023, platforms like Facebook , YouTube , Instagram , TikTok , and Twitter  have become essential in healthcare, offering patient communication, professional development, and knowledge-sharing opportunities. However, challenges such as breaches of patient confidentiality and unprofessional conduct remain. Social media has transformed medical education, providing unique networking and professional development opportunities. Further studies are needed to determine its educational value. Healthcare professionals must follow ethical and professional guidelines, particularly regarding patient privacy, confidentiality, disclosure rules, and copyright laws. Social media significantly impacts patient education and healthcare research. Platforms like WhatsApp  effectively improve patient compliance and outcomes. Yet, the rapid dissemination of false news and misinformation on social media platforms presents risks. Researchers must consider potential biases and content quality when extracting data. Quality control and regulation are crucial in addressing potential dangers and misinformation in social media and healthcare. Stricter regulations and monitoring are needed due to cases of deaths resulting from social media trends and false news spread. Ethical frameworks, informed consent practices, risk assessments, and appropriate data management strategies are essential for responsible research using social media technologies. Healthcare professionals and researchers must judiciously use social media, considering its risks to maximize benefits and mitigate potential drawbacks. By striking the right balance, healthcare professionals can enhance patient outcomes, medical education, research, and the overall healthcare experience. Social media includes an array of digital communication platforms, including but not limited to Facebook , WhatsApp , Instagram , Twitter , YouTube , Instagram , TikTok , LinkedIn , Quora , Discord , etc. which facilitate the creation and sharing of information and ideas on levels ranging from a peer-to-peer basis to a broader scale. These platforms are built upon the principles of Web 2.0 technologies and have emerged as essential tools in healthcare, medical education, and research . The utiSocial media platformsOver the years, social media platforms have experienced substantial growth and diverse levels of user engagement. In 2023, the predominant platforms utilized by consumers are Facebook 69%), YouTube 57%), Instagram (45%), TikTok (33%), and Twitter (30%) [7%, Insta9%, YouTuFacebook, the largest platform with 2.9 billion monthly active users, is being used in healthcare for purposes such as facilitating patient support groups, disseminating information, and promoting awareness campaigns. YouTube, distinguished by its video-centric content, serves as an invaluable resource for patient education, expert interviews, and the communication of health-related updates. Instagram, predominantly preferred by younger audiences, is conducive to visual storytelling, promoting wellness and healthy lifestyles, and establishing connections with healthcare influencers. Twitter, characterized by its real-time updates, is an outstanding platform for healthcare organizations to share news, interact with patients, and engage in health-related discussions.Social media platforms have emerged as essential tools for healthcare marketers and professionals to connect with patients and disseminate health-related information . As of tSocial media and its importance in healthcareSocial media platforms have emerged as indispensable tools in the healthcare sector, playing a crucial role in disseminating health-related information, medical research, education, patient communication, and professional development. With a significant percentage of patients utilizing social media to search for and share health information, these platforms have gained prominence in various health topics, such as vaccines, drugs, smoking, noncommunicable diseases, pandemics, eating disorders, and medical treatments -11. MediIn medical education, social media usage has expanded among healthcare professionals and organizations, with younger populations' media device use indicating that social media can play a critical role in delivering medical education to future healthcare professionals .\u00a0Social Ramasubramanian et al. analyzed the accuracy of Instagram posts, finding that 88.1% of the posts on stroke were factually accurate, although healthcare professionals' contributions to social media posts were minimal . von MuhSocial media in medical educationSocial media has become an indispensable resource for medical education, offering unique opportunities for professional development, networking, and knowledge sharing. In nursing education, Peck emphasized the potential of social media as a teaching tool while underscoring the importance of protecting student privacy and providing appropriate guidelines for its use to ensure safety in the learning environment . She advRukavina et al. identified three key benefits of social media on the e-professionalism of healthcare professionals, namely professional networking and collaboration, professional education and training, and patient education and health promotion . They alBernhardt et al.\u00a0suggested that social media platforms present immense potential for professional development and networking, despite the potential risks, and should be used judiciously to maximize the benefits . They coBryan et al. found that parents of pediatric patients perceived blog posts written in the third-person objective voice as more reliable and accurate than those written in the personal or mixed voice . The topSocial media platforms in healthcareIn a study by Ramasubramanian et al., Instagram's role in healthcare communication was analyzed, finding that 88.1% of the posts on stroke were factually accurate, yet the contribution of healthcare professionals in social media posts remained minimal . von MuhThe complexity of social media requires ongoing modification of guidelines as technology advances , with hePatient education and social mediaSocial media plays a crucial role in patient education, addressing patient needs, and promoting patient compliance. Mouelhi et al. highlight the need for accessible and easy-to-find medical information on social media to keep patients informed , while MBryan et al.\u00a0found that the narrative voice and topic of blog posts affected parental trust in their content, with sleep-related posts deemed more accurate than vaccine-related posts . They reSocial media in healthcare researchRamasubramanian et al. and Alves et al. demonstrate the use of social media data in healthcare research and its potential as a stimulant for research questions ,38. AbroPatienstLikeMe.com (PLM) framework through two experiments, underscoring the potential of social media in research and data collection [Sohn et al.\u00a0introduced the Crowdsourced Health Experience-ontologies-based healthcare Knowledge Creation (CHEKC) framework, which leverages experience-ontologies to integrate healthcare knowledge and provides patients with healthcare information based on similar healthcare experiences, symptoms, and conditions, demonstrating superior efficiency and accuracy over the llection . Numeroullection ,32. In allection .Despite potential drawbacks, various papers have demonstrated the benefits of using social media in healthcare research. For example, Davies et al. found that internet-delivered interventions effectively increased physical activity , while ZQuality control and regulation of healthcare information in social mediaQuality control and regulation of healthcare information in social media are crucial to address potential dangers and misinformation. Gabarron et al. discovered that social media had a significant impact on disseminating both accurate and inaccurate information about COVID-19, with misinformation ranging from 0.2% to 28.8% of posts, and all the studies that were included in their review\u00a0evaluated the effects of such misinformation and reported that it caused fear or panic . Farsi eNebeker et al. examined the ethical considerations associated with the use of mobile imaging, pervasive sensing, social media, and location tracking (MISST) technologies in behavioral research, highlighting the need for developing an ethical framework, informed consent practices, assessing potential risks to participants, and identifying appropriate data management strategies to guide the responsible design and ethical review of research using these technologies . TagliabStriking the right balance in social mediaSocial media has become an indispensable tool in healthcare, providing valuable opportunities for patient education, medical education, healthcare research, and professional development. However, it is crucial to strike the right balance between maximizing the benefits and mitigating the potential risks associated with its use. For patients, it is essential to be cautious and assess the credibility of the information obtained and its source . HealthcSocial media holds immense potential for healthcare, but it is essential to strike the right balance by using it responsibly, adhering to ethical and professional guidelines, and implementing effective policies and regulations. By doing so, healthcare professionals, organizations, and patients can harness the power of social media to improve patient outcomes, advance medical knowledge, and enhance the overall healthcare experience. The present article highlights the importance of social media platforms, which play a crucial role in healthcare, medical education, and research by enabling collaboration, communication, knowledge sharing, patient communication, professional development, and networking. However, they are also associated with challenges like\u00a0breaches of patient confidentiality, unprofessional conduct, and misinformation, making ethical and professional guidelines essential. Also, social media significantly impacts patient education and healthcare research but is prone to the spread of false news and misinformation. Therefore, quality control, stricter regulations, and ethical frameworks are necessary to address potential dangers and misinformation in social media and healthcare. Healthcare professionals must judiciously use social media to maximize benefits and minimize risks, thus enhancing patient outcomes, medical education, research, and the overall healthcare\u00a0experience."}
+{"text": "Hypnotherapy has been increasingly used in recent years in healthcare, with several applications during pregnancy, labor, birth and the postpartum.This review was performed to assess the effects of Hypnotherapy before, during and after pregnancy.A narrative review methodology using keywords determined by the Medical Subject Headings (MeSH) thesaurus was adopted in this study. For this purpose, the databases of PubMed, Scopus,Web of Science, GoogleScholar, and Scientific Information Database (SID) were searched using the keywords of \u201cHypnosis, Hypnotherapy, Pregnancy, Labor, and Childbirth \u201d from March11 to April 5, 2022; and finally, the related articles published from 2000 to 2022 were retrieved.According to the findings, the effects ofHypnotherapy on pregnancy and delivery and postpartumoutcomes were classified into several categories as the following: Hypnotherapy-based interventions improve childbirth experience, with less anxiety, increased satisfaction, fewer birth interventions, more postnatal well-being and better childbirth experience overall. Hypnotherapy may reduce the overall use of analgesia during labour, but not epidural use.Hypnotherapy intervention during pregnancy aided in reducing physical and psychological symptoms during pregnancy.With reference to the related literature on this subject matter, women can safely pursue hypnotherapy during pregnancy, labor, birth and the postpartum. Hypnotherapy can be presented as a technique enabling patients to have a positive birth experience; however, high quality trials are needed to demonstrate its complete efficacy.None Declared"}
+{"text": "Bacteria have been used to increase crop yields. For their application on crops, bacteria are provided in inoculant formulations that are continuously changing, with liquid- and solid-based products. Bacteria for inoculants are mainly selected from natural isolates. In nature, microorganisms that favor plants exhibit various strategies to succeed and prevail in the rhizosphere, such as biological nitrogen fixation, phosphorus solubilization, and siderophore production. On the other hand, plants have strategies to maintain beneficial microorganisms, such as the exudation of chemoattractanst for specific microorganisms and signaling pathways that regulate plant\u2013bacteria interactions. Transcriptomic approaches are helpful in attempting to elucidate plant\u2013microorganism interactions. Here, we present a review of these issues. The need to produce food in large quantities driven the implementation of several production techniques, increased inputs, more productive varieties, and an increasing acceleration in crop cycles. Intensive agricultural use of these production technologies has caused an excessive use of chemical fertilizers and therefore a damage to the environment ,2. AlterOver time, the use of microbial inoculants or biofertilizers in agriculture has increased. Biofertilizers are products formulated from living microorganisms that are capable of promoting growth in plants of agricultural interest. The first microorganisms used as inoculants were \u201crhizobia\u201d, diazotrophic bacteria capable of colonizing the rhizosphere and establishing nodules in the roots of their host legume. The first commercial biofertilizer was the so-called \u201cNitragin\u201d, formulated from rhizobia; Nobbe and Hiltner 1896) patented this biofertilizer, which used gelatin as a nutrient medium for microorganisms. Later, at the beginning of the 20th century, formulations were based on solid carriers such as soil and peat ,8. Years96 patentAminobacter, Arthrobacter, Azoarcus, Azospirillum, Azotobacter, Bacillus, Bradyrhizobium, Brevundimonas, Burkholderia, Clostridium, Delftia, Enterobacter, Gluconoacetobacter, Herbaspirillum, Klebsiella, Paenibacillus, Rhiseudobacillus, Serratia, Sphingomonas, and Xanthomonas. However, the most used bacteria for the formulation of biofertilizers are Azospirillum, Bacillus, and Pseudomonas, in addition to some endo-ectomycorrhizal fungi such as Rhizophagus irregularis, Gigaspora margarita, Pisolithus tinctorius, and Scleroderma citrinum [Currently, many products on the market are composed of one or combinations of plant-growth-promoting rhizobacteria (PGPRs). Among the most commonly studied rhizobacteria are citrinum ,12,13,14PGPRs can act in two ways to improve the fitness of its hosts, either directly or indirectly. Among the direct mechanisms are those that promote plant growth. Within these, we find the production of hormones, such as auxins, cytokinins, and gibberellins, as well as nitrogen fixation and phosphorus solubilization. The indirect mechanisms are related to inhibiting the function of one or more plant-pathogenic organisms . These mBacillus spp., Achromobacter xylosoxidans, Gluconobacter diazotrophicus, Acinetobacter calcoaceticus, Rhizobium, Azotobacter spp., Herbaspirillum seropedicae, Enterococcus faecium, Pseudomonas spp., Promicromonospora spp., and Azospirillum spp. [Bacillus subtilis, Methylobacterium, and Sinorhizobium meliloti [The production of auxins is one of the most frequently reported for the promotion of plant growth: it has been found that 80% of microorganisms colonizing the rhizosphere can produce this metabolite. For decades, an increase in the number of root hairs and lateral roots and a shortening of root length have been reported when plants are inoculated with PGPRs. These root morphological changes have been attributed to bacterial auxin production, and studies with plant mutants altered in IAA production confirmed its role . The plalum spp. ,35. Othelum spp. ,37. The meliloti ,39.Rhizobium, Sinorhizobium, Azorhizobium, Allorhizobium, Mesorhizobium, Bradyrhizobium, Burkholderia, and Herbaspirillum [Nostoc and Anabaena), Azoarcus, Azospirillum, Azotobacter, Enterobacter, Gluconacetobacter, Klebsiella, Herbaspirillum, and Pseudomonas can be free-living nitrogen fixers or establish associations with plants as endophytes [Nitrogen is one of the most important macronutrients for plant growth. The abundance of nitrogen in the atmosphere is approximately 78%, and plants cannot assimilate it. Many PGPRs have been identified that can carry out biological nitrogen fixation freely or under symbiotic associations with legumes. Some examples of symbiotic nitrogen fixers are pirillum ,40. Cyandophytes ,42,43. Tdophytes .Arthrobacter, Bacillus, Burkholderia, Enterobacter, Microbacterium, Pseudomonas, Rhizobium, Mesorhizobium, Flavobacterium, Rhodococcus, and Serratia, are listed in that category [3+, associated with hydroxides and oxyhydroxides [3+ and make it available to cells [Pseudomonas, Bacillus, Rhizobium, Azotobacter, Enterobacter, and Serratia [Phosphorus is another essential plant macronutrient since it functions in different metabolic processes, such as photosynthesis. It is found in molecules such as ATP and nucleic acids and is involved in signal transduction. However, there is a drawback since more than 90% of the phosphorus in the soil is insoluble, immobilized, or precipitated, making it difficult for plants to absorb it. In the soil, some bacteria solubilize inorganic phosphorus; these bacteria are called phosphate-solubilizing bacteria . They cocategory . In addicategory . Anotherdroxides . Some PGto cells . Some siSerratia .Rhizoctonia, Fusarium, Pythium, Alternaria, Phytophthora, and Botrytis. PGPRs belonging to the genera of Bacillus, Pseudomonas, and Streptomyces have been exploited or control plant diseases in many economically important crops [Among the indirect mechanisms, the most important is the production of antibiotics such as surfactin, fengycin, rhamnolipids, phenazine-1-carboxylic acid (PCA), pyrrolnitrine, butyrolactones, zwittermicin A, aerugin, azomycin, cepafungins, kanosamine, and karalicin . They cant crops ,51,52.Pseudomonas fluorescens, Bacillus amyloliquefaciens, and Bacillus licheniformis [Bacillus, Agrobacterium, Rhodococcus, Streptomyces, Arthrobacter, Pseudomonas, and Klebsiella [Some organisms can produce enzymes that can degrade the fungal cell wall of some phytopathogens. Among the enzymes with this ability are chitinase, \u03b2-1,3-glucanase, protease, and lipase, which are responsible for the degradation of the components of fungi cell walls ,54,55. Oniformis ,57,58. Bniformis . Disruptniformis . Among tebsiella .Bacillus subtilis and Pseudomonas sp., induce ISR and produce antimicrobial peptides that control infection through phytopathogens  [Induced systemic resistance (ISR) is a plant defense mechanism triggered by pathogen infection, injuries, or root colonization. Induced systemic resistance (ISR) can be elicited by PGPRs through their cell wall components or metabolites . Some PGotrytis) ,63.Bacillus subtilis FB17 but not of other Bacillus sp. [Plants can select their microbiota by releasing root exudates. Microbes are attracted by chemotaxis to the rhizosphere by secondary metabolites, low molecular weight , and high molecular weight compounds  . L-malicllus sp. . The micllus sp. . Microor6\u2013108 bacterial cells/cm2 in each leaf [Sphingomonas, Streptomyces, Pseudomonas, Methylobacterium, and Bacillus are commonly found as phyllosphere residents in maize, rice, soybean, sugarcane, and fruit trees [Although the rhizosphere has been the main source of growth-promoting bacteria, the phyllosphere is also a reservoir of microorganisms with outstanding metabolic potential. The term phyllosphere refers to the aerial parts of plants, including stems, leaves, fruits and reproductive structures . Leaves ach leaf . Phyllosach leaf . They muach leaf . Moreoveach leaf . Other rach leaf . Sphingoit trees . Some ofit trees . A combiIn both natural and agricultural ecosystems, beneficial and pathogenic microorganisms, mainly bacteria and fungi, colonize plants . The plaSo far, numerous studies have revealed plant\u2013microbe interaction processes such as how plants respond to microbial colonization, including pathogens. However, there are still questions on how plants differentiate between beneficial and pathogenic microbes or between different species of pathogens or how gene regulatory networks and signal transduction pathways control these processes . The besMedicago truncatula were affected inbeneficial and pathogenic interactions [Many genes necessary for the interactions between plants and bacteria and plants and fungi have been discovered and described including. The common symbiotic signaling pathway (CSSP) pathway. This pathway includes kinases and co-receptor proteins that sense the presence of rhizobial bacteria or AM fungi and a series of signaling proteins, calcium/calmodulin, which induce gene expression necessary for establishing mutualism. There is evidence that certain CSSP elements are sequestered during the colonization stage of plant tissues in plants. CSSP mutations in ractions .Plants recognize conserved molecules from microbes; these metabolites are also known as microbial- or pathogen-associated molecular patterns (MAMPs or PAMPs). Plants have evolved different pattern recognition receptors (PRRs) in the plasma membrane that bind MAMPs and PAMPs and control plant immune responses. In response to PAMPs, plants elicit a defense response termed PAMP-activated immunity (PTI) or basal resistance, the first level of defense that restricts infection by pathogens in most plant species .Verticillium dahliae infection; in tomatoes, the decrease in the expression of miR482 and the increase in the expression of BS -LRR confer resistance to V. dahliae [The role of plant miRNAs in recent years has gained considerable interest since it is known that miRNAs are involved in signaling pathways associated with symbiotic interactions. miRNAs are small, endogenous non-coding RNA fragments (18 to 24 nucleotides) that affect the stability and translation of mRNAs and act as the primary post-transcriptional regulators of gene expression . Differe dahliae .Arabidopsis thaliana and the common pathogen Pseudomonas syringae, identifying genes and specific bacterial processes of \u201cimmune response\u201d. In P. syringae, it was possible to identify bacterial transcriptomic signatures influenced by plant immune activation and the overexpression of the sigma factor gene involved in iron regulation and how this partially decreases bacterial growth during plant immunity [Arabidopsis symbionts genomes, has revealed that these peptides allow for evasion of the immune response. Therefore, plants can identify the type of bacterial flagellin and use this information to identify pathogens [Nobori et al. (2018) evaluated 27 combinations of plant interaction and immunity between immunity . The anaathogens .In general, plants may differentiat beneficial microorganisms from pathogens in different ways, such as recognizing different flagellar epitopes, receptor competition, and post-transcriptional regulation through miRNAs.Plant\u2013microbe interactions involve chemical signaling in which microorganisms detect plant-derived metabolites and express genes associated with chemotaxis, nutrient metabolism, and the synthesis of plant growth regulators ,90. ThisBacillus subtilis OKB105 expressed genes for glucose, arabinose, and malic acid transport in response to rice exudates [B. amyloliquefaciens SQR9 expressed genes for the metabolism of inositol, mannitol, alanine, glutamate, lysine, and aspartate [Rhizobium leguminosarum and R. phaseoli interacting with different host plants showed the preference of rhizobia for the uptake of organic acids based on the overexpression of genes encoding specialized C4-dicarboxylate and tricarboxylate transport systems [Bradyrhizobium to soybean exudates has been linked to the expression of genes involved in the IAA metabolism, suggesting that legumes may regulate the production of auxin by bacteria [Azospirillum brasilense reaches high levels of expression of genes for auxin production and for biological nitrogen fixation when colonizing maize rhizoplane in the presence of other PGPRs, indicating that metabolites produced by one member of the rhizosphere community can affect the gene expression of others [The composition of root exudates differs according to genotype, age, and nutritional conditions, but they generally consist of sugars, amino acids, organic acids, and secondary metabolites . Trials exudates , whereasspartate   necessary to establish effective nodulation and nitrogen fixation with soybean (Glycine max) [Rhizobium etli Mim1 is essential for symbiosis with common beans [Azoarcus sp. BH72 expressed genes encoding a T6SS and pili in response to rice exudates. Mutants in these genes are deficient in root invasion [R. phaseoli in the presence of maize exudates [Nitrospirillum amazonense expressed a type IV secretion system and RND efflux pumps for toxic compounds in sugarcane apoplast [In poor soils, the plants activate a \u201ccry for help\u201d system which attracts microorganisms with outstanding metabolic capabilities. Root exudates can activate genes of PGPRs involved in root attachment and colonization, including those encoding secretion systems, fimbriae, flagella, plant wall-degrading enzymes , and quorum-sensing systems ,103. Somine max) . Likewison beans . Secretiinvasion . The genexudates . In contexudates . A fasciapoplast .Pseudomonas, including P. fluorescens, P. brassicacearum, P. chlororaphis, P. protegens, and P. synxantha showed an overexpression of genes for the cleavage of catechol, benzoate, and phenolic acids in interaction with the grass Brachypodium distachyon [Rhizobium etli CFN42 harbors an efflux pump, RmrAB, that confers tolerance to naringenin, phaseollin, phaseollidin, coumaric acid, and salicylic acid [Pseudomonas syringae pv. tomato DC3000, the MexAB-OprM efflux pump genes confer protection to flavonoids and phenolic compounds, providing it with a good fitness in the rhizosphere and an advantage in the colonization of tomato plants [Root exudates are rich in nutrients and have phytoalexins, flavonoids, phenolic acids, and alkaloids with antimicrobial activity . The abustachyon  and sugastachyon . Rhizobilic acid  , transcriptomic responses that modulate antioxidant mechanisms and metal homeostasis were detected. However, infection with the pathogen Sphingomonas melonis Fr1 increased gene expression in phytoalexin biosynthesis [A. thaliana were upregulated in the presence of the pathogenic bacterium Ralstonia solanacearum [Abscisic acid is a sesquiterpenoid that regulates adaptive responses to abiotic and biotic stresses [The beneficial effects of bioinoculants on different crops have been widely described at the agronomic level ,120; howBacillus , and Pseudomonas , as welludomonas  and filaudomonas . A signiynthesis . Phytoalnacearum . Abscisistresses .A. brasilense sp245 induced the activation of genes of maize associated with apoplast metabolism, while Herbaspirillum seropedicae HRC54 induced the expression of genes associated with auxin-dependent signaling and antioxidant mechanisms and activated gibberellic-acid-regulated pathways in plants but repressed abscisic acid biosynthesis. In agreement, the interaction of P. putida with chickpea (Cicer arietinum L.) modulated the expression of miRNAs targeting genes associated with drought survival [Paenibacillus polymyxa YC0136, including genes for the production of phenylpropanoids and laccases [Other types of responses have been detected during interaction with PGPR. Hardoim et al. (2020)  found thsurvival . In tobalaccases . Jasmonilaccases .Microbacterium aurantiacum GX14001 modified the tobacco transcriptome by positively regulating genes associated with phenylpropanoid, flavonoid, and gingerol biosynthesis [B. subtilis GB03 was shown to activate cytokinin pathways in Arabidopsis thaliana through its VOCs, mainly by 2,3-butanediol and 3-hydroxy-2-butanone [Pseudomonas pseudoalcaligenes produces dimethyl disulfide, 2,3-butanediol, and 2-pentyl furan; these VOCs are responsible for increasing germination, modulating osmolyte concentration, and alleviating drought stress in maize [Medicago truncatula and sorghum (Sorghum bicolor) and to protect tomato (Solanum lycopersicum) against infection by P. syringae pv. tomato [Not all the interactions between plants and microorganisms are physical; volatile organic compounds (VOCs) also serve as a communication channel. The gases emitted by the actinobacterium ynthesis . Likewisbutanone . Pseudomin maize . Recentl. tomato . KnowingMany works involving PGPRs have been published for over 50 years and different companies producing biologicals have emerged and, applied research using PGPRs has shown crop yield increments. However, the effects of PGPR applications on yield in different crops have been variable; in some cases increases in root length, foliage, and grain yield, were found when bacteria are used in combination with arbuscular mycorrhizal fungi. Knowledge about plant\u2013microbe interactions using molecular and omics tools can help us improve these interactions and make the plants resilient to environmental changes due to global warming. Exploring the microbial diversity associated with crop wild relatives is also an alternative for detecting PGPRs with better phytostimulant characteristics. On the other hand, the sequencing of the PGPR genome allows for the identification of virulence factors to ensure that they do not pose a threat to human health or the environment as a result of their release.The diversity and functionality of soil microbiota depend on the type of agricultural management, which is higher when crop rotation or intercropping systems are implemented. Tillage systems also have a decisive influence on the composition of microbial populations. The management of the soil microbiome is even more complex in the soil microbiome, the action of PGPRs is only a part of the agroecosystem in such a way that the introduction of foreign microorganisms to each site or plot does not always offer a positive behavior since the homeostasis of the soils tend to limit their establishment. Hence, a large number of local evaluations must be carried out.The current challenge is to ensure crop success when using PGPRs to further encourage an increase in their usage, which must undergo rigorous evaluation methods to ensure product safety, viability, purity, and genetic stability. For the efficiency of PGPRs to be more significant, a series of factors must be considered, such as soil characteristics, type of plant, and agronomic practices, which determine the presence, dominance, or survival of specific bacteria populations ."}
+{"text": "PLOS ONE Editors retract this article [The  article  because AMES, MH, and SF did not agree with the retraction. MKH, AA, HMAD, MFA, SH, and NM either did not respond directly or could not be reached."}
+{"text": "Pharmaceutics entitled \u201cAdvances of membrane vesicles in drug delivery systems\u201d. These papers cover many related topics including the source, preparation, modification, drug loading, and in vivo administration and biodistribution of membrane vesicles , as well as application of membrane vesicles as DDSs in the treatment of various diseases.Bioinspired  drug delivery systems (DDSs) have been intensively studied in the last decades. As bioinspired DDSs, membrane vesicles, including extracellular vesicles (EVs) released from eukaryotic cells, outer membrane vesicles (OMVs) from bacteria, cell-bound membrane vesicles (CBMVs) isolated in situ from cell surfaces, membrane vesicles reorganized after the isolation of the plasma membrane of cells, and others have been rapidly developed and are attracting more and more attention. Most recently, a collection of 25 papers on the advances in membrane vesicle-based drug delivery systems was published in a Special Issue of  Drug delivery systems (DDSs) are defined as formulations or devices that deliver therapeutic substances specifically to their sites of action without reaching nontarget sites . Many benefits to drugs can be achieved by drug delivery systems, including an elevated stability, higher water solubility, prolonged circulation time, better sustained drug release, stronger tissue/cell targetability, lower drug dosage, impaired side effects, enhanced efficacy, etc. Over the latest two decades, bioinspired  drug delivery systems have been intensively studied. Compared with traditional DDSs, the advantages of bioinspired DDSs include lower/no immunogenicity, biocompatibility, biodegradability, better safety, among others. By mimicking (or being prepared from) natural components inside the body, many bioinspired DDSs have been tested, including biomolecule -, lipid-protein complex , membPharmaceutics which belongs to the section \u201cDrug Delivery and Controlled Release\u201d, 25 papers on the recent advances in membrane vesicle-based drug delivery systems have been collected and arranged in this Editorial article in the following order: the source, preparation, modification, drug loading, and in vivo administration and biodistribution of membrane vesicles , as well as application of membrane vesicles as DDSs in the treatment of various diseases.As one specific type of bioinspired DDSs, membrane vesicles have a membranous structure derived from natural cells. Several types of membrane vesicles have been reported including well-known extracellular vesicles (EVs) released from eukaryotic cells, outer membrane vesicles (OMVs) from bacteria, cell-bound membrane vesicles (CBMVs) isolated in situ from cell surfaces ,4,5, memThe selection of the sources for membrane vesicle production is crucial and needs to be prioritized during studies since it determines the composition and biological activity of membrane vesicles and influences the functional state of membrane vesicles as DDSs. Some studies have shown that extracellular vesicles exerted a better therapeutic efficacy than the cells releasing the EVs . At presTM Exosome Precipitation Solution was used for the isolation of dendritic cell-derived exosomes [Citrus sinensis) juice [The preparation of membrane vesicles is important for the following characterizations and applications of membrane vesicles as DDSs, and high vesicle yield and separation efficiency are required for practical production of membrane vesicles. The methods for membrane vesicle preparation should have the characteristics of robustness, ease of use, economy, repeatability, time-saving, and high throughput, and sometimes depend on the sources of membrane vesicles to a certain degree. The frequently used methods include differential ultrafiltration centrifugation (dUC), density gradient centrifugation, ultrafiltration (UF), precipitation, dimensional exclusion chromatography (SEC), and immunoaffinity capture, as well as emerging technologies  . In thisexosomes  and of hexosomes ; differeexosomes  or from s) juice ; and dens) juice . Physiochemical or biological modification can improve the targeting, bioactivity, kinetics, and biodistribution of membrane vesicles. At present, multiple methods have been applied for membrane vesicle modification, including modification of donor cells , direct modification of isolated vesicles , combination strategy, and others ,20. In tE. coli and A. baumannii, respectively [It has been proved that membrane vesicles of various origins contain specific biomolecules. For example, extracellular vesicles can carry proteins, lipids, nucleic acids, and other signaling molecules to neighboring and distant cells, affecting various physiological and pathological functions of the recipient and parental cells, and participating in the development of various diseases. Not only can membrane vesicles be used as a \u201cmessenger\u201d to modulate cells, but also as a \u201cshooter\u201d to target diseases. As a promising tool for drug delivery, membrane vesicles have been recruited to load different types of drugs. In this Special Issue, curcumin was loaded in extracellular vesicles for neuroinflammation ; peroxidectively . Moreoveectively .With the rapid development of membrane vesicles, corresponding characterization methods have been developed. The characterization methods can be utilized according to the physical properties of membrane vesicles including vesicle structure, size, buoyancy density, optical property, zeta potential, among others . A surveStudying the in vivo drug administration and biodistribution of DDSs has a constructive role for membrane vesicles. In this Special Issue, Tolomeo et al. explored the biodistribution patterns of membrane vesicles derived from human mesenchymal stromal cells (MSCs) following different administration routes, including intratracheal, intranasal, and intravenous injections . Using fWith the development of different types of membrane vesicles, almost all types of membrane vesicles were tested to serve as DDSs or drug carriers for treating various diseases, shedding light on the therapeutic potential of membrane vesicle-based drug delivery systems across various medical conditions. A lot of related studies have been reported and summarized in many review articles. In this Special Issue, the applications of membrane vesicles as DDSs in bone-related diseases , anticanMembrane vesicles  serve as effective carriers for delivering specific cell-derived molecules or therapeutic molecules or drugs, leveraging their targeted nature and intercellular communication properties ,11,25. T"}
+{"text": "In a patient with persistent hypokalemia, it is important to consider Gitelman syndrome, a rare, salt-wasting tubulopathy inherited in an autosomal recessive pattern. Gitelman syndrome leads to electrolyte abnormalities like hypokalemia, hypomagnesemia, and metabolic alkalosis. Typical clinical features include muscle cramps, fatigue, polydipsia, and salt cravings. Our case involves a female patient in her early 40s who visited the endocrinology clinic with symptoms of polyuria, constipation, muscle weakness, and fatigue. Electrolyte abnormalities included hypokalemia, hypomagnesemia, hypochloremia, and hyperreninemia. Initial tests, such as\u00a0renal function tests, renal ultrasound, and CT scan, yielded normal results. Differential diagnosis of Gitelman syndrome and Bartter\u00a0syndrome was considered due to the mutual electrolyte abnormalities of hypokalemia and metabolic alkalosis. Bartter\u00a0syndrome was ruled out in our patient due to the presence of hypomagnesemia, which indicates a different defective receptor. Ultimately, genetic testing would be necessary to confirm the diagnosis of Gitelman syndrome considering the characteristic electrolyte disturbances and classic clinical presentation of fatigue, weakness, and salt craving. Gitelman syndrome has a prevalence of 1 per 40,000 people. Salt-wasting tubulopathies include Gitelman syndrome and Bartter syndrome, which are inherited disorders causing salt depletion in patients . GitelmaA 41-year-old female patient presented to the endocrinology clinic with complaints of fatigue, decreased appetite, polydipsia, polyuria, and constipation. She also complained of decreased sex drive, irritability, headaches, dizziness, muscle weakness, and wrist pain. The patient had a long history of hypertension. She was prescribed multiple antihypertensive drugs and a low-salt diet to help control her blood pressure. The patient had no significant findings on general physical exam, abdominal exam, and cardiac examination. Subsequent lab work showed low potassium, high renin, and high aldosterone , and management involves potassium and magnesium supplementation, which our patient is taking ,11. The The typical clinical presentation in Gitelman syndrome is milder than in Bartter syndrome; muscle cramps, lethargy, salt cravings, polydipsia, and polyuria. Severe cases may be seen in children less than six years of age with chondrocalcinosis, stunted growth, seizures, tetany, rhabdomyolysis, as well as ventricular arrhythmias ,13. In aOur patient\u2019s labs showed hypokalemia, hypomagnesemia, hyperreninemia, and hyperaldosteronism typical of Gitelman syndrome. Hypomagnesemia subsequently improved with magnesium supplements. In the setting of hypokalemia, differential diagnoses included Bartter syndrome. In Bartter\u2019s syndrome, the defect is in Na-Cl reabsorption in the thick ascending limb of Henle leading to hypercalciuria .\u00a0DiuretiOur case report describes a case of Gitelman syndrome presenting in adulthood with fatigue, muscle weakness, constipation, mood disturbances, and decreased sex drive. Due to its relatively sparse incidence and lack of clinical familiarity, Gitleman syndrome can be easily misdiagnosed, leading to delayed or inappropriate treatment.\u00a0Unlike most cases, our patient\u00a0presented with hypertension. We emphasize the significance of considering this diagnosis in patients with typical electrolyte abnormalities and varied clinical presentations. Lab results showed persistent hypokalemia and hypomagnesemia\u00a0with elevated renin and aldosterone typical of Gitelman syndrome.\u00a0Renal workup showed no abnormalities of structure. The patient is being managed with potassium and magnesium supplements to alleviate symptoms and antihypertensives to control blood pressure."}
+{"text": "Genomic epidemiology is promising for precision Healthcare Associated Infection (HAI) tracking, and reducing the cost of infection prevention. Despite growing access to whole-genome sequencing (WGS), genomic healthcare epidemiology is not mainstream. For healthcare genomic epidemiology to become standard, tools for analysis and interpretation that are automated, reproducible, and accessible are required.Bacillus cereus in a neonatal intensive care unit (NICU) at an academic medical center.We have extended One Codex to support analysis and interactive data visualization for genomic pathogen surveillance and outbreak investigation. First, these capabilities were evaluated for concordance with previous results including probable transmission, strain, antimicrobial resistance and virulence marker detection. Next, we describe the use of One Codex Genomic Epidemiology to investigate a potential HAI cluster of . WGS data can be generated or uploaded manually or through an interface with lab information systems. Data QC, taxonomic classification, antimicrobial resistance and strain detection, variant calling and phylogenetics are automatically conducted. Analysis modes include an epidemiologic curve, patient exposure and location history across isolate phylogenies . Clinical and sequence data and analysis results are versioned, allowing for review and audit, and are available through the application programming interface. Investigation of datasets demonstrated concordance with previous results (Table 1). Evaluation of a B. cereus cluster revealed unlikely transmission involving two patients and an environmental NICU isolate. This analysis pinpointed a single plausible transmission event requiring further investigation by Infection Prevention .We developed a platform integrating sequencing, analysis, health record tracking, interactive visualization and interpretation Investigation of a B. cereus cluster using the Genomic Epidemiology interface showing summary of SNP distances, spatiotemporal information for patients, MLST designation, epidemiologic curve and metadata summary. Patients 1 and 3 had isolates from MLST 73 which had a pairwise distance of 17 core SNPs, warranting further investigation by infection prevention to evaluate plausibility of transmission.One Codex facilitated accurate, and reproducible sequence to epidemiologic insight. Applications include evaluation of prospective surveillance, early outbreak detection, and genomics-driven deployment of infection prevention resources.Austin Davis-Richardson, PhD, Invitae: Employee|One Codex: employee Petras Zdanavicius, MS, Invitae: employee|One Codex: employee Timothy Reynolds, PhD, Invitae: Employee|One Codex: employee Shawn Hawken, PhD, MPH, Invitae: employee|One Codex: employee"}
+{"text": "Neglected Tropical Diseases (NTDs) are the varying tropical infections that are prevalent in the low-income and developing countries of Asia, Africa, and America , Echinococcosis, foodborne trematodiases, human African trypanosomiasis (sleeping sickness), Leishmaniasis, Leprosy (Hansen's disease), Lymphatic Filariasis, Mycetoma, Chromoblastomycosis and other deep mycoses, Onchocerciasis (river blindness), Rabies, Scabies and other ectoparasitoses, Schistosomiasis, soil-transmitted helminthiases, snakebite envenoming, taeniasis/cysticercosis, Trachoma, and Yaws and other endemic treponematoses  are a subset of NTDs that are transmitted among humans and other vertebrates directly or indirectly via vectors like mosquitoes spreading malaria, Dengue, etc. , which can regulate the immune response in malarial infection. The long-lived antibodies produced by B-cells in the germinal center can pave a path for Malarial vaccine development. The potency in targeting the B-cell is a crucial area of study in serious and life-threatening Malaria cases  bites; however, evidence of maternal transmission has also been found. DENV and ZIKV flavivirus showed high structural similarity and cross-reactive immune response, which results in false positives during serological tests, precisely in secondary infections. The present serological test includes NS1 and E proteins as antigenic targets (Tan et al., SG conceptualized the content and wrote the manuscript."}
+{"text": "Following an institutional investigation by the University of Sargodha, the authors regret the omission of Tahir Mehmood in the original author list.The correct authorship list and affiliations list is displayed herein. The updated acknowledgements and author contributions are shown below.Conceptualization, Aliya Ajaz and Muhammad Ashraf Shaheen; methodology, Muhammad Ashraf Shaheen, Aliya Ajaz, Abu Bakar Siddique; software, Maqsood Ahmed; data collection, structure solution, refinement, validation, Khurram Shahzad Munawar, Muhammad Fayyaz ur Rehman and Abdul Karim; formal analysis, Nazir Ahmad; investigation, Abdul Karim; resources, Muhammad Ashraf Shaheen; data curation, Aliya Ajaz; writing\u2014original draft preparation, Aliya Ajaz; writing\u2014review and editing, Abu Bakar Siddique; visualization, Muhammad Fayyaz ur Rehman; supervision, Muhammad Ashraf Shaheen, Tahir Mehmood; project administration, Muhammad Ashraf Shaheen. All authors have read and agreed to the published version of the manuscript.We are thankful to the Higher Education Commission of Pakistan (HEC) for providing financial assistance to PhD Scholar (Aliya Ajaz) to conduct a part of her research work in the United States under the International Research Support Initiative Program (IRSIP).The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "Synthetic antioxidants have shown adverse effects on consumers. The review, thus, aims to assess the effect of marinating broiler meat with plant leaves-derived antioxidants potential for improving shelf-life and human health. Broiler meat loss and waste due to spoilage is more than three million kg annually, thus, extending shelf-life by reducing initial microbial load and autoxidation is essential. Adding various antioxidants would reduce oxidation of protein and fatty acids improving nutritional shelf-life through synergic interactions. Antioxidant synergetic effects also improves reduction in microbiota proliferation leading to the delayed development of off flavours and deterioration of meat colour. To reduce initial microbial load and autoxidation effects, the inclusion of polyphenols and antioxidants from varying sources by mixing various antioxidants would lead to improved synergic effects. The dem weights ,4. To scSynthetic antioxidants such as butylated hydroxy anisole, butylated hydroxy toluene, and synthetic tocopherol are being added to stabilize free radicals and delay nutrient oxidation. Adding synthetic antioxidants to reduce oxidative damage, however, may potentially cause adverse health effects and consumers prefer natural antioxidants, therefore, it remains a challenge to the meat industry ,6. In reNatural antioxidants sources include legumes, tree leaves, cereals, fruits, seeds, spices, vegetables, teas, and herbs ,15. CereAdding natural antioxidants may reduce the rapid oxidation of protein and extend nutritional shelf-life. The rapid alteration in visual appearance during storage would be reduced and an improved quality product would motivate consumers to trust and buy the meat . The redThe global meat industry is constantly evolving because of consumer preference change, lifestyle concerns, monetary, geographical, political, cultural, religious factors and food loss and waste . Most vaThe industry has added cold logistical chains, thermal treatment which includes super chilling, ultrarapid freezing, immersion vacuum cooling, pressure-shift freezing, dielectric heating and ohmic heating to extend shelf-life. In efforts to increase consumer safety, meat quality and nutritional shelf-life; traditional cutting and paper or waxed paper wrapping was replaced by store cutting and display on packages in fridges for self-service . PackagiPunica gratun L species which is rich in polyphenolic compounds and flavonoids reduces lipid oxidation in human bladder cells [Various literature has established the potential capacity of plant derived natural antioxidants to delay oxidation process and extend the shelf-life of meat products. Poultry producers have been encouraged to use natural antioxidant, such as, natural dietary alternatives and plant extracts to reduce the negative effect of lipid and protein oxidation. Plants extracts rich in polyphenol are known for several health benefits, examples being, er cells . This nePlants amino acids and minerals are reduced as the plant ages, however, pre-harvest they are greater than after processing. Polyphenols increase as the plant ages pre-harvest, thus, the chemical component the plant is needed for is important. This also demonstrates that one plant may not be ideal for the best antioxidants\u2019 composition and capability. The use of plants at a younger age may assist improve shelf-life by providing amino acids and minerals which may scavenge free radicals, such as, carbonyls leading to a greater meat colour, tenderness, juiciness, and off odour shelf-life. This, however, would not scavenge sufficient hydroxyls, peroxyls and alkyl radicals which ultimately lead to the carbonyls, hydroperoxides, hydrocarbons and alcohols produced by protein oxidation. Ultimately, the shelf-life of the meats\u2019 nutritional value, flavour, tenderness, and colour is not efficiently extended. The consumers recurring purchase may also be reduced by the reduction in flavour, tenderness, and colour.Polyphenols assist with hydrogen abstraction; their reduction may lead to a reduced hydrogen abstraction efficiency, thus, greater autoxidation and deteriorated fatty acid profile. Amino acids may have a weak antioxidant capability; however, amino acids improve polyphenols\u2019 ability to scavenge on free radicals leading to an efficient oxidation reduction in meat fats and protein. Polyphenols and essential oils have a synergistic relationship that reduces microbial load which may ultimately extend shelf-life. The use of blended sources has been documented to be superior to individual sources, thus, fresh leaves may be difficult to incorporate . ExtractAs plants dry, their antioxidant capacity is significantly reduced. There was a 6.4% loss in antioxidant capacity for celery vegetable plants dried by air and 33.7% for coriander dried by oven . Some plPseudomonas spp. and Lactobacillus spp. lead to off odour, discoloration, gas production, slime production and pH reduction [Lipid oxidation, protein oxidation, and meat spoilage bacteria are the main contributors to the reduction in the shelf-life of meat; thus, these leaf meal characteristics may be beneficial. Oxidation reduces the nutritional value of meat by deteriorating essential fatty acids, proteins leading to an unacceptable flavour, and toxins generation. Oxidation of meat in human leads to the nutrients losing its function causing disorders, such as, cancer, diabetes, obesity, dysfunction of red blood cells, and heart diseases. Bacteria, such as, eduction . Applicaeduction ,32. PlanBlending of antioxidants sources may be superior as it would allow the use of various plant sources which assists with keeping the environmental resources at balance. Further, increases sources may increase chances of high radical affinity antioxidants threshold is met to optimize antioxidation in meat. It is noteworthy that synergic relationships may occur between chemical components within a leaf meal and between leaf meals as most these relationships are chemically related. It is also, however, evident that minimal plants have sufficient within plant synergic relationships to efficiently improve meat quality and shelf-life.The effects various antioxidant sources have on meat which is not limited to shelf-life, however, limited to parameters that determine shelf-life. Oreganos\u2019 documented effect is its antibacterial activity which may increase shelf-life \u201335. RoseVachellia tortilis) (high flavonoid), Umunga (Vachellia karroo) (low flavonoids), Paperback thorn (Vachellia sieberiana), babul (Vachellia nilotica) (medium flavonoids), Moringa (Moringa oliefera), uMhlonyane (Artemisia afra) (medium flavonoids), Buffalo thorn, Umphafa (Ziziphus mucronata) (low flavonoids), Rooibos  (high flavonoids) are potential plants that may be blended. They have not been studied extensively, however; the minimal studies published have demonstrated their potential if blended as they have antimicrobial and antioxidant capabilities. Blending these various antioxidant sources may yield superior shelf-life compared to individual sources.Umsasane  that activate oxygen to ROS, such as, hydrogen peroxide (forms hydroxyls) and superoxide.Antioxidants, such as, vitamin C, E, selenium, calcium, magnesium, cysteine, methionine, flavonoids, tannic acid and phenolic acid scavenge on the ROS and have various affinity to various ROS. The incorporation of multiple sources of antioxidants will supply substrate for activated species reducing free radicals that may abstract hydrogen from unsaturated fatty acids. Blending rooibos, radicals ,49. The radicals . This alradicals . In mostV. tortilis, V. nilotica, Artemisia afra, Ziziphus mucronate, and V. karroo synergic relationship is not well understood, thus, blending them may lead to better understanding of synergistic action of leaf meals which improves meats stability. The high quantity of PUFAs ensured by antioxidants ensures essential fatty acids are also maintained improving life expectancy, immune systems, and healthier brains especially for developing children.Rooibos, Essential fatty acids are omega 3, omega 6, omega 9 acids and saturated fatty acids in relation to the total fatty acids. Omega 3, omega 6 arachidonic, eicosapentaenoic acid are regarded as inflammatory markers which is why their ratio is essential to study . Only alReducing oxidation in meat samples by using antioxidants stabilised meat colour during storage. Some leaf meals however may not have sufficient antioxidizing power leading to more yellowness and lightness appearance, such as, garlic leading to consumer reduced acceptability. Due to the oxidised protein that leads to light being scattered making meat appear lighter. Shear force may also be increased due to antioxidant sources that do not have sufficient antioxidizing power leading to protein oxidation, thus, lower water holding capability along higher drip loss. To improve oxidizing power synergy may be essential for blended plants.V. karroo, V. nolitica, Artemisia afra, Ziziphus mucronate, V. tortilis and rooibos need to be explored to make it easier to extrapolate how they may affect meat shelf-life once polyphenol combination is established. Concentrations needed of these leaf meals and of individual polyphenols to be combined are also essential and need more attention.The addition of polyphenols in efforts to improve broiler meat quality and increase meat shelf-life should be explored more to reduce loss/waste of meat. Using polyphenols as marinade may increase broiler meat shelf-life by at least 3 days which may be longer with varying antioxidant sources. Feeding and marinating the meat may be advisable as feeding is a first line of defence during rearing and when enzymes are defeated nutritional components and antioxidants may be of assistance. Meat shelf-life parameters, such as, redness are hard to extend as the metmyoglobin formation delay has not been well studied. The inclusion of medicinal plants may, however, have an added advantages as they may prevent or reduce humans\u2019 susceptibility to a wide range of sickness. Marinating broiler meat with medicinal plants which are not widely used may assist maintain biodiversity and combat sickness in humans. It is, therefore, advisable to use these hardly used bush encroaching plants for human benefits. More studies, however, need to be conducted to determine which antioxidant combination works better on which parameters and/or microbes. An extensive chemical composition of polyphenols especially of"}
+{"text": "Cardiovascular diseases are one of the leading global causes of morbidity and mortality, posing considerable health and economic burden on patients and medical systems worldwide. This phenomenon is attributed to two main motives: poor regeneration capacity of adult cardiac tissues and insufficient therapeutic options. Thus, the context calls for upgrading treatments to deliver better outcomes. In this respect, recent research has approached the topic from an interdisciplinary perspective. Combining the advances encountered in chemistry, biology, material science, medicine, and nanotechnology, performant biomaterial-based structures have been created to carry different cells and bioactive molecules for repairing and restoring heart tissues. In this regard, this paper aims to present the advantages of biomaterial-based approaches for cardiac tissue engineering and regeneration, focusing on four main strategies: cardiac patches, injectable hydrogels, extracellular vesicles, and scaffolds and reviewing the most recent developments in these fields. Cardiovascular diseases (CVD) comprise a group of life-threatening pathological disorders that represent the leading cause of mortality worldwide. As the adult heart has a limited regeneration ability, cardiac injury leads to progressive function deterioration, resulting in heart failure ,2,3,4. PImmediately after an MI, no histological change is visible under the microscope. However, within the period of 30 min\u20134 h, swollen fibers are observed in the margins of the affected tissues, and glycogen is lost. Within the next 8 h, myocardial coagulation necrosis occurs, leading to swelling of the area. During the 12\u201324 h period, the darkening of damaged tissue is noticed, with the accumulation of neutrophils. The cell nucleus is destroyed on days 1\u20133, while in the following period , macrophages clear apoptotic cells from the injured area. On days 7\u201310, the formation of granulation tissue occurs, after which type I collagen settles in the area. Finally, within 2 months, the formation of fibrous tissue is observed, thus replacing dead cells and scars [In the necrosis phase, apoptotic cardiomyocytes release reactive oxygen species (ROS) and other intracellular contents into the niche, triggering pro-inflammatory cytokines and the recruitment of immune cells into the injured area. The inflammatory microenvironment further contributes to homeostasis disruption and increases oxidative damage, aggravating inflammation and fibrosis. Thus, an orchestrated biological and mechanical therapeutic strategy is imposed to efficiently mediate pathological processes in the necrosis, inflammation, and fibrosis phases .Unfortunately, beyond pharmacological therapy, the main treatment possibilities for post-MI heart failure remain heart transplantation and cell-based therapies ,10,11. NIn this context, better strategies must be sought to ensure effective and efficient cardiac regeneration. Therefore, intense research efforts have been directed to integrate bioengineering concepts in optimized cardiovascular treatments to overcome the shortcomings of current therapies ,14. One In this respect, recent studies have exploited the variety and versatility of biomaterials for creating innovative patches, hydrogels, scaffolds, and delivery platforms that hold tremendous promise for future clinical utility. Even though some of these topics have been addressed in previous reviews ,19,20,21More specifically, this paper briefly discusses cell-based therapy limitations, emphasizing the need for biomaterial-based approaches. Then, the following sections aim to present in more detail the identified novelties in the field of cardiac tissue engineering and regeneration, focusing on recently developed cardiac patches, injectable hydrogels, extracellular vesicle-based therapies, and advanced scaffolds. Through this comprehensive pathway, this review aspires to present the progress in the field of biomaterials for cardiac repair, serve as an inception point for future research, and help envisage more efficient treatment strategies.Cell therapy is one of the recently considered strategies for cardiac regeneration, consisting of direct injection of exogenous therapeutic cell suspension into the affected heart or activation of endogenous regenerative processes through stimulation of adult tissue-restricted stem cells ,22. In tIn addition to their pluripotency and self-renewal capacity, stem cells are also endowed with paracrine effects, anti-inflammatory activity, and immunomodulatory capacity ,26,39. MNonetheless, the efficacy of cell-based therapies is impeded by several drawbacks, counting low retention and engraftment of transplanted cells, the potential for differentiation into host cell types, viability under the harsh conditions of damaged tissue, and risk of inflammation and immunoreaction ,7,24,42.Biomaterials comprise a broad field of different scaled materials from macro- to micro- and nano-sized polymers, ceramics, metals, and composites that can work with living matter to replace or restore damaged tissues . They caFor the specific purpose of cardiac tissue engineering, biomaterial structure and function should mimic the native features of cardiac ECM and furnish a proper microenvironment for enhancing cell viability ,5. SpeciDespite the complex requirements for a suitable biomaterial, various natural  and synthetic polymers , polylactic acid (PLA), polylactic-co-glycolic acid (PLGA), polyurethane (PU) and their derivatives) have been reported to resemble (in various degrees) several ECM properties of interest ,12,44,46Further processing of convenient materials allows their tailoring with appropriate morphology and characteristics for application in cardiac tissue engineering . MoreoveAs the heart has a contractile nature, multiple mechanical forces act upon cardiac tissues, inducing non-uniform 3D deformations ,48.For clarity, Biomaterial-based approaches have gained increasing attention for cardiac tissue engineering and regeneration as recent developments demonstrated promising results in improving cardiac function, promoting angiogenesis, and diminishing adverse immune responses in animal testing and clinical trials ,50. To hOne of the significant focuses of cardiac regeneration approaches is represented by cardiac patches. Such structures can be made from both natural and synthetic materials engineered to have a microstructure that mimics native heart tissues, provides a microenvironment for the incorporated biological moieties, and ensures the necessary support for the construct itself ,50. CardWhen placed on the heart surface at the infarction site, these biomaterial structures can improve cardiac function by delivering various bioactive factors or cells . SpecifiIn terms of substrate materials, recent studies mainly approached the use of decellularized porcine biological materials ,62, natuThus, there is an increased scientific interest in developing cardiac patches from non-animal natural sources or biocompatible synthetic materials. One particularly interesting recent research direction is proposed by He and colleagues . The autFor an at-glance perspective over newly designed cardiac patches, Sustained efforts to develop strategies for improving the retention of cell therapy have also resulted in the design and fabrication of various hydrogels that can be injected at the damaged site. The viscoelastic properties of hydrogels contribute to inhibiting applied tensions on the injured region, preventing the formation of fibrous and scar tissue. Moreover, their porosity facilitates stem cell migration to the affected site, positively impacting their retention and survival ,66,67.Hydrogel-type biomaterials can be employed in the delivery of both cellular and acellular biological components. For instance, natural polymers, including alginate, chitosan, collagen, fibrin, fucoidan, hyaluronic acid, and keratin, have been used as efficient injectable carrier materials for active factors . NonetheIn what concerns its working principle, hydrogel material in its liquid form can be mixed with cells and biomolecules of interest and injected as a solution to the target myocardial area, where it undergoes gelation, becoming a mixed 3D cell polymeric network ready for integration with the surrounding tissue. Thus, injectable hydrogels offer a minimally invasive therapeutic alternative for creating the protective environment cells need to survive and bioactive agents to exert their intended activity ,11,69,70Depending on the nature of the base material, hydrogels can be divided into natural and synthetic. Natural hydrogels made of polysaccharides or proteins are considered appealing due to their non-toxicity, immunogenicity, and excretion of metabolites. Moreover, superior water-swelling properties allow them to easily adsorb and contain nutrients and small molecules, upgrading cell survival and boosting exercise performance. In contrast, synthetic hydrogels are recognized for their stronger mechanical properties and the feasibility of physically or chemically linking to new functional groups to enhance functionality. Synthetic hydrogels also benefit from a low risk of immune rejection but present low adhesion and not as good biocompatibility as that of natural materials .One particularly appealing cardiac repair strategy is the use of self-healing injectable hydrogels that mechanically support infarcted tissue and prevent pathological ventricular remodeling while repairing their own structure and regaining original properties following damage ,72,73. SGiven the tremendous potential of injectable hydrogels, researchers have investigated various formulations for cardiac repair and regeneration. For instance, Traverse Jay et al.  have invAlternatively, Contessotto et al.  proposedIn contrast, Bai et al.  have creFollowing a different approach, Xu and colleagues  have dev\u20133 S\u00b7cm\u20131, which is similar to native cardiac tissue.Dong et al.  have fabAnother self-healing hydrogel was proposed by Hu et al. , who useNavaei and colleagues  have man\u00ae-based injectable hydrogel to deliver therapeutic biomolecules (secretome) secreted by human adipose-derived stem cells. The biocompatible system significantly increased capillary density, reduced scar area, and improved cardiac function, demonstrating its potential as an MI treatment.On a different note, Waters et al.  have preBesides the above-discussed cardiac repair techniques, extracellular vesicles in general and exosomes in particular hold great promise for designing performant alternative or complementary formulations for cell therapies, cardiac patches, and injectable hydrogels . Their pExtracellular vesicles originating from various cells have demonstrated potential for cardiac regeneration therapy either alone or in different combination approaches . The use2O2-induced apoptosis, and hindered TGF-\u03b2 induced transformation of fibroblast cells into myofibroblast, leading to better therapeutic activity than MSCs.For instance, Lv et al.  tackled Exosomes derived from human umbilical cord MSCs can also be employed in cardiac regeneration, as demonstrated by Han et al. . The autAlternatively, Chen and colleagues  harvesteDifferently, Liu et al.  have choInteresting possibilities have also been envisaged by creating myocardial tissue grafts based on preformed implantable scaffolds. Cardiac tissue engineering scaffolds can be fabricated via crosslinking of biomaterial solution into the desired shape, followed by solidification and/or drying/freeze-drying to generate a porous ECM-like matrix. Compared to hydrogels, scaffold preparation allows more control over the porosity of the structure before cell seeding, also significantly reducing cell exposure to stress during mixing and molding procedures . MoreoveSeveral factors have been observed to be particularly relevant for cardiac applications, counting substrate geometry, stiffness, matrix topography, and electrical stimulation. These aspects must be thoroughly tailored to ensure the differentiation of seeded cells toward achieving high specific functionality as they are known to significantly influence cellular behavior, regulation of motility, proliferation, and differentiation responses ,45,93. IHayoun-Neeman et al.  have creTamimi et al.  have conLiang et al.  have recAlternatively, Li and colleagues  have incSaravanan et al.  have alsOn a different note, Feiner and colleagues  have fabTo address the limitations of current cardiac injury treatments, extensive research has been noted in developing biomaterial-based strategies. Special focus was observed on using various natural and synthetic polymeric materials to create delivery platforms for different cells and bioactive molecules relevant to cardiac tissue engineering and regeneration. Recent research efforts have materialized into a number of cardiac patches, injectable hydrogels, extracellular vesicle-based therapies, and advanced scaffolds that showed promising results when tested in vitro and in vivo. Nonetheless, the proposed innovative treatment strategies have not yet reached the stage of clinical testing, except for a few studies . SpecifiMost of the tabulated studies do not have publicly posted results, with the exception of NCT02887768 , whose pMoreover, undergoing clinical studies may soon confirm the utility of novel biomaterials for cardiac tissue engineering and regeneration, leading to the entrance into the clinical practice of performant treatment alternatives. In addition, investigating the effectiveness and safety of the discussed biomaterial formulations in humans represents a mandatory step in introducing improved therapeutic approaches in the clinical setting.Another appealing future research direction consists in producing multi-material structures via 3D printing for accurately recapitulating natural cardiac tissues and customizing the implanted device to particular patient needs ,106,107.One more perspective for creating personalized treatment approaches is machine learning. These advanced computational models are expected to play greater and greater roles in tissue culture, biomaterial development and fabrication, animal models, and clinical research . In combNanotechnology also offers good prospects for tissue engineering and regeneration ,118,119.The emerging technology of tissue-on-a-chip platforms also holds great promise for finding better treatments for cardiovascular diseases. Microfluidic chips allow the investigation of human physiology in a controlled, isolated, and accessible environment, being suitable devices for relevant disease models and drug screening systems ,135,136.To conclude, tailoring biomaterials to meet the complex set of requirements imposed by cardiac tissue engineering and regeneration is gaining increasing attention from the scientific community. The ingenious combinatorial use of natural and synthetic polymers, electrically conductive materials, stem and/or progenitor cells, and bioactive molecules can revolutionize the manner cardiac injuries are managed. Embracing an interdisciplinary approach, a recently developed series of cardiac patches, injectable hydrogels, extracellular vesicle-based formulations, and biomaterial scaffolds have already been demonstrated effective when tested in vitro and in vivo. However, there is still room for improvement to optimize the proposed approaches and deepen investigations to ensure technology transfer to the clinical setting."}
+{"text": "However, for a significant proportion of patients SSRIs either lack efficacy or are poorly tolerated. Even when SSRIs are effective in treating mood symptoms, there are often residual symptoms that are not well treated, including cognitive impairment and anhedonia. The development of novel treatment for depression is particularly challenging given the limited predictive validity of animal models. Human neurocognitive models of antidepressant action can help to bridge the translational gap and allow rapid investigation of novel compounds in healthy volunteers and people with depression. In this talk, using the 5-HTS. Murphy Grant / Research support from: Zogenix, UCB, Janssen, Consultant of: Zogenix, Sumitomo Danippon, Janssen, UCB, Speakers bureau of: Zogenix"}
+{"text": "PLOS ONE Editors retract this article [The  article  because SS, KSA, and RQ did not agree with the retraction. MM, AK, BZR, BGN, AMK, and IF either did not respond directly or could not be reached."}
+{"text": "Inflammatory bowel disease (IBD) is a long-term, progressive, and recurrent intestinal inflammatory disorder. The pathogenic mechanisms of IBD are multifaceted and associated with oxidative stress, unbalanced gut microbiota, and aberrant immune response. Indeed, oxidative stress can affect the progression and development of IBD by regulating the homeostasis of the gut microbiota and immune response. Therefore, redox-targeted therapy is a promising treatment option for IBD. Recent evidence has verified that Chinese herbal medicine (CHM)-derived polyphenols, natural antioxidants, are able to maintain redox equilibrium in the intestinal tract to prevent abnormal gut microbiota and radical inflammatory responses. Here, we provide a comprehensive perspective for implementing natural antioxidants as potential IBD candidate medications. In addition, we demonstrate novel technologies and stratagems for promoting the antioxidative properties of CHM-derived polyphenols, including novel delivery systems, chemical modifications, and combination strategies. Inflammatory bowel disease (IBD), a chronic inflammatory disease primarily affecting the intestinal tract, includes Crohn\u2019s disease (CD) and ulcerative colitis (UC) ,2. Both Bifidobacterium, Lactobacillus, and fructooligosaccharides, can alter the composition of intestinal bacteria, which is also beneficial for the attenuation of inflammation and oxidative stress [Current therapeutics for IBD treatment have focused on targeting the immune system and intestinal bacteria. For example, monoclonal antibodies  have been used to neutralize proinflammatory cytokines ,23,24, ae stress ,29,30. Ie stress ,32. Recee stress . TherefoPolyphenols, a broad family of natural products, are the most common natural antioxidants and are characterized by multiple phenolic units in their structures ,35. PolyOur search approach was centered on the utilization of several public databases, namely, PubMed, ClinicalTrials, Google Scholar, and Web of Science, for sourcing data available up to April 2023. The search terms employed included Inflammatory Bowel Disease, Oxidative Stress, Redox, ROS, Gut Dysbiosis, Gut Microbiota, and Polyphenols. The selection process entailed the application of specific inclusion and exclusion criteria. The inclusion criteria were as follows: (1) only papers published in the English language and within the last 20 years; (2) articles with a high citation rate; (3) studies with broad application prospects. On the other hand, the exclusion criteria were as follows: (1) articles with low credibility ratings; (2) papers published in languages other than English; (3) articles that were not available in full-text format. In this review, we summarize the underlying therapeutic mechanisms of polyphenols for modulating redox homeostasis to repair the intestinal mucosal barrier and focus on the application of polyphenols as potential protective and therapeutic drugs in IBD treatment based on redox-targeted therapeutics. In addition, we also discuss novel technologies or methods for overcoming the limitations of polyphenols for effective IBD treatment and prevention.The gut microbiota in the human intestinal tract has a rich diversity and contains more than 1000 species ,44, 90% Clostridium sporogenes, can regulate intestinal inflammation by activating the aryl hydrocarbon receptor [Bacteroides species with dietary fiber [Briefly, the gut microbiota can metabolize dietary fiber into SCFAs , such asreceptor . Interesreceptor . Moreovereceptor ,58. Simiry fiber . Importary fiber . Sphingory fiber ,62,63. BBacteroides, Lactobacillus, and Eubacterium, causing oxidative stress and leading to gut dysbiosis and inflammation [Escherichia coli (E. coli) [The host provides an indispensable nutrient environment for the gut microbiota, which in turn feeds back essential vitamins, neurotransmitters, and SCFAs to form a symbiotic relationship . Notablyammation ,67. In pE. coli) , can leaE. coli) ,70,71. IPrebiotics and probiotics, the conventional adjuvants in treating IBD, have been widely used to restore gut microbiota diversity. Interestingly, polyphenols have prebiotic-like properties that enhance the relative abundance of beneficial bacteria, strengthening their antioxidant capability ,73. In aCrocus sativus L., and Curcuma longa L.) [Clostridium and Bacteroides [Lactobacillales and decreasing the proportion of Coriobacterales in azoxymethane (AOM)-induced persistent colitis [Curcumin, a widely applied natural polyphenol mainly derived from CHMs  ,82, has onga L.) . The antteroides . In expeteroides . A curcu colitis . Interes colitis . A recen colitis .2O2)-induced oxidative damage by elevating intracellular glutathione (GSH) content. This is in concordance with the in vivo model [Bacteroides, Bifidobacterium, Clostridium, and Lactobacillus, and in turn, it distinctly weakens that of Enterococcus and Fusobacterium [Clostridium and Bacteroides, are able to induce cycloreversion of quercetin and release critical microbial metabolites  [Quercetin has been shown to have excellent modulation potential on bacteria in many types of diseases, including neurodegenerative disease, metabolic disease, and IBD ,90,91,92vo model . Similarvo model . DSS-indvo model . In geneacterium . Quercetacterium . Some spic acid) , which aic acid) ,100.Polygonum cuspidatum, Morus alba L., and Panax notoginseng (Burkill) [Bacteroides acidifaciens, while downregulating Ruminococcus gnavus and Akkermansia mucinphilia and reducing SCFAs to homeostatic levels [lactobacilli and bifidobacteria [Resveratrol is a well-known polyphenolic compound extracted at high levels from grape skins, peanuts, blueberries, and the roots of some CHMs, especially Burkill) ,102. DueBurkill) ,104,105.Burkill) . In addic levels . Likewisc levels . As a unbacteria . In a clbacteria . Additiobacteria .Akkermansia abundance and butyrate production [Punica granatum L.) peel, has shown anti-inflammatory and antioxidant properties in many disorders. EA can regulate the NF-\u03baB signaling pathway, intimately related to inflammation and oxidative stress, to decrease the expression of COX-2 and iNOS and phosphorylated MAPKs and impair nuclear NF-\u03baB translocation, thus assuaging chronic colonic inflammation and oxidative stress in rats [Streptococcus abundance in the gut [Many other polyphenolic compounds can be effective in IBD treatment and prevention by regulating the gut microbiota. For example, green tea is one of the most consumed beverages and widely used CHMs worldwide. It contains abundant tea polyphenols, such as epigallocatechin, epicatechin-3-gallate, epicatechin, and EGCG ,112. Notoduction . Similar in rats . Meanwhi in rats ,118 and  the gut . In addi the gut . ) and endogenous damage-associated molecular patterns (DAMPs) through germline-encoded pattern recognition receptors (PRRs), including Toll-like receptors (TLRs) and nucleotide oligomerization domains (NODs), to distinguish \u201cself\u201d from \u201cnonself\u201d ,122,123.Many immune tissue cells reside in the different layers of the intestinal tract, acting as guardians for intestinal immune homeostasis ,129. TheAs mentioned above, immunomodulators, monoclonal antibodies, and corticosteroids, which affect proinflammatory cytokines and immune cells, have been routinely used as therapeutics for IBD treatment. However, poor response and systemic side effects still limit the development of curative treatment schemes and impair their therapeutic effect.Polyphenols have exhibited excellent pharmacodynamic functions, including antioxidant and anti-inflammatory functions, by reducing oxidative stress, regulating the Nrf2 and NF-\u03baB signaling pathways, and modulating the immune system ,145,146.2O2)-induced oxidative damage by stimulating the heme oxygenase-1 (HO-1) signaling pathway [CM) cells and effector memory (TEM) cells in experimental colitis, which downregulates the levels of proinflammatory cytokines such as IL-7, IL-15, and IL-21 by inhibiting the JAK1/STAT5 signaling pathway [Dietary curcumin has been suggested as a daily adjuvant to maintain body health. In IBD, the pharmacologic properties of curcumin not only modulate the gut microbiota but also promote homeostasis between oxidative stress and inflammation. Primarily, curcumin is able to enhance the expression of tight junction proteins, such as occludin, ZO-1, and claudin-3, and maintain the integrity of the intestinal mucosal barrier by preventing endoplasmic reticulum stress-mediated IEC apoptosis ,147. In  pathway . Likewis pathway . As ment pathway . Further pathway . AccordiQuercetin has been investigated as a significant adjuvant for IBD treatment or prevention due to its acknowledged antioxidant and anti-inflammatory characteristics. Oral administration of quercetin works on the intestinal mucosa, thus exerting its therapeutic effects. Quercetin can strengthen the intestinal mucosal barrier by promoting the expression of tight junction proteins, such as ZO-1 and claudin-1, thereby attenuating the hyperpermeability of the intestine during the development of IBD ,152. In Resveratrol has the potential to improve the intestinal mucosal barrier. Evidence suggests that resveratrol can suppress IECs apoptosis while maintaining colonic mucosal architecture, perhaps sustaining the intestinal mucosal barrier ,156. TigThe potential modulatory properties of EGCG on the gut microbiota have been illustrated previously. EGCG can still affect oxidative stress and the immune response in IBD treatment. Notably, supplementation with EGCG can thicken the intestinal mucus and reduce intestinal permeability by enhancing tight junctions. It enhances the thickness of the mucus of colon tissue and reduces intestinal permeability in experimental colitis ,162. In Due to their versatility, polyphenols are increasingly used in bioimaging, therapeutic delivery, and other biomedical applications ,168. ThiRecently, structural modifications, including esterification, methylation, glycosylation, and other chemical modifications, have been developed which exhibit superior properties to circumvent the natural weakness of polyphenols and thus expand their application in antioxidant and anti-inflammatory therapy. For instance, compared to the parent curcumin, the hydrophilicity and bioavailability of the curcumin\u2013alginate esterification products are markedly increased. The ester bond between curcumin and alginate is dissolved with the help of esterases secreted by the commensal anaerobes of the colon, releasing the antioxidant curcumin to treat UC . Similar2PO3)\u2013OH, was capable of local self-assembly into hydrogels via dephosphorylation and then disassembly for release by esterase in inflamed regions. This novel strategy can markedly enhance the anti-inflammatory effect of curcumin and was found to alleviate two types of IBD [In addition to chemical modification, lipid nanocarriers and liposomes, biodegradable polymeric nanoparticles, nanoemulsions, micelles, and protein-based nanocarriers have been employed to form polyphenol-containing nanoparticles to overcome the shortcomings of polyphenols . Due to s of IBD . Human ss of IBD . In addis of IBD . Interess of IBD . Taken tLigilactobacillus salivarius Li01 (Li01), a probiotic strain capable of promoting the recovery of the gut microbiota and gut barrier, showed favorable synergetic effects in treating colitis mice. Resveratrol promotes the growth of Li01 in vivo, which in turn affects the turnover of resveratrol into more bioactive metabolites, such as dihydroresveratrol, which can facilitate the suppression of inflammation by activating the environmental sensor mammalian aryl hydrocarbon receptor (AHR) and affecting the serotonin pathway [Lactobacillaceae and Lactobacillus, and thus improved the intestinal barrier function, thereby alleviating colitis [Recent evidence has highlighted that single drug administration sometimes cannot achieve successful therapeutic goals in IBD treatment . Due to  pathway . In anot colitis . In addi colitis ,197. ColThe pathogenesis of IBD is extremely complex and is related to the genes, environment, immune system, oxidative stress, gut microbiota, and other psychological factors. Common symptoms  aggravate the risk of depression and anxiety . In addi"}
+{"text": "Endoscopic retrograde cholangiopancreatography (ERCP) is an advanced technique using a side-viewing upper endoscope to diagnose and treat pancreaticobiliary diseases. ERCP is generally considered a safe procedure; however, it is associated with risks of certain complications such as pancreatitis, bowel perforation, bleeding, and infections. Very rarely, ERCP can result in abscess formation in different organs, such as the pancreas, liver, and intestines. Physicians should be vigilant for rare post-ERCP complications such as clinically significant bacteremia and hepatic abscess, especially in high-risk populations, as if left untreated, they can result in significant morbidity and mortality. We present an interesting and rare case of an 80-year-old patient who presented with nausea, vomiting, and abdominal pain post-ERCP and was found to have a polymicrobial bloodstream infection and a hepatic abscess. The patient was treated with medical therapy alone, with an appropriate clinical response. Endoscopic retrograde cholangiopancreatography (ERCP) is an advanced endoscopic procedure used for diagnosing and managing various pancreaticobiliary disorders . During Infections following ERCP, if not diagnosed and treated promptly, can lead to severe complications, such as ascending cholangitis, which carries significant morbidity and mortality . One of 3), mildly elevated aspartate aminotransferase 44 U/L , and alanine aminotransferase 66 U/L , and normal amylase, lipase, lactic acid, alkaline phosphatase, and total bilirubin. Blood cultures demonstrated polymicrobial bloodstream infections: Klebsiella pneumoniae and Enterococcus faecalis, both susceptible to multiple first-line antibiotics. The patient was started on ampicillin-sulbactam and monitored closely. A computed tomography (CT) scan showed a poorly defined 3.4 cm hypoattenuation region in the right hepatic lobe, suggestive of a hepatic abscess  not on steroids, hypertension, and rheumatoid arthritis not on immunosuppressants, with a recent hospitalization for choledocholithiasis requiring ERCP and biliary stent placement. The patient returned six weeks later for elective ERCP with stent removal and was discharged home. Five days later, the patient returned to the hospital with nausea, vomiting, and abdominal pain. On examination, the patient was not in acute distress, though she had mild tenderness over the right upper quadrant of the abdomen. Blood work revealed an elevated white blood cell count of 24 k/mm3 . The incidence of bacteremia and hepatic abscesses post-endoscopic procedure is on the rise, and continued research and vigilance are necessary to further understand and prevent these rare complications and ensure optimal patient outcomes."}
+{"text": "The prevalence of obesity and other metabolic disorders is increasing worldwide , leadingThroughout evolution, mechanisms have developed to sense nutrients, store energy in case of food abundance and adapt physiological responses to nutrient availability, preventing reproduction in nutrient-poor environments; this strict interplay reached its highest degree of complexity in female mammals . FemalesIn the current obesogenic world, this evolutionary strategy has negative effects on overall health and is also impacting fertility, especially in women, who thus lose the metabolic advantages over men guaranteed by female hormones ,5,6. In trans fatty acids. It is known that high-fat diet (HFD) regimens negatively impact on several reproductive processes, such as folliculogenesis, oogenesis, and embryo development/implantation, leading to female infertility and transgenerational disorders [As summarized in the review by Jurczewska et al. , ovulatiisorders . Althougisorders . The burisorders ,11. In women, subfertility and low success of assisted reproductive technology (ART) have been also associated with low trace elements of copper, selenium, and zinc , showingIn men, over-exposure to heavy metals such as Cadmium (Cd), which can also occur through the consumption of contaminated water and food, induces structural and functional testicular damage due to oxidative stress, inflammation, and apoptosis .Among the several risk factors for infertility , gestatiDietary interventions might represent the most promising and invaluable strategy to limit or prevent metabolic and inflammatory complications associated with, or consequent to, subfertility ,11,20. GIn males, moderate calorie restriction may have the potential to improve the metabolic profile  and reproductive parameters  . DietaryBesides fertility, environmentally induced abnormalities in the reproductive cycle should be considered as an important risk factor for female metabolic health. Accordingly, women with impaired or null reproductive cycles  experience increased incidence of metabolic/inflammatory pathologies, such as non-alcoholic fatty liver disease (NAFLD), metabolic syndrome (MetS), and cardiovascular diseases (CVDs) ,22. NeveOverall, this Special Issue provides compelling evidence of the relevance of the nutritional status on the mutual relationship between fertility and metabolic homeostasis, as well as between subfertility and metabolic disorders both in males and females. More studies are required to unravel the underlying mechanisms of action and explore the potential of sex-specific nutritional strategies to preserve metabolic homeostasis and fertility in both sexes."}
+{"text": "Heat stress is a threat that can lead to significant financial losses in the production of poultry in the world\u2019s tropical and arid regions. The degree of heat stress  experienced by poultry depends mainly on thermal radiation, humidity, the animal\u2019s thermoregulatory ability, metabolic rate, age, intensity, and duration of the heat stress. Contemporary commercial broiler chickens have a rapid metabolism, which makes them produce higher heat and be prone to heat stress. The negative effect of heat stress on poultry birds\u2019 physiology, health, production, welfare, and behaviors are reviewed in detail in this work. The appropriate mitigation strategies for heat stress in poultry are equally explored in this review. Interestingly, each of these strategies finds its applicability at different stages of a poultry\u2019s lifecycle. For instance, gene mapping prior to breeding and genetic selection during breeding are promising tools for developing heat-resistant breeds. Thermal conditioning during embryonic development or early life enhances the ability of birds to tolerate heat during their adult life. Nutritional management such as dietary manipulations, nighttime feeding, and wet feeding often, applied with timely and effective correction of environmental conditions have been proven to ameliorate the effect of heat stress in chicks and adult birds. As long as the climatic crises persist, heat stress may continue to require considerable attention; thus, it is imperative to explore the current happenings and pay attention to the future trajectory of heat stress effects on poultry production. Every animal production system experiences stress because of the numerous stressors on the farms. Stress is a biologically adaptive response to re-establish homeostasis . Heat stThe adaptive response of poultry to heat stress conditions is intricate and complex . When heThe negative effect of heat stress has been reported on the physiology, health, production, welfare and behaviors of poultry birds. In heat-stressed chickens, oxidative stress, acid\u2013base imbalance, and suppressed immunity are some of the physiological changes accompanying heat stress. Oxidative stress is frequently caused by an imbalance between the generation of ROS and the efficacy of the antioxidant defence system . NumerouAn animal\u2019s physiological response to stress involves a variety of systems such as the neuroendocrine, immune system, circulatory and digestive systems. For instance, heat stress can impair the feeding process, nutrient absorption and utilization although water intake increases rapidly. Richards et al.  and MoreUnder heat stress conditions, hypoperfusion and an increase in blood flow to the skin surface occur as an adaptive response of the circulatory system to stabilize blood pressure and promote heat loss . HypoperImmunosuppressing effect of thermal challenge has been documented and this demonstrates that the neuroendocrine system plays an important role in the normal physiological functioning and homeostasis of birds during thermal challenge. The sympathoadrenal medullary axis is activated and controls homeostasis during the early phases of thermal challenge. A hormonal increase of catecholamines (epinephrine and norepinephrine) and glucocorticoids occurs in the adrenal medulla as a result of the impulse transmitted by the sympathetic nerves as a result of elevated temperature. Due to this, a decrease in muscle and liver glycogen and an increase in respiratory rate are experienced . The hypBlood glucose levels are raised by corticosteroid-stimulated gluconeogenesis. Corticosterone concentration changes have an impact on body composition, meat quality, and protein and lipid metabolism . ThyroidModern-day commercial broiler chickens have a rapid metabolic rate and greater heat production, thus prone to heat stress . EssentiPoor growth performance in poultry has been ascribed to heat stress, which disrupts immune and intestinal functions, causes endocrine dysfunction, and increases oxidative stress , 32, 33.Generally, exposing birds to adverse environmental temperatures results in a decline in thyroid activity and protein contents while increasing protein catabolism, metabolic acidosis and anaerobic glycolysis. By disrupting mitochondrial function, heat stress reduces aerobic metabolism, reduces aerobic metabolic activity, and increases glycolysis, which leads to an increase in muscular fat deposition . In homoThe decline in the blood thyroid hormone during heat stress serves as an adaptive mechanism to reduce maintenance energy requirements and metabolic heat production and increase fat deposition by disabling lipolysis to escape additional heat load . The demThe HPA axis is activated by thermal challenge, which also alters the neuroendocrine system\u2019s function in poultry. Elevated plasma corticosterone levels can also impact cellular transport, proliferation, cytokine release, and antibody formation . The incRecently, Yuanyuan et al.  indicateColiforms spp., Clostridium perfringens, and Escherichia coli while decreasing levels of Bifidobacterium and Lactobacillus spp., causing dysbiosis  is a promising tool in heat stress management and has been demonstrated to enhance the ability of birds to tolerate heat during their adult life. The application of thermal conditioning within the first few days of life is capable of decreasing body temperature at an older age  by enhanThe mechanism through which early thermal conditioning enhances heat tolerance is by inhibiting the production of an uncoupled protein and by enhancing HSP70 synthesis , 76. EmbGenetics has a role to play in response to heat challenge . GeneticMolecular markers have recently been developed to locate potential candidate genes connected to heat-tolerant features for chicken bird selection to increase resistance to heat stress . By incrIn chicken, the naked neck (Na), dwarf (Dw) and frizzle (F) genes are considered as candidates for temperature stress tolerance. They offer a practical, sustainable, and cost-effective solution to the heat stress challenge . UtiliziWhen compared to hens with normal plumage, homozygous chickens with the naked neck gene (Na) have roughly 40% less feather coverage, and heterozygous siblings have between 20 and 30% less , 94. WheAnother gene that could be targeted for producing heat-tolerant chickens is the frizzle gene. The frizzle gene (F) is a partially dominant gene that decreases feather intensity, thereby increasing the excessive heat-dissipating ability of birds . AccordiApproaches that emphasize heat tolerance and investigate the potential of indigenous chicken features such as dwarfism (dw), are important for thermoregulation . HomozygThe HSP70 gene polymorphisms may help poultry produce heat-tolerant capacity. In heat-tolerant chickens, polymorphisms occur in the coding and regulatory regions of HSP70 . HSP70 eNutritional manipulation is an acceptable method for the amelioration of heat stress effects in poultry and it is often applied with other management, environmental and genetic strategies . It invoTypically, feed consumption and nutrient intake decrease during heat stress in poultry, negatively affecting the performance and productivity of birds. Therefore, modifying the nutrient composition to improve the feed intake of chickens is an important consideration during heat stress. Feeding strategies that would maximize feed intake, minimize heat load, and alleviate the negative effects of heat stress in poultry are highly desirable for the nutritional management of birds under high temperatures . SyafwanFeed withdrawal, which is usually practiced for 6 to 8\u2009h per day during the hottest periods of the day can potentially minimize heat increment and the adverse effects of heat stress in poultry. Feed withdrawal limits heat load accretion occurring from metabolic heat generated during the processes of feed digestion, absorption, assimilation, and excretion. Thus, it is important to limit feeding to the cool hours of the day or preferably feed during the morning, evening, or nighttime to minimize the impacts of heat stress. The heat produced from feed consumption is high, such that feeding at 06:00\u2009h will cause a peak heat load between 09:00 to 11:00\u2009h. Therefore, feeding toward mid-day would accrue negative additive effects since the heat generated from feed utilization would coincide with the hottest part of the day, especially during the summer period in the tropical and subtropical regions . With feThe practice of wet feeding is considerably beneficial compared to feeding conventional dry mash/pellet feed since the birds may fail to consume sufficient quantities of the dried feed under heat-stress conditions. During the summer season, laying hens given wet feed had higher yolk index, shell weight, yolk percentage, moisture percentage, and feed conversion efficiency , 121, thUnder high temperatures, evaporation serves as a medium for heat loss in poultry. This mainly occurs during panting activity which helps dissipate internal heat through water evaporation from the moist lining of the respiratory tract during the breathing process . ChickenThe supply of cold water as against tap water influenced various physiological variables since it decreased the tonic immobility, body temperature, and blood levels of cholesterol, AST, and ALT, whereas, it increased the globulin, glucose, and total antioxidant capacity of the birds . ImportaSupplementing with fats and oil to increase the energy content of feeds is another method for the nutritional manipulation of heat-stressed poultry. Fats and oils have high energy value, lower heat increment, and are crucial to the absorption of fat-soluble vitamins, nutrient digestibility, and utilization. In heat-stressed animals, the dietary inclusion of fats and oils promotes feed intake, enhances productivity, and minimizes heat load . The impUltimately, increasing the fat content of the diet contributes to minimizing heat production since fat metabolism requires greater efficiency and produces lesser heat increment compared to protein or carbohydrate metabolism . CompareExposure to heat stress negatively affects the availability, transport, intestinal uptake, absorption, and utilization of amino acids , 131. ThAdditionally, some non-essential amino acids and derivatives including taurine, L-theanine, betaine, and L-citrulline have emerged as functional nutraceuticals for heat stress alleviation in poultry. These bioactive compounds possess potent biological properties that enable them to function as anti-stressors, antioxidants, anti-inflammatories, immunomodulators, and gut stimulants when supplied to heat-stress poultry . ImportaVitamins supplementation is a nutritional approach that is highly useful during heat stress in poultry. Importantly, most of these vitamins play crucial roles as anti-stressors, antioxidants, immunomodulators, anti-inflammatories, gut protectants, and growth promoters. It is known that chickens do not undergo significant endogenous synthesis of vitamins to meet nutritional needs, especially under heat stress conditions, since high ambient temperature may decrease their biosynthesis and retention, and alter metabolic functions . As suchThe combination of vitamins is considered more efficient than the use of an individual vitamin in alleviating heat stress in poultry. It has been demonstrated that supplementing the combination of vitamins C and E would prove more beneficial than their sole supply due to their synergism and antioxidant properties in combating heat stress . VitaminDecreased feed intake results in an unmet fulfillment of the mineral requirements of heat-stress birds. Minerals support various cellular and biological functions, sustain growth and productivity, improve nutrient utilization, boost immunity, and attenuate oxidative stress in heat-stressed poultry . ExposurZinc is a trace element that serves as a cofactor for several enzymes and its supplementation is essential since it cannot be stored within the body . Zinc elThe use of plant extracts has gained precedence as a nutritional strategy to ameliorate thermal stress in poultry owing to their ease of availability, potency, and numerous biological effects . In receThe thermoregulatory potentials of some herbs and plant products including ginger, turmeric, sweet wormwood, hot red pepper, thyme, rosemary, moringa, licorice, cinnamon, ginkgo, and resveratrol have been extensively reviewed in poultry. Dietary supplementation of these herbs is efficacious in ameliorating the negative effects of heat stress in poultry via enhancing the production performance, scavenging free radicals, promoting the antioxidant defense system, stimulating the immune system, regulating heat shock response, exerting antimicrobial effects, decreasing corticosterone release, improvements in nutrient digestibility, protecting intestinal health, regulating blood biochemical properties, influencing behavioral patterns and significantly reducing mortality of birds . In addiA multifaceted strategy for managing heat stress should be adopted in the poultry industry. Future trends in the poultry farming industry should be poised to change how heat stress is handled in chickens. Precision climate control, utilizing cutting-edge sensors and automated systems to dynamically adjust temperature, humidity, and ventilation within poultry houses, is needed to take center stage with the growing environmental temperatures. Targeted breeding techniques are needed to generate heat-resistant poultry breeds as a result of genetic developments, and specialized diets and nutritional supplements rich in nutrients that regulate body temperature are crucial instruments for boosting birds\u2019 resistance to heat stress. Innovative cooling techniques like evaporative cooling and radiant surfaces should also be explored. Furthermore, attention should focus on behavioral monitoring using AI-powered sensors to detect heat stress and the use of prediction algorithms to foresee heat stress and enable prompt responses. The genetic selection of heat-tolerant poultry breeds, precise climate control systems, creative cooling methods, and specialized nutritional interventions should also be fine-tuned to mitigate the influence of thermal challenges on poultry production.OMO: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing \u2013 original draft, Writing \u2013 review & editing. VU: Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing \u2013 original draft, Writing \u2013 review & editing. OO: Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Validation, Visualization, Writing \u2013 original draft, Writing \u2013 review & editing, Data curation. KT: Conceptualization, Methodology, Project administration, Resources, Validation, Writing \u2013 review & editing, Supervision. OEO: Conceptualization, Methodology, Project administration, Resources, Supervision, Validation, Writing \u2013 review & editing, Data curation, Formal analysis, Funding acquisition, Investigation, Software, Visualization, Writing \u2013 original draft."}
+{"text": "Plants differ widely in their ability to find tolerable climatic ranges through seed dispersal, depending on their life-history traits and habitat characteristics. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic review on seed dispersal mechanisms was conducted to elucidate plant seed movements amid changing environments. Here, the highest relative count of studies was found in Spain (16.47%), followed by Brazil (14.12%), and the USA (14.12%). The megadiverse, hotspot countries  and Africa  have very low to no data about the reviewed topic. The effects of land use changes, habitat degradation/disturbances, climate, and extreme weather conditions on seed dispersal mechanisms and agents had the highest share of studies across topics and countries. Plant diversity and distribution of anemochorous, endozoochorous, epizoochorous, hydrochorous, myrmecochorous, and ornithochorous species are seriously affected by changing environments due to altered long-distance seed dispersal. The fruit types commonly associated with endozoochory and ornithochory are species with achene, capsule, drupe, fleshy, and nut fruits/seeds, whereas achene, capsule, samara/winged seeds are associated with anemochory. The present review provides a summary of evidence on how plants are affected by climate change as populations of dispersal vectors decline. Finally, recommendations for further study were made based on the identified knowledge gaps. Many  regimes . One waySeed dispersal, defined as the transport of seeds, spores, or propagules away from the mother plant, is one of the key processes in ecology and biodiversity conservation. Dispersion of seeds is the first spatial demographic process that can determine potential range shifts . It is aHowever, the literature on seed dispersal is focused on the dispersal syndrome hypothesis (DSH) or co-adapted syndrome, which states that fruits and dispersal vectors co-evolved  influencing the foraging strategies of dispersers . A largConsequently, a systematic review of the current state of the literature about seed dispersal mechanisms in a changing environment was conducted to help us understand how plants keep up with climate change as populations of dispersal vectors decline. The obtained literature was summarized and analyzed to give insight into (1) the geographical distribution of studies about seed dispersal in a changing environment; (2) how the changing environment affects seed dispersal; (3) whether changing environment reduces or enhances plants dispersal abilities; (4) seed/fruit dispersal-related traits, and (5) research directions. The present review is relevant to understanding plant seed movements in the face of anthropogenic climate change.The literature search returned 10,651 articles from three databases  and direct search. After the selection process, only 118 peer-reviewed articles were left for further analysis. The present systematic review found the highest number of studies in Spain (16.47%), followed by Brazil (14.12%), and the USA (14.12%) . AustralThe effects of land use changes, habitat degradation/disturbances, climate, and weather on seed dispersal had the highest share of studies across topics and countries . Under lStudies about the effects of topography , drought/water stress, and air movement  ranked second in the relative count of topics. Natural fires and floods and seed dispersal patterns had the lowest relative count of studies across countries.Results of the present systematic review revealed the most and least frequently studied dispersal modes depending on fruit type . Here, tTristerix corymbosus, Ficus carica, Duckeodendron cestroides. Ornithochorous (bird-dispersed) and endozoochorous species typically have the same fruit types. Contrarily, fruits or seeds of wind-dispersed species  are generally achene, capsule, or samara/winged.In the reviewed studies, the commonly associated fruit types with endozoochory or animal-mediated seed dispersal are species with achene, capsule, drupe, fleshy, and nut fruits/seeds, such as those in Overall, the seed dispersal modes as affected by the ever-changing environment are summarized in Seed dispersal is critical for plant population recruitment, gene flow, long-term survival, and other ecological processes amid climate change ,25. ThisToxicodendron radicans (L.) Kuntze [Here, land use changes, habitat degradation/disturbances, and climate and extreme weather conditions have a significant influence on seed dispersal mechanisms of various groups of plants across different ecosystems in temperate and tropical regions  33,34,3,36. Prev) Kuntze ,41.Increasing habitat fragmentation has shown direct and indirect effects on seed dispersal patterns, including the negative effect of connectivity on seed dispersal potential and reduced dispersal abundance ,43,44. HThe fate of biodiversity will be heavily influenced by species\u2019 ability to adapt to climate change, yet very little is known about how many species will disperse in a changing environment . A modelThe impacts of climate change directly and indirectly affect seed dispersal by altering the biophysical environment  and plant/seed traits by means of temperature, rainfall, wind speed, windstorms, etc. . AccordiDispersal potential is one of the factors influencing the migration of plant species . This hiOrnithochorous species also aid plant species in adapting to climate change through long-distance seed dispersal, although bird migration to disperse seeds is potentially limited to cooler latitudes . The autHydrochory , which is common in low-lying areas that are frequently flooded, is one of the adaptations of plants in changing environments ,88. The E. tetrodonta). Myrmecochory seed dispersal, which involves ants collecting and transporting seeds with elaiosomes (rich in lipids and proteins found in fleshy fruits that are attached to the seeds), is a dominant dispersal mode in sclerophyll habitats [Ants are one of the dominant terrestrial organisms with high seed dispersal capacities through myrmecochory, which also plays an important role in shaping plant communities. Climatic warming, however, alters ant\u2013plant seed dispersal mutualism , therebyhabitats . These hhabitats . Thus, chabitats ,96, partEndiandra species revealed that large-fruited species had lower geographical ranges than small-fruited species [Seed dispersal responses to changing environmental conditions can be influenced by plant traits, specifically fruit and seed morphological and biochemical characteristics. Studies have suggested that traits such as fruit or seed size, color and odor influence the way dispersers choose them as food , thereby species . Such a  species ,98. Seco species . Moreove species ,101. ThiMutualistic seed-dispersal relationships exist also between a range of nut-producing plants and animals  that scatter their nuts in the soil . HoweverMature, dehiscent fruits, such as capsule, silique, follicle, and legume, have dead pericarp that is dry and hard, which helps in long-term storage of biologically active proteins, nutritional elements , and other substances . These sSenecio species varied significantly with changes in the site, surroundings, height, time of release, direction, and achene type, indicating that distances of dispersal can be influenced by local conditions of humidity, wind, and vegetation structure [Indehiscent achenes are also dispersed by animals through adherence to the body of the dispersers. Hence, different sizes and structures of achenes can influence their dispersal over long distances. For example, the pappus geometry of achenes affects the aerodynamic properties of the seeds and responses to turbulence and humidity, which influence seed dispersal efficiency . A studytructure .The effects of environmental changes were largely unrepresented in some seed dispersal vectors , which can be attributed to geographical, technical, and logistical constraints. For example, there are fewer scientists specializing in ants or insects in general compared with other research fields. Studying seed dispersal ecology  is also difficult due to seed dispersal dependence, environmental heterogeneity, and interdependent processes operating at various spatial and temporal scales . More reA systematic literature review (SLR) was performed from September to December 2022 to collect relevant literature on seed dispersal processes in a changing climate, and included all records published between 1990 and 2022. Following the literature search strategy typically utilized in biological science research, the SLR returned an initial total of 10,651 articles from ScienceDirect, PubMed, and Google Scholar search databases. These databases are among the most prominent peer-reviewed original article search engines, and they are frequently cited in published SLR articles across disciplines . Some arFirst, a search test was run to narrow the search keywords. The final search phrases were constructed, with the most significant keywords in each set of search terms, namely seed dispersal, spore dispersal, propagule dispersal, climate change, and changing climate . BooleanThe articles were assessed for inclusion in the review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for article screening and appraisal. The screening procedure is shown in Using the extraction criteria listed in Only peer-reviewed, freely available publications written in English, at least indexed in Scopus, and published between 1990 and 2022 were included in the present systematic review. Other materials such as perspective papers, editorial notes, commentary, news articles, brochures or technical manuals were not considered in the present systematic review. The present SLR relies on the three most popular databases  for peer-reviewed original articles for the identification of potentially eligible studies.This systematic review summarizes the existing understanding of the projected effects of changing environments on the complex processes of seed dispersal across regions. Results revealed that global climate changes, by means of altering air temperature, rainfall, wind speed, the biophysical environment  and plant/seed traits, may negatively affect the seed dispersal patterns of vertebrate-dispersed plants, thereby influencing the fate of local and global biodiversity. The six groups of plants whose long-distance seed dispersal are seriously affected by changing environments include anemochorous, endozoochorous, epizoochorous, hydrochorous, myrmecochorous, and ornithochorous species. The present review also found that fruit/seed traits control the fate of seed dispersal depending on environmental conditions. Overall, the findings of the present systematic review provide a summary of evidence on how plants keep up with climate change as populations of seed dispersers decline. However, increased research investments in the less-studied seed dispersal vectors in megadiverse, hotspot countries are recommended to enhance understanding of how plants would keep up with climate change. Future research endeavors will also benefit significantly from investigations that advance interdisciplinary perspectives and collaboration to study seed dispersal processes across landscapes, plant growth forms, and taxa of dispersers amid climate change. Lastly, all the recommendations provided will be critical for evidence-based biodiversity conservation and informed policy formation in changing ecosystems."}
+{"text": "In the original published version of this article, an author was replaced with another during production. The original author list has been reinstated (given below).Elahe Sasani, Fares Bahrami, Mohammadreza Salehi, Farzad Aala, Ronak Bakhtiari, Alireza Abdollahi, Aleksandra Barac, Mahsa Abdorahimi, Sadegh Khodavaisy.The authors apologize for the errors. Both the HTML and PDF versions of the article have been updated to correct the errors.The authors declare no conflict of interest."}
+{"text": "Aging is a progressive and irreversible pathophysiological process that manifests as the decline in tissue and cellular functions, along with a significant increase in the risk of various aging-related diseases, including metabolic diseases. While advances in modern medicine have significantly promoted human health and extended human lifespan, metabolic diseases such as obesity and type 2 diabetes among the older adults pose a major challenge to global public health as societies age. Therefore, understanding the complex interaction between risk factors and metabolic diseases is crucial for promoting well-being and healthy aging. This review article explores the environmental and behavioral risk factors associated with metabolic diseases and their impact on healthy aging. The environment, including an obesogenic environment and exposure to environmental toxins, is strongly correlated with the rising prevalence of obesity and its comorbidities. Behavioral factors, such as diet, physical activity, smoking, alcohol consumption, and sleep patterns, significantly influence the risk of metabolic diseases throughout aging. Public health interventions targeting modifiable risk factors can effectively promote healthier lifestyles and prevent metabolic diseases. Collaboration between government agencies, healthcare providers and community organizations is essential for implementing these interventions and creating supportive environments that foster healthy aging. While rEffective strategies must be implemented to promote healthy aging and prevent metabolic diseases. This involves understanding the underlying risk factors and their impact on public health, which can then inform the development of targeted interventions and policies that encourage healthier lifestyles. Public health initiatives can address these risks to promote healthier choices among the population by identifying modifiable environmental and behavioral factors .This review article aims to explore the intricate relationship between metabolic diseases and healthy aging by examining the environmental and behavioral risk factors contributing to their onset and progression. By analyzing current research and existing literature, we will delve into the multifaceted nature of these diseases, considering factors such as diet, physical activity, stress, sleep patterns, and socioeconomic determinants. Furthermore, we will explore the potential of public health interventions to mitigate the impact of metabolic diseases and promote healthy aging .2.2.1.Aging is a significant risk factor for developing and progressing metabolic diseases in older adults due to various physiological changes that occur with age , 20. TheFurthermore, aging is associated with a higher prevalence of additional risk factors for metabolic diseases. Reduced physical activity, sedentary behavior, underlying genetic predispositions, and cumulative exposure to environmental factors over a lifetime increase risk in older adults , 35. Whe2.2.Metabolic diseases, particularly diabetes and hypertension, significantly impact aging by accelerating age-related decline in health and functionality , 20. Bot3.Environmental pollutants, including air pollutants, pesticides, heavy metals, and endocrine-disrupting compounds (EDCs), pose substantial risks to metabolic health and can accelerate aging , 50, 51.EDCs are present in various consumer products and can interfere with the production, transport, or metabolism of hormones. It is estimated that there are more than one thousand different EDCs. EDCs disrupt hormonal action, while metabolic disruptors affect metabolism. It is crucial to clarify that not all metabolic disruptors are EDCs. EDCs specifically pertain to substances that interfere with the hormonal aspects of metabolism , 53\u201356. The term \u201cexposome\u201d encompasses both external and internal environmental factors that impact human health. It includes the ecto-exposome, which pertains to external environmental influences, and the endo-exposome, which relates to the immediate adjacent extracellular environment. Both the ecto-exposome and the endo-exposome are conditions that support cell survival and organ/system function. According to reports, persistent organic pollutants, also known as \u2018EDCs,\u2019 interfere with the endocrine system and are found in the environment, causing lifelong exposure in certain populations , 58. Occ4.4.1.Diet plays a significant role in the onset and progression of metabolic diseases, with varying dietary habits yielding distinct impacts on these conditions. A well-balanced diet, rich in fruits, vegetables, whole grains, lean meats, and healthy fats, contributes to weight maintenance, blood sugar regulation, lowered cholesterol levels, and reduced risk of chronic diseases . SpecifiFirmicutes and a decrease in Bacteroidetes are commonly observed in these conditions (Enterobacteriaceae, which includes potentially harmful species such as Escherichia coli, is often found to increase in metabolic diseases (Akkermansia muciniphila, known to help maintain the health of the gut lining and Bifidobacterium, a genus often used in probiotics known for its health-promoting effects (Moreover, diet significantly influences gut microbiota homeostasis, impacting energy metabolism and fat storage. Imbalances in gut flora, or dysbiosis, can lead to increased energy extraction and fat storage, contributing to obesity and diabetes , 80. Spenditions , 82. In diseases . These b effects . These b effects , 86. Add effects , 88. Und4.2.Declining activity and unhealthful changes in body composition are linked to aging. Physical activity and sedentary behavior have significant impacts on metabolic health.Exercise prevents many chronic diseases and mitigates certain undesirable physiological changes brought on by aging. Interestingly, the impact of physical training on the reward system is a topic of growing interest. Engaging in regular physical activity reduces the motivation to seek unhealthy rewards like high-fat, sugary foods, and drugs. Additionally, it changes attitudes toward overeating, making individuals more mindful of their food choices. This transformation promotes healthier lifestyle preferences , 90.Regular exercise also promotes glucose metabolism by increasing cells\u2019 sensitivity to insulin, reducing the risk of developing T2D characterized by IR . EngaginThe World Health Organization recommends that adults engage in at least 150\u2009min of moderate-intensity aerobic exercise or 75\u2009min of vigorous exercise per week, or a combination of both , 102. ItConversely, a sedentary lifestyle characterized by prolonged sitting or inactivity is associated with an elevated risk of metabolic diseases, including obesity, T2D, and cardiovascular problems . Sedenta4.3.Tobacco smoking significantly elevates the risk for metabolic diseases and negatively affects the aging process. Cigarette smoke contains harmful compounds such as nicotine, carbon monoxide, and carcinogens that damage tissues and organs throughout the body. Smoking is linked to metabolic diseases like T2D, IR, obesity, and CVD, primarily due to nicotine\u2019s contribution to IR and impaired glucose metabolism . In addi4.4.Alcohol consumption\u2019s impact on metabolic health hinges on individual factors and the quantity consumed. While moderate consumption might confer some cardiovascular benefits, excessive and chronic alcohol intake poses severe risks to metabolic health, particularly in aging populations . Heavy a4.5.Sleep quality and patterns profoundly affect metabolic health and the aging process. Chronic sleep deprivation and disturbances are linked to increased metabolic disease risk and accelerated aging-related complications . Insuffi4.6.Psychological stress and mental health significantly influence metabolic diseases and aging. Stress, depression, anxiety, and other mental health conditions are linked with metabolic diseases and can hasten the aging process . Stress 5.Healthy aging is the focus of the World Health Organization\u2019s aging policy by 2030 . The devThese interventions should tackle determinants of metabolic diseases such as unhealthy dietary patterns, sedentary lifestyles, tobacco use, and environmental factors to effectively reduce their incidence and complications , 124. LoPromoting physical activity or community volunteer work through community initiatives, workplace wellness programs, and accessible recreational facilities can improve metabolic health by maintaining healthy weight and enhancing insulin sensitivity. Infrastructure that prioritizes active transportation, green spaces, and safe recreational areas can further promote activity and reduce sedentary behavior , 159. AdThis article has certain limitations. It offers a comprehensive overview of metabolic diseases, but it fails to carry out in-depth analysis of the molecular processes associated with healthy aging and account for individual differences and subtle nuances, such as genetic factors and socio-economic circumstances. These elements play a significant role in the risk and progression of these diseases. Moreover, due to the complexity of the system and confounding variables, determining the causality between environmental/behavioral factors and metabolic diseases presents a challenge. For a complete understanding of metabolic diseases and healthy aging, further research and personalized assessments are critically essential.6.In summary, this review article emphasizes the important contribution of environmental and behavioral risk factors to the emergence of metabolic diseases and healthy aging. Key risk factors, including diet, physical activity, smoking, alcohol consumption, environmental pollutants, and sleep patterns, have been identified and linked to various metabolic disorders and age-related complications. The findings underscore the importance of public health interventions in addressing metabolic diseases and promoting healthy aging. Further research is needed to understand risk factor interactions, mechanisms, and intervention effects. Addressing metabolic diseases is vital for healthy aging, reducing chronic conditions, and improving quality of life. A holistic approach combining behavior changes, supportive environments, and public health interventions can lead to a healthier future with lower metabolic disease rates and improved well-being in aging populations.KZ: Conceptualization, Data curation, Methodology, Writing \u2013 original draft. YuM: Conceptualization, Data curation, Methodology, Writing \u2013 original draft. YL: Conceptualization, Data curation, Investigation, Methodology, Writing \u2013 original draft. YS: Conceptualization, Data curation, Investigation, Writing \u2013 review & editing. GX: Data curation, Investigation, Writing \u2013 review & editing. YaM: Data curation, Investigation, Conceptualization, Writing \u2013 review & editing. XS: Conceptualization, Funding acquisition, Supervision, Writing \u2013 review & editing. CK: Conceptualization, Data curation, Investigation, Methodology, Supervision, Validation, Writing \u2013 review & editing."}
+{"text": "For many individuals, asthma has great impact on their everyday life, not least in terms of medication treatment and disease management. Therefore, it is important to evaluate recommended treatments on an individual level. In that respect, estimations of health-related quality of life (HRQL) function as an essential health outcome, as they capture personal perspectives and experiences of everyday life with a chronic disease such as asthma. The aim was to identify determinants of health-related quality of life in adult individuals with asthma.Participants with asthma (n=487) derived from a population-based study completed questionnaires on asthma control, emotional status, adherence and HRQL. Additionally, data on the Five-factor model personality traits: neuroticism, extraversion, openness, agreeableness, conscientiousness were gathered. Data were statistically analyzed using t-tests, bivariate correlations and multiple regressions.Participants, who perceived their asthma as being poorly controlled , reported both poorer emotional status and HRQL. Participants with poor physical HRQL seemed to have both poorer emotional status and asthma control. Moreover, participants with low levels of Extraversion were more likely to perceive their physical HRQL as worse. Participants with poor mental HRQL reported poorer emotional status and adherence to asthma medication as well as poorer asthma control. Additionally, participants with high levels of neuroticism and low levels of extraversion, agreeableness and/or conscientiousness perceived their mental HRQL as worse. Asthma control was identified as predictor for physical HRQL. Emotional status, adherence to asthma medication, asthma control, neuroticism and agreeableness were identified as predictors for mental HRQL.The current findings argue that in addition to medical examinations, we also need to consider asthmatics emotional status, adherence behavior, asthma control but also personality characteristics in evaluations of their health outcome."}
+{"text": "Airway responses to injury, noxious stimuli, or microbes lead to leukocyte recruitment for host defense. As leukocytes respond, they interact with lung resident cells and can elaborate specific mediators that are enzymatically generated from polyunsaturated fatty acids via transcellular biosynthesis. These bioactive, lipid-derived, small molecules serve as agonists at specific receptors and are rapidly inactivated in the local environment. This review will focus on the biosynthesis, receptors, cellular responses, and"}
+{"text": "Globally, 210 million women become pregnant each year, and 130 million births occur. However, 1,600 women die every day worldwide from childbirth; 99% of these deaths occur in the developing world. Annually, 10 million women experience related illness.Antenatal care varies worldwide. Hemorrhage, infection, abortion, hypertension, and obstructed labor contribute to maternal illness and death. Many infectious diseases complicate antepartum care, including malaria, HIV infection, pneumonia, tuberculosis, and herpesvirus infection. Pregnancy appears to increase the severity of malaria. Recent strategies to control malaria in pregnancy include preventive treatment with antimicrobial drugs, insecticide-treated nets, and rapid diagnosis and treatment.Throughout the world, 42 million adults and children are living with HIV/AIDS, with the largest number in sub-Saharan Africa (29.4 million). Approximately 27% of these cases are in women and adolescent girls who have been exposed through heterosexual transmission, injection drug use, sex with an injection drug user, or other unspecified risk. Eighty percent of perinatal transmission is from intrapartum transmission.Haemophilus influenzae, group A streptococcus, malaria, tuberculosis, influenza, respiratory syncytial virus, and varicella-zoster virus. Maternal or neonatal death may occur as well as intrauterine growth retardation.Pneumonia of any cause is less well tolerated in pregnancy. Ventilatory capacity is decreased, and the fetus may suffer hypoxemia and acidosis. Factors that can cause or lead to pneumonia in pregnancy include common viral upper respiratory infection, severe acute respiratory syndrome (SARS)\u2013associated coronavirus, mycoplasma, chlamydia, Tuberculosis in pregnancy doubles the risk for prematurity and low birth weight. The risk for perinatal death increases threefold, and the risk of maternal illness increases fourfold. Miscarriage and intrapartum complications increase markedly. Antenatal care in early pregnancy permits diagnosis and treatment of many of the diseases discussed above and the management of their complications.A number of risk factors exist for postpartum infections, including prolonged and obstructed labor, frequent vaginal examinations, prelabor rupture of the membranes, preterm birth, cesarean section, episiotomies, vacuum extractions, forceps delivery, maternal anemia, micronutrient deficiencies, poor maternal hygiene, and associated sexually transmitted diseases. Maternal illness from postpartum infections includes pelvic inflammatory disease, chronic pelvic pain, dysmenorrhea, menorrhagia, and infertility. Prevention strategies for postpartum infections include antenatal care, skilled delivery, and appropriate postpartum care. Additional strategies are minimum manipulation, high level disinfected or sterile gloves for examination, and avoiding unnecessary procedures.Challenges in low-resource settings include lack of standards and guidelines, inappropriate training, inadequate supervision, and insufficient supplies. Infection prevention criteria should include adequate running water, cleanliness of all areas, appropriate sharps disposal, correct preparation and use of antiseptics and decontamination, correct cleaning and preparation of instruments, appropriate waste collection and disposal, and good hand washing practices.Gender dynamics affect transmission in the community and the empowerment of nursing staff to initiate infection control. Pregnant women and the maternity care system have special vulnerabilities; however, data disaggregated by sex and pregnancy status are lacking. The outbreaks of Ebola hemorrhagic fever and SARS have some aspects in common: both have gender-related transmission patterns; have been amplified in hospital settings; were halted by better infection control measures, isolation, and contact tracing; and lack data about pregnancies, despite nosocomial outbreaks in maternity clinics.Ebola hemorrhagic fever is transmitted by contact with secretions or organs of infected people or animals with infected cadavers of people or animals who died. Patient isolation and contact tracing, barrier nursing methods, and safe burial practices have been used successfully to halt some outbreaks. The largest outbreaks have been amplified in healthcare settings. Most healthcare workers affected have been nurses.The risk for Ebola hemorrhagic fever transmission is high during pregnancy. Ebola hemorrhagic fever causes spontaneous abortions with heavy bleeding in the first and second trimesters. Transmission in maternal healthcare settings was important in two of the three largest outbreaks in Yambuku and Kikwit. Recommendations for pregnant women when an Ebola hemorrhagic fever outbreak occurs include the following: surveillance of maternity clinics; careful screening of maternity patients to isolate those with complications suggestive of Ebola hemorrhagic fever; empowerment of maternity clinics staff and traditional midwives to protect themselves; and a policy on whether pregnant workers should work on Ebola hemorrhagic fever isolation wards.Overall, 53% of SARS patients were women. The death rate is higher in men than in women. More than 21% of patients were healthcare workers, which contributed to the increased number of infected women. Little information exists on SARS and pregnancy. The World Health Organization has created an informal network of clinicians to pool experience and knowledge, develop a clinical database, and share infection control experiences."}
+{"text": "The relationship between autonomic nervous system (ANS) dysfunction and Familial Mediterranean Fever (FMF) is controversial. Heart rate variability (HRV) is a powerful, simple and reliable technique for the evaluation of ANS dysfunction. Recently, we reported on normal HRV parameters, suggestive of normal ANS function, in patients with uncomplicated FMF. Also, we reported on an association between decreased HRV parameters (suggestive of ANS dysfunction), and amyloidosis of FMF, particularly at a progressive stage.The aim of the current study was to evaluate whether FMF patients, who do not respond to colchicine treatment, and thereby endure persistent inflammation, have abnormal ANS function, using the HRV tool.Twenty-four FMF patients suffering from recurrent FMF attacks despite treatment with a maximal colchicine dose, were selected for the study. Electrocardiogram was measured under strict conditions and HRV parameters were calculated. Results were compared with age- and sex- matched unaffected controls.No statistically significant difference was found between the groups in any determined HRV parameter: maximal RR, minimal RR and average RR intervals, standard deviation of RR interval, square root of the mean squared differences of successive RR intervals, HRV triangular index, NN50, pNN50, and power spectral analysis. Nevertheless, a statistically non-significant trend towards lower HRV parameters was observed in the colchicine non-responders group.Although a small difference in HRV parameters cannot be entirely excluded in the current study design, FMF patients, in whom colchicine did not provide adequate symptomatic relief and who did not develop amyloidosis, seem to have HRV parameters similar to those of healthy subjects, suggestive of normal ANS function.None declared."}
+{"text": "From 1997-2007, the proportion of individuals presenting for HIV care who were \u226550-years-old increased from 17% to 27% . The median CD4 count among \u226550 year-olds was consistently lower than younger adults. The interaction of age group and calendar year was significant  with both age groups experiencing modest annual improvements over time , after adjusting for sex, race/ethnicity, HIV transmission risk group and cohort; however, increases in the two groups were similar after 2000. A greater proportion of older individuals had an AIDS-defining diagnosis at, or within three months prior to, first presentation for HIV care compared to younger individuals . Due to the increasing proportion, consistently lower CD4 counts, and more advanced HIV disease in adults \u226550-year-old at first presentation for HIV care, renewed HIV testing efforts are needed.We assessed CD4 count at initial presentation for HIV care among \u226550-year-olds from 1997-2007 in 13 US and Canadian clinical cohorts and compared to <50-year-olds. 44,491 HIV-infected individuals in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) were included in our study. Trends in mean CD4 count (measured as cells/mm The proportions who had an AIDS-defining diagnosis at first presentation for care decreased from 1997 to 2007 in both age groups (Table Our study has three important findings: 1) the proportion of individuals at first presentation for care who are aged \u226550 years has increased over the past 11 years; 2) older individuals at first presentation of care consistently had a lower median CD4 count compared to younger individuals; and 3) a greater proportion of older individuals have an AIDS-defining diagnosis at, or within three months prior to, first presentation for HIV care compared to younger individuals.The increase in the proportion of individuals who were \u226550 years at first presentation for care has implications for effective HIV management and survival for older infected individuals. Older individuals initiating HAART have a decreased immune response -18 and m3 increased in all age groups, however, the proportion was approximately 10% lower among \u226550-year-olds. This suggests the potential for greater HIV treatment initiation guideline adherence if effective testing and treatment interventions target older individuals.The estimated mean annual increase in CD4 count for individuals aged < and \u226550 years is small and likely of little clinical relevance as the within-patient variation in CD4 counts is ~25%. More importantly, the annual median CD4 count is still well below the CD4 recommended for initiation of HAART . The proFinally, our data suggest older individuals are entering into care with advanced HIV disease. The CDC recently reported an increase in the proportion of \u226550-year-olds in the US who had a first HIV diagnosis within a year before AIDS diagnosis compared to 30-< 50-year-olds ; the PubThere are limitations to our study, including our lack of data regarding time since seroconversion. We chose to stratify the data using a cut-off of 50 years. Although there were more than enough individuals for additional stratification at younger ages, additional stratification at older ages was not possible.While all age groups are experiencing modest improvements in CD4 count at presentation over time, older individuals have not \"caught up.\" These data suggest that targeted renewed prevention and testing strategies are needed in all age groups, including those \u226550-years-old.Dr. Gebo reports receiving consulting fees from Tibotec and grant support from Johns Hopkins University Richard Ross Award, and Agency for Healthcare Research and Quality; Dr. Klein reports receiving consulting fees from GlaxoSmithKline, Abbott, Pfizer, and Merck, lecture fees from Abbott, Gilead, Tibotec, Bristol-Myers Squibb, and GlaxoSmithKline and research support from Canadian Institutes of Health Research/Fonds de la recherche en sant\u00e9 du Qu\u00e9bec, Canadian HIV Trials Network, Ontario HIV Treatment Network, and Schering Plough Canada; Dr. Hogg reports receiving payment from a commercial entity that sponsored his study and grant support from Merck; Dr. Horberg reports receiving grant support from Pfizer, Merck, and Kaiser Permanente Community Benefits; Dr. Saag reports receiving consulting fees from Ardea Biosciences, Avexa, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Monogram Biosciences, Pain Therapeutics, Pfizer, Progenics, Tibotec, Tobira Therapeutics, and Vicro and research support from Avexa, Achillion Pharmaceuticals, Boehringer-Ingelheim, Merck, Pfizer, Progenics, and Tibotec; Dr. Kitahata has served as a consultant to Gilead Sciences; Dr. Eron reports receiving consulting fees from Tibotec, Bristol-Myers Squibb, Merck, GlaxoSmithKline, Avexa, Tobira and Virco Labs, lecture fees from Roche, Bristol-Myers Squibb Virco Labs, and grant support from GlaxoSmithKline, Merck, and TaiMed; Dr. Gill reports receiving consulting fees from GlaxoSmithKline, Gilead, Abbott, Merck, Boehringer-Ingelheim, Thera, Tibotec, and Pfizer and grant support from GlaxoSmithKline, Abbott, Canadian Institutes of Health Research, Gilead, Tibotec, and Pfizer; Dr. Rodriguez reports receiving consulting fees from Gilead and Bristol-Myers Squibb, lecture fees from Bristol-Myers Squibb, and grant support from STERIS; Dr. Sterling reports receiving grant support from Pfizer; Dr. Deeks reports receiving grant support from Merck, Gilead, Bristol-Myers Squibb, and Pfizer; Dr. Collier reports receiving consulting fees from Merck, Pfizer, and GlaxoSmithKline, equity ownership/stock options in Bristol-Myers Squibb and Abbott, and grant support from Schering-Plough, Tibotec-Virco, Gilead, Boeringer-Ingelheim and Merck; Dr. Benson reports receiving consulting fees from GlaxoSmithKline, Pfizer, Merck, and Achillion, and grant support from Gilead; Dr. Silverberg reports receiving grant support from Pfizer and Merck; Dr. Rachlis reports receiving honoraria and research support from Bristol Myers Squibb, GlaxoSmithKline, Pfizer, Gilead, Tibotec, Schering-Plough, Merck, Theratechnologies, Abbott and the Ontario HIV Treatment Network; and Dr. Moore reports receiving consulting fees from Bristol-Myers Squibb and GlaxoSmithKline, lecture fees from Gilead, and grant support from Pfizer, Merck, Gilead, and Agency for Healthcare Research and Quality.Drs. Althoff, Gange, Brooks, Rourke, Bosch, Martin, Jacobson, Kirk, Napravnik, Goedert, Buchacz, Thorne, McKaig and Justice declare they have no conflict of interest.KNA, KAG, SJG, RDM, and ACJ designed the study, interpreted the data, and drafted the manuscript; KNA also conducted the analysis. MBK, JTB, RSH, RJB, MAH made substantial contributions to the design of the study, interpretation of the data, and revised the manuscript critically for important intellectual content. MSS, MMK, JJE, SN, SBR, MJG, BR, TRS, SGD, JNM, LPJ, SDK, ACC, CAB, MJS, JJG, RGM, JT, AR oversee acquisition of data and revised the manuscript critically for important intellectual content. All authors approved the final manuscript."}
+{"text": "Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease affecting various organs, with lupus nephritis being one of the most important and common serious manifestations. Antimalarials (AM) are one of the many immunomodifying medications used in SLE, however less known is its role in lupus nephritis. Our study examined the history of AM use, theorized mechanisms of action, efficacy in SLE, in particular in lupus nephritis, safety in pregnancy, and overall safety profile.We conducted a search of all relevant literature using Medline (OVID and EMBASE) and PubMed. We included randomized-controlled trials, observational cohort studies, and case-control studies. Case reports were only included for the adverse effect profile of AM.\u2022AM use benefits patients with SLE including improving survival, reducing disease activity, new organ involvement, integument damage, risk of infection, risk of thrombosis, and possible cardioprotective and anti-malignancy effects.\u2022In lupus nephritis, AM use improves time to end-stage renal disease, disease activity, flare rates, disease remission as an adjunct with other immunomodifying drugs, and reduced cumulative corticosteroid use.\u2022AM are safe to use and should be continued in pregnant SLE patients for its beneficial effects of reducing disease activity, flare rates, cumulative corticosteroid requirements, and possible reduction in development of cardiac neonatal lupus erythematosus.\u2022AM have a good safety profile, with gastrointestinal symptoms being the most common. Careful regular monitoring for retinopathy is recommended as per American Academy of Ophthalmology.\u2022In patients with renal disease, caution with dosing and careful monitoring for adverse events should be taken.AM are medications which confer many benefits to patients with SLE and lupus nephritis, with a good safety profile.Senq-J. Lee: None; Earl D. Silverman: None; Joanne M. Bargman: None."}
+{"text": "Epileptic encephalopathy can be induced by inborn metabolic defects that may be rare individually but in aggregate represent a substantial clinical portion of child neurology. These may present with various epilepsy phenotypes including refractory neonatal seizures, early myoclonic encephalopathy, early infantile epileptic encephalopathy, infantile spasms, and generalized epilepsies which in particular include myoclonic seizures. There are varying degrees of treatability, but the outcome if untreated can often be catastrophic. The importance of early recognition cannot be overemphasized. This paper provides an overview of inborn metabolic errors associated with persistent brain disturbances due to highly active clinical or electrographic ictal activity. Selected diseases are organized by the defective molecule or mechanism and categorized as small molecule disorders  and large molecule disorders . Details including key clinical features, salient electrophysiological and neuroradiological findings, biochemical findings, and treatment options are summarized for prominent disorders in each category.  Inherited metabolic epilepsies are disorders that, while individually rare, are in aggregate a substantial clinical portion of child neurology, as well as a complex field of knowledge for physicians, investigators, and students to tackle. A subset of these disorders can lead to the development of epileptic encephalopathy, that is, a brain disturbance due to highly active clinical or electrographic ictal activity. The epileptologist may view these from the viewpoint of syndromic phenotypes such as early myoclonic encephalopathy, early infantile epileptic encephalopathy, infantile spasms, and myoclonic epilepsies. They have various degrees of treatability at present, with some requiring prompt diagnosis and intervention to avoid otherwise catastrophic outcomes. Careful consideration of metabolic disorders in patients presenting with epileptic encephalopathy is therefore warranted, and to this end, we hope a review may be helpful.This paper provides an overview of inborn metabolic errors associated with epileptic encephalopathy, summarizing key clinical features and underlying biochemistry, salient electrophysiological and neuroradiological findings, and primary treatment options where appropriate. Examples of specific disorders are discussed, with full listings of the multiple enzyme defects and diseases in particular categories presented in tables. The range of inherited metabolic disorders has been organized by the category of molecules or the biochemical process involved: for example, small molecule disorders include dysfunction involving amino, organic, or fatty acids, neurotransmitters, the urea cycle, vitamers and cofactors, and disorders of the mitochondria. Large molecule diseases cover defects in glycosylation, lysosomal and peroxisomal function, and leukodystrophies.Amino acidopathies and organic acidemias, resulting from disorders in amino or fatty acid catabolism, present with seizures and cognitive, behavioral, or motor disturbances resulting from the accumulation of toxic intermediaries, or possible structural damage . Some maThe finding of elevated methylmalonic acid can be caused by a number of distinct disorders including defects in the vitamin B12-related enzymes cobalamin A, B, C, or D and methylmalonyl CoA mutase (MUT). Early myoclonic encephalopathy, as well as other epilepsies and epileptic encephalopathies, has been associated with this finding. The most common methylmalonic acidemia involving cobalamin is cobalamin C deficiency ; individPropionic acidemia (PA) is caused by defects in the enzyme propionyl CoA carboxylase and commonly presents with lethargy, vomiting, metabolic acidemia, and sometimes hyperammonemia . A severEthylmalonic encephalopathy is usually lethal in infancy or early childhood and has a severe presentation including seizures, brain structural malformations, neurodevelopmental regression, pyramidal and extrapyramidal symptoms, chronic diarrhea, and dermatological findings including petechiae and acrocyanosis. MRI has shown frontotemporal atrophy, enlargement of the subarachnoid spaces, and basal ganglia T2-weighted hyperintensities . EEGs maWhen untreated, dysfunction of the enzyme 3-hydroxy-3-methylglutaryl CoA lyase (which cleaves 3-hydroxy-3-methylglutaryl CoA into acetyl CoA and acetoacetate) leads to metabolic acidosis with absent ketone production, lactic acidemia, hypoglycemia hepatomegaly, and lethargy, possibly progressing to coma and death. Seizures are linked in most cases to lactic acidemia or hypoglycemia and are associated with multifocal spike-wave discharges on EEG . Some prDysfunction of the enzyme glutaryl CoA dehydrogenase prevents the metabolism of tryptophan, hydroxylysine, and lysine, resulting in increased urine glutaric acid metabolites. This is a cerebral organic acidopathy, with predominantly neurological symptoms featuring macrocephaly, increased subarachnoid spaces, and progressive dystonia and athetosis with striatal injury . SeizureFive subtypes of 3-methylglutaconic aciduria (MGA) have been categorized ; all are-acetylaspartic acid (NAA) catabolism . Tr. Tr82]. Sulfite oxidase deficiency due to molybdenum cofactor deficiency (MOCOD) and isolated sulfite oxidase deficiency (ISOD) are inherited disorders of the metabolism of sulfated amino acids . They tyEEG findings include burst suppression patterns and multifocal spike-wave discharges , and neuDisorders involving homocysteine metabolism, specifically methionine and cystathionine synthesis, are characterized by elevated urine and serum homocysteine in the context of neurological symptoms. The spectrum of neurological dysfunction in homocysteine metabolism disorders is wide, including epilepsy, encephalopathy, peripheral neuropathy, ataxia, microcephaly, and psychiatric disorders. Cystathionine beta-synthetase (CBS) deficiency is the most common of the homocysteinemias, with severe defects involving multiple systems due to the essentiality of homocysteine and methionine to normal biochemical function. Focal seizures, stroke, neurodevelopmental delay, and cognitive deficiency, as well as psychosis are common neurological findings. Marfan-like skeletal symptoms, connective tissue abnormalities in the optic lens, and vasculopathies causing thrombosis and multiorgan infarcts may also be present. Treatment and biochemical findings in CBS, as well as other homocysteine disorders are summarized in Autosomal recessively inherited deficiency of methylene tetrahydrofolate reductase (MTHFR) may present in early infancy with severe epileptic encephalopathy . The preDisorders of purine and pyrimidine metabolism may present with epileptic encephalopathies , includiDisorders of protein glycosylation, due to defects in the synthesis of N- and O-linked glycoproteins, are characterized by multiple organ system dysfunction, developmental delay, hypotonia, and epilepsy. Certain of these disorders are associated with severe encephalopathy, particularly those involving alpha-dystroglycan, a protein component of the extracellular matrix, essential to muscle integrity. These are known as dystroglycanopathies.Walker-Warburg syndrome (WWS) is a severe dystroglycanopathy which can present at birth or prenatally with hydrocephalus and encephaloceles on imaging. Seizures and significant structural abnormalities , migrational defects , hypomyelination, and ophthalmologic defects are seen. Life expectancy is less than three years , 94.Fukuyama congenital muscular dystrophy (FCMD) classically presents in the neonatorum or even prenatally  with frequent seizures and severe brain abnormalities . By the age of 3, most patients develop epilepsy. Muscular degeneration and cardiac involvement are progressive , 96.Lysosomal storage disorders (LSD) are a major category of diseases that involve defects in lysosomal enzyme function, lysosomal biogenesis, activation, trafficking, or membrane transporters. Over two-thirds of LSDs are neurodegenerative and some are associated with epileptic encephalopathy. Neuronal ceroid lipofuscinoses are genetically heterogeneous neurodegenerative disorders associated with defects in transmembrane proteins and are characterized by the accumulation of autofluorescent lipopigments in lysosomes. The symptoms include cognitive decline, seizures, vision loss, and motor impairment, though age of onset and clinical course vary . The devDefects in the degradation of sphingolipids, an essential component of myelin sheaths and neuronal tissue, lead to progressive neurodegeneration, epilepsy, peripheral neuropathy, extrapyramidal symptoms, and characteristic \u201ccherry-red spots.\u201d Subtypes (II and III) of Gaucher Disease, which result from a deficiency in glucocerebrosidase, can cause devastating and rapid neurological deterioration. Neuroimaging is usually normal in patients with Gaucher Disease, but EEG can show several abnormalities including polyspikes with occipital predominance sensitive to photostimulation, diffuse slowing with high-voltage sharp waves during sleep, and multifocal spike-and-wave paroxysms , 101.Tay-Sachs disease is an example of defects involving the degradation of gangliosides, which are vital signaling, transport, and regulatory proteins in the lysosomal membrane. Seizures typically begin within the first year of life and worsen in frequency and severity. They are difficult to control with antiepileptics and can acutely and rapidly progress; in these cases, EEG and clinical deterioration can follow until death .As a participant in cellular detoxification, lipid metabolism, as well as myelin, neuronal function, migration, and brain development , peroxisRhizomelic chondrodysplasia punctata is a peroxisomal biogenesis disorder characterized by white matter abnormalities including inflammatory demyelination and noninflammatory dysmyelination, as well as cerebellar degeneration and loss of Purkinje cells, leading to profound intellectual deficiency. Almost all patients develop seizures, with nonspecific EEG findings. Neurological defects and degeneration are severe, and most individuals do not survive the first two years of life .Genetic leukoencephalopathies, or inherited white matter disorders, are diseases that primarily affect myelinated structures in the brain and peripheral nervous system. The majority of leukodystrophies primarily feature motor dysfunction rather than encephalopathy, particularly early on in the development of the disease. Epilepsy, however, can be a prominent symptom in certain classic leukodystrophies  such as Epileptic encephalopathies represent a challenging area of pediatric neurology and epilepsy and have a broad differential diagnosis . There aThe small molecule disorders include amino and organic acidopathies such as maple syrup urine disease, homocysteinemia, multiple organic acid disorders, and cobalamin deficiencies. Dietary intervention is key in preventing encephalopathy in maple syrup urine disease and glutaric aciduria, and hydroxycobalamin has a therapeutic role starting in prenatal intervention in cobalamin C deficiency. Neurotransmitter and fatty acid oxidation disorders may result in epileptic encephalopathies, and mitochondrial disorders present with a range of epilepsy phenotypes, including intractable epilepsy and epilepsia partialis continua in polymerase gamma mutations. Cerebral folate deficiency appears to result from a variety of causes but primary deficiency, associated with mutations of the folate receptor or blocking antibodies, has a phenotype of intractable generalized tonic-clonic seizures in infancy which may respond to folinic acid. Disorders of serine synthesis may respond to pre- and postnatal supplementation with serine and glycine. There are several potassium channelopathies involving the pancreas and brain, presenting either with neonatal diabetes or hypoglycemia, specifically  DEND and (hyperinsulinism-hyperammonemia) HI-HA with specific therapeutic implications. Glucose transporter deficiency appears to be the prototype of transport defects causing epilepsy and having specific therapy, in this case being the ketogenic diet to supply an alternative brain fuel to glucose, and the disorders related to the pyridoxine vitamers, specifically pyridoxine and pyridoxal-5-phosphate, require prompt identification and therapy to avert a catastrophic outcome. Autosomal recessively inherited deficiency of MTHFR may be reversible with use of betaine, whereas other small molecule defects causing epileptic encephalopathy, for example, glycine encephalopathy and sulfite oxidase deficiency, have no specific therapy at this time.Large molecule disorders involve a complex constellation of disorders of glycosylation, lysosomal storage diseases, and peroxisomal disorders. Those including severe epilepsy include Walker-Warburg syndrome, Fukuyama congenital muscular dystrophy, gangliosidoses such as Tay-Sachs and Sandhoff diseases, and the neuronal ceroid lipofuscinoses. While epilepsy represents significant gray matter involvement in neurological disease, seizures can be a prominent aspect of leukodystrophies such as Alexander's disease. The epileptologist should consider these hereditary disorders in the investigation of patients with epileptic encephalopathies, leading to specific diagnostic steps and, in some cases, potential therapeutic maneuvers to address the metabolic defect."}
+{"text": "Constant malaria monitoring and surveillance systems have been highlighted as critical for malaria elimination. The absence of robust monitoring and surveillance systems able to respond to outbreaks in a timely manner undeniably contributed to the failure of the last global attempt to eradicate malaria. Today, technological advances could allow for rapid detection of focal outbreaks and improved deployment of diagnostic and treatment supplies to areas needing support. However, optimizing diffusion activities  requires networks of diverse scholars to monitor, learn, and evaluate data and multiple organizations to coordinate their intervention activities. Surveillance systems that can gather, store and process information, from communities to national levels, in a centralized, widely accessible system will allow tailoring of surveillance and intervention efforts. Different systems and, thus reactions, will be effective in different endemic, geographical or socio-cultural contexts. Investing in carefully designed monitoring technologies, built for a multiple-acter, dynamic system, will help to improve malaria elimination efforts by improving the coordination, timing, coverage, and deployment of malaria technologies. For those countries close to malaria elimination, real-time, on-going monitoring systems are important for at least four reasons. They allow for 1) rapid detection of existing, new or re-introduced  infections  rapid de; (2) ideA real-time, on-going, integrated data reservoir capturing multiple scales of disease dynamics - from cells to society is a plausible, achievable enterprise for malaria elimination in the next decade. The finest, comprehensive, malaria-monitoring systems include portable and sensitive diagnostic tests, real-time data about patients showing drug resistant parasites and vectors showing insecticide resistance, transmission intensity markers , climatic data , geo-spatial and demographic information for villages known to be particularly at risk, and continuous, frequent  local-level malaria incidence counts -13. TogeHowever, monitoring is not enough: learning and evaluation are also needed, which is complicated in a multiple-organization , government ministries, international health agencies, private industry, non-governmental organizations, funding agencies, and local health organizations, etc.,) multiple-acter  effort . To optiHowever, the use and maintenance of MLE systems requires a level of infrastructure (communication networks) absent in some malaria-burdened countries. For example, in some of the most remote parts of Africa, there are few landline telephones, computers with fast internet-access, or roads in good condition, for the rapid transfer of disease information ,17. MobiNotably, real-time, comprehensive monitoring does not inherently lead to access or to collaboration and coordination among different organizations and acters. For enriched MLE technologies, such as mobile phones, to improve coordination, optimization, and deployment of intervention resources ,20, therPlatforms are already being developed by those who recognize the benefits of integrating global positioning systems (GPS), geographic information systems (GIS) and mobile computing technology into modern reporting applications . PlatforFirst, MLE systems should be designed with local communities in mind, such as allowing for data entry interfaces and reports to be personalized by the user. Different systems may be more effective in one setting over another. Existing models suggest that in communities where disease incidence is low, a simple \u2018eyes and ears\u2019 approach for early treatment - seeking could be equally effective as more technical methods of disease detection ,26. CommAs in the development of agricultural innovations and systems , end-useIn essence, ensuring access to data within and across different regions and countries is as important as developing and diffusing technologies to monitor malaria dynamics and intervention activities. Data collected and stored in an accessible manner can quicken the speed at which scientists can evaluate an intervention\u2019s impact, forecast possible changes to improve future efforts, and adjust to incoming results. Speed plays an important role in malaria management, where outbreaks occur across numerous ecosystems and throughout the seasonal variation . With cuIn summary, malaria MLE systems from community to national levels, and informed reactions (interventions), can provide valuable insights needed to understand, forecast, and evaluate complex, multiple-organization-and-acter efforts, such as eliminating malaria. In order to meet malaria elimination objectives, monitoring systems must be able to respond rapidly to the heterogeneity in malaria epidemiology. Many malaria-burdened countries are experiencing advances in technology and research, which may be harnessed to optimize the feasibility, efficiency and cost-effectiveness of readily accessible, shared data collection, evaluation, and collaboration systems. This research should strive to improve MLE systems in even the most remote locations. Investment in integrated MLE systems alone will not eradicate malaria, but it will bring us closer.MLE: Monitoring learning and evaluation; NMCPs: National malaria control programmes; GPS: Global positioning systems; GIS: Geographic information systems; SMS: Short message service.The authors declare that they have no competing interests.VB reviewed the literature and drafted the paper. RAS reviewed the literature and edited the manuscript. JFL edited the manuscript. All three authors conceived the idea equally. All authors read and approved the final manuscript."}
+{"text": "Hypoproteinemia is one of complications of severe atopic dermatitis. The aim of this study was to investigate the risk factors for hypoproteinemia in atopic dermatitis.Seventy seven infants with atopic dermatitis were enrolled, who visited pediatric allergy clinic of Busan St. Mary\u2019s Medical Center from January 2005 to January 2012. Infants with serum protein level was lower than normal range for age were classified to Group A (n=27) and normalto Group B (n=50). Age, sex, family history of allergy, and SCORAD score were studied. We examined platelet count, CRP, eosinophil count, serum albumin and protein, also serum ECP, total IgE, and allergen specific IgE by immuno CAP system . We identified skin wound culture and mycoplasma infection.Group A (Atopic dermatitis with hypoproteinemia) had higher SCORAD score, eosinophil count, CRP, ECP, and total IgE, and lower albumin than control group. Serum protein had statistically significant correlations with SCORAD score, eosinophil count, albumin, total IgE and number of sensitized allergens, but had not with CRP and ECP.The lower serum protein, the more severe atopic dermatitis. Our study suggests that the risk factors for hypoproteinemia in infantile atopic dermatitis were high SCORAD score, eosinophil count, total IgE, and number of sensitized allergens, and low albumin."}
+{"text": "Myzobdella lugubris. Among the eight lakes examined, Lake Orion and Devils Lake had the highest prevalence of leech parasitism  and mouth ulcerations . Statistical analyses demonstrated that leech and ulcer prevalence varied significantly from one lake to the other. Additionally, it was determined that the relationship between the prevalence of ulcers and the prevalence of leech attachment is significant, indicating that leech parasitism is most likely the cause of ulceration. The ulcers exhibited deep hemorrhagic centers and raised irregular edges. Affected areas lost their epithelial lining and submucosa, with masses of bacteria colonizing the damaged tissues. Since largemouth bass is a popular global sportfish and critical to the food web of inland lakes, there are concerns that the presence of leeches, damaged buccal mucosa, and general unsightliness may negatively affect this important sportfishery.Widespread mouth ulcerations were observed in largemouth bass collected from eight inland lakes in the Lower Peninsula of Michigan during the summer months of 2002 and 2003. These ulcerations were associated with, and most likely caused by, leech parasitism. Through the use of morphological dichotomous keys, it was determined that all leeches collected are of one species:  Micropterus salmoides) is an important species in the food web of inland lakes in the Laurentian Great Lakes basin , white catfish (I. catus), mottled sculpin (Cottus bairdi), and burbot (Lota lota) . Leeches can be semi-permanent, attaching to only one host for the greater part of their adult life, or their attachment can be intermittent, attaching to several hosts throughout their lifetime . Adult leeches generally detach themselves from their fish hosts to deposit egg cocoons, from which juvenile leeches emerge after a few months to find their own fish hosts on which to feed, and grow into adults . The piscicolid leech  sapidus .M. lugubris is primarily on the fin soft rays, causing erosion and epithelial hyperplasia  and their buccal cavity thoroughly examined for the presence of ulcers and leeches. Leeches, when present, were collected, their numbers/fish recorded, and kept separately in vials containing saline (0.6% NaCl solution). Leeches were allowed to relax using menthol crystals  added to a Petri dish of water and were then compressed gently with a glass slide . They weP-value less than 0.05 was considered significant. Calculations were performed using the SAS version 9.2 software .A one-way analysis of variance (ANOVA) was conducted to determine the significance of mouth ulcerations and leech prevalence. Additionally, Tukeyadjusted multiple comparisons were used to compare the prevalences of mouth ulcerations and leeches among lakes. A Examining the buccal cavity of largemouth bass revealed the presence of leeches crawling freely, attached to buccal mucosa, or buried in furrows within the mucosa. The overall prevalence of leeches in largemouth bass\u2019 buccal cavity in the eight lakes combined was relatively high . Most fish harbored more than three leeches, but as many as six or seven leeches were common in fish from Lake Orion and Devils Lake. There were significant differences in leech prevalence among lakes with Lake Orion and Devils Lake being the highest at 34% and 29%, respectively . On the All leeches attached to the buccal mucosa of largemouth bass shared the same morphological criteria. Leech bodies were grayish to dark red, often contained scattered pigment cells, and measured 24-36\u00a0mm in length when relaxed . All leeClinical examination revealed the presence of widespread ulcerations of the buccal mucosa at the roof of the mouth as well as on the tongue mucosa. The prevalence of buccal ulcerations was relatively high since it was found in 105 out of 326 largemouth bass examined (32%). In several fish, leeches were found embedded in the buccal mucosa, particularly at the roof of the mouth . Even thP\u00a0<\u00a00.01). The difference in ulceration prevalence between Randall Lake and Jordan and Norvell lakes was statistically significant (P\u00a0<\u00a00.05). Additionally, the prevalence of ulcers in fish from Lake Orion was greater than the prevalence of ulcers in fish from Randall, Union, Eagle, and Independence lakes, and was statistically significant (P\u00a0<\u00a00.05). When the individual fish data of the eight lakes was combined, statistical analysis revealed that the interaction between the prevalence of ulcers and the prevalence of leeches was statistically significant (P\u00a0<\u00a00.05).Similar to leech prevalence, buccal ulceration prevalence was highest in Lake Orion (53%) and Devils Lake (68%) and did not exist in the leech-free Union Lake. Moreover, ulcer prevalence varied significantly among lakes. For example, the prevalence of ulcers in fish from Devils Lake was significantly higher than Eagle, Independence, Randall, and Union lakes .. Site of infection: buccal cavity.. Type host: largemouth bass.Acipenser brevirostrum, Acrocheilus alutaceus, Ambloplites rupestris, Ancylopsetta quadrocellata, Aplodinotus grunniens, Awaous guamensis, Callinectes sapidus, Carpiodes cyprinus, Catostomus macrocheilus, C. columbianus, Cottus bairdi, Eleotris sandwicensis, Esox lucius, Fundulus grandus, F. heteroclitus, F. majalis, F. similes, Ictalurus catus, I. melas, I. natalis, I. nebulosus, I. punctatus, Lepomis cyanellus, L. macrochirus, Lota lota, Micropterus dolomieu, M. salmoides, M. saxatilis, Moxostoma macrolepidotum, Mugil cephalus, Notemigonus crysoleucas, Notropis atherinoides, Palaemontetes pugio, Paralichthys lethostigma, Penaeus setiferus, Perca flavescens, Percina caprodes, Pomoxis annularis, P. nibromaculatus, Pterois volitans, Ptychocheilus oregonensis, Sander vitreus, and Sicyopterus stimpsoni.. Other reported hosts: . New location(s) based on the present study: the following inland lakes in Michigan\u2019s Lower Peninsula: Lakes Devil, Eagle, Independence, Jordan, Norvell, Orion, Randall, and Union.. Other reported localities in North America: The U.S. states of Alabama, Arizona, California, Connecticut, Florida, Georgia, Hawaii, Kentucky, Louisiana, New Jersey, Maryland, Massachusetts, Michigan, Mississippi, North Carolina, South Carolina, Texas, Virginia, Washington, and West Virginia. It was also reported from the Canadian provinces of New Brunswick and Ontario.. Representative publications: . Specimen deposited: AMNH, in submittal process."}
+{"text": "To the Editor: Leptospirosis, caused by Leptospira spp. bacteria, and dengue, caused by dengue viruses (DENVs), are potentially fatal acute febrile illnesses (AFI) endemic to the tropics  saline, and results of laboratory tests performed afterward showed leukocytosis with a predominance of neutrophils, thrombocytopenia, increased blood urea nitrogen (BUN)\u2013to-creatinine ratio, hyponatremia, hyperglycemia, and elevated aspartate aminotransferase. He was given IV ampicillin, meperidine, and promethazine and was transferred to a local hospital for admission, with a presumptive diagnosis of pre\u2013renal azotemia and leptospirosis.2). He was given IV saline again, and vancomycin and ceftriaxone were added to his medication regimen.On arrival at the emergency department on the same day, the patient was febrile, tachycardic, and hypotensive, with cold, clammy skin. Results of an electrocardiogram showed sinus tachycardia; cardiac enzymes were not elevated. He was given repeat IV saline and piperacillin/tazobactam. New laboratory findings included anemia, prolonged prothrombin time, elevated creatinine kinase, hematuria, and a further increase in BUN-to-creatine ratio. Chest radiograph showed cardiomegaly with increased pulmonary vascularity and perihilar alveolar densities. Arterial blood gas (ABG) results showed compensated metabolic acidosis, with low oxygen partial pressure  protein 1 was detected in whole blood, and flavivirus NS5 gene was amplified from RNA extracted from the liver; sequencing showed 98% homology with DENV-1.All results of bacterial cultures were negative, as was detection of anti-necrosis , panel Anecrosis , panel Bnecrosis , panel Cnecrosis , panel DLeptospira IgM  for AFI patients. All available leptospirosis RDTs detect anti-Leptospira spp. and DENVs are endemic should include both pathogens in the differential diagnosis when evaluating AFI patients and should consider the possibility of co-infection. Early administration of doxycycline and penicillin G to treat mild and severe leptospirosis, respectively, may reduce the duration and severity of illness (Nonetheless, even if leptospirosis had been diagnosed in this patient, dengue virus infection would likely still have been overlooked. Therefore, clinicians in areas where both"}
+{"text": "The planar cell polarity (PCP) proteins govern diverse cellular behaviors, are essential for embryonic development, and are associated in a variety of human birth defects, including ciliopathies. While many PCP proteins have been extensively characterized, the \u201cPCP effector\u201d proteins, Inturned, Fuzzy and Fritz, remain largely unstudied. We have shown that each of these novel proteins is broadly essential for ciliogenesis in vertebrate animals. Here, we will discuss our efforts to combine bioinformatics, genomics, mouse genetics, and in vivo time-lapse imaging of intraflagellar transport to understand the mechanisms by which the PCP proteins govern cilia structure and function."}
+{"text": "Environmental Health Perspectives (EHP) established the Paper of the Year in 2008  had already emerged. BPA, a high production volume chemical, is used worldwide to manufacture many consumer items, such as reusable water bottles and food containers; linings of metal food cans; medical devices and impact-resistant safety equipment; and polyvinyl chloride, paper, and cardboard products. Results from animal studies suggested that exposures to BPA can lead to developmental, reproductive, and other adverse health effects. Yet, important knowledge gaps remained regarding the relevance of these findings to human health, in part, because of limited information on human exposure to BPA. EHP congratulates Calafat and colleagues for their contribution to the environmental health science literature. Their work clearly illustrates the utility of human biomonitoring to estimate population-based exposures. These exposure and health effects studies will ultimately inform policy decisions regarding human exposure levels and direct appropriate public health actions.Environmental Health Perspectives will begin charging a flat fee for processing manuscripts for publication. On acceptance of a manuscript, authors will be required to pay $750, $1,500, or $1,000 for a Commentary, Review Article, or Research Article, respectively. An additional $500 will be charged for Supplemental Material exceeding 2,000 words, which includes tables, figure legends, text, and references. Each figure counts as 250 words. The manuscript processing fee replaces the page charge of $35 per accepted Microsoft Word manuscript page and charges for color figures. Word limits for Commentaries, Review Articles, and Research Articles will remain at 5,000, 10,000, and 7,000 words, respectively.Starting 1 August 2012,"}
+{"text": "The authors would like to disclose the following Competing Interests: Dr. Wiendl has received funding for travel and speaker honoraria from Bayer Schering Pharma, Biogen Idec/Elan Corporation, Sanofi-Aventis, Merck Serono, and Teva Pharmaceutical Industries Ltd.; has served/serves as a consultant for Merck Serono, Medac, Inc., Sanofi-Aventis/Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, Novartis, and Novo Nordisk; and receives research support from Bayer Schering Pharma, Biogen Idec/Elan Corporation, Sanofi-Aventis, Merck Serono, and Novo Nordisk. The study was partly supported by funds from BiogenIdec, the manufacturer of the monoclonal antibody Natalizumab (Tysabri)."}
+{"text": "In our article , we did Declaration of competing interests:Prof. Dr. med. Ludwig KapposLK has participated in the last 24 months as principal investigator, member or chair of planning and steering committees or advisory boards in corporate-sponsored clinical trials in multiple sclerosis and other neurological diseases. The sponsoring pharmaceutical companies for these trials include Actelion, Advancell, Allozyne, BaroFold, Bayer Health Care Pharmaceuticals, Bayer Schering Pharma, Bayhill, Biogen Idec, BioMarin, CLC Behring, Elan, Genmab, GeNeuro SA, Genmark, GlaxoSmithKline, Lilly, Merck Serono, MediciNova, Novartis, Novonordisk, Peptimmune, sanofi-aventis, Santhera, Roche, Teva, UCB and Wyeth.I have also lectured at medical conferences or in public on various aspects of the diagnosis and management of multiple sclerosis. In many cases these talks have been sponsored by non-restricted educational grants from one or another of the above listed companies.Honoraria and other payments for all these activities have been exclusively used for funding of research of my department.Research and the clinical operations (nursing and patient care services) of the MS Center in Basel have been supported by non-restricted grants from one or more of these companies and by grants from the Swiss MS Society, the Swiss National Research Foundation, the European Union, the Gianni Rubatto, Novartis and Roche Research Foundations.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2377/11/19/prepub"}
+{"text": "Infectious diseases are leading causes of death in developing countries. According to 1998 data from the World Health Organization, 1.2% of total deaths from infectious and parasitic diseases occurred in industrialized countries, compared to 43% in developing countries. Women in developing countries disproportionately suffer from a host of infectious diseases, including tuberculosis, upper respiratory tract infectious, skin infections, visceral leishmaniasis, malaria, sexually transmitted infections, and HIV/AIDS.Poverty, poor education, low health knowledge, poor infrastructure, geographic factors, life style, and environmental factors  have been identified as primary factors contributing to the high incidence of infectious diseases among women in developing countries. Also, such women tend to have limited or no access to health care, be vitamin deficient, and have lower status in their communities.Often, infectious diseases may run a substantially longer course for women in developing countries because of stigma, family needs, and shame. Another important barrier to combating infectious diseases among women in developing countries is the lack of use and the misuse of prescription medication. A substantial percentage of women rely on traditional treatment methods. When women do seek healthcare services and are prescribed medication, women frequently do not adhere to the dosage and quantities prescribed."}
+{"text": "Prepona Boisduval and Archaeoprepona Fruhstorfer, and are in accord with the recent taxonomic classification proposed by Ortiz-Acevado and Willmott  has a worldwide distribution, although it occurs mainly between the tropics. Most species occur in the Neotropics, where three tribes, Preponini, Anaeomorphini, and Anaenini, can be found. Collectively, these three tribes encompass 109 species. Because of its relevance to systematics and taxonomy, the male genitalia of Lepidoptera have been extensively studied. The male genitalia are composed of the last two abdominal segments and their modifications for mating, known as claspers of the bodies. In order to improve upon the systematic classification of the subfamily, 31 species of 13 genera of Neotropical Charaxinae were analyzed. All characters relevant to species and generic taxonomy were analyzed. Most structures showed morphological variations among tribes, genera, and species. These variations demonstrated to be important to Preponini, because the structural patterns of the genitalia allow the separation in two groups, Willmott , whereinmorphini . Substan The male genitalia of butterflies has been the subject of several very detailed studies, as its morphology can provide the basis for work of taxonomy, systematic analysis, and phylogenetic analysis (Simonsen 2006a). Some recent work on the comparative morphology of male genitalia has examined genital muscles  and intraspecific structural variations .Charaxinae  are a group of medium to large, robust butterflies. They fly fast and circulate around tree canopies, behaviors that make them difficult to observe. Males and females are easily attracted by bait containing fruit, decomposing animals, feces, urine, and/or sweat . CharaxiNoreppa to Archaeoprepona and Agrias to Prepona; the fifth genus (monotypic), Anaeomorpha splendida, had its tribe status revalidated to Anaeomorphini. So, the neotropical Charaxinae contained two tribes, 17 genera, and 109 species  and Prepona claudina annetta (Gray).The Charaxinae are characterized by the following synapomorphies: parapatagium sclerotized ; forewineveloped . These seveloped , b, c, wWith the goal to clarify the classification and systematics of the Neotropical Charaxinae, we have illustrated, compared, and ascertained variation in the male genitalia of 31 species of 13 genera. Some of the characters mentioned have been previously mentioned in other literature, whereas others are new.The species studied and material studied are listed in The abdomen of each exemplar was removed and immersed in potassium hydroxide 10% for at least 24 hours (depending on the size of the abdomen) to soften the tissues. After that, the abdomen was washed in water.th abdominal segment. After study, the genital parts were stored in a microvial containing glycerin, which was attached to the same pin as the exemplar.The genitalia were removed through a slit on the pleura of the 7Drawings were made using a camera lucida attached to a dissecting microscope. The main lines were inked and watercolor was used to mark each sclerite with a different color.Illustrations were coded as follows: full lines represent the boundaries of morphological structures on the first focal plane; dashed lines represent the boundaries of structures that lay underneath the main structure under study. As with structures represented by dotted lines, structures represented by dashed lines were only shown when they were important for the interpretation of the genital anatomy. Sclerites lacking a well-defined boundary were represented by intermediate colors. Sclerites, and their respective color codes, are as follows: tegumen - yellow; saccus - cadmium red; uncus - navy blue; gnathos - alizarin red; fultura inferior - turquoise; valvae - lemon yellow; penis - green.In some illustrations, the sclerites were omitted in order to facilitate interpretation. For instance, the fultura inferior was omitted from illustrations showing the lateral aspect of the genitalia. A minimum of nine drawings were produced for each species as follows: lateral, dorsal, and posterior aspects of the genitalia; inner and outer aspects of the valva; and lateral (left and right), dorsal, and ventral aspects of the penis. In the descriptions and comparisons, only the greatest values are given for width and length.SEM photographs were taken following standard procedures. First, the parts were dehydrated by immersion in decreasing ethanol dilutions  for 10 minutes, and then immersed for an additional 10 minutes in ethanol absolute. Second, they were subjected to critical point drying, glued to a stub, and coated.The main terminology used was adopted from Niculescu  Figure , with adAnaea troglodyta (Fabricius) (bricius) . Tegumen triangular in lateral view, anterior projection and appendices angulares wider than long. Arms from tegumen and saccus distinct. Anterior projection from saccus elongated in lateral view; posterior projection shorter than anterior.Uncus slender, with distal portion descending, in dorsal view fused with tegumen, uncus differing from tegumen by a light sclerotization. Anal tube reduced and entirely membranous. Gnathos open, in lateral view forming two distinct plates, with distal portion flattened on anterior ventral portion, gnathos extended dorsoventrally toward the proximal portion, with spines of various sizes that give the dorsal distal section a serrated aspect.Valva subtriangular, with inner ends expanded. Fultura inferior forming a semicircle.Penis: aedeagus sclerotized, with bulbus ejaculatorius projecting from antero-dorsal openingCoenophlebta archidona (Hewitson) (ewitson) . Tegumen subtriangular in lateral view, anterior projection wider than long, tegument fold projecting outward from median to ventral region, appendices angulares longer than wide. Arms from tegumen and saccus distinct. Anterior projection from saccus elongate in lateral view; posterior projection absent.Uncus thick, with distal portion descending, in dorsal view fused with tegumen, uncus differing from tegumen by a light sclerotization. Anal tube developed, with ventral portion sclerotized (subscaphium). Gnathos open, in lateral view with proximal portion entirely fused with tegumen, C-shaped, in posterior view curved with distal portion descending.Valva subrectangular, with a dorso-proximal notch and a small spine on distal portion. Fultura inferior bilobed, V-shaped, with a deep dorsal notch.Penis: aedeagus sinuous and completely sclerotized, with bulbus ejaculatorius projecting from antero-dorsal opening.Consul electra (Westwood) (estwood) . Tegumen subtriangular in lateral view, anterior projection wider than long, tegument fold projecting outward from anteromedian portion of arms from tegument to their apex, appendices angulares longer than wide. Arms from tegumen and saccus distinct. Anterior projection from saccus elongate in lateral view, about twice as long as wide; posterior projection of saccus present, shorter than anterior projection.Uncus slender, with distal portion descending, in dorsal view fused with tegumen, uncus differing from tegumen by a light sclerotization. Anal tube developed, with ventral portion sclerotized (subscaphium). Gnathos open, in lateral view with the distal portion of each gnathos close to each other, with two parts, one dorsal and one ventral distal, ventral part more developed and subrectangular; ventral distal part elongate and with a small descending apical club; in posterior view L-shaped aspect, expanded apically.Valva rounded, inner tegument expanded over outer tegument on ventral distal portion. Fultura inferior bilobed and linked ventrally with the diaphragma rather than with the valva.Penis: aedeagus sclerotized, expanded ventrally up to insertion of manica, and bulbus ejaculatorius projecting from antero-dorsal opening.Consul fabius drurii (Butler) ((Butler) , 33 C, D Tegumen subtriangular in lateral view; anterior projection and appendices angulares wider than long. Arms from tegumen and saccus distinct. Anterior projection from saccus elongated in lateral view, at least three times longer than wide; posterior projection present, shorter than anterior projection.Uncus slender, with distal portion descending, in dorsal view fused with tegumen, uncus differing from tegumen by a light sclerotization. Anal tube developed, with ventral portion sclerotized (subscaphium), enveloped by the gnathos ventrally. Gnathos open, in lateral view with two parts: dorsal and ventral-distal, both elongated, ventral-distal part descending, with a slight fold in the tegument.Valva approximately rounded; inner tegument expanded over outer tegument on ventral distal portion and bearing small spines on the harpe. Fultura inferior bilobed.Penis: aedeagus completely sclerotized, with bulbus ejaculatorius projecting from anterodorsal opening, posterior opening large, originating underneath the manica.Fountainea glycerium cratais (Hewitson) (ewitson) . Tegumen subtriangular in lateral view; without anterior projection, appendices angulares longer than wide. Arms from tegumen and saccus distinct. Anterior projection from saccus elongated in lateral view, at least three times longer than wide; posterior projection absent.Uncus slender, apex slender and descending, in dorsal view fused with tegumen, uncus differing from tegumen by a light sclerotization. Anal tube developed, with ventral portion sclerotized (subscaphium) and enveloped by the gnathos ventrally. Gnathos closed and distally forming a round plate, projecting posteriorly.Valva subrectangular and outer tegument forming a distal spine. Fultura inferior bilobed, with medium ventral notch, and small dorsal spines.Penis: aedeagus sclerotized, bulbus ejaculatorius projecting from antero-dorsal opening; posterior opening irregular, with deep notches.Fountainea halice halice (Godart) ((Godart) . Tegumen subtriangular in lateral view, without anterior projection, appendices angulares longer than wide. Arms from tegumen and saccus distinct. Anterior projection from saccus elongated in lateral view, at least twice longer than wide; posterior projection absent.Uncus slender, with proximal ventral expansion and distal portion descending, in dorsal view fused with tegumen, uncus differing from tegumen by a light sclerotization. Anal tube developed, with ventral portion sclerotized (subscaphium) and enveloped by the gnathos ventrally. Gnathos closed, in lateral view sub rectangular, with anterior and posterior margins sinuous and fused mediallyValva subrectangular, with small spines near dorsal region and a distal spine. Fultura inferior bilobed, formed by two plates joined medially.Penis: aedeagus sclerotized, with bulbus ejaculatorius projecting from antero-dorsal opening.Fountainea nessus (Latreille) (treille) . Tegumen subtriangular in lateral view, without anterior projection, appendices angulares longer than wide. Arms from tegumen and saccus fused. Anterior projection from saccus elongated in lateral view, at least three times longer than wide; posterior projection absent.Fountainea.Uncus slender, basal portion enlarged, with distal portion descending, in dorsal view fused with tegumen, uncus differing from tegumen by a light sclerotization. Anal tube developed and entirely membranous. Gnathos open, in lateral view rounded and with distal portion of both gnathos close to each other, differing from the remaining species of Valva subrectangular, bearing distal spine. Fultura inferior large and bilobed.Penis: aedeagus sclerotized, with bulbus ejaculatorius projecting from antero-dorsal opening, posterior opening sinuous.Fountainea ryphea phidile (Geyer) ( (Geyer) , 33 A, B Tegumen subtriangular in lateral view, anterior projection wider than long, appendices angulares longer than wide. Arms from tegumen and saccus distinct. Anterior projection from saccus elongated in lateral view, at least twice as long as wide; posterior projection absent.F. glycerium cratais.Uncus slender, with distal portion descending, in dorsal view fused with tegumen, uncus differing from tegumen by a light sclerotization. Anal tube reduced and entirely membranous. Gnathos closed, in lateral view forming a single round plate, similar to the gnathos of Valva subrectangular, bearing distal spine. Fultura inferior wide and semi-circular, with reduced spines on apical dorsal tips.Penis: aedeagus sclerotized, with bulbus ejaculatorius projecting from antero-dorsal opening.Hypna clytemnestra forbesi Godman and Salvin  (. Druce) . Tegumen subtriangular in lateral view, without anterior projection, appendices angulares longer than wide. Arms from tegumen and saccus fused. Anterior projection from saccus elongated in lateral view, distal portion enlarged; posterior projection absent.Uncus slender, ventral margin sinuous, apex slender and descending, in dorsal view fused with tegumen. Anal tube developed and with ventral portion sclerotized (subscaphium). Gnathos open, in lateral view elongated, with proximal portion wider than long, descending distally and with tegument fold projecting outward like a shell, in ventral view with conspicuous suture indicating the fusion between lateral arms of gnathos.Valva semi-circular, with reduced spines on sacculus, a small notch on dorsal margin and a spine on distal portion. Fultura inferior bilobed.Penis: aedeagus sclerotized, with bulbus ejaculatorius projecting from antero-dorsal opening, anterior portion curved descending, and posterior portion with sinuous of different shapes and dimensions.Memphis glauce glauce (C. Felder and R. Felder) ( Felder) . Tegumen subtriangular in lateral view, anterior projection wider than long, tegument fold extended over entire anterior margin, projecting outward, appendices angulares wider than long. Arms from tegumen and saccus distinct. Anterior projection from saccus triangular in lateral view, descending, slender distally, projecting toward the left side; posterior projection present, shorter than anterior projection.Uncus slender, with ventral margin sinuous, apex descending, in dorsal view fused with tegumen, uncus differing from tegumen by a light sclerotization. Anal tube developed and with ventral portion slcerotized (subscaphium). Gnathos open, in lateral view elongated, proximal portion expanded and distal portion semi-triangular, with median constriction, giving the structure a shovel-like appearance.Valva subrectangular, each bearing a distal spine; spines reduced on sacculus and costa. Fultura inferior with narrow stripe.Penis: aedeagus sclerotized, with bulbus ejaculatorius projecting from anterio-dorsal opening, posterior portion with tegument fold near posterior opening.Memphis hirta (Weymer) ((Weymer) . Tegumen subtriangular in lateral view, anterior projection wider than long, appendices angulares longer than wide. Arms from tegumen and saccus distinct, arm from tegumen with small distal expansions projecting anteriorly. Anterior projection from saccus subrectangular in lateral view, twice as long as wide; posterior projection present, shorter than anterior projection.Uncus slender, with distal portion descending, in dorsal view fused with tegumen, uncus differing from tegumen by a light esclerotization. Anal tube developed and with ventral portion sclerotized (subscaphium). Gnathos open, in lateral view elongated, proximal portion wider than distal, from posterior view with tegument fold projecting posteriorly on distal portion, shell-like.Valva semi-circular, each bearing a distal spine, conspicuous spine on dorsal margin and areas with reduced spines on costa and sacculus. Fultura inferior wide and bilobed.Penis: aedeagus sclerotized, with bulbus ejaculatorius projecting from antero-dorsal opening.Memphis lemnos (H. Druce) (. Druce) . Tegumen semi-trapezoidal in lateral view, without anterior projection, tegument fold projecting outward, following anterior margin, appendices angulares longer than wide. Arms from tegumen and saccus fused. Anterior projection from saccus subtriangular in lateral view, slightly longer than wide; posterior projection present, shorter than anterior.Uncus slender, ventral margin sinuous, apex slender and descending, in dorsal view fused with tegumen, but with proximal lateral portions distinct. Anal tube developed, with ventral portion sclerotized (subscaphium). Gnathos closed, in lateral view elongate, proximal portion wider than distal; distal portion with posterior and anterior projections in posterior view.Valva subrectangular, bearing distal spine and tufts of setae on inner tegument. Fultura inferior bilobed.Penis: aedeagus sclerotized, with bulbus ejaculatorius projecting from antero-dorsal opening, posterior-dorsal opening extended to manica.Memphis moruus stheno (Prittwitz) (ittwitz) . Tegumen subtriangular in lateral view, anterior projection wider than long, appendices angulares longer than wide. Arms from tegumen and saccus distinct. Anterior projection from saccus elongated in lateral view, at least three times longer than wide; posterior projection absent.Uncus slender, ventral margin sinuous and distal portion descending, in dorsal view fused with tegumen, uncus differing from tegumen by a light sclerotization. Anal tube developed, with ventral portion sclerotized (subscaphium). Gnathos closed, in lateral view elongate, proximal portion wider than distal, and with a tegument fold projecting outward.Valva subrectangular, with small spines on sacculus. Fultura inferior bilobed.Penis: aedeagus sclerotized, with bulbus ejaculatorius projecting from antero-dorsal opening, posterior-dorsal opening extended to manica.Memphis philumena corita (Fruhstorfer) (storfer) . Tegumen subtrapezoidal in lateral view, anterior projection wider than long, tegument fold projecting outward, appendices angulares longer than wide. Arms from tegumen and saccus distinct. Anterior projection from saccus elongated in lateral view, about four times longer than wide; posterior projection present, shorter than anterior.Uncus slender, with distal portion descending, in dorsal view fused with tegumen, uncus differing from tegumen by a light sclarotization. Anal tube reduced and entirely membranous. Gnathos open, in lateral view elongate, with proximal portion wider than distal; ventral proximal portion underneath tegumen, with distal tegument fold and dorsal distal notch.Valva subrectangular and unmodified. Fultura inferior bilobed.Penis: aedeagus sclerotized, with bulbus ejaculatorius projecting from antero-dorsal opening, posterior opening sinuous.Memphis polyxo (H. Druce) (. Druce) . Tegumen subtrapezoidal in lateral view, anterior projection wider than long, tegument fold on anterior margin, projected outward, appendices angulares longer than wide. Arms from tegumen and saccus distinct. Anterior projection from saccus elongated in lateral view, twice as long as wide; posterior projection absent.Uncus slender, with proximal portion enlarged and distal portion descending, in dorsal view fused with tegumen, uncus differing from tegumen by a light sclerotization. Anal tube developed, with ventral portion sclerotized (subscaphium). Gnathos closed, in lateral view elongate, proximal portion about twice wider than distal portion, tegument fold projecting outward.Valva subrectangular, each bearing a distal spine, spines on sacculus and inner tegument small, near costa. Fultura inferior bilobed.Penis: aedeagus sclerotized and sinuous, with bulbus ejaculatorius projecting from anterodorsal opening, posterior portion with tegument fold, posterior opening sinuous.Prozikania suprema (Schaus) ((Schaus) . Tegumen subtriangular in lateral view, without anterior projection, tegument fold projected outwards on anterior margin, appendices angulares longer than wide. Arms from tegumen and saccus fused. Anterior projection from saccus elongated in lateral view, at least twice longer than wide; posterior projection absent.Uncus slender, apex slender and descending, in dorsal view fused with tegumen, uncus differing from tegumen by a light sclerotization. Anal tube developed, with ventral portion sclerotized (subscaphium). Gnathos closed, in lateral view elongate, proximal portion twice as wide as distal, outer margin sinuous, distal tegument fold projecting outward.Valva subrectangular, distally with outer tegument expanded. Fultura inferior wide and forming a semi-circle.Penis: aedeagus sclerotized, with bulbus ejaculatorius projecting from antero-dorsal opening, posterior opening irregular.Pseudocharaxes xenocrates punctimarginale (Kaye) (e (Kaye) . Tegumen subtriangular in lateral view, anterior projection wider than long, tegument fold of anterior margin projected outward, appendices angulares longer than wide. Arms from tegumen and saccus separated, arms from tegumen long, the longest among the species studied in this work. Anterior projection fom saccus semi-triangular in lateral view, about twice as long as wide; posterior projection absent.Uncus slender, ventral margin sinuous, apex slender and descending, in dorsal view fused with tegument, with triangular fenestra medially. Anal tube developed, with ventral portion sclerotized (subscaphium). Gnathos closed, in lateral view elongate, with distal tegument fold projected outward, giving the ghathos a shell-like appearance.Valva rectangular, dorsal margin sinuous, spine on distal portion and setae on inner region, setae more numerous than in other species analyzed. Fultura inferior small and semi-circular.Penis: aedeagus sclerotized, with bulbus ejaculatorius projecting from antero-dorsal opening, posterior opening sinuous.Siderone nemesis catarina Dottax and Pierre . Gnathos open, in lateral view elongate, completely enveloped by membranes.Valva rectangular. Fultura inferior narrow and semi-circular.Penis: aedeagus sclerotized, with bulbus ejaculatorius projecting from antero-dorsal opening, posterior opening large and sinuous.Zaretis isidora (Cramer) ((Cramer) . Tegumen subtriangular in lateral view, anterior projection wider than long, appendices angulares as wide as long. Arms from tegumen and saccus distinct. Anterior projection from saccus elongated in lateral view, at least three times longer than wide; posterior projection from saccus absent.Uncus slender, apex slender and descending, in dorsal view fused with tegumen, distinct from tegumen by light sclerotization. Anal tube developed, with ventral portion sclerotized (subscaphium). Gnathos open, in lateral view elongate, distal portion of both gnathos close to each other, tegument fold on distal portion shell-like.Valva rectangular, with inner and outer ends conspicuous. Fultura inferior narrow and semi-circular.Penis: aedeagus sclerotized, with bulbus ejaculatorius projecting from antero-dorsal opening.Anaeomorpha splendida Rothschild  (storfer) , 33 E. Tegumen rectangular, anterior projection as wide as long, anterior tegument fold projecting outward; appendices angulares wider than long. Arms from tegumen and saccus fused. Anterior projection from saccus subrectangular in lateral view; posterior projection present, shorter than anterior.Uncus thick, with short setae on ventral distal portion, apex slender, in dorsal view fused with tegumen, uncus differing from tegumen by a light sclerotization. Anal tube reduced and entirely membranous. Gnathos open, in lateral view long, with descending projection, apex shaped like a club, concave, striated.Valva semi-triangular, distal expansion of inner tegument with short setae, conspicuous spine arising from outer tegument. Fultura inferior bilobed with dorsal median notch.Penis: aedeagus membranous ventrally, with bulbus ejaculatorius projecting from antero-drosal opening.Archaeoprepona chromus chromus (Gu\u00e9rin-M\u00e9neville) (neville) . Tegumen rectangular in lateral view, anterior projection wider than long, fold from anterior tegument projecting outward, appendices angulares longer than wide. Arms from tegumen and saccus distinct. Anterior projection from saccus elongated dorsoventrally in lateral view; posterior projection shorter than anterior projection, with sharp apex.Uncus thick, in dorsal view fused with tegumen, uncus differing from tegumen by a light sclerotization, dorsal lobe with conspicuous boundaries. Anal tube reduced and entirely membranous. Gnathos open, in lateral view with proximal portion elongated, distal portion descending and striated.Valva semi-triangular, distal expansion of tegument, and distal spine. Fultura inferior bilobed, with dorsal and ventral notches.Penis: aedeagus with ventral portion membranous, bulbus ejaculatorius projecting from antero-ventral opening.Archaeoprepona demophon muson(Fruhstorfer) (storfer) . Tegumen rectangular in lateral view, anterior projection as wide as long, anterior tegument fold projected outward, appendices angulares wider than long. Arms from tegumen and saccus fused. Anterior projection from saccus absent; posterior projection present, developed, subtriangular with distal portion sharp.Uncus thick, in dorsal view fused with tegumen, uncus differing from tegumen by a light sclerotization, dorsal lobe with conspicuous boundaries and enveloped by numerous spines on lateral portion. Anal tube reduced and entirely membranous. Gnathos open, in lateral view comma-like, striated on medial distal portion.Valva subtriangular, distal expansions of inner tegument, with spine arising from outer tegument and with long setae. Fultura inferior bilobed and articulated with ventral area of valva.Penis: aedeagus, ventral portion membranous, medial-anterior region dilated in lateral view, narrow in dorsal or ventral views, bulbus ejaculatorius projecting from antero-dorsal opening.Archaeoprepona demophoon andicola (Fruhstorfer) (storfer) , 27 A\u2013E. Tegumen rectangular in lateral view, anterior projection wider than long, tegument fold reduced and covering part of the hollow, which distinguishes the arms from tegumen; appendices angulares wider than long. Arms from tegumen and saccus distinct. Anterior projection from saccus subrectangular in lateral view, twice as long as wide; posterior projection present shorter than anterior projection, slender distally and descending.Uncus thick, in dorsal view fused with tegumen, uncus differing from tegumen by a light sclerotization, dorsal lobe with conspicuous boundaries. Anal tube reduced and entirely membranous. Gnathos open, in lateral view comma-like, striated on distal two thirds.Valva semi-triangular, distal expansion of inner tegument, spine arising from outer tegument. Fultura inferior bilobed and dorsal inner margins rounded.Penis: aedeagus wider dorsoventrally when compared with other species of the genus, anterior ventral portion rounded, small anterodorsal lobe and median constriction preceding manica, ventral portion membranous, bulbus ejaculatorius projecting from antero-dorsal opening.Archaeoprepona licomedes licomedes (Cramer) ((Cramer) . Tegumen rectangular in lateral view, anterior projection wider than long, anterior ventral fold projected outward, appendices angulares wider than long, ventral margin sinuous. Arms from tegumen and saccus distinct. Anterior projection from saccus subtriangular in lateral view; posterior projection shorter than anterior, diamond-shaped.Uncus thick, in dorsal view fused with tegument, uncus differing from tegumen by a light sclerotization, dorsal lobe with conspicuous boundaries. Anal tube reduced and entirely membranous. Gnathos open, in lateral view with two flattened, folded plates in lateral view, distal plate descending and striated on outer portion.Valva subtriangular, distal expansion of inner tegument, and distal spine arising from outer tegument. Fultura inferior bilobed, lateral margins sinuous, a smooth ventral-median notch and deep dorsal median notch.Penis: aedeagus, ventral portion entirely membranous, bulbus ejaculatorius projecting apicallyArchaeoprepona meander castorina (E. Mayr) (E. Mayr) . Tegumen rectangular in lateral view, anterior projection wider than long, tegument fold small and projected outward, appendices angulares longer than wide. Arms from tegumen and saccus distinct. Anterior projection of saccus semi-triangular in lateral view, longer than wide; posterior projection present, shorter than anterior projection.Uncus slender, with expansion from median to distal portion, ventral margin sinuous, apex slender and descending, in dorsal view fused with tegumen, uncus differing from tegumen by a light sclerotization. Anal tube reduced and entirely membranous. Gnathos open with distal portion striated.Valva semi-triangular, distal expansion arising from inner tegument, and distal spine arising from outer tegument. Fultura inferior bilobed.Penis: aedeagus with a concavity on ventral median portion, membranous ventrally, bulbus ejaculatorius projecting apically.Prepona claudina annetta (Gray) (a (Gray) . Tegumen semi-trapezoidal in lateral view, anterior projection wider than long, deep depression on posterior ventral portion, appendices angulares wider than long. Arms from tegumen and saccus distinct. Anterior projection from saccus oval in lateral view, longer than wide; posterior projection present, shorter than anterior.Uncus thick, elevated on proximal dorsal portion, with distal portion descending, in dorsal view fused with tegumen, uncus differing from tegumen by a light sclarotization. Anal tube reduced, entirely membranous and linked to the gnathos. Gnathos open, in lateral view elongate, with long arm and with spiny apical club on, projected dorsally.Valva triangular. Fultura inferior rectangular, taller than wide, dorsally with two convex areas covered with small spines, tegument fold projecting laterally.Penis: aedeagus sclerotized dorsally and with ventral sclerotization restricted to median region, bulbus ejaculatorius projects from antero-ventral opening.Prepona laertes laertes (Hubner) ((Hubner) . Tegumen semi-trapezoidal in lateral view, anterior projection wider than long, dorsal margin with small folds, appendices angulares wider than long. Arms from tegumen and saccus distinct. Anterior projection from saccus oval in lateral view; posterior projection absent.Uncus thick, apex slender and descending, in dorsal view fused with tegumen, conspicuous constriction between uncus and tegumen. Anal tube reduced and entirely membranous. Gnathos open, in lateral view long, with spiny club projected dorsally, and extended beyond uncus.Valva triangular. Fultura inferior rectangular, taller than wide, with basal lateral folds projected outward.Penis: aedeagus sclerotized, with tegument fold preceding manica, bulbus ejaculatorius projecting from antero-ventral opening.Prepona pylene pylene Hewitson  rectangular, common to species of Archaeoprepona and Noreppa; (3) triangular, clustering Anaea troglodyta with Anaeomorpha splendida; and (4) subtriangular, common among species of Anaeini, and clustering species of Coenophlebia, Consul, Fountainea, Prozikania, Pseudocharaxes, Siderone, Zaretis, and most species of Memphis.This sclerite is structurally diverse across the group, with differences in at least five areas. Four shapes have been identified in lateral view: (1) semi-trapezoidal, clustering species of Fountainea  and a few species of Anaeini . When present, the anterior projection of the tegumen is often developed, longer than wide or as wide as long. Such projection is reduced or is as wide as long only in Anaeomorpha splendida, Archaeoprepona amphimachus pseudomeander, and Archaeoprepna demophon muson.With a few exceptions, enumerated below, the anterior projection of the tegumen is developed. It is lacking in most species of Other modifications in the tegumen were the presence or absence of a fold in the tegument on the anterior margin and appendices angulares. The latter are ubiquitous among the species studied and vary in their dimensions, being wider than long, as wide as long, or longer than wide.P. xenocrates punctimarginale, with the arms of the tegumen separated and distant from the arms of the saccus. Therefore, the fusion between these two structures has not revealed a suitable character to group species or genera.Some differentiation between the ventral arms from the tegumen and the dorsal arms from the saccus was found in 23 of the 31 species analyzed, with special emphasis for Agrias and Prepona; rectangular, a shape found only in Anaea troglodyta; subtriangular, characteristic of Anaeomorpha splendida, Archaeoprepona demophoon andicola, Archaeoprepona licomedes licomedes, Pseudocharaxes xenocrates punctimarginale, and Memphis lemnos; subrectangular, as in Archaeoprepona amphimachus pseudomeander, Archaeoprepona domophon muson, and Memphis hirta; triangular, as in Archaeoprepona meander castorina and Memphis glauce glauce; and elongated, characteristic of species of Consul, Fountainea and Hypna, as well as Coenophlebia archidona, Noreppa chromus chromus, Prozikania suprema, Siderone nemesis catarina, Zaretis isidora, Memphis acidalia victoria, Memphis moruus stheno, Memphis phlilumena corita, and Memphis polyxo.Thirty species have a saccus with an anterior projection. The degree of development of this projection varies among species, and six shapes have been identified for it: oval, common among species of Anaeomorpha splendida and Archaeoprepona domophon muson.A posterior projection arising from the saccus was present in approximately 50% of the species studied. This projection can be shorter than the anterior projection, a widespread state, or it can be subequal to or longer than the anterior projection, a state present in Preponini contains only one species with a slender uncus, Archaeoprepona meander meander. All other species in this tribe, as well as the species Hypna and Coenophlebia (Anaeini), have a thick uncus. The uncus is slender in species of Anaea, Consul, Memphis, Fountainea, Siderone, Prozikania, Pseudocharaxes, and Zaretis.Among the structural differences found in the uncus, we highlight its shape in lateral view, which can be thick (three times longer than wide) or slender (more than three times longer than wide). The tribe Anaeomorpha splendida, Archaeoprepona amphimachus pseudomeander, and Prepona laertes laertes have a dorsal seta. Other differences in this structure among species are as follows: the presence or absence of crests (present only in two subspecies of Hypna clytemnestra), presence or absence of spines on the dorsal portion , and the presence or absence of a fenestra. When present, the fenestra may be found either on the central portion  or at the base of the uncus (Hypna clytemnestra forbesi and Hypna clytemnestra huebneri).The uncus also varies in the presence or absence of setae on its dorsal portion. The uncus of Fountainea nessus and Fountainea ryphea phidile.The degree of sclerotization of the ventral portion was the only difference found in the anal tube. Species that have the ventral portion of the anal tube sclerotized were considered as having a subscaphium. This character can be used to separate between Anaeini, Anaeomorphini and Preponini. Species of Preponini and Anaeomorphini do not have a subscaphium, whereas species of Anaeini do, with two exceptions, The gnathos has two basic shapes in the species studied. It may form a handle enveloping the anal tube, in which case it is called \u201csingle\u201d or \u201cclose,\u201d or it may be divided into two distinct arms, and be called \u201cdouble\u201d or \u201copen.\u201d In our sample, the gnathos is single in species of Anaeini and double in species of and Anaeomorphini Preponini, with some modifications among species.Agrias and Prepona; shaped as an anvil, unique to Anaea troglodyta; covered by the tegument, unique to Anaeomorpha splendida; thick, present in Archaeoprepona and Noreppa; with base wider than distal portion, as in Anaeini, except for Anaea troglodyta. Regarding the modifications on the distal portion, they can be smooth, with spiny club, or with distal margin serrated or striated and enveloped by membranes.Five aspects were identified concerning the shape of the gnathos: elongated, present in species of Agrias and Prepona; subtriangular, in species of Anaea, Anaeomorpha, and Archaeoprepona; circular, common to the species of Hypna and Consul, as well as Memphis acidalia victoria, Memphis hirta, and Memhis polyxo; rectangular, as in Pseudocharaxes xenocrates punctimarginale,Siderone nemesis catarina, and Zaretis isidora; and subrectangular, as in all species of Fountainea, Coenophlebia archidona, Memphis philumena corita, Memphis moruus stheno, Memphis lemnos, Memphis glauce glauce, and Prozikania suprema.The valvae assume various shapes: triangular, as in Archaeoprepona, Fountainea, Consul, Prozikania, Pseudocharaxes, and Memphis (except for Memphis moruus stheno) had an apical projection.Besides the shape, the structure of the valvae may also vary. For instance, the presence of an apical projection is a variable feature within tribes, but stable within genera. In our sample, the valva of all species of Fountainea halice halice, Memphis glauce glauce, Memphis hirta, Memphis polyxo); presence or absence of spines on the saccus (present in species of Memphis); presence or absence of an apical projection of the valva, presence or absence of setae on the inner tegument of the valva . These characters can be further investigated, and the location and shape of spines can be detailed.Beyond the characters described above, the following features have been found to be variable: presence or absence of spines on costa  and Archaeoprepona (including Archaeoprepona chromus chromus), thus confirming the arrangement of the genera proposed by Ortiz-Acevedo and Willmott  that had not been previously used in the taxonomy of the group. Therefore, they include structures not previously considered. These characters can be used in the future in a phylogenetic analysis or when devising more consistent diagnostic characters for species and genera.Prozikania and Pseudocharaxes as genera, synonymized by Lamas , and again used by Salazar (The detailing of such structures can be geared towards the maintenance of the status of by Lamas  with Pol Salazar . The sig Salazar , Rydon ( Salazar , and Sal Salazar , justify"}
+{"text": "Children with malignancies, including neuroblastoma (NB), may present to their primary physician with complaints that mimic those seen in systemic juvenile idiopathic arthritis (sJIA). The purpose of this investgation was to identify significant distinctions between patients with systemic JIA and neuroblastoma at the time of disease presentation.A retrospective chart review was completed on all patients less than age 18, between 1990 and 2009 at Pennsylvania State University Children\u2019s Hospital, with a diagnosis of either sJIA or NB. The following variables were identified at the time of presentation; gender, age, race, time to diagnosis, presenting signs and symptoms, neuroblastoma stage, LDH, uric acid, sedimentation rate, CRP, platelet count, hemoglobin, peripheral white blood cell count, percentage of neutrophils and lymphocytes, ferritin, and d-dimer. Other categorical information included whether or not the patients had gait disturbance or extremity pain, fever, rash, abdominal mass, arthritis, fatigue, or weight loss. Individual logistic regression models were evaluated for each variable, with sJIA or NB as the outcome. Given that patients with NB and extremity pain may be referred to orthopedics or rheumatology first, instead of a timely referral to hematology/oncology, a subgroup analysis was completed for those patients.There was a total of 65 sJIA and 89 NB patients. Demographically, sJIA patients were significantly older . Symptomatically, the sJIA patients had fever, rash,arthritis, and extemity pain or gait disturbance (41% vs. 18%) more frequently . Laboratories were also significantly different between the groups. NB patients had higher LDH and uric acid levels, while sJIA patients had higher platelet counts, total peripheral WBC, had relative neutrophilia , and had higher ferritin levels than the NB patients (p=0.001), see Table There are significantly different demographic, presenting symptoms, and laboratories at the time of presentation of patients who are ultimately diagnosed with sJIA or NB. In particular, there are discerning laboratories that may help facilitate an appropriate and timely referal to oncology when extremity pain or gait disturbance are among the intial signs and symptoms.Lisabeth Scalzi: None; Greg Hychko: None; Barbara E. Ostrov: None; Catherine A. Bingham: None; David Ungar: None; Brandt P. Groh: None."}
+{"text": "To the Editor: Torquetenovirus (TTV) and torquetenominivirus (TTMV) are characterized by a small, negative-sense, circular, single-stranded DNA genome and by an extraordinary ability to produce chronic plasma viremia. Indeed, >80% of humans harbor variably high viral loads of TTV, TTMV, or both, in plasma, regardless of geographic provenance, age, sex, and health conditions (Circoviridae) genus Anellovirus, but their extreme genetic heterogeneity and some distinctive features in genomic organization have led some to suggest that they should be classified as an independent family  and, for comparison, 35 healthy donors  for SAV in plasma by using the polymerase chain reaction (PCR) primers described by Jones et al.  of anelloviruses , our results suggest that, similar to TTV ("}
+{"text": "Opercular syndrome, also known as Foix-Chavany-Marie syndrome, is a paralysis of the facial, pharyngeal, masticatory, tongue, laryngeal, and brachial muscles. It is a rare cortical form of pseudobulbar palsies caused by vascular insults to bilateral operculum. Its clinical presentations include anarthria, weakness of voluntary muscles involving face, tongue, pharynx, larynx, and masticatory muscles. However, autonomic reflexes and emotional activities of these structures are preserved. In the present case, an 81-year-old male presented with acute onset of anarthria with difficulties in chewing, speaking, and swallowing that was diagnosed with opercular syndrome. Opercular syndrome (OPS) is a rarely seen cortical type of pseudobulbar palsy that is characterized by paralysis of facial, lingual, pharyngeal, and masticatory voluntary muscles with preservation of autonomic, involuntary, and reflexive functions . OPS, faHerein, we report an 81-year-old male presenting with acute onset of aphonia, and facio-labio-glosso-pharyngo-laryngeal paralysis with preservation of involuntary and emotional activities. An 81-year-old right-handed male presented with acute onset of sound volume loss, inability to swallow and speak, inability to move tongue, and difficulties in chewing the foods. The past medical history was remarkable for diabetes mellitus, hypertension, coronary artery disease, and benign prostate hypertrophy. His first cerebral vascular event presenting with right-sided arm and leg weakness was observed about 4 years ago and his weakness was recovered completely. However, he has not used suggested antiplatelet treatment up to now. The family history was unremarkable. In neurological assessment, he was aphonic, but his verbal and reading perception was normal. He was able to answer the questions with signs and writing. The pupillary, corneal reflexes, and extraocular movements were intact. The left nasolabial sulcus disappeared. He was not able to open the mouth, protrude the tongue, show the teeth, whistle, chew, and swallow. The tongue was on the midline and immobile. No tongue atrophy, fibrillation, and deviation were observed. The taste sensation was intact. Palatal, laryngeal, blink, and gag reflexes, spontaneous smiling, and yawning were protected. The upper and lower limbs muscles strengths were 5/5. Deep tendon reflex was normoactive. Babinski response was absent. Extrapyramidal, coordination, and sensory examinations were normal. No vocal cord paralysis was detected on the laryngoscopic examination. The laboratory investigation including liver and kidney function, complete cell count, urinalysis, and erythrocyte sedimentation rate was normal. A transthoracic echocardiogram showed biatrial dilatation, mild calcification of mitral and aortic valves, and mild aortic and mitral valves insufficiency. A doppler ultrasonography of carotid and vertebral arteries was unremarkable. The magnetic resonance imaging (MRI) of brain indicated right frontal opercular acute infarct with 3.3 \u00d7 2.6\u2009cm on dimensions  and bilaOPS is characterized by anarthria and paralysis of the facial, pharyngeal, masticatory, tongue, laryngeal, and brachial voluntary muscles. Operculum refers to the brain cortex covering the insula, inferior frontal, pre- and postcentral, supramarginal, angular , and superior temporal gyrus. OPS is particularly originated from the damages that are located in posterior part of the inferior frontal gyrus and inferior part of precentral gyrus . There aThe voluntary muscle controls of the face, tongue, and pharynx are provided by primary motor cortex and pyramidal tract, whereas the spontaneous and emotional controls are provided by thalamus, hypothalamus, and extrapyramidal tract . The selThe etiologic factors of OPS include thrombotic or embolic multiple strokes, head trauma, tumor, developmental perisylvian dysplasia, multiple sclerosis, acute disseminated encephalomyelitis, moyamoya disease, vasculitis, and neurodegenerative disease . IschemiPseudobulbar paralysis in OPS is clinically distinguished from bulbar paralysis, disorders of the cranial nerves and neuromuscular junction  by normal eye movements, preserved or hyperactive brainstem reflexes , the dissociation of automatic and volitional movements of the bulbar muscles with preservation of automatic movements, and the absence of atrophy and fasciculations of the lower motor neuron-innervated muscles .The treatment and prognosis of OPB is related to underlying etiological factors. However, clinical improvement is usually poor. Chewing, swallowing, and speech functions do not usually recover completely. Patients with OPS have a significant risk for aspiration pneumonia. Therefore, during acute treatment and rehabilitation process, speech dysfunction and feeding are two most important issues. In our case, no improvement in speech, swallowing, and chewing functions was observed. He could produce nonsense sounds and open the mouth at the end of the 3rd weeks. Preserving patients from OPS can be possible via preventive treatment of repetitive stroke."}
+{"text": "Affiliation 2 for the third, ninth and last authors is incorrect. The correct affiliation is: Genomics and Bioinformatics Unit, Agriaquaculture Nutritional Genomic Center (CGNA), Temuco, La Araucan\u00eda, Chile."}
+{"text": "Pangi Valley is the interior most tribal area in Himachal Pradesh of Northwest Himalaya. An ethnobotanical investigation is attempted to highlight the traditional knowledge of medicinal plants being used by the tribes of Pangi Valley. Various localities visited in the valley 2-3 times in a year and ethnobotanical information was collected through interviews with elderly people, women, shepherds, and local vaids during May 2009 to September 2013. This paper documented 67 plant species from 59 genera and 36 families along with their botanical name, local name, family name, habit, medicinal parts used, and traditional usage, including the use of 35 plants with new ethnomedicinal and other use from the study area for the first time. Wild plants represent an important part of their medicinal, dietary, handicraft, fuel wood, veterinary, and fodder components. These tribal inhabitants and migrants depend on the wild plant resources for food, medicines, fuel, fibre, timber, and household articles for their livelihood security. The present study documents and contributes significant ethnobotanical information from the remote high altitude and difficult region of the world, which remains cut off from rest of the world for 6-7 months due to heavy snowfall. Pangwali and Bhoti. Both Hinduism and Budhism are practised in the valley. The tribal people of Pangi are called the \u201cPangwal.\u201d The high altitudinal villages of Pangi Valley are called Bhatories and their residents are referred to as \u201cbhots.\u201d These people are mostly Buddhists and have Tibet-Mongolian features. Adjoining hills of Pangi Valley towards the southern side are visited frequently by migratory pastoralist tribal Gaddis and nomadic Gujjars with their herds. These migrants go to higher altitudes in summer along with their herds in search of grazing ground and meadows. They also collect different parts of various medicinal and aromatic plants for their earnings. Local songs, dance (Nati by gents and Ghurei by ladies), and locally brewed liquor \u201cpaatar,\u201d play a significant role on the life style of the people of Pangi Valley. One of the major festivals celebrated in the mid of February is \u201cJukaru,\u201d praying to local god or deities with words of celebration and thanks for helping the people to survive the harsh winter. One is compelled to think of how and why people thought of settling down in this most inaccessible part of the state. The vegetation of Pangi can be broadly categorized into three types:- Himalayan Temperate Forests\u2014At low altitude between 1,900\u20132,800\u2009m; the vegetation is typically of Himalayan temperate type. Pinus gerardiana, Cedrus deodara, Pinus wallichiana, Picea smithiana, Abies spectabilis, Taxus baccata ssp. wallichiana, Juniperus macropoda, Populus ciliata, Salix viminalis, Crataegus songarica, and Acer pentapomicum forming the top canopy. The second storey is constituted by Fraxinus xanthoxyloides, Rhus succedana, Parrotiopsis jacquemontiana, and Olea ferruginea. Shrubby and scrub elements include species of Berberis lycium, Ribes orientale, R. nigrum, Rosa webbiana, Viburnum cotonifolium, Lonicera quinquelocularis, Hippophae rhamnoides, Myricaria squamosa, Daphne oleoides, Rubus saxatilis, and Sorbus foliosa. Rabdosia rugosa, Ephedra gerardiana, Artemisia brevifolia, A. maritima, and A. parviflora form dense scrubs covering vast tracts of slopes in the region. At altitude between 2,800\u20133,800\u2009m, the vegetation is subalpine type represented by Allium humile, Bunium persicum, Carum carvi, Geranium wallichianum, Angelica glauca, Bupleurum falcatum, Elsholtzia ciliata, Heracleum lanatum, Arisaema flavum, Primula denticulata, P. macrophylla, Saussurea costus, S. auriculata, Tanacetum gracile, T. tomentosum, T. tenuifolium, Impatiens glandulifera, Arnebia benthamii, Eritrichium canum, Ranunculus laetus, R. hirtellus, Rhododendron campanulatum, Ribes orientale, R. alpestre, Polygonatum multiflorum, P. verticillatum, Plantago depressa, Lepidium latifolium, Polygonum sibiricum, Potentilla atrosanguinea, Anemone obtusifolia, Aconitum ferox, A. falconeri, Dactylorhiza hatagirea, Picrorhiza kurroa, Pedicularis pectinata, Elymus dahuricus, Aesculus indica, Corylus jacquemontii, and Juglans regia. Alpine zone ranging from 3,800\u2009m onwards, the vegetation is mainly dominated by species of Betula utilis, Rhododendron campanulatum, Myricaria squamosa, Capparis himalayensis, Cassiope fastigiata, Cortia depressa, Selinium tenuifolium, Heracleum wallichii, Inula royleana, Saussurea graminifolia, S. obvallata, S. gossypiphora, Arnebia euchroma, Corydalis meifolia, Iris kumaonensis, Fritillaria roylei, Polygonum affine, Rhododendron anthopogon, Rheum spiciforme, R. moorcroftianum, Rhodiola imbricata, Rheum australe, Picrorhiza kurroa, Aconitum heterophyllum, A. rotundifolium, A. violaceum, A. spicatum, Elymus nutans, E. dahuricus, Delphinium cashmerianum, D. vestitum, and Nardostachys grandiflora. Other herbaceous vegetation consists of Saussurea jacea, Triglochin maritima, Aquilegia fragrans, Potentilla spp., Onosma hispidum, Spinosa stracheyi, Geranium wallichianum, Jurinea macrocephela, Picrorhiza kurroa, Dracocephalum heterophyllum, Impatiens brachycentra, and Primula macrophylla. Covering an area of 103\u2009sq\u2009km, Saichu Tuan Nala Wild Life Sanctuary has been established in the valley for the protection and conservation of wildlife. The wild animals found in the valley are ibex, himalayan tahr, brown bear, black bear, musk deer, snow leopard, and bharal. The birds include the monal and koklas pheasants, himalayan western tragopan, snow peacock, snow pigeon, and chukor. This area was difficult to explore due to its remoteness, difficult geographic condition, and poor connectivity via roads due to heavy snow fall during winter season which keeps the area cut off from rest of the world for nearly six to seven months. These tribal inhabitants and migrants are dependent on the wild plant resources for medicines, food, fuel, fibre, timber, and household articles to a great extent for their livelihood security. The area due to its remoteness and difficult geographic conditions has not been included in the earlier floristic surveys of Chamba district by Singh and Sharma [The cold arid region of India also called \u201cTrans Himalayan region\u201d lies in the western edge of the Himalayas. It comprises Ladakh in J&K, Lahaul and Spiti, Kinnaur, Pangi Valley of district Chamba in Himachal Pradesh, and Niti and Nelong Valley of Uttarakhand. The vegetation here is subjected to extreme climatic conditions such as temperature variation (low temperature), scanty rainfall, speedy winds, exposure to ultraviolet radiations, reduced oxygen levels, low humidity, and many small glaciers. Pangi Valley, a subdivision of Chamba district is the remote high-altitudinal area and one of the most beautiful valley in the Northwest Himalaya. The river Chandrabhaga flows through deep narrow gorges in the Pangi Valley. It originates from Baralacha glacier in Lahaul-Spiti and enters in Pangi Valley near Karhu Nala. It becomes the Chenab when it joins the Marau River at Bhandera Kot, 12\u2009km from Kishtwar town in Jammu and Kashmir. The Valley has recently been connected by road via Sach Pass at a height of 4,350\u2009m, the highest road in Himachal Pradesh. It is also the shortest route from Chamba to Killar (170\u2009km) and is open for vehicular traffic between mid June and September, but it remained closed due to heavy snowfall at other times of the year. One can approach the Valley via Chamba-Manali-Killar (680\u2009km) and Chamba-Jammu-Doda-Gulabgarh-Killar (570\u2009km), but these are very long routes compared to the Chamba-Sach Pass-Killar route. The old trade routes still exist which connect Pangi Valley to Ladakh of Zanskar range in the adjoining state of Jammu and Kashmir. Practically all the people live in small and fairly isolated villages. The languages spoken by the people are Ethnobotanical surveys were carried out from May 2009 to September 2012, when the area is snow-free. Different localities visited in the Pangi valley 2-3 times a year to document the utilization of medicinal plants  includinInula racemosa and Saussurea costus are domesticated and cultivated for medicinal or commercial purposes. However, people also trying to grow some medicinal plants such as Aconitum heterophyllum, Podophyllum hexandrum, Angelica glauca, Valeriana jatamansi, and Picrorhiza kurroa as kitchen garden plants at high altitudinal villages of Sural-Bhatroi, Hudan-Bhatorri, and Devi Kothi for their use and marketing purpose at local level. Different parts of the plants in powdered form/plant extracts/decoctions/concoction or paste are administered in various human ailments and other uses in their daily life. In most of the cases leaves are used followed by stems, fruits, roots, and flowers. Wood, seeds, and bark are the least used plant parts  is used against snake bite while a decoction of Viola canescens with  Cinnamon, Fennel, and Clove is recommended for cough, asthma, and other respiratory tract problems. Flowers of Morina coulteriana and M. longifolia are mixed with guggal  are used as incense for ritual performances and for pleasant aroma during meditation and prayer. By comparing the earlier reported ethnobotanical/ethnopharmacological uses/biological activities/chemical constituents , Charaka Samhita (1000\u2013800 BC), Sushruta Samhita (800\u2013700 BC), and others. In India, the art of herbal healing has very deep roots in tribal culture and folklore. Even today, most of the tribal communities are dependent upon local traditional healing systems for their primary health care. Tribes of Pangi Valley depend highly on the wild plants for their livelihood security and medicines for various ailments. The ethnobotanical information discussed here is the first ever comprehensive ethnobotanical information gathered from the \u201cPangwal\u201d tribe. The herbal medicines are considered to be of great importance among different rural or indigenous communities in many developing countries [Onosma hispida and Ranunculus laetus were reported for cuts and wounds from the research area are new to use. Smoke of flowers of Morina coulteriana and M. longifolia mixed with guggal  is used as incense during meditation and prayer. Use of pleasant aroma of smoke during meditation is also performed in Chinese culture [ Cicer microphyllum, Desmodium elegans, Hedera nepalensis, Impatiens sulcata, Lonicera quinquelocularis, Morus serrata, Origanum vulgare, Rumex acetosa, Silene vulgaris, Smilax aspera, and Ulmus wallichiana have also been documented as fodder plants in this study. Preparation of paste for the treatment of ailments is a common practice among the other tribal communities in India [The widespread use of herbal materials for the maintenance of health and treatment of diseases can be traced back to prehistoric times throughout many cultures and regions. The history of herbal medicine in India is very old. The oldest use of plants has been documented in ancient Hindu scriptures like ountries . During ountries . The Himountries , 59. Culda 4500\u201310 BC, Chaountries , 61, 62 ountries , 44, 49 ountries \u201367. Some culture . Livestoin India , 70. Plain India , 72. Pre"}
+{"text": "After publication of this work , we noteThe authors declare that they have no competing interests.JL and JW conceived and designed the experiments. MW, LW, QL and PK performed the experiments. MW, LW, QL, PK, JL, JQ and JW analyzed the data. JW wrote the paper. All authors read and approved the final manuscript."}
+{"text": "Cardiocascular Journal of Africa (CVJA) is making great strides but faces considerable challenges. It is now well accredited in all of the major databases in the world and is widely read. The increase in readership over the past year was 33% and 3 000 articles are downloaded monthly via Pubmed LinkOut. This reflects usage of only four years of the CVJA, which has a dataset of 400 full-text articles in Pubmed.The However, we are facing a bottleneck due to insufficient appropriate reviewers for the submitted articles, and this is causing a delay in publishing these articles. It appears that South African reviewers take greater pride in reviewing articles for foreign journals. The CVJA is as well rated as any foreign journal. We are now as a matter of policy also registering authors as reviewers.Please note that because of the backlog in printed publications we have provided authors with the opportunity to publish ahead of print. This implies that your article will appear in an electronic version such as PubMed and elsewhere. There will, however, be an additional charge of R1 000 for African authors and R3 000 for overseas authors.We now have CrossCheck available to check for any suspected plagiarism in articles.Ek wil graag outeurs nooi om ook wetenskaplike werk voor te l\u00ea vir publikasie in CVJA in Afrikaans of ander inheemse Afrika tale. Dit sal gelyke aandag geniet as die engelse artikels met dieselfde soort erkenning en verspreiding. Die tydskrif wil baie graag jonger navorsers op die gebied van hartsiektes aanmoedig om navorsingswerk op te skryf. Ons oorweeg tans \u2019n toekenning vir \u2019n artikel wat in Afrikaans of \u2019n inheemse taal geskryf is en toepaslik is vir Afrika siektes en omstandighede.Indien daar geen eweknie beoordeelaars (peer reviewers) beskikbaar is vir \u2019n bepaalde artikel, word die manuskrip terug gestuur aan die outeur.If no reviewers are available for reviewing the article, it will unfortunately have to be sent back to the author.We thank the following South Africans who reviewed articles for the CVJA during 2010:Julia Aalbers, M Abelson, J Badenhorst, Piet Becker, Megan Bester, Paul Brink, Geoffrey Candy, R Chauke, Ashley Chin, Daneel Dietrich, Stefan du Plessis, Anna-Mart Engelbrecht, Rajiv Erasmus, Rafique Essop, M Faadiel Essop, Mieke Faber, Julia Goedecke, Vladimir Grigorov, Dave Harris, Mbuilu Jody, James Ker (jun), James Ker (sen), John Lawrenson, Melanie Louw, Leon\u00e9 Malan, Maurice Mars, J Marx, Indres Moodley, M Mpe, Cephas Musabayane, M Ntsekhe, Andrzej Okreglicki, Brian Rayner, Paul Rheeder, Saartjie Roux, Robert Schall, Aletta Schutte, R Scott-Millar, Y Seedat, Brandon Shaw, Karen Sliwa, Jan Smedema, Cornelius Smuts, Harris Steinman, Krisela Steyn, Nicky Sulzer, H Theron, Nico van der Merwe, Lynette van der Merwe, Willie van Heerden, Jacques van Rooyen, W Venter, Corinna Walsh, Paul Williams, Angela Woodiwiss, Liesl Z\u00e4uhlke, Makhosazane Zungu"}
+{"text": "Phthalic acid esters (PAEs) have been employed in polymer materials as a plasticizer to form them more flexible, adhesive, and soluble. These compounds are mainly used in paints, varnishes, personal cares, cosmetics, paper coatings, and adhesives even in bottled waters, shampoo, body deodorant, hairspray, and gels. Phthalates are able to possess remarkable toxic variations depending on their structures. So far, Di-(2-EthylHexyl) Phthalate DEHP and Di-n- Butyl Phthalate DBP have been found to cause reproductive and developmental toxicities. The U.S. Environmental Protection Agency (EPA) classified DEHP as probable human carcinogen. To the best of our knowledge, phthalates showed diverse toxicity profiles according to their structures in the liver, kidneys, thyroid, and testes, which are involved in general toxicity. Furthermore, they are introduced as hormonally-active agents, because they can interfere with the endocrine system in human. Incidence of developmental abnormalities  seems increasing via high exposure to phthalate metabolites. Although, increasing the capacity for phthalate free plasticizer productions is the first step to restrict the distribution of these toxic manmade compounds, finding the new ways for phthalate absorption from the soil in agricultural fields may have benefits. Also, evaluation and examination of diverse sources of medicinal and food plants to determine the level of phthalate accumulation in their organs are extremely recommended to avoid creating toxicity particularly in reproductive systems. Phthalic acid esters (PAEs) have been employed in polymer materials as a plasticizer to form them more flexible, adhesive, and soluble. These compounds are mainly used in paints, varnishes, personal cares, cosmetics, paper coating, and adhesives even in bottled waters, shampoo, body deodorant, hairspray and gels . Di-n-BuPhthalates are able to possess remarkable toxic variations depending on their structures. So far, DEHP and DBP have been found to cause reproductive and developmental toxicities. The U.S. Environmental Protection Agency (EPA) classified DEHP as probable human carcinogen. To the best of our knowledge, phthalates showed diverse toxicity profiles according to their structures in the liver, kidneys, thyroid, and testes, which are involved in general toxicity. Furthermore, they are introduced as hormonally-active agents, because they can interfere with the endocrine system in human .via high exposure to phthalate metabolites [via mouthing items as well as breast milk, infant formulas, plastic food container and toys, cups and bowls, and even indoor air. Epidemiological evidence revealed that boys, whose mothers exposed to phthalates during pregnancy, showed an augmented incidence of inborn genital malformations and spermatogenic dysfunction [Incidence of developmental abnormalities  seems increasing abolites . The impabolites . Anotherfunction . RegardiTriticum aestivum, Brassica napus, Zea mays) have been specifically mentioned [Raphanus salivas) and wheat (T. aestivum) exposed to the vapor of DBP, the accumulation of phthalate (106 times per 3 days) was observed significantly in the cuticular and wax layers [Interestingly, plants receive both nutrients and toxic substances through the roots as well as above-ground green parts. High accumulation of phthalates in stems of some types of crops has been reported . For insentioned . Actuallx layers .Phyllanthus, the famous medicinal plants, have been reported to produce phthalates (bis (2-ethyloctyl) phthalate and bis (2-ethylicosyl) phthalate), which most often exhibited antimicrobial activities [Calotropis gigantea led to separation of DEHP. The minimum inhibitory concentration (MIC) of this compound was measured between 13 and 128 \u03bcg/mL against Staphylococcus aureus, Bacillus subtilis, B. megaterium, Sarcina lutea, Escherichia coli, Shigella sonnei, S. shiga, S. dysenteriae, Aspergillus niger, A. flavus, A. fumigatus and Fusarium sp. This compound showed toxicity against Artemia salina larvae (IC50 = 9.2 \u03bcg/mL) too [Pongamia pinnata, an Indian medicinal plant, have been reported to consist of bis (2-methylheptyl) phthalate and the mentioned compound exhibited inhibitory activity against White Spot Syndrome Virus (WSSV) [Surprisingly, some species of the genus tivities . Moreovee IC50 = .2 \u03bcg/mL s (WSSV) . There is (WSSV) .Sargassum) can synthesize phthalate esters, but their production process and physiological role have not been clear so far [Phyllophora neruosa, Acanthophora delilei and Hypnea musciformis, while DBP is isolated from brown and green algae  raised a concern that DBP might be generated naturally [Nevertheless, the presence of phthalates in plant and algae sources might be associated with environmental exposure, production or formation of new brands of phthalates in plants is still in doubt and case of discussion between scientists. Additionally, it is proved that brown algae (like r so far . Dimethyaturally . The chae.g. Lythrum, that are usually grown in water flow in rivers and canals. In such cases, wastewater might be the origin of pollution and phthalate exposure to these plants. Sometimes, high exposure to phthalates resulted in about half part of essential oil extraction, which can cause worries to consume such medicinal plants, crops or vegetables. Although, increasing the capacity for phthalate free plasticizer productions is the first step to restrict the distribution of these toxic manmade compounds, finding the new ways for phthalate absorption from the soil in agricultural fields may have benefits. Also, evaluation and examination of diverse sources of medicinal and food plants to determine the level of phthalate accumulation in their organs are extremely recommended to avoid creating toxicity particularly in reproductive systems.Based on our unpublished data, accumulation of phthalates can occur in some medicinal plants The authors declared that there is no conflict of interest.Both authors contributed equally to the paper. Both authors read and approved the final manuscript."}
+{"text": "Complementary and alternative medicine (CAM) plays a significant role in many aspects of healthcare worldwide, including cardiovascular disease (CVD). This review describes some of the challenges of CAM in terms of scientific research. Biologically-based therapies, mind-body therapies, manipulative and body-based therapies, whole medical systems, and energy medicine are reviewed in detail with regard to cardiovascular risk factors and mediation or modulation of cardiovascular disease pathogenesis. CAM use among patients with CVD is prevalent and in many instances provides positive and significant effects, with biologically-based and mind-body therapies being the most commonly used treatment modalities. More rigorous research to determine the precise physiologic effects and long-term benefits on cardiovascular morbidity and mortality with CAM usage, as well as more open lines of communication between patients and physicians regarding CAM use, is essential when determining optimal treatment plans. The National Center for Complementary and Alternative Medicine (NCCAM) defines complementary and alternative medicine (CAM) as \u201ca group of diverse medical and health care systems, practices, and products that are not generally considered part of conventional medicine\u201d . Complem The 2007 NHIS report demonstrated that the top five most frequently used CAM therapies (excluding prayer) were natural products, such as fish oil/omega 3, glucosamine, echinacea, and flaxseed (17.7%), deep breathing (12.7%), meditation (9.4%), chiropractic and osteopathic (8.6%), and massage (8.3%), followed by yoga, diet-based therapies, progressive relaxation, guided imagery, and homeopathic treatment [qi or chi in Chinese medicine). The placebo effect must also be considered. Because many of the popular CAM therapies are in fact physical methods  of treatment, it is difficult to formulate a placebo that is both inert and indistinguishable from the real treatment. Additionally, the lack of a uniform definition of CAM and the huge diversity of the different methods, therapies, and dogmas of CAM make the studies difficult to compare [ The scientific study of CAM poses several unique challenges that must be taken into consideration in order to adequately produce and assess evidence-based data. Many forms of CAM are elements of broader healing systems based on unique theoretical constructs and systems of analysis, rather than stand-alone treatments\u2014isolating a particular therapy  from its broader discipline  may not do it justice. There is the potential for disparity in disciplines: Chinese, Korean, and Japanese acupuncture styles are different, and adjunct therapies such as manual or electrical needle stimulation and use of herbal preparations orally or through moxibustion add to the disparity. Another potential confounder is that traditional outcome measures may not capture the full effect of treatment, since many such therapies do not have well-recognized and understood physiologic mechanisms of action  is the leading cause of mortality in the United States for both men and women . ApproxiAnother study with an international basis of patient information found that the prevalence of CAM use among people with CVD ranged from 4% to 61%  [ CAM may be broadly divided into 5 separate categories: biologically-based therapies, mind-body therapies, manipulative and body-based therapies, whole medical systems, and energy medicine . The biologically-based therapies include aromatherapy, chelation therapy, diet-based therapies, folk medicine, iridology, megavitamin therapy, neural therapy, and phytotherapy/herbal medicine . A numbeMarine-derived omega-3 polyunsaturated fatty acids (fish oil) are often touted as being preventative of major cardiovascular adverse outcomes by the postulated mechanisms of lowering triglyceride levels (for which they are approved by the United States Food and Drug Administration (FDA)), preventing arrhythmias, decreasing platelet aggregation, or lowering blood pressure . And whi Garlic is used most frequently as a dietary supplement for treatment of hyperlipidemia, heart disease, and hypertension. A well-conducted, randomized trial demonstrated that there was no significant difference in LDL-cholesterol, HDL-cholesterol, triglycerides, or total cholesterol-HDL ratio after six months of treatment with three preparations of garlic versus placebo . There i There is some evidence that ginseng has a plethora of cardiovascular benefits, including cardioprotection, antihypertensive effects, and attenuation of myocardial hypertrophy and heart failure . However Ginkgo biloba is purported to have cardioprotective effects by several studies through its antioxidant, antiplatelet, antithrombotic, vasodilatory, and antihypertensive properties . A doubl Hawthorn leaf and flower extracts are advocated as an oral treatment option for patients with chronic heart failure; in fact, the German Commission E approved the use of hawthorn extracts in patients with heart failure graded stage II . The res A meta-analysis determined that overall, flaxseed supplementation was associated with a decrease in blood total and LDL-cholesterol concentrations but did not significantly affect HDL-cholesterol and triglycerides . The stu Antioxidants, which include anthocyanins, beta-carotene, catechins, coenzyme Q10, flavonoids, lipoic acid, lutein, lycopene, selenium, and vitamins C and E, have shown promising results in laboratory and observational studies; however, systematic reviews of the literature and large, randomized, controlled trials have generally found no beneficial effects of antioxidant supplements for primary or secondary prevention. In fact, vitamin A, beta-carotene, and vitamin E may actually increase mortality . The Phy Red yeast rice contains monacolin K, which has the same chemical structure as lovastatin, an inhibitor of HMG-CoA reductase . Monacol Soy protein and isoflavones (phytoestrogens) have gained attention for their potential role in improving risk factors for CVD . An Amer L-carnitine is FDA approved for replacement therapy in primary  and secondary  L-carnitine deficiencies . Many cl Chelation therapy is used to rid the body of excess or toxic metals . Some physicians and CAM practitioners have recommended EDTA chelation as a treatment for coronary heart disease (CHD) . The bul The results of a systematic review indicate that supplement use is common in cardiac patients (26%\u201342%) and that the concomitant use of dietary supplements and prescription medication also appears to be frequent (16%\u201364%) . These rThe general public regards biologically-based therapies as safe, natural, and as having fewer side effects than conventional medications (29%\u201360% of CAM users) . The lac The mind-body therapies (MBT) include anthroposophical medicine, autogenic training, biofeedback, bioresonance, cognitive-behavioral therapies, deep-breathing exercises, group support, hypnosis, imagery, meditation, prayer, relaxation, Qigong, tai chi, yoga, and shiatsu . One rev Relaxation techniques include practices such as progressive relaxation, guided imagery, biofeedback, self-hypnosis, and deep-breathing exercises . The goa Meditation refers to a group of techniques such as mantra meditation, mindfulness meditation, transcendental meditation, and Zen Buddhist meditation . There i Yoga has many different styles, some more physically demanding than others. In general, practicing yoga, as well as other forms of regular exercise, leads to several cardiovascular benefits. Yoga typically causes increased heart rate during the act, but following prolonged training, a decrease occurs in exercise-induced heart rate . One stu Tai chi, sometimes referred to as \u201cmoving meditation,\u201d encompasses many styles, but all involve slow, relaxed, gentle movements . A syste The manipulative and body-based therapies include acupressure, Alexander technique, Bowen technique, chiropractic manipulation, Feldenkrais method, massage, osteopathic manipulation, reflexology, Rolfing, Trager bodywork, and Tui na . Massage therapy encompasses many different techniques, such as Swedish massage, sports massage, deep tissue massage, and trigger point massage . Our stu Spinal manipulation, as found in chiropractic and osteopathic manipulation, has been reported to successfully treat hypertension . A syste The whole medical systems include acupuncture , Ayurveda, homeopathy, and naturopathy . Acupuncture is a therapeutic modality anchored in traditional Chinese medicine  . A syste Most rigorous clinical trials and systematic analyses of the research on homeopathy have concluded that there is little evidence to support it as an effective treatment for any specific condition . There a Energy medicine includes healing touch, light therapy, magnetic therapy, millimeter wave therapy, Qigong, Reiki, and sound energy therapy . This ca The biofield therapies of Reiki, therapeutic touch, and healing touch are known as \u201chand-mediated\u201d therapies and are used to reduce pain and anxiety and to promote health through the direction of healing energy . There a CAM use among patients with CVD is prevalent, with biologically-based and mind-body therapies being the most commonly used treatment modalities. This review illustrates the necessity of both more rigorous research to determine the precise physiologic effects and long-term benefits on cardiovascular morbidity and mortality with CAM usage as well as more open lines of communication between patients and physicians regarding CAM use. Finally, it is hoped that both physicians and patients gain an appreciation of what the evidence does and does not say with respect to CAM use for CVD and take this into consideration when determining optimal treatment plans."}
+{"text": "Background: The use of two-way audio-visual technology for delivery of acute stroke is supported by a well established literature base. The use of telemedicine for general neurologic consultation has been reported across most subspecialties within the field, but a comprehensive systematic review of these reports is lacking. Purpose: To conduct a systematic review of the published literature on teleneurologic consultation beyond stroke. Data sources: Databases Ovid MEDLINE, EMBASE, PsychINFO, CINAHL, and Cochrane were searched with keywords, \u201cteleneurology,\u201d and numerous synonyms and cross-referenced with neurology subspecialties. The search yielded 6,615 potentially eligible hits, which were independently reviewed by two investigators. Ultimately 375 unique studies met eligibility criteria and were included in the review. Study selection: Studies were included if the title or abstract expressed use of two-way AV communication for a clinical neurologic indication other than stroke. Data extraction: Each article was classified using a novel scoring rubric to assess the level of functionality, application, technology, and evaluative stage. Data analysis: Articles were hierarchized within a subspecialty category. Overall subspecialty scores were assigned based on aggregate of scores across papers in each category. Conclusion: Use of telemedicine for general and most subspecialty neurologic consultation, beyond stroke, appears very promising but the clinical science is nascent. This basic set included the MeSH terms Telemedicine, Telecommunications, and Remote Consultation. Textwords included telestrokolog:, telestroke, teleneurolog:, telemedicine, telecare, telehealth, telerehabilitation, telediagnosis, remote monitoring, remote evaluation, and teleconsult. Search terms were truncated to include variant endings. Journals included were All MeSH, textwords, and journals were combined using the Boolean operator OR. The resulting set was limited to humans and the publication types \u201ccomment\u201d and \u201cletter\u201d were removed. This basic search was altered as needed when searching additional databases including EMBASE, PsychINFO, CINAHL, and Cochrane.Search strategies were created in subspecialties of neurology including: autoimmune diseases, autonomic nervous system diseases, cerebrovascular disorders, critical care, epilepsy, geriatric neurology, headache, inflammatory and infectious diseases, movement disorders, multiple sclerosis, neural repair and rehabilitation, neurobehavioral diseases, neurodegenerative diseases, neuromuscular diseases, neuro-oncology, neuro-ophthalmology, neuro-otology, neurointervention, pain, pediatric and adolescent neurology, peripheral nervous system disorders, and sleep disorders. The number of results for each section, as well as a graphical depiction of the study selection process, can be seen in Figure The initial search yielded 6,625 abstracts that were independently reviewed by authors MNR and BMD. Studies that met predetermined inclusion criteria were selected for further appraisal. To be included, a study had to offer an approach to a neurologic condition using two-way AV communication. There was strong agreement in the abstract screening process (\u03ba\u2009=\u20090.94) and consensus to include 688 of the studies. Of note, there were numerous \u201crepeat hits,\u201d where different facets of the search strategy yielded the same study, thus there were only 366 unique studies for review. The subspecialty categories were further coalesced based on available studies (as depicted in Figure All studies were then independently reviewed by MNR and BMD within the context of their respective subspecialty category. A rubric, inspired by Bashshur et al.  and deveTo the best of our knowledge, we present the first large-scale comprehensive systematic review of teleneurological consultation studies (see Figure In addition, we offer our novel rubric (see Figure As the telemedical literature becomes rife with studies of stronger methodologic quality, the FATE rubric might then have a greater impact in hierarchizing the publications.The authors declare that the research was conducted in the absence of any commercial or financial relationship that could be construed as a potential conflict of interest."}
+{"text": "Noma, or cancrum oris, is a rapidly progressive bacterial disease that results in painless gangrenous necrosis of the mouth.Noma is a disease of multifactorial etiology that presupposes a state of malnutrition; historically, it has been found worldwide during times of poverty, starvation, and war, including within the concentration camps of WWII.Estimated incidence of noma is 100,000 to 140,000 per year with a worldwide prevalence documented at over 700,000 cases. This may severely underestimate the actual figures, though, as it is believed that fewer than 15% of acute cases present for care.Untreated, acute noma in children is 80%\u201390% lethal. Antibiotic treatment and nutritional support decreases mortality to less than 10%. Nevertheless, plastic orofacial reconstruction is often necessary for both functionality and cosmesis.A young adult male villager in Madagascar developed painful, perioral swelling over a period of weeks. The stomatitis subsequently evolved into an anesthetic, rapidly expansive, necrotic ulcer with oral incontinence . A perioNoma.Noma, or cancrum oris, is a multi-stage,opportunistic, rapidly progressive, and painless necrotizing stomatitis. There are isolated reports of noma affecting other areas of the body, including the perineum, vulva, scalp, neck, and shoulders Historically, noma is a disease of extreme poverty and malnourishment, reported throughout history in Asia, Europe, South America, and Africa The true prevalence and incidence of noma are not fully known, because it is believed that only <15% of patients with acute cases of the disease seek medical care Tremponema vicentii, other spirochetes or fusiform bacteria, Staphyloccus aureus, \u03b1-hemolytic Streptococcus, and PseudomonasInfection is multifactorial in nature and not clearly understood. Noma generally arises in the presence of preexisting malnutrition, poor oral hygiene, and an inciting illness, in combination. This triad allows for a polymicrobial infection to take hold. The specific infectious agent and inciting illness are less well-defined. Hypotheses about triggers for the illness include systemic febrile illness , neurotrophic viral infection , periodontal disease, or other trauma leading to mucosal ulceration. Because of the polymicrobial environment of the oropharynx, it is unclear which infectious agents are the driving forces of the disease. Frequently, identified flora have included The clinical presentation of noma includes malodorous breath, excessive salivation, severe dehydration, anemia, and symptoms of both acute and chronic illnesses such as kwashiorkor In children, noma can be associated with various stages of growth retardation The differential diagnosis of noma includes leprosy, leishmaniasis, post Kala-azar dermal leishmaniasis (PKDL), oral cancer, acute herpetic gingivostomatitis, syphilitic yaws, mucormycosis, chemical burns, acute necrotizing ulcerative gingivitis , clostridial or streptococcal gangrene, and lethal midline granuloma  Noma is devastating clinically and socially. Untreated, 10%\u201320% of children survive acute noma After onset, mucosal ulceration may stay relatively static for a long time before progressing to tender stomatitis and edema Treatment is aimed at arresting the acute infection and at correcting underlying deficits in nutrition and hydration. Fluid hydration , correction of electrolyte abnormalities, nutritional support, vitamin supplementation, and broad spectrum antibiotics are first line"}
+{"text": "Cellular assays for suspension cells provide investigators the opportunity to interrogate the biology of cellular function of immune cells or immunotherapeutic drugs. Despite significant technical advances made during the last few years, working with suspension cells, such as primary blood cells, PBMCs , leukemia, myeloma, or lymphoma cells, cellular assays still suffer from limitations. For example, even for HEK 293 cells, a commonly used semi-adherent cell line, significant cell loss can occur during assay process. This loss can be further exacerbated when multi-step staining procedures are required.We applied DropArray plates, which employ surface tension to retain cells on the plate surface, for our suspension cellular assays. For a variety of suspension cells, including PBMCs, AML cells, or B cells, efficient retention (50% to 80%) is achieved during multiple washes. Reproducibility and quality of the experimental results are improved with DropArray plates. Furthermore, the specific cytotoxic action of bispecific antibody on tumor cells can be also observed in real time."}
+{"text": "This presentation will review highlights from the 12th International Workshop on Adverse Drug Reactions and Co-morbidities in HIV that will be held in London on 4-6 November 2010. As in the past, the meeting will consist of plenary lectures by experts from outside the field of HIV medicine as well as oral presentations and posters selected from abstracts submitted by attendees. The plenary speakers for this year's meeting include John Adams (vit D insufficiency), Remy Burcellin , Kenneth Feingold (TLRs and lipid metabolism), Rolf J\u00e4ger (neuroimaging), Cliff Rosen (bone and fat) and Heiner Wedemeyer (ADRs in HBV treatment.). Abstract categories include: adipocyte biology, insulin resistance, aging and associated disorders, lipid metabolism, body composition, liver disease and hepatotoxicity, bone metabolism and toxicities, mitochondrial disorders, cancer in patients with HIV/AIDS, neurocognitive disorders, cardiovascular disease, renal toxicities, clinical management of ADRs, other toxicities and hepatitis."}
+{"text": "Adults with Eosinophilic Oesophagitis (EO) often present with a history of dysphagia and food impaction. Many are also atopic and sensitisation to foods is common; 81% of adults with EO in one study were sensitised to one or more food or inhalant allergen, and 50% had positive skin prick tests to one or more foods. Exclusion of foods has been reported to improve clinical symptoms; 94% of adults improved on a 6 food elimination diet, and in children, the use of an elemental formula has been proven to be effective.We describe an adult male patient aged 30 years with a diagnosis of EO. Skin prick testing with fresh foods and specific IgE blood tests (Phadia ImmunoCAP) revealed sensitisation to a number of foods. Following an acute episode of dysphagia requiring dilatation, the patient commenced a complete exclusion diet. Nutritional support was maintained solely through the consumption of a nutritionally complete liquid elemental diet . After six weeks, one new food was introduced every 2-3 days.The patient was sensitised to birch and grass pollen and a wide variety of foods including potatoes, carrots, broccoli, lettuce, spinach, beer, wine, grapes, apple juice, mango, peanut, mustard, marmite, rice, wheat, barley, yeast and the peach lipid transfer protein allergen Pru p 3. Following the 6-week elemental diet, to date the following foods have been successfully re-introduced into the diet; rice, fish, onions, eggs, olives, lamb, corn, barley, milk, vodka, red wine, champagne, barley, peas, pak choi, pork, turkey. Soy and grapes, both previously eaten regularly caused immediate symptoms upon re-introduction.This case demonstrates that in the face of multiple sensitisation to foods, an elemental diet followed by planned and careful staged re-introduction of foods may be effective in establishing which foods can be safely be consumed."}
+{"text": "Drug addiction is a chronic, relapsing disorder, which is caused by many factors including genetic, epigenetic, environmental, and drug-related , neuropeptide Y, and dynorphin are stress-related. Furthermore, these neuropeptides are involved in the modulation of negative emotional states associated with drug addiction  system is also highly dysregulated during chronic, excessive alcohol consumption and both contribute to the negative emotional state experienced during withdrawal (Koob and Volkow, Feduccia et al.  in theirRecently, a growing body of evidence shows that epigenetic mechanisms play a pivotal role in long-lasting changes in gene expression by regulation of transcriptional potential (McClung and Nestler, In her focused review, Kovacs  summarizNylander and Roman  providedTaken together, this research topic delivered new visions to our knowledge about the neuroplastic changes in chronic escalated drug consumption and in the following withdrawal."}
+{"text": "We present a novel super-resolution microscope for the study of chromatin architecture. In eukaryotic cells, chromatin is organized into two distinct domains: lightly packed, and actively transcribed euchromatin, and highly condensed, and transcriptionally silent heterochromatin. While being transcriptionally repressive, heterochromatin is known to serve as binding sites for regulatory proteins, and therefore, plays an important role in the epigenetic regulation of gene expression . However"}
+{"text": "Following the acquisition of multicellularity, organisms with increasing levels of specialized cells, tissues, and organs emerged during evolution. To coordinate specialized organs, long-distance interorgan communication systems appeared. The central nervous system evolved to regulate many organ behaviors, using hormones or neurons. In addition, organs developed systems to directly communicate their states to one another. This is illustrated by the lack of nervous systems in plants and simple animals like sponges, which can perform complex systemic functions . The ICN is the network of peptides, proteins, and metabolites that act between organs to coordinate essential and specialized cellular processes under homeostasis and stress Figure . We propC. elegans, and Drosophila showed that perturbed tissues affect organismal growth and metabolism via largely unknown signals. The Drosophila fat-body  responds to dietary signals by releasing factors affecting insulin secretion, growth, and metabolism (Britton and Edgar, A limited number of studies in mammals, Drosophila Unpaired-2 deficiency, and both function through similar neuronal circuits (Vong et al., In mammals, leptin is secreted by adipose tissue with nutritional surplus, controlling the neuroendocrine system (Zhang et al., C. elegans, germ-line absence extends life-span (Arantes-Oliveira et al., Intracellular pathways induce factors which regulate aging, stress resistance, and distal cellular functions. In Drosophila, gut, muscles, and fat-body are essential in stress resistance and aging. Gut infection or oxidative stress induces fat-body anti-microbial peptide secretion via unknown mechanisms (Foley and O'Farrell, In Also, exposure of old mice to young blood results in restoration of muscle and liver regeneration, suggesting that systemic factors control aging (Conboy et al., Drosophila, distal wounds control gut proliferative homeostasis via unknown mechanisms (Takeishi et al., Systemic factors also control cell proliferation and tissue regeneration. In Drosophila females, mating increases mating receptivity, feeding, and egg-laying; changes movement; and decreases lifespan (Fowler and Partridge, Drosophila, insulin controls female germline stem cell proliferation (LaFever and Drummond-Barbosa, C. elegans, oocyte and germline maintenance during aging is regulated by TGF-\u03b2 and insulin via unknown relay signals (Luo et al., Unknown factors may also be controlled by reproduction. In insects, mating and fertilization induces numerous uncharacterized transcriptional changes in multiple organs (Rogers et al., Drosophila, tissue-specific stress causes heritable developmental alterations (Stern et al., In addition, systemic factors may regulate offspring fitness. In mice, paternal diet influences offspring metabolism (Carone et al., Finally, because alterations in its composition influence systemic physiology (e.g., metabolism; Claus et al., In conclusion, there is growing evidence that many organismal functions mediate various aspects of interorgan communication through secreted factors. Understanding the roles of these factors, and how their activities are integrated to the organism's functions is the next big challenge. Further, as systematic screens have not been performed for such factors, it is likely that many additional ones remain to be identified.Gene-expression analyses of organs have shown the existence of organ-to-organ coexpression networks that change in disease and aging, suggesting of unexplored interorgan processes and common responses of tissues to systemic factors (Keller et al., What are the factors/nodes that connect the organs/hubs in the ICN? At their simplest and most evolutionary ancient form, signals may be nutrients, wastes, toxins, or metabolites. For instance, liver-produced beta-hydroxybutyrate inhibits histone deacetylases (Shimazu et al., Drosophila insulin-binding proteins ImpL2 (Honegger et al., An important feature that differentiates local tissue and developmental networks from the ICN, is the large distance over which signaling acts, meaning that concentration and specificity of the factors could be lower. To remedy this, a dense network of closely acting factors could exist, such that one factor acts on a neighboring tissue, which secretes a relay signal. Alternatively, signals may be carried along \u201cmolecular tracks\u201d to their destination. These may be blood vessels or tissue regions containing \u201cguidance factors\u201d\u2014putative weak affinity receptors to common structural features to groups of secreted factors. In addition, binding proteins (Mantovani et al., Drosophila spatzle-Toll; Morisato and Anderson, Factors may also be modified with fatty-acids, cholesterol, or glycans, regulating their stability, transport Nusse, , and intElucidation of the ICN will be valuable for disease biology. Many disorders begin locally, and ultimately involve the entire organism by affecting behavior, cell recruitment, metabolism, proliferation, and activation (McCance and Huether, Also, organ failure patients who receive organ function replacement therapy eventually succumb to disease, with systemic defects. For instance, kidney failure patients receiving kidney function replacement hemodialysis suffer from malnutrition and lung defects (McCance and Huether, in vivo identification of systemic factors is impractical in mammals. Thus, the ICN may be constructed for Drosophila, for which all of the above tools are available, and applied to mammals. Thus, \u201corgan-sensing\u201d RNAi screens can now be done, where genes are inactivated by tissue-specific RNAi, and function of another organ is assessed. Within the next decade, we expect a surge of interest to define the structure and function of the ICN.Great strides are being made toward understanding intracellular and tissue homeostasis. The next step is to understand the structure, function, and components of the ICN. The main questions are the nature of the interorgan communication factors and their roles in maintaining whole-organism homeostasis. Also, how does the ICN change during development, aging, and disease? The current transcriptomic, proteomic, metabolomic, and genome-wide tissue-specific genetic manipulation technologies will allow answering these questions. Importantly, systematic"}
+{"text": "Functional neuroimaging techniques are currently used in fundamental neuroscience as well as in cognitive neuroscience and clinics to study brain function at large spatial scales. They include Blood Oxygenation Level Dependent-functional Magnetic Resonance Imaging  express receptors for neuromodulators such as noradrenaline, which is known to regulate both the vascular tone Hamel,  and astrin vivo imaging of awake mice to avoid any anesthetic effects on neuronal and astrocytic activity   Thrane, , (2) spe Thrane,  have run Thrane,  have per Thrane,  have rec Thrane,  or pyram Thrane, , with bo Thrane,  who stud Thrane,  will als Thrane,  and opto Thrane,  stimulat Thrane, . The pro Thrane, . A combiIn conclusion, determining the relative role of astrocytes vs. neurons in functional hyperemia and BOLD signals is still an exciting challenge. Since technical tools are now available, experiments should follow soon to lighten up the cellular dark side of BOLD."}
+{"text": "Joubert syndrome and related disorders are autosomal recessive or X-linked ciliopathies characterized by a complex midbrain-hindbrain malformation (the Molar Tooth Sign), consisting of vermis dysplasia, a deepened interpeduncular fossa, and thickened, elongated and mal-orientated superior cerebellar peduncles. Common clinical features include hypotonia, ataxia, psychomotor delay, oculomotor apraxia and neonatal breathing dysregulation, variably associated with multiorgan involvement, mainly of the eyes, kidneys and liver. Other central nervous system malformations, polydactyly, and laterality defects may also be present. Genetic heterogeneity mirrors the clinical heterogeneity of JSRD. Over 17 genes have been identified, all encoding for proteins of the primary cilium, with intriguing allelic series and clinical correlations that have made these conditions a paradigmatic example of \u201csplitting and lumping\u201d in human genetics. Indeed, the same phenotype can be caused by mutations in distinct genes, and conversely the same gene can be responsible of distinct ciliopathies, such as JSRD, nephronophthisis, Senior-Loken, Bardet-Biedl and Meckel syndromes. Of note, there is clinical heterogeneity even within families, with affected siblings discordant for features such as encephalocele or retinal involvement. This extreme phenotypic variability associated with mutations in one and the same gene remains a main open question. An intriguing explanation has implicated an oligogenic model of inheritance , in which mutations, rare variants and even polymorphisms at distinct loci epistatically interplay to modulate the ciliopathy phenotype. To date, mutation analyses of most JSRD-causative genes have not been performed in large cohorts, and the systematic genetic screening of multiple ciliopathy genes remains a still unmet need to address the complexity of JSRD genetics."}
+{"text": "After publication of our article , it has Gennaro Limite, Emanuela Esposito, Viviana Sollazzo, Giuseppe Ciancia, Cesare Formisano, Rosa Di Micco, Dario De Rosa and Pietro Forestieri.We apologise for any inconvenience caused by this error."}
+{"text": "The patient was a 1.5-year-old boy who presented with growth failure, inability to walk, polyuria, and polydipsia. On physical examination, he had fair skin and blond hair. He did not have organomegaly. Ophthalmologic examination by an ophthalmologist was normal. Hypophosphatemia, hypovitaminosis D, mild acidosis, glucosuria, proteinuria, and generalized aminoaciduria were found upon laboratory studies. He underwent bone marrow aspiration that revealed increased numbers of macrophages containing polygonal crystals. Severe and widespread deposition of crystals in bone marrow particles  was obseThe authors of this paper have no conflicts of interest, including specific financial interests, relationships, and/ or affiliations relevant to the subject matter or materials included."}
+{"text": "Severe sepsis is an important cause of morbidity and mortality for patients in ICUs . Since iCase-control study conducted in the ICU of Hospital Anchieta, Bras\u00edlia, DF, Brazil, during 5 months. Patients were divided into two groups: survivors group (SG) and nonsurvivors group (NSG).n = 18). Upon admission, the patients in the NSG presented higher values of: SAPS3 score , heart rate , serum creatinine , decreased level of consciousness , need for vasopressor , need for invasive mechanical ventilation  and previous cardiac arrest . The platelet count was lower in the NSG . There was no significant difference between the groups regarding the following factors: age , respiratory rate , axillary temperature , leukocyte count , immunosuppression , and prior use of corticosteroids .During the study, 38 patients were admitted with severe sepsis, with a mortality rate of 47% (SAPS3 score, metastatic cancer, decreased level of consciousness, need for vasopressors, invasive mechanical ventilation, previous cardiac arrest, heart rate, serum creatinine, and platelet count were associated with mortality in severe sepsis for this sample of patients."}
+{"text": "The association among food and health is momentous as consumers now demand healthy, tasty and natural functional foods. Knowledge of such food is mainly transmitted through the contribution of individuals of households. Throughout the world the traditions of using wild edible plants as food and medicine are at risk of disappearing, hence present appraisal was conducted to explore ethnomedicinal and cultural importance of wild edible vegetables used by the populace of Lesser Himalayas-Pakistan.Data was collected through informed consent semi-structured interviews, questionnaires, market survey and focus group conversation with key respondents of the study sites including 45 female, 30 children and 25 males. Cultural significance of each species was calculated based on use report.Ficus carica was found most cited species with in top ten vegetables followed by Ficus palmata, Bauhinia variegata, Solanum nigrum, Amaranthus viridis, Medicago polymorpha, Chenopodium album, Cichorium intybus, Amaranthus hybridus and Vicia faba.A total of 45 wild edible vegetables belonging to 38 genera and 24 families were used for the treatment of various diseases and consumed. Asteraceae and Papilionoideae were found dominating families with (6 spp. each), followed by Amaranthaceae and Polygonaceae. Vegetables were cooked in water (51%) followed by diluted milk (42%) and both in water and diluted milk (7%). Leaves were among highly utilized plant parts (70%) in medicines followed by seeds (10%), roots (6%), latex (4%), bark, bulb, flowers, tubers and rhizomes (2% each). Modes of preparation fall into seven categories like paste (29%), decoction (24%), powder (14%), eaten fresh (12%), extract (10%), cooked vegetable (8%) and juice (4%). Patterns of wild edible plant usage depend mainly on socio-economic factors compare to climatic conditions or wealth of flora but during past few decades have harshly eroded due to change in the life style of the inhabitants. Use reports verified common cultural heritage and cultural worth of quoted taxa is analogous. Phytochemical analysis, antioxidant activities, pharmacological applications; skill training in farming and biotechnological techniques to improve the yield are important feature prospective regarding of wild edible vegetables. Since the beginning of human civilization, people have used plants as food and medicine. The ethnobotanical pharmacology is as old as man himself. In Indo-Pak first record of plant medicine were compiled in Rig Veda between 4500\u20131600 BC and Ayurveda between 2500\u2013600BC ,4. ThereWild edible plants play an important socio-economic role as medicines, dyes, poisons, shelter, fibers and religious and cultural ceremonies . About 4Previous epidemiologic studies have consistently shown that diet plays a crucial role in the prevention of chronic diseases . This co2[Present study was conducted from January 2010 to May 2012 in different sites of Lesser Himalayas. Data was collected from 85 localities of five major sampling sites including Abbottabad, Haripur, Mansehra districts of Khyber Pakhtunkhwa province (KPK), Margalla Hills National Park Islamabad, Murree Hills and its allied areas in the province of Punjab  key informants ranged from 15\u201370\u00a0years including farmers, herdsmen, shepherds, housewives, school boys and children having sound traditional knowledge of useful wild edible plants ,24. Adul key infoQuestions about wild edible vegetables consumption were mainly focused on local name of plant, part/parts of the plants used, flowering period, place, season and quantity of collection, habitat, mode of preparation and consumption, medicinal uses , other ethnobotanical uses as  and threats to wild edible vegetables. Authenticity of the claims was verified by cross checking of the collected data at different villages either by showing the fresh specimen, telling local names or showing field photographs to local informants.A total of 45 wild edible vegetables were included in the present investigation based on their use in the study area. Taxonomic identification of the collected plant samples was carried out with the help of flora of Pakistan . The plaIn order to find out cultural significance of each species in every locality cultural importance index (CI) was calculated as the summation of the use report (UR) in every use category mentioned for a species in the locality divided by number of participants (N) in that locality. Similarly mean cultural importance index (mCI) of each, specie was also deliberate . The culIn order to know local peoples\u2019 awareness on various activities intimidating wild edible plants, a number of threatening factors like agricultural, over grazing, harvesting and fire were identified with the community . The facFlora of Lesser Himalayas is a rich source of diverse useful plant species. A total of 45 wild edible vegetables belonging to 38 genera and 24 families are collected and consumed by the local inhabitants of the study areas as mentioned in Table\u00a0Amaranthus spp. Digera muricata, Bidens bipinnata, Capsella bursa-pastoris, Nasturtium officinale, Stellaria media, Commelina benghalensis, Malva parviflora, Lathyrus aphaca, Medicago polymorpha, Melilotus spp. Vicia spp. Portulaca quardifida, Galium aprine, Solanum nigrum and Torilis leptophyll; in diluted milk (42%) e.g. Cichorium intybus, Launaea procumbens, Sonchus spp. Taraxacum officinale, Bauhinia variegate, Silene conoidea, Tulip stellata, Plantago lanceoplata, Bistorta amplexicaulis, Pimpinella diversifolia, Ficus and Rumex species; and in both water and diluted milk (Lussii) (7%) e.g. Ficus and Sonchus species. Flowers and rhizome of some vegetables species were also consumed fried in vegetable oil or ghee such as Bombax malabaracum and Dioscorea deltoidea. Present findings are in agreement to [Different parts of wild edible vegetables were consumed in diverse ways according to local traditions Table\u00a0. Wild edement to  regardinNo one knows when or where plants first began to be used in the treatment of diseases, but the grave of a Neanderthal man buried 60,000\u00a0years ago, revealed that connection between plants and health has existed for thousands of years . The norDuring present survey decline was categorically observed in the trends of using conventional phytotherapies which is obviously because, the younger generation usually consider the belief in plant remedies a sort of superstition and less efficient compared to modern medicine. It was observed that leaves are highly utilized (70%) plant parts followed by seeds 10%), roots (6%), latex (4%), bark, bulb, flowers, tubers and rhizomes 2% each). Data presented in , respiratory problems , skin infections , bone fracture, rheumatism, diabetes, earache, tooth ache, eye infection, fever, heart problems, inflammation, jaundice, kidney problems, menstrual disorders, milk production, piles, scorpion sting and general weakness which were treated through different plant based remedies; twelve medications were used to cure gastrointestinal disorders followed by eleven to treat skin infections, ten against constipation, eight to cure rheumatism, four for each eye diseases, fever and jaundice, two for each inflammation, kidney problems and scorpion sting, where as other diseases were treated by one recipe each Figure\u00a0.Cichorium intybus, Stellaria media, Launaea procumbens, Chenopodium album, Dioscorea deltoidea, Oxalis corniculata, Lathyrus aphaca, Vicia sativa, Plantago lanceoplata, Rumex dentatus, Rumex hastatus, Solanum nigrum, Pimpinella diversifolia and Torilis leptophylla were in agreement to [Amaranthus hybridus, A. spinosus and A. viridis was used to improve eye vision problems, whereas according to [Amaranthus hybridus were used for internal inflammation, headache, stomach pain and to antidote snake and scorpion sting. Leaves of Amaranthus viridis and A. spinosus were found effective against scorpion sting, skin infections, mouth gums, piles, tooth ache diarrhoea and as laxative [Bidens bipinnata is used to cure leprosy and skin cuts, while same species was reported against stomach problems, menstruation, pain, influenza, scurvy, rheumatism, diarrhoea and for cold [Sonchus asper and S. oleraceous are used against constipation and for body weakness, whereas [S. oleraceous were effective against internal inflammation and wound healing. According to [S. asper were found useful for stomach problems and Jaundice.Medicinal uses of wild edible vegetables were compared with the available ethnobotanical literature which indicated that present applications of ement to ,33-53. Srding to  leaves olaxative ,52,55,56for cold ,53,57. L whereas ,53 documrding to ,48,55,58Taraxacum officinale rhizome is used to cure jaundice, whereas [Bombax malabaracum were found similar to that of reported by [Capsella bursa-pastoris to cure menstrual disorders, whereas [Nasturtium officinale were found effective against constipation, but [Bauhinia variegata was found useful to control diarrhoea, whereas [Silene conoidea was used against skin infections, but [Decoction of  whereas ,52 mentiorted by ,33,57. Lion, but ,55 mentions, but  mentioneCommelina benghalensis to cure epilepsy and stomach disorders, whereas [Evolvulus alsinoides was found effectual against constipation and indigestion, whereas [Origanum vulgare were used to cure mouth gums and toothache, while according to [Malva parviflora was used to treat constipation, cough and fever, but according to [Ficus carica and F. palmata were used to cure boils, warts, tumours and bowel complaints, whereas fruits of these species were found laxative [Polygonum amplexicaule was found effective against fever, joint pain and flue; whereas [Tribal communities of Himalayas use roots of  whereas  document whereas  recognizrding to ,52 same rding to  same plalaxative . Leaf de whereas  reportedPortulaca quadrifida were applied topically on swelling joints, but according to [Galium aparine were found effective for wound healing and jaundice, whereas [Digeramuricata, Dryopteris ramosa, Lamium amplexicaule, Tulipa stellata, Medicago polymorpha, Melilotus albus, Melilotus indicus, Vicia faba, Polygonum aviculare and Veronica arvensis documented during present work were found hardly ever reported in adjacent areas and other parts of the world.Fresh leaves of rding to  whole pl whereas  recognizFicus carica, F. palmata and Bauhinia variegata were used by the local inhabitants of Lesser Himalayas in making shelters, in fencing and hedging, as ornamental plant and for miscellaneous purpose, 2 species (4%) were used in making tools handles and furniture  were used as fodder and forage for life stock, 4 species (9%) were used as fuel, 3 species each (7%) of wild vegetables such as Ficus carica was found most cited species followed by Ficus palmata, Bauhinia variegata, Solanum nigrum, Amaranthus viridis, Medicago polymorpha, Chenopodium album, Cichorium intybus, Amaranthus hybridus and Vicia faba . It was also observed that because of cultural values or decision, local inhabitants use only a small part of their natural flora present in their surrounding.The terms \u201ccultural importance\u201d and \u201crelative importance\u201d usually are used interchangeably in the literature to refer to the importance of certain plants to a given culture . The cula Figure\u00a0. All TheVicia sativa, Lamium amplexicaule. These are based on a common cultural background. Interestingly CI values for wild edible vegetables species in Margalla Hills (50.30) and district Haripur (44.26) were found higher than for species in other areas  of wild edible vegetables mentioned in Figure\u00a0 revealedDryopteris ramosa, Nasturtium officinale, Bauhinia variegata, Chenopodium album, Malva parviflora, Portulaca quardifida and Solanum nigrum were soled as vegetables at local markets of Abbottabad, Rawalpindi and Haripur , agricultural fields (33.4%), forests (20%) and water bodies (2.2%). These plant species were found under threats in their natural habitats because of different human activities. According to local inhabitants agricultural land expansion, over-harvesting, over-grazing, uncontrolled fire setting and fuel wood collection are among the common threats to these alternative food resources and their impacts varies from place to place. In order to find out local inhabitants perception on threats to wild edible vegetables, pair wise ranking of five factors  were conducted.Bauhinia variegata, Chenopodium album, Solanum nigrum, Ficus carica and Ficus palmata which are protected, cultivated and marketed by some formers. This shows that achievement of economic payback from plant species might endorse local people\u2019s interest in the conservation, maintenance and preservation of significant and endangered species [However, the overall rating for all communities mentioned in Table\u00a0 species .Ficus carica, Ficus palmata, Bauhinia variegata and Solanum nigrum exhibited maximum cultural importance index (CI). Present findings also revealed that many wild edible vegetables species are under pressure from various anthropogenic factors, demand public awareness, community based management and urgent collection of germplasm. Further exploration is suggested into nutritional profile, phytochemical analysis, antioxidant potential, essential and toxic components in conventional food resources; pharmacological applications; dietary requirements; skill training in farming and biotechnological techniques to improve yields.Major populace of Lesser Himalayas still use wild edible plants as food and to cure various ailments but, this traditional knowledge have severely eroded due to change in the life style of local inhabitants, which needs to be documented before it is too late. Present investigation revealed that patterns of wild edible plant usage depend mainly on socio-economic factors compare to climatic conditions or wealth of flora. Analysis of results indicated that in all the surveyed areas, most of the plants are consumed by poor families during normal and difficult times. However, decline in use of some species may lead to the diminishing of the traditional knowledge about such plants. Use reports and citation of majority of wild edible vegetables, confirmed a universal cultural heritage in the study sites regarding the gathered food plants, because most of the quoted taxa are same and their cultural worth is analogous. However, a few differences in the cultural importance indices of wild edible vegetables were also observed, which may be due to the similar live hood and difference in indigenous knowledge of the local communities. The authors declare that they have no competing interests.a) AMA: Present paper is a part of my PhD work, I have Carried out field survey, sampling, data collection and compilation of manuscript. b) MAK: Supervised the work. c) MHS: Supervised the work and technical checking the manuscript. d) MMS: Help in field work and Moral Support. e) AP: Support in data collection. f) MA: Plants identification. All authors read and approved the final manuscript, there is no objection or further suggestion.Cultural important index (CI), mean cultural importance index (mCI) of wild edible vegetables.Click here for fileSocio-economic values of wild edible vegetables.Click here for file"}
+{"text": "Dipterans are attracted to and colonize decomposing corpses immediately after death. From the forensic perspective, their identification is mandatory for postmortem interval estimation. Morphological identification may be difficult or even impossible. Thus, molecular identification has been suggested as an alternative. Many workers suggested that the cytochrome oxidase I (COI) gene is the most suitable gene, but the assignment of a genetic marker within that gene has not been determined yet . PreviouChrysomya megacephala, C. rufifacies, C. albiceps, Lucilia sericata, L. cuprina, L. bazini, L. porphyrina, L. caesar], Sarcophagidae , and Muscidae [Musca domestica and M. autumnalis]. Furthermore, we included the Egyptian species of L. sericata, C. albiceps, and M. domestica, which are considered the most common taxa associated with corpses in Egypt . The present study showed there was no overlap between maximum intraspecific and minimum interspecific nucleotide divergence. The absence of that overlap was previously interpreted as an indicator of successful species-level resolution (All tested species displayed 0\u20131% intraspecific variations. This study showed low intraspecific variation in the three species collected from two different countries, which is in agreement with other previous studies that elucidated the value of mitochondrial genetic markers in general in interspecific distinction , 7. The solution . At specIn conclusion, although the 296-bp COI marker is a simple, cheap, and reproducible tool, the phylogenetic data were not completely in accordance with the traditional morphological classification, indicating limitation in its usefulness, especially for database construction. This indicates that reliance on this short genetic marker for identification is unsafe.Sanaa Mohamed AlyPathology and Forensic Sciences departmentSchool of Basic Medical Sciences, Central South UniversityChangsha, Hunan, ChinaForensic Medicine and Clinical Toxicology departmentFaculty of Medicine, Suez Canal UniversityIsmailia, EgyptJifang WenPathology and Forensic Sciences departmentSchool of Basic Medical SciencesCentral South UniversityChangsha, Hunan, China"}
+{"text": "To the Editor:Dirofilaria repens is a vector-borne, zoonotic, filarial nematode thatinfects dogs, cats, and humans. In humans, D. repens worms causesubcutaneous dirofilariasis, characterized by the development of benign subcutaneousnodules that mimic skin carcinomas .High-resolution ultrasound examination ,panel CDirofilaria spp. nodules are benign,their detection may raise suspicion for a malignant tumor; thus, differentialdiagnosis is the key point in the management of human dirofilariasis (Although human subcutaneous D. repens nematodes are spreading in Europe from the south towardthe north and east ("}
+{"text": "We report the case of a 78-year-old male who developed acute pancreatitis related to quetiapine that was administered for the treatment of delirium. No evidence of hypertriglyceridemia, infection, ischemia, chololithiasis or hypercalcemia could be documented.Clinicians should be alerted when treating critical care patients with antipsychotics, as risks might present and potentially lead to hazardous results. Quetiapine is a widely used antipsychotic in the treatment of delirium . AlthougPancreatitis could be attributed to various causes such as gallstones, alcohol use, medication toxicity, hypercalcemia and hypertriglyceridemia, trauma from endoscopic retrograde cholangiopancreatography, abdominal trauma, various infections, autoimmune, ischemia, and hereditary causes . Our pat"}
+{"text": "Hypersensitivity diseases caused by nonsteroidal anti-inflammatory agents arerelatively common in the population. This article summarizes the presentunderstanding on the various allergic and nonallergic clinical pictures producedthrough hypersensitivity to these drugs using the pathogenic classification ofhypersensitivity reactions recently proposed by the Nomenclature Committee of theWorld Allergy Organization to guide clinicians in the diagnosis and management ofpatients with these conditions. A large proportion of the population is exposed to nonsteroidal anti-inflammatory drugs(NSAIDs) worldwide from either medical prescription or self-medicated . It is tThe prevalence of these reactions in the population varies between 0.1% and 0.3%,  and therPharmacology textbooks define NSAIDs as compounds that antagonize inflammation throughthe inhibition of a group of enzymes known as cyclooxygenases (COXs) . Some drClassic NSAIDs that inhibit both major COX isoen-zymes, COX-1 and COX-2, can beclassified according to their chemical structure as depicted in Table A wide variety of clinical manifestations can be produced by NSAIDs. Using theclassification proposed by the Nomenclature Committee of the World Allergy Organization,  the follImmunologic reactions to NSAIDs can be subdivided into immediate (mediated byimmunoglobulin E [IgE]) and delayed (mediated by lymphocytes).Immunoglobulin E-mediated cutaneous reactions have been described forpyrazolones,  acetaminReported for ibuprofen,  ketorolaThese include cell (T lymphocyte)-mediated type IV hypersensitivity reactionsinvolving specific organs and systems.Characterized by erythematous plaques recurring in the same anatomical sitein every occasion the drug is administered. Metamizole, piroxicam,phenylbutazone, paracetamol, aspirin, mefenamic acid, diclofenac,indomethacin, ibuprofen, diflunisal, naproxen, and nimesulide have beenincriminated .These serious skin reactions belong to the erythema multiforme spectrum ofbullous eruptions and can be associated with NSAIDs .Stevens-Johnson syndrome (SJS) is a severe diffuse mucocutaneous eruptioncausing erythematous or purpuric macules, blisters, or target lesions withno more than 10% skin detachment, accompanied by systemic manifestations,occurring 1 to 8 weeks after administration of incriminated medications . Toxic eAmong NSAIDs, oxicams, phenylbutazone, and oxyphenbutazone have beenresponsible more often ,18. ReceAcute generalized exanthematous pustulosis is a rare condition characterizedby a rapid-onset pustular eruption involving most of the body. Typicallesions are generalized, nonfollicular, pinhead-sized sterile pustules on anerythematous background that are associated with fever and neutrophilia . HistopaContact with NSAIDs can induce itchy, erythematous, edematous, and vesicularlesions, and photocontact dermatitis, an exaggerated or abnormal cutaneousresponse to light. Among NSAIDs, diclofenac, indomethacin, flurbiprofen,bufexamac, etofenamate, flufenamic acid, ibuprofen, ketoprofen, andtiaprofenic acid are the most common inducers of contact dermatitis.Cross-reactivity between some chemically related NSAIDs has been observed .Virtually all NSAIDs are able to produce maculopapular eruptions, one of themost common cutaneous adverse effects of NSAIDs. Ibuprofen, pyrazolones,flurbiprofen, diclofenac, and celecoxib have been more frequentlyinvolved.Some NSAIDs such as aspirin, sulindac, ibuprofen, and naproxen can induceallergic pneumonitis. The NSAID-induced pneumonitis can be suspected from atemporal relationship between lung infiltrates and drug administration . Most paThe NSAIDs are the medications more often involved in the production ofdrug-induced meningitis. Clinical features include fever, headache,photophobia, neck stiffness, nausea, vomiting, arthralgia, myalgia, rash, andabdominal pain . IbuprofRarely, in aged patients with normal kidneys, NSAIDs may trigger a spectrum ofnephritides (\"NSAID nephropathy\"), including tubular, interstitial, acute orsubacute tubulointerstitial nephritis, chronic interstitial nephritis withpapillary necrosis, and tubulointerstitial nephritis combined with nephroticsyndrome. The NSAIDs may also produce glomerulopathies such as minimal changenephropathy, membranous glomerulonephritis, and focal sclerosis ,28.Rarely, NSAIDs, among them niflumic acid, tolfenamic acid, diclofenac,fenoprofen, ibuprofen, indomethacin, naproxen, piroxicam, pirprofen, andsulindac, induce allergic hepatitis that can be mixed, cytolytic, orcholestatic. It is observed in elderly women taking multiple medications .Herdeg et al  reportedComposed of manifestations at the respiratory tract and skin, and nonallergicanaphylaxis.Aspirin-induced asthma, aspirin-intolerant asthma, or aspirin-exacerbatedrespiratory disease (AERD) is characterized by asthma, rhinosinusitis, nasalpolyposis, and aspirin/NSAID hypersensitivity. Asthmatic reactions induced byNSAIDs occur in 5% to 20% of adult asthmatic patients . The patThe cutaneous pattern of NSAID-induced cross-reactions includes cross-reactingurticaria and angioedema in patients with or without chronic idiopathic urticaria(CIU) Figure . The mecPreviously known as anaphylactoid or pseudoallergic reaction, it is observed incross-reactive patients and presumably mediated by inhibition of COX-1 .The choice of diagnostic tests is based on the clinical picture and possiblepathogenesis.Although intradermal injection of pyrazolones has been proposed for diagnosticpurposes, no correlation with the clinical picture was observed . PresentPatch tests constitute a simple, fast, and relatively safe method for the diagnosisof delayed reactions to NSAIDs. For fixed-drug eruptions, lesional skin should beused for the test -40. WhenIt must be noticed that in some cases, a rechallenge with the drug is not recommendedbecause of the high risk of severe and generalized reactions . IntradeThe lymphocyte transformation test measures the in vitro proliferative response of Tcells stimulated by the drug. Although this test is worth to be considered, it isonly available in some laboratory facilities in specialized centers .For respiratory and cutaneous cross-reactions, the criterion standard continues to bethe controlled oral provocation test carried out in the appropriate medicalfacilities by physicians experienced in this kind of test and with easy access tomedications and equipments necessary for the treatment of reactions ,46. BronDe Weck et al  have devPatients reacting to a single NSAID can receive NSAIDs from a different chemicalgroup . Acetaminophen and other weak inhibitors of COX-1 aregenerally well tolerated by these patients at lower doses, but if the dose isincreased, respiratory reactions can occur .\u2022 Specific COX-2 inhibitors are tolerated by most patients with AERD .\u2022 Desensitization is indicated for selected sensitive patients who need toreceive NSAIDs for other medical conditions and for patients with severecorticosteroid-dependent AERD .Patients with cross-reacting urticaria/angioedema and nonallergic anaphylaxisshould be managed as follows:\u2022 Avoidance of COX-1 inhibitors.\u2022 Alternative medications as mentioned above (see aspirin-exacerbatedrespiratory disease).\u2022 COX-2 inhibitors are safe for most of these patients, but long-term use ofcoxibs is not recommended because of the cardiovascular risks associated withthem. In such cases, preferential inhibitors of COX-2 may be helpful ,58.\u2022 Desensitization is generally not recommended."}
+{"text": "Sir,\u00ae), a drug from Sanofi-Aventis, was approved by the FDA on July 2, 2009.[As a new therapeutic agent for cardiac arrhythmias, dronedarone , significantly better maintenance of the sinus rhythm was observed with dronedarone than with placebo. In the short term, lung and thyroid function remained unaffected. ConverseThe typical adverse effects observed with dronedarone include nausea, diarrhea, rash, and creatinine elevation."}
+{"text": "Botanical compounds have been widely used throughout history as cures for various diseases and ailments. Many of these compounds exhibit strong antioxidative, anti-inflammatory, and antiapoptotic properties. These are also common damaging mechanisms apparent in several ocular diseases, including age-related macular degeneration (AMD), glaucoma, diabetic retinopathy, cataract, and retinitis pigmentosa. In recent years, there have been many epidemiological and clinical studies that have demonstrated the beneficial effects of plant-derived compounds, such as curcumin, lutein and zeaxanthin, danshen, ginseng, and many more, on these ocular pathologies. Studies in cell cultures and animal models showed promising results for their uses in eye diseases. While there are many apparent significant correlations, further investigation is needed to uncover the mechanistic pathways of these botanical compounds in order to reach widespread pharmaceutical use and provide noninvasive alternatives for prevention and treatments of the major eye diseases. Cupressus sempervirens, also known as cypress, in the treatment of coughing, colds, and inflammation . Si. SiSalviBrassica vegetables, and many types of berries [In vitro studies using RF/6A rhesus choroids-retinal endothelial cells showed dose-dependent inhibition of cellular migration and tube formation, important steps of retinal angiogenesis, which is a characteristic of AMD, by treatment with quercetin [2+-induced oxidative stress in retinal cell cultures [in vivo; contrary to the untreated controls, choroidal neovascularization size was significantly diminished by administration of quercetin [Quercetin is one of the most widely studied flavonoids and is found in a variety of plant foods, including black and green teas,  berries . Interes berries . While t berries . Recent  berries . In vitruercetin . Furtheruercetin . Similarcultures . Howeveruercetin . Howeveruercetin . Quercetuercetin  through uercetin . In addiuercetin . In factuercetin , 81. Whiuercetin , 129, anuercetin . Even thBotanical compounds have been used throughout history for the prevention and treatment of various diseases. Previously, botanical supplements had not been awarded much scientific consideration; however, in the recent years, researchers and pharmaceutical companies have raised increasing interest for active ingredients from plants and nutraceuticals. Several major eye diseases in particular, AMD, glaucoma, cataract, and other retinal pathologies, are under investigation for potential beneficial effects of botanicals. These diseases can lead to ocular damage and visual problems primarily through oxidative stress, inflammation, and ocular pressure. Similarly, the active chemical ingredients in many botanicals contain strong antioxidative, anti-inflammatory, and anti-apoptotic properties. Although this review only addresses some of the well-studied and common botanical compounds for treatment of ocular diseases, there are numerous other compounds that may help with treatment of these diseases as well. While some botanical compounds, such as curcumin or quercetin, have been the subject of several studies and clinical trials, the benefits of many compounds have not been examined as extensively. In"}
+{"text": "In the paper titled \u201cRobot-Assisted Radical Hysterectomy for Cervical Cancer: Review of Surgical and Oncological Outcomes\u201d, all the authors' names and surnames are in reverse order. The authors list should be corrected as follows: Renato Seracchioli, Mohamed Mabrouk, Serena Solfrini, Giulia Montanari, Giulia Ferrini, Giulia Giovanardi, Diego Raimondo, and Riccardo Schiavina."}
+{"text": "Kikuchi Fujimoto's disease (KFD) is a rare, immune-mediated, self-limiting disorder with unique histopathological features. KFD is usually seen in young Asian females; however, cases have been reported throughout the world and in all ethnicities. It has been recognized that there is a rare association between Systemic Lupus Erythematosus (SLE) and KFD via sporadic case reports. The exact pathophysiological relationship between these two diseases is still unclear. We report a case of a young Asian female who presented with persistent fever and lymphadenopathy and was diagnosed with Kikuchi Fujimoto's disease based on lymph node biopsy; although an SLE workup was done, she did not meet the American Rheumatology Association (ARA) diagnostic criteria for lupus, and the lymph node biopsy did not show features of SLE. She improved clinically with a short course of steroid therapy. Two months later, the patient presented with central facial rash and arthralgia. SLE workup was repeated, a skin biopsy was done, and the results at this time supported a diagnosis of SLE. Kikuchi Fujimoto's disease (KFD) is a rare, immune-mediated, typically self-limiting disease first described in Japan in 1972 . ClinicaA 23-year-old Asian previously healthy woman presented with persistent fever and cervical, supraclavicular, and axillary lymphadenopathy. She denied chest pain, SOB, nausea, vomiting, weight loss, dizziness, diarrhea, urinary symptoms, rash, joint pain, headache, or vaginal discharge. She denied sick contacts, recent travel, exposure to pets/animals, bug bites, new medications, and herbal supplements. Prior to admission, the patient was evaluated at a community urgent care center where she had negative monospot test, Epstein-Barr Virus (EBV) PCR, and Cytomegalovirus (CMV) IgG. Upon admission, pt had a fever of 102.7, tachycardia at 115, and BP 109/74. Physical exam showed diffuse, rubbery, mobile, and tender lymphadenopathy of bilateral anterior cervical lymph nodes, bilateral axillary lymph nodes, and left supraclavicular lymph nodes. No rash was seen on her skin. There was no joint tenderness, warmness, erythema, or swelling. Cardiovascular and respiratory exams were otherwise unremarkable. CT scan showed enlarged axillary lymph nodes with partially necrotic appearing centers , partialKFD is a rare, benign, self-limiting, immune-mediated disorder that usually resolves spontaneously after 1\u20134 months . It occuOur patient fits into the epidemiological traits of KFD and has a typical KFD clinical presentation. She is a young, Asian, previously healthy female who presented with persistent fever and lymphadenopathy. No joint pain or skin manifestation was present initially. Infectious disease workup has all been negative. ESR was elevated. She did have a positive ANA but with a low titer. Anti-dsDNA was in the equivocal range. SSA and SSB were negative. Lymph node biopsy shows partially preserved lymphoid architecture with rare lymphoid follicles and extensive coagulative necrosis. The necrotic areas contain abundant karyorrhectic debris. The necrosis is often surrounded by and intermingled with many histiocytes that occasionally contain engulfed nuclear debris with the nuclei pushed to the periphery giving the nuclei crescent appearances . The hisShe did not meet the diagnosis criteria for SLE upon admission. History, clinical, laboratory, and biopsy findings all support a diagnosis of KFD. Two months later, the patient presented with malar rash, joint pain, positive ANA at high titer, increased anti-ds DNA, and positive anti-RNP antibodies; at that point, the patient met the American Rheumatology Association diagnostic criteria for SLE. Her skin core biopsy finding is consistent with discoid lupus erythematosus which further confirms a diagnosis of SLE.In conclusion, although KFD is a rare and self-limiting condition, it is important to recognize this condition in a patient who fits the epidemiological background with typical clinical features to avoid burdensome investigative workup and adding unnecessary anxiety to patients. In addition, when managing patient with KFD, it is crucial to recognize the relationship between SLE and KFD and carry out careful clinical surveillance to identify potential coexistence of SLE and to monitor for future development of SLE."}
+{"text": "AbstractNeodiogmites hirtuosus , two males and one female, deposited at the Museum f\u00fcr Naturkunde der Humboldt-Universit\u00e4t (ZMHB), Berlin were examined. The specimens show the diagnostic characters of Apoxyria Schiner, 1866: face strongly pronounced, swollen and curved hind tibia, and terminalia with epandrium large and hypandrium short and obtuse. A new combination is suggested, Apoxyria hirtuosa , and lectotype and paralectotypes are designated. The species is redescribed, the male terminalia is described and illustrated for the first time, and an identification key to Apoxyria is presented.                The type specimens of  Dasypogon hirtuosus Wiedemann, 1821, a species classified in the subfamily Dasypogoninae   based on specimens collected in Brazil, however without examination of the type material. Subsequently, Laustauroides with Neodiogmites Carrera, 1949, another genus of Dasypogoninae, and therefore the current name of the species is Neodiogmites hirtuosus.            ogoninae , is knowyntypes) .Carrera Neodigmites, the three syntypes of Neodigmites hirtuosus were examined. It was apparent that this species is not a Dasypogoninae and consequently, is not a member of Neodiogmites. Here, we propose a new combination for this species, with a lectotype designation.            During a revision of the genus The specimens studied are deposited in the Museum f\u00fcr Naturkunde der Humboldt-Universit\u00e4t (ZMHB), Berlin, Germany. The material includes three syntypes, two males and one female; and their labels read only \u201cBrazil\u201d. To observe the terminalia, it was detached from the abdomen and cleared in cold 10% KOH, followed by neutralization in acetic acid, dehydration in ethanol, and washing in distilled water. The dissected terminalia was placed in glycerin in a microvial pinned with the respective specimen. Morphological terms follow  comb. n.http://species-id.net/wiki/Apoxyria_hirtuosaDasypogon hirtuosus Lastauroides hirtuosus ;Neodiogmites hirtuosus ;PageBreak little dust, lacking flagellum, mesonotum broken posteriorly, abdomen cracked between the second and third segment. Paralectotype female (ZMHB ) in good condition, but the mesonotum is perforated posteriorly and the left flagellum is lost.Lectotype male (ZMHB), present designation, labeled: \u201cBrazil\\ ?, [without date] V. Olfers coll.\u201d A red label written \u201cLectotype\u201d was added. Specimen in reasonable condition, head slightly dusty, flagellum and middle leg lost, right wing mounted on permanent slides, abdomen dissected and placed in a micro-vial with glycerin, pinned together with the specimen. Paralectotypes: 1 male and 1 female, same locality as lectotype. Paralectotype male (ZMHB ) in reasonable condition, head with aLectotype male: Measurements: 12.5 mm (body length excluding antennae); 9.0 mm (wings).Face pronounced, covered by yellow pruinescence; dorsocentral setae of the same length as the scutum setae, however black; scutellum covered by short yellow setae, with several yellow long and slender apical scutellar setae; wings with r1 open.Lectotype male. Head (PageBreakapex obtuse, with short yellow setae ventrally; palpus black, longer than half length of proboscis, yellow setae basally and black on the remainder; antenna black, scape and pedicel almost the same length with black setae, scape with some basal yellow setae.                     le. Head : face blPageBreak with black setae anteriorly and yellow posteriorly; proepisternum and proepimeron with yellow pruinescence and yellow setae; scutum covered by short yellow setae; dorsocentral setae of the same length as the scutum setae, however black; two notopleural setae; three to four supra-alar setae and two postalar setae, all black; scutellum covered by short yellow setae, with several yellow long and slender apical scutellar setae; mesopleura covered by yellow pruinescence, except anteriorly on the anepisternum and katepisternum; anepisternum with yellow setae and some black setae posteriorly; katepisternum with yellow setae; katatergite with brownish setae.                    Thorax : black; Legs : shiny bWing : membranAbdomen : black, Female : flagell Brazil.Dasypogon hirtuosus by PageBreakthe male with only six abdominal tergites visible dorsally, as defined by After the original description of Apoxyria: numerous long and slender apical scutellar setae, the face strongly pronounced, swollen hind femora, swollen and curved hind tibia, and terminalia with a large epandrium and short and obtuse hypandrium.                    Among the genera of Laphriinae, the specimens show the diagnostic characters of Apoxyria is known only from Brazil, now with three species: Apoxyria apicata Schiner, 1866, Apoxyria americana Carrera, 1955 and Apoxyria hirtuosa .There are insufficient data to determine their distributions in detail, because few specimens of this genus have been collected.                    At the moment, the genus"}
+{"text": "Unnoticed and unpainted, these vectors nurture the dark underpinning of untamed nature, including arthropod-borne disease: in this issue of Emerging Infectious Diseases alone, sleeping sickness in Uganda; dengue in Cuba, French Guiana, Bangladesh, and Myanmar; cutaneous leishmaniasis in Colombia; malaria in Western Kenya; West Nile virus in Guadeloupe; murine virus in the Canary Islands."}
+{"text": "Banxia Baishu Tianma Tang , Da Chaihu Tang (Major Bupleurum Decoction), and Liu Wei Dihuang Wan (Pill of Rehmannia). And the common herb syndromes include Tian Ma (Gastrodia elata) syndrome, Sheng Di Huang (Radix Rehmanniae) syndrome, Niu Xi (Achyranthes Root) syndrome, and Chuan Xiong  syndrome.Hypertension is a clinical common disease, with high mortality and disability. Although there have also been significant advances in therapeutic concepts and measures, it has shown a certain value and significance in the treatment of Chinese medicine. The control strategy on hypertension is described from the following aspects such as differentiation of symptoms, pathogenesis, formula syndrome, and herb syndrome. As the common clinical manifestations of hypertension are dizziness, headache, fatigue, lassitude in the loins and knees, and so on, the pathogeneses of them are analysed. The author found that the main pathogenesis of the disease is heat, excessive fluid, and deficiency, which occurred incorporatively and interacted with each other in patients. Although the pathogenesis of the disease is complicated, the distribution of formula syndromes and herb syndromes is regular. The common formula syndromes include  Hypertension is a clinical common disease, with high mortality and disability. Additionally, it is also an independent risk factor for stroke, coronary heart disease, heart failure, renal insufficiency, peripheral vascular diseases, early death, and many other major diseases . In numeSymptoms are not only the basis for syndrome differential diagnosis but also the therapeutic targets. As Chinese medicine had no idea of blood pressure originally, it treated patients mainly by differentiating the syndromes according to the symptoms and signs caused by hypertension and paid more attention to relieve symptoms and improve the quality of life. The most common clinical manifestations of hypertension are dizziness, headache, fatigue, shortness of breath, lassitude in the loins and knees, memory loss, dry eye, palpitation, and so on .  Shang Han Lun (Treatise on Febrile Diseases). Dizziness caused by excessive fluid syndrome is always accompanied by chest distress, palpitation, nausea, and vomiting. Paroxysmal dizziness is one of the typical symptoms in Shaoyang syndrome. Persistent dizziness, headache, nausea, and vomiting can be found in Shaoyang syndrome accompanied by heat and excessive fluid syndrome. The disease belongs to \u201cvertigo\u201d in Chinese medicine. The main pathogenesis of vertigo is stagnation of phlegm, excess of liver yang, deficiency of qi and blood, liver-kidney yin deficiency, and stagnation of blood. In addition, there are important pathogenesis such as excessive fluid and pathogenic factor in Shaoyang meridians according to the clinical experience inThe syndrome differentiation of headache is similar to vertigo. The main pathogenesis of headache is excess of liver yang, deficiency of qi and blood, kidney deficiency, stagnation of phlegm and blood. We found that headache is caused by the flaring-up of fire in patients with hypertension. Flaring-up of stomach fire and intestinal fire followed by meridians are also very common, besides excess of liver yang. Severe headache generally suggests blood stasis; therefore, blood-activating and stasis-dissolving drugs should be used to relieve pain quickly. Moreover, cold accumulation in the liver and stomach should not be neglected, which can result in severe headache in the disease. Weakness and fatigue are extremely common symptoms of the disease. Generally speaking, it is caused by deficiency of qi, blood, yin, and yang. However, they are not the characteristic symptoms of deficiency syndrome. Some are caused by dampness and water accumulated inside. As the characteristic of pathogenic dampness is weight and sticky, which leads to stagnation of the functional qi and consumption of yang qi, weakness, fatigue, heaviness in head and body, and lassitude in loins and limbs often appear. Fu Ling (Poria cocos) and Bai Shu  (Atractylodes) contained in Gancao Ganjiang Fuling Baishu Tang  treating lassitude in loins and limbs can invigorate spleen to resolve dampness. Fu Ling (Poria cocos) and Ze Xie (Alisma) contained in Liu Wei Dihuang Wan (Pill of Rehmannia) and Shen Qi Wan (Pill of Kidney Qi) have the identical effection.In addition, although lassitude in loins and limbs is the characteristic symptom of kidney deficiency, excessive fluid is also an important factor of the symptom. The identification of the etiology and pathogenesis of hypertension in TCM viewpoint is directly related to the syndrome differentiation and therapeutic methods. According to the traditional view, the pathogenesis of hypertension is considered as founding on yin deficiency, with yang hyperactivity in the superficiality and phlegm-dampness and blood stasis penetrating all along; therefore, the basic therapeutic methods should be to supplement qi and nourish yin . HoweverLongdan Xie Gan Tang (Decoction of Radix Gentianae for Purging Liver Fire) noted in Yi Fang Ji Jie (Collection of Prescriptions with Notes), Tianma Gouteng Yin  (Decoction of Gastrodia and Uncaria) noted in Za Bing Zheng Zhi Xin Yi (New Meanings in Syndrome and Therapy of Miscellaneous Diseases), and San Cao Jiang Ya Tang (Decoction of Antihypertensive Effect) which is Professor Liu Duzhou's experienced prescription containing Long Dan Cao (Gentian), Xia Ku Cao (Prunella vulgaris), Yi Mu Cao (Leonurus japonicus), Shao Yao (Chinese Peony), and Gan Cao (Glycyrrhiza) all can be used for clearing liver fire and lowering blood pressure. Patients with heart fire syndrome often present with distraction, distress in chest, vexation, palpitation, nervousness, insomnia and dreaminess, hard to sleep, and easy to wake. Zhizi Chi Tang (Decoction of Gardenia and Lobster Sauce) and Huanglian Jie Du Tang (Detoxicant Decoction of Coptis) all can be used for clearing away heart fire and lowering blood pressure. Patients with stomach fire syndrome often present with dry mouth, thirst with desire for cold drinks, easy to starve, foul breath, smelly stool, and right guan pulse powerful alone. Bai Hu Tang (White Tiger Decoction) can be used to clear away stomach fire and lower blood pressure. Intestinal fire syndrome often shows foul breath, constipation, abdominal distension and pain, strength, and deep-hidden-powerful pulse. Da Chaihu Tang (Major Bupleurum Decoction) can be used for clearing away intestinal fire, dredging intestines, and descending turbid substance. Liver fire and heart fire often appear simultaneously, which result in hyperactivity of heart fire and liver fire syndrome in the disease. In addition, the liver restricting the spleen and stomach may also result in hyperactivity of liver fire, stomach fire, and intestinal fire. Heat syndrome can be found in various stages of hypertension, especially when target organ damage is not found. Heat syndrome includes liver fire, heart fire, stomach fire, and intestinal fire. Liver fire syndrome often shows clinical symptoms such as vertigo, headache, facial flush with perspires, conjunctival congestion, bitter taste in the mouth, irritability, wiry-rapid-powerful pulse, or powerful cunkou pulse alone, or wiry and long pulse even well beyond cunkou pulse. Zexie Tang (Decoction of American water Plantain), Fuling Xingren Gancao Tang , Wu Ling San (Wuling Powder), Ling Gui Zhu Gan Tang , Banxia Baishu Tianma Tang , Wu Zhu Yu Tang (Decoction of Evodia rutaecarpa), Er Miao Wan (Ermiao Pill), San Miao Wan (Sanmiao Pill), and Si Miao Wan (Simiao Pill) all can be used for dissipating excessive fluid. Fluid retention syndrome is a special type of the disease, containing morbid fluid retained in Shangjiao, Zhongjiao, and Xiajiao syndromes, cold fluid retention syndrome, fluid retention turning into heat syndrome, and downward flow of damp-heat syndrome. Morbid fluid retained in Shangjiao syndrome often shows dizziness aggravated by body position change, chest distress, palpitation, and cough. Morbid fluid retained in Zhongjiao syndrome often shows gastric distension, abdominal distension, nausea, vomiting, poor appetite, thirst without desire to drink, or not thirsty, daytime sleepiness, and greasy fur. Morbid fluid retained in Xiajiao syndrome often shows soreness, lumbar heaviness, low back pain, weakness and heaviness in lower extremity, edema, abnormal leucorrhea, dysuria and thick-greasy fur of tongue root. Cold fluid retention syndrome can appear retching, headache, cold hands and feet in syncope and dysphoria. Fluid retention turning into heat syndrome and downward flow of damp-heat syndrome can shows weakness and heaviness of lower extremity, thirst, yellow and ropiness leukorrhea, beriberi, and thick-greasy fur of tongue root. Atractylodes macrocephala), Fu Ling (Poria cocos), Ze Xie (American water Plantain), and Gan Cao (Glycyrrhiza) all can be used for removing dampness by strengthening spleen and replenishing qi. Kidney deficiency syndrome includes kidney yin deficiency syndrome and kidney yang deficiency syndrome. As prolonged disease involves kidney, we found that kidney deficiency syndrome is always related to hypertension. The longer the course of illness, the higher the incidence rate of kidney deficiency syndrome. Furthermore, it is not to be neglected that the antihypertensive drugs can also lead to kidney deficiency. Diuretic and \u03b2-blocker have greater impact on sexual function than other antihypertensive drugs. Sexual function will decrease when the above two antihypertensive drugs are sustained using more than ten years. Liu Wei Dihuang Wan (Pill of Rehmannia), Shen Qi Wan (Pill of Kidney Qi), Qi Ju Dihuang Wan  and Ji Sheng Shen Qi Wan (Pill for Reinforcing Kidney Qi) all can be used for reinforcing kidney.Deficiency syndrome includes spleen deficiency syndrome and kidney deficiency syndrome. As spleen promotes transportation and transformation of dampness, excessive fluid retention is related to dysfunction of spleen. Cang Zhu (Rhizoma Atractylodes), Bai Zhu , Da Chaihu Tang (Major Bupleurum Decoction), and Liu Wei Dihuang Wan (Pill of Rehmannia). Banxia Baishu Tianma Tang  is the classical representative famous prescription for calming liver, suppressing liver yang hyperactivity, dissipating excessive fluid, and expelling phlegm in Chinese medicine. It has been used widely in clinical practice for treatment of hypertension, which is also the author's experienced prescription. Prestigious Chinese physicians such as Yue Meizhong and Jiang Erxun are skilled in using the decoction in both China and the world. Japan's Chinese physicians often use it to treat hypertensive patients with weakness of gastrointestinal function. It can treat liver fire and morbid fluid retained in Zhongjiao, the indications of which are dizziness, headache, palpitation, abundant sputum, or without phlegm, poor appetite, nausea, and vomiting aggravated by tooth brushing, abdominal distension, soreness, lumbar heaviness, heaviness in lower extremity, edema, dysuria, constipation, or loose stool, big and light tongue with greasy fur and slippery pulse. The decoction is suitable for patients lacking physical activity for a long time, especially for old women, the physical characteristics of which are obesity of abdominal type with yellow and white skin, soft muscle, ease of dizziness, and headache. It is often combined with Zexie Tang (Decoction of American water Plantain), Wu Ling San (Wuling Powder), and Er Miao Wan (Ermiao Pill) in treating hypertension. Although the pathogenesis of the disease is complicated, the distribution of formula syndromes is regular. The common formula syndromes include Da Chaihu Tang (Major Bupleurum Decoction) syndrome is a special type of the disease, which can be used for reconciling Shaoyang meridian and descending turbid substance. It has been used for treating liver fire, stomach fire, and intestinal fire. The composing herbs such as Chai Hu (Bupleurum) and Huang Qin (Scutellaria) can sooth liver and clear liver fire. Da Huang (Rhubarb), Zhi Shi (Citrus aurantium), and Shao Yao (Peony) can clear stomach fire and relieve constipation. Professor Huang Huang, coming from Nanjing University of Chinese Medicine, is skilled in using the decoction, the indications of which are dizziness, headache, facial flushing, conjunctival congestion, dry mouth, bitter taste in the mouth, halitosis, abdominal distension, constipation, yellow urine, red tongue, and wiry-rapid-powerful pulse. Professor Huang Huang pointed out that the physical characteristics are obesity type, strength, hard fullness, and distending pain of upper abdomin mostly accompanied by biliary-pancreatic diseases, poor appetite, nausea, vomiting, constipation, suppressive emotions, stress, sleep disorders, and so on. We found that the decoction is suitable for the young and middle-aged men with hypertension. Professor Huang Huang often combined San Huang Xie Xin Tang (Decoction of Sanhuang for Purging Heart Fire) to clear heart and liver fire [ver fire . Liu Wei Dihuang Wan (Pill of Rehmannia) is the classical representative famous prescription for nourishing kidney yin, which has been widely used for treating kidney deficiency and excessive fluid syndrome. The indications of the decoction include dizziness, headache, tinnitus, low back pain, lassitude in loins and legs, edema, big and light tongue with less fur, and deep thready pulse. Due to the speciality of the disease, two therapeutic principles should be followed. The first one is that herbs should be prescribed according to the rule of syndrome differentiation and treatment, and the second one is that the pharmacological action of herbs should act on the pathological mechanism of the disease. Liu Wei Dihuang Wan (Pill of Rehmannia) not only accords with the pathogenesis but also aims at the pathological mechanism. This compound prescription has broad pharmacological activities, especially the action of protecting vascular endothelial cells, dilating peripheral blood vessels, decreasing peripheral vascular resistance, lowing blood pressure synergistically, and delaying the development and progression of arteriosclerosis. If accompanied by blurred vision, Gou Qi (Chinese Wolfberry) and Ju Hua (Chrysanthemum) should be added into the prescription, which composed Qi Ju Dihuang Wan . If accompanied by facial flushing and conjunctival congestion, Tian Ma (Gastrodia elata) and Gou Teng (Uncaria) should be added into the prescription for calming liver and suppressing liver-yang hyperactivity.Gastrodia elata) syndrome, Sheng Di Huang (Radix Rehmanniae) syndrome, Niu Xi (Achyranthes root) syndrome, and Chuan Xiong  syndrome. As the distribution of herb syndromes of hypertension is regular, we could find rules of formula syndromes from herb syndromes if we grasp the treatment rules of herb syndromes neatly and masterly. We found that the common herb syndromes include Tian Ma (Gastrodia elata) can calm liver and suppress liver yang hyperactivity. The indications of Tian Ma (Gastrodia elata) are dizziness, tinnitus, distending feeling in head, headache, facial flushing and conjunctival congestion, the pathogenesis of which belongs to flaming up of liver fire and hyperactivity of liver yang. It is noteworthy that if dizziness and headache are more severe, the dose of Tian Ma (Gastrodia elata) must be larger to control blood pressure, and we often use 30\u2009g, while routine dose such as 10 to 20\u2009g has unsatisfactory results. The dose of Tian Ma (Gastrodia elata) in academician Chen Keji's experienced prescription \u201cQing Xuan Jiang Ya Tang (Decoction for Eliminating Vertigo and Lowering Blood Pressure)\u201d is 30\u2009g, while the dose of another key herb Gou Teng (Uncaria) is 30 to 60\u2009g [Tian Ma ( to 60\u2009g . Shengnong Ben Cao Jing (Shennong's Classic of Meteria Medica), it can activate blood circulation. Yoshimasu T's \u201cYao Zheng (Indications of Herbs)\u201d recorded that it can treat blood syndrome and fluid retention. Therefore, the indications of Sheng Di Huang (Radix Rehmanniae) are low back pain, lassitude in loins and legs, edema, hypodynamia, dry mouth, constipation, thin and less fur. We often use it to treat liver fire, intestinal fire, kidney fire, kidney deficiency, and excessive fluid. The dose of Sheng Di Huang (Radix Rehmanniae) needs our attention as well as Tian Ma (Gastrodia elata). Low dosees enrich yin and nourishes kidney, while large dose could activate blood to dredge vessels. According to the author's experience, the clinical dose is 60 to 120\u2009g. It is not necessary to be too tense if patients present with gastrointestinal symptoms such as diarrhea and smelly stool after taking medicine, which means pathogenic fire is downgoing and eliminating. Sheng Di Huang (Radix Rehmanniae) could remove pathogenic heat from blood, nourish yin, and generate body fluid. In accordance with record of Shengnong Ben Cao Jing (Shennong's Classic of Meteria Medica), Niu Xi (Achyranthes root) can nourish liver and kidney, promote blood circulation to remove blood stasis, guide fire, and fluid downgoing. Therefore, dizziness, headache, facial flushing, conjunctival congestion, lassitude in loins and legs, and edema due to upward attack by qi and fire are the typical indications of Niu Xi (Achyranthes root). Professor Xu Wenhua, a prestigious Chinese physician of Jiangsu, is skilled in using Niu Xi (Achyranthes Root) treating pheochromocytoma, malignant abdominal tumors, and so on in clinical practice. The dose of Niu Xi (Achyranthes Root) is very large even up to 250\u2009g sometimes. He had taken herbal decoction with Niu Xi (Achyranthes Root) of 200\u2009g, and no serious side effect was found during the course of the treatment. Motivated by this, Professor Huang Huang often use large dose of Niu Xi (Achyranthes Root) to treat lower limb dropsy due to hemocirculatory disorder, cirrhosis ascites, hypertension patients with obesity, and so on. We often use it to treat liver fire, kidney deficiency, and fluid retention disease. Significant curative effect can occur when the dose is above 60\u2009g, and simultaneous use of both Chuan Niu Xi (Achyranthes bidentata) and Huai Niu Xi (Achyranthes bidentata Blume) could improve the curative effect. According to recordation in Ligusticum wallichii) could promote qi and activate blood circulation to relieve pain. According to recordation in Shengnong Ben Cao Jing (Shennong's Classic of Meteria Medica), it can treat headache. Famous Chinese physician Li Dongyuan also said that Chuan Xiong  must be used in treating headache. Therefore, the classical indication of Chuan Xiong  is headache. Severe headache always suggests qi stagnation, blood stasis, and meridians and collaterals impassable. The dose of Chuan Xiong  also deserves attention greatly. We had treated one case of intractable migraine patients with Xue Fu Zhu Yu Tang (Decoction for Removing Blood Stasis), in which the dose of Chuan Xiong  is 10\u2009g. However, after taking 10 doses, the pain was not alleviated satisfactorily. It is found that routine dose such as 10 to 20\u2009g cannot get satisfactory effect when headache is severe through many experiments afterwards. However, headache were relieved rapidly when the dosages was increased up to 30\u2009g. Chuan Xiong , peripheral nervous system (PNS), and endothelial system. Hypertension is caused by a variety of factors such as the interaction of environment and heredity factors leading to disturbances of blood pressure regulation, the pathological mechanism of which includes sympathetic nervous system (SNS), renin-angiotensin-aldosterone system (RAAS), vasopressin (VP), nitric oxide (NO), endothelin (ET), adrenal medulla, and a variety of vasoactive peptide secreted by other endothelial cells and smooth muscle cells \u201317. AlthPheretima, Laminaria japonica, Rhizoma Gastrodiae, Rhizoma Chuanxiong, and so on, with multicenter, randomized, double-blind, positive controlled clinical design in elderly patients with isolated systolic hypertension (EISH). It showed that Chinese medical regimen had affirmative effect in treating EISH patients and could lower the systolic blood pressurea and improve quality of life and early renal impairment of the patients [Although antihypertensive drugs have great advantage in reducing blood pressure rapidly with reliable effect, Chinese medicine can work at different levels and targets quite different from western drug which works relatively at few targets . Researcpatients . Professpatients . Furthermore, we found that there are laws for treatment according to many of years experience of large number of patients with hypertension. It has important significance in carefully analyzing common symptoms of hypertension, the etiology and pathogenesis, formula syndrome rules, herb syndrome rules, dose rules, combined diseases, and uncontrollable factors of blood pressure under the guidance of theory of Chinese medicine , 27."}
+{"text": "Sir,st century, has now officially become the most dangerous killer in the world according to the World Health Organization. Who can deny the fact that cancer is related to adversary of modernization and advanced pattern of irregular and stressed life dominated by Western medicine. Scientists are making their best efforts to fight this disease; however the sure-shot cure is still awaited.Cancer, one of the most deadly challenges spreading drastically in 21Ayurveda, the oldest Indian indigenous medicine system of plant drugs is known from very early times for preventing or suppressing various tumors using these natural drugs. And nowadays scientists are keener to researches on complementary and alternative medicine for the management of cancer. In Ayurvedic concept, according to \u2018Charaka\u2019 and \u2018Sushruta Samhitas\u2019 cancer is described as inflammatory or non-inflammatory swelling and mentioned either as \u2018Granthi\u2019 (minor neoplasm) or \u2018Arbuda\u2018 (major neoplasm). The nervThe modern cancer therapy which is known to burdened by drug-induced toxic side effects hoping perfect cure of disease form the complementary and alternative medicine system. The main goal of Ayurvedic therapy is to find the ultimate cause of an illness while the therapeutic approach of Ayurveda is divided into four categories as Prakritisthapani chikitsa , Rasayana chikitsa, , Roganashani chikitsa (disease cure) and Naishthiki chikitsa . CommonlyAndrographis paniculata, Annona atemoya, Phyllanthus niruri, Piper longum, Podophyllum hexandrum, Tinospora cordifolia, Semecarpus anacardium, Vitis vinifera, Baliospermum montanum, Madhuca indica, Pandanus odoratissimum, Pterospermum acerifolium, Raphanus sativus, Barleria prionitis, Prosopis cineraria, Amorphopallus campanulatus, Oxoxylum indicum, Basella rubra, Flacourtia romantchi, Moringa oleifera, Ficus bengalensis, Curcuma domestica, Allium sativum, Calotropis gigantean, Datura metel, Hygrophila spinosa, Juniperus indica, Moringa oleifera, Nigella sativa, Picrorrhiza kurroa, Rubia cordifolia, etc. are various plants having scientific evidence of anticancer property. Nowadays, many herbs are under clinical studies and being investigated phytochemically to understand their anticancer potential. More than 25% of drugs used during the last 20 years are directly derived from plants, while the other 25% are chemically altered natural products. Nine plant-derived compounds including vinblastine, vincristine, etoposide, teniposide, taxol, navelbine, taxotere, topotecan and irinotecan have been approved for use as anticancer drugs. 10-hydroxycamptothecin, monocrotaline, d-tetrandrine, lycobetaine, indirubin, colchicinamide, curcumol, curdione, gossypol and homoharringtonine are few more plant-derived compounds of high hope.[5Herbs help total healing, reduces the side effects and cancer-associated complications. Androgragh hope.5Each herb contains multiple active principles that often operate synergistically producing therapeutic benefits and lowering the risks of adverse effects; and avoids the need for supplemental therapy to manage cancer cachexia. Now it is important to raise awareness and encourage implementation of Ayurvedic therapies for combating cancer and suggest an integrated approach in tumor management and treatment."}
+{"text": "Dear Editor,We read the article entitled \u201cMean Platelet Volume as a potential prognostic marker in patients with acute mesenteric ischemia (AMI)-retrospective study\u201d by Altintoprak et al with interest . The autFirstly, the prognosis of AMI is related to late diagnosis, sepsis and colonic involvement . Early eSecondly, previous studies have demonstrated that diabetes mellitus, peripheral artery disease, acute coronary syndromes, autoimmune disorders, thrombocytopenia, congestive heart failure, acute pulmonary emboli, thyroid functional abnormalities, local or systemic infections, malignancy, inflammatory diseases, and many drugs may potentially affect MPV levels . AlthougAdditionally, the authors did not mention about the type of the tube (ethylenediaminetetraacetic acid (EDTA) or citrate tube) in which blood tests were performed. As reported earlier on in previous studies, MPV levels increase over time in EDTA anti coagulated samples ,5. So, iWe believe that the findings of Altintoprak et al will lead to further research concerning the relationship between MPV and AMI . NeverthThe authors declare that they have no competing interests."}
+{"text": "The authors would like to add the following to the Competing Interests section: \"Dr. Wiendl has received funding for travel and speaker honoraria from Bayer Schering Pharma, Biogen Idec/Elan Corporation, Sanofi-Aventis, Merck Serono, and Teva Pharmaceutical Industries Ltd.; has served/serves as a consultant for Merck Serono, Medac, Inc., Sanofi-Aventis/Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, Novartis, and Novo Nordisk; and receives research support from Bayer Schering Pharma, Biogen Idec/Elan Corporation, Sanofi-Aventis, Merck Serono, and Novo Nordisk.\""}
+{"text": "Sir,An 84-year-old male, resident of Delhi, India presented to our hospital with complaints of maculopapular rashes in bilateral extremities since 2 days. There was no orogenital involvement. Rashes did not involve the trunk or abdomen and were also not associated with itching. There was history of starting category I antitubercular therapy, comprising of rifampicin, isoniazid, ethambutol, and pyrazinamide, two months prior to present admission for pulmonary tuberculosis. Patient was not taking any other drugs, besides antitubercular drugs. Apart from the maculopapular rashes in the extremities  there weSkin involvement in tuberculosis can be due to tuberculosis itself or due to the antitubercular drugs. A tuberculous chancre, erythema nodosum, scrofuloderma, lupus vulgaris, tuberculosis verrucosa cutis or a tubercular gumma are various types of cutaneous tuberculosis. Other than this, tuberculids are skin reactions that exhibit tuberculoid features histologically but do not contain detectable mycobacteria. Papulonecrotic and lichen scrofulosorum are the two types of tuberculids.Erythema multiforme (EM) is a relatively common, acute, often recurrent inflammatory disease. Many factors have been implicated in the etiology of EM, including numerous infectious agents, drugs, physical agents, X-ray therapy, pregnancy, and internal malignancies. The drugs implicated in etiology of EM are Sulfonamides including hypoglycemics, nonsteroidal anti-inflammatory drugs (NSAIDs), anticonvulsants, barbiturates, antituberculous drugs, antibiotics, pyrazolones, phenylbutazone, oxyphenbutazone, and phenazone and salicylates. EM is commonly associated with a preceding acute upper respiratory tract infection, herpes simplex infection (HSV), or mycoplasma pneumoniae infection such as primary atypical pneumonia. Studies"}
+{"text": "Myoepitheliomas are rare benign tumors of myoepithelial cell origin, most commonly seen in parotid gland. These tumors are also reported in oral cavity, soft palate being the most common site of involvement. Imaging findings are nonspecific, and histopathology is necessary to differentiate from other tumors. Our case showed mildly enhancing well-circumscribed mass in soft palate with histological findings consistent with myoepithelioma. The aim of this case report is to increase the awareness about this rare benign tumor regarding its morphological, histopathological, and radiological features along with its possible differential diagnosis. Myoepitheliomas are rare benign neoplasm composed of ectodermally derived contractile smooth muscle cells, that is, myoepithelial cells which lack ductal differentiation. Myoepithelial cells are present in salivary glands, breast, larynx, and sweat glands of skin; hence, myoepitheliomas are reported in these sites \u20133. AboutA 40-year-old nonalcoholic, nonsmoker male presented with an asymptomatic slowly progressive palatal mass for four years. There was no history dysphagia, odynophagia, sleep apnea, voice change, weight loss, loss of appetite, and fever. The clinical examination revealed a firm, nontender, nonpulsatile, round, pinkish mass originating from the midline and right side of soft palate with no ulceration or erosion of overlying mucosa. No significant cervical lymphadenopathy was noted. X-ray soft tissue of nasopharynx lateral view  showed w Myoepitheliomas show four different morphological patterns which include nonmyxoid (solid), myxoid (pleomorphic adenoma like), reticular , and mixed . The celMyoepithelioma should be differentiated from its malignant counterpart that is, malignant myoepithelioma which is more aggressive and show recurrence even after adequate treatment. Histopathologically presence of cellular atypia, cellular pleomorphism, cellular necrosis, increased mitotic figures, invasive growth pattern, or combination of these favour the diagnosis of malignant myoepithelioma . Myoepitheliomas of soft palate needs to be differentiated from other tumors of soft palate like pleomorphic adenoma, neurinomas, hemangiomas, malignant tumors, metastatic tumors, lymphoma, solitary fibrous tumor, nerve sheath tumors, fibrous histiocytoma, paraganglioma, leiomyoma, leiomyosarcoma, hemangiopericytoma, and other inflammatory diseases , 13. ManMyoepitheliomas showed varying enhancement pattern on CT: faint enhancement, no significant enhancement or marked enhancement. Factors influencing enhancement pattern of myoepithelioma include histological component, stroma, vascularity, and histological cell type. The cellular myoepithelioma with fibrous stroma being more vascular showed more enhancement than those myoepithelioma being rich in myxoid stromal component. In our case the tumor showed mild heterogeneous enhancement after contrast administration. Enhancement patterns may have a role in differentiating the slow growing well demarcated masses of soft palate , 14, 15.Pleomorphic adenoma is the most common minor salivary gland constituting 40% of total cases having epithelial and ductal cells in its tissue. Presence of chondromyxoid matrix is considered most specific for pleomorphic adenoma while it is absent in myoepithelioma along with absence of glanduloductal differentiation . PeripheMyoepitheliomas are rare benign tumors most commonly presenting as slowly growing asymptomatic masses. The other salivary glands tumor like pleomorphic adenoma and adenoid cystic carcinoma should be kept in the differential diagnosis of this tumor. Various enhancement patterns of myoepithelioma are seen on contrast enhanced CT, which could be helpful in differentiating it from other soft tissue tumors."}
+{"text": "Surgical site infection (SSI) rates are the markers of health care quality. We have been prospectively following-up procedure specific surgical interventions in our center since 2005. Turkish National Hospital \u0130nfection surveillance for procedure specific hospital infections was begun in 2007 and a very first report on this subject was published in 2010.To compare and evaluate procedure specific SSI rates of our institution and Turkish National surveillance system.This study was carried out in Hacettepe University Adult Hospital between 01 January 2011 and 31 December 2012. Surgical procedures were selected according to NHSN surgical intervention categories and local data.  Centers for disease Prevention and Control (CDC) Hospital Infections Diagnostic Criteria were implemented to determine SSI rates. Active surveillance for each procedure was carried out during hospital stay however; surveillance was ended after hospital discharge. Data were entered in hospital infection program of our hospital (NosOnline\u00ae). Procedure specific infection rates were compared with National data and \u2018Standardized Infection Ratio\u2019 was calculated for each procedure.Total of 7075 surgical interventions was followed in 2 years. SSI rates were found to be higher in BILI, KTP, GAST,CBGB, COLO, OVRY,REC,XLAP, interventions when compared to National data. SSI rates for other intervention AMP, NECK, KPRO, FX, FUSN, HYST, SB,CARD, CBGC, CBGB.CRAN, HPRO,LAM,NEPH, PACE, PRST,SPLE, THOR, VSHN, were found to be compatible with National data.As our center is the tertiary referral center in Turkey, many patients with underlying risk factors for SSI were operated readily. Duration of postoperative hospital admission was longer when compared to National data. Longer hospital admissions and risky operations may lead to higher procedure specific SSI in certain interventions.None declared"}
+{"text": "AbstractTachinidae genera. The full list of terminal taxa included in the key, which is the most updated list of genera currently recorded for the Palaearctic Region, is given. We also briefly discuss the need for dealing with detailed and standardized taxa descriptions as a base to keep matrix-based interactive tools easily updated, by proposing a standardized protocol.We provide a general overview of features and technical specifications of an original interactive key web application for the identification of Palaearctic  Diptera family Tachinidae represents a good model to which \u201calternative\u201d diagnostic tools to the traditional dichotomous keys can be applied. We here propose an original interactive/multi-entry key web application, MOSCHweb , for the identification of 423 terminal taxa (at generic and subgeneric rank) of Palaearctic Tachinidae  based on a <characters x taxa> data matrix approach , the graphic representation of main measurements, and an iconographic database for each character state used in the interactive key. Also included are images and information concerning morphological features and distributions.Newly described taxa or nomenclatural changes will not alter the logic of the system, as new species can be added as terminal taxa just by adding a row of listed characters for the new species.This paper was prepared following the outlines for data papers provided by Tachinidae that are currently recorded in the Palaearctic Region   .Acemya Robineau-Desvoidy, 1830; Actia Robineau-Desvoidy, 1830; Actinochaetopteryx Townsend, 1927; Adenia Robineau-Desvoidy, 1863 [subgenus of Exorista]; Admontia Brauer & Bergenstamm, 1889; Allophorocera Hendel, 1901; Alloprosopaea Villeneuve, 1923; Alophorophasia Townsend, 1927; Alsomyia Brauer & Bergenstamm, 1891; Amelibaea Mesnil, 1955; Amnonia Kugler, 1971; Amphicestonia Villeneuve, 1939; Anaeudora Townsend, 1933; Ancistrophora Schiner, 1865; Anechuromyia Mesnil & Shima, 1979; Aneogmena Brauer & Bergenstamm, 1891; Anthomyiopsis Townsend, 1916; Anurophylla Villeneuve, 1938; Aphantorhaphopsis Townsend, 1926 [subgenus of Siphona]; Aphria Robineau-Desvoidy, 1830; Aplomya Robineau-Desvoidy, 1830; Arama Richter, 1972; Arcona Richter, 1988; Argyrophylax Brauer & Bergenstamm, 1889; Athrycia Robineau-Desvoidy, 1830; Atylomyia Brauer, 1898; Atylostoma Brauer & Bergenstamm, 1889; Aulacephala Macquart, 1851; Austrophorocera Townsend, 1916; Bactromyia Brauer & Bergenstamm, 1891; Bampura Tschorsnig, 1983; Baumhaueria Meigen, 1838; Belida Robineau-Desvoidy, 1863; Bessa Robineau-Desvoidy, 1863; Besseria Robineau-Desvoidy, 1830; Billaea Robineau-Desvoidy, 1830; Biomeigenia Mesnil, 1961; Bithia Robineau-Desvoidy, 1863; Blepharella Macquart, 1951; Blepharipa Rondani, 1856; Blepharomyia Brauer & Bergenstamm, 1889; Blondelia Robineau-Desvoidy, 1830; Botria Rondani, 1856; Brachicheta Rondani, 1861; Brachymera Brauer & Bergenstamm, 1889; Bracteola Richter, 1972; Brullaea Robineau-Desvoidy, 1863; Buquetia Robineau-Desvoidy, 1847; Cadurcia Villeneuve, 1926; Cadurciella Villeneuve, 1927; Calliethilla Shima, 1979; Calozenillia Townsend, 1927; Calyptromyia Villeneuve, 1915; Campylocheta Rondani, 1859; Carbonilla Mesnil, 1974; Carcelia Robineau-Desvoidy, 1830; Carcelina Mesnil, 1944; Catagonia Brauer & Bergenstamm, 1891; Catena Richter, 1975; Catharosia Rondani, 1868; Cavalieria Villeneuve, 1908; Cavillatrix Richter, 1986; Ceracia Rondani, 1865; Ceranthia Robineau-Desvoidy, 1830 [subgenus of Siphona]; Ceratochaetops Mesnil, 1954; Ceromasia Rondani, 1856; Ceromya Robineau-Desvoidy, 1830; Cestonia Rondani, 1861; Cestonionerva Villeneuve, 1929; Cestonioptera Villeneuve, 1939; Chaetexorista Brauer & Bergenstamm, 1895; Chaetoria Becker, 1908; Chaetovoria Villeneuve, 1920; Chetina Rondani, 1856; Chetogena Rondani, 1856 [except subgenus Diplostichus]; Chetoptilia Rondani, 1862; Chrysomikia Mesnil, 1970; ChrysosomopsisPageBreak Townsend, 1916; Ciala Richter, 1976; Cinochira Zetterstedt, 1845; Cistogaster Latreille, 1829; Clairvillia Robineau-Desvoidy, 1830; Clairvilliops Mesnil, 1959; Clausicella Rondani, 1856; Clemelis Robineau-Desvoidy, 1863; Cleonice Robineau-Desvoidy, 1863; Clytiomya Rondani, 1861; Cnephaotachina Brauer & Bergenstamm, 1894 [subgenus of Nowickia]; Compsilura Bouch\u00e9, 1834; Compsiluroides Mesnil, 1953; Conogaster Brauer & Bergenstamm, 1891; Conoptina Richter, 1995 [subgenus of Lixophaga]; Corybantia Richter, 1986; Crapivnicia Richter, 1995; Crassicornia Kugler, 1980; Crosskeya Shima & Chao, 1988; Crypsina Brauer & Bergenstamm, 1889; Ctenophorinia Mesnil, 1963; Cucuba Richter, 2008; Cylindromyia Meigen, 1803; Cyrtophloeba Rondani, 1856; Cyzenis Robineau-Desvoidy, 1863; Datvia Richter, 1972; Demoticoides Mesnil, 1953; Demoticus Macquart, 1854; Dexia Meigen, 1826; Dexiomimops Townsend, 1926; Dexiosoma Rondani, 1856; Dexiotrix Villeneuve, 1936; Dicarca Richter, 1993; Dinera Robineau-Desvoidy, 1830; Dionaea Robineau-Desvoidy, 1830; Dionomelia Kugler, 1978; Diplostichus Brauer & Bergenstamm, 1889 [subgenus of Chetogena]; Dolichocolon Brauer & Bergenstamm, 1889; Dolichocoxys Townsend, 1927; Dolichopodomintho Townsend, 1927; Drino Robineau-Desvoidy, 1863; Drinomyia Mesnil, 1962; Dufouria Robineau-Desvoidy, 1830; Ectophasia Townsend, 1912; Elfriedella Mesnil, 1957; Eliozeta Rondani, 1856; Eloceria Robineau-Desvoidy, 1863; Elodia Robineau-Desvoidy, 1863; Elomya Robineau-Desvoidy, 1830; Emporomyia Brauer & Bergenstamm, 1891; Engeddia Kugler, 1977; Entomophaga Lioy, 1864; Epicampocera Macquart, 1849; Erebiomima Mesnil, 1953; Eriothrix Meigen, 1803; Erycesta Herting, 1967; Erycia Robineau-Desvoidy, 1830; Erynnia Robineau-Desvoidy, 1830; Erynniopsis Townsend, 1926; Erythrocera Robineau-Desvoidy, 1848; Estheria Robineau-Desvoidy, 1830; Ethilla Robineau-Desvoidy, 1863; Etroga Richter, 1995; Eubrachymera Townsend, 1919; Euexorista Townsend, 1912; Eugymnopeza Townsend, 1933; Euhygia Mesnil, 1960; Eulabidogaster Belanovsky, 1951; Eulasiona Townsend, 1892; Eumea Robineau-Desvoidy, 1863; Eumeella Mesnil, 1939; Eurysthaea Robineau-Desvoidy, 1863; Euthera Loew, 1866; Eutrixopsis Townsend, 1919; Euvespivora Baranov, 1942; Everestiomyia Townsend, 1933; Exorista Meigen, 1803 [except subgenus Adenia]; Feriola Mesnil, 1957; Fischeria Robineau-Desvoidy, 1830; Flavicorniculum Chao & Shi, 1981; Freraea Robineau-Desvoidy, 1830; Frontina Meigen, 1838; Gaedia Meigen, 1838; Galsania Richter, 1993; Gastrolepta Rondani, 1862; Gastroptilops Mesnil, 1957; Germaria Robineau-Desvoidy, 1830; Germariochaeta Villeneuve, 1937; Glaurocara Thomson, 1869; Gnadochaeta Macquart, 1851; Gonia Meigen, 1803; Goniocera Brauer & Bergenstamm, 1891; Goniophthalmus Villeneuve, 1910; Graphogaster Rondani, 1868; Gymnocheta Robineau-Desvoidy, 1830; Gymnoglossa Mik, 1898; Gymnomacquartia Mesnil & Shima, 1979; Gymnophryxe Villeneuve, 1922; Gymnosoma Meigen, 1803; Halidaya Egger, 1856; Hamaxia Walker, 1860; Hamaxiella Mesnil, 1967; Hapalioloemus Baranov, 1934; Haracca Richter, 1995; Hasmica Richter, 1972; Hebia Robineau-Desvoidy, 1830; Hemimacquartia Brauer & Bergenstamm, 1893; Hemyda Robineau-Desvoidy, 1830; Heraultia Villeneuve, 1920; Hermya Robineau-Desvoidy, 1830;PageBreakHubneria Robineau-Desvoidy, 1847; Hyalurgus Brauer & Bergenstamm, 1893; Hyleorus Aldrich, 1926; Hyperaea Robineau-Desvoidy, 1863; Hypovoria Villeneuve, 1912; Hystriomyia Portshinsky, 1881; Imitomyia Townsend, 1912; Isafarus Richter, 1976; Isosturmia Townsend, 1927; Istocheta Rondani, 1859; Janthinomyia Brauer & Bergenstamm, 1893; Kallisomyia Borisova-Zinov\u2019eva, 1964; Kirbya Robineau-Desvoidy, 1830; Klugia Robineau-Desvoidy, 1863; Kuwanimyia Townsend, 1916; Labigastera Macquart, 1834; Lambrusca Richter, 1998; Lasiopales Villeneuve, 1922; Laufferiella Villeneuve, 1929; Lecanipa Rondani, 1859; Leiophora Robineau-Desvoidy, 1863; Leptothelaira Mesnil & Shima, 1979; Leskia Robineau-Desvoidy, 1830; Leucostoma Meigen, 1803; Ligeria Robineau-Desvoidy, 1863; Ligeriella Mesnil, 1961; Linnaemya Robineau-Desvoidy, 1830; Lissoglossa Villeneuve, 1912; Litophasia Girschner, 1887; Lixophaga Townsend, 1908 [sensu stricto]; Loewia Egger, 1856; Lomachantha Rondani, 1859; Lophosia Meigen, 1824; Lydella Robineau-Desvoidy, 1830; Lydina Robineau-Desvoidy, 1830; Lypha Robineau-Desvoidy, 1830; Lyphosia Mesnil, 1957; Macquartia Robineau-Desvoidy, 1830; Macroprosopa Brauer & Bergenstamm, 1889; Maculosalia Mesnil, 1946; Madremyia Townsend, 1916; Magripa Richter, 1988; Manola Richter, 1982; Masicera Macquart, 1834; Masistyloides Mesnil, 1963; Masistylum Brauer & Bergenstamm, 1893; Medina Robineau-Desvoidy, 1830; Meigenia Robineau-Desvoidy, 1830; Melisoneura Rondani, 1861; Mendelssohnia Kugler, 1971; Mesnilisca Zimin, 1974; Metacemyia Herting, 1969; Metadrinomyia Shima, 1980; Microcerophina Kugler, 1977; Microphthalma Macquart, 1843; Microsoma Macquart, 1855; Mikia Kowarz, 1885; Milada Richter, 1973; Mintho Robineau-Desvoidy, 1830; Minthodes Brauer & Bergenstamm, 1889; Mitannia Herting, 1987; Mongolomintho Richter, 1976; Munira Richter, 1974; Mycteromyiella Mesnil, 1966; Myxexoristops Townsend, 1911; Naira Richter, 1970; Nanoplagia Villeneuve, 1929   were excluded from this version. The characters used are divided into seven sections , with the easiest and most selective characters being highlighted in green. The user can also enter the length of the specimen in a dedicated box to exclude genera outside the length of the specimen under examination. Moreover, the key allows the user to sort out genera by their subfamily placement or by their parasitized host group affiliation.HEAD: eye pubescence; ocelli; width of frons ; width of frons ; outer vertical setae ; outer vertical setae ; length of ocellar setae; inclination of ocellar setae; frontal setae; fronto-orbital plate; upper reclinate orbital setae; proclinate orbital setae ; proclinate orbital setae ; parafacial setae; width of parafacial; parafacial ratio; shape of facial ridge ; setae of facial ridge; type of setae on facial ridge; vibrissa; face; lower facial margin; genal dilation; ventral part of occiput; dorsal part of occiput; height of gena.ANTENNAE: colour of antennal pedicel; length of antenna; length of first flagellomere; apex of first flagellomere; pubescence of arista; thickness of arista; length of first aristomere; lenght of second aristomere.MOUTHPARTS: length of prementum; labella; colour of palpus; size and shape of palpus.THORAX: presutural dark vittae of scutum; prosternal setulae; shape of prosternum; proepisternum; postpronotum; presutural acrostichal setae; presutural dorsocentral setae; postsutural dorsocentral setae; postsutural intra-alar setae; supra-alar setae; katepisternal setae; katepimeron; anepimeral seta; colour of scutellum; number of marginal setae of scutellum; lateral setae of scutellum; length of subapical setae of scutellum; apical scutellar setae; preapical scutellar setae; anatergite; posterior spiracle; postmetacoxal area.1; basal seta on vein R4+5; setae on vein R4+5; vein CuA1; bend of vein M; stub and prolongation of vein M; fourth costal sector (CS4); ratios of sections of vein M; crossvein DM-Cu; petiole.WING: position of lower calypter; marginal shape of lower calypter; setulae on lower calypter surface; wing colour; tegula colour; basicosta colour; second costal segment; costal spine; vein RLEGS: colour of legs; fore coxa; fore tibia; mid tibia; number of preapical setae on hind tibia; length of preapical setae on hind tibia; anterodorsal setae on hind tibia; hind coxa.ABDOMEN: ground colour of abdomen; abdominal microtomentum (pattern); fusion of abdominal tergites; mid-dorsal depression on syntergite 1+2; marginal setae on syntergite 1+2; median marginal setae on tergites 3 and 4; median discal setae on tergites 3 and 4; tergite 5 length; sternite 4; male abdominal patches of setulae (pattern); female ovipositor.COLOUR: general body ground colour.Platform: Framework.NetWeb Server: Microsoft Internet Information Service 6.0Programming language: C#Application version: MOSCHweb 1.0Data base: Microsoft SQL ServerData: 1.0betaLanguage: EnglishLicense for use of the key:Creative Commons Attribution License 3.0 (CC-BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Use of the primary data: Primary data are available from the authors by agreement.Web Location: www.tachinidae.euPageBreak Genera window: an updating real-time box containing all the genera that share selected character states. The name of the genus is followed by the author name, the year and page of the original description paper. Clicking on the genus name, a new window opens to show the general distribution, body length range and general remarks of the genus, the name of the subfamily it belongs to and the images available for it.1.Specimen length box: a small box in which user can insert an approximate specimen length as an integer number expressed in millimeters.2.  Subfamilies menu: a menu giving the possibility to reduce the query to the taxa belonging to just one of the four subfamilies or, by default, to work with the entire data set.3.Morphology\u2014Chaetotaxy\u2014Terminology button: a button that refers to a dedicated window .5. PageBreakBody parts bar: a bar with buttons referring to the body sections where used characters are divided. A \u201crefresh\u201d button clears the checkboxes for characters (without refreshing the host or subfamily selection).6. Character window: a window with all the characters used in the key. Each character has from two to nine states; for every state the user can see the pictures in the archive that refer to that state just by clicking on the camera icon to the left of the checkboxes. The characters can be used in any order; easiest and more selective characters are highlighted in green. MOSCHweb allows also for \u201cuncertainty\u201d to be expressed by the selection of more than one state for each character, as is useful for qualitative or morphometric characters. Taking into account that morphometric ratios are often continuous, we chose to subdivide arbitrarily such characters in more or less regular intervals. For specimens showing values at the extremes of the intervals, it is possible and suggested to select both the states with contiguous values.7. PageBreakSelected choice box: an updating real-time box showing the chosen characters and states selected by the user, ordered as they appear in the Character window; this represents an ID code which is linked to the specimen under examination.8. Export data: a button allowing the user to export in TXT format the terminal taxon/taxa name (depending upon the accuracy of the inquiry) followed by the list of selected states (point 8) in the form of a code  to be uploaded to the web application, along with a statement declaring that the images are original or copyright free.Instead, the author of a new taxon is encouraged to download the form of the encoded description from Corresponding authors  keep updated both the web application, by implementing new functions, and the data matrix, by improving encoded descriptions of terminal taxa. Every change can be monitored on the homepage and reported in the TXT export data file, by updating the number of the application version and by changing the date of the last modification to the data matrix. A short message on the homepage may describe differences from the previous version, if needed.It is well known how the high rate of description of new taxa and the many nomenclatural changes  quickly make conventional dichotomous keys obsolete. It is not always easy to update a dichotomous key especially when one or more taxa are split and new \u201ccouplets\u201d are needed. Generally, taxonomic and nomenclatorial changes are not a big problem for specialists, but for beginners or general users the only solution is to wait (often in vain) for the publication of a new updated key. In MOSCHweb this problem can be easily solved by augmenting the database (taxa x characters) with the new taxon/taxa. In this way the newly inserted entities will not alter the logic of the system, and automatically become part of the interactive key.An online open-access resource like MOSCHweb may enhance taxonomic reliability in two ways:PageBreak description protocol would represent the minimum amount of information recommended for describing a new taxon.i) By being easily updated once a new genus (or subgenus) is described and published. To do this, taxonomists may simply follow the same strict protocol for taxa description as used in MOSCHweb as a base. The mandatory fields of theii) By allowing the recording of the character states selected to identify a given specimen in the form of a TXT file, as a record for the user of the key and for the recipient of the identification.Tachinidae, is to be considered a platform to use also with other taxonomic groups. Those interested in testing MOSCHweb with other groups can send us a list of terminal taxa, a list of characters and character states and the resulting <characters x taxa> matrix. Moreover, we strongly encourage to provide images of treated taxa and pictures referring to the character states present in the key, as well as images illustrating morphological terminology adopted.MOSCHweb, although originally conceived for the identification of a difficult group of parasitoids like the"}
+{"text": "Chronic obstructive pulmonary disease (COPD) symptoms in the morning, including dyspnea and sputum production, affect patients\u2019 quality of life and limit their ability to carry out even simple morning activities. It is now emerging that these symptoms are associated with increased risk of exacerbations and work absenteeism, suggesting that they have a more profound impact on patients than previously thought. The development of validated patient-reported outcome (PRO) questionnaires to capture patients\u2019 experience of COPD symptoms in the morning is, therefore, vital for establishing effective and comprehensive management strategies. Although it is well established that long-acting bronchodilators are effective in improving COPD symptoms, the limited available data on their impact on morning symptoms and activities have been obtained with non-validated PRO questionnaires. In this review, we discuss the impact of COPD symptoms in the morning and available tools used to evaluate them, and highlight specific gaps that need to be addressed to develop standardized instruments able to meet regulatory requirement. We also present available evidence on the effect of pharmacological therapies on morning symptoms. Chronic obstructive pulmonary disease (COPD) is a progressive disease associated with substantial morbidity and mortality . It reprCharacteristic symptoms of COPD, including progressive dyspnea, cough and sputum production, have a considerable impact on patients\u2019 lives, in particular on those of patients with severe COPD . Breathl2-agonists (LABAs)  Patient responses were: not at all, a little, moderately, very or extremely.[B] If the patient answered 'Yes, I did it myself\u2019 (question 1\u2009\u2212\u20093) or 'Yes, I did' (question 4\u2009\u2212\u20096)The question was followed by 'How difficult was it to complete the activity?' .Each time was scored on a scale ranging from 0 (so difficult that the activity could not be carried out by the patients themselves) to 5 .2-agonists; MIDs: Minimal important differences; PRO: Patient-reported outcome; SGRQ: St George\u2019s Respiratory Questionnaire; TDI: Transition Dyspnoea Index.CDLM: Capacity of Daily Living during the Morning questionnaire; COPD: Chronic obstructive pulmonary disease; EMSCI: Early Morning Symptoms of COPD Instrument; FEV1: Forced expiratory volume in 1 second; GCSQ: Global Chest Symptoms Questionnaire; GOLD: Global Initiative for Chronic Obstructive Lung Disease; IC: Inspiratory capacity; ICS: Inhaled corticosteroids; LAMA: Long-acting muscarinic antagonists; LABA: Long-acting \u03b2In the past 5 years, Nicolas Roche received fees for speaking, organizing education, or consulting from Aerocrine, Almirall, Altana Pharma-Nycomed, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, MEDA, MSD-Chibret, Mundipharma, Novartis, Pfizer, Teva; and research grants from Novartis, Nycomed and Boehringer Ingelheim. NHC has received consultancy fees from Pfizer, Boehringer Ingelheim, AstraZeneca, Novartis and Chiesi and research grants from Pfizer, Boehringer Ingelheim, Novartis, Mundipharma and GlaxoSmithKline. MM has received speaker fees from Boehringer Ingelheim, Pfizer, AstraZeneca, Bayer Schering, Novartis, Talecris-Grifols, Takeda-Nycomed, Merck, Sharp & Dohme and Novartis, and consulting fees from Boehringer Ingelheim, Pfizer, GSK, AstraZeneca, Bayer Schering, Novartis, Almirall, Merck, Sharp & Dohme, Talecris-Grifols and Takeda-Nycomed.All authors were involved in the concept and design of this article. All authors revised the article critically for important intellectual content and gave their final approval of the version to be published."}
+{"text": "Everyone has gone homebut you and the janitor. The nurseshave driven away, fluttering across the parking lotlike white confetti.Sparrows sing themselves to sleep and even the hospitallongs to dream. You read X-raysin the view box glow, your patients\u2032 namesmarked in black, their lungssurprised in full inhale, hearts stoppedmid-pump, strangerswho keep you company as you scan for ribscracked like barrel staves, for emphysema'sburst balloon, for pinpoint tumourslight years away, only beginning to burn.The janitor knocks.You close the light, wishing each patient safe,every diagnosis exact. Outside,stars ignite, like cancers inflaming the sky.Cortney Davis"}
+{"text": "The European Union Committee of Experts on Rare Diseases (EUCERD 51/02 (8 The scope of CE in terms of disease coverage is an important issue as the expectation is to provide CE for all RD patients\u2019 needs at national level. Denmark, France, Norway, Spain and the UK, for example, have already identified existing expertise at national level and/or established centres specialised in some RD/groups of RD which have proven to be very efficient in improving quality of care. The Scientific Secretariat of the EUCERD examined the current scope of CE in countries where they exist. CE were grouped by medical area. Three or more MS have designated centres for: juvenile arthritis/ paediatric rheumatological diseases, developmental anomalies and malformations/dysmorphology, hereditary cardiac diseases, dermatological diseases, epidermolysis bullosa, pituitary diseases or hypothalamic-hypophyseal diseases, lysosomal diseases, Prader-Willi syndrome, Fabry disease, mitochondrial diseases, haemophilia/ constitutional bleeding disorders, mastocytosis, hereditary diseases of the metabolism, porphyrias, epilepsies, neuromuscular diseases, amyotrophic lateral sclerosis, pulmonary diseases, severe pulmonary hypertension, cystic fibrosis, hereditary immune deficiencies, opthalmological diseases, genetic kidney disease, cranofacial anomalies, neurofibromatosis, Rendu-Osler disease.On the basis of this experience, a consensus can be thus identified that centres are required for around 12 groups of RD, 30 subgroups, and 26 individual diseases where centres currently exist in two or more countries. Most of these groups of RD fit into the traditional organisation of healthcare by medical area. However some grouping outside of traditional medical specialities is necessary, e.g. diseases of connective tissue, rare bone diseases, neurofibromatosis, multimalformation syndromes with intellectual disability, mitochondrial diseases, lysosomal diseases, any multi-systemic complex disease, etc. This analysis could be of use for MS currently considering the organisation of CE for RD.This work was carried out by the EUCERD Scientific Secretariat with the support of EC Joint Action N\u00b020082291."}
+{"text": "The popular perception of herb-drug and drug-nutrient interactions is that they are unintended and problematic. Actually, purposeful coadministration of therapeutic agents within a clinical strategy represents a valuable approach to complex and evolving patient-centered care. As individuals age, they are more likely to be prescribed pharmaceutical medications: many also take herbs and nutrients, which may interact. The occurrence of polypharmacy may be orchestrated or unsupervised, beneficial or risky, depending upon the individual patient\u2019s physiology, health status and medical condition(s) and the communication and collaboration among the involved healthcare providers.A literature review was conducted using the following keywords: polypharmacy, herb-drug interactions, nutrient-drug interactions, safety, herbs, vitamins, minerals, amino acids, essential fatty acids, physiologics, nutraceuticals, nutritional supplements, adverse drug events, drug-induced nutrient depletion, integrative healthcare delivery, trans-disciplinary models, collaborative care, multidisciplinary care, therapeutic strategies, patient self-care, patient-centered medicine, aging, middle-aged, elderly.The challenges of multidisciplinary care involving diverse philosophical and clinical traditions bring forth the opportunity and necessity of formulating new models of proactive polypharmacy focused on patient safety, therapeutic efficacy and evidence-informed clinical-decision making. Patient demographics of medication, herb and nutrient usage, adverse drug event occurrence, and typical risk patterns are reviewed. Cardiovascular, degenerative bone and mind/mood conditions illustrate specific areas of concern.Within the standard literature of pharmacy practice, several clinical management tools have been developed for eliciting, assessing, and managing multiple prescribed and over the counter drugs. By extending the tools for coordinating polypharmacy to encompass the full range of therapeutic agents, whether pharmaceutical, nutrient or botanical, clinicians can formulate and implement a patient-centered model of safe and effective polypharmacy."}
+{"text": "Many diseases related to aging have been increasing because the aged population rapidly increases in the world. Therefore, the importance of antiaging active natural products has been increasing. Aging brings many disorders like cardiovascular problems, diabetes, senile dementia, Alzheimer's disease, cerebral infarction, degenerative neural disease, sleeping problems, various kinds of cancer, and so on. Since the side effects of modern medicines for aged bodies frequently occurs, the therapeutic use of natural products like herb medicines and/or phytomedicines having antiaging activity has been expanding widely depending on the accumulation of evidence-based experiences. As traditional medicines have a historical background of thousands of years based on a huge number of experiments for human bodies, such real evidence-based traditional medicine becomes important to accumulate the knowledge of antiaging activities. The authors in this special issue provide a comprehensive summary of their most recent knowledge on antiaging natural products. The more than 60 plant species including several pure compounds have been introduced in this issue. Also 500 or more references found at the end of individual chapters will help not only antiaging researchers but also many researchers, research scholars, academician, industrialists, and so on, for working in the numerous fields of natural products. This issue has encompassed all branches of antiaging phenomena like skin aging, hepatoprotective, antioxidant activity, Alzheimer's disease, cerebral ischemia, memory impairment, and brain damage, neuroprotection, inflammation, and anticancer. Therefore, this issue is widely related to pharmacognosy, pharmacology, pharmaceutical chemistry, natural product research, clinical, and hospital pharmacy and cosmetics and so on. All interested readers around the world can freely access articles online.Yukihiro ShoyamaYukihiro ShoyamaChun-Su YuanChun-Su YuanDaofeng ChenDaofeng ChenTibor WengerTibor Wenger"}
+{"text": "After publication of this work , we noteC. elegans experiments were performed by VF, VD, CMR, PG, and CDL. Neuro 2a experiments were performed by GHS. Characterization of ADDL preps was performed by PTV. ADDL-binding and toxicity assays in hippocampal cultures were performed and analyzed by PNL, and Tau phosphorylation analysis done by ND, EYF and MAS. Adenovirus transfection of cortical neurons was performed by JM. GHS, PNL, MAS, JM and CDL prepared the manuscript. All authors have read and approved the final manuscript."}
+{"text": "Rhodococcus erythropolis strain CCM2595. This bacterium is interesting in the context of bioremediation for its capability to degrade phenol, catechol, resorcinol, hydroxybenzoate, hydroquinone, p-chlorophenol, p-nitrophenol, pyrimidines, and sterols.We announce the completion of the genome sequence of a phenol derivative-degrading bacterium,  Rhodococcus possess a wide range of metabolic capabilities applicable for biodegradation of diverse environmental pollutants  was isolated from soil. Originally, it was classified as a strain of the species Jensenia canicruria . The annotation results were combined and verified within Artemis  and CP003762 (plasmid pRECF1).The genome sequences were deposited at DDBJ/EMBL/GenBank under the accession numbers"}
+{"text": "The mood disorder prodrome is conceptualized as a symptomatic, but not yet clinically diagnosable stage of an affective disorder. Although a growing area, more focused research is needed in the pediatric population to better characterize psychopathological symptoms and biological markers that can reliably identify this very early stage in the evolution of mood disorder pathology. Such information will facilitate early prevention and intervention, which has the potential to affect a person\u2019s disease course. This review focuses on the prodromal characteristics, risk factors, and neurobiological mechanisms of mood disorders. In particular, we consider the influence of early-life stress, inflammation, and allostatic load in mediating neural mechanisms of neuroprogression. These inherently modifiable factors have known neuroadaptive and neurodegenerative implications, and consequently may provide useful biomarker targets. Identification of these factors early in the course of the disease will accordingly allow for the introduction of early interventions which augment an individual\u2019s capacity for psychological resilience through maintenance of synaptic integrity and cellular resilience. A targeted and complementary approach to boosting both psychological and physiological resilience simultaneously during the prodromal stage of mood disorder pathology has the greatest promise for optimizing the neurodevelopmental potential of those individuals at risk of disabling mood disorders. There is increasing appreciation for the need to both identify and treat mood disorders during their earliest stages . AlthougStress is one of the best-studied mediators by which genetic vulnerabilities are translated into mood disorder pathology through the process of neuroprogression \u201318. NumeFKBP5), were prone to developing persistent cortisol dysregulation  , 54, 55.It is noteworthy to mention several other findings regarding altered inflammation in youth with psychiatric pathology. Increased mRNA and protein expression levels of IL-1\u03b2, IL-6, and TNF-\u03b1 were reported in the anterior prefrontal cortex of adolescent suicide victims compared with normal control subjects . ElevateHomeostatic control of synaptic connections within key mood-related circuits plays a critical role in the etiology of mood disorders . Stress Glycogen synthase kinase-3 (GSK-3), part of the signaling cascade regulated by BDNF, plays an important role in synaptic homeostasis through regulation of synaptic deconsolidation (pruning) and glutamate receptor cycling . IncreasStress, allostatic overload, and neuroinflammation function together to impair synaptic plasticity and cellular resilience. Disrupted plasticity along with increased cellular vulnerability contributes significantly to the pathophysiology of mood disorders and directly to the neuroprogressive nature of the disease course , 76. SomCellular vulnerability and resilience are mediated by apoptotic and anti-apoptotic intracellular signaling cascades, respectively. Apoptosis is important for the regulation of developmental processes and prevention of cancerous growths. Excessive apoptosis in neuronal systems, however, leads to neurodegeneration and certain cell populations are at increased risk of stress-mediated apoptotic cell death . ApoptosIdentification of individuals at risk of developing a mood disorder, or those in the prodromal stage, provides a potential opportunity to target these mechanisms for neuroprotective interventions that enhance cellular resilience, maintain synaptic plasticity and boost psychological resilience Figure  85). On. On85). Individuals provided with effective social and emotional support to help cope with stressors that are adverse and potentially taxing will be much better placed to limit associated biological costs and maintain allostasis . The absHealthy lifestyle, similar to optimism, provides a solid foundation for adaptation, and increases available resources for buffering the neurodegenerative effects of stress. Specifically, previous literature highlights the importance of healthy diet, adequate sleep, avoidance of smoking, and sufficient exercise . A populEarly intervention offers the possibility of altering the trajectory of mood disorder pathology. In so doing, we may curtail the progressive nature of the illness, both through neuroprotection and maintenance of peripheral health. Prevention and intervention treatments should go beyond stabilizing mood to include various and complementary strategies for reducing allostatic load, perhaps through psychoeducation and lifestyle-related interventions, including effective stress management. The combination of these techniques with specific pharmacotherapies may significantly improve functional outcomes by both reducing cellular insults and enhancing resilience. In so doing, this optimizes the capacity for maintenance of synaptic integrity and cellular resilience, which must be aggressively targeted as a therapeutic strategy during the prodromal stage of mood disorder pathology . This neAdam J. Walker, Yesul Kim, J. Blair Price, Rajas P. Kale, Jane A. McGillivray, Michael Berk, and Susannah J. Tye each made contributions to the writing of this manuscript.Michael Berk has received grant/research support from the NIH, Cooperative Research Centre, Simons Autism Foundation, Cancer Council of Victoria, Stanley Medical Research Foundation, MBF, NHMRC, Beyond Blue, Rotary Health, Geelong Medical Research Foundation, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Meat and Livestock Board, Organon, Novartis, Mayne Pharma, Servier and Woolworths, has been a speaker for Astra Zeneca, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen Cilag, Lundbeck, Merck, Pfizer, Sanofi Synthelabo, Servier, Solvay, and Wyeth, and served as a consultant to Astra Zeneca, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen Cilag, Lundbeck, Merck, and Servier. The other authors have no conflicts to report."}
+{"text": "The cause and pathophysiology of mood and psychotic disorders, including unipolar depression, bipolar disorder, and schizophrenia, is variable. Several scenarios have been proposed to explain the development of psychoses, one of which is mitochondrial dysfunction  ,2. ImpaiA recent study, published in this journal , aimed tThe study did not address whether, and to what degree, anti-psychotic or other medication may worsen the underlying defect due to mitochondrion-toxicity of the applied medication . This isSome agents described in the study have been reported to cause severe, sometimes even fatal, adverse reactions, such as valproic acid, which may cause irreversible liver failure, particularly in patients carrying POLG1 mutations . Other dBased on these considerations, it is advisable that patients with mitochondrial disorders receive special attention when treated with agents whose effects on mitochondria are uncertain or definitively toxic . Not onl"}
+{"text": "In \u201cAdverse Effects of Methylmercury: Environmental Health Research Implications,\u201d First, However, with no specific causative substance [etiologic agent] determined, there was no legal basis for a ban on fishing. However, in Japan, even with no specific etiologic agent determined, the Food Sanitation Act has routinely been enacted when causal food and/or causal facility was determined.Second, Third, Fourth, Finally, because the JME and local governments have been defendants in Minamata disease lawsuits, research funds from JME and the local governments may affect researchers\u2019 attitudes, possibly causing conflicts of interest."}
+{"text": "Plant species have long been regarded as possessing the principal ingredients used in widely disseminated ethnomedical practices. Different surveys showed that medicinal plant species used by the inhabitants of Jordan for the traditional treatment of diabetes are inadequately screened for their therapeutic/preventive potential and phytochemical findings. In this review, traditional herbal medicine pursued indigenously with its methods of preparation and its active constituents are listed. Studies of random screening for selective antidiabetic bioactivity and plausible mechanisms of action of local species, domesticated greens, or wild plants are briefly discussed. Recommended future directives incurring the design and conduct of comprehensive trials are pointed out to validate the usefulness of these active plants or bioactive secondary metabolites either alone or in combination with existing conventional therapies. Diabetes mellitus (DM) is highly recognised as the most common metabolic and endocrine disorder worldwide. It is linked to disturbances in carbohydrate, fat, and protein metabolism . It is eThe regional prevalence of diabetes in MENA (Middle Eastern and North Africa) countries is 7.7%. Locally, endocrine, nutritional, and metabolic diseases represent 7.9% of deaths in Jordan \u20135. With Undoubtedly, Jordan\u2019s habitat is exceptional. It is at the intersection of arid desert, dense forest, and tropical geography, thus bestowing the country with a rich variety of plants and microorganisms that can be resourcefully studied  9]. The. The9]. Apparently, there is a repository of ethnobotanical studies in the Mediterranean basin, providing a new and key tool for a quest after invaluable phytopharmaceuticals or the development of functional foods or nutraceuticals \u201320. TradThe objective of this review is to emphasize the ethnopharmacological practices related to 20 selected ethnobotanicals with claimed antidiabetic properties in light of their comprehensive scientific evaluation and bioactive plant secondary metabolites. Considering the hugely diverse plant species in diabetes traditional medicine, the present manuscript can be complementary to our previous report of 30 indigenous plants . In factZingiber officinalis, Terminalia chebula, or Emblica officinalis, alongside the likely obtainable native ones [Based on centuries of beliefs and observations, plants are primarily used in preparatory forms of infusions or decoctions in ethnomedicinal practices. Worldwide, more than 1,200 species of plants have been reported to be used empirically for their claimed antidiabetic activity  while inive ones , 35, 36.Camellia sinensis, Pimpinella anisum, Zingiber officinale, Matricaria recutita, Salvia fruticosa, Trigonella foenum-graecum, Nigella sativa, Lupinus albus, Teucrium polium, Allium sativum, Cinnamomum zeylanicum, and Olea europea. It is tempting to speculate that the high frequency of use is related to the high efficacy and safety of the plant material, such as green tea, aniseed, or chamomile, although there are no clinical studies to indicate monitoring of glucose and haemoglobin A1c levels in diabetic patients using these plants [Lupinus albus), fenugreek (Trigonella foenum-graecum), garlic (Allium sativum), olive leaves (Olea europea), ginger , felty germander (Teucrium polium), or black fennel (Nigella sativa) were not the top/main preference herbs of choice by the Jordanian diabetic patients [On the other hand, reports on the concomitant use of plants in orthodox therapy are evidently understated. In this aspect, interviews with diabetes patients in specialized health centres in Jordan further signified a more diversified list of selected plants , 26. Thee plants . Also, tpatients , 26, desTeucrium polium in normal and streptozocin (STZ)-diabetic rats. Additionally, the hypoglycaemic effects of Ballota nigra[Artemisia sieberi[Eriobotrya japonica[Ferula asafoetida were reported [in vitro and in vivo examinations of indigenous herbs valued as antidiabetic phytomedicines, including Achillea santolina, Eryngium creticum, Geranium graveolens, Paronychia argentea, Pistacia atlantica, Rheum ribes, Sarcopoterium spinosum, Teucrium polium, and Varthemia iphionoides, have been recognised with elaboration [Obviously, the significant efficacy of hypoglycaemic herbs, obtainable, via functioning as pancreatic insulin secretagogues and extrapancreatic insulin mimetics, enhancing glucose uptake by adipose and muscle tissues, or via inhibiting hepatic gluconeogenesis and intestinal carbohydrate digestibility and absorption, is comparable to conventional diabetes pharmacotherapeutics \u201339. Liteota nigra and Artea sieberi were evia sieberi. In othe japonica and Ferureported . Furtherboration \u201349. ThesAchillea santolina and A. fragrantissima are widely distributed in Jordan and used for their claimed antidiabetic activities. In STZ diabetic rats, hypoglycaemic activity was only evaluated for the former species though both species are rich in flavonoids among other similar volatile oil constituents. Hence, an antidiabetic activity can be likely assumed and verified for flavonoid-rich A. fragrantissima[Anthemis pseudocotula might be due largely to its flavonoid content. On equal footing, similar postulations can be deduced for plant species with reported antioxidative capacities. Basically, natural antioxidants are well-linked with antidiabetic therapeutic/preventive pharmacology [Alhagi marourum, Alchemilla vulgaris, Cucurbita maxima, Juniperus phoenicea, Quercus coccifera, and Ambrosia maritima can in principle justify their reported phytotherapeutic claims and ethnomedicinal uses.antissima. Also, tmacology , 52\u201355. Ajuga iva, Cleoma droserifolia, Urtica dioica, Sarco-poterium spinosum, Rheum ribes, Zea mays, and Geranium graveolens exhibited hypoglycemic activity in STZ and/ or alloxan diabetic animal models via inhibition of \u03b1-amylase and/or \u03b1-glucosidase or glucose absorption as plausible in vitro action mechanisms among many others (in vivo nor in vitro bioactivity could be detected in antidiabetes pharmacology appraisals with Peganum harmala or Ferula persica. These findings strongly negate the claimed ethnotherapeutic uses promoted for these plant species. As for Varthemia iphionoides and Zizyphus spina-christi, the lack of complementary in vivo or in vitro testing necessitates further experimental design and verification on future accounts [Six of the enlisted plants, namely y others . On the accounts .The hypoglycaemic properties of several classes of phytochemicals, including alkaloids, flavonoids, glycosides, glycolipids, polysaccharides, peptidoglycans, carbohydrates, amino acids, saponins, and terpenoids, have been exhaustively reported in the literature , 57\u201360. In conclusion, the reported findings, uniquely indicating the potential use of medicinal plants as antidiabetic agents, are among the very few that explored Jordanian flora from semi-arid and arid bioclimatic areas for pharmaceutical leads. Comprehensive research aiming at fully exploiting any of the promising species from the Jordanian flora, either alone or in combination with existing therapies, might lead to discovery of new avenues for medicinal plants/natural compounds in reducing the major public health impact of diabetes. Characterization of molecular targets and elucidation of relevant mechanisms of action also stand for another set of plausible requirements. Then, despite modern medicine accessibility, traditional medicine can be propagated as a viable health alternative."}
+{"text": "Analysis of complete response by MRI following neoadjuvant chemotherapy predicts pathological tumor responses differently for molecular subtypes of breast cancerYUJI HAYASHI, HIROYUKI TAKEI, SATOSHI NOZU, YOSHIHIRO TOCHIGI, AKIHIRO ICHIKAWA, NAOKI KOBAYASHI, MASAFUMI KUROSUMI, KENICHI INOUE, TAKASHI YOSHIDA, SHIGENORI E. NAGAI, HANAKO OBA, TOSHIO TABEI, JUN HORIGUCHI and IZUMI TAKEYOSHIOncology Letters 5: 83\u201389, 2013; DOI: 10.3892/ol.2012.1004After the publication of the article, the authors noted that they had made an error regarding certain data in their manuscript. The error relates to the calculations made in On page 88 of our article, in the left-handed column, we identified an erroneous statistical result with respect to the percentages calculated in"}
+{"text": "Chronic venous insufficiency, infection, diabetes mellitus, excess malnutrition, exposure to pressure and shear, all conditions included in obesity, prolong the healing process. Moreover, a growing body of evidence clearly indicates that dietary supplementation or intravenous administration of Arg is beneficial in facilitating wound healing, enhancing insulin sensitivity, and maintaining tissue integrity. Arginine produces physiologic effects via nitric oxide dependent and independent pathways. Nitric oxide is important for the modulation of vascular tone, inflammation, immune function, endothelial function, platelet and leukocyte adherence, and neurotransmission. Nitric oxide modulates many biochemical processes important for the response to sepsis. Arginine, independent of nitric oxide, is important for growth, wound healing, cardiovascular function, immune function, inflammatory responses, energy metabolism, urea cycle function, and other metabolic processes. Arginine supplementation improves outcomes in animals with sepsis, wounds, ischemia-reperfusion injury, and following thermal injury. Enteral administration of arginine improves endothelial function but has little effect upon hemodynamics during human sepsis. An analysis of clinical studies using enteral formulas with supplemental arginine suggests benefits upon outcome, with no evidence of significant detrimental effects. The aim of this study was to evaluate the healing effects of a normocaloric diet enriched in arginine, eicosapentanoic acid (EPA) and gamma-linolenic acid (GLA) and vitamins  on laparotomies wound dehiscence.2) patients with acute wound infections were included in a study evaluating the effects of protein, lipids and vitamins on healing of wound dehiscence. A diet enriched with nutritional supplements of arginine, lipids  and vitamins  was compared with a diet not enriched. The healing of wound dehiscence was evaluated weekly. Nutritional assessment included levels of serum albumin, C-reactive protein.Thirty obese . There was no significant difference in the nutritional parameters between the two groups.A diet enriched with arginine, EPA, GLA and vitamins A, C and E is associated with a significantly lower healing time of wound dehiscences in critically obese patients"}
+{"text": "Bowel and gastrointestinal dysfunctions are common post- spinal cord injury (SCI) complications affecting both physical and psychological aspects of the quality of life. More common and important gastrointestinal problems include constipation and fecal retention, constipation with frequent incontinence, hemorrhoids and serious abdominal complications such as cholecystitis, upper gastrointestinal bleeding, pancreatitis, appendicitis and the superior mesenteric artery syndrome. Therefore, the present study aims to review current evidence-based methods for bowel management among SCI patients.The MedLine/PubMed was used as the data source to identify studies published from January 1, 1995 to August 1, 2012. Cross referencing of discovered articles was also performed. All of the evidences related to bowel management in SCI patients were extracted. We designed search strategies using following keywords in both text word and subject heading forms: Constipation, incontinence, fecal retention, hemorrhoids, superior mesenteric artery syndrome, spinal cord injury, veteran, evidence, assessment, prevention and treatment. According to the inclusion criteria, 122 studies were selected for further analyses.For Constipation and fecal retention, a consistent and structured regimen was recommended. For constipation with frequent incontinence several methods were investigated such as digital rectal stimulation, abdominal massage, deep breathing , Valsalva maneuver, forward-leaning position, oral bowel medications, regular diet, Prokinetic medications, Prucalopride, Fampridine, colostomy, sacral electrical stimulation, functional magnetic stimulation, neuromuscular electrical stimulation and posterior tibial nerve stimulation. Hemorrhoids can be prevented THROUGH suppositories, enemas, digital rectal stimulation, stool softeners, minimizing trauma, and topical anti-inflammatory creams. The superior mesenteric artery syndrome would be treated by conservative management.In addition to prevention, training plays an important role in bowel management among SCI patients. Although different prevention methods have been reported, there are few well designed studies for managing gastrointestinal (GI) complications. In conclusion, training plays an important role in preventing bowel complications among SCI patients. However, more investigation is necessary to develop more evidence-based techniques to approach and manage GI complications in individuals with SCI.Constipation, Fecal incontinence, Hemorrhoids, Superior mesenteric artery syndrome, Spinal cord injury"}
+{"text": "After the publication of the article \u2018A hybrid BAC physical map of potato: a framework for sequencing a heterozygous genome. BMC Genomics 2011, 12:594\u2019 [Jan M. de Boer, Theo J.A. Borm, Taco Jesse, Bart Brugmans, Lian Wiggers-Perebolte, Linda de Leeuw, Xiaomin Tang, Glenn J. Bryan, Jaap Bakker, Herman J. van Eck, and Richard G.F. Visser.The authors declare that this publication has competing interests, due to the affiliation of authors TJ, LWP and LdL with the company Keygene N.V. in Wageningen. The AFLP\u00ae, KeyMaps and WGP\u2122 technologies are covered by patents and patent applications owned by Keygene N.V. AFLP and WGP are (registered) trademarks owned by Keygene N.V.JMdB performed band calling of AFLP fingerprints, processed AFLP and WGP fingerprint data, constructed AFLP and WGP physical maps, supervised and performed AFLP marker localisation in radioactive gel patterns of the genetic map, performed AFLP marker size conversion and anchoring, analysed and curated physical map data, isolated BAC DNA and prepared BAC QPP pool DNAs, wrote software for data processing and analysis, and drafted the manuscript. TJAB characterized and improved BAC AFLP fingerprints, constructed AFLP physical maps, analysed AFLP physical map data, contributed to AFLP marker anchoring, isolated BAC DNA, designed and prepared BAC DNA superpools, wrote software for analysis and presentation of physical map data and provided critical comments on the manuscript. TJ supervised RHPOTKEY BAC library construction and AFLP BAC fingerprinting, conceived and developed the KeyMaps anchoring procedure and provided critical comments on the manuscript. BB performed BAC fingerprint AFLP reactions. LWP performed BAC AFLP fingerprinting. LdL performed BAC pool AFLP reactions and BAC pool AFLP fingerprinting. XT performed the BAC FISH experiment to identify the NOR and performed AFLP anchor verifications with BAC FISH. GJB facilitated part of the data analysis work by JMdB at the J Hutton Institute, performed BAC library marker screening, contributed AFLP anchor BACs and provided critical comments on the manuscript. JB conceived and wrote the APOPHYS physical map project proposal. HJvE was involved in project writing, provided support for genetic map-related issues, and gave critical comments on the manuscript. RGFV was involved in project writing and funding acquisition, supervised the physical map project and provided critical input on composing the manuscript. All authors read and approved the final manuscript."}
+{"text": "We report an adolescent with respiratory symptoms admitted for clinical signs of an acute abdomen. The only diagnostic finding was influenza A viral RNA detected in an upper respiratory tract specimen. Influenza should be considered in the differential diagnosis of children with respiratory illness and abdominal pain during influenza season. Seasonal influenza A or B virus infection generally causes self-limited, uncomplicated febrile upper respiratory tract illness. However, children may experience severe complications, such as pneumonia, encephalopathy, encephalitis, secondary invasive bacterial infection, myocarditis, myositis, rhabdomyolysis, hepatitis, and sudden death.1Chlamydia trachomatis genitourinary infection. Other acute symptoms included rhinorrhea, cough, feverishness, myalgias, and headache. Workup included pelvic exam, complete blood count, electrolytes, urinalysis, and chest Xray\u2014all unremarkable. She received intravenous hydromorphone for analgesia and was discharged without a definitive diagnosis.A 17-year-old female adolescent presented to a hospital complaining of 2 days of diffuse abdominal pain. She also reported daily heavy vaginal bleeding and had a history of The next day, the patient presented with worsening abdominal pain, nausea, anorexia, and diarrhea. She was febrile, tachycardic, toxic-appearing, and mildly dehydrated. Abdominal exam was significant for hypo-active bowel sounds, exquisite tenderness to light palpation, worst in the right lower quadrant, with rebound tenderness and guarding, concerning for an acute abdomen requiring emergency surgical intervention. The patient was admitted for urgent evaluation of gastrointestinal, gynecologic, and genitourinary etiologies.Laboratory results revealed mild leukopenia and lymphopenia, slightly elevated transaminases, and elevated partial thromboplastin time and D-dimer. Abdominal computed tomography, transvaginal ultrasound, gynecologic examination, and genitourinary workup were non-diagnostic. The only significant finding was influenza A viral RNA detected by RT-PCR in a nasopharyngeal specimen collected on the 3rd illness day. She was discharged after 2\u00b75 days of supportive care, intravenous opiate analgesia, and hydration.Gastrointestinal symptoms associated with influenza include anorexia, nausea, vomiting, and diarrhea, all of which are more common in children than in adults. Diarrhea is more frequent in younger children with influenza and with influenza B.7The pathogenesis of gastrointestinal symptoms associated with influenza is unclear. Seasonal influenza A and B viral RNA has been detected in stool specimens from patients with respiratory symptoms and diarrhea.15in vitro studies, human influenza viruses have been shown to elicit cytokine dysregulation, attracting inflammatory leukocytes, and inducing excessive cytokine levels. This process can result in diffuse capillary permeability, resulting in systemic shock and distal organ injury such as cerebral edema and potentially also intestinal damage.16Rather than extrapulmonary influenza virus infection, the pathogenesis of abdominal pain is more likely attributable to influenza virus infection of the upper respiratory tract triggering an exuberant host inflammatory response. In murine models and In summary, influenza should be considered in the differential diagnosis of children with febrile respiratory illness and severe abdominal pain during influenza season, after excluding those diagnoses that require urgent surgical intervention. Early empiric antiviral treatment and influenza testing are recommended if influenza is suspected, especially if the patient is hospitalized."}
+{"text": "The affiliation for the second author is incorrect. Stephan Albrecht Ender is affiliated with: Department of Orthopaedics and Orthopaedic Surgery, University Medicine Greifswald, Ferdinand-Sauerbruch Stra\u00dfe, 17475 Greifswald, Germany."}
+{"text": "Chinese marine materia medica (CMMM) is a vital part of traditional Chinese medicine (TCM). Compared with terrestrial TCM, CMMM, derived from specific marine habitats, possesses peculiar chemical components with unique structures reflecting as potent pharmacological activities, distinct drug properties and functions. Nowadays, CMMM appears to be especially effective in treating such difficult diseases as cancers, diabetes, cardio-cerebrovascular diseases, immunodeficiency diseases and senile dementia, and therefore has become an important medicinal resource for the research and development of new drugs. In recent years, such development has attracted wide attention in the field of medicine. In this study, the CMMM resources in China were systematically investigated and evaluated. It was found that the historic experiences of Chinese people using CMMM have continuously accumulated over a period of more than 3600 years, and that the achievements of the research on modern CMMM are especially outstanding. By June 2015, 725 kinds of CMMMs from Chinese coastal sea areas have been identified and recorded, covering 1552 organisms and minerals. More than 3100 traditional prescriptions containing CMMMs have been imparted and inherited. However, the number of CMMMs is less than the 8188 terrestrial TCMs, from more than 12,100 medicinal terrestrial plants, animals and minerals. In the future, the research and development of CMMM should focus on the channel entries (TCM drug properties), compatibility, effective ingredients, acting mechanisms, drug metabolism and quality standard. This study reveals the high potential of CMMM development. By Qin and Han dynasties (about 1800 years ago), more knowledge of marine medicines was acquired. Especially, Shennong Bencaojing (Shennong\u2019s Classic of Materia Medica) [Sargassum, CheloniaTestudinis, SepiaeEndoconcha, Meretriciset CyclinaeConcha, and Eriocheir et Gaetice. Thanks to the herbological development in Tang and Song dynasties, CMMM had achieved a remarkable progress in the Ming and Qing dynasties. Tang Ben Cao (TangMateria Medica) [Corallium, Cyrtiospirif, Notorynchi et MusteliCortex, Mauritiaeet CypraeaeConcha, TurbinisOperculum, Mactra etLutraria, Silvetia, and PorphyraeThallus. Compendium of Materia Medica [Macreophtalmus, Tylorrhynchus etNectoneantheset Neanthes, Gelidium, and Gracilaria. Supplement to Compendium of Materia Medica [CaloglossaLeprieurii, EucheumaDenticulateKappaphycus, Notarchi etAplysiaeOvumSaccus, Trichiuruset Eupleurogrammus etLepturacanthus, and Syngnathus. In addition to the CMMM, the ancient books above also recorded thousands of formulas (prescriptions and dietary therapy formulas) with the CMMMs as principal drugs. During the latter half of the 20th century, new CMMMs have been consecutively discovered along with the rapid development of TCM and modern marine drugs. In recent decades, it was found that there are a large number of marine drug formulas with CMMMs commonly applied in Chinese coastal areas, including proved formulas, secret prescriptions and folk formulas. These prescriptions and formulas have been dug out by long time investigation and practice, and their clinical effects have been verified in modern clinical use by traditional Chinese medicine physicians. As a result, these proved and effective recipes have been recorded in modern medical books, for instance, Chinese Materia Medica [Chinese Marine Materia Medica [Chinese Marine Materia Medica [According to HaiChing , marine  Medica) \u2014an ancie Medica) , an impea Medica , a mastea Medica  compiledi.e., Liaoning, Hebei, Tianjin, Shandong, Jiangsu, Shanghai, Zhejiang, Fujian, Taiwan, Guangdong, Hong Kong, Macao, Hainan, and Guangxi). Some marine medicinal species only exist in China, and some of them are labeled as world rare species. By June 2015, a total of 725 CMMMs have been recorded and studied in terms of modern pharmacology and chemistry, involving 1552 species of medicinal organisms and minerals , Laminariae, Ostreae, and Margarita, have been artificially bred in large scale for drug use [The CMMM resources were investigated by field inspection and literature survey. The field investigation focused on four main areas, including the tropical coral reef ecosystem, the tropical and subtropical mangrove ecosystem, the estuary and intertidal zone ecosystem, and the aquatic ecosystem surrounding islands. The tropical coral reef ecosystem with extremely prolific biodiversity has become a vital biological source of marine natural products and modern marine drugs. The tropical and subtropical mangrove ecosystem features abundant of medicinal mangrove forests as well as epiorganisms or symbionts. The estuary and intertidal zone ecosystem, a coastal zone connecting with land and fresh waters, is the most convenient place for people to obtain and utilize medicinal marine organisms, while the aquatic ecosystem surrounding islands is less influenced by human activities, and thus the biocommunity maintains a native ecological state. Our investigation and statistical analysis indicated that CMMM resources are distributed within all Chinese seas, including the Bohai Sea, the Yellow Sea, the East China Sea, and the South China Sea, covering coastal areas and wetlands in 58 counties under the jurisdiction of 14 provinces, cities and special administrative regions  [Arcae Concha, Haliotidis Concha, Ostreae Concha, Margaritifera Concha, Meretricis Concha, Hippocampus, Syngnathus, Sepiae Endoconcha, and Margarita) and three botanic MMMs  , salty-warm (Hippocampus and Syngnathus), sweet-neutral (ApostichopusetStichopusetThelenota and ChlamydisetMimachlamydisetArgopectinis Adduotor) are representative in the natures and flavors of CMMMs, with salty flavor up to more than 90% of the total flavors. In terms of medicinal effects, the most representative efficacies of CMMMs include softening hard mass and removing stasis , removing heat to cool blood, neutralizing poison and eliminating purpura , invigorating kidney and strengthening essence , and calming liver and suppressing Yang  [Specifically, 12 CMMMs have been recorded in the a (2015) , which ce Radix) . The Med Concha) . TherefoLaminariae is a very common CMMM used in China. Its functions mainly focused on dissolving phlegm, relieving cough and asthma, softening hard mass and eliminating stagnation, and promoting diuresis and dredging stranguria. The Capsule of Laminariae Thallus powder was used for treating hypertensive patients of I\u2013II period. The systolic pressure and diastolic pressure of the patients were effectively reduced when they took 12 g Laminariae Thallus powder every day. The Capsule of Laminariae Thallus powder was found to enhance the function of conventional antihypertensive drugs when co-administrated [Arcae Concha is also a common CMMM possessing the efficiency of dissolving phlegm, breaking stagnate and relieving pain. It has been reported that the superfine powder of Arcae Concha was applied exteriorly for different levels of chilblain, and all 35 patients recovered after 2\u20136 times [In recent decades, the efficacies of CMMMs have been verified continuously by modern clinic research. For example, istrated . Arcae C\u20136 times .Sepiae Endoconcha and Bletillae Rhizoma with a ratio of 2:1, was applied to treat 100 patients of hematemesis or hematochezia induced by duodenal ulcer. The patients took Ulcer Styptic Powder, 2\u20134 g or 4\u20136 g per time, and 3\u20134 times one day. The results indicated that 97 patients stopped bleeding or recovered from hematemesis or hematochezia [Rhei Radixet Rhizoma and Ostreae Concha Decoction was prepared with 30 g calcine Ostreae Concha, 30 g fresh Rhei Radixet Rhizoma, and other TCM materials. This decoction was used to treat 38 uremia patients by high retention-enema of rectum with 200 mL one day. A 10-day treatment course was designed, and the treatment period was 1\u20133 courses depending on the patient situation. The results revealed that this prescription was effective for 33 cases, of which 17 cases exhibited excellent effects [In most cases, the CMMMs are usually used with other TCMs by compatibility rule in traditional Chinese prescriptions. Ulcer Styptic Powder, a compound recipe consisting of tochezia . Rhei Ra effects .Laminariae, a traditional CMMM from brown alga. Chemical component analysis indicated that Laminariae contains abundant laminarin including algin, fucoidan and laminaran, as well as other ingredients, such as mannitol, iodine and inorganic elements. Laminariae is a rich source of algin, mannitol and iodine. Several modern drugs have been developed from Laminariae. Particularly, based on the main component algin, Alginic Sodium Diester (PSS\u00ae) was developed into the market in 1985 as a marine polysaccharide sulfated drug with anti-hyperlipidemia function [Laminariae [\u00ae, an OTC calcium replenisher against rachitis and osteomalacia, is also a widely used marine prescription with calcium extracted from Ostreae Concha [Specifically, the studies on the effective components of CMMMs have also been executed by modern technology in recent decades. From most CMMMs, the main chemical components have been identified and analyzed and their pharmacological activities have been tested and evaluated. A series of effective constituents have been extracted and developed as modern component drugs. The most famous example is the research and development of the function ,45. Up tfunction . Mannitominariae . In addie Concha .Chinese Marine Materia Medica have not been developed by modern technology. It may be predicted that the potential resources of CMMMs that have not yet been identified or utilized will be discovered and studied in the coming decades. These resources will no doubt become a prolific source for development of CMMMs under the guidance of Chinese traditional medicine theory, as well as a strategy resource to exploit modern marine drugs by high technology [Currently, 20 single CMMM preparations and 200 compound CMMM preparations have been developed into the market. Nevertheless, it should be noted that the majority of the 3100 ancient marine herbal formulas and proved formulas as recorded in chnology ,49.With IRB approval and informed consent, CMMMs were investigated mainly in the TCM national markets of China, including Anguo TCM Market in Hebei, Bozhou TCM Market in Anhui, Qingping TCM Market in Guangdong, and Yulin TCM Market in Guangxi. The investigation was also conducted in coastal drug markets and marine product markets. Diverse ways and methods ,10,11 weThe literature survey was conducted by searching ancient medical literature and modern databases. The ancient medical literature looked up covered 500 pieces of traditional Chinese Medicine text concerning CMMMs. Ten databases were used as the main origin of medicinal information, including Traditional Chinese Medical Database System, Scientific Database of China Plant Species, Scientific Database of China Animal Species, Medline, Marinlit, ScienceDirect, SpringerLink, Wiley Online Library, ACS Publication, and RSC Publication. The data and information were collected and extracted from over 20,000 pieces of modern literature, including CMMM assortments, original organisms, chemical components, pharmacological activities, toxicity, clinical application, production areas, resource status, medicament portions, processing methods, storage conditions, storage duration, quality grades, prices, usages, outputs, and sales volumes.The investigation was focused on the common endemic CMMMs in China. The original data were collected, summarized and analyzed. The inaccurate or invalid data were removed, and the valid data were transformed to charts using Excel and SPSS. The CMMM status was assessed based on the above data and information.The fieldwork and historical document survey were carried out to investigate the original organisms of CMMMs and the distribution of marine medical species in China. A specific field investigation on marine medicinal bioresources was conducted in the South China Sea, the East China Sea, the Yellow Sea, and the Bohai Sea. The main areas for field investigation were selected based on the features of the Chinese oceanic geographical environment, marine ecosystem and marine medicinal bioresources, including tropical coral reef ecosystem, tropical and subtropical mangrove ecosystem, estuary and intertidal zone ecosystem, and aquatic ecosystem surrounding islands. The tropical coral reef ecosystem areas covered the South China Sea and those coastal waters near Hainan, Guangdong and Guangxi provinces. Specifically, the medicinal marine organisms were collected in the sea areas around Hainan Island , Leizhou Peninsula (near Xuwen), Naozhou Island, Weizhou Island, and Xisha Islands. The key investigation areas of tropical and subtropical mangrove ecosystem included Qiongshan in Hainan , Wenchang in Hainan , Sanya in Hainan , Danzhou in Hainan , Lingao in Hainan , Zhanjiang in Guangdong , Hepu in Guangxi , Leizhou Peninsula, Xiamen and Longhai in Fujian, and Wenzhou in Zhejiang. The key investigation areas in estuary and intertidal zone ecosystem included roundabout Hainan Island, coastal areas of Guangdong, Guangxi, Zhejiang, and Shandong, Bohai gulf, and estuaries of Zhujiang River, Yangtze River, and Yellow River. The key investigation areas of the aquatic ecosystem surrounding islands included the sea areas around Weizhou Island, Naozhou Island, Nanao Island, Nanji Island, Zhoushan Islands, Lingshan Island and Miaodao Islands. The collection methods for the marine organisms included trawling sampling , bottom characteristics sampling, and SCUBA diving sampling ,51. FromMedicinal coral species were identified by Hui Huang and Xiubao Li from South China Sea Institute, Chinese Academy of Sciences, China; medicinal sponge species were identified by Nicole J. de Voogd from Netherlands Centre for Biodiversity Naturalis, The Netherlands; medicinal mangrove species were identified by Cairong Zhong from Dongzhaigang National Mangrove Natural Reserve, China; medicinal algae were identified by Shuben Qian from Ocean University of China, and Bangmei Xia from Institute of Oceanology, Chinese Academy of Sciences, China; medicinal coastal wetland plants were identified by Fengqin Zhou from Shandong Traditional Chinese Medicine University, China; and medicinal fish, shellfish, and other invertebrates were identified by Yunfei Wu, Xiaoqi Zeng, Shichun Sun and Zhenjiang Ye from Ocean University of China, and Daohai Chen from Zhanjiang Normal University.The folk interviews included personal interview, telephone interview, conversazione, and consulting to fishers and folk doctors. The folk recipes, nostrums and informal prescriptions using CMMMs were collected and uncovered from Chinese coastal areas, mainly in coastal villages and small towns. The folk investigation and interview routes were along the Chinese southeast coastlines passing through the residential communities, involving Liaoning, Hebei, Shandong, Zhejiang, Guangdong, Guangxi, and Hainan provinces.In present study, CMMM resources in China were investigated by systematical evaluation and statistical analysis. It was found that there are totally 725 kinds of CMMMs, covering 1552 original medicinal marine plants, animals and minerals. More than 3100 prescriptions containing CMMMs have been used with compatibility. CMMM, possessing distinct drug properties and functions, has been proven to be especially effective for treating chronic, complex and difficult diseases. It has now become an important medicinal resource for the research and development of drugs. From a perspective of historical origin of CMMM research and application, we know that CMMM, which has become an integral part of TCM treasury, plays a unique role in the history of TCM development. It is imperative to comprehend its essence from modern views, interpret its mystery with modern science, and dig into its potential using modern technology. Many CMMMs have been proven their medical usage as recorded in ancient TCM literature and also turned out to be effective after long-term clinical practices. Nevertheless, compared with the terrestrial TCM, from an overall view, the level of CMMM development is relatively low. The knowledge of CMMM as a special TCM resource is insufficient, while the research and development of its modern application is still in the infancy. Therefore, in future research and development of CMMMs, the key approaches to study should be the nature of the drugs, channel entries, compatible applications, efficient substances, action mechanisms, drug metabolism and quality standards. The development of marine compound preparations and component drugs under the guidance of TCM theories using CMMMs and their formulas could be expected."}
+{"text": "Scientific Reports5: Article number: 1282510.1038/srep12825; published online: 08112015; updated: 02092016In the HTML version of this Article, Gemma Lancaster and Aneta Stefanovska were incorrectly listed as being affiliated with \u2018Department of Clinical and Experimental Medicine, University of Pisa, Italy\u2019. The correct affiliation is listed below:Department of Physics, Lancaster University, UK.In addition, Margherita Pesce, Gian Marco Vezzoni, Paolo Barachini, Gregorio Cervadoro, Marco Romanelli and Marco Rossi were incorrectly listed as being affiliated with \u2018Department of Physics, Lancaster University, UK.\u2019 The correct affiliation is listed below:Department of Clinical and Experimental Medicine, University of Pisa, ItalyThese errors have now been corrected.An incorrect Supplementary Information file was inadvertently published with this Article. The correct Supplementary Information now accompanies the Article."}
+{"text": "In the past decade, several studies have shown a significant association between migraine and several features of the metabolic syndrome (MetS), including insulin resistance, systemic hypertension, and obesity. In addition, headache is a highly prevalent symptom in several metabolic disorders. The purpose of this review was to discuss recent findings regarding the relationship between headache, migraine, and metabolic disorders.A computerized search of the PubMed and Cochrane Library databases was performed to identify English-language articles published between January 1, 2000, and June 30, 2015. Search terms included migraine, headache, diabetes, hypertension, obesity, and metabolic syndrome. Out of 241 articles screened, 41 were selected for review.MetS is characterized by a cluster of metabolic abnormalities including insulin resistance, hypertension, dyslipidemia, obesity, and a proinflammatory state. Over the last two decades, different definitions and diagnostic criteria for MetS have been proposed, like the EGIR, the NCEP ATP III and the AACE criteria. Migraine, as defined by the International Headache Society (ICHD-3 beta), is a chronic neurovascular disease characterized by recurrent, disabling headache attacks. MetS and migraine are highly prevalent medical conditions, affecting 15-20% of the population. Both conditions are associated with increased risk for atherosclerotic cardiovascular disease.The two conditions often coexist, but the pathophysiological mechanisms of this comorbidity are still under investigation. Several studies have clearly shown that insulin sensitivity is impaired in migraine, even in young, non-obese, non-diabetic, normotensive patients. Association between polymorphism of the insulin receptor gene and migraine provided inconclusive results. Prevalence and characteristics of headache in patients with diabetes have been scarcely investigated. Elevated blood pressure is a frequent clinical feature of MetS. Few studies investigated blood pressure (systolic or diastolic) abnormalities in migraine. Recently, a large demographic study found a positive association between migraine and systolic hypertension. The relationship between obesity, migraine and headache is still controversial. Weight gain is not associated with migraine prevalence but may be associated with increased headache frequency. Intriguingly, several studies suggested that neuropeptides involved in the regulations of appetite, like adiponectin, leptin, orexin-A and B, may be involved in migraine pathogenesis. In conclusion, additional research is needed to better investigate the common biological mechanisms underlying metabolic syndrome and migraine and to define the best clinical practices in patients who present with both diseases. Increased physical activity, weight loss, and management of cardiovascular risk factors may be of relevance for prevention and treatment of both conditions."}
+{"text": "Unfortunately, the original version of this article  containeAdditionally, the following section has been corrected:However, after adjustment MBL for these confounders levels remained associated with cardiovascular events, indicating a direct and independent effect of MBL on cardiovascular risk.Should read:However, after adjustment for these confounders, MBL levels remained associated with cardiovascular events, indicating a direct and independent effect of MBL on cardiovascular risk."}
+{"text": "According to Yet, nobody knows the extent to which potentially toxic chemicals remaining in rivers and drinking water supplies after advanced treatment may compromise health, development, and reproductive capabilities of humans, birds, fish, aquatic organisms, and other species. Many experts believe even the most rigorous water treatment technologies, including reverse osmosis and advanced membrane technology, allow low levels of contaminants to remain. This is a particular concern in regards to endocrine-disrupting chemicals (EDCs). Approximately 1,000 EDCs have been identified over the last 20 years , while mThe Clean Water Act is charged to protect all beneficial uses of U.S. waters, but currently, neither this nor any other federal law regulates direct potable reuse . Further"}
+{"text": "Today\u2019s ready access to electronic devices and the internet often substitute for social interaction. Such situation, if it starts in early childhood, in certain vulnerable individuals, who crave immediate rewards, can decrease the ability to maintain prolonged attention  and tolein utero drug exposure, low birth weight, premature delivery, endocrine deregulation, early developmental neglect, environmental toxins, head trauma, and genetic vulnerability, we can understand the vulnerability and deregulation of these networks (On the other hand, neuroscientists focus primarily on the relationship between the symptoms and brain structures such as the dorsal lateral prefrontal cortex, ventral lateral prefrontal cortex, insula, anterior cingulate, and default networks and functions linked to neurotransmitter systems -10. Theynetworks .Quantitative EEG has helped define ADHD\u2019s physiological underpinnings by clearly identifying electrical patterns such as increased frontal slowing and excessive frontal theta  that corThen we should ask what happens to the child as they become an adult? To answer this question, we need to understand the adult presentation of attention deficit disorder ,19. GeneNevertheless, our current data support the idea that, in many cases, ADHD persists throughout one\u2019s life: when untreated, ADHD can have significant psychiatric comorbidities that include anxiety, depression, substance abuse, conduct disorder, and bipolar disorder . Therefo"}
+{"text": "The affiliations for the sixth and seventh authors are incorrect. The affiliation for AbdulAziz AlFahed is: Salman Bin Abdulaziz University, Al kharj, Saudi Arabia. The affiliation for Glowi Alasiri is: Al-Imam Muhammad Ibn Saud Islamic University, Riyadh, Saudi Arabia."}
+{"text": "Brain and Behavior is a peer-reviewed, interdisciplinary journal, providing rapid publication of high-quality research across neurology, neuroscience, psychology and psychiatry. The journal will publish quality research reports that enhance understanding of the brain and behavior.Brain and Behavior will give rapid consideration to papers in all areas of clinical and basic research. Molecular, cellular, systems and population-level research in humans and animal models are welcome. The journal will consider empirical and theoretical submissions in areas including but not limited to mechanisms and treatment of all neurological diseases and psychiatric disorders, behavioral and cognitive science, neuronal and glial cell biology, neurosurgery, neurophysiology, neuropharmacology, neuroimmunology, neuropathology, computational neuroscience, functional and structural neuroimaging, neurogenetics and psychiatric genetics, child and adolescent psychiatry, psychiatry of affective and cognitive disorders, epidemiology, emerging technologies and new research methods, translational research, neuropsychology, clinical psychology, and developmental, cognitive, and social psychology.Brain and Behavior features original research articles, reviews, methods papers, editorials, and commentaries. Original research papers must report well-conducted research with conclusions supported by the data presented in the paper.Brain and Behavior publishes papers submitted directly to the journal and those referred from a select group of prestigious journals published by Wiley-Blackwell. Brain and Behavior is a Wiley Open Access journal, one of a new series of peer-reviewed titles publishing quality research with speed and efficiency. For further information visit the Wiley Open Access website at http://www.wileyopenaccess.com.Brain and Behavior are fully open access: immediately freely available to read, download and share. All articles accepted from 14 August 2012 are published under the terms of the Creative Commons Attribution License. All articles accepted before this date were published under a Creative Commons Attribution Non-Commercial License. The Creative Commons Attribution License permits use, distribution and reproduction in any medium, provided the original work is properly cited and allows the commercial use of published articles.All articles published by Brain and Behavior is retained by the author(s). Authors grant Wiley a license to publish the article and identify itself as the original publisher. Authors also grant any third party the right to use the article freely as long as its integrity is maintained and its original authors, citation details and publisher are identified. Further information about open access license and copyright can be found at http://www.wileyopenaccess.com/details/content/12f25db4c87/Copyright--License.html.Copyright on any research article in a journal published by corporatesales@wiley.com.Print reprints of Wiley Open Access articles can be purchased from The Publisher and Editors cannot be held responsible for errors or any consequences arising from the use of information contained in this journal; the views and opinions expressed do not necessarily reflect those of the Publisher and Editors, neither does the publication of advertisements constitute any endorsements by the Publisher and Editors of the products advertised.Wiley Open Access articles posted to repositories or websites are without warranty from Wiley of any kind, either express or implied, including, but not limited to, warranties of merchantability, fitness for a particular purpose, or non-infringement. To the fullest extent permitted by law Wiley disclaims all liability for any loss or damage arising out of, or in connection with, the use of or inability to use the content.Andrei V. Alexandrov, MDMaryann E. Martone, PhDbrain@wiley.comAddress correspondence to the Editorial Office: Dona Lee WongHarvard Medical School, McLean Hospital, USAHubert AmreinTexas A&M, USAIsabelle AubertUniversity of Toronto, CanadaDavid BelinUniversity of Poitiers, FranceSandra BlackUniversity of Toronto, CanadaSandra BosackiBrock University, CanadaRobert BryanBaylor College of Medicine, USAHans CrombagUniversity of Sussex, United KingdomMirella DaprettoUniversity of California, Los Angeles, USADavid DiamondUniversity of South Florida, USAScott GraftonUniversity of California, Santa Barbara, USAIlona Grunwald-KadowMax Planck Institute of Neurobiology, GermanyMartin HaggerCurtin University, AustraliaJozsef HallerHungarian Academy of Sciences, HungaryAhmad HaririDuke University, USAShu-Leong HoUniversity of Hong Kong, Hong KongAndrea Huber Br\u00f6samleHelmholtz Center Munich, GermanyKazuhiro IkenakaNational Institute for Physiological Sciences, JapanStephen JacksonUniversity of Nottingham, UK and Korea University, South KoreaTakeshi KanekoKyoto University, JapanKenneth KosikUniversity of California, Santa Barbara, USAKlas KullanderUppsala University, SwedenJonathan LeeUniversity of Birmingham, United KingdomEdward LevinDuke University, USABai LuTsinghua University and GlaxoSmithKline, ChinaRandolph MarshallColumbia University Medical Center, USACheryl McCormickBrock University, CanadaDouglas MenninHunter College, USAMartin M. MortazaviUniversity of Alabama, Birmingham, USADeclan MurphyKings College London, United KingdomHeinz ReichmannUniversity of Dresden, GermanyRichard RendeBrown University, USAGiacomo RizzolattiUniversity of Parma, ItalyFred SabbUniversity of California, Los Angeles, USAVeronika SkvortsovaRussian State Medical University, Russian FederationKai-Christian SonntagHarvard Medical School, McLean Hospital, USATakashi SuzukiTokyo Institute of Technology, JapanWai Kwong TangChinese University of Hong Kong, Hong KongTanya N. TuranMedical University of South Carolina, USAHartmut WekerleMax Planck Institute of Neurobiology, GermanyJianhong ZhuFudan University, ChinaConsulting EditorsAlexander BystritskyUniversity of California, Los Angeles, USAWesley ThompsonUniversity of California, San Diego, USA"}
+{"text": "People can become addicted to behaviors as well as substances Marks, . BehavioHigh-risk high-skill adventure recreation has been analyzed previously from the perspectives of commercial tourism products Buckley, ; particiThe criteria used for this test are derived principally from those used by Marks , Brown  and LichBrown  proposedThe adventure activities used for this test are: surfing, sailboarding, kiteboarding, hang-gliding, helicopter snowboarding, and whitewater rafting and kayaking Buckley, , 2012. AThe six criteria are considered below in order, from more general social-behavioral to more specific physiological-biochemical. The first group of criteria includes salience, self-image, selective association and discretionary expenditure. Data from numerous individuals and multiple adventure activities, as outlined above, show that adventure enthusiasts identify themselves through their preferred activities, pick their friends and partners from the same activity, and judge themselves on adventure peer esteem. They spend their money and allocate their discretionary time largely on adventure equipment and trips, including commercial tourism products, to practice their preferred activities. They organize their lives to minimize other costs, to save money for these activities. Their lives revolve around these activities, and they spend considerable time planning, selecting and designing them.The second group of criteria is preoccupation with the activity prior to participation, and prioritization of the preferred activity over other obligations. Both of these are also very widespread amongst proponents of adventure activities. Many ski slopes and surf beaches, for example, are watchable continuously through live webcams; and wave heights, wind speeds and river flows are updated continually from automatic recorders. Surfers, skiers, snowboarders, sailboarders, kiteboarders and kayakers watch these feeds and cameras routinely, continually, and indeed compulsively, during work or social activities, and cancel or abandon everything else when conditions look favorable.In coastal surf towns, surfers don't show up for work when the surf is good, even if they put their jobs at risk. In ski towns and resorts, new-fallen snow overrides all social obligations. At some iconic sailboarding and kiteboarding sites, in order to retain skilled staff, businesses offer employment contracts containing wind clauses, which allow sailboarders and kiteboarders to leave work when wind speed exceeds a fixed threshold. At sites where hangglider pilots must predict wind conditions in advance in order to arrive in time for a relatively short favorable window, they will routinely abandon social or professional events at a moment's notice when such conditions are predicted. Individual adventure practitioners commonly depart mid-work or mid-meal when conditions become suitable, and have been known to abandon social obligations even including a wedding still in progress.The third criterion is mood modification and emotional reward. Both of these occur powerfully amongst skilled adventure practitioners. In adventure tourism destinations, many inhabitants show major mood swings depending on recent conditions. If they have been able to surf, ski, ride or paddle, they are happy. During adventure activities, air-punch \u201cclaim\u201d gestures and uninhibited yells of triumph and excitement are commonplace, even from otherwise undemonstrative individuals. Practitioners who have just engaged successfully in high-thrill adventure activities become emotionally immunized, for periods of hours or even days, against negative emotions which would otherwise arise from otherwise depressing news. Examples including loss of employment and termination of relationships. All these effects indicate powerful biochemical as well as behavioral and psychological responses, demonstrating addiction at a fundamental level.The fourth criterion is tolerance, or diminishing rewards, from continuing exposure to an addictive behavior. This is indeed commonplace amongst adventure practitioners.Individuals learning adventure activities initially experience thrill from relatively low-key achievements. As their skills and experience increase, however, they need more and more difficult challenges to achieve the same emotional response. This may include, for example, larger and steeper waves, rapids or snow slopes; stronger winds; more difficult terrain, and so on Buckley, , 2014a. The fifth criterion for recognizing addictive behavior is withdrawal symptoms, when the activity is not available. Such symptoms are widespread and powerful. When adventure practitioners have been unable to enjoy their preferred activities, e.g., through work or weather conditions, they become depressed and bad-tempered. When high winds or heavy snowfalls keep heli-skiers grounded, for example, they suffer great gloom. When conditions improve, gloom is replaced by euphoria and higher tolerance to risk, e.g., from avalanches associated with new heavy snowfalls. At crowded surf breaks, some surfers succumb to \u201csurf rage\u201d through frustration and fury if others steal their waves. When adventure practitioners are unexpectedly prevented from practicing their preferred activities because of broken, mislaid or forgotten equipment, they suffer powerful distress, with physiological symptoms such as pain, perspiration and palpitations. All of these are strong indicators of addiction.At intermediate and expert level, therefore, skilled participants in high-risk adventure recreation activities do indeed show symptoms of strong behavioral addiction. Adventure aficionados become addicted to thrills, at least as strongly as participants can become addicted to sports or exercise (Berczik et al., From a marketing perspective, adventure enterprises catering for experienced clients are thus essentially selling fixes to addicts, a strategy which depends only on the cash reserves of the addicts. Experienced clients, however, form only a small component of the adventure tourism sector overall Buckley, . For lesFrom a psychological research perspective, many adventure aficionados do indeed behave as addicts. Addiction to the thrills obtained through adventure recreation can therefore provide a large pool of potential subjects for psychological, neurophysiological and biochemical research on behavioral addictions, with straightforward ethical considerations in research design. This offers addiction researchers new opportunities for controlled experimental designs involving direct measurements on well-informed and willing volunteers.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Streptococcus pneumoniae (pneumococcus) and Haemophilus influenzae type b (Hib) infections  released the Global Action Plan for Pneumonia and Diarrhoea, which promotes pneumococcal conjugate vaccine use as an important strategy for achieving United Nations Millennium Development Goal 4 to reduce child mortality (In spite of this progress, many gaps remain. Respiratory viruses, such as respiratory syncytial virus, influenza, and measles, also are major causes of pneumonia globally. Expanded use of influenza and measles vaccines, antiviral medications, and supportive health care can reduce the burden of pneumonia caused by these viruses. Additional research on diagnostics, prevention, and treatment of viral-associated pneumonia also is needed.http://worldpneumoniaday.org.World Pneumonia Day is being observed November 12, 2013, to raise awareness about pneumonia\u2019s toll and to promote interventions to protect against, treat, and prevent the disease globally. Activities are being promoted by a coalition of more than 140 community-based organizations, academic institutions, government agencies, and foundations. More information is available at"}
+{"text": "Pseudoskusea, Rusticoidus and Protomacleaya were well-recognized, morphologically distinct subgenera within the genus Aedes prior to a series of taxonomic changes over the past 15 years by Reinert, Harbach and Kitching, when they were recognized as subgenera of the genus Ochlerotatus. In our recent effort to stabilize the Tribe Aedini, we synonymized these subgenera and associated species back into the genus Aedes, but incorrectly assigned them as putative informal groups, instead of reinstating them to subgenera.Pseudoskusea, Rusticoidus and Protomacleaya) within the genus Aedes.Here we formally elevate three traditionally recognized subgenera ( Aedes, in the traditional sense, is the largest genus in the tribe with 932 species. Other aedine genera are Armigeres, Eretmapodites, Haemagogus, Heizmannia, Opifex, Psorophora, Udaya and Verrallina. During the past 11 years, based on a series of morphological phylogenetic studies by Reinert, Harbach & Kitching (RH&K) [Aedes was split into 74 genera, reducing the genus Aedes from over 900 species [Aedes , an invasive species and proven vector of West Nile virus and Cache Valley virus, was known variously as Aedes (Finlaya) japonicus [Ochlerotatus (Finlaya) japonicus [Ochlerotatus\u2019 (\u2018Finlaya\u2019) japonicus [Hulecoeteomyia japonica [The tribe Aedini is comprised of about a third of all recognized mosquito species, and includes many vectors of debilitating viral diseases to humans, such as Dengue and Chikungunya. Within the tribe, the genus g (RH&K) , and the species \u20138, to on species  and resue one in ). For exaponicus , Ochlero. [Aedes into so many genera, were not warranted. Aedes was therefore reinstated [Aedes. Any subgenera in the fragmented RH&K system were reduced to putative informal group status [Aedes to include all \u201ctraditionally\u201d accepted species was based on opinions promoting a conservative approach to classification change based on new phylogenetic analyses [Aedes [Aedes, while retaining other traditional aedine genera were: TNC 2, Clade Stability; TNC 3, Phenotypic Diagnosibility; TNC 8, Manageability; TNC 10, Nomenclatural Stability, and; TNC 11, Community Consensus. Since, to these authors [Close scrutiny of the RH&K phylogenetic results and a reanalysis of their dataset led Wilkerson et al.  to the cinstated , but to p status . Rationaanalyses \u201315. Thesanalyses  who, in s [Aedes . Central authors , there wAedes [Aedes subgenera , recognized as subgenera by RH&K in their genus Ochlerotatus, were incorrectly synonymized as putative informal groups [bona fide subgenera of the genus Aedes. All are diagnosable, well-known traditional groupings and should be retained as such. Taxonomic information for each subgenus, including important references and component species are given in Following our recent publication reinstating the genus Aedes , we revil groups , when thPseudoskusea, Rusticoidus and Protomacleaya from synonymy within the Aedes subgenus Ochlerotatus [Aedes.Here, we formally retrieve erotatus , and ele"}
+{"text": "Nager syndrome is a rare syndrome resulting from developmental abnormalities of the first and second branchial arches. Nager syndrome is rare and mostly sporadic. The main clinical features consist of craniofacial, limb, and musculoskeletal morphogenesis. These findings included malar hypoplasia, maxillomandibular hypoplasia, micrognathia, downslanting palpebral fissures, cleft palate, ear anomalies, hypoplastic thumb, short forearm, proximal radioulnar synostosis, atrial septal defect, lower limb deformities, and flat nasal bridge. The prevalence is unknown; about 100 cases of Nager syndrome have been published up to now. Patients with Nager syndrome are found worldwide among all racial and ethnic groups. Trismus and glossoptosis resulting in oropharyngeal airway narrowing cause life-threatening respiratory distress for patients with Nager syndrome. In this case report, dental rehabilitation of a 10-year-old child with Nager syndrome is presented. Nager syndrome is a rare syndrome resulting from developmental abnormalities of the first and second branchial arches and is mostly sporadic; however, autosomal dominant or autosomal recessive inheritance has been reported. Nager syndrome has an alteration of the 9q32 chromosome, 1q12q21 deletion. The prevalence is unknown; about 100 cases of Nager syndrome have been published up to now. Patients with Nager syndrome are found worldwide among all racial and ethnic groups [The main clinical features consist of craniofacial, limb, and musculoskeletal morphogenesis. Oropharyngeal airway narrowing causes life-threatening respiratory distress for patients with Nager syndrome. The craniofacial abnormalities include zygomatic and maxillomandibular hypoplasia, micrognathia, downwards palpebral fissures, absence of the lower lid eyelashes, lower lid coloboma, flat nasal bridge, cleft lip and palate, short soft palate, low-set and posterior-rotated ear, ear canal atresia, lack of development of the internal and external ear, hearing problems, speech problems, and feeding problems. Respiration and feeding problems are due to the mandibular hypoplasia with micrognathia, tongue and severely restricted jaw opening. The hearing loss is due to the severity of the ear abnormalities. There may be speech problems due to the impaired hearing. The musculoskeletal abnormalities include preaxial upper-limb deformities, radial defect, radioulnar synostosis, short forearm, and absence of digits. Cardiovascular anomalies include Fallot tetralogy and/or ventricular septum defect. Nager syndrome does not affect a child's intelligence \u20134. In thThe purpose of this case report is to present oral findings and dental treatment of a patient with Nager syndrome.A 10-year-old boy was referred to Yeditepe University, Faculty of Dentistry, Department of Pedodontics, in Istanbul with complaint of dental caries. The patient was born to a healthy mother and healthy father at 40 weeks of gestation. The pregnancy of mother was uncomplicated. The mother's history regarding alcohol, smoking, and drug abuse was negative. Family history was not noted regarding craniofacial disorder. He has two normal sisters. A diagnosis of Nager syndrome was made around the age of 2 years when facial and limb anomalies became obvious.Craniofacial anomalies present in the patient include hemifacial atrophy, maxillomandibular hypoplasia, severe micrognathia, restricted jaw opening, malar hypoplasia, flat nasal bridge, cleft palate, shortened soft palate, uvula atresia, left ear canal atresia, and lack of development of the internal and external ear Figures  and 2. OIntraoral and radiographic examination revealed that oral hygiene is a major problem. He had numerous carious teeth  and hypomineralisation teeth #16, #26, #36, and #46, restricted mouth opening, severe maxillomandibular hypoplasia with severe micrognathia, and space deficiency in maxillary and mandibular arch . Teeth #16, #55, #26, #65, #63, #36, #75, #74, #46, #85, and #84 were extracted. Teeth #15, #14, #25, #24, #34, #45, and #44 were restored with fissure sealant followed by topical fluoride application . Oral hyMost of the patients with Nager syndrome are mostly sporadic. These abnormalities can be diagnosed prenatally with the help of ultrasonography. Perinatal mortality is about 20% because of oropharyngeal airway narrowing , 5. The The differential diagnosis of Nager syndrome is done with Treacher-Collins, trisomy 18, Pierre-Robin, and Goldenhar syndrome. The craniofacial features of Nager syndrome resemble Treacher-Collins syndrome, including micrognathia, malar hypoplasia, downslanting palpebral fissures, and ear anomalies but mandibular hypoplasia is more severe in Treacher-Collins syndrome. Nager syndrome can be distinguished from Treacher-Collins syndrome by preaxial upper-limb deformities, such as thumb anomaly, radial defect, and radioulnar synostosis. The facial features and upper-limb anomalies are diagnostic for Nager syndrome. Trisomy 18 is usually associated with clinodactyly, not with absence of digits . In thisMandibular malformations, missing joint structures, restriction in jaw movements, and limb abnormalities cause oral hygiene deficiency. In this case report, the patient had limited mouth opening and multiple carious teeth. Restricted mouth opening also made dental treatment extremely difficult and requires treatment under general anaesthetic. Treatment under general anaesthesia can be challenging in Nager syndrome because of oropharyngeal airway narrowing. Severe airway obstruction is derived from mandibular hypoplasia with micrognathia, retroplaced tongue, and strabismus. Moreover, hearing and speech difficulty lead to communication problems with patients . The patNager syndrome is a rare disorder which inhibits treatment under general anaesthesia because of oropharyngeal airway narrowing. It is important that these patients receive comprehensive prevention and regular dental review in an effort to improve their oral health and therefore avoid, when possible, the need for dental treatment under general anaesthesia. Patients with Nager syndrome should be referred to pedodontics for oral hygiene instruction, dietary advice, and fluoride prevention."}
+{"text": "After the introduction of highly active antiretroviral therapy for the treatment of HIV infection, metabolic abnormalities were increasingly observed, associated with both protease inhibitors and nucleoside reverse transcriptase inhibitors, characterized by abnormal fat distribution in the body , hyperglycemia and lean tissue mass wasting. However such metabolic changes are not always treatment related, having a multifactorial etiology. Dual-energy X-ray absorptiometry (DXA) evaluates the quantity of body fat and lean tissue and their distribution, allowing the diagnosis of both quantitative and qualitative changes.We evaluated 58 patients , aged between 19 and 65 years, by whole body DXA scan. Biological tests on the patients included: leptin, adiponectin, resistin, TNFa, IL6, LT CD4+, viral load. Body mass index, waist/hip ratio and waist/height ratio were also calculated.We obtained significant correlations between the DXA data and the biological, clinical parameters, type and duration of the treatment.DXA represent an essential tool in evaluation of HIV lipodystrophy and wasting syndrome and can be used for both treatment monitoring and disease metabolic evaluation of HIV patients."}
+{"text": "The handling editor, Pierre J. Magistretti, declares that, despite being affiliated to the same institution as author, Blanca Lizarbe, the review was handled objectively and no conflict of interest exists."}
+{"text": "Peroxidases are enzymes catalyzing redox reactions that cleave peroxides. Their active redox centers have heme, cysteine thiols, selenium, manganese, and other chemical moieties. Peroxidases and their mimetic systems have several technological and biomedical applications such as environment protection, energy production, bioremediation, sensors and immunoassays design, and drug delivery devices. The combination of peroxidases or systems with peroxidase-like activity with nanostructures such as nanoparticles, nanotubes, thin films, liposomes, micelles, nanoflowers, nanorods and others is often an efficient strategy to improve catalytic activity, targeting, and reusability. HRP certainly is the analyst's friend  often used to explore aspects of the chemistry of iron porphyrins, and as mimics for some reactions catalyzed by peroxidases  that enhance HRP activity by 5\u20137 times when compared to free HRP; this is due to high local HRP concentration, appropriate HRP conformation, less mass transfer limitations, and Fe2+ activation (Ocsoy et al., For biomedical and technological applications, peroxidases in nanostructures represent a rapidly growing area for innovative research improving enzyme activity, protection, targeting, and reusability. Free peroxidases have some inherent disadvantages including loss of catalytic activity in solution during the reaction, high cost and lack of reusability. To overcome these issues, several supports including various nanomaterials for instance metal and magnetic nanomaterials, polymer based nanofibers, silicon and carbon based nanomaterials, have been used for peroxidases immobilization (Lei et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "A 68-year-old woman presented with a pruritic, blistering rash. Three months prior, she had developed itchy lesions on her hands and feet, spreading to her chest and abdomen. For the past week, she had developed painful, tense blisters. The patient had seen her primary care doctor at symptom onset and failed to improve with topical clobetasol proprionate and hydroxyzine. She took amlodipine for blood pressure and denied any new medications or exposures. Physical examination was notable for bullae with mucosal-sparing, urticaria, negative Nikolsky\u2019s sign, and the absence of scarring over ruptured bullae \u20133. Her cBullous pemphigoid, first identified in 1953, is the most common autoimmune blistering disorder.4In the early, non-bullous phase, patients develop eczematous or urticarial lesions associated with severe pruritus, lasting weeks or months.3First-line treatment consists of topical and systemic corticosteroids and azathioprine. Other treatments include mycophenolate mofetil, leflunomide, cyclophosphamide, methotrexate, dapsone, intravenous immunoglobulin, and plasmapharesis.6Our patient was fluid resuscitated and admitted for intravenous steroids. A skin biopsy confirmed the diagnosis. She was eventually discharged home on oral prednisone and mycophenolate mofetil."}
+{"text": "Mucopolysaccharidosis type VI or Maroteaux Lamy syndrome is an autosomal recessive lysosomal storage disorder resulting from a deficiency of arylsulfatase B, the clinical features include short stature, hepatosplenomegaly, dysostosis multiplex, stiff joints, corneal clouding, cardiac abnormalities, and facial dysmorphism, with intelligence usually normal. We present evidence of the possible existence of Maroteaux Lamy syndrome in pre-Columbian pottery 2000 years ago, in the Colombo-Ecuadorian Pacific coast of the Tumaco-Tolita culture.  Maroteaux Clinical features and severity are variable, but usually include short stature, hepatosplenomegaly, dysostosis multiplex, stiff joints, corneal clouding, cardiac abnormalities, and facial dysmorphism, with intelligence usually normal We present a collection of pottery from the Tumaco-Tolita culture close to 2,000 years old with a possible representation of Maroteaux Lamy syndrome, which were evaluated by an archaeologist and a medical geneticist succeeded in identifying about 20 ceramic artifacts with representations of individuals with mucopolysaccharidosis type VI in about 10 museums and private collections in Ecuador and Colombia. The ceramic artifacts present phenotypical features like skeletal dysplasia, macrocephaly, mildly coarse facial features, broad mouth, prominent sternum, kyphosis, scoliosis  probably-The Tumaco-Tolita culture inhabited the region of the Pacific Colombo-Ecuadorian coast during the years 300 BCE to 600 CE. This culture was characterized for realistically representing the different pathologies affecting their population. In their pottery work, they show evidence of genetic illnesses like Down syndrome, achondroplasia, sirenomelia, and other congenital malformations It is noteworthy that the figures represented are of young people or infants, clearly suggesting that the complications experienced by people with mucopolysaccharidosis type VI as cervical cord compression may have regulated the mortality of people with this disease, because at that time there was no orthopedic spine surgery. These types of pre-Hispanic indigenous communities, and especially the Tumaco-Tolita, lived in isolation, probably engaging in consanguineous marriages, as done by current indigenous Colombian communities, increasing the occurrence of recessive diseases and the possible existence of a founder effect.Currently, the presence of this syndrome has been documented in indigenous communities in Cauca"}
+{"text": "In S1 FileThis file contains:Image file for gel showing BM, Muscle, and Small Intestine samples, employed to generate the revised figure.Image file for gel showing Macrophage samples, employed to generate the revised figure.Image file containing gel showing Testis samples, employed to generate the revised figure.Image file for gel showing Brain, Spleen, and Thymus samples, employed to generate the revised figure.Image file for gel showing Colon, PBL, Stomach, Ovary, and WAT samples, employed to generate the revised figure.(ZIP)Click here for additional data file."}
+{"text": "Brain injury can lead to impaired cortical inhibition of the hypothalamus, resulting in increased sympathetic nervous system activation. Symptoms of paroxysmal sympathetic hyperactivity may include hyperthermia, tachycardia, tachypnea, vasodilation, and hyperhidrosis. We report the case of a 41-year-old man who suffered from a left middle cerebral artery stroke and subsequently developed central fever, contralateral temperature change, and hyperhidrosis. His symptoms abated with low-dose propranolol and then returned upon discontinuation. Restarting propranolol again stopped his symptoms. This represents the first report of propranolol being used for unilateral dysautonomia after stroke. Propranolol is a lipophilic nonselective beta-blocker which easily crosses the blood-brain barrier and may be used to treat paroxysmal sympathetic hyperactivity. Stroke, among other causes of brain injury, may impair central autonomic regulatory centers leading to development of tachycardia, hyperhidrosis, hypertension, and hyperthermia. Although the parasympathetic system may also be involved, sympathetic overactivity is more common . These sAlthough the pathophysiology of PSH is poorly understood, the dominant theories currently revolve around failures of the central autonomic network (CAN), including the insular cortex, amygdala, hypothalamus, medulla, periaqueductal gray matter, parabrachial complex, and nucleus of the tractus solitarius. With stroke, PSH has been attributed to damage to the insular cortex, amygdala, and hypothalamus, which mediate high-order autonomic controls . The losA 41-year-old man was admitted for acute rehabilitation after a right middle cerebral artery ischemic stroke which was not treated with a thrombolytic agent. His past medical history included poorly controlled hypertension, type 2 diabetes mellitus (DM), and prior transient ischemic attacks. He had no known allergies to medications and denied having had surgeries.Eight days after the stroke, he complained of a cold sensation and excessive perspiration on the right side of his face and body. He also began having daily fevers (max 101.5\u00b0F) associated with tachycardia (max 119 beats per minute). He had no significant tachypnea (range 18\u201320 breaths per minute) or hypertension , although he was taking fosinopril. Extensive workup revealed no infectious source, and his fever did not abate with repeated doses of acetaminophen.He was fully conscious, alert, and oriented at each examination and fully participating in physical therapy. On inspection, excessive sweating was noted along the right side of his body and lower right side of his face. On palpation, his right arm was cool to the touch. Neurologic examination revealed normal mental status and cranial nerves II\u2013XII were intact. Strength testing revealed right upper extremity strength of 4/5 for shoulder abduction, elbow flexion, elbow extension, and handgrip. The right lower extremity exhibited 3/5 strength for hip flexion, 4/5 for knee flexion, and 2/5 for ankle dorsiflexion. Tone was diffusely increased on the right, rated 1/4 on the modified Ashworth scale. Reflexes were 2+ and symmetrical in the biceps brachioradialis, triceps, and gastrocnemius-soleus complex; however, the right great toe was upgoing. Sensation was impaired to temperature and light touch along the right side of his body and face.Magnetic resonance imaging (MRI) revealed a large area of infarction in the left periventricular white matter, left internal capsule posterior limb, and dorsal aspect of left lateral basal ganglia extending into white matter adjacent to the left occipital horn.With a presumptive diagnosis of PSH, propranolol 10\u2009mg twice daily was started. After demonstrating tolerance and persistent breakthrough symptoms, dosing was increased to three times daily. The patient's symptoms of unilateral cold sensations, hyperhidrosis, tachycardia, and fever resolved within one day. As a trial, propranolol was discontinued, and, although no fever or tachycardia was documented, symptoms of unilateral hyperhidrosis, cold sensations, and subjective fever returned. Propranolol was then restarted, and the patient continued to have symptomatic relief at follow-up.Using the PSH Assessment Measure , our patNormally, the efferent sympathetic sudomotor and vasomotor pathways which originate in the hypothalamus and descend into the brainstem uncrossed receive inhibitory input from the contralateral insular cortex , 7. InfaSeveral central autonomic regulatory centers have been implicated in various disconnection theories. Korpelainen et al. noted that frontoparietal cortex, hypothalamus, and brainstem injuries in stroke patients resulted in tachycardia, flushed skin, hyperhidrosis, and cutaneous sensory changes . AnotherMore recently, Meyer et al. proposed that autonomic control could be lateralized to the right insular cortex, as injury there led to more severe and frequent autonomic symptoms such as hyperhidrosis . SweatinAlthough our patient experienced relatively common PSH symptoms, he also experienced an unusual daily fever. Paroxysmal persistent hyperthermia, although rare in occurrence, can be due to various intracranial etiologies but is usually associated with injury of the hypothalamus in poststroke patients . AlthougIn our patient, propranolol 10\u2009mg three times daily was effective in alleviating not only his fever but also his unilateral hyperhidrosis, tachycardia, and cold sensations. Propranolol is a nonselective beta-blocker which is lipophilic and easily crosses the blood-brain barrier. It has been FDA-approved for treatment of hypertension, angina pectoris due to coronary artery atherosclerosis, migraine, hypertrophic subaortic stenosis, tachyarrhythmias, and certain tremors. It has also been noted for its use in PSH . Other mHemispheric stroke may impair autonomic regulation resulting in paroxysmal sympathetic hyperactivity, which may present with central fever, tachycardia, tachypnea, hypertension, hyperhidrosis, dystonic posturing, and sympathetic overreactivity to nonpainful stimuli. Our case demonstrated the successful use of propranolol in controlling symptoms of fever, tachycardia, unilateral hyperhidrosis, and coldness. The precise effect that propranolol has on the impaired central autonomic network and autonomic nervous system has yet to be elucidated, and this warrants further investigation."}
+{"text": "Early detection of metastatic disease within the liver by advanced diagnostic imaging has driven the rise of image-guided intervention for hepatic metastases. In this talk, we will explore the rationale, indications, technique and post procedure imaging findings of percutaneous treatments of liver metastases. Curative intent ablative therapies, such as radiofrequency ablation, microwave ablation, cryoablation, and irreversible electroporation will be discussed, including the common pitfalls of reading post ablative imaging studies. In addition, bridging and palliative therapies embolotherapies for liver dominant metastatic disease, such as hepatic artery embolization, transarterial chemoembolization, drug eluting beads, and yttrium-90 selective internal radiation therapy, will be reviewed."}
+{"text": "In adult respiratory distress syndrome (ARDS), life-threatening hypoxemia may occur, dictating the need for differentiated ventilator strategies. Pronounced consolidation and/or atelectasis have been well documented in ARDS, but the contribution of regional perfusion to oxygenation has been poorly addressed. Evidence has accumulated that, in ARDS, regional perfusion is extremely variable and may affect oxygenation, independently from the amount of atelectatic-consolidated lung regions. Thus, the response in oxygenation to different ventilatory settings, both during controlled and assisted mechanical ventilation, should be interpreted with caution. In fact, gas exchange may be not determined solely by changes in aeration, but also redistribution of perfusion. Furthermore, regional perfusion can play an important role in worsening of lung injury due to increased transmural pressures. In addition, distribution of perfusion in lungs might affect the delivery of drugs through the pulmonary circulation, including antibiotics. In recent years, several techniques have been developed to determine pulmonary blood flow with increasing level of spatial resolution, allowing a better understanding of normal physiology and various pathophysiological conditions, but most of them are restricted to experimental or clinical research. Lung ultrasound and novel algorithms for electrical impedance tomography represent new promising techniques that could enable physicians to assess the distribution of pulmonary blood flow at the bedside. In ARDS, we cannot afford missing regional lung perfusion!http://dx.doi.org/10.1186/s12871-015-0013-0.Please see related article:  The acute respiratory distress syndrome (ARDS) is an acute life-threatening condition, triggered by different clinical disorders, and characterized by severe hypoxemia refractory to increased inspired oxygen fraction, and high mortality . HypoxemDifferent imaging techniques such as computed tomography , electriRichter et al.  investigThe role of pulmonary perfusion in ARDS is important for different reasons. First, perfusion potentially interacts with and modulates ventilator induced lung injury. Second, it is a major determinant of pulmonary gas-exchange. Third, it reflects pulmonary vascular resistance, heart-lung interactions, venous return to the heart, and even systemic hemodynamics . Fourth,Different mechanisms can explain shifts in regional perfusion, including obstruction or compression of pulmonary capillaries due to swelling of endothelial cells, and pulmonary hypoxic vasoconstriction. In ARDS patients, redistribution of pulmonary blood flow contributes only slightly to maintenance of oxygenation , suggestDuring pressure support ventilation, improvements in oxygenation were associated with a redistribution of perfusion towards well-aerated, non-dependent lung regions, without evident alveolar recruitment ,11. In cIdeally, assessment of lung perfusion should be performed in real-time. Unfortunately, such methods are not available at bedside yet. For research, different techniques have been proposed, including single photon emission computed tomography, positron emission tomography , and mulThe better understanding of the role of regional perfusion could have important implications for daily clinical practice. First, the response in oxygenation to different ventilatory settings should be interpreted always with caution, since they might be not determined by lung recruitment or derecruitment, but redistribution of perfusion. Second, an excessive pulmonary blood flow, either global or regional, can contribute to ventilator-induced lung injury; thus, optimal fluid balance and adequate monitoring should be mandatory. Third, low tidal volume should be used to prevent or minimize ventilator-induced lung injury, and positive end-expiratory pressure preferably titrated on respiratory mechanics changes than oxygenation. A more detailed and comprehensive approach, including bedside lung imaging, hemodynamics, gas-exchange and mechanics should be preferred, at least in most severe cases. Fourth, due to the unpredictable distribution of blood flow, it is likely that drugs delivered to the lungs, like intravenous antibiotics, will not reach in adequate amount the affected regions, possibly compromising their effectiveness, specially in assisted ventilation. We believe that the evaluation of regional perfusion at the bedside should be implemented more often to follow the course of the disease and clinical treatment.The experimental study by Richter et al.  provides"}
+{"text": "To assess the availability and quality of population size estimations of female sex workers (FSW), men who have sex with men (MSM), people who inject drug (PWID) and transgender women.Size estimation data since 2010 were retrieved from global reporting databases, Global Fund grant application documents, and the peer-reviewed and grey literature. Overall quality and availability were assessed against a defined set of criteria, including estimation methods, geographic coverage, and extrapolation approaches. Estimates were compositely categorized into \u2018nationally adequate\u2019, \u2018nationally inadequate but locally adequate\u2019, \u2018documented but inadequate methods\u2019, \u2018undocumented or untimely\u2019 and \u2018no data.\u2019Of 140 countries assessed, 41 did not report any estimates since 2010. Among 99 countries with at least one estimate, 38 were categorized as having nationally adequate estimates and 30 as having nationally inadequate but locally adequate estimates. Multiplier, capture-recapture, census and enumeration, and programmatic mapping were the most commonly used methods. Most countries relied on only one estimate for a given population while about half of all reports included national estimates. A variety of approaches were applied to extrapolate from sites-level numbers to national estimates in two-thirds of countries.Size estimates for FSW, MSM, PWID and transgender women are increasingly available but quality varies widely. The different approaches present challenges for data use in design, implementation and evaluation of programs for these populations in half of the countries assessed. Guidance should be further developed to recommend: a) applying multiple estimation methods; b) estimating size for a minimum number of sites; and, c) documenting extrapolation approaches. Globally, the HIV epidemic affects key populations, such as female sex workers (FSW), men who had sex with men (MSM), people who inject drugs (PWID) and transgender women, disproportionately \u20135. LegalThe use of services among key populations, which is low across different groups in many countries . Only a To plan, monitor and evaluate programs designed to mitigate the impact of the HIV epidemic on these key populations, reasonable estimates of the population sizes are necessary. Size estimates have greatest programmatic value when used locally but there remains an important need for national figures for planning and resource allocation \u201310.The size of key populations can be estimated using different methods, each having strengths and weaknesses . Multiplwww.aidsinforonline.org.United Nations and donor agencies have held numerous training workshops in many countries to expand and improve population size estimates of each of the four aforementioned key populations, as well as piloted new approaches . MethodsThe following data sources were examined: Country Progress Reports for the United Nations General Assembly Special Session on AIDS (UNGASS) and Global AIDS Response Progress Report (GARPR) to UNAIDS , AIDS DaSize estimates were only considered if they were generated since 2010. Categories were developed to reflect the utility of the estimates to HIV programmes. A full assessment of the underlying data quality was beyond the scope of this analysis. They were categorized, with the availability and quality in descending order from (a) to  according to criteria that considered compositely: estimation methods, geographic coverage, extrapolation approached and key population groups covered. In each domain, a determination was made as to whether empirical data could be used for national planning, local planning, or did not exist. Data with no documented methods could be used for planning but would be considered of lesser value than empirical estimates.Nationally adequate: estimates are empirically derived using one of the following methods: 1) multiplier; 2) capture-recapture; 3) mapping/enumeration; 4) network scale up method (NSUM) or population-based survey; 5) respondent driven sampling\u2013successive sampling (RDS-SS). Estimates had to be national or a combination of multiple sites with a clear approach to extrapolating to a national estimate; and at least two major population groups of national interest are included.Nationally inadequate but locally adequate in selected sites: estimates are empirically derived using 1) multiplier; 2) capture-recapture; 3) mapping; 4) NSUM or population-based survey; 5) RDS-SS. Estimates are only from sites where targeted programs are available but are insufficient for national program use. Estimates are available for at least two major population groups of national interest.Documented estimates but inadequate methods: estimates are derived from 1) expert opinions; 2) Delphi; 3) wisdom of crowds; 4) programmatic results or registry or 5) regional benchmarks. Estimates may or may not be national;Undocumented or untimely: estimates are reported but not documented or were derived prior to 2010.No data: no size estimates are reported.Geographic coverage was assessed using the following criteria, bearing in mind that a) and b) give national or close to national estimates, while c-e provide local estimates:National sample designed to generate a national estimate, or estimates are reported as national.More than 50% of subnational divisions: 50% or more of the first order subnational divisions are covered by estimates with both urban and rural sites included.Less than 50% of subnational divisions: less than 50% of the first order subnational divisions are covered with both urban and rural sites included.Major cities: the exercise was done in selected major cities with no rural areas covered.Capital city: estimate only from the capital.The extrapolation approach is classified by strength of approach toward yielding a national estimate.Proportion of adult males or females: national estimates are calculated based on a proportion or a range of proportions of adult males or females, who are key population community members.Summed up: national estimate is the sum of site-specific estimates with no adjustment.Regression or probability formula: regression models were used to estimate populations in areas without an estimation exercise using information from those areas where estimations are available.Based on one selected number: national estimate is extrapolated based on one estimate among a number of estimated numbers.Delphi or consensus: a formal process considering different factors to arrive at an estimate.No extrapolation.The number of different estimates for a site was based on the actual number of estimates provided in the report, irrespective of methods used. For example, the number of estimates will be 2 if two multipliers were used.http://www.qgis.org/en/site/). UNAIDS regional divisions were used, while country specific shape files were downloaded from Global Administrative Areas (http://www.gadm.org/country).Maps were generated using Q-GIS  were broadly similar to previously published, decade-old estimates , 20\u201322. Globally there is no detailed guidance for extrapolation from estimate(s) made at discrete site(s) to determine national numbers. Currently, the proportion of key populations out of adult males or females is widely used. In the process of deriving such a proportion, some countries adjusted based on understanding of differences between site(s) where exercises were done and remaining sites. Some adopted directly the proportion obtained from the exercises at site(s). Some countries used regression models to extrapolate their estimates. In these countries, additional information, related to the key population, were entered into a model. For example, for FSW estimates, degree of urbanization, number of hotels, development of tourism, adult male to female ratio, extent of migration, and business opportunities were collected and used for refining extrapolations . Some coEach size estimation method has both strengths and limitations, there is no gold standard for size estimation for key populations. It is important to apply multiple methods to generate multiple estimates to triangulate to reach both a point estimate and a range. This assumes the combined trueness of all estimates. Application of multiple methods can generate a wrong estimate whenever the truth is outside the range of the estimates. Among countries with known estimation methods, more than half generated national estimates based on a single estimate and therefore are making national policy decisions based on very limited data and local decisions in the absence of important data. Less than one fifth of national estimates were based on 3 or more estimates, suggesting that few countries have adequate estimates from which to plan nationally. Among countries with national estimates, only 9 countries provided a point and a range of estimates for FSW, 13 for MSM, 7 for PWID, 4 for transgender women (data not shown). It is possible to have multiple estimates in one estimation process, for example, several multipliers in one IBBS. Multiple estimates may balance the biases among them. Multiple estimates should be triangulated with programmatic data to generate possible boundaries of the estimates \u201325.Traditional estimation methods, such as multiplier and capture-recapture, remain the most commonly applied in estimating sizes of all four key populations. For FSW and MSM, one-third of estimates used census, enumeration or programmatic mapping. These methods not only estimate the sizes of the populations, but, if employed to their full power, can improve the understanding the typology and places where risk behaviors happen \u201328. New Most estimates in countries with known methods covered both urban and rural areas. However, few of the reports in these countries provided descriptions of how urban sites compare with rural sites, or urban to rural ratios. Less than a quarter of estimates were built upon the exercises in major cities or capital cities only. While it is fair to assume key populations in cities have more episodes of risky behavior, understanding the size and behavioral patterns of key populations in rural areas is crucial for tailored, efficient response planning and implementation as evidenced by recent rural HIV outbreaks among PWID .Definitions of each of the populations were diverse. Definitions differ by description of sexual behaviors  or sex work  or injection (intravenous or intramuscular or subcutaneous or other routes) or drug  and time frame  These local definitions may accommodate local programming. However, they render comparability across countries and regional or global aggregation more challenging.This assessment is confined to the data and reports available to UNAIDS, WHO and the Global Fund, and in the published literature. However, we believe the assessment captured the majority of available estimates made between 2010 and 2014 for the four key populations in low- and middle-income countries. There might be some missed reports from estimation exercises but the bias resulted from unfound reports is hard to quantify.Population size estimates for FSW, MSM, PWID and transgender women are increasingly available but still limited globally, hampering national programs\u2019 abilities to monitor the HIV prevention, care and treatment needs of key populations and national programs\u2019 ability to evaluate their service coverage. Current guidance would benefit from reemphasizing that multiple size estimation methods should be applied whenever possible to generate multiple estimates with uncertainty bounds in a large number of sites with appropriate urban and rural distribution. Technical guidance on extrapolation approaches should be further developed. Guidance for national programs should emphasize that: a) population size estimates primarily help monitor and evaluate local HIV service programs for the respective populations; b) HIV case-based surveillance data should be analyzed to indicate where communities of the populations exist and might benefit from programs, which will subsequently require size estimates; c) key population communities should be engaged to mitigate any risks related to such exercises; and, d)national size estimates are most useful for national planning needs and international donors; while local size estimates are useful to each locality that has or needs adequate HIV prevention or intervention services.The list of countries: Afghanistan, Albania, Algeria, Angola, Argentina, Armenia, Azerbaijan, Bangladesh, Belarus, Belize, Benin, Bhutan, Bolivia, Bosnia and Herzegovina, Botswana, Brazil, Bulgaria, Burkina Faso, Burundi, Cabo Verde, Cambodia, Cameroon, Central Africa Republic, Chad, Chile, China, Columbia, Comoros, Republic of Congo, Democratic Republic of Congo, Costa Rica, Cote d\u2019Ivoire, Croatia, Cuba, Djibouti, Dominica, Dominica Republic, Ecuador, Egypt, El Salvador, Equatorial Guinea, Eritrea, Estonia, Ethiopia, Fiji, Gabon, Gambia, Georgia, Ghana, Grenada, Guatemala, Guinea, Guinea Bissau, Guyana, Haiti, Honduras, India, Indonesia, Iran, Iraq, Jamaica, Jordan, Kazakhstan, Kenya, Kiribati, Democratic People\u2019s Republic of Korea, Kosovo, Kyrgyzstan, Laos, Lebanon, Lesotho, Liberia, Lithuania, Macedonia, Madagascar, Malawi, Malaysia, Maldives, Mali, Marshall Islands, Mauritania, Mauritius, Mexico, Micronesia, Moldova, Mongolia, Montenegro, Morocco, Mozambique, Myanmar, Namibia, Nepal, Nicaragua, Niger, Nigeria, Pakistan, Palestine (West Bank and Gaza), Panama, Papua New Guinea, Paraguay, Peru, Philippines, Romania, Russia Federation, Rwanda, Samoa, Sao Tome and Principe, Senegal, Serbia, Seychelles, Sierra Leone, Solomon Islands, Somalia, South Africa, South Sudan, Sri Lanka, St. Lucia, St. Vincent & Grenadines, Sudan, Suriname, Swaziland, Syria, Tajikistan, Tanzania, Thailand, Timor Leste, Togo, Tonga, Tunisia, Turkmenistan, Tuvalu, Uganda, Ukraine, Uruguay, Uzbekistan, Vanuatu, Viet Nam, Yemen, Zambia, ZimbabweS1 Table(XLS)Click here for additional data file."}
+{"text": "The first three authors, Zhen-Yu Zhang, Jian Xu, and Yong Ren, should be noted as contributing equally to this work."}
+{"text": "Autonomic, cognitive, and neuropsychologic deficits appear in heart failure (HF) subjects, and these compromised functions depend on cerebral cortex integrity in addition to that of subcortical and brainstem sites. Impaired autoregulation, low cardiac output, sleep-disordered-breathing, hypertension, and diabetic conditions in HF offer considerable potential to affect cortical areas by loss of neurons and glia, which would be expressed as reduced cortical thicknesses. However, except for gross descriptions of cortical volume loss/injury, regional cortical thickness integrity in HF is unknown. Our goal was to assess regional cortical thicknesses across the brain in HF, compared to control subjects.We examined localized cortical thicknesses in 35 HF and 61 control subjects with high-resolution T1-weighted images (3.0-Tesla MRI) using FreeSurfer software, and assessed group differences with analysis-of-covariance . Significantly-reduced cortical thicknesses appeared in HF over controls in multiple areas, including the frontal, parietal, temporal, and occipital lobes, more markedly on the left side, within areas that control autonomic, cognitive, affective, language, and visual functions.Heart failure subjects show reduced regional cortical thicknesses in sites that control autonomic, cognitive, affective, language, and visual functions that are deficient in the condition. The findings suggest chronic tissue alterations, with regional changes reflecting loss of neurons and glia, and presumably are related to earlier-described axonal changes. The pathological mechanisms contributing to reduced cortical thicknesses likely include hypoxia/ischemia, accompanying impaired cerebral perfusion from reduced cardiac output and sleep-disordered-breathing and other comorbidities in HF. Multiple autonomic, cognitive, and neuropsychologic deficits appear in heart failure (HF) subjects \u20133. The iVoxel-based MRI and visual examination procedures used to detect structural changes in HF, although useful for the first demonstrations of neural injury in the condition, have certain drawbacks, especially for cortical tissue evaluation. Visual examination procedures are poor for cortical injury detection over quantitative methods. However, both regional gray matter volumes and tissue integrity, assessed with voxel-based gray matter volumetric, T2-relaxometry, and DTI-based procedures, may be influenced by analytical differences in extra-cortical cerebrospinal fluid and surface curvature/complexities. An alternative approach is to examine regional cortical thicknesses, which can be performed with specialized software designed to assess regional cortical changes, and such assessment is provided by FreeSurfer software . FreeSurHeart failure is accompanied by low cardiac output and sleep-disordered breathing ,3,10; boOur aim was to examine regional cortical thicknesses across the whole brain in HF, compared to control subjects, using high-resolution T1-weighted images. We hypothesized that local cortical thinning would appear in HF over control subjects, especially in cortical areas, including the cingulate, insular, prefrontal, right middle frontal, hippocampus, and temporal sites serving autonomic, mood, and cognitive functions which are impaired in the condition.We studied 35 hemodynamically-optimized HF and 61 control subjects. Demographic, clinical, body mass index (BMI), education, neuropsychologic, cognitive, and sleep data of HF and control subjects are summarized in Both hemodynamically-optimized HF and control subjects were scanned largely before noon. All HF and control subjects were asked to refrain from caffeine, nicotine, and alcohol at least 24-hours prior to the study. Once subjects arrived at the MRI suite, we reviewed the study inclusion and exclusion criteria, explained the project, obtained written informed consent, and collected required information including age, gender, ethnicity, medications, measured height and weight, and introduced neuropsychologic, cognitive, and sleep questionnaires. All subjects were then taken to the MRI scanner room to become familiar with the scanner noise and equipment environment. Electrocardiogram, respiration, and blood oxygenation levels were monitored continuously to assure safety of HF and control subjects using MRI-compatible electrodes, air-filled bag for thoracic excursion, and a pulse oximeter. Subjects were positioned in the MRI scanner, and RK collected the required MRI data. Control and HF sample sizes were determined with the assumption of large effect sizes between groups, based on previous studies which included the majority of the same patient population ,7,11.All HF and control subjects were assessed for sleep quality with the Pittsburgh sleep quality (PSQI), and daytime sleepiness with the Epworth sleepiness scale (ESS),19. The Both depression and anxiety symptoms of HF and control subjects were assessed using the Beck depression inventory (BDI-II) and the Beck anxiety inventory (BAI), respectively \u201322. The Cognitive deficits in HF and control subjects were examined with the Montreal Cognitive Assessment (MoCA) test , which i2; slice-thickness = 0.9, 1.0 mm]. We performed simultaneous proton-density (PD) and T2-weighted imaging , covering the whole-brain in the axial plane using a dual-echo turbo spin-echo pulse sequence.We used a 3.0-Tesla MRI scanner  for the brain studies. All subjects lay supine during MRI scanning, and foam pads were used on both sides of the head to minimize head movement. Two high-resolution T1-weighted image volumes were acquired using a magnetization prepared rapid acquisition gradient-echo (MPRAGE) pulse sequence [repetition time (TR) = 2200 ms; echo-time (TE) = 2.34, 2.60 ms; inversion time = 900 ms; flip angle (FA) = 9\u00b0; matrix size = 256\u00d7256, 320 \u00d7320; field of view (FOV) = 230\u00d7230 mmBoth high-resolution T1-weighted, PD-, and T2-weighted images were examined for any gross brain pathology, such as cysts, tumors, or any other mass lesions. None of the included HF and control subjects in this study showed any major brain pathology.http://surfer.nmr.mgh.harvard.edu/). Data processing included removal of non-brain tissue using a hybrid watershed/surface deformation procedure, automated Talairach transformation, intensity normalization, segmentation of sub-cortical white and deep gray matter tissue types, tessellation of the gray and white matter boundaries, automated topology correction, and surface registration to the FreeSurfer atlas [We used high-resolution T1-weighted images to measure regional cortical thicknesses in HF and control subjects using FreeSurfer (v 5.3.0) . Both hier atlas . All subThe IBM statistical package for the social sciences  was used for data analyses. Demographic, BMI, neuropsychologic, sleep, cognitive, and clinical characteristics were assessed by independent samples t-tests and Chi-square. Relationships between BMI and regional cortical thicknesses were examined with Pearson\u2019s correlation procedures. A p<0.05 value was considered statistically significant.Gray matter surface maps were smoothed using a Gaussian kernel . Regional changes in cortical thicknesses between HF and control subjects were examined using a vertex-wise general linear model, implemented in FreeSurfer, with regional cortical thicknesses modeled as a function of groups, and age and gender included as covariates in the analysis . The statistical parametric maps with regional cortical thickness differences between HF and control groups were generated separately for left and right hemispheres. We overlaid clusters with significant differences between groups onto averaged inflated cortical surface maps for structural identification.Demographic, BMI, neuropsychologic, sleep, cognitive, and clinical data of HF and control subjects are summarized in HF patients showed significant cortical thinning in multiple areas, after controlling for age and gender Tables  and 2. TAlthough BMI significantly differed between groups, only limited brain sites showed significant relationships between BMI and regional cortical thicknesses in HF subjects. These sites with significant relationships with BMI included the pars triangularis  and middle temporal gyrus  on the left side, and precentral gyrus , superior frontal gyrus , and pars opercularis  on the right hemisphere.Multiple areas of the cerebral cortex in HF that play crucial roles in autonomic, cognitive, affective, language, and visual functions, showed reduced cortical thickness compared to control subjects. The laterality and location of the thinned regions reflect the spatial organization of cortical areas that mediate those deficient functions in HF. Thus, the right medial orbitofrontal cortex, which plays an important role in blood pressure regulation shows significant injury, while the analogous region on the left showed little damage. The affected cortical regions included temporal, frontal, occipital, and parietal areas, as well as cingulate and insular cortices that normally contribute substantially to deficient functions in the condition . AlthougCortical thinning should not be unexpected, given the already demonstrated axonal injury in HF subjects, which showed significant loss of fibers and injury to supporting glia. Many of those axons represent projections derived from cortical neurons, and if injured, will be reflected as injury to those cortical neurons and supporting cells.HF subjects show increased sympathetic tone and altered heart rate and blood pressure responses to blood pressure challenges, characteristics which are dependent upon appropriate functioning of right insular, cingulate, and right orbitofrontal cortices ,3; theseHF subjects show various cognitive and affective issues and symptoms of dyspnea . Along wHF patients show high levels of depressive symptoms and an increased incidence of mood disorders ; both moSigns of dyspnea are also a common characteristic of HF . DyspneaAbnormal visual, language, and speech functions are common in HF subjects. Multiple brain areas, including the superior temporal cortex, and tissue underlying the superior temporal sulcus, inferior parietal, lateral occipital, lingual, precuneus, superior parietal, and supra marginal cortical areas, which help regulate these deficient functions \u201336, showAlthough cortical thickening appeared on both hemispheres, more wide-spread injury emerged in the precentral, mid temporal, and lateral occipital regions on the left side of the brain, and in the ventral-mid temporal and entrorhinal cortices on the right side. The left ventral precentral cortex is particularly involved in speech expression, with damage resulting in major motor difficulty in speech, an aspect which involves the tongue and other upper airway muscles. Mid temporal and entorhinal cortices are involved in memory and spatial cognition, and occipital areas in visual function. Although consequences of the lateralized injury are unclear, damage in these cortical sites may contribute to language , breathiNeuronal and glial changes or losses lead to cortical thinning, and such changes contribute to Alzheimer\u2019s disease. Vascular dementia is accompanied by cortical thickness reduction as well, and regional cortical thinning found here in HF subjects poses a potential to contribute to symptoms of Alzheimer\u2019s disease in the condition.Various pathological processes may contribute to the regional changes in cortical thicknesses found here. These pathological processes include cerebral perfusion issues, resulting from low cardiac output , and hypMicronutrient deficiencies, including low levels of thiamine and magnesium, are very common in HF subjects ,40. The The findings reemphasize that HF is accompanied by seriously compromised brain tissue, as shown here as thinning in high-level brain areas, sites within the neocortex. These areas reflect both neuronal and other cell loss, and appear in specific regions that serve many of the autonomic, cognitive, and neuropsychological functions affected in the condition. Standard HF treatment does little or nothing to address those neural changes. However, it would be perhaps useful to develop strategies for neuroprotection found helpful in other \u201cbrain\u201d conditions, such as stroke and neurodegenerative diseases. Those strategies might include interventions for defective blood brain barrier processes, known to be affected in HF , and speLimitations include selection of HF subjects with NYHA Functional Class II. We included HF subjects with relatively low severity , and excluded subjects with NYHA Functional Class III and IV. HF subjects with Functional Class III and IV are often unable to lay supine in the MRI scanner for significant periods of time, which restricted selection to Functional Class II patients only. Thus, these findings cannot be extended to NYHA Functional Classes III and IV. Use of diuretics is very common in HF subjects, and thus, hydration status may affect over-all brain volume and regional cortical thicknesses . HoweverLateralized cortical thinning emerged in HF compared to control subjects in multiple brain sites that regulate autonomic, cognitive, affective, language, and visual functions. The findings indicate chronic tissue alterations, with changes reflecting loss of neurons and glial cells in affected cortical sites. The pathological mechanisms contributing to reduced regional cortical thicknesses in HF likely include hypoxic/ischemic processes, resulting from impaired cerebral perfusion due to low cardiac output and sleep-disordered breathing, comorbid conditions, including diabetes and hypertension, or initial injury in autonomic regulatory sites from stroke, maldevelopment, or infection, leading to secondary damage to other brain regions. Injury also may be contributed by low levels of micronutrients, especially thiamine and magnesium, accompanying the condition."}
+{"text": "Water kefir is a slightly sweet, acidic, fruity, sparkling, and slightly alcoholic fermented beverage produced with water kefir grains, the latter consisting of polysaccharides and micro-organisms. The micro-organisms involved in water kefir fermentation comprise yeast, lactic acid bacteria, bifidobacteria, and acetic acid bacteria. Some strains of micro-organisms in water kefir might possess probiotic activity. Also, water kefir is a beverage with relatively low sugar content, providing an interesting alternative to sugary soft drinks. To be able to exploit water kefir for its probiotic potential or as a low-sugar soft-drink, in-depth research is needed to unravel the species diversity and community dynamics of water kefir fermentation. In particular, substrate consumption and metabolite production in water kefir have not been studied until now.Water kefir fermentation processes were followed as a function of time for 192 h. At each sampling point, the pH, microbial counts , and residual substrate and metabolite concentrations were measured, including volatile aroma compounds. The species diversity was unravelled through both culture-dependent and culture-independent techniques.Lactobacillus casei/paracasei, Lactobacillus harbinensis, Lactobacillus hilgardii, Bifidobacterium psychraerophilum/crudilactis, Saccharomyces cerevisiae, and Dekkera bruxellensis. This microbial species diversity was similar in the water kefir liquor and on the water kefir grains, and remained stable during the whole fermentation process. Some strains of these species, such as Lb. casei and Bifidobacterium spp., might possess probiotic activities. Sucrose, the major substrate of the fermentation was completely converted after 24 h of fermentation, which coincided with the production of the water kefir grain polysaccharide. The main metabolites of the fermentation were ethanol and lactic acid, whereas glycerol, acetic acid, and mannitol were produced in low concentrations. The most prevailing volatile aroma compounds  were ethyl acetate, isoamyl acetate, ethyl hexanoate, ethyl octanoate, and ethyl decanoate. These are fruity esters which might have a positive impact on the aroma of the end-product.Species diversity analyses indicated that the most important microbial species were In this study the species diversity, community dynamics, substrate consumption, and metabolite production during water kefir fermentation were described in detail. This work provides a basis for further developments of water kefir as healthy, low-sugar, probiotic fermented beverage."}
+{"text": "The atlas, an interactive, online mapping tool and platform for accessing data collected by NCHHSTP, allows users to observe disease trends and patterns of HIV, acquired immunodeficiency syndrome (AIDS), certain sexually transmitted infections , tuberculosis, and acute viral hepatitis A, B, and C. The atlas also allows users to create detailed reports, maps, and other graphics based on these surveillance data. The NCHHSTP Atlas is available at"}
+{"text": "Biophysics Reports, a peer-reviewed international journal in cooperation with SpringerOpen, one of the largest open-access publishers in the biological science field.Welcome to Biophysics continues to be a crucial driving force for biological and biomedical research. Our goal is to provide a highly visible forum for the dissemination of innovative theories, methods and protocols, and novel findings based on technological developments. The current publication formats include Methods, Protocols, Research Articles, Puncta, and Reviews/Minireviews.Although the journal focuses on biophysics, we believe there is a growing need for integration across multiple disciplines to respond to biological and biomedical challenges. As such, this journal will address a broad audience of researchers in the life sciences working on technological developments including but not limited to biophysics, cell biology, immunology, membrane biology, redox biology, photobiology, neurobiology, oncology, biochemistry, biomechanics and mechanobiology, structural biology, biomedical imaging, electron microscopy, nuclear magnetic resonance spectroscopy, computational biology, bioinformatics, nanomedicine, genetics, model organisms, protein science, developmental biology, stem cells, omics, and biomedical big data. We also encourage authors to submit research articles that include data based on specific methods or techniques. Unlike the \u2018methods sections\u2019 of specialized journals, we place a strong emphasis on detailed technical information, rigorous validation, and practical relevance to the journal\u2019s content. It is our aim to encourage interdisciplinary exchange of technical tool boxes.Biophysics Reports. With the journal Nature Methods as a model, we aim to work with scientific and publishing colleagues worldwide to establish Biophysics Reports as a high-quality, high-visibility, and high-impact international journal. We call upon our colleagues around the globe to join us in supporting Biophysics Reports, and making this journal a significant platform that promotes method and technique innovation.We are proud to present our distinguished Editorial Board consisting of worldwide experts from multiple disciplines. Our Editorial Office ensures that we offer rigorous and rapid peer review, free submission/publication, rapid publication upon acceptance, and compliance with all open-access mandates. We would like to acknowledge all those who have worked tirelessly to ensure the successful launch of Tao XuBiophysics ReportsEditor-in-Chief, Director, Institute of Biophysics,Chinese Academy of Sciences"}
+{"text": "Dear EditorThe use of smokeless tobacco, especially paan and gutka, is prevalent in Southeast Asian countries . No exacNumerous social and cultural factors such as religious opinions, addiction, social popularity, and misassumptions about health benefits influence the use of smokeless tobacco . Some stAlthough Desalu introduces social acceptance as the main reason for the use of smokeless tobacco , conventAlso, due to cultural, social and economic differences, ethnicity greatly influences the amount of consumption . Various"}
+{"text": "Liver transplantation has become a widely accepted therapy for the management of the complications of cirrhosis and liver failure.To analyze the patients undergoing the Liver transplant Recipients and the factors influencing the outcome of the patients at our tertiary care hospital.The patients underwent liver transplantation recepients between May 2014 to Jan 2015 were analysed. The data was collected from patient records after ethics committee approval. The data captured were Age,sex, ICU and hospital length of stay, bilirubin, albumin, INR, creatinine, intubation days, readmission,cold ischemia, warm ischemia, portal vein thrombosis, SGOT, SGPT, Vasopressors use, APACHE II, SOFA Score, MELD Score, arterial anatomy, graft complications, hospital and 60day mortality, readmissions, hospital acquired infections are monitored.The total number of patients enrolled are 34. See tables 3The hospital mortality rate in our study is 2.94% (one patient).All the patients are ABO compatable, 2 patients had early graft rejection of which one patient liver functions has completely recovered and the other had not fully recovered. The hospital acquired infections are nil in these patients.26 (76.47%) liver donors are brain death patients. 5 (14.71%) receipient patients are HCV positive. The factors increasing the the mortality are Increased ICU and hospital length of stay, reintubation, readmission and renal replacement therapy.The statistically significant factors which increase the ICU length of stay are increased Bilurubin, decreased Albumin, increased ventilator days, increased Cold Ischemia and Warm Ischemia time, use of Vasopressors, lowest Platelets and raised INR.The statistically significant factors which increase the Hospital length of stay are decreased Albumin, increased ventilator days, reintubation, use of Vasopressors, readmission and lower platelets. The 60 day mortality is similar to hospital mortality.The patients undergoing the Liver transplant Recipients had good outcomes with less mortality and is comparable to the best centres in the world.Hospital acquired infections are nil in these patients.We need larger number to analyse the patients."}
+{"text": "Agitation is common across neuropsychiatric disorders and contributes to disability,institutionalization, and diminished quality of life for patients and their caregivers.There is no consensus definition of agitation and no widespread agreement on whatelements should be included in the syndrome. The International PsychogeriatricAssociation formed an Agitation Definition Work Group (ADWG) to develop a provisionalconsensus definition of agitation in patients with cognitive disorders that can beapplied in epidemiologic, non-interventional clinical, pharmacologic, non-pharmacologicinterventional, and neurobiological studies. A consensus definition will facilitatecommunication and cross-study comparison and may have regulatory applications in drugdevelopment programs.The ADWG developed a transparent process using a combination of electronic,face-to-face, and survey-based strategies to develop a consensus based on agreement of amajority of participants. Nine-hundred twenty-eight respondents participated in thedifferent phases of the process.Agitation was defined broadly as: (1) occurring in patients with a cognitive impairmentor dementia syndrome; (2) exhibiting behavior consistent with emotional distress; (3)manifesting excessive motor activity, verbal aggression, or physical aggression; and (4)evidencing behaviors that cause excess disability and are not solely attributable toanother disorder . A majority of therespondents rated all surveyed elements of the definition as \u201cstrongly agree\u201d or\u201csomewhat agree\u201d (68\u201388% across elements). A majority of the respondents agreed that thedefinition is appropriate for clinical and research applications.A provisional consensus definition of agitation has been developed. This definition canbe used to advance interventional and non-interventional research of agitation inpatients with cognitive impairment. It is afrequent manifestation of Alzheimer's disease (AD), frontotemporal dementia (FTD), dementiawith Lewy bodies (DLB), and other dementia syndromes  has an established leadership role inthe field of geriatric behavioral health, including agitation, and has led initiativesinvolved with this topic (Finkel The literature was reviewed (by Jeffrey Cummings), past definitions of agitationidentified, and common elements of the definitions reviewed. A preliminary survey ofthese definitions and elements to be considered for inclusion was developed andpresented to the IPA leadership.The ADWG was formed to guide this project. The ADWG reviewed the proposed survey,adding or deleting elements to enhance the focus and clarity of the questions. Therevised survey was sent electronically to the IPA membership and affiliate members. The survey collected demographicinformation on the respondents, determined the preferences among five definitions ofagitation used in the literature Kong, ,asked iFollowing completion and analysis of the first survey, an international expertconsensus meeting was held to develop a draft definition based on a review of theliterature and information derived from the survey. The members of the ADWG present atthe meeting include the authors of this paper. In this meeting a draft definition wasdeveloped that represented a consensus of those present. Following the expert meeting, apreliminary draft of the definition was developed and circulated to all members of theADWG. Through multiple electronic exchanges a final consensus was reached . Not allet al., To develop further consensus beyond the ADWG, other key stakeholder groups received theprovisional definition for comments, including the members of the NeuropsychiatricSyndrome Professional Interest Area of ISTAART  in this phase of theconsensus development process.International Psychogeriatrics for review.Once the second survey was complete, this report containing a description of theconsensus process, the definition, and the elements of the definition was prepared(Jeffrey Cummings) and circulated among the ADWG members. Agreement was reached on thetext describing the provisional definition and the manuscript was submitted toSix thousand emails were sent; 557 individuals responded. The response rate from IPAmembers was 30.1%. Many members of the IPA and affiliate organizations are involvedpredominantly with mood disorders, psychosis, or other non-dementia aspects of geriatricpsychiatry. Of the 557 respondents, 382 were physicians, including 292 psychiatrists.Other professional disciplines providing responses included nurses (57), psychologists(50), occupational therapists (13), social workers (14), and others/no responses (41).Three hundred eighty-eight (70%) of the respondents had been in practice for more than tenyears.This initial survey provided valuable insights from those involved in the care ofagitated patients, and key elements of the definition were identified. The ADWG surveyed essential elements of the definition of agitation. The percentage ofrespondents identifying specific adjectives as key behavioral elements of the definitionincluded: excessive (71%), inappropriate (54%), repetitive (46%), observable (64%),dangerous (24%), and disruptive (56%) . Table 3Of the items listed as possible behaviors to be included in a definition of agitation,the following were endorsed by at least 50% of the respondents: pacing, aimless wandering,verbal aggression, constant unwarranted requests for attention or help, hitting others,hitting self, pushing people, throwing things, general restlessness, screaming,resistiveness, hurting self, hurting others, tearing things or destroying property,shouting, and kicking furniture . ThisinWhen queried as to whether agitation and anxiety were the same, overlapping, or distinctconcepts, most of the respondents found them to be overlapping . When asked whether agitation and aggression are the same, overlapping, ordistinct, 0.8%, 66%, and 32% endorsed each option.When queried whether the definition should be limited to cognitive impairment syndromes \u2013the approach taken by the ADWG \u2013 67.4% said \u201cyes.\u201dThe provisional consensus definition uses the DSM style for defining a disorder as onethat produces disability  but not to the patient.Requiring the subjective element of the definition makes this less likely. It is notpossible to directly observe emotional states, and they must be inferred from observablebehaviors. In all, 78.2% of the Survey 2 respondents strongly (42.8%) or somewhat(35.4%) agreed that this aspect of agitation was captured appropriately by the proposeddefinition.A single episode or short-lived period of behavioral change would not meet thedefinition for agitation developed by the ADWG. The definition applies to a chronic orat least long-lasting state that has been sustained, persisted, or been frequentlyrecurrent for at least two weeks. This aspect of the definition will assist withintervention studies (pharmacologic and non-pharmacologic) where interventional groupsare compared and sustained behavioral changes are required to see a difference in thestudy outcomes.The ADWG limited the definition of agitation to patients with cognitive impairment.Behaviors that preceded the onset of the associated cognitive disorder would not beincluded in this definition. This aspect of the consensus definition is similar to theprecedent adapted in the definition of psychosis of AD ,verbal aggression , or physical aggression. These behaviors are the core aspects of the agitation syndrome;they reflect the behaviors endorsed in Survey 1 as comprising agitation. The ADWGrecognized that agitated patients exhibit different repertoires of behaviors and that,in the presence of emotional distress, any of the behaviors described would fulfill thiscriterion of the definition. Clinician judgment is not prohibited by the definition andbehaviors other than those listed may be present in agitated patients. In all, 88.8% ofthe Survey 2 respondents strongly (65.7%) or somewhat (23.1%) agreed that the proposeddefinition appropriately captured the physical aggression aspects of agitation, and87.9% strongly (59.7%) or somewhat (28.2%) agreed regarding the verbal aspects ofagitation.The patient must have at least one type of observable agitated behavior. The behaviorscan include A disorder is defined as producing disability , severalpsychosocial interventions have shown benefit in reducing agitated behavior  and the approval ofdextromethorphan/quinidine for PBA across neurologic disorders after having demonstratedefficacy in amyotrophic lateral sclerosis and multiple sclerosis. A similar strategy ofshowing efficacy for anti-agitation agents across several disorders could be adopted inanti-agitation drug development programs.The relationship of agitation to aggression sparked discussion. These are overlapping butnot identical concepts  control group. It may be useful to control for otherbehavioral features such as mood changes or psychosis. The ADWG definition could play acritical role in defining the patient population for such trials.The development of a provisional definition of agitation is the first step in advancing aresearch agenda for the definition. Validity studies using other agitation assessments,reliability of the application of the definition, usefulness in clinical trials,usefulness in non-pharmacologic research, and real-world application in clinical andhealthcare settings will lead to refinements and adjustments that will enhance thedefinition and advance the study of neuropsychiatric syndromes in cognitive impairmentdisorders.The sponsors, Otsuka and Avanir Pharmaceutricals, gave unrestricted education grants tohelp support the international meeting that was part of the definition-building process.Dr. Jeffrey Cummings has provided consultation to Acadia, ADAMAS, Anavex, Avanir,Boehinger-Ingelheim, Eisai, EnVivo, GE Healthcare, Genentech, Lilly, Lundbeck, Medavante,Merck, Novartis, Otsuka, Pfizer, Prana, QR Pharma, Resverlogix, Roche, Sonexa, Suven,Takeda, and Toyoma companies. Dr. Cummings owns the copyright of the NeuropsychiatricInventory.Professor Sube Banerjee has received consultancy fees, honoraria for speaking, and supportin attending conferences from the makers of anti-dementia medication and otherpsychotropics, including Abbvie, Eisai, Pfizer, Novartis, Lilly, and Shire.Professor Henry Brodaty has served as investigator for Janssen, Lilly, Medivation, Merck,Sanofi, Servier, and Tau Therapeutics, and has been on the advisory boards of Pfizer,Novartis, Janssen, Lundbeck, and Nutricia. Dr. Brodaty has provided consultation to Baxter,Lilly, Merck, and Nutricia.D.P. Devanand has received research support from Eli Lilly, and has provided consultationto AbbVie.Dr. Serge Gauthier has been on the scientific advisory board or investigator with Abbvie,Affiris, Eisai, Lilly, Navidea, Novartis, Pfizer, Sanofi-Synthelabo, Servier, and TauRx.Professor Robert Howard reports that he has no relevant disclosures to make.Dr. Krista Lanct\u00f4t has had research support and/or speaker's honoraria from Abbvie Canada,Lundbeck Canada Inc., Pfizer Canada Inc., Janssen Ortho, and Rocheand Wyeth.Dr. Constantine Lyketsos has received grant support (research or CME) from AssociatedJewish Federation of Baltimore, Weinberg Foundation, Forest, GlaxoSmithKline, Eisai, Pfizer,Astra-Zeneca, Lilly, Ortho-McNeil, Bristol-Myers, Novartis, National Football League, Elan,and Functional Neuromodulation. Dr. Lyketsos has been a consultant or advisor toAstra-Zeneca, GlaxoSmithKline, Eisai, Novartis, Forest, Supernus, Adlyfe, Takeda, Wyeth,Lundbeck, Merz, Lilly, Pfizer, Genentech, Elan, NFL Players Association, NFL BenefitsOffice, Avanir, Zinfandel, BMS, Abvie, Janssen, and Orion. Honorarium or travel support hasbeen received from Pfizer, Forest, GlaxoSmithKline, and Health Monitor.Dr. Jacobo Mintzer reports receipt of grants to his institution from Takeda Global Researchand Development Center, Pfizer, Genentech, Merck, Accera, Elan, Avanir, F. Hoffmann-LaRoche, Novartis, Baxter, Eli Lilly, Wyeth, and Janssen Alzheimer Initiative; and employmentwith NeuroQuest, and BioPharma Connex.Dr. Elaine Peskind has been on the speakers\u2019 bureau for Forest Pharmaceuticals and on theAdvisory Committee for Avanir. Dr. Peskind served on the Adjudication Committee for TakedaPharmaceuticals.Dr. Anton Porsteinsson has received a grant for his institution from Avanir, Eisai, Elan,Genentech/Roche, Janssen Alzheimer Initiative, Merck, Pfizer, and Toyama. He has providedconsultation for Elan, Janssen Alzheimer Initiative, and TransTech Pharma. Dr. Porsteinssonhas membership on data safety and monitoring boards for Quintiles.Dr. Edgardo Reich has participated as investigator in different pharmaceutical-sponsoredtrials for Ely Lilly, Glaxo, Forest, Mertz. Astra Zeneca, Novartis, Roche, and Janssen. Hehas received travel grants from Bayer, MerckSerono, Novartis, Mertz, and Teva.Dr. Cristina Sampaio has been a consultant for Abbvie, Alkermes, AstraZeneca, Avanir,Biogen, BMS, Chelsea, Genzyme, Lilly, Lundbeck, Otsuka, Pfizer, Roche, Sanofi, Servier,Takeda, and Teva.Dr. Mary Sano has been on the Scientific Advisory Board for Medication and as a consultantfor Bayer Schering Pharma, Bristol-Meyers Squibb, Elan, Genentech, Medivation, Medpace,Pfizer, Janssen, Takeda, and United Biosource.Dr. David Steffens is supported through grants from the National Institute of MentalHealth, and he receives textbook royalties from the American Psychiatric Press.Dr. Marc Wortmann reports no other salaries than from Alzheimer's Disease International.Dr. Kate Zhong has provided consultation to Avanir, Pfizer, Janssen, and WyethPharmaceuticals.J. Cummings, J. Mintzer, H. Brodaty, and M. Sano formulated the research questions,designed the study, carried out the study, analyzed the data, and wrote the paper.S. Banerjee, D. Devanand, S. Gauthier, R. Howard, K. Lanct\u00f4t, C. Lyketsos, E. Peskind, A.Porsteinsson, E. Reich, C. Sampaio, D. Steffens, M. Wortmann, and K. Zhong carried out thestudy, analyzed the data, and wrote the article."}
+{"text": "Exiguobacterium strains in order to provide insight into their evolutionary strategies for speciation and environmental adaptation. The selected genomes include psychrotrophic and thermophilic species from a range of habitats, which will allow for a comparison of metabolic pathways and stress response genes.High-quality draft genome sequences were determined for 10  Exiguobacterium, belonging to the order Bacillales of the phylum Firmicutes, was proposed as a new genus in 1983 by Collins et al.  and vary slightly in their genome size, number of CDSs, and ribosomal RNA (rrn) operons (605 (orfB), are present in all strains. The strains contain two to seven cold shock protein genes (COG1278), one molecular chaperone GrpE , one ribosome-associated heat shock protein , three chaperonin GroEL , three cochaperonin GroES , and four fatty acid desaturase (COG3239) genes per strain.The  operons . Whole-g operons , 13. TheExiguobacterium strains to colonize and thrive in diverse ecological niches.The presence of multiple genes encoding stress-responsive proteins may explain the broad temperature range for growth and the ability of the JNIR00000000, JNIS00000000, JHZV00000000, JMKS00000000, JHZS00000000, JHZU00000000, JNIQ00000000, JHZT00000000, JNIP00000000, and JPOD00000000. The versions described in this paper are the first versions, JNIR01000000, JNIS01000000, JHZV01000000, JMKS01000000, JHZS01000000, JHZU01000000, JNIQ01000000, JHZT01000000, JNIP01000000, and JPOD01000000.These whole-genome shotgun projects have been deposited in DDBJ/EMBL/GenBank under accession numbers"}
+{"text": "Seye Abimbola, Titilope Olanipekun, Uchenna Igbokwe, Joel Negin, Stephen Jan, Alexandra Martiniuk, Nnenna Ihebuzor, Muyi AinaRegarding the paper titled: \u2018How decentralisation influences the retention of primary health care workers in rural Nigeria\u2019 by Global Health Action  03 March 2015. Citation: Glob Health Action 2015, 8: 26616 - http://dx.doi.org/10.3402/gha.v8.26616Published in In the Methods section, under the third sub-heading (Study participants), the third sentence is incorrect. It should read: In addition, we conducted IDIs with community members, and PHC managers working at local, state, and federal tiers of government .This sentence currently reads:In addition, we conducted IDIs with PHC workers, community members, and PHC managers working at local, state, and federal tiers of government .The section should read:The study participants were purposively selected to ensure that participants have the potential to provide rich, relevant, and diverse information on the research question. In each of six states, we conducted three FGDs with groups of PHC workers and three FGDs with groups of community members. In addition, we conducted IDIs with community members, and PHC managers working at local, state, and federal tiers of government . Each FGD involved 8\u201310 participants and lasted approximately 90 min, and each interview lasted approximately 60 min. We included as study participants all formal and full-time PHC workers involved in direct health-care provision such as nurses, midwives, community health workers, counsellors, and environmental health, laboratory and pharmacy personnel. Support staff such as cleaners and security guards were excluded, as were potential participants who could not communicate in any Nigerian language or who declined to sign consent forms. Given limited resources and time for this study, we also excluded all potential participants who were less than 18 years old because of logistic and ethical concerns associated with obtaining consent from and interviewing minors or involving them in group discussions."}
+{"text": "To the Editor: Four strains of cetacean morbillivirus  have been detected in the global cetacean population: porpoise morbillivirus (Tursiops aduncus) and the Guiana dolphin  have been recently reported in the Southern Hemisphere  (G. macrorhynchus)  were found dead along the coasts of the Canary Islands . CompletGrossly, the most remarkable findings in animal 1 were severe suppurative rhinitis, with clogged nasal passages by the accumulation of large quantity of purulent material, otitis media, sacculitis, and laryngitis. Severe diffuse epithelial hyperplasia and hyperkeratosis was observed along the upper respiratory tract and keratinized stomach. Animal 2 had severe proliferative dermatitis and cheilitis, and severe, suppurative, laryngeal tonsillitis. Animal 3 had advanced autolysis, which precluded pathologic analysis.Histologically, moderate, multifocal, bronchointerstitial pneumonia, severe suppurative tonsillitis and systemic lymphoid depletion were identified in animals 1 and 2. Severe nonsuppurative meningoencephalitis with neuronal and glial cell degeneration and necrosis, microgliosis and syncytial cells were observed in animal 2.Immunohistochemical analysis showed morbillivirus antigen in the bronchiolar epithelium, type 2 pneumocytes, and alveolar multinucleate cells. Syncytia from lymph nodes, laryngeal tonsil, spleen, and intestine also showed positive immunolabeling for morbillivirus. Epithelial tropism caused by the virus was suggested by identification of viral antigen in epithelia of the lung, larynx, keratinized stomach, intestine, kidney, urinary bladder, epididymis, and endometrial glands. In addition, intense immunolabeling was detected in neurons  and glial cells, primarily throughout the cerebral gray matter of animal 2.Molecular detection of CeMV was performed by a using a 1-step reverse transcription PCR for a 426-bp conserved region of the phosphoprotein gene (http://www.ncbi.nlm.nih.gov/blast/Blast.cgi) showed that amplified samples were nearly identical to reference PWMV sequences , a PCR amplicon for the brain sample from animal 2 (GenBank accession no. KT006291), and a PCR amplicon for the larynx from animal 3 were sequenced. A BLAST search  from the eastern Atlantic Ocean stranded along the Canary Islands, Spain, 2015."}
+{"text": "Twenty-five to sixty percent of physicians report burnout across all specialties. Changes in the healthcare environment have created marked and growing external pressures. In addition, physicians are predisposed to burnout due to internal traits such as compulsiveness, guilt, and self-denial, and a medical culture that emphasizes perfectionism, denial of personal vulnerability, and delayed gratification. Professional coaching, long utilized in the business world, provides a results-oriented and stigma-free method to address burnout, primarily by increasing one\u2019s internal locus of control. Coaching enhances self-awareness, drawing on individual strengths, questioning self-defeating thoughts and beliefs, examining new perspectives, and aligning personal values with professional duties. Coaching utilizes established techniques to increase one\u2019s sense of accomplishment, purpose, and engagement, all critical in ameliorating burnout. Coaching presumes that the client already possesses strengths and skills to handle life\u2019s challenges, but is not accessing them maximally. Although an evidence base is not yet established, the theoretical basis of coaching\u2019s efficacy derives from the fields of positive psychology, mindfulness, and self-determination theory. Using a case example, this article demonstrates the potential of professional coaching to address physician burnout. Dr. Greenley,54, is a well-respected internist. Recently, he has become short-tempered with staff, persistently late with paperwork, exhausted, and emotionally distant. Dwelling on negative aspects of his personality, he feels like an imposter. Greenley feels disconnected from his earlier sense of purpose. Piano and tennis, past enjoyable pursuits, are long lost.Changes in medical practice have augmented stressors for already overburdened physicians, including increased scrutiny, accountability, time constraints, and increasing role definition by non-physicians, all with a concomitant decrease in workplace control., p.186 Numerous studies note rates of burnout between 25\u00a0% and 60\u00a0% in a wide spectrum of specialties.Burnout is characterized by a low sense of personal accomplishment, emotional exhaustion, cynicism and depersonalization.In addition to deleterious effects on physician well-being, burnout contributes to decreased physician retention,A friend of Dr. Greenley\u2019s, a pharma executive, suggested coaching to improve his workplace function and state of mind.The etiology of physician burnout not only includes growing external demands and decreased workplace control; socialization factors also play a role. Medical training emphasizes perfectionism, denial of personal vulnerability, and delayed gratification.Professional coaching, long used by executives and making inroads within the medical profession,At the heart of coaching lies an iterative process of examining seemingly fixed thoughts and circumstances.Dr. Greenley contacted a certified coach specializing in physician clients. After completing life-balance  In addition, coaches encourage clients to focus awareness of their cognitive, emotional, and physical experience in the present, a central tenet of mindfulness.Coaches help clients clarify values and align them with professional and personal goals, an objective of known importance in decreasing physician burnout.Helping clients identify, bolster, and apply strengths in challenging situations is another technique, important in a medical culture known to malign personal weakness. Coaching applies techniques from the field of positive psychology, the scientific study of the strengths and virtues that enable optimal functioning of individuals and communities. Without minimizing painful emotions, positive psychology emphasizes engagement, meaning, and accomplishment.Dr. Greenley\u2019s strengths assessment identified curiosity and gratitude as his foremost strengths. After receiving complaints about his anger, the coach and Dr. Greenley brainstormed ways to leverage his strengths with specific behaviors. For example, when feeling short-tempered with staff, he pushed himself to be more curious about their experience.Co-creating action steps and maintaining accountability are essential for successful coaching. Coaches hold clients to mutually agreed-upon actions, promoting active experimentation and self-discovery, teaching self-discipline, and helping to build on small successes to create rapid and sustainable change.Other successful interventions for physician burnout include many strategies embedded in professional coaching. Mindfulness training decreases burnout in physicians,Integral for coaching and vitally important for quality patient care and the overall integrity of health systems is helping physicians reach their highest potential.It is important to compare coaching with other behavioral interventions. Cognitive-behavioral therapy  a diagnosis-driven and goal-oriented method of improving coping, modifies thought patterns to improve coping and encourages clients to question whether negative thoughts are actually untested assumptions. Unlike coaching, CBT is classically delivered in a prescriptive and standardized manner.Although all involve behavioral change, coaching is not psychological treatment and is oriented toward high-functioning individuals. Coaching is not appropriate with active psychiatric illness , and not effective in the setting of active substance abuse. Coaches are not trained mental health professionals and should have a low threshold for recommending psychological and/or psychiatric evaluation. Since burnout and depression often co-exist, in the absence of a major depressive episode, physicians can choose whichever approach they prefer, as overlap exists.The highly supportive coaching partnership promoted gradual change. Dr. Greenley adopted more effective responses to anger triggers. A heightened sense of purpose, agency, and accomplishment led to greater efficiency in paperwork. He began playing tennis and piano again. Most significantly, he now viewed his daily accomplishments as personal victories providing ballast against what once seemed like immutable oppression. Although his external circumstances remained unchanged, he became more energized and hopeful. After 9\u00a0months, he switched to monthly coaching sessions and continued his growth.Coaching takes place in person or by phone. For physicians suffering from burnout, weekly or biweekly 1-hour sessions would likely be required for 6 to 12 months.Widely employed in the business world, studies reveal financial return of 2.2\u20135.7 times on investment.Coaching physicians is an emerging field; scant supporting evidence is currently available. The only studies with physician subjects involve peer-coaching, a model distinct from professional coaching.Recent meta-analyses of coaching in non-healthcare corporate settings showed improvement in well-being, self-efficacy, and goal-directed self-regulation; however, heterogeneity of interventions and mixed study quality limits applicability.Research from the field of wellness coaching provides evidence that the professional coaching model can build self-efficacy, and effect behavioral and attitudinal change.The authors identified only one study utilizing professional coaching with burnout as an outcome measure, finding that seven to nine coaching sessions decreased burnout and increased life satisfaction.Although more data is needed, influences from positive psychology, mindfulness, and self-determination and self-efficacy theories are embedded in the practice of coaching, and are receiving increasing attention in the medical literature.In particular, self-determination theory, seen as a guide for medical education,While coaching has the potential to help physicians, limitations include financial cost, typically born by the physician. In addition, motivation, essential for any behavioral and attitudinal change, is required. Further, coaching cannot alter the many external factors contributing to burnout.Training standards for coaches are essential. Given physicians\u2019 vital societal role, standards for physician coaching are needed, including accredited training, certification, ongoing supervision, periodic recertification, and continuing education. Training in psychiatry or psychology alone, or providing non-physician coaches superficial education about healthcare, will not suffice.The role of coaching in managing physician burnout warrants further exploration, due to its accessibility and potential for return on investment. Well-designed research studies will be critical going forward.The case of Dr. Greenley demonstrates how coaching can provide a means of increasing self-awareness, aligning personal values with professional duties, focusing on strengths, questioning thought patterns and beliefs, as well as providing a supportive sounding board and partnership. These strategies increase one\u2019s internal locus of control, promote resilience, and provide ballast against the demands of professional life in an era of diminishing external control.Although coaching deserves further study, its efficient, results-oriented approach could prove valuable to physicians and health systems worldwide. Hospitals, medical schools, insurers, and practices could consider coaching to improve physician quality of life. Given increasing external pressures, if we hope to lessen physician burnout, we must provide supports that strengthen the internal locus of control and provide a stigma-free method of ameliorating burnout."}
+{"text": "Migraine and headache are life-threatening ill-conditions that affect the active, industrious class, which may likely reduce productivity.Because plants serve as source of 1 in every 4 drugs on drug market, there is need for survey of literatures with a view to identifying Nigerian medicinal plants with potential activity against migraine and headache.Literature survey and photography of medicinal plants that are used in Nigeria was carried out with a view to identify medicinal plants with therapeutic potentials against headache and migraine.Out of 184 medicinal plants identified, 23 have activity against migraine 29 have activity against both headache and migraine and 132 have activity against headache respectively. Orchis mascula, Hollarhena floribunda, Malaleuca leucodeudron, Cinnamomum zeylanicum, Citrus aurantifolium, Luffa accutangula Brassica juncea, Brassica nigra, Ocimum basilicum, Citrus aurantium Petasites hybridus, Rothmania whitfeildi, Palisota hirsuta, Crassocephalum crepidioides, Pridelia micrantha, Parkia bicolor, Cycodiscus gabonensis, Abelmoschus maschattus, Adenia venenata, Culcasia scandens, Dioscorea dumentorun, Galinsoga parviflora, Kolobopetalun auriculatum, Matricaria recutita, Petveria alliance, Piper nigran, Spilanthes filicaulis, Tragia benthani and Nigella sativa have activity against migraine and headache. Decoctions, infusions, concoctions and vapour of roots, leaves, stembark, flowers, and oil of the plants are used for the relief of the conditions. Since hypertension can cause headache plants such as Nigella sativa, Ocimum basilicum, chloriandrum sativum may be used to treat both migraine and headache caused by hypertension.Therefore medicinal plant resources from Africa should be harnessed with a view to discovering additional novel drugs with activity against headache and migraine.No conflict of interest."}
+{"text": "Psychological interventions are considered a central part of the individual psychotherapy in the rehabilitation counseling of psychiatrically symptomatic drug-dependent patients during methadone maintenance treatment in community programs. The need for psychological counseling should be evaluated for each individual patient.Medication is an important part of the treatment and individual psychotherapy focuses on the reduction or total cessation of drug use.The Recipient is G.M. 31, sentenced to a seven-year term of imprisonment for trafficking and use of and high-risk drugs, diagnosed on admission with opioid and methadone dependence, withdrawal syndrome.Following the observation and psychological evaluation, psychiatric and clinical examination, initiation of methadone substitution treatment was recommended, according to the following regimen: twelve 2.5 mg tablets for the first 2 days, followed by increase with about 5 mg per week until the complete remission of withdrawal symptoms, stabilization of the dose but not exceeding 200 mg methadone hydrochloride per day.Specialist monitoring, specialized counseling and individual and group psychotherapy were provided. Patients with concurrent mental illnesses may benefit from targeted therapies such as cognitive behavioral therapy .Focusing on the achievement of changes in the addictive behavior, individual therapy provides the patient with the knowledge and skills able to help them achieve and maintain abstinence [On admission, the patient to be placed in the methadone program undergoes:- Assessment at the reception point reception conducted by the multidisciplinary team  for the establishment of the degree of motivation for replacement therapy initiation;- Positive urine test for opioids on admission \u2013 mandatory prerequisite for inclusion in the treatment;- Signing of the consent to treatment - agreement with medical, psychological and social assistance;- Assessment of the current clinical condition.The Recipient is G.M., 31 years old, sentenced to a seven years term of imprisonment for trafficking and use of and high-risk drugs, diagnosed on admission with opioid and methadone dependence, withdrawal syndrome. The following were revealed after the application of the toxophilic sheet: \u2022 drug user since 1993, \u2022 history of overdose in 2007; \u2022 polyvalent drug user: \u2022 inhibitors: frequent heroin, methadone use; codeine and buprenorphine, occasionally; \u2022 stimulants: frequent use of cocaine, methamphetamine and ecstasy; speed-ball, occasionally;\u2022 hallucinogens: frequent consumption of Joints and blunts  and ketamine; LSD, occasionally;\u2022 anxiolytics: diazepam, nitrazepam, lorazepam, fluorazepam, occasionally, but in large quantities (ca.10-15 tablets) together with the heroin dose;\u2022 hypnotics: dormital, ciclobarbital, Phenobarbital, occasionally; mushrooms and ethers, occasionally; \u2022 mixtures of alcohol and drugs, alcohol and tablets, drugs and tablets, alcohol, drugs and tablets;Following the observation and psychological evaluation, the following conclusions were revealed: \u2022 appropriate contact psychic; \u2022 adequate sensory - perceptual development;\u2022 fine and gross motor skills within normal parameters; \u2022 average cognitive level, appropriate knowledge base;\u2022 satisfactory operational functions without quantitative or qualitative disorders at assessment time; \u2022 short- and long- term memory within the normal parameters; \u2022 amnesic efficiency; \u2022 temporo-spatially oriented, spontaneous and distributive attention in place, appropriate eye contact; \u2022 positive affective tone, slight tendency towards the simulation of emotional behavior, adequate dispositional state, slight relational immaturity; \u2022 partly reproductive voluntary imagination type, appropriate developmental stage; \u2022 predominantly extrinsic, selective motivation, unrealistic decision - motivational balance; \u2022 slow reaction, withdrawn, average adaptability, passive-aggressive, predominantly sanguine temperament, predominantly extroverted personality; \u2022 voluntary control in place, minimal voluntary effort; \u2022 optimistic, appropriate attitude behavior approving; \u2022 literary inclinations; psychosocial immaturity, personality with elements of antisocial behavior.In result of the application of the motivational interview, the subject was revealed to be in the preparation stage, combining intentional and behavioral criteria; the patient intends to change in the near future and has already made minor changes, however, not yet meeting the criteria for the action stage, i.e. long-term abstinence (minimum 3 months) has not been achieved yet.On psychiatric examination, the patient complained of the following: - withdrawal symptoms: insomnia, chills, sweating, feeling cold, musculoskeletal, abdominal pain, rhinorrhea, nausea, vomiting, diarrhea; - overall careless looks, immobile facial expression, focused gaze, cooperative attitude, proper psychic contact, auto- and allo-psychologically oriented;- spontaneous and distributive attention, short- and long- term memory within normal parameters;- average cognitive level without quantitative or qualitative changes in the sphere of thought; - prevailingly impulsive, irritable, impulsive, demanding dispositional tone, diminished psychomotor agitation.Heroin, methadone and benzodiazepines tests were positive.The initiation of methadone substitution treatment was recommended, according to the following regimen: twelve 2.5 mg tablets for the first 2 days, followed by an increase with about 5 mg per week until the complete remission of withdrawal symptoms, stabilization of the dose but not exceeding 200 mg methadone hydrochloride per day.Additionally, specialist monitoring, specialized counseling and individual and group psychotherapy were provided.Following the corroboration of overall investigations established on admission, the patient was recommended for inclusion in a therapeutic module for drug users.Behavioral therapies can be used to make effective pharmacotherapies available to a wider proportion of substance abusers being a point that has considerable implications beyond making methadone a more viable treatment option."}
+{"text": "This study aimed to investigate the potential risk factors of idiopathic central precocious puberty (ICPP) girls in Fujian province.A case-control study was conducted in 566 girls who were diagnosed with ICPP at endocrinology department and 547 healthy girls for routine physical examination in Fuzhou Children\u2019s Hospital of Fujian from October 2011 to October 2013. Parents were asked to fulfill the questionnaires on children\u2019s diets, behaviors, parents and family conditions, and Logistic regression analysis was conducted for risk factors.Chi-square test showed that 23 variables had significant statistically difference. Logistic regression analysis indicated that some variables were entered the final model: mother's age at menarche were older than 13 years , intaking organic fruits , daily exercise time, intaking ordinary vegetables , intaking general livestock , BMI, income of parents , heavy study burden , intaking instant food, intaking nourishment , using adult cosmetics . Among the variables, mother's age at menarche were older than 13 years, intaking organic fruit and doing more exercise for a long time were demonstrated to be the protective factors for ICPP, and others were risk factors.There were many factors related to ICPP girls in Fujian province, such as mother\u2019s age at menarche, diet and behaviors, BMI, parental income, and heavy study burden."}
+{"text": "Centrality is a primary index and a promising method for identifying essential nodes, particularly in biological networks. The newly created CentiServer is a comprehensive online resource that provides over 110 definitions of different centrality indices, their computational methods, and algorithms in the form of an encyclopedia. In addition, CentiServer allows users to calculate 55 centralities with the help of an interactive web-based application tool and provides a numerical result as a comma separated value (csv) file format or a mapped graphical format as a graph modeling language (GML) file. The standalone version of this application has been developed in the form of an R package. The web-based application (CentiServer) and R package (centiserve) are freely available at  Network biology and related approaches are fundamental tools used for simplification, reconstruction, analysis, and comprehension of complex behavior in biological systems. Finding the most relevant elements in a network is crucial in network analysis. In various fields, this concept is discussed under different terms such as influential users, influential spreaders, authorities, hubs, key players, spread nodes, essentiality, lethality, and centrality. Although the centrality concept, which has its origin in social sciences, has been adopted into biology , there iThere are applications for network analysis on different platforms. Majority of these tools compute classical and common centralities, with a maximum of less than 20 computable measures. We categorized these tools into five groups. Group 1 consisted of the tools that are in the form of a standalone software such as CentiBin, which calculates 16 indices \u20139. GroupThis comprehensive encyclopedia mainly covers fundamental centrality definitions and computational algorithms in the field of network biology. Nearly all papers related to centrality were carefully reviewed for this survey. To make the materials accessible, a web page of pertinent materials, tools , and relevant references was created. At present, the encyclopedia contains 113 entries.For the computation of centralities, a web-based application was developed employing the R  programmResults of the centrality-measured calculation are provided in two formats. The numerical result of the calculated centrality can be downloaded in a csv file format. The computed result will be mapped into a GML graph file format for downloading and online visualization.Additionally, we have prepared a list of available tools for centrality calculation and have categorized these tools based on their platforms and licenses. The accessing addresses and the measures, which are calculable by them, have been presented . The meaAll centrality indices were listed alphabetically with a link to their specific page. Furthermore, indices that are more applicable in biological networks were categorized into separate list. The brief definition of each centrality has been explained according to their related source and all references mentioned.A step-by-step process was designed for creating a new job and calculating network centralities via a web-based application. Each job was queued on server for calculation. In step one, users will upload his/her network file. Supported formats for network file include Edge list (.txt), Pajek (.net), UCINET (.dl), GML (.gml), and GraphML (.graphml). For demo and/or test purposes, two sample networks, Human immunodeficiency virus network from BioGRID and Zachary's karate club network, are selectable. Other network features such as network directionality (undirected or directed), unweighted or weighted option for removal of multiple edges, and loops have been specified in this step. In step two, users will select one or multiple centrality(s) for calculation and specify each index option(s) if applicable. Finally, in step three, users will enter an optional description for the job and will create the job by clicking the \u201cCreate job\u201d button. After creation, the job will stay on queue for calculation and web-based tool provides a job unique ID for future follow-up. Users can see job status and result files for download. If users create an optional account, all of uploaded network files, created jobs and its results will be available in users profile section.This page lists totally 43 stand-alone applications, libraries, packages, plugins, and toolboxes that calculate centrality measures. This list is categorized alphabetically and according to system platforms. Additionally, a brief description about each tool and access link has been provided. Some other features like platform, license type, and publication reference are also provided.A commenting system at the bottom of each centrality page allows researchers to comment on the page, related measures, and share their experiences or make any suggestions.http://www.centiserver.org. Despite web applications that have some limitations in network size due to shared resources, use of centiserve R package provides the ability to calculate centrality indices for any size of network and only has a limit based on local system resources.We have also developed centiserve, an R package for the statistical R software , which chttp://www.centiserver.org/?q1=rpackage. Then, use the install.packages command as below: install.packages where path_to_file would represent the full path and file name. In the windows operating system and RGui, select Install package(s) from local zip files under the Packages menu. After installation, use the below command to see complete helps for centralities:First, download the package according to an operating system, \u201cPackage source\u201d for Linux and \u201cWindows binaries\u201d for windows system via this address, > library(\"centiserve\")> help(package = \"centiserve\")The following node centralities are calculable by CentiServer: Alpha centrality, Average distance, Bargaining centrality (Bonacich power), Barycenter centrality, Bottleneck, Bridging centrality, Burt's constraint, Centroid value, Closeness centrality (Freeman and Latora), Closeness vitality, ClusterRank, Communicability betweenness centrality, Community centrality, Cross clique connectivity, Current flow betweenness centrality, Current flow closeness centrality, Dangalchev closeness centrality, Decay centrality, Degree centrality, Diffusion degree, DMNC (Density of Maximum Neighborhood Component), Eccentricity centrality, Eigenvector centrality, Entropy centrality, EPC (Edge Percolated Component), Flow betweenness centrality, Geodesic K-path centrality, Graphlet degree centrality, Hubbell index, Information centrality, Katz status index, K-core decomposition, Kleinberg's (HITS), Laplacian centrality, LeaderRank, Leverage centrality, Lin centrality, Load centrality, Lobby index, Local clustering coefficients, Markov centrality, MNC (Maximum Neighborhood Component), PageRank, Pairwise disconnectivity index, Radiality centrality, SALSA , Semi local centrality, Shortest-paths betweenness centrality, Strength (weighted vertex degree), Stress centrality, Subgraph centrality, and Topological coefficient. The centrality indices calculate for undirected or directed and for unweighted or weighted networks.The other indices which described in site, including ATC , Bayesian centrality, Bipartivity, CCIS, Co-Betweenness centrality, Communicability centrality, Composite centrality, Control centrality, Covertness centrality, Degree sphere centrality, DelayFlow centrality, DFC , DSS (Double Screening Scheme), Edge disjoint K-path centrality, Edge weighted, Effectiveness, EGC, Eigentrust, Flux centrality, Fuzzy closeness centrality, Game centrality, Group betweenness centrality, Harary graph centrality, Harmonic centrality, Integration centrality, \u03ba-betweenness centrality, \u03ba-path centrality, KatzR centrality, Kleinberg's centrality, Knotty centrality, KSC , LA , LAC , Maximum influence degree, MCC , Motif-Based centrality, Modularity centrality, Modularity density centrality, NC , NC , Neighbor based centrality, Neighborhood connectivity, Neighborhood coreness centrality, Network motif centrality, NFC , PeC centrality, Percolation centrality, Personalized PageRank, Perturbation centrality, Principal component centrality, Random-walk betweenness centrality, Random-walk closeness centrality, Ranking-betweenness centrality, SoECC (Sum of Edge Clustering Coefficient), Straightness centrality, Trust transitivity, TwitterRank, WDC , and Weighted LeaderRank.The network centrality in social and biology science is still an open field and we strive to improve currently available measures and also develop new ones. The authors and contributors of CentiServer monitor publish literatures and other scientific sources frequently and will update the site with newly developed indices and methods. The CentiServer site is hosted on an academic internet platform that ensures greater accuracy and reliable access to site.Recently, many approaches and models have been developed to computationally identify the essential genes according to two main ideas. 1) Essential genes have a common feature in all organisms and they are evolutionary conserved . This feCentrality indices are a local network property that ranks the graph nodes. The higher the rank, the more important the node is in the network and may play key roles in controlling cellular responses .Escherichia coli K12 from STRING  [E. coli were obtained from the Online GEne Essentiality (OGEE) database [As a simple illustration, we downloaded the protein-protein interaction network of roteins)  version database . Thirty database . In our groL (b4143), dnaK (b0014), rplB (b3317), rpsD (b3296), rpsB (b0169), rplD (b3319), rplA (b3984), rpsE (b3303), rpsC (b3314), htpG (b0473), tufB (b3980), tufA (b3339), fusA (b3340), rpsG (b3341), rpsI (b3230), rplC (b3320), rplM (b3231), rplQ (b3294), rpoC (b3988) and ybcV (b0558). Except rplA (b3984) and htpG (b0473), all of these genes were marked as essential ones previously.Each centrality measure provides an ordered list of proteins . For comE. coli were marked as essential genes, the centrality index predicted about 74% of these proteins ranked in the top 100. Moreover, the aggregation method is a promising way for predicting more reliable and accurate essential proteins by unifying all ordered protein lists extracted from each centrality index. Discussing the biological significance of the RankAggreg result is beyond the scope of this article.The result of this analysis emphasized that the centrality is an anticipative topological measurement for predicting essential nodes in biological networks, because although about 20 percent of proteins in the protein interaction network of Centrality and essentiality are important and ongoing topics in the areas of social and biological networks. The centrality concept and related algorithms have found wide spread use in identifying essential nodes in a distinct network. With respect to the expansion of networks in all scientific fields, much efforts have been done in this regard. Since these methods have not met the needs, continuing efforts for optimizing indices and creating more efficient indices are expected. Determining the prominent nodes in a network completely depends on our importance definition and the measure we use for a specific purpose. Therefore, selecting an appropriate measure is critical. Additionally, uninformed use of measures without considering the essence of the network and the desired goal could result in misleading results, especially in biology . A queryThe site's materials will be kept updated and new contents will be added. The number of computable measures will be increased to improve the capability of the website. Adding practical applications of each index could significantly contribute the functionality of the site.S1 File(DOC)Click here for additional data file.S2 File(DOC)Click here for additional data file.S3 File(CSV)Click here for additional data file."}
+{"text": "As opiate use has increased, there has been a corresponding increase in the number of opiate users presenting for treatment. Questions regarding the challenges of treating opiate users in residential treatment remain largely unanswered. This study seeks to determine what, if any, meaningful differences exist between opiate and non-opiate users, as well as within opiate users who enter voluntary, private, or residential dual-diagnosis treatment, and the impact of any differences relative to treatment motivation, length, and outcomes.Data for this study were drawn from 1972 individuals, utilizing the Addiction Severity Index, the Treatment Service Review, the University of Rhode Island Change Assessment, and a satisfaction measure. Interviews were conducted at program intake, and 1 and 6-month interviews post-discharge.The results suggest that although there are similarities there are also some important differences in characteristics, motivation, completion, engagement, retention, levels of satisfaction, and post-treatment service use. Additional analyses were conducted when significant within-group differences by age for opiate users were revealed.Results suggest different strategies within treatment programs may provide benefit in targeting the disparate needs of younger opiate users. Outcome results at 6 months for all groups demonstrated significant improvement over pretreatment, suggesting that abstinence-based treatment can be an effective form of treatment for opiate users."}
+{"text": "In 1961, Mauro first discovered that skeletal muscle fibers of frogs contain mononuclear cells underneath the basal lamina by electron microscope and termed these \u201csatellite cells\u201d Mauro, . Adult sin vivo  were first isolated from the inner cell mass of a mouse blastocyst, an early-stage embryo, by Evans and Kaufman . Since tMyoD, in various cell types, including fibroblasts, pigment, nerve, fat and liver cells, is able to initiate myogenic reprogramming , by Weintraub group , Oct4, Sox2, cMyc, and Klf4 generate induced pluripotent stem cells (iPSCs) from fibroblasts (Takahashi and Yamanaka, Stem Cell Research is to publish all aspects of stem cell research ranging from molecular and cellular biology to developmental biology and tissue regeneration. In addition, the journal will consider papers in areas of the field in progenitor or stem cells related to cloning, pluripotency, reprogramming, proteomics, genetics, epigenetics, genomics, non-coding RNAs, and cancer stem cells. Our aim is to foster research that integrates all levels of stem cell biology, including developmental biology, tissue growth and regeneration, diseases, aging, and cancer. We welcome original papers on a broad range of subjects relating to stem cells, developmental biology, tissue regeneration, disease models, drug screening, and bioinformatics, related to stem cell biology and tissue regeneration.The goal of"}
+{"text": "Immunity, Inflammation and Diseaseis a peer-reviewed, open access,interdisciplinary journal providing rapid publication of cutting-edge research across the broadfield of immunology. Immunity, Inflammation and Diseasegives rapid consideration topapers in all areas of clinical and basic research. The journal welcomes original work that enhancesthe understanding of immunology in areas including cellular and molecular immunology, clinicalimmunology, allergy, immunochemistry, immunogenetics, cancer immunology, and many others.Immunity, Inflammation and Diseaseconsiders for publication bothpapers submitted directly to the journal and those referred from a select group of prestigiousjournals published by Wiley Blackwell. For further information, please refer to our AuthorGuidelines available at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2050-4527/homepage/ForAuthors.htmlOriginal research articles, methods papers, editorials and commentaries are published. Originalresearch papers must report well-conducted research with conclusions supported by the data presentedin the paper. Immunity, Inflammation and Diseaseis a Wiley Open Access journal, one of aseries of peer-reviewed titles publishing quality research with speed and efficiency. For furtherinformation, please visit the Wiley Open Access website at http://www.wileyopenaccess.com/view/index.htmlImmunity, Inflammation and Diseaseare fully openaccess: immediately freely available to read, download and share. Articles are published under theterms of the Creative Commons Attribution License which permits use, distribution and reproductionin any medium, provided the original work is properly cited.All articles published by Immunity, Inflammation andDiseaseis retained by the author(s). Authors grant Wiley a licence to publish the articleand identify itself as the original publisher. Authors also grant any third party the right to usethe article freely as long as its integrity is maintained and its original authors, citation detailsand publisher are identified. Further information about open access license and copyright can befound in this website: http://www. wileyopenaccess.com/details/content/12f25db4c87/Copyright--License.htmlCopyright on any research article in a journal published by The Publisher and Editors cannot be held responsible for errors or any consequences arising fromthe use of information contained in this journal; the views and opinions expressed do notnecessarily reflect those of the Publisher and Editors, neither does the publication ofadvertisements constitute any endorsements by the Publisher and Editors of the productsadvertised.Wiley Open Access articles posted to repositories or websites are without warranty from Wiley ofany kind, either express or implied, including, but not limited to, warranties of merchantability,fitness for a particular purpose, or non-infringement. To the fullest extent permitted by law Wileydisclaims all liability for any loss or damage arising out of, or in connection with, the use of orinability to use the content.Dr. Marc VeldhoenBabraham Institute, UKIIDeditorial@wiley.comAddress correspondence to the Editorial Office: Email:Omid AkbariUniversity of Southern California, USAMark ColesUniversity of York, UKAnselm EndersThe Australian National University, AustraliaJochen HuehnHelmholz Centre for Infection Research, GermanySt\u00e9phanie HuguesUniversity of Geneva, SwitzerlandIgor JurakHarvard University, USA and University of Rijeka, CroatiaLudger KleinLudwig Maximilian University of Munich, GermanyJun KunisawaNational Institute of Biomedical Innovation, JapanArian LaurenceBethesda, MD, USAKathy McCoyUniversity of Bern, SwitzerlandOsamu TakeuchiKyoto University, JapanHai QiTsinghua University, ChinaTim RadstakeUniversity Medical Center Utrecht, NetherlandsBruno Silva-SantosUniversity of Lisbon, PortugalMark TravisUniversity of Manchester, UKDavid WithersUniversity of Birmingham, UK"}
+{"text": "Technical advances in ultrasound, multi-detector computed tomography (MDCT) and magnetic resonance imaging (MRI) have increased our ability to detect small-sized hepatic lesions and low-contrast lesions, which would have escaped detection some years ago ,2. PrevaImaging appearance of focal fatty infiltration and focal sparing of fat, which may mimic malignant disease, is presented. Small benign lesions, such as flash-filling hemangiomas, FNH, biliary hamartomas, or solitary necrotizing nodules can be difficult to diagnose in the setting of primary tumors with either hypervascular or hypovascular metastases, respectively. Strategies to approach these lesions and guide further management are presented."}
+{"text": "Dear Editor,A 51-year-old female patient complained of mild frontotemporal headache of insidious-onsetfor two years. One year ago, she had an episode of focal, tonic-clonic seizures (with rightlower limb paresthesia) and was prescribed carbamazepine. Cerebrospinal fluid demonstratedincreased protein levels and intrathecal immunoglobulin (IgG) synthesis, suggesting aninflammatory component. Magnetic resonance imaging was performed .. There is agenetic predisposition, with T-lymphocyte receptor activation by some unknown antigen. Thedisease affects preferentially the respiratory system. In the lungs, granulomas are observed in the interstitialcompartment, showing a perilymphatic distribution along the peribronchovascular sheaths,interlobular septa and pleural surface.Sarcoidosis is a multisystem disease of unknown etiology characterized by noncaseatinggranulomatous inflammation.It is estimated that in about 5% to 15% of cases sarcoidosis affects the central nervoussystem. Rarely the patient presents with exclusively neurological manifestations like inthe present case. Most commonly, neurosarcoidosis is observed in cases of disseminateddisease.The clinical manifestations of neurosarcoidosis are pleomorphic. Cranial nerve compromise,visual alterations, headache, weakness, paresis, paresthesia, psychiatric alterations andsigns of meningeal irritation may be observed. Although rare, symptoms of diabetesinsipidus such as polydipsia and polyuria may also occur due to the involvement of thehypothalamus and hypophysis. In cases of spinal cord involvement, weakness of lower limbsand other nonspecific signs of myelopathy are observed. At magnetic resonance imaging, a commonfinding is intraparenchymal lesions with hypersignal on T2-weighted and FLAIR sequences,generally multifocal, periventricular, subcortical or in the deep white matter. Suchfindings can hardly be differentiated from vasculitis or demyelinating diseases.Intraparenchymal lesions are generally located near the areas with leptomeningealinvolvement (with enhancement by paramagnetic contrast medium), and may be either single ormultiple, possibly also involving cranial nerves.Although sarcoidosis may manifest in all the regions of the central nervous system, it ismost commonly seen in the skull base, hypothalamus, pituitary and optic chiasm. In the present case,the anatomopathological findings corresponded to typical noncaseating granulomas in thepachymeninges (Like in the present case, diffuse pachymeningeal thickening may be observed, withhyposignal on T2-weighted, isosignal on T1-weighted sequences and contrast enhancement.Thus, differential diagnoses such as neurotuberculosis, dural lymphoma, meningioma enplaque, IgG4 deposition disease, pseudotumor, adenocarcinoma metastasis, Wegener'sgranulomatosis, idiopathic hypertrophic pachymeningitis might be considered, requiringbiopsy to define the etiology. Simultaneous dural and leptomeningeal involvement is rarelyobservedmeninges . Intracr.A consensus is still to be reached on the treatment for sarcoidosis. In cases where thepatient is symptomatic the treatment is initiated with high doses of corticosteroids,gradually reduced along the treatment up to complete withdrawal"}
+{"text": "After publication of this work , it has Yi Su, Weigui Luo, Wanhuang Lin, Liying Ma and Mohammed Humayun Kabir."}
+{"text": "In the nonrandomized observational study by Kim et al.  evaluatiMoore et al.  validateFinally, increases in sCr and AKI 7\u00a0days after surgery are probably subjected to confounding postoperative events, such as low cardiac output syndrome, anemia, hypoalbuminemia, reoperation for bleeding, blood transfusion, sepsis, etc. Also, the postoperative events mentioned above can significantly affect clinical outcomes of patients, for example the extubation time, duration of hospital stay, and mortality. However, it was unclear whether the postoperative events associated with AKI and clinical outcomes were comparable between groups or required statistical adjustments.We thus argue that addressing these issues would further clarify the transparency of this study."}
+{"text": "Idiopathic pulmonary fibrosis is a progressive, irreversible, debilitating, and fatal lung disease, characterized by parenchymal fibrosis with reduced lung volumes and respiratory failure. No lasting option for therapy is available other than transplantation. Mesenchymal stem/stromal cells home to sites of injury, decrease inflammation, have antifibrotic properties, and promote epithelial tissue repair, so their use has been suggested as potential therapy for idiopathic pulmonary fibrosis. Despite reported benefits, the amount of mesenchymal stromal cells engrafting to the lung decreases substantially soon after administration. New strategies, such as hypoxia preconditioning, have thus been investigated in an attempt to optimize the engraftment, survival, and paracrine properties of stem cells. Hypoxia induces the expression of prosurvival mediators, chemoattractants, and growth factors involved in cell proliferation, migration, angiogenesis, antioxidant, antiapoptotic, and antifibrotic properties in mesenchymal stromal cells, optimizing their lung repair capability in an animal model of idiopathic pulmonary fibrosis.http://www.stemcellres.com/content/6/1/97See related research by Lan et al.,  Idiopathic pulmonary fibrosis (IPF) is a chronic, diffuse, fibrotic disease of the lung parenchyma of unknown etiology. Progressive deposition of collagen fibers in the lung interstitium inevitably leads to fatigue, dyspnea, hypoxia, and respiratory failure in patients with end-stage IPF. Although current pharmacological and nonpharmacological therapies can temporarily lessen the severity of symptoms, no effective treatment for IPF has been developed to rescue the impaired lung, prevent lesion progression, or both. Lung transplantation is considered the only curative approach. However, the significant shortage of suitable donor lungs and the many complications related to post-transplantation immunosuppression mean there is a dire need for new therapeutic approaches. In this context, mesenchymal stem/stromal cell (MSC)-based therapy is a promising alternative for the treatment of lung diseases. Novel strategies to optimize the beneficial effects of cell therapy have been investigated, seeking to enhance the proliferation, survival, engraftment, and paracrine properties of MSCs.Stem Cell Research & Therapy, Lan et al. [In a recent issue of n et al.  demonstrRepair of fibrotic lung parenchyma remains a significant clinical challenge. All currently available therapeutic trials in IPF are severely limited due to the lack of a clear understanding of the natural history of the disease. To date, treatment of IPF has been based on the concept that inflammation leads to injury; thus, most therapies have been based on eliminating or suppressing the inflammatory component through administration of anti-inflammatory agents including corticosteroids, immunosuppressants/cytotoxic drugs , and anti-fibrotic agents , alone or in combination . DespiteMSC-based therapy is an attractive alternative approach for the treatment of IPF, as MSCs home to sites of injury, inhibit inflammation, and contribute to epithelial tissue repair . In addiThe main insight of Lan et al.\u2019s study was the use of hypoxic preconditioning (HP), which upregulated cytoprotective and regenerative genes, stabilized mitochondrial membrane potentials, increased homing ability, promoted cell proliferation, and acted against hydrogen peroxide-induced cell death in the treated MSCs. Moreover, hypoxia-preconditioned mesenchymal stem/stromal cells (HP-MSCs) attenuated bleomycin-induced cell apoptosis and extracellular matrix (ECM) production through transforming growth factor (TGF)-\u03b21-mediated Akt signaling via paracrine effects. Lan et al. were the first to show that engraftment of HP-MSCs had therapeutic effects superior to those of untreated MSCs in a model of bleomycin-induced pulmonary fibrosis. Engafted HP-MSCs improved lung function, reduced lung edema, and reduced levels of proinflammatory and fibrotic factors. HP and stem cell transplantation have been extensively studied in a number of organs and tissues as a means of enhancing therapeutic effects in diseases such as stroke, myocardial infarction, traumatic brain injury, diabetes mellitus, inflammatory bowel disease, and acute kidney and liver injuries \u20139. HowevFurthermore, Lan et al. demonstrated that transplantation of HP-MSCs attenuated ECM deposition, in a mechanism attributed to upregulation of HGF in the fibrotic lung. In this process, HGF plays a key role in preventing fibrosis or scar formation after injury, by inhibiting TGF-\u03b2-mediated myofibroblast differentiation and ECM production. HGF also exerts multiple protective effects on injured tissues via mitogenic, antiapoptotic, anti-inflammatory, and antifibrogenic signaling .Lan et al.  suggest"}
+{"text": "The authors' names were incorrectly listed as Docampo Jorge, Gonzalez Nadia, Vazquez Claudio, Morales Carlos, and Gonzalez-Toledo Eduardo; this error is corrected here."}
+{"text": "Aspergillus spp. and in some centers by Mucorales. However, over the last decade, a number of uncommon filamentous fungi, such as Scedosporium, Fusarium, Penicillium, melanized moulds, and basidiomycetes, have emerged as etiological agents of well-characterized respiratory disorders. It is therefore that the term \u201crespiratory mycosis\u201d has now broadened to include not just invasive disease but also lesser-recognized entities such as fungal ball, severe asthma with fungal sensitization (SAFS), fungus-associated chronic cough (FACC), allergic bronchopulmonary mycosis (ABPM), and allergic fungal rhinosinusitis (AFRS) . Anfatality . Sporotrdiseases . Lately,neumonia ,24. The S. commune and Bjerkandera adusta , wh, whS. coablished . Furtherablished . The FBMhe cough . In FACChe cough . It is pith FACC . Low-dosith FACC . Anotherl hyphae .Exophiala), Pleosporales , Sordiales (Chaetomium), and Venturiales (Verruconis) of Ascomycota [Alternaria alternata and species of Bipolaris, Curvularia, and Exserohilum are associated with AFRS, bronchial asthma, hypersensitivity pneumonitis, ABPM, and invasive lung disease [Aspergillus species are the most common cause of fungal sinus disease worldwide, allergic fungal rhinosinusitis is more commonly caused by black fungi [A. alternata is known to produce a severe form of asthma through outdoor allergen sensitization [Chaetomium spp. are rarely reported as agents of human disease, although Chaetomium globosum has been characterized as a cause of fatal pneumonia in patients with haematological malignancies or organ transplants [Chaetomium spp. include sinusitis and empyema [Verruconis gallopava and Ochroconis spp. have been isolated from lower respiratory tract secretions and are responsible for invasive and probably allergic lower respiratory tract disease [Most melanized fungi that cause infections are free-living plant saprobes implanted into human tissue as a result of trauma, but respiratory mycoses occur secondary to inhalation of fungal spores. The moulds implicated in respiratory infections belong to the orders Chaetothyriales (comycota . Among t disease ,31\u201334. Ack fungi . Additionsplants ,34. Othe empyema . Also, V disease ,34.Curvularia and Exophiala could be resistant [The majority of clinical experience with the above-mentioned diverse fungi represents isolated cases or small series of infections. Therefore, evidence-based algorithms for specific treatment are not available and therapy remains a challenge. Corticosteroids, administered systemically or locally, remain the mainstay of treatment for allergic sinopulmonary manifestations. The management of these disorders focuses on three facets. Firstly, as environmental modification is usually impractical, the main focus is to suppress the inflammation with steroids. Alternatively, systemic antifungal agents have been used successfully with the aim of reducing the fungal load albeit best as adjuncts to steroids. Oral itraconazole has proven to be of benefit in disorders such as FACC, SAFS, and ABPM ,9,15. Noesistant .Aspergillus and mucoralean fungi remains unexplored. Clinical suspicion and broader recognition of FBM-associated diseases among clinicians and microbiologists would improve therapeutic experience and, ultimately, selection of better treatment strategies. It is pertinent to emphasize that thorough identification of non-sporulating moulds in clinical specimens is warranted in order to recognize the clinical entities associated with FBM. Further, prima facie, there appears to be geographical clustering of certain agents and their clinical associations, specifically in Asian countries, which may either be attributable to the expertise and recognition of these agents from clinical samples or other unknown factors that need to be determined. Lastly, to improve the outcome of the diseases associated with these diverse fungi, more studies on pathogenicity, antifungal drug trials, and standardized optimal treatment strategies are warranted.To conclude, systematic studies examining the true burden, geographical distribution, and underlying risk factors in patients with respiratory mycoses due to non-"}
+{"text": "Thanks are due to Dr. Ucak and colleagues for their valuable research evaluating the levels of serum ghrelin in patients with psoriasis . However\u03b1 therapy drugs were suggested to affect serum ghrelin levels [Ghrelin is a hormone secreted mainly by stomach. Some types of antipsychotics, antidepressants, corticosteroids, bromocriptine, and anti-TNF-n levels , 3. Alson levels . In this Helicobacter pylori infection could affect serum ghrelin [In addition, several studies revealed that certain diseases such as functional dyspepsia, celiac disease, cachexia, inflammatory bowel disease, asthma, ankylosing spondylitis, coronary artery disease, iron deficiency anemia, hepatocellular cancer, chronic liver disease, chronic renal disease, epilepsy, and ghrelin , 6. The Ucak and colleagues stated that they questioned the patients' alcohol and cigarette smoking habits. As known, serum ghrelin levels are associated with alcohol intake and smoking , 8. In tIn conclusion, we believe that the study of Ucak et al. contributes important data to medical literature and could lead other researchers to design a study. However clarifying above concerns will provide clearer picture to the readers."}
+{"text": "Hypertension is considered as a major risk of cardiovascular diseases worldwide. It has been evidenced that oxidative stress is increased in patients with salt-sensitive hypertension, essential hypertension, malignant hypertension, renovascular hypertension, preeclampsia as well as cyclosporine-induced hypertension. Plants and animals have complex systems of multiple types of antioxidants, including glutathione, vitamins A, C, and E, and enzymes like superoxide dismutase, catalase, and several peroxidases. The diets rich in fruits and vegetables can reduce blood pressure in hypertensive and normotensive patients.Cardiovascular disease is accompanied with enhanced oxidative stress (OS) in the vascular wall, heart, kidney, and brain. OS contributes to vascular injury by promoting inflammation, endothelial dysfunction and increased vascular tone, leading to altered vascular contractility, structural remodeling, and hypertension as well as other forms of cardiovascular disease. Hypertension is considered as a major risk of cardiovascular diseases worldwide. It has been evidenced that OS is increased in patients with salt-sensitive hypertension, essential hypertension, malignant hypertension, renovascular hypertension, preeclampsia as well as cyclosporine-induced hypertension . The mecAll authors wrote the manuscript equally.The author declared no competing interests.Ethical issues  have been completely observed by the author.None."}
+{"text": "This retracts article Dental caries and oral health practices among 12 year old children in Nairobi West and Mathira West Districts, Kenya. Gladwell Gathecha, AnselimoMakokha, Peter Wanzala, Jared Omolo, Perry Smith. The Pan African Medical Journal. 2013;12:42. Dental caries and oral health practices among 12 years old children in Nairobi West and Mathira West Districts, Kenya. Gladwell Gathecha, Anselimo Makokha, Peter Wanzala, Jared Omolo, Perry Smith. From our investigation, it clearly appears that the article was published in the Journal of the Kenya Dental Association in January 2011 [We hereby inform to our readership of the retraction of the article"}
+{"text": "Identification of a chrXq27.3 microRNA cluster associated with early relapse in advanced stage ovarian cancer patientsMarina Bagnoli, Loris De Cecco, Anna Granata, Roberta Nicoletti, Edoardo Marchesi, Paola Alberti, Barbara Valeri, Massimo Libra, Mattia Barbareschi, Francesco Raspagliesi, Delia Mezzanzanica and Silvana Canevari1265 \u2013 1278.Oncotarget 2011; 2: AddendumWe submitted to GEO repository new information to be added to the SuperSeries GSE25204 including: a new dataset, GSE67819, reporting the microRNA microarray profiling of our validation set; an update of the characteristic files including clinical data of patients in the GSE25202, GSE25203 and GSE67819 datasets."}
+{"text": "Numerous engineered and natural environments suffer deleterious effects from biofouling and/or biofilm formation. For instance, bacterial contamination on biomedical devices pose serious health concerns. In membrane-based technologies, such as desalination and wastewater reuse, biofouling decreases membrane lifetime, and increases the energy required to produce clean water. Traditionally, approaches have combatted bacteria using bactericidal agents. However, due to globalization, a decline in antibiotic discovery, and the widespread resistance of microbes to many commercial antibiotics and metallic nanoparticles, new materials, and approaches to reduce biofilm formation are needed. In this mini-review, we cover the recent strategies that have been explored to combat microbial contamination without exerting evolutionary pressure on microorganisms. Renewable feedstocks, relying on structure-property relationships, bioinspired/nature-derived compounds, and green processing methods are discussed. Greener strategies that mitigate biofouling hold great potential to positively impact human health and safety. Biofilms are communities of aggregated microorganisms surrounded by a self-produced matrix of extracellular polymeric substances. Across industries, including, healthcare, food production, and membrane-based separation processes, biofilms yield detrimental results . Within In membrane-based technologies, one approach to eliminate biofouling is to attach biocidal nanomaterials, including silver , copper In this mini-review, we discuss the benefits of engineering biopolymers and cover recent strategies from medical and membrane-based technologies that have been reported to combat microbial contamination with less evolutionary pressure on microorganisms, meaning that bacteria have shown less resistance to these greener approaches. Biopolymers, surface topography, nature-derived antimicrobials, and green processing are discussed. These green strategies hold great potential to positively impact human health and safety.Biopolymers are polymers derived from naturally occurring matter such as crustacean shells, mushrooms, or wood. In addition to being sustainable, biopolymers also offer inherent properties such as, antibacterial activity, biodegradability, biocompatibility, chelation, and coagulation capabilities . One exaAs noted previously, biopolymers offer intrinsic functionality and biocompatibility making them ideal hydrogel tissue engineering scaffolds . BiodegrEscherichia coli and Pseudomonas aeruginosa  . Higher embranes . Membranembranes . Explori fouling . Recentl fouling .Polydopamine (PDA) is a bio-inspired polymer that mimics the adhesion secretions of mussels . The sel-2h-1 for the pristine and treated membranes, respectively  particles (Biological molecules have also been explored to improve membrane properties. This includes attaching serine protease to the surface of cellulose acetate UF membranes, which resulted in a relative flux reduction ratio of 97\u201388%, along with an increase in steady state flux from 8 to 34 L mectively . Polyethectively . The surectively . The bodectively . Capsaciectively . RO membsubtilis . When hesubtilis . The essarticles . Howeverarticles . PSf memarticles .Improvements to the membrane fabrication process have recycled and reduced the amount of noxious and waste solvent. In an effort to replace the flammable, toxic, and teratogenic membrane-casting solvents, dimethylformamide, and dimethyl sulfoxide, the use of non-toxic, non-flammable, and inexpensive supercritical carbon dioxide has been investigated . PolyacrBacteria colonization and biofilm formation are pressing challenges that yield infections, higher energy consumption, and subsequent costs. New, innovative, and green solutions that mitigate these detrimental effects in medical and membrane-based technologies without exerting evolutionary pressure on microbes or on our environment are needed. The intrinsic properties of historically employed biopolymers, naturally derived antimicrobials, and bio-inspired agents can improve the surface hydrophilicity, protein adhesion resistance, and antibacterial activity of materials. However, the long-term viability of surfaces that have been modified with chemical antimicrobials is often limited by microbial and solution surface conditioning. Namely, ions and proteins adsorb onto the surface and mask the surface activity . PerhapsWhile organized topography certainly influences microbial behavior, virtually all examples from literature use PDMS. Further effort is needed to elucidate whether structure is a universal effect across all hard and soft surfaces. Incorporating spatially organized topography to medical implants and membranes, potentially, can be synergistically employed with non-specific antimicrobial compounds to extend surface functionality. With economy of scale, many of the same approaches employed to decrease biofouling on high-value biomedical devices may be appropriate for separation membranes. In the future, green materials science and engineering strategies that mitigate biofouling will allow us to overcome current challenges to positively impact human health.The Review Editor, James F. Holden, declares that, despite being affiliated with the same institution as authors Kerianne M. Dobosz, Kristopher W. Kolewe, Jessica D. Schiffman, the review process was handled objectively and no conflict of interest exists. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "COPD is the fourth leading cause of death worldwide, with particularly high rates in the People\u2019s Republic of China, even among never smokers. Large population-based cohort studies should allow for reliable assessment of the determinants of diseases, which is dependent on the quality of disease diagnoses. We assessed the validity of COPD diagnoses collected through electronic health records in the People\u2019s Republic of China.The CKB study recruited 0.5 million adults aged 30\u201379 years from ten diverse regions in the People\u2019s Republic of China during the period 2004\u20132008. During 7 years of follow-up, 11,800 COPD cases were identified by linkage with mortality registries and the national health insurance system. We randomly selected ~10% of the reported COPD cases and then undertook an independent adjudication of retrieved hospital medical records in 1,069 cases.Overall, these 1,069 cases were accrued over a 9-year period (2004\u20132013) involving 153 hospitals across ten regions. A diagnosis of COPD was confirmed in 911 (85%) cases, corresponding to a positive predictive value of 85% , even though spirometry testing was not widely used (14%) in routine hospital care. The positive predictive value for COPD did not vary significantly by hospital ranking or calendar period, but was higher in men than women (89% vs 79%), at age \u226570 years than in younger people , and when the cases were reported from both death registry and health insurance systems . Among the remaining cases, 87 (8.1%) had other respiratory diseases  and 71 (6.6%) cases showed no evidence of any respiratory disease on their clinical records.In the People\u2019s Republic of China, COPD diagnoses obtained from electronic health records are of good quality and suitable for large population-based studies and do not warrant systematic adjudication of all the reported cases. COPD is the fourth leading cause of death worldwide.7Population-based prospective cohort studies are essential to investigate the relevance of lifestyle, environmental, and genetic factors for a wide range of disease outcomes. To enable efficient and cost-effective collection and ascertainment of large number of disease outcomes, many studies are increasingly using routinely collected electronic medical records during follow-up. However, the quality of such disease outcome data may vary greatly between different countries, and between different settings within the same countries, and hence need to be carefully assessed, perhaps through independent review and adjudication of a sample of the reported disease cases to inform strategies for analyses.The CKB is a nationwide prospective cohort study of 0.5 million adults from ten diverse Chinese regions,Details of the CKB study design, procedures, and study participants have been previously described.The morbidity and mortality of each participant was monitored regularly through the People\u2019s Republic of China\u2019s CDC Disease Surveillance Points (DSP) system, checked annually against local residential records and HI records, and by active confirmation through street committee or village administrators. Causes of death from official death certificates were reported to the local CDC and coded using the tenth International Classification of Diseases (ICD-10) by trained staff, blinded to baseline information. If necessary, information from death certificates was supplemented by a review of medical records. For four major diseases , information on incidence was also collected through linkage with existing disease registries. In addition, electronic record linkage was established with the HI system that records details of all hospital admissions . All records for COPD from any source were checked and standardized. By January 1, 2014, a total of 11,799 COPD (ICD-10: J41\u2013J44) cases were identified from various sources , with 87Among the 11,799 reported cases of COPD durin\u011d7 years of follow-up, we randomly selected ~10% for retrieval of medical records. In the event that the relevant medical records could not be retrieved for certain cases, especially those who were admitted to hospital many years ago, a backup list of cases was provided to ensure that at least 1,000 cases  were adjudicated. Based on the information generated and provided centrally by the CKB coordinating centers, the medical notes were collected by trained CKB staff who visited the hospital following formal approval from local health authorities and relevant hospital administration. Electronic photographs of all relevant sections of the medical records were collected and sent to the National Coordinating Centre for review of the data completeness. Although a total of 1,138 medical records were retrieved, 69 cases were subsequently excluded as they were duplicates, leaving 1,069 cases with relevant medical records for adjudication.Following verification of completeness of data by the National Coordinating Centre, the collected medical records were sent for independent adjudication to five physicians with a working knowledge of respiratory diseases, who, in turn, were supervised by a senior consultant with specialist accreditation in respiratory diseases. Based on the medical records, the physicians then completed a specific electronic database designed on the basis of extracted information and completed a disease validation form  that inc1}/forced vital capacity {FVC} <70%]). In addition, based on the medical records, confirmed COPD cases were classified into the following subcategories: 1) chronic bronchitis, 2) emphysema, and 3) mixture of chronic bronchitis and emphysema. Similarly, the adjudication aimed to identify the actual medical condition(s) in misdiagnosed COPD cases . Finally, to ascertain the completeness of the electronic database generated by the adjudicators, ~10% of the adjudicated cases were randomly selected for central review at the Clinical Trial Service Unit (CTSU), Oxford, UK. Following the review, we observed that completeness of data acquisition was high, with 95% of the cases meeting the requirements of the adjudication process and consensus reached on the remainder following discussion.Although multiple medical and other related criteria help inform the diagnosis of COPD, the disease remains a clinical diagnosis and no single test result is, on its own, diagnostic for COPD. COPD cases were thus adjudicated on the basis of the clinical judgment of the respiratory physicians, blinded to any other study-related information collected. Each case was independently reviewed by one respiratory physician taking account of information collected from the following sources, where available: 1) medical history (including risk factors and respiratory symptoms such as chronic phlegm and breathlessness); 2) radiological examinations; and 3) spirometry , defined as the proportion of participants with an original diagnosis of COPD that was confirmed, was used as a direct measure of the validity of COPD diagnoses. We used SAS 9.3  for all the statistical analyses.Overall, relevant medical records were retrieved for 1,069 cases from 153 hospitals for adjudication, which covered a 9-year period from 2004 to 2013. Among the 1,069 cases, 71 (6.6%) had no mention of any respiratory disease in their medical records . In the I2=82%, P<0.001) (P=0.027) in Tier 2 hospital  compared to Tier 3 hospital . There was a significant positive trend (P for trend =0.01) for increased validity of COPD diagnoses with increasing age, with PPV of 79% (95% CI: 73%\u201385%), 85% (95% CI: 82%\u201389%), and 88% (95% CI: 85%\u201391%) for age groups <60 years, 60\u201369 years, and \u226570 years, respectively. Prebronchodilator spirometry was used in 13.9% (n=139) of the total 998 adjudicated cases, and postbronchodilator spirometry was used in only 5.7% (n=57).The validity of COPD diagnoses, assessed by PPV, was 85%  overall, higher for ICD-10 J44 , followed by J43 , and then J42 . The PPV varied across regions  . The PPVThis outcome validation study of more than 1,000 COPD cases covered 153 hospitals across ten regions, and it showed that COPD diagnoses reported through routine health record systems are of good quality in the People\u2019s Republic of China, with an overall PPV of 85%. Invalid diagnoses arose from either misdiagnoses (~8%) of other respiratory diseases or reporting errors (~7%). The high validity of COPD diagnoses in CKB should facilitate reliable assessment of the determinants of COPD in the population.From an international perspective, the 85% true positive estimate for COPD diagnoses in the present study is higher than that reported previously in several studiesThe difference in the reported validity of COPD diagnoses between different studies may reflect the calendar period when the disease was diagnosed and continuous improvement in diagnosis of COPD over the last few decades. The GOLD Initiative, launched in 1997, represented an important strategy to address the worldwide burden of COPD. Even before the GOLD initiative was proposed, a studyThe validity of COPD diagnoses in the present study was 84% for cases that were solely reported through the electronic HI system, but increased to 97% when a combination of death registry and electronic HI data were used, even though the latter accounted for only a small proportion of the reported cases. Although the HI system followed common frameworks and procedures, it was developed mainly to facilitate reimbursement of hospital care, with the data collected by different HI agencies in each region lacking a uniform reporting system. This may explain some reporting errors that could have occurred either during the recording of the cases in the different regional systems or during the coding processes themselves. The HI agencies are currently endeavoring to develop a uniform and standardized reporting system, and some of the agencies have merged; therefore, administrative errors should decrease in the future.The validity of the COPD diagnoses was slightly higher in rural regions than in the urban ones. This observation is surprising since rural health care facilities in the People\u2019s Republic of China are less well equipped (including poor access to spirometry testing).There are some limitations to this study. First, the sample of adjudicated cases may not be representative of all the COPD cases in CKB or, indeed, in the People\u2019s Republic of China. Indeed, some baseline characteristics differed between adjudicated and nonadjudicated cases. For example, lung function was lower in the sample analyzed, which could have yielded more severe cases of COPD that could have been more easily diagnosed and have had more comorbidity. This situation could reflect the fact that the medical records of participants with more hospital admissions, and consequently with more recent ones, may have been more likely to be retrieved. Second, the vast majority of COPD cases hospitalized were not assessed with spirometry, reflecting a well-recognized phenomenon of COPD management in the People\u2019s Republic of China.In conclusion, COPD diagnoses reported through electronic HI systems in the People\u2019s Republic of China are generally of high quality, facilitating the conduct of large-scale epidemiological investigations of determinants of COPD, and do not warrant systematic adjudication of all reported COPD cases.International Steering Committee: Junshi Chen, Zhengming Chen , Rory Collins, Liming Li , Richard Peto.International Co-ordinating Centre, Oxford: Daniel Avery, Derrick Bennett, Yumei Chang, Yiping Chen, Zhengming Chen, Robert Clarke, Huaidong Du, Xuejuan Fan, Simon Gilbert, Alex Hacker, Michael Holmes, Andri Iona, Christiana Kartsonaki, Rene Kerosi, Ling Kong, Om Kurmi, Garry Lancaster, Sarah Lewington, John McDonnell, Winnie Mei, Iona Millwood, Qunhua Nie, Jayakrishnan Radhakrishnan, Sajjad Rafiq, Paul Ryder, Sam Sansome, Dan Schmidt, Paul Sherliker, Rajani Sohoni, Iain Turnbull, Robin Walters, Jenny Wang, Lin Wang, Ling Yang, Xiaoming Yang.National Co-ordinating Centre, Beijing: Zheng Bian, Ge Chen, Yu Guo, Bingyang Han, Can Hou, Jun Lv, Pei Pei, Shuzhen Qu, Yunlong Tan, Canqing Yu, Huiyan Zhou.Qingdao Qingdao CDC: Zengchang Pang, Ruqin Gao, Shaojie Wang, Yongmei Liu, Ranran Du, Yajing Zang, Liang Cheng, Xiaocao Tian, Hua Zhang. Licang CDC: Silu Lv, Junzheng Wang, Wei Hou.Heilongjiang Provincial CDC: Jiyuan Yin, Ge Jiang, Shumei Liu, Zhigang Pang, Xue Zhou. Nangang CDC: Liqiu Yang, Hui He, Bo Yu, Yanjie Li, Huaiyi Mu, Qinai Xu, Meiling Dou, Jiaojiao Ren.Hainan Provincial CDC: Jianwei Du, Shanqing Wang, Ximin Hu, Hongmei Wang, Jinyan Chen, Yan Fu, Zhenwang Fu, Xiaohuan Wang, Hua Dong. Meilan CDC: Min Weng, Xiangyang Zheng, Yijun Li, Huimei Li, Chenglong Li.Jiangsu Provincial CDC: Ming Wu, Jinyi Zhou, Ran Tao, Jie Yang. Suzhou CDC: Jie Shen, Yihe Hu, Yan Lu, Yan Gao, Liangcai Ma, Renxian Zhou, Aiyu Tang, Shuo Zhang, Jianrong Jin.Guangxi Provincial CDC: Zhenzhu Tang, Naying Chen, Ying Huang. Liuzhou CDC: Mingqiang Li, Jinhuai Meng, Rong Pan, Qilian Jiang, Jingxin Qing, Weiyuan Zhang, Yun Liu, Liuping Wei, Liyuan Zhou, Ningyu Chen, Jun Yang, Hairong Guan.Sichuan Provincial CDC: Xianping Wu, Ningmei Zhang, Xiaofang Chen, Xuefeng Tang. Pengzhou CDC: Guojin Luo, Jianguo Li, Xiaofang Chen, Jian Wang, Jiaqiu Liu, Qiang Sun.Gansu Provincial CDC: Pengfei Ge, Xiaolan Ren, Caixia Dong. Maiji CDC: Hui Zhang, Enke Mao, Xiaoping Wang, Tao Wang.Henan Provincial CDC: Guohua Liu, Baoyu Zhu, Gang Zhou, Shixian Feng, Liang Chang, Lei Fan. Huixian CDC: Yulian Gao, Tianyou He, Li Jiang, Huarong Sun, Pan He, Chen Hu, Qiannan Lv, Xukui Zhang.Zhejiang Provincial CDC: Min Yu, Ruying Hu, Le Fang, Hao Wang. Tongxiang CDC: Yijian Qian, Chunmei Wang, Kaixue Xie, Lingli Chen, Yaxing Pan, Dongxia Pan.Hunan Provincial CDC: Yuelong Huang, Biyun Chen, Donghui Jin, Huilin Liu, Zhongxi Fu, Qiaohua Xu. Liuyang CDC: Xin Xu, Youping Xiong, Weifang Jia, Xianzhi Li, Libo Zhang, Zhe Qiu.Figure S1The location of ten survey sites in China Kadoorie Biobank (CKB).Figure S2Venn diagram showing the breakdown of sources for total COPD outcomes in China Kadoorie Biobank (CKB).Figure S3China Kadoorie Biobank (CKB) disease validation form for chronic respiratory diseases (CRD).Abbreviations: OSAS, obstructive sleep apnea syndrome; IHD, ischemic heart diseases; FEV1/FVC, forced expiratory volume in 1 second/forced vital capacity; DLCO, diffusing capacity of the lungs for carbon monoxide; CT, computed tomography; IgE, immunoglobulin E; PHD, Pulmonary Heart Disease; ID, identification."}
+{"text": "Leishmania species isolated from cutaneous lesions, there are still no records of visceral leishmaniasis in the state. However, studies on the sand fly fauna in this region are still limited.Notifications concerning American Cutaneous Leishmaniasis have increased in recent years in the state of Acre, Brazil. Despite identification of distinct Trichophoromyia auraensis, Nyssomyia whitmani, Nyssomyia antunesi, Pressatia choti, Evandromyia saulensis, Evandromyia walkeri, Evandromyia begonae, Migonemyia migonei, Pintomyia serrana, Psychodopygus paraensis, Sciopemyia sordelii, Migonemyia pusilla, Pintomyia nevesi, Brumptomyia avellari, Micropygomyia acanthopharynx, Micropygomyia micropyga, Pintomyia odax, Lutzomyia sherlocki, Pressatia calcarata, Pressatia duncanae, Bichromomyia flaviscutellata, Evandromyia bourrouli and Evandromyia bacula. From this group, Tr. auraensis and Ny. whitmani were the most abundant species in both forested areas and the peridomiciliary environment.Insects were collected from April 2011 to April 2012, using HP light traps distributed in four residential areas and one recreational area in Rio Branco, Capital of the State of Acre in the Amazon region of Brazil. A total of 456 sand flies were collected, comprising 256 females and 200 males. Taxonomic identification revealed 16 Phlebotominae genera and 23 species, as follows: Nyssomyia whitmani, Ny. antunesi and Bichromomyia flaviscutellata are known vectors of parasites responsible for cutaneous leishmaniasis, and Trichophoromyia auraensis is a putative vector in this Amazonian region.We find that the sand fly fauna in the urban and peri urban areas of Rio Branco is very diverse comprising 23 species, as diverse as that in areas of primary forest. Some species, such as  Leishmania species and a great diversity of these parasites are found in the Amazon Region. Except in primary forest areas in North Brazil and the Amazon region, Leishmania (Viannia) braziliensis is the main widespread etiologic agent of CL in the country , conNyssomyia whitmani, Ny. antunesi and Bichromomyia flaviscutellata are known vectors of parasites responsible for cutaneous leishmaniasis, and Trichophoromyia auraensis the putative vector in this Amazonian region.In summary, we found that the sand fly fauna in the urban and periurban areas of Rio Branco is very diverse with 23 species, as observed in other areas of primary forest. Some species such as"}
+{"text": "There is an error in affiliation 5 for authors Francesco Gianfagna and Licia Iacoviello. Affiliation 5 should be: Department of Epidemiology and Prevention, Laboratory of Molecular and Nutritional Epidemiology, Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Neurologico Mediterraneo Neuromed, Pozzilli, Italy."}
+{"text": "We describe a 74-year-old man with purpura fulminans and altered sensorium following an acute febrile illness. Intensive sepsis management was to no avail, until institution of doxycycline therapy following confirmation of scrub typhus. Empirical doxycycline needs to be considered in endemic areas for patients presenting with purpura fulminans. Orientia tsutsugamushi and Rickettsia africae, resp.) and eruptions which may be either macular, maculopapular, vesicular, or purpuric [Skin manifestations of rickettsial infections include eschars  is a triad of skin ecchymoses, infarction/necrosis, and hemorrhagic bullae which occurs due to both infectious and noninfectious causes . Accordialbicans . Congenialbicans , vasculialbicans , 4. Leptalbicans , malariaalbicans , and denalbicans  are somefatal PF , 10. Antof India \u201313. But Management of PF requires a multidepartment effort that involves physicians/pediatricians, surgeons, radiologists, nurses, and physiotherapists. Interventions such as debridement, fasciotomy, amputations, and thrombolysis may be sometimes necessary , 14. ForIn conclusion, PF is a potentially fatal dermatological emergency that requires intensive and multidisciplinary care. Purpura fulminans may be treated more appropriately by familiarizing oneself with prevalence of illnesses in the locality, which could reduce morbidity, mortality, and hospitalization stay. Although scrub typhus has been widely reported from many states in India, the exact prevalence is not known. Though Indian tick typhus much more commonly causes rickettsia-related purpuric eruptions, scrub typhus, by virtue of its prevalence in the tsutsugamushi triangle, should not be forgotten in the Indian subcontinent."}
+{"text": "Optical metrology provides full field, noncontact, precise measurement of various physical parameters of materials, structures, and devices. These properties include kinematic parameters , deformation parameters , surface parameters (shape and roughness), and mechanical properties of materials . Researchers have developed many delicate optical measurement techniques and methods, such as photoelasticity, holographic interferometry, speckle metrology, Moir\u00e9 methods, fiber sensing, laser Doppler vibrometry and velocimetry, and computer-vision-based techniques. However, new requirements arise with the recent development in fundamental research and industry applications to fulfill nondestructive and precise measurement under extreme conditions, such as high temperature or pressure, micro/nanoscale samples, large-scale curved structures, and transient events.It is our pleasure to have this opportunity to present the readers of The Scientific World Journal (SWJ) to some of the current research being performed in optical techniques and image processing under some extreme conditions. There are 10 papers in this special issue, which cover a broad range of topics from microscopic image analysis to nanoscale strain field research, from interfacial mechanical analysis to Raman spectroscopy detection, and from high temperature measurement to large-scale structure optical tracking and dynamical or transient optical metrology. All of the published papers are peer-reviewed.Xide LiXide LiGiancarlo PedriniGiancarlo PedriniYu FuYu Fu"}
+{"text": "In the original publication of this article , the seqPegah Khosrav, Vahid H Gazestani, Leila Pirhaji, Brian Law, Mehdi Sadeghi, Gary D Bader and Bahram Goliaei.In addition, Pegah Khosravi and Gary D Bader were both listed as joint corresponding authors of the article, however this was incorrect. Pegah Khosravi is the sole corresponding author for the article.Please note the affiliations for Brian Law and Gary D Bader were amended as above."}
+{"text": "AbstractTeredorus Hancock is reviewed. Two new species, Teredorus parvipulvillussp. n. and Teredorus hunanensissp. n. are described from China and an updated identification key to all known species of the genus is given, as well as brief comments on phylogenetic relationships, biology and ecology.Taxonomy of a tetrigid genus  PageBreakTeredorus was erected by Hancock in Teredorus stenofrons Hancock as its type species; it was collected from Peru in South America. Teredorus carmichaeli Hancock, 1915 and Teredorus frontalis Hancock, 1915 from India. Since Teredorus longipulvillus Zheng, 1988, Teredorus bhattacharyi Shishodia, 1991, Teredorus truncates Shishodia, 1991, Teredorus hainanensis Zheng, 1993, Teredorus wuyishanensis Zheng, 1993, Teredorus bashanensis Zheng, 1993, Teredorus guizhouensis Zheng, 1993, Teredorus prominemarginis Zheng & Jiang, 1993, Teredorus albimarginus Zheng & Zhou, 1996, Teredorus camurimarginus Zheng, 1998, Teredorus bidentatus Zheng, Huo & Zhang, 2000, Teredorus flatimarginus Zheng & Liang, 2000, Teredorus ebenotus Zheng & Li, 2001, Teredorus fujianensis Zheng & Li, 2001, Teredorus guangxiensis Zheng, Shi & Luo, 2003, Teredorus xishuiensis Zheng, Li & Shi, 2003, Teredorus flavistrial Zheng, 2006, Teredorus bipulvillus Zheng, 2006, Teredorus eurylobatus Zheng, Shi & Mao, 2010, Teredorus taibeiensis Zheng & Xu, 2010, Teredorus brachinota Zheng & Xu, 2010, Teredorus brachinotoides Zheng, Ou & Lin, 2012, Teredorus choui Zheng, Ou & Lin, 2012, Teredorus nigropennis Deng, Zheng & Lu, 2013. Additionally, Teredorus from China and adjacent countries, Systolederus grasveli G\u00fcnther, 1939 was transferred into the genus Teredorus Hancock and Teredorus truncates Shishodia, 1991 was transferred into the genus Systolederus Bolivar by them. Thus, to date, the genus includes 27 known species worldwide, distributed mainly in South America, China, India and Nepal.The genus Teredorus Hancock is considered as a member of the subfamily Tetriginae based on the following characters: the filiform antennae; width of frontal costa narrower than first segment of antenna; lateral lobes of pronotum turned downwards, posterior angles rounded; the first segment of posterior tarsi equal to or slightly longer than the third one.The genus Teredorus is problematic due to the absence of an identification key at the species level, so the original descriptions of the genus Teredorus are brief and imprecise. In this paper, the clarification of the taxonomic status of the genus Teredorus is revised and the utility of the characters used to diagnose is determined. In addition, Teredorus parvipulvillus sp. n. and Teredorus hunanensis sp. n. are described from China and an updated key to the species of Teredorus is given, as well as brief comments on phylogenetic relationships, biology and ecology.The identification of the genus Specimens examined are deposited in the following institutions: Institute of Zoology, Shaanxi Normal University, Xi\u2019an, China (IZSNU); School of Chemistry and Bioengineering, Hechi University, Yizhou, China (SCBHU).Photographs were taken with an Olympus digital camera with a series of images montaged using the program CombineZ5.3 .Tetriginae males are usually difficult to discriminate and thus the identification is usually done by association with females collected at the same time and place. Measurements are given in millimetres (mm). The specimens measured correspond to the material designated as holotypes, allotypes and paratypes.Morphological terminology and measurement landmarks method followed those of PageBreakTaxon classificationAnimaliaOrthopteraTetrigidaeHancock, 1906TeredorusTeredorus stenofrons Hancock, 1906, Southern America, by original designation.Size small or medium. Colour varying from ashy to brown and dark brown. body smooth, interspersed with granules.Head a little or not elevated above the pronotal surface; vertex very strongly narrowed toward the front drawing the eyes together and in front forming a triangular shape, median carinula distinct and not advanced in front of the eyes; face slightly oblique; frontal costa bifurcate just behind lateral ocelli, elevated and compressed between antennae, sinuate in front, moderately sulcate. Antennae filiform, located below the eyes. Eyes more or less globose or pear-shaped, a little or not elevated above the pronotal surface, drawing antero-medially to each other; lateral ocelli situated below middle of eyes.Pronotum anteriorly truncate, dorsum smoothly granulate, somewhat flattened, but subcylindrical, all the carinae low, median carina depressed or indistinct forward in front shoulders, posteriorly moderately distinct; prozonal carinae obsolete; humeral angles obtuse; pronotal process extend beyond apex of hind femora; lateral lobes of pronotum turned downwards, posterior angles rounded, posterior margin of each lateral lobe with two concavities. Elytra elongate, ovate with acuminate apex. Wings extended beyond the pronotal apex. Fore femora elongate, a little broadened, very finely serrated; middle femora elongate, broadened, bicarinate, margins finely serrated; hind femora elongate, a little crassate, margins finely serrated; first and third segment of hind tarsi equal in length, first pulvilli a little smaller than the second and third, second and third pulvilli equal in length.Teredorus is quite homogeneous, and this genus can be easily distinguished from other genera of the subfamily Tetriginae by vertex very strongly narrowed toward the front drawing the eyes together and in front forming a triangular shape.The morphology of Taxon classificationAnimaliaOrthopteraTetrigidaehttp://zoobank.org/4458D6D2-167F-439E-8203-D1F3771E09EESize small, slender. Length of body (from vertex to apex of hind process) 3.8 times as its width , head distinctly exerted above upper level of pronotum . In dorsDisc of pronotum smooth, with numerous small granules, mid keel of pronotum entire, upper margin of pronotum slightly undulating before shoulders and straight behind shoulders in profile . AnterioColouration. Disc of pronotum and head blackish-brown with numerous light marks , SCBHU (7\u26424\u2640).Holotype female and allotype male, China, Guangxi, Ningming, Aidian, Teredorus ebenotus Zheng & Li, 2001, from which it differs in: antenna inserted between lower margin of eyes; upper margin of pronotum slightly undulating before shoulders and straight behind shoulders in profile; posterior process of pronotum reaching apex of hind tibia; width of mid femur distinctly narrower than tegmina. Teredorus ebenotus Zheng & Li, 2001 exhibits antenna inserted below lower margin of eyes; upper margin of pronotum straight in profile; posterior process of pronotum reaching middle of hind tibia; width of mid femur equal to tegmina.This species can be easily distinguished from other species of the genus by inner side of hind tibia without spine; second pulvillus of posterior tarsus degenerated, distinctly smaller than first and third. It is only similar to parv and pulvillus, meaning second pulvillus of posterior tarsus degenerated and very small.The new species' name is derived from Latin The new species lives in moist stony on the border of streams in tropical rainforests.China (Guangxi).Taxon classificationAnimaliaOrthopteraTetrigidaehttp://zoobank.org/564AAF62-3BB8-4324-BEF2-3D916E448019Size small, slender. Length of body (from vertex to apex of hind process) 3.2 times as its width , head not exerted above upper level of pronotum . In dorsPageBreak, SCBHU (4\u26426\u2640).Holotype female and allotype male, China, Hunan, Yuanling, Jiemuxi National Nature Reserve, Teredorus flavistrial Zheng, 2006, from which it differs in: frontal ridge slight concave between lateral ocelli in profile; posterior process of pronotum reaching one third of hind tibia; width of mid femur equal to tegmina; first segment of posterior tarsus equal to third in length, three pulvilli of first segment of posterior tarsus equal in length. Teredorus flavistrial Zheng, 2006, exhibits frontal ridge straight before lateral ocellus in profile; posterior process of pronotum reaching apex of hind tibia; width of mid femur narrower than width of tegmina; length of first segment of posterior tarsus longer than third segment, third pulvillus of first segment of hind tarsi longer than the first and second pulvilli.This species is similar to The new species was named after the type locality, Hunan, China.The new species lives in moist stony on the border of streams in rainforests.China (Hunan).PageBreakTeredorus Hancock is based on characters from the external morphology exclusively. The morphology of Teredorus is quite homogeneous, and the species can be differentiated mostly by having vertex very strongly narrowed toward the front drawing the eyes together and in front forming a triangular shape. Recent molecular studies, based on Teredorus guangxiensis cytochrome c oxidase subunit I gene  to be closely related to the genus Systolederus Bolivar, 1887 (subfamily Metrodorinae)  , but FanTeredorus may be widely distributed all over the world, but they have not been collected and studied at present in most of continents, e.g. Africa, Europe, American Continent, etc.The genus shows a striking disjunct distribution, with its type species known from Peru in South America and other members of the genus from China, India and Nepal in Asia. We infer that PageBreakTetriginae (Teredorus parvipulvillus sp. n. and Teredorus hunanensis sp. n. clearly belong to this subfamily. We place two new species in Teredorus based on lateral lobes of pronotum turned downwards, posterior angles rounded. Additional characters support this placement, as pronotum generally not produced above head in front, antenna filiform, frontal costa moderately forked between antennae, not forming a frontal scutellum, its width narrower than the basic segment of antenna, usually separated by a sulcus.According to the diagnosis of the triginae , TeredorTeredorus are usually associated with, but not limited to, moist environments, living along the moist stony on the border of streams. Some have suggested that with the pronotum subcylindrical and smooth, the often flattened front and median limbs are used like paddles for swimming. Their diet consists mostly of algae growing on the moist stony surface, along with lichens and other forms of humus. They generally overwinter as adults. Teredorus are likely to disappear if environments become polluted or disturbed by human beings.Many species of the genus"}
+{"text": "The first four authors, Yanhui Jia, Zhao Zheng, Yunchuan Wang, and Qin Zhou, should be noted as contributing equally to this work. Weixia Cai is not included in this group of equal contributors."}
+{"text": "In the original publication, the first and last names of all the authors have been interchanged and published incorrectly.The correct names are as follows:Hayan Rammal, Philippe Gicquel, Ludovic Schneider, Claude Karger, Jean-Michel Clavert."}
+{"text": "The present paper aims to review the main pathophysiological links between red blood cell disorders and cardiovascular diseases, provides a brief description of the latest studies in this area, and considers implications for clinical practice and therapy. Anemia is associated with a special risk in proatherosclerotic conditions and heart disease and became a new therapeutic target. Guidelines must be updated for the management of patients with red blood cell disorders and cardiovascular diseases, and targets for hemoglobin level should be established. Risk scores in several cardiovascular diseases should include red blood cell count and RDW. Complete blood count and hemorheological parameters represent useful, inexpensive, widely available tools for the management and prognosis of patients with coronary heart disease, heart failure, hypertension, arrhythmias, and stroke. Hypoxia and iron accumulation cause the most important cardiovascular effects of sickle cell disease and thalassemia. Patients with congenital chronic hemolytic anemia undergoing splenectomy should be monitored, considering thromboembolic and cardiovascular risk. There are several criteria enabling the diagnosis of anemia. Hemoglobin below 13\u2009g/dL and 12\u2009g/dL in men and women, respectively, according to the criteria of the World Health Organization defines anemia.Anemia, a condition frequently associated with chronic diseases, is an independent risk factor for cardiovascular complications  and a 1\u2009The present paper aims to review the main pathophysiological links between red blood cell disorders and cardiovascular diseases, provides a brief description of the latest studies in this area, and considers implications for clinical practice and therapy. The present review will enable updating of the guidelines for the management of patients with both red cell disorders and cardiovascular pathology.Multimorbidity is common in patients with cardiovascular diseases . Prognos Cardiovascular compensatory consequences of anemia include tachycardia, increased cardiac output, a hyperdynamic state due to reduced blood viscosity, and vasodilation enabling tissue perfusion. Arterial dilatation involves also the recruitment of new vessels and formation of collaterals and arteriovenous shunts [Anemia causes hypoxia due to decreased hemoglobin level, and there are several nonhemodynamic  and hemodynamic compensatory mechanisms . The clis shunts , hypoxics shunts . Anemia s shunts . Increass shunts , 11. Tiss shunts .Anemia increases morbidity and mortality in cardiovascular diseases, due to compensatory consequences of hypoxia, such as a hyperdynamic state with increased cardiac output, left ventricular hypertrophy and progressive cardiac enlargement, and, probably, a proatherogenic role. chronic heart failure and is associated with an increased all-cause and cardiovascular mortality, reduced exercise capacity due to reduced oxygen carrying and storage capacity, impaired quality of life, a higher risk for hospitalization [Congestive heart failure is uncommon in patients with anemia without heart disease and may occur only in cases of severe anemia with hemoglobin of 5\u2009g/dL or less . Anemia lization , 13, femlization . The inclization  and due lization , 17.Anemia in patients with heart failure is often normochromic and normocytic, with a low reticulocyte count , 18. VitAnemia impairs prognosis in heart failure patients due to a reduced oxygen supply, ventricular remodeling, the neurohumoral profile, the proinflammatory state, and several comorbidities, including renal failure and cardiac cachexia. Probably, anemia is both a mediator and a marker of a poor outcome in heart failure .\u03bcg/L [Therapy includes iron, folic acid, blood transfusions, and erythropoiesis-stimulating agents (ESA). ESA may be considered as adjunctive therapy in patients with heart failure, improving, besides hemoglobin level, also left ventricular ejection fraction and functional class and reducing diuretic doses and left ventricular remodeling \u201332. EPO \u03bcg/L . Markers acute heart failure and is associated with poor outcome [Iron deficiency, defined as depleted body iron stores (low serum hepcidin) and unmet cellular iron requirements (high-serum soluble transferrin receptor), is common in outcome .The simultaneous presence of anemia, heart failure, and chronic kidney diseases forms a pathological triangle called cardiorenal anemia syndrome . The preThe main mechanisms of anemia in patients with heart failure are renal dysfunction, increased sympathetic and renin-angiotensin-aldosterone activity, hemodilution, absolute or functional iron deficiency, impaired erythropoietin production and activity, activation of the inflammatory cascade, angiotensin converting enzyme inhibition and angiotensin receptor blockade, and vitamin B12 and folic acid deficiency . Therapy ischemic heart disease and a frequent finding in patients with acute coronary syndrome [Anemia is a known risk factor forsyndrome \u201344. Multsyndrome . Severalsyndrome , 43, 46,syndrome , 48. A rsyndrome . A few ssyndrome . Thrombosyndrome .The anemia of inflammation can reduce hemoglobin within 1-2 days, due to hemolysis of red blood cells and a suppression of the response to erythropoiesis mediated by tumor necrosis factor and acute changes in iron metabolism , 51, 52.The prevalence of anemia increases during hospitalization. Both the admission hemoglobin level and the subsequent fall in hemoglobin level >1.8\u2009g/dL were associated with an increased risk of all-cause mortality or cardiogenic shock in patients with acute coronary syndrome . The mai erythrocyte membrane fluidity and cardiovascular events during long term follow-up [Sargento et al. evaluated the prognostic value of biohemorheological profile in transmural infarction survivors, revealing a close relationship between leukocyte count, protein C activity, andollow-up . Membranollow-up , 56. red cell distribution width (RDW), reflecting mean corpuscular volume heterogeneity, is an early parameter of iron deficiency, sideroblastic, vitamin B12, and folic acid deficiencies [Theciencies . In paticiencies . The menciencies . RDW wasciencies , 59. hemoglobin level and adverse cardiovascular outcomes in women with chest pain, in the absence of myocardial infarction or congestive heart failure, reporting a higher risk of death from any causes, a higher risk of adverse outcomes, and shorter survival time free of adverse outcome, but no correlation between hemoglobin level and presence or severity of coronary atherosclerosis [Freudenberger and Carson investigated the relationship betweenclerosis . hematocrit was less than 25% [It has been suggested to correct anemia in patients with coronary artery disease, if hemoglobin levels have fallen to 9-10\u2009g/dL in symptomatic angina . In sevethan 25% . Other athan 25% , 64. Thethan 25% . Well dethan 25% .Components of the complete blood count, such as hematocrit, white blood cell count, and their subtypes, are associated with coronary heart disease and can improve our ability to predict coronary heart disease risk . SeveralAn imbalance between oxygen demand and supply, bleeding episodes due to invasive procedures and anticoagulation, inflammation, hemodilution, and kidney failure are the main mechanisms linking anemia and coronary heart disease . Red bloNormocytic anemia is common among hypertensive patients. Lower hemoglobin concentrations were found in patients with uncontrolled than among those with well controlled hypertension, indicating a higher cardiovascular risk in uncontrolled hypertension . PatientAnemia is associated with higher cardiovascular risk, higher blood pressure values, and lower dipping status in hypertensive patients, and hemoglobin should be monitored in hypertensive patients.Several electrocardiographic changes were described in patients with anemia, including ST segment depression, T wave inversion, QT interval prolongation, and reduced amplitude of the QRS complex \u201372. A loBindra et al. reported both supraventricular  and ventricular arrhythmias  in patients with coronary heart disease and anemia . PatientProlonged QT intervals and arrhythmia risk are linked to anemia, macrocytosis, anisocytosis, serum ferritin, and hemoglobin, and hypoxemia supports these links.Stroke is the leading cause of adult disability and the third cause of mortality and has a high prevalence, considering the growth and aging of the population. Complete blood count abnormalities represent a useful tool for stroke patients' prognosis . A low hAnemia enables cerebral ischemia, blood flow turbulence, migration of a thrombus, and embolism and reduces penumbra oxygen reserves. Besides that, anemia was associated with increased mortality after ischemic and hemorrhagic stroke. beta-thalassemia, which explains the appearance of premature ventricular contractions, ventricular tachycardia, and late ventricular potentials [Thalassemia is the most common hereditary disease, a genetic blood disorder due to reduced synthesis of beta or alpha globin chains , 85. Regtentials , 89. Irotentials . Bradicatentials . Tachycatentials . The abstentials . Impairmtentials , 86. ECGtentials , 91. Wittentials . The cartentials . Thalasstentials . A protetentials , 95.The survival of patients with thalassemia major has improved lately, as a result of regular transfusions and chelation therapy and new imaging methods, which allow better management of iron overload . There aThe main cardiovascular effects of thalassemia are due to hypoxia and iron accumulation. Iron overload explains most cardiovascular problems in thalassemic patients, such as left ventricular systolic and diastolic dysfunction, reentry ventricular arrhythmias, atrial mechanical depression, myocardial fibrosis, vascular inflammation with early vascular aging, and hypercoagulability.Sickle cell anemia is caused by hemoglobin S, which changes the shape of the red blood cells from discs to sickles, reduces their deformability, and enhances stickiness, leading to obstructive adhesion of sickle cells . ReperfuMeloni et al. compared biventricular dimensions and function using cardiovascular magnetic resonance in pediatric, chronically transfused patients with sickle cell disease and thalassemia major and normal cardiac iron levels, reporting significantly greater biventricular dilation and left ventricular hypertrophy and lower left ventricular ejection fraction in the first group .Tantawy et al. investigated 50 young patients with sickle cell disease, revealing hypercoagulability, significantly higher aortic stiffness, and pulmonary artery pressure compared to healthy controls . The hypThe main cardiovascular effects of sickle cell disease are due to the rigid erythrocytes with hemoglobin S, impairing blood flow, enabling vasoocclusive crises, and explaining the appearance of myocardial infarction, stroke, microcirculation damage, and degeneration of the excitoconductor system. Sickle cell anemia is also associated with other cardiovascular complications, such as cardiac autonomic neuropathy, arrhythmias, tricuspid regurgitation, and increased arterial stiffness. Besides disordered hemoglobin structure and function, a prothrombotic state due to changes in the hemostatic system, such as thrombin activation, decreased levels of anticoagulants, impaired fibrinolysis, and platelet activation are also involved in the pathogenesis of sickle cell disease .Hereditary spherocytosis is the most common inherited hemolytic anemia , charactSplenectomy is recommended in patients with moderate and severe forms, considering that it results in near complete resolution of hemolysis . PersonsAnticoagulation prophylaxis and lipid lowering drugs should be considered after splenectomy in patients with chronic hemolytic disorders, besides postsplenectomy sepsis prophylaxis, especially if there is an additional high thromboembolic risk due to surgery or immobilisation .The presence of anemia is associated with a special risk for patients with any form of proatherosclerotic condition and heart disease. Anemia became a new therapeutic target in patients with cardiovascular pathology, improving oxygen supply. Guidelines must be updated for the management of patients with anemia and cardiovascular diseases, and targets for hemoglobin level should be established, in order to improve prognosis. Early primary care diagnosis, monitoring, and management of patients with anemia and cardiovascular morbidity and evaluation of iron, vitamin B12, folic acid, and nutritional status may be worthwhile. On the other hand, the unfavorable effects of therapy should also be considered, including blood pressure elevation, the prothrombotic effect, and increased viscosity. Risk scores in several cardiovascular diseases should include red blood cell count and RDW.Complete blood count abnormalities and hemorheological parameters represent useful, inexpensive, widely available tools for the management and prognosis of patients with coronary heart disease, heart failure, hypertension, arrhythmias, and stroke.The main cardiovascular effects of sickle cell disease and thalassemia are due to hypoxia and iron accumulation, respectively. Thromboembolic risk and lipid profile should be monitored after splenectomy in patients with congenital chronic hemolytic anemia."}
+{"text": "Plasmodium knowlesi infection) causes severe morbidity in Malaysia. Melioidosis has emerged as an important bacterial NTD, as have selected rickettsial infections, and leptospirosis. Leprosy, yaws, and trachoma are still endemic in focal areas. Almost 70 million cases of dengue fever occur annually in ASEAN countries, such that this arboviral infection is now one of the most common and economically important NTDs in the region. A number of other arboviral and zoonotic viral infections have also emerged, including Japanese encephalitis; tick-borne viral infections; Nipah virus, a zoonosis present in fruit bats; and enterovirus 71 infection. There are urgent needs to expand surveillance activities in ASEAN countries, as well as to ensure mass drug administration is provided to populations at risk for intestinal helminth and fluke infections, LF, trachoma, and yaws. An ASEAN Network for Drugs, Diagnostics, Vaccines, and Traditional Medicines Innovation provides a policy framework for the development of new control and elimination tools. Together with prominent research institutions and universities, the World Health Organization (WHO), and its regional offices, these organizations could implement important public health improvements through NTD control and elimination in the coming decade.The ten member states of the Association of Southeast Asian Nations (ASEAN) constitute an economic powerhouse, yet these countries also harbor a mostly hidden burden of poverty and neglected tropical diseases (NTDs). Almost 200 million people live in extreme poverty in ASEAN countries, mostly in the low or lower middle-income countries of Indonesia, the Philippines, Myanmar, Viet Nam, and Cambodia, and many of them are affected by at least one NTD. However, NTDs are prevalent even among upper middle-income ASEAN countries such as Malaysia and Thailand, especially among the indigenous populations. The three major intestinal helminth infections are the most common NTDs; each helminthiasis is associated with approximately 100 million infections in the region. In addition, more than 10 million people suffer from either liver or intestinal fluke infections, as well as schistosomiasis and lymphatic filariasis (LF). Intestinal protozoan infections are widespread, while leishmaniasis has emerged in Thailand, and zoonotic malaria ( ASEAN was founded in 1967 in order to promote economic and cultural development; to promote trade, agricultural, industrial, and scientific collaboration; and to promote peace and stability in the region ,3. The lThe countries that comprise ASEAN have experienced impressive economic growth in recent years. According to the Organization of Economic Cooperation and Development (OECD), the six major ASEAN economies\u2014Indonesia, Malaysia, the Philippines, Singapore, Thailand, and Viet Nam\u2014have averaged between 4.6% and 7.1% economic growth since 2011 (and as projected into 2015) [Neglected tropical diseases (NTDs) mostly affect people who live in extreme poverty; these diseases are also known to promote poverty even further because of their chronic and debilitating effects ,9. IndeeHelminthsCysticercosis/Taeniasis*Dracunculiasis (guinea-worm disease)Echinococcosis*Foodborne trematodiases*Lymphatic filariasis*Onchocerciasis (river blindness)Schistosomiasis*Soil-transmitted helminthiases*ProtozoaChagas diseaseHuman African trypanosomiasis (sleeping sickness)Leishmaniasis*BacteriaBuruli ulcer*Leprosy (Hansen\u2019s disease)*Trachoma*Yaws*VirusDengue/Severe dengue*Rabies**Major NTDs affecting ASEAN CountriesAdditional Major NTDs Affecting ASEAN CountriesStrongyloidiasis and ToxocariasisIntestinal Protozoan InfectionsPlasmodium knowlesiMalaria caused by MelioidosisJapanese EncephalitisNipah Virus InfectionEnterovirus 71http://www.who.int/neglected_diseases/diseases/en/, accessed July 20, 2014) human malaria species, with a large human focus first reported in 2004 from Sarawak, Malaysian Borneo, and, subsequently, elsewhere in Peninsular Malaysia and Southeast Asia (except Lao PDR) [P. knowlesi malaria is found in wild monkey populations, where it is the most common cause of clinical and severe malaria in Malaysia [While not ordinarily classified as an NTD, Southeast Asia faces a serious disease burden from malaria, with both  country . An esti country ,54. P. kLao PDR) \u201357. TodaMalaysia . There aMalaysia  recentlyOrientia tsutsugamushi), murine typhus (Rickettsia typhi), and members of the spotted fever group rickettsiae as important etiologies, as are leptospirosis (Leptospira spp.), salmonellosis , and melioidosis  [Tuberculosis (TB) is also not classified as an NTD, although WHO has determined that a high disease burden of TB occurs in six ASEAN countries\u2014Cambodia, Indonesia, Myanmar, the Philippines, Thailand, and Viet Nam . Cases oomallei) ,65. Indeomallei) \u201368. Whilomallei) , there aomallei) ,70, suchomallei) . Leptospomallei) .Dengue  and rabies are the two major viral NTDs. New estimates by Bhatt et al.  indicateP. knowlesi, toxoplasmosis, all of the bacterial NTDs other than leprosy, and all of the viral NTDs other than dengue fever. Only fragmentary information is available from local settings, with no national and/or regional burdens comprehensively assessed. This calls for urgent action to conduct active surveillance for these NTDs and to define the full extent of NTD-caused illnesses within the respective countries and collectively within the region. Efforts incorporating advanced tools, such as remote sensing or geographic information systems, as was initiated for the soil-transmitted helminth infections [A summary of the number of cases of the major NTDs affecting ASEAN is shown in fections , should Through integrated mass drug administration, there are needs to expand coverage for the soil-transmitted helminth infections, LF, schistosomiasis, and trachoma. Currently, the United States Agency for International Development (USAID) through its Neglected Diseases Program is supporting integrated mass drug administration for these diseases in the nations of Cambodia, Indonesia, Lao PDR, the Philippines, and Viet Nam . Given hFor many of the NTDs affecting the region though, new drugs, diagnostics, and vaccines are needed. Therefore, there is dire urgency to identify mechanisms for support of the development of such products even though return on investment may be through poverty reductions rather than more traditional mechanisms. Meaningful outcomes can be generated with active involvement of universities and biotechnology enterprises, which have the capabilities for translational research and development, especially in some of the major research institutes in Singapore, Malaysia, Thailand, and elsewhere, as well as through developing country vaccine manufacturers in Thailand, Indonesia, and Viet Nam. These activities must include efforts to engage innovative financing schemes through organizations such as the Asian Development Bank or the Malaysian Investment Development Authority (MIDA), among others. Great benefits have been achieved in the past through collaborative efforts such as the Regional Network on Asian Schistosomiasis and Other Important Zoonosis (RNAS+), founded in 1998. By strengthening the collaboration between control and research authorities in the region (and including China), RNAS+ now provides advice on regional strategies on the mobilization of resources with respect to multinational projects on several parasitic diseases in Southeast Asia, primarily schistosomiasis but also other helminth infections ,93. A neAlmost 200 million people live in extreme poverty in the ten ASEAN countries.Helminth infections are the most common NTD, especially the intestinal helminthiases and fluke infections.Plasmodium knowlesi infection is an important cause of severe malaria.Intestinal protozoan infections are widespread and Vector-borne bacterial and viral infections are major causes of morbidity and mortality in the region, as are Nipah virus and enterovirus 71 infection.An ASEAN Network for Drugs, Diagnostics, Vaccines, and Traditional Medicines Innovation (ASEAN-NDI) provides a policy framework for the development of new control and elimination tools.Ngui R, Lim YA, Chong Kin L, Sek Chuen C, Jaffar S. Association between anaemia, iron deficiency anaemia, neglected parasitic infections and socioeconomic factors in rural children of West Malaysia. PLoS neglected tropical diseases. 2012;6(3):e1550.Furst T, Keiser J, Utzinger J. Global burden of human food-borne trematodiasis: a systematic review and meta-analysis. The Lancet Infectious diseases. 2012;12(3):210\u201321.Moyes CL, Henry AJ, Golding N, Huang Z, Singh B, Baird JK, et al. Defining the geographical range of the Plasmodium knowlesi reservoir. PLoS neglected tropical diseases. 2014;8(3):e2780.Limmathurotsakul D, Dance DA, Wuthiekanun V, Kaestli M, Mayo M, Warner J, et al. Systematic review and consensus guidelines for environmental sampling of Burkholderia pseudomallei. PLoS neglected tropical diseases. 2013;7(3):e2105.Shepard DS, Undurraga EA, Halasa YA. Economic and disease burden of dengue in Southeast Asia. PLoS neglected tropical diseases. 2013;7(2):e2055."}
+{"text": "Drugs administered during the anaesthetic procedure and postoperative period belong to different pharmacological groups and are to ensure the best possible conditions for surgery and maximum safety of patients. Their adverse side effects are often dependent on immune responses. The diversity and number of the agents administered hinder precise determination of the drug eliciting the adverse drug reaction.Report 3 research cases of anaphylactic reactions during the perioperative period. The skin tests and provocation tests was realized on emergency service in the hospital, consentiment terms was obtained.Investigation of 3 adult patients anaphylactic reactions using general anesthesia in underwent surgeries, skin prick test and intradermal was performed with medications used during surgery and medications indicate by anaesthesiologists for next surgery. In case 1, skin prick test and intradermal with cefazolin, propofol, atracurium, fentanyl, morphine and oral provocation with dipirona e ibuprofen was performed, only morphine was positive. In case 2, skin prick test and intradermal with propofol, midazolam, etomidate, atracurium, suxa-methonium, rocuronium, fentanyl, remifentanyl, methadone and tramadol was performed, result atracurium, propofol, midazolam, tramadol and methadone was positive. In case 3, skin prick test and intradermal with propofol, atracurium, fentanyl, midazolam and morphine was performed, result atracurium and fentanyl was positive. The same protocol was used for drugs dilutions. Negative and positive controls was performed. The serum latex IgE was negative. All patients underwent surgery without positive drugs and none had positive reactions during procedure.Is possible to investigate intraoperative anaphylaxis outside the university hospital, ensuring patients safety at the next surgery."}
+{"text": "In the last decades, many reports have focused the attention on deleterious effects of novel environmental chemical compounds, including bisphenol A (BPA), on human health. BPA, a common and widely chemical contaminant acting as endocrine disruptor, accumulates in adipose tissue and may affect adipocyte metabolic and inflammatory functions. BPA, at low chronic doses, is now considered as an obesogen compound, and might contribute to the rise of metabolic syndrome, visceral adiposity and diabetes epidemics. The BPA worldwide presence in the environment is responsible for chronic exposure during vulnerable periods, such as foetal and neonatal life. The BPA source of contamination can occur via food, beverage, wastewater, air, dust and soil. BPA, as lipophilic compound, may accumulate into the adipose tissue already during foetal life and may affect adulthood health, through adverse effects on the growth and development of organs and tissues. Thus, based on several studies, it would be crucial to consider further actions aimed to refine risk assessment at least in vulnerable population, such as foetuses, infants and young children, to prevent metabolic diseases and obesity. Recent advances have confirmed the role of chemical environmental pollutants, together with excessive nutrients, in the global obesity epidemic, mainly via adipose tissue dysfunction and inflammation. In particular, these pollutants interfere with several function of endocrine system and so they are called endocrine disrupting chemicals (EDC). Among these compounds, bisphenol A (BPA), primarily used to make polycarbonate plastic and epoxy resins, could represent a causative link between chemical exposure and the \u201cobesogen hypothesis\u201d , 2, 4. BHuman BPA exposure is controversially discussed in non-occupational subjects. For its worldwide chronic presence, BPA is detectable in human serum, urine, amniotic fluid, placental tissue and umbilical cord blood , 5. The A modified synthesis of the most relevant sources of BPA reported in literature has been shown in Table\u00a0In humans, BPA chronic exposure, even at nanomolar concentrations, has been reported to be deleterious, mainly involving human reproduction, development, metabolic and inflammatory pathways , 2, 4\u20136.Besides these well-documented molecular mechanisms on adipose tissue, inflammation and glucose metabolisms, several biological effects have been attributed to low-dose environmental BPA exposure , 3\u20136 Ta, 3. Due The detrimental effects of BPA on tissue and organ development during foetal life are now well documented in literature, mainly in animal models Table\u00a0. In humaIt should be noticed that BPA doses, considered \u201csafe\u201d by the European Food Safety Authority (EFSA) , may reaConsidering the significant difference in BPA pharmacokinetic between animals and humans and in low-dose vs high-dose effects, additional in vivo and in vitro studies involving humans are needed to better define BPA metabolic effects. In particular, BPA deleterious effects should be better defined in vulnerable population, such as foetuses, infants and young children, where also cumulative with mixture of different environmental chemical pollutants may affect the correct tissue development and organogenesis. The embryonic critical window of exposure, can involve systemic metabolic homeostasis and adulthood health programming, in agreement with the new concept of \u201cdevelopmental origins of health and disease\u201d, which underlies foetal basis for adult diseases .In other words, BPA foetal/neonatal exposure levels, which may be responsible for increased human health risk, should not be underestimated. Current researches are in progress to sort the effect of foetal programming as a contributing factor in adult metabolic diseases, particularly in obesity, insulin resistance, metabolic syndrome and diabetic epidemics , 12.Thus, although all of these hypotheses need thorough examination, caution should be given by National and International Regulatory Agencies, on the potential deleterious role of BPA  but alsoIn humans, the continuous BPA chronic exposure from canned goods, drinking plastic packaging and thermal paper must be reduced. To avoid the contact between plastic containers and food and beverage, particularly during foetal/neonatal life, must be the future goal, for example by privileging fresh foods. Interestingly, France has recently abolished BPA from all packaging food, to reduce drastically the BPA intake. Safety guidelines should give more attention to the potential consequence in vulnerable people worldwide, also considering that the BPA environmental exposure is modifiable through behavioural changes. A reduction of BPA exposure can represent an attractive target for prevention of diseases which represent a serious problem of global proportion and economic and social emergencies, such as obesity, metabolic syndrome and diabetes."}
+{"text": "Anasa tristis (De Geer), is a major piercing/sucking pest of cucurbits, causing extensive damage to plants and fruits, and transmitting phytopathogens. No genomic resources to facilitate field and laboratory studies of this pest were available; therefore the first de novo exome for this destructive pest was assembled. RNA was extracted from insects challenged with bacterial and fungal immunoelicitors, insects fed on different cucurbit species, and insects from all life stages from egg to adult. All treatments and replicates were separately barcoded for subsequent analyses, then pooled for sequencing in a single lane using the Illumina HiSeq2000 platform. Over 211 million 100-base tags generated in this manner were trimmed, filtered, and cleaned, then assembled into a de novo reference transcriptome using the Broad Institute Trinity assembly algorithm. The assembly was annotated using NCBIx NR, BLAST2GO, KEGG and other databases. Of the >130,000 total assemblies 37,327 were annotated identifying the sequences of candidate gene silencing targets from immune, endocrine, reproductive, cuticle, and other physiological systems. Expression profiling of the adult immune response was accomplished by aligning the 100-base tags from each biological replicate from each treatment and controls to the annotated reference assembly of the A. tristis transcriptome.The Squash bug,  Anasa tristis (De Geer), is a major pest of squash, pumpkin, watermelon, cucumber and cantaloupe production, causing substantial economic losses throughout its range , and leucine-rich repeat proteins (A. tristis adults (The immune response is triggered by the presence of pathogen associated molecular patterns (PAMPs) such as bacterial cell wall or flagellar components in the presence of host damage associated molecular patterns and chemokines . Patternproteins . Elicitas adults .toll pathway responsive to gram-positive bacteria and fungi; the imd pathway responsive to gram-negative bacteria; and the JAK/STAT pathway which responds to bacterial or viral infection [imd pathway components identified were dFADD, JNK-interacting protein 1, JNK-interacting protein 3, .Although gene silencing entified . An orthentified . As therSerratia marcescens, the bacterial pathogen of Cucurbit yellow vine disease [Next generation sequencing approaches such as RNA-seq seem ideal methodologies to delineate and to sample the plant-pathogenic virome of plant feeding insect vectors such as squash bugs. Aphids and whiteflies are the major vectors of cucurbit viruses. Squash bugs are known vectors of  disease ,60,61. TA. tristis virome all reads from the combined RNA pools that did not align to the Trinity assembly were BLASTx screened against the NCBI gbvrl database resulting in 915 significant hits logged. Major taxa of insect viruses detected within these hits included ascoviridae, iridoviridae, granuloviridae, entomopoxviridae, baculoviridae, nudiviridae, even ichnoviridae and bracoviridae. Among these were sequences of plant infecting viruses sequences were detected of viroids, bromoviridae, closteroviridae, genimiviridae, luteoviridae, potyviridae, secoviridae, tombusviridae and virgaviridae. The presence of several of the 17 cucurbit associated viruses such as Cucurbit aphid-borne yellows virus, Melon yellow spot virus, and Papaya ringspot virus within the squash bug colony was indicated [A. tristis is warranted. Next generation deep sequencing of small RNAs extracted from infected cells or insects yields short interfering RNAs, which are products of the Dicer-dependent antiviral pathway, could enable the in silico reconstruction of viral transcripts or entire RNA/DNA virus genomes [in toto. Transcriptomes and genomes have recently been completed for several cucurbits [To obtain a preliminary survey of the ndicated . Transcr genomes ,65,66,67 genomes ,69. Viro genomes ,71, thei genomes ,73, thei genomes , and eveucurbits  which woucurbits . A. tristis immunotranscriptome, adults were subjected to microbial elicitation of the immune response. The resulting de novo assembly contained many A. tristis orthologs of immune system proteins known from other insect species, including those of phylogenetically related hemipterans. Key components of the entomopathogen recognition system, humoral and cellular immune responses, and second messenger regulatory networks were identified. Interestingly, a partial virome of A. tristis was noted within the de novo assembly, along with the presence of known insect transmitted bacterial species which will become the subject of future studies. Novel approaches are needed to target the unique mode of A. tristis feeding on the phloem of its cucurbit hosts. The de novo transcriptome generated in this report consists of the vast majority of transcript categories synthesized by this insect to support life processes, such as olfaction, neuroendocrinology, reproduction, digestion, and the immune response against bacterial and fungal elicitation. Targeted disruption of one or more of these transcripts, or the proteins that they encode, could reduce the severe economic impact of A. tristis on horticultural production.To construct a reasonably complete"}
+{"text": "Polyphenolic compounds are plant nutraceuticals showing a huge structural diversity, including chlorogenic acids, hydrolyzable tannins, and flavonoids . Most of them occur as glycosylated derivatives in plants and foods. In order to become bioactive at human body, these polyphenols must undergo diverse intestinal transformations, due to the action of digestive enzymes, but also by the action of microbiota metabolism. After elimination of sugar tailoring (generating the corresponding aglycons) and diverse hydroxyl moieties, as well as further backbone reorganizations, the final absorbed compounds enter the portal vein circulation towards liver (where other enzymatic transformations take place) and from there to other organs, including behind the digestive tract or via blood towards urine excretion. During this transit along diverse tissues and organs, they are able to carry out strong antiviral, antibacterial, and antiparasitic activities. This paper revises and discusses these antimicrobial activities of dietary polyphenols and their relevance for human health, shedding light on the importance of polyphenols structure recognition by specific enzymes produced by intestinal microbial taxa. Flavonoids are very abundant 15C secondary metabolites in plants, containing two aromatic rings (connected by a heterocycle pyrone ring), which are tailored with diverse hydroxyl moieties. Some are produced at chloroplasts as defense against oxidative damage generated during photosynthesis , at the  p-coumaric acid (by cinnamate-4-hydroxylase (C4H)), and its transformation in p-coumaroyl-CoA (by 4-coumaroyl-CoA ligase (4CL)) .. p-couma p-coumaroyl-CoA and three molecules of malonyl-CoA are used by the chalcone synthase (CHS) in order to generate a bicyclic chalcone as naringenin chalcone , at C3 , or at C7  positions. Most common bound sugars are glucose, galactose, rhamnose, xylose, rutinose, arabinopyranose, and arabinofuranose . These m\u03b2-glucosidase (CBG)  hydrolyze glycosylated flavonoids and then aglycones enter epithelial cells by passive diffusion    , linked  E. coli, B. lactis, and Lactobacillus gasseri , replication and reduction of HRV-induced cytopathic effectactivity  were fouactivity . Terminalia nigrovenulosa bark has shown strong antifungal activity against Fusarium solani and strong nematicidal activity against Meloidogyne incognita [Gallic acid purified fromncognita , 174.Lactobacillus, Eubacterium, and Bifidobacterium), as well as further transformations in these aglycones' level, giving rise to more stable bioactive compounds that are incorporated into the blood stream, as a vast array of benzoic acids, phenolic acids, urolithins, and the phytoestrogens (S)-equol, enterodiol, and enterolactone. In most cases, a complex network of different intestinal microbiota species is necessary for full biotransformation, whereas earlier and simple reactions as deglycosylation can be carried out individually by specific gut strains. The individual variability, at consumer level, with respect to richness, and biodiversity of own intestinal microbiota taxa are key determinants regarding the ability of a person to get the most fully bioactive derivatives from ingested polyphenols. Final absorbed bioactive derivatives have shown antimicrobial properties against viruses (as HBV), Gram-positive bacteria , and Gram-negative bacteria , but also against eukaryote species as fungi  or protozoans . Therefore, consumption of food with high levels of polyphenols, together with having appropriate gut microbiota diversity, is extremely important, in order to help in the fight against infectious diseases. Fermented dairy foods, as well as other ones with high levels of beneficial microorganisms, can therefore contribute to maintaining this appropriate gut microbiota diversity, facilitating intestinal production of bioactive metabolites from dietary polyphenols, as well as their absorption and bioavailability.Most polyphenol nutraceuticals from plant origin must undergo intestinal transformations, by microbiota and enterocyte enzymes, in order to be absorbed at enterocyte and colonocyte levels. This gives rise to diverse beneficial effects in the consumer, including a vast array of protective effects against viruses, bacteria, and protozoan parasites. These enzymatic transformations include elimination of glycosidic tailoring by gut microbiota of diverse genera ("}
+{"text": "Scientific Reports6: Article number: 19715;10.1038/srep19715 Published online: 01212016; Updated: 05112016The original version of this Article contained errors in the spelling of the authors Ghandi Anfoka, Adi Moshe, Lilia Fridman, Linoy Amrani, Or Rotem, Mikhail Kolot, Mouhammad Zeidan, Henryk Czosnek and Rena Gorovits which were incorrectly given as Anfoka Ghandi, Moshe Adi, Fridman Lilia, Amrani Linoy, Rotem Or, Kolot Mikhail, Zeidan Mouhammad, Czosnek Henryk and Gorovits Rena respectively.In addition, the \u2018How to cite this article\u2019 section quoted an incorrect abbreviation for Ghandi Anfoka.These errors have now been corrected in the PDF and HTML versions of the Article."}
+{"text": "We report a case of a 50-year-old female with diabetes mellitus who presented with progressive second, third, fifth, sixth, and eighth cranial nerve palsy. Diagnostic investigation revealed hyperglycemic state, and brain imaging showed a right cavernous sinus enhancement suggestive of and consistent with Tolosa-Hunt syndrome. The patient was started on steroids with tight glycemic control for eight weeks; subsequently, the cranial nerve palsies resolved as well as documented resolution of the right cavernous sinus enhancement. Tolosa-Hunt-like syndrome in diabetes mellitus is a challenging phenomenon that may pose a diagnostic dilemma and, subsequently, a treatment modality.A 50-year-old woman with an uncontrolled type II diabetes mellitus presented with right- sided eyelid droop, right facial weakness and sag, right-sided forehead paresthesia, and difficulty abducting the right eye for at least seven days. She also had chronic right eye blurry vision and a decreased right ear hearing acuity. She denied any weakness in her arms and legs, slurred speech, or difficulty swallowing. There is no history of sudden fall, trauma, camping, hiking, recent illness, sick contact, or recent travel. She also had history of hypertension, and it has been controlled. She has not been compliant with her diabetic regimen and, currently, was not taking glycemic medications upon presentation. She was nonsmoker, nonalcoholic, and nonillicit drug user. Her examination was remarkable for optic, oculomotor, trigeminal, facial, and vestibulocochlear dysfunction. Pupils were equally reactive to light and accommodation with no note of anisocoria. There was no appreciable diabetic nor hypertensive retinopathy changes on fundoscopy. Extraocular muscles were full and intact except for inability to fully abduct the right eye. There was significant right ptosis, right-sided facial droop, and decreased sensation to pain, touch, and temperature in the distribution of the ophthalmic division of the right trigeminal nerve. She has diminished hearing acuity on the right ear. Motor strength was normal symmetrically on her extremities. Vibration, proprioception, and sensation to other body parts have been intact. Deep tendon reflexes were normal. She was able to ambulate with steady gait with no note of ataxia or other cerebellar dysfunction. During her course, she also complained of pressure-like intermittent right-sided headache associated with steady periorbital pain with retroorbital extension.Her glycosylated hemoglobin was 12.4%, and her initial blood sugar readings range from 200 to 300\u2009mg/dL which improved to 100\u2013200\u2009mg/dL with initiation of insulin regimen. Investigatory laboratory studies were normal including complete blood count, comprehensive metabolic panel, lipid profile, thyroid function studies, coagulation studies, serum cyanocobalamin levels, serum rapid plasma reagin, human immunodeficiency virus antibody, serum angiotensin converting enzyme, toxoplasmosis antibody titer, cryptococcal antigen titer, cytomegalovirus deoxyribonucleic acid polymerase chain reaction, and anti-neutrophil cytoplasmic antibodies. Erythrocyte sedimentation rate was 38\u2009mm/hr, while C-reactive protein was normal. She had past exposure to Epstein-Barr virus and parvovirus, as evidenced by reactive IgG antibody titers. Cerebrospinal fluid studies were unremarkable including cell count, culture, angiotensin converting enzyme levels, acid-fast bacilli culture, Epstein-Barr virus polymerase chain reaction, lyme polymerase chain reaction, venereal disease research laboratory test, oligoclonal bands, myelin basic protein, and flow cytometry for lymphoma. Mantoux test was negative. Her chest, abdomen, and pelvis computed tomography were unremarkable. Brain magnetic resonance imaging showed abnormal enhancement involving the right cavernous sinus extending along the tracks of the right fifth, seventh, and eighth cranial nerves . Also, iTolosa-Hunt syndrome (THS) is a rare condition that is hallmarked by painful ophthalmoplegia described as recurrent unilateral orbital pain and ipsilateral third, fourth, and/or sixth cranial palsies which significantly improves with steroids. Tolosa in 1954 elucidated the syndrome's clinical features . The annThe onset of the disease is the continuous pain induced by pressure and dysfunction of the structures within the cavernous sinus, superior orbital fissure, or the apex of the orbit. Ophthalmoparesis ensues when granulomatous inflammation in the cavernous sinus extends to oculomotor, trochlear, and abducens cranial nerves, whereas paresthesia of the forehead occurs with involvement of the superior division of the trigeminal nerve. Seventy-five percent of patients who manifest painful ophthalmoplegia will not have the diagnosis of THS , 5. PainThe concomitant occurrence of Tolosa-Hunt syndrome and diabetes mellitus especially if poorly controlled has not been clearly elucidated and reported. Cranial neuropathies in diabetic patients are extremely rare and occur in older patients with poorly controlled diabetes . HyperglThe syndrome has been characterized by episodic orbital pain accompanied by paralysis of the oculomotor, trochlear, and/or abducens cranial nerves that tends to resolve spontaneously but may remit and relapse . The paiSpecific diagnostic criteria have been recommended by the International Headache Society which includes unilateral headache; granulomatous inflammation of the cavernous sinus and superior orbital fissure or orbit seen on magnetic resonance imaging or biopsy; paresis of one or more of the ipsilateral third, fourth, and/or sixth cranial nerves; evidence of causation demonstrated by both headache preceded by oculomotor paresis by less than 2 weeks or developed with it and headache that is localized around the ipsilateral brow and eye; and symptoms not better accounted for by an alternative diagnosis . The diaCorticosteroid has been utilized for diagnostic purposes as well as therapeutic modality and the rapid response to pain relief within a day and up to three days assists in committing to the diagnosis , 21, 22.Tolosa-Hunt-like syndrome in DM necessitates early initiation of corticosteroids with tight glycemic control to resolve symptoms and prevent neurological sequela especially cranial nerve palsies."}
+{"text": "The lacrimal gland plays an important role in maintaining a homeostatic environment for healthy ocular surfaces via tear secretion. Dry eye disease, which is caused by lacrimal gland dysfunction, is one of the most prevalent eye disorders and causes ocular discomfort, significant visual disturbances, and a reduced quality of life. Current therapies for dry eye disease, including artificial tear eye drops, are transient and palliative. The lacrimal gland, which consists of acini, ducts, and myoepithelial cells, develops from its organ germ via reciprocal epithelial-mesenchymal interactions during embryogenesis. Lacrimal tissue stem cells have been identified for use in regenerative therapeutic approaches aimed at restoring lacrimal gland functions. Fully functional organ replacement, such as for tooth and hair follicles, has also been developed via a novel three-dimensional stem cell manipulation, designated the Organ Germ Method, as a next-generation regenerative medicine. Recently, we successfully developed fully functional bioengineered lacrimal gland replacements after transplanting a bioengineered organ germ using this method. This study represented a significant advance in potential lacrimal gland organ replacement as a novel regenerative therapy for dry eye disease. In this review, we will summarize recent progress in lacrimal regeneration research and the development of bioengineered lacrimal gland organ replacement therapy. Advances in regenerative medicine, influenced by our understanding of developmental biology, stem cell biology, and tissue engineering, are expected to underlie next-generation medical therapies ,2,3. Regin vitro three-dimensional cell manipulation, is one of the ultimate goals for regenerative medicine: the replacement of dysfunctional organs arising from disease, injury, or aging [in vitro, through the precise arrangement of several different cell species and organ culture methods, is required to realize the next generation of three-dimensional, functional, bioengineered organ replacement regenerative therapy [Clinically transplanting donor organs is an important therapeutic approach for severe organ dysfunctions; however, there are related medical issues, including allogenic immunological rejection and critical donor shortage . The useor aging . Develop therapy .This review details the physiological functions, diseases, and development of the lacrimal gland obtained from published stem cell research. We illustrate that there is potential for novel, fully functional lacrimal gland regeneration as a next-generation regenerative medicine ,23.The lacrimal glands are essential for maintaining the physiological function and homeostasis of the ocular surface microenvironment via tear secretion ,25. The Dry-eye disease (DED) is caused by a tear shortage due to lacrimal gland dysfunction that results from systemic diseases and environmental exposures, such as Sjogren\u2019s syndrome and ocular cicatricial pemphigoid, or other causes, including aging, long-term work with visual displays, the use of contact lenses, low-humidity environments, and refractive surgery ,47,48,49Organs, including the lacrimal glands, are functional units composed of various cells with the appropriate three-dimensiona histological architecture, which is achieved through developmental processes in the embryo, to work efficiently. Almost all ectodermal organs, such as teeth, hair follicles, and lacrimal glands, exhibit similar embryonic development from their organ germs that involves reciprocal epithelial and mesenchymal interactions . Branchiin vivo [To restore lacrimal gland function, several therapeutic approaches have been reported, such as ectopic salivary gland transplantation in vivo ,68 and rin vivo . Secretoin vivo ,71, and in vivo , can selin vivo ,74. For in vivo ,79,80,81in vivo , c-kit-pin vivo , salivarin vivo . For stein vivo ,82. Tissin vivo ,84,85,86in vivo ,88. Tissin vivo ,90.in vitro as an organ engineering technology (To further these biological technologies, the development of methods for the manipulation of multiple cells is required to realize three-dimensional organ regeneration for functional bioengineered organ replacement therapy . A novelchnology a,b [91,9chnology c,d [91,9in vitro. Bioengineered harderian gland germs were also regenerated via the organ germ method (We investigated whether our organ germ method could regenerate a bioengineered lacrimal gland and restore its physiological function. The bioengineered lacrimal gland germ, which was reconstituted using the epithelial and mesenchymal cells from the lacrimal gland germ of an ED 16.5 mouse, successfully developed branching morphogenesis followed by stalk elongation and cleft formation in organ culture m method a.in vivo orthotopic or ectopic transplantation.A duct association between the bioengineered lacrimal gland and the mouse receiving the ocular surface discharge is required for tear secretion from the bioengineered lacrimal gland. The bioengineered lacrimal gland germ and the bioengineered harderian gland germ were successfully engrafted to a mouse from which an extra-orbital lacrimal gland had been removed, and the bioengineered lacrimal gland duct was connected to the recipient lacrimal excretory duct using our thread-guided transplant method b,c. AfteReconstituting neural pathways between the bioengineered lacrimal gland and the recipient\u2019s neural system is important to protect the ocular surface via restored tear secretion ,100,101.Protecting the ocular surface is the main purpose of using the bioengineered lacrimal gland to restore lacrimal gland function. Punctate staining of the impaired area on the ocular surface ,116 and Bioengineered lacrimal gland germs exhibit appropriate physiological functions, such as tear secretion, in response to nervous stimulation and ocular surface protection. These studies are a proof-of-concept for bioengineered organs that can functionally restore the lacrimal gland. Our bioengineered organ regeneration concept, which has also been applied to salivary gland regeneration , provide"}
+{"text": "Phoniatrics is the medical specialty for communicative disorders. It is related with the normal, pathological, and professional processes that involve voice, speech, language, swallowing, and hearing. Besides being a specific discipline, it is also a discipline that combines the accumulation of knowledge from both medical and nonmedical fields of science. Most important medical specialties that contribute to phoniatrics are otorhinolaryngology, neurology, pediatrics, psychiatry, pediatric psychiatry, dentistry, gastroenterology, geriatrics, endocrinology, radiology, genetics, and physical therapy. Otorhinolaryngology (ORL) Section and Board of European Union of Medical Specialists (UEMS) decided \u201cphoniatrics\u2014communication disorders\u201d as one of the seven subspecialities of otorhinolaryngology in 2010 [ voice ranges from acoustics and aerodynamics, to the biomechanics of voice, articulation, and resonance, to voice training, vocal ergonomics, and vocal hygiene, to the complex neurologic, psychiatric, and sociological basis of interpersonal communication. The incidence of voice disorders in the general population is considered between 3% and 9% [The field of% and 9% , 3. This% and 9% . These rUnderstanding vocal production is a crucial step in diagnosing and treating voice ailments. In this issue, you will find an article by A. A. Poznyakovskiy et al. that discusses the importance of vocal tract morphology in voice production by using a 3-tesla magnetic resonance imaging model. They showed that the method is suitable for an improved in-detail analysis of the vocal tract morphology during speech and singing. The development of new diagnostic tools continues to improve our ability to properly identify vocal pathologies. To this end, E. Gonzalez-Moreira and colleagues discussed the utilization of computational speech analysis to identify dementia in elderly patients. Also in this issue, L. Moro-Vel\u00e1zquez and colleagues discuss the efficacy of automatized evaluation of subjective voice parameters by modulation spectra morphological parameters. They demonstrate efficiencies of 81.6% and 84.7% for Grade and Roughness, respectively, using modulation spectra parameters. In another article, L. M. T. Jesus et al. pointed out the acoustic correlates of compensatory adjustment in vocal fold paralysis patients. Proper understanding and diagnosis lead to optimization of vocal restoration. This issue shares several modern methods of managing laryngeal pathology. B. Svensson and colleagues continued to work on restoring vocal fold function after injury in an animal study. In their study they have shown that human embryonic stem cells transplanted to injured rabbit vocal folds restored their vibratory characteristics. H. K. Byeon and colleagues reported their experience with pulsed dye laser in treatment of hemorrhagic vocal fold polyps. It was shown that PDL-assisted enucleation laryngeal microsurgery for the treatment of hemorrhagic vocal polyps can be a safe and effective surgical technique, with improvements in subjective voice perception. Speech and Language Disorders Encompass Articulation Disorders. Diagnostics, evaluation methods, intelligibility, motor examination, nasalance, preventive counselling, speech therapy, and medical and surgical treatment; developmental language disorders: psychomotor, cognitive, auditory, and language development of normal and diseased children, evaluation of verbal and nonverbal communication, psychomotor, vestibular, and kinesthetic development and disorders, prevention, and rehabilitation; acquired language disorders: evaluation of verbal and nonverbal communication, speech perception, speech and motor evaluation, neurological, laboratory and radiological examination, rehabilitation, and treatment are all discussed. The first human speech dates to at least 50,000 years ago [ears ago . The preears ago . The preears ago . Anyone ears ago , 3. Stutears ago . In the Swallowing Disorders. Diagnosis, developmental stages of swallowing, drooling, penetration, retention, regurgitation, aspiration, endoscopic and radiological evaluation, rehabilitation, and medical and surgical treatment are all discussed. Swallowing disorders are seen more frequently in the elderly. The prevalence of solid food dysphagia is 7% in elderly patients [patients . This mapatients . Untreatpatients . Hearing Disorders. Physiology and pathology of hearing, tympanometry, audiological evaluation, otoacoustic emission, evoked response audiometry, sensorineural, conductive, and mixed hearing loss, diseases of external, middle, and inner ear, diseases of cochlear nerve, brainstem, and auditory cortex, auditory processing disorders, cochlear implants, hearing aids, prevention, medical and surgical treatment, rehabilitation, and tinnitus are all discussed. According to World Health Organization estimates, 5.3% of world's population have disabling hearing loss [ing loss . 9% of ting loss . The art"}
+{"text": "In most cases, it passes through the gastrointestinal tract spontaneously and does not cause any considerable damage. When the impaction occurs in the gastrointestinal tract, the most common level is the upper third of the esophagus. Approximately 10-20% of the cases requires endoscopic intervention and less than 1% needs some surgical procedureMale, 52, alcoholic and user of crack, previously healthy. Accidentally swallowed a Soy fish of approximately 15 cm. It quickly progressed with hematemesis and respiratory failure before medical care. At the emergency room, it was observed respiratory arrest, being promptly intubated and laryngoscopy displayed the foreign body to the cervical esophagus. He was subjected to mechanical ventilation and remained hemodynamically stable. Endoscopy was performed soon after stabilization, but without success due to an intense inflammatory process and total occlusion of the esophageal lumen by the foreign body. Cervical and thoracic computed tomography showed the whole fish on cervical esophagus . The patThe greater part of foreign bodies (80%) pass through the gastrointestinal tract without difficulties, but 20% can obstruct the lumen, requiring endoscopic or surgical removal (1% of cases). As the esophagus is a narrow portion of the gastrointestinal tract, 28-68% objects are found in this region,A medical review of database present several accidents involving foreign bodies ingestion, including food-bolus impactions, coins, fish bones, dental prostheses, chicken bones, iron slices, lighters, little metallic foreign bodies, toothbrushes, needles, and spoons"}
+{"text": "Histoplasma capsulatum (H. capsulatum, and the CT scan showing involvement of both adrenals.A 40-year-old gentleman from West Bengal, who is a farmer by profession, presented with easy fatigability, significant loss of weight, and asymptomatic, progressive nodulo-ulcerative lesions on his groins of 1 year duration. He gave no history of exploring caves or exposure to any large areas contaminated with bird droppings. General examination revealed firm, non-tender, discrete cervical, axillary, and inguinal lymphadenopathy. Systemic examination was within normal limits. Cutaneous examination showed dull erythematous, non-tender, and firm papules and nodules, few with central ulceration on both groins (psulatum \u20137.BloodH. capsulatum. Histoplasmosis is endemic in the Ohio and Mississippi River Valleys of the United States, central and South America, and Africa, but is less frequently reported in Asia and Europe.Histoplasmosis is a highly infectious mycosis caused by an intracellular fungus"}
+{"text": "To the Editor: Zika virus (ZIKV), a mosquito-borne flavivirus, causes Zika fever, a self-limiting febrile and exanthematic arthralgia syndrome closely resembling dengue fever. Most often, signs and symptoms are maculopapular rash, fever, arthralgia, myalgia, headache, and conjunctivitis; edema, sore throat, cough, and vomiting occur less frequently (Macaca mulatta) in 1947 in Uganda, has come to attention recently after a large outbreak occurred in the western Pacific region, including French Polynesia, New Caledonia, Easter Island, and the Cook Islands , but liver function test and complete blood count results were within reference range. During the next 3 days, the fever subsided, but the patient experienced a sore throat, bilateral conjunctivitis, and a burning sensation of the palms and soles. These symptoms were accompanied by swelling of the hands and increasing arthralgia of the wrists, palms, and fingers. There was no lymphadenopathy. An indirect immunofluorescence assay for ZIKV . An indiTwo days later, the patient experienced sudden bilateral dull and metallic hearing; in her left ear, she experienced a very short delay between a sound and her perception of the sound. Follow-up ZIKV serologic testing on day 11 of illness showed a decreased IgM titer of 1:160 and an increased IgG titer of 1:2,560 . Viral nDuring her journey to several cities and villages in Sabah, Malaysian Borneo, the patient had noticed several mosquito bites even though she had used repellents. She had stayed in hotels, private homes, and remote church homes under various conditions .,,,,Ae. aegypti mosquitoes in peninsular Malaysia in 1969 (Pongo pygmaeus)  (Neurologic complications of ZIKV infections had previously been reported only as Guillain-Barr\u00e9 syndrome, and hearing difficulties in Zika fever patients have not been reported. Because this symptom resolved spontaneously, no audiometry or auditory brainstem response testing was performed, and the cause of the disorder remains unclear. Because of increasing travel and migration and heightened clinical and laboratory awareness, more ZIKV infections are likely to be diagnosed outside of epidemic events.Travel itinerary of a patient with Zika fever."}
+{"text": "Scientific Reports6: Article number: 2109410.1038/srep21094; published online: 02192016; updated: 04202016.The original version of this Article contained errors in the spelling of the authors Jana Ninkovic, Vidhu Anand, Raini Dutta, Lisa Koodie, Santanu Banerjee and Sabita Roy which were incorrectly given as Ninkovic Jana, Anand Vidhu, Dutta Raini, Koodie Lisa, Banerjee Santanu and Roy Sabita. These errors have now been corrected in the PDF and HTML versions of the Article."}
+{"text": "The patient recovered rapidly and without complications.A 28-year-old, otherwise healthy Chilean man presented in December 2015 with fever, headache, and myalgia. He had returned, 2 days ago, from a tourist trip to Colombia, where he had visited Bogota and the northern region including Cartagena de Indias, Santa Marta, and Tayrona National Park. During his return, he suffered nonspecific symptoms including sore throat, anorexia, and myalgia. A day later, he noted high grade fever and tender nodules behind his ears (Aedes genus. However, the virus is also transmitted by blood transfusion and, as recently suggested, by contact with infectious semen.Since 2015, ZIKV is rapidly emerging within the Americas, where it is disseminated by mosquitos of the"}
+{"text": "PLOS ONE Editors retract this article [The  article  because RS, DS, AKS, SD, KB, PM, MJA, and RD did not agree with the retraction. SHS and PMB either did not respond directly or could not be reached."}
+{"text": "Previous research has found higher levels of educational attainment to be strongly associated with better health outcomes in later life, such as better cognitive functioning and fewer functional and sensory impairments. However, most studies have grouped General Educational Development (GED) recipients with high school graduates, neglecting potential differences in socioeconomic status, health behaviours, and health outcomes among these two groups. The aim of the current study is to identify differences in the age-sex-race-poverty adjusted prevalence and odds of cognitive impairment, hearing impairment, vision impairment, limitations in activities of daily living (ADLs), and ambulation limitations among three groups of older American adults: high school dropouts, GED recipients, and high school graduates with no post-secondary education. The present study uses secondary analysis of the 2017 American Community Survey, a nationally representative survey of community-dwelling and institutionalized older adults aged 65 years and older, of whom 20,489 were GED recipients, 154,892 had a high school diploma and 49,912 had finished grade 8 but had not completed high school. Our findings indicate that there is a gradient in health outcomes among Americans aged 65-84, with the highest prevalence and odds of cognitive impairment, hearing impairment, vision impairment, ADL limitations, and ambulation limitations occurring among high school dropouts, followed by GED recipients, and the lowest prevalence among high school graduates. These findings suggestion that although GED recipients have better health outcomes than high school dropouts, there is still a significant disparity in health status between GED recipients and high school graduates."}
+{"text": "Ehlers-Danlos syndrome (EDS) is a group of hereditary disorders characterized by fragility of connective tissue. Clinical manifestations of the disorder involve the skin, joints, blood vessels, and other internal organs. We report the case of a 29-year-old female suffering from EDS and mast cell activation syndrome (MCAS). Her history includes multiple orthopedic surgeries leading to the worsening of her symptoms. This was determined to be due to medical implants placed during her multiple procedures predisposing her to severe immunological reactions. This case report emphasizes the importance of meticulous surgical intervention when managing patients with EDS. Ehlers-Danlos syndrome (EDS) comprises a heterogenous group of connective tissue disorders. It is classified into six main types including classical, vascular, hypermobile, arthrochalasis, kyphoscoliotic, and dermatosparaxis with different mutations in the gene responsible for the synthesis of collagen. Clinical presentation is variable; but is not limited to skin hyperextensibility, impaired wound healing, ecchymosis and hematomas, joint hypermobility, vascular fragility, and gastrointestinal (GI) symptoms\u00a0. The preThe patient in the case presented was struggling with hypersensitivity reactions to medical implants from her extensive orthopedic surgical history related to progression of EDS. MCAS is a known complication documented in patients with EDS. After careful removal of polymer clips left over from a cholecystectomy performed five years ago, the patient reported resolution of all hypersensitivity reaction symptoms without any postoperative complications. This case study reviews the importance of noninvasive surgical intervention in a patient with EDS to avoid complications such as bleeding and spontaneous perforations\u00a0.\u00a0A 29-year-old Caucasian female patient presented to the surgery out-patient clinic requesting for foreign body removal. The patient was diagnosed with EDS and MCAS when she was a child. During her lifetime, the patient has suffered from endless anaphylactic reactions due to immunological hypersensitivity of MCAS. According to the patient, her clinical symptoms include nausea, vomiting, constipation, intestinal swelling, migraines, facial edema,\u00a0hives, acne, fatigue, bloating, fever, chills, night sweats, and acute pulmonary inflammatory reactions. The patient stated that she has had subclinical symptoms of MCAS since childhood that became more problematic when she reached puberty. The patient\u2019s past medical history is remarkable for EDS, MCAS, postural orthostatic hypotension, mitral valve regurgitation, tricuspid valve regurgitation, atrial fibrillation, brain fenestration , pineal gland cyst, migraines, cystinuria, hypothyroidism, anemia, hypokalemia, vitamin B-12 deficiency, menorrhagia, celiac disease, osteopenia in the right hip, bowel hypomotility, post-traumatic stress disorder (PTSD), mild urinary bladder prolapse, and MCAS-induced asthma. The patient\u2019s past surgical history includes tonsillectomy, lithotripsy, plica shelf removal of right knee, medial patella-femoral ligament (MPFL)\u00a0reconstruction\u00a0and lateral\u00a0patella-femoral ligament (LPFL)\u00a0reconstruction\u00a0cadaver graft and stabilization of right knee, peroneal tendon cadaver graft and deltoid debridement of left ankle, peroneal tendon cadaver graft of right ankle, hardware removal and replacement of right ankle, labrum repair of right hip, labrum hardware removal of right hip, 360 degree labrum repair of right shoulder, hardware repair and replacement of right shoulder, 360 degree labrum repair of left shoulder, cholecystectomy, and gallbladder clip removal.According to the patient, allergies include plastic and synthetic surgical materials, latex, plastic medical tape, soy, lecithin, gluten, wheat dextrin and wheat derived maltodextrin, seafood, mold, nickel, butter, sea salt, beef, tomatoes, watermelon, kiwis, banana, yellow #5, eggs, cheese, and phytoestrogens. She also reports hypersensitivity reactions to the flu vaccine, amoxicillin, Augmentin, Bactrim, Betadine, Bystolic, Cefaclor, Corlanor/ivabradine, duloxetine, gabapentin, iodine, ketotifen fumarate, Marcaine HCl/bupivacaine, methylprednisolone, midodrine, Motegrity, Norco, propranolol, pyridostigmine bromide, ranitidine, and tramadol. Currently, the patient\u2019s medications include acetaminophen/butalbital, Allegra-D, Ativan, Benadryl, Bisoprolol, buffered salt tablets, calamine, cromolyn sodium, desonide cream, topical drysol, Epi-pen, Errin, fludrocortisone, glucose tabs, Linzess, loratadine, montelukast, mupirocin, naproxen, olopatadine, Pennsaid, Pepcid, Percocet, Plaquenil, potassium chloride, quercetin, Robaxin, triamcinolone cream, Ubrelvy, IM B12, Xolair injections, Xyzal, Zofran, Zyrtec, and toradol injections. Family medical history includes maternal EDS. She has no history of smoking or alcohol use.\u00a0Due to the pathological progression of EDS, the patient underwent multiple orthopedic procedures for her hip, knee, shoulders, and ankles. After the procedures, she started having worsening symptoms such as increased joint pain and facial swelling. After looking through the patient\u2019s past medical and surgical history, her immunologist concluded that the aggravation of symptoms was strongly associated with medical implants placed during the procedures that triggered mast cells to initiate an immune response. The patient was advised to remove the foreign bodies which were implanted. This report highlights the removal of three Weck clips that were placed during her cholecystectomy.\u00a0On the day of the operation, she was taken to the operating room, and prepped under general anesthesia. At this time, pneumoperitoneum was obtained periumbilically, and the abdomen was explored. Epigastric, midepigastric, and right mid quadrant ports were placed percutaneously under direct vision. During the procedure, fluoroscopy was utilized and there was no evidence of metal clips in the right upper quadrant. Next, the gallbladder fossa was examined where three separate Weck clips were found. Two clips were located on the cystic duct and one on the cystic artery. All clips were removed and sent to pathology Figure . No bleePatients with EDS display a diversified group of conditions characterized by skin hyperextensibility, atrophic scarring, joint hypermobility, and generalized tissue fragility\u00a0-8. ThereMast cell activation syndrome refers to a group of disorders with diverse causes involving the skin and multiple organ systems such as the gastrointestinal, cardiovascular, respiratory, and neurologic systems. MCAs can also be classified as primary, secondary, and idiopathic. Criteria of diagnosis are based on insult on two or more organ system with urticaria, angioedema, flushing, nausea, vomiting, diarrhea, abdominal cramping, hypotensive syncope, tachycardia, wheezing, conjunctival injection, pruritus, and nasal stuffiness\u00a0.\u00a0The cliTreatment modalities for MCAS mainly revolves around supportive care. Symptoms of MCAS can be managed by blockade of mediator receptors , inhibition of mediator synthesis , mediator release (sodium cromolyn), and anti-IgE therapy\u00a0. Other mOther studies have well documented the association between EDS and MCAS; according to a studies conducted by Wang\u00a0et al.,\u00a0a total of 195 medical records of demographics of the patients and diagnoses of POTS, EDS, or MCAS were recorded.\u00a0The percentage of MCAS within the group of POTS and EDS was 31% in comparison with 2% within the non\u2010POTS and EDS group. The 95% confidence interval calculated for the MCAS in the POTS and EDS group did not overlap with 2%, which showed a statistically significant result. There was a marked percentage of MCAS among the patients with diagnoses of POTS and EDS\u00a0.Among the most common complications of surgical treatment associated in patients with EDS are vessel ruptures and spontaneous perforations. Therefore, careful preoperative indications should be considered when evaluating patients with EDS for surgical treatment. Moreover, clinicians need to be aware of patients\u2019 past medical history and prior history of MCAS. Often, a nonsurgical approach can be the best treatment approach\u00a0for these patients, depending on the condition\u00a0.Previous studies have documented the use of the Weck polymer clips during laparoscopic intervention and their efficacy over the use of metal automatic clip appliers\u00a0, 14. TheEhlers-Danlos syndrome is a diversified group of connective tissue disorders with varying manifestations including hypermobility EDS and vascular EDS, which are characterized by defective collagen synthesis and processing. Symptoms include different degrees of hyperextensive skin, joint hypermobility, and tissue fragility. MCAS refers to a group of disorders with diverse causes presenting with symptoms involving multiple organ systems and the skin as the result of mast cell mediator release.\u00a0We reported a rare case of hypersensitivity to permanent polymer clips placed during a cholecystectomy in a patient with EDS with\u00a0a turbulent medical history of MCAS. This case report provides valuable insight to clinicians in the management of patients with EDS and history of MCAS with prior surgical intervention using polymer clips. Despite introduction of diagnostic criteria and some advances in treatment in the last decade, further investigation is needed\u00a0to provide more insight with the medical and surgical management of patients with connective tissue disorders and MCAS."}
+{"text": "Innate and adaptive immunity are essential for neurodevelopment and central nervous system (CNS) homeostasis; however, the fragile equilibrium between immune and brain cells can be disturbed by any immune dysregulation and cause detrimental effects. Accumulating evidence indicates that, despite the blood\u2013brain barrier (BBB), overactivation of the immune system leads to brain vulnerability that increases the risk of neuropsychiatric disorders, particularly upon subsequent exposure later in life. Disruption of microglial function in later life can be triggered by various environmental and psychological factors, including obesity-driven chronic low-grade inflammation and gut dysbiosis. Increased visceral adiposity has been recognized as an important risk factor for multiple neuropsychiatric conditions. The review aims to present our current understanding of the topic. Interactions between the immune and nervous system are gaining attention across multiple neuropsychiatric diseases . The claAccumulating data suggest the complex interactions between neurons and microglia, the brain parenchyma-resident macrophages that account for approximately 10% of CNS cells . It seemIn contrast to resident microglia, which comprise the innate CNS immune cells compartment, the presence of adaptive immune cells in the brain had long been regarded as pathologic. However, in healthy subjects, dendritic cells, macrophages, innate lymphoid cells (ILC)2, B cells, and T cells that reside in the meninges, the choroid plexus, and the cerebrospinal fluid monitor the brain\u2019s borders, providing additional protection to the BBB . It seemPreclinical studies demonstrate that adaptive immunity promotes cognitive performance: mice with severe combined immune deficiency exhibit altered spatial learning and memory, although those symptoms are reversed by transferring exogenous T cells . SimilarThis review discusses the most recent studies of the influence of obesity on a broad spectrum of different disorders, mainly metabolic syndrome, diabetes, systemic hypertension, heart failure, or kidney failure. Most recent studies have shown that the roles of overnutrition can induce hypothalamic inflammation in neurodegeneration. These studies have provided consistent evidence of smaller cortical thickness or reduction in the gray matter volume in people with overweight and obesity. Moreover, adipocytes, macrophages of the adipose tissue, and gut dysbiosis can result in the secretion of the cytokines and chemokines, crossing the blood\u2013brain barrier. They also can induce microglia, which release proinflammatory cytokines. Consequently, it can lead to chronic low-grade neuroinflammation and may be a key factor for apoptotic signaling and neuronal death . FurtherMounting evidence indicates that both innate and adaptive immunities are essential for CNS homeostasis. Therefore, any immune dysregulation could disrupt the fragile equilibrium between immune cells, neurons, and microglia, resulting in a spectrum of neuropsychiatric diseases.Evidence indicates that infection-related inflammation can substantially alter cognitive function. For instance, the data from a Danish longitudinal study shows that prior hospitalization that involved infection increased the risk of a major mood disorder (MMD) by 60%, while hospital contact with infection occurred in nearly 24% of individuals before a MMD . BacteriAnother compelling example includes sickness behavior (SB), characterized by a reduction in motor activity, motivation, social interactions and appetite, impairment of learning and memory, and often accompanied by fever . This unAs mentioned, pathogen infections can involve molecular mimicry, triggering the autoimmune processes ,50. NeurAnother example includes psychosis occurring due to the autoantibodies against neutrophils, developed spontaneously in neoplastic diseases or after viral infections . The autInterestingly, recent data indicates that autoimmune processes within the CNS induce a broad migration of intestinal IgA+ plasma cells differentiated from B cells stimulated with intestinal antigens, into the brain and spinal cord fluid to attenuate neuroinflammation in an IL-10-dependent manner . The preIn contrast to transient inflammation, chronic low-grade inflammation can occur and cause neurotoxicity and neurodegeneration . The proSterile chronic low-grade inflammation also occurs in obesity , and it Immunomodulatory drugs have been long used for the treatment of neurological autoimmune disorders. Standard treatment for acute exacerbations includes steroids, intravenous immunoglobulin, cyclophosphamide, immunosuppressants, and monoclonal antibodies . Many ofAccumulating evidence has linked obesity to a wide spectrum of neurologic disorders ,102,103.In line with clinical evidence, studies on animal models of high-fat diet (HFD)-induced obesity demonstrate altered hippocampal structure and function that correlate with learning and memory deficits and impaired executive functions . LTP is Another factor contributing to obesity-mediated cognitive impairment involves gut microbes, which affect different aspects of human physiology, including maturation and function of the immune system ,129. GivAkkermansia) is increased, while the abundance of Firmicutes is decreased [Multiple animal studies have demonstrated an immediate and significant effect of diet on gut microbiota composition and function that affects essential host-microbe interactions . Specifiecreased .Alterations of gut microbiota composition and signaling pathways can affect brain function and behavior via several mechanisms. Activation of the innate immune response following exposure to microbial factors requires the recognition of microbe-associated molecular patterns (MAMPs) via pattern recognition receptors (PRR), including TLRs and NOD-like receptors (NLRs), which are expressed both in neurons and glial cells ,150. SinFor instance, SCFAs, a microbial product of dietary fiber fermentation, play several roles, and their alterations have been associated with behavioral disorders, including depression , neurodeMany microbial species can also modify primary bile acids , changinde novo. Thereupon, it can modulate the bioavailability and collaborate with the nervous system in the regulation of distinct functions [It has also been shown that gut microbiota could modulate the production of various neurotransmitters and synthesize neurotransmitters unctions ,174. Forunctions . Furtherunctions . The abuunctions , and abnunctions ,177,178.unctions . In partunctions . Moreoveunctions ,180. GF unctions . Gut-derunctions . By induunctions .Corynebacterium glutamicum, Brevibacterium lactofermentum, Brevibacterium flavum, and Lactobacillus plantarum, is another important neurotransmitter system affected by microbes [Escherichiacoli, Proteus vulgaris, and Bacillus subtilis produce relatively high levels of dopamine and norepinephrine as growth factors. The precise systemic pathways that affect this production are not well understood [Glutamate, produced by various bacteria-namely microbes ,185. In derstood . Immune Lactobacillus rhamnosus increases center exploration in the open field test and decreases immobility time in the forced swim test, and this effect is eliminated by vagotomy [Gut microbes can communicate with the CNS via the vagus nerve. This nerve directly links the muscular and mucosal layers along the GI tract to the brainstem. Hence, it is a well-established signaling pathway affecting feeding, anxiety-like, depressive-like, and social behavior ,187,188.vagotomy . Increasvagotomy . Cholinevagotomy . Furthervagotomy . Hormonevagotomy ,191. Strvagotomy . The gutvagotomy . Altogetvagotomy . It is avagotomy . For insvagotomy ,195. It vagotomy .Accumulating evidence supports the concept that changes in the composition of gut microbiota can impact cognitive function at multiple levels. For instance, the complete absence of intestinal microorganisms can induce various alterations in host cognition. GF mice exhibit an impaired ability to remember a familiar object when presented with a novel object, as well as impaired working memory in remembering a familiar environment in the spontaneous alteration task ,198. TheHowever, there is only a limited number of studies supporting the role of gut microbiota in modulating human cognition. For instance, the microbiota composition of obese and non-obese individuals was associated with results in speed, attention, and flexibility in a Trail Making Test coupled with alterations in neural activity in the thalamus, hypothalamus, and amygdala, implying that obesity affects the microbiota composition and subsequent cognitive function . AnotherBifidobacterium Longum administration has been shown to reduce depression and alter brain activity in IBS individuals [Various intrinsic and extrinsic factors can trigger an imbalance in the interplay between gut microbiota and the brain ,214. In ividuals .Clostridia genera [Gut dysbiosis has been also implicated in the pathogenesis of a growing list of neurological and psychiatric disorders . For insa genera ,227. Soma genera . Althouga genera ,230. TheCoprococcus, Faecalibacterium, Ruminococcus, Bifidobacterium, and Escherichia, and an increased abundance of Paraprevotella in MMD subjects [Faecalibacterium, in addition to overall reduced microbial diversity. Further analysis showed that higher quality of life indicators was associated with higher levels of bacteria producing SCFA butyrate, including Faecalibacterium and Coprococcus. MDD has been also associated with physiological changes, including the alterations in gut permeability and systemic inflammation manifested with increased levels of IL-1\u03b2, IL-6, TNF-\u03b1, and CRP [There is also growing evidence of a role for the microbiota\u2013brain axis in MDD ,232, altsubjects . Similarsubjects . Individ and CRP . Numerou and CRP ,242, imp and CRP ,244, and and CRP  in MDD s and CRP . Other i and CRP ,247. It  and CRP .Toxoplasma gondii infections, food intolerance, GI inflammation, and altered intestinal permeability [Proteobacteria, Firmicutes, Bacteroidetes and Actinobacteria among both groups, with the fungi Ascomycota present in great abundance in schizophrenic individuals [phylum Proteobacteria [Succinvibrio and Coryneobacterium with the severity of disease symptoms, which might a diagnostic potential [Evidence also suggests a role of the GI immune response in the pathogenesis of schizophrenia, where risk factors include eability ,250,251.ividuals . Resultsbacteria . One recotential . FMT in otential . A smallotential ,257.Bacteroides and Firmicutes, particularly Faecalibacterium, and overall reduced diversity of gut microbiota [Another serious neuropsychiatric illness, BD, has been also linked to dysbiosis . Implicacrobiota . Prelimicrobiota .Provotellacae, increased abundance of Enterobacteriaceae [Verrucomicrobiaceae and Firmicutes and decreased abundance of Prevotellaceae and Erysipelotrichaceae in PD subjects [Growing evidence also suggests an important role of the gut\u2013brain axis in the etiopathogenesis of PD, AD and dementia, MS, and epilepsy. Altered microbiota composition has been linked to PD in multiple studies ,263,264.eriaceae , or increriaceae , comparesubjects . The rolsubjects ,275,276.Escherichia and Shigella [Bacteroides, Actinobacteria, Ruminococcus, Lachnospiraceae, and Selenomonadales [Similarly, there is growing evidence supporting the concept of microbial origin and progression of AD and dementia ,277. In Shigella , along wonadales . Other sonadales ,280. Exponadales  supportsonadales . Interesonadales . It is wonadales .Akkermansia muciniphila and Acinetobacter calcoaceticus in fecal samples of MS subjects [Parabacteroides distasonis, a species associated with anti-inflammatory effects.MS is a CNS-related autoimmune disorder defined by accruing motor deficits, blurred vision, and changes in sensibility that appear spontaneously with little to no prodromal signals . Based osubjects . In addiAccumulating evidence indicates that overactivation of the immune system increases brain vulnerability, heightening the likelihood of psychiatric symptoms . At the Current evidence indicates that innate and adaptive immunity can have an influence on neurodevelopment and CNS homeostasis, however, any immune dysregulation can disturb the fragile equilibrium between immune cells, neurons, and glial cells. As a result, harmful effects refer to neurological symptoms and also to higher-order network function. Increased visceral adiposity has been considered as a main reason for the development of a wide range of neuropsychiatric conditions . The pre"}
+{"text": "The ability of microorganisms to detoxify xenobiotic compounds allows them to thrive in a toxic environment using carbon, phosphorus, sulfur, and nitrogen from the available sources. Biotransformation is the most effective and useful metabolic process to degrade xenobiotic compounds. Microorganisms have an exceptional ability due to particular genes, enzymes, and degradative mechanisms. Microorganisms such as bacteria and fungi have unique properties that enable them to partially or completely metabolize the xenobiotic substances in various ecosystems.There are many cutting-edge approaches available to understand the molecular mechanism of degradative processes and pathways to decontaminate or change the core structure of xenobiotics in nature. These methods examine microorganisms, their metabolic machinery, novel proteins, and catabolic genes. This article addresses recent advances and current trends to characterize the catabolic genes, enzymes and the techniques involved in combating the threat of xenobiotic compounds using an eco-friendly approach. In the industrial revolution and urbanization era, the global environment\u2019s poisoning by a complex mixture of xenobiotics has become a major environmental threat worldwide ,2. XenobOver the past few decades, microbial-assisted degradation (bioremediation) of xenobiotic pollutants has evolved into the most effective, environment-friendly, cost-effective method for removing these noxious contaminants. Bioremediation is a method that involves the destruction, eradication, immobilization, or detoxification of a wide range of chemical waste and other harmful chemicals from the environment by an inclusive action of microorganisms. Bioremediation-related technologies include phytoremediation, rhizofilteration, bioaugmentation, biostimulation, landfarming, bioreactors, and composting. It is now gaining popularity; this method takes advantage of microorganisms\u2019 metabolic capabilities to eliminate contaminants, making them the most appropriate and promising. Persistent organic pollutants (POPs) cleanup with microbial enzymes is eco-friendly, cost-effective, and inventive ,16.Various laws and rules have been formulated to address the problems of xenobiotics, and many patents have been adopted and are in use in the EU and around the world, with an increased focus on reducing xenobiotics from the environment in a way that is economically, environmentally, and socially acceptable and viable with reduced accumulation or generating other toxic components in nature . FurtherXenobiotic pollution of the environment is a global concern caused by anthropogenic activities such as urbanization and population expansion. The enormous amounts of harmful compounds released into the environment result in widespread ecosystem contamination. Prominent substances such as polycyclic aromatic hydrocarbons (PAHs), heavy metal ions, pesticides, fertilizers, and oil derivatives are found in soil, sediment, and water .During the Industrial Revolution, scientific and technological advances became a source of people\u2019s over-exploitation of resources, which destroyed various ecosystems . The irrMajor xenobiotic compounds have hazardous effects on the environment, plants, animals, and humans .Xenobiotics such as dioxins, 1,1,1-trichloro-2,2-bis (4-chlorophenyl) ethane (DDT), polychlorinated biphenyls (PCBs), chlordane, polycyclic aromatic hydrocarbons (PAHs), and nitroaromatics are the primary threat to the soil ecosystems of developed nations. However, there are reports that a few other pollutants such as benzene, nitrobenzene, toluene, xylene, aniline, ethylbenzene, trinitrotoluene/dibenzofurans, and chlorinated solvents could be xenobiotic, especially in the soil ecosystem . CosmetiAnthropogenic activities that stimulate these chemical compounds in soil include industrial activities, fuel combustion, military movement, use of pesticides, fertilizers, and soil modifications in high-production agricultural practices that cause detrimental effects ,36. ChemThe diffusive and point contributions of anthropogenic activities such as urban industrial production, transportation, building construction, and housing pollute surface and groundwater in urban areas. The presence of chemical substances and indicators of human activity in urban water systems has been the subject of numerous kinds of research . In sewaA study reported that xenobiotic compounds alter the homeostasis in fishes and cause oxidative stress by producing large numbers of reactive oxygen species and suppressing the antioxidant system . Xenobiotics affect the plant\u2019s physiological and morphological characteristics in many ways; for example, particulate matter from the automobile sector changes the photosynthetic pigments, protein, cysteine contents, leaf area, and the foliar surface of plants . The extXenobiotics negatively impact several metabolic processes of marine animals, particularly in developing fish embryos, causing morphological and functional abnormalities, retarded growth leading to death. Altered body shape, body abnormalities, hatching delays, and death have also been recorded in fishes . Dyes anXenobiotic exposure is also possible due to application or inoculation of pharmacologic drugs or other chemicals as part of a typical conditioning or experimental operation. The consumption pattern and disposition of xenobiotics determine their toxicity. In addition, the mechanical and chemical properties also play a vital role in determining the toxicity of these xenobiotics\u2019 compounds . The xenXenobiotics pollute the environment, so their assimilation by living species has increased dramatically in recent decades. Introducing these substances into ecosystems may increase allergic reactions, organism mortality, genetic alterations, immune system lowering, metabolic disorders, and disruptions in natural ecosystem processes . Humans Alcaligenes . In. In58]. aligenes , Pseudomudomonas , Enterobacterium , Microcodococcus , Aeromoneromonas , Sphingoingobium , Aspergiocillium , Penicilchoderma , Rhodoto Candida  etc. Hen Candida ,69. Few phomonas . The domapproach .Burkholderia, Bradyrhizobium, Koribacter and Acidomicrobium were the most abundant genera in soil contaminated with pesticides . Th. Th79]. The patents are highly relevant to xenobiotic degradation; many such patents were retrieved from different databases on the basis of priority of filing and properties relevant in use to handle xenobiotics. Therefore, the search includes publicly available databases, i.e., Espacenet, DPMA, USPTO, JPO, EPO, PatFT, WIPO which cover databases produced by the Canadian Intellectual Property Office, German patents, German Patent and Trademark Office, European Patents and Chinese Patents etc .Regarding the environmental threats of xenobiotic compounds, there are many proven methods and products in the form of patents and process patents ,148,149.Omics approaches are an effective way to understand environmental toxicology and its remediation by employing a hybrid or integrated approach to decipher various effects of xenobiotics and other pollutants on flora, fauna including various ecosystems. The advantages include a better understanding of catabolic genes, degradative enzymes and involved metabolic pathways. In xenobiotic-contaminated soil/water ecosystems, microbial communities have the potential to play an influential role in mediating the successful biodegradation processes. Various molecular techniques provide potential measures to tackle the in-depth assessment of microbial communities at all levels, from the gene to molecule and organism to ecosystem. Many microbes with strong catabolic capability have been identified and described. The omics technique has uncovered many enzymes, especially those produced by unculturable microbes. These innovative steps have discovered various biocatalysts that are organically fitted to industrial restrictions. In this review, several patents have been discussed that employed either single isolates or mixed microbial strains to biotransform xenobiotics from contaminated environments. Resistant microbial technologies must be considered from a practical perspective; however, there is still some controversy on their field applications.However, more research is required to accomplish exceptional advancements in bioremediation by developing novel genetically modified strains with potent catabolizing genes to have xenobiotics-free ecosystems. Furthermore, the combined approach of green nanotechnology and microbe-mediated bioremediation must be given close attention to combat xenobiotic pollution. Sustainable policies should be developed frequently using contemporary technologies; they need support from government, policymakers, and stakeholders."}
+{"text": "Medicinal plants have been treating various ailments and diseases since ancient times. Aquatic and semiaquatic medicinal plants play an essential role in human welfare to fulfill their daily needs. They have shown biological, pharmacological, nutraceutical, and commercial applications. This review aims to collect and update all recent information on ethnomedicinal, phytochemistry, pharmacological activities, and nanoparticle synthesis and their uses in aquatic and semiaquatic medicinal plants. Original research papers, review papers, short communications, and book chapters on aquatic and semiaquatic plants have been retrieved from PubMed, Web of Science, Scopus, and Google Scholar. Keywords, ethnomedicinal studies, phytochemistry, pharmacological activities, and nanoparticle synthesis from aquatic and semiaquatic medicinal plants are used for the search. Different aquatic and semiaquatic medicinal plants belonging to the families Acanthaceae, Alismataceae, Amaranthaceae, Apiaceae, Araceae, Asteraceae, Boraginaceae, Ceratophyllaceae, Cyperaceae, Fabaceae, Hydrocharitaceae, Lythraceae, Marsileaceae, Menyanthaceae, Nelumbonaceae, Nymphaeaceae, Onagraceae, Plantaginaceae, Poaceae, Polygonaceae, Pontederiaceae, Primulaceae, Scrophulariaceae, and Zingiberaceae have been studied. They are rich in alkaloids, flavonoids, terpenoids, phenolics, saponins, tannins, dietary fiber, glycosidic derivatives, carbohydrates, and proteins. These phytochemicals have been used for their antimicrobial, antioxidant, hepatoprotective, sedative, anticonvulsant, cytotoxic, antiparasitic, and antidiabetic activities. Besides this, various parts of the plants are used as dietary supplements and green nanoparticle synthesis. These plants are also known for their commercial value and are used as an ingredient in some pharmaceutical industries. Natural products from medicinal plants are known for their various uses, such as treating infectious diseases, biological applications in the industry as ingredients, food additives, and green synthesis of nanomaterials , 2. AbouAquatic and semiaquatic medicinal plants and their phytochemicals have been widely practiced as traditional medicines worldwide. For instance, 50\u201360% of people in India live closer to aquatic bodies and use these plants for various practices such as medicinal, ornamental, and religious offspring , 41. Rec\u03b2-asarone (27.4\u201345.5%), acorenone (20.86%), and isocalamendiol (12.75%) are reported from its leaves and rhizomes, respectively [Sweet flag is an important aquatic medicinal plant belonging to the Araceae family, as shown in ectively , 51.This semiaquatic plant species belong to the Asteraceae family , distrib\u03b1-tetralone, tetralin-4O-\u03b2-D-glucopyranoside, and ammaniol [This semiaquatic medicinal plant belongs to the Lythraceae family , distribammaniol .\u03b2-myrcene, \u03b1-terpineol, terpinene-4-ol, \u03b1-pinene, and \u03b2-pinene [This aquatic medicinal plant belongs to the Zingiberaceae family , distrib\u03b2-pinene .\u03b2-sitosterol, betulinic acid, luteolin, apigenin, D-mannitol, hersaponin, and stigmasterol [This aquatic plant species belong to the Plantaginaceae family and is native to India, the United States, East Asia, and Australia, as shown in masterol .This aquatic medicinal plant belongs to the Apiaceae family , found iThis aquatic medicinal plant belongs to the Asteraceae family . It is fCeratophyllaceae family  displayed that extracts and compounds from the activity . The rooactivity . Severalactivity , 160. Thactivity . Hydroal studies .Ipomea aquatic showed a cytoprotective role in the liver and other organs [Acorus calamus have been known for their cytotoxicity effects [Mollugo cerviana, Trichosanthes cucumerina, and Vetiveria zizanioides plants have been reported for their cytotoxicity against cancer cells such as HeLa and MCF-7 cell lines [Enhydra fluctuations, Andrographis peniculata, and Clerodendrum viscosum exhibited potent cytotoxicity against brine shrimp compared to ampicillin trihydrate as a positive control [Centella asiatica exhibited weak cytotoxicity effects compared to the standard drugs [Samanta and coworkers (2020) reported that extract from the aerial part of r organs . Methano effects , 163. Thll lines . Alcohol control , 165. Thrd drugs .Spilanthes, such as dichloromethane extract of flowers, methanol extract of flowers, and cold dichloromethane extract of plant stems, have been shown to have significant activity against malaria and sleeping sickness diseases [Several studies on aquatic and semiaquatic medicinal plants show their antiparasitic properties. Nymphoides plant species possess antiprotozoal, antimalarial, and anthelmintic properties . Organicdiseases .Centella asiatica, Hedychium coronarium, Ipomea aquatic, Pistia stratiotes, Spergularia marina, and Nymphaea nouchali have been reported as medicinal plants with effective antidiabetic properties due to their potency in the wide range of bioactive compounds [Acorus calamus plant species have been reported for their strong antidiabetic effects [Ipomea aquatic are also used to treat diabetes [Different plant extracts treat diabetes mellitus \u2013168. Cenompounds , 169. Et effects . The shodiabetes .Oryza sativa (rice) is its grain. In contrast, the leaves of Nasturtium officinale (Watercress), Neptunia oleracea (Water mimosa), and Oenanthe javanica (Japanese parsley) are used as human food [Enhydra fluctuation, an edible semiaquatic herbaceous vegetable, is a rich source of phytochemicals such as \u03b2-carotene and ascorbic acid, which are required in diet supplements [Ipomea aquatic is commonly used as a leafy vegetable or salad, which contains medicinally important flavonoids, alkaloids, and carotenes [Nymphaea nouchali plant species have been eaten in times of food scarcity [Ludwigia adscendens plant has been known to be consumed in the vegetable diet in China [Alternanthera sessilis plant species are used in the vegetable diet for their potential nutritional and medicinal values [the Alternanthera sessilis plant had been consumed raw or cooked as a food supplement [Acorus calamus, Aeschynomene aspera, Alternanthera philoxeroides, Centella asiatica, Colocasia esculent, Cyperus rotundus, Eleocharis dulcis, Hydrolea zeylanica, Hygroryza aristata, Nymphoides hydrophylla, Oryza sativa, Pistia stratiotes, Polygonum plebeium, Trapa natans, Vallisneria spiralis, and Spilanthes calva [Several aquatic and semiaquatic plant species are available as food using their various parts, such as stems, leaves, roots, rhizomes, flowers, flower heads, and fruits. For example, the edible part of man food . Some prplements . Ipomea arotenes . The leascarcity , 41. Ludin China . Leaves l values . Chia anpplement . SeaweedTrapa bispinosa is reported to have important commercial uses in the milk industry and as a filler in the pharmaceutical industry [Acorus calamus are widely used in the flavoring industry and for commercial purposes [The use of macro-algae in pharmaceutical industries showed their importance for humans as they were applied as antibiotic, antifouling, antiviral, anti-inflammatory, cytotoxic, and antimitotic agents. The flour of fruits of industry . Similarpurposes , 175.Alternanthera sessilis and Withania somnifera for their applications in the assays of cytotoxicity effects and antibacterial activities with promising results [Alternanthera sessilis have been used for the biosynthesis of gold nanoparticles (AuNPs) and AgNPs. These synthesized nanoparticles have antibacterial, antifungicidal, antiplasmodial, anti-inflammatory, anticancer, antidiabetic, antiviral, and antioxidant activities [Alternanthera sessilis demonstrated significant cytotoxicity effects on the breast cancer cells [Nanoparticles have more advanced properties than bulk materials due to their superior behavior with defined shape and size . The inc results . The phytivities . Other ser cells .Aquatic and semiaquatic medicinal plant products have remarkable biological, pharmacological, agricultural, green materials synthesis, and industrial applications. They are also used as nutraceuticals, food, and medicine. These plants contain diverse natural compounds with numerous biological and chemical properties. Crude extracts or pure compounds from various parts of aquatic and semiaquatic plants possess potential nutritional and medicinal values. Phytochemicals are widely used to treat various infectious and noninfectious health ailments. Further, several aquatic and semiaquatic plants are used for the green synthesis of metal and metal oxide nanomaterials, which have shown many potential applications. Moreover, they are also helpful for various commercial product preparations. Even though these plant species have a wide range of phytochemicals with potential bioactive properties, enough research work is missing. Thus, this review article was designed. However, in the future, more extensive and specific research is required to investigate the natural phytochemicals from these aquatic and semiaquatic medicinal plants for various commercial uses."}
+{"text": "Kerria. Lac is commercially cultivated in southeastern Asian countries, including China (Kerria yunnanensis), India (K. lacca), Thailand (K. chinensis), and Myanmar . It is non-toxic, insulating, moisture-resistant, adhesive, tasteless, and has a smooth texture. Lac has been historically employed to finish a small number of products, but it is currently used in various fields. In this review, we mainly focus on the importance of lac genes that are responsible for lac secretion. In addition, information gaps, potential future research directions, and areas that require further research are highlighted.Since ancient times, people have used insects, such as scale insects , honey bees (honey and wax), and silkworms (silk), to make natural products in many ways. Lac is the only natural raw material derived from insects, being obtained from several species of the genus In the current era, products made from organic materials enjoy a privileged position because of their inherent safety. The eco-friendly properties of natural lac resins have increased their demand in many industries. It is secreted by sucking insects  and comprises three major components, viz., resin, dye, and wax. Lac insects are generally bivoltine in nature and are distributed in tropical and sub-tropical regions with complex multi-trophic habitats. Because of their sedentary habits, lac insects are more vulnerable to predators, parasitoids, squirrels, and rats, leading to a more than 50% reduction in production yield. To increase lac production, advanced-level molecular research is required to figure out the mechanism behind lac synthesis and secretion to improve lac yield and quality. The present review highlights metamorphosis, sexual dimorphism, multi-trophic habitat, host plants, and natural enemies of lac insects, lac composition, and applications, emphasizing the role of microbes, potential lac genes, and lac synthesis mechanisms in enhancing lac quality and production. The information provided here might be useful for lac researchers and for stakeholders aiming to make their products more eco-friendly. Lac is a combination of natural resins produced by scale insects . At firsLac insects are members of the family Kerriidae (Hemiptera), also known as scale insects, which produce a resinous material that forms a hard scale test over their bodies ,13. ThisKerria can produce true lac ..SchleichFicus religiosa), ber (Ziziphus mauritiana), litchi (Litchi chinensis), kikar (Acacia nilotica), and sirin (Albizia spp.) are known as major host plants of lac insects [Acacia nilotica, A. catechu, Samanea saman, Butea monosperma, and Ziziphus mauritiana are common lac host plants in Bangladesh [Dalbergia assamica, D. szemaoensis, D. obtusifolia, Ficus altissima, F. racemosa, and Pueraria tonkinensis [Indian wild ber serves as a host plant for lac insects in different agro-climatic zones of Punjab, India . In Indi insects ,88,89, wngladesh . The varkinensis ,91.K. chinensis, K. fici, K. lacca, K. pusana, K. maduraiensis, K. destructor, and K. canalis, are known to feed on the rain tree host plant Samanea saman with slight to severe levels of lac encrustation [K. destructor has been reported to kill large rain trees [Seven species, including ustation . Neverthin trees  via repeAprostocetus (Tetrastichus) purpureus (Cameron), Tachardiaephagus tachardiae (Howard), and Parechthrodryinus clavicornis (Cameron) [Eublemma amabilis Moore (white moth), Pseudohypatopa pulverea Meyr (black moth), and Chrysopa sp. (green lace wing) [Chrysopa lacciperda and C. madestes are most prevalent and cause significant mortality in lac insects [Lac crop losses are higher than agricultural crop losses . Lac pesCameron) . Howeverce wing) ,16, whicce wing) ,95. In t insects ,92. Duri insects  observed insects .Pseudohypatopa pulverea and Eublemma amabilis can be achieved by the use of the biopesticide Bacillus thuringiensis Berliner in the field. Two ant predators (Solenopsis geminata and Camponotus compressus) have been evaluated for control of lac predators via attacking the pupae and larvae of P. pulverea and E. amabilis. Several egg parasitoids have been used for the management of lac predators such as Telenomus remus, Trichogrammatoidea bactrae, Trichogramma brasiliensis, T. pretiosum, and T. chilonis. Pests can be controlled by applying systemic insecticides that are safe for lac nymphs and effective against predators. A combination of the above components may reduce the pest population and increase lac yield [The best way to protect crops from pests is to follow preventive measures such as (a) selecting mature, healthy, and brood lac free of parasitoids and predators for crop inoculation (b) after 2\u20133 weeks of inoculation, removing sticks with no brood lac  (c) scraac yield ,20,27.In view of the biosafety of natural products, this review highlights detailed information, including the life stages, distribution, and interaction of lac insects; their applications and composition and the lac genes involved in lac synthesis; and microbial diversity, host plants, and natural enemies of lac insects. The factors contributing to yield reduction during lac crop cultivation are highlighted, as well as how they might be improved. Lac insects are attacked by vertebrate and invertebrate pests, resulting in yield losses of up to 50%. This loss can be reduced through timely and effective management. Earlier investigations identified a few genes that may be responsible for lac production, and at least four to five common genes that need to be verified through gene knockout or gene silencing techniques. Until now, there has been no information about indigenous associations involved in lac production. Further investigations are required to determine the role of native microbes in the female lac insect, as this is one of the most important factors in lac yield because commercial lac is obtained solely from female lac insects. In addition, the response of native microbes already present in lac insects and the lac resins on trees during the introduction of identified candidate microbes from different parts of lac insects could be investigated. Advanced omics research  could help us to identify the mechanisms and pathways of lac synthesis, which would enhance lac yield."}
+{"text": "Over 6 weeks, we collected 406 unique responses across all of our interactions. We then identified basic themes for interdisciplinary improvement in each phase of sepsis recognition and response. We executed a keyword analysis to quantitatively evaluate the responses and highlight opportunities for improvement. Figure Figure The keyword analysis helped illustrate the interaction of human behavior, technology, and working environments influencing our interdisciplinary workflows surrounding sepsis response. With data as our driver, we partnered with the frontline staff to develop and operationalize our new huddle checklist, IV algorithm triage resource, and sepsis orderset while continuing to monitor both our process and outcome measures. The result was a continuous increase in sepsis bundle utilization for critical sepsis patients with a center line shift from 41% to 70%. One of our biggest drivers of this shift was the centerline shift in sepsis orderset utilization increase from 36% to 61% across all sepsis patients. Finally, in response to our results, we are also working diligently to develop a simulation experience focusing on the huddle process.Monica Kleinman, MD, Medical/Surgical Intensive Care, Boston Children\u2019s Hospital; Matthew Eisenberg, MD, Division of Emergency Medicine, Boston Children\u2019s Hospital; Daniel Kelly, MD, Division of Medicine Critical Care, Boston Children\u2019s Hospital; Kate Madden, MD, Medical/Surgical Intensive Care, Boston Children\u2019s Hospital; Teresa Shannon, MSN, RN, CPN; Sue Dixon, RN; and Marlena Smith-Millman, MPH."}
+{"text": "JCI, Hollenhorst, Nandigama, et al. demonstrated that tracheal chemosensory brush cells detected bitter-tasting substances, including quorum-sensing molecules (QSMs) generated by pathogenic Pseudomonas aeruginosa. The authors used various techniques, including genetic deletion of brush cells, genetic manipulation of brush cell signaling, deletion of sensory neurons, in vivo imaging, and infection models with P. aeruginosa, to show that QSMs increased vascular permeability and innate immune cell influx into the trachea. These findings link the recognition of bacterial QSMs to the innate immune response in the airways, with translational implications for airway inflammation and infectious pathology.Airway epithelial cells, once considered a simple barrier layer, are now recognized as providing an active site for antigen sensing and immune response initiation. Most mucosal sites contain chemosensory epithelial cells, rare and specialized cells gaining recognition for their unique functions in sensing and directing the immune response symphony. In this issue of the  Chemosensory brush cells are found at nearly all mucosal sites, including the nose, trachea, intestine, gallbladder, urethra, and pancreas, where they are referred to as solitary chemosensory cells (SCCs), brush cells, or tuft cells \u20134. They JCI, Hollenhorst, Nandigama, et al. uncovered how brush cells direct the mucosal host defense to impending Pseudomonasaeruginosa infection  through bitter-taste receptors leads to similar sensory nerve\u2013 and substance P\u2013dependent plasma extravasation . This seStaphylococcus aureus infection  mechanism . Subsequent signaling leads to the generation of acetylcholine and cysteinyl leukotrienes that independently promote bacterial clearance . In the Altogether, brush cells are poised to respond to bacterial metabolites, stress signals, allergens, and helminths, by engaging a variety of receptors. They either expel pathogens mechanically and promote innate immune cell influx or initiate type 2 inflammation when they sense helminths or allergens .Hollenhorst, Nandigama, et al.  demonstr"}
+{"text": "Nelumbo nucifera Gaertn.) is a well-known food and medicinal plant. Lotus seedpod (Receptaculum Nelumbinis) is the by-products during lotus products processing, which is considered as waste. Numerous studies have been conducted on its phytochemicals, biological activity and industrial application. However, the information on lotus seedpod is scattered and has been rarely summarized. In this review, summaries on preparation and identification of phytochemicals, the biological activities of extracts and phytochemicals, and applications of raw material, extracts and phytochemicals for lotus seedpod were made. Meanwhile, the future study trend was proposed. Recent evidence indicated that lotus seedpods extracts, obtained by non-organic and organic solvents, possessed several activities, which were influenced by extraction solvents and methods. Lotus seedpods were rich in phytochemicals categorized as different chemical groups, such as proanthocyanidins, oligomeric procyanidins, flavonoids, alkaloids, terpenoids, etc. These phytochemicals exhibited various bioactivities, including ameliorating cognitive impairment, antioxidation, antibacterial, anti-glycative, neuroprotection, anti-tyrosinase and other activities. Raw material, extracts and phytochemicals of lotus seedpods could be utilized as sources for biochar and biomass material, in food industry and as dye. This review gives well-understanding on lotus seedpod, and provides theoretical basis for its future research and application.Lotus ( Nelumbo nucifera Gaertn. , belonging to the mono-generic family Nelumbonaceae, is widely distributed in Asia, Americas and Oceania ( Oceania . Lotus h Oceania . Accordi Oceania . Almost  Oceania . Among t Oceania .Receptaculum Nelumbinis) is the mature receptacle of lotus house  fractionation -catechin had much better inhibition activity on AGE formation and methylglyoxal scavenging effect, while syringic acid showed the best scavenging ability on DPPH radical. Furthermore, Wu et al.  from lotus seedpods exhibited broad-spectrum biological activities, including ameliorating cognitive impairment, antioxidation, antibacterial, anti-glycative, neuroprotection, anti-tyrosinase, retinal protection, anti-insomnia, anti-cancer, immunomodulatory, ameliorating intestinal injury, anti-diabetes, regulating lipid homeostasis, anti-inflammatory and \u03b1-glucosidase inhibitory effects. Furthermore, raw material, extracts and phytochemicals of lotus seedpods have been applied as sources for biochar and biomass material, in food industry, and as dye. In contrast, other parts of lotus like seeds, stems, leaves, flowers, epicarps, plumules, stamens, petals and rhizomes have been reported to contain phytochemicals included flavonoids, glycosides, alkaloids, monosaccharides, essential oils, organic acids, chlorophylls, sesquiterpenoids, steroids, sapogenins, etc . BiologiHowever, there are some issues should be resolved in future: (1) the phytochemicals from lotus seedpod is mainly prepared using conventional solvent method, more attempts should be made to novel means; (2) although many phytochemicals with small molecular weight have been isolated and identified from lotus seedpods, the exploitations of those (like proteins and polysaccharides) with large molecular weight have been rarely done; (3) there is little information on digestion, absorption, distribution, structure-activity relationship, metabolism of phytochemicals from lotus seedpod, which need to be disclose with more work; (4) the current researches on biological activities of phytochemicals from lotus seedpods mostly foucused on proanthocyanidins and oligomeric procyanidin, the biological activities of other phytochemicals from lotus seedpod; (5) biological activities of extracts and phytochemicals from lotus seedpods have been indicated in chemical assays as well as cell and animal experiments, but have not been demonstrated by clinical research; (6) the action mechanisms about the relevant activities of extracts and phytochemicals from lotus seedpods are unclear as they have been preliminarily explored.Y-FW: conceptualization, investigation, visualization, and writing\u2014original draft. Z-CS and JL: investigation and visualization. TL, J-LS, and X-FL: investigation. Y-PL: project administration and funding acquisition. WZ: writing\u2014review and editing. QZ: funding acquisition. X-YW: project administration, writing\u2014review and editing, supervision, and funding acquisition. All authors contributed to the article and approved the submitted version."}
+{"text": "Papers in this collection address multiple research areas within human physiological, biological, and biocultural anthropology. Applying ecological and evolutionary theory, physiological anthropologists explore and document influences of environmental, biocultural, and social stressors on human variation across the life span by sex, location, and migratory status within and among groups. Using biocultural perspectives, each paper explores ecological, bioethnographic, and/or life history factors to understand variable human responses to stressors across environmental and sociocultural settings. Jointly, they address responses to climate, migration, aging, reproduction, frailty, and human adaptability. Applying variable research methods and data acquisition techniques and ranging from a literature review to empirically focused research, these papers share a common thread, exploring human adaptability in response to stressful environments as a biocultural process.Included are a bioethnographic exploration of stress, allostatic load, and perceived health among migrants from Mexico to the USA, frailty as a possible adjunct to activities of daily living and other scales when designing senior housing, influences of reproductive histories on frailty among US and Philippine women, and assessing the thermoregulatory physiology of brown adipose tissue and its importance for maintaining body temperature in a subarctic setting. Each paper addresses human physiological variation as a response to variable environmental and sociocultural settings, lifeways, population, and individual histories, all current issues in physiological anthropology and human biology. These papers include stress, migration, and allostatic load, a model based on Mexican migrants in Columbus, Ohio ; aging, Tuggle et al.  developeIn the second contribution, Crews  suggestsThe third report included herein is Ocobock and colleagues\u2019  researchN = 67, average age 73.0) and USA . Frailty was assessed as grip strength, gait speed, and the sit-to-stand exercise. Menstrual cycles were assessed by number of months not pregnant or lactating. Estimated lifetime cycles (ELC) failed to associate significantly with frailty assessments or overall health. ELC did associate significantly with BMI. Furthermore, while ELC did not associate significantly with frailty in the US sample, among the Philippine women, higher ELC trended toward being associated with lower frailty. No estimate of frailty differed significantly between high and low ELC subgroups within samples. They suggest other factors, activity levels, health parameters, or exogenous exposure to sex steroids may influence lifetime sex steroids and frailty, as\u00a0may additional factors not assayed, e.g., activity patterns, type of labor, or physical limitations.In the final contribution, Dorne and Zoorob  explore Papers in this collection integrate physiological, social, cultural, and environmental variability as a framework to assess quantitative and qualitative aspects of health, frailty, allostatic load, and thermal response. Each applies a multifaceted biocultural and bioethnographic model of human adaptability and variation as responses to environmental and ecological stressors. By assessing and contextualizing environmental, social, and cultural influences on human physiological, functional, and physical variability, these human biologists and physiological and biological anthropologists were able to develop and test holistic models of human health, well-being, and responses to stressors across populations."}
+{"text": "Obesity and diabetes are common among older Americans. While obesity is a risk factor for diabetes, research on rural-urban health disparities among older adults has reported paradoxical results. That is, living in rural areas is a risk marker of obesity, whereas rural residency is inversely associated with diabetes. This study utilized multiple national data resources to diagnose the inconsistency, including the 2006-2016 RAND HRS Longitudinal data, biomarker data, the 2010 US Census, and the USDA food access information. HRS survey participants 65 to 97 years of age comprised the study sample . General generalized estimating equation models with survey weights were used to estimate associations with measured obesity and diabetes. Age, race, Hispanic status, foreign-born status, education, marital status, working status, wealth, physical activity, smoking, drinking, ADL, IADL, loneliness, depression, cholesterol, HDL, CRP, and Cystatin C were included as control variables. Findings suggest that rurality is associated with a higher likelihood of obesity and a lower likelihood of diabetes, particularly for older women. However, by adjusting for confounders, these relationships disappeared. Instead, social isolation indicated significant associations with a lower likelihood of obesity and a higher likelihood of diabetes among older women. Contrary to prior research, the food desert and food insecurity measures did not correlate with both outcome variables. Further investigation on food consumption and dietary behavior among socially isolated older women is needed."}
+{"text": "Curcumin, a polyphenolic derivative of Curcuma longa rhizome, has numerous beneficial effects, including antibacterial, anti-inflammatory, antiviral, antioxidant, antifungal, anti-ischemic, anti-cancer, hypoglycemic, nephroprotective, antirheumatic, hepato-protective, and antimutagenic. Curcumin has indicated the capability to exert anti-cancer activity by multifunctional mechanisms, such as induction of apoptosis, inhibition of cancer cell proliferation, cell cycle regulation, chemotherapeutic intestinal absorption, and modification of several cancer cell types signaling pathways. Several studies have shown that curcumin may have protective effects against tumors of the reproductive system. Reproductive system cancers may cause many undesirable physical and, especially, mental disorders. Infertility and its mental consequences, sexual problems, chemotherapy and surgery-related adverse effects, substantial economic burden, and death are the most common complications regarding the cancers of the reproductive system. By modulating several reproductive cancer hallmarks such as signaling pathways, multiple drug resistance, cancer cell growth and proliferation, tumor angiogenesis, and transcription factors, curcumin could be used as a safe, non-toxic, cheap, and easily accessible drug for treating different types of reproductive cancers. Traditional medicine and medicinal plants came into focus in the recent decade as a result of the credence that herbal products are healthier, having fewer adverse and toxic effects than synthetic drugs . The usaProstate cancer is considered the second cause of death among men in Western countries . ChronicThe most prevalent cancer in women, especially in developed countries, is breast cancer . Based oThe most lethal cancer of the reproductive system is ovarian cancer . It has Furthermore, ovarian cancer drug resistance could be ameliorated by curcumin. The sen-sitivity of ovarian cancer cells to cisplatin has been shown to increase by FA/BRCA path-way inhibition in a dose-dependent manner . MultiplThe findings from previous studies have shown that curcumin exerts its anti-cancer ef-fects by targeting several signaling pathways and molecules. By modulating several repro-ductive cancer hallmarks such as signaling pathways, multiple drug resistance, cancer cell growth and proliferation, tumor angio-genesis, and transcription factors, curcum-in could be used as a safe, non-toxic, cheap, and easily accessible drug for treating differ-ent types of reproductive cancers. However, the poor availability of curcumin restricts its clinical use, and specific novel approaches are required to solve this problem. Many in-vestigations are in progress on new delivery systems, including encapsulating curcumin into liposomes or lipid micelles, nanotech-nology-based formulations, conjugation with antibodies or other specific ligands, and the use of curcumin analogs, which consist of the same properties but better bioavailability to overcome the limitations regarding curcumin poor bioavailability.None."}
+{"text": "Gastro-oesophageal reflux disease (GORD) is a common gastrointestinal dysfunction that significantly affects the quality of daily life, and health interventions are challenging to prevent the risk of GORD. In this study, we used Mendelian randomization framework to genetically determine the causal associations between multifaceted modifiable factors and the risk of GORD.Neale, Ncases = 29975, Ncontrols = 390556) and FinnGen . Using the METAL software, meta-analysis for single nucleotide polymorphisms (SNPs) from GORDNeale and GORDFinn was conducted with an inverse variance weighted (IVW) fixed-effect model. Moreover, we leveraged partition around medoids (PAM) clustering algorithm to cluster genetic correlation subtypes, whose hub exposures were conditioned for multivariable MR (MVMR) analyses. P-values were adjusted with Bonferroni multiple comparisons.Sixty-six exposures with available instrumental variables (IVs) across 6 modifiable pathways were included in the univariable MR analysis (UVMR). Summary-level genome-wide association studies (GWAS) datasets for GORD were retrieved from the Neale Lab  and the risk of GORD. Among them, 13 risk exposures , and 10 protective exposures (leisure sedentary behavior (computer use), sitting height, hand grip strength (left and right), birth weight, life satisfaction, positive affect, income, educational attainment, and intelligence) showed novel significant causal associations with the risk of GORD. Moreover, 13 exposures still demonstrated independent associations with the risk of GORD following MVMR analyses conditioned for hub exposures . In addition, 12 exposures showed suggestive causal associations with the risk of GORD.This study systematically elucidated the modifiable factors causally associated with the risk of GORD from multifaceted perspectives, which provided implications for prevention and treatment of GORD. As a common digestive system disease, GORD clinically presents with intraesophageal symptoms, such as acid regurgitation, heartburn and chest pain, and extraesophageal symptoms, including bronchial asthma, chronic cough, and hoarseness . Long-teMR mainly relies on IVs to detect and quantify causality between exposure and outcome . This deIn this study, we screened a total of 66 exposures across 6 modifiable pathways  for the purpose of identifying the factors that causally associated with the risk of GORD using MR analysis in the discovery and replication phases. Moreover, a meta-analysis based on the above two-phase determined the factors that were causally associated with the risk of GORD to the greatest extent, and also enhanced the statistical efficacy of MR results in the discovery and replication phases.We retrieved factors from PubMed that were associated with the risk of GORD with the query strategy \u201c) AND ((relative[Title/Abstract] AND risk[Title/Abstract]) OR (relative risk[Text Word]) OR (risks[Text Word])).\u201d Reviews, meta-analyses and population-based studies were included, and we identified 58 modifiable factors  related 1 performed GWAS across more than 7,000 phenotypes from 6 ethnic groups  with the UK Biobank (UKB) approval. Similarly, FinnGen2 is a large public consortium for genetic and health data from Finnish participants. The summary-level GWAS datasets in the Neale Lab and FinnGen consortiums are free and publicly available.Neale LabNeale)3 was used for the discovery phase. GORDNeale GWAS dataset, which contained 29975 cases and 390556 controls and was adjusted for covariates , was analyzed with Scalable and Accurate Implementation of Generalized mixed model (SAIGE)  obtained from FinnGen (GORDFinn) was analyzed using SAIGE  for the SNPs of summary-level GORDNeale and GORDFinnGen datasets.For the outcome cohort, the \u2018\u2018K21 Gastro-oesophageal reflux disease\u2019\u2019 GWAS dataset obtained from the Neale Lab (GORD (SAIGE) , and impng SAIGE 5 and adjP < 5*10\u20138) without linkage disequilibrium  were used as independent IVs. Meanwhile, the effect values of exposures and outcomes were harmonized to the same effect allele to ensure accurate MR analysis  and genetic correlations (rg) between different phenotypes based on summary-level GWAS datasets  was considered as the threshold of genetic correlation with significantly statistical significance.The linkage disequilibrium score regression (LDSC) is an effective method for estimating heritability , the slope of MR-Egger represents the causal estimate of exposure on the outcome (P \u2264 7.576E-04 (0.05/66) were deemed as significant, and causal associations with 7.576E-04 < P \u2264 0.05 were defined as suggestive causal associations.The process of UVMR is shown in  outcome . Therefo outcome . In thisP \u2264 7.576E-04). A vital advantage of the PAM clustering algorithm included the ability to robustly cluster different data types within limited samples, minimizing the influences of data noise and isolated points on the clustering results. Inter-exposure similarity was measured using Euclidean distance, 80% of the exposures were taken at one time, 1,000 replicate samplings were conducted, and the slope of the CDF curve and area under the CDF curve determined the most appropriate number of clusters to be placed. Exposures that were genetically correlated with all other exposures with statistical significance (P \u2264 0.05) in each cluster were defined as the hub exposures. MVMR principle hypothesizes that genetic-level links existed in individual exposures, and that SNPs are strongly associated with at least one of these exposures (P < 5*10\u20138) to be IVs and GORDmeta GWAS dataset as the source of outcome GWAS dataset. MVMR-IVW method 2]. The general assumption is that there are no weak instrumental variable biases when the SNPs F statistics are greater than 10  to highest schizophrenia . GORDNeale  and GORDFinn  possessed largely consistent heritability. The exposure-exposure, exposure-GORDNeale, exposure-GORDFinn, and GORDNeale-GORDFinn genetic correlations were shown in Neale and GORDFinn shared a high degree of genetic correlation , and 39 of 48 exposures that showed a statistically significant genetic correlation with GORDNeale also had a similar pattern of genetic correlation with GORDFinn.We estimated heritability and genetic correlation using LDSC for 66 exposures, GORDGORDFinn . Total oP \u2264 0.05). Among them, the following 20 exposures were causally associated with an increased risk of GORD: smoking initiation, lifetime smoking, cigarette consumption, smoking cessation, insomnia, short sleep, daytime sleepiness, daytime napping, leisure sedentary behavior (TV watching), type 2 diabetes, coronary artery disease, BMI, body fat percentage, whole body fat mass, visceral adipose tissue, waist circumference, hip circumference, waist-to-hip ratio, major depressive disorder, and anxious feeling. The other 14 exposures showed causal associations with a decreased risk of GORD: leisure sedentary behavior (computer use), 10+ min vigorous activity, strenuous sports or other exercises, height (standing and sitting), hand grip strength (left and right), birth weight, life satisfaction, positive affect, income, educational attainment, and intelligence. Moreover, heterogeneities were observed in the SNPs corresponding to the following exposures that causally were associated with the risk of GORD (P \u2264 0.05): smoking initiation, lifetime smoking, insomnia, short sleep, daytime sleepiness, daytime napping, leisure sedentary behavior (TV watching), BMI, body fat percentage, whole body fat mass, visceral adipose tissue, waist circumference, hip circumference, waist-to-hip ratio, height (standing and sitting), hand grip strength (left and right), birth weight, anxious feeling, life satisfaction, positive affect, income, educational attainment, and intelligence , among which, the causal associations between the following 25 exposures were consistent with the results in the discovery phase: smoking initiation, lifetime smoking, cigarette consumption, insomnia, short sleep, leisure sedentary behaviors (TV watching and computer use), strenuous sports or other exercises, type 2 diabetes, BMI, body fat percentage, whole body fat mass, visceral adipose tissue, waist circumference, waist-to-hip ratio, height (standing and sitting), hand grip strength (left and right), birth weight, major depressive disorder, life satisfaction, positive affect, income, and educational attainment. Meanwhile, exposures \u201cchild-onset asthma,\u201d \u201culcerative colitis,\u201d \u201cwhole body fat-free mass,\u201d and \u201cschizophrenia,\u201d which had not previously shown causal associations with the risk of GORD in the discovery phase, also showed causal associations with the risk of GORD in the replication phase. SNPs in the educational attainment, BMI, smoking initiation, sitting height, waist circumference, whole body fat mass, standing height, body fat percentage, birth weight, type 2 diabetes, visceral adipose tissue and short sleep suggested heterogeneities  was detected in the causal association between the smoking initiation and the risk of GORD, the result from MR-Egger method was still robust .In the replication phase , a totaleneities \u20135. Althometa, which contained 43116 GORD cases and 580251 controls from the GORDNeale and GORDFinn, to complement and consolidate the causal associations between exposures and the risk of GORD. In total, as shown in P \u2264 7.463E-04), which included 15 risk exposures: smoking initiation , lifetime smoking , cigarette consumption , insomnia , short sleep , leisure sedentary behavior (TV watching) , BMI , body fat percentage , whole body fat mass , visceral adipose tissue , waist circumference , hip circumference , waist-to-hip ratio , major depressive disorder , and anxious feeling ; 11 protective exposures: leisure sedentary behavior (computer use) , height (standing and sitting) , hand grip strength (left and right) , birth weight , life satisfaction , positive affect , income , educational attainment , and intelligence . Meanwhile, smoking cessation, daytime sleepiness, daytime napping, adult-onset asthma, type 2 diabetes, coronary artery disease, ulcerative colitis suggestively causally increased risk of GORD, and strenuous sports or other exercises, HDL cholesterol, LDL cholesterol, leptin, and whole body fat-free mass suggestively causally decreased risk of GORD.We performed UVMR for the 66 exposures and GORDK = 3  , smoking initiation , and BMI  all showed independent causal effects on the risk of GORD. As the results of statistically significant genetic correlation of the other exposures with educational attainment, smoking initiation and BMI, we evaluated the independent causal effects of cigarette consumption, insomnia, short sleep, leisure sedentary behavior (TV watching), waist-to-hip ratio, height (standing and sitting), major depressive disorder, anxious feeling, life satisfaction and positive affect with adjustment of educational attainment , whole body fat mass , visceral adipose tissue , waist circumference , and hip circumference ], smoking initiation [lifetime smoking ], and educational attainment [income  and intelligence ] were excluded from MVMR analyses. After MVMR analyses , short sleep , waist-to-hip ratio , height (standing and sitting) , hand grip strength (left and right) , birth weight , major depressive disorder , anxious feeling , life satisfaction , and positive affect  retained their causal effects on the risk of GORD, similar to the UVMR analyses. Moreover, cigarette consumption and leisure sedentary behaviors (TV watching and computer use) did not exhibit independent causal associations with the risk of GORD following MVMR analyses.According to the results of the Bonferroni multiple comparisons from UVMR analyses, 26 causal exposures were identified to have significant causal effects on the risk of GORD. uster C)  was useduster C) . Among ttainment , smokingtainment , and BMItainment , and indtainment  and BMI tainment . Exposuranalyses , it was Previous MR studies examined the causal associations between smoking initiation, asthma, type 2 diabetes, BMI, waist circumference, waist-to-hip ratio, standing height, and the risk of GORD primarily among European-ancestry individuals in the UKB database , 35\u201337, Obesity, especially central obesity, contributes the risk of GORD by increasing the frequency of the transient lower oesophageal sphincter relaxation (TLESR) , intra-aSeveral large cohort studies and meta-analyses have demonstrated evidence linking smoking to GORD , 43, 44.Poor sleep quality appeared to be closely related to the risk of GORD. Mody et al. recorded 68.3% of 11685 GORD respondents with sleep difficulties, 49.1% experiencing difficulty falling sleep, and 58.3% struggling to stay asleep . This stAs of now, epidemiological studies are lacking regarding the direct impact of sedentary behavior on the risk of GORD. In a UK prospective cohort study, sedentary occupations had a higher risk of Barrett\u2019s oesophagitis comparing with standing occupations . In thisGastro-oesophageal reflux disease is common in individuals with anxious feeling and depression. A recent large cross-sectional study based on 19,099 participants provided evidence that anxious feeling and depression were associated with an increased risk of GORD . CorticoHand grip strength are customarily considered as surrogates for skeletal muscle mass, which is typically influenced by malnutrition and aging , 56. In It has been demonstrated that specific negative emotions have causal effects on the increased risk of GORD; however, there have been rare studies to investigate the correlations between positive emotions and the risk of GORD. An enlightening finding revealed that effective psychological intervention therapy has been shown to significantly improve GORD symptoms, such as globus sensation and non-cardiac chest pain , or, to Socioeconomic factors are also strongly associated with the risk of GORD in many aspects as well. According to a global meta-analysis containing 102 studies , the lowWe reviewed and summarized the modifiable factors and previous MR results that were associated with the risk of GORD to expand the scope of exposures included in the MR analysis to the largest extent, ensuring comprehensiveness of MR analysis. This study was also the first to rigorously and systematically examine genetic liabilities of modifiable factors for the risk of GORD, mitigating the impacts of potential confounders and reverse causalities as much as possible. Moreover, MR results in the discovery phase and replication phase were complementary, and meta-analysis for the above two phases enhanced the causal associations between exposures and the risk of GORD. MVMR analyses adjusted for hub exposures  estimated from PAM clustering algorithm also revealed novel insights into the independent causal effects of specific exposures on the risk of GORD.Some limitations were also taken into consideration in this study. Firstly, despite the fact that we systematically searched and summarized the factors related to the risk of GORD and SNPs recruited from exposures, the limitations of review scope design, as well as the lack of SNPs for some exposures might result in omissions or deviations when assessing causal associations. Secondly, it is generally accepted in MR analysis that there are two mechanisms for pleiotropy: one is that a genetic variant directly affects multiple phenotypes, which is defined as type I pleiotropy , and the second is that a genetic variant affects one exposure, while simultaneously also affecting other phenotypes through this expose, which is defined as type II pleiotropy  . As a geIn summary, we performed MR analysis in this study to identify the factors causally associated with the risk of GORD from 66 exposures across 6 modifiable pathways, which also provided references on the public preventive and therapeutic strategies for GORD from multiple perspectives, such as weight loss, proper high-level physical activities, high-quality sleep, non-smoking, and positive mental state.The original contributions presented in this study are included in the article/Consents for GWAS datasets were all acquired from public database.YS and JJ designed this study. YS, XC, and KS drafted the manuscript. YS, XC, DC, YC, KS, ZJ, and JJ conducted data collection and analysis. YW and JJ provided medical ethical reference. All authors contributed to the article and approved the submitted version."}
+{"text": "Sarcoptes scabiei and is believed to be consequent to certain predisposing factors such as immunosuppression, systemic lupus erythematosus, Down syndrome, immunodeficiency disorders, neurological disorders, and more, rather than by progression from ordinary scabies.Crusted scabies results from hyperinfestation with A 23-year-old woman, a known case of psoriasis vulgaris with an unstable disease course, presented twice within a span of 6 months with crusted scabies localized to acral parts. Both these episodes occurred while she was taking methotrexate . On both occasions, the patient was treated with two weekly doses of ivermectin, to which she responded completely, and methotrexate was continued.However, 1 year later, she presented with thick, grayish yellowish crusting, which was extensive over the body , while tThe older literature is contradictory with reports of both flare of scabies with methotrexate"}
+{"text": "Aging constitutes progressive physiological changes in an organism. These changes alter the normal biological functions, such as the ability to manage metabolic stress, and eventually lead to cellular senescence. The process itself is characterized by nine hallmarks: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. These hallmarks are risk factors for pathologies, such as cardiovascular diseases, neurodegenerative diseases, and cancer. Emerging evidence has been focused on examining the genetic pathways and biological processes in organisms surrounding these nine hallmarks. From here, the therapeutic approaches can be addressed in hopes of slowing the progression of aging. In this review, data have been collected on the hallmarks and their relative contributions to aging and supplemented with in vitro and in vivo antiaging research experiments. It is the intention of this article to highlight the most important antiaging strategies that researchers have proposed, including preventive measures, systemic therapeutic agents, and invasive procedures, that will promote healthy aging and increase human life expectancy with decreased side effects. Aging is depicted by a gradual functional decline causing the progressive deterioration that occurs heterogeneously across multiple organs, leading to organ dysfunction in mammals. It is a major risk factor for common chronic diseases, such as heart disease, cancer, diabetes, and Alzheimer\u2019s diseases . In receRecently, scientific achievements have been focused on producing effective antiaging therapeutics that have dramatically improved human life expectancy. Many studies on animal models looking at genetics and dietary and pharmacological interventions have shown an enhanced lifespan ,4,5. OthIn this review, we have attempted to collect various in vitro and in vivo research experiments for antiaging approaches based on the major hallmarks of aging. Here, we describe antiaging strategies such as telomere reactivation, epigenetic drugs, activation of chaperons and proteolytic systems, and dietary restriction. Mitophagy and the clearance of senescent cells, etc. will be beneficial in understanding the unique approaches for successful aging and to extend healthy lifespans.Caenorhabditis elegans and mice [Saccharomyces cerevisiae, Caenorhabditis elegans, and Drosophila melanogaster [2, GST, iNOS, and MPO genes and reduce the risk of inflammatory diseases through its immunosuppressive effects, with no adverse side effects on the enzymatic and nonenzymatic determinants [Chronic inflammation is one of the major contributors to age-associated diseases and aging and disrupts the normal functioning of tissues ,8,9. Incand mice ,35,36. Inogaster ,38. A norminants . This carminants ,41. Manyrminants ,43,44,45Phytochemicals such as phenolic acids and flavonoids have antioxidant activity, which acts by scavenging free radicals and increasing the levels of antioxidant enzymes in plasma . The funAstragalus membranaceus), a telomerase activator that can restore telomere length without cancer occurrence and improve age-related indicators, including glucose tolerance, bone health, and skin quality [(Centella asiatica), Nutrient 4 , TA-65 , OA (oleanolic acid), and MA (maslinic acid); and Nutrients 1, 2, and 3 have telomerase activation, and among all, 08AGTLF has the greatest potential to activate telomerase [Telomeres are conserved microsatellite repeats TTAGGG that protect the ends of chromosomes from DNA breakage and prevent DNA end-joining, recombination, and DNA repair . DNA pol quality . Additio quality ,72. Evid quality . A recen quality . Anotherlomerase . The implomerase .The effects of chromatin on aging are probably complex and bidirectional. Chromatin remodeling appears to counter aging and age-associated diseases and extend organismal lifespan . ChromatSaccharomyces cerevisiae [Caenorhabditis elegans [Drosophila melanogaster [Caenorhabditis elegans [Caenorhabditis elegans [c (cellular), which is a key component of the infectious agent responsible for transmission, and the disease-associated version of PrPc can be partially resistant to the protease\u2013digestion system, designated PrPsc (scrapie) [Loss of proteostasis is a common feature of aging that leads to protein aggregation, unfolding, oxidative damage, posttranslational modification, and an altered rate of protein turnover and, ultimately, to cellular dysfunction ,93,94,95revisiae ,104,105.revisiae ,107. Therevisiae . Promoti elegans  or in hu elegans  and the nogaster  increase elegans . Spermid elegans . In a re elegans . The pro elegans . It has  elegans . The priscrapie) . Variousscrapie) . This sy\u00fe precursors (NMN and NR), and resveratrol, have been shown to modulate mitophagy and repair mitochondrial functions [Mitochondrial dysfunction is one of the hallmarks of aging  that is unctions ,129,130 eNOS, GABARAP, LC3B, and ATG3 genes, which is a beneficial compound for extending the lifespan [Resveratrol  is a natural polyphenol that can induce autophagy and mitophagy by different mechanisms, such as activation of AMPK and SIRT1; induction of P38 MAPK; suppression of mTOR and p70S6K; and upregulation of lifespan ,137,138.Some natural compounds, such as spermidine and urolithin, preserve mitochondrial function and extend longevity through mitophagy induction, which has been demonstrated in several model organisms, such as yeast, nematodes, flies, and mice ,140,141.Caenorhabditis elegans [Drosophila melanogaster [Saccharomyces cerevisiae [Mus musculus [S. cerevisiae) [Drosophila melanogaster [C. elegans) [M. musculus) [C. elegans [D. melanogaster [M. musculus [Ribes fasciculatum (ERF) downregulate the insulin/IGF-1 signaling cascade and extend the lifespan in Caenorhabditis elegans [Caenorhabditis elegans by regulating the insulin/IGF-1 signaling (IIS) pathway [mTOR promotes cell growth by either promoting protein synthesis or inhibiting autophagy activity. It is involved in senescence-associated phenotypes. The mTOR pathway acts as a nutrient sensor through regulation of mitochondrial biogenesis , regulat elegans , Drosophnogaster ,155, Sacrevisiae ,157, andmusculus . Thus, ievisiae) , Drosophnogaster ,163,164,elegans) , and micusculus) ,186,187.usculus) ,199,200.usculus) . Another elegans , D. melanogaster ,204, andmusculus ,206. It musculus ,208,209. elegans ,210. Rec pathway ,212.C. elegans [5\u2032adenosine monophosphate-activated protein kinase (AMPK) is a master regulator of energy metabolism in the cell that plays a critical role in regulating health and longevity . AMPK is elegans .Cellular senescence is a central component of aging that leads to cell cycle arrest in a damaged cell by preventing the cell from promulgating further damaged tissues ,244,245.INK4a have been closely linked to a decline in stem cell populations with aging [+) can be used in stem cell-based transplantation therapies with better results [Stem cell exhaustion (decline in stem cell number and function) is one of the causes of aging that is observed in all tissues and organs and is maintained by adult stem cells through repair and regeneration during life ,265. Theth aging . Age-assth aging ,270,271.th aging ,273. Metth aging . Studies results . A study results . A recen results .The evidence highlighted that microbiome composition may affect the rate of aging ,279, altLong noncoding RNAs (lncRNAs) can affect key cellular processes, such as proliferation, differentiation, quiescence, senescence, the cellular response to stress and immune agents, and other cellular functions related to the biology of aging. LncRNAs have the ability to modulate gene expression patterns at the transcriptional, posttranscriptional, and posttranslational levels ,291,292.This review has attempted to explain the various antiaging strategies used based on the major hallmarks of aging. Data have been collected from scientific evidence, such as studies conducted on organisms and species targeting aging. These approaches would not only postpone chronic diseases but also prevent many age-related disorders and extend healthy lifespans. Aging and age-related diseases are due to abnormalities in normal biological pathways, such as metabolism, inflammation, growth, and protein synthesis, which also alter the rate of aging. Interestingly, modifications in the normal epigenetic pathway appear to be a major cause of chronic disorders. This review presents various protective interventions as antiaging strategies that are valuable to extend the human healthy lifespan. These include telomere reactivation, epigenetic drugs, activation of chaperons and the proteolytic system, caloric restriction, mitophagy activation, clearance of senescent cells, antioxidant and anti-inflammatory drugs, inhibition of mTOR and insulin/IGF-1 signaling (IIS), and stem cell-based therapy. Targeting senescent cells and inflammation plays a prominent role in aging, such as employing anti-inflammatory bioactive molecules in recent studies or, in some cases, nonsteroidal anti-inflammatory drugs (NSAIDs), senolytics, and SASP suppressors. To achieve adequate telomere length through telomerase activators, HDAC (histone deacetylase) inhibitors may be considered as antiaging agents. To rescue mitochondrial function and promote proteasomal activity, SIRT1 and AMPK activators and mTOR suppressors may be an effective way to combat aging. Reprogramming technology such as iPSCs and stem cell therapy, are emerging pieces of evidence for supplementing stem cells to rejuvenate tissues and organ functions. Thus, exploring the aging process at the molecular level is still a challenge, but the possibility of developing novel therapeutics by using nutraceuticals, molecular medicine, and pharmacogenomics approaches may be options for successful aging .Various scientific achievements have been focused on producing effective antiaging therapeutics that have dramatically improved human life expectancy. Many studies on animal models looking at genetics and dietary and pharmacological intervention have shown an enhanced lifespan. Thus, in this article, we have highlighted various antiaging strategies that have targeted approach-based hallmarks of aging. Researchers have proposed various strategies, such as preventive measurements, systemic therapeutic agents, and invasive procedures, that will promote healthy aging and increase human life expectancy with decreased side effects."}
+{"text": "Knee osteoarthritis (OA) and aging, may be viewed differently by various patients and health care providers. Aging is now considered as a systemic interplay of molecular, cellular, tissue, hormonal, and body dysfunctions. Important drivers of these factors lead to osteoarthritis, coronary artery disease, cancer and dementia. An understanding of each as its progresses can alter morbidity. The proposed theories of aging hold true for knee OA. A simple joint compartment model, such as the knee, may help this understanding. A degenerative knee OA joint is a progressive disorder, just like aging. Knee OA may be accelerated by trauma, aging, decreased autophagy, cellular changes, cytokine production, disruption of the matrix, and cellular senescence. The associated SASP leads to the progressive cascade of degenerative changes. Understanding how to mitigate these affects provides a framework for a longer healthspan. Obesity, and it\u2019s adipokines exacerbate the inflammation, and compound weigh bearing stress. Promotion of longevity pathways, stimulate repair via Sirt, AMPK, FOXO and decreased stimulation of MTor, and FOXO4- P53 coupling. The resulting changes can altering the nature of the accelerated nature of progressive knee OA. Joint conservation, unregulated IL-4, IL-10, IRAP, and down regulation of NF-kB, and the ensuing cascade of HMBG1, and DAMP. Hippocrates wrote walking is man\u2019s best medicine, however, with knee OA this may need amendment, to encourage proper medical guidance for appropriate exercise and diet. It is time to merge knee OA and aging models to work in harmony for prolonged health span."}
+{"text": "Despite significant progress regarding clinical detection/imaging evaluation modalities and genetic/molecular characterization of pathogenesis, advanced renal cell carcinoma (RCC) remains an incurable disease and overall RCC mortality has been steadily rising for decades. Concomitantly, clinical definitions have been greatly nuanced and refined. RCCs are currently viewed as a heterogeneous series of cancers, with the same anatomical origin, but fundamentally different metabolisms and clinical behaviors. Thus, RCC pathological diagnosis/subtyping guidelines have become increasingly intricate and cumbersome, routinely requiring ancillary studies, mainly immunohistochemistry. Meanwhile, RCC-associated-antigen targeted systemic therapy has been greatly diversified and emerging, novel clinical applications for RCC immunotherapy have already reported significant survival benefits, at least in the adjuvant setting. Even so, systemically disseminated RCCs still associate very poor clinical outcomes, with currently available therapeutic modalities only being able to prolong survival. In lack of a definitive cure for advanced RCCs, integration of the amounting scientific knowledge regarding RCC pathogenesis into RCC clinical management has been paramount for improving patient outcomes. The current review aims to offer an integrative perspective regarding contemporary RCC clinical definitions, proper RCC clinical work-up at initial diagnosis , RCC pathological evaluation, differential diagnosis/subtyping protocols, and novel clinical tools for RCC screening, risk stratification and therapeutic response prediction. Over the past decades, major technological and scientific breakthroughs have allowed for the development of important clinical tools for better RCC detection, evaluation, and therapeutic decision-making, while also reshaping medical understanding of RCC pathogenesis and progression-driving molecularities. Even so, RCC remains, to this day, one of the deadliest urological malignancies, accounting for ~3% of the total cancer burden in the global adult population .The widespread integration of ultrasonography (US) and computer tomography (CT) in routine clinical practice has significantly improved RCC detection yields, reflected in the long-standing and still ongoing stable increase in RCC incidence rates globally . ConcurrTo address these pervasive clinical limitations, regarding systemic/recurrent RCC therapeutic management and outcomes, contemporary RCC clinical definitions have been greatly nuanced and refined to better serve in RCC subtyping, prognosis assessment, and therapeutic response prediction. Classically, RCCs were simply defined as malignant parenchymatous renal neoplasms, spawning from tubular epithelial cellularity. However, in light of recent extensive RCC genomic profiling efforts and comprehensive metabolic molecular analyses, RCCs are currently viewed as an extremely heterogenic group of distinctive tumor subtypes, which only share an anatomical origin, while having different cellular progenitors, within the renal parenchyma. In fact, individual RCC subtypes demonstrate relatively specific, yet widely pleomorphic, tumor-driving molecular pathologies and pathognomonic genomics. This emerging intricate molecular amalgamation of novel RCC metabolic profiles, is firmly corroborated by the similarly extensive and well-documented clinical variability in RCC malignant behavior and therapeutic response, both between different RCC cases and disease phenotypes comparatively, but also during the natural evolution of individual RCCs  ,6.In lack of a definitive systemic treatment modality for advanced RCCs, integration of the amounting fundamental medical knowledge regarding RCC molecular pathology into RCC clinical management has been paramount to obtaining improved risk stratification and evidence-based therapeutic decision-making. As a result, definitive pathological diagnosis and RCC subtyping have become more nuanced and cumbersome, with the latest guidelines  identifying almost twenty distinct subtypes of malignant renal cell tumors, alongside mesenchymal, neuroendocrine, nephroblastic, and cystic variants ,7. Even To further complicate the already elaborate and dynamic landscape of RCC clinical management, systemic RCC therapy has been greatly diversified recently, with the advent of personalized oncological therapy and RCC tumor microenvironment molecular/genomic characterization initiatives. Notably, focused evaluation of the biologic implications of various inflammatory pathways regarding RCC metabolomics and proliferation, mainly the Von Hippel\u2013Lindau (VHL), mechanistic target of rapamycin (mTOR), tumor necrosis factor (TNF), and Janus kinase/signal transducer and activator of transcription (JAK/STAT)  pathwaysWith this acute need for harmonization in mind, between the effervescent field of RCC molecular pathology and the resulting best practice guidelines for RCC clinical management, we have elaborated the current literature review. The overarching aim is to facilitate RCC clinical management by offering a comprehensive review of contemporary RCC clinical definitions, semiology, and currently available imaging modalities for RCC detection and clinical work-up, while also focusing on RCC differential and definitive pathological diagnosis, subtyping, and prognosis assessment. Finally, we investigate and provide relevant data regarding emerging clinical tools for RCC screening, risk stratification, and therapeutic response prediction.Anatomically, the kidneys are relatively isolated and inherently inaccessible, as there are paired organs located in the retroperitoneum. Thus, many renal tumors remain undiagnosed at an early stage and develop unencumbered, being asymptomatic and non-palpable. Currently, more than 60% of RRCs are detected incidentally, given the routine use of non-invasive imagining procedures, in the evaluation process of other non-specific symptoms or basic workup for other unrelated diseases ,19,20. TDuring natural evolution , RCC-related symptomatology occurs due to the following pathological mechanisms: local growth, hemorrhage, paraneoplastic syndromes, or metastatic disease . If the Some of the rare clinical features of RCC are the paraneoplastic syndromes found in 10\u201320% of patients. Thus, RCC was previously considered the \u201cinternist\u2019s tumor\u201d due to the predominant systemic symptoms rather than local manifestations. Paraneoplastic syndromes rarely occur in small renal masses and are more common in end-stage disease ,25. ConsIt is important to identify paraneoplastic syndromes early on, as they can be a major source of morbidity and affect the decision-making process, during the management of patients with RCC. The most consistent clinical indicator, seen in >50% of RCC cases complicated with paraneoplastic syndromes, is an elevated erythrocyte sedimentation rate. Although non-specific, it may raise clinical suspicion and aid in early detection .The kidneys are biologically active organs, regulating and maintaining systemic homeostasis, by producing multiple essential molecules involved in fundamental systemic processes, i.e., 1,25-dihydroxycholecalciferol, renin, erythropoietin, and various prostaglandins. In the presence of RCC, the kidneys produce a pathological amount of these molecular mediators, as well as additional, biologically active, de novo molecules, similar in structure to other innate human hormones, such as parathyroid hormone-like peptides, lupus-type anticoagulant, human chorionic gonadotropin, insulin, various cytokines, and inflammatory mediators. Collectively, these hormonal imbalances appear to be responsible for the development of paraneoplastic syndromes, alongside constitutional symptoms, i.e., weight loss. The RCC-derived hormonal alterations associate a range of endocrine dysregulations, with clinically significant systemic consequences: Cushing syndrome, hyperglycemia, galactorrhea, neuromyopathy, clotting disorders, and cerebellar ataxia . In fact, as much as 13% of patients with RCC develop hypercalcemia due to either the paraneoplastic syndromes or an osteolytic metastasis of the skeletal system ,30. HypeOther important paraneoplastic syndromes seen in RCC patients are hypertension and polycythemia ,33. HypeAnother paraneoplastic syndrome associated with RCC is non-metastatic hepatic dysfunction, also known as Stauffer syndrome, reported in 3\u201320% of cases ,36. AlmoThe optimal treatment of RCC-associated paraneoplastic syndromes involves surgical cytoreduction and/or systemic targeted oncological therapy, aiming to reduce tumor burden, if curability is no longer attainable. Except for the therapeutic management of hypercalcemia, other non-oncological medical therapies have not proved helpful.The incidental detection of asymptomatic renal tumors has increased due to the inexpensive and widespread use of ultrasound (US) technology. The initial evaluation of parenchymal kidney lesions is usually done using B-mode US, which mainly distinguishes between cystic lesions and solid renal masses. For RCCs, gray scale US imaging shows an isoechoic or mildly hyperechoic, homogeneous or, especially for larger tumors, heterogeneous, solid parenchymal renal mass, with or without capsular bulging . The addIn recent years, contrast-enhanced US (CEUS), a highly accurate, and, as compared to MRI/CT, very cost-effective diagnostic tool, has found increasingly wider applications in the clinical evaluation of RCCs. CEUS plays an important role in assessing renal lesions in patients with significant contraindications for the use of conventional contrast-enhanced imaging techniques, i.e., impaired renal function, hyperthyroidism or metallic implants. Since the contrast agent used in CEUS remains confined to the vascular system, the investigation has the major advantage of being usable regardless of renal and/or thyroid function. Moreover, it is very helpful in the case of patients who are allergic to gadolinium or iodine-based contrast agents ,40,41. ARegarding the clinical evaluation of RCCs using CEUS, it is essential to keep in mind that RCCs are intensely angiogenic tumors, demonstrating a high density of thin-walled blood vessels. This inherent conformation may facilitate the rapid circulation of CEUS contrast agents, while also possibly shortening the perfusion and clearance of set agents. Conversely, angiomyolipomas usually demonstrate irregular blood vessels, with narrow lumens, leading to slower circulation and longer perfusion and clearance of contrast agents. Thus, as a general principle, when using CEUS for the clinical evaluation of solid renal masses, malignant lesions display higher perfusion rates and shorter time-intensity curves than their benign counterparts. Notably, RCCs have a pronounced tendency to develop areas of necrosis, calcification, and/or active hemorrhage, and the absence of perfusion within these tumor areas may alter the reading of parameters during CEUS. Moreover, preexisting renal hypotrophy, especially when associating endophytic tumor growth, may impair RCC identification and lower CEUS image quality, due to the intrinsically greater distance from the body surface to the evaluated lesion, as compared to exophytic focal lesions in normotrophic kidneys. Even so, recently, the largest European investigation focusing on the ability of CEUS to predict malignancy within the clinical evaluation of renal lesions, using histological validation, reported a high effectiveness and predictive accuracy for CEUS, comparable to, if not greater than those of more expensive imaging modalities . Beyond Moving on to the more modern, multiphasic, cross-sectional, contrast-enhanced, imaging techniques\u2014CT, MRI, molecular positron-emission tomography (PET-CT)\u2014we most note that, even though these tools have greatly improved both the sensitivity of RCC detection/initial diagnosis, as well as clinical staging abilities  for overtly malignant lesions, little progress has been made regarding the specificity of primary renal malignancy differential diagnosis through non-invasive imaging modalities. Aside from the Bosniak classification system for cystic renal lesions  and comp-infiltrative growth pattern of solid renal masses, although suggestive for malignancy, is not pathognomonic for RCC, only broadening the differential diagnosis ;-enhancement of \u02c315\u201320 Hounsfield units (HU) on CT is indicative of RCC, without excluding benign histology ;-large areas with negative CT attenuation numbers (<\u221220 HU) are indicative of intralesional fat and diagnostic for angiomyolipoma (AML) ,57;-enhancement of >20% with intravenous gadolinium-based contrast on MRI is suggestive of RCC  ;-papillary RCCs are often hypo-enhancing relative to other subtypes of RCC ,59.Due to the significant overlap of cross-sectional imaging characteristics for oncocytoma, clear cell RCC, and papillary RCC subtypes ,54, a coNovel molecular imaging tracers, i.e., high-affinity, radio-labeled, targeted molecules, aim to exploit and quantify known, high-specificity, key cellular processes involved in malignant tumor biology, in order to improve diagnostic imaging. Fluorodeoxyglucose (FDG), the most widely available tracer for PET-CT, has a very limited role in RCC differential diagnosis, due to its renal excretion and implicit high levels of visual conspicuity in the kidney and at the most common sites of metastatic disease . FurtherCurrently, as clinical definitions have become greatly nuanced, a complete RCC diagnosis requires careful multimodal evaluation, in a well-coordinated and phased approach, involving, at times, very difficult differentials.Notwithstanding the long-held, central role of RCC morphological evaluation, using standard microscopy and conventional hematoxylin\u2013eosin (HE) staining, in RCC definitive pathological diagnosis, essential for further therapeutic decision-making and predicting prognosis/risk stratification, in light of recent insights into RCC molecular pathology, the method, although still important, has become insufficient for adequate RCC subtyping. Even within the classical triad of conventional morphologies, namely clear cell (ccRCC), papillary (pRCC), and chromophobe (chRCC), which demonstrate relatively distinctive architectures and cellular features, microscopic evaluation of morphology remains subjective and user-dependent. Additionally, more often than not, meticulous evaluation will encounter, at least focally, overlapping patterns and/or atypical architectures, hindering definitive RCC subtyping. High-grade cellularity and severely dedifferentiated renal tumors lose characteristic morphological traits completely and cannot be subtyped using solely conventional staining microscopy. Determining metastatic cell origin, in advanced RCCs, with the additional difficulty of non-renal origin differentials, will most certainly require ancillary studies . In fact, as a general consensus among pathologists, no truly reliable, objective, and validated histologic/ultrastructural criteria exist for distinguishing between benign and malignant renal epithelial tumors , with thAll in all, conventional microscopic evaluation of RCC morphology remains an important initial step in tumor pathological analysis. It allows for an essential primary classification into RCC predominant morphological trait subgroups, simplifying the differential diagnosis and guiding further targeted analysis, while greatly reducing financial costs. Even so, it has become insufficient for an accurate definitive RCC diagnosis and prognosis assessment.Definitive RCC pathological diagnosis, meaning irrefutable demonstration of tumor renal cell origin and accurate RCC subtype identification, as well as the subsequent prognosis assessment, requires careful integration of clinical, pathological, and molecular characteristics, to allow for objective carcinogenic metabolic profiling and characterization of progression-driving tumor biology. Thus, as our understanding of RCC molecular pathology has become more nuanced, ancillary studies, mainly immunohistochemistry (IHC), has become integrated in clinical practice, as essential tools for routine RCC pathological evaluation. Despite the plethora of seemingly promising diagnostic and predictive applications reported, for the dozens of novel tumor-associated molecules and their corresponding IHC targeted-antibodies, due to the lack of validation studies, these data constitute no more than level 2/3 evidence. Moreover, heterogeneity within existing data regarding specific IHC methodology and antibody clone used  further encumbers comparisons between existing results ,69,70,71A recurring issue is represented by the indiscriminate use of an inordinate number of antibodies, without a reasonable, structured, diagnostic approach, which only serves to generate additional confusion, while simultaneously wasting valuable resources. For this reason, in 2012, the International Society of Urological Pathology (ISUP) reviewed the use of IHC antibodies in adult renal tumors, in order to develop best practice recommendations regarding determining site of origin, typing, and prognosis, with the ultimate goal of establishing formal panels of biomarkers for specific diagnostic difficulties and, implicitly, establishing adequate guidelines for stewardship ,64. For Overall, Paired box (PAX) 8, a transcription factor (415 aminoacids/48 kDa), involved in kidney, thyroid, and paramesonephric duct-derived, organogenesis, and homeostasis, represents the most useful IHC marker for establishing the diagnosis of metastatic RCC(mRCC) , being eOut of the PAX gene family for tissue specific transcription factors , PAX8 isNovel PAX8 antibodies (PAX8R1), to address the specificity issues of polyclonal PAX8 preparations, have been developed. They bind to the C-terminal of PAX8, targeting amino acids 318\u2013426, which are highly divergent among PAX proteins, thus abolishing cross-reactivity with other PAX species .Further nuancing of IHC differential diagnosis in mRCC involves markers almost always negative in RCC, such as pulmonary marker TTF-1, the intestinal marker homeobox protein CDX2, p63, prostate-specific antigen, and estrogen receptor, which will be useful in excluding other carcinomas that may manifest cross-positivity for PAX8. Positive staining with any of the aforementioned markers represents a strong argument against the diagnosis of mRCC ,164.Other supportive IHC markers of mRCC, currently in common practice\u2014cluster of differentiation (CD)10, RCC marker antigen (RCCm), Kidney-Specific Cadherin (Ksp-cadherin)\u2014manifest inadequate specificity and are not usually indicated or useful, outside of very specific, punctual, diagnostic subtleties.RCCm stains a proximal tubular antigen and demonstrates focal labeling in approximately 80% of RCC ,166, yetAnother proximal tubular marker, CD10, also manifests high sensitivity, but again very low specificity for RCC, as lung, bladder, colon, and ovarian carcinomas all label for CD10 . HoweverLastly, Ksp-cadherin, a distal tubular marker, manifests high sensitivity for chromophobe RCC (chRCC), although it is not so useful in the metastatic diagnosis context, as the chromophobe variant rarely disseminates systemically . Even soIn spite of the substantial improvements achieved so far, regarding RCC detection, diagnosis , and systemic treatment modalities, systemically disseminated RCC remains an incurable disease, while RCC mortality rates continue to rise. Thus, further investigations into RCC carcinogenesis are urgently needed to better comprehend the intimate mechanisms involved in disease occurrence and progression, and to possibly identify adequate biomarkers for RCC screening and risk stratification .For decades now, the scientific community has struggled to find predictive tools for the adequate and individualized characterization of RCC prognosis. Despite significant progress in RCC molecular pathology, RCC prognosis is still best evaluated by using traditional parameters, evaluating tumor anatomy and loco-regional extension/systemic dissemination , tumor histology , and clvon Hippel\u2013Lindau (VHL) and Polybromo 1 (PBRM1) genes [VHL/PBRM1), together with other recurrent mutations in non-specific genes, i.e., SETD2, KDM5C, PTEN, BAP1, MTOR, and TP53 [TP53 and PTEN (phosphatase and tensin homolog) mutations were encountered ubiquitously, in all conventional RCCs evaluated (ccRCC/pRCC/chRCC), yet prognostic value remained RCC subtype-specific. Thus, TP53 mutations in ccRCCs and pRCCs were indicative of diminished survival rates, while PTEN mutations associated the same decrease in survival, but only for chRCCs [As we enter a new era of personalized medicinal oncology, long-term, large-scale, and carefully coordinated genomic sequencing investigations, i.e., The Cancer Genome Atlas (TCGA), have already achieved full genome mapping for most cancers. Thus far, total RCC genome analysis has been achieved , resulti1) genes . Additioand TP53 , which ar chRCCs .MTOR) gene. Unsurprisingly, targeting these metabolic pathways in advanced ccRCCs using VEGF/mTOR inhibitors has demonstrated therapeutic value, improving disease-free survival rates, albeit with no effect on overall survival [Furthermore, it seems that, through various mechanisms, i.e., 3p chromosomal loss, gene mutations, or epigenetic alterations, the VHL metabolic pathway usually becomes inactivated in virtually all ccRCCs. Consequentially, the hypoxia-inducible factor (HIF) pathway undergoes uninhibited hyper-activation, upregulating downstream molecular mediators, such as carbonic anhydrase IX(CAIX), and vascular endothelial growth factor (VEGF) ,181,184,survival ,186,189.survival ,196,197,PBRM1 is mutated in a third of ccRCCs, according to TCGA data, being the second most common gene affected by (cc)RCC signature mutations, after VHL (~52%) [PBRM1 mutations are seemingly indicative of advanced local extension , in otherwise inconspicuous small renal masses, predicting perinephric/sinus fat/small vessel RCC invasion, which was not apparent on contrast enhanced imaging [Histone-Lysine N-Methyltransferase (SETD2) and Ubiquitin Carboxyl-Terminal Hydrolase (BAP1), have shown significant correlations with higher Fuhrman grades and unfavorable clinical outcomes [BAP1-mutant RCCs have more unfavorable clinical outcomes than PBRM1-mutant RCCs [Moreover, regarding ccRCCs exclusively, a distinct set of recurring mutations at the level of multiple chromatin remodeling and histone modifying genes has been reported. Interestingly, these genes are located on chromosome 3p, in the proximity of the pathognomonic VHL sequence ,201,202 L (~52%) . Althoug imaging . Conversoutcomes ,201,202.ant RCCs .Beyond the 3p chromosomal loss, mainly characteristic of ccRCCs, loss of 9p and 14q have also consistently associated with more aggressive RCC behavior and poor survival rates ,203,204.VHL), epigenetic modifications , and growth factor mediated intracellular signaling (MTOR). These major ccRCC metabolic alterations are evolutionarily advantageous for tumor cells, mainly translating to increased glycolysis, enhanced pentose phosphate pathways, downregulation of the tricarboxylic acid cycle, and augmented glutamine uptake. Thus, metabolic reprogramming allows ccRCC cells to survive in a hostile microenvironment, despite energy/nutrient deprivation and hypoxia, and to synthesize new building blocks for proliferation , while bypassing host immunosurveillance and counteracting oxidative stress [In fact, ongoing integrative molecular profiling efforts, focused on ccRCC pathophysiology, have highlighted the fact that ccRCC is much more than just the aberrant proliferation of renal cellularity, but rather a fundamentally metabolic disease, defined by specific key genetic mutations in target metabolic pathways, resulting in ccRCC metabolic reprogramming, throughout various cellular processes\u2014cellular oxygenation , which distinguished them from healthy individuals and post-nephrectomy patients. Upon further analysis, most of these metabolites were linked to pathogenic processes\u2014i.e., glomerular injury, renal inflammation, and renal necrosis/cell death. When comparing the urinary metabolome of the same ccRCC patients, prior to and post-nephrectomy, these pathogenic processes had apparently become inactive as a consequence of radical treatment .Additionally, regarding the adaptive alterations of the energetic metabolism in ccRCCs, a negative and proportional correlation has been established between the expression levels of glycolytic enzymes and progression-free/cancer-specific survival rates, i.e., higher expression levels associate poor disease outcomes. Apparently, the oncogenic signaling pathways responsible for rerouting the glucidic metabolism in ccRCCs are also central promoters of ccRCC carcinogenesis and progression. More specifically, the enhanced flux of glucides metabolized through the pentose phosphate pathway, in association with the upregulation of glucose-6-phosphate dehydrogenase, promote both anabolic reactions and redox homeostasis in ccRCCs. Promisingly, an inhibitory intervention within this metabolic adaptation may serve as a novel ccRCC therapeutic target .Focused and ongoing efforts to better understand ccRCC metabolic signatures, characterized by an anaerobic switch within the physiological energetic/glucidic cellular metabolism, towards the pentose phosphate pathway, have already proven to be fruitful, yielding multiple and seemingly promising novel RCC-associated molecular targets. Specifically, NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4-like 2 (NDUFA4L2), a HIF-1 target gene, encoding for a protein that attenuates mitochondrial oxygen consumption through inhibiting the electron transport chain Complex I, has been recently reported as being one of the most highly expressed genes in ccRCCs. NDUFA4L2 seemingly plays an important role within the process of ccRCC bioenergetic metabolic reprogramming , while also being involved in various other fundamental cellular processes . Also noteworthy is the fact that NDUFA4L2 over-expression apparently stimulates ccRCC drug resistance, seeing as NDUFA4L2 knockdown results in decreased ccRCC cell viability, and improved cisplatin susceptibility, implying that this protein can regulate chemotherapy resistance in ccRCCs .Conversely, despite both the well-established relationship between RCC stage at initial diagnosis and subsequent clinical aggressivity/overall survival , but also the grade-dependent nature of RCC metabolic reprogramming patterns , proliferation/cell cycle , cellulIdeally, beyond prognosis evaluation and systemic treatment case selection, after initial differential diagnosis, the ultimate oncological biomarker must also have cancer screening abilities, predicting the risk of disease occurrence even before carcinogenesis initiates. Promisingly, Kidney-Injury Molecule-1 (KIM-1), a glycoprotein specific to proximal tubular structures and well-established as a reliable urinary/plasmatic immunocytochemistry marker for the diagnosis of acute tubular necrosis/injury in acute renal insufficiency, has shown the ability to predict RCC occurrence, as early as five years before initial diagnosis ,224. AddEssentially, all types of malignancies, regardless of carcinogenic origin, occur when a cell/population of cells, regardless of specific causal molecular pathology mechanisms, acquire the ability to evade immune cytotoxic control and divide uncontrollably. Therefore, implicitly, a certain degree of local immune response dysfunction within the tumor microenvironment (TME) is a prerequisite for the occurrence of any malignant tumor, i.e., a disparity between cytotoxic tumor-targeted responses versus tumor-promoting inflammation. In the case of RCCs in particular, an intensely neoangiogenic and immunogenic subset of epithelial tumors, TMEs are generally volatile and remarkably dynamic, manifesting extreme cellular pleomorphism. The main bioactive cellular populations consistently expressed in the RCC TME are as follows: (myo)fibroblasts, adipocytes, sporadic neuro-endocrine cells, immune and inflammatory response cells, and endothelial cells. This cellularity can be found dispersed within an equally bioactive extracellular supportive matrix. Thus, RCC cells must constantly interact with this amalgamation of cells with distinct origins  and metabolic profiles, either directly, via secretion of autocrine/paracrine-acting mediators, but also indirectly, during RCC proliferation, via the occurrence of hypoxic/necrotic events. This elaborate and extremely disruptive interplay ceaselessly reshapes and metabolically redefines RCC biology. The resulting heterogeneity will most likely prove to be essential for obtaining an accurate and complete understanding of RCC carcinogenesis, not to mention an integrative perspective upon the plethora of already described molecular mechanisms allowing for RCC progression and therapy resistance .To date, the most significant breakthroughs achieved in RCC systemic therapy are a direct result of extensive assessment efforts of the biological significance of specific key inflammatory pathways within RCC metabolomics and in relationship to the RCC TME. As a result, multiple clinically relevant RCC-associated-antigens were identified and targeted therapeutic agents were subsequently developed . Subsequently, the RCC TME proved essential once again, within the process of defining and objectively quantifying the extent of RCC treatment responses. The meticulous evaluation of RCC TME treatment-induced modifications and the quantification of specific cellular TME constituents and the variations within their expression patterns after systemic treatment, facilitated the development of a more profound and nuanced understanding of these recently developed targeted systemic therapies, revealing their biological effects and specific molecular dynamics ,226.The ongoing effort to define the relationship more comprehensively between RCC cells and the various immuno-inflammatory host responses, has recently been additionally bolstered by an extensive analysis of the potential roles of complement system activation within the ccRCC TME, centered around the quantification of expression levels for Pentraxin-3 (PTX3), an innate immune regulator, both in ccRCC tumor samples and patient serum. PTX3 is able to activate the classical pathway of the complement system (C1q) and to release pro-angiogenic factors , thus stimulating ccRCC proliferation and dissemination. Furthermore, ccRCC patients consistently showed higher PTX3 serum levels, when compared to non-neoplastic controls. Additionally, higher PTX3 serum levels were strongly associated with higher Fuhrman grades, lymph node involvement, visceral metastases, and significantly diminished survival rates .Conversely, RCC TME investigations focused on local immunosuppressive molecular mechanisms, responsible for RCC carcinogenesis and progression due to the facilitation of host cytoxic immune response evasion, have provided promising, albeit still unvalidated, predictive tools for the assessment of RCC prognosis and risk stratification. A recent investigation quantifying the stratified expression levels for individual constituents of the kynurenine (KYN) pathway, through which tryptophane is metabolized in ccRCCs reported the involvement of KYN pathway enzymes/catabolites in ccRCC carcinogenesis, defining both immune and non-immune mechanisms. The most useful parameter evaluated was the KYN-to-tryptophan ratio (KTR), which was able to accurately predict ccRCC aggressiveness, while also demonstrating prognostic significance regarding cancer-specific survival and progression-free survival .Sustained RCC sequencing initiatives and big data processing are paramount for further pathway-targeted treatment development and a deeper understanding of RCC carcinogenesis. Furthermore, molecular characterization of anti-tumor immune responses vs. tumor progression facilitating inflammation will most likely offer a definitive cure for RCCs and, actually, for cancer in general. In fact, immunotherapy, the most recent oncotherapy, based on the novel principle of innate anti-tumor immune response activation, is the only available therapeutic modality which has the ability to target and destroy all types of tumor cells, regardless of cellular maturation, cell cycle, and metabolic status. More specifically, mitotically inactive, metabolically dormant, immature stem-like tumor cells are implicitly immune to other specific metabolic pathway-targeted systemic therapies, as they require tumor cells to manifest the targeted metabolic activity.Importantly, in the first clinical trial of its kind, KEYNOTE-564 evaluated the benefits of adjuvant immunotherapy (Pembrolizumab) in RCC patients, post radical/partial nephrectomy, and reported a significant improvement in disease-free survival, as compared to placebo, among RCC patients with a high risk of disease recurrence . CurrentDespite this burning need, to date, for metastatic RCC systemic therapy case selection, no specific molecular biomarker has shown treatment response predictive value ,230,231 The JAVELIN trial (NCT02684006) identified specific gene signatures (immunomodulatory-associated vs. angiogenesis-associated gene clusters), which seemingly had the ability to accurately and differentially predict progression free survival (PFS) rates for specific therapeutic modalities individually, namely for ICIs (avelumab + axitinib) vs. TKIs (sunitinib), respectively. Additionally, significant associations were also seen between PFS rates and mutational profiles, as well as histocompatibility leukocyte antigen variability, whereas PD-L1 expression and tumor mutational burden did not demonstrate any predictive value .In a conceptually similar manner but targeting different individual genes and evaluating a different combination of ICIs (atezolizumab + bevacizumab), the Immotion151 (NCT02420821) trial also established predictive immune response vs. angiogenesis-associated gene clusters, which showed simultaneous, yet opposing, correlations with improved PFS rates under ICIs (high immune response and/or low angiogenesis), as compared to sunitinib. Conversely, high angiogenesis signature expression associated improved PFS in the sunitinib group . CorroboHopefully, further investigations will be able to validate existing data and provide much needed clarity regarding the role of biomarkers in RCC treatment response assessment, ultimately allowing for the elaboration and standardization of a formal and integrative, clinical/molecular case selection protocol.In hindsight, the past five decades have seen significant developments in RCC detection and clinical evaluation modalities, as well as paradigm-shifting discoveries regarding RCC molecular pathology and RCC-driving metabolomics. Clinically, these developments have already translated into greatly improved detection capacities for occult RCCs, increasingly accurate and reliable RCC clinical staging protocols based on multimodal imaging evaluation, and more comprehensive RCC clinical definitions. Molecular insights into RCC carcinogenesis and proliferation have greatly nuanced contemporary clinical guidelines for the pathological evaluation of RCCs, providing better substantiated RCC differential diagnosis and subtyping protocols, and more objective risk stratification models. Notwithstanding the advent of RCC-associated-antigen targeted systemic therapy, nor the promising developments seen within the emerging, novel RCC immunotherapy clinical applications, advanced/systemically disseminated RCC remains incurable, with currently available therapeutic modalities only being able to prolong survival. Confoundingly, overall RCC mortality rates have been steadily rising for decades, in small but constant yearly increments, seemingly uninfluenced by the vast improvements made in RCC clinical management. Thus, although increasingly complex, currently available RCC clinical tools for prognosis assessment, treatment response prediction and systemic therapy are still seemingly insufficient for achieving true RCC curability and require urgent further improvement. The pressing and long-standing need for adequate RCC biomarkers, to resolve these deficits, remains unaddressed. The vast amount of existing data, regarding individual, promising RCC biomarkers must undergo extensive reevaluation and validation by external investigators in order to establish reproducibility, clearly define clinical utility, and standardize reporting and technical methodology. These are crucial conditions for assuring the transition from fundamental research initiatives to clinical tool development."}
+{"text": "Background:Candida bloodstream infections (candidemia) have significant mortality and morbidity rates, as well as healthcare cost implications. Emerging multidrug-resistant Candida spp such as Candida auris, as well as increasing resistance among non\u2013albicans species, which are becoming more prevalent, also raise concern. Understanding the epidemiology of this infection could enhance prevention and management efforts. We studied risk factors for candidemia. Methods: This matched case\u2013control study was conducted at a university hospital from December 2019 through May 2021. Cases of candidemia were identified using positive blood-culture results. Controls were matched 5:1 to cases by age, sex, and month and year of admission. Risk factors of interest included total parenteral nutrition (TPN), central venous access (CVA), neutropenia, Clostridium difficile, pancreatic disease, Candida in urine culture, cancer, invasive procedures, H2 blockers, chemotherapy, antibiotic use, immunosuppression, and antifungal use. Bivariate conditional logistic regression models were used to study the association of individual factors with candidemia. Multivariable conditional logistic regression models were performed using factors with a P Results: Overall, 101 patients with candidemia and 505 matched controls were included. In the bivariate analysis, associations were detected between candidemia and TPN, CVA, pancreatic disease, invasive procedures, H2 blocker use, antibiotic use, and antifungal use (all Ps Conclusions: Associations of candidemia with recent antifungal use and pancreatic disease were relatively novel findings. Neutropenia was not an independent risk factor for candidemia in this study. Future directions include further evaluations of previous antifungal use in patients with candidemia to identify opportunities for possible intervention and antifungal stewardship.Funding: NoneDisclosures: None"}
+{"text": "The patient voice is becoming increasingly prominent across all stages of therapeutic innovation. It pervades research domains from funding and recruitment, to translation, care, and support. Advances in genomic technologies have facilitated novel breakthrough therapies, whose global developments, regulatory approvals, and confined governmental subsidisations have stimulated renewed hope amongst rare disease patient organisations (RDPOs). With intensifying optimism characterising the therapeutic landscape, researcher-advocate partnerships have reached an inflexion point, at which stakeholders may evaluate their achievements and formulate frameworks for future refinement.Through this narrative review, we surveyed relevant literature around the roles of RDPOs catering to the rare paediatric neurological disease community. Via available literature, we considered RDPO interactions within seven domains of therapeutic development: research grant funding, industry sponsorship, study recruitment, clinical care and support, patient-reported outcome measures, and research prioritisation. In doing so, we explored practical and ethical challenges, gaps in understanding, and future directions of inquiry. Current literature highlights the increasing significance of ethical and financial challenges to patient advocacy. Biomedical venture philanthropy is gaining momentum amongst RDPOs, whose small grants can incrementally assist laboratories in research, training, and pursuits of more substantial grants. However, RDPO seed funding may encounter long-term sustainability issues and difficulties in selecting appropriate research investments. Further challenges include advocate-industry collaborations, commercial biases, and unresolved controversies regarding orphan drug subsidisation. Beyond their financial interactions, RDPOs serve instrumental roles in project promotion, participant recruitment, biobank creation, and patient registry establishment. They are communication conduits between carers, patients, and other stakeholders, but their contributions may be susceptible to bias and unrealistic expectations.Further insights into how RDPOs navigate practical and ethical challenges in therapeutic development may enhance cooperative efforts. They may also inform resources, whose distribution among advocates, parents, and clinicians, may assist decision-making processes around rare disease clinical trials and treatments. According to its widely accepted definition, a rare disease (RD) is a condition affecting no more than 5 in 10,000 people . Of 7000bella contra morbum, war against disease, they increasingly engage with researchers through sponsorship, recruitment, and logistical support [RD research has historically been neglected due to its limited target markets, patient renumeration capacities, and treatment profitability . Across  support . They re support , 15.Fig.Advances in genomic diagnostic and therapeutic technologies facilitate disease identification and novel treatment development. They potentially offer breakthrough therapies for many RDs, including neuromuscular and neurometabolic conditions like spinal muscular atrophy (SMA) and Batten disease , 17. EviMany advocacy foundations are adopting biomedical venture philanthropy models . In the Several studies describe potential difficulties associated with RDPO research fund allocation. Specifically, they identify poorly informed grant assignment, use of \u2018lay expertise\u2019 for decision-making, and insufficient communication between scientists and patient representatives regarding expectations as potential issues , 21, 26.By allocating funding specifically to RD research, public initiatives may secure financial backing without forfeiting the rigour of grant submission peer review processes . For insAccording to Dear et al. , dedicatAustralia\u2019s National Strategic Action Plan for Rare Diseases  highlights the importance of commercial research grants independent of governmental and volunteer-out-of-pocket funding in providing financial continuity, a sustainable workforce, and effective operation . This isIndustry intervention may introduce commercial biases into the representation of patient interests, misaligning public health priorities and advocacy-driven policies . This isThe sparse numbers and geographical distributions of people with RD can represent considerable research barriers. Studies highlight the unique ability of RDPOs to accumulate resources for researchers, commending RDPO support in project promotion, active participant recruitment, biobank creation, and patient registry establishment , 42, 44.Recent studies support the catalytic effect of researcher-RDPO partnerships on trial recruitment and retention. Peay et al.  surveyedAccording to a qualitative study in Australian mothers of children with SMA, financial, opportunity, and psychosocial caregiving costs affect all elements of family wellbeing, from career changes to biopsychosocial distress . Some caWhile constructing a 2015 policy framework for RD therapeutic development, Menon et al.  reportedRegarding the roles that RDPOs may assume in facilitating therapeutic access, there remains active academic discourse. Alongside their meaningful contributions to approval and reimbursement processes, RDPOs may advise pharmaceutical companies on managed access programs, enabling treatment prior to local approval, treatment subsidisation, and advocacy . Future Interventional studies increasingly focus on PROMs and PREMs, which may help align patient and researcher perceptions of clinically meaningful improvements . ConsumeIn translating clinical trial data to meaningful everyday outcomes, RDPOs serve a bidirectional role. Firstly, they may offer a comprehensive understanding of outcomes beyond clinical outcome measures and inform therapeutic benefits, acceptability, and expectations . In partSecondly, RDPOs can advise patients on the relevance of risk, benefit and outcome data to their lives . OptimisHistorically, relationships between scientists and advocacy leaders encounter varying degrees of tension, with conflicting research priorities serving a common source . PreviouNonetheless, these studies overlook the feasibility of demands for immediately applicable clinical breakthroughs and sometimes limited support ascribed to basic research. Pinto et al.  categoriAmong advocacy groups, there exists scope for improvement in efficiency and standardisation in order to meaningfully set and address research priorities. Interview-based studies demonstrate a positive correlation between organisational size and research contributions, noting that small, under-resourced groups often struggle to achieve research goals, due to high workloads, administrative costs, and replicative efforts , 21. In In the context of \u2018silo mentalities\u2019, data sharing is complicated by commercial conflicts of interest and concerns around forfeiting professional advantages secured through data ownership. However, limitations in data sharing hinder reciprocal operations between institutions . InsularTo many RDPOs, RD registries remain a notable research prioritiy. However, siloed efforts by small RDPOs may contribute to pitfalls of external completeness. An interview-based study reported that, of ten RDPO-run registries, the largest two still represented fractions of patients nationally, despite high absolute numbers . UmbrellRecent studies recommend further investment in international collaborative infrastructure to support therapeutic innovation , 79, 80.The past decade has observed a steady increase in therapeutic development, especially pertaining to rare paediatric neurological diseases . AlongsiBidirectional communication between patients and other stakeholders is becoming increasingly critical to the success of therapeutic innovation, with various umbrella organisations publishing guidelines and policy frameworks around RD research , 86. Pae"}
+{"text": "The fungal kingdom represents an extraordinary diversity of organisms with profound impacts across animal, plant, and ecosystem health. Fungi simultaneously support life, by forming beneficial symbioses with plants and producing life-saving medicines, and bring death, by causing devastating diseases in humans, plants, and animals. With climate change, increased antimicrobial resistance, global trade, environmental degradation, and novel viruses altering the impact of fungi on health and disease, developing new approaches is now more crucial than ever to combat the threats posed by fungi and to harness their extraordinary potential for applications in human health, food supply, and environmental remediation. To address this aim, the Canadian Institute for Advanced Research (CIFAR) and the Burroughs Wellcome Fund convened a workshop to unite leading experts on fungal biology from academia and industry to strategize innovative solutions to global challenges and fungal threats. This report provides recommendations to accelerate fungal research and highlights the major research advances and ideas discussed at the meeting pertaining to 5 major topics: (1) Connections between fungi and climate change and ways to avert climate catastrophe; (2) Fungal threats to humans and ways to mitigate them; (3) Fungal threats to agriculture and food security and approaches to ensure a robust global food supply; (4) Fungal threats to animals and approaches to avoid species collapse and extinction; and (5) Opportunities presented by the fungal kingdom, including novel medicines and enzymes. Workshop ParticipantsAlan Bernstein, PhD, CIFAR President & CEOKate Geddie, PhD, CIFAR Senior Director, ResearchLouis Muglia, MD, PhD, Burroughs Wellcome Fund President & CEOVictoria McGovern, PhD, Burroughs Wellcome Fund Senior Program OfficerLeah Cowen, PhD, CIFAR Fungal Kingdom Co-Director, University of TorontoJoseph Heitman, MD, PhD, CIFAR Fungal Kingdom Co-Director, Duke UniversityNeil Gow, PhD, CIFAR Fungal Kingdom Advisory Committee Member, University of ExeterJohn Taylor, PhD, CIFAR Fungal Kingdom Advisory Committee Member, University of California, BerkeleyDavid Blehert, PhD, CIFAR Fungal Kingdom Fellow, U.S. Geological SurveyChristina Cuomo, PhD, CIFAR Fungal Kingdom Fellow, Broad InstituteCameron Currie, PhD, CIFAR Fungal Kingdom Fellow, University of Wisconsin-MadisonMatthew Fisher, PhD, CIFAR Fungal Kingdom Fellow, Imperial College LondonLillian Fritz-Laylin, PhD, CIFAR Fungal Kingdom Fellow, University of Massachusetts AmherstSarah Gurr, PhD, CIFAR Fungal Kingdom Fellow, University of ExeterTimothy James, PhD, CIFAR Fungal Kingdom Fellow, University of MichiganHailing Jin, PhD, CIFAR Fungal Kingdom Fellow, University of California, RiversideBruce Klein, MD, PhD, CIFAR Fungal Kingdom Fellow, University of Wisconsin-MadisonJames Kronstad, PhD, CIFAR Fungal Kingdom Fellow, University of British ColumbiaDon Sheppard, MD, PhD, CIFAR Fungal Kingdom Fellow, McGill UniversityJason Stajich, PhD, CIFAR Fungal Kingdom Fellow, University of California, RiversideEva Stukenbrock, PhD, CIFAR Fungal Kingdom Fellow, Kiel University and Max Planck Institute of Evolutionary BiologyGerard Wright, PhD, CIFAR Fungal Kingdom Fellow, McMaster UniversityIuliana Ene, PhD, CIFAR Fungal Kingdom Azrieli Global Scholar, Institut PasteurAleeza Gerstein, PhD, CIFAR Fungal Kingdom Azrieli Global Scholar, University of ManitobaRebecca Shapiro, PhD, CIFAR Fungal Kingdom Azrieli Global Scholar, University of GuelphNicola Case, CIFAR Fungal Kingdom Meeting Reporter, University of TorontoJudith Berman, PhD, Tel Aviv UniversityRobert Cramer, PhD, DartmouthN. Louise Glass, PhD, University of California, BerkeleyChris Todd Hittinger, PhD, University of Wisconsin-MadisonTobias Hohl, MD, PhD, Memorial Sloan Kettering Cancer CenterIliyan Iliev, PhD, Weill Cornell Medical CollegeJeffrey Lorch, PhD, U.S. Geological SurveyAaron Mitchell, PhD, University of GeorgiaJulie Segre, PhD, National Human Genome Research InstituteAnita Sil, MD, PhD, University of California San FranciscoDawn Thompson, PhD, LifeMine Therapeutics, Vice President, Head of Microbiology and AutomationDespite their perception as something found in the forest or served up on a dinner plate, fungi are more than just mushrooms. They span an impressive range of sizes, from microscopic cells to among the largest organisms on Earth , produciFungal Kingdom: Threats & Opportunities research program (Inspired by colloquia held by the American Academy of Microbiology (AAM) in 2007  and 2017 program  and 2017 program  reports 2, is expected to raise global temperatures by 2\u20135\u00b0C in the coming decades  Cancer Centers and would enable efficient growth and translation of scientific knowledge for application in medicine, agriculture, and ecosystem conservation.Enhance and Sustain Training in Fungal Biology. There is a clear benefit to training more individuals to address the diverse facets of fungal biology and the impact of fungi on human, plant, and animal health. In particular, enhanced training in medical mycology, especially in areas where mycoses are endemic, would improve accurate diagnosis and informed treatment of patients. Moreover, the development of programs to train domestic animal and wildlife veterinarians, and to include them in discussions on managing fungal diseases of livestock and wild animals, would serve to further mitigate the impacts of fungi on animal health.Develop and Sustain Public Education and Outreach Programs to Increase Awareness of Fungal Diseases. Fungi are not widely regarded as major agents of infectious disease, despite the substantial burden they pose to human, plant, and animal health. Programs could be developed for implementation in schools and national parks to increase public awareness of the threats posed by fungal pathogens and the actions by which humans contribute to their spread.Develop Programs to Promote Partnerships Between Industry and Academia. Programs offering financial support, such as funding of graduate students and postdoctoral fellows, would promote collaboration between industry and academia. In addition, these partnerships would enable sharing of resources and expertise, as well as recruit talent to work in industry, ultimately accelerating the pace of innovation.Support and Sustain Fungal Genome Databases. Fungal genomics, transcriptomics, proteomics, and other \u201comics\u201d methods, as well as an increasing number of fungal genome sequences, have generated abundant and rich datasets. Compiling, storing, and annotating these data in an integrated format that is accessible to the community is critical to informing research and promoting advances. Developing and implementing unified taxonomy and standardized pipelines for next-generation sequencing methods would be beneficial.Support and Sustain Fungal Specimen and Culture Collections. Fungal specimen and culture collections are critical resources for understanding fungal biology, genetic variation, and evolution. These collections are likely to become increasingly important for examining the impact of climate change on fungi, tracking invasive species, and preserving fungal diversity. Moreover, fungal culture collections represent a rich source of chemical diversity for the identification of natural products that can be developed for clinical use. The long-term availability of these existing and new collections would be valuable in enabling fungal research.Report and Track Fungi That Cause Disease in Humans, Plants, and Animals. Documenting the global burden of fungal disease would enable increased understanding of disease emergence, range expansion, and the impact of drug resistance. To achieve this objective, public, domestic animal, and wildlife health agencies could implement programs to transparently report cases of fungal disease, and crop monitoring services could report fungal disease surveillance data to publicly accessible databases.Limit the Global Transport of Living Plants and Animals. Global trade can promote the spread of plant and animal fungal pathogens (Explore Strategies to Manage Wildlife Populations for Health. Management of wildlife infectious diseases has historically been reactive despite these diseases being difficult to treat. A paradigm shift toward proactive strategies that act to or are predicted to support ecosystem health and enable wildlife populations to build resilience and recover in the face of disease would be beneficial.Identify Fungal Threats and Opportunities That Have Emerged as a Result of the COVID-19 Global Pandemic. The COVID-19 pandemic has produced new patient populations that are vulnerable to fungal infection (The fungal kingdom presents enormous opportunities for applications in medicine, biotechnology, and environmental sustainability, while also posing devastating threats to human, plant, and animal health. Moreover, the breadth of fungal diversity remains relatively underexplored and the impact of climate change and emergent infectious diseases like COVID-19 on fungi have yet to be appreciated. Novel approaches would be beneficial to harness fungi to avert climate catastrophe, support plant health, mitigate wildlife disease, and identify new medicines. The goal of this report is to raise awareness on the diverse ways fungi impact health and disease, to spark innovative solutions to global challenges and fungal threats, and to provide suggestions for advancing the field of fungal biology. As highlighted in the recommendations herein, developing and sustaining infrastructure to support fungal research would catalyze the development of new strategies to mitigate the threats posed by fungi and harness their extraordinary potential."}
+{"text": "Esophageal stroke, also known as acute esophageal necrosis or Gurvits syndrome, is an entity that has gained more and more recognition in the last two decades. It is also named \u201cblack esophagus\u201d because of striking black discoloration of the esophageal mucosa, with an abrupt transition to normal mucosa at the gastroesophageal junction. Its most common clinical presentation is represented by upper gastrointestinal bleeding and esophagogastroduodenoscopy is the main diagnostic tool. Among the etiopathogenetic and multiple predisposing factors described are hypovolemia, shock state, ischemia, congestive heart failure, acute renal failure, infections, trauma, and diabetes mellitus. Current management of this condition consists of treating the underlying pathology, nil per os, and antacid administration in uncomplicated cases. Although most of the cases have favorable prognosis, complications such as pneumomediastinum or esophageal stricture may occur and fatal cases are a consequence of underlying comorbidities.  Computed Tomography (CT) showed the presence of necrosis around the pancreatic head and moderate ascites and minimal pleural effusion , but dysphagia, chest pain, epigastric pain, and vomiting can be experienced ,4,5. TheEndoscopy is the main diagnostic tool, but computed tomography could be helpful if complications such as esophageal perforation, mediastinitis, or pneumomediastinum are suspected ,9. The d"}
+{"text": "In the published article, there was an error regarding the affiliations for Jiangtao Li, Dong Zhao, Qiuju Deng, Yongchen Hao, Miao Wang, Jiayi Sun, Jun Liu, Guandi Ren, Huiqi Li, Yue Qi and Jing Liu.As well as having affiliation(s) 1,2, Jiangtao Li, Dong Zhao, Qiuju Deng, Yongchen Hao, Miao Wang, Jiayi Sun, Jun Liu, Yue Qi and Jing Liu should also have affiliation 3. Guandi Ren and Huiqi Li should not have affiliation 3.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "Community based participatory research (CBPR) builds mutually beneficial partnerships between diverse communities and researchers, yielding improved communication among stakeholders, more interest in research participation among community older adults, and improved insights on health disparities. CBPR approaches have great utility for culturally appropriate research design, data collection and analyses, and dissemination with minority underserved communities. We describe outreach, research methods, and community capacity-building from three projects with refugee communities in Greensboro, NC: the Montagnard Hypertension Research Project; The Refugee Older Adults Needs Assessment Project; and the Elder Abuse and Neglect exploratory study. These projects were initiated by community leaders, with technical partnership provided by university researchers and students. We used community-centric methods, and collected a range of data including interviews, photographs, oral histories, surveys, and biological specimens. These efforts have advanced social justice and health equity agendas for both academic and community partners, working to advance health of older adults."}
+{"text": "The estimated increase in world population will lead to a deterioration in global food security, aggravated in developing countries by hidden hunger resulting from protein deficiency. To reduce or avoid this crisis, a dietary shift towards the consumption of sustainable, nutrient-rich, and calorically efficient food products has been recommended by the FAO and WHO. Plant proteins derived from grains and seeds provide nutritionally balanced diets, improve health status, reduce poverty, enhance food security, and contain several functional compounds. In this review, the current evidence on the nutritional and functional properties of underutilized grains is summarized, focusing on their incorporation into functional foods and the role of their proteins as novel source of bioactive peptides with health benefits. In recent years, the continuous and concerning rise in world population and the consequent increase in food demand have challenged global food security. To aid with this global crisis, international organizations, governments, industries, and consumers are claiming sustainable, nutrient-rich and calorically efficient foods as an alternative or complement to animal products, and also reducing their associated negative-environmental impacts . Food inGramineae family) contain approximately 70\u201372% carbohydrates, 7\u201315% protein and 1\u201312% lipids, providing a significant source of energy in most diets when consumed as whole grains or in their refined form. Wheat, rice, and maize represent the major cereal crops sustaining over 50% of the worldwide caloric demand [Grain- and seed-enriched proteins include wheat, brown rice, maize, millet, cornmeal, oatmeal, amaranth, buckwheat, couscous, teff, quinoa, flax, chia, and pumpkin, as well as sunflower seeds, peanuts, walnuts, almonds, cashews, dates, kiwi, and cumin. Cereal grains  inhibition was found in serum, and the blood pressure of hypertensive rats was also reduced . Hence, Puffed snacks and muffins are other functional foods that have been targeted with amaranth. Regarding their nutritional composition, their higher protein, iron, zinc, and dietary fiber, as well as increased total phenolics, flavonoid content and antioxidant  diammonium salt (ABTS), and DPPH) activities have been described in puffed snacks and muffins enriched with amaranth, respectively ,15. More2+ chelation, and inhibition of Fe2+-induced lipid peroxidation, coupled to an increase of \u03b1-amylase and \u03b1-glucosidase inhibitory abilities, and a decrease in glycaemic indices in comparison to white-flour bread [When it comes to bread, Olagunju and colleagues  reportedur bread . Moreoveur bread . The cruIt is also possible to formulate beverages with amaranth proteins, as reported by two independent studies. In the study of Malgor and colleagues , amarantPolygonaceae family, buckwheat grains are rich in high flavonoids, dietary fiber, essential minerals, vitamins , and quality protein contents [Belonging to the contents . Apart fcontents . This reF. tartaricum) and chia were combinedly used in bread manufacture resulting in an increased amount of protein, insoluble dietary fibers, ash, alpha-linolenic acid, and in vitro antioxidant power, parallel to reduced energy and carbohydrate contents [Due to its protein, flavonoids, and rutin contents, buckwheat flour was used in bread production and found to increase iron content while the porosity and specificity of loaf volume became reduced . Likewiscontents .p-coumaric, sinapic, syringic, vanillic, protocatechuic acids, kaempherol, quercetin, apigenin, and orientin, and could partially correlate ACE inhibitory activity with the content of total phenolic compounds. Indeed, they observed a decrease in ACE inhibition, which was reverted by simulated gastrointestinal digestion, whereas higher anti-AGEs activity, antioxidant/reducing capacity and total phenolics contents were found following simulated digestion of biscuits [Buckwheat has been also used to formulate functional biscuits. Zieli\u0144ski and colleagues ,24 perfobiscuits ,24. It ibiscuits . Furtherbiscuits .F. esculentum Moench) and tartary buckwheat were comparatively studied for their cooking, textural, sensorial, and antioxidant activities in the noodling process [Common buckwheat  grains are included in the group of alternative food products that have attracted the interest of both consumers and the food industry in recent years because of its nutritional quality, functional effects, and proposed health benefits ranging from cardiovascular health to chemopreventive properties against chronic disorders. Chia belongs to the Lamiaceae family, and its seeds have high dietary fiber (35%), lipids (40%), high-quality protein (19%), natural minerals, antioxidants, vitamins, and polyphenol and tocopherol contents [Chia  in chia cannot be diminished. In the formulation of beef burgers, chia seeds and goji puree were evaluated for their effects on the fatty acid profile, lipid peroxidation, total phenols, and antioxidant capacity of cooked beef burgers . An incrThe use of chia in bread manufacture is another area for functional food development. Recently, chia seeds and kinako flour were utilized in the improvement of lipid profile in bread . The autFunctional yogurts are popular among consumers of functional foods. Hence, the study of Kowaleski et al.  developeOther functional food ingredients and products such as pineapple jam , cake 3, kulfi dLupinus albus L.) are distinguished by their high-quality protein and dietary fiber contents, which are associated with cholesterol-lowering activity. Their seeds are enriched with high levels of total unsaturated fatty acids and contain vitamins such as thiamine, niacin, riboflavin, and tocopherols, as well as minerals including iron, zinc, and manganese [Lupins  has been grown for more than five millennia and it is a good source of starch, vitamins, minerals, protein, fat, dietary fiber, and polyphenols [Quinoa . As some examples, optimal sensorial characteristics included good scores for bread quality indicators , improveInterestingly, the present review has found that confectionery items compiled the group of products with more positive entries in the sensorial analysis, while most of the negative outcomes have been reported in the case of grain-supplemented pasta products B. It hasOne of the benefits reported for underutilized grains are those associated with their protein component as novel source for bioactive peptides. On this basis, many reports have supported the idea that hydrolyzates and bioactive peptides produced from underutilized grains may provide healthful outcomes. The production technique, the degree of hydrolysis, the chain length of peptides and their physicochemical properties, as well as the amino acid profile will affect the activity of the resultant hydrolyzates. To release bioactive peptides from underutilized grains, the enzymatic hydrolytic method is an interesting alternative to solvent extraction, fermentation, and chemical treatments, as no residual organic solvents or toxic chemicals are released in the final products .Once the grain protein is treated with various proteases, broad hydrolyzates and peptides are produced, and may then be purified to attain and characterize specific bioactive peptides. Hence, the sequence of amino acids and chain lengths become altered after hydrolysis, creating novel functionalities, an attestation to the fact that different proteases produce different types of peptides from the same protein substrate ,62. TherThe protein component of amaranth makes this grain an ideal candidate for peptides exploitation. Alcalase, bromelain, chymotrypsin, trypsin, or protease have been repeatedly used in this process with observable activities reported after in vitro, in vivo, and ex vivo studies. For example, antimicrobial, ACE- and dipeptidyl peptidase (DPP)-IV-inhibitory, antihypertensive, antihaemolytic, anti-inflammatory, renin-inhibitory, radical-scavenging, and apoptotic activities of amaranth protein hydrolyzates have been reported ,70,71,72Specific sequences such as the fragment SSEDIKE have been associated with anti-inflammatory activity in human intestinal epithelial cells . LikewisStaphylococcus aureus, Salmonella typhimurium, Escherichia coli, and Enterobacter aerogenes), and antihaemolytic activities in human erythrocytes [Alcalase-treated quinoa peptides with a molecular weight lower than 5000 Da could confer ACE inhibition and radical scavenging activities . Howeverhrocytes .The chia protein hydrolyzates offer a wide range of biological benefits ranging from radical scavenging , metal chelating, and antimicrobial actions to ACE inhibition, hypocholesterolemic, antidiabetic, and antioxidant activities, among others .\u03b1-amylase and \u03b1-glucosidase inhibitory activities.San Pablo-Osorio et al.  reportedS. aureus and hypocholesterolemic effect through inhibition of \u03b2-hydroxy \u03b2-methylglutaryl-CoA (HMG-CoA) reductase [E. coli, Salmonella enterica, and Listeria monocytogenes [Recently, three different groups of researchers used fractions lower than 3 kDa obtained by the application of different enzymes for their bioactivity studies. The first group used alcalase, flavourzyme, and sequential alcalase-flavourzyme in the production of chia hydrolyzates with the capacity of displaying antimicrobial activity against eductase . The othytogenes . Lastly,ytogenes  demonstr\u03b1-amylase and \u03b1-glucosidase inhibitory activity [The buckwheat protein, specifically albumin, hydrolyzed by alkaline protease, and the isolated peptides GEVPW, YMENF, and AFYRW, possessed radical scavenging, metal chelating, and lipid peroxidation inhibitory effects . Earlieractivity . Howeveractivity .\u03b1-glucosidase inhibition. The antidiabetic and radical scavenging potential was also reported for peptides FEI, FEL, FIE, FKN, FGKG, and MEE derived from the albumin and globulin fractions of alcalase-treated chickpea protein [Very recently, chickpea peptides, namely SPGAGKG, GLAR, and STSA were identified after hydrolysis of germinated chickpea protein with papain or ficin . These p protein . In vivo protein .The synthetic peptide GPETAFLR, identified from lupin protein hydrolyzate, could play a preventive role against age-related macular degeneration as demonstrated by in vitro experiments in RPE cells and determination of protection of oxidative and inflammatory markers . HoweverBoth pearl and finger millet hydrolyzates have been studied for their health benefits . TrypticCalcium and iron-binding activities have been associated with mung bean peptides LLLGI, AIVIL, HADAD, and PAIDL, which were produced from a series of enzymatic hydrolyzates by alcalase, flavourzyme, trypsin, pancreatin, pepsin, pancreatin + alcalase, pancreatin + flavourzyme, neutral protease, or papain ,103. TheWhite, green, or sweet sorghum hydrolyzates also have healthful potential . AlcalasGastrointestinal digestion induces changes to food proteins by protein breakdown and peptide release derived from the physiological systems in the gastrointestinal tract including the action of digestive enzymes . Indeed,\u03b1-amylase inhibitory activities [Simulated gastrointestinal digestion of amaranth proteins, its sprout or germinated forms has allowed both the production of numerous protein hydrolyzates and the identification of multiple sequences including YESGSQ, GGEDE, NRPET, FLISCLL, TALEPT, HVIKPPS, SVFDEELS, DFIILE, ASANEPDEN and STHASGFFFFHPT, TIEPHGLLLPSFTSAPELIYIEQGNGITGMMIPGCPETYESGSQQFQGGEDE, GLTEVWDSNEQEF, STNYFLISCLLFVLFNGCMGEG with reported bioactivities such as anticancer and anti-inflammatory activities, ACE inhibition, radical scavenging, and DPP-IV and tivities ,114,115.\u03b1-amylase, and \u03b1-glucosidase inhibitory activities in different enzymatic assays [The use of biochemical assays has provided the examination of multiple peptides with several bioactivities derived from underutilized grains; this is an interesting screening method for food research before application of cellular systems . Hence, c assays . Simulatc assays . Trypticc assays ,120. DPPc assays . As for c assays .In cellular bioassays, antiproliferative activity has been recently discovered for amaranth proteins by independent groups ,109,115.In a step forward, some studies using protein digests have characterized specific peptides with antihypertensive properties in vitro which was further combined with proven health impact in animal models. This is the case of intestinal digests of quinoa, which showed antihypertensive effects in spontaneously hypertensive rats and ACE inhibitory action specifically associated with FHPFPR, NWFPLPR, and NIFRPF peptides . LikewisTrichoderma koningii, Rhizopus sp., and Fusarium oxysporum [B. cinerea [A few cases when enzymatic or gastrointestinal digestion techniques were not reported as the main proteolytic strategy, some alternative grain proteins have shown biological functions . As an exysporum . In anot cinerea .Lactobacillus casei Shirota and Streptococcus thermophilus 54102, in mono and combined culture, showed promising results for peptides bioactivity, as represented by ACE inhibition, radical scavenging and FRAP potential, and anti-thrombotic activities in some biochemical assays [Alternately, amaranth protein isolates on their own could produce several metabolic effects on animal models by reducing plasma and liver cholesterol levels, increasing FRAP values and diminishing thiobarbituric acid (TBA) values in plasma and liver as well as superoxide dismutase (SOD) activity in plasma, and finally decreasing blood pressure . Howeverl assays .In addition of the population rise, other factors such as the expanding knowledge of the negative environmental impact of farming practices and the adverse effects associated with the excessive consumption of certain animal proteins are promoting the demand for plant-based healthy and sustainable foods. In this changing agricultural system, grains and seeds (including underutilized grains) play an important role in terms of both supporting sustainable and cost-affordable agronomic practices and maintaining healthier diets. Although the nutritional and functional properties of underutilized grains and their protein components may be already known, the evaluation of the bioactive effects of hydrolyzates and peptides thereof is now represented as an emerging area of research with promising applications facing future challenges. These innovative studies are based on their alternative value as new ingredients for the development of functional foods, infant/elderly formulas, supplemented beverages, or pharma-cosmetics.Bioactive peptides are released from the parent protein through different approaches, being the enzymatic hydrolysis and gastrointestinal digestion the most studied. Enzymes such as pepsin, pancreatin, trypsin, papain, and alcalase, alone or in combination, have been recognized as suitable proteases to hydrolyze underutilized grains and liberate peptides with multifunctional peptides. Factors affecting the proteolysis process such as the type of enzyme and protein substrate, the substrate:enzyme ratio, and hydrolysis conditions , will result in different protein hydrolyzates, and consequently, different peptide profiles and a range of functional activities. Noteworthy, these bioactivities may be increased but also lowered and even lost during peptide production. Once identified, the use of in silico tools and the study of the physico-chemical properties, acid/basic/aromatic profile of amino acids, hydrophobicity, chain length, and molecular weight of bioactive peptides, along with the application of docking methods and omics analysis will help at deciphering of the mechanisms of action involved in their attributed physiological effects and health impacts. Also, stability, absorption and bioavailability models must be considered to provide additional information needed to confirm the potential of these bioactive peptides as novel functional food and nutraceutical ingredients."}
+{"text": "Yarlung Zangbo Grand Canyon National Nature Reserve has the most complete vertical vegetation belts in China. However, identification and distribution of vertical vegetation belts is still uncertain and in debate. To explore the above issues, 190 plots were surveyed within the reserve from 2019 to 2021. Based on the vegetation plot data, cluster analysis, ordination analysis, and biodiversity statistics were performed to reveal the structure of vertical vegetation belts\u2013the driving factors of vegetation distribution\u2013to describe the main biodiversity patterns. Five vertical vegetation belts were identified by clustering. NMDS ordination showed that the main factor of vegetation distribution is elevation. Based on the results of the analysis and previous literature, a new scheme of vertical vegetation belts in the south slope of the reserve was proposed. There was a lower montane seasonal rainforest belt (600\u20131100 m), a lower montane evergreen broadleaf forest belt (1100\u20131800 m), a middle montane semi-evergreen broadleaf forest belt (1800\u20132400 m), a subalpine evergreen needleleaf forest belt (2400\u20133800 m), a alpine shrubland and meadow belt (3800\u20134400 m), an alpine sparse vegetation belt (4400\u20134800 m), and a nival belt (4800\u20137782 m). Among them, the seasonal rainforest belts are the northernmost distribution of this type, and the semi-evergreen broadleaf forest belts exist only in the Eastern Himalayas. The study showed a unimodal pattern in plant species diversity, the peak of which is about 1900 m. The middle montane semi-evergreen broadleaf forest belt had the highest species diversity in the reserve. This study settled the issues regarding the vertical vegetation belts, the main drivers of vegetation and assessment of plant species diversity in the south slope of the Yarlung Zangbo Grand Canyon National Nature Reserve. It provides essential support for the management and conservation of these ecosystems in the reserve. Recognizing and using elevational subdivisions is at the core of biogeographical and ecological studies in mountain ecosystems . One of The Yarlung Zangbo Grand canyon, located in the Eastern Himalayas, has the most complete vertical vegetation belts in China, and is one of the most complete vertical vegetation belts in the world . In addi2 [The Yarlung Zangbo Grand canyon is also one of the global biodiversity hotspots ,17. Comp2 . In rece2 ,25,26,272 . In ordeHowever, vegetation surveys and research in Yarlung Zangbo Grand Canyon National Nature Reserve are hampered by the complicated environments and inconvenient transportation. It was until 1980 that Li et al. systematically reported the vegetation here for the first time, based on fifteen months of fieldwork . VegetatThe purpose of this study is to identify main vertical vegetation belts, the main environmental drivers of vegetation distribution, as well as to assess composition of plant communities and plant species diversity in the south slope of Yarlung Zangbo Grand Canyon National Nature Reserve. There are notable conservation gaps for disturbance of future climate change on ecosystem functioning and services , which rThe vertical vegetation belts were identified by ward\u2019s clustering and indicator species analysis. The clustering of all the 190 plots in the south slope of Yarlung Zangbo Grand Canyon National Nature Reserve produced five different groups by defining a K value = 5, based on fusion level value and silhouette width . The figTerminalia myriocarpa forest alliance. The mean cover of the alliance is 70\u201380%. The mean height is 30\u201340 m. The community structure can be divided into tree layer, shrub layer and herb layer. In some primitive forests, the epiphytes and lianas are well developed. In tree layer, Terminalia myriocarpa is the dominant species and usually has plank buttresses root. Common species mainly are Garcinia pedunculata, Cordia dichotoma, Gynocardia odorata, Homalium ceylanicum, Syzygium balsameum, Turpinia pomifera and Talauma hodgsonii. In shrub layer, Dendrocnide sinuate, Boehmeria macrophylla var. rotundifolia, Glochidion hirsutum, Ficus heteropleura and Rhynchotechum ellipticum are common species. In herb layer, Phrynium placentarium, Curculigo capitulate, Nephrolepis cordifolia, Pteris wallichiana and Pronephrium medogensis are common species. Epiphytes and lianas mainly are Neottopteris nidus, Lysionotus serratus, Lemmaphyllum drymoglossoides, Tetrastigma hypoglaucum, Rhaphidophora luchunensis and Rhaphidophora decursiva.Altingia excels is white, this alliance was protected as fengshui forest near the village. But shrub layer and herb layer were more damaged. The community structure can be divided into tree layer, shrub layer and herb layer. In tree layer, Altingia excels is the dominant species. Common species mainly are Meliosma pinnata, Brassaiopsis hainla, Albizia sherriffii and Macaranga denticulate. In shrub layer, Oxyspora paniculata, Saurauia griffithii, Maesa montana, Glochidion hirsutum and Buddleja myriantha are common species. In herb layer, Nephrolepis cordifolia, Amischotolype hispida, Selaginella effuse, Impatiens namchabarwensis and Elatostema hookerianum are common species. Epiphytes and lianas mainly are Millettia pachycarpa, Pothos chinensis, Aeschynanthus stenosepalus, Poikilospermum suaveolens and Dalbergia mimosoides. Macaranga denticulate forest alliance. The slash-and-burn farming method basically destroyed all the vegetation in the elevation range of 600\u20131900 m. After farmland was abandoned, secondary forest dominated by Macaranga denticulate was gradually formed. The forest has a simple structure and low species diversity. The mean cover of the alliance is 60\u201380%. The mean height is 22\u201328 m. Common species mainly are Castanopsis indica, Saurauia punduana, Ficus semicordata, Oxyspora paniculata, Phrynium placentarium and Piper thomsonii. Castanopsis indica forest alliance. The mean cover of the alliance is 70\u201380%. The mean height is 22\u201328 m. The alliance is seriously disturbed by human activities. In tree layer, Castanopsis indica is the dominant species. Common species mainly are Macaranga denticulate, Musa balbisiana, Saurauia napaulensis, Engelhardtia spicata, Ficus semicordata, Meliosma pinnata, Radermachera sinica. In shrub layer, Saurauia griffithii, Ardisia crenata, Glochidion hirsutum, Luculia pinceana and Maesa montana are common species. In herb layer, Phrynium placentarium, Pronephrium medogensis, Piper thomsonii, Curculigo capitulate, Nephrolepis cordifolia, Dicranopteris ampla, Impatiens namchabarwensis, Colocasia esculentum var. antiquorum and Elatostema acuminatum are common species. Epiphytes and lianas mainly are Embelia floribunda, Embelia parviflora, Dalbergia mimosoides, Smilax aspericaulis, Hedyotis scandens, Loxostigma griffithii, Lysionotus serratus and Lemmaphyllum drymoglossoides. Castanopsis ceratacantha forest alliance. The mean cover of the alliance is 80\u201390%. The mean height is 22\u201323 m. In tree layer, Castanopsis ceratacantha is the dominant species. Common species mainly are Macaranga denticulate, Meliosma pinnata, Saurauia punduana, Eurya trichocarpa, Cyclobalanopsis kiukiangensis and Pyrenaria tibetana. In shrub layer, Coriaria nepalensis, Oxyspora paniculata, Dendrocalamus tibeticus, Pyrenaria tibetana and Ardisia crenata are common species. In herb layer, Rubus metoensis, Oplismenus compositus, Nephrolepis cordifolia, Impatiens nyimana, Onychium siliculosum and Carpesium abrotanoides are common species. Epiphytes and lianas mainly are Helixanthera terrestris, Piper petiolatum, Tripterospermum volubile and Neottopteris simonsiana. Cyclobalanopsis kiukiangensis forest alliance. The mean cover of the alliance is 70\u201380%. The mean height is 35\u201345 m. The community structure can be divided into tree layer, shrub layer and herb layer. Primitive forests were well preserved, with well epiphytes and lianas. In tree layer, Cyclobalanopsis kiukiangensis is the dominant species and usually has plank buttresses root. In April and May, Cyclobalanopsis kiukiangensis shed all their leaves and quickly grow new ones in a dozen days. Common species mainly are Cyclobalanopsis kiukiangensis, Cinnamomum iners, Cerasus conadenia, Sorbus medogensis, Rhododendron arboretum, Acer pectinatum, Toxicodendron wallichii var. microcarpum, Machilus duthiei, Helicia tibetensis, Styrax grandifloras, Ilex longecaudata and Elaeocarpus varunua. In shrub layer, Chimonocalamus tortuosus, Smilax myrtillus, Damnacanthus indicus, Edgeworthia gardneri, Viburnum sympodiale, Ficus neriifolia, Skimmia melanocarpa and Lasianthus chinensis are common species. In herb layer, Campylandra aurantiaca, Arisaema concinnum, Elatostema hookerianum, Elatostema medogense, Rubus fockeanus, Pilea anisophylla, Ophiorrhiza rosea, Hydrocotyle salwinica, Laportea bulbifera, Sarcopyramis nepalensis, Fagopyrum dibotrys, Galium hoffmeisteri, Monotropastrum humile, Arisaema erubescens and Disporum longistylum are common species. Epiphytes and lianas mainly are Uncaria scandens, Embelia parviflora, Tetrastigma serrulatum, Trachelospermum jasminoides, Piper petiolatum, Rhaphidophora luchunensis, Rhaphidophora decursiva, Hedera nepalensis var. sinensis, Holboellia latifolia, Haplopteris doniana, Polypodiodes amoena, Hymenophyllum simonsianum, Pholidota articulate, Remusatia vivipara, Agapetes forrestii, Agapetes praeclara, Aeschynanthus angustissimus, Thladiantha cordifolia, Pleione hookeriana and Dendrobium salaccense. There are also more mosses and lichens in the forest. Its mean cover about is 20\u201330%. Cyclobalanopsis lamellose forest alliance. This alliance is very similar to Cyclobalanopsis kiukiangensis forest alliance in community structure and species composition. Both of them share the same range of elevation and are the main type of middle mountain semi-evergreen broadleaf forest belt. Exbucklandia populnea forest alliance. After forest of the belt was damaged, secondary forest dominated by Exbucklandia populnea was gradually formed. At the beginning of the succession, the alliance is small and dense with low species diversity. The mean cover of the alliance is 80\u201395%. The mean height is 15\u201325 m. In tree layer, Common species mainly are Schima parviflora, Symplocos lucida, Pinus bhutanica. Common shrubs and herbs mainly are Myrsine semiserrata, Ternstroemia biangulipes, Daphne bholua, Ardisia garrettii, Calanthe brevicornu, Tricholepidium normale, Campylandra aurantiaca, Ainsliaea latifolia. There are more litter on the ground, and its coverage about is 90%. Pinus bhutanica forest alliance. On a degraded swamp, or bare ground after a landslide, secondary forest dominated by Pinus bhutanica was gradually formed. At the beginning of the succession, the alliance is small and sparse with low species diversity. But Pinus bhutanica grows very fast, it can grow more than 40 m high in about 60 years. The mean cover of the alliance is 50\u201380%. The mean height is 15\u201345 m. In tree layer, Common species mainly are Gaultheria leucocarpa var. cumingiana, Ilex denticulate, Houpoea rostrate, Diploknema butyracea, Cyclobalanopsis lamellose, Exbucklandia populnea, Cinnamomum tamala, Elaeocarpus varunua and Alsophila spinulosa. In shrub layer, Viburnum erubescens, Enkianthus deflexus, Litsea cubeba, Rosa sericea, Ilex nothofagifolia, Calamus acanthospathus, Mycetia nepalensis, Lasianthus biermannii and Psychotria calocarpa are common species. In herb layer, Beccarinda tonkinensis, Ophiorrhiza rosea, Elatostema hookerianum, Sarcopyramis nepalensis, Elatostema nasutum, Pilea anisophylla and Balanophora harlandii are common species. Epiphytes and lianas mainly are Melocalamus elevatissimus, Rhaphidophora luchunensis, Rhaphidophora decursiva, Trachelospermum jasminoides, Hymenophyllum simonsianum, Neottopteris nidus, Pothos chinensis, Epigeneium rotundatum, Aeschynanthus lasiocalyx, Pyrrosia lanceolate, Odontochilus lanceolatus, Eria tenuicaulis, Bulbophyllum reptans, Dendrobium hookerianum, Pholidota articulate and Pyrrosia sheareri. Tsuga dumosa forest alliance. Tall and sparse primitive forests were well preserved. The mean cover of the alliance is 70\u201380%. The mean height is 35\u201345 m. The community structure can be divided into tree layer, shrub layer and herb layer. In tree layer, Tsuga dumosa is the dominant species. Common species mainly are Gamblea ciliate var. evodiifolia, Acer campbellii, Helwingia japonica, Lindera obtusiloba and Euonymus frigidus. In shrub layer, Daphne bholua, Berberis wilsoniae, Neillia thyrsiflora, Edgeworthia gardneri, Decaisnea insignis, Ribes glaciale, Leycesteria formosa, Euonymus sanguineus and Rhododendron delavayi are common species. In herb layer, Oxalis leucolepis, Circaea alpine, Ainsliaea latifolia, Plagiogyria glauca, Epipogium aphyllum, Pilea anisophylla, Anaphalis margaritacea, Botrychium robustum, Hydrocotyle salwinica, Maianthemum fuscum, Arisaema wattii and Impatiens tenuibracteata are common species. Epiphytes and lianas mainly are Lepisorus scolopendrium, Coelogyne corymbosa, Pleione bulbocodioides, Hymenophyllum simonsianum, Agapetes praeclara, Aristolochia griffithii, Actinidia venosa, Schisandra rubriflora and Vaccinium dendrocharis. There are also more mosses and lichens in the forest. Its mean cover about is 80\u201390%. Abies delavayi var. motuoensis forest alliance. Tall and sparse primitive forests are well preserved. But near the forest line, the alliance becomes sparse and small. The mean cover of the alliance is 50\u201380%. The mean height is 15\u201345 m. The community structure can be divided into tree layer, shrub layer and herb layer. Lianas and epiphytes are almost absent. In tree layer, Abies delavayi var. motuoensis is the dominant species. Common species are Gamblea ciliate var. evodiifolia, Acer campbellii, Sorbus wilsoniana, Daphniphyllum himalense and Betula utilis. In shrub layer, Fargesia melanostachys, Ribes glaciale, Lonicera tangutica, Enkianthus quinqueflorus, Hydrangea aspera and Clethra delavayi are common species. In herb layer, Sinopodophyllum hexandrum, Aletris pauciflora, Impatiens nyimana, Circaea alpine, Maianthemum atropurpureum, Synotis longipes, Arisaema elephas, Arisaema decipiens and Dryopteris wallichiana are common species. Epiphytes and lianas mainly are Haplopteris linearifolia, Rhododendron dendrocharis and Agapetes praeclara. There are also more mosses and lichens in the forest. Its mean cover about is 80\u201390%. Salix annulifera deciduous broadleaf shrubland alliance. The mean cover of the alliance is 70\u201390%. The mean height about is 0.2\u20130.4 m. In shrub layer, Salix annulifera is the dominant species. Common species are Gaultheria trichophylla, Berberis taronensis, Cassiope selaginoides, Diplarche multiflora, Rhododendron viridescens and Aster albescens var. levissimus. In herb layer, Polygonum viviparum, Cremanthodium phyllodineum, Bergenia purpurascens, Potentilla leuconota are common species. In winter, it will be covered by snow with a thickness of about 6 m. Rhododendron chamaethomsonii evergreen broadleaf shrubland alliance. The mean cover of the alliance is 70\u201390%. The mean height about is 0.1\u20130.2 m. In shrub layer, Rhododendron chamaethomsonii which creeps and grows on the ground is the dominant species. Common species are Diplarche multiflora, Rhododendron mekongense, Salix anticecrenata, Lonicera myrtillus and Gaultheria trichophylla. In herb layer, Polygonum viviparum, Cremanthodium rhodocephalum, Cardamine macrophylla, Saxifraga wardii and Saxifraga melanocentra are common species. In winter, it will be covered by snow with a thickness of about 6 m. Bergenia purpurascens alpine meadow grassland alliance. The mean cover of the alliance is 50\u201375%. The mean height about is 0.25 m. In herb layer, Bergenia purpurascens is the dominant species. Common species are Cardamine macrophylla, Senecio lingianus, Dryopteris lepidopoda, Saussurea nimborum. There are many large outcrops in the meadow. In winter, it will be covered by snow with a thickness of about 6 m.Altingia excels, Impatiens stenantha, Phrynium placentarium, Sambucus adnata, Impatiens namchabarwensis, Blumea balsamifera, Mussaenda decipiens, Terminalia myriocarpa, Boehmeria macrophylla var. rotundifolia, and Lagerstroemia minuticarpa.The elevation range of this belt was 600\u20131100 m. It lies at the base of the valley, which had experienced considerable slash-and-burn farming and longtime logging. Most of the primary vegetation had been destroyed, with some remnants in the valleys and steep slopes. There was a large area of secondary forests, but some saplings of dominant species from primary vegetation can be found in the underlayer. The top ten indicator species were Terminalia myriocarpa forest alliance, Altingia excels forest alliance, and Lagerstroemia minuticarpa forest alliance were the mainly primeval vegetation type. The secondary vegetation mainly included the Ficus semicordata forest alliance, Macaranga denticulate forest alliance, Saurauia polyneura var. paucinervis forest alliance, Albizia sherriffii forest alliance, Castanopsis indica forest alliance, Castanopsis hystrix forest alliance, Dendrocalamus tibeticus bamboo shrubland alliance, Ostodes paniculata forest alliance, Oxyspora paniculata evergreen broadleaf shrubland alliance, and Musa balbisiana shrubby grassland alliance. The Castanopsis indica, Glochidion hirsutum, Oplismenus compositus, Triumfetta cana, Desmodium sequax, Polygonum capitatum, Pteris cretica, Impatiens arguta, Colocasia antiquorum, and Strobilanthes dimorphotricha.The elevation range of this belt was 1100\u20131800 m. This vertical belt, which lies within the scope of human cultivation, had also experienced considerable destruction. The main reasons for primary forest destruction were slash-and-burn farming and longtime logging. The top ten indicator species were Castanopsis indica forest alliance, Castanopsis hystrix forest alliance, and Castanopsis ceratacantha forest alliance were the main primeval vegetation types. The secondary forest was similar to the lower montane seasonal rainforest belt. The Cyclobalanopsis lamellose, Exbucklandia populnea, Pholidota articulata, Ficus sarmentosa, Damnacanthus indicus, Disporum bodinieri, Cyclobalanopsis kiukiangensis, Arisaema concinum, Vaccinium kingdom-wardii, and Myrsine semiserrata.The elevation range of this belt was 1800\u20132400 m. The top ten indicator species were Cyclobalanopsis lamellose forest alliance and Cyclobalanopsis kiukiangensis forest alliance were the main primeval vegetation types. The Exbucklandia populnea forest alliance and Pinus bhutanica forest alliance were the main secondary forests. In addition, there were small contributions of the Alcimandra cathcartii forest alliance, Salix psilostigma forest alliance, Juglans sigillata forest alliance, and Populus wilsonii forest alliance. Usually, the Cyclobalanopsis lamellose forest alliance and Cyclobalanopsis kiukiangensis forest alliance were called the evergreen broadleaf forest. However, in the region, Cyclobalanopsis lamellose and Cyclobalanopsis kiukiangensis shed their leaves and grow new leaves within a month before the rainy season (April to May). Therefore, the alliances growing in Yarlung Zangbo Grand Canyon National Nature Reserve should be called a semi-evergreen broadleaf forest due to short time deciduous phenology. The Tsuga dumosa, Abies delavayi var. motuoensis, Acanthopanax evodiaefolius, Ribes glaciale, Acer campbellii, Pilea symmeria, Galium hoffmeisteri, Lindera obtusiloba var. heterophylla, Smilacina fusca, and Oxalis Leucolepis. The elevation range of this belt was 2400\u20133800 m. The top ten indicator species were Tsuga dumosa forest alliance and Abies delavayi var. motuoensis forest alliance. The primeval vegetation in the range was subject to little human interference. In some plots, the average height of the dominant species was over 40 m and its average diameter at breast height was also over 1 m. However, above 3400 m, Abies delavayi var. motuoensis forests were often stunted by perennial avalanches. The thickness of the snow in the area in March can reach up to 6 m.The main primeval vegetation types were the Pleurospermum angelicoides, Dryopteris barbigera, Viola biflora, Athyrium attenuatum, Geranium polyanthes, Cardamine macrophylla, Polygonum polystachyum, Pedicularis lineata, Rosa taronensis, and Rhododendron viridescens. The elevation range of this belt was 3800\u20134400 m. It was covered by snow for 6 months each year. There were frequent avalanches here that cause habitat fragmentation. Therefore, meadows and shrublands were mixed in the same vertical belt. The top ten indicator species were Rhododendron chamaethomsonii evergreen broadleaf shrubland alliance, Rhododendron viridescens evergreen broadleaf shrubland alliance, Rhododendron pumilum evergreen broadleaf shrubland alliance, Salix annulifera deciduous broadleaf shrubland alliance, Salix flabellaris deciduous broadleaf shrubland alliance, Salix rehderiana deciduous broadleaf shrubland alliance, Bergenia purpurascens alpine meadow grassland alliance, Polygonum viviparum alpine meadow grassland alliance, and Polygonum macrophyllum alpine meadow grassland alliance.The main primeval vegetation types were the The joint ordination diagram was obtained through overlaying the classification results onto the NMDS diagram . The NMDIn the reserve, 1416 vascular plants from 190 plots were recorded, belonging to 165 families and 609 genera. Angiosperms included 136 families, 543 genera, and 1273 species; Gymnosperms included 3 families, 6 genera, and 10 species; Pteridophytes included 26 families, 60 genera, and 133 species. The family with the highest number of species was Orchidaceae, including 35 genera and 81 species.The species richness, Shannon diversity index, Simpson diversity index, and Pielou diversity index were compared among five groups . The maxBased on these results and previous literature, we proposed a new scheme for vertical vegetation belts in Yarlung Zangbo Grand Canyon National Nature Reserve. There were seven vertical vegetation belts: the lower montane seasonal rainforest belt (600\u20131100 m), lower montane evergreen broadleaf forest belt (1100\u20131800 m), middle montane semi-evergreen broadleaf forest belt (1800\u20132400 m), subalpine evergreen needleleaf forest belt (2400\u20133800 m), alpine shrubland and meadow belt (3800\u20134400 m), alpine sparse vegetation belt (4400\u20134800 m), and nival belt (4800\u20137782 m). This scheme was similar to the previous schemes in the lower montane seasonal rainforest belt, alpine shrubland and meadow belt, alpine sparse vegetation belt, and nival belt, but different in the lower montane evergreen broadleaf forest belt, middle montane semi-evergreen broadleaf forest belt, and subalpine evergreen needleleaf forest belt .Castanopsis and Cyclobalanopsis species, are considered as evergreen broadleaf species [Cyclobalanopsis lamellose and C. kiukiangensis, had a special deciduous phenological period, which was remarkably different from other Cyclobalanopsis species that dominated the evergreen forests in the subtropical region of eastern China. The special seasonal variation had been observed from 2019 to 2021 ). By using the Spearman correlation coefficient, the correlations between 22 environmental variables were calculated. For variables with spearman correlation coefficients greater than 0.4, the most ecologically important factors were chosen to vegetation analyses. Finally, six variables were reserved. They are: elevation, slope, aspect, annual precipitation (Bio12), precipitation of driest month (Bio14), and precipitation seasonality (Bio15).Vegetation surveys were conducted from May 2019 to July 2020. Along the elevation gradients of Xirang 550 m)\u2013Duoxiongla (4200 m) and Xiranng (550 m)\u2013Galongla (4300 m), the survey was conducted by every 100 m elevation span . In addi m\u2013DuoxioThe primary data from the field surveys were transformed in a matrix of 190 plots \u00d7 1416 species, which were log (x + 1) transformed. Alliances were named according to the vegetation classification system of China ,56. The To relate the species composition of the accepted groups to environmental variables, Nonmetric Multidimensional Scaling (NMDS) ordination was used based on Bray\u2013Curtis dissimilarity . The lowThe species richness, Shannon diversity index, Simpson diversity index, and Pielou diversity index were calculated by using the vegan package . The BarWe reviewed and summarized previous literature about vertical vegetation belts in Yarlung Zangbo Grand Canyon National Nature Reserve. Based on previous literature and the results of cluster analysis and ordination analysis, we proposed a new scheme for the vertical vegetation belts of the reserve. The new scheme was compared with previous schemes by histogram. Their similarities and differences were discussed.We proposed a new division scheme of vertical vegetation belts in Yarlung Zangbo Grand Canyon National Nature Reserve and discussed differences and similarities with previous schemes. The establishment of the semi-evergreen broadleaf forest was supported in the new scheme. The main factor affecting vegetation distribution is elevation. However, the elevation range of the lower montane seasonal rainforest belt and lower montane evergreen broadleaf forest belt was similar. The main reason is that slash-and-burn farming and longtime logging are greatest and most frequent in the region. Thus, the biodiversity of the region has decreased significantly. Meanwhile, the middle montane semi-evergreen broadleaf forests had the highest biodiversity. Therefore, we recommended that tropical seasonal rainforests and semi-evergreen broadleaf forests should be protected as soon as possible. Based on the distribution of vegetation and the condition of biodiversity, local governments can better formulate conservation strategies to optimize conservation efforts and cope with global climate change."}
+{"text": "This study sought to determine the impact of selected social determinants of health on psychological health and well-being  among Black and Hispanic/Latinx adults relative to White adults aged 51 to 89. We measured disparities in depression, cognition, and self-rated health among 2,306 Non-Hispanic/Latinx Black, 1,593 Hispanic/Latinx, and 7,244 Non-Hispanic/Latinx White adults from the Health and Retirement Study . Blinder-Oaxaca decomposition was used to examine whether differences in selected social determinants of health explained a larger share of the disparities than age, sex, measures of health, health behaviors, and healthcare utilization. Selected social determinants included education, parents\u2019 education, number of years worked, marital status, veteran status, geographic residence, nativity status, income, and insurance coverage. Black and Hispanic/Latinx adults reported worse depression, cognition, and self-rated health compared to White adults. Selected social determinants of health explained a larger proportion of the Black-White disparities in depression (51%), cognition (39%), and self-rated health (37%) than did age, sex, measures of health, health behaviors, and healthcare utilization. Social determinants of health explained a larger proportion of the Hispanic/Latinx-White disparity in cognition (76%) and self-rated health (75%), but age and functional status primarily drove the disparity in depression (28%). Education, parents\u2019 education, years worked, income, and insurance parity were social determinants associated with the disparities.In conclusion, differences in social determinants of health underlie racial/ethnic disparities in depression, cognition, and self-rated health among older adults. Education, income, number of years worked, and insurance parity are key social determinants of health."}
+{"text": "UTI admission rates are 3.4 times higher among persons with dementia (PWD) than among those without dementia. The hospitalizations often result in adverse health complications such as the increased risk of delirium, cognitive decline, and higher mortality. To date, several UTI guidelines exist for specific populations, including women, children, people with catheters, and long-term care patients; however, there has been little focus on non-pharmacological prevention and management in PWD. The goal of this work is to propose a theoretical framework for UTI prevention and management in community-dwelling older PWD with the following three aims: 1) identify factors and outcomes of UTIs in community-dwelling older PWD; 2) generate a conceptual framework informed by Bronfenbrenner\u2019s 1977 ecological model; 3) integrate preventive measures to the adapted framework. We conducted a scoping literature review utilizing the following keywords and concepts: risk factors, UTI management and prevention, community-dwelling older adults, and dementia. The UTIP framework was generated with four levels of risk factors  and four domains of affected outcomes . Additionally, seven themes of preventive measures emerged: physical activity and mobility, behavioral therapy, personal hygiene, phytotherapy, dietary, compound, and hormone. Finally, a table of care management opportunities was proposed according to dementia severity and caregivers\u2019 involvement. In conclusion, the UTIP framework synthesizes exciting and is flexible to accommodate new evidence. As such, the framework is informative for programs, practices, and policies to lower the risks of preventable admission in PWD."}
+{"text": "After an initial improvement, the patient became suddenly hypotensive, and passed away soon after. The autopsy revealed widespread cryptococcal involvement, with the most severely affected organs being the brain, lungs, pancreas, adrenal glands, and spleen. The pancreas and one of the adrenal glands revealed diffuse granulomatous cryptococcal infection, with large areas of necrosis. The spleen also showed a large area of cryptococcal necrosis. In addition, the patient had chylous ascites, without histologically identifiable organisms. (3) Conclusions: This is a rare case of disseminated cryptococcal infection with severe necrotizing adrenalitis and pancreatitis, in addition to significant spleen, lung, and central nervous system involvement. The early recognition and treatment of the adrenal gland and pancreas cryptococcosis with surgical interventions may lead to better outcomes in affected patients. Furthermore, steroid treatment and diabetes mellitus may be risk factors for adrenal gland involvement. Additionally, clinicians should keep cryptococcal infection in their differential diagnosis for isolated adrenal gland and pancreas lesions.  Cryptococcus [Cryptococcal infections most commonly cause meningoencephalitis and pneumonia in immunocompromised patients, including patients with HIV infection/AIDS, hematologic malignancies, severe liver disease, or patients on chemotherapy or immunosuppressant medications . In additococcus ,5. ReporThe purpose of this case report is to highlight the possible pancreatic and adrenal gland involvement with cryptococcal infection, which can significantly worsen the affected patient`s morbidity and mortality. Additionally, these cases might require surgical interventions in addition to anti-fungal therapy, in order to eradicate those foci of infection, ultimately improving outcomes.Cryptococcus neoformans (var grubii), amphotericin and flucytosine were added to his treatment, which initially improved his condition, allowing for extubation. His mental status also significantly improved, with low/normal sodium levels (~135 mmol/L), and normal renal function. His clinical course later, however, was complicated by increased intracranial pressures, requiring intermittent cerebrospinal fluid drainage. Weeks later, he had a sudden deterioration with hypothermia, repeated hyponatremia (128 mmol/L), intermittent hypoglycemias (down to 50 mg/dL), altered mental status, and severe hypotension, requiring vasopressor therapy. This was followed by multiorgan failure, including renal failure, and despite all the treatment efforts, he passed away a few days after his deterioration.Here, we report the case of a 75-year-old gentleman who had a medical autopsy in our department. His past medical history was significant for type 2 diabetes mellitus (T2DM) and immunocompromised state following a cadaveric kidney transplant two years before his last hospital admission. His pre-admission medications included mycophenolate, tacrolimus, and prednisolone. He initially presented to the hospital with generalized weakness, altered mental status, hypoxemia, mild hyponatremia (130 mmol/L) and hypochloremia (96 mmol/L), and normal renal function , C. deneoformans , and C. gattii species complex  [C. neoformans has a widespread distribution and is found in high concentrations in bird droppings and in the soil, C. gattii has been described in tropical and subtropical regions, and also in parts of Canada and the Pacific Northwest USA [Cryptococcus is a basidiomycete fungus disguised in a polysaccharide capsule, spreading via inhalation or skin inoculation with fungal cells from the environment. The human pathogen  gattii) . While Cwest USA ,6.C. neoformans most often causes infection in immunocompromised patients, there are reports of cryptococcal infection in people with diabetes mellitus, autoimmune diseases, liver disease, and in seemingly healthy people too. C. gattii, on the other hand, often causes infection in immunocompetent hosts [Although nt hosts ,7,8. Cryptococcal infection typically causes granulomatous infection at the primary site of entry, which can be cleared or cause acute or chronic infection. Additionally, this facultative intracellular organism can survive in phagocyting cells, using them as \u201cTrojan horses\u201d. Disseminated disease can occur shortly after the primary infection or after a latency phase. During the latency period, the organism remains dormant, possibly for decades, and can be reactivated when the immune system weakens, for example during immunosuppressant therapy ,7,9,10.Cryptococci frequently involve the eye, spleen, liver, bone marrow, kidney, prostate, lymph nodes, peritoneum, or skin [Cryptococci without inflammation, along with occasional necrosis [As previously mentioned, besides lung or CNS infection,  or skin ,11,12. Cnecrosis . Anothernecrosis . In addinecrosis . Interesnecrosis . Severe,Cytomegalovirus and Mycobacterium tuberculosis , with fungal infection also rarely described. As opposed to H. capsulatum or paracoccidiomycosis, however, adrenal insufficiency is rare in other fungal infections, such as in cryptococcosis [The other unusual site of Cryptococcal infection in our case was the adrenal glands, where multiple small and large foci of necrosis were seen, both in the cortex and medulla. It is, however, more often seen than pancreatic involvement. In developing countries, the most common infectious causes of adrenal gland destruction are coccosis ,18. Indecoccosis ,18,19. Icoccosis ,36,37,38coccosis ,33,36,37coccosis ,36,37,38coccosis ,24,31 orcoccosis ,36,37,38coccosis ,28,30,35coccosis ,36. Sympcoccosis ,29,30,37coccosis ,21,25. Icoccosis ,24,31,32Cryptococci have a tropism to lipids, such as the brain or possibly to the retroperitoneum, this is unclear. However, besides their main virulence factor, the large polysaccharide capsule, fungal metalloproteases are known to play an important role in CNS invasion [Cryptococci [Cryptococci have tropism to organs high in lipids, or with a significant amount of peri-organ fat; as in our patient\u2019s case. It also highlights that these organs may serve as reservoirs for the fungus, enhancing cryptococcal infection and proliferation. Finally, Cryptococcus might be similar to H. capsulatum in its tropism to areas of high local concentrations of corticosteroids, such as the adrenal gland [As to why invasion ,39. Fungptococci ,41,42,43ptococci . Taken tThis is a case of disseminated cryptococcosis in an immunocompromised patient that was complicated by severe cryptococcal adrenalitis and pancreatitis, along with significant CNS, lung, prostate gland, and splenic involvement. The adrenal gland and pancreas involvement resulted in large areas of necrosis, which contributed to the patient`s morbidity, and likely to his mortality. Although these two organs are less known as involved in cryptococcal infections, this case highlights the need for clinicians to have a high index of suspicion for adrenal gland or pancreatic involvement in certain patient populations, such as patients on steroid treatments or patients with diabetes, as the symptoms can be non-specific or can be masked by severe illness. Cases of significant adrenal gland or pancreas involvements or in isolated infections may go unrecognized, allowing for significant morbidity before an appropriate treatment is initiated. Surgical intervention, in many of these cases, might alter the course of the disease."}
+{"text": "Infectious diseases constitute an increasing threat to public health and medical systems worldwide. Particularly, the emergence of multidrug-resistant pathogens has left the pharmaceutical arsenal unarmed to fight against such severe microbial infections. Thus, the context has called for a paradigm shift in managing bacterial, fungal, viral, and parasitic infections, leading to the collision of medicine with nanotechnology. As a result, renewed research interest has been noted in utilizing various nanoparticles as drug delivery vehicles, aiming to overcome the limitations of current treatment options. In more detail, numerous studies have loaded natural and synthetic antimicrobial agents into different inorganic, lipid, and polymeric-based nanomaterials and tested them against clinically relevant pathogens. In this respect, this paper reviews the most recently reported successfully fabricated nanoformulations that demonstrated a great potential against bacteria, fungi, viruses, and parasites of interest for human medicine.  Even though humans and pathogens have always dynamically interacted, this relationship became unbalanced. Human activities have caused pathogenic microbes, such as bacteria, fungi, viruses, and parasites, to appear and spread at a progressively distressing rate, rendering infectious diseases a common and burdensome health issue worldwide ,2,3,4. NUnfortunately, biofilms have become a highly frequent problem in the clinical environment as microorganisms may adhere to and colonize the surfaces of biomedical devices. Thus, in order to avoid the acquiring of nosocomial infections, the burden of biofilms must be especially considered when using implantable and indwelling medical devices  ,21,22,23Despite existing therapies and medicines, infectious diseases in general, and biofilms in particular, remain difficult-to-eradicate problems . TherefoIn this respect, the present paper aims to overview the most recently developed antimicrobial nanoformulations, fabricated mainly between 2018 and 2022, that showed promising results when tested against clinically relevant pathogens, emphasizing their utility and versatility. Even though the topic has been previously addressed by several works ,34,35,36NPs represent a key component in developing innovative anti-infectious strategies merging therapeutics and new materials toward enhancing antimicrobial potential. Their advantageous intrinsic properties, such as the high specific surface area in relation to volume and increased particle surface energy, render these materials more reactive and effective than their bulk counterparts ,38,39. MMoreover, the efficacy of NPs as antimicrobial agents\u2019 carriers can be improved for specific goals  through various surface-functionalization approaches. Specifically, stimuli-responsive ligands or functional groups can be used for modifying the surface layer of NPs through different physical, chemical, or biological methods toward achieving optimal antimicrobial activity . In thisTaking into account the inherent beneficial properties of NPs and the variety of surface engineering possibilities, numerous studies have developed a wide range of antimicrobial nanoformulations aiming to bring effective solutions against relevant infections . In this respect, the following subsections emphasize the recent progress in the fabrication of nanosystems for the delivery of antibacterial, antifungal, antiviral, and antiparasitic agents.When discussing nanomaterials fabrication, two main approaches can be distinguished: top-down and bottom-up. The top-down approach implies starting from larger structures and reducing their size by means of mechanical force and the aid of finer and finer tools until reaching dimensions in the nano range ,47. ThesA variety of physical, chemical, and biological fabrication methods are available for the synthesis of nanostructures , includiMoreover, for producing NPs with tailored structures, mixed approaches can be employed, generally involving a preprocessing step followed by a high-energy step. As each method has its advantages and limitations, thoughtful consideration is required when choosing the synthesis method so that the final nanostructures would have physicochemical stability, low polydispersity, reproducible size, high purity, and optimum morphology for antimicrobial drug delivery purposes .Bacterial infections represent one of the biggest global health problems, remaining a significant cause of morbidity and mortality despite the numerous available antibiotics . This isTherefore, a different approach had to be taken to enhance the antibacterial properties of existing drugs. Nanomaterials have become an attractive solution for transporting and releasing hydrophilic and lipophilic antibiotics or natural antimicrobial agents, as they can overpower bacterial resistance through several mechanisms. In more detail, NPs can ensure targeted delivery, allow passage through biological barriers, permeate and destroy the bacterial cell membrane, induce antimicrobial effects within cells, and impede biofilm formation ,65,66,67Inorganic nanomaterials such as metal and metal oxide NPs have been of particular interest in creating antibacterial nanoformulations given their advantageous properties  ,68. ThesStaphylococcus aureus (S. aureus) [Pseudomonas aeruginosa (P. aeruginosa) [Bacillus subtilis (B. subtilis) [Bacillus cereus (B. cereus) [Streptococcus [Escherichia coli (E. coli) [Salmonella typhimurium (S. typhimurium) [Some of the most commonly employed inorganic NPs for antibacterial applications are based on silver, iron oxide, zinc oxide, titanium oxide, magnesium oxide, and silica ,70,71. D aureus) ,73,75,76uginosa) , Bacilluubtilis) , Bacillutococcus , EscheriE. coli) ,75, and Moreover, the nanosystems\u2019 antimicrobial properties and safety can be enhanced by adding biocompatible coatings ,75,77. IPolymers represent another class of highly convenient materials for fabricating antimicrobial drug-delivery NPs. The main advantages of polymeric materials reside in their variety, versatility, and ease of functionalization. These characteristics render polymers suitable for improving drug solubility, delivering the cargo to the desired site, and targeting bacterial pathogens ,67,81. Recent studies have focused on developing vehicles from natural polymers, as they are generally recognized to possess superior biocompatibility to synthetic materials. The most commonly employed natural polymers for antibacterial agents encapsulation are polysaccharides, chitosan and alginate being the choice of numerous studies ,91,92,93Cinnamomum zeylanicum (C. zeylanicum) essential oil [Pistacia lentiscus (P. lentiscus) L. var. chia essential oil [In what concerns the freight, a broad range of antimicrobial agents has been reported in the literature as suitable for polymer encapsulation. Synthetic drugs  have beS. aureus [E. coli [P. aeruginosa [Erwinia carotovora (E. carotovora) [Pseudomonas fluorescens (P. fluorescens) [Enterococcus faecalis  [Proteus mirabilis (P. mirabilis) [Bacillus haynesii (B. haynesii) [Streptococcus pyogenes (S. pyogenes) [Yersinia enterocolitica (Y. enerocolitica) [Listeria monocytogenes (L. monocytogenes) [B. subtilis [Streptococcus pneumoniae (S. pneumoniae) [Haemophilus influenzae (H. influenzae) [Klebsiella pneumonia (K. pneumoniae) [The synergic properties of engineered polymeric NPs and carried antibacterial moieties have led to the obtaining of promising candidates for anti-infective therapeutics against . aureus ,99,100, [E. coli ,92,95,99ruginosa ,92,93,96otovora) , Pseudomrescens) , Enterocaecalis) ,90, Protrabilis) , Bacilluaynesii) , Streptoumoniae) , Haemophluenzae) , and KleTo emphasize the variety and versatility of recently developed antibacterial nanoformulations, Fungal infections represent a significant health issue, being associated with high morbidity and mortality. Immunocompromised hosts are particularly susceptible to invasive infections, with the mortality rates in such patients going above 60% in certain situations ,102,103.Vitis vinifera (V. vinifera) [Lippia sidoides (L. sidoides) essential oil [Therefore, recent research tried to solve these issues by orienting to safer strategies, including encapsulation into biocompatible NPs and replacement with natural alternatives. In this regard, scientists have explored a plethora of nanomaterials for designing performant delivery systems for antifungal agents. Promising results have been reported when using metal and metal oxide-based NPs ,110, natinifera) , oreganoinifera) , Lippia tial oil , pterosttial oil , farnesotial oil ) have alCandida albicans  [C. albicans is recognized as the leading cause of invasive candidiasis [Aspergillus brasiliensis (A. brasiliens) [Aspergilus niger (A. niger) [Cryptococcus neoformans (C. neoformans) [Histoplasma capsulatum (H. capsulatum) [Trichophyton rubrum (T. rubrum) [Trichophyton mentagrophytes (T. mentagrophytes) [Microsporum gypseum (M. gypseum) [Candida dubliniensis (C. dubliniensis) [Candida krusei (C. krusei) [Candida parapsilosis (C. parapsilosis) [Candida tropicalis  [Candida auris (C. auris) [In what concerns the species of interest, most studies have focused on developing antifungal nanoformulations targeting lbicans) ,118,119,didiasis ,122. Nonsiliens) ,113, Asp. niger) , Cryptocformans) , Histoplsulatum) , Trichop. auris) .For clarity, Viruses are another class of dangerous pathogens, as they are responsible for around two million deaths per year . Their sIn the fight against infections, NPs offer certain advantages for delivering antivirals to the target sites as they have the ability to surpass biological barriers thanks to their small size and tailored surface characteristics. Through their unique properties, NPs allow antivirals to be released at the infection site, followed by their attachment to viral receptors on the surface of host cells or internalization within the cell resulting in the disruption of the viral replication cycle . Taking into account the benefits of NPs, several research studies explored the antimicrobial potential of a number of antiviral drugs encapsulated in different nanomaterials. Examples of investigated nanocarriers include silver NPs , titaniuTo better clarify the features of the newly developed antiviral drug delivery systems, Leishmania spp., which comprises a group of flagellated protozoans responsible for neglected tropical diseases known as leishmaniasis. Characterized by high mortality, disability, and morbidity rates, leishmaniasis represents a major global health concern, being endemic in 102 countries worldwide [Leishmania. Aside from bacteria, fungi, and viruses, several parasites have also been recognized for their infective potential. One example is represented by orldwide ,137,138.Leishmania parasite in a single treatment. Alternatively, Snoussi et al. [Leishmania donovani, Leishmania amazonensis, and epimastigotes of Trypanosoma cruzi. On a different note, Durak and colleagues [For instance, Badirzadeh et al.  proposedi et al.  preparedlleagues  encapsulBalamuthia mandrillaris and Naegleria fowleri. In contrast, Real et al. [Several studies have also directed their efforts toward creating delivery nanosystems aimed at other pathogens. For example, Kanwal et al.  reportedl et al.  developel et al.  created Humans are exposed to numerous pathogens that can trigger burdensome bacterial, fungal, viral, and parasitic infections. Conventional treatment approaches revolve around the systemic administration of synthetic drugs that, due to the emergence of drug-resistant microbial strains, exhibit low efficacy, in addition to the disadvantages of poor solubility, toxicity, and adverse effects. In this context, nanotechnology started being increasingly explored for designing improved antimicrobial agentsNPs of many sorts  have beeIn addition to their stand-alone utility, NPs may further be incorporated in different other materials to create bionanocomposites with enhanced antimicrobial properties. In this respect, researchers propose the use of various nanostructured gels ,100,151,To summarize, various NPs have been investigated as drug delivery vehicles to surpass traditional drugs\u2019 limitations. Numerous studies have successfully loaded natural and synthetic drugs into inorganic, lipid, and polymeric-based nanosystems, obtaining promising results against a broad range of pathogens, but mostly bacterial strains. To conclude, there is an increased research interest in developing alternative antimicrobial agents, and current progress demonstrates the great potential of nanostructured materials in preventing and treating infectious diseases. Nonetheless, there is still room for improvement in the field, especially concerning the expansion of antiviral, antifungal, and antiparasitic applications of drug delivery nanosystems. Further studies should also focus on managing complex and mixed biofilms, an understudied and challenging niche of microbial infections. Moreover, being so new, most of the discussed nano-therapeutic options have not yet advanced beyond preclinical testing. Thus, rigorous additional studies are required before they become clinically and commercially available solutions."}
+{"text": "Plants evolve diverse mechanisms to eliminate the drastic effect of biotic and abiotic stresses. Drought is the most hazardous abiotic stress causing huge losses to crop yield worldwide. Osmotic stress decreases relative water and chlorophyll content and increases the accumulation of osmolytes, epicuticular wax content, antioxidant enzymatic activities, reactive oxygen species, secondary metabolites, membrane lipid peroxidation, and abscisic acid. Plant growth-promoting rhizobacteria (PGPR) eliminate the effect of drought stress by altering root morphology, regulating the stress-responsive genes, producing phytohormones, osmolytes, siderophores, volatile organic compounds, and exopolysaccharides, and improving the 1-aminocyclopropane-1-carboxylate deaminase activities. The use of PGPR is an alternative approach to traditional breeding and biotechnology for enhancing crop productivity. Hence, that can promote drought tolerance in important agricultural crops and could be used to minimize crop losses under limited water conditions. This review deals with recent progress on the use of PGPR to eliminate the harmful effects of drought stress in traditional agriculture crops. Water is the most indispensable requirement for the growth and development of agricultural crops . The terFive different types of soil microbes, namely, bacteria, actinomycetes, fungi, protozoa, and nematodes, play an important role in increasing plant and soil health . MicrobiPlants growing in the soil develop a close relationship with soil microbes residing around, on, or inside the plant roots. Certain soil microbes, including bacteria, archaea, fungi, and oomycetes, colonize the root surface and inner root tissues , thus plThis review aims to understand the effects of drought stress on the morphological, physiological, and molecular traits of plants. Moreover, we discuss how soil microbial communities are useful in minimizing or reducing the effects of drought stress in various plants. In this review, we explore the recent progress achieved by researchers in understanding the interaction between plant growth-promoting rhizobacteria (PGPR) and crop plants under drought stress conditions. We also explore several useful aspects of PGPR and crop plants, such as developmental stages, genotypes, and climatic variables, which have not been covered in detail earlier. We conclude the review with a discussion on technical challenges and limitations in recent research methods with regard to drought stress and soil microbe interactions along with future directions and suggestions.Impaired germination along with poor stand establishment is the basic and foremost effects of dehydration stress on plants . It has Although drought stress does not affect photochemical activities at the initial stage, it reduces the maximum quantum yield from photosystem II at an advanced stage; however, the yield can be completely recovered after 3 days of re-watering . Variati2) assimilation leading to reduced ribulose biphosphate activity. This is because metabolic impairment decreases the photosynthetic rate in plants, ultimately resulting in the reduction of ribulose biphosphate synthesis. Water stress restricts the photosynthetic assimilation of CO2 because of closed stomata and restricted diffusion of CO2 under water stress; second, it inhibits the metabolism of CO2 , polyamines, sugars , polyhydric alcohols, and dehydrins. Plant growth-promoting microorganisms (PGPMs) introduce osmotic stress by increasing the accumulation of osmolytes in the host plant . Recent nditions .P. putida strain GAP-P45 improved the accumulation of proline in maize plants subjected to drought stress  are high-molecular-weight, biodegradable polymers composed of monosaccharide residues and their derivatives and are biosynthesized by a wide range of bacteria, algae, and plants . EPSs plRhizobium leguminosarum, Agrobacterium vinelandii, Bacillus drentensis, Enterobacter cloacae, Agrobacterium spp., Xanthomonas sp., and Rhizobium sp., are vital for nourishing the soil and maintaining crop production , indole 3 acetic acid (IAA), auxin, cytokinin (CK), gibberellin (GA), ethylene (ET), salicylic acid (SA), strigolactones (STs), jasmonate (JA), and brassinosteroid (BRs), help plants in their defense mechanism . Among tIn addition to the production of phytohormones, such as IAA, GA, CK, and ethylene, the solubilization of phosphates, nitrogen fixation, and generation of siderophores are all direct mechanisms of drought effect mitigation , which sAzospirillum , with improved relative and absolute water content, water capacity, and apoplastic water fraction and lower volumetric cell wall elasticity, suggesting that \u201celastic change\u201d is crucial during increased drought status. Similarly, Azospirillum introduced to wheat induced a decreased water potential and increased water quality of leaves because plant hormones, such as IAA, secreted by the bacteria enhanced the general and lateral root growth by increasing the water and nutrient consumption under drought conditions  are chemical compounds produced by plant cells during metabolic pathways. Major SMs include alkaloids, terpenoids, steroids, saponins, flavonoids, glycosides, phenol, and glucosinolates. Studies have been conducted previously to verify the role of plant SMs against environmental stresses that lead to enhanced production of these metabolites in plant cells through various lkaloids . Plant mlkaloids . Changesst plant . During st plant , which ist plant . Not onl2\u2013), hydrogen peroxide (H2O2), hydroxyl radicals (OH), singlet oxygen (O12), and alkoxy radicals (RO), which can cause damage to membranes, DNA, and proteins  in populus leaves, potentially demonstrating a high universal drought association between the host and its phytobiome -2-morpholinocyclohexene, dodecane, benzene (1-methylnonadecyl), 1-chlorooctadecane, tetradecane, 2,6,10-trimethyl, dotriacontane, and 11-decyldocosane, has been reported for various soil microorganisms; however, their concentrations and uniqueness varies among the species  against various biotic and abiotic stresses. However, the study of the interaction between VOC with plant growth-promoting phytohormones is at a preliminary level. The earliest reported plant growth-promoting VOCs were 2,3-butanediol, acetoin, and pentyl furan . A few Vo plants . The VOCo plants . Genera  biomass . VOCs ar biomass . Product species .Pseudomonas sp., uses the siderophores produced by other microbes in the rhizosphere to meet their essential ion requirements , nitrogen fixation (nifU), spermidine (speB), and siderophore (sbnA) biosynthesis, which facilitate plant growth and tolerance under stress conditions (Gene expression studies are useful to understand and compare the responses of an organism to its environment . Gene exthaliana . RNA disd plants . Using tl plants . Using rnse NO40 . Using mt stress . PGPR conditions ; Table 9Capsicum annum (Drought and other abiotic stresses, including salinity, temperature extremes, biotic stress, and malnutrition, mostly occur simultaneously. The combination of drought and other stresses causes a severe inhibition of physiochemical activities and growth in food crops. For example, plants demonstrate identical physiochemical and morphological symptoms when subjected to drought and salt stress . Higher um annum .2 assimilation in plants. The interactive effect of heat and drought stress reduces RuBisCO, photosystem II, and chlorophyll biosynthesis activities while enhancing the foliage temperature (The joint stress caused by heat and drought in arid, semiarid, and tropical regions reduces photosynthetic activity, stomatal conductance, and COperature . It was perature . The incperature . Howeverperature .Uromyces phaseoli, which causes leaf rust in R. phaseoli, decrease the stomatal openings, leading to conciliated drought resistance (Fusarium culmorum, which causes seedling blight and root rot disease in wheat, exhibited reduced plant growth and biomass production owing to enhanced levels of MDA content under drought stress regimes (Bacillus and Pseudomonas bacterial strains may induce disease resistance in crop plants through the modulation of antioxidant enzymes and osmoregulators (Drought may enhance the chances of pathogenic attack and infection in crop plants. Drought-stressed plants will close their stomata to reduce water loss through transpiration. Nevertheless, pathogen-infected plants enhance their rate of transpiration . The toxsistance . Althougsistance . Wheat p regimes . Severalgulators .Catharanthus roseus plants inoculated with Bela fortis 162 exhibited improved root and shoot growth in addition to oxidative stress tolerance under chromium exposure (P. fluorescens RB4 and B. subtilis 189 mitigated the combined stress induced by Cu and Pb in assisted plants (Bacillus spp. and B. megaterium MCR-8 in plants growing under nickel stress improved their antioxidative potential and gas exchange attributes (B. subtilis FBL-10 and silicon reduced the effect of lead toxicity in eggplant (B. subtilis S4 alleviated arsenic toxicity in Cucurbita moschata (Bradyrhizobium japonicum EI09 and selenium improved chromium stress tolerance in C. annum (B. thuringiensis IAGS 199 and putrescine alleviated cadmium-induced phytotoxicity in C. annum (Enterobacter sp. CS2 and ethylenediaminetetraacetic acid exhibited positive effects on the growth of plants subjected to Ni stress (Plants growing in areas with metal pollution exhibit curtailed routine physiochemical and molecular activities . The intexposure . Similard plants . Inoculatributes . In addieggplant . The synmoschata . ApplicaC. annum . SimilarC. annum . Furtheri stress .via an increase in the root surface area and root production. We also enumerated various crop data to demonstrate the way PGPR are involved in managing the metabolic changes, EPS production, 1-aminocyclopropane-1-carboxylate deaminase activity, phytohormone production, antioxidant activities, ROS accumulation, siderophore production, and transcriptional response to drought stress.Thus, drought stress not only affects the morphological and physiological characteristics of plants, leading to a loss in crop production but also affects the soil microbe interactions. We discussed the ways that PGPR adopt to enhance drought stress resistance. Soil microorganisms associated with the root system of a plant change the cell membrane elasticity of the roots, which eventually increases the drought tolerance capacity. However, during drought stress conditions, plant growth can be improved by the rhizosphere microbial community HA conceived the idea and collected a literature review. SH, SZ, OA, and Mahmood-Ur-Rahman helped in the original draft. AS, XW, and YC critically reviewed the initial draft and streamlined the idea. MR, BG, and AF prepared and revised the figures. SY and SF helped in funding acquisition and revision of the manuscript. All authors carefully read, revised, and approved the manuscript for submission.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "A spinal cord injury (SCI) is one of the most devastating lesions, as it can damage the continuity and conductivity of the central nervous system, resulting in complex pathophysiology. Encouraged by the advances in nanotechnology, stem cell biology, and materials science, researchers have proposed various interdisciplinary approaches for spinal cord regeneration. In this respect, the present review aims to explore the most recent developments in SCI treatment and spinal cord repair. Specifically, it briefly describes the characteristics of SCIs, followed by an extensive discussion on newly developed nanocarriers  for spinal cord delivery, relevant biomolecules  for SCI treatment, innovative cell therapies, and novel natural and synthetic biomaterial scaffolds for spinal cord regeneration. The spinal cord represents the main communicating system between the brain and the body, ensuring information and signal exchanges for coordinating activities ,2. InjurTherefore, spinal cord injury (SCI) is one of the most complicated diseases, due to its pathological consequences affecting sensory, motor, and/or autonomic functions ,5,6. SpeMoreover, SCI is a frequent condition, affecting more than 20 million people worldwide, increasing ~700,000 patients per annum . The treIn this context, it is important to research better performing therapeutic alternatives geared towards reducing treatment duration and improving its results. Thus, increasing research interest has been noticed in designing advanced repair strategies for spinal cord regeneration. Particular attention has been drawn to biomaterials and nanotechnology-enabled products for the controlled delivery and sustained release of various moieties, including drugs, bioactive molecules, imaging agents, and cells ,16,17,18Aiming to set a framework for future research, this paper briefly describes the characteristics of SCI, further reviewing the newest developments reported in spinal regeneration, counting innovative nanocarrier systems, biomolecules of interest for SCI treatment, recent cell therapies, and promising cell-free and cell-seeded biomaterial scaffolds.Spinal cord injury (SCI) is one of the most devastating traumas, as it can interrupt the connection between the brain and peripheral organs, producing complex pathophysiology ,8,11. SCIt is also essential to mention that the severity of the SCI depends on whether the lesion is complete or incomplete and, if it is incomplete, what part of the spinal cord is affected . In the However, intervention is required as soon after trauma as possible, irrespective of the type of SCI, in order to avoid secondary injury . The maiIn their research efforts to find more performant treatment strategies for spinal cord regeneration, scientists have recently focused their works on a series of advanced repair strategies, as presented in Most therapeutic agents implied in treating traumatic central nervous system injuries face limitations in reaching the target site and exerting their intended pharmacological effects. The obstacles encountered by drugs include physiological barriers , instability in physiological conditions, rapid elimination from the injured tissue or cerebrospinal fluid, and off-target toxicity ,28,29.One of the biggest challenges in treating SCIs remains the blood\u2013spinal cord barrier. This physical barrier between the blood and spinal cord parenchyma prevents toxins, blood cells, and pathogens from entering, and the spinal cord becomes an obstacle for therapeutic agents\u2019 delivery to the injured site ,31. ThisThus, increasing focus has been directed to creating central nervous system (CNS) delivery systems that would allow a more efficient treatment. Particularly, nanomaterials of various compositions have been reported as promising nanocarriers, overcoming low drug permeability and ensuring targeted and controlled release. A large variety of nanoparticulate systems can be loaded with drugs, imaging moieties, enzymes, cell components, and other biomolecules. The ingenious design of nanovehicles brings unprecedented advantages in terms of reducing cargo degradation, improving drug absorption, promoting selective interactions with cell compartments, diminishing adverse effects, and increasing the bioavailability of drugs ,34,35,36In this respect, numerous nanomaterials have been investigated, leading to encouraging results. The following subsections discuss some of the most recent strategies for SCI management, classified according to nanocarrier type.Metal-based nanomaterials represent an attractive possibility for encapsulating and delivering bioactive molecules to the site of interest ,38. PartJuglans regia and further loaded them with zonisamide. The particles offered high stability and solubility under room temperature conditions, ensuring a controlled release of the incorporated drug. The authors concluded that the as-designed nanomedicine could serve as a promising clinical drug for future spinal cord injury repair applications.For instance, Fang et al.  have bioAlternatively, Zhou et al.  reportedPursuing a similar aim, Kim et al.  have fabA different approach has been recently proposed by Lin et al. . The autIn addition to gold, other metal-based nanoproducts can be of good use in this biomedical field . For exaTo summarize the characteristics of the above-discussed nanosystems in a clear and concise manner, Attracted by the variety and versatility of polymers, many researchers opted to deliver therapeutic agents via polymer-based nanocarriers. These materials benefit from good solubility, stability, safety, and controlled cargo release with slow degradation ,47,48.Poly(lactic-co-glycolic acid) (PLGA) nanoparticles started to gather attention for treating traumatic CNS injuries . For exaInteresting results have also been reported for other polymer-based nanosystems. Liu et al.  have pre2O2, holding great promise as candidates for SCI functional integrated therapy.Differently, Nie et al.  have fab2 nanoparticles. The nanosystem was observed to increase auto-regenerative and neuroprotective activity in spinal cord regeneration, being a promising biocompatible material for SCI repair.Natural polymers were also successfully employed in designing nanovehicles for spinal cord delivery. For instance, Wang et al.  have devFor clarity, Liposomes have also attracted attention for creating effective delivery nanosystems. These spherical vesicles can protect the payload from degradation, ensuring its accumulation at the lesion site and enhancing therapeutic effects. Moreover, the ease of functionalization of these structures renders liposomes suitable for creating biomimicking nanoconstructs ,55.One example of liposomal formulation for spinal cord regeneration is offered by Zhang et al. . The autA different approach is proposed by Tang et al. , who havAlternatively, Wang and colleagues  have focSeveral other nanomaterials were reported in the literature as potential candidates for innovative and performant spinal cord therapy. For instance, nanogels attracted scientific interest in the field due to their capacity to reach the smallest capillary vessels, penetrate tissues via transcellular pathways, and release drug freight at the injury site . Taking On a different note, Yu et al.  have recAn interesting approach is offered by Mahya et al. , who havAnother recent study conducted by Wu and colleagues  presente2+ concentration, alleviating the inflammatory response, and attenuating neural apoptosis. Moreover, the motor function of the treated mice significantly improved, demonstrating great potential for SCI treatment.Encouraging results have also been obtained by using drug-loaded nanovesicles. Particularly, Liu et al.  have recThe above-described nanosystems are synthesized in Growth factors have been increasingly studied in relation to spinal cord regeneration. They can regulate neurons\u2019 survival, stimulate the release of neurotransmitters and recovery of synaptic function, promote the growth and remodeling of axons, and regenerate nerve cells. Particularly, neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), and neurotrophin-5 (NT-5) have been recognized for their ability to protect damaged neurons and promote neuron growth and differentiation ,21. InteNerve growth factor (NGF) was also noticed to have an important role in spinal cord regeneration, supporting the neurons\u2019 survival, growth, differentiation, and synapse formation, thereby stimulating nerve regeneration, remodeling the neural network, and aiding in the recovery of motor function ,67,68. TAlternatively, Cheng et al.  investigValuable characteristics have also been reported for the brain-derived neurotrophic factor (BDNF). BDNF is recognized for its neuroprotective effects on 5-serotonin, dopaminergic, cholinergic, and GABA neurons via neuron growth promotion, axon sprouting and regeneration, and axon remyelination . On the In recent years, the importance of intercellular communication has been emphasized through signaling organelles . According to the size of these double-layered membrane vesicles, they can be divided into three classes: apoptotic bodies (1000\u20135000 nm), microvesicles (100\u20131000 nm), and exosomes (30\u2013150 nm). Particular attention has been drawn to the small structures, as they can deliver information among cells in different pathological and physiological statuses ,72.Exosomes are important paracrine mediators of their parent cells that have been recently reported to hold great promise in medical treatments and tissue regeneration ,74. ExosFor instance, Sun et al.  studied Mu et al.  have alsDifferently, Luo et al.  have creSCI regeneration and repair can also be achieved through various cell therapies via two main methods: transplanting exogenous cells and directing or enhancing the functions of endogenous progenitor cells. The cell types studied in relation to spinal cord regeneration include embryonic, pluripotent, neural, and mesenchymal stem cells, oligodendrocyte and endothelial precursor cells, Schwann cells, olfactory ensheathing cells, and more ,21,78 F.NSCs\u2019 transplantation was especially studied in the spinal crush injury model, displaying encouraging results, such as differentiating into neurons, providing a neuronal substrate for electrical signals to bridge or circumvent the lesion area, accelerating axonal growth, and improving axonal conduction. Moreover, NSCs promote the survival and growth of damaged neurons to a series of secreted growth-promoting factors  .Important results have also been registered by grafting human spinal-cord-derived neural progenitor cells into cervical SCI sites of rhesus monkeys. Specifically, Rosenzweig et al.  reportedAnother type of cell with great potential in SCI treatment is represented by embryonic stem cells (ESCs). ESCs can differentiate into neurons and glial cells that can reverse cell defects in the wounded area, while secreted active factors have the ability to impede further damage, support nerve tissue regeneration, achieve therapeutic effects, and improve motor dysfunction in tested animals .Progress has been noted in the use of adipose-derived stem cells (ASCs). ASCs are considered promising therapeutic cells for SCI treatment, especially due to the plethora of molecules they secrete for modulating inflammatory response, stimulating axonal growth, promoting vascular remodeling, and ensuring cellular survival ,81. ThusAn interesting emerging possibility for spinal cord regeneration is suggested by R\u00f6vekamp et al. . The resNumerous other studies have used cell therapy for spinal cord regeneration, yet researchers opted for delivering cells via biomaterial scaffolds instead of direct transplantation. Recent works of this kind are reviewed in In spinal cord regeneration, biomaterial scaffolds can be employed to refurbish the continuity of the injured site and ensure a suitable environment for tissue repair, axonal regeneration, and vascularization . Both naIn particular, polymers have attracted special focus for designing biomaterial scaffolds due to their appropriate mechanical properties, fabrication versatility, and ability for multiple functionalization ,85,86,87Numerous polymer-based cell-free scaffolds have been reported with different degrees of success in the literature. For instance, Ma and colleagues  have devOn a different note, Qian et al.  have preAlternatively, Zhang et al.  utilizedEncouraging results have also been published concerning various hydrogel-based cell-free scaffolds. For instance, Zhai et al.  used an Natural polymer-based scaffolds are considered equally or more suitable materials for tissue engineering and regeneration as an alternative to synthetic polymers. These natural materials present a series of advantageous properties, including biocompatibility, biodegradability, low immunogenicity, large surface area, similarity with extracellular matrix (ECM), tunable mechanical strength and conductivity, and easy large-scale production. Moreover, they are excellent support materials for living cells, small molecules, growth factors, and liposomes, ensuring their controlled and sustained release at the implantation site ,112,113 For instance, Yeh and colleagues  fabricatAdditionally tackling the benefits of collagen scaffolds, Yin et al.  have devDifferently, Sun et al.  have creIn contrast, Han et al.  utilizedIncorporating various cells into biomaterial scaffolds is another promising regenerative approach for spinal cord repair, as several studies have reported encouraging outcomes.2 nanoparticles and seeded with MSCs. The nanoparticles could alleviate the oxidative environment and improve MSCs viability, whereas the hydrogel enables adhesive growth of the seeded cells. The scaffold was noted to considerably restore motor function, induce in vivo integration and neural differentiation, and efficiently regenerate spinal cord tissue.One such example is offered by Li and colleagues , who havAlternatively, Yuan et al.  have fabKourgiantaki et al.  have creYou et al.  utilizedAnother interesting regenerative strategy is proposed by Ham et al. , who useAlternatively, Lai and colleagues  have recHe and colleagues  have conIn addition to the above-presented spinal cord repair strategies, several other rehabilitation approaches have been recently reported in the literature, particularly based on electrostimulation (ES) .One recent rehabilitation approach is offered by Lemos et al. , who havSimilarly, Adeel et al.  investigAn interesting therapeutic alternative is also offered by Olmsted and colleagues . The autRecent research also focused on improving spinal-cord-related clinical procedures to enhance repair outcomes. In this respect, Kubelick and Emelianov  have devAs the spinal cord cannot regenerate itself and no treatment is yet clinically available for its complete healing, spinal cord injury remains one of the most devastating diseases, affecting the quality of life of millions of patients and imposing an economic burden on healthcare systems worldwide.Considering the impetuous need for developing efficient treatment strategies, scientists have recently approached SCIs from an interdisciplinary perspective. Thus, a series of promising discoveries concerning biomolecules and stem cells mechanisms in the SCI microenvironment have been reported in the literature, while tremendous progress has been noticed in designing various drug delivery vehicles and biomaterial scaffolds. However, most of the studies have been conducted in vitro and/or in vivo on small animals; only two of the cited studies were performed on larger animals , while none of the potential therapies have reached the clinical testing stage. There are a number of challenges and limitations associated with translating these advanced therapeutic strategies, such as improperly powered studies with insufficient animal numbers, heterogeneity of SCI models, and interspecies variations in neuroanatomy. Moreover, factors such as animal age, inbreeding, and housing may also represent obstacles in clinical translation, as humans have very different immune systems and behaviors than inbred mouse strains living in a sterile environment; hence, the neuroplasticity, regeneration, and recovery after an SCI is also expected to be different. More specifically, before moving into the clinic, the newly developed delivery nanosystems must be thoroughly investigated from the points of view of their cytotoxicity  and their ability to translate from laboratory to scaled-up synthesis without affecting their quality. The advanced repair strategies involving different biomolecules and stem cells require further research to fully understand these entities\u2019 mechanisms of action and their long-term effects. On the other hand, the main challenge in using biomaterial scaffolds resides in finding the balance between adequate physicochemical properties and maximum therapeutic efficacy.To conclude, encouraging results have been obtained by testing a wide range of therapeutic options for accomplishing spinal cord regeneration and repair, yet further research is required concerning their effects in human use before these strategies can be implemented in clinical practice."}
+{"text": "May 17, 2022, there were two errors.In the article, \u201cHistochemical Characterization of the Dorsal Raphe-Periaqueductal Grey Dopamine Transporter Neurons Projecting to the Extended Amygdala,\u201d by Qin Zhao, Tetsufumi Ito, Chika Soko, Yoshie Hori, Takafumi Furuyama, Hiroyuki Hioki, Kohtarou Konno, Miwako Yamasaki, Masahiko Watanabe, Satoshi Ohtsuka, Munenori Ono, Nobuo Kato, and Ryo Yamamoto, which published online on The city name in affiliation two was misspelled; the correct affiliation should instead appear as \u201cSystems Function and Morphology Laboratory, Graduate School of Innovative Life Science, University of Toyama, Toyama, Toyama 930\u20130194, Japan.\u201dDR-PAG neurons in various behaviorsApproaches to investigate physiological roles of DAT, Stuber et al., 2015 was incorrectly cited in line 13.On page 14, in the section The online version has been corrected."}
+{"text": "PLOS ONE Editors retract this article [The  article  because HM and KSB did not agree with the retraction. MAA, SH, HS, SAHN, MNS, SA, EAA, and RD either did not respond directly or could not be reached."}
+{"text": "AGENAS supports the implementation of health policies in direct collaboration with Italian Regions and Autonomous Provinces. To improve public reporting, we aimed to complement the production of technical reports with new forms of timely communication, using National Portals.Between October-December 2020, we designed and implemented the Covid-19 National Portal, including a suite of targeted indicators, fully automated via ad hoc scripts written in php and R on top of a relational database using internal and external data sources. Targeted information was widely communicated and continuously updated. Dedicated sections on forecasting and resilience were delivered in collaboration with specialised academic institutions. In 2021, we deployed the Portal for the Transparency of Health Services, broadly oriented towards health issues, the location of services and performance indicators.Pre-post comparisons of web analytics for Jan-Apr 2020-2022 showed clear advantages of Covid-19 Portal. By Apr 2020, Italy had introduced national lockdown, while AGENAS covered the topic traditionally, recording 48,122 users overall, with daily peaks below 5,000 sessions. In 2021-2022, the number of users skyrocketed at 436,280, with daily peaks of 100,000 sessions, and 421,123 respectively, with daily peaks of 150,000 sessions. Visits to the Transparency Portal were considerably more limited.To be widely used, public health information needs to be relevant , understandable, accurate and timely. National Portals can gain efficiency through the mediation of search engines, enhanced by: targeted naming (url), coherent semantic perimeter , continuous updating, and impact factor (linked by authoritative websites). The Transparency Portal will take stock of these lessons to succeed in a new funded program of NextGenerationEU.\u2022\u2002Relevant, understandable, accurate and timely dissemination for different types of audience may be effectively organised through National Portals.\u2022\u2002Productive collaboration between health specialists and communication experts can enhance usability and actionability of National Portals for public health."}
+{"text": "Objective: Recent evidence suggests that adequate fruit and vegetables intake (FVI) might be associated with lower risk of common mental disorders (CMDs) in adults, but studies in youth are also beginning to emerge and are synthesized in this systematic review.Methods: Online databases were searched from inception to 30 October 2020 to locate cross-sectional, cohort, and case-control studies focusing on the FVI and CMDs in youth . The risk of bias of studies was assessed using Joanna Briggs Institute Critical Appraisal Tool and the Newcastle-Ottawa quality assessment scale.Results: Among 3,944 records identified, 12 studies  were included in the final synthesis. None of the prospective cohort studies identified a statistically significant association between FVI and CMDs in youth, although inconsistent associations were reported in cross-sectional and case-control studies.Conclusion: The lack of associations between FVI and CMDs in youth, along with consistent associations in adults, might be explained by the accumulation of risk theoretical model and methodological challenges. Mental disorders constitute a significant global public health burden \u20133 and reWith one in five adolescents living with mental disorders worldwide , there iA systematic review  of 16 crA medical librarian [SC (Sandra Campbell)] searched the following databases: Prospero, Wiley Cochrane Library, Ovid Embase, Ovid Medline, Ovid PsycInfo, EBSCO CINAHL, ProQuest Dissertations and Theses Global, Food Science and Technology Abstracts (WOS) and CAB Abstracts (WOS). Each of the databases was searched from inception to 30 October 2020. The search strategy included both text words and controlled vocabulary  for the terms \u201cfruits or vegetables\u201d and \u201canxiety or depression\u201d see . StudiesTwo reviewers [JD and SM] independently reviewed the titles and abstracts on the Covidence platform .  contacted corresponding authors for additional information. Where the results of several models where presented, data were extracted for all models. Study-specific methods and results  are presented in Upon finalizing the list of included studies, [JD and SM] independently extracted the following data: study details  and exposure assessment tools, comparator, description of the outcome(s) and outcome assessment tools, sample size, mean age or age range at baseline, sex of participants included in the study); analysis and results  reporting guidelines .The search yielded 3,944 records to assess for eligibility, 903 duplicates were removed. Among 117 records that were examined in full, 12 studies were included in the final analysis. The articles were published between 2012 and 2020 and included analysis of data collected in United States, United Kingdom, Greece, Australia, Canada, South Korea, Saint Lucia, Egypt, Saint Vincent and the Grenadines, Djibouti, Morocco, Myanmar, Zambia, Tanzania, Venezuela, Grenada, Lebanon, China, Indonesia, Thailand, Uganda, Tunisia, Botswana, Sri Lanka, India, Seychelles, Guyana, Ecuador, Jordan, Argentina, and Kenya. Only self-reported dietary assessment instruments were used. Eight studies \u201330, 35 aAll studies assessed depression, two assessed anxiety , 29, andOf 10 cross-sectional studies, eight , 31, 32 There was one  case-conAmong three prospective cohort studies, samples were representative of 10\u201311\u00a0years old children in corresponding communities in one study . In all Eight studies  [Four studies reported on the association between combined FVI and depression. Two studies were cross-sectional, while two others included both cross-sectional and longitudinal analyses. One cross-sectional study  reported5; 0.43) .Two studies , 29 examOne study  concludeFruit and vegetables have long been recognized for their beneficial effects on gastrointestinal health, weight management, prevention of cardiovascular and metabolic disorders, respiratory health, and high bone mineral density, among other conditions and diseases . MoreovePreviously proposed biological mechanisms to explain the association between FVI and CMDs revolve around the high content of fiber, nutrients , and phytochemicals   found inConsistent with other literature on the diet-mental health relationship , 18, 44,First of all, SES is an established confounder linked to both diet and mental disorders and therefore should be controlled for in all studies investigating this focal relationship; SES was measured and adjusted for in two , 34 out In addition, there are measurement errors associated with both self-reported diet and mental disorders. Given the potential for recall and social desirability biases associated with self-report measures, sensitivity analyses to delineate the effects of measurement errors on the focal relationship are needed . AdjustmThis systematic review showed that while inconsistent associations between FVI and CMDs in youth were reported in cross-sectional and case-control studies, no association was detected in prospective cohort studies. This evidence differs from what has recently been concluded in a systematic review on the association between FVI and depression in adults , which c"}
+{"text": "Breast reconstruction operations have been on the rise over the last two decades; with recent advances in medical practice, different options of breast reconstruction have been readily available. However, it is challenging for patients to grasp the knowledge and digest differences, advantages, and disadvantages of each and every procedure to be able to choose the best procedure for them. Following the Thefaut and Montgomery cases, clinicians are obliged to make sure that all the required information is presented to the patients in a structured manner and suitable environment to aid them in deciding the best procedure for them and guiding them through the informed consent process. The consent process is the patient's agreement to proceed with physical examination, investigation, medical/surgical treatment, organ donation or enrolment in a clinical trial proposed by the healthcare provider. Consent is not a one-off event, but is an ongoing process. The conscious patient can withhold or withdraw consent before or during treatment . The priThe informed consent term was first used by attorney Pace E in a medical malpractice United States court case in 1957 . In modeA professionally conducted consent process ensures that clinicians are prompted to consider the evidence base concerning the proposed treatment and its alternatives. The patients are appropriately informed, their autonomy respected, and their expectations managed . FulfillOver the last two decades, a significant increase in breast reconstructions has been noted, with a 29% increase from 2000 to 2018 . TherefoGeneral information: include documenting the patient's height, weight, BMI, smoking status, pre-existing body dysmorphia or breast asymmetry (consider attaching preoperative photo). Also, discuss different reconstruction options, scar placement, operative and recovery time, and follow up.Implant-based reconstruction: the general information section should include different types of implants , the plain of implant placement , as well as the possible use of a mesh  or synthetic mesh) to cover the lower pole. In addition to highlighting the need for other operations in future such as pocket adjustment, port removal, implant exchange, fat grafting, and contralateral symmetrising reduction. The agreed procedure which the patient is willing to proceed with needs to be clearly documented.The possible complications' section should include general complications such as bleeding, collection, infection, pain, scar formation, delayed healing, alteration of sensation or reoperation, cardiac and pulmonary complications, venous thrombosis related complications, allergic reactions, lymphoedema and unsatisfactory results and its physical and psychological impact. Plus, implant-based reconstruction associated complications as the increased risk of infection, increased risk of implant loss following radiotherapy, shape and size miss-match, asymmetry, contour irregularity due to wrinkling and rippling, capsular contracture, calcification- implant displacement, implant failure, silicone gel bleed, silicone laden lymph nodes, and implant extrusion, chest wall irregularities, immune system diseases and unknown risks, Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL).Autologous reconstruction: the general information section should include different types of autologous reconstruction (pedicled/free flap). In addition, the agreed operation that the patient is willing to proceed with must be documented. Possible complications' section should include general complications as bleeding, collection, infection, pain, scar formation, delayed healing, alteration of sensation or reoperation, cardiac and pulmonary complications, venous thrombosis related complications, allergic reactions, lymphoedema and unsatisfactory results and its physical and psychological impact. Plus, autologous reconstruction specific complications such as weakness or the donor area, hernia formation, asymmetry, infection, delayed healing, fat necrosis and scar formation, complete or partial flap loss. Based on my practice and previous literature, patient satisfaction is clearly linked to their expectations, hence following good medical practice through a valid consent process leads to better patient outcomes.Limitations: my opinion was based on my practice and available literature, which I am sure if more international collaborative work is carried out, we will come up with more robust data."}
+{"text": "According to recent findings, variances in autism spectrum disorder (ASD) risk factors might be determined by several factors, including molecular genetic variants. Accumulated evidence has also revealed the important role of biological and chemical pathways in ASD aetiology. In this paper, we assess several reviews with regard to their quality of evidence and provide a brief outline of the presumed mechanisms of the genetic, epigenetic, and environmental risk factors of ASD. We also review some of the critical literature, which supports the basis of each factor in the underlying and specific risk patterns of ASD. Finally, we consider some of the implications of recent research regarding potential molecular targets for future investigations. Autistic disorder\u2014or, more broadly, autism spectrum disorders (ASD)\u2014is a lifelong syndrome with a childhood inception, characterised by challenges in social interaction and communication, the presence of stereotype rigidity, and ritualistic/repetitive patterns of behaviour . ASD synIncontrovertible evidence found in twin studies has proven that genetic factors contribute to susceptibility to this disorder ,12. The There are over 600 confirmed human genes related to NDD (such as ID and ASD), including DNA methyltransferase 3A (DNMT3A), HECT, UBA, WWE domain-containing E3 ubiquitin-protein ligase 1 (HUWE1), and chromodomain helicase DNA-binding protein 8 (CHD8) ,22,23. ECurrently, ASD is considered to have a strong genetic component, likely resulting from interactions between various genes. Previous and current twin studies have reported an estimate of more than 30 percent heritability ,28,29. DRecent genomic studies have identified many common and rare inherited variants in ASD families ,45. In aSince 2011, a large number of studies have already been published using WGS in ASD populations, with the identification of rare variants in autism susceptibility genes already described or newly identified ,47,48,49Several studies have shown that various ASD genomic risk variants are involved in congregating pathways relevant to the natural basis of ASD. These include cell proliferation and differentiation, neural development, synaptic activity, transcriptional regulators, and chromatin modifiers ,51,52,53In addition, strong evidence supports the role of epigenetics in the molecular aetiology of ASD, some of which indicates that other genetic syndromes may have direct control over its expression. Studies have proven that they contribute to syndromic ASD in approximately 15 percent of cases ,56. FuncOther lines of evidence implicate other epigenetic markers in the expression of ASD, such as differentially methylated variants (DMVs) at specific CpG sites (CpGs) or differentially methylated regions (DMRs). Studies have identified multiple CpGs in a variety of tissue types, including whole blood , post-moPrevious studies have reported the enrichment of genome-wide results by primarily using quantitative trait loci (QTLs) for the purposes of gene expression; supposing these polymorphisms present some ASD risk through regulatory mechanisms, QTLs offer insights into the functional biology of GWAS variants ,79,80. BGenetic expression levels and epigenetic markers are molecular sensors for many environmental factors, including diet and chemical toxins, over the course of human development . At critMoreover, exogenous exposures, for example, smoking, medication , alcohol, zinc deficiency, metal ion toxicity, viral infection, and chemical agents , are often associated with adverse foetal neurodevelopmental outcomes ,99. HoweFinally, interactions between the genome and epigenome will allow scientists to enhance methylation studies through increased genomic coverage, expanding our knowledge of the role of ASD-specific biomarkers. For instance, changes in specific epigenetic markers (CpG methylation) in noncoding regions, including promoters, enhancers, silencers, insulators, intergenic regions, and ncRNAs, have been observed during neurogenesis ,109,110.In summary, the studies cited in this paper should guide the study of ASD by classifying genetic expressions, epigenetic biomarkers, and environmental conditions for the better prediction of individuals with ASD. Ultimately, they have brought to light several important factors that urgently need to be investigated in order to improve both research design and the interpretation of data going forward.Molecular mechanisms can help fill the gap in defining ASD pathogenesis where epigenetic or genetic information alone is inadequate to describe the aetiology of all cases. In terms of effect, genetic and epigenetic profiles are expected to be heterogeneous. Combining genetic, epigenetic, and environmental data is likely to represent a more comprehensive understanding of molecular settings with respect to the aetiology of ASD. The early detection of the molecular basis  and biological associations with intellectual or ASD-related risk factors will allow health providers to better classify affected individuals, facilitate earlier diagnosis, and improve prognosis. Altogether, improving our molecular understanding of the disorder will also aid in uncovering more homogeneous subgroups of individuals, which will allow for better patient stratification for behavioural and pharmacological therapies."}
+{"text": "Non-alcoholic fatty liver disease (NAFLD) is a metabolic disease characterized by multiple pathologies. The progression of dementia with NAFLD may be affected by various risk factors, including brain insulin resistance, cerebrovascular dysfunction, gut dysbiosis, and neuroinflammation. Many recent studies have focused on the increasing prevalence of dementia in patients with NAFLD. Dementia is characterized by cognitive and memory deficits and has diverse subtypes, including vascular dementia, Alzheimer\u2019s dementia, and diabetes mellitus-induced dementia. Considering the common pathological features of NAFLD and dementia, further studies on the association between them are needed to find appropriate therapeutic solutions for diseases. This review summarizes the common pathological characteristics and mechanisms of NAFLD and dementia. Additionally, it describes recent evidence on association between NAFLD and dementia progression and provides novel perspectives with regard to the treatment of patients with dementia secondary to NAFLD. Non-alcoholic fatty liver disease (NAFLD), one of the most common causes of liver disorders worldwide, is a progressive chronic disease and a metabolic-associated fatty liver disease . It rangRecently, NAFLD has emerged as an important disease associated with the development of cognitive impairment and dementia , 11 , and ApoE-\u03b54 [42) plaque due to impairment of the clearance system is found in AD brains, which can induce hyperphosphorylated tau and tau deposition, resulting in neuritic dystrophy [The common pathological features of AD are mutation of the amyloid precursor gene (APP), excessive amyloid beta deposition, senile plaque and neurofibrillary tangle formation, tau protein hyperphosphorylation, oxidative stress, blood\u2013brain barrier (BBB) disruption, neuroinflammation, and gut dysbiosis \u201358 Fig.. The ons ApoE-\u03b54 . Depositystrophy . AD braiystrophy . Changesystrophy . AD braiystrophy , poor inystrophy , hypometystrophy . MoreoveMany studies have proven that a positive correlation exists between NAFLD and AD \u201364. In pDiabetes mellitus (DM), particularly T2DM, is a common chronic metabolic disease worldwide, characterized by hyperglycemia and insulin resistance . BecauseBlautia, Fusobacterium, and Ruminococcus have been found in patients with T2DM, which have an impact on gut permeability, inflammatory response, and glucose metabolism [The pathological factors of diabetes, particularly T2DM, are insulin resistance, tau hyperphosphorylation, hyperglycemia, vascular dysfunction, inflammatory responses, BBB breakdown, and gut dysbiosis \u201382 , and improved the gut barrier integrity, thereby leading to improved haptic status in patients with liver disease [Lactobacillus plantarum) improved cognitive impairment by modulating hippocampal TLR4/BDNF signaling in an NASH model [Gut dysbiosis is closely associated with NAFLD and dementia \u2013164. Theteroides , Gammaprevotella  were fouevotella . Adminisevotella . The adm disease \u2013175. AdmSH model . ImportaSH model \u2013164. OneSH model . Gut dysSH model . A reducSH model , 180.As mentioned above, gut dysbiosis and increased gut permeability are important factors in accelerating both NAFLD progression and cognitive dysfunction, leading to dementia. The manipulation of the gut microbiome may be beneficial in NAFLD and dementia. The finding of common microbiome species between NAFLD and dementia may provide a basis for developing treatments for the pathologies associated with these two diseases.The neurovascular unit is formed by diverse cell types, such as astrocytes, endothelial cells, pericytes, smooth muscle cells, and neurons . NeurovaAPOE4), which is associated with atherosclerosis and coronary heart disease, is strongly related to an increased risk for AD development [Vascular abnormalities are risk factors for the progression of NAFLD and dementia , 184. Prelopment . Cerebraelopment , 191. Mielopment , 192.Given these relationships between NAFLD and vascular complications, modulation of the cerebrovascular system is needed to treat NAFLD and dementia. Controlling the vascular risk factors may be a good approach in the treatment of NAFLD and dementia.In this review, we summarized the dementia-related pathological features of NAFLD, such as insulin resistance, neuroinflammation, hyperammonemia, gut dysbiosis, and cerebrovascular dysfunction Fig.\u00a0. InsulinMany etiological factors are known to contribute; however, a limited number of prescription drugs are approved for dementia by the Food and Drug Administration (FDA) . Moreove"}
+{"text": "Mobile zoos are events in which non-domesticated (exotic) and domesticated species are transported to different venues for the purposes of education, entertainment, or social and therapeutic assistance. We conducted literature searches and surveyed related government agencies regarding existing provisions within laws and policies, number of mobile zoos, and formal guidance issued concerning operation of such events in 74 countries or regions. We also examined guidance standards for mobile zoos, assessed promotional or educational materials for scientific accuracy, recorded the diversity of species in use, and evaluated those species for their suitability for keeping. We recorded 14 areas of concern regarding animal biology and public health and safety, and 8 areas of false and misleading content in promotional or educational materials. At least 341 species were used for mobile zoos, which are largely unregulated, unmonitored, and uncontrolled, and appear to be increasing. Poor animal welfare, public health and safety, and education raise serious concerns. Using the precautionary principle, we advise that exotic species should not be used for mobile zoos.Mobile zoos are events in which non-domesticated (exotic) and domesticated species are transported to venues such as schools, hospitals, parties, and community centres, for the purposes of education, entertainment, or social and therapeutic assistance. We conducted literature searches and surveyed related government agencies regarding existing provisions within laws and policies, number of mobile zoos, and formal guidance issued concerning operation of such events in 74 countries or regions. We also examined governmental and non-governmental guidance standards for mobile zoos, as well as websites for mobile zoo operations, assessed promotional or educational materials for scientific accuracy, and recorded the diversity of species in use. We used the EMODE  algorithm, to evaluate identified species associated with mobile zoos for their suitability for keeping. We recorded 14 areas of concern regarding animal biology and public health and safety, and 8 areas of false and misleading content in promotional or educational materials. We identified at least 341 species used for mobile zoos. Mobile zoos are largely unregulated, unmonitored, and uncontrolled, and appear to be increasing. Issues regarding poor animal welfare, public health and safety, and education raise several serious concerns. Using the precautionary principle when empirical evidence was not available, we advise that exotic species should not be used for mobile zoos and similar itinerant events. Mobile zoos and other itinerant live animal programs are known by various descriptions, including mobile live animal experiences, animal workshops, animal educational visits, travelling animal shows, animal education events, animal assisted interventions, and others ,2,3,4. MEssentially, both non-domesticated species  and domesticated species  are transported to venues such as schools, hospitals, parties, and community centres, for the stated purposes of education, entertainment, or social and therapeutic assistance as part of broader-termed \u2018mobile live animal experiences\u2019 ,2,3,4. WMobile zoos, in particular where exotic animals are involved, have raised concerns regarding animal welfare, public health and safety, spread of emerging diseases, and miseducation from numerous organisations, which call for greater controls, boycotts, or bans on key activities ,7,8,9,10In contrast, certain animal assisted interventions, especially for therapeutic reasons, are frequently acknowledged for their potentially positive roles, in which species with affiliative or socially adapted histories, such as, domesticated dogs, cats, horses, farm animals, guinea pigs, rats, and birds are involved ,7,15,16.Features of nature, whether plant life, animal life, or habitat scenery, have long been documented as providing interactive health benefits for humans ,32,33, tIn addition, for animal assisted events (and other mobile situations), whilst some animals probably experience positive states, others probably experience negative states. For example, some animals, such as human-familiarised dogs, can display positive engagement with people and experience good welfare within their home environments, transportation, and handling . HoweverWhilst a substantial number of reports are available regarding animal-assisted therapies, comparatively few reports are available regarding mobile zoos in their various forms. This report will focus primarily on mobile zoo-type events that involve exotic species. The general lack of data available for mobile zoos means that issues related to scale of operations and proportionality of certain practices could not be estimated. Nevertheless, by our adoption of the precautionary principle, as outlined below, we consider that available information sufficiently allows for numerous relevant generalities to be identified and related recommendations to be formed.Animal interactions with humans are potentially problematic, especially relating to animal welfare and human health and safety, and the aim of this study is to characterise the types of animals used in mobile zoos, and to identify these risks. We will achieve this aim by presenting a brief review of existing provisions within laws, policies, status, scale of operations, and guidance in relation to mobile zoos in Australia, North America, and Europe, as well as providing guidance and recommendations for both formal and informal policy-making, relying on the precautionary principle when empirical evidence was not available.Throughout this report we adopt the precautionary principle (or precautionary approach), which is frequently applied in situations where there is scientific uncertainty or evidential deficiency, so that presumptive and cautious actions or policies are promoted in order to guide decision-making ,41. For We conducted a literature search using Google Scholar and the following terms for reports published from 2000 :Box 1Combined with Search Terms for Public Health and WelfareCombined with Terms to Further Refine the Search (- Sign Indicates Exclusion)Mobile OR traveling animal experiencesZoonoses, zoonoticExoticMobile OR traveling zoosWelfareWildlifeMobile OR traveling menageriePublic Health-DogMobile OR traveling animal shows-EquineMobile OR traveling animal exhibit-CatMobile OR traveling animal encounters-HorseAnimal assisted intervention OR therapy-DomesticAdditional items were supplemented from authors\u2019 libraries. Reports were excluded on the basis of low relevance, for example, articles focused on popular history of events or duplication of same information. We also conducted a limited search using the first five pages of Google and approximately 10 items per page for mobile zoos using the single term \u2018mobile zoo\u2019. A separate search was performed for businesses offering mobile zoo services in Australia, North America and Spain, The Netherlands, and United Kingdom . Test searches in the UK using the term \u2018mobile zoo\u2019 versus the alternative terms on the first page of Google as listed above for the Google Scholar search were also conducted to check for cross-referencing matches for capture of relevant operations.We examined websites for all mobile zoo operations identified during the limited search using the first five pages of Google and recorded the diversity of species in use. We used the EMODE algorithm ,52 to evWe also assessed promotional or educational materials produced by mobile zoo operators for scientific quality and compared information using recent peer-reviewed texts. We contacted government agencies in 74 countries or regions  for information regarding existing provisions within laws and policies, number of mobile zoos, and formal guidance issued concerning operation of such events. We evaluated governmental and non-governmental guidance standards for information quality regarding mobile zoos, including matters of animal husbandry and public health and safety. Contacts with government agencies were made through emailed surveys using predetermined questions, which were: 1. Do you have mobile zoos in your jurisdiction? If so, how many? 2. What laws/regulations, if any, do you have regarding mobile zoos? and 3. What guidance, if any, do you provide to regulate mobile zoos?v 26 (73%); thus, the term \u2018mobile zoo\u2019 was efficient at identifying relevant targets. Searches performed in naturally non-English speaking countries (Spain and The Netherlands) using respective terms for \u2018mobile zoo\u2019 located similar average numbers for page listings . Thus, the common terms used probably located significant examples of relevant events.A total of 473 peer-reviewed reports were identified, and 121 relevant reports were analysed. The test searches in the UK using the term \u2018mobile zoo\u2019 versus the alternative terms listed above for the Google Scholar search resulted in cross-referencing matches of 19 Of the 74 countries or regions contacted for information regarding existing provisions within laws and policies, number of mobile zoos, and formal guidance issued concerning operation of such events, 37 survey responses were received from Australia (5 States), USA (26 States), Canada (3 Provinces), and from Belgium, Wales and England, although the information provided was largely incomplete. Supplementary information was located through online searches.Identifying consistent laws and policies across local countries or regions regarding mobile zoos and related events was challenging. Much information provided by governments was incomplete, thus n = 25; USA n = 25; Canada n = 13; Spain n = 20; The Netherlands n = 17; UK n = 19. Only partial information regarding number of mobile zoos and individual events per selected country was established. Very few government agencies contacted could provide information on number of mobile zoos operating in their region, largely because such events are either unregulated or only partially regulated with only certain species requiring permits. In Australia, Queensland, 85 mobile zoos were registered ) may be rationalised to constitute a domesticated form.The biological basis for domestication is highly specific, and few species or animal types  may meet the stringent criteria required, which include essential, psychobehavioural affiliative traits, particular social group profiles, and other factors, which enable these species to successfully live among humans ,205,210.All animals are considered to have key needs that must be met for in order to achieve good welfare, for which certain fundamental principles and provisions are set out in many established guidelines, laws, and practices, such as the following (summarised): The Five Freedoms, 1. freedom from hunger or thirst, 2. freedom from discomfort, 3. freedom from pain, injury, or disease, 4. freedom to express normal behaviour, 5. freedom from fear and distress ,212; theAccordingly, these principles and provisions variously promote either aspirational- or requirement-based conditions for securing limited animal welfare safeguards. However, biological information aimed at addressing particular specialised needs, such as climate-specific thermal conditions, lighting, humidity, as well as specialised dietary, psychological, and behavioural factors  are not emphasised. Mobile zoos inherently involve several potentially problematic issues, including: animal handling, transportation, forced confinement, spatial restriction, environments unregulated regarding temperatures, light invasion, humidity, noise disturbance, vibration, enclosure microclimate-microhabitat conditions, and other factors  and bearded dragons (Pogona vitticeps), which are widely promoted as docility or even affiliative to humans, manifest signs of stress during human handling, which may go unnoticed by many keepers [Tiliqua scincoides) are commonly regarded as unstressed by environmental disturbances, whereas behavioural studies infer their sensitivity to generalised noise and light invasions, and resultant stress [Apparent docility or compliance during handling may not imply absence of stress. For example, studies have shown that Mediterranean tortoises , Q-fever, cryptosporidiosis, helminthiasis, ringworm, allergic alveolitis, lymphocytic choriomeningitis virus, and leishmaniasis [Several well-understood public health and safety issues are relevant to mobile zoos, notably risks regarding: zoonotic infections, allergic reactions, and injuries. Generally, zoonoses refers to diseases that are transmitted from animals to humans ,274. At maniasis ,152,274.Research has also revealed that many animals, for example reptiles, are potential reservoirs for several antibiotic-resistant bacteria ,281. CurThe proportionality of threat from zoonoses caused by exotic versus domesticated species raises various considerations. Exotic species harbour a substantial diversity of atypical pathogens , for whiIn contrast, domesticated species, such as dogs, are typically sourced via known suppliers and routes, and almost all are captive-bred , thus thIn addition, the objective literature widely guards against handling or keeping exotic species, notably all reptiles, due to disproportionate threats from naturally endemic  salmonella pathogenesis e.g., ,289,290),290289,2Human injuries from bites, envenomation, stings, or constriction constitute a relatively small yet medically important and problematic concern ,137,294.As provided in In terms of scale of potential physical threat, in the United Kingdom there are, for example, many more dogs (approximately 12\u201313 million) than exotics  ,305. TheEscherichia coli was effective in 10 out of 35 participants, 10 out of 55 participants, and 6 out of 20 participants, respectively [Available government and other guidance for infection control at mobile zoos typically emphasises post animal contact handwashing as well as cautions when eating or drinking around novel animals, e.g., ,308,309),309308,3ectively . A systeectively .Studies of handwashing and other hygiene protocols amongst medical staff, including at intensive care units, in which infection control is a heightened concern, was found to be variable, but overall poor and involve low levels of adherence to best practices ,313. It At animal contact events, general contact behaviours are likely to result in rapid recontamination of even cleaned hands from microbes dispersed prior to washing , largely negating any sanitisation advice or practices ,201,202,Campylobacter spp., Cryptosporidium spp., Escherichia spp., Listeria monocytogenes, Salmonella spp., and Yersinia enterocolitica are estimated to arise from animal contact alone [Approximately 14% of all infections from ct alone . Whilst ct alone ,296. ConAs reported previously, some guidance issued by relevant \u2018thinktank\u2019 non-governmental organisations and academic researchers recommends against the use of exotic species in assisted therapy contexts, due to zoonotic risk factors and difficulties of pathogens control e.g., ,319,320),320319,3Establishing or estimating the incidence or prevalence of infections linked to mobile zoos is confounded by several well-known factors. Many zoonoses superficially present as common infections, such as gastrointestinal, flu-like, and dermal diseases; albeit that zoonotic episodes often manifest as more severe or persistent forms ,322,323.The terms \u2018one health\u2019 and \u2018one-welfare\u2019 are co-relevant paradigms linking environment, animals, and people, implying that negative effects in one part of this complex may be transferred to another, warranting multi-disciplinary resolutions ,329,330.As summarised in Regarding hygiene and other disease transmission issues, as well as injury risk prevention, the standard of information and apparent knowledge was again considered to be poor based on accepted peer-reviewed public health guidance information , and to Importantly, even if objective information was universally mandated and accepted by mobile zoo advocates and followed by attendees at events, such information would not prevent animal welfare and public health and safety problems inherent to mobile zoos, because it would unlikely translate into dependable outcomes ,313,332.Traditional static zoos attract some criticisms on both animal welfare and public health and safety grounds, which are based largely around issues of spatial restriction, lack of environmental enrichment, deficient or problematic social groupings, general captivity-associated stressors and stress, and hygiene concerns ,334,335.Animals at traditional static zoos are typically not subject to frequent handling , whereas in mobile zoos they are frequently handled. At traditional zoos, transportation is minimal, and animals are proportionately better insulated against human disturbances associated with sound, vibration, light, smell, and visual confrontation than animals at mobile zoos, which strongly expose animals to all such disturbances. These disturbances are now well-known to impose significant stressors of animals, including formerly poorly understood species, such as reptiles ,215,254.Traditional static zoos have been associated with a number of zoonotic outbreaks ,346, incVarious principles are used as measures of control to regulate activities involving humans and animals. The most effective \u2018gold-standard\u2019 control approach is to prohibit or ban relevant activities ,350,351.Searches during this study for mobile zoos and related operations for each targeted country were limited to the first five pages of Google; thus, capture of a representative sample is uncertain. Relatedly, ascertaining or estimating the number of mobile zoo operators regionally or globally was not feasible. Also, whilst there were strong commonalities between species used for mobile zoos across various regions or countries, some variation was noted, thus the list of species herein may be considered a partial compilation. For example, whilst our survey identified 13 mobile zoos operating in Canada, anecdotal reporting indicates that the actual number is considerably greater . SimilarMinimal or absent regional and global monitoring or control of mobile zoos causes large gaps in information regarding scale that could not be determined. Lack of available data regarding confirmed cases of disease associated with mobile zoos and similar activities prevents detailed projections regarding epidemiological risk.Our survey of provisions within laws and policies indicated that mobile zoos are largely unregulated, unmonitored, uncontrolled globally, and appear to be increasing in scale. Existing provisions laws and policies are few, mostly under-developed, require urgent reform, lag behind some modern scientific approaches to both safeguarding animal welfare and public health and safety messaging, fail to adequately control the raft of problematic issues inherent to mobile zoos, and require urgent reform. Similarly, governmental guidance in general for managing mobile zoos is minimal and deficient, in particular due to reliance on minimalist and arbitrary husbandry practices and overemphasis on handwashing and public compliance, which invites risk complacency. Our investigation found that educational messaging by mobile zoo proponents was highly variable and frequently false or misleading, and this deficiency raises fundamental questions regarding the supposed role of mobile zoos as information, or misinformation, providers to the general public.Animal welfare), As presented in There is no formal methodological monitoring for case infections or epidemic outbreaks linked to mobile zoos, despite there being clear evidence of such associations, and the likely attendance of significant proportions of immunologically vulnerable groups. This lack of monitoring is concerning given the prevalence of key pathogens that are both common in society and known to be linked to mobile zoos. As presented in Governmental and nongovernmental guidance) and Education and miseducation at mobile zoos), the uptake of high-quality objective guidance, even in highly regulated and professional sectors including highly regarded zoological institutions and in medicine and surgery, as well as for privately kept animals, is known to be subject to significant inertia and applied difficulty. Therefore, it is probably overly optimistic to presume that (even if improved and mandatory) governmental guidance in respect of animal welfare or public health and safety for operating mobile zoos, or the messaging by operators of these events, can be relied on to meaningfully filter into actual practices or achieve desired benefits, especially where exotic species are involved.As presented in Control measures), we agree that prohibitions on certain practices provide the most secure and reliable method for control and prevention of major areas of concerns regarding mobile zoos. On the basis of the precautionary principle as described earlier, we have developed several recommendations for the control and monitoring of mobile zoos and similar live animal programs.Our evaluations using the EMODE system concur with previous reports that exotic species are not suitable for inclusion in mobile zoo and other similar live animal programs. Accordingly, the use of exotic species at mobile zoos and other handling events infers disproportionate risks to animal welfare and public health and safety. Relatedly, as presented in Exotic (non-domesticated) species, as well as large and potentially physically dangerous domesticated species, should not be used for the purposes of mobile zoos, petting zoos, animal assisted therapies, or any other mobile live animal program. This recommendation is to better protect animals against welfare problems that are associated with the frequently highly specialised biological needs and sensitivities associated with captive wildlife, and to public health and safety from atypical zoonoses and injuries.Animals used for the purposes of mobile live animal programs, should be limited to species that are highly adaptable to and suitable for human interaction, such as amenable individuals of certain types of domesticated dog.All mobile zoos, petting zoos, animal assisted therapies, or any other mobile live animal program operations, should be subject to government mandatory registration and frequent inspection by veterinary or other independent qualified personnel to assess health and welfare states, long-term and short-term or otherwise temporary accommodations, transportation protocols, and operator knowledge.All cases or epidemiological outbreaks of disease at or associated with any mobile zoos, petting zoos, animal assisted therapies, or any other mobile live animal program should be subject to government mandatory notification to regional and national public health authorities.Health and carrier-state screening of all animals, including faecal analysis, for potential pathogens, should be performed frequently to target common relevant zoonotic bacteria and parasites.Formal surveillance of patients at both primary and secondary care interfaces should be increased to target relevant pathogens with overlapping zoonotic histories."}
+{"text": "Hysterectomy is one of the most common non-obstetric gynecological surgical procedures carried out in Western countries . In the The surgical approach to performing hysterectomy include abdominal, vaginal, traditional laparoscopic, robot-assisted laparoscopic, single-port laparoscopic/robotic surgery, and vaginal natural orifice transluminal endoscopic surgery (vNOTES) ,10. The The use of MIS techniques has increased for the treatment of gynecological cancers too, particularly for early-stage cervical cancer (ECC) . The utiDespite the high diffusion of the minimally invasive approach, abdominal hysterectomy remains a very common surgical intervention. The knowledge of this surgical intervention is essential for new generations of gynecologists. The most common indications for the abdominal hysterectomy are large uterine size, previous abdominal surgeries, severe endometriosis and adhesions history. However, there are no specific indications for uterine weight or size and abdominal hysterectomy, and studies show that minimally invasive techniques, such as laparoscopy, can safely remove large uteri too ,26.There are also obstetric indications for abdominal hysterectomy, in most cases in an emergency regime: severe postpartum hemorrhage (PPH)/atony refractory to pharmacological treatments, placenta accrete spectrum disorders (PAS), hypertensive disorders, disseminated intravascular coagulation (DIC) . NonetheHysterectomy is a surgical procedure with potential surgical complications, with the highest rate within 30 days: infectious consequences, hemorrhage, thromboembolic disease, urinary and/or intestinal tract injury, nerve injury and vaginal cuff dehiscence . The comHysterectomy can be a difficult choice for women, with sexual and psychological changes that may led to a non-negligible risk of post-traumatic stress . Therefo"}
+{"text": "Looked-after-children are defined as children who are in the care of their local authority. Previous studies have reported that looked-after-children have poorer mental and physical health, increased behavioural problems, and increased self-harm and mortality compared to peers. They also experience poorer educational outcomes yet population wide research into the latter is lacking, particularly in the UK. Education and health share a bidirectional relationship therefore it is important to dually investigate both outcomes. Our study aimed to compare educational and health outcomes for looked-after-children with peers, adjusting for sociodemographic, maternity and comorbidity confounders.Linkage of nine Scotland-wide databases, covering dispensed prescriptions, hospital admissions, maternity records, death certificates, annual pupil census, examinations, school absences/exclusions, unemployment, and looked-after-children provided retrospective data on 715,111 children attending Scottish schools between 2009 and 2012.Compared to peers, 13,898 (1.9%) looked-after-children were more likely to be absent and excluded from school, have special educational need and neurodevelopmental multimorbidity, achieve the lowest level of academic attainment, and be unemployed after leaving school. They were more likely to require treatment for epilepsy, attention deficit hyperactivity disorder and depression, be hospitalised overall, for injury and self-harm, and die prematurely. Compared to children looked after at home, children looked after away from home had less absenteeism, less exclusion, less unemployment, and better attainment. Therefore, amongst those in care, being cared for away from home appeared to be a protective factor resulting in better educational outcomes.Looked-after-children had poorer health and educational outcomes than peers independent of increased neurodevelopmental conditions and special educational need. Further work is required to understand whether poorer outcomes relate to reasons for entering care, including maltreatment and adverse childhood events, neurodevelopmental vulnerabilities, or characteristics of the care system."}
+{"text": "I thank all authors, reviewers and the editorial staff who contributed to this Special Issue. In recent years, an increasing body of evidence has shown a direct or indirect correlation between oral health and chronic systemic diseases, including diabetes mellitus, atherosclerosis, rheumatoid arthritis, cancer, cardiovascular disease, and other non-communicable chronic diseases, although these findings remain controversial ,2. TypicArtificial intelligence (AI) refers to the ability of a machine that possesses its own form of intelligence to perform tasks that require human cognition. AI-based technology has emerged as a promising approach in the healthcare domain since the 2000s ,8. AI anAI-based algorithms will facilitate rapid, accurate, and reliable diagnosis of oral diseases and adoption of preventive strategies, as well as prompt intervention for improved treatment outcomes. Therefore, AI scores over traditional analytics and clinical decision making techniques through unbiased, consistent, and good-quality diagnosis and treatment in clinical and epidemiological scenarios. AI is particularly useful for standardized diagnosis and treatment of oral disease, which will benefit dental professionals in clinical practice. Several AI-based deep learning architectures have already been approved by the FDA and are being applied in clinical practice. In the dental field, the usefulness of AI has been assessed for the detection, classification, and segmentation of anatomical variables for orthodontic landmarks, dental caries, periodontal disease, and osteoporosis; however, these applications are still in very preliminary stages. This Special Issue is intended to lay the foundation of AI applications focusing on oral health, including general dentistry, periodontology, implantology, oral surgery, oral radiology, orthodontics, and prosthodontics, among others."}
+{"text": "Bee products have been extensively employed in traditional therapeutic practices to treat several diseases and microbial infections. Numerous bioactive components of bee products have exhibited several antibacterial, antifungal, antiviral, anticancer, antiprotozoal, hepatoprotective, and immunomodulatory properties. Apitherapy is a form of alternative medicine that uses the bioactive properties of bee products to prevent and/or treat different diseases. This review aims to provide an elaborated vision of the antiviral activities of bee products with recent advances in research. Since ancient times, bee products have been well known for their several medicinal properties. The antiviral and immunomodulatory effects of bee products and their bioactive components are emerging as a promising alternative therapy against several viral infections. Numerous studies have been performed, but many clinical trials should be conducted to evaluate the potential of apitherapy against pathogenic viruses. In that direction, here, we review and highlight the potential roles of bee products as apitherapeutics in combating numerous viral infections. Available studies validate the effectiveness of bee products in virus inhibition. With such significant antiviral potential, bee products and their bioactive components/extracts can be effectively employed as an alternative strategy to improve human health from individual to communal levels as well. Bee products offer propitious health benefits and are more and more popular in the era of medicinal research. They have also been well known for their nutritional benefits and therapeutic activity since approximately 5500 years ago . In anciHoney is an oxidizing agent with anti-inflammatory, antiproliferative, immunomodulatory, proapoptotic, antimetastatic, and antimicrobial properties ,11,12. BGiardia lamblia and Caenorhabditis . No. No44]. in honey . The minin honey .All of these components are of important nutritional value, with honey being a food product with valuable nutritional properties.Viral infections are considered the most prevalent and deadly infections among all other microbial infections because many viruses remain infectious for a long period in dry mucous . As viruHoney can be considered a significant strategy to treat VZV infection, as it can be easily applied to the skin. A study showed the safe and effective topical application of honey for the treatment of genital and herpes lesions ,61. An iRhododendron ponticum and Rhododendron luteum plants species of the rhododendron [Several toxic components have been identified in honey, such as diterpene grayanotoxins in honey from odendron . This tyodendron ,67.Fabaceae, Boraginaceae, and Asteraceae plants generate pyrrolizidine alkaloid substances that are not toxic but can be transformed into harmful substances (pyrrolic metabolites) via the liver after the ingestion of honey [Apocynaceae), gelsemine and strychnine (Gelsemiaceae), saponins (Sapindaceae), hyoscine, and hyoscyamine (Solanaceae) [of honey . Intoxicof honey ,70,71. Sanaceae) ,70,71,72Bee pollen is a mixture of flower pollen, nectar, and bee secretions, which honeybees transform into bee bread inside the hive, providing a nutritional source for colony formation and maintenance . The insThe composition of bee pollen  varies gCallendula officinalis, Taraxacum officinale, and Anthylis sp. bee pollen from Romania [Mineral components, including Ca, Cu, Fe, K, Mg, and Na, have been found in bee pollen. Several enzymes and vitamins, such as vitamin E (tocopherol), thiamine, folic acid, provitamin A (\u03b2-carotene), biotin, and niacin, have also been identified . The fat Romania , as wellBee pollen has been documented as a significant nutritional supplement with several therapeutic actions, such as antibacterial, antifungal, antiallergic, antioxidant, anticancer, immunomodulatory, and hepatoprotective activities . Only onEchium vulgare, Senecio jacobaea, and Symphytum officinale, may have hepatotoxic properties due to the presence of pyrrolizidine alkaloids at toxic levels [Bee pollen derived from different sources, such as c levels . Health c levels ,94.Lactobacillus spp. of bee pollen in the hive. It contains different proteins, lipids, carbohydrates, fatty acids, free amino acids, water, vitamins, and some bioactive compounds [Bee bread is formed by anaerobic fermentation by different ompounds . It is uompounds .Bee bread  is prepaThe lipid content in bee bread composition varies depending upon the pollen-producing plant origin. Icosa-tetraenoic and octadecenoic acids, accounting for about 15%, are abundantly found unsaturated fatty acids . The car50 values ranging from 0.048 and 5.45 mg/mL, respectively. This study suggested that bee bread and bee pollen are auspicious antiviral agents and should be further investigated against various viruses to scrutinize their antiviral potentiality.A few investigations have evaluated the microbicidal activity of bee bread against several bacterial and fungal pathogens ,101. HowApis mellifera bees with a waxy texture. Bees use their mandibles for the collection of plant resins to produce propolis. Chemically, it can be described as a complex mixture constituting several bioactive compounds with antifungal, antibacterial, antiparasitic, antiviral, immunomodulatory, and hepatoprotective actions [Propolis is a resinous bee product produced by different plants and collected by  actions .The composition of propolis  varies dFlavanones, another substantial group of flavonoids, have also been identified in propolis. Forty different types of flavanones have been identified in propolis. Pinostrobin, liquiritigenin, pinocembrin, naringenin, isosakuranetin, and sakuranetin are the most commonly reported flavanones . In addip-coumaric acids) and hydroxybenzoic acids . The biological activities  of propolis are directly dependent upon its composition . In ancient times, the Egyptians, Romans, and Greeks used propolis as a disinfectant and wound-healing substance. It has been reported as a safe (non-toxic) product for human use [Two major types of phenolic acids present in propolis are hydroxycinnamic acids . The obtained results revealed that all samples of propolis significantly decreased the infectivity of viruses . EgyptiaToxic effects of propolis have been observed at high doses, such as 15 g/day . DespiteBee venom is a transparent and inodorous liquid amalgam of proteins (with 4.5\u20135.5 pH), mostly used by bees to protect themselves against different predators. In liquid form, one drop of it contains only 0.1 \u00b5g of venom (dried weight) and about 88% water. It is a complex mixture of different peptides, enzymes, minerals, and amino acids .Bee venom is prepared by female worker bees and constitutes several active compounds, including peptides such as apamin, melittin, adolapin, and mast cell degranulating peptide (MCD); enzymes such as hyaluronidase and phospholipase A2 (PLA2); minerals ; bioactive amines such as histamine, dopamine, and noradrenaline; and some volatile compounds containing complex ethers  128,129129. MeliVarious studies have reported the positive impacts of bee venom, providing antimicrobial, antiviral, anticancer, anti-inflammatory, antimalarial, and hemolytic effects based on the bioactive compounds of bee venom. The therapeutic efficacy of its bioactive compounds has been tested in the treatment of central nervous system diseases (Alzheimer\u2019s disease and Parkinson\u2019s disease), human inflammatory diseases, prostate and ovarian cancers, amyotrophic lateral sclerosis (ALS), HIV, and several other conditions ,134,135.Bee venom and its components have exhibited significant antiviral activities against several viruses  136,137,139, inc+\u2013CD8+, and CD4+\u2013CD8+, causing a decrease in viral load and a reduction in infection severity (in pigs infected with PRRSV) [50 117 \u00b1 43, 49 \u00b1 13, and 183 \u00b1 38 ng/mL, respectively [Melittin, a bee venom peptide, can activate the immune system against porcine reproductive and respiratory syndrome viruses (PRRSV) by upregulating Th1 cytokines (IL-12 and IFN-) and other immune cells, such as gd-T cells, CD3h PRRSV) . Phosphoh PRRSV) . Secreteectively .Royal jelly (RJ) is a substance enriched with lipids and proteins developed by mandibular and hypopharyngeal bee glands . This beRoyal jelly  is an acThe lipid components are the unique feature of RJ composition. About 90% of lipids are composed of fatty acids, and the remaining components include waxes (5\u20136%), phenols (4\u201310%), steroids (3\u20134%), and phospholipids (0.4\u20130.8%) ,149. SevThe mineral elements include Ca, Cu, Fe, K, Mn, Mg, Na, and Zn. Some trace elements have also been identified, including Cd, Al, Cr, Ba, Co, Bi, Mo, Ni, Sr, Sb, Sn, Hg, V, Pb, Te, Ti, and Tl . Some miSeveral investigations were found on its potential antibacterial and antifungal activities against various pathogenic microbes. Only a few studies have investigated its antiviral activities, and they showed significant antiviral activities against SARS-CoV-2  and HSV-Royal jelly can become contaminated with different environmental contaminants, such as carbamates, organochlorines, and organophosphorus (present in pesticides), which have less toxicity. Meanwhile, highly toxic chloramphenicol has also been identified . ConsumpBeeswax is an intricate compound produced in its liquified form in younger bees aged 12\u201318 days via particular wax glands. Its color changes from white to yellowish-brown following contact with bee honey and pollen. It partially dissolves in alcohol and completely dissolves in chloroform .Staphylococcus aureus and Salmonella enterica) and fungi  [Beeswax  containslbicans) .Only one study evaluated the antiviral potential of four different beeswax extracts and the bee venom, alone and in combination, against DNA (Adeno-7 virus) and RNA  viruses . AccordiBee products, including honey, bee venom, propolis, royal jelly, bee bread, and beeswax, have high nutritional importance due to their chemical compositions. However, their consumption is conditioned by possible allergenic action. The increasing therapeutic potential of natural products, particularly bee products, has grabbed the attention of researchers over the last decades. Recent research developments and discernment of the biological properties of bee products and their bioactive compounds, responsible for generating antiviral, antibacterial, antifungal, anticancer, antiparasitic, hepatoprotective, and immunomodulatory effects, need to be extensively assimilated in an effort to upgrade the use of bee products for the management of viral infections and other diseases as well. Bee products contain several bioactive components that possess antiviral properties derived from plant sources. This review demonstrates the highly encouraging antiviral potential of bee products against various viruses. The antiviral components of bee products may often exert antimicrobial activities. Conclusively, this review also suggests that the consumption of bee products, i.e., honey, propolis, bee venom, bee pollen, royal jelly, bee bread, and beeswax, can be an integral approach to enhancing immunity and reducing human health problems."}
+{"text": "CREBBP gene, located on exons 30 or 31. There are only around 30 cases reported by now.Menke-Hennekam syndrome (MHS) is a relatively new genetic condition characterized by intellectual disabilities, autistic behavior, auditory defects, recurrent upper respiratory tract infections, microcephaly and short stature. Facial characteristics include short palpebral fissures, telecanthus, depressed nasal bridge, short nose, anteverted nares, short columella, and long philtrum. The genetic defect is represented by missense variants of The aim of the paper is to report a new case of MHS.The case is a 3-year-old boy admitted in our department for developmental delay. The clinical examination revealed dysmorphic features; severe speech delay, mild intellectual disability, autistic behaviour.The patient had a personal history of recurrent respiratory infections, visual defect and bilateral sensorineural hearing loss. Other investigations included EEG, abdominal echography, and cerebral MRI all were normal. The genetic studies included array CGH and WES.The array CGH was normal. WES identified a pathogenic heterozygote variant c.5600G>A in the exon 31 of CREBBP gene, confirming MHS.Overall, the features of our patient are consistent with those reported in the previous reports, including developmental and speech delay, autistic behavior, dysmorphic features, recurrent upper way infections, sensorineural hearing loss, and visual defects. Other common features, such as growth delay and microcephaly were not present in our patient. Our case contributes to the clinical characterisation of the new syndrome. Funding: The research leading to these results has received funding from the EEA Grant 2014-2021, under the project contract No 6/2019.No significant relationships."}
+{"text": "We searched PubMed, Cochrane Library, and Epistemonikos to identify systematic reviews and meta-analysis (SRs). We searched for neurological diseases and psychiatric disorders, including Alzheimer's disease (AD), attention deficit hyperactivity disorder (ADHD), amyotrophic lateral sclerosis (ALS), autism spectrum disorder (ASD), anorexia nervosa (AN), bipolar disorder (BD), eating disorder (ED), generalized anxiety disorder (GAD), major depressive disorder (MDD), multiple sclerosis (MS), obsessive compulsive disorder (OCD), Parkinson's disease (PD), posttraumatic stress disorder (PTSD), spinal cord injury (SCI), schizophrenia, and stroke. We used A Measurement Tool to Assess Systematic Reviews (AMSTAR-2) to evaluate the quality of included SRs. We also created an evidence map showing the role of gut microbiota in neurological diseases and the certainty of the evidence. Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, and Verrucomicrobia were more researched. At the genus level, Prevotella, Coprococcus, Parabacteroides, Phascolarctobacterium, Escherichia Shigella, Alistipes, Sutteralla, Veillonella, Odoribacter, Faecalibacterium, Bacteroides, Bifidobacterium, Dialister, and Blautia were more researched. Some diseases have been found to have specific flora changes, and some diseases have been found to have common intestinal microbiological changes.  In total, 42 studies were included in this evidence mapping. Most findings were obtained from observational studies. According to the AMSTAR-2 assessment, 21 SRs scored \u201ccritically low\u201d in terms of methodological quality, 16 SR scored \u201clow,\u201d and 5 SR scored \u201cmoderate.\u201d A total of 15 diseases have been investigated for the potential association between gut microbiome alpha diversity and disease, with the Shannon index and Simpson index being the most widely studied. A total of 12 diseases were investigated for potential link between beta diversity and disease. At the phylum level,  We found varied levels of evidence for the associations between gut microbiota and neurological diseases; some gut microbiota increased the risk of neurological diseases, whereas others showed evidence of benefit that gut microbiota might be promising therapeutic targets for such diseases. The intestinal flora mainly exists in the digestive tract and is an important part of the human microbiome. Intestinal flora is characterized by abundant species and large quantity, and the functional potential of different intestinal flora is increasingly understood. Intestinal flora can not only help the body to decompose and store fat but also regulate the immune, endocrine, metabolic, and neurological functions through immune, neuroendocrine, and vagus nerves. Therefore, the occurrence of various diseases of the human body is closely related to the disorder of intestinal flora, such as obesity , cardiovStudies have found that there are channels in the human body that connect nerves between the gut and the brain, which is known as the microbiota-gut-brain axis . The gutIndeed, since each person features a unique microbiota composition, some systematic review and meta-analysis (SRs) have investigated differences in the composition of the gut microbiota between patients with neurological and psychiatric disorders and healthy individuals \u201312. For Therefore, the aim of this evidence mapping was to summarize the gut microbiota associated with neurological and psychiatric disorders and to identify common or differential gut microbiota present in different neurological and psychiatric disorders. Such associations may afford opportunities for both understanding aetiology and making targeted treatment strategies, including probiotic supplements, dietary changes, and even fecal microbial transplants (FMT).To summarize the associations of gut microbiota with neurological or psychiatric disorders on a larger scale, we used evidence mapping. This study was conducted on the basis of the methodology proposed by global evidence mapping . The stuA systematic search of the literature was conducted in PubMed, Embase, Cochrane Library, and Epistemonikos databases up to March 21, 2022. Medical subject heading (MeSH) terms and keywords used in the search included various neurological diseases and psychiatric disorders, gastrointestinal microbiome, gut-brain axis, enteric nervous system, and meta-analysis or systematic review. Search results were independently reviewed for eligibility by two independent researchers (Yaning Zang and Ying Wang), with discrepancies resolved by a third researcher (Yi Zhu). Studies were included based on the following criteria . FurtherThe quality of included studies was assessed using the AMSTAR-2 tool, which uses 16 items  to assess the methodological quality of systematic reviews or meta-analysis. For each item, there are three answers: yes, partially yes, no. Studies were rated in four categories: \u201chigh,\u201d no critical weakness and no more than one noncritical weakness; \u201cmoderate,\u201d no critical weakness and more than one noncritical weakness; \u201clow,\u201d one critical flaw with or without noncritical weaknesses; and \u201ccritically low,\u201d more than one critical flaw with or without noncritical weaknesses. The evaluation results were presented through heat maps. Two reviewers (Yaning Zang and Xigui Lai) independently evaluated each study and rated the studies according to the AMSTAR-2 tool. Discrepancies in risk assessment were resolved by consensus and, if required, consultation with a third reviewer (Yi Zhu).\u03b1 and \u03b2 diversity indices of the microbiome, and gut microbiota's taxonomic composition at different levels, such as phylum, order, family, genus, and species.Two reviewers (Yaning Zang and Dongfang Ding) independently extracted data using a predesigned table included: the author and year, study design included in this paper, search date of included study, study design and number of studies included in SRs, sample of SRs, flora sample, methods of microbiology assessment, participants type, diversity indices included Studies included in this paper reported the comparison of gut microbiota between patients and controls, including alpha diversity, beta diversity, and the relative abundance of bacteria of different phylum, class, order, families, genus, and species. Evidence mapping was used to compare the different microbiota involved in the studies' pathologies. The evidence mapping displayed information in two dimensions: (1) The different colors show changes in the abundance of the flora in neurological or psychiatric disorders which included increase, decrease, significant difference, no difference, mixed, and unclear. It should be noted that when different studies show inconsistent changes in the microbiome, it was classified as mixed. (2) The different shapes in the cells indicate the strength of the evidence.In total, 42 studies were included in this evidence mapping. A flow diagram of study selection is presented in According to the AMSTAR-2 criteria, 21 SRs , 17\u201336 sThe earliest articles included in this paper are from 2018. From 2018 forward, the number of studies in this field increased rapidly. Most of the primary studies were observational, including cohort studies, case-control studies, and case series. For the studies that used marker-gene analysis, 16S ribosomal RNA was the most amplified gene .The most studied neuropsychiatric disorder is autism spectrum disorder (ASD) with 11 studies , 53, 55 Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, and Verrucomicrobia. At the genus level, 14 genera were more identified: Prevotella, Coprococcus, Parabacteroides, Phascolarctobacterium, Escherichia Shigella, Alistipes, Sutteralla, Veillonella, Odoribacter, Faecalibacterium, Bacteroides, Bifidobacterium, Dialister, and Blautia.A total of 15 diseases have been investigated for the potential association between gut microbiome alpha diversity and disease, with the Shannon index and Simpson index being the most widely studied. A total of 12 diseases were investigated for potential link between beta diversity and disease. The Bray-Curtis distance, weighted UniFrac distances, and unweighted UniFrac distances were the most widely examined. Regarding the microbiota assessment, it is the most classified the bacteria detected according to both phylum and genus, with a wide variety of bacteria being studied. Few studies included the level of species when classifying the bacteria detected. At the phylum level, 5 phyla were more identified: Coriobacteriaceae was only observed in AN patients, and Deferribacter, Lactobacillale, and Tropheryma were only observed in SCZ patients. At the order level, Alteromonadales, Bifidonbacteriales, Coriobacteriales, Cytophagales, Deltaproteobacteria, Eerysipelotrichales, Flavobacteriales, Pasteurellales, and Sphingobacteriales were only observed in MDD patients, and Desulfovibrio was only observed in stroke patients. At the family level, Acidaminococcaceae, Bifidobacteriaceae, Nocardiaceae, Tannerellaceae, and Thermoanaerobacteriaceae were only observed in MDD patients, Catabacteriaceae, Enterococcaceae, and Xanthomonadaceae were only observed in ADHD patients, Flavobacteriaceae and Helicobacteraceae were only observed in stroke patients, Pasteurellaceae was only observed in SCZ patients, and Sutterellaceae was only observed in ASD patients. At the genus level, Acetanaerobacterium, Burkholderia, and lkaliflexus were only observed in ASD patients, Kineothrix was only observed in ALS patients, Bulleidia, Butyricicoccus, Olsenella, Oxalobacter, Paraprevotella, and Parvimonas were only observed in MDD patients, Butyricicoccus was only observed in stroke patients, and Pseudomonas was only observed in MS patients. At the species level, Acidovorax was only observed in stroke patients, Bacteroides caccae, Bacteroides coprocola, Bacteroides ovatus, Bacteroides uniformis, Collinsella, Gemmiger, Lachnospiraceae, Lachnospiraceae, Lachnospiraceae, Streptococcus, Streptococcus, Uricibacter, and Veillonella parvula were only observed in ADHD patients, Bacteroidetes genera, Desulfovibrio, Devosia, Dialister invisus, Dialister invisus, and Dialister invisus were only observed in ASD patients.In particular, some diseases have been found to have specific flora changes. At the phylum level, Actinobacteria. The most consistent change of AD, ADHD, ALS, GAD, and MDD was the depletion of Firmicutes. At the genus level, the consistent change of ALS, MS, SCI, and stroke was the increase of Akkermansia and the increase of Bacteroides in ADHD, AN, GAD, MS, and SCI patients.Although different studies draw many inconsistent conclusions, we found some overlaps between certain diseases when comparing the direction of association. At the phylum level, the most consistent change of ADHD, AN, and BD was the increase of In conclusion, our findings are as follows: first, studies on gut microbiomes among individuals with SCI, stroke, and AD are limited. The gastrointestinal symptoms (GI), such as diarrhea, constipation, and abdominal pain, inflammatory bowel disease, and irritable bowel syndrome (IBS) are often comorbid with SCI, stroke, AD, and so on. The simultaneous occurrence of neurological, psychiatric, and gastrointestinal diseases increases the risk of disease progression and poor outcomes, and the treatment of one disease can reverse the risk of another disease , 57. TheLactobacillus rhamnosus as a therapeutic supplement can reduce the risk of neuropsychiatric disorders in infants with autism spectrum disorders [Lactobacillus and Bifidobacterium can reduce the occurrence of anxiety and depression-related symptoms and positively affect memory, learning and cognition [Second, we found evidence of disease specificity, suggesting that these microbiota may be involved in the pathogenesis. And, identifying biotypes may provide opportunities to make targeted treatment strategies in clinic, including probiotic supplements, dietary changes, and even fecal microbial transplants (FMT). For example, isorders . In a vaognition . Nutritiognition . Increasognition . FMT infognition , 63. Neuognition .Clostridium, and the content of short chain fatty acids (SCFA) was significantly lower than that of healthy people, indicating that the intestinal ecological imbalance of PD patients was related to the decrease of SCFA level; then, the reduction of SCFA can promote \u03b1. The accumulation of synuclein in the intestinal nervous system leads to PD [Third, certain diseases have similar patterns of microbial changes. Specifically, we observed that ADHD, AN, and BD; AD, ADHD, ALS, GAD, and MDD; ALS, MS, SCI, and stroke; and ADHD, AN, GAD, MS, and SCI overlapped in the categories of changes in abundance, suggesting that these overlaps may be related to transdiagnostic of pathophysiology. There are several possible explanations for the mechanisms that drive the gut microbiota to affect different neurological and psychiatric disorders , 65, 66:ds to PD . Althougds to PD .Finally, it is worth noting that systematic reviews included in our study summarized differences in gut microbiota between the patients group and healthy group and draw a conflicting or even opposite conclusion, which may suggest the excess or dearth of a microbe may lead to deranged pathophysiology, so any microbe if not present in suitable amounts may be harmful . AnotherDue to the limitations of the included studies, we did not conduct analyses of sampling method, sampling time, sequencing, or analysis pipelines. Given that most findings were obtained from observational studies cannot infer causality or explain temporal changes in gut microbiota, so the possibility of reverse causality should be taken into account.Another point that needs to be emphasized is that this article mainly analyzes the changes of single flora. Some studies have shown that the use of probiotics or probiotics may improve the symptoms of patients with neurological or mental disorders. In further research, we will analyze the effects of different probiotics, diets, and flora transplantation on patients to find the optimal combination of flora.Analyzing the changes in the microbiome could be an essential source of knowledge for better understanding neurological or psychiatric disorders. Some diseases have specific flora changes, while others have consistent changes. Although the exact mechanism of action is unclear, regulating gut microbiota and maintaining physical stability and health by improving diet, supplementing special probiotics and probiotics, or FMT transplantation can open up new ideas for the treatment of neurological and mental diseases."}
+{"text": "With the move to virtual interviewing, residency websites are an important recruitment resource, introducing applicants to programs across the country and allowing for comparison. Recruitment is highly competitive from a common potential pool between vascular surgery, thoracic surgery, and interventional radiology with the ratio of applicants to positions being highest in interventional radiology, followed by thoracic surgery and lastly vascular surgery, as reported by the National Resident Matching Program.The aim of this study is to evaluate the accessibility and availability of online content for those integrated residency programs.A list of accredited vascular surgery, thoracic surgery, and interventional radiology residencies was obtained from the Accreditation Council for Graduate Medical Education (ACGME) database. Program websites were evaluated by trained independent reviewers (n=2) for content items pertaining to program recruitment and education (scored absent or present). Statistical analysis was performed in R software.P=.12). Vascular surgery websites contained a median of 26 (IQR 20-32) content items, thoracic surgery websites contained a median of 27 (IQR 21-32) content items, and interventional radiology websites contained a median of 23 (IQR 18-27) content items. Two content items considered highly influential to applicant program decisions are procedural experience and faculty mentorship, which were reported at 32% (18/56) and 11% (6/56) for vascular surgery, 19% (5/27) and 11% (3/27) for thoracic surgery, and 50% (37/74) and 15% (11/74) for interventional radiology (P=.008 and P=.75), respectively. Key deficits were work hours, debt management, and curriculum for interventional radiology; resident profiles, sample contracts, and research interests in vascular surgery; and operative experiences and the program director\u2019s contact and message for thoracic surgery. Interventional radiology deficits were work hours, and thoracic surgery deficits were procedural experience. Both interventional radiology and thoracic surgery websites lacked information on evaluation criteria and faculty mentorship.Of ACGME-accredited programs, 56 of 61 (92%) vascular surgery, 27 of 27 (100%) thoracic surgery, and 74 of 85 (87%) interventional radiology programs had functional websites (This study has uncovered key differences in the availability of online content for residencies recruiting from the same pool of applicants. Thoracic surgery has the most information, followed by vascular surgery, with interventional radiology reporting the least content. In the era of virtual interviewing from the same potential pool of applicants, programs should review and revise their web presence with the aim to increase the availability of online content to attract valuable candidates. The role of vascular surgeons in the medical environment has changed considerably with the increasing use of endovascular approaches for treatment of vascular lesions . By 2026Candidates for residency programs increasingly use the internet to research potential programs for application -6. OnlinA comprehensive list of accredited integrated vascular surgery, thoracic surgery, and interventional radiology residencies was obtained from the Accreditation Council for Graduate Medical Education (ACGME) database. Programs participating in the 2020 National Resident Matching Program (NRMP) were eligible for study inclusion. Following identification of all programs with websites, programs were accessed and evaluated by two independent reviewers  for availability of recruitment and educational content items. The websites were viewed independently by each reviewer. The program search and review was performed in November 2019.Are there key differences in the three specialty program websites for integrated residencies that could potentially impair recruitment efforts in the virtual environment?direct (landing directly on the program webpage) or indirect .Accessibility of websites was determined by surveying the ACGME database for the total number of programs listed and the presence or absence of website links. Links, if they were provided, were characterized as either functional or nonfunctional. Functional links led to a website. Nonfunctional links led to an error page. Functional links were then evaluated as being either Websites for integrated vascular surgery, thoracic surgery, and interventional radiology residency programs were analyzed for availability of information used to inform and recruit prospective applicants. Content items on recruitment and education (listed in Program recruitment (n=41)Program descriptionNumber incoming positions availableFaculty listingFaculty education and training historyFaculty profile (descriptive)Faculty publicationsFaculty contact informationCurrent residentsResident education historyResident profilesResident contact informationAlumni listingAlumni education historyAlumni contact informationAlumni career placementBoard examination performanceProgram chair messageProgram director messageProgram director contactAdministrative/coordinator contactFacility descriptionApplication requirementsSelection processInterview datesInterview day detailsElectronic Residency Application Service (ERAS) linkIf present, is ERAS link functional?Call requirementContractSalaryWork hoursBenefitsVacationCity informationDomestic considerationsWell-being strategiesDebt managementMeal allowanceEducational fundParkingVisaProgram education (n=16)Rotation scheduleDidactic instructionResearch requirementsResearch interests (department/faculty)Operative experienceJournal clubConference scheduleNational/regional meetings attendedEvaluation criteriaFaculty mentorshipNational organization linkCurriculumCompany linkElective rotationSimulation trainingVascular labWebsites were evaluated for content relevant to program recruitment and education. Program recruitment information included faculty listings, faculty and departmental research interests, alumni career placements, and information on current residents. Recruitment information regarding the application and interview process as well as general resident quality of life metrics were also evaluated see . ProgramEach website was accessed and evaluated by two reviewers  for availability of content items as well as quality of websites . Each reviewer was trained by examining an optimal website, an average website, and a below average website with the senior author. Disputed assessments were resolved by consensus following discussion with the senior author. Reviewers were not blinded.\u03ba=0.74).Overall, there was considerable interrater reliability with 81% agreement .Intergroup analysis of continuous variables was performed using ANOVA. Categorical variables were compared using chi-square analysis. Statistical significance was defined as All data reviewed was open to the public, and there was no contact with fellowship staff; thus, no institutional review board review, ethics approval, or informed consent was necessary.P=.18). Of those programs that provided links, the majority of the links were functional with no difference between the specialties (P=.24). However, few links landed directly on the program webpage. Less than one-third of the programs with functional links provided links that landed directly on the program webpage (P=.52). Overall, 56 of 61 (92%) vascular surgery, 27 of 27 (100%) thoracic surgery, and 74 of 85 (87%) interventional radiology programs had a dedicated webpage  of the vascular surgery, 89% (24/27) of the thoracic surgery, and 95% (81/85) of the interventional radiology programs provided a link to their program webpage on the ACGME webpage  content items, thoracic surgery program webpages contained a median of 27 (IQR 21-32) content items, and interventional radiology program webpages contained a median of 23 (IQR 18-27) content items. Of the 41 recruitment content items included in this analysis, vascular surgery program webpages contained a median of 19.5 (IQR 15-24) content items, thoracic surgery program webpages contained a median of 20 (IQR 16-24) content items, and interventional radiology program webpages contained a median of 18 (IQR 15-21) content items. Of the 16 education content items included in this analysis, vascular surgery program webpages contained a median of 7 (IQR 4-9) content items, thoracic surgery program webpages contained a median of 6 (IQR 4-7) content items, and interventional radiology program webpages contained a median of 4 (IQR 3-7) content items .For program recruitment, almost all programs provided information on program description, faculty listing, faculty education, administrator or coordinator contact information, facility description, descriptive faculty profiles, and the number of incoming positions. The majority of programs provided information on application requirements, a functional link to the Electronic Residency Application Service (ERAS), benefits, salary, current residents, city information, resident education history, domestic considerations, vacation policy, and interview dates. Less than one-half of programs provided information on program director contact information, faculty publications, well-being strategies, faculty contact information, program director message, alumni listing, alumni career placement, educational fund, parking, nonnational visa information, meal allowance, call requirement, alumni career placement, and debt management. Fewer than one-quarter of the programs provided information on sample contracts, resident profiles, interview details, work hours, and alumni education history. Almost no programs provided information on their selection process, resident contact information, program director message, board examination performance, and alumni contact information .For program education, almost all programs provided information on rotation schedule . The majority of programs provided information on didactic instruction, research requirements, journal club, and vascular lab training (Registered Physician in Vascular Interpretation [RPVI]). Less than one-half of programs provided information on departmental research interests, operative experience, meetings attended, elective rotations, conference schedule, curriculum, and simulation training. Fewer than one-quarter of the programs provided information on evaluation criteria and faculty mentorship. Almost no programs provided information on national organizational links and cardiovascular product company links .For program recruitment, almost all programs provided information on program description, faculty listing, faculty education, administrator or coordinator contact information, facility description, and application requirements. The majority of programs provided information on descriptive faculty profiles, a functional link to ERAS, benefits, the number of incoming positions available, salary, current residents, faculty publications, well-being strategy, city information, resident education history, vacation policy, call requirements, and domestic considerations. Less than one-half of programs provided information on program director contact information, interview date, faculty contact information, sample contracts, resident profiles, alumni listings, debt management, educational fund, parking, nonnational visa information, meal allowance, and work hours. Fewer than one-quarter of the programs provided information on program director message, alumni career placement, interview details, and resident contact information. Almost no programs provided information on selection process, alumni education history, program chair message, board examination performance, and alumni contact information .For program education, the majority of programs provided information on rotation schedule, departmental research interests, didactic instruction, and research requirements. Less than one-half of programs provided information on journal club, meetings attended, elective rotation, curriculum, national organization links, and simulation training. Fewer than one-quarter of the programs provided information on operative experiences, conference schedule, faculty mentorship, and evaluation criteria . Almost For program recruitment, almost all programs provided information on program description, faculty listing, faculty education, administrator or coordinator contact information, and descriptive faculty profiles. The majority of programs provided information on application requirements, a functional link to ERAS, facility description, vacation policy, benefits, the number of incoming positions available, salary, current residents, program director contact information, and faculty publications. Less than one-half of programs provided information on well-being strategies, city information, educational fund, parking, nonnational visa information, meal allowance, call requirement, resident education history, domestic considerations, interview dates, faculty contact information, and sample contracts. -quarter of the programs provided information on a program director message, resident profiles, interview details, alumni listing, alumni career placement, selection process, and debt management. Almost no programs provided information on resident contact information, work hours, alumni education history, program chair message, board examination performance, and alumni contact information .For program education, the majority of programs provided information on rotation schedule, departmental research interests , didactic instruction, and research requirements. Less than one-half of programs provided information on operative experiences, journal club, meetings attended, and elective rotations. Fewer than one-quarter of the programs provided information on conference schedule, curriculum, faculty mentorship, vascular lab training (RPVI), and national organization links. Almost no programs provided information on evaluation criteria, simulation training, and cardiovascular product company links .P=.02, P=.008, and P<.001, respectively). Vascular surgery webpages provided less information on departmental research interests as compared to thoracic surgery and interventional radiology webpages . Thoracic surgery webpages provided less information on descriptive faculty profile as compared to vascular surgery and interventional radiology webpages . Interventional radiology webpages provided less information on facility description, debt management (P=.007), research requirements (P<.001), curriculum (P=.04), and simulation training (P<.001) as compared to vascular surgery and thoracic surgery webpages , the average thoracic surgery website score was 2.18 (SD 0.92), and the average interventional radiology website score was 2.25 (SD 0.88). The vascular surgery websites had the highest scores in content, design, organization, and user-friendliness. The thoracic surgery websites had the lowest scores in content, organization, and user-friendliness, while the interventional radiology websites had the lowest score in design. Additional details regarding website quality, broken down by category, are visible in As resident recruitment moves to a virtual platform, the internet is an increasingly important resource for residency applicants as they research programs. Thoracic surgery program webpages had the most information, followed by vascular surgery program webpages, with interventional radiology program webpages reporting the least content. This trend in availability of content items mirrors the percent of positions filled by each specialty, with 100% of PGY-1 thoracic surgery positions filled, 97% of vascular surgery PGY-1 positions filled, and 97% of PGY-1 interventional radiology positions filled , as reported by the NRMP 2020 Main Residency Match Results and Data report .Other factors, beyond program websites, that have been identified to influence applicant interest in a program include geography, advice from a mentor, advice from a peer, and other online information. The integrated vascular track was first accredited by the ACGME in 2006 , the firOf ACGME-accredited programs, 56 of 61 (92%) vascular surgery programs, 27 of 27 (100%) thoracic surgery programs, and 74 of 85 (87%) interventional radiology programs had functional websites. Thoracic surgery program webpages had the most information , then vascular surgery program webpages , with interventional radiology program webpages reporting the least content . The greater amount of content on vascular surgery and thoracic surgery program webpages could be expected, given the young age of many interventional radiology programs. Previous studies have acknowledged integrated interventional radiology program webpages to be a work in progress . This stP=.008 and P=.75), respectively. Additional notable deficits for vascular surgery websites were resident profiles, sample contracts, and departmental research interests. Thoracic surgery websites lacked program director contact information and message as well as information on operative experience. Interventional radiology websites had deficits in work hours, debt management, and curriculum. All specialty websites had deficits in evaluation criteria and faculty mentorship. In addition to addressing the deficits in program recruitment and education content items, the deficits in lifestyle management cannot be disregarded; medical students increasingly report controllable lifestyle as a major factor in specialty choice [Two content items that have been identified to be highly influential to the applicant program decision are operative experience and faculty mentorship -33. Thisy choice ,35.The deficits identified by this analysis are comparable to deficits identified for other specialties. Other studies have found considerable deficits in newsletter, resident listings and photographs, faculty contact information, and away elective rotation information for dermatology websites ; residenOverall, we recommend that programs address the deficits in specific content items identified by this analysis. Given the increasingly important role of online information in the residency application process and the anticipated transition to a virtual application process for the 2021 cycle, it would behoove programs to increase their online presence. In addition to the content items included in this analysis, it might be fitting for programs to include more personal information  to give applicants a better idea of the personality of different programs, replacing the role previously served by in-person away rotations and interviews.This study had several limitations. First, this data is representative of what information was available online at the time of data collection. It is possible that websites could have been edited or new program websites could have been published since that time. Additionally, though an extensive list of content items were evaluated by reviewers regarding program recruitment and education, it is possible that other unmentioned content items could hold bearing on an applicant\u2019s decision. Finally, reviewers were not blinded to what program they were evaluating. Thus, any inherent bias reviewers might have had for particular programs was not controlled for. The nature of this study did not lend itself to evaluating the association between website content, to what specialty and to what programs applicants apply, and ultimate applicant program placement. Future studies could seek to characterize this trajectory.This study has uncovered key differences in the availability of online content for residency programs recruiting from the same pool of applicants. Thoracic surgery program webpages have the most information, then vascular surgery program webpages, with interventional radiology program webpages reporting the least content. Recruitment is highly competitive between vascular surgery, thoracic surgery, and interventional radiology with the ratio of applicants to positions being highest for thoracic surgery, then interventional radiology, and lastly vascular surgery, as reported by ERAS. To attract valuable candidates, programs should aim to increase the availability of online content for potential applicants."}
+{"text": "PLOS ONE Editors retract this article [The  article  because At the time of retraction, the original article was republished to correct the affiliation for author Huma Khan.MB responded but expressed neither agreement nor disagreement with the editorial decision. MAB, HK, MSN, HF, MH, SA, MAE-Z, RAA, MT and RJ did not reply or could not be reached."}
+{"text": "Essential oils\u2019 therapeutic potential is highly recognized, with many applications rising due to reported anti-inflammatory, cardioprotective, neuroprotective, anti-aging, and anti-cancer effects. Nevertheless, clinical translation still remains a challenge, mainly due to essential oils\u2019 volatility and low water solubility and stability. The present review gathers relevant information and postulates on the potential application of plant nanovesicles to effectively deliver essential oils to target organs. Indeed, plant nanovesicles are emerging as alternatives to mammalian vesicles and synthetic carriers due to their safety, stability, non-toxicity, and low immunogenicity. Moreover, they can be produced on a large scale from various plant parts, enabling an easier, more rapid, and less costly industrial application that could add value to waste products and boost the circular economy. Importantly, the use of plant nanovesicles as delivery platforms could increase essential oils\u2019 bioavailability and improve chemical stability while reducing volatility and toxicity issues. Additionally, using targeting strategies, essential oils\u2019 selectivity, drug delivery, and efficacy could be improved, ultimately leading to dose reduction and patient compliance. Bearing this in mind, information on current pharmaceutical technologies available to enable distinct routes of administration of loaded vesicles is also discussed. The field of plant nanovesicles has recently emerged and is evolving quite rapidly, with the number of publications growing exponentially in the last year . Since iZingiber sp.), grapes (Vitis sp.), lemons, and grapefruits (Citrus sp.), which enables a large-scale, more rapid, and less costly industrial application [Plant nanovesicles are generally obtained from edible plants such as ginger , with some differences in comparison to mammalian EVs, as shown in In addition to their relevant role in plant growth, defense, and symbiotic relations , many stIn addition to plant nanovesicles\u2019 bioactive potential and their use in preventive and therapeutic approaches, these vesicles can also be explored as drug-delivery platforms. In fact, plant nanovesicles are emerging as promising alternatives to mammalian nanocarriers due to their safety, stability, non-toxicity, and low immunogenicity . MoreoveBearing all this in mind, breakthrough scientific advances in the field are expected in the next years, with innovative applications definitely being disclosed. Herein, we gather relevant information and postulate on a potential application of plant nanovesicles as the next-generation drug platform for essential oils\u2019 delivery. The clinical use of these secondary metabolites continues to be a challenge mainly due to their high volatility and low water solubility and stability. Nanoencapsulation of essential oils in plant vesicles could represent a suitable and effective strategy to overcome these limitations and surpass deficiencies identified in other nanoencapsulation strategies such as liposomes, solid lipid nanoparticles, nano- and micro-emulsions, or polymeric nanoparticles. To avoid confusion with existing terminology, we decided to use the broader term plant nanovesicles to refer to all nanovesicles obtained from plants, disregarding their origin and isolation method.Citrus aurantifolia, Citrus limon, Citrus sinensis, Cymbopogon nardus, Cymbopogon winterianus, Eucalyptus citriodora, Eucalyptus globulus, Lavandula \u00d7 intermedia, Mentha canadensis, Mentha \u00d7 gracilis, Mentha \u00d7 piperita, Ocotea odorifera, Pogostemon cablin, Sassafras albidum, and Syzygium aromaticum being the most traded, with plant production reaching over 1000 t/year [Essential oils are a complex liquid mixture of volatile, lipophilic, and fragrant secondary metabolites obtained from aromatic plants . These v0 t/year .Citrus fruits [To obtain these volatile extracts from plants, international guidelines recommend the use of distillation or expression in the case of s fruits , thus exs fruits ,32.An important aspect to consider in essential oils production is their high variability due to physiological, environmental, and genetic factors. Therefore, to ensure the high quality of commercialized oils, specific analytical guidelines published by several institutions, such as the European Pharmacopoeia, the International Standard Organization (ISO), and the World Health Organization (WHO), must be considered.Essential oils are generally associated with antimicrobial, antiviral, and antioxidant properties ,34,35. NChronic inflammation is associated with highly prevalent diseases such as cancer, obesity, diabetes, rheumatoid arthritis, cardiovascular, respiratory, and neurodegenerative diseases, and aging. Common therapies resort to non-steroidal anti-inflammatory drugs (NSAIDs) that induce severe gastrointestinal and cardiovascular adverse effects, and although biopharmaceuticals, with safer profiles, have been used, these therapeutic agents present several limitations, including the lack of responsiveness and drug resistance, delivery problems, and production costs . TherefoAlpinia species showed very broad effects on major risk factors associated with cardiovascular diseases and related ion channels activity; those from Citrus species were very effective against hypertension, and Foeniculum vulgare essential oil was very effective as an antidiabetic and antiplatelet agent, as already pointed out in a recent review carried out by our group [Essential oils and their volatile compounds have shown promising effects on cardiovascular diseases and associated risk factors. A search on Pubmed (assessed on 20 September 2022), combining \u2018essential oil\u2019 and \u2018cardiovascular disease\u2019, encountered 604 studies. In general, monoterpenes such as 1,8-cineole, terpinene-4-ol, geraniol, limonene, \u03b1-pinene, thymol, and carvacrol seem to be the most studied volatile compounds showing hypotensive and anti-dyslipidemic/antidiabetic properties, whereas phenylpropanoids, such as anethol and hydroxychavicol, are very effective at avoiding platelet aggregation. Regarding essential oils, those from ur group . Of notiSalvia officinalis, Salvia lavandulifolia, Melissa officinalis, Lavandula angustifolia, and Rosmarinus officinalis essential oils [A relevant effect that has been associated with essential oils is their potential to exert neuroprotective and anti-aging effects, thus justifying their use in dementia, epilepsy, anxiety, and other neurological disorders such as Alzheimer\u2019s disease (AD) and Parkinson\u2019s disease. Indeed, currently available therapies for these disorders have limited efficacy and many times only enable symptom relief; therefore, the development of effective therapeutic strategies able to delay their progression is an urgent clinical need. Moreover, the anti-aging effects of essential oils are also relevant as they could contribute to prevent age-associated disorders. Overall, the majority of the studies carried out focus on AD as several preclinical models are available and mimic the mechanisms of action underlying this disease and behavioral features, namely memory and learning alterations . Indeed,ial oils .Regarding the anti-cancer potential of essential oils, a Pubmed search produced 1696 (assessed on 20 September 2022) results for the combined words \u2018essential oil\u2019 and \u2018cancer\u2019. The majority of the studies performed so far showed direct correlations between the eradication of tumors and cancer cell lines, with the beneficial effects of the essential oils being due to their cytotoxic, anti-proliferative, anti-tumor, or apoptotic effects as previously reviewed . Indeed,Interestingly, analgesic, anti-inflammatory, calming, and relaxing properties are also ascribed to essential oils, rendering them adjuvant effects and alleviating cancer-related physical and emotional complaints. In addition, the combination of essential oils/volatile compounds with conventional chemotherapy has also shown promising effects and could be applied to improve cancer treatment and reduce drug toxicity, as reviewed elsewhere ,48. InteDespite the number of studies performed highlighting several bioactive properties, clinical trials using essential oils are sparse and additional studies are still required to assess the pharmacokinetic profile, safety, and toxicity of these compounds. Additionally, bearing in mind their high variability, standardization of the composition of essential oils and their constituents deserves special attention, and specific features such as high volatility need to be considered in order to guarantee their efficacy in a clinical setting. In this context, nanoencapsulation strategies, namely those using plant nanovesicles, emerge as promising delivery platforms, as explained in the next section.Essential oils have been employed in several pharmaceutical applications due to their bioactive potential. However, their conversion into dosage forms or cosmetic products poses several technological challenges, such as solubilization and storage stability issues, loss of activity due to volatile properties, and potential cytotoxicity, which may impair their performance . To addrThe transport and distribution of plant vesicles in vivo is the next relevant feature to take into account. Plant nanovesicles can reach distant organs and deliver their cargo by attaching to cellular membranes through receptor\u2013ligand interactions. However, similarly to mammalian EVs, knowledge of cargo delivery is still puzzling, but it may potentially occur via the endocytic pathway, phagocytosis, micropinocytosis, or through fusion with the plasma membrane ,53,54. IPlant nanovesicles seem to present some targeting properties. For example, it has been demonstrated that doxorubicin can be targeted to tumors using plant nanovesicles from grapefruit . Also, gFollowing standardized isolation, detailed characterization, and proper functionalization, plant nanovesicles could constitute a very powerful delivery platform for essential oils and their main compounds . RecentlAiming to profile the requirements for the successful development of plant-derived nanocarriers, specific issues are next addressed per route of administration, followed by a compilation of the different routes of administration, advantages, and applications of essential oils encapsulation in plant nanovesicles .Essential oils have huge potential as preventive or therapeutic agents for various oral diseases, ascribed to their anti-bacterial, antifungal, and antibiofilm properties . When usAlthough external application in the form of gargles and mouthwashes is still the most frequent and effective way of using essential oils, they can also be taken by ingestion. In the latter case, they are generally diluted with milk, soy milk, or olive oil, as they usually have a strong aroma and flavor that can cause undesirable organoleptic properties and compromise compliance . In addiApplications of plant nanovesicles as oral drug delivery systems have been directed to the treatment of colitis, bowel and liver diseases, Alzheimer\u2019s disease, and numerous other inflammatory, neurodegenerative, and metabolic diseases. Such applications could be extended to and the therapeutic effect synergistically complemented with the essential oil administration ,68,69. AInhalation provides the most rapid way to administer essential oils, prompting a fast therapeutic onset. Notwithstanding, limitations of dosages and amount of activity in inhalation administration, together with some ocular irritation as adverse effects, could hamper their continued application .Encapsulation of these bioactive compounds using plant nanovesicles represents a feasible and efficient approach to modulate essential oil release throughout the respiratory tract. Increased physical stability is expected by encapsulating the essential oils, affording them protection from interactions with the environment and decreasing their volatility, therefore, sustainably enhancing their bioactivity and reducing toxicity.Depending on the therapeutic purpose, a local or systemic effect could be retrieved. Thus, such systems could be channelled to deliver essential oils, for example, to mediate anti-inflammatory effects in allergic rhinitis patients or, alternatively, for treating mood disorders, especially depression, anxiety, and mental disorders such as sleep disorders ,71. SuchThe development of these nanosystems should specifically account for the characterization of aerodynamic properties of the particulate matter and delivered dose uniformity .Plant nanovesicle characteristics, especially biocompatibility, cellular uptake, and targeting capability, place these nanosystems as avant-garde nanocarrier systems for intravenous administration. Their natural and endogenic nature endow them with low potential toxicity and immunogenicity when compared with equivalent synthetic drug delivery systems, which, along with their reduced particle size and narrow distributions, enable them to remain undetected by the immune system, thereby extending the circulation period and prolonging the action time of bioactive molecules, ultimately resulting in a higher bioavailability. Additionally, their production capability in large quantities is pointed out as an advantage, being deemed critical when considering the scaling-up process .As safe nanocarriers for intravenous delivery, plant nanovesicles are therefore considered promising vectors for targeted delivery in tumor diseases. For example, in a study conducted by Wang et al., grapefruit-derived nanovectors coated with membranes of activated leukocytes (IGNVs) related inflammatory receptors were found to enhance their homing ability to inflammatory tumor tissues, suggesting their potential for targeting certain cancers in the context of personalized medicine . MoreoveSkin delivery stands out as the main pathway for essential oil administration. It can encompass a topical or systemic action, the latter if transdermally driven. Essential oils are often framed within the conventional profile of a typical candidate profile for dermal administration, which must have certain physicochemical characteristics to enhance permeation through the skin. These include low molecular weight (less than 500 Da), log P between 1 and 3, unionizability, adequate solubility in water (>1 mg/L), a melting point below 200 \u00b0C, and a daily dose lower than 20 mg . HoweverNote that the main barrier for skin permeation, the stratum corneum, consists of 10\u221215 nonviable layers of corneocytes composed of keratin, surrounded by a lipid matrix made of ceramides, long-chain fatty acids, triglycerides, and cholesterol . DiffereAs with other nanosystems, especially those structurally similar to liposomes, plant nanovesicles can be embedded in passive methods that could enhance the permeation of essential oils through the skin due to several features: (i) hydrophobic character, which confers skin resemblance; (ii) biocompatibility, which ensures a well-tolerated profile compatible with long-term use; (iii) nanometric size along with a high specific surface area that allows closer contact with the skin; (iv) high loading capacity, along with a decrease in volatile properties, which contributes to retain the essential oil and acts as a reservoir. This increases the gradient between the formulation and the stratum corneum and acts as a driving force promoting a higher absorption rate of the essential oil, resulting in greater efficacy as a delivery system. In addition, their compelling physicochemical properties underpin their modulatory role in physiological uptake processes. From a mechanism standpoint, it is hypothesized that after topical skin application, plant nanovesicles could penetrate via a trans-follicle route by a \u201clipid-rich channel\u201d coating on hair follicles or intact stratum corneum, intercellular or transcellular through the lipid fusion effect, similar to what has been reported for other lipid vesicular nanosystems .In addition, encapsulation of essential oils using plant nanovesicles could prevent degradation when exposed to light, oxygen, or higher temperatures (above 26 \u00b0C), improving essential oil and formulation stability .Plant nanovesicles can also be combined with other inorganic nanomaterials, such as magnetic nanoparticles, to impart photothermal properties or even theranostic functions . Such anDifferent therapeutic effects could be envisaged when addressing topical or transdermal routes of essential oil administration, depending on the ever-stringent clinical demands, and taking advantage of their inherent anti-inflammatory, antioxidant, antimicrobial, or anti-cancer properties .In addition to their therapeutic application, the use of plant nanovesicles as essential oil carriers for cosmetic purposes is also highlighted. Given the dual natural renewable source of the carrier and the essential oils, either as active ingredients or preservatives, more eco-sustainable and safer products could be produced. Indeed, several products could benefit from the advantages of encapsulating essential oils in plant nanovesicles. These range from moisturizers, lotions, and cleansers for skin care, conditioners, masks, or anti-dandruff products for hair care to lipsticks or fragrances for perfumery .An enhanced cosmetic effect, given the ability to control essential oil release and counterbalance their volatility, resulting in more pleasant sensorial properties and attenuating some strong odors, sometimes unsuitable for certain cosmetic applications, a lower allergenic potential, and improved stability without the addition of chemical preservatives are pointed out as advantages that may generate increased interest in these biological nanocarriers for the cosmetics industry ,87.As mentioned earlier, the use of essential oils in product formulation poses some challenges in terms of their manipulation and application, ascribed to their poor water solubility, volatility, thermal and chemical lability, inappropriate organoleptic properties, immunogenicity, and toxicological concerns. Encapsulation of essential oils in plant nanovesicles could be a very attractive option to tackle these issues. However, leveraging this environmentally sustainable strategy still requires standardized procedures to ensure the reproducibility of the process, the possibility of scale-up, in-depth physicochemical characterization to substantiate identity, and specific requirements depending on the route of administration, e.g., sterility if intravenous administration is planned, to ensure regulatory approval of these bionanosystems.In addition, other relevant aspects need to be taken into account to enable an effective essential oil delivery, namely vesicle preparation, characterization, functionalization, stability, targeting, and delivery. Indeed, as stated above, several isolation techniques are available to obtain plant nanovesicles. Many reviews have detailed the different processes available, highlighting their pros and cons , and theThe next point to consider is loading efficiency, as the nanostructure of plant nanovesicles allows for the encapsulation of hydrophilic compounds in the core or lipophilic compounds in the surrounding lipid layer. As essential oils and their volatile compounds are lipophilic, their encapsulation would occur preferentially in the lipid layer, and both passive and active cargo loading could be used. In the first, diffusion and hydrophobic interactions between the lipid layer and the active compounds take place. This type of loading has already been used to successfully incorporate curcumin, a lipophilic compound, in mammalian EVs . For actDendropanax morbifera leaf-derived EVs (LEVs) alone or combined with the preservatives (3-butylene glycol or TMO), it was found that different storage temperatures and number of freeze\u2013thaw cycles induced stability changes. Size distribution, protein content, surface charge, and cellular uptake of LEVs were altered compared to those of freshly isolated LEVs, indicating the combination LEVs-TMO as one exhibiting higher stability when stored at 4 \u00b0C [Stability is another key issue that determines storage time and scalability. The evaluation of the stability in biorelevant media and under storage conditions is a requirement to avoid undesirable aggregation that may negatively affect the quality and performance of the plant nanovesicles. In a study performed by Kim and colleagues, conducted to evaluate the stability of  at 4 \u00b0C . However at 4 \u00b0C ,93.The present review provides a thorough and comprehensive overview that supports the use of plant nanovesicles as innovative essential oil delivery platforms. Indeed, these volatile extracts, despite their huge preventive/therapeutic potential, continue to be disregarded in clinical practices mainly due to stability, volatility, and toxicity issues that could be surpassed by efficient delivery strategies. Plant nanovesicles have interesting carrier features and targeting properties and are known to be untaken by mammalian cells; they open very exciting avenues for future essential oil applications in the health sector. Nevertheless, standardized isolation protocols and more robust characterization procedures are needed to comply with good manufacturing practices. Moreover, despite the expected low toxicity of vesicles obtained from edible plants, further studies should be considered to better disclose plant vesicles\u2019 pharmacokinetics, pharmacodynamics, and safety profile. Nevertheless, it seems undeniable that in the next years, the scientific knowledge in this field will continue to grow, advocating an exciting era for therapeutic plant-based nano-delivery platforms."}
+{"text": "Human body is colonized by trillions of microbes, influenced by several factors, both endogenous, as hormones and circadian regulation, and exogenous as, life-style habits and nutrition. The alteration of such factors can lead to microbial dysbiosis, a phenomenon which, in turn, represents a risk factor in many different pathologies including cancer, diabetes, autoimmune and cardiovascular disease, and infertility. Female microbiota dysbiosis  and male microbiota dysbiosis  can influence the fertility, determining a detrimental impact on various conditions, as pre-term birth, neonatal illnesses, and macroscopic sperm parameters impairments. Furthermore, unprotected sexual intercourse creates a bacterial exchange between partners, and, in addition, each partner can influence the microbiota composition of partner\u2019s reproductive tracts. This comprehensive overview of the effects of bacterial dysbiosis in both sexes and how partners might influence each other will allow for better personalization of infertility management. In recent years, the existence of a human associated microbial fauna was the topic of many and very detailed studies. Scientific projects like the U.S.A. National Institutes of Health (NIS) \u201cHuman Microbiome Project\u201d (HMP), which started in 2007 and lasted for almost a decade, provided methods and resources to detect firstly, the existence of a microbial fauna in many human body niches, and secondly, to detect microbial effects on human health .Most of the human microbiota 80%) resides in the intestinal tract and is considered as an additional human organ. As a matter of fact, the gut microbiota strongly affect human health, by hindering pathogen colonization , exertin0% resideIntestinal epithelial barrier harbors a large microbial community characterized by four major phyla, Bacteroidetes, Firmicutes, Actinobacteria, Proteobacteria, and an intestinal healthy microbiota composition able to maintaining intestinal homeostasis, that is characterized by\u2009>\u200990% of Firmicutes and Bacteroidetes, and is correlated with a low Firmicutes/ Bacteroidetes (F/B) ratio [Lactobacillus bacteria, which exert many protective functions connected to lactic acid production and to the keep of vaginal acid pH [Lactobacillus, Pseudomonas and Prevotella could exert influence on sperm quality parameters and specifically Pseudomonas was associated with sperm count in opposite way respect to Prevotella, which was instead inversely associated. Interestingly, Prevotella abundance was inversely associated with sperm concentration, and Pseudomonas was directly associated with total motile sperm count. Using a shotgun metagenomics a recent work demonstrated that the gut and urinary dysbiosis represent a risk factor for infertility, while the testicular one may have a role in mammalian spermatogenesis [Only the 9% of the human microbiota was detected as harbored in urogenital tracts , and man acid pH . Female  acid pH  and in v acid pH , and the acid pH . In maleogenesis .The aim of this review is to summarize the available findings on the most recent data about microbial colonization of the female and male genital tracts, and to highlight the features of the dysbiosis and its role on infertility.The circadian regulation is the biological mechanism by the organisms living on the planet adapt their physiology and their behaviors to the astronomical day-night alternation. This system is hierarchically structured with a central clock located in the suprachiasmatic nucleus and a series of peripheral clocks present in the cells of all tissues. At the base of the mechanism there are a series of genes, called \"Clock genes\", , 17 whosGut microbiota abundance and metabolic activity presents diurnal circadian rhythm, that are mainly regulated by host nutrition and hormones. The rhythmicity gut microbiota could be loss by the disruption of clock genes highlighting a link among these factors . A role Growth Hormone (GH)-sexual development, implicated in gonadal development, was related to gut microbiota. Gut microbiota circadian disruption can determine GH signaling impairment, and represent a risk factor for many pathologies \u201327. FurtMicrobiota regulation may be influenced also by Melatonin even if the specific mechanisms are still not well understood, but it seems derived by their rhythm typically of a period of\u2009~\u200924\u00a0h regulated also by Melatonin release .Microbiota, circadian regulation and hormones appear to be as linked factors able to influence reciprocally, although the topic is recent, and the more studies are needed to clarify the topic Fig. Lactobacillus which represents 90\u201395% of vaginal bacteria. Four most abundant species detected in vaginal tract are Lactobacillus crispatus, Lactobacillus iners, Lactobacillus jensenii and Lactobacillus gasseri [Lactobacillus and its species is linked to its ability to synthesize lactic acid (2-Hydroxypropanoic acid) by anaerobic fermentation [. Estradiol (E2) controls lactic acid production [Lactobacillus bacteria harboring, and enabling them to grow, multiply, and dominate the cervico-vaginal niche [Lactobacillus bacteria, through lactic acid production, are able to up-regulate the autophagy process through cyclic adenosine monophosphate (cAMP) inhibition, promoting pathogen bacteria clearing. In order to kill other bacteria and to prevent vaginal colonization by pathogen species, Lactobacillus bacteria synthesize hydrogen peroxide (H2O2) and bacteriocins proteins [. Many other bacterial genera were detected in healthy or not-healthy vaginal microbiota, including Actinomyces, Bacteroides, Campylobacter, Corynebacterium, Enterobacter, Escherichia, Gardnerella, Haemophilus, Salmonella, Shigella, Staphylococcus, Streptococcus, Ureaplasma [The balance of hosted microbiota, metabolites synthesized, and immune components is necessary for female genital tracts health. Vaginal microbiota (VMB) composition is dominated by  gasseri . The impentation , produceoduction  that conal niche . In addial niche . Lactobaproteins , 37, coneaplasma , 39  compared to the left one  [Concerning the fallopian tubes microbial colonization, tubal microbiota (TMB) existence is a topic under study, and it was explored on bilateral salpingectomy surgical samples. In both fertile and menopausal bilateral salpingectomy patients, bacterial phyla Proteobacteria, Actinobacteria, Bacteroidetes, nt Table  and thervotella)  in pre-pMesorhizobium, Ralstonia, Lactobacillus and Ureaplasma genera were found in placenta, although microbial composition changes in the different placental areas were examined [In placental samples were identified Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, and Fusobacteria phyla Table  similar examined .Lactobacillus dominance, and, in addition, its concentration depends on patient\u2019s age , on menstrual cycle phase  and on pregnancy state. During menopause, a E2 lower concentration determines a lower glycogen and lactic acid production, with a vaginal pH shift from mild acid-to a less acid  environment, and a consequent loss of the Lactobacillus dominance [. A non-Lactobacillus-dominated environment is positively related with colonization/infection by potentially pathogenic bacteria. Postmenopausal patients, which generally have a low E2 serum concentration, show an increase of Escherichia, Shigella, Gardnerella, Prevotella and Enterococcus genera, and menopause state was also positively related with the increase of potential pathogenic genera Varibaculum, Streptococcus, and Veillonella [Lactobacillus dominance was detected in post-menopausal chronic atrophic vaginitis affected patients, however it was highlighted a negative correlation between E2 concentration and the Streptococcus abundance [Many factors act in shaping female genital tracts microbiota composition including lifestyle, hormone, and reproductive age , 46. Curominance . A non-Lllonella . A positbundance , a commobundance .Lactobacillus and a relevant decrease in overall diversity [Lactobacillus abundance, an increase in diversity and enrichment of bacteria associated with vaginosis, such as Actinobacteria [The E2 levels rise during pregnancy, with an increased abundance of iversity . The majbacteria .Paraprevotella abundance was found higher in younger patients, that have a higher FSH concentration [Aerococcus, Atopobium, and LH hormone concentration since their abundance is high in fertility age when the LH concentration rises [Gemella was detected as positively related with both FSH and LH, because its abundance is low during fertility age and rises in menopause [VMB composition also depends on gonadotropins, as follicle-stimulating hormone (FSH) and luteinizing hormone (LH) concentration. A negative correlation between FSH concentration and its composition in VMB was detected, and ntration . Furtheron rises . On the enopause .Lactobacillus dominance and the rise of anaerobic bacteria, as Prevotella, Mobiluncus, Gardnerella, Ureaplasma and Mycoplasma [Chlamydia, Neisseria, Trichomonas) [Lactobacillus abundance was identified as a predictive factor for unfavorable IVF outcome [Lactobacillus iners as a positive IVF procedure marker and a vaginal microbiota health signal [A dysbiotic VMB is characterized by the loss of coplasma , 57. Suchomonas)  and virahomonas) . A dysbihomonas) , maternahomonas) , late mihomonas)  and highhomonas) . VMB dyshomonas) , 63. Int outcome , while Lh signal .Lactobacillus abundance. EMB dysbiosis was related to a significant decrease of IVF live birth rate positive outcomes\u00a0[The problems connected with microbial contamination, make it hard to define precisely endometrial microbiota (EMB) composition due to outcomes\u00a0.Bacteroides, Pelomonas [Flavobacterium, Corynebacterium, Bifidobacterium, Staphylococcus, Streptococcus in infertile patients [The EMB composition related to reproductive failures was detected as also characterized by high elomonas , 67. Howpatients .In placenta, the microbiota composition exerts an influence on pre-term birth or neonatal illnesses. The placental microbiota composition of spontaneous pre-term birth patients with a chorioamnionitis are characterized by high abundance of both urogenital and oral commensal bacteria , 70. HowEnterococcus faecalis, Escherichia coli, Streptococcus agalactiae, Ureaplasma urealyticum species [Ureaplasma, Enterococcus, Mycoplasma, and Prevotella, in opposition to healthy, which showed a major presence of Lactobacillus [Bacteroides ureolyticus [Many evidences suggest how male genitourinary tracts harbor a commensal microbial fauna, and how the seminal microbiota (SMB) have a multiple combined origin from different urogenital tissues as bladder, prostate and urethra. The seminal fluid represents a particularly suitable environment for the trophic needs of a microbial community, due to the wide range of nutrients, proteins, carbohydrates, and inorganic ions contained in its composition . Both in species  , and the use of prognostic markers for dispermic conditions , azoospermia and in post-finasteride syndrome .Lactobacillus, Pseudomonas, Prevotella and Proteobacteria, Firmicutes, Actinobacteria, Bacteroidetes, and Fusobacteria [Prevotella, and Anaerococcus [Prevotella\u2019s abundance was inversely associated with sperm concentration, while Pseudomonas was directly correlated with sperm motility [Lactobacillus genus was significantly decreased in oligo-asthenozoospermic patients. Interestingly, different bacterial genera and species including Ureaplasma, Bacteroides, Anaerococcus, Finegoldia, Lactobacillus and Acinetobacter iwoffii could be used as asthenozoospermia biomarkers [The most abundant microbial genera detected in dispermic patients and healthy donors are bacteria . In low rococcus . Prevotemotility   from idiopathic non-obstructive azoospermic (NOA) patients [Clostridium abundance in NOA patients with a unsuccessful sperm retrieval compared to successful sperm-retrieval patients [In azoospermic patients it was shown an increase of Bacteroidetes and Firmicutes, and a decrease of Proteobacteria and Actinobacteria, compared to the healthy. In the oligo-astheno-teratozoospermic (OATs) Firmicutes phylum and bacillus . In the patients , show a patients .Gardnerella vaginalis in young women , highlighting also the sexual transmission of potentially pathogenic bacteria [Unprotected sexual intercourse determines a bacterial exchange between partners, and in addition, each partner can influence the microbiota composition of other\u2019s reproductive tracts . Regardibacteria . Howeverbacteria .Lactobacillus crispatus, Lactobacillus iners, Gardnerella vaginalis resulted associated to younger men seminal microbiota, while, other genera, as, Pseudomonas, Flavobacterium and Acidovorax were detected in seminal fluid bacterial communities of older men [Streptococcus agalactiae, Gardnerella vaginalis and other bacterial vaginosis-related bacteria presence [Streptococcus agalactiae is present in bacteriospermic samples and that Gardnerella vaginalis is the predominant microorganism in women with partner that had significant leukocytospermia [Several evidence point also to an action of the female microbiota on male\u2019s microbial fauna. Young men with no sexual experience showed lower bacterial diversity and relative abundance in their seminal microbiota, compared with men of the same age with sexual experience . Some valder men , 89. Evepresence . It was ospermia . Bacteriospermia .Thus, scientific evidence highlighted how both male and female genital microbiota are able to interact by microbial trade off, mainly during sexual intercourses, although specific clinical trial studies are needed to clarify the topic.Lactobacillus-dominated healthy microbiota, and a VMB dysbiosis constitutes a risk factor for both fertility and pregnancy onset. As well, in upper genital tracts it was highlights the existence of endometrial, tubal and placental microbiota. The connections among endometrial and placental microbiota dysbiosis and fertility impairments were deepened even if in the tubal microbiota, there is no study link between dysbiosis and fertility detrimental effects. Seminal fluid dysbiosis is associated with dispermic-azoospermic detrimental conditions. The interactions among female and male genital tracts microbiota during sexual intercourse, and their microbial exchanges were strengthened, highlighting also their parallel and reciprocal effects.In recent years, great progress was made in the study of the microbial fauna associated to gut and genital tracts, detecting the existence of associated microbial communities and determining the effects of bacterial dysbiosis on fertility. Female lower genital tracts showed Sex hormones participate in communication between microorganisms and their hosts and play several important physiological roles in reproduction and in sexual development and function.Alterations in the genital tract microbiota have specific impacts on the reproductive endocrine system and correcting abnormal microbiomes may lead to improved reproductive outcomes. Specific linear correlations between microbiota and serum hormone levels, which may have additional effects on the health of the body, have been reported in some studies.The knowledge of the infertility problem could be increasingly linked to the understanding of this vast network of interactions on genital tracts microbiota. Furthermore, also a greater experience of the role that the gut microbiota plays on fertility it could be useful to identify novel microbiome-based diagnostics and therapeutics for patients with this complex disease."}
+{"text": "Older HUD residents were vulnerable to COVID-19 due to their age, health, income, race, ethnicity, and resources. In combination, these factors increased risk to health and housing stability. While many HUD properties employ a service coordinator, this role is not universally adopted and impacts of these services are not well understood. This research surveyed service coordinators in mid-2020 and late-2021 to characterize older adult experiences living in public housing during the pandemic and ways service coordinators helped manage disruptions. Surveys were disseminated to 3,500 service coordinators. Findings identified needs in transportation, personal care, sociality, mental and physical healthcare, and food. Interventions included resource procurement, benefits management, technology access improvement, and linking residents to services. Tools included information dissemination, needs assessments, and partnership development. This work offers insight into the role of a service coordinator to mitigate health and housing risk. It becomes increasingly salient as HUD residents trend demographically older."}
+{"text": "A 45 year-old white housewife, came with a slightly purple and painless nodular lesion that had been growing for 4 years, bleeding spontaneously and sporadically, on her left ear . The lesPathology exam showed a benign vascular proliferation, with enlarged endothelial cells and histiocytic appearance, inflammatory infiltrate with lymphocytes and some eosinophils and rare lymphoid follicular formations . We inje,There is certain confusion between Kimura's Disease and angiolymphoid hyperplasia with eosinophilia; however, they represent different entities, with different clinical manifestations and behaviors, despite their histopathological similarities. It is possible to differentiate them clinically and histopathologically.,,In general, the former takes on a more systemic and tumoral characteristic, preferably affecting Asian patients. It is possible to find an increase in total IgE and eosinophils in their serum. Pathology shows inflammatory cells forming large clusters, like lymphoid follicles with germinative centers, large number of eosinophils and mild vascular alterations.,The latter, which is the present case, manifests a lonely nodule in the subcutaneous or the mucosa, usually on the head and neck. It can be asymptomatic or present with pruritus. It is rarely found on other parts of the body, such as shoulders, penis, lungs, nail beds and adjacent phalanx. It has been reported associations with nephrotic syndromes or kidney diseases, squamous cell carcinoma and arteriovenous malformations. These associations are influenced by chance, sometimes making it difficult to explain the cause, thus the patient requires further investigation. Histology shows vascular alterations, with proliferated endothelial cells, large in size and with histiocytic appearance, chronic infiltrate made up of lymphocytes, with varied number of eosinophils, which can appear in lesser number. Lymphoid follicles are few or inexistent.Differential diagnosis to consider: cavernous hemangioma, granuloma pyogenic, facial granuloma, Kaposi sarcoma, angiomatous lymphoid hamartoma, periarteritis nodosa, pseudolymphoma.There are different treatment modalities, such as conventional surgery, Mohs's procedure, laser, steroids, alpha 2-a interferon, intralesional chemotherapy, calcineurin inhibitors and imiquimod, cryotherapy and radiotherapy, with variable results, but usually positive.Most of this literature is present in dermatology journals; however, professionals who work with diseases that may involve the head and neck should also be attentive and consider the diagnosis of angiolymphoid hyperplasia with eosinophilia in nodular lesions, such as Kimura disease in tumoral lesions. Histopathology is obviously essential. Intra-lesion steroid injection is a viable treatment option."}
+{"text": "Pseudorabies virus (PRV) has received widespread attention for its potential health effects on humans, wildlife, domestic animals, and livestock. In this review, we focus on PRV dynamics in wildlife, given the importance of wild-origin PRV transmission to domestic and farm animals. Wild boars, pigs, and raccoons can serve as reservoirs of PRV, with viral transmission to domestic livestock occurring via several routes, such as wild herd exposure, contaminated meat consumption, and insect vector transmission. Many endangered feline and canine species can be infected with PRV, with acute disease and death within 48 h. The first confirmed human case of PRV infection in mainland China was reported in 2017. Thus, PRV exhibits potentially dangerous cross-host transmission, which is likely associated with inappropriate vaccination, poor awareness, and insufficient biosecurity. Currently, no vaccine provides full protection against PRV in all animals. Here, we summarize the epidemiology and pathogenesis of PRV infection in wild, domestic, and farmed animals, which may facilitate the design of novel therapeutics and strategies for controlling PRV infection and improving wildlife protection in China.  Herpesviridae and subfamily Alphaherpesvirinae [Belonging to the family svirinae , the psesvirinae  based onsvirinae  and is aWild boars and pigs are the primary natural hosts of PRV and the only latent carriers . PRV-relIn this review, we provide a brief overview of the traceability, transmission, and vaccination of PRV infection in animals with the aim to strengthen PR control measures.At present, the epizootiology of PR disease is not completely understood. One hypothesis for herd-to-herd transmission is that wild animals  act as disease reservoir hosts and spread the virus from one farm to another . AlternaWild boars are reservoirs for various infectious diseases in livestock and humans, including classical (CSFV) and African swine fever viruses (ASFV), porcine circovirus 2 (PCV2), porcine reproductive and respiratory syndrome virus (PRRSV), porcine parvovirus (PPV), hepatitis E virus (HEV), swine influenza virus (SIV), Japanese encephalitis virus (JEV), and torque teno virus (TTV) ,40.PRV infection is enzootic and widespread in Eurasian wild boars ,42, withAs wild boar populations expand their range, there is increased potential risk for disease transmission that may affect healthy of humans and domestic swine, and conservation of wildlife. Based on long-term serological field studies, PRV is considered endemic in wild boar populations in the USA, including in the southern and central states  [Ursus arctos) in Slovakia [Detection of antibodies to canine distemper virus (CDV), canine herpesvirus type 1 (CHV-1), canine parvovirus type 2 (CPV-2), canine parainfluenza virus type 2 (CPIV-2), canine coronavirus (CCV), West Nile virus (WNN), and PRV is positive in European brown bears ( arctos) . PreviouSlovakia  and PRV-Slovakia ,9,76,77.In most cases, PR disease is fatal in bears, with death occurring within 1\u20133 days of clinical symptoms. Upon consuming infected pig offal or pig heads, bears can show acute and asymptomatic infections. In Himalayan bears, however, only mild clinical signs are reported, with negative neutralizing antibody tests .Procyon lotor) are considered a natural reservoir of PRV [Raccoons  is an endangered feline species [+ and TK+ genotype [The Florida panther ( species . Similar species . Necropsgenotype .Lynx pardinus), one of the most endangered feline species in the world [Cytauxzoon sp. by using PCR assay [The Iberian lynx  based on the testing of brain tissue. Clinical symptoms include anorexia, abnormal vocalizations, and nervousness [PRV infection has been reported in coyotes  non-natural hosts may become infected via contact with immunized pigs ; (2) befPRV has a wide host range and can be transmitted across wild, domestic, and farm animals. The DIVA strategy  has been used in various European countries and the USA based on gE- or gI-deleted vaccines ,72. AttegB, gC, gD, and gE genes play central roles in receptor binding, pathogenicity, and induction of antibodies, with various residues shown to be under positive selection, including residues 43, 75, 848, and 922 in the gB protein, residues 59 and 194 in the gC protein, and residue 348 in gE protein [PRV was previously considered to be limited to host species only. However, there are three possible pathways that have allowed cross-host transmission from wild boars and pigs to non-natural hosts, namely, positive selection, adaptive evolution, and recombination. The  protein , thus su protein . Thus, t protein . Intracl protein . These r protein , and mayIn addition, the receptors of PRV have been identified, including 3-O-sulfonated-heparan sulfate (3-O-S-HS) , the herIn this review, we summarize the epidemiology and pathogenesis of PRV infection in wild, domestic, and farm animals. Recently, various field strains have shown virulence against non-natural hosts, such as bears, coyotes, and panthers, with some found to be epidemiologically associated with swine isolates, wild boar isolates, and vaccine strains. Thus, novel and safe vaccines should be developed for different animals, particularly endangered species, to control cross-host transmission of PRV."}
+{"text": "Biomaterials play a vital role in regenerative medicine, aiming to regenerate and replace lost/dysfunctional tissues. For instance, biomaterials are widely used for joint replacement, dental implants, orthopedic fixations, stents, and so on. Once biomaterials are implanted into the human body, there are inevitable interactions between biomaterial surfaces and the biological environment, such as proteins, cells, and bacteria. Therefore, implant failures still happen due to the implant-related complications resulting from poor implant integration, infections, mechanical instability, inflammation, etc. . Thus, mMany nanostructures can be found in nature. For example, the surface of lotus leaves is composed of fine-branched nanostructures that show super-hydrophobicity . AlignedBacterial infection is one of the major post-surgery complications in clinics. Antibiotics have been considered as effective weapons against bacterial infections. However, antibiotic resistance is presently an emerging public health threat, caused by the overuse and abuse of antibiotics. Therefore, it is urgent to develop new methods to combat bacteria. In the past decade, mechanical and physical sterilization has attracted considerable attention, which does not cause bacterial resistance, as the morphology of nanometers can directly cause bacterial death through physical and mechanical interactions .Based on this, various types of nanostructured biomaterials have been developed and many surface modification techniques have been adopted to produce nano-functionalized biomaterials surface. Due to the advantages of nanoscale features, nanostructured biomaterials show enhanced biocompatibilities, such as cell adhesion, proliferation, and differentiation, and present excellent antibacterial activity. These nanostructured biomaterials exhibit promising applications in biomedical fields.This Special Issue, \u201cNanostructured Biomaterials for Tissue Repair and Anti-infection\u201d, focuses on the latest research progress of nanostructured biomaterials for tissue repair and anti-infection. Both original research articles and review articles covering the current progress on nanostructured biomaterials for tissue repair and anti-infection are welcomed. This Special Issue includes, but is not limited to, the following research topics, surface nano-functionalization of biomedical metals, ceramics, polymers for tissue repair, and anti-infection."}
+{"text": "Polyploid cells demonstrate biological plasticity and stress adaptation in evolution; development; and pathologies, including cardiovascular diseases, neurodegeneration, and cancer. The nature of ploidy-related advantages is still not completely understood. Here, we summarize the literature on molecular mechanisms underlying ploidy-related adaptive features. Polyploidy can regulate gene expression via chromatin opening, reawakening ancient evolutionary programs of embryonality. Chromatin opening switches on genes with bivalent chromatin domains that promote adaptation via rapid induction in response to signals of stress or morphogenesis. Therefore, stress-associated polyploidy can activate Myc proto-oncogenes, which further promote chromatin opening. Moreover, Myc proto-oncogenes can trigger polyploidization de novo and accelerate genome accumulation in already polyploid cells. As a result of these cooperative effects, polyploidy can increase the ability of cells to search for adaptive states of cellular programs through gene regulatory network rewiring. This ability is manifested in epigenetic plasticity associated with traits of stemness, unicellularity, flexible energy metabolism, and a complex system of DNA damage protection, combining primitive error-prone unicellular repair pathways, advanced error-free multicellular repair pathways, and DNA damage-buffering ability. These three features can be considered important components of the increased adaptability of polyploid cells. The evidence presented here contribute to the understanding of the nature of stress resistance associated with ploidy and may be useful in the development of new methods for the prevention and treatment of cardiovascular and oncological diseases. Somatic polyploidy exists in tissues of nearly all multicellular organisms, including higher and lower plants, invertebrates, and vertebrates ,2,3,4,5.Notwithstanding the benefits under stress, polyploid cells cannot outcompete their diploid counterparts under normal conditions because of their slower proliferation, DNA instability, high energetic cost, and mitotic defects ,25,48,49Ploidy-associated epigenetic regulation has attracted increasing attention because it enables genome reorganization and cell fate change in adverse environments and in response to extreme stress ,41,42,50Oncogenes of the Myc family (c-Myc and N-myc) are the most powerful and well-studied stress-response-related amplifiers of global transcription ,52,53. RStress-related Myc overexpression can trigger and enhance polyploidy. Supraphysiological Myc expression is sufficient to trigger polyploidy in cells with various mitotic potentials. Myc induces DNA replication in quiescent, terminally differentiated cells, including mammalian cardiomyocytes, neurons, kidney cells, and post-mitotic epithelial cells of Drosophila ,54. Myc Surprisingly, Myc-associated S-phase enforcement is not accompanied by the acceleration of mitotic cellular division ,58,67. RDrosophila arising in development and wound healing [In normal cells, polyploidy is associated with the induction of Myc and its interactants in human and mouse heart, liver, and placenta ,71,72,73 healing ,75,76. P healing . A simil healing . These c healing . An exte healing  . Accord healing ), which  healing ), confir healing . These dThus, Myc and polyploidy respond to similar stimuli, including a wide variety of stressful and pathological conditions. Overexpressed Myc promotes polyploidy via the stimulation of rapid S-phase entry, DNA replication, and mitotic spindle abnormalities, whereas polyploidy activates Myc through stress response, genetic instability, and replicative stress associated with chromatin opening ,78,79. It is well-established that Myc enhances stress tolerance to various environmental clues. Myc promotes protection from hypoxia, oxidative stress, drugs, and DNA instability ,81,82. MPolyploidy is also associated with stress and protects cells from hypoxic, hyperoxic, and genotoxic environments and increases resistance to drugs ,80,81,87Polyploidy mitigates consequences of DNA instability via the upregulation of pathways related to DNA damage response and DNA repair. This connection was well-established based on mRNA sequencing data from roughly 10,000 primary human cancer samples and essentiality data from approximately 600 cancer cell lines . The linData obtained from B cells indicate that c-Myc can accelerate chromatin decondensation via its repositioning from the nuclear periphery to the inner part and by promoting a nuclear architectural shift from long-range to short-range contacts, leading to a near doubling of loops and topologically associated domains (TADs) ,99. DataPolyploidy can also potentially boost the effect of overexpressed Myc related to chromatin remodeling. It is well-established that genome duplication decreases the nucleus surface-to-volume ratio, which suggests the ability to affect high levels of chromatin organization ,102. IniMyc proteins bind enhancer-box (E-box)-containing CACGTC sites . E-box-cMyc oncogenes can also activate chromatin via the induction of Pol I-, II-, and III-transcribing rRNA, tRNA, and mRNA ,120. PolMyc-related facilitation of transcription can also be executed via the interaction with chromatin-remodeling partners. Myc isoforms interact with transformation/transcription-domain-associated protein (TRRAP), which is a scaffold protein of several large protein complexes involved in chromatin remodeling . TRRAP aThus, the literature provides evidence that Myc overexpression can promote chromatin opening via the repositioning from the surface to the periphery of the nucleus (high level of chromatin organization) and via interaction with E boxes, RNA polymerases, and chromatin remodelers (low level). Because polyploidy can open chromatin, we speculate that when Myc overexpression coincides with polyploidy, their effects on chromatin can be cooperative. Therefore, it is reasonable to suggest that overexpressed c-Myc and polyploidy can cause prominent chromatin decompaction, leading to global activation of transcription and alteration of gene regulatory networks and cell fate decision. The abundance, diversity, and evolutionary conservatism of biological processes and functions that are coregulated by polyploidy and Myc indicate that they are responsible for transcriptional regulation via global epigenetic changes.Medicago truncatula symbiotic nodule cells, neotetraploid rice, Arabidopsis, and soybean, reveal causal relationships between polyploidy and chromatin opening, mostly via DNA hypomethylation and/or demethylation of DNA packaging protein histone H3  [Triticum aestivum L [Ploidy-associated chromatin activation and opening at high levels of organization induce a coherent response at lower levels. Genome duplications promote DNA hypomethylation and an increase in the amount of various open chromatin marks activating gene expression. For example, an study performed with colorectal cancer cells (line LS174T) showed that the onset of tetraploidy is associated with the demethylation of non-mobile pericentromeric repetitive elements SST1 and transposable elements LINE-1, comprising approximately 17% of the entire genome . In linee3 mark) ,138. Polstivum L ,140. In stivum L ,141. ThuChromatin opening affects basic biological processes and cell fate. In multicellular organisms, open chromatin is a feature of undifferentiated pluripotent stem cells that maintain plasticity in biological regulation, specific metabolic state, and dual capacity to self-renew and differentiate into all cell types ,144,145.Drosophila epidermis and mouse cornea endothelial cells that participate in wound healing promote stemness through the activation of the Hippo pathway [Myc oncogenes activate signaling pathways involved in pluripotency and embryogenesis , as well as pathways of epithelial to mesenchymal transition and cell cycle progression, contributing to self-renewal through maintenance of undifferentiated states ,147,148. pathway . Researc pathway ,75,158.  pathway ,159,160.Another common feature of polyploidy and Myc is the upregulation of bivalent genes ,114,161.The activation of genes with bivalent chromatin was also observed in pathologies associated with cell polyploidization and manifestations of stemness, including cardiovascular diseases and cancer ,165,166.It is well-known that Myc induces metabolic modification with features of metabostemness observed in enhanced glycolysis, glutaminolysis, ribosome biogenesis, and hypertranscription, which collectively enable cells to acquire continuous energy supply via reserved energy-producing pathways ,172,173.Metabolic pathways of polyploid cells also demonstrate manifestations of stemness ,71,72. SDrosophila in development and wound healing, in cancer polyploid cells, and in cells of normal mammalian tissues [Under hypoxia, lack of nutrients, starvation, or severe genotoxic stress, polyploid cells can be in a state of dormancy with predominantly glycolytic energy supply, which is a feature of metabostemness ,88,92,93 tissues ,184,188.According to the ancient origin of Myc, it can be traced to unicellular organisms using deep phylostratigraphy , and sevPolyploidy and overexpressed Myc appear in response to physiological and pathological stress. Both exert similar effects on chromatin architecture and many biological processes, including chromatin relaxation, phenotype plasticity, stemness, metabolic rearrangements, regulation of gene expression, and adaptation. Myc is a sensor of intrinsic and extrinsic stress belonging to early response master regulators that reacts to a wide variety of stimuli . In respWhy might the Myc\u2013polyploidy partnership enable particular adaptation to extreme stress? Data obtained from therapy-resistant giant polyploid cancer cells (GPCCs) suggest that the polyploid-related ability to \u201csurvive at the brink\u201d  originatIn humans, polyploidy, in partnership with Myc, may help cells to survive under pathologic conditions associated with various diseases, including hypertension, congenital heart diseases, neurodegeneration, inflammation, and even cancer ,14,17,43Polyploid cells demonstrate particular plasticity and adaptation to stress. On the one hand, this feature is beneficial because it helps to adapt to various pathological states, including cardiovascular diseases, neurodegeneration, inflammation, wound healing, and regeneration. On the other hand, this feature is detrimental because it promotes carcinogenesis, metastasis, and cancer relapse caused by cancer therapy resistance. Currently, the nature of ploidy-related adaptability is not completely understood. Here, we highlight literature data indicating that polyploidy can regulate gene expression via extensive epigenetic changes promoting chromatin relaxation. Owing to increased nuclear volume in polyploid cells, the decreased surface-to-volume ratio results in partial detachment of LADs from the nuclear lamina, thereby changing the structure of LADs and TADs and increasing the proportion of euchromatin. Polyploidy also promotes DNA hypomethylation and chromatin modifications, relaxing chromatin. Altogether, these changes awaken bivalent genes that are rapidly activated in response to stress or signals of morphogenesis. Contributing to the opening of chromatin, polyploidy also activates global transcription amplifier oncogenes of the Myc family, which, like polyploidy, contribute to the opening of chromatin. Myc oncogenes can also accelerate the accumulation of genomes, enhancing polyploidization. As a result of these cooperative effects of polyploidy and activated Myc, genetic instability occurs, which, together with chromatin opening and induction of bivalent genes, can result in genomic chaos, increasing epigenetic and phenotypic plasticity and the ability to search for adaptive states of cellular programs through gene regulatory network rewiring. Ploidy-related regulatory and phenotypic plasticity is manifested in (1) traits of stemness, dedifferentiation, and unicellularity; (2) flexible energy metabolism; and (3) effective protection from genome instability consisting via buffering of DNA damage and mutation effects and in complex DNA repair that combines primitive unicellular error-prone repair pathways and advanced multicellular error-free repair pathways. We suggest that these three features are important components of the increased adaptability of polyploid cells. The presented evidence can be useful in the development of new types of therapy with the aim of eliminating polyploid cancer cells. The evidence presented herein could also be useful for the development of new measures of preventive medicine with the aim of preventing excessive polyploidization of cardiomyocytes and neurons in order to reduce the risk of cardiovascular and neurodegenerative diseases."}
+{"text": "Clostridium difficile infection (CDI) with beneficial outcomes. FMT is also promising in improving bowel diseases, such as ulcerative colitis (UC). Pre-clinical and clinical studies suggest that this microbiota-based intervention may influence the development and progression of chronic kidney disease (CKD) via modifying a dysregulated gut\u2013kidney axis. Despite the high morbidity and mortality due to CKD, there are limited options for treatment until end-stage kidney disease occurs, which results in death, dialysis, or kidney transplantation. This imposes a significant financial and health burden on the individual, their families and careers, and the health system. Recent studies have suggested that strategies to reverse gut dysbiosis using FMT are a promising therapy in CKD. This review summarises the preclinical and clinical evidence and postulates the potential therapeutic effect of FMT in the management of CKD.Faecal microbiota transplantation (FMT) has attracted increasing attention as an intervention in many clinical conditions, including autoimmune, enteroendocrine, gastroenterological, and neurological diseases. For years, FMT has been an effective second-line treatment for  Clostridium difficile infection (CDI) induced diarrhea [Chronic kidney disease (CKD) affects approximately 10% of adults worldwide . CKD is diarrhea , irritabdiarrhea , obesitydiarrhea . These sdiarrhea .14 bacteria, which encode 100 times more genetic information than the human genome [Firmicutes and Bacteroides, with a relatively low population of Proteobacteria, Actinobacteria, Fusobacteria, Verrucomicrobia, etc. [The gut microbiota is the broad spectrum of microorganisms accommodated in the gastrointestinal (GI) tract, consisting of bacteria, viruses, archaea, protists, and fungi. A healthy human GI tract harbors more than 10n genome . The curn genome . In healia, etc. . In addiia, etc. ,19, previa, etc. , maintaiia, etc. ,22, and ia, etc. ,24,25. Wia, etc. , such asia, etc. , irritabia, etc. , and autia, etc. . Increasia, etc. , bile acia, etc. , brancheia, etc. , trimethia, etc. , tryptopia, etc. . Appreciation of the importance of the gut microbiome for human health and disease derives from clinical practices affecting gut bacteria, such as antibiotic use. Disturbance of healthy gut microbiota, also termed gut dysbiosis, contributes to the pathogenesis of many clinical diseases, such as metabolic disorders , inflammAs a potent microbiome-based invention, faecal microbiota transplantation (FMT) transfers the gut microbial community from healthy donors to recipients to restore gut microbiota homeostasis. FMT is an established therapy for recurrent CDI, with a treatment efficacy above 85% . MoreoveThis review will demonstrate gut dysbiosis occurring in CKD and summarise its predominant pathogenic mechanisms that contribute to progressive kidney dysfunction, including the regulation of the immune system, gut microbiota-derived metabolites, renin\u2013angiotensin system, and gut barrier. The application of FMT in CKD as a potential therapeutic option will also be discussed.Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, Fusobacteria, and Verrucomicrobia compared to controls. Gut dysbiosis is both a quantitative and qualitative alteration in the composition and metabolic profiles of the gut microbiome. Increasing evidence has confirmed gut dysbiosis occurs at the onset of CKD, including in the development of CKD and progression to end-stage kidney disease (ESKD) ,48,49. RFirmicutes, Proteobacteria, and Verrucomicrobia but a significantly lower presence of Bacteriodetes in the DKD group compared to the healthy controls [Firmicutes but a lower abundance of Bacteroides in the CKD group compared to the normal rats. Additionally, a reduced amount of Ruminococcaceae UCG-014, Prevotellaceae_NK3B31_group, Ruminococcus 1, Lachnospiraceae UCG-001, and Clostridium leptum group bacteria have been found in the adenine-induced CKD rat or mouse models, respectively [In the diabetic kidney disease (DKD) mouse model, the microbiome analysis of operational taxonomic units (OTUs) identified an increased abundance of controls . Similarectively . Fusobacteria and Proteobacteria, genera Streptococcus, Desulfovibrio, and Escherichia_Shigella, and a reduced presence of genera Faecalibacterium, Roseburia, Pyramidobacter, Prevotella_9, and Prevotellaceae_UCG-001. Moreover, elevated levels of bacterial metabolites trimethylamine n-oxide (TMAO) and p-cresol sulfate (PCS) and lower production of SCFAs were found in CKD patients [Clostridia, Eubacterium, and Alistipes compared with healthy controls, indicating the pathogenic role of depletion of SCFA-producing bacteria in systemic inflammation and IgAN progression [Coriobacteriia and genera Legionella, Enhydrobacter, and Parabacteroides was present in the blood, and genera Bacteroides, Escherichia-Shigella, and Ruminococcus in stool in comparison with healthy controls [Akkermansia, Dialester, Enterococcus, Rominicoccus, Blautia, and Bacteroides, that contributed to the elevated levels of uraemic toxins [Verrucomicrobia, Proteobacteria, and a lower amount of Bacteroidetes at the phylum level, with Escherichia-Shigella, Enter Klebsiella, Streptococcus, Akkermansia, and lactobacillus increased at the genus level. In particular, SCFA-producing bacteria, such as Blautia and Faecalibacterium, were decreased in DKD patients compared to healthy controls [Oscillibacter and Alistipes and a decreased abundance of Veillonella, Lachnospira, and Dialister in CKD patients compared to the healthy controls [Bifidobacterium and Streptococcus, in CKD patients. Interestingly, kidney function loss was positively related to a higher proportion of Enterobacteriaceae and E. coli [In a recent systematic review incorporating twenty-five studies with 1436 CKD patients and 918 healthy adults, Zhao et al. found that the gut microbiome in CKD patients had an increased abundance of phylums patients . A studygression . In paticontrols . Additioc toxins . Patientcontrols . Kim et controls . Another E. coli .In CKD, the gut\u2013kidney axis is potently affected by the gut microbiota in a bidirectional manner . CKD incIt is postulated that gut dysbiosis promotes CKD by modulating the host\u2019s immunity, which depends on the activation of the host\u2019s innate and adaptive immune responses . PreviouLactobacilli, Ruminococacceae, and an increase in Enterobacteriaceae. Depleting gut bacteria by oral antibiotics or FMT derived from sham-operated mice prevented mice from developing IRI, which was confirmed to be associated with reduced Th 17, Th 1 activation, and the expansion of M2 macrophage and Treg [H17) cells but a deficit in the immune-mediating regulatory T (Treg) cells, leading to susceptibility to colitis after FMT from IBD patients [Bacteroides fragilis could \u2018educate\u2019 the host immune system to be tolerant to residing microbes, primarily by modulating CD4+ Tregs to secrete IL-10, which was dependent on Toll-like receptor (TLR) in mice [H17 cells are present in high density in the gut, and their presence and activation rely on the adjacent gut microbiota. Krebs and his team directly identified that microbiota-induced TH17 cells migrated from the gut and accumulated in kidneys, which was mediated by the chemokine C-C motif chemokine ligand 20 (CCL20) and its receptor C-C Motif Chemokine Receptor 6 (CCR6) in autoimmune kidney disease [Gut microbiota dysbiosis contributes to the impaired gut barrier, excessive production of uremic toxins, and translocation of the gut microbiome, leading to the abnormal activation of the immune cells . The actand Treg . Germ-frpatients . Notably in mice . TH17 ce disease . Individual compartmentalized gut-associated lymphoid tissues (GALTs) inhabit the interface between the intestinal lymphatic and blood systems, allowing mature immune cells constant access to the epithelial layers and lamina propria. In humans, the GALT interplay with the gut microbiota to exert immune responses and tolerance . HoweverDue to the relative richness of proteolytic bacteria, gut bacterial metabolites are profoundly altered in CKD, resulting in reduced local and systemic SCFAs and increased uremic toxins . Blautia, Bacteroides, Butyricoccus, Bifidobacterium, Prevotella, Megasphaera, and Butyrivibrio [SCFAs are aliphatic carboxylic acids with fewer than six carbon (c) atoms produced by bacteria inhabiting the colon after fermentation of dietary fibre or protein catabolism. In humans, the major SCFAs are acetate, propionate, and butyrate, which are produced by prebiotic fermentation via specific gut bacteria, such as rivibrio  in the irivibrio . In prevrivibrio ,75,76. Srivibrio , and mitrivibrio . SCFAs privibrio .In a cohort clinical study, Wang et al. measured the levels of SCFAs in 127 patients with CKD and 63 healthy controls. The results showed that the serum SCFAs levels, especially butyrate, were significantly decreased in CKD patients compared with healthy controls, and supplementation of butyrate might slow the progression of CKD . An inveThe accumulation of serum uremic toxins due to gut microbiota dysregulation is strongly associated with oxidative stress and systemic inflammation, which is increasingly recognized to play a pivotal role in the onset and progression of CKD . ProteinFirmicutes and Proteobacteria [n = 105) demonstrated that elevated plasma TMAO induces peritoneal inflammation and increases the risk of peritonitis in patients undergoing PD [In addition to IS and pCS, trimethylamine-N-oxide (TMAO) has been recognized as a gut microbiota-derived uremic retention product associated with higher mortality and risk of cardiovascular events ,89. TMAObacteria . Elevategoing PD . The renin\u2013angiotensin system (RAS) has been recently confirmed as a critical link between gut microbiota and CKD . RAS inhHealthy gut microbiota homeostasis may assist with the development of host immunity, while a disturbed gut microbiome hampers and damages it . Gut dysCKD can further impair gut barrier function due to decreased SCFAs production and the accumulation of uremic toxins, which contributes to inflammation, oxidative stress and further damages the gut epithelial monolayer. A reduction in SCFAs and excessive production of uremic toxins lead to a downward spiral of worsening CKD in association with worsening gut function ,106. CKDFMT potently \u2018rebuilds\u2019 the gut microflora\u2019s dynamic homeostasis, structure, and diversity by transferring healthy gut microbiota into recipients. The significant relationship between gut microbiota dysregulation and many clinical conditions has enabled FMT to treat multiple clinical conditions, such as autoimmune , neurodeIl6, Il7, Ifng, Tnf, and Il1b were downregulated significantly compared with the non-FMT group [FMT plays a vital role in shaping and modulating the immune system, significantly impacting the peripheral immune system and inflammatory responses. Burrello et al. demonstrated that FMT could attenuate inflammatory responses in the colon and restore gut homeostasis via activating different immunoregulatory signalling pathways. Consequently, FMT increased IL-10 secretion from innate and adaptive immune cells and inhibited the activity of monocytes, dendritic cells, and macrophages to acquire, process, and present antigens to T cells inhabiting the intestine . In anotMT group .FMT has been used as a \u201cbrute-force\u201d therapeutic strategy to restore or improve gut homeostasis mediated through the regulation of gut bacteria-derived metabolites. In mouse models with atopic dermatitis (AD), gut microbiota dysbiosis was restored to the donor state together with elevated concentrations of SCFAs . FMT alsAlthough a wide variety of the gut microbiota-based approaches, such as probiotics and prebiotics, have shown positive outcomes in managing CKD, a considerable number of studies generated controversial results ,125,126.Accumulating evidence has highlighted the pathogenic role of gut microbiota dysbiosis in the setting and progression of CKD ,128,129,FMT from patients, donors or CKD rodent models has been used to investigate the correlation between gut dysbiosis and CKD progression. For example, Wang et al. administered FMT from patients with ESKD or healthy donors to germ-free CKD mice or antibiotic-treated CKD rats. They found that the gut microbiome in the recipient mice was modulated and exhibited the features of the ESKD patients or control donors. The gut microbiota from patients with ESKD increased the production of uraemic toxins, aggravated interstitial fibrosis, and oxidative stress, which further confirmed the causative relationship between the aberrant gut microbiota and kidney disease development . ConsistAstragalus membranaceus and Salvia miltiorrhiza (AS), the administration of FMT from the AS-treated group attenuated cyclosporin A-induced kidney damage and fatty acid metabolism through modulation of the \u201cgut\u2013kidney axis.\u201d Those benefits were positively correlated with an improved intestinal barrier, restored intestinal flora structure, increased abundance of bacteria producing butyric acid and lactic acid, and improvement in the miRNA\u2013mRNA interaction profiles related to Butanoate and Tryptophan metabolism [In addition, FMT has been a helpful tool to demonstrate that the modulation of the intestinal microbiota may account for one of the key mechanisms mediating the renal protective effect of therapeutic interventions for CKD, as demonstrated in various FMT studies. By transplanting the resveratrol-modified faecal microbial, Cai et al. confirmed that resveratrol, a stilbene polyphenolic compound, exerted its renal protective effect by improving the faecal microbial community. They reported that FMT from healthy resveratrol-treated control mice restored the gut microbiome and regulated intestinal permeability accompanied by an inhibited inflammatory response and improved renal function . Similartabolism .ob/ob DKD mice [FMT, using a homeostatic gut microbiome collected from healthy donors, has been investigated as a potential therapeutic strategy for managing CKD. In a mouse model of adenine-induced CKD, FMT significantly reduced the production of uremic toxins derived from the intestinal cresol pathway with a profound improvement of gut microbiota disturbance, as evidenced by the increased alpha diversity. These studies suggested that FMT is an effective intervention for gut microbiota . Hu et aDKD mice .Escherichia.coli, Bacillus subtilis, and Lactobacllus acidophilus, showed benefits without any evident adverse effects by eliminating nitrogenous waste products in multiple animal models of kidney failure, including murine AKI, murine chronic kidney failure, and porcine kidney failure models. Importantly, this study provides a direction for microbiome-based therapies using a bioengineering strategy [Interestingly, instead of transplantation of the whole gut microbiome, Zheng et al. constructed a bacterial micro-ecosystem (BME) with a small bacterial consortium encapsulated in calcium alginate microspheres coated with a layer of polydopamine nanofilm. The administration of a microencapsulated bacterial cocktail consisting of three different bacteria, including strategy .FMT has also been applied in clinical case studies to improve kidney function . In a clThis review summarises the role of the gut microbiome in the pathogenesis of CKD, the primary mechanisms of FMT as a novel microbiota-based intervention and, most importantly, an update in animal and clinical studies on managing CKD using FMT. The predominant effects of FMT on CKD include modulating immune responses, gut microbiota metabolites, the RAS axis, and gut barrier function. Although FMT has yielded clinical benefits in several diseases, its utilization in extended clinical practice may be limited due to numerous factors, such as the definition of the healthy donor, screening procedures, sample preparation, storage condition, dose\u2013response, methods of delivery, settings, and progression of different diseases. Clinical studies using FMT in patients with CKD are primarily small-scale and underpowered, as they were generally designed as pilot studies for safety reasons.It is well recognized that \u201cone stool does not fit all\u201d. Hence, donor selection and administration methods in specific diseases are dominant determinants of FMT success rates. Therefore, decoding FMT strategies have to rely on the advantage of artificial intelligence, advanced bioinformatic techniques, and machine learning algorithms, such as multi-omics correlation analysis. A set of parameters for the gut microbiota, plasma, uraemic toxins, faecal metabolites, and kidney function need to be linked and systemically analysed, which will strongly support researchers in understanding the role of FMT and standardizing procedures and protocol evolution in the future.Considering the potential pathogenic factors derived from overall gut microbiome transplantation, novel FMT consisting of several specific bacterial strains extracted from healthy stool might be an alternative intervention with much lower risks. For example, FMT could be further optimized in alternative ways, such as bacterial consortia and BME, to reduce potential pathogenic factors before application in patients to improve or slow CKD progression. Bacterial consortia are derived from culturing selected gut bacteria from the donor faecal samples, allowing for mass production, increased consistency, and thorough bacterial community characterization, including eliminating pathogenic microorganisms. Biomedical engineering techniques could also contribute to FMT development.To conclude, standardization of FMT procedures in CKD treatment is urgently needed, both clinically and commercially. Clinical trials should evaluate the impact of FMT on hard clinical endpoints in CKD with the assistance of sophisticated artificial intelligence and up-to-date bioinformatics interpretation before successfully moving FMT therapy for CKD into clinical practice."}
+{"text": "N-oxide, isoleucine, leucine, tryptophan, creatine, serotonin, valine, betaine, and low-density lipoprotein were elevated. In contrast, levels of alpha-d-glucose, lactic acid, N-acetyl glycoprotein, glutamine, beta-d-glucose, corticosterone, alanine, phenylacetylglycine, glycine, high-density lipoprotein, arachidonic acid, myo-inositol, allantoin, and taurine were decreased. Moreover, 12 metabolites in urine and nine metabolites in the liver were dysregulated after treatment. Pharmacological treatment also increased fecal levels of butyric acid, acetic acid, propionic acid, and isovaleric acid. Collectively, metabolite disturbances induced by depression were reversed by pharmacological treatment. Pharmacological medication reversed the reduction of brain neurotransmitters caused by depression, modulated disturbance of the tryptophan-kynurenine pathway and inflammatory activation, and alleviated abnormalities of amino acid metabolism, energy metabolism, lipid metabolism, and gut microbiota-derived metabolites.Numerous studies have investigated metabolite alterations resulting from pharmacological treatment in depression models although few quantitative studies explored metabolites exhibiting constant alterations. This study aimed to identify consistently dysregulated metabolites across such studies using a knowledgebase-driven approach. This study was based on 157 studies that identified an assembly of 2757 differential metabolites in the brain, blood, urine, liver, and feces samples of depression models with pharmacological medication. The use of a vote-counting approach to identify consistently upregulated and downregulated metabolites showed that serotonin, dopamine, norepinephrine, gamma-aminobutyric acid, anandamide, tryptophan, hypoxanthine, and 3-methoxytyramine were upregulated in the brain, while quinolinic acid, glutamic acid, 5-hydroxyindoleacetic acid, myo-inositol, lactic acid, and the kynurenine/tryptophan ratio were downregulated. Circulating levels of trimethylamine  Depression is a common mental illness characterized by low mood, diminished interest, and a reduced sense of pleasure, with an incidence of 6.4 to 10.4% . DepressClassical antidepressants exert antidepressant properties by modulating monoaminergic targets. A recent meta-analysis concluded that all licensed antidepressants have a significant therapeutic effect in adults with acute depression . ExtensiMetabolomics has been widely used to quantify metabolites in an organism or tissue and identify relationships between metabolites and physiological or pathological processes . Indeed,Several issues have been raised for metabolomics studies investigating potential molecular mechanisms of antidepressant action. First, although extensive studies have been carried out, it remains difficult to detect panoramic alterations of metabolites induced by pharmacological treatment in individual studies; accordingly, a systematic understanding of the neurochemical effects of these medications is still lacking. Second, the generalizability of much-published research on this issue is problematic, as experimental data are rather controversial due to small sample sizes and differences in experimental design. Faced with challenges surrounding how to systematically analyze these massive metabolomics data and a lack of accessible quantitative data , 24, fewThus, the purpose of this study was to investigate metabolite changes consistently resulting from pharmacological treatment in depression models using a knowledgebase-driven approach. To this end, a vote-counting method was used to identify consistently upregulated and downregulated metabolites in the brain and peripheral tissues of animal models induced by pharmacological treatment from large-scale metabolomics studies.The dataset used in this study was obtained from the MENDA database. Details of the study design and procedures for data collection and annotation are described elsewhere . In brieAs a result of the current study, we updated the MENDA database as follows. After screening more than 18,000 citations as of 11 August 2021, we cumulatively retrieved 2278 potentially eligible articles and then excluded 1461 full-text studies. Excluded studies are listed in Supplementary Data For further study, we selected the candidate metabolite set according to the following steps. Only studies that aimed to identify differential metabolites resulting from pharmacological treatment in animal models of depression were included. Therefore, we excluded studies that (i) compared metabolite levels between depressed and control conditions; (ii) focused on non-pharmacological treatments, such as repetitive transcranial magnetic stimulation, electroacupuncture, or exercise therapy; (iii) explored metabolic changes after pharmacological treatment in a healthy state; or (iv) investigated metabolic characteristics associated with treatment response. Human and nonhuman primate models were also excluded. This decision was made a priori because metabolic profiles are clearly different between rodents, humans, and nonhuman primates . We focuIn this study, we used the vote-counting method to identify metabolites consistently upregulated or downregulated in the candidate metabolite set. Although combining effect sizes has been the mainstream method for integrating multiple clinical metabolomics studies \u201329, metaIn the current study, the following analyses were performed based on the vote-counting procedure. In the primary analysis, we analyzed metabolite alterations in brain, blood, urine, liver, and feces samples of animal models resulting from all available pharmacological treatments. Next, secondary analyses were performed based on tissue types and pharmacological treatments. For the types of tissues, we analyzed candidate metabolites in the hippocampus, prefrontal cortex, hypothalamus, plasma, and serum samples. For the types of pharmacological treatments, eight licensed drugs for depression  were classified as antidepressants , and phaP value of the binomial test was estimated to compare hypothesized versus obtained counts of upregulation and downregulation trends, using the binom.test function in R version 4.0.4 (https://www.R-project.org/). A P value < 0.05 was considered statistically significant. Metabolites with total counts of dysregulation less than four were not introduced into the vote-counting procedures because their minimum P values were 0.125.The vote-counting method is based on the hypothesis that the probability of upregulation or downregulation of a differential metabolite follows a binomial distribution, i.e., there is a random occurrence of significant upregulation or downregulation for the altered metabolite in each study. In this study, we calculated the vote-counting statistic (VCS) for each metabolite in the vote-counting procedure. Each metabolite entry exhibiting an upregulation or downregulation trend was scored with 1 or \u22121 points, respectively. Next, the VCS for each metabolite was calculated by computing the total score of all studies, with VCS values more than 0 indicating that the candidate metabolite was predisposed to be upregulated across studies, and vice versa. Duplicate metabolites curated from the same study but with different study designs  were considered to be derived from independent studies. For each metabolite, the one-tailed After data selection, we excluded 660 studies from the MENDA database (listed in Supplementary Data P\u2009<\u20090.001), dopamine , norepinephrine , gamma-aminobutyric acid , anandamide , hypoxanthine , tryptophan , and 3-methoxytyramine  were upregulated, while quinolinic acid , glutamic acid , 5-hydroxyindoleacetic acid , myo-inositol , lactic acid , and the kynurenine/tryptophan ratio  were downregulated , GABA , norepinephrine , dopamine , glycine , and hypoxanthine  were increased, whereas concentrations of glutamic acid , myo-inositol , and lactic acid  were decreased (Supplementary Table P\u2009<\u20090.001), norepinephrine , GABA , and dopamine  were upregulated (Supplementary Table P\u2009=\u20090.031), dopamine , and GABA  were upregulated , prefrontal cortex (164 metabolite entries), and hypothalamus (39 metabolite entries). Of the 28 candidate metabolites in the hippocampus, six were upregulated and three were downregulated. Specifically, concentrations of serotonin , isoleucine , leucine , tryptophan , creatine , serotonin , valine , betaine , and low-density lipoprotein  were upregulated, while levels of alpha-d-glucose , lactic acid , N-acetyl glycoprotein , glutamine , beta-d-glucose , corticosterone , alanine , phenylacetylglycine , glycine , high-density lipoprotein , arachidonic acid , myo-inositol , allantoin , and taurine  were downregulated  was increased, and concentrations of corticosterone , arachidonic acid , glycine , d-glucose , and glutamine  were decreased , isoleucine , creatine , leucine , pyruvic acid , betaine , valine , and serotonin  were upregulated, and N-acetyl glycoprotein , alpha-d-glucose , lactic acid , glutamine , HDL , alanine , beta-d-glucose , allantoin , phenylacetylglycine , and taurine  were downregulated  and serum samples (663 metabolite entries). Among the 29 candidate metabolites in plasma, six were dysregulated. Specifically, the concentration of tryptophan , acetic acid , creatinine , betaine , phenylacetylglycine , xanthurenic acid , creatine , indoleacetic acid , and tryptophan  were increased, while levels of glycine , cortisol , and glutamine  were decreased  was increased, while concentrations of beta-d-glucose , lactic acid , arachidonic acid , alpha-d-glucose , tryptophan , 3\u2032-AMP , creatine , and tyrosine  were decreased , acetic acid , propionic acid , and isovaleric acid   Fig. .To further explore which metabolite disturbances induced by depression can be reversed by pharmacological treatment, we compared the current data with our previous data showing dysregulated metabolites in the brain, blood, and urine samples of depression models . An overN-acetyl-L-aspartic acid were not attenuated following treatment.Among the 11 dysregulated metabolites or metabolite ratios in the brains of depression models, eight were reversed by pharmacological treatment Fig. . SpecifiN-oxide, as well as increased concentrations of N-acetyl glycoprotein, corticosterone, and glutamine  were reversed by pharmacological treatment Fig. . DysreguWe further explored the commonalities and differences of metabolic effects resulting from antidepressants and non-antidepressants. For metabolites in the brain, a total of 344 and 555 metabolite entries resulting from antidepressants and non-antidepressants were voted, respectively. Of the 15 candidate metabolites of antidepressants, six were dysregulated  were decreased in the liver  axis , disturbN-methyl-d-aspartate receptor to exert neurotoxic and oxidative actions [N-acetyl glycoprotein as one of the inflammatory markers in patients with depression [N-acetyl glycoprotein levels in the blood of depression models. In addition, we found that pharmacological treatment reversed the elevation of myo-inositol in the brain, whereby it is regarded as a glial cell marker [In this study, we found that pharmacological treatment increased central and circulating levels of tryptophan, while brain levels of quinolinic acid, kynurenine, and the kynurenine/tryptophan ratio showed a decreasing trend or statistically significant decrease. Tryptophan and its two metabolites (indoleacetic acid and xanthurenic acid) were also upregulated in urine, suggesting that tryptophan levels were increased throughout the body after treatment. In line with this finding, recent meta-analyses suggested that disturbance of the tryptophan-kynurenine pathway is an important signature of patients with MDD , 44. Qui actions . Existin actions , 47. Ourpression . Herein,l marker . An in vl marker . Taken tN-oxide is a gut-microbe-derived metabolite produced from dietary choline and carnitine [N-oxide in the blood of depression models, suggesting that these treatments could improve nutritional status and modulate gut microbiota. Phenylacetylglycine, a metabolite transformed from dietary phenylalanine that acts on adrenergic receptors, has been implicated in platelet hyperresponsiveness [Another important finding was that pharmacological treatment modulated microbiota-derived metabolites. We found that the levels of four short-chain fatty acids (SCFAs), including acetic acid, butyric acid, isovaleric acid, and propionic acid, were increased in feces and urine following treatment. SCFAs are mainly derived from dietary fiber and maintain the function of the innate gut barrier . Preclinarnitine . In the siveness . Interessiveness , 59. We The results of vote counting suggest that pharmacological treatment improved abnormalities of amino acid metabolism in animal models of depression. Branched-chain amino acids, including leucine, isoleucine, and valine, play important roles in promoting protein synthesis . We founWe found that pharmacological medications modulated energy metabolism in animal models of depression. The results of vote counting showed that pharmacological treatment reduced blood glucose levels and alleviated the accumulation of lactic acid in the brain and periphery. One possible reason for this observation is that stress conditions in animal models promoted insulin resistance and mobilized glucose , which wOur findings also suggest that pharmacological medication improved peripheral lipid abnormalities in depression models. Following treatment, LDL levels were elevated and HDL levels were reduced in blood. A previous study demonstrated that antidepressant therapy decreased blood LDL levels without affecting HDL levels , while aFinally, the present study compared metabolomic changes associated with different pharmacological treatments in depression models. The results of vote-counting procedures showed that both antidepressants and non-antidepressants modulated levels of monoamine neurotransmitters and GABA in the brain. However, the regulatory effect of antidepressants on anandamide was unclear. Moreover, we found that antidepressants increased central and peripheral levels of tryptophan, while non-antidepressants did not show similar effects. Notably, we found that most of the dysregulated metabolites in the blood resulting from antidepressants were also altered by non-antidepressants, suggesting a significant overlap in the metabolic changes elicited by antidepressants and non-antidepressants, although the latter caused more diverse molecular changes. Despite these findings, more studies are needed to further verify our results.There are some limitations to this study. First, we could not identify dysregulated metabolites other than the candidate metabolites due to the shortcomings of the vote-counting method. Second, although more comprehensive statistical results could be provided by merging raw data or combining mean concentrations of the candidate metabolites, this remains a difficult task to complete. In addition, it is difficult to compare metabolomic changes brought about by different types of pharmacological treatments, such as fluoxetine and venlafaxine, due to the limited number of metabolite entries.We present a systematic characterization of metabolomic alterations resulting from pharmacological treatment in depression models, which contributes to the understanding of the molecular mechanism of antidepressant effects. The results of vote-counting procedures suggested that pharmacological medications reversed the reduction of brain neurotransmitter levels caused by depression, modulated disturbance of the tryptophan-kynurenine pathway and inflammatory activation, and alleviated abnormalities of amino acid, energy, and lipid metabolism. Pharmacological treatment reversed metabolite disturbances induced by depression, however further studies with more metabolite entries are needed to verify our results.Supplemental MaterialDataset 1Dataset 2Dataset 3Dataset 4"}
+{"text": "Prior work suggests that vision and hearing loss may be risk factors for depressive symptoms in older adults. However, few studies have focused on the relationship of both vision and hearing loss  and depressive symptoms. Using the first nationally representative population study from LASI in India conducted from 2017-2019, Poisson models tested the association of DSL with depressive symptoms. Self-reported vision and hearing loss were associated with increased depressive symptoms  after adjusting for age, sex, education, economic status, marital status, urbanicity, region, diabetes, heart disease, hypertension, stroke, and smoking. DSL had a 46% higher risk  of depressive symptoms. Poor vision and/or hearing loss may be a risk factor for depressive symptoms in adults in India aged \u226545 years. The risk of depressive symptoms in those with sensory loss should be investigated in further studies."}
+{"text": "Previous research has found higher levels of educational attainment to be strongly associated with better health outcomes in later life, such as better cognitive functioning and fewer functional and sensory impairments. However, most studies have grouped General Educational Development (GED) recipients with high school graduates, neglecting potential differences in socioeconomic status, health behaviours, and health outcomes among these two groups. The aim of the current study is to identify differences in the age-sex-race-poverty adjusted prevalence and odds of cognitive impairment, hearing impairment, vision impairment, limitations in activities of daily living (ADLs), and ambulation limitations among three groups of older American adults: high school dropouts, GED recipients, and high school graduates with no post-secondary education. The present study uses secondary analysis of the 2017 American Community Survey, a nationally representative survey of community-dwelling and institutionalized older adults aged 65 years and older, of whom 20,489 were GED recipients, 154,892 had a high school diploma and 49,912 had finished grade 8 but had not completed high school. Our findings indicate that there is a gradient in health outcomes among Americans aged 65-84, with the highest prevalence and odds of cognitive impairment, hearing impairment, vision impairment, ADL limitations, and ambulation limitations occurring among high school dropouts, followed by GED recipients, and the lowest prevalence among high school graduates. These findings suggestion that although GED recipients have better health outcomes than high school dropouts, there is still a significant disparity in health status between GED recipients and high school graduates."}
+{"text": "Describe outcomes of an equity-centered community design (ECCD) project examining the impact of COVID-19 restrictions and social isolation on nursing home (NH) owners, administrators, community leaders, clergy, and urban homeless shelter staff. \u20223-phase, ECCD project. Key informants (KI) were recruited through snowball sampling if experienced in caring for older adults (OA) in NH, in the community, or were engaged in spiritual care of OA.\u2022Perceptions of fear, anger, frustration, sadness, and concern. Categories of Lost Communication and Socialization Strategies, Lost Freedom, Residents\u2019 Dying Alone and Inability to Pause to Grieve, Helplessness and Hopelessness, Inability to Take Time to Grieve, and Behavior Changes. KI offered New Ways of Communicating, and interventions and solutions were generated in Phase III.\u2022 Implications. Understanding of Stakeholder experiences and perceptions is important to achieving inclusive, equity-centered solutions. Future policy decisions must consider what matters most to those most directly impacted by those decisions."}
+{"text": "Ultra-precision machining technology has been widely used in the manufacture of many mission-critical components for various industrial areas, such as the advanced optics, photonics aerospace, automotive, telecommunications, biomedical and energy and environmental sectors, among others. The increasing degree of geometrical complexity, requirement of high precision and the evolution of the materials used for machined workpieces have led to many research challenges in different fields, including ultra-precision machining technologies, novel machining processes, cutting mechanics, surface generation mechanisms, novel machine design, advanced sensing, machine metrology, accurate control of the machining process through modeling and simulation of ultra-precision machining processes, error compensation, materials sciences, measurement and on-machine metrology, as well as advanced applications for functional uses.This Special Issue offers a high-quality collection of 17 papers detailing the latest research results and findings in the field of ultra-precision machining technology and related applications. These papers cover various aspects of this topic, including multi-physical coupling simulation of electrochemical machining and aerostatic spindle, error measurement and compensation, femtosecond-laser-assisted etching, numerical modeling of cutting force and stress, prediction of milling stability, influence of tribological characteristics, tribochemical mechanical polishing, low-pressure lapping, thermal effect, micromachining innovation design, single-particle erosion mechanism, dynamic performance of aerostatic thrust bearing, fly-cutting process and ultrasonic-vibration-assisted cutting.Highlights of this collection of papers are as follows. Li et al.  present"}
+{"text": "The conservation of wildlife species is a major goal globally, due to the declining number of total populations. Fungal diseases are frequently diagnosed in veterinary practice, so knowing their characteristics, along with knowing the appropriate laboratory methods to make a correct diagnosis, are extremely important for the veterinarian. This article is the continuation of an extensive review that presents the main fungal diseases of wild animals. In this part, the second, four of these mycoses are discussed .Wild animals are an important component of the ecosystem, and play a major role in it. However, in recent years, there has been an astronomical increase in the incidence of wildlife mycotic diseases leading to wildlife extermination. It is important to note that most of these mycotic diseases are zoonotic, and since there is a lot of attention given to zoonosis of a bacterial or viral origin in recent times, it is important to look into the mycotic diseases which may have zoonotic potential. Previously, the authors expatiated on some major wildlife mycotic diseases. In this review, we shed light on the etiology, epidemiology, diagnosis, pathogenesis, pathogenicity, macroscopic and microscopic pathology, and hematological and serum biochemical findings of dermatophytosis, coccidioidomycosis, blastomycosis, and sporotrichosis, which are very important mycoses of wildlife. Fungi are not yet considered a major public health issue, whereas diseases caused by bacteria and viruses have been identified as a more critical public health concern for many decades ,2. Opportunistic fungi are found in various natural habitats, and can only occasionally produce infection after penetrating the intact skin of a host with a feeble immune system, or in cases of other devitalizing conditions . LamentaThe early diagnosis of fungal infection is essential to effective treatment . TherefoFungi are a relevant cause of diseases in wild animals. They cause mycosis, and allergic disease involving the development of hypersensitivity or mycotoxicosis . InhalatEpidermophyton exclusively affects humans, whereas Microsporum and Trichophyton mainly affect animals [This mycotic disease, also known as tinea corporis, capitis tinea, or ringworm, is a very contagious and infectious skin disease ,14,15. D animals . Dermato animals . It is t animals . Dermato animals . Dermato animals .Trichophyton, Microsporum, and Epidermophyton, together make up the fungal agents that cause dermatophytosis [Trichophyton gallinae is the prime cause of ringworm or fowl favus in birds [Trichophyton erinacei is the most diagnosed in European hedgehogs (Erinaceus europaeus) [Atelerix albiventris) [Puma concolor), Microsporum gypseum was isolated from one, whereas Trichophyton mentagrophytes were recovered from the remaining two [M. canis caused a small focus of ringworm in an African lion (Panthera leo) [Microsporum spp. were also isolated from the haircoat of a tiger (Panthera tigris) [Leopardus pardalis), a lion, and a tiger presented lesions likened to dermatophytosis, but Microsporum gypseum was only isolated from the ocelot [Aepyceros melampus) had ectothrix spores  and yielded Microsporum gypseum on culture [Gazella gazella) had a Microsporum gypseum infection [Trichophyton schoenleinii and Microsporum gypseum. The disease has spread and has been identified in giraffes , with Trichophyton schoenlenii being isolated on culture [Trichophyton tonsurans has been isolated from a brown fish owl (Ketupa zeylonensis) [Trichophyton concentricum from an Asian elephant (Elephas maximus) [Microsporum nanum from a leopard (Panthera pardus), Epidermophyton floccosum from a white tiger (Panthera tigris) [Microsporumaudouinii from a chimpanzee (Pan troglodytes), and Microsporum canis from a maned wolf (Chrysocyon brachyurus) [The genera, phytosis . Trichopin birds . It has in birds . Trichopropaeus)  and Afriventris) . In the ning two ,25. M. c culture . A gazelnfection , and two culture . Trichoponensis) , Trichopmaximus) , Microsp tigris) , Microspchyurus) .The predisposing factors to dermatophytosis include a compromise in the integrity of the mucosa or skin surface, exposure to ultraviolet radiation, physical-chemical factors, the presence of concurrent disease, or the effect of immunosuppressing medications ,28,29. GTrichophyton [Trichophyton spp., Microsporum canis, and M. audouinii directly in clinical specimens has been developed. Random amplified polymorphic DNA, (RAPD)-PCR, has been used to differentiate M. canis isolates from different animal species, including wild foxes (Vulpes vulpes) [M. canis [A direct physical examination of hair and scales is a field technique used to confirm the presence of dermatophytosis ,33. Dermhophyton . A multi vulpes) ,36. UnipM. canis .Trichophyton can survive for up to one year on the skin of affected animals [The ability to adhere and adapt to the host environment is critical for the establishment of infection by a dermatophyte. In the early stages of fungal\u2013host interaction, transcription factors, such as PacC, Hfs1, and heat shock proteins, are involved in sensing and adapting to the acidic pH of the skin . During  animals .Vulpes vulpes), Trichophyton mentagrophytes associated with dermatophytosis appeared as diffused alopecic skin areas and scattered crusty foci [Elephas maximus) with a mixed-dermatophyte infection [Panthera pardus), aside from pruritus, depression, and anorexia, dermatophytosis manifested as scab formation and alopecia in the thoracic, dorsum, and lumbar regions, as well as the distal part of the tail [Ketupa zeylonensis), crusted granular type lesions with defoliating scales were observed on the eyelid. Decreased flight, inappetence, and scab formation on the legs were also observed in these owls [Erinaceus europaeus), Trichophyton erinacei is most isolated from the head [Dermatophytosis may appear as one or as a combination of hair loss, papules, scales, crusts, erythema, hyperpigmentation, and pruritus . In wildsty foci . Dermatonfection . During the tail . In threese owls . In Eurothe head .Microsporum-audouinii-associated dermatophytosis in a chimpanzee (Pan troglodytes) manifested as non-pruriginous alopecia, erythema, and scales [Chrysocyon brachyurus), Microsporum canis infection appeared as alopecic, but non-pruritic, lesions with scales and crusts on the left pina region [Gavia sp.) that had lesions that resembled ringworm [Desquamation, alopecia, and erythema of the skin are the major gross lesions observed in dermatophytosis ,38. Micrd scales . In a maa region . Alopeciringworm .Erethizon dorsatum), diffused severe epidermal hyperkeratosis; mild hyperplasia; and dermatitis with, predominantly, lymphocytes and plasma cells were reported [In porcupines , the isolation of fungus by culture, and routine histopathologic examinations supported by special histochemical stains such as PAS and CFW fluorescent stain (which offers the best detection of the organism) have all proved important in the diagnosis of coccidioidomycosis . Other cCoccidioides [3/NH4+ and urease enzyme, which catalyzes the hydrolysis of urea into two ammonia molecules that neutralize the acid [Infection is triggered following the inhalation of arthroconidia, and once the spore is in the host\u2019s respiratory system, it undergoes a thermally-induced switch to the pathogenic and parasitic phase of the fungus\u2019 life cycle . It is sidioides . This fuidioides ,52. For the acid ,52,53. Uthe acid .Papio sp.) and chimpanzees (Pan troglodytes) with coccidioidomycosis were majorly those of dyspnea, tachypnea, lethargy, or neurologic and locomotion abnormalities [Macaca sp.) were mostly coughing, gagging, urinary incontinence, paresis of the hind limb, dyspnoea, ruptured bladder, diarrhea with some hemorrhagic dehydration, and subcutaneous edema [The clinical signs shown by baboons  with disseminated coccidioidomycosis, pleuritis, pleural effusion, peritonitis, peritoneal effusions, lymphadenopathy, myocarditis/epicarditis, and thickened pericardial sacs were observed [Phoca vitulina), Coccidioides disseminated to the thoracic and abdominal lymph nodes, liver, and spleen, thereby triggering multifocal pulmonary granulomas and emphysema [Papio sp.), gross lesions were observed within the thoracic organs, including adhesions, granulomas, abscesses, or ulcers [Pan troglodytes), aside from granulomatous lesions in the respiratory system, abscesses, hydropericardium, and ascites containing fluid that was clear, seropurulent with fibrin tags or suppurative were noted [Macaca sp.), the lung and thoracic wall lesions had yellow foci of abscessation, nodules, miliary foci, or areas of infarction. Additionally, subcutaneous and scrotal edema, hydropericardium, and ascites were also present [In sea lions (observed . In a hamphysema . In babor ulcers . In somer ulcers . In chimre noted . In maca present . Grossly present .Enhydra lutris), respiratory system involvement with pyogranulomatous pleuritis, pleural effusion, and pulmonary nodules was a common finding [Macaca sp.), pulmonary consolidation with pyogranulomatous bronchopneumonia and the presence of round, non-budding fungal yeast structures that were morphologically consistent with Coccidioides immitis was observed [In sea otters ( finding . Pneumot finding . The pla finding . In macaobserved .Ajellomycetaceae). This fungus is a thermally dimorphic fungus, and causes diseases of lethal proportions in humans, canids (wolves (Canis lupus), coyotes (Canis latrans)), and other mammals [Zalophus californianus), dolphins (Delphinus delphis)), elands (Taurotragus oryx), ferrets (Mustela furo), Indian fruit bats (Pteropus medius), American black bears (Ursus americanus), African lions (Panthera leo) [Lemuroidea) [B. gilchristii is the other fungal etiologic agent that can cause blastomycosis [Blastomycosis is caused by Blastomyces dermatitidis  ,58, and uroidea) . It is nuroidea) . B. gilcomycosis .Vulpes vulpes) and wolves (Canis lupus) are the main reservoirs and main vectors involved in transmitting the disease [Blastomycosis is primarily a canine disease . Infecti disease . The aer disease ,62. The  disease ,62. Auto disease .Blastomyces spp. from a clinical specimen using Sabouraud\u2019s dextrose or potato dextrose agar [Blastomyces colonies are white-to-buff in color, and usually appear within 10\u201314 days of incubation at 25\u201330 \u00b0C. However, some strains may require up to 6 weeks of incubation to grow [B. dermatitidis/gilchristii characteristically has conidiophores of varying lengths resembling \u201clollipops\u201d [Blastomyces is identified by its characteristics, which include a classic appearance of large, round, multinucleate yeast-like cells with thick and double refractile walls [B. dermatitidis agar gel immunodiffusion serology could be carried out in endemic areas to rule out blastomycosis [Blastomyces [The standard technique for diagnosing blastomycosis is the isolation of ose agar ,62. Blas to grow ,62. Micrllipops\u201d ,62. A dillipops\u201d . Blastomle walls ,63. Thoromycosis . Fluoresomycosis . Nested stomyces .Blastomyces spp. is converted into a pathogenic yeast (which is difficult to phagocytose due to the thick capsule) through a reversible morphological change [Blastomyces regulates the essential virulence factor, BAD1, which facilitates adhesion to the host, impairs activation of immune cells, and blunts the cytokine release [Blastomyces yeast also secretes dipeptidyl-peptidase IVA (DPPIVA) enzyme, which blunts the action of cytokines released from host immune cells [Following the inhalation of mycelial fragments, conidia, and spores, l change . This chl change . In the  release ,66. Blasne cells ,67. Thusne cells ,65.Zalophus californianus) with blastomycosis showed anorexia and lethargy, which resulted in emaciation and its eventual death [Panthera leo) [Panthera leo persica), and one each of African lion (Panthera leo), Siberian tiger , cheetah (Acinonyx jubatus), and snow leopard (Panthera uncia)) diagnosed with blastomycosis showed signs of lethargy, anorexia, cachexia, dyspnea, ataxia, and paresis [A sea lion  . Six wil paresis .Canis latrans) revealed randomly distributed white nodules in the lungs [Zalophus californianus) diagnosed with blastomycosis revealed a focally perforated jejunum; abundant brown-to-black, fetid-smelling fluid in the abdominal cavity; discolored serosal surfaces of all abdominal organs; moderately enlarged mesenteric lymph nodes; and diffusely congested lungs with fibrosis of the right caudal lung lobe and a calcified nodule which contained purulent material centrally [Vulpes vulpes) with blastomycosis consistently had nodules, and B. dermatitidis yeasts were recovered from them [Mustela furo) that died of blastomycosis [Postmortem examination of a wild coyote  diagnosed with blastomycosis revealed multifocal coalescing granulomas with abundant macrophages, numerous neutrophils, fibroblasts, plasma cells, and lymphocytes [Zalophus californianus) with disseminated blastomycosis revealed extensive multifocal-to-coalescing aggregation of large numbers of macrophages and neutrophils, and scattered giant cells and lymphocytes admixed with fibrin and abundant necrotic debris [Panthera tigris) and cheetahs (Acinonyx jubatus)) yielded B. dermatitidis, which triggered a florid pyogranulomatous reaction [The lung section of a wild coyote , which has a worldwide distribution, especially in tropical and subtropical regions. Infection generally occurs following the inoculation of trauma by soil, plants, and organic matter contaminated with the fungus [Sporotrichosis is a chronic fungal disease of cutaneous and subcutaneous tissues , and is e fungus .Sporothrix schenckii has been considered the only etiologic agent of sporotrichosis. However, more Sporothrix species have been identified due to advances in research. S. brasiliensis and S. globosa were recently described, and they are reported to be prevalent in Latin America and East Asia, respectively [Sporothrix species. S. schenckii causes benign chronic subcutaneous mycosis; Sporothrix brasiliensis is highly virulent, whereas Sporothrix globosa more often causes fixed cutaneous lesions [For many years, ectively ,77. Thesectively . S. mexiectively . There i lesions .Sporothrix schenckii complex species thrive in warm and humid climates. Some may be thermo-resistant, whereas others grow at a pH ranging from 3.5 to 9.6 [Camelus sp.), guinea pigs (Cavia porcellus), foxes (Vulpes vulpes), dolphins (Delphinus delphis), armadillos (Dasypus novemcinctus), and non-human primates [5 to 9.6 ,81,82. T5 to 9.6 . The disprimates .The major route of entry is percutaneous, through injury and wounds in contact with contaminated material. Aerogenous entry is not common, but entrance through this route incites pulmonary cases ,81. SporThe fungus is sensitive to common disinfectants, especially alcohol-based ones .The gold standard for the diagnosis of sporotrichosis is the isolation of the organism from active lesions, pus, secretions, or biopsy ,74,83. HIn felines, sporotrichosis is characterized by a high fungal load in the lesions; as such, a direct examination is used for the rapid diagnosis of the disease in this species ,89. In tS. schenckii complex. For example, S. brasiliensis has been reported to be more virulent than S. schenckii [S. schenkii complex is attributed to fungal dimorphism, thermotolerance, conidia production, extracellular proteins, epithelial adhesion, and the antigenic properties of l-rhamnose [S. schenckii, S. brasiliensis, and S. globosa have the highest zoonotic potential [There have been dissimilarities in the pathogenicity of organisms that make up the chenckii ,94, but rhamnose ,94. S. sotential .The main lesions noticed on the skin are consequences of the fistulated lymph nodes. Thus, ulcers, crusts, microabscesses, nodules, or verrucous lesions can be noticed .Dasyurus viverrinus) with S. humicola infection [Crustaceous skin alterations and alopecia were observed in an Eastern quoll (nfection .Dasyurus viverrinus) [Non-purulent perivascular inflammation was observed in the lungs of a male Eastern quoll (errinus) .Dasyurus sp.) [S. schenckii infection commonly presents a mixed suppurative and granulomatous inflammatory reaction in the dermis and subcutaneous tissue, mostly associated with microabscess and fibrosis . Cutaneorus sp.) . The skirus sp.) .Mycotic parasites are major plant and insect pathogens, but they are also important as etiologies of disease in vertebrates, causing a wide variety of infections in humans and animals ,99,100."}
+{"text": "Ornamentals come in a variety of shapes, sizes, and colors to suit a wide range of climates, landscapes, and gardening needs. Compared to demand, a shortage of plant materials and diversity force the search for solutions for their constant acquisition and improvement to increase their commercial value, respectively. In vitro cultures are a suitable solution to meet expectations using callus culture, somatic embryogenesis, protoplast culture, and the organogenesis of protocorm-like bodies; many of these techniques are commercially practiced. Factors such as culture media, explants, carbohydrates, plant growth regulators, and light are associated with the success of in vitro propagation. Techniques, especially embryo rescue and somatic hybridization, are widely used to improve ornamentals. The development of synthetic seed allows season-independent seed production and preservation in the long term. Despite the advantages of propagation and the improvement of ornamentals, many barriers still need to be resolved. In contrast to propagation and crop developmental studies, there is also a high scope for molecular studies, especially epigenetic changes caused by plant tissue culture of ornamentals. In this review, we have accumulated and discussed an overall update on cultivation factors, propagation techniques in ornamental plant tissue culture, in vitro plant improvement techniques, and future perspectives. Ornamental horticulture, flowering, and landscape horticulture are economically viable industries in the agricultural sector. It deals with producing and commercializing flowers, flowering plants, foliage plants, and landscape plants; plants used in ornamental horticulture are collectively called ornamentals. Plant tissue culture, including micropropagation, is the most applicable plant propagation technique in ornamentals. It allows the production of several exact genetic copies from small pieces of plant tissue (known as explants), and the propagation of uniform, season-independent, and seed-borne diseases free seedlings is an additional advantage . Thus, mTorenia fournieri) extended twice its vegetative culture period in a trehalose-based culture medium over a sucrose-based medium without alteration in plant viability [Phalaenopsis and Doritaenopsos orchids [Plant tissues, cells, and organs usually go through either heterotrophic or mixotrophic conditions in vitro. Heterotrophic conditions are the primary obstacle to in vitro plant growth and development where cultured tissue or cell or organ can only synthesize their required nutrients from the basal media, and mixotrophy conditions where plants depend on heterotrophy and can produce food by photosynthesis as well . Plants iability . Trehalo orchids ,26. Gluc orchids ,28. On t orchids . Plants  orchids . From th orchids ,31,32.3) is the most used gibberellin, which is used to accelerate in vitro plant growth, while the function of ABA can be stimulatory or inhibitory depending on different factors such as media ingredients, light intensity and quality, or plant species [The application of PGRs in basal media accelerates the induction of a new plant from a cell or tissue. Auxins (Au), gibberellins (GA), cytokinins (CK), abscisic acid (ABA), and ethylene (ET) are the five groups of PGRs; Au and CK are widely used, while GA, ABA, and ET are less used for vitro micropropagation of ornamentals . The in  species . We havePhalaenopsis orchid [N-acetylglucosamine (NAG), salicylic acid (SA), hyaluronic acid (HA), silver nitrate (AgNO3), jasmonic acid (JA), methyl jasmonate (MeJA), phloroglucinol (PG), pectin, casein hydrolysate, and yeast extracts are some common elicitors [3, HA, Ch, and PG trigger PLBs, root shoots, and flower organogenesis in ornamentals (2), has been used in the culture media for in vitro plant regeneration in chrysanthemum and gerbera, and it accelerates plant shoot and root regeneration [Different growth retardants, such as paclobutrazol, daminozide, chlorocholine chloride (CCC), ancymidol, etc., can be beneficial for plants propagated in vitro media . Growth s orchid ,46. In vs orchid ,48. The s orchid . Chitosalicitors . Like gramentals . In tulineration ,53. AddiIn vitro culture conditions can be manipulated by altering the light color and intensity for effective morphogenesis or organogenesis. Plants can respond well to a wide spectrum of light in terms of plant growth and development with wavelengths of <400 nm (UV radiation), 400~700 nm (visible), and 700~800 nm (far-red) . White fPhalaenopsis, Rosa \u00d7 kordesii, chrysanthemum (cv. Ellen), gerbera, anthurium, heliconia, peony, and spurflower, while some other ratios of red and blue LED mixture were found to be effective in some ornamentals , in D. okinawense [Dendrobium and seed germination and rhizoid development of Bletilla ochracea  were noticed for the first time during the shoot-tip culture by Morel (1960) [Dendrobium [Phalaenopsis [In l (1960) . Protocol (1960) ,205. PLBl (1960) , and thel (1960) . Meristel (1960) ,204,208.l (1960) . Settingl (1960) . Light qndrobium ,213,214 aenopsis ,216,217.Besides these techniques, seed culture, meristem culture, anther culture, embryo culture, ovule culture, cell suspension culture, and direct shoot organogenesis are also practiced for in vitro plantlet generation in ornamentals. Plant tissue culture is well known for producing disease-free plantlets by clonal propagation. In vitro culture offers a wide range of possibilities for manipulating plant materials to improve their quality. In vitro techniques are used for hybridization with the assistance of micropropagation, embryo rescue, and somatic hybridization.Linum perenne L. \u00d7 Linum austriacum L.) in 1925 [The technique of developing a viable plant from an embryo is known as embryo culture or embryo rescue . The emb in 1925 . Since t in 1925 ,222. Campanula carpatica \u2018White\u2019) and interspecific (C. medium and C. formanekiana) hybrid, respectively, were developed in bellflowers [Primula [Camellia [Gypsophila [Rhododendron [It allows for the culture of the ovary, ovule, and embryo ,224,225.lflowers . Intersplflowers ,240,241,lflowers , lisiantlflowers , lily [2lflowers , day lillflowers , calla llflowers , alstroelflowers ,249,250,[Primula ,252, nig[Primula ,254,255,[Primula ,257,258,Camellia , begoniaCamellia , ChristmCamellia , carnatiCamellia ,263, Gyppsophila , Rhododeodendron , cyclameodendron , and ornodendron ,268. EmbIn addition, embryo rescue is generally used to overcome post-fertilization barriers in plants, while many ornamentals have pre-fertilization barriers ,270 thatSomatic hybridization has been proven to be a great source to produce genetic variability which is known as somaclonal variation. Many somaclones have been considered superior hybrids. Two methods are usually followed to produce the somatic hybrid, one is cytoplast-protoplast fusion and the other is the donor-recipient method. In cytoplast\u2013protoplast fusion, protoplasts are allowed to fuse for combining somatic cells either fully or partially from different cultivars or species or genera . 3), calcium nitrate (Ca(NO3)2), dextran sulfate, polyvinyl alcohol, and polyethylene glycol are common fusogens [The combination of the nuclear genome of one parent with the mitochondrial and/or chloroplast genome of the other parent proceeds in somatic hybridization. An alternative and improved somatic incompatibility is the donor\u2013recipient fusion method, where specific genes or chromosomes can be transferred ,273. Chefusogens . SomaticNicotiana tabacum (tobacco) and Petroselium hortense (parsley) [The first asymmetric hybrid was found in somatic hybridization through fusion between parsley) ,276. Manparsley) ,278. It Dendrobium [Calibrachoa [Saintpaulia [Somatic hybridization has been applied for the genetic improvements of various flowering and ornamentals, such as rose , Dendrobndrobium , chrysanndrobium , dianthundrobium , gentin ndrobium ,282, irindrobium , lily [2ndrobium , petuniandrobium , betweenibrachoa , hydrangibrachoa , cyclameibrachoa , conefloibrachoa , and Saintpaulia .Somaclonal variants or somatic hybrids can be confirmed by morphological, biochemical, protein marker, cytogenetic, and molecular analyses. Restriction fragment length polymorphism (RFLP), simple sequence repeat (SSR), amplified fragment length polymorphism (AFLP), methylation-sensitive amplification polymorphism (MSAP), transposon-based marker systems, and Next-Generation Sequencing (NGS) have been applied for the validation of somatic hybrids at the molecular level in several ornamentals . SomacloCaladium bicolor , Eustoma grandiflorum (lishianthus), Pinus patula (pine), Genista monosperma , Hyoscyamus muticus (Egyptian henbane), and Clitoria ternatea (bluepea or bluebellvine) from the somatic embryo; Gypsophila paniculata (gypsophila), Saintpaulia ionantha (saintpaulia), Urginea altissima , and Taraxacum pieninicum (Mniszek pieninski) from shoot tip; Rosa \u00d7 damascena f. trigintipetala (Damask rose), Syringa vulgaris (lilac), Nerium oleander (oleander), Centella asiatica (Asiatic pennywort), Eclipta alba , Erythrina variegata (tiger\u2019s claw), Photinia fraseri (red tip photinia), Ruta graveolens (rue), Salix tetrasperma (Indian willow) from axillary buds/nodes, Anthurium andreanum (anthurium) from callus, Lilium longiflorum (easter lily) from bulb, and different species of orchids from PLBs  [Any encapsulated plant tissue, somatic embryos, or any other micropropagules is known as a synthetic seed or artificial seed . Syntheta, etc.) ,293. 2). A range of 2\u20133% sucrose, 2\u20133% Na-alginate, and 50\u2013100 mM CaCl2 was found to be effective concentrations for synthetic seed development in ornamentals [In vitro synthetic seeds in ornamentals allow season-independent seed production, to preserve for long term, and to supply in time to the growers. Some factors are crucial for the synthesis of artificial seeds in ornamentals; these are concentrations of sucrose, sodium alginate , and calcium chloride , deviation from the normal structure, loss of embryogenic potential with time, etc. Synthetic seed technology can be used more effectively in the commercial ornamental plant propagation sector after resolving these limitations.Hedychium gardnerianum Shepard ex Ker Gawl. and H. coronarium J. Koenig were used for chromosome doubling using colchicine or oryzalin and successfully developed the tetraploid ginger lily [Caladium \u00d7 hortulanum Birdsey) that showed variation in leaf shape, color, and thickness compared to the wild type [Agastache foeniculum L.) was induced by the application of colchicine, which showed a wide range of variation compared to diploid plants in their morphophysiological characteristics [Dendrobium, Phalaenopsis, Epidendrum, and Odontioda orchids by the application of oryzalin [In vitro ploidy manipulation is a way of developing genetic diversification by increasing or decreasing chromosome numbers . The indger lily . Forty\u2014eild type . Tetrapleristics . Polyplooryzalin . Diverseoryzalin . BesidesDiverse phenotypic variations were observed in the in vitro-generated polyploids in roses, lilies, phlox, petunia, bellflowers, rhododendron, etc. . BesidesIn vitro plant propagation and multiplication offer significant potential for the advancement of both basic and applied biological sciences. Rapid multiplication and propagation by callus culture, protoplast culture, somatic embryogenesis, PLB organogenesis, and direct plantlet regeneration allowed for the cheaper and disease-free seedling of a diverse ornamental plant species. Millions of in vitro plantlets of different ornamentals are generated worldwide for commercial purposes. However, it is important to put more effort into reducing the cost of production. In contrast to propagation, it also facilitates plant improvement following diverse techniques, such as embryo rescue, somatic hybridization, in vitro pollination, ploidy manipulation, the development of synthetic seeds, etc., and large numbers of hybrids in various ornamentals have already been developed. In addition, the in vitro technique is largely used for phytochemicals and secondary metabolite production. However, more effort is needed to reduce species-specific and other factor-specific responses for the efficient regeneration of ornamentals.Agrobacterium tumefaciens-mediated transformation [Phalaenopsis and petunia, have suitable and efficient transformation techniques. Some studies have revealed that many genes and transcriptions are involved in the in vitro organogenic callus, shoot, root, somatic embryos, and PLBs, and the transcriptions of those genes are also regulated by the exogenous application of different growth regulators [In recent years, researchers have started to study at the molecular level, including genetic transformation, using in vitro technology in ornamentals . About 4ormation ; howevergulators . Arabidopsis and crop plants, such as rice, wheat, corn, barley, and rye, have suggested that tissue culture can alter the genetic nature by point mutations [Arabidopsis or crop plants, and this suggests the scope of future study in genetic and epigenetic aspects , and these alterations change the gene expression that might be regulating factors for in vitro plant growth and development. DNA methylation was studied in the callus and somatic embryos of pression ,304. Invbidopsis , while Hbidopsis . These rbidopsis . HoweverStudies on Arabidopsis and crop plants provide fundamental knowledge for disclosing the molecular mechanisms in ornamental plant species. Therefore, it is high time for advanced study of the genetic and epigenetic mechanisms that would provide a breakthrough in the commercialization of in vitro propagation of ornamental plant species."}
+{"text": "PLOS ONE Editors retract this article [The  article  because EA, MAR, MA, and PS did not agree with the retraction. MC, NH, ANS, MH and SAHB either did not respond directly or could not be reached."}
+{"text": "Agriculture is the very basic foundation of the modern human society and civilization. In a broad sense, agriculture comprises planting, animal husbandry, aquaculture, and forestry. Agricultural species provide food, feed, fiber, fuel, etc., on which we rely to nourish and sustain ourselves and the next-generation. Agricultural species, however, face various stresses during development, including but not limited to bacteria, viruses, drought, temperature, feed, and chemicals. Each of these adverse conditions may compromise physiological and cellular functions, as well as activate the reprogramming of transcription to maintain the homeostasis of an individual. Understanding the molecular mechanisms and regulations underlying these processes could help select breeding populations, genetically modify organisms, facilitate diagnosis, and improve welfare, ultimately benefiting human society and the whole world.According to the announcement of United Nations , fish , cereals and legumes , vegetable (eggplant), fruit (pear), and ornamental plants , in response to various stresses and conditions, such as heat, cold, drought, hypoxia, bacteria, chemicals, weaning, and mastitis. Most studies in this Research Topic examined the whole transcriptome to reveal the underlying molecular mechanisms following stresses. For example, in the context of global warming, Nayan et al. utilized MeDIP-Seq to investigate the genome-wide methylation specific to pathogen-caused subclinical mastitis in water buffalo and its consequential effect on the gene expression landscape. Furthermore, the authors built a Buffalo Subclinical Mastitis Methylome-Transcriptome database (BSCM2TDb) to catalogue the results of this study, which could help buffalo breeders in breed improvement and disease management programs.In addition to the transcriptome profiling, Wang et al. identified 719 putative Type 2C protein phosphatase (PP2C) genes in eight Rosaceae species , and further studied the evolution of PP2C genes. Moreover, the authors performed gene expression analyses specifically in Chinese white pear and identified candidate genes that participated in stress responses, including heat, cold, drought, NaCl, and abscisic acid.Some articles focus on the studies of gene families, instead of the whole transcriptome. For instance, Lu et al. revealed the regulatory mechanisms of the lncRNAs and mRNAs in the adaptation of Tibetan sheep to hypoxia, by comparing lung tissues from high-altitude Tibetan sheep and low-altitude Hu sheep. Functional enrichment and interaction network analysis results showed that lncRNA and mRNA may adapt to hypoxia via lipid metabolism, facilitating further analyses of plateau adaptability.Researchers of this Research Topic also studied post-transcriptional regulations, such as the profiles of lncRNA, miRNA, and circRNA in Tibetan sheep, hybrid hens, and Duroc pigs, respectively. For example, This Research Topic produced vast and valuable data and information, identified crucial biological pathways and candidate genes, and increased our knowledge of the underlying mechanisms of stress responses in agricultural species. These laid a solid foundation to move forward to use genomic breeding approaches, including marker-assisted selection, genomic selection and editing, to speed breeding of resistant populations and subspecies. In addition, the enriched transcriptomics data of this Research Topic, integrated with other omics data of genomics, proteomics, metabolomics, and phenomics, i.e., multi-omics strategies with systems biology, could enhance our understanding and accelerate the breeding improvement . FurtherWe would like to thank all authors and reviewers who contribute to this Research Topic. Besides, we want to pay tribute to agricultural practitioners for their hard work, especially the sacrifices of our father and mother, grandfather and grandmother, extending to our ancestors, who tried their best to feed us well and make our lives better, with the help of agriculture. Similarly, we need to do more to ensure our children have enough food in the future and make them proud of us. To achieve the daunting task, concerted efforts of farmers, researchers, engineers, and policymakers are much-needed."}
+{"text": "Systemic lupus erythematosus (SLE), is the most common type of lupus. Systemic lupus erythematosus is an autoimmune disease in which the immune system attacks its tissues, causing widespread inflammation and tissue damage in the affected organs. It can affect the joints, skin, brain, lungs, kidneys, and blood vessels. A 12-year-girl visited the outpatient department with the complaint of skin lesions (red color) over sun-exposed areas on the hand, feet, and face. Oral mucosal bleeding, joint pain including knee, shoulder, elbow, and wrist. On physical examination, photosensitive rash and oral bleeding were observed. Laboratories investigation revealed the patient had systemic lupus erythematosus. The patient was referred to the dermatology department for further medical management."}
+{"text": "A myocardial infarction (MI) is the leading cause of morbidity and mortality, seriously threatens human health, and becomes a major health burden of our society. It is urgent to pursue effective therapeutic strategies for the regeneration and restore myocardial function after MI. This review discusses the role of hydrogel in cardiac repair and regeneration for MI. Hydrogel-based cardiac patches and injectable hydrogels are the most commonly used applications in cardiac regeneration medicine. With injectable hydrogels, bioactive compounds and cells can be delivered in situ, promoting in situ repair and regeneration, while hydrogel-based cardiac patches reduce myocardial wall stress, which passively inhibits ventricular expansion. Hydrogel-based cardiac patches work as mechanically supportive biomaterials. In cardiac regeneration medicine, clinical trials and commercial products are limited. Biomaterials, biochemistry, and biological actives, such as intelligent hydrogels and hydrogel-based exosome patches, which may serve as an effective treatment for MI in the future, are still under development. Further investigation of clinical feasibility is warranted. We can anticipate hydrogels having immense translational potential for cardiac regeneration in the near future. Myocardial infarction (MI), which is caused by energy and oxygen demand blockage of the coronary artery, leads to massive amounts of cardiomyocytes death, exacerbated inflammatory response, pathological ventricle remodeling, disruption of electrical signaling, decreased systolic and diastolic function, eventually leading to heart failure (HF) ,2. MI kiThe current treatment approaches, including pharmacological treatment, percutaneous coronary intervention (PCI), and coronary artery bypass surgery (CABG), mainly focus on the restoration of blood supply to the ischemic cardiomyocytes . No avaiCell therapy and extracellular vesicle (EV)-based therapy have been extensively studied for tissue regeneration, and shown promising therapeutic potential in restoring cardiac function in MI. Cell therapy, which mainly focused on mesenchymal stem cells (MSCs) and cardiac stem cells (CSCs), suffers from low cell survival, engraftment and retention, and risk from immunogenicity and tumorgenicity . EV-baseBiomaterials can be used to encapsulate compounds, including cells or EVs, provide a suitable microenvironment for the survival of compounds, and show enormous potential in cardiac regeneration. Numerous advantages of biomaterials, including unlimited availability, stabilizability, unique bioactivities, and biocompatibility, arouse great interest in research regarding their potential for cardiac repair and regeneration  13]. Ad. Ad13]. Biomaterials have unique advantages over non-degradable materials, which harmfully influence the biocompatibility of tissue with immune activation due to the alloying elements ,17. As aVarious criteria have been proposed for the classification of biomaterials. Generally, biomaterials fell into three categories: organic, inorganic, and bio-based materials. Meanwhile, biomaterials are categorized as natural and synthetic materials based on their origins . BiotherThe property of biomaterials, including mechanical properties, biocompatibility, biostability, biodegradability, unique bioactivities, and maneuverability influences the function of biomaterials in biomedical and clinical research . As an iIt is essential to optimize biomaterials for the heart to mimic the natural heart\u2019s specific characteristics, including heartbeat, electrical conductivity , and theHydrogels are polymer-based materials with a three-dimensional network structure that attracts, contains, and becomes swollen with water ,36. TherDue to their biocompatibility and biomimetic nature, hydrogel-based biomaterials gained prior attention for cardiac regeneration. Since hydrogels fulfill most of these requirements, they serve as ideal biomaterials for cardiac implants and delivery systems. They have a cross-linked spatial structure, high biocompatibility, low immunogenicity, and can administer multiple bioactive agents into damaged organs or tissues ,45; theyAs is well known, chemical and physical characteristics influence the properties of hydrogels. The rigidity and rheological parameters contribute to the mechanical stability of hydrogels, while the characteristics of the porosity, conductivity, contractibility, density, and stiffness impart the mechanical strength of hydrogels, which contributes to their potential applications. Natural biomaterials have several chemical and physical characteristics, such as structural similarity to natural tissue, which makes them bioactive, biodegradable, nonimmunogenic, and non-thrombogenic biomaterials. The high stiffness of natural biomaterial-based hydrogels provides sufficient mechanical strength. However, the limited composition consistency may incur immunogenicity events. The gelation time and degradation pattern also can be easily interfered with the low composition consistency. Synthetic biomaterial-based hydrogels show high consistency in their production, and great control over their production, which can allow changing their composition and physical features such as porosity, conductivity, contractibility, density, and stiffness in a reproducible way.Hydrogels as water-enriched polymeric biomaterials mimic the extracellular matrix of the heart. The polymeric backbone of hydrogels makes structural rearrangements by physiochemical alterations in the surrounding medium, transforming into stimuli-responsive hydrogels, which are called intelligent hydrogels. The base polymer of hydrogels with responsive function is designed in vivo, and the rearrangements react appropriately in response to stimuli in the target site . The phyTemperature can change the conformations of hydrogels. Hydrogel undergoes a reversible transition from the soluble liquid to the insoluble gel phase at lower critical solution temperature, and transitions to hydrophobic from the hydrophilic phase above the temperature limitation .\u00ae F-127 [N,N-dimethylaminoethyl methacrylate methacrylate) (PDMAEMA) [Temperature-responsive hydrogels are mainly based on the amphiphilic polymer, poly(N-isopropylacrylamide) (PNIPAAm) , poly- . Due to PDMAEMA) ,59.Moreover, a minimally invasive delivery system is being developed for thermo-responsive hydrogels ,61,62,63Using a temperature-responsive injectable polymer-mediated delivery system for adipose-derived stem cells, the cells can remain at the injection site longer and recover more quickly from ischemia . With a A pH-sensitive hydrogel is made up of a polymer backbone with an acid or basic group that hydrolyzes at an accelerated rate in acidic conditions . When poSome research concerning the function of pH-responsive hydrogel confirmed these properties on cardiac tissue engineering after MI. pH-switchable supramolecular hydrogel has self-healing properties and delivered growth factors to the MI heart with a reduction in infarct scars in MI pigs . An injeIon-sensitive hydrogels have properties that electrical conductivity can be changed in different ionic conditions. Typically, a hydrogel is in a liquid state with fixed charges on the polymer backbone after synthesis, and transitions from solution state to gel with the interaction between charged ions and counterions in a specific electric field . The metSalt- or temperature-induced cooperative swelling\u2013shrinking properties control the speed, amplitude, and degree of bidirectional bending, as well as the angle at which it occurs and the degree at which it occurs . The conHypoxia plays an essential role in the process of MI, which can accelerate cell death, tissue necrosis, the loss of membrane integrity, and cardiomyocyte apoptosis. Mitigating hypoxia and promoting cell survival has been recognized as a promising therapeutic strategy and is taken into consideration in hydrogel design . Oxygen-2O2) reacting with water. The H2O2 can release oxygen, undergoing a catalase reaction [2O2 [Calcium peroxide (CPO) is an important material for oxygen-generating hydrogels, which can release hydrogen peroxide  in hyperbaric conditions. Angiogenesis-induced tissue infiltration and vascular recruitment are promoted by this hydrogel in wound healing . By poly2O2, and hydroxyl radicals in the post-MI microenvironments, have been targeted for therapeutic interventions and scavenger the ROS levels in the heart is effective in treatments after MI [As a consequence of cardiomyocytes having the highest number of mitochondria, they suffer from impaired mitochondrial function and impaired ATP metabolism following acute MI . ROS plaafter MI ,91.Research confirmed that ROS-responsive hydrogels with antioxidant properties can ameliorate excess ROS signaling and suppress oxidative stress injury in cardiomyocytes after MI . HydrogeThrough the H-abstraction reaction, the glutathione (GSH) conjugated chitosan chloride (CSCl) chain can weaken hydrogen bonds and scavenge ROS . In addiThe CSCl-GSH hydrogel can effectively reduce intracellular ROS production, scavenge ROS, suppress oxidative stress, enhance the adhesion and survival of cardiomyocytes, and diminish cardiomyocyte apoptosis with excellent biocompatibility at the condition of high ROS after MI . An injeThe ROS-responsive hydrogels aim to reduce intracellular ROS production, scavenge ROS, ameliorate excess ROS signaling, and suppress the oxidative stress in the cardiac microenvironment to reduce the damage after MI.There are two main approaches to cardiac regeneration based on hydrogels: injectable hydrogels and hydrogel-based cardiac patches . InjectaGenerally, injectable hydrogels are liquid systems in vitro, but when they reach the myocardium, they transform into semisolid gels under specific physiological conditions. Microenvironment stimulation contributes to hydrogel gelation, retention, and controlled release of bioactive agents, including temperature, pH, ion, ROS, hypoxia electrical stimulation, and ischemia, which makes the hydrogel into a stimuli-responsive hydrogel and broadens its application scenarios. To prevent an immune response and similarity with native tissue, hydrogels must be biocompatible, biodegradable, and absorbable by the surrounding environment. It is important to take into account the contractility and elasticity of the material for coping with periodic contractions and relaxations . FurtherAs an injectable biomaterial, these factors should be taken into consideration for the design of injectable hydrogels, the bioactive compound encapsulated in the hydrogel in vivo, administration route and time of hydrogels, the required stimuli for release of bioactive compound, gelation time, the controlled release of bioactive compounds, and the clearing of hydrogels .Typically, injectable hydrogels are administered intramyocardially, intracoronary, or intravenously with the help of a cardiac catheter. As a minimally invasive administration method, injection decreases healing time, facilitates the encapsulation of cells and biomolecules, and minimizes infection risk.A key function of injectable hydrogels is to promote angiogenesis, which is a crucial element of cardiac regeneration. Injecting hydrogels into the superficial myocardium promotes neoangiogenesis and attenuates pathologic remodeling . There aAs well as increasing the thickness of the ventricular wall, an injectable hydrogel enhances the geometry of the left ventricle, supports myocardial tissue, and promotes myocardial tissue regeneration . MeanwhiRestoration of cardiac function has been shown to be accompanied by an increase in healing, cardiomyocyte survival, and a decrease in pathological remodeling of the myocardium . Cell trResearch confirmed that injectable hydrogels with preliminary feasibility have the potential as endogenous tissue repair for cardiac regeneration, mainly due to their ability to improve cell adhesion and proliferation, and are regarded as the candidates of translatable agent carriers.The mechanisms of injectable hydrogels in cardiac regeneration are still unclear, and these factors involve the role of cardiac regeneration after MI. The injectable hydrogel can prevent inflammatory response, improve local neovascularization, rescue at-risk cardiac cells via the loaded miRNA, rescue the ischemic myocardium through promoting angiogenesis by the delivered proangiogenic factors, and improve and optimize the microenvironment in the damaged heart tissue.Overall, the type and number of encapsulated compositions in hydrogels, composition consistency, biocompatibility, gelation, retention, controlled release of bioactive agents, and biodegradation can influence the function and potential harm. Different stimuli types make the application of injectable hydrogels more complicated; thus, additional work is needed to resolve this issue.Injectable hydrogels have demonstrated promise as an alternative biotherapeutic for cardiac regeneration following MI. Despite injection systems\u2019 ability to prevent ventricular dilatation and enhance myocardial repair, there are still significant limitations. These include poor mechanical properties, potential immunogenicity, being washed away rapidly from the beating heart, and low retention of cells or drugs, which limit their therapeutic efficacy. These limitations can be overcome by hydrogen-based cardiac patches, which have received attention from various medical fields. The hydrogen-based cardiac patches enable drug retention with enhanced loading capability, bioavailability, biodistribution, stimulation responsiveness, controlled on-demand drug release, and multifunctional therapeutic demands, thus improving efficacy and reducing systemic toxicity. Due to electrically conductive and nanofibrous networks, optimal adhesion, organization, and communication between cells are achieved. Three-dimensional biohybrid actuators formed from patches exhibit controllable linear contraction and extension, pumping, and swimming behaviors. The degradation including the degradation time and the nanotubes after the degradation is a critical property of hydrogel-based cardiac patches. The cardiac patch must persist for the repair process, and research confirmed the hydrogel did not significantly degrade over 21 days when tested in vitro . Long-teHydrogel-based cardiac patches, which are incorporated with carbon nanotubes as electrical nano-bridges and electrical coupling, can achieve synchronous beating between cardiomyocytes as native myocardial tissue and can be used for various heart defects repair  and damaUsing hydrogel patches with electronic conductivity, cardiomyocytes in a rat MI model showed attenuated remodeling, improved contractility, and restored heart function . A hydroResearch in rats with MI showed that hydrogel-based cardiomyocyte-incorporated cardiac patches with good electronic conductivity attenuated left ventricular remodeling, improved contractile activity, and restored heart function . The repWhile hydrogel-based patches provide injectable viscoelasticity and myocardial-like toughness, their mechanical strength is low ,125. MorIn order to provide a strong wet adhesive property, conductive ions, and mechanical stability, a self-polymerized paintable hydrogel-based patch was developed . RecentlThe mechanical\u2013electrical interactions of hydrogel patches with myocardium remain unclear, despite some hydrogel patches showing good therapeutic efficacy. Hydrogel\u2019s mechanical properties, for example, should be explored to determine how they affect ventricular dilation and stroke volume, or how they affect the reconstruction of electrophysiological propagation. It is, therefore, imperative to develop hydrogel patches that can communicate mechanically and electrically with infarcted myocardium .As an important biomaterial, hydrogel shows exceptional promise in a wide range of applications including drug/gene delivery carriers , sensorsOverall, the use of hydrogels in cardiac repair and regeneration after MI holds great promise. Hydrogel properties, such as bioactivity, biocompatibility, and biodegradability, improve cardiac regeneration and restore cardiac function in MI. Due to its rapid and repeated contraction, high conductivity, and high blood circulation, the heart has a lower colonization resistance and a high clearance from the blood, which limits the application scenarios of biomaterial-based therapy in MI. Hydrogels are ideal biomaterials for cardiac implants and agent delivery systems due to their high binding affinity, swelling ability, and absorption ability. Enhanced colonization resistance can be achieved through the cross-linked spatial structure of hydrogels, extending their half-life in vivo and preventing rapid degradation. Meanwhile, the hydrogel can enhance electrical conductivity, which is beneficial to the contraction. A hydrogel, whose physiochemical structure can be modified in response to external and intrinsic stimuli, such as temperature, pH, iron, hypoxia, and ROS, can be used as direct implantation onto the left ventricle with a controlled drug release system to improve the post-ischemic environment with angiogenic factors, to provide structural support to the injured region, and to enhance conductivity.Hydrogel-based cardiac patches and injectable hydrogels are the most commonly used applications in cardiac regeneration medicine. With injectable hydrogels, bioactive compounds and cells can be delivered in situ, promoting in situ repair and regeneration, while hydrogel-based cardiac patches reduce myocardial wall stress, which passively inhibits ventricular expansion. The physiochemical structure rearrangements of intelligent hydrogels in response to intrinsic and extrinsic stimuli improved the maneuverability of hydrogels in cardiac research. Different stimulus types make the application of injectable hydrogels more complicated. Hydrogel-based cardiac patches work as mechanically supportive biomaterials. The advantages of intelligent hydrogels broaden the applications, enrich the regulation methods, and enhance the controllability of injectable hydrogels and hydrogel-based cardiac patches.Hydrogels provide structural support to the injured area and are used to deliver therapeutic agents with controlled release. Hydrogels are synergistic with encapsulated bioactive agents. Therefore, both must act simultaneously in order for the effects of cardiac regeneration to be observed, which makes the mechanism complex and urgently needs clarification. The mechanism of hydrogels in cardiac regeneration medicine may involve reducing inflammation, limiting fibrosis, and enhancing angiogenesis. Further studies concerning hydrogel-based therapies are needed to understand their mechanisms.Hydrogels must overcome certain challenges to be used clinically for cardiac regeneration. A majority of hydrogel research is performed on animals, and the immunogenic potential of hydrogels is completely unlocked, especially in vivo. From the bench to the bedside, hydrogels can still be improved. In addition, hydrogels can reduce the electroconductive ability of the heart, as hydrogels are electroconductive materials. Research confirmed that none of the hydrogels satisfy all the requirements for successful in vivo use. Hydrogel implantation procedures have dramatically reduced the risk of injury, but minimally invasive methods are still to be expected, especially for hydrogel-based cardiac patches. Electrical conductivity is influenced by the cardiac microenvironment, which is affected by the implantation of hydrogel patches. For patients with mild or moderate heart failure, open-heart surgery is not a feasible option. In the future, minimally invasive approaches and reliable delivery systems, such as injectable hydrogels, paintable patches, and adhesive patches without sutures, may offer promise. Taking these hydrogels from the lab to the clinic is challenging.In cardiac regeneration medicine, clinical trials and commercial products are limited. Biomaterials, biochemistry, and biological actives, such as intelligent hydrogels and hydrogel-based exosome patches, which may serve as an effective treatment for MI in the future, are still under development. Further investigation of clinical feasibility is warranted. We can anticipate hydrogels having immense translational potential for cardiac regeneration in the future.In conclusion, hydrogels hold great promise in cardiac repair and regeneration after MI. Intelligent hydrogels make structural rearrangements by physiochemical alterations in the surrounding medium, which broaden the application scenarios of hydrogels in cardiac tissue engineering. Injectable hydrogels are agents\u2019 carriers of bioactive compounds and cells, while hydrogel-based cardiac patches reduce myocardial wall stress as mechanically supportive biomaterials. The challenges and opportunities coexist in cardiac tissue engineering. Further investigation of clinical feasibility is warranted. We can anticipate hydrogels having immense translational potential for cardiac repair and regeneration shortly."}
+{"text": "In the US education sector, data are captured on learners at all stages of the life course with rich, sensitive information on learner demographics, enrollment, achievement, borrowing, and outcomes. Most data are controlled by institutions, who increasingly want to monitor progress from cradle to career, tracking students from early childhood through primary and secondary schools (K-12), on to degrees granted in postsecondary institutions, including continuing and technical education that grant credentials. Collecting, storing, and using such data raises privacy concerns.This presentation describes privacy preserving technologies (PPTs) that have been discussed, tested, implemented \u2013 and abandoned \u2013 in the education domain. These include both input and output privacy protection methods ranging from absolute lockdowns of learner data to cryptographically-protected data access and analysis systems. We describe most familiar and tested PPTs including secure hashing, secure multiparty computation, trusted execution environments, and differential privacy, highlighting actual applications in schools, departments of education, and educational technology nonprofits and companies.We summarize the factors that limit PPT use and success, including legal, institutional, technical, and cultural barriers and offer recommendations to overcome these barriers. For example, we find gaps in understanding what PPTs are and what problems they solve; a lack of engagement with data controllers, subjects, and regulators; and a lack of human capital to implement and use PPTs. There are also significant research and development needs to continue making PPTs less costly in financial, compute, and complexity terms. Our recommendations suggest topics for continued research into methods that produce disaggregate statistics to analyze equity while protecting privacy, have clear and fair privacy loss budgets, and produce open-source technology, ideally pairing scientists with education experts."}
+{"text": "This national study presents key informant interview data (N=28) collected 2017-2018 identifying capacity building needs in professional skills, organizational operations, service/care models, and public policies to effectively serve older adults with long-term serious mental illness, intellectual/developmental disabilities, physical and sensory disabilities. A multi-university, interdisciplinary team collected data through phone interviews, coded, and analyzed transcripts thematically and using content analysis. Key informants worked in national affinity organizations, state-level organizations, academia, and social care organizations. Findings are broad in scope, highlighting variances in rural/urban areas, state government dispositions, workforce characteristics, social and health care infrastructure, beliefs about disability and chronic conditions, and other factors. Findings will informed the development of a larger survey study aiming to articulate an agenda for building capacity to meet the needs of aging with disability populations."}
+{"text": "Honey bees are model organisms for microbiota research. Gut microbiomes are very interesting for surveys due to their simple structure and relationship with hive production. Long-term studies reveal the gut microbiota patterns of various hive members, as well as the functions, sources, and interactions of the majority of its bacteria. But the fungal non-pathogenic part of gut microbiota is almost unexplored, likewise some other related microbiota. Honey bees, as superorganisms, interact with their own microorganisms, the microbial communities of food stores, hive surfaces, and other environments. Understanding microbiota diversity, its transition ways, and hive niche colonization control are necessary for understanding any separate microbiota niche because of their interplay. The long coevolution of bees with the microorganisms populating these niches makes these systems co-dependent, integrated, and stable. Interaction with the environment, hive, and other bees determines caste lifestyle as well as individual microbiota. In this article, we bring together studies on the microbiota of the western honey bee. We show a possible relationship between caste determination and microbiota composition. And what is primary: caste differentiation or microbiota composition? We now assume that all metazoans have symbiotic microbiota. It can affect any living process: metabolism, development, the work of defense systems, reproduction, and even speciation . BalanceApis mellifera, the honey bee, is a well-known model organism for studying microbiota. It represents a simple microbiome consisting of only a small subset of phylotypes and associated species, regardless of geographic location [location . As in mlocation  and evenlocation . In contlocation .Honey bees are social insects with different castes: drones, queens, and workers . There aAll types of honey bees\u2019 related microbiota can be divided into several groups: gut symbiotic bacteria and fungi (which show differences between both life stages and castes); body surface microbiota ; normal hive microorganisms in several ecological niches: honey combs, brood combs, their composing wax, propolis, and royal jelly; and the pathosphere .In researching honey bees, the gut microbiota is the most studied part. In comparison with other animals, the honey bee\u2019s gut microbiota has a very simple composition. Most bacteria live in the rectum and ileum, and 98% of their population belongs to 9 taxa 12 species) . Most of species Any organism interacts with the environment and environmental bacteria through its surfaces. In contrast, these aspects of the microbiota have only been studied in part. Only a few articles analyze whole-body metagenomics data ,13,14. TExtra-hive environmental communities are deeply researched because of the high economic impact of related plants . These sMelissococcus, Paenibacillus, and Spiroplasma [Aspergillus, Nosema, and Varroa species [On the one hand, hive niches are intermediate between the environment and gut communities. Social interactions between hive members and stored food make these transitions possible. On the other hand, some microorganisms take part in honey, propolis, and royal jelly production, development of preimaginal stages. The pathosphere of honey bees includes more than 20 virus groups, mainly from Dicistroviridae and Iflaviridae ,17,18. Troplasma ,20. But  species ,20,21,22Snodgrassella alvi, Gilliamella apicola, Lactobacillus Firm-4, Lactobacillus Firm-5, Bifidobacterium asteroides. Less numerous groups are: Frischella perrara, Bartonella apis, Bombella apis and Commensalibacter sp.   core gut bacteria, including Lactobacillus Firm-5 and Firm-4 bacteria, which are not found anywhere else except gut [One of the royal jelly metagenomes was used in the analysis of colony collapse disorder . Anothercept gut . As a recept gut .Aspergillus spp. might be pathogenic or weaken the immune system, but their negative impact varies greatly [Penicillum, Fusaria, and Ascosphaera species were also found in hive environments [Hive surfaces contain all varieties of in-hive communities, but in small quantities. Despite this, its role in the transmission and control of pathogens should be important. Different  greatly . The Penronments . Diverseronments .L. kunkeei has been found all over the world in different plant environments, especially pollen [Lactobacillus species and non-core Bifidobacterium spp. and Bombella apis in nectars [Environmental microbiomes influence hive microbiota. Microorganisms are shared between plants and bees because of their contact in extra-hive environments and the transfer of plant resources to hives. The biochemistry of these sources controls their further colonization. Most of the non-core gut microbiota originate from nectar or pollen and normally occur in the air and on plant surfaces ,115,116.y pollen . Metagen nectars ,116. The nectars ,66,117.  nectars . Coloniz nectars .Plant surfaces, nectar, and pollen microbiota are widely researched ,119,120.As it was mentioned above, several core species can be transferred between different pollinators. The role of this process in nature is unexplored. However, strains from different species have different specializations and have different colonization efficiencies .Honey bee pathogens interact with normal microbiota and influence pattern differentiation ,19,22. SVarroa destructor might be associated with bee pathogenic Erwinia sp., Enterococcus faecalis, Stenotrophomonas maltophilia, Staphylococcus spp., Bacillus cereus, and several other species [Aethina tumida, are vectors for several normal gut species: S. alvi, G. apicola, F. perrara, and L. kunkeei [Multicellular pathogens also share some microorganisms.  species ,124. Sma kunkeei . They ca kunkeei ,126.But many interactions and the extent of the roles of non-gut microbial communities associated with honey bees are still unclear.The honey bee gut microbiota is a model object to study host\u2013bacteria interactions. Small diversity, high stability, and a set of composition patterns distinct due to caste, climate, and diet make various impact analyses and understanding the roles of different bacteria simple. Studies on various microbiota members allow one to figure out the metabolic role of bacteria under study, but often show similar results when researching their influence on honey bee fitness. It might indicate the complexity of their impact on development, reproduction, and defense system processes.Apis mellifera superorganism.Almost always, all kinds of organism-related environments contain a great variety of microorganisms. Of course, the core whole-body microbiota has the greatest impact on the organism\u2019s life. In contrast, other associated germs drive organism colonization processes and influence microbiota diversity and composition. Metabolic interactions are stronger between organisms\u2019 gut microbiota, but food and body surface microbes also play a role in digestion and other biochemical processes. Therefore, both normal gut and environmental honey bee microbiota are parts of the"}
+{"text": "In \u201cA Web-Based Prostate Cancer\u2013Specific Holistic Needs Assessment (CHAT-P): Multimethod Study From Concept to Clinical Practice\u201d : e32153]) the authors noted one error in the order of the authors.The author list appeared as:Rebecca Appleton, Veronica Nanton, Nisar Ahmed, Joelle Loew, Julia Roscoe, Radha Muthuswamy, Prashant Patel, Jeremy Dale, Sam H AhmedzaiWhereas it should have been:Veronica Nanton, Rebecca Appleton, Nisar Ahmed, Joelle Loew, Julia Roscoe, Radha Muthuswamy, Prashant Patel, Jeremy Dale, Sam H Ahmedzaist November 2022, together with the publication of this correction notice. Because this was made after submission to PubMed, PubMed Central, and other full-text repositories, the corrected article has also been resubmitted to those repositories.The correction will appear in the online version of the paper on the JMIR Publications website on 1"}
+{"text": "Young refugees often face barriers in accessing youth-friendly health information and care. Differing cultural norms, languages, laws, financial difficulties, gender disparities, and stigma pose additional challenges for youth in forced migration settings.REACH is a regional initiative of Columbia University, which aims to bridge the gap in health literacy and health care access among refugee and disadvantaged youth in Turkey, Lebanon, and Jordan, which are heavily affected by the Syrian conflict. Supported by TaiwanICDF, Blue Chip Foundation, and Columbia University, the REACH Project uses a community-based participatory action research approach and aims to assess the impact of mHealth technologies on improving health literacy and health care access among youth in host countries. With a strong adult-youth partnership, the project includes stakeholder meetings, mixed-methods studies with youth, health service providers and policy makers, in addition to health advocacy, communication and dissemination activities such as photo exhibitions, panels, and production of policy briefs and scientific publications. REACH has been working with youth, software developers, health professionals, academia, and I/NGOs to develop the multilingual and freely available REACH4Health app to promote youth health.Findings from three countries show that mHealth technologies have the potential to provide innovative, youth-friendly and widely used solutions to address the health education, health communication, and health care needs of disadvantaged and marginalized youth.Youth-adult partnerships, working with mixed groups of refugee and local youth, using community-based participatory research, peer-to-peer methodologies, and co-design approaches, as well as using social media tools contribute to the overall success of mHealth and health promotion interventions for disadvantaged youth in countries affected by forced migration.\u2022\u2002mHealth technologies have a strong potential to improve health literacy and health care access of refugee and disadvantaged youth in countries affected by forced migration.\u2022\u2002Youth-adult partnerships, working with mixed groups of refugee and local youth, using participatory approaches and peer-to-peer methodologies significantly contribute to youth health interventions."}
+{"text": "PLOS ONE Editors retract this article [The  article  because AS, AZ, MZA, SH, MTK, MZ, ATKZ, and KMA did not agree with the retraction. SMA either did not respond directly or could not be reached."}
+{"text": "This article was submitted and published without the knowledge of the senior faculty directly involved in the management of the case. An internal investigation was conducted by the Islamabad Medical Complex Department of Surgery and it was determined that although the submitting authors did neglect to notify and include the appropriate authors, this was done out of ignorance and did not constitute intentional academic fraud. At the request of the senior faculty involved in the case, they have been added as the first, second and third authors. The published article has been updated to include the following author list:Muhammad Hanif (Corresponding Author)Surgical Unit II, Benazir Bhutto Hospital, Rawalpindi Medical University, Rawalpindi, PAKRiaz SiddiquiSurgery, Islamabad Medical Complex, Islamabad, PAKAyesha JavedSurgery, Islamabad Medical Complex, Islamabad, PAKMuhammad AliInternal Medicine, Islamabad Medical Complex, Islamabad, PAKOmama FarooqInternal Medicine, Islamabad Medical Complex, Islamabad, PAKMishal FatimaGeneral Surgery, Islamabad Medical Complex, Islamabad, PAKHajrah FarooqInternal Medicine, Islamabad Medical Complex, Islamabad, PAK"}
+{"text": "We agree that cognitive dysfunction after COVID-19 is likely mediated by indirect mechanisms. A possible mechanism we are currently exploring is autoinflammatory/autoimmune injury, evidenced by elevated brain-injury biomarkers that scale with systemic illness. Similar elevations occur in intensive care unit (ICU) patients with severe influenza. Lasting cognitive problems after COVID-19 occur following other critical illnesses.Our supplemental analyses suggested that patients without mechanical ventilation also had significant cognitive deficits. Associations between our computerised tests and diverse conditions including depression, anxiety, insomnia, diabetes, cardiovascular disease, autoimmune disorders are of negligible-small scale,As noted in our discussion, caution is needed before inferring cause and effect from correlational analyses. This is also because people follow different cognitive developmental and decline trajectories through their lifespans, which may correlate with vulnerability to severe COVID-19. We can therefore suggest inference only by synthesising the body of available information. Objective, self-report, clinical and epidemiological evidence converge in indicating chronic cognitive deficits after severe COVID-19. Indeed, in agreement, a subsequent larger study than ours has reported broadly similar findings.Drafting of the letter: A.H. & D.K.M.Professor Hampshire reports grants from UK Dementia Research Institute, grants from NIHR Imperial Biomedical Research Centre, and grants from NIHR, outside the submitted work; and is Co-director and owner of H2 Cognitive Designs Ltd and director and owner of Future Cognition Ltd, which support online cognitive studies and develop custom cognitive assessment software respectively. Professor Menon reports grants from Lantmannen AB, grants from GlaxoSmithKline Ltd, personal fees from Calico LLC, personal fees from GlaxoSmithKline Ltd, personal fees from Lantmannen AB, other from Integra Neurosciences, outside the submitted work; and reports leadership and fiduciary roles for Queens\u2019 College, Cambridge, Intensive Care National Audit and Research Centre, London, and European Brain Injury Consortium."}
+{"text": "RSC Advances article due to a lack of reproducibility in the results of the paper. We have been unable to replicate the results of miRNA detection, shown in Fig. 8, and as a result, the conclusions of this paper are not supported.We, the named authors, hereby wholly retract this Signed: Erlin Sun, Lining Wang, Xiaodong Zhou, Chengquan Ma, Yan Sun, Mingde Lei, Bingxin Lu and Ruifa Hanth July 2020Date: 14RSC AdvancesRetraction endorsed by Laura Fisher, Executive Editor,"}
+{"text": "Female genital fistulas are abnormal communications that lead to urinary and/or fecal incontinence. This analysis compares the characteristics of women with fistulas to understand how countries differ from one another in the circumstances of genital fistula development.This retrospective records review evaluated demographics and circumstances of fistula development for 6,787 women who sought fistula treatment between 1994 and 2017 in Tanzania, Uganda, Kenya, Malawi, Rwanda, Somalia, South Sudan, Zambia, and Ethiopia.Most women developed fistula during childbirth, whether vaginal  or by cesarean section . Others had fistulas attributable to gynecological surgery  or rare causes . Somalia, South Sudan, and Ethiopia had comparatively high proportions following vaginal birth and birth at home, where access to care was extremely difficult. Fistulas with live births were most common in Kenya, Malawi, Rwanda, Uganda, Tanzania, and Zambia, indicating more easily accessible care.Characteristics of women who develop genital fistula point to geographic differences in obstetric care. Access to care remains a clear challenge in South Sudan, Somalia, and Ethiopia. Higher proportions of fistula after cesarean birth and gynecological surgery in Kenya, Malawi, Rwanda, Uganda, Tanzania, and Zambia signal potential progress in obstetric fistula prevention while compelling attention to surgical safety and quality of care. Female genital fistulas include vesico-vaginal fistulas, recto-vaginal fistulas, and ureteric injuries: abnormal communications between the genital tract and the bladder, urethra, ureters, colon, or rectum that lead to urinary and/or fecal incontinence. Most genital fistulas are obstetric, arising from pressure necrosis during prolonged, obstructed labor. Obstruction occurs when the presenting part of the fetus cannot progress into the birth canal despite strong uterine contractions, due to cephalo-pelvic disproportion, malpresentation, or malposition. Obstructed labor occurs in an estimated 4.6% of childbirths, causing 8% of maternal deaths . Over 90Obstetric fistula prevention requires appropriate labor monitoring and access to quality basic and comprehensive emergency obstetric care. High-income countries eliminated obstetric fistula by the mid-twentieth century . These cThe relative rarity of genital fistula makes prevalence estimation difficult. Pooled prevalence from population-based studies indicates that one million women may have fistulas in sub-Saharan Africa and South Asia, with over 6,000 new cases per year . DemograThe objective of this paper is to compare the characteristics of women with fistula to understand how countries differ from one another in the circumstances of genital fistula development. Documenting geographic differences can help policymakers to tailor appropriate strategies to reduce fistula incidence.This retrospective records review evaluated the circumstances of fistula development for women who sought fistula treatment in nine African countries. Women were interviewed in 89 facilities in Tanzania, Uganda, Kenya, Malawi, Zambia, Rwanda, Ethiopia, Somalia, and South Sudan. Women consented to fistula repair, following each hospital\u2019s counseling and informed consent process. The number of women in each country reflects the number of repairs conducted by the second and third author and colleagues in those countries. Data were collected between June 1994 and December 2017. We excluded women whose fistulas were of unclear origin or developed before 1980.One of the surgeons interviewed each woman and recorded information on a standard form, documenting demographics, obstetric history, and duration of leaking . Women wData were entered into an Excel database, with names changed to unique identification numbers to protect women\u2019s privacy. Data were analyzed using Stata 16 software (StataCorp).This review includes 6,787 women who sought treatment for genital fistula. Table Most women had a single fistula , while 1,049 (15.5%) presented with multiple fistulas, meaning a combination of fistulas in different locations. Ethiopia had the highest proportion of women incontinent of both urine and feces due to the combination of vesico- and recto-vaginal fistulas , followed by South Sudan  , South Sudan , and Kenya , while the proportion of women developing fistula after age 30 was highest in Malawi  and Rwanda . More than one quarter of women with fistula had been incontinent for ten years or longer in Rwanda  and Zambia .Most women with fistula had not completed primary school, and 39.2%  had not attended formal school at all. Low educational access was particularly pronounced in Somalia , South Sudan , and Ethiopia .Women who developed fistula during labor and childbirth most commonly reported giving birth in health facilities , with proportions near or above 90% in Zambia , Tanzania , Rwanda , and Uganda . In contrast, between 60 and 70% of women with fistula had given birth in health facilities in South Sudan , Ethiopia , and Somalia . The proportion of women with fistula who gave birth to a live baby varied by country. While 5,216/6,490 (80.4%) women reported a stillbirth overall, the percentage varied from 94/102 (92.2%) in Ethiopia to 120/161 (74.5%) in Zambia  or by cesarean section  , while 1.1% of women developed fistula through other circumstances . The proportion of fistulas following gynecological surgery was highest in Kenya , Tanzania , Uganda  and Malawi , while fistulas following gynecological surgery constituted less than 2% of fistulas repaired in Somalia, South Sudan, and Ethiopia . Others included two bilateral tubal ligations, two myomectomies, one myomectomy and salpingectomy, and four other laparotomies . In this series over 10% of women with fistula after childbirth reported previous abdominal surgery in Rwanda , Kenya , and Uganda  . Additional research is needed on surgical complications from cesarean birth.Continued progress toward fistula elimination requires countries to ensure adequate infrastructure and security for women to access basic and comprehensive emergency obstetric care. Providers should have the knowledge, experience, and environment to be able to provide quality care to all women, particularly those who experience labor complications. Facilities and providers should consider the quality of emergency obstetric care, including timing and decision-making for cesarean birth. Safe surgical care requires robust provider training, supervision, and mentoring, appropriate work environments, and clear safety standards. Fistula elimination will require a holistic systems approach that improves emergency obstetric care and surgical safety."}
+{"text": "Microfluidics is a multidisciplinary science that includes physics, chemistry, engineering, and biotechnology. Such microscale systems are receiving growing interest in applications such as analysis, diagnostics, and biomedical research. Thermoplastic polymers have emerged as one of the most attractive materials for microfluidic device fabrication owing to advantages such as being optically transparent, biocompatible, cost-effective, and mass producible. However, thermoplastic bonding is a key challenge for sealing microfluidic devices. Given the wide range of bonding methods, the appropriate bonding approach should be carefully selected depending on the thermoplastic material and functional requirements. In this review, we aim to provide a comprehensive overview of thermoplastic fabricating and bonding approaches, presenting their advantages and disadvantages, to assist in finding suitable microfluidic device bonding methods. In addition, we highlight current applications of thermoplastic microfluidics to analyses and diagnostics and introduce future perspectives on thermoplastic bonding strategies. Microfluidics is a multidisciplinary technology that is used in various applications including analyses, diagnostics, and biomedical research ,2,3,4. HApart from material selection and microchannel fabrication, microdevice bonding is a concern in the development of thermoplastic microfluidics. Although thermoplastics share common characteristics, each material possesses unique properties including chemical composition, glass transition temperature, mechanical rigidity, and solvent compatibility . Therefog) of the plastic material and the microfluidic structure is formed. This technique enables the fabrication of complex structures, but the fabrication cost is high and it is difficult to assemble separate layers for the construction of closed microfluidic devices . I. I2 plas bonding d 112]. . 2 plasmProtein and biomarker analyses are crucial in medical diagnostics and laboratory research. Due to the advantages of thermoplastics, ongoing efforts have focused on developing electrophoresis in microfluidic devices. Hot embossing and thermal bonding have been successfully applied to fabricate PMMA microfluidic systems for high-resolution electrophoretic separations of fluorescently labeled amino acids . SimilarIn this review, we recapitulated the available knowledge of thermoplastic bonding for fabricating microfluidic devices as well as their applications. Numerous thermoplastic bonding approaches such as thermal bonding, solvent bonding, adhesive bonding, chemical/physical bonding, ultrasonic/laser welding, and microwave bonding are available for microfluidic devices. Researchers should select the appropriate bonding technique depending on the specific properties of the thermoplastic substrate and the requirements of the microfluidic chips. Furthermore, post-process applications could help determine the suitable approach for thermoplastic bonding. Typically, on the one hand, thermal bonding and solvent bonding techniques are used for thermal cycling (such as CF-PCR) microchips due to their thermostability and high bond strength. On the other hand, cell-based microdevices require biocompatible materials, preferring adhesive bonding.With the development of microfluidic technology, thermoplastic microfluidics have great potential for applications such as nucleic acid analysis , cell-based research , and electrophoresis. In addition to its robustness, low cost, and high throughput, its commercialization has allowed the research and development of thermoplastic microfluidic chips. In the future, microfluidic devices will become more complex and integrated, promoting all-in-one devices, wherein thermoplastic bonding allows large-scale bonding of multilayers and dissimilar materials."}
+{"text": "The Philippines is among one of the most gender-equal countries in the Western Pacific region.\u200b\u200bLike in other Asian countries, Filipino women are stifled by a patriarchal society emphasizing male dominance in family structures and larger social institutions.Through public debasing of women, condoning rape jokes and sexual remarks, openly harassing female supporters, associating femininity with weakness, and encouraging the military to \u201cshoot women \u2018communist rebels\u2019 in the vagina,\u201d the current administration under President Duterte personifies sexism, shaping society's perception of women. This misogyny is tolerated by many citizens, including some women of power. Coined \u201cfeminists of convenience,\u201d these individuals advocate women's rights yet remain silent about the President's behavior for personal and family gains and to avoid political backlash.It is apparent that women's rights is not the administration's priority, and this manifests systemically through complex referral pathways, fragmented documentation systems, and a slow judicial process. With stringent policies  restricting mobility, this unsettling reality has intensified during the COVID-19 pandemic. VAW victims are trapped in their homes, unable to seek help and alternative shelter.,,Also vulnerable are women facing multiple and intersecting forms of discrimination, such as transgender women, indigenous women, women with disabilities, poverty-stricken women, and internally displaced women. The additional barriers of stigma, discrimination, State neglect, and harassment from law enforcers contribute to their distrust in the system, making them less likely to report to the police.With the pandemic further threatening women's safety, the priority is ensuring functional, responsive, and accessible VAW responses that are survivor-centered and trauma-informed. Community-based first responders should still be reachable during quarantine. Healthcare providers must be trained for selective enquiry and first-line support of survivors.Referral pathways should be simplified to expedite care and assistance: upon identification of victims, a blanket referral to sexual and reproductive health providers, psychiatric aid, legal assistance, protective shelters, and livelihood assistance can be made. Establishing an active, centralized VAW surveillance system must take into consideration mobility under community restrictions. More accessible communication channels, like social media, must be made available and maximized. Marginalized women should be included in surveillance and protected in legislation, and VAW survivors should be consulted to improve service delivery.Organizing women, educating them of their rights, promoting rights to pleasure and safety, and encouraging help-seeking behaviors while changing policies that increase vulnerability to VAW will foster women empowerment. Ensuring full implementation of the Magna Carta of WomenIKMV and MVPNA were in charge of literature search, data analysis, interpretation, and writing. IKMV, MVPNA, JPGR, MABE, SLSG, MAJV, GRL, EDP, and KSTAR all worked to revise and review the manuscript.We declare no conflicts of interest."}
+{"text": "Increased knowledge suggests that disturbed gut microbiota, termed dysbiosis, might promote the development of irritable bowel syndrome (IBS) symptoms. Accordingly, gut microbiota manipulation has evolved in the last decade as a novel treatment strategy in order to improve IBS symptoms. In using different approaches, dietary management stands first in line, including dietary fiber supplements, prebiotics, and probiotics that are shown to change the composition of gut microbiota, fecal short-chain fatty acids and enteroendocrine cells densities and improve IBS symptoms. However, the exact mixture of beneficial bacteria for each individual remains to be identified. Prescribing nonabsorbable antibiotics still needs confirmation, although using rifaximin has been approved for diarrhea-predominant IBS. Fecal microbiota transplantation (FMT) has recently gained a lot of attention, and five out of seven placebo-controlled trials investigating FMT in IBS obtain promising results regarding symptom reduction and gut microbiota manipulation. However, more data, including larger cohorts and studying long-term effects, are needed before FMT can be regarded as a treatment for IBS in clinical practice. Irritable bowel syndrome (IBS) has become the most common gastrointestinal disease for referral to the gastroenterologists due to the patients\u2019 complaints of abdominal pain, bloating and mixed bowel movements of diarrhea and/or constipation, which can range from mild to severe ,2. IBS cAccording to a systemic review and meta-analysis , the gloThe cause of IBS is not yet known; however, multiple factors play an important role in the pathogenesis of IBS, such as disturbed gut microbiota (dysbiosis) , alteredBoth pharmacological and non-pharmacological treatments have been used to reduce IBS symptoms . PharmacIn the past decade, research has focused on dietary management and the usage of probiotics, antibiotics and FMT to treat IBS and the current review is an attempt to summarize the effect of these treatment methods on manipulating the gut microbiota.Lactobacillus. Delivery using cesarean section results in colonization by skin bacteria or hospital-acquired bacteria, for example, Staphylococcus and Acinetobacter [Bacteroides, Firmicutes, Actinobacteria and Proteobacteria [Clostridium difficile after using broad-spectrum antibiotics, proton pump inhibitor and immunosuppression [Bacteroidetes and Clostridia [Firmicutes to Bacteroides ratio as well as increased Clostridia and Clostridiales, which has been confirmed by a systematic review including 16 articles and involving 777 IBS patients and 461 healthy controls [Bifidobacteria and Faecalibacterum  and increased levels of Lactobacilli and Bacteroides [Streptococci and Ruminococcus species when compared to healthy controls [Clostridium thermosuccinogenes phylotype [The development of healthy gut microbiota essentially begins with its colonization at birth during vaginal delivery with vaginal microbes such as tobacter ,31, thattobacter . The guttobacter  and becobacteria . A healtbacteria . Some ofbacteria . Dysbiosbacteria ,38 and cbacteria . A typicpression . Anotherostridia . Decreasostridia  and incrcontrols . Howeverteroides , and othcontrols ,45,46. Phylotype , whereashylotype .The first-line treatment for IBS has concentrated on changing the patient\u2019s dietary habits . DietaryBifidobacterium, Clostridium and Faecalibacterium prausnitzii in feces and increase the richness of Actinobacteria, Firmicutes and Clostridiales [Phascolarctobacterium are more abundant in responders, and Firmicutes (Bacilli and Clostridia), Streptococcus, Dorea, Coprobacillus and Ruminococcus gnavus are more abundant in non-responders [Streptococcus thermophilus, Bifidobacterium breve, B. longum, B. infantis, Lactobacillus acidophilus, L. plantarum, L. paracasei, L. delbrueckii subsp. bulgaricus, to the low FODMAPs diet restores levels of Bifidobacterium species [Several studies showed that using a low FODMAPs diet can reduce the abundance of several bacteria such as ridiales ,53,54, bridiales . Howeverridiales . The sturidiales . The ressponders . However species .Bifidobacterium due to their prebiotic activity, thus having a beneficial effect on the colon. Moreover, fermenting the dietary fibers by the colonic bacteria leads to the production of fecal short-chain fatty acids (propionate and butyrate) that reflect the activity of the gut microbiota [Dietary fibers play an important role as stool bulking agents as they cause water retention and may increase transit time . They arcrobiota ,58,59,60In studies performed by our group, the aforementioned dietary modifications, using low FODMAPs and changing the dietary fiber intake, also showed significant changes in the densities of the enteroendocrine cells . These cBifidobacterium and Lactobacillus, and have an anti-inflammatory effect that deters harmful pathogens in the bowels, which may contribute to the improvement of the global symptoms of IBS [Bifidobacterium and Lactobacillus) and yeast, which are friendly to the gut and confer health benefits to the host when given in adequate amounts, usually in tablet forms or consumed in yogurt [Bifidobacterium longum, B. bifidum, B. lactis, Lactobacillus acidophilus, L. rhamnosus and Streptococcus thermophilus, known as LacClean Gold [Lactobacillus acidophilus, L. plantarum, L. rhamnosus, Bifidobacterium breve, B. lactis, B. longum and Streptococcus thermophilus [Prebiotics, such as trans-galactooligosaccharide, are fermentable poorly-absorbable food elements that provide essential nutrients to enhance the growth of beneficial bacteria, such as s of IBS ,68. Probn yogurt . Probiotn yogurt , normalin yogurt , Figure n yogurt . When itean Gold ,73 or thmophilus , are mormophilus ,75.On the other hand, the use of nonabsorbable antibiotics, such as rifixamin, has been investigated in several double-blinded and placebo-controlled randomized controlled trials ,76 and hC. difficile infection [Fecal microbiota transplantation (FMT) has recently become popular as a novel method for modulating gut microbiota in gastrointestinal disorders such as inflammatory bowel syndrome, IBS and recurrent nfection ,81,82,83nfection . During nfection . Before nfection . It is anfection . It is nnfection . After pnfection . Table 3A recent meta-analysis, including seven placebo-controlled randomized controlled studies, has investigated the effect of this novel method involving 470 patients with IBS . Five ouEubacterium halli, Eubacterium rectale, Megasphera elsdenii, Faecalibacterium prausnitzii [Alistipes spp. [Eubacterium biforme and Lactobacillus spp. [Bacteroides spp. was decreased in responders following FMT [Lactobacillus spp. was negatively correlated with the clinical outcome of IBS-symptom severity score [Alistipes spp. were most likely to not respond to FMT [In several studies, butyrate-producing bacteria in fecal samples of the recipient IBS patients were not lower than that of the donors, for example, usnitzii , Alistippes spp. ,91, Eubad to FMT ,95 and td to FMT ,96, whicd to FMT ,97 or mid to FMT ,94, but d to FMT .Ruminococcus gnavus, Actinobacteria and Bifidobacteria and the fecal short-chain fatty acids were significantly different between IBS patients and their donors, which became insignificantly different starting at 3 weeks after FMT and lasting up to 6 months following FMT [In several open-labeled studies performed by our group, we investigated the effect of FMT from the healthy relatives of the patients on IBS symptoms, gut microbiota, short-chain fatty acids, stem cells and enteroendocrine cells in diarrhea-predominant IBS patients ,99,100. wing FMT . Howeverwing FMT ,80,89,91wing FMT ,80, whicwing FMT ,99,100. There is strong evidence that dysbiosis plays an important role in the pathophysiology of IBS. There are different non-pharmacological methods that can improve the symptoms of IBS, which affect the gut microenvironment. Manipulating the gut microenvironment not only changes the composition of gut microbiota but also affects the other components of the gut microenvironment, namely short-chain fatty acids that represent the gut microbiota function and the enteroendocrine cells densities with a total impact on the symptoms of IBS. More studies with larger cohorts and for longer terms are required to investigate this issue."}
+{"text": "Drought is one of the biggest concerns in agriculture due to the projected reduction of global freshwater supply with a concurrent increase in global food demand. Roots can significantly contribute to improving drought adaptation and productivity. Plants increase water uptake by adjusting root architecture and cooperating with symbiotic soil microbes. Thus, emphasis has been given to root architectural responses and root\u2013microbe relationships in drought-resilient crop development. However, root responses to drought adaptation are continuous and complex processes and involve additional root traits and interactions among themselves. This review comprehensively compiles and discusses several of these root traits such as structural, physiological, molecular, hydraulic, anatomical, and plasticity, which are important to consider together, with architectural changes, when developing drought resilient crop varieties. In addition, it describes the significance of root contribution in improving soil structure and water holding capacity and its implication on long-term resilience to drought. In addition, various drought adaptive root ideotypes of monocot and dicot crops are compared and proposed for given agroclimatic conditions. Overall, this review provides a broader perspective of understanding root structural, physiological, and molecular regulators, and describes the considerations for simultaneously integrating multiple traits for drought tolerance and crop improvement, under specific growing environments. In response to drought, roots adjust their traits, improving plant adaptation, survival, and yield. Among these traits, root system architecture (RSA) is essential in increasing water uptake ,2, thereEXO70A3 regulates the auxin pathway by acting on the distribution of the PIN4 (auxin efflux carrier), resulting in the regulation of gravitropic growth (rooting depth) in RSA [To anchor and forage through the soil for water and nutrient uptake, roots dynamically modify their spatial distribution by changing their length, depth, number, angle, diameter, density, and biomass\u2014this spatial distribution and shape is referred as root system architecture (RSA) ,13. The ) in RSA . Whereas) in RSA .2+ signaling, affecting shoot activities, such as stomatal closure to conserve water [Trifolium repens), the genotype with increased root weight in proportion to total plant weight had improved growth, survival, and seed yield during drought [During drought, root and shoot crosstalk and influence each other\u2019s growth. A plant\u2019s ability to sense drought and its intensity depends on soil moisture, temperature, radiation, and other environmental factors . When rove water . The plave water ,26, affeve water . Investive water . In whit drought . Chen et drought  reportedRoots adapt their structure in response to drought to increase penetration, distribution, and contact with the soil for improved water and nutrient uptake ,15. ThesRoot drought-responsive structural traits are not static but fluctuate readily in conjunction with the environment, management practice, soil microbes, and genotype. Moreover, different root traits interact, sometimes synergistically or antagonistically, affecting drought adaptation. Thus, careful consideration is needed when planning drought-resistant crops based on structural traits only. However, crop-specific drought-responsive structural traits  are easySimilar to architectural traits, roots also adapt their anatomical characteristics in response to drought. Roots increase penetration in soil, reduce metabolic cost, regulate hydraulic conductivity, and facilitate microbial symbiosis to increase resource acquisition ,31,32,332 assimilation, and greater shoot biomass and grain yield. Colombi et al. [Plants invest photosynthates in establishing root systems for exploring water and nutrients needed for metabolic processes. During drought, the expenditure of photosynthates is high, firstly to invest more in root growth to increase water uptake, and secondly to increase respiration to maintain roots in drying soil, thus, compromising plant productivity ,35. Anati et al.  reportedi et al.   hyphae. The AM colonize in root cortical cells and extend their hyphae into the soil, sometimes expanding soil volume exploration at least 15 cm beyond the root surface . The AM Olea eurpaea) increased root conductivity during drought stress, allowing deep rooting and extended water acquisition [Root anatomical traits have a substantial influence on water uptake. Through concentric layers of root cells, water first enters from the soil to the root stele, then into the xylem, and finally into the shoot . Transpouisition .Phenotyping root anatomical traits is still low throughout, therefore, less research has focused on drought adaptive root anatomical traits. Further research in this area will improve phenotypic efficiency, accelerate the discovery of additional anatomical traits that assist directly in drought adaptation or indirectly through the facilitation of AM colonization, and ultimately contribute to developing drought-resilient crops.Root water permeability, known as root hydraulic conductivity, plays a crucial role in water uptake from soil ,39,54,55XDN1 influences root hydraulic conductivity by negatively regulating xylem differentiation  to influence xylem formation, as the presence of the bacteria enhance the expression of XND1, resulting in the reduction of root hydraulic conductivity. XND1, on the other hand, restricts bacterial growth and thus its pathogenicity [Malus domestica), MdMYB46 was reported to regulate root xylem vessel formation, thus root hydraulic conductivity and tolerance to drought [Transcription factor ntiation . Loss ofgenicity ,57. In a drought   also control root hydraulic conductivity by facilitating water diffusion across cell membranes, thus regulating radial water transport  Figure . Root hyRoots form a thicker suberized endodermis in response to drought . Calvo-PMost research has been focused on RSA, its adaptive response and role of individual RSA elements and the hormonal regulation of those elements in response to drought. However, Vadez  gave exaPhaseolus vulgaris), where shallow roots with low axial conductance metaxylem improved water status by reducing water uptake [Plants respond to various environmental conditions and stresses in the field with multiple root traits simultaneously, dynamically, and through the interaction of several traits . These tr uptake . This inr uptake . Howeverr uptake , and roor uptake . Sometimr uptake , but thir uptake ,79,80,81DRO1 (DEEPER ROOTING 1) gene changes rooting depth by changing root angle and increasing gravitropism, thus increasing yield [EXOCYST70A3 gene also alters root gravitropic responses, resulting in greater rooting depth, by acting on PIN4 protein distribution, influencing auxin transport [LBD/ASL genes are responsible for lateral root formation with AUXIN RESPONSE FACTORs, ARF7 and ARF19, directly regulating these genes [ARF7, inducing differential expression of LBD16 in the lateral root, with ARF7 expression itself regulated by the small ubiquitin-like modifier (SUMO) proteins. Arabidopsis plants lacking the SUMO protein had defective hydropatterning similar to arf7 mutants [TaLBD16-D [Oryza sativa L.), auxin transporter, OsAUX1 controls lateral root initiation [The adaptive abilities of roots to diverse environments, known as root plasticity, are crucial along with RSA for breeding climate resilience crops . In respng yield ,82,83. Transport . During ransport . Conversransport . Plasticse genes ,86. Orosse genes  found ro mutants ,87. In waLBD16-D , while iitiation   also plays a key role in drought adaptation. In response to heterogeneous low water potentials, root tips overcome gravity-driven growth and increase branching towards higher water regions, i.e., hydropatterning . When emPlants release exudates and root litter into the soil, which microbes feed on and decompose, enhancing nutrient availability in the soil and promoting root growth. Through this symbiotic relationship, root exudates and root-associated microbes can improve plant resilience and performance under drought ,94. Out Bacillus subtilis known to aid plant drought resistance [Plants change their exudate composition during drought, impacting the plant itself, neighboring plants, soil properties, and organisms . Exudatesistance . Naylor sistance  found disistance ,108, as Citrus limon L.) [PIP gene that regulates plasma-membrane proteins (PIPs). The downregulation of PIPs reduces water loss during drought [Phaseolus vulgaris was strongly correlated with the regulation of PIP2 protein and reduced hydraulic conductivity during drought. In Ulmus americana, AM increased apoplastic water transport and root hydraulic conductivity [Poncirus trifoliata L.) [Avascular mycorrhiza can increase drought resistance and reduce drought susceptibility  by improimon L.)  and maizimon L.) . Symbios drought . Aroca e drought  found AMuctivity . During uctivity . Howeveructivity . AM can uctivity , such asiata L.) . In addiiata L.) , which aPseudomonas chlororaphis O6, produced volatile metabolites, 2R, 3R-butanediol, mediating stomatal closure [Medicago truncatula had an enhanced concentration of osmolytes, resulting in a delay in drought-induced leaf senescence. Under stress, ethylene regulates defense and growth responses, reducing root and shoot growth [Vicia faba) [Pisum sativum L.) and tomato (Solanum lycopersicum L.) [Rhizobacteria release phytohormone, for example, IAA, which promotes lateral root formation . Rhizoba closure . Water d closure ,124. In  closure . Staudin closure  found Rht growth , with 1-t growth . Rhizobat growth . During ia faba)  pea (Pisicum L.) ,130. Rhiicum L.)  (Figure Although some advances have been made in understanding the role of exudates and microbe symbiosis in plant adaptation to drought under a controlled environment, the study of root exudation in a natural setting is in its infancy . TherefoRoot and soil interchangeably alter each other, heterogeneous soil can change RSA, similarly root change, and improve soil . Soil stRoots change soil structure through compaction , dispersThe root rhizosphere influences spatial heterogeneities and changes the hydrophilic nature of soil ,137,145,Due to current cultivation practices, soil C is reduced in agricultural land, therefore affecting the water storage capacity. Currently, the global C debt in agricultural land for the top two meters of soil is 133 petagram . DroughtProposing an ideotype for drought defines idealized approaches for a breeding program to work towards. A universal ideotype for drought in a broader range of crops might not be applicable for a specific crop because roots of each crop interact and respond differently in response to soil type  and growWasson et al.  proposedContrasting root architectures\u2014deep  versus sThe success of a drought-resistant ideotype for a cropping system will depend on genotype, environment, and management practices. Formulating a root ideotype that performs well in broader and varied areas will require incorporating multiple drought response traits. Moreover, developing plants based on a particular root ideotype for a large area will reduce the root diversity and might lack the necessary adaptive ability to cope with climate change. Thus, a root ideotype targeted for a small and specific area might be efficient and facilitate root diversity. When formulating ideotypes, we should also consider incorporating sustainability and soil regeneration along with maximizing productivity. Incorporating root soil-building attributes in the drought ideotype offers a scope of soil regeneration and long-term resilience to drought.XDN1, MdMYB46, and aquaporins (Roots are the other half of plants that can significantly contribute to sustain productivity under drought conditions. A range of root attributes, namely RSA, root structural, anatomical, and hydraulic traits are important for drought adaptation. Equally, interactions among these traits, their plasticity and root soil building attributes also affect the overall adaption process. Research has largely been focused on root architectural responses when developing drought-resilient plants. However, root structural, physiological, and cellular regulators, and their interactions with microbes, are also important. Several root structural traits, such as taproot diameter and length, root hair number, density and length, and root angle are phenotyping-friendly, high-throughput, and relatively easy to deploy in plant breeding. Whereas, root anatomical trait screening is still low throughput, requiring further research to find traits that improve root penetration in dry soil, reduce metabolic cost, improve water uptake, and facilitate AM colonization. Consideration also needs to be taken to incorporate root hydraulics and associated molecular regulators such as uaporins  to ensuruaporins  to harneImprovements in root exudate collection and rhizosphere-microbe phenotyping methods will increase understanding of plant\u2013microbes responses during drought. Improving soil C can significantly augment water absorption and storage and offers potential for a long-term solution to continue increasing agricultural production under a limited water supply. Overall, careful selection and incorporation of root architectural, structural, anatomical, hydraulic, molecular, and soil building traits, and consideration of root trait plasticity and interaction are integral in developing desirable ideotypes to sustain agricultural production in drought-prone areas."}
+{"text": "Chitosan displays a dual function, acting as both an active ingredient and/or carrier for pharmaceutical bioactive molecules and metal ions. Its hydroxyl- and amino-reactive groups and acetylation degree can be used to adjust this biopolymer\u2019s physicochemical and pharmacological properties in different forms, including scaffolds, nanoparticles, fibers, sponges, films, and hydrogels, among others. In terms of pharmacological purposes, chitosan association with different polymers and the immobilization or entrapment of bioactive agents are effective strategies to achieve desired biological responses. Chitosan biocompatibility, water entrapment within nanofibrils, antioxidant character, and antimicrobial and anti-inflammatory properties, whether enhanced by other active components or not, ensure skin moisturization, as well as protection against bacteria colonization and oxidative imbalance. Chitosan-based nanomaterials can maintain or reconstruct skin architecture through topical or systemic delivery of hydrophilic or hydrophobic pharmaceuticals at controlled rates to treat skin affections, such as acne, inflammatory manifestations, wounds, or even tumorigenesis, by coating chemotherapy drugs. Herein, chitosan obtention, physicochemical characteristics, chemical modifications, and interactions with bioactive agents are presented and discussed. Molecular mechanisms involved in chitosan skin protection and recovery are highlighted by overlapping the events orchestrated by the signaling molecules secreted by different cell types to reconstitute healthy skin tissue structures and components. Natural polymers exist in many forms present in wood, leaves, fruits, seeds, insects, algae, crustaceans, and animal skins and have been employed in many industrial sectors, such as clothing, energy production, construction, furniture, paper, wastewater treatment, and bioremediation for thousands of years. More recently, these polymers have also been used in sophisticated applications, such as in food and biodegradable food packaging, as well as the production of fine chemicals, biomedical products, and pharmaceutical formulations. Natural polymers have also been used for human tissue reconstruction to recover, maintain, or improve organ and tissue functions. Each polymer\u2019s structure and chemical characteristics dictate the behavior of composites applied to living organisms ,2,3,4.Edible polysaccharides can provide cells with energy-maintaining cellular functions, and structural polysaccharides, such as cellulose and chitin, are enrolled in the structural maintenance of plant cell walls or as part of arthropod, mollusk, and insect exoskeletons ,6,7.10 tons of biomass every year, of which humans use only 3.5% as food and in chemical transformations ..StaphyloCandida spp., with fungal growth inactivation due to cytoplasmic degeneration and membrane and cell wall rupture. Ag-nanochitosans in combination with fluconazole and amphotericin B demonstrated an additive effect. Low nanocomposite cytotoxicity against mammalian cells has been reported in Galleria mellonella larvae, suggesting potential in vivo use. When tested as a topical treatment against murine cutaneous candidiasis, nanocomposites were found to reduce fungal skin loads in a dose-response behavior and favored tissue repair . It. It60]. Chitin derivatives exhibiting controlled molecular weight and/or deacetylation degree variations have been reported to display antitumorigenic activity against several cancer cell lines, including human myeloid leukemia HL-60 cells, human melanoma cells , HeLa cells, human hepatoma, and human monocyte leukemia cells ,73,74,752 groups can be used for many different applications compared to isolated chitosan fibers, mainly concerning polymer strength. This material can be coated with other polymers, forming surface films bonded by hydrogen bonds. With the aim of increasing the resistance of crosslinked polymers, Sun, et al. .,86.85,86Collagens, such as chitosan, are also abundant biopolymers of considerable importance in organismal structures. Although they do not exist together as mixtures in nature, cellular structures obtained from chitosan or collagen are similar in composition and mechanical behavior to many human tissues. Chitosan and collagen exhibit structural properties capable of interacting with each other through the interaction of hydrogen bonds, producing artificial mixtures with special rheological and mechanical features that are suitable for use as support materials for extracellular matrix regeneration in mammals. These supramolecular chitosan and collagen structures can be used in tissue recomposition, including skin recomposition ,89. ReceChitosan and collagen composites can also be modified with the addition of a third component comprising organic or metallic compounds, such as silver, resulting in novel properties for these composites . Tannic Additionally, Lin et al.  synthesiIn cosmetic science, both chitin and chitosan have been investigated as excipients and active biological agents, mainly due to certain specific properties, such as lack of toxicity, biocompatibility, and biodegradability. Chitin nanofibrils, as the purest crystal form of chitin, have positive surface charges and can electrostatically interact with electronegative bioactive compounds, generating innovative antiaging cosmetics and novel formulations to treat sensitive skin . AdditioNanomaterial-based cosmetics, cosmeceuticals, and pharmaceuticals designed for skin exhibit many advantages compared to microscale cosmetics, as they are long-lasting and display relatively higher stability. The high surface area of nanomaterials allows for more efficient ingredient transport across the skin, providing new shade and color elements, which are very important in lipsticks and nail polish, as well as transparency, a desirable feature for sunscreens . BiopolyChitin nanofibers can form an amalgam with active pharmaceutical and cosmeceutical complexes, improving their bioactivities ,100,101.In addition, multipurpose nanochitosans can be obtained for skin treatment, as these compounds can be formulated as gels, fibers, or porous matrices that can be used for skin and mucous membrane hydration for antiaging or antiacne cosmetic therapy  94]..94].Regarding skin hydration, nanochitosans in emulsions can generate a hygroscopic molecular film that delays water evaporation and contributes to skin hydration ,107.Chitin-derived nanofibrils and nanocrystals were found to improve granular epithelial layers and increase granular density in a three-dimensional skin culture model and Franz cells, making them excellent candidates for nanocosmetics and personal care products . The proN-acetylglucosamine molecules are involved in diverse cellular metabolic pathways and are critical for health of the body, particularly the skin. In turn, glucosamine can be further catabolized to supply the systemic cellular metabolism with its precursors, glucose and glutamic acid, whereas locally, in the extracellular dermal matrix, it can limit water loss by retaining water molecules. Glycosaminoglycans synthesized from glucosamine and N-acetylglucosamine are involved in dermis hydration maintenance; on the other hand, they represent the monosaccharide unit responsible for the structural stability of the extracellular dermal matrix. N-acetylglucosamine can reduce skin hyperpigmentation and therefore reduce the appearance of blemishes by inhibiting melanin production, which is effective in reducing wrinkles and acne, as well as increasing skin exfoliation and skin hydration [N-acetylglucosamine controls collagen synthesis during wound healing, promoting granulation tissue and skin lesion repair [When nanochitosans encounter the stratum corneum, they are hydrolyzed by skin enzymes into smaller units, disaccharides, and tetrasaccharides, which can undergo the repolymerization process once they reach the inner epidermis and dermis layers. On the other hand, complete hydrolysis of nanochitosans results in the release of glucosamine, and its acetyl derivative ydration . Addition repair ,109.Concerning sunscreen development, nanochitosan in multifunctional emulsions can act as an active carriers and/or potentiator of antioxidant and immunomodulatory compounds, such as lutein, melatonin, and ectoin, to enhance the photoprotective effect against UV-induced damage. Nanoparticles combined with urocanic acid, a natural protective agent against UVB radiation, have been proven more effective than conventional products. Additionally, the protective effect of NCs against UV radiation can be attributed to their ability to reduce TGF-\u03b2 (transforming growth factor \u03b2) production, a multifunctional cytokine responsible for regulating the inflammatory response .Propionibacterium acnes, the bacteria associated with acne pathogenesis. These nanocopolymers inactivate P. acnes growth by inducing bacterial cell membrane disruption  induces a proinflammatory response, whereas larger sizes have been reported as inert [Nanochitosans are also used to produce biodegradable face masks, as they are non-toxic and compatible with human keratinocytes. It is important to emphasize that chitin exhibits a differentiated ability to modulate the inflammatory cascade, depending on \u2013NHas inert ,115.Biocompatibility, biodegradability, non-toxicity, and other physicochemical features make chitosan and its derivatives suitable for repairing injured skin due to their overall effects on skin architecture, as described previously ,128.Injured tissue can only recover with the completion of four sequential steps, which may overlap: (i) hemostasis, (ii) inflammation, (iii) migration and proliferation, and (iv) remodeling . This na2O2), damage-associated molecular patterns (DAMPs), lipid mediators, vasodilator agents, vascular permeability factor, and proteases. All of these mediators promote vasodilatation, enhancing vessel permeability, as well as promoting neutrophil recruitment. These cells are attracted to the wound site and, alongside M1 macrophages, participate in the first line of defense or innate immune response against microorganisms. In response to signaling molecules secreted during the innate immune response, T lymphocytes also migrate to the wound site, representing the second line of adaptive immune response defense to ensure efficient clearance and avoid infection with the aid of antigen-presenting cells, such as B lymphocytes and dendritic cells. Under healthy physiological conditions, inflammatory reactions are terminated, and the tissue regeneration process predominates, characterizing phases iii and iv. Following inflammation, M2 macrophages, epidermal cells, platelets, and subcutaneous adipose tissue secrete vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), transforming growth factor-\u03b2 (TGF-\u03b2), and angiopoietins, which stimulate endothelial cell proliferation and migration, forming new capillaries. Moreover, wound contraction is achieved by the deposition of collagen III to recover the extracellular matrix (ECM) synthesized by M2 macrophages and other fibroblasts, constituting a temporary granulation tissue. Furthermore, dermal fibroblasts respond to TNF-\u03b2 secreted by epidermal stem cells differentiating to myofibroblasts, which participate in wound contraction. Tissue regeneration proceeds with re-epithelization when unipotent stem cells in hair follicles undergo proliferation alongside resident stem cells from the epidermis, followed by differentiation and migration to reconstitute epidermis cell types, including keratinocytes belonging to spinal and granular layers and cornified cells from the upper-most layer, the stratum corneum. The epidermal growth factor family regulates this stage, including EGF, TGF-\u03b1, and FGF, affecting migrating and proliferating keratinocytes. In the last phase, when the wound is already closed, regenerated tissue undergoes maturation and remodeling, lasting for months or years. New blood vessels generated during previous neovascularization are remodeled to originate mature, non-leaky, and well-perfused vessels through the regression of selected branches and a pruning process. Granulation tissue is reorganized by the replacement of collagen III with collagen I, which is stronger and lasts longer, resulting in scar formation. Collagen III is degraded through the action of matrix metalloproteinases (MMPs), which can be released by proinflammatory macrophages and fibroblasts , delta-like homolog 1 (DLK1), and proliferating cell nuclear antigen (PCNA) in the mouse fibroblast cell line L929. Moreover, the chitosan/TiO2 composite membrane also inhibited Staphylococcus aureus growth, one of the most common causes of wound infection  against external and severe injuries.The use of natural bioactive compounds has increased in response to several restraints concerning environmental preservation, guaranteeing the safety of personal care products, cosmetics, cosmeceuticals, and their ingredients. However, equally importantly, these products must fulfill consumer expectations and feelings in a very competitive market with increasing pressure and growing awareness regarding the effect of the use of fossil-derived ingredients or those obtained from unsustainable raw materials. Personal care and cosmetic companies have become increasingly concerned about the ingredients used in the formulation of their products and interested in developing products from sustainable and ecological raw materials to create long-term value, preparing companies to compete in the global economy. The same is noted for cosmeceuticals, a novel class of very technologically sophisticated products categorized between cosmetics and pharmaceuticals containing bioactive compounds intended to maintain and enhance health and skin beauty. Furthermore, skin care ingredients should be devoid of genotoxic, carcinogenic, or reproductive risks, making them safe and effective. Chitosan is metabolized by humans and hydrolyzed by environmental enzymes into a linear polysaccharide that can be used as a carbohydrate source by living organisms, promoting nutrition and energy and acting as a signaling molecule.Chitosans are unique polymeric compounds obtained from seafood waste with broad applicability. Due to their physicochemical features, variable molecular weights, and degree of deacetylation, chitosan can assume several physical forms, such as films, sponges, hydrogels, fibers, and nanoparticles. Nanocapsules and nanofilms can self-assemble following ecofriendly treatments, such as sonication, without generating secondary products. The edible nature of chitosan also allows for its inclusion as an excipient in cosmeceuticals or pharmaceuticals designed for oral administrations to protect active principles during gastrointestinal tract digestion, intestinal absorption, and when in the bloodstream environment, improving the solubility of hydrophobic compounds and controlling their release.Despite the considerable potential of employing chitosan in its nanocounterpart form for systemic protein, as well as peptide or gene delivery, the need to develop preclinical and clinical trials has not accompanied technological development. On the other hand, the prospects for the non-parenteral application of nanochitosan and its composites in cosmetics, cosmeceuticals, and pharmaceuticals to protect, repair, and regenerate skin have developed faster, as, among novel composites, most are obtained from non-toxic compounds or natural biopolymers, and all of them are obtained from environmentally sustainable matrices. The biological effects of chitosan or nanochitosan, either intrinsic or acquired from binding or association with different composites, can affect the dermis and epidermis, avoiding blotting, inflammatory responses, and infection, re-establishing oxidative balance and allowing the skin to regenerate while also reducing scars."}
+{"text": "Despite the discovery and development of an array of antimicrobial agents, multidrug resistance poses a major threat to public health and progressively increases mortality. Recently, several studies have focused on developing promising solutions to overcome these problems. This has led to the development of effective alternative methods of controlling antibiotic-resistant pathogens. The use of antimicrobial agents in combination can produce synergistic effects if each drug invades a different target or signaling pathway with a different mechanism of action. Therefore, drug combinations can achieve a higher probability and selectivity of therapeutic responses than single drugs. In this systematic review, we discuss the combined effects of different antimicrobial agents, such as plant extracts, essential oils, and nanomaterials. Furthermore, we review their synergistic interactions and antimicrobial activities with the mechanism of action, toxicity, and future directions of different antimicrobial agents in combination. Upon combination at an optimum synergistic ratio, two or more drugs can have a significantly enhanced therapeutic effect at lower concentrations. Hence, using drug combinations could be a new, simple, and effective alternative to solve the problem of antibiotic resistance and reduce susceptibility. Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecium, and Enterococcus faecalis are the most common. Among Gram-negative strains, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii are the most common MDR species [Staphylococcus aureus causes pneumonia, bacteremia, soft tissue infections, and other fatal diseases [Acinetobacter spp. and Klebsiella spp. are the most commonly reported.The rapid emergence and spread of multidrug-resistant (MDR) bacteria has become a serious global public health threat . Long-te species . Howeverdiseases . SimilarRecent studies suggest that biofilm-associated infections account for more than 65% of all infections, and antibiotics lack effectiveness against biofilm-associated bacteria . PathogeMany plants have been used as sources of natural products to maintain good health, especially antimicrobial compounds . Plants Similarly, combining plant extracts or active phytochemicals with antibiotics improves their efficacy against resistant bacterial pathogens . SynergiAntimicrobial nanomaterials represent another strategic approach to fighting MDR bacteria in clinical practice. Metal and metal oxide-based nanoparticles (NPs) have been widely investigated over the last decade, owing to their favorable chemical, physical, magnetic, electrical, thermal, optical, and biological properties . ConsequAlthough different kinds of synthetic antimicrobial agents have been introduced to the market in many countries, natural medicine from plants might effectively treat certain diseases such as diarrhea, cold, labor pain, and dental diseases. Globally, approximately 60,000 plant species are used for medicinal purposes, of which approximately 28,000 are well-documented, and only 3000 are estimated to be traded internationally . As a reEnterobacter species and S. aureus and E. coli, respectively [Staphylococcus aureus, Pseudomonas aeruginosa, Vibrio cholerae, and Candida spp. [Mycobacterium tuberculosis. The combination of rifampicin and oleanolic acid has shown synergistic antibacterial effects against some pathogens [S. aureus and S. epidermidis [Terpenes are an extensive and diverse group of naturally occurring, highly enriched compounds of secondary plant metabolites. On the basis of the number of their isoprene structures or units, they are classified as monoterpenes, diterpenes, triterpenes, tetraterpenes, or sesquiterpenes. Terpenes are also called isoprenoids, and their derivatives that contain additional elements, such as oxygen, are usually termed terpenoids. Monoterpenes are the smallest terpenes, comprising two isoprene units. Monoterpenes contain volatile compounds found in EOs extracted from different flowers, fruits, and leaves and are commonly used in fragrances and aromatherapy. The antimicrobial properties of these compounds have been studied for two decades, and several studies have reported that thymol, carvacrol, eugenol, and menthol exhibit significant activity against many pathogens . Geranioectively ,30. Diteida spp. . Triterpathogens . Tetrateathogens . Sesquitdermidis .Phenols are the simplest bioactive phytochemicals. They are monomeric components of polyphenols and acids with a single substituted phenolic ring and are typically found in plant tissues such as melanin and lignin. The components catechol, orcinol, tarragon, pyrogallol, phloroglucinol, pyrocatechol, resorcinol, and thyme are effective against viruses, bacteria, and fungi . Both caPiper nigrum and Piper longum inhibited the growth of mutant S. aureus when co-administered with ciprofloxacin [Alkaloids are cyclic-nitrogen-containing organic compounds that have various chemical structures. More than 18,000 alkaloids have been discovered and studied phytochemically from different sources. Alkaloids are grouped into several classes, as natural, semi-synthetic, or synthetic, on the basis of their heterocyclic ring systems and biosynthetic precursors . Alkaloifloxacin . A list EOs are aromatic, lipophilic, and complex mixtures of volatile secondary metabolites that are mainly obtained from different parts of plants, such as leaves, herbs, flowers, buds, fruits, twigs, wood, bark, roots, and seeds . EOs areThe amount of the different components of EOs varies with the parts and species of plants, as they are chemically derived from compounds and their derivatives . The majThymus serrulatus and Thymus schimperi were shown to possess strong antibacterial activity against Lactobacillus and S. mutans, with higher contents of thymol and carvacrol compounds reported to be the cause of this inhibition [Eugenia caryophylata, such as the buds, leaves, and stems, with the main components being eugenol, \u03b2-caryophyllene, and eugenyl acetate. These EOs are effective against S. aureus, E. coli, B. subtilis, and S. typhimurium [Monilinia fructicola [A. hydrophila, A. caviae, A. dhakensis, C. freundii, P. mirabilis, and S. enterica showed the presence of the major compounds linalool and linalyl acetate [Candida spp., with thymol as the major compound [S. typhimurium and E. coli, with thymol as its major compound [EOs of hibition . Similarhimurium . Likewisucticola . Further acetate . In anotcompound . It has compound . Some ofE. faecalis, B. subtilis, S. epidermidis, multidrug-resistant S. aureus, and E. coli strains.With the emergence of bacterial resistance and biofilm-associated infections, clinical research is needed to develop novel, effective, long-term antibacterial and biofilm-preventative agents. Metals have been extensively studied among the most promising novel antimicrobial agents . Recentl2, NiO2, SiO2, and Fe3O4 are known to display various antimicrobial properties, which have been known and applied for decades [Metal NPs such as Ag, Au, Cu, Zn, Ti, Ga, Al, and Pt  and meta decades . In addi decades . Multime decades .Metallic biopolymer-based nanocomposite systems are well-known candidates as antimicrobial nanomaterials. In particular, cationic chitosan-based NPs bind to anionic cell membranes, resulting in alterations to the cell membrane, leakage of intracellular compounds, and eventually cell death . Antimic2+ ions and generating ROS, owing to their electrostatic interaction and internalization. In contrast, smaller ZnO NPs increased the interaction and abrasiveness of the bacterial cell wall [2+ ions and stimulating ROS production [2 NPs against E. coli and S. aureus [2 NPs adversely affect human cells and tissues, so their use remains limited. SiO2 NPs, especially mesoporous NPs, have attracted considerable attention because their properties, such as size, matrix, and surface functions, which can be tuned to improve their interaction with and penetration of biofilm-producing bacteria [AgNPs are considered the most common antimicrobial agents that can destroy a wide range of Gram-negative and Gram-positive bacteria. Ag ions combine with disulfide or sulfhydryl groups of enzymes, disrupt normal metabolic processes, and ultimately lead to cell death . The bacell wall . Cu and oduction . Various. aureus ,124; howbacteria .Compared to monometallic NPs, multimetallic NPs, such as bi-, tri-, and quadrametallic NPs, have gained great importance and interest due to their unique physical, chemical, electrical, optical, and catalytic properties and applications in different fields . MultimeCore\u2013shell quantum dots (CSQDs) are a new type of fluorescent antibacterial nanomaterial with unique physical and chemical properties. Owing to their high electron transfer, CSQDs produce a large number of free electrons and holes that accumulate ROS inside the cell, inhibiting their respiration and replication . CSQDs eAdditionally, the antibacterial properties of graphene involve both chemical and physical modes of action. The chemical action is associated with oxidative stress generated by charge transfer and ROS, while the physical action is induced by the direct contact of graphene with bacterial membranes . SimilarDendrimers are macromolecules with highly branched tree-like dendritic structures, narrow sizes, relatively large molecular masses, and well-defined globular structures . DendrimA synergistic effect is a process in which chemical substances or biological structures interact or combine to create an effect greater than the sum of the effects of the individual components. Synergy is the concept wherein the performance of two or more antimicrobial agents is combined and the effects of such mixtures are greater than those of the separate or individual components, enhancing solubility. In recent years, the synergistic combination of different antimicrobials and plant extracts has been considered a unique strategy to increase the spectrum of antimicrobial activity of these substances and prevent the development of resistant strains . Plant eS. aureus. Their results showed the strongest synergistic effect compared with the effects observed with individual extracts [Bulbine frutescens and Vernonia lasiopus plant extracts showed improved antimicrobial activity against E. coli [S. aureus using a combination of Ocimum gratissimum and Ficus exasperate, and Bryophyllum pinnatum and Ocimum gratissimum against E. coli [S. aureus (MRSA), and extended-spectrum \u03b2-lactamase (ESBL)-producing Escherichia coli [R. abyssinicus and D. penninervium EOs showed strong synergistic effects against MRSA and P. aeruginosa [Combinations of antimicrobial agents, such as EOs/EOs, plant extract/plant extract, and NPs/NPs, already have confirmed antimicrobial activities . Ncube eextracts . Similar E. coli . Obuekwe E. coli . Recentlhia coli . A mixturuginosa .C. coli and C. jejuni have been reported [S. aureus, L. monocytogenes, S. typhimurium, and P. aeruginosa [E. coli and B. subtilis increased up to eightfold when compared to the individual metals [The synergistic antibacterial activities of cumin, cardamom, and dill weed EOs against reported . In a prruginosa . Garza-Cl metals . Similarl metals . \u03b2-Lactal metals .Currently, there are 32 antibacterial agents in clinical development phases 1\u20133 targeting WHO priority pathogens, 12 of which have activity against Gram-negative pathogens. Since 2018, several new products have entered phase 1 trials, and two new recombinant topoisomerase inhibitors, zoliflodacin and gepotidacin, have moved from phase 2 to phase 3 trials. Similarly, lefamulin and relebactum moved from phase 3 trials to FDA approval, and omadacycline and eravacycline have moved from NDA submission to gaining FDA approval. An additional product of \u03b2-lactam (cefideocol) is more stable against a variety of \u03b2-lactamases and has activity against all three critical priority pathogens . \u03b2-LactaThe antimicrobial mechanism of plant extracts is more strongly correlated with the levels of their constituent phenolic compounds, especially flavonoids and their derivatives. The interaction of polyphenols with lipid bilayers can trigger and disrupt plasma membrane function, change its permeability, and form small pores. These could lead to the leakage of cell components, altering the surface electrical charge potential and bacterial polarity, modifying membrane fluidity, delocalizing membrane lipids and proteins, as well as other phenomena responsible for antibacterial activity. These alterations can cause severe damage to the bacteria by partitioning their membrane and cell wall, interrupting DNA and RNA synthesis and function, disrupting normal cell communication, and preventing biofilm formation . Some stThe antibacterial mechanism of EOs does not comprise a single action; however, various biochemical and structural mechanisms are simultaneously engaged at multiple sites in the bacterial cell membrane and cytoplasm. The primary antimicrobial effects of EOs are correlated with an increase in membrane permeability and plasma membrane disruption. The bioactive components found in EOs, such as thymol, eugenol, and carvacrol, might attach to the cell surface and penetrate the target region, especially the phospholipid bilayer of the cell membrane . It has The bactericidal mechanism of nanomaterials mainly depends on the type of NPs used, such as metals, metal oxides, and other nanocomposites. NPs bind to the bacterial cell wall, form membrane-penetrating pores, and release metal ions due to deposition. The adhesion of nanomaterials and microbial cells can be achieved through electrostatic attractions, hydrophobic interactions, Van der Waals forces, and receptor\u2013ligand interactions, leading to cell wall destruction . FurtherAlthough the pharmaceutical industry has introduced many new antibiotics, the increasing prevalence of serious clinical complications related to MDR pathogens is a great challenge for researchers, clinicians, and the pharmacological industries. Therefore, searching for the most promising novel antibacterial agents with alternative strategies to combat bacterial infections is an ideal solution to treat infections that threaten human health. The ultimate goal is to offer appropriate and effective antimicrobial drugs to infected patients. The use of combination therapies is an effective way to improve the treatment of many health conditions, prevent the development of MDR pathogens, and reduce the treatment duration. Combination therapies can target and interact in multiple pathways and exhibit greater therapeutic efficacy than single antimicrobial-agent-based therapies. Moreover, they have recently been regarded as promising, cost-effective, and potentially able to mitigate side effects to the body with lower drug concentrations. There is plenty of evidence to support the effectiveness of medicinal plants in the treatment of infectious diseases. However, very few studies have reported the synergistic effects of plant extracts and phytochemical combinations of herbal remedies.Combinations of different plant species or mixtures of different phytochemicals have been shown to exert potential antimicrobial activity against several human pathogens with diverse mechanisms of action. The curative effects of plant extract combinations showed both intrinsic and antibiotic-resistance-modifying activities. Some plant extracts are not effective as antibiotic agents alone; however, when combined with other antibacterial plant extracts, their bioavailability and antibacterial activity are enhanced. Similarly, there is much evidence suggesting the antimicrobial effects of individual EOs against different pathogens in vitro, but very few studies have reported the effects of EO combinations. Compared to a single EO or its chemical constituents, combining more than two EOs can increase and improve their antimicrobial activities due to an increased diversity of components and multiple sites of action. Furthermore, many studies have reported the potential antimicrobial activities of different nanomaterials against MDR pathogens. However, only a small percentage of studies have discussed the synergistic effects of multimetallic NPs, such as bi-, tri-, and quadrametallic and metal oxide nanocomposites. The synergistic effects of these multimetallic NPs have attracted considerable attention, owing to their diverse and tunable physicochemical properties and favorable catalytic properties compared with monometallic NPs.The present review describes the synergistic effects of plant extracts/plant extracts, EOs/EOs, and nanomaterials/nanomaterials as efficient alternative strategies for pathogen inactivation or infectious diseases. However, further research is needed to assess the synergistic effects of combinations of plant extracts/EOs, plant extracts/nanomaterials, and nanomaterials/EOs to achieve better antimicrobial results. In addition, more effort is required to investigate the synergistic effects of combinations of plant extracts/EOs/nanomaterials. Consequently, \u03b2-lactam/\u03b2-lactamase inhibitor combinations are more effective on the different bacterial species. Combinations comprising three different antimicrobial agents might have enhanced synergistic antimicrobial activity compared to the effects of a combination of only two antimicrobial agents. Furthermore, the concentrations of the plant extracts, EOs, nanomaterial types, proper dosage, and choice of materials are essential to maximizing their therapeutic benefit. It is also important to consider environmental issues, health and safety concerns, risk assessments, potential toxicity, and hazards before considering them novel antimicrobial agents. These new, modern, and creative therapeutic strategies may exert a critical synergistic effect and serve as alternatives to conventional antibiotics for controlling the spread of pathogens. Finally, we believe this review provides necessary information about the combination of different antimicrobial agents to produce synergistic effects for the control and treatment of a wide range of pathogenic infections and may also play an essential role in many medical applications."}
+{"text": "Breast and prostate cancers are serious public health issues that create considerable burden to both people and healthcare systems worldwide. Cancer is a heterogeneous disease influenced by numerous components, and its diverse intricate pathology challenges disease prevention, diagnosis, treatment, and survival. Although recent statistics suggest improvements in cancer diagnosis and treatment, many challenges remain before cancers are curable. This review presents relevant summarized information related to breast and prostate cancer.Cancer is a global issue, and it is expected to have a major impact on our continuing global health crisis. As populations age, we see an increased incidence in cancer rates, but considerable variation is observed in survival rates across different geographical regions and cancer types. Both breast and prostate cancer are leading causes of morbidity and mortality worldwide. Although cancer statistics indicate improvements in some areas of breast and prostate cancer prevention, diagnosis, and treatment, such statistics clearly convey the need for improvements in our understanding of the disease, risk factors, and interventions to improve life span and quality of life for all patients, and hopefully to effect a cure for people living in developed and developing countries. This concise review compiles the current information on statistics, pathophysiology, risk factors, and treatments associated with breast and prostate cancer. The worldwide burden of cancer incidence and mortality is considerable and is projected to increase despite the progress made in cancer diagnosis, treatment, and management. Of the well over 200 different types of human cancers, breast cancer (BC) and prostate cancer (PC) are among the top cancers owing to their unique features encompassing their origin, acquired mutations, gene expression patterns, modified transcriptional and signaling networks, metabolic activities, the impact of their microenvironments, and host immune responses and overall health  ,5,6,7,8.World Health Organization (WHO) estimates indicate that cancer is among the top two causes of death in 112 of 183 countries ,10. In aGLOBOCAN 2020 reported deaths for female-BC and PC as 6.9% and 3.8% respectively . AccountBC is a common form of malignancy among women in the developing and developed world ,16,17. IPC is the second most frequent and fifth major cause of cancer-associated death among men in 2020 . PC attrBC and PC consist of heterogeneous subtypes classified according to various clinical and pathological features ,33. The In general, the breast is composed of adipose tissue, glandular tissue, and fibrous stromal  tissue in the breast parenchyma, the superficial fascia, deep fascia, the nipple\u2013areola complex, and skin ,44,45 F. It is sBreast tumors can be cancerous  or non-cancerous  ,45. Non-Weighing ~20 g and ~3 cm long, the human prostate consists of glandular tissue and requires testosterone for optimal function ,66. The Molecular taxonomy is continually changing and progressing . The besUsing data from gene expression profiling, four intrinsic BC subtypes with clinical implications were initially identified by Perou and colleagues . SubsequHighly differentiated luminal secretory cells and a small fraction of basal cells can be found in the prostate gland epithelium and, therefore, adenocarcinomas may arise from both luminal and basal tumor progenitor cells . AlthougPC is considered a highly heterogeneous disease because some tumors cannot be categorized purely based on a molecular subtype ,95,99. ADisease burden is the salient determinant of survival . DetermiThe development of BC is associated with several risk factors.  These inAn initial diagnosis of BC typically follows from a physical exam and history, clinical breast exam, mammogram, ultrasound, magnetic resonance imaging, blood chemistry, and biopsy ,61,112. Diagnosis, prognosis, and treatment are complicated by the tremendous clinical and genetic heterogeneity of BC . AneuploEpithelial cells, smooth muscle cells, autonomic nerve fibers and associated ganglia, endothelial cells, immune cells, and fibroblasts can shape the biology and clinical behavior of the prostate and associated malignancies . Based oSeveral standard treatment options are currently available for the treatment of BC including surgery, radiation therapy, chemotherapy , hormoneEarly PC is typically asymptomatic but may show similar symptoms as BPH, such as nocturia, hematuria, dysuria, and problems with urination . The devOther factors with association to cancer risk include diet , smoking, vasectomy, inflammation, sexually transmitted diseases, infections, chemical, and ionizing radiation exposures, alcohol abuse (>15 g ethanol/day), lower ejaculatory frequency, physical inactivity, and obesity ,143,145.Depending upon the PC case, treatment option(s) may include active surveillance, surgery, radiation therapy, chemotherapy, cryotherapy (cryosurgery), hormone therapy, vaccines, bone-directed treatments, and pain medication  Table 2Table 2. Cancer presents a substantial and increasing impact on many populations and health care systems around the world. The number of patients with cancer will continue to rise over the next several decades, mainly due to the influence of changing population demographics, like aging and growth ,185. DurThe past couple of decades has witnessed rising incidence rates  and notaAt present, failure of treatment contributes considerably to cancer-related morbidity and mortality . AlthougMultidrug resistance (MDR) is reported to cause over 90% of deaths among cancer patients undergoing or having undergone broad spectrum chemotherapeutic therapy or treatment with other newer therapeutics such as targeted drugs ,200. MDRBreast and prostate cancer are known to be associated with DTP . DTP canThe presence of drug resistant and DTP cell populations speak to a need to exploit multiple approaches to inhibit proliferation and promote cancer cell death. The literature identifies many cell death or anti-survival modalities, and these include accidental cell death, anoikis, autophagy-dependent cell death, autosis, efferocytosis, entotic cell death, ferroptosis, immunogenic cell death, lysosome-dependent cell death, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, NETotic cell death, parthanatos, pyroptosis, mitotic catastrophe and mitotic death, extrinsic apoptosis, intrinsic apoptosis, and methuosis ,217,218.Our incomplete understanding of the underlying molecular underpinnings of cancer and inability to effectively use consistent disease taxonomy classification systems ,233 undeDuring a person\u2019s lifetime, cells can accumulate different mutations as a result of aging, heritable and familial genetic factors, and exposure to physical, biological, and chemical substances ,235. The"}
+{"text": "In recent years, nanotechnology has improved life with continuous growth in different fields. Nanoparticles can be employed in industry, imaging, engineering, and various biomedical filed because of their special physicochemical properties like rapid, effective, highly specific solutions, higher stability, biodegradability, biocompatibility, and cost. In this line, veterinary medicine has been influenced by nanotechnology in prevention, diagnosis, and treatment of diseases, cancer therapy, immunization, vaccine production, drug delivery, and health besides to related issues of animal production, maintenance, and welfare. The other important point is the interwoven linkage between animals and humans whether as a food source or as a companionship. Inorganic nanoparticles, polymeric, solid lipid, liposomal, nanocrystal, nanotubes, nanoemulsions, micelles, mesoporous silica nanoparticles, and dendrimers are kinds of nanoparticles that can be used widely. In this review, the impacts of nanotechnology on veterinary medicine have been summarized, criticized, and acknowledged as \u201cveterinary nanomedicine\u201d discipline.  The aforementioned properties of nanoparticles (NP) besides their unique surface phenomenon, tunable absorption, and emission properties make them candidates to be used in carrying therapeutics, gene\u2010therapy for diagnostics, treating diseases, especially cancer and central nervous system\u2010related diseases besides being used as magnetic resonance imaging (MRI) or bio\u2010molecular imaging contrast agents , silver (Ag), cadmium (Cd), selenium (Se), palladium (Pd), barium titanate (BaTiO3), titanium (Ti), and manganese (Mn) and there are many advantages in using these NPs such as being safe, being eco\u2010friendly, easy to make, rational cost, decreasing synthesis time, increasing permeability  techniques, Atomic Force Microscopy (AFM), Chemical Force Microscopy (CFM), Fluidic Force Microscopy (Fluid FM), Near\u2010field Scanning Optical Microscopy (NSOM), SNOM Raman spectroscopy (RS), Modulated Raman spectroscopy (MRS), Surface\u2010enhanced Raman spectroscopy (SERS), Tip\u2010enhanced Raman spectroscopy (TERS), Confocal Raman spectroscopy (CRS), and Scanning electron microscopy (SEM) were applied to confirm the correct synthesis and to investigate the function and properties of them in cells and tissues , diagnostics , and therapeutics  , zinc oxide (ZnO), Ag, colloidal metal, active nano iron (Fe)\u2010incorporated, complex nanoscale, nano\u2010sized nutrients, nano\u2010composite, silicate (Si), nanomicelle + glycerine, surface functional materials  NP, Ag NP, metal NP, NT, fullerene, and solid lipid nanoparticles (SLNs) or lipid carriers,  , nano Se, ZnO NP, and Fe NP  , \u03b3\u2010globulins, superoxide dismutase (SOD), total globulin protein (TGP), catalase, glutathione peroxidase (GSHPX) besides decreasing pro\u2010inflammatory tumor necrosis factor\u2010alpha (TNF\u03b1) and DNA\u2010 fragmentation , liposomes, magnetic NP such as FeO2 and polymeric NP like metal NP , malfunction detection, location of tumor cells besides intercellular chemical analysis, and finding targeted cells with dendrimer, NT, nanoshells, iron oxide (FeO) NP and QD  \u2010carbon dioxide (CO2) input\u2010output changes  pathogens, 2 delivery in blood by respirocytes or increased phagocytosis potential and infectious clearing by using Microbivore , oral]nanotechnology also makes a big change in different stages of the reproductive system to optimize the general reproductive performance and assisted to improve reproductive technology. The different NPs have been prescribed in this field include magnetic NPs, Si NP, nucleic acid, protein, polymeric ; it should be mentioned that the aims of these applications focused on increased fertility, diagnosis, and treatment of reproductive disorders, sustained release of reproductive hormones, the addition of effective compounds to extenders,spermatozoa preservation, sperm purification, sperm cryopreservation, sorting and freezing sperms, more success in female insemination, supporting female animals against possible infections, genetic engineering, longer and safer sperm transformation to other countries, increasing success in artificial insemination rate and consequently more economic profitability , increased shelf life and maintenance time in stores, and nanosensors in an electronic barcode  \u2010system in the meat industry is very effective because food issues become more important for people than past. Therefore, a system can be successful that gives the most details and specific information to the customers. The nano IP system provides data from origin farm, animal birth, animal history, and its activity, feed and welfare to slaughter and meat packaging factories , Ca, SiO2, Cd, Ti, Iridium (Ir) and Platinium (Pl)  include physiochemical characteristics and posologies (Martirosyan & Schneider, 2 specifically in high doses; In contrast to this report, increased sperm capacitation and final maturation stage were occurred after exposure to low dose TiO2 (Hill & Li, The increased reactive oxygen species activity in inflammatory digestive diseases has been reported following NP intake (Gopi et\u00a0al., 2 can be carcinogenic and genotoxic, especially in sensitive groups (Bergin & Witzmann, 2 NP is a very stable and toxic NP that passes the barrier like BBB and blood\u2010placenta barrier besides its carcinogenic potential (Martirosyan & Schneider, The NP affects the reproductive system through oocyte cytotoxicity, genotoxicity, damaged oogenesis, follicle maturation, spermatogenesis, testis morphology, and gonadal tissue viability (Martirosyan & Schneider, In essence, with regard to the limited NM toxicological studies and several unknown issues in this field (Bergin & Witzmann, 3.3nanotechnology has caused many advances in different fields. The various materials and modifications of pristine materials have been used in this avenue of research. The NMs have special characteristics including high strength weight ratio, higher stability, biodegradability, and biocompatibility. Different nanocomposite classifications include many structures and shapes\u2010ceramic, metal, polymer, glass, fiber, and particle. These materials have wide usages in many fields from engineering to medicine.The nanoindustry applications in veterinary medicine may have not become routine in professional tasks yet. Of course, according to the progressive world of NMs which originated from different materials in many shapes, the application fields of this technology are going to have many unknown pathways in the future Figure\u00a0. This wa4Many reasons determine the necessity for employing novel, more effective, and safer technology and materials. These reasons include fading present materials and fuel resources, surging environmental pollution, and world concern phenomena, i.e., global warming, besides several biological issues Figure\u00a0. NanotecIn sum, it is necessary to perform wide and cohort studies about the NMs, their effects, their posology for different purposes, determination of their toxicities, and possible impacts on animal products due to entrance into the human food chain. Regard to changes in nowadays lifestyle, modern and new technology are an inseparable part of the human future. So, it seems that veterinary nanomedicine has a bright future ahead.Fariba jafary: Data collection and analysis. Shima Motamedi: Data collection and analysis. Isaac Karimi: Content approval and information.The authors declare that they have no conflict of interest.https://publons.com/publon/10.1002/vms3.1050The peer review history for this article is available at"}
+{"text": "Oncofertility practice continues to grow in developing countries despite thelack of health care services, especially those related to cancer care. Thepurpose of this study is to further explore oncofertility practice in thesecountries and identify opportunities for field-wide coalescence.We generated a survey to learn more about oncofertility practice in ninedeveloping countries within our Oncofertility Consortium Global PartnersNetwork\u2014Mexico, Colombia, Guatemala, Argentina, Chile, Nigeria, SouthAfrica, Saudi Arabia, and India. Their responses were collected, reviewed,and discussed.Surveyed centers from the nine developing countries continue to experience asimilar set of common challenges, including a lack of awareness amongproviders and patients, cultural and religious constraints, lack ofinsurance coverage and funding to help to support oncofertility programs,and high out-of-pocket costs for patients. Despite these barriers, manyopportunities exist and there is great potential for the future.The current need is to unify the new technologies and best practices thatemerge from rural communities and developing countries with those in largemetropolitan cities, both domestically (US based) and abroad, into afunctional unit: the Oncofertility Professional Engagement Network. TheOncofertility Professional Engagement Network will bridge the gap betweendomestic and international programs to establish a strong global network inwhich members share resources, methodologies and experiences and furtherbuild cultural competency. Recently, OCGPN has publisheda pilot survey concerning oncofertility practice in five developingcountries\u2014Egypt, Tunisia, Brazil, Peru, and Panama.4 The study concluded that, despite barriers to care,many opportunities exist to grow the field of oncofertility in these five developingcountries. The study also encouraged engaging stakeholders in developing countriesand using powerful networks in the United States and other developed countries toaid in the acceptance of oncofertility on a global level.4 As a consequent step, OCGPN has expanded theoncofertility survey and involved in the current study nine developing countriesfrom Latin America, Africa, and Asia\u2014Mexico, Colombia, Guatemala, Argentina,Chile, Nigeria, South Africa, Saudi Arabia, and India\u2014to help theminvestigate their own barriers and highlight their own opportunities.The Oncofertility Consortium Global Partners Network (OCGPN), established at theFeinberg School of Medicine, Northwestern University, Chicago, IL, aims to provideedification and modeling to oncofertility providers around the globe, especially indeveloping countries that lack several health services related to cancercare.Survey questions were sent by e-mail to nine centers from Latin America, Africa, andAsia within the OCGPN. Surveyed centers from Mexico, Colombia, Guatemala, Argentina,Chile, Nigeria, South Africa, Saudi Arabia, and India are listed in Appendix TableAAll surveyed centers from the nine developing countries\u2014Mexico, Colombia,Guatemala, Argentina, Chile, Nigeria, South Africa, Saudi Arabia, andIndia\u2014responded to all questions. Responses are listed in detail in the DataSupplement\u2014developing country profile 2016 and 2017, cancer care, fertilitytreatments, fertility preservation treatments, barriers to oncofertility, andopportunities of oncofertility.5 most developing countries includedin this survey have lower-to-upper-middle income economies with a low public healthexpenditure as a percentage of gross domestic product (less than 4%). State healthinsurance is still developing and does not cover the majority of the population inlower-middle-income countries, such as India, South Africa, and Nigeria. Ofinterest, Nigeria showed the highest fertility rates (5.59 births per woman) and thelowest life expectancy .According to the United Nations Human Development Reports 2016 and 2017,6 most developing countries showed lower cancer incidence ratescompared with developed countries because of a lack of national programs forscreening, diagnosis, and registration. Surveyed centers reported that the mostcommon cancers among women are breast, cervical, uterine, lung, colorectal, andstomach, whereas the most common cancers among men are lung, liver, stomach,prostate, and colorectal. Most cancer treatments are provided for free or arecovered by insurance. Cancer treatment providers include national cancer institutes,university hospitals, specialized cancer hospitals, and public hospitals, and all ofwhich provide services that are either free or covered by insurance. Some majorprivate hospitals provide cancer treatments that are covered by insurance orout-of-pocket payment. Despite of the growing attention to the disease, cancerprevention and treatment services are still not sufficient, and the officialnational registries are still under development in some countries, such as Mexico,Guatemala, and Nigeria (Data Supplement).According to the WHO GLOBOCAN Study 2012,As a result of cultural reasons, most developing countries have high fertility rates,as in Nigeria (5.59 births per woman). In the case of infertility, patients seektreatments early to avoid future social pressure. In Saudi Arabia, Nigeria, andIndia, fertility treatments are provided only to married heterosexual couplesbecause of conservative cultural and religious reasons. In most countries, thefollowing assisted reproductive techniques are available: intrauterine insemination,in vitro fertilization and intracytoplasmic sperm injection, and cryopreservation ofsperm, embryo, and oocytes. Third-party reproduction is unregulated or prohibited inmost countries as a result of conservative cultural and religious reasons. Themajority of fertility services are provided in private centers and are not coveredby insurance. Some public centers at university hospitals may offer low-costfertility services and some charities may support patients with limited resources.The average cost of a single cycle of in vitro fertilization and intracytoplasmicsperm injection is widely variable, starting from 1,500 USD in India and reaching10,000 USD in Chile. Success rates of fertility treatments seem to be comparable tointernational standards, although official national registries are still missing insome countries, such as Mexico, Colombia, Guatemala, Nigeria, and Saudi Arabia (DataSupplement).In most countries that participated in this survey, fertility preservation treatmentsare provided mainly to patients without cancer during assisted reproductivetechnique treatments to cryopreserve embryos, sperm, or oocytes. Unfortunately,patients with cancer are usually not informed about the available fertilitypreservation options because of a lack of awareness among providers. Availablefertility preservation treatments are cryopreservation of sperm, embryo, andoocytes; however, in vitro maturation, ovarian tissue freezing, and testiculartissue freezing are not yet available in most countries as a result of a lack oftechnology and trained teams. Social egg freezing is still uncommon because of alack of awareness. Success rates of fertility preservation treatments in mostcountries are still below international standards and no national registry forfertility preservation services is available in any country included in this survey(Data Supplement).There are several common medical, economic, social, and legal barriers tooncofertility practice in the surveyed countries. Medical barriers include a lack ofawareness among oncologists and gynecologists, lack of advances in early diagnosisand treatment of cancer, low referrals from oncologists, deficientinterinstitutional communication, and the absence of oncofertility specialists.Economic barriers include the lack of health insurance coverage for fertilityservices, lack of institution and research funding, and exclusively high costs; amajority of fertility services are provided in private centers and paid asout-of-pocket services. All of these factors create a financial burden to patients.Social and legal barriers include conservative religious, cultural, and ethicalattitudes that prohibit third-party reproduction in some countries (DataSupplement).Despite different barriers, oncofertility still has great potential in the surveyedcountries for the following reasons: Fertility preservation is the most suitable wayfor patients with cancer to have children, especially in countries with conservativeculture and high fertility rates; cryopreservation of sperm, embryo, and oocytes isalready available; cancer diagnosis and treatments are improving at new cancerhospitals; spreading awareness among oncologists, gynecologists, and patients can beachieved via oncofertility networks, media, and repeated promotion campaigns; andfinancial support for patients, technology, training, and research can be achievedvia national and international grants, charities, and fundraising campaigns (DataSupplement).24 As a testament to the success ofthe OCGPN, the network continues to grow in terms of the number of participatingcenters, which can be equated to an increase in the number of patients reachedworldwide. Through our efforts, the OCGPN now spans six continents, including morethan 40 countries around the globe and 85 sites in the United States. After athoughtful evaluation of the status of the field and the evolving needs of itsmembers, it became clear that as the number of participating centers increases,there is no longer a need to separate these centers geographically . We now aim to move toward the coalescence ofthe individual stakeholders in the field to OPEN  and abroad, into afunctional unit, OPEN. OPEN will bridge the gap between domestic and internationalprograms to establish a strong global network in which members share resources,methodologies, and experiences, and further build cultural competency in the fieldof oncofertility."}
+{"text": "Autoimmune hemolytic anemia (AIHA) is usually categorized, as other immune-mediated cytopenias, in so-called benign hematology, and it is consequently managed in various settings, namely, internal medicine, transfusion centers, hematology and, more rarely, onco-hematology departments. The disease is highly heterogeneous; while most cases are mild/moderate and easy to diagnose and treat, an increasing proportion of patients experiences hyper-acute onset and may present to the emergency room or develop chronic behavior with multiple relapses. Moreover, AIHA may be secondary or associated with a variety of conditions such as lymphoproliferative syndromes, other autoimmune diseases, infections, immunodeficiencies, transplants, and drugs, including novel anti-cancer therapies, which may further complicate the diagnosis and management. Steroids, immunosuppressants, and splenectomy had been the sole therapies available for decades, while recently, several target therapies became available or are now under active development.In this Special Issue, several aspects of this complex scenario are addressed, starting with pathogenesis , which iThis underestimated issue is further expanded in a dedicated review  that proAIHAs may be challenging and life threatening. This issue is addressed in several manuscripts, firstly in the review on Evans syndrome , a very real life, although it is not available/indicated worldwide. However, severe, refractory, and early-relapsed patients represent a challenge and an unmet clinical need. Luckily, in recent years, a growing number of trials have been running, which will raise the problem of how to choose the right therapy for each patient in the future. At the same time, this expanded therapeutic arsenal will increase the possibility to treat (and hopefully cure) the disease.In conclusion, this Special Issue encompasses the numerous and heterogeneous aspects of AIHA, starting with some elements regarding disease pathogenesis and the basic distinction between cold and warm forms that require quite different therapies. Another pivotal issue is a prompt recognition of the underlying disease, which may complicate the diagnosis and management. Additionally, several specific settings  may further complicate AIHA diagnosis and require special attention. Besides steroids and splenectomy (when indicated), rituximab is becoming a well-consolidated practice in"}
+{"text": "PLOS ONE Editors retract this article [The  article  because NM, SK, SY, KtK, SAAlrumman, and EMA did not agree with the retraction. SFA responded but expressed neither agreement nor disagreement with the editorial decision. HS, SAMA, GM, SAAli, and SD either did not respond directly or could not be reached."}
+{"text": "Mounting evidence shows that the complex gut microbial ecosystem in the human gastrointestinal (GI) tract regulates the physiology of the central nervous system (CNS) via microbiota and the gut\u2013brain (MGB) axis. The GI microbial ecosystem communicates with the brain through the neuroendocrine, immune, and autonomic nervous systems. Recent studies have bolstered the involvement of dysfunctional MGB axis signaling in the pathophysiology of several neurodegenerative, neurodevelopmental, and neuropsychiatric disorders (NPDs). Several investigations on the dynamic microbial system and genetic\u2013environmental interactions with the gut microbiota (GM) have shown that changes in the composition, diversity and/or functions of gut microbes (termed \u201cgut dysbiosis\u201d (GD)) affect neuropsychiatric health by inducing alterations in the signaling pathways of the MGB axis. Interestingly, both preclinical and clinical evidence shows a positive correlation between GD and the pathogenesis and progression of NPDs. Long-term GD leads to overstimulation of hypothalamic\u2013pituitary\u2013adrenal (HPA) axis and the neuroimmune system, along with altered neurotransmitter levels, resulting in dysfunctional signal transduction, inflammation, increased oxidative stress (OS), mitochondrial dysfunction, and neuronal death. Further studies on the MGB axis have highlighted the significance of GM in the development of brain regions specific to stress-related behaviors, including depression and anxiety, and the immune system in the early life. GD-mediated deregulation of the MGB axis imbalances host homeostasis significantly by disrupting the integrity of the intestinal and blood\u2013brain barrier (BBB), mucus secretion, and gut immune and brain immune functions. This review collates evidence on the potential interaction between GD and NPDs from preclinical and clinical data. Additionally, we summarize the use of non-therapeutic modulators such as pro-, pre-, syn- and post-biotics, and specific diets or fecal microbiota transplantation (FMT), which are promising targets for the management of NPDs. Trillions of microorganisms colonizing the skin, as well as the nasal, oral, pulmonary, GI and vaginal mucosal cavities, have been found to be crucial regulators of human metabolic, immune and GI homeostasis . The entSpecifically, the pathogenic involvement of GD in a plethora of NPDs, including stress-induced disorders ), psychiatric disorders (schizophrenia (SZ) and bipolar disorders (BD)), and neurodevelopmental disorders (attention deficit hyperactivity disorders (ADHD) and Asperger\u2019s syndrome or autism spectrum disorders (ASD)) ,21,22,2313\u20131018 different microorganisms, including bacteria , archaea, fungi, and viruses, form the human microbiota [13, which is greater than the total number of human cells (approximately 3.0 \u00d7 1013) [Approximately 10crobiota . The tercrobiota . More thcrobiota . Each hucrobiota . The tot \u00d7 1013) . The mai \u00d7 1013) .A typical GM comprises four major phyla, Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria, and two minor phyla, Fusobacteria and Verrucomicrobia ,28. BothThe GM ferment undigested complex dietary fibers and produce essential bioactive metabolic products, known as gut-derived metabolites, such as short-chain fatty acids (SCFAs), long-chain fatty acids, branched-chain amino acids, trimethylamine-N-oxide (TMAO), lipopolysaccharide (LPS), bile acids, and catecholamines ,38,39,40\u25aaThe neural network  ,43.\u25aaThe endocrine system (via HPA axis) ,56.\u25aaThe immune system  .\u25aaBarriers such as the BBB and the gut mucosal barrier ,59,60.Research on the signaling pathways involved in the MGB axis and its regulatory functions is still being explored ,51. The On the other hand, gut microbes can indirectly influence the CNS via the production of metabolites like SCFAs and neural mediators or inducing the release of 5-HT from EECs ,38,39,40Conversely, the brain signals the gut mainly via the HPA axis in the presence of stressful stimuli. Importantly, the HPA axis provides the fundamental response to the environmental, social and physiological stressors by hyperactivating the immune cells to release proinflammatory cytokines. Increased levels of cortisol increase the permeability of the intestinal barrier, which leads to leaky gut and increased LPS levels , eventually resulting in GD ,62,63,64\u25aaAltered microbial composition and diversity and metabolites, which in turn alter the levels and/or synthesis of neurotransmitters , leading to deregulated MGB signaling.\u25aaReduction in the number of goblet cells leads to a decrease in mucus production and mucosal layer becomes thin.\u25aaDecreased expression of tight junction proteins (including claudin-5 and occludin) between the intestinal epithelial cells leading to increased permeability, resulting in leaky gut  ,73.\u25aaIncreased translocation of pathobionts and its toxic components such as LPS and peptidoglycan into the systemic circulation leading increased secretion of pro-inflammatory cytokines (like interleukin (IL)-18, IL-1, IL-6, and TNF-\u03b1).\u25aaLeaky gut evokes chronic systemic inflammation by breaking down the integrity of the BBB by disrupting the tight and anchoring junction proteins in the frontal cortical, hippocampal, and striatal regions, which eventually alters the brain functions.\u25aaIncreased BBB permeability results in excessive translocation of immune cells and toxic microbial metabolites into the brain, which in turn enhance cytokines, chemokines, and endocrine (stress) messengers in the brain parenchyma.\u25aaAltered neuroimmune status is marked by alterations in microglial maturation, neurogenesis, myelination, neurotrophin expression, neurotransmitters, and their respective receptors ,60,74,75Specifically, GD can be defined as an increased number of pathogenic microbes or pathobionts (microbes producing pro-inflammatory cytokines) and decreased number of beneficial microbes or symbionts (microbes producing anti-inflammatory cytokines). The pathogenic representation of GD-induced NPDs ,72 incluCollectively, these findings indicate that GD deregulates MGB signaling and begins the pro-inflammatory cascade, which correlates directly with the development of symptoms of NPDs ,77.Database sources include SCOPUS, MEDLINE, PubMed, Cochrane, PsycINFO, Nature, and ScienceDirect. The relevant randomized controlled trials from the Journals of neuropsychiatry, neuroimmunology, neuroscience, neurogasteroenterology, immunology and microbiology were hand searched and selected. In addition, recent articles investigating the correlation of gut microbial alterations and neuropsychiatric disorders were selected, and citation searches of selected articles were performed.The pathogenic link between GD and NPDs on disease onset and progression results from the abnormal physiology of the immune system. During the early stages of human development, the dynamics, composition and distribution of GM is regulated by the immune system , in turnCommensal GM are actively involved in priming the innate and/or adaptive immune responses ,81. The Exposure to stress leads to increased production of HPA axis hormones with elevated levels of corticotrophin releasing factor, adrenocorticotropic hormone (ACTH), corticosterone/cortisol levels and a reduced level of glucocorticoid receptor expression in GF mice . These cClinically, activated inflammasome and elevated levels of proinflammatory cytokines  have been noted in patients with MDD. Campylobacter jejuni infection induces GD by overstimulating NF-\u03baB signaling pathways, leading to excessive release of various cytokines and activation of immune cells . ExperimMicroglia are the important sentinel immune cells in the CNS. Aberrations of normal microglial functions such as synaptic pruning, phagocytosis of cellular debris, and the release of cell signaling factors such as neurotrophins, proinflammatory cytokines, and extracellular matrix components, which results in the abnormal brain connections and brain volumes, are found more commonly in brain samples of NPDs ,99,100. Taken together, ASD children have an increased brain volume due to excessive presence of neurons and synaptic networks in the brain cortex ,130,131.These findings highlight that stress-induced GD in different developmental stages of life  may exert behavioral alterations in adulthood by hyperactivating the HPA response, redesigning the neural circuitry and affecting the maturation and functions of CNS immune cells.Numerous studies on animal models have confirmed the link between GD and the onset and/or progression of NPDs. To investigate how GM regulate brain development and function, researchers developed animals completely lacking microbiota, referred to as germ-free (GF) mice, and treated animals with antibiotics or animals colonized with complex microbiota except particular pathogenic flora (specific pathogen free (SPF)). Also, the interlink between gut microbiome and chronic unpredictable mild stress (CUMS) induced depression is well established . GF mice have deficiencies in spatial learning, working memory, recognition, and emotional behaviors, indicating neural dysfunction ,142. GF GF mice have higher tryptophan and lower 5-HT levels in blood compared to WT mice . AdditioGF mice showed enhanced exploratory and reduced anxiety-like behavior than SPF mice in the standard behavioral tests ,155. HeiSPF mice receiving cocktail of neomycin, bacitracin and pimaricin showed GD to be accompanied by increased exploratory behavior, reduced anxiety, and altered BDNF levels in the hippocampus and amygdala . SPF micTaken together, preclinical studies dictate the physiological role of gut microbes and its metabolites in optimum functioning of immune, metabolic and neural systems. GD provokes dysfunctions in these systems stemming from pathological changes such as increased inflammatory cascade, aberrated levels of neurotransmitters or neural growth factors , synaptic processes, neuronal death, or volumetric changes. Taken together, these pathological changes translate into psychological symptoms such as increased or reduced anxiety, increased stress or fearful response, altered social behavior, cognitive decline or memory deficit. Specifically targeted deletion of microbial species dictates their specific role in these regulatory functions. These results clearly indicate the importance of MGB axis and healthy gut microbial composition in the regulation of brain functions.Much evidence from clinical data strongly suggests a positive correlation between GD and the development and/or manifestation of different neuropsychiatric conditions including depression, anxiety, schizophrenia, ASD, and ADHD. High-throughput genetic sequencing and metabolomics also reported alterations in GI microbiota and fecal metabolic phenotype related to depressive disorders ,160. TheFirmicutes and Bacteroidetes as well as Verrucomicrobia and Actinobacteria [Stress is a physiological response to environmental or psychological challenges. Different types of stress such as acute/chronic, mild/severe, only once/monotonous  due to ebacteria . CollectRuminococcus gnavus [Anxiety and depression are the most commonly reported mood disorders. Anxiety is characterized by frequent nervous behavior, rumination, fidgeting, worried thoughts, negative thinking, and restlessness or agitation, causing significant functional impairment in life activities. The pathogenesis involves abnormal changes in nervous, endocrinal, and immunological systems . Exposurs gnavus . GD causs gnavus , while is gnavus . Howevers gnavus .The most common form of mood disorder in the digital epoch, found in millions, is depression, which is characterized by anhedonia, lack of motivation, low state of mood, hopelessness, morbidity of depression and anxiety affects important functioning of life areas, such as low self-esteem, severe fatigue, frustration, intrusive thoughts, and restlessness . Co-acadSeveral observational and clinical research studies have proved the direct correlation of depression with GD, confirming its role in depression pathology ,180,181.Blautia Klebsiella, Anaerostipes, Clostridium, Parasutterella, Parabacteroides, Phascolarctobacterium, Lachnospiraceae incertae sedis, and Streptococcus; lower relative abundance of Dialister, Faecalibacterium, Bifidobacterium, Ruminococcus, and Escherichia/Shigella; and altered composition of Alistipes, Megamonas, Bacteroides, Roseburia, Prevotella, and Oscillibacter [A recent cross-sectional study in post partum women with severe and suicidal depression indicated the presence of higher levels of IL-6 and IL-8 and reduced concentrations of IL-2, 5-HT, and quinolinic acid in plasma due to dysregulation of kynurenine pathway . MDD patlibacter ,191,192.Alistipes, Mollicutes, Lactobacillales, and Enterorhabdus [Autism spectrum disorders (ASD) are defined as a progressive developmental disabilities found commonly in children and adolescents, which are characterized by impaired social behavior and communication, along with presence of limited, repetitive and stereotyped interests and behavior. In utero valproate animal model of autism show an increase in the Firmicutes/Bacteroidetes ratio as well as increases in cecal butyrate levels and genera orhabdus . Almost orhabdus . Moreoveorhabdus ,195,196.orhabdus , and chrorhabdus .In ASD patients, GD is represented by mucosal inflammation indicated by the increased presence of inflammatory markers  in cerebrospinal fluid ,199,200 ASD children showed a significant change in the dynamics, \u03b1 and \u03b2 diversity, stability and relative abundance of GM when compared to healthy controls  and neurBacteriodes uniformis, Bacteriodes ovatus, and Sutterella stercoricanis, and a decrease in B. coprocola species [B. ovatus and S. stercoricanis abundantly showed a positive link with ADHD symptoms, and consumption of dairy products, nuts, legumes, seeds, ferritin, and magnesium correlate with S. stercoricanis abundance, while ingestion of fat and carbohydrate correlate with B. uniformis [Attention deficit hyperactivity disorder (ADHD) is the most prevalent neurodevelopmental disorder, and is found mostly in children and adolescents, and characterized by triad symptoms like inattentiveness, impulsivity and hyperactivity ,213. Inc species ,208. Theniformis .Schizophrenia (SZ) is a heterogeneous psychiatric disorder characterized by \u2018positive symptoms\u2019  and \u2018negative symptoms\u2019  along with speech difficulty and cognitive decline ,216,217.In SZ patients, GD is marked by leaky gut syndrome caused by deregulated MGB signaling disturbances resulting in increased inflammatory markers . Serum lFaecalibacterium prausnitzii, genera Bacteroides, Parabacteroides and Halomonas or Bacteroides\u2013Prevotella group [Bipolar disorders (BD) are chronic mood disorders, defined by the presence of prolonged depressive episodes and short manic or hypomanic episodes . The chrla group ,242,243.la group  and butyla group ,243.The results reported in clinical studies and post mortem studies of NPD patients concur with the results of the preclinical studies. Moreover, GD-related pathological alterations in the systemic and nervous system vary depending on epigenetic and genetic factors, diet, and age of onset. A positive correlation between the deregulation of synaptic pruning process and onset of psychiatric symptoms with GD-induced MGB axis dysregulation was bolstered in several NPDs. Specific NPDs showed certain typical pattern of changes in diversity and composition. Anatomical alterations include grey matter reduction, cortical thinning, abnormal synaptic density, and abnormal firing pattern with defective neural circuitry. Reversal of GD using specific nutritional interventions or FMT have shown improvement of clinical symptoms and reduction of gastric symptoms.Alternative approaches targeting gut dysbiosis in NPDs are gaining much popularity after two decades of promising effects of GM and MGB on higher brain function, with enough evidence proving that significant effects of GD on anxiety and mood-related behaviors ,247. RecBifidobacterium (B.) longum + B. infantis + Lactobacillus (L.) helveticus + L. rhamnosus alone or in combination with normalized behavioral phenotypes showed positive effects either by reversing the immune pro-inflammatory factors or upregulating the expression of GABA receptors [of Lactobacillus rhamnosus (JB-1) for prolonged periods reversed the altered GABA receptor levels in specific brain areas, and reduced corticosterone levels and depressive symptoms in mice [B. longum supplementation reversed anxiety-like behavior and BDNF levels in brain samples of mice co-morbid with infectious colitis [L. farciminis strains reduced leaky gut syndrome and HPA axis hyperactivity in rats exposed to stress [L. helveticus (strain R0052) + B. longum (strain R0175) prevented the reduction of neurogenesis in hippocampal regions of stressed mice [L. helveticus and B. longum showed anxiolytic-like activities in rats when exposed to physiological stress [L. reuteri + B. longum increased the relative abundance of Lactobacillus. A mixture of Bifidobacteria, Streptococci and Lactobacilli significantly improved behavioral symptoms and reduced GI symptoms in ASD patients [B. pseudocatenulatum CECT 7765) intake promotes positive consequences with improved brain biochemistry and behavior in adulthood who were exposed to chronic stress in early life [Probiotic or probiotic mixtures consist of live microbes that, when ingested, stimulate the growth of beneficial microbial species . The tereceptors ,252,253. in mice . B. long colitis . L. farco stress . A mixtused mice . Additiosed mice  showed tl stress  and allel stress . Previoul stress ,189 was l stress  in whichpatients ,259. Propatients . Bifidobrly life .B. longum and reduced stress-induced activation of the HPA axis in healthy young participants [Prebiotics are dietary ingredients that selectively promote the growth of beneficial microbes conferring health benefits to the host . Studiesicipants ,190. A picipants . BGOS adicipants . Prebioticipants ,269,270.icipants , and impicipants ,273. Shoicipants .Lactobacillus acidophilus T16 + Bifidobacterium bifidum BIA-6 + Bifidobacterium lactis BIA-7 + Bifidobacterium longum BIA-8 reduced the negative symptoms in severely depressed patients along with higher serum levels of BDNF when compared to controls [Limosilactobacillus (L.) reuteri + Bifidobacterium (B.) longum alone + GOS showed higher GI resistance, and improved the gut microbial activity and metabolism, marked by high levels of short-chain fatty acid and reduced levels of ammonium in autistic children [Lactobacillus paracasei HII01 + Bifidobacterium animalis subsp. Lactis + galacto-oligosaccharides + oligofructose) in stressed individuals reduced the negative feelings, mainly by regulating the activation of HPA-axis and production of IL-10, IgA, and LPS [Synbiotics refer to the synergistic combination of prebiotics and probiotics that confer benefits to the host by promoting the survival of beneficial microorganisms in the gut. Mild reduction in depressive symptoms and better cognitive functioning was found in aged people consuming synbiotic supplementation of FOS + probiotic for 24 weeks . A randocontrols . A synbichildren . Adminis and LPS . A syste and LPS .The main determinant of the composition and diversity of GM is diet . Beef-fed mice showed increased diversity of gut microbes, enhanced memory, and reduced anxiety compared to control mice  . PopulatLatalova et al. (2017)  showed pA common method used in various NPDs is FMT, which includes transfer of complete or specific microbial components of a healthy donor to the recipient through endoscopy, enema, and oral feeding of frozen fecal materials in order to establish a healthy complex microbial composition and function (termed \u201ceubiosis\u201d) . FMT treTechnical advancements and developments in recent times in the fields of neuroscience, neuroimmunology and gut microbiome research have provided ample evidence for the regulatory role of GM on the development, maturation, and function of the brain, as well as immune cells. Numerous GF studies using rodent models, antibiotic-treated animal studies, and transgenic animal models have specifically addressed the physiology of GM and gut-derived metabolites on the regulation of immune, metabolic, and brain functions via the MGB axis. These findings are further emphasized by the fecal transplantation experiments recently. Additionally, several animal experimental studies and observational clinical studies have demonstrated the correlation of GD with the development of complex mental disorders such as depression, ASD, SZ and ADHD. The common denominators of several NPDs include the presence of prolonged gastric symptoms, GD, increased inflammation (both at periphery and brain), altered microglial function, aberrated pruning process, abnormal neural circuitry and neuronal death in certain specific brain regions. Therefore, there is an urgent need to investigate the association between gut-derived microbial signals with microglial activation and neuroinflammation in order to effectively tailor the therapeutic process to obtain better efficacy and prevent disease progression in patients with NPDs.Studies using microbial-based interventions have shown promising results in the improvement of patients\u2019 health, as reversal of health gut microbiome improved the immune, endocrine and neural functions, which in turn reduced their psychiatric and gastric symptoms. Numerous studies in experimental animal models and humans testify to the potential benefits of special nutritional interventions such as prebiotics, probiotics and synbiotics, as well as dietary alterations and FMT in the treatment of wide array of NPDs by targeting GD. To develop personalized microbiota-based interventions in humans, better knowledge of the exact pathways underlying the MGB axis is mandatory. Specifically, immune-mediated inflammatory response is the central pathological feature of many mental disorders, and this can serve as better target for microbiota-based non-therapeutic approaches. Several plants-based supplements provide beneficial effects on establishing healthy GM and reducing the onset or progression of psychological disorders. Additionally, large longitudinal clinical studies investigating the pathogenic intestinal microbial changes in subjects with different NPDs are needed to discern their role in the pathophysiology of mental disorders."}
+{"text": "Aloe vera, Angelica sinensis, pumpkin, Lycium barbarum, Ginseng, Schisandra chinensis, Dioscorea pposite, Poria cocos, and tea in metabolic diseases. Finally, this review will provide directions and a reference for future research and for the development of PPS into potential drugs for the treatment of metabolic diseases.Plant polysaccharides (PPS) composed of more than 10 monosaccharides show high safety and various pharmacological activities, including immunoregulatory, antitumor, antioxidative, antiaging, and other effects. In recent years, emerging evidence has indicated that many PPS are beneficial for metabolic diseases, such as cardiovascular disease (CVD), diabetes, obesity, and neurological diseases, which are usually caused by the metabolic disorder of fat, sugar, and protein. In this review, we introduce the common characteristics and functional activity of many representative PPS, emphasize the common risks and molecular mechanism of metabolic diseases, and discuss the pharmacological activity and mechanism of action of representative PPS obtained from plants including  With the successful treatment of many infectious diseases worldwide, noncommunicable diseases (NCDs) have become a major risk factor for human health and life. Of all these NCDs, metabolic syndrome (MetS) affecting metabolic health poses the largest global threat . MetabolAloe polysaccharides (APs) improve diabetes by activating the PERK and IRE1 pathways [Angelica sinensis polysaccharides(ASPs) exert a neuroprotective effect in Alzheimer\u2019s disease (AD) by regulating the A\u03b225-35 neurotransmitter balance, free radiation metabolism, inflammation, and neuronal apoptosis [Poria cocos polysaccharides (PCPs) improve atherosclerosis (AS) by regulating blood lipid levels, decreasing malondialdehyde (MDA) levels, and increasing superoxide dismutase (SOD) activity [Currently, with the improvement in quality of life, an increasing number of people tend to choose natural medicines, especially plant-based supplements, for the prevention and treatment of diseases ,5. Polyspathways . Angelicpoptosis . In addiactivity . Althougactivity , there aactivity ,12. In tPhytochemical studies reveal that polysaccharides are the most abundant components in plants . To dateAloe vera is mainly composed of acetylated Man, Glc, and Gal [Angelica sinensis are mainly composed of glucuronic acid, glucose, arabinose, and galactose [Cucurbita moschata Duch.) mainly comprises rhamnose, glucose, arabinose, galactose, and uronic acid [Recent studies have found that PPS are an important class of biological polymers composed of more than 10 monosaccharides and are linked by glycosidic bonds, and the molecular weight is up to tens of thousands or even millions . As show and Gal . ASPs inalactose ,18. The nic acid .Aloe vera [Angelica sinensis [Schisandra chinensis [Poria cocos [Panax ginseng [Cucurbita moschata) [Camellia sinensis) [Dioscorea opposita [Lycium barbarum [The structure of PPS comprises monosaccharides linked by glycosidic bonds. The glycosidic bonds of PPS are mainly \u03b1-1\u2192 6)-D, \u03b1-(1\u2192 4)-D, and \u03b2-(1\u2192 4)-D [-D, \u03b1- , Tea (Cainensis) , Dioscoropposita , and Lycbarbarum , are shoAloe vera [Angelica sinensis polysaccharide (ASPs) has immunological [Panax ginseng polysaccharides (GPs) have hypoglycemic, blood pressure-lowering, and antidepression effects [It was found that the vast majority of PPS are relatively nontoxic and do not cause significant side effects . Studiesloe vera , was reploe vera . The higloe vera . Acemannloe vera  and promloe vera . Angelicological , hypoglyological , and livological . Panax g effects . TherefoMetabolic diseases are characterized by disorder of the generation and storage of energy. In general, the substances, including sugar, protein, fat, vitamins, and minerals, in the human body cannot be metabolized effectively, resulting in the occurrence and development of metabolic diseases, such as obesity, diabetes, CVD, nonalcoholic steatohepatitis (NASH), nervous system disease (NSDs), and cancer. These metabolic diseases are thought to be affected by a complex interplay between genetics, epigenetics, susceptibility, environmental factors, and nutrition .MetS is a progressive, interdependent pathophysiological state consisting of a number of causal risk factors that become increasingly resistant to illness. Inflammation, visceral obesity, ectopic , IR, and sugar consumption play key roles in disease pathogenesis . To bettCVD is the general term for cardiovascular and cerebrovascular diseases, including systemic vascular disease or systemic vascular disease in the heart and brain. It mainly includes AS, aneurysm disease, coronary heart disease, cerebral infarction, and hypertension . NumerouType 2 diabetes mellitus (T2DM) is a group of MetS that is characterized by absolute or relative insufficiency of insulin secretion, and decreased sensitivity of target organs to insulin, followed by metabolic disorders of fat, protein, water, and electrolytes . In receMetabolic disorders can also cause NSDs, of which stroke  and deprNASH is a condition of chronic liver injury and inflammation caused by excess lipid accumulation in the liver , and is In addition, metabolic diseases also include cancer , gout 4, and ostAloe vera, belonging to the Liliaceae family, is a short-stemmed plant that stores water in its plants. Phytochemical studies have shown that Aloe vera contains polysaccharides, sugars, vitamins, minerals, amino acids, enzymes, sugars, and anthraquinones. APs, being the most abundant compounds, are required for skin care, health care, antioxidative qualities, and wound healing [ healing . In addi healing . In addi healing . TherefoAngelica sinensis is an important medicinal herb in China. Its medicinal value has been commonly known for a long time, among which the effects of promoting blood circulation and relieving pain, dredging meridians, and regulating meridians are remarkable [Angelica sinensis that exhibits beneficial effects in some metabolic diseases, such as AD and diabetes , belonging to the family of Solanaceae, is a shrub native to China. Phytochemical studies have shown that Lycium barbarum contains polysaccharides, carotenoids, and polyphenols such as caffeic acid, chlorogenic acid, and p-coumaric acid [Lycium barbarum polysaccharides (LBPs) are the major components and have a variety of medicinal values, including antioxidative, anticancer, antifatigue, and antiaging effects [ric acid . Among t effects . Recentl effects . In addi effects . TherefoGinseng has a long history as a medicinal herb for the treatment of human diseases in many Eastern countries, including China, Korea, and Japan. Phytochemical studies have shown that Ginseng contains terpenoids, flavonoids, lignans, sterols, and other compounds. To date, polysaccharides have been identified and extensively studied for their pharmacological activities, including immunoregulation, antitumor, antibacterial, anti-inflammatory, and antioxidative effects [Ginseng polysaccharides (GPs) exhibit a regulatory effect on metabolic disorders in many diseases  improve metabolic diseases via regulating metabolism pathways  are one of the main bioactive substances that exhibit many important biological activities, such as hypoglycemic, immunomodulatory, antioxidative, and antitumor activities [tivities . In additivities . In dexativities . TherefoPoria cocos, belonging to the fungus family of Polyporaceae, is an edible fungus. In addition, Poria cocos has been used as a TCM for more than 2000 years. Phytochemical studies have shown that polysaccharides, triterpenes, sterols, amino acids, fatty acids, etc., are the major components in Poria cocos. Among them, PCPs have a wide range of biological activities, including antidiabetic, antitumor, immunoregulation, anti-inflammatory, antioxidation, and antiaging effects [ effects . In high effects . In addi effects . TherefoBifidobacterium, Blautia, Dorea, Oscillospira, Desulfovibrio, and Lactobacillus species. Mechanistic studies revealed that TPs regulated the primary and secondary bile acid biosynthesis and downregulated the NOD-like receptor signaling pathway, lipopolysaccharide biosynthesis, and the insulin signaling pathway [Tea is a nonalcoholic drink containing polyphenols such as catechin, epicatechin, epicatechin gallate, gallocatechin, and epigallocatechin. In addition, tea polysaccharides (TPs) are also recognized as the main bioactive components. Increasing studies have shown that TPs have various biological activities, including antioxidative, antitumor, hypoglycemic, and hypolipidemic effects . In STZ- pathway . In the  pathway . TherefoMetabolic diseases, including obesity, diabetes, CVD, NASH, NSDs, and cancer, are characterized by the disorder of the generation and storage of energy. They can be affected by the common risks from genetics, epigenetics, susceptibility, environmental factors, and nutrition. PPS are an important class of biopolymers with a wide range of sources and varieties. They contain more than 10 monosaccharides linked by glycosidic bonds. Most PPS from edible plants have high safety and exhibit beneficial effects in many metabolic diseases such as cerebral ischemia, T2DM, AD, CFS, NASH, AS, and NAFLD. Their mechanisms of action are associated with the regulation of apoptotic, inflammatory, oxidative stress, gut microbiota, and many metabolic pathways . As a na"}
+{"text": "In the published article, there was an error in the author list, and author [Daiwen Chen] was erroneously excluded as corresponding author. The corrected author list appears below.*, Bing Yu, Jun He, Zhiqing Huang, Ping Zheng, Xiangbing Mao, Hua Li, Jie Yu, Junqiu Luo, Hui Yan and Yuheng Luo*Jiayan Li, Daiwen Chen*Correspondence:Daiwen Chendwchen@sicau.edu.cnYuheng Luoluoluo212@126.comThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "Inherited cardiomyopathies caused by pathological genetic variants include multiple subtypes of heart disease. Advances in next-generation sequencing (NGS) techniques have allowed for the identification of numerous genetic variants as pathological variants. However, the disease penetrance varies among mutated genes. Some can be associated with more than one disease subtype, leading to a complex genotype-phenotype relationship in inherited cardiomyopathies. Previous studies have demonstrated disrupted metabolism in inherited cardiomyopathies and the importance of metabolic adaptations in disease onset and progression. In addition, genotype- and phenotype-specific metabolic alterations, especially in lipid metabolism, have been revealed. In this mini-review, we describe the metabolic changes that are associated with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM), which account for the largest proportion of inherited cardiomyopathies. We also summarize the affected expression of genes involved in fatty acid oxidation (FAO) in DCM and HCM, highlighting the potential of PPARA-targeting drugs as FAO modulators in treating patients with inherited cardiomyopathies. TTN, LMNA, MYH7, and PLN, exhibits a stronger gene-disease relationship with DCM compared to the rest , dilated cardiomyopathy (DCM), arrhythmogenic cardiomyopathy (ACM), and restrictive cardiomyopathy (RCM) , 2. Amonthe rest . Unlike the rest . MYH7 anvariants , leadingThe heart has a very high energy demand to fulfill its basic functions. Therefore, sufficient cardiac energy metabolism is crucial. In a healthy adult heart, over 95% of produced ATP is derived from mitochondrial oxidative phosphorylation, and this is predominantly by fatty acid oxidation (FAO) , 11. TheTTN variants, which account for 15\u201320% of DCM populations, showed affected genes and metabolites involved in metabolic regulation when compared to DCM patients without TTN variants  levels are seen in HCM due to sarcomeric variants, resulting in metabolic changes . m in DCM . Interesomal FAO , remaineomal FAO . NotablyPPARA, PPARD, and PPARG are three isoforms of the peroxisome proliferator-activated receptors (PPARs), which are ligand-activated transcription factors. Since their DNA binding regions are highly similar, they show overlapping biological functions, especially in lipid metabolism . PPARA iDsg2 ACM murine hearts showed that improved myocardial fibrosis was observed after the activation of PPARA by either fenofibrate treatment or adeno-associated virus injections of PPARA (The cardioprotective effects of ligand-activated PPARA have been reported, including the restored balance between fatty acid uptake and FAO, increased insulin sensitivity, reduced ROS production, and attenuated fibrosis formation , 84. Botof PPARA . Neverthof PPARA \u201399, whicMetabolic homeostasis plays an important role in cardiac performance and disrupted metabolism is generally present in inherited cardiomyopathies, regardless of the pathogenic DNA variant and the phenotypes. Despite the shared metabolism alterations among different subtypes of inherited cardiomyopathies, etiology- and phenotype-specific metabolic impairments have been revealed, particularly in relation to FAO . Those sKG-H, AB, and JP wrote the manuscript. KG-H, AB, MW, JP, and MH collected and interpreted public datasets. FWA, FvS, and MH edited the text and provided the critical input. All authors contributed to the article and approved the submitted version."}
+{"text": "In the year of 2000, the Nobel prize in chemistry was awarded to three professors, Alan Heeger, Alan MacDiarmid, and Hideki Shirakawa, for their contributions to discovery and development of conducting polymers. Their works altered the previously-held idea that organic and polymer materials are electrically insulating. Instead, conjugated organic or polymeric materials can be conductors and semiconductors. Compared with traditional inorganic counterparts, organic conductors and semiconductors have advantages of excellent mechanical flexibility, easy processing, potentially low cost, recyclability and easy tuning of their optoelectronic properties by molecular tailoring. In the past years, various organic optoelectronic devices have been demonstrated, including organic light-emitting diodes (OLED), organic photovoltaics (OPV), organic photodiodes (OPD), organic field-effect transistors (OFET), organic energy storage devices, etc. OLEDs have become mature technology for displays and lighting. Other organic optoelectronic devices are still being researched for practical applications. Novel organic optoelectronic materials, physics, devices and applications are ripe for investigation and exploration for a more sustainable society.m-ACSO2) that could be used as a universal host material for sensitizing conventional fluorescent polymers to substantially enhance their external quantum efficiency.This special issue on \u201cOrganic Optoelectronics\u201d contains eight papers. Three of them are review articles, the other five are four research article and one letter. Li et al.  reviewedThe eight papers contained in the issue cover materials, their underlying physics, and their device applications. The devices include OPD, OFET, OPV, perovskite PV, and batteries. We believe these contents are comprehensive, interdisciplinary and inspiring, and can stimulate more cutting-edge work in the community of organic functional materials and organic optoelectronics."}
+{"text": "Natural products are compounds produced by living organisms and can be divided into two main categories: primary (PMs) and secondary metabolites (SMs). Plant PMs are crucial for plant growth and reproduction since they are directly involved in living cell processes, whereas plant SMs are organic substances directly involved in plant defense and resistance. SMs are divided into three main groups: terpenoids, phenolics and nitrogen-containing compounds. The SMs contain a variety of biological capabilities that can be used as flavoring agents, food additives, plant-disease control, strengthen plant defenses against herbivores and, additionally, it can help plant cells to be better adapted to the physiological stress response. The current review is mainly focusing on certain key elements related to the significance, biosynthesis, classification, biochemical characterization and medical/pharmaceutical uses of the major categories of plant SMs. In addition, the usefulness of SMs in controlling plant diseases, boosting plant resistance and as potential natural, safe, eco-friendly substitutes for chemosynthetic pesticides were also reported in this review. Natural products (NPs) are chemical substances isolated from living organisms and can be originated from microbial, plant or animal origins ,2. In adThe PMs include carbohydrates, proteins, fats and alcohol, which are involved in growth, development and reproduction ,5,6. PlaUnlike the PMs, the absence of SMs does not lead to direct cell death, but it can adversely affect the organism\u2019s survivability in the long term. The SMs are often restricted to a narrow set of species within a phylogenetic group . Plant SFor thousands of years, nature has provided medicinal agents, and an astounding number of modern medications have been developed from natural sources, many of which are used in traditional medicine . NaturalPenicillium notatum and was discovered by Fleming in 1929 [During the last century, the term \u2019secondary metabolites\u2019 was first suggested by Albrecht Kossel in 1910 and then by a Polish botanist Friedrich Czapek, 30 years later, who described SMs as the end products of nitrogen metabolism ,21. The  in 1929 ,23. The  in 1929 ,25. The For the comprehension of their distribution and abundance, plant SMs were considered not only as plant waste products but as specialized single substances with specific characteristics that originated from different chemical functional groups, and they can be useful in the pharmaceutical industry for discovering new bio-drugs for different purposes. Attempts to create models of allocation to SMs were immediately met with two difficulties: (i) comprehending the development and upkeep of the astonishing diversity of chemicals produced in the plant world; (ii) identifying the patterns underlying the variance in quantities that may be seen in both inside and between plants of the same and different species.The plant NPs and their semisynthetic derivatives are the richest sources of biologically active compounds . PrimaryOn the other hand, there are promising efforts have recently been conducted in order to increase the discovery of plant SMs and their uses, focusing mainly on the following areas: (i) increasing the productivity of target single natural substance through the cell culturing process by altering the processing and bioreactor performance, or by using elicitors and/or other techniques, regardless of their underlying processes ; (ii) esRecently, there has been a great interest in the benefits of a wide variety of fruits and vegetables, which provide different bioactive SMs, including phytochemicals, vitamins, essential amino acids, minerals and fibers. However, the stability of those substances can be adversely influenced by various ecological and physical factors such as light, temperature and relative humidity . On the Some essential amino acids (EAA), such as histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine, are very important for diet and for several bodily processes, such as protein synthesis, tissue repair and nutrient absorption . Some EAAmong the main functions of plant metabolites, they can influence the physical food characteristics such as color, taste, consistency and smell . In addiThe use of some plant SMs in cosmetic preparations is principally due to their low mammalian toxicity . They arPlant SMs and their derivatives have been employed as therapeutic agents for the treatment of numerous diseases and illnesses since ancient times . Many naPapaver somniferum) in 1806 and used as drug precursors for several medicines [Artemisia annua has been used as an antimalarial drug containing sesquiterpene lactone, which treats malignant cerebral malaria caused by Plasmodium falciparum [Taxus brevifolia, a highly oxygenated tetracyclic diterpenoid, acts as an antimitotic agent that inhibits the polymerization of tubulin to form microtubules. The same substance has also been used as an effective drug against ovarian and breast cancers [Calophyllum lanigerum, is a non-nucleoside reverse transcriptase inhibitor (NNRTi) of type-1 HIV and an inhibitor of AZT-resistant strains of HIV [Some specific examples of plant SMs have been used as drug precursors, such as morphine, the first NPs isolated from the opium poppy  are involved directly in plant growth and metabolisms, such as carbohydrates, lipids and proteins; secondary metabolites (SMs) are considered the end products of primary ones, but not involved in the metabolic activity, such as  sesquiterpenes consist of three isoprene units and have the molecular formula C15H24; (iii) diterpenes are composed of four isoprene units and have the molecular formula C20H32; (iv) for sesterterpenes, terpenes have 25 carbons and five isoprene units; (v) triterpenes consist of six isoprene units and have the molecular formula C30H48; (vi) sesquarterpenes are composed of seven isoprene units and have the molecular formula C35H56; (vii) tetraterpenes contain eight isoprene units and have the molecular formula C40H64; (viii) polyterpenes consist of long chains of many isoprene units; (ix) norisoprenoids are characterized by the shortening of a chain or ring by the removal of a methylene group or substitution of one or more methyl side chains by hydrogen atoms.Terpenes are the largest group of plant SMs derived chemically from 5-carbon isoprene units ,84. The Lamiaceae, Pinaceae, Rutaceae and Apiaceae. Monoterpenes are classified into unsaturated hydrocarbons , alcohols , alcohol esters , aldehydes  and ketones  [In particular, monoterpenes consist of two isoprene units. They are important components of plant essential oils in the families of carvone) . Sesquitcarvone) . Diterpecarvone) . Among tcarvone) . GAs andcarvone) .Azadirachta indica), has an insecticidal activity; in fact, it is considered the main active ingredient in many pesticides such as treeAzin, azaMax, azaSol and terramera Cirkil [Pinus silvestris, Pinus taeda and Pinus ponderosa and has important antimicrobial, antioxidant, anti-inflammatory, anti-carcinogenic and insecticidal activities [Allium species, asparagus, oats, spinach, sugar beet, tea and sweet potato, are characterized by hypolipidemic properties. In addition, saponins can reduce cholesterol and lipoprotein levels and show anti-diabetic and cytotoxic activity [a Cirkil . Bornyl a Cirkil . Camphena Cirkil ,93. Limoa Cirkil ,95. \u03b1-Pitivities ,97,98. Sactivity ,100. 3-Cactivity ,102. ThePhenolic compounds (PCs) are one of the most important groups of plant SMs. The common characteristic of PCs is the presence of one or more phenol groups . The PCsFlavonoids are the largest group of naturally occurring phenols . FlavonoFlavones, derived from some fruit skins, red wine, buckwheat, red pepper and tomato skin, showed interesting antimutagenic activity and anti-inflammatory and antiviral effects ,114. FlaCaryophyllales, Magnoliales, Rosales and Gentiales [Nitrogen-containing compounds include alkaloids, cyanogenic glucoside and glucosinate . Alkaloientiales . Alkaloientiales ,113.Many alkaloids are valuable medicinal agents that can be utilized for treating various diseases, including malaria, diabetics, cancer, cardiac dysfunction, etc., such as quinine, ephedrine and homoharringtonine, which are used effectively for the treatment of malaria, inflammatory diseases and cancer therapy, respectively. Alkaloids play different roles for the plant during the metabolism process, such as storage reservoirs of nitrogen, protective agents against predators\u2019 attacks and growth regulators. Among the alkaloids, cyanogenic glucosides are present in more than 2500 plant species and play an important role in plant defense against herbivores. It has a bitter taste and releases toxic hydrogen cyanide upon tissue disruption. Cyanogenic glycoside was present principally in the bitter almonds seeds and other fruits such as apricots, almonds, peaches and apples. It can also be present in wine; however, its content depends on the levels in respective fruits and other factors such as temperature and alcohol concentration .Remijia sp. has antimalarial activity [Ephedra sp. and has anti-inflammatory activity [Cephalotaxus fortuneiand [activity . Quinineactivity . Quinineactivity . Ephedriactivity , and it activity . Homohartuneiand  was apprtuneiand . Homohartuneiand .Vinca minor play an important role as vasodilatory [Chelidonium majus has antibacterial activity [Piper longum and P. officinarum and is used as an antihyperglycemic agent [Vincamine extracted from dilatory . Vincamidilatory . Cheleryactivity ,131. Thiic agent . The cheFor several centuries, the natural products based-plant origins, particularly plant SMs, have been effectively used in agriculture, the food industry and pharmacological fields for controlling different phytopathogens, destructive insects, harmful weeds, food preservation and pharmaceutical drugs for humans .Among the most common plant SMs with antimicrobial effects against different pathogenic microorganisms are saponin, flavonoids, thiosulfinates, glucosinolates, phenolics, alkaloids and organic acids. The antimicrobial activity of plant SMs depends mainly on their chemical structures, principal constituents and effective dose. In particular, some terpenoids  and some phenolic compounds (isoflavonoids) are considered the main plant components demonstrating efficient antimicrobial activity . Shan etAsteraceae, Rosaceae and Punicaceae, produce bioactive SMs, including flavonoids, lignans, vitamins, carotenoids and terpenoid, which are characterized by strong antioxidant activities [Antioxidants are compounds able to inhibit the oxidation process, the chemical process that can produce free radicals and chain reactions and may damage the cells. Antioxidants are useful for increasing the quality of processed food and avoiding spoilage . The soutivities , as repoPunica granatum L.) fruits in the family Punicaceae are rich in acids, sugars, vitamins, minerals and phenolic compounds as strong antioxidant agents [In particular, pomegranate , a fungus-derived pleuromutilin extracted from Pleurotus mutilus, Pleurotus passeckerianus and Clitopilus scyphoides [Among the most recent common antibiotics from natural sources, we underline fidaxomicin (2010) and lipopeptide daptomycin (2003) derived from yphoides . A recenyphoides  reportedyphoides .There is no efficient therapy against viruses because they use the biological mechanism of host cells for their replication; for this reason, all possible virus treatments have serious side effects on the host cells . NaturalCalophyllum langigerum and showed effective HIV-RT inhibitory activity [Citrus sp.), Atropine (isolated from Atropa belladonna) and Scopolamine (isolated from Datura stramonium) illustrated antiviral activity against many viruses such as HSV [Shu  reportedactivity . SP-303 activity . Severalh as HSV ,163. Howh as HSV . In parth as HSV  reportedCurcuma longa, Zingiber officinale, Rosmarinus officinalis and Borago officinalis, which have promising applications in some clinical aspects [Zanthoxylum beecheyanum, chili pepper and Erythrina velutina, respectively, can be used as new promising anti-inflammatory drugs.Inflammation is a complex biological protective response of body tissues to microbial infection, tissue damage or irritants involving immune cells, blood vessels and molecular mediators . Several aspects . Natural aspects ,166. Rec aspects  reportedSeveral plant SMs have been reported to possess potential anticancer activity due to their capacity to prevent oxidative stress and inflammation that causes damage to DNA, which in turn leads to carcinogenesis . Natural1HNMR spectroscopic technology, a two-dimensional (2D) 1H\u201313C NMR strategy for the analysis of metabolites as multivariate statistical objects has been developed [Metabolomics is defined as a comprehensive quantitative and qualitative analysis of all metabolites present in a specific cell, tissue or organism. Targeted and global (or unbiased) metabolite analysis are the two main metabolomics methodologies. The chemical characterization for plant metabolites, particularly SMs, is a subset of analytic techniques such as gas chromatography\u2013mass spectrometry (GC\u2013MS) and liquid chromatography\u2013mass spectrometry (LC\u2013MS), together with an estimate of quantity. Various other techniques, including thin layer chromatography (TLC), Fourier transform infrared spectroscopy (FT-IR), Raman spectroscopy and nuclear magnetic resonance (NMR) are also part of the metabolite analysis ,172. Oneeveloped . The neweveloped . Mass speveloped ,176.Plants are a significant source of NPs that are used in various fields, including agro-pharmaceuticals, plant protection, plant growth-promoting, food preservatives, novel drugs, etc. Additionally, plant metabolites are considered a significant source of food additives due to their potent antioxidant action. Recently, plant SMs have gained considerable economic attention, which has enhanced their production and led to the identification of potential new biological applications for them. The current review study focused mainly on a number of biological and pharmacological characteristics of plant bioactive metabolites. In particular, this review has underlined the following points of plant metabolites: historical overview, nutritional, cosmetic, medical and agricultural uses, as well as their impact on plant protection and growth-promoting. The classification of plant metabolites was also considered in this review, focusing mainly on the main common SMs such as terpenoids, phenolic compounds (flavonoids) and nitrogen-containing compounds . Furthermore, the biological activity of plant SMs, either antimicrobial and/or antioxidant, was also discussed. Different pharmacological properties of plant SMs, such as antibiotic, antiviral, anti-inflammatory, anticancer and hepatoprotective activities, were also discussed. In conclusion, we hope that the information reported in this review will be helpful for whom are interested in studying plant NPs particularly secondary metabolites."}
+{"text": "Dear Editor,Hypotrichosis simplex (HS) is a rare form of hereditary nonsyndromic alopecia characterized by sparse or absent scalp hair, without other ectodermal or systemic abnormalities.We report the case of a 14\u2010year\u2010old girl who showed an improvement in her alopecia after 3\u00a0months of treatment with oral minoxidil. Since birth, the patient presented with progressive hair loss. In addition, since the first year of life she referred short and fragile eyelashes and eyebrows. The patient had normal physical development without other neurological or ectodermal alterations. Family history of any type of alopecia was denied.Clinically, the patient presented diffuse alopecia with sparse, short, and thin hair. Pull test was positive. Trichological examination highlighted yellow dots and vellus hairs on the whole scalp Figure\u00a0. TrichogThe following analyses were requested: blood count, erythrocyte sedimentation rate, liver, thyroid and renal function tests, serum electrolytes, urinalysis, blood glucose, the glucose tolerance test, Hb A1C, copper, zinc, and ferritin proteins, quantitative immunoglobulins, and amino acids all within normal values.Given the variety of differential diagnoses, especially in pediatric age with hair shaft disorders with or without fragility,HS is a rare form of hereditary nonsyndromic alopecia characterized by progressive hair loss confined to the scalp. This disorder occurs at similar rates in males and females. This process leads patients to almost complete baldness by the third decade. It can be inherited in an autosomal dominant or autosomal recessive manner. In almost 50% of the cases, the genetic etiology is not identified,Moreover, some articles document the efficacy of oral treatment with oral minoxidil and growth factors specifically for our patient's type of mutation.Fabrizio Martora, Gabriella Fabbrocini, Teresa Battista, Sonia Ocampo\u2010Garza, and Marina Vastarella performed the research. Fabrizio Martora, Teresa Battista, and Gabriella Fabbrocini designed the research study. Angela Patri and Gabriella Fabbrocini contributed essential reagents or tools. Fabrizio Martora, Paola Nappa, and Mariateresa Cantelli analyzed the data. Fabrizio Martora and Teresa Battista wrote the paper.Gabriella Fabbrocini acted as a speaker or consultant for Abbvie, Amgen, Eli Lilly, Janssen, Leo\u2010Pharma, Almyrall, Novartis, and UCB. None of the contributing authors has any conflict of interest, including specific financial interests of relationships and affiliation relevant to the subject matter or discussed materials in the manuscript."}
+{"text": "Grief is also associated with social isolation, poor mental health  and sleep difficulties. Screening efforts, guidance, and counseling from professionals of mental health care, primary health care, and universities health care services during and after the COVID-19 pandemic could be extremely beneficial for bereaved students, particularly for those at higher risk of developing prolonged grief disorder.No significant relationships."}
+{"text": "Rupture of an aneurysm is the leading cause of subarachnoid hemorrhage (SAH) which results in accumulation of blood between the arachnoid and pia mater, consequently increasing intracranial pressure. This often results in life threatening conditions like herniation or clinical presentations including focal neurological deficits. In children, these events, although rare, have significant implications. Pediatric SAH is associated with better outcomes in the hospital setting and may even be prevented proactively by the recognition of potential risk factors. Specifically, better recognition of genetic predispositions, metastatic lesions, and infectious causes of aneurysms is important to understand their growth and prevent hemorrhagic events. This review highlights the causes of pediatric SAH, reviews the models of current understanding of this etiology, and discusses the current treatment schema to provide a succinct summary and highlight gaps in current knowledge. This may lead to future investigations aimed at further improving prevention strategies, patient care, and patient outcomes. Pediatric subarachnoid hemorrhage (pSAH) is a relatively rare clinical event with life-threatening implications that affect 0.5 percent to 4.6 percent of children , 44, 49], 4944, 4Aneurysms in children are thought to be characterized by changes in arterial flow, extracellular matrix, and arterial wall deterioration or repair, all of which may trigger molecular alterations that lead to formation of aneurysms , 76. GenAlthough uncommon, pSAH secondary to neoplasms has been recorded in 3\u201310% of cases, with medulloblastoma , primitive neuroectodermal tumors, malignant astrocytomas, and ependymomas being the most prevalent , 72. PosPediatric aneurysms differ from classical adult aneurysms; they are rarer, tend to be larger, have an overall male predominance, are commonly caused by infection or trauma, and have increased predilection for the posterior circulation , 52, 70.Intracranial aneurysms may present in children commonly 2\u20134 weeks (but up to 10 years) following trauma, usually a closed head injury (72% of cases) and may present with massive epistaxis , 57. TraArteriovenous malformation (AVM) is perhaps the most important cause of intracranial vascular aneurysm formation responsible for 30\u201350% of spontaneous intracranial hemorrhages in this population . An AVM Intracranial aneurysms associated with infection, or infectious intracranial aneurysms (IIAs), account for about 15% of all pediatric intracranial aneurysms. The most common etiology of IIAs is septic emboli secondary to bacterial endocarditis, an intravascular source of infection which causes vegetation of an infected cardiac valve and subsequent embolization , 37, 46.Due to the rarity of SAH in the pediatric population, proposed models regarding this fatal condition are limited. However, retrospective studies help in better understanding the factors that contribute to SAH between the adult and the pediatric population. For example, male children develop cerebral aneurysms more commonly than female children. In adulthood, however, this pattern reverses and females have a greater tendency to develop aneurysms . AneurysAlthough, AVM or neoplasm development present a risk for SAH, most pediatric SAHs mostly occur when a cerebral aneurysm develops due to these etiologies or independently of them . Trauma SirT1 is another protein that has gotten attention because of its involvement in regulating the vasculature through various mechanisms but importantly vascular smooth muscle structural and functional homeostasis , 25, 41.Mycotic aneurysms usually arise from the arterial adventitia and present at arterial branches. They typically hemorrhage due to vessel wall impairment . BacteriPediatric SAH may be treated effectively by either microsurgery or endovascular techniques such as coil embolization whereby an aneurysm is stabilized to prevent rupture by placing a coil that prevents enlarging of false lumen , 60, 71.Treatment options also include endovascular embolization and stereotactic radiosurgery alone or in combination. The Spetzler-Martin (SM) grading scale, which estimates the risk for patient with undergoing neurosurgery by evaluating the AVM size, location, and pattern of venous flow, is often used to determine the treatment modality, with low grade, accessible SM grade 1\u20133 AVMs being best managed with surgery, while low grade inaccessible AVMs are best treated with stereotactic radiosurgery. High grade (SM grade 4\u20135) AVMs in pediatric patients are often deep or inaccessible making surgical excision less possible. The best treatment modality for these AVMs is unclear . ConservAggressive management is likely to result in superior clinical outcomes in pediatric patients , 53, 74.Pediatric patients are more likely to have favorable post-surgical outcomes, compared to adults . FavorabAs in adults, it is important to prevent rebleeding and vasospasm in pSAH. Rebleeding appears to occur more frequently in children (as high as 60%), perhaps because of delayed SAH diagnosis , 68. ThiFurthermore, postoperative angiographs confirmed vasospasm may be asymptomatic more often in children , 50. ProOf note, perimesencephalic nonaneurysmal subarachnoid hemorrhage (PNSH) is a benign, idiopathic SAH seen in approximately 15% of children with atraumatic SAH and presents with perimesencephalic or prepontine blood products on CT with negative subsequent angiogram . Up to 1Prior to surgical intervention, common pSAH management practices include Hunt and Hess grading, CT scan, digital subtraction angiography, aggressive intensive care, vasospasm prophylaxis, and EVD and ICP monitoring for those with poor preoperative grade , 56, 60.Postoperatively, a standard protocol should include nimodipine, seizure prophylaxis, steroids, and \u201ctriple-H\u201d therapy for those who develop vasospasm , 56. TheSAH is associated with trauma, infection, and vascular abnormalities in the pediatric population, and it requires high levels of care during management and after discharge. However, when identified in a timely manner, the outcomes for patients with pSAH are more favorable in this population. Specifically, preventing rebleeding and vasospasms, using pharmacotherapy to improve blood flow, and closely monitoring symptoms and vitals help prevent neurologic and hemodynamic complications. Patients who may develop such complications may require extended hospital stay, additional surgeries, and therapies like Triple-H. Many SAH survivors may develop chronically disabling medical disorders, including issues with mood, neurophysiological function, and memory. For populations with predisposing genetic conditions that affect vasculature (e.g. AVM formations), early monitoring may be an effective preventative measure for these acute events. Moreover, closing the knowledge gap on epidemiological and biochemical predisposition to aneurysmal growth and rupture will inspire better preventive, management, and treatment protocols for pSAH."}
+{"text": "Dementia and pain can challenge mobility, increase fall risk, and result in psychological consequences; however, the extent of these relationships among community-dwelling people living with dementia (PLWD) is unclear. Using the National Health and Aging Trends Study, we examined 9,974 community-dwelling older adults  for pain prevalence, mobility , falls, and psychological outcomes  using four groups with and without dementia (+PLWD/-PLWD) and pain (+Pain/-Pain). Groups were compared at baseline with ANOVA and chi-square and over time with repeated-measures ANOVA models. Pain  most commonly affected the low-back and knee. Group differences were significant for baseline mobility, falls, and psychosocial outcomes, p<0.01, but not SPPB over time. Therefore, pain is common, especially at low back and knee, and associated with health and function among PLWD, indicating a need for early and effective interventions that can preserve quality of life."}
+{"text": "Demodex folliculorum, Staphylococcus epidermidis, Bacillus oleronius, Cutibacterium acnes, and Helicobacter pylori and identified their role in the pathogenesis. Besides, we summarized the influence factors such as temperature and age on rosacea patients. We also systematically reviewed the commonly used clinical treatment methods, including antibiotics, probiotics. as well as their treatment mechanism and application precautions.Rosacea is a chronic inflammatory cutaneous disorder of uncertain etiology that mainly affects the centrofacial region, including cheeks, nose, chin, forehead, and eyes. The pathogenesis of rosacea remains unclear because it involves several complex factors. Additionally, the potential treatment methods need to be explored. We reviewed the common bacterial species in the skin microbiota and gut microbiota of rosacea patients such as  Rosacea is a chronic inflammatory cutaneous disorder of uncertain etiology that mainly affects the centrofacial region, including cheeks, nose, chin, forehead, and eyes. There are four subtypes of rosacea, which are erythematotelangiectatic rosacea, papulopustular rosacea, phymatous rosacea, and ocular rosacea . HoweverIn the pathogenesis of rosacea, there has been extensive discussion on the skin microbiota and its related inflammatory effects. Many different communities of microorganisms have been studied in the skin, formed by hundreds of microbial species occupying different environmental niches in the skin . The skiDemodex folliculorum, Staphylococcus epidermidis, Bacillus oleronius, and Cutibacterium acnes . After TLR 2 expression, antimicrobial peptides can be abnormally produced, and the expression and activity of serine kallikrein were also increased . Further factors . Moreove factors . At the thy skin . It coulthy skin .S. epidermidis, can replicate at different rates and can also secrete more virulence factors , These compounds can affect the intestinal microbiota and improve the environment of the skin, by increasing the number of beneficial gut microbes .Helicobacter pylori colonizes the human stomach and duodenum and is a microaerophilic Gram-negative bacterial species  and beta blockers . Persistent erythema: brimonidine , IPL and PDL. Inflammatory papules/pustules: azelaic acid , ivermectin , doxycycline  and metronidazole . Telangiectasia: electrodessication, IPL, and lasers. Phyma: doxycycline  and Isotretinoin . If there are multiple symptoms in a single patient, a variety of drugs could be used simultaneously to treat them. If treatment is unsatisfactory within a certain period, another treatment, or the addition of another first-line drug is recommended. The type of treatment and the patient\u2019s preference determine whether to continue treatment .Weissella confusa, a potentially beneficial microbe . MH was supported by US NIH Grants R01AI050875 and R21AI121700.MH declares the following potential conflicts of interest. Scientific Advisory Boards: Transdermal Cap Inc., Cleveland, OH; Hologenix Inc. Santa Monica, CA; Vielight, Toronto, Canada; JOOVV Inc., Minneapolis-St. Paul MN; Sunlighten, Kansas City, MO; Consulting; USHIO Corp, Japan; Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany; Klox Asia, Guangzhou, China. Stockholding: Niraxx Light Therapeutics, Inc., Irvine CA; JelikaLite Corp, New York NY.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Solid waste management (SWM) is one of the key responsibilities of city administrators and one of the effective proxies for good governance. Effective SWM mitigates adverse health and environmental impacts, conserves resources, and improves the livability of cities. However, unsustainable SWM practices, exacerbated by rapid urbanization and financial and institutional limitations, negatively impact public health and environmental sustainability. This review article assesses the human and environmental health impacts of SWM practices in the Global South cities that are the future of global urbanization. The study employs desktop research methodology based on in-depth analysis of secondary data and literature, including official documents and published articles. It finds that the commonplace SWM practices include mixing household and commercial garbage with hazardous waste during storage and handling. While waste storage is largely in old or poorly managed facilities such as storage containers, the transportation system is often deficient and informal. The disposal methods are predominantly via uncontrolled dumping, open-air incinerators, and landfills. The negative impacts of such practices include air and water pollution, land degradation, emissions of methane and hazardous leachate, and climate change. These impacts impose significant environmental and public health costs on residents with marginalized social groups mostly affected. The paper concludes with recommendations for mitigating the public and environmental health risks associated with the existing SWM practices in the Global South. It also fosters a circular urban economy that promotes reductions in the consumption of finite resources, materials reuse and recycling for waste elimination, pollution reduction, cost saving, and green growthSolid waste management (SWM) continues to dominate as a major societal and governance challenge, especially in urban areas overwhelmed by the high rate of population growth and garbage generation. The role of SWM in achieving sustainable development is emphasized in several international development agendas, charters, and visions. For example, sustainable SWM can help meet several United Nations\u2019 Sustainable Development Goals (SDG), such as ensuring clean water and sanitation (SDG6), creating sustainable cities and inclusive communities (SDG11), mitigating climate change (SDG13), protecting life on land (SDG15), and demonstrating sustainable consumption and production patterns (SDG12)  as well as the gray literature. The literature that satisfied the following three inclusion criteria was identified and downloaded: (1) It is related to the study\u2019s objective; (2) it is in the English language; and (3) it was published within the last twenty years, although some old documents about established concepts and approaches were also accessed. The downloaded gray literature includes newspaper articles, statistics, technical reports, and website contents from international development organizations such as the World Health Organization (WHO), the United Nations, and the World Bank.In the last stage, the authors organized, analyzed, and synthesized the data collected from the literature. The downloaded works were organized according to the similarity of topics, even though some fit in more than one category. Then, each document was thoroughly examined, and themes concerned with SWM practices and their human and environmental impacts were collated, synthesized, and harmonized. Finally, the themes were summarized in Global municipal solid waste (MSW) generation rose from 1.3 billion tons in 2012 to 2.1 billion tons (0.74 kg/capita/day) as of 2016, which by 2050 is expected to increase by 70% to reach a total of 3.40 billion tons or 1.42 kg/capita/day . The perIn Malaysia, while the average rate of MSW generation was about 0.5\u20130.8 kg/person/day, Kuala Lumpur\u2019s daily per capita generation rate was 1.62 kg in 2008 , which iMoreover, global SWM costs are anticipated to increase to about $375.5 billion in 2025, with more than four-fold increases in lower- to middle-income countries and five-fold increases in low-income countries . Globall(a)\u00a0Weak and Inadequate SWM SystemMany problems in the cities of the global South are often associated with a weak or inadequate SWM system, which leads to severe direct and indirect environmental and public health issues at every stage of waste collection, handling, treatment, and disposal ,32,33,34The problems associated with such practices are GHG emissions ,48, leac(b)\u00a0Irregular Waste Collection and Handling4) emissions, foul odor, air pollution, land and water contamination, and the breeding of rodents, insects, and flies that transmit diseases to humans. Decomposition of biodegradable waste under anaerobic conditions contributes to about 18% and 2.9% of global methane and GHG emissions, respectively [2) emissions [Uncollected and untreated waste has socioeconomic and environmental costs extending beyond city boundaries. Environmental sustainability impacts of this practice include methane  entered ocean ecosystems . Moreove.4% enterIn the global South, scavengers often throw the remaining unwanted garbage on the street. Waste collectors are rarely protected from direct contact and injury, thereby facing serious health threats. Because garbage trucks are often derelict and uncovered, exhaust fumes and dust stemming from waste collection and transportation contribute to environmental pollution and widespread health problems . In Indi(c)\u00a0Landfilling and Open Dumping4), a major GHG [Most municipal solid waste in the Global South goes into unsanitary landfills or open dumps. Even during the economic downturn during the COVID-19 pandemic, the amount of waste heading to landfill sites in Brazil, for example, increased due to lower recycling rates . In Johoajor GHG ,68. Landajor GHG . About 2ajor GHG . The ratajor GHG ,69,70,71ajor GHG .Open dumping sites with organic waste create the environment for the breeding of disease-carrying vectors, including rodents, flies, and mosquitoes ,77,78,793) from landfill sites can damage species\u2019 composition and plant leaves [Odors from landfill sites, and their physical appearance, affect the lives of nearby residents by threatening their health and undermining their livelihoods, lowering their property values ,82,83,84t leaves . In addit leaves ,84. Landt leaves .2 from landfill sites produce adverse health effects such as skin, eyes, nose, and respiratory diseases [Air and water pollution are intense in the hot and rainy seasons due to the emission of offensive odor, disease-carrying leachates, and runoff. Considerable amounts of methane and COdiseases ,87,88. Tdiseases ,89. Othediseases .3 per day. On the other hand, a properly engineered facility for waste disposal can protect public health, preserve important environmental resources, prevent clogging of drainages, and prevent the migration of leachates to contaminate ground and surface water, farmlands, animals, and air from which they enter the human body [Several studies report leachate from landfill sites contaminating water sources used for drinking and other household applications, which pose significant risks to public health ,93,94,95man body ,96. Moreman body ,97,98. Iman body .Co-mingled disposal of industrial and medical waste alongside municipal waste endangers people with chemical and radioactive hazards, Hepatitis B and C, tetanus, human immune deficiency, HIV infections, and other related diseases ,60,100. (d)\u00a0Open Burning and IncinerationOpen burning of MSW is a main cause of smog and respiratory diseases, including nose, throat, chest infections and inflammation, breathing difficulty, anemia, low immunity, allergies, and asthma. Similar health effects were reported from Nepal , India , Mexico,(e)\u00a0Composting2 emissions than other disposal approaches. In Korea, for example, composting has the highest environmental impact than incineration and anaerobic digestion methods [Composting is a biological method of waste disposal that entails the decomposing or breaking down of organic wastes into simpler forms by naturally occurring microorganisms, such as bacteria and fungi. However, despite its advantage of reducing organic waste by at least half and using compost in agriculture, the composting method has much higher CO methods . The aut methods . Some re methods ,106.As discussed in the section above, there are many negative impacts of unsustainable SWM practices on the people and the environment. Although all waste treatment methods have their respective negative impacts, some have fewer debilitating impacts on people and the environment than others. The following is the summary of key implications of such unsustainable SWM practices.Uncollected organic waste from bins, containers and open dumps harbors rodents, insects, and reptiles that transmit diseases to humans. It also produces odor due to the decomposition of organic wastes, especially in the summer, and leachates that migrate and contaminate receiving underground and surface waters.Open dumps and non-engineered landfills release methane from decomposing biodegradable waste under anaerobiotic conditions. Methane is a key contributor to global warming, and it can cause fires and explosions.Non-biodegradable waste, such as discarded tires, plastics, bottles, and tins, pollutes the ground and collects water, thus creating breeding grounds for mosquitoes and increasing the risk of diseases such as malaria, dengue, and West Nile fever.Open burning of MSW emits pollutants into the atmosphere thereby increasing the incidences of nose and throat infections and inflammation, inhalation difficulties, bacterial infections, anemia, reduced immunity, allergies, and asthma.Uncontrolled incineration causes smog and releases fine particles, which are a major cause of respiratory disease. It also contributes to urban air pollution and GHG emissions significantly.Incineration and landfilling are associated with reproductive defects in women, developmental defects in children, cancer, hepatitis C, psychosocial impacts, poisoning, biomarkers, injuries, and mortality.Therefore, measures toward more sustainable SWM that can mitigate such impacts must be worked out and followed. The growing complexity, costs, and coordination of SWM require multi-stakeholder involvement at each process stage . EarmarkFirst, cities should plan and implement an integrated SWM approach that emphasizes improving the operation of municipalities to manage all stages of SWM sustainably: generation, separation, transportation, transfer/sorting, treatment, and disposal ,71,77,86Second, local governments should strictly enforce environmental regulations and better monitor civic responsibilities for sustainable waste storage, collection, and disposal, as well as health hazards of poor SWM, reflected in garbage littering observable throughout most cities of the Global South ,84. In aThird, effective SWM requires promoting positive public attitudes toward sustainable waste management ,117,118.Fourth, there is the need to use environmentally friendly technologies or upgrade existing facilities. Some researchers prefer incineration over other methods, particularly for non-recyclable waste ,65. For Fifth, extraction and reuse of materials, energy, and nutrients are essential to effective SWM, which provides livelihoods for many people, improves their health, and protects the environment ,135,136.Lastly, for effective SWM, local authorities should comprehensively address SWM challenges, such as lack of strategic SWM plans, inefficient waste collection/segregation and recycling, insufficient budgets, shortage of qualified waste management professionals, and weak governance, and then form a financial regulatory framework in an integrated manner ,141,142.As global solid waste generation rates increase faster than urbanization, coupled with inadequate SWM systems, local governments and urban residents often resort to unsustainable SWM practices. These practices include mixing household and commercial garbage with hazardous waste during storage and handling, storing garbage in old or poorly managed facilities, deficient transportation practices, open-air incinerators, informal/uncontrolled dumping, and non-engineered landfills. The implications of such practices include air and water pollution, land degradation, climate change, and methane and hazardous leachate emissions. In addition, these impacts impose significant environmental and public health costs on residents with marginalized social groups affected mostly.Inadequate SWM is associated with poor public health, and it is one of the major problems affecting environmental quality and cities\u2019 sustainable development. Effective community involvement in the SWM requires promoting positive public attitudes. Public awareness campaigns through print, electronic, and social media are required to encourage people to desist from littering and follow proper waste-dropping practices. Improper SWM also resulted in water pollution and unhealthy air in cities. Future research is needed to investigate how the peculiarity of each Global South country can influence selecting the SWM approach, elements, aspects, technology, and legal/institutional frameworks appropriate to each locality."}
+{"text": "Rising rates of substance use, particularly synthetic opioids, have led to increases in fatal overdoses and injection-associated infections. Harm reduction, including infection prevention via provision of supplies and education, is an approach to minimize risk of severe outcomes. Although harm reduction services (HRS) are highly evidence-based, implementation in most healthcare settings is limited. The aim of this study was to identify facilitators and barriers to the implementation of HRS to inform strategies for increasing access and adoption of a comprehensive bundle of harm reduction resources within the VHA.Qualitative interviews were conducted using a semi-structured interview guide and explored how harm reduction is currently understood and implemented by VHA providers and was designed to identify perceived gaps and barriers. Data were analyzed using a directed content analysis. After barriers and facilitators were identified, they were mapped to relevant implementation strategies using the Consolidated Framework for Implementation Research - Expert Recommendations for Implementing Change (CFIR \u2013 ERIC) tool.15 interviews with VHA providers  were conducted across 5 sites. Multiple barriers and few facilitators to the provision of HRS were identified (Table\u00a01). Currently, HRS were thought to be fragmented and dependent on the knowledge, time, and comfort level of individual providers. Participants also highlighted stigma around substance use, limited support, and burdensome regulatory requirements. Existing infrastructure, social programming, and local champions were highlighted as facilitators. Given these factors, implementation strategies that may be bundled to promote adoption of HRS include engagement of champions, communications and educational strategies, existing policies, and creation of dashboards and tracking and feedback systems (Table\u00a01).HRS are effective, evidence-based, and patient-centered tools. Mapping of barriers to evidence-based implementation strategies may help improve integration of HRS into VHA healthcare, however, challenges addressing stigma remain a substantial barrier.Westyn Branch-Elliman, MD, MMSc, DLA Piper,LLC/Medtronic: Advisor/Consultant|Gilead Pharmaceuticals: Grant/Research Support."}
+{"text": "Robust, tightly regulated DNA repair is critical to maintaining genome stability and preventing cancer. Eukaryotic DNA is packaged into chromatin, which has a profound, yet incompletely understood, regulatory influence on DNA repair and genome stability. The chromatin remodeler HELLS  has emerged as an important epigenetic regulator of DNA repair, genome stability, and multiple cancer-associated pathways. HELLS belongs to a subfamily of the conserved SNF2 ATP-dependent chromatin-remodeling complexes, which use energy from ATP hydrolysis to alter nucleosome structure and packaging of chromatin during the processes of DNA replication, transcription, and repair. The mouse homologue, LSH (lymphoid-specific helicase), plays an important role in the maintenance of heterochromatin and genome-wide DNA methylation, and is crucial in embryonic development, gametogenesis, and maturation of the immune system. Human HELLS is abundantly expressed in highly proliferating cells of the lymphoid tissue, skin, germ cells, and embryonic stem cells. Mutations in HELLS cause the human immunodeficiency syndrome ICF . HELLS has been implicated in many types of cancer, including retinoblastoma, colorectal cancer, hepatocellular carcinoma, and glioblastoma. Here, we review and summarize accumulating evidence highlighting important roles for HELLS in DNA repair, genome maintenance, and key pathways relevant to cancer development, progression, and treatment. Maintenance of genome stability is critical for proper cell function, viability, tissue homeostasis, and cancer suppression. Indeed, significant levels of genomic instability are frequently associated with cancer ,2. The DIn eukaryotes, the genome is packaged with histone proteins into nucleosomes and higher-order structures, creating structurally and functionally distinct chromatin domains. Chromatin packaging and dynamic reorganization via nucleosome remodeling have a profound, yet incompletely understood regulatory influence on DNA repair, replication, and genome maintenance. Indeed, packaging of DNA into nucleosomes and assembly of higher order chromatin structures restrict access of repair factors to damaged DNA templates and substantially inhibits DNA repair processes ,5,6. TheOver the past decade, significant effort has been made towards understanding how genome stability is maintained in the context of nuclear chromatin. Several studies in yeast and human cells revealed that SNF2 ATP-dependent chromatin remodelers (ACR) play important roles in genome maintenance by facilitating and integrating various steps in the DNA damage response, including DNA accessibility, damage signaling, and repair ,9. ConseSaccharomyces cerevisiae (IRC5) and Neurospora crassa (MUS-30). HELLS is abundantly expressed in highly proliferating cells of the lymphoid tissue , skin, germ cells, and embryonic stem cells .,55.49,55and CCNA . It actsand CCNA . In glioand CCNA . One-thiand CCNA . In headand CCNA . HELLS iand CCNA . In keraand CCNA .The inability to effectively cope with genotoxic stress can lead to genome instability, mutagenesis, or cell death, molecular events that play critical roles in cancer development, progression, and treatment. Chromatin creates a functional platform for tight, multi-level regulation of DNA repair and genome maintenance pathways. HELLS has emerged as an important, chromatin-based regulator of DNA repair, genome stability, and multiple cancer pathways. However, several questions remain to be addressed concerning the cellular specificity, chromatin context, and mechanistic details of HELLS-mediated genome maintenance. Is HELLS involved in DNA repair in specific cell types, such as highly proliferating cells? Does HELLS coordinate multiple DNA repair pathways? Is HELLS necessary for modulating DNA repair across the entire genome, or are there specific genes and domains that rely on HELLS function? What is the influence of HELLS-mediated DNA methylation loss on DNA repair? How does overexpression of HELLS affect DNA repair, genome stability, and responses to chemotherapy-induced genotoxic stress? Understanding the molecular functions of HELLS as they pertain to DNA repair is important for advancing our understanding of chromatin-based genome maintenance and genome instability in cancer. Future studies investigating the role of HELLS in genome maintenance pathways will advance current understanding of cancer development and progression, and will likely uncover new therapeutic approaches, such as targeting HELLS to sensitize cancer cells to chemotherapy treatments.HELLS is emerging as an attractive potential therapeutic target because it is associated with regulation of a multitude of cancer pathways through enzymatic ATPase-mediated chromatin remodeling. Therefore, targeting HELLS could lead to simultaneous inactivation of multiple oncogenic pathways that sustain cancer proliferative potential, underlie genomic instability and collectively contribute to cancer progression and invasion. Specific small molecule inhibitors or proteolysis-targeting chimera degrader (PROTAC) could be developed to target HELLS. Several ATPase inhibitors, and degraders targeting number of SNF2 remodelers have been previously developed highlighting the feasibility of the approach ,62,63. T"}
+{"text": "Male infertility is an increasing and serious medical concern, though the mechanism remains poorly understood. Impaired male reproductive function affects approximately half of infertile couples worldwide. Multiple factors related to the environment, genetics, age, and comorbidities have been associated with impaired sperm function. Present-day clinicians rely primarily on standard semen analysis to diagnose male reproductive potential and develop treatment strategies. To address sperm quality assessment bias and enhance analysis accuracy, the World Health Organization (WHO) has recommended standardized sperm testing; however, conventional diagnostic and therapeutic options for male infertility, including physical examination and semen standard analysis, remain ineffective in relieving the associated social burden. Instead, assisted reproductive techniques are becoming the primary therapeutic approach. In the post-genomic era, multiomics technologies that deeply interrogate the genome, transcriptome, proteome, and/or the epigenome, even at single-cell level, besides the breakthroughs in robotic surgery, stem cell therapy, and big data, offer promises towards solving semen quality deterioration and male factor infertility. This review highlights the complex etiology of male infertility, especially the roles of lifestyle and environmental factors, and discusses advanced technologies/methodologies used in characterizing its pathophysiology. A comprehensive combination of these innovative approaches in a global and multi-centric setting and fulfilling the suitable ethical consent could ensure optimal reproductive and developmental outcomes. These combinatorial approaches should allow for the development of diagnostic markers, molecular stratification classes, and personalized treatment strategies. Since lifestyle choices and environmental factors influence male fertility, their integration in any comprehensive approach is required for safe, proactive, cost-effective, and noninvasive precision male infertility theranostics that are affordable, accessible, and facilitate couples realizing their procreation dream. Infertility has been defined as a reproductive disease that prevents a healthy woman from conceiving after at least 12 months of regular unprotected sexual intercourse . Th. Th21]. High alcohol intake and smoking have adverse effects on several sperm parameters , reducinAging, a complex multifactorial process, progressively impairs cellular function and promotes vulnerability to diseases. It is associated with disturbances in reproductive endocrinology that potentially causes andropause or late-onset hypogonadism in males ,43. HoweAndropause increases the risk of spontaneous abortions and complications in infancy, including lower birth weights, genetic diseases, schizophrenia, and autism ,46. AginThe multiple facets affecting male infertility , deeply Given the complex etiology of male infertility, several factors possibly interact. In the era of precision medicine, more comprehensive biomarker sets, combining conventional parameters  and omics-technology-driven markers , transcripts, proteins, and metabolites), are required to elucidate the molecular and pathophysiological basis of male infertility. Hence, improved molecular stratification using effective testing approaches can be implemented towards developing more accurate diagnostics and effective therapeutics.https://www.who.int/news/item/27-07-2021-who-launches-updated-manual-to-ensure-high-quality-testing-of-human-semen-in-clinical-and-research-settings, accessed on 21 February 2022). According to these guidelines, the two primary quantifiable attributes are spermatozoa number and the fluid volume secreted by various accessory glands [Sperm morphology and seminal fluid parameters are considered primary morphological and physicochemical diagnostic markers of male infertility and are crucial for the development of suitable treatments. To avoid inter-laboratory bias, the WHO published a standardized laboratory manual in 1980 for the examination and processing of human semen; the most recent revision was published in 2021 and includes the latest techniques  has become an important prognostic and diagnostic marker  and corrDNA damage can broadly be classified into two categories: endogenous and exogenous. Endogenous DNA damage arises from naturally present factors or chemicals; exogenous DNA damage is induced by foreign agents or factors . The maiDNA replication errors and base mismatches can occur during cell division. These errors or mismatches escape proofreading and mismatch repair (MMR) pathways and become mutations in the ensuing replication round or result in DNA damage ,64. TopoSeveral assays are used to assess SDF, despite varying results between tests . Based oSeveral techniques are used to assess sperm DNA fragmentation, including: (i) aniline blue staining and the chromomycin A3 test, (ii) sperm chromatin structure assay (SCSA), (iii) sperm chromatin dispersion (SCD) test, (iv) comet assay or single-cell gel electrophoresis (SCGE), and (v) DNA-breakage detection-fluorescence in-situ hybridization ,68 Tabl.However, these tests do not reveal the type and location of DNA damage. Therefore, high-throughput DNA sequencing platforms are recommended for improved specificity, accuracy, coverage, and discovery of DNA fractures, microdeletions, and SNPs, besides improved statistical power in infertility status analysis.Approximately 2000 protein-coding genes contribute to the genesis and maturation of millions of male gametes, which takes 72 days to complete. Therefore, the genetic landscape of male infertility is highly complex and is an emerging area of research. Genetic factors impact all major etiological categories of male infertility, and some can be tested by routine diagnostics . GeneticAlthough karyotype is the oldest known genetic testing of azoospermia/oligozoospermia, Y-CMs have become increasingly relevant genetic causes of male infertility, thanks to the development of potent molecular analysis tools. Y-CM is more prevalent in spermatogenic failure than in normochromic men, and occurs in 5% of oligozoospermic men and 10% of men with azoospermia . The vasThe X chromosome does not undergo replication during meiosis; therefore, it is seemingly protected from unpaired chromosome inactivation, similar to the Y chromosome. Although the X chromosome may have an important function in germ cell survival, X-linked palindromic genes might not be essential for spermatogenesis . Most siMAGEA9, a gene on the X chromosome that is specifically expressed in the testis under physiological conditions [RBMY1 and DAZ. However, other male-fertility-related Y-linked genes may be involved, given that some show clear up- or down-regulation in infertile men [CNVs are structural variants with changes in the number of copies of specific DNA regions compared with the reference genome. CNVs are major causes of human genome variability due to deletion or duplication of the original sequence, without any additional mutation, resulting in unequal crossover between or within chromosomes. Quantitative spermatogenic disturbance analysis revealed that X-linked CNVs were associated more with infertile men than controls . For exanditions . Similarnditions . Indeed,nditions ; thus, atile men .Gene polymorphisms are genomic variations, in which two or more discontinuous genotypes or alleles are simultaneously present in a population. SNPs are variations caused by mutations at a single position in a DNA sequence. Disease-associated genetic variants are highly penetrant monogenic variants\u2014a single gene mutation leading to a consistent disease phenotype. Although these variants may be associated with the disease, they do not directly affect gene function . The majMLH1 is involved in spermatogenesis and is associated with male infertility , likely through epigenetic regulation  [The MMR pathway plays a critical role in the maintenance of genome integrity, meiotic recombination, and gametogenesis. SNPs in MMR genes reduce MMR function and may lead to mutations in other genes. SNPs  in MMR genes result in male infertility ,64,89. Tylation) .Mitochondrial genes are the key molecular components of sperm cells. Mature mammalian spermatozoa contain large amounts of mitochondria required for energy production to support motility. Mitochondria also regulate several pathways involved in spermatogenesis . A higheSpermatozoa are considered sophisticated paternal-genome-delivery vehicles that contain several nucleic acids (DNA and RNA) in their cytoplasm . More thEpigenomics is the main route of environmental impact on male (in)fertility . DNA metHistones are suitable candidates for the transmission of epigenetic information, given their involvement in chromatin folding and transcription regulation . AberranThe emergence of high-throughput techniques has enabled exploration of the relationship between DNA methylation and male infertility . These gThe spermatozoon is a highly specialized and easily accessible cell. Therefore, it is remarkably suitable for proteomic analysis, as a whole cell or isolated organelles, of the expression of functional and structural proteins, during either spermatogenesis or spermiogenesis and all their post-translational modifications. Other techniques, including Western blotting and ELISA, are used to identify targeted proteins. Despite the progress made in understanding some molecular events associated with sperm maturation and fecundity, additional studies are required to unravel the pathophysiology of male infertility at the proteomic level ,121.Proteomics of mature sperm cells generally reveals two types of proteins: (i) proteins of extracellular origin , adsorbed on the surface of the ejaculated sperm cell, such as seminogelin-1 and prostate-specific antigen (PSA), and (ii) sperm cell proteins divided into detergent soluble and insoluble fractions. The detergent-soluble fraction comprises proteins in the cytoplasm, signaling molecules, and membrane receptors, whereas the detergent-insoluble fraction comprises cytoskeletal/structural and nuclear-chromatin-binding proteins. Up to 11% of sperm proteins participate in cell defense against OS and apoptosis. Therefore, the differential expression of these protective factors in the sperm of infertile men with leukocytospermia may explain the generation of OS in these patients. Additionally, several proteins that correlate with sperm DNA integrity have been identified and can serve as markers to discriminate obstructive from nonobstructive azoospermia ,123. CluMetabolomics is another high-throughput technology used to study disease mechanisms and diagnosis, with seminal fluid, serum, and urine samples being commonly used for metabolomic fingerprint research in male infertility ,127. A sDespite efforts to use omics technologies in identifying clinically actionable biomarkers, the studies are scattered and performed mostly at an institutional level, therefore, requiring multicentric validation and association with other omics and clinical settings to be translated safely and effectively. High-throughput technologies are required to study the genomic, transcriptomic, proteomic, metabolomic, and metagenomic profiles of infertile men and their association with sperm DNA damage, inflammation, and ROS using appropriate controls (fertile donors).So far, no pharmacological treatments for stimulating spermatogenesis in primary testicular failure have been approved. The main therapeutic option for infertile men is assisted reproductive technologies (ARTs) followed by surgery.6 motile cells) can be retrieved. When >3 cycles of IUI fail, optimized in-vitro fertilization (IVF) using ICSI is usually recommended. Sperm cells, in this case, are recovered either surgically or from seminal fluid [In the USA, ~1% of successful births were attributed to ARTs in 2001. ARTs encompass ovarian stimulation, sperm retrieval, in-vitro gamete assessment, intrauterine insemination (IUI), intracytoplasmic sperm injection (ICSI), gamete and/or embryo cryopreservation, and IVF. Other procedures, such as preimplantation genetic diagnosis and -screening (PGD and PGS), are also considered adjunctive tools for ART. In the absence of evidence-based science, management of male factor infertility relies extensively on ARTs. IUI is the primary option when the female partner is fertile and enough motile spermatozoa , using microsurgical epididymal sperm aspiration (MESA), percutaneous epididymal sperm aspiration (PESA), or reconstructive surgery. TESE/micro-TESE can retrieve testicular sperm in up to 50% of NOA patients . HoweverReconstruction of the testes and scrotum for male infertility treatment may fall under simple hydrocelectomy; however, this could be complex in some cases. In adults, hydroceles were found in 1% of fertile men, while 0.7% were found in infertile conditions. In the primary stage, tetracycline or phenol is injected into the hydrocele, a technique known as sclerosing or sclerotherapy, which can alleviate 60\u201390% of scrotal problems. This constitutes a simple option for removing hydroceles and improving male fertility .Although conventional penile reconstruction has many disadvantages , advance2O2 into molecular oxygen and water; however, its usage and effect in human sperm remain uninvestigated [Antioxidants can scavenge free radicals and treat OS in infertile patients . The thestigated . Glutathstigated . Anotherstigated ,152.A non-enzymatic antioxidant group, obtained either through endogenous metabolism or diet, can be used to address male infertility . This grOther antioxidants, such as N-acetylcysteine (NAC), melatonin, alpha-lipoic acid (ALA), and omega-3 fatty acids (OFA), can also be applied in fertility management. NAC, a precursor of GPX, can directly stabilize free radicals by donating an electron from its outer layer. Multiple studies involving NAC have shown that it improves male fertility by increasing seminal fluid , reducinVitamins play an essential role in the normal functioning of the human body, with vitamins C, E, and B9 (folic acid) being the most relevant in male fertility . In sperMinerals, especially zinc and selenium, influence male fertility. Zinc is a micronutrient that participates in cell signaling, enzyme activity, normal growth and sexual maturation regulation, and management of mitochondrial OS. Zinc incorporation into sperm may protect against sperm decondensation and alleviate sperm motility, membrane stabilization, antioxidant capacity ,196, andHormone-based therapy involves the use of hormones or their antagonists in medical treatment. Hormone therapy improved endogenous follicle-stimulating hormone and/or androgen levels and, subsequently, spermatogenesis in infertile men . GonadotSelective lifestyle choices are cost effective, accessible, and useful as male infertility prevention and treatment tools. The duration of infertility, age of the couple, and comorbidities are among the main factors influencing spontaneous conception . FrequenLifestyle changes associated with a healthy diet represent a potentially important treatment for male infertility . A high In the post-genomic era, advanced multiomics and digital approaches have revolutionized biomedical research. These omics technologies have allowed unprecedented resolution of molecular processes, as well as the accurate diagnosis and molecular stratification of diseases, including idiopathic male infertility. Advances in whole-genome and whole-transcriptome amplification have expedited the sequencing of minute amounts of DNA and RNA from a single cell and provide a more representative scope of the nature of genomic and transcriptomic heterogeneity that occurs in both normal and diseased cells .Stem cell therapy has recently emerged as a new approach to infertility management. In addition, advanced cell culture technology and in-vitro cell proliferation models allow somatic cell use in infertility treatment . AdvanceMale infertility microsurgery has significantly progressed, with new and emerging techniques, technologies, and methodologies being continuously developed . RoboticAmong others, genomics, transcriptomics, epigenomics, proteomics, metabolomics, reactomics, pharmacogenomics, and bioinformatics are particularly relevant \u201cspermomics\u201d/multiomics technologies in the assessment of sperm cells and seminal fluids and can enhance our understanding of the molecular events driving spermatogenesis and spermiogenesis in fertile versus infertile men. These approaches provide unprecedented power of data analysis, visualization, interpretation, and compilation .In male reproductive medicine, efforts in \u201cspermomics\u201d technologies and associated efforts are scattered, hampering tangible, reproducible, and clinically actionable outcomes . TherefoWhile advanced molecular biology and DNA damage assays allow clinicians to assess idiopathic male infertility, microsurgery has increased the success rates of spermatozoa retrieval for assisted conception. In reproductive endocrinology, PGD and PGS are used for genetic and aneuploidy testing to identify the relevant cause(s) of infertility, provide personalized management, and improve IVF outcomes. Although some individuals with antioxidant/ROS imbalance could be treated with oral supplementation of antioxidants , deeper Precision medicine aims to provide an effective and individualized treatment plan through a comprehensive data-driven approach based on omics techniques. Personalized molecular treatment is the basis of all ongoing efforts in the development of male reproductive medicine. Demystifying the complex etiology of male infertility requires a comprehensive approach that combines all relevant aspects to achieve precision male infertility theranostics , includiOf note, the progress in male infertility management and treatment have been associated with several ethical issues that need to be addressed, especially that more couples are deferring having children to older ages due to several reasons. In fact, the IVF, ICSI, sperm donation, long-term gametes freezing, posthumous sperm retrieval are ART procedures that have been concomitantly associated with ethical debates, consenting dilemmas, and socio-legal issues. The desire of having a child using the latest technologies, discussed herein and elsewhere, is far from being a smooth decision for couples and/or doctors. The rights and values of couples, their families, and their future children, should be integrated together while considering the values and ideals of the society to reach an informed, concerted, and balanced decision/judgement that maximizes the benefits while minimizing/preventing the harms.Since the pathophysiology of male infertility is still obscure, it is worthwhile to combine the advanced approaches, especially high-throughput multiomics technologies and big data tools, into comprehensive and large-scale strategies, along with lifestyle choices and environmental factors, in order to develop diagnostic clues, management avenues, and promising therapeutic options towards precision male infertility therapeutics and diagnostics.This review highlights the importance of integrative approaches that combine conventional sperm analyses, omics technologies, digital tools, as well as the effects of lifestyle and environmental determinants of male infertility. Sperm cells, along with the seminal fluid, are the host of key biomarkers/bioindicators to assess male fertility power, accurately diagnose possible infertility, and predict potential effects on embryo development and offspring health. Given the increasing burden of male infertility on populations worldwide, global networking and collaboration is urgently needed to establish comprehensive strategies that are representative of the population being treated, consider the most immediate environmental factors, and incorporate the latest advances in analytical technologies, including omics tools, stem cell therapy, robotic surgery, ART, big data, and digital algorithms. Therefore, collaboration across all relevant fields and the involvement of all stakeholders would facilitate the success of future clinical approaches. Incorporation of biological, environmental, socioeconomic, and lifestyle determinants will not only help elucidate the intricate networks that govern susceptibility, causes, and molecular progression in male infertility, but will also advance the characterization of accurate biomarkers, from genes to metabolites, and establishment of comprehensive, proactive, cost-effective, precise, and accessible curative strategies.Multi-institutional efforts are crucial not only in alleviating the tremendous technical and infrastructural limitations, but also to address cultural, educational, logistic, and socioeconomic limitations. Most importantly, unless the public is educated to improve awareness, break down stigmas, and inform patients of potential curative options and their possible side effects , no clinical advance will be successful. Additionally, omics-driven medicine training should be provided to a broader range of healthcare professionals to accelerate the application of new diagnostic tools and innovative therapeutic options. Finally, the advent of digital health applications could also equip patients to become proactive in addressing infertility."}
+{"text": "Increased exposure to greenspace is potentially associated with lower risk of Alzheimer\u2019s disease and related disorders (ADRD) through increased physical activity, decreased stress, cleaner air, and social cohesion. Previous studies have primarily used global measures of greenspace, thus specific aspects of different types of greenspaces are overlooked. We assess how different measures of greenspaces associate with global cognitive functioning. We examined data from year 10 of the Pittsburgh site of Health, Aging, and Body Composition Study, a longitudinal cohort study of community-dwelling, Black and White adults aged 70\u201379 years at baseline. Measures derived from the National Land Cover Database (NLCD) use satellite imaging and include total greenspace, forests, and an index of greenspace diversity. Measures from Google Street View virtual neighborhood audits include dedicated greenspace that promotes physical activity, abandoned buildings, and undeveloped land. We measured global cognitive functioning using the Modified Mini-Mental State Examination (3MS). We conducted cross-sectional linear regression models. Covariates included race, education, and neighborhood socioeconomic status. Age was not included as a covariate because the range was narrow, and results did not vary by age. The sample (n=584) was 82.2 years old on average, 57% female, and 35% Black. Total greenspace , forests, and greenspace diversity, dedicated greenspace for physical activity , undeveloped land , and abandoned buildings  were not associated with 3MS, although the relation with abandoned buildings approached significance. We found no association between greenspaces and ADRD, although specific measures, such as abandoned buildings, may need further investigation."}
+{"text": "Linear immunoglobulin A (IgA) bullous dermatosis (LABD) is an autoimmune disease affecting children or adults that leads to subepithelial vesiculobullous lesions on the skin and/or mucosa. Due to the histologic and clinical appearance of the disease with tense and pruritic blisters, direct immunofluorescence is required for diagnosis, which features the characteristic linear deposition of IgA autoantibodies along the basement membrane zone. LABD can be idiopathic, drug-induced, or associated with a systemic disease such as inflammatory bowel disease. Many drugs have been implicated, such as antibiotics, anti-hypertensives, anti-epileptics, analgesics, and immunosuppressive medications. Treatment of LABD centers on discontinuation of the offending drug, if applicable, as well as pharmacotherapy with dapsone as the first-line treatment. Adjunctive therapy with sulphonamides, systemic corticosteroids, cyclosporine, colchicine, intravenous immunoglobulins, tetracyclines, erythromycin, and dicloxacillin has also shown benefits. We report the case of a young adult patient who developed LABD with a background of recent initiation of treatment with imipramine and newly diagnosed ulcerative colitis. Linear immunoglobin A (IgA) bullous dermatosis (LABD) is a rare autoimmune disease featuring subepithelial vesiculobullous lesions on the skin and/or mucous membranes . LABD isAn 18-year-old male with a history of epilepsy on levetiracetam, chronic constipation and abdominal pain since infancy, and chronic nocturnal enuresis since infancy started on imipramine one week prior and presented with a painful, itchy, diffuse skin eruption that worsened over 24 hours. The patient initially had tense vesicles on his neck, ears, and upper chest the previous day when evaluated by outpatient Allergy and Immunology. He was advised to discontinue imipramine due to concern for drug allergies and was prescribed empiric valacyclovir for herpes simplex virus and trimethoprim-sulfamethoxazole for bullous impetigo. However, the eruption then quickly spread to include his lower lip, abdomen, arms, and legs. The patient noted that the vesicles were tense and painful, especially after bursting. Additionally, the patient noted fatigue, generalized weakness, chronic constipation, abdominal pain in the bilateral lower quadrants with bowel movements, and occasional bright, blood-coated stools. The patient denied fever, chills, intraoral or esophageal lesions, odynophagia, dysphagia, arthralgia, myalgia, melena, nausea, vomiting, headache, and new exposures prior to the rash eruption, including poison ivy, new hygiene products, or new detergents.Initial physical examination revealed the patient was afebrile, hemodynamically stable, with vesicles noted in the external auditory canals, moist mucous membranes without mucosal lesions, and a diffuse eruption with vesicles and bullae noted on the outer aspect of the lower lip, posterior neck, upper back, chest, arms sparing the palms, and legs sparing the soles. Some of the lesions appeared to be tense bullae, while others were less tense and umbilicated primarily on the dorsal hands and feet. Some of the lesions had burst, but most notably, there was a negative Nikolsky sign. Over the next few days, bullous lesions clustered in the classical pattern of a \"string of pearls,\" as demonstrated in Figures Initial work-up included negative swabs via PCR for herpes simplex virus 1, herpes simplex virus 2, and varicella zoster, as well as a superficial wound culture of the posterior neck with rare Staphylococcus aureus. Laboratory findings included leukocytosis with eosinophilia, neutrophilia, mild monocytosis, microcytic anemia with iron deficiency, reticulocytosis, thrombocytosis, elevated inflammatory markers, elevated haptoglobin, and low ferritin (Table The patient underwent esophagogastroduodenoscopy (EGD) and colonoscopy; EGD revealed a non-bleeding duodenal erosion, and duodenal biopsies were taken Figure . DuodenaImipramine was discontinued before hospitalization and not resumed due to the suggestion of drug-induced dermatosis. The patient was started on oral prednisone 10 mg when eruption failed to improve with supportive care after receiving one dose. The corticosteroid regimen was up-titrated the following day for worsening pain to methylprednisolone 125 mg intravenously twice daily, for which the patient received four days of treatment. As the eruption had improved, the patient was weaned to oral prednisone 40 mg daily, receiving two days of therapy before the eruption worsened again. Oral prednisone was increased to 60 mg with the addition of oral azathioprine 50 mg twice daily. Despite this, the eruption worsened, which necessitated further up-titration of corticosteroids to methylprednisolone 500 mg intravenously daily for three days while continuing azathioprine at the current dose. Treatment with oral dapsone was initiated, partly as a steroid-sparing medication for LABD and partly for\u00a0Pneumocystis jirovecii prophylaxis. After completion of the intravenous methylprednisolone three-day course, the patient was transitioned to oral methylprednisolone 64 mg daily, at which point azathioprine was also stopped. Treatment with infliximab was initiated after discharge due to findings of ulcerative colitis on a colonoscopy. The patient was ultimately discharged on oral methylprednisolone, dapsone, and infliximab infusion as an outpatient. On follow-up four weeks and three months later, the patient had complete resolution of skin lesions, with moderate pigmentation at the site of some previous skin lesions but no scars and no abdominal pain.We report a case of newly diagnosed ulcerative colitis (UC) with recent imipramine use for chronic nocturnal enuresis who subsequently developed biopsy-proven linear IgA bullous dermatosis and was found to also have UC. The patient was successfully treated with a corticosteroid regimen and dapsone during his inpatient stay, followed by infliximab.The pathogenesis of linear IgA bullous dermatosis involves circulating IgA autoantibodies targeting the basement membrane zone specifically at the lamina lucida\u2019s BP180, BP280, and LAD285 molecules. For BP180, also known as bullous pemphigoid antigen 2 (BPAG2), autoantibodies tend to target the 97 kDa subunit at the NC16A domain or the 120 kDa/97 kDa ectodomain of the molecule in immunobullous diseases such as bullous pemphigoid or LABD. Collagen type 7 has also been identified as an IgA autoantibody target, particularly in the sub-lamina densa variant of LABD, though the complete pathophysiology is not yet well understood ,6. The pLinear IgA bullous dermatosis can be idiopathic, drug-induced, or associated with systemic disease. As mentioned above, there are many systemic diseases that have been associated with LABD: rheumatoid arthritis, psoriasis, systemic lupus erythematosus, dermatomyositis, multiple sclerosis, celiac disease, Crohn\u2019s disease, and UC ,6. UlcerDrug-induced LABD represents a significant portion of cases for adult patients ,4,6. TypTreatment of LABD largely centers on pharmacotherapy but also must consider instigating agents. Drug-induced LABD treatment starts with discontinuation of the offending drug, which can result in gradual, spontaneous resolution of the eruption within several weeks ,4. HowevIn conclusion, we present a case of biopsy-proven linear IgA bullous dermatosis associated with newly diagnosed ulcerative colitis and imipramine use. Regarding this case, it is challenging to truly isolate the primary etiology of LABD in this patient. The etiology could be a purely ulcerative colitis-induced LABD that is triggered to manifest by imipramine due to the timing of the initiation of this medication and the onset of skin manifestations. LABD has a frequent association with ulcerative colitis; however, imipramine has yet to be identified as a causative drug in the literature. We suggest that this patient likely has drug-induced linear IgA bullous dermatosis from imipramine with underlying ulcerative colitis."}
+{"text": "Necrotizing enterocolitis (NEC), the most common gastrointestinal emergency in the neonatal intensive care unit (NICU), is a leading cause of preterm infant morbidity and mortality. This multifactorial disease is heavily predicated on intestinal barrier immaturity, hyperinflammatory immune cells, and dysbiosis. Intestinal inflammation, often closely following enteral feeds, results in bacterial translocation of the intestinal barrier, sepsis, multiorgan failure, and, frequently, death . DespiteRecently, animal modeling in germ-free or Toll-like receptor knockout (TLR KO) mice has indicated dysbiosis is likely required, but not sufficient, in driving NEC pathogenesis ,4. A numThe development of the infant microbiome is highly dynamic and easily influenced by host, maternal, and environmental factors. While research has implicated a number of pathogenic constituents of the NEC microbiome, interactions between host epithelial and immune cells, including alleles predisposing these infants to NEC risk, and the collective intestinal microbiome, likely dictate NEC pathogenesis. Compared with healthy term infants, the microbiome of preterm infants is characterized by distinct, but less diverse, taxa, with a progression dictated largely by postmenstrual age . ComponeVolatile organic compounds (VOCs) have recently emerged as noninvasive fecal biomarkers of microbiome shifts, with the potential to diagnose NEC before obvious symptoms are present. VOCs are detectable through gas chromatography (GC), mass spectrometry (MS), and, very recently, electronic nose (eNose) technology. Use of eNose technology to detect NEC in animal models has been promising, but clinical applications have been limited due to non-standardized protocols for stool acquisition, as well as differences in signals among age groups and dietary patterns . MetagenPrebiotics , probiotics (microorganisms with a demonstrated host benefit), and synbiotics (mixtures of pre- and probiotics) are of continuing interest for prevention or therapeutic use in NEC. These supplements, when used in the early postnatal period, are capable of modulating preterm infant microbiome development, thus potentially mitigating or preventing the development of NEC. Differences in study designs, enrollment criteria, and supplement composition have resulted in wide variability among randomized controlled trial (RCT) outcomes thus far, but more targeted study populations and higher standards for purity using commercially produced supplements are likely to show benefit in preterm infants at risk of developing NEC .In this Special Issue, entitled \u201cNeonatal Microbiome, Intestinal Inflammation, and Necrotizing Enterocolitis\u201d, recent influences on, iterative improvements in, and challenges to healthy neonatal microbiome development, particularly in relation to intestinal inflammation and necrotizing enterocolitis, are reported."}
+{"text": "Pork quality is a factor increasingly considered in consumer preferences for pork. The formation mechanisms determining meat quality are complicated, including endogenous and exogenous factors. Despite a lot of research on meat quality, unexpected variation in meat quality is still a major problem in the meat industry. Currently, gut microbiota and their metabolites have attracted increased attention in the animal breeding industry, and recent research demonstrated their significance in muscle fiber development and fat deposition. The purpose of this paper is to summarize the research on the effects of gut microbiota on pig muscle and fat deposition. The factors affecting gut microbiota composition will also be discussed, including host genetics, dietary composition, antibiotics, prebiotics, and probiotics. We provide an overall understanding of the relationship between gut microbiota and meat quality in pigs, and how manipulation of gut microbiota may contribute to increasing pork quality for human consumption. Pork, a vital source of animal protein for human growth and development, is one of the most commonly consumed meats in the world. According to the UN\u2019s Food and Agriculture Organization, a powerful growth with an expected increase of 13% by 2030 will occur in pig husbandry [Like other farm animals and humans, the gastrointestinal tract of pigs contains trillions of commensal microorganisms, mainly bacteria, which constitute the gut microbiota and are closely associated with host physiological functions , feed efSkeletal muscle accounts for approximately 50% of body mass in mammals and its growth and development affect indirectly the quantity and quality of pork  ,18,19. IMYH7, MYH2, MYH1, and MYH4 genes, respectively [Gut microbiota are involved in maintaining skeletal muscle mass. For example, germ-free mouse skeletal muscle showed a reduction in skeletal muscle mass compared to the pathogen-free mouse skeletal muscle. However, the mouse muscle mass lost could be restored partially following fecal microbiota transplantation from pathogen-free mice into germ-free mice ,23. Simiectively . Importaectively . Growingectively . Moreoveectively  found thectively .Prevotella, Treponema, Bacteroides, and Clostridium, which are involved in polysaccharide degradation and amino acid metabolism [Prevotellaceae UCG-001, Alistipes in the cecum and Clostridium sensu stricto 1 in the jejunum) were identified to be highly positively correlated to IMF by 16S rRNA gene sequencing [Intramuscular fat (IMF), deposited among muscle fibers or within muscle cells, is a vital factor influencing pork quality. With the development of omics technology, the gut microbiota associated with IMF deposition have been gradually elucidated. For instance, Fang et al. revealed that the vast bulk of the IMF-associated operational taxonomic units (OTUs) belonged to bacterial genera such as tabolism . A furthquencing . Furtherquencing . The aboShort-chain fatty acids (SCFAs)  are gut-derived metabolites produced by anaerobic microbes through fermentation of indigestible dietary fiber in the host . These SIt is known that changes in protein metabolism ultimately result in the changes in skeletal muscle mass and phenotype. Therefore, changes in mass and phenotype can be used to infer changes in protein metabolism within skeletal muscle. Mounting evidence suggested that SCFAs supplementation influences skeletal muscle mass in mice ,38,39. MSimilarly, the direct impacts of the SCFAs on skeletal muscle lipid metabolism have been documented in vivo and in vitro studies. In L6 myotubes, butyrate or acetate treatment was able to enhance fatty acid oxidation or uptake, respectively ,42. StudLachnospiraceae, Ruminococcaceae, Prevotella, Treponema, and Bacteroides, have been shown to significantly influence fatness in pigs [Globally, the incidence of obesity and obesity-related complications is increasing quickly , which h in pigs ,46. TherGut microbiota are essential to host health and well-being , dependiSCFAs are the ligand of G protein-coupled receptors 43 (GPR43) or GRP41 on enteroendocrine cells , and itsPrevotella copri triggered chronic inflammation through promoting the production of several metabolites , resulting in porcine fat deposition [It was reported that the ability to produce branched-chain amino acids  and aromatic amino acids  by gut microbiota of obese individuals was higher than that of lean controls , implyinposition . In pigsposition , liver [position , subcutaposition ,58 are dposition , some ofposition . Similarposition ,62. In aposition . The aboBacteroides thetaiotaomicron, Bifidobacterium longum, Enteroccocus faecalis, Ligilactobacillus salivarius, and Clostridium perfringens [The primary bile acids (BAs) are synthesized from cholesterol and essential for lipid/vitamin digestion and absorption, and are subsequently converted into secondary bile acids by microbial deconjugation, dehydrogenation, dihydroxylation, and epimerization . Bacterifringens . Criticafringens , which ifringens ,68. Indefringens . HoweverIt is well known that several avenues, including the immune system, direct enteric nervous system routes and the vagus nerve, can be a bridge of bidirectional communication between the microbiota and the brain . They caBifidobacterium longum, Lactobacillus rhamnosus, and Limosilactobacillus reuteri. However, these effects are blunted after vagotomy [Metabolites derived from gut microbiota can modulate brain function by the vagus nerve (VN), blood\u2013brain barrier (BBB), and immune system ,71. Notavagotomy ,74,75,76vagotomy ,78. In avagotomy . Moreovevagotomy . Apart fvagotomy . This devagotomy , indicatvagotomy . Importavagotomy . Specifivagotomy . These svagotomy . NeverthCollectively, the study of microbiota\u2013gut\u2013brain axis is of great significance to the regulation of nutrient metabolism in animals. Dietary behavior controlled by the central system can be regulated through the microbiota\u2013gut\u2013brain axis to affect the body lipid metabolism. In addition, the regulation of the microbiota\u2013gut\u2013brain axis provides ideas to cure metabolic diseases (such as obesity) or to improve animal fat deposition related to meat quality.FMT has been used to treat multiple diseases in humans including obesity related complications . FMT is Interestingly, FMT from obese humans or mice into germ-free or antibiotic treated mice leads to body fat accumulation ,89, implIn conclusion, gut microbiota contribute to the fat deposition in pigs, and their fat deposition phenotype can be transferred across species. Therefore, transplantation of gut microbiota will provide new approaches to change host metabolism and adipogenesis, with a huge significance in the improvement of meat quality.Lactobacillus amylovorus, Lactobacillus johnsonii, and Clostridium butyricum, compared with Yorkshire pigs [Akkermansia, CF231, Phascolarctobacterium, Prevotella, SMB53, and Streptococcus [Faecalibacterium, Butyrococcus, and Coprococcus) and identified candidate genes previously reported as associated with microbiota profile in mice and human, such as SLIT3, SLC39A8, NOS1, IL1R2, DAB1, TOX3, SPP1, THSD7B, ELF2, PIANP, A2ML1, and IFNAR1 [Host genetics are crucial to shape the composition gut microbiota . Mountinire pigs . Interesire pigs , which itococcus . Recentld IFNAR1 . Moreoved IFNAR1 . ConsequSuch data confirm the significance of host genomics in regulating the microbiota composition. This area merits further research to understand the complicated interplay between the host genotype and gut microbiota taxa, identifying genetic markers and candidate genes that can be used to incorporate in pig breeding program to reshape microbial composition, and thus improving host performance. However, previous study suggested that host genetics play a secondary role in shaping microbiota composition, perhaps because conditions are difficult to standardize between individuals. Recently, a study showed that environment dominates over host genetics in determining host gut microbiota . Among eLactobacillus, Prevotella, Alloprevotella, and Clostridium sensu stricto, but increase opportunistic pathogen including Bacteroides, Alistipes, and Anaerotruncus [Salmonella and E. coli), thereby reducing the odds of gastrointestinal infections [Proteobacteria as well as decreasing the abundance of Firmicutes [Prevotella [Importantly, dietary fat quantity has been reported to consistently influence gut microbiota composition. For instance, a large-scale meta-analysis of sequencing-based studies suggested from rodents and humans that a high-fat diet (HFD) influence microbial diversity and reproducibly changes gut microbial community structure, including the increase in Firmicutes/Bacteroidetes ratio, which was significantly correlated with fat content . This maotruncus . Therefootruncus ,108. Curfections ,110. Morevotella . Moreoveevotella . TogetheFirmicutes and Bacteroidetes in weaned piglets compared with wheat bran [In addition, recently, due to the critical role in shaping gut microbiota, dietary fiber has increasingly attracted the attention of researchers. Dietary fiber, a feed component that cannot be digested effectively by monogastric digestive enzymes, serves as the major energy source for gut microbiota, which implies that intake of the right amount of dietary fiber could enhance the abundance of specific microbiota . As receeat bran . The aboCollectively, the available evidence suggests that manipulation of the dietary composition can influence the gut microbiota structure and function in pigs and thus could contribute a key role to the pig growth and development, and thus, reasonable diet formula is conductive to the production of better pork in pig industry.Actinobacillus pleuropneumonia and Pasteurella multocida. Colistin was most commonly used in gastrointestinal conditions of piglets and weaners, while tylosin was used in fatteners and sows [Clostridium, Bacillus, and Sharpea in the digesta of the stomach, duodenum, and jejunum as well as a minor decrease in Prevotella in colon, thus affecting metabolic phenotype [In intensive swine husbandry systems, antibiotics are often added to porcine feed or water to fight against the infections of the respiratory system and gastro-intestinal tract, and promote pig\u2019s growth and development. In addition, the use of different types of antibiotics is associated with specific diseases, age, or farm management. For example, penicillins were widely used for prophylaxis and treatment of septicaemia and respiratory and urinary tract infections in various animal species. Tetracyclines were commonly used to treat respiratory diseases caused by and sows . Howeverand sows . Thus, aand sows . Howeverand sows ,125,126.and sows . Studieshenotype ,129. Sevhenotype ,131,132.henotype . Additiohenotype ,135. As henotype . The dyshenotype ,139,140.Defluviicoccus and Gardnerella) that cause gut dysbiosis. Additionally, prebiotics can modulate lipid metabolism and result in a higher IMF level in finishing pigs [Prebiotics and probiotics have been applied as functional feed additives to improve animal health and production performance for many years. Prebiotics were defined as \u201ca selectively fermented ingredient that allows specific changes, both in the composition and/or activity in the gastrointestinal microflora, thus conferring benefits upon host wellbeing and health\u201d . So, preing pigs , possibling pigs . In brieLactobacillus, Bacillus, Enterococcus, and Pediococcus are already widely used in swine production [lactic acid bacteria and Saccharomyces cerevisiae, can prevent ETEC K88/F4 colonization [L. rhamnosus, L. plantarum, and Bacillus has been reported to clear pathogens via triggering host immune response [L. plantarum, L. acidophilus NCDC-15, and P. acidilactici FT28 exhibited beneficial impact on growth performance of grower\u2013finisher pigs [Probiotics applied in animal diets are predominantly bacterial strains of Gram-positive bacteria, and are already widely used for replenishing the gut microbial population and modulate gut microbiota composition imbalance , while roduction . Owing tnization ,158,159,response ,161,162.her pigs . Samoli\u0144her pigs . In concIt is generally acknowledged that there is a complex relationship between gut microbiota and the pig, suggesting that microbiota modifications induce alternations in the pig growth and metabolism, which potentially contribute to changes in fiber characteristics, fiber type distribution, and lipid metabolism in skeletal muscle, and regulation of fat deposition. Hence, factors affecting gut microbiota composition and function have taken a pivotal role in pig production .The gastrointestinal tract of pigs harbors a rich and highly complicated microbiota, affecting digestion and absorption of nutrients; however, the composition and function of the gut microbiota are dynamic and regulated by many factors, such as host genetics, diet properties, antibiotic, prebiotics, and probiotics. Dietary compositions have been shown to significantly affect gut microbiota composition in terms of richness and diversity. On one hand, consumption of HFD (particularly saturated fat) may induce the growth of pathogenic bacteria, while suppressing the growth and reproduction of beneficial bacteria, resulting in gut microbiota dysbiosis. On the other hand, the consumption of different dietary fat type has been proven to differently change gut microbial composition and function. Moreover, the consumption of dietary fiber may increase the number of the of beneficial bacteria, promoting SCFAs production and subsequently affecting energy metabolism. Although antibiotic administration reduced pathogens colonization, the extensive and long-term use of antibiotics caused the generation of resistant bacteria and antibiotic residue in pigs. Therefore, alternative sources to antibiotics are urgently need to discover promoting the development of pig industry. More recently, prebiotics and probiotics, which reinforce the gut microbiota for improved animal health and colonization resistance to gut pathogens, show promise as alternatives for antibiotics for growth promotion in swine industry. Therefore, modifying the gut microbiota via dietary interventions is a vital strategy to improve the health and meat quality of the pig.Future investigation on the association between specific gut microbiota and pig skeletal muscle development, fat deposition, and further exploration of factors affecting gut microbiota composition, structure, and function would be beneficial to better understand the role of gut microbiota in pigs, which would contribute to the production of better pork."}
+{"text": "Systemic corticosteroids (SCS) are a highly effective treatment for acute exacerbations and long-term symptom control in asthma. Long-term SCS use is highly prevalent across all asthma severities, occurring in over 20% of patients with severe or uncontrolled disease globally. It is now well known that exposure to both long-term and repeated acute courses of SCS is associated with a high risk of serious adverse effects (AEs), such as osteoporosis, and metabolic and cardiovascular complications, especially when prescribed onto a background of other corticosteroids. The aim of this call-to-action article, endorsed by the World Allergy Organization and the Respiratory Effectiveness Group, is to review the accumulating evidence on the burden of SCS on patients with asthma and provide an overview of potential strategies for implementing SCS Stewardship.Primary prevention of exacerbations and improvement of asthma control is a key first step in achieving SCS Stewardship, by optimizing maintenance asthma medications and addressing modifiable risk factors, such as adherence and inhaler technique. Other key elements of SCS Stewardship include increasing appropriate specialist referrals for multidisciplinary review, assessment of biomarkers, and consideration of oral corticosteroid-sparing add-on therapies . In cases where SCS use is deemed clinically justified, it should be tapered to the lowest possible dose. In addition, patients receiving long-term SCS or frequent acute courses should be closely monitored for emergence of SCS-related AEs.Because of the extensive data available on the costly and burdensome AEs associated with SCS use, as well as the range of treatment options now available, there is a need for healthcare providers (HCPs) to carefully evaluate whether the benefits of SCS outweigh the potential harms, to adopt SCS-sparing and Stewardship strategies, and to consider alternative therapies where possible. Development of a structured and collaborative SCS Stewardship approach is urgently required to protect patients from the potential harm of SCS use. For example, as these studies were each completed in a single country , the results are not likely to take into account variation in clinical characteristics based on country or ethnicity, and the methodologies used did not adjust for all potential confounders.,Although patients may rely on SCS and prefer to use them because of the impacts they have on perceived asthma control and well-being  and costs due to inappropriate SCS exposure,Furthermore, an analysis of data from the SANI registry estimated the total annual healthcare cost of OCS-related AEs for patients with severe asthma in Italy at \u20ac242.7 million, representing an incremental expenditure of \u223c\u20ac110.6 million and \u223c\u20ac75.2 million compared with the non-asthmatic and moderate asthma populations, respectively.,,,,Accumulating evidence indicates that SCS Stewardship, defined as a collaborative systematic effort to protect patients and reduce the harm from inappropriate or cumulative SCS use, is urgently needed.Strategies for SCS tapering and actionable steps for achieving SCS sparing and Stewardship are reviewed in 2-agonists only during the 6-month baseline study period.Primary prevention of exacerbations requiring SCS by optimizing maintenance asthma therapies, in line with guideline-recommended care, is the first crucial step in reducing inappropriate SCS use.,,,,,,Patients with uncontrolled asthma need to be identified and systematically assessed to aid differentiation of difficult-to-treat and treatment-resistant asthma from severe asthma,,,Ideally, all patients with severe or difficult-to-treat asthma should be referred to specialist care whenever possible; however, many patients with asthma who could benefit from such a referral remain in primary care, which may lead to further inappropriate SCS use.,Severe asthma comprises multiple phenotypes that underlie the need for a personalized treatment approach through specialist care.,,,,,,,,Although there may be some overlap, T2 biomarkers  play a central role in successful SCS Stewardship in asthma as they can aid in determining treatment responsiveness to SCS and SCS-sparing add-on therapies.,,SCS-sparing therapies can be utilized to eliminate inappropriate SCS use.,,In patients with T2 inflammation, add-on biologic T2-targeted therapies should be considered prior to the use of long-term SCS .1 As wel,According to national and international registry data, OCS sparing should be considered as the primary outcome in managing severe asthma owing to the impact that OCS exposure has on the patient's QOL (eg absence from work or decreased productivity) and reduction in AE-associated costs.,,,,,,,,,A treatment aim is to achieve remission. A proposed criterion for asthma remission is no need for SCS;,Tapering involves slowly reducing the dosage of a medicine to the lowest possible dose, often followed by continuous monitoring.,,,One challenge that can impede successful tapering of SCS is that withdrawal of long-term CS can result in suppression of the hypothalamic-pituitary-adrenal (HPA) axis, leading to AI, which becomes evident after SCS withdrawal.Although SCS use has not historically been closely monitored in the past, geographic mapping of severe uncontrolled asthma across the USA has been recently completed in order to assess CS usage to guide therapies and improve outcomes in patients with severe asthma.It was concluded in a Delphi consensus that when SCS use is deemed appropriate, patients should be closely monitored for glycemic control, bone density, and blood pressure.The Patient Charter for severe asthma was created to empower patients through mobilizing stakeholders in asthma healthcare to address the unmet need and burden in severe asthma.Shared decision making between patients and HCPs should be encouraged to ensure that care focuses on reducing the impact of AEs and symptoms on patients\" daily lives.It is of utmost importance for HCPs to take ownership of increasing awareness of the risks associated with inappropriate long- and short-term SCS use by implementing SCS Stewardship and by following the strategies outlined in this review to prevent and reduce the harm to patients. SCS use should be reduced to the lowest possible dose and managed through tapering and sparing strategies. Close monitoring of SCS use is crucial, as well as frequent reassessment of treatments, asthma control, exacerbation occurrence, and modifiable risk factors. Although the focus remains on OCS, other CS  contribute to systemic steroid load and should be considered as part of SCS Stewardship.Future directions include additional research to develop alternative treatments to SCS for potentially life-threatening exacerbations and development of standardized guidelines to aid HCPs in adopting efficient tapering schemas that are individualized for each patient and the severity of their asthma. Increasing access and affordability of asthma therapies, including SCS alternatives, is of great importance. There is also a need for global and local guideline reform to ensure adoption of structured SCS Stewardship programs in clinical practice to enable a robust, joined-up approach.1; forced expiratory volume in 1 second, GINA; Global Initiative for Asthma, HCP; healthcare provider, HCRU; healthcare resource utilization, HPA; hypothalamic-pituitary-adrenal, HR; hazard ratio, ICS; inhaled corticosteroid(s), LABA; long-acting \u03b22-agonist(s), LAMA; long-acting muscarinic antagonist, OCS; oral corticosteroid(s), PCP; primary care physician, QOL; quality of life, SABA; short-acting \u03b22-agonist(s), SANI; Severe Asthma Network in Italy, SCS; systemic corticosteroid(s), T2; type 2.AE; adverse effect, AI; adrenal insufficiency, CI; confidence interval, CS; corticosteroid(s), FeNO; fractional exhaled nitric oxide, FEVAll authors contributed equally to the conception, design, acquisition of resources and development of the paper. All authors approved the final version.Not applicable.The authors consent to the publication of this work in World Allergy Organization Journal.AstraZeneca. The authors retained full control. AstraZeneca provided a review for scientific accuracy and did not participate in the content development.This manuscript was funded by a grant from Not applicable.MA-A, LB, CM, AY declare that they have no competing interests.ALK-Abello, AstraZeneca, GlaxoSmithKline, MedImmune, Novartis, Regeneron, Sanofi Genzyme, and TEVA, outside the submitted work.EB reports that he has undertaken clinical trials through his employer, Wake Forest School of Medicine and the University of Arizona for AstraZeneca, MedImmune, Boehringer Ingelheim, Genentech, Novartis, Regeneron, and Sanofi Genzyme; personal fees as a paid consultant for A. Menarini, Alk-Abello, Allergy Therapeutics, AstraZeneca, Chiesi Farmaceutici, Firma, Genentech, Guidotti-Malesci, GlaxoSmithKline, Hal Allergy, Mylan, Novartis, Regeneron, Roche, Sanofi-Aventis, Sanofi-Genzyme, Stallergenes-Greer, Valeas, Om-Pharma, outside of the submitted work.GWC reports having received research grants as well as being a lecturer or having received advisory board fees from AstraZeneca; personal fees from AstraZeneca, Behring, Boehringer Ingelheim, Covis, Cipla, GSK, Eisai, Novartis, NovoNordisk, Pfizer, Sanofi, Teva, Trudel, Valeo, outside the submitted work.AK non-financial support from Novartis and Nutricia, outside the submitted work.NP reports personal fees from Boehringer Ingelheim, Novartis, Pfizer, GSK and personal fees from MSD, AstraZeneca, Chiesi, Sanofi, Zambon, outside the submitted work.NR reports grants and personal fees from Viatris, Regeneron, and Novartis, outside the submitted work.DR reports personal fees from AstraZeneca, Kyorin Pharmaceuticals, and Sanofi, outside the submitted work.YT reports support from DP reports advisory board membership with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Viatris, Mundipharma, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals and Thermofisher; consultancy agreements with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Viatris, Mundipharma, Novartis, Pfizer, Teva Pharmaceuticals and Theravance; grants and unrestricted funding for investigator-initiated studies  from AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Viatris, Mundipharma, Novartis, Pfizer, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals, Theravance and UK National Health Service; payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Viatris, Mundipharma, Novartis, Pfizer, Regeneron Pharmaceuticals, Sanofi Genzyme and Teva Pharmaceuticals; payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Circassia, Mundipharma, Novartis, Teva Pharmaceuticals and Thermofisher; funding for patient enrolment or completion of research from Novartis; stock/stock options from AKL Research and Development Ltd which produces phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care Ltd  and 74% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); 5% shareholding in Timestamp which develops adherence monitoring technology; is peer reviewer for grant committees of the UK Efficacy and Mechanism Evaluation programme, and Health Technology Assessment; and was an expert witness for GlaxoSmithKline.10.13039/100004325AstraZeneca and was provided by Katherine Hardy, PhD of Helios Medical Communications, Oxford, Oxfordshire, UK.This manuscript was endorsed by the World Allergy Organization and the Respiratory Effectiveness Group. Editorial support was funded by The authors declare that this is an original work that has not been previously published in any form. The manuscript is not being considered for publication elsewhere.All authors have read and approved the submitted manuscript and consent to publish the work."}
+{"text": "Stroke is a leading cause of death and disability in the world, and the provision of reperfusion therapy and endovascular therapy, in particular, have revolutionized the treatment of patients with stroke and opened opportunities to look at brain clots retrieved after the procedure. The use of histopathology and molecular profiling of clots is of growing research and clinical interest. However, its clinical implications and incorporation within stroke workflows remain suboptimal. Recent studies have indicated that the study of brain clots may inform the mechanism of stroke and hence guide treatment decision-making in select groups of patients, especially patients without a defined cause or known mechanism. This article provides a comprehensive overview of various clot histopathological examinations in acute stroke-care settings, their clinical utility, and existing gaps and opportunities for further research. We also provide targeted recommendations to improve clot analysis workflow, hence standardizing its incorporation into clinical practice. Stroke is classically defined by the World Health Organization as \u201crapidly developed clinical signs of focal  disturbance of cerebral function, lasting more than 24 h or leading to death, with no apparent cause other than of vascular origin\u201d . In 2019The opportunity to investigate clot histopathology was limited prior to 2015, when the publication of five randomized controlled trials ,10,11,12Currently, the AIS workup includes neuroimaging, typically with non-contrast computed tomography (NCCT) or magnetic resonance imaging (MRI), along with CT angiography, CT perfusion, and other advanced imaging techniques, in order to exclude hemorrhagic stroke and guide intervention decisions . IntraveThis scoping review presents an overview of the current knowledge about clot histopathological features, and their relation to stroke etiology, outcomes, imaging, and management. The process of thrombus formation is initiated by damage to the endothelium, such as in atherosclerosis or following myocardial infarction. Exposed collagen causes platelets to change shape and adhere to the vessel wall. Activated platelets and von Willebrand Factor (VWF) help promote further platelet aggregation . Immune An overview of these components will be discussed, followed by a critical evaluation of the evidence regarding the association of clot features with stroke etiology, imaging, management, and prognosis, all of which are summarized in Various clot components and their clinical significance are discussed below. RBCs are a major component of thrombi and had been perceived to play a passive role in clot formation, but recent research has revealed direct rheological mechanisms contributing to thrombosis as well as interactions with platelets, endothelium, thrombin, and plasmin ,73,74,75Polyhedrocytes form when activated contractile platelets pull on fibrin, causing compression of RBCs . They foPlatelet-fibrin (PF) rich clots are more complex than RBC-rich areas, containing VWF , WBCs, NThe role of WBCs in thrombosis is being expanded upon in recent research, playing a part in releasing proinflammatory and procoagulant mediators ,81, but Neutrophil Extracellular Traps (NETs) are formed when activated neutrophils release DNA as decondensed chromatin, histones, proteolytic enzymes, and neutrophil granule proteins, such as MPO and neutrophil elastase ,83. NETsVWF is a large glycoprotein produced by megakaryocytes and endothelial cells. It plays an essential role in hemostasis and thrombosis by promoting platelet adhesion and supporting the action of important proteins involved in coagulation such as Factor VIII . A higheExtracellular DNA is mainly found on the interface between PF-rich and RBC-rich areas, alongside WBCs ,47. ExtrEndothelial cells have also been observed, indicating a potential role in thrombus formation via endothelialization over and within the thrombus , as wellThe presence of bacteria within clots can indicate infectious stroke etiologies such as septic emboli from infective endocarditis, though infections generally have been associated with a higher risk of thrombosis and AIS . One stuCalcified thrombi are uncommonly extracted and studied in stroke thrombectomy, despite the high prevalence of atherosclerotic plaque calcification. Potential sources include calcified aortic stenosis, carotid atherosclerosis, and mitral annular calcification, on top of cardiovascular procedural causes ,71. CalcOther rare components that have been identified within stroke thrombi include cholesterol, collagen, vascular wall components, myxomatous material, and non-infective vegetations ,52,89,90n = 187) [Delineation of stroke etiology is important in guiding the appropriate treatment strategy for both acute management and secondary stroke prevention. Most studies, including one of the largest by Sporns et al. (n = 187)  found ann = 187) ,40,44,49n = 187)  reportedn = 187)  found ann = 187)  in 2015 n = 187) ,35,42, Nn = 187) , and DNAn = 187)  seem to n = 187) . Determin = 187) ,35,36. Pn = 187) . A PFO mn = 187) . Interesn = 187) . EVs cann = 187) ,95. In tImaging is a crucial investigation before stroke management decisions can be made. Most studies concur that RBC-rich thrombi are associated with hyper-attenuation or the presence of the HMCAS and SVS, seen on CT and MRI, respectively ,54,80. CSeveral studies have found that IVT is more successful with RBC-rich clots, explained by the thin fibrin meshwork which it is easier for the rt-PA to dissolve ,53,76,77No contradictory evidence was found; however, several studies have reported no significant association between composition and treatment success ,37,38,56While successful recanalization is a therapeutic goal, for 30% of stroke patients who achieve complete reperfusion it is not conducive to good clinical outcomes . Better While many significant advancements have been made in clot histopathology, we have identified several gaps in this literature review. Selection bias is inevitable, as only patients with successful EVT could be studied. Irretrievable clots, clots that were rapidly dissolved by thrombolysis, or those ineligible for treatment are therefore underrepresented. Furthermore, several studies included patients regardless of rt-PA administration, or EVT technique, both of which could influence clot characteristics. One study found that stent retrievers \u2018crush\u2019 and reduce thrombus size . AnotherDespite the correlation between the HMCAS or SVS with RBC-rich thrombi, the clinical utility of imaging markers is limited. Bridging this gap comes with determining which EVT methods are most suitable for RBC-rich vs PF-rich thrombi. Utilizing bioimpedance and electrical impedance spectroscopy to observe clot morphology could provide insight during procedures, alongside new-generation guidewires, sensors, and catheters . One recGiven the small number of patients who can benefit from rt-PA thrombolysis, there is a compelling need for novel thrombolytic agents targeting non-fibrin clot components. Studies have shown that ADAMTS13 or DNAse-1 which cleave VWF and DNA, respectively, are more successful at dissolving rt-PA-resistant clots than rt-PA alone ,31,82. TApplication of machine learning and computer vision platforms are an important avenue of future research that may automate the analysis and reporting of clot histopathology, hence expediting clinicopathological workflows. Employing algorithms in the process of stroke etiology delineation could aid clinicians in predicting stroke causes and minimizing cryptogenic stroke .Clot immunohistopathology has divulged valuable information in recent years and is still developing. Several studies have reported that RBC-rich clots predict better reperfusion and patient outcomes, have an arteriogenic origin and are identifiable as hyperdense on imaging. Conversely, clots dense in platelets and fibrin tend to be comprised of more WBCs, VWF, and NETs which release DNA, complicating treatment success. The variability between studies remains a notable barrier to the clinical applicability of these results, which may pertain to factors such as inconsistencies in immunohistochemical analysis protocols, and small sample sizes. Future multi-center large-scale studies investigating clot composition and its implications on stroke causes and outcomes, with harmonized clot collection, processing, examination, and reporting protocol, may address these gaps and provide a means to develop evidence-based clinical indications or guidelines."}
+{"text": "Schizophrenia is highly comorbid with substance use disorders (SUD) but large epidemiological cohorts exploring the prevalence and prognostic significance of SUD are lacking.To investigate the prevalence of SUD in patients with schizophrenia in Finland and Sweden, and the effect of these co-occurring disorders on risks of psychiatric hospitalization and mortality.45,476 individuals with schizophrenia from two independent national cohort studies, aged <46 years at cohort entry, were followed during 22  and 11 years . We first assessed SUD prevalence (excluding smoking). Then we performed Cox regression on risk of psychiatric hospitalization and mortality in patients with schizohrenia and SUD compared with those without SUD.The prevalence of SUD in specialized healthcare ranged from 26% (Finland) to 31% (Sweden). Multiple drug use and alcohol use disorders were the most prevalent SUD, followed by cannabis use disorders. Any SUD comorbidity, and particularly multiple drug use and alcohol use, were associated with 50% to 100% increases in hospitalization and mortality compared to individuals without SUD. Elevated mortality risks were observed especially for deaths due to suicide and other external causes. All results were similar across countries.Co-occurring SUD, and particularly alcohol and multiple drug use, are associated with high rates of hospitalization and mortality in patients with schizophrenia. Preventive interventions should prioritize detection and tailored treatments for these co-morbidities, which often remain underdiagnosed and untreated.ML: Genomi Solutions Ltd, Nursie Health Ltd, Sunovion, Orion Pharma, Janssen-Cilag, Finnish Medical Foundation, Emil Aaltonen Foundation. HT, EMR, AT: Eli Lilly, Janssen\u2013Cilag. JT: Eli Lilly, Janssen-Cilag, Lundbeck, Otsuka."}
+{"text": "Precision medicine is particularly relevant for cancer and microenvironment deconvolution for therapeutic purposes in hematological and non-hematological malignancies ,2,3,4. MMultimodality spans clinical, molecular, and imaging levels. Several factors such as demographics, biochemical properties, staging, tumor burden (BMPC), minimal measurable disease, transplant status, treatments, and outcomes should be combined with cytogenetics, RNAseq, microarray, and novel tools . Imaging techniques, such as PET-CT scans and MRIs are also relevant. This landscape represents a typical framework for a machine learning approach . The maiAn integrative modeling approach might represent a possible integration of the data and prior biomedical knowledge to overcome data limitations ,25. ThisSimilar approaches have also been applied to more complicated projects, namely a personalized assessment of the risk of progression from MGUS/SMM to MM . These sThere is an urgent need for precision medicine in cancer and multiple myeloma . The spaOverall, we are confident that the issues raised in this editorial might help to interpret the findings of the current clinical and pre-clinical practice. The authors plan to generate questions about the optimal treatment approach for cancer therapy and its microenvironment, considering the novel tools presented."}
+{"text": "Limited research has examined the extent neighborhood disadvantage relates to subclinical CVD such as carotid atherosclerosis, arterial stiffness, and endothelial dysfunction which are key, understudied CVD risk markers. Our objective was to examine associations between neighborhood disadvantage and subclinical CVD and whether associations vary by age, sex, race, and education. The analysis included 165 Black and White older adults (mean age=64.5y). Neighborhood disadvantage was characterized using the Area Deprivation Index (ADI). Multivariable regression analysis, adjusted for age, sex, race, education, and depression, showed that national and state ADI were significant, inverse predictors of carotid atherosclerosis  and state ADI was a significant, inverse predictor of flow-mediated dilation (p=.04). A significant interaction between state and national ADI and education predicting carotid IMT emerged, but the simple slopes were non-significant . Future research should consider the role of neighborhood as a predictor of early cardiovascular risk."}
+{"text": "Eosinophilic esophagitis (EoE) is a chronic, immune-mediated inflammatory disease, characterized by esophageal dysfunction and intense eosinophil infiltration localized in the esophagus. In recent decades, EoE has become a growing concern as a major cause of dysphagia and food impaction in adolescents and adults. EoE is a clinicopathological disease for which the histological demonstration of esophageal eosinophilia is essential for diagnosis. Therefore, the recognition of the characteristic endoscopic features with subsequent biopsy are critical for early definitive diagnosis and treatment, in order to prevent complications. Accumulating reports have revealed that EoE has several non-specific characteristic endoscopic findings, such as rings, furrows, white exudates, stricture/narrowing, edema, and crepe-paper esophagus. These findings were recently unified under the EoE endoscopic reference score (EREFS), which has been widely used as an objective, standard measurement for endoscopic EoE assessment. However, the diagnostic consistency of those findings among endoscopists is still inadequate, leading to underdiagnosis or misdiagnosis. Some endoscopic findings suggestive of EoE, such as multiple polypoid lesions, caterpillar sign, ankylosaurus back sign, and tug sign/pull sign, will aid the diagnosis. In addition, image-enhanced endoscopy represented by narrow band imaging, endocytoscopy, and artificial intelligence are expected to render endoscopic diagnosis more efficient and less invasive. This review focuses on suggestions for endoscopic assessment and biopsy, including recent advances in optical technology which may improve the diagnosis of EoE. Eosinophilic gastrointestinal disorders (EGIDs) are refractory gastrointestinal inflammatory entities that cause chronic eosinophilic inflammation and dysfunction in the gastrointestinal tract based on excessive Th2-dominant immunological responses to dietary antigens . EGIDs a2), excluding diseases and conditions inducing secondary esophageal eosinophilia such as EGE, hyper eosinophilic syndrome, drug-induced esophagitis or achalasia [EoE is diagnosed based on the presence of clinical symptoms and histologically-proven esophageal eosinophilia with a peak of \u226515 eosinophils/hpf  used prior to endoscopic examination can mask EoE endoscopically and histologically . HillmanThe disease entity of EoE has been distinctly established by the report of Attwood et al. in 1993, in which they described a case series of 12 patients characterized by dysphagia as a chief complaint, young male predominance, no pathological gastro-esophageal reflux, intense, eosinophilic inflammation localized in the esophagus, and normal endoscopy . HoweverIn a previous meta-analysis, EoE was reported to be endoscopically \u201cnormal\u201d in 20% of retrospective studies, but the ratio decreased to only 7% in prospective studies [The EoE endoscopic reference score (EREFS) was developed by Hirano et al. in 2013 for objective assessment of endoscopic findings: Edema, Rings, Exudates, Furrows, and Stricture are comprehensively assessed as major features . Soon afThe EREFS acronym consists of the initials of the aforementioned five endoscopic findings. Since the first E (Edema) and second E (Exudates) may be confused, the term ERExFS may be preferred . Ma et aEdema, used synonymously with loss of or decreased vascularity, is quite an unspecific finding seen in many other esophageal conditions, including GERD, and has endoscopically lower diagnostic agreement compared with other findings ,34.Rings occur as a result of esophageal remodeling with subepithelial fibrosis as well stricture, and correlate with a risk of food impaction attributed to impaired esophageal distensibility . The sevExudates appear as white plaques or white spots, corresponding to histological eosinophilic microabscesses . AttentiFurrows are crack-like fissures longitudinally running in the esophagus, different from the epithelial erosions seen in GERD . FurrowsStricture with EoE, unlike that in GERD, can occur at a more proximal site of the esophagus ,32,46. IConsidering their relevant pathophysiology, rings and stricture are separately assessed as fibrostenotic changes, apart from the remaining three inflammatory changes edema, exudates, and furrows. ,47.The optimal cutoff value for the ERERS score to predict EoE has not been determined. Some reports showed that an EREFS \u2265 2 can predict EoE with relatively high sensitivity and specificity ,48, whilFeline esophagus, narrow caliber esophagus, and crepe paper esophagus were considered in the EREFS as minor features .Feline esophagus is a term derived from the morphological similarity to a cat\u2019s esophagus, in which multiple rings are physiologically present. However, this term now refers to fine and subtle contractile rings observed transiently or intermittently during endoscopy in non-EoE conditions, including normal esophagus ,52,53 F.Narrow/small caliber esophagus indicates the diffuse narrowing of the tubular esophagus with a certain longitudinal length, which is different from the strictures seen in GERD or in postoperative anastomotic stricture, presenting as shorter, localized narrowing along with proximal esophageal dilatation. These two conditions are not clearly defined or differentiated from each other ,55. CarlCrepe-paper esophagus is an uncommon but pathognomonic finding with EoE, presenting with friable, delicate esophageal mucosa which ulcerates after minor trauma, such as by contact with an endoscope . Of thosIn EoE, diagnostic delay without effective therapeutic intervention not only exacerbates the degree of esophageal stricture , but alsPreviously reported endoscopic diagnostic agreement of individual components of EREFS, and the overall diagnosis of EoE, are summarized in Over the past decade, image enhanced endoscopy (IEE) such as narrow band imaging (NBI) has been widely used in endoscopic diagnosis, especially for gastrointestinal cancerous lesions ,65,66. TLCI is a newly-developed IEE created by short-wavelength narrow-band laser light combined with white laser light, enabling brighter light in a distant area, and enhancing color differences between red and white . It has With an increased awareness of EoE in clinical practice, endoscopic findings suggestive of EoE, other than the characteristic features such as EREFS, have been known to endoscopists. These findings are summarized in It has been recently reported that endocytoscopy, using super-magnifying technology, can microscopically detect infiltrated intraepithelial eosinophils, characterized by bilobed nuclei ,91. EndoArtificial intelligence (AI) can endoscopically discriminate EoE from normal esophagus with > 95% accuracy, higher than that of the endoscopist, leading to decreasing diagnostic delay by recommending re-endoscopy with esophageal biopsies, or consultation with a specialist for EoE\u2014especially in cases with non-expert endoscopists ,93. AlthMultiple biopsies are favorable to diagnose EoE more effectively, due to a heterogeneous distribution of intraepithelial eosinophil infiltration ,101,102.A peak eosinophil count with \u226515 eosinophils/hpf has been conventionally used as a reliable histological criterion for the definitive diagnosis in EoE , which gBesides absolute counts of eosinophils, EoE has various histological features such as eosinophilic microabscesses, surface laying of eosinophils, eosinophil degranulation, basal cell hyperplasia, lengthening of lamina propria papillae, increased intraepithelial lymphocytes and mast cells, increased intercellular edema, and increased lamina propria fibrosis . RecentlIn the absence of gastroenteritis-like symptoms or apparent endoscopic abnormalities in the stomach or the duodenum, gastroduodenal biopsies seem not to be necessary, at least in adult patients because esophageal involvement of eosinophilic gastroenteritis is unlikely ,113.A variety of factors\u2014differences in endoscopists\u2019 interests and experience, differences in endoscopic equipment performance, the presence of cases with weak or normal appearing esophagus, and the variability in eosinophil infiltration\u2014have influenced diagnostic accuracy in EoE. However, increasing awareness of EoE and its clinical guidelines have led to a decrease in diagnostic delay, endoscopic severity at first diagnosis, and number of endoscopic examinations performed before diagnosis, and consequently more cases are being diagnosed at an earlier stage . In addi"}
+{"text": "PLOS ONE Editors retract this article [The  article  because AFN and SF did not agree with the retraction. MArif and XW responded but expressed neither agreement nor disagreement with the editorial decision. MSKK, SUK, SSaeed, AMK, RAK, MAfzal, MAZ, HOE, SShokralla, AA, and AG either did not respond directly or could not be reached."}
+{"text": "PLOS ONE Editors retract this article [The  article  because TN, TZ, YQ, PW, DAAB, MSAH, XG, and XY did not agree with the retraction. GZ and EL either did not respond directly or could not be reached."}
+{"text": "This paper aims to explore complex realities and nuanced lived experiences in how diverse older adults are making sense of and dealing with the COVID-19 pandemic. We conducted semi-structured video and phone interviews with 57 COVID-19 Coping Study participants  from May-July 2021. Qualitative thematic analysis identified physical, mental, social, and economic struggles. These included heightened COVID-19 risk given comorbidities, difficulties accessing healthcare, distressing political events, diminished sense of safety, distance to family and support networks, inability to collectively mourn, and exacerbated financial instability. Coping strategies included exercise, hobbies, spirituality, online activities, engaging with family and friends, and self-care practices. Community-level sources of resilience included vaccines, telemedicine, stimulus checks, and community groups/services. These results highlight profound resiliency and strength to cope with adversities of the pandemic and may inform strategies to support underrepresented and underserved older adults during and after the pandemic."}
+{"text": "The SARS-CoV-2 pandemic started in March 2020, and, to date, has killed over 6 million people. Vaccines were developed with remarkable speed and reduced the death toll. Notwithstanding, the pandemic endures, and accumulating viral mutations are progressively reducing vaccine efficacy, which is short-lived, even against the original virus. Thus, the UK is recording 4.9 million infections per week, despite evidence that 99% of its 68 million population have anti-SARS-CoV-2 antibodies. Before we embark on endless booster immunizations, it is time to review our strategies against COVID-19.And, for that, we must go back to the beginning.Globally, most countries are using mRNA or adenovirus (Ad) vector vaccines that to produce viral spike (S) protein, and to mount an immune response against it. In large (but brief) clinical trials, two-dose mRNA vaccines (Pfizer-BioNTech and Moderna) prevented symptomatic infections in >90% of recipients. The four Ad vector vaccines  vector from Johnson & Johnson, the two-dose chimpanzee Ad vector from AstraZeneca; the two-dose Sputnik V vaccine, which primes with HAdV-26 and boosts with HAdV-5  and the None of these vaccines induces sterilizing immunity and, whilst they reduce severe disease, hospitalization, and death, protection against infection and transmission is limited. For the mRNA vaccines, used in >95% of US vaccine recipients, protection against infection wanes over circa 6 months, prompting booster immunizations , which pThe wide preference for mRNA vaccines reflected their initial high efficacy and safety profile; Ad vector vaccines appeared less protective and were linked to thrombotic thrombocytopenia, a rare and potentially fatal adverse event. Recent evidence, however, suggests that Ad vectors may induce more durable antibody responses. Coupled with lower acquisition cost and better heat stability, this may confer advantage over mRNA vaccines .Uncertainty on the relative merits of mRNA and Ad vaccines for providing prolonged protection against severe disease in the elderly/vulnerable populations\u2013who most direly need to be vaccinated\u2013reflects the early emphasis on developing and distributing vaccines as quickly as possible. Consequently, there was limited effort on optimizing regimens, assessing immunological correlates of protection, or identifying how the different vaccines affect lymphocyte differentiation, along with widespread naivety that vaccines would terminate the pandemic.Now, over 1 year after the first COVID-19 vaccine's emergency approval, we know that the initial intervals between two vaccine doses were too short. Both mRNA vaccines and Ad vectors induce germinal center formation, which is essential for affinity-matured antibody responses, but apparently fail to stimulate long-lived plasma cells . NeverthThe longevity of protective immunity by other types of COVID-19 vaccines  remains uncertain, but the curious finding that the very different mRNA and Ad vector vaccine platforms both fail to achieve the sustained efficacy of other licensed vaccines , warrants reflection.Seasonal human coronaviruses have circulated for centuries, and likewise fail to induce prolonged immunity, but rarely causing severe illness. Notably, although neutralizing antibodies to these viruses fail to cross-react with SARS-CoV-2, the epitopes for other adaptive immune effectors, notably T cells, are shared and an individual's recent infection with seasonal coronaviruses may explain the considerable variability in COVID-19 severity. A better understand of this type of protection may allow design of strategies tailored to confer prolonged protection against severe COVID-19, whether with current or future vaccines.SARS-CoV-2 will not be eradicated. Variants that are even more transmissible and better equipped to evade immune responses will doubtlessly evolve, triggering new waves of infections. Eventually populations will achieve, via a mixture of infection and vaccination, the same immunological balance with SARS-CoV-2, as with seasonal coronaviruses. The concept that one can vaccinate the world every 4\u20136 months against COVID-19 is unreasonable. Instead, candid discussions about the future of SARS-CoV-2 vaccination are needed.repeated vaccination is also questionable for healthy young and middle-aged adults, especially as natural infections induce stronger and more sustained protection against further infections than mRNA vaccines  with: Freelance, Inc, Takeda, Biogen (board), Regenxbio, Ring Therapeutics (board), Canine Rabies Treatment Initiative (board). DL has the following disclosures: Advisory roles (board or consultancy): Accelerate, Antabio, Centauri, Entasis, GenPax, GSK, Meiji, Menarini, Mutabilis, Nordic, Paion, ParaPharm, ParaGraf, Pfizer, QPEX, Shionogi, Summit/Discuva, Sumitovant, T.A.Z., VenatoRx, Wockhardt, Zambon; was on the Russian Direct Investment Fund's Advisory Board for the Sputnik V but resigned following the invasion of the Ukraine. Paid lectures: bioM\u00e9rieux, Beckman Coulter, Cardiome, GSK, Hikma, Merck/MSD, Menarini, Nordic, Pfizer and Shionogi. Relevant shareholdings: Dechra, GSK, Merck, Pfizer and Perkin Elmer amounting to <10% of portfolio value; Share options: T.A.Z. He also has nominated holdings in Avacta, Diaceutics, Destiny, Evgen, Faron, Genedrive, Poolbeg, Renalytics, Saietta, Synairgen and Verici through Enterprise Investment Schemes but has no authority to trade these shares directly. SC has the following disclosures: COO, Virion Therapeutics, Stock, Nektar Therapeutics.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Today, numerous studies have focused on the design of novel scaffolds for tissue engineering and regenerative medicine applications; however, several challenges still exist in terms of biocompatibility/cytocompatibility, degradability, cell attachment/proliferation, nutrient diffusion, large-scale production, and clinical translation studies. Greener and safer technologies can help to produce scaffolds with the benefits of cost-effectiveness, high biocompatibility, and biorenewability/sustainability, reducing their toxicity and possible side effects. However, some challenges persist regarding their degradability, purity, having enough porosity, and possible immunogenicity. In this context, naturally derived cellulose-based scaffolds with high biocompatibility, ease of production, availability, sustainability/renewability, and environmentally benign attributes can be applied for designing scaffolds. These cellulose-based scaffolds have shown unique mechanical properties, improved cell attachment/proliferation, multifunctionality, and enhanced biocompatibility/cytocompatibility, which make them promising candidates for tissue engineering applications. Herein, the salient developments pertaining to cellulose-based scaffolds for neural, bone, cardiovascular, and skin tissue engineering are deliberated, focusing on the challenges and opportunities. Cellulose with the fascinating properties of renewability, cost-effectiveness, and mechanical resilience has been widely deployed in designing composite scaffolds for tissue engineering  1,2,3,4,3,42,3,4Komagataeibacter xylinus and Gluconacetobacter xylinum) have been widely exploited by researchers in recent years  becauseineering ,19,20,21ineering . For insNanocellulose-based hydrogels are receiving immense consideration in drug delivery, tissue engineering, wound dressings, and biosensing because of their unique mechanical properties, flexibility, surface chemistry, moldability, biocompatibility, and high water-holding capacity ,23,24. TCellulose-based materials with environment-friendly properties have been widely employed for the low-cost manufacturing of tissue engineering scaffolds ,53,54. HSeveral cellulose-based composite scaffolds have been introduced with unique architectures, surface chemistry, and excellent cell attachment/proliferation ,63. HoweTypically, biomaterials applied for neural tissue engineering for restoring lost functions in nervous systems should have biocompatibility, flexibility, a suitable degradation rate, longitudinal channels for enhancing the regeneration of axons, and bioactivity. To overcome biological restraints on neural regeneration and restoration, these biomaterials should have enough capabilities for cellular growth and behavior . In a stN-vinylpyrrole and electrospun cellulose/poly(3-hexylthiophene) have been fabricated using an in-situ polymerization technique . Th. Th77]. For cartilage tissue engineering, scaffolds should have high porosity and pore-to-pore inter-connectivity as well as enough space for in vitro cell adhesion, in-growth, and the rearrangement of cells. Interconnected porous organization can facilitate the migration of cells, the spread of physiological nutrients/gasses to cells, and the release of metabolic waste and by-products from the cells . In one Starch/cellulose nanofiber composites were designed with enhanced biodegradability, porosity, and mechanical strength for cartilage tissue engineering . An enha2, an organized network in the hydrogels could be promoted. The sterilization technique could also affect the pore size and swelling of hydrogels; all the introduced sterilization techniques could structurally alter the alginate and nanocellulose-based hydrogels. In addition, ethanol sterilization could improve the mechanical features of the alginate, nanocellulose crystal, and nanocellulose fibrils. Notably, autoclaving was suggested as the optimal technique for ensuring the removal of possible contaminants . Th. Th27]. Vascularization is an important criterion in tissue engineering/regeneration, as it affects the long-term survival of scaffolds . In thisBiocompatible cellulose-based scaffolds were developed using microcrystal cellulose and a cellulose whisker through deacetylation and electrospinning techniques for vascular-tissue-engineering applications . The add\u00ae) has been introduced for the implantation and long-term maintenance of carotid arteries in animals (rats and pigs) [For preventing myocardial post-infarction pathology, bacterial cellulose membrane patches containing co-cultured cells were designed . Accordind pigs) .Andrade et al.  developeLimited studies have been undertaken on the skin-tissue-engineering applications of cellulose-based composites. In one study, ulvan-cellulose scaffolds were synthesized via skin tissue engineering that were endowed with good biocompatibility (in vivo) and that exhibited enhanced cell growth and angiogenesis . AdditioCellulose-based scaffolds have been extensively designed for tissue regeneration and engineering applications ,90. HoweA wide variety of tissue regeneration techniques have been introduced for clinically treating damaged organs/tissues using scaffolds, but still some challenging issues need to be addressed such as insufficiency in mechanical strength, lack of vascularity, biocompatibility, degradation/resorption kinetics, nutrient diffusion, and cell proliferation/tissue growth rate ,97,98. IOverall, several physicochemical features can affect the cell adhesion and proliferation in tissue-engineering scaffolds . Indeed,Compared to animal-derived or synthetic materials, cellulose-based materials, with their unique attributes of inexpensiveness, renewability, and environmentally benign nature, can be considered as promising alternatives for designing future tissue engineering scaffolds; synthetic biomaterials produced by chemical processes may increase the utilization of perilous agents as well as the formation of unwanted/hazardous by-products . DespiteCellulose-based composites have garnered immense attention from researchers in recent years due to their high biocompatibility, nontoxicity, sustainability, and biodegradability advantages. Cellulose as a renewable and abundant material has been broadly utilized in designing composite scaffolds with tissue regeneration and engineering applications. In this context, safer and greener technologies with the utilization of safer solvents/auxiliaries can enhance the biosafety and biocompatibility properties of scaffolds, thus reducing their possible side effects in tissue engineering. Finding optimal synthesis and functionalization conditions can help assist in the design of cellulose-based scaffolds with improved functionality, stability, degradability, and biocompatibility. Although plant and bacterial celluloses have several similarities in terms of chemical structure, bacterial celluloses show some salient advantages such as higher flexibility and purity, which make them promising candidates for tissue engineering. The mechanical features  of cellulose-based scaffolds are very important and should be optimized for their future clinical and biomedical applications. Despite various toxicological and biosafety/biocompatibility analyses of cellulose-based scaffolds, the next steps should embark on their long-term biosafety, systemic toxicity, and immunogenicity/hemocompatibility along with clinical translation studies and clinical trials. Several sterilization techniques such as ultraviolet or gamma radiation, argon plasma, or autoclaving have been introduced, but still more evaluations are required to uncover an efficient method that is without effects on the structural and functional properties of scaffolds."}
+{"text": "In the original version of this article, the given and family names of the authors below were incorrectly structured.The correct author names should read asWojciech Kosiek, Zuzanna Rauk, Piotr Szulc, Anna Cichy, Marzena Rugie\u0142, Joanna Chwiej, Krzysztof Janeczko, Zuzanna SetkowiczThe original article has been corrected."}
+{"text": "Vector-borne infectious diseases are an important global public health concern, with new pathogens emerging over the past few decades due to the socioeconomic, environmental, and climate change factors , were identified using meta-transcriptome analysis. Importantly, most of these viruses were genetically associated with the viruses reported in Turkey, Trinidad and Tobago, Australia, Thailand, northern Europe, and Brazil, suggesting that it is necessary to continuously survey tick-borne viruses in southern China.Lin et al. reported high prevalence of Rickettsia spp. in Dermacentor everestianus and Haemaphysalis qinghaiensis ticks collected from yaks in Shiqu county, eastern Tibetan Plateau, China. In this region, the primary mammalian hosts of ticks included domesticated yaks and wild mammals, such as rodents and plateau pika. Lu et al. revealed a high diversity of Anaplasma, Ehrlichia, and Rickettsia in ticks collected from Yunnan Province, and a novel species of Rickettsia was identified. Moreover, most of these bacteria can cause diseases in humans, such as E. canis, E. chaffeensis, and A. ovis, with high infection rates in these detected ticks. Therefore, there is potential risk of zoonoses transmitted from ticks to humans, resulting from the frequent contact between humans and domestic animals (goats and cattle) that act as tick hosts in these regions. Zawada et al. described high levels of B. burgdorferi genetic diversity in white-footed mice, with tongue and ear samples containing 90% of detected subtypes. The work emphasized the need to incorporate metagenomic sequencing into ongoing Lyme disease surveillance efforts.Zhao et al. investigated the subcellular distribution and possible functions of viral proteins in host cells, and found that the ALSV proteins had distinct subcellular distribution in different tissue-deriving cells, and caused endoplasmic reticulum morphological changes, and NSP1 could induce mitophagy to reduce mitochondria quantity. These findings help to understand the pathogenic mechanisms of emerging segmented flaviviruses. Babesia microti, a tick-transmitted hematoprotozoan, can infect small rodents and humans  is a newly discovered segmented tick-borne flavivirus that can cause human febrile illness (Wang et al., The Topic was intended to focus on new infectious agents in mosquitoes, ticks, fleas, flies, midges, and other blood-sucking arthropods. However, a majority of submitted and all accepted manuscripts focused on tick-borne pathogens in China. These results suggest a high diversity of tick-borne pathogens in China, especially viruses and bacteria, whose epidemiology, biology and public health significance should be further investigated. Moreover, further Research Topics specific to other medically relevant arthropods vectors is recommended.QL and QC drafted the manuscript. All authors corrected, edited, and approved the manuscript. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
+{"text": "Ischemic heart disease (IHD) and heart failure (HF) remain the leading causes of death worldwide , despiteJCM team.As a Guest Editor, I thank the authors, reviewers, and the"}
+{"text": "Substantial evidence documents gender and racial disparities in C-reactive protein (CRP), a measure of systemic inflammation, among older adults. Yet, the comparative approaches of these studies may obscure distinct risk and protective factors associated with elevated CRP among older Black Americans. To pinpoint opportunities for intervention, this study utilizes a \u201cwithin-group approach\u201d to identify the sociodemographic, psychosocial, behavioral, and health-related determinants of elevated CRP among older Black women and men. The sample consisted of 2,420 Black respondents aged 51+ in the Health and Retirement Study (2006-2016). Gender-stratified, random effects logistic regression models were used to examine determinants of elevated CRP (>3.0 mg/L). More than 50% of Black women had elevated CRP, and we found that younger age, Medicaid, lower mastery, religiosity, overweight/obesity, physical inactivity, and ADLs contributed to elevated CRP among this group. In contrast, elevated CRP was reported among only 37.25% of Black men, for whom financial distress was associated with lower odds of elevated CRP; religiosity, less neighborhood cohesion, current smoking, overweight/obesity, ADLs, and more chronic conditions were associated with greater odds of elevated CRP among this group. Sociodemographic factors had a limited association with elevated CRP among older Black Americans. Rather, a range of psychosocial, behavioral, and health-related factors were more influential determinants of elevated CRP among older Black Americans. Most notably, findings demonstrate distinct determinants of CRP among Black women and men, underscoring the critical need to further evaluate the risk and protective mechanisms undergirding disparities among this aging population."}
+{"text": "Human cytomegalovirus (HCMV) is a herpesvirus that alternates lytic and latent infection, infecting between 40 and 95% of the population worldwide, usually without symptoms. During its lytic cycle, HCMV can result in fever, asthenia, and, in some cases, can lead to severe symptoms such as hepatitis, pneumonitis, meningitis, retinitis, and severe cytomegalovirus disease, especially in immunocompromised individuals. Usually, the host immune response keeps the virus in a latent stage, although HCMV can reactivate in an inflammatory context, which could result in sequential lytic/latent viral cycles during the lifetime and thereby participate in the HCMV genomic diversity in humans and the high level of HCMV intrahost genomic variability. The oncomodulatory role of HCMV has been reported, where the virus will favor the development and spread of cancerous cells. Recently, an oncogenic role of HCMV has been highlighted in which the virus will directly transform primary cells and might therefore be defined as the eighth human oncovirus. In light of these new findings, it is critical to understand the role of the immune landscape, including the tumor microenvironment present in HCMV-harboring tumors. Finally, the oncomodulatory/oncogenic potential of HCMV could lead to the development of novel adapted therapeutic approaches against HCMV, especially since immunotherapy has revolutionized cancer therapeutic strategies and new therapeutic approaches are actively needed, particularly to fight tumors of poor prognosis. Human cytomegalovirus (HCMV) or human herpesvirus 5 (HHV-5), one of the eight human herpesviruses, can establish lifelong latency within its corresponding host, as well as possessing reactivation potential. An exquisite equilibrium between the immunocompetent host and the virus itself allows viral presence for a lifetime parallel to improved viral fitness over time. Besides birth defects and congenital infections in the adult host, HCMV can cause symptoms due to its reactivation in immunosuppressed patients (organ transplant recipients) and immunocompromised patients  and favor age-related diseases such as atherosclerosis, immunosenescence, and malignancies ,2. RecenSo far, seven human oncogenic viruses have been listed: Epstein\u2013Barr virus (EBV), Kaposi sarcoma human virus (KSHV), human papillomavirus (HPV), hepatitis B and C viruses , human T-lymphotropic virus-1 (HTLV-1), and the most recently discovered Merkel cell polyomavirus (MCPyV) in January 2008. Although HCMV is not yet included in the oncogenic viruses list, it becomes more and more likely that HCMV is the eighth human oncovirus ,10. AlthHCMV contributes to carcinogenesis as an initiator or promoter ,12,13. HMost of the oncoviruses, and especially oncoviruses, of the Herpesviridae family, namely EBV and KSHV, alternate lytic and latent phases to favor tumor initiation and spread . SimilarUL135 and UL136 genes promote viral maturation, but most importantly, this locus involves the main molecular switch among latency and reactivation, including the opposing roles of UL135 and UL138 . The imiewed in . This reHCMV, through its oncomodulatory effect, catalyzes the oncogenic process within the cancerous cells by expressing viral proteins known to possess a pro-oncogenic power such as IE1 and US28, among others, helping tumor cells to evade the immune system, preventing cell death, and favoring cell survival . In addi+ and CD8+ T cells by preventing MHC class I and II antigen processing and appearance . Fir. Fir6]. Tumors are renowned as intricate systems that harbor heterogeneous cancer cells with distinctly diverse molecular signatures, sizes, and genomic contents. Among those various genomic clonal populations within the complex tumoral architecture are the polyploid giant cancer cells (PGCCs). Although described for over a century, PGCCs are increasingly being recognized for their prominent role in tumorigenesis, metastasis, therapy resistance, and tumor repopulation after therapy. A shared characteristic among all tumors triggered by oncoviruses is the presence of polyploidy . RecentlNonetheless, our data indicate that the oncogenic potency of HCMV clinical strains varies between low- and high-risk strains ,71,118. HCMV infection fulfills all the hallmarks of cancer, including sustained proliferative signaling, deregulating cellular energetics, resisting cell death, favoring genome instability and mutation, inducing angiogenesis, activating invasion and metastasis, tumor-promoting inflammation, enabling replicative immortality, and avoiding immune destruction  reviewe. Thus, tTo confirm the role of HCMV in cancer development, glioblastoma (GBM) patients treated with valganciclovir, in addition to standard therapy, have demonstrated increased overall survival . PatientHCMV has been considered for decades as a herpesvirus involved mostly in asymptomatic or mild disease in immunocompetent individuals, which could lead to an important disease burden during congenital infection and in immunocompromised patients. Recently, the long-lasting effects of HCMV started to arise with its role in atherosclerosis, immunosenescence, and cancer. The oncomodulation paradigm could explain the accelerated progression of cancers when HCMV superinfection of the tumor occurs. Finally, very recently, a direct oncogenic effect of some HCMV strains, named high-risk strains, has been observed with cellular stress, appearance of PGCCs, stemness, and EMT, which could explain the appearance of aggressive cancers, especially adenocarcinoma, with poor prognosis, metastasis, and resistance to treatment. The oncomodulation and direct oncogenesis triggered by HCMV are not mutually exclusive and benefit from the same immunosuppressive tumor microenvironment. Overall, a better understanding of the complex role of HCMV in cancer and its immune landscape will lead to new therapeutic approaches that will curtail cancers, especially with poor prognosis."}
+{"text": "Poor academic performance has been linked to factors such as sleep, health, illicit drug use, physical fighting, social media use, cyber bullying, physical activity, homelessness, times spent in video games and television. It is difficult to get a sense of the interplay between and relative importance of different behaviours/factors on academic performance as only limited research has been aimed at quantifying these factors.To evaluate association of school performance and variables in five categories of the YRBSS: physical fighting, diet/lifestyle, electronic device usage, concurrent substance use, and violence/self-harm.The CDC Youth Risk Behavior Surveillance System (YRBSS) data from 1991-2019 was used in study. Respondents were grouped by good and poor school performance and variables related to nutrition/lifestyle, electronic device use, concurrent substance use, mood/violence/self-harm were analyzed using chi-squaretest.A total of 41,235 student respondents.Nutrition/Lifestyle, electronic device use, concurrent substance use, mood/violence/self-harm are found to be significantly correlated with school performance.In national data, we found school performance is affected by nutrition, lifestyle, substance use, mood and exposure to surrounding violence, and self-harm. Further studies should be planned to evaluate benefits from the risk stratification to reduce this burden amongst US adolescents.No significant relationships."}
+{"text": "Oral and craniofacial tissues are uniquely adapted for continuous and intricatefunctioning, including breathing, feeding, and communication. To achieve thesevital processes, this complex is supported by incredible tissue diversity,variously composed of epithelia, vessels, cartilage, bone, teeth, ligaments, andmuscles, as well as mesenchymal, adipose, and peripheral nervous tissue. Recentsingle cell and spatial multiomics assays\u2014specifically, genomics, epigenomics,transcriptomics, proteomics, and metabolomics\u2014have annotated known and new celltypes and cell states in human tissues and animal models, but these conceptsremain limitedly explored in the human postnatal oral and craniofacial complex.Here, we highlight the collaborative and coordinated efforts of the newlyestablished Oral and Craniofacial Bionetwork as part of the Human Cell Atlas,which aims to leverage single cell and spatial multiomics approaches to firstunderstand the cellular and molecular makeup of human oral and craniofacialtissues in health and to then address common and rare diseases. These powerfulassays have already revealed the cell types that support oral tissues, and theywill unravel cell types and molecular networks utilized across development,maintenance, and aging as well as those affected in diseases of the craniofacialcomplex. This level of integration and cell annotation with partner laboratoriesacross the globe will be critical for understanding how multiple variables, suchas age, sex, race, and ancestry, influence these oral and craniofacial niches.Here, we 1) highlight these recent collaborative efforts to employ new singlecell and spatial approaches to resolve our collective biology at a higherresolution in health and disease, 2) discuss the vision behind the Oral andCraniofacial Bionetwork, 3) outline the stakeholders who contribute to and willbenefit from this network, and 4) outline directions for creating the firstHuman Oral and Craniofacial Cell Atlas. Thoughoften preventable, oral diseases are increasingly burdensome worldwide, affectingover one-third of the globe with a disproportionate effect on socially disadvantagedpopulations. In addition, chronic oral inflammatory diseases, such as periodontaldisease, have been increasingly associated with >60 systemic diseases, such ascardiovascular diseases, diabetes, cancer, pneumonia, inflammatory bowel diseases,obesity, and premature birth . To achihttps://www.humancellatlas.org) initiative was officially launched wasfounded in 2020 as a research network focused on postnatal adult oral andcraniofacial tissues within the HCA . AdditioThe oral and craniofacial complex is supported by highly diverse tissue niches,composed of epithelia, blood and lymphatic vessels, cartilage, bone, ligaments,and muscles, as well as adipose and peripheral nervous tissue . ThisanImportantly, oral and craniofacial tissue heterogeneity is not defined at justthe level of biology  as it is wellestablished that human sex, age, and ancestry influence tissue physiology. Thereis an urgent need to increase representation in scientific research, as ~85% oftoday\u2019s genomic data are derived from European ancestry; therefore, it iscrucial to account not only for tissue heterogeneity but also for expanding intohuman geographic, sex/gender, age, ethnic, and ancestral diversity in the donordata sets ,3. The https://data.humancellatlas.org/). While there are an estimated40 trillion cells in the human body, we estimate that there are about 2 trillionin the oral and craniofacial tissues. Although progress in the single cellprofiling of human oral tissues has been slow in comparison, researchers havemade significant progress as of 2022, publishing atlases of the oral mucosa,including the buccal mucosa, tongue, and gingiva ,OCBN made significant strides forward to the modern age of single cell biology, includiWhile early efforts have primarily focused on the adult oral soft tissues,craniofacial structures such as the cranial ganglia, cranial vault, cranialbase, nasopharynx, nasal bones and cartilages, neck, pinna, and middle ear boneswill be essential to allow a more detailed investigation into the molecularmechanisms controlling tendogenesis, chondrogenesis, and osteogenesis, whichsupport craniofacial function and enhance cranial skeletal repair, therebyleading to a better understanding of craniofacial anomalies. Achieving thesegoals will require more collaborative efforts among established and new OCBNinvestigators, other HCA networks, as well as other consortia.With this reference data set, we aspire to accelerate discoveries in the domainsof basic and clinically applied research with further downstream analyses.Expression profiling of different cell types in adult human tissues has shownhow intercellular communication contributes to tissue function by coordinatingcell functions in development and homeostasis; thus, when there are signalingdefects, disease will follow. The study of intercellular communication hassignificantly accelerated with advances in the single cell field with severalstudies discovering novel signaling, mediating cellular differentiation andimmune responses. Intercellular crosstalk has been investigated in oral tissues,with OCBN studies demonstrating how in periodontal disease there is a shift inthe transcriptional signatures of stromal and epithelial oral mucosa cells to aninflammatory profile . In diseGiven that most cellular crosstalk is spatially restricted with signals workingfrom 0 to 200 \u00b5m, spatial transcriptomics data are essential to understandintercellular communication in healthy and diseased tissues. To investigate howsurrounding cells may regulate signaling, several computational methods havebeen recently developed to integrate spatial information with ligand-receptoranalyses . HoweverWhile these initial OCBN projects have started to construct high-resolution mapsof organs and tissues, there is an unmet need to integrate these atlases tointerrogate analogous cellular components across tissue niches and to develop acommon coordinate framework for the healthy oral and craniofacial human tissues. So far,Furthermore, future work incorporating these clinical and biological data willhighlight the niche-specific cellular diversity that may help to explain whysome oral diseases manifest in some oral and craniofacial niches while sparingothers. For example, understanding niche-specific cellular heterogeneity inpediatric tissues from neonatal to infancy, juvenile, and adolescence periodswill allow the identification of cell states and cell lineages involved intissue maturation and a better understanding of early disease onset inchildhood. However, given the vast literature on immune training in earlydevelopment, these efforts should also reveal the mechanisms of healthy andpathologic aging that may lead to early and accurate prognostic tools allowingfor early intervention, similar to what is proposed by the LifeTime Initiative, 2021.This additional level of annotation is already relevant. For example, the conceptof structural immunity  has recently been described acrossthe body, suggesting that each tissue\u2019s cell-specific composition can instructits niche-distinct immune response . This leA fundamental challenge when constructing biological systems is the correctdefinition of cell state, which is achieved by applying complementaryapproaches, such as molecular characterization  and functional testing . UnderstMultimodal sequencing has the capacity to move the field from descriptive\u201csnapshots\u201d toward a mechanistic understanding of gene regulatory networks and,importantly, to refine sources of cellular heterogeneity as already applied tothe immune system . The useOvercoming data set\u2013specific batch effects through data integration of suchpopulation-level single cell data has remained a limitation. New computationaltools recently developed outside the OCBN address this , allowinUnderstanding the cellular context, including extracellular components andsignaling molecules that contribute to organ homeostasis, will help to furtheridentify the functions of specific cell types and interactions as well asprovide mechanistic insights into fundamental biological processes in health anddisease. Next, it will be necessary to integrate human multiomics data withcommon model organisms as well as patient-derived experimental disease modelsduring the progression from health to disease. The interrogation of these inparallel will be essential for functional assays for data validation and thedevelopment of new testable hypotheses, ultimately accelerating targetedfollow-up studies to enter the clinical research space.For the construction of future oral and craniofacial atlases in disease, itremains paramount to assess the functions, gene expression, and intercellularinteractions of all resident cells in healthy tissue as a reference. This levelof annotation will allow for a clearer understanding of how these processes aredisrupted in disease states. For instance, small subsets of cells are importantin the pathogenesis of a variety of complex diseases , and stuThe clinical significance of single cell approaches has been successfullydemonstrated in various human diseases by allowing the identification ofdisease-associated cell phenotypes\u2014for example, malignant tumor cells within atumor\u2019s mass  or the iMany oral conditions will benefit from the molecular characterization of cellularsubpopulations. It will provide valuable insights into factors that affectdisease progression of head and neck tumors, such as oral carcinoma; potentiallymalignant disorders of the oral cavity, such as proliferative verrucousleukoplakia ; oral muOrganizing such a large-scale project is dependent on a multidisciplinaryapproach relying on the close collaboration between oral surgeons and oralhealth care providers , with wet laboratory scientists and bioinformaticians . From the clinician\u2019s view, it iscrucial to carefully consider 1) sample collection criteria checkpoints, such asmedical history screening; 2) the recording of the precise anatomic location ofeach sample; and 3) review and collection of associated donor and samplemetadata, including health and disease states. Furthermore, this sort ofcollaboration will accelerate a shift from description to knowledge and thesolving of complex clinical questions.While work from the OCBN has just begun to reveal the diverse tissues and fluidsof the oral and craniofacial complex (phase 1), we are already planning toconduct studies that illuminate how these niches harmoniously integrate into thevital functions of communication, defense, breathing, and digestion (phase 2).The OCBN is committed to establishing an initial version of the oral andcraniofacial atlas within 2 y with phase 1 of all other HCA bionetwork atlases.As such, the OCBN is currently integrating the existing OCBN data sets (Table)with new unpublished data using harmonized nomenclature and annotation of celltypes.By taking an agnostic approach to tissue and organ physical location  should allow forshared discoveries to accelerate human health clinical benefit. For example,while the oral cavity is an important ecosystem, it is also a crossroads that isaffected by the condition of other, even distant, body sites. This is not asurprise; these tissues are intimately connected to the nervous, immune,cardiovascular, and endocrine systems . In abihttps://data.humancellatlas.org; https://oral.cellatlas.io;https://www.covid19cellatlas.org/byrd20/).Progress toward comprehensive mapping of oral and craniofacial tissues requiresnot only careful experimental design to robustly capture variation within andacross individuals but, importantly, a physiologic insight to interpret data andcurate data sets. To this end, it is essential to increase dialogue amongbiologists, computational data scientists, clinicians, pathologists, andstatisticians to achieve a consensus on data curation and cell annotation and todeliver data analysis platforms that are relevant and user-friendly . MoreoveFinally, the Human Oral and Craniofacial Cell Atlas encourages and supports theparticipation of scientists and clinicians from countries around the globe byrecognizing the need to integrate different ethnicities, environments, andregional diseases, and we invite any interested stakeholder to join the network,participate in our meetings, and contribute data for the integrated atlas (seecontact details in Conclusions). We are aware of potential challenges andlimitations, including available resources and tissue sampling, but we arecommitted to shared protocols , open anoral@humancellatlas.org.In sum, there is an enormous opportunity for integrated and precise oral health careinitiatives that leverage the accessibility of this space to improve oral andsystemic health. Profiling of these conditions from a patient-centered perspectivewill increase our understanding of disease cellular origin, mechanisms, etiology,and diagnostics\u2014rendering them experimentally tractable to test new hypotheses forbetter diagnosis and drug discovery. To achieve this grand vision requires thecollaboration of a multidisciplinary international team\u2014spanning the basic andcomputational sciences to clinical practice . This teA.J. Caetano, contributed to data analysis, drafted and critically revised themanuscript; I. Sequeira, K.M. Byrd, contributed to conception, design and dataanalysis, drafted and critically revised the manuscript; P.T. Sharpe, A. Kimple,M.A. Shazib, A. Opasawatchai, B.M. Warner, J. Krivanek, K. Kretzschmar, L.K. McKay,M. Freire, O. Klein, P.R. Tata, S. Pringle, S. Teichmann, D.W. Williams, I. MillerZmora, Q. Easter, W.J. Lu, P. Perez, T. Pranzatelli, S. Lwin, R. Boucher, M. Bush,C.D. Conde, M. Haniffa, J.S. Hagood, A.A. Volponi, V. Yianni, J. Macken, M.Efremova, E. Todres, B. Matuck, F. Fortune, A.O. Pisco, D. Boffelli, Y. Kapila, F.Momen-Heravi, A. Gulati, N. Moutsopoulos, P. Beachy, S. Wallet, T. Biddinger, D.Pereira, R. Kumar, contributed to data analysis, critically revised the manuscript.All authors gave final approval and agree to be accountable for all aspects of thework."}
+{"text": "How many patients with psychosis secondary to genetic conditions or congenital brain malformation have been diagnosed with schizophrenia, since its initial conception more than one hundred years ago? A case report of a young man, with antecedents of Capgras and Cotard syndromes, sent to a schizophrenia treatment-resistant outpatient clinic is presented. Instead of true, primary, idiopathic schizophrenia, a diagnosis of secondary schizophrenia (pseudo-schizophrenia or schizophrenia-like psychosis) was made, corresponding to a secondary psychotic syndrome, with hallucinations and delusions due to congenital cavum septi pellucidi, cavum vergae, cavum veli interpositi and progressive brain atrophy due to cystinosis. Extreme caution is recommended when diagnosing schizophrenia in severely psychotic patients independent of their acute or chronic condition. Schizophrenia shall never be forgotten as the great imitated of medicine. Cavum septi pellucidi and schizophrenia have been correlated for years . Some stInfantile or nephropathic cystinosis is a rare autosomal recessive lysosomal storage disorder, classically thought of as a childhood disease with bad prognosis. Nowadays, with modern, lifelong, improved treatments, patients are reaching adulthood more easily. However, survival has a price, with patients suffering increasingly more of other less common complications, such as neurologic dysfunction  that canA 32-year-old man came to the treatment-resistant schizophrenia outpatient clinic, asking for a second opinion. The patient presented depressive mood, low-self-esteem, anhedonia, adynamia, asthenia, hypersomnia, polyphagia, and bladder and fecal incontinence, with serious compromise of his social life. He admitted, in the past, auditory hallucinations, autoreferential, persecutory and grandiose delusions. In his electronic clinical records, three psychiatric admissions were found over the past ten years. Different doctors described misidentification with Sosia delusion (Capgras syndrome)\u2014with the patient believing his family had been substituted by doppelgangers with sadistic intent\u2014and ruin delusion (Cotard syndrome)\u2014with the patient complaining that he was kept dead by doctors wanting his internal organs for transplant. The patient had previously been on lorazepam, fluoxetine, sodium valproate, olanzapine, risperidone and amisulpride, reaching full remission. He had participated at the day hospital activities with relative success. While not admitted in the hospital, he was living at home with his family, with some support, regarding the therapeutic project. Still, there was contradictory information regarding the diagnosis: borderline personality disorder, bipolar disorder, schizoaffective psychosis, and schizophrenia.During his early infancy, he had been diagnosed by pediatric nephrology with infantile (nephropathic) cystinosis, after presenting Fancony syndrome and rickets. Genetic testing revealed cystinosin mutation, at the lysosomal cystine transporter (CNTS) gene with homozygotic deletion at chromosome 17p13. Since then, the patient had been living on a rigorous diet, plus chronic treatment with increasing or alternating doses of cysteamine, phosphocysteamine, mercaptamine bitartrate, enalapril, hydroxycholecalciferol, sodium phosphate, sodium citrate, potassium citrate and potassium chloride. During adolescence, he struggled with shyness and introversion, suffering bullying at school. As a young adult he had temporary experiences with nicotine, caffeine, alcohol, cannabinoids and cocaine. Nevertheless, he managed to finish his master\u2019s thesis in anthropology.Regarding the patient\u2019s familial history, both the living mother and the deceased father were described as having an unspecified personality disorder. One brother and one sister suffered from depression and alcoholism. Two uncles, one aunt and one cousin were diagnosed with unspecified psychosis. Unfortunately, his family support decayed a lot after his father\u2019s death with lung cancer.While at the three past psychiatric admissions, various blood and urine tests, chest radiographs and electrocardiograms were normal. One psychological assessment revealed no signs of personality disorder. One neuropsychological showed a discrepancy between medium verbal and inferior non-verbal intellectual efficiencies, with dyscalculia and deficits in attention and working memory. Two recent electroencephalograms, in a two year span, showed no changes. At the first admission, brain magnetic resonance imaging revealed cavum septi pellucidi and septum vergae a. Ten yeThe patient was diagnosed with secondary psychotic syndrome, with hallucinations and delusions (code 6E61.2), according to the World Health Organization\u2019s International Classification of Diseases, eleventh revision (WHO\u2019s ICD 11), due to cavum septi pellucidi, cavum vergae, cavum veli interpositi and brain atrophy due to cystinosis. A neurosurgery appointment was recommended. Psychoeducation was provided to the patient and his principal caretaker. Group therapy was suggested. Psychiatric medication was adjusted to amisulpride 600 mg and mirtazapine 30 mg, taken together both at night.For years, anecdotal case reports have described psychosis among patients with cavum septi pellucidi , cavum vThere is no known cause for schizophrenia, so it shall be considered a primary or an idiopathic disorder. This is written in the major psychiatric nosological systems, not only in the WHO\u2019s ICD-11, but also in the American Psychiatric Association\u2019s Diagnostic and Statistical Manual of mental disorders, fifth edition (APA\u2019s DSM-5). Whenever there is a probable cause for psychosis, schizophrenia shall not be diagnosed. Epistemologically speaking, Kraepelin\u2019s dementia praecox concept is obsolete; Bleuler\u2019s schizophrenias idea is outdated, and Schneider\u2019s first rank symptoms are pathognomonic of nothing . On the Sometimes, psychiatric patients do not receive the comorbid diagnoses of organic conditions. More often, many patients are sent to psychiatry with the hurried diagnosis of schizophrenia, without the integration of the so-called organic findings. At our personal cohort of two hundred patients previously diagnosed with schizophrenia, we found a new diagnosis of organic psychosis in 25%, with a mean delay, until the correct diagnosis, of twelve years.  Among thIn this particular patient, the cavum septi pellucidi, the cavum vergae, the cavum veli interpositi, plus the cystinosis-related neurological dysfunction mostly probably had a synergically contribution to the pathophysiology of an organic psychosis, not schizophrenia. Without this kind of rigorous clinical approach, psychiatry will be doomed, keeping on repeating decades of epistemological and nosological mistakes, therefore remaining the underdog of medicine.Every case of first-episode psychosis deserves a full medical workup ,23. Some"}
+{"text": "The purpose of this study was to investigate factors related to the levels of health-related quality of life (HRQoL) in elderly women based on Wilson and Cleary\u2019s HRQoL model.This study analyzed data from the eighth Korea National Health and Nutrition Examination Survey 2019 on 868 women over the age of 65 years. Based on the HRQoL model, parameters were categorized as personal, environmental, and physiological characteristics; symptom status; functional status; and perception of health status. The data were analyzed by quantile regression. The overall level of HRQoL was 0.87. Factors related to HRQoL in the 10% quantile were higher education level, higher economic status, economic activity, more walking days, fewer diseases, lower stress, less activity limitation, and higher perceived health status. Factors related to the 25% quantile of HRQoL were more walking days, fewer diseases, less activity limitation, and higher perceived health status. Factors related to the 50% quantile were age, economic activity, more walking days, fewer disease, lower stress, less activity limitation, and higher perceived health status. Factors related to the 75% quantile of HRQoL were smoking, more walking days, fewer diseases, lower stress, less activity limitation, and higher perceived health status.While differing parameters were identified according to the level of HRQoL of elderly women in Korea, there were five common factors. Interventions that focus on increasing walking, mitigating diseases, stress, and activity limitations, and improving perceived health status can improve HRQoL."}
+{"text": "Creutzfeldt-Jakob disease (CJD) is a rare, progressive, fatal neurodegenerative disorder caused by an abnormal glycoprotein known as the prion protein. The core features include progressive cognitive decline, cerebellar dysfunction, personality changes, and visual disturbances. Although psychiatric symptoms are rare, they can be the primary symptom of CJD, and such presentations can pose diagnostic difficulties. In this paper, we describe the case of Ms. R, who manifested psychotic symptoms as the first signs of CJD.Ms. R, was a 49-year-old white British female not previously known to psychiatric services, who presented with acute onset of florid psychotic symptoms. Her symptoms included auditory hallucinations, paranoia, and thought disorder. She was treated with antipsychotics for over four weeks, following her admission, but no improvement was seen. Instead, her psychosis worsened with cognitive decline, mutism, and the appearance of neurological symptoms such as jerky body movement, ataxia, and falls. All screening blood tests, chest X-ray, and CT abdomen were normal. The MRI, however revealed few patches of high T2/FLAIR signal in the deep white matter. Cerebrospinal fluid showed increased protein. Neurologist reviews suggested the possibility of sporadic CJD (sCJD) as a probable diagnosis. As her condition deteriorated, she became comatose and died four months after the appearance of the first psychiatric symptoms.It can be challenging to diagnose CJD since the clinical picture overlaps with other neuropsychiatric and neurodegenerative conditions. It requires the presence of relevant clinical findings along with positive CSF, EEG, or MRI findings to make a probable diagnosis. Regarding our case, some noteworthy observations were psychosis as the initial symptom, relatively delayed onset of neurological signs, rapid deterioration with brief duration of illness. The MRI findings were typical of those seen in sCJD, although the EEG did not suggest sCJD. A differential of variant CJD was considered because of her age, prominent psychiatric symptoms, and delayed neurological signs.Creutzfeldt-Jakob disease course is rapidly progressive, and majority of patients die within one year. Therefore, awareness of early clinical features is of great significance. Among other things, this would enable patients and their families time to understand the nature of CJD, prognosis and prepare advanced directives. This case adds to the growing number of atypical presentation of CJD as well as pointing to an expanding spectrum of the disease. Therefore, clinicians should consider CJD in the differential diagnosis of new-onset psychosis, particularly if symptoms persist and worsen despite standard psychiatric treatment."}
+{"text": "This review paper focuses on the current state of poultry waste generation, composition, and management techniques in commercial poultry farms and trading in Bangladesh, to reduce pollution and generate economic benefits from poultry waste. It also underlines the negative impact of poultry waste disposal on the environment. In Bangladesh, collection of poultry waste into bags and, subsequently, direct use as fertilizer in agricultural fields and aquaculture is common, while alternative disposal methods such as composting and biogas generation are now attracting commercial poultry producers. Direct use of poultry manure results in poor air and soil quality, environmental deterioration, detrimental effects on global health, climate change due to high levels of atmospheric ammonia, and the creation of significant amounts of greenhouse gases. Lack of knowledge and investment, as well as high demand for free land for composting, are important obstacles. Future research on precise waste characterization, improved understanding of poultry waste management, and increased efforts on developed waste disposal for a safe environment are therefore recommended. So, poultry waste, which is currently a burden for the environment, could be turned into a useful agricultural resource, which would be useful for the poultry industry. Poultry is an important subsector of the livestock industry and the fastest-growing agricultural enterprise in Bangladesh. It contributes significantly to the economy of Bangladesh by providing employment opportunities in rural and semiurban areas, as well as accessible protein sources for the growing population . PoultryBangladesh has a long history of poultry production in traditional backyard farming. Initially, poor rural women and unemployed youngsters were involved in commercial poultry rearing on a modest scale. It also included semiurban and urban poultry raisers who contributed to meeting the growing demand for eggs and meat. Since 1990, the commercial poultry sector has grown at a steady pace of 15%\u201320% per year, with a slight slowdown after 2007 due to the avian influenza outbreak by Hamid et al., contribPoultry production, on the other hand, is a complicated process that combines the economic, social, and environmental aspects of a given product within a socioeconomic context. Unfortunately, as poultry production has become more concentrated and operation sizes have expanded, major environmental challenges have arisen . DespiteThe primary issue facing the poultry industry is the large-scale accumulation of wastes  from hatAs a result, poultry waste management is essential for environmental protection, human health and safety, and safe poultry production. Such a significant volume of waste may cause disposal and pollution difficulties unless environmentally and economically sustainable alternatives are discovered. Resolving these issues requires serious attention to managing poultry waste so that the environmental impacts of such a huge volume of waste are minimized.Therefore, this review focuses on the current state of the commercial poultry waste management practices in Bangladesh, emphasizing their significance as well as proposing a successful guideline to manage the waste properly. Researchers or scientists will quickly understand what is happening, which will help improve waste management and a recycling system that will last.Poultry wastes or manure consist of excreta, feathers, spilled feeds and water, dead birds, broken eggs, wastewater, litter or bedding materials , dead birds, and slaughterhouse and hatchery wastes. The primary components of poultry wastes are water and carbon; small amounts of nitrogen and phosphorous; and trace amounts of chlorine, calcium, magnesium, sodium, manganese, iron, copper, zinc, potassium, arsenic, cobalt, selenium, molybdenum, and boron ,12,13.4) generation potential, whereas chicken feathers contain approximately 91% protein (mostly keratin), 1% lipids, and 8% water [According to previous research, offal (slaughterhouse waste) contains 5.3% of the total Kjeldahl nitrogen, 32% protein, 54% lipids, and 0.6%\u20130.9% methane . It is currently gaining popularity due to its superior quality for the soil, plants, and vegetable fields. Nowadays, private companies in Bangladesh are currently marketing vermicompost at a low cost to farmers (https://www.garden.com.bd/fertilizers/2-vermicompost-fertilizer.html).Composting, an anaerobic conversion process that turns organic compounds into a soil-friendly product in a controlled manner, is one of the most successful and widely used methods for dealing with poultry waste ,34,35. Ccomposes . HoweverMoreover, government and nongovernment organizations (NGOs), as well as research and extension institutes, such as Bangladesh Agricultural University and Bangladesh Agriculture Research Institute, are bridging farmers\u2019 access to the most appropriate and cost-effective composting technologies . Private4, carbon dioxide (CO2), and a trace amount of hydrogen sulfide [Biogas is a gas mixture formed by the anaerobic digestion of various organic materials. It is largely composed of CH sulfide ,39. Poul sulfide ,41. Biog sulfide ,42. More sulfide . Banglad sulfide ,44. Appr sulfide  in the cUsing biochar, a solid formed from carbonized biomass, on land can enhance soil properties and lower greenhouse gas emissions brought on by biomass degradation . In subtProcessed poultry litter is used in diets for poultry, swine, lambs, ewes, lactating cows, wintering cattle, and brood cows \u201351. FeatRendering is a process of both physical and chemical transformation that involves the use of a variety of equipment and processes, including the application of heat, de-moisturizing, and the separation of fat.RenderinIn addition, there are many other uses of poultry waste, like preparation of biodiesel, reuse of litter, and mass burning or direct combustion. Feather meal is boiled in water at 70\u00b0C to remove the fat, which is then trans-esterified to produce biodiesel . ReusingThere are approximately 8 grandparent stocks, 100 breeder farms and hatcheries, and over 70,000 commercial layer and broiler farms in Bangladesh , produciGenerally, the large poultry breeder companies, such as Aftab Bahumukhi Farms Ltd., Nourish Poultry and Hatchery Ltd., Kazi Farms Group, Nahar Agro Ltd., Provita, Paragon Group, and others, have strong relationships with local brokers who collect spent litter and sell it to crop and fish farmers. These companies manage their poultry in contact housing, either in floor or slat cum floor systems, or in cage systems, with birds kept for 64\u201366 weeks (broiler breeders), 72\u201380 weeks (layer breeders), and approximately 90 weeks (layers). They usually practice proper poultry waste management, primarily through composting . The litIn most cases, large commercial companies have their own disposal pit  to dispoThe common hatchery wastes  producedDuring slaughtering and processing, retailers keep the offal and leftover chicken parts, except the feathers, and sell these as fish feed, chicken feces, feathers, and other solid chicken waste are disposed of in municipal waste disposal bins . PoultryOverall, waste management practices by small- and medium-scale commercial farms are minimal, whereas large-scale producers try to maintain the scientific method. However, a lack of capital and insufficient land often impede the process. So, waste use in all types of poultry production in Bangladesh  depends greatly on capital, technical knowledge, awareness, and available facilities .2, and CH4, through microbial activity and changes in temperature, pH, moisture, and oxygen concentrations [Despite the huge benefits of poultry waste, now it is becoming an undisputable concern around the world. The constant production of poultry waste causes environmental annoyances that are hazardous to animal and human health ,62\u201366. Ptrations ,70\u201375. Rtrations \u201378. Longtrations ,80. Howetrations .Poultry litter may include human and animal infections, such as zoonotic avian influenza. Therefore, appropriate hygiene must be used when handling poultry manure ,81. MoreScientific and safe methods of utilizing poultry waste and by-products have the potential to increase farmer revenue. In areas where intensive poultry production is practiced, and population density is high, improper poultry waste storage and disposal pose a risk of air and water pollution, as well as health hazards. Manure collection, treatment, storage, and effective utilization of poultry waste benefit the industry, the environment, and the country. The rendering process is commonly used to convert by-products into marketable products for agricultural and industrial uses . The proPerfectly managed poultry waste could be a valuable source of income and contribute to the country\u2019s GDP, and will contribute to the United Nations Sustainable Development Goal. This is a very important problem that needs to be fixed because it is hurting the natural biological system. It should be brought to the attention of all poultry business owners and other important people."}
+{"text": "Polyphenol, one of the major components that exert the therapeutic effect of Chinese herbal medicine (CHM), comprises several categories, including flavonoids, phenolic acids, lignans and stilbenes, and has long been studied in oncology due to its significant efficacy against cancers in vitro and in vivo. Recent evidence has linked this antitumor activity to the role of polyphenols in the modulation of redox homeostasis  in cancer cells. Dysregulation of redox homeostasis could lead to the overproduction of reactive oxygen species (ROS), resulting in oxidative stress, which is essential for many aspects of tumors, such as tumorigenesis, progression, and drug resistance. Thus, investigating the ROS-mediated anticancer properties of polyphenols is beneficial for the discovery and development of novel pharmacologic agents. In this review, we summarized these extensively studied polyphenols and discussed the regulatory mechanisms related to the modulation of redox homeostasis that are involved in their antitumor property. In addition, we discussed novel technologies and strategies that could promote the development of CHM-derived polyphenols to improve their versatile anticancer properties, including the development of novel delivery systems, chemical modification, and combination with other agents. Polyphenols, the most common natural antioxidants extracted from plants, primarily function as secondary metabolites to protect plants against reactive oxygen species (ROS), ultraviolet radiation, mechanical damage, pathogens, parasites, and predators ,2. It coPolyphenols can be classified into four major categories, including flavonoids, phenolic acids, lignans, and stilbenes, according to their chemical structure . FlavonoROS contradictorily influence cancer evolution, either triggering tumorigenesis, promoting cancer cell transformation, or leading to tumor regression and even cell death . IntraceDisrupting the homeostasis of oxidative stress and a reduced state have been proven to be significant strategies for cancer treatment ,43. SomeIn this review, we summarize the therapeutic mechanisms underlying the polyphenol-mediated modulation of redox homeostasis in cancer treatment and drug resistance surmounting. In addition, we discuss novel technologies or methods for optimizing the delivery, targeting, and preservation of polyphenols for effective cancer treatment.In cancer cells, moderate ROS  function as second messengers in cellular physiological processes to modulate cellular signaling and biological reactions to maintain endogenous homeostasis , therebyA variety of polyphenols, including kaempferol, resveratrol, catechins, curcumin, wogonin, quercetin, etc., have been reported to suppress tumors by suspending oxidative stress via various mechanisms. Primarily, the hydroxyl group on polyphenols undergoes hydrogen atom transfer or single electron transfer reactions, thereby scavenging radicals such as hydroxyl, peroxyl, or peroxynitrite . In addiTetrastigma hemsleyanum Diels et Gilg, Sparganii Rhizoma, Lysimachiae Herba (dried whole part of Lysimachia christinae Hance)) [Kaempferol, a well-known natural polyphenol derived from CHMs ) ,89,90),  Hance)) ,92,93. K Hance)) . Accordi Hance)) , kaempfe Hance)) . Mechani Hance)) . Notably Hance)) ,99, whic Hance)) ,101. As  Hance)) , the com Hance)) . These fResveratrol, one of the most investigated polyphenols from CHMs ,105, hasCatechins are the most abundant polyphenols in tea , maScutellaria baicalensis Georgi (a kind of CHM), has been used to treat inflammatory diseases [There are many other polyphenols that can be applied in cancer treatment due to their antioxidant capability. Curcumin, a well-known polyphenol extracted from the rhizomes of Curcuma longa, was reported to inhibit the proliferation of breast cancer cells through the NRF2-mediated downregulation of Flap endonuclease 1, a DNA repair-specific nuclease. In detail, curcumin could trigger NRF2 translocation from the cytoplasm to the nucleus to bind to the promoter of Fen1 and decrease its transcriptional activity . In recediseases . It is ndiseases . Moreovediseases . Quercetdiseases . In factdiseases ,135.Taken together, polyphenols can directly eliminate ROS to relieve oxidative stress. Additionally, they manipulate the activity of some redox signaling pathways and antioxidant enzymes to retard tumor progression, including carcinogenesis, proliferation, metastasis, and drug resistance, in a variety of cancer types .Several kinds of polyphenols also exhibit prooxidant capabilities in cancer therapy. Intriguingly, some kinds of polyphenols exhibit antioxidant activity, but high doses of them induce pro-oxidative stress and lead to DNA damage, lipid peroxidation, inflammasomes, and autophagosome augmentation ,138,139,A high dosage of curcumin also exhibits a pro-oxidant potential to suppress tumors. For example, curcumin could evoke cytotoxic cell death in non-small cell lung cancer (NSCLC) by promoting ROS accumulation and mitochondrial transmembrane potential reduction, thus causing DNA damage, G2/M arrest, and subsequent mitochondrial apoptosis . In addiWogonin is another compound that shows prooxidant effects in cancer treatment. For example, wogonin could elicit abundant ROS to activate caspase 3/8/9 and subsequent apoptosis, thus contributing to the inhibition of lung cancer cell proliferation . In someNotably, resveratrol has been observed to have outstanding anticancer potential in many types of cancer cells, such as bladder, prostate, glioblastoma, colon, breast, lung, and ovarian cancer cells ,160,161.Perilla frutescens and Glechoma hederacea L. [Some other polyphenols could also display prooxidant potential in cancer treatment. Similar to resveratrol, kaempferol can act as an oxidative stress inducer. The downregulation of NRF2 by kaempferol impaired the transcription of its target genes, including NQO-1, HO-1, AKR1C1, and GST, to enhance ROS accumulation and apoptosis in NSCLC cells . Rosmariracea L. ,167, alsracea L. . In addiracea L. . Similarracea L. . For exaracea L. . Furtherracea L. . Severalracea L. ,174.Taken together, the prooxidant function of polyphenols is indispensable to manipulating redox homeostasis in cancer cells. The aberration of redox signaling and intracellular oxidative stress induced by polyphenols can lead to macromolecule damage, such as DNA or protein damage, and lipid peroxidation, which triggers programmed cell death (PCD), such as apoptosis, ferroptosis, and pyroptosis, thereby playing an essential role in cancer prevention and treatment, as well as in overcoming drug resistance .The characteristics of polyphenols in modulating redox homeostasis have been widely applied in cancer prevention and treatment, which lays the basis for the discovery and development of natural anticancer drugs. Indeed, many polyphenols have been explored in preclinical or clinical trials, but the drawbacks of polyphenols generally disturb their versatile properties in clinical settings . For insStructural modifications, such as esterification, methylation, and glycosylation, can avoid degradation and enhance the bioactivities of polyphenols. For example, the esterification of EGCG through the substitution of hydroxyl groups with the chain of fatty acids not only increased lipophilicity, but also promoted its antioxidant capacity via enhanced hydrogen atom donation . SimilarRecent evidence has shown that nano strategies can aid in overcoming polyphenols\u2019 inherent drawbacks, including their low water solubility, poor stability, and nontargeting ability ,192. A mStrategies to combine polyphenols with other agents play important roles in preclinical evaluation and clinical implementation, including amplifying ROS-mediated therapeutic efficiency and avoiding chemotherapy-induced side effects . The comOxidative stress acts as a double-edged sword in tumor progression; thus, the strategy to manipulate ROS levels to influence redox homeostasis is significant for targeting tumors. Notably, polyphenols can regulate oxidative stress in cancer treatment. In this review, focusing on redox homeostasis modulation and the involved molecular mechanisms, we have summarized several polyphenols that can function at different stages of cancer progression. We have also discussed several novel strategies, including chemical modification, nanotechnology, and combined treatment, that polyphenols could facilitate as optimum therapeutic agents in clinical settings.A myriad of preclinical and clinical trials has demonstrated the potential value of polyphenols in the prevention of carcinogenesis, limitation of proliferation, inhibition of metastasis, and overcoming of drug resistance. Given that a large number of polyphenols are derived from CHMs and are easily acquired from a common daily diet, polyphenols are recognized as promising candidates for cancer therapy. However, several issues remain to be resolved before they can actually be used in the clinic. Primarily, their poor solvability, targeting ability, and stability seriously impede their application. In addition, some reports revealed that several antioxidants lead to the progression of tumors ,213,214."}
+{"text": "The growth of data-driven technologies, 5G, and the Internet pose enormous pressure on underlying information infrastructure. There are numerous proposals on how to deal with the possible capacity crunch . HoweverThe topics addressed in this Special Issue include physical-layer security , quantumIn the review paper , authorsIn the perspective paper , the autIn the first article paper , authorsIn the second article paper , the autIn the third article paper , authorsIn the fourth article paper , authorsIn the fifth article paper , authorsIn the sixth article , authorsIn the seventh article , authorsIn the eight article , authorsIn the nineth article paper , an entaIn the 10th article paper , relatedIn the 11th article , authorsIn the final article paper , related"}
+{"text": "PLOS ONE Editors retract this article [The  article  because NS did not agree with the retraction. AuR, RQ, AH, HS, HMRJ, AM, and MH either did not respond directly or could not be reached."}
+{"text": "Meat by-products such as bones, skin, horns, hooves, feet, skull, etc., are produced from slaughtered mammals. Innovative solutions are very important to achieving sustainability and obtaining the added value of meat by-products with the least impact on the environment. Gelatin, which is obtained from products high in collagen, such as dried skin and bones, is used in food processing, and pharmaceuticals. Chitosan is derived from chitin and is well recognized as an edible polymer. It is a natural product that is non-toxic and environmentally friendly. Recently, chitosan has attracted researchers\u2019 interests due to its biological activities, including antimicrobial, antitumor, and antioxidant properties. In this review, article, we highlighted the recent available information on the application of gelatin and chitosan as antioxidants, antimicrobials, food edible coating, enzyme immobilization, biologically active compound encapsulation, water treatment, and cancer diagnosis. Among the many meat by-products studied in the literature, gelatin and chitosan are the most abundant polysaccharides in nature . Their uGelatin is a natural ingredient derived from animal by-products such as cattle bones, pork skins, and split cattle hides. It has healthy properties and has many applications, such as in confectionery, pharmaceutical products, meat, cosmetic and health care products, desserts, dairy products, and juices . ChitosaGelatin is mainly derived from untanned bovine hide wastes or by-products, fish skins, pigs, and poultry. It can be used in packaging and coatings, whereas chromium-tanned leather waste can be used in agriculture as fertilizer . GelatinCollagen  is well Animal-derived collagen is used in the food industry, as well as gelatin in its denatured form which, traditionally, is derived as a by-product of meat rendering from connective tissue. In the food industry, gelatin is used to form gels, gums, emulsifiers and as a polyelectrolyte to aid flocculation.Katsuwonus pelamis) canning by-products was purified to give nineteen peptides that showed a high level of antioxidant activity. A high concentration of amino acids gives the gel exceptional clarity and strength. These results indicated that the antioxidant peptides generated from this gelatin might be used as possible additives in health-beneficial goods to prevent ultraviolet-A injury [It is recognized that oxidation is one of the most significant problems in the quality of food products, and during the high-temperature processing of protein foods, heterocyclic amines are generated, which are known as carcinogenic substances . Some faA injury . ChitosaA injury . Oz et aA injury  examinedA injury  showed tA injury . The IC5A injury  publisheA injury  evaluateA injury  to assesA injury . SeveralA injury , apple eA injury , banana A injury , purple A injury , and blaA injury  can incrA injury . Escherichia coli [Pseudomonas aeruginosa [Pseudomonas fluorescens [Klebsiella pneumoniae [Shewanella putrefaciens, Shewanella baltica, Serratia spp. and Gram-positive bacteria such as Staphylococcus saprophyticus [Staphylococcus aureus [Penicillium italicum in combination with bergamot essential oil and showed a great inhibitory effect, but the inhibitory potency of the composite sheets decreased during the storage period [Aspergillus flavus. The application of Eucalyptus globulus essential oil\u2013chitosan matrix successfully inhibited yeasts such as Candida parapsilosis and Candida albicans [Salmonella typhimurium, E. coli, Proteus mirabilis, Salmonella enterica, P. aeruginosa, and Proteus vulgaris and showed significant antibacterial activities [Streptococcus mutans, S. aureus, Bacillus cereus, Bacillus subtilis, Listeria monocytogenes, Bacillus thuringiensis, Lactobacillus sakei, Lactobacillus plantarum, and Listeria innocua [Kavoosi et al.  discoverhia coli , Pseudomruginosa , Pseudomorescens , Klebsieeumoniae , Shewanephyticus  and Staps aureus . Howevers aureus . Chitosae period . The vole period ,89. Li ee period  observedalbicans . Chitosaalbicans , green talbicans , spirulialbicans , propolialbicans , black palbicans , and puralbicans . It was albicans . The blealbicans . Accordialbicans , gelatinalbicans . They acalbicans , leadingalbicans . Chitosativities ,101. Chi innocua ,93,102.2 nanoparticles in chitosan sheets imparts ethylene-scavenging properties [2 production by developing a pH-CO2-generated link, these substances are primarily used as markers of food pH and freshness. The most significant category of flavonoids and a significant component of phenolic compounds is anthocyanins. These dyes exhibit color alterations in response to pH variations. However, further research is required before chitosan-based biosensors can be used in intelligent food packaging. Depending on variations in impedance, sophisticated humidity and temperature sensors were created using chitosan and CuMn2O4 spinel nanopowder. The reduction in the sensor\u2019s impedance with rising temperature is due to charge carrier production, which is influenced by temperature [Artemisia campestris [Perilla frustescens [Pimpinella anisum L.) [Artemisia campestris [Pistacia terebinthus leaf extract [Recently, gelatin and chitosan have been used in food packaging because the use of petroleum-based materials has detrimental effects on the environment because they are not sustainably sourced, reusable, recyclable, or renewable ,104. Resoperties . Chitosaoperties , includioperties  employedoperties  added sooperties . Anotheroperties . Zhang eoperties  developeoperties , becauseoperties . The senperature . Researcperature . El-Giouperature  studied perature . This efmpestris , Perillastescens , basil [stescens , ginger isum L.) , and Artmpestris . The addmpestris , apple empestris , banana mpestris , Chinesempestris , root exmpestris , mango kmpestris , Pistaci extract , syringi extract , protoca extract , resulteAspergillus flavus, Aspergillus parasiticus, Aspergillus niger, and Penicillium chrysogenum, resulting in the control and inhibition of these pathogens [Microencapsulation technology is used to prevent product base materials from deteriorating by enhancing the active components\u2019 bioavailability, which increases their solubility and enables the preparation of solid formulations of oils. The efficiency of the capsule is determined by the properties of the wall and the base materials. Excellent results can be obtained by using the mixture of the wall material to prepare the microcapsules. Rosmarinic acid and carvacrol, the two main active components in Turkish oregano extract, have been found to release more readily in vitro when gelatin, gum arabic, Tween 20, and cyclodextrin were used as coating materials . Chitosaathogens .Heavy metals such as copper, nickel, lead, zinc, cadmium, mercury, arsenic, chromium, bismuth, cobalt, and iron are harmful to the environment and human health even when present in trace amounts . Elimina2) particles. It was found to be non-cytotoxic to L-929 cell culture when used in extraction forms in engineered membranes. Furthermore, the macroporous membrane showed excellent cell adhesion and proliferation after 24 h and 48 h of cultivation [Gelatin methacryloyl (GelMA) hydrogels with cell-responsive arginylglycyl aspartic acid and matrix metalloproteinases peptide sequences have been frequently used in tissue engineering because of their adaptable mechanical, superior processing performance, and outstanding biocompatibility properties. GelMA-based hydrogel microstructures can be precisely controlled using modern production techniques such as 3D printing and electrospinning. GelMA hydrogels with different microstructures have been designed and studied to mimic the natural extracellular matrix and to control the proliferation, migration and differentiation of different cell types . Chitosativation . Chitosativation .The potential use of chitosan and gelatin as drug delivery carriers has been reported in several studies ,145,146.Gelatin and chitosan could be used in many industrial fields, including in foods, medicines, and pharmaceuticals . They haIn this review, we highlighted recently available information about chitosan and gelatin and their applications in food, medicine, pharmaceuticals, and wastewater treatment. Gelatin and chitosan are attracting great interest due to their numerous applications in food, medicine and pharmaceutical products. They are interesting biomaterials for product development of widespread application due to their excellent inherent properties including biodegradability and food ability nature. With the development of technology and the economy, gelatin and chitosan are often produced according to legislation or standards that consider safety and health. Gelatin derived from meat by-products is an ideal material for food packaging due to its many advantages such as low price, polymerization, biodegradability, and good antibacterial and antioxidant properties. However, the gelatin film has poor water and mechanical resistance, which is an obstacle to its development and application in food packaging. The application of gelatin and chitosan as alternative biomaterials for edible biodegradable polymers for packaging is considered to be one of the best ways to reduce plastic pollution in the environment."}
+{"text": "Recently, renowned athletes have shown increasing willingness to discuss mental health. For instance, Olympic-winning gymnast, Simone Biles , tennis Sports psychiatry shares connections with neighboring disciplines like sports psychology, clinical psychology, psychotherapy, pharmacology, and sports science, amongst others . HoweverDue to these overlapping concerns, we believe that increased knowledge exchanges are essential between sports psychiatry, forensic psychiatry, and the law, in relation to elite-level sport. To that end, we outline possible interconnections and advocate for more epistemological interactions. In doing so, we hope to raise awareness about these medicolegal intersections, with the aim of improving psychiatric support for athletes and enhancing professional standards across these domains.Sport-specific mental health issues are a composite clinical phenomenon. Elite athletes from different sports might be vulnerable to psychiatric morbidities . Albeit With their unique position in a competitive environment, elite athletes may be prone to psychopathological risk factors. Hughes and Leavey summarize these determinants , includiAmidst this compound clinical environment, sports psychiatrists provide treatment for competitive athletes, delineating prevention and care pathways either independently or as part of a medical team . As an iAs scientific investigations within sports psychiatry develop, there have been proposals to broaden the scope of this subdiscipline . Yet, toGiven these medicolegal intersections, we advocate for closer collaborations between the nascent area of sports psychiatry and the forensic-psychiatric subdiscipline. Below, we outline potential scenarios, theoretical considerations, and directions for future research in competitive sporting frameworks.Elite-level sport spans diverse civil and criminal jurisdictions, notwithstanding apposite rules enforced by regulatory bodies . ResultaOwing to their potential involvement with TUE processes, prescribing psychotropic medications, and providing medical advice, sports psychiatrists might face ethical and legal issues, either through deliberate actions or inadvertent negligence. As an example, a sports psychiatrist may be caring for an athlete-patient who is traveling between different international sporting events. This could mean that they are asked to prescribe psychopharmaceuticals in jurisdictions where they are not licensed to practice. Alongside inherent legal risks and ethical concerns, this may increase the possibilities of an athlete self-medicating, creating higher chances of doping contraventions and adversely affecting patient safety. Alternatively, this could also lead to treatment provision by non-psychiatric specialists, again jeopardizing an athlete's welfare. Furthermore, Landis has explicated numerous situations that can necessitate juridical interactions for sports physicians . In notoWhilst sports psychiatrists must have sufficient expertise about anti-doping rules, WADA and governance bodies continuously (and separately) update them, causing inconsistencies. For instance, at the time of writing, the opioid, Tramadol, is prohibited in-competition by the international cycling federation, the Union Cycliste Internationale, but not by WADA  Tramado] and furNavigating legal scenarios could require extensive judicial insights, which might be lacking in the developing subspeciality of sports psychiatry. With this in mind, additional training about legal conventions and forensic psychiatry will prove beneficial to sports psychiatry, like in general psychiatry . RecentlAcross diverse legal settings, a forensic psychiatrist might encounter an elite-level athlete in the context of criminal and civil matters, like in cases of interpersonal violence, substance use and doping-related offenses, or during medical malpractice complaints, as outlined.Specifically, medical malpractice constitutes a compound issue and presumes that a sports psychiatrist has demonstrated non-compliance with recognized professional standards in the therapeutic relationship, thus requiring forensic-psychiatric expertise . CausatiTo uphold best practice, forensic psychiatrists must be aware of the unique risk factors of high-performance competitors. For example, B\u00e4r and Markser have ascribed a specificity to sporting mental health, which may influence etiology and clinical presentation . LikewisAmidst these frameworks, cultural competency in forensic-psychiatric practice would assume greater importance. Researchers argue that cultural and socioeconomic determinants can help contextualize psychopathology and inform legal outcomes . AccordiPossible biases might be introduced by forensic psychiatrists toward athletes. Alongside others, the anchoring effect could shape decision-making processes given prominent media narratives about athletes in the public eye. Notably, this may be pertinent in anti-doping incidents, which can provoke emotive press reports . Other cSports psychiatry is a burgeoning subspecialty with multidisciplinary implications for elite-level sports. However, there is scant awareness about its jurisdictional intersections with forensic psychiatry and the law. We sought to bridge this gap by examining prospective overlaps and presenting broad questions, concerns, and potential research directions in elite and high-performance sports. Consequently, we hope this forms the basis for increased knowledge exchanges, with the aim of raising awareness about medicolegal issues, enhancing professional standards, and optimizing cross-disciplinary psychiatric support.AS, AB, and ML-R conceptualized this paper. AS and ML-R wrote the first draft of the paper. All authors contributed to manuscript edits and provided feedback for subsequent drafts and read and approved the submitted version of this manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Confluent and reticulated papillomatosis\u00a0(CARP) of Gougerot and Carteaud is a rare chronic disease with exacerbation and remissions typically affecting young people. Classic clinical characteristics include asymptomatic scaly hyperpigmented macules, patches, and papules in the trunk's confluent and reticular pattern.A 12-year-old girl, otherwise healthy, presented with itchy, persistent skin lesions all over her body for one year. Skin examination revealed generalized scaly brownish patches, thin papules, and plaques all over her body, including her face, neck, middle of the chest, abdomen, back, upper extremities, elbows, lower extremities, and knees. Wood's lamp examination of her skin lesions was unrevealing. Skin biopsy showed papillomatosis, hyperkeratosis, acanthosis, and hypergranulosis. The dermis showed perivascular inflammatory cellular infiltrate. Based on the above clinicopathological findings, the patient was diagnosed with CARP. In our case, a generalized form was reported. CARP is diagnosed based on clinical and histopathological features. Oral antibiotics are the cornerstone of treatment.\u00a0Our patient responded well to oral minocycline 85 mg one tablet daily, tacrolimus 0.1% ointment twice daily, and selenium sulfide shampoo twice weekly for two months.The classic clinical characteristics of CARP include asymptomatic scaly hyperpigmented macules, patches, and papules in a confluent and reticular pattern on the trunk. A generalized form, as in our case, has been reported. CARP is diagnosed based on clinical and histopathological features. Oral antibiotics are the cornerstone of treatment. Pityrosporum organisms or bacteria, hyperinsulinemia, insulin resistance, Cushing disease, menstrual irregularities, thyroid disease, pituitary dysfunction, hirsutism or hypertrichosis, obesity, acanthosis nigricans, ultraviolet light exposure, amyloidosis, and the disorder of keratinization with overexpression of keratin-16 have been suggested to play a role in the development of the disease [Confluent and reticulated papillomatosis (CARP) of Gougerot and Carteaud is a rare chronic disease, consisting of exacerbations and remissions, and it typically affects young people. It is characterized by asymptomatic scaly, hyperpigmented papules and plaques that are reticulated at the periphery and confluent in the center. A hypopigmented variant of CARP was previously described . This va disease . Pregnan disease ,3. Treat disease . TopicalA 12-year-old girl, otherwise healthy, presented with a new onset of itchy, persistent, and slowly progressing skin lesions over her body for one year. Systemic examinations, past medical history, drug history, and family background were unremarkable. Skin examination revealed generalized scaly brownish patches, thin papules, and plaques covering her body, including her face, neck, middle of the chest, abdomen, back, upper extremities, elbows, lower extremities, and knees\u00a0Figures . Hair, nWood\u2019s lamp examination of her skin lesions was unrevealing. Skin biopsy showed papillomatosis, hyperkeratosis, acanthosis, and hypergranulosis. The dermis showed perivascular inflammatory cellular infiltrate\u00a0Figure . AccordiCARP was described first in 1927 by two French dermatologists, Gougerot and Carteaud . CARP isCARP is a rare condition most often occurring in young adults. Classic clinical characteristics include asymptomatic scaly hyperpigmented macules, patches, and papules in a confluent and reticular pattern on the trunk. A generalized form of CARP, as described in our case, was previously reported. CARP is diagnosed based on clinical and histopathological features. Oral antibiotics are the cornerstone of treatment."}
+{"text": "Systemic insulin resistance is characterized by reduced insulin metabolic signaling and glucose intolerance. Mineralocorticoid receptors (MRs), the principal receptors for the hormone aldosterone, play an important role in regulating renal sodium handling and blood pressure. Recent studies suggest that MRs also exist in tissues outside the kidney, including vascular endothelial cells, smooth muscle cells, fibroblasts, perivascular adipose tissue, and immune cells. Risk factors, including excessive salt intake/salt sensitivity, hypertension, and obesity, can lead to the activation of vascular MRs to promote inflammation, oxidative stress, remodeling, and fibrosis, as well as cardiovascular stiffening and microcirculatory impairment. These pathophysiological changes are associated with a diminished ability of insulin to initiate appropriate intracellular signaling events, resulting in a reduced glucose uptake within the microcirculation and related vascular insulin resistance. Therefore, the pharmacological inhibition of MR activation provides a potential therapeutic option for improving vascular function, glucose uptake, and vascular insulin sensitivity. This review highlights recent experimental and clinical data that support the contribution of abnormal MR activation to the development of vascular insulin resistance and dysfunction.  Reduced tissue insulin sensitivity and glucose intolerance are common manifestations of obesity, insulin resistance, and a prelude to type 2 diabetes . Human a+) in ECs (EnNaC) are related to activated MRs-induced genomic pathways . Fo. Fo+) inolerance  19]..+) in ECGenetic, epigenetic, and posttranslational modifications affect MR expression and activity. For instance, MRI180V rs5522) and the MR-2G/C rs2070951) are two single nucleotide polymorphisms that regulate the transactivational capacity of the MR gene in response to dexamethasone or cortisol stimulation 70951 are. Posttra and the Previous studies have also demonstrated that MR mutations are associated with the regulation of salt sensitivity, blood pressure, and stress responses . InactivThe Framingham Heart Study has highlighted the coexistence of insulin resistance, diabetes, and cardiometabolic syndrome, specifically reporting that 19% of patients with heart failure have insulin resistance and diabetes and that the risk of heart failure increases by 2\u20138-fold in diabetic individuals ,29. To tThe blood vessel wall is principally composed of intima vascular ECs, media VSMCs, adventitial fibroblasts, perivascular adipose tissue, and immune cells . While tOur recent and other studies support an important role for endothelial MRs (ECMRs) in the development of endothelial damage that underlies impaired endothelial dependent vasodilation. For instance, in a diet-induced obesity mouse model, impaired endothelial-dependent (NO-mediated) vasodilation is prevented by either MR inhibition with spironolactone  or ECMR MRs are also expressed in VSMCs. In response to enhanced mechanical or physiological stress, VSMC MRs are activated to induce VSMC hypertrophy, migration, proliferation, and vascular remodeling, as well as overt vascular fibrosis ,38. For MRs also exist in fibroblasts, and their activation facilitates ECM remodeling and vascular fibrosis . Data deFunctional MRs are widely expressed in a variety of immune cells, including macrophages, T lymphocytes, and dendritic cells. The in vitro treatment of macrophages with aldosterone results in MR activation and further promotes the expression of the classical M1 activation markers, namely TNF\u03b1, monocyte chemoattractant protein-1 (MCP1), and interleukin (IL)-12, in mouse peritoneal macrophages ,51. SimiAldosterone, although predominantly synthesized and secreted in the adrenocortical cells of the zona glomerulosa within the adrenal cortex, is also produced in adipocytes, including in PVAT ,6. AdipoInsulin resistance is characterized by a diminished ability of insulin to initiate insulin metabolic signaling and glucose uptake . The pri2+ MLCK sensitization, leading to decreased VSMC relaxation, vascular stiffening, and impaired microcirculation [Experimental studies indicate the fact that excessive MR activation directly impairs insulin metabolic signaling and induces vascular stiffness ,31,33. R2-terminal kinase (JNK) to directly promote the serine phosphorylation of IRS-1 and induce impaired insulin metabolic signaling [Enhanced vascular MR signaling induces vascular insulin resistance by increased inflammation and oxidative stress . On the ignaling . These dVascular MR activation and insulin resistance independently or synergistically contribute to arterial stiffening and hypertension. For instance, a prospective study of 566 individuals with uncontrolled hypertension demonstrated that MR inhibition with spironolactone alleviates arterial stiffening in parallel with reduced blood pressure . AnotherPrimary adrenal insufficiency is characterized by the insufficient secretion of glucocorticoids, mineralocorticoids, and androgens . SecondaMR antagonists, eplerenone and spironolactone, are currently approved for clinical patients. MR antagonists have a conclusive beneficial role in reducing blood pressure, especially in resistant hypertension . Recent MRs exist in vascular tissue, including ECs, VSMCs, ECM fibroblasts, and vascular immune cells, as well as PVAT. Excessive salt consumption/salt sensitivity, hypertension, and obesity are CVD risk factors associated with the excessive activation of vascular MR signaling that causes vascular inflammation, oxidative stress, remodeling, and fibrosis, leading to vascular insulin resistance, vascular stiffening, impaired vascular relaxation, and hypertension. Of note, the MRs have three ligands: aldosterone, cortisol, and progesterone. While ECs and VSMCs express the enzyme 11-beta hydroxysteroid dehydrogenase 2 (11\u03b2HSD2), allowing aldosterone to selectively activate MRs by inactivating cortisol, vascular fibroblasts, immune cells, and PVAT do not express 11\u03b2HSD2, and thus the main ligand for MRs is cortisol in these cells . Indeed,"}
+{"text": "Field of medicine: Neurosurgery, otorhinolaryngology, neurology, medical educationAudience: Neurosurgeons, otorhinolaryngologists, neurologists, senior residents engaged in skull base surgery, and other interested physiciansPurpose: The book provides a well-written, comprehensive overview of the vascular challenges in skull base surgery. It details management strategies and algorithms regarding skull base and endoscopic endonasal approaches, surgical techniques, related pathologies, and potential complications. In each chapter, numerous illustrations allow a detailed representation of surgical anatomy. The content is presented through text, tables, graphs, and neuroradiological, cadaveric, and intraoperative pictures. The book provides a wealth of information and can serve as a useful resource for all interested readers.Content: The content is divided into 22 well-organized chapters, each focused on a specific topic.Vascular Anatomy of the Head and the Neck/Circle of Willis, briefly reviews the important anatomical concepts of the head and neck vasculature and their relation to skull base and cerebrovascular surgery. The head and neck circulatory system is presented as anterior and posterior circulation, with a review of the major branches, common variants, and their clinical significance.The first chapter, Evaluation of Tumor-Involved Vasculature , briefly discusses arterial and venous anatomy of the skull base and imaging techniques for the skull base vascular tumors. Here, the authors propose balloon test occlusion as a method to adequately and safely resect a vascular base tumor.The second chapter, Embolization of Skull Base Tumors, reviews different methods for embolizing skull base tumors including common pitfalls and perils with a few case examples, management strategies, and complications.The third chapter, Vascular Supply of Local-Regional Flaps in Skull Base Surgery, briefly describes the reconstruction of skull base defects using extranasal and endonasal reconstructive flaps. Different flaps are described in tables, and various figure examples are given.The fourth chapter, Bypass in the Treatment of Skull Base Tumors, describes vascular challenges and ways to avoid injury when performing bypass, as well as management strategy, technical considerations, outcomes, and complications. Various case examples and alternative strategies are presented.The fifth chapter, Alternatives to Standard Bypass Techniques for Skull Base Tumors (Including Direct Imax Bypass), briefly describes indications, the operative technique, and the alternative technique to traditional bypass in the context of skull base tumors. A novel method using the internal maxillary artery as donor vessel is presented, with an overview of its indications, operative method, graft choices, and potential problems.The sixth chapter, Skull Base Approaches for Aneurysms, details the application of approaches to the skull base for intracranial aneurysm surgery, ie, transzygomatic, transpetrosal, fat lateral suboccipital, and transcondylar approach. The chapter also lists vascular challenges and related pathologies, as well as provides case examples with description of management strategies and potential complications.The seventh chapter, Endoscopic Endonasal Aneurysm Treatment, reviews the current application of endoscopic endonasal surgery for intracranial aneurysms. The chapter gives the technical details when it comes to managing these aneurysms and provides various case examples with description of management strategies and algorithms, as well as potential complications.The eighth chapter, Dealing with Major Intraoperative Vascular Injury during Endonasal Approaches to the Anterior Skull Base, reviews the relevant anatomy of endoscopic endonasal approach to the anterior skull base, the common vascular complications, and the methods to minimize these complications. Case examples with management algorithm and potential complications are also provided.The ninth chapter, Dealing with Major Intraoperative Vascular Injury, reviews the key elements in understanding vascular and endoscopic challenges, preoperative planning, landmarks, rescue steps, as well as postoperative management and complication avoidance in the setting of major vascular injury. Case examples with management algorithms and strategies are also provided.The tenth chapter, Dealing with Major Intraoperative Vascular Injuries During Endonasal Posterior Fossa Surgery, provides a brief overview of the prevention and surgical management of major vascular injuries during endoscopic endonasal posterior fossa surgery. Illustrative cases with management analysis are also given.The eleventh chapter, Vascular Challenges in Anterior Skull Base Open Surgery, provides an overview of relevant surgical anatomy of the anterior skull base. It also lists common anterior and anterolateral skull base approaches, pathologies involving the anterior cranial base vasculature, relevant vascular challenges, common vascular complications, and microsurgical techniques to avoid such complications.The twelfth chapter, Dealing with Vascular Injury During Middle Fossa Surgery, briefly describes vascular control and avoidance of injury and related pathologies of the middle cranial fossa. Case examples with management strategies and potential complications are also described.The thirteenth chapter, Posterior Fossa during Open Skull Base Surgery, reviews the relevant and normal anatomy of the posterior fossa to help surgeons avoid major intraoperative injuries. It also discusses techniques for controlling bleeding and for the management of consequences.The fourteenth chapter, Perforator Injury During Endoscopic Endonasal Skull Base Surgery, describes the anatomy of the perforators in a way that is logical for endoscopic skull base surgeons; different ways to prevent their injuries; and measures to take when injuries happen. Clinical examples are also discussed.The fifteenth chapter, Perforator Injury during Open Skull Base Surgery, briefly discusses the vascular challenges with a detailed overview of basal perforator vessels derived from major cerebral arteries. It also lists the techniques to avoid perforator injury and related pathologies. Case examples with management algorithm are described.The sixteenth chapter, Endovascular Options to Treat Iatrogenic Vascular Injury and Tumor Involvement of the Skull Base, describes the endovascular treatment options for acute and delayed vascular injury after skull base surgery; the utility and interpretation of balloon test occlusion; preoperative stenting for arterial protection during skull base tumor resection; and treatment strategies for concomitant internal carotid artery aneurysms and skull base tumors.The seventeenth chapter, Extracranial Anterior Cranial Base Surgery for Vascular Tumors, focuses on angiofibromas as a good model for discussing the principles of management of all vascular tumors. It details preoperative assessment of tumor vascularity, tumor staging based on vascularity, preoperative devascularization, surgical strategy including the role of endoscopy, hemostatic surgical techniques, and prevention of complications.The eighteenth chapter, Extracranial Lateral Cranial Base Vascular Tumor Surgery, briefly describes the pathophysiology, anatomy, diagnostic workup, and intraoperative management of the extracranial vascular lesions of the lateral skull base, focusing on the preoperative assessment of tumors involving the petrous internal carotid artery.The nineteenth chapter, Venous Considerations in Skull Base Surgery, gives details of venous anatomy, alternative approaches, and dissection and preservation of the veins. Injury to venous sinuses with a number of figure examples is also discussed.The twentieth chapter, Neurophysiologic Monitoring and Its Role during Cerebrovascular Injury, reviews the principles, technical aspects, interpretation, and limitations of each modality of intraoperative neurophysiologic monitoring, such as somatosensory, brainstem auditory, or transcranial motor-evoked potentials and EEG.The twenty-first chapter, Simulation and Training \u2013 Preparing for Vascular Injury, provides overview of different surgical trainings such as simulation, including vascular injury simulation, cadaveric models, as well as different techniques that can improve the patients\u2019 outcome.The twenty-second chapter, Highlights: The book contains all essential information about skull base surgery and provides an excellent overview of the topic and all accompanied challenges. In almost every chapter, relevant anatomy is reviewed through numerous schemes and cadaver images. In addition, a number of skull base approaches, as well as endoscopic endonasal approach for anterior, middle, and posterior cranial fossa with special considerations are described, as well as potential vascular injuries. Specific conditions regarding endovascular treatment, intraoperative neurophysiologic monitoring, and surgeon training are discussed in separate chapters. The comprehensive index at the end of the book enables quick orientation and selective reading. The text is accompanied by color figures, schematic presentations, and neuroradiological images, which make the learning both easy and exciting.Related reading: A number of other comprehensive medical references either in book or pocket-size handbook are available, such as: Vasculature of the Brain and Cranial Base, Thieme, 2015; Atlas of 360 Degree Skull Base Surgery, Thieme, 2021; Skull Base Surgery: Strategies, Thieme, 2019; Endonasal Endoscopic Surgery of Skull Base Tumors: An Interdisciplinary Approach, Thieme, 2015; Handbook of Skull Base Surgery, Thieme, 2015; Surgery of the Skull Base, Elsevier, 2018; Atlas of Endoscopic Sinus and Skull Base Surgery, 2nd Edition, Elsevier, 2018."}
+{"text": "Prior work has investigated the correlates and consequences of early life stress within a person\u2019s lifetime, but less is known about whether early life stressors are sustained across generations. Using multi-generational data from 1,312 offspring and their fathers (N = 518 families), we examined the extent to which there is intergenerational continuity in childhood social class, childhood home atmosphere, parent-child relationship quality, and childhood health, as well as whether person-level and family-level factors strengthen (or weaken) intergenerational continuity. Results suggest notable intergenerational continuity in childhood social class, but no continuity in childhood home atmosphere, parent-child relationship quality, or childhood health. Moreover, the intergenerational continuity of early life stressors was modified by father education level and education mobility, such that low education level conferred risks, and upward education mobility conferred benefits, for offspring adverse experiences. We discuss broader implications of the findings for future research, clinical interventions, and social policy."}
+{"text": "There is a high comorbidity between psychiatric disorders and juvenile myoclonic epilepsy (JME), observed in up to 58% of these patients; specifically, mood disorders, anxiety and personality disorders (PD). In some patients with PD there are nonspecific alterations in the EEG, which nevertheless sometimes involve pathology. The presence of personality disorders along with JME has been repeatedly described. Previous studies have emphasized the difficulties in treating patients with JME, which have been attributed to some specific psychiatric, psychological and psychosocial characteristics.Describing distinctive personality traits in JMEReview of scientific literature based on a relevant clinical case.19-year-old woman, single. Psychiatric history since she was 12 due to anxiety-depressive symptoms, after being diagnosed with JME. 4 admissions in Psychiatry, with a variety of diagnoses: eating disorder, attention deficit hyperactivity disorder and borderline personality disorder. The evolution of both disorders has been parallel, presenting epileptic seizures due to irregular therapeutic adherence together with pseudo-seizures, which made difficult their differential diagnosis. In addition, he has had frequent visits to the emergency room for suicide attempts and impulsive behaviors.In 1957, for the first time, distinctive personality traits were described in patients with JME: lack of control and perseverance, emotional instability, variable self-concept and reactive mood, which have been confirmed in subsequent studies. It is believed as epilepsy progresses, patients tend to develop symptoms of depression, anxiety, social problems, and attention deficit. Therefore, these patients have difficulty in following medical recommendations, especially precautions regarding precipitating factors for seizures.No significant relationships."}
+{"text": "PLOS ONE Editors retract this article [The  article  because IZ, QM, UI, MI, FH, AI, and RN did not agree with the retraction. ABI and AP either did not respond directly or could not be reached."}
+{"text": "Flow diverters are flexible stents with a much higher metal coverage and lower porosity than traditional intracranial stents for aneurysm treatment. They work by redirecting blood away from the aneurysm through the parent artery, leading to aneurysm stasis, progressive thrombosis, and subsequent stent endothelialization, the mechanism for excluding the aneurysm from circulation. Remarkably, flow diverters still allow blood flow through perforators given the demand through these small critical vessels. Since the approval of flow diversion for the treatment of large and giant previously difficult-to-treat carotid sidewall aneurysms,1 its indication has expanded to include smaller aneurysms2 and other off-label uses, such as posterior circulation aneurysms, distal aneurysms, bifurcation aneurysms, blister aneurysms, and other ruptured aneurysms, with good results. However, despite a decade of experience, giant, partially thrombosed, fusiform vertebrobasilar aneurysms remain a challenging entity for flow diversion in which the results remain relatively poor in comparison,3 although newer devices and a better understanding of antiplatelet and anticoagulation management may improve the outcome in this devastating disease. Lastly, although the risk of ischemic strokes associated with flow diversion is now less than 5% for unruptured aneurysms,5 thromboembolic events remain the most common complication. At the same time, dual antiplatelet therapy, a requirement for flow diverter placement, can be associated with bleeding complications and is suboptimal in the setting of subarachnoid hemorrhage. Newer devices with surface modification are emerging to address the unmet need of reducing thrombogenicity and antiplatelet requirements for flow diverters. This issue of Neurosurgical Focus: Video includes representative videos that illustrate the spectrum of cases discussed above.IDr. Levy: personal fees from NeXtGen Biologics, RAPUID Medical, Claret Medical, Cognition Medical, Imperative Care, Rebound Therapeutics, StimMed, Three Rivers Medical, Medtronic, Penumbra, MicroVention, Integra, Clarion, GLG Consulting, Guidepoint Global, Misionix, Mosiac, Haniva Technology, Endostream, MEDX, and IRRAS AB outside the submitted work; patent pending for Bone Scalpel; leadership or fiduciary role in CNS, ABNS, and UBNS; and rendering of medical/legal opinions as an expert witness."}
+{"text": "In the original version of this article, the given and family names of Paulina Malczynska-Sims, Ma\u0142gorzata Chalimoniuk, Zbigniew Wronski, Jaroslaw Marusiak, Anna Sulek have been incorrectly published. Now they have been corrected.The original article has been updated."}
+{"text": "Intestinal mucositis is a clinically related adverse reaction of antitumor treatment. Majority of patients receiving high-dose chemical therapy, radiotherapy, and bone-marrow transplant suffer from intestinal mucositis. Clinical manifestations of intestinal mucositis mainly include pain, body-weight reduction, inflammatory symptom, diarrhea, hemoproctia, and infection, which all affect regular nutritional input and enteric function. Intestinal mucositis often influences adherence to antitumor treatment because it frequently restricts the sufferer\u2019s capacity to tolerate treatment, thus resulting in schedule delay, interruption, or premature suspension. In certain circumstances, partial and general secondary infections are found, increasing the expenditures on medical care and hospitalization. Current methods of treating intestinal mucositis are provided, which do not always counteract this disorder. Against this background, novel therapeutical measures are extremely required to prevent and treat intestinal mucositis. Plant-derived natural compounds have lately become potential candidates against enteric injury ascribed to the capacity to facilitate mucosal healing and anti-inflammatory effects. These roles are associated with the improvement of intestinal mucosal barrier, suppression of inflammatory response and oxidant stress, and modulation of gut microflora and immune system. The present article aims at systematically discussing the recent progress of plant-derived natural compounds as promising treatments for intestinal mucositis. Intestinal mucositis, a clinically significant adverse reaction of antitumor treatment, is characterized by ulcerative lesions along the gastroenteric mucosa . It appeThe clinical signs of intestinal mucositis result from epithelial damage, which is followed by a range of complicated biological events that occur in the diverse cellular and tissular chambers of the mucosa . LocalizUnder the circumstances, natural products have attracted much attention and recognition as their prominent bioactivities, including anti-inflammation, antioxidation, immune regulation, and metabolic functions, in the prevention and treatment of intestinal mucositis, cancers, angiocardiopathies, and metabolic and respiratory disorders . A rangeFor recognizing the studies associated with the effect and mechanism of natural compounds against intestinal mucositis, our team consulted the articles in the following scientific databases from inception until July 2022: Web of Science, PubMed, Google Scholar, and CNKI. The keyword \u201cintestinal mucositis\u201d was adopted for the literature retrieval. All articles with abstracts were taken into account.After retrieval, the gained articles were strictly filtered. The first screening was conducted in line with the titles and abstracts. The second screening was performed on the basis of the full-text. Finally, all the studies fitting the theme were gathered as the supportive resource of the present review. The exclusion criteria were as follows: crude extracts or oils, not plant-derived natural compounds, and combined therapies.As is well-known, plants are the most significant natural resources for human survival due to their large variety, quantity, and convenient access. The original sources of human food and drugs were mostly derived from plants. To date, the studies on active constituents have primarily concentrated upon edible and medicinal plants. It is noteworthy that there are plentiful research works on plant-derived natural compounds against intestinal mucositis. In the present research, natural compounds against intestinal mucositis are divided into seven classes, namely, terpenoids, flavonoids, quinones, phenylethanoid glycosides, polyphenols, alkylamides, and alkaloids. The basic, chemical, and pharmacological information of natural compounds used in the therapy of intestinal mucositis is exhibited in Aucklandia lappa. Researches have shown that they have anti-inflammatory, antitumor, and antimicrobial activities , other inflammatory mediators , and oxidant stress . Carvacrol also facilitated the recovery of the structure of villus and recess in the small intestine and improved clinical indexes, including livability, weight changes, leukocyte, and blood bacteria count. Therefore, carvacrol is a prospective candidate drug for treating gut mucositis, and TRPA1 may be a significant therapeutical target for intestinal mucositis.Carvacrol is a phenolic monoterpene originating from various essential plants, such as  effects . TRPA1 r effects have condThymus vulgaris, Origanum vulgare, and Ocimum gratissimum. Owing to its various bioactivities, thymol is widely employed in healthcare, animal medicine, food industry, and agriculture. Modern studies have indicated that thymol possesses remarkable beneficial actions, including antimicrobial, antioxidative, anti-inflammatory, anticancer, and immunoregulatory properties  recovered the antiapoptotic effect of andrographolide in NCM460 cells. In addition, via decreasing the proteic expressions of p-TBK1 and p-IRF3, suppressing the mRNA levels of inflammatory factors , IFN-\u03b2, Cxcl10, and Ccl5, and inhibiting the infiltration of immunocytes, including CD11b, CD4, and CD8. The double-stranded DNA release and DNA damage triggered by irinotecan were also mitigated by andrographolide. In conclusion, andrographolide may be beneficial to the sufferers receiving 5-fluorouracil-based chemical therapy.Andrographolide is the main active constituent of operties . Xiang eoperties  probed tBupleurum falcatum and Bupleurum scorzonerifolium, which manifests anti-inflammatory, antidepressive, antitumor, and immunoregulatory activities (Saikosaponin-A is a main triterpenoid saponin existed in tivities . Ali et tivities demonstraPogostemon cablin. Up to now, many beneficial effects of patchouli alcohol have been demonstrated, such as anti-inflammatory, antibacterial, anticancer, and anticolitis effects (Patchouli alcohol, a tricyclic sesquiterpene, is an important active constituent of  effects . Wu et a effects  built thPogostemon cablin (\u03b2-patchoulene, a natural sesquiterpene, is one of the active ingredients in n cablin . Studiesn cablin  probed tGlycyrrhiza uralensis, Glycyrrhiza inflata, and Glycyrrhiza glabra. Research works have shown that glycyrrhizic acid has anti-inflammatory, antiviral, antioxidative, anticancerous, and immunoregulatory properties (in vitro drug release. Then, induction of mucositis was conducted by giving 5-fluorouracil to the murines for the first three days, and GA-PLGA nanoparticles were administered to the animals for seven days. GA-PLGA nanoparticle observably decreased the mucositis seriousness concerning body weight, diarrhea scoring, pain, and asitia. Furthermore, 5-fluorouracil caused intestinal histopathologic injury, increased villus-crypt length, decreased goblet-cell quantity, increased pro-inflammatory factors, and restrained antioxidases. Nevertheless, all the deteriorations were restored by GA-PLGA nanoparticle. The results of morphology, behavior, histology, and biochemistry indicated that GA-PLGA nanoparticle was effective, biocompatible, targeted and slow-release nanovehicle drug delivery for enhancing mucoprotective, antiphlogistic, and antioxidative actions in 5-fluorouracil-induced intestinal mucositis.Glycyrrhizic acid, a triterpene glycoside, is the most significant active constituent of operties . In consoperties  investigSaussurea involucrata, Hippophae rhamnoides, Ruta graveolenslens, and Sophora japonica. Extensive research works have shown that rutin possesses antimicrobial, anti-inflammatory, anticancerous, and antidiabetic effects (via reducing MPO vitality, enteric mastocytosis, and COX-2 activity. The result indicated that the COX-2 pathway might be one of the potential protective targets of rutin in treating 5-fluorouracil-induced intestinal mucositis.Rutin, also known as vitamin P, is a glycoside of the flavonoid quercetin, derived from many edible and officinal plants, such as  effects . Fideles effects investigaSophora japonica, Platycladus orientalis, and Alpinia officinarum. Modern studies have shown that quercetin has antioxidative, anti-inflammatory, antibacterial, and antineoplastic activities (via increasing CAT level and decreasing MDA concentration, and HIF-1\u03b1 and NF-\u03baB expression.Quercetin, a natural flavonoid, isolated from many medicinal and edible plants, such as tivities . Sukhotntivities assessed tivities further fLuteolin is a usual flavone derived from many kinds of plants, including fruits, vegetables, and Chinese herbal medicines. A great deal of research has shown that luteolin possesses antioxidative, anticancerous, antiallergic, and anti-inflammatory activities . Boeing Scutellaria baicalensis. It has been proven that baicalein possesses antioxidative, antiviral, antibacterial, anti-inflammatory, antiallergenic, and antitumor effects (a-diversity, \u00df-diversity and the species discrepancies. In comparison with the normal group, the Ruminococcaceae_UCG_014 and Lachnospiraceae in murines of the model group were markedly reduced, while Bacteroides, Escherichia_Shigella, Enterococcus, Parabacteroides, Clostridium_ sensu_stricto_1, and Lactococcus were observably elevated. After baicalein treatment, the levels of Bacteroides, Escherichia_Shigella, Parabacteroides, Enterococcus, Clostridium_sensu_stricto_1, and Lactococcus were notably reduced and Muribaculaceae was elevated. The levels of IL-6 and TNF-\u03b1 in the serum of the three groups were positively related to the levels of Clostridium_sensu_stricto_1, Lactococcus, Bacteroides. and Enterococcus based on the association analysis. The present research indicated the promising efficacy of baicalein on intestinal mucositis murines. Modulation of intestinal microflora possibly exerted a crucial role in the therapeutic effect of baicalein.Baicalein, a natural flavone, is predominantly found in the roots of  effects . Wang et effects  estimatePueraria lobata and soybeans. Extensive pharmacologic actions of diadzein were proven, including anticancer, anti-inflammatory, and antidiabetic activities (via 5-fluorouracil treatment. Nitrite levels in enteral tissues were decreased by diadzein, which accorded with the regulation of inflammatory mediators. In addition, diadzein also improved the microbial profile through decreasing the count of pathogens and increasing the level of probiotic bacteria. Collectively, this research indicated that diadzein possessed prominent protective effect against mucositis in 5-fluorouracil-treated mucositis model, and the therapeutical effect of diadzein may be associated with the restraint of oxidant stress and inflammatory response.Diadzein is a natural isoflavone mainly extracted from tivities . Atiq ettivities investigaPueraria lobata. Research works have shown that puerarin has antitumor, antiviral, antioxidative, and anti-inflammatory effects (via suppressing JAK activation. This work suggested that puerarin might be a promising natural JAK depressor for the treatment of 5-fluorouracil-induced intestinal mucositis.Puerarin, a natural isoflavone, is the major constituent derived from the roots of  effects . Wang L. effects  built a Salvia miltiorrhiza, which has been reported to exert antitumor, anti-inflammatory, and cardioprotective roles (via 16S rRNA high throughput sequencing. Spearman association analyses were employed to assess the relevance between fecal microbiome and inflammatory cytokines. Tax4Fun was used to explore the possible role of gut microflora. The result indicated that dihydrotanshinone I markedly decreased the DAI score, enteric mucosa injury, and inflammatory reaction in gut mucositis murines by reducing the serum IL-6 and TNF-\u03b1 levels. Moreover, there was close relationship between fecal microbiome and inflammatory cytokines. Dihydrotanshinone I effectively restored the maladjusted faecal microbiome and increased the level of Akkermansia. Dihydrotanshinone I also improved bacteria species, which facilitated butyric acid metabolism or were negatively related to inflammatory cytokines. In addition, species improved by dihydrotanshinone I in faecal microbiome were possibly associated with the glutamine level and ammonia oxidization. In brief, this research indicated that dihydrotanshinone I effectually alleviated gut mucositis caused by 5-fluorouracil and irinotecan in murines. Adjustment of the composition and function of fecal microbiome possibly exerted an important effect in the therapeutical action of dihydrotanshinone I in intestinal mucositis animals.Dihydrotanshinone I is an important active constituent in ve roles . Wang etve roles  probed tSalvia miltiorrhiza. Studies have indicated that cryptotanshinone has anti-inflammatory, anticancerous, antibacterial, neuroprotective, and cardioprotective effects (Muribaculaceae and Ruminococcaceae_UCG-014. Specially, Ruminiclostridium and Muribaculaceae showed a remarkable positive relation to TG but a negative relation to DAO, MPO, IL-6, lipase, and TC. In brief, cryptotanshinone effectually relieved gut mucositis in murines induced by 5-fluorouracil and irinotecan through modulating the fecal microbiome, inflammatory cytokines, and serum lipids.Cryptotanshinone is a natural quinone compound predominantly existed in  effects . Wang et effects  exploredForsythia suspensa and has excellent biological activities. Pharmacological research works have proven that forsythiaside A has remarkable activities in treating multiple diseases, including inflammation, virus and bacterial infection, oxidative stress, and hepatic damage (Forsythiaside A is the major active constituent derived from c damage . Lang etc damage  exploredRehmannia glutinosa and Cistanche deserticola. At present, acteoside has been found to exert anti-inflammatory, antioxidative, and anticancer effects (Acteoside is an important active component, which mainly exists in medicinal plants like  effects . Reinke  effects  exploredMelastoma malabathricum is a common herb and mainly adopted to treat multiple gastrointestinal diseases in China (Melastoma malabathricum and explored the therapeutic effect and mechanism of casuarinin in 5-fluorouracil-treated gut mucositis murines. Results indicated that casuarinin notably improved 5-fluorouracil-induced body weight loss and ingestive reduction, and also prominently reversed villus atrophy, restored the proliferative activity of the enteric crypts, and restrained inflammatory symptoms and enteric barrier dysfunction in the murine model of 5-fluorouracil-treated gut mucositis. Moreover, casuarinin also reversed 5-fluorouracil-induced intestinal microflora dysbiosis, especially the level of Actinobacteria, Candidatus Arthromitus, Lactobacillus murinus, and the Firmicutes-to-Bacteroidetes ratio. In conclusion, casuarinin could improve 5-fluorouracil-treated gut mucositis by favorably regulating inflammation, gut barrier dysfunction, and intestinal microflora imbalance. Therefore, casuarinin might be a prospective candidate for the treatment of intestinal mucositis.in China . Chen etin China  isolatedCurcuma longa, Curcuma aromatica, Curcuma zedoaria, and Acorus calamus. For a long time, curcumin has been widely used in the food industry as a common natural pigment, and also exhibits antioxidative, antibacterial, antiviral, antitumor, and anti-inflammatory activities (Curcumin, a natural diketone, mainly exists in tivities . Considetivities explored Acmella oleracea, possesses narcose, analgesic, and anti-inflammatory actions (Spilanthol, a major alkylamide from  actions . de Frei actions assessed Coptis chinensis, Phellodendron chinense, and Berberis soulieana. Modern pharmacological studies have shown that berberine possesses hypoglycemic, hypolipidemic, antibacterial, and anti-inflammatory activities (d-lactic acid content in serum. In addition, berberine prominently restrained inflammatory response through inhibiting the production of intestinal inflammatory cytokines TNF-\u03b1, IL-6, and IL-1\u03b2. Moreover, berberine reversed the changes of fecal metabolites and regulated metabolic pathways via increasing the levels of acetate, butyrate, propionate, and glutamine. Importantly, berberine effectively modulated the gut microbiota structure. The relative abundance of Firmicutes, Porphyromonadaceae, Lachnospiraceae, Lactobacillus, Clostridiales, Ruminococcus, Prevotella, and Clostridium IV was upregulated, while Proteobacteria and Escherichia_Shigella were decreased by berberine treatment. Significantly, fecal transplantation from berberine-treated rats could relieve intestinal mucosal injury. Berberine is a natural isoquinoline alkaloid existed in a lot of medicinal plants including tivities . Chen H.tivities explored Chemotherapy for malignant tumors can cause changes in the structure and function of the gastrointestinal tract. 5-fluorouracil, an important chemotherapeutic drug, is widely used to treat advanced colorectal carcinoma and malignant tumors in head and neck . ConsecuIntestinal barrier is composed of epithelia barrier and mucosal layer. The intact mucosal layer is a barrier to stop water runoff and eliminate inspiratory foreign matters, including microorganisms, inflammatory cells, and pollutants . When inIntestinal epithelia establish the maximal and most significant barrier between inner and outer surroundings. Research works have indicated that enteric epithelium barrier is destroyed in gastrointestinal disorders, such as ulcerative colitis and gut mucositis . TJs areInflammatory infiltration is a typical feature of mucositis. MPO vitality and pro-inflammatory factors have been found to increase under inflammatory conditions . ExcessiTLRs possess critical effects in adjusting the enteric epithelia barrier and congenital immunization. TLR2 induce NF-\u03baB activation to regulate the gene levels of inflammatory mediators by Toll/IL-1 receptor domain with adapter protein MyD88 . Proper Bacteroides, Bifidobacterial, Lactobacilli, Escherichia, Helicobacter, and Parabacteroides are strongly associated with the progression and seriousness of mucositis. Bifidobacterial and Lactobacilli are indicated to be capable of restraining NF-\u03baB activation, increasing TJs protein level, and reducing enteric penetrability (Bacteroides, Escherichia, Helicobacter, and Parabacteroides are often deemed to be the pathogenic bacteria or conditioned pathogens (Parabacteroides and Bacteroides amounts contribute to colitis in murines, Helicobacter pylori infection contributes to peptic ulcer disorder and stomach tumors, and Escherichia is profitable for gut inflammation in vivo. Bifidobacterium infantis alleviates Th1 cell reaction through adjusting cell factors and differentiation-related factors in chemotherapy-induced gut mucositis murines (Lactobacillus, it contributes to reducing the colonic pH and the development of pathogens (Bacteroides, Escherichia coli, Proteobacteria, Bacteroidia, Proteobacteria, Helicobacter, Pasteurellaceae, Verrucomicrobiaceae, and reduced relative abundances of Bacteriodetes, Lactobacillus spp., Actinobacteria, and Lactobacillus murinus, which were reversed by saikosaponin A, patchouli alcohol, baicalein, daidzein, dihydrotanshinone, casuarinin, and berberine treatment.Intestinal microbiota homeostasis is a significant element for gastrointestinal health. Numerous research works have shown that gut microflora disorder exhibits a crucial effect in gastrointestinal diseases, including colitis, bacterial dysentery, and chemotherapy-induced mucositis . Microbirability . Bacteroathogens . For ins murines . In termathogens . In thisThe present review generalizes the significant and beneficial roles of plant-derived natural compounds in attenuating intestinal mucositis in pioneering endeavor. Their protective mechanisms against intestinal mucositis might involve improving intestinal barrier function, decreasing enterocyte apoptosis, regulating gut microbiota, and inhibiting inflammatory reaction and oxidant stress predominantly through blocking TLR2/MyD88/NF-\u03baB, TGF-\u03b2/MAPK, JAK2/STAT3, Nrf2/HO-1, and NLRP3 inflammasome pathways , 4. Take"}
+{"text": "DEAC05-00OR22725 with the U.S. Department of Energy. The United States Government and the publisher, by accepting the article for publication, acknowledges that the United States Government retains a nonexclusive, paid-up, irrevocable, worldwide license to publish or reproduce the published form of this manuscript, or allow others to do so, for United States Government purposes. DOE will provide public access to these results of federally sponsored research in accordance with the DOE Public Access Plan  synthetic polymers, (ii) biological materials, and (iii) inorganic crystallites, respectively.(i) For synthetic polymers and soft complexes, (semi-) crystalline or self-assembled nanostructures play important roles in technologies such as sensors, actuators, solar cells, transistors, supercapacitors, new battery designs, solid electrolytes, biomimetic designs, and smart materials as well as structural components . For exa(ii) Self-assembly in biological materials can be well-suited for medical applications. Materials found in nature, such as spider silk, shells, and bones, often rely on crystallization or assembly mechanism to achieve extraordinary performance. For example, extracellular vesicles (EV) have attracted attention as new drug carriers due to their unique structural properties and self-assembly . Referen(iii) Controlling the crystalline components of inorganic materials attracts an intense scientific interest, in efforts to achieve optimization in crystallography, crystallization process (including dynamics), hierarchical morphology, nanostructure, nanopattern, or assembly-driven interfaces and composites. These changes largely contribute to the further enhancements in mechanical, ionic, electronic, and other functional behaviors of current-generation inorganic nanomaterials ,4,5. For"}
+{"text": "Korean Journal of Women Health Nursing (KJWHN), we had a dynamic year as well, which I hope to summarize in this editorial, while sharing plans for the upcoming year.What a year it has been, which started as the Year of the Nurse and the Midwife, designated by the World Health Organization, but was swiftly consumed by the coronavirus disease 2019 (COVID-19) pandemic world-wide. Looking back on the This year KJWHN transitioned to a greater number of review articles and an increase in manuscripts available in English. Out of the total number of original manuscripts this year we have published six review papers (including four in this issue), and will continue to welcome integrative reviews, scoping reviews, and systematic reviews and/or meta-analyses that fit our aims and scope. As for increasing English manuscripts in 2020, 13 out of 38 published papers  and seven out of 32 unsolicited articles (21.9%) were published in English, which will no doubt promote visibility of the important contributions of our authors. KJWHN seeks to steadily increase the proportion of English manuscripts for the benefit of our readers, especially those that offer an international perspective.Issues and Perspectives section, starting with the push for nurses to become more familiar with artificial intelligence (AI) in research, education, and practice [This year KJWHN published rich topics in our practice . COVID-1Another issue paper analyzed the impact of COVID-19 on women and underscored the need for a gendered perspective of data collection in Korea . Since thttps://women-health-nursing.or.kr/).In response to our third issue paper\u2019s challenge to nurses and midwives to share their stories as a way to inform the public and promote our profession , the KorOur last issue paper (December issue) presents a call to action for strengthening midwives as a strategy to alleviate the ultra-low birth rate in Korea. The challenge of Korea\u2019s low birth rate demands serious attention and the Presidential Committee on Ageing Society and Population Policy (PCASPP) has announced the Fourth Framework Plans for Korea on December 15, 2020, which will be the road map for the period 2021 to 2025 . This FrOn another note, author guidelines have been updated as of the December 2020 issue for manuscript length  and removing the restriction of overall number of references . These changes have been made to reflect international trends and are available online.I am indebted to our reviewers, not to mention our tireless editors and editorial board members, for their commitment and support for KJWHN.Ahn, Suk Hee Bae, Kyung Eui (Dongseo University)Chae, Hyun Ju (Joongbu University)Chae, Myung-Ock (Cheongju University)Cheon, Suk Hee (Sangji University)Cho, In Sook (Inha University)Cho, Ok Hee Choi, Mi Young Choi, So Young Chung, Chae Weon Drake, Emily E. (University of Virginia)Ha, Ju Young Han, Yong Hee Hong, Se Hoon (CHA University)Hwang, Kyung Hye (Suwon Science College)Hwang, Moon Sook (Woosuk University)Jeong, Geum Hee Chung, Mi Young (SunMoon University)Go, Gee Youn (Dongguk University)Jo, Myung Ju (The Catholic University of Korea)Kang, Hee Sun (Chung-Ang University)Kang, Sook Jung (Ewha Womans University)Kim, Bo Yeoul (Eulji University)Kim, Hee Kyung Kim, Hee Sook Kim, Hyun Kyoung Kim, Jeung Im (Soonchunhyang University)Kim, Mi Ok (Dankook University)Kim, Ju Hee (Kyunghee University)Kim, Kyung Won (Daegue Hanny University)Kim, Mi Jong (Hannam University)Kim, Mi Young (Woosuk University)Kim, Moon Jeong Kim, Myoung hee (Semyung University)Kim, Su Hyun (Nambu University)Kim, Sun Hee (Daegu Catholic University)Kim, Young Ju Kim, Yun Mi (Eulji University)Ko, Eun Lee, Nae Young (Silla University)Lee, Kyoung-Eun (Texas A & M University)Moon, So Hyun (Chosun University)Nho, Ju Hee Park, Hyun Jung (Pyeongtaek University)Park, Hye Sook (Dongyang University)Park, Mi Kyung (Nambu University)Park, Mee Ra (Changshin University)Park, Seo A Park, So Mi (Yonsei University)Shin, Gi Soo (Chung-Ang University)Son, Hae Kyoung (Eulji University)Song, Ju Eun (Ajou University)Sung, Mi Hae (Inje University)Yeo, Jung Hee (Dong-A University)Yeom, Gye Jeong Yoon, Ji Won (Shinhan University)Data on manuscripts submitted to KJWHN this year, as of December 19, 2020, are presented in In 2021 KJWHN will offer a series of methods papers on instrument development and validity and reliability, and statistical reports relevant to women\u2019s health in Korea, as collaborative work with Statistics Korea. As noted above, KJWHN will also continue to follow the issues on the ultra-low birth rate in Korea. We hope you will stay tuned for these developments and consider becoming an active part of the dialogue by submitting your scholarly works for publication."}
+{"text": "The authors regret that the author list was shown incorrectly in the original article. The correct author list is as shown below:a, Archana Kanwade\u2020a, Akash Kankanea, Manish Kumar Tiwaria, Abhishek Srivastavaa, Jena Akash Kumar Satrughnab, Subhash Chand Yadava and Parasharam M. Shirage*aSheetal Gupta\u2020aDepartment of Metallurgy Engineering and Materials Science, Indian Institute of Technology, Indore 453552, India, E-mail: pmshirage@iiti.ac.in, paras.shirage@gmail.combDepartment of Physics, Indian Institute of Technology, Indore 453552, India\u2020 Equal contributions.Additionally, the authors regret that the photos of Ms Archana Kanwade and Ms Sheetal Gupta are incorrectly displayed. The correct photos are shown below:(1) The photo of Ms Sheetal Gupta is as follows:(2) The photo of Ms Archana Kanwade is as follows:The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "A wide range of phenolic compounds participate in oilseed growth, regulate oxidative stability of corresponding vegetable oil, and serve as important minor food components with health-promoting effects. Composition distribution of phenolic compounds varied in oilseeds. Isoflavones, sinapic acid derivatives, catechin and epicatechin, phenolic alcohols, chlorogenic acid, and lignans were the main phenolic compounds in soybean, rapeseed, peanut skin, olive, sunflower seed, sesame and flaxseed, respectively. Among which, the total isoflavones content in soybean seeds reached from 1,431 to 2,130 mg/100 g; the main phenolic compound in rapeseed was sinapine, representing 70\u201390%; chlorogenic acid as the predominant phenolic compound in sunflower kernels, represented around 77% of the total phenolic content. With the rapid development of analytical techniques, it is becoming possible for the comprehensive profiling of these phenolic compounds from oilseeds. This review aims to provide recently developments about the composition distribution of phenolic compounds in common oilseeds, advanced technologies for profiling of phenolic compounds by the metabolomics approaches based on mass spectrometry. As there is still limited research focused on the comprehensive extraction and determination of phenolics with different bound-forms, future efforts should take into account the non-targeted, pseudo-targeted, and spatial metabolomic profiling of phenolic compounds, and the construction of phenolic compound database for identifying and quantifying new types of phenolic compounds in oilseeds and their derived products. Oilseeds normally possess high economic value, thereby the oilseed cultivation area has expanded over 82% and approximately 240% for total world production of oilseeds in the past 30 years . OilseedAccording to the chemical structures, phenolic compounds are characterized by having at least one benzene ring bearing one or more hydroxyl groups . NumerouComposition of phenolic compounds in different oilseeds is different, resulting in the difference of physiological characters and nutritional value of oilseeds . ComposiOilseeds are a group of seeds used to extract oil, including soybean, rapeseed, peanut, olive, sesame, sunflower seed, flaxseed and so on. A full scope of the type and structure of phenolic compounds in oilseeds is of great significance for the evaluation of the nutritional and functional properties of oilseeds. According to the existent form, phenolic compounds can be classified into free, soluble conjugated, and insoluble-bonded forms. As shown in p-coumaric acid, chlorogenic acid, caffeic acid, syringic acid, vanillic acid, salicylic acid, protocatechuic acid, etc.) and anthocyanins  is a member of the Pedaliaceae plant family , flavonoids, and lignans  a pharmaceutical source  and extraction methods, including Soxhlet extraction, liquid-liquid extraction, solid-liquid extraction, ultrasound or microwave or enzyme-assisted extraction, solid phase extraction, dispersive solid-phase extraction, magnetic solid-phase extraction, subcritical fluid extraction, pulsed electric fields extraction, pressurized solvent extraction, homogenate assisted extraction, and high hydrostatic pressure assisted extraction have been utilized , 48, 49.Various analytical methods have been reported for the profiling of phenolic compounds. The total phenolic, flavonoid, tannin and lignan content were often measured by spectroscopic analysis . Althougn to separate and identify the phenolic constituents in peanut skins. By this method, phenolic compounds, including proanthocyanidins, phenolic acids, stilbenes, and flavonoids, could be found from peanut skins , including quadrupole time of flight (QTOF) MS, Orbitrap MS, Fourier transform ion cyclotron resonance MS, have gained wide acceptance in untargeted metabolomics for better performance in collection of full-scan spectra with high resolution mass to charge ratios , 54. Fulut skins . Negro eut skins . Kr\u00f3l-Grut skins . DespiteTargeted metabolomic methods are usually used for identification and absolute quantitation of phenolic compounds of interest. Normally, multiple reaction monitoring (MRM) mode in triple quadrupole (QqQ) MS is the most frequently used strategy in targeted metabolomic profiling with high sensitivity, high specificity, and excellent quantification ability . MRM modTo establish a high-coverage, high-throughput, sensitive, selective method for quantification of phenolics in oilseeds, a new strategy named pseudo-targeted or widely targeted metabolomics has been proposed. This strategy can simultaneously monitor hundreds to thousands of metabolites by dynamic MRM mode. Pseudo-targeted method merged the advantages of untargeted and targeted metabolomics and can provide high-quality and rich-information data for the analysis of large-scale samples . During Imaging the spatial distributions and dynamics of phenolic compounds in oilseeds is significant for our understanding of oilseed metabolism. Mass spectrometry imaging (MSI) is a sensitive and label-free approach for the localization of the metabolites in biological samples , 60. MSI3C2Tx/MWCNTs composite material was reported by Liu et al. for the detection of luteolin, and the method showed advantages of low detection limit, good selectivity and high sensitivity  compound discoverer software for automatically performing peak alignment, MS and MS/MS spectra extraction; (b) available database with the retention time, accurate mass, precursor and product ion spectrum, fragmentation patterns, etc. information; (c) new powerful software package for data mining; (d) new data mining method, such as machine learning based method . Up to dt-tests and analysis of variance are often used to identify the significant changes of metabolites between different groups. For multivariate analysis, principal component analysis (PCA) and hierarchical clustering analysis are the frequently used explorative multivariate methods. Miho et al. used PCA of phenolic concentrations to distinguish between virgin olive oils and found that virgin olive oils obtained in three consecutive crop seasons could be effectively distinguished by PCA  Phenolic database can be established according to the characteristics of the inherent phenolic composition in oilseeds. (b) More sophisticated extraction techniques, especially techniques with low-solvent and low-time consuming, high efficiency, high coverage, and automated analytical techniques should be developed. (c) Information about the modification and fate of phenolic compounds in oilseeds during various processing and storage progress needs further exploration. (d) The knowledge gap between traditional applications and scientific evidence of phenolic compounds should be bridged. (e) The physiological effects of phenolic compounds on human body is still an urgently subject to be detailed investigated.YZ: methodology, investigation, and writing. HX: original draft preparation. XL: methodology and investigation. DW: reviewing. HC: supervision. FW: supervision, reviewing, and editing. All authors contributed to the article and approved the submitted version."}
+{"text": "Modern biomedicine aims to develop integrated solutions that use medical, biotechnological, materials science, and engineering concepts to create functional alternatives for the specific, selective, and accurate management of medical conditions. In the particular case of tissue engineering, designing a model that simulates all tissue qualities and fulfills all tissue requirements is a continuous challenge in the field of bone regeneration. The therapeutic protocols used for bone healing applications are limited by the hierarchical nature and extensive vascularization of osseous tissue, especially in large bone lesions. In this regard, nanotechnology paves the way for a new era in bone treatment, repair and regeneration, by enabling the fabrication of complex nanostructures that are similar to those found in the natural bone and which exhibit multifunctional bioactivity. This review aims to lay out the tremendous outcomes of using inorganic nanoparticles in bone healing applications, including bone repair and regeneration, and modern therapeutic strategies for bone-related pathologies. Bone is a dynamic tissue that is constantly renewed and repaired through its intrinsic remodeling process, which involves interactions between resident cells (osteoclasts and osteoblasts) and signaling factors, that remove old and damaged tissue and create new bone, respectively ,2. This Nanobiomaterials include nanometer-sized and nanostructured bioactive materials, which peculiar behavior and new properties strongly impact the emerging trends of modern biomedicine and biotechnology ,10. NanoWith the aim to overcome the drawbacks of classical restorative and replacement procedures of hard tissues  ,20, an iAs the size-related behavior of NPs is also responsible for the occurrence of circumstantial toxic effects, a real challenge consists in maximizing their therapeutic effects by properly tuning the biocompatibility/multifunctionality balance. Nanosized particles can invade surrounding cells or tissues, and they frequently cluster or migrate inside blood vessels, causing additional damage to distant tissues or organs ,25. The Nanoparticle-based delivery systems have many advantages over conventional pharmaceutical formulations. These include reduced side effects, enhanced therapeutic effects, prolonged circulation half-life, improved permeability, and patient compliance ,29. DesiThanks to their high surface reactivity, unique surface physics and chemistry, increased chemical stability and photostability, facile surface modification, quantum yields, improved bioavailability, reduced or absent intrinsic toxicity, extended lifetime, great drug-loading capacity, and controlled drug release ability, inorganic NPs have indisputable advantages as active therapeutic carriers ,33. MoreThis review aims to point out the significance of inorganic nanoparticles in bone healing by including relevant and recent data on the NP-based repair and regeneration of bone tissue.The conventional therapeutic strategy in bone grafting mainly includes the use of allografts and autogenous grafts, and also different isolated or combined substitutes based on calcium phosphate (CaP) materials ,54. CaP-10(PO4)6(OH)2 [Particularly successful and promising outcomes in designing biomaterials for hard tissue repair and replacement are related to synthetic hydroxyapatite (HA), Ca4)6(OH)2 ,59. Natu4)6(OH)2 ,61. Trem4)6(OH)2 ,63,64,654)6(OH)2 ,67,68, o4)6(OH)2 ,70, and 4)6(OH)2 ,72 bones4)6(OH)2 ,74, cutt4)6(OH)2 ,76, and 4)6(OH)2 ,78; (iii4)6(OH)2 ,80, clam4)6(OH)2 ,82, muss4)6(OH)2 ,84, snai4)6(OH)2 ,86, and 4)6(OH)2 ,88; and 4)6(OH)2 ,90.Nanosized HA particles have more unique properties than micro-sized HA particles. For example, it has been reported that nanosized HA exhibits greater protein adsorption, improved cell adhesion, and superior bioactivity when compared to micro-sized HA ,91. It aPossessing excellent biocompatibility and being highly bioactive and biodegradable, HA is widely used for orthopedic, dental, and maxillofacial applications, especially thanks to the unique features of HANPs, which include anti-tumor activity and drug/gene delivery potential ,97,98. Egold standard growth factor for enhancing bone healing, and it has been successfully used in various research studies. In terms of osteogenic activity and augmented bone healing, superior results were reported for BMP-2-modified nanostructured formulations based on HA/natural polymers [Although HA is considered to be a suitable material for bone tissue repair and regeneration, its osteoinductive qualities are insufficient to allow large bone defects to mend. To circumvent these drawbacks, several bioactive compounds including growth factors that play a key role during the bone remodeling process, have been employed in bone tissue engineering ,103,104.polymers ,109 and polymers ,111. Howpolymers . Promisipolymers ,114, fibpolymers ,115, andpolymers ,117  anti-osteoporotic drug, a variety of studies have been conducted, ranging from strontium (Sr) mapping in bones and teeth to investigating Sr incorporation into bone mineral  and a decrease in calcium content, and to evaluating Sr effects in synthetic HA. Sr has a dual positive effect during osteogenesis and bone remodeling, by boosting the development of pre-osteoblastic cells, while suppressing the generation and functionality of osteoclastic cells [Following the development of the promising strontium ranelate (SR) -enriched HA nanomaterials for the repair and regeneration of traumatic and osteoporotic bone tissues, as it has been evidenced that Zn addition is beneficial for enhanced osteogenesis and the prevention of osteoclast-mediated resorption ,139,140.Selenium (Se) is a vital micronutrient for human health, as it plays an important role in disease prevention and cellular pathophysiological balance maintenance. In this respect, Se-modified HA nanomaterials proved to be promising alternatives for bone tissue therapy, since the presence of Se synergistically determines enhanced cellular processes in healthy cells  ,142 and In order to increase the structural integrity and to modulate interactions between the biological microenvironment and inorganic nanostructures, the surface modification of HA-based nanomaterials was explored ,146. TheParticular attention was oriented towards the fabrication of HANP-modified polymeric scaffolds, given the fact that a higher amount of nanoparticles triggers and accelerates the nucleation of biomimetic apatite, finally resulting in increased bone formation ,163. DesOwing to their excellent biodegradability and nontoxicity, and particular resemblance with the natural extracellular matrix, natural polymers\u2014such as proteins  ,179, polAs particular representatives of HANPs, mesoporous nanostructures have gained great attention regarding the development of nanostructured platforms for the controlled therapy of bone tissue ,187. It HANP-based therapeutic strategies have a lot of promise for bone tissue engineering, which represents a complex and challenging research field of modern biomedicine . The chaBioactive glasses (BGs), with their indisputable and versatile silica-based representatives, are amorphous solids which compositional and structural characteristics have been proved beneficial for the development of bioactive substitutes and platforms for bone tissue repair and regeneration ,203. BGs2 content in silica-based BGs (of maximum 60%) is responsible for their strong bonding with the bone tissue , which further provides enhanced interactions between surface-generated bone-like apatite layer and collagen fibers [An increased SiOn fibers ,205. Besn fibers ,207, it n fibers ,209,210.n fibers ,212, zinn fibers ,214, copn fibers ,216, siln fibers ,218, andn fibers ,220. In n fibers ,222,223 n fibers ,225,226 n fibers ,228.Besides encouraging stable bonding with host tissues, BGs also provide active sites for favorable interactions with polymers, both natural and synthetic, as briefly evidenced in Because of their large specific surface area and rapid ion release rate in biological fluids, nanoscale bioactive glass particles display higher bioactivity than microscale bioactive glass particles. However, the conventional synthesis of bioactive glass nanoparticles (BGNPs) is challenging and problematic due to the difficulty of doping high amounts of calcium ions within the silica network, resulting in uneven distribution and low calcium content. Furthermore, BGNPs are often synthesized by using dilute solutions in order to avoid nanoparticle aggregation, thus reducing the production efficiency and raising the costs. Reactive flash nanoprecipitation  and ultrThe ability to incorporate active ions within their composition is a significant advantage of BGNPs over other inorganic nanoparticles, as the release of such ions during dissolution opens up a world of possibilities for enhancing the biofunctional outcome of nanoengineered composites. Doping BGs with antimicrobial ions represents a promising strategy for the fabrication of bone fillers or bone grafts that can allow bone repair and regeneration without the risk of post-implant infections ,239. TheDespite the promising results reported in BGNP-based composites and devices, significant efforts must be made in order to fully explore and beneficially revalue the biological potential of such nanomaterials, as there is a lack of data regarding the long-term in vivo safety and performance of BGNPs ,245.In comparison with conventional BGNPs, mesoporous bioactive glass nanoparticles (MBGNPs) provide additional advantages regarding the microstructure-related ability to load and release therapeutic agents, representing multifunctional platforms for bone healing applications. MBGNPs are usually obtained by sol\u2013gel-mediated protocols ,247, andIn addition to their intrinsic capabilities , MBGNPs represent attractive nanocarriers for the controlled and targeted delivery of antibiotics ,262 Fig, anti-os2)-based nanomaterials\u2014especially mesoporous silica nanoparticles (MSNs)\u2014provide attractive and tunable characteristics for biomedical applications, including drug/biomolecule delivery systems [Silicon (Si) is naturally found in the human body, and it has a regulatory role during the normal development of the skeleton and connective tissues, and also has beneficial effects during collagen synthesis and matrix mineralization ,272. Bes systems ,274,275, systems ,277,278, systems ,280,281, systems ,283,284.A large surface area and pore volume ratio, adjustable particle size, well-structured internal and external porosity, uniform and controllable pore size, impressive surface functionalization, and intrinsic biocompatibility, represent the key features of MSNs used for the fabrication of therapeutic biomaterials and devices ,286,287.Although MSNs represent one of the most appealing nanomaterials for the fabrication of performance-enhanced constructs for bone healing applications, some critical parameters must be considered in order to achieve the desired therapeutic effects. By optimizing the synthesis parameters , the size, morphology, and porosity of MSNs can be modified ,294. ConVital events involved in bone repair and regeneration, including cellular proliferation and differentiation, bone matrix mineralization, osteoinduction, and osteogenesis, can all be triggered or boosted by means of Si-enriched nanosized and nanostructured materials ,298. ThrMSNs possess an impressive ability to transport therapeutic biomolecules and active targeting molecules into impaired bone cells, thus representing attractive multifunctional platforms for bone tissue therapy. In addition, the premature and non-specific release of the therapeutic cargo can be limited or even eliminated by using gatekeepers  that block pores and provide on-demand pore opening and closing in response to certain stimuli  307,308308,309. The incorporation of MSNs within three-dimensional nanoengineered networks provides tremendous possibilities for the specific and selective management of bone infection and bone cancer ,311,312.MSN-based nanosystems have been evaluated as efficient loading/releasing vehicles for several antibiotics ,315,316.The specific and selective management of bone cancer can be achieved with MSNs-based carriers that target particular receptors that are overexpressed in cancer cells ,319,320.Magnetic nanoparticles (MNPs) possess magnetic, semiconductor, nontoxic, and bioactive properties all at once, and play a critical role in the progress of modern biomedicine, with particular outcomes towards the specific and selective therapy of bone tissue ,330. TheBesides their intrinsic size-governed anti-infective ,334,335 Following their exposure to an alternating magnetic field, MNPs undergo important magnetic relaxation, as their magnetic moment (given by unpaired spin electrons in the outermost electron shell) rapidly flips its orientation between two stable states, but they also can undergo physical rotation and circumstantial collisions, finally resulting in converting the external energy into heat ,352. ThiMagneto-responsive HA/SPIONs composites have been investigated particularly for bone healing applications owing to their synergistic effects. HA/SPIONs formulations exhibit intrinsic antimicrobial effects ,369 whilGiven the extensive use of metallic implants in the clinical restoration and replacement of bone tissue, an attractive nanotechnology-derived approach consists of enhancing their bioactivity and osteogenic activity using surface coatings ,375,376.The therapeutic implications of other oxide nanoparticles in bone healing applications have been also explored ,386. ForFollowing their dissolution, MgO NPs provide mineral nutrients that are essential for most biological processes, including new bone formation, by promoting osteogenic proliferation and differentiation and bone-like mineral deposition ,398,399.Given the fact that an imbalance in the normal zinc deposits and cellular zinc homeostasis may occur after bone tissue injuries (as the human skeleton is a major source of zinc), producing zinc-enriched substitutes is of great importance for bone healing and normal skeletal development ,404. ZnOIt has been evidenced that cerium oxide (ceria) NPs stimulate the osteogenic differentiation of stem cells and regulate bone mineralization, and also exhibit antioxidant effects  ,414,415.Recently, hollow manganese oxide NPs were proposed as efficient platforms for the immunotherapy of osteosarcoma, with their additional tumor-targeting ability and imaging-guided drug delivery . These oA significant improvement in the mechanical behavior and thermal stability of polymeric biomaterials has been evidenced after the incorporation of titanium oxide (titania) NPs, with such nanostructured platforms being proposed for the long-term use in bone regeneration ,430. TheThis review also covers the implications of metal-based nanoparticles in bone tissue therapy. Owing to their peculiar nanosize-related characteristics, which include biomechanics and thermochemistry, stability and optical behavior, reduced toxicity and good biocompatibility, proliferative and intrinsic osteogenic potential, cellular development modulation, and intrinsic antimicrobial and anti-cancer effects, metallic NPs are versatile candidates for bone healing applications ,435.Gold nanoparticles (AuNPs) are biocompatible and inert nanosized structures with high monodispersity, electroconductivity, and excellent optical properties ,437. TheIn relation to bone healing therapy, it has been evidenced that AuNPs exhibit intrinsic osteogenic effects (by promoting the differentiation of pluripotent cells and biomimetic apatite formation) ,442, inhWhat is more, AuNPs also exhibit important antimicrobial ,455 and Silver nanoparticles (AgNPs) are one of the most explored nanosized noble metals in modern industrial and biomedical applications, owing to their intrinsic catalytic effect, chemical stability, good electrical conductivity, optical behavior, and versatile biological activity ,461. In In the realm of orthopedics and dentistry, where the infection susceptibility of implanted devices is a continuous danger, the clinical potential of nano-silver is of special interest ,470,471.Modifying surface coatings with AgNPs represents an attractive strategy to enhance the bioactivity and osseointegration of metallic implants used in orthopedics and orthodontics. The use of AgNPs in oxide and non-oxide ceramic coatings can minimize the infection susceptibility of metallic implants by modulating the coating\u2019s resistance to bacterial contamination and colonization, and exerting broad-spectrum antibacterial effects, while they maintain or improve their beneficial effects on osteogenic activity ,478,479.In bone healing therapy, particular attention was oriented towards the incorporation of AgNPs within biomimetic constructs, such as HA-based coatings and polymer/HA scaffolds. Besides their anti-pathogenic effects, such nanomaterials proved to be beneficial substrates for mineralization and osteogenic differentiation, finally resulting in enhanced osseointegration of the metallic implants ,487,488 AgNPs exhibit nanosize-governed intrinsic anti-cancer activity (as evidenced against various cancer types) ,492, andCopper (Cu) is one essential trace element found in the human body that has a vital role in the cellular events that maintain the normal function of bones, blood vessels, and nerves, and it also contributes to wound healing speed, antioxidant defense, and immune function ,509,510.Copper deficiency has been linked with several disorders that mostly affect the connective and bone tissues. Cu plays a vital role in bone metabolism, and its lack may cause bone anomalies and deformities ,511. It Given its beneficial role in bone metabolism, the use of Cu-based formulations\u2014with particular emphasis on metallic ions and nanoparticles\u2014is of great interest for bone healing applications. Following their incorporation or immobilization within different materials, copper nanoparticles (CuNPs) exhibit increased chemical stability and a self-tuned ability to gradually release the metallic ions without affecting the stability of matrix materials ,515.Furthermore, all forms of copper, including ions, nanoparticles, and alloys, possess excellent antibacterial properties, alongside osteogenic and angiogenic effects ,516. In Even if substantial studies must be performed to properly and accurately revalue their therapeutic potential ,525, Cu-Designing successful devices and substitutes for bone therapy still represents a challenge for modern biomedicine, as it implies the accurate understanding of bone pathophysiology, the proper selection of biomaterials and fabrication protocols, and maximal therapeutic efficiency.Nanoparticle-based biomaterials and biotechnologies have been lately validated as viable alternatives to traditional scaffolding protocols. In particular, bioceramic, oxide, and metallic nanoparticles demonstrated impressive therapeutic outcomes for bone repair and regeneration, and also for bone pathologies management.Owing to their bioactivity, biomimetic composition, and good incorporation within the natural bone structure, bioceramic nanoparticles represent the best choice for reparative and regenerative bone therapy. Their acknowledged cytocompatibility and beneficial interactions with living tissues can be explored in conjunction with polymeric constructs and other inorganic  or organic substances (drugs and biomolecules) in order to fabricate bone-mimicking platforms for the specific and selective management of bone pathologies.Even if substantial efforts should be made to completely understand and finely tune the implications of oxide and metallic nanoparticles in bone healing, their functional versatility  and intrinsic therapeutic activity are impressive. Such peculiar characteristics pave the way towards the development of multifunctional bone substitutes, including platforms for targeted and localized drug delivery , specific and selective detection and diagnosis, and effective combined therapy.Besides being active components for bone processes , the previously discussed inorganic nanomaterials exhibit additional biological activities . The nanosize-governed surface chemistry of these nanoparticles provides active sites for the conjugation of various therapeutic agents , and also enables their immobilization or incorporation into more complex constructs, finally resulting in the development of versatile and performance-enhanced candidates for bone healing applications."}
+{"text": "Polysaccharides are natural polymers widely present in animals, plants, and several microorganisms. Polysaccharides have remarkable properties, including easy extractions, degradability, and renewability, and have no apparent toxicity, making them ideal for biomedical applications. Moreover, polysaccharides are suitable for repairing oral tissue defects and treating oral diseases due to their excellent biocompatibility, biosafety, anti-inflammatory, and antibacterial properties. The oral cavity is a relatively complex environment vulnerable to numerous conditions, including soft tissue diseases, hard tissue disorders, and as well as soft and hard tissue diseases, all of which are complex to treat. In this article, we reviewed different structures of natural polysaccharides with high commercial values and their applications in treating various oral disease, such as drug delivery, tissue regeneration, material modification, and tissue repair. Oral diseases are a global public health concern, often affecting the aesthetics and diet of patients, and in some cases, they cause systematic diseases . Treatinvia glycosidic bonds  glycosidic bonds. Chitosan is positively charged due to the presence of the amino group  has approved chitosan for food and drug use . Chitosano group . The molno group . Chitosano group , drug reno group , target no group , and druno group . Studiesl caries . Severall caries . Chitosal caries   is a glycosaminoglycan composed of repeated N-acetyl id units . It is tid units . HA is aid units . Notablyid units . HA has id units .d-mannuronic acid , and a- l-guluronic acid , joined together via the 1 \u2192 4 linkages. The compound is stable, soluble, viscous, and safe, suitable for pharmaceutical use  and periodontal ligament cells (PDLCs), the alkaline phosphatase activity, and mineralization level. The CS scaffolds, combined with other polymer biomaterials and bioceramics, promote rapid periodontal regeneration . Mesoporneration . Mice moneration . Howeverneration . In geneEscherichia coli and Staphylococcus aureus and, thus, is suitable for topical wound care and periodontitis and oral cancer treatment  They have poor mechanical properties. The inferior adhesiveness and the short-term efficacy . 2) The efficacy . 3) Natuefficacy .Natural polysaccharides are generated through natural processes. However, researches are needed to explore strategies for modifying the chemical structure of these molecules to broaden their biomedical applications. Moreover, the natural polysaccharides are made to the namomaterials , which m"}
+{"text": "Despite his treatment, our patient developed multiple organ failure, leading to prioritizing his comfort.In conclusion, this case report highlights the importance of a close up cytological monitoring in postallograft myeloid neoplasms with hypereosinophilia.The authors declare no conflict of interest.None.Salwa Hamdash, Corentin Deckers, and Virginie Chapelle collected, analyzed the data, and performed the diagnosis with Madeleine Rousseaux. Salwa Hamdash, Corentin Deckers, Virginie Chapelle, and Martin Vanderdonck wrote the manuscript and cover letter. Madeleine Rousseaux and Pascale Saussoy reviewed the manuscript. All authors have reviewed and approved the manuscript."}
+{"text": "PLOS ONE Editors retract this article [The  article  because MBH, MMM, SI, and ZH either did not respond directly or could not be reached. SafdarB responded but expressed neither agreement nor disagreement with the editorial decision. AB, AMES, BSA, MSS, SaqibB, SK, and YL did not agree with the retraction."}
+{"text": "In \u201cRelationship Between Protein Intake in Each Traditional Meal and Physical Activity: Cross-sectional Study\u201d :e35898), four errors were noted.1. Due to a system error, in the originally published web version of the article, the name of one author, Lyie Nitta, was replaced with the name of another author, Mai Kuwahara. The order of authors appeared as follows:Takae Shinto, Saneyuki Makino, Yu Tahara, Mai Kuwahara, Mai Kuwahara, Ayako Tada, Nanako Abe, Mikiko Michie, Shigenobu ShibataThis has been corrected to:Takae Shinto, Saneyuki Makino, Yu Tahara, Lyie Nitta, Mai Kuwahara, Ayako Tada, Nanako Abe, Mikiko Michie, Shigenobu Shibata2. In the originally published PDF version of the article, author Lyie Nitta's name appeared incorrectly as Lie Nitta. It has now been corrected in the article.3. In the originally published web version of the article, author Mai Kuwahara was incorrectly linked to author Lyie Nitta\u2019s ORCID iD. This discrepancy has now been corrected in the article.4. In the originally published article, the copyright statement erroneously appeared as follows:\u00a9Takae Shinto, Saneyuki Makino, Yu Tahara, Mai Kuwahara, Mai Kuwahara, Ayako Tada, Nanako Abe, Mikiko Michie, Shigenobu Shibata.This has been corrected to:\u00a9Takae Shinto, Saneyuki Makino, Yu Tahara, Lyie Nitta, Mai Kuwahara, Ayako Tada, Nanako Abe, Mikiko Michie, Shigenobu Shibata.The correction will appear in the online version of the paper on the JMIR Publications website on August 4, 2022, together with the publication of this correction notice. Because this was made after submission to PubMed, PubMed Central, and other full-text repositories, the corrected article has also been resubmitted to those repositories."}
+{"text": "Traditional herbs played a crucial role in the health care of the Hakka people. However, studies to identify these traditional herbs are few. Here we document and assess the potential of these plants for treating microbial infections. Many herbs used by the Hakka people could potentially be a novel medicinal resource.Local herb markets were surveyed via semi-structured interviews, complemented by direct observations to obtain information on herbal usage. For each herb selected for this study, extracts in four different solvents were prepared, and tested for activity against 20 microorganisms, as well as cancerous and noncancerous cells. All data were subjected to cluster analysis to discover relationships among herbs, plant types, administration forms, solvents, microorganisms, cells, etc., with the aim to discern promising herbs for medicine.Staphylococcus aureus (67%), Listeria innocua (64%), etc. Cytotoxicity was often observed against a tumor cell, but rarely against normal cells. Considering both antimicrobial activity and cytotoxicity, many herbs reported in this study show promise as medicine.Ninety-seven Hakka herbs in Ganzhou were documented from 93 plants in 62 families; most are used for bathing (97%), or as food, such as tea (32%), soup (12%), etc. Compared with the Chinese Pharmacopoeia and Chinese Materia Medica, 24 Hakka medicines use different plant parts, and 5 plants are recorded here for the first time as traditional medicines. The plant parts used were closely related with the life cycle: annual and perennial herbs were normally used as a whole plant, and woody plants as (tender) stem and leaf, indicating a trend to use the parts that are easily collected. Encouragingly, 311 extracts (94%) were active against one or more microorganisms. Most herbs were active against Gram-positive bacteria, such as Hakka people commonly use easily-collected plant parts  as medicine. External use of decoctions dominated, and may help combating microbial infections. The results offer promising perspectives for further research since little phytopharmacology and phytochemistry has been published to date.The online version contains supplementary material available at 10.1186/s12906-022-03712-z. As the primary source of natural products, plants have provided abundant health benefits to man from prehistoric times, especially as food and medicine . In the Glycyrrhizae radix et rhizoma, Rhei radix et rhizoma, Astragali radix , as a kind of folk medicine, originated from the migration of the Hakka people, who belong to a branch of the Han nationality, and are therefore not an ethnic minority. The Hakkas moved South from the Central Plains (North of China) over more than 1000\u2009km to settle down in South China; this migration occurred in various stages  has housed one of the largest Hakka populations, accounting for nearly 10 million, with southern Jiangxi as the largest administrative area. After several centuries of migrations, more and more local herbs were utilized by Hakkas in Ganzhou, and a tradition of trading HTMs has developed, with very prosperous local herb markets. Especially when the season changes between spring and summer, herb markets are held, and many Hakka people collect herbs from the wild mountains to sell them in those markets . Most HaAs the largest Hakka area in the world , GanzhouThe study team was composed of pharmacognosts, ethnopharmacologists, botanists, and TCM students from the School of Pharmacy, Gannan Medical University. The eighteen counties or districts of Ganzhou were chosen as the study sites to investigate the local herb markets during the Dragon Boat Festival  from 201A total of 97 Hakka herbs were collected from herbal medicinal hawkers in 2018, and all the herb data were confirmed by more than 3 hawkers or herb buyers, including the local use, the preparation, forms of administration, etc. In this paper, we focused on the administration forms. The herbs were identified by Prof. Haibo Hu and Prof. Jialin Li based on the \u201cFlora of China\u201d, or their morphological, microscopic, physical or chemical characteristics by following standard authentication methods of TCM . VoucherHPLC-grade n-hexane, ethyl acetate, methanol, and dimethyl sulfoxide  were purchased from Sigma\u2013Aldrich Co. . Sterile deionized water was produced by a Milli\u2013Q Reagent Water System . Bacto\u2122 peptone and yeast extract were from Lab M Ltd. . Ciprofloxacin , chloramphenicol  , (\u00b1)-\u00a0mi50  [Hakka herbs were obtained directly from the aforesaid local markets, where most herbs were collected from the wild by local Hakkas and were in a fresh state, viz. whole plant, root, stem, bark, leaf, etc. Depending on the water content of the plant parts, they were dried at 40\u2009\u00b0C for 12 to 60\u2009h in an electro-thermostatic blast oven , in an attempt to maintain volatile components if present. Then they were milled into a fine powder by a high-speed multifunctional grinder. All the materials were kept as dry as possible to prevent the growth of microorganisms. For each herb, at least 50\u2009g dry medicinal crude preparation was purchased. One gram of each powder was extracted with pure water, methanol, ethyl acetate, and hexane, and after evaporation of the solvent, a working stock with a final concentration of 20\u2009mg/mL was prepared in DMSO (solvent extracts) or water (water extracts) for antimicrobial tests against 20 pathogens as described previously , 39. An 4 cells were plated in each well of a multiwell-96 plate; calculation of the cell number was performed by a NucleoCounter  [50 (cytotoxic concentration with 50% adverse effect).A resazurin-based cell viability assay with some modifications was used to investigate the cytotoxicity on human lung epithelial tumor cells , and non-tumoural human lung fibroblast cells  . All celDenmark) . Then, t50 and CC50 values were calculated by GraphPad Prism 7.0 Software  [https://biit.cs.ut.ee/clustvis/) to obtain hierarchical clustering heat maps [All the tests described in this study were performed repeatedly to ensure reproducibility. The ICego, CA) . The dateat maps . To prodThe therapeutic effect of TCM against infectious diseases has drawn attention from international scientific research, and triggered a surge of publications on Chinese herbal medicine, also in top journals \u201348. The Lycopodium japonicum, Picrasma quassioides, Lonicera japonica, Smilax glabra, Lophatherum gracile, Acorus gramineus, Solidago decurrens, Uncaria rhynchophylla, etc. However, most of them are used differently by Hakkas , such as foot soak, body bathing, water fumigation, and washing . Most bathing plants were used for treating or preventing skin diseases , rheumatism syndrome, or against inflammation, such as Callerya dielsiana was used to prepare soups not only because of the good taste, but also to prevent or treat diseases . The leaves of Nekemias grossedentata are used to prepare a locally famous tea, \u201cHakka Bai Cha\u201d, which was widely used to increase body strength and cold resistance. With people yearning for a sense of nature and health, medicinal food became increasingly popular in China. HTM is a treasure trove for developing new types of medicinal food.The second common use is for food, including tea (31 herbs), soup (12 herbs), vegetables (5 herbs), and food additives . Hakka people were used to developing local plants for medicine/food purposes, which could help them fight hunger and disease at the same time. For instance, the stem of Elatostema involucratum  and Saxifraga stolonifera . Decoctions and infusions are also widely used by Hakkas for medicinal purposes, for 42 and 9 herbs, respectively. They are used for a range of indications, like hepatitis, detumescence, pain, rheumatism syndrome, common cold, flu, etc. Figure\u00a0Herbal plaster or paste (9 herbs) for external use, a healing, cleansing application with antiseptic action, was also mainly used for skin diseases, such as Fissistigma oldhamii, for instance, is recorded in TCM to only use its roots with the effect on rheumatism syndrome, promoting blood circulation, and relieving pain; Hakka people on the other hand use the leaves and stems for treating gynecology inflammation, in addition to rheumatism syndrome [Camellia oleifera, locally called \u201cCha Er\u201d, is used by Hakkas for food and drink (tea), while people normally use its seed, oil, root, leaf, flowers, or even oil-dregs. For Lindera glauca, the root, leaf, and fruit are documented as three different medicines in CMM, but the tender stem and leaves are typically used by Hakkas. There are also many medicinal plants, whose root and/or rhizome are recorded as their medical parts in CMM and CPH, but Hakkas use their aerial part instead, such as Lindera glauca, Lindera glauca, Sabia japonica, Liquidambar formosana, Ficus formosana f. shimadai, Ficus simplicissima, Phytolacca americana, Urena lobata, Dalbergia hupeana, Phyllanthus glaucus, Cynanchum stauntonii, Alpinia zerumbet, Alpinia japonica.For many Hakka herbs, there were discrepancies between the data we collected and published information, e.g., regarding the therapeutic application, administration forms, etc. Especially for the medicinal plant parts, there were 24 herbs used locally with different parts compared to previous documents , Pseudomonas aeruginosa (12), and Candida glabrata (15), implying that it is difficult to find activities against certain fungi and G\u2212 bacteria, a pattern previously reported by others [\u2212 bacteria and some fungi have a multilayer outer membrane structure, preventing many antibiotics from passing through [+ and G\u2212 bacteria, except for Staphylococcus epidermidis, Brevundimonas diminuta, Candida albicans, and Candida parapsilosis.The inhibition values of all 388 Hakka herbal extracts against human pathogens were clustered and presented in a heat map , Staphylococcus aureus (67%), Listeria innocua (64%), Enterococcus faecalis (57%), and Bacillus cereus (55%). However, far fewer extracts were active against S. epidermidis (16%), suggesting different mechanisms of action in the same Staphylococcus genus, and that the S. epidermidis used in this study (a biofilm-forming strain) has higher resistance against botanical extracts. On the other hand, most herbs did not show much activity against G\u2212 bacteria, except Brevundimonas diminuta (84%), which is an emerging global opportunistic pathogen, that causes bloodstream infections [Shigella sonnei (38%), Aeromonas hydrophila (33%), and Shigella flexneri (32%). For fungi, the herbs were most active against C. parapsilosis (49%), which increasingly causes infections since the turn of the century: fungemia, endocarditis, meningitis, skin infections, etc. [Saccharomyces cerevisiae (31%), C. albicans (26%), C. auris (24%), and C. glabrata (13%).Most activities were detected against Gs cereus %. Howevefections . The othfaecalis %, and Bans, etc. . HTMs alMicrococcus luteus . This bacterium can survive in both salt and fresh water, and it has been detected in many kinds of food. It causes various human infections, including wound infections, septicemia, pneumonia, meningitis, and gastroenteritis, due to the most potent virulence factors of Aeromonas species via type-II and the recently proposed type-III secretion system [A. hydrophila may be that water-soluble chemicals  prevent the toxin secretion or their reaction with host cells; this hypothesis is worth studying further [Notably, the water extracts were more active than other solvent extracts for n system \u201365. The  further \u201370.50 tests were performed against cancer and non-cancer lung cells  only inhibited WI-26 VA4, 12 were active against both, and 45 only against A549. The last group, showing inhibition only for cancer cells but not against noncancerous cells, may have potential in oncology, and includes Fissistigma oldhamii, Uncaria rhynchophylla, Strobilanthes cusia, Aster pekinensis, Picrasma quassioides, Liquidambar formosana, Verbena officinalis, Adinandra nitida, Eurya acuminatissima, Agrimonia pilosa, etc. Remarkably, for Fissistigma oldhamii, the root and leaf showed strong inhibition of A549 cells, but not its stem, suggesting significant differences in the chemical composition of different plant parts [Picrasma quassioides, both the stem and leaf extracts inhibited A549 growth.All 388 extracts of the 97 herbs were tested for cytotoxicity against a human lung epithelial cancerous cell line A549) and a noncancerous lung cell line (WI-26 VA4). The data were analyzed by a heat map clustering  and Shigella sonnei (ethyl acetate extract). The broadest spectrum (\u2265 20 activities in each of 4 extracts over 20 microbes) was from 14 herbs: Lysimachia fortunei, Fissistigma oldhamii's root, Agrimonia pilosa, Corchoropsis crenata, Turpinia arguta, Physalis angulata, Maclura cochinchinensis, infected leaf of Camellia oleifera, Alpinia zerumbet, Hypericum japonicum, Fissistigma oldhamii's leaf, Adinandra nitida, Salvia prionitis, Mosla scabra.Based on their antimicrobial and cytotoxic tests, all the active herbs were graphed on a radar plot Fig.\u00a0. Each ofEquisetum ramosissimum, Saururus chinensis, Physalis angulata, Salvia prionitis, Fissistigma oldhamii root, Fissistigma oldhamii leaf, Chimonanthus grammatus, Lindera glauca, Dalbergia hupeana, Buxus sinica, Turpinia arguta, Buddleja lindleyana, Hedyotis mellii, Alpinia zerumbet, and Alpinia japonica leaf.On the other hand, the cytotoxic tests found 15 anticancer herbs with optimum activity : Lycopodium japonicum, Selliguea hastata, Loxogramme salicifolia, leaf or stem of Fissistigma oldhamii, Chimonanthus grammatus, Asarum caudigerum, Semiliquidambar cathayensis, Ficus formosana f. shimadai, Elatostema involucratum, Persicaria chinensis var. paradoxa, Eurya acuminatissima, infected leaf of Camellia oleifera, Corchoropsis crenata, Lysimachia alfredii, Haloragis micrantha, Polygala angustifolia, Hedyotis mellii, etc.As far as we know, most bioactivities for many herbs in this study are reported here for the first time. Based on the two kinds of tests , the following plants were considered as the most promising for further study, with quite limited reports on their phytopharmacology and phytochemistry: The present survey is the first comprehensive report of Hakka traditional herbs in the cradle area, Ganzhou. It documented 97 Hakka herbs from 93 plants belonging to 84 genera in 62 families. Only 22 Hakka herbs were recorded as TCM according to the Chinese Pharmacopoeia 2020. Compared with the most comprehensive book on medicinal plants: the Chinese Materia Medica, 24 Hakka herbs were reported here as using different plant parts for medicine. Moreover, 5 Hakka herbs are recorded here for the first time as traditional medicine. Given the loss of traditional knowledge due to the fast progress of urbanization, this study contributes to the conservation of scientifically and culturally valuable knowledge of Hakka traditional herbs , 74.Duhaldea cappa which was earlier classified as Inula, and many more research reports can be found under the former name Inula cappa; the same goes for Callerya dielsiana, Nekemias grossedentata, Acorus gramineus, etc. Hence, both current and earlier plant names were compared and checked systematically with flora of China, flora of Jiangxi, and the plant list database (http://www.theplantlist.org/).Notably, during their identification and literature study, many herbal records could be easily missed because some Latin taxonomic names have been revised several times, such as For their medicinal usage, bathing herbs constituted the overwhelming majority (97%); they are used for foot soak, body bathing, water fumigation, and washing to treat or prevent skin diseases. The second common usage was for medicine-food purposes, including 31 tea herbs, 12 soup herbs, 5 vegetables, and 6 food additives. Hakkas are used to collecting the aerial plant parts as medicine, which play crucial roles in their daily life, especially during the period between spring and summer, when epidemic diseases easily break out. In south China, the temperature and humidity of the Hakka area keep increasing during these seasons, and microbes become more and more active, which causes more infections, including human skin diseases, respiratory disease, rheumatism syndrome, etc. \u201377. TherThis study is a starting point for the discovery of anti-infectious agents from traditional botanical medicine used by Hakkas in Ganzhou, China. The pharmacology and phytochemistry of many of these plants have not been reported so far, offering attractive perspectives for further research. Besides, this research provided a way to access and analyze the activity of traditional herbs, and can guide the selection of active ones. Further work is necessary to purify and identify the bioactive compounds, especially for the most promising or newly recorded Hakka herbs.Additional file 1.Additional file 2.Additional file 3.Additional file 4.Additional file 5."}
+{"text": "Dysbiosis\u2014disturbance of quantitative ratios of individual bacteria or appearance of pathogenic species\u2014rarely results in symptomatic disease. Inflammation results in decreased sperm production, lower motility, or morphological changes and, in the long term, can cause ejaculatory duct obstruction, leading to infertility. Moreover, it may cause infection of the partner\u2019s female genital tract. Dysbiosis in both partners results in fertility problems, disorders in embryo implantation, or miscarriages. In addition, chronic inflammation of the male genitourinary system may accelerate the appearance of antisperm antibodies. A comprehensive examination of seminal microflora can clarify the causes of infertility or prevent pathological conditions that affect seminal parameters. Seminal microflora as a direct impact on fertility problems as well as a decrease in the effectiveness of assisted reproduction methods, insemination, or  Semen is usually examined bacteriologically only when genitourinary infection is suspected and the results of standard physical and biochemical examination indicate it . InitialMolecular diagnostics allowed the detection of numerous bacteria and viruses in the urine and semen of healthy men. In particular, recent advances in next-generation sequencing, which do not require classical culture, have made it possible to characterize the microbiome, including non-culturable species, in various areas of the human body, such as sperm microbiome . There aRalstonia, Corynebacterium, Lactobacillus, Streptococcus, Staphylococcus, Prevotella, Finegoldia, Anaerococcus, Peptoniphilus, Incertae Sedis XI, Veillonella, Pelomonas, Porphyromonas, Uma, Acopidoblas, Acopidoblasov, Aerococcus, Gemella, Granulicatella, Clostridiales, and Cloacibacterium  data, infertility affects approximately 15% of couples trying to have children. In 20%\u201350% of all cases, decreased male partner fertility is responsible for difficulties in procreation . Male geEscherichia coli, Staphylococcus aureus, Enterococcus faecalis, Klebsiella sp., Streptococcus sp., Chlamydia trachomatis, Ureaplasma urealyticum, and Mycoplasma hominis  urinale (Actinomyces radingae (Mobiluncus spp. (Acidovorax spp. (Aeromonas spp. (Aggregatibacter spp. (Acinetobacter johnsonii (The present review of recent studies on the seminal microbiome by using sequence analysis revealed that there is a great diversity of microorganisms in the male genital tract. However, there is no clear definition of the importance of individual groups and the proportion of bacteria in infertility. Those who conduct research on seminal microbiota must define which of these microorganisms are tourists, residents, and invaders . Previou urinale , Actinomradingae , Mobiluncus spp. , Acidovorax spp. , Aeromonnas spp. , Aggregater spp. , or Acinohnsonii . These rohnsonii . NumerouThe manuscript was equally drafted, revised, and approved by AW, EM, MC, and AB-C. All authors contributed to the article and approved the submitted version.EM was employed by the company Gyncentrum.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Precarious employment (PE), characterized by reduced worker rights, and employment and income insecurity, has complex public health implications including negative impacts on workers\u2019 mental and physical health, occupational health and safety, wellbeing, and inequities in access to health and social protections. There is, however, a knowledge gap regarding effectiveness of interventions. We describe findings from a review of evaluated interventions with potential to address PE.Our systematic review followed the 2020 PRISMA framework and covered PubMed, Scopus, Web of Science, and sources of grey literature. We included qualitative, quantitative, or mixed-methods studies evaluating initiatives to reduce workers\u2019 PE published from 2000 to 2021 and focused on adult workers.The 23 eligible studies from across the world evaluated diverse strategies addressing PE including tax and trade reforms, industrial disputes legislation, business registration, and use of incentives to stimulate permanent contracts. Also included were union strategies to reach precarious workers, the provision of social benefits, and youth apprenticeships. Generally, while most initiatives had the potential to tackle certain PE aspects, they usually acted only on one or two PE dimensions. Additionally, the evaluation components were missing key details, thus, limiting the generalizability of findings, as did the heterogeneity of study designs, initiative purposes, economic and political context, and diverse populations targeted.The increase in PE prevalence and its complex health implications requires sustainable upstream public health solutions. Multidisciplinary collaborations among public health and occupational health practitioners along with researchers, evaluation specialists, economists, and politicians could facilitate the implementation and evaluation of policies and standards regulating and monitoring PE and its health impacts.\u2022\u2002Precarious employment has complex public health implications.\u2022\u2002Sustainable solutions to address precarious employment must be upstream and multidisciplinary."}
+{"text": "Epigenetic changes drive early embryonic and later stages of development. Through this molecular mechanism, transcriptional programs are altered, influencing outcomes for cellular differentiation patterns in early life and throughout adulthood . A multiAlzheimer\u2019s disease, cancer, cardiovascular disease, and diabetes are some of the more well-studied diseases associated with an aged epigenetic landscape ,11,12,13This Special Issue aims to explore current research concerning epigenetic changes that govern human development, both embryonic and later cell stages, along with age-related epigenetic changes that drive pathologies later in life. We invite the submission of manuscripts that concern epigenetic contributions to development, aging, and transgenerational inheritance. Additional manuscript topics include, but are not limited to, embryonic development, differentiation, metabolic signaling, DNA methylation, histone modifications, miRNAs, transposable elements, and the epigenetic clock. Finally, manuscripts regarding possible treatment targets and early intervention via the modification of these molecular mechanisms are also welcomed, e.g., ."}
+{"text": "Hurler syndrome is the most severe form of mucopolysaccharidosis type I (MPS I), It is a hereditary, metabolic disorder due to an enzymatic deficiency in alpha-Liduronidase with tissue accumulation of glycosaminoglycans (GAGs) leading gradually to chronic multiple visceral dysfunction.We report three cases of multiple dysostosis in Hurler's disease.Case 1:Hurler's disease. The radiological assessment showed thickening of the cranial vault with poorly developed paranasal sinuses. Vertebral bodies collapse with oval shape, thoracolumbar kyphosis, hypoplasia of the iliac bones and the superior acetabular region, coxa-valga, with dysplastic femoral heads; cortical thinning of the long bones with a tapered appearance of the distal portions of the radius and ulna, small and deformed carpal bones, thin metacarpal bones, and dysplastic interphalangeal joints.Mr S.O, 26 years old man, presenting a dysmorphic syndrome associating short stature, facial dysmorphism, dental staining, gingival retractions, recurrent bronchial infections, mitral valve disease and joint deformities with a tunnel syndrome. Alpha L iduronidase dosage was performed confirming the diagnosis of Case 2:Patient B.M 17 years old girl, born of a consanguineous marriage, presenting with a malformation syndrome with short stature, facial dysmorphism, umbilical hernia, valvular heart disease, hepatomegaly, joint stiffness and deformity. Standard x-rays revealed macrocephaly with thickening of the cranial vault, flattened mandibular condyles, with hypertrophy of the clinoid processes; pectus excavatum, platyspondyly with thoracolumbar kyphoscoliosis, small and narrowed pelvis, enlarged and obliquus cotyles, coxa-valga with dysplastic femoral heads; long curved bones with metaphyseal and diaphyseal enlargement, short and enlarged proximal and intermediate phalanx and hypoplastic distal phalanx.Case 3:Patient D.W, 31-year-old female, born of a consanguineous marriage. The patient\u2019s physical examination shows a dysmorphic syndrome with short stature, facial dysmorphism, corneal opacity, recurrent otorhinolaryngological and bronchial infections, joint deformities with carpal tunnel syndrome. An alpha L iduronidase assay was performed confirming the diagnosis. The radiological assessment revealed macrocephaly, thickening of the cranial vault, an elongated J-shaped sella turcica, a short thorax, short and thick clavicles, widened, oar-shaped ribs tapering at their vertebral insertion, \u201cspur\u201d vertebrae, thoracolumbar kyphoscoliosis, narrowed pelvis with coxa-valga and genu valgum, small and deformed carpal and tarsal bones with cortical thinning of long bones.The term dysostosis multiplex is used to describe skeletal abnormalities seen in MPS I that are often early and prominent. The progressive accumulation of GAGs led to an increase in chondrocyte apoptosis favoring the production of pro-inflammatory cytokines , chemokines and metalloproteases. This results in a degradation of the cartilaginous matrix, increased by the mechanical stresses, the disturbance of endochondral ossification, particularly in the sites subjected to articular mechanical stresses. That could explain the focal defect of the ossification of certain cartilaginous sites leading to this multiple dysplasia. At the axial level, the vertebrae can be oval shaped and flattened (platyspondyly). In the lower limbs, coxo-femoral abnormalities , epiphyseal alterations, genu valgum, and hypoplasia of the iliac bones can be found. The metacarpal bones take on a tapered appearance like sucked candy cane and the interphalangeal joints of the hands and feet are dysplastic. Hypoplasia of the odontoid process leads to potentially serious cervical instability. Regular monitoring by MRI is necessary to avoid the risk of spinal cord section. The early introduction of enzyme replacement therapy led to a slower progression of symptoms, with improved growth, joint mobility and physical capacity, and stability over time, especially when associated with an appropriate rehabilitation care.Even if Hurler syndrome is rare, it is still underdiagnosed, it can give various and varied clinico-radiographic features and potentially severe disabilities. Early diagnosis is essential since enzyme replacement therapy could stop or slow down the evolution to irreversible tissue damage."}
+{"text": "Due to its anticholinergic action, antipsychotic drugs, especially phenothiazines and atypical antipsychotics, have been described as a rare cause of drug-induced ischemic colitis. We present two cases of patients that were admitted to the gastroenterology unit of a general hospital and were diagnosed of quetiapine-induced ischemic colitis.To describe an uncommon side effect of neuroleptic treatment.Case report and literature review.First patient, aged 73, with history of dysthymia, in treatment with desvenlafaxine, quetiapine, ketazolam, lorazepam, enalapril/hidroclorothiazide, omeprazole, simvastatin, tramadol/paracetamol, alendronate/colecalciferol and hidroferol, consulted in the emergency room for malaise, disorientation, haematuria, abdominal pain and changes in deposition rhythm; family members admitted frequent use of higher than prescribed doses of quetiapine and benzodiazepines. Second patient, aged 63, with history of histrionic personality disorder, in psychopharmacologic treatment with venlafaxine, quetiapine, diazepam, fentanyl, rupatadine, cinitapride, omeprazole, levosulpiride, simvastatin, fluticasone/salmeterol and celecoxib, consulted for abdominal pain and bloody diarrhoea. Colonoscopy findings in both of them were compatible with ischemic colitis. Quetiapine was withdrawn in both cases, as the main diagnostic hypothesis was quetiapine-induced ischemic colitis. The patients achieved full recovery.Ischemic colitis is a rare but potentially fatal adverse effect of antipsychotic drugs, with clozapine being the most reported atypical antipsychotic thought to cause it. The risk associated with quetiapine is thought to be lower given its milder anticholinergic effect. Co-prescription with other drugs with anticholinergic actions increases the risk. Clinicians should be aware of this association and the onset of constipation should alert medical staff.No significant relationships."}
+{"text": "Direct care workers (DCWs) play a crucial role in delivering long-term services in nursing homes, assisted living, and in-home care. The work is physically and emotionally demanding and generally low-paid, which makes retaining and managing the workforce extremely challenging and has resulted in an unending workforce crisis. This study provides data on retention-promoting factors from the perspective of DCWs working in high-performing facilities and home care agencies that were identified through national and state retention data and reviews from case management agencies. Qualitative interviews were conducted in the spring of 2022 with a purposive sample of DCWs (n=16). Interviews were transcribed, checked for accuracy, and coded via thematic analysis. Three overarching themes emerged: work culture, appreciation, and monetary benefits. Retention was supported by a work culture that emphasizes person-centered care, family atmosphere, relationship building, staff empowerment, coaching supervision, participative leadership, effective communication, and flexible working conditions. DCWs experienced appreciation from employers, supervisors, and clients, which they perceived to promote retention. This theme includes valuing, respecting, recognizing, and acknowledging the efforts of DCWs. Monetary benefits promoting retention were seen as regular wage raises, employee assistance funds, gift cards, bonuses, paid time off, health insurance benefits, and travel reimbursement. This study demonstrates that while worker retention is a crisis, there are modifiable aspects of the job that can promote workers\u2019 retention. DCWs\u2019 retention can be impacted by work culture and appreciation practices. Study findings have implications for facility policy and practice pertaining to DCW\u2019s retention."}
+{"text": "Advanced drug delivery micro- and nanosystems have been widely explored due to their appealing specificity/selectivity, biodegradability, biocompatibility, and low toxicity. They can be applied for the targeted delivery of pharmaceuticals, with the benefits of good biocompatibility/stability, non-immunogenicity, large surface area, high drug loading capacity, and low leakage of drugs. Cardiovascular diseases, as one of the primary mortalities cause worldwide with significant impacts on the quality of patients\u2019 life, comprise a variety of heart and circulatory system pathologies, such as peripheral vascular diseases, myocardial infarction, heart failure, and coronary artery diseases. Designing novel micro- and nanosystems with suitable targeting properties and smart release behaviors can help circumvent crucial challenges of the tolerability, low stability, high toxicity, and possible side- and off-target effects of conventional drug delivery routes. To overcome different challenging issues, namely physiological barriers, low efficiency of drugs, and possible adverse side effects, various biomaterials-mediated drug delivery systems have been formulated with reduced toxicity, improved pharmacokinetics, high bioavailability, sustained release behavior, and enhanced therapeutic efficacy for targeted therapy of cardiovascular diseases. Despite the existing drug delivery systems encompassing a variety of biomaterials for treating cardiovascular diseases, the number of formulations currently approved for clinical use is limited due to the regulatory and experimental obstacles. Herein, the most recent advancements in drug delivery micro- and nanosystems designed from different biomaterials for the treatment of cardiovascular diseases are deliberated, with a focus on the important challenges and future perspectives. One of the areas of interest in nanomedicine is the design of novel targeted drug delivery systems (DDSs) with high specificity/selectivity, biodegradability, biocompatibility, and low toxicity ,2,3,4. CThere are numerous innovatively designed micro- and nanosystems with diagnosis and therapeutic potentials in various forms of implants, nanorobotics, real-time monitoring systems/devices, nano-/microneedles, nanoblades, combinational therapeutic systems, among others ,28. Micr\u03b2-glycerophosphate injectable hydrogels, chitosan/silk fibroin-modified cellulose nanofibrous patches, chitosan-gelatin based systems loaded with therapeutic/functional agents , and alginate- or collagen-chitosan hydrogels are some of these systems formulated for improving vascularization, heart function, cell survival/proliferation, cell delivery for MI therapy, and expression of vascular endothelial growth factor, in addition to the sustained release of therapeutic agents . Fo\u03b2-glycerophosphate loaded with human mesenchymal stem cells for cardiac healing after acute MI. The designed nanosystem exhibited significant stability with unique physicochemical properties suitable for cardiac regeneration appliances. After in vitro evaluations, it was established that the cell survival rate was improved and the expression of pro-inflammatory factors was increased. The analysis of pro-angiogenic factors illustrated promising outcomes regarding the fibrosis area, vessel density with reduced size of infractions, and ejection fraction, providing superb opportunities for healing cardiac function after MIs [Several explorations have been conducted on designing micro-/nanosystems loaded with cardiac stem cells (CSCs) in CVDs. As an example, vascularized cardiac patches containing biomimetic microvessels encapsulated in a fibrin gel spiked with human CSCs were constructed for promoting the proliferation of cardiomyocytes and neovascularization after acute MI, providing vast opportunities for treating ischemic heart injuries . In one fter MIs . Impressfter MIs . These bfter MIs .Liposomes with unique physicochemical and biophysical characteristics have shown suitable biocompatibility, self-assembly potentials, high drug loading, and encapsulating capacity, and their controllable/sustained release behavior can be considered for designing smart DDSs in treating CVDs . VariousN-acetylcysteine conjugate nanosystems were developed for targeting activated microglial cells subsequent to cardiac arrest to provide improvements in survival rate, neurological recovery, and short-term motor shortfalls. These nanosystems offer as promising strategies for the treatment of post-cardiac arrest syndrome [Dendrimers with drug delivery capability along with the availability of multiple functional groups can be employed for stabilizing drugs, enhancing the solubility of therapeutic agents, and improving the sustained/controllable release of drugs/bioactive agents ,77. For syndrome .Niosomes have shown some salient advantages, compared to liposomes, including the suitable physicochemical stability, cost-effectiveness, simple formulation processes, and up-scalable potentials. They have been utilized for constructing a variety of formulations in treating CVDs. In one study, to solve the broad pre-systemic disposition and low rate of dissolution, chitosan-encapsulated niosomes were formulated to improve the oral delivery of atorvastatin, providing enhanced anti-hyperlipidemic effects . AdditioLipid-based nanosystems have shown alluring benefits, such as up-scalable production, biocompatibility, biodegradability, low toxicity, controllable/sustained drug release behavior, and possibility of drug solubility improvements . For insNanocapsules have been widely prepared for controlled drug release to specifically target the sites with a variety of drugs, bioactive agents, and protein/peptide compounds . Chaves Organ-on-chip platforms comprising microfluidics, cell tissue/organ, stimulation, and sensor systems can be applied in the development and discovery of new drugs for treating CVDs due to their excellent potentials in achieving a physiological resemblance in vitro, offering new opportunities to evaluate the efficiency and toxicity of drugs and study the cardiovascular pathophysiology instead of using traditional in vitro cell cultures ,89,90. IGenerally, several materials have been explored for manufacturing different organ-on-chip platforms, such as poly(dimethylsiloxane) and poly(methyl methacrylate) ,99. Somehttps://clinicaltrials.gov/ (9 August 2022).One of the most important challenging issues in designing advanced DDSs for treating CVDs is clinical trials/studies. Since limited studies have been introduced on micro-/nanosystems for targeted drug delivery in CVDs, future explorations ought to focus on this crucial step ,104,105.To overcome several challenges, such as physiological barriers, off-target effects, low efficiency of drugs, and possible adverse side effects, various biomaterials-mediated DDSs have been formulated with reduced toxicity, improved pharmacokinetics, high bioavailability, sustained release behavior, and increased therapeutic efficacy for targeted therapy of CVDs. Despite the pervasiveness of numerous micro- and nano-DDSs comprising various biomaterials introduced for treating CVDs, the number of formulations currently approved for clinical use is rather limited due to the regulatory and experimental obstacles. Indeterminate toxicity (study on mechanisms of toxicity) and the lack of systematical analysis of these materials restrict their further applications. There is limited relevant research evidence on the biological endpoints to evaluate the relationship between the physicochemical features of micro- and nano-DDSs, such as morphology, size, size distribution, chemical/surface structure, and electrochemical features, with their inflammatory and toxic effects. Comprehensive toxicological evaluations and cost benefits of designed DDSs are essential for their future clinical applicability. In addition, several issues pertaining to the good manufacturing practice (GMP), biosafety/tolerability, stability, immune reactions, biocompatibility/biodegradability, drug clearance, drug release/loading, pharmacokinetics/pharmacodynamics, and scaling up processes should be systematically studied to translate micro- and nano-DDSs from laboratory and preclinical phases into clinical stages. In this context, smart stimuli-responsive biomaterials-mediated DDSs should be further designed that can respond to the modified environmental signals with alterations in their morphologies and physicochemical characteristics, thus offering targeted therapy opportunities. One of the most important challenges is to simultaneously improve the multifunctionality, biocompatibility, and targeting properties of micro- and nano-DDSs, which need to be explored in future.For clinical applications of nanomedicine in treating CVDs, there are still limited studies performed. Future explorations should be planned in both pre- and clinical trial stages for designing smart micro-/nanosystems for treating atherosclerosis, thrombosis, stroke, MI, hypertension, and pulmonary arterial hypertension with improved body circulation and drug solubility, as well as reduced amount of drugs and low cytotoxicity. Notably, some grant challenges, such as understanding the related mechanisms of actions, designing smart micro-/nano-DDSs with personalized therapy purposes, improving drug bioavailability and circulation time, and evaluating clinical safety and translation, are still remained. Controlled and sustained delivery of pharmaceuticals/therapeutic agents with advantages of disease-specific treatment can reduce off-target influences by a stimuli-mediated drug release in the affected area . In this context, cardiovascular organ-on-chip platforms can help to specifically evaluate the efficiency and possible off-target toxicity of new drugs and their metabolites, thus offering new opportunities for better pre-clinical evaluations, drug discovery/development, and personalized medicine."}
+{"text": "Childhood interstitial lung disease (chILD) includes a heterogeneous spectrum of rare respiratory disorders in children associated with substantial morbi-mortality. Interstitial tissue, and other pulmonary structures, epithelium, blood vessels, or pleura are involved, resulting in a restrictive lung disfunction. Respiratory symptoms set in progressively and are often subtle, making thorough clinical history and physical examination fundamental. The etiology often is obscure. The clinical presentation mimics pneumonia or asthma, leading to a diagnostic delay. Challenging diagnosis may require genetic tests, bronchoalveolar lavage, or lung biopsy. Alongside general supportive therapeutic measures, anti-inflammatory, immunosuppressive or antifibrotic agents may be used, based on data derived from adult studies. However, if accurate diagnosis and treatment are delayed, irreversible chronic respiratory failure may ensue, impacting prognosis. The most frequent chILD is hypersensitivity pneumonitis (HP), although it is rare in children. HP is associated with exposure to an environmental antigen, resulting in inflammation of the airways. Detailed antigen exposure history and identification of the inciting trigger are the cornerstones of diagnostic. This article provides the current state of chILD, revealing specific features of HP, based on a clinical case report of a patient admitted in our clinic, requiring extensive investigations for diagnosis, with a favorable long-term outcome. Childhood interstitial lung disease (chILD) comprises a broad spectrum of rare respiratory disorders in children, with important differences compared with adults, including immunological and developmental abnormalities. The causes of this disorder often remain unknown. Information on chILD global epidemiology remains extremely limited because of a lack of systematic registries to collect these cases. Incidence estimates varied from 0.13 to 16.2 cases/100,000 children < 17 years of age/year, these figures underestimating the actual number of cases, considering the lack of a standardized definition system, and collected data being reported to small series of patients .Hypersensitivity pneumonitis (HP), also called extrinsic allergic alveolitis, is a form of immune-mediated inflammatory interstitial lung disease involving the distal respiratory airways, alveoli, and pulmonary interstitial tissue, which results from repeated exposure to a variety of inhaled environmental organic antigens. Being associated with the occupational setting, it is relatively uncommon in pediatric patients. It accounts for approximately 50 percent of all forms of interstitial lung disease in this age group of patients, but its real pediatric incidence is usually underestimated because of underdiagnosis . BetweenThe purpose of this article is to provide the current state of interstitial lung disease in children, revealing specific features of HP in this age group, underlined by a clinical case report of a child admitted to the Pediatric Department of the \u201cMarie S. Curie\u201d Emergency Children\u2019s Clinical Hospital, Bucharest, Romania.The diagnosis of chILD is most frequent in the first year of life, and more than 10 percent of cases are familial . In oldeThe chILD more common in infancy is further divided into four main categories, and each of these entities is subdivided into multiple pathologic conditions: diffuse developmental disorders ; lung growth abnormalities ; surfactant dysfunction disorders; and other specific conditions of unknown or poorly understood etiology  ,11,12.In older children, the classification system of chILD, according to history and clinical presentation, includes the host immune status (disorders of the immunocompetent or immunocompromised host), the presence of a systemic disease process  and the association of a vascular disorder masquerading as interstitial lung disease . The main causes of chILD in a normal host are related to infectious and post-infectious processes, exposure to environmental agents (HP), aspiration syndromes, and eosinophilic pneumonia. Interstitial lung disease etiology in immune-compromised hosts includes opportunistic infections, disorders related to therapeutic intervention or transplantation, and lymphoid infiltrates ,10,12.The clinical manifestations are often subtle or nonspecific. They vary from an asymptomatic presentation with accidental radiologic features suggestive of interstitial lung disease, to typical characteristic respiratory symptoms such as dyspnea, tachypnea, cough, exercise intolerance, tiring during feeding, respiratory infections, and hemoptysis. The onset of chILD is usually insidious, and the age of the patient is a key factor ,13,14. The physical examination of chILD is frequently abnormal, but the findings are nonspecific. Tachypnea, retractions, and basal inspiratory crackles are typically present. Chronic dry cough, cyanosis, clubbing, failure to thrive, and loud second heart sound due to pulmonary hypertension can be related, suggesting advanced disease . ExtrapuA systematic approach to the diagnosis of chILD is essential and it should begin with preparing a careful clinical history and performing a detailed physical examination, followed by non-invasive  and invasive  investigations . DetailsAfter excluding the most common known causes of lung disease, such as pulmonary infections, recurrent aspiration, structural airway abnormalities, bronchopulmonary dysplasia, congenital heart disease, immunodeficiencies, and cystic fibrosis, a chILD syndrome may be considered if the child meets at least three of the criteria presented in Once the chILD syndrome is established, further non-invasive investigations are performed. Laboratory tests rarely establish the diagnosis, but they may be helpful to exclude other systemic disorders that can be associated with interstitial lung disease. These can be grouped into immune function tests, autoantibodies studies, infection and inflammation markers, tests specific for environmental antigen exposure, and other non-specific analyses. Genetic tests are now available, allowing for the non-invasive diagnosis of a growing number of genetic etiologies in chILD .Pulmonary function tests and pulse oximetry are used for the assessment of severity in chILD . SpiromeImagistic techniques are necessary for the assessment of chILD. Chest radiography is usually the preferred initial imaging study. Frequently, it shows pulmonary abnormalities, with interstitial, alveolar, or mixed infiltrates, and hyperinflation. However, it rarely provides a specific diagnosis and, also, it may appear normal in early or mild forms of chILD ,23. ThusEvaluation for pulmonary hypertension should be considered early because of the significant impact on the prognosis. Echocardiography is usually preferred, and it should be performed to estimate pulmonary artery pressure and exclude cardiac defects. In rare situations, cardiac catheterization is necessary for a more accurate evaluation ,26.If the diagnosis cannot be made using non-invasive or less invasive investigations, and the patient has had persistent symptoms for at least three months or is progressively worsening, an invasive technique such as bronchoscopy with bronchoalveolar lavage (BAL) and lung biopsy for histopathological characteristics are recommended to determine a specific diagnosis ,27. The Treatment of chILD consists of supportive and pharmacologic therapy that is tailored to different types of disease. Few children do not require any treatment and recover spontaneously. Various drugs  are used based on data derived from small numbers of patients or studies in adults. However, no guidelines for the treatment of chILD have been proposed so far ,3,30.General supportive measures are recommended in all patients. These include adequate nutritional support, oxygen therapy for chronic hypoxemia, bronchodilators for reversible airway obstruction, treatment of intercurrent infections, avoiding exposure to environmental agents, and close attention to childhood immunizations, including annual influenza vaccinations and respiratory syncytial virus prophylaxis .Patients with underlying systemic disorders need specific treatment for the basal disease, such as anti-infective therapy for chronic respiratory infections, chemotherapy for malignancy, management of swallowing dysfunction, and gastroesophageal reflux in patients with chronic aspiration, or avoidance of the offending antigen in HP .If no specific therapy is available, systemic corticosteroids are still the most commonly used drug for selected chILD, considering that suppression of inflammation may be beneficial. A trial of corticosteroids  for >6\u20138 weeks may be used ,32. If gLung or heart\u2013lung transplantation may be an option for children who have severe and progressive disease and no response to therapy, including highly lethal diseases ,35,36.Aspergillus sp., Penicillium sp., Candida sp., and multiple molds) or inorganic agents , are rarely reported in this age group. Drugs, such as methotrexate, rituximab, and azathioprine, may also induce HP [Numerous organic  and inorganic  agents have been implicated in HP. The number of these factors is constantly growing. The most common etiologic agents in children result from pastime activities and consist of avian antigens, such as immunoglobulins, intestinal mucin presented in avian feces, and bloom covering birds\u2019 feathers. They induce a form of HP called pigeon-breeder lung or bird fancier\u2019s disease. Fungi, the causative antigen of classic farmer\u2019s lung disease  of allergen, the intensity, duration, and frequency of exposure, and the host immune response in susceptible subjects, are most likely involved. The repetitive or prolonged exposure to environmental inhalant allergens causes type III and type IV hypersensitivity reactions and secondary inflammation of the airways .HP has acute, subacute, and chronic phases, depending on the duration and intensity of exposure to the causative allergen and the patient\u2019s susceptibility. The clinical presentation includes respiratory symptoms such as cough, dyspnea during exercise or rest, tachypnea, and, less frequently, wheezing. Weight loss and fever can also be present. In patients with an acute form of HP, a temporal relation between the respiratory symptoms and antigen exposure can usually be identified. Symptoms mimic a flu-like disease with fever, cough, dyspnea, chest tightness, nausea, and malaise, beginning several hours (4\u20136) after exposure to the allergen and diminishing over the next 24 h. In cases of subacute or chronic HP, the association between antigen exposure and the development of symptoms may not be evident. Subacute HP develops gradually after prolonged low-dose exposure to the allergen. It is a common presentation of HP in children because of exposure to pet birds at home. Subacute HP with continued exposure to the antigen leads to a chronic form of the disease. Irreversible pulmonary fibrosis, honeycomb lung, and chronic respiratory failure may develop in the absence of exposure interrupting ,38,39.As with other forms of chILD, the diagnostic of HP is difficult and challenging in children and depends on integrating the clinical presentation, laboratory tests, imagistic findings, and histologic examination, but no study alone is diagnostic. The key consists of detailed environmental exposure history and, to make a correct diagnosis, the identification of the inciting antigen is essential. Elevated serum immunoglobulins precipitins against the inciting agents are detected in most affected patients . ImagistAspergillus sp., Penicillium sp., Candida sp., multiple molds, paints, or plastics). He also denied exposure to any drugs.We present the case of a previously apparently healthy 12-year-old boy, who was admitted to our clinic with a three-month history of repeated episodes of dry cough, dyspnea, wheezing, and exercise intolerance. Firstly, symptoms were suggestive of an acute respiratory tract infection , requiring recurrent hospitalizations. A diagnosis of asthma and bacterial pneumonia were suspected, and different therapeutic regimens were indicated, including oral antibiotics, short cures of oral steroids, antihistamines, antileukotrienes, inhaled bronchodilators, inhaled anti-inflammatory drugs, and antitussive agents, without any clinical improvement. Respiratory symptoms persisted, with periodic exacerbations, without an apparent trigger factor, and weight loss (2 kg) was additionally observed. Three months after the onset of symptoms, the patient was admitted to our clinic. Family history was negative for chronic disorders and he denied any environmental exposure to organic or inorganic agents , normocapnia (PaCO2 = 35 mmHg), normal complete blood count (CBC), negative inflammatory tests, and normal hepatic and renal function tests. Chest radiography showed diffuse interstitial infiltrates, predominantly perihilar , bronchodilator agents , systemic corticosteroids (intravenous Methylprednisolone), oxygen therapy, and respiratory nursing, with slight clinical improvement, relief of dyspnea, and oxygen therapy withdrawal one week after admission. However, pulmonary anomalies on clinical auscultation , dry cough and abnormal lung function tests persisted, with minimal alleviation. An HRCT scan of the chest was performed, showing a heterogeneous aspect of lung structure, with diffuse bilateral ground-glass opacities. See .As part of a differential diagnosis and to establish the etiology of an interstitial lung disease syndrome, we performed additional complex biological analysis. Considering the patient\u2019s age and his unremarkable perinatal history, infancy-specific diseases, such as developmental disorders, alveolar growth abnormalities or surfactant dysfunction disorders, were unlikely. We evaluated the patient\u2019s immune status, with no evidence of tumors on imagistic investigations and negative tests for immunodeficiencies . Thus, causes of chILD associated with the immune-compromised host were excluded so we continued work-up for pulmonary disorders of a normal host. Bacterial and fungal cultures, as well as the viral respiratory panel, including SARS-CoV testing, were negative, excluding infectious etiology. Persistent cough, dyspnea, weight loss, and anorexia were suggestive of pulmonary tuberculosis. However, the patient had no history of exposure, and a direct smear examination of sputum along with QuantiFERON-TB Gold evaluation was negative. Considering recurrent respiratory symptoms with tachypnea, hypoxemia, cough, and exercise intolerance, the sweat chloride test and serum alpha 1 antitrypsin level were evaluated, with normal values, excluding cystic fibrosis and alpha 1 antitrypsin deficiency, respectively. A normal cardiovascular system clinical examination and electrocardiogram (ECG), along with a normal echocardiography aspect, excluded a cardiac etiology of the symptoms, as well as pulmonary hypertension. We also performed immunology studies to identify connective-tissue disorders predisposing to diffuse lung disease. Inflammatory markers , rheumatoid factor, antinuclear antibody, anti-double-stranded DNA antibody, perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA), cytoplasmic anti-neutrophil cytoplasmic antibody (c-ANCA), complement system measurements  and circulating immune complexes (CICs) in blood were all negative. Thus, together with the absence of extrapulmonary manifestations, they excluded the autoimmune etiology. HP was also considered, but anamnesis was repeatedly negative for antigen exposure. For additional diagnostic purposes, we performed a flexible bronchoscopy, which showed a normal airway anatomy. BAL bacterial and fungal cultures were negative, and cytologic studies excluded alternative causes of chILD such as pulmonary hemorrhage, pulmonary histiocytosis, alveolar proteinosis, and aspiration. BAL cellular analysis revealed lymphocytosis (56%), with an important predominance of CD8+ lymphocytes and a decreased CD4+/CD8+ lymphocytes ratio, strengthening the suspicion of interstitial lung disease. However, considering that, unlike adults, examining BAL fluid can be distinctive but not pathognomonic for certain diseases in children, we decided to perform a lung biopsy using a video-assisted thoracoscopy procedure. Histopathological examination revealed diffuse interstitial and alveolar inflammatory infiltration with numerous lymphocytes, and the absence of neutrophils. Cellular inflammation surrounding bronchioles and reducing alveolar spaces, and reactive type II pneumocyte hyperplasia were present. Lung parenchyma with non-necrotizing granuloma, and peribronchiolar and interstitial fibrosis were also described. Tissue special stains for mycobacteria and fungus were negative. The histopathological aspect of the lung biopsy was characteristic of subacute hypersensitive pneumonitis . Considering all these data, we resumed the rigorous history of the patient from all family members regarding a possible contact of the patient with environmental factors, revealing significant exposure to a large quantity of avian antigens (quail and parakeet feathers and droppings), near his home, for one year before the onset of symptoms. To confirm the causative relation between avian antigen exposure, clinical manifestations and imagistic features, we performed lymphocyte transformation testing for quail and parakeets, demonstrating type IV sensitization against quail feathers. We could not measure bird-associated IgG antibodies; this test was not accessible in our clinic. Thus, considering anamnestic, clinical and paraclinical exams, we confirmed the diagnosis of subacute HP secondary to avian antigen (quail) exposure. To obtain acute symptomatic relief, we continued systemic corticosteroid therapy using intravenous Methylprednisolone (1 mg/kg/day) for two weeks, followed by a gradual taper to the maintenance dose of 0.5 mg/kg/day of oral prednisolone, which permitted symptom control. High doses of inhaled corticosteroids were added, and the family was advised to eliminate the offending avian antigens from the child\u2019s environment. We established monthly follow-up, and treatment resulted in gradual alleviation of symptoms and slow improvement of pulmonary function. The three months\u2019 follow-up examination revealed normal pulmonary auscultation and cough remission, with the persistence of moderate exercise intolerance. Imagistic evaluation using chest HRCT showed improvement of pulmonary opacities with the resolution of ground-glass attenuation but the presence of some diffuse hypoventilation zones. The treatment was guided by a favorable clinical response, pulmonary function, and radiological improvement, permitting intermittent administration of prednisone. As a second anti-inflammatory line, we added Azithromycin  for the next three months. Exposure to the causative avian antigen was completely excluded from the patient\u2019s environment, and he remained asymptomatic on the next follow-up visits. Significant improvement of respiratory symptoms and pulmonary function permitted weaning of the oral corticosteroid six months after following initial presentation See . HoweverHypersensitive pneumonitis is an exceptional interstitial lung disease in children. The diagnosis is difficult and complex investigations are usually needed. Exposure history to an environmental antigen is the key element for diagnosis. A rigorous anamnesis is required in a patient with respiratory symptoms that cannot be explained. Clinical characteristics and routine test abnormalities are suggestive. Still, they are not usually pathognomonic for HP and they often overlap with a multitude of other immune-mediated or infectious lung diseases, as well as cystic fibrosis ,43. RadiThis paper\u2019s aim is to present the current state of interstitial lung disease in children, regarding specific aspects of diagnostic investigation in this age group, based on a case report of a pediatric patient with histologically confirmed subacute hypersensitive pneumonitis. The peculiarity of this case was the difficulty of establishing the positive diagnosis, the initial anamnesis being nonspecific with denial of exposure to any antigen. Thus, complex paraclinical examinations, including invasive investigations, were necessary. The history of prolonged exposure to avian antigen (quail) was later confirmed by the patient\u2019s parents and the immune response to this trigger was highlighted. The initial evaluation included clinical assessment, laboratory testing and imagistic investigations, suggesting interstitial lung disease. Chest HRCT, revealing ground-glass opacities, was suggestive for hypersensitive pneumonitis, but the absence of environmental antigen exposure did not sustain this diagnosis, and more invasive procedures, including flexible bronchoscopy with BAL and lung biopsy, for histopathological analysis were necessary. Particularly in our case, BAL cellular analyses revealed a decreased CD4+/CD8+ lymphocytes ratio, a typical but rare feature of chILD. We made the diagnosis of chILD syndrome, but we could only determine the causative agent after performing lung tissue analysis because of the clinical history that, firstly, was not suggestive of allergen exposure. As in our patient, histopathologic examination of lung biopsy is usually confirmatory, especially when the initial evaluation is not sufficiently convincing of HP. The patient\u2019s family finally revealed anamnestic data of prolonged exposure to avian antigens. Therefore, considering this information, together with recurrent and persistent pulmonary manifestation worsening after antigen exposure, pulmonary auscultation anomalies with bibasilar rales, severe restrictive and obstructive ventilatory dysfunction, compatible changes in chest HRCT, BAL lymphocytosis, and characteristic histopathological features of lung biopsy, the diagnosis of subacute HP secondary to quail antigen exposure was sustained. The positive lymphocyte transformation testing supported HP diagnosis and confirmed the causative relation between avian antigen exposure, clinical manifestations, and imagistic features. A difficult anamnesis created a delay in etiology determination so that anatomopathological examination represented the key to diagnosis in our case. However, until the lung biopsy result was available, we performed extensive biological and imagistic work-up since numerous systemic diseases can mimic HP. Having all the clinical, biological and imagistic data suggestive for the diagnostic, we strongly believe that, if the history of chronic exposure to avian antigens had been revealed earlier, we would not have needed to perform a VATS lung biopsy. Thus, the anamnesis revealing chronic exposure to avian antigens, leading to a positive diagnosis, was the key element in this case. However, initiating treatment and avian antigen exposure removal in time permitted significant clinical improvement and complete resolution of imagistic abnormalities. The early diagnosis of chILD, including HP, is very important for the therapeutic approach. The timely administration of effective treatment help avoid frequent hospitalizations and prevent progression to irreversible lung damage and pulmonary sequela such as fibrosis, chronic respiratory failure, and cardiac insufficiency.Childhood ILD represents a large spectrum of rare and heterogeneous disorders, with important differences compared with adults. Although an increasing proportion of cases can be diagnosed using laboratory, genetic or imagistic investigations, histopathological exam of the lung biopsy still has a significant practical use. While HP is a very rare condition in children, it represents the most frequent interstitial lung disease in this age group. The diagnosis may be challenging because of difficulty identifying triggering factors and overlapping with other forms of ILD. However, it must be considered in any patient with recurrent or prolonged respiratory symptoms, without an obvious etiology. A good prognosis of HP depends on timely recognition and early treatment, preventing progressive pulmonary fibrosis instauration."}
+{"text": "Six years ago, in 2015, the Focused Ultrasound Foundation sponsored a workshop to discuss, and subsequently transition the landscape, of focused ultrasound as a new therapy for treating glioblastoma.This year, in 2021, a second workshop was held to review progress made in the field. Discussion topics included blood\u2013brain barrier opening, thermal and nonthermal tumor ablation, immunotherapy, sonodynamic therapy, and desired focused ultrasound device improvements.The outcome of the 2021 workshop was the creation of a new roadmap to address knowledge gaps and reduce the time it takes for focused ultrasound to become part of the treatment armamentarium and reach clinical adoption for the treatment of patients with glioblastoma. Priority projects identified in the roadmap include determining a well-defined algorithm to confirm and quantify drug delivery following blood\u2013brain barrier opening, identifying a focused ultrasound-specific microbubble, exploring the role of focused ultrasound for liquid biopsy in glioblastoma, and making device modifications that better support clinical needs.This article reviews the key preclinical and clinical updates from the workshop, outlines next steps to research, and provides relevant references for focused ultrasound in the treatment of glioblastoma. The technology has made great advancements since the first workshop on this topic, which was held in 2015 [Focused ultrasound is an early stage, therapeutic technology that offers possible adjuvant or alternative treatment strategies for glioblastoma (GBM). In May 2021, the Focused Ultrasound Foundation (The blood\u2013brain barrier (BBB) is an obstacle to the effective treatment of brain tumors with therapeutic agents. Although there are some portions of gliomas that display magnetic resonance imaging (MRI) contrast enhancement suggesting \u201cleaky\u201d vessels that allow extravasation of large molecules, it is known that tumor cells extend far beyond the borders of these enhancing areas; therefore, the intact BBB remains an obstacle in the effective delivery of anti-cancer therapies . When coMicrobubbles are an essential component for focused ultrasound\u2013induced BBBO, because the focused ultrasound makes them oscillate, and this vibration creates penetrable gaps in the BBB\u2019s tight endothelial junctions. Various microbubbles have been used for focused ultrasound\u2013induced BBBO, including commercial ultrasound contrast agents and bubbles specifically designed for focused ultrasound BBBO. Agents that are designed for BBBO should (i) easily reach stable cavitation with ultrasound, (ii) have in vivo stability in the blood circulation, and (iii) have shelf stability for storage purposes , 11. Theoptimal sonication parameters for BBBO; ideally, the parameters used for each patient will lead to maximum drug delivery with minimal tissue damage. They agreed that the best focused ultrasound settings for inducing BBBO will vary based on the size of the molecule being delivered and the type of microbubble being used.Several focused ultrasound parameters should be considered for safely and effectively inducing BBBO. The sonication parameters used affect the depth of ultrasound penetration and the duration of opening. Nathan McDannold, PhD, reviewed these variables and their common values Table . Other fAfter microbubble administration and the application of low-intensity focused ultrasound to the target area, the desired effect of increased permeability of the BBB must be confirmed. Michael Canney, PhD, Nathan McDannold, PhD, Antonis Pouliopoulos, PhD, and Raag Airan, MD, PhD, discussed methods used to confirm BBBO , 15. TheFour presentations highlighted clinical trials involving targeted drug delivery with focused ultrasound\u2013induced BBBO. Nir Lipsman, MD, PhD, Graeme Woodworth, MD, Adam Sonabend, MD, and Ko-Ting Chen, MD, each shared their Phase I and II clinical trial experience. To date, the safety and feasibility of focused ultrasound\u2013induced BBBO has been established with three different clinical devices: InSightec ExAblate, CarThera Sonocloud, and NaviFUS Fig.\u00a0. OngoingThe panel discussion moderated by Nir Lipsman, MD, PhD, included Jin Woo Chang, MD, PhD, Alexandra Golby, MD, Adam Sonabend, MD, Roger Stupp, MD, and Graeme Woodworth, MD, who raised important unanswered questions surrounding ongoing and future clinical trials. Most of the current clinical trials are treating patients with recurrent GBM, but there should be more consideration for upfront treatment when there is less tumor heterogeneity. Outcome measures should include progression-free survival and overall survival. Previous studies have shown that greater doses of temozolomide (TMZ) do not affect outcome, so increasing the concentration of TMZ at the site of BBBO is not likely to increase efficacy . A contrManmeet Ahluwalia, MD, moderated a panel that included John de Groot, MD, Amy Heimberger, MD, and Patrick Wen, MD, who commented on focused ultrasound\u2013enhanced delivery of immunotherapeutic agents to brain tumors. Immunotherapy has become a pillar of cancer therapy, yet GBMs have yet to be impacted by immunotherapeutics that have helped treat other cancers. Focused ultrasound is a promising technology to potentiate immunotherapeutics . No clinKelsie Timbie, PhD, presented a prerecorded talk on the current state of focused ultrasound immunomodulation research. She provided a review of the literature \u201324 and dDuring the panel discussion, moderator Michael Lim, MD, and panelists Costas Arvanitis, PhD, Timothy Bullock, PhD, Theresa LaVallee, PhD, and Tao Sun, PhD, described several of these immune responses to focused ultrasound and discussed ways to monitor them. Future research suggestions included considering the intersection of focused ultrasound\u2013enhanced immunomodulation with GBM lymphatics and more exactly determining the role of focused ultrasound for GBM immunomodulation. Additional studies are needed to understand the interplay between the various focused ultrasound mechanisms and immunomodulation. New projects could investigate whether focused ultrasound can induce trafficking and activation of immune cells and explore whether focused ultrasound can activate microglia and whether this microglia activation is beneficial in GBM.Other focused ultrasound mechanisms of action, such as sonodynamic therapy (SDT), radiation sensitization, and histotripsy have been investigated in preclinical models and are emerging in clinical trials.Francesco Prada, MD, discussed \u201cSonodynamic Therapy: Concept, Mechanisms, and Application to Brain Cancer\u201d in his prerecorded presentation see C has beeA prerecorded lecture by Frederic Padilla, PhD, the \u201cRole of Focused Ultrasound for Radiosensitization of GBM,\u201d see D 33, 3434. Greg Zhen Xu, PhD, moderated a discussion on histotripsy as a form of mechanical focused ultrasound ablation. Panelists Tatiana Khoklova, PhD, Joan Vidal-Jove, MD, PhD, and Eli Vlaisavljevich, PhD, provided prerecorded videos on histotripsy for brain applications  are being developed for use in treatment monitoring in focused ultrasound GBM applications.Benjamin Ellingson, PhD, provided an overview lecture on imaging modalities for GBM monitoring see  below. TPatrick Wen, MD, moderated a discussion with Benjamin Ellingson, PhD, Ali Nabavizadeh, MD, and Max Wintermark, MD, as panelists. Various challenges still exist while evaluating MR imaging studies for extent of tumor infiltration, treatment response, and differentiating progression from pseudo progression. Positron emission tomography scanning with varying tracers has contributed to our understanding of tumor metabolism and can be used to understand how focused ultrasound works and help differentiate progression from pseudo progression. In the future, machine learning and artificial intelligence will assist in evaluating subtle changes in imaging findings during treatment monitoring.Ying Meng, MD, PhD, summarized the current knowledge of focused ultrasound\u2013enabled LB for brain tumors see  below. TModerator Chetan Bettegowda, MD, PhD, and panelists Hong Chen, PhD, Ying Meng, MD, and Houtan Noushmehr, PhD, discussed numerous technical issues, such as when to obtain LB after focused ultrasound\u2013induced BBBO, what volume of tissue should be targeted, and which sonication parameters are optimal and how they will vary depending on the size of the analyte. There was consensus regarding the promise of focused ultrasound\u2013induced LB to be used as a progression monitoring tool and to discern progression from pseudo progression. A specific advantage of focused ultrasound is its ability to spatially target a discrete region of the tumor or peritumoral tissues to interrogate the analytes in that specific region.Gautam Mehta, MD, and Gregory Clement, PhD, provided the US Food and Drug Administration perspective on how oncology trials are monitored and described regulatory considerations for conducting combination trials using focused ultrasound. Jessica Foley, PhD, moderated a panel discussion that included Amy Barone, MD, Bennet Blumenkopf, MD, Greg Clement, PhD, Subha Maruvada, PhD, Gautam Mehta, MD, and Matthew Myers, PhD, who commented on on what the FDA requires for drug-device combination procedures and those that combine the use of microbubbles and focused ultrasound. The FDA considers both microbubbles and focused ultrasound devices. A lively discussion covered several aspects of this type of clinical trial design. Evidence for reimbursement, another important aspect of clinical trial design, was discussed by Stephanie Kennan, MBA, and Dee Kolanek, AAS, and moderated by Jessica Foley, PhD. The workshop\u2019s white paper includes more information on these topics .The Focused Ultrasound Foundation\u2019s second glioblastoma workshop convened an expert group of clinicians and scientists to share the most current preclinical and clinical advancements in the field of focused ultrasound for GBM. The most advanced application is focused ultrasound\u2013induced BBBO to enhance the delivery of therapeutics to brain tumors, with several ongoing clinical trials. Gaps still exist with this therapy, and most notably include the lack of a well-defined algorithm to confirm and quantify drug delivery following BBBO and a lack of generalizable knowledge on the effect that the type and administration route of microbubbles has on BBBO. These gaps have been identified, and the Foundation is actively working with teams of researchers to address them.In addition to focused ultrasound\u2013induced BBBO, other promising mechanisms are beginning to gain traction for treating brain tumors. SDT and histotripsy are among the newer focused ultrasound techniques that have particularly encouraging outlooks. Focused ultrasound\u2013enhanced LB is another promising application. The Foundation is dedicated to leveraging its resources to strengthen the science, encourage collaboration, and move these applications forward to improve the lives of patients with GBM as soon as possible.https://www.fusfoundation.org/the-foundation/programs/research.If you have research or research questions that align with the Focused Ultrasound Foundation\u2019s mission and would like to speak to one of the Brain Tumor Program leads, please contact Lauren Powlovich or Suzanne LeBlang or submit an abstract for funding at:"}
+{"text": "Alphavirus, family Togaviridae. Typically spread by mosquitoes, EEEV, VEEV, and WEEV induce febrile illness that may develop into more severe encephalitic disease, resulting in myriad severe neurologic sequelae for which there are no vaccines or therapeutics. Here, we summarize the clinical neurologic findings and sequelae induced by these three encephalitic viruses and describe the various animal models available to study them. We emphasize the crucial need for the development of advanced animal modeling combined with the use of telemetry, behavioral testing, and neuroimaging to facilitate a detailed mechanistic understanding of these encephalitic signs and sequelae. Through the use of these systems, much-needed therapeutics and vaccines can be developed.Eastern (EEEV), Venezuelan (VEEV), and western equine encephalitis viruses (WEEV) are members of the genus  Togaviridae family [Alphaviruses are members of the e family . These ve family . The 9.7e family ,4. The fAlphavirus can be grouped both antigenically and geographically into eight antigenic/genetic complexes [There are over 30 identified species of alphaviruses . Membersomplexes ,5. Geogromplexes ,5,6. Oldomplexes . Human pomplexes . New Woromplexes , and easomplexes . Most alphaviruses are transmitted by hematophagous arthropods ,8. WhileThe objective of this review is to briefly summarize the clinical findings and sequelae of the three main encephalitic alphaviruses causing severe disease and sequelae in humans: EEEV, VEEV, and WEEV. Current animal models will also be reviewed, with a focus on their manifestations of various sequelae. Complete understanding of the mechanisms driving pathogenesis and sequelae for these encephalitic viruses is crucial for the development of vaccines and therapeutics. Examining where the deficiencies and advantages lie within the available animal models can inform the development of models that will accurately portray the diseases they study. In doing so, therapeutics can be developed for those suffering these debilitating sequelae. New World alphaviruses are known to induce encephalitic sequelae. The three predominant viruses in this category include EEEV, VEEV, and WEEV . There aEEEV occurs predominately throughout eastern North America as well as periodically in the Caribbean ,19. VariFew cases of EEE are reported each year, an average of 11, and epidemiologic investigations suggest that only around 4\u20135% of infections result in reported disease ,22. The At least half or as high as 90% of neurologic cases develop lasting sequelae ,24,27, iAnimal modeling of EEE in mice, guinea pigs, and macaques suggests that viral entry into the brain, inducing the associated neurologic disease and sequelae, may occur through the olfactory bulb in the case of aerosol exposure ,27,32. HHowever, due to the small number of annual cases and typically high mortality rate, further clinical characterization of EEEV-induced sequelae is difficult. The development of therapies to minimize sequelae and promote recovery relies on animal modeling. Current lethal models resulting in neurologic signs include mice, golden hamsters, guinea pigs, and non-human primates including cynomolgus macaques and the common marmoset see  23,27,3,40,41,42BALB/c mice intranasally inoculated with EEEV develop encephalitis and neurologic signs just prior to death, including tremors and altered behavior, as indicated by a fixed gaze, inability to respond to stimuli, and reduced motor control . C57BL/6Advancements in the application of telemetry and remote monitoring have given researchers great insight into the development of sequelae using a cynomolgus macaque model for EEE ,38,41,43Recently, more advanced telemetric devices have been implanted into macaques prior to infection, allowing researchers to conduct constant monitoring of EEG, ECG, heart rate, activity, body temperature, respiration rate, and blood pressure . These pVenezuelan equine encephalitis virus (VEEV) occurs from Mexico through northern South America ,44, and The majority of VEE cases are symptomatic but present only with signs of nonspecific febrile illness, which occur after a short incubation time ranging from 27.5 h to four days post-exposure ,45. SignNeurologic signs appear in an estimated 14% of cases, with case fatality rates ranging from 1 to 10% ,49. ThesDue to the high rates of misdiagnosis and a paucity of autopsy and other clinical samples, full characterization of clinical VEE is difficult. Current data indicate that VEEV entry to the murine brain after subcutaneous exposure may occur in areas lacking a blood\u2013brain barrier, including the hypothalamus, pineal body, area postrema, and the anteroventral third ventricle region . Other rBALB/c mice receiving either aerosol or subcutaneous inoculation develop lethal illness, succumbing to infection before the neurologic phase of disease ,53,54. CVEEV infection is non-lethal in the cynomolgus macaque model and rarely results in neurologic signs or sequelae, consistent with most human infections . CutaneoAs neurologic signs of disease in macaques have been unreliable, recent applications of advanced telemetry to monitor intracranial pressure, body temperature, and EEG measurements have contributed greatly to the understanding of neurologic disease . CombineWEEV is found throughout Canada, northern South America, Central America, and the western and central United States ,14,66. IThe WEEV incubation time ranges from 5 to 10 days . SimilarNeurologic sequelae following infection occur in up to 30% of cases . Half ofHistorically, WEE case reports offer perhaps the most insights on neurologic sequelae following any alphavirus infection . AdditioMurine WEE lethality appears to be age and strain specific ,84,85. WCynomolgus macaques infected with WEEV via the subcutaneous route do not develop measurable viremia or readily detected clinical signs of disease . AerosolIn summary, alphavirus infections may cause debilitating disease with sequelae, whose mechanisms are yet to be fully elucidated. New World alphaviruses, including EEEV, VEEV, and WEEV, induce myriad neurologic sequelae, including seizures, coma, behavioral changes, cognitive impairments, and convulsions, among others ,73,74,75Despite the importance of these alphaviral sequelae, animal modeling has yet to fully elucidate their mechanisms; no model reliably reproduces all neurologic aspects of human alphaviral encephalitis. Small animal models including mice and hamsters are often inconsistent in their reproduction of neurologic signs and sequelae based on age, route of infection, and virus strain ,81,84,85Arguably the greatest recent contribution to understanding the various sequelae of neurologic alphaviral disease is the addition of advanced telemetry to non-human primate models ,41,43,59"}
+{"text": "Following the publication of the original article  we were The correct author names are shown here below:Paolo Cavarzere, Andrea Gastaldi, Francesca Marta Elli, Rossella Gaudino, Erika Peverelli, Milena Brugnara, Susanne Thiele, Francesca Granata, Giovanna Mantovani and Franco AntoniazziThe author names have been corrected in the author list of this Correction and updated in the original article."}
+{"text": "Bee pollen is a natural cocktail of floral nectar, flower pollen, enzymes, and salivary secretions produced by honeybees. Bee pollen is one of the bee products most enriched in proteins, polysaccharides, polyphenols, lipids, minerals, and vitamins. It has a significant health and medicinal impact and provides protection against many diseases, including diabetes, cancer, infectious, and cardiovascular. Bee pollen is commonly promoted as a cost-effective functional food. In particular, bee pollen has been applied in clinical trials for allergies and prostate illnesses, with a few investigations on cancer and skin problems. However, it is involved in several patents and health recipes to combat chronic health problems. This review aimed to highlight the clinical trials and patents involving bee pollen for different cases and to present the role of bee pollen as a supplementary food and a potential product in cosmetic applications. Apis mellifera L.) produces several beneficial entities, including honey, propolis, royal jelly, bee venom, bee pollen, beehive air, and beebread. These products have been used in traditional medicine for thousands of years, and there is increasing interest in their application in modern medicine kaempferol, 3-O-[6\u2032-O-(trans-p-coumaroyl)-\u03b2-D-glucopyranosyl]kaempferol, and gallic acid (GA), had a hypoglycemic effect for patients with type 2 diabetes. Through interactions with glucose transporters, the three phenolic compounds decrease glucose absorption and transport. In addition, molecular docking showed that phenolic compounds have the ability to form hydrogen bonds with D-glucose and amino acids . Be. Be72]. NK cells . Four huNK cells ,74.Fructus lycii bee pollen, which are beneficial for immunological function and additionally have anti-aging and anticancer effects [According to the patents published, bee pollen in combination with other materials has a positive impact on immunity, as shown in  effects  . The levels of total cholesterol (TC), asymmetric di-methylarginine (ADMA), oxidized low-density lipoprotein (ox-LDL), angiotensin-converting enzyme (ACE), and angiotensin-converting factor (ACEF) decreased significantly .Salviae miltiorrhizae, bee pollen, and kudzuvine root were used in a mixture that improved cardiovascular disease symptoms [As shown in symptoms .Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeurgionsa, as well as fungi such as Candida albicans [Helicobacter pylori [Because bee pollen comprises flavonoids and phenolic acids, its ethanol extracts are beneficial against Gram-positive and Gram-negative bacteria such as albicans ,123. Thealbicans . Wall-brr pylori . Bee polr pylori . Furtherr pylori .Bee pollen is used in food processing due to its nutritive, chemical, physical, and techno-functional properties . It has Rose bee pollen has a substantial impact on acne therapy when taken as tablets, oral liquid, capsules, electuary, recreational food, or a beverage. It contains proteins, minerals, vitamins, vital amino acids, and fatty acids such as linoleic and linolenic acids . MelissaPollen from bees has been used since prehistoric times due to its remarkable medical potential. Bee pollen has gained considerable interest because of its proven nutritional value, particularly in the fields of functional and health-beneficial manufacturing. Many ailments, including diabetes, cancer, cardiovascular diseases, prostatitis, and microbial and immune diseases, have been treated with bee pollen. The use of bee pollen in bread, fried, stewed, and canned foods, pastries, and beverages increases the nutritional value of the product, as well as its antioxidant and sterilizing properties. Scientists should apply the results from patent reports in clinical trials.However, there are limitations in the use of bee pollen-based products due to their complexity and variability, which highlight the need for standardization before safe therapeutic usage."}
+{"text": "Microorganisms have dynamic and complex interactions with their hosts. Diverse microbial communities residing near, on, and within the plants, called phytobiome, are an essential part of plant health and productivity. Exploiting citrus-associated microbiomes represents a scientific approach toward sustained and environment-friendly module of citrus production, though periodically exposed to several threats, with Huanglongbing (HLB) predominantly being most influential. Exploring the composition and function of the citrus microbiome, and possible microbial redesigning under HLB disease pressure has sparked renewed interest in recent times. A concise account of various achievements in understanding the citrus-associated microbiome, in various niche environments viz., rhizosphere, phyllosphere, endosphere, and core microbiota alongside their functional attributes has been thoroughly reviewed and presented. Efforts were also made to analyze the actual role of the citrus microbiome in soil fertility and resilience, interaction with and suppression of invading pathogens along with native microbial communities and their consequences thereupon. Despite the desired potential of the citrus microbiota to counter different pathogenic diseases, utilizing the citrus microbiome for beneficial applications at the field level is yet to be translated as a commercial product. We anticipate that advancement in multiomics technologies, high-throughput sequencing and culturing, genome editing tools, artificial intelligence, and microbial consortia will provide some exciting avenues for citrus microbiome research and microbial manipulation to improve the health and productivity of citrus plants. Plants recruit a broad array of microbes surviving in different tiers of their habitat viz., rhizosphere, phyllosphere, and endosphere, predominantly represented by bacteria, archaea, fungi, actinomycetes, protists, and other living entities. These microbial communities constitute structural, as well as functional micro-communities, associated with various parts of the plants under natural environment, are collectively coined as plant microbiomes or phytobiome . These mRhizosphere microbiome plays an important role in channelizing many essential soil activities such as decomposition, mineralization, aggregate formation, and plant disease biocontrol, all of which are crucial to optimize citrus productivity . A betteCandidatus Liberibacter asiaticus (CLas) is restricted to grow and colonize within phloem tissues and does not interact with other microbial flora of the citrus microbiome directly, unless they survive in the phloem of citrus  could be successfully cultured in the system of co-culture with Pseudomonadaceae, Comamonadaceae, Microbacteriaceae, and Flavobacteriaceae in a modified culture medium with the addition of essential vitamins and nutrients  based studies have suggested that the core microbiome is a cluster of micro-communities that typically reside inside the host\u2019s microbiome . The corPseudomonas, Sphingobium, Chittinophaga, Agrobacterium, Steroidobacter, Mesorhizobium, Dokdonella, Cupriavidus, Novosphingobium, Rhizobium, Hylemonella, PhenylobacteriumRoseateles, Niastella, Devosia, Halomonas, Rhodoplanes, Sphingomonas, Streptomyces, and Bacillus. Numerous genera of microbes are associated with these core microbiota, identified as beneficial microorganisms for the plant in other systems. These beneficial microbial members might benefit in regulating root development, upholding hormonal balance, facilitating mobilization and acquisition of nutrients, and suppressing the disease expression in the host plants  during 1900\u20132021 showed as an upsurge in systematic research on proposal theme, only after 2010. Whereas prior to the year 2000, hardly any research work on these issues could gather any news in the research arena. Of 4,739 publications, a maximum of 2,239 publications dealing with nutrients and HLB followed by 1,135\u20131,152 publications covering the issues like citrus metagenome or metagenome and soil health, and only 213 publications touching metagenome and HHLB, vividly showcase the temporal shifts in research interest worldwide. The rise in publications after 2010 was accountable for increased access to technology at affordable prices.The functionality of the citrus microbiome, where different microbial communities keep interacting with plants is now more precisely decoded through HTS sequencing and metagenomics (metatranscriptomics and metaproteomics).HTS-based marker gene tags (iTAG) targeting taxonomic as well as functional genes are employed for profiling the composition, organization, and spatial distribution of micro-communities. With the help of iTAG sequencing, studies on microbiome residing inside or on the members of crops such as rice , millet Agrobacterium, Bradyrhizobium, Burkholderia, Cellvibrio, Cupriavidus, Mesorhizobium, Paraburkholderia, Pseudomonas, Rhizobium, Sphingomonas, Variovorax, and to harness the power of the microbiome for improving plant health and fruit yield  is an essential element for the synthesis of chlorophyll, nucleic acid, amino acids, and the energy transfer molecule adenosine triphosphate (ATP) for the plants . In the Bacillus, Burkholderia, Pseudomonas, Sphingobium, Chittinophaga, Agrobacterium, Steroidobacter, Mesorhizobium, Dokdonella, Cupriavidus, Novosphingobium, Rhizobium, Hylemonella, Phenylobacterium, Roseateles, Niastella, Devosia, Halomonas, Rhodoplanes, Sphingomonas, and Enterobacter), actively involved in the solubilization and availability of micronutrients in the soil  infected the citrus roots causing shifts in the rhizosphere microbiome, leading to an increase in the population of Bacillus megaterium and Burkholderia cepacia having a deleterious effect on the growth of root rot pathogen, Phytophthoranicotianae , is considered the most pathogenic amongst all the Liberibacter species reported until now , ascorbate peroxidase (APX), and catalase (CAT)] for the enzymatic antioxidants were down-regulated, resulting in depleting the plant\u2019s ability to scavenge an increased level of H2O2  loaded in CLas-infected roots, while Rhizobiumpopulation depleted. The abundance of genes involved in carbohydrate metabolism, glycolysis, starch and sucrose metabolism, amino sugar, and nucleotide sugar metabolism was reduced in the citrus rhizosphere microbial community of citrus rhizosphere during the process of HLB-infection. These results were highly effective in understanding the rhizosphere responses to HLB disease and the possible development of microbial antagonists-based products against HLB , Lysobacteris (known to suppress damping-off disease), and Methylobacillus . While Pseudomonas protegens known to produce 2,4diacetylphlorogucinol and pyoluteorin were detected in CLas infected leaves for protecting the host plants. These changes in microbial patterns in CLas infected citrus trees offer some useful insights into the successful management of HLB  and Bacillus, Curtobacterium, and Pantoea . Purified natural products having anti- CLas were also identified from the fungus, C. cladosporioides  in protecting citrus against HLB was unfolded  systematic determination of structural makeup, linking citrus plant traits with microbial traits in a mutually beneficial domain and genetic potential of the citrus-associated microbiome to unlock multilateral interspecies interactions and metabolic features; (ii) ensuring efficacy, accuracy, and reproducibility in experimental vs. natural environments to move beyond cause-and-effect relationship; (iii) bioprospecting of novel growth-promoting and antagonistic microorganisms (and/or their biomolecules) isolated from citrus-associated microbiomes; (iv) development and prediction of host genotype, microbiome genotype, associated environment, and controlling interactions to modify microbial formulations; and (v) advancement and implementation of standardized processes for collating consistent and well-annotated metadata analysis through HTS and metagenomics. These suggested gaps are major challenges to be explored to maintain and protect soil and plant health in a cost-effective manner, where the citrus microbiome would be a service provider.Broader use of multi-omics approaches, network analysis, microbial consortia, genome editing, artificial intelligence, and high throughput culturing would greatly elevate our understanding of the citrus microbiome and further unravel the microbiome\u2019s potential toward improving citrus health via better rhizosphere ecological interventions. The full potential of citrus-associated functional genes and secondary metabolites is barely explored as yet and therefore warrants continued experimentation.AS, AD, PJ, and PB developed the concept of review. AS, AD, FA, and RB compiled the literature. FA and RB designed the manuscript. AS, AD, PJ, PB, FA, and RB involved in writing and editing the manuscript in its present form. All authors contributed during the preparation of this study.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Halorhynchusremii Chamorro & Steiner, sp. nov. is described from Madagascar. This new species is the third known species of the genus and the first for Africa. Halorhynchusremii is compared to other psammophilous, anophthalmous onycholipine cossonines. Transoceanic dispersal between Australia and Madagascar and sand burrowing adaptation are briefly discussed. A key to the species is provided. Halorhynchus Wollaston, 1873, is a cossonine genus known from two species in Western Australia: Halorhynchuscaecus Wollaston, 1873 .On the sandy shores of southwestern Madagascar, the second author (WS) dug around the roots of sprawling vegetation, under natural beach debris of twigs and seaweed and hand collected, during the day, a single anophthalmous cossonine weevil with psammophilous features. Since 1993 the specimen has remained identified only to family-level in the National Weevil Collection  LCh determined this species to belong to Halorhynchus, a cossonine genus, known until now only from Western Australia. In the results we indicate the characters that support this determination.During an ongoing study of the weevils of Madagascar, the first author (LCh) was made aware of this weevil. Initially, the specimen appeared to represent a new genus, as research into possible African anophthalmous, psammophilous cossonines did not yield any results. However, in 2019, while studying Caulophilus Wollaston  in the \u2018outer beach\u2019, which we assume corresponds to the back shore or coastal sand dune area. Halorhynchuscaecus was collected by Spinifex sp. (Poaceae).Not much is known about the biology of Pentebathmusinsularis Richard and P.ovalis Richard (Dryotribini)  . Here weHalorhynchus was created using SimpleMappr  in Washington, D.C. As part of the permit agreement reached with the Malagasy government, holotypes were to be kept at the USNM with identified duplicates, if any, at the University of Madagascar Collection. No duplicates exist.Habitus photographs were captured with the Macropod Pro (Microscopic Solutions). Individual images were taken at various focal planes and combined with Zerene Stacker . Plates were created and labeled with a combination of Adobe Photoshop and InDesign (Adobe Products). The map of the distribution of pleMappr . The holHalorhynchus, until now, known only from Western Australia: presence of a five-segmented funicle, club glabrous with apical tomentose area circular and reduced, rostrum approximately as long as wide, pronounced longitudinal constriction between frons and base of rostrum, parallel body outline, absence of a scutellum, elytral striae forming regular rows and punctation distinct, interstriae moderately raised, weakly serrate, body reddish-brown, shiny, with elongate stramineous lateral setae, eyes absent, legs moderately-sized, femora unarmed; tibiae apically expanded, with strong, curved uncus on outer, anterior  margin, hind tibiae fossorial; tarsi with 4 subequal tarsomeres, linear, fourth tarsomere absent, fifth tarsomere apically acute with 2 distal setae; tarsal claws obsolete [applies to only fore- and midlegs since holotype of Halorhynchuscaecus is missing the apical tarsomeres of the hind leg .Halorhynchuscaecus, but can be distinguished from it by the pronotum being wider 2/3 from the base, the shallower and relatively smaller pronotal punctation, the more acutely pointed apex (uncus) of the foretibiae, the hind tarsi in lateral view with setose, elongate, sclerotized tarsal extensions, and clawlessness.The new species strongly resembles the Western Australian species Head: short, not basally constricted. Frons convex, foveola reduced. Eyes absent. Rostrum as long as wide , narrower than frons and head, widening apically, dorsally with weak longitudinal depression at base of rostrum; apex truncate. Scrobes short, reaching base of rostrum, directed ventrad, expanding proximally, shallow. Antennae short, located approximately one-third from base of rostrum; scape short, almost subequal to first funicular segment; funicle 5-segmented, segment 1 equal to 2 and 3 combined, segments 2\u20135 dorso-ventrally compressed, subequal size and shape; club short, elliptical, as long as segments 2\u20135 combined, shiny, appearing 1-segmented, apex with clump of medially directed elongate, stout, stramineous setae. Hypostomal tooth pronounced. Proventriculus not dissected. Thorax: Prothorax trapezoidal with rounded anterior and posterior angles, widest at basal third, narrowed anteriorly but not compressed or rimmed; punctation sparse, shallow, small. Scutellum absent. Elytra oval; with 9 well-marked striae, interstriae slightly raised, rugous almost serrate, toothed apicad (posterad) and laterad humeri weak. Hind wing not dissected. Forecoxae narrowly separated, distance less than tarsal width, mid-coxae slightly more separate than forecoxae, hind coxae widely separated, distance twice greatest coxal diameter. Mesanepisternal suture distinct, mesanepisternum broadly deltoid, widest anterad, mesepimeral suture distinct, mesepimeron small, deltoid, approximately a quarter the size of mesanepisternum. Metasternum three times wider than long, femoral impression absent; sclerolepidia present; metanepisternum narrow, elongate, almost four times longer than wide; metanepisternal suture becoming obscure posterad; venter sparsely and shallowly punctate, apically. Legs: moderately-sized, femora unarmed; tibiae apically expanded, with strong, curved uncus on outer, anterior  margin, foretibia bearing a row of stramineous setae, uncus of mid- and hind tibiae shorter and more blunt, hind tibiae fossorial; tarsi with 4 subequal tarsomeres, linear, fourth tarsomere absent, fifth tarsomere apically acute with 2 distal setae ; tarsal claws obsolete, hind tarsi in lateral view with setose, elongate, sclerotized tarsal extensions  given the weevil\u2019s sand burrowing and \u2018rowing\u2019 habit.The species is named in honor of the late R\u00e9my Lemagnen, who was devoted to the study of weevils on the island of Reunion. The specific epithet also suggests the Latin word for oar  from Geraldton, Western Australia  of the species is probably not due to convergent evolution as a result of adaptation to similar niche space.Halorhynchusremii and other psammophilous weevils have converged in other beetle families with similar habits, as in some species of burrowing Tenebrionidae: Phaleria Latreille, Trachyscelis Latreille and Chaerodes White, as well as several ultra-psammophilous tenebrionids in the Molurini and Tentyriini  may aid in locomotion through sand . The eloPselactusspadix (Herbst) can tolerate immersion within a saline environment for up to 7 hours per day (Elassoptesmarinus Horn (Cossoninae) is found on the beach and is associated with driftwood.Several weevils, especially cossonines, are masters at long-distance overseas dispersal and are able to colonize even the most remote areas on the planet . Many we per day . This sp per day . In NortDryotribusmimeticus Champion, which probably drifts on warm oceanic surface currents  and once from Eurasia or America (9.8\u20137.8 Mya)  . HalorhyCenozoic  the possoduction . HoweverCossonine classification and assessment of higher-level groups requires a global perspective. This subfamily presents a unique challenge due to the ability of its members to readily disperse, colonize, and radiate, which hints to potentially high levels of taxonomic synonymy in the group.Halorhynchus on other parts of Africa may continue to shed light on the dispersal of this and other groups of cossonine weevils.We hope that this research sheds light on the ability of these cossonine weevils to disperse long distances and informs future work on the group as new species and genera continue to be discovered and described. We also hope this stimulates research on coastal areas where insects are rarely surveyed; particularly in areas in the African continent. Discovery of"}
+{"text": "Natural and/or human-caused salinization of soils has become a growing problem in the world, and salinization endangers agro-ecosystems by causing salt stress in most cultivated plants, which has a direct effect on food quality and quantity. Several techniques, as well as numerous strategies, have been developed in recent years to help plants cope with the negative consequences of salt stress and mitigate the impacts of salt stress on agricultural plants. Some of them are not environmentally friendly. In this regard, it is crucial to develop long-term solutions that boost saline soil productivity while also protecting the ecosystem. Organic amendments, such as vermicompost (VC), vermiwash (VW), biochar (BC), bio-fertilizer (BF), and plant growth promoting rhizobacteria (PGPR) are gaining attention in research. The organic amendment reduces salt stress and improves crops growth, development and yield. The literature shows that organic amendment enhances salinity tolerance and improves the growth and yield of plants by modifying ionic homeostasis, photosynthetic apparatus, antioxidant machineries, and reducing oxidative damages. However, the positive regulatory role of organic amendments in plants and their stress mitigation mechanisms is not reviewed adequately. Therefore, the present review discusses the recent reports of organic amendments in plants under salt stress and how stress is mitigated by organic amendments. The current assessment also analyzes the limitations of applying organic amendments and their future potential. Furthery stress ,16,17,18To reduce excess soil salinity, plant scientists are employing techniques such as sub-soiling, mixing sand, seed bed preparation, and salt scraping, as well as modern agronomic practices, hydrophilic polymer, gypsum, sulfur acids, green manuring, humic substance, farm yard manures, irrigation system, and salt-tolerant crops ,20,21,22The world\u2019s population grows significantly every day. To feed the increasing millions, researchers are attempting to develop modern, effective agronomic and eco-friendly organic ways to reduce salinity stress and boost crop yields. Furthermore, investigating environmentally safe and sustainable methods to lessen the negative consequences of salinity is necessary due to the ongoing environmental degradation. The literature suggests that organic approaches can alter biochemical and molecular systems to enable plants to withstand salinity stress, and these strategies are proving to be quite effective. As a result, this report highlighted the recent findings about organic amendments like VC, VW, BC, BF, and PGPR used for salinity stress mitigation. Correspondingly, keeping in view the role of organic amendments during saline conditions, this review explores the potentiality of the modern and widely used organic amendments for the alleviation of salt stress and their regulatory mechanisms. Despite the fact that other reviews of organic amendments for reducing salt stress have been published independently, this study offers a thorough analysis of all commonly used organic amendments for reducing salt stress in a single frame.The VC is an organic fertilizer that is prepared through the conversion of organic wastes by worms , and is The VW and vermicompost leachate (VCL) are two important derivatives prepared from vermicompost. The VW is a clear, translucent, pale-yellow fluid obtained by passing water through a column of the vermi-worms\u2019 excreta, which contains mucus secretions as well as micronutrients from decomposed organic sources . Khan et+ exclusion and K+ accumulation, alleviated stomatal restriction, raised leaf pigment concentrations, improved root activity, decreased oxidative damage in Fountain Grass, and improved salt tolerance [2O2 and MDA [+, Ca2+, and Mg2+, plant height, total dry matter content, and decreased exchangeable Na+ in the saline soil [A number of studies show that VC enhanced salinity tolerance and improved the morphological characteristics such as stem and root length, fresh and dry weight of root-shoot, vigor index, leaf area, and dry weight per plant ,57,58,59olerance . In addi and MDA ,61. The  and MDA . Liu et  and MDA  found thine soil ,64,65. Iine soil ,66,67,68BC is a carbon-rich organic substance with a porous structure, a wide surface area, and a high ion exchange ability that improves the physical qualities of agricultural soil ,84. A nuMorphological attributes such as seedling emergence, plant height, shoot biomass, root biomass, leaf area, dry matter, and yield of plants under salinity stress have been shown to be improved by BC incorporation ,86,87. M+ in soil, releasing mineral nutrients and decreasing osmotic stress [+ and decreased the Na+/K+ ratio in a variety of plants, assisting in the reduction of the negative effects of salt on plants [2 assimilation, which ultimately results in a better photosynthetic rate, stomatal conductance, and transcription rate [2O2, and MDA [Furthermore, in saline conditions, BC traps excess Nac stress . Studiesn plants ,90. Moreion rate ,83,86. Iion rate ,92. Addi and MDA . In addi and MDA . Similar and MDA  reported and MDA . Given tTriticum aestivum L.), okra (Abelmoschus esculentus L.), yellow passion fruit (Passiflora edulis), cowpea (Vigna unguiculata L.), corn (Zea mays L.), and olive plants (Olea europaea L.) enhanced growth and yield metrics, micro and macronutrient content, and relieved salinity-related detrimental effects [BFs are one kind of fertilizer that contains living cells from various microorganisms and can transform via biological mechanisms; nutrients are converted from the inaccessible to the accessible form ,100. Rec effects ,105,106. effects  showed t effects .2O2 production in lettuce (Lactuca sativa L.), safflower (Carthamus tinctorius L.) and cowpea (Vigna unguiculata L.) [Lactuca sativa L.). It has been reported that BF ameliorates the effects of salt stress via the production of phytohormones  and secondary metabolites (proline) in plants [BF application increased antioxidant activity through the up-regulating of POX, SOD, and CAT, and reduced MDA and Hlata L.) ,108,109.n plants ,111.Overall, the discussion concluded that BFs increased plant growth and production while also inducing salt tolerance by enhancing antioxidant enzyme activities, secondary metabolite accumulation and phytohormone synthesis.Enterobacter cloacae, Pseudomonas fluorescence, Bacillus pumilus, and Exiguobacterium aurantiacum were found to greatly alleviate the toxic effect of salt stress in Triticum aestivum plants [Enterobacter cloacae PM23 boosted maize growth, biomass, photosynthetic pigment contents, carotenoids, and relative water content compared to control treatment. Similar effects were observed when co-inoculation of Rhizobium sp. and Enterococcus mundtii in Vigna radiata were carried out and obtained the grain production was improved under saline stress by regulating ion homeostasis [B. megaterium, Solanum lycopersicum and Arabidopsis thaliana both grew roots, shoots, and more leaves under salt stress [S. marcescens inoculation enhanced Triticum aestivum shoot length, fresh weight, and chlorophyll (Chl) content [Enterobacter cloacae in Brassica napus enhanced seedling development [Triticum aestivum with Pseudomonas fluorescens led to similar outcomes, as did inoculating Oryza sativa with Alcaligenes faecalis, B. pumilus, and Ochrobactrum sp. [Rhizobium sp. and Bradyrhizobium japonicum\u2019s co-inoculation improved root nodule formation in Glycine max compared to control conditions, resulting in increased stress tolerance, plant growth, and higher yield [Bacillus aryabhattai and Azotobacter vinelandii inoculation enhanced root nodule numbers and N-contents in Trifolium repens compared with the non-inoculated plants [Plant-growth-promoting rhizobacteria (PGPR) are microorganisms that colonize plant roots and are used as chemical alternatives in agricultural fields for crop production and protection ,118. PGPm plants ,123. Morm plants  reportedeostasis . Additiot stress ,126. Fur content . Under selopment . Inoculatrum sp. . In additrum sp. . For exaer yield . Likewisd plants . Howeverd plants .Pisum sativum) by enhancing the plants\u2019 proline and soluble sugar contents while lowering sodium (Na+) contents, which in turn reduced the amount of electrolyte leakage and H2O2 content [+, K+, and Ca2+ under salt stress and thus maintains ionic balance due to ion homeostasis. Moreover, inoculating Pseudomonas sp. or Glutamicibacter sp. with the halophte Suaeda fruticosa led to noticeably greater shoot dry weight and decreased buildup of Na+ and Cl\u2212 in shoots of salt-treated plants [Piriformospora indica inoculation in Zea mays decreased K+ flow from roots while increasing K+ concentration in shoots under saline condition; this effect may be linked to a high-affinity K+ transporter where PGPR produced a proton-driven force through H+-ATPase [Azotobacter isolates under salinity stress had greater K+/Na+ proportions in shoots and decreased Na+ and Cl\u2212 amounts in maize leaves [2 and NO2 concentrations and increased the K+/Na+ ratio, which contributed to enhanced stomatal conductance, and maintained hormonal balance and photosynthesis under salt stress [Thalassobacillus denorans, Oceanobacillus kapialis, Pseudomonas strains, Bacillus tequilensis and Bacillus aryabhattai synthesized more auxin and ABA, accumulated osmolytes in cell cytoplasm that sustain their cell turgor to make ensure plant growth under osmotic stress in Oryza sativa to endure high saline conditions [Enterobacter cloacae PM23 increased APX, SOD, POD, total soluble sugars, and proteins while decreasing flavonoids and phenolic contents under salt stress. Additionally, in Suaeda fruticosa under high salinity, Glutamicibacter sp. inoculation dramatically decreased MDA levels while enhancing the activities of SOD, CAT, APX, and GR. Habib et al. [B. megaterium and Enterobacter sp. It has also been found that the treatment of Arabidopsis seedlings with Enterobacter sp. increased APX function and boosted salt tolerance [Many studies described that PGPR can alleviate the salt-induced growth inhibition of plants by positively regulating ion homeostasis and antioxidant enzyme activity, improving photosynthetic attributes, secondary metabolite accumulation, and oxidative stress reduction , can produce very helpful tools for detecting, guarding against, and controlling salinization, thereby minimizing the harm brought on by salt stress. However, many reports have been published about the role of organic amendments in the alterations of physio-biochemical reactions to plants under salt stress. To counteract salt stress, however, additional approaches and strategies based on breeding assisted by genetic markers, genome editing, and advanced biotechnological procedures can be applied in addition to all standard treatments. In addition, there is currently a paucity of knowledge regarding how secondary metabolites, distinct stress-responsive genes, and the primary metabolic pathways that govern due to salinity. More studies are required to better understand the morphological, physio-biochemical, transcriptomics, and proteomics of organic amendment application in a saline environment to improve crop productivity.Abiotic stressors are significant barriers that reduce agricultural yields around the world. One of the most damaging environmental variables limiting agricultural productivity is salinity. Salinity-induced oxidative stress and Na+ ion absorption lead to cellular damage including ionic instability, which inhibits growth and has detrimental effects on the morphological and biochemical characteristics of plants. It is absolutely necessary to look for environmentally sound and long-term solutions to reduce the negative effects of salt on plants. However, these negative impacts of salinity were lessened by the applications of VC, VW, BC, BF, and PGPR. It is clear from the discussion that VC, VW, BC, BF, and PGPR promote plant growth and increase salt tolerance by maintaining ionic homeostasis, enhancing antioxidant enzyme activities, lowering osmotic and oxidative stress, and regulating gene expression, all of which lead to improved plant growth and productivity. Although several studies on the regulatory functions of VC, VW, BC, BF, and PGPR in various crops under salt stress have been carried out, there is still much that needs to be investigated at the molecular, biochemical, and physiological level."}
+{"text": "Clinical and Translational Medicine, 2021:e541. The above article, published online on 12 October 2021 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors, the journal Editor in Chief Xiangdong Wang, and John Wiley & Sons Australia, Ltd. The retraction has been agreed due to the shortcomings of the cynomolgus monkey depression model. The isolated conditions applied, and the flawed behavioural classification method and the insufficient experimental duration of the animal model render the conclusions of the article inaccurate.Weixin Yan, Lingpeng Xie, Yanmeng Bi, Ting Zeng, Di Zhao, Yuqi Lai, Tingting Gao, Xuegang Sun, Yafei Shi, Zhaoyang Dong, Ge Wen, Lei Gao, Zhiping Lv. Combined rs\u2010fMRI study on brain functional imaging and mechanism of RAGE\u2010DAMPs of depression: Evidence from MDD patients to chronic stress\u2010induced depression models in cynomolgus monkeys and mice."}
+{"text": "Gender-based violence (GBV) is a global health, human rights, and protection issue, which can increase during emergencies. GBV coordination is an essential component of every humanitarian response, ensuring that, from the earliest phases of a crisis, accessible and safe services are available and prevention and mitigation mechanisms are implemented to reduce GBV. We sought to address the limited evidence on GBV coordination, by reviewing literature on GBV coordination in emergencies, identifying facilitators and barriers influencing effectiveness.We conducted a scoping review on GBV coordination in emergencies from 1990 to 2020. Studies explicitly discussing GBV coordination in humanitarian, natural disaster and public health emergencies, in low or middle-income countries, were included. Using thematic analysis, we developed a six-topic framework to synthesise evidence on effective GBV coordination and present recommendations for strengthening GBV coordination in emergencies.We included 28 of 964 sources identified, covering 30 different emergency settings across 22 countries. Sources spanned emergency settings, with minimal evidence in public health emergencies and none focussed solely on GBV coordination. Several sources suggested that timely establishment of GBV coordination mechanisms, led by dedicated, experienced coordinators, increased funding and strengthened service provision. GBV risk mitigation was compromised by weak commitment across sectors, poor accountability systems, and limited engagement of affected women. Inclusive GBV coordination, involving national and local actors is vital but engagement efforts have been inadequate and localisation funding targets not yet achieved. Implementation of the GBV Information Management System has reinforced coordination, funding allocation and service provision. While specialist GBV services remain insufficient, emergencies can present opportunities for expansion. Sustainability and long-term impact are compromised by over-reliance on international leadership and funding, weak commitment by governments, and limited attention to GBV prevention.Despite enhanced global commitments to addressing GBV in recent years, it remains consistently under-prioritised and under-resourced. Recommendations to strengthen GBV coordination in emergencies include: funding dedicated GBV coordination positions across all types of\u00a0emergencies, building the global GBV coordination workforce, expanding inclusion of national actors and investing in GBV risk mitigation and prevention through multiyear funding. The evidence-based framework for effective GBV coordination presented here, can guide further research in diverse emergencies.The online version contains supplementary material available at 10.1186/s13031-022-00471-z. Gender-based violence (GBV) is a global health, human rights, and protection issue, which often goes underreported and unaddressed . The IntDeeply entrenched in gender inequality, GBV is often reinforced by patriarchal norms, discriminatory laws, and socio-cultural norms that undermine women\u2019s rights , 9. GBV GBV coordination in humanitarian emergencies falls within the protection cluster in the United Nations (UN)-led international humanitarian cluster system adopted in 2005 , with thAddressing GBV requires a broad multi-sectorial, interagency approach, therefore, successful GBV coordination, depends on a wide variety of actors collaborating to achieve safe, ethical and comprehensive GBV programming . GBV cooInternational attention and commitment to addressing GBV in emergencies has rapidly expanded in recent years . The UN Within this rapidly evolving context, understanding what influences effective GBV coordination in different contexts is critical. While several systematic reviews address GBV prevention and response in humanitarian settings, literature exploring GBV coordination is limited. This review aimed to examine literature on GBV coordination in humanitarian and public health emergencies, to identify facilitators and barriers to effective GBV coordination, and to draw out lessons for strengthening GBV coordination in emergencies.We conducted a scoping review from October 2020 to January 2021 using Arksey & O\u2019Malley\u2019s five-stage approach , 29. TheOur research question was intentionally broad to capture a range of sources : \u2018What iWe initially searched six databases  humanitarian response/crisis/emergency; (b) emergency response coordination; and (c) gender-based violence/GBV . Figure\u00a0To visualise the complex matrix of agencies, relationships, and mechanisms constituting GBV coordination, we developed a graphic overview of GBV coordination from global to frontline level Fig.\u00a0 based onTable All 28 sources included reflections on implementing a GBV sub-cluster. Timely GBV sub-cluster activation, with dedicated GBV coordinators and funding were noted as critical for effective GBV coordination. However, over-reliance on international funding, technical support and leadership, compromised sustainability.Several sources noted a growing awareness and commitment to addressing GBV early in humanitarian response \u201337. UNICConversely, late or non-activation of a GBV coordination mechanism and MISP implementation compromised GBV service delivery. For example, the GBV sub-cluster in Pakistan\u2019s 2010 emergency, was established almost two months after emergency declaration , in 2014Strong coordinators with good leadership qualities and dedicated time and funding for coordination were highlighted as critical facilitators for effective GBV coordination. In Lebanon, national coordination was considered strong, attributed to having dedicated coordinators with allocated budgets , 46. In In many settings, GBV coordination relied on international donor funding, technical support and leadership, with limited ownership of government, compromising sustainability. In Northern Uganda, for example, concerns were raised about government ownership of GBV activities, political commitment to GBV, and capacity to sustain GBV coordination and service delivery . In the Seventeen sources noted prioritisation, advocacy and access to resources as critical for GBV coordination at global and frontline levels , 50\u201355. Grand Bargain and New Way of Working focused on increasing multi-year, collaborative, and flexible funding and planning, moving towards longer-term GBV strategies [Since 2013, the Call to Action has promoted senior leaders in donor and implementing agencies to prioritise GBV, galvanising collective action, accountability, and investments . Followirategies , 57. A 2rategies . Supportrategies , 41, 46.Despite this progress, humanitarian leadership and sectoral actors on the ground, overwhelmed with competing priorities, often dismiss GBV as non-essential, particularly in acute emergency stages , 42. LacGBV funding is insufficient and inconsistent across settings and is often subsumed within protection sector budgets, making it difficult to track specific GBV investments , 51. OneNineteen sources highlighted the importance of GBV risk mitigation and cross-sector coordination in emergency responses , 58, 59.Since 2016, when UNICEF noted a lack of systematic integration of GBV risk mitigation by clusters/sectors , the rolStudies noted low levels of commitment to GBV minimum standards, limited understanding of how to operationalise the 2015 IASC GBV Guidelines, and weak accountability mechanisms to donors, humanitarian leadership, and beneficiaries  as well Non-compliance of response actors to their responsibilities within the GBV guidelines exacerbated GBV risks for women and girls. One study noted minimum GBV risk reduction was overlooked during the Sierra Leone Ebola crisis, with cases and suspected cases not separated by sex in facilities, and few treatment centres able to treat pregnant women, resulting in denial of care and some women giving birth and dying on the street . Lack ofFourteen sources explored issues of GBV localisation and inclusion of local actors in GBV coordination \u201353, 55. In 2019, findings showed minimal GBV localisation in three of four contexts studied , with only Turkey reporting high perceived localisation, which was necessitated by the lack of access of international organisations in Syrian cross-border operations . Women-lSeveral sources noted cultural, linguistic and logistical barriers for local and national NGOs engaging in humanitarian coordination mechanisms, including meetings not being held in appropriate languages to facilitate participation , 46, 52.Nevertheless, some positive examples of engagement were highlighted. For example, in Lebanon, Jordan and South Sudan, UN organisations invested in capacity-building partnerships with local GBV actors, involving ongoing mentoring, which was seen as practical and sustainable , 41. In Eight sources noted data and information management as influencing effective coordination , 46\u201348. GBV coordinators are frequently asked for 'evidence' of GBV in the early days of a crisis, particularly in funding discussions. A 2016 multi-country study in Ethiopia, Tanzania and Lebanon, reported that donors and humanitarian leaderships\u2019 need for \u2018evidence\u2019 of GBV prevalence was a fundamental challenge and when donors failed to earmark GBV funding at the beginning of a crisis, frontline implementation was delayed .A 2014 global evaluation noted that implementation of the GBVIMS had contributed to effective and safe collection, storage, analysis and ethical sharing of GBV data at country level . ServiceTwenty-six sources included reflections on the importance of GBV coordination to support service provision \u201355, 59. Many specialist GBV services, such as CMR and MHPSS, were insufficient across settings and lack of trained staff hampered services delivery in many contexts. In Central African Republic, Uganda, South Sudan, Iraq, and Sierra Leone, establishment of essential GBV services was hindered by insufficient availability prior to the crisis, slow deployment of GBV experts, limited funding, and sometimes weak advocacy for GBV prioritisation , 43, 54.In Central African Republic, Jordan, Lebanon, Uganda, Somalia, and South Sudan, humanitarian GBV responses expanded GBV services provision and access, especially CMR, MHPSS, safe spaces, and community outreach , 53, 54.GBV prevention programming is essential for long-term impact but often deprioritised in emergencies. Long-term GBV reduction requires addressing root causes, namely gender inequality and unequal power relations, and is often seen as too complex and long-term to implement in emergency contexts , 50. In To our knowledge, this review is the first to explore GBV coordination in emergencies and revealed the near absence of academic literature systematically examining the effectiveness of GBV coordination. However, by maintaining a broad inclusion criteria and analysis framework, we were able to synthesise relevant findings for policy, practice, and research. Included sources spanned 2008 to 2020, and while the global policy context has evolved significantly in this period with many notable advancements, our findings highlight several remaining barriers to effective coordination, some of which were also noted in a 2021 gap analysis on GBV in humanitarian settings . This reThe overview of GBV coordination graphic highlights the complex network of organisations and actors involved in addressing GBV in emergencies. The UNFPA-led GBV AoR take the lead in non-refugee settings and have developed comprehensive guidance, standards and toolkits for application in the cluster system, in addition to providing training and technical support . CoordinFindings indicated major improvements in GBV coordination in emergencies, attributed to rapid activation of coordination mechanisms and organisational investments in building and deploying GBV coordination experts . DeployiMajor gaps remain between global GBV policy commitments and funding allocations, with a lack of prioritisation, commitment and accountability across the humanitarian sector. GBV is consistently de-prioritised, with less than 1% of humanitarian funding allocated to the GBV sector over the past 5 years . Our finSignificant benefits of investing in subnational coordination include faster and more contextually-relevant decision-making and greater participation by local actors\u2014particularly civil society\u2014to advance the localisation agenda, but requires strengthening in emergencies , 66\u201369. Limited commitment to GBV risk mitigation across sectors suggested stronger inter-sectorial engagement and improved inter-agency accountability systems are needed to improve multi-sectoral resourcing and attention , 40, 49.Collecting and sharing GBV information is both extremely challenging and important in emergencies. Despite global guidance, our review highlighted that donor requests for \u2018evidence\u2019 of GBV remains a consistent challenge, delaying funding allocation and GBV responses , 46. FurEffective GBV coordination ensures comprehensive multi-sectorial, survivor-centred services, strong referral mechanisms, and collaborative, culturally-appropriate programming. However, our review highlighted significant gaps in both availability of services and access of survivors across emergency settings. Stigma, shame and lack of appropriately trained staff are common barriers to survivors accessing GBV services, and practical guidance on approaching these culturally-sensitive issues within GBV coordination structures is needed , 48. WhiIn settings without existing GBV coordination mechanisms, emergencies can provide an opportunity to introduce GBV coordination and expand services . ParticuThis study has several limitations and should be interpreted accordingly. Firstly, we only included sources within our search and language capacity, and it is possible that other relevant sources were inaccessible due to search terms or unavailable electronically. Secondly, only the first author searched and selected sources, however, discussion and oversight of other authors minimised bias. Finally, sources were not excluded on evidence quality, allowing inclusion of a broader range of data from peer-reviewed and grey literature.While GBV coordination is increasingly recognised as vital to global efforts to respond to, mitigate and prevent GBV, it is rarely researched, demonstrated by the lack of peer-reviewed sources, with literature on GBV coordination during public health emergencies particularly scant. Recommendations to strengthen GBV coordination include to, increase multi-year and flexible funding for GBV across emergencies, fund dedicated GBV coordination positions in all emergencies, build the global GBV coordination workforce including for deployment in public health emergencies, strengthen subnational coordination mechanisms, expand inclusion and leadership of national and local actors and channel more funding to these organisations. In addition, guidance and tools developed by the\u00a0GBV AoR should be adapted for application in refugee settings and public health emergencies, and investment in context appropriate GBV risk mitigation and prevention should be promoted through multiyear planning and funding, especially in protracted emergencies. We present a series of recommendations Table  to improAdditional file 1.Box 1: Search strategy."}
+{"text": "Schizophrenia is highly comorbid with substance use disorders (SUD), which may negatively impact the course of illness. However, large studies exploring the best lines of treatment for this combination are lacking.We investigated what are the most effective antipsychotics for patients with schizophrenia in preventing the development of substance use disorders and preventing hospitalizations in patients already having substance use disorder.We used two independent national cohort registries including all patient with schizophrenia aged under 46 years. Participants were followed during 22  and 11 years . We studied risk of rehospitalization, and risk of developing an SUD when using vs. not using antipsychotics, using Cox proportional hazards regression analysis models.45,476 patients with schizophrenia were identified . For patients without SUD, clozapine and antipsychotic polytherapy were associated with the lowest risks of developing SUD in both countries. For patients with co-existing SUD, the risk of hospitalization was the lowest during clozapine, polytherapy and long-acting injectable use.In patients with schizophrenia and comorbid SUD, antipsychotic medications were effective in preventing relapses. In those without an SUD, antipsychotic use was associated with a markedly reduced risk of developing an initial SUD. Clozapine and long-acting injectables should be considered treatments of choice in patients with schizophrenia and SUD, or at risk of developing co-morbid SUD.ML: Genomi Solutions Ltd, DNE Ltd, Sunovion, Orion Pharma, Janssen-Cilag, Finnish Medical Foundation, Emil Aaltonen Foundation. HT, EMR, AT: Eli Lilly, Janssen\u2013Cilag. JT: Eli Lilly, Janssen-Cilag, Lundbeck, Otsuka."}
+{"text": "Porokeratosis ptychotropica represents an unusual form of porokeratosis characterized by symmetrical dyskeratotic skin lesions on the gluteal clefts. Herein, we report a case of porokeratosis ptychotropica.A 33-year-old man, who complained of itching papules and plaques in the gluteal cleft and the buttocks for the last 7 years. Clinical examination showed a large well-defined reddish brown verrucous plaque located on both buttocks along with satellite papules on the inner thigh. Dermoscopy and histopathological findings were consistent with porokeratosis.He was diagnosed with porokeratosis ptychotropica.No significant improvement was observed following treatment with oral acitretin and a topical retinoid.The case report highlights the need for awareness amongst dermatologists for porokeratosis ptychotropica as a differential diagnosis for pruritic papules in the gluteal fold. Interestingly, another rare variant, porokeratosis ptychotropica, localized to the gluteal cleft and the buttocks, was first reported by the Lucker et al in 1995. Herein, we present the case report of a patient with porokeratosis ptychotropica, an unusual diagnosis, and describe the findings of clinical routine, dermoscopy and histology.Porokeratosis is a spectrum of clinical disorders characterized by the histological features of a cornoid lamella. Several variants have been described, including linear porokeratosis, classical porokeratosis of Mibeli, disseminated superficial actinic porokeratosis, and prokeratosis plantaris and palmaris.A 33-year-old Chinese male presented with a 7-year history of itching brown papules and plaques on the gluteal cleft and the buttocks. The lesion began as a small brown scaly papule and increasingly coalesced to form larger plaques. There was no discernable history or underlying cutaneous diseases. He did not respond to treatment with topical glucocorticoid and antihistamine drugs. Physical examination revealed a large well-defined reddish brown verrucous plaque located on both buttocks, and satellite papules were found at the inner thigh Figs.  and 2. D,3,4 Porokeratosis ptychotropica the preferred term, is localized to the gluteal folds, buttocks and genitalia with a butterfly morphology. It increasingly progresses through satellite lesions that develop and coalesce, accompanied by mild-to-severe itching. Moreover, this disease is more likely to occur in males, as in the present case.Porokeratosis ptychotropica was previously referred to as verrucous porokeratosis or genitogluteal porokeratosis is rare.,5 Interestingly, none of these factors were implicated in our case. The prevalence of malignant transformation of the porokeratotic rash is 7.5%, especially the linear and large-sized lesions. Previously, a case of a 6-year-porokeratosis ptychotropica transforming into invasive squamous cell carcinoma has been reported. Periodic follow up plays a vital role in the early diagnosis of potential transformation, especially to malignant basal cell carcinoma, squamous cell carcinomas or malignant melanoma.To date, several scholars have suggested that numerous factors are associated with porokeratosis ptychotropica, including repeated trauma, organ transplantation, HIV infection and other diseases related to immunosuppression, but its pathogenesis remains unclear. but not a specific manifestations of porokeratosis ptychotropica.Dermoscopic findings revealed a sharply demarcated annular lesion with a thick, peripheral light brown rim, limiting an erythematous non-atrophic center with regular dotted vessels, which were vital clues suggesting a subtype of porokeratosis. Cornoid lamellae are present throughout the lesion in porokeratosis ptychotropica, while in the other variants, these are localized to the periphery. Multiple of cornoid lamellae were present in our patient.Among histological features, the differences between porokeratosis ptychotropica and other variants are in the number and distribution of the cornoid lamellae.,11 Surgical excision may be a good option for early-stage lesions.,11Differential diagnosis includes psoriasis, tuberculosis verrucosa cutis, and lichen planus verrucose. Numerous conventional treatments, including acitretin, corticosteroids, 5-fluorouracil, cryotherapy, and laser therapy are available but their efficacy is limited for porokeratosis ptychotropica.In summary, dermoscopic findings are helpful, but the clinical characteristics and histological examinations have significant roles in the definite diagnosis of porokeratosis ptychotropica. This case report is expected to raise awareness of porokeratosis ptychotropica, an identified diagnosis variant of porokeratosis. We also hope to improve diagnostic accuracy and prevent the long-term complications related to the disease.The patients in this case have given written informed consent to publication of her case details.Conceptualization: Yu Xiao, Xiangjun Li, Wenzheng Ye, Muping Fang.Data curation: Yu Xiao, Shanshan Peng, Tianyi Mao, Xiangjun Li, Wenzheng Ye, Muping Fang.Formal analysis: Yu Xiao, Wenzheng Ye, Muping Fang.Funding acquisition: Yu Xiao.Investigation: Yu Xiao.Methodology: Yu Xiao.Resources: Yu Xiao.Software: Yu Xiao, Muping Fang.Supervision: Shanshan Peng, Xiangjun Li, Wenzheng Ye, Muping Fang.Validation: Yu Xiao, Muping Fang.Visualization: Yu Xiao, Muping Fang.Writing \u2013 original draft: Yu Xiao, Shanshan Peng, Tianyi Mao, Wenzheng Ye, Muping Fang.Writing \u2013 review & editing: Yu Xiao, Wenzheng Ye, Muping Fang."}
+{"text": "The incidence of inflammatory bowel disease (IBD) has increased in recent years. Considering the potential side effects of conventional drugs, safe and efficient treatment methods for IBD are required urgently. Natural polysaccharides (NPs) have attracted considerable attention as potential therapeutic agents for IBD owing to their high efficiency, low toxicity, and wide range of biological activities. Intestinal microbiota and their fermentative products, mainly short-chain fatty acids (SCFAs), are thought to mediate the effect of NPs in IBDs. This review explores the beneficial effects of NPs on IBD, with a special focus on the role of intestinal microbes. Intestinal microbiota exert alleviation effects via various mechanisms, such as increasing the intestinal immunity, anti-inflammatory activities, and intestinal barrier protection via microbiota-dependent and microbiota-independent strategies. The aim of this paper was to document evidence of NP\u2013intestinal microbiota-associated IBD prevention, which would be helpful for guidance in the treatment and management of IBD. Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn\u2019s disease (CD), is a multifactorial disease characterized by immune system relapse and inflammation of the gastrointestinal tract. An epidemiological study in 2017 reported that more than 6.8 million people suffered from IBD globally . AlthougLentinus, Cordyceps, and Ganoderma species were shown to have potent immunomodulatory, antitumor, and antivirus effects . I. I+ T celistipes . Morus aficantly . In addibundance . Exopolyficantly . Similarnhibited . D. indubacillus . Ramulusse model .Dendrobium officinum prevented UC by decreasing the expression of TLR4 [Bacteroides, Lactobacillus and Ruminococcus while decreasing the abundance of Proteobacteria [Radix pseudostellaria polysaccharides restored intestinal microbiota, upregulated TLR4 expression, increased the abundance of Bacteroides and Pseudomonas, and decreased the abundance of Verrucomicrobia and Akkermansia [Ganoderma lucidum polysaccharides reduced the abundance of Lachnoclostridium, Oscillibacter, Desulfovibrio, Alipipes, and Parasutterella, and they inhibited the expression of MyD88, thereby alleviating DSS-induced colitis in mice [Lactobacillus, Bifidobacteria, and Enterobacteriaceae, and they inhibited the activation of the MyD88 signaling pathway so as to alleviate intestinal inflammation [Alistipes and Helicobacter abundance [S. baicalensis Georgi ameliorated colitis via suppression of the NF-\u03baB signaling pathway [Bifidobacterium, Lactobacillus, and Roseburia and reducing the levels of Bacteroides, Proteobacteria, and Staphylococcus [Muribaculaceae and Lachnospiraceae abundance, and decrease Bacteroidaceae, Prevotellaceae, and Rickenellaceae abundance [The activation of inflammatory signaling pathways induces the production of pro-inflammatory cytokines, leading to the aggravation of IBD. NPs can improve intestinal inflammation by modulating TLR4, MyD88, and NF-\u03baB signaling pathways  122,123123. Poly of TLR4 , restoribacteria . Radix permansia . MyD88 iermansia . Ganoder in mice . Astragaammation . The NF-ammation . Polysacbundance . Polysac pathway  while inlococcus . Similarbundance .Obviously, NPs were effective in IBD diseases, and their mechanisms were possibly related to the following three aspects: (1) repairing the damaged intestinal barrier, including mucosa, microbiota, intestinal permeability, etc.; (2) maintaining the intestinal microenvironment by modulating the diversity and richness of the intestinal microbiota community, for example, increasing the beneficial intestinal bacteria, improving bacterial translocation, and production of SCFAs; (3) ameliorating the severe immune responses of the host mucosa, such as promoting the secretion of anti-inflammatory cytokines and reducing the production of pro-inflammatory cytokines, activating epithelial lymphocytes and mucosal lamina propria immune cells, etc. In that way, they improve intestinal immunity and inflammatory responses in various IBD mice models.Although NPs have been demonstrated to inhibit the activation of several inflammatory signaling pathways, no direct evidence of SCFAs produced by NPs fermentation with inflammatory responses or expression of peroxisome proliferator-activated receptor has been presented. In addition, glycan chain length and linkage type have been found to influence the immunogenicity and efficacy of glycoconjugate vaccines ; however"}
+{"text": "Life Plan Communities, also known as Continuing Care Retirement Communities, typically offer a wide range of wellness programs and services, including fitness classes, educational lectures, volunteer opportunities, and social events. Despite the convenience of onsite wellness resources, some residents choose not to participate in wellness offerings available at the community. One factor that may influence engagement in wellness behaviors is older adults\u2019 attitudes toward aging, which has been associated with differences in health and well-being over time. The purpose of this research was to examine the relationship between attitudes toward aging and wellness engagement among residents of Life Plan Communities. A total of 447 residents  of 10 communities completed surveys that measured their attitudes toward aging, self-reported wellness, interest in improving wellness, participation in wellness programs, and barriers to wellness participation. Multiple regression analyses revealed that more positive attitudes toward aging were associated with better wellness, higher interest, more frequent participation, and fewer barriers, controlling for age, gender health, education, and marital status. Follow-up analyses revealed that these effects could be accounted for by specific types of aging attitudes . For example, greater psychological growth was associated with greater wellness, interest in improving wellness, and wellness participation, whereas greater psychosocial losses was associated with greater perceived barriers and lower wellness. These findings have implications for the development, implementation, and promotion of wellness programs for older adults."}
+{"text": "The presence of non-biomedical foreign objects (NBFO), such as coins, buttons and jewelry, and biomedical foreign objects (BFO), such as medical tubes and devices in chest X-rays (CXRs), make accurate interpretation difficult, as they do not indicate known biological abnormalities like excess fluids, tuberculosis (TB) or cysts. Such foreign objects need to be detected, localized, categorized as either NBFO or BFO, and removed from CXR or highlighted in CXR for effective abnormality analysis. Very specifically, NBFOs can adversely impact the process, as typical machine learning algorithms would consider these objects to be biological abnormalities producing false-positive cases. It holds true for BFOs in CXRs. This paper examines detailed discussions on numerous clinical reports in addition to computer-aided detection (CADe) with diagnosis (CADx) tools, where both shallow learning and deep learning algorithms are applied. Our discussion reflects the importance of accurately detecting, isolating, classifying, and either removing or highlighting NBFOs and BFOs in CXRs by taking 29 peer-reviewed research reports and articles into account. Chest X-rays are the most common, widely available, and affordable diagnostic imaging technique for cardiothoracic and pulmonary disorders . Chest rThe detection of pulmonary abnormalities concerning tuberculosis (TB) with the presence of foreign objects could influence decision-making procedures . An exteThis paper focuses on the impact of NBFOs in CXRs by reviewing clinical studies and how much work has been done to detect and classify NBFOs and BFOs using artificial intelligence (AI)-guided tools. In Our review process includes search keywords, search space, inclusion criteria, and exclusion criteria.Search keywords: (chest X-ray OR chest radiograph) AND (foreign object detection) OR object detection.Search spaces: PubMed and Web of Science.As we primarily consider experimental papers with clinical significance that are primarily aimed for pulmonary abnormality screening, we reviewed 29 papers in total. We did not consider preprint papers  as they are not peer-reviewed.In this section, we review the impact of BFOs and NBFOs from a clinical perspective, and based on literature from the 1980s onward, we consider the following types of NBFOs: magnets, button batteries, coins, disk magnets, scarf pins, metallic candy wrappers, as well as BFOs which turned out to be chest tubes, automatic implantable cardiovascular defibrillators, cardiopulmonary devices, pacemakers, catheters, intra-aortic counter pulsation balloon pumps, ventricular assist devices, endotracheal and tracheostomy tubes, nasogastric and nasoenteric tubes, and medically implanted wires, to name a few. The following discussion highlights these NBFOs and BFOs as they appear in CXRs.Batteries and magnets are common in children\u2019s toys and the ingestion of these items is an increasingly common theme with children. The harm in swallowing these items is often difficult to express for young children, including autistic, developmentally delayed, non-verbal, or non-disclosing children. In the Ref.  the authThe growing number of small electronic devices with an electric supply by lithium button batteries (LBBs) has increased the number of cases of LBB ingestions, causing severe medical complications . In the The radiographic evaluation of the support and monitoring devices used in patients in the intensive care unit (ICU) is critically important because the potentially serious complications arising from their introduction and use are often not clinically apparent. For example, central venous catheters, pulmonary artery catheters, left atrial catheters, transvenous pacemakers, automatic implantable cardioverter defibrillators, intra-aortic counter pulsation balloon pumps, and ventricular assist devices are frequently used in critically ill patients. Godoy et al. ,23 discuIn the Ref.  Grier etMurthy et al., in the Ref.  providedCoins currently represent the most retained esophageal foreign body among children in the United States ,29,30. SIn the Ref.  Ullal etTypical AI-guided tools work as demonstrated in Automatically detecting foreign objects in CXRs is not trivial  and it dSchultheiss et al.  developeDeshpande et al.  proposedSantosh et al.  created In this section, we summarize datasets used in Zohora et al. ,40 used For evaluation of the detection and removal of NBFO, Hogeweg, et al.  used a lA dataset of 391 CXRs was collected from Schultheiss et al.  and the In this paper, we analyzed overlaid foreign objects in chest X-ray (CXR) images by considering two factors: clinical significance and AI-guided tools. Both non-biomedical foreign objects (NBFOs) and biomedical foreign objects (BFOs) were considered in our study since we were required to have effective reading and accurate interpretation of CXRs. While reviewing, we observed that NBFOs range from accidentally ingested batteries, coins, hair pins, jewelry, candy wrappers, hardware, or toys, and BFOs include biomedical devices like pacemakers, medical device wiring, medically installed prostheses, and medical tubing. In addition to clinical significance, we examined the detailed discussions on numerous clinical reports in addition to computer-aided detection (CADe) with diagnosis (CADx) tools. In CADe and CADx, both shallow learning and deep learning algorithms were considered. When it comes to automation, AI-guided tools (with the possibility of having explainability and/or interpretability) are a must, but they require larger datasets."}
+{"text": "Vaccination remains one of the most effective ways to limit spread of disease. Waning public confidence in COVID-19 vaccines has resulted in reduced vaccination rates. In fact, despite vaccine availability, many individuals choose to delay COVID-19 vaccination resulting in suboptimal herd immunity and increased viral mutations. A number of qualitative and quantitative studies have been conducted to identify, understand, and address modifiable barriers and factors contributing to COVID-19 vaccine hesitancy among individuals with access to vaccine. Vaccine confidence may be improved through targeted patient\u2013provider discussion. More patients are turning to pharmacists to receive their vaccinations across the lifespan. The primary goal of this commentary is to share evidence-based, patient talking points, tailored by practicing pharmacists, to better communicate and address factors contributing to vaccine hesitancy and reduced vaccine confidence. Vaccination remains one of the most effective ways to limit spread of disease, reducing both mortality and morbidity. Waning public confidence in safety and efficacy of vaccinations, especially COVID-19 vaccines, has been shown to foster complacency and hesitancy among patients, reducing immunization uptake and vaccination rates ,3. AccorA number of qualitative and quantitative studies have been conducted to identify, understand, and address modifiable barriers and factors contributing to COVID-19 vaccine hesitancy among individuals who have access to vaccine(s) ,11,12,13Medical decision making, the ability of a patient to understand the benefits, risks, and treatment/intervention options, is necessary to make an informed medical care decision . AmericaMore and more patients are turning to pharmacists to receive immunizations across the lifespan ,19,20,21Confidence and/or trust, both which are critical for vaccine uptake by patients, are impacted directly by patient\u2013provider communication, and the patient\u2013provider relationship. Patient satisfaction, adherence, engagement, and health outcomes have all been shown to correlate with patient\u2013provider communication and perceived provider empathy. Pharmacists, who are among the most accessible, trusted, healthcare providers, are well-positioned to listen to and address patient concerns related to immunization safety and effectiveness, especially in under-resourced communities. As of 15 September 2022, pharmacists in the Federal Retail Pharmacy Program, a collaboration between the Federal government, states, territories, and 21 national pharmacy partners and independent pharmacy networks nationwide, were responsible for administering more than 266.5 million doses of the COVID-19 vaccine; however, if communication were improved, knowledge better demonstrated, culture taken into consideration, and empathy displayed, the number of all vaccinations administered could be far greater ,28,29,30The primary goal of this paper is to share evidence-based strategies and patient talking points, tailored by practicing pharmacists , to bettOver the past year, our research team worked with vaccine-hesitant patients in both Alaska and Idaho to identify and understand the many factors contributing to their hesitancy to receive the COVID-19 vaccine. Grounded by the current scientific literature, published guidelines and concerns voiced by patients, providers, healthcare administrators, and public health leaders in the lay literature, our team co-developed a moderator\u2019s guide which was used to better understand the underlying factors contributing to vaccine hesitancy ,27,57. SFear, driven primarily by unaddressed information needs and sharing of misinformation , remains the primary factor contributing to identified vaccine confidence concerns ,58,59. PTo better address factors contributing to vaccine hesitancy, delays in vaccination, and reduced vaccine confidence, pharmacists and pharmacy technicians must understand, address, and effectively communicate evidence-based information to patients to alleviate patient fears. Evidence-based, community, and practice-guided patient information resources can be used by pharmacists to improve patient communication, address vaccine hesitancy concerns, and increase vaccination uptake, especially among under-served and poorly resourced communities where vaccine access remains a concern."}
+{"text": "The inclusion process allows children with special educational needs to be included in a normative environment. A large group consists of children with intellectual disabilities and behavioral disorders, hey need medical and pedagogical rehabilitation due to their low learning ability, neurotic disorders, and mental distortion.Study of psychophysical characteristics of children with intellectual disability and behavioral disorders.140 children with intellectual disabilities who have impairments in the neuro-psychological sphere (2017-2020 \u0433.\u0433.). Methods: medical and pedagogical, observation, examination, assessment.Variants of the child\u2019s psychophysical development: Option 1. (75%): children with a predominance of violations in behavior, emotional and volitional sphere. There is aggressiveness, inconsistency and impulsiveness of actions, lack of distance with an adult, and difficulties in complying with accepted norms and rules. Option 2 (25%): children with the following manifestations: timidity, tearfulness, distrust, fears, lack of initiative. All children have difficulty sleeping, eating disorders, and frequent psychosomatic illnesses.Children with intellectual disabilities in an inclusive practice need comprehensive assistance, taking into account different variants of their psychophysical characteristics. The studied children were found to have neurotic and neurosis-like disorders, as well as pathological personality development. All children have: low performance, lability of the nervous system, lack of voluntary regulation, impaired activity, learning difficulties. There are behavioral and mental disorders that require medical, psychological and pedagogical rehabilitation."}
+{"text": "Urological cancer is a collective term for cancers of the bladder, kidney, ureter, penis, prostate, and testicles. Last year, more than 444,000 people were diagnosed with urinary cancers in the United States. In this review, we talk about the complexity of prostate and kidney cancer. Prostate cancer covers a rather long natural disease history. During this time, the nature of this disease undergoes drastic shifts. In most cases, patients are diagnosed with localized hormone-sensitive prostate cancer (HSPC), and some will eventually enter the lethal stage called metastatic castration-resistant prostate cancer (mCRPC). Besides the most common TNM classification, there are two other angles to clinically evaluate the disease: one according to the invasion of tumor cells , and the other based on the sensitivity of tumors cells to androgen-deprivation therapy (ADT) . The combination of these two methods enables clinicians to understand the comprehensive aggressiveness and severity of a patient\u2019s tumor.Prostate cancer cells generally begin as hormone-sensitive, meaning their growth relies upon the presence of androgens, making ADT the cornerstone therapy. The initial responses to ADT are rather good; however, this is not long-lasting, and all patients become insensitive to the treatment sooner or later. On a cellular level, the treatment resistance denotes that these tumor cells have managed to bypass the dependence on androgens, either through androgen receptor (AR)-driven  or AR-indifferent (neuroendocrine differentiation) mechanisms .Currently, treatment for prostate cancer includes active surveillance, radical prostatectomy, radiotherapy, anti-androgen therapy, and some investigative therapies ,3. EspecIt has been well established that prostate cancer is of a multifocal nature, i.e., multiple tumor foci that occur and develop independently, suggesting a polyclonal origin. This distinctive feature intrinsically denotes the significant heterogeneity of prostate cancer. Recent years have seen the emergence of many valuable descriptive sequencing studies that revealed prostate cancer\u2019s complexity in different disease stages ,6,7,8,9.The mutational profiles differ considerably between localized and metastatic diseases. The Cancer Genome Atlas Research Network sequenced 333 primary prostate carcinomas and demonstrated that this cohort could be divided into seven subtypes featured by ETS fusions or SPOP, FOXA1, and IDH1 mutations. Furthermore, 26% of tumors are still included in neither of the subgroups, which reinforces that prostate cancer is indeed highly molecularly heterogeneous . SignifiBesides disease stages, differences also exist among different pathological subtypes. According to the 2016 WHO classification of prostate tumors, there are at least twelve subtypes, including acinar adenocarcinoma, prostatic intraepithelial neoplasia, intraductal carcinoma, ductal adenocarcinoma, urothelial carcinoma, squamous neoplasms, basal cell carcinoma, neuroendocrine tumors, mesenchymal tumors, hematolymphoid tumors, miscellaneous tumors, metastatic tumors, tumors of the seminal vesicles . Acinar The name IDC-P describes tumor cells growing within the pre-existing ducts and acini of the prostate. Our group has focused on IDC-P for a decade. We discovered that IDC-P indicated a worse patient prognosis in almost each disease stage  ,16,17. WNEPC belongs to neuroendocrine tumors of the prostate and is a lethal stage that often occurs due to lineage plasticity after long-term ADT treatment. Tumors in this stage no longer depend on AR signaling; therefore, the expression of AR, PSA, and PSMA is generally down-regulated. Tumor suppressors RB1 and TP53 losses, activation of certain oncogenes, and some epigenetic changes are believed to be key players during this process . BesidesRenal cell carcinoma (RCC) also represents a spectrum of heterogeneous diseases with different histological subtypes and distinct molecular alterations. Histologically, RCC consists of three major subtypes: clear cell RCC (ccRCC), papillary RCC (pRCC), and chromophobe RCC (chRCC). Despite a lower incidence, there are over ten other subtypes, such as collecting duct carcinoma, tubulocystic RCC, TFE3-translocation RCC, TCEB1-mutated RCC, fumarate hydratase\u2013deficient RCC (FH-RCC), medullary carcinoma, and oncocytoma . Among tDifferent subtypes of RCC manifest distinct histological features . MicroscThe metastatic patterns vary significantly between histological subtypes. Lung, adrenal, brain, and pancreatic metastases are more frequent in ccRCC; lymph node and peritoneal metastases are more frequent in pRCC; and liver metastases are more common in chRCC . The cliThe molecular differences may be the basis of the heterogeneity in the clinicopathologic characteristics of different histological subtypes. Genetically, 3p loss is ubiquitously observed in ccRCC and has been reported to be the earliest event in ccRCC tumorigenesis . VHL, SEDifferences in RNA expression patterns also contribute to the heterogeneity of different RCC histological subtypes. Compared with pRCC and chRCC, ccRCC shows an elevated expression of angiogenesis, metabolic processes, and cell cycle signatures, which provides the molecular rationale for the use of anti-angiogenesis treatments in patients with advanced ccRCC . The incHeterogeneity exists even within one specific histological subtype. A multi-omics study revealed seven molecular subsets with distinct angiogenesis, immune, cell-cycle, metabolism, and stromal signatures in patients with advanced ccRCC from the IMmotion 151 trial . MoreoveIn addition to inter-tumoral heterogeneity, intra-tumoral heterogeneity is also significant in understanding the tumor biology and evolutionary trajectory. A previous study from the UK performed whole-exome and RNA multi-region spatial sequencing on four patients with metastatic RCC and reported that over 60% of all somatic mutations were not detected across every tumor region . In addi"}
+{"text": "Since the early 1980s, HIV/AIDS has been an ongoing public health concern. By 2021, HIV/AIDS had killed more than 40 million people worldwide, and there were 38 million people live with HIV globally. With tremendous efforts from health professionals, policymakers, and community workers, HIV incidence has continued to fall [In this current Special Issue, we invited researchers from different regions  working with different key groups , people living with HIV, pregnant women, and elderly individuals) to contribute their work. In total, twelve studies were published in the current Special Issue, including six original research articles, four secondary data analyses, one review paper, and one modeling study. In this Special Issue, we covered various topics using different study designs  and methodologies . Specifically, Zhang et al., Liu et al., and Wang et al. assessed the determinants of HIV testing and its corresponding associations among a group of young MSM ,3,4. In In summary, with efforts from researchers, health professionals, and stakeholders worldwide, we will continue to scale-up science-based approaches among key populations. Using innovative behavioral and biomedical treatment and prevention strategies, we will work together towards the goal of ending the HIV epidemic soon."}
+{"text": "Microplastics , as an environmental stressor, have become the focus of the problematization of plastics in the environment due to their serious global pollution. The literature on the presence of MPs in the worldwide water environment and stress on the aquatic animals associated with MP pollution were reviewed.Microplastics (MPs), which are particles with a diameter of less than 5 mm, have been extensively studied due to their serious global pollution. Typically, MPs in water originate from terrestrial input. A number of studies have reported the presence of MPs as a stressor in water environments worldwide, and their potential threat to the aquatic animals, affecting the growth, oxidative stress responses, body composition, histopathology, intestinal flora, and immune and reproduction systems. During the plastic degradation process, a large variety of toxic substances are released. MPs have been proposed to be the carriers of toxic chemicals and harmful microorganisms. A study of the literature on MP pollution and stress on the aquatic animals associated with MPs was carried out. Plastics are produced and used in considerable quantities due to their low cost, excellent mechanical properties, stable chemical properties, and other optimal properties. In 2020, plastics production had reached 367 million tons worldwide . MicroplThe pollution caused by marine MPs was already reported in the early 1970s [6 items [Currently, MPs are an urgent and growing section of global water pollution. MPs in water mainly originate from terrestrial input. Dumped plastic waste, polystyrene flotation gears heavily used in aquaculture, and plastic devices discarded by the offshore drilling platforms are the leading causes of contamination . Synthet6 items . Thus, t3, while it was 1150\u20132154 items/m3 in the plain countryside and mountainous areas, indicating that there was no correlation between abundance of MPs and serviced population [The degree of MP pollution is influenced not only by the migration and transformation of MPs, but also by population density, human activities, and the proportion of development within watersheds . The abundance of MPs in four estuarine rivers in Chesapeake Bay demonstrated statistically significant positive correlations with population density and proportion of development within watersheds . The denpulation . Furtherpulation  and a tepulation  can easiThe continuous discharge of large quantities of plastics can cause serious environmental challenges, and the aquatic animals will be increasingly exposed to MP stress and inevitably forced to ingest MPs. To make matters worse, MPs will be accumulated through the food chain, causing stress responses, and posing a serious threat to aquatic animals and, subsequently, human health.Procambarus clarkii from a pond breeding station and rice-crayfish co-culture breeding station in Hubei in China [Squalius cephalus in the Marne and Seine rivers around Paris [Atherina bleekeri and Stolephorus commersonnii [Cyprinus carpio fed with commercial fish meal made of the above fish [In size, shape, and color, MPs as an environmental stressor resemble plankton, which makes it difficult for small fish and invertebrates to distinguish MPs from food ,8. As shin China , 6 fish in China , 38 of 4in China , bivalvein China , 7 of thin China , 9 speciin China , 60 specnd Paris , 27 specnd Paris , 73 of tnd Paris , 32 fishersonnii , and 13 ersonnii  were fouove fish . The abuove fish , and proove fish  was 50\u20131Chironomus tepperi larvae, and adult emergence rate of the sediment-dwelling invertebrates were reported to decrease [Artemia salina [Artemia salina [Sebastes schlegelii [Dicentrarchus labrax L. [Poecilia reticulata [Eriocheir sinensis [Oryzias melastigma [Danio rerio by 37% at 500 mg/L [cd36, mttp, and dgat2, which are associated with triglyceride resynthesis and transportation to cause lipid malabsorption and growth inhibition in zebrafish larvae [Perca flavescens [Oreochromis urolepis [Oryzias latipes, affecting nutrient absorption and antioxidant production [decrease . As a sta salina , but alsa salina . Bioaccua salina , indicathlegelii , depressabrax L. . They alticulata , and affsinensis . It has lastigma , and inh500 mg/L . Additioh larvae . The MPsavescens , impair urolepis , and infoduction .Dicentrarchus labrax L. [Carassius auratus larvae [Xenopus laevis tadpoles [Oreochromis niloticus under the environmental stress caused by MPs [Cyprinus carpio var. larvae [However, a few studies reported that a significant fraction of MPs can be excreted out of the body ,86,87, aabrax L. , Carassis larvae , and Xentadpoles . No deatd by MPs . Similar. larvae . There iIn summary, stress caused by MPs on aquatic animals is described. These findings motivate the needs for further research on their toxicity associated mechanism(s) which could provide possible solutions for pollution abatement.Danio rerio [Pagrosomus major [Oryzias latipes [Oreochromis niloticus [Danio rerio DNA methylation modification [Salmo trutta, causing endocrine disruption and genotoxic effects [Carassius auratus [A variety of fillers, plasticizers, stabilizers, lubricants, and pigments are incorporated into plastics during the production process to enhance their performance. The additives in plastics may be released after long-term physical, chemical, or biological processes, increasing environmental stress. These processes produce the toxic intermediate products, most of which can cause reproductive toxicity, development deficiency, and death in aquatic animals . Guo et io rerio . Phthalaio rerio , were deio rerio , as wellus major , which a latipes , and cauiloticus . In addification . Moreovefication . Indeed,fication ; it coul effects , and cou auratus . The pos auratus .2+ > Cu2+ > Cd2+ > Ni2+ [Hippocampus kuda [Cyprinus carpio [Pomatoschistus microps [Moina Monogolica Daday, negatively impacting their reproduction [Danio rerio [Danio rerio embryos [Symphysodon aequifasciatus were affected by MPs and Cd, while, in the interaction between the two stressors, MT level was affected by Cd and the interaction between MPs and Cd [Cyprinus carpio [The characteristics of MPs, such as small volume, large specific surface area, high hydrophobicity, and a strong affinity to heavy metals, enable them to easily interact with organic pollutants . In addition, MPs can also adsorb heavy metal pollutants, such as lead, zinc, and copper. Thus, MPs act as the carriers of many marine pollutants. It is important to note that MPs of different sizes and types exhibit variable adsorption of organic and heavy metal pollutants. For instance, the small-sized MPs have been reported to exhibit a strong adsorption capacity towards metal ions (0.261\u20130.579 mg/g) as compared to the large-sized MPs (0.243\u20130.525 mg/g), and the order of affinity of heavy metals to MPs is as follows: Pb+ > Ni2+ . Further+ > Ni2+ . The den+ > Ni2+ . Table 4pus kuda . In addis carpio , as well microps . The intoduction . It has io rerio , and let embryos  were obss and Cd . Combines carpio , and inds carpio . HoweverCyanobacteria were particularly overrepresented in plastic marine debris, collected during the TARA Mediterranean expedition, together with essential functions for biofilm formation and maturation [Bacillus subtilis exhibited greater biofilm formation than Staphylococcus aureus, with submicron-sized and conventional plastics [Vibrio, Muricauda and Ruegeria. In multi-antibiotic resistant bacteria (MARB) isolates, the positive detection rate of antibiotic resistance genes was up to 80.0% in MPs, while it was 65.3% in water, suggesting that MPs served as the hotspot for MARB and as a carrier for the spread of antibiotic resistance [Agrobacterium, nosocomial pathogens Chryseobacterium, and fish pathogens Flavobacterium) [Additionally, the porous surface structure of MPs also provides an optimal habitat for colonization, diffusion, the alimentary cycle, and biofilm formation . Biofilmturation . A studyturation . In addiplastics . The divsistance . Half ofcterium) . Furthercterium) , seriousAs plastic disposal and sewage treatment technologies have still not yet been optimized, MPs have become a focus of social and environmental concern. Currently, the research efforts on MPs worldwide mainly focus on the stress of MPs on aquatic animals. The prevention and control of plastic pollution at its origin is the best way to safeguard aquatic organisms. The following aspects are needed to strengthen this in the future.Laws and regulations, along with effective enforcement, are fundamental. Necessary regulation includes implementing and promoting a ban on plastics, enforcing the classification and recycling of plastic waste, improving the sewage treatment technology, and regularly cleaning water bodies.The plastic industry must abide by the laws and regulations and must standardize the application and treatment of plastic products along with other environmental-friendly business practices. For example, biodegradable plastic substitutes are needed to be developed urgently. The industrial plastic waste must not be randomly discarded, and the enterprises must uptake mutual supervision.The environmental awareness of the public should be improved through education programs. The public should consciously commit to garbage sorting, avoid (or reduce) the use of disposable plastic products, and encourage friends and family to strictly adhere to any plastic ban."}
+{"text": "The number of patients requiring prolonged mechanical ventilation (PMV) is increasing worldwide, placing a burden on healthcare systems. Therefore, investigating the pathophysiology, risk factors, and treatment for PMV is crucial. Various underlying comorbidities have been associated with PMV. The pathophysiology of PMV includes the presence of an abnormal respiratory drive or ventilator-induced diaphragm dysfunction. Numerous studies have demonstrated that ventilator-induced diaphragm dysfunction is related to increases in in-hospital deaths, nosocomial pneumonia, oxidative stress, lung tissue hypoxia, ventilator dependence, and costs. Thus far, the pathophysiologic evidence for PMV has been derived from clinical human studies and experimental studies in animals. Moreover, recent studies have demonstrated the outcome benefits of pharmacological agents and rehabilitative programs for patients requiring PMV. However, methodological limitations affected these studies. Controlled prospective studies with an adequate number of participants are necessary to provide evidence of the mechanism, prognosis, and treatment of PMV. The great epidemiologic impact of PMV and the potential development of treatment make this a key research field. A percentage of critically ill patients experience chronic respiratory failure and require prolonged mechanical ventilation (PMV) . PMV is Patients receiving PMV may experience complications, including limb muscle atrophy, impaired functional status, and diaphragm dysfunction . Moreove2, CO2, and pH in the blood and cerebrospinal fluid through chemoreceptive neurons and initiates automatic respiration [2 induces an increase in the ventilatory drive and the level of P0.1 recorded by bedside capnograph and pneumotachograph [2O after the hypercapnic challenge is a predictor of weaning success [The brain stem responds to levels of Opiration . Airway piration ,11,13. Pchograph ,15,16. IMechanical power is the energy transferred to the respiratory system per unit of time, which is the product of respiratory rate, tidal volume, and the airway pressure during pressure-controlled ventilation ,18. HighThe diaphragm is the primary skeletal muscle responsible for effective lung expansion . The diaReactive oxygen species (ROS), which are produced in mitochondria, sarcoplasmic reticula, sarcolemma, and transverse tubes, are the major oxidants and upstream regulators of proteolysis and mitochondrial dysfunction in the diaphragm ,32. CaspAn MV-induced oxidative load may impair diaphragm contractility, which is vital for increased proteolytic pathway expression ,38,39. TNuclear factor-\u03baB (NF-\u03baB) activation has been implicated in diaphragm injury and atrophy through measurements of the maximal twitch airway pressure after magnetic stimulation of the phrenic nerve of patients receiving MV ,36,48. AIn addition to the maximal inspiratory pressure and magnetic stimulation of the phrenic nerves, ultrasonography, a noninvasive tool, is used to evaluate the diaphragm movements of patients requiring PMV ,26. SeveThe current approach to reducing VIDD is to avoid controlled MV and the use of unnecessary neuromuscular blocking agents. Notably, low-molecular-weight heparin (LMWH) can reduce lipopolysaccharide-induced acute lung injury and systemic inflammation in animal models of endotoxemia ,57. A raThe clinical outcomes for patients requiring PMV globally have been summarized through a systemic review and meta-analysis : 50% of The prognosis for patients requiring PMV is poor. Among 29 studies of PMV, the pooled mortality rate was 62% at year 1 . HoweverComorbidities exacerbate diseases and have a severe impact on the outcomes of patients requiring PMV. Chronic obstructive pulmonary disease (COPD), cardiac disease, cerebral vascular or neuromuscular disease, end-stage renal disease, and malignancy are common comorbidities in patients requiring PMV ,72,73,74Patients with PMV and kidney injury requiring renal replacement therapy (RRT) have a lower weaning rate and poor prognosis . PMV patThe prognosis for patients with cancer requiring PMV is generally poorer than that for patients with other comorbidities . PatientCardiac dysfunction is a common cause of unsuccessful weaning and PMV . PatientPatients with acute stroke or brain trauma may have impaired consciousness, hypoventilation, or aspiration ,83,84,85COPD is characterized by systemic inflammation, airflow limitation, and episodes of acute exacerbation . Severe Pulmonary emphysema, diaphragm flattening, and dynamic hyperinflation increase the work of breathing and may result in diaphragm dysfunction in COPD ,91. The Patients requiring PMV often experience long-term immobilization complications, including limb muscle atrophy, diaphragm dysfunction, pressure ulcers, joint contracture, and deconditioning ,99. MuscA comprehensive physical exercise program includes cardiopulmonary endurance exercises and peripheral muscle training. Upper and lower limb exercises include passive leg raising, weighted resistance, and stationary cycle ergometry training ,109,110.2O to the baseline PS level increased the exercise duration in patients requiring PMV, especially in those with low respiratory muscle power [In patients requiring PMV, immobility and long-term ventilator use result in complications, such as the atrophy of respiratory muscles, decreased lung volume, and atelectasis . When pele power . Inspirale power ,115, whiIntermittent positive pressure breathing (IPPB) can increase the delivery of inspiratory positive pressure to the airway to achieve homogeneous gas distribution, recruit collapsed alveoli, and facilitate lung expansion . During Electrical muscle stimulation triggers muscle contraction and could be used to recover muscle atrophy and improve muscle strength after prolonged bed rest ,120,121.The majority of patients requiring PMV have increased muscle catabolism and decreased muscle mass synthesis after prolonged bed rest, particularly in the lower limbs ,123. In Malnutrition is common in PMV patients and associated with poor outcomes, including difficult wound healing, nosocomial infections, and increased mortality . NutritiAlthough studies suggest that the use of N-acetylcysteine and specific mitochondrial-targeted peptides i.e., SS-31) can protect against muscle atrophy during long-term inactivity, additional studies are needed to determine whether mitochondrial-targeted treatments are effective in specific cellular locations and transporting across multiple biological barriers to prevent muscle weakness during a long duration of muscle inactivity ,31,40. can protBecause there\u2019s a lack of wide scientific investigation in the field of PMV and diaphragm dysfunction, future research should involve a shared definition of this condition for the appropriate recruitment of patients. Large, multicentric, multinational RCT are also needed on pathophysiology, molecular pathways , drug therapy, diaphragmatic pacing, immune modulation and rehabilitative programs for these patients, and need to be distinct from acute critical illness patients.The number of patients requiring PMV globally is increasing, with consequences for healthcare systems. Numerous studies have proposed risk and prognostic factors for PMV, and the underlying pathogenic mechanisms include an abnormal respiratory drive and VIDD. After PMV, the diaphragm and limb muscles may exhibit muscle atrophy and impaired contractile force, resulting from accelerated protein degradation. Mitochondrial dysfunction and increased oxidative stress have been identified in animal studies mimicking sepsis and multisystem organ failure. Because multiple comorbidities are associated with PMV, physicians should treat the underlying diseases, prescribe early mobilization and avoid the risk of complications. Furthermore, adequate preventive and therapeutic strategies should be used early to attenuate the effects of PMV on the diaphragm and limb muscles. Research on the mechanisms, prognosis, and treatment  of PMV is required for improved management."}
+{"text": "Binge-eating disorder (BED) is a difficult-to-manage clinical entity, that may associate both organic  and psychiatric  co-morbidity. Psychotherapeutic and pharmacological approaches are usually combined in order to reach the best outcome for these patients, but the disorder seems to have prolonged evolution even under appropriate therapeutic managment.To evaluate the most evidence-based therapies focused on BED.A literature review was conducted through main electronic databases, and papers published between January 2000 and August 2020 were included in the analysis.Cognitive-behavioral therapy (CBT) is supported by multiple trials, and it led to decreased number of binge episodes and increased rates of remission. Behavioral activation may improve certain symptoms of BED , but not the binge episodes frequency. Interpersonal group therapy (IPT) may be helpful for BED patients with an external locus of control and significant interpersonal dificulties. Dialectical behavior therapy (DBT) has been applied in BED patients, but the results have been inconclusive. Lisdexamfetamine dimesylate is the only FDA approved drug for this indication, as dasotraline was rejected by FDA and its research discontinued by the manufacturer. Fluoxetine, sertraline, escitalopram, duloxetine, bupropion, atomoxetine, reboxetine, armodafinil, disulfiram, baclofen, zonisamide, lamotrigine, topiramate, samidorphan, liraglutid, and orlistat need more trials in order to validate their efficacy, especially on long term.There is only one drug currently FDA approved for this indication, lisdexamfetamine, and a number of psychotherapies, with CBT and IPT being the most supported by evidence."}
+{"text": "The WHO\u2019s Mental Health Gap Action Programme Intervention Guide (mhGAP-IG) has been widely used in low and middle-income countries. We reviewed literature describing interventions and training programmes beyond the mhGAP-IG, in primary healthcare (PHC) and community-based healthcare (CBH).We searched studies excluded from our updated mhGAP-IG systematic review, and included in other relevant systematic reviews, for evidence and experience of initiatives integrating mental health into PHC and CBH. Our 24 November 2020 mhGAP-IG search encompassed MEDLINE, Embase, PsycINFO, Web of Knowledge, Scopus, CINAHL, LILACS, ScieELO, Cochrane, PubMed databases, 3ie and Google Scholar. Although heterogeneity prevented meta-analysis, we descriptively summarised the evidence-base.Out of 1827 results, we identified 208 relevant records. They described randomised controlled trials of mental health interventions , non-randomised studies measuring clinical outcomes , training outcomes  and implementation outcomes , plus descriptive accounts , baseline surveys and exploratory studies  and commentaries (7 studies). Most (40%) were conducted in the African region, region of the Americas (16%), and South-East Asia (13%). Randomised and non-randomised studies reported improved symptoms, substance use, functioning, parenting and child outcomes. Non-randomised studies reported improved clinical knowledge, confidence and skills following training.The literature beyond the mhGAP-IG is extensive and shares common findings. Future priorities are less-studied regions, interventions for severe mental illness, exploring ways that mhGAP-IG and alternative approaches complement each other in different contexts and scaling-up mental health integration.PROSPERO registration numberCRD42017068459. The WHO\u2019s Mental Health Gap Action Programme Intervention Guide (mhGAP-IG) provides clinical guidelines to enable non-specialist staff to deliver evidence-based mental healthcare in primary healthcare (PHC) and community-based healthcare (CBH) settings.Despite widespread implementation, alternative approaches to integrating mental health into PHC and CBH continue to be developed and evaluated.This review identified and synthesised the evidence base for approaches to integrating mental health into PHC and CBH beyond the mhGAP-IG, worldwide.We identified a substantial literature, not only from the African and South-East Asian regions but also from locations in which the mhGAP-IG has been less widely implemented, including the region of the Americas.Common findings with the mhGAP-IG evidence base support the need for research and policy addressing barriers to successful integration of mental health into PHC and CBH settings, and the need to prioritise neglected disorders, including severe mental illness.The WHODuring public health emergencies such as the coronavirus pandemic, clinical priorities and care pathways are adjusted, and travel to centralised services may be compromised, increasing the need for stepped care.The availability of PHC and CBH personnel, trained in mental health, is essential to stepped mental healthcare. However, there is a chronic shortage of non-specialists trained in mental healthcare in low and middle-income countries (LMICs).The WHO Mental Health Gap Action Programme (mhGAP) was launched in 2008, to address the gap between the need for and availability of mental healthcare.In the most recent review,While the reach of the mhGAP-IG, HIG and app in LMICs is impressive, extensive literature on integrating mental health into PHC and CBH predates their inception or employs alternative approaches.A recently-updatedOther reviews meta-analysed LMIC RCTs of psychological treatments for depression and anxiety disorders (n=17 interventions),We aimed to identify and synthesise evidence for programmes outside the WHO mhGAP-IG, HIG and app, which integrated mental health into PHC and CBH.Given prior systematic reviews with a narrower focus, we adopted a pragmatic approach, following principles advocated by WHO.We originally searched the following databases on 24 November 2020: 3ie, Cochrane Library, CINAHL, EMBASE, LILACS, Medline, PsycInfo, PubMed, SciELO, Scopus, Web of Knowledge and Google Scholar. Search terms were \u2018mental health gap action programme\u2019 OR \u2018mental health gap action programme\u2019 OR \u2018mhGAP\u2019. We searched these databases in English, but results in other languages were eligible. We screened individual articles and the reference lists of relevant systematic reviews, for eligibility.RCK removed duplicates and then screened titles and abstracts for eligibility. Inclusion criteria were: any study design describing evidence or experience of integrating mental healthcare into PHC and CBH without using the mhGAP-IG, conducted in any country (including HICs), reported in any language. JS screened the list of relevant systematic reviews, before extracting first author, publication year, country of implementation, study design, sample and findings from each eligible study, into a table. RK reviewed the eligibility of studies for which inclusion was uncertain. On 21 February 2022, we searched for published records of included protocol results.We used the WHO definition of PHC,10.1136/ebmental-2021-300401.supp1Supplementary dataIncluded studies described RCTs assessing mental health intervention impacts in PHC and CBH  were RCTs assessing mental health intervention impact in PHC and CBH . EighteeOther interventions included home visits, exercise programmes, pharmacotherapy and collaborations between PHC staff to holistically address health and social determinants. A proportion of RCTs also described the training provided to a range of counsellors, nurses, peer and group leaders, community health workers, volunteers, non-specialist refugee or migrant facilitators, therapists, lay facilitators, social workers, PHC staff and research assistants.RCTs reported depression remission, reduced depressive symptoms and prevalence, CMD symptoms, psychiatric morbidity and severity of mental health conditions. Findings also showed reduced substance use and symptom scores, levels of stress, emotion regulation intensity in children, caregiver burden, caregiver mental health and distress, trauma, anxiety, stress, PTSD symptoms, anger, aggression and intimate partner violence.Included RCTs reported improved functioning, well-being, quality of life, recovery from CMDs, treatment completion and reach, medication adherence, substance use abstinence, health-related self-efficacy, self-care, nutrition, overall health behaviours, contraception use, breast feeding and service satisfaction.Studies identified impacts on knowledge about parenting, knowledge and attitudes towards infant development, parenting self-efficacy and competence, home safety attitudes, social support and interpersonal relationships, children\u2019s weight gain or healthy weight, self-rated harsh discipline, positive behavioural management, caregiver\u2013child interactions, initiation of communication by children, mood and mothers\u2019 health and mental health. RCTs also reported reduced separation distress in infants, child internalising behaviours, improved cognitive and receptive language scores, motor skills, adaptive behaviours, emotion regulation and school behaviour.Studies which also evaluated the training delivered to non-specialist providers reported its acceptability and feasibility, increased confidence in diagnosing or treating depression, improved routine detection of mental health conditions, higher digital training completion, greater objective competence and subjective confidence in applying CBT techniques.Of 208 included studies, 22 (11%) were non-randomised studies measuring clinical outcomes of initiatives integrating mental health into PHC and CBH . Four  were non-randomised studies of mental health integration into PHC and CBH focused on training outcomes . Ten  were non-randomised studies of mental health integration into PHC and CBH, focused on implementation outcomes . One  were descriptive accounts of mental health integration into PHC and CBH . They deFindings included reduced emergency psychiatric presentations following community mental healthcare, the need for mental health legislation and policy reform, scaling up PHC mental health training and balanced care models integrating PHC and secondary mental healthcare and the potential for humanitarian responses to develop sustainable mental healthcare.Opportunities included service user, caregiver, traditional healer and religious leader engagement. Challenges included continuity of care, providing services in rural areas, clinical complexity, limited mental health specialists, staff and supervisor attrition, limited provision for psychiatric emergencies, competing priorities, sporadic medication supply, constrained budgets and stigma.Of 208 included studies, six (3%) were baseline surveys and exploratory studies of mental health integration into PHC and community settings ; all werOf 208 included studies, seven (3%) were commentaries on mental health integration into PHC and CBH . CommentThis review of non-mhGAP initiatives integrating mental health into PHC and CBH worldwide identified a range of literature describing RCTs of primary and community mental health interventions, non-randomised studies measuring clinical outcomes, training outcomes and implementation outcomes, descriptive accounts, baseline surveys and exploratory studies and commentaries, of which between 72% and 100% were conducted in LMICs. Targeted disorders largely corresponded to those addressed in the mhGAP-IG, while clinical interventions were almost exclusively those recommended by the mhGAP-IG, bar a small number of trauma-focused studies.In comparison to our previous systematic reviews of mhGAP-IG evidence,Clinical interventions focused on psychoeducation, psychosocial support and brief psychological therapies (including recent innovations, such as self-help plusMany included interventions did, however, target anxiety symptoms, which lack a dedicated mhGAP-IG module, and PTSD symptoms, which are addressed in a separate mhGAP-IG moduleThe depth with which interventions were described and evaluated varied considerably, perhaps indicating the benefits of standardised programmes, which can be adapted to the context. However, stigma, cultural differences and differing perspective on treatments can be barriers to mhGAP-IG implementation and use.The literature on mental health integration into PHC and CBH beyond the mhGAP-IG demonstrates substantial commonality. Barriers to implementation, challenges and opportunities in the non-mhGAP-IG literature had much in common with the mhGAP-IG literature. Insufficient basic mental health training meant that PHC staff members\u2019 interest in and understanding of mental health was often low. Competing priorities and lack of prioritisation by managers limited staff motivation for training, acquiring and implementing new mental health skills. The need for ongoing supervision and refresher training within a task-sharing model was often under-resourced. Resource constraints were a common barrier. Stakeholder support for mental healthcare, novel technologies and longer term approaches to mental health integration was facilitators also found by mhGAP-IG reviews.Our search strategy enabled us to compare learning from mhGAP-IG literature with other relevant studies, using efficient and transparent methods to avoid duplicating existing systematic reviews. A limitation is that we did not conduct a dedicated systematic review of all published studies in this field, raising the risk of missing some relevant evidence. Our study complements the existing literature, however, by synthesising a variety of study designs, capturing the diversity of global evidence for integrating mental health into PHC and CBH, beyond the WHO mhGAP-IG.Future priorities are less-studied regions, interventions for SMI, understanding how mhGAP-IG and alternative approaches can complement each other and scaling-up mental health integration beyond brief research studies and grant-funded projects."}
+{"text": "During and following the processing of a plant\u2019s raw material, considerable amounts are wasted, composted, or redistributed in non-alimentary sectors for further use . However, many of these forms of waste still consist of critical bioactive compounds used in the food industry or medicine. Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders. The primary treatment is based on symptomatology alleviation and controlled dietary management. Thus, this review aimed to describe the possible relevance of molecules residing in plant waste that can be used to manage IBS and co-occurring symptoms. Significant evidence was found that many forms of fruit, vegetable, and medicinal plant waste could be the source of some molecules that could be used to treat or prevent stool consistency and frequency impairments and abdominal pain, these being the main IBS symptoms. While many of these molecules could be recovered from plant waste during or following primary processing, the studies suggested that enriched food could offer efficient valorization and prevent further changes in properties or stability. In this way, root, stem, straw, leaf, fruit, and vegetable pomaces were found to consist of biomolecules that could modulate intestinal permeability, pain perception, and overall gastrointestinal digestive processes. Plant wastes are common end-products of the industries developed by humankind across the centuries. The food industry, animal husbandry, pharmaceutical industry, and clothing industry use plants as raw materials in obtaining different products for whom use is essential. However, substantial wastes resulting from fruit, vegetable, and medicinal plant processing could often pose an important threat to the environment and lead to economic imbalance. For instance, some fruits, leaves, straws, or even roots are wasted in proportions varying from 10 to 65% of the whole plant\u2019s weight [It is generally accepted that many forms of plant processing waste can be reutilized, as some bioactive components could still be retained. In this way, it was shown that plant waste could be valorized in obtaining biofuels, bio-fertilizers, and bioethanol. Additionally, it was shown that plant waste could be used in the food industry to improve nutritional food quality or design foods that address some special dietary needs of individuals . Thus, fIrritable bowel syndrome currently affects one in every five individuals ,9. DespiWhile it was shown that an imbalanced and nutritionally deficient diet could promote, maintain, and worsen IBS symptoms , severalConsidering these aspects, this review aims to identify and describe the potential beneficial components of plant processing waste in IBS management and propose possible uses for this waste according to recent studies on food processing, industry, and the nutritional values of fruit- and vegetable-waste-enriched food products.While dietary fibers\u2019 exact definitions and classifications are still incomplete, they were initially considered bulk material in vegetable food sources. Their properties enable them to be of extreme use in gastrointestinal tract health. In this way, the soluble dietary fibers  were demonstrated to interact with some of the molecules which contribute to digestive processes, such as bile acids, gastric hydrochloric acid, and heavy metals, while the insoluble dietary fibers  contribute to stool bulk weight and intestinal peristalsis  ,28. FurtIn this context, the fact that the management of IBS includes dietary control offers sufficient background to consider diet one of the best ways to manage IBS. It was previously shown that food could be the primary method through which IBS symptom burden could be modulated . In thisCitrus x sinensis and Mangifera indica fruits). It was suggested that the pomace originating from juice manufacturing could be rich in dietary fibers. The most abundant pomace, resulting from Citrus fruit processing, was demonstrated to be extremely rich in pectin [Psidium guajava and Mangifera indica fruit pomaces resulting from juice manufacturing as a possible dietary fiber source. Additionally, Malus domestica and Pyrus communis fruit pomaces were described as rich in pectin content [Now, quantity is always significant, but more important is quality. It is relevant to mention that many studies suggest that almost all vegetable food source waste could offer good quality dietary fibers. Hussain et al.  extensivn pectin , which cn pectin ,36. Rodrn pectin  mentione content .Ribes nigrum and Vitis vinifera fruits are particularly rich in this type of fiber [Malus domestica, Aronia arbutifolia, Ribes nigrum, Fragaria \u00d7 ananassa fruits and Brassica oleracea (var. capitata f. rubra) and Daucus carota pomaces are high in neutral and acidic dietary fiber content. The highest dietary fibers were observed in Aronia arbutifolia and Ribes nigrum fruit pomaces, while the lowest content was observed in the Malus domestica fruit pomace. Considering that each dietary fraction could exhibit a different role in IBS management, significant differences between soluble and insoluble fibers were noted. In this way, Aronia arbutifolia and Ribes nigrum fruit pomaces were rich in insoluble dietary fibers. In contrast, Daucus carota roots and Malus domestica fruit pomaces were rich in soluble dietary fibers [Ribes nigrum and Vitis vinifera fruits could be abundant sources of this fiber. Moreover, it was suggested that grape pomace could be an essential component of the human diet due to other constituents besides dietary fibers, anthocyanins, and ellagitannins, as Alba et al. [Regarding the soluble fiber content, it was reported that of fiber . Nawirskof fiber  showed ty fibers . Considey fibers  discussea et al.  describeAsparagus officinalis spears, which include almost 50% of the harvested part of the plant that are lost mainly during the preparation process [Asparagus officinalis is rich in soluble and insoluble dietary fibers and phenolic compounds, which could partly motivate its increased antioxidant activity [Musa sp., Mangifera indica, Psidium guajava, Colocasia esculenta, Averrhoa carambola, Pouteria sapota, Manilkara zapota, and other exotic fruits were described to be ideal as dietary fiber sources [Actinidia deliciosa and Olea europaea fruit waste and Ananas comosus peels.Other plant processing wastes that could be successfully used to produce dietary fiber-enriched foods are  process . Studiesactivity . Further sources . Additio sources  and Schi sources , which a sources , who argTriticum aestivum bran, Solanum tuberosum tubercle peel), biscuits and cookies , yogurts , cheese , ice cream (Ananas comosus waste products), sweets , meat products  were demonstrated to be efficient and nutritionally improved products in which dietary fibers originating from plant waste fit perfectly and offered health benefits [Considering their properties, how the discussed plant waste dietary fiber extracts could be used were previously discussed. Thus, many dietary fiber extracts could be used as soluble powders, and those already available for commercial use  could be added to different food products. In this way, bread  could be used in different bakery products considering their dietary fiber content and properties [Pisum sativum, Lens lenticularis, and Phaseolus vulgaris seed peels could also be used as a source of dietary fiber that could play an essential role in alleviating the digestive symptoms of IBS . Persea americana fruit peels and seeds were also a good source of dietary fiber, protein, and micronutrients [operties . Potato utrients  which caBrassica oleracea, Allium cepa stems, Pisum sativum/Phaseolus vulgaris, Lens lenticularis seeds, Solanum tuberosum tubercles), grains, and fruits (Musa sp. and some Citrus varieties) [Daucus carota root pomace.However, Capili et al.  suggesterieties) ,42, coulrieties)  discusseElaeis guineensis, Cocos nucifera, and Olea europaea fruits, Helianthus annuus, Brassica napus (canola), Sesamum indicum, Camelina sativa, and Sinapis alba seeds, and others, are currently used to produce edible oils, while the residues are wasted [Many forms of lipid-rich plant waste are currently used in the biofuel industry. In the oil industries, the consistent amounts of plant residues following edible oil extraction, generally achieved by processing the seeds through mechanical pressing, results in oil cakes. Due to their increased fat and other oily components, they pose an essential threat to the environment, with their disposal often leading to pollution . Thus, re wasted . Howevere wasted .However, the overall effects of dietary lipids on the IBS-affected gastrointestinal tract are somewhat controversial. Since lipid metabolism was described as impaired in IBS, the high intake of dietary lipids could lead to bloating, gas retention, and flatus . As prevDespite this, several classes of lipids are of extreme use in human health and gastrointestinal tract active function. For instance, Chua et al.  suggesteRecent studies showed that just a few types of plant waste could be a relevant source of lipids and free fatty acids used in the human diet. An important source of lipids could be medicinal plant wastes, as Khomova et al.  describeTriticum aestivum, Hordeum vulgare, Oryza sativa, and Zea mays plant processing  and legume seed waste (mainly lignocellulose sources) can be used for fermentative bacteria and fungi growth [Arachis hypogaea, Sesamum indicum seed cakes, Vigna radiata wastes, and Glycine max wastes. The most important aspect of discussing these waste valorization products is the potential benefits of alleviating IBS symptoms. Despite the increased content of raffinose, stachyose, and phytic acid (capable of producing bloating and gas retention), IBS patients could trigger supplemental gastrointestinal symptoms. These side effects could be successfully overcome if Rhizopus oligosporus and Neurospora sitophyta carry out the fermentation, both being able to hydrolyze phytic acid and the mentioned saccharides, thus eliminating the risk for flatulence development [Other ways of obtaining good quality edible lipids include using plant waste as a substrate for lipid-producing microorganisms and genetically engineering plants. In this way, a wide range of plant waste is currently used as substrates for lipid-rich biomass production: cereal grains waste originating from i growth . Two of elopment . Moreoveelopment . Furtherelopment ,58.Yarrowia lipolytica) that produce lipid-rich biomass and an important lipid metabolism enzyme (lipase) [Yarrowia lipolytica in meat and dairy products. They observed its lipolysis activity and its capacity to produce proteases and esterases, which promote maturation processes. However, protease-rich sources could lead to the inflammatory response [Yarrowia lipolytica yeast could be genetically engineered to produce heptadecenoic acid, which was demonstrated to increase intestinal motility in a rat model of diarrhea in neo-maternal separation by modulating the frequency of colonic muscle contractions [Non-edible oil waste could also be valorized in the food industry by being used as a substrate for yeasts  . Zinjard(lipase)  documentresponse , and thuresponse , Yarrowiractions .Camelina sativa, Glycine max, Brassica carinata, and Brassica nigra seeds could all produce 15 to 25% eicosapentaenoic acid and docosahexaenoic acid [Regarding transgenic plants that exhibit increased contents of polyunsaturated fatty acids, Khan et al.  reviewedoic acid , both heoic acid ,65,66.The importance of micronutrients in the diet of IBS patients was discussed by several studies, which suggested that supplementation with some vitamins could be of extreme use in the alleviation of IBS symptoms. Considering the gastrointestinal impairments occurring in IBS and the tendency of the patients to avoid consuming certain aliments and foods, it was also discussed that some vitamins and minerals could be deficient or lacking in IBS patients, which could lead to further impairments. Thus, it was shown that IBS patients often lack vitamin D and minerals, such as zinc, iron, and magnesium ,68. TherGlycine max seed isoflavone and cholecalciferol (vitamin D3) administration to IBS patients could significantly improve gastrointestinal symptoms by reducing inflammation and gut permeability. B complex vitamin deficiency was documented in IBS patients in correlation to gastrointestinal symptomatology and comorbid psychiatric manifestations [Furthermore, Jalili et al.  showed tstations ,75,76. TBeta vulgaris, Brassica rapa, Daucus carota, and Raphanus sativus roots, Zingiber officinale rhizomes, and Ipomoea batatas and Solanum tuberosum tubercles, increased levels of vitamin C , riboflavin (Ipomoea batatas), niacin (Brassica rapa), and thiamine (Solanum tuberosum) were reported. Furthermore, they compared their results with other studies. They reported that similar levels of the mentioned vitamins were observed in Solanum melongena, Abelmoschus esculentus, Capsicum annuum, Brassica oleracea var. botrytis, Solanum lycopersicum, and Lagenaria siceraria fruits, and Spinacia oleracea, Brassica oleracea, and Lactuca sativa leaves [Sambucus nigra, Sorbus aucuparia, and Rosa canina fruit pomace [Psidium guajava, Carica papaya, Prunus domestica, Prunus persica var. nucipersica, and Vitis vinifera fruit peels, were evaluated for their vitamin content. Spondias tuberosa fruit pulp contains increased amounts of vitamin C and B complex vitamins [Khattak and Rahman  reporteda leaves ,79,80. Vt pomace . Moreovevitamins ,82,83.Musa sp. fruit peels, which are more than one-third of the fruit and are often wasted or composted [Carica papaya fruit peels to be used in medicinal applications, and considering the rich range of minerals, vitamins, phenolic antioxidants, and dietary fibers, they reported that papaya peels could successfully be used in food, cosmetic, and pharmaceutic industries, as they have the potential to exert anti-inflammatory effects, prevent aging and colon cancer, and facilitate pain relief, muscular relaxation, and smooth muscular contraction. Thus, papaya peels could be considered to be of possible relevance in the alleviation of IBS symptomatology.Some of the B complex vitamins, as well as vitamin C and E, were reported in omposted ,84. Moreomposted  demonstromposted  reviewedVitis vinifera seeds [Mangifera indica fruits, which can successfully be processed into biscuits and gelatins [Another essential vitamin for the integrity and health of the gastrointestinal tract is vitamin E, which is present in a vital amount in ra seeds . At the ra seeds ,88 and ira seeds  in variogelatins .In a close relationship with vitamins, metal microelements are also important in human health and nutrition. Thus, it was shown that trace elements such as magnesium, zinc, copper, and iron are important modulators of the innate immune system . PreviouFagopyrum esculentum grain flour in gluten-free bread. Knowing that IBS patients are often challenged by digestive sensitivity to gluten [Fagopyrum esculentum grain flour. Fagopyrum esculentum processing waste (straws and husk) are currently used in bioethanol production [Considering these aspects, different formulations or functional foods obtained using plant waste as raw material could bring the discussed micronutrients into the IBS diet. For instance, Krupa-Kozak et al.  examinedo gluten , it coulo gluten . It was oduction  or as sooduction , but theoduction  reportedBeta vulgaris, Brassica rapa, Daucus carota, Raphanus sativus roots, Zingiber officinale rhizomes and Solanum tuberosum tubercles carry increased levels of microelements, including sodium, calcium, magnesium, iron, zinc, potassium, and phosphorus, which could be of nutritional interest in the human diet. Additionally, the authors [Punica granatum fruit peel powder  [Moreover, Khattak and Rahman  showed t authors  reviewedontents)  and leafontents) .Digestive enzyme supplementation is a current treatment for gastrointestinal symptoms of IBS based on the administration of digestive enzymes in different formulations to facilitate or modulate digestion and intestinal motility in IBS patients ,107. In Carica papaya fruit peel extract, of which the principal constituent, papain, is considered relevant in alleviating digestive symptoms occurring in IBS [Carica papaya fruit wastes could be considered in being valorized with the purpose to manage IBS symptoms.The best-known example is g in IBS . Thus, tg in IBS  and thatg in IBS ,111, CarAnanas comosus [Additionally, similar effects were reported for bromelain, naturally found in the fruits and the stems of  comosus . Bromela comosus , suggest comosus ,114.A recent report showed that oxidative stress is an essential component of IBS\u2019s complex and multifactorial pathophysiology . MoreoveCamelina sativa. We showed that the oil obtained from the Camelina seeds could improve antioxidant enzyme activity and prevent lipid peroxidation in a rat model of stress exposure (IBS model) [Considering the new guidelines in IBS diagnosis and treatments, an antioxidant-rich diet is encouraged due to the significant improvement seen with antioxidant administration. In this context, there are plenty of antioxidant sources that can provide quality components to the human diet, including plant waste from the food industry. In this way, our group previously studied the antioxidant potential of S model) . MoreoveS model)  showed tVitis vinifera fruit pomace could exhibit antidepressant and anxiolytic properties, which could also help manage IBS, as depression and anxiety are burdensome components of IBS comorbid impairments [Malus domestica, Aronia melanocarpa, Daucus carota ssp. sativus var. atrorubens [Citrus sp. wastes [Additionally, it was previously shown that airments ,122. Basairments , consistairments  and Tenaairments . Signifirorubens , and Cit. wastes . An exte. wastes .Vitis vinifera, Malus domestica, Euterpe oleracea, Opuntia humifusa, Psidium guajava, Cucumis melo, Passiflora edulis, Citrus limetta, Ananas comosus, Solanum lycopersicum fruits, Daucus carota roots, Brassica oleracea leaves, and the seeds wastes of Theobroma cacao and Coffea sp. [Aronia melanocarpa, Ribes nigrum, Rosa canina, Sambucus nigra, Sorbus aucuparia, Morus alba, Morus nigra) [Punica granatum fruit peels [Castanea sativa seed epicarps [Another essential antioxidant class that can be found in fruits and vegetables is polyphenols. Eskicioglu et al.  reviewedffea sp. ,128. Dess nigra) ,128,129.it peels  and Castepicarps .Vitis vinifera fruit pomaces were incorporated. Similarly, Ajila et al. [Mangifera indica fruit peel powder when added to biscuits and macaroni. Additionally, it was recently reported that fruit pomaces could significantly improve the nutritional value of biscuits, cookies, cakes, and bread products and exhibit antioxidant potential [Armoracia rusticana [Daucus carota [Beta vulgaris roots [Regarding the industrial ways in which the mentioned pomaces could be valorized to bring significant nutritional value and symptomatologic relief, Yu  reporteda et al. ,133 descotential ,138,139.s carota , and Betis roots  were sugThymus vulgaris and Origanum vulgare) could be a possible source of antioxidants and phenolic compounds [Matricaria chamomilla waste could be a significant source of antioxidants. These forms of plant waste could also be valorized in food products. In this context, Ning et al. [Camellia sinensis waste could significantly improve the quality of bread products by adding antioxidant potential.Antioxidants could also be found in medicinal plant wastes originating from essential oils or tea/juice concentrate extractions. Thus, it was previously shown that waste resulting from aromatic plant distillation (ompounds . Similarompounds  reportedg et al.  reportedHowever, the antioxidant capacity decreases with increased processing steps until the end product . Thus, iSignificant evidence has shown that many forms of fruit, vegetable, and medicinal plant waste could be a source of critical bioactive molecules that could be implicated in IBS treatment or prevention: dietary fibers, lipids, vitamins, minerals, enzymes, and, last but not least, antioxidants, many of which could be recovered during or following processing without interfering with or hindering the primary technological processes. Root, stem, straw, leaf, fruit, and vegetable pomaces were rich in the mentioned biomolecules and thus relevant in further strategies of IBS management."}
+{"text": "Attention-Deficit/Hyperactivity Disorder (ADHD) is characterized by impairing symptoms of inattention and/or hyperactivity/impulsivity. Although Emotional Dysregulation (ED) is not current criteria for ADHD, several clinical, imaging and genetic studies have been suggesting its inclusion. ED seems to impair social and occupational capacities, leading to poor quality life. In this regard, managing this situation is fundamental.ED in ADHD review and its management, including pharmacological and nonpharmacological approaches.Non-systematic review through literature using databases as Pubmed and UpToDate. Keywords used: Attention-Deficit/Hyperactivity Disorder, Emotional Dysregulation, management, pharmacotherapy.Literature refers to ADHD drugs, such as psychostimulants and atomoxetine, as the first line managing ED. However, some studies demonstrated that ADHD drugs have lower efficacy while treating emotional symptoms, when compared to attention or hyperactivity/impulsivity symptom control. Other medications, such as antidepressants or mood stabilizers, are not considered due to low efficacy and side effects . Regarding non pharmacological approaches, there have been results with cognitive behavioral treatment, and management techniques for anger, frustration and communication skills.Although the majority of studies demonstrate psychostimulants and atomoxetine role, there is an important lack of information regarding management of ADHD emotional dysregulation. It is a multifactorial condition, and, as such, non pharmacological and pharmacological management are needed to address this issue. More research is necessary, in order to improve patients\u2019 quality of life.No significant relationships."}
+{"text": "Over the years, the vaste expansion of plastic manufacturing has dramatically increased the environmental impact of microplastics [MPs] and nanoplastics [NPs], making them a threat to marine and terrestrial biota because they contain endocrine disrupting chemicals [EDCs] and other harmful compounds. MPs and NPs have deleteriouse impacts on mammalian endocrine components such as hypothalamus, pituitary, thyroid, adrenal, testes, and ovaries. MPs and NPs absorb and act as a transport medium for harmful chemicals such as bisphenols, phthalates, polybrominated diphenyl ether, polychlorinated biphenyl ether, organotin, perfluorinated compounds, dioxins, polycyclic aromatic hydrocarbons, organic contaminants, and heavy metals, which are commonly used as additives in plastic production. As the EDCs are not covalently bonded to plastics, they can easily leach into milk, water, and other liquids affecting the endocrine system of mammals upon exposure. The toxicity induced by MPs and NPs is size-dependent, as smaller particles have better absorption capacity and larger surface area, releasing more EDC and toxic chemicals. Various EDCs contained or carried by MPs and NPs share structural similarities with specific hormone receptors; hence they interfere with normal hormone receptors, altering the hormonal action of the endocrine glands. This review demonstrates size-dependent MPs\u2019 bioaccumulation, distribution, and translocation with potential hazards to the endocrine gland. We reviewed that MPs and NPs disrupt hypothalamic-pituitary axes, including the hypothalamic-pituitary-thyroid/adrenal/testicular/ovarian axis leading to oxidative stress, reproductive toxicity, neurotoxicity, cytotoxicity, developmental abnormalities, decreased sperm quality, and immunotoxicity. The direct consequences of MPs and NPs on the thyroid, testis, and ovaries are documented. Still, studies need to be carried out to identify the direct effects of MPs and NPs on the hypothalamus, pituitary, and adrenal glands. All authors contributed to the article and approved the submitted version."}
+{"text": "There have been numerous progresses recently made in the knowledge of different types of stress involvement in human pathology, in an effort to counteract or to prevent their etiopathogenic pathways or to find novel therapeutic approaches. Given the numerous types of stress factors or stressors, a brief classification of different kinds includes environmental , metabolic (high body-mass index), and drug-related , in association with oxidative stress.Many epidemiological studies have demonstrated an increased risk of death related to exposure to extreme temperatures, in correlation to temperature threshold, humidity, and the lagged effect of temperature on mortality ,2. CurreUltraviolet radiation (UVR) is an important environmental stressor, considering its ability to induce oxidative DNA damage, by wavelength-dependent manner photoproducts, such as cyclobutane pyrimidine dimers (CPD) and 6-4-pyrimidone photoproducts (6-4PP), along with UV-induced reactive oxygen species (ROS), leading to melanoma . AlthougNumerous evidences, certified by molecular techniques and culture methods, confirm the origin of various chronic syndromes from viral infectious agents\u2014for instance, the association between Epstein-Barr virus and Burkitt lymphoma, Human papillomavirus and cervical cancer, hepatitis B virus (HBV) infection and chronic liver disease as well as hepatocellular carcinoma, hepatitis C virus and mixed cryoglobulinemia, KSHV (human herpesvirus 8) and Kaposi sarcoma, poliovirus as well as West Nile virus and paralysis, Human T-lymphotrophic virus type 1 and tropical spastic paraparesis as well as chronic arthropathy , and, moIncreased white adipose tissue (WAT) accumulation, especially of visceral type, is correlated with metabolic stress or metabolic diseases. WAT hypertrophy or hyperplasia have been analysed in adults with body-mass index (BMI) \u226530 or percentage of body fat \u226535% in women or \u226525% in men, according to World Health Organization (WHO) diagnosis criteria . CurrentEnvironmental factors, such as nutritional stressors or pollutants, including exposure to pesticides, can be also associated with the onset of obesity by epigenetic modifications, increasing the risk of diabetes development. Interestingly, chronic elevation of glucocorticoids induced by stress leads to stimulation of adipocytes leptin production and pancreatic insulin, followed by a reduced brain sensitivity for both of them, resulting in leptin and insulin resistance and, consequently, appetite suppression loss . AdditioThe increased glucose levels in diabetes results in an increased production of reactive oxygen species (ROS), associated with impairment of normal body antioxidative defence mechanisms, resulting in oxidative stress or tissue damage through different signalling pathways, promoting diabetic complications. ROS-induced oxidative stress results in protein modifications, by carbonylation, nitrosylation, glutathionylation, and glycation, with their accumulation, mediating the advance of diabetes pathogenesis, and this process contributes to hyperglycaemia-induced macro- and microvascular complications . Moreovee or drug clearance- CL), as basic pharmacokinetic parameters. In correlation with the drug structure, different families of enzymes perform its metabolism, such as cytochrome P450s (CYPs), epoxide hydrolases (EH), flavin-containing monoxygenases (FMO), N-acetyltransferases (NAT), UDP-glucuronosyltransferases (UGT), glutathione S-transferases (GST), and sulfotransferases (SULT) [Recent progresses have been registered in pharmacokinetics (PK), related to absorption, metabolism, distribution, and elimination of medications, pharmacodynamics (PD), related to the response of stimulation of the drug target receptor, or ADME  , resultis (SULT) .Alternatively, numerous pro-drugs have been obtained by metabolic activation, characterized by less generalized toxicity and high levels of biologically active molecules in the target tissues. This metabolic activation is catalysed by cytochromes, including levodopa, diazepam, cyclophosphamide, talampicillin, ftorafur, prednisone, enalapril, and protonsil, which are converted to dopamine, oxazepam, phosphoramide mustard, ampicillin, fluorouracil, prednisolone, enalaprilat, and sulfanilamide, respectively . CYPs, tA relatively new notion is that of anaesthetic-induced developmental neurotoxicity (AIDN) correlated to surgeries performed in periods of time when the brain is highly vulnerable to environmental stress, such as young children, pregnant women, mainly related to the use of propofol (i.v.) and sevoflurane (volatile), with deleterious effects on neonatal brain development . AIDN isThe benefits and side-effects of opioids are currently considered in the context of addiction and respiratory depression. A potentially lethal condition is that of opioid-induced respiratory depression (OIRD), mainly when the opioid is abused, in association with sedatives, alcohol, or illicit substances . RecentlAlcohol abuse is related to more pathologies than all other drugs combined, while alcohol dependence results in high rates of mortality and morbidity, being associated to adverse individual and social consequences. Alcohol use leads to alteration of the communication between brain neurotransmitters, hepatocytes alteration by alcohol\u2019s by-products, allowing ammonia and manganese to cause hepatic encephalopathy, or increasing the risk of strokes, regardless of a history of coronary heart disease . It is a+/K+/2Cl\u2212 cotransporter in the blood-brain barrier (BBB) [Nicotine, in association with oxidants, such as nitrogen oxides and free radicals, and carbon monoxide, contained by tobacco smoke (TS), is considered both neurotoxic and cardiotoxic . TS has er (BBB) . Nicotiner (BBB) , with iner (BBB) , reachiner (BBB) . Its prier (BBB) . The reiWith a marked impact in therapy, recent knowledge in pharmacokinetics and pharmacodynamics has led to various strategies meant to counteract the low stability, low bioavailability, and poor solubility of oral anti-diabetics or to enhance the transdermal delivery of different active pharmaceutical ingredients by nanotechnology. Starting from the use of vesicular systems, such as conventional liposomes (firm lipid bilayered vesicles), the technology has been largely extended to niosomes (non-ionic surfactant distinct layer vesicles)  and to eWithin this context, further research is needed for a deep insight into the complex influences of different types of stressors in pathology, along with the new tools of diagnosis currently available, and the possibilities to exploit their pharmacokinetics and pharmacodynamics, such as therapies using microparticles and nanoparticles. Furthermore, promising perspectives are emerging for early diagnosis, disease monitoring, and identification of complex pathways involved in their pathophysiology, along with histopathological and molecular characteristics in various stress-induced disorders, leading to novel, tailored therapeutic approaches."}
+{"text": "Monkeypox virus (MPXV) is characterized by painful skin lesions and fever, sometimes with lymphadenopathy, pharyngitis and myalgia, and a prodromal period . AlthougVaccines exist. Single-dose and dual-dose smallpox vaccines seem efficacious against MPXV . Both reWe can predict spread. MPXV DNA has been detected in feces , nasophaSpillover to other vulnerable populations should be anticipated due to close associations between MPXV and rodents, oral\u2013fecal contamination, and transmission between close contacts. This includes people experiencing homelessness, incarceration, addiction, and forced migration due to intersecting risks such as poverty, stigma, discrimination, mobility, and low health literacy, which can foster medical mistrust and vaccine hesitancy. Minority groups who face systemic prejudices in healthcare settings are being disproportionately affected. Congregate settings such as homeless encampments, prisons/jails, nursing homes, daycares, and refugee/migrant camps are also at risk. Mathematical modeling scenarios can be used to predict trends in transmission, morbidity, and mortality to inform prevention efforts, as was done for HIV and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).Potential treatment exists. Smallpox antivirals (tecovirimat and brincidofovir) may reduce disease severity and duration , but safLearn from past successes. Smallpox was eradicated in 1980 following a globally coordinated plan involving testing, contact tracing, and ring vaccination. Similar approaches should be undertaken for MPXV, using sero-surveillance, molecular testing of high-risk populations, and wastewater surveillance.Learn from past mistakes. Although MPXV is very different from SARS-CoV-2 and HIV, the Coronavirus Disease 2019 (COVID-19) and HIV/AIDS pandemics offer lessons. Testing, vaccination, and treatment should be immediately scaled up and offered free to high-risk populations globally, through coordinated strategies that minimize bureaucracy  and includes timely contact tracing. Affordable health care, paid sick leave, and tele-health should be expanded. Health communication requires mandated reporting, consistent messaging and transparency, being clear about what we know and what we don\u2019t. Concerted efforts should be made to quell stigma, misinformation, and disinformation through meaningful consultation with affected populations.Address global health inequities. International multiagency coordination is needed so high-income countries do not hoard vaccines, treatments, or protect patents at the expense of lower and middle-income countries where MPXV is endemic. Global cooperation and political will is needed to assist lower income countries with access and last-mile delivery of testing, treatment, and vaccines. Affected populations need to be consulted at all stages to ensure that interventions are regionally and culturally appropriate.Take action. Decriminalizing substance use, sex work, homosexuality, and homelessness would decrease stigma and encourage vulnerable populations to seek testing, improving case-finding, and treatment. During the COVID-19 pandemic, some regions depopulated prisons or included sex workers in government subsidies . RegionsInvest in research. Studies to characterize the epidemiology, social networks, clinical presentation, morbidity, and mortality associated with MPXV infection are critically needed to inform primary and secondary prevention. Sero-surveillance should extend to animals, including pets and wildlife that could serve as reservoirs . TreatmeMPXV isn\u2019t the first pandemic of the 21st century, but it has already shown how unprepared we continue to be. Declaring a public health emergency of international concern (PHEIC) has limited impact if not met with action, building upon COVID-19 mitigation approaches, with an eye towards other threats . Addressing root causes of syndemics that disproportionately affect socially disadvantaged populations could significantly reduce health disparities associated with multiple disease outcomes and would ultimately be cost saving. Ensuring that we leave no one behind requires global cooperation to strengthen infrastructures for public health surveillance and capacities of health care systems and their workers. Without addressing global health inequities, we will continue to be unprepared for future pandemics."}
+{"text": "Achiella millefolium, Aloe vera, Althaea officinalis, Calendula officinalis, Matricaria chamomilla, Curcuma longa, Eucalyptus, Jojoba, plantain, pine, green tea, pomegranate, and Inula. This review addresses the most often used medicinal plants from the Northern Hemisphere that facilitate the treatment of wounds, and also suggests viable natural alternatives that can be used in the field of wound care.The skin serves as the body\u2019s first line of defense, guarding against mechanical, chemical, and thermal damage to the interior organs. It includes a highly developed immune response that serves as a barrier against pathogenic infections. Wound healing is a dynamic process underpinned by numerous cellular activities, including homeostasis, inflammation, proliferation, and remodeling, that require proper harmonious integration to effectively repair the damaged tissue. Following cutaneous damage, microorganisms can quickly enter the tissues beneath the skin, which can result in chronic wounds and fatal infections. Natural phytomedicines that possess considerable pharmacological properties have been widely and effectively employed forwound treatment and infection prevention. Since ancient times, phytotherapy has been able to efficiently treat cutaneous wounds, reduce the onset of infections, and minimize the usage of antibiotics that cause critical antibiotic resistance. There are a remarkable number of wound-healing botanicals that have been widely used in the Northern Hemisphere, including  The entire body\u2019s surface is covered by the intricate organ known as skin. It acts as both a physical shield and a barrier between the body and the outside environment, preventing the loss of water and electrolytes, limiting chemical penetration, and guarding against pathogenic microbes . In deveStarting from the homeostasis phase, damaged blood vessels rapidly contract after injury, and a blood clot forms to stop exsanguination caused by vascular damage; platelets are then triggered when they come into contact with the vascular sub-endothelial matrix, homeostasis, and coagulation ,8. PlateOne of the fundamental steps in wound treatment is preserving a clean wound bed. If done correctly, wound washing can lessen the bioburden and postpone the formation of biofilms. Although antiseptic solutions are used to clean wounds in order to avoid infection, it is not generally known whether antiseptic solutions such as irrigation liquids speed up the healing process . An imprHerbal medicines (HM), which are known as complementary and alternative medicines, have been used over the decades to treat medical ailments and promote wellness through their bioactive ingredients . Over tiMany nations and international organizations have included a one-health strategy in their action plans to deal with antibiotic resistance, where improvements in antimicrobial usage policies/regulations, infection control, sanitation and alternatives to antimicrobials are all necessary measures . An incrThere are sequential steps for any drug\u2019s discovery, development, and approval . Many laAchillea) species have been used in ethnopharmacology for quite some time. A. millefolium is among the most frequently utilized natural plant species for treating wounds, bleeding, stomachaches, gastrointestinal disorders, colds, flu, and stomach issues [millefolium\u201d alludes to the delicately split, feather-like leaves [Numerous yarrow  plants of the Zingiberaceae family. Approximately 200 years ago, Harvard College laboratory scientists Vogel and Pelletier first identified Curcumin in the Curcuma longa rhizomes (turmeric) [urmeric) . Traditiurmeric) . Turmeriurmeric) .Curcumin treatment, the wounds of mice closed rapidly with well-formed granulation tissue that was predominantly composed of deposited collagen and a regenerating epithelium. Furthermore, Curcumin treatment significantly reduced matrix metallopeptidase-9 and tumor necrosis factor alpha and sped up the healing of wounds in mice via controlling the amounts of different cytokines [Curcumin essential oils are illustrated in A previous study showed that, following topical ytokines . SeveralCurcumin and ginger extract enhances wound healing and skin function simultaneously, lowering the development of non-healing wounds [In hairless rats with skin injured by corticosteroids, a combination of g wounds .Althaea officinalis L. , often known as marshmallow, has a long history of use as a medicine to treat laryngopharyngeal mucosal irritation and its associated dry cough. The medicinal plant marshmallow  has roots, leaves, and flowers that are frequently used in traditional medicine throughout the world [A. officinalis has a variety of substances which have been extracted, including starch, pectins, saccharose, mucilage, flavonoids, caffeic acid, p-coumaric acid, isoquercitrin, coumarins, phytosterols, tannins, and several amino acids [Althaea officinalis is a medicinal herb used to treat lipemia, nose and oral cavity inflammation, and other conditions such as stomach ulcers and platelet aggregation. It has been proven that A. officinalis extract displays significant antioxidant activity [he world . A. offino acids . In addiactivity .Althaea officinalis has been used to cure wounds and inflammations. The root\u2019s capacity to hold water and its abundance of polysaccharides can boost the immune system [A. officinalis extract on a rat excision wound model was studied, and the wound healing percentage was much higher in the extract-treated wounds compared to the control, as shown in A. officinalis hydroethanolic extract includes phytochemicals that can serve as antibiotics to kill gram-positive bacteria and can quicken the healing of wounds through other mechanisms [For many years, an extract from e system . Thetopichanisms .Calendula officinalis (pot marigold) have a long history in ethnopharmacology. Traditional medicines for treating mild skin inflammation and promoting the healing of minor wounds include lipophilic and aqueous Calendula alcoholic extracts [C. officinalis extracts have been linked to several pharmacological actions, the most significant of which include anti-inflammatory, anti-edematous, antioxidant, antibacterial, antifungal, and immunostimulant properties. Terpenoids, flavonoids, phenolic acids, carotenoids, coumarins, quinones, volatile oils, amino acids, and lipids make up the majority of the chemical composition of C. officinalis [C. officinalis include antimicrobial, antiviral, effective treatment for breast cancer, antioxidant and anti-immunomodulatory activity, treatment of acne, potent anti-gastric ulcer activity, wound healing properties, treatment of bacterial infections in animals, and hepatoprotective and renoprotective activity [Flower extracts from extracts . C. offiicinalis . Other pactivity .Calendula officinalis was used topically and orally to examine its effects on rat excision wounds. The results showed that on the eighth day after the wound was formed, the extract-treated group had a 90.0% wound closure rate (in contrast to the control group\u2019s 51.1% wound closure), and the hydroxyproline and hexosamine contents were significantly higher in the extract-treated group than in the untreated group . The therapeutic and fragrant qualities of German chamomile (M. chamomilla) make it a well-known star herb. German chamomile (M. chamomilla) is a perennial herb that grows in south-eastern Europe and neighboring Asian nations. Both the flower heads and the essential oils are used in traditional medicine [M. chamomilla, including Sesquiterpenes, polyacetylenes, coumarins, and flavonoids, which are the main ingredients of chamomile. Additionally, luteolin and luteolin-7-Oglucoside, quercetin and rutin, apigenin and apigenin-7-O-glucoside, apigenin and apigenin-7-O-glucoside, and naringenin are among the bioactive phenolic compounds contained in chamomile extracts  and regular gentamycin, the optimized nanoemulsion of EEO was chosen for wound healing investigation, collagen estimation, and histological evaluation in rats. The optimized EEO nanoemulsion showed considerable wound healing activity in rats . Other rferation .Simmondsia chinensis, also known as Jojoba, is a dioecious desert shrub. S. chinensis produces seeds that produce liquid wax esters, a valuable ingredient in lubricants used in industry and cosmetics [The Jojoba plant, which is adapted to a warm, dry climate, is now commercially grown in areas with a severe lack of water, as well as in places where conventional farming methods were previously not financially sustainable. This shrub can withstand high temperatures, requires very little soil fertility and watering, and is also believed to be drought-tolerant . Simmondosmetics .Jojoba oil is a naturally occurring light yellow oil that can bead ministered topically and is capable of healing wounds and rebuilding skin barriers. Jojoba oil is made up of bioactive substances such as polyphenols, flavonoids, and alkaloids in addition to 97% linear long-chain esters. The administration of Jojoba oil dry nanoemulsion powders (JND) resulted in reduced bleeding and inflammatory cell infiltrations in acute lung injury models (ALI), emphasizing its efficiency as natural oil-based anti-inflammatory and free radical scavengers used to treat ALI . FurtherPlantago major L., are also often known as plantain\u2014a perennial herb with rosette-shaped leaves that are 15 to 30 cm in diameter [Plantago major, thrives in a variety of habitats, including roadside ditches, developed fields, canal water, and waste sites [The Plantaginaceae family, which includes diameter . The plate sites . The plate sites .Plantago major contains a number of active substances, including caffeic acid derivatives, polysaccharides, terpenoids, lipids, and flavonoids, as is shown in P. major ointment, which not only contains qualities for healing wounds but also functions as an analgesic and an antibacterial agent [P. major extract effectively accelerated the healing of dorsal cervical injuries in mice [P. major leaves can accelerate wound-healing processes in an ex vivo pig wound-healing model. That extracts of freeze-dried leaves made from both ethanol and water have shown a stimulating effect suggests that P. major might be a useful source of many bioactive compounds with wound healing potential. Moreover, a concentration of 1.0 mg/mL (dry weight) has the best results for both types of extracts [al agent . Further in mice . P. majoextracts .Inula is a vast genus of about 100 species of flowering plants that are native to Europe, Asia, and Africa. Many of these species have been used as sources of medicines [Inula contains several terpenoids, flavonoids, and lignins. Sesquiterpenoids from the genus Inula, including eudesmanes, xanthanes, dimers and trimers of sesquiterpenoids, are also widely distributed [Inula species against oxidative stress-related illnesses, inflammation, diabetes, cancer, and neurological diseases [edicines . Inula ctributed . Many didiseases .Inula viscosa, often locally known as \u201cMagramane\u201d, is found throughout the Mediterranean basin. As a result, the plant has been employed in traditional medicine to treat a variety of illnesses; this is attributed to its anti-inflammatory, anthelmintic, antipyretic, antiseptic, and antiphlogistic properties [Inula viscosa leaves could serve as a source of bioactive substances, volatile oils and phenolic compounds. Additionally, its potential for the development of natural preservatives with applications in agro-food is indicated by its antioxidant, antibacterial, and antifungal capabilities [Inula genus is a source of structurally diversified antioxidant chemicals that can combat many oxidative stress-related human diseases via various pathways, making it beneficial for the creation of new medications [Inula racemose (Ir) significantly increases total phenolic content and free radical scavenging activity, and the protein expression of p53, bax, and bcl-2 are returned to near-normal levels. Thus, the extracts of Ir may be potential therapeutic agents for providing several beneficial effects in hepatic injury following orthotopic liver transplantation [A perennial herbaceous plant called operties . Inula vbilities . The Inuications . The admantation .Althaea officinalis, Calendula officinalis, Matricaria chamomilla, Eucalyptus, Plantago major, Jojoba, and Inula are presented in The pharmacological wound healing bioactivities possessed by To produce a variety of products, pine trees are planted all over the world. For building materials, there are wood and cellulose . Pine prThe pine tree is constituted of several parts, including wood, bark, resin, needles, cones, and seeds ; the chePinus pinea and P. halepensis cones. However, other essential oils did not exhibit any notable anti-inflammatory or wound healing properties [Pine pollen polysaccharides (PPPS) can speed up the recovery of mouse skin wounds and encourage the growth of chicken embryo chorioallantoic vasculature by encouraging cell division, shifting the cell cycle from G1 to S and G2, and upregulating Cyclin B1 expression in vitro. These effects of PPPS were accomplished by JAK2-STAT3 signaling pathway activation . The laroperties . Abieticoperties .Camellia sinensis plant [Camellia sinensis (L.) plant (green tea) and is mostly grown in Japan, China, and Taiwan [More than two-thirds of the world\u2019s population drink tea, including green tea brewed from the leaves of the is plant . One of d Taiwan . Green td Taiwan .Numerous variables, including agricultural methods, climate, season, and plant types, can affect the content of tea. Green tea\u2019s key ingredients are polyphenols, mainly flavonoids. Catechins make up 6%\u201316% of the dried green tea leaves. The four main catechins are: epigallocatechin (EGCG), which accounts for roughly 59% of the total number of catechins; epigallocatechin (EGC), accounting for roughly 19%; epicatechin-3-gallate (ECG), accounting for roughly 13.6%; and epicatechin (EC), accounting for roughly 6.4%amount .Numerous studies have been conducted on the health advantages of green tea, especially epigallocatechin gallate(EGCG); it iswell recognized that these effects are mostly related to its polyphenols . The mosEpisiotomy pain seems to be effectively reduced by green tea ointment, which also helps to speed up wound healing . MoreovePunica granatum L., is an old fruit full of bioactive components including total phenols, flavonoids, hydrolysable tannins, proteins, vitamins, and minerals [Pomegranate, known as minerals . A pomegminerals . Pomegraminerals . It has minerals . Pomegraminerals .P. granatum flower extract experienced faster wound healing on day 25 of the treatment than those given other treatments\u2014where the wound healing was accelerated by the P. granatum flower extract, which can also be utilized to treat burn injuries [Moreover, rats given cream containing injuries . Accordiinjuries . The phaEach of the botanicals we have studied possesses chemical complexities that are connected to several pharmacological activities. These specifically shared characteristics include anti-microbial, anti-inflammatory, and anti-oxidative properties. Future medications may emerge from medicinal herbs, which have fewer side effects and better bioavailability for healing wounds. Particularly when treating patients with persistent or resistant skin ulcers, topical or systemic usage of phytotherapeutic drugs alone or as a supplement to other healing medications should be considered."}
+{"text": "REDI-NET) has been established to enhance surveillance approaches and characterize natural pathogens in temperate, tropical forest, and tropical grassland biomes. The REDI-NET is envisioned to be a long-term, phased initiative. All phases will integrate accompanying training resources such as videos reflecting SOPs and Quick Reference Guides. Routine bio- and xenosurveillance will facilitate the characterization of ecological parameters, enhance the accuracy of vector species identification using artificial intelligence technology, and guide the establishment of epidemiological risk thresholds critical for mitigating disease outbreaks in a timely manner. A key deliverable of the REDI-NET is a custom-designed electronically merged (e-MERGE) data pipeline and alert dashboard that integrates remotely captured data with state-of-the-art metagenomic next-generation sequencing technology. This pipeline incorporates data generated from field and laboratory best practices, to furnish health decision-makers with a centralized, timely, and rigorous database to efficiently search interdisciplinary and heterogeneous data sources necessary to alert, prepare and mitigate health threats. The e-MERGE pipeline, once fully established, will be a flexible, scalable, and expandable tool for varied health applications. Program success will result in an operational framework that addresses resource gaps in pathogen surveillance and enhances health protection with broad global applicability. The objective of this manuscript is to introduce the REDI-NET framework to anticipated stakeholders engaged in metagenomics, epidemiological surveillance, and One Health with a focus on Phase 1.Accurate prediction of zoonotic spillover events requires a detailed understanding of baseline pathogens circulating in differing global environments. By characterizing the diversity and determining the natural baseline of pathogens in a given biological system, any perturbations to this balance can be detected, leading to estimates of risk for emerging diseases. As epidemics and probability for pandemics increase, there is a fundamental need for building global collaborations to fill gaps in the surveillance effort, especially to build remote in-county capacity and standardize timely sample processing and data analysis. To this point, a new consortium, the Remote Emerging Disease Intelligence-NETwork ( An estimated 75% of emerging infectious diseases are zoonotic in nature, arising when pathogens in animals are passed to humans , with veUniversities can serve as important resources for technical training and education related to estimating disease threats and are leaders in the development of risk models and forecasting. Local health jurisdictions represent the first line of defense for preventing and controlling disease outbreaks and are tasked with carrying out limited surveillance activities in response to emerging pathogens; however, surveillance efforts are often narrow in scope  and reports can be seriously delayed if samples are sent to overloaded reach-back laboratories, taking weeks or months to be processed with data release occurring much later. Despite this heavy reliance on local authorities for a coordinated response to emerging pathogens, critical gaps exist in their ability to effectively do so. A recent evaluation found that local health personnel \u201cexpressed a lack of capacity to respond appropriately and effectively to emerging pathogens\u201d . RespondREDI-NET is to develop a new U.S. and international laboratory consortium between academia and the Department of Defense (DoD) along with domestic and international partnering institutions to detect, predict, and mitigate emerging and re-emerging infectious disease threats and improve the accuracy and timeliness of the \u201cdata-to-decision\u201d pipeline. Key expected deliverables include state-of-the-art standard operating procedures (SOPs), a functional e-MERGE data pipeline and REDI-NET database that includes custom-designed field data collection and web-based laboratory data collection applications, and a dashboard with built-in functionality to forecast emerging pathogens with user-friendly actionable outputs. Program success will result in an operational framework that addresses resource gaps in emerging disease surveillance and health protection with broad applicability.The overarching aim of the Greater numbers of empowered remote laboratory and field personnel with a foundational background in monitoring and detecting pathogens will immediately benefit institutions and serve as local source guidance on appropriate surveillance methods, sample processing, and data usage to detect and mitigate potential zoonoses spill-over events. The computational infrastructure interface designed, built, and validated in this program will offer a broad range of tools for modeling data, simulations, data analysis, and the management of distributed data sources for health-decision making and future development of potential novel technologies such as vaccines and drugs.REDI-NET is envisioned to be a long-term, phased initiative ], tropical forest (OCONUS\u2014Belize), and tropical grassland (OCONUS\u2014Kenya) sites. Sentinel sample types will include ticks, leeches, water, and sediment . These iThe four specific aims in Phase 1 :Aim 1: Establish Robust Sops for Rigorous Data Capture and Matched Laboratory Capabilities.REDI-NET e-MERGE pipeline. Training, and enabling of Gold and Silver laboratories through capacity strengthening to proficiently perform SOPs, has occurred either in-person or through remote sessions due to COVID-19 restrictions to ensure reproducibility of electronically sourced results from the remote locations using the REDI-NET e-MERGE pipeline. To maintain data rigor and identify any initial capability deficiencies, aliquots of reference materials containing the same mixture of bacteria , viruses (Epstein\u2013Barr virus and Human Immunodeficiency Virus 1), and fungi (Saccharomyces cerevisiae and Cryptococcus neoformans) organisms have been distributed to all current Consortium laboratories for output verification. Proficiency testing based on nanopore sequencing read number, length, quality, and coverage depth of each microbe has been conducted for current Gold/Silver individual operators and will be performed for any future laboratories joining the Consortium. This proficiency testing will be performed on an annual basis across the entire Consortium to ensure optimal and consistent data output from each partner laboratory. A second layer of verification has been implemented to have periodical submission of subsets of field-collected samples from Silver laboratories to the Gold reach-back laboratories to allow verification on the sequencing output and resultant microbe classification and abundance. In the event that human pathogens are detected, an Illumina sequencer equipped in all Gold laboratories will be used to confirm the initial findings from nanopore data.To ensure consistent and reproducible pathogen detection results, a set of robust SOPs encompassing field collection, sample storage, laboratory processing and testing, and sample shipping have been developed, tested, optimized, and validated by all consortium laboratories through an iterative process. Corresponding digital data collection sheets (DCS) have also been developed from each SOP, which reflects the essential field and laboratory data required to capture throughout the Aim 2: Active Field Surveillance Across Varied Ecologies for Broad-Spectrum Pathogen Detection.REDI-NET Silver field locations using a fixed sampling scheme, allowing aggregated analysis of presence/absence data along with densities and species composition. Ticks from domestic and/or wild animal collection based on the local approved protocols with the assistance of local veterinarians are also being processed as opportunistic samples. Standardized tick species identification capability in Gold laboratories will be developed from computer-vision, deep-learning algorithms using the IDX device (Silver laboratories at 4\u00b0C. All field samples will be stored at \u221280\u00b0C where possible or placed in the best RNA stabilizers (as determined by REDI-NET SOP development) or kept alive at 4\u00b0C . Tick dragging is standardized across X device  originalX device . Free-liX device . EnvironAim 3: Enable Remote, Verified in-Situ, Near Real-Time Data Acquisition for Actionable Reporting.REDI-NET data warehouse with seamless integration of environmental and bio-/xeno-surveillance pathogen data will facilitate the development of the comprehensive e-MERGE pipeline, accessed through the newly established REDI-NET website , training videos, and reference materials. The digital library holds datasets of extracted parameter values for all primary vectors. Along with raw access to the data and metadata, the data portal will provide access to filterable visualizations of risk projections. Ultimately, the data portal provides decision-support tools and brings together the data, cutting-edge mathematical and statistical methods to improve emerging infectious disease modeling, validation, and prediction.An important aspect of the study will be the ability for REDI-NET mobile and web-based applications have been designed to assure data rigor based on SOPs. The DCSs were developed from the SOPs to establish quality control rules  and inform the logic of the field data entry mobile application and REDI-NET database. In addition, the DCSs can be utilized if the field mobile application is unavailable all the while ensuring seamless data ingestion into the e-MERGE pipeline. The result will be a repository of both raw data and de-identified data, with accompanying metadata, immediately available for modeling, statistical analyses, and actionable reporting requirements. The data warehouse and file repository are backed up daily and weekly at the operating system level to ease recovery as needed. All data are stripped of personal identifiers (GPS information blurred) at the central data warehouse prior to any subsequent analysis and/or data sharing restrictions pursuant to DoD data sharing policies. Descriptive visualizations of pathogen occurrence or predicted trends in risk will be available via end-user interactive sessions with the database dashboard.The Aim 4: Institute a Data Management Pipeline for Actionable Reporting and Threat Forecasting.REDI-NET e-MERGE analysis pipeline will be the development of novel risk maps and models. Outputs from these models will be accessible to the end user via the REDI-NET dashboard. Expected modeling outputs include pathogen presence/absence estimates, seasonal projections of vector abundance and pathogen prevalence, and predictive disease and pathogen spillover risk maps. Surveillance data collected through REDI-NET will be combined with environmental and ecological data to generate predictive disease risk maps via a hierarchical Bayesian modeling framework. Such a framework enables the incorporation of multiple data types into the modeling process, including both historical and prospective data, both epidemiological and environmental data, and data collected at different spatial and temporal scales. At the same time, this modeling framework allows for the incorporation of associations between outcomes of interest and numerous spatial covariates, such as satellite-derived measures of temperature, wetness, land cover, and elevation. While some data\u2014e.g., satellite-derived covariates, data collected prospectively by the REDI-NET\u2014are available globally, others are unique to a given setting\u2014e.g., historical surveillance data. The modeling framework allows for all such data types to jointly inform model-based predictions of pathogen risk.A central function of the Several types of model predictions will be generated. We will use the Bayesian modeling framework to map infection thresholds in the environment, and in arthropod and vertebrate animal populations. Among other available data types, the e-MERGE data analysis pipeline will allow us to integrate novel covariate datasets into these models. Surveillance data will be divided into training and testing sets, with the training data used to fit the models and the testing data used for model validation. Predicted infection thresholds from the model will then be resampled to generate predictive risk maps that can be used to estimate risk in unsampled locations. Where appropriate, we will also integrate point-based and polygon-based  data into the predictive models using techniques to deal with the spatial misalignment of different datasets . Last, oREDI-NET SOPs has been capable of generating sequencing data leading to the detection of human pathogens in ticks, leeches, water, and soil. In addition, testing of reference material has generated consistent sequencing outputs indicating standardized capabilities throughout Consortium laboratories. Barcoding schemes have been developed to enable rigorous sample tracking and relating field metadata with laboratory pathogen testing outputs. The computer-vision algorithm for tick species identification has been developed from sample images taken with IDX submitted by all Gold laboratories for preliminary deployment in the IDX devices. The custom-designed REDI-NET database and both mobile field data entry and web-based lab data entry applications have been developed and verification of remotely captured data sync along with metadata relation functionality completed. The custom-developed REDI-NET technology  includes built-in functionality to ensure data integrity and data quality assurances. Additionally, quick reference guides and training videos have been developed for assuring standardization in methodology. A custom-designed REDI-NET sample storage web application has been integrated into the REDI-NET data portal to allow users to manage sample storage location for individual specimen records. A custom-designed REDI-NET dashboard and data portal have been designed as a resource repository to the database that hosts SOPs and DCSs, training videos, quick reference guides, equipment manufacturer data, and REDI-NET presentation templates with the ability to search/filter based on keywords. A NGS data upload mechanism has been established for the REDI-NET database and NGS software and data pipelines have been evaluated to identify those most appropriate for the REDI-NET pipeline. Risk models have been developed using publicly available databases , published literature, and de-identified human case data from repositories to validate the mathematical model framework(s) for tick-borne disease risk estimation in Florida, Belize, and Kenya with model outputs available to visualize on the REDI-NET data portal. To ensure that the technical feasibility and viability of the REDI-NET framework is sustainable, and practical, as an early alarm of emerging infection threats, the Consortium will host end-user training sessions in each Phase to assess broad platform functionality and incorporate user feedback. Additionally, a digital REDI-NET resource package will be developed to facilitate ease of roll-out to global end users.A total of 21 SOPs spanning field sampling, laboratory specimen processing, pathogen testing, specimen storage, shipment, and data management have been developed . CurrentEpidemics of emerging and exotic nature are becoming more frequent and diverse worldwide and these outbreaks will inevitably continue into the foreseeable future . RecentlREDI-NET was founded on the requirement of having tools and processes for near real-time, evidence-based, health decision-making with capacity strengthening for knowledgeable, competent health professionals and facilities for appropriate environmental pathogen surveillance, detection, and response. The REDI-NET has connected tangible, measurable partnerships amongst stakeholders to leverage expertise and resources for disease surveillance and management. The initial launch of the REDI-NET program has resulted in an operational framework that is meant to address some of the known resource gaps in infectious disease surveillance. The REDI-NET military/civilian collaborations have and will continue to broaden the reach of emerging disease surveillance activities for more accurate and timely predictive tools. We anticipate continued success in capacity-strengthening to occur as the REDI-NET initiative progresses. New consortium members will join the REDI-NET, remote data collection methodologies will be expanded using AI technologies, including drones for semi-autonomous and/or autonomous sample collection and we will consider adding machine learning algorithms to our spatial modeling platform, as these methods do not assume an underlying model and are robust to sampling biases , 503 Robert Grant Avenue, Silver Spring, MD 20910, United States; Henry M Jackson Foundation for the Advancement of Military Medicine, 6720A Rockledge Dr., Bethesda, MD, United States.Erica Cimo, Naval Medical Research Center (NMRC), 503 Robert Grant Avenue, Silver Spring, MD 20910, United States; Henry M Jackson Foundation for the Advancement of Military Medicine, 6720A Rockledge Dr., Bethesda, MD, United States.Le Jiang, Naval Medical Research Center (NMRC), 503 Robert Grant Avenue, Silver Spring, MD 20910, United States; Henry M Jackson Foundation for the Advancement of Military Medicine, 6720A Rockledge Dr., Bethesda, MD, United States.Hsiao-Mei Liao, Naval Medical Research Center (NMRC), 503 Robert Grant Avenue, Silver Spring, MD 20910, United States; Henry M Jackson Foundation for the Advancement of Military Medicine, 6720A Rockledge Dr., Bethesda, MD, United States.Zhiwen Zhang, Naval Medical Research Center (NMRC), 503 Robert Grant Avenue, Silver Spring, MD 20910, United States; Henry M Jackson Foundation for the Advancement of Military Medicine, 6720A Rockledge Dr., Bethesda, MD, United States.Jason Fajardo, Navy Entomology Center of Excellence, 937 Child St, Jacksonville, FL 32212, United States; Henry M Jackson Foundation for the Advancement of Military Medicine, 6720A Rockledge Dr., Bethesda, MD.Edward Traczyk, Navy Entomology Center of Excellence, 937 Child St, Jacksonville, FL 32212, United States.Melissa Vizza, Navy Entomology Center of Excellence, 937 Child St, Jacksonville, FL 32212, United States; Henry M Jackson Foundation for the Advancement of Military Medicine, 6720A Rockledge Dr., Bethesda, MD.Christy Waits, Navy Entomology Center of Excellence, 937 Child St, Jacksonville, FL 32212, United States; Henry M Jackson Foundation for the Advancement of Military Medicine, 6720A Rockledge Dr., Bethesda, MD.Brian Bourke, Walter Reed Biosystematics Unit (WRBU), Smithsonian Institution Museum Support Center, Suitland, MD, United States; One Health Branch, Center for Infectious Disease Research, Walter Reed Army Institute of Research (WRAIR), Silver Spring, MD, United States.Laura Caicedo-Quiroga, Walter Reed Biosystematics Unit (WRBU), Smithsonian Institution Museum Support Center, Suitland, MD, United States; One Health Branch, Center for Infectious Disease Research, Walter Reed Army Institute of Research (WRAIR), Silver Spring, MD, United States.Koray Ergunay, Walter Reed Biosystematics Unit (WRBU), Smithsonian Institution Museum Support Center, Suitland, MD, United States; One Health Branch, Center for Infectious Disease Research, Walter Reed Army Institute of Research (WRAIR), Silver Spring, MD, United States; Virology Unit, Department of Medical Microbiology, Faculty of Medicine, Hacettepe University Ankara, Turkey.Yvonne-Marie Linton, Walter Reed Biosystematics Unit (WRBU), Smithsonian Institution Museum Support Center, Suitland, MD, United States; One Health Branch, Center for Infectious Disease Research, Walter Reed Army Institute of Research (WRAIR), Silver Spring, MD, United States; Department of Entomology, Smithsonian Institution National Museum of Natural History, Washington, DC, United States.Suppaluck Nelson, Walter Reed Biosystematics Unit (WRBU), Smithsonian Institution Museum Support Center, Suitland, MD, United States; One Health Branch, Center for Infectious Disease Research, Walter Reed Army Institute of Research (WRAIR), Silver Spring, MD, United States.David B. Pecor, Walter Reed Biosystematics Unit (WRBU), Smithsonian Institution Museum Support Center, Suitland, MD, United States; One Health Branch, Center for Infectious Disease Research, Walter Reed Army Institute of Research (WRAIR), Silver Spring, MD, United States.Alexander Potter, Walter Reed Biosystematics Unit (WRBU), Smithsonian Institution Museum Support Center, Suitland, MD, United States; One Health Branch, Center for Infectious Disease Research, Walter Reed Army Institute of Research (WRAIR), Silver Spring, MD, United States.Dawn Zimmerman, Walter Reed Biosystematics Unit (WRBU), Smithsonian Institution Museum Support Center, Suitland, MD, United States; Department of Epidemiology of Microbial Disease, Yale School of Public Health, New Haven, CT, United States.James Hassell, Global Health Program, Smithsonian\u2019s National Zoo and Conservation Biology Institute, Washington, DC, United States; Department of Epidemiology of Microbial Disease, Yale School of Public Health, New Haven, CT, United States.Maureen Kamau, Mpala Research Centre, Laikipia, Kenya; Global Health Program, Smithsonian\u2019s National Zoo and Conservation Biology Institute, Washington, DC, United States.Rashid Lebunge, Mpala Research Centre, Laikipia, Kenya.Janerose Mutura, Mpala Research Centre, Laikipia, Kenya.Michael von Fricken, George Mason University, 4,400 University Drive, Fairfax, VA, United States.Abigail A. Lilak, George Mason University, 4,400 University Drive, Fairfax, VA, United States.Graham A. Matulis, George Mason University, 4,400 University Drive, Fairfax, VA, United States.Jewell Brey, Vectech, 3,600 Clipper Mill Rd., STE 205, Baltimore MD, United States.Tristan Ford, Vectech, 3,600 Clipper Mill Rd., STE 205, Baltimore MD, United States.Adam Goodwin, Vectech, 3,600 Clipper Mill Rd., STE 205, Baltimore MD, United States.Ghnana Madineni, Vectech, 3,600 Clipper Mill Rd., STE 205, Baltimore MD, United States.Bala Murali Manoghar Sai Sudhakar, Vectech, 3,600 Clipper Mill Rd., STE 205, Baltimore MD, United States.Sanket Padmanabhan, Vectech, 3,600 Clipper Mill Rd., STE 205, Baltimore MD, United States.Robert Ang\u2019ila, Mpala Research Centre, Laikipia, Kenya.Margaret Elliott, Department of Biological Sciences, University of Notre Dame, 301 Galvin Life Science Center, Notre Dame, IN, United States.Joanna Gomez, Belize Vector and Ecology Center, Slaughterhouse St, Orange Walk Town, Orange Walk, Belize.Lauren Maestas, Navy Entomology Center of Excellence, 937 Child St, Jacksonville, FL, United States.Marla S. Maga\u00f1a, Belize Vector and Ecology Center, Slaughterhouse St, Orange Walk Town, Orange Walk, Belize.Mohamed Sallam, Navy Entomology Center of Excellence, 937 Child St, Jacksonville, FL, United States.Alexia Thompson, Belize Vector and Ecology Center, Slaughterhouse St, Orange Walk Town, Orange Walk, Belize.redinet@nd.edu.The datasets presented in this article are not readily available because REDI-NET Phase 1 data generation and analysis is ongoing with associated datasets to become available at the time specific outcomes are published. Requests to access the datasets should be directed to NA, The REDI-NET was conceived by JPG, LJ, Y-ML, and NA. LJ and H-ML led the development of laboratory sample processing and testing SOPs. NA, JPG, LJ, Y-ML, BF, MD, and CP contributed to the development of field sampling, storage, and shipment SOPs. Gold laboratory data are being generated by BF, DL, CP, H-ML, TB, ZZ, EC, BB, LC-Q, KE, SN, DP, and APo. Silver field and laboratory data are being generated in Belize by ACa, JC, ACr, MP, and UR, in Florida by ET, JF, MV, and CW, and in Kenya by DZ, JH, MK, RL, JM, MF, AL, and GM. Management of the central data repository is led by JN, SN, MN, KP, CR, and BS. Mathematical modeling is being conducted by APe, SMoo, and SMow. Literature searches were conducted by ME, BR, and MG. Human and animal use applications are managed by NA. Tick e-ID platform development led by TF, AG, JB, GM, BS, and SP. The first draft of the manuscript was written by JG, LJ, Y-ML, MF, MD, BS, APe, SMoo, SMow, and NA. All authors contributed to the article and approved the submitted version.This work was supported by the United States Army Medical Research and Development Command under contract no. W81XWH-21-C-0001.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.The views, opinions, and/or findings contained in this report are those of the author(s) and should not be construed as an official Department of the Army position, policy, or decision unless so designated by other documentation. The views expressed in this article are those of the author and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, nor the U.S. Government."}
+{"text": "These hard-bottom habitats can provide a variety of ecosystem services, ranging from the enhancement of fish biomass and production to providing erosion control. Management decisions regarding the construction or fate of hard-bottom habitats require information on the ecological functions of these habitats, particularly for species targeted in ecosystem-based fisheries management. This study provides a systematic review of the relationships of various hard-bottom habitats to individual commercially harvested species that are managed jointly across the Atlantic by the International Council for the Exploration of the Sea (ICES). We systemically reviewed peer-reviewed publications on hard-bottom habitats including both natural and artificial reefs, after applying various exclusion criteria. Most studies were conducted on near-shore hard-bottom habitats, and habitat importance varied according to fish species and region. We quantified the frequency with which studies demonstrate that natural and artificial hard-bottom habitats function as spawning grounds, settlement and nursery areas, and foraging grounds, as well as provide stepping-stones during migration, or new home ranges. Hard-bottom habitats generally support higher fish densities than surrounding habitat types, although not all fish species benefit from hard-bottom habitats. Of the commercially important species, cod (Gadus morhua) was the most frequently studied species, with enhanced biomass, density, feeding, and spawning on hard-bottom habitats compared to unstructured habitats. Moreover, hard-bottom habitats appear to be of particular importance for spawning of herring (Clupea harengus). Collectively, data indicate that loss of hard-bottom habitats may translate into less-favourable conditions for spawning and biomass of diverse commercial species, including cod and herring.Hard-bottom habitats span a range of natural substrates ( Artificial reefs generally harbor higher fish densities and biomass than surrounding natural reefs  for individual commercial fishery species associated with hard-bottom habitats, and (2) highlighting the importance of these habitats for certain fish species so that managers and conservation groups can act on this knowledge. The spatial focus was on temperate, hard-bottom habitats , and we excluded some natural hard-bottom habitats such as coral reefs and biogenic habitats (see negative keywords in the search string below). We also focused on species important for management by ICES (see species-related keywords below), therefore, we did not include all commercially important species. In addition, we excluded rockfish in the Pacific Ocean, which have a separate body of literature targeted towards them, and which are not managed by ICES. Thus, our conclusions cannot be applied to all species in every area, and our focus was on non-biogenic or anthropogenically created reefs. We were most interested in habitat enhancement from the physical structure provided by hard-bottom habitats, and thus excluded biogenic reefs, which provide additional ecological benefits such as increased nutrients  summarizing increases or decreases in demographic variables . Therefore, interpretations of these data apply only to the species and habitats we incorporate. Additionally, we examined the current literature (2017\u20132022) for more recent articles on the same ICES-managed species using hard bottom habitats , which allowed us to identify a couple of case studies to serve as a check on validity of conclusions from our systematic search.We followed the protocol for a systematic literature review proposed by The following search keywords were chosen for each of the ecological variables we wanted to examine: Biomass, Density, Biodiversity, Condition, Mortality, Growth, Feeding, Spawning, Nursery, Settling, Diel cycle, Site fidelity, Migration. Separate searches with all other keywords in combination with each of the ecological search keywords were conducted . LocatioImportance-related keywords (note: asterisks represent a search engine wild-card and were used to broaden the search by finding multiple words that start with the same letters):Fish attraction, fish production, fish biomass, fish diversity, fish growth, fish survival, fish density, fish migration, demographic rate*, fish reproduction, fish mortality and fish juvenile*, feeding, nursery, spawn*.Ecosystem-related keywords: Hard bottom, rocky reef*, stone reef*, riprap, seawall*, groin*, groyne*, offshore wind energy structure*, wind farm*, wind turbine*, artificial reef*, fish attraction device*, FAD*, shipwreck*, oil rig*, oil platform* oil pipe*, gas rig*, gas platform*, gas pipe*, offshore platform*, rig* to reef*, decommission*.Species-related keywords:Alopias spp., Amblyraja radiata, Ammodytes spp., Anguilla anguilla, Aphanopus carbo, Argentina silus, Beryx spp., Brosme brosme, Capros aper, Centrophorus squamosus, Centroscymnus coelolepis, Cetorhinus maximus, Chelidonichthys cuculus, Clupea harengus, Coryphaenoides rupestris, Dalatias licha, Dicentrarchus labrax, Dipturus batis-complex, Engraulis encrasicolus, Gadus morhua, Galeorhinus galeus, Galeus melastomus, Hoplostethus atlanticus, Lamna nasus, Lepidorhombus spp., Leucoraja circularis, Leucoraja fullonica, Leucoraja naevus, Limanda limanda, Lophius budegassa, Lophius piscatorius, Macrourus berglax, Mallotus villosus, Melanogrammus aeglefinus, Merlangius merlangus, Merluccius merluccius, Micromesistius poutassou, Molva dypterygia, Molva molva, Mullus surmuletus, Mustelus spp., Pagellus bogaraveo, Phycis blennoides, Platichthys flesus, Pleuronectes platessa, Pollachius pollachius, Pollachius virens, Raja brachyura, Raja clavata, Raja microocellata, Raja montagui, Raja undulata, Reinhardtius hippoglossoides, Rostroraja alba, Salmo salar, Salmo trutta, Sardina pilchardus, Scomber scombrus, Scophthalmus maximus, Scophthalmus rhombus, Scyliorhinus canicula, Scyliorhinus stellaris, Sebastes spp., Solea solea, Sprattus sprattus, Squalus acanthias, Squatina squatina, Trachurus picturatus, Trachurus trachurus, Trachyrincus scabrus, and Trisopterus esmarkii.Location-related keywords: Belgium, Canada, Denmark, Estonia, Finland, France, Germany, Iceland, Ireland, Latvia, Lithuania, Netherlands, Norway, Poland, Portugal, Russia, Spain, Sweden, United Kingdom, United States of America, Northeast Atlantic, Atlantic Iberian, Biscay, English Channel, Bristol Channel, North Sea*, Irish Sea*, Cantabrian Sea*, Belt Sea*, Bothnian Sea*, Celtic Sea*, Azores, Skagerrak, Kattegat, Bornholm, Baltic, Gulf of Gdansk, Gulf of Riga, east Gotland, Faroe grounds, Iceland grounds, Greenland, Rockall, Bothnian bay, Reykjanes Ridge, Dogger bank*, Viking bank*, Bergen bank*.Negative (Excluded) keywords: Biogenic reef*, eelgrass, mussel bed*, coral reef*, tropical, subtropical, Australia, Mediterranean, Caribbean, Indian Sea.Our primary question was: \u201cWhat is the habitat importance of hard-bottom natural and artificial structures for temperate fish species managed by ICES?\u201d To answer this question, for each article we determined the studied habitat, the ecosystem type, and species targeted, as detailed below. We broke down habitat importance into the following four main components: (1) distribution-related variables, (2) community-related variables, (3) fitness-related variables, and (4) reproduction-related variables (see details below).e.g., growth, survival, biomass, spawning rates), which allow researchers to assess the importance of various habitats. We initially grouped the data into the following four broad categories: (1) species distribution, (2) community, (3) fitness, and (4) reproduction. Distribution-related variables included articles targeting diel cycles, site fidelity, or migration patterns. Community-related variables included articles targeting fish biomass, density, or biodiversity. Fitness-related variables included articles targeting condition, mortality rates, growth, and feeding. Lastly, reproduction-related variables included articles targeting spawning habitats, nursery potential, and settling (both of adults to newly formed habitats or of juveniles).Fish species receive numerous benefits from benthic habitats, such as food, shelter, or spawning grounds. Such benefits may translate into measurable demographic variables . Targeted species are listed above in \u201cSpecies-related keywords.\u201de.g., e.g., Dicentrarchus labrax; Our study indicates that hard-bottom substrates may benefit multiple fish groups, such as elasmobranchs e.g., , gadoidsThe search process returned an initial 2,651 articles, paring down to 2,333 articles after exclusion of duplicate references. Of those, 45 articles were returned after the subsequent screening criteria and were examined for full-text data extraction . A total of 9.5% excluded articles that either studied non-target locations or other ecosystems . Lastly, 1.4% of the excluded titles either did not correspond to peer-reviewed articles or were not written in English.The title reviewing process led to the exclusion of 2,036 articles , leaving 297 articles for abstract analysis. Most of the exclusions (54%) represented off-topic articles dealing with, for example, energy production, aquaculture, human health, oil spills, or physiology. Additionally, 35% of the excluded articles were explicitly related to non-target organisms , leaving 161 articles for full text analysis. Most of the exclusions represented articles related to non-target species (32%), followed by articles that did not relate to the target topics (25%). A total of 30% excluded articles either studied non-target locations or other ecosystems. Additionally, 13% of the analysed search results were not from the peer-reviewed literature.From the 161 full texts analysed, 116 (72%) did not comply with the exclusion criteria. Most of the articles were excluded based on location (49%), corresponding mostly to studies targeting rockfish in the Pacific Ocean. A total of 21% exclusions represented articles related to non-target species, while 13% studied non-target ecosystems and 7% did not relate to the target topics. A total of 11 articles were excluded for \u201cother\u201d reasons: four were not peer-reviewed, four were reviews, and for three it was not possible to obtain a full text version of the document. Therefore, the review focused on 45 studies distributed along the Baltic and North Seas and northern Atlantic Ocean . We quani.e., diel cycle, site fidelity, migration) were studied in six articles (13.4%). These targeted primarily site fidelity and migration patterns of Atlantic cod  were the most frequently studied amongst the articles reviewed, being analysed in two thirds of the studies , and saithe (Pollachius virens)) and a limited set of variables . Cod was the species most commonly studied in community-related  studies  were studied in 17 articles . Feeding was studied primarily on cod and saithe, showing a tendency for fish use of hard-bottom habitats for foraging  were studied in six articles (13.4%). Spawning was studied primarily on herring and cod, with articles on nursery and settling being almost absent for other species in the reviewed literature .There was a clear predominance in the study of community-related variables in the analysed research . Broadende facto reefs, and only one article targeting intentional artificial reefs. Conversely, in the North Sea, only three out of 15 articles targeted natural reefs, while 14 targeted de facto artificial reefs (most of which explored the effects of wind farms). Finally, on the north-eastern coast of the Atlantic Ocean, there were nearly equal numbers of articles on natural and artificial reef research . However, of the articles targeting artificial reefs, only one studied de facto artificial reefs, while the remaining explored artificial intentional artificial reefs. There was a noticeable paucity of studies in the northern regions. Additionally, most of the analysed research has been conducted near-shore. Broadening the scientific knowledge on the importance of different habitats, areas, and regions along a depth gradient away from shore may provide crucial insights for future management.Research was nearly equally distributed across natural and artificial reef structures, with 26 and 27 articles related to each, respectively, and eight targeting both natural and artificial structures simultaneously , Table 3vs 12 articles, respectively; i.e., species distribution, community, fitness, reproduction), research is lacking for most reviewed species on variables not related with community , whiting, pollock (Pollachius pollachius), plaice (Pleuronectes platessa), and sole (Solea solea). Cod, herring, saithe, striped red mullet, whiting, and pollock appeared to benefit from foraging on hard-bottom habitat . Few articles targeted spawning on hard-bottom habitats, and those that did reported associated benefits for cod and herring.The presence of hard-bottom habitat was associated with enhanced biomass in cod and saithe and, conversely, was negatively associated with biomass in herring and whiting , sugges., e.g., , suggestMelanogrammus aeglefinus) and cod were the most common species at the \u201cMiller\u201d oil and gas platform in the North Sea (Scyliorhinus canicula) occurring at higher densities on hard than soft substrate.Gadoids such as saithe, haddock (orth Sea . Cod abuPagellus acarne), horse mackerel (Trachurus trachurus), and striped red mullet demonstrated significant increases in biomass. The observation that horse mackerel responded positively to the addition of artificial reefs demonstrates that schooling pelagic species may also benefit from these hard-bottom habitats.Within four years after the deployment of artificial reefs in an area previously closed to trawl fisheries in the Bay of Biscay, there was a rapid increase in the biomass of small-spotted catshark . ImportaReefs (excluding biogenic reefs) may also enhance economic returns. For example, in one location, reefs near Algarve and Faro, Portugal, raised catch rates and economic returns . Specifie.g., cod; i.e., hard bottoms) will be populated first according to the ideal free distribution theory of The inclusion of quantitative data on hard-bottom habitats in the monitoring of fish populations may further resolve a mismatch between fish population assessments and catches in fisheries of several fish species with a patchy distribution due to their high affinity for hard-bottom habitats (Pleuronectes platessa) and sole (Solea solea), as well as for whiting (Merlangius merlangus). For example, Not all fish species benefit from hard-bottom or marine constructed structures. Neutral or negative relationships with biomass and density were recorded for flatfish such as plaice (de facto marine protected areas (MPAs) could be relatively easy to enforce, serve as broodstock sanctuaries that benefit fished populations, and optimize use of the seafloor  can be many orders of magnitude greater in areal footprint than artificial reefs, it is important to recognize that unstructured habitats can serve as effective juvenile habitat  and unstructured habitats, subtidal soft-bottom was the habitat used as a spawning or nursery area by the largest proportion of ICES species examined, with intertidal soft-bottom habitat as the next most important habitat , they represent beacons of habitat heterogeneity that are capable of attracting new residents (Trisopterus luscus) can have high residency and site fidelity to the bases of marine wind turbines, feeding on the dominant epifaunal prey growing on these introduced habitats , horse mackerel, and axillary sea-bream may make them more vulnerable to predation, as the probability of prey\u2013predator encounters increases compared to unstructured habitats (Limanda limanda) and sole, may avoid rocky substrates, with decreasing abundances whenever there is a shift from soft to hard bottom , this may have had little effect on the larger spatial scale . In a related example, oil and gas platforms in the North Sea provided unique feeding grounds for commercially important gadoids such as cod, saithe, and haddock . In a survey of natural hard bottoms in the northern Baltic Sea (Sweden), herring eggs were only found on filamentous algae  attached to hard substrates (Cladophora sp.), brown algae  and Potamogeton pectinatus made up the most common vegetation where divers observed eggs  compared to areas that are fished with dredges or trawls that damage the seafloor and reduce complexity . We highlight several recent case studies below that reflect this updated literature review. In the first example , stereo in situ ecosystem value of platforms and the negative impacts of removal are not factored into decommissioning decisions in regions such as the North Sea, where over 80% of oil structures are more than a decade old , and accade old . Fowler cade old . Each dei.e., density, biodiversity, biomass). However, not all responses to the presence of hard-bottom habitat were positive. For herring, saithe, striped red mullet, whiting, pollock, plaice, and sole, we quantified positive and negative relationships between fish density and hard-bottom habitats. Thus, we achieved our goal of summarizing the existing information on ICES-managed fish species and their use of temperate hard-bottom habitats. This information should help inform scientists interested in the ecological function of hard-bottom habitats for some key fish species, and inform managers and conservation groups focused on coastal habitats of the potential importance of hard-bottom habitats to certain fish species.Our systematic review found that Atlantic cod, the most frequently studied species of the group of species managed by ICES, had increased biomass, density, feeding, and spawning associated with hard-bottom habitats compared to unstructured habitats. Spawning of herring increased on hard-bottom habitats, which appear to be of importance for this species. We detected that most research was conducted on Atlantic cod, herring, and saithe, and the most commonly studied variables included biomass, density, biodiversity, and feeding. Cod was the species most commonly studied, and studies were mostly on community-related variables  where several recent studies have estimated the annual economic values per area (e.g., de facto reefs and are generally not removed.Natural hard-bottom reefs, if removed or destroyed, can only be restored by human intervention. Thus, it would be wise if management focuses on protecting natural reefs and finding the most cost-effective solutions for restoring reefs. In support of ecosystem-based fisheries management, research should provide additional scientific information on the value of hard-bottom habitats for biodiversity or for individual species on a local, national and regional scale. While this information is slowly being produced e.g., , the ecoper area . Similarea e.g., . These sThe value of reef habitats and the need for their protection ultimately depends on the occurrence of that habitat type in the area/region and the potential for hard-bottom habitats to represent value as a resource. For example, in Denmark, although the extraction of boulders and larger stones from reef areas has ceased, extraction of smaller stones or gravel continues to take place, even though these hard bottom types are important habitats for juvenile eel and cod .Research should provide the necessary information to allow for an effective restoration of the functions of destroyed reefs. Studies are increasingly investigating restoration methodologies for hard-bottom reefs . However10.7717/peerj.14681/supp-1Supplemental Information 1Click here for additional data file.10.7717/peerj.14681/supp-2Supplemental Information 2Click here for additional data file.10.7717/peerj.14681/supp-3Supplemental Information 3Click here for additional data file."}
+{"text": "Tuberculosis is a disease with serious consequences in terms of morbidity and mortality. Pancreatic localization is very rare and is mostly encountered in patients with immunosuppressive disorders. A 59-year-old woman with arterial hypertension, grade 2 obesity, and a history of cholecystectomy, was admitted for fever (38.5 \u00b0C), jaundice, and marked physical asthenia. The blood tests showed severe metabolic acidosis, with partial respiratory compensation, mild microcytic normochromic anemia, inflammatory syndrome, procalcitonin value ten times the upper limit of normal, nitrogen retention syndrome, hypoalbuminemia, hypertriglyceridemia, hypercholesterolemia, and moderate hyponatremia. The electrocardiogram, chest X-ray, and abdominal ultrasound did not show any significant pathological changes. Contrast-enhanced computed tomography raised the suspicion of acute-on-chronic pancreatitis and subsequent evaluation by magnetic resonance imaging raised the suspicion of a pancreatic tumor. Pancreatic fine needle biopsy under echoendoscopic guidance revealed purulent material, which was sent for cytological and bacteriological examination. The Ziehl-Neelsen stain showed acid-alcoholic resistant bacilli, while bacterial cultures were positive for gentamicin and tigecycline-sensitive Klebsiella. The diagnosis of pancreatic tuberculosis was established. Pancreatic tuberculosis is a very rare condition that often mimics pancreatic cancer. The peculiarity of the case is the appearance of pancreatic tuberculosis in an immunocompetent woman and the association with Klebsiella infection. Tuberculosis is a condition caused by Mycobacterium tuberculosis, that most commonly affects the lungs . All ageIn Romania, the overall incidence of tuberculosis decreased by 27.9% between 1995 and 2016  .In most cases of tuberculosis, the infection is localized in the lungs. Only 12.5% of cases have extrapulmonary involvement, and of these 11\u201316% have abdominal localization ,5. PossiPancreatic tuberculosis is one of the rarest forms of tuberculosis, and it presents with non-specific clinical manifestations. However, recently there has been an increase in the number of cases of tuberculosis with pancreatic localization ,8,9,10. A 59-year-old female, known with stage 2 arterial hypertension, grade 2 obesity, with a history of cholecystectomy, was admitted for fever (38.5 \u00b0C), jaundice, and marked physical asthenia. The symptoms began about 3 weeks before admission and gradually worsened. The patient denied any significant family medical history. Upon examination, the patient was ill-appearing, conscious, with icteric skin, sclera, and mucous membranes, without any palpable lymph nodes; lung sounds were clear bilaterally, oxygen saturation 98\u2013100% with additional oxygen on face mask; blood pressure of 98/58 mmHg and heart rate of 102 beats per minute; non-tender abdomen; acholic stool and hyperchromic urine. The neurological examination revealed no focal deficit. The laboratory tests showed severe metabolic acidosis with partial respiratory compensation, mild microcytic normochromic anemia, elevated acute phase reactants, procalcitonin ten times the upper normal limit, azotemia, hypoalbuminemia, hypertriglyceridemia, hypercholesterolemia, and moderate hyponatremia. The electrocardiogram and chest X-ray revealed normal findings. Abdominal ultrasound identified a normal-looking liver, without dilatations of intrahepatic or extrahepatic bile ducts, a spleen of 13 cm, without other pathological changes. Based on these results, the diagnosis of sepsis of unknown origin, jaundice, and acute renal failure was established. A gastroenterology consultation was requested, that excluded liver cirrhosis , obstructive jaundice, and angiocolitis (absence of biliary ducts dilatations and biliary stones). The association of cholestasis, hepatocytolysis, and azotemia raised the suspicion of leptospirosis. This diagnosis was later refuted by performing anti-leptospira antibodies, with a negative result. A few hours after admission, the patient\u2019s condition deteriorated, manifesting signs of septic distributive shock. The patient was transferred to the intensive care unit, where her condition remained severe, with hemodynamic instability and need for vasopressor support with norepinephrine in moderate doses. Infectious screening was performed and broad-spectrum antibiotherapy was initiated. Moreover, the CA 19-9 level was dosed, with values 20 times the upper normal limit, and CA-125 with values five times the upper normal limit. Contrast-enhanced abdominal pelvic computed tomography revealed a globally enlarged, irregularly shaped, inhomogeneous cephalic contours of the pancreas, with hypocaptive images and microcalcifications; peripancreatic fluid collections with a diameter of up to 2.5 cm, two cystic images with a diameter of 2.4 cm and 2.7 cm, respectively, that come in contact with the portal vein and the head of the pancreas , as well as multiple periaortic and interaortocaval lymph nodes with a maximum axial diameter of 17 mm . These fUnder broad-spectrum antibiotic, antifungal, and vasopressor treatment, fluid and electrolyte balance restoration treatment, analgesic, antipyretic and oxygen therapy, the patient\u2019s general condition improved, allowing the transfer to the internal medicine ward. The patient was hemodynamically stable, with normochromic urine and normal-looking stool. Laboratory investigations revealed mildly elevated aminotranspherases, moderate to severe anemia (without bleeding signs), normal white blood cell count, and no cholestasis. The upper endoscopy identified class A Los Angeles esophagitis; the colonoscopy had normal findings. During hospitalization, the patient continued to have multiple episodes of fever; blood cultures and urine cultures were collected. Blood cultures were positive for Acinetobacter, and antibiotic treatment according to antibiogram was initiated, with persistent fever. Infectious screening was continued, showing negative results for urine cultures, samples were collected from the top of the central venous catheter, and blood cultures. Echocardiography was also performed and ruled out endocarditis. To further evaluate the pancreatic lesions, nuclear magnetic resonance imaging (MRI) was performed, revealing a multicystic pancreatic lesion that raised the suspicion of a pancreatic tumor .The echoendoscopy revealed changes suggestive of chronic pancreatitis, but also a cephalic pancreatic lesion whose differential diagnosis included cystadenoma, cystadenocarcinoma, and infected pseudocyst .A fine needle pancreatic biopsy was performed under echoendoscopic guidance, with extraction of purulent material, that was sent for cytological and bacteriological examination. The Ziehl-Neelsen stain highlighted acid-alcoholic resistant bacilli (300 AARB/300 fields), while bacterial cultures were positive for gentamicin and tigecycline-sensitive Klebsiella. The histological examination identified necrotic and cellular detritus, polymorphonuclear cells, neutrophils, and lymphocytes, without epithelial cells . At thisTuberculosis has remained a major cause of morbidity and mortality in developing countries. Pancreatic tuberculosis is very rare and, in most cases, has been reported in immunosuppressed patients or in the context of disseminated disease . The lowRegarding the age and sex of patients with pancreatic tuberculosis, according to data from the literature, most cases occur in men in the fourth to fifth decade of life ,18,19. TClinical manifestations are usually nonspecific, which may delay the diagnosis ,21. PatiOther clinical presentations in patients with pancreatic tuberculosis, rarely reported, are dyspepsia , signs oLaboratory tests may show anemia, changes in biological markers that assess liver function, changes in serum bilirubin or glucose levels ,29. MoreThe imaging methods that can be used to diagnose pancreatic tuberculosis are abdominal ultrasonography, CT, MRI, endoscopic retrograde cholangiopancreatography (ERCP), and endoscopic ultrasound (EUS) . The radMRI can also provide valuable information to help establish the diagnosis of pancreatic tuberculosis . De BackERCP is not commonly used in the management of patients with pancreatic tuberculosis. In case of the development of complications such as pancreaticobiliary fistulas or biliary obstruction, this imaging investigation can be useful both for diagnostic and therapeutic purposes ,40. BiopCurrently, the imaging method of choice in patients with suspected pancreatic tuberculosis is EUS . In addiClinical manifestations in association with imaging findings in patients with pancreatic tuberculosis frequently lead to diagnostic confusion, as pancreatic tuberculosis may mimic pancreatic cancer. The only way of establishing a definite diagnosis is by collecting biopsy samples with subsequent histopathological examination, Ziehl-Neelsen staining, cultures, and polymerase chain reaction (PCR). These diagnostic methods may reveal the presence of Mycobacterium tuberculosis; the histopathological examination usually reveals necrotizing granuloma . The diaRegarding extrapancreatic involvement, most patients with tuberculosis have peripancreatic lymphadenopathy . These cIn conclusion, the particularities of our case consist in the presence of pancreatic tuberculosis in an immunocompetent patient, with an initial severe presentation, and also the association of pancreatic infection with Klebsiella. Establishing a positive diagnosis proved difficult, as the patient initially showed a diffuse form of pancreatic tuberculosis, with subsequent localization. The differential diagnosis included acute-on-chronic pancreatitis and pancreatic cancer. However, the patient showed no risk factors for pancreatitis or other signs of neoplastic disease. Although the histopathological diagnosis identified only nonspecific inflammatory changes, the Ziehl-Neelsen stain highlighted AFB. Like other cases of pancreatic tuberculosis reported in the literature, the diagnostic process was challenging, despite the accessibility of various diagnostic tools."}
+{"text": "Psychogenic nonepileptic seizures (PNES) consist of paroxysmal changes in responsiveness, movements, or behaviour that superficially resemble epileptic seizures.Presentation of a clinical case of a PNES in a patient with a diagnose of secondary epilepsy, illustrating the relevance of an adequate evaluation, differential diagnosis, and intervention.Description of the clinical case, with brief literature review and discussion. A search was conducted on PubMed and other databases, using the MeSH terms \u201cnonepileptic seizure\u201d, and \u201cepileptic seizure\u201d.We report the case of a 45-year-old female patient, brought to the emergency department because of tonic axial and limb nonsynchronous movements, closed eyes, long duration, with immediate awareness, no desaturation, tongue bite, facial flushing, dyspnoea or sphincter incontinency. She was medicated with clonazepam 1 mg and levetiracetam 1000 mg ev. TC-CE had no acute alteration. Bloodwork had no other major alteration except valproic acid below therapeutic levels . The antecedents of the patient: mild intellectual disability and an accidental traumatic brain injury in infancy, with secondary epilepsy. She was transferred to Psychiatry department. No electroencephalogram (EEG) was realized, because she had a recent one confirming PNES, and many other emergency observations with the diagnosis of PNES.This clinical case showcases the diagnostic difficulties that clinicians face when there is an overlap in symptoms, emphasizing the need to combine patient history, witness reports, clinician observations, and ictal and interictal EEG to help distinguish these different clinical identities.No significant relationships."}
+{"text": "Synthetic and Natural Fiber Reinforced Polymer Matrix Composites for Advanced Applications\u201d is a recently opened Special Issue (SI) of Materials that focuses on the fundamentals, characterization, and applications of fiber-reinforced polymer composites. This SI intends to publish reviews and research articles on the new scientific, applied investigations, product development, and lifecycle analysis of enhanced synthetic and natural fiber-reinforced polymer composites for advanced applications.\u201cFiber-reinforced polymer (FRP) composites are an emerging type of material employed by various sectors to substitute heavy and expensive conventional materials to produce lightweight products. From this point of view, FRP composites have been considered hugely important among researchers because of their versatile properties, applications, and fabrication process. Thus, this composite has been applied in most engineering industries, including defense , civil aIn general, synthetic FRP composites have remarkable properties over monolithic polymer materials, such as long creep, fatigue life, and adaptability to the proposed product functions ,10. FurtNatural fiber-based composites are composed of natural fibers reinforced either in thermoplastic or thermoset composites. Generally, the natural fiber composites offer various ecological values and technical merits, such as low cost, wide availability, and low energy consumption. These values led the global community to change their interest in environmentally friendly materials. These environmentally friendly materials include natural fibers, biopolymers, and biocomposites . Biocomposites are mainly manufactured from plant fibers such as flax, hemp, wood, sugarcane, bamboo, grass, kenaf, sisal, coir, sugar palm, banana, and pineapple leaf fibers ,18. HoweEven though synthetic FRP composites exhibit excellent mechanical performance, these materials have some issues, namely high raw material cost, poor recycling, high density, and non-biodegradability. From this perspective, biocomposites have emerged as a new biomaterial with good mechanical strength, making them a viable option for replacing synthetic FRP composites. Furthermore, natural fibers currently have various advantages compared to synthetic fibers, making them attractive as reinforcement materials in composite technology. In this case, natural fibers were usually obtained from abundant renewable resources, allowing continuous supply and substantial cost savings for composite sectors.This Special Issue captures cutting-edge, state-of-the-art research on the recent findings and the technological development of synthetic and natural FRP composites for advanced applications. The topic themes cover recent achievements in terms of modifications of synthetic and natural fibers, characterization techniques of FRP composites, additive manufacturing processes, manufacturing processes, design and product development, material selections, and structure\u2013property relationships."}
+{"text": "In the originally published version of this manuscript, the following authors were identified as affiliated to UK Health Security Agency in error: Jennifer L Y Yip, Cyril Eshareturi, Julie Billett, and Joanna Inskip.These errors have been corrected and, where necessary, the correct affiliation added instead."}
+{"text": "Wound healing is known to be a complicated and intricate process and commonly classified as chronic or acute. Patients with chronic wounds are of public health concern, and require more attention onto skin lesions, including atopic dermatitis. Despite being a natural process, healing can be impaired by existing chronic de diseases such as diabetes, for example. Recently, wound dressings based in nanotechnology systems have emerged as a viable option to improve the healing process. Current advances in nanotechnology-based systems to release growth factors and bioactive agents represent a great opportunity to develop new therapies for wound treatments. It is essential that healthcare professionals understand the key processes involved in the healing cascade, to maximize care with these patients and minimize the undesirable outcomes of non-healing wounds. Therefore, this review aims to summarize the healing process phases and provide a general overview of dressings based in nanotechnology using biomaterials for the release of active agents in wound site. The formation of a wound is the result of a disruption of skin integrity, or mucosal surfaces, or organ tissue , that haDespite being natural process, healing comprises a cascade of physiological events , with inHowever, this body capacity is dependent on many known factors, such as patient\u2019s underlying health and nutritional status , and canAlthough it is difficult to quantify the economic effects of chronic wounds, some estimations have been performed. In the USA, it is estimated that wound related problems incur an annual expenditure exceeding one billion dollars ,8. A morThus, wound treatment should enhance natural wound healing process, which might require dressings. The development of new technologies can guarantee an effective and efficient healing, thus reducing healing time and recurrence . MateriaNowadays, contamination is the most challenging subject in wound care. To overcome the problem, researches have been intensified and antimicrobial wound dressings have demonstrated promising results in prevention of contamination . Those dThe development of nanotechnology-based systems has aroused great interest, mainly for biomedical and pharmaceutical applications for preventing or treating diseases, including wound healing ,20,21. BThus, this review aims to summarize relevant and overlapping phases of the healing process and provide a general overview of dressings based in nanotechnology using biomaterials for the release of active agents in the wound site.According to the Wound Healing Society, a wound is the disarrangement of natural anatomic structure and function  that canHealing initiates in response to an injury, with the aim to restore the function and integrity of damaged tissue, and consequently homeostasis ,27,28,29Complete wound healing is only possible when all stages occur in the correct sequence, at the specific time, and immunological/biological systems participate in a coordinated way ,32,33. IThe strength increase in the final healing stage is due to a slower rate of collagen deposition and, more importantly, to collagen reshaping with the formation of larger bundles of collagen and an increase in intermolecular crosslinks . HoweverNot only tensile strength, but certain skin components also never fully recover after wound closure. This is the case of subepidermal appendages as hair follicles and sweat glands, that could not heal or grow back after serious injury. The resulting scar epidermis after healing differs from non-injured skin due to the lack of rete pegs, which are normally anchored in the underlying connective tissue matrix and are responsible for tight connections between the epidermis and dermis ,40. HypeThe wounds generally heal without issues. However, some factors  interrupt the healing cascade, leading to a chronic wound by establishing a cycle of hypoxia, inflammation, necrosis and infection . StudiesIn 1962, Winter concluded that moisturized wounds in piglet skin epithelizes two times faster than air exposed wounds . Since tNowadays, it is known that this physiological process can be accelerated and enhanced by the use of dressing techniques, products, and actives ,31,45. WIn the medical community, there is a consensus that to accelerate wound healing process, an ideal wound dressing should present specific characteristics, such as biocompatibility, adequate water vapor permeability, retain moisture to help wound healing, and provide an antibacterial environment ,54,55,56Some authors pointed out some characteristics of an ideal wound dressing material. Those characteristics include: keep the local environment moisturized; have good gas permeability; remove excess exudates; protect wound from exterior contaminations; stop wound desiccation; reduce the tissue necrosis; stimulate new tissue formation; mechanically protect the wound; be easily and comfortably removable, non-toxic, non-allergic, biocompatible, biodegradable, and elastic; reduce pain around wound; not be costly, i.e., commercially viable; and easily sterilized ,53,57,58Dressing products can be classified using different criteria depending on their function, employed material used in the production, dressing physical form, and their contact with wound surface, among others . They caEven though traditional wound dressings are less widely used nowadays, they were commonly used in the past and still provide benefits in certain clinical conditions . Gauze iOn the other hand, modern wound dressings have been developed to facilitate wound and not only to cover it , and thuSimilar to traditional dressings, passive dressings are used to cover the wound, however they are non-occlusive . Most moMore recently, attention was directed to biological dressings, especially those containing bioactive agents as growth factors ,18,33,61Biomaterials have a wide variety of interesting characteristics for development of dressings such as biocompatibility and biodegradability, controlled release, high drug-loading and special mechanical properties ,63. The Natural or synthetic new biodegradable materials have been used for many applications, such as food and cosmetic/pharmaceutical industries, biosensor design and wound dressings. Chitosan, silk fibroin, starch, phospholipids, cellulose, chitin, alginate, gelatin, collagen, natural rubber, hyaluronic acid, and carrageenan composites or blends are some examples of these materials ,72,73,74Although natural polymers are the most used ones, synthetic polymers have also gained more attention because they exhibit better mechanical properties and have the advantage of easily control physicochemical properties. Among them, polylactic acid (PLA), poly(\u03b5-caprolactone) (PCL), polyhydroxyalkanoates (PHAs), polyglicolic acid (PGA), as well as their combinations, are the most used synthetic polymers. Moreover, some of these polymers have a great biocompatibility and formulations that include both natural and synthetic polymers present an interesting approach to wound dressing development ,63,75.Interactive and biological dressings can be designed in different pharmaceutical forms, such as hydrogels, films, foams, sponges, hydrocolloids, hydrofiber and hydrofilms, which have been previously reviewed ,76,77,78Nanotechnology is applied in various medical therapies, including the treatment of different types of wounds ,89. In rIn most cases, nanotechnology-based dressings are used to deliver actives to the wound bead, and then the mechanism by which wound healing is accelerated is dependent on the agent mechanism ,20,21. HVarious materials  were used to produce a myriad of nanoparticles with desired physicochemical properties and biological functions . MoreoveNanoparticles emerged as a promising strategy to minimize microbial resistance, due their ability to enhance the antimicrobial properties , for exaSilver nanoparticles or nanoparticles containing silver have also been studied for wound healing applications . Cotton Zinc oxide nanoparticles are known for their antibacterial effect ,105,113,Bacillus subtilis and Staphylococcus aureus) and Gram-negative (Escherichia coli and Pseudomonas aeruginosa) bacteria and Candida albicans on an infected wound [Polymeric nanoparticles provide a controlled release of the encapsulated compounds used for wound healing applications . Chitosaed wound . Chitosaed wound ,98,99.Among lipid nanoparticles, liposomes present the ability to increase drug accumulation in the skin, which contributes for wound healing and atopic dermatitis ,116,117.As demonstrated above, nanoparticles have several advantages, in addition to high carrier capacity, high stability, ability to incorporate both hydrophilic and hydrophobic materials, ability to use a variety of delivery methods , biocompAloe vera L. and recombinant human epidermal growth factor, for example were incorporated and results indicated that high concentrations of this active might be a suitable strategy for chronic wounds treatment [Different polymers can be used to produce fibers in the nanometric range and they are called nanofibers, presenting different final properties and potential applications. Examples of natural or synthetic polymers include collagen, cellulose, silk fibroin, poly(lactic acid) (PLA), polycaprolactone (PCL), polyurethane (PU), and poly(lactic-co-glycolic acid) (PLGA). Nanofiber dressings could be an alternative for chronic wounds by replacing natural provisional extracellular matrix until it is regenerated . They alreatment .w/v), and fiber diameter as proportional to PVA concentration and inversely proportional to applied voltage (diameter decreased with lower concentrations and higher voltages). Clindamycin-loaded fibers inhibited Staphylococcus aureus growth more effectively than commercial clindamycin gel product. This nanofiber was later improved using Eudragit\u00ae S100 to form a bilayer patch, enhancing its durability and easiness of use [Sangnim et al.  developes of use .Another example of polymeric nanofibers is bacterial nanocellulose, which has been studied for medical purposes, including its application in wound healing, due to its favorable properties . BromelaAmong the advantages of polymeric nanofibers, their high protein adsorption rates, a crucial modulator of cell attachment to a biomaterial surface , similarNanohybrids represent a combination of multiple nanostructures into one cohesive structure . These cPolyvinyl/chitosan/nano zinc oxide nanocomposite hydrogels were investigated regarding their potential use as dressing for wounds. In this case, hydrogel development parameters were studied to optimize conditions. Other important parameters, such as morphology, mechanical properties, toxicity, protein absorption, antibacterial activity, and in vitro wound healing, were analysed. The resultant hydrogel presented antibacterial properties, was biocompatible, showed no toxicity and in vitro potential to treat wounds .Bletilla striata polysaccharide, which presented better properties than chitosan crosslinked only with genipin. However, this material did not show good antibacterial activity, and to overcome this issue, a nanohybrid was proposed by the incorporation of silver nanoparticles in the final formulation. The nanohybrid dressing provided gas permeation and water retention ability, supressed bacterial proliferation, and enhanced fibroblasts proliferation, showing great potential to be further to be used to promote wound healing.Ding et al.  developeE. coli, P. aeruginosa, S. aureus, and C. freundii. In a burn mice model, bacterial cellulose containing zinc oxide nanocomposites showed significant healing activity, with fine tissue regeneration proven by histological analyses when compared to bacterial cellulose [Escherichia coli and Staphylococcus aureus, which can contaminate wound beads [Bacterial nanocellulose membranes have also been studied for the impregnation of nanoparticles to form nanohybrid systems ,110. Zinellulose . In anotThe benefits of nanohybrids include improved esthetic qualities, easy handling, low polymerization shrinkage, great polishability and durability ,138,139,Wound healing is a well-orchestrated process comprising four overlapping and dependent phases, which are regulated by cellular, humoral, and molecular mechanisms. This complex and intricate sequence occurs naturally but could be enhanced and accelerated by dressing techniques, products, and actives. Wound management has proven to avoid non-healing complications, and the use of topical chemotherapy has improved the survival of patients with major chronic wounds and burns. Over the past years, dressings have developed with the arrival of new alternatives, including mixtures of different polymers and nanotechnology tools to create improved materials while guaranteeing an optimal environment. Improvements in hydrogel manufacturing along with nanotechnology can provide new, versatile, and innovative technologies for the future of wound dressing and wound repair. Therefore, besides focusing on the enhancement of nanotechnology-dressings characteristics, researchers should consider the development of cost-effective products, aiming towards the improvement of patients\u2019 quality of life and expenditure reduction."}
+{"text": "Individuals with inflammatory bowel disease (IBD) are known to have a higher risk of digestive tract cancers and cancers associated with immunosuppression. As the IBD population is ageing, age-related cancers may be more commonly diagnosed.To assess whether IBD patients were at a higher odds of incident cancers than their matched controls stratified by age above and below 65 years.A population-based surveillance study was conducted in Alberta, Canada . A validated algorithm identified cases of IBD. Each case was age and sex matched to up to 10 non-IBD cases from the general population and linked to the Alberta provincial cancer registry to extract pathology-confirmed incident cancer. Controls were removed if they were not residents of Alberta at the time the matched case was diagnosed with IBD. Only incident cancers diagnosed after the diagnosis of IBD (or matched indexed date for controls) were considered. Age was calculated based on year of inclusion in the cohort or, if applicable, the year of cancer diagnosis. Cancer diagnoses were classified: bladder, biliary and liver, breast, cervix, colorectal, endometrium, gastrointestinal, gynecological, head and neck, hematological, kidney, lung, melanoma, neurological, non-melanoma, pancreas, prostate, renal and bladder, small intestine, thyroid, and miscellaneous. Odds ratios (OR), with 95% confidence intervals (CI), compared IBD cases to matched controls using conditional logistic regression. Stratified analysis at age 65 (<65 and \u226565) was done for all cancers.Overall, 3695 incident cancers were diagnosed among 35,763 individuals with IBD as compared to 22,687 cancers among 289,212 controls . Those less than 65 years old were at higher odds of developing cancer  than those \u226565 . Those with IBD had a higher odds biliary and liver  and gastrointestinal , which including: colorectal , pancreas , and small intestine . Melanoma and non-melanoma, head and neck, and thyroid cancers did not have an increased odds but hematological, lung, neurological, and kidney cancers did show an increased odds among those with IBD. Cancers outside of the gastrointestinal tract were at a lower odds for IBD patients, including: bladder , breast , gynecological  and endometrium , and prostate .Under the age of 65, individuals with IBD have a higher odds of being diagnosed with cancer than the general population, with cancers of the digestive tract driving this association across the age spectrum. Healthcare providers should be aware of higher occurrence of hematological, neurological, lung and renal cancers in those with IBD.CIHRS. Coward: None Declared, S. Murthy: None Declared, H. Singh Consultant of: Pendopharm, Amgen Canada, Bristol Myers Squibb Canada, Roche Canada, Sandoz Canada, Takeda Canada, and Guardant Health, Inc., E. Benchimol Consultant of: Hoffman La-Roche Limited and Peabody & Arnold LLP for matters unrelated to medications used to treat inflammatory bowel disease and McKesson Canada and the Dairy Farmers of Ontario for matters unrelated to medications used to treat inflammatory bowel disease., E. Kuenzig: None Declared, G. Kaplan Grant / Research support from: Ferring, Janssen, AbbVie, GlaxoSmith Kline, Merck, and Shire, Consultant of: Gilead, Speakers bureau of: AbbVie, Janssen, Pfizer, Amgen, and Takeda"}
+{"text": "PLOS ONE Editors retract this article [The  article  because MSS did not agree with retraction. MMM, AA, SF, KAK, SA, MIK, AH, MArif, MAhmad, and MT either did not reply directly or could not be reached. MIuH and SK responded but expressed neither agreement nor disagreement with the editorial decision."}
+{"text": "The main dermatological manifestations of TSC are hypochromic macules (ash leaf spots), facial angiofibromas, fibrous cephalic plaques, periungual fibroids, shagreen patch, and confetti lesions.Tuberous sclerosis (TSC) is an autosomal dominant neurocutaneous syndrome characterized by several abnormalities, including benign tumors of the embryonic ectoderm in multiple organs, such as skin, eyes, and central nervous system.A 26-year-old woman presented with a giant angiofibroma with an atypical and rare symptom of TSC, the main symptom being the skin lesions  and 4. T"}
+{"text": "Indonesia is prone to natural hazards, which have continued to occur even during the coronavirus disease 2019 (COVID-19) pandemic. Therefore, this study explored the response and strategy employed by Muhammadiyah, one of Indonesia\u2019s moderate Islamic organisations, in dealing with natural hazards during this pandemic. A qualitative descriptive method was used in this study, and the data collection procedure involved finding related literature, reports, and decrees. Online interviews were also conducted with the Muhammadiyah Disaster Management Center (MDMC) administration to strengthen the data. Subsequently, this study discovered that Muhammadiyah responded by aiding victims of natural hazards, which occurred in various regions in Indonesia during the COVID-19 pandemic. The strategies employed comprise Muhammadiyah COVID-19 Command Center (MCCC) to handle COVID-19, alongside essential recommendations to the MDMC network throughout Indonesia and the various arms of the government for dealing with natural hazards during the pandemic. Also, it showed commitment to handling these hazards by establishing a standard operating procedure for Muhammadiyah volunteers and represented Indonesia during a presentation at the World Health Organization. Indonesia is prone to natural hazards Djalante , which iFiqh [deep understanding], namely the Muhammadiyah product document for answering contemporary problems, mainly geological and non-geological hazards. This subsequently became the normative basis for alleviating health hazards and has been actualised in the mitigation of COVID-19, medical health movements, the reconstruction of fiqh worship during the emergency, and handling hazards theologically.Before the COVID-19 pandemic erupted in Indonesia in early 2020, studies about Muhammadiyah and its relation to hazards solely examined their role during these events. However, since the outbreak of the pandemic, many studies have focused on the organisation\u2019s role in dealing with the pandemic from various aspects, such as health, education, social, and religious guidance. Falahuddin  of the MDMC of the Muhammadiyah Central Leadership have conducted 103 hazard responses, involving 49 floods, 14 landslides, one earthquake, 9 fires, 7 search and rescues, 6 tornadoes, 5 droughts, 6 fallen trees, and 6 mountain eruptions.There have been three responses in Aceh, West Sumatra, Central Sulawesi, and Banten each, two each in North Sumatra, West and Central Kalimantan, alongside DKI Jakarta, East Java, and Nusa Tenggara Barat (NBT). Also, there have been one each in South Sumatra, Bengkulu, Lampung, South and East Kalimantan, Gorontalo, Maluku, West Papua, and Nusa Tenggara Timur, alongside four South Sulawesi, 10 West Java, 16 Central Java, and 12 DIYogyakarta responses.Total expenditure was Rp 7 552 887 757.There were 1965 Muhammadiyah Response Team members, consisting of 174 psychosocial personnel, 1234 general volunteers, alongside seven assistance teams, 77 post-management, 116 health team, 145 available kitchen, 175 SAR team, and 37 logistic team personnel.Total beneficiaries include 86 200 people, comprising the cleanup of areas affected by floods, landslides, fallen trees, and fires. There were 94 temporary housing units, 3200 recipients of clean water, 2753 psychosocial assistances, 42 888 logistics distributions, 7700 mask receivers, 4010 healthcare beneficiaries, 25 052 ready meals, and evacuation and rescue operations, and 315 school kits. All of the above data is included in Secondly, the data concerning Muhammadiyah\u2019s response to natural hazards between January \u2013 April 2021 showed that:TDRR of MDMC of Muhammadiyah Central Leadership implemented 80 hazard responses from January to April 23, 2021.Central Java had the most responses of 19, followed by East Java, West, Yogyakarta, and NTB, at 10, 6, 5, and 4 times. The rest were in 14 other provinces, which occurred below three times in each region.Of the total 80 responses that were implemented, MDMC distributed Rp. 8 121 779 632. These funds came from donations from various parties, including extended Muhammadiyah members and the public channeled through Lazismu, and assistance from MDMC partner agencies, such as Swiss Solitaire, CRS, and Allianz.There were 298 891 beneficiaries of MDMC funds through various response activities, namely SAR operations, ready-to-eat food distribution, COVID-19 kits, clean water, logistics and non-logistics, psychosocial assistance, health services, environmental cleaning, emergency, temporary or permanent shelters, socialisation, and emergency bridges.There were 2870 volunteers, comprising about 2268 general, 200 medical, 76 psychosocial, 7 assistants, 150 available kitchen, 86 SAR team, 57 logistics, 3 media personnel, and 4 drivers.In April 2021, Muhammadiyah volunteers plunged into three hazard areas, namely West Nusa Tenggara, particularly Bima and Dompu due to extreme rainfall, East Nusa Tenggara because of the cyclone Seroja, and East Java due to the earthquake that hit the southern regions, such as Blitar, Lumajang, Malang, and Jember.In West Nusa Tenggara, the local volunteers helped flood-affected residents in Bima and Dompu by performing an intensive environmental cleanup, logistical assistance, ready meals, and accessible health services.After the landslide in East Nusa Tenggara, the MDMC Head sent National Muhammadiyah Emergency Medical Team (EMT) to support the local volunteers. The services conducted include free medical treatment, logistical and psychosocial assistance, and improved clean water advice for the residents.The volunteers in Blitar, Lumajang, Malang, and Jember of East Java performed various activities to help the survivors, such as distributing logistics and ready meals, cleaning earthquake debris, psychosocial assistance, and free medical examinations. All of the above data is included in Muhammadiyah employs various strategies in handling natural hazards during general or everyday circumstances. However, new strategies were formulated during the COVID-19 pandemic to suit the situation and conditions, including:The Muhammadiyah Central Leadership formed the MCCC on March 14, 2020, based on the Decree of Muhammadiyah Central Leadership Number 2825/KEP/I.0/D/2020 concerning the Establishment of MCCC in charge of coordinating various COVID-19 pandemic prevention programmes involving Muhammadiyah potential and networks  for volunteers to maintain their health as well as that of the victims of natural hazards during the pandemic  programme, hosted virtually in Geneva, Switzerland on Thursday 29 April 2021  programme, which was hosted virtually in Geneva, Switzerland on Thursday 29 April 2021, by the EMT Muhammadiyah Deployment during the COVID-19 pandemic serves as a strategy to publicise the organisation\u2019s role and contribution in disaster management to the world.This study showed that Muhammadiyah still experiences significant challenges and obstacles, although it employs a comprehensive response and proper strategy in handling natural hazards during the pandemic. These challenges are recognised while facing multi-hazards due to the increased complexity of personnel capacity, team logistics, and facility modifications. Other obstacles are the tracing, testing, treatment, and referral system used in assessing affected areas during the pandemic, increased risk of transmission in affected areas, and the need to suspect every patient until confirmed negative Nihayati .Based on the study results showing these challenges and constraints, future policies and budgets should apply the principles of community-based disaster risk reduction during a pandemic. Another important suggestion is that the cooperation between governments and community organisations should be improved, especially the efforts to handle natural hazards and the COVID-19 pandemic, based on the strength of thecommunity.Muhammadiyah has been instrumental in helping the victims of natural hazards in Indonesia, both in regular times and especially during the COVID-19 outbreak. Subsequently, this study showed that natural hazards worsened the suffering of people who are already affected by the adverse effects of the COVID-19 pandemic. Muhammadiyah has played an active role by providing assistance in various regions via an appropriate strategy. Through MDMC, the organisation has followed the stages of prevention before disasters and adhered to adequate practical measures, namely disaster management methods such as mitigation, preparedness, emergency response, and recovery after a hazard during the COVID-19 pandemic.The response and strategy used by this organisation in dealing with natural hazards during the COVID-19 pandemic, which is the study\u2019s finding, are not only able to address the problem of this article that has not been discussed by other researchers, but can also be exemplified by other community organisations and the government. In the Muhammadiyah approach, experts understand and have practised disaster theories in many natural and non-natural management situations inside and outside Indonesia.This study was limited to assessing Muhammadiyah\u2019s response and strategy in managing natural hazards while the COVID-19 pandemic is still ongoing. Consequently, further comparative research should identify and map the advantages and weaknesses of actions implemented by Muhammadiyah and other organisations to facilitate mutual support and complement in helping the community overcome the multi-hazardous disasters. This is based on the idea that an organisation, no matter its size, cannot handle a hazard alone. The government cannot solely manage natural hazards without including the community. Hence, a collaboration between all parties in handling natural hazards, especially during the COVID-19 pandemic, is encouraged, as this will assist the community and lighten their burden, thereby fostering gratitude."}
+{"text": "Multiple indices currently exist to measure a country's preparedness for health emergencies.The dynamic preparedness metric (DPM) is a composite measure with three main conceptual dimensions: hazard, vulnerability, and capacity . Hazard Two metrics have been developed to assess the country preparedness status: (1) the risk-based DPM index, which supports countries in understanding current and changing capacities in line with hazards and vulnerabilities to strengthen their preparedness capacities for managing health emergencies effectively; and (2) the preparedness capacity gap, which helps countries identify gaps and prioritise actions necessary to address those gaps\u2014such as those from the WHO benchmarks for International Health Regulations (IHR) capacities.The DPM index is dynamic as it is frequently updated with publicly available data and addresses five specific disease syndromes . The potential pathways of spread and the impact on society for each syndrome are heterogeneous; thus, the preparedness capacities and actions needed to contain each syndrome are specific. The ability of the DPM index to estimate preparedness status relative to specific syndromes and risks will better inform effective actions to increase capacities and reduce epidemic spread and its management.Moreover, the aim of the DPM index is not to rank countries but rather to facilitate the identification of countries\u2019 specific limitations in preparedness and possible mitigation strategies. Therefore, the DPM index is designed to support countries and regions to make evidence-based improvements in emergency preparedness considering the unique contributions of multiple sectors and disciplines. This dynamic and multisectoral approach is in line with best practices to limit the impact of future epidemics or pandemics through a health systems for health security approach.The WHO has finalised phase 1 of the DPM through ongoing discussion with experts in the disciplines of health security, data science, animal\u2013human interface, infrastructure, and epidemiology, among others. The DPM index is in use for the Universal Health and Preparedness Review (UHPR) to inform the baseline preparedness status in three dimensions in addition to UHRP indicators.I declare no competing interests. The members of the WHO Technical Working Group of the Dynamic Preparedness Metric are Woody Ang Woo Teck, Cynthia Bell, Lucy Boulanger, Garrett Brown, Orlando Cenciarelli, Matthew H Cochran, Stephane De La Rocque, Khassoum Diallo, Ande Elisha Ashasim, Kaylee Errecaborde, Sane Jussi, Julie Kae, Nirmal Kandel, Masaya Kato, Benjamin Downs Lane, Lorenzo Lionello, Rafael Lozano, Aragaw Merawi, Robert Nguni, Jennifer Nuzzo, Heather Page, Ihor Perehinets, Amit Prasad, Amelie Rioux, Dalia Samhouri, Reuben Samuel, Nahoko Shindo, Jonathan Suk, Ambrose Otau Talisuna, Schmidt Tanja, Andrew Thow, and Luca Vernaccini. The members of the Health Security Preparedness Department at WHO are Stella Chungong, Marc Ho, Qudsia Huda, Abbas Omaar, Rajesh Sreedharan, Ludy Suryantoro, Liviu Vedrasco, and Jun Xing."}
+{"text": "Catatonia is a complex neuropsychiatric syndrome, occurring in the context of different psychiatric and neurodevelopmental disorders, in neurological and medical disorders, and after substance abuse or withdrawal. The relationship between Autism Spectrum Disorder (ASD), Schizophrenia Spectrum Disorders (SSDs) and catatonia has been previously discussed, with the three disorders interpreted as different manifestations of the same underlying brain disorder (the \u201cIron Triangle\u201d). We discuss in this paper the diagnostic, clinical and therapeutic implications of this complex relationship in an adolescent with ASD, who presented an acute psychotic onset with catatonia, associated with mixed mood symptoms. Second-generation antipsychotics were used to manage psychotic, behavioral and affective symptoms, with worsening of the catatonic symptoms. In this clinical condition, antipsychotics may be useful at the lowest dosages, with increases only in the acute phases, especially when benzodiazepines are ineffective. Mood stabilizers with higher GABAergic effects  and Lithium salts may be more useful and well tolerated, given the frequent association of depressive and manic symptoms with mixed features. Catatonia is a complex neuropsychiatric syndrome, firstly described by Kahlbaum in 1874 as a motor syndrome occurring in association with affective disorders, epilepsy and tuberculosis ,3, contrCatatonia is characterized by three specific clusters of motor, speech and behavioral features. DSM-5 diagnostic criteria require three of twelve symptoms, including stupor, catalepsy, waxy flexibility, mutism, negativism, posturing, mannerism, stereotypy, agitation, grimacing, echolalia and echopraxia . HoweverAlbeit often underdiagnosed or misdiagnosed, catatonia is not rare in pediatric and adolescent populations , especiaIn this report, we describe the case of a 16-year-old patient with a history of ASD, presenting with an acute-onset severe catatonic symptomatology in the context of an SSD and affective symptoms. Clinical, developmental and treatment implications will be discussed. Particularly, we focus on the treatment implications of this \u201ctriad\u201d, in terms of poorer efficacy and tolerability of antipsychotic treatments, with a possible worsening of catatonic symptoms after the increase in antipsychotics dosage.L. is a 16-year-old Caucasian boy with a healthy heterozygous twin and a negative psychiatric family history. He presented in early years isolation and impaired relationships with peers, due to low reciprocity, inflexibility and stereotyped behaviors. These features were associated to a hyperactive and impulsive behavior, inattention with persisting difficulty organizing tasks and activities, and emotional dysregulation, with excessive reactivity and irritability. Intellectual functioning was borderline, with co-occurring learning difficulties and related difficult school achievements since primary school. All these features can be retrospectively referred to a mixed NDD with ASD, ADHD, learning disorders, borderline intellectual functioning and impaired emotional regulation.During adolescence, isolation, low reciprocity, inflexibility, and stereotyped behaviors and interests persisted, with increasing difficulties with peers. ADHD and emotional dysregulation worsened, with superimposed oppositional and defiant behaviors, hostility, low adherence to social rules, intolerance to frustrations, poor school performances and frequent cannabis use. At age 15, L. and his brother were involved in a fight with other boys, and L. reported a facial trauma with multiple fractures and need for reconstructive surgery. After a few months from this stressful event, and during a phase of cannabis use, L. presented an acute-onset SSD, characterized by persecutory delusions, isolation, disorganized behavior and confusion, agitation (escape from home because of the fear of being killed), and reversal of sleep\u2013wake rhythm. This condition was associated to a severe catatonic symptomatology, according to the Bush-Francis Catatonia Rating Scale , a 14-itB, MGA (Myelin-Associated Glycoprotein), anti-neuronal antibodies associated with cerebellar degeneration , and the additional antibody profile for paraneoplastic neurological syndromes .After six months, while the patient was still assuming Lurasidone 111 mg/day, a sudden, acute recurrence of illness occurred without apparent triggers (including substance use), with a new, severe worsening of catatonic features , social withdrawal, alternating with agitation, dysphoria, and refusal of medications. At the admittance for hospitalization in emergency room, mutism and negativism, postural stiffness and staring were associated with agitation, irritability, disorganized persecutory thoughts and behavior, inner tension, suspiciousness, episodic elated mood, grandiosity, verbal and physical aggression, episodic inappropriate disinhibition and hypersexual behavior, and decreased need for sleep. The patient was treated with IM Aripiprazole (7.5 mg twice a day) and IM Delorazepam. After a two-week treatment, the agitated catatonia persisted, with the following symptoms: alternation of extreme hyperactivity, unprovoked agitation, impulsivity and hostility, immobility, mutism, negativism, lack of facial expression, staring gaze, poor eye contact, bizarre posture, repetitive behaviors, perseveration and verbiage, refusal to eat and autonomic abnormalities (increased blood pressure and heart rate). On the Bush\u2013Francis Catatonia Rating Scale , the patGiven the poor treatment efficacy and the prominence of catatonic and affective symptoms, intravenous (IV) Lorazepam  and IV Sodium Valproate (400 mg three times a day), followed after three days by oral Sodium Valproate 1000 mg/day, Lithium salts (up to 20 mmol/L) and Gabapentin 900 mg/day were prescribed, with discontinuation of the antipsychotics. A gradual but evident improvement of catatonic symptoms occurred in the next two weeks. Unfortunately, after the discharge, psychomotor agitation rapidly worsened, with accelerated thought and speech, grandiosity and hypersexuality, so Olanzapine was restarted up to 10 mg/day, with improvement of mood and behavior, but a new worsening of catatonic signs. The antipsychotic was newly reduced to 7.5 mg/day, Lorazepam increased up to 10 mg/day, Lithium salts increased up to 32 mmol/day, Sodium valproate 1000 mg/day and Gabapentin 900 mg/day. Bizarre postures were restricted to parts of the body , associated to perseveration, suspiciousness, abnormal prosody, bizarre thought and flat mood, and poor eye contact. Psychotic (delusions) and behavioral (hostility) symptoms also moderately improved in the next months, but global functioning has not returned to baseline.L. presents a complex, multiple neurodevelopmental disorder (NDD), with early impairment of social communication/interaction area, associated with inattention and impulsive/hyperactive symptoms, cognitive impairment  and emotion dysregulation, complicated in the secondary school by defiant, oppositional and rule-breaking behaviors. In this neurodevelopmental context of vulnerability, the cannabis use and a significant traumatic event  may have triggered the acute onset of an SSD with both positive and negative symptoms, with prominent component of a catatonic syndrome, co-occurring affective symptoms (both depressive and manic) and a progressive regression in social and adaptive skills. This case report highlights the complex connection between three psychopathological realms : (1) ASThe ASD, with altered peer relationships and low reciprocity, can be a precursor of a schizotypal personality disorder, and possibly of an SSD ,23. The These intertwined developmental pathways underline the need for a developmental approach to psychopathology, more centered on a careful exploration of the trajectories over the years , and of Antipsychotics have been often necessary in our clinical case to manage psychotic symptoms (delusions), behavioral symptoms (impulsivity and aggression), and manic symptoms , but their use had negative implications on catatonia, flat affect, anhedonia and abulia. The atypical response to antipsychotic treatments is in line with literature data, suggesting that individuals with comorbid ASD and psychosis may be less likely to experience benefit from multiple antipsychotics . At the In summary, we submit that a complex clinical condition can be characterized, with ASD , SSD (with mixed schizophrenic and affective symptoms) and catatonia. In this condition, antipsychotics should be used at the lowest dosages, with increases only in the acute phases, when BDZs are poorly effective. The use of mood stabilizers, both those with higher GABAergic effect  and Lithium salts, may be more useful and well tolerated."}
+{"text": "In \u201cA Telehealth-Delivered Tai Chi Intervention (TaiChi4Joint) for Managing Aromatase Inhibitor\u2013Induced Arthralgia in Patients With Breast Cancer During COVID-19: Longitudinal Pilot Study\u201d : e34995), the authors made the following corrections in the corresponding authorship:1. In the originally published article, author Sameh Gomaa was erroneously listed as the corresponding author. The corresponding authorship is now correctly attributed to Kuang-Yi Wen.2. Accordingly, the address and contact details of the corresponding author have been changed as follows:Kuang-Yi Wen, PhDDepartment of Medical OncologyThomas Jefferson University834 Chestnut Street Suite 300Philadelphia, PA, 19106United StatesPhone: 1 21550346233. In the originally published article, author Tingting Zhan was incorrectly associated with the following affiliation:Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, United StatesThe author is now correctly associated with newly added Affiliation 2:Department of Pharmacology & Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA, United States 4. In the originally published article, author Andrew Newberg was incorrectly associated with the following affiliation:Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, United StatesThe author is now correctly associated with newly added Affiliation 3:Department of Integrative Medicine and Nutritional Sciences, Thomas Jefferson University, Philadelphia, PA, United StatesThe correction will appear in the online version of the paper on the JMIR Publications website on July 19, 2022, together with the publication of this correction notice. Because this was made after submission to PubMed, PubMed Central, and other full-text repositories, the corrected article has also been resubmitted to those repositories."}
+{"text": "Poor food environments and disproportionate food insecurity among African Americans (AAs) represent determinants of chronic disease disparities by race/ethnicity. We used PhotoVoice to explore the food environment in Baltimore, MD, through the perspectives of Black residents with hypertension. Findings illuminated structural racism and classism as root causes of \u201cfood desert\u201d conditions. Respondents provided critical analysis of existing food access barriers, including problematic policies, and offered asset-based solutions. Using an exhibition of participants\u2019 photographs to set the tone of the discussion, we will convene a stakeholder meeting including study participants, community advisory board members, local and state government agencies, civic organizations, community farmers, agricultural organizations, non-profit food providers, churches, local restauranteurs, convenience store owners, insurance payers, and transportation providers. Discussion will center on three areas of action informed by findings: systems level issues; individual activation, agency, and advocacy; and community-based solutions. Meeting proceedings will be disseminated through academic and lay publications."}
+{"text": "There are various SFN clinical manifestations, the most common being pain, dysesthesia, and dysautonomia. In recent literature, pruritus occurred in 68.3% of patients with SFN . MoreoveDiagnostic tools for SFN detection include skin biopsy with intraepidermal nerve fiber density (IENFD), quantitative sensory testing (QST), quantitative sudomotor axon reflex testing, corneal confocal microscopy, electromyography, and nerve-conduction studies that quantify and assess small nerve fiber function . SFN diaPain is a common and crucial SFN manifestation; thus, therapy is based on the underlying cause and pain management. Several classes of medications are commonly used, including antidepressants, anticonvulsants, opioids, and topical treatments. In previous studies, tricyclic antidepressants (TCAs), serotonin\u2013norepinephrine reuptake inhibitors (SNRIs), and anticonvulsants such as gabapentin and pregabalin, were routinely recommended for neuropathic pain treatment .Rosacea, a chronic inflammatory skin condition, primarily manifests as recurrent flushing and erythema in the central facial area. Rosacea can be divided into four subtypes: erythematotelangiectatic, papulopustular, phymatous, and ocular. Neurogenic rosacea (NR), a new variant suggested by Scharschmidt in 2011, is characterized by facial burning, stinging, and dysesthesia disproportionate to flushing, which manifested as more severe neurogenic inflammation and recalcitrant to traditional therapy . The disInnate immune system and neurovascular dysregulation play major roles in neurogenic rosacea pathophysiology. TNF-\u03b1 expression, a known mediator of mast cell degranulation and vasodilation, is upregulated in patients with rosacea, promoting release of inflammatory mediators such as IL-6 and IL-8 . NeurogeA study conducted in France revealed pruritus as one of the most frequent symptoms in patients with SFN. Sensory symptoms of SFN are often described as length-dependent and stocking-glove distribution; however, non-length-dependent distribution also occurs, frequently involving head-related areas . CoincidPatients with rosacea frequently present with gastrointestinal symptoms. A nationwide cohort study of the Danish population revealed rosacea is significantly associated with gastrointestinal disorders, such as celiac disease, irritable bowel syndrome, and inflammatory bowel disease; although specific underlying mechanisms remain unclear . PatientNeurogenic rosacea generally does not respond well to traditional therapy. However, drugs used to treat SFN, such as TCAs, pregabalin, gabapentin, and duloxetine, are effective in treating neurogenic rosacea . FurtherNotably, there is a lack of case\u2013control studies comparing IENFD in patients with NR to healthy controls, probably for the reason that only a small proportion of rosacea might be NR and also patients tend to refuse the invasive skin biopsy from facial skin for aesthetic reasons. Therefore, more clinical exploration is required. IENFD varies with body regions, suggesting that SFN criteria, such as skin biopsy from the lower leg, is not applicable for facial NR. Nevertheless, NR and SFN have similarity in the pathogenesis, manifestations, complications, and treatment strategies .In conclusion, neurogenic rosacea could be a particular phenotype of SFN that involves facial skin. The current SFN diagnostic criteria are far from perfect, and more attention is required for facial manifestations."}
+{"text": "Micro-/nano-scaled structures, materials, and devices enable the continuous monitoring of human physical activities and behaviors, as well as physiological and biochemical parameters during daily life. The most commonly measured data include vital signs such as heart rate, blood pressure, and body temperature, as well as blood oxygen saturation, posture, and physical activities through the use of an electrocardiogram (ECG), ballistocardiogram (BCG), and other devices. Potentially, wearable photo or video devices could provide additional clinical information. Wearable devices can be attached to shoes, eyeglasses, earrings, clothing, gloves, and watches and may evolve to be skin-attachable devices. Sensors can be embedded into the environment, such as chairs, car seats, and mattresses. Healthcare is undergoing a rapid transformation from a traditional hospital- and specialist-focused approach to a distributed patient-centric approach. Advances in several technologies fuel this rapid transformation of healthcare vertically. Among the various technologies, communication technologies have enabled us to deliver personalized and remote healthcare services.The Special Issue consists of five contributions in the area of security and sensing devices for healthcare technologies.In the paper , A FiberIn the paper , Design In the paper , Full GrIn the paper , High GaIn the paper , Portabl"}
+{"text": "Many insect pests directly compete with humans for food, damaging several crops in the field and during the processing and storage. Every year, about 20% of the global production of agricultural goods is lost due to more than 20,000 species of harmful insects. Moreover, some parasites can act as vectors of viruses and microorganisms, both pathogenic to humans and other vertebrates. The control of those species is, therefore, a crucial focus for the medical, veterinary, and agro-food chain operators. Scientific evidence revealed that the massive and continuous use of synthetic pesticides results in an accumulation of residues in the environment , and have neurotoxic, carcinogenic, teratogenic, and mutagenic effects on human and non-target animals. Furthermore, the insurgence of resistance to the more commonly used chemicals in repeatedly treated pests is thoroughly stated in a multitude of scientific publications. Despite all the drawbacks reported, insect pest control still mainly relies on synthetic insecticides. Since the 1980s, research on natural products, also known as biopesticides, has highlighted their numerous helpful effects against insect pests. To fully understand and exploit the potential of natural substances, though, more improvement in the knowledge of their vast and various bioactivities is essential. Biopesticides comprise a broad group of different materials, which includes botanical products , inert dust , as well as microorganisms . Because of their natural origin, biopesticides are supposed to have fewer side effects than synthetic pesticides, although they are not free from intrinsic limits. This \u201cNatural Substances against Insect Pests: Assets and Liabilities\u201d Special Issue (SI) addresses current basic and applied research on the isolation, chemical characterization, biochemistry, bioactivity, mode of action, benefits, and risks related to the use of natural substances as insecticides.Origanum vulgare [Citrus reticulata, Melaleuca alternifolia [Mentha arvensis [Cymbopogon citratus, C. winterianus, Eucalyptus citriodora, and E. camaldulensis [Calliphora vomitoria [Aedes aegypti [Drosophila suzukii [Ajuga iva [Ludwigia tomentosa, L. longifolia [Sophora alopecuroides [Psiadia penninervia, Salvia officinalis, Ochradenus baccatus, Pulicaria crispa, and Euryops arabicus [Spodoptera littoralis [Plutella xylostella [Aedes albopictus [Aphis craccivora, and its predator, the Neuroptera Chrysoperla carnea [In detail, this SI includes studies on the bioactivities of some essential oils, such as  vulgare , Citrus rnifolia , Mentha arvensis , Cymbopodulensis . These eomitoria  and the  aegypti ,4 to the suzukii , demonstjuga iva , Ludwigingifolia , Sophoracuroides , Psiadiaarabicus  extractsttoralis  and the lostella , the mosbopictus , the beaa carnea . Vegetala carnea . The maia carnea . The usea carnea  and sulpa carnea , againstTephrosia species against stored product pests [The SI also comprises two reviews: one on the bioactivity of vegetal extracts of ct pests , and onect pests .Last but not least, the SI contains a meta-analysis concerning 74 years of scientific literature, surveying over 2500 papers on botanical insecticides published between 1945 and 2019. This paper gives us a 360\u00b0 view of the research in the bioinsecticides field, without neglecting the effects on non-target species, sub-lethal effects, and knowledge gaps .In conclusion, this \u201cNatural Substances against Insect Pests: Assets and Liabilities\u201d Special Issue offers innovative empirical results and starting points to unravel the bioinsecticides\u2019 complex bioactivity and role in the ecosystem.I am very grateful to all the contributing authors, all the reviewers involved, and the editorial staff for their invaluable help in the assembly and editing of this very Special Issue."}
+{"text": "These European Stroke Organisation (ESO) guidelines provide evidence-based recommendations to assist with clinical decisions about management of ccSVD, specifically white matter hyperintensities and lacunes, to prevent adverse clinical outcomes. The guidelines were developed according to ESO standard operating procedures and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. We prioritised the clinical outcomes of stroke, cognitive decline or dementia, dependency, death, mobility and mood disorders, and interventions of blood pressure lowering, antiplatelet drugs, lipid lowering, lifestyle modifications, glucose lowering and conventional treatments for dementia. We systematically reviewed the literature, assessed the evidence, formulated evidence-based recommendations where feasible, and expert consensus statements. We found little direct evidence, mostly of low quality. We recommend patients with ccSVD and hypertension to have their blood pressure well controlled; lower blood pressure targets may reduce ccSVD progression. We do not recommend antiplatelet drugs such as aspirin in ccSVD. We found little evidence on lipid lowering in ccSVD. Smoking cessation is a health priority. We recommend regular exercise which may benefit cognition, and a healthy diet, good sleep habits, avoiding obesity and stress for general health reasons. In ccSVD, we found no evidence for glucose control in the absence of diabetes or for conventional Alzheimer dementia treatments. Randomised controlled trials with clinical endpoints are a priority for ccSVD."}
+{"text": "Recently in agriculture, the usage of chemical pesticides and fertilizers has increased tremendously. Additionally, it shows severe effects on human health, ecosystem, and groundwater. Environment-friendly methods are used to improve soil fertility, pests, and disease control. Biopesticide and biofertilizers have the future to upgrade sustainable agriculture for many years. This review highlights the efficacy of biofertilizers and biopesticides in improving crop yielding. It provides an eco-friendly and cost-effective method to get more yield for farmers. It describes the prominence of microbial inoculants in plant cultivation.Farmers are now facing a reduction in agricultural crop yield, due to the infertility of soils and poor farming. The application of chemical fertilizers distresses soil fertility and also human health. Inappropriate use of chemical fertilizer leads to the rapid decline in production levels in most parts of the world, and hence requires the necessary standards of good cultivation practice. Biofertilizers and biopesticides have been used in recent years by farmers worldwide to preserve natural soil conditions. Biofertilizer, a replacement for chemical fertilizer, is cost-effective and prevents environmental contamination to the atmosphere, and is a source of renewable energy. In contrast to chemical fertilizers, biofertilizers are cost-effective and a source of renewable energy that preserves long-term soil fertility. The use of biofertilizers is, therefore, inevitable to increase the earth\u2019s productivity. A low-input scheme is feasible to achieve farm sustainability through the use of biological and organic fertilizers. This study investigates the use of microbial inoculants as biofertilizers to increase crop production. Chemical fertilizers and pesticide dependence in conventional agriculture have increased, due to the significant growth of the human population and food demands . Plant nFor a healthy environment, the management of integrated nutrient systems and sustained agricultural productivity is greatly influenced by microbial inoculants . MicrobiBacillus thuringiensis (Bt) [\u2018Biopesticide\u2019 implies the use of beneficial microorganisms to control the insects. However, the major constraint is the availability of biopesticides relative to the total cropped area. Specific pesticides, derived from natural materials, act as biopesticides, such as plants, animals, bacteria, and certain minerals . Biopestsis (Bt) . Modern sis (Bt) . Therefo2 fixers, phytohormones, siderophores, and antibiotics) and biopesticides .The objective of this review is the improvement of plant growth and yield through various microbes, such as bacterial, fungal, virus, and algae inoculants as biofertilizer , sulfur solubilizer, PGPR, VAM, and Azolla), PGPR , vesicular-arbuscular mycorrhiza (VAM), and Anabaena, as nitrogen-fixing cyanobacteria [Microbial inoculants or biofertilizers are preparation containing viable algae, fungi, and bacteria alone or consortium together to support the plant growth and increase crop yield . Biofertbacteria ,16. Thesbacteria ,18.Biofertilizers are eco-friendly, cost-effective, and can be produced in bulk on the farm itself if necessary. The crop yield is increased by 10\u201340% and up to 50 percent of nitrogen is fixed. The continuous application of biofertilizer of the land for 3\u20134 years can retain fertility, due to the efficiency of parental inoculums, which could maintain the growth and multiplication of plants effectively. They improve soil texture, pH, and other properties .Biofertilizers are renewable sources of plant nutrients complementing chemical fertilizers at a low cost. In comparison to chemical fertilizers, biofertilizers are environmentally friendly; can be produced from natural sources, prevented from damage but also helps in building up healthy soil, and to some extent, plants are cleansed from chemical fertilizers that are precipitated . Conside2 by nitrogen-fixing bacteria [2 fixing species are used as fertilizers containing living microbial inoculants or microorganism classes. Microbial inoculants, such as Azotobacter, Rhizobium, Blue-Green Algae (BGA), Azospirillum, and Azolla, are used as biofertilizers, which help in nitrogen fixation by converting atmospheric nitrogen to plant useable form. Legume plants have root nodules inhabiting bacteria belonging to the genera Sinorhizobium, Azorhizobium, Rhizobium, Bradyrhizobium, and Mesorhizobium, collectively called rhizobia [Nitrogen fixation is a dynamic and high-energy demanding process . Elementbacteria . In biofrhizobia . When rhrhizobia .Azotobacter chroococcum. Therefore changing over of ammonium ions improves plant development by root architecture advancing and seed germination enhancement [A. irakense, A. lipoferum, A. halopraeferens, A. amazonense, and A. brasilense, shows improved crop yield and plant growth [Azospirillum brasilense is competent enough to promote the growth of plants by fixation of nitrogen, which helps to save money.By nature, Azotobacter has a major role in the nitrogen cycle as it has a range of metabolic capabilities . Along wancement . Azotobaancement . Azospirancement , supportancement . Infieldt growth   extracellular enzyme release; and (iii) substrate degradation and P release, the soil microorganism employs P-solubilization mechanisms [The most popular inoculants for phosphorus solubilizing bacteria (PSB) belong to the genera Bacillus ,58. Otheordonia, , Xanthomthomonas , Azotobatobacter , Enterobebsiella ,41, Vibrolyticus , Beijerihizobium , Xanthobr agilis . By relechanisms . Organicchanisms . The phochanisms . Heavy mchanisms ,63.Burkholderia vietnamiensis produces gluconic acids, and 2-ketogluconic, which is involved in solubilizing phosphate [Vigna mungo) and lentil (Lens esculentus) inoculated with B. firmus, a phosphate solubilizing bacteria showed significant results in the increase of seed yield. Chabot et al. [Rhizobium leguminosarum leads to the growth of maize and lettuce. Some fungi, such as Penicillium and Aspergillus, act as phosphorus solubilizers [Penicillium citrinum, and two strains of A. awamori, from the rhizosphere of various crops. A. awamori showed shoot height increase of 7\u201312%, seed number increase to three-fold, and increase in seed weight to two-fold, in comparison to uninoculated plants. Hajra et al. [Phosphate solubilizing and stress-tolerant bacteria hosphate . Tomar ehosphate  reportedt et al.  describebilizers . Mittal bilizers  isolateda et al.  reportedAspergillus, Bacillus sp., Clostridium, Burkholderia, Acidothiobacillus ferrooxidans, Pseudomonas, Paenibacillus sp., Bacillus mucilaginosus, B. circulans, and B. edaphicus has been reported to be released from potassium-bearing minerals in soils in an accessible form [Potassium is the third important plant growth nutrient that plays a vital role in plant metabolism, growth, and development. The plants would have poorly formed roots, grow slowly, produce small seeds and have lower yields without a sufficient supply of potassium  and incrble form .Bacillus mucilagenosus and Bacillus edaphicus, in the solubilization of rock potassium [Bacillus mucilaginosus, Azotobacter chroococcum, and Rhizobium [Organic acids are produced and secreted by microbial inoculants, such as otassium . Potassiotassium , sorghumotassium , wheat [otassium , sudangrotassium , cucumbeotassium . The sighizobium .Thiobacillus), seeds of high S-demanding crops have proved to be very effective, making sulfur more accessible to the plants. Some autotrophic species also exhibit chemolithotrophic growth on inorganic sulfur compounds, such as Acidothiobacillus, Thiosphaera, and Thiomicrospira, but some heterotrophs, such as Xanthobacter, Paracoccus, Pseudomonas, and Alcaligens [Thiobacillus novellus is considered an optional chemoautotroph, while chemoautotrophs are obligatory for Thiobacillus ferrooxidans, T. thiooxidans, T. denitrificans and T. thioparus. Inorganic sulfur compounds are reduced or partially oxidized by a heterogeneous group of sulfur bacteria. Thiobacilli plays a significant function in the sulfur oxidation and oxidation process, producing acidity, which aids to solubilize plant nutrients and enhances soil fertility [T. ferrooxidans and T. thioxidans inoculation increased sulfur oxidation to pyrite and subsequently, rock phosphate solubilization [Penicillium species, Epicoccum nigrum, Alternaria tenius, Scolecobasidium constrictum, Aspergillus, Aureobasidium pullulans, and Myrothecium cinctum [For the growth and development of plants, sulfur is one of the sixteen elements and the fourth main nutrient in crop production, after N, P, and K. As a result of microbial activity, which includes mineralization, immobilization, oxidation, and reduction processes, sulfur transformations in the soil. Sulfur oxidizing bacteria synthesis of organic compounds from carbon dioxide by sulfur oxidation process and produce sulfuric acids. Enzyme sulfatase was used in the catalyzation of sulfur compound mineralization and transformation into forms accessible to plants . After tcaligens . Thiobacertility . T. ferrlization . Element cinctum  , zinc oxide (ZnO), zinc carbonate (ZnCO3), and with cheap zinc compounds. Zinc, an important micronutrient for growth and metabolism, is needed by plants and microorganisms. Zinc is the main compound in an enzyme system, acting as a metal activator and co-factor for many enzymes [Gluconacetobacter diazotrophicus, Pseudomonas, Aspergillus niger, and Penicillium luteum producing organic acid, such as gluconic acids; it derivatives as 2- and 2,5-keto-derivatives are Zn compound solubilizers [Thiobacillus ferroxidans, T. thioxidans, and facultative oxidizers of thermophilic iron have enormous ability to solubilize sulfide ore zinc [Aspergillus niger has been found to withstand a high level of zinc capable of growing below 1000 mg Zn and is used for zinc quantification in soils containing low zinc , and cytokinins, play a key role . Gutierrytokinin ,101. Tisytokinin . Auxin iytokinin . Indole-ytokinin . IAA proytokinin . Azospirynthesis . Lateralynthesis . For theopedicae . Gutierropedicae  document pumilus .Siderophore is an essential element for various biological processes in all organisms in the biosphere. Bacteria, fungi, actinomycetes, and certain algae developing under low iron stress synthesize siderophores. It is an iron-binding protein that has a molecular weight range of 400\u20131500 Da . AccordiEscherichia coli, Salmonella, Klebsiella pneumonia, Aerobacter aerogens, Mycobacterium sp., Yersinia, Enterobacter, Vibrio cholera, Aeromonas and Vibrio anguillarum); Fungi include  [Nocardia asteroids, Streptomyces griseus, and Actinomadura madurae), and Algae (Anabaena cylindrica and Anabaena flosaquae) [Organisms producing siderophore includes bacteria (evisiae) , Actinomosaquae)  (Table 2osaquae) ,112.Azospirillum brasilense [Pseudomonas putida, and P. fluorescens PGPR have been successfully assessed under states of contaminated soils and hyperosmolarity [Streptomyces acidiscabies E13 strain applies positive growth developing effects in nickel contaminated soil of cowpea most likely by producing hydroxamate siderophores and binding of iron and nickel [Phytoremediation is an energy proficient and cheap method of detoxification. Plant metabolism is influenced by reducing the metal bioavailability by absorbing them in the biomass of shoot . Heavy masilense . Intensemolarity . In addimolarity . Streptod nickel .Several bacterial antibiotics were used, such as aldehydes, hydrogen cyanide, alcohols, sulfides and ketones, diacetyl phloroglucinol, xanthobaccin, 2,4-diacetylphloroglucinol (DAPG), viscosinamide, mupirocin, pyocyanin, phenazine-1-carboxylic acid, phenazine-1-carboxamide (PCN), phenazine-1-carboxylic acid (PCA), hydroxy phenazines, zwittermicin A, butyrolactones, pyrrolnitrin, pyoluteorin, phenazine-1-carboxylic acid, kanosamine, oligomycin A, 2,4-diacetyl phloroglucinol, oomycin A, pyrrolnitrin ,118, AgrBacillus sp. produces by circulin, polymyxin, and colistin, the majority of active compounds gram-negative and gram-positive bacteria along with many fungi [Pseudomonas sp., producing HCN and DAPG, are contributing to the biological control of tomato canker bacteria [Pseudomonas was reported; phenazine, pyoluteorin [Arabidopsis thaliana infected with Pseudomonas syringae gets protection against surfactin, which is produced by Bacillus subtilis. In addition, it protected the pathogen and also necessary for root colonization [ny fungi . Siddiquny fungi  reportedbacteria . Expressluteorin , lipopepluteorin  2, 4-dialuteorin  and bactnization .The carrier is the significant group of inoculants, which help deliver the appropriate volume of PGPM in superior physiological state. Assorted materials are used as inoculants carriers for having improved biological effectiveness, endurance, and shielding bacteria from abiotic and biotic stresses. The comprising elements of the carrier materials can be organic, inorganic, or synthetic. An appropriate carrier is chosen, depending on properties such as availability, low cost, easy use, packageability, and mixability. Additionally, the gas exchange must be allowed by the carrier, especially oxygen, which must have a high water-holding capacity and increased content of organic matter . The phyAzospirillum and survival up to 31 weeks. For the production of inoculants, carriers such as vermiculite clay, farmyard manure, coconut shell powder, teak leaf powder, and compost were used [Tilak  wrote abere used . Locallyere used . Singaraere used  reportedNucleopolyhedrosis virus and Bacillus thuringiensis, Trichoderma), plants (Azadirachta and Chrysanthemum), and animals (nematodes) contain their products  or by-products  and live species  [Compared to conventional pesticides, biopesticides pose less risk to humans and the environment, gaining global attention as a new instrument for destroying or controlling pest species such as weeds, plant diseases, and insects ,135. Mosenemies) . Biopestenemies) . Biopestenemies)  , which targets larvae. Bacillus thuringiensis (Berliner), the entomopathogenic bacterium, commonly recognized as a microbial biopesticide, which, during bacterial sporulation, generates crystal protein (d-endotoxin) when ingested by the susceptible insects triggers lysis of gut cells [Pseudomonas aeroginosa, Serratia marcesens, Bacillus thuringiensis, and Bacillus popilliae, are used commercially for their efficacy and safety [P. fluorescence, P. syringae, and P. aeruginosa, are used to develop biopesticides. Some strains of Pseudomonas aureofaciens control plant pathogens, causing soft rots and damping-off [Helicoverpa armigera and Spodoptera litura is by Pseudomonas sp., Bacillus subtilis, B. megaterium, and B. amyloliquefaciens [B. subtilis, B. pumilus, B. licheniformis, and B. amyloliquefaciens are marketed as biopesticides [Bacillus sphaericus has been reported to have a dual role in larvicidal toxicity to Culex pipien, the blood-feeding mosquito, and the ability to excrete extracellular alkaline protease (AP) in the medium used for growth [Streptomyces griseoviridis is the first biofungicides available to combat root infecting fungi in greenhouse crops. Despite such products\u2019 long-term accomplishments, the global demand for new biopesticides remains [Bacillus thuringiensis is sporulated, and it contains the proteins Cyt and Cry. Commercialized insecticides are products made up of 2% Bt, a combination of spores and protein crystals [Bacillus thuringiensis can be more effective on Aedes aegypti, while the strain of B. sphaericus may be more effective on various mosquitoes, such as Culex quinquefasciatus [Bacillus thuringiensis (Bt) to manage insects, such as the velvet bean caterpillar, cabbage looper diamondback moth, and armyworm [B. thuringiensis are moderately active against Metarhizium anisopliae, while newer pesticides, such as spinosad and indoxacarb, were highly effective in controlling Maruca vitrata. Schunemann et al. [B. thuringiensis to control insect pests of agriculture, including mosquito species. Most formulations of spore-crystal toxins are obtained from a variety of strains, such as B. thuringiensis var. kurstaki, B. thuringiensis var. tenebrionis, B. thuringiensis var. israelensis, B. thuringiensis var. aizawai, and B. thuringiensis var. San Diego [Bacterial biopesticides are used to monitor weeds, plant diseases, nematodes, and insects. Pest is controlled in various manners: delivering toxins, outcompeting and harming pathogens, promoting shoot and root growth, and producing anti-fungal compounds. Examples of bacterial biopesticides are ut cells . Spore fd safety . Pseudomping-off . Over haefaciens . Microbesticides . Bacillur growth . Strepto remains ,154. Baccrystals . Bacilluasciatus . In vegearmyworm . Sunithaarmyworm  found thn et al.  recommenan Diego .Trichoderma harzianum, targeting Pythium, Rhizoctonia, and Fusarium, is also a fungicide [Paecilomyces fumosoroseus, Beauveria bassiana, Verticillium lecani, Nomuraea rileyi, and Metarhizium anisopliae are used in insect control [Beauveria bassiana is active against larvae of mosquito [Metarhizium anisopliae and Beauveria bassiana have a lengthy- history in the perspective of agricultural pests. Current molecular techniques allow for the characterization and monitoring isolates of fungi, as well as for recognizing fungal isolates in the environment [Beauveria bassiana [M. anisopliae are commercially available, which controls several insect species [M. anisopliae, which has two separate virulence mechanisms, includes invading and destroying the insects, and third mechanisms by invading the ticks by a strategy of integument breakdown [In killing mites, weeds, nematodes, insects, or other fungi, new fungal biopesticides are used. Like bacteria, they produce toxins, such as bacteria, that outcompete targeted pathogens. These can also paralyze plant pathogens or insects by attacking them. ungicide . Fungal  control . Beauvermosquito . Fungal ironment ,161. Thebassiana . Biopest species . Destruxreakdown .Steinernema sp. and Heterorhabditis sp., that attack the hosts as contagious juveniles (IJs) are widely used [Heterorhabditis megidis, H. bacteriophora, Steinernema scapterisci, S. carpocapsae, S. riobrave, S. glaseri, and S. feltiae are common entomogenous nematodes used as insecticides [Several round colorless parasites, nematodes, and microscopic worms of the plant cause severe crop damage. Though targeting plants, some are essentially advantageous in attacking soil-dwelling insect pests, such as root weevils and cutworms . Nematodely used . Heterorcticides .Protozoans are single-celled organisms surviving both in soil and water. Most species are parasites of insects, typically feeding on bacteria, while others feed on organic decay. More than any other insects, lepidopteran and orthopteran, hoppers especially are killed by Vairimorpha and Nosema comparing to other insects . Nosema Heliothis/Helicoverpa sp. by nuclear polyhedrosis virus and the codling moth of Cydia pomonella by granulosis virus are some examples. In contrast with traditional synthetic insecticides, Baculoviruses can control lepidopteran pests causing slight or no damage to the targeted species. The first viral biopesticide detected is the Heliothis nuclear polyhedrosis virus (NPV) [Autographa californica nucleopolyhedro virus (AcMNPV). Autographa gemmatalis control the soybean velvet bean caterpillar [Baculoviruses are a family of viral biopesticides believed to infect insects and arthropods related to them. Potential pesticides are the family Baculoviridae. This biopesticide is used in many parts of the world for the prevention of destructive caterpillar pests . Nucleopus (NPV) . Expresserpillar .Biochemical pesticides are equivalent to the naturally occurring or compounds, derived synthetically, that are used in pest control. The influence of growth and develop-ment of insect pests is achieved by the biochemical pesticides which are nontoxic in action destroying or attacking pest. Pheromones are substances that attract or repel pest or growth regulators of plant growth produced by biochemical pesticides that interfere in mating and growth of pests, including elements, such as insect sex pheromones interfering in mating, as well as attracting insect pests to traps using extracts of the scented plant. Chemical substances, such as pheromones, are emitted by living organisms that are used in sending messages to the same species individuals of mostly opposite sex . MinimalBacillus thuringiensis insecticidal protein into the plant\u2019s genetic material thereby allow the plants to kill the pest. Environmental Protection Agency controls the protein, genetic material, and not the plant itself [Substances producing pesticides (PIPs) are introduced into the target crop plant ge-nome, thereby providing the plant with capability of killing the pest. Scientists insert a insecticidal protein gene of t itself .Biofertilizers based on microbial inoculants are attractive because they act in fixing nitrogen, phosphate, sulfate, potassium, zinc, and solubilize nutrients and enhance plant growth by hormonal action or antibiosis and decomposing organic residues. Plant reinforcers and phytostimulators can be used by plants to improve their growth when insufficient quantities of nitrogens are present. Moreover, they emerged from the soil and appeared to be competent in the rhizosphere. Plant growth-promoting rhizobacteria with numerous activities, such as nitrogen fixation, phytohormone production, micro- and macro-mineral solubilization, enzymes production, or fungicidal compounds of antibiotics synthesis. Siderophores, a competition with detrimental microorganisms, have bioremediation potentials by detoxifying contaminants, such as pesticides, heavy metals, and regulate phytopathogens, as biopesticides. They also improve and maintain the soil rhizosphere biologically by microbes, such as bacteria, fungi, algae, and actinomycetes. This review discusses the multiple activities of single organisms or consortia, such as nitrogen-fixing, phosphate, sulfate, and zinc solubilization, through enzyme and acid production. The effect of microorganisms as biofertilizers and the role of biopesticides enhance plant growth by rendering them as tolerant to pests and to improve the crop health and food safety."}
+{"text": "Following publication of the original article [1], the authors identified that the given name and family name were erroneously transposed.The incorrect authors name is:Zachariou Athanasios, Paschopoulos Minas, Kaltsas Aris, Dimitriadis Fotios, Zikopoulos Athanasios, Mamoulakis Charalampos, Takenaka Atsushi and Sofkitis NikolaosThe correct authors name is:Athanasios Zachariou, Minas Paschopoulos, Aris Kaltsas, Fotios Dimitriadis, Athanasios Zikopoulos, Charalampos Mamoulakis, Atsushi Takenaka and Nikolaos SofkitisThe author group has been updated above and the original article [1] has been corrected."}
+{"text": "Human performance optimization of tactical personnel requires accurate, meticulous, and effective monitoring of biological adaptations and systemic recovery. Due to an increased understanding of its importance and the commercial availability of assessment tools, the use of heart rate variability (HRV) to address this need is becoming more common in the tactical community. Measuring HRV is a non-invasive, practical method for objectively assessing a performer\u2019s readiness, workload, and recovery status; when combined with additional data sources and practitioner input, it provides an affordable and scalable solution for gaining actionable information to support the facilitation and maintenance of operational performance. This narrative review discusses the non-clinical use of HRV for assessing, monitoring, and interpreting autonomic nervous system resource availability, modulation, effectiveness, and efficiency in tactical populations. Broadly, HRV metrics represent a complex series of interactions resulting from internal and external stimuli; therefore, a general overview of HRV applications in tactical personnel is discussed, including the influence of occupational specific demands, interactions between cognitive and physical domains, and recommendations on implementing HRV for training and recovery insights into critical health and performance outcomes. The health, well-being, and preparedness of tactical personnel are crucial to mission success . In tactThe need for accurate, meticulous, and effective monitoring of biological adaptations and systemic recovery is certainly critical for all domains under HPO . In addiIn HPO programs, the utilization of heart rate variability (HRV) provides a non-invasive, practical method for assessing an individual\u2019s response to internal load ,18. The The ANS influences body functions by regulating systemic resource allocation to maintain homeostasis and accomplish goal specific actions in the face of fluctuating internal and external environmental stimuli ,31. PracThe primary ANS (excluding enteric) is comprised of the sympathetic nervous system (SNS) and parasympathetic nervous system (PNS), which are associated with arousal (often perceived as stress) or relaxation, respectively ,37,38. VSince the ANS is intimately connected with other psychological and physiological systems throughout the body, quantifying responsiveness can provide vital information regarding functional occupational performance capacity or adaptions during/after exercise and training iterations . This isThe term HRV describes a series of mathematical calculations for modeling psychophysiological responses based on the time between consecutive heart beats, also known as beat-to-beat or inter-beat-intervals (IBI) ,47,48,49With respect to training loads and recovery, the most frequently implemented and practically useful HRV parameters are analyzed using time- and frequency-domain methods ,20,26. TFrequency domain metrics use mathematical transformations of R-R data to quantify the modulation of a given signal at specific frequency ranges : ultra-low frequency (ULF), very low frequency (VLF), low frequency (LF), and high frequency (HF) . CompareThe ratio of LF to HF is often used to represent sympathetic-parasympathetic balance ,63,64. TConsequently, in a resting state, increases in HF and TP can indicate desired training adaptations and complete systemic recovery, whereas a decrease in HF and TP typically indicates unwanted training effects, maladaptation, and incomplete recovery ,34,35. MField based HRV monitoring is considered user friendly, objective, and a particularly reliable tool, which can be easily used to manage training loads and facilitate proper recovery ,53. AddiPractical devices, such as chest straps, clothing garments, and wrist or finger worn photoplethysmography (PPG), are unobtrusive, but their validity and reliability can be significantly impacted by the fit of the device, which should be \u201csnug\u201d to avoid missing data from disconnections . The accA measurement\u2019s purpose dictates the appropriate schedule of data collection timepoints  . MonitorEstablishing a resting state, baseline, HRV is important for assessing overall ANS modulation and cardiac vagal tone. Following the principles of resource theory, baseline HRV identifies the pool of available ANS resources affecting the cardiac cycle . The volTo establish an individual baseline for consistent daily and actionable assessments, HRV measurements should be recorded over a minimum 1\u20132 week period , before Nocturnal and morning HRV indicate different psychophysiological processes; however, both inform recovery and readiness status. In long-term monitoring, HRV quantification represents the amount of recovery in relation to average baseline HRV pre-awakening  . NocturnMeasuring HRV pre-, intra-, and post-task  may indicate autonomic resources roused in the anticipation of completing a task, the resources required to execute said task, and the rate of resource recovery following completion . HRV resThe modulation of HRV measures can be used to assess various tasks, such as the observe-orient-decide-act cycle of an advanced marksmanship/close quarter battle (CQB) assessment or intense training session, but require more precise time stamping and data parsing compared to pre- and post-task measures . FurtherContinuous measurements over a 24 h period may represent HRV responses to all the various stimuli encountered during typical, daily occupational endeavors. In daily HRV, values below an individual\u2019s normative rolling baseline could indicate incomplete recovery from high training volume, high training intensity, onset of illness, chronic stress, or poor sleep . HoweverStressors experienced by tactical personnel occur in many forms, such as; physical training, deployments, vigilance, emotions, cognitive strain, environmental conditions, lives at stake, low margins for error, and illness . The higStudies investigating the effects of physical activity on HRV have exponentially increased in recent years ,38,39,94Conventionally, HRV is mainly directed at capturing internal cardiovascular strain resulting from (or required to accomplish) a given external training load. However, for the tactical athlete, quantifying responses to external workloads and cardiovascular homeostatic balance is only one of many actionable insights HRV can afford. Theoretically, running faster and lifting heavier require more resources through PNS withdrawal and SNS stimulation, which influences cardiac output to become more forceful, rapid, and less variable. The scientific literature supports the link between HRV metrics, aerobic adaptations, and general fitness levels ,96,97, aMechanistic underpinnings ,103,104 When presented with a specific task/stimulus, an individual\u2019s HRV response can be altered or vary depending on their knowledge set, skill level, and performance abilities. For the tactical athlete, maintaining emotional  control in the face of extreme pressure or danger is vital and influences the entire cognitive performance cascade ,78. The HRV analysis, specifically the fluctuation in HF resource availability and utilization rate/volume, can provide a direct quantification of autonomic efficiency, enabling the measurement of cognitive/motor workload, determination of skill proficiency development across time, and identification of resiliency in the face of other resource demands ,35,59. PSimilar to general resource theory, conservation of autonomic tone  tends to associate with superior performance across numerous facets of perception , cognition , and action (motor control under duress) ,104,111.Much like training load, recovery loads influence HRV responses and may be used to maintain workload capacities over time ,121. ProPost-exercise recovery has gained a great deal of attention in the past decade, leading to a rise in scientific understanding of accelerated recovery techniques to elicit restored autonomic and cardiovascular homeostasis ,125. FloPhotobiomodulation (PBM), formerly known as Low-Level Laser Therapy (LLLT) , uses reCold Water Immersion consists of 6\u201320 min immersions in water temperatures below 15 \u00b0C (59 \u00b0F) ,125. TheMany of the aforementioned methods show promise for improving sleep, HRV, and recovery, but require further investigation as to their true efficacy and practicality. However, through the use of a holistic physiological monitoring program, including consistent HRV assessments, it is likely that individual prescription of recovery can be established for the tactical athlete.The key parameters of HRV to be concerned with are rMSSD, HF, and TP. Each provides essential information regarding ANS regulation, making HRV a valuable tool to assess the overall health, wellness, and fitness of tactical personnel ,27. TraiWithin high performing populations, HRV assessment and monitoring has recently risen in popularity as one method to foster awareness and avoid overtraining or non-functional overreaching ,53. The"}
+{"text": "Cancer continues to represent a global health concern, imposing an ongoing need to research for better treatment alternatives. In this context, nanomedicine seems to be the solution to existing problems, bringing unprecedented results in various biomedical applications, including cancer therapy, diagnosing, and imaging. As numerous studies have uncovered the advantageous properties of various nanoscale metals, this review aims to present metal-based nanoparticles that are most frequently employed for cancer applications. This paper follows the description of relevant nanoparticles made of metals, metal derivatives, hybrids, and alloys, further discussing in more detail their potential applications in cancer management, ranging from the delivery of chemotherapeutics, vaccines, and genes to ablative hyperthermia therapies and theranostic platforms. Cancer comprises a complex array of diseases that represent one-third of the leading causes of morbidity and mortality worldwide. As traditional therapeutic approaches  may result in severe adverse effects or/and unsatisfactory treatment outcomes, intense research has been shifted to integrating nanotechnology in cancer management ,2,3,4.Nanomedicine, the overlapping field of nanotechnology and medicine, brings a series of advantages over conventional cancer therapeutics, including multifunctionality, efficient drug delivery, and controlled release of chemotherapeutic agents. These benefits are possible due to the unique physical and chemical properties of nanoparticles (NPs), such as small size, chemical composition, large surface area, tailored shape, and morphology ,6,7,8,9.Whether based on polymeric, liposomal, or metallic formulations, NPs naturally traffic to the spleen and lymph organs, being good candidates for delivering immunotherapeutic agents . MoreoveMetal-based NPs are particularly appealing in nanomedicine due to their relatively narrow size and shape distribution, long activity period, dense surface functionalization, and capability for optical or heat-based therapeutic strategies. Compared to nonmetallic NPs of similar sizes, the higher density of metallic NPs allows them to be more readily taken up by cells, thus proving advantageous for cancer management strategies ,11. In aMetallic nanoconstructs can remodel the tumor microenvironment (TME) by turning unfavorable conditions into therapeutically accessible ones. For instance, external stimuli  can enhance the targeting ability of metallic NPs towards altering the redox potential of biological systems and generating reactive oxygen species (ROS) that further sensitize target tissues . FurtherGiven these advantageous properties, numerous studies have investigated various metal-based nanoparticles as an innovative technology for fighting cancer. NPs made of metals , metal derivatives, metal alloys, metal hybrids, and combinations of metals with other nanomaterials have been increasingly reported in the specialty literature.In this respect, the present paper aims to thoroughly review metallic nanomaterials that present attractive features for treating malignant diseases and present the possible applications of metal-based NPs in various therapeutic, diagnosis, and imaging approaches, focusing on the newest developments in the field.Gold nanoparticles (Au NPs) represent one of the most investigated metal-based NPs in medicine . The appAu NPs have also been reported to have tunable optical properties, surface plasmon resonance (SPR), photothermal properties, and surface-enhanced Raman scattering (SERS), being useful tools in phototherapy and photoimaging . SPR is Additionally, green-synthesized Au NPs were demonstrated to have intrinsic antitumor properties , showingSilver nanoparticles (Ag NPs) are another highly investigated material in nanomedicine. Ag NPs have been extensively explored due to their physicochemical and biological properties, including biocompatibility, large surface-to-volume ratio, potent antimicrobial activity, excellent SPR, ease of functionalization, and cytotoxicity against cancer cells ,40.Ag NPs have attracted increasing interest in the oncological domain, possessing intrinsic anticancer activity and being demonstrated as effective antitumor drug delivery systems ,42. Rese+ cations that capture electrons, increase intracellular oxidative stress, increase ROS production, reduce ATP levels of cancer cells, and decrease cell proliferation rates [+ ions are reportedly released mainly in mitochondria and secondarily in the nuclei; there, they interact with DNA, resulting in its fragmentation and resulting in cell death [Concerning the mechanisms of anticancer action, Ag NPs were noted to affect membrane fluidity, resulting in facile entry and accumulation in cancer cells, thus causing cancer cells death or hindering their uncontrolled proliferation. Ag NPs can also act by regulating signaling pathways, inducing early apoptosis in the absence of the p53 tumor suppressor ,40,43. Mon rates ,44. Ag+ ll death . The desll death ,46, platll death , and palll death .Significant results concerning Ag NPs antitumor activity were reported against several human cancer cell lines  Table 1Table 1, 3O4), hematite (\u03b1-Fe2O3), and maghemite (\u03b3-Fe2O3 and \u03b2-Fe2O3) [Different types of iron oxides found in nature have started to be explored for synthesizing magnetic NPs, such as magnetite FeO4, hemat\u03b2-Fe2O3) ,72. Iron\u03b2-Fe2O3) ,73,74.Regarding cancer care, IONPs have been FDA-approved for clinical testing in cancer diagnosis, imaging, and magnetic hyperthermia therapy, also demonstrating potential in preclinical settings for photothermal and photodynamic therapies ,76. One Moreover, IONPs have attracted particular interest in developing magnetic nanoparticle-based drug delivery systems. This is particularly because drug-loaded IONPs have strong targeting ability under external magnetic guidance . SpecifiVarious such IONPs-based nanosystems have been tested in vitro and in vivo, being reported effective against several types of cancer, including breast cancer ,85, lungIn addition to the above-discussed NPs, several other metals and metal derivatives started to be investigated in their nanoform as potential candidates for applications in cancer management. For instance, zinc oxide nanoparticles (ZnO NPs) have recently become used in biomedical and cancer applications due to their favorable chemical properties . ZnO NPsCuprous and copper oxide NPs are other nanomaterials with potential applications in the biomedical field . In part2 NPs) represent a useful material for photodynamic therapy. Its mechanism of action is based on the excitation of hydrophobic molecules with electromagnetic radiation in the range of visible or UV light towards ROS generation and further induction of apoptosis [2 NPs were reported cytotoxic in several human cancer cell lines, such as colon cancer [Titanium dioxide NPs  present antioxidant, anticancer, antimicrobial, antiproliferative, and photothermal activities while being biocompatible and less toxic than their chemically-synthesized counterparts . Thus, tAdvantageous properties have also been reported for platinum nanoparticles (Pt NPs), resulting in increasing interest for applications in biotechnology, nanomedicine, and pharmacology fields. Specifically, Pt NPs exhibit potent antimicrobial, antioxidant, and anticancer activities; SPR; and photothermal properties, which are all highly valuable characteristics for designing performant nanotherapeutics, drug-delivery systems, and bioimaging agents ,123,124.In addition to their remarkable individual potential, metals can also be manufactured into hybrid metal NPs towards creating synergistic effects. For instance, bifunctional iron-gold NPs of different shapes, sizes, and structures  are bein2Se3 core-shell nanostructures, FeSe2/Bi2Se3 nanoparticles, Pt@Fe2O3 nanorods, Au@FeS nanoparticles, Au@Pt nanodendrites, Au@MnO2 nanoparticles, and Au@Se nanoparticles [Other hybrid metal-based NPs that are relevant for cancer management include, but are not limited to, MnSe@Biarticles .Synergistic effects were also reported when using bimetallic  and trimEither alone, as alloys, in various metallic combinations or in association with other nanomaterials, metal-based nanoparticles can be employed in a plethora of applications for better cancer management . In thisMetal-based NPs can circumvent the limitations of conventional chemotherapy by providing targeted and controlled release of carried anticancer agents. Thus, carrying drugs via nanoplatforms made of gold, silver, or metal derivatives has become an intense research topic. Studies have reported promising results for a variety of metal-based nanocarriers, either in pristine form, functionalized with targeting moieties or coated with biocompatible layers. Such nanosystems have been proven to enhance in vivo stability, increase drug accumulation in the tumor site, improve the therapeutic effectiveness of carried drugs, and reduce systemic toxicity. Moreover, they can ensure sustained/programmable or on-demand drug release by responding to internal or external stimuli, respectively ,129,130.In order to emphasize the versatility of metal-based NPs for drug delivery, As it can be observed from Another interesting novel approach is the use of supramolecular drug self-delivery systems (SDSDSs), which comprise active drug-building blocks linked through supramolecular interactions. One metal-based SDSDS is proposed by Liu et al. , who havw/w magnetic beads). The designed scaffold is biocompatible, durable, and effectively attracts nanodrugs to its surface, achieving targeted delivery without the application of an external magnetic field. Thus, it aids in the accumulation of drugs to tumor cells, improving therapeutic outcomes. This approach holds great promise for developing more precise medical treatments in the future.One more drug delivery strategy gaining interest in recent years is the use of implantable systems for targeted delivery without involving an external magnet. Specifically, implants can be employed as delivery vehicles of drugs, antimicrobial, anti-inflammatory, and immunomodulatory agents to desired sites, including surgery cavities to prevent potential cancer recurrence. Nonetheless, specific requirements must be fulfilled by these implants, counting drug release at a proper concentration and distance from the tumor, biocompatibility, antibacterial activity, and ability to surpass immune system recognition . In thisIn addition to the use of chemotherapeutic agents, cancer vaccination represents another effective method for preventing or curing cancers. Cancer vaccines are based on tumor antigens administered as nucleic acids, tumor lysates, full proteins, or short peptides that can induce strong cellular and humoral immunity. Nonetheless, vaccines necessitate adjuvants to reach their maximum efficacy potential, improve the strength and longevity of immune responses, and reduce doses and side effects ,146,147.2+, K+, Fe2+/3+, Zn2+, and Mn2+) play important roles in many biological activities, including key immune processes. Thus, a wide variety of metals can be considered good adjuvants for nanovaccines, enhancing the generated immune responses through transcellular or intracellular signaling cascades against neoplastic transformation. More specifically, metal ions are suitable candidates for ensuring abrupt and timely immune responses, achieving effective immune regulation, and producing fewer toxicity concerns than conventional therapies [In this respect, metalloimmunology has the potential to revitalize cancer vaccines, as nutritional metal ions , particularly due to their high positive surface charge. One specific phenomenon for which metal-based NPs hold great promise is gene silencing. They can carry antisense nucleotides that downregulate specific gene expression in tumor cells. As the strength and duration of the silencing response depends on the amount of siRNA delivered to the target site, metal NPs protective capacity can be enhanced by lipid or polymer coatings. Consequently, the load is not affected by RNase, increasing the half-life of siRNA and decreasing the required dose .A valuable tool in cancer management that uses the unique properties of metallic NPs is ablative hyperthermia . This geMagnetic hyperthermia is the noninvasive technique in which an alternate magnetic field (AMF) remotely induces local heating through magnetic energy losses of magnetic nanoparticles. By ensuring precise uptake of magnetic NPs by tumor cells, the adverse effects in surrounding normal tissues can be significantly reduced. Generally, iron oxide NPs can be delivered intratumorally and heated at 41\u201350 \u00b0C under an AMF . NonetheThe inherent optical, electrical, and conductive properties of metal-based nanoparticles have rendered them appealing for use in radiotherapy. Metal NPs can increase the specificity of radiations to the desired site in such a manner that the maximum dose is delivered to the tumor tissue, while toxicity and damage are avoided in healthy tissues. Metal-based NPs were reported to increase intracellular ROS production from the ionizing radiations, increase oxidative stress levels in tumor cells, increase apoptosis rates, and reduce clonogenic survival ,6.A variety of metals and metal derivatives can be used in radiotherapy, including gold, silver, platinum, titanium oxide, zinc oxide, and more. Metallic materials with atomic number between 22 and 83 have been researched in radiation therapy for a broad range of purposes, such as radiation dose enhancement, hyperthermia induction, controlled drug delivery, and theranostic applications . In partDespite the physical concepts, the role of biological mechanisms has also started being investigated in recent years for radiosensitization purposes. Specifically, gold nanoparticles have been investigated whether they could influence cell response to radiation by five \u201cR\u201d factors  . For ins2 and H2O into ROS, while the MnTCPP ligand was included owing to its enzyme-like ability to decompose endogenous H2O2 into O2 for enhancing radiotherapy in hypoxic conditions. The as-designed MOF NPs were reported to effectively inhibit melanoma growth and prevent recurrence with only one X-ray irradiation after intravenous injection. Therefore, the nanosystem has great potential for overcoming the radioresistance challenge of hypoxic tumors.Tumor tissues generally lack a proper amount of oxygen; thus, special strategies  must be Light has been long used for its healing potential in the treatment of various diseases. In the context of cancer treatment, two major therapeutic alternatives exploit light, namely photothermal therapy (PTT) and photodynamic therapy (PDT) . These pPTT can be considered a form of ablative hyperthermia in which photothermal agents (PTAs) are used for the conversion of light into heat, resulting in the selective death of cancer cells under laser application . More sp2O2 into ROS. Moreover, NPs were further optimized by modification with polyethylene glycol, resulting in improved biocompatibility, efficient tumor homing after intravenous injection, and effective NIR-triggered photothermal-chemodynamic synergistic outcomes in a mouse tumor model.Nonetheless, recent studies also directed their investigations towards designing and evaluating PTAs made of other less-explored metal-based nanomaterials. For instance, Sharker and colleagues  reportedPDT is another promising cancer treatment that can benefit from advancements in the field of metal-based NPs. PDT requires the use of light with specific wavelengths for the activation of photosensitive chemicals (known as photosensitizers PS) towards generation of ROS and further destruction of cancer cells. However, conventional PS may face a poor specific uptake in tumor cells, posing a threat on healthy neighboring tissues. Thus, involving nanotechnology in this type of therapy became fundamental for obtaining maximum results while avoiding side effects ,16,178.2 in situ by reacting with H2O2 from TME, while also consuming glutathione. Thus, it represents an interesting delivery vehicle for PSs, especially in hypoxic tumors [In order to improve PS accumulation in the target tissue, these substances can be carried and delivered to the site by metal-based NPs. Compared to bare PS, such nanoplatforms exhibit long cycle time, slow degradation, and targeted and controlled release, benefiting also form enhanced permeability and retention effect . Au NPs c tumors ,181,182.Early detection and thorough monitoring of cancer evolution are essential processes in controlling and preventing the disease . Thus, dAs there is only a low content of cancer biomarkers in the early phase of cancer, ultrasensitive and selective tools are mandatory for their detection. In this context, metal NPs have emerged as convenient solutions due to their unique optoelectronic properties and ease of functionalization. Materials such as gold, silver, and copper represent appealing candidates for developing analytical scaffolds, especially because their SPR bands are in the visible region. However, copper use is limited by its ease of oxidation, most of the studies involving Au and Ag-based nanoconstructs .\u03c3), demonstrating potential applications in clinical diagnosis.One innovative example of ultrasensitive surface-enhanced Raman scattering (SERS) immunoassay was recently developed by Yang et al. . The sci64Cu. The as-designed metal-based nanoplatform displayed favorable diagnostic properties concerning detection, biodistribution, and clearance, recommending these constructs for future therapeutic concepts.Interesting possibilities also arise from the use of Au NPs in the dual detection of prostate cancer via optical imaging (OI) and positron emission tomography (PET). In this respect, Pretze et al.  developeSuperparamagnetic iron oxide nanoparticles (SPIONs) represent another extensively researched metal derivative extensively studied for imaging applications. More specifically, SPIONs are investigated as contrast agents for visualizing tumors and metastatic cancer in different tissues, including the liver, spleen, and lymph nodes. SPIONs are attractive for such applications as they can reduce the relaxation time of the surrounding protons owing to their superparamagnetic behavior, being particularly suitable candidates for MRI .In the continuous effort to create better tools for cancer management, multifunctional nanoparticles, called theranostics, emerged as performant alternatives to conventional therapeutics and imaging agents. Thus, numerous studies have recently investigated a myriad of nanomaterials that can encapsulate and co-deliver drugs, imaging moieties and genes, and even detect tumor cells by binding to specific receptors. In order to emphasize the developments encountered for metal-based NPs as theranostics, several examples have been gathered in As described in In summary, the development of metal nanoparticles is rapid and multidirectional, providing alternative treatment strategies and enhancing the outcomes of many cancer therapies. An increasing number of in vitro and in vivo studies has emerged in the specialty literature, showing promising results in the treatment of various cancers when using metal-based NPs with intrinsic anticancer properties or metallic nanoplatform in combinatorial approaches with other therapeutic options. In particular, the use of controlled-release systems triggered by pH, temperature, electromagnetic waves, light, and enzymes brings critical precision to the delivery of chemotherapeutics, improving accumulation in tumor tissues and strengthening therapeutic results.However, most metal-based formulations have not yet been translated to clinical settings, mainly due to toxicity concerns. The abilities of metallic NPs to generate ROS, induce oxidative stress, disturb cytoskeleton integrity, and damage DNA, which are the main reasons for choosing them as cytotoxic agents, also represent obstacles in their approval. Thus, it is important that future tests also focus on enhancing the biocompatibility of these platforms in healthy tissues, gathering more evidence on their safety profiles and long-term outcomes. Another significant concern related to metallic nanoparticles is their stability in biological media, which must be carefully tailored by using surface functionalization with various organic molecules, macromolecules, or noble metal coatings.In conclusion, metal-based nanoconstructs hold great promise for developing more performant anticancer therapies, and they deserve further special interdisciplinary research efforts towards overcoming current limitations."}
+{"text": "There is an error in the affiliation for authors Stephane Perrey and Makii Muthalib. The correct affiliation is: EuroMov Digital Health in Motion, Univ Montpellier, IMT Mines Ales, Montpellier, France."}
+{"text": "To slow the spread of Covid-19, many states instituted restrictions on group size for religious services, exercise, and social engagement. We are beginning to understand the effect of these mandates on older adults. The purpose of this study was to examine the relationships between sleep health, depression, pain, and quality of life (QOL) among older adults during the initial months of the Covid-19 pandemic. Older adults completed an anonymous online survey to collect data including personal characteristics, behaviors, and health conditions during May-September 2020. Sleep Health was assessed with a survey of satisfaction, timing, efficiency, and duration of sleep along with daytime alertness. Pearson correlations were used to explore relationships between age, education, socioeconomic status, pain, depression, and QOL. Participants (N=509) were primarily female , white , college educated  and with a mean age of 75.6 years . Mean Sleep Health score was 7.4 . Higher (better) Sleep Health scores were associated with education  and socioeconomic status  and lower scores with depression , pain , and QOL . Poorer Sleep Health among older adults during the initial months of the pandemic were associated with depression, pain, and reduced QOL. Sleep, depression, and pain have reciprocal relationships that may have lasting consequences on physical and mental health among older adults. These findings suggest that poor sleep health should be identified and treated to improve QOL among older adults."}
+{"text": "Declining arthropod communities have recently gained a lot of attention, with climate and land-use change among the most frequently discussed drivers. Here, we focus on a seemingly underrepresented driver of arthropod community decline: biological invasions. For approximately 12 000 years, earthworms have been absent from wide parts of northern North America, but they have been re-introduced with dramatic consequences. Most studies investigating earthworm-invasion impacts focus on the belowground world, resulting in limited knowledge on aboveground-community changes. We present observational data on earthworm, plant and aboveground arthropod communities in 60 plots, distributed across areas with increasing invasion status  in a Canadian forest. We analysed how earthworm-invasion status and biomass impact aboveground arthropod community abundance, biomass and species richness, and how earthworm impacts cascade across trophic levels. We sampled approximately 13 000 arthropods, dominated by Hemiptera, Diptera, Araneae, Thysanoptera and Hymenoptera. Total arthropod abundance, biomass and species richness declined significantly from areas of low to those with high invasion status, with reductions of 61, 27 and 18%, respectively. Structural equation models suggest that earthworms directly and indirectly impact arthropods across trophic levels. We show that earthworm invasion can alter aboveground multi-trophic arthropod communities and suggest that belowground invasions might be underappreciated drivers of aboveground arthropod decline. Given their importance as broad global change drivers , it is uAlthough commonly perceived as having mostly positive impacts on their environment ,15, eartEarthworm invasion alters soil abiotic conditions ,19, plan. 2Populus tremuloides) interspersed with balsam poplar , with a dense understorey vegetation and a grey luvisol soil. It has a long history of earthworm-invasion research, including investigations on soil abiotic (soil chemistry and physics) and biotic  aspects )Across community properties, there were consistent and strong, direct positive effects of earthworm biomass on predators, and on parasitoid abundance, that were not mediated by plant richness or cover, or by intermediate trophic levels. Such effects might be mediated by altered habitat structure, such as reduced litter layers , or planAs one of the first studies reporting effects of invasive earthworms on aboveground arthropod communities see ,31), our, our31])"}
+{"text": "Drosophila encompasses a low complexity intestinal microbiome and has recently emerged as a system that might uncover evolutionarily conserved mechanisms of microbiota-derived nutrient ISC regulation. Here, we review recent studies using the Drosophila model that directly link microbiota-derived metabolites and ISC function. This research field provides exciting perspectives for putative future treatments of ISC-related diseases based on monitoring and manipulating intestinal microbiota.Host-microbiota interactions are key modulators of host physiology and behavior. Accumulating evidence suggests that the complex interplay between microbiota, diet and the intestine controls host health. Great emphasis has been given on how gut microbes have evolved to harvest energy from the diet to control energy balance, host metabolism and fitness. In addition, many metabolites essential for intestinal homeostasis are mainly derived from gut microbiota and can alleviate nutritional imbalances. However, due to the high complexity of the system, the molecular mechanisms that control host-microbiota mutualism, as well as whether and how microbiota affects host intestinal stem cells (ISCs) remain elusive.  The physiological inhabitants of the intestine, the gut microbiota, include bacteria, archaea, viruses and fungi that have coevolved with their hosts. The intestine offers an excellent mucosal environment for reciprocal host\u2013microbe interactions and harbors a vast number of microorganisms, which are separated from the internal milieu by a single epithelial cell layer ,2. The sThe host-gut microbiome interactions are central modulators of different aspects of host physiology, including growth, development, nutritional status, behavior and immunity ,7 Figur. The micContrariwise, imbalance in microbiota composition or abundance leads to microbial dysbiosis, which is associated with autoimmune and allergic diseases, diabetes, obesity and inflammatory bowel disease . IncreasDrosophila perspective on the effects of dietary interventions on the composition of bacterial communities within the gut and the impact of commensals on metabolism, with a special focus on the effects of microbe-derived nutrients on ISC behavior and epithelial renewal.In this minireview we provide a Drosophila melanogaster has contributed fundamental insights into our understanding of processes governing multicellular organism development, physiology, homeostasis, signaling pathways and aging [Drosophila digestive tract, in particular, resembles the gastrointestinal tract of mammals at the structural, functional and cellular levels [Drosophila intestine, the midgut, corresponds to the mammalian small intestine and encompasses ISCs, which, similar to their mammalian counterparts, are self-renewing, multipotent cells, able to generate all the differentiated gut cell types. In the Drosophila midgut, the ISCs are distributed throughout the basal side of the pseudo-stratified epithelial monolayer [Drosophila, ISCs transiently differentiate to either enteroblasts (EBs) or pre-enteroendocrine cells (pre-EEs), which, in turn, terminally differentiate into absorptive enterocytes (ECs) or secretory enteroendocrine cells (EEs), respectively [Drosophila midgut epithelial tube is ensheathed by longitudinal and circular visceral muscle fibers involved in peristalsis, is oxygenated by visceral tracheae, and is innervated by neuronal termini at the anterior and posterior ends [The genetically powerful invertebrate model nd aging . The Dror levels . Importaonolayer ,22. In monolayer . ISCs aronolayer . ISCs arectively ,25,26. Sectively ,28. The ior ends ,30,31,32Drosophila midgut, similar to the mammalian intestine, acts as a barrier to ingested environmental fluids and microorganisms and, at the same time, allows for nutrient absorption. To achieve these functions, the polarized midgut ECs encompass apical occluding or septate junctions above the lateral adherens junctions, contrary to other Drosophila epithelia, whereby the junctional complexes are reversed. This junctional arrangement, which is similar to mammalian epithelia, may have evolved to prevent luminal contents and intestinal microbiota to access the lateral sides of the cells [Drosophila midgut is morphologically divided into 5 broad domains (R1-R5), which are further subdivided into 14 regions exhibiting differential gene expression [The he cells . The aduhe cells ,35. Specpression ,37.Drosophila can also benefit microbial research by deconstructing the complex multi-microbial interactions in vivo. Contrary to the mouse and human gut, which are populated by hundreds of microbial species, the Drosophila intestine is populated by a simple microbial flora composed by less than 20 culturable bacterial species [Drosophila, it is easier to generate and manipulate germ-free flies, as well as gnotobiotic individuals, which are germ-free animals re-associated with selected microbes. The simplicity and intrinsic-tractability of the Drosophila intestinal microbiome, as well as its inexpensive maintenance and fast life cycle, facilitate the molecular characterization of the mutualistic host\u2013microbiota relationships [In addition to the cellular simplicity observed in the fly midgut,  species . The gol species . In Drosionships ,40, whicionships .Even though the fly lacks an adaptive immune system, it has been instrumental in the identification of innate immunity mechanisms and the characterization of the role of conserved signaling pathways  in this process . MicrobiDrosophila. Microbiota composition is altered significantly upon shifts from plant-based to animal-based diets, as well as by alterations in protein and carbohydrate intake levels [Drosophila that vary significantly in the type and number of components used [Firmicutes phylum, represented by the Lactobacillaceae and Enterococcacea families, and the two groups  of the Proteobacteria phylum, represented by the Acetobacteraceae and Enterobacteriaceae families. Acetobacter pomorum, A. tropicalis, Lactobacillus brevis, L. fructivorans and L. plantarum are among the most abundant species [Providencia, Serratia, Erwinia, Pantoea and Pseudomonas [Lactobacillus species, whereas sugar-rich diets increase abundance of Acetobacteraceae, and particularly the Acetobacter and Gluconobacter species. In addition, increased yeast intake steeply induces the abundance of the predominant species [Similar to mammals, the diet is considered among the most significant determinants of interindividual microbiome variability in e levels ,47,48. Tnts used . The mic species . Less abudomonas . Diets r species .Issatchenkia orientalis, a fungus isolated from wild-caught flies, promotes dietary amino acid harvest and rescues lifespan of flies feeding on protein-deficient diets [L. plantarum is sufficient to promote growth by regulating hormonal signals via the TOR-dependent host nutrient sensing system [Strikingly, intestinal microbes can substitute dietary components in nutrient-scarce conditions. For example, nt diets . Moreoveg system . In addig system . Under ng system ,57,58.Drosophila larvae need a protein-rich diet to support their fast growth, whereas the adult flies feed less to maintain energy homeostasis, and young female flies require more energy for egg production [Drosophila life cycle, with dominant fluctuations between Lactobacillacea and Acetobacteraceae [Drosophila lifespan. Nevertheless, whether the microbiota-lifespan link is positive or negative remains contradictory. For example, although the presence of gut bacteria during the first week of the fly\u2019s adult life impinges positively on longevity [Drosophila longevity [dMyc levels in ECs, maintaining their fitness and ISC proliferation, thus, improving gut homeostasis [During development, nutritional needs change constantly due to the different energy demands of the growing animal. For example, oduction . In addioduction . Specifioduction . Similarteraceae . Strikinongevity , a numbeongevity ,64,65,66ongevity . Lifespaeostasis . Taken tThe gut epithelium is a highly plastic tissue. It responds quickly to nutrient scarcity by reducing its volume via EC apoptosis and attenuation of ISC divisions, whereas food intake triggers expansion of progenitor cells and subsequent tissue growth ,69. DietA. pomorum produces the essential amino acid isoleucine (Ile). In turn, A. pomorum-produced Ile promotes L. plantarum growth in Ile-free media. Growing L. plantarum produces lactate that is essential for A. pomorum growth. Lactate production is also responsible for suppression of host protein appetite, in the presence of A. pomorum, highlighting the syntrophic interaction between these two species [A. pomorum supports the growth of L. plantarum by providing not only Ile, but also other essential amino acids for which L. plantarum is an auxotroph, such as arginine, leucine, valine and cysteine [Dietary amino acids, as the building blocks of proteins, are crucial for the fitness of all animals. Most animals are unable to produce essential amino acids and, therefore, must acquire them from their environment: their diet or their microbiota . An inte species . In an ecysteine . While tcysteine , there icysteine ,78,79.Drosophila by controlling protein synthesis autonomously in ISCs and induction of the Jak/STAT ligand Unpaired 3 (Upd3) non-autonomously in ECs [Drosophila insulin-like peptides (dILPs) [L. plantarum (L. plantarum gnotobiotic model) can substitute dietary amino acids during nutrient deprivation conditions. Nonetheless, genetic modulation of the TOR pathway cancels the beneficial impact of the bacteria, indicating that the host nutrient-sensing system acts genetically downstream of the microbiota [Particularly, depletion of the essential amino acid, methionine, and the methionine-derived S-adenosylmethionine, reduces midgut mitosis in y in ECs . Moreovey in ECs . Glutamiy in ECs , is usedy in ECs . Gfat2, y in ECs , is a cry in ECs . In addiy in ECs . In fliey in ECs ,86,87,88 (dILPs) , and mai (dILPs) . Both microbiota .Drosophila Type 2 diabetes model, whereby flies feed on increased sucrose concentrations, revealed that high sugar disrupts epithelial homeostasis by altering signaling pathways of the gut, as well as microbiota composition [A. tropicalis exhibit increased consumption of dietary glucose, and reduced triglyceride content, which might be advantageous to the host during malnutrition [Sugar is the major energy source for most cells and, due to its high caloric content, supports essential organismal functions. However, a sugar-rich diet is associated with obesity  and chroposition . Specifiposition . Howeverposition ,95. SpecEnterobacteriales and Caulobacterales, possibly due to the high energy gut content that benefits their growth. Mechanistically, HFD-induced stress leads to JNK pathway activation in ECs, secretion of the Upd3 ligand and activation of ISC proliferation through the Jak/STAT signaling pathway. Subsequent increase in the number of EEs, correlates with previous findings supporting that HFD alters the expression and release of gut hormones [Similar to high-sugar diet, high-fat diet (HFD) is strongly linked to obesity and obesity-related diseases . HFD indhormones . Juvenilhormones . In mammhormones .Prebiotics are non-digestible fermentable food ingredients, which, upon ingestion, promote the growth of beneficial bacterial species already present in the intestine. Fermentation of prebiotics by intestinal microbiota directly produces beneficial end products, such as short chain fatty acids (SCFAs) . SCFAs aDrosophila, microbiota-derived SCFAs have been shown to [A. pomorum, modulates the IIS pathway in flies. Specifically, it controls growth and metabolic homeostasis, ensures maintenance of basal ISC numbers and epithelial cell turn over via the JNK-mediated Jak/STAT pathway induction [In shown to  regulateshown to ,109. Forshown to . Anothernduction .Drosophila, the addition of sodium butyrate in the diet can effectively extend viability and life span [Apart from acetate, the SCFA butyrate has key roles in intestinal epithelial homeostasis in both mammals and flies. In mammals, butyrate stimulates growth and proliferation of epithelial cells, reduces inflammation and oxidative stress, improves barrier function and inhibits colon cancer development . Interesife span  and micrife span . Sodium ife span .Cholesterol is a key molecule involved in various physiological host functions, while its interaction with intestinal bacteria is known for decades. Nonetheless, the significance of this interaction in host health, and whether gut microbiota modulates cholesterol to benefit the host, has only started to be studied recently ,117. MicDrosophila, high cholesterol diets alter ISC cell differentiation by modulating the Delta ligand and Notch stability in the endoplasmic reticulum [Ecdysone-induced-protein-75B (Eip75B) to adapt midgut homeostasis [In eticulum . This dieticulum . In addieticulum ,120. Theeostasis . The impDrosophila are unable to synthesize essential vitamins, they must acquire them from their diet or from enteric bacteria. Microbiota-derived vitamins can shape the intestinal microbial community and prevent dysbiosis. As not every bacterial strain can synthesize all different vitamins, some symbiotic species possess complementary biosynthetic pathways to maintain their growth [Vitamins are essential micronutrients ensuring normal development and organismal health due to their involvement in vital cellular processes, such as fat and carbohydrate metabolism, as well as DNA synthesis . Since mr growth .Drosophila with the dietary B vitamins and sustain their growth in low-nutrient diets [A. pomorum, managed to rescue their development [Acetobacter species and L. plantarum including, not only supplementation of amino acids, but also B vitamins, such as biotin and pantothenate, when flies are reared on holidic diets, supports growth of the two species that, in turn, supports host systemic growth [Drosophila midgut has revealed that the biotin (Vitamin B7) sodium multivitamin transporter (Smvt) is specifically expressed in ISCs and EBs, highlighting the metabolic requirements of ISCs for this vitamin. Smvt has been found to be essential for ISC maintenance and tissue homeostasis, as well as for fly survival [Smvt silencing leads to dysbiosis caused by increased load of the opportunistic pathogen Providencia sneebia. Strikingly, in biotin-scarce conditions, microbiota-produced biotin could directly induce ISC mitosis [Previously, microbiota was found to supplement nt diets . A recenelopment . Moreovec growth . Additiosurvival . In a re mitosis . Taken tLactobacillus spp., specifically L. plantarum, and increased abundance of opportunistic pathogens, such as Providencia spp., have been shown to mediate activation of ISC mitosis in histone demethylase KDM5-deficient flies. KDM5 deficiency causes aberrant immune activation and abnormal social behavior in flies that can be rescued by L. plantarum administration [L. plantarum produces excessive lactate, an essential metabolite that triggers ROS production by the NADPH oxidase Nox. ROS, in turn, induce increased ISC proliferation [Lactobacillus spp. is crucial for maintaining epithelial homeostasis in a lactate-dependent manner. Several studies have reported that microbiota-derived metabolites, such as the previously described SCFAs and bacteriocins, control pathogenic intestinal infection. Bacteriocins are released predominantly by lactic acid-producing bacteria [In previous studies, intestinal dysbiosis due to reduced abundance of stration . On the feration . Thus, tbacteria  and inhibacteria . Geneticbacteria  and theibacteria . This trbacteria .Drosophila and other animals, including mammals, microbiota can ensure or disrupt optimal host nutrient utilization and trigger host immune function. Commensal-induced low damage levels trigger immunity, which modulates basal ISC activity mostly through the JNK and Jak/STAT pathways. Despite the plethora of studies on the impact of different dietary molecules on ISC activity and the impact of microbiota on intestinal renewal, the mechanisms that directly link microbiota-derived metabolites and ISC function remain to be identified. The long application record of Drosophila as a successful alternative to mammalian models, makes it a promising system for unsheathing the complex host-microbiome interactions, which are most likely conserved across the animal kingdom.Nutrient availability is a critical modulator of intestinal microbiota and host metabolic homeostasis. In Drosophila gut shares many similarities with the human gut, they also have differences. For example, although the fly midgut offers a unique model to bypass mammalian microbiome complexity, it cannot be humanized, i.e., to be colonized with obligate anaerobic microorganisms. Despite the extent to which it matches the human condition, the real potential of this model is the discovery of vital biological mechanisms linking the microbiome, host nutrition and intestinal function, and homeostasis. Importantly, these findings will also provide important links for the effect of microbiota in immunity, fly physiology and behavior. For example, age-related microbial changes have been correlated with gut inflammation [Although the ammation ,133, wheammation , directeammation ,135, socammation  and mateammation  has been"}
+{"text": "Obesity is a major determinant of many noncommunicable diseases (NCDs), including cardiovascular diseases, nonalcoholic fatty liver disease, Type 2 diabetes, and several types of cancer.Although adipose tissue dysfunction seems to play a critical role in the development and progression of low-grade systemic inflammation and cardiometabolic complications, it often coexists with perturbations in other organs involved in the regulation of inflammatory and/or metabolic status.Function, Petrick et al.ob/ob or db/db mice.In this issue of pair feeding of a standard rodent diet in 5-week-old obese mice to lean controls did not alter white adipocyte size, macrophage/dendritic markers, or inflammatory markers. However, pair feeding markedly decreased the number of crown-like structures (reflecting macrophage number) and partially reduced markers of cytotoxic, helper and memory T cells, which was accompanied by improved insulin sensitivity and whole-body glucose tolerance. The authors go further with a crucial experiment to address the study objective and show intriguingly that feeding an obesogenic HFD to a separate subset of lean and obese mice not only elicited adipose tissue inflammation, but also altered the composition of the gut microbiome, induced skeletal muscle mitochondrial dysfunction, and evoked glucose intolerance compared to low fat diet feeding.The team of investigators next assessed the changes in skeletal muscle, adipose tissue, liver, the intestinal microbiome, whole-body substrate oxidation, and glucose homeostasis in these spontaneously obese mice relative to lean controls on different diets. The spontaneously obese C57Bl/6J mice were characterized by hyperphagia, adipocyte hypertrophy, adipose inflammation, and mitochondrial redox imbalance, hepatic steatosis, and severe insulin resistance in adipose tissue, the liver, and skeletal muscle, despite consuming a standard rodent diet. Interestingly, however, the spontaneously obese mice showed normolipidemia, no signs of mitochondrial dysfunction in adipose tissue, skeletal muscle, the liver, and heart, and no differences in the gut microbiome relative to lean littermates. Interestingly, caloric restriction induced by Altogether, the results from the elegant and well-performed experiments by Petrick et al.A number of important issues raised by these series of experiments remain to be addressed. First, the spontaneously hyperphagic, obese C57Bl/6J mice not only developed adipose tissue inflammation but also hepatic steatosis. In addition, caloric restriction reduced liver lipid droplet size and mitigated some but not all proinflammatory markers in adipose tissue. Therefore, it can be questioned whether adipose tissue dysfunction is the culprit in obesity-related glucose intolerance, since lipid accumulation in the liver may also have significantly contributed to the metabolic phenotype observed in these animals, for example, through alterations in hepatokine secretion, or might even have driven adipose tissue dysfunction. Second, in contrast to the identical genetic background and similar laboratory conditions in the spontaneously hyperphagic, obese C57Bl/6J mice that were studied by Petrick et al.,The authors have no potential conflicts of interest related to this article."}
+{"text": "Fingolimod (FTY) is a disease modifying therapy for relapsing remitting multiple sclerosis (RRMS) which can lead to severe lymphopenia requiring therapy discontinuation in order to avoid adverse events. However, this can result in severe disease reactivation occasionally presenting with tumefactive demyelinating lesions (TDLs). TDLs, which are thought to originate from a massive re-entry of activated lymphocytes into the central nervous system, are larger than 2 cm in diameter and may feature mass effect, perifocal edema, and gadolinium enhancement. In these cases, it can be challenging to exclude important differential diagnoses for TDLs such as progressive multifocal leukoencephalopathy (PML) or other opportunistic infections. Here, we present the case of a 26-year-old female patient who suffered a massive rebound with TDLs following FTY discontinuation with primarily neuropsychiatric symptoms despite persisting lymphopenia. Two cycles of seven plasmaphereses each were necessary to achieve remission and ocrelizumab was used for long-term stabilization. Fingolimod (FTY), an effective oral disease modifying therapy (DMT) for relapsing remitting multiple sclerosis (RRMS), sequesters lymphocytes in lymphatic tissue such as the lymph nodes. Accordingly, in some cases it can lead to severe lymphopenia. This prompts many neurologists to discontinue therapy in order to avoid opportunistic infections even though clear proof of such a risk is still lacking . Since 2In a 26-year-old female patient with a 9-year history of RRMS, FTY treatment was discontinued due to lymphopenia of 225/\u03bcl and persisting disease activity in the form of optic neuritis. Prior to FTY she had been treated with interferon beta 1a and dimethylfumarate under which she had developed several relapses. Six weeks after FTY withdrawal the patient developed neuropsychiatric symptoms over the course of a few days including apathy, affective incontinence, and motoric aphasia. MRI revealed numerous tumefactive lesions with Gad enhancement and edema atypical of her prior disease course . After cpost-hoc analyses of the FREEDOMS and FREEDOMS II trials did not find a significantly increased risk of severe disease reactivation after FTY discontinuation  for the publication of any potentially identifiable images or data included in this article.VK, SM, and DK gave the idea of case reporting. VK and DK analyzed the case and prepared the MRI scans as well as the figure and the table. VK drafted the manuscript for intellectual content. MF, KB, EA, PA, OA, PK, SM, and DK critically reviewed the manuscript and were involved inpatients' healthcare. All the authors contributed to the article and approved the submitted version.PA received compensation for serving on Scientific Advisory Boards for Allergan, Biogen, Celgene, Ipsen, Merck Serono, Merz Pharmaceuticals, Novartis, and Roche. He received speaker honoraria and travel support from Allergan, Bayer Vital GmbH, Biogen, Celgene, Ipsen, Merck Serono, Merz Pharmaceuticals, Novartis, Roche and research support from Allergan, Biogen, Celgene, Ipsen, Merck Serono, Merz Pharmaceuticals, Novartis, and Roche. OA has received grant support from Bayer, Biogen, Novartis, and Sanofi and consultancy or speaking fees and fees for serving on steering committees from Bayer, Biogen, Celgene, Medimmune, Merck, Novartis, Roche, Sanofi, and Teva. PK was supported by the Stifterverband/Novartisstiftung. SM received honoraria for lecturing and travel expenses for attending meetings from Almirall, Amicus Therapeutics Germany, Bayer Health Care, Biogen, Celgene, Diamed, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, Roche, Sanofi-Aventis, Chugai Pharma, QuintilesIMS, and Teva. His research was funded by the German Ministry for Education and Research (BMBF), Deutsche Forschungsgemeinschaft (DFG), Else Kr\u00f6ner Fresenius Foundation, German Academic Exchange Service, Hertie Foundation, Interdisciplinary Center for Clinical Studies (IZKF) Muenster, German Foundation Neurology and by Almirall, Amicus Therapeutics Germany, Biogen, Diamed, Fresenius Medical Care, Genzyme, Merck Serono, Novartis, ONO Pharma, Roche, and Teva. DK received travel grants from GeNeuro and Merck, refund of congress participation fees from GeNeuro, Merck and Servier, consulting fees from Grifols, payment for lectures from Grifols, support for research projects from Teva and was funded by the Deutsche Forschungsgemeinschaft (DFG) while carrying research on human endogenous retroviruses at Cleveland Clinic. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "The purpose of this presentation is to compare success of recruitment methods by race/ethnicity, age, and kinship of dementia family caregivers. We conducted a cross-sectional study and recruited a convenience sample of dementia family caregivers using community-based and online methods. Recruitment success was tracked through survey questions, direct referrals, and community event sign-ups. Using chi-squared statistics, we examined the success of each method by caregiver race/ethnicity, age, and relationship to person with dementia (kinship). There were significant differences in recruitment source based on race/ethnicity, age, and kinship (P<.001). Specifically, referrals and newspaper advertisements were most successful for recruiting older (54 years+), White, non-Hispanic, and spousal or child caregivers; community events and reputable websites for recruiting older, minority, child caregivers; ResearchMatch for recruiting younger, minority, child/grandchild caregivers; and social media for recruiting younger, White, non-Hispanic, and child caregivers. Findings support the importance of implementing tailored methods to reach diverse dementia caregivers."}
+{"text": "Introduction: This paper describes a case of bi-frontal vasogenic oedema associated with bilateral frontal lobe and left parietal lobe white matter lesions where extensive investigations, including brain biopsy, failed to establish a diagnosis. Case Report: A 67-year-old female presented with three weeks\u2019 history of memory loss, fatigue, insomnia, nausea, and occasional dysphasia. Physical examination was unremarkable, yet cerebral CT and MRI showed bilateral frontal lobe vasogenic oedema. Extensive investigations, including: biochemical; radiological; immunological; microbiological; haematological; histopathological; and cytological, failed to establish a confirmed diagnosis. A multidisciplinary team could not achieve a consensus for this atypical presentation. Brain biopsy was unusual, showing destructive inflammatory and subtly granulomatous disease, but an exhaustive list of auxiliary tests could not confirm a cause, and consensus favoured glial fibrillary acidic protein (GFAP) autoimmune encephalopathy. Discussion: A definitive diagnosis could not be established for this patient despite a gamut of investigations. Although some of the presenting features were consistent with GFAP astrocytopathy, initial staining of the patient\u2019s CSF for neuronal antibodies was negative. Her symptoms and radiological changes of brain imaging improved without any corticosteroid therapy. Conclusions: Through this case report, the aim is to add to the repository of neurological sciences in the hope that future similar presentations could potentially lead to discovery of a new aetiology or contribute towards better understanding of an existing disease process. Cerebral oedema is often associated with trauma, intracranial space occupying lesions, vascular ischemia, or obstructive hydrocephalus ,2,3. VasA 67-year-old Caucasian female of Lebanese ethnicity presented following a 3 week history of retrograde amnesia, intermittent emesis, lethargy, and insomnia. Her family reported occasional expressive dysphasia which spontaneously resolved. Cerebral Computed Tomography (CT), performed on presentation, showed left frontal lobe oedema with associated mild mass effect . PhysicaNeisseria meningitidis, Streptococcus pneumoniae, Varicella Zoster, Herpes simplex virus 1 and 2, and Enterovirus), mycobacteria, and fungal cultures were also negative. Although oligoclonal bands were detected in the CSF, without associated presence in serum, the patient\u2019s clinical presentation and examination did not satisfy the diagnosis of multiple sclerosis. She also underwent central nervous system (CNS) lymphoma and autoimmune screen, including an extended panel of antibodies for limbic encephalitis that included antibodies for Neuromyelitis Optica (NMO), N-methyl-D-aspartate receptor (NMDA), and Myelin Oligodendrocyte Glycoprotein (MOG) in the CSF. Further tests were performed to provide inflammatory and infectious screening on the patient\u2019s serum, targeting other uncommon viral, bacterial, fungal, and mycobacterial etiologies, which also returned negative results for an acute infection. Her serum was also negative for the screening of common autoimmune pathologies. Magnetic resonance imaging (MRI) of her brain showed bi-frontal, left parietal, and temporal vasogenic oedema with associated punctate white matter contrast enhancement A,B. TherA brain biopsy was performed and neurohistopathological analysis of the biopsy tissue showed an unusual destructive inflammatory process with a prominence of macrophages/microglia and plasma cells involving the white matter . The whiIn the absence of any use of steroids, during this admission, the patient had not undergone any treatment which could have raised the possibility of a partially treated CNS lymphoma. A Positron-Emission Tomograph (PET) and whole body CT scans showed no evidence of high grade lymphoma in the CNS and the only positive feature on the PET scanning was a moderately metabolically active left inguinal lymph node. This was biopsied and showed only reactive changes, presumably due to infection, with no evidence of malignancy. A progress PET scan, performed two months later, showed significantly reduced activity within this lymph node.Further testing, to investigate for an array of rare auto-immune and typical paraneoplastic conditions, was performed. This included antibodies against CASPR2, GABA-B, DPPX, IgLON5, Amphiphysin, ANNA1 Hu, ANNA2 Ri, PCA Yo, PNMA2, MA2 Ta, CV-2 CRMP5, Recoverin, Sox-1, Titin, Zic4, GAD65, and Tr(DNER), and did not yield a positive result. Multidisciplinary teams, consisting of neurologists, radiologists, immunologists, haematologists, and histopathologists were convened to discuss this atypical presentation and, despite casting the net \u2018far and wide\u2019, the case remained a diagnostic dilemma after multiple deliberations. The consensus opinion favoured Glial Fibrillary Acid Protein (GFAP) astrocytopathy autoimmune encephalopathy, although initial staining of the CSF, for neuronal antibodies, was not supportive of the diagnosis, thereby restricting access to further testing which was not available within Australia.The patient\u2019s confusion, lethargy and insomnia improved over the course of her admission, and she was discharged home, with plans for outpatient follow up. An ensuing cerebral MRI, performed three months following the initial presentation, showed an interval reduction in the previously noted multifocal enhancing foci, with only subtle residual punctate foci of enhancement within the left periventricular white matter . The patThis case represents an unusual presentation of bilateral cerebral oedema and white matter abnormalities in a patient who initially presented with confusion, amnesia, and lethargy associated with occasional dysphasia. Vasogenic oedema and hippocampal volume increase, associated with ECT, is well described . A clearExtensive investigation, including tests performed on her CSF, brain biopsy, inguinal lymph node biopsy, and serum were all unremarkable, and a final diagnosis remains elusive. The consensus opinion favoured GFAP autoimmune encephalopathy, although the available tests, at the time of reporting her case, did not support that diagnosis and the definitive testing was not available in Australia.GFAP astrocytopathy is a newer addition to the list of autoimmune conditions affecting the CNS. It was first described by Fang et al. in 2016, following a retrospective review of autoimmune profiles of patients that had presented to a neuroimmunology centre, between 1998 and 2016 . In thatThe patient\u2019s symptoms and radiological findings have improved over the 3-month period, and this case remains a diagnostic puzzle, in the absence of definitive testing. This case raises serious implications for clinical neurology as, despite very detailed investigations, employing the latest technology available in Australia, including brain biopsy, MRI, PET, CSF analysis, and sophisticated neuro-immunological investigation, the team was unable to confirm a diagnosis. Even resorting to a multi-dimensional, multi-disciplinary consultative process, including neurologists, neuro-pathologists, neuro-radiologists, and neuro-immunologists, across three of the major teaching hospitals in Sydney and involving two Australian universities, the team could not progress the diagnosis beyond a presumptive consensus favouring GFAP encephalopathy, without definitive proof. The presentation may represent a hitherto unrecognised condition which, despite a lack of any form of aggressive intervention, is improving dramatically. It highlights the fact that, even with the major advances encountered in clinical neurology, there remains a great deal about which there is still so much to learn. It is imperative that those involved in the clinical management of difficult diagnostic problems share cases in which the final diagnosis remains a conundrum, especially where the consultative process has already been involved.Through this case report, the aim is to add to the repository of neurological sciences, in the hope that future similar presentations could potentially lead to discovery of a new aetiology or contribute towards better understanding of an existing disease process."}
+{"text": "In the Covid-19 context, researchers and policy makers have turned their attention to long-standing disparities in health equity, including by race, ethnicity, poverty, sexuality, and gender. Yet, scholarship to date does not conceptualize age as a critical aspect of difference requiring an equity lens. In this presentation, we utilize an Age Equity Framework to investigate ageism based on research findings from the 2018 National Health, Aging and Sexuality/Gender Study (NHAS): Aging with Pride. Investigating ageism, stigma, and bias, we found nearly half of LGBTQ older adults feel invisible and disrespected. After adjusting for background characteristics, experiences of ageism were associated with higher rates of stigma, lifetime victimization, discrimination, lower support and community engagement, and adverse outcomes . The rapidly growing older adult population highlights the pressing need to consider age inequities and the importance of achieving age equity across the life course."}
+{"text": "Scientific Reports 10.1038/s41598-021-01639-y, published online 12 November 2021Correction to: The original version of this Article contained an error in the Acknowledgments section.\u201cWe thank Michael Oppenheimer, Suzi Kerr, Kelley Kizzier, Sam Kotis, Jon Coifman, Anne Marie Borrego, Jordan Faires, and Christina Baute for thoughtful feedback and discussions. Two anonymous reviewers provided constructive suggestions that have considerably strengthened the manuscript. This work is supported by the Robertson Foundation, Heising-Simons Foundation, and Klarman Family Foundation.\u201dnow reads:\u201cWe thank Michael Oppenheimer, Suzi Kerr, Kelley Kizzier, Sam Kotis, Jon Coifman, Anne Marie Borrego, Jordan Faires, and Christina Baute for thoughtful feedback and discussions. Two anonymous reviewers provided constructive suggestions that have considerably strengthened the manuscript. This work is supported by the Robertson Foundation and Heising-Simons Foundation.\u201dThe original Article has been corrected."}
+{"text": "Child abuse and intimate partner violence rates are known to increase during and in the aftermath of disasters. Research on elder abuse during disasters, including the current pandemic, is limited. As part of an online survey that explored older Canadians\u2019 current experiences and future care plans during the COVID-19 pandemic, we aimed to determine the prevalence, contributing factors and potential outcomes of frequent family discord involving physical violence (FFD/PV) as a proxy for elder abuse. The survey was conducted between Aug 10 and Oct 10, 2021. Respondents (n=4380) were recruited using social media, direct email, Facebook advertising and with the assistance of 85 local community, regional and national organizations. The sub-sample reporting FFD/PV  was compared with other survey respondents regarding socio-demographic characteristics, negative and positive emotions, difficulty accessing basic needs, food, health care and support. Respondents experiencing FFD/PV were found to be significantly younger and less educated and were more likely to be non-white and not working than other respondents. The subgroup sustaining FFD/PV reported significantly higher rates of feeling depressed, lonely, isolated, anxious, sad, and judged/shamed and felt less happy, relaxed and accepted in their community. They also reported higher rates of challenges in accessing basic material needs such as food, support, medical care, mental health treatment and experienced more changes in life routines. Although only a small percentage reported FFD/PV, our results highlight a disturbing pattern that merits serious attention of adult protection agencies, seniors' advocates and disaster response organizations."}
+{"text": "Protein from plant sources is claimed alternatives to animal sources in the human diet. Suitable protein sources need high protein digestibility and amino acid bioavailability. In terms of protein functionality and food applications, they also need high-quality attributes, such as solubility, gelling, water- and oil-holding capacities, emulsifying, and foaming. Thermal processing can improve the nutritional quality of plants with some disadvantages, like reducing the assimilation of micronutrients . Emerging technologies\u2014such as ultrasound, high-pressure, ohmic heating, microwave, pulsed electric field, cold plasma, and enzymatic processes\u2014can overcome those disadvantages. Recent studies demonstrate their enormous potential to improve protein techno-functional properties, protein quality, and decrease protein allergenicity. However, the literature lacks a broader evaluation, including protein digestibility, industrial-scale optimization, and exploring applications to these alternative protein sources. Proteins are vital macronutrients in human nutrition, supplying the essential amino acids. It performs relevant functional roles in food formulation, processing, storage, and consumption. They also benefit food sensory and quality attributes, depending on their functional properties, such as solubility, gelling, water- and oil-holding capacities, emulsifying, and foaming , 2.The main current challenges regarding protein food sources are supply and distribution guarantees. Regarding animal protein production and consumption, there are concerns about adverse impacts on human health, natural resource depletion, climate change, and animal welfare . These cIn general, thermal processing improves plant protein nutritional quality. However, some disadvantages are high time- and energy-consuming procedures, large water expenditure, and losses of desirable compounds in the final product . The maiAlternatively, some emerging food processing technologies have been investigated for the best protein employment, such as ultrasound, microwave, supercritical fluids, pulsed electric field, high-pressure, ohmic heating, cold plasma, and enzymatic processes , 11. FigPlants have been studied and used worldwide as protein sources, including legumes, cereals, pseudocereals, and seeds . HoweverTherefore, this critical review aims to discuss the advances and perspectives of the emerging processing methods\u2014non-thermal or performed at mild temperatures/short times\u2014to improve plant protein quality and properties. It is focused on the nutritional aspects, protein digestibility, protein allergenicity, and techno-functional properties.Protein functionality is critical in determining the applicability of plant proteins flours, concentrates, and isolates , 18. TheFood macromolecules  are inherently functional by their molecular structure and ability to interact and form complexes. Protein molecular structures have important roles in determining food functionality and can be used as targets to alter protein functionality . IntrinsMost proteins are functional due to their globular component properties, especially solubility, which is attributed to the amphiphilicity of these molecules. Proteins have both inwardly bounded apolar (hydrophobic) amino acids and outwardly exposed polar (hydrophilic) side-chain amino acid residues. This arrangement allows dipole-dipole interactions with solvents by twisting and unfolding the amino acid side chains, placing the polar groups at the protein's surface. It leads to networks that can form gels and develop films, hold water, absorb fat, foam, emulsify, and dissolve under various pH conditions . Also, tSome studies assessed the techno-functional properties of plant proteins, such as soybean, chickpea, kidney bean , mung befoaming capacity and stability, like soybean, pea, chickpea, lupin, and rapeseed  of plant proteins. Bell peppers are suggested to food products requiring high WHC  reporting poor gelation properties . Withal, the complexity of the food matrix influences the extraction process: proteins are generally bonded to other macromolecules ; the presence of salts and different pH values change proteins' charge, ionic strength, conformation, and solubility; previous matrix processing  and the presence of water/solvents alters the matrix structure; and the fractionation of the plant sources \u201346. AlsoProtein extraction can be categorized into wet and dry methods . SubsequThe main consequence of many extraction methods is protein denaturation, which alters the proteins' secondary, tertiary, and quaternary structures due to changes in temperature, pH, and organic solvents and salts presence . In geneAlkaline extraction pH 8\u201311), followed by isoelectric precipitation (pH 4\u20135) of solubilized proteins, is the most usual technique employed for the extraction of plant proteins to make enriched flours (up to 65% of protein), protein concentrates 65\u201390%), and protein isolates (more than 90%) . Several0%, and p, followeThe existing drawbacks of conventional extraction methods   may be oAlthough these emerging processes were evaluated about protein valorization and recovery, studies concerning protein quality improvement  are rare for plant protein sources. Few evaluations have been made for the inactivating trypsin inhibitors in plant proteins in soybeans, chickpeas, and beans . HoweverHigh-pressure processing (HPP)\u2014also known as high hydrostatic pressure (HHP) or high isostatic pressure (HIP)\u2014is a non-thermal technology using hydrostatic pressures up to 1,000 MPa into a product in controlled temperature and time conditions . HPP affHigh-pressure homogenization (HPH)\u2014also called dynamic high-pressure (DHP) or ultra-high pressure homogenization (UHPH)\u2014imposes high-pressure conditions by pumping liquid food through a tiny gap in a valve, increasing velocity and causing high shear stresses. Consequently, it causes changes in food rheological properties. HPH utilizes the combined effectiveness of high-frequency vibration, high-velocity impact, quick pressure drop, cavitation, and intense shear stress in a short time, which causes a significant effect on proteins conformation . HPH wasTypical HPH pressures are moderate and usually up to 100 MPa , while HUltrasound (US) is a non-thermal technology using high-intensity and low-frequency sound waves, ranging from 20 to 100 kHz . The basAs a novel technology, the US appealed to environmental sustainability. High-intensity ultrasound is a quick and cost-effective technology used to modify globular proteins' structural and functional properties . The US \u22124 to 10\u22122 s) and relatively high amplitude (0.1\u201380 kV/cm). It induces a critical electrical potential across cell membranes, enabling an easier extraction of proteins (Pulsed electric field (PEF) treatment consists of electric pulses of short duration , and reduced energy costs . The appRecent studies used PEF on the recovery of bioactive compounds from plants , agri-food residues, such as pomace, peels, kernels, and oilseed meals , and marine microalgae without killing the cells , 49, 70.Ohmic heating (OH) is an advanced thermal processing method that applies electrical current to generate heat inside a food material by the well-known Joule effect . OH emerIt was shown that OH inactivates trypsin inhibitors due to the electrochemical effects, depending on the electric voltage used. Studies using OH  showed more efficient inactivation of the trypsin inhibitors than the electric stove over the same processing time . The heaMicrowave heating (MH) uses non-ionizing electromagnetic waves from 300 MHz to 300 GHz . MicrowaMicrowave is mostly applied to foods for shorting cooking time, with less energy consumption. However, this technique can also influence the extraction of proteins  and otheLiterature shows some studies that use microwave heating to reduce the cooking time of plants, reduce the concentration of antinutritional factors, and enhance protein digestibility . HoweverPlasma technology (or gas discharge plasma) involves producing and using ionized gas molecules to treat a material for superficial effects, e.g., polymers functionalization and food decontamination. The gas ionization produces reactive species, e.g., ions, electrons, excited atoms, ultraviolet (UV) photons, and free radicals \u201383, thatCold atmospheric plasma processing (CAPP) is an emerging, sustainable, and environmentally friendly technology that has received significant attention in the food industry for the recent decade , 83, 86.Reactions initiated by reactive oxygen species (ROS) with the synergistic effect of reactive nitrogen species (RNS) are the leading cause of protein structure modification, triggering the cleavage of proteins into peptides . Also, CThere are few studies regarding CAPP effects on protein modification and the techno-functional properties of plant proteins and by-products. Enzymes are biocatalysts in many industries . The enzyme-assisted extraction processing (EAEP) simultaneously extracts oil and protein from plants. EAEP has a low environmental impact due to avoiding organic solvents and can be labeled as an eco-friendly technique that produces valuable products in mild conditions without losing quality .EAEP causes plant cell walls disruption by specific enzyme activity . These enzymes enhance the extraction yield by decoupling proteins attached to the plant polysaccharide matrix . ProteasBesides the high extraction yield, EAEP can also improve the functional properties of plant proteins, depending on extraction conditions, such as temperature, pH, ionic strength, and presence of salts . High-quIn addition to enzyme-assisted extraction, the enzymatic hydrolysis (EH) technique may generate protein hydrolysates, such as di- and tri-peptides , and bio\u00ae) and the exopeptidases  used in the EAEP process break down some peptide bonds  without affecting the essential amino acid composition .CTD and RW are emerging techniques used for dehydrating liquid and semi-liquid foods , 103. ThGamma irradiation (GI) may improve protein extraction and cause conformational changes (secondary structure rearrangement), crosslinking, and break covalent bonds. The protein structure and concentration and the presence of oxygen are the main factors affecting this process. However, GI may promote amino acid oxidation , 100.Some studies show the combined effect of some presented emerging technologies  with the enzymatic processes on enhancing protein recovery, extraction yield, and improving protein functional properties , 105. ThThe emerging technologies for food processing are alternatives to traditional thermal processing to enhance plant proteins' nutritional quality or techno-functional properties. Protein quality is the main concern when replacing traditional sources, particularly meat by plants. It was observed that the selected processing technologies could interact with the protein structure (from primary to quaternary) and inactivate/eliminate the antinutritional factors, which indicate changes toward higher protein digestibility. This effect was demonstrated for high-pressure, ultrasound, microwave, ohmic heating, gamma irradiation, and enzymatic processes. In particular, trypsin inhibitors were inactivated by ultrasound, microwave, and ohmic heating, while gamma irradiation was suitable to inactivate the phytic acid. Protein allergenicity is also a concern for adding alternative protein sources in a diet, and it was demonstrated that enzymatic processes, cold plasma, and high-pressure were also efficient in reducing the allergenicity of these alternative proteins.High-pressure processing is the most extensively explored process and presented many good results for techno-functional properties , reducing allergenicity and antinutritional factors, and, as a consequence, improving plant protein digestibility and food applications. Those techno-functionality improvements result from changing the protein structure (from secondary to quaternary). Most of the emerging technologies discussed here can promote similar changes to the protein molecules, and, in this way, they are potential methods to impact those properties positively. In some studies, these properties were affected by ultrasound, pulsed electric field, microwave, cold plasma, direct steam injection, refractance-window drying, and enzymatic processes. In addition to the mentioned benefits, both ultrasound and enzymatic processes are suitable for increasing protein extraction yield and bioactive compounds recovery.The promising results found about these technologies can be explored to nutritionally enrich traditional plant origin sources, such as soybean, peas, beans, and chickpeas. This work claims the broad perspective of these emerging technologies for achieving the adequate protein quality of plant origin sources. However, there are scarce studies evaluating protein digestibility and amino acid composition of plant proteins when using these emerging technologies. There is no published data on ohmic heating and cold plasma impact on plant protein quality enhancement or functional properties. Furthermore, combining some of these technologies has been indicated as a suitable strategy for better results, and many further investigations can be carried out to find optimal conditions.Finally, the industrial application feasibility needs additional development at scales more extensive than those implemented at the laboratory. An actual industrial processing method must consider economic, environmental, and food security issues, which will supply sufficient proteins to the growing global population. Besides, the technological selection must meet human nutritional and sensory requirements and the consumer's cultural aspects. A key question is whether plant proteins can be extracted efficiently and cost-effectively and preserve nutritional value for human consumption worldwide.AS conceived and designed the work, performed the data search, figure and tables preparation, and wrote the draft. JL and YM revised the draft. BC conceived and designed the work, and revised the draft. All authors contributed to the article and approved the submitted version.The authors thank the financial support from Brazilian Agencies CNPq  and CAPES .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Continuous planting has a negative impact on sugarcane plant growth and reduces global sugarcane crop production, including in China. The response of soil bacteria, fungal, and arbuscular mycorrhizae (AM) fungal communities to continuous sugarcane cultivation has not been thoroughly documented. Using MiSeq sequencing technology, we analyzed soil samples from sugarcane fields with 1, 10, and 30 years of continuous cropping to see how monoculture time affected sugarcane yield, its rhizosphere soil characteristics and microbiota. The results showed that continuous sugarcane planting reduced sugarcane quality and yield. Continuous sugarcane planting for 30 years resulted in soil acidification, as well as C/N, alkali hydrolyzable nitrogen, organic matter, and total sulfur content significantly lower than in newly planted fields. Continuous sugarcane planting affected soil bacterial, fungal, and AM fungal communities, according to PCoA and ANOSIM analysis. Redundancy analysis (RDA) results showed that bacterial, fungal, and AM fungal community composition were strongly associated with soil properties and attributes, e.g., soil AN, OM, and TS were critical environmental factors in transforming the bacterial community. The LEfSe analysis revealed bacterial families  were more prevalent in the newly planted field than in continuously cultivated fields (10 and 30 years), whereas Sphingomonadaceae, Coleofasciculaceae, and Oxyphotobacteria were depleted. Concerning fungal families, the newly planted field was more dominated than the continuously planted field (30 years) with Mrakiaceae and Ceratocystidaceae, whereas Piskurozymaceae, Trimorphomycetaceae, Lachnocladiaceae, and Stigmatodisc were significantly enriched in the continuously planted fields (10 and 30 years). Regarding AMF families, Diversisporaceae was considerably depleted in continuously planted fields (10 and 30 years) compared to the newly planted field. These changes in microbial composition may ultimately lead to a decrease in sugarcane yield and quality in the monoculture system, which provides a theoretical basis for the obstruction mechanism of the continuous sugarcane planting system. However, continuous planting obstacles remain uncertain and further need to be coupled with root exudates, soil metabolomics, proteomics, nematodes, and other exploratory methods. Fusarium, which caused root rot disease and reduced crop yield. Similarly, potato monoculture increased soil-borne pathogens, such as Fusarium, which increased disease incidence and reduced crop yield ..57]. On Bacillus, Streptomyces, and Talaromyces  were continuously cropped with similar agronomic practices; hence we carried out the correlation among the consecutive monoculture time with microbial taxa (at phylum and genus level) of these fields D. Under aromyces . Previoudiseases ,76, promdiseases , Brachypdium sp. , pepper dium sp. , and Arapsis sp. . Likewisl agents . Speciesxysporum ,85,86. TOverall, our results demonstrated that low sugarcane production under the long-term continuous cropping system might be associated with changes in microbial communities and soil physiochemical features, such as declines in microbial diversity and potentially beneficial microbes, reductions in soil pH, and soil fertility. More studies are required to further disentangle the triangle associations among sugarcane yield, soil characteristics, and potentially pathogenic microbiota. This research grants us an invaluable avenue for progressing sustainable agricultural measures to enhance microbial activity and boost sugarcane production in continuous cropping soils, which is essential for sugarcane production in China."}
+{"text": "Citrullus lanatus), melons (Cucumis melo), cucumbers (Cucumis sativus), and pumpkins and squashes (Cucurbita spp.). Centers of domestication in Africa, Asia, and the Americas were followed by distribution throughout the world and the evolution of secondary centers of diversity. Each of these crops is challenged by multiple fungal, oomycete, bacterial, and viral diseases and insects that vector disease and cause feeding damage. Cultivated varieties are constrained by market demands, the necessity for climatic adaptations, domestication bottlenecks, and in most cases, limited capacity for interspecific hybridization, creating narrow genetic bases for crop improvement. This analysis of crop vulnerabilities examines the four major cucurbit crops, their uses, challenges, and genetic resources. ex situ germplasm banks, the primary strategy to preserve genetic diversity, have been extensively utilized by cucurbit breeders, especially for resistances to biotic and abiotic stresses. Recent genomic efforts have documented genetic diversity, population structure, and genetic relationships among accessions within collections. Collection size and accessibility are impacted by historical collections, current ability to collect, and ability to store and maintain collections. The biology of cucurbits, with insect-pollinated, outcrossing plants, and large, spreading vines, pose additional challenges for regeneration and maintenance. Our ability to address ongoing and future cucurbit crop vulnerabilities will require a combination of investment, agricultural, and conservation policies, and technological advances to facilitate collection, preservation, and access to critical Cucurbitaceae diversity.The Cucurbitaceae family provides numerous important crops including watermelons ( Citrullus lanatus (Thunb.) Matsum. and Nakai), melons (Cucumis melo L.), cucumbers (Cucumis sativus L.), and pumpkins and squashes (Cucurbita spp.). These crops, which are primarily consumed for fruits and seeds, are noted for remarkable diversity in fruit size, shape, and color, providing both culinary and aesthetic value (Momordica charantia L.), bottle gourd (Lagenaria siceraria (Molina) Standley), wax gourd (Benincasa hispida (Tunb.)), snake gourd (Trichosanthes spp.), and sponge and ridge gourd (Luffa spp.), are also eaten as vegetables or seeds, used as sources of oils or medicines, or purposed as sponges or containers ), stem blight (Mycosphaerella citrullina), verticillium wilt (Verticillium dahlia), gummy stem blight, and root-knot nematode (Meloidogyne incognita acrita). Consistent with the extensive genetic diversity associated with the center of domestication, germplasm from India has proven to be a treasure trove of biotic and abiotic stress resistance, e.g., host plant resistance to downy and powdery mildews, Alternaria, Anthracnose, and aphid- and whitefly transmitted viruses [The global melon research community has extensively used the NPGS melon collection, especially for resistance to diseases, insects, and abiotic stresses. Evaluation data sets available on GRIN-Global for  viruses ,44,45. C. melo, different kinds of cucumbers are produced depending on regional preferences and purposes. The two types most typically grown in the US and Europe serve distinct purposes. Processing or pickling cucumbers have comparatively short fruit (5 to 15 cm long) with thin, mottled, warty skin that is permeable to brining salt. Fresh-market, or slicing, cucumbers have somewhat longer fruit (20 to 23 cm) and smooth, uniformly green, thick skin. Long-fruited, parthenocarpic greenhouse cucumbers (30\u201340 cm), and mini (12\u201315 cm) cucumbers , are also grown for the fresh market. Cucumbers in east Asia, which are eaten fresh, typically have very long fruits (40\u201350 cm). Three major market classes, north China, south China, and Japanese, vary in appearance , flavor, and crispness [C. sativus L. var. xishuangbannanesis, is also cultivated in some subtropical parts of Asia  [Xishuangbannanesis, which exhibits some unique traits including very large fruits (up to 5 kg), and orange flesh color due to accumulation of \u03b2-carotene, is eaten both immature and mature.Cucumbers are an important vegetable consumed throughout the world. FAO statistics indicate that in 2019, more than 130 countries planted cucumber on 2.23 million hectares. Cucumber fruit, which are generally eaten when immature, are harvested at an early stage of fruit development. While less morphologically variable than rispness ,47. A seMyanmar) ,49. XishPseudoperonospora cubensis), Cucurbit yellow stunting disorder virus (CYSDV), and Cucumber green mottle mosaic virus (CGMMV). Priority issues for specific market classes or geographic regions of cucumber production have also been identified. For North American pickling and slicing cucumbers, top research priorities included resistances to the post-2004 downy mildew strains, Phytophthora fruit rot (Phytophthora capsici), and angular leaf spot (Pseudomonas lachrymans). Other economically important diseases worldwide include anthracnose (Colletotrichum lagenarium), Fusarium wilt (Fusarium oxysporum f. sp. cucumerinum), gummy stem blight (Didymella bryoniae), scab (Cladosporium cucumerinum), target leaf spot (Corynespora cassiicola), and viruses including Cucumber mosaic virus (CMV) and several potyviruses [In 2014, a survey of the global cucumber community was conducted to identify breeding needs . Severalyviruses . Changindm1 locus originating from PI 197087, which was very effective in protecting cucumbers from DM infection for nearly four decades [dm1 less effective. The breakdown has devastated the cucumber industry, emphasizing the importance of diversifying sources of disease resistance. The demand by growers, buyers, and processors for uniformity in plant type, fruit type, and flowering time, combined with the need for resistance to the major disease problems in each production area, has restricted genetic diversity. In the US, a phenotypic and molecular survey of available cultivars has indicated that many are similar in parentage . Many of decades ,54. HoweC. sativus is also genetically isolated from other Cucumis species, as it is the only Cucumis with 2n = 14 chromosomes [C. sativus species have been described to include four cross-compatible botanical varieties: the cultivated var. sativus; wild cucumber var. hardwickii (Royle) Alef; semiwild var. xishuangbannanesis Qi et Yuan [sikkimensis Hook [Sativus, xishuangbannanesis, and sikkimensis all share several chromosomal inversions and translocations in relationship to wild var. hardwickii, suggesting chromosomal changes during domestication [C. sativus, not worthy of formal taxonomic recognition [In addition to genetic constraints imposed upon cucumber breeding by market demands, omosomes . The C.  et Yuan , and varsis Hook   [C. hystrix (2n = 24), although with limited success as the chromosomal differences cause significant barriers to obtaining viable seed [C. x hytivus (2n = 4x = 38) as a bridge species allowed for increased cross-compatibility with C. sativus, raising the potential for eventual introgression of valuable traits [C. sativus vars. hardwickii and xishuangbannanesis, and C. hystrix, as they may harbor unique genes important for cucumber improvement.Numerous investigations have indicated that avanica) ,71,72,73ble seed ,75. Devee traits . These sC. lanatus, is a monoecious, warm climate, annual plant with a vining growth habit that requires a long growing season. It is consumed throughout the world for its sweet, juicy fruits. The vast majority of the more than 100 Mt of watermelon fruit produced annually are sold fresh or freshly cut. However, it can also be eaten as jams, glazed candy, or pickled rinds [Citrullus mucosospermus, a close relative of C. lanatus, is native to west Africa and has a modified fleshy mucilaginous seed coat that becomes paper-thin when dried. The thin seed coat makes it easier to de-hull the seed. In China, specific varieties of watermelon bred for edible seeds are produced on nearly a quarter-million hectares annually [Watermelon, ed rinds ,77. Overed rinds . Consumeed rinds . Severalannually . The ediFusarium oxysporum f. sp. niveum), gummy stem blight (Stagonosporopsis spp), anthracnose (Colletochrichum spp.), powdery mildew (Podosphaera xanthii) Phytophthora fruit rot (Phytophthora capsici), bacterial fruit blotch (Acidovorax citrulli), and several viruses including the watermelon strain of Papaya ringspot virus (PRSV-W), Zucchini yellow mosaic virus (ZYMV), and Cucumber green mottle mosaic virus (CGMMV) [There are numerous current, emerging, and evolving pathogens, insects, and pests that threaten watermelon production . Among t (CGMMV) ,81. Whit (CGMMV) ,83. Ther (CGMMV) ,85. Fluc (CGMMV) ,86. 1 hybrids, to seedless triploid hybrids that now dominate the market [C. lanatus accessions, despite different geographic origins of these accessions, likely due to strong bottlenecks during domestication [Preferred types of watermelon vary in different parts of the world. Most of the modern watermelon cultivars in China, which are characterized by round fruits with a thin rind, are derived from local, older cultivars crossed with cultivars introduced from Japan and the US ,13. In te market ,87. Seede market . Pollenie market ,90. Despe market ,92. Furttication .Citrullus in Brazil, the US, Sudan, and Spain  (Russian Federation) maintains >3500 Citrullus accessions, including many collected in southern Africa [C. lanatus accessions along with extensive phenotypic data, and the University of Cukurova in Turkey with seed for several hundred diverse cultivars and landraces, representing both European and Asian types, that were collected throughout the country [Citrullus accessions, of which approximately 75% are available for distribution. Along with 1613 accessions of C. lanatus, the collection includes at least one accession of each of the other six species of Citrullus , including 151 of C. amarus and 75 of C. mucosospermus , transmitted by aphids, whiteflies, and other insects are particularly devastating [Podosphaera xanthii and Golovinomyces cichoracearum), downy mildew (Pseudoperonospora cubensis), Phytophthora capsici, gummy stem blight (Didymella bryoniae), and Fusarium spp. [Cucurbita, but only a single dominant gene has widespread use to control the powdery mildew pathogen [Cucurbita crops is constrained by limited investment in breeding. For example, despite multiple species and cultivar types, there are fewer than three full-time public Cucurbita breeding programs in the US. Cucurbita crops face numerous biotic and abiotic challenges. An increasing and evolving list of diseases, especially viruses ), with more than 6000 accessions , C. moschata (844), C. maxima (838), and C. argyrosperma (278). Seed-borne diseases such as Squash mosaic virus, and daylength sensitivities, especially for many accessions of C. moschata which limit the ability to carry out seed regenerations, make only about half of the accessions available for distribution. The largest cessions . Howeverrosperma . The US Cucurbita collections have been of great value to squash and pumpkin breeding for decades. Resistances to the potyviruses Zucchini yellow mosaic virus and Papaya ringspot virus have been utilized from C. moschata lines \u2018Nigerian Local\u2019 and \u2018Menina\u2019 [C. okeechobeensis subsp. martinezii into C. moschata, and later also into cultivars of C. pepo [Phytophthora capsici has been deployed in C. pepo breeding lines and shared with the seed industry [The \u2018Menina\u2019 . Resista C. pepo . Recentlindustry . DespiteGermplasm management to ensure viability for the future is a common challenge across all crops. Several reports have emphasized the importance of documenting genetic diversity present within collections ,121,122.Cucumis sativus. Zhao et al. (2019) [C. melo accessions assembled from Chinese and US collections . Whole-genome resequencing of 414 accessions representing the seven extant Citrullus species allowed for the reconstruction of the evolutionary history in this genus [Several recent studies have performed genomic analyses of cucurbit accessions. Lv et al.  used a s. (2019)  mapped gis genus .Cucurbita spp. was undertaken by the US CucCAP project [Cucumis sativus, C. melo, Citrullus lanatus, and Cucurbita pepo, maxima, and moschata accessions were genotyped by sequencing (GBS) for each crop: 1234 for cucumber [C. pepo; 534 for C. maxima; 314 for C. moschata . The resulting data provided information about the nature and extent of relationships, genetic diversity, and population structure among the accessions within each collection as well as their relationship to geographical origin and morphotype. The genetic information was used to construct core populations of 380\u2013400 PIs/crop representing 95\u201398% of the variation in each collection . Efforts are underway to produce inbred lines, increase seed phenotype, and resequence the accessions within the core collections. These populations will provide genome-wide association study (GWAS) panels for further marker-trait association analyses. It is intended to make seeds of these inbred lines accessible for the scientific and breeding community.A systematic effort to genetically characterize the USDA NPGS collections for watermelon, melon, cucumber, and  project . All avacucumber ; 1365 focucumber ; 2083 foCucurbita moschata and maxima, respectively. Opportunities for improvement of current collections also include the increased collection of related, interfertile species or wild relatives that can provide valuable novel sources of important traits such as Citrullus amarus and C. mucosospermus for watermelon, Cucumis sativus var. hardwickii, xishuangbannanesis, and C. hystrix for cucumber, and several Cucurbita species. Even wild species and relatives that are not interfertile may afford new opportunities to provide abiotic and biotic stress resistances by serving as rootstocks for grafted cropping systems. The prior crop sections emphasize the important role that genetic resources have played in cucurbit breeding and crop improvement. These genetic resources also harbor valuable natural variation for our fundamental understanding of unique biological phenomena in cucurbits such as sex expression, vascular structure, and fruit quality. Future efforts to preserve, increase and improve these resources should include renewed efforts to collect, both in centers of origin and regions with secondary sources of diversity such as southern Africa for watermelon, north and west Africa for melon, east Asia for cucumber, and south and east Asia for http://cucurbitgenomics.org) (Accessed 7 March 2021) [Further genetic analyses of collections around the world will enable the assessment of diversity within collections as well the opportunity to identify overlaps and gaps among collections. Along with these analyses, it is imperative that the resultant data be made available according to findable, accessible, interoperable, reusable (FAIR) principles ,124. USDch 2021) . Future The Cucurbitaceae family is a rich source of nutritionally valuable crops with extensive diversity distributed throughout the world. Successful production of cucurbit crops is increasingly challenged by biotic and abiotic threats as pests and pathogens are moved from one part of the world to another and climate change alters local temperature and rainfall patterns. One of the most valuable resources to help manage these problems is genetic diversity. Preservation of this diversity, especially in the face of the ongoing loss of habitat of wild or feral populations, is imperative. Various national and international efforts to preserve diversity via ex situ collections provide tremendous resources that have been extensively utilized by the breeding community. However, many of these collections are challenged by limited resources, restricted access, and declining opportunities to expand collections to capture additional sources of diversity. While these challenges are not unique to cucurbits, the cucurbit community must continue to work with broader national and international efforts to assure that critical diversity is maintained, characterized, and made available for scientific inquiry and crop improvement."}
+{"text": "Climate change has devastating effects on plant growth and yield. During ontogenesis, plants are subjected to a variety of abiotic stresses, including drought and salinity, affecting the crop loss (20\u201350%) and making them vulnerable in terms of survival. These stresses lead to the excessive production of reactive oxygen species (ROS) that damage nucleic acid, proteins, and lipids. Plant growth-promoting bacteria (PGPB) have remarkable capabilities in combating drought and salinity stress and improving plant growth, which enhances the crop productivity and contributes to food security. PGPB inoculation under abiotic stresses promotes plant growth through several modes of actions, such as the production of phytohormones, 1-aminocyclopropane-1-carboxylic acid deaminase, exopolysaccharide, siderophore, hydrogen cyanide, extracellular polymeric substances, volatile organic compounds, modulate antioxidants defense machinery, and abscisic acid, thereby preventing oxidative stress. These bacteria also provide osmotic balance; maintain ion homeostasis; and induce drought and salt-responsive genes, metabolic reprogramming, provide transcriptional changes in ion transporter genes, etc. Therefore, in this review, we summarize the effects of PGPB on drought and salinity stress to mitigate its detrimental effects. Furthermore, we also discuss the mechanistic insights of PGPB towards drought and salinity stress tolerance for sustainable agriculture. Plants have been increasingly vulnerable to environmental stresses due to climate change during ontogenesis , and the\u22121 (approximately 40-mM NaCl) and has an exchangeable sodium content of 15% ,26150,26tivities . In addiynthesis , and nutynthesis . Plants ynthesis . To mainynthesis . Apart fpirillum , Burkholholderia ,267, Artrobacter , BacilluBacillus ,269, Psehizobium  also ledhizobium ,253,265.hizobium . Furtherhizobium ,253. Furcavenged ,271. Furreported . A high-reported ,253,273. dS m\u22121) . Under ty plants .+, Cl\u2212, Ca2+, Mg2+, SO32\u2212, or CO32\u2212, which leads to ion toxicity. The influx of these ions is greater than the rate of exclusion when exposed to high salt concentrations for a prolonged period of time . I. IP. polse genes ,293.In plants, abiotic stress, including drought and salinity, causes not only environmental problems but also social and economic ones. The changing environmental conditions are negatively affecting plants, causing lower growth and yields. As abiotic stresses intensify, plant cells produce ROS, which impairs the ecological fitness. The crisis will be exacerbated in the coming decades, threatening plant survival. Antioxidants are recruited by plants to maintain equilibrium between ROS quenching and its generation. The plant\u2019s response to these events is so rapid that it cannot withstand adverse conditions. PGPB promote the plant\u2019s growth by various mechanisms such as phosphate solubilization, nutrient mobilization, production of phytohormones, VOCs, vitamins and modulating the antioxidant machinery, osmotic adjustment, maintaining ion homeostasis, metabolic reprogramming, and modulating biochemical and molecular pathways, regulating drought/salt responsive genes and making the crop more tolerant to drought and salinity stress conditions. Thus, PGPB are a good alternative to conventional fertilizers due to cost-effectiveness, eco-friendliness, and sustainability to increase plant tolerance to multiple stresses, including drought and salinity.PGPBs that may induce plant resistance to a variety of abiotic stressors, particularly those that resemble field environments, should be investigated for future research projects aimed at promoting sustainable agriculture. For the widespread and efficient use of beneficial microbes, scientists need to embark on field studies and make farmers familiar with the benefits that microbes can have on plant health and soil quality. Furthermore, nanoencapsulation technology has just been invented and can be used in field testing. The approach may be used to protect PGPR against abrupt environmental shocks, increase their distribution, and help regulate microbial release in the rhizosphere/field. Additional research is needed to discover if tripartite \u201cplant\u2013fungal\u2013bacterial\u201d symbioses can generate synergistic effects on plants. These approaches appear promising for drought and saline agriculture in the future. With the above information, it is evident that we are on the right path towards achieving our goal of sustainable food production in a climate that keeps changing. Governments and federal agencies need to promote the utilization of PGPB-formulated biofertilizers as eco-friendly alternatives for crop improvement. More investments should be done by entrepreneurs in biofertilizer companies and allocate financial assistance for start-ups. Additionally, public awareness is needed to show farmers and consumers the benefits of PGPB-based biofertilizers for sustainable agriculture."}
+{"text": "Background: The disease concept is increasingly being replaced by a functional approach to address the healthcare needs of the older people. WHO proposed the Integrated Care for Older People (ICOPE) screening tool to identify older people with priority conditions associated with declines in intrinsic capacity (IC). Very few evidence on the clinical utility of the ICOPE tool is available. Objectives: To determine if the tool can identify adults with poor physical and mental function. Method: 376 participants aged 50\u201397 years were included. IC was assessed with the WHO ICOPE screening tool, covering the following five domains: cognitive decline, limited mobility, malnutrition, sensory loss, and depressive symptoms. We assessed the activities of daily living, the Fried frailty phenotype, FRAIL scale, SARC-F scale, MMSE, GDS, social frailty, and quality of life. Peak expiratory flow, bones mineral density, body composition were obtained. Results: 69.1% of the participants showed declines in IC. Participants with declines in IC were older, had more chronic diseases, worse general health, worse physical function as indicated by lower Barthel index, walk speed, grip strength, and physical fatigue, worse mental function indicated by lower MMSE scores, higher GDS scores, more mental fatigue, and worse social function. After adjusting for age, IC was positively correlated with walking speed, resilience score, and MMSE score and negatively correlated with frailty, SARC-F score, IADL score, GDS score, and physical and mental fatigue. Conclusion: The WHO ICOPE screening tool is useful to identify adults with poor physical and mental function in Chinese older adults."}
+{"text": "Bone represents a common metastatic site for patients with advanced cancers while also being associated with rare but challenging primary tumors. As the treatment of bone sarcomas and metastases encountered a slowdown in its development, complementary and alternative strategies to conventional therapies started being investigated. In this respect, this paper proposes a comprehensive path, beginning with the types of bone tumors and current treatment options, and further detailing the recent advancements in the field, including adjuvant therapies, targeted drug delivery, novel bone substitutes, and multifunctional tissue-engineered scaffolds with synergic properties. In the last decades, the treatment of primary and secondary bone tumors has faced a slow-down in its development, being mainly based on chemotherapy, radiotherapy, and surgical interventions. However, these conventional therapeutic strategies present a series of disadvantages , which limit their application and efficacy. In recent years, these procedures were combined with several adjuvant therapies, with different degrees of success. To overcome the drawbacks of current therapies and improve treatment outcomes, other strategies started being investigated, like carrier-mediated drug delivery, bone substitutes for repairing bone defects, and multifunctional scaffolds with bone tissue regeneration and antitumor properties. Thus, this paper aims to present the types of bone tumors and their current treatment approaches, further focusing on the recent advances in new therapeutic alternatives. Bone is a highly active and dynamic connective tissue, which provides vital organ protection, mechanical support, locomotion, and structural body framework ,2. Bone In this respect, several complementary therapies started to be used in clinical practice . AdjuvanWhen critical-sized defects result from bone weakening due to metastases or after surgical resection of tumors, the restoration of skeletal segment integrity requires clinical intervention ,16,17,18Therefore, this paper proposes a comprehensive approach to bone tumors, detailing their types, current treatments, adjuvant therapies, drug carriers and formulations, and bone replacement options, aiming to set a clear context for future research in this field.Bone tumors can be mainly divided into primary bone tumors (sarcomas) and secondary bone tumors (metastases). The most common sarcomas are osteosarcomas, chondrosarcomas, and Ewing sarcomas, accounting for more than two-thirds of such malignancies . In whatBone sarcomas are tumors of mesenchymal origin ,19. TheyThe most frequent malignant primary bone tumors are, in this order, osteosarcomas (35%), chondrosarcomas (25%), and Ewing sarcomas 16%) [% 6,10,2,210,20 . These bone-originating tumors are a rare group of malignancies, comprising less than 0.2% of overall cancer diagnosis, with an adjusted incidence rate for all bone and joint malignancies around 0.9 per 100,000 persons annually ,21. AlthThese tumors consist of heterogeneous cell populations, including cancer stem cells (CSC). CSC have the abilities of normal stem cells, especially their self-renewal and differentiation capacity. CSC can be more appropriately called \u201ctumor-initiating cells\u201d because it can produce all cells found in a particular tumor. . Thus, COsteosarcoma is the most prevalent primary malignant bone tumor, especially in adolescents and young adults ,19,20. SDespite the adoption of aggressive, multimodal treatment schedules, the survival rate of osteosarcoma patients did not significantly improve over the last 30 years. The median 5-year survival rate is reported around 68%; however, it is highly dependent on the SEER stage, as follows: localized\u201474%, regional\u201466%, distant\u201427% ,26,27. PChondrosarcomas are rare mesenchymal tumors, accounting for 10\u201320% of all malignant bone tumors. They have a cartilage-like appearance, being characterized by variously differentiated cells producing chondroid matrix ,28. UnliNonetheless, chondrosarcomas are a heterogeneous group of tumors, both from the morphological and clinical points of view. From this category of tumors, 80\u201390% are conventional chondrosarcoma, while about 10% are highly aggressive dedifferentiated chondrosarcoma. Conventional chondrosarcomas begin intramedullary growth, usually affecting the pelvis, femur, humerus, ribs, and ilium. However, femur, humerus, and pelvis are also the most frequent sites of dedifferentiated chondrosarcomas, which comprise chondroid and non-chondroid parts often looking like fibroblastic or osteoblastic tissue, indicating two types of mesenchymal differentiation in one tumor ,29. MoreThe anatomic depth of these lesions often leads to a late diagnosis, which, coupled with the high resistance towards chemotherapy, radiation therapy, and even targeted approaches, results in poorer prognoses ,14,28,31Ewing sarcoma is the second most common malignant bone tumor in children and adolescents, with a peak incidence at 15 years ,8,19,32.The conventional treatment approach of such tumors includes neoadjuvant chemotherapy, local treatment, and adjuvant chemotherapy. Local treatment may imply surgical intervention and/or radiation therapy. When possible, resection within healthy margins seems preferable to radiation therapy alone . There iBone represents a common metastatic site in patients with advanced cancer . Bone meSkeletal sarcoma and metastases share the same tissue microenvironment and niches . EvidencDepending on the primary mechanism of interference with normal bone remodeling, bone metastases can be split into three categories: osteolytic, osteoblastic, and mixed .As described in Bone tumors represent a medical challenge, especially due to their complexity, heterogeneity, aggressive behavior, and insignificant improvement in their treatment protocols for decades. The treatment of bone cancer has received considerable attention from scientists and clinicians, yet the therapeutic options for bone sarcomas have remained largely the same as in the late 1970s ,10,11. Treatment choice depends on various factors, such as the type of cancer and its characteristics, if the disease is localized or widespread, evidence of extraskeletal metastases, prior treatment history, symptoms, general state of health . The most common approach for bone tumor eradication is surgical resection with adequate margins, combined or not with radiotherapy and/or chemotherapy ,9. TreatNeoadjuvant chemotherapy regimens are employed to produce tumor necrosis, decrease primary tumor size, and reduce the number and size of pulmonary metastases ,47. The Chemotherapy is generally not effective for treating chondrosarcomas due to multidrug resistance ,49. SomeIntensified treatments with combinations of cytotoxic drugs have also failed to improve the cure rates of conventional high-grade osteosarcoma significantly. The main cause is the inherent or acquired drug resistance, which, coupled with metastasis development, causes the dismal prognosis of relapsed patients, for whom cure probability is at most 20\u201325% ,51. Radiotherapy is a physical modality of destroying cancer cells. The applied radiation is called ionization radiation as it forms electrically charged particles and deposits energy in the cells it passes through. The high-energy radiation can directly kill tumor cells or damage their genetic material, impeding further division and proliferation .Radiation therapy can be successfully employed as a palliative intervention to maintain and improve a patient\u2019s quality of life, reduce analgesic requirements, and maintain or ameliorate skeletal function . BesidesIn contrast, chondrosarcomas are considered radioresistant tumors, but the resistance mechanism has not been fully elucidated yet. Nonetheless, radiation therapy is used for metastatic disease as symptomatic treatment in selected cases after incomplete resection or unresectable tumors in difficult-to-reach anatomical sites ,54. In recent years, promising therapeutic options have risen from the combination of radiotherapy and ablative approaches, such as radiofrequency ablation, high-intensity focused ultrasound, and cryoablation .One of the most common strategies for bone cancer therapy is surgical intervention . In maliThe treatment protocol in osteosarcoma includes surgical resection of both primary tumor and bony metastasis, the surgical margin, reconstruction, and adjuvant therapy plan being further delineated by the subtype of osteosarcoma. Similarly, surgical management of Ewing sarcoma implies wide resection of lesions in the appendicular skeleton and selected resection for lesions in the axial skeleton . The surDespite achieving high local tumor control rates, wide resection is associated with significant impairment of function due to the violation of the adjacent joint and formation of bone defects ,55. HencThe two main challenges of bone tumor therapy are repairing large bone defects and eradicating all possible residual tumor cells . Even wiIn this respect, there is an imperative need to find better treatment strategies and overcome the limitations of conventional therapies either by replacing them or working in tandem towards reaching higher survival rates and avoiding disease recurrence. Adjuvant therapies can be employed for decreasing the high rates of local recurrence after curettage, consequently avoiding the need for extensive resection and reconstruction ,59,60. VOut of these procedures, radiofrequency ablation is the most widespread and most thoroughly analyzed thermoablative technique . RadiofrCryoablation is an adjuvant therapy that has been associated with a median local tumor recurrence rate of 11.2% in a large variety of benign\u2013aggressive and malignant bone tumors . It suppMicrowave ablation is another effective method for treating and achieving short- and mid-term pain relief for painful osteoid osteoma and malignant bone tumors, respectively ,73,74. DLaser ablation is an alternative hyperthermal complementary procedure for the treatment of bone tumors. It uses optical fibers to transmit infrared light energy into a tumor to induce rapid heating of the targeted tissue, thus producing protein denaturation and consequent coagulative necrosis ,76,77. IHigh-intensity focused ultrasound (HIFU) is considered a revolutionary non-invasive technique that combines ultrasound energy with thermal feedback. Specifically, an ultrasound beam is focused on the lesion, and the generated heat induces coagulative necrosis and cell death ,76,79. MAnother possibility is using phenol as a local adjuvant, a straightforward alternative with a low risk of procedural complications. It works on the principle of denaturation and coagulation of cellular proteins and DNA damage, thus inducing tumor cell necrosis. Phenol is considered an effective and safe adjuvant that can destroy about 1\u20131.5 mm of tumor tissue ,80,81. IPolymethyl methacrylate (PMMA) can also be employed in tumor management, as it was assumed that its heat of polymerization and direct toxic effect of monomers could be a mechanism of adjacent cellular toxicity ,59,83. HArgon Beam Coagulation (ABC) can also help in bone tumor treatment ,83. For 2O2 decomposition inside the tumor. Thus, reactive oxygen species are produced, which further damage lipids, proteins, and DNA, being harmful to tumor cells [Recently, photothermal therapy (PTT) has also attracted interest in cancer ablation. It is considered promising for tumor treatment especially due to its minimally invasive nature and specific spatiotemporal selectivity. Besides, PTT is economically viable, allows fast recovery, and prevents damage to the non-target regions ,55,85. For cells . Such syor cells ,86Another promising option in treating bone cancer is represented by immune-modulating therapies ,87. MacrAs drug resistance is a common challenge in treating bone tumors, special attention has been attracted to developing better delivery systems to improve chemotherapy outcomes. To avoid using small systemic dose or large local dose of plain chemotherapeutics, nanocarrier systems with controlled drug release can be employed. Particularly, bone-targeted drug delivery systems aim to concentrate drugs in tumor sites, protect drugs from rapid clearance, prolong their circulation times, enhance therapeutic efficacy, and reduce the systemic adverse effects ,15,88,89Bone-targeting carriers combined with the desired drugs or bioactive agents have been extensively investigated to enhance bone healing, while minimizing off-target effects ,90. In tTo overcome the limitations of systemic administration of drugs, micro-, and nano-sized vehicles have been developed to treat bone pathologies that exhibit specific affinity for bone . TargetiNatural and synthetic polymers have been extensively researched for delivering drugs to target tissues ,95. NatuChitosan is a deacetylated derivative of chitin that can enhance the absorption of hydrophobic macromolecular drugs when used as a carrier. Nanoparticles of this natural polysaccharide can extend the encapsulated drug\u2019s activity by holding the therapeutic agent in closer proximity to the site of action due to its mucoadhesive cationic nature, thus facilitating trans-mucosal chemo-drug delivery ,99,100. Synthetic polymers also have properties of interest for drug delivery, such as defined chemistry, ease of modification, tunable porosity, and degradation time . ParticuOther organic delivery vehicles are lipid-based nanoparticles, which have great potential as chemotherapeutics carriers due to their biocompatibility and low toxicity . ParticuInorganic nanomaterials, including metallic nanoparticles, mesoporous silica nanomaterials, carbon-based nanomaterials, and bioactive glasses, can also be employed in the delivery of chemotherapeutics required in bone tumor therapies . Their mSeveral drugs and factors have been studied for their potential in enhancing bone tissue healing . One of Denosumab is another agent of interest in managing bone tumors. It is a human monoclonal antibody that inhibits RANKL, thus preventing the development of osteoclasts. Denosumab has the ability to prevent or delay fractures\u2019 occurrence in patients with bone metastases, being safe to administer even to individuals with impaired renal function ,114,115.Cisplatin is a first-line chemotherapeutic in bone sarcomas . DespiteDoxorubicin is also an important drug in cancer management . NonetheThe inclusion of paclitaxel in nanoparticles is another viable strategy for bone cancer treatment ,125,126.Other chemotherapeutic agents that have attracted interest for nanoparticle encapsulation include, but are not limited to, rapamycin, gentamicin, chloroquinone, etoposide, arsenic trioxide, pirarubicin, curcumin, ifosfamide, gemcitabine, and methotrexate ,134,135.Oncolytic virus therapy is a novel approach that has emerged as an alternative to conventional chemotherapeutics ,136,137.As the use of a single drug-based treatment may be unsatisfactory, the use of combinatorial therapies has emerged as a promising strategy in treating bone tumors . In thisUnlike other tissues, bone has a great capacity to regenerate. However, massive bone defects may be generated after curettage or aspiration of bone tumors, requiring clinical intervention. The restoration of the continuity and integrity of skeletal segments represents a challenge for orthopedists and a hot topic of research ,16,17,18Even though bones have a high potential for self-regeneration, the efficacious repair of large bone defects still requires the implantation of bone grafts . SeveralThe gold standard for reconstructing bone defects is still represented by autologous grafts  ,149,150.To overcome the issue of quantity, bone allografts or xenografts can be used instead ,152. AllIn an effort to avoid the issues associated with natural grafts, artificial grafts (synthetic substitutes) have been fabricated to repair critical-sized bone defects ,16,147. In the last decade, synthetic bone substitutes have become a promising alternative to autografts, allografts, and xenografts . As thesAn ideal artificial graft must be biocompatible and biodegradable while supporting osteoconduction, osteoinduction, and osteointegration ,160. Add\u00ae (HAp) and Cerasorb\u00ae (\u03b2-TCP) are sintered ceramics, while Cytrans\u00ae (CO3Ap) granules are fabricated through a dissolution\u2013precipitation reaction in an aqueous solution using a calcite block [A chemical composition similar to natural bone is considered advantageous for artificial bone substitutes . It has te block .Another limb-salvage option is the endoprosthetic reconstruction using modular prostheses with either cemented or cementless fixations. This approach is considered reliable in periarticular tumor resections, offering component modularity, improved fixation, and good-to-excellent functional results. Moreover, cementless systems minimize the risk of failure, having favorable outcomes regarding infection and aseptic loosening .Efforts have also been directed to combining bone substitutes with antibiotics to prevent potential infections at their implantation site. However, only a few such synthetic grafts are commercially available due to their challenging fabrication. Specifically, the major problem in combining antibiotics with bone substitutes is the exothermic polymerization reaction during material processing, which has fatal consequences on heat-sensitive antibiotics . AlternaThe field of tissue engineering allows the creation of smart multifunctional bone substitutes that use a porous structure  serving as a template for cell attachment, differentiation, proliferation, and tissue regeneration ,9,149. The choice of a suitable material for the scaffold is an essential step in designing tissue-engineered bone substitutes. The material should mimic the native extracellular matrix guiding resident stem cells to regenerate the functional tissue . Thus, tNatural polymers can be employed to fabricate bone scaffolds due to their resemblance with native ECM, biocompatibility, and high osteoinductive properties. Such structures can be derived by cells or directly obtained from decellularized bone tissue. Nonetheless, synthetic polymers provide better control of porosity and physicochemical properties, being promising biomaterials for bone tissue engineering ,178,179.Moreover, several advancements were reported in the development of novel bone replacements from classic metallic materials. Metals, such as titanium alloys, cobalt-chromium-molybdenum alloys, and stainless steel, are conventionally employed in orthopedic surgery . HoweverTo improve the inherent properties of the base material, bone scaffold surfaces can also be functionalized through several methods, such as coatings and immobilized molecules ,16,186 .The functionalization of the bone replacement with factors is a promising approach for attracting and stimulating cells from the surrounding host tissue after implantation, promoting osteogenic cells\u2019 ingrowth, and forming a vascular network within the implant . Growth Besides bone tissue regeneration, novel functional bioceramic scaffolds have also been endowed with tumor therapy ability. Hence, such innovative smart bone substitutes can repair the bone defects resulted after surgery, while also destroying possibly residual tumor cells. Specifically, the high temperature-induced by functional scaffolds produces irreversible protein denaturation, cell membrane damage, and late progressive apoptosis. Hence, they can serve as photothermal or magnetothermal agents locally and further promote new bone formation in vivo ,189.Moreover, biomaterials can act as local drug delivery systems. Synthetic scaffolds can incorporate antitumor, antibiotic, and anti-inflammatory compounds, ensuring their release in the target area, aiming to achieve a high local concentration, while maintaining the side effects at a minimum level. Therefore, treatment efficiency is enhanced, and bone function and integrity are restored ,190,191.To summarize, the complexity, aggressive progression, and lack of significant improvement in treatment protocols over the last decades still render bone tumors a medical challenge. Whether bone sarcomas or metastases of advanced cancers originated elsewhere in the organism, bone tumors require extensive attention and prompt treatment. For these reasons, special focus is directed towards improving conventional approaches by implementing complementary therapies, delivering drugs through carrier systems instead of systemic administration, and designing multifunctional scaffolds for repairing bone defects resulting from bone malignancies or tumor resection. Nonetheless, some of the presented therapeutic strategies have not reached the stage of clinical trials, requiring further investigations before moving to humans. Hence, more detailed studies are to be expected in the near future before the clinical implementation of innovative chemotherapeutic-loaded nanosystems. Moreover, novel pharmacological formulations can be more efficiently tested by assessing improved 3D cellular models , maintained in controllable microenvironments, and functioning as a whole organ. Other promising directions may emerge from research on bone turnover markers, predictive biomarkers, multimodality imaging, and co-delivery of multiple theragnostic agents.To conclude, the recent advancements in the therapeutic strategies against bone tumors are encouraging, paving the way for the standardization of new treatments. Through the interdisciplinary approach of medicine, material science, and nanotechnology, bone metastases and sarcomas can be successfully fought against."}
+{"text": "This study examined whether long-term care service use (LTCSU) is associated with informal caregivers\u2019 burden, depression, and health status. Eligible articles collected data directly from caregivers, written in English, and allowed for extraction or computation of effect sizes. MEDLINE, PsycINFO and ProQuest Dissertations & Theses Global databases were searched between September 2017 and January 2018. The risk of bias of individual studies was assessed regarding confounding, study power, and other biases. This unfunded study was registered with PROSPERO: CRD42018108827. Of the 419, 209 and 346 articles identified, 24, 14 and 15 articles that involved 12,530, 6,687 and 7,331 informal caregivers respectively, were eligible for analyses regarding the above associations. With unadjusted effect sizes, omnibus tests found statistically non-significant overall effect estimates in the association of LTCSU with caregiver burden, depression, and health status. Subgroup analyses, however, revealed that the above associations differed by service type, caregiver sex, and country, respectively."}
+{"text": "High-throughput experiments enable researchers to explore complex multifactorialdiseases through large-scale analysis of omics data. Challenges for suchhigh-dimensional data sets include storage, analyses, and sharing. Recentinnovations in computational technologies and approaches, especially in cloudcomputing, offer a promising, low-cost, and highly flexible solution in thebioinformatics domain. Cloud computing is rapidly proving increasingly useful inmolecular modeling, omics data analytics , and for the integration, analysis, and interpretation ofphenotypic data. We review the adoption of advanced cloud-based and big datatechnologies for processing and analyzing omics data and provide insights intostate-of-the-art cloud bioinformatics applications. So as to cater advanced bio-data analytics, big data and cloud computingtechnologies need to be tightly integrated and applied in a uniform fashion. Cloudcomputing has been demonstrated to be reliably scalable for the analysis of genomicdata over single machines, as well as clusters and public cloud infrastructures. Thelimitations of current data workflows, geared toward high-throughput experimentsanalytics , include security, confidentiality, and limitedcloud management technologies. By using multi-omics data available on the cloud,users are able to apply advanced pipelines or workflows, which facilitate theirtransformation and analysis, reduce the upload and download time while takingadvantage of cost-effective computing resources. For example, the Cancer GenomeAtlas (TCGA) project, one of the largest and most complete cancer genomics data setsavailable, is now making its data available, via an Application ProgrammingInterface (API), on a number of public and private cloud repositories. These effortsprovide viable replacements for redundant and costly local infrastructure settingsand enable a secure, effective, and reproducible analysis of shared data sets andresults. Scalable, cloud-based platforms, such as the National Cancer Institute(NCI) Cloud Pilots program FireCloud, can then be developed that diminish the needfor ad hoc, in-house high-performance computing architectures and expensive datatransfer.4To mitigate data storage and analytical challenges surfaced by the development ofomics technologies, over the recent years, numerous novel big data innovations andscalable cloud-based solutions have been proposed and developed. Advanced big dataanalytics frameworks accelerate the storage and analysis of big omics data byfacilitating the provision of scalable analytic infrastructures, such as the HadoopDistributed File System (HDFS) for storage and the Spark Machine Learning libraries(MLlib) for analysis.Our literature review was carried out across 5 stages , namely,Within this review, we considered the concepts of multi-omics data integration,storage, and analysis frameworks within the context of publications related to theadaption of cloud computing and big data analytics within the molecular medicine andgenomics research areas .Our review is organized around 2 primary objectives.To review the main bioinformatics concepts, standards, terminologies, andparadigms related to biomedical big data integration, analysis, storage, andcloud computing.To provide an account of the main characteristics, advantages, disadvantages,and differences across multiple cloud-based tools. Bioinformatics researchers typically use multiple data from differentplatforms, such as genomics, proteomics, transcriptome, epigenomics,metabolomics, and imaging, in conjunction with clinical data derived acrossdifferent modalities, from structured to semi-structured and unstructured. As aresult, large-scale and complex data sets are increasingly being consideredresulting in several challenges. For example, existing next-generationsequencers produce over 100\u2009GB of raw sequence reads per genome. Together withvarious clinical and phenotypic features, these data can greatly improve ourknowledge of complex diseases but present storage and bioinformatic analysischallenges. Appropriate storage infrastructures capable of hosting suchbiomedical data can then be exploited to cater applications that exploit theirfeatures so as to formulate novel hypotheses related to disease prevention andtreatment. Undeniably, nevertheless, big biomedical data tools and technologiescurrently have a limited translational impact in clinical care. Biomedical bigdata offer the tantalizing possibility of aiding the identification of novel andkey molecules and disentangling their biological and physiological roles andfunctions. Moreover, their effective use can potentially aid clinical decisions,effective disease treatment, and so on, ultimately improving health care.The exponential growth of biomedical data sets over the recent years has resultedin the identification of a wealth of molecular signatures vital for therealization of the personalized diagnosis and treatment era.611 Various platforms areavailable to profile whole genomes using many samples, enabling a betterunderstanding of complex diseases, like cancer, and complex phenotypic traits.Some of the molecular experimental omics technologies are based onhigh-throughput mass spectrometry, microarray, RNA sequencing, and DNAsequencing. The analysis of the resulting large-scale data necessitates advancedbioinformatics software or pipelines. Typically, the analysis of omics datainvolves the imputation of raw data, noise elimination, and identification ofrelevant features. Other examples of computational pipelines revolve aroundcomparing DNA sequence fragments, or an entire chromosome, with a referencegenome to identify variations. Multi-omics data sets derived by the 4 major omics technologies, namely,genomics, transcriptomics, proteomics, and metabolomics, ultimately representin-depth characterizations of interactions between genes, proteins, andmetabolites. There is a need for integrating different omics data for asystematic, in-depth characterization and understanding of the biologicalprocesses, eg, those related to adverse outcomes and typical multi-omics studiespertain to the integration of different omics types in an effort to gain abetter understanding of the overall complex underlying biologicalmechanisms. parallel processing techniques, such as Hadoop MapReduce, and data miningtools. Several large data applications, such as the Apache Hadoop softwarelibrary, are used in biomedical research to overcome scalability, accuracy, andcomputational complexity issues. Cloud computing helps data scientists by providing access to computingframeworks, such as the Microsoft Windows Azure platform (https://azure.microsoft.com/en-in/), and to cloud services thatcan be used to develop particular tools or applications. Adopting andefficiently implementing public cloud repositories to store genomic and patienthealth information involves critical privacy and security issues. The majorityof such public cloud repositories are the result of community-based effortstypically suffering from data curation quality, privacy, and security issues andpresent complexity and sustainability challenges.Implementing a large-scale data environment to analyze large-scale genomics datain health care necessitates the effective combination and application of varioustechnologies, such as artificial intelligence, At present, sequence alignment and mapping of high-throughput sequencingdata sets remains time-consuming. The numerous de novo assemblers that have beendeveloped, some of which based on message passing interface (MPI) , exhibit limited scalability, accuracy, and computational efficiency. Inaddition, DNA analysis pipelines designed to address scalability, such as Halvade, are characterized by several limitations, including accuracy, andcomputational efficiency. Similar limitations are aberrant within thesingle-cell RNA sequencing domain.Typically, multi-omics frameworks rely on traditional statistical techniques fordata retrieval, integration, and analysis. Such traditional approaches sufferfrom scalability, time, computational efficiency, and accuracy limitations. As a result, data scientists commonly use big data analytics tools, suchas Hadoop to store data, MapReduce for data analysis, and use tools such as Pig(https://pig.apache.org/) and Hive (https://hive.apache.org/)for data retrieval. Such tools are frequently used in conjunction with severalopen-source tools, eg, R, Python, and scalable machine learning tools, andcommercially available tools, eg, MS SQL, Tableau, and Oracle Rdb.The advantages of parallel computation frameworks include high availability andparallel processing, with data being processed by multiple machines,significantly reducing processing times. By bringing computation to data , the cost of moving processing units to data resources is removed, andprocessing times are reduced because all cluster nodes can work in parallel andsimultaneously. Large data frameworks, encompassing parallel processing andin-memory processing, achieve higher memory efficiency.Supplementary Table S1 for more recent examples of omics datasources).There are numerous publicly available data sources that cater the storage,indexing, and provision of omics data sets, offering a variety of analysis andvisualization tools. For example, in 2005, the Cancer Genome Atlas (TCGA) and2008 International Cancer Genome Consortium (ICGC) projects releasedcomprehensive cancer genomics profiles using new analysis technologies and madethem freely available within a number of repositories (see  The cloud computing model is composed of 5 key features: (1) resourcepooling, (2) on-demand service, (3) broad network access, (4) rapid elasticity,and (5) measured services. In addition, cloud computing also comprised 3 servicemodels, namely, Software as a Service (SaaS), Platform as a Service (PaaS), andInfrastructure as a Service (IaaS), plus 4 deployment models: private, public,hybrid, and community clouds. The main essential characteristics of Cloudcomputing are scalability, redundancy, reliability of hardware,cost-effectiveness, robustness, flexibility for data, and applications. Within the bioinformatics domain, cloud-based services adopt the abovecategorization and are typically grouped as Data as a Service (DaaS), SaaS,PaaS, and IaaS  characterizes cloudcomputing as a model for enabling ubiquitous, convenient, on-demand networkaccess to a shared pool of configurable computing resources  that can be rapidly provisionedand released with minimal management, effort, or service provider interaction.nd IaaS . compared big genomics data with other sources of big data generation,such as business, social network, and the Internet of things and found thatgenomics data will become much more extensive concerning creation, storing,processing, analyzing, and transmitting by 2025. Biological data acquisitionis distributed and heterogeneous, which reaches 1 zetta-bases. Biologicaldata distribution extends from a few base comparisons, or many smalltransfers of gene sequences (10\u2009MB/s), to fewer large multiples of terabyte(10\u2009TB/s) bulk transfer/downloads from central repositories. Due to itsability to overcome access limitations, DaaS is the most importantbiological study service that provision big data. For example, Amazon WebService (AWS) is a cloud-based application that provides data as a service,which gives dynamic access to public data sets to users on demand. AWSincludes publicly available data sets from multiple sources, including largebiological resources, such as Ensembl and GenBank.Data as a Service is a cloud strategy used to provide and distributeon-demand access to biological data over a network for analysis andknowledge discovery. The objective of DaaS is to overcome data accesslimitations the current state-of-the-art approaches face by enabling theuser to store and access data from any location for sharing and processing.Stephens et alhttps://www.ncitech.co.uk/business/cloud-computing/microsoft-office-365).Some examples for cloud-based SaaS solutions for genome resequencing includerainbow, short-read aligner CloudBurst, variant annotation VAT, and RNA-seq Myrna. These tools have several advantages and limitations  (http://clovr.org) and CloudBioLinux (http://cloudbiolinux.org/). These are portable virtualmachines for automated sequence analysis and provide on-demandhigh-performance environments.Infrastructure as a Service is a cloud paradigm that facilitates virtualinfrastructure, such as computing, storage, and networking, over theInternet. IaaS now provides databases, messaging queues, and other serviceson top of the virtualization layer. Examples of IaaS are the MicrosoftAzure, the Amazon cloud, the Google computing engine, and theJoyent.https://www.dnanexus.com/).DNAnexus  provides an API-basedplatform for sharing and managing genomic data and tools to accelerategenomic research benefiting from transparency and reproducibility.DNAnexus has scaled to over 56\u2009000 concurrent computing cores, numerouspetabytes of storage, and tens of millions of core hours of analysisusing Amazon Web Services. Users can upload raw DNA data straight fromsequencing machines to the cloud using both a graphical user interface(GUI) and a command-line tool, avoiding the need for costly, on-premise,processing and storage infrastructures .Terra is a cloud-native platform that allows biomedical researchers tointeract, access data, and execute analysis tools with security beingprominent. It provides a scalable architecture connecting cloud datarepositories and enabling researchers to conduct integrative analysisover big data sets in a reproducible manner. Researchers are alsoprovided can with the option of federating various data sets and performintegrative studies (https://sapac.illumina.com/products/by-type/informatics-products/basespace-sequence-hub.html).Illumina has the flexibility to accommodate its users\u2019 need for on-demandresearch by operating BaseSpace Sequence Hub on AWS. Illumina offers tospin up 2000 instances in just a few hours using AWS, eliminating theneed to load a data center with hardware. Workloads can be executed inparallel, without incurring a substantial initial cost. Users can set upruns and assess the quality of instrument runs and computationalresources without having to invest through infrastructure. In addition,ease of accessibility to a multitude of genomic analysis software boostsorganizational efficiency  is the most widely used library for developing GPU-basedtools in bioinformatics, systems biology, and computational biology.Although CUDA can only be deployed over Nvidia GPUs, there are otheroptions, including Microsoft DirectCompute catering its use inconjunction with Microsoft\u2019s Windows operating system as well asdeployment over the platform-independent library OpenCL (which can useAMD/ATI GPUs).https://databricks.com/product/genomics).The Databricks Genomics Platform offers preconfigured GATK processes,hosted on AWS and Azure, to enable quicker genomic data preparation andprocessing. Data can be processed 15 times faster when workflows areoptimized to operate in parallel and prepackaged genomic analytics, andmachine learning frameworks can be used for it interactive evaluation.With autoscaling on AWS and Azure, users can analyze hundreds ofthousands of genomes while lowering expenses. Connect processed geneticdata to downstream analytics in real time for faster outcomes (https://aws.amazon.com/government-education/cromwell-on-aws/).Cromwell is an AWS Cloud\u2013based workflow execution engine developed byBroad Institute. It renders orchestrating computational operations forgenomics analysis much easier, offering considerably more flexibility inscaling genomics research by leveraging cloud computing capabilitiesrather than competing for limited on-premise resources. Based on thevolume and particular resource requirements of the batch jobs submitted,AWS Batch, a fully managed batch computing solution on Amazon WebServices, automatically provisioned the optimal quantity and kind ofcompute resources ,and the Seven Bridge Platform are part of the National CancerInstitute\u2019s Cancer Research Data Commons. Data access via a Web-baseduser interface is available in all 3 NCI cloud resources and providesaccess to analytic tools and workflows via a programmatic interface andthe opportunity to share results with collaborators. Each Cloud Resourceconstantly adds new features to improve the user experience and provideresearchers with new tools. Each Cloud Resource has built itsinfrastructure, along with a variety of tools for accessing, exploring,and analyzing molecular data. Other data types, like medical imaging andproteomic data, Radiologic and pathology images, are accessible throughall 3 NCI Cloud Resources. NCI FireCloud runs on the Google CloudPlatform (GCP). Data uploading, cloning, and creating a new TCGA workspace.Bioinformatics experimental data continue to increase due to technological growthand reduced cost of the experiments with current resources extending fromterabytes to petabytes. The efficient computational analysis of such enormousdata sets requires approaches that facilitate their volume reduction. One suchan approach lies with the implementation of stringent quality control usingpost-experimental processing. These implementations, however, require scalableand robust computing solutions, such as the one offered by cloud computing.https://hadoop.apache.org/), are now integrated with cloudcomputing to improve system speed, agility, and time to maintain hardware andsoftware resources. The implementation of SaaS, PaaS and IaaS services allowscloud computing approaches to provide dynamic scalable resources that caterdifferent hosting and analysis workloads as virtualization services that operateacross different levels of stacks.Many big data frameworks, eg, Apache Hadoop , and limitsredundancy by the abstraction of individual applications, eg, VMwareThinApp. Virtualization can also be achieved by combining scalable andelastic solutions hosting multiple Virtual Machines (VMs) on a singlemachine. VMs allow operating systems (OSs) and other applications to runacross multiple VMs installed on a single machine. A hypervisor is avirtualization management layer that controls resource allocation. Dynamic, on-demand resource management helps reduceboth the cost and the time required to build and maintain complexcomputational infrastructure for multi-omics data analysis and storage. Singularity, on the contrary, is a computing framework for providingcomputational mobility to users and HPC facilities, allowing for the secureacquisition and distribution of software and computing environments. Itallows users to execute environments from a range of resources (includingDocker) without requiring privileged access. By combining Singularity andDocker, the user may be highly flexible in how, when, and where to use theirown and others\u2019 computing environments.Containerization is referred to as lightweight virtualization and allowsbioinformatics workflows to accelerate portability and reproducibility andensure scalability. Container technologies, such as Docker and Singularity,are a component of cloud computing frameworks, with Kubernetes being used tomanage container orchestration. Docker is the most extensively usedframework allowing users to create, store, and manage Linux-basedenvironments deployed on almost any computer.By containerizing applications, the reproducibility and portability areensured, allowing for sophisticated workflow management solutions, such asNextflow, to accelerate the generation of portable and scalablepipeline. that facilitate a number of tasks, frequently necessitatingconcurrent execution of processes, such as quality control, alignment, andgenomic features extraction. Such features render them ideal to addresscomputational challenges, eg, complexity, and implementation requirements,such as multimode scalability and typical genomic data processing, pipelinesface. Moreover, faster heuristic solutions are increasingly becomingavailable, such as the ones developed for search and sequence alignment. Forexample, GenBank uses a cloud-based tool, termed BLAST , to query sequences and reduce the time complexity while decreasing the sensitivity ofthe resulting alignment.Cloud computing systems are reliable, scalable, and cost-effectiveinformation technology (IT) platforms that are increasingly being adoptedfor large-scale bioinformatics analysis. They typically use distributedresource management solutions, such as the SunGrid Engine (SGE) and LoadSharing Facility (LSF),69Cloud computing offers a variety of both CPU and Graphics Processing Unit(GPU) acceleration frameworks for enhanced performance. GPU-based cloudcomputing is a promising biological data analysis approach as theperformance to price (P/P) ratio is more favorable for GPU than for CPU. GPUreduces the cost of hardware and accelerates data processing by usingparallel processing over several GPU cores. However, GPU-based cloudapplications suffer from the slow data exchange between GPU and CPU due toslow input-output (I/O) operations and the relatively small GPU memorylimiting input data storage .68,69Recent technological advances have led to the generation of large biomedical datasets of various datatypes generated from different platforms, necessitatinginteroperable integration frameworks for their analysis. The adoption and use ofcloud computing are a promising and viable solution to overcome these challenges dueto its virtualization, advanced analytics, storage optimization, and scalabilityproperties. Furthermore, cloud computing facilitates simultaneous multivariableprocessing, and the development of efficient methods to reduce computational timeand memory utilization will be a crucial step-change to systems biologyresearch.Collecting, integrating, and systematically analyzing heterogeneous big data withdistinct characteristics are a challenging task that may lead to datamismanagement, raising issues, including privacy, security, and related ethicalones. Big data analytics frameworks are useful in performing a series of tasksin a distributed manner, reducing the hardware workload to overcome scalabilitychallenges, specifically supporting simultaneous high-performance genomics dataprocessing, achieving scalability and reliability, and addressing redundancyissues related to large genomics data processing. Big data frameworks helpovercome fault tolerance by replicating data in a distributed mannersidestepping software or hardware failures due to unreliable data replications.Distributed data processing frameworks additional advantages include highavailability and distributed data replication for complex systems. Parallelprocessing, whereby multiple machines simultaneously process data, reducesprocessing time and presents another advantage of distributed data processingframeworks. Data locality reduces costs and single nodes\u2019 burden. Furthermore,parallel and in-memory processing ensures higher memory efficiency. Authentication, authorization, and access control within the cloud\u2019svirtualized network are essential and several data security concerns, includingdata leakage and loss issues related ones, still need to be addressed. Some other significant challenges to cloud-based omics relate toinfrastructure requirements for systematic analysis and advanced queryframeworks of big data sets, which are particularly applicable to large-scale,integrated, heterogeneous bioinformatics data sets that are increasinglybecoming available. Different omics repositories need to be incorporated to provide reliableand practical solutions, and standardized approaches are needed to eliminatetheir inherent variability. Cloud applications are required to perform tasksalongside distributed data, necessitating interoperability and portability whichpresent a further challenge. Other challenges include the lack of homogeneity,including qualitative and quantitative variables measured at different scales,to characterize a phenotype or trait.Although cloud computing offers considerable advantages, there are somechallenges and limitations. Some of the challenges are related to data privacyand security and can be considered the biggest threat to cloud computing in thehealth care data analytics domain.Crucially, while cloud computing is inexpensive, the platform adaption to meetthe demands of the users can be costly. In addition, the cost of transferringdata to public clouds can be expensive. Cloud computing downtime, which istypically listed alongside system failure, human error, network failures, a lackof resources, and the provision of multicloud environment management andmulticloud strategies for building hybrid clouds that combine public and privatecloud resources, is critical. Finally, law and regulation compliance, inparticular for health-related data sets, is crucial.https://aws.amazon.com/emr/), are increasingly beingadopted.Nevertheless, cloud computing allows cost-effective distributed storage andanalysis of such large data sets, and it operates on self-deployment models withpay-per-use, on-demand, scalability, and elasticity features. Big dataapproaches exploit previously ignored data sets, providing valuable insightsgained by their ability to exploit data sets that traditional methods cannotinterrogate. Cloud computing enables software versatility and speed tostreamline such tasks. Big data approaches typically adopt a strategy ofsplitting large data sets into manageable chunks and distributing them acrossthe various computer systems, helping to parallelize computation over large datasets. Cloud computing allows for storage and analysis on remote physical serversmanaged and operated by service providers, accessed by the user through thenetwork. So as to deal with performance and scalability for big genomic data,parallel programming models in a distributed environment, such as MapReduce(Sequencing technologies continue to decrease costs while the amount of dataproduced increases. New data processing and storage platforms are becoming moreand more essential, and the scaling behavior of these emerging technologiesdirectly impacts biomedical research. It is challenging for data scientists todesign and develop practical algorithms in working applications for secureoutsourcing of encrypted biomedical data. Moreover, developing standardapproaches to enable secure coordination of data integration across multiplesources can be very demanding. The establishment of secure computationframeworks can ensure the efficient analysis of such data sets. Cloud computingpractice could solve the big data analysis problem of efficiency in time, memoryusage, and storage, albeit it is still at quite an early stage in itsdevelopment and its subsequent adoption in real-world applications andenvironments.We reviewed big data technologies within the context of biomedical research andthe adoption of cloud-based architecture by processes geared for big omics dataanalytics. The advent of cloud technologies capable of handling big data offersthe opportunity for efficient, scalable, and secure biomedical data analysis.While reviewing the current omics data processing and analysis landscape, wenoted significant challenges related to the need to perform systematic scalablelarge-scale multi-omics integrative analytics encompassing data handling andstorage demands. Currently, the available cloud infrastructures face significantchallenges related to providing the necessary resources to handle the rapidlyincreasing, heterogeneous, and large-scale omics data. These challenges directlyaffect our ability to harness available resources to understand diseasepathobiology and pathophysiology better, ultimately identifying multifactorialgenetic disease\u2013related biomarkers for advanced personalized and targeted healthcare solutions. Undeniably, therefore, there is a need to develop novelstandardized approaches that will cater efficient multimodal multi-omicsintegrative analytics that are exploiting cloud computing infrastructures thatare increasingly edging us closer to the tantalizing potential of a sustainable,secure, scalable, and cost-effective technology that can address thischallenge.Click here for additional data file.Supplemental material, sj-pdf-1-bbi-10.1177_11779322211035921 for Cloud ComputingEnabled Big Multi-Omics Data Analytics by Saraswati Koppad, Annappa B, GeorgiosV Gkoutos and Animesh Acharjee in Bioinformatics and Biology Insights"}
+{"text": "Following the publication of this article , the corIn light of the data ownership issues, the PLOS ONE Editors retract the article.CJW, YQL, LLL, LW, AGY, YRG, and WJL agreed with the retraction. JZZ either did not respond directly or could not be reached."}
+{"text": "Calciphylaxis is a rare but very serious disease associated with high morbidity andmortality. It most commonly affects patients undergoing dialysis, but it may occur inindividuals with chronic kidney disease (CKD) under conservative treatment, transplantrecipients, and even in those without kidney disease (Evidence).2. Its pathophysiology is not completely known. However, histological findings showcalcification of arterioles, besides thrombosis and endothelial damage of these vessels.These changes cause ischemia and necrosis of the subcutaneous tissue, with necroticulcers appearing in more advanced stages (Evidence).3. The diagnosis of calciphylaxis is clinical. Calciphylaxis should be suspected in CKDpatients presenting with nodular, purpuric/erythematous lesions or painful subcutaneousplaques, livedo reticularis, non-healing ulcers and/or skin necrosis, especially on thethighs and other areas of increased adiposity (Evidence). mellitus, warfarin use, obesity, hypoalbuminemia, and alterationsin mineral metabolism  (Evidence).4. Risk factors associated with the onset of calciphylaxis are: female gender, diabetes5. Skin biopsy should be performed in those patients with atypical lesions  or in those patients without CKD who have classiccalciphylaxis lesions (Evidence).5.1 The skin sample should be collected by puncture, with 4 to 5 mm in diameter,preferably at the periphery of the lesion, avoiding necrotic areas. 5.2 Biopsy is contraindicated if there is underlying infection (Evidence).6. Treatment is based on risk factor control , effective pain control, treatment of secondary infection (Evidence). 7. Specific treatment of calciphylaxis should be performed with sodium thiosulfate,bisphosphonates, or hyperbaric oxygen therapy (Opinion).Calciphylaxis is a rare, life-threatening syndrome characterized by occlusion ofmicrovessels in the subcutaneous adipose tissue and dermis, in addition to othertissues, resulting in extremely painful ischemic lesions,Calciphylaxis is associated with the use of vitamin K inhibitorssine qua non conditionfor the onset of calciphylaxis. The presence of alterations in mineral metabolism, as hypercalcemia,hyperphosphatemia and PTH extremes is another risk factor. These changes mightpromote the appearance of all forms of vascular calcification (VC): of the intimalayer of the arteries (atherosclerosis), of the media layer , valve calcification and calciphylaxis. VC isnot only a passive process of mineral deposition, but rather an active one. Vascularsmooth muscle cells, depending on various stimuli, modify their phenotype andexpress factors such as RUNX2, which is a key transcription factor for osteoblastdifferentiation. Once transdifferentiated, the smooth muscle cells produce matrixvesicles containing calcium and phosphorus, which will promote vesselmineralization, or calcificationObesity is also acknowledged as a risk factor, suggesting the contribution ofadipocytes in the processinvitro. A recent study using patients from the German Registry ofCalciphylaxis has assessed the genetic profile of patients with and withoutcalciphylaxis and has demonstrated that, in addition to the CD73 gene, others, suchas the vitamin D receptor and FGF-23, were associated with this complicationThe deficiency of CD73, also referred to as NT5E , leadsto a syndrome in which the phenotype resembles calciphylaxis. This moleculeregulates the proliferation, migration and invasion of cancer cells Other risk factors associated with calciphylaxis are: presence of CKD ,female gender , diabetes mellitus , hereditary thrombophilia, protein Cdeficiency, lupus anticoagulant, autoimmune diseases, repeated subcutaneousinjections, accelerated weight loss, and use of other drugs, such as intravenousiron and recombinant PTHpyoderma gangrenosum, vasculitis, andcryoglobulinemiaThe main differential diagnoses with chalciphylaxis are: cholesterol embolism,warfarin- or heparin-induced skin necrosis, antiphospholipid syndrome, nephrogenicsystemic fibrosis, The diagnosis of calciphylaxis is clinicalStaphylococcusaureus, and streptococciThe treatment of calciphylaxis is multidisciplinary, involving a specialized woundcare team, dermatologists, plastic surgeons, pain management specialists, amongothers. Nevertheless, the first item is pain control. The use of opioids may benecessary, associated with gabapentin, ketamine, as well as, spinal anesthesia, ifunresponsive. As for surgical debridement, the main goals would be to removenecrotic tissue and avoid secondary infection. However, wounds are difficult to healdue to the ischemic bed of the lesions and pain during manipulation. Ulcers withsigns of infection should be treated with broad-spectrum antibiotics with coveragefor oxacillin-resistant, gram-negative, anaerobic The main drugs used in the treatment of chalciphylaxis are:,- Sodium thiosulfate: antioxidant agent, vasodilator, which might inhibit the abilityof adipocytes to induce vascular calcification. The recommended dose is 25 g,diluted in 100 mL of saline/glucose three times a week, in the last 30 to 60 minutesof hemodialysis, for approximately up to three months after healing of the lesions.The main side effects are fluid overload, hypocalcemia, prolonged QT interval,hypotension, and metabolic acidosis. However, these effects are irrelevant whenadministered during the last hour of dialysis. Doses for patients under conservativetreatment, peritoneal dialysis, and for children are not standardized,- Bisphosphonates: these drugs would act by modulating the effects of alkalinephosphatase on vascular smooth muscle cells, inhibiting phosphorus transport andthus decreasing the formation of calcium phosphate crystals, besides theanti-inflammatory effects, involving macrophages, tumor necrosis factor,interleukins and other cytokines. There is no consensus on the standardized dose.One suggestion is the use of sodium pamidronate at a dose of 1 mg/kg diluted inglucose serum with a 2-hour infusion time. The dose should be repeated after 30days- Hyperbaric oxygen therapy: it is a complement justified by greater oxygen supply todamaged tissue. The exact mechanism of wound healing promoted by oxygen therapy isnot fully understood. Oxygen therapy apparently improves fibroblast function,angiogenesis and neutrophil bactericidal activity, attenuating local infectionFinally, as general measures, we recommend:1. Optimizing the dialysis dose, especially in the presence of persistenthyperphosphatemia2. Avoiding positive calcium balance .3. Recommending parathyroidectomy in patients with secondary hyperparathyroidism andcalciphylaxis.4. Avoiding PTH levels persistently below 100 pg/mL. In this condition, the decreasein bone turnover will also decrease the buffering capacity of the skeleton, favoringthe onset of hypercalcemia and/or hyperphosphatemia."}
+{"text": "Before developing agriculture, herding or metallurgy, humans occupied most of the world. Multiple socioculturally-based responses supported their migration, including building shelters and constructing niches to limit environmental stressors. Sheltered settings provided social support and security during stressful times, along with opportunities for injured, aging, and frail members to survive. Modern built environments are designed for similar purposes, to support human growth, development, reproduction, and maintenance. However, extended survival in modern settings has costs. With age, muscle (sarcopenia) and bone loss , along with somatic, physiological, and sensory dysfunction, reduce our physical capabilities, increase our frailty, and impede our abilities to interface with built and natural environments and manufactured artifacts. Thereby, increasing our dependence on built environments to maintain autonomy and quality of life.What follows is a conceptual review of how frailty may limit seniors within modern built environments. It suggests age-related frailty among seniors provides specific data for those designing environments for accessibility to all users. It is based in human ecological theory, and physiological and gerontological research showing senescent alterations, including losses of muscle, bone, and sensory perceptions, produce a frail phenotype with increasing age limiting our mobility, activity, use of space, and physical abilities. As an individual phenotype, frailty leads to age-related physical and performance declines. As a physiological assessment, frailty indices amalgamate individual measures of functional abilities into a single score. Such frailty indices increase with age and differ betwixt individuals and across groups. To design built environments that improve access, usability, and safety for aging and frail citizens, today\u2019s seniors provide living samples and evidence for determining their future abilities, limitations, and design needs. Designing built environments to accommodate and improve the quality of human-environment interactions for frail seniors will improve usability and accessibility for most user groups. Human habitation of Earth\u2019s many environments prior to developing agriculture or metallurgy depended on sociocultural and biocultural systems organized to build livable microenvironments wherever they roamed , 2. AlonThis shared adaptive suite in conjunction with humankind\u2019s physiological adaptability produced an array of modern regionally successful phenotypes, inhabiting multiple environments, all maintaining sufficient physiological capacity to survive 75+ years Table\u00a0 1, 2, 66, 7. HigLong-term evolutionary trends pattern senescent related somatic, physiological, and functional declines. The pace of declines varies between individuals and groups due to genomic attributes, environmental settings, sociocultural conditions, physiological resilience, and individual experiences \u201310. MultAcross built environments of the 20th - twenty-first century, increased survival Table\u00a0 reflectsBased on human ecological theory and research across physiological anthropology indicating environments become more influential on human function and physical abilities with age, this conceptual review explores age-related declines in human abilities and increasing frailty , 20\u201322. Although paced differently across individuals, everyone\u2019s cognitive and physical abilities, physiological function, resilience, and strength decline with age. Similarly, all who achieve late life eventually experience frailty, leaving them dependent on residential and environmental settings for accommodating their limitations. Given all seniors experience unique socioenvironmental stressors over their lives, sources of age-related variation are complex. However, in aggregate late-life somatic declines and frailty are predictable, patterned, and trackable. Understanding this late-life frailty potentially aids in developing built environments to better accommodate not only frail seniors but all who require such. This requires empirical and observational data on how seniors\u2019 capabilities change, and frailty increases with age. Attention to functional and physiological changes and increasing frailty of seniors during late life while designing and redesigning residential settings is likely to aid in supporting their mobility, activity level, health, and QOL, while also possibly limiting additional frailty , 23\u201325.Major demographic changes shaping populations over the twentieth century and into the 21st were declining birth rates and increasing survival rates. Improved survival led to worldwide increases in septuagenarians, octogenarians, and nonagenarians and 50% survival to 85\u2009years in some populations (Table\u00a0Following reproductive adulthood ~\u200955\u2009years), mortality increases exponentially as lifelong stressor exposures, deteriorating molecular, physiological, and cognitive processes differentially affect individuals . Current5\u2009years, Following reproductive maturation, humans generally maintain their maximum capacities through an adult period of reproductive effort, approximately ages 20\u201350\u2009years , 30, 31.As we age, our phenotypes differ significantly from earlier optima , 31, 35., and latter decades. To design spaces capable of accommodating frail seniors while fitting their ergonomic needs requires population-specific data on variability in quantitative and qualitative phenotypes as these change through late-life  and physiological biomarkers  vary with age. More extreme phenotypes  tend to experience earlier mortality. Those closer to their cohort averages, tend to survive into later decades. Consistent associations of such biomarkers, along with other neurological, physiological, somatic, and immunological assessments of dysfunction with mortality support use of biomarker composites as estimates of individual health, frailty, disease, and death \u201348. SuchAnthropometric assessments originally were developed to monitor child growth and development and led to standardized growth charts . Later, Osteoporosis (loss of bone matrix) is a universal of human aging . As boneDysregulated bone physiology has somawide detrimental effects. Altered skeletal biology may limit hematopoietic cell output, alter immune function, or reduce systemic oxygen-carrying capacity, compromising overall health and increasing frailty. Consequent to differences in physical activity, nutrition, trauma, and senescent biology, bone loss and skeletal dysfunction occur at variable rates and ages, but ultimately affects all. United States Medicare beneficiaries illustrate the ubiquity of age-related bone loss. In 1999\u20132005, of recipients aged 65+ years, 25% reported osteoporosis; among those receiving benefits 6\u20137\u2009years, 42% of women had osteoporosis, 10% of men did , suggestAt all ages, appropriate skeletal function and biomechanical stability promote mobility, sociality, physical activity, health, and survival. Skeletal and muscle cells are integral to systemic biology, participating in blood cell production, immune competency, calcium and potassium balance, and mineral storage. As we age, bone microfractures are less fully repaired, leaving bones weaker; collagen glycation contributes to brittle, hard, and less elastic cartilage and compressed intervertebral disks, further limiting activity. Concurrently, cartilage on articular surfaces hardens, becoming brittle and compressed, while damage from wear and tear, accidents, injuries, and fractures accumulate. With cellular senescence aggravating this cycle, integrated systems supporting mobility deteriorate and functional losses lead to low physical activity and greater frailty.In addition to musculoskeletal changes leading to sitting height reductions with age, secular trends in stature contribute to older cohorts being shorter and lighter than their younger counterparts and themselves during middle-age Tables\u00a0 and 4. IMuscle loss is directly and independently associated with chronic disease and shorter life spans . With inAcross populations anthropometric dimensions of seniors differ from younger adults, indicating less robust physiques Tables\u00a0 and 4 2, 66. WitA major goal of aggregate senior housing designs is providing support for residents\u2019 continuing function, independence, physical activity, and mobility, while enhancing their abilities and accommodating their limitations. For example, walking gaits and mobility aids used by many frail seniors are less compatible with some indoor walking surfaces  and outdoor , than they are with some natural surfaces  or even concrete. However, tile, concrete, and asphalt are compatible with the wheeled carts, chairs, equipment, and sanitation needs common to congregate residential settings. When wet, these increase risks for falls, muscle, and skeletal damage, particularly among mobility impaired residents.Over recent decades, newly designed and renovated residential senior housing projects have moved toward more accommodating designs. Many have replaced steps with ramps where possible, installed wider elevators, doorways, and hallways, and/or improved resident access to interior and exterior environments. Incorporating access to outdoor areas, gardens, interior/exterior courtyards, internal and exterior walking, wandering, and rolling pathways also supports resident mobility and physical activity, while enhancing their sociality, well-being, and health, and possibly limiting additional frailty . Still, Physical abilities likely directly influence seniors\u2019 housing choices. Both quantitatively (accelerometer) and qualitatively (self-reports), at ages 60+ years seniors in private homes engage in and report greater physical activity than those in congregate settings . In geneBeyond somatic and physiological limitations, with age our neurological innervation and signal processing speed and capacity decline, reducing sensory acuity , 70, 71.Even without obvious pathology, visual acuity declines with age . SecondaLighting, along with furnishings and color, set the mood for a space, influencing perceptions, emotions, and behavior even in identical spaces \u201374. By aMany natural and artificial lighting options are available to fulfill interior and exterior illumination needs for safety, mobility, and activities whether in congregate or private housing. For task-specific spaces: e.g., completing activities of daily living (ADLs) and instrumental activities of daily living (IADLs), bathing, self-care, food preparation/consumption, entertainment, physical activity, and sleep; multiple possibilities are available. Importantly, within congregate communities, lighting type identifies specific locations, pathways to them, stairwells, and elevators. Variable lighting also demarks personal, community, interior, and exterior areas. As individuals vary in their perceptions of comfort, brightness (lumens) and color (light appearance) of lighting within spaces should be adjustable to user preferences for that settings. Determining appropriate illumination depends on knowing intended purpose of the space, types of activities, expected occupants, and proposed furnishings. For senior residences, one suggestion is general lighting within the community be high lumen (1600+) with a relatively cool color temperature (3000\u20134000) . This shBefore designing lighting and illumination patterns for new or existing residential communities, participation observation, including interviews with and reports from current residents, staff, visitors, and administrators of existing communities, is necessary to determine specific lighting goals and appropriate designs to achieve them. An important final design step is post-occupancy follow-up with residents and stakeholders to determine how designs fit needs, thereby contributing to a growing database on accommodating lighting and other design items to frail and hale seniors , 78.As does sight, auditory acuity fades with age, altering our perceptions and awareness of others, social cues, environmental risks, and stressors. Faded hearing also slows response time to alarms, announcements, and traffic and leads to loud voices, televisions, radios, and phones. With age, reduced sensitivity to audio frequencies, tinnitus, and other issues interferes with auditory comprehension, and hearing aids become common. Many existing homes and congregate residences were designed with less attention to accommodating late-life auditory impairments than today . ExterioAs taste buds and olfactory neurons decline in number, cease function, alter internally, senesce, or do not respond due to dysfunction elsewhere with age, acuity of taste (gustation) and smell (olfaction) decline. Of our five tastes , salty and sweet tend to decline most with age. Subsequent reduced taste sensitivity may predispose to overuse of salt and sugar as condiments, thereby contributing to risks for hypertension, diabetes, and other NCD. Taste bud losses and aroma-sensing neuron declines may reduce intakes of necessary dietary components, e.g., vitamins, proteins, carbohydrates, fiber, fats, increasing risks for malnutrition, undernutrition, and associated health problems. As such, altered taste and olfactory sensitivity may lead to reduced dietary breath and nutritional insufficiencies. Nutritionally complete diets are basic to good nutrition for all, but particularly seniors. Undernutrition and malnutrition increase seniors\u2019 risks for frailty, morbidity, and mortality .How prepared food appears, smells, tastes, and its mouthfeel (tactile perception) influence food choice and thereby dietary adequacy. Olfactory losses may alter aromas and tastes of foods. Other than proper ventilation and sanitation facilities, few design features are available to attenuate dietary issues related to food taste and aroma. Among those with visual problems, food may appear unnatural in color or texture, making it less appealing to eat and difficult to distinguish among different food types. Olfaction determines how food aromas are cognitively interpreted, and related cognitive losses may reduce or alter food intake, thereby influencing health. Besides limiting nutritional intakes, reduced olfactory sensitivity is a physiological risk, Rawson et al.  reportedTactile sensitivity (touch), kinesthetic perceptions, and sensitivity of skin to temperature fluctuations decline with age. Responsiveness of proprioceptors along with output from fibroblasts  and dermal cell numbers decline, while underlying skin layers atrophy, dermal layers shrink, thin, and become less pliable. Losses of subcutaneous fat and dermal tissues, cross-linking of collagen fibers, and decreased innervation reduce sensitivity to external temperature changes, while increasing response time to core temperature changes. During heat waves, poor response to overheating contributes to higher mortality among older and immature age groups than among reproductive age individuals  , InstrumAcross modern populations, a major contributor to frailty is sarcopenia. For example, grip strength assesses muscle atrophy/loss and documents increasing muscular frailty with age Table\u00a0 109, 11. Among ULimiting negative impacts of frailty on older adults provides a specific goal for designs of built environments to house them. Frail seniors provide the evidence-based framework necessary for designing built environments that enable and accommodate frail phenotypes of all ages. Spaces designed to limit frailty progression, encourage physical activity and social interactions, and improve users\u2019 abilities to complete daily activities will help limit frailty and benefit all user groups. Physical activity, exercise, walking, and strength training all help limit frailty and maintain mobility. Similarly, positive social interactions are associated with physical and mental health, fewer functional limitations, and lower frailty. Innovatively designed environments, interior furnishings, and appliances directly addressing frailty among seniors will encourage physical and social activity, improve access for while better accommodating frail seniors, and aid them in maintaining their abilities while slowing their frailty trajectory.Frailty limits our physical capabilities, thereby inhibiting abilities to access and use private and public environments, built spaces, and manufactured objects. Accommodating environments and products to specific-needs and user groups is a universal design (UD) principal. Others include accessibility, equitability, and flexibility in use; simple and intuitive to use items; perceptible information on proper use; high tolerance for user error; usable with low effort; and available in sizes and spaces appropriate for all users . WhetherOriginally, senior congregate residential housing was viewed as an extension of medical care, leading to designs reminiscent of hospitals, as health care for mental and physical ills were primary concerns. Viewed as healthcare sites, through the 1970s designs for senior housing communities reflected this medical model. Designs for maintaining and improving lost capabilities, while accommodating age-related declines and impairments were seldom emphasized. Research among seniors in congregate housing during the late twentieth century led to new views of senior congregate housing as living environments wherein design innovations accommodating long-lived and frail residents could improve their QOL, mental health, well-being, and life spans. As increasing frailty is an inevitable correlate of increasing age, accessible designs supporting seniors must keep pace. Within many previously built congregate settings, neither exterior nor interior designs, private or public areas, room arrangements, kitchens, bathrooms, lighting systems, nor furniture and furnishings directly addressed the reduced strength, heights, perceptual and sensory acuities that limit seniors\u2019 abilities to interact with their natural and built environments. Such limitations include, most reproductive-age adults being able to open a can of fruit, pressurized jar, or childproof medicine container and raise a 10\u2009kg weight over their heads with little effort, while many over age 75+ fail to accomplish these tasks. Those surviving eight-plus decades are members of a highly variable and unique group. Designing built environments to maintain and improve their limited mobility, physical capabilities, and frailty, while anticipating their increased frailty will best serve their and others\u2019 needs.Across populations, although taller people may tend to survive longer today , 64, mosA major theme within physiological anthropology is documenting how interacting biological, environmental, and sociocultural factors, shape lifelong human variation . DesigniMany design features, indoor and outdoor courtyards, gardens, and open spaces provide visual and auditory stimuli for, enhance moods of, and allow residents to exercise their physical and sensory abilities , 114. HoToday, common congregate care designs include multiple amenities, indoor walking spaces, bird aviaries, sunrooms, fishbowls, along with outdoor porches, courtyards, and walkways. Such additions allow persons with limited abilities or frailty access to outdoor spaces and exterior views, providing sensory stimulation, interactions with nature, and opportunities to exercise distance vision. Although, designing enabling environments for frail seniors is challenging , ecologiA seemingly endless array of furnishings, furniture, wallcoverings, textures, accessories, and lighting systems are available for built interiors. For seniors, the simple approach among these many options may be incorporating natural and traditional elements reflecting those they have known throughout their lives into their living spaces. Such additions address seniors\u2019 societal sensibilities and likely will enhance their subjective well-being. For example, Tsunetsugu and colleagues , 73 obseAs described earlier, during the late twentieth century, more homelike designs were incorporated into senior residential communities worldwide. Currently, trends toward decentralized, modular designs continue, with short hallways leading to clusters of individual rooms radiating off a central core and opening onto common activity areas, e.g., dining, recreation, courtyards, seating, with access to interior aviaries, exterior views, and patios , 115\u2013117Our ancestors of 30\u201340,000\u2009years ago were lucky to survive 40\u2009years . Today, With age, we all will develop frailer phenotypes. These hamper our abilities to interact with natural and built environments and make some design attributes in private and public spaces sources of limitation. Designing built spaces supportive of well-being, physical abilities, and accommodating of limitations among frail users provides opportunities for extending health spans among seniors. Frailty indices directly assess such individual capabilities and limitations. Documenting the range of frailty among seniors provides evidence to aid development of supportive designs for improving frail residents\u2019 experiences in senior housing. Designs that provide a common denominator for improving accessibility, inclusivity, and universal usability within built environments, including their furnishings, for all ages and ability levels.Frailty is a well-documented clinical, epidemiological, and gerontological model and measurable phenotype of age-related functional declines , 102. ItThis review addresses accessibility and accommodation for frail seniors in congregate residential settings. Most elders prefer to remain in private homes as they age while accommodating their increasing frailty and decreasing mobility by modifying their homes. For seniors, residing in homes apparently requires greater physical abilities, as such individuals tend to engage in more physical activity, while showing and self-reporting better health and well-being than those in congregate housing , 120. Wh"}
+{"text": "The Children\u2019s Hospital Association\u2019s Improving Pediatric Sepsis Outcomes (IPSO) collaborative is a multi-center quality improvement (QI) learning collaborative of 61 U.S. children\u2019s hospitals that seeks to improve sepsis outcomes through collaborative learning and reliable implementation of evidence-based interventions in pediatric emergency departments, intensive care units, general care units, and hematology/oncology units. Specifically, IPSO\u2019s goals are to decrease sepsis-attributable mortality and prevent hospital-onset sepsis among children.The following 10 abstracts represent a select group of projects undertaken by IPSO participating hospitals that were presented at one of three collaborative events in 2020 and 2021. IPSO\u2019s Research Workgroup reviewed all submitted abstracts and selected the top 10 for inclusion in this Supplement Without a standardized pathway, clinical decision support, and data infrastructure, a high degree of variability was observed between care teams. The objective was to utilize a data-driven approach to standardize the sepsis screening process and to hardwire the response of care teams, ultimately leading to timely recognition and treatment of sepsis, thereby reducing mortality.2Given the specialization of the patient population, observed practice variability within care teams, and the need for both tools at the point of care as well as data dissemination and feedback, multiple high-yield interventions were developed. To support the identification and treatment of patients at risk for sepsis, the team designed an electronic triggering system and electronic medical record-integrated tools. To drive ongoing improvement and sustainability, they built a new clinical dashboard to measure performance and outcomes, automated daily reports, facilitated staff meetings to share \u201cgood catches\u201d and \u201cnear misses\u201d associated with individual sepsis events, and targeted rounding and education within the clinical areas.Since the rolling go-live of the acute care sepsis pathway, the hospital has achieved and sustained a 0% sepsis-related mortality rate on acute care units Fig. .Accurate and timely feedback regarding process metrics and sepsis events yielded improved patient outcomes. Sustained reliability of the sepsis pathway with a resultant decrease in sepsis-related mortality was achieved. Daily distribution of automated compliance reports distributed locally and to leadership is critical for buy-in.Assistance with the study: Johanna Rosen, MD; Lauren Alessi, MD; Vikram Raghu, MD; Joseph Carcillo, MD; Vikram Raghu, MD; Zachary Aldewereld, MD; Ashley Kimble, MD; Daniel Loeb, MD; Kristina Gaietto, MD; Michael Freedman, MD; Allison Rometo, MD; Neema Shah, MD; Katharina Hayes, MD; James Bowen, MD; Jeffrey Rudolph, MD; Matthew Valente, MD; Priya Marathe, MD; Sylvia Choi, MD; Elizabeth Landsberg, MD; Elizabeth Ferguson, Pharm.D.; Kelli Crowley, Pharm.D.; Sheila Hahner, MSN; Kelly Bricker, BSN; Celia Pulver, BSISM; Stacey Cote, MSN; Ann Terzis, MSN; Amanda Petrill, MSN; Tonya Evangelista, MSN; Susan Wible, MSN; Jacqueline Kwasniewski, BSN; Scott Coglio; Derek Whitehurst; Michael Hennigan."}
+{"text": "Lysosomal storage disorders (LSDs) are a group of 60 rare inherited diseases characterized by a heterogeneous spectrum of clinical symptoms, ranging from severe intellectual disabilities, cardiac abnormalities, visceromegaly, and bone deformities to slowly progressive muscle weakness, respiratory insufficiency, eye defects , and skin alterations . PioneerAltogether, the articles of this Special Issue have broadened our concepts in the field of lysosomal storage disorders, offering a reference cue for the pathogenic aspects and evolving therapeutic approaches related to these rare diseases."}
+{"text": "Despite limited evidence on clinical efficacy and increasing resistance problems, topical antibiotics are still used in everyday clinical practice. However, topical antiseptic agents such, as octenidine and polyhexanide, often have a broader efficacy spectrum. They also have a broader target tropism because of their non-specific cellular mechanisms of action. Repeated use of topical antibiotics also carries the risk of contact sensitization, which could limit potential subsequent use as systemic antibiotics. Contact allergy is a clinically relevant problem, particularly in patients with barrier-damaged skin, pre-existing dermatosis, or occupational exposure. It can be concluded that with the use of modern antiseptics, topical antibiotic therapy is rarely indicated and should be avoided, not only because of the risk of contact sensitization but also because of the unfavorable and potentially consequential resistance problem.  Topical antibiotics (AB) are generally used for the treatment of superficial infections of the skin, eye, and ear . Their uThe prevalence of contact allergy (CA) is generally quite low but may be underdiagnosed. CA is a clinically relevant problem, especially in high-risk patients , 2. CS rCA, as a result of occupational exposure, is often triggered by antibiotics that are usually administered systemically, for example, via improper handling, such as repeated accidental skin contact when preparing antibiotic infusions to be administered systemically  without protective gloves . A transAmong topical ABs, aminoglycosides, such as neomycin, gentamycin, and framycetin, appear to have the highest risk of CS ; other tPseudomonas aeruginosa and anaerobic bacteria) and Gram-positive bacteria, particularly Staphylococcus aureus, neomycin is widely prescribed for the treatment of superficial skin infections . Retapamulin is a semi-synthetic derivative of pleuromutilin with activity against staphylococci and streptococci. It is approved in Europe as a 1% topical preparation for the treatment of impetigo and minor infected wounds . CA to rAfter CA has healed, epicutaneous patch testing is the most important tool for further allergological clarification . CurrentAfter diagnosis, the patient must be informed about the substances to be avoided. This also includes information about possible immunological cross-reactions. Repeated or long-term use of topical antibiotics and an existing skin barrier defect are risk factors for the development of CA. In many cases, topical antibiotic treatment is not necessary with the use of modern antiseptics. Therefore, the indication must always be critically questioned not only because of the sensitization potential but also because of the unfavorable and potentially consequential resistance problem. None. J. Wohlrab has received grants for scientific projects, clinical studies, lectures and/or consulting from the following relevant companies in the last 5 years: Allergika, Almirall, Aristo, BayPharma, Dermapharm, Galderma, GSK, Helm, Hexal, Infectopharm, Jenapharm, Klinge, Leo, Medac, Medice, Mibe, MSD, Mylan, Novartis, Pierre Fabre, Pfizer, Skinomics, Wolff. B. Kreft has received grants for scientific projects, clinical studies, lectures or consulting in the last 5 years outside the submitted work from Jenapharm, Novartis, Biogen."}
+{"text": "RSC Advances article due to a calibration error in the CVD tool used when fabricating the inverted UV-OLED devices. As a result, the subsequent data collected is not reliable and the conclusions of this paper are not supported.We, the named authors, hereby wholly retract this Signed: Runze Chen, Chuan Liu, Kyeiwaa Asare-Yeboah, Ziyang Zhang, Zhengran He and Yun Liuth November 2020Date: 29RSC AdvancesRetraction endorsed by Laura Fisher, Executive Editor,"}
+{"text": "Pineal neoplasms are tumors with different and variable morphological, histological, and radiological characteristics and, consequently different diagnosis and management. Due to their rarity, pineal tumors may be misdiagnosed. Pineal tumors, are divided into germ cell tumors, pineal parenchymal tumors and tumors that derive from adjacent structures. In this review, we report the clinical relevance of the main pineal gland tumors, underlining the importance of studying the triggering causes of pineal region carcinogenesis, to realize appropriate diagnosis and, consequently, better clinical management.The pineal gland is a small, pinecone-shaped endocrine gland that participates in the biological rhythm regulation of vertebrates. The recognized major product of the pineal gland is melatonin\u2014a multifunctional endogenous indoleamine. Accumulating evidence suggests that the pineal gland is important for preserving ideal health conditions in vertebrate. Tumors of the pineal region account for approximately 3\u201311% of pediatric brain neoplasms but fewer than 1% of brain neoplasms in adults. It is fundamental to expand advanced imaging techniques together with both clinical and laboratory knowledge, to help to differentiate among pineal neoplasms and thus facilitate accurate primary diagnoses and proper therapeutic interventions. In this review, we report the gross anatomy of the pineal gland and its functional significance and discuss the clinical relevance of pineal gland tumors, underlining the importance of identifying the leading causes of pineal region masses. The pineal gland is a pinecone-shaped neuroendocrine gland located in the epithalamus that participates in the biological rhythm regulation of vertebrates. The gland projects posteriorly and inferiorly into the quadrigeminal cistern, and the anatomic boundaries include the backside of the third ventricle wall forming the gland\u2019s base, the splenium of the corpus callosum superiorly, and the thalamus surrounding both sides ,2,3,4. FThe pineal gland\u2019s primary purpose is the production and immediate release of melatonin, a pleiotropic and multifunctional indoleamine ,7,8,9,10The pineal gland possesses two populations of cells: about 95% are pinealocytes with dendritic processes, and the other 5% are neuroglial supporting cells that resemble astrocytes. Both these types of cells can form neoplasms, as well as residual germ cells from primordial neural crest cell migration and cells derived from nearby structures ,14,15,16Pineal neoplasms are fairly uncommon tumors, and they are predominantly childhood malignancies representing 3\u201311% of all pediatric brain tumors compared to <1% of brain tumors in adults ,18,19,20Pineal region masses may produce nonspecific signs and symptoms, and they usually cause syndromes of mass effect, including headaches, aqueductal stenosis, and hydrocephalus, or compressive hypothalamic syndromes, such as diabetes insipidus and slowed growth ,16,25. AIt is fundamental to expand advanced imaging techniques, together with both clinical and laboratory knowledge to help to differentiate among the pineal neoplasms and thus realize accurate primary diagnoses and correct treatment and patient management plans. Open surgical resection and stereotactic or endoscopic biopsy are needed for pineal tissue diagnosis ,28. HoweIn this review, we report the features and clinical relevance of the main pineal gland tumors, underlining the importance of studying the triggering causes of pineal region masses, to enable effective primary diagnosis and, consequently, correct treatment and clinical management.Germ cell neoplasms are derived from primordial germ cells that develop primarily in the gonads but also in the anterior mediastinum, pineal gland, and brain . Germ ceGerminomas are the most common pineal tumor type, representing up to 50% of pineal tumors in Europe, the United States, and Japan ,23. OnlyGerminomas are malignant tumors characterized by a mix of large multipotential primitive germ cells and smaller cells that resemble lymphocytes. Germinomas often present severe inflammatory infiltrates . FurtherOn imaging, germinomas show heterogeneous features, often presenting as solid or solid/cystic masses with engulfed calcifications , differeImaging alone does not allow us to distinguish among germinomas, nongerminomatous germ cell tumors and pineal parenchymal tumors. Therefore, a complete evaluation is fundamental. In fact, germinomas are diagnosed using imaging together with serum and CSF markers. These tumors present high serum and CSF expression of oncoproteins such as alpha-fetoprotein, beta human chorionic gonadotropin, lactate dehydrogenase, and placental alkaline phosphatase .The treatment regimens used against germinomas include chemo- and radio-therapy or a combination of both, resulting in a positive prognosis and five-year survival of at least 90% . GerminoPineal choriocarcinomas are uncommon malignant nongerminomatous germ cell neoplasms   and the Qi et al.  observedUnfortunately, classic treatments frequently fail due to choriocarcinomas being extremely resistant tumors. The first clinical choice is total resection . However, to treat choriocarcinoma, a mix of total tumor removal, chemotherapy, and radiotherapy is frequently used as a therapeutic combination and seems to show positive outcomes ,47,48,49Intracranial teratomas account for up to 50% of fetal brain neoplasms; in neonates, they comprise 33% of intracranial tumors, but they comprise only 2%\u20134% of intracranial tumors in patients aged <15 years ,55. IntrPineal parenchymal tumors are neuroepithelial neoplasms arising from pineocytes. These tumors are uncommon accounting for fewer than 1% of all primitive central nervous system tumors and constituting 15% to 30% of pineal gland tumors ,58. PinePineal parenchymal tumors seem to have no sexual predominance and occur most frequently in pediatric patients ,14,58. PPineocytomas are slow-growing grade I/II pineal parenchymal neoplasms derived from the pineal epithelium ,51,60,67On MRI, pineocytomas appear as hyperintense, round or lobular masses ,15,56,70As previously reported, pineal parenchymal cell tumors also include pineoblastomas, aggressive, grade IV neoplasms derived from primitive neuroectoderm ,17. TheyPineoblastomas are composed of undifferentiated or immature pineal cells ,74. SynaAggressive surgical resection is the first-line therapy against pineoblastoma. Notably, radiotherapy after resection helps in increasing patient survival. As also reported for other pineal gland tumors, combined therapy seems to be an effective approach . A reporPineal papillary tumors are uncommon WHO grade II or III neuroepithelial neoplasms ,15,56. APineal papillary tumors at MRI appear as partially cystic masses with obstructive hydrocephalus .Pineal papillary tumors show some papillary morphological features forming ependymal rosettes and pseudorosettes. The rosetted cells have thick processes resting on collagen from adjacent blood vessels. Vascular connective tissue present various layers of cells with a large cuboidal or columnar epithelial-like growth pattern. These cells show small round/oval nuclei, stippled chromatin, small nucleoli, and eosinophilic cytoplasm with distinct cell borders ,85,90,91Pineal papillary tumors often recur, and radiotherapy is frequently effective ,99,100. Pineal parenchymal tumors of intermediate differentiation are uncommon tumors arising from the pineal parenchyma that present features between those of pineocytomas and pineoblastomas ,102,103.Metastatic cancer spreading to the pineal gland is exceedingly uncommon and originates from lung carcinoma in most cases . Other tMetastasis to the central nervous system is usually an end-stage disease features and the treatment of pineal region metastases varies due to systemic conditions and neurological symptoms ,112. HowBlas John et al.  discusseNon-neoplastic pineal cysts are frequently observed during both MRI scans and autopsy studies, and the prevalence of benign pineal cysts ranges between 0.6% and 23% in the general population ,120,121.It is, in our opinion, important to at least introduce pineal cysts because they are pineal non-neoplastic masses that are relatively common in the general population, and a heterogeneous group of tumors, such as pineoblastomas, astrocytomas, meningiomas and pineocytomas, may feature a cystic nature on MRI, without showing hemorrhage within the masses ,123. PinBarboriak et al.  undertooChoque-Velasquez et al.  reportedAs reported in the present review and summarized in Furthermore, due to their rarity, pineal tumors may be misdiagnosed. Establishing a means of specific tissue diagnosis for patients with pineal region tumors is needed to distinguish among the variety of possible histomorphological tumor subtypes. In the last decade, specialized surgical and stereotactic techniques have evolved to provide specific, safer, and more effective options for obtaining, at least, correct tissue diagnosis. Advanced microsurgical techniques combined with improved preoperative management and postoperative critical care methods have made surgical resection the optimal therapy for almost all pineal tumors. However, the identification of new therapeutic targets and the development of more effective adjuvant therapies, as well as follow-up guidelines, are needed to improve pineal tumor outcomes."}
+{"text": "Antibiotic prophylaxis decreases rates of febrile neutropenia and systemic infection in children with acute lymphoblastic leukemia (ALL). However, it is unknown whether prophylaxis prevents or ameliorates the severity of specific types of infections like upper respiratory tract infections (URTI) or lower respiratory tract infections (LRTI). This is a retrospective, observational convenience cohort study of children with newly-diagnosed ALL, comparing respiratory tract infections (RTI) in participants receiving no antibiotic prophylaxis, levofloxacin prophylaxis, or non-levofloxacin prophylaxis. Information regarding the presence of URTI or LRTI, identified respiratory viruses, hospitalization, oxygen supplementation, and ICU admission was collected through medical record review. The proportion of participants in each group was estimated and compared between groups using Fisher\u2019s exact test and the Kruskal-Wallis test.Of 262 evaluable participants, 126 received no antibiotic prophylaxis, 59 received levofloxacin prophylaxis, and 77 received non-levofloxacin prophylaxis, with a total of 136 children getting any antibiotic prophylaxis regimen. In the no-prophylaxis group, 22/126 (17.4%) had RTI, compared to 23/136 (16.9%) in the prophylaxis group. There was no significant difference in the numbers of LRTI and URTI, with or without an identified respiratory virus, regardless of the presence or type of antibiotic prophylaxis. Participants receiving prophylaxis did not have a significantly different risk of hospitalization, oxygen supplementation, or ICU admission.Participant CharacteristicsComparisons of levofloxacin prophylaxis, other prophylaxis, any prophylaxis, and no prophylaxisThere was no observed difference in RTI, hospitalization, oxygen supplementation, or ICU admission for RTI between participants receiving or not receiving antibiotic prophylaxis in this cohort. Because of the relatively low number and severity of respiratory infections, and the high proportion that are viral in etiology, it would likely take a very large sample size to determine the impact of antibacterial prophylaxis on respiratory infections during induction therapy for pediatric ALL.Joshua Wolf, MBBS, PhD, FRACP, Karius Inc. (Research Grant or Support) Joshua Wolf, MBBS, PhD, FRACP, Nothing to disclose"}
+{"text": "Trypanosoma spp. include Trypanosoma brucei rhodesiense, Trypanosoma brucei gambiense, and Trypanosoma cruzi, pathogenic for humans, and Trypanosoma vivax, Trypanosoma congolense, Trypanosoma evansi, Trypanosoma brucei brucei, Trypanosoma dionisii, Trypanosoma thomasbancrofti, Trypanosma elephantis, Trypanosoma vegrandis, Trypanosoma copemani, Trypanosoma irwini, Trypanosoma copemani, Trypanosoma gilletti, Trypanosoma theileri, Trypanosoma godfreyi, Trypansoma simiae, and Trypanosoma (Megatrypanum) pestanai. Wildlife hosts for the trypansomatidae include subfamilies of Bovinae, Suidae, Pantherinae, Equidae, Alcephinae, Cercopithecinae, Crocodilinae, Pteropodidae, Peramelidae, Sigmodontidae, and Meliphagidae. Wildlife species are generally considered tolerant to trypanosome infection following centuries of coexistence of vectors and wildlife hosts. Tolerance is influenced by age, sex, species, and physiological condition and parasite challenge. Cyclic transmission through Glossina species occurs for T. congolense, T. simiae, T. vivax, T. brucei, and T. b. rhodesiense, T. b. gambiense, and within Reduviid bugs for T. cruzi. T. evansi is mechanically transmitted, and T. vixax is also commonly transmitted by biting flies including tsetse. Wildlife animal species serve as long-term reservoirs of infection, but the delicate acquired balance between trypanotolerance and trypanosome challenge can be disrupted by an increase in challenge and/or the introduction of new more virulent species into the ecosystem. There is a need to protect wildlife, animal, and human populations from the infectious consequences of encroachment to preserve and protect these populations. In this review, we explore the ecology and epidemiology of Trypanosoma spp. in wildlife.While both human and animal trypanosomiasis continue to present as major human and animal public health constraints globally, detailed analyses of trypanosome wildlife reservoir hosts remain sparse. African animal trypanosomiasis (AAT) affects both livestock and wildlife carrying a significant risk of spillover and cross-transmission of species and strains between populations. Increased human activity together with pressure on land resources is increasing wildlife\u2013livestock\u2013human infections. Increasing proximity between human settlements and grazing lands to wildlife reserves and game parks only serves to exacerbate zoonotic risk. Communities living and maintaining livestock on the fringes of wildlife-rich ecosystems require to have in place methods of vector control for prevention of AAT transmission and for the treatment of their livestock. Major  Rattus nativitatis and Macleay's rats (Rattus macleari)  .Trypanosoma are primarily transmitted by vectors , elephants (Loxodanta africana), hippopotamus (Hippopotamus amphibius), lions, hyenas, jackals, caracals, and wild ruminants , impala (Aepyceros melampus), lion (Panthera leo), zebra (Equus quagga boehma), warthog (Phacocoerus africanus), and duiker (Sylvicapra grimmia)  . TrypanoInfection with trypanosomes can predispose infected animals to other infections , and conT. vivax and T. congolense as well as human infective T. brucei  also transmit trypanosomiasis ; and mechanical transmission through tsetse and alternative vectors including biting flies of the Tabanidae family (horse flies) as well as Stomoxys species. T. evansi and T. vivax can be mechanically transmitted  as is common for nsmitted .Preservation of natural resources including game parks and game reserves has led to an expansion of wildlife populations that serve as reservoirs for AAT and HAT . Human eTrypanosomiasis affects one-third of Africa's land mass \u201337. TsetDifferences in wildlife food sources, particularly for wild bovidae, influence their exposure to trypanosomiasis. Among ruminant wildlife hosts, browsers are more at risk of trypanosomiasis compared with grazers; semi-browsers are moderately susceptible. Eland, Waterbuck, Kudu, and Bushbuck are more heavily infected, associated with their preference for inhabiting thickets during tsetse feeding hours, predisposing them to more bites , 18.Diurnal wildlife hosts are more susceptible to trypanosome infection compared with the nocturnal species. Warthogs are most active in the morning and late afternoon and show high infection rates for trypanosomiasis in correlation to vector feeding hours . Lions aTrypanosome infection leads to erythrophagocytosis and heme catabolism resulting in iron accumulation in tissues and hyperbilirubinemia, liver dysfunction, and multiple organ failure . At necrT. vivax present with severe anemia, lethargy, photophobia, lacrimation, and inappetence  have been identified in wild animals including, but not limited to, the northern brown bandicoot (Isoodon macrourus), common brushtail possum (Trichosurus vulpecula), northern quoll , and brush-tailed rabbit-rat (Conilurus penicillatus)  have been found to infect bats and other mammalian wildlife in Europe and South America (T. cruzi (Chagas) has been identified in kidney tissue, heart muscle, and blood, urine, and peritoneal fluid of wild spp. including foxes, opossums, raccoons, and striped skunks (The majority of trypanosome species require multiple obligatory hosts to complete their life cycles (heteroxenous), and the transmission of the parasites is mainly via hematophagous invertebrate vectors , 88. Tryillatus) . Trypano America . Bats, p America , 22. T. d skunks , 90, andd skunks , 90.Hosts are classified according to their role as a definitive host [if the mature sexual stage(s) of the parasite occurs within them] or intermediate hosts when the more mature sexual stages of the parasite only aid part of the life cycle . TransfeTrypanosoma brucei, T. rhodesiense, T. equiperdum, T. vivax, and T. congolense are transmitted in tsetse fly (Glossina spp.) saliva to the host spp. Hosts are as follows: T. brucei s.l. , T. vivax , T. equiperdum (equines), T. simiae (pigs), and T. congolense (dogs and cats) causing T. evansi , and other numerous wildlife hosts such as monkeys, guinea pigs, rabbits, rats, etc., are also affected  to host skin where they gain access to tissues. Other vectors of transmission for stercorians include Tabanid flies, stable flies, ticks, and mosquitoes. Stercorians include Trypanosoma cruzi, T. lewisi, T. melophagium, T. nabiasi, T. rangeli, T. theileri, T. theodori, T. lewisi, T. cruzi, bat spp. , and others: Trypanosoma conorhini and Trypanosoma rangeli  , 97. Salaffected , 98. Ste rangeli , 98, 99.d skunks , 89, 90.Trypanosoma cell membranes are covered with dense variable surface glycoprotein (VSG) homodimers\u2014immunodominant antigens that trigger infected host B- and Th-cell-mediated immune responses. Over 1,000 different VSG genes and pseudogenes are present in the trypanosome genome that can undergo segmental gene recombination to encode an estimated 10,000 different VSG surface coats. High antigenic variability in VSG molecules hinders vaccine development ; however, the same animals appeared to have developed cross-immunity following infections to multiple trypanosome species including T. brucei rhodesiense  and body tissues. Resistance in wildlife species has been associated with serum xanthine oxidase and catalase and other trypanolytic molecules , 109. StIn Cape buffalo, resistance has been associated with non-specific trypanocidal activity in serum, which helps to lower the parasitemia following action of xanthine oxidase (XO), which generates reactive oxygen species (ROS). Since trypanosomes cannot metabolize XO, this cripples parasitic binding and endocytosis , trypanoT. rhodesiense and T. brucei, whereas the common duiker, eland, bohor reedbuck, spotted hyena, oribi, bushbuck, impala, warthog, bushpig, porcupine, and baboon are considered resistant (or less susceptible) to T. b. rhodesiense and T. brucei infection , oryxes (Oryx beisa), eland (Taurotragus oryx), and waterbuck (Kobus defassa) following infection with T. congolense, T. vivax, or T. brucei. These animals showed resistance in the form of negligible parasitemia and minimal anemia    demonstrClimate change, population pressure, and incentives to end poverty through farming have forced humans to encroach into land previously occupied by wildlife , 120. HuEndemic zones are created by encroaching on places of game parks. This has caused a wildlife and livestock interface, and development of the trypanosome parasite reservoirs . WildlifT. b. rhodesiense is common in communities living proximal to, or that are dependent on, wildlife or eco-tourism  can be reservoir hosts for Trypanosoma spp., e.g., T. evansi and T. cruzi that could infect humans and other wildlife populations without affecting the rodent spp.  to bushy areas and thickets have predisposed them to higher exposure rates to tsetse and other biting flies, intensifying the spread of trypanosomes . Trypanoemiology .T. melophagium, T. nabasi, T. theieri, and T. evansi in Australia following the introduction of various mammals into their wildlife populations, which had a great impact on the native marsupials , launched in 2003, comprises a One Health team of socioeconomic scientists, ecobiologists, veterinarians, agriculturalists, wildlife, and public health specialists that address issues at the wildlife, human, and domestic livestock interface. This includes efforts to monitor parasitic diversity in wildlife species to assist in the strengthening of disease surveillance in LMICs . ManagemCommunities in the wildlife zones sometimes agree on coexistence with wildlife and the creation of buffer zones . HoweverRenowned trypanosome hosts like bats need to be removed from urban centers and human dwellings. Bats also live in human dwellings in ceilings and other dark points. African bats are hosts of trypanosomes . It is nResearch on possible vaccine candidates has not broken through despite emphasis on the VSG pathway , 156. ThT. cruzi (Wildlife are usually in contact with insects other than the tsetse flies. It is known that lice can transmit T. cruzi . The posT. cruzi , and it T. cruzi \u2013165. TheThere is a need to study the interactions of trypanosomes with other blood parasites. Trypanosomes interact with babesia especially to worsen the stress conditions of translocation \u2013168. TheTrypanosoma spp. is a challenge, both exacerbating the risk of increased virulence and making the development of a vaccine unlikely. One Health strategies that are community and environmentally friendly are needed to support stakeholders to mitigate risk. There is a need to strengthen trypanosomiasis research, particularly in LMICs, especially at the human\u2013domestic\u2013wildlife interface to prevent cross-species infection.Trypanosomiasis continues to be a major global challenge, particularly so at the wildlife\u2013domestic livestock interface. Multiple wildlife species serve as maintenance hosts promoting infections at the livestock\u2013wildlife interface. There is a high risk of infection spillover from game parks and conservation areas where parasites and vectors are concentrated in high numbers, and domestic livestock pose risks to wildlife-protected species. The basis of trypanotolerance in wildlife species is not well-understood. The wide genetic diversity exhibited by KIK and SCW conceptualized the study, designed the study, and analyzed and interpreted the data. KIK, GZ, FS, BB, KJA, KM, HNN, LA, DO, PB, JJO, SI, WM, DPN, GESB, LOO, TS, MA, LO, and SCW collected the data. KIK wrote initial draft while SCW critically reviewed it for intellectual content. All authors approved the manuscript for publication and remain in agreement on all aspects of the work.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Collaborative Drug Therapy Management (CDTM) protocols allow qualified clinical pharmacists working within a defined context to independently assume responsibility for a variety of direct patient care activities. The goal of this model is to improve access to care, often in a more affordable and timely manner. Pharmacists in our burn center have historically assisted with discharge planning and transitions of care for patients being sent home or to a facility. Despite these efforts, pharmacists were not formally involved in managing Burn Clinic patients. The objective of implementing a CDTM Protocol in Burn Clinic was to streamline management of burn-related pharmacologic issues.The CDTM protocol allows the pharmacist to assess patients\u2019 therapeutic needs related to thermal injury, inhalation injury, or dermatologic disorder. Disease states managed include: pain, agitation, delirium, insomnia, venous thromboembolism, skin and soft tissue infections, and complications of hypermetabolic burn response.In Burn Clinic, via in-person or telephone visits, pharmacists can independently evaluate and modify pharmacologic treatment regimens in accordance with state legislation, including initiation, renewal, and adjustment of drugs and vitamins. The pharmacist can also review, order, interpret, and conduct pertinent laboratory studies and wound culture results. In addition, the pharmacist completes medication reconciliation, performs patient education, and consults other healthcare providers, as needed. All visits, patient care, education, and treatment decisions are documented in the electronic record. \u201cIncident-to\u201d billing is completed at Level 99211, as this is a hospital-based clinic.Historically, pharmacists were peripherally involved with Burn Clinic patients when issues arose, serving in an \u201cas-needed\u201d capacity. With more proactive involvement, pharmacists are uniquely positioned to help with de-prescribing, drug interactions, insurance issues, access to medications, adherence, and dose optimization. Implementing a CDTM protocol allows pharmacists to become more formally involved in post-discharge follow-up and to help manage ambulatory burn patients."}
+{"text": "Daily energy and nutrient intakes were adjusted for a complex sample design of NHANES using appropriate weights. Mango consumption was not associated with daily energy intake, compared with non-consumption, in both children and adults. Children consuming mangoes had a significantly lower daily intake of added sugar, sodium, total fat, and a higher intake of dietary fiber, magnesium, potassium, total choline, vitamin C, and vitamin D, compared with non-consumers. In adults, mango consumers had significantly higher daily intakes of dietary fiber, magnesium, potassium, folate, vitamin A, vitamin C, and vitamin E and significantly lower intakes of added sugar and cholesterol, compared with non-consumers. Mango consumption was also associated with a better diet quality vs. mango non-consumers (p < 0.0001). Mango consumption in adolescents was associated with lower BMI z-scores, compared with non-consumption. In adults, BMI scores, waist circumference, and body weight were significantly lower only in male mango consumers when compared with mango non-consumers. The current results support that mango consumption is associated with improved nutrient intakes, diet quality, and certain health outcomes. Thus, dietary strategies that aim to increase mango consumption in the American population should be evaluated as part of future dietary guidance.As nutrient-dense fruits, mangoes are commonly consumed globally and are important sources of nutrients in the diet. Nonetheless, mangoes remain relatively under-consumed in the United States. The objective of the present analysis was to examine nutrient intakes, diet quality, and health outcomes using data from NHANES 2001\u20132018 in children and adult mango consumers ( Consumption of fruits in the American diet remains below authoritative dietary guidance. The 2020\u20132025 Dietary Guidelines for Americans (2020\u20132025 DGA) focuses on the inclusion of food groups that provide nutrient density while concurrently achieving caloric limits. The key recommendations comprising a healthy dietary pattern include greater consumption of vegetables, fruits, especially whole fruit, whole grains, low-fat and fat-free dairy, and lean protein foods . Fruit cWhile dietary guidance suggests increased fruit consumption as part of healthy dietary patterns, certain fruits, including mango, remain under-consumed by Americans, even while global demand remains elevated . FurtherThe United States National Health and Nutrition Examination Survey (NHANES) is a nationally representative, cross-sectional survey of free-living, civilian residents in the US. NHANES data were collected by the National Center for Health Statistics of the Centers for Disease Control and Prevention. Detailed descriptions and analytics of NHANES have been previously documented in the scientific, peer-reviewed literature ,13,14. AWWEIA was collected using the automated multiple-pass method (AMPM). USDA\u2019s AMPM represents a validated dietary data collection instrument that provides an evidence-based, efficient, and accurate format for collecting dietary intake data for large-scale national surveys . The AMPn = 291; adults n = 449) or mango non-consumers . Only data that were determined to be reliable and included completed 24 h recalled dietary data were used in the analysis. Exclusions included pregnant and lactating females and subjects presenting energy intakes equal to zero. Mango consumption was defined as participants that consumed raw mango (NHANES food code 63129010), dried mango (NHANES food code 62114050), pickled mango (NHANES food code 63129020), canned mango (NHANES food code 63129030), and frozen mango (NHANES food code 63129050). Mixed dishes containing mango were not included in the analysis. Further, the analysis used Day 1 data to define mango consumers and non-consumers, as Day 1 represented the in-person, validated data collection process.Sex-combined data on children (2\u201318 years old) and adults (19+ years old) were combined for the present analysis and differentiated as mango consumers . The investigation used survey weights to develop nationally representative estimates for children and adults, followed by adjustments to consider the complex sample design of the database. The least-square means for mango consumers were compared with the least-square means for mango non-consumers, in both children and adults. Adjusted means (\u00b1standard errors) for daily intake of energy , nutrients, and diet quality were determined. USDA\u2019s validated Healthy Eating Index-2015 (HEI-2015) tool was used to measure total diet quality\u2014a measurement of alignment to authoritative dietary guidance. Energy, nutrient, and diet quality included adjustment for several variables, including age, ethnicity, sex, kilocalories , socioeconomic status , physical activity level, current smoking status and alcohol intake where applicable. Body mass index (BMI) was assessed in adults, and a BMI z-score was used for analyses in children. A Estimated mango consumer percentages by demographic variables are presented in Daily nutrient and energy intake comparisons for mango consumers and non-consumers can be seen in The scores for the total and sub-categories of HEI-2015 are presented in The key health outcome examined in the present analysis related to body weight and waist circumference. In younger children, no significant differences were observed with body mass index (BMI) z-scores when comparing mango consumers and non-consumers (data not shown). BMI z-scores in older children (14\u201318 years old) demonstrated significant differences, which are summarized in Our analysis of combined NHANES data shows that mangoes can be an integral part of a healthy dietary pattern. Overall, mango consumption in children was related to improved daily nutrient intakes, including higher intake of dietary fiber, magnesium, potassium, total choline, vitamin B, vitamin C, and vitamin D, and reduced intake of sodium and total fat, compared with mango non-consumers. Similarly, adult mango consumers had significantly greater daily intakes of dietary fiber, magnesium, potassium, folate DFE, vitamin A, vitamin B12, vitamin C, and vitamin E and significantly lower intakes of added sugar, sodium, and cholesterol, compared with mango non-consumers. Interestingly, dietary fiber, magnesium, potassium, folate, and vitamin A have been previously identified by authoritative dietary guidance as shortfall nutrients in the American population . The curThe present findings align with previous research using data from NHANES 2001\u20132008 in children and adults where results demonstrated similar improvements in nutrient intakes, diet quality, and health outcomes . The resWhile significant scientific consensus supports that fruit represents an integral part of any dietary pattern, the American population falls alarming short of meeting recommendations ,3,22. InThe current analyses have limitations inherent in observational research and have previously been reported ,28. FirsA significant benefit of using NHANES data for the current analyses includes access to a large and nationally representative dataset of adults of various age groups in the US and corresponding food and nutrient intake data. As the present research was observational, and since growth and development are multifactorial, future research designs will need to consider randomized, controlled trials.Our analysis demonstrated several associations between mango consumers, nutrient intakes, diet quality, and weight-related health outcomes. Mango consumption in children was associated with a higher intake of dietary fiber, magnesium, potassium, total choline, vitamins B6, C, and D, and reduced intake of sodium and total fat, compared with mango non-consumers. Adults including mangoes in their diet had significantly greater daily intakes of dietary fiber, magnesium, potassium, folate DFE, vitamins A, B12, C, and E, and significantly lower intakes of added sugar, sodium, and cholesterol, compared with mango non-consumers. Mango consumers also demonstrated a better overall diet quality when compared with mango non-consumers. Weight-related health outcome assessment showed that adolescent mango consumers had significantly lower BMI z-scores and waist circumferences, compared with mango non-consumers, which were primarily due to male mango consumers rather than females. Likewise, BMI, waist circumference, and body weight were significantly lower only in adult male mango consumers when compared with mango non-consumers. The present findings are aligned with previously published data documenting numerous benefits associated with the inclusion of fruit within healthy dietary patterns."}
+{"text": "Androgens have diverse functions in muscle physiology, lean body mass, the regulation of adipose tissue, bone density, neurocognitive regulation, and spermatogenesis, the male reproductive and sexual function. Male hypogonadism, characterized by reduced testosterone, is commonly seen in ageing males, and has a complex relationship as a risk factor and a comorbidity in age-related noncommunicable chronic diseases (NCDs), such as obesity, metabolic syndrome, type 2 diabetes, and malignancy. Oxidative stress, as a significant contributor to the ageing process, is a common feature between ageing and NCDs, and the related comorbidities, including hypertension, dyslipidemia, hyperglycemia, hyperinsulinemia, and chronic inflammation. Oxidative stress may also be a mediator of hypogonadism in males. Consequently, the management of oxidative stress may represent a novel therapeutic approach in this context. Therefore, this narrative review aims to discuss the mechanisms of age-related oxidative stress in male hypogonadism associated with NCDs and discusses current and potential approaches for the clinical management of these patients, which may include conventional hormone replacement therapy, nutrition and lifestyle changes, adherence to the optimal body mass index, and dietary antioxidant supplementation and/or phytomedicines. Steroid sex hormones are classified as androgens, estrogens, and progestogens. Although all three classes are important in male and female physiology, androgens are associated with \"musculisation\" effects and are considered primarily male sex hormones . AndrogeWhen testosterone synthesis is impaired, a condition of hypogonadism arises that affects quality of life and wellbeing . BecauseAll these conditions have in common an imbalance in the redox homeostasis in favor of higher levels of oxidants, leading to the development of oxidative stress . OxidatiIn males, testosterone is synthesized primarily in Leydig cells through LH receptor (LHR) binding, with the activation of G-coupled protein and adenylyl cyclase, which increases intracellular cyclic adenosine monophosphate (cAMP). This leads to the activation of the steroidogenic acute regulatory (StAR) protein that mediates the mitochondrial uptake of cholesterol, which is converted to pregnenolone by the cytochrome P450 side chain cleavage enzyme ,10. In hMale hypogonadism is a clinical syndrome caused by a disruption of the hypothalamic\u2013pituitary\u2013gonadal (HPG) axis that affects the testicular synthesis of testosterone . VariousThe classification of hypogonadism is based on testicular or non-testicular causes. Testicular failure is classified as primary (hypergonadotropic) hypogonadism, and the causes include Klinefelter syndrome, Sertoli-cell-only syndrome, cryptorchidism, testicular trauma, mumps orchitis, radiation or chemotherapy treatment, and autoimmune diseases . PituitaHypogonadism presents clinically with sexual dysfunction, prominently including erectile dysfunction, infertility, increased adiposity with decreased muscle mass, reduced bone density, and osteoporosis, fatigue, and depression . DiagnosIn living cells, redox (reduction and oxidation) reactions mediate numerous physiological pathways; hence, the intracellular levels of oxidants and antioxidants play an important role in this fine regulation ,16. Reac2O2), which can react with ferrous ions in the Fenton reaction and lead to the generation of hydroxyl radical. Other oxidants originate from nitrogen and are classified as reactive nitrogen species (RNS) [The former are molecules with unpaired electrons in the outer orbit; hence, they easily react with any other cellular molecule, including lipids, proteins, and DNA. Nonradical species include hydrogen peroxide (Hes (RNS) . Redox hes (RNS) .When the fine redox equilibrium is shifted in favour of oxidants through increased ROS or reduced antioxidants, a condition of oxidative stress arises. As numerous cellular signaling pathways respond to variations in redox status, oxidative stress can consequently result in the disruption of the cellular signalling and cause cellular damage . SeveralROS are physiologically produced during the enzymatic reactions of steroidogenesis. Monooxygenase reactions require electron donation from NADPH through adrenodoxin reductase and adrenodoxin ,27. HereHowever, a switch of the redox status towards oxidative stress can affect steroidogenesis, resulting in the reduced synthesis of androgens .High levels of ROS hyperactivates the JNK signalling, which suppresses the activity of Nur77, a transcriptional factor regulating the expression of several steroidogenic enzymes . MoreoveROS scavenging relies on antioxidant systems. The reduced synthesis of testosterone was observed in Nrf2 knock-out mice, where Nrf2 is a transcription factor regulating the expression of antioxidant systems in response to oxidative stress . ExperimAgeing is a complex, multifactorial, and gradual deterioration in biological function over time, which affects the neurological, immune, and endocrine systems, and is responsible for cellular dysfunction and genetic mutations ,44. ThisObesity, metabolic syndrome, T2DM, and numerous malignancies have common risk factors. These include an increased consumption of energy-dense foods, a sedentary lifestyle, alcohol and tobacco use, exposure to environmental toxins and endocrine-disrupting chemicals, as well as numerous medications ,48. ThesAlthough frequently caused by overnutrition, obesity and T2DM paradoxically present with micronutrient deficiencies . PromineThe role of oxidative stress in T2DM has been described in the literature . In factIn human observational studies, oxidative stress in obesity and T2DM correlates with male hypogonadism ,58. SimiIn this context, oxidative stress plays an important role. Studies conducted in rats showed that the depletion of the GSH antioxidant was associated with reduced testosterone synthesis, which was reverted once that antioxidant pool was restored . OxidatiMale reproduction can be affected in cases of obesity and metabolic syndrome. In fact, the adipose tissue present in excess expresses the enzyme aromatase, which mediates the conversion of testosterone to estradiol. Moreover, hyperinsulinemia is associated with reduced SHBG levels . This reOxidative stress, along with chronic inflammation, has been widely reported to be associated with cancer . OxidatiOxidative stress is therefore a common mediator between physiological ageing, hypogonadism, and the development of NCDs in males. Furthermore, hypogonadism, which is also partly mediated by oxidative stress, is a common consequence of ageing, as well as a contributor to, and/or a consequence of, NCDs in males. In fact, a reduced intake of exogenous antioxidants, or the presence of SNP in endogenous antioxidant genes that promote oxidative stress, are associated with an increased risk of developing obesity, systemic inflammation, insulin resistance, and hyperglycemia, all of which further increase oxidative stress. Therefore, oxidative stress may be an important mediator in the inter-relationships between ageing, hypogonadism, and NCDs that can be a target for management and prevention.Pharmaceuticals commonly marketed for hypogonadism include testosterone cypionate (cypionate), testosterone enanthate (enanthate), or testosterone undecanoate as injections, or, alternatively, transdermal administration . In the The impact of TRT on oxidative stress is unclear. TRT in male patients with postsurgical hypopituitaric hypogonadism results in increased coenzyme Q10 and reduced ROS levels . TM3 LeyThe benefit and long-term safety of TRT in ageing males is unclear . TRT is Metformin is an effective antiglycemic agent that improves insulin resistance in diabetic and metabolic syndrome patients, and that can lead to weight loss in diabetic and nondiabetic obese patients. Through the activation of AMPK and the inhibition of the NF-\u03baB pathway, metformin improves oxidative stress, inflammation, and the regulation of insulin, glucose, and lipoproteins ,103. ParGood nutritional habits regulate immune function and redox biology, reducing inflammation and oxidative stress . MediterWeight management improves male fertility and endocrine function, where a healthy lifestyle can improve sexual dysfunction and many comorbidities in obesity, metabolic syndrome, and diabetes ,122. FurAs the long-term safety of TRT is unclear in obese males with nonclassical hypogonadism, lifestyle changes or bariatric surgery for weight loss should be the first-line treatments . An apprC. elegans, Drosophila melanogaster, S. cerevisiae), as well as in vertebrates, reported decreased levels of oxidative products and ROS generation in cases of caloric restriction . This ipic, see ,132,133.pic, see . Howeverpic, see ,136. In pic, see . HoweverBariatric surgery improves male obesity-associated secondary hypogonadism . This isAntioxidants may be beneficial in extending the lifespan, and evidence for this includes catechins from green tea, theaflavins from black tea, polyphenols from apples and blueberries, and anthocyanins from black rice, sesemin, curcumin, as well as DHA from marine microalgae . Antioxiin vitro studies that have investigated the antioxidant effects of micronutrients and herbal medicine extractions on both testosterone production and oxidative stress are listed in in vitro models of Leydig cells treated with different antioxidant compounds [N-acetylcysteine (NAC) [Nigella sativa seed oil [Lycium chinense Mill [Eruca sativa seeds [Moringa oleifera leaves [Schisandra chinensis [Antioxidants, and other micronutrients, may be beneficial for reducing testicular oxidative stress and Leydig cell apoptosis. There are few studies investigating the effects of antioxidants on male hypogonadism and the oxidative stress markers in humans. Curcumin nanomicelle improved semen parameters and testosterone levels, reduced FSH, LH, and prolactin, and improved oxidative stress through the reduction of serum MDA, CRP, and TNF and by increasing the serum total antioxidant capacity in infertile males . Animal ompounds ,169,170.ompounds , zinc [1ompounds , N-acetyne (NAC) ,174, galne (NAC) , lycopenne (NAC) , forskolne (NAC) , resverane (NAC) ,178, Nigseed oil , Lycium nse Mill , Eruca sva seeds , Moringaa leaves , Schisanhinensis , Ojayeonhinensis ,185, andhinensis   provide secondary metabolites  that are beneficial in the prevention and management of human disease ,193. TheAnacyclus pyrethrum, Arctium lappa, Cinnamomum zeylanicum, Coleus forskohlii, Corchorus depressus, Cynanchum wilfordii, Cyperus esculentus, Eurycoma longifolia, Garcinia cambogia, Lepidium meyenii, Moringa oleifera, Mucuna pruriens, Nigella sativa, Panax ginseng, Pedalium murex, Rhodiola rosea and Tribulus terrestris, Trigonella foenum-graecum Urtica doica, and Withania somnifera [Trigonella foenum-graecum and Withania somnifera showed promising positive effects in clinical studies, whereas Lepidium meyenii, Rhodiola rosea, Tribulus terrestris, and Panax ginseng appeared to have less clinical evidence for increasing male testosterone, but may improve erectile dysfunction [Numerous plants with antioxidant properties have been associated with increased testosterone in males, including improvements in male sexual behaviour, libido, and sexual function. The more common plants investigated include: omnifera ,199,200.function . Importafunction .Although oxidative stress is an important mediator in ageing and NCDs, the use of antioxidants in clinical trials have been generally disappointing ,45,202. Oxidative stress contributes significantly to the ageing process and the pathogenesis of age- and lifestyle-related NCDs through numerous mechanisms, and is closely related to comorbidities, such as hypertension, dyslipidaemia, hyperglycemia, hyperinsulinemia, and chronic inflammation. Furthermore, evidence suggests that oxidative stress may be a mediator of hypogonadism in these males through the regulation of enzymatic and transcriptional activities. The relationship between ageing, oxidative stress, male hypogonadism, and NCDs in males requires further investigation. These are complex mechanisms that appear to be closely interrelated; hence, a detailed understanding of the impact of ROS on steroidogenesis is required to identify novel therapeutic targets. On the basis of the current evidence, molecular mediators that activate the PI3K/Akt, BMI1, and MAPK family members, as well as p38, may improve Leydig cell steroidogenesis under oxidative stress conditions using nutritional and phytomedicinal antioxidants that require further investigation. In fact, although TRT may be beneficial in these males, alternative therapeutic approaches require consideration where TRT is contraindicated. Weight loss, through nutritional and lifestyle intervention, as well as the use of nutritional and phytomedicinal antioxidants, may provide novel therapeutic options in the management of age-related NCDs in males through an improvement in oxidative stress and steroidogenesis."}
+{"text": "Sleep complaints can be both common and complex in the older patient. Their consideration is an important aspect of holistic care, and may have an impact on quality of life, mortality, falls and disease risk. Sleep assessment should form part of the comprehensive geriatric assessment. If sleep disturbance is brought to light, consideration of sleep disorders, co-morbidity and medication management should form part of a multifaceted approach. Appreciation of the bi-directional relationship and complex interplay between co-morbidity and sleep in older patients is an important element of patient care. This article provides a brief overview of sleep disturbance and sleep disorders in older patients, in addition to their association with specific co-morbidities including depression, heart failure, respiratory disorders, gastro-oesophageal reflux disease, nocturia, pain, Parkinson\u2019s disease, dementia, polypharmacy and falls. A potential systematic multidomain approach to assessment and management is outlined, with an emphasis on non-pharmacological treatment where possible. Sleep, which has an important role in human health, is commonly disrupted in those aged \u226565 years ,2,3,4. TWhile not a consequence of healthy ageing, older patients are at a higher risk of sleep impairment than their younger counterparts ,11. TypiFrom a neurological and endocrinal perspective, there are a lot of potential factors that can impair sleep. Neurotoxin deposition, age related blood brain barrier dysfunction and local small vessel disease may cause grey and white matter loss, disrupting sleep spindle and SWS generation. In addition, neurotransmitter dysregulation may directly impair sleep drive, and neurodegeneration in the suprachiasmatic nucleus can impact the normal circadian rhythm . AccumulLife events, such as bereavement and loss, are more common in older age, and are also associated with sleep problems ,18. In aThe prevalence of primary sleep disorders, such as insomnia, sleep disordered breathing (SDB) and REM sleep are also common in older people ,22,23,24Insomnia is common in older age, although reported prevalence varies . DiagnosWhere possible, non-pharmacologic therapy should be considered as first-line treatment. A recent systematic review of sleep hygiene education (SHE) for treatment of insomnia found that SHE was associated with sleep improvements . CognitiPharmacological management of insomnia in older patients should be undertaken with absolute caution. While statistically significant effects on sleep continuity have been seen with hypnotic use, the magnitude of the effects are small, and associated risks are both significant and clinically relevant . These rSDB is the umbrella term used to describe many disorders of the respiratory pattern occurring periodically during sleep, including obstructive sleep apnoea (OSA) and central sleep apnoea (CSA) . The incThe typical presentation of OSA in a younger patient of nocturnal snoring, choking, nocturia and excessive daytime sleepiness does not necessarily occur in the older patient ,61. ScreSDB has been associated with stroke, nocturnal hypertension, glaucoma, falls and mortality in the older population ,70,71,72Restless leg syndrome (RLS) is a movement disorder characterised by an urge to move the limbs in response to an uncomfortable sensation . The lowSleep symptoms are common in RLS, with patients reporting an inability to fall or stay asleep . AssociaEvidence based non-pharmacological therapy for RLS is scarce. A recent systematic review found that exercise, counter-strain manipulation, compression devices, repetitive transcranial magnetic stimulation, infrared therapy, acupuncture, vibration pads and yoga were associated with improved outcomes . StudiesObtaining serum ferritin levels in patients with RLS should be considered, as replacement of iron in deficient patients can improve symptoms ,103,104.Pharmacological options, including dopamine agonists, alpha-2 delta calcium channel ligands and levodopa, should be considered in cases where sleep, QOL or daytime functioning is impaired . OpioidsREM sleep behaviour disorder (RBD) is a parasomnia characterised by the lack of paralysis during REM sleep, resulting in patients \u201cacting out their dreams\u201d. Unpleasant and vivid dreams are also a common symptom ,118. It RBD has been associated with poorer QOL in addition to poorer subjective sleep quality in comparison to healthy controls . Sleep-rRBD\u2019s definitive diagnosis requires PSG . The sinNo established guidelines exist in relation to the management of RBD, and large RCTs have not been undertaken ,129. TheModification of the sleep environment, including removing dangerous items, placing the mattress on the floor and sleeping in separate beds, may help prevent injury in cases with injurious behaviour . ConsideDepression in the older population may present differently than in the younger population, and older patients with depression may be more likely to report sleep disturbance ,137. A bIn younger patients with concomitant depression and insomnia, augmenting treatment for depression with CBT-I has been associated with improved depressive and sleep symptoms . CBT-I hPatients with heart failure (HF) commonly complain of non-restorative sleep, increased sleep onset latency, night time awakenings and early morning wakening ,149. InsOptimising HF management may positively impact sleep quality, while diagnosis and treatment of underlying sleep disorders should also be considered. There is some evidence, for example, suggesting that angiotensin converting enzyme (ACE) inhibitors may positively impact sleep in heart failure patients ,161. BetReduced sleep quality has been associated with chronic respiratory disorders, including chronic obstructive pulmonary disease (COPD) and asthma ,165. In Optimal treatment of patients with sleep problems and respiratory disorders is complex. Sleep and stages of sleep can affect breathing through multiple mechanisms, including reduction in skeletal muscle tone and reduced ventilatory response to chemical and mechanical stimulus, potentially leading to inadequate ventilation during sleep in compromised lungs . The posManagement should include optimisation of the underlying respiratory condition. Improved asthma control, for example, has been associated with improved sleep quality . MedicalChronic pain and insomnia are closely associated, with 50.4% of chronic insomnia participants in one cross-sectional study reporting chronic pain . The relGastro-oesophageal Reflux Disease (GORD) has been associated with insomnia and impaired sleep quality and quantity, after adjusting for multiple confounders . In one Nocturia may significantly effect sleep . SeveritNocturia may be caused by benign prostatic hypertrophy (BPH), primary or secondary detrusor overactivity and pathologies associated with impaired bladder contractility . In addiDetermining the underlying mechanism of nocturia is the first step in management. Detailed history taking and examination is recommended. Investigations, when indicated, may include frequency volume charts, urinalysis, serum analysis  and measurement of post-void residual volume (PVR) . SpecialIt has been postulated that sleep and circadian dysfunction may partially drive neurodegeneration in the early phases of PD, and that neurodegeneration may also negatively impact sleep, with a potential self-perpetuating cycle in PD ,209. SleImpaired sleep in PD is likely multifactorial, related to neurodegeneration, underlying sleep disorders, PD symptoms and treatment. Nocturia is common in PD, and negatively impacts sleep continuity ,216. NocTreatment of sleep disruption in PD is complex. Exacerbating factors and whether underlying sleep disorders are present should be considered and treated as appropriate, with both insomnia and RBD being common in PD ,220. CarThere also appears to be a bi-directional relationship between dementia and sleep, with sleep disruption representing both a risk factor for, and symptom of, the neurocognitive syndrome ,234,235.Evidence is lacking for many commonly used medications for sleep disturbance in dementia . In someGiven the risk associated with hypnotics, non-pharmacological management has an important role . EvidencCommonly prescribed medications in the context of co-morbidity may also negatively impact sleep. Antihypertensives, antidepressants, antiepileptics, corticosteroids, decongestants and diuretics are among many medications that have been associated with insomnia, and may represent potentially inappropriate medications in the older patient ,253,254.Sleep disturbance has also been associated with falls, a major cause of morbidity and mortality in older patients ,257,258.Sleep disturbance and disorders have also been associated with many other co-morbidities, many in potential bi-directional relationships. These include HTN, diabetes, obesity, stroke, renal disease and cancer, among others ,274,275.Snoring or apnoeic episodes at night;Abnormal movement during sleep;Restless leg symptoms;Nocturia;Medications and comorbidities;Pain;Psychological symptoms;Social circumstances;Sleep hygiene issues i.e., caffeine consumption, routine, light exposure, etc.The author suggests that assessment of sleep health, and further assessment where warranted, form part of every comprehensive geriatric assessment (CGA). Although there has been little validation in the older population, screening and assessment tools can be considered, with some screening and assessment tools explored in Furthermore, focused physical exams and investigations may be necessary, including referrals for PSG. Assessment-based treatment for particular sleep disorders may be indicated in addition to optimising underlying co-morbidities, pain, addressing exacerbating medications, psychosocial factors and sleep hygiene . A synopSleep complaints are both common and complex in the older person. Their consideration is an important aspect of holistic care, and may have an impact on QOL, mortality, falls and disease risk. Considering sleep disorders, co-morbidity, medication management and non-pharmacological options are important aspects of a multifaceted approach in this group. The author provides a brief overview of sleep disturbance in the context of sleep disorders and several co-morbidities, and a suggested general assessment approach that may be helpful in this complex task."}
+{"text": "The Conducting of polymers belongs to the class of polymers exhibiting excellence in electrical performances because of their intrinsic delocalized \u03c0- electrons and their tunability ranges from semi-conductive to metallic conductive regime. Conducting polymers and their composites serve greater functionality in the application of strain and pressure sensors, especially in yielding a better figure of merits, such as improved sensitivity, sensing range, durability, and mechanical robustness. The electrospinning process allows the formation of micro to nano-dimensional fibers with solution-processing attributes and offers an exciting aspect ratio by forming ultra-long fibrous structures. This review comprehensively covers the fundamentals of conducting polymers, sensor fabrication, working modes, and recent trends in achieving the sensitivity, wide-sensing range, reduced hysteresis, and durability of thin film, porous, and nanofibrous sensors. Furthermore, nanofiber and textile-based sensory device importance and its growth towards futuristic wearable electronics in a technological era was systematically reviewed to overcome the existing challenges. Recent trends have evolved to numerous stimuli-based electronic appliances, especially in terms of understanding human biological and physiological fitness. Numerous credible establishments have achieved this via a spectrum of factors that include materials, design, fabrication, processing, and stability conditions. An emerging demonstration of efficient high resolution sensors in recent years has caused significant progress in elucidating the chemical, biochemical, biological, toxic, organic effluents, inorganic metals, strain, and pressure signals through chemical bonding interactions, aggregation-induced, optical, colorimetric, and structural color responses ,2,3,4. APolymer composites not only limit their arms to sensors and energy generators, but they also govern breakthroughs in fields such as light-emitting diodes (LEDs), lasers, solar cells, field effect transistors, memory devices, and soft robots ,13,14. FApart from optoelectronics, polymer composites and their influence in generating gamut of strain and pressure sensors is appreciable. Energy generators play a critical role in enhancing the sensors\u2019 utilities, as they reduce the power consumption, i.e., self-powered complexities, in coupling the energy source or other energy storage components . Both inSensors are generally denoted as devices that can brilliantly respond to analyte or external stimuli selectively  with good sensitivity and linear response. In particular, strain sensors respond intelligently in response to various physical stimuli, such as tensile, compression, twist, etc. The strain sensor performances can be evaluated and compared effectively with their sensitivity, operational range, response and recovery time, stability, and reusability ,41.Sensitivity: A variation of electrical sensory signals in accordance to the strain experienced can be termed as sensitivity. The majority of the strain sensor response can be widely recorded as electrical outputs and, in a few studies, it has been analyzed with optical measurements. The gauge factor (GF) value can be derived with the help of the following equation , which exerts non-covalent binding on graphite and graphene oxide sheets, was considered to evaluate the combinatorial effect of structure and doping towards cyclic stability . . 189]. VThe cellular porous materials tend to effectively accommodate both compressive and tensile strains, which is quite common with different human motions. Freeze-drying followed by chemical crosslinking with 4,4\u2032-diazido-2,2\u2032-stilbenedisulfonic acid disodium salt, which was added to PEDOT solution, followed by freeze-drying offers porous structures b. The asCompared with the strain sensors based on highly conductive metal nanostructures or carbon nanomaterials, the strain sensors based on PEDOT:PSS exhibit combined advantages, including conformable attachment on skin, easy configurable, processing simplicity, fabrication, and biocompatibility. Furthermore, the trade-off relationship between high sensitivity and wide sensing range existing for majority of strain sensors remains common in PEDOT:PSS-based strain sensors. PEDOT:PSS sensing network develops multi conductive networks in the strain sensor, ensuring the existence of the conductive networks even at large strains and granting the sensor with a large sensing range. Porous structure of the PEDOT:PSS aerogel lead to its interlacing with the infiltrated PDMS substrate, thus withholding the sensing composite structures, firmly causing the better sensor response\u2019s reliability and stability .Textile tends to possess greater potential, and it has revolutionized various functional components, as it provides good comfort and protection to the users. Research projects and industrial collaborations are bringing rapid growth, and it is anticipated that a variety of electronic components can be made out of textile basic component fibers. Major developments have been vividly visible in wearable electronics such as sensors, solar cells, batteries, supercapacitors, LEDs, energy generators, etc. Various methodologies have followed to fabricate fiber-drawing, templating, self-assembly, phase separation, centrifugal spinning, wet spinning, electrospinning, etc., ,201,202.The major complication in achieving the conducting polymer fibrous structures is their poor solubility in common solvents, which seriously restricts the electrospinning process. Another crucial issue was conducting polymer\u2019s low molecular weight and high molecular chain rigidity, which complicates the electrospun nanofibers\u2019 formation ,210. OxiMicrofluidic method of forming core\u2013shell fibers were designed with carbon nanotube (CNT)/PEDOT:PSS composite in natural rubber matrix. Outer shell coagulants diffuse into the core structure and stabilize the core\u2013shell structured strain sensor fabrication. Long, uniform, stretchable, and composite microfibers were prepared in a single-step microfluidic device, subsequently allowing the mass production. The as-developed microfibrous composite strain sensors exhibited high stretchability accompanied by a high linearity of about 1000% . The impLim et al. decorated PANI hairy nanostructures over the PU electrospun microfibers, and the results suggest the importance of nanofiber alignments in achieving higher sensitivity (40-fold increments) a 219]. . 219]. TElectrospinning of the conductive polymers is made viable through the utilization of carrier polymers. Carrier polymer doped with oxidant solution promotes the mechanical integrity of the nanofibers. Vapor phase deposition of EDOT monomer can convert the oxidant nanofibers into the resulting conductive PEDOT fibers . Similar2 hybrids formed on the polyester knitted fabrics. Pristine PANI-coated polyester fabric suffers from weaker abrasion resistance. PANI/TiO2 hybrid fabric\u2019s abrasion resistance improved gradually with an increase in the TiO2 blend ratio. Average GF values of vertical strain were 21.71 and 20.26, respectively, for pristine and hybrid sensors, whereas the GF of the horizontal strain remained 2.25 and 2.06, suggesting the directional behavior of the fabricated sensors. The strain sensor directional response in terms of GF value reflects with connection and slippage of knit loops in which the strain was applied [Commercial fabric materials ease the fabrication of strain sensors. Thin film silicon rubber based strain sensors exert good sensitivity, with a good strain sensing resolution limit of 0.05% . Low-cos applied .\u22123 S cm\u22121, respectively [Nanofibers are comparatively better than commercial fibers, as they offers improved surface to volume ratio and improved sensitivity. Electrospinning processed with a PU/DMF spinning solution, followed by a conventional in situ chemical polymerization of aniline monomers on the surface of PU nanofibers to deposit a conductive PANI layer. Strain sensitivity, i.e., average strain GF values, could reach 17.15 with applied stretching deformation (0\u223c110%) . The graectively . Purposeectively .\u22121 in a wide linear sensing range [\u22121), pressure sensing range (10 kPa), along with the low hysteresis deviation (6%) [\u22121, and it also offered good clinical health monitoring with a better distinction among the atrial contraction, right ventricular contraction, atrial venous filling, atrium relaxation, and tricuspid valve opening [Fiber alignments can be of simple and effective methodology to harvest wearable strain sensors with high sensitivity and high stretchability. Interesting anisotropic sensing along the sensing directions governed by the aligned microstructure of the conductive networks are constructed by TPU fiber joints in the electrospun network and fish scale-like sensing layer on the fibers d. The asng range . Similarion (6%) . More re opening . The cri opening . Hydroph opening . The dur opening . Another opening . Due to  opening .The processing and fabrication steps can still be made facile with other approaches such as dip coating, brush painting, and printing techniques to attain scalable and low cost wearable sensors. Control of fillers\u2019 aggregation with a number of brush painting cycles can aid in the formation of low resistive textile sensors . Indeed,The conducting polymers and its composites offer a broad spectrum of applicability, with lowered fabrication complications and cost factors. Although several breakthroughs have been achieved with carbon based nanostructures, ranging from carbon black, graphene, carbon nanotube, and carbon dots, there is still a much left to accomplish. Nevertheless, the emergence of carbon nanostructures remain limited due to their poor dispersion, processing of toxic conditions, and production cost and time factors. A variety of metallic nanostructures, alloys, and metallic oxides have been taking up the challenging tasks of reigning the wearable electronics. Due to the cytotoxicity and heavy metal leakage issues, liquid metal and various alloys have not been successful in forming human- and eco-friendly wearable sensors and electronics. Conducting polymers stays unique in establishing the relationship between the device performance and fabrication, due to their chemical stability, facile fabrication, low cost, biocompatible, and tunable morphology. Additionally, the conducting of experiments involving polymer composite has, in recent years, grown rapidly, and is anticipated to be the stardom of the optoelectronic industry. Conducting composites serve promisingly in attaining the adhesion and durable nature of forming the conductive networks over the diverse substrates. In particular, this review highlighted the evolution and importance of conducting polymer and its composites in strain and pressure sensing applications. Conducting polymers and its composites can possibly extend its arms towards energy production, energy storage, internet of things, artificial intelligence, soft robots, artificial prosthetics, in the near future.From the above progress, it is perceptible that strain and pressure sensing studies have significantly grown, which has led to obvious developments in terms of e-skin, soft-robots, actuators, synaptic devices, and smart textiles. Self-powered energy-generating systems capable of harvesting biomechanical motions and other environmental stimuli including noise, wind, water, etc. Wearable electronics have captivated futuristic plots of research, and it is anticipated to achieve scalability and industrialization. Wearable sensors alone cannot fulfill the facile durable monitoring, wearable displays and LEDs can drive the futuristic view of integrating self-powered wearable sensors as point-of-care diagnostics to trace finer health details. Recently, following the green chemistry aspects, one pot synthetic conjugated block copolymer based touch a responsive LED working intelligently in achieving the wearable electronics . Novel bAlthough several strategies worked satisfactorily in achieving the better figure of merit with strain and pressure sensory devices, there are still other plausible routes to explore and accomplish in near future. We have herein presented various fields of interest, demonstrating the reliability of thin film and porous and nanofibrous sensory systems. Biocompatible, eco-friendly elastomers and conducting networks that can sustain higher strains and fatigue can empower the field of strain and pressure sensors. Recently, wearable devices with good elasticity, recovery ratio, toughness, stability, hysteresis free, self-healable, adhesiveness, and breathability factors have been achieved with better balances. It is of greater importance to balance the mechanical, electrical, and ambient condition\u2019s stability of the wearable devices to reduce the probability of mechanical and electrical failure. Fabrication methodology and simple architectures can drastically reduce the fabrication cost and time factors. By integrating greener composites, biodegradable and self-healable characters can significantly contribute to the development of next-generation sensory devices. Conducting polymer composites have a promising potential for use as stretchable and wearable sensors, field effect transistors, memory devices, LEDs, and human interactive devices to strengthen and develop the internet of things\u2019 technological era."}
+{"text": "Allium cepa L.) is a common vegetable, widely consumed all over the world. Onion contains diverse phytochemicals, including organosulfur compounds, phenolic compounds, polysaccharides, and saponins. The phenolic and sulfur-containing compounds, including onionin A, cysteine sulfoxides, quercetin, and quercetin glucosides, are the major bioactive constituents of onion. Accumulated studies have revealed that onion and its bioactive compounds possess various health functions, such as antioxidant, antimicrobial, anti-inflammatory, anti-obesity, anti-diabetic, anticancer, cardiovascular protective, neuroprotective, hepatorenal protective, respiratory protective, digestive system protective, reproductive protective, and immunomodulatory properties. Herein, the main bioactive compounds in onion are summarized, followed by intensively discussing its major health functions as well as relevant molecular mechanisms. Moreover, the potential safety concerns about onion contamination and the ways to mitigate these issues are also discussed. We hope that this paper can attract broader attention to onion and its bioactive compounds, which are promising ingredients in the development of functional foods and nutraceuticals for preventing and managing certain chronic diseases.Onion ( Allium cepa L.) is widely cultivated and consumed around the world  (ABTS), 1,1-diphenyl-2-picrilhydrazyl (DPPH), ferric reducing antioxidant power (FRAP), lipid peroxidation, oxygen radical absorbance capacity (ORAC), total antioxidant capacity (TAC), and trolox equivalent antioxidant capacity (TEAC) assays.Onion is a good source of natural antioxidants . Many st2 , NAD(P)H quinone dehydrogenase 1 (NQO1), and hemeoxygenase-1 (HO-1), was upregulated by onion extract in N27-A cells . In addiOverall, onion exhibits strong antioxidant effects, and many factors could affect the antioxidant capability of onion. Although the antioxidant activity of onion has been extensively investigated, the related antioxidant molecular mechanism has been much less explored, which should be further clarified in the future.Onion extracts and their derived bioactive compounds, such as thiosulfinate compounds, phenolic compounds, polysaccharides, and essential oils, have been reported to possess potent antibacterial properties , 58, 146Staphylococcus aureus and Escherichia coli  (Allium ampeloprasum L.) (Allium schoenoprasum L.), Welsh onion (Allium fistulosum L.) (Allium chinense) (Allium flavum and Allium carinatum)  , 172, leasum L.) , chive (osum L.) , Chinesehinense) , 175, anrinatum) . By in sopilin-1 . Onion Aopilin-1 . Spiraeoopilin-1 . Recentlopilin-1 . Besidesh models . Moreoveh models . TherefoStudies have revealed that onion can effectively improve lipid profile and inhibit platelet aggregation, attenuating the incidence of cardiovascular diseases. The methanol extract, quercetin, and quercetin glucosides from onion were found to inhibit collagen-induced platelet aggregation by using rat platelet-rich plasma .via fecal excretion. The fecal bile acid content was reported to be modified by the dietary addition of onion in high-cholesterol diet-fed rats , and nitrate (NO3\u2212), were reduced , has triggered the worldwide pandemic of coronavirus disease 2019 (COVID-19). Up to January 2021, data from the web-based COVID-19 dashboard has shown that more than 100 million people were infected with more than two million deaths . The infOnion has been shown to have a protective effect on the digestive system, such as mitigate gastric ulcer , 182, moIt has been reported that raw onion could inhibit histamine-induced gastric acid secretion and mitigate ethanol-stimulated gastric ulcer in rats, whereas boiled onion showed reduced potency . AlqasouInfertility has been considered a public health problem. Studies have shown that onion exhibited protective effects against adverse effects of chemical toxicity \u2013122 and Escherichia coli infection were reduced in male rats receiving onion juice, while the total antioxidant capacity and testosterone level was increased  and immunoglobulins (IgG and IgM)  . Moreoveand IgM) , 186.Browning of agro-products can lead to the deterioration of product quality and nutritional value, resulting in a decrease in consumer acceptance. Onion has been demonstrated to possess an inhibitory activity against the enzymatic browning reaction in fresh foods, such as fruit juice, mushrooms, and potato slices \u2013190. In Onion has been consumed as a vegetable and applied as an herbal medicine for a long history. Normally, onion and its bioactive compounds are quite safe for humans. However, several potential safety risks have raised concerns, for example, the residue of pesticides , bioaccuPesticides with low toxicity and rapid degradation can be recommended for use in crops. However, the improper use of some pesticides in the onion crop may still cause health risks from onion consumption. Several studies have been carried out to investigate the degradation behavior, residue distribution, and dietary risk of different pesticides, including insecticides , 192, fuin situ imaging strategy for the fast evaluation of heavy metal enrichment in onion. Besides, Cd uptake in onion and other crops was revealed to be affected by environmental and edaphic factors , lead (Pb), chromium (Cr), and nickel (Ni), in the farmland growing onion may induce the accumulation of heavy metals in onion and induce food safety issue. Bystricka et al.  reported factors . Indeed, factors  or the a factors .2/reduced O2 in package atmosphere was found beneficial for the safety and quality of fresh-cut onion, which showed effective inhibitory effects on the growth of Salmonella typhimurium, mesophilic aerobic bacteria, yeasts, and molds during storage (Listeria monocytogenes (Escherichia coli (Salmonella spp. (The use of sanitizer, sodium hypochlorite, combined with elevated CO storage . Moreoveytogenes , Escherihia coli , 204, Salla spp. , and mollla spp. . In addiOnion is a widely cultivated and consumed vegetable, and contains various bioactive components. The sulfur-containing compounds, such as onionin A and cysteine sulfoxide, as well as the phenolic compounds, such as quercetin and quercetin glucosides, are the main bioactive constituents in onion and contribute to its multiple health functions, including antioxidant, antimicrobial, anti-inflammatory, and immunomodulatory properties. Moreover, onion can be a promising natural resource to develop functional foods or nutraceuticals for the prevention and management of certain diseases, such as obesity, diabetes, cancers, cardiovascular diseases, neurodegenerative diseases, nephropathy, respiratory disorders, colitis, and infertility.in vitro and in vivo evidence suggests that onion powder, juice, and extracts exhibit multiple health functions. Although several bioactive compounds have been found to contribute to these functions, more bioactive compounds from onion or its by-products should be identified, and their health functions, the relevant molecular mechanisms, and whether they have synergistic effects need to be illuminated in the future. Currently, most studies focused on the health functions of the raw onion, it is necessary to investigate whether the cooking processing can impact its health benefits. Moreover, more well-designed clinical trials are still required to verify the health benefits of onion and onion-derived bioactive compounds in humans. Last but not the least, safety issues of onion should always be aware of, not only the contaminations mentioned in this review, but also other potential risks, such as the overdose of bioactive compounds.At present, both X-XZ, F-JL, and HL drafted the manuscript. H-BL, D-TW, FG, WM, YW, B-HM, and R-YG critically revised the manuscript. R-YG and B-HM conceived the idea and scientific guidance through the process. All authors have read and agreed to the published version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Emerging data demonstrate the important roles of altered gut microbiomes (dysbiosis) in many disease states in the peripheral tissues and the central nervous system. Gut dysbiosis with decreased ratios of Bacteroidetes/Firmicutes and other changes are reported to be caused by many disease states and various environmental factors, such as ethanol , Western-style high-fat diets, high fructose, etc. It is also caused by genetic factors, including genetic polymorphisms and epigenetic changes in different individuals. Gut dysbiosis, impaired intestinal barrier function, and elevated serum endotoxin levels can be observed in human patients and/or experimental rodent models exposed to these factors or with certain disease states. However, gut dysbiosis and leaky gut can be normalized through lifestyle alterations such as increased consumption of healthy diets with various fruits and vegetables containing many different kinds of antioxidant phytochemicals. In this review, we describe the mechanisms of gut dysbiosis, leaky gut, endotoxemia, and fatty liver disease with a specific focus on the alcohol-associated pathways. We also mention translational approaches by discussing the benefits of many antioxidant phytochemicals and/or their metabolites against alcohol-mediated oxidative stress, gut dysbiosis, intestinal barrier dysfunction, and fatty liver disease. Ample research conducted over the past decade has revealed the expansive and critical role of the human microbiota in numerous physiological processes and pathological consequences. Before elaborating further on these microbial communities and their abundance, the terms microbiota and microbiome should first be distinguished, considering they are sometimes used interchangeably. A microbiota specifically refers to the \u201cassemblage of microorganisms present in a defined environment\u201d , while tVarious microbiomes within the human body have been well defined, including the gastrointestinal (GI) tract, lung, skin, urinary, and oral microbiomes, and collectively amount to trillions of bacterial cells that work in concert with (or sometimes in opposition to) human cells and experimental rodent models ,3. CurreBacteroides, Alistipes, and Prevotella from the Bacteroidetes phylum, Faecalibacterium, and Ruminococcus from the Firmicutes phylum, and Bifidobacterium and Collinsella from the Actinobacteria phylum  are also implicated in gut barrier damage, since they are observed to be phosphorylated (activated) in Caco-2 cells and played a role in TJ disruption and gut barrier dysfunction, particularly through increasing MLCK mRNA [Furthermore, it is also possible that ROS can be provided through activated NADPH-oxidase isozyme(s) (NOXs) present in the colon and in immune cells in the lamina propria of the GI tract ,160,161.ed to do . The oxiLCK mRNA , whose aLCK mRNA . The oxiLCK mRNA . AdditioLCK mRNA .Bidirectional gut\u2013liver communication occurs as gut-derived molecules pass through the intestinal barrier and enter the portal vein to reach the liver, while liver-derived molecules pass through the biliary tract to interact with the intestines ,167. TypThe non-luminal side of the intestinal barrier is home to the lamina propria containing a wide variety of immune cells, which can respond to changes in gut barrier dysfunction. The response of immune cells  to alcohol consumption does not appear to be uniform across the lower GI tract , possiblLPS and other luminal-derived molecules will travel through the portal vein and reach the liver, where they will interact with various cell types and influence the different stages of ALD pathogenesis ,182,183.A recent study demonstrated that increased ROS levels, likely generated by CYP2E1, occur alongside ethanol-induced decreases in autophagy in alcohol-exposed mice . FurtherKupffer cell-localized NADPH oxidase (NOX) was hypothesized early on to generate ROS during infiltration of LPS and/or neutrophils following alcohol exposure  and the As described in the previous sections, gut dysbiosis with decreased ratios of Bacteroidetes/Firmicutes and changes in the levels of various endogenous metabolites, including ethanol and SCFAs, are associated with many disease states. Thus, there have been many efforts to normalize or restore the gut microbiome by using different diets, such as microbiota-targeted vegan (vegetarian) diets and/or consuming microbiota-accessible carbohydrates (oligocarbohydrates) or dietary supplements with various phytochemicals . In addiOne of the characteristic properties of these phytochemicals is their very low water solubility, despite the presence of many hydroxyl groups in polyphenols ,207. It +-dependent non-histone deacetylase Sirt-1 [As illustrated in e Sirt-1  and its e Sirt-1 , may resThe presence of pathogenic microbes and their metabolites in the gut may potentially promote ALD and its progression, since pretreatment with non-absorbable antibiotics such as neomycin and polymyxin B  or rifaxLactococcus chungangensis CAU 28 [Lactobacillus fermentum administration, depending on time point [Roseburia intestinalis-mediated reduction in gut permeability through increased occludin mRNA and protein levels [Lactobacillus plantarum, have been shown to reduce inflammatory markers, triglyceride levels and gut leakiness associated with ALD by way of epidermal growth factor receptor (EGFR) activity [Akkermansia muciniphila gut population [Numerous studies have reported the beneficial effects of commensal microbial (probiotics) supplementation on ALD manifestations and gut dysbiosis . Recent s CAU 28 , the decme point , and then levels . Additioactivity . Inflammpulation , which, pulation  and alcopulation ,102.Gryllus bimaculatus prior to acute alcohol exposure was demonstrated to mitigate ethanol-induced increases in intestinal oxidative stress (8-OHdG levels), hepatic apoptotic markers, and hepatic triglyceride accumulation [Alongside probiotics, certain dietary supplements have been shown to attenuate ALD pathogenesis and limit gut dysbiosis and leakiness. For example, administration of the comestible cricket mulation . Pomegramulation  and chromulation ; althougmulation , I3C supmulation . Additiomulation . Furthermulation ,159 and mulation , which smulation ,159. Pommulation . Additiomulation . Additiomulation , were efmulation . When comulation , plasma mulation , alcoholmulation  and evenmulation  and an imulation . Howevermulation . Thus, pmulation , possiblmulation .Supplementation of zinc  may alsoWolfporia cocos  decreased the hepatic triglyceride levels and MCP-1 levels, indicating decreased steatosis and inflammation of the liver [Dendropanax morbifera leaf extract also altered microbial composition in rats acutely exposed to alcohol, whereby, for example, members of the Bacteroides operational taxonomic unit (OTU) increased upon co-administration of leaf extract with ethanol, compared to the ethanol group [Dendropanax morbifera leaf extract co-administered with ethanol contained several phytochemicals  [Some alternative and complimentary remedies, such as traditional herbal medicines in China ,261,262,ol group . The Dend, etc.)  and it iPediococcus pentosaceus, which increased the levels of the SCFAs possibly due to the partial recovery of bacterial genera, such as Clostridium, whose levels were decreased in the mouse model of chronic plus binge alcohol exposure and whose recovery could increase SCFA production, as suggested by the positive correlation found between Clostridium and butyric acid levels in this study [Microbiota-derived molecules may also help combat alcohol-induced tissue damage and ALD pathogenesis. Indeed, while microbial products derived from the colon and feces of alcohol-exposed mice were demonstrated to increase intestinal permeability in vitro, in addition to instigating in vitro T-cell activation , certainis study . Adminisis study . Howeveris study . NeverthCertain synthetic drugs, such as sennoside A  and metfN-acetylcysteine (NAC) was shown to mitigate LPS-induced intestinal permeability in the IPEC-J2 intestinal porcine enterocyte cell line [Lactobacillus, Akkermansia, and Bifidobacteria, while decreasing the population of potentially harmful microbes, as suggested elsewhere [The benefits of naturally occurring compounds found in many edible plants, fruits, vegetables, and dietary supplements should also be considered as alternative approaches. For instance, various phytochemicals  from different foods and plants can prevent NAFLD and, in some cases, can normalize gut dysbiosis and intestinal permeability changes, especially in rodent models . The antell line , and expell line . Some ofell line . In theoell line ,226,278.ell line . For insell line ,280 possell line . Part ofell line  and CYP2ell line ,283. Altell line . Additioell line , alcoholell line ,79, may lsewhere ,262,286.lsewhere , certainlsewhere ,121, altlsewhere ,288,289.lsewhere ,291. Earlsewhere ,245,246,In this review, we have briefly described the role of gut microbiota alteration during normal development as well as in pathological conditions. We also mentioned the role of gut dysbiosis caused by various environmental factors as well as epigenetic and/or genetic risks. We also describe the patterns of gut microbiome changes in various pathophysiological conditions and provide evidence for the benefits of ameliorating gut dysbiosis by many different agents in human populations and experimental rodents as well as cell culture models. Moreover, we describe the causal role of increased oxidative stress in promoting intestinal barrier dysfunction, subsequently leading to elevated endotoxemia and fatty liver disease. We also described potentially safe methods of translational approaches against alcohol-mediated oxidative stress, gut dysbiosis, leaky gut, and ALD. These beneficial methods and agents include healthy lifestyle changes with proper intake of healthy diets, containing beneficial chemicals contained in many fruits and vegetables, or n-3 polyunsaturated fatty acids. Indeed, these beneficial agents have demonstrated their effectiveness against gut dysbiosis, intestinal barrier dysfunction, endotoxemia, and ALD and NAFLD in many experimental models. In particular, supplementation with certain phytochemicals represents an exciting prospective therapeutic option for mitigating alcohol-mediated tissue damage owing to the breadth of known phytochemicals and the observed benefits of these chemicals and/or their metabolites on the gut microbiome and redox regulation, despite many compounds having low bioavailabilities. Importantly, future certification of many phytochemicals in various fruits, vegetables, and plants as GRAS could permit usage of these chemicals as dietary supplements in treating ALD. However, randomized large-scale clinical studies need to be conducted in the future to accurately demonstrate the efficacy of some of these antioxidant phytochemicals."}
+{"text": "Navigating the challenge of obesity in extracorporeal support requires careful attention.335.See Article page In this article, Javidfar and colleagues,Recent metanalysis has demonstrated that obesity may exacerbate COVID-19 by an increased expression of angiotensin-converting enzyme, to which the virus spike protein binds and renders the lungs susceptible to attack.It is plausible, nevertheless, that the greater potential for cannulation injury may be responsible for most of the excess mortality. In stark contradistinction, however, once on extracorporeal support, obesity may, nevertheless, proffer a survival advantage. Indeed, using the Predicting Death for Severe ARDS (PRESERVE) scoring to identify factors associated with death, for instance, one observes that obesity represents a 2-point reduction in risk. Ostensibly, therefore, this would favor a lower mortality in patients with obesity."}
+{"text": "Resident and family engagement  is a necessary component of keeping assisted living (AL) residents safe. Barriers to engagement include differing priorities between the resident/family and staff. This presentation outlines the results of a content analysis of qualitative interviews with 105 AL staff, residents, and family members, in which we examined AL stakeholder priorities for safety. Qualitative interviews were analyzed to first identify safety priorities by stakeholder type , and then compared across stakeholder group. Stakeholder-specific safety priorities were identified, including infection management (COVID-19 and others), medications errors, falls, elopement, lack of AL resources/staffing, conflict, adverse events, nutrition, physical hazards, building security, chemical agents, fire/natural disasters, and abuse/neglect \u2013 the importance of these priorities vary by stakeholder type. Presentation discussion will include implications for future intervention to address the top safety problems in AL."}
+{"text": "Phlorotannins are secondary metabolites produced by brown seaweeds with antiviral, antibacterial, antifungal, and larvicidal activities. Phlorotannins\u2019 structures are formed by dibenzodioxin, ether and phenyl, ether, or phenyl linkages. The polymerization of phlorotannins is used to classify and characterize. The structural diversity of phlorotannins grows as polymerization increases. They have been characterized extensively with respect to chemical properties and functionality. However, review papers of the biological activities of phlorotannins have focused on their antibacterial and antiviral effects, and reviews of their broad antifungal and larvicidal effects are lacking. Accordingly, evidence for the effectiveness of phlorotannins as antifungal and larvicidal agents is discussed in this review. Online databases  were used to identify relevant articles. In total, 11 articles were retrieved after duplicates were removed and exclusion criteria were applied. Phlorotannins from brown seaweeds show antifungal activity against dermal and plant fungi, and larvicidal activity against mosquitos and marine invertebrate larvae. However, further studies of the biological activity of phlorotannins against fungal and parasitic infections in aquaculture fish, livestock, and companion animals are needed for systematic analyses of their effectiveness. The research described in this review emphasizes the potential applications of phlorotannins as pharmaceutical, functional food, pesticide, and antifouling agents. Seaweeds are abundant in coastal regions and have become valuable sources of biologically active compounds and secondary metabolites, such as agar, carrageenan, alginate, alkaloids, phenolics, and phlorotannins, with extensive practical applications . PhlorotIshige okamurae, Ecklonia cava, E. kurome, E. stolonifera, Pelvetia siliquosa, Eisenia arborea, and E. bicyclis as well as species in the genera Cystophora and Fucus have been reported to contain phlorotannins. Purified phlorotannins from these brown algae have antioxidant, antitumor, anticancer, anti-inflammatory, antiviral, antimicrobial, antifungal, and larvicidal activities, which are beneficial properties for the development of new functional agents [l agents ,4,5,6,7.Increasing antibiotic resistance and the spread of new variants of viruses are growing global problems . AdditioThe five review papers on biological activities of phlorotannins reported by Eom et al.  focused Phlorotannins are produced and found in physodes, which are located in cells\u2019 periphery and perinuclear regions . PhlorotEcklonia cava, E. stolonifera, Sargassum ringgoldianum, Ishige okamurae, Fucus vesiculosus, and Eisenia bicyclis, as well as species in the genera Cystophora and Fucus. Eckol, phloroglucinol, dieckol, diphlorethohydroxycarmalol, 6,6\u2032-bieckol, phlorofucofuroeckol A, dioxinodehydroeckol, and 7-phloroeckol have been extracted from these seaweeds. Phlorotannins have been isolated from brown seaweed such as Candida albicans, Epidermophyton floccosum, Trichophyton rubrum, and Trichophyton mentagrophytes, and plant fungi, such as Botrytis cinerea and Monilinia laxa, as summarized in The antifungal activity of phlorotannins has been evaluated by Kim et al. , Lopes eCystoseira nodicaulis, Crassiphycus usneoides, and Fucus spiralis using n-hexane and then extracted using acetone:water (7:3). These phlorotannins exhibit antifungal activity against C. albicans, E. floccosum, and T. mentagrophytes. The MIC values of phlorotannins against these fungi range from 3.9 to 31.3 mg/mL. Fucofuroeckol-A, isolated from Eisenia bicyclis, and dieckol, isolated from Ecklonia cava, have antifungal activities [C. albicans [Trichophyton rubrum [Laminaria digitata are effective against plant fungal pathogens, such as B. cinerea and M. laxa, with 100% mycelial growth inhibition.The effects of phlorotannins against dermal fungal pathogens have been evaluated. Lopes et al.  extractetivities ,31. Fucoalbicans , whereasn rubrum . Corato n rubrum  have shoIn fungal cell, phlorotannins block dimorphic complexes, resulting in the appearance of pseudohyphae with decreasing surface adhesive properties. The virulence and capacity to invade fungal host cells are also decreased by phlorotannins. On the other hand, phlorotannins induced reactive oxygen species (ROS) production and triggered early apoptosis, resulting in the activation of the CaMCA1 gene (Metacaspase 1) and membrane disruption. These inhibitory effects promote phlorotannins as new antifungal agents ,30,32.The effectiveness of phlorotannins as antifungal agents depends on numerous factors, such as the complex interactions between chemical compounds and the host and rates of degradation, hydrolysis, and polymerization. In the first step of nature compound discovery as new drug candidate, MICs are usually the starting point for larger preclinical evaluations of novel drug agents, and to ensure that compounds efficiently increase the success of treatment ,32.Increased rates of fungal infections in humans, animals, and plants necessitate the development of new antifungal agents. The antifungal effects of phlorotannin extracts, phlorethols, fucophloretols, fucofuroeckol-A, and dieckol have been evaluated. However, other subclasses of phlorotannins remain to be explored and should be a focus of further research aimed at the identification of novel antifungals.Aedes aegypti and Culex quinquefasciatus, and against marine invertebrate larvae, such as Acropora millepora, Balanus improvises, Hydroides elegans, Halocynthia roretzi, and Ciona savignyi, as summarized in The larvicidal activity of phlorotannins has been reported by Thangam and Kathiresan , RavikumDictyota dichotoma, Lobophora variegata, Stoechospermum marginatum, and Sargassum wightii, exhibit LC50 values ranging from 0.0683 to 85.11 \u03bcg/mL against mosquito larvae\u2014namely, A. aegypti and C. quinquefasciatus. Phlorotannins show potential activity against mosquito larvae. Thangam and Kathiresan , RavikumPadina sp. reduce the settlement of Acropora millepora larvae by 30%. Furthermore, phlorotannins from Fucus vesiculosus inhibit the larval settlement of Balanus improvises [Birrell et al.  reportedprovises . Sargassum tenerrimum showed larvicidal activity in Hydroides elegans with an LC50 of 13.98 \u03bcg/mL. Tsukamoto et al. [Ciona savignyi and Halocynthia roretzi at low concentrations (25 \u03bcg/mL). Study by Lau and Qian  reportedo et al.  demonstrIn mosquito larvae, acute mortality and sublethality are the two main effects observed. With respect to sublethal effects, morphogenetic and external structural changes occur during the exposure period . Other tCiona savignyi and Halocynthia roretzi compared to sulfoquinovosyl diacylglycerol at the same concentrations [As larvae settlement inhibition agents, phlorotannins can influence the coral larval settlement process. In nature, phlorotannins delay the settlement process before larvae attach to substrates, even in areas free of macroalgae or with suitable substrates . Furthertrations . These fHowever, most studies of the larvicidal activity of phlorotannins have focused on crude phlorotannins. To the best of our knowledge, other subclasses of phlorotannins, such as fuhalols, phlorethols, fucols, and fucophloroethols, have not been tested. These phlorotannins have a wide range of biological activities and further studies should evaluate their larvicidal effects and underlying mechanisms.Solid\u2013liquid extraction using organic solvents is the most common method for obtaining phlorotannins from brown seaweeds. Phlorotannins can be extracted using polar solvents, including acetone, ethanol, and methanol. A mixture of polar solvents and water is often used to extract phlorotannins ,49,50,51Naturally, concentration of phlorotannins in brown seaweeds is affected by biological factors, such as the species, tissue type, size, and age, as well as environmental conditions, such as nutrient levels, water temperature, season, herbivore intensity, and light intensity ,47. The Although solid\u2013liquid extraction has been used to obtain phlorotannins from brown seaweeds, this method has a number of weaknesses, such as long extraction times for high yields, a lack of specificity, and the need to purify the extract ,47,48. SSargassum polycystum by the enzymatic method (21\u201338% phlorotannins) than by the solid solid\u2013liquid method (3\u201315%). Similar to the enzymatic extraction method, the ultrasonic extraction method enables a high yield by destroying cell walls using mass transfer during the process [Enzymatic extraction offers high yield values by the destruction of the cell wall. Puspita et al.  obtained process . Further process ,48,49,51Since phlorotannins possess many biological activities, these compounds have attracted substantial research attention. The high effectiveness and low toxicity of these compounds support their utilization as components of pharmaceuticals, cosmetics, and food products .According to Paradis et al. , BaldricCandida albicans, Epidermophyton floccosum, Trichophyton rubrum, and Trichophyton mentagrophytes, which cause skin infections. Accordingly, phlorotannins are promising compounds for the development of dermal creams with antifungal effects. In addition, Corato et al. [Kim et al. , Lopes eo et al.  reportedThe larvicidal activity of phlorotannins in mosquitos reported by Thangam and Kathiresan , RavikumTherefore, recent research clearly supports the use of phlorotannins as pharmaceutical, cosmetic, antifouling, and food preservation agents. However, in-depth studies of phlorotannins are needed to determine their precise effects.Following Systematic Reviews and Meta-Analyses (PRISMA) guidelines, various online databases  were used for literature searches . \u201cPhloroOur review revealed that phlorotannins from brown seaweeds exhibit activities against dermal and plant fungi, and mosquito and marine organism larvae. These findings provide a basis for the development of phlorotannins as new functional foods, feeds, pharmaceuticals, and larvicidal agents. To the best of our knowledge, their effects against viral, microbial, and parasitic infections have not been evaluated in fish, livestock, and companion animals; further studies on the biological activities of phlorotannins in these organisms are needed."}
+{"text": "The cranial nerves, which represent extensions of the functional structures ofthe brain, traverse the head and neck. They are connected to various cranialstructures and are associated with several diseases. An in-depth understandingof their complex anatomy and normal imaging appearance allows the examiner toidentify and characterize abnormalities with greater precision. One importanttool for evaluating the cranial nerves is contrast-enhanced magnetic resonanceimaging, especially that employing three-dimensional steady-state freeprecession sequences, which provide high soft-tissue and spatial resolution,despite the slen-derness of the nerves. In most cases of cranial nerveabnormalities, the imaging findings are nonspecific. Therefore, to narrow thedifferential diagnosis, it is necessary to take a full patient history, performa focused physical examination, and order laboratory tests. In this pictorialessay, we review, illustrate, and discuss, from a pathophysiologicalperspective, infectious, neoplastic, and demyelinating disorders, as well asother inflammatory disorders, affecting the cranial nerves, the aim being toprovide a practical, tangible reference for radiologists to use in dailypractice. Infections of the central nervous system (CNS) are common, arising from hematogenousdissemination, contiguous propagation , traumatic injuries, or surgical manipulation. Those mostfrequently affected are the optic, trochlear, trigeminal, abducens, and facialnerves . On magnetic resonanceimaging (MRI), abnormal leptomeningeal enhancement along cerebral surfaces and thecisternal segments of cranial nerves is a hallmark of infection and should becorrelated with the results of cerebrospinal fluid (CSF) analysis.Neoplastic conditions of the cranial nerves may be primary or secondary, and theformer may be further divided into benign and malignant conditions. To make thediagnosis, it is useful to determine the location of abnormal enhancement and itscharacter (regular or nodular); to identify cystic, necrotic, or hemorrhagiccomponents; and to correlate those data with other imaging findings in the CNS.Inflammatory and demyelinating diseases may arise from parainfectious and autoimmuneprocesses, presenting with a monophasic, relapsing\u2013remitting, or progressive course.Some of these diseases may cause cranial nerve thickening and abnormal enhancement.The correlation with specific local alterations in the brainstem and spinal cordhelp distinguish specific etiologies.(1), wereviewed congenital, traumatic, and vascular diseases of the cranial nerves. Thispictorial essay goes further, illustrating infectious, neo-plastic, anddemyelinating diseases, as well as other inflammatory diseases. Although all of thepathologic conditions we review in this paper share the common finding of abnormalcontrast enhancement in cranial nerves, each has specific epidemiological, clinical,biochemical, and imaging findings.In a previous articleIxodesscapularis and inoculation of complex spirochetes of the genusBorrelia . The disease occurs in stages, with avariety of signs and symptoms. When there is neurologic involvement, whichoccurs in 10\u201315% of infected individuals, it is known as Lymeneuroborreliosis, the mechanisms of which include vasculitis, cytotoxicity,neurotoxic mediators, and immune reactions. Lymphocytic meningitis, cranialneuropathy , and radiculoneuritisconstitute the classic triad of acute Lyme neuroborreliosis. An MRI scan candepict enhancement of multiple cranial nerves, with or without signalchanges in the white matter ((2).Neuroborreliosis is a systemic inflammatory disease, with a worldwidedistribution, that occurs after a bite from the deer tick e matter .In endeTaenia solium pork tapeworm, and its neurologicfindings may include cranial nerve pathology(3). A cysticercus may have one of two shapes:cystic  or grape-like . Racemose cysts,which are typically located in the subarachnoid space, cisterns, orventricles, can grow to large dimensions, occasionally displacing orconstricting adjacent structures . Cranialneuropathy, which may be caused by vasculitis or inflammation, is seen in17\u201370% of patients with CNS tuberculosis(4). Radiological features of CNS tuberculosis includebasal leptomeningeal enhancement, hydrocephalus, and infarctions in thesupratentorial brain parenchyma or brainstem, as well as, in some cases,cranial nerve enhancement  and illustrated in Neurosyphilis is a reemerging infectious disease that can be transmittedsexually and vertically. It has a wide spectrum of neurologicalmanifestations and can mimic many other infectious and inflammatorydiseases, as well as tumors and demyelinating processes. Recently,highresolution vessel wall imaging (HR-VWI) has proven useful todifferentiate ischemic lesions from vessel wall inflammation associated withinfectious vasculitis, and HR-VWI sequences can depict cranial nerveenhancement in infectious conditions, as demonstrated by Feitoza etal.((7).Facial nerve palsy results from edema and compression of the facial nerve within the narrow facial canal and is accompanied bysensorineural hearing loss, tinnitus, vertigo, nystagmus, and erythematousvesicular rash around the ear (herpes zoster oticus). The MRI features offacial nerve palsy are nonspecific, although contrast enhancement at thefundus of the inner ear canal, representing inflammatory changes, is common.In rare cases, Ramsay Hunt syndrome occurs as a component of multiplecranial nerve involvement, especially that of the trigeminal,glossopharyngeal, and vagus nerves . Edema and enhancement of trigeminal brainstem nuclei can alsobe seen.Ramsay Hunt syndrome is one of several causes of peripheral facial nervepalsy in the geniculate ganglion. It occurs due to reactivation of latentinfection with the varicella-zoster virus, which causes inflammation andneural degenerationThe condition known as Bell\u2019s palsy is a type of facial nerve palsy that canbe idiopathic or of suspected viral etiology.(7). Laboratory tests areusually not indicated. However, because at least 10% of affected patientsare diabetic, a blood glucose test may be performed. There are severaldifferential diagnoses, including Lyme disease, Ramsay Hunt syndrome,neoplasia, and sarcoidosis. A detailed history-taking usually facilitatesthe diagnosis. The MRI findings are nonspecific and typically includeunilateral facial nerve enhancement.It is the most common cause of acute spontaneous peripheral facial paralysis.Herpes simplex virus activation is the likely cause of Bell\u2019s palsy in mostcases, although there is no well-established, widely available method ofconfirming a viral mechanism in clinical practice. Inflammation starts atthe geniculate ganglion, extending proximally and distally, causing facialpalsy due to neural edema inside the narrow facial canalParacoccidioides spp. (P. brasiliensisor P. lutzii), which can result in systemic granulomatousinfection. It is most commonly observed in adult male laborers in ruralsubtropical areas of Latin America(8). Involvement of the CNS occurs in 10% of chroniccases, and patients with CNS paracoccidioidomycosis may present with focalneurological deficits, cognitive changes, weight loss, headache, andseizures. The most common CNS lesions are due to granulomatous reactions inthe supratentorial and infratentorial parenchyma. However, in some cases,there can be leptomeningeal and pachymeningeal inflammation caused bycranial nerve inflammation. The diagnosis of CNS paracoccidioidomycosis isestablished by direct detection of the fungus, through biopsy or resectionof a granuloma, CSF analysis, or culture. Although the MRI findings arenonspecific, they can contribute to the diagnosis by depictingring-enhancing lesions in the parenchyma. Leptomeningeal or pachymeningealenhancement may also be seen.Paracoccidioidomycosis is a fungal disease caused byEchinococcus multilocularis andEchinococcus granulosus, which cause alveolar andcystic echinococcosis, respectively. Alveolar echinococcosis is uncommon andoccurs secondary to intrahepatic growth of parasitic larvae. Cestodes reachother organs  by direct infiltrationor hematogenous spread. In individuals with alveolar echinococcosis, cranialnerve palsies have been reported and the symptoms depend on the location ofthe lesions(9). Wild canidsand domestic dogs act as the definitive hosts of E.granulosus, the causative agent of cystic echinococcosis , and human infection with E.granulosus occurs through contact with contaminated animals.Neurological involvement, which is rare, may include the brain parenchyma orsubarachnoid space .Among petrous apex meningiomas, the most common types are petroclival andcerebellopontine angle meningiomas. Petroclival meningiomas arise from themedial aspect of the petrous apex and progress through its wall or toDorello\u2019s canal, whereas cerebellopontine angle meningiomas arise from theposterior petrous apex and extend to the internal auditory canal. The MRIfindings are variable, although dural-based masses with intense contrastenhancement, often hypointense to brain tissue on T1-weighted imaging (T1WI)and isointense on T2WI, are common findings(11).Pilocytic astrocytoma is the most common primary brain tumor in children. Thestructures most often affected are the cerebellum, optic nerve/chiasm,hypothalamus, and thalami. It is commonly associated with neurofibromatosistype 1, especially when it occurs in the optic pathways. In individuals withoptic nerve pilocytic astrocytoma, MRI shows well-circumscribed,slow-growing tumors that are hypointense or isointense to brain tissue onT1WI and hyperintense on T2WI/FLAIR sequences, with little or no edema.Enhancement is variable, usually intense. Another common presentation is acystic lesion with a mural noduleSchwannoma is a benign nerve sheath tumor derived from Schwann cells. It isthe most common tumor of the peripheral nervous system. The cranial nervethat is most often affected (in 90% of cases) is the vestibulocochlear nerve, followed by the trigeminal nerve .Acoustic schwannomas grow into the cerebellopontine angle, displacing thebrainstem and cerebellum. In most cases, these originate from within theinternal auditory canal, the dilation of which is an early radiological signof tumor growth. Bilateral acoustic schwannomas are pathognomonic ofneurofibromatosis type 2, which is a phakomatosis that also increases thechances of meningiomas and ependymomas , as illustrated in (12),as demonstrated in An esthesioneuroblastoma, also known as an olfactory neuroblastoma, is amalignant neuroectodermal tumor arising from the olfactory mucosa in theupper nasal cavity. It typically affects men, being most common among thosein their twenties, with a second peak among those in their sixties. Itusually involves the cribriform plate, extending to the upper nasal cavity.Smaller esthesioneuroblastomas will show local spread in the nose andsinuses, whereas larger ones may invade anterior the cranial fossa, brain,and dura mater. Imaging depicts a dumbbell-shaped mass with its narrowsegment at the level of cribriform plate, causing local bonedestruction(13)and depicted in Figure 8Temporal bone paragangliomas, also known as jugulotympanic paragangliomas,are tumors that arise from the extra-adrenal neuroendocrine system, arecomposed of neural crest progenitor cells, and are usually benign.Involvement of the jugular foramen is most prevalent among individuals intheir fifties or sixties, representing the main cause of pulsatile tinnitusassociated with a vascular retrotympanic mass, as identified on physicalexamination(13).Paragangliomas may also occur in the carotid space, presenting as a massbetween the internal and external carotid arteries. Cranial neuropathy,which is seen in 20% of patients with carotid body paraganglioma, caninvolve the glossopharyngeal, vagus, accessory, and hypoglossal nerves. Unenhanced MRI showspunctate vascular flow voids , whereascontrast-enhanced MRI shows a mass with rapid, intense contrastenhancement(14). The general imaging features of acute multiplesclerosis are swollen, enhancing areas that are isointense on T1WI andusually bright on T2WI/FLAIR sequences, with or without restricted diffusionon DWI. In the chronic phase, the lesions are usually hypointense andnonenhancing on T1WI (\u201cblack holes\u201d), being bright on T2WI/FLAIR sequences,sometimes with visible volume loss or cavitation. Cranial nerves may appearenlarged with marked enhancement(15).Multiple sclerosis is a multifactorial disorder with an inflammatoryautoimmune component, characterized by inflammatory and immune attacks onoligodendrocytes, resulting in demyelination and axonal injury. It is themost common disabling CNS disease in young adults, more often affectingwomen than men and being most prevalent among individuals 20\u201340 years ofage. The lesions are predominantly located in the white matter, typically inthe periventricular region (Dawson\u2019s fingers), corpus callosum, subcorticalregions, brainstem, and spinal cord, although they may occur in the graymatter as well. Isolated cranial nerve involvement is uncommon, and cranialnerve injury is frequently seen in conjunction with other brain lesions. Theoptic and trigeminal nerves  are themost affected, although cases of isolated oculomotor nerve  dysfunction have also been reported(16).Neuromyelitis optica spectrum disorders constitute a group of autoimmunedemyelinating CNS diseases that preferentially affect the optic nerve,periventricular regions (including the area postrema), and spinal cord. Theyare typically associated with an immune response (neuromyelitisoptica-immunoglobulin G antibody against aquaporin 4 channels). In general,the imaging features are longitudinally extensive T2WI hyperintensity withinthe spinal cord , as well asenlargement and enhancement of the optic nerve . On T2WI,the abnormality tends to involve the spinal cord more centrally or theentire cross-section of the cord, unlike the more peripheral involvementseen in multiple sclerosis(17).Chronic inflammatory demyelinating polyneuropathy is an acquired sensorimotoridiopathic neuropathy that primarily involves the distal motor nerve.Cranial nerve involvement is seen in 5% of patients, in which MRI may showthickened, enhancing nerves .It has (18), which may involve other cranial nerves as well. TheMRI findings include high signal intensity of the inflamed brainstem segmenton T2WI and contrast enhancement of the affected nerve on T1WI  into the brainstem, albeit rare, maycause rhombencephalitis on T1WI . We pres(19).Hemophagocytic syndrome, Erdheim-Chester disease, and Rosai-Dorfman diseaseare all forms of non-Langerhans cell histiocytosis, which is a raremultisystemic disease of the monocyte-macrophage system, with variableseverity and radiological presentation. Among children under 15 years ofage, it has an incidence of 0.2\u20132.0 cases per 100,000 population, with aslight predominance of males. The cranial and intracranial changes seen onMRI may include craniofacial bone and skull base lesions, with or withoutsoft-tissue involvement, as well as intracranial and extra-axial changes inthe hypothalamic-pituitary region, leptomeninges, cranial nerves, andcircumventricular organsThis pictorial essay could help narrow the differential diagnosis of nonspecificimaging findings of cranial nerves, which typically include thickening andenhancement. Although infectious, neoplastic, demyelinating, and inflammatorydiseases of the cranial nerves may look alike on MRI, scrutiny of other brainimaging findings, correlated with the clinical and biochemical data, facilitates thedifferential diagnosis. Therefore, radiologists play a key role in making theaccurate diagnosis of such diseases."}
+{"text": "H. pylori status, among others. Although H. pylori colonization has been reported across the world, chronic H. pylori infection may lead to serious consequences; therefore, the infection must be treated. Multiple antibiotic therapy improvements are not always successful because of the lack of adherence to the prescribed antibiotic treatment. However, the abuse of eradication treatments can generate gastric dysbiotic states. Dysbiosis of the gastric microenvironment induces microbial resilience, due to the loss of relevant commensal bacteria and simultaneous colonization by other pathobiont bacteria, which can generate metabolic and physiological changes or even initiate and develop other gastric disorders by non-H. pylori bacteria. This systematic review opens a discussion on the effects of multiple environmental factors on gastric microbial communities.Microbiomes are defined as complex microbial communities, which are mainly composed of bacteria, fungi, and viruses residing in diverse regions of the human body. The human stomach consists of a unique and heterogeneous habitat of microbial communities owing to its anatomical and functional characteristics, that allow the optimal growth of characteristic bacteria in this environment. Gastric dysbiosis, which is defined as compositional and functional alterations of the gastric microbiota, can be induced by multiple environmental factors, such as age, diet, multiple antibiotic therapies, proton pump inhibitor abuse,  Relative abundances of Bacteroidaceae, Enterobacteriaceae, and Porphyromonadaceae families and genera Bacteroides, Parabacteroides, Streptococcus, and Lactococcus were observed to be significantly increased in H. pylori-positive patients when compared to the microbiota of healthy subjects. H. pylori-positive patients also showed a significantly higher abundance of Bacteroidaceae and Enterobacteriaceae, while the families Bifidobacteriaceae, Lactobacillaceae, and Lachnospiraceae showed a lower relative abundance in both H. pylori-positive and negative patients when compared to healthy subjects [A study performed with pediatric patients who were diagnosed with dyspepsia, both, subjects .n = 15) shared phyla Proteobacteria and Firmicutes with a relative abundance of 70%. In this work, gradual microbiota alterations were found, specifically decreasing relative abundances of TM7, Porphyromonas, and Neisseria, while specific genera such as Lactobacillus coleohominis, and Lachnospiraceae gradually increased in the microbiota of patients with non-atrophic gastritis to intestinal metaplasia to gastric cancer, respectively [Aviles-Jim\u00e9nez et al. observed that all patients with non-atrophic gastritis, intestinal metaplasia, and gastric cancer , Bacteroides fragilis, B. uniformis, Bacillus cereus, and Akkermansia muciniphila were significantly different across the three microenvironments. Interestingly, C. acnes, S. anginosus, and P. melaninogenica were abundantly present in tumoral microhabitats, while the presence of B. uniformis and P. copri decreased significantly; meanwhile, A. muciniphila and B. fragilis demonstrated similar bacterial alteration patterns when analysing the variation between peritumoral and tumoral microhabitats [A study performed by Liu et al. on 276 patients with gastric cancer, assessed the diversity and composition of the gastric microbiota across three microenvironments: tumoral and peritumoral microhabitats and compared them with subjects having normal gastric mucosal morphology . They observed that habitats .It has been recently hypothesized that bacterial species with nitrate-reducing metabolism contribute to gastric malignant transformation by crescent intragastric concentrations of nitrite and N-nitroso compounds. Ferreira et al. fully reconstituted the gastric metagenomes from patients with gastric carcinoma revealing that the functional composition of total microbiota from these patients increased the nitrate reductase functions, promoting the reduction of nitrate to nitrite, and nitrite reductase functions, promoting the reduction of nitrite to nitric oxide when compared to the functional composition of chronic gastritis patient\u2019s microbiota. These findings provide evidence that microbial communities with genotoxic potential are present in patients with gastric carcinoma .C. acnes, H. pylori, and P. copri relative abundances in patients with gastric cancer when compared with the controls, whereas the relative abundance of L. lactis was significantly higher. Patients with these significantly higher relative abundances showed a higher risk of developing gastric cancer. Although H. pylori infection was observed to be the strongest single risk factor for gastric cancer, researchers also observed high C. acnes relative abundance in these patients, revealing that this bacterium increases the risk for the development of gastric cancer, highlighting a commensal skin bacterium recently identified as a gastric microbiota resident [A case-control study performed by Gunathilake et al. which involved 556 participants, showed high resident .H. pylori with multiple antibiotic therapies combined with PPIs was observed to reduce the risk of gastric cancer; an effect that may be limited to gastric cancer patients without atrophy and metaplasia [H. pylori eradication was observed to reduce symptomatology, but did not stop the progression of the neoplasia, indicating that cancer can occur even ten years after H. pylori eradication treatment [Eradication of taplasia ,47,48. Ireatment .Self-medication is considered a potential contributor to human pathogen resistance to antibiotics. However, adverse consequences of such practices are difficult to evaluate due to affected bacteria by some aggressive drugs  are just not pathogens, but also gastrointestinal commensal bacteria, altering the native microbiota.a \u2264 4). These compounds are rapidly activated by the acids previously secreted by gastric parietal cells. High acidity acts as a protonation factor for activation of these weak bases to form disulphides (thiophilic drugs) by binding to cysteine residues residing in the (H+/K+ ATPase) proton pumps. Disulphides react with luminally accessed cysteines on the acid pump enzyme, blocking acid transport and altering gastric acidity to pH = 7 [The use of PPIs is common in patients diagnosed with gastroesophageal reflux and functional dyspepsia. PPIs are defined as prodrugs that are activated by acid and lower pH of the local microenvironment. PPIs are known as weak bases  presented with a significantly fewer number of species. In PPI-treated patients, Streptococcaceae (17%) was the most abundant family, outranking Prevotellaceae (11%), Campylobacteraceae (5%), and Leptotrichiaceae (4%). At the operational taxonomic unit (OTU) level, Cyanobacteria and Streptococcus relative abundances were significantly increased in PPI-treated patients; however, the relative abundances of genera Actinobacillus, Porphyromonas, Leptotrichiaceae, Prevotella, Treponema, Haemophilus, Fusobacterium, and Tannerella were significantly decreased in patients treated with PPIs [The microenvironmental changes generated by PPIs alter the native gastric conditions significantly and develop histopathological damage including the enlargement of fundic glands E,F and mith PPIs .Helicobacter, Prevotella, Streptococcus, Veillonella, Neisseria, Porphyromonas, Fusobacterium, Gemella, Haemophilus, and Leptotrichia, representing the ten most abundant genera  [In a second study performed on 12 patients who presented dyspepsia and were treated with a PPI, the phyla Proteobacteria, Actinobacteria, Fusobacteria, Bacteroidetes, and Firmicutes represented the five most abundant phyla in 98% of total sequence reads. Among them, Proteobacteria, Bacteroidetes, and Firmicutes were dominantly abundant; 115 genera were identified in total, including the genera ctively) .Successful bacterial eradication treatments significantly affect the gastrointestinal microbiota . IncreasDysbiosis is the most important consequence of adverse effects of antibiotic therapies, which has favored the presence of microorganisms carrying antibiotic resistance genes, facilitating horizontal gene transfer between commensal and pathogen bacteria, as well as assisting in the recolonization of gastrointestinal mucosa by pathobionts . AntibioH. pylori infection induces a mild-to-severe inflammatory process; however, the gastric mucosa of patients with different gastric alterations can harbor non-H. pylori bacteria, which can induce and potentialize inflammatory processes that can lead to a malignant transformation in the stomach, e.g., genera Acinetobacter and Klebsiella, associated with gastric carcinogenic processes [Cutibacterium, which is a dominant genus in pilosebaceous follicles and a native member of mucosa and skin microbiota, was recently named a pathobiont related to the microbiota of immunocompromised patients and considered as a trigger of corpus-dominant lymphocytic gastritis [Corynebacterium, as a member of human native microbiota, is frequently isolated from the skin, mucosal membranes, and gastrointestinal tract [rocesses ,57; genuastritis ,59,60; aal tract ,62,63.Peptococcus, Eubacterium, Clostridium difficile, C. perfringens, Veillonella, Bacteroides fragilis, Fusobacterium, and Peptostreptococcus [H. pylori infection with several therapies  in patients with distinct diseases are shown. As can be seen, not only microaerophilic or anaerobic bacteria are affected by these therapies, but also facultative and aerobic bacteria, although in different relative abundances and richness parameters. This observation may be attributed to the interindividual variability of the study subjects, which usually makes it difficult to identify the distinctive pathogenic species among patients at risk of developing gastric diseases from those who are not at risk [H. pylori eradication on the gastrointestinal microbiota of patients with duodenal ulcers. Before the eradication treatment, the Clostridium leptum and Prevotella subgroups were aberrantly different between gastric corpus and antrum. Pre-treatment peptic ulcer patients who were administered with antibiotic therapies  for H. pylori eradication demonstrated that the relative abundances of the Lactobacillus group, Enterobacteria, and C. leptum subgroup were significantly increased in antrum, while for the Clostridium coccoides subgroup relative abundances were lower. After treatment, recolonization with Lactobacillus was more abundant in antrum than in the corpus. H. pylori-negative patients with antral gastritis showed higher Enterobacteria relative abundances, suggesting that H. pylori inhibited the distribution of these bacterial families [For more than 30 years, it has been observed that multiple antibiotic therapies, which usually include metronidazole, mainly affect anaerobic and microaerophilic microorganisms. The metronidazole antimicrobial spectrum activity includes anaerobic bacteria, such as tococcus . However at risk ,65. Li efamilies . H. pylori eradication can result in resilience, which is defined as the microbial composition recovery whether by growth, physiological or genetic adaptation, after composition alterations due to the host, or environmental factors of the gastric microbiota. Gastric resilience can occur with specific bacterial species such as Granulicatella, Streptococcus, Rothia, Leptotrichia, Acinetobacter, Faecalibacterium, Rahnella, Kaistobacter, Blautia, Caulobacter, Nocardioides, and Brevundimonas. However, recolonization and the increase in relative abundances with these bacterial species can be associated with the emergence of atrophy or intestinal metaplasia (IM) following one year of H. pylori eradication , or the presence of persistent inflammation processes  [votella) .Antibiotic therapies (monotherapies or multiple antibiotic combinations) are one of the most extreme disturbances occurring in the human microbiome . TherefoThe search for new alternatives in antimicrobial therapies for pathogen eradication is much needed, with a special interest in natural product-based therapies , such asEnterococcus faecalis, Bacteroides fragilis, and Escherichia coli) may increase the risk of developing cancer. Rare cases have been documented, where FTM-associated bacteria can cause serious problems, or even death [Defined as the transfer of stool from a healthy donor into the gastrointestinal tract of a patient to restore the composition of the microbiota , faecal en death , suggestH. pylori treatment [2O2, and NO molecules [Probiotic supplementation therapies are emerging therapies for reatment . Probiotreatment . Lactic olecules ,77. ThesH. pylori through metabolite production, secretion, or bacterial cells. Several studies have determined the capability of four strains of Lactobacillus for inhibiting H. pylori growth [L. pentosus LPS16 [L. bulgaricus, that can inhibit not only antibiotic-sensitive H. pylori strains but also inhibit antibiotic-resistant strains [H. pylori growth inhibition for maintenance of both gastric and intestinal microbiota has also been demonstrated [In vitro experiments have demonstrated that several probiotics have the potential to antagonize i growth , urease i growth , drug-seus LPS16 ; bacterius LPS16 , such as strains . Moreovenstrated .Roseburia intestinalis, Faecalibacterium prausnitzii, Eubacterium spp., Bacteroides spp., Akkermansia municiphila), thus expanding the possibilities of research on probiotics and their relationship with emerging healthcare challenges [The recent development of low-cost whole-genome sequencing has allowed the characterization of new bacteria with high potential for health benefits, with the opportunity to be developed as probiotics . Althougallenges .Helicobacter pylori usually induces dysbiosis in the stomach, in some cases defining serious diseases, e.g., gastric cancer. Its eradication with different therapies causes significant alterations that might not always carry optimal colonization, e.g., metabolic and immunological implications, or even the initiation and development of gastric disorders caused by non-H. pylori bacteria. The use of alternative antibiotic therapies, such as probiotics, can improve, in most cases, the process of bacterial resilience.During the development of gastric diseases and their therapeutic treatments, the native microbial composition of the patient can be altered, generating dysbiotic states. The presence of"}
+{"text": "Inappropriate antibiotic (AB) use for viral respiratory illnesses remains widespread in the United States (US) with strong seasonal fluctuations. In contrast to outpatient AB use, the seasonality inpatient AB utilization (IAU) and its correlation with the influenza season are not well understood. We sought to describe trends, seasonality, and the association between IAU use and the 2015-2019 influenza seasons.BD Insights Research Database  to identify IAU that were prescribed in patients >17 years old from up to 236 US acute care facilities from July 2015 to December 2019. We included the following AB categories: extended spectrum cephalosporins (ESCs), macrolides, \u03b2-lactam inhibitor combination (BLIC), fluoroquinolones, carbapenems, glycopeptides, lipopeptide, tetracyclines, and others. We defined IAU use as days of therapy (DOT) per 1000 patient days present. We used influenza laboratory data to identify facility-level positivity ratio per 100 tests. We used random effect models to estimate IAU: 1) trends overtime, 2) seasonality, and 3) association with influenza positivity rate.We used the For IAU from 2015 to 2019, BLICs, ESCs, and glycopeptides were the most used . Visually, we observed strong seasonality that matches the influenza season for macrolide, ESC, and quinolone use . Unadjusted bivariate results showed ascending trends over time for BLICs , ESCs , and macrolides . Unadjusted bivariate results showed descending trends with quinolones  and others . In the adjusted analysis, increased influenza positivity rate was associated with use of ESCs, glycopeptides, lipopeptides, macrolides, fluoroquinolone, and tetracyclines (see Table). No correlation was observed with BLICs, carbapenems, lipopeptides, and Others.IAU (DOT/1000 days presents) and Flu Rate (% Positive) Trends Over TimeOur study shows that IAU is on the rise for the ESC and BLIC classes. ESC and macrolide use was strongly correlated with influenza season. Monitoring influenza signals may provide more insights that can inform the interpretation of IAU trends and be incorporated into antimicrobial stewardship programs.Amine Amiche, PhD, Sanofi  Heidi Kabler, MD, Sanofi Pasteur (Employee) Janet Weeks, PhD, Becton, Dickinson and Company (Employee) Kalvin Yu, MD, BD (Employee) Vikas Gupta, PharmD, BCPS, Becton, Dickinson and Company"}
+{"text": "Bioactive compounds with unique functional attributes such as hypoglycemic, hypolipidemic, antidiabetic, anti-inflammatory, antimicrobial and antioxidant are of growing interest due to their widespread food, nutraceutical, medicine, cosmetics, chemical and agricultural applications. Their commercial use, however, is sparse due to poor solubility, instability and susceptibility to light, heat, oxygen, acid and alkaline conditions. Their low and inconsistent bioavailability and efficacy further hamper the large-scale utilization. To overcome these predicaments, design and development of innovative and high-performance protection and delivery systems are in great demand. Toward this end, food-grade materials gained much attention due to their intrinsic biocompatibility, biodegradability and reduced environmental impact . NanostrDespite significant progress and knowledge advancement, there are many lingering issues and challenges, for example, need for more diverse source of environmentally friendly materials to build delivery cargos, delivery systems design with multi-functionality, facile and low manufacture cost fabrication protocols along with cost-effective analytical characterization tools on bioactive bioavailability, to name a few. In this special issue, researchers around the world were invited to contribute their seminal works on the bioactive compounds delivery with an emphasis on the current updates and design strategies. Experimental data and reviews are reported along with nanotechnology-based delivery systems to administer the lipophilic ingredients with improved solubility and bioavailability.Wang et al. These nanoparticles possess smooth spherical shape with a size range of 180\u2013250\u00a0nm. The DSS located on the hydrophilic exterior reduces the surface hydrophobicity and increases the encapsulation efficiency with improved bioavailability of quercetin, which certainly stands-out as an attractive carrier system for bioactive compounds. A bird\u2019s eye view on various aspects of lipid nanoparticles (solid lipid nanoparticles and nanostructure lipid carriers) as carriers of bioactive molecules, including synthesis, characterization, advantages, disadvantages, toxicity and applications have been narrated by Dhiman et al. A comprehensive literature review on the recent advances of protein/peptide-based nanohydrogels toward bioactive delivery, including preparation, biophysiochemical aspects and applications in diverse disciplines like in drug delivery, immunotherapy, intracellular delivery, nutraceutical delivery, cell adhesion and wound dressing has been exemplified by Chander et al. Nanohydrogels are excellent biomaterials with three-dimensional cross-linked networks and are composed of diverse types of proteins with high biocompatibility and metabolic degradability. The advantages, limitations, overview of clinical potential, toxicity aspects, stability issues, and future perspectives of protein nanohydrogels have also been discussed. Acevedo-Fani et al. reviewed the nature-assembled structures for delivery of bioactive compounds and their potential in functional foods. They bring out the nature-origin structure and biological function of different nature-assembled carriers, namely casein micelles, milk fat globules and oleosomes along with preparation/isolation methods, advantages and challenges, and the behavior of these structures during digestion.A nano-formulation of zein and dextran sulfate sodium (DSS) binary complex for sustained delivery of quercetin has been reported by This collection is deemed to provide a central venue for researchers and scientists with interests to create high quality, safer, nutritious, sustainable and more abundant delivery systems supply of bioactive compounds."}
+{"text": "There are errors in the Author Contributions. The correct contributions are: All authors contributed equally to conceptualization, data curation, formal analysis, investigation and writing."}
+{"text": "Traditional diagnostic strategies for infectious disease detection require benchtop instruments that are inappropriate for point-of-care testing (POCT). Emerging microfluidics, a highly miniaturized, automatic, and integrated technology, are a potential substitute for traditional methods in performing rapid, low-cost, accurate, and on-site diagnoses. Molecular diagnostics are widely used in microfluidic devices as the most effective approaches for pathogen detection. This review summarizes the latest advances in microfluidics-based molecular diagnostics for infectious diseases from academic perspectives and industrial outlooks. First, we introduce the typical on-chip nucleic acid processes, including sample preprocessing, amplification, and signal read-out. Then, four categories of microfluidic platforms are compared with respect to features, merits, and demerits. We further discuss application of the digital assay in absolute nucleic acid quantification. Both the classic and recent microfluidics-based commercial molecular diagnostic devices are summarized as proof of the current market status. Finally, we propose future directions for microfluidics-based infectious disease diagnosis. Infectious diseases arise from pathogens, including bacteria, viruses, and parasites, with a global distribution. Unlike other diseases, pathogens rapidly infect and are transmitted between human and animal carriers through inoculation, air, and water media . It is eAmong the existing strategies for diagnosing infectious diseases, molecular diagnostics are among the most sensitive methods , 16. MorBased on the implemented functions, the modules of a microfluidic chip for nucleic acid testing can be divided into three categories  . Among tThe foremost step of nucleic acid testing is nucleic acid extraction, which refers to the isolation of targeted nucleic acid from the original samples. Nucleic acid extraction is performed to purify nucleic acids from other molecular pollutants, ensure the integrity of the primary structure of nucleic acid molecules, and to optimize outturns. Nucleic acid extraction requires essential sample lysis and nucleic acid capture, the quality and efficiency of which have a huge impact on the research and diagnosis results. Any subtle adverse effects during extraction limit downstream detections. For example, polymerase chain reaction (PCR) and loop-mediated isothermal amplification (LAMP) approaches are inhibited by some residual organic solvents in nucleic acid extraction reagents such as ethanol and isopropanol . Liquid\u2013Silicon is a compatible substrate material for nucleic acids because silicon is biocompatible, stable, and has easily modifiable properties . Importa2\u2013108 colony-forming units (CFU)/ml of Vibrio parahaemolyticus were successfully detected, and the existence of the virus was easily visualized. Powell et al. . The advantages of magnetic beads in combination with microfluidics for automated nucleic acid extraction with high efficiency have the potential to facilitate the growth of molecular diagnostics; however, magnetic beads in combination with microfluidics are still largely dependent on complex control systems to precisely manipulate magnetic beads, which explains why prevailing commercial products are bulky and expensive, restricting the further application of magnetic beads in POCT.The magnetic bead methods provide the possibility for automated extraction, of which some commercial automatic nucleic acid extractors exist  [\u00ae [BOHUI ] [\u2122-A  [\u2122-W  [\u2122 [Cue health ] [\u2122 [Focus Diagnostics ] [\u00ae [Mobidiag ] [\u00ae Liat\u00ae [Roche ] [\u2122 [Visby Medical ] [\u2122 F-150 Real-time PCR Systems [Wizbiosolutions ]  [\u2122 [Biocartis ] to target clinically-significant test sites of genes, such as BRAF, KRAS, NRAS, and EGFR  , GenPlex China)] , Vivalyt China)] , RTisochitalBio) , RTisochitalBio) , 179, DxitalBio) , Cue\u2122  , Simplex, U.S.)] , QuanPLE, U.S.)] , a micro, U.S.)] , Novodiainland)] , Cobas\u00ae , U.S.)] , iGeneTe, U.S.)] , BINAS  , Visby M, U.S.)]  and WizD Korea)] . Most of Korea)] , 192 can, U.S.)]  and matcand EGFR . Becauseand EGFR  and Onesand EGFR  from Bai EGFR [\u2122  from BD A, U.S.) , UnyveroA, U.S.)  from CurU.S.) [\u00ae  from GenU.S.) [\u00ae  from Generigene\u00ae  from NanCommercial microfluidic POCT devices are attempting to keep up with the modern medical tests conducted at hospitals and laboratories on test sensitivity and specificity. Commercial microfluidic POCT devices are showing exclusive advantages, especially in detecting diversity and degree of integration. In an epidemic, commercial microfluidic devices are of great importance in diagnosis because of efficient technologies, optimized reaction conditions, and convenience without the need for a large-scale laboratory or testing center. Because commercial microfluidic POCT devices were developed during a disease outbreak in a short time by transplanting conventional steps, there is still much room for development with respect to the level of efficiency, automation, integration, sensitivity, specificity, portability, and affordability, thus making the industry in its early stage of application. We are expecting qualified techniques combined with elaborately designed and fabricated chips to get sample-to-result instruments.Infectious diseases are posing problems for public medical systems and attracted much attention from the public and scientists. Microfluidics is one of the best technologies to conduct molecular diagnostics for infectious diseases and has made great achievements, especially during the outbreak of COVID-19. In this review we presented the applications of microfluidics-based strategies for infectious disease detection. In the first part, we systematically discussed the common processes of molecular testing based on microfluidics, including sample preprocessing , nucleic acid amplification , and signal reading-out . Next, various microfluidic platforms, including LOCC, LOAD, \u03bcPADs, and LFA, were compared to highlight the features, advantages, and disadvantages. We further discussed and emphasized the novel applications of the digital nucleic acid assay for absolute quantification. Subsequently, we investigated 27 commercial microfluidics-based POCT devices for molecular diagnostics from a decade ago and displayed the targeting objectives and performances.There is still ample room for the development of microfluidics to deal with the severe, ongoing pandemic. More significantly, new infectious diseases may emerge in the near future. The traditional technologies are mature and optimized, but require multiple steps and frequent transfers of samples between platforms. These sophisticated processes lead to unnecessary pollution and complicated manual operations. Thus, the trend of fully integrated microfluidics is unstoppable, which combines sampling, sensing, and signaling modules. In the sampling module, a large quantity of molecules is expected to be extracted from the limit sample, therefore providing efficient cleavage enzymes, nucleic acid transport carriers, and cleaning agents. In the sensing module, the false-negative results caused by low-sensitive detection usually lead to misdiagnosis and create a burden in the public medical system. Prevention of pandemics calls for high-throughput testing that can precisely detect very few nucleic acids. In practical applications, the diagnostic requirements are so diverse that multiplex diagnostics are more suitable for future tests with expended testing items. In the signaling module, great efforts have been made to accurately identify signals transformed from amplified molecules by algorithms incorporating artificial intelligence, avoiding errors and limitations of manual judgments. There are also some novel strategies still in their early stages; for example, target molecules can be directly tested from sample solutions omitting the pretreatment process. Therefore, nucleic acids must be specifically distinguished between cluttered background molecules, which is challenging. In addition, detecting nucleic acids bypassing sensing modules demands more sensitive testing methods, such as CRISPR, which can respond significantly to individual molecules.. Fortunately, in dealing with infectious diseases currently and in the future, microfluidic-based molecular diagnostic strategies are indispensable and receiving more attention from frontier scientists. Microfluidics-based molecular diagnostic strategies will become the mainstream of large-scale detection, utilizing rarely required samples, to conduct diagnosis automatically at a low cost.Moreover, the industrialization of microfluidics is still in the start-up phase, reflected in complex channel design, expensive substrate materials, necessary optimization of reactions, liquid leakage, valve failure, and difficulty in reproduction and recyclability. These issues are the main barriers for large-scale adoption, so further improvement is needed to build a convenient chip-design platform, combined with material science to find less expensive substrate substitutes, enhance functional modularity, and push automation of chip producing"}
+{"text": "Leishmania, Endotrypanum, and Crithidia, which span the phylogenetic diversity of the subfamily Leishmaniinae within the kinetoplastid order of the phylum Euglenazoa. These resources will support studies on the origins of parasitism.We report the high-quality draft assemblies and gene annotations for 13 species and/or strains of the protozoan parasite genera  Leishmania species are widespread parasites of mammals transmitted by biting insects. Over 1.7 billion people worldwide are at risk, with hundreds of millions of people infected  , a successor to ABACAS  . The totciences)  softwarer et al.  for 454 r et al.  for Illur et al.  for longr et al. . Contigso ABACAS , by aligegabases .de novo prediction criteria, as well as information from closely related genomes when available (Leishmania species (www.tritrypdb.org).Gene annotations were performed using the comprehensive Companion tool, which incorporates a variety of vailable . The num species . Full anPRJNA50303, PRJNA50301, PRJNA192717, PRJNA192712, PRJNA192710, PRJNA169676, PRJNA169673, PRJNA165955, PRJNA165959, PRJNA192711, PRJNA192703, PRJNA165953, and PRJNA165885). The chromosome builds are available through the TriTrypDB portal (http://tritrypdb.org/tritrypdb).The assemblies have been deposited in the NCBI GenBank repository under the BioProject accession numbers in"}
+{"text": "Maintaining independence while aging in place at home requires support, especially for older adults aging with long-term mobility disabilities. As age-related changes progress, individuals with long-term mobility disabilities experience more challenges engaging with daily living activities (ADLs) and instrumental activities of daily living (IADLs). To understand the activity challenges of these older adults, we analyzed the interview data from the Aging Concerns, Challenges, and Everyday Solution Strategies (ACCESS) study, a comprehensive user needs assessment of 60 older adults who have had mobility disabilities for at least ten years . We selected interview data that focused on the conduct of ten activities at home: bathing, dressing, moving around, toileting, transferring, doing hobbies, housekeeping, home maintenance, managing diet and nutrition, and caring for others. This archival study used the coding schemes from the ACCESS study that were developed using both conceptual- and data-driven approaches . The ecological theory of adaptation and aging  was the underlying framework to identify the challenges related to older adults' functional capacity  and physical environmental barriers . We identified five main challenges: physical strength, general health limitations, mobility limitations, physical access, and transferring. Older adults' responses to overcoming the challenges involved personal, environmental, and person-environment interaction strategies. This study provides insights into the relationship between the source of environmental barriers and personal coping strategies to guide the design of appropriate aging in place supports for older adults with mobility disabilities."}
+{"text": "Metabolomics has been applied to measure the dynamic metabolic responses, to understand the systematic biological networks, to reveal the potential genetic architecture, etc., for human diseases and livestock traits. For example, the current published results include the detected relevant candidate metabolites, identified metabolic pathways, potential systematic networks, etc., for different cattle traits that can be applied for further metabolomic and integrated omics studies. Therefore, summarizing the applications of metabolomics for economic traits is required in cattle. We here provide a comprehensive review about metabolomic analysis and its integration with other omics in five aspects: (1) characterization of the metabolomic profile of cattle; (2) metabolomic applications in cattle; (3) integrated metabolomic analysis with other omics; (4) methods and tools in metabolomic analysis; and (5) further potentialities. The review aims to investigate the existing metabolomic studies by highlighting the results in cattle, integrated with other omics studies, to understand the metabolic mechanisms underlying the economic traits and to provide useful information for further research and practical breeding programs in cattle. The omics, such as genomics, transcriptomics, epigenomics, proteomics and metabolomics, have emerged, whereas the terms genome, transcriptome, epigenome, proteome and metabolome are used to address the objects of such studies, respectively ,2,3,4,5.Currently, the applications of metabolomics have increased to measure metabolic responses dynamically, identify biologically relevant candidate metabolic markers, reveal potential genetic architecture and understand the systematic networks underlying the economic traits for cattle ,11,12,13Given the previous findings in different traits , it is essential to summarize the major results of metabolomic analysis for further research and applications in cattle, as well further ingratiation analysis with other omics. Therefore, this review aims to investigate the existing metabolomic studies by highlighting the results from five aspects in cattle, integrated by other omics studies, e.g., genomics, transcriptomics, epigenomics, microbiomics, etc., to understand the metabolic mechanisms underlying the economic traits in cattle and to provide useful information for further cattle research and practical breeding programs.The diversities of metabolome characterization occurring in cattle depend on the different breeds, traits, tissues, times, etc. To generate a better understanding of the underlying metabolic mechanisms in cattle, candidate metabolic biomarkers for various tissues and their enriched metabolic pathways are summarized in this review for important economic traits, such as feed efficiency and disease.Based on previous studies, we found that researchers investigated the metabolomics of plasma, serum, milk, rumen fluid for feed efficiency, body performance, disease, etc., traits in cattle . Feed efMetabolic disease is another important trait that affects efficient cattle production, where metabolomic applications are helping to understand the mechanisms and define the predictive metabolic biomarkers for incident diseases . Many meMetaboAnalyst software (version 5.0) [Bos taurus library were also realized to show the relative betweenness centrality against pathway impact value. The results showed that nine significantly metabolic pathways (FDR < 0.05) were revealed  [For the feed efficiency trait, the enrichment of the retinol metabolic pathway was revealed in beef cattle, where two metabolites in the pathway  were found in the low feed efficient animals . Howeverion 5.0) , and metrevealed , where trevealed . Six metrevealed  and the ion 5.0) .https://www.genome.jp/kegg/, accessed on 20 September 2021) of Bos taurus species. It is suggested that the aminoacyl-tRNA biosynthesis pathway is mainly related to the other nine pathways. They are the alanine, aspartate and glutamate metabolism (bta00250), the glycine, serine and threonine metabolism (bta00260), the cysteine and methionine metabolism (bta00270), the valine, leucine and isoleucine biosynthesis (bta00290), the lysine biosynthesis (bta00300), the arginine and proline metabolism (bta00330), the histidine metabolism (bta00340), the phenylalanine, tyrosine and tryptophan biosynthesis (bta00400), and the tryptophan metabolism (bta00380) (The aminoacyl-tRNA biosynthesis pathway is an amino acid metabolism and biosynthesis related pathway that has been identified as associated with RFI in dairy cows  and pigsta00380) . It was is bta0020, the lyMetabolomics has been applied in metabolic biomarker identification, genetic mechanism revelation, genomic prediction, understanding nutritional physiology, etc., for different economic traits of different species, which promotes the applications of metabolomics in cattle.The application of metabolomics and the other integrated omics data analysis lead to the clear cognition of the complex metabolic mechanisms ; for exaMetabolomic-based genomic prediction has been conducted in plant species, such as wheat and barley, to display the potentiality of metabolite application as the predictor variables when no genotype is available ,48,49,50Diet-based rumen metabolomic analysis can help reveal the nutritional biochemical physiology after feeding different diets ,54. For Metabolomic analysis integrated with other omics data could contribute to the better understanding of the metabolomic complexity based on systems biology, but multiple layer integration would cause the challenge of statistics under the appropriate hypothesis ,58. The Metabolomics is the joint to connect genotypes with phenotypes , so theiiJL463 and iDZ470 were constructed for Riemerella anatipestifer wild type strain CH-1  and Riemerella anatipestifer wild type strain CH-2 , respectively [The genome-metabolite network has been constructed in bacterial species ,60; for ectively . In beefectively  detectedectively . System ectively  found thEMMAX (efficient mixed-model association eXpedited), FaST-LMM , GCTA , GEMMA (genome-wide efficient mixed-model association) [The mGWAS is the direct association model between genomics and metabolomics to test the candidate SNPs or QTLs related to metabolites. It can be analyzed in the tools that are applied for GWAS, such as ciation) ,65,66,67 control ,69), a iMetaboAnalyst [HACL1)) associated with two metabolites (\u03b1-ketoglutarate and succinic acid) was identified in high-low feed efficient dairy cattle [IMPaLA, Metabox (R based), XCMS, etc., [The gene-metabolite interplay network can be constructed for transcriptomic-metabolomic analysis based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways using oAnalyst ,71; for y cattle . LikewisS, etc., ,73,74,75S, etc., ,73. BaseS, etc., , KEGG [7S, etc.,  and UnipS, etc.,  databaseIntLIM [IntLIM [p-value indicates the gene-metabolite association is different from the cases to the controls [R package IntLIM  was usedIntLIM , where tIntLIM . The lin [IntLIM  used is controls ,81.For the two-layer omics data integration, epigenomic\u2212metabolomic interactions could discover novel molecular targets via epigenetic mechanisms regulating the expression levels of metabolic genes and thereby altering the metabolome ,83. WongAMON [MIMOSA [So far, the analysis between microbiome and metabolome could predict which compounds have been produced by a community of bacteria or the host in an R package AMON . However [MIMOSA  is a rel [MIMOSA  developeLipidome is one subset of the metabolome as same to amino acids, sugars and nucleic acids, but lipidomics has emerged as an independent field due to the functionally structural diversity and high endogenous abundance of lipids resulting in the complexities of the organismal lipidomes ,88. The CARM-1, Ube2g2, Cactin and Ndufaf6) during macrophage differentiation and osteoclastogenesis and the metabolic profile of cells to potentially influence the apoptotic and proliferative states [In the previous study, transcriptomic, proteomic and metabolomic integrated analysis was used to investigate the overexpression and inhibition of miR-223 affecting gene regulation in the cytoplasm of the monocyte\u2212macrophage cell line . They che states . Jamil ee states  also proe states  firstly The current metabolomics analysis methods and tools are widely applied for metabolic biomarker detection, cluster classification, pathway and network identification, two-layer data integration, etc., which is usually limited in the metabolomics category . StatistMetabR, glmnet, IntLIM, etc., [Generally, a linear regression model is considered to analyze metabolomics data for significant metabolite identification by fitting phenotypes  as covariates ,80. SomeM, etc., ,93,94.MetaboAnalyst, VOCCluster [MetaboClust) [hcapca) [In order to cluster the metabolites, principal component analysis (PCA), linear discriminant analysis (LDA) and partial least squares discriminant analysis (PLS-DA) are normally used in the R packages or other tools, such as CCluster ,95. ToolboClust) , automat[hcapca)  are also[hcapca) . The pre[hcapca) .Notably, metabolomics data is complex and nonlinear, so machine-learning methods are applied for the nonlinear data interpretation based on random forest, support vector machine, artificial neural network algorithms, etc., ,103,104.limma and WGCNA [WGCNA  can construct a similarity matrix by Pearson correlation coefficients to measure the profiles\u2019 similarity for the further network construction, and then identify the metabolically relevant key modules [Some transcriptomic expression and co-expression analysis approaches are also available for metabolic data by considering the metabolite values as the expression levels to perform the metabolite analysis and the interacted networks, such as using R package nd WGCNA ,109,110. modules .Metabolomic and integrated other omics data analysis are available for the measurement of dynamically metabolic responses, identification of biologically metabolic markers, revelation of potentially genetic architecture, understanding of systematic networks. In cattle, the classified metabolome clusters, detected relevant candidate metabolites, identified metabolic pathways, potential systematic networks have been studied to achieve promising and meaningful results. We summarized the previous results of one-layer metabolomic analysis and potential two-layer integration analysis that can be presented in Multiple integrated omics analysis would become critical and favorable in a further study, especially for the integration of genomics, epigenomics, transcriptomics, proteomics, microbiomics and lipidomics to reveal the metabolic-related mechanisms, identify multiple-layer biomarkers and improve genomic predictions, etc. Theoretically, metabolite QTLs, DNA methylation QTLs, expression QTLs (eQTLs), protein QTLs (pQTLs), microbe QTLs could be integrated on the genome level by constructing a multiple-omics network using those QTLs as the joint. In the meantime, the annotated genes/proteins to QTLs affecting metabolite concentrations that are regulated by the genetic/epigenetic variants could be connected together based on the biological pathways . Thus, tIn summary, this review concludes the useful metabolic information from the previous research results including the characterizations of metabolomics profiles, metabolomics applications, integrated metabolomics analysis with other omics, methods and tools in metabolomics analysis, and the further potentialities and implications in cattle, which may contribute to the production improvement, disease reduction, efficient farming for the cattle economically important traits."}
+{"text": "Reactive oxygen species (ROS) are highly reactive molecules that can oxidize proteins, lipids, and DNA. Under physiological conditions, ROS are mainly generated in the mitochondria during aerobic metabolism. Under pathological conditions, excessive ROS disrupt cellular homeostasis. High levels of ROS result in severe oxidative damage to the cellular machinery. However, a low/mild level of ROS could serve as a signal to trigger cell survival mechanisms. To prevent and cope with oxidative damage to biomolecules, cells have developed various antioxidant and detoxifying mechanisms. Meanwhile, ROS can initiate autophagy, a process of self-clearance, which helps to reduce oxidative damage by engulfing and degrading oxidized substance. This review summarizes the interactions among ROS, autophagy, and antioxidant pathways. The effects of natural phytochemicals on autophagy induction, antioxidation, and dual-function are also discussed. Reactive oxygen species (ROS) are generally small, short-lived, and highly reactive molecules that are formed by incomplete one-electron reduction of oxygen. ROS are generated by multiple cellular organelles, including mitochondria, peroxisomes, and endoplasmic reticulum \u20133. ROS cUnder pathological conditions, dysfunctional mitochondria produced excessive ROS, breaking cellular homeostasis. The process of removal of damaged mitochondria through autophagyis called mitophagy, which is thus critical for maintaining cellular functions , 6. AutoIn response to oxidative stress, autophagy is found to contribute to antioxidant function , 13. RecThe purpose of this review is to summarize the molecular mechanisms of ROS signals, autophagy, and redox regulation in health and disease. Furthermore, dual-target phytochemicals based on autophagy and antioxidant regulation are exemplified and discussed.2\u2013), hydrogen peroxide (H2O2), and hydroxyl radical (HO\u2219), but also diverse peroxides, such as lipid peroxides, peroxides of proteins, and nucleic acids , 6665, 6Mammalian target of rapamycin (mTOR), a critical nutrient sensor, can regulate TFEB . Under nRapamycin has been shown to upregulate autophagy in cell models, fruit fly models, and mouse models of neurodegenerative diseases, respectively \u201383. In t\u03b2, leading to the stimulation of mTOR kinase and the inhibition of autophagy. Recently, the combined use of lithium and rapamycin is found to be much more effective than rapamycin alone [Lithium can negatively regulate the activity of GSK-3in alone . In addiin alone , 88.Many diseases such as NPC are associated with both oxidative stress and autophagy dysfunction. So far, none of single therapy against one target is shown to be effective. Thus, the dual-target therapeutic drugs will shed new light on the future directions. A number of natural compounds are identified to reduce oxidative stress and promote autophagy. Moreover, preclinical and clinical studies have shown that natural compounds, such as resveratrol, have therapeutic potential in several diseases including diabetes, aging, neuropathy, cardiovascular diseases, and cancer .Sulforaphane, an Nrf2 activator enriched in cruciferous vegetables, has several biological activities such as reduction of oxidative stress and inflammation in several diseases including AD, sclerosis, and traumatic brain injury \u201393. ReceFlavonoids, a family of natural products enriched in fruits, have biological activities including anticancer, antiproliferation, antioxidant, and anti-inflammation via regulation of the cell cycle, induction of apoptosis, and inhibition of extracellular protein kinase phosphorylation . FlavonoIsoflavones are a variety of secondary metabolites mainly distributed in legumes . They reResveratrol, a ROS scavenger extracted from red grape skins and peas , 105, haCurcumin, a major active component of turmeric , has anticancer, anti-inflammatory, and antioxidant effects and has been applied to cancer, atherosclerosis, and neurodegenerative diseases \u2013120. LowExcessive ROS have been implicated in many diseases including cancer, neurodegenerative diseases and aging. Low/mild levels of ROS have been identified as important cellular signals, which can induce autophagy and antioxidant pathways under both physiological and pathological conditions. Increasing evidence suggests that there may be an important link ROS, antioxidant pathways, and autophagy. The detailed molecular mechanism underlying this linkage remains elusive. Antioxidants or autophagy activator alone is not ideal treatment for diseases characterized by both oxidative stress and autophagy dysfunction. Natural compounds with dual targeting of antioxidant and autophagy such as sulforaphane could be the potential therapeutic drug and direction for future research."}
+{"text": "AIRE) gene, which lead to impaired central immune tolerance and autoimmune organ destruction including pneumonitis, an underrecognized, life-threatening complication. When clinicians evaluate patients with pneumonitis, recurrent mucosal candidiasis, and autoimmunity, APECED should be considered in the differential. Additionally, in patients with established APECED, a chest computed tomography is preferred to identify pneumonitis early on and to promptly initiate lymphocyte-directed immunomodulatory treatment, which can prevent irreversible lung destruction.We present a severe case of progressive autoimmune pneumonitis requiring surgical intervention in a patient with the monogenic syndrome, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). APECED is caused by loss-of-function mutations in the autoimmune regulator ( APECEDAutoimmune polyendocrinopathy-candidiasis-ectodermal dystrophyCMCChronic mucocutaneous candidiasisAPS-1Autoimmune polyglandular syndrome type 1AIREAutoimmune regulatorTSAsTissue-specific antigensmTECsMedullary thymic epithelial cellsBPIFB1Bactericidal/permeability-increasing fold-containing B1GGOGround glass opacitiesTIBTree-in-budNTMNontuberculous mycobacteria1AIRE) gene .,17.12,17Candida albicans, Candida dubliniensis, Graphium species, Exophiala species, and Scedosporium apiospermum. Despite antifungal therapy and optimized pulmonary toilet, he clinically worsened with radiographic evidence of new apical hydropneumothorax, consolidations, and pleural effusions. Consequently, he returned to NIH for further evaluation and management spanning a 13-month hospitalization , bronchoalveolar lavage  and pleural effusions . He required placement of three chest tubes for drainage of pleural effusions and multiple bronchoscopic placements of endobronchial valves throughout the right lung to seal off air leaks from a right lower lobe pneumatocele complicated by bronchopleural fistula and empyema. He underwent right middle and lower bilobectomy with decortication of right upper lobe and tracheostomy  flap repair, an omental flap closure was ultimately successful . SecondaFollowing surgery, he developed recurrent pulmonary infiltrates and GGOs responsive to steroids. This finding in conjunction with histological evidence of lymphocytic inflammation in the tissue prompted treatment of autoimmune pneumonitis . He was Pseudomonas aeruginosa, Aspergillus nidulans, Aspergillus fumigatus, and Stenotrophomonas maltophilia which were treated with 8 weeks of meropenem, minocycline, and posaconazole. Upon completion of antibiotic therapy and confirmation of radiographic improvement of pulmonary infections, he received rituximab for treatment of underlying autoimmune pneumonitis flare  to include an adjunct triad of urticarial eruption (APECED rash), intestinal dysfunction, and enamel hypoplasia ,17. In aPneumonitis is a common manifestation of APECED that presents early in life with chronic cough and radiographic abnormalities and can progress to irreversible bronchiectasis, acting as a nidus for recurrent lung infections ,17,18. I4\u2022When untreated, APECED pneumonitis can cause progressive irreversible structural lung disease, leading to chronic and recurrent infections, hypoxemic respiratory failure, and death.\u2022In patients not diagnosed with APECED, the presence of pneumonitis in combination with other autoimmune manifestations should raise suspicion for APECED.\u2022Because of the potential catastrophic sequelae of untreated lung disease, all patients with confirmed APECED require periodic chest CT imaging to assess for the radiologic findings of previously underrecognized pneumonitis, particularly when respiratory symptoms arise.\u2022If discovered early, pneumonitis could be successfully treated with lymphocyte-targeted immunomodulation, preventing the cycle of inflammation and infection that leads to irreversible lung tissue destruction.SAK, HMD, and EMNF reviewed and evaluated all records and wrote the case report; DSS, KNO, JGW, MSL, and LRF provided clinical care and critically reviewed the manuscript. All authors approved the final manuscript as submitted and agreed to be accountable for all aspects of the work.10.13039/100000060NIAID, 10.13039/100000054NCI, 10.13039/100000050NHLBI, and 10.13039/100000098NIH Clinical Center, NIH.This work was funded, in part, by the Division of Intramural Research, Dr. Les Folio is a primary investigator in a corporate research agreement with Philips Health , the PACS used in this initiative. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Resilience, purpose in life (PIL), and loneliness have been linked, and used to characterize the health and well-being of older adults. Studies demonstrate that higher resilience, PIL, and minimal loneliness are associated with better late-life outcomes. However, research on how these constructs negatively impact medical costs is limited. Using survey and claims data from a large sample of older adults age 65+ , resilience, PIL, and loneliness were examined to determine associations with medical costs. Among study participants, 11% exhibited low resilience, 19% severe loneliness, and 35% low PIL. Low resilience was associated with 24% higher medical costs compared to participants with high resilience, severe loneliness with 20% higher costs compared to participants with no loneliness, and low PIL marginally associated with 12% higher costs compared to participants with high PIL. Interventions targeting resilience, PIL, and loneliness could be beneficial to promoting successful aging and lowering medical costs."}
+{"text": "This presentation reports the results of a scoping review which identified and evaluated existing engagement strategies, tools, and interventions for their fit with assisted living (AL). Using the PRISMA criteria, we evaluated 54 empirical studies in assisted living/residential care or nursing homes (NH) for how they engaged families and residents, promoted person-centered and/or safety in AL/NH care, and assessed relevant outcomes . The strategies, tools, and interventions aimed to improve residents\u2019 activities of daily living, function, and quality of life. Studies also targeted staff and family caregivers to increase knowledge, improve relationships, and decrease caregiving stress. Overall, the studies reported statistically significant changes in resident quality of life, agitation, antipsychotic use, staff knowledge and job satisfaction. Results from this systematic review will inform the development of a testable toolkit to increase engagement and improve safety in AL."}
+{"text": "Acetone is a chemical found naturally in the environment, and acetone poisoning can occur through contact with household products that contain acetone, including nail polish removers, paint removers, some polishes, as well as certain detergents\u00a0and cleaners. Acetone toxicity affects almost all body systems, including the nervous, respiratory, cardiovascular, and endocrine systems. The incidence of life-threatening medical problems from acetone exposure is very rare. However, in this report, we present a case of acetone toxicity resulting in death. Our patient presented with cardiopulmonary arrest, hypotension, tachycardia, hyperglycemia, acute kidney injury (AKI), thrombocytopenia, elevated liver enzymes, and extensive esophageal and gastric erosion with associated upper gastrointestinal bleeding. Acetone is a colorless chemical with a distinct taste\u00a0and smell, and it is found naturally in the environment and produced by industries. Low levels of acetone are usually present in the body from body fat breakdown. Additionally, people are exposed to small amounts of acetone from drinking water, food, or breathing the air that contains acetone. Exposure to acetone can also occur through contact with household products that contain acetone, including nail polish removers, paint removers, some polishes, and certain detergents and cleaners. Acetone exposure also occurs through exposure to isopropyl alcohol since isopropyl alcohol is converted to acetone in the body ,2.Several cases of acetone poisoning and accidental human exposure to acetone have been reported, and acetone has been shown to affect almost all body systems, including the nervous, respiratory, cardiovascular, and endocrine systems, among others . HoweverA 41-year-old female patient with underlying chronic obstructive pulmonary disease (COPD) was brought in\u00a0to evaluate cardiopulmonary arrest after ingesting acetone. Per emergency medical services (EMS), the patient had swallowed two-thirds of a bottle of acetone, and EMS had found drug paraphernalia on site. EMS had found the patient in asystole and started chest compressions, and had administered epinephrine. There had been a return of spontaneous circulation following chest compressions, and the patient had been intubated in the field, and an orogastric tube had been placed. On arrival at the emergency department (ED), the patient's blood pressure was 55/43 mmHg, heart rate was 117 beats per minute, temperature was 98.4 \u00b0F, and respiratory rate was 22 breaths per minute. The orogastric tube had bright red blood, pupils were unreactive, and the patient had a Glasgow Coma Scale (GCS) score of 3. Laboratory results showed normal white blood cell count, hemoglobin of 11.8 g/dl with mean corpuscular volume (MCV) of 118 fl, and low platelet count of 69,000/ml. Potassium was low at 3.1 meq/l, and magnesium was low at 1.2 mg/dl  on day five of admission showed ulcerated and necrotic esophagus and stomach  depression, confusion, coma, ataxia, coordination impairment, dizziness, weakness, headache, irritability, stupor, seizure, sleep disturbance, memory difficulty, and difficulty in speaking -10.Gastrointestinal SystemInhalational and dermal exposure to acetone has been associated with nausea, abdominal pain, loss of appetite, vomiting, and gastrointestinal hemorrhage, possibly due to repeated vomiting -12. ErosRespiratory SystemInhaled acetone irritates the nose, throat, trachea, and lungs, which is likely due to the local action of acetone on the respiratory tract -15. BronCardiovascular SystemDifferent cardiovascular effects have been reported with acetone exposure, including hypotension, hypertension, sinus tachycardia, and cardiovascular collapse -19. Our Hematological SystemIncreased white blood cells (leukocytosis) have been reported in humans exposed to acetone ,20. Our Renal SystemAcute kidney injury (AKI) has been reported in humans exposed to acetone ,21. PolyEndocrine SystemAcetone exposure has been associated with hyperglycemia and anion gap metabolic acidosis ,17. AcetManagement of acetone poisoningManagement of acetone poisoning is mainly supportive and begins with the assessment and stabilization of breathing, airway, and circulation. In addition, the patient's vital signs, including temperature, pulse, respiratory rate, and blood pressure, should be monitored. Due to the rapid acetone absorption after oral ingestion, gastric lavage is usually not indicated in most cases of isolated acetone ingestion. Still, it may be considered in cases of massive ingestion if the patient presents within one hour of ingestion. In addition, hemodialysis should be considered in patients with massive ingestion of acetone with persistent hemodynamic instability despite aggressive treatment with intravenous fluid and pressors. Although hemodialysis has been shown to increase the elimination of acetone and isopropanol substantially, it should only be considered in severe life-threatening poisonings and is rarely required ,23.We presented a case that proved to be fatal following ingestion of a large dose of acetone. Mortality secondary to acetone is very rare. Our patient presented with cardiopulmonary arrest, hypotension, tachycardia, hyperglycemia, AKI, thrombocytopenia, and elevated liver enzymes; she also had extensive esophageal and gastric erosion with associated upper gastrointestinal bleeding. Management of acetone poisoning involves mainly supportive care."}
+{"text": "The authors regret this omission. The paper has since been corrected online, including the author list, acknowledgments, and author contributions, which also appear here."}
+{"text": "Microfluidic devices emerged due to an interdisciplinary \u201ccollision\u201d between chemistry, physics, biology, fluid dynamics, microelectronics, and material science. Such devices can act as reaction vessels for many chemical and biological processes, reducing the occupied space, equipment costs, and reaction times while enhancing the quality of the synthesized products. Due to this series of advantages compared to classical synthesis methods, microfluidic technology managed to gather considerable scientific interest towards nanomaterials production. Thus, a new era of possibilities regarding the design and development of numerous applications within the pharmaceutical and medical fields has emerged. In this context, the present review provides a thorough comparison between conventional methods and microfluidic approaches for nanomaterials synthesis, presenting the most recent research advancements within the field. Nanotechnology gained significant importance when scientists realized that the size of the material is a major factor that influences the properties of a substance. Since then, several conventional methods have been employed for nanomaterials production, including condensation, chemical precipitation, and hydrothermal synthesis as the most common approaches ,2,3. Cho\u22129 to 10\u221218 L) amounts of fluids, using channels with dimensions of tens to hundreds of micrometers\u201d .,83.16,83When it comes to nanoparticle production within microfluidic devices, single-phase systems are the most commonly used. This pattern flow is the variant of choice in many studies due to its simplicity, homogeneity, and versatility in controlling process parameters, such as flow, reagent amount, reaction time, and temperature ,11.Generally, single-phase synthesis is performed under laminar flow (with a Reynolds number lower than 10). Due to the absence of turbulence, the main mixing mechanism is molecular interdiffusion ,11,16. TNonetheless, molecular interdiffusion is a slow process, limiting reaction speed . MoreoveUnlike single-phase microfluidics, multi-phase flow  systems involve two or more immiscible fluids . Such heAs the name implies, droplet-based microfluidics concerns the formation and manipulation of discrete droplets inside microchannels . DropletThere are two subcategories of multi-phase flow: gas\u2013liquid (bubbles) and liquid\u2013liquid segmented flows . Gas\u2013liqDue to rapid production and analysis, droplets can be employed when developing reproducible and scalable particles with specific sizes, shapes, and morphologies, which are difficult to achieve otherwise ,89. In aHowever, several downsides to multi-phase flow systems must be considered when designing these applications. One of the disadvantages is the poor stability of droplets. This can be overcome through the addition of surfactants, but this solution is not suitable for all situations. Another issue comes from the fact that droplets are never completely isolated, as almost always, an extent of material exchange between droplets takes place . HoweverFor a better understanding of microfluidic methods, the most common microreactor flow types are gathered in As more and more synthesis reactions are moving towards microfluidic production, it is clear that there are several advantages in comparison to classic methods. In this context, There is no doubt that microfluidic technology has many advantages compared to preexisting synthesis and testing methods. However, certain aspects become more pronounced when miniaturizing equipment down to the microscale, e.g., surface roughness, capillary forces, and chemical interactions between materials . Hence, The enhancement of material properties can cause unexpected experimental complications as the reactor behaves differently from traditional laboratory equipment . The smaMoreover, the small diameters of the channels make them susceptible to clogging . The solAnother challenge consists of choosing the right device substrate, especially because many materials have poor solvent compatibility and low resistance to high temperature. In this respect, novel materials should be developed to manufacture reliable and cost-effective chips . FurtherAs nanotechnology is still in its infancy, nanoparticles\u2019 production and application are expected to continuously improve . In receTo correlate these aspects with the synthesis methods and the obtained products, several research studies concerning nanomaterials synthesis through microfluidic methods were summarized in Inorganic nanoparticles find use in various fields, ranging from electronics, energy, and textiles to biotechnology, bio-imaging, and bio-sensing. Most of these applications are based on materials such as gold, silver, silica, alumina, titanium oxide, and zinc oxide, but not exclusively ,41,113.Noble metal nanoparticles, such as gold, silver, and platinum, are of special interest in medical applications due to their size and shape properties ,88. VariGold nanoparticles (Au NPs) were produced via microfluidic methods by several researchers, inspired by the outstanding properties and potential applications of this material. Generally, the reduction of a gold precursor takes place in the presence of different types of ligands and stabilizers. The use of strong reducing agents, such as sodium borohydride, ensures fast nucleation and small sizes of finite products. The reduction of gold ions fits in a timeframe of seconds, following fast kinetic crystallization at the nanoscale . SpheresSilver nanoparticles (Ag NPs) are another category of noble metal nanoparticles with properties much different from the bulk material . Over thZinc oxide nanoparticles (ZnO NPs) have drawn much attention recently in the field of nanomedicine, especially for tissue engineering, targeted drug delivery, contrast agents, and therapeutics against cancer . To obta2 NPs) of uniform size can also be rapidly and economically produced in microreactors [Titanium oxide nanoparticles  are also considered valuable in various fields, attracting interest in their microfluidic production [Silica nanoparticles  are an important class of nanomaterials due to their unique properties, such as chemical stability, magnetic response, biocompatibility, and low cost . These aQuantum dots (QDs) can be produced in microfluidic systems by miniaturizing the traditional synthesis methods, leading to high-quality, monodisperse particles . SemiconBesides metallic-based nanoparticles, microfluidics has attracted recent interest for the synthesis of non-metallic materials, as well. One such example is represented by sulfur, the ability of which to inhibit bacteria and fungi makes these nanoparticles suitable for sterilization of food and utensils. The controllable particle size and uniform morphology attained through microfluidic technology improve sulfur nanoparticles\u2019 bactericidal performance .Microfluidic methods have also been employed for the synthesis of organic nanoparticles due to their potential use in pharmaceutical formulations . This emLiposomes are of special interest, being efficient transport vehicles for in vivo applications, as hydrophilic drugs can be entrapped in their interior aqueous core while lipophilic and amphiphilic substances can be incorporated into the lipid bilayers ,124. LipPolymer-based nanoparticles (PNPs) synthesis within microfluidic devices is considered promising as well, as it offers improved control over size, size distribution, morphology, and composition of such particles ,78. PolyThe pharmaceutical industry benefits from microfluidic approaches as they allow for cheaper, more effective, and more accessible production of drug formulations ,144. EnhUp to date, various active pharmaceutical ingredients have been reportedly produced within microfluidic systems. Their list includes but is not limited to nitroglycerin , ibuprofMultifunctional entities can be formed by loading inorganic nanomaterials in polymer particles ,155, benAnother promising combination is the creation of lipid\u2013polymer nanoparticles for drug delivery . What maOther interesting delivery systems that can be synthesized in microfluidic devices are lipid nanoparticles loaded with nucleic acids. In the context of the COVID-19 pandemic, the fabrication of monodispersed lipid vesicles became essential for the encapsulation of messenger RNA (mRNA) required in vaccines\u2019 formulation ,159,160.Moreover, artificial leukocytes and lipoproteins can be fabricated via assembling proteins with lipid molecules. Thus, by assembling phospholipids with apolipoproteins within a microfluidic device, high-density lipoproteins were mimicked .Nanomaterials can have many different shapes and chemical compositions, which means that their properties  can be tailored to meet specific application requirements. However, conventional synthesis methods do not offer precise control over reaction parameters, affecting the desired outcomes. By precise manipulation of nanoliter volumes, microfluidic devices enable the synthesis of high-quality nanoparticles, drug carrier systems, active pharmaceutical ingredients, composite nanomaterials, and even cells. As there is a long list of advantages of microfluidic production over conventional synthesis, it is expected that this technology would exponentially gain interest in developing new materials, processes, and functionalities. Moreover, translating microfluidics to large-scale production should be considered to make this technology more popular and industrially appealing. Hence, research should also be directed towards standardization, automation, and high-throughput."}
+{"text": "Low birth weight is associated with adult mental health, cognitive, and socioeconomic problems. However, the causal nature of these associations remains difficult to establish due to confounding. We aimed to estimate the contribution of birth weight to adult mental health, cognitive, and socioeconomic outcomes using two-sample Mendelian randomisation, an instrumental variable approach strengthening causal inference.We used 48 independent single-nucleotide polymorphisms as genetic instruments for birth weight , and considered mental health , cognitive (intelligence), and socioeconomic  outcomes. We performed a two-sample Mendelian randomisation using the random-effect Inverse Variance Weighing method as primary analysis, supplemented by a wide range of sensitivity analyses, including Egger regression, weighted median, and Pleiotropy Residual Sum and Outlier. Results were considered statistically significant after accounting for multiple testing using False Discovery Rate (q = 0.05).After correction for multiple testing, we found evidence for a contribution of birth weight to ADHD , PTSD , and suicide attempt , as well as for intelligence , and socioeconomic outcomes, ie, educational attainment , income , and social deprivation . However, no evidence was found for a contribution of birth weight to the other examined mental health outcomes. Results were consistent across main and sensitivity analyses.These findings support that birthweight could be an important element on the causal pathway to mental health, cognitive and socioeconomic outcomes. Early interventions targeting birth weight may therefore have a positive impact on promoting mental health and improving socioeconomic outcomes.This project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sk\u0142odowska-Curie grant agreement No 793396"}
+{"text": "Maintaining ability to drive is critical to independent living among older adults residing in suburban and rural communities. We administrated structured questionnaire about driving behaviors to 370 persons age 65 and older living in Central Massachusetts between 2018 and 2020. Of them, 307 were active drivers. Driving in the past year was strongly associated with being male, White race, higher income, non-urban resident, and good-to-excellent health. Advancing age was associated with lower frequency of driving, less miles driven, lower percentage of the day spent in transportation. Men and women drove with nearly equal frequency (~26 days/month), but men drove significantly more miles. Non-White drivers were significantly more likely to avoid driving out of town or in difficult conditions, even after controlling for age, sex, income, and density of residential area. In conclusion, driving behaviors differed significantly by age, sex, income, race, and housing density. Further investigation is warranted."}
+{"text": "Field of medicine: neurosurgery, spine surgery, orthopedics, neurology, medical education.Audience: neurosurgeons, spine surgeons, orthopedic surgeons, residents, interested physicians.Purpose: The book gives a well-written, comprehensive overview of minimally invasive surgery of the cervical, thoracic, and lumbar spine and provides details of various surgical techniques. History and evolution of the minimally invasive spine surgery techniques are described. Detailed surgical anatomy is presented through a number of illustrations in each chapter. The content is presented through text, intra-operative photographs, illustrations, neuroradiological images, graphs, and video content. The wealth of information provided by the book can serve as a useful source for all interested readers.Content: Each of the thirteen chapters contains relevant information regarding a specific topic, accompanied by illustrations, images, and graphs, and followed by a list of references. The introductory part lists the included video content. Chapters dealing with specific operative techniques contain appropriate case illustrations, followed by a chapter conclusion.A Minimally Invasive Perspective: The Conversation, briefly describes the premises and the main principles of learning minimally invasive spine treatment and overviews the three-dimensional spinal anatomy and essential tools such as operating table, microscope, and drill attachments. It also emphasizes the importance of the surgical team.The first chapter, Minimally Invasive Microdiscectomy, gives a historical perspective of the muscle-retractor interface and the efficiency of the exposure, and describes the anatomical basis, as well as the operating room setup in detail. Special attention is given to the surgical technique; conceptualization, incision planning, exposure, bone work, division and resection of the ligamentum flavum, disc removal and closure; as well as operative time and postoperative management. Furthermore, revision microdiscectomies, complication avoidance, and repair of the cerebrospinal fluid leaks are described.The second chapter, Minimally Invasive Lumbar Laminectomy, gives a historical perspective and describes patient selection, anatomical basis, and operating room setup in detail. It discusses the localization and details of the surgical technique, such as dilation and docking of the retractor, drilling, direct resection concerning canal diameter and canal depth, closure and postoperative care, long-term outcome, and complication avoidance.The third chapter, Minimally Invasive Transforaminal Lumbar Interbody Fusion, describes various pedicle screw placements, the anatomical basis of the surgery, preoperative considerations, and operating room setup. Special attention is given to the surgical technique; the three phases of the operation are described in detail: the first phase , second phase , and third phase ; as well as postoperative management and complication avoidance.The fourth chapter, Minimally Invasive Far Lateral Microdiscectomy, gives a historical perspective, and describes the anatomical basis, the anatomy of lumbar foramen, and the operating room setup. Incision planning, docking the minimal access port, bone work, pedicle, and nerve root identification, closure and postoperative care are all discussed.The fifth chapter, Minimally Invasive Lateral Transpsoas Interbody Lumbar Fusion, describes advantages and disadvantages of the transpsoas approach, as well as patient selection, with special attention given to the transpsoas approach to the L IV/L V segment. Surgical anatomy is discussed in detail, with an outline of the branches of the lumbar plexus and blood vessels of the posterior abdominal wall. The chapter discusses the positioning of the patient and operating room setup, surgical planning, and the principles of electrophysiologic monitoring. Surgical technique, especially transversing the layers of the abdominal wall, orientation in the retroperitoneal space and transversing through the psoas muscle is meticulously described, followed by a description of interbody trials, device placement, fluoroscopy, potential posterior or lateral instrumentation, and closure.The sixth chapter, Minimally Invasive Posterior Cervical Foraminotomy, describes the anatomical basis for minimally invasive approach, skull clamp and patient positioning, operating room setup, fluoroscopy and workflow, including incision, securing the access port, exposure using dilation, decompression in two phases , posterior cervical microdiscectomy if necessary, closure, and postoperative management.The seventh chapter, Minimally Invasive Posterior Cervical Laminectomy, describes unique clinical circumstances, cervical interlaminar measurements, anatomical basis, operating room setup, skull clamp and positioning, localization, lamina exposure and drilling, hemostasis and closure.The eighth chapter, Anterior Cervical Discectomy with Arthroplasty or Fusion, gives a historical perspective and describes the anatomical basis, operating room setup, patient positioning, localization, incision, exposure for single or multilevel anterior cervical discectomy and fusion, Caspar distraction posts, discectomy and osteophyte removal, spinal cord and nerve roots decompression, division and resection of the posterior longitudinal ligament, and interbody graft placement. A special part focuses on multilevel cases with instrumentation, closure, and postoperative management.The ninth chapter, Minimally Invasive Decompressions for Metastatic Spinal Disease, describes the rationale for these procedures, operating room setup, patient positioning, and localization with fluoroscopy. Clinical decision making, radiological evaluation, surgical approaches and techniques with postoperative course are presented through a number of cases. In addition, minimally invasive anterior column reconstruction is presented.The tenth chapter, Minimally Invasive Resection of Intradural Extramedullary Lesions within the Thoracic Spine, gives a historical perspective and rationale for these procedures, as well as describes anatomical variations and intradural extramedullary lesion on the lumbar vs the thoracic spine. Patient positioning and localization are discussed alongside the incision planning, operative technique, including docking the minimal access port, exposure, bone work, lesion exposure, opening of the dura, resection of the lesion, dural and skin closure and postoperative care.The eleventh chapter, Radiation and Minimally Invasive Spine Surgery, describes the fundamentals of fluoroscopy, origin of x-rays and components of the fluoroscope, as well as basic principles of x-ray production, emission spectrum, voltage, and current.The twelfth chapter, Minimizing Ionizing Radiation in Minimally Invasive Spine Surgery, emphasizes the principle to keep radiation as low as reasonably achievable and describes limitation of the dose, dosimetry, collimation, justification, optimization, types of fluoroscopy, acquisition time, and the digital spot technique, presenting cases managed by techniques and approaches described in the previous chapters. It also discusses the future of spinal imaging for minimally invasive spine surgery.The thirteenth chapter, Highlights: The book contains essential information and provides an excellent overview of minimally invasive surgical procedures on the cervical, thoracic, and lumbar spine, including details of various surgical techniques accompanied by meticulous and detailed surgical anatomical illustrations. A comprehensive index at the end of the book enables quick orientation and selective reading. The text is complemented by numerous color figures, schematic presentations, neuroradiological images, and photographs, which make learning easy and exciting. Additional video content is useful for acquiring new skills, and in everyday clinical work.Related reading: A number of other comprehensive medical references either in book or pocket-size handbook format are available, such as: Bridwell and DeWald's Textbook of Spinal Surgery, 4th Edition, LWW, 2019; Emory's Illustrated Tips and Tricks in Spine Surgery, 1st Edition, LWW, 2019; Pocket Atlas of Spine Surgery, 2nd Edition, Thieme, 2018; Rothman-Simeone and Herkowitz\u2019s The Spine, 7th Edition, Elsevier, 2017; Benzel's Spine Surgery: Techniques, Complication Avoidance and Management, 4th Edition, Elsevier, 2016; Orthopedic Surgery Essentials: Spine, 2nd Edition, LWW, 2016; Minimally Invasive Spine Surgery: Advanced Surgical Techniques, 1st Edition, Jaypee Brothers Medical Pub, 2015; Handbook of Spine Surgery, 1st Edition, Thieme, 2011; Spinal Instrumentation: Surgical Techniques, 1st Edition, Thieme, 2005."}
+{"text": "Introduction to Biostatistics and Critical Thinking \u2013 focus on pitfalls in inferential statistics, consequences of poor research, and errors in published research.Scientific Writing \u2013 teaches methods and procedures in writing to ensure reproducibility. Lecture SeriesEstablished nine lectures on topics related to R3, including Data Management, Statistical Methods, Genomic Analyses, Data Repositories, Data Sharing, Pharmacy Formulation, and e-lab notebooks. WebsiteCreating a comprehensive website as repository for research, methods, programs, updates, and improvements related to R3. KL2 Clinical Scholars Seminars and NavigationScholars participate in seminars and tutorials to discuss opportunities to improve R3 across the research life-course.OBJECTIVES/GOALS: Irreproducible and incompletely reported research lead to misallocated resources, wasted effort in pursing inappropriate avenues of investigation, and loss of public trust. To address this challenge, we employed a Team Science approach to create a multi-modal program to support Rigor, Reproducibility, and Reporting in Translational Science. METHODS/STUDY POPULATION: We conducted literature searches to reveal sources of irreproducibility and recommended corrective actions, invited leaders in the field to give lectures on opportunities to support reproducible science, and worked with the Rockefeller team science leadership group to instill an overarching rigor approach, infused into all training efforts. This multifaceted program was labeled R3 (R-cubed) for Enhancing Scientific Rigor, Reproducibility, and Reporting. RESULTS/ANTICIPATED RESULTS: Didactic Courses:DISCUSSION/SIGNIFICANCE OF IMPACT: Striving for research reproducibility takes focused energy, discipline, and vigilance, but the effort is worthwhile as rigorous and reproducible science is the prerequisite for successful translation of great discoveries into improved health. CONFLICT OF INTEREST DESCRIPTION: none"}
+{"text": "This paper describes a qualitative content analysis of assisted living emergency rules, revised regulations, and executive orders responding to the COVID-19 pandemic. Using key search terms, we identified 36 states that enacted policies between February and October 2020. The following themes occurred most frequently: testing, infection control, access restrictions, suspension of requirements, and reporting. The convoys of care model recognizes internal, external, formal, and informal caregivers as essential members of an AL resident\u2019s care network. We found that non-staff care providers, including external formal caregivers  and informal caregivers (e.g. family), were most often addressed in policies limiting access. Informal caregivers were the least often specifically addressed in these policies. Given the importance of these network members in the AL context, these policies have implications for the wellbeing of the resident and care network."}
+{"text": "Internationally sharable common data elements on residential long-term care (LTC) settings, such as nursing homes and assisted living facilities, can facilitate comparisons across diverse LTC settings for valuable insights on LTC regulation and oversight, practice and operations, infrastructure development, human resources issues, and quality and safety. However, such insights are predicated on the premise that data elements capture information that matters to the full LTC community, including residents, relatives and staff, and are able to be collected across diverse care settings, including low-resource contexts. A critique of much current LTC measurement is its focus on deficits and loss, rather than thriving, person-centered care, and healthy aging, which have been established as important to LTC communities internationally. Further, measurement burden, cultural differences in perceptions of data sharing, and data infrastructure differences are key issues for international data. An international collaborative of LTC researchers\u2014Worldwide Elements to Harmonize Research in Long-Term Care Living Environments (WE-THRIVE)\u2014has developed a set of common data elements that are recommended for parsimoniously assessing key outcomes, workforce and staffing, person-centered care, and the contexts within which LTC settings operate. The studies in this symposium provide insights into the validation and implementation of WE-THRIVE recommended measures in diverse, low-resource LTC contexts, including LTC settings in Brazil, China, and rural Midwest US. Study findings validate WE-THRIVE measures, and provide new knowledge to inform capacity-building for the measurement of person-centered care and healthy aging outcomes in diverse, low-resource, LTC settings."}
+{"text": "Nanotechnology is a fast-expanding and multidisciplinary field with many applications in science and technology ,11,12,13During the last decade, the concept of \u201cGreen Chemistry\u201d for \u201cSustainable Development\u201d has been widely investigated . SustainIt is essential that these NPs be precisely and thoroughly characterized in order to ensure reproducibility in their production, biological activity, and safety. For this purpose, a wide range of physicochemical methods are used to very precisely characterized the synthesized NPs including ultraviolet-visible spectroscopy, Fourier transform infrared spectroscopy (FTIR), attenuated total reflection (ATR), Raman spectroscopy, photoluminescence analysis (PL), dynamic light scattering (DLS), UV-visible diffuse reflectance spectroscopy (UV-DRS), transmission electron microscopy (TEM), scanning electron microscopy (SEM), atomic force microscopy (AFM), field emission scanning electron microscopy (FE-SEM), X-ray diffractometer (XRD), X-ray photoelectron microscopy (XPS), energy dispersion analysis of X-ray (EDAX), thermal gravimetric differential thermal analysis (TG-DTA), or nuclear magnetic resonance (NMR) ,36,37,38Different types of plant-derived NPs are presented, and their synthesis, characterization, and applications are discussed and published in this Special Issue.Plant-based silver nanoparticles (AgNPs) are among the easiest to prepare ,30,35,38Gold nanoparticles (AuNPs) have received tremendous attention because of their facile synthesis, easy surface functionalization , and uniZinc oxide nanoparticles (ZnONPs) have received considerable attention over the last years because of their wide array of potential applications in biomedicine, cosmetic, optics, and electronics. Thus far, several investigations on the synthesis and utilization of ZnONPs by plants, microorganisms, and other species have been reported. Many studies have raised interest in their low-cost, safe, and simple synthesis. ZnONPs may be made from a variety of plant components, including flowers, roots, seeds, and leaves. Remarkably, these nanoparticles exhibit a high exciton binding energy of 60 meV and a huge bandgap of 3.37 eV, giving them a wide range of semiconducting properties ,31,32,36Copper (Cu) is a comparatively low-cost metal that is more cost-effective than Au and Ag, and CuNPs have been synthesized by the reduction of aqueous Cu ions by different plant extracts ,33. The Other metals, such as nickel (Ni)  or manga-Nanomedicine and human health protection  ,10,13,45-Agriculture  ,46;-Food science and technology , in bioengineering  ;-Cosmetics  .NPs are currently in high demand commercially due to their wide range of applications in industries, electronics, environment, energy, and more particularly in biomedical fields. NPs, such as the most commonly known Ag and Au NPs, have been widely explored in this sector and are of tremendous interest for biological applications. In general, plant-derived green NPs are also less likely to cause severe side effects in humans when compared to chemically synthesized NPs, and have a great application potential with applications in a variety of areas, including but not limited to:With two review papers dealing with algae-based NPs synthesis and CuNPs, the current Special Issue sheds light on two less investigated tools and methodologies of green plant-based nanotechnology .Algae are definitely ideal candidates for the green synthesis of NPs because they are rich in secondary metabolites that act as reducing and capping agents. Many potential applications have been already described including antimicrobial or anticancer actions, but also as antifouling, bioremediation or biosensing agents. However, unlike terrestrial medicinal and aromatic plants, algae were underutilized in the beginning of studies on the green synthesis of NPs using plant extracts. As this sector is still in its onset, scaling up for commercial applications is still challenging .Cu is a relatively low-cost metal that is for example more cost-effective than Au and Ag. CuNPs have been produced via the reduction of aqueous Cu ions by various plant extracts. The review by Letchumanan et al.  providesNanomedicine is the use of nanotechnology in the treatment, screening, and diagnosis of a variety of diseases, including cancer ,11,12,47Cassia auriculata leaf extract, in particular, has shown tumoricidal activity against MCF-7 breast cancer cells while having no detrimental effect on normal MCF-12A human breast cells [Many plant-derived NPs have shown some potential against cancer cells. ZnONPs produced from a st cells .Trachyspermum ammi seed extract inhibited cellular growth in HepG2 cancer cell lines in a concentration-dependent manner, which was linked to a reactive oxygen species (ROS)-driven apoptosis [Similarly, green AuNPs produced from a poptosis . This mepoptosis ,47.However, in addition to a deeper understanding of the molecular mechanism of action of NPs against cancer cells, there is also a need to properly understand the fate of NPs. These questions include how long NPs stay in the body, what conditions influence the duration of NP degradation, how to make NPs stay for longer or shorter periods, what are the long-term and short-term effects of NPs, how the body behaves towards these outsider entities on a micro and macro level, and how we can standardize NPs to ensure experiment reproducibility. These should be solved before introducing nanotechnologies into the healthcare industry. Aside from this, there are several questions that require further research and testing. In order to avoid any unanticipated consequences, we must also determine the possible risks linked with these nanomaterials. Furthermore, in order to obtain the safest and most successful therapy regimen, the numerous nanomedicines and nanoformulations targeting specific cancer cells must be thoroughly constructed. We conclude with the hope that nanotechnology will propel the development of more viable medicines to treat cancer, as well as offer researchers with powerful tools to overcome several bottlenecks in this health sector.Leishmania amazonensis promastigote viability, whereas xylan alone had no effect [Leishmaniasis is a protozoan vector-borne illness that affects almost 350 million people worldwide. Chemotherapeutic medicines were initially used to treat leishmaniasis, but they had adverse side effects. Due to their unique properties, such as bioavailability, reduced toxicity, targeted drug delivery, and biodegradability, a variety of nanotechnology-based techniques and products have emerged as anti-leishmanial drugs, including liposomes, lipid nano-capsules, metal and metallic oxide nanoparticles, polymeric nanoparticles, nanotubes, and nanovaccines . AgNPs cAntibiotic resistance is one of the most pressing issues of recent years, and it is only going to become worse. Bacteria have developed resistance to antimicrobial agents as a result of the rapid evolution of the bacterial genome. Thus, in the search for a new therapy, biogenic NPs have shown encouraging results in the treatment of multidrug-resistant bacteria and might be a potential choice in the fight against such resistant pathogenesis . To imprCarissa carandas leaf extract demonstrated antibacterial efficacy against a variety of human pathogenic bacteria, with Gram-negative bacteria, particularly Shigella flexineri responsible for shigellosis, being more likely to be inhibited [Escherichia coli [Sisymbrium irio showed potent inhibition potential against multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumanii that are responsible for ventilator-associated pneumonia [Candida albicans, Candida parapsilosis, and Cryptococcus neoformans has been described [Clerodendrum inerme showed a dual antibacterial and antifungal actions against a wide range of human pathogenic strains [Ag has long been known for its antibacterial properties against a variety of bacterial strains. In particular, green AgNPs prepared from a nhibited . Similarhia coli . AgNPs oneumonia . Furtherescribed , whereas strains .C. inerme extract also showed very similar inhibition capacity [T. amni seed extract was also observed against Listeria monocytogenes and Serratia marcescens, most likely as a result of intracellular ROS production [Interestingly, AuNPs produced from the same capacity . The autcapacity . Antibiooduction .Cinnamomum verum bark extract against E. coli and Staphylococcus aureus [C. auriculata leaf extract exhibited antibacterial activity due to direct cell contact, which disrupted bacterial cell integrity [ZnONPs also showed potential antimicrobial activity as evidenced by the action of ZnONPs derived from a s aureus . Similarntegrity .Cymbopogon citratus, can exhibit significant antimicrobial activity, including antibiofilm properties [Abutilon indicum leaf extract demonstrated potent antibacterial activity against both Gram-negative and Gram-positive bacteria [Other metallic NPs, such as CuONPs derived from operties . Interesoperties . MnONPs bacteria , whereasbacteria . This shCell wall disruption, cell membrane disintegration, massive free radical production, specific (targeted) and/or specific actions against proteins, DNA fragmentation, vital enzyme inhibition, loss of cellular fluids, and disruption in electron transport have all been proposed as possible mechanisms for NPs antibacterial activity . Bio-medDickeya dadantii [Eucalyptus globules extract against major pathogens of apple orchards [2NPs produced from lemon fruit showed antibacterial activity comparable to ZnONPs against D. dadantii [When agricultural pathogens are targeted, the antimicrobial activity outlined in the previous Section may be effective for crop protection. In particular, ZnONPs have demonstrated their wide agricultural interest showing an anti-phytopathogenic action against both bacteria as evidenced by ZnONPs derived from lemon fruit against soft rot bacteria pathogen dadantii , and funorchards . It is ndadantii .Through modifying abscisic acid concentration, ion homeostasis, and defense mechanisms comprising both enzymatic and non-enzymatic antioxidants, AgNPs synthesized from a wheat extract significantly contributed to alleviate the negative effects of salinity stress in wheat . InteresC. carandas leaf extract [C. inerme leaf extract [Excessive oxidative stress generated by the action of mitochondria and other internal or external sources may result in oxidative damages to various cell macromolecules , leading to functional declines, degenerative diseases, and aging . Antioxi extract , AuNPs a extract , or NiON extract . The phy extract . TherefoMatricaria chamomilla showed effective catalytic activity against Rhodamine B under UV light, which could make it a promising material for wastewater treatment [Abutilon indicum leaf extract has shown efficient absorption activity against the heavy metal CrVI as well as strong photocatalytic activity, indicating the potential to remediate various organic and inorganic contaminants [2 production, mediated by Pd-Ag bimetallic nanostructures coated with reduced graphene oxide produced from a stevia leaf extract, can be noted [Other potential applications, such as (photo)catalytic and/or absorption potential applications, are also described. AgNPs produced by reatment . MnONPs aminants . Finallybe noted .The growing demand for green chemistry and nanotechnology has pushed for the development of green synthetic methods for the production of nanomaterials using plants, microbes, and other natural resources. Researchers have been focusing on the green synthesis of NPs, using an environmentally favorable technique. Due to their cost-effectiveness, nontoxic approach, simple availability, and ecofriendly nature, considerable research has been conducted on plant extract-mediated NPs production and their prospective uses in numerous industries. Plants have a variety of unique compounds that help in the synthesis process and accelerate the synthesis kinetic. The use of plants for green nanoparticle synthesis is an interesting and emerging aspect of nanotechnology that has a significant impact on the environment and contributes to nanoscience\u2019s long-term sustainability and progress. Catalysis, medicine, cosmetic, agriculture, food packaging, water treatment, dye degradation, textile engineering, bioengineering sciences, sensors, imaging, biotechnology, electronics, optics, and other biological sectors are just some of the potential applications of these green plant-based NPs. These NPs might be the future impetus for the biomedical field in the drug delivery system. These green NPs might be also employed in a variety of ways, including phytopathogen treatment in agriculture or water disinfection for environmental cleanup. This green approach of NPs synthesis is becoming more popular and is expected to develop exponentially in the future; nevertheless, long-term impacts on animals and humans, as well as the accumulation of these NPs in the environment and their influence, must be addressed in the future. This Special Issue gathered cutting-edge research and review articles on the plant-based green synthesis of NPs, their production, characterization, and applications, with the goal of providing the most comprehensive overview of all these features and future challenges."}
+{"text": "Canis lupus familiaris Linnaeus, 1758) is used as a natural model for psychiatric disorders, but the similarity between dog and human personality and the association between dog personality and unwanted behavioral traits, such as fearfulness, aggressiveness, and impulsivity/inattention, remain unknown. This study utilized structural equation modeling (SEM) with survey data of 11,360 dogs to examine the associations and correlations between seven personality and ten unwanted behavioral traits. Personality traits included insecurity, energy, training focus, aggressiveness/dominance, human sociability, dog sociability, and perseverance. Unwanted behavioral traits included fearfulness, noise sensitivity, fear of surfaces/heights, separation anxiety, barking, stranger-directed aggression, owner-directed aggression, dog-directed aggression, hyperactivity/impulsivity, and inattention. We first fitted confirmatory factor models for the unwanted behavioral traits and the best model grouped unwanted behaviors into four latent traits: fear-related behavior, fear-aggression, aggression, and impulsivity/inattention and used this structure in the subsequent SEM model. Especially, insecurity, which resembles the human neuroticism trait, was strongly associated with unwanted behavior, paralleling the association between neuroticism and psychopathology. Similarly, training focus, resembling conscientiousness, was negatively related to impulsivity/inattention, and aggressiveness/dominance was associated with aggressive behaviors, resembling associations of conscientiousness and agreeableness with attention deficit hyperactivity disorder and aggression-related psychopathology, respectively. These results indicate that dog personality traits resemble human personality traits, suggesting that their neurological and genetic basis may also be similar and making the dog a suitable animal model for human behavior and psychiatric disorders.Personality traits, especially neuroticism, strongly predict psychopathology. The domestic dog ( Although personality psychologists do not completely agree on the structure of human personality, the five-factor model of personality has gained the most support . This fiPersonality traits are connected to mental health. Especially, neuroticism is associated with mental health, with a high level of neuroticism predicting and preceding psychopathology, particularly mood and anxiety disorders , 11\u201319. Based on decades of studies, it has been proposed that categorical mental health diagnoses would instead form a hierarchical, quantitative construct . This hiDogs have been proposed and used as models for human psychiatric disorders , 28. TheThe association between personality traits and pathological, abnormal, or unwanted behavioral traits has not been studied in dogs. Thus, here, we examined the association of personality with unwanted behavior, namely aggressiveness, fearfulness, and impulsiveness. Many unwanted behavioral traits and psychopathological traits, especially fear and anxiety-related traits, are highly correlated , 44\u201349. We used our validated  dog persWe previously utilized factor analysis to reduce the questionnaire items into factors in each section separately , except We utilized the behavior questionnaire data collected in our previous study , which, The final dataset included questionnaire responses for 11,360 dogs (Supplementary Table S2) of 316 breeds and breed variants. Due to the small number of responses in many breeds, most breeds were grouped based on genetic relationships , historiBefore SEM, we utilized CFA to model the structure of unwanted behavioral traits, as they were expected to correlate highly. We used precalculated factor scores instead of defining the latent variables in the CFA, as dog owners could answer the questionnaire sections separately and many owners only answered one or a few of the sections. Therefore, we performed factor analysis for each section separately and removed individuals and questions with more than 20% missing responses, with the mean imputation used for other missing responses . Despitecaret [lavaan [nonnest2 [We defined seven competing unwanted behavioral trait structures  the model failed to converge. Therefore, we calculated the mean trait score for all 52 breed groups in all personality and unwanted behavior factors and range-standardized them between 0 and 1. We used these standardized mean scores as continuous covariates in the model. For example, noise sensitivity score was explained by breed mean scores in noise sensitivity, and human sociability score was likewise explained by breed mean scores in human sociability.Dog\u2019s age was calculated by subtracting its birthdate from the time of questionnaire section response and averaged over all questionnaire sections. Dog\u2019s breed proved challenging to use as a covariate, as psych [psych [We included socialization as a covariate, as it previously had a highly significant association with fear-related behaviors , 63. Socpsych  to ensurh [psych . The besThe SEM model was complex and included many variables. Firstly, we defined latent unwanted behavior variables based on the best CFA model. Secondly, we defined regressions for these latent traits, in which each latent trait was explained with all personality traits. Thirdly, as covariates may influence personality and unwanted behavior, we defined regressions for all personality and unwanted behavior traits, in which these traits were explained with the dog\u2019s age, sex, breed, and socialization score. We defined these regressions for each unwanted behavioral trait instead for latent traits, as our previous studies indicated that sex, age, breed, and socialization experiences are differentially associated with correlated unwanted behaviors , 63, 65.The study was approved by the University of Helsinki Viikki Campus Research Ethics Committee . Informed consent was obtained from all participants.N\u2009=\u2009475, 4.2%), retrievers and flushing dogs , and Border Collie . The most prevalent breeds and breed groups were Finnish Lapponian dog  was associated with lower fearfulness, barking, owner-directed aggression, stranger-directed aggression, insecurity, aggressiveness/dominance, and energy scores but with higher fear of surfaces/heights, perseverance, training focus, human sociability, and dog sociability scores (Supplementary Table We defined in total 12 correlations between the seven personality traits, all of which were significant (Supplementary Table All personality traits were associated with two or more latent unwanted behaviors (Supplementary Table When examining estimates over 0.10 and under \u20130.10, the most associated explanatory personality trait was insecurity, which was associated with all four latent unwanted behaviors. Of these associations, two were over 0.30. In contrast, energy score was associated only with impulsivity/inattention, perseverance and human sociability were associated only with fear-aggression, and dog sociability achieved a moderate estimate only in fear-related behavior. Regressions with standardized estimates over 0.10 and under \u20130.10 are shown in Fig. We utilized our extensive dog personality and unwanted behavior questionnaire to examine the structure of unwanted behavioral traits with CFA and the association of personality traits with unwanted behavioral traits with SEM. We discovered that many traits were related to each other. Some of these associations were replicated from previous studies, including the comorbidities between unwanted behavioral traits. We also discovered novel findings, for example, the associations between training focus and unwanted behaviors and the correlation between training focus and insecurity. Furthermore, several of these associations, including the strong association of insecurity with fear-related behaviors, were similar to associations in humans, strengthening the use of dogs as models for human behavior and psychopathology.Based on the content of the dog personality traits  and prevWe examined the structure of unwanted behavioral traits by comparing latent models based on previous literature with CFA. The best fitting model was based on previous dog behavior studies , 56\u201362. Personality traits also correlated with each other, as suspected based on previous studies. The strongest correlations were observed between insecurity and training focus and between aggressiveness/dominance and dog sociability. Both correlations were negative. Aggressiveness/dominance describes aggressive reactions toward other dogs, and therefore, the negative correlation between these traits is not surprising. Similarly in humans, extraversion and agreeableness, both including social behaviors, correlate positively phenotypically and genetically , 66, 67.Many personality traits were significant predictors of unwanted behavioral traits. Training focus was highly negatively associated with impulsivity/inattention. This is not surprising, as training focus describes the ability to stay focused and orient to tasks, whereas impulsivity/inattention describes the opposite. Paralleling this result, in humans, low impulsivity and conscientiousness are also highly related , with imCovariates influenced all personality traits and unwanted behavioral traits. Not surprisingly, breed mean score significantly explained variation in personality and unwanted behaviors, indicating that breed indeed influences a dog\u2019s behavior, as discovered in many earlier studies as well , 74\u201378. Our study has limitations. Firstly, our study was cross-sectional, and thus, causal relationships between personality traits and unwanted behavior cannot be inferred. Secondly, the study utilized an online behavioral questionnaire and collected a convenience sample, which may not represent the entire population and can, thus, influence the results. Thirdly, our study had missing answers in many variables, and we had to use mean imputation to conduct the factor analyses. Fourthly, some unmeasured confounding variables might have influenced the results. In future, longitudinal studies should be designed to examine whether personality traits can predict unwanted behavior in dogs.In conclusion, this study discovered several associations between personality and unwanted behavioral traits. Many of these associations paralleled associations between human personality and psychopathology. For example, Insecurity, resembling the personality trait neuroticism, was highly associated with unwanted behavioral traits. Similarly in humans, neuroticism is the strongest predictor of psychopathology, especially anxiety and mood disorders. These similarities between dogs and humans suggest that shared genetic and neurobiological factors might underlie these behavioral traits in both dogs and humans. Furthermore, our results indicate that the dog is a good model for both psychiatric disorders and human personality.Supplementary informationSupplementary material: R code"}
+{"text": "In vivo, the lignified hypodermis blocked the entry of ions into the cortex, while root exodermis absorbed ions and restricted them to the cortex. The roots of the hyperaccumulators Pteris vittata and Cardamine hupingshanensis, as well as the aquatic invasives Alternanthera philoxeroides, Eichhornia crassipes, and Pistia stratiotes, contained lignin and pectins. These compounds may trap and store ions before hypodermis maturation, facilitating ion hyperaccumulation and retention in the apoplastic spaces of the roots. These apoplastic histochemical features were consistent with certain species-specific characters, including ion hyperaccumulation, invasive behaviors in aquatic environments, or tolerance of oligotrophic conditions. We suggest that apoplastic histochemical features of the root may act as invasion mechanisms, allowing these invasive aquatic plants to outcompete indigenous plants for ions.We used brightfield and epifluorescence microscopy, as well as permeability tests, to investigate the apoplastic histochemical features of plant roots associated with ion hyperaccumulation, invasion, and tolerance of oligotrophic conditions. In hyperaccumulator species with a hypodermis (exodermis absent), ions penetrated the root apex, including the root cap. By contrast, in non-hyperaccumulator species possessing an exodermis, ions did not penetrate the root cap.  Tronments ,6,7. Carium (Cd) ,9,10. Soronments ,18,19,20ronments ,22,23. Pronments  and outcronments . Thus, cronments . Paspaluts roots .Alternanthera philoxeroides and brassicas [Brasenia schreberi (Cabombaceae) have polysaccharides in various patterns that absorb berberine during different development stages in vivo [In vascular plants, the lignified, suberized endodermis and exodermis act as apoplastic barriers, restricting water-solute exchange, reducing oxygen loss after submersion, and supporting adaptation to terrestrial environments ,35,36,37rassicas ,42,43,44rassicas ,50,51,52rassicas ,54,55. T in vivo ,56.Pteris vittata and Chlorophytum comosum; the wetland species, Cardamine hupingshanensis and Paspalum distichum; and the aquatic species, Alternanthera philoxeroides, Eichhornia crassipes, and Pistia stratiotes. We also tested the apoplastic permeability of Pteris vittata and Paspalum distichum. An improved understanding of these plant roots\u2019 apoplastic histochemical features might help explain how these plants become invasive, tolerate oligotrophic conditions, and hyperaccumulate ions [In this study, we aimed to identify the apoplastic histochemical features of the root cortical walls that facilitate ion uptake and retention, leading to ion hyperaccumulation and reflecting an adaptation to nutrient-deprived environments. To identify these features, we investigated the roots of seven representative hyperaccumulator, invasive, and/or oligotrophic plants: the aerial species, ate ions ,23,25,26ate ions ,23,25,2622.1Pteris vittata, Paspalum distichum, Chlorophytum comosum, Cardamine hupingshanensis, Alternanthera philoxeroides, Eichhornia crassipes, and Pistia stratiotes were identified in the Testing Ground of Yangtze University  in October 2020. We collected samples of the adventitious aerial roots of Pteris vittata, which grow on walls in the cracks between bricks, and of Chlorophytum comosum, which propagate via shoots with adventitious aerial roots. We collected the roots of Cardamine hupingshanensis and Paspalum distichum from a wetland area. We collected the roots of Alternanthera philoxeroides, Eichhornia crassipes, and Pistia stratiotes from ponds. Ten roots were collected from each species of five plants and immediately fixed in formaldehyde-alcohol-acetic acid [Pteris vittata and Paspalum distichum were used for the apoplastic permeability tests [Mature specimens of tic acid . Eight fty tests ,33,34,352.2Root tissues were sectioned freehand, using a two-sided razor blade, under a stereoscope . Root sections were cut at 10 and 20\u2009mm from the root tip, as well as at the point where the cortex began to slough off. Sections were divided into three sets, such that each set included sections of each plant and at same distance from the root tip. Each set of sections was then stained with one of three stains: 0.1% (w/v) berberine hemisulfate-aniline blue (BAB) to test for Casparian bands and lignin in the cell walls ,58, phloAll sections were washed 2\u20133 times with sterile water, mounted with sterile water, and examined using brightfield microscopy under a Leica DME microscope (Germany). Specimens were photographed with a digital camera and a micrometer . Specimens stained with BAB were viewed under ultraviolet light on an Olympus IX71 epifluorescence microscope with excitation filter G 365\u2009nm, absorption filter barriers U-WB (blue light), dichromatic mirror DM 500, compensation excitation filter BP 450\u2013480, and compensation absorption filter BA 515. BAB-stained specimens were photographed using a digital camera and a micrometer  .2.3Pteris vittata and Paspalum distichum. We tested ion uptake using the apoplastic permeability tests of Seago et al., Meyer et al., and Meyer and Peterson [We tested the apoplastic permeability of whole fresh specimens of Peterson ,61,62, wPeterson .3Pteris vittata, the root wall contained pectins from the endodermis to the rhizodermis and hairs  lacked an exodermis but possessed a hypodermis with lignin, as has been described in a variety of other plants, including Adiantum reniforme var. sinense, Brassica sp., Oenanthe javanica, Lycopodium obscurum, Pelargonium hortorum, Platycerium bifurcatum, and Selaginella sp. [Banksia, Grevillea, and Hakea) have a hypodermis containing soluble phenolic or lignin-like compounds, which have similar histochemical features with lignin of hypodermis in this studied species [The endodermis and the exodermis are key impermeable apoplastic barriers that are common in vascular plant roots ,66,67,68xodermis ,75. The ella sp. ,77,78,79 species ,50,51,52Brassica, Noccaea, and Cardamine [Pelargonium hortorum has larger \u03a6 thickenings at the hypodermis [Platycerium bifurcatum, Pleopeltis sp., and Doryopteris triphylla have lignified sclerenchyma layers around the endodermis [Selaginella sp. have an exodermis [Noccaea caerulescens, the inner cortical walls of roots contain pectins and lignin [Pteris vittata [Cardamine hupingshanensis [Alternanthera philoxeroides [Eichhornia crassipes, and Pistia stratiotes.Lignified \u03a6 and even thickenings that are distributed between the endodermis and the hypodermis of the cortical walls are typical of roots in the Brassicaceae, including in the genera ardamine ,42,43,44podermis . The roododermis ,82,83,84xodermis . In the  vittata , Cardamihanensis , Alternaxeroides , EichhorPteris vittata and Chlorophytum comosum, the rhizodermis and hair walls contained pectins and accumulated a large amount of berberine. Similarly, the orchid root velamen also contains pectins and accumulates ions [Sedum alfredii accumulated substantial Leadmium Green AM dye [Chlorophytum comosum retained berberine, similar to retention of polysaccharides by the smooth, immature mucilage hairs of Brasenia schreberi; the retention of berberine thiocyanate grains by the Pteris vittata root surfaces was similar to that of the mature mucilage hairs of Brasenia schreberi in vivo [Adiantum reniforme var. sinense [Metasequoia glyptostroboides [Cardamine hupingshanensis [Alternanthera philoxeroides [Pteris vittata and Chlorophytum comosum retained substantial berberine. Pectins were present from the endodermis to the rhizodermis walls in Cardamine hupingshanensis, Alternanthera philoxeroides, Eichhornia crassipes, and Pistia stratiotes. However, pectins are only found in the peri-endodermal thickenings of Noccaea caerulescens [In tes ions ,54,55. Tn AM dye ; roots in AM dye . The roo in vivo ,56. The  sinense  and retaroboides , Cardamihanensis , and Altxeroides . By contulescens ,43.Pteris vittata (exodermis absent) and Paspalum distichum (exodermis present) near the root tips [Iris germanica (exodermis present) [Pteris vittata, similar to the results in Vicia faba (exodermis absent) [Paspalum distichum, similar to what has been shown in Zea mays (exodermis present) and Iris germanica (exodermis present) [Pteris vittata. By contrast, few berberine thiocyanate grains adhered to the mature exodermis of Paspalum distichum at the root surface [Alternanthera philoxeroides blocks the entrance of ions into the cortex [in vivo in Phalaris arundinacea, Zizania latifolia, and Artemisia spp. [In the apoplastic permeability test, the berberine tracer penetrated to the cortex of both oot tips ,75, simipresent) ,86. The present) ,86. Many surface ,75. The e cortex . The roosia spp. ,34,35.Pteris vittata and Chlorophytum comosum have pectins that capture ions from the atmosphere, which helps these plants to survive in an oligotrophic aerial environment. Like Pteris vittata and Chlorophytum comosum, the epiphytic Orchidaceae use pectins to capture ions from the atmosphere [Brasenia schreberi uses polysaccharides to capture ions [Pteris vittata has many adventitious roots that absorb captured ions, leading to the hyperaccumulation of ions such as As and Cr [Cardamine hupingshanensis, Alternanthera philoxeroides, Eichhornia crassipes, and Pistia stratiotes may trap ions before the hypodermis matures. These ions are then retained in the lignified walls, giving these species a competitive advantage over indigenous plants, particularly in oligotrophic environments [Cardamine hupingshanensis may allow the plant to hyperaccumulate Se in a manner that is similar to the hyperaccumulation of Cd in the dense root hairs of certain Arabidopsis thaliana genotypes [Based on the apoplastic histochemical features of the roots and their permeability, we hypothesize that the root hairs of mosphere ,54,55. Sure ions ,54,55,56s and Cr ,81,86,87ronments ,42,43,44enotypes ,88 and ienotypes ,50,51,52enotypes ,26,50,524in vivo that the lignified hypodermis of the root blocks the entry of ions into the cortex [Pteris vittata and Chlorophytum comosum are pectin-rich, reflecting an adaptation to the oligotrophic aerial environment [Pteris vittata and Cardamine hupingshanensis, as well as those of the invasive aquatic plants Alternanthera philoxeroides, Eichhornia crassipes, and Pistia stratiotes, have lignin and pectins in the cortex and rhizodermis; these structures may trap and store ions before hypodermis maturation. This hyperaccumulation of ions supports the survival of these plants in oligotrophic environments [Histochemical analyses indicate that pectins and lignin are present in several parts of the plant root walls, including the cortex, endodermis, exodermis or hypodermis, rhizodermis, and hairs ,80,81,86e cortex ,86, while cortex ,61,75,86ironment ,56,80,81ronments ,43,44,52ronments ,18,19,20ronments ,92,93,94"}
+{"text": "Cardiometabolic diseases (CMD) represent a growing socioeconomic burden and concern for healthcare systems worldwide. Improving patients\u2019 metabolic phenotyping in clinical practice will enable clinicians to better tailor prevention and treatment strategy to individual needs. Recently, elevated levels of specific lipid species, known as ceramides, were shown to predict cardiometabolic outcomes beyond traditional biomarkers such as cholesterol. Preliminary data showed that physical activity, a potent, low-cost, and patient-empowering means to reduce CMD-related burden, influences ceramide levels. While a single bout of physical exercise increases circulating and muscular ceramide levels, regular exercise reduces ceramide content. Additionally, several ceramide species have been reported to be negatively associated with cardiorespiratory fitness, which is a potent health marker reflecting training level. Thus, regular exercise could optimize cardiometabolic health, partly by reversing altered ceramide profiles. This short review provides an overview of ceramide metabolism and its role in cardiometabolic health and diseases, before presenting the effects of exercise on ceramides in humans. According to the Global Burden of Diseases, Injuries and Risk Factor Study, the rate of mortality from noncommunicable diseases (NCD) has increased from 1990 to 2019, to account for 74% of total mortality . WhereasBlood lipid analysis has been part of cardiometabolic risk stratification strategy since the middle of the last century . DespiteRegular physical activity is, indeed, essential to maintain general health ,15,16,17Ceramides are synthesized through three major metabolic pathways: the de novo pathway that mainly results from the combination of serine and palmitoyl-CoA in the endoplasmic reticulum, the salvage pathway, which consists of the breakdown of sphingomyelins or glycosphingolipids in lysosomes, and the sphingomyelinase pathway, where sphingomyelins are converted into ceramides in cell membrane  28,29].,29.28,29In the Golgi apparatus, ceramides are transformed into various complex sphingolipids such as ceramide-1-phosphate, sphingomyelin or glycosphingolipids ,29 CeramLess frequently, substrates other than serine and palmitoyl-CoA, such as alanine or glycine plus stearate or myristate, can also enter the de novo pathway . This leCeramides and their derivatives are involved in many, if not all, essential cellular processes such as cell growth, cell adhesion and migration, senescence, apoptosis, inflammation, immune responses, and angiogenesis ,29. TheyChanges in ceramide levels have been observed in diverse pathological processes such as NAFLD ,35, obesElevated circulating ceramide levels have been reported in obese patients with T2DM ,45. FurtFrom a cardiovascular perspective, ceramides located at the surface of LDL drive their transcytosis through the endothelium and uptake into macrophages, which results in foam cell formation, vascular inflammation, and atherosclerosis ,41,42. TLiquid chromatography-tandem mass spectrometry (LC-MS/MS) is the technique of choice for ceramide measurement as it offers a high sensitivity to detect low abundant species and a large breadth of coverage with respect to chemical diversity ,63. CurrNevertheless, plasma ceramides are already measured in daily practice in some clinical facilities, such as at the Mayo Clinic  ,67. ConcOverall, circulating ceramides can predict cardiovascular outcomes beyond traditional cardiovascular risk factors in healthy individuals and patients with CAD  9,10,12,79,80,81Physical activity and exercise represent cost-effective means to prevent and treat NCD ,85,86,87Circulating ceramide levels were increased following a single session of moderate-intensity continuous training (MICT) in endurance athletes, sedentary obese individuals and patients with T2DM . Likewis2peak), is inversely associated with incidence of cancer, cardiometabolic diseases and all-cause mortality [Cardiorespiratory fitness (CRF), defined as the peak oxygen uptake (VOortality ,97,98,99ortality ,101,102.ortality , Cer (18ortality , Cer (18ortality , Cer (18ortality ,104,105,ortality , Cer (18ortality , Cer (18ortality  and Cer ortality ,79. Finaortality ,107, Hexortality ,105, Lacortality  and LacCortality .To summarize, acute bouts of physical activity tend to elevate both circulating and muscle ceramide levels, while regular exercise leads to a reduction of ceramides in the circulation and myocytes . It has Upgrading patients\u2019 metabolic stratification in clinical practice has the potential to improve personalization of CMD prevention and treatment. Specific ceramide species were shown to predict cardiometabolic outcomes beyond classical biomarkers such as cholesterol. While an acute bout of physical exercise tends to increase circulating and muscular ceramide levels, regular exercise leads to a reduction of ceramide levels. This is also reflected by the fact that CRF, a powerful marker reflecting cardiometabolic health and training status, has been negatively associated with several ceramide species. Preventive and therapeutic effectiveness of a well-conducted exercise intervention to mitigate ceramides profile remains to be investigated."}
+{"text": "Pericardial effusions can be caused by diverse etiologies, including heart-related conditions, kidney failure, trauma, infections, autoimmune diseases, and cancer. This systematic review aimed to assess the role of cytology in identifying the most prevalent cancers related to malignant pericardial effusions (MPEs), the ability of cytology, compared to histology, to detect cancer while evaluating pericardial effusions, and the prognostic impact of MPEs. Four electronic databases were investigated using a predefined algorithm, and specific inclusion and exclusion criteria. We found that the most prevalent primaries associated with MPEs were lung , breast, hematolymphoid, and gastrointestinal cancers. MPEs tended to be hemorrhagic rather than serous or serosanguinous and to occupy larger volumes compared to non-neoplastic effusions. In addition, cytology was shown to exhibit an enhanced ability to detect cancer compared to biopsy in most of the included studies. Lastly, the presence of an MPE was associated with poor prognosis, while survival depended on the specific cancer type detected. Particularly, prognosis was found to be worse when MPEs were caused by lung or gastric cancer, rather than breast or hematolymphoid malignancies. In conclusion, evidence suggests that cytologic evaluation has a significant diagnostic and prognostic impact in patients with MPEs. A pericardial effusion, which is formed by the accumulation of excessive fluid within the pericardial cavity, is a prevalent manifestation clinicians face . It can To our knowledge, while the cytology of MPEs has previously been described in multiple studies, no systematic review has been performed up to date. Our study aimed to highlight the diagnostic and prognostic impact of cytology while evaluating pericardial effusions.\u201cpericardi* AND (cytolog* OR cytopatholog*) AND (effusion* OR fluid) AND (cancer* OR carcinoma* OR metasta*)\u201d, while no specific search filters were applied . Duplicates were removed with the Paperpile reference manager. Then, the remaining records were inserted into the Rayyan App for title\u2013abstract selection [We performed this systematic review following the Preferred Reporting Item for Systematic Review and Meta-Analysis (PRISMA) guidelines . We compelection .Two authors  selected independently the eligible studies using predefined inclusion and exclusion criteria . This wa\u00ae spreadsheet: first author and year, country, study design, study period, follow-up duration, mean and/or median age of the enrolled patients, total number of patients and samples included, number of samples with malignant cytology and histology, malignancy rate between females and males, number of serous, hemorrhagic, serosanguinous, or purulent effusions, mean or median effusion volume of the benign, malignant or all effusions evaluated, main symptoms reported, cancer types described, and selected prognostic data .The following data were extracted from each eligible study onto an ExcelThe role of cytology in identifying specific cancer primaries associated with MPEs;The ability of cytology, compared to histology, to detect cancer while evaluating pericardial effusions;The prognostic impact of MPEs.The outcomes of this systematic review were used to assess the following:The flowchart of our study is displayed in n = 21) in the U.S.A. The majority of them had a retrospective design. p < 0.001). Likewise, statistically significant results were reported by Cullinane et al. [p = 0.02 and p = 0.04, respectively), both highlighting the value of cytology detecting MPEs. In contrast, in none of the studies where histology detected more cancers than cytology [e et al.  and Lopee et al.  , hematolymphoid, genitourinary, and gastrointestinal primaries, whereas they were derived from breast, Mullerian, lung, and hematolymphoid primaries in females. They also found that hematolymphoid, gastrointestinal, and genitourinary malignancies were the most common ones associated with malignant peritoneal effusions in males; in contrast, primaries of Mullerian origin, the breast, and the gastrointestinal system were most often found in females . Of inteOur study additionally reported that MPEs were more likely to be hemorrhagic and occupy larger volumes than non-malignant effusions. Likewise, the presence of hemorrhage has also been associated with malignant pleural effusions . A potenAccording to our results, cytology tended to be positive for malignancy in cases where histology was negative ,43,44,46Our review highlighted that MPEs were linked with higher mortality rates, while positive pericardial cytology was a significantly dismal prognostic factor ,31,33,38This systematic review has some important limitations. It was composed mainly of retrospective studies, while most were of a small size. In addition, many of the included studies exhibited possible selection bias, while their results were largely reported in a heterogenous way. Furthermore, a cytohistological correlation could not be performed in all studies, let alone in all samples in each study individually. In five of the studies included in the cytology/histology correlation analysis , cytologThis study showed that the most prevalent primaries associated with MPEs are lung , breast, hematolymphoid, and gastrointestinal cancers. MPEs tend to be hemorrhagic rather than serous or serosanguinous and occupy larger volumes than non-neoplastic effusions. Notably, cytology may exhibit enhanced cancer detection ability while assessing pericardial effusions, compared to histology. Lastly, MPEs show poor prognosis, while evidence suggests that the latter is worse when MPEs are caused by lung or gastric cancer, rather than breast or hematolymphoid malignancies."}
+{"text": "Damage-associated molecular patterns (DAMPs) are endogenous danger molecules released from the extracellular and intracellular space of damaged tissue or dead cells. Recent evidence indicates that DAMPs are associated with the sterile inflammation caused by aging, increased ocular pressure, high glucose, oxidative stress, ischemia, mechanical trauma, stress, or environmental conditions, in retinal diseases. DAMPs activate the innate immune system, suggesting their role to be protective, but may promote pathological inflammation and angiogenesis in response to the chronic insult or injury. DAMPs are recognized by specialized innate immune receptors, such as receptors for advanced glycation end products (RAGE), toll-like receptors (TLRs) and the NOD-like receptor family (NLRs), and purine receptor 7 (P2X7), in systemic diseases. However, studies describing the role of DAMPs in retinal disorders are meager. Here, we extensively reviewed the role of DAMPs in retinal disorders, including endophthalmitis, uveitis, glaucoma, ocular cancer, ischemic retinopathies, diabetic retinopathy, age-related macular degeneration, rhegmatogenous retinal detachment, proliferative vitreoretinopathy, and inherited retinal disorders. Finally, we discussed DAMPs as biomarkers, therapeutic targets, and therapeutic agents for retinal disorders. Damage-associated molecular patterns (DAMPs) are endogenous danger molecules released from the extracellular and intracellular space of the damaged tissue or dead cells . DAMPs areg cells. The anterior and posterior segment of the eye contains immunosuppressive fluid containing neuropeptides such as transforming growth factor-\u03b2 (TGF-\u03b2), vasoactive intestinal peptide (VIP), somatostatin, calcitonin, gene-related peptide, alpha-melanocyte-stimulating hormone, neuropeptide Y, and pigment epithelial-derived factor (PEDF) . TheThe innate immune system is the first line of defense against injury in the retina. DAMPs and PAMPs released by injured retinal cells are recognized by PRRs such as TLRs. The interaction of DAMPS with TLRs has been highly explored in retinal disorders , includiThe nucleotide-binding and oligomerization domain NLRs are multi-domain, cytosolic receptors involved in the activation of signaling cascades in ocular disorders. The activation of NLRP3 by DAMPs has been reported in various retinal disorders such as endophthalmitis, uveitis, glaucoma, ischemic retinopathies, DR, AMD, and IRDs ,272,273.DAMPs can also activate several other pathways in retinal disorders . The actIn retinal disorders, DAMPs are released by necrotic and apoptotic cells to elicit multiple downstream signaling effects to activate the innate immune system. The emerging evidence from preclinical and clinical studies suggests that DAMPs play both pathogenic and protective roles in retinal disorders. A deeper understanding of the mechanisms of DAMPs will open new opportunities to discover potential biomarkers, therapeutic agents, and therapeutic targets to combat retinal disorders.The release of DAMPs may promote chronic and sterile inflammation involved in the pathogenesis of several retinal disorders. Consequently, DAMPs can be valuable diagnostic and prognostic biomarkers in retinal disorders. The potential biomarkers for retinal disorders are tabulated in DAMPs may have utility in designing treatment modalities . In juveThe excessive production of DAMPs in response to infection, inflammation, or injury has led to the discovery of several proteins and molecules that can be targeted to develop novel therapeutics or repurpose existing drugs to treat retinal disorders. The potential drug targeting DAMPs suggested in the retinal disorders are tabulated in DAMPs such as decorin, LIF, defensins, IL-33, syndecan-1, and SAA have been described for their anti-inflammatory, anti-angiogenic or anti-fibrotic properties, and are presented in In this comprehensive review, we have: (i) described the role of DAMPs in various retinal disorders; (ii) demonstrated that DAMP-driven signaling pathways are involved in the pathogenesis of retinal disorders, and iii) discussed the possibility of DAMPs acting as biomarkers, therapeutic targets, and therapeutic agents for the management of vision-threatening retinal disorders. Epigenetic mechanisms have emerged as critical modulators of the host defense system in the retina. Epigenetic modifications have been implicated in various retinal disorders, including uveitis, glaucoma, ocular cancer, IR, DR, AMD, PVR, RRD, and IRDs . Though"}
+{"text": "In \u201cUse of Deep Learning to Predict Acute Kidney Injury After Intravenous Contrast Media Administration: Prediction Model Development Study\u201d :e27177), one error was noted.In the originally published paper, names of 5 authors  were inadvertently formatted with middle initials instead of the full author names.The full authorship list was listed as follows in the originally published paper.Donghwan Yun, Semin Cho, Yong C Kim, Dong K Kim, Kook-Hwan Oh, Kwon W Joo, Yon S Kim, Seung S HanThis has been corrected to:Donghwan Yun, Semin Cho, Yong Chul Kim, Dong Ki Kim, Kook-Hwan Oh, Kwon Wook Joo, Yon Su Kim, Seung Seok HanThe correction will appear in the online version of the paper on the JMIR Publications website on November 1, 2021, together with the publication of this correction notice. Because this was made after submission to PubMed, PubMed Central, and other full-text repositories, the corrected article has also been resubmitted to those repositories."}
+{"text": "Proper cement selection in fixed prosthesis plays a determinative role in providing long-term serviceability, retention, caries prevention, and patient satisfaction. This study, reviews different luting agent characteristics and their application based on different clinical situations and different types of full coverage restorations.An electronic search was conducted through PubMed, Medline, and Google scholar using following keywords or combinations: restoration, full coverage, PFM, porcelain fused to metal, all ceramic, zirconia, ceramic, casting, fixed partial denture, cement*, dental cement, cement selection, and retention. The most related articles were selected for review.Choosing a proper luting agent is highly dependent on scientific knowledge regarding the characteristics of restorative materials and luting agents. Conventional cements could be indicated in various situations; however, some restorative materials or clinical situations call for resin-cements to provide predictable retention, support, and durability.Conscious selection of retentive cement for each type of restoration/material is necessary to provide predictable successful treatment and reduce the potential complications. Key words:Adhesive cement, dental bridgework, dental cements, dental crowns, dental porcelain, prostheses and implants. Full coverage restorations are among the most prevalent prosthetic treatments used in dentistry. This type of restoration could be indicated in varieties of conditions, ranged from heavily damaged, heavily restored, or cracked tooth to one with aesthetic or positional problems -3 and coSingle or multiunit tooth- or implant-supported full-coverage prostheses are among the most prevalent prosthetic treatments used in routine dental practices. Retention of indirect restorations, is the main single factor determines their survival and durability ,13. AlthAn electronic search was performed in PubMed, Medline, and Google scholar using following keyword or combinations: restoration, full coverage, PFM, porcelain fused to metal, all ceramic, zirconia, ceramic, casting, fixed partial denture, cement*, dental cement, selection, comparison, retention. The articles were selected from data bases as well as the related references of selected articles. Using reference management software , duplicated studies were eliminated. Afterwards, articles were selected based on title/abstract, and full text review. Two independent reviewers evaluated the studies and discussed to reach the same decision. In cases of disagreement, the third reviewer was asked to participate in decision. Peer-reviewed article focused on full-coverage restorations, different cements properties, and cement selection were included, while studies on other types of restorations were excluded, as well as case reports.Number of search results for the selected keywords was 8459 (PubMed), 10256 (Google scholar) and 6956 (Scopus). After duplicate removal and title/abstract analysis, 146 studies were selected for full-text review. Finally, 97 studies met the requirement of inclusion/exclusion criteria and were included to be discussed.Dental cements have a long history. Zinc oxide eugenol (ZOE) was the first luting agent developed in 1850s ,20. ZincZinc phosphate (ZP) cement is the oldest definitive cement introduced in 1800s, and has a wide range of applications ,18,21,22Zinc Polycarboxylate (ZPC) cement, introduced in 1968 , shows mGlass-ionomer (GI) cement or glass polyalkenoate was first introduced in 1969 . The abiResin modified glass ionomer (RMGI) cement, the result of combining resin and GI , has impResin cement (RC), the only true adhesive cement ,29, beneA suitable long-term dental cement should have good biocompatibility, long working and short setting time, low film thickness, low solubility, caries prevention potential, chemical bond to tooth structure, an elastic modulus between tooth structure and restoration, plastic deformation resistance, and accepTable strength and toughness ,37-39. TGeneral guidelines for cement selection: Selecting proper luting agents should be based on patient requirements, clinical situations, and the restorative material. Having enough information on cements will help the clinician to make a conscious choice; however, there are guidelines that could help to select appropriate cement in each situation: when access and moisture control are difficult to achieve, conventional cements are preferred over resin cements provided that acceptable retention and resistance form is achieved in preparation design  could be routinely used in normal single or multi-unit fixed prostheses (-ostheses . Howeverostheses ,48. RMGIostheses . When hiostheses  with higostheses ,50.The important factor for cement selection in ceramic restorations is the composition and structure of ceramic material . CeramicGlass ceramic has good esthetic, high biocompatibility, acceptable abrasion and fracture resistance , and lowPolycrystalline ceramics are densely sintered oxide ceramics with no glassy content ,57. TheiHybrid ceramic were introduced to provide an ideal material with close elastic modulus to the remaining tooth structure while satisfy the esthetic appearance and durability of ceramic materials ,70. The Resin-composite has also been developed as indirect restorative material in CAD/CAM systems . They arChallenging situations call for increased retention: Some situations namely extensive destructive caries, abfraction, developmental anomalies, and short height of existing clinical crown are considered challenging for providing adequate retentive and resistance form in abutment teeth (-nt teeth . The tapnt teeth -84. Certnt teeth .Cement selection in implant restorations: Fabrication of implant restorations needs a high degree of accuracy since small errors may lead to positional distortion and unfavorable stress on implants (et al., stated that Polycarboxylate cement showed the highest retention between Eugenol-free zinc oxide, resin-bonded, ZOE cement, zinc phosphate luting agents (-implants ,86. Althimplants . Akca stimplants , and Gulimplants . HoweverSelecting proper cement is the result of clinician information regarding available luting agents, and the restoration type/material, as well as the patients\u2019 clinical situations. It is mandatory for clinicians to consider the patient and treatment situation and choose the appropriate cement. Reviewing available articles concerning cement selection, the following conclusions can be made:\u2022 Metallic and metal-ceramic full coverage restorations could be cemented by varieties of luting cements and proper cement selection is the result of evaluating tooth preparation, patient clinical situation, and special parafunctional or diet habits.\u2022 Resin cements are indicated for high-glass ceramic restorations to provide reliable adhesive support, while low-glass and polycrystalline ceramics might be cemented by conventional luting agents.\u2022 Resin cements are the only cements indicated in hybrid ceramics.\u2022 Resin cements could be used for full coverage restorations in case of need for increased retention."}
+{"text": "Pagetoid spread of melanocytes in the epidermis is a common indicator of melanocytic atypia, both histopathologically and with reflectance confocal microscopy (RCM). Specifically on RCM, large, bright, atypical dendritic and/or roundish cells are characteristic of melanoma. However, intraepidermal Langerhans cells (ILC) create the potential for diagnostic ambiguity on RCM. We describe one case of a pigmented facial lesion that was initially diagnosed as lentigo maligna (LM) due to numerous atypical perifollicular dendritic cells on RCM. Additionally, we present the findings of a literature review for similar reported cases conducted by searching the following terms on PubMed: reflectance confocal microscopy, RCM, lentigo maligna, melanoma, Langerhans cells, dendritic cells, and atypical cells. In our case, the lesion was determined to be a solar lentigo on histopathology. Immunohistochemistry (IHC) with CD1a identified the atypical-appearing cells as ILC, as it did in 54 reported cases of benign lesions  misdiagnosed as malignant on RCM . According to our case and the literature, both ILC and atypical melanocytes can present with atypical-appearing dendritic and/or roundish cells under RCM. Currently, there is no method to distinguish the two without IHC. Therefore, the presence of pagetoid cells should continue to alert the confocalist of a potential neoplastic process, prompting biopsy, histopathologic diagnosis, and IHC differentiation. Confocal images have a resolution comparable to traditional histopathology [Reflectance confocal microscopy (RCM) is a technique that acquires athology . This enathology . Melanoc device 80 nm. Conathology \u20137. Whileathology ,6,8 and athology \u20136,8 for 2), pleomorphic with large and unusual morphology , roundish, diffuse, and extend to the stratum corneum [Suspicion for melanoma on RCM increases when atypical cells are densely distributed  atypical dendritic pagetoid cells, including some in a perifollicular distribution, consistent with LM . The derA shave biopsy was performed, and tissue sections were stained with hematoxylin and eosin (H&E) . HistopaRCM is an accurate tool for non-invasive differentiation between benign and malignant melanocytic lesions. For the diagnosis of LM specifically, Guitera et al  isolatedIn this case, the diagnosis was compromised due to shared morphologic features of Langerhans cells and atypical melanocytes on RCM . Both ceIn the literature, ILC presence has been confirmed in several cases of benign lesions that were perceived to be malignant under RCM. These include suspected cases of melanoma ,18,19, lComparatively high densities of Langerhans cells exist within the head, neck, trunk, and limbs , correspSome malignant and pre-malignant lesions, particularly pigmented basal cell carcinomas ,24, in sWhile atypical cells have been identified as ILC rather than atypical melanocytes across benign lesions including BMN, Sutton  nevi, labial melanotic macules, and SL, the presence of dendritic pagetoid cells should continue to alert the confocalist of a potential neoplastic process, prompting biopsy, histopathologic diagnosis, and IHC differentiation."}
+{"text": "The Editor in Chief has retracted this article. Concerns were raised after publication, and subsequent post publication peer review concluded that there was insufficient experimental work for this article. Therefore, the Editor in Chief has lost confidence in the results of the study. The authors have been offered to submit a revised manuscript for further peer review.Tsuyoshi Saito, Keita Sasa, Taisei Kurihara, Daisuke Kubota, and Muneaki Ishijima agree to this retraction. Nobuhiko Hasegawa, Kei Sano, Keisuke Akaike, Taketo Okubo, Takuo Hayashi, Tatsuya Takagi, Takashi Yao, and Yoshiyuki Suehara have not responded to any correspondence from the editor about this retraction."}
+{"text": "Dear Editor,We read with appreciation the succinct and informative systematic review by Zweers et al.  on the eWhile this review covered studies pertaining to epilepsy, skeletal and heart muscle, tonus dysregulation, movement disorder, developmental delay/intellectual disability, food intake, weight gain/growth, and hair growth, we note that the multiple symmetric lipomatosis phenotype, frequently associated with the MT-TK genetic mutation, was not covered.We would like to highlight that a version of the ketogenic diet was employed successfully, along with other simultaneous lifestyle interventions, in treating a disabling multiple symmetric lipomatosis phenotype. This successful intervention was reported in 2020 [Sincerely,Andre Mattman, MD, FRCPCAdult Metabolic Diseases ClinicVancouver, Canada."}
+{"text": "Consumers are increasingly interested in nutritious, safe and healthy muscle food products with reduced salt and fat that benefit their well-being. Hence, food processors are constantly in search of natural bioactive ingredients that offer health benefits beyond their nutritive values without affecting the quality of the products. Mushrooms are considered as next-generation healthy food components. Owing to their low content of fat, high-quality proteins, dietary fibre and the presence of nutraceuticals, they are ideally preferred in formulation of low-caloric functional foods. There is a growing trend to fortify muscle food with edible mushrooms to harness their goodness in terms of nutritive, bioactive and therapeutic values. The incorporation of mushrooms in muscle foods assumes significance, as it is favourably accepted by consumers because of its fibrous structure that mimics the texture with meat analogues offering unique taste and umami flavour. This review outlines the current knowledge in the literature about the nutritional richness, functional bioactive compounds and medicinal values of mushrooms offering various health benefits. Furthermore, the effects of functional ingredients of mushrooms in improving the quality and sensory attributes of nutritionally superior and next-generation healthier muscle food products are also highlighted in this paper. Muscle foods, such as meat and fish, play an important role in the daily diet of most consumers due to their desirable sensorial attributes and beneficial nutritional properties, including high levels of good quality proteins, vitamins, and minerals. However, muscle foods are deficient in vitamin C, calcium, dietary fibre, and antioxidants . MoreoveAs a result of these concerns, the food industry is reformulating existing products and creating new products to make them healthier and more sustainable ,8. In thThis review outlines the utilization of the edible parts of mushrooms as functional ingredients in muscle food products, such as meat and fish. In particular, the impact of mushrooms on the nutritional and quality attributes of these products are critically reviewed, including their physicochemical properties, microbiological stability, chemical stability, and sensory aspects.http://www.zionmarketresearch.com/report/mushroom-market, accessed on 8 January 2021). Commercially, mushrooms are mainly cultivated on agricultural residues, which enables these waste materials to be converted into a valuable human food source [Mushrooms are valued around the word as culinary delicacies and are popularly known as \u201cvegetable meat\u201d in many cultures. Botanically, they are the fruiting bodies of macroscopic filamentous saprophytic fungi that grow above ground. Their beneficial effects on human health and nutrition were recognized in early Greek, Egyptian, Roman, and Chinese civilizations ,26,27. Md source , while aAgaricus bisporus (agaric or button), Lentinula edodes (shiitake), Flammulina velutipes (enoki or winter mushroom), Pleurotus eryngii (king trumpet mushroom), Pleurotus ostreatus (oyster mushroom), Volvariella volvacea (paddy straw mushroom), Calocybe indica (milky mushroom), Hericium erinaceus (pom pom or lion\u2019s mane mushroom), Boletus edulis , Grifola frondosa (maitake or hen of the woods mushroom), and Agrocybe aegerita (pioppini) [Lentinula, Agaricus, Pleurotus, Auricularia and Flammulina [Some of the most important commercially cultivated mushrooms are ioppini) . Notablyammulina , despiteAlthough many ingredients are used while preparing processed food products, the role of food ingredients that merits special mention are those with inherent nutritional as well as functional properties that influence the quality of finished food products. Therefore, ingredients are now considered as an essential part and parcel of any food product development process. However, the ingredients or compounds obtained from natural sources and generally regarded as safe are of great interest because of their safety and health characteristics . As per Mushrooms, which belong to filamentous higher fungi, are known for their nutritional richness, low caloric value, taste, and nutraceutical properties. Due to their unique nutritional as well as textural properties, they are used as a dietary supplement and often considered as an alternative source of meat, fish, vegetables, fruits, etc. . MoreoveGenerally, mushrooms possess all three functionalities of food\u2014nutrition, taste, and physiological functionalities. Mushrooms have a peculiarly pleasant savory taste called umami due to presence of sodium salts of free amino acids such as glutamic and aspartic amino acids and 5\u2032-nucleotides . The umaAgaricus bisporus are reported to act as key molecules for kokumi taste [Agaricus bisporus can elicit new taste sensations, such as mouthfulness and complexity [Again, the umami taste peptides and umami-enhancing peptides are also considered to be important components which influence the sensory quality of mushroom. Peptides with different structures and length possess unique taste properties including sweet, bitter, umami, sour and salty. They are usually tasteless in water, but they can increase the salty, sweet, sour, bitter or umami taste in combination with corresponding tastants . Variousmi taste . Kokumi mi taste . Interesmplexity .Flammulina velutipes) reported to contain 32% dietary fibre [As stated earlier, mushrooms are excellent sources of dietary fibre and rich in protein possessing all nine amino acids that are essential for humans  but low ry fibre . Again, ry fibre . Mushroory fibre . Mushroory fibre ,57. The ry fibre .1, B2, B12, C, D, E, niacin, and folate [2) content of mushrooms increases appreciably, which can play a significant role in the bone and cartilage health of vegans and vegetarians [Being an excellent source of dietary fibres and proteins, mushrooms also have a low sodium content, and contain a diverse range of micronutrients, such as vitamins Bd folate . Despiteetarians ,61,62.Furthermore, mushrooms are a rich source of essential minerals like iron, copper, manganese, and zinc that play an important role in the proper functioning of different metabolic pathways. Indeed, the levels of some important trace elements (such as potassium and phosphorus) are typically considerably higher in mushrooms than in most vegetables . Edible It should be noted that the nutritional composition of mushrooms varies considerably depending on factors such as species, intra-species genetic variability, maturity, growth conditions, geographic location, environmental conditions, and post-harvest conditions ,66. The Mushroom nutraceuticals are natural compounds found in mushrooms that may have health benefits by reducing the risks of certain diseases or by improving human performance ,81,82. TMushrooms have been reported to contain different kinds of nutraceuticals, including lectins, triterpenoids, ganoderic acid, \u03b2-glucan, phenolics, flavonoids, hispolon, calcaelin, proteoglycan, lentinan, laccase, nucleosides, nucleotides, and ergosterol ,83,84,85Lactobacillus and Bifidobacterium, while suppressing the growth of detrimental bacteria such as Clostridia and Bacteroides, may promote health [L. edodes (Shiitake), Trametes versicolor (Yunzhi), and Ganoderma lucidum (Reishi). There is growing evidence that human health can be promoted by consuming a diet that establishes a diverse microbiome in the colon . In parte health ,91. Prebe health ,92,93. Me health . Some ofLactobaccilus acidophilus and Bifidobacterium longum subsp.). Similarly, glucans from P. ostreatus and P. eryngii [G. lucidum [Bifidobacterium sp. and Lactobacillus sp. In a study, Chou et al.  reported eryngii  and G. l lucidum  have alsin vitro studies have also reported that extracts from G. lucidum can modulate the gut microbiota in a manner that may help prevent obesity [Agaricus brasiliensis, Agrocybe chaxingu, Catathelasma ventricosum, Pleurotus abalonus, Tremella fuciformis, G. frondosa, and G. lucidum [Prebiotic mushroom polysaccharides are also reported to exhibit antiobesity and antidiabetic effects by regulating the energy homeostasis and plasma glucose levels of the host . The res obesity ,98. Othe lucidum ,99. The Edible mushrooms, due to richness in nutritive value and functional food components, make them an unmatched source of healthy food and are regarded as superior nutritional supplements ,53. To hConsidering their enormous benefits, varieties of food products such as breads , fish anAgaricus sp. contain 396 mg sodium/kg [Incorporation of mushroom and its parts not only influences the desirable texture, taste, flavour, and stability of muscle food products considerably but also enriches them with nutritive and functional health values ,108,109.odium/kg  which isodium/kg . On the odium/kg . Dietaryodium/kg . Therefoodium/kg . Over the years, a number of researchers have successfully incorporated mushrooms and its various parts (stipes and stem wastes) in formulation of various muscle food products like chicken sausages , salted F. velutipes) powder into emulsion-type pork sausages increased their pH, WHC, and cooking yield by decreasing the exudation of fat and water from the sausages [T. fuciformis) into pork patties significantly increased their oil retention and cooking yield. Moreover, the introduction of 25% fresh mushroom into chicken patties has been reported to give an improved moisture retention (77%) and cooking yield (81%) [F. velutipes) stem wastes into goat meat nuggets was shown to give a higher pH, emulsion stability, cooking yield, and WHC [L. edodes) extracts were found to reduce the pH of fermented sausages during 30 days storage at 15 \u00b0C [The quality and acceptability of muscle foods depends on a number of different physicochemical properties including chemical composition, pH, water-holding capacity (WHC), emulsion stability, and cooking yield ,132. Thesausages . Similarsausages  reportedld (81%) . The inc and WHC . Likewis and WHC  reported and WHC , as well and WHC . In contat 15 \u00b0C , which mP. ostreatus) into beef patties has been reported to increase the protein, fat, and ash content of the end product [P. sajor caju, PSC) powder into chicken meat decreased the fat content but increased the dietary fibre content in frankfurters in a dose-dependent manner. The addition of mushroom also influences the chemical composition and nutritional profil of muscle foods. As discussed earlier, these effects can be attributed to the presence of relatively high levels of protein, minerals, and dietary fibres in mushrooms. The incorporation of dried mushroom  are also known to have strong antioxidant activity because they contain phenolic compounds such as quercetin, chlorogenic acid, gallic acid, proto-catechuic acid, and flavonoids [B. edulis have also been reported to contain constituents that are known antioxidants, such as ascorbic acid (18.7 mg/g dw), tocopherols (18.7 mg/g dw) and phenolic acids (9.74 mg/kg dw) [L. edodes) mushroom have also been reported to contain various kinds of natural antioxidants [Amanita rubescens, Lepista nuda, Cantharellus cibarius, Hypsizigus marmoreus, Lactarius piperatus, Polyporus squamosus, Mucor circinelloides, Russula cyanoxantha A. bisporus, L. edodes, and V. volvacea have also been reported to exhibit strong antioxidant activity, which is mainly attributed to their high levels of phenolics and flavonoids [Mushrooms contain a wide range of natural antioxidants, including phenolic compounds, ergothioneine, ascorbic acid, tocopherols, and carotenoids ,153,154.avonoids ,156. Metg/kg dw) . Waste moxidants ,158. Aceavonoids ,161,162.F. velutipes) have been reported to inhibit lipid and protein oxidation in raw beef and fish (bigeye tuna) during storage, which was attributed to the presence of natural antioxidants [A. bisporus powder into salted cooked ground beef and tested its ability to protect the lipids and proteins from oxidation during storage. The mushroom extract was found to effectively inhibit lipid and protein oxidation, with about 88\u201394% lower malonaldehyde values and 99% lower volatile aldehydes being produced after 16 days storage compared to the control sample. In another study, Nayak et al. [Pangasius hypophthalmus) patties after a button mushroom (A. bisporus) extract was incorporated, leading to an appreciable increase in shelf life. The antioxidative activity of mushrooms and their extracts have also been demonstrated in various other studies, including B. edulis extracts in beef burger patties [F. velutipes extract in bigeye tuna [F. velutipes extract in kuruma shrimp [L. edodes extracts in fermented pork sausages [Mushroom extracts from the fruiting bodies of edible mushrooms  meat paste [A number of researchers have examined the impact of mushrooms on the textural properties of muscle foods. Choe et al.  reportedat paste . In general, these results suggest that incorporation of mushrooms into muscle foods usually leads to softening of the final products. There are a number of possible physicochemical phenomena that may account for this effect. For instance, mushrooms contain relatively high levels of dietary fibres that can form a 3D biopolymer network that traps fluids, thereby leading to a softer texture in the muscle food products ,165. MorThe appearance of muscle foods, such as their opacity, colour, and surface sheen, provide a visible indication of their quality and freshness, thereby playing an important role in determining consumer purchasing decisions ,167. TheBao et al.  monitoreA. bisporus mushroom into beef burgers did not strongly affect their appearance [In another study, researchers reported that the presence of 50% oyster mushroom in cooked chicken patties did not affect their redness (a*) but did decrease their lightness (L*) and yellowness (b*) . Incorpopearance . The intpearance . In a stpearance  reportedIn contrast to the above studies, the addition of white jelly mushroom was found to slightly decrease the redness and increase the yellowness of cooked pork patties, which might be due to the transparent white colour of these mushrooms . In geneAleurodiscus, Coprinus, Clitocybe, Daedalea, Marasmius, Merulius, Pleurotus, Polyporus, Poria, Psathyrella, and Tricholoma spp. have been used as a source of natural antibiotics for the treatment of various types of disease because of the immunomodulatory properties of \u03b2-glucans and the antibacterial properties of secondary metabolites [Muscle foods contain high levels of macronutrients and micronutrients that spoilage or pathogenic microorganisms can utilize to grow. Therefore, it is important to have effective strategies to extend the shelf-life and ensure the safety of this type of food . Many muabolites ,176. In L. edodes, P. ostreatus and Hypsizigus tessulatus demonstrated antimicrobial activity against all bacteria and fungi tested, with minimum inhibitory concentration (MIC) values ranging from 1 to 9 mg/mL. In this study, the L. edodes extracts were more effective than those from the other two mushroom species. Similarly, shiitake (L. edodes) mushroom extracts, isolated using organic solvents and supercritical fluids, exhibited antibacterial effects against pathogenic microorganisms such as Streptococcus pyogenes and Staphylococcus aureus [Micrococcus luteus and Bacillus cereus [Pleurotus florida mushroom have also been reported to exhibit strong inhibitory effects on the growth of both Gram-positive and Gram-negative bacteria and could, therefore, be considered as an alternative to traditional antibiotics [Chowdhury et al.  reporteds aureus , whereass cereus . Extractibiotics .L. edodes) extracts were shown to exhibit good antimicrobial activity in fermented sausages, thereby extending their shelf-life and inhibiting the growth of pathogens such as S. aureus, Listeria monocytogenes, and Escherichia coli O157 [Boletus aereus was effective at controlling microbial growth against food-poisoning organisms in pork meat, including S. aureus, L. monocytogenes, E. coli, and Salmonella Typhimurium. Overall, these studies show that incorporating mushrooms into muscle foods, like meat or fish, may be an effective means of increasing their shelf-life and safety.Other studies suggest that mushrooms or their extracts can be used as natural preservatives that improve the shelf-life of foods by inhibiting the growth of spoilage microorganisms in muscle foods. Button mushrooms have been reported to exhibit antimicrobial activity in sutchi catfish patties, leading to a considerable extension in their shelf-life . In anotoli O157 . Stojkovoli O157  reportedThe sensory attributes of food products play an important role in determining their quality and desirability. The overall sensory impression of muscle foods depends on their appearance, flavour, texture, and oral processing . The incS. esculenta) paste led to higher overall acceptability scores than the control paste [Myrdal Miller et al.  found thol paste . A numbeol paste  and grouol paste .Mushrooms are a rich source of important nutrients and bioactive components, including proteins, fibres, vitamins, minerals, and nutraceuticals, while also being low in calories, sodium, fat, and cholesterol. They can also be produced more sustainably than meat products, with less damaging effects on the environment . MoreoveThere are many species of edible mushrooms that have not yet been explored for their potential application in food products. These novel mushroom species may have different nutritional, sensory, and environmental impacts than those exhibited by the species used so far. Consequently, there is a need for research on these other species. Moreover, further research is required to identify the mechanisms of action of different constituents in mushrooms, e.g., their antimicrobial activity, antioxidant activity, structures, textural attributes, and flavour profiles. Given the increasing demand of consumers for healthier and more sustainable foods, it is likely that the utilization of mushrooms within muscle foods is likely to continue to grow."}
+{"text": "American Sign Language (ASL) is the primary form of communication for approximately 250,000 people in the U.S. . As these individuals age, they may experience challenges in their everyday activities. For example, ASL users rely on visual cues, but have age-related change in vision. Moreover, ASL users may need to utilize technology to communicate with non-ASL users, but the technology may not be suitable/usable for older adults. We explored these issues in the Aging Concerns, Challenges, and Everyday Solution Strategies (ACCESS) study, wherein we interviewed Deaf older adults (N=60) in ASL, who provided insights into unique, everyday challenges they encounter. We will focus on the technology solution strategies they incorporate to address and overcome challenges with daily activities. Understanding how participants think about, adapt, and utilize different technologies can inform future technology design to successfully support diverse, aging populations."}
+{"text": "Brown spider (genus Loxosceles) bites are frequent in South America, occurring in the upper limbs, thorax, and inner thigh. Genital area involvement is rare, with few reports in the literatureSurgical debridement was performed . The patLoxosceles bite is characterized by two painless punctiform orifices, progressing to an erythematous plaque with central clearing. After minutes or hours, a local reaction with intense pain accompanied by erythema, edema, vesicles, and blisters may occur. However, severe and systemic symptoms are uncommon; necrotic lesions are rare, measuring 1-2 cm, and typically resolve within weeks. Surgical debridement and reconstruction are rarely necessary"}
+{"text": "Ralstonia solanacearum. It was found that the stem endophytic fungal community was significantly altered by pathogen invasion in terms of community diversity, structure, and composition. The associations among fungal species in the rhizosphere and endosphere infected by R. solanacearum showed more complex network structures than those of healthy plants. By integrating the bacterial dataset, associations between fungi and bacteria were inferred by Inter-Domain Ecological Network (IDEN) approach. It also revealed that infected samples, including both the rhizosphere and endosphere, had more complex interdomain networks than the corresponding healthy samples. Additionally, the bacterial wilt pathogenic Ralstonia members were identified as the keystone genus within the IDENs of both root and stem endophytic compartments. Ralstonia members was negatively correlated with the fungal genera Phoma, Gibberella, and Alternaria in infected roots, as well as Phoma, Gibberella, and Diaporthe in infected stems. This suggested that those endophytic fungi may play an important role in resisting the invasion of R. solanacearum.In the plant rhizosphere and endosphere, some fungal and bacterial species regularly co-exist, however, our knowledge about their co-existence patterns is quite limited, especially during invasion by bacterial wilt pathogens. In this study, the fungal communities from soil to endophytic compartments were surveyed during an outbreak of tobacco wilt disease caused by  Ralstonia solanacearum, the causative agent of soil-borne bacterial wilt disease in plants, is often found in agricultural land used for tobacco cultivation. Once the pathogen invades the plant root system, it rapidly spreads to the stem, causing an internal system imbalance of the entire tobacco plant, accelerating senescence and death  Reveal the associations among species of fungal communities from various zones of the plant-soil microecosystem via molecular ecological network analysis; (iii) Explore the associations between fungi and bacteria through interdomain ecological network (IDEN) analysis; (iv) Study the associations between pathogenic Ralstonia members and fungi through sub-network analysis, and to explore fungal biocontrol resources that may antagonize the bacterial wilt pathogen. From the obtained results, we will provide a new strategy and theoretical support for enriching the study of tobacco endophytic fungal resources and for exploring the antagonistic fungal resources targeting R. solanacearum.The purposes of the current study are to: (i) Illuminate the characteristics of fungal communities in the bulk and rhizosphere soils and the root and stem endophytic compartments of healthy tobacco plants and those infected by R. solanacearum (grade 5\u20139 infection)  , were coTotal DNA was extracted in duplicate using the FastDNATM SPIN kit  following the manufacturer\u2019s instructions. Methods of PCR amplification and high-throughput sequencing for 16S rRNA genes followed those of 1 integrated with various bioinformatics tools  via a Random Matrix Theory (RMT)-based approach  in molec2 .The topology of ecological networks can represent the assembly process of microbial communities , and thePRJNA540089), interdomain ecological networks via SparCC approaches based on the inter-domain ecological network analysis pipeline3 workflow . As shown in P < 0.05).Using high-throughput sequencing, a total of 8, 317 operational taxonomic units (OTUs) were obtained from 80 samples, 7, 216 OTUs among the soil samples and 2, 786 OTUs among the endophytic samples. Both observed Chao1  and estiAscomycota, Basidiomycota, and Zygomycota, followed by Chytridiomycota and Glomeromycota. In the tobacco endophytic fungal communities, the most abundant fungal phyla were Ascomycota and Basidiomycota, followed by Zygomycota, Chytridiomycota, and Glomeromycota. The composition of tobacco soil and endophytic fungal communities at the genus level is shown in Mortierella, Aleuria, Cyberlindnera, Cryptococcus, Plectosphaerella, Gibberella, Mucor, Debaryomyces, Podospora, Entoloma, Paraphoma, Rhodotorula, Fusarium, Conocybe, and Guehomyces. In the tobacco endophytic fungal communities, the fungal genera with higher relative abundance included Plectosphaerella, Paraphoma, Gibberella, Rhodotorula, Alternaria, Ceratobasidium, Nectria, Davidiella, Haematonectria, Bionectria, and Thanatephorus. The genera whose abundance increased significantly in the infected soil samples as compared to healthy soil samples were Gibberella, Cryptococcus, Mucor, Nectria, Debaryomyces, and Haematonectria, and the genera that displayed significantly deceased abundance were Rhodotorula, Ceratobasidium, Cyberlindnera, Podospora, Conocybe, Monoblepharis, Paraconiothyrium, and Phoma. The genera whose abundance increased significantly in the endophytic communities of infected samples compared to those of healthy samples were Haematonectria, Gibberella, Ceratobasidium, Nectria, Bionectria, and Didymella, and the genera with significantly deceased abundance were Cryptococcus, Didymella, Mortierella, Paraphoma, Davidiealla, Phoma, and Mucor. In summary, the fungal community compositions and relative abundance were different between the healthy and infected soil communities, between the healthy and infected endophytic communities, and between the soil and endophytic communities (P < 0.05).The composition of tobacco soils and endophytic fungal communities at the phylum level is shown in M) values of all empirical networks (0.534\u20130.91) were significantly higher than the M-values of the corresponding random networks (0.339\u20130.860), indicating modular topological features of constructed networks  and among-module connectivity (Pi = 0.62). According to the simplified categorization, all nodes in the networks were distributed among four subcategories: Peripherals, Connectors, Module hubs and Network hubs. Nodes that belonged to the latter three subcategories were considered to be keystone microbial microorganisms playing a critical role in the network  and two plant bacterial pathogens (Xanthomonas campestris and Xanthomonas oryzae)  against Staphylococcus aureus was 20% larger than the standard antibiotic vancomycin (To further clarify which fungi interacted closely with the pathogenic rganisms . Accordihimurium . The pur oryzae) . The secndifolia , exhibithia coli . The endhia coli . The antncomycin . It can Ralstonia members and the infected root endophytic fungal genera Phoma, Gibberella, Alternaria, Haematonectria, Cryptococcus, Podospora, Spodiobolus, Malassezia, Aleuria, Dioszgia, and Davidiealla, as well as the infected stem endophytic fungal genera Phoma, Gibberella, Didymella, and Diaporthe, were negatively correlated, and these fungi may be potential biocontrol resources in dealing with tobacco bacterial wilt disease. At present, there are few reports on the exploration and application of tobacco endophytic fungal resources. This study will provide potential ideas and theoretical support for enriching the study of tobacco endophytic fungal resources and controlling tobacco bacterial wilt disease. Further experiment with species isolation and verification is needed to confirm these findings.The bacteria wilt pathogen https://www.ncbi.nlm.nih.gov/) under accession numbers PRJNA540089 and PRJNA735450, respectively.16S rRNA and ITS gene sequencing data of all samples were submitted to the NCBI SRA database (LT, WZ, YX, and SG performed the main experiments and analyzed data. LT, YD, and QH planned and designed the research, wrote the manuscript with substantial input from PL, SW, ZZ, and KF. All authors have read and agreed to the published version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Research on caring for older adult with health problems by Informal caregivers (IC) in the community in developing countries like India is increasing. However, IC in institutions is largely unacknowledged. This exploratory study examines the perceived role, demands, and rewards of informal caring for residents in independent LTC facilities in South India. A total of 187 residents were interviewed in Tamil and Kannada using structured and open-ended questions on demographics, health, mental health, residents\u2019 interactions, tasks performed and personal experiences. About 50% reported assisting other residents with ADLs, 30% helped with IADLs, and 75% provided emotional support. The caregivers\u2019 appraisals as residents and their relationship with care-recipient was both positive and negative. In addition to socialization, personal accomplishment, caregivers reported emotional exhaustion, stress, and burnout. Implications related to paid and unpaid labor policy in LTC and reducing IC stress are discussed."}
+{"text": "Several recent studies have shown that citric acid/citrate (CA) can confer abiotic stress tolerance to plants. Exogenous CA application leads to improved growth and yield in crop plants under various abiotic stress conditions. Improved physiological outcomes are associated with higher photosynthetic rates, reduced reactive oxygen species, and better osmoregulation. Application of CA also induces antioxidant defense systems, promotes increased chlorophyll content, and affects secondary metabolism to limit plant growth restrictions under stress. In particular, CA has a major impact on relieving heavy metal stress by promoting precipitation, chelation, and sequestration of metal ions. This review summarizes the mechanisms that mediate CA-regulated changes in plants, primarily CA\u2019s involvement in the control of physiological and molecular processes in plants under abiotic stress conditions. We also review genetic engineering strategies for CA-mediated abiotic stress tolerance. Finally, we propose a model to explain how CA\u2019s position in complex metabolic networks involving the biosynthesis of phytohormones, amino acids, signaling molecules, and other secondary metabolites could explain some of its abiotic stress-ameliorating properties. This review summarizes our current understanding of CA-mediated abiotic stress tolerance and highlights areas where additional research is needed. Abiotic stresses such as drought, flooding, high temperature, low temperature, salinity, and heavy metals (HM) inhibit plant growth and lower yield potentialities in crops . As climCitric acid, a 6-carbon tricarboxylic acid synthesized by the citrate synthase (CS)-catalyzed condensation of oxaloacetate (OAA) and acetyl-CoA, is an intermediate of the mitochondrial tricarboxylic acid (TCA) cycle . In the Polianthes tuberosa Thlaspi sreaction , and Cu reaction . The molecular nature of exogenous CA-mediated HM stress tolerance remains poorly understood. In general, a specific tolerance mechanism is adopted by plants for a given HM stress. It is possible that several mechanisms may be involved in reducing the toxicity of HMs. From the above discussion, we can hypothesize exogenous CA application in rooting media may promote HM stress tolerance by directly impairing the uptake of HMs. Moreover, increased intracellular CA accumulation in cells resulting from exogenous application likely improves HM tolerance by acting as an HM chelator, promoting sequestration of HMs into vacuoles .Secale cereale, wheat, soybean, rice, maize, pea, and barley grown under Al stress contain high levels of CA .,154.9,15In summary, CA and other CA-derived TCA cycle intermediates are intimately involved in the complex metabolic networks leading to the biosynthesis of many phytohormones, amino acids, SMs, and OAs. Many of these compounds play roles in amelioration of abiotic stresses including drought, salinity, light, temperature, air pollution, and HM toxicity . As discCitrus sinensis (blood orange) [ACLA-1 gene of Saccharum officinarum, associated with CA catabolism in the ACL pathway, enhanced drought tolerance in tobacco [B. napus, a response associated with higher total soluble sugars, Chl, and carotenoid contents [Several studies have corroborated the hypothesis that stress ameliorating effect of CA may involve its position in secondary metabolism. For example, the GABA pathway is associated with temperature stress response in  orange) ,164. Hot orange) . Alterna tobacco . Exogenocontents  and Sadacontents , each ofEnhances growth, photosynthesis, and many physio-biochemical parameters that promote crop productivity under abiotic stress conditions.Alleviates the abiotic stress-induced osmotic imbalance by increasing osmoregulators and protecting membranes from damage.Reduces the severity of oxidative stress by upregulating non-enzymatic and enzymatic antioxidants.Accelerates the HM stress tolerance of plants by chelating and sequestering HMs and improves HM phytoextraction from HM-polluted soils.Provides the substrate for a wide variety of metabolic pathways synthesizing stress protectant metabolites including phytohormones, amino acids, organic acids, and fatty acids.It can be concluded from the above discussion that exogenous CA application by foliar sprays or through rooting medium can effectively modulate various plant growth responses under diverse environmental stress conditions. In sum, exogenous CA: Still, the role of CA in abiotic stress tolerance has not yet been studied exhaustively and additional research is needed. A number of important relationships between CA and stress responses have not been examined. For example, the role of CA in cold stress tolerance has not been reported. The influence of CA on plant growth regulators, such as auxins, ABA, CK, GA, ethylene, salicylic acid, jasmonates, BRs, etc. are largely unknown. The interaction between exogenous CA and AOX has not been shown. Moreover, malate, an OA structurally similar to CA, can regulate anion channels in guard cells and involved in stomatal signaling , but theThe use of biostimulants and chemical protectants has potential to overcome abiotic stress-caused losses on crops yields . Many reCA is a weak OA that occurs naturally in plants and to particularly high levels in citrus fruits. It is generally recognized as safe by the Food and Drug Administration and has no associated health concerns. CA is inexpensive to synthesize and to apply exogenously to crops, most cost-effectively by foliar spray along with post-emergent herbicides, insecticides, or fungicides. Exogenous application of CA is a promising low-cost approach to help alleviate abiotic stresses and promote crop yield."}
+{"text": "OBJECTIVES/GOALS: We conducted interviews with investigators, clinicians, and health system and health agency leaders to assess regional educational needs in implementation and improvement science, including content (knowledge and skill), format, experiential learning, and mentoring, to identify barriers and guide planning. METHODS/STUDY POPULATION: Five CTSAs in the University of California Biomedical Research Acceleration, Integration, & Development consortium (UC BRAID) plus a fifth affiliated CTSA developed a common protocol and interviewed 31 California-based learners  and system leaders from health care and health agencies. Interviews focused on impact goals, educational needs in dissemination, implementation, and improvement (DII) science, challenges in DII research, preferred learning formats, desired proficiencies and skills, and barriers such as cost, time, awareness, terminology, and suitability and availability of training. A rapid review of literature identified potential domains of knowledge and skills for a proposed curriculum. RESULTS/ANTICIPATED RESULTS: Areas of emphasis varied among interviewees; identified learning needs differed between traditional research perspectives  and applied perspectives . Learners had a range of preferences; most interviewees desired formats that are longitudinal, experiential, applied, cooperative, and affordable. Variation in knowledge of, and interpretations of, DII terms and goals limited the ability of some interviewees to specify educational needs. A synthesis reveals areas for potential future co-development and networked approaches to regional training and capacity enhancement. DISCUSSION/SIGNIFICANCE OF IMPACT: In response to a rapidly changing health landscape, our academic health systems are developing capabilities to improve care for their populations. Our work informs the training and education needs that are critical to translation at a system-wide level. Regional convenings can raise awareness while translational programs fill educational gaps."}
+{"text": "In humans, inhibition of Notch oncogenic signaling leads to tumor regression. Preclinical studies indicate that Notch signaling contributes to the maintenance of intestinal homeostasis. Here, we sought to describe the intestinal effects of a first-in-human Notch inhibitor in an indication of refractory cancer. Between 2014 and 2017, adult patients treated for refractory cancer with the novel Notch inhibitor LY3039478 and who had grade \u2265 2 diarrhea were referred to the gastroenterology department of a tertiary hospital in the Paris region of France. Eleven patients (median (range) age: 72 (29-83)) were included in the study. All patients had advanced cancer: adenoid cystic carcinoma , sarcoma , and other types . In all cases, digestive tract endoscopy revealed abundant mucus in the intestinal lumen, and digestive tract biopsies showed an abnormally low proportion of enterocytes and marked elevation of the proportion of pseudostratified goblet cells. Microscopic inflammation was seen in colon biopsies from 2 of the 11 patients (18 %). The clinical, endoscopic and histological abnormalities were dependent on the dose of Notch inhibitor. All patients resolved their digestive signs or symptoms after discontinuing the dose and the median (range) time interval between discontinuation of the Notch inhibitor and resolution of all the gastrointestinal signs and symptoms was 7 days (4-24). Likewise, the median time interval between discontinuation and resolution of the histological abnormalities was 7 days (1-10). Blocking Notch signaling induces secretory cell metaplasia of the intestinal epithelium, which in turn leads to transient diarrhea. Our results confirm the role of Notch signaling in intestinal homeostasis in humans. The human intestinal epithelium forms villi, each of which comprises three distinct compartments. The crypt is located at the bottom of the villus, and the intermediate compartment lies between the crypt and the apex (the most differentiated part). Progenitor stem cells and Paneth cells are prominent in the crypt epithelium, whereas the apex contains most of the enterocytes and approximately 10 % of the goblet cells and neuroendocrine cells  have been described in several malignancies, including lymphoid leukemia, melanoma, glioblastoma, and cancers of the breast, ovary, lung, pancreas, colon, head and neck, cervix, and kidney  were ruled out in order to establish a causal relationship between diarrhea and exposure to the gamma secretase inhibitor. The study was approved by an independent ethics committee , and referenced in clinicaltrials.gov: NCT01695005 and conducted in accordance with the tenets of the Declaration of Helsinki and its updates.This was a retrospective, observational study of a cohort of consecutive adult patients treated with a novel Notch inhibitor  in phase I clinical trials at Gustave Roussy  and who were referred for drug-induced diarrhea to the gastroenterology department at Bic\u00eatre University Hospital  between October 2014 and October 2017. LY3039478 is a novel, potent, gamma secretase inhibitor that is in clinical development . All drugs received within the three months before initiation of the gamma secretase inhibitor and during the trial were recorded. Colonoscopies or flexible sigmoidoscopies were performed by two gastroenterologists (MC or FC). The endoscopy findings were rated on a semi-quantitative scale: 0 for normal findings, 1 for mild abnormalities, 2 for moderate abnormalities, and 3 for severe abnormalities. All gastrointestinal biopsies were centrally reviewed by a single pathologist (CM). Tissue sections were stained with hematoxylin-eosin-saffron reagent or probed in an immunohistochemical assessment for carcinoembryonic antigen (CEA) antibody and the mucin MUC2.Quantitative variables were described as the median (range), and qualitative variables were described as the number (percentage). Correlations were tested with a non-parametric Spearman test. All statistical analyses were conducted with R studio software (version 1.1.383).n=7). The participants' main clinical characteristics are summarized in Table 1Among the 130 patients treated with the novel Notch inhibitor LY3039478 at Gustave Roussy cancer centre , mucus in the lumen was either absent (n=2), slightly visible (n=2) or moderately visible (n=1). Mild inflammation (erythema and loss of the vascular pattern) was observed in the rectum of one patient. The patient having received 100 mg TIW and the 5 patients having received 75 mg TIW had abundant mucus in the lumen (grade 3 - severe), whereas patients who had received 50 mg TIW had either no visible mucus (n= 2), slightly visible mucus (n=2), or moderately visible mucus (n=1).Endoscopic biopsies of the colon revealed hypercrinia in all the patients. This was characterized by an abnormally low proportion of enterocytes and an abnormally high proportion of pseudostratified goblet cells. In patients who had received 100 mg or 75 mg TIW, all the enterocytes had been replaced by pseudostratified goblet cells .Two patients had evidence of microscopic inflammation of the colonic mucosa, including a few cryptic abscesses and mild neutrophil infiltration. One patient had an elevated intraepithelial lymphocyte count (>50 CD3All patients resolved their digestive signs or symptoms after discontinuing the dose and the median (range) time interval between discontinuation of the Notch inhibitor and resolution of all the gastrointestinal signs and symptoms was 7 days (4-24). The patient who received 100 mg TIW had diarrhea for 8 days. The 5 patients who received 75 mg TIW had diarrhea for 8 days (5-24), and patients who received 50 mg TIW had diarrhea for 5 (4-9) days. There was no correlation between the dose received and duration of diarrhea . The diarrhea in the patient with an elevated intraepithelial lymphocyte count resolved after four days. Flexible sigmoidoscopy was performed in four patients at a median of 7 (1-10) days after resolution of diarrhea; the findings were normal in all of cases. Biopsies showed a normal brush border, normal enterocytes but persistent, partial hyperplasia of the goblet cells.One patient with a locally advanced uterine leiomyosarcoma died of tumor progression. Among the six patients who had received 100 mg or 75 mg TIW, four resumed treatment with LY3039478 at a dose of 50 mg TIW. Three of the six did not have diarrhea thereafter. One of the three patients with renewed diarrhea discontinued the study. Three patients received corticosteroids with a view to treating diarrhea but there were no obvious beneficial or harmful effects.See also the Supplementary data.The present study is the first to have described the intestinal adverse events associated with Notch inhibition in humans. The clinical/pathological picture was remarkably homogeneous and was specific for this class of drugs. The main adverse event was diarrhea related to hypercrinia, with a dose-dependent decrease in the proportion of enterocytes and marked hyperplasia of goblet cells. Diarrhea and goblet cell metaplasia resolved seven days after treatment discontinuation, which is consistent with the intestinal epithelium's turnover time. In murine models, Notch inhibitors induce goblet cell hyperplasia and the accumulation of mucins in the lumen; full recovery is observed after 5 days  that prevent pathogens from accessing the epithelium. Ulcerative colitis is associated with goblet cell depletion, thinning of the mucus layer, and MUC2 glycosylation defects; these may lead to intestinal inflammation . Althoual., 2018). Notch inhibitors have shown antitumor activity in phase 1 and 2 trials in patients with relapsed or refractory hematological malignancies or solid tumors. Intestinal adverse events are frequent and appear to be a class effect with gamma secretase inhibitor and is consistent with the inhibition of Notch signaling. We showed that these intestinal adverse events are dose-dependent and recedes rapidly after treatment cessation.Gamma secretase inhibitors dose-dependently induce diarrhea, hypercrinia and secretory cell metaplasia, as characterized by an abnormally low proportion of enterocytes and marked hyperplasia of goblet cells. All these changes had reversed one week after treatment cessation. Our findings confirm the Notch pathway's role in intestinal homeostasis.Michael Collins and Jean-Marie Michot contributed equally as first author.Dr Jean-Marie Michot discloses to be principal/sub-investigator of clinical trials for: Abbvie, Aduro, Agios, Amgen, Argen-x, Astex, AstraZeneca, Aveo pharmaceuticals, Bayer, Beigene, Blueprint, BMS, Boeringer Ingelheim, Celgene, Chugai, Clovis, Daiichi Sankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Gamamabs, Genentech, Gortec, GSK, H3 biomedecine, Incyte, Innate Pharma, Janssen, Kura Oncology, Kyowa, Lilly, Loxo, Lysarc, Lytix Biopharma, Medimmune, Menarini, Merus, MSD, Nanobiotix, Nektar Therapeutics, Novartis, Octimet, Oncoethix, Oncopeptides AB, Orion, Pfizer, Pharmamar, Pierre Fabre, Roche, Sanofi, Seattle Genetics, Servier, Sierra Oncology, Taiho, Takeda, Tesaro, XencorPr Christophe Massard discloses to be principal/sub-investigator of clinical trials for: Abbvie, Aduro, Agios, Amgen, Argen-x, Astex, AstraZeneca, Aveo pharmaceuticals, Bayer, Beigene, Blueprint, BMS, Boeringer Ingelheim, Celgene, Chugai, Clovis, Daiichi Sankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Gamamabs, Genentech, Gortec, GSK, H3 biomedecine, Incyte, Innate Pharma, Janssen, Kura Oncology, Kyowa, Lilly, Loxo, Lysarc, Lytix Biopharma, Medimmune, Menarini, Merus, MSD, Nanobiotix, Nektar Therapeutics, Novartis, Octimet, Oncoethix, Oncopeptides AB, Orion, Pfizer, Pharmamar, Pierre Fabre, Roche, Sanofi, Seattle Genetics, Servier, Sierra Oncology, Taiho, Takeda, Tesaro, XencorDr Karim Benhadji discloses to be employed by Eli Lilly and Company, Indianapolis, USA.NCT01695005 study was funded by Eli Lilly and Company, Indianapolis, USA.Drugs, equipment supplied by the entity, travel paid by the entity, writing assistance, administrative support, etc.: AstraZeneca, Roche, Novartis, Gilead, Celgene, Bristol-Myers Squibb, GSK.Study concepts: MC, FC, JMM, KBStudy design: FC, MCData acquisition: CB, CM, CM, JMM, MC Quality control of data and algorithms: MC, FCData analysis and interpretation: MC, FC, JMMStatistical analysis: MC, CBManuscript preparation: JMM, MC Manuscript editing: JMM, MCManuscript review: all authors.The authors thank David Fraser PhD  for copy-editing assistance."}
+{"text": "A greater understanding of factors associated with favourable health may help increase longevity and healthy life expectancy. We examined sociodemographic, psychosocial, lifestyle, and environmental exposures associated with multiple health indicators. The UK Biobank study recruited >500,000 participants, aged 37-73, between 2006\u20132010. Health indicators examined were 81 cancer and 443 non-cancer illnesses used to classify participants by health status; long-standing illness; and self-rated health. Exposures were sociodemographic , psychosocial , lifestyle  and environmental  factors. 307,378 participants  were selected for cross-sectional analyses. Low income, being male, neighbourhood deprivation, loneliness, social isolation, short or long sleep duration, low or high BMI and smoking was associated with poor health. Walking, vigorous-intensity physical activity and more frequent alcohol intake was associated with good health. There was some evidence that airborne pollutants  and noise (Lden) were associated with poor health, though findings were not consistent across all models. Our findings highlight the multifactorial nature of health, the importance of non-medical factors, such as loneliness, healthy lifestyle behaviours and weight management, and the need to examine efforts to improve health outcomes of individuals with low income."}
+{"text": "Streptomyces spp.; archaea; fungi including endophytic, filamentous, and marine-derived fungi, mushroom; and microalgae are briefly described. Furthermore, this review briefly summarizes bacteriocins, halocins, sulfolobicin, etc., that target multiple-drug resistant pathogens and considers next-generation antibiotics. This review highlights the possibility of using microorganisms as an antimicrobial resource for biotechnological, nutraceutical, and pharmaceutical applications. However, more investigations are required to isolate, separate, purify, and characterize these bioactive compounds and transfer these primary drugs into clinically approved antibiotics.Microorganisms including actinomycetes, archaea, bacteria, fungi, yeast, and microalgae are an auspicious source of vital bioactive compounds. In this review, the existing research regarding antimicrobial molecules from microorganisms is summarized. The potential antimicrobial compounds from actinomycetes, particularly  Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are one of the greatest challenges faced by medical practices as many of them are multidrug-resistant isolates  beside three already reported polyketides, namely phaeochromycin B, C, and E, which are active against Gram-positive pathogenic MRSA. Sebak et al. Sulfolobuactivity ; H4 . M. M173]. ll death . Chlorella, is composed of a mixture of fatty acid and was isolated by Pratt et al. [Arthrospira platensis, commercially known as Spirulina had MICs of 0.20% for L. innocua and P. fluorescens, and an MIC of 0.25% for Serratia, whereas minimal bactericidal concentration (MBC) value was 0.30% for all of these species [Tetraselmis suecica exhibited an antibacterial activity resulting in decreasing cell viability (human embryonic kidney cells) (HEK293) up to 75% after 24 h of treatment. AQ-1766 was more active against Gram-positive than Gram-negative bacteria, with MBC values between 40 and 50 \u00b5M [Chaetoceros muelleri by the supercritical CO2 method have antibacterial activity against Staphyloccocus aureus and E. coli. In contrast, extraction via classic methods using hexane, dichloromethane, and methanol solvent did not result in any activity against E. coli. However, these studies were unable to elaborate the mode of action of these antibacterial compounds. Chlorellin, the first antibacterial compound from a microalga t et al. . Chlorel species . HPTLC snd 50 \u00b5M . Mendiolnd 50 \u00b5M  demonstrTetraselmis chui, Chlorella minutissima, Isochrysis sp. and Nannochloropsis sp. inhibit Vibrio\u00a0harveyi. The potent activity of microalgal compounds against microorganisms requires further development in the search for drugs and food preservatives. Therefore, the exploitation in medicine deserves to be further investigated.Axenic microalgae co-culture can produce compounds with potent activity against pathogenic bacteria. Kokou et al.  reportedOne of the significant challenges healthcare services face worldwide is the excessive use of antibiotics in medicine and food production, leading to microbiome disruption. With the outburst of antimicrobial resistance strains, there is a continuous decline in the antimicrobial drug pipeline, and it has become necessary to discover and develop new agents/metabolites to tackle antibiotic resistance. Novel compounds that target microbial resistance can be developed to regulate the huge risk posed by multi-drug resistance. However, the production cost needs to be reduced by isolating these compounds from natural sources such as microorganisms and then synthesizing them or modifying derivative compounds. Along with this, further research into their toxicity against human cells, their mode of action, in vivo effects, and their interactions with commonly available antibiotics must be conducted. After the discovery of penicillin, many drug discoveries from microbial sources were reported. In addition, the advancement of techniques such as genetic engineering during the 1970s opened the door to the ignored source, i.e., microbial metabolites . Ample research is being conducted to search for novel antimicrobial agents from biological sources, including bacteria, actinomycetes, fungi, yeast, etc. Streptomyces spp., exhibited effective antagonistic activity and played a significant role in drug discovery and development. LAB producing bacteriocins are a promising candidate for the food industry as they help to extend shelf life and safeguarde consumers\u2019 health. Actinomycetes, particularly In the ongoing rearch for novel antibiotics, archaeocins have generally been overlooked, and further studies on purifications and characterizations of archaeocins and sulfolobicins are in progress, resulting in the economical production of bioactive compounds for pharmaceutical applications. It is desirable to expand our understanding of the effectiveness and use of other naturally occurring ribosomally-synthesized peptide antimicrobials to understand their implantation and survival strategies, and to quantitatively estimate their efficacy for future applications in the pharmaceutical and health care sectors. Fungi synthesized small quantities of bioactive compounds in response to explicit environmental conditions which cannot be reproduced easily in the laboratory. Therefore, to develop new antimicrobial drugs from these fungal metabolites, commercial-scale synthesis must be accomplished potentially through strain improvement, optimizing growth conditions, and incorporating techniques, such as metabolomics, genomics, and pathway engineering. Endophytic, filamentous, and marine-derived fungi also offer a suitable substitute against toxic, ineffective, and expensive antimicrobial drugs because they act as a warehouse filled with bioactive compounds with endless potential for biological properties. Antimicrobials, isolated from mushrooms, act as essential substitutes to synthetic drugs and preservatives, whose protection and influence on the health of humans, animals, and food are still uncertain. Although there are many edible mushrooms, the mushroom species identified have antimicrobial properties which are quite small. The current review demonstrates potent bioactive substances with antimicrobial activities from edible mushrooms. Hence, they must not be considered only as a culinary delicacy, but also taken as therapeutic agents. However, methods for isolation, purification, identification, and characterization of antimicrobial compounds from mushrooms need to be developed. Chlorella sp. and Chlamydomonas sp. Many hurdles exist in developing the marine product, including resource supply issues, large-scale production, production cost, and determination of the efficacy target. These obstacles must be bypassed by optimizing mass culturing conditions, utilizing biotechnological techniques, etc. Along with these measures, extensive clinical trials will be needed to determine the in vivo fortune of antimicrobials from microbial extracts on mammalian cells. Microalgae are a promising source of high-value products, and large-scale screening programs have been conducted to discover the antimicrobial potential of microalgal extracts against pathogenic and foodborne organisms. However, major antibacterial and antifungal activity reports were predominantly from the Therefore, developing and using robust screening and high-throughput methods will be essential to study their antimicrobial activity, thereby increasing the chances of discovering and identifying new antibiotic molecules. To achieve this goal, the experimental design must include all possible variables, such as recovering both intra- and extracellular extracts produced by microorganisms under variable growth conditions, utilizing potential inducers of antimicrobial activity, and testing these compounds against a more significant number of targets. In recent years, nanoencapsulation has gained much attention. It is a technique used for formulating and stacking a compound in nanosized carriers that can carry and deliver the molecules to the targeted site. Nanoencapsulation allows the conservation and controlled release of bioactive compounds, followed by resistance to pH and temperature variations, lesser product contamination, economic viability, and stability. Chromatographic separation techniques were used recently for purifying antimicrobials, followed by their chemical characterization using spectroscopic techniques, and response surface methodology (RSM) to predict the yield of the crude antimicrobial extract. Detailed functional and structural knowledge would explain antimicrobials\u2019 mode of action and performance at cellular and molecular levels. However, for this, a better understanding of the structure, function and, existing mode of action of newly identified antimicrobials is required.In conclusion, microorganisms are probable sources of bioactive compounds, and this review has explored of microorganisms\u2019 aptitudes to deliver novel bioactive compounds with potential pharmaceutical and nutraceutical applications. Microorganisms have fascinated many researchers due to the ease of growth and understanding of their chemical interactions. The development of new biotechnological tools and techniques contributes to the discovery of next-generation antimicrobial compounds. The application of microorganisms in human foods, animal feeds, agriculture, and an increased market demand motivates the research and development of novel antibiotics and preservatives. Furthermore, the molecular docking and structural analysis approaches can design potent pathogen-specific antimicrobial agents that exhibit lesser toxicity, higher selectivity, and biodegradability. Therefore, exploiting microbial biodiversity and biotechnological potential to discover novel bioactive compounds to treat life-threatening diseases and safeguard human health."}
+{"text": "Concerning human and environmental health, safe alternatives to synthetic pesticides are urgently needed. Many of the currently used synthetic pesticides are not authorized for application in organic agriculture. In addition, the developed resistances of various pests against classical pesticides necessitate the urgent demand for efficient and safe products with novel modes of action. Botanical pesticides are assumed to be effective against various crop pests, and they are easily biodegradable and available in high quantities and at a reasonable cost. Many of them may act by diverse yet unexplored mechanisms of action. It is therefore surprising that only few plant species have been developed for commercial usage as biopesticides. This article reviews the status of botanical pesticides, especially in Europe and Mediterranean countries, deepening their active principles and mechanisms of action. Moreover, some constraints and challenges in the development of novel biopesticides are highlighted. To maximize food production for feeding the ever-increasing human population, a remarkable growth in the agrochemical market has been recorded worldwide. This increased demand has resulted in the development and wide acceptance of synthetic agrochemicals for managing crop pests and weeds. Plant protection products, such as synthetic insecticides and herbicides, have helped to maintain and increase agricultural yields for a long time. However, the use of chemical pesticides has also had numerous negative effects on human health and the environment ,2,3,4. TIn the first part of the present review, the structural basis and mechanistic principles of the currently used botanical insecticides, herbicides and fungicides in Europe and Mediterranean countries are summarized. In the second part, recent challenges and prospects in developing novel biopesticides are discussed.Botanical pesticides  are characterized by bioactive mixtures/extracts/compounds from plant materials, which serve as insecticides and repellents but also as bactericides, fungicides, herbicides and nematicides . In retrThe industrial development and production of new botanical pesticides are challenging and, e.g., require (i) availability of pesticidal plant resources in a sustainable and large-scale manner, (ii) standardization in the processing of phytochemical substrates and performance of quality assurance protocols, and (iii) authorization approval, which implies extended record data on the environmental fate of the bioactive substrates and possible toxic effects on non-target organisms. Moreover, the combined use of biopesticides and biofertilizers can improve soil health status and prevent environmental pollution, thereby promoting sustainable agriculture . Yadav eThe active principles of botanical pesticides, especially the unique structural motifs of secondary metabolites, e.g., alkaloids, essential oils including terpenes, flavonoids, phenolics, phytosterols and polyketides as well as resins, are qualified to confer antibacterial, antifungal, herbicidal and insecticidal action ,18 Figu. EssentiAnabasis aphylla), nicotine (from Nicotiana species), ryanodine  and veratridine  [Alkaloids, with more than 12,000 structures, form an exceptionally broad group with highly diverse chemical structures. Therefore, a structural definition of alkaloids is difficult, but criteria are (i) the low or medium molecular mass and the presence of one or more heterocyclic nitrogen-containing rings derived from amino acids in their molecule and (ii) the ability to provide an alkaline reaction in aqueous solution . Alkaloiicinale)   are derived from more than 17,500 known aromatic plants, mainly belonging to angiosperms, e.g., Asteraceae, Lamiaceae, Myrtaceae, Rutaceae and Zingiberaceae . They cavulgaris ,35,36. Evulgaris .Azadirachta indica (Meliaceae) produces a great variety of phytochemicals, including alkaloids, fatty acids, polyphenols, saponins, terpenes and terpenoids [A. indica, especially from the seeds, with reported concentrations of 4\u20136 mg/g seed [The neem tree rpenoids ,39. Its g/g seed .Tanacetum cinerariifolium), also called pyrethrum daisy, produces a potent insecticide, commonly named pyrethrin. Commercially, pyrethrin represents the most exploited bioinsecticide with a long history of successful applications against various insect pests [Tanacetum, especially in the flower heads (10\u201330 mg/g dry weight) [Dalmatian pyrethrum  .Leptospermum scoparium (manuka). \u03b2-Triketones can act as herbicides by inhibition of 4-hydroxyphenylpyruvate dioxygenase (HPPD), an enzyme that is relevant in the plant metabolism of tyrosine and the production of its downstream products.Polyketides, e.g., \u03b2-triketones , represePelargonium roseum showed post-emergent herbicidal effects towards different broadleaf and grassy weeds, for example, in Abutilon theophrast, Avena fatua, Brassica napus, Chenopodium spp. and Portulaca oleracea [Lipids and fatty acids typically serve as solvents that, in conjunction with emulgators, stabilize the active principles (such as azadirachtin or pyrethrins) in commercial biopesticides. However recently, conjugated unsaturated fatty acids, such as rumenic acid, which can be described as a conjugated linoleic acid (CLA) , have beoleracea ,47,48,49It is well established that botanical insecticides can repel the attacking insects, inhibit their food ingestion, reduce their growth at various developmental stages, inhibit egg-laying activities, or even directly kill the insects by irreversible inhibition of one or more essential reactions in their metabolism. There is a wealth of literature documenting the insecticidal properties of plants extracts and isolates therefrom ,50,51,52Azadirachta indica), pyrethrins (from Chrysanthemum or Tanacetum) and various plant EOs to arthropod pests, has expanded greatly over the last 20 years [Along with these studies, especially relevant for Mediterranean countries, our knowledge about the molecular mechanisms and bioactivities of plant derivatives, such as neem  or membrane sodium channels  of the insects. It is well known that alkaloids also can exert a feeding deterrent action against numerous insects, such as Choristoneura fumiferana [Spodoptera littoralis [Tribolium castaneum, but their modes of action are not fully understood [Ryania speciosa, exerts a strong insecticidal activity, acting at the sarcoplasmic reticulum, with ryanodine receptors influencing the secretion of Ca2+ [+ channels in a similar manner to pyrethrins, causing neurotoxic effects on insect pests [miferana  and Spodttoralis . Other aderstood . Ryanodi of Ca2+ . Moreovect pests .Essential oils: Their mode of action virtually depends on the main constituents present in the respective plant oil as well as the targeted insect pest. Generally, it ranges from repellent and antifeedant effects to neurotoxic effects [ effects ,63 but a effects ,67,68,76 effects . HoweverPhenolics and O-heterocyclic compounds: Plant phenolics and related compounds such as coumarines or anthraquinones are considered as an important defensive line against insects [ insects ,77,78,79 insects . At the  insects .Limonoids: The impacts of limonoids  include antifeedant and/or physiological effects [ effects . Azadira effects . The mai effects ,40,63. A effects ,84. In c effects . Pyrethrins: Pyrethrins exhibit a neurotoxic mode of action by interfering with the ion channels of the insects, which are kept open and thus cause nerve impulses to fail [+, K+ exchange pump in nerve cells of target pests, leading to rapid nerve impulses and causing paralysis [ to fail . In partaralysis . This rearalysis ,87. Manyaralysis .Achillea millefolium, Artemisia absinthium, Santolina chamaecyparissus, Tanacetum patula and T. vulgare, exhibited anti-settling activity when used against Myzus persicae females (green peach aphids) [Rhopalosiphum padi [Repellents are substances that act from a distance and repel the insects from the treated plants or stored crops ,88. Due  aphids) , and EOshum padi .Nevertheless, there are drawbacks in relation to the use of EO repellents, especially due to their volatility, low water solubility and oxidizability. However, the use of these compounds in nanoparticles could solve, to some extent, such limitations by reducing their degradation rate and increasing their residuality through evaporation prevention . Panax ginseng, possess potent antifeedant activities against Pieris rapae. Singh and Kaur [Trichoplusia ni.Antifeedants are defined as compounds that \u201creduce consumption by an insect\u201d or as \u201ca peripherally mediated behaviour modifying substance  resulting in feeding deterrence\u201d . There iand Kaur  revealedand Kaur  reportedCalceolaria integrifolia were attributed to inhibition of phenol oxidase, proteinase or tyrosinase, to cuticle synthesis inhibition and to moulting sclerotization toxicity [Different molecular mechanisms may be involved in these antifeedant effects. It has been assumed that phenolic compounds inhibit important enzymes, such as proteases and other digestive hydrolases, and polyphenol oxidases (PPOs) , therebytoxicity . Some metoxicity . It was The toxic effects of plant bioactive compounds are quite complex and rely on the chemical composition, the kind of insect pest, and the developmental stage of the insect . In partAChE is a crucial enzyme in terminating the nerve impulse through the hydrolysis of neurotransmitters. Approximately 70% of the world market for insecticides is based on synthetic AChE inhibitors , including those insecticides acting on the voltage-gated sodium channels  . In receSeveral EOs from aromatic plants, mostly monoterpenes, were shown to act as efficient AChE inhibitors in various insects . More spPeriplaneta americana via interaction with nAChRs [The toxicity of alkaloids is also based on their anti-cholinesterase activity in the central nervous system, on disrupting cell membranes by interacting with the 3\u03b2-hydroxysterols of the membranes, and on modulating the active transport of ions through membranes, finally leading to metabolic dysfunction . As an eh nAChRs .In this context, synergistic effects (\u201centourage effects\u201d) could occur when dealing with complex mixtures of bioactive constituents, for example, EOs or plant extracts containing alkaloids plus terpenes or fatty acids. These mixtures are qualified to multiply the desired insecticidal activities. This effect should also not be underestimated in preventing resistance against pathogens and pests. Taking advantage from the entourage effect is probably one of the most important benefits of future biopesticides based on botanical compound mixtures ,108,109.Plant secondary metabolites can confer properties similar to synthetic growth regulators, such as teflubenzuron ,111. ActCalceolaria talcana and Condalia microphylla were found as efficient IGRs, with similar activity to phytoecdysteroids, as indicated by their strong inhibition of the moulting process [Zanthoxylum chalybeum are due to impacts on the ecdysteroid pathway, finally inducing larval retardation.As examples, extracts from  process ,115. The process . Muema e process  suggesteQuiroz-Carre\u00f1o et al.  reportedDamalinia limbata was detected in neem-exposed female lice. Abdellaoui et al. [Many previous studies reported that some EOs and plant extracts from various species have strong effects on the reproduction of insects by reducing adults\u2019 weight, the longevity of females, fecundity and fertility, and egg hatchability, or by increasing neonate larval mortality ,121. IGRi et al.  reportedThese examples underline that reproduction and hormonal regulation in insects are key targets for the development of novel insecticides . AcquireMany of the effects described above are also associated with a reprogramming of the core carbon and nitrogen metabolism of the insects. For example, toxic effects due to inhibition of hydrolytic enzymes or effects upon hormonal signalling cascades finally end in changes of substrate usages and/or the rerouting of metabolic fluxes. It appears that metabolic targets are under-represented in the classes of insecticides and, therefore, have high potential for the discovery of novel bioinsecticides based on new modes of action.Helicoverpa armigera larvae [H. armigera is unable to metabolize azadirachtin; thus, the insect could not neutralize the toxic effects of azadirachtin. Another study reported a significant reduction of the quantity and relative composition of fatty acids as well as the downregulation of carbohydrate metabolism in Bactrocera dorsalis, due to azadirachtin treatment [In support of this hypothesis, a recent study using metabolomics investigated the effect(s) of azadirachtin on a larvae . It was a larvae . This sereatment .Syzygium, family Myrtaceae, contains various species, such as Syzygium aromaticum, syn. Eugenia caryophyllus [Syzygium sp.  are \u03b2-caryophyllene, eugenol, and eugenol acetate [Avena fatua [Abutilon theophrasti, Amaranthus spp., broccoli (Brassica oleracea), Chenopodium album [Portulaca oleracea, and Urtica urens [Chenopodium album, Melilotus indicus, Raphanus raphanistrum, Sisymbrium irio [Amaranthus retroflexus, and Brassica oleracea [Several extracts from plants have been described to exhibit herbicidal activities . The genophyllus ,128,129. acetate ,131. Forna fatua , Abutiloum album ,134, Poroleracea . Both cloleracea . SeveralCymbopogon, family Poaceae, contains more than 140 species of tropical and subtropical plants cultivated in Asia, South America, Australia and Africa [Cymbopogon citratus, C. nardus and C. winterianus, exhibit phytotoxic effects. The phytotoxic effect of Cymbopogon-derived herbicides is attributed to the presence of citronellal, geraniol and citronellol and are well documented against germination of wheat seeds, Ageratum conyzoides, Amaranthus tricolor, Cassia occidentalis, Cenchrus echinatus, Chenopodium album, Digitaria horizontalis, Malvastrum coromandelianum, Parthenium hysterophorus, and little seed canary grass [Amaranthus thaliana and Senecio jacobaea leaves [The genus d Africa . Severalry grass , as wella leaves .Cinnamomum, family Lauraceae, is an important fragrant spice plant containing more than 250 evergreen trees [Cinnamomum verum, C. zeylanicum and Cinnamon cassiacae [Ageratum conyziodes, Amarantus retroflexus, Ambrosia artemisiifolia, Bidens pilosa, Cassia occidentalis, Chenopodium album, Commelina benghalensis, Echinochloa crus-galli, Leptochloa chinensis, Lolium spp., Phalaris minor, Sinapis arvensis, Sorghum halepense, and Taraxacum officinale [Amaranthus tricolor and Echinochloa crus-galli [The genus en trees ,139. Theen trees . Speciesassiacae ,140. Theassiacae ,138,141.ficinale ,143,144.us-galli ,145.Eucalyptus, family Myrtaceae, is a plant originating from Australia, which is currently cultivated in subtropical areas and in the Mediterranean region and includes more than 800 species [Eucalyptus camaldulensis, E. citriodora and E. globulus, were reported to exhibit herbicidal effects [Cassia occidentalis, Lolium rigidum, Portulaca oleracea, Vicia sativa [Celtis occidentalis and Echinochloa crus-galli [Lactuca sativa, Pisum sativum, Triticum durum, Zea mays [Acroptilon repens and Portulaca oleracea [The genus  species . Various effects ,147,148.a sativa ,150, CelZea mays , Acroptioleracea .Leptospermum is a member of the Myrtaceae family that originated from Australia and New Zealand [L. lanigerum, L. liversidgei, L. nitens, L. polygalifolium, L. scoparium, L. speciosum and L. whitei [Leptospermum scoparium (manuka) is caused by high concentrations of herbicidal \u03b2-triketones, especially leptospermone , Portulaca oleraceae, Zea mays (maize), and Solanum lycopersicum [Ocimum spp. are more effective on post-emerged seeds and young weeds than on pre-emerged seeds [The genus ean area . This fa sanctum ,164. The sanctum ,167,168.persicum ,169,170.ed seeds , suggestOriganum, family Lamiaceae, originated in the Mediterranean basin, particularly from Spain and France. Origanum onites, O. vulgare subsp. hirtum, O. vulgare subsp. vulgare and O. vulgare subsp. virens are the most common species of this family [Origanum vulgare essential oil has a high content of carvacrol, \u03b3-terpinene and thymol [Origanum vulgare essential oil, has antigerminative functions against Alcea pallida, Amaranthus retroflexus, Capsicum annuum, Centaurea solstitalis, Chenopodium album, Echinochloa crus-galli, Lactuca sativa, Lolium perenne, Portulaca oleracea, Raphanus raphanistrum, Rumex crispus, R. nepalensis, and Sinapis arvensis [Origanum onites and O. vulgare caused inhibition of germination of Avena sterilis, Cucumis sativus, Sinapis arvensis, Solanum lycopersicum, and a number of wheat cultivars [Origanum vulgare, as of now, no commercial bioherbicides based on Oregano essential oil or carvacrol are available.The genus s family ,172. Orid thymol ,173,174.arvensis ,177,178.ultivars ,179,180.Pelargonium, family Geraniaceae, has origins from India, Pakistan, and South Africa [Pelargonium graveolens, P. reniforme, and P. sidoides [P. graveolens has a high content of essential oil [Abutilon theophrast, Avena fatua, Brassica napus, Chenopodium spp., Portulaca oleracea, and many more [Pelargonium essential oil is available.The genus h Africa ,182,183.tial oil ,185, wittial oil ,187. Theany more ,47,48,49any more . Taking Thymus belongs to the Lamiaceae family and originates from Central and South Europe [Thymus callieri, T. serpyllum, and T. vulgaris [Amaranthus retroflexus, Avena fatua, Echinochloa crus-galli, Erigeron bonariensis, and Portulaca oleracea [Thymus species also show pre-emergent allelopathic performance. Thymus fontanesii inhibited seed germination of Avena fatua, Cyperus rotundus, Sinapis arvensis, Sonchus oleraceus, and Xanthium strumarium [Thymus proximus suppressed the seed germination of Amaranthus retroflexus and Poa anuua [Thymus algeriensis inhibited Medicago sativa and Triticum astivum seedling growth [Thymus species also showed phytotoxic effects to further herbs [Echinochloa crus-galli [Portulaca oleracea [The genus h Europe . Examplevulgaris ,189,190.vulgaris ,174,190,oleracea ,191. Thyrumarium . Thymus oa anuua . Thymus g growth . Many oter herbs , indicatus-galli , suggestoleracea .Lavandula, part of the Lamiaceae family, originates from the Mediterranean region but is also currently cultivated in other countries [Lavandula angustifolia, L. latifolia, and L. spica [L. angustifolia, for example, being an important Lavandula species, has a high content of linalool and linalyl acetate [Cassia occidentalis [Lavandula species showed allelopathic action in several plants. Lavandula spp. exhibited phytotoxicity against seeds of Amarantus retroflexus, Lolium spp., and Sinapis arvensis [Lavandula stoechas and L. angustifolia reduced seed germination of A. retroflexus and P. oleracea [Lavandula x intermedia Emeric ex Loisel. cv. Super A influenced the germination and seedling emergence of A. retroflexus, Rumex crispus, and Sinapis arvensis [Cicer arietinum, Helianthus annuus cv. Sirena, Solanum lycopersicum, and Triticum aestivum cv. G\u00fcn-91 were not sensitive to lavender essential oil [Lavandula species could work as a selective bioherbicide in tomato fields and other cash crops [The genus ountries ,195. TheL. spica , showing acetate ,197. Fur acetate . Linaloodentalis . Certainarvensis . Lavanduoleracea . Lavanduarvensis . Remarkatial oil ,199, indsh crops . To reviEugenol: The phenylpropanoid eugenol is known to elicit the generation of active oxygen species in plants, which leads to cell membrane damage and inhibition of photosynthesis. The enhanced activity of ROS-scavenging enzymes inhibits further metabolic pathways [pathways ,143,144.Cinnamic aldehyde: In contrast to eugenol, cinnamic aldehyde does not peroxidate lipids of the cell membrane but interacts with the integrated receptors on the surface, leading to manipulation of ligand-based metabolic pathways [pathways ,200.Monoterpenes: The monoterpenes citronellal, citronellol and gerniol regulate the phospholipid synthesis in the cytoplasmic membrane during oxidative stress, altering membrane permeability and causing electrolyte losses [Ageratum conyzoide, Amaranthus virdis and Cassia occidentalis [Cymbopogon essential oil [e losses . Citronee losses ,183. Citdentalis ,202,203.tial oil ,137. Negtial oil ,146,204.tial oil , which ltial oil . It was tial oil . TherefoThe monoterpenes carvacrol, \u03b3-terpinene, and thymol are known to disrupt the cell membrane and to influence several metabolic pathways, photosynthesis, cell respiration and mitosis ,206. HowLinalool is a highly potent monoterpene, affecting several metabolic pathways. Similar to other monoterpenes, linalool reduces photosynthesis, respiratory activity and alteration of water status . FurtherPelargonic acid: Pelargonic acid has a strong allelopathy effect [y effect ,208 withy effect ,137.\u03b2-Triketones: Herbicidal \u03b2-triketones, such as leptospermone from L. scoparium, regulate carotenoid synthesis by inhibiting para-hydroxyphenylpyruvate dioxygenase (HPPD), an essential enzyme cofactor for plant defence systems [ systems . Accordi systems , which s systems . Leptosp systems ,161. Fur systems . Leptosp systems .Botanical fungicides have recently gained ground since they have less or no negative impact compared to synthetic antifungal agents, including residual effects and induced resistance. In this regard, they may be effective, selective, biodegradable or less toxic to the ecosystem . HoweverNevertheless, today\u2019s farmers are increasingly aware of the hazards of synthetic fungicides and are looking for botanical alternatives. Thus, the demand for botanical fungicides is rapidly increasing, and there is ongoing research on the exploration of potential plants having fungicidal activities, the development of effective extraction methods, and the elucidation of the mode of action on target fungi. Phenolics: Research on botanical pesticides has shown that extracts from various plants exerted activity against various phytopathogenic fungi without imposing negative effects. According to Lattanzio et al. [o et al. , the anto et al. . In partTerpenes: To date, several terpenes have proven to be active against a wide variety of fungal species [Aspergillus and Fusarium species, respectively, resulting in reduced pathogenicity of mycotoxin-producing fungi [ species . Mendoza species  revealedng fungi .Alkaloids: Zhou et al. [Veratrum taliense that the verazine and jerveratrum-type alkaloids exhibit strong suppressive properties against the phytopathogenic oomycete Phytophthora capisis. This antioomycete activity is due to the fact that these alkaloids intercalate into the cell wall and/or DNA [u et al.  have shod/or DNA .Directive 67/548/EEC on products that might affect human health and Directive 78/631/EEC on plant protection products were the main legislative documents providing rules on the use of pesticides. In the EU, the authorization of plant protection agents initially relied on Directives 91/414/EEC and 98/8/EC, concerning the placing of plant protection and biocidal products on the market, respectively, as amended in Regulation (EU) No. 528/2012 on the authorization of biocides. Directive 91/414/EEC was further amended by Directives 2001/36/EC and 2005/25/EC to include regulatory issues regarding microbial biological control agents. Moreover, minimum requirements for biological control agents used in organic farming are stated in Regulation (EU) No. 889/2008. Both agrochemicals and biopesticides are enclosed under the term \u201cplant protection products\u201d.https://ec.europa.eu/environment/archives/ppps/pdf/pesticides_en.pdf accessed on 14 December 2021).Meanwhile, the Common Agricultural Policy (CAP), which regulates the use of pesticides and give guidelines for more sustainable practices in the agricultural sector, the Water Framework Directive (WFD), Regulation (EU) No. 396/2005 on upper residue limits of pesticidal products in food and feed, the Waste Framework Directive, the Directive on hazardous waste and the Directives on health and the safety of workers and on the preservation of the biodiversity also affected the use of pesticides. Moreover, the Directives for wild birds and habitats and on the preservation of the biodiversity proliferate the use of biopesticides. Directive 1999/45/EC, on the classification and labelling identity of harmful chemical preparations, should also be taken into consideration. In addition, specific strategies were taken place in the Sixth Environmental Action Programme of the European Council and Parliament to promote the sustainable use of pesticides through a thorough analysis of the subject, focusing on identifying pressures on the environment and on the selection of appropriate technological and law-based tools to face ecological concerns, including legislative proposals, communication actions and impact assessment reports  No. 546/2011, Regulation (EU) No. 2017/1432, amending Regulation (EU) No. 1107/2009 concerning market placement of plant protection agents, Regulation (EU) No. 396/2005 \u201con maximum residue levels of pesticides\u201d and Regulation (EU) No. 284/2013 on the data requirements for phytoprotective products are the main drivers in the authorization and use of plant protection products ,220. Howfile:///C:/Users/Asus/Downloads/NA0219035ENN.en.pdf accessed on 14 December 2021). A response of the Commission Green Deal commitment towards sustainable practices is the \u201cFarm to Fork\u201d and the \u201cBiodiversity\u201d strategies, promoting a reduced use of agrochemicals, a fact that can promote biopesticide market growth. According to the evaluation report of Regulations (EU) No. 1107/2009 and No. 396/2005, \u201cThe aim of EU legislation on pesticides is therefore not to eliminate pesticides but rather to minimize their impact on human health and the environment through reduced dependency on pesticides, alternative methods and through increased use of low risk and non-chemical pesticides\u201d [The EU Reflection Paper \u201cTowards a Sustainable Europe by 2030\u201d and the United Nations 2030 Agenda and its Sustainable Development goals set as a priority the sustainable use of pesticides , being a good paradigm to follow by the other countries [Regulation stringency in using chemical pesticides, environmental and safety considerations, and new technological achievements are among the factors boosting biopesticide consumption and global market share. Besides, many countries in North Europe and North America have possessed the political willingness in recent years to reduce conventional pesticides by strengthening biopesticide consumption through restrictions in the use of synthetic pesticides and investments in biological agents . Conversountries . The facA concern has arisen regarding the low number of SMEs registering plant protection products in Europe due to high requirements for authorization, with the stakeholders to emphasize the disproportionation in authorization occurring for low-risk substrates, such as biopesticides. Several researchers argue that European legislation on pesticides was initially designed for chemical substrates and not for the approval of biopesticides since the latter have distinct properties compared to synthetic pesticides . MoreoveEnforcement of policies promoting natural biological products through legislative acts can play a pivotal role in boosting the biopesticides market. For instance, a ban on the use of chemical pesticides within the limits of cities in some municipalities led the federal government of Canada to include such measures in the Pest Control Products Act, as the consequence of the public\u2019s awareness to abate pesticide application , creatinThe adoption of biopesticides as reduced-risk products and the harmonization with registration practices promoting biopesticide use as those followed by US EPA and proposed by OECD can increase the relatively low number of commercially available biological products, which is among the main drawbacks for the expansion of this safer pest management approach . ImmaturConversely, the wide biodiversity of pesticidal plant species in Africa, which are commonly used by low-income farmers to manage pests, suggests the existence of a new market segment that caters to both resource-poor farmers and organic producers in developed countries . As an eIsman and Grieneisen  reportedBiopesticides and related products should be evaluated in a more biological and ecological context.A simplification of authorization should be enacted to enhance the further penetration of biopesticides into plant protection markets, shifting agriculture to more sustainable integrated pest management systems.There is a need for unification of legislation for low-risk biologically based plant protection products, separating their evaluation from conventional chemical pesticides, with a focus on food safety, human health and protection of the environment.Financial and in-depth scientific support through research programmes should be provided to facilitate SMEs to develop more biological control products and key pesticides producers to switch to more sustainable products.Support of networking approaches and effective links within farmers, SMEs and the industry will further stimulate the biopesticides market.Based on the current status of EU legislation on biopesticides, the following conclusions can be drawn:"}
+{"text": "Discrimination is linked to poor health outcomes, but most studies examine young or midlife populations. We assessed associations between discrimination and disability in African Americans. The Detroit Areas Study Everyday Discrimination Scale quantified experiences of interpersonal mistreatment. Separate Cox-proportional hazards models tested the associations between baseline discrimination and incident mobility, activities of daily living (ADLs), and instrumental activities of daily living (IADLs) disability, adjusting for age, sex, education, BMI, smoking, depressive symptoms, and vascular diseases. At baseline, 441, 674, and 469, participants were initially free of mobility, ADL, and IADL disability, respectively, and 257, 185, and 269 new cases of mobility, ADL, and IADL disability were observed over approximately 8.5 years. Discrimination was associated with higher risk of ADL disability  but no other disability type. Everyday discrimination is associated with risk of ADL disability."}
+{"text": "The COVID-19 pandemic may fundamentally change neighborhood environments and ways of aging in place. This research aimed to investigate perceptions of and engagement in neighborhoods since the pandemic onset among online survey respondents of the COVID-19 Coping Study. We analyzed a random stratified sample of 500 open-ended responses collected July-September 2020 with quotas for age, gender, race/ethnicity, and education to match the US population aged 55+. Qualitative thematic analysis identified both increased and decreased local activity and varying levels of social interaction, support, and civic engagement. Community characteristics including age structure, socioeconomic diversity, density, housing patterns, weather, and social infrastructure were related to neighborhood perceptions. These interacted with personal characteristics such as duration of residence, living arrangements, family closeness, health status, and preferred lifestyle. Results highlight coping strategies among aging adults and their neighbors, sources of individual and community vulnerability, and opportunities to strengthen social infrastructure and resiliency within neighborhoods."}
+{"text": "Recent research on the gut microbiome has revealed the influence of gut microbiota (GM) on ischemic stroke pathogenesis and treatment outcomes. Alterations in the diversity, abundance, and functions of the gut microbiome, termed gut dysbiosis, results in dysregulated gut\u2013brain signaling, which induces intestinal barrier changes, endotoxemia, systemic inflammation, and infection, affecting post-stroke outcomes. Gut\u2013brain interactions are bidirectional, and the signals from the gut to the brain are mediated by microbially derived metabolites, such as trimethylamine N-oxide (TMAO) and short-chain fatty acids (SCFAs); bacterial components, such as lipopolysaccharide (LPS); immune cells, such as T helper cells; and bacterial translocation via hormonal, immune, and neural pathways. Ischemic stroke affects gut microbial composition via neural and hypothalamic\u2013pituitary\u2013adrenal (HPA) pathways, which can contribute to post-stroke outcomes. Experimental and clinical studies have demonstrated that the restoration of the gut microbiome usually improves stroke treatment outcomes by regulating metabolic, immune, and inflammatory responses via the gut\u2013brain axis (GBA). Therefore, restoring healthy microbial ecology in the gut may be a key therapeutic target for the effective management and treatment of ischemic stroke. Stroke is the second and third leading causative factor for death and disability, respectively , and impAlthough intravenous thrombolysis, endovascular thrombectomy, and stroke therapeutic agents can improve physical, motor-behavioural, and mental deficits in some patients, the prognosis for most post-stroke patients is very poor ,7. SeverRecent studies have demonstrated the existence of bidirectional communications between the gut and brain through gut microbiota. The intimate bidirectional interactions between the gut and brain occur through the neural , hormonal (endocrine system), and immunological (innate and acquired immune system) routes ,14, whicInterestingly, several studies have demonstrated the direct influence of gut dysbiosis on the development of clinical risk factors for stroke  and trimethyl amine-N-oxide (TMAO), into the bloodstream. These changes accelerate systemic inflammation and the worsening of symptoms, often contributing to poor prognosis . NotablyBifidobacteria genera), Spirochaetes, Proteobacteria, Cyanobacteria, Leptosphaeria, Fusobacteria, and Verrucomicrobia phyla are found to be at relatively lower abundance [The human gastrointestinal (GI) tract constitutes trillions of microorganisms, such as viruses, bacteria, fungi, and protozoa ,32. Micrbundance ,40. In abundance ,42,43. Tbundance . Gut dysbundance ,46,47, ubundance . Increasbundance ,49.Gut microbes produce essential bioactive metabolites that play a crucial role in the maintenance of homeostasis, immune maturation, mucosal integrity, and host energy metabolism ,50. ShorThe gut\u2013brain axis (GBA) refers to the bidirectional link between the GI tract and the central nervous system (CNS) ,79. ReceIn the top-down pathway, the brain influences the gut wall via both direct and indirect pathways. (i) Direct pathways include (a) the extrinsic parasympathetic and sympathetic branches of the autonomic nervous system and (b) the endocrine system  ,92,93. FBottom-up signals are carried by afferent vagal branches to the brain . PrimariAltogether, these bidirectional interactions highlight the crucial role of GBA in regulating host health and its involvement in association with the plethora of diseases, ranging from cardiovascular complications to neurologic illnesses  and neurThe prominent role of gut dysbiosis in stroke can be explained by answering three important questions.(a)How does stroke alter the GM?Megasphaera, Enterobacter, and Desulfovibrio), and decreased abundance of beneficial SCFA-producing bacteria . A clinical study investigating the microbiome of patients after cerebral stroke showed a reduced abundance of Roseburia, Bacteroides, and Faecalibacterium prausnitzii and an increased abundance of Enterobacteriaceae, Bifidobacteriaceae, and Clostridium difficile in intestinal samples when compared to healthy subjects, intensive care patients, and patients with active ulcerative colitis or irritable bowel syndrome [In stroke-induced gut dysbiosis, the ischemic brain dysregulates GBA signaling either via the neural or HPA axis pathways. Metabolic endotoxemia occurs to elevated levels of plasma LPS, which contributes to increased intestinal permeability . Metabolsyndrome . Symptomsyndrome ,114,115.(b)How doe GM influence the stroke outcome/prognosis?Approximately 50% of stroke patients report GI symptoms, supporting the presence of gut dysbiosis . Ischemi(c)How does GM contribute to stroke pathology or pathogenesis of risk factors for stroke development?Reports from rodent and human clinical studies indicate that gut dysbiosis influences several pathways implicated in the development of risk factors associated with cerebral stroke, such as hypertension and metabolic diseases like obesity, T2DM, atherosclerosis, and vascular dysfunctions ,21,22. FAltogether, these results explain the pathogenic role of gut dysbiosis in the onset, progression, and outcomes of stroke; therefore, potential therapeutic approaches targeting gut dysbiosis can be considered in the treatment and management of stroke. (a)Macrophages and monocytes;(b)+ T helper (Th) cell subsets , CD8+ T cells, Treg cells, and natural killer T-cells;T lymphocytes, such as CD4(c)B lymphocytes;(d)Microglia;(e)Astrocytes;(f)Dendritic cells;(g)Neutrophils;(h)Mast cells.The key inflammatory and immune cells involved in stroke and gut dysbiosis are: The pathophysiology of stroke-induced gut dysbiosis includes a series of inflammatory responses induced by the activation of gut immune cells, increased gut permeability with elevated endotoxin levels, and their trafficking pathways to the brain. After stroke, the innate immune response is produced by innate immune cells, such as neutrophils, macrophages, microglia, mast cells, lymphocytes (\u03b3\u03b4 T-cells), and natural killer T-cells, followed by the activation of the adaptive immune response, which is mainly mediated by T and B lymphocytes . The patDuring stroke-induced gut dysbiosis, reinforcement of chronic inflammation by the excessive recruitment or infiltration of peripheral immune cells , gut-derived toxic metabolites, and bacterial translocation suppresses the polarization of anti-inflammatory Treg cells . NotablyThese toxic changes in the GI tract can lead to the excessive translocation of pathogenic bacteria, bacterial toxins, and toxic metabolites, all of which in turn leak more gut inflammatory and immune cells into circulation and then to the stroke-injured sites. Furthermore, breakdown of the intestinal epithelial barrier and BBB, a decrease in enteric nerves, loss of goblet cells, and thinning of the mucus barrier bolster chronic systemic inflammation . Thus, gGut dysbiosis influences stroke pathology or prognosis mainly by affecting the key immunological signaling pathways. The three most important pathways that have serious implications in gut-dysbiosis-associated neurological diseases are:(i) Inflammasome signaling pathway\u2014This pathway comprises an innate immune signaling complex that responds to a variety of microbial and endogenous pathogenic signals. Inflammasome activation by SCFAs leads to IL-18 secretion, thus contributing to gut homeostasis, and was able to prevent intestinal injury in a colitis model . Inflamm(ii) Type I interferon (IFN-1) signaling pathway\u2014IFN-1 is a pleiotropic and universal cytokine, playing a significant role in both innate and adaptive immunity, and thus contributes to host homeostasis. Host IFN-I can affect the composition of GM, suggesting a bidirectional link between GM and IFN-I signaling in stroke . Thus, f(iii) Nuclear factor (NF)-\u03baB signaling pathway\u2014The NF-\u03baB pathway is a central hub for inflammatory processes in the host. The NF-\u03baB family comprises several key transcription factors that regulate innate and adaptive immune responses. The NF-\u03baB pathway determines the expression of proinflammatory and proapoptotic genes and thus maintains immune homeostasis . SpecifiIn both humans and rodent models of ischemic stroke, NF-\u03baB signaling was shown to play a major role in tissue viability and recovery from ischemic insult . In a raSeveral experimental studies in stroke-related animal models have demonstrated a direct association between dysregulated GBA signaling and gut motility, dysbiosis, intestinal permeability, inflammation, and altered immune response ,100,141.Peptococcaceae and Prevotellaceae), along with increased abundance of proinflammatory microbiota  and reduced abundance of anti-inflammatory microbiota (Firmicutes and Actinobacteria phyla). Gut dysbiosis is usually associated with changes in T-cell homeostasis and induction of a proinflammatory response by migrating T cells, T helper cells, and monocytes from Peyer patches to the peri-infarct brain region, which negatively affects post-stroke outcomes. Moreover, the presence of gut dysbiosis predisposed to the induction of larger infarct lesions and impaired recovery in an ischemic mouse model [Reports of microbial pathogenic changes occurring in stroke animal models include a decrease in species diversity  and germ-free (GF) mice devoid of complex microbiota, developed by growing under GF conditions or treatment with antibiotics, are considered powerful models for studying the ecosystem and influence of the human intestinal flora ,147,148.db/db) mice exhibited increased intestinal permeability and higher plasma LPS levels, along with elevated abundance of Bacteroidetes phyla and Enterobacteriaceae family members . There were also lower levels of Firmicutes, Actinobacteria, and Tenericutes in the diabetic mice compared to the non-diabetic mice [Induction of stroke in GF mice is associated with larger infarct areas compared with recolonized or specific pathogen-free mice, indicating that the composition of the gut bacteria plays an important role in modulating post-stroke outcome . For instic mice ,153. Indtic mice .Benakis and colleagues showed that mice with an anti-inflammatory gut microbiome (induced by antibiotics to decrease species abundance and diversity) showed reduced cerebral infarct volume (60%) and better-preserved sensory\u2013motor function for at least 1 week following proximal MCAO . FurtherSingh and his team (2016) demonstrated that FMT from the stroke donor mice  to recipient mice  induced a significant increase in infarct volumes and functional impairment when compared to mice receiving FMT from sham-operated mice . MoreoveIn a recent study , GF maleAtg) 12, with increased levels of ROS, NADPH oxidase 2/4 (NOX2/4), lipid peroxide malondialdehyde, homocysteine, and free fatty acids (triglyceride and cholesterol), reflecting ischemia-induced neuronal damage [Acute ischemic stroke in mice was shown to upregulate the protein expression of autophagy markers, such as light-chain 3-II Beclin-1 and autophagy-related gene  and decreased abundance of commensal or beneficial genera  compared to asymptomatic controls with or without carotid atherosclerotic plaques. In addition, blood TMAO levels were reported to be lower in patients with large-artery atherosclerotic stroke or acute brain ischemia.A clinical study  showed tLactobacillus ruminis Atopobium cluster and reduced abundance of Lactobacillus sakei subgroup, hypertension, independent of age, and T2DM when compared to control subjects. Ischemic stroke is associated with decreased acetic acid levels (negatively correlated with levels of low-density lipoprotein cholesterol and glycated haemoglobin) and with increased valeric acid levels (positively correlated with the level of white blood cell counts and high-sensitivity C-reactive protein), indicating that ischemic stroke induces altered host metabolism and systemic inflammation. Patients with coronary artery disease showed a dysbiosis pattern with enrichment in Enterococcus and Escherichia-Shigella, as well as a reduced abundance of Faecalibacterium, Roseburia, Subdoligranulum, and Eubacterium rectale [Faecalibacterium prausnitzii and increased abundance of Ruminococcus gnavus [A Japanese cohort study  revealed rectale . Metagens gnavus .Akkermansia, Odoribacter, Ruminococcaceae_UCG_005, and Victivallis. Furthermore, the abundance of the genera norank_f_Ruminococcaceae, Christensenellaceae_R-7_group, and Enterobacter positively correlated with stroke severity, whereas the abundance of Christensenellaceae_R-7group positively correlated with the clinical outcome of CI patients. Within the CI group, Pyramidobacter, Enterobacter, and Lachnospiraceae_UCG_001 were increased in patients with mild CI stroke, whereas the genera Ruminococcaceae_UCG-005, Ruminococcaceae_UCG002, Christensenellaceae_R-7_group, and norank_f_Ruminococcaceae were increased in severe stroke patients, suggesting that alterations in intestinal microbiota correlate directly with severity of CI in humans  and lactate-producing bacteria  with lower abundance of butyrate-producing bacteria  and Ruminococcaceae ) compared to those of the individuals with a low-risk of stroke. Additionally, the relative abundance of Proteobacteria, Lactobacillales, Bacilli, Streptococcaceae, and Fusobacterium was also higher in the high-risk group than that in the low-risk group. Interestingly, an increase in the abundance of Lactobacillus and Bifidobacterium was reported in high-risk patients. Similarly, faecal butyrate levels were also lower in the high-risk group than the low-risk group.Another clinical study  investigEnterobacteriaceae, Oscillospira, Parabacteroides, and Bacteroidaceae and reduced abundance of butyrate-producing Faecalibacterium, Clostridiaceae, and Lachnospira. Intriguingly, FMT from patients with higher SDI to na\u00efve mice subjected to stroke procedures showed larger infarct volumes and severe neurological deficits, along with a higher number of proinflammatory (IL17+) \u03b3\u03b4 T cells and a lower number of (CD4+CD25+) T cells in the spleen than those of the corresponding mice after FMT from patients with a low SDI.A clinical study demonstrated the presence of gut microbial dysbiosis in individuals with acute ischemic stroke when compared to healthy controls by employing a Stroke Dysbiosis Index model (SDI) for measuring the gut microbial dysbiosis in stroke subjects . The resRoseburia, Blautia, Bacteroides, Faecalibacterium, Lachnospiraceae, and Anaerostipes, and an increased abundance of opportunistic pathogens, such as Akkermansia, Lactobacillaceae, Enterobacteriaceae, and Porphyromonadaceae, confirming gut dysbiosis in patients with acute ischemic stroke, especially in those with increased severity, when compared to the healthy controls. Patients with higher stroke severity had reduced levels of faecal SCFAs. An increased ratio of Bacteroidetes/Firmicutes was observed in acute ischemic stroke patients compared to healthy controls [A recent clinical study  revealedcontrols .Bacteroides, Ruminococcus, Eubacterium, and Faecalibacterium and low abundance of butyrate-producing bacterium SSC/2. The shotgun sequencing of the gut metagenome showed that the genus Collinsella was enriched in stroke patients, whereas Eubacterium and Roseburia were enriched in healthy controls. Moreover, gut metagenomes showed that genes associated with peptidoglycan biosynthesis were elevated, whereas genes encoding phytoene dehydrogenase K10027 were decreased in patients, along with reduced levels of antioxidants, such as \u03b2-carotene, when compared to control subjects. These results indicate that gut microbiota may contribute to symptomatic atherosclerosis by priming the associated inflammation and innate immune system pathways [Karlsson and colleagues (2012) demonstrated that patients with symptomatic atherosclerotic plaques showed abundant genera of pathways .Taken together, these clinical studies suggest that toxic changes in gut microbial composition and their abundance correlate directly with the magnitude of stroke severity. However, the timing of microbial changes and their impact on the onset of ischemic stroke in patients remain poorly understood.The complexity of neural, immune, hormonal, and (neuro) endocrine interactions between the GI tract and gut microbiota, cardiovascular system, and the brain presents therapeutic challenges. The results of animal and human clinical studies reveal that gut dysbiosis can be a potential risk factor for onset, severity, and outcome in stroke patients. Thus, new therapeutic strategies seek to restore a healthy gut microbiome for the prevention and treatment of stroke ,165. ModClinical studies showed that treatment with broad-spectrum antibiotics reduced the risk of infection in stroke patients ,171. HowProbiotics and prebiotics have been shown to help establish eubiosis in stroke patients. However, the precise mechanisms for their beneficial effects remain largely unknown and are the topic of intense study. Probiotics refer to the living microorganisms that, when ingested by humans or animals, can confer a health benefit ,173. PreClostridium butyricum attenuated hippocampal apoptosis and improved neurological deficit scores in mice following BCCAO. Intragastric pretreatment with 1 \u00d7 109 CFU of C. butyricum (200 \u00b5L once daily for 2 successive weeks) before bilateral common carotid artery occlusion (for 20 min) showed increased butyrate levels and reduced oxidative stress in the brain of male ICR mice, indicating the neuroprotective effects [ reduced cerebral ischemia by 52% and significantly improved the neurological outcome [Another study showed that probiotic supplementation reduces blood pressure, one of the major risk factors for stroke . Supplem effects . In a ra effects . In a mo outcome .Prebiotics help restore the gut microbiota and negatively correlate with risk of cardiometabolic diseases. Diets rich in fibre and plant polyphenols alter gut microbial ecology to eubiosis . Fibres FMT therapy refers to an administration of stool from healthy donors via enema, nasoenteric, nasogastric, or endoscopic  routes or oral capsules ,194 thatRag1\u2212/\u2212 mice showed that FMT had no effect on lesion size, indicating that gut-microbiota-mediated neuroprotective effects on brain injury are mediated by modulating lymphocytes or immune cells [Lactobacillus, Butyricicoccus, and Meganonas, with concomitant reduction of opportunistic pathogens, such as Alistipes, Klebsiella, Bacteroides, Shuttleworthia, Fusobacterium, Haemophilus, Faecalibacterium, Proteus, and Papillibacter [In an MCAO-induced stroke model , FMT notne cells , similarne cells . In a ralibacter .Antibiotics (neomycin (450 mg/L) and Polymyxin B (150 mg/L) mixed with drinking water) also significantly relieved cerebral edema, reduced serum total cholesterol levels, and restored the integrity of the intestinal wall with the elevated faecal levels of acetic, is butyric, butyric, valeric and isovaleric acids. FMT also significantly reduced the infarct volume, neurological deficit, serum total cholesterol, and triglyceride levels; eliminated brain edema; restored intestinal permeability; and enhanced isobutyric, butyric, and isovaleric acid levels in faeces. Moreover, butyric acid supplementation significantly reduced neurological impairment, cerebral infarct volume, serum total cholesterol, triglycerides and fibrinogen levels, whole blood viscosity, and intestinal permeability, whereas it relieved cerebral edema . These sMicrobial transplantation studies have shown a positive correlation between gut-microbe-dependent TMA/TMAO production atherosclerosis plaque formation and elevated susceptibility for vascular thrombosis . AlthougSeveral preclinical and clinical studies have clearly stated that natural bioactive compounds, such as legumes, fruits, vegetables, wine, olive oil, and whole grains, consumed as food in diet or as dietary supplements, or other plant-derived compounds, possess cardioprotective effects. Many in vitro studies have suggested that several molecules with distinct chemical structures, such as polyphenolic compounds, peptides, oligosaccharides, vitamins, and n-3 fatty acids, are found to be potent cardioprotective agents ,203. AmoNrf2\u2212/\u2212) mice compared with wild-type controls [S-allyl cysteine, diallyl trisulfide, dihydrocapsaicin, curcumin and rosmarinic acid, respectively [The principle bioactive molecules found in teas are polyphenols, such as catechins in green tea and the aflavins in black tea. Both in vivo and in vitro models of cerebral ischemic/reperfusion (I/R) have shown the beneficial effects of aflavin by obliterating miRNA-128-3p-induced nuclear factor erythroid 2-related factor 2 (Nrf2) suppression and thus decreasing oxidative stress . Anothercontrols . Nomilincontrols ,212. Botcontrols ,214,215.ectively . In vivoectively ,220,221.ectively . Anthocyectively .Lycium barbarum fruits (known as Goji berries) contain monoterpenes, flavanols, phenolic acids, and lyceum amides [Among the fruit-based bioactive compounds, m amides . Lycium m amides . In vivom amides . Mangifem amides . Interesm amides . Procyanm amides . Specifim amides . The antBacteroides, Klebsiella, and Haemophilus); and increase the population of beneficial bacteria , which in turn inhibit the apoptosis of neural cells, oxidative stress, and cerebral infarction volume, leading to prevention of neurobehavioral impairments. Conclusively, FMT with enriched SCFA-producing bacteria and butyric acid supplementation is found to be an effective treatment for cerebral ischemic stroke, although additional large-scale randomized clinical studies are needed in the future to demonstrate the efficacy and safety of FMT in treating patients with stroke or other cardiovascular complications. It will be important to identify conserved and reliable biomarkers of the gut microbiome to help with the design of next-generation microbiome-based therapeutics for the early prevention of neurodegenerative diseases, stroke, and post-stroke neurobehavioral deficits or dementia, as well as the monitoring of disease progression and the efficacy of therapeutic agents. These efforts will be greatly facilitated by longitudinal human clinical trial work, which shuld assess the effects of these microbial drugs on stroke through the gut-microbiota\u2013brain axis.In the present review, we have briefly discussed the association of gut dysbiosis with the pathogenesis and treatment outcome of stroke. Clinical and preclinical studies over the last decade have demonstrated a compelling link between gut dysbiosis and the development of well-known stroke risk factors, such as dyslipidemia; insulin resistance; obesity; hypertension; T2DM; and cardiovascular, cerebrovascular, and neurological disorders. Recent research findings have confirmed a positive correlation between gut dysbiosis and poor post-stroke outcomes. The pathophysiological mechanisms underlying stroke-induced gut dysbiosis include breakdown of the intestinal epithelial barrier, tight and adherent junction proteins, gut dysmotility, altered mucus secretion, loss of goblet cells, alterations of local immune homeostasis, elevated LPS levels, and intestinal inflammation. Consequently, immune-driven systemic inflammation or endotoxemia takes place, and this event leads to elevated inflammation, breakdown of BBB, and neurotoxicity, marked by increased production of ROS, RNS, TMAO, and NOX2/4 and neuroinflammation. The damaging consequences are caused by high levels of LPS, C-reactive protein, TLR4, bacterial toxins, toxic metabolites, abnormally activated immune cells, and pro-inflammatory cytokines in the ischemic brain region. These changes result in larger infarct size, neuronal death, synapse loss, and glial dysfunction, which accounts for poor outcomes. Inflammatory signals from the infarct site further enhance gut dysbiosis, thus resulting in a proinflammatory loop. To break the vicious proinflammatory cycle, the gut microbiome has been considered a promising target in the treatment and prevention of stroke in experimental and clinical studies. Deleterious effects of gut dysbiosis can be prevented by pharmacological and non-pharmacological methods, such as dietary interventions, antibiotics, prebiotics, probiotics, and synbiotics, as well as FMT. Several studies have confirmed that gut microbiome dynamics can be regulated toward a healthy state by restoring the beneficial microbial population and elevated levels of SCFAs . In cerebral ischemic stroke, supplementations rich in SCFA-producing bacteria have been shown to significantly reduce intestinal leakage and inflammation; decrease the abundance of pathogenic bacteria (e.g.,"}
+{"text": "In their recent volume, Critical Rural Gerontology, Skinner et al (2021) challenge us to set aside unidimensional notions of rural communities as bypassed vs very supportive; and to identify the elements of rurality that empower or exclude older people and how these differ across cultures and settings. Covid-19 has highlighted the need for safe and inclusive communities. Given that LMIC will be home to the majority of older adults , we undertook a scoping review of features of rural communities that influence wellbeing of older people in countries across Latin America and Sub-Saharan Africa. The review included literature in English, French, Spanish and Portuguese, using search engines MEDLINE, CINAHL Complete, PsycInfo, SocINDEX, SciELO, AJOL , LILACS, Redalyc, LatinIndex and Clacso. Findings illustrate diversity in how community features including remoteness, infrastructure and belonging influence material, social and subjective wellbeing of older residents."}
+{"text": "Introduction: Chondral and soft tissue injuries can be associated with first time patellar dislocation, but it is unclear how common they are, and which tissues are affected. A systematic review of the literature was performed to investigate the frequency, location, and extent of chondral and medial patellofemoral ligament (MPFL) injuries in patients following first time patellar dislocation. Methods: This systematic review was conducted according to the PRISMA guidelines. PubMed, Google Scholar, Embase, and Web of Science databases were accessed in November 2021. All the published clinical studies reporting the frequency, location, and extent of soft tissue lesions following first time patellar dislocation were accessed. Studies reporting data on habitual, congenital, or recurrent patellofemoral instability were excluded. Results: Data from 42 articles  were retrieved. Ninety-eight percent of patients who experienced first time patellar dislocation demonstrated MPFL rupture at MRI. Forty-eight percent of MPFL ruptures were located at the patellar side, 34% at the femoral insertion site, and 18% in the midportion. Eighty-five percent of patients showed signs of patellar chondral damage at MRI, and trochlear chondral injuries were evidenced in 47% of patients. Intra-articular loose bodies were observed in 11.5% of patients. At arthroscopy, the medial facet and the crest of the patella more commonly exhibited chondral lesions than the lateral facet and femoral trochlea. Conclusions: Most patients suffer chondral damage and MPFL tears following after a first time patellar dislocation. Acute patellar dislocation is common, especially in adolescents . Acute pThe frequency, location, and extent of chondral injuries, along with the rate of medio patellofemoral ligament (MPFL) tears following first time patellar dislocation are unclear ,16,17,18Problem: first time patellar dislocation;Outcome: soft tissue injuries.This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines . The litpatella, dislocation, acute, instability, soft tissue, chondral, cartilage, lesion, osteochondral, injury, loose body, ligament, tear, muscle injury, tendon tear, ACL, PCL, MCL, meniscus, MRI, arthroscopy, medial patellofemoral ligament, MPFL, damage, insertion, rupture, Outerbridge, International Cartilage Repair Society, ICRS. The same authors performed the screening of the resulting titles in a separate fashion, accessing the full-text of the articles of interest. A cross-reference of the bibliographies was also performed. Disagreements were resolved by a third author (**).Two authors  independently performed the literature search in November 2021. PubMed and Google Scholar were accessed. Embase and Web of Science were also accessed to identify further articles. The following keywords were used in combination: All the published clinical studies which reported the frequency, location, and extent of chondral injuries and MPFL ruptures following first time patellar dislocations were accessed. Given the authors language capabilities, articles in English, German, Italian, French, and Spanish were eligible. Level I to IV of evidence, according to Oxford Centre of Evidence-Based Medicine , were coData extraction was performed by two authors . Study generalities were collected: author, year, journal, study design, number of patients. MRI findings were retrieved: rate of free loose bodies, rate, extent, and location of MPFL, trochlear, and patellar chondral injuries. Arthroscopy findings were also collected: location and extent of trochlear and patellar chondral injuries. The MRI findings were evaluated using the Outerbridge classification , whereasTwo authors  independently performed the methodological quality assessment using the PEDro Score. PEDro is an 11-item scale designed for rating methodological quality of the included studies. These items evaluated the eligibility criteria, allocation and blinding procedures, the length of the follow-up, the intention-to-treat and between-group analyses, point estimates, and variability. Items were scored either as present (1) or absent (0). Mean values of 6/11 were considered satisfactory.For the statistical analysis, IBM SPSS  software version 25 was used. For continuous variables, the Shapiro\u2013Wilk test was performed to investigate data distribution. For normal data, mean and standard deviation were calculated. For nonparametric data, median and interquartile range were calculated. Dichotomic data was evaluated as follow:n = 250), study design (n = 201), recurrent, congenital, or habitual patellofemoral instability (n = 103), language limitation (n = 4), and uncertain results (n = 2). This left 150 articles for inclusion. A further 108 articles were excluded because of lack of quantitative data under the outcomes of interest. Finally, 42 articles were considered for analysis  ,73,74,75Ten studies (236 patients) ,66,67,68According to the main findings of the present systematic review, 98% of patients who experienced first time patellar dislocation demonstrated MPFL rupture at MRI. This rupture is more frequent at the patellar site (48%), whereas femoral (34%) and midportion (18.2%) tears are less common. Eighty-five percent of patients following patellar dislocation reported signs of patellar chondral damage at MRI, whereas 47% demonstrated trochlear chondral injuries. Arthroscopic findings evidenced that the medial chondral facet and median crest of the patella were affected more commonly by advanced chondral injuries than the lateral patellar facet and femoral trochlea. Loose bodies were observed in 11.5% of patients.The patellofemoral joint is complex, with intricate architecture and biomechanics. Following patellar dislocation, ruptures of the MPFL have been demonstrated in 81% to 100% of patients ,80,81,82The exact incidence of chondral defects after patellar dislocation is unclear. Up to 96% of patients demonstrated cartilage injuries after the first episode of patellar dislocation ,15,16,17Given the multifactorial aetiology along with the juvenile onset, the management of patellar dislocation can be challenging ,89. PrimThe present investigation has certain limitations. The retrospective design and the relatively short length of follow-up in most available studies represents important limitations. Most of the included studies were case series or case reports, which lead to an increased risk of selection and allocation biases, negatively impacting the conclusions of the present systematic review. A formal control group was missing in most studies. Elias et al.  includedAlmost all patients following first time patellar dislocation presented chondral damages and MPFL rupture."}
+{"text": "In response to the COVID-19 pandemic, Saint Louis University GWEP quickly pivoted service initiatives to online formats. Despite challenges of technology literacy and access, GWEP faculty, staff, and students creatively adapted in-person programming to online delivery and developed new virtually-delivered services. These service delivery adaptations provided opportunities for educating students, residents, faculty, community partners, and older adults and their caregivers to gain new knowledge and skills while continuing to participate in programming. This presentation will highlight innovations in the area of services to persons with dementia through Cognitive Stimulation Therapy, caregivers through education and support programs, older adults experiencing loneliness and social isolation through Circle of Friends, and older adults and caregivers through a virtual geriatric assessment clinic. We share highlights here of our efforts to pivot programming, access new funding streams, and, in some cases, create online delivery, including valuable lessons learned."}
+{"text": "Fish muscle, which accounts for 15%\u201325% of the total protein in fish, is a desirable protein source. Their hydrolysate is in high demand nutritionally as a functional food and thus has high potential added value. The hydrolysate contains physiologically active amino acids and various essential nutrients, the contents of which depend on the source of protein, protease, hydrolysis method, hydrolysis conditions, and degree of hydrolysis. Therefore, it can be utilized for various industrial applications including use in nutraceuticals and pharmaceuticals to help improve the health of humans. This review discusses muscle protein hydrolysates generated from the muscles of various fish species, as well as their amino acid composition, and highlights their functional properties and bioactivity. In addition, the role of the amino acid profile in regulating the biological and physiological activities, nutrition, and bitter taste of hydrolysates is discussed. The use of fish and seafood products, including aquatic plants, has increased by ~8% over the last 30 years, with high growth rates of global livestock production . From 19Various clinical studies have identified the health-promoting effects of consuming fish proteins. Mozaffarian et al. 2005, ) found t,  found Fish muscle, which contains 15%\u201325% of total protein in fish, can be divided into myofibrillar (50%\u201360%), sarcoplasmic (30%), and stromal 10%\u201320%) proteins . The mus%\u201320% proHuman food is produced from protein that comprises ~60% of the body weight of fish. Skeletal muscle proteins in fish facilitate muscle movement by contraction. The heterogeneous fibrous populations of cells in fish proteins differ in terms of molecular, structural, contractile, and metabolic functions and influence the growth rate and properties of muscle, such as the onset of firmness, pH decline, color, and cohesiveness, and ultimately the functional properties of meat ,12,13. TIn contrast to terrestrial animals, fish have shorter muscle fibers and less connective tissue, and these muscles are segmented into myotomes by fine connective tissue layers called myocommata or myosepta, which lie primarily in thin sheets that separate muscle fibers into orderly layers ,16. In aMuscle proteins from fish are easily digestible and rich in more essential amino acids than most terrestrial meat proteins . Fish muFish protein hydrolysates are produced by chemical hydrolysis with either alkali or acid ,25, fermAlkaline or acid hydrolysis results in reduced consumer acceptance due to the high variability of hydrolysates because the chemical cleavage of peptide bonds is not specific. Hydrolysis damages amino acid profiles by oxidizing cysteine and methionine, destroying some serine and threonine residues, and possibly converting asparagine and glutamine to aspartate and glutamate . Fermentation with proteolytic microorganisms can enhance the nutritive and bioactive characteristics of fish matrices and improve human health benefits via the enzymatic activity of the raw material and the metabolic activity of microorganisms . For insEnzymatic hydrolysis generates specific peptides by cleaving site-specific chains according to the specificity of the enzyme; this allows more efficient control of the manufacturing process by easily inactivating the enzyme after a specific degree of hydrolysis (DH) has been achieved . The comPterois volitans L., [Rachycentron canadum, [Pangasius hypophthalmus, [Meuchenia sp., [Katsuwonus pelamis, [Collichthys niveatus, [Merluccius productus, [Nemipterus hexodon, [Lutjanus vitta, [Sepia officinalis, [Salmon salar, [Sardina pilchardus, [Raja clavate, [Syngnathus schlegeli, [Daralichthys olivaceus, [tans L., ), cobia canadum, ), catfisthalmus, ), leathenia sp., ), skipjapelamis, ), bigheaiveatus, ), Pacifioductus, ), ornatehexodon, ), brownss vitta, ), cuttlecinalis, ), salmonn salar, ), sardinchardus, ), thornbclavate, ), Pipefihlegeli, ), and flivaceus, ).Raja clavate) generated by >7 Bacillus subtilis A26 proteases [The antioxidant properties of protein hydrolysates of monkfish muscle have been evaluated . Endogenroteases ,55. Thisroteases ,49. 2, enzymes, and structural proteins [Proteolytic enzymes break down proteins into hydrolysates that comprise small peptides consisting of 2\u201320 amino acids . The molproteins ,61. 2+ and Cu2+, thereby reducing their activity, and can inhibit lipid peroxidation [The amino acid profiles of fish proteins play significant roles in various biological and physiological activities and in maintaining the health of humans. Amino acids such as aspartic acid, glycine, and glutamic acid enhance wound healing . Tyrosinxidation . The aroxidation . In the xidation , and lowxidation . Aspartixidation . Fish proteins are easily digested and abundant in essential amino acids that are limited in terrestrial meat proteins such as methionine and lysine   and founSelaroides leptolepis, [tolepis, ), bigheatolepis, , whitemotolepis, , Atlantitolepis, , coho satolepis, , and Alatolepis, .Mallotus villosus) myofibrils using Flavourzime and the original protein were similar [Micropogonias furnieri) hydrolysates increase its solubility in lipids, resulting in stronger antioxidant activity [Saidi et al. 2014) reported that among the hydrolysates from tuna dark muscle, the 1\u20134 kDa fractions with the strongest superoxide scavenging and reducing activities accounted for the high amounts of hydrophobic tyrosine, phenylalanine, proline, alanine, histidine, and leucine , corresp14 report similar . Another similar . They re similar . Thiansi similar . The bit similar ,75. Abunactivity . Nakajimactivity . The present tendency towards health consciousness among fish consumers has resulted in concern about the nutritional quality of fish, which is associated with the muscle protein content and their amino acids. Protein from fish muscle is easily digested and abundant in several essential amino acids compared with that from most terrestrial meats. The hydrolysate and amino acid profiles of fish muscle protein significantly impact numerous human biological and physiological activities. The composition and physical activities of the resulting hydrolysates are affected by the protein source (fish species), proteolytic enzymes, hydrolytic methods and conditions, and the DH. Amino acids in hydrolysates have various functional and bioactive properties."}
+{"text": "We tested for differences in data sources and modeling techniques using multinomial regressions and used a linear discriminant analysis to distinguish differences in predictors among fish guilds. Our results show predictive studies increased over time, but studies of forage fish, sharks, coral reef fish, and other fish guilds remain sparse. Research themes emphasized habitat suitability and distribution shifts, but also addressed abundance, occurrence, stock assessment, and biomass. Methodologies differed by fish guilds based on data limitations and research theme. The most frequent predictors overall were depth and temperature, but most fish guilds were distinguished by their own set of predictors that focused on their specific life history and ecology. A one-size-fits-all approach is not suitable for predicting marine fish distributions. However, given the paucity of studies for some fish guilds, researchers would benefit from utilizing predictors and methods derived from more commonly studied fish when similar habitat requirements are expected. Overall, the findings provide a guide for determining predictor variables to test and identifies novel opportunities to apply non-spatial knowledge and mechanisms to models.As species distribution models, and similar techniques, have emerged in marine ecology, a vast array of predictor variables have been created and diverse methodologies have been applied. Marine fish are vital food resources worldwide, yet identifying the most suitable methodology and predictors to characterize spatial habitat associations, and the subsequent distributions, often remains ambiguous. Our objectives were to identify knowledge gaps in fish guilds, identify research themes, and to determine how data sources, statistics, and predictor variables differ among fish guilds. Data were obtained from an international literature search of peer-reviewed articles (2007\u20132018;  Species distribution models (SDMs), and similar methods of spatial modeling, have proliferated in the last two decades with the growing availability of geospatial data, increased computational capacity, and new approaches to model building. Spatial modeling approaches have changed dramatically from habitat suitability indices developed in the 1970s , shape-cin situ or buoy measures, digital elevation models, hindcast ocean models, or earth system models. For example, the online database \"Bio-Oracle 2.0\" provides worldwide data on 14 oceanographic predictor variables that are described with a minimum, mean, maximum, long-term metrics, and range for three depth zones, totaling 252 variables [The choice of predictor variables is a central challenge for SDM development , 14, andariables . Season-ariables , 19. Preariables  to thoseariables , 22. Eacariables , which ca. In contrast, long-lived species responded to depth rather than chlorophyll-a; these species had a moderate, or even a negative association, with SST and its seasonality [The importance of considering multiple scales of predictors is exemplified by Mannocci et al.  who propsonality . Larger sonality . Regardisonality  analyzedGiven the recent growth of marine spatial modeling, the complex array of potential predictor variables available to modelers, the diversity of marine fish species, and evolving statistical methods, we aimed to provide guidance to the development and interpretation of predictive models of marine fish distribution. We conducted a literature synthesis and meta-analysis with the following objectives: 1) identify the most and least frequently studied fish guilds, 2) test how fish data sources, statistical techniques, and predictor variables differ by fish guild, 3) identify common research themes, and 4) discuss implications and recommendations for future modeling of marine fish distributions.We conducted a literature search of peer-reviewed research articles with the Web of Science database. Articles ranging from 2007\u20132018 were included, and the search was conducted January 16, 2019. The following topic key words were searched within the title, abstract, and key words: \"species distribution\" OR \"ecological niche*\" OR \"bioclimatic envelope\" OR \"habitat suitability\" OR \"habitat model*\" OR \"spatial distribution\" OR \"seascape\" AND \"fish\" AND \"marine\" OR \"ocean.\" We then conducted the same search, but replaced \"fish\" with \"shark\" because we found shark articles were better represented with this search. A total of 1,648 articles were obtained from this search. We acknowledge that we were not likely to find 100% of articles related to marine fish predictive modeling, but the search is likely to be representative of such studies.The review included only fish species, therefore, taxonomic groups such as squid, shrimp, crabs, other crustaceans, corals, and bivalves were not investigated. We limited the review to those research articles that resulted in a spatial prediction of fish distribution beyond fish survey locations. Although studies without spatial predictions may greatly improve our understanding of fish ecology and distribution, ultimately, we were interested in predicting and mapping the distribution of fish over relatively broad areas. No limitations were placed on the dependent variables. Predictions of individual species presence, relative abundance, or relative biomass were considered alongside studies that focused on species richness, species diversity, or similar measures. Of the latter studies, 38 of the 40 studies were based on an accumulation of individual species predictive models. Two studies used species richness directly as a dependent variable, but the methodology of these studies did not differ from the other papers reviewed. For example, predictors focused on temperature and productivity. Given the objectives and scope, we removed the following types of studies from the initial search (see Gadus spp.), but did not fit into the other categories . Large pelagics included highly mobile fish of high economic value such as tuna and billfish, and medium pelagics included mackerel (Scombridae) or similar-sized pelagic fish. Forage fish are commonly studied as a group, and this guild included species such as anchovy (Engraulidae), sardine and menhaden (Clupeidae). Anadromous fish were excluded from the forage fish guild. The invasive category included all studies of non-native species, and these studies were excluded from being in other fish guilds. Generalized studies included research of two or more of the above fish guilds. These generalized studies often examined species richness, species diversity, or all of the species captured in a particular survey.For each study, we categorized the fish species into one of ten mutually exclusive guilds . The guiTo quantify fish data sources, we determined if a study used fishery independent, fishery dependent, both fishery independent and dependent, international database, and previous research/museum specimens. Categories were not mutually exclusive. Fishery-dependent data included logbooks, landings, catch observations, incidental catch observations, and recreational catch. International databases included \"Sea Around Us,\" geographic range polygons from \"SeaLifebase,\" and databases of raw species data such as the \"Ocean Biogeographic Information System.\" The modeling, or statistical, technique(s) was recorded and the total number of modeling techniques applied for each study was calculated. For the assessment of statistics, techniques were recorded in the categories of generalized additive model, generalized linear model, Maxent presence-only model, habitat suitability index, multivariate statistic, envelope or bioclimatic envelope models, geostatistics, occupancy model, Bayesian statistic, quantile regression, individual-based models, ordinary least squares, and general machine-learning techniques. We summarized the machine-learning techniques of artificial neural networks, classification and regression trees, random forest, boosted regression trees, support vector machines, and multivariate adaptive regression splines, into a single group of \"general machine learning\" because of their similarity. Although Maxent modeling is a machine-learning technique, it was treated separately because Maxent is distinctly used for presence-only modeling. We grouped the different methods that applied the principal of bioclimatic envelopes . The category of multivariate techniques included ecological niche factor analysis, flexible discriminant analysis, and the non-parametric probabilistic ecological niche model. We did not distinguish models with only fixed effects from those with random effects. Tests of spatial autocorrelation were not recorded except for geostatistical techniques, such as kriging, that directly used autocorrelation for modeling purposes.a, upwelling events, and ocean currents. Although depth may affect physiology of species, the variable was considered physical oceanographic because it is often a proxy for associations with other physical characteristics. Geographic variables focused on location or proximity to surrounding ecosystems, such as latitude/longitude, distance to shore, distance to shelf, and distance to other ecosystems like mangroves or estuaries. Substrate variables characterized components such as sediment grain size, sessile biota, hardbottom, rugosity, and topography. Biological variables included prey, predators, conspecifics, fishing pressure, competitors, and anthropogenic stress.We recorded each predictor variable tested, or otherwise utilized , in models of fish distribution. For our purposes, the calculations of variables as a mean, minimum, or maximum were considered the same variable . However, standard deviation (SD), coefficient of variation (CV), and range were distinguished as a distinct set of variables because they describe heterogeneity or gradients. The wide breadth of habitat descriptors did necessitate some consolidation of predictor variables when the meaning of the predictors were similar , and words that had a generic meaning . Plural R [We reviewed 225 peer-reviewed scientific articles , and allR . A singlR , was notR  and usedTo distinguish specific predictor variables associated with fish guilds, we invoked linear discriminant analysis (LDA), which is a machine-learning analysis used for identifying linear combinations of variables that maximize the separation of known data groupings , 36. We n = 225) (habitat (frequency = 518), change (261), environmental (220), climate (197), fishery (193), temperature (176), suitability (163), management (159), and abundance (149) (fishing (116), conservation (108), spawning (104), shift (96), occurrence (66), stock (64), and biomass (63).The number of marine fish predictive modeling articles had a strong upward trend from 2007 to 2018 . Only twn = 225)  revealedce (149) . Other nRhincodon typus), constituted the subject for 5 of 19 shark studies and tuna (Thunnus spp. or Katsuwonus pelamis) constituted 20 of 29 large pelagic fish studies. The majority of data sources were fishery-independent surveys (61%) followed by fishery dependent (25%), international databases (14%), fishery independent and dependent surveys (7%), and previous research or museum specimens (5%)  . Compareens (5%) . StudiesOf the modeling techniques, generalized additive models (GAMs) were the most frequently used, encompassing 32% of studies . Maxent n = 224 studies)  . Of the studies) . GeograpAcross all studies, depth, SST, chlorophyll, and surface salinity were the most common predictor variables . FurtherThe findings presented here show that methodologies, data sources, and predictors of marine fish are not homogeneous across guilds. Previous research has found that the most frequently expressed goals of marine SDMs are to inform theoretical ecology, current distributions, conservation planning, climate change, and methodology evaluation , 12.habitat was the most frequent theme and was complemented with terms of suitability and environmental. Our findings concurred with strong interest in climate, temperature, change, and shift. The frequency of terms such as biomass, catch, population, fishery, stock, management, abundance, and spawning suggest a more detailed understanding of distribution may be necessary for fish, and management of fish populations is a key motivator of studies. As examples, Dell et al. [However, our investigation found l et al.  estimatel et al.  aimed tol et al. \u201345, and Demersal fish were most frequently studied, likely because of their importance as a food resource  and the availability of fishery-independent trawl surveys. In comparison, there were relatively few studies of sharks, forage fish, anadromous fish, and reef fish. Melo-Merino et al.  found 45The selection of predictor variables is a key component for SDM development and interpretation . PredictMakaira nigricans) based on temperature that varied by horizontal location and depth; vertical habitat selection differed between diurnal and nocturnal periods. These high resolution data are ideal, but disadvantages include the high cost of tag deployment, risk of failure to collect and/or retrieve the data, and sample size may be relatively small because each tag deployed represents only one fish. Another possible solution is to expand the use of citizen science. Citizen science data has been shown to be as effective as expert surveys for reef fish given some species identification limitations [Our findings show models of pelagic fish and sharks often rely on fishery-dependent data, yet fishery-independent data provide distinct benefits. For example, demersal fish models benefit from widespread fishery-independent bottom trawl surveys, which have the potential to address climate change and species\u2019 range shifts . The incitations , and cititations \u201357. Preditations .Explicitly justify the technique. Extensive testing has been conducted to determine the most accurate SDM techniques \u201361, but Carcharodon carcharias) associate with eddies [Prionace glauca) associate with SSH anomalies [Oncorhynchus spp.) suggests upwelling or downwelling, mixed layer depth, thermal fronts, and prey abundance contribute to salmon distribution, abundance, and stomach fullness [Our study shows clear differences in predictor variables considered among fish guilds, and the findings can act as a guide for variable inclusion. As predictive modeling research is still nascent for several marine fish guilds, there is tremendous potential to learn from studies of other fish guilds. For instance, sharks and large pelagic fish prey on smaller fish, and presumably, select for extremely productive marine environments. However, studies of tuna and other large pelagics are distinguished by a predictor of sea level height anomalies (or fronts), which have rarely been used to predict sharks. Indeed, non-predictive studies of habitat associations have recently found great white shark  feed extensively on sand lance (Ammodytes spp.) in the mid-Atlantic, USA [Multiscale predictors, defined as predictors that represent environmental conditions at multiple spatial scales, are recognized as being critical to characterize species\u2019 distributions , 71, 72 tic, USA , 77, whitic, USA . For demtic, USA , 21, butSDMs developed with direct resource predictors, characterized as variables having a direct link to species\u2019 physiology , are idea priori hypotheses, using process-based models, and joint species distribution models that which can account for environmental influences before quantifying associations with biotic variables [Biological predictors were considered in only 3% of studies, and prey, conspecifics , and fishing pressure were most common. Prey species are expected to be valuable predictors when there is a mismatch between environmental conditions and prey , which mariables . UnderstKnowledge of the current and future distribution of marine fish is critical to food security, economics, and conservation of the world\u2019s fishes. Marine fish SDMs have emerged to map distributions, better understand environmental factors driving habitat suitability, inform management decisions, and to inform policy. We have illuminated knowledge gaps in fish guilds studied as well as identified that predictor variables of fish are not one-size-fits-all. As SDMs of marine fish develop further, there will be new opportunities to integrate new multiscale predictors, quantify complex ecological interactions, and to test existing knowledge on taxonomic groups that are less studied.S1 Text(DOC)Click here for additional data file.S2 Text(DOCX)Click here for additional data file.S3 Text(DOCX)Click here for additional data file.S4 Text(DOC)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Tablen = 224).Categories were defined for statistical analyses of studies predicting the spatial distribution of marine fish ((DOCX)Click here for additional data file.S1 Appendix(CSV)Click here for additional data file."}
+{"text": "Roth GA, Mensah GA, Johnson CO, Addolorato G, Ammirati E, Baddour LM, Barengo NC, Beaton AZ, Benjamin EJ, Benziger CP, Bonny A, Brauer M, Brodmann M, Cahill TJ, Carapetis J, Catapano AL, Chugh SS, Cooper LT, Coresh J, Criqui M, DeCleene N, Eagle KA, Emmons-Bell S, Feigin VL, Fern\u00e1ndez-Sol\u00e0 J, Fowkes G, Gakidou E, Grundy SM, He FJ, Howard G, Hu F, Inker L, Karthikeyan G, Kassebaum N, Koroshetz W, Lavie C, Lloyd-Jones D, Lu HS, Mirijello A, Temesgen AM, Mokdad A, Moran AE, Muntner P, Narula J, Neal B, Ntsekhe M, Moraes de Oliveira G, Otto C, Owolabi M, Pratt M, Rajagopalan S, Reitsma M, Ribeiro ALP, Rigotti N, Rodgers A, Sable C, Shakil S, Sliwa-Hahnle K, Stark B, Sundstr\u00f6m J, Timpel P, Tleyjeh IM, Valgimigli M, Vos T, Whelton PK, Yacoub M, Zuhlke L, Murray C, Fuster V, for the GBD-NHLBI-JACC Global Burden of Cardiovascular Diseases Writing GroupGlobal Burden of Cardiovascular Diseases and Risk Factors, 1990\u20132019: Update From the GBD 2019 StudyJ Am Coll Cardiol 2020;76:2982\u20133021.On page 2994, the last sentence in the left column read:Health systems in LMICs should support the recommendations of the 2018 World Health Assembly Global RHD Resolution with increased multisector investment in primary health care, improved sanitation and housing, infrastructure, secure medication supply chains, evidence-based RHD screening, prevention and management, and tertiary capacity to care for patients at the severe end of the RHD spectrum.But should have read:The 2018 World Health Assembly Global RHD Resolution recommends to increase multisector investment in primary health care, improve sanitation and housing, infrastructure, secure medication supply chains, evidence-based RHD screening, prevention and management, and tertiary capacity to care for patients at the severe end of the RHD spectrum.On page 2996, the last sentence in the left column read:Additional policy support for public education and awareness is needed to reduce the harmful use of alcohol. Because alcohol negatively affects cardiovascular function, increased clinician emphasis on eliminating alcohol use among people with coexisting CVD is advisable. Research should be aimed at understanding the exact mechanisms of disease, susceptibility to alcohol damage, effective public health interventions, and treatments for AC.But should have read:Additional support for public education and awareness can help to reduce the harmful use of alcohol. Since alcohol negatively impacts cardiovascular function, increased clinician emphasis on eliminating alcohol use among people with co-existing CVD is advisable. A deeper understanding of the exact mechanisms of disease, susceptibility to alcohol damage, effective public health interventions and treatments for AC, can optimize preventive measures.On page 2999, the last sentence in the left column read:As such, investing health system resources in these risk factors, including hypertension management and smoking cessation, could reduce the burden of other diseases in addition to aortic aneurysm. Combined with implementation of inexpensive screening technology, such as ultrasonography, where indicated, the morbidity and mortality due to aortic aneurysm can be significantly decreased globally.But should have read:As such, mitigating risk factors through, for example, hypertension management and smoking cessation, could reduce the burden of other diseases in addition to aortic aneurysm. Combined with effective and accessible screening technology, such as ultrasound, where indicated, the morbidity and mortality due to aortic aneurysm can be significantly decreased globally.On page 3001, the last sentence in the second paragraph in the left column read:Countries will need to invest in health care infrastructure and health workers to provide timely valve interventions for these patients to reduce related morbidity and mortality.But should have read:An improved health care infrastructure and an augmented healthcare workforce could provide timely valve interventions for these patients and thereby reduce related morbidity and mortality.On page 3015, the third sentence in the third paragraph in the left column read:Effective tobacco control measures available to governments and private sector institutions include policies that increase taxes on tobacco, fund mass media education campaigns, ban tobacco marketing and sponsorship, require prominent warning labels on tobacco products, require environments to be smoke-free, and ensure access to and delivery of tobacco cessation treatments in health care systems.But should have read:Tobacco control measures include increased taxes on tobacco, mass media education campaigns, bans on tobacco marketing and sponsorship, required prominent warning labels on tobacco products, required environments to be smoke-free, and ensuring access to and delivery of tobacco cessation treatments in health care systems.On page 3015, the first sentence in the fourth paragraph in the right column read:Strong commercial interests driving the sales of unhealthy foods have made it challenging to persuade policy makers, clinicians, or community members to act decisively on diet quality.But should have read:Strong commercial interests driving sales of unhealthy foods have made it challenging to make significant progress toward improving diet quality.The authors apologize for these errors.The online version of the article has been corrected to reflect these changes."}
+{"text": "Meliponula ferruginea as its study objective [Honey continues to be the most studied bee product, with 60% of articles addressing this thematic ,3,4,5,6 bjective ,8, cerumbjective , and probjective  were alsbjective ,10.Robinia pseudoacacia), rapeseed (Brassica napus), dandelion , mint (Mentha spicata), sunflower (Helianthus annuus), buckwheat (Fagopyrum esculentum), raspberry (Rubus idaeus), and meadow honey. Despite the ban of antibiotic residues in honey, the results obtained showed that antibiotic residue incidence was 25%, with nitrofurantoin present at the highest concentration in mint honey (5.528 ng/g). In contrast, meadow honeys were free from antibiotics, and the lowest antibiotic concentration (0.2 ng/g) was found in raspberry and black locust honeys. The lowest pesticide content was also found in raspberry and meadow honeys, maybe because they are coming from wild areas without the pressure of pesticide and fertilizer utilization in crops. Pesticide residues were found in 68% of samples, but, in all cases, the presence of these pesticide residues was lower than the maximum residue limits (MRLs) required by European legislation.Scripc\u0103 and Amarici  studied Euphorbia origin from Morocco for scavenging the free radicals nitric oxide (\u2022NO), superoxide anion radicals (O\u2022\u2212), and 2,2-diphenyl-1-picrylhydrazyl (DPPH) could be attributed to the phenolic fraction since they presented better activity after separating these secondary metabolites from the honey. In contrast, Alevia et al. [Antioxidant ,2,4, antStaphylococcus aureus, Listeria monocytogenes, Escherichia coli, Streptococcus mutans, Pseudomona aeruginosa, and one yeast . Nevertheless, the digested honeys showed higher antimicrobial activity against S. aureus and L. monocytogenes. According to these results, the authors [All Spanish samples (honeys and digested honeys) showed antimicrobial activity against  authors  pointed Haemophilus spp., P. aeruginosa, and S. pneumoniae. All honey samples at the MIC/2 concentration were able to inhibit the formation of biofilm by each bacterium strain tested, linden honey being the most effective and the black locust honey being the least. Propolis and cerumen of the African Meliponula ferruginea from Tanzania  also had antimicrobial activity against Staphylococcus aureus ATCC 25923, Enterococcus faecalis ATCC 29212, Listeria monocytogenes ATCC 7644, Pseudomonas aeruginosa ATCC 27853, Salmonella typhi ATCC 14028, Escherichia coli ATCC 25922, and Candida albicans ATCC 10239, as well as anti-biofilm activity at MIC levels (53\u201389.0% of inhibition) [Meliponula ferruginea, the authors considered trehalulose as a potential marker for African stingless bee honey. Concerning propolis and cerumen, di- and triterpenoids dominated, although with qualitative and quantitative differences among samples.Currently, the resistance of microorganisms to antibiotics is rising and constitutes a major health problem. This resistance seems to be correlated to the formation of biofilm by bacteria . For thiOnly one work about bee pollen has its discrimination spectroscopic identification as the sole target. In this context, Bleha et al. , in a coCastanea, Rubus, and Cistus) Tuscan bee pollen previously determined. For this purpose, they added the results obtained from ex vivo biological tests using human erythrocytes to the existing information. The presence of bee pollen samples of Castanea and Cistus origins were able to prevent lipid peroxidation and hemolysis, thus being good free radical scavengers. The anti-hemolytic activity of samples was even better than trolox, the standard used for comparison. In addition, the authors [Castanea bee pollen in human microvascular endothelial cells (HMEC-1) under endoplasmic reticulum stress conditions induced by thapsigargin. The authors [Castanea bee pollen was able to reduce gene overproduction (C/EBP-homologous protein (CHOP), cyclooxygenase-2 (COX-2), intercellular adhesion molecule 1 (ICAM-1)) and oxidation processes. In contrast, the antimicrobial activity evaluated by the authors against Escherichia coli, Salmonella typhimurium, Enterobacter erogene, Enterococcus faecalis, and Staphylococcus aureus was poor.The biological effects of bee products, such as pollen samples, are related to the content and composition of polyphenol compounds (hydroxycinnamic acid and flavonol glycosides) and carotenoids, although many other compounds can be found , that exert antioxidant, anti-inflammatory, antimicrobial, antifungal, anti-mutagenic, and antitumor effects . The aut authors  investig authors  found thDrone brood (DB) is collected from beehives as young male larvae, usually between days 4 and 14 of development. DB and royal jelly (RJ) are both yellow, and the former is sometimes used to counterfeit RJ since it can be easily obtained and in larger quantities than RJ . For theA review on the biological properties of propolis, particularly antibacterial, antiviral, antifungal, and antiparasitic activities, as well as the human clinical trials developed so far, was carried out by Zulhendri et al. , demonst\u2212finding easier methods to discriminate honey;\u2212finding possible markers for royal jelly and drone brood in order to prevent the royal jelly counterfeit;\u2212Meliponula ferruginea;finding possible markers for honey, propolis, and cerumen of the African \u2212finding the factors that contribute to the antimicrobial, antioxidant, and anti-inflammatory properties of honey from different floral and geographical origins;\u2212finding the effect of heavy metals, pesticides, and antibiotic residues on the quality of Romanian honeys;\u2212finding the mechanisms involved in antibacterial, antiviral, antifungal, and antiparasitic activities of propolis.These articles extended the knowledge on bee products by:"}
+{"text": "Consumer voices are often left out from assessments of nursing home (NH) quality. For this reason, consumer allegations and complaints against nursing homes were studied in relation to facility rates of nurse aide retention. Analyses involved means and frequencies, correlations, ANOVAs with Tukey correction to examine the independent and dependent variables (N=690). Four quartiles of retention were created. In the final models, medium, high, and extremely high retention facilities are compared to the low retention facilities. Negative binomial regressions were estimated on total, substantiated, and unsubstantiated counts of allegations and complaints. All regressions controlled for the same characteristics, including nurse aide empowerment, consistent assignment, administrator turnover, director of nursing turnover, average age of residents, and percent female. The correlation between retention and the dependent variables was negative and statistically significant . The ANOVAs showed that high retention NHs (61-72%) received significantly fewer allegations than low (0-48%) and medium (49-60%) retention NHs; they also received fewer unsubstantiated allegations, and fewer complaints, both substantiated and unsubstantiated. After controlling for other variables, each retention group was significantly related to having fewer allegations and complaints compared to the low retention NHs. Notably, high retention NHs received between 29 and 35% fewer allegations and complaints of all types. Unexpectedly, extremely high retention NHs had more allegations, complaints, and unsubstantiated allegations than high retention NHs. Policy and practice have a role to promote nurse aide retention, improve job quality, and ensure adequate support for this critical, in-demand workforce."}
+{"text": "Electrochemical sensors have shown potential in recent years for plant species identification and phylogenetic studies. These works have been used to investigate the affinities of different species in many genera. However, the ability of electrochemical sensors to study relationships between different genera within a family has not been investigated. In this work, we selected 31 species in the Labiatae and 5 exotaxa as subjects to investigate the feasibility of electrochemical sensors at the genus level. The results show that electrochemical sensors are still very effective for the identification of these plants. Different pattern recognition techniques can make the identification more efficient. Also, the fingerprint profiles collected by the sensors can be used for phylogenetic studies of Labiatae. The phylogram divides all the species into five clusters, where the exotaxa are in one cluster. Species in the Labiatae are mainly distributed in four other clusters. Importantly, the different genera of species all showed close affinities, representing that electrochemical fingerprinting can well distinguish the affinities between the different genera. The results of this work demonstrate the great potential of electrochemical sensors in the study of plant phylogeny. Its application is not limited to the study at the species level, but can be extended to the genus level. Lycoris [Pueraria [Chimonanthus [Taxodium [Electrochemical sensors capture the electrochemical oxidation and reduction signals of electrochemically active substances in a sample. This sensing technique can be used for the highly sensitive detection of a target substance and also for the recording of the overall electrochemically active profile in the sample. The use of electrochemical techniques for the recording of electrochemically active substances in plant tissues has been shown to be useful for species identification and species level phylogenetic studies ,2,3. EleLycoris , PuerariPueraria , Chimonaonanthus , and TaxTaxodium . These mMentha haplocalyx, Thymus mandschuricus, Lavandula pedunculata, and Ocimum basilicum. The Labiatae also contain important aromatic oil plants, such as Leonurus sibiricus, Agastache rugosa, Salvia miltiorrhiza, Perilla frutescens and Elsholtzia ciliate. The most widely influential taxonomic system of the Labiatae is that of J. Briquet [Lamiaceae is one of the more widely distributed families worldwide, with about 220 genera and more than 3500 species . Labiata Briquet . This sy Briquet ,16,17,18Agastache rugosa, Ajuga multiflora, Calamintha debilis, Galeobdolon chinense, Isodon nervosus, Lamium barbatum, Leonurus japonicus, Lycopus lucidus, Mentha canadensis, Mentha crispate, Mentha spicata, Mentha vagans, Monarda didyma, Ocimum basilicum, Origanum vulgare, Perilla frutescens, Physostegia virginiana, Prunella vulgaris, Salvia elegans, Salvia leucantha, Salvia miltiorrhiza, Salvia splendens, Salvia meiliensis, Salvia uliginosa, Salvia cavaleriei, Stachys japonica, Elsholtzia cyprianii, Hyptis suaveolens, Rosmarinus officinalis, Vitex negundo, Buddleja lindleyana, Scrophularia ningpoensis, Peristrophe japonica, Asystasiella neesiana and Nepeta cataria were supplied by Nanjing Botanic Garden. All fresh leaves were collected from March to July 2021. When collecting, only mature and healthy leaves were harvested. All reagents were analytical grade and used without further purification. Leaves of The extraction process was conducted using ethanol or water as solvent. For a typical extraction process, 1 g of leaves were added into 2 mL of solvent. Then, 2 mill beads were added and the mixture was sonicated at a high throughput tissue grinding machine . The extracts after grinding were taken from the supernatant after resting. PBS (pH 7.0) and ABS (pH 4.5) were used as electrolyte. All electrochemical fingerprint recordings were conducted using a CHI760 electrochemical workstation. A three-electrode system has been used for electrochemical fingerprint recording, where a commercial glassy carbon electrode , an Ag/AgCl electrode and a Pt electrode were used as the working electrode, reference electrode and counter electrode, respectively. For a typical electrochemical fingerprint recording process, 1 mL of plant extract was injected into a 4 mL electrolyte. Then, a differential pulse voltammetry (DPV) was recorded from 0 to 1.3 V. The experimental data was then normalized for further analysis. Principal component analysis (PCA) and cluster analysis were carried out using Origin software with its build-in function. Isodon grandifolius vs. Lycopus lucidus; Perilla frutescens vs. Salvia meiliensis; Salvia splendens vs. Peristrophe japonica. This does not necessarily mean that the leaves of these species contain very similar chemical components, but only that the aqueous extracts of these species have similar electrochemically active substances involved in the oxidation under PBS.Electrochemical fingerprinting is a technique used to record the profile of electrochemical substances in a sample. There is a positive correlation between the difference in electrochemical signals and the type and amount of electrochemically active substances. Therefore, this technique can be used for the identification of complex samples. The electrochemical fingerprints of all plant species under PBS after extraction with water are shown in Lycopus lucidus has a relatively small oxidation peak near 0.9 V and Isodon grandifolius does not. Perilla frutescens has a very large oxidation band between 0.8 and 1.0 V, but Salvia meiliensis has two relatively small oxidation peaks. However, using these small differences to distinguish different species is not a very effective method. Therefore, we chose to perform multidimensional fingerprinting of these species. As shown in Isodon grandifolius and Lycopus lucidus exhibit completely different fingerprint profiles. This is because the ethanol extracts of these two species are very different in terms of the substances involved in the electrochemical oxidation under ABS. The same can be observed in Perilla frutescens and Salvia meiliensis, as well as in Salvia splendens and Peristrophe japonica. Therefore, multidimensional fingerprinting of plant tissues can increase the abundance of fingerprints and thus improve the correspondence between fingerprints and species. At the same time, multidimensional fingerprinting represents a more comprehensive collection of electrochemical information. For example, more electrochemically active substances can be extracted using polar and non-polar solvents. The use of electrolytes with different pHs also allows more electrochemically active substances to participate in electrochemical reactions.Although there are some differences between these similar fingerprints, for example, Agastache rugosa, Ajuga multiflora, Calamintha debilis, Galeobdolon chinense, Isodon nervosus, Lamium barbatum, Leonurus japonicus Lycopus lucidus, Mentha cana-densis, Mentha crispate, Mentha spicata, Mentha vagans, Monarda didyma, Ocimum basilicum, Origanum vulgare, Perilla frutescens, Physostegia virginiana, Prunella vulgaris, Salvia elegans, Salvia leucantha, Salvia miltiorrhiza, Salvia splendens, Salvia meiliensis, Salvia uliginosa, Salvia cavaleriei, Stachys japonica, Elsholtzia cyprianii, Hyptis suaveolens, Rosmarinus officinalis, Vitex negundo, Buddleja lindleyana, Scrophularia ningpoensis, Peristrophe japonica, Asystasiella neesiana and Nepeta cataria. It can be seen from the figure that hardly any two species have very similar scatter plots. Since the points closer to the distal end of the X and Y axes indicate that the oxidation peaks in the original fingerprint profiles, the positioning of the data in the upper right corner of the scatter plot is reflective of the differences between the different species.To further enhance the variability of multidimensional fingerprint profiles in species identification, we deleted the potential information in the fingerprint profiles. Therefore, we can make a scatter plot with the electrochemical fingerprint profiles collected under two different conditions ,25. FiguAgastache rugosa, Ajuga multiflora, Calamintha debilis, Galeobdo-lon chinense, Isodon nervosus, Lamium barbatum, Leonurus japonicus Lycopus lucidus, Mentha cana-densis, Mentha crispate, Mentha spicata, Mentha vagans, Monarda didyma, Ocimum basili-cum, Origanum vulgare Perilla frutescens, Physostegia virginiana, Prunella vulgaris, Salvia ele-gans, Salvia leucantha, Salvia miltiorrhiza, Salvia splendens, Salvia uliginensis meiliensis, Salvia uliginosa, Salvia cavaleriei, Stachys japonica, Elsholtzia cyprianii, Hyptis suaveolens, Rosmarinus officinalis, Vitex negundo, Buddleja lindleyana, Scrophularia ningpoensis, Peristrophe japonica, Asystasiella neesiana and Nepeta cataria. In the 2D density maps, the data-dense regions are highlighted. These highlighted areas represent that different fingerprints on the same interval of potential all show similar electrochemical correspondence. At the same time, some points with more dispersed data are weakened in the 2D density maps. Therefore, only the highlighted areas need to be located to correlate to the corresponding species.Similarly, the localization of the density of data points can be used for the identification of different species and is more effective than scatter plots. Agastache rugosa, Ajuga multiflora, Calamintha debilis, Galeobdo-lon chinense, Isodon nervosus, Lamium barbatum, Leonurus japonicus Lycopus lucidus, Mentha cana-densis, Mentha crispate, Mentha spicata, Mentha vagans, Monarda didyma, Ocimum basili-cum, Origanum vulgare Perilla frutescens, Physostegia virginiana, Prunella vulgaris, Salvia ele-gans, Salvia leucantha, Salvia miltiorrhiza, Salvia splendens, Salvia uliginensis meiliensis, Salvia uliginosa, Salvia cavaleriei, Stachys japonica, Elsholtzia cyprianii, Hyptis suaveolens, Rosmarinus officinalis, Vitex negundo, Buddleja lindleyana, Scrophularia ningpoensis, Peristrophe japonica, Asystasiella neesiana and Nepeta cataria. As can be seen in the figure, the heatmap has the whole graph segmented in addition to the highlighted regions. Therefore, in this case, in addition to locating hot areas, counting the number of hot areas can be used for the identification of different species. Overall, these previously established pattern recognition techniques can be used well for the identification of species in Lamiaceae. It can be seen from the different output patterns that the differences in the pattern of plants under different genera are greater than the previous differences between different species under the same genus [Heatmaps can improve the accuracy of pattern recognition even further based on 2D density maps. me genus ,27,28,29me genus ,31.Agastache rugosa, Ajuga multiflora, Calamintha debilis, Galeobdolon chinense, Isodon nervosus, Lamium barbatum, Leonurus japonicus, Lycopus lucidus, Mentha canadensis, Mentha crispate, Mentha spicata, Mentha vagans, Monarda didyma, Ocimum basilicum, Origa-num vulgare, Perilla frutescens, Physostegia virginiana, Prunella vulgaris, Salvia elegans, Salvia leucantha, Salvia miltiorrhiza, Salvia splendens, Salvia meiliensis, Salvia uliginosa, Salvia cava-leriei, Stachys japonica, Elsholtzia cyprianii, Hyptis suaveolens, Rosmarinus officinalis, Vitex negundo, Buddleja lindleyana, Scrophularia ningpoensis, Peristrophe japonica, Asystasiella neesiana and Nepeta cataria. After extracting three factors, PCA could reach 87% interpretation, indicating the electrochemical fingerprint contains representative information that can be used to represent different data sets. Since here we use 3D PCA, the distance between different species is difficult to measure. The distances between different species will be presented with dendrogram.Phytochemical taxonomy has always been a methodological approach in plant taxonomy . The basAgastache rugosa, Ajuga multiflora, Calamintha debilis, Galeobdolon chinense, Isodon grandifolous and Isodon nervosus. The second clade contains Lamium barbatum, Leonurus japonicus, Lycopus lucidus, Mentha canadensis, Mentha crispate, Mentha spicata and Mentha vagans. The third clade contains Monarda didyma, Ocimum basilicum, Origanum vulgare, Perilla frutescens, Physostegia virginiana, Prunella vulgaris, Salvia elegans and Salvia leucantha. The fourth clade contains Salvia miltiorrhiza, Salvia splendens, Salvia meiliensis, Salvia uliginosa, and Salvia cavaleriei. The fifth clade contains Stachys japonica, Elsholtzia cyprianii, Hyptis suaveolens, Rosmarinus officinalis, Vitex negundo, Buddleja lindleyana, Scrophularia ningpoensis, Peristrophe japonica, Asystasiella neesiana and Nepeta cataria.The entire phylogenetic tree is divided into five main clades . The firVitex negundo and Nepeta cataria from the Lamiaceae can be confirmed by recent molecular study. Ayaz et al. [Vitex negundo and Nepeta cataria showed genetically different from the rest of species from Lamiaceae. The close relationship between Buddleja lindleyana with genus Scrophularia was confirmed by the recent complete chloroplast genome analysis [Peristrophe japonica indicated its close relationship with Scrophularia and Asystasiella [Surprisingly, all five exotaxa were clustered in the last cluster. The distant affinity of z et al.  isolatedanalysis . Similartasiella .Mentha were clustered together, which fits well with the results of either classical morphological classification or molecular studies. Since the genus Mentha was established in 1753 by the Linnaeus, scholars have conducted extensive research on the genus in terms of morphology, cytology, physiology, biochemistry, phytochemistry and molecular biology. The chemical classification of Mentha is mainly based on monoterpene components. Pulotova [Mentha [Mentha. Since species of the Mentha share a greater similarity in chemical composition, they also possess minor differences in electrochemical fingerprinting and are thus clustered together. Khanuja et al. had analyzed the genetic relationships of 11 mint plants using RAPD technique with 60 random primers [Mentha arvensis and Mentha spicata were highly correlated by RAPD analysis. This is consistent with the conclusion we proposed. Isodon grandifolius and Isodon nervosus were clustered together, which is also consistent with previous molecular phylogenetic studies [All the plants of the genus Pulotova  classifiPulotova  also stu [Mentha . Murray  [Mentha  pointed  primers . Both Me studies ,45,46,47Salvia were clustered together in the same clade. The close relationship between Salvia meiliensis and Salvia miltiorrhiza can be confirmed by the chloroplast genome analysis, and they all belong to sub-genus Glutinaria [Salvia splendens did not exactly correspond to the results of the previous chloroplast genome analysis. Although the chloroplast genome analysis showed the close relationship of Salvia splendens to sub-genus Glutinaria, it belongs to sub-genus Calosphace, while its phylogenetic status showed a very close relationship to Salvia miltiorrhiza in our result. Since the remaining Salvia species were not included in the previously published molecular studies, our results could provide a direction for future studies. The complete chloroplast genomes analysis of Lycopus lucidus and Agastache rugosa showed they belong to tribe Mentheae of Lamiaceae family [Most species of utinaria . Howevere family . Our resIn conclusion, this work attempts to use fingerprinting collected with electrochemical biosensors for the identification and phylogenetic study of species in Lamiaceae. The results demonstrate that electrochemical fingerprinting is more effective in the identification of species of a family than previously in the identification of species of a genus. This observation is due to the fact that the phytochemical composition of species differs much more between genera than those in the same genus. In phylogenetic studies, electrochemical fingerprinting shows the potential to be studied among different genera."}
+{"text": "Interprofessional education (IPE) is critical in undergraduate medical student curriculum to promote teamwork, increase effective communication, and improve patient-centered care especially in medically underserved populations, including those living with HIV.Medical students participated in 2-week elective rotations at a freestanding, multidisciplinary HIV clinic providing comprehensive HIV care for more than 6,000 people in an urban, ethnically diverse, resource-limited population. The interprofessional faculty included physicians, pharmacists, case managers, social workers, service-linkage workers, substance use counselors, and medication access specialists. Students interviewed patients, rotated with at least four multidisciplinary health professionals at the clinic, and rounded with the HIV inpatient consult team and service linkage worker in the hospital. Each student completed a reflection paper on the barriers and facilitators of HIV care engagement. Student feedback was collected through course evaluations and debriefing sessions with course directors. Knowledge and ability to perform HIV-related services were assessed through student assessments at baseline and within 2 weeks of completing the rotation.IPE competenciesFrom January 20, 2020 to May 21, 2021, 17 medical students completed the 2-week elective . Student reflection papers demonstrated understanding of barriers to care, social determinants of health, and potential solutions to improve health outcomes. Open-ended feedback was positive, with many commenting on the benefits of learning from diverse healthcare professionals in HIV care. At follow up, 80% of students rated their knowledge of ideal functioning of interprofessional teams as very good or excellent. Students reported increased ability to deliver team-based care, provide services to culturally diverse people, and coordinate care for non-medical needs.Interprofessional education enhanced students\u2019 knowledge of care coordination, interprofessional communication skills, competency in teamwork, and understanding of socioeconomic barriers to care in an underserved population with HIV. All Authors: No reported disclosures"}
+{"text": "Polymeric nanocomposites have received significant attention in both scientific and industrial research in recent years. The demand for new methods of food preservation to ensure high-quality, healthy foods with an extended shelf life has increased. Packaging, a crucial feature of the food industry, plays a vital role in satisfying this demand. Polymeric nanocomposites exhibit remarkably improved packaging properties, including barrier properties, oxygen impermeability, solvent resistance, moisture permeability, thermal stability, and antimicrobial characteristics. Bio-based polymers have drawn considerable interest to mitigate the influence and application of petroleum-derived polymeric materials and related environmental concerns. The integration of nanotechnology in food packaging systems has shown promise for enhancing the quality and shelf life of food. This article provides a general overview of bio-based polymeric nanocomposites comprising polymer matrices and inorganic nanoparticles, and describes their classification, fabrication, properties, and applications for active food packaging systems with future perspectives. Nanoscience and nanotechnology have matured into extremely active, vital, and expanding fields of research for developing small particles with multidimensional applications in the areas of nutrition, agriculture, cosmetics, paints and coatings, personal care products, catalysts, energy production, lubricants, security printing, molecular computing, structural materials, drug delivery, medical therapeutics, pharmaceuticals, and diagnostics . The remPolymeric nanocomposites are produced by dispersing NPs or nanofillers into polymeric matrices. This reinforcement results in a matrix with unique, enhanced physical and mechanical properties . The comBiopolymers or biodegradable polymers are renewable natural resources generated from biological systems, such as plants, animals, and microorganisms, and/or chemically synthesized from the starting materials of natural fats or oils, sugars, and starch . NaturalFood packaging is a particularly critical step in the protection and preservation of food to ensure its safety and increase its shelf life. This factor plays a key role in the global food industry in terms of satisfying consumer demand for safe, fresh, high-quality, durable, and healthy food, along with addressing certain challenges such as cost efficiency, environmental issues, consumer convenience, and food safety regulations . Food paBiopolymer-based nanocomposites are a new type of material that exhibit considerably enhanced properties such as barrier, mechanical, and thermal characteristics, and have been considered as novel and alternative packaging materials . BiopolyComposite materials are produced by combining two or more distinct constituents or phases with different physical or chemical properties . Althougco-hydroxyvalerate) (PHVB), polyvinyl alcohol (PVOH), and PCL, which are polyesters produced by numerous microorganisms and the bacterial fermentation of sugars or lipids, are also similarly employed [Polymeric nanocomposites are a combination of a polymer matrix (continuous phase) and inorganic NPs (discontinuous phase) with at least one dimension at the nanometer scale. These composites exhibit improved properties compared to those of polymers, such as high strength, thermal stability, electrical conductivity, chemical resistance, flame retardancy, and optical characteristics . Commonlemployed . Variousemployed ,33,34. Aemployed . The uniemployed .Polymer nanocomposites can be categorized based on the dimensions of nanofillers , type of nanofiller , type of polymer matrix , and synthesis methods .Nanofillers can be categorized into zero- (0D), one- (1D), two- (2D), or three-dimensional (3D) nanoparticles according to their dimensions at the nanoscale .Zero-dimensional (0D) nanofillers have dimensions that are all within the nano-range, such as NPs, that is, they do not have any dimension beyond 100 nm. These nanofillers may be amorphous, crystalline, metallic, ceramic, or polymeric in nature , and incMetal or metal oxide NPs are homogenously dispersed or spread onto the polymer matrix to form a homogenous nanophase-separated structure that imparts the nanocomposites with flame retardancy and thermal stability. Silica, zinc, magnesium, titanium oxide, zirconium oxide, aluminum oxide, and iron oxide are typical examples in this regard . Metal-sAs the name suggests, thermoplastic resins are polymers that can be molded/softened under pressure and heat, and hardened by cooling. Thermoplastic resins exhibit remarkable properties such, as high strength, high moldability, and chemical resistance, remolding, and recycling characteristics. For example, PS, PA, polyethylene (PE), and polyvinyl chloride (PVC) form thermoplastic networks . ThermosNanocomposites are prepared by incorporating nanofillers into polymer matrices to provide or improve the barrier, thermal, and mechanical properties of polymers. Polymer nanocomposites can be formulated by various approaches, including in situ polymerization, melt processing, and solution blending or casting methods.This is an effective method that has been extensively used in the last few decades to prepare polymer nanocomposites. Typically, nanomaterials and monomers or multiple monomers are mixed in a suitable solvent, followed by polymerization with an appropriate reagent to yield polymer nanocomposites . This meThe melt processing technique is frequently used for thermoplastic polymers and is recognized as an economically viable, environmentally friendly, and green (solvent-free) technique. In this method, nanofillers or clay materials are incorporated into the polymer matrix by high-temperature annealing and rigorous mixing for a certain duration to encourage the intercalation and exfoliation of silicates, clay, or nanofillers, until a uniform distribution is achieved . The uniThis is the classical method for the production of polymer thin films with distinct thicknesses. In this technique, the polymer is dissolved in a specific solvent by continuous stirring, and the nanofillers are dispersed into the polymer solution to form a homogeneous mixture. This mixture is subsequently cast in a mold to evaporate the solvent and eventually yield thin films with polymer-oriented layers of intercalated clay . Both orThe properties of polymer nanocomposites based on their microstructure, such as the degree of crystallinity, polar or non-polar groups, the presence of an amorphous phase, and the degree of crosslinking, are correlated with their high aspect ratios, the nature of nanofillers, the chemistry of polymer matrices, and the preparation method. The uniform dispersion of nanofillers in polymer matrices is essential for achieving the desired physical and mechanical characteristics. The barrier, mechanical, thermal, optical, and functional properties of nanocomposites are important parameters in food packaging systems.max) for polystyrene nanocomposites [max, and heat resistance, and improves the shear resistance, exfoliation, and corrosion resistance [The primary intention of packaging is to preserve food from extrinsic deficiencies and influences, such as cracks and random breaks, in the packaging materials. The mechanical properties of polymers, such as strain at break, tenacity, and maximum stress, can be upgraded for use in food packaging systems . Therefomposites . An adeqsistance . Differesistance .Particle/polymer matrix interface plays the key role in determining the performance of advanced composite materials such as mechanical properties and dimensional stability. Interfacial adhesion occurs when two different materials such as particle and polymer matrix are blended or combined and create a better dispersion of materials into the matrices. However, the combination of materials must have the same properties, such as hydrophobic fillers and hydrophobic matrices or hydrophilic and hydrophilic materials to achieve a better interfacial adhesion and a strong bond between both materials . Recent Although polymeric materials offer several advantages in the packaging sector, a significant benefit is their intrinsic permeability to small molecules and other gases. Therefore, the loss of quality of packaged food products is due to either oxygen exposure or consistent changes in the movement of water vapor via the walls of the polymer packaging . The perE (Young\u2019s modulus) values and lower thermal expansion coefficients than those of the polymer components [Thermal properties are crucial for the use of polymeric materials in a variety of applications, including packaging for consumer products. The low thermal conductivity of polymers or the mismatch between the thermal expansion characteristics of fillers and polymeric components is a major technological barrier . Thermalmponents . Nanofilmponents .The propensity of materials to spread flame away from a fire source must be clearly understood, particularly for several thermoplastic materials, which tend to melt and produce flammable flow or drips, causing fire hazards. Therefore, the flame retardancy of polymeric materials must be improved by the incorporation of flame retardants . NanofilThe incorporation of nanomaterials into polymer matrices provides the possibility of remarkable improvements in the optical properties of polymeric nanocomposites. The unique optical properties of nanomaterials are associated with the effects of dielectric restriction, dimensional quantization, and the excitation of local surface plasmons . The spePetroleum-based polymers have the ability to satisfy all the packaging requirements of the food industry. However, they are non-biodegradable, non-renewable, or non-compostable, which can lead to serious issues related to disposal and waste generation worldwide, consequently leading to environmental damage. Therefore, the research on packaging must be focused on promoting and developing bio-based plastics that are alternatives or replacements for fossil fuels or synthetic polymers to effectively minimize waste disposal . Biodegrco-terephthalate (PBAT), and polybutylene succinate-co-butylene adipate (PBSA)) [Biopolymers can be classified into the following groups based on the origin of the raw materials (renewable or non-renewable) and their manufacturing process : natural (PBSA)) ,77.Biopolymers are regarded as the most promising materials for food packaging applications. However, they generally exhibit poor barrier and mechanical properties with regard to processing ability and end-use applications. In particular, the high gas and vapor permeability, brittleness, low heat-distortion temperature, and poor resistance to protracted processing operations of biopolymers significantly limit their industrial applications . HoweverThe plastic industry promised to be a boon compared to other industries in its initial stages. Recent research and developments focused on the production and optimization of bio-derived products from various plant matters or biomass in a sustainable and economical way. Nevertheless, biopolymers occupy their own position and have the largest market share in plastic industries. Besides biodegradable plastics, natural biopolymers from polysaccharides and polypeptides have also been widely used for their biostability, sustainability, mechanical properties, biocompatibility, and minimum cytotoxicity in food packaging and other multifarious applications . However2, SiO2, TiO2, Fe2O3, and Al2O3), layered double hydroxides, nanotubes (CNTs), fullerenes, nanorods, and salts, are typically employed as nanoreinforcements [The incorporation of functional nanomaterials into polymer matrices can assist in the development of food packaging materials with improved mechanical and barrier properties. Moreover, the fundamental properties of packaging materials, such as flexibility, durability, resistance to temperature and humidity, and flame resistance, can be further altered by the addition and modification of different nanomaterials to improve the shelf life and quality of the food products . Differercements . Among trcements .Clay and silicates are natural inorganic compounds with variable chemical compositions, relative simplicity, and low cost, which have attracted research attention as potential nanomaterials owing to their availability and barrier, mechanical, and thermal properties. The combination of clays/silicates and polymers yields superior barrier properties and lengthens the diffusive path for infiltrating molecules. Nanoclays can be categorized into several subclasses, including montmorillonite (MMT), kaolinite, bentonite, halloysite, hectorite, sepiolite, and cloisite . Prior t2, SiO2, and MgO, have been examined for diverse active-food-packaging applications. The properties of metal and metal oxide nanomaterials, such as mechanical strength, thermal and chemical stability, gas and water barrier properties, heat resistance, biodegradability, and active antimicrobial activities, have led to an improved performance in active food packaging applications [CNTs, such as single-wall carbon nanotubes (SWCNTs) or multi-walled carbon nanotubes (MWCNTs), have also been incorporated into various polymers such as PVA, PA, and PET. CNTs also exhibit antibacterial properties, which are associated with their direct penetration of microbial cells and chemiresistive sensing . Starch ications . VariousActive and intelligent packaging are two forms of smart packaging that have been recently developed to enable the marketing of food products and provide passive protection against environmental conditions and contamination to extend the shelf life of food products. An active packaging material is a neat or modified substance that increases the shelf life of food products or enhances their safety or sensorial properties to maintain their quality . Active Intelligent packaging materials apply intelligent functions related to responsive packaging throughout the food supply chain, which include locating, registering, detecting, communicating, monitoring, and applying scientific logic. Therefore, these materials can trigger alerts for consumers by detecting microorganisms and food spoilage, extend shelf life, ease decision-making, improve the quality and safety of food, provide information, and warn of possible problems . In addi2), natural biopolymers (chitosan), organic nanoclay (Ag-zeolite and MMT), enzymes (peroxidase and lysozyme), natural bioactive compounds , and synthetic agents  [Antimicrobial packaging is a robust technology that protects packaged food products from spoilage, which can occur via contamination by food-borne pathogens , leading to food-borne diseases . This tyc acids) .Salmonella spp., Staphylococcus aureus, Staphylococcus epidermis, Escherichia coli, Listeria monocytogenes, Pseudomonas aeruginosa, Enterococcus faecalis, Vibrio cholera, and Bacillus cereus, are responsible for food spoilage. In addition, Aspergillus and Rhizopus (molds), and Candida and Torulopsis (yeasts) are also involved in foodborne infections [S. aureus and E. coli [E. coli, B. cereus, S. aureus, and Micrococcus luteus [2) and GC-SiO2-octadecyldimethyl-(3-trimethoxysilylpropyl)-ammonium chloride (ODDMAC) nanocomposites were effective against B. cereus and S. aureus [E. coli in white-brined cheese [Different species of Gram-negative and Gram-positive bacteria, including fections . A few r E. coli ; cellulo E. coli . AuNPs ws luteus . Gellan . aureus . Chitosad cheese . Table 3Nanomaterials or nanocomposites can be employed as antimicrobial agents, growth inhibitors, antimicrobial carriers, and antimicrobial packaging films. Antimicrobial bio-nanocomposite films are applied as food packaging materials primarily for cheese, meat, bread, fish, poultry, vegetables, and fruits . These nNanocomposites have a remarkably positive zeta potential, which promotes their interaction with cell membranes by electrostatic binding to cell walls and releasing metal ions. The negatively charged bacterial membranes and positively charged nanocomposites induce electrostatic attraction and modify the permeability of the cell membrane. Therefore, disrupting the integrity of bacterial membranes is an efficient mechanism of action . ROS proFood packaging plays a critical role in protecting food products from external contamination and maintaining their quality, integrity, and safety throughout their shelf life. Synthetic-polymer-based materials are predominantly used as packaging materials in the food industry because of their ease of production, versatility, affordability, functionality, and properties of low weight, flexibility, and low cost. However, these synthetic polymers are non-degradable, and most of the plastic waste and debris heavily pollute the environment. This necessitates the development and use of biodegradable polymer materials to resolve these environmental problems. Bio-based polymers or renewable-resource-based biopolymers, such as cellulosic plastics, starch, corn-derived plastics such as PHAs, and PLA are sustainable, high-performance materials with tremendous potential for replacing conventional petroleum-based food packaging materials. However, biopolymers have certain disadvantages compared to synthetic polymers, such as inferior thermal and mechanical properties (tensile strength and brittleness), moisture sensitivity, and water-vapor barrier performance.2, graphene, and carbon dots, in bio-nanocomposite films enables their use as new active packaging materials to improve the quality and safety of food products over a longer period. Nanosensors for intelligent packaging can be designed to control the internal  and external conditions of food products (detecting atmospheric influences).The use of nanotechnology in the food sector can ensure food quality and safety by enhancing the potency of food packaging and the shelf life of food products. The application of nanotechnology to develop novel food packaging functions can enable enhancements in the properties of food, such as taste, healthiness, and nutritiousness via the packaging. The incorporation of nanoparticles or nanofillers in food packaging materials can improve various properties of biopolymers, such as mechanical properties, barrier properties against water and oxygen, protection against UV radiation, absorption of moisture, release of antimicrobials, and other environmental factors. The biodegradability of these nanocomposites can be modified by selecting appropriate polymers and nanomaterials to yield desired properties and enable their application in food packaging. In addition, biologically active substances, such as antimicrobials, growth inhibitors, and antimicrobial carriers, can be added to enable the desired functional properties. These nanocomposites can be modified by incorporating either organic or inorganic antimicrobial agents that exhibit excellent antibacterial activity against both Gram-positive and Gram-negative food-borne pathogens. The inclusion of antibacterial NPs, such as Ag, MgO, ZnO, TiOThe present review provides information related to the development of bio-based polymeric nanocomposites to improve the quality, safety, and shelf life of packaged food products. However, further research should focus on the effects of combinations of nanomaterials, such as bi-, tri-, and multi-metallic nanocomposites, to achieve better results. In addition, the molecular interactions of biopolymers with food matrices and the formulations of nanomaterials in polymer matrices to minimize organoleptic effects should be investigated. Furthermore, standard methods and probable toxicity evaluations of nanofillers and biopolymers should be established. Current toxicity tests have revealed that the toxicity of nanomaterials primarily depends on their size, shape, surface-to-volume ratio, doping concentration, and duration. Future research on active packaging must focus on improving the safety of nanomaterials, owing to the limited studies on the possible toxic influence of these packaging films. In addition, health and safety aspects, the management of environmental issues, and a hazard and risk assessment must be considered prior to their application as safe and effective food packaging materials. The use of these modern and alternative preservation techniques can significantly inhibit pathogens, extend the shelf life, and fulfill consumer demands such as the high quality, convenience, safety, freshness, taste, aroma, color, and texture of packaged food. These biopolymer-based nanocomposites exhibit tremendous potential for a wide range of applications in the food industry as sustainable, cost-effective, active, and intelligent packaging materials for food preservation."}
+{"text": "The COVID-19 pandemic has halted activities in the global tourism industry, and the situation has only been worsened by the general air of uncertainty and lack of effective vaccinations. Consequently, people have begun testing various remedies to enhance their immunity, primarily turning to traditional medical practices and home remedies. The medicinal use of spices, given their immune-boosting properties, is increasingly popular globally and has enhanced global awareness of spices and their products. In light of this surging popularity, this study examines spice tourism as a concept of niche tourism. This study proposes spice tourism as a valuable post-COVID-19 strategy by providing four different approaches to position spice tourism within special interest tourism. This paper also suggests a tourism development plan for spice tourism and proposes a strategy for its resilience post-COVID-19. As a significant tourism resource, food is firmly related to tourism in several ways, in that food strengthens and is key to the visitor\u2019s experience. Food has played a leading role in tourism decision-making and experience, tourism goods, and lobbying campaigns, and it can act as a valuable tool for destination development. Thus, tourists and the tourism sector around the world share valuing cuisine. However, specific issues require resolution to ensure that guest standards are fulfilled and even surpassed . Food haCuisines act as both a push and a pull factor of travel motivation, on the one hand, \u201cpushing people away from their familiar foods and eating patterns and pulling them toward new and exciting foods\u201d . HoweverMoreover, a nation\u2019s cuisines are an integral part of destination branding, marking, and acting as factors in the destination\u2019s distinctiveness. This cultural significance of food often creates identity and image for many destinations\u2014for instance, kimchi in South Korea, samosa in India, and pizza in Italy. Ethnic food and cuisine could be a great tourism draw for rural destinations; consuming regional cuisine also could play an essential role as a leisure and cultural practice .Related research covers the spectrum of food-based tourism experiences across several product categories, such as speciality tourism, agritourism, culinary tourism, food-tourism destinations, and incentive schemes to purchase food . PromotiFood tourism forms, such as tea, coffee, beer, or spice tourism, are promoted with their specificities. For example, tea tourism is connected with tea diplomacy, concerning tea\u2019s presence and popularity in diplomatic meetings and conferences. Similarly, this paper tries to position spice tourism as concerning the health benefits of spices. Compared to other food tourism, spice tourism is currently an unresearched area, yet with great potential for becoming a top attraction. Thus, the development of synergy and the introduction of efficient marketing approaches to enhance regional food items and tourism have enabled regions to grow into unique destinations . Spices Given the international health crisis resulting from the COVID-19 pandemic, concerns are being raised about its short-term and long-term impacts on the tourism sector . ChangesTo this end, the COVID-19 pandemic has also appeared to (re)create demand for several forms of special interest tourism (SIT) is predicted to grow as a trend. These changes can be both positive and negative. As an example, while COVID-19 troubled cruise tourism, luxury tourism is precited to be a trendsetter. Similarly, spice tourism could be considered an emerging sector of SIT post-COVID-19. Spice tourism could be expanded due to spices\u2019 immunity-boosting properties\u2014specifically Indian kitchen spices such as turmeric, cardamom, fenugreek, garlic, and pepper. However, compared to other forms of plantation or food tourism, spice tourism is relatively unexplored within tourism landscapes and is still in its infancy as a topic of study .This momIf adequately marketed and developed, spice tourism could become one of the most prominent special interest tourism (SIT) forms globally. Rural agrarian efficiency is facing severe difficulties due to the pandemic, and this could help revive the tourism sector in spice-producing nations with substantial rural facilities in the developing world. The following section describes four approaches to develop spice tourism within the current industry.Despite rapid advances in technology and research, spices have maintained their value in both the culinary and pharmaceutical industries. Many spices have antimicrobial, anti-inflammatory, and anticarcinogenic properties \u201319. ThesToday, herbs and spices are consumed as functional foods. A World Health Organization (WHO) survey found that 70\u201380% of the world population depends on modern medicine sourced mainly from herbs for primary healthcare . LikewisIn food and beverages preparation, spices can be used whole-dried, powdered, or as a paste. Spices are an essential component of human nutrition and contain essential proteins, fibers, fats, essential oils, minerals, and pigments, apart from bioactive compounds such as phenolic acids, sterols, and pungent substances piperine, and capsaicin , buds (clove), bark (cinnamon), rhizomes , berries (black pepper), seeds (cumin), or even flower stigma (saffron).Cumin seeds have been used to treat colic pain, abdominal discomfort, flatulence, deficient lactation, piles (hemorrhoids), and worm infestation .Turmeric rhizomes have traditionally been used for skin diseases, blood impurities, coughs, asthma, insufficient lactation, obesity, and diabetes .Ginger and garlic are widely used spices in every household and are cultivated throughout India, particularly along the Western Ghats. Its rhizomes have traditionally been used to treat anorexia, colic pain, coughs, asthma, piles, pyrexia, and rheumatic diseases. Garlic bulbs were also used as medicine for rheumatism, colic pain, worm infestations, anorexia, and obesity .Cardamom and cinnamon have been used to cure bad breath, vomiting, excessive thirst, weakness, pyrexia, and burning sensations . CinnamoPungent cloves and black pepper have been used to treat dental and oral diseases, throat infections, coughs, asthma, hiccoughs, colic pain, and anorexia, pyrexia obesity, and liver disease .Bay leaves have traditionally been used for urinary, pyrexia, rheumatic, and anorectic disorders .Curry leaves have traditionally treated diabetes, dysentery, anorexia, and flatulence .Nutmeg fruits and seeds have traditionally been used to treat dysentery, sexual disorders, and weakness.Mustard seeds have been used in treating skin diseases, dental disorders, worm infestations, obesity, dry skin, and anorexia.Various anise-scented spices have been used medicinally. Carom seeds have been used for flatulence, anorexia, diarrhea, colic pain, abdominal distress, flatulence, worm infestations, chronic fevers, and asthma. Star anise has historically been used for treating abdominal pain, flatulence, worm infestations, persistent fevers, and asthma. Fennel seeds have been used to treat colic pain, anorexia, difficult labor, and deficient lactation .Saffron flowers were used to treat bleeding disorders, vertigo, inflammation, skin and eye diseases, and headaches .In Ayurveda, a conventional and ancient medicine system, many Indian kitchen spices are used and applied as immune-boosting ingredients; these spices deliver a wide array of health benefits to consumers\u2019 various needs. Spices of Indian origin have flexible properties and are commonly used from the kitchen to the clinic. For instance:During the COVID-19 pandemic, the medicinal properties of spices are becoming increasingly recognized. This can perhaps be attributed to uncertainties about the coronavirus\u2019s genetic mutations and strains, as well as the lack of any effective vaccines thus far. The resulting panic has incited people to try home remedies or natural medicines to boost their immunity. This can be one reason for the steady increase in spice exports in the global spice market since mid-June 2020. This moment could be used as an opportunity to enhance opportunities for spice tourism through effective marketing. Notably, spices are an integral part of many traditional medicines and wellness treatments that are now in high demand in medical tourism.Spices constitute many countries\u2019 agricultural commodities, and they are essential to the culinary industry. Spice tourism is a type of \u201cagro-tourism\u201d that allows guests to acquire expertise and knowledge of various spices while exploring practices surrounding their cultivation and enjoying their fragrances. As an underdeveloped sub-sector of agro-tourism, attractions in spice tourism operate in the same context as similar tourism forms. However, it is likely a type of tourism that most tourists have never previously seen nor experienced. \u201cAt least 60 species of spice and herbs with its special value, in which these species have opportunities to conceived as tourism\u201d .Spice tourism can also contribute to the development of sustainable rural tourism . Rural tTraditional foods and ancient foodways are deeply rooted in many cultures\u2019 traditional lifestyles and form essential parts of food-associated tourism . Spices The use of herbs and spices has been documented since ancient Egypt, and they have been used for centuries in India and China. \u201cExploration, trade, and wars were related to the search for spices contributing to the establishment of spice trading routes. Through colonization and migration space, cultivation was spread around the world\u201d . There aThe Spice Route Project by Kerala Tourism guides tourists and travelers along a 2000-year-old trade route, one of many that connected ancient South India with approximately 30 countries worldwide. UNESCO recently recognized the project, and the Netherlands, Portugal, Myanmar, Britain, Iraq, Afghanistan, Iraq, Indonesia, China, and Iran all consented to these initiatives. Archeological excavations at Muziris  unearthed concrete evidence that Muziris had traded with the West; these discoveries kicked off the Spice Route Project. This project aims to educate people on the history of the region and open opportunities for east-to-west travel. This has the potential to strengthen international relations and help promote shared heritage through tourism.The health benefits and immunity-boosting properties of spices could be exploited to reformulate spice tourism. Many Indian kitchen spices are regularly used as immune-boosting ingredients in traditional and Ayurvedic medicine; these spices continue to offer ample health benefits for consumers\u2019 various needs. COVID-19 has been found to affect those with weaker immune systems, particularly the elderly. The immune system is based on live microbiota that shields the body against infectious illnesses. Several studies suggest that plant-based foods enhance and strengthen protective microbial populations and gut microbiome\u2019s general health, comprising 85% of the human immune system .Herbs and spices are renowned for boosting immunity. Immunity-building functional foods such as garlic, turmeric, ginger, ashwagandha, herbal tea, and intensely antioxidant-rich fruit have the potential to enhance immunity, and that people should more greatly incorporate these products into their diets .In conjunction with these epidemiological survey, the demand for Indian spices skyrocketed in mid-2020, with spice sales increasing 23%, or by $359 million, in June of 2020 , 39 FurtThis paper recommends several product development strategies for spice tourism Fig. . First, There are many opportunities for developing or reformulating spice tourism, especially in light of growing demand. Many countries already have spice tourism projects or have identified their potential. These projects can be centered on the specific local spices growing in a region  or highlight many spices collectively in tourist attractions . In whatever form they take, infrastructure development and adequate marketing are crucial moving forward."}
+{"text": "Americans, on average, can anticipate living 85 years or perhaps 100 if born in this millennium. This extension of the lifespan has introduced a new stage of human development presenting unfamiliar challenges to policy makers, health care providers, employers, religious institutions, families, individuals, and schools. Education about longevity should begin in adolescence (ages 10-20) with the merger of science, experiences of older generations, and imagination of youth. Content of this online course focuses on the years after adolescence: early adulthood, middle age, retirement, and old age. After reading each of the 16 lessons, cooperative learning teams conduct structured interviews with older relatives, friends or neighbors who are further along in life's journey. All the lessons are augmented by 'what do you think? tasks used to motivate discussions, structure interviews, decide on reasoning and problem-solving scenarios, identify key concepts to apply, group lesson reviews, and self-evaluation for comparison with peers. If society wants to encourage adolescents to appreciate their national and ethnic heritage, benefit from learning how older generations see situations and interpret current events, and acknowledge the common need for maturity and spiritual development, then older people should become resources for education about longevity."}
+{"text": "Sleep disturbances, such as insomnia, obstructive sleep apnea, and daytime sleepiness, are common in people diagnosed with epilepsy. These disturbances can be attributed to nocturnal seizures, psychosocial factors, and/or the use of anti-epileptic drugs with sleep-modifying side effects. Epilepsy patients with poor sleep quality have intensified seizure frequency and disease progression compared to their well-rested counterparts. A better understanding of the complex relationship between sleep and epilepsy is needed, since approximately 20% of seizures and more than 90% of sudden unexpected deaths in epilepsy occur during sleep. Emerging studies suggest that neuroinflammation,  may be a potential link between sleep deprivation and seizures. Here, we review the mechanisms by which sleep deprivation induces neuroinflammation and propose that neuroinflammation synergizes with seizure activity to worsen neurodegeneration in the epileptic brain. Additionally, we highlight the relevance of sleep interventions, often overlooked by physicians, to manage seizures, prevent epilepsy-related mortality, and improve quality of life. Sleep is one of the most basic homeostatic processes of human life. It can be defined as a condition of rest with suspended consciousness and is a necessary biological function with numerous restorative effects on brain function. In 2015, the National Sleep Foundation announced 7\u20139 h as the updated daily sleep duration recommended for healthy adults . R. R221]. Multiple signaling pathways play a role in the neuroinflammatory response associated with epilepsy, including danger signals release, pro-inflammatory cytokine production, and glial activation  7,216,2,221,222.High mobility group box-1 (HMGB1), a ubiquitous nuclear protein, is one of the many danger signals released by immune cells or necrotic cells after brain injuries. Several studies have reported elevated HMGB1 levels in the serum/plasma/CSF ,234,235 Besides inflammasome activation and pro-inflammatory cytokine production, seizures induce other inflammatory mediators, such as cyclooxygenase-2 (COX-2). COX-2, a critical mediator of the inflammatory response, is constitutively expressed in hippocampal and cortical neurons. Within hours after status epilepticus (SE) onset, COX-2 is induced in neurons, and its upregulation persists up to several days after SE . COX-2 iIn addition to danger signals, seizures cause the extracellular release of toxic molecules, such as ATP, reactive oxygen species (ROS), or glutamate, which can also activate microglia. Activated microglia produce pro-inflammatory mediators , which in turn transform resting astrocytes into reactive astrocytes . ActivatBesides their role in neuronal excitability and inflammation, recent studies have shown that glia cells can also be protective ,264. On The BBB, composed of endothelial cells, astrocytes, pericytes, and microglia, acts as a selective barrier between the periphery and the brain . SeizureEmerging research suggests an important role for numerous upregulated/downregulated miRNAs in seizure-induced neuronal death/apoptosis, excitatory/inhibitory neurotransmission, and neuroinflammation ,279. ForTherapies interfering with HMGB1/TLR4, NF-\u03baB, IL-1\u03b2, COX-2, PGE2/EP2, and TGF-\u03b2 signaling pathways, and other inflammatory targets have been proposed to treat epilepsy ,221,254.Multiple studies demonstrate that sleep disturbances activate the immune system. Once activated, the immune system triggers an inflammatory response, which, depending on its magnitude and time course, can induce either a longer sleep duration or a disruption of sleep ,193. TheAn early diagnosis and treatment of specific sleep disturbances in PWE are key for improving clinical outcomes and quality of life ,19. HereSurgical treatment  of refractory epilepsy significantly improved sleep quality , as wellA steady energy level may reduce seizures in some PWE. The ketogenic diet, a dietary treatment consisting of a high fat and low protein/carbohydrate content, has been shown to be beneficial for intractable epilepsy ,300,301 Recent studies have found a positive association between OSA and SUDEP risk in PWE, suggesting that screening symptoms for OSA could reduce epilepsy-related mortality, and lead to more effective treatments ,336. PosThe role of melatonin, a pineal hormone involved in the regulation of the sleep\u2013wake cycle, has been extensively investigated as an alternative treatment for sleep disorders in PWE, especially pediatric patients ,348. UnfChronotherapies and personalization of treatment schedules to accommodate sleep-related epilepsy also provides a useful avenue for personalized seizure prevention ,353,354.Cognitive behavioral therapy (CBT) for insomnia has shown some promising results in PWE . HoweverThe effects of various AEDs on sleep efficiency have been previously revised ,360,361.Sleep is essential for cleaning the brain and maintaining its normal functioning. People with epilepsy often have a reduced sleep duration and poor sleep quality. Nocturnal seizures, psychosocial stress, and the effects of antiepileptic drugs, are the main underlying causes of sleep disturbances in people with epilepsy. The most common sleep disturbances are insomnia, obstructive sleep apnea, and excessive daytime sleepiness, which negatively impact seizure frequency and quality of life (discussed above). Unfortunately, there are methodological limitations for epilepsy patients in the clinic, including a lack of a detailed medical history, inaccurate tools to diagnose sleep problems, and misinterpretation of apneic events as seizure activity, to name just a few. If untreated, sleep disturbances lead to cognitive decline, impaired memory, and comorbid psychiatric conditions  that worsen sleep quality and epilepsy .The molecular and cellular mechanisms underlying sleep disturbances in epilepsy include but are not restricted to neuroinflammation. Damaged neurons release danger signals, which trigger peripheral and brain inflammatory responses, promoting loss of BBB integrity, leukocyte infiltration into the brain, microglial and astrocytic activation, and pro-inflammatory mediator production. Numerous clinical studies demonstrate that PWE and comorbid sleep disturbances have higher levels of inflammatory markers, correlating with a higher frequency of seizures as compared to PWE who experience good-quality sleep. There are limited studies combining animal seizure models with sleep deprivation; however, findings showed that sleep deprivation similarly increases seizure frequency and exacerbates neuroinflammation. Therefore, therapeutic agents targeting inflammatory signaling pathways could be promising candidates for disease modification in treating epilepsy and should be further investigated for their efficacy in controlling seizures and sleep disturbances in PWE. The findings summarized in this review suggest that routine assessments of systemic inflammatory markers could be useful for identifying existing sleep disturbances in PWE. Furthermore, additional preclinical and clinical studies are urgently needed to definitively clarify the role neuroinflammation plays in the relationship between sleep disturbances and epilepsy progression. With further investigation of this mechanistic pathway, the field will get closer to achieving the ultimate goal of finding useful disease-modifying agents for patients with epilepsy."}
+{"text": "Team-based learning (TBL) was chosen for its learner-centered approach to intentional engagement and purposeful application of course material in a cross-listed, upper-level gerontology class . Intedashboard, an online TBL platform, was utilized to support the online synchronous course, which is especially useful for its integration of class material, module assessments, peer/course evaluations, and dashboard display of live team activity. From the perspective of an emerging scholar, this symposia session will explore the application of TBL as a tool for developing teams, helping students personally connect with course material, and support inclusive teaching initiatives. More specifically, this presentation examines how a scaffolded TBL exercise on cumulative advantage/disadvantage, intersectionality, and social identities led to increased identification and awareness of students\u2019 social location, and the perceived impacts on their later lives."}
+{"text": "Introduction. Primitive malignant heart tumours are rare, specific cases. The presence of cardiac metastases, often in the pericardium, besides indicating disseminated oncological disease, represents a diagnostic challenge since they tend to be asymptomatic. Malignant cutaneous melanoma (MCM) is the neoplasm that most often affects the heart. Patients and Methods. The authors describe a case report of a 59-year-old female patient with a history of non-insulin-treated diabetes mellitus, arterial hypertension, dyslipidemia, and remitting cutaneous malignant melanoma who underwent skin excision, lymphadenectomy, and adjuvant chemotherapy in 1996. In April 2014, she resorted to emergency service due to epigastric pain and progressive tiredness. Due to the persistence of the complaints, abdominal ultrasound was performed, which showed a large pericardial effusion, corroborated later by teleradiography and echocardiography. The patient underwent pericardiocentesis, which isolated neoplastic cells. A computed tomography study of the chest, abdomen, and pelvis revealed bilateral and pericardial pleural effusion, as well as alterations suggestive of pericardial and pulmonary metastasis. Later, fine-needle aspiration puncture of the left posterior cervical nodule confirmed histologically malignant melanoma metastasis. Discussion. Given the natural history of melanoma that when metastasized has an overall survival of 15\u201320% for 5 years, its metastatic spread may occur several years after its surgical excision. Thus, patients with a history of melanoma and heart failure who develop new cardiac symptoms of unknown aetiology should undergo imaging studies such as echocardiography, computed tomography, and magnetic resonance imaging. Primary cardiac tumours are specific cases, and in adults, the most frequent malignant tumours are angiosarcomas, rhabdomyosarcomas, and fibrosarcomas \u20133. RegarThe heart and pericardium are often affected in the context of disseminated metastatic tumour , 4\u20136. SeThe main malignancies with frequent cardiac involvement are the lung and breast cancers, mainly due to their anatomical proximity and high prevalence , 2, 6, 7Cardiac metastases indicate a state of advanced oncological disease, which usually are asymptomatic , 5. In sCardiac tamponade as the first manifestation of neoplasia is unlikely since, in addition to pericardial infiltration by malignant cells, the presence of other circumstances, such as an acute event or even lymphatic obstruction, is necessary , 6.A 59-year-old female patient presented with a personal history of non-insulin-treated diabetes mellitus, dyslipidemia, and hypertension, usually medicated with metformin, perindopril, and simvastatin.The patient attended to emergency service (ES) due to epigastric pain and feeling of fullness, for which was submitted to dioctyl sulfosuccinate enema and later discharged. Due to the persistence of the complaints and, now, with progressive tiredness, the patient frequented the ES two days later, where she underwent an abdominal ultrasound, which revealed pericardial effusion.Objectively, on admission, the patient was conscious, oriented, collaborative, eupneic at rest and hemodynamically stable with rhythmic heart tones, no murmurs, decreased vesicular murmur in the right pulmonary base, free and defenceless abdomen, and lower limbs without oedema.The patient displayed on electrocardiogram a sinus rhythm, 90\u2009bpm heart rate, low amplitude QRS complexes, and nonspecific alterations in ventricular repolarization; chest X-ray was performed with increased cardiothoracic index and bilateral pleural effusion, especially at the base of the right hemithorax; echocardiogram was with large pericardial effusion \u201cswinging heart\u201d and partial collapse of the right heart chambers. The patient is admitted to the cardiac intensive care unit, in the context of cardiac tamponade.During hospitalization, the patient underwent: pericardiocentesis, with a total drainage of 1250 cc, whose fluid, according to the pathological anatomy, evidenced neoplastic cells. She also underwent a thoracic-abdominal-pelvic computed tomography which revealed bilateral pleural effusion, with adjacent parenchymal atelectasis, slight pericardial effusion , and zonDuring hospitalization, the patient had several periods of paroxysmal atrial fibrillation, despite chemical cardioversion with amiodarone. The patient was discharged with oral anticoagulation and digoxin, as an effective heart rate management agent.Melanoma most often affects the heart . Its carPericardiocentesis besides being lifesaving in the context of cardiac tamponade also allows establishing the etiological diagnosis. Treatment in these scenarios is limited to serous sclerosis or the establishment of pericardial windows .New therapeutic regimens for malignant cutaneous melanoma (MCM)\u2014immunotherapy, BRAF, and MEK inhibitors\u2014demonstrated a significant improvement in relapse-free survival, although they are associated with cardiotoxicity. Among the documented adverse effects, the prolongation of QTc implies a monthly electrocardiographic evaluation .The authors intend to emphasize that given the natural and unpredictable history of melanoma, the patient's history must be taken into account. Cardiac events can occur several years after surgical excision of skin melanoma , 5.Due to the abovementioned conditions, all patients with the diagnosis of MCM should be followed and treated by a multidisciplinary team with Oncologists, Cardiologists, Radiologists, Endocrinologists, Surgeons, and Internal Medicine specialists, for proper treatment of the disease and adverse events from its' treatment."}
+{"text": "Moving from concept to quantitative measurement can be complex. There were several challenges in co-designing measures to assess the impact of Age-Friendly Care, PA, a geriatric workforce enhancement program. First as a FQHC, our clinical partner had not captured the metrics of interest. Second, the co-developed operational definitions for our metrics should be feasible, relevant, and useful for all project members. Third, funder reporting requirements must also be addressed. Working within this context, we co-created 11 outcome indicators structured around the 4Ms (IHI) now with 9 months of data. EMR changes to make data reportable included measuring opioid misuse mitigation, high-risk medication elimination, cognitive assessment and dementia care management, advanced care planning, care partner presence, annual wellness visit completion, pneumonia vaccination rates, colorectal screening rates, mobility goal tracking, and presence of a caregiver. Work continues around formulating themes to create a reportable mechanism for assessing What Matters."}
+{"text": "Following the publication of the original article , the autThe incorrect author names are: Bozzola Elena, Carsetti Rita, Piano Mortari Eva and Villani Alberto.The correct author names are: Elena Bozzola, Rita Carsetti, Eva Piano Mortari, and Alberto Villani.The author group has been updated above and the original article  has been"}
+{"text": "Concurrent chemoradiation therapy (CRT) is the standard of care for patients with unresectable stage II/III lung cancer. However, systemic chemotherapy is required for patients who are ineligible for radical radiation therapy. There is little evidence to date for the safety and efficacy of CRT administered after treatment with immune checkpoint inhibitors (ICIs). The cases reported here had inoperable stage III lung cancer  and were ineligible for radical radiation therapy. They were administered ICIs plus chemotherapy and subsequently underwent late concurrent CRT. Because of the remarkable tumor shrinkage achieved by the ICIs plus chemotherapy, adverse events of CRT were tolerable. They were alive without tumor progression as of this report, over 1\u2009year after CRT was terminated. CRT is administered with curative intent, while the intent of immunochemotherapy is palliative. Late concurrent CRT after immunochemotherapy is probably effective and tolerable. After treatment with systemic chemotherapy in patients judged ineligible for radical radiation therapy, radiation therapy should be reconsidered because of its importance once tumor shrinkage has been achieved. Late concurrent chemoradiation therapy following systemic therapy (immunotherapy or immunochemotherapy) should be considered as an important treatment option for patients initially judged ineligible for definitive chemoradiation therapy. Chemotherapy combined with thoracic radiotherapy improves the prognosis of patients with non\u2010small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).ICIs are currently the foremost treatment strategy for patients with advanced lung cancer. Notably, combining ICIs and platinum\u2010based chemotherapy achieves favorable tumor responses and prognosis compared with standard chemotherapy administered to patients with advanced NSCLC and SCLC.The first patient was a woman in her 60s who was diagnosed with stage IIIB NSCLC (cT4N2M0 according to the eighth edition of the TNM classification).The second patient was a man in his 60s who visited our hospital because of a chronic cough and mild respiratory difficulty. He was diagnosed with SCLC on the basis of histological analysis of a transbronchial biopsy. Enhanced CT and PET revealed a primary tumor in the right upper lobe and showed multiple lymph node metastases in the right mediastinum and right hilum. Pleural effusion was also noted. A cytological examination did not find malignancy in the pleural effusion, and he was therefore diagnosed with limited\u2010stage SCLC.The lung V20 in the radical radiation field was >35% (V20 was approximately 50%), and the patient was treated with systemic immunochemotherapy (atezolizumab + CBDCA + etoposide [ETP]). After two cycles of immunochemotherapy, marked shrinkage of the tumor was observed on CT, including the primary site and lymph nodes, which involved 15.0% of the lung V20. After completion of immunochemotherapy, the patient underwent concurrent CRT  (Figure\u00a0Here, we report the cases of two patients who received late concurrent CRT subsequent to ICI plus platinum\u2010based chemotherapy for locally advanced NSCLC and SCLC. Remarkable tumor volume shrinkage in each case was induced with immunochemotherapy before CRT, allowing both patients to undergo successful radical radiation therapy with tolerable AEs.The preferred treatment for locally advanced NSCLC or stage III SCLC combines chemotherapy with radical radiotherapy. Although concurrent CRT should be considered first, the Royal College of Radiologists recommends sequential chemotherapy and radical radiotherapy as an appropriate treatment option if the patient is insufficiently fit to undergo concurrent CRT. Therefore, even if systemic chemotherapy is introduced, definitive radiotherapy should be considered when the tumor shrinks during treatment.Currently, ICI plus chemotherapy achieves a higher antitumor response compared with conventional standard chemotherapy,Here, we report two cases of patients who underwent late concurrent CRT after ICI plus chemotherapy, with a good safety profile. These findings highlight an important treatment option for patients initially judged ineligible for definitive CRT.S.T. received honoraria from AstraZeneca, Chugai Pharmaceutical, and Taiho Pharmaceutical. T.F. received honoraria from Taiho Pharmaceutical. R.T. received grants from Abbvie, Amgen, Daiichi Sankyo, Pfizer Japan, Takeda Pharmaceutical, Eli Lilly Japan, and Novartis Pharma, and honoraria from Bristol\u2010Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan, Kyowa Hakko Kirin, MSD, Nippon Boehringer Ingelheim, Nippon Kayaku, Novartis Pharma, and Taiho Pharmaceutical. M.Y. received grants from Chugai Pharmaceutical, Daiichi Sankyo, MSD, and Pfizer Japan, and honoraria from AstraZeneca, Chugai Pharmaceutical, Covidien Japan, Nippon Boehringer Ingelheim, Ono Pharmaceutical, and Taiho Pharmaceutical. T.S. received grants from Abbvie, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, Kissei Pharmaceutical, Merck Biopharma, MSD, Novartis Pharma, Pfizer Japan, and Takeda Pharmaceutical, and honoraria from AstraZeneca, Bristol\u2010Myers Squibb, Chugai Pharmaceutical, Covidien Japan, Daiichi Sankyo, Eli Lilly Japan, Kyowa Hakko Kirin, MSD, Mochida Pharmaceutical, Nippon Boehringer Ingelheim, Novartis Pharma, Ono Pharmaceutical, Pfizer Japan, Taiho Pharmaceutical, Takeda Pharmaceutical, and Thermo Fisher Scientific, as well as salary compensation from Precision Medicine Asia. T.O. received grants from Bristol\u2010Myers Squibb, Chugai Pharmaceutical, Covidien Japan, Pfizer Japan, AstraZeneca, MSD, Nippon Boehringer Ingelheim, and Taiho Pharmaceutical, and honoraria from Eli Lilly Japan, Johnson & Johnson, AstraZeneca, MSD, Nippon Boehringer Ingelheim, and Taiho Pharmaceutical. The other authors have stated that they have no conflict of interest."}
+{"text": "A 40-year-old woman presented to the dermatology clinic after pregnancy for new-onset of asymptomatic patches of superficial telangiectasia, partially blanchable, mostly arranged unilaterally on the right side of her upper body, including neck, shoulder, and arm. Lesions also involved bilaterally the cervical dermatomes on the chest . DermoscDiagnosis of unilateral nevoid telangiectasia (UNT) was made upon clinical and dermoscopic findings.UNT is a rare, nevertheless underdiagnosed, and underreported capillary malformation, associated with increased estrogen levels . It may"}
+{"text": "Granuloma annulare (GA) is a noninfectious granulomatous dermatitis that is more common in children and young adults. It manifests clinically as localized or generalized rash in micropapular, nodular, perforating, patch, or subcutaneous forms. Insect bites, trauma, tuberculin skin testing, ultraviolet radiation exposure, and bacterial and viral infections have been proposed as inciting factors; however, the exact pathophysiology of GA remains elusive .A 36-year-old male with a history of diabetes mellitus, hypertension, hyperlipidemia, fatty liver, gout, nephrolithiasis, benign thyroid nodules, and glaucoma presented to our outpatient dermatology clinic with nontender papulonodular lesions of 1 year\u2019s duration. Skin examination revealed purple-brown papules and nodules distributed symmetrically on the abdomen with accentuation and accumulation of the lesions mostly over areas of striae distensae (SD), and to a lesser degree on the thighs . Punch bGranuloma annulare is known to be diverse in morphology, distribution, and histology. Yet, the unique distribution pattern of the lesions in our case, localized mainly to the SD, was intriguing. Lesions of GA were reported to occur at sites of previous skin conditions, such as herpes zoster, and at sites of trauma and inflammation, such as following vaccinations, tattoos and surgical incisions .Striae distensae have been previously associated with several skin lesions, including leukemia cutis, keloid, linear focal elastosis, urticarial vasculitis, lupus erythematosus, chronic graft-versus-host disease, and a granulomatous reaction following microneedling. The formation of striae alba (SA), the mature scar-like form of SD, is accompanied by several immune events that include mast cell degranulation, macrophage activation, perivascular lymphocytic cuffing, and dermal edema. These immune events eventually allow the maturation  of the primary erythematous striae rubra into the pale, atrophic, scar-like SA. The various immune processes involved in the formation of SD may, in susceptible patients, recruit T-helper and other immune cells to promote the formation of GA in the context of aberrant wound healing .Our case suggests a possible connection between GA and SD. Previous reports have associated the formation of GA with scarred or irritated skin. Therefore, the development of GA in the distribution of SD, which is a phenomenon of dermal scarring, is biologically plausible."}
+{"text": "Polyaniline (PANI) is a famous conductive polymer, and it has received tremendous consideration from researchers in the field of nanotechnology for the improvement of sensors, optoelectronic devices, and photonic devices. PANI is doped easily by different acids and dopants because of its easy synthesis and remarkable environmental stability. This review focuses on different preparation processes of PANI thin film by chemical and physical methods. Several features of PANI thin films, such as their magnetic, redox, and antioxidant, anti-corrosion, and electrical and sensing properties, are discussed in this review. PANI is a highly conductive polymer. Given its unique properties, easy synthesis, low cost, and high environmental stability in various applications such as electronics, drugs, and anti-corrosion materials, it has attracted extensive attention. The most important PANI applications are briefly reviewed at the end of this review. In previous work, researchers focused on producing conductive polymers, which are achieved in the fields of optics, electronics, energy, and so on ,2,3,4. BPolyaniline (PANI) was first known as black aniline and came in different forms depending on its oxidation level. Furthermore, PANI is known for its simplicity , environConjugated conductive polymers principally involve polyaniline (PANI), polythiophene (PTH), polypyrrole (PPY), and their products ,8. They Although conductive polymers, particularly PANI, have several unique advantages, they have several disadvantages as well. For example, the biological applications of PANI are limited because of its low processing capacity, inflexibility, and lack of biodegradability. The main problem with PANI is the poor solubility affected by the hard spine . Various2 ) to achieve counter electrodes ..248].People with central nervous structure syndromes suffer from the inability to communicate, move, and control their environment. Brain\u2013computer edge (BCI)/brain\u2013machine interface (BMI) via neural prostheses can be considered to compensate for such weaknesses . Cochlea2, which is necessary to generate neuronal activity during stimulation. Electrochemical impedance spectroscopy characterizes the neuronal interface , a, a161], 2 and H2O, and it is even superior to pristine PANI and PANI\u2013clay composite; its remarkable surface area for properly dispersed functionalized graphene in the polymer matrix results in improved diffusion, which postpones corrosion (The nanocomposite of PANI/graphene demonstrates brilliant anti-corrosion properties in contrast to Oorrosion  236]. C. C2 and This review is a comprehensive overview of PANI and PANI thin films with several preparation methods and properties, highlighting the advantages of different applications. Several non-conventional polymerization methods have been employed to synthesize PANI and are extensively used by dissimilar oxidants and dopants. However, the most common method for the preparation of thin films of PANI is oxidative polymerization. Likewise, thin films of PANI can be prepared via polymerization of surface-initiated electron method, Langmuir\u2013Blodgett method, polymerization of atmospheric pressure plasma method, and mSILAR method. These novel synthetic approaches allow PANI to show different physiochemical properties and facilitate control of high electrical conductivity, environmental stability, and thermal stability. Given that PANI shows various properties such as magnetic features, electrical and dielectric properties, charge\u2013discharge behavior, redox features, antioxidant properties, anti-corrosion features, capacitive properties, and sensing features, it is suitable in several fields for numerous applications. Such applications include electrochromic glass, LED production with electroluminescent properties, solar cell production technology due to low-cost features, PANI-based sensors such as gas and glucose sensors for heavy metal detection, and supercapacitors because of various oxidation. In addition, PANI applications in medicine involve engineering, and advances in this area require new and intelligent equipment. Neuroscientists require devices that improve nerve weakness and contribute to the development of neuroscience. Scaffolding has been utilized to correct organ disorders, and biocompatible conductive scaffolding shows appropriate biocompatibility properties. As a result, PANI utilized in delivery systems has attracted a great deal of attention, resulting in innovative delivery systems, such as electro-drug delivery systems. Conductive PANI-based nanocomposites represent a new, but not yet completely explored, area of quantum dots where promising results and unresolved technology challenges both call for opportunities for deeper studies and developed research. There are some major limitations, such as processability and physicochemical properties on PANI applications and its nanocomposites into sensor practice. PANI is gaining increasing interest from the scientific community. However, from an industrial perspective, some of the challenges have important drawbacks on regulatory and quality assurance issues, thereby explaining the relatively low amount of sensor data related to PANI. Lastly, the use of PANI based on quantum dots as a sensor barrier was studied and performed successfully."}
+{"text": "H-function distributions, are comprehensively examined and compared. Their advantages and limitations are further demonstrated via security performance metrics, which are designed as vivid indicators to measure how perfect secrecy is ensured. Two clusters of secrecy metrics, namely (i) secrecy outage probability (SOP), and the lower bound of SOP; and (ii) the probability of nonzero secrecy capacity (PNZ), the intercept probability, average secrecy capacity (ASC), and ergodic secrecy capacity, are displayed and, respectively, deployed in passive and active eavesdropping scenarios. Apart from those, revisiting the secrecy enhancement techniques based on Wyner\u2019s wiretap model, the on-off transmission scheme, jamming approach, antenna selection, and security region are discussed.Physical layer security (PLS) has been proposed to afford an extra layer of security on top of the conventional cryptographic techniques. Unlike the conventional complexity-based cryptographic techniques at the upper layers, physical layer security exploits the characteristics of wireless channels, e.g., fading, noise, interference, etc., to enhance wireless security. It is proved that secure transmission can benefit from fading channels. Accordingly, numerous researchers have explored what fading can offer for physical layer security, especially the investigation of physical layer security over wiretap fading channels. Therefore, this paper aims at reviewing the existing and ongoing research works on this topic. More specifically, we present a classification of research works in terms of the four categories of fading models: (i) small-scale, (ii) large-scale, (iii) composite, and (iv) cascaded. To elaborate these fading models with a generic and flexible tool, three promising candidates, including the mixture gamma (MG), mixture of Gaussian (MoG), and Fox\u2019s  As stated in the latest released statistics by the International Telecommunications Union (ITU) in 2020 , COVID-1Traditionally, cryptography is an appealing approach to achieve data confidentiality. It is designed to prevent data disclosure to unauthorized devices and malicious users . AlthougUnlike the conventional complexity-based cryptographic techniques at upper layers via encryption, physical layer security (PLS), being a promising technology complementary to cryptography and certainly not as a replacement, takes full advantage of the physical properties of the wireless propagation environment via the combination of signaling and coding mechanism to provide additional secrecy at the bottom layer , 5. It iAs a promising approach, physical layer security is built on the two pioneering works laid by Shannon  and Wynes, e.g., . The insObserving the existing books, surveys, and tutorials related to the PLS \u20135, 11\u201330As an indispensable element of PLS techniques, information-theoretic security has been further classified into three categories according to different wiretap channels: (i) memoryless wiretap channels; (ii) Gaussian wiretap channels; and (iii) fading wiretap channels. However, the majority of information-theoretic security is centered around the fading wiretap channels, e.g., see references , 10, 31.m, Weibull ),H-function distributions, to simplify the analysis of security performance metrics. The three approaches are highly beneficial and advantageous since they can broadly encompass the existing fading models. Besides, we discussed four secrecy enhancement techniques deployed on Wyner\u2019s wiretap channel model, including on-off transmission, jamming approach, TAS technique, and protected zones. Hopefully, this paper can serve as a valuable reference for interested readers on better understanding the physical layer security over wiretap fading channels.In this paper, we have comprehensively reviewed the development of PLS over various wiretap fading channels. Based on the characteristics of wireless channels, research works focusing on investigating security performance metrics are thereafter classified into four categories: (i) small-scale fading; (ii) large-scale fading; (iii) cascaded fading; and (iv) composite fading models. After comparing some significant existing and ongoing research works, we introduced three valuable and practical approaches, i.e., the MG, MoG, and Fox\u2019s"}
+{"text": "Koebner phenomenon regards the formation of a psoriatic lesion after a trauma, including tattoo, insect bite or other injuries. Although this manifestation is not specific for psoriasis, physicians should be aware because early recognition may be helpful in making the diagnosis when present. Koebner phenomenon regards the formation of a psoriatic lesion after a trauma, including tattoo, insect bite, or other injuries. Although this manifestation is not specific for psoriasis, physicians should be aware because early recognition may be helpful in making the diagnosis when present. A large erythematous scaly plaque, 10\u00a0cm. in diameter, with sharply demarcated borders, was observed on the left abdominal side, around the stoma  was made.Koebner phenomenon, also known as isomorphic response, describes the sudden occurrence of an inflammatory dermatosis, including psoriasis, lichen planus, vitiligo, or lupus erythematosus, on previously unaffected skin after traumatic stimuli Table . This phThe authors have no conflict of interest.MLP, DA, MP, and ADA: All authors have participated in the work, giving substantial contributions to conception and design, acquisition of data, drafting the manuscript, and final approval of the version to be published."}
+{"text": "Oral diseases such as dental caries and periodontal disease are reported to be associated with various systemic diseases such as heart disease, respiratory disease, diabetes, rheumatism, and metabolic syndrome, thus increasing the importance of prevention and early treatment ,2,3,4,5.Malocclusion is defined as \u201cdeviation from normal occlusion\u201d. However, the concept of malocclusion is broad and vague ,9. In ouThe association of malocclusion with 18 systemic disorders, excluding acute illnesses and relatively rare diseases , were analyzed. The disorders were as follows: pollinosis, food/drug allergy, inhaled antigen allergy, allergic rhinitis, otitis media/externa, sinusitis, pneumothorax/mediastinal emphysema, asthma/cough-variant asthma, atopic dermatitis, urticaria, scoliosis, spondylosis/spondylolisthesis/hernia, strabismus, myopia/hyperopia/astigmatism, arrhythmia, abnormal electrocardiogram (ECG) other than arrhythmia, anemia, and gum bleeding.As result of the analysis, histories of allergic rhinitis, asthma, and arrhythmia were found to be closely associated with (I) occlusal disorder, with high odds ratios of 2.18, 1.84, and 2.81, respectively, by multivariate analysis  . On the Allergic rhinitis and pollinosis are both allergic diseases; allergic rhinitis was associated with occlusal disorders, while pollinosis was associated with teeth-alignment disorder. In both cases with allergic rhinitis and pollinosis, mouth breathing is considered a cause of malocclusion. Allergic rhinitis is a perennial disease and is considered to induce occlusal disorder via continuous mouth breathing ,11. On tClose association between asthma and occlusal disorder has been demonstrated previously. In one study, malocclusion, particularly anterior open bite, was closely associated with asthma in adolescents . Faria eArrhythmia was closely associated with occlusal disorder. Recent studies have shown that chronic stress can be a risk factor for atrial fibrillation (AF), one of the most prevalent arrhythmias, through mechanisms such as increased inflammation and increased activity in the autonomic nervous system . It has Gum bleeding, a typical symptom of periodontal disease, has been found to be associated with teeth-alignment disorder. Although there are several reports on the relationship between malocclusion and gingivitis in adolescence, the details are not clear ,23. FoodThe association between occlusion and overall health has not received much attention in the past; however, in recent years, the importance of the association has begun to be demonstrated. Although further knowledge and clarification of the mechanisms involved are needed, improving malocclusion through orthodontic or prosthodontic treatment might contribute to the prevention and treatment of systemic diseases."}
+{"text": "Animal products, in particular dairy and fermented products, are major natural sources of lactic acid bacteria (LAB). These are known for their antimicrobial properties, as well as for their roles in organoleptic changes, antioxidant activity, nutrient digestibility, the release of peptides and polysaccharides, amino acid decarboxylation, and biogenic amine production and degradation. Due to their antimicrobial properties, LAB are used in humans and in animals, with beneficial effects, as probiotics or in the treatment of a variety of diseases. In livestock production, LAB contribute to animal performance, health, and productivity. In the food industry, LAB are applied as bioprotective and biopreservation agents, contributing to improve food safety and quality. However, some studies have described resistance to relevant antibiotics in LAB, with the concomitant risks associated with the transfer of antibiotic resistance genes to foodborne pathogens and their potential dissemination throughout the food chain and the environment. Here, we summarize the application of LAB in livestock and animal products, as well as the health impact of LAB in animal food products. In general, the beneficial effects of LAB on the human food chain seem to outweigh the potential risks associated with their consumption as part of animal and human diets. However, further studies and continuous monitorization efforts are needed to ensure their safe application in animal products and in the control of pathogenic microorganisms, preventing the possible risks associated with antibiotic resistance and, thus, protecting public health. Bacillus genus, which evolved by adapting to nutrient-rich environments, accumulating, in the process, multiple auxotrophies that rendered them fastidious [2, and ethanol, in addition to lactic acid [2, and ethanol when using fructose as a substrate [Lactic acid bacterial (LAB) are an informal group of prokaryotes that share certain distinctive morphological, metabolic, and physiological characteristics. They are non-respiring, aerotolerant, catalase-negative, fastidious cocci, or rods. Most LAB are non-motile, non-sporulated, may grow in high salt concentrations, and at a low pH ,2. Theirstidious ,4. Thus,tic acid ,2,5. A rubstrate .Lactobacillales order of the Firmicutes phylum and encompassing the Aerococcaceae, Carnobacteriaceae, Enterococcaceae, Lactobacillaceae (including those formerly part of the Leuconostocaceae), and Streptococcaceae families. In 2015, 40 bacterial genera were included in this group [Lactobacillaceae, with the reclassification of the Lactobacillus genus giving rise to 23 new genera, substantially increased this number [Actinobacteria phylum, Bifidobacteria have been included in the LAB group by some authors, because both have probiotic potential and occupy similar ecological niches [The LAB are a genetically and ecologically diverse, but functionally related, group of genera belonging to the is group ; a recens number . Althougl niches .Oenococcus oeni plays a significant role in wine fermentation [Lactiplantibacillus plantarum and Lactiplantibacillus pentosus are important for table olive fermentation [LAB are predominantly found in nutrient-rich habitats. They are part of the normal microbiota of the gastrointestinal tract (GIT) and of the vagina of animals and humans, and they constitute an important element of the non-starter microbial communities found in dairy products , fish, meat, and vegetables ,10,11,12entation , whereasentation . On the entation ,19,20,21entation .The unique characteristics that LAB have demonstrated in different biotechnological processes have fueled decades of research by the scientific community. This ongoing research effort has shown the importance of their ability to produce antimicrobial compounds for the control of pathogens, health-promoting applications, the process of food preservation, and agroindustry ,10,11. ASeveral studies have described the positive effects of LAB on human and animal health, as well as in food industry and agriculture ,6,10. InIn animals, LAB are also employed to obtain health benefits. The gut microbiota of animals can easily undergo dysregulation (dysbiosis) due to stress, medication, and changes in diet. As probiotics, LAB are used in cattle, other ruminants, swine, poultry, and in beekeeping to improve overall animal health and enhance growth, reproductive performance, and disease resistance .Many studies have reported a diversity of LAB applications in the control of infectious diseases, both in animals and humans, due to their significant antimicrobial activity and probiotic properties. These antimicrobial effects have also been applied to control and inhibit foodborne microorganisms, promoting the safety and preservation of foods and feeds. However, few studies have investigated the impacts of antimicrobial-resistant LAB emergence in animal products on humans and on the environment ,29. The L. plantarum, are used as the main crop silage additive that contributes to preserve the nutritional quality of ensilaged forages by inhibiting pathogenic microorganisms and promoting the early onset of lactic acid fermentation. Inoculating forages with homo- and heterofermentative LAB inoculants improved silage fermentation, decreased its final pH, and minimized the production of butyric acid and ammonia-nitrogen, as well as fungal and clostridial growth [Weissella paramesenteroides, have been applied in biological fish silage for aquaculture production [In livestock production, LAB are introduced by the diet or as probiotic supplements . These ml growth ,31. In aoduction .At any age, perturbations of the native gastrointestinal tract microbiota can have severe consequences for the health, productivity, and development in production animals . To imprKlebsiella oxytoca, Escherichia coli, Salmonella enterica, and Staphylococcus intermedius. In addition, Pediococcus acidilactici demonstrated potential probiotic properties in vitro, leading to higher nutrient digestibility, antioxidant activity, and improved hematological profile in weaned piglets [P. acidilactici not only maintained balance in the gastrointestinal microbiota, but also enhanced the physicochemical properties of swine meat and carcass quality in comparison to Lactobacillus acidophilus supplementation [The use of LAB as probiotics in livestock production has been the subject of numerous studies, in which novel strains with different origins and properties have been screened for use in several animal species. Dowarah et al.  isolated piglets . A diet entation ,37.L. acidophilus and a non-LAB bacterial species (Propionibacterium freudenreichii) induced better nutrient digestibility\u2014in particular, of crude protein and neutral and acid detergent fibers\u2014and increased milk production [L. acidophilus, L. plantarum, Ligilactobacillus salivarius, Enterococcus faecium, Lacticaseibacillus casei/paracasei, or Bifidobacterium spp., improved feed use efficiency and increased body weight gain in young calves. In addition, L. acidophilus reduced diarrhea incidence in calves [Supplementing the diet of lactating Holstein cows with oduction . Frizzo oduction  reportedn calves ,40. Anotn calves .P. acidilactici from rectal samples of poultry showed significant antibacterial activities against E. coli and S. enterica [Salmonella infections in broilers proved to be advantageous. Feng et al. [L. plantarum, L. salivarius, and P. acidilactici, were more efficient in achieving a reduction in Salmonella counts in the intestinal tract and in minimizing its adhesion to and invasion of broiler livers and spleens. Moreover, broilers fed diets containing Lactobacillus showed lower cecal coliform counts, as well as lower cholesterol levels than the control group [In poultry production, the effects of dietary supplementations with probiotics are well documented ,42,43. Henterica . The appg et al.  reportedA diverse, numerous, LAB symbiotic community is present in the honey crop of bees, defending these important pollinators from invasion by pathogens . The appIn general, when applied as probiotics, beneficial LAB have the following positive effects in animals: prevention against colonization by (antibiotic-resistant) pathogens, modulation of the intestinal microbiota, reduction in inflammatory reactions, improvement of carcass traits, modulation of the immune response, performance enhancement, increase in nutrient digestibility and absorption, and decrease in urea and ammonia excretion  6,34,3838,43. ThA variety of LAB strains, which are either part of the autochthonous microbiota or introduced into animal products, have potential beneficial applications for the preservation of such products and/or for consumer health . Many foIn their fermentative processes, LAB\u2014the main group of bacteria used for food and feed fermentations\u2014release a number of bioactive metabolites, such as biogenic amines, exopolysaccharides, bacteriocins, and other biologically active, proteolytically released peptides ,51,52. HDuring food fermentations, LAB are known to decarboxylate amino acids, leading to the accumulation of biogenic amines (BA)\u2014histamine, cadaverine, putrescine, tyramine, and 2-phenylethylamine\u2014under certain environmental circumstances. Enterococci, lactobacilli, streptococci, lactococci, pediococci, and oenococci are regarded as the main BA producers in fermented foods, whereas leuconostocha and weisellae are thought to play a minor role. Decarboxylase activity is, however, a strain-related rather than a species- or genus-related trait . On the Although LAB have demonstrated enormous environmental and health benefits in fermented food products, which could lead to an increase in the demand and consumption of such products, regulation has, in some instances, limited their application ,65,66. SEnterococcus, Lactobacillus (in its former taxonomic composition), Streptococcus, Lactococcus, Leuconostoc, Weissella, and Pediococcus [LAB are ubiquitous in dairy environment and are an important part of the microbiota present in raw milk, fermented milks , and cheeses ,70,71. Aiococcus .Lactococcus spp. are the most frequently isolated LAB in artisanal dairy products [Lactococcus lactis [Lactococcus raffinolactis and Lactococcus garviae [Lac. lactis, but also, to a lesser extent, Lac. raffinolactis [8 cells [products ,74. In sproducts ,75,76. Ts lactis ,77,78, w garviae . Althoug garviae . Lactoconolactis . Ferment[8 cells .L. casei [L. paracasei [Latilactobacillus curvatus [L. plantarum [L. acidophilus, Lactobacillus delbrueckii [Lentilactobacilus otakiensis [Levilactobacillus brevis, and Limosilactobacillus fermentum [L. paracasei, Lacticaseibacillus rhamnosus, L. plantarum, and L. curvatus, play a role in cheese ripening [L. delbruecki in yogurt [Lentilactobacillus kefiri, the most representative of the former Lactobacillus species in kefir, a fermented milk drink from the Caucasus Mountains. The kefir grain includes other lactic acid bacteria, such as L. brevis, L. paracasei, Lactobacillus helveticus, Lactobacillus kefiranofaciens, L. plantarum, L. kefiri, Lac. lactis, Streptococcus salivarius subsp. thermophilus, and Leuconostoc mesenteroides, besides acetic acid bacteria and yeasts. During fermentation, the production of lactic acid, ethanol, flavor-generating components, and carbon dioxide are responsible for the unique kefir sensorial characteristics. Kefir demonstrated health benefits on the gastrointestinal microbiota and function, as well as in vitro antimicrobial activity against several pathogens, such as Staphylococcus aureus, Enterococcus faecalis, S. enterica, E. coli, Shigella sonnei, Bacillus subtilis, and Candida albicans [L. delbrueckii and L. helveticus are the main lactobacilli used as starter cultures in the dairy industry. Probiotic properties have been attributed to several lactobacillus species. For instance, Pino et al. [L. paracasei and L. rhamnosus as the main LAB species with promising probiotic properties. Dairy products have been frequently used as carriers for probiotic lactobacillus strains, such as L. acidophilus and L. rahmnosus [Lactobacilli  are freL. casei ,84, L. paracasei ,86,87, Llantarum ,86,87, Lakiensis ,85,86, Lripening . In othen yogurt  and Lentalbicans . L. delbo et al.  isolatedahmnosus . Many, bahmnosus .Ln. mesenteroides, Leuconostoc lactis [Leuconostoc pseudomesenteroides [Leuconostoc citreum [Leuconostoc spp. participate in the maturation of non-hard cheese varieties, including Camembert, where they may contribute to flavor formation, to their rheological properties by producing exopolysaccharides, and/or to open texture due to CO2 production [Ln. lactis and Ln. mesenteroides are used in the production of butter, sour cream, and other non-maturated dairy products [Lac. lactis and Ln. mesenteroides in fecal samples during the consumption of Camembert cheese, which, in the case of Ln. mesenteroides, persisted 15 days after the end of consumption.Leuconostocha are part of the core microbiota in several artisanal cheeses, although their populations are, in general, numerically lower than those of lactococci . The maic lactis , Leuconoteroides , and Leu citreum . All theoduction ,91,92. Lproducts . Dairy pEnterococcus avium, Enterococcus casseliflavus, Enterococcus devriesei, Enterococcus durans, E. faecalis, E. faecium, Enterococcus gallinarum, Enterococcus gilvus, Enterococcus hirae, Enterococcus italicus, Enterococcus lactis, Enterococcus malodoratus, Enterococcus mundtii, Enterococcus pallens, Enterococcus pseudoavium, Enterococcus ratti, Enterococcus saccharominimus, Enterococcus sulfureus, and Enterococcus villorum [Enterococci are members of the non-starter microbiota in many artisanal cheeses, where their role in flavor development has been documented ,93. A tovillorum . Their pvillorum . The potvillorum ,94.Strep. salivarius ssp. thermophilus [Streptococcus gallolyticus subsp. macedonicus [Strep. salivarius subsp. thermophilus is typically used as a starter culture to ferment milk, usually of ruminant origin, giving rise to a diversity of products with unique flavors, textures, and nutritional properties [L. delbrueckii, where this bacterial consortium acidifies the milk and produces acetaldehyde\u2014a key compound for the flavor of this product. In cheeses, it also contributes to acidification of the curd and to flavor formation during ripening. Furthermore, there are reports of exopolysaccharide (EPS) and bacteriocin production by this species, as well as probiotic characteristics [Certain streptococci, such as mophilus  and Streedonicus , are paroperties . In yogueristics .Staph. aureus, E. coli, Listeria monocytogenes, and Salmonella sp., can be transferred from livestock animals to humans through the consumption of milk and dairy products, causing severe diseases. Although the bacterial contaminants in milk are largely eliminated by the pasteurization process, the application of LAB producing bacteriocin-like compounds in fermented and nonfermented dairy products could improve their quality and safety, decreasing the associated food-borne infection risks [L. acidophilus have a broad spectrum of inhibitory activity against species of Gram-negative and Gram-positive bacteria , yeasts (Candida), and protozoa (Trypanosoma) in dairy products [Lac. lactis inactivated L. monocytogenes in cottage cheese and yogurt. Nisin, the best known of the bacteriocins produced by Lac. lactis, demonstrated bactericidal activity against L. monocytogenes and Clostridium in milk, preventing the spoilage process known as late blowing in cheese [Lactobacillus genus is through competitive exclusion by expression of the mntH1 gene. This novel and natural mechanism was demonstrated to inhibit the growth of spoilage microorganisms, such as molds and yeasts, in dairy products  [Dairy products can act as reservoirs of lactic acid bacteria for their human consumers. The lactic acid bacteria in these products may impact human health, with several species included in this group presenting potential as protective and/or probiotic cultures. Bacteriocin production is of particular interest in this respect. Pathogenic microorganisms found in raw milk, such as on risks . The bacproducts . Moreoven cheese ,98. A reyogurts) . It can yogurts) .Latilactobacillus sakei, L. curvatus, and L. plantarum) usually predominate [Ln. mesenteroides, Leuconostoc carnosum) and enterococci (E. casseliflavus) are also present [Meat products harbor a diverse LAB microbiota, in which lactobacilli  and deterioration microorganisms [L. curvatus has been successfully employed to extend the shelf life and improve microbial safety in meats, effectively controlling L. monocytogenes and Brochothix thermosphacta in fresh beef, without negatively impacting its sensory properties [L. sakei isolated from sausage produce the sakacin K bacteriocin, that is active against some listerial strains, leading to inactivation of Listeria innocua during the sausage fermentation process. In another study, 813 bacteriocin-producing LAB strains that demonstrated the ability to inhibit the growth of L. innocua and Staph. aureus were isolated from 174 meats and meat products [Lac. lactis and L. plantarum, were analyzed in greater detail. All of them displayed traits consistent with probiotic potential, such as tolerance to very low pH, survival/growth at gastrointestinal tract and at food storage temperatures, as well as biofilm production [2O2, organic acids, sugars, and additives) have a negative effect on probiotic viability. However, the selection of the adequate strains and/or techniques such as microencapsulation might help probiotic LAB survive under these conditions, enabling their addition to fermented meats [Several of the LAB associated with fermented meats are bacteriocinogenic and possess, therefore, the ability to modulate the microbiota of the product, combatting the proliferation of pathogenic  [Fish and seafood can spoil very rapidly; the required hygienic quality and safety standards are, therefore, difficult to maintain. Due to the production of antimicrobial metabolites, such as organic acids and bacteriocins, LAB can be regarded as natural biopreservative agents, although scarce commercial applications of these bacteria have been developed from/for fish and fishery products . LAB of ytogenes . Additioytogenes  demonstraculans) . The appaculans) .Scombridae family) that are rich in their precursor amino acids [Fermented fish products are not an important component of Western diets. In Asia, however, traditional fermented fish products, such as plaa-som, hoi-dorng, som-fak, pa-ra, pla-chom, kung-chom (Thailand), bekasam, chao (Indonesia), chouguiyu (China), burong baugus, burong isda (Philippines), budu, pekasam , ngari, hentak, and tungtap (India), may constitute important sources of dietary protein . Fermentno acids .P. acidilactici in the early laying phase improved the market value of carcasses and eggshell quality. A significant decrease in the number of broken shells, absent shells, and downgraded eggs, as well as an increase in egg weight, relative weight, and thickness of the eggshells were observed. In addition, probiotic supplementation improved feed efficiency ratio and hen performance. However, the main objective in studies on probiotic application in egg production has been to reduce the cholesterol content of this product. Several studies have demonstrated evidence that LAB supplementation reduces cholesterol content in the egg yolk [P. acidilactici and L. acidophilus. In these studies, egg yolk cholesterol content depended on the administered dose and on the bacteria used as probiotics.The application of dietary LAB in apicultural and poultry production has demonstrated promising effects on animals, their products, and their human consumers. Mikulski et al.  reportedegg yolk ,131,132,egg yolk  and Haddegg yolk  reportinLactobacillus genus was the most frequently identified in the beehive, and Apilactobacillus kunkeei was predominantly isolated from honey, bee pollen, bee bread, and royal jelly. Immunomodulatory activity through the secretion of IgA has been reported in this species [Enterococcus, and Weissella demonstrated in vitro inhibitory effects against Paenibacillus larvae, an enthomopathogen that affects bee larvae [Staph. aureus, Pseudomonas aeruginosa, E. coli, Bacillus cereus, and Salmonella spp. [Honeybees are distributed worldwide, and besides producing honey, these insects are considered one of the main crop pollinators. The products and byproducts resulting from apicultural production, such as honey and pollen, are known for their medicinal and nutritional properties, and are classified as safe, health-promoting foods . Within  species . In anot species . Lactobae larvae . Moreovella spp. . Not onllla spp. ,135. Howlla spp. .Measures have been implemented worldwide to limit the inadequate use and overuse of antibiotics in animals, particularly in livestock production. The increase in antimicrobial resistance to antibiotics in animal production chains and the presence of antibiotic residues in animal products can pose serious health risks for humans as final consumers of these products . ProbiotLactobacillus genus, the presence of antibiotic resistance genes has been reported [Most LAB used in animal feed or animal-derived foods occur naturally in the animals  or in the resulting products. Although LAB with probiotic potential are considered non-pathogenic, the risks associated with the possible genetic transfer of antimicrobial resistance or toxin production to pathogenic microorganisms cannot be disregarded ,73. Horireported . Some LAreported .Several studies on autochthonous food bacteria have highlighted the potential role of LAB as reservoirs of antibiotic resistance genes, from where resistance determinants could be transferred to the human microbiome via food chain ,138,139.Enterococcus spp., Lac. lactis, and several lactobacilli from fermented meat and milk products [L. delbrueckii subsp. bulgaricus, L. plantarum, L. paracasei, and L. acidophilus) and Strep. salivarius subsp. thermophilus. In this study, most of the strains belonging to the former Lactobacillus genus were resistant to streptomycin (84%) and gentamycin (84%); less frequently, these strains showed resistance to erythromycin, sulfamethoxazole, and tetracycline. Most Strep. salivarius subsp. thermophilus also harbored resistance genes to the aminoglycosides streptomycin (92%) and gentamycin (87%), as well as to ciprofloxacin (79%), chloramphenicol (72%), and erythromycin (8%) [L. plantarum isolated from raw-milk cheese showed erythromycin resistance [Streptococcus and former Lactobacillus genera, as well as in bifidobacteria [L. delbrueckii subsp. bulgaricus and L. plantarum can successfully transfer the tetM and tetS tetracycline resistance genes to L. monocytogenes [Genetic determinants of tetracycline, vancomycin, and erythromycin resistance have been described in products ,138. Theproducts  and theiproducts . A recencin (8%) . In anotsistance . The resbacteria . Additioytogenes .Lac. lactis and L. plantarum demonstrated in vitro resistance to erythromycin, and some were also resistant to vancomycin, tetracycline, and chloramphenicol, as previously described [tetM and tetS tetracycline resistance genes were found in the raw meat isolates, but tet(M), found exclusively in the lactobacilli, was the only gene detected after sausage fermentation. This study confirms that raw meat already contains a subpopulation of resistant bacteria and that the resulting fermented meat can act as a vehicle for tetracycline-resistant LAB. However, Jha et al. [In meat products, all strains of escribed . Antibioescribed . Gevers escribed  analyzeda et al.  reporteda et al. . TherefoWith the surge in human population and the rising threat of antibiotic resistances, the necessity to promote research on alternatives to antibiotics has also increased. LAB use, especially as probiotics, are becoming popular, and they have, indeed, been proven useful, both for humans and animals ,38. LAB With the exception of the enterococci, LAB infections are extremely rare. However, some cases of bacteremia, endocarditis, lactobacillemia, and antibiotic-resistant infections have been reported in severely immunocompromised individuals . It mustOn the other hand, more information is required on potential non-food uses of LAB with inhibitory potential or antimicrobial activity against human and animal pathogens, that could aid in limiting medical antibiotic use. For instance, a high number of pathogens implicated in urinary tract infections have demonstrated antibiotic resistance, making the treatment of these infections more difficult. LAB demonstrated, in vitro, the ability to inhibit uropathogens  and theiAnimal products, in particular dairy products, are natural and major sources of LAB with several beneficial effects for humans and animals. LAB can be advantageously applied in animal production to improve animal performance, health, and productivity; in the food industry, they have demonstrated potential as biopreservatives due to their antimicrobial properties. Their consumption in animal products has been demonstrated to have beneficial effects on human health, although a residual risk of antibiotic resistance transfer through these foods exists. This review demonstrated that, under the light of the present knowledge, the beneficial effects of LAB on the human food chain outweigh their potential harmful impacts. However, further studies and a continuous monitorization effort are necessary for the safe application of LAB in animal food products and in the treatment of pathogenic microorganisms, providing a thorough assessment of the possible risks associated with the dissemination of antimicrobial resistance genes and, thereby, protecting public health."}
+{"text": "Graft regeneration after anterior cruciate ligament (ACL) reconstruction surgery is a complex three-stage process, which usually takes a long duration and often results in fibrous scar tissue formation that exerts a detrimental impact on the patients' prognosis. Hence, as a regeneration technique, stem cell transplantation has attracted increasing attention. Several different stem cell types have been utilized in animal experiments, and almost all of these have shown good capacity in improving tendon-bone regeneration. Various differentiation inducers have been widely applied together with stem cells to enhance specific lineage differentiation, such as recombinant gene transfection, growth factors, and biomaterials. Among the various different types of stem cells, bone marrow-derived mesenchymal stem cells (BMSCs) have been investigated the most, while ligament stem progenitor cells (LDSCs) have demonstrated the best potential in generating tendon/ligament lineage cells. In the clinic, 4 relevant completed trials have been reported, but only one trial with BMSCs showed improved outcomes, while 5 relevant trials are still in progress. This review describes the process of ACL graft regeneration after implantation and summarizes the current application of stem cells from bench to bedside, as well as discusses future perspectives in this field. Anterior cruciate ligament (ACL) injuries account for more than 50% of all knee injuries , which mAfter transplantation, the graft goes through a complex three-staged healing process involving necrosis, remodeling, and ligamentization, which may take around 2 years . MoreoveThe purpose of this review is to describe the natural healing process after ACL graft implantation and summarize the current application of stem cells from bench to bedside, as well as discuss future prospects in this field.From the posterior part of the inner surface of the lateral femoral condyle, the ACL runs anteriorly, medially, and distally to the tibia . The mai\u03b1, interleukin (IL) 1-\u03b2, IL-6, and chemokines, which may trigger growth factor expression [During the early stage, necrosis occurs in the graft centra, which leads to a release of various cytokines, such as tumor necrosis factor- (TNF-) pression , 22. Sompression , 12, 21,pression . Collagepression , and no pression , 24. Thepression , 26.During the remodeling stage, large amounts of growth factors are released, which stimulates cell migration and proliferation as well as extracellular matrix synthesis and revascularization , 27, 28.During the maturation stage, cellularity and mechanical properties become gradually similar to intact ACL but never reach the original levels , 32. ProBased on the above description, the graft healing process is slow and requires a long duration. The remodeling stage is finished by 9 months at the earliest , 34, andStem cells show remarkable ability for self-renewal, long-term viability, and multilinear culture , which iin vitro. Cells from different sources have varying propensities to differentiate into various tendon/ligament lineages, and hence, it is imperative to weigh the pros and cons of various different stem cell types , induced pluripotent stem cell (iPSC), adipose tissue-derived stem cells (ADSCs), bone marrow-derived mesenchymal stem cells (BMSCs), and tendon/ligament stem/progenitor cells (TDSCs/LDSCs). In particular, MSC is the focus of much interest, as these cells are easily isolated from a variety of adult tissues and cultured ll types .BMSCs have multipotential capacity to differentiate into osteoblasts, chondrocytes, and adipocytes and hence have been most widely studied for enhancing tendon-bone healing, yielding satisfactory outcomes . SakagucLim et al.  implantein vitro, as it exhibits a bias towards adipogenic differentiation [ADSCs have the advantages of abundant and ready availability, as well as capacity for secreting various factors, such as VEGF, hematopoietic factors, and immunoregulatory factors, to promote tissue repair and growth. Over 500 times more stem cells can be obtained from adipose tissue than from an equal tissue volume of bone marrow , and prontiation .It has been reported that ADSCs promote the early healing processes of tendon and bone in rabbits . But TeuIt has been reported that tissue-specific stem cells may retain a residual \u201cepigenetic memory\u201d of their tissue of origin . When bain vivo has yielded generally positive results, when combined with silk scaffold, cell sheet, and injection [Originating from the ligament tissue , CD90+CDnjection , 66. In njection . As a prnjection . The comhUCB-MSCs: hUCB-MSCs have the advantages of noninvasive isolation method, superior tropism, and high differentiation potential. Transplantation in rabbits enhanced bone-tendon healing effectively, without immune rejection , 70, whiSynovium-derived MSCs (sMSCs): after injury, a local increase of MSCs was observed, and these MSCs were identified as sMSCs rather than BMSCs . sMSCs cESC/iPSCs: ESCs could differentiate into any tissue or cell type, but therapeutic applications of these cells have been subjected to serious and prolonged legal/ethical discussion. On the other hand, iPSCs avoided ethical issues associated with ESC and also offered the possibility for autologous regeneration of any tissue. Cord and peripheral blood are attractive sources of reprogrammable cells for generating iPSCs , 74. As Exosome: no related research studies have been reported yet. However, the application of exosomes in tendon injury and tendinopathy in animal models showed satisfactory outcomes, which enhanced osseointegration, biomechanics, and histology \u201379, whicIt is a consensus that growth factors could regulate cell proliferation, ECM elaboration, neovascularization, and mechanical properties. Hence, knowing the exact signaling mechanisms involved in ligament development and repair are essential for improving ACL regeneration, but our current knowledge is much limited and further research needs to be done. Functionally, it has been empirically shown that various growth factors exert positive effects on ligament tissues. Such as transforming growth factor (TGF), fibroblast growth factor (FGF), insulin-like growth factor (IGF), platelet-derived growth factor (PDGF), and epidermal growth factor (EGF), with all having been proven to increase cell proliferation, fibroblastic differentiation, and ECM deposition. As a combination of these factors, PRP could induce mass release of growth factors within one hour following intra-articular administration, which seems a convenient and efficient tool, but related meta-analysis studies found no significant benefit for ACLR in the clinic , 81.in vitro. Moreover, PRP+BMSCs yielded better tendon-bone healing in rabbits [Teng et al. found that PRP promoted BMSC osteodifferentiation  rabbits . Single  rabbits , also ac rabbits . The sam rabbits .In vitro, BMSC/TC coculture stimulated by mechanical stretch showed higher expression levels of collagen I/III, alkaline phosphatase, osteopontin, and tenascin C [in vivo, so we need further investigations of the cultured environment before implantation. These could explain how prolonged immobilization would result in the mechanics of damage within the clinic [Mechanical loading has been demonstrated to influence cell proliferation, differentiation, apoptosis, and ECM production without growth factors \u201388. In fnascin C , as wellnascin C . 8% but nascin C . But it e clinic .In tissue engineering, cell differentiation can be induced by growing the cells on scaffolds with specific composition, architecture, and physicochemical and mechanical properties. Biomaterials not only play a load-bearing role in ACL reconstruction but is also a differentiation inducer.In native ACL, type I collagen constitutes roughly 90% of the tissue volume, so the use of collagen-based scaffolds has been extensively investigated. Collagen could promote tenogenic differentiation induction, and the collagen-induced tenogenic cells could then arrest osteogenic differentiation mediated by paracrine signals . But immSo far, silk scaffold, electrospun scaffold, and decellularized allograft with BMSCs have demonstrated good osseointegration capacity \u2013107. To The fate of implanted stem cells remains controversial. Ju et al. used the fluorescent marker Dil dye to track implanted sMSCs, which initially stayed at the tendon-bone interface, and then differentiated into fibroblasts, with the potential of producing collagen fibers or secreting various cytokines for collagen fiber synthesis. But DiI-labeled cells could no longer be observed after 4 weeks . There a\u03b2, which promote native ACL cell proliferation and migration [In some ACL injury models, exogenous cells were detected in the synovium, injured ACL, meniscus, cartilage of femoral condyles, and myotendinous junction of the quadriceps , 110. Trigration . Maerz eThe objective of these studies was to form a normal insertion structure, but the source of newly formed fibrocartilage cells remains a mystery. Due to differentiation of the original cells, whether these are derived from transplanted exogenous stem cells or recruited endogenous cells remains ambiguous. How do these MSCs differentiate into fibroblast or other lineages? Tracking of cell fate needs to be more rigorously investigated.The search in electronic databases such as PubMed, Embase, and Cochrane Library resulted in 9 clinical trials , includiBased on the published results of completed clinical trials, the overall outcome was quite disappointing . Wang etThough preclinical studies have shown promising outcomes, the general clinical effects of stem cells on ACL graft regeneration are controversial, and the heterogeneity of transplanted stem cells needs to be further investigated with more high-quality research studies needed for an accurate and comprehensive conclusion. The clinical application of stem cells is a complex process, in view of the host tissue environment, time, cell adhesion, and dose. Due to the poor blood supply and insufficient nutrition provided by the articular cavity, too much cell injection will lead to necrosis, while too little will not yield a satisfactory effect. Dose- and time-dependent clinical research studies need to be carried out.\u03b21, and PDGF [The timing of injecting or transplanting stem cells requires further consideration. Based on the process of graft regeneration as described above, two different therapeutic strategies for utilizing stem cells in ACL regeneration have been proposed: (a) during the early stage, transplanted stem cells make up for the hypocellularity, and the immunoregulatory property of MSCs  reduces inflammation reaction, as well as facilitate recruitment/activation of endogenous stem cells. Macrophages would accumulate for repair at the tendon-bone interface but often result in the formation of a scar tissue rather than normal insertion site , and so and PDGF  have demand PDGF \u2013121.Different delivery methods have their own pros and cons. To attract stem cells into the scaffold, chemokines can be applied . To simu\u03b2, BMP, and FGF [in vitro and in vivo [In embryos, tendon development requires both physiological and biomechanical stimulation , 124. Te and FGF \u2013127, as  and FGF , promote and FGF , of whic and FGF . Scx+/So and FGF , althoug in vivo .\u03b22, Tnmd, Col I, and elastin) in MSCs but can only downregulate the mRNA levels of elastin in TDSC [Learning from embryonic tendon development can improve tendon tissue engineering strategies with adult stem cells, and tenogenic cues and markers will need to be established for step-wise induction . Some st in TDSC . The BMP in TDSC , which m in TDSC , 134. In in TDSC . CTGF al in TDSC , 137. In in TDSC . These sAll stem cell therapies have the inherent risk of tumorigenicity, due to the aberration of chromosomal, copy number, and single nucleotide, hindering clinical translation , 140. HeAlthough challenges exist, preclinical evidence predicts a promising future for stem cell approach to ACLR, despite most (3/4) clinical research studies showing controversial outcomes. Currently, there are several ongoing human clinical trials in this area. Due to few studies on stem cell therapy for ACLR, we are unable to conduct a deep meta-analysis in this systematic review. In general, how exactly stem cells participate in human ACL regeneration and whether it has clinical benefits will require further study.In addition, because stem cell transplantation is a biological therapeutic strategy, the stability and oncogenicity of stem cells require consistent long-term safety verification. The published scientific literature confirms the short-term (<24 months) safety and tolerance of stem cells in ACLR, but the implanted cells need long-term tracking, which has been poorly studied to date.in vitro or in vivo will be particularly crucial, because they are capable of differentiating into multiple tissue types. Current applications in humans are at the primary stage, so the differentiation induction in vivo is not mature and safe. Moreover, the implantation methodology and cell fate have been discussed previously, including the dose, time, supplementary agent, and material.Third, the choice of the stem cell source is another important consideration. Stem cells derived from different sources all showed good capacity in promoting regeneration, but their relative effects need to be compared to optimize the therapeutic efficacy. With respect to availability and ease of isolation, ADSCs and BMSCs may have advantages over other stem cell types. In terms of proliferative capacity and ligamentous differentiation potential, TDSC/LDSC is regarded as having the most potential, but limited cell quantity may limit clinical applications. Proper differentiation of alternative stem cell lineages either Almost all utilized stem cell lineages showed good capacity in promoting tendon-bone regeneration in animal models. Among the various different stem cell types, BMSCs are most commonly investigated, while LDSC/TDCS showed better potential for tendon/ligament lineage-specific differentiation. With differentiation inducers, such as growth factors, mechanical stimuli, and biomaterials, stem cells have better capacity to differentiate into ligament, fibrocartilage, and bone, as well as regulate inflammation through paracrine pathways, promoting graft regeneration. The application of stem cells in the clinic often results in disappointing outcomes and needs further investigations."}
+{"text": "Conceptualizing social isolation as a multidimensional construct encompassing social networks, social contacts, perceived support and loneliness, this research aims to: (1) identify patterns of social isolation trajectory among middle-aged and older adults in the U.S.; (2) investigate how different patterns of social isolation trajectory are related to adults\u2019 physical, mental, cognitive, and overall health. Latent class growth modeling was used to examine social isolation trajectory patterns over nine years in a national sample of 6,457 adults aged 51+. Four patterns of social isolation trajectory were identified: severely isolated, moderately isolated, subjectively integrated, and objectively integrated. The objectively integrated group reported the best physical, mental, cognitive, and overall health, whereas the severely isolated group reported the worst. The moderately isolated and subjectively integrated groups fell in between, with the latter displaying relatively better health outcomes. Findings support a close relationship between poor health and long-term social isolation."}
+{"text": "Consumer voices are often left out from assessments of nursing home (NH) quality. For this reason, consumer allegations and complaints against nursing homes were studied in relation to facility rates of nurse aide retention. Analyses involved means and frequencies, correlations, ANOVAs with Tukey correction to examine the independent and dependent variables (N=690). Four quartiles of retention were created. In the final models, medium, high, and extremely high retention facilities are compared to the low retention facilities. Negative binomial regressions were estimated on total, substantiated, and unsubstantiated counts of allegations and complaints. All regressions controlled for the same characteristics, including nurse aide empowerment, consistent assignment, administrator turnover, director of nursing turnover, average age of residents, and percent female. The correlation between retention and the dependent variables was negative and statistically significant . The ANOVAs showed that high retention NHs (61-72%) received significantly fewer allegations than low (0-48%) and medium (49-60%) retention NHs; they also received fewer unsubstantiated allegations, and fewer complaints, both substantiated and unsubstantiated. After controlling for other variables, each retention group was significantly related to having fewer allegations and complaints compared to the low retention NHs. Notably, high retention NHs received between 29 and 35% fewer allegations and complaints of all types. Unexpectedly, extremely high retention NHs had more allegations, complaints, and unsubstantiated allegations than high retention NHs. Policy and practice have a role to promote nurse aide retention, improve job quality, and ensure adequate support for this critical, in-demand workforce."}
+{"text": "Older adults with more ageist attitudes and aging anxiety and who endorse an external health locus of control (HLOC) have poorer mental and physical health and less engagement in healthy behaviors than those who report less ageist attitudes, aging anxiety, and endorse an internal HLOC. However, middle-aged adults have not been examined in this literature. Using Terror Management Theory as a framework, this study examined the relationship of middle-aged adults\u2019 aging anxiety, ageist attitudes, and HLOC with health behaviors and mental and physical health outcomes. 391 middle-aged participants (40-55 years) completed measures of ageist attitudes, aging anxiety, HLOC , engagement in health behaviors, mental health, and physical health. The path analysis model demonstrated acceptable fit, \u03c72(2)=7.794, p=.02, CFI=.99, TLI=.92, RMSEA=.09). For health behaviors, eight of the 10 paths were significant; higher aging anxiety, higher ageist attitudes, and less endorsement of internal HLOC were related to less engagement in healthy behaviors. For mental health and physical health, five of the 10 paths were significant; in general, higher aging anxiety, higher ageist attitudes, and less endorsement of internal HLOC were related to poorer mental and physical health. This study demonstrated that middle-aged adults\u2019 aging anxiety, ageist attitudes, and health locus of control are related to their health behaviors and mental and physical health. Furthermore, higher endorsement of specific forms of ageist attitudes and aging anxiety were related to worse reported mental and physical health and to less engagement in health behaviors. Implications of these findings will be discussed."}
+{"text": "Coupling remote sensing with microbial omics-based approaches provides a promising new frontier for scientists to scale microbial interactions across space and time. These data-rich, interdisciplinary methods allow us to better understand interactions between microbial communities and their environments and, in turn, their impact on ecosystem structure and function. Here, we highlight current and novel examples of applying remote sensing, machine learning, spatial statistics, and omics data approaches to marine, aquatic, and terrestrial systems. We emphasize the importance of integrating biochemical and spatiotemporal environmental data to move toward a predictive framework of microbiome interactions and their ecosystem-level effects. Finally, we emphasize lessons learned from our collaborative research with recommendations to foster productive and interdisciplinary teamwork. Prochlorococcus  research, the future is big\u2014and small. Scientists can leverage powerful, cross-disciplinary approaches that pair omics tools with remote sensing and spatial statistics to study spatiotemporal variation in microbiome interactions. For example, by studying utbreaks \u201312. Leveapevines \u201315, illuAdvances in remote sensing technologies provide new opportunities to understand microbial dynamics. Global-scale observations from satellites enable spatial resolution of 10 m to 1\u2009km with a revisit cycle of days to weeks . More rea and phycocyanin pigments) (Combining microbiome and remote sensing methods can advance our understanding of phytoplankton bloom dynamics . Harmfuligments)  to quantigments) , 26. Theigments)  but cannInteractions within plankton communities and among heterotrophic bacteria and bloom-forming species , 27 indiDisease outbreaks in seagrass meadows present another promising case study for applying remote sensing to understand microbial dynamics. Seagrasses create habitat that supports biodiversity but are declining globally due to multiple stressors, including disease , 30. Meaa and phycocyanin, warming from thermal sensors, and freshwater discharge events , near-infrared, microwave, and thermal bands, we can derive variables such as chlorophyll-a levels, spectral signatures for green leaf index (GLI), normalized difference vegetation index (NDVI) for above-ground plant biomass, phycocyanin for cyanobacterial biomass, and temperature   . In situbolomics  processebolomics , 43. Furbolomics , 45. Witbolomics , 26, plabolomics , 35, 46,bolomics , 14, 18.Between-system comparisons reveal shared knowledge gaps in understanding how microbial interactions influence ecosystem-level change. Microbes underpin ecosystem function , 47, parA deeper understanding of host-microbe interactions can help identify microbial signs of ecosystem perturbations. For example, commensal nutrient cycling bacteria are critical to productivity of seagrasses , corals in situ samples to continuous, remotely sensed data (Synthesizing omics data with physiochemical environmental drivers can address important knowledge gaps. In some cases, microbial data can be early warning indicators, revealing ecosystem impacts like disease outbreaks or microbial dysbiosis prior to macroscale observations , 48, 50.sed data . Couplinsed data .The need for predictive ecological modeling is accelerating in tandem with global environmental change . MicrobiWhat can we learn from an interdisciplinary approach of integrating microbial, remote sensing, and machine learning methods? Coupling microbial and remote sensing data may allow more accurate predictions about how microbiomes may shift in future climate change scenarios , 14, 56 13\u2013Successful implementation of paired geospatial and omics research approaches will require collaboration among ecologists, microbiologists, computer scientists, and geographers. To push our fields forward, we need structured workshops to foster connections, develop skills, and infuse expertise and creativity into our shared research initiatives. For example, training workshops that bring together users of geospatial, machine learning, and omics tools to brainstorm unique data use, storage, and analyses are needed to create efficient data pipelines and promote novel findings. Importantly, teams should include and support individuals from historically excluded and marginalized groups, disparate research fields, and career stages. Doing so will create more equitable opportunities to engage in research . We advo"}
+{"text": "Vegetable cultivation is a promising economic activity, and vegetable consumption is important for human health due to the high nutritional content of vegetables. Vegetables are rich in vitamins, minerals, dietary fiber, and several phytochemical compounds. However, the production of vegetables is insufficient to meet the demand of the ever-increasing population. Plant-growth-promoting rhizobacteria (PGPR) facilitate the growth and production of vegetable crops by acquiring nutrients, producing phytohormones, and protecting them from various detrimental effects. In this review, we highlight well-developed and cutting-edge findings focusing on the role of a PGPR-based bioinoculant formulation in enhancing vegetable crop production. We also discuss the role of PGPR in promoting vegetable crop growth and resisting the adverse effects arising from various abiotic  and biotic  stresses. Vegetables are an important component of food and nutrition as they provide energy, vitamins, body-building nutrients, and minerals for human health . VegetabSolanum tuberosum L.) is a staple, nutrient-intensive, short-duration crop grown in 79% of countries [Solanum lycopersicum) is widely cultivated worldwide due to its versatility, high dietary fiber and vitamin content, and health benefits. It is a major source of lycopene and antioxidants that can potentially reduce the risk of cancer, osteoporosis, and cardiovascular disease [Brassica oleraceae) also provides a range of nutritive and health benefits, including anticarcinogenic, antioxidant, and anti-inflamantory properties [Capsicum annuum L.) is widely cultivated in East Asia, including India [Potato (ountries . Tomato  disease . Cabbageoperties . Pepper Brassica oleracea) belongs to the Brassicaceae family and is eaten as a vegetable in many countries. It exhibits many health benefits and contains good-quality phytochemicals [Abelmoschus esculentus L.) is a popular vegetable rich in vitamins, carbohydrates, minerals, and fats [In addition to the major crops, cucumbers, which belong to the Cucurbitaceae family, are important vegetables due to their economic and nutritional value. Immature cucumbers are used for pickles, and the mature fruit are used for salads. The fruit is soft, succulent, and rich in water, vitamins, and potassium (K). In addition to dietary fiber, cucumber contains copper, pantothenic acid, manganese, magnesium, and phosphorus (P) . Cucumbehemicals . Broccolhemicals . Severalhemicals . Among vand fats .Capsicum annuum, Lactuca sativa, Allium cepa, Brassica oleracea var. sabellica, and orange-fleshed Ipomoea batatas are the richest vegetable sources of phytochemicals with possible anti-obesity activity [Vegetables are important for human nutrition and disease prevention as they boost the intake of calcium, dietary fiber, folate, iron, magnesium, K, and vitamin C . Adequatactivity .Petroselinum crispum) and celery (Apium graveolens) are popular vegetables and the best sources of flavonoid apigenin and vitamin E [Daucus carota) contains a unique combination of three flavonoids\u2014quercetin, kaempferol, and luteolin [Vegetables in the Alliaceae family, including onion, garlic, leek, chive, and Welsh onion, are rich sources of thiosulfides, which are associated with a decline in several chronic diseases . Tomato itamin E . Carrot luteolin ,30,31\u2014thModern vegetable cultivation depends mainly on chemical fertilizers and pesticides. Chemical fertilizer application is one of the most endorsed systems in developing rigorous agriculture ,33, leadSolanum lycopersicum), a popular vegetable cultivated in more than 140 countries [Trichoderma spp. application as bio-organic fertilizer could be combined with chemical fertilizer application to achieve optimal yields and quality [Organic farming can supply quality food without adversely affecting soil health or the environment. Organic fertilizer improves soil dynamics and increases the soil\u2019s potential to retain water and nutrients in comparison to the effect of chemical fertilizers. Several studies have established that organic farming, which stringently restricts synthetic fertilizer use, is a potential substitute for minimizing the negative effect of chemical fertilizers, with the added benefit that organic farming products usually have enhanced nutritional and soil-quality properties ,37,38,39ountries , containountries . Organicountries . Ye et aountries  reported quality . Thus, aAzospirillum brasilense, Azotobacter salinestris, Burkholderia phytofirmans, Bacillus megaterium, Bacillus subtilis, Paenibacillus favisporus, Paenibacillus polymyxa, Pseudomonas fluorescens, Pseudomonas stutzeri, and Rahnella aquatilis, are consistently part of the PGPR-diversified taxa [Azospirillum, Azotobacter, Arthrobacter, Alcaligenes, Bacillus, Burkholderia, Enterobacter, Klebsiella, Pseudomonas, and Serratia have been linked with solanaceous vegetable crops [Pseudomonas putida and Bacillus amyloliquefaciens decreased the negative impact of three pesticides , maintained soil enzyme activities, and enhanced soil health and fertility [Plant-growth-promoting rhizobacteria are free-living soil microorganisms that naturally colonize the rhizospheric zone of plant roots. These bacteria increase plant growth and control several diseases , and theied taxa . These bied taxa ,47. Theyle crops . Thus, Ple crops . The PGPertility .Bacillus strains improved growth under greenhouse/field conditions of several vegetable crops, such as broccoli, cucumber, lettuce, pepper, and tomato [Biofertilizer contains living microbes that colonize and promote plant growth by enhancing nutrient availability to the host plant . The appd tomato ,66,67. Td tomato , involvid tomato , such asd tomato .This review summarizes the most updated findings on the role of PGPR as biofertilizers for vegetable crop growth and production. We also discuss the impact of PGPR on vegetables under biotic and abiotic stresses and provide a mechanistic overview for ameliorating several stresses.PGPR play an important role in enhancing soil quality, bioremediation, and stress control to develop eco-friendly sustainable agriculture . PGPR caSolanum tuberosum) requires high soil P for high biomass production. Limited P supply in soils reduces potato production by about 40% worldwide [Pantoea agglomerans strain P5, Microbacterium laevaniformans strain P7, and Pseudomonas putida, significantly impacted P solubilization and potato production [Various PGPR can be used as biofertilizers in vegetable crop production. orldwide . Potato orldwide . The synoduction . Moreoveoduction .Pseudomonas fluorescens, a solubilizing bacteria, increased broccoli growth when applied with a significant amount of fertilizer [Cauliflower is an important crop due to its high dietary fiber and nutritional value and belongs to the Brassicaceae family. Cauliflower also benefits from bioinoculation with PSB and other PGPR. Kushwaha et al.  reportedrtilizer .Fusarium infection in tomato causing wilt disease, are a serious concern worldwide. Nabi et al. [Bacillus aryabhattai to control Fusarium wilt disease in tomatoes and found higher amounts of amino acid and phytohormones in PGPR-treated plants. In addition to Fusarium, approximately 80% of tomato crop losses involve Alternaria solani, a causative agent of early blight disease [Bacillus subtilis) inhibited the mycelial growth of A. solani by up to 55% in tomato [Capsicum annuum) yield by applying a consortium of Klebsiella, Burkholderia, Panibacillus, and Bacillus spp. in the field for up to 30 days. The results revealed steady yield increases per acre with increasing PGPR formulations. Significant phenotypic and genotypic correlations also occurred between yield per acre and yield in each treatment.PGPR applied to vegetable crops can act as a biocontrol agent by protecting the plant from pathogens and pests. They achieve this directly by suppressing a broad spectrum of viral, bacterial, fungal, and nematode diseases and indirectly by altering the rhizosphere to favor beneficial microorganisms. Soilborne fungal pathogens that affect vegetable crops, such as i et al.  evaluate disease . The synn tomato . Tariq en tomato  evaluateSolanum melongena), a member of the Solanaceae family, is cultivated in tropical, subtropical, and Mediterranean countries. Increased Na+ uptake in saline soils hampers eggplant growth and yield [Xanthobacter autotrophicus BM13, Enterobacter aerogenes BM10, and Bacillus brevis FK2 decreased Na+ uptake and increased K+ uptake, which enhanced plant growth [Lactuca sativa L.) is sensitive to abiotic stress [Macrocystis pyrifera algal extracts and the PGPR Azospirillum brasilense, which increased germination rate and lettuce growth in saline conditions. In another study, PGPR-inoculated lettuce had a higher phenolic and flavonoid content than uninoculated plants under greenhouse conditions [Bacillus and Pseudomonas spp. increase salt tolerance in lettuce [Abelmoschus esculentus L. Moench), a vitamin- and mineral-rich vegetable widely used by humans, is a secret weapon for diabetic people [Pseudomonas spp. colonizes the rhizospheric region of okra roots and enhances plant growth [Bioinoculation of PGPR on vegetable crops can support plant growth by alleviating the impact of soil constraints . Eggplant . The accumulation of high ROS levels in plant cells is evident as oxidative damage, disrupting cellular homeostasis. Plant cells are furnished with sophisticated antioxidative mechanisms involving antioxidative defense enzymes, such as ascorbate peroxidase (APX), catalase (CAT), peroxidase (PO), superoxide dismutase (SOD), glutathione reductase, glutathione S-transferase, and guaiacol peroxidase (GPX). These defense enzymes are involved in scavenging and transforming ROS into nontoxic end-products and protecting cells from oxidative damage. In addition, plant cells induce several antioxidant molecules, such as carotenoids and phenylpropanoids, to conquer oxidative damage. Induced systemic resistance primes host plants to resist pathogen colonization through defense-related antioxidative enzymes and molecule production . Other mPseudomonas aeruginosa enhances proline accumulation and modulates superoxide dismutase activity in tomato infected with Spodoptera litura, increasing root and shoot biomass [The increasing demand for agriproducts can be met by enhancing yield efficiency and minimizing losses due to plant parasites (nematodes). However, the current chemical-based strategy exerts inappropriate and adverse effects on flora and fauna. There is a need for a biocontrol agent for nematode management, such as PGPR, that can suppress nematodes directly by producing enzymes, toxins, and other metabolic products or indirectly by regulating nematode behavior and altering root diffusates. PGPR induce the production of repellents by the host plant that adversely affect host recognition and alter nematode feeding site development or sex ratios inside root tissue . PGPR al biomass .In plants, physiological and chemical changes induced by PGPR that enhance environmental stress tolerance, including that to drought, salinity, cold, high temperature, and heavy metals, are recognized as induced systemic tolerance (IST)  Table 2Table 2. Achromobacter, Bacillus, Citrobacter, Mesorhizobium, Pseudomonas, and Variovorax could be used to enhance tolerance against drought stress in potato and tomato [Pseudomonas putida, Bacillus amyloliquefaciens, Azospirillum brasilense, and Bacillus subtilis, play an important role in plants for drought tolerance [Bacillus subtilis HAS31 reduced the impact of drought and maintained potato production  under severe water stress [Bacillus cereus AR156 to tomato plants also maintained productivity. The mechanisms involved in drought tolerance were attributed to increased SOD, POD, and CAT synthesis and upregulation of cytosolic ascorbate peroxidase gene (cAPX) and monodehydroascorbate reductase gene (MDHAR) [Bacillus licheniformis K11 reduced drought stress in pepper plants by increasing auxin and ACC deaminase production [PGPR such as d tomato ,172. Tomd tomato . Droughtd tomato . Droughtd tomato . Droughtd tomato . Severalolerance ,178,179.r stress  by alter (MDHAR) . In anotoduction .Abelmoschus esculentus) through ROS-scavenging enzymes and improved water use efficiency [Bacillus spp. to mineral nutrient solutions (MNS) [Most vegetable crops are affected by salinity stress , reducinficiency . Lettuceficiency ,187. Monficiency  studied ns (MNS) , which sns (MNS)  studied ns (MNS) , eggplanns (MNS) , tobaccons (MNS) .Burkholderia phytofirmans strain PsJN had enhanced survival under high heat stress. Martin and Stutz [Capsicum annuum L.), increasing the amount of dry substance and P uptake at higher temperatures. Similarly, Mukhtar et al. [Bacillus cereus for mitigating the heat stress effect in tomato and found that ACC-deaminase, exopolysaccharides, and the extracellular enzymatic attributes of PGPR modulated tomato growth traits under elevated temperature.Elevated temperatures constrain vital plant functions and reduce yield in various agroclimatic zones. It is a major environmental concern globally. However, PGPR have been implicated in heat stress tolerance in several plants  and improved nutrient absorption . Considering the positive impact of PGPR as biofertilizer in terms of crop yield and productivity. In addition, PGPR protect plants from various abiotic and biotic stresses through osmotic adjustment, biocontrol activity, siderophore production, and ACC-deaminase production, among others. PGPR are useful soil bacteria that can stimulate biological, chemical, and physical modifications and alleviate the detrimental effects of abiotic and biotic stresses in vegetable crops. Frequent application of PGPR-mediated bioinoculants will enhance vegetable yields and production, particularly under stress conditions. Governments and private agencies should promote biofertilizer use as an environmentally friendly replacement for chemical fertilizers. In addition, farmers need to be educated on the beneficial effects of PGPR-based biofertilizers for sustainable agriculture."}
+{"text": "Escherichia coli are remarkably versatile microorganisms and important members of the normal intestinal microbiota of humans and animals. This harmless commensal organism can acquire a mixture of comprehensive mobile genetic elements that contain genes encoding virulence factors, becoming an emerging human pathogen capable of causing a broad spectrum of intestinal and extraintestinal diseases. Nine definite enteric E. coli pathotypes have been well characterized, causing diseases ranging from various gastrointestinal disorders to urinary tract infections. These pathotypes employ many virulence factors and effectors subverting the functions of host cells to mediate their virulence and pathogenesis. This review summarizes new developments in our understanding of diverse virulence factors associated with encoding genes used by different pathotypes of enteric pathogenic E. coli to cause intestinal and extraintestinal diseases in humans. Escherichia coli, rod-shaped and gram-negative bacteria belonging to the Enterobacteriaceae family, were first isolated from infant stool and characterized by Theodor Escherich in 1885 ..Vibrio cShigella and EIEC as invasive foodborne pathogens [Bacillus dysenteriae, Shigella was previously characterized in 1897 by Kiyoshi Shiga in Japan after a severe epidemic causing more than 91,000 cases, with 20% mortality [Shigella. Thus, they may be categorized in a single pathovar. However, a considerable distinction is still maintained regarding the clinical significance of Shigella species [Shigella are unable to ferment lactose, are non-motile, and lysine decarboxylase negative. These properties are considered to differentiate Shigella species and EIEC from other bacteria [E. coli because it is an obligate intracellular pathogen with neither adherence nor flagella factors [Shigella comprise four species, including S. sonnei, S. flexneri, S. boydii and S. dysenteriae, which are responsible for varying degrees of diarrhea and acute intestinal and extra-intestinal diseases in humans [Severe mucosal and bloody diarrhea with abdominal cramps and fever are typical clinical features of bacillary dysentery or shigellosis caused by different species of athogens ,71. Initortality . Fifty y species . EIEC anbacteria . EIEC din humans ,75,76. En humans .Shigella infection commences with the penetration of the pathogen into the epithelial cells in the colon, passing through the microfold cells and reaching the underlying submucosa by a transcytosis mechanism [IpaBCD complex and IpaB genes to the \u03b11\u03b25 integrin and hyaluronan CD44 receptors, respectively. Membrane ruffling and epithelial cell cytoskeleton reorganization are mediated by IpaA, IpaC, IpgB1, IpgD, and virA to provide pathogen uptake [IpaH7.8, IpaB, IpaD, and IpaC have also been implicated in phagosome escape [VirG nucleates actin by inducing the acquisition of N-WASP, contributing to ARP2/3 formation and mediated unipolar actin tail formation on the surface of the bacteria [IpaC also activates SRC-family protein kinases to recruit the ARP2/3 complex at the site of the bacterial contact and induces actin polymerization to form a ruffle for bacterial entry. IpgB1 as mimicry of RhoG also promotes ruffle formation by the activation of RAC1. Actin microfilaments and their polymerization provide the propulsive forces needed for the directed movement of the pathogen throughout the host cell cytoplasm [OspE and IpaB, respectively. Some effectors, including VirA, IpaA, and IpgD, destabilize microtubules and actin and mediate the blockage of death in host cells to promote colonization and maintain its replicative niche [EIEC/echanism ,79. The echanism . EIEC isechanism . The virechanism . A T3SS echanism . Before n uptake . IpaH7.8e escape . VirG nubacteria . IpaC alytoplasm . EIEC prve niche .OspF and OspG inhibit the activation and gene transcription of NF-\u043aB. IpaH9.8 and OspB also suppress the expression of inflammatory cytokine levels such as interleukin-8. Other effectors, including OspZ, OspI, and IpaH4.5, also help EIEC downregulate and dampen the inflammatory responses [IcsB and VirA promote host-cell-autophagy-mediated degradation in EIEC by sequestering the VirG and destabilizing microtubules, respectively [Pic, SepA, SigA, and Sat are expressed and secreted in EIEC and Shigella species. Pic, encoded by chromosome locus, regulates ShET1 expression [SepA and Pic toxin genes belong to the serine protease autotransporters of the Enterobacteriaceae (SPATEs) family toxin. SPATEs are protease-based toxins released by autotransporter pathways and secreted usually by pathogenic E. coli and Shigella species [SigA-encoded cytotoxin contributes to intestinal fluid accumulation in the EIEC or Shigella-infected hosts [Shigella isolates, including iutA, iucB, EatA, VirF, VirB, IpaJ, and OspC3 implicated for aerobactin synthesis, complex siderophore iron receptor, SPATE toxin, the regulation of virulence factor gene expression, the control of virulence factor gene synthesis, the inhibition of the host cell trafficking membrane, and the inhibition of inflammasomes, respectively  encoded by aaiA-Y genes, located on a pathogenicity island identified on the chromosome and activated by AggR, mediates biofilm formation in EAEC. However, aaiA and aaiC genes have more commonly been found in typical EAEC strains worldwide [The virulence factors of EAEC are encoded on a family of virulence plasmids, the plasmid of aggregative adherence called pAA, and pathogenicity islands distributed throughout the chromosome . AggR isthotypes . The adhthotypes . The isothotypes . Regardithotypes . This prthotypes . Biofilmorldwide ,101.Shigella extracellular enterotoxin, a secreted autotransporter toxin, and an enteroaggregative heat-stable toxin, which are encoded by the pet, pic, sigA, sepA, sat, and astA genes, respectively [sigA and pic genes are located on pathogenicity islands, and the other toxin genes are localized on pAA [Shigella extracellular enterotoxins (ShET1) are cytotoxin, enterotoxin, and IgA protease like homologues inducing intestinal cyclic GMP (cGMP) and cAMP-mediated secretion. This toxin has also been found in EAEC/STEC hybrid strains [Sat, a SPATE toxin with cytotoxic and enterotoxic activities, impairs the tight junction and mediates autophagy in the epithelial cells. The enteroaggregative heat-stable toxin has mechanistic and physical similarities to the enterotoxin STa secreted by ETEC  and afimbrial adhesins (homotrimers or single proteins) ,112,113.ectively ,114. F18ectively ,88. The ectively . Some Afectively . Moreoveectively . The intectively ,112. Theectively .sigA toxins, encoded by sat, pet, EspP, and sigA genes, respectively; class II, which are not cytotoxic and consist of a protein involved in intestinal colonization encoded by the pic gene [pap, fim, and astA genes, respectively, have been recently detected in DAEC strains  strain that caused fatal outbreaks throughout Europe shows the importance of having a surveillance system in place. As food, water, animals, and people are potential vectors of enteric pathogenic E. coli transmission and contamination [E. coli pathotypes. This involves a broad spectrum of virulence factors encoded by specific gene clusters on the chromosome or mobile genetics elements. Therefore, for an optimal surveillance, new technologies such as high-throughput sequencing are required to gather precise information about the virulence profiles of E. coli pathotypes [E. coli pathotype virulence factors in pathogenesis will facilitate the development of novel therapeutics, the improvement of the design of effective vaccines, and the prevention of a further spreading of these diverse and widespread pathogens.Enteric thotypes . The ememination , such suthotypes ,135. In"}
+{"text": "Cutaneous examination revealed dry, desquamative, hyperpigmented, patchy, and macular lesions on the face, trunk, and bilateral upper and lower limbs , particularly over the buttocks and limbs. The most common skin finding is the shiny, varnished-looking nature of hyperpigmentation. The hair is usually sparse, dry, and brittle, with a reddish yellow hue. The alternate bands of normal and pale hair (flag sign) reflect periods of good and poor nutrition. The nail plate changes and exhibits thinning, fissuring, ridging, or prominent koilonychia.,The differential diagnosis includes marasmus, acrodermatitis enteropathica, free fatty acid deficiency, multiple carboxylase deficiency, pellagra (niacin deficiency), and malabsorptive syndromes. Kwashiorkor can be corrected by improving the intake of calories and protein."}
+{"text": "Reproductive disorders, including intrauterine adhesion (IUA), premature ovarian insufficiency (POI), and polycystic ovary syndrome (PCOS), are great threats to female reproduction. Recently, mesenchymal stem cells derived\u2013extracellular vesicles (MSC-EVs) have presented their potentials to cure these diseases, not only for the propensity ability they stemmed from the parent cells, but also for the higher biology stability and lower immunogenicity, compared to MSCs. EVs are lipid bilayer complexes, functional as mediators by transferring multiple molecules to recipient cells, such as proteins, microRNAs, lipids, and cytokines. EVs appeared to have a therapeutic effect on the female reproductive disorder, such as repairing injured endometrium, suppressing fibrosis of endometrium, regulating immunity and anti-inflammatory, and repressing apoptosis of granulosa cells (GCs) in ovaries. Although the underlying mechanisms of MSC-EVs have reached a consensus, several theories have been proposed, including promoting angiogenesis, regulating immunity, and reducing oxidate stress levels. In the current study, we summarized the current knowledge of functions of MSC-EVs on IUA, POI, and PCOS. Given the great potentials of MSC-EVs on reproductive health, the critical issues discussed will guide new insights in this rapidly expanding field. Mesenchymal stem cells (MSCs), a type of adult stem cells, could be harvested from various tissues, including bone marrow, umbilical cord, menstrual blood, endometrial tissue, adipose tissue, etc. . Given tFemale reproductive disorders are great threats to women\u2019s reproductive health and contribute to infertility , 16. AltConsidering the abovementioned advantages and great potentials in regenerative medicine, MSCs-EVs hold great promise as an alternative therapy for IUA and POI , 20. MorFor this review, an extensive literature search was performed in PubMed, Embase, and Cochrane libraries. Literature published in English and available up to January 2021 was included.in vitro fertilization treatment, angiogenesis, immune regulation, immunosuppressive, collagen remodel, anti-apoptosis, oxidative stress, embryo transfer. Then, the resulting articles were selected by screening titles and reviewing full-text of papers, only articles correlating to the interest topics and its relatives were selected for this review. In addition, we hand-searched references of relevant reviews, and included ongoing studies to locate other potentially eligible materials.The following keywords were used for the search, alone or in combination: mesenchymal stem cells, extracellular vesicles, exosomes, female reproductive diseases, intrauterine adhesion, thin endometrium, injured endometrium, endometrial fibrosis, premature ovarian insufficiency, premature ovarian failure, diminished ovarian reserve, polycystic ovary syndrome, follicles, Almost all cell types can generate EVs, and MSCs are no exception . There aAccording to the statement of the International Society for Extracellular Vesicles, ultracentrifugation has been the most commonly used technique to isolate exosomes or MVs, but the resultant EVs are a mixed population owing to the overlaps in the density or size of different EV types . As a coGenerally, the function of EVs is up to their originating cells . The theCompared with small animals, primates or human needs a higher dose of EVs. Currently, small-scale production of EVs is a restriction for the clinical application, thus, it is important to find new methods to scale up EV production . PreviouIUA, also known as Asherman\u2019s syndrome (AS), is characterized by the damage of the endometrial basalis layer and consequent obliteration of endometrium by fibrous tissues . PatientThe pathogenesis of IUA is shown in via regulating AKT/NF-\u03baB pathway, which could be attenuated by microRNA (miR)-466 -466 . In contmiR)-466 . In addimiR)-466 . Herein,miR)-466 . Zhu et\u00a0miR)-466 . Taken tin vitro experiments , and fluctuant reduction of estradiol (E2) \u201377. It aSTAG3, SMC1B, or REC8 gene related to meiosis, would result in oocyte arrested with concomitant POI  and P53 to reduce cisplatin or cyclophosphamide (CTX)-induced GCs apoptosis  outcome in aged murine model  into ovaries of POI patients, suggested CS/MSC-EVs could also be transferred by intra-ovarian injection . Howeverne model . IVF-embne model . Perhapsin vitro maturation (IVM) protocol based on heterologous follicular fluid and GCs supernatant (HFF/GC-IVM protocol) could improve the maturation rate of immature denuded oocytes, fertilization rate, and hatched blastocysts rate for women with PCOS  , 143. ADin vivo and in vitro  and increasing superoxide dismutase 1 (SOD1) and catalase expression \u00a0standardized purification and identification protocols for MSC-EVs, b) convenient storage and transportation methods for MSC-EVs, c) determined cargo of large-scale generation of MSC-EVs, d) determined the exact mechanism of MSC-EVs treatment, e) safety issues of MSC-EVs .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Background: Many older adults struggle with late-life depression, stress, and anxiety, especially when facing age-related transitions including retirement, relocation, and the death of a spouse. Given the consequences of depression among older adults, which include higher rates of suicide, timely interventions that help to manage depressive symptoms are essential. Objective: The primary purpose of this study was to explore the perceived efficacy of an online program in improving subjective depressive feelings. Methods: Older adult participants were recruited for semi-structured interviews (n = 24) in a web-based intervention that included interactive games and activities undergirded by a cognitive behavioral therapy (CBT) approach. Participants were asked to provide feedback about program features, including weekly module content, games, interactive activities and community interactions, and any perceived effects on their health behaviors and/or emotional well-being. Participants\u2019 responses were analyzed using qualitative content analysis. Results: Participants reported several gains, including developing the habit of forming ongoing, incremental goals, achieving wellness-related goals, and experiencing an overall positive shift in perspective. In addition, participants reported feeling greater gratitude, increased positivity, and improvement in mood. Featured games and activities helped to promote stress relief and entertainment, and mindfulness exercises were cited as the most helpful and/or enjoyable among participants. Participants expressed a preference for program content related to aging and aging-related transitions. Conclusions: This study demonstrated feasibility of an interactive web-based intervention for older adults with subjective depressive feelings, while also providing important findings about users\u2019 preferences for personalized, aging-related feedback."}
+{"text": "Ageism is an insidious form of injustice that is internalized from an early age with accumulating negative health impacts across the lifespan. Internalized ageism is associated with numerous public health outcomes, including physical and mental health, functional impairment, cognition, cardiovascular stress, hospitalizations, and longevity. Research has begun to document how ageism negatively impacts health through psychological, behavioral, and physiological pathways. Yet, limited research has addressed interventions to reduce internalized ageism. This study integrates stereotype embodiment theory, theories of successful and productive aging, and recent scholarly literature to present a conceptual model with potential downstream, midstream, and upstream interventions at micro, meso, and macro levels. Micro interventions include: social, physical, and cognitive engagement, as well as stress management. Meso interventions include: education, intergenerational contact, and narrative reframing. Macro interventions include anti-ageism policy, such as amendments to the Age Discrimination in Employment Act (ADEA). The conceptual model is described in detail, and implications for practitioners are discussed. The need to examine how policy influences health through the three pathways in stereotype embodiment theory is discussed. This study provides a working model for scholars and practitioners to use when considering paths toward reducing internalized ageism and optimizing well-being for aging adults."}
+{"text": "Paracoccidioides (P. brasiliensis and P. lutzi), endemic in tropical and subtropical areas of Latin America and more prevalent in Brazil,Paracoccidioidomycosis is a systemic mycosis caused by fungi of the genus A 45-year-old male patient living on the street sought care for tegumental lesions without improvement by antibiotic therapies that he had been taking for five months. He presented erythematous papules on the trunk, slightly painful ulcers with well-delimited and slightly elevated edges, and a granular and bleeding background in the anterior cervical area, face, nape, upper limbs, and thorax , and pur,As an opportunistic disease, paracoccidioidomycosis occurs in individuals with advanced immunodeficiency, suggesting exuberant lymphatic involvement, fistulization, polymorphic skin lesions, and severe and disseminated symptoms, and it has high morbidity and mortality,,Endemic systemic mycoses have increased in frequency in recent years in immunocompromised patients"}
+{"text": "Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has aggressed in more than 200 countries and territories since Dec 2019, and 30\u00a0million cases of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 have been reported, including 950,000 deaths. Supportive treatment remains the mainstay of therapy for COVID-19. There are no small-molecule\u2013specific antiviral drugs available to prevent and treat COVID-19 until recently. Herbal medicine can facilitate syndrome differentiation and treatment according to the clinical manifestations of patients and has demonstrated effectiveness in epidemic prevention and control. The National Health Commission (NHC) of China has recommended \u201cthree TCM prescriptions and three medicines,\u201d as a group of six effective herbal formulas against COVID-19 in the released official file \u201cDiagnosis and Treatment Protocol for COVID-19 Patients: Herbal Medicine for the Priority Treatment of COVID-19.\u201d This study aimed to develop a collaborative filtering approach to signaling drug combinations that are similar to the six herbal formulas as potential therapeutic treatments for treating COVID-19. The results have been evaluated by herbal medicine experts\u2019 domain knowledge. The novel coronavirus disease 2019 (COVID-19) pandemic caused by SARS-CoV-2 continues to cause a rush threat to global health. The outbreak that started in early December 2019 has spread worldwide. As of October 2nd, 2021, the overall number of patients confirmed to have the disease has exceeded 235,063,766 in more than 180 countries, though the number of people infected is probably much higher. More than 4,805,700 people have died from COVID-19.Although SARS-CoV-2 is widespread and causes multiple organ damage, no specific antiviral drugs or vaccines are currently available. Development of these treatments usually takes a long period, meaning that a more immediate treatment should be found if at all possible. A report issued by the World Health Organization (WHO) presented that the herbal medicine could be a potentially valuable resource to this end.The summarized clinical features of COVID-19 are shown in HuangDi Neijing  obtained from the TCMSP database with the SARS-CoV-2 proteins (24 proteins) obtained from the RCSB website. We docked the herbal medicine compounds with the SARS-CoV-2 proteins 10\u00a0times each and took the average of the 10\u00a0times as the docking results. Then the molecular fingerprints and trait characteristics of each herbal medicine are embedded into a vector. Based on the embedded vector, the similarity between each of the 482 herbal medicines and each of the herbal medicine in each prescription of \u201cthree TCM prescriptions and three medicines\u201d is calculated by collaborative filtering. Finally, based on the aforementioned \u201cthree TCM prescriptions and three medicines\u201d ranking list, the herbal medicine with the highest similarity value is selected and formed into a prescription . Finally, based on the ranking list of each herbal medicine in each prescription of \u201cthree TCM prescriptions and three medicines,\u201d the one with the highest similarity value is selected and formed into a prescription .Collaborative filtering algorithm is one of the more well-known and commonly used recommendation algorithms to predict possible herbal medicine combinations based on the docking results of molecules . We perfx and py, then the result of the reaction of drug combination  with neo-crown proteins is defined asThe training set for this task is a list of combinations of specific herbs with 482 herbs in the three-drug triad and their synergistic labels. First, given a drug combination , a molecular docking technique is used to output their respective vector representation x,y as a continuous vector representation xy. This combination vector describes how the two drugs interact through their respective biological targets. This combined vector is then docked to the new crown protein to predict its synergistic effects based on the Bliss score . We usedxy > exy. Therefore, we define its synergistic score as , and the similarity value between the herbal medicine. The formula is obtained by weighting the herbal medicine contained in the formula by the position of the ruler, subject, and coordinator.The similarity between the 482 herbal medicines and the herbal medicines in three TCM prescriptions and three medicines is calculated, and the top 20 herbal medicines with the highest similarity in each Lianhua Qingwen capsule are taken to form a 12 The 482 TCMs obtained from the TCMSP database contained a total of 13,448 compounds, of which 3,243 compounds appeared in multiple TCMs, with beta-sitosterol appearing most frequently in 237 herbal medicines, followed by palmitic acid and Sitogluside which appeared in 227 and 180 herbal medicines, respectively. After absorption, distribution, metabolism, and excretion (ADME) screening, 1665 compounds remained, of which 342 compounds are found in multiple herbal medicines, with beta-sitosterol occurring most frequently in 237 herbal medicines, followed by quercetin and sitosterol, appearing in 178 and 156 herbal medicines, respectively.There are 49 herbal medicines in the triad of three TCM prescriptions and three medicines, of which 17 herbal medicines appear in multiple formulations, with ephedra, bitter almond, and licorice appearing the most frequently with a total of five occurrences, followed by patchouli with four occurrences. These 49 herbal medicines contain a total of 3289 compounds, of which 760 compounds appeared in multiple herbal medicines, with the most frequent being palmitic acid, which appeared in 29 herbal medicines, followed by beta-sitosterol and CAM, which appeared in 21 and 20 herbal medicines, respectively. After ADME screening, 49 herbal medicines also contain 409 compounds, of which 62 compounds appear in multiple herbal medicines, with the highest number of occurrences being beta-sitosterol in 21 herbal medicines, followed by stigmasterol and kaempferol in 18 herbal medicines, respectively.When the compounds are docked to the herbal medicine results without ADME screening, the average of free energy values for 24 proteins is found to be below \u22127\u00a0kcal/mol for 3151 compounds, with chelidimerine having the lowest result of \u221210.73\u00a0kcal/mol. This compound obtained the lowest free energy value in 12 proteins  and is also low in the other 12 proteins, which is present in the Chinese herb C. alba. The next highest free energy is neo-przewaquinone-a with a mean free energy of \u221210.21\u00a0kcal/mol, which is present in the TCM Salvia miltiorrhiza.After screening by ADME, there are 388 compounds below \u22127\u00a0kcal/mol, of which -4-((S)-2- propoxy)-5\u2032,5\u2032,6a,8a-tetramethyl-8-methylenedocosahydro-1Hspirophenanthrene-10,2\u2032-pyran] has the lowest free energy value of \u22129.29\u00a0kcal/mol and is present in the TCM Puncturevine Caltrop Fruit. It is followed by bisindigotin with a free energy of -9.24\u00a0kcal/mol, which is present in the TCM indigoplant and natural indigo.Salvia divinorum. It is followed by Xambioona with a mean free energy of \u22128.89\u00a0kcal/mol, which is present in the herbal medicine licorice. The top ten compounds with the lowest free energy without ADME screening are shown in Without ADME screening, the results of compound-herbal medicine docking in three TCM prescriptions and three medicines in average over 24 protein free energy values show that 548 compounds are below \u22127\u00a0kcal/mol, with the lowest result of \u221210.21\u00a0kcal/mol for neo-przewaquinone-a. The compound obtained the lowest free energy value in seven proteins  and is found in the herbal medicine After ADME screening, 90 compounds are found to be below \u22127\u00a0kcal/mol, with compound Xambioona having the lowest free energy value. The next compound is 6-(3-oxoindolin-2-ylidene)indoloquinazolin-12-one with a mean free energy of \u22128.51\u00a0kcal/mol, which is present in the herbal medicines Panax quinquefolium, Da Qing Ye, and Qing Dai.In six separate ways, the results of the top ten are summarized in According to the vector value of herbal medicines and the situation of different herbal medicines in the prescription, the weighted average of three TCM prescriptions and three medicines is calculated, respectively. When not weighted according to the composing principle, Jinhua Qinggan granules have the highest vector value regardless of the way they are ranked, followed by the Lianhua Qinggan capsule and Xuebijing. According to the composing principle, Jinhua Qinggan granules have the highest docking value when sorted in three ways. The specific sorting results are shown in The distance \u22127\u00a0kcal/mol is used as the criterion for whether the receptor protein is bound to the compound. The binding position of the compound and the protein is determined, and the docking sites of the compound on the protein are divided. The results are shown in The results of collaborative filtration of herbal medicine in Xuebijing are shown in Cassia Twig, and Fortune Eupatorium Herb. The herbal medicines with the highest similarity in the ministerial medicines Bitter Apricot Seed, Gypsum, and Ephedra Herb are Willowleaf Swallowwort Rhizome, Chinese Gall, and Perilla Fruit, respectively, with a total of 13 herbal medicines in the guide. The ministerial medicines Rhubarb, Cablin Potchouli Herb, Peppermint, Cyrtomium Rhizome, Rhodiola, Indigowoad Root, and Heartleaf Houttuynia Herb have the highest similarity, including Chinaberry Bark and Root-bark, Storax, Wild Chrysanthemum, Java Brucea Fruit, Common Selfheal Fruit-Spike, Indigoplant, and Airpotato Yam Rhizome. A total of 24 herbal medicines are recommended by COVID-19.The top 20 herbal medicines with the highest degree of similarity between the 12 herbal medicines of Lianhua Qingwen capsule and the 482 herbal medicines docking are shown in The top 20 herbal medicines with the highest degree of similarity between the 12 herbal medicines of Xuanfei Baidu prescription and the 482 herbal medicines docking are shown in Astragalus membranaceus. This is followed by Ephedra, Radix et Rhizoma, Zedoary, and Yam, with six of the top 20 herbal medicines with the highest docking similarity appearing in the SARS-CoV-2\u2013recommended herbal medicine.The top 20 herbal medicines with the highest degree of similarity between the 20 herbal medicines of Qingfei Baidu decoction and 482 herbal medicines docking are shown in The top 20 herbal medicines with the highest degree of similarity between the 11 herbal medicines of Jinhua Qinggan granule and 482 herbal medicines docking are shown in Astragalus are among the top 20 herbal medicines with the highest similarity, and five of them appear in the SARS-CoV-2\u2013recommended herbal medicine. The herbal medicine with the highest similarity are Bai Qian, Suhe Xiang, mustard seed, and Han Xia, and the herbal medicine that appeared in the SARS-CoV-2\u2013recommended herbal medicine with the highest similarity are Mu Xiang, Suhe Xiang, Zhi Mu, and Han Xia.The top 20 herbal medicines with the highest degree of similarity between the 13 herbal medicines of Huashi Baidu prescription and the 482 herbal medicines docking are shown in Qingfei Baidu decoction, the lung soup, is suitable for light, normal, and heavy patients; Xuanfei Baidu prescription is suitable for normal type of dampness and toxin stagnation of the lung evidence; and Huashi Baidu prescription is suitable for heavy type of epidemic and toxin occlusion of the lung evidence. Lianhua Qingwen Capsule and Jinhua Qinggan granule are indicated for clinical symptoms of malaise with fever during the medical observation period, while Xuebijing is indicated for heavy- and critical-type patients during the clinical treatment period. Our recommended drug combinations can be used and adjusted according to the different clinical manifestations and the actual situation of the patients.Xuebijing-recommended Xuebijing-recommended Chrysanthemum, Crow\u2019s Nest, White Hair Xia Kuo Cao, Polygonum macrophyllum, Huang Yao Zi, and Perilla (repeated drugs will not be repeated). Humulus: clearing heat and detoxifying, diuretic, and laxative; neem bark: killing insects and healing ringworm; Suhe Xiang: opening the orifice to remove obscenity, opening up phlegm, moving Qi, and relieving pain; Crow\u2019s bile: clearing heat, detoxifying, killing insects, and intercepting malaria; white hair Xia Gu Cao: clearing heat and detoxifying, resolving phlegm and relieving cough, cooling blood, and dispersing blood; and yellow herb seed: dispersing knots and eliminating galls, clearing heat and detoxifying, cooling blood, and stopping bleeding.The recommended formula of Lianhua Qingwen Capsule 1: North Schisandra, Humulus, Bai Qian, Wu Bei Zi, Perilla, Neem Bark, Suhe Xiang, Wild The recommended formula of Lianhua Qingwen Capsule 2: Gonglao wood, Radix Codonopsis pilosulae, Tianshan snow lotus, Corrugated seeds, Moxa, Mugwort leaf, Semen lily of the valley, Lungwort, Mallow leaf, Big green leaf, Sansho root, and Coriander. Muxiang: Promotes the flow of Qi and relieves pain, regulates the middle, and directs stagnation; Mugwort: warms the menstruation and stops bleeding, disperses cold and pain, dispels dampness, and relieves itching; Lungwort: clears heat and detoxifies the blood, activates blood circulation, and reduces swelling; Malvaceae: clears heat and detoxifies the blood, relieves phlegm, diuresis, and laxative; and Sander root: clears heat and detoxifies the blood, disperses blood stasis, and relieves pain.The effects of each drug in the original formula of Xuanfei Baidu prescription include dispelling phlegm, and relieving cough and asthma; moistening the intestines; lowering Qi, opening paralysis, drying dampness, and strengthening the spleen; dispelling wind and dampness; brightening the eyes, activating blood circulation, and dispersing blood stasis; dispelling wind and clearing ligaments; clearing heat and dampness; detoxifying sweating and relieving symptoms; promoting the lung; cooling the blood and stopping bleeding; clearing heat and generating fluid; diuresis and laxative; relieving summer heat; removing steam; aromatizing dampness; harmonizing the stomach and stopping vomiting; dispelling summer heat and relieving toxins; activating blood and clearing menstruation; promoting water retention and decongesting swelling; intercepting malaria, benefiting Qi, and tonifying the middle; relieving pain; moistening the lung relieving cough; diaphoretic and detoxifying; harmonizing various herbs, resolving phlegm and Qi; eliminating food, dipping the lung, and lowering Qi; promoting water retention and swelling; expelling evil and clearing heat from the muscle; and relieving irritation and thirst.The first group of recommended drug combinations are snake bed seed, white front, chicory, perilla seed, yucca, Xia Gu Cao, Suhe Xiang, perilla, and mustard seed, with five times the seed. Among them, the snake bed seeds and mustard seeds dispel wind, Bai Qian and perilla seeds lower qi and relieve cough, chicory and Xia Gu Cao clear heat, Su He Xiang and Pei Lan aromatize dampness, and Wu Bei Zi is an astringent to the lung; the drugs in Xuanfei Baidu prescription also have these effects, and the two formulas have similar efficacy.The second recommended combination of drugs is one branch yellow flower, Tianshan snow lotus, hooked vine, shepherd\u2019s purse, coix seeds, Chuan Shao Gan, mugwort leaf, stretching grass, coriander, peony seeds, polygonum grandiflorum, and corrugated seeds. A branch of yellow flower, hooked vine, shepherd\u2019s purse, and coix seeds clear heat; Tianshan snow lotus dispels wind; mud bramble calms asthma; mugwort and elongated tendon grass dispel dampness; coriander detoxifies; and corrugated seeds dissolve phlegm. All these recommended drugs are consistent with the effects in the formula.The effects of each drug in the original formula of Qingfei Baidu decoction include diuresis and dampness, dispersing cold and relieving symptoms, warming the meridians, promoting the flow of Yang and Qi, dispelling phlegm and relieving cough, calming asthma, moistening the intestines, lowering Qi and opening paralysis, permeating dampness and water, strengthening the spleen and stomach, tranquilizing the mind and tranquilizing the spirit, generating sweat and relieving symptoms, promoting the lung and relieving asthma, relieving symptoms and fever, relieving the liver and depression, raising Yang Qi, promoting water and swelling, strengthening the spleen and Qi, drying dampness and water, stopping sweating, aromatizing dampness in the fetus, relieving stomach and vomiting, dispelling summer heat and relieving symptoms, clearing heat and fire, drying dampness and detoxifying the blood, stopping bleeding, moistening the lung, and lowering Qi in the fetus. It is used to relieve phlegm and cough, moisten the lung and lower the qi, relieve phlegm and cough, dispel cold and relieve symptoms, subdue rebelliousness and vomiting, dry dampness and phlegm, subdue rebelliousness and vomiting, eliminate lumpiness and disperse knots, induce diuresis and permeate dampness, relieve heat and promote drenching, tonify the spleen, nourish the lung, consolidate the kidney, benefit the essence, benefit the qi and tonify the middle, relieve acute pain, moisten the lung and relieve cough, relieve fire and detoxify, harmonize all medicines, lower the qi, regulate the middle, awaken the body, dispel cold and wind, relieve pain, warm the lung and dissolve drinks, open the orifices, relieve muscle and clear heat, relieve irritability and thirst, break up Qi and eliminate accumulation, and resolve phlegm and disperse phlegm.Astragalus to strengthen the spleen and benefit qi, and sour date palm to tranquilize the mind, and the original formula has the same effect.The first group of drug combinations recommended are powdered dioscorea, pepper, Bai Qian, cat\u2019s claw herb, Zizyphus, sericea, Suhe Xiang, Ping Bei Mu, Huang Lian, Chang Shan, Tu Fu Ling, Huang Qi, Xuan Shen, Sour date palm, Pei Lan, Atractylodes, and pepper. The drugs include powdered dioscorea, pepper, silkworm sand, Suhe Xiang, Tu Fu Ling, Pei Lan, Atractylodes, pepper to benefit dampness, Bai Qian, purple sage to lower qi, cat\u2019s claw herb, Ping Bei Mo, Chang Shan to resolve phlegm, Huang Lian, Xuan Shen to clear heat, The second group of recommended drug combinations is Panax ginseng flower, Ganoderma lucidum, Tianshan snow lotus, white ganoderma, cape berry, chicken bone herb, mugwort leaf, cornus, northern schisandra, earth maidenha, goldenrod, dried ginger, sandalwood, earth poria, black sesame, coriander, sea gold sand, ganoderma lucidum, and manzanita. Among these medicines, Panax ginseng flower, white creeper, shepherd\u2019s purse, chicken bone herb, and earthen berries clear heat; Ganoderma lucidum benefits qi; Tianshan snow lotus dispels wind; mugwort leaf, corn mullein, Tu Fu Ling, and Hai Jin Sha dispel dampness; northern schisandra, dry ginger, and Ganoderma lucidum strengthen the spleen; Yang Jin Hua and Manshan Hong stop cough; sandalwood stops pain; black sesame benefits essence; and coriander detoxifies toxins. The recommended drugs have the same efficacy as the original formula.in vitro; Daphyllum: clearing heat and detoxifying, cooling blood, and eliminating blemishes; Phellodendron: treating summer exopathogenic, fever, headache, generalized bone pain, stabbing pain in both eyes, chest tightness and nausea, and irregular bowel movement. In conclusion, this recommended formula is suitable for both light and common types of novel coronavirus pneumonia.Jinhua Qinggan granule\u2013recommended Tribulus terrestris, and coriander. Daphyllanthus: clearing heat and removing toxins, cooling the blood, and eliminating blemishes; semen lotus: clearing heat and removing toxins, dispersing blood stasis and stopping bleeding, diuretic, and decongesting; Tribulus terrestris: calming the liver, relieving depression, dispelling wind, and brightening the eyes; coriander: publishing and penetrating rashes, eliminating food and appetite, relieving pain, and detoxifying. In summary, the recommended formula is suitable for patients with novel coronavirus, mild pneumonia, common type, or with hypertensive underlying disease and concurrent Qi deficiency.Jinhua Qinggan granule\u2013recommended The effects of each drug in the original formula of Huashi Baidu prescription include lowering rebelliousness and stopping vomiting; dispersing lumpiness and dissipating knots, drying dampness and warming the middle class, dispelling phlegm and intercepting malaria, benefiting Qi, and tonifying the middle class; relieving urgency and pain; moistening the lung and stopping cough; dipping fire and detoxicating; harmonizing the herbs, dipping the lung, and lowering Qi; dispelling phlegm and calming asthma; inducing diuresis and subduing swelling; expelling and expelling evil, tonifying Qi, and fixing the surface; promoting diuresis; promoting toxicity and draining pus; astringing sores, clearing heat, and cooling the blood; invigorating blood, removing blood stasis, and relieving heat in the muscles; and relieving irritability and thirst.Astragalus, persimmon tip, pelargonium, mustard seed, half summer, bramble seed, and fivefold seed. Among them, cat\u2019s claw herb and halfsia can dissolve phlegm; red ginseng and Astragalus strengthen the spleen; neem bark, mustard seed, and bramble seed dispel wind; Suhexiang and pelargonium aromatize and dissolve dampness; snake bed seed, bai qian, and persimmon tip lower the qi; and five-fold seed is an astringent to the lung, which are consistent with the efficacy of the original formula and can be recommended.The recommended first group of drug combinations includes snake\u2019s bed sedge, white foreskin, cat\u2019s claw herb, red ginseng, perilla seed, neem bark, sulforaphane, The second group of recommended drug combinations is one branch of yellow flower, Tianshan snow lotus, white creeper, Pu huang, shepherd\u2019s purse, mullein, mugwort, sandalwood, atractylodes, coriander, polygonum grandiflorum, chicken bone grass, Xia Ku Cao, and corrugated seeds. Among them, one branch yellow flower, white creeper, shepherd\u2019s purse, polygonum officinale, chicken bone herb, and summer cress clear heat; Tianshan snow lotus dispels wind; corrugated root dissolves phlegm; Pu Huang facilitates water; Mu Xiang and sandalwood move qi; mugwort and atractylodes dispel dampness; and coriander detoxifies. The efficacy of all these drugs is consistent with the efficacy of the original formula.In summary, the recommended drugs are consistent with the efficacy of the drugs in the three triads, so the recommended prescription can be considered reasonable from the perspective of Chinese medicine."}
+{"text": "African Americans (AA) family caregivers provide the bulk of unpaid care to persons living with dementia (PLWD). This role leaves little time for the adoption of self-care behaviors\u2014critical to the prevention and management of chronic diseases. In this systematic review, we appraise caregiver self-care interventions that include AA caregivers of PLWD. PubMed, CINAHL, PsycINFO, Cochrane, and Embase databases were searched. Terms included AA/Black, self-care, caregiving, lifestyle, intervention, psychological stress, and faith/community. We initially found 250 references and after application of exclusion criteria and removal of redundant references, 18 articles were analyzed. Most interventions focused on impacting levels of caregiver burden, depression, physical activity, anxiety, or wellbeing. Psychoeducation, physical activity, and spiritually-focused interventions were most effective in improving outcomes in caregivers. Future studies should examine the impact of interventions on the prevention and management of chronic disease in AA caregivers of PLWD."}
+{"text": "Thali\u2019 (meaning plate) concept, emphasize combinations  of local, seasonal, and predominantly plant-based ingredients. These practices ensure that all of the necessary food groups are provided and fit well with current evidence-based recommendations, including the International Society for Pediatric and Adolescent Diabetes (ISPAD) 2018 Guidelines. Techniques for the preparation, cooking, and preservation of food further impact the GI and nutrient availability. These practices benefit nutrient density, diet diversity, and palatability and thus improve adherence to meal plans and glycemic control. This narrative review describes the ancient wisdom, food composition, and culinary practices from across India which are still valuable today. These may be of benefit worldwide to improve glycemic control as well as quality of life, especially in PwD.Nutrition is crucial for maintaining normal growth, development, and glycemic control in young people with diabetes (PwD). Undue restrictions cause nutrient deficiencies as well as poor adherence to meal plans. Widespread availability of low-cost, ultra-processed, and hyperpalatable food is further damaging. Most families struggle to find ways to provide nutritious, yet attractive, food with a low glycemic index (GI). India is one of the oldest continuous civilizations with a rich and diverse cultural and culinary heritage. Traditional dietary practices, including the centuries-old \u2018 India is one of the oldest continuous civilizations with diverse religions, cultures, traditions, socioeconomic strata, and agricultural practices living in harmony for millennia. The highly varied geography includes mountains, plains, deserts, tropical and subtropical forests, as well as a long coastline; from this geographical diversity comes an extensive biodiversity in plant species and food traditions ,2,3. An Diabetes, particularly type 1 diabetes, forces families to pay attention to food. Meal plans, timings, and discipline are key components in managing the intricate balancing act of a good glycemic control. The 2018 International Society for Pediatric and Adolescent Diabetes (ISPAD) Clinical Practice Consensus Guidelines recommend a diet \u201cbased on healthy eating principles suitable for all children and families, with the aim of improving diabetes outcomes and reducing cardiovascular risk\u201d . Post-prladoo) prepared from wheat, barley, chickpea, and oilseeds from the 4000-year-old Harappan civilization [A recent report of an excavation in a northwestern Indian state revealed multigrain, high-protein, handmade sweet balls , prepared from milk, to provide energy and to improve both palatability and the absorption of fat-soluble nutrients [A traditional meal was mostly plant-based, consisting of grains , pulses ,13, a vautrients . Meals wutrients , helped Over the centuries, with travel and migration, \u2018foreign\u2019 plants and ingredients were assimilated into local Indian cuisines. There were innovations, intermingling, and adaptation of food traditions.Thali\u2019 [Thali means plate in many Indian languages. The principle of Thali is to provide nutritionally balanced meals in a variety of textures and flavors with portion control by using small bowls for each food. Foods from all food groups, including whole grains, vegetables, pulses or non-vegetarian items, and a dairy product are incorporated.The \u2018Plate Method\u2019 has been in practice for centuries as \u2018Thali\u2019 ; Thali mThali meals included all food groups, providing a balance of proteins, fats, carbohydrates, dietary fiber, and a plethora of phytochemicals by incorporating a variety of plant foods in different colors [Thali meal.Traditional Indian t colors ,2,3,32. Thali matches well with the ISPAD 2018 recommendations \u201cchildren and adolescents with diabetes should eat a variety of healthy foods, including fruits, vegetables, dairy, whole grains, legumes and lean meat in amounts appropriate for age, stage of growth and energy requirements\u201d [The Indian rements\u201d .Medical nutrition therapy (MNT) forms one of the pillars for the management of type 1 diabetes . The goaThe primary determinants of the dose of the pre-meal insulin bolus are the amount and type of carbohydrates in the meal, the GI, and GL. Low GI foods are preferred, except when a rapid rise in blood glucose (BG) is desired . Choosing low to moderate GI and GL foods over high GI and GL foods , maintaiAlthough low carbohydrate diets are sometimes attempted to improve glycemic control, they can be nutritionally inadequate, impair growth and development, increase the risk of disordered eating behaviors, increase hypoglycemia or potentially impair the effect of glucagon in hypoglycemia, and increase cardiovascular risk ,17,36,37The increasingly popular hyper-palatable, ultra-processed, commercial foods, with high sugar, salt, and saturated and total fat content, have caused a sharp rise in the prevalence of obesity, type 2 diabetes, hypertension, and other non-communicable diseases ,40,41. PCarbohydrates provide 65\u201370% of calories across all regions in India, as shown in the starch study . Rice, wchutneys); or mixed with curd (raita). Some vegetables are pickled , or dried , for later use.Soluble fiber is an essential ingredient for healthy nutrition ,45. The A wide variety of seasonal, green, leafy plants such as spinach, fenugreek, amaranth, and mustard leaves are used. These provide iron, calcium, vitamins, antioxidants, and fiber without increasing the calorie and carbohydrate content . The leaThe abundance of leaves, fresh fruits, and vegetables provide fiber and micronutrients to the daily diet. These ideas can be incorporated in the cooking repertoire for children with diabetes and/or celiac disease (as they are gluten-free), making vegetables more acceptable and palatable.Lente carbohydrates are slowly absorbed in the body as they contain high amounts of viscous fiber, thereby delaying gastric emptying time and blunting the post-meal BG response. Sources of lente carbohydrates are lentils, split grams, chickpeas, kidney beans, green peas, soaked pulses and barley, which are commonly consumed in Indian cuisine ,49.Many starchy foods have a high GI, causing post-meal hyperglycemia in people with type 1 diabetes. Resistant starch (RS), present in a variety of starchy foods, acts like fiber in the large intestine as it is not digested in the small intestine. Hence, RS blunts the glycemic response, apart from having prebiotic benefits. Several traditional Indian preparations and whole-grain products such as cereals, legumes, nuts, seeds, and starchy vegetables contain high amounts of RS. RS type 1 (RS1) is a physically inaccessible starch found in partially milled grains, legumes such as beans or lentils, and seeds . Unripe Rice is the predominant cereal in southern, eastern, and north-eastern India , with thThe preparation and preservation of rice have an important impact on its GI and need to be considered to maintain good glycemic control.The rice kernel consists of four parts: the outermost inedible husk, bran, endosperm, and embryo. The bran contains fiber, vitamins, iron, fat, anthocyanin (pigment), non-starchy polysaccharides, and polyphenols. The endosperm is predominantly starch and encloses the embryo. Milling removes the husk and part of the bran; polishing further removes more bran and yields white rice ,55. CurrThe grain structure of rice also has an impact on the GI; unpolished rice with bran, long grain basmati rice, parboiled rice, and brown rice have a lower GI than short-grain rice, milled, or polished white rice ,57.Brown rice is a good source of magnesium, phosphorus, selenium, thiamine, niacin, and vitamin B6 . Other vA traditional rice preparation method is parboiling: a hydrothermal treatment that involves soaking the paddy in water, heating, drying, and then milling. This causes gelatinization of the starch into tightly packed structures, resulting in harder and glassier-looking kernels, and a much lower GI ,61,62,63Traditionally, old  rice was preferred to freshly harvested rice. The aging of rice increases the peak viscosity, making starch granules more resistant to swelling and rupture during cooking, thereby lowering the GI .chutney, and peanuts, which further blunt the GI and make it a wholesome meal. This would be particularly beneficial to PwD, even more so if accompanied by a bowl of plain yogurt or raita [A further reduction in GI is observed after refrigerating cooked rice for 24 h and reheating at low temperatures. This is due to the process of retrogradation, which increases resistant starch type 3 (RS 3) content . The cooor raita .Fermentation is frequently used across the country for different foods. A popular dish was cooked rice that is then soaked in water and allowed to ferment overnight. The superfluent water with added salt is an excellent hydrating agent in the hot and humid summers, while the fermentation improves the bioavailability of iron, potassium, and calcium by several folds, providing B-complex vitamins, especially B12, and probiotics . The resBox 1Using hand-pounded rice: brown/red/black riceUsing parboiled rice instead of polished white riceUsing old  riceUsing cooked rice that has been cooled overnightCombining rice with protein sources like pulses, yogurt, cottage cheese, egg, fish, poultry, meatghee or nuts and seeds in moderate amountsAdding Combining rice with a variety of vegetables as a part of a mixed mealSqueezing lemon or adding tamarind to rice mealsWheat is the staple grain in northern and central India. Whole wheat contains complex carbohydrates, dietary fiber, B vitamins, phytochemicals, and some minerals. Milling of wheat into all-purpose flour (refined flour), or even semolina, destroys the intact cell wall structure in which the starch granules are entrapped and increases the surface area, thereby exposing the starch to enzymatic digestion and increasing the GI. Nutrients are also lost when the husk is removed after milling. Therefore, the consumption of food made from whole wheat flour is recommended over refined flour-based products ,59,65,66roti or chapati\u2014made of whole wheat flour, despite increasing use of refined carbohydrates like polished white rice, or refined flour products in industrial foods. The chapati has a GI of 45\u201372 [chapati by adding pulses, vegetables, eggs, meat, or spices, as well as by cooking them in different ways. These modifications are described in detail in Wheat is still widely consumed in India as homemade unleavened flatbread\u2014of 45\u201372 ,67, whilof 45\u201372 , due to Apart from being ground into whole wheat flour, wheat is sprouted and made into porridge. Sprouting for a limited period increases the activities of hydrolytic enzymes, improves the content of some essential amino acids and vitamin B, and decreases dry matter, starch, and anti-nutrients . The par\u2018Khapli\u2019 wheat (Triticum dicoccum), one of the world\u2019s ancient cereals, was among the first cereals to be grown in the fertile plains of India and is being revived. Compared to polished wheat, it is more disease-resistant, has higher dietary fiber , amylose, protein and ash content, has a lower fat and carbohydrate content, and therefore has a lower GI [Emmer or lower GI ,72.Box 2Khapli (Emmer) wheatUsing whole wheat flour and Using broken wheat and larger grit semolinaMixing bran and pulse flours like gram flour, soya flour, or millet flour with whole wheat flourAdding grated or pureed vegetables, green leafy vegetables, herbs, and spices to whole wheat flourKneading whole wheat flour with yogurt, whey, milk, leftover pulse curry, or vegetable currieschapati/paratha made from whole wheat flour with protein sources such as egg, minced meat, cottage cheese, pulses, and vegetablesStuffing the Adding fat in moderate amountschapati when mixed with whole wheat flour [Barley is mentioned in the Rigveda (4000\u20138000 years ago) as a staple food, predating wheat. It has a low GI of 25  and is rat flour .Wheat and rice were grown and consumed mostly in the fertile northern Gangetic plains. However, large parts of the subcontinent were arid or semi-arid and relied on a variety of millets as their staple grain. Some of the better-known millets are finger millet, pearl millet, sorghum, barnyard millet, foxtail millet, kodu, proso millet, and little millet. The consumption of millets is gaining prominence today.Millets are hardy plants with a short growing season of 45\u201360 days, can grow in poorer soil, need much less water or pesticides than cereals, and contain more protein, fiber, phytochemicals, antioxidants, and minerals . The pecidlis, pancakes, soups, salads, and other dishes. Most millets have lower GI than wheat as well as rice, and thus beneficial in diabetes. However, finger millet is an exception, with a high GI of 84 [Pearl millet, a staple in the western part of India, has a GI of 55  and is aGI of 84 . Being gMaize was introduced in India as late as the 16\u201317th century by Portuguese traders and is now grown across the country. Rich in magnesium and other minerals ,79, the Starchy vegetables, such as potatoes, sweet potatoes, corn, yams, or taro root (colocasia) have become popular in Indian cooking in the last 500 years. The carbohydrate content of these vegetables must be factored in for insulin dosing. Two popular starchy vegetables with prebiotic properties and moderate GI, which are native to India, are raw banana (plantain) and tender jackfruit ,53,81,82Bananas have been considered sacred and are part of many religious ceremonies in India. All parts of the plant are used: the raw and ripe fruit, the flowers, and the pith are eaten; the leaves are used to wrap food for cooking and to serve food. They are a good source of resistant starch ,27,50,51Another native plant is jackfruit. Tender jackfruit is a delicacy in India. Apart from being prepared as vegetables, curries, and pickles, its flour is also used as a cereal substitute due to its fiber and resistant starch content, lower GI and high nutritive value when compared to wheat and rice ,82,84,85Pseudocereals, such as buckwheat, amaranth, and bamboo rice, have been used since ancient times, particularly on holy days as cereal substitutes. Buckwheat, native to the Himalayas, has a high fiber content (27.4%) that is closer to vegetables than other cereals. There is also a high proportion of resistant starch (33.5\u201337.8%) and proteins with a well-balanced amino acid composition. It also contains minerals including zinc, copper, and manganese; bioflavonoids, especially rutin and quercetin; and high antioxidant activity. With a GI of about 50 ,86, it iISPAD 2018 guidelines recommend that sucrose use should be minimized in diabetes and can provide up to 10% of total daily energy intake . This ma(ladoos) are made from sesame, peanuts, Bengal gram, green gram, black gram, and other seeds. Many had milk or milk-based products as the base ingredient, such as desserts made of thickened milk, low-fat hung curd, and cottage cheese [A wide range of healthy traditional dessert options, with variable degrees of sweetness, evolved in different regions. They could have a base of pulses, nuts, appropriate dry fruits, fruits, or vegetables. For example, sweetened balls e cheese ,2,88.chutneys, pickles, and preserves in significant quantities and can give rise to unexpected glucose spikes. In some cuisines, sugar or jaggery is added to all gravies and vegetables, which needs to be factored in when counting carbohydrates [Sugars may be present in hydrates .In summary, it is possible for PwD to get 45\u201350% of their energy from carbohydrates and achieve good glycemic control by switching to whole grains, especially unpolished millets, that provide low to moderate GI complex carbohydrates with resistant starch, high fiber, and micronutrients.India has the highest number of vegetarians (20\u201330%) in the world  and evenWhole pulses have less carbohydrates and twice the amount of protein than whole-grain cereals . The carbohydrate is mainly complex and non-digestible , and is hence a \u201cgood\u201d (low GI) carbohydrate . Pulses ghee. Soaking before cooking reduces cooking time, improves digestibility, and reduces anti-nutritional factors like phytates, tannins, and enzyme inhibitors. This increases the absorption of the nutrients and reduces the bloating effect of the lectins and phytates [Kokum (Garcinia indica), tamarind, raw mango, gooseberry, or lemon to the pulses are common and lower the GI while adding nutritive value and taste to the dishes [There is a wide variety of pulses grown in India, and of recipes using them. They can be easily integrated into food practices across the world, improving glycemic control, protein and fiber content, and overall nutritive value and palatability. The most popular pulses include pigeon pea, green gram, Bengal gram, chickpea, black gram, moth beans, lentil, cowpea or black-eyed beans, horse gram, peas, and kidney beans. These whole or split pulses (with or without skin) are a part of major meals. They are usually soaked, boiled, and tempered with spices or curry leaves cooked in a little oil or phytates ,24,25. Se dishes .Pulses are often cooked with vegetables and/or sometimes meat. Many pulses can be sprouted (germinated) and then eaten raw, steamed, or pureed to make pancakes. Sprouting furthers the advantages of soaking, increasing the bioavailability of protein and micronutrients  .Soybeans (Glycine max) are particularly rich in proteins: 100 g has 36 g protein , equivalFor pulses, soy, and other beans, it is important to consider the increase in GI with increased processing  and smaller particle size . InsulinSome commonly used ways to include more pulses in the meals are presented in Box 3Using whole pulses or pulses with skinUsing sprouted pulses (raw/steamed/ground/pureed)Adding pulses (and/or its flours) like soybean to grains like wheat, rice, and millets in meals and snacksAdding pulses to vegetables and meat curriesSubstituting cereals with pulses in snacks and meals e.g., in pancakes, roasted gramchutneys) with mealsConsuming pulse-based spiced pastes (ghee) for cooking. Apart from being consumed plain, healthy additives like powdered nuts or spices improve the taste and nutritive value. Adding raw turmeric powder to milk was traditionally popular for enhancing immunity against infections and improving sleep quality; this is now popular globally as Golden Milk or Turmeric Latte. Curcumin is also known to be beneficial in type 2 diabetes [The consumption of dairy products has been traditionally encouraged across the country. Milk was consumed in various forms and was also used for obtaining fat  , providepaneer), containing 20 g proteins, 12 g carbohydrate/100 g, is a very popular food item which has been used in a wide variety of ways [Indian cottage cheese/soft cheese . Consuming milk in recommended amounts at bedtime can prevent nocturnal hypoglycemia, especially in PwD using regular and intermediate-acting insulins at night .Fish and other seafood are consumed regularly in the coastal areas and provide essential fatty acids and good quality protein. The meat most widely available is goat meat (mutton) and chicken, which is less fatty than beef, pork, or lamb meat . Being nIt is important to have adequate fats in the diet, particularly for the growing child, to provide palatability, energy, and essential fatty acids especially fat-soluble nutrients. In PwD, the added fats also reduce the GI of the meal. However, in excess, fats impair glycemic control and cause obesity and dyslipidemia, increasing the risk of cardiovascular disease. The American Heart Association advises children to be given more polyunsaturated (PUFA) and monounsaturated (MUFA) fatty acids than saturated fats to reduce cardiovascular risk later in life . ISPAD 2ghee, and milk products, with a small percentage coming from meat and fish [Traditionally, the fat sources in Indian cooking were edible vegetable oils, and fish . The vegghee) is condemned as being a saturated fat. However, they are less atherogenic than animal and other plant fats like lard and vanaspati [ghee to chapatis/steamed rice/idlis/dals flattens post-meal glucose spikes, apart from adding taste and aroma to the meal [Coconut oil is often vilified for its 91% saturated fatty acid content; similarly, clarified butter  and docosahexaenoic acid (DHA), are consumed in coastal areas [Marine fish such as salmon, sardines, or al areas .Though carbohydrates are the primary determinants of insulin doses, fat and total calories must also be considered when calculating pre-meal doses. It is easier to reduce post-meal spikes and enhance satiety by consuming some healthy fat in each meal.chutneys, or desserts. They are low in carbohydrates, and are a good source of MUFA, protein, fiber, and antioxidants. Some nuts like walnuts and flax seeds are good sources of omega 3 fatty acids [chutney with idli or dosa, as is commonly done, lowers the GI [A variety of nuts, such as cashews, almonds, walnuts, sesame, pistachio, and pine nuts, as well as the less expensive seeds, including melon, watermelon, pumpkin, cucumber, flaxseed, and peanuts, are commonly used. Roasted peanuts or foxnuts, and other seeds, can be eaten by themselves, mixed with other nuts, or added to gravies, salads, rice, drinks, tangy ty acids . Peanutss the GI . Many prs the GI . This isladoos or bars (chikki) with jaggery/dates make excellent healthy desserts, especially before, during, and after vigorous play, or at bedtime, to prevent hypoglycemia.The range of low GI snacks made with lentils, nuts, and seeds are invaluable for PwD. Bengal gram, peanuts, or sesame seeds made into Children and adolescents with diabetes have the same vitamin and mineral requirements as their peers. Deficiencies impact growth, intelligence, immune function, and wellbeing. The ISPAD 2018 Guidelines emphasize that these needs should be met by consuming a mixed, balanced diet rather than artificial supplements . The Indkoshimbir , improved the absorption of fat-soluble nutrients such as retinol and provitamin-A carotenoids. Adequate calcium, phosphorus, and magnesium intake is ensured by consuming low-fat dairy and fresh, green vegetables. Milk and milk products, finger millet, beans, dark green leafy vegetables, sesame seeds, amaranth seeds, and horse gram are rich sources of calcium. Magnesium is abundant in nuts, seeds, legumes, whole grains, and leafy greens [Traditional Indian food-processing styles ensured the daily consumption of greens, colored fruits and vegetables, grains, legumes, herbs, and spices . The addy greens . The bioy greens .Hydration is important for good health and requires extra attention in PwD, particularly during and after exercise, and during periods of poor glycemic control, when polyuria may occur. Current-day commercial sugar-sweetened beverages (SSB), juices (sweetened or unsweetened), and even sugar-free drinks are linked to obesity . High glThe traditional Indian drink of choice was water stored in an earthenware pot. This helped purify and alkalinize the water while cooling it naturally. A wide range of refreshing beverage options were popular, some giving a \u2018cooling\u2019 effect in the summer, others were \u2018warming\u2019 for the winter. These beverages also provided electrolytes and nutrients.rasam, ginger cumin water, unsweetened lemon juice, amongst others [The impact of these beverages on glycemic control is variable and depends on the composition. Beverages recommended routinely in PwD are low calorie, low carbohydrate fluids, like thin buttermilk, t others ,2,111. Skokum, vinegar, onion, garlic, and fresh/dry raw mango) commonly replace salt as taste enhancers and therefore reduce the need for salt.PwD should be as careful about sodium intake as the general population . A rangemasalas) used in Indian cooking provides immense flavor and function. Some common Indian spices used in daily cooking are listed in The wide array of spices , and a short afternoon siesta. This was appropriate for the tropics and was a practical form of intermittent fasting. In communities where schools start early and close by early afternoon, this routine can be emulated by early waking, post-lunch nap, and early night meal, since late dinner or late bedtime have been shown to contribute to obesity [The  obesity .thali, with greens, complex carbohydrates, proteins, and healthy fats, can be adjusted to ensure smooth post-prandial glycemic excursions, which the insulin bolus can handle well. The child using pre-meal regular insulin may experience hypoglycemia after 2\u20133 h and would benefit from a mid-meal, portioned, moderate carbohydrate snack like fruit or a pulse-based snack . Individuals on rapid-acting insulin could benefit from a mid-meal, portioned, low-carbohydrate snack such as peanuts, nuts and seeds, cottage cheese (stir-fried/grilled/with vegetables), yogurt, buttermilk raita, or egg. Many of the Indian snacks and beverages can be prepared in a low-carbohydrate form, which may not need a pre-meal insulin bolus.In children with type 1 diabetes, insulin type and regimens would differ, based on affordability, school timings, and schedule. These may vary from regimens combining once or twice daily intermediate-acting insulin with pre-meal regular insulin before breakfast, lunch, and dinner; to a once-daily long-acting analog with boluses of regular insulin or rapid-acting analog before each meal and large snack; to rapid-acting analog on an insulin pump. The mixed meal in a Celiac disease is more common in people with type 1 diabetes. The diagnosis can be devastating for families, who fear the severe dietary restrictions. The variety of gluten-free options available in traditional Indian food ease the problem. These include rice, millets, maize, pulses, buckwheat, amaranth, and flours of raw banana or jackfruit. Vegetables and fruits, nuts and seeds, spices and chutneys, dairy products, eggs, and other non-vegetarian foods, can all be enjoyed in a gluten-free diet .neem had medicinal qualities [prasad), along with moderate GI foods such as spiced gram, peanuts, green gram, or other pulses with coconut. Ripe bananas were also often given as prasad: the comparatively higher GI was particularly helpful after fasting. Similar principles can be followed during parties and functions, with wise choices, small portions, and covering extra carbohydrates, protein, and fat with adequate extra insulin and extra physical activity [India celebrates multiple festivals that are associated with festive foods\u2014sweet and savory. These were usually season-specific, mostly using fresh ingredients. Many items have a low GI, and include healthy cereal-pulse combinations, nuts and seeds, pseudocereals, vegetables, and fruits. Preparations with ingredients like ualities . Howeveractivity .Some examples of festive foods of India are provided in This is not a systematic review of the literature. An attempt has been made in this narrative review to revisit traditional Indian food wisdom and healthy ancient culinary practices, discussing how the principles might be useful and applicable in children and adolescents living with type 1 or type 2 diabetes globally. Many common use practices do not have peer-reviewed evidence published to specifically support children with type 1 diabetes.Thali matches well with the current ISPAD Clinical Practice Guidelines for type 1 diabetes. Various cooking methods and meal combinations enhance the nutrient bioavailability and lower the GI, thus making it beneficial to both the general population and for people with diabetes. Many of these ancient traditions continue or are being revived. It would be helpful to incorporate these food concepts, combinations, and techniques in our daily lives. Diabetes care teams across the world can help people with diabetes, and their families, explore these options to improve glycemic control and quality of life.Traditional Indian food practices evolved over thousands of years and provide a holistic approach. The emphasis was to provide wholesome, balanced, nourishing meals, which were also visually appealing and palatable. Meal combinations were guided by scientifically sound principles, ensuring nutrient density and diet diversity. The traditional Indian Thali is schematically represented in Some common, practical, simple suggestions for lowering GI are listed in Box 5Processing grains to the minimum. Using unpolished, coarse, long grain, and aged grainsUsing slow digesting (lente) carbohydrates with higher amylose and soluble fiber content such as pulses and barleyUsing meal combinations to add protein, fiber, and healthy fat to mealsUsing resistant-starch-rich foods and methods which enhance resistant starch contentUsing an acidic medium such as lemon, vinegar, or tamarindUsing slightly unripe fruits, since the GI increases as fruit ripens"}
+{"text": "Presently, notwithstanding the progress regarding wound-healing management, the treatment of the majority of skin lesions still represents a serious challenge for biomedical and pharmaceutical industries. Thus, the attention of the researchers has turned to the development of novel materials based on cellulose derivatives. Cellulose derivatives are semi-synthetic biopolymers, which exhibit high solubility in water and represent an advantageous alternative to water-insoluble cellulose. These biopolymers possess excellent properties, such as biocompatibility, biodegradability, sustainability, non-toxicity, non-immunogenicity, thermo-gelling behavior, mechanical strength, abundance, low costs, antibacterial effect, and high hydrophilicity. They have an efficient ability to absorb and retain a large quantity of wound exudates in the interstitial sites of their networks and can maintain optimal local moisture. Cellulose derivatives also represent a proper scaffold to incorporate various bioactive agents with beneficial therapeutic effects on skin tissue restoration. Due to these suitable and versatile characteristics, cellulose derivatives are attractive and captivating materials for wound-healing applications. This review presents an extensive overview of recent research regarding promising cellulose derivatives-based materials for the development of multiple biomedical and pharmaceutical applications, such as wound dressings, drug delivery devices, and tissue engineering. Skin is the largest and the main organ that forms the body covering, with a complex structure of tissues, and creates an exterior defense barrier, which protects the internal organs from mechanical impairments, radiation, chemicals, and foreign invaders (bacteria and viruses) . More thThe epidermis is a physical protective barrier against the external factors, which does not contain blood vessels. It is comprised of two main categories of cells: dendritic cells and keratinocytes (keratin synthesis), along with Langerhans cells (engaged in the immune reaction), Merkel cells (sensory corpuscles), and melanocytes (melanin synthesis) ,7. The dThere are many factors and systemic diseases that can alter skin functions, for example, pathogens, pollution, radiation exposure, smoking, malnutrition, obesity, diabetes mellitus, peripheral vascular diseases, pressure ulcer, inflammatory, bleeding, or metabolic conditions and immunosuppression ,16. In mIn this review, we mainly present studies from the last 10 years regarding the cellulose derivatives-based wound dressings with various bioactive agents to accelerate the regeneration of skin tissue injuries. Cellulose derivatives have proper and optimal applicability to develop novel wound dressings that can enhance wound healing, obtained by substituting the hydroxyl groups from cellulose molecule with different alkyl groups . Thus, tA wound represents a lesion, break, tear, or damage of skin structure and function, produced by physical, mechanical (surgery), thermal, chemical, and electrical (burns) factors; an injury can also be the result of an underlying medical or physiological disorder  ,31,32. Tetiology: surgical, traumatic, radiation and malignant wound, chemical or thermal injury, pressure ulcer, diabetic foot ulcer, vascular ulcer, or atypical injury;healing time (duration) and nature of the injury restoration process: acute or chronic wounds;depth of injury or number of skin layers affected: superficial, partial thickness  or full-thickness wounds;complexity: simple, complex, or complicated wounds;contamination and postoperative infection risk: clean wound (class I), clean/contaminated wound (class II), contaminated wound (class III) or dirty wound (class IV);mode of lesion: abrasion, ulceration, incision, laceration or degloving;tissue loss: without tissue loss  and with tissue loss ;appearance: necrotic, sloughy, infected, malodorous, granulating, and epithelializing wound;injured tissue coloration: black, green, yellow, white, brown, purple, beefy red, or pale pink wounds ,36,37.Wounds are classified according to many parameters:From all of the classification criteria, the most significant and decisive criterion for selection of an adequate dressing and for optimal wound-healing management is the healing time (duration) and the nature of the injury restoration process. Hence, an acute injury heals totally, without external support, with minimum scarring, and usually demands a period for healing from 8 to 12 weeks . An acutWound healing is a sophisticated and well-coordinated process , which iThe wound repair process consists of four different, overlapping, and exactly programmed stages: hemostasis, inflammation, proliferation, and remodeling (maturation) phases , illustrThe first and the shortest stage (5\u201310 min) of the wound repair process is hemostasis, an instantaneous reaction towards lesion , whose mMany factors can interfere with the wound-healing phases, the consequence being an improper or damaged wound repair process. In general, these factors can be categorized as local and systemic. Local factors affect features of the lesion itself, and systemic factors represent the general health or condition states of one person, which influence the capacity to heal . The maiIn injured tissues, vascular disruption generates depletion of oxygen, causing hypoxia, and, consequently, impaired wound healing. Temporary hypoxia stimulates the lesion repair process, but persistent hypoxia prolongs this process . HypoxiaA main risk factor for the damaged lesion repair process is increased age due to multiple comorbidities . Acute iIn past years, due to the technology\u2019s noteworthy progress, various wound dressings were formulated worldwide to cure all types of tissue lesion. Dressings play a fundamental role in wound-healing management because these protect tissue lesions from external invasion  , preventFor the development of dressings, which allow rapid healing, with minimal scars on the body surface, it is necessary to develop new biopolymeric materials that accomplish some properties to create the ideal wound dressing that are reviewed in 2 and CO2), to absorb exudates that form on the lesion site [The ideal wound dressing preferably presents the following features: biocompatibility, biodegradability, non-toxicity, chemical inertness , to be aion site , to stimion site , to be aion site , to adjuion site . Also, wion site , to haveion site . A potential classification of wound dressings comprises passive dressings and active dressings, depending on the presence or absence of one or more pharmacologically active substances or natural substances , which cPassive dressings can be considered dry traditional dressings, which are fundamental for a faster wound-healing process. There is a wide simple range of passive dressings for several types of skin lesion: cotton wool, lint, gauze, natural, and synthetic bandages\u2013they work as primary dressing or secondary dressing ,84. ActiModern or advanced dressings were designed to cover tissue lesions and in this category are included the hydrogels, hydrocolloids, semi-permeable films, semi-permeable foams, and alginate dressings ,85. The The main materials underlying the modern wound dressings are polymers, which can be natural  ,88, semiThe first class of modern wound dressings includes hydrogels, also called hungry or smart networks, which can be defined as three-dimensional networks, consisting of cross-linked polymeric materials , with a Hydrocolloids are another class of modern wound dressings, which are based on a combination between elastomers, alginates, and colloidal materials. They present the ability to take in a small or medium quantity of exudates, have good biocompatibility, biodegradability, and adhere to the skin . These dThe third class of modern wound dressing includes semi-permeable films. They are flexible and elastic sheets, made from transparent polyurethane. For a good attachment to the skin, polyurethane films present an acrylic adhesive on one part ,105. FilThe following category of modern dressing includes semi-permeable foams, which showed a vast improvement and favorable biocompatibility . They haThe last class of modern wound dressings is represented by alginates, a category of polysaccharides extracted from brown algae and kelp, with remarkable absorption properties . AlginatDuring the last decades, cellulose derivatives, also known as cellulosics, have become extensively used in many fields, from food, cosmetics, biomedical, and pharmaceutical industry  to biofu6H10O5)n [2, C3, and C6 of each molecule of glucose, which have a good capacity to form powerful inter- and intramolecular hydrogen bonds [Cellulose, discovered by Anselme Payen in the 19th century, is a natural polymer, an organic polysaccharide from plant origin, non-toxic, with a structural role, being the most plentiful and renewable biopolymer on Earth . Structu6H10O5)n . The cheen bonds . As a reen bonds ,121. Celen bonds . To improve the solubility problems of cellulose and to extend its applications, the chemical structure of this polymer can suffer several changes to obtain the cellulose derivatives, which have suitable physicochemical properties to be used in many fields, especially in the pharmaceutical and biomedical industry . The modCellulose ethers derivatives are characterized by high molecular weight and the greatest applicability in the pharmaceutical domain of all these derivatives are: sodium carboxymethylcellulose (NaCMC), hydroxypropylmethylcellulose (HPMC), methylcellulose (MC), hydroxyethylcellulose (HEC), ethylcellulose (EC), hydroxypropylcellulose (HPC), hydroxyethylmethylcellulose (HEMC) and benzylcellulose (BC) ,127. TheCellulose esters derivatives are extensively used in the pharmaceutical industry as enteric coated drug delivery devices, and they also have excellent properties to form films. There are two categories of cellulose esters: organic and inorganic, but the most common in the pharmaceutical practice are organic esters . Among tAnother classification of cellulose derivatives depends on the water solubility of these polymers; thus, there are described in water-soluble cellulose derivatives and water-insoluble cellulose derivatives. In the first category are included the majority of cellulose ethers (methylcellulose (MC), sodium carboxymethylcellulose (NaCMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxyethylmethylcellulose (HEMC) and hydroxypropylmethylcellulose (HPMC)) , while tDue to the general properties of wound dressings presented in Cellulose ethers derivatives  are the Carboxymethylcellulose (CMC), also known as carmellose, is a semi-synthetic and hydrophilic polymer, a water-soluble cellulose ether derivative, and one of the polymers with the lowest price . Sodium The NaCMC network illustrates a thixotropic behavior to generate 3D structures through intermolecular attraction. Its thixotropy is influenced by concentration and degree of substitution . NaCMC pNaCMC can be combined with other polymers to enhance its properties and to develop its applicability. Thus, it is more advantageous to blend two or more polymers for the development of a new material comparative to the chemical industrial development of that material. Moreover, the new material obtained by mixing other well-known polymers presents all the properties or is more favorable than the component polymers . FurtherHydroxypropylmethylcellulose (HPMC), hypromellose , is a seTherefore, HPMC presents many degrees of substitution, that give to this biopolymer different molecular weight and physicochemical features  ,191. TheAccording to United States Pharmacopeia (USP), there are four distinct forms of HPMC, which are categorized by the content of methoxy, respectively hydroxypropoxy groups in: HPMC 1828, HPMC 2208, HPMC 2906, and HPMC 2910 . This biHPMC has a proper solubility in water, and it is one of the most used cellulose derivatives in many industries. It is widely used in the biotechnological field , due to its excellent characteristics, such as biocompatibility, biodegradability, superior stability, large availability, excellent swelling, high surface activity, and mechanical properties , remarkaHPMC can be combined with other polymers to enhance its properties and to develop its applicability . To imprMethylcellulose (MC) is a semi-synthetic and non-ionic polymer, a cellulose ether derivative with high solubility in water, which is influenced by temperature . It formAt a variation of temperature, MC has a thermo-sensitive behavior with a reversible sol-gel transition in an aqueous solution . At a loThe degree of substitution for commercial MC varies from 1.7 to 2.2 when it results in a semiflexible biopolymer because the inter-and intra- hydrogen bonds from cellulose molecule break off . There aTo improve the characteristics of MC, it can be blended with other polymers in different ratios to enhance the physicochemical, morphological, and structural properties of both polymers and of the resulting composite . Abu et Hydroxyethylcellulose (HEC) is a semi-synthetic, nonionic, and inert polymer, a water-soluble cellulose ether derivative . It formIt has a low price, without taste and smell, with no color to light yellowish ; presentTo enhance its properties, HEC can be blended with other polymers. For example, Zia et al., mixed HEC with poly(lactic acid) and polyurethane. They obtained a new composite with higher thermal stability and mechanical (tensile strength and elongation) properties compared to other polymers ,304. MorEthylcellulose (EC) is a nonionic semi-synthetic polymer, a cellulose ether derivative insoluble in water . It formThis biopolymer presents numerous advantageous characteristics, such as mechanical properties, biodegradability, flexibility, low toxicity, hydrophobicity, gelling capacity , light, EC can be mixed with various polymers to enhance the physicochemical and mechanical properties and thus, its applicability. To develop a novel drug-delivery device, Li et al., blended EC by electrospinning method with poly(di(ethylene glycol) methyl ether methacrylate), a thermosensitive polymer. The new formulation showed normal morphology, a large porosity, and an increased wettability at a higher temperature, which led to more hydrophobic behavior, causing an extended release of the drug . EC was EC can also be combined with other polymers to develop new wound dressings, with enhanced physicochemical and mechanical properties that can accelerate the wound-healing process. Principal blends are presented in Hydroxypropyl cellulose (HPC) is a semi-synthetic hydrophilic polymer, a cellulose ether derivative, with proper solubility in water and organic solvents . Its solg (glass transition temperature) at excessive humidity. The LCST  water value is about 41 \u00b0C. At a slightly higher temperature than LCST, HPC presents a phase change because the water solution of this biopolymer generates metastable nanosphere aggregates [It has numerous advantageous properties, such as amphiphilicity, low price, electrical neutrality, biocompatibility, biodegradability, non-toxicity, high power of swelling the wounds exudate ,342, adegregates . Moreovegregates . Thus, tgregates ,348 and gregates . It can gregates .HPC can be blended with other polymers to improve the physicochemical and mechanical properties and thus, to extend its applicability. For instance, Veerapur et al., combined HPC and chitosan, and the new formulated composite presented higher hydrophilicity, swelling capacity, and permeation rate . By mixiOne or more cellulose derivatives may combine with other cellulose derivatives to formulate novel wound dressings, with enhanced properties that can accelerate the wound-healing process and alleviate the pain, inflammation, and stress caused by damaged skin tissue. Moreover, they can be combined to counteract their drawbacks . The maiThis review has focused on different types of wound dressing  based on cellulose derivatives as biopolymeric scaffolds, and various bioactive agents, from plant extracts to chemical drugs. We have considered the cellulose ethers derivatives . It has been illustrated that cellulose derivatives can manifest a therapeutic effect on wound healing, alone or in combination with other natural, semi-synthetic, and synthetic polymers. The major advantage of mixing two or more biopolymers is, besides the beneficial action on damaged tissue, the improvement of physicochemical properties of the novel dressing. Cellulose derivatives have a particular chemical structure, obtained by etherification of hydroxyl groups from cellulose molecule with different alkyl groups, the consequence being the improvement of water solubility. Therefore, these biopolymers can be successfully used as a base for diverse formulations, due to their high gelation properties. Cellulose derivatives exhibit an efficient capacity to absorb the exudates on the site of the lesion, retain them, and swell. Consequently, the newly formulated wound dressings show an excellent ability to maintain relevant moisture on the wound bed and allow gas exchanges with the environment. Due to their high biocompatibility, biodegradability, physicochemical properties, eco-friendliness, and low cost, cellulose derivatives are promising materials for biomedical and pharmaceutical domains , for oilfields, carbon capture and the food industry."}
+{"text": "Metabolic syndrome (MetS) is a complex pathophysiological state with incidence similar to that of a global epidemic and represents a risk factor for the onset of chronic non-communicable degenerative diseases (NCDDs), including cardiovascular disease (CVD), type 2 diabetes mellitus, chronic kidney disease, and some types of cancer. A plethora of literature data suggest the potential role of gut microbiota in interfering with the host metabolism, thus influencing several MetS risk factors. Perturbation of the gut microbiota\u2019s composition and activity, a condition known as dysbiosis, is involved in the etiopathogenesis of multiple chronic diseases. Recent studies have shown that some micro-organism-derived metabolites (including trimethylamine N-oxide (TMAO), lipopolysaccharide (LPS) of Gram-negative bacteria, indoxyl sulfate and p-cresol sulfate) induce subclinical inflammatory processes involved in MetS. Gut microbiota\u2019s taxonomic species or abundance are modified by many factors, including diet, lifestyle and medications. The main purpose of this review is to highlight the correlation between different dietary strategies and changes in gut microbiota metabolites. We mainly focus on the validity/inadequacy of specific dietary patterns to reduce inflammatory processes, including leaky gut and subsequent endotoxemia. We also describe the chance of probiotic supplementation to interact with the immune system and limit negative consequences associated with MetS. Metabolic syndrome (MetS) is defined by WHO as a pathological condition characterized by obesity, insulin resistance, hypertension, hyperlipidemia and waist-to-hip ratio; MetS is present if three or more of the above-mentioned criteria are present .Main MetS risk factors are a sedentary lifestyle and high sugar or fat diets , which oRecent scientific data have linked MetS development also to intestinal dysbiosis ,6: becauThe complex ecosystem of microorganisms  living in different districts of the human body  is defined as microbiota. Most microbiotas reside in the gastrointestinal tube . The micHuman microbiotas vary according to diet, lifestyle and the presence or absence of specific diseases. Indeed, it has been shown that a high fat and sugar diet alters the intestinal ecosystem , triggering changes in metabolic pathways and inducing pro-inflammatory cascade signals ,12. SomeThere is growing evidence about the role of bacterial metabolites as pathophysiological biomarkers of cardio-metabolic diseases, with applications in diagnostics and prognosis ; for exaThe habitual diet plays an important role in defining the composition of the intestinal microbiota and determining the microbial metabolites that can affect the host metabolism. In the literature, several studies have shown positive effects of some dietary models in MetS management. For example, adherence to the Mediterranean diet (MD) leads to significantly higher levels of total short-chain fatty acids (SCFAs), important gut microbiota metabolites that modulate immune\u2013endocrine processes .The purpose of this review is to examine and evaluate potential microbial metabolites involved in MetS to define nutritional interventions aimed at modulating the intestinal microbiota and personalizing MetS treatment.Most bacteria found in the gastrointestinal tract belong to Firmicutes  and Bacteroidetes  and Rikenellaceae (Alistipes) genera) phyla, followed by Actinobacteria (Bifidobacteria), Proteobacteria (Escherichia coli), Fusobacteria, Verrucomicrobia and Cyanobacteria phyla ,46,47.Intestinal bacteria play an important role in regulation of the host metabolism  and modulation of the immune system, through the production of SCFAs, vitamins, metabolites, and neuropeptides  48,49].,49.48,49Firmicutes bacteria produce SCFAs as products of the hydrolysis and fermentation of dietary polysaccharides; once taken up by enterocytes, butyrate is usually used as an energy source for intestinal epithelium, while acetate and propionate enter in systemic circulation and reach peripheral tissues, where they are used for lipogenesis and gluconeogenesis.SCFAs also act as signaling molecules, thereby exerting beneficial metabolic effects, including the regulation of intestinal transit time ; modulatSpecifically, SCFAs stimulate colonic L cells through activation of the G protein-coupled receptors GPR41 (Free Fatty Acid Receptor 3 or FFA3) and GPR43 (Free Fatty Acid Receptor 2 or FFA2); the first receptor triggers the release of the anorexigenic peptide PYY, which increases the gut transit rate and satiety, while the second one reduces inflammation, stimulates release of glucagon-like peptide 1 and 2 (GLP1 and GLP2) and increases concentrations of peripheral hormones, such as insulin, leptin and ghrelin, thus influencing appetite control .In healthy conditions, the integrity of the intestinal epithelial barrier, guaranteed by a tight junction network, blocks passage of antigens or microbe-derived endotoxins. Some pathological conditions give rise to gut microbiota perturbations (referred to as dysbiosis) and a subsequent impairment of intestinal barrier function ; in these circumstances, microbial metabolites can cross the intestinal barrier and move to the bloodstream, triggering systemic pro-inflammatory signaling that, in turn, causes metabolic alterations ) in distant tissues ,53. MicrE. coli LPS exposure (3 ng/kg) has been shown to promote systemic insulin resistance and adipose tissue-related inflammation -labeled phosphatidylcholine and the ingestion of two hard-boiled eggs have been shown to increase plasma TMAO concentrations that are reduced to baseline levels by oral broad-spectrum antibiotics . The samWhat are the molecular pathways by which TMAO exerts its pathogenic effects? TMAO may promote dyslipidemia by regulating hepatic lipogenesis and gluconeogenesis , macrophClostridium sporogenes produces indole propionic acid from dietary Trp that plays an important role in the integrity of the intestinal barrier.Tryptophan (Trp) is an essential aromatic amino acid that is present in oats, bananas, dried prunes, milk, tuna fish, cheese, bread, poultry, peanuts, and chocolate. Gut microbiota can directly utilize Trp (approximately 4\u20136%), limiting its bioavailability . BacteriTrp metabolites are also involved in MetS. Indeed, in human patients with MetS, overactivation of indoleamine 2,3-dioxygenase and increased serum levels of kynurenine have been reported . IndoxylPrevotella and Xylanibacter genera, while European children had significantly less SCFAs and more Enterobacteriaceae (Shigella and Escherichia) [Roseburia, Eubacterium rectale and Ruminococcus bromii), while increasing the abundance of bile-tolerant microorganisms  [Eubacterium [Diet strongly affects gut microbiota composition. Comparison of the fecal microbiota of European children and of children from a rural African village of Burkina Faso (following a polysaccharide-rich diet), for example, revealed significant differences: in Burkina Faso children, the predominant bacteria were Bacteroidetes, mainly erichia) . Diet-baeroides) . Accordiacterium ,94,95,96Bacteroides, associated with animal proteins/saturated fats, and Prevotella, associated with carbohydrates) [The gut microbiome is able to respond to short-term macronutrient changes; volunteers placed on either plant- or animal- based diets for five days showed significant temporal alterations in their microbial communities . In contydrates) . Neverthydrates) ,98. FurtIn MetS patients, nutritional intervention should firstly aim at reducing CVD and type 2 diabetes risk and usually includes reduction of body weight by 7\u201310%, followed by weight maintenance and lifestyle changes . Losing as little as 5% of initial weight results in insulin sensitivity improvement, serum triglycerides and LDL-cholesterol reduction and decrease in systolic and diastolic blood pressure ,100.Obesity is one of the five fundamental features of MetS; the relationship between obesity and microbes is clearly established. Colonization of germ-free mice with gut microbiotas derived from obese subjects led to increases in total weight, compared with transplantation of lean gut microbiotas . SimilarIn obese subjects, main microbiota changes concern the reduction of Bacteroidetes and a proportional increase in Firmicutes and Actinobacteria ,106,107;Eubacterium, Roseburia, Anaerostipes, and Coprococcus [The Western diet, rich in saturated and trans fatty acids as well as sucrose intake, and low in fiber from fruits and vegetables, is linked to insulin resistance, dysbiosis and chronic non-infectious degenerative diseases ,113,114.rococcus ,118. Mokrococcus  showed tBifidobacterium genus. Accordingly, fatty acid profiles, by modulating the microbiota composition and integrity of the epithelial barrier, may contribute to low-intensity inflammation and, consequently, endotoxemia [Parabacteroides, Prevotella, Turicibacter, and Enterobacteriaceae\u2019s populations, and changes in gut microbiota profiles were more evident in obese subjects [Several in vivo studies have underlined the relevance of dietary fat quality on metabolic health and gut microbiota composition. Patterson and co-workers  demonstrotoxemia ,121. Simotoxemia ,126,127.subjects .MD adherence reduces chronic inflammation, improves lipid profile, insulin sensitivity and endothelial function, while decreasing CVD incidence and all causes of mortality  ,129. MD Prevotella and fiber-degrading Firmicutes [Bacteroides, Prevotella and Faecalibacterium genera. In addition, MD also increased Roseburia and Ruminococcus genera, suggesting the greater potential of MD to restore gut microbiota functionality, as compared to a low-fat diet [High adherence to MD positively impacts the gut microbiota composition and microbial metabolomes. Individuals with low adherence show high urinary TMAO levels, while compliance to MD is linked to increased SCFA levels, and an abundance of rmicutes ,134. Likrmicutes . Haro\u2019s rmicutes  analyzedfat diet . These rBifidobacterium species [Some findings indicated that nutritional ketosis, induced by very low carbohydrate ketogenic diets , allowed weight management and improved metabolic and inflammatory markers, including lipids, glycated hemoglobin, high-sensitivity C-reactive protein, fasting insulin and glucose levels ,138. A r species . HoweverA diet rich in proteins and low in carbohydrates promotes dysbiosis, causing an increase in pro-inflammatory bacteria and a reduction in SCFA-producing bacteria, with subsequent changes in bacterial metabolites; indeed, increased branched-chain fatty acids, indoxyl sulfate, p-cresol sulfate and TMAO have been observed with this dietary regimen ,140,141.Bifidobacterium and Lactobacillus species, elevating SCFA-producing bacteria and promoting Ruminococcus enterotype. Accordingly, indoxyl sulfate and p-cresol sulfate mean excretion is approximately 60% lower in vegetarians than in omnivores [Bacteroides, Coliform, and Clostridium. Inhibition of these potential pathogens is often associated with the restoration of micro-ecosystem homeostasis by reducing the release of enterotoxins and adverse microbial metabolites [Epidemiological evidence identifies the benefits of vegetarian dietary patterns  in both the prevention and treatment of MetS, CVD mortality and risk of coronary heart disease ,143. In abolites .Bifidobacterium and Lactobacillus growth [Bifidobacterium spp. and Lactobacillus spp., as well as elevated levels of fecal butyrate [Prebiotics are selectively fermented components leading to specific changes in the composition and/or activity of gut microorganisms that may be beneficial for the host\u2019s health and wellbeing . Among ts growth : 30 g pebutyrate . Howeverbutyrate . The widbutyrate .Lactobacillus and Bifidobacterium genera [Lactobacillus and Bifidobacterium has been found to (i) improve epithelial and mucosal barrier functions, (ii) inhibit the growth of pathogenic enteric bacteria and reduce production of pathogenic toxins, (iii) mediate some of the negative consequences associated with the consumption of high-fat diets; (iv) modulate the immune system, blood glucose levels and lipid profiles [Current probiotics include microorganisms proven to exert positive effects on human health, such as m genera . Most inm genera ,152, eveprofiles .Lactobacillus rhamnosus reduced visceral adiposity and diet-induced obesity, while improving the integrity of the gastrointestinal microbial lining [Lactobacillus rhamnosus GG changed a proportion of gut microbiotas and significantly reduced atherosclerotic plaque size [Lactobacillus reuteri V340 added to a hypocaloric diet, together with regular physical activity, has shown promising results for MetS management in animals and adult patients: supplementation once daily for 12 weeks, indeed, reduced IL-6 and soluble VCAM-1 [B. lactis HN019 reduced classical MetS parameters and related cardiovascular risk factors  [Investigations on animal experimental models and humans suggested an important role of probiotics on MetS and its complications. In a mouse model of obesity, supplementation with l lining . In expeque size . Lactobae VCAM-1 . In the tokines) .Akkermansia municiphila is a major propionate-producing bacterium, while Eubacterium hallii, Eubacterium rectale, Roseburia inulinivorans, Faecalibacterium prausnitzii, Clostridium lavalense, Bacteroides uniformis and Ruminococcus bromii are responsible for most butyrate production [Akkermansia muciniphila  is inversely associated with obesity, diabetes, cardiometabolic diseases, inflammatory bowel disease, hypertension, and liver diseases [A. muciniphila, is involved in gut epithelium integrity and is negatively associated with metabolic endotoxemia [Specific commensal species, as novel probiotics , exert positive effects by reducing inflammation and strengthening the epithelial barrier . Among toduction . Akkermadiseases ,164,165.Akkermansia muciniphila supplementation, for 3 months, resulted in improved insulin sensitivity and reduced insulinemia and plasma total cholesterol [A. muciniphila [A. muciniphila may be a promising new therapeutic agent for MetS, although safety and absence of side effects must be assessed.In overweight and obese volunteers, daily lesterol ; accordiiniphila . These pLactobacillus, Lactococcus, Streptococcus Leuconostoc, and acetic acid bacteria) and yeasts , which exert anticarcinogenic, antimicrobial and anti-inflammatory activities [Consumption of yogurt and other fermented products is positively associated with gastrointestinal and cardiovascular health, cancer risk, weight management, diabetes, and bone density . Severaltivities ,169. In tivities . In a prtivities . HoweverA relationship between microbiota metabolites, endotoxiemia and MetS is clearly emerging. Recent findings have shown that some microorganism-derived metabolites  induce subclinical inflammatory processes involved in MetS and CVD ,33,35,36Prevotella and fiber-degrading Firmicutes [Among factors  influencing microbiota composition, dietary habits play a key role; much evidence underlines that some dietary patterns are more effective than others in modifying the gut community. In particular, MD, rich in beneficial nutrients and bioactive compounds, is particularly effective in modulating gut microbiota composition and inflammatory processes (including leaky gut and subsequent endotoxemia); compliance with MD is indeed linked to resolved dysbiosis, increased SCFA levels, reduced TMAO levels, and an abundance of rmicutes ,135. ConFunctional foods enriched with probiotic or synbiotic bacteria may also be useful in targeting microbiota composition or specific biochemical pathways, as they have been shown to significantly improve insulin sensitivity and the lipid profile . NeverthIn conclusion, although promising, microbiotas and microbiota-derived metabolites may not actually represent diagnostic MetS markers and/or have real therapeutic power, since many limitations must be overcome. The future challenge is to fully understand how different dietary patterns may specifically modulate the composition of gut microbiota and whether these changes are long-lasting; only a strong and robust knowledge will allow stabilizing the microbial community toward a healthy phenotype and reducing the risk of MetS."}
+{"text": "The COVID-19 pandemic poses serious physical and mental health risks for older adults worldwide. To develop culturally and contextually congruent services to mitigate these risks requires understanding their stress and coping processes, which remain understudied in Latin America. This study examines qualitative data from 51 adults aged 60 and over who participated in an ongoing study of older Puerto Ricans\u2019 knowledge, attitudes, and practices about COVID-19. Trained interviewers collected the data by telephone from January to August, 2021. Two-thirds of participants were female, 60% had less than high school education and 90% had poverty-level incomes. Drawing on Lazarus and Folkman\u2019s Stress and Coping Theory, we conducted a thematic analysis of responses to open-ended questions about the nature and extent of COVID-related stressors, stress management, and meanings and guidance they had gleaned from their experience. Participants perceived the pandemic as an added threat to ongoing chronic stressors ; disruptions in daily routines, family cohesion, and grief and loss processes; and increased isolation and loneliness. They reported using cognitive, behavioral, socioemotional and spiritual coping, including positive thinking, keeping occupied, relaxation, religious practices and, in a few cases, social media. Participants highlighted a revitalized appreciation for emotional qualities of relationships, freedom and life in general. Consistent with our guiding theory, cultural, contextual, religious, and socio-political factors shaped their appraisals of stress and their coping strategies. Future research should examine how these practices relate to health outcomes and quality of life and how they can inform effective, appropriate interventions."}
+{"text": "Racial minorities have been recognized to experience worse health outcomes for many medical conditions. However, it is not clear if these outcomes are associated with pre-existing conditions or the quality of care those patients receive. In burns, little information on the relationship between race and burn comorbidities is available. This study examines the risk association between race and burn complications, such as pneumonia, sepsis, and ARDS while controlling for common comorbidities that affect burn recovery such as diabetes and hypertension.Burn patient cohorts were identified by ICD10 codes for burn injury using TriNetX, a federated network of real-world data. The cohorts were stratified by race and balanced in terms of age at index, gender, BMI, and pre-existing comorbidities such as diabetes and hypertension. The following post burn outcomes were selected for analysis: renal failure, cardiovascular disease, sepsis, ARDS, graft complication, pneumonia, ICU admit, respiratory failure, hypertrophic scarring (HTS), hyperglycemia, and mortality. A measure of association analysis was performed to compare risk outcomes in black vs. white burn patients. Statistical significance was set at p< 0.05. The same cohorts were analyzed for treatment pathways to compare critical care billing CPT codes for the amount of time seen by a physician: Critical Care and Evaluation, first 30-74 minutes, and Critical Care and Evaluation, each additional 30 minutes.The balanced patient cohorts comprised 78,974 patients per cohort. Black patients experience a positive relative risk ratio (RR) to renal failure , cardiovascular disease , sepsis , and ARDS  following burn injury. However, black patients experience a negative risk ratio to mortality  and pneumonia . The risk ratio was not significant for outcomes between black and white burn patients for respiratory failure, HTS, hyperglycemia, and ICU admit. Analysis of treatment pathways did not show significant differences in Critical Care and Evaluation billing between the two races.Black burn patients are more likely to experience renal failure, cardiovascular disease, sepsis, and ARDS compared to white burn patients despite controlling for common comorbidities. They are less likely to experience pneumonia and mortality."}
+{"text": "There are several reasons for forming an aging international research collaboration; however, creating a successful and productive research team during the global crisis may require extensive planning and efforts. Our team consists of ten scholars from five countries, including Hong Kong, Nepal, Singapore, Thailand, and the United States. To accomplish this initiative, we employ ten simple rules for establishing international research collaborations proposed by R. de Grijs (2015). We aim to examine impacts of the pandemic on physical activity, frailty, falls, depression and social networks in diverse older adults. We collect data by online survey and/or face-to \u2013face survey using questionnaires including fear of the COVID, face mask use, Social Network, Rapid Assessment of Physical Activity, a simple frailty questionnaire, CDC fall risk checklist, short Fall-Efficacy Scale International and Patient Health Questionnaire-9. Topics of discussion included: research progression, lessons learned and barriers to international collaboration during the COVID-19 crisis."}
+{"text": "Globally, around 1 in 6 older adults experienced some form of elder mistreatment in community settings. However, little is known about the prevalence of polyvictimization, or experience of multiple forms of abuse, which may exacerbate negative outcomes over that of any one form of victimization in isolation. Data were drawn from the PINE study. Polyvictimization was defined as exposure to multiple forms of victimization, including psychological, physical, and sexual mistreatment, financial exploitation, and caregiver neglect. Cognitive function was evaluated by global cognition, episodic memory, executive function, working memory, and MMSE. Regression analyses were performed. Among 3153 participants, 128 experienced two forms of abuse while 12 experienced three or more forms of abuse. Polyvictimization was associated with lower global cognition , episodic memory , working memory , and processing speed . Interventions could target older adults with polyvictimization and protect their cognitive function."}
+{"text": "OBJECTIVES/GOALS: The goal of this project was to inform four chronic disease initiatives, working together on the team Connections IN Health, and counties in Indiana on certain areas of need to assist them in collaborative planning. The chronic diseases focused on include diabetes, cardiovascular disease, stroke, asthma, lung cancer and obesity. METHODS/STUDY POPULATION: Chronic disease health outcomes and social determinants of health indicators were identified in all 92 Indiana counties. Counties were compared by composite z scores in a matrix to determine the 23 counties with the poorest health statistics for diabetes, cardiovascular disease, stroke, asthma, lung cancer, obesity and life expectancy. Qualitative data were used to identify local health coalitions that have the capacity and desire to work with Connections IN Health to improve these health outcomes. With input from partners, the counties were narrowed to 10 that were identified as those with the most need in the specific areas of chronic disease that the initiatives focus on. The team will begin listening sessions with two of these counties to identify strategic partnerships, funding sources, and evidence-based programs to address community-identified health priorities. RESULTS/ANTICIPATED RESULTS: The 23 counties with the poorest health outcomes related to chronic disease and factors were Blackford, Clark, Clay, Fayette, Fulton, Grant, Greene, Howard, Jay, Jennings, Knox, Lake, LaPorte, Madison, Marion, Pike, Scott, Starke, Sullivan, Vanderburgh, Vermillion, Vigo, and Washington. There was significant overlap in low z score rankings for individual health and social determinants of health measures among these 23 counties. The following 10 counties were selected for focus in the next five years based on partner input: Blackford, Clay, Grant, Jennings, Lake, Madison, Marion, Starke, Vermillion, and Washington. The Connections IN Health team has initiated listening sessions in Grant and Vermillion Counties (with data for presentation at the ACTS meeting). DISCUSSION/SIGNIFICANCE OF IMPACT: This mixed methods approach using existing data and partner input on county capacity/readiness directed Connections IN Health to counties with the most need for coalition efforts. Engagement within each county will inform next steps  and specific health focus area(s)."}
+{"text": "Public health guidelines to prevent spreading COVID-19 place older adults at risk of loneliness and social isolation. Evidence suggests that participation protects older adults from such detrimental outcomes, therefore we aimed to identify the factors associated with participation in life roles among older adults living in the community during the COVID-19 pandemic. We conducted a telesurvey on a random sample of community-dwelling older adults living in Hamilton, Ontario, Canada, between May and July 2020. Outcome measures included participation in life roles, physical function, physical activity, mobility, mental health, nutrition, and demographics. We conducted two multivariate regression analyses with the Late Life Disability Instrument\u2019s (LLDI) frequency and limitations scales as the dependent variables. Candidate factors were organized by International Classification of Functioning, Disability, and Health (ICF) framework domains; personal factors, body functions and structures, activities, and environmental factors. A total of 272 older adults completed the telesurvey . Age, using walking aids, driving status, household income, education, mental health, nutrition, physical function, and dwelling type explained 47.1% (p<0.001) of the variance observed in LLDI frequency scores. Using walking aids, driving status, receiving health assistance, mental health, and physical function explained 33.9% (p<0.001) of the variance observed in LLDI limitation scores. These findings highlight factors from multiple ICF domains that are associated with participation limitation and frequency among older adults during the pandemic. Our findings have implications for developing public health initiatives to mitigate the effects of the pandemic on the participation of older adults."}
+{"text": "OBJECTIVES/GOALS: Many clinical prediction models have been developed to guide tuberculosis (TB) treatment, but their results and methods have not been formally evaluated. We aimed to identify and synthesize existing models for predicting TB treatment outcomes, including bias and applicability assessment. METHODS/STUDY POPULATION: Our review will adhere to methods that developed specifically for systematic reviews of prediction model studies. We will search PubMed, Embase, Web of Science, and Google Scholar (first 200 citations) to identify studies that internally and/or externally validate a model for TB treatment outcomes . Study screening, data extraction, and bias assessment will be conducted independently by two reviewers with a third party to resolve discrepancies. Study quality will be assessed using the Prediction model Risk Of Bias Assessment Tool (PROBAST). RESULTS/ANTICIPATED RESULTS: Our search strategy yielded 6,242 articles in PubMed, 10,585 in Embase, 10,511 in Web of Science, and 200 from Google Scholar, totaling 27,538 articles. After de-duplication, 14,029 articles remain. After screening titles, abstracts, and full-text, we will extract data from relevant studies, including publication details, study characteristics, methods, and results. Data will be summarized with narrative review and in detailed tables with descriptive statistics. We anticipate finding disparate outcome definitions, contrasting predictors across models, and high risk of bias in methods. Meta-analysis of performance measures for model validation studies will be performed if possible. DISCUSSION/SIGNIFICANCE OF IMPACT: TB outcome prediction models are important but existing ones have not been rigorously evaluated. This systematic review will synthesize TB outcome prediction models and serve as guidance to future studies that aim to use or develop TB outcome prediction models."}
+{"text": "Snakebite envenomation causes >\u200981,000 deaths and incapacities in another 400,000 people worldwide every year. Snake venoms are complex natural secretions comprised of hundreds of different molecules with a wide range of biological functions, which after injection cause local and systemic toxic manifestations , Lyso-PCs, phosphatidylethanolamines (PE), Lyso-PE, phosphatidylserine, phosphatidylinositol, ceramides, and sphingomyelin species were detected. The lipids included bioactive compounds such as platelet-activating factor (PAF) precursor, PAF-like molecules, plasmalogens, ceramides, and sphingomyelins with long fatty acid chain lengths, which may be associated with the systemic responses triggered by Crotalus durissus terrificus and Bothrops moojeni envenomation. The responses include platelet aggregation, activation of intercellular adhesion molecule 1 (ICAM1), apoptosis, as well as the production of pro-inflammatory lipid mediators, cytokines, and reactive species. The new lipidomics aspects will contribute to an increased understanding of the complex pathology elicited by snakebite envenomation.The majority of studies have focused on the protein portion (toxins), without paying significant attention to other fractions. A heretofore neglected field is that of lipid constituents of snake venoms. A breakthrough in this new area was just reported in this journal. Acunha et al  reported"}
+{"text": "The current study examined the associations between daily financial thoughts, socioeconomic status (SES), and indices of emotional (positive and negative affect (PA/NA)) and physical health . Participants (N = 782) from the National Study of Daily Experiences, a subsample of the Midlife in the United States Refresher survey, completed daily diary interviews and provided saliva samples, from which cortisol was assayed. Participants who, on average, reported more daily financial thoughts also reported more NA, less PA, more physical symptoms, and had higher cortisol AUCg . These effects were more pronounced among people reporting lower SES. Daily fluctuations in financial thoughts also predicted daily fluctuations in NA, PA, and physical symptoms . Again, these associations were more pronounced among people reporting lower SES. Results indicate that intrusive, daily financial thoughts may be one pathway explaining the link between SES and health outcomes."}
+{"text": "Despite exceptional morphological and physicochemical attributes, mesoporous silica nanoparticles (MSNs) are often employed as carriers or vectors. Moreover, these conventional MSNs often suffer from various limitations in biomedicine, such as reduced drug encapsulation efficacy, deprived compatibility, and poor degradability, resulting in poor therapeutic outcomes. To address these limitations, several modifications have been corroborated to fabricating hierarchically-engineered MSNs in terms of tuning the pore sizes, modifying the surfaces, and engineering of siliceous networks. Interestingly, the further advancements of engineered MSNs lead to the generation of highly complex and nature-mimicking structures, such as Janus-type, multi-podal, and flower-like architectures, as well as streamlined tadpole-like nanomotors. In this review, we present explicit discussions relevant to these advanced hierarchical architectures in different fields of biomedicine, including drug delivery, bioimaging, tissue engineering, and miscellaneous applications, such as photoluminescence, artificial enzymes, peptide enrichment, DNA detection, and biosensing, among others. Initially, we give a brief overview of diverse, innovative stimuli-responsive - and targeted drug delivery strategies, along with discussions on recent advancements in cancer immune therapy and applicability of advanced MSNs in other ailments related to cardiac, vascular, and nervous systems, as well as diabetes. Then, we provide initiatives taken so far in clinical translation of various silica-based materials and their scope towards clinical translation. Finally, we summarize the review with interesting perspectives on lessons learned in exploring the biomedical applications of advanced MSNs and further requirements to be explored. Since the mid-1950s, immense progress has evidenced the development of various nanoplatforms (size of 1 to 100\u00a0nm) with intrinsic functionalities for diverse applications, such as agriculture, adsorption, engineering, medicine, energy, and environment-related fields , 3. In a2/g, tunable mesopores of 2\u201310\u00a0nm, and arbitrary sizes, as well as shapes . Such impressive attributes are of particular interest in adsorption . M. M358]. Tissue engineering aims to repair malfunctioned tissues by fabricating 3D biomimetic constructs at arbitrary geometries while managing the physiological microenvironment and biochemical cues by emulating their native counterparts due to the shortage of donors for organ replacement therapy , 378. In-azacytidine (5-Aza) from MSNs, specifically at pH 5.0. The delivered therapeutic guests successfully induced/regulated their differentiation of ESCs (P19 cells) to cardiomyocytes 386] for Recently, in addition to drug delivery and bioimaging, these complex types of advanced MSNs have been applied in diverse advanced biomedical applications, such as peptide enrichment, photoluminescence, artificial enzymes or nanozymes, and DNA detection, among others. Owing to the exceptional physicochemical and morphological attributes, integrating MNPs offers exciting and intriguing features to this versatile MSN carrier. Herein, we give a brief synopsis and insights on the specific functional attributes of these advanced prototypes of MSNs for various innovative miscellaneous biomedical applications.Currently, enormous interest has been gained by researchers in exploring the enrichment of peptides from biological samples towards safe diagnosis and other biomedical applications. Several conventional approaches have been utilized based on biomarkers for physical separation towards the quantitative and qualitative assessments of various endogenous peptides in the biological specimens (urine and blood). In this context, centrifugal ultrafiltration is the most acceptable strategy to obtain pure peptides by removing the high Mol. Wt. molecules based on the mechanism of size-exclusion . To thisThe artificial enzymes often referred to as nanozymes, have emerged as promising alternatives to biological enzymes due to the specific limitations of natural biocatalysts or enzymes, such as difficulties in recovery and recycling, higher efficiency to particular substrates, high sensitivity to external conditions, and low operational stability, which limited their applicability in practical applications \u2013399. Des2) for label-free nucleic acid detection [2 containers. The efficacy was confirmed by substantially preventing the intrinsic peroxidase-like catalysis of its specific substrate, TMB. Further, upon DNA hybridization in the presence of complementary DNA for detection, the Pt nanoparticles were typically available for catalysis function. In addition, the authors demonstrated that this label-free approach presented efficient, and self-signal amplifying detection, requiring no auxiliary labeling with ssDNA. Further, several efforts have been dedicated recently to exploring the applicability of DNA detection using these advanced prototypes of MSNs  and then guided the formation of mesophase, enabling the deposition of ZnO species inside the mesopores during calcination -based drug delivery strategies and imaging, as well as artificial enzymes, peptide enrichment, photoluminescence, and biosensing, among others, highlighting their structural and physicochemical attributes in biomedical applications. Finally, discussions on the critical necessities and progress in translating these innovative architectures to clinics are provided.Although several efforts have been dedicated to exploring various progressions in the generation and applicability of these innovative MSNs, there still exist some challenges in terms of fabrication and performance attributes towards their adequate translation and commercialization. The astonishing gap between the current progress in lab-scale and future advancement towards their applicability and commercialization lies in various factors, such as biosafety, colloidal stability, and degradability regarding performance attributes and scale-up in terms of processing . In termSince their inception, several reports have demonstrated the scalability and reproducibility of conventional MSNs. As the lab scale is different from the industrial scale in processing, several predominant reasons include the batch-to-batch challenges relevant to reproducibility maintaining uniform-size distribution, encapsulation efficacy in high yields, and non-availability of cheap silica sources, resulting in increased cost. These challenges always hindered the adoption of these materials. Concerning the advanced prototypes, it is still a long way to go towards the scale-up of these innovative prototypes, requiring the facile synthesis procedures, cheap silica sources, reduced fabrication steps, saving time of production. However, the rapid pace of research and steps towards translation would certainly address these challenges and see the advanced prototypes in the future."}
+{"text": "Nanotechnology has found applications in different fields, such as food security, agriculture, medicine, energy, automotive, environmental protection, electronics, textiles and cosmetics.Nanotechnology is a broad area integrating different research disciplines, including but not limited to material science, engineering, physics, chemistry, polymer science, optics, electronics, robotic, metallurgy, pharmacology, pharmacy and medicine. The Nanotechnology appellation has been used in different contexts: designing materials at the nanometric scale  and manipulation of nanomaterials and investigation properties at the nanodimensional level , is crucial to control their properties and allow their applications in various fields, such as electronics, photonics, energy, life sciences and the environment. The aim of this section is to focus on nanoprocessing approaches that allow us to create novel nanostructures and architecture by using innovative synthesis, fabrication and manufacturing methods, enabling the control of their properties, as well as their applications.https://www.sciencedirect.com/science/article/abs/pii/S2352940719305414 (accessed on 30 November 2021)); 2D materials and their heterostructures ; coatings and thin films ); hybrid nanostructures (organic/inorganic); nanocomposites; self-assembly and organization; nanostructured materials, such as Zeolites, MOFs and membranes (https://www.mdpi.com/2079-4991/9/11/1552 (accessed on 30 November 2021)); nanomaterial features tuned by the nanofabrication/nanomanufacturing approaches .Research interests in the Section \u201cNanofabrication and Nanomanufacturing\u201d include but are not limited to the following: synthesis, fabrication and manufacturing of nanostructured and nanoscale materials (bottom up and/or top down approaches); design of nanoparticles, quantum dots and clusters with control morphology and complex structures ; formation of 1D nanostructures (nanofibers, nanotubes, nanowires, nanorods, etc."}
+{"text": "Ileosigmoid knotting (ISK) is the wrapping of ileum or sigmoid colon around the other structure causing a double-loop intestinal obstruction. Both ISK and ISK complicating mental retardation are very rare clinical entities. In this commentary, I would like to discuss some details of ISK complicating mental retardation regarding to a published paper in The Pan African Medical Journal. Althouget al. , it is ret al. . In the First, ISK in mental retarded patients is a very rare clinical entity . For thiSecond, although abdominal pain, distention, and obstipation, which are known as classical volvulus triad, suspect ISK and abdominal X-ray radiography helps to diagnosis by demonstrating coffee been sign, they generally cause an underdiagnosis by directing to nonspecific intestinal obstruction ,5, as waThird, in past, many different classifications have been documented for ISK evaluating prevalence (sporadic or endemic), clinical course , active component (ileum or sigmoid colon), volvulus direction (clockwise or counterclockwise), and volvulus degree  . Among tLast, following the resection of gangrenous bowel segment, a stoma generally saves the life ,10. NeveI congratulate the authors for their interesting presentation and look forward to their reply on my comments."}
+{"text": "Algae are photoautotrophs like plants, produce their food by fixing atmospheric carbon dioxide in the presence of sunlight. They produce half of the total atmospheric oxygen, hence supporting all lifeforms on the earth. They can be unicellular or multicellular, microalgae or macroalgae and occur naturally in moist areas, freshwater, and marine environments. Being the primary producers in marine ecosystems, they form the base of most aquatic food webs. They multiply rapidly, have short generation time, and hence can spread across large areas in less time. They can withstand harsh environments without compromising survival due to their highly adaptive nature and can accumulate a wide range of products like fatty acids (oils), carbohydrates, chromophores , antioxidants, vitamins, enzymes, polymers, peptides, toxins, and sterols. These high-value products find diverse applications in biofuel production, food/feed supplements, nutraceuticals, cosmetics, natural colouring agents, and therapeutic and pharmaceutical fields. Apart from these, algae became extensively used in bioremediation, wastewater treatment, biochar and biofertilizers.Microalgae has gained high interest in the global bioenergy sector as a third-generation biofuel feedstock with, potential to meet global transportation fuel demand. The algal biomass serves as sources of biofuels such as biodiesel, bioethanol, biohydrogen, biomethane, and gasoline. Algae-based fuels are carbon-neutral because they tend to not disturb carbon emission-fixation balance and could significantly reduce the rising threats of global warming, unlike coal-based fossil fuels. Microalgal strains with higher lipid and/or fermentable sugar content are exploited for biodiesel and bioethanol production. These strains are isolated, cultivated under controlled conditions of optimized pH, temperature, nutrients, and light in photobioreactors and open raceway ponds over large areas, followed by harvesting and downstream processing to obtain the required product. The natural oil content in algae comes in the range of 20\u201350 percent of its dry weight and the oil yield far exceeds that from terrestrial crops. However, algal cultivation requires higher maintenance and harvesting costs, and advanced technologies for conversion to biofuels. Achieving indefinite availability of algal biofuels in higher volumes for fulfilling future demands is a big challenge in terms of capital investment and technological support. This makes algal-based biofuel production not commercially viable and economically feasible when compared to other conventional biofuels.2 and liberation of oxygen in near future.Various cost-effective strategies for improving commercial viability of algae-based biofuels have been proposed, one of them being co-production of value-added products from algae. The algal biomass is a rich natural source of antioxidants, polyunsaturated fatty acids (PUFAs), vitamins, and minerals and has the potential to serve as nutrient-enriched supplements to food diets, in therapeutic, cosmetic, and pharmaceutical applications. Their supplementation in small quantities would be suffice for meeting adequate nutritional demands of the larger population. Microalgal PUFAs like omega-3-fatty acids [Docosahexaenoic acid (DHA) and Eicosapentaenoic acid (EPA)] and omega-6-fatty acids [Arachidonic acid and gamma-linolenic acid (GLA)] offer many health-promoting benefits and treatment of diseases related to the cardiac and vascular system, nervous system, arthritis, obesity, mental health, and various autoimmune disorders. The supplementation of these nutrient-rich algal sources into dietary intakes of poultry, aquaculture, animal feeds and human diets enhance food quality and overall health of the consuming population. This ensures greater food security to maintain the nutritional status of population, foreseeing a disease-free healthy future. Considering the reckless usage of fossil fuels and shrinking of cultivable land, the Alga, primary producer of aquatic ecosystem may gain a significant place in ensuring the food security, environment conservation by sequestering CO"}
+{"text": "Low back pain is consistently documented as the most expensive and leading cause of disability. The majority of cases have non-specific etiologies. However, a subset of vertebral diseases has well-documented pain generators, including vertebral body tumors, vertebral body fractures, and vertebral endplate injury. Over the past two decades, specific interventional procedures targeting these anatomical pain generators have been widely studied, including spinal tumor ablation, vertebral augmentation, and basivertebral nerve ablation. This scoping review summarizes safety and clinical efficacy and discusses the impact on healthcare utilization of these interventions. Vertebral-related diseases remain a top concern with regard to prevalence and amount of health care spending worldwide. Our study shows that for a subset of disorders related to the vertebrae, spinal tumor ablation, vertebral augmentation, and basivertebral nerve ablation are safe and clinically effective interventions to decrease pain, improve function and quality of life, and potentially reduce mortality, improve survival, and overall offer cost-saving opportunities. As the most expensive condition, over USD 100 billion dollars per year, and the top cause of disability worldwide, prevalent in up to 70\u201380% of adults, low back pain (LBP) is a prime target for effective treatments ,3,4. LBPDisorders specific to the vertebrae, on the other hand, have fairly distinctive anatomical etiologies, such as vertebral body tumors, vertebral body fractures, or vertebral endplate disruption or inflammation. These can be addressed by interventional pain procedures, such as vertebral body spinal tumor ablation (STA), vertebral augmentation (VA), and basivertebral nerve ablation (BVNA). Therefore, our review aims to describe the pathoanatomical and diagnostic findings of these etiologies and the safety and clinical effectiveness of these interventions in the management of highly prevalent and costly vertebral disorders.This study is a scoping review aimed at appraising vertebral disorders, pathoanatomical considerations, diagnostic findings, clinical efficacy, and safety of interventional pain management procedures. Data sources included PubMed, MEDLINE, Google Scholar, and Cochrane Library indexed manuscripts. The literature search was conducted between May 2021 and August 2021 using the following keywords: vertebral body spinal tumor ablation, vertebral augmentation, and basivertebral nerve ablation. Inclusion criteria were human studies in the English language, such as randomized trials, meta-analyses, observational studies, case series, and review articles. All records identified in the search were independently appraised by two reviewers in a standardized, unblinded fashion, using the same strategy to ensure proper cross-checking of the results with the preferred reporting items for systematic reviews and meta-analyses extension for scoping reviews (PRISMA-ScR) methodology . The PRIOur search found 3801 studies with the selected keywords. Of these, 115 studies were filtered based on our inclusion criteria and reviewed. Seventy-one studies were excluded based on predetermined criteria of original studies related to human subjects related to STA, VA, and BVNA and using the PRISMA-ScR protocol. Forty-four studies were included in our data analysis. A summary of clinically and statistically significant findings from landmark studies and level I and level II studies were compiled, qualitatively analyzed, and reported on Vertebral disorders are associated with significant socioeconomic and medical sequelae due to high prevalence and heavy burden in health care cost utilization . ApproprVertebral tumors are benign or malignant growths that involve the vertebral body of the spinal column . Nearly Tumors of the spine most often initially present with a slow, gradual onset of back pain that is persistent at night and at rest . Aside fIn settings of metastatic spine tumors, spinal surgery aims to correct spinal instability, decompress spaces, remove tumor growth, improve neurological function, and reduce pain . It is cSpinal tumor ablation (STA) is an innovative, minimally invasive option to address pain from vertebral body tumors. Percutaneous treatment of non-spinal bone tumors was described first in 1992 with subsequent analysis of radiofrequency ablation (RFA) in a variety of non-spinal osseous structures ,71. The Most studies on STA are retrospective analyses. A few studies are worthy of a more detailed discussion. Anchala et al. published the first available multicenter retrospective analysis of STA with the majority (95%) of lesions also treated with augmentation . The patAlthough radiofrequency alone has been demonstrated to decrease tumor size, ameliorate pain, and improve function, augmentation is often used during the same procedure. Cement  is typically chosen for its resistance to vertebral compressive forces, especially when addressing osteolytic metastases. There are limited studies with a head-to-head comparison of VA alone versus STA combined with augmentation, although the combination therapy supports enhanced pain reduction and either similar or improved benefit to functional and quality of life statuses ,11,78.It is important to note that osteoblastic metastatic lesions cause thickened bone that is resistant to the high-frequency alternating current applied in RFA. Therefore, cryoablation has been proposed as an alternative treatment approach. Tomaisian et al. used liquid argon to induce lesion temperature reduction via the cryoprobe tip during a series of freeze and thaw cycles . This isVertebral fractures (VFs) are among the leading causes of debilitating acute back pain in the elderly population. VFs are associated with limited function and poor quality of life and are prone to increased mortality over time ,82,83,84VFs may result from low-energy or high-energy trauma. Low-energy fractures are defined as fragility fractures, associated with decreased bone mineral density, infections, and cancer, while high-energy trauma is usually associated with high-impact axial loading with or without flexion, extension, or rotational components ,88. The Management of VF aims to reduce pain and the severe disability caused by the injury, improve range of motion and function, and restore quality of life to pre-injury level. Conservative treatment includes oral medications such as analgesics, gabapentinoids, hormone therapy with calcitonin, bisphosphonates, physical modalities, and bracing. Although the majority of VF may be managed with conservative non-surgical treatment, a subset of these with significant vertebral height loss, mechanical disruption, and uncontrollable pain (around 40%) may warrant minimally invasive vertebral augmentation (VA)  92]. De. De92]. VA has been evaluated extensively over the past two decades. The landmark VERTOS study compared percutaneous vertebroplasty (PVP) with optimal pain medication . ImmediaIn 2016, Wang et al. compared VA with facet joint blocks . DespiteThere are few studies that did not present favorable outcomes of VA compared to conservative treatment. Buchbinder et al. and Kallmes et al. reported no benefit with VA compared to sham treatment at short-term and long-term follow-ups, with similar improvements in pain and function in both groups ,39. The A substantial body of evidence favors the use of VA in the management of VF for clinical improvement. Overall mortality and health care cost optimization must also be considered ,102,103.Hopkins et al. compared VA to non-surgical treatment from a cost perspective in 7541 patients . This dep, and calcitonin gene-related peptide (CGRP), histologically confirmed with protein gene product (PGP) 9.5 positive staining under microscopy [Vertebrogenic pain from endplate disruption is an etiology of chronic LBP that presents clinically different from other sources. Historically, the etiology of axial lumbar spine pain has been attributed to many anatomical structures, such as intervertebral disc degeneration, spinal canal narrowing, zygapophyseal joint pain, spinal ligaments hypertrophy, muscles and nerve root inflammation, etc. However, due to limited success with interventions targeting these structures, a recent shift in the vertebral pain treatment paradigm towards vertebral endplates has emerged. The basivertebral nerve (BVN) carries nociceptive input from damaged vertebral endplates related to inflammatory cytokines, substance croscopy ,112. Thecroscopy ,114. Bascroscopy ,116. Vercroscopy ,118,119.croscopy ,121,122.croscopy ,124. Vercroscopy ,130,131.Numerous clinical studies, reviews, meta-analyses, and society guidelines have reported the safety and clinical efficacy of BVNA in the treatment of vertebral pain ,135,136.Several recent clinical studies, reviews, meta-analyses, and society guidelines reported BVNA safety and efficacy alone or in comparison to the standard of care for BVNA. Markman et al. reported a significant association between opioid utilization reduction and improved ODI post-procedure through a post hoc analysis of the Fischgrund et al. (2018) study . FischgrThis study is a scoping review that followed the PRISMA-ScR methodology. It is prudent to comment on the limitations of generalizability in such settings, as three different interventions were evaluated for respectively distinct vertebral pathologies. Therefore, a high level of heterogeneity is introduced, restricting further statistical analysis. A meta-analysis was not possible given the lack of standardization between studies, lack of control in some studies, and different patient selection criteria, treatment groups and outcome measurements.The determination of the specific etiology of spinal pain remains a challenge despite its significant prevalence. The subset of these diagnoses attributed to vertebral etiologies from fractures, tumors, metastases, or vertebral endplate injury may be addressed with interventional options, including STA, VA, and BVNA. STA has the potential to reduce health care utilization while significantly improving immediate and sustained outcomes, including a reduction in opioid use, increased function, and improvement mood and QoL metrics. VA may reduce more than USD 1 billion spent annually addressing VF, as evidenced by multiple studies favoring its early use to reduce pain, improve QoL, facilitate ambulatory status and early mobilization, and ultimately improve morbidity and mortality in patients with VF. Finally, BVNA offers reproducible, sustainable, and clinically meaningful improvement in pain and function, with a few studies reporting reduced opioid consumption and disability and improvement in QoL."}
+{"text": "In \u201cA Clinician-Controlled Just-in-time Adaptive Intervention System (CBT+) Designed to Promote Acquisition and Utilization of Cognitive Behavioral Therapy Skills in Bulimia Nervosa: Development and Preliminary Evaluation Study\u201d :e18261), one error was noted.In the originally published article, the authorship order was incorrect. The article was originally published with the following authorship order:Adrienne Juarascio, Paakhi Srivastava, Kelsey Clark, Emily Presseller, Stephanie Manasse, Evan FormanIn the corrected article, the authorship order has been updated as follows:Adrienne Juarascio, Paakhi Srivastava, Emily Presseller, Kelsey Clark, Stephanie Manasse, Evan FormanThe correction will appear in the online version of the paper on the JMIR Publications website on July 29, 2021, together with the publication of this correction notice. Because this was made after submission to PubMed, PubMed Central, and other full-text repositories, the corrected article has also been resubmitted to those repositories."}
+{"text": "Objectives: This study aimed to explore the risk factors associated with cognitive frailty(CF) among community-dwelling older adults, and to provide the impact of CF on health-related outcomes. Methods: PubMed, EMBASE, Cochrane, PsycINFO, CINAHL, RISS, DBpia, NDSL, and KoreaMed databases were searched to retrieve studies. Two reviewers independently screened titles, abstracts and articles. The inclusion criteria are peer-reviewed articles written in English or Korean for community-dwelling older adults with both physical frailty and cognitive impairment present at the same time. Results: A total of 3,513 were searched, and the final 33 were extracted according to the inclusion criteria. Physical factors affecting CF were the number of chronic disease, cardiovascular disease, activity of daily living(ADL), making telephone calls and shopping during instrumental ADL, and a Mini Nutrition Assessment\u2013Short Form score. Psychological factor was depressive symptoms. Significant behavioral factors included self-reported physical activity, low vitamin D, smoking, frequent insomnia, and sedentary lifestyle. In social factors, social participation such as volunteering was identified as a protective factor. Mortality, followed by dementia was health related outcomes on CF, including ADL dependence, poor quality of life, and hospitalization. However, the CF-related fall was inconsistent. Conclusion: A wide variety of factors have been presented in studies related to CF. In order to understand CF and improve health-related outcomes, older adults in CF should be screened as high-risk group. When the risk factors and protective factors of CF managed, better health-related outcomes will lead to successful aging of community-dwelling older adults."}
+{"text": "Epithelial and immune cells from intestinal mucosa have Pattern-recognition receptors and G-protein coupled receptors (receptor of butyrate), suggesting that their activation can be regulated by intestinal microbiota and metabolites. In this review, we discuss how dynamics in the gut microbiota, their metabolites, and tumor microenvironment interplays in sporadic and hereditary CRC, modulating tumor progression.Colorectal cancer (CRC) is one of the most common cancers worldwide. As with other cancers, CRC is a multifactorial disease due to the combined effect of genetic and environmental factors. Most cases are sporadic, but a small proportion is hereditary, estimated at around 5-10%. In both, the tumor interacts with heterogeneous cell populations, such as endothelial, stromal, and immune cells, secreting different signals  to generate a favorable tumor microenvironment for cancer cell invasion and metastasis. There is ample evidence that inflammatory processes have a role in carcinogenesis and tumor progression in CCR. Different profiles of cell activation of the tumor microenvironment can promote pro or anti-tumor pathways; hence they are studied as a key target for the control of cancer progression. Additionally, the intestinal mucosa is in close contact with a microorganism community, including bacteria, bacteriophages, viruses, archaea, and fungi composing the gut microbiota. Aberrant composition of this microbiota, together with alteration in the diet\u2010derived microbial metabolites content (such as butyrate and polyamines) and environmental compounds has been related to CRC. Some bacteria, such as  Colorectal cancer (CRC) is the third most common cancer in both sex worldwide with an estimated 1.8 million new cases and mortality rates in 2018 over 800,000 . The mosDiverse studies have highlighted the role of gut commensal microbiota in host physiology and diseases such as cancer by modulating the immune response, genetic damage, and apoptosis \u20136. The iE. coli strain or epithelial invasion by Fusobacterium nucleatum , interacting with tumor cells, generating a favorable microenvironment to support tumor growth and progression , 11. Morucleatum , 13. Adducleatum , 14, conHere we aim to review the role of tumor microenvironment components in sporadic and hereditary CRC, with an emphasis in interactions between microbiota, immune system, and diet-derived metabolites.The tumor microenvironment (TME) has a wide diversity of molecules and cell types, including immune cells, fibroblast, adipocytes, endothelial cell and microbiome , 15. TheImmunosurveillance refers to the role of the immune system in recognizing antigens from transformed cells, thus generating memory and effector cells, which seek out and control generation of new tumor cells .Tumor cells undergo a selection process called immunoediting consisting of 3 stages: elimination, equilibrium, and escape. In the first phase, the antitumor immune response eliminates initiating tumor cells; the tumor then evolves into a static phase (equilibrium) in which some malignant cells avoid the immune response, without tumor elimination. Finally, the resistant clones manage to evade the immune system acquiring pro-tumorigenic properties and reducing their immunogenicity, allowing tumor development and clinical manifestations .+ T cells lyse tumor cells and release cytokines enhancing cytotoxic responses, such as IFN\u03b3; CD4+ Th1 T cells release cytokines improving lymphocyte cytotoxic function; regulatory CD4+ T cells (Treg) are immunosuppressive cells, preventing chronic inflammation and maintaining immune tolerance, by suppressing effector T cell proliferation and activation  density in CRC  expression, by Fas/FasL pathway, by releasing perforin and granzyme, or DCs and macrophages-activating cytokines . MHC-I lTumor-associated macrophages (TAMs) are usually associated with M2-profile macrophages, possess immunosuppressive properties, promote tumor progression, and, M2-TAMs marker expression is a poor prognostic factor in CRC .Other essential cells in the tumor microenvironment are myeloid-derived suppressor cells (MDSCs), that probably through T reg cell induction, in addition to NK and T effector cell suppression, inhibit antitumor responses . In CRC Additionally, tumor associated neutrophils (TAN) appear to be an important component of tumor-infiltrating cell populations in CRC. Indeed, high TAN content is associated with improved survival in CRC patients \u201343 possiContradictions between murine models and human sample data possibly associate with differing neutrophil functions and biology, along with tumor formation, as mice form faster and do not fully mirror human tumor development stages and cellular interactions . ConsequThere exists vast information regarding immunity in CRC, revealing a complex interaction between components of the immune system and the tumor. The immune system plays a double role, at the beginning and in the development of CRC, where immune-tumor interactions present opportunities for creating treatments preventing tumor development or improving current treatments.A healthy gut microbiome varies according to the high grade of interindividual differences, influenced by diet, lifestyle, age, gender, and geography. In 2018, the International Life Sciences Institute (ILSI) of North America workshop concluded that \u201cmechanistic links of specific changes in gut microbiome structure with function or markers of human health are not yet established\u201d . HoweverFusobacterium nucleatum in CRC  techniques \u201366 and hm in CRC , 66.Proteobacteria, Fusobacteria, and Lentisphaerae enrichment in fecal samples, and Firmicutes and Actinobacteria reduced , and some species stage-specific. The Atopobium parvulum, Actinomyces odontolyticus, Desulfovibrio longreachensis and Phascolarctobacterium succinatutens species increased only in early stage S0, in contrast, Colinsella aerofaciens, Porphyromonas uenonis and Dorea longicatena increased only in late stages III/IV  section),  inhibiting HDAC in adenomas, by increasing H3 histone acetylation and downmodulating the calcineurin-NFATc3 pathway  content and accompany prolonged CRC patient survival. Whereas, Prevotella, Bacteroides, and Fretibacterium, are overrepresented in CD3 low tumors by regulating chemokine expression from tumor cells  , suggesting pks+ Escherichia coli and enterotoxigenic Bacteroides fragilis act as protumorigenic bacteria in early colonic tumor development in genetically susceptible patients (In the inherited condition FAP (caused mainly by a germline mutation of the or gene) , intestipatients .Fusobacterium mortiferum and a decreased representation of Faecalibacterium prausnitzii and Bifidofacterium pseudocatenulatur, compared to patients without an identified mutation , with strains possibly linked to CRC as they produce inflammation and secrete toxins, such as cyclomodulins (toxins interfering with the eukaryotic cell cycle) (pks) (+ E. colipks are abundant in CRC and IBD patients (l cycle) . Among te) (pks) , and relpatients .-/- germ-free mice colonized with + E. colipks or E. faecalis induces aggressive inflammation; however, only + E. colipks developed invasive adenocarcinoma, demonstrating that E. coli-specific factors promote colitis-associated cancer  administered to IL10d cancer , as colid cancer , 86, 99.sertions   in the invasive CRC margin is associated with  E. coli . Moreoveironment .+ E. colipks strain compared to non genotoxic-strain exposed mice, suggesting colibactin exert a direct effect on gut microbiota, additional to its other host effects , and shares a proinflammatory signature with Fusobacterium-associated human colorectal cancer, suggesting these bacteria promotes a tumor microenvironment favoring neoplasia progression  and CpG island methylator phenotype in colorectal carcinoma, suggesting that this bacteria is involved in a molecular specific CRC subtype , supporting the bacterial pro-tumoral role  activating the autophagy pathway in response to chemotherapy , including acetate, propionate, and butyrate, corresponding to fermentation products of complex polysaccharides, such as starches and fiber . The BacFFAR3, GPR43/FFAR2, GPR109A/HCAR2) or transporters   .Administration of SCFAs mixture restores intestinal epithelial cell turnover in antibiotic-treated SPF mice, previously having reduced amounts of acetate, propionate, and butyrate , demonstBacteroides vulgaris, Bacteroides uniformis, Roseburia, and the Lachnospiracea family  inhibition and interrupting cell cycle  downregulation , suggestGenerally, butyrate inhibits inflammation and carcinogenesis, reducing NF-kB and Wnt signaling, both active pathways in CRC , 141. AdPolyamines are organic polycations involved in cell proliferation and differentiation, tissue repair, apoptosis, angiogenesis, immune response, signal transduction, and gene expression , 142\u2013144Myc -enriched diets (whole grain rye flour bread/rye kernels bread + resistant starch) , or cookF. nucleatum)  , togethecleatum) . Protococleatum)  will conConsidering the evidence of the influence of the diet in protecting and decreasing the risk of cancer, the 4th edition of the European Code against Cancer recommends that \u201cpeople have a healthy diet to reduce their risk of cancer: eating plenty of whole grains, pulses, vegetables and fruits; limit high-calorie foods (high in sugar or fat); avoid sugary drinks and processed meat; and limit red meat and foods high in salt\u201d .In health, microbiota participates in functions such as immunity regulation, digestion, and nutrition. As dysbiosis has been associated with diverse pathologies including CRC, microbiota could play a role in carcinogenesis, as previously demonstrated.+ E. colipks and F. nucleatum, cause DNA damage, increased epithelial cell proliferation, and immune system modulation, thus altering the microenvironment favoring tumorigenesis. Moreover, hereditary CRC reflects dysbiosis, suggesting microbiota changes during CRC progression occur in genetically susceptible subjects.The immune system, microbiota and their metabolites participate in the carcinogenic process, acting differently in each tumor development stage. In sporadic CRC, specific strains have been involved in its initiation and development. Specifically, carcinogenic effects of synthesized toxins and virulence factors from Some diet and microbiota metabolites associated with CRC, such as SCFAs and Polyamines, directly affect tumors and TME cells, thus becoming potential therapeutic targets.Lactobacillus acidophilus, Bifidobacteria bifidum) appears beneficial, reducing tumor growth and potentially carcinogenic bacteria, while increasing butyrate concentration and NK and NKT cell number  and apigenin (present in fruits and vegetables) possibly reduce aberrant crypt foci numbers , increasin vitro and inhibit xenograft tumor growth  in patients reduces adenoma recurrence , PBT wour growth .Another option in CRC carcinogenesis is blocking-cytokine antibodies, since IL-17 and IL-23 receptor blockade inhibits colorectal tumor formation .F. nucleatum in APCMin/+ mice, and revert chemotherapy resistance in CRC cell lines  (Fondecyt iniciaci\u00f3n #11190990).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Quantum Materials is a new open section of Materials aimed at publishing original and review articles on novel scientific and applied research that significantly contribute to the understanding and discovery of quantum materials and related phenomena, functions, and applications. Quantum materials can be classically defined as solids with exotic physical properties stemming from the quantum mechanical properties of their constituent electrons [lectrons . AlthougQuantum materials are at the forefront of contemporary physics and materials science, as they offer a valuable platform to explore the complex interplay among various factors of electron\u2013electron correlation, spin\u2013orbit interaction, symmetry, topology of wavefunctions, low dimensionality, quantum confinement, quantum coherence, quantum fluctuation, and so forth, thus holding promise for next-generation electronic/photonic and energy technologies with currently unavailable functionalities ,2. DiscoQuantum Materials includes, but is not limited to, the following: superconducting materials: novel superconductors, cuprates, iron-based systems, and heavy fermion superconductors; correlated electronic materials: Mott insulators, magnetism in correlated electron systems, colossal magnetoresistance, multiferroicity and multiferroics, and related theories and methods; topological quantum materials: topological insulators/superconductors, Dirac semimetals and Weyl semimetals, magnetic topological insulators, and topological heterostructures and devices; quantum phenomena in advanced materials: finite-size and low-dimensional  systems, photovoltaic/light-emitting systems, photocatalysis, and advanced energy generation systems.Research interest to Section"}
+{"text": "Ageism is an insidious form of injustice that is internalized from an early age with accumulating negative health impacts across the lifespan. Internalized ageism is associated with numerous public health outcomes, including physical and mental health, functional impairment, cognition, cardiovascular stress, hospitalizations, and longevity. Research has begun to document how ageism negatively impacts health through psychological, behavioral, and physiological pathways. Yet, limited research has addressed interventions to reduce internalized ageism. This study integrates stereotype embodiment theory, theories of successful and productive aging, and recent scholarly literature to present a conceptual model with potential downstream, midstream, and upstream interventions at micro, meso, and macro levels. Micro interventions include: social, physical, and cognitive engagement, as well as stress management. Meso interventions include: education, intergenerational contact, and narrative reframing. Macro interventions include anti-ageism policy, such as amendments to the Age Discrimination in Employment Act (ADEA). The conceptual model is described in detail, and implications for practitioners are discussed. The need to examine how policy influences health through the three pathways in stereotype embodiment theory is discussed. This study provides a working model for scholars and practitioners to use when considering paths toward reducing internalized ageism and optimizing well-being for aging adults."}
+{"text": "The wide access to varied, attractive, and aggressively promoted information can induce pregnant women to think that any form of complementary therapy can be a saving solution for a medical problem because these therapies are natural, therefore, harmless. Updated information from literature about indications, benefits, limits, and risks of phytotherapy in pregnancy was presented. Valuable therapeutic resources with proven clinical efficacy (evidence-based medicine) were presented for each trimester of pregnancy, during labor, postpartum, but also during breastfeeding. For some phytotherapeutics, there are scientific studies. There is also a detailed presentation about some possibilities for therapeutic errors, which should be avoided during pregnancy. Positive results of phytotherapy deserve to be known and applied by the obstetrician for the certain benefit of future mothers. Wide access to varied, attractive, and aggressively promoted information can induce patients, especially pregnant women, to perceive that a certain type of complementary therapy can be a saving solution for a medical problem because these therapies are natural, so harmless. For an experienced clinician, there are sometimes medical situations in which it would be desirable to have \u201csomething else\u201d as a therapeutic tool, to intercede for a better evolution of the patient when usual medicine seems to be inadequate. The various branches of complementary medicine, which never exclude modern medicine, can sometimes provide solutions. Pregnancy, the time of birth, but also the period of breastfeeding can be challenging for both obstetricians and patients and sometimes require a plus in the therapeutic panoply .Complementary medicine consists of diagnostic and treatment methods outside modern, conventional, or classical medicine. An important part is represented by natural therapies . Another important part is represented by the traditional medicine  to which, due to the intense circulation, many people have access: homeopathy, osteopathy etc. The strongest criticism of these methods is that therapeutic efficacy is not tested by scientific methods, and many experts are intrigued with the consumption of natural products that are increasing in the Western world, despite the absence of these scientific demonstrations of efficiency and/or safety. This article reviews exactly that branch of natural medicine that came beyond the tradition of folk medicine with scientific studies as a support for both clinicians and patients \u2013 phytotherapy. Phytotherapeutics use is estimated to be 10\u201374% of pregnant women  . StatistPhytotherapy is a branch of medicine that uses pharmaceutical preparations obtained from herbal products in prophylaxis and treatment. These preparations can be macerates, infusions, decoctions, tinctures, extracts, fresh or fermented juices, and powders. The origin of plant products is spontaneous flora, crop flora, industrial cell and tissue cultures, and the marine environment . There aWe can distinguish between traditional phytotherapy  and modern phytotherapy, which is based on scientific data of phytochemistry, pharmacognosy, and toxicology . The theRegarding the scientific proof of the action of phytotherapeutic drugs, there are both clinical studies and reports of \u201cevidence-based medicine\u201d, but criticized when meta-analyzes are made due to either small groups of control or lack of double-blind experiments, or other error factors. However, there are multiple sources of documentation available for specialists. In this regard, the Drugs.com website contains data on phytotherapeutics in the Professional section. This is of interest to obstetricians because a small section of action in pregnancy and lactation is dedicated to each phytotherapeutic/plant, including the bibliographic source.Of particular interest are preparations containing herbal combinations, which have multiple indications and whose components do not always have beneficial effects but also some toxic effects by accumulation. In case of these insufficiently verified \u201cfood supplements\u201d, especially in pregnant or lactating women, these herbal combinations must be used with caution and only on the recommendation of a phytotherapy specialist.The most harmless application of herbal therapy is by inhalation (in respiratory diseases) followed by infusion and then plant extracts. The most hazardous active substances in pregnancy are alkaloids, coumarins, saponins, cucurbitacins, sesquiterpene lactones, and anthraquinones.It should be noted from the beginning that some phytotherapeutics are prohibited during pregnancy or should be used with caution due to the emmenagogue effect . Plants with a laxative and diuretic effect are also prohibited .Achillea millefolium), virnant (Ruta greveolens), sage , mother root (Leonuri herba), sweet flag , but also marigolds , licorice (G glabra), parsley (Petroselinum crispum), thyme (Satureja hortensis L), fennel (Foeniculum vulgare), wormwood (Arthemisia absinthium), Syrian weevil (Hybiscus syriacus), horsetail (Tussilago farfara), verbena , senna , buckthorn (Rhamnus frangula), nettle (Urtica dioica), juniper (Juniperus communis L.), lavender (Lavender Angustifolia), anise (Pimpinella anisum), and gentian (Gentiana lutea).The plants with the emmenagogue effect are common yarrow (Berberis vulgaris), hollyhock (Chelidonium majus), carrion (Ephedra sp), Hydrastis (Hydrastis Canadensis). Due to the bitter substances, essential oils, and the emmenagogue effect, the following plants are forbidden in pregnancy: aloe vera (Aloe vera), hot pepper tincture (Capsicum annuum), sorrel , thimble (Pulsatilla sp), mistletoe , juniper, and cinnamon essential oil (Cinnamonum verum) [Plants banned in pregnancy primarily due to the embryotoxic effect of alkaloids are dragonfly (m verum) .Serenoa repens), Dong-Quai (Angelica Sinensis), and yohimbine. Some plants are allowed only for occasional consumption: hyssop, St. John\u2019s wort, burdock, plantain, armory, fenugreek, and thyme.Certain herbs used as spices should be avoided or consumed occasionally and, of course, in small quantities . The plants of Asian medicine forbidden in pregnancy are the dwarf palm (Pregnant patients may use preparations (simple infusions or mixtures) containing the following plants: chamomile, mint, raspberry leaves, rosehip, ginger, cranberry, blueberry, rhubarb, and echinacea, which are allowed in reasonable quantities and have no side effects .Aspalathus linearis), raspberry leaves, nettle, ginger, alfalfa (Medicago sativa), lime fruit, parsley (the plants highlighted are emmenagogues). There is also another \u201ctea for pregnant women\u201d, which contains rosehip (Rosa canina), elder (Sambucus L.), pear root (Elymus repens), wild pansy (Viola tricolor), dandelion , linden (Tilia tomentosa), blueberry leaves (Vaccinium myrtillus) \u2013 indicated in \u201cpregnancy edema\u201d, an extremely complex clinical entity, which can hide a dangerous pathology, both for mother and fetus. It must be correctly diagnosed and treated. In terms of preparations containing ginger , there is a highly varied offer, especially in terms of doses , one capsule per day being recommended.There are countless combinations of tea or tablets indicated for pregnancy, but their composition must always be carefully checked. If these products are consumed in larger quantities than recommended, the side effects may occur (most often exaggerated uterine contractility) . In RomaOn the other hand, not every combination containing ginger extract is allowed in pregnancy:\u2022Ginger 300 mg, wild peppermint essential oil 0.5 mg, rhubarb essential oil 0.5 mg \u2013 tablets ;\u2022Gentiana lutea). Although the preparation contains gentian, which is contraindicated in pregnancy, the leaflet in the chapter \u201cContraindications\u201d states that they are unknown.Ginger 160 mg, artichoke, yellow gentian  is the most valuable gemmotherapeutic remedy for women during the reproductive period and perimenopause. Buds and branches are characterized phytochemically. They contain organic acids, vitamins, and catechins, which have an anti-inflammatory and antioxidant effect. Catechins (13.25%), flavonoids (8.71%), cinnamic acid, and benzoic acid predominate. Its indications are habitual abortion or the risk of abortion  and the risk of premature birth [Raspberry  acts on the hypothalamic-pituitary-adrenal gland and ovarian axis, having a progesterone-like effect [The gemmotherapeutic from crab (e effect . It is aViburnum lantana) can be used in obstetrics: the risk of abortion or premature birth and can be prophylactically administered to the patients with abortive disease when the pregnancy is detected.The gemmoderivative from viburnum (Ribes nigrum) is one of the most studied gemmotherapeutic [The blackcurrant hemoderivative  affects the neuro-vegetative system, being useful in pregnancy in case of insomnia and anxiety, being preferably administered in the evening.The hemoderivative from linden  extracted from plants. Volatile oils (aetherolea) are products of secondary plant metabolism secreted by specialized cells. Volatile oils are stored outside the plant (in glandular brushes or papillae) or inside the plant (in secretory channels or bags) in the form of oily, volatile, aromatic-smelling liquids . In the Volatile oils used for medical purposes must be of high quality. Unfortunately, many synthetic or counterfeit oils do not have the expected therapeutic effects or can even be dangerous. Therefore, the source and the producers of volatile oil must be rigorously checked. In pregnancy, volatile oils are administered strictly externally by massage or inhalation  . The folFrom the data published in the literature and personal clinical experience, we discussed the indications of the main phytotherapeutics used in obstetrical practice, possible interactions with various drugs, side effects, and plants contraindicated in pregnancy .Indications are preparation of birth by stimulating the uterine contractility, having an indirect hemostatic effect in the immediate postpartum. It is also indicated in term labor induction or post-term pregnancy . AlthougWe cannot draw clear conclusions on the beneficial effect  from clinical trials. The therapeutic dose appears to be four grams/day, and the only randomized, double-blind study used 2.4 g/day, which may explain the lack of significant conclusions. Based on meta-analyzes, a scientifically based recommendation for the use of raspberry leaves in pregnancy cannot be made at this time .It is used mainly at the beginning of pregnancy, in the first trimester dysgravidia, and the last weeks, when a digestive discomfort may appear . We recoBryophyllum extract has a tocolytic effect, being used in Germany in abortion or premature birth . The pecAs pregnant women generally receive classical medication for various pathological situations, and at least one in five pregnant women consumes natural products simultaneously, the potential interactions between them must be considered .\u2022Ginger \u2013 possible interactions with Insulin, Metformin, Nifedipine;\u2022Chamomile \u2013 possible interactions with benzodiazepines  and Ondansetron (decreases the antiemetic effect);\u2022Raspberries \u2013 it is discussed that polyphenols may decrease the intestinal absorption of iron, but there is no solid scientific evidence in this regard.\u2022Gastrointestinal effects  \u2013 capsaicin from hot peppers ; gastroesophageal reflux, abdominal discomfort, increased nausea \u2013 ginger (first-trimester dysgravidia) ;\u2022Premature birth ; topical \u2013 almond oil, for massage ;\u2022Preeclampsia \u2013 consumption of licorice in the second trimester;\u2022Maternal hypoglycemia \u2013 Raspberry leaves (used as an inducer or stimulator of labor) ;\u2022Polyhydramnios \u2013 senna leaves;\u2022Hepatotoxicity \u2013 preparations from plants contaminated with lead, senecionine;\u2022Malformative effects \u2013 however, the correlations are weak: Angelica Sinensis used to prevent abortion could induce musculoskeletal and connective tissue malformations or ocular malformations .Various phytopreparations have also been studied, no adverse reactions appear to have been recorded, but the quality of these studies is low to mediocre. Therefore, caution is recommended for the following substances: evening light capsules or saffron or dill infusions to induce labor, red sage for oligohydramnios, ginger, or quince for first trimester dysgravidia, ointments with green tea extract to heal the episiotomy scar.Excessive consumption of fennel by lactating women can lead to increased absorption of anethole (phytoestrogen) and estragole (etheric component). Estragole, which is also found in many plants and spices , has been shown to have a carcinogenic effect in mice (at a dose of more than 1 g/kg body weight) , 27. ExcBased on scientific data from literature and meta-analyses, several therapeutic schemes can be recommended for the most common pathologies in pregnancy, some of them with scientific documentation.\u2022Alchemilla vulgaris), one or two cups a day, or passion flower (Passiflora incarnata or Passiflora caerulea) are useful. Traditional Chinese medicine recommends Angelica sinensis;Phytotherapy: The infusion of Lady\u2019s mantle , viburnum, and hornbeam .\u2022Humulus lupulus), chamomile (Matricaria recutita), fennel;Phytotherapy: infusions in small quantities, even cold ones, from the following plants: ginger, mint (weak infusion), hop .\u2022Valeriana officinalis), hop cones, lavender, or rhubarb  (simple or mixtures);Phytotherapy: mild sedative infusions of linden flowers, valerian . However, mild laxatives \u2013 flax seeds or certain laxatives of volume -psyllium) may be administered;\u2013diarrhea: infusion of dried blueberries.\u2022\u2022in gastro-esophageal reflux and heartburn: fig extract 2 ml x 2/day;\u2022cranberry extract in constipation.Gemmotherapy:\u2022Phytotherapy: creams with poplar buds, hamamelis, oak bark or suppositories with marigold flower extract, hamamelis, poplar buds, chestnut seeds may be recommended;\u2022Gemmotherapy: extract of wild chestnut and edible chestnut.Phytotherapy: for the prophylaxis of varicose veins, infusions of nettle, hamamelis, Lady\u2019s mantle combined, one cup daily are recommended. There are many gels, creams, or capsules with known plant extracts with venotropic effects . Oral preparations containing standardized extracts of Citrus Aurantium, containing 500 mg of micronized purified flavonoid fraction corresponding to 450 mg of diosmin and 50 mg of hesperidin, extracted from citrus peel, may be used from the second trimester of pregnancy).\u2022Phytotherapy: infusion of nettle, dandelion, elder juice.\u2022Vaccinium macrocarpon), cranberry (Vaccinium Vitis-idaea), goldenrod (Solidago virgaurea);Phytotherapy: blueberry infusions, cranberries. Many over-the-counter preparations contain blueberry extracts, American blueberry , known in traditional European phytotherapy, which optimizes uterine contractility. Infusions of yarrow plant, raspberry leaves, verbena, blackberry leaves (Rubus fructicosus), and Cimicifuga can be added;Phytotherapy: The phytotherapy of choice is Lady\u2019s mantle (\u2022Rosa damascena) reduces fear, the essential oil of sage  stimulates contractility but calms the parturition. Cinnamon leaf oil also stimulates uterine contractility. Studies show a shortening of the active phase of labor but not a decrease in its entire duration. The third period of labor is shortened. Jasmine essential oil calms the perception of painful uterine contractions, but also galactagogue.Aromatherapy: its use seems to reduce fear, anxiety , pain, nausea in labor, and increase uterine contractility. Thus, the essential oil of lavender, jasmine, lemon, and rose . It should be noted that the intake of these teas is not a substitute for proper hydration, so consumption should be moderate. Tea made from mallow, chamomile, and rhubarb flowers can also be combined;\u2022Cymbopogon citratus) restores the mother\u2019s body after birth, stimulates lactation, fights postnatal depression, sweet cumin (fennel), sage, and jasmine.Aromatherapy: Essential oil from lemongrass , local applications of cabbage (crushed leaves), jasmine (flowers), and parsley (leaves);Phytotherapy: mint and sage tea, preparations from \u2022Aromatherapy: essential oil of cypress, geranium, lavender, mint .\u2022Phytotherapy: poultice from concentrated infusion of thyme, which is kept for one hour a day on the inflamed area of the breast; poultice from crushed fresh cabbage leaf ;\u2022Aromatherapy: chamomile, geranium, lavender, mint \u2013 compress applied to the inflamed area.Adding aromatherapy  to analgesia  appears \u2022Phytotherapy: locally, for episiotomy wounds, concentrated infusions of wormwood, horsetail, marigold, chamomile, combined with antiseptic and healing creams of marigold and arnica;\u2022Aromatherapy: chamomile oil, lavender, tea-tree, cypress, incense, myrrh.\u2022Phytotherapy: reasonable amounts of St. John\u2019s wort infusion or St. John\u2019s wort extract may be recommended;\u2022Aromatherapy applied in labor and postpartum  seems to decrease the incidence of postpartum depression.\u2022Phytotherapy: general tonics such as fruits of Prunus spinosa, fig, or dates fruits paste;\u2022Phytotherapy: infusions of lime, mint, lemon, rosehip, echinacea, ginger \u201333;\u2022Gemmotherapy: combinations of blackcurrant, hornbeam, rosehip, and silver birch bud extracts.\u2022Phytotherapy: infusions of rosehip and echinacea, which are associated with an extremely favorable effect. Apitherapy ;\u2022Aromatherapy: essential oil of fir, pine, lemon (antiseptics); lavender or bergamot essential oil (anxiolytics).Even if complementary therapies have been proven beneficial for pregnant women, they should not be applied without care because they can sometimes do more harm than good. Some examples of this are lower limb edema, hypertension in pregnancy, preeclampsia , gestatiPositive results of many complementary therapies deserve to be known and applied by the obstetrician, benefiting the future mother. On the other hand, few systematic reviews highlight the adverse effects of this therapy. Pregnant women can be supported to use these therapies during pregnancy rationally and while breastfeeding if indicated by a specialized doctor with experience in phytotherapy. The obstetrician and the family physician or pharmacist must encourage a pregnant woman to ask for special information. Also, pregnant women must not use self-diagnosis and self-medication in any form during pregnancy because the mistakes can be extremely severe, both for the mother and the fetus.The authors declare that there is no conflict of interest.CG and REB contributed to conceptualizing, VV and TS contributed to the methodology, CG and GC contributed to writing the original draft, AMB, TS, and NB contributed to editing the manuscript. CMG and CAZ contributed to data collection. CAZ and REB contributed to data analysis."}
+{"text": "Pyrethroid insecticides are extensively used in controlling agricultural insects and treatment of ectoparasitic infestation in farm animals. However, the unhygienic disposable and seepage of pyrethroids from the agricultural runoff will lead to contamination of the aquatic ecosystems, which will, in turn, induce harmful toxic effects in the exposed living aquatic organisms, including fish. Cypermethrin (CYP) is a commonly and widely used type II pyrethroid insecticide with known dangerous toxic effects on the exposed organisms. Serious hazardous effects of these toxicants have been reported in several fish species leading to high mortalities and economic losses of the exposed fish.Pesticides are chemicals used to control pests, such as aquatic weeds, insects, aquatic snails, and plant diseases. They are extensively used in forestry, agriculture, veterinary practices, and of great public health importance. Pesticides can be categorized according to their use into three major types . Water contamination by pesticides is known to induce harmful impacts on the production, reproduction, and survivability of living aquatic organisms, such as algae, aquatic plants, and fish (shellfish and finfish species). The literature and information present in this review article facilitate evaluating the toxic effects from exposure to various fish species to different concentrations of pesticides. Moreover, a brief overview of sources, classification, mechanisms of action, and toxicity signs of pyrethroid insecticides in several fish species will be illustrated with special emphasis on Cypermethrin toxicity. The present era of the green revolution, witnessing a swift increase in human populations across the globe, depicts the dependency of human beings on available natural resources. The current scenario has led to efforts for technological advancements to cope with the need of societies. This, in turn, is ensured by evolving ever-increasing dissolution of different synthesized chemicals in the environment, which induce pollution, specifically in aquatic bodies used as dumping sites in most parts of the world ,2,3. PolA pest refers to a rodent, insect, nematode, weed, fungus, or any other form of terrestrial or aquatic plant or animal virus, bacteria, or other microorganisms that harm the foodstuffs, garden plants, household articles, or trees, as a vector of diseases ,7. For fWater pollution with pesticides may be due to direct application of these chemicals for controlling aquatic flora and/or seepage from agricultural lands through agricultural runoffs . These aPesticide residues can be sustained for long periods in the fields after application due to their decreased biodegradation properties , which cPyrethroids are from commonly used insecticides worldwide ,24,25,26Danio rerio) , is one of extensively used and highly effective synthetic pyrethroids. It is lipophilic and synthetically obtained from a natural source known as pyrethrin. CYP is broadly engaged mainly in commercial agriculture, forestry, gardens, buildings, and farmyards to prevent and control insects . InteresFurthermore, CYP is commercially registered to kill soybean and cotton pests successfully ,113. TheThe study conducted by Laabs et al.  revealedBrycon amazonicus [Anabas testudineus [Heteropneustes fossilis [Prochilodus lineatus [C. batrachus [azonicus , Anabas tudineus , rohu [1tudineus , Heteropfossilis , Prochillineatus , and C. atrachus . Moreoveatrachus , developatrachus , immunotatrachus , neurotoatrachus , genotoxatrachus ,33,130, atrachus ,132. Furatrachus , Nile tiatrachus , common atrachus .Our rapidly growing population requires intensification of crop production. Thus, it is essential to control pests and insects that cause economic losses in crop production. Pesticides have become a necessary part of the production cycle for eliminating plant diseases and killing pests that can drastically reduce harvestable products. Moreover, a polluted environment with a high concentration of synesthetic pyrethroids has caused several adverse effects in living aquatic organisms. This literature explained the biological modes of action of some pyrethroids in fish species and the underlying biological impacts of pyrethroid-contaminated water on reared fish. Furthermore, toxicological experiments showed individual responses against pyrethroid lethality. This review article provides insight for future research studies to evaluate the toxic effects of pyrethroid insecticides and sheds light on CYP toxicity mechanisms in fish."}
+{"text": "Lactic acid bacteria (LAB) have been used for various food fermentations for thousands of years. Recently, LAB are receiving increased attention due to their great potential as probiotics for man and animals, and also as cell factories for producing enzymes, antibodies, vitamins, exopolysaccharides, and various feedstocks. LAB are safe organisms with GRAS  status and possess relatively simple metabolic pathways easily subjected to modifications. However, relatively few studies have been carried out on LAB inhabiting plants compared to dairy LAB. Kimchi is a Korean traditional fermented vegetable, and its fermentation is carried out by LAB inhabiting plant raw materials of kimchi. Kimchi represents a model food with low pH and is fermented at low temperatures and in anaerobic environments. LAB have been adjusting to kimchi environments, and produce various metabolites such as bacteriocins, \u03b3-aminobutyric acid, ornithine, exopolysaccharides, mannitol, etc. as products of metabolic efforts to adjust to the environments. The metabolites also contribute to the known health-promoting effects of kimchi. Due to the recent progress in multi-omics technologies, identification of genes and gene products responsible for the synthesis of functional metabolites becomes easier than before. With the aid of tools of metabolic engineering and synthetic biology, it can be envisioned that LAB strains producing valuable metabolites in large quantities will be constructed and used as starters for foods and probiotics for improving human health. Such LAB strains can also be useful as production hosts for value-added products for food, feed, and pharmaceutical industries. In this review, recent findings on the selected metabolites produced by kimchi LAB are discussed, and the potentials of metabolites will be mentioned. Other minor compounds such as \u03b3-aminobutyric acid (GABA), ornithine, mannitol, exopolysaccharide (EPS), 2-hydroxyisocaproic acid (HICA) and 3-phenyllactic acid (PLA) are derived from amino acids or sugars by enzyme activities of LAB. The production of some compounds helps LAB hosts to adjust to adverse environments. GABA and mannitol are the examples (see below).Kimchi is a traditional Korean vegetable food produced through fermentation carried out by lactic acid bacteria (LAB) originated from the raw ingredients of kimchi ,2. The mLeuconostoc, Lactobacillus, and Weissella, and they include Leuconostoc mesenteroides, Leuconostoc citreum, Leuconostoc gelidium, Lactobacillus brevis , Lactobacillus plantarum , Lactobacillus sakei , Weissella confusa, Weissella koreensis, and Weissella cibaria . . hicD) (hicD) B 106]. . hicD)  and acted as a fungistatic at lower concentrations [L. mesenteroides or Lb. plantarum (107 CFU/g kimchi) to kimchi increased HICA content compared to control kimchi [HICA effectively inhibited the growth of tal cary . HICA incidic pH . HICA excidic pH . HICA ancidic pH . HICA actrations . HICA antrations . Antimicl kimchi . For thil kimchi . SimilarPlants inhabiting LAB have great potential not only as starters for fermented foods such as kimchi, sauerkraut, and pickles but also as probiotics for humans, animals, poultries, and fishes. LAB also have good potential and receive interest as cell factories for the production of value-added products, including vitamins, 1, 3-propandiol, diacetyl, hyaluronic acid, exopolysaccharides, platform chemicals for bioplastics and biofuels, antibodies, etc.  LAB tranLb. plantarum CJLP133, which was obtained through screening of 3500 LAB isolates from kimchi. The administration of the strain improves conditions of sensitive skin such as atopic dermatitis, and the effect was proven scientifically [Kimchi serves as a model food for studying the biochemical, physiological, and genetic strategies of LAB species to adapt to acidic, low-temperature, and anaerobic kimchi environments. Metabolites such as GABA, ornithine, bacteriocins, exopolysaccharides, etc. are the products resulting from efforts of LAB to thrive and outcompete other microorganisms under kimchi environments. Therefore, it is necessary to have a deep understanding of the metabolites including the production pathways, key enzymes, regulatory mechanisms, and the roles and potentials as functional materials if a better or novel utilization of LAB is tried. Isolation of novel LAB strains with some functionalities is important for the development of products with commercial value. For example, one popular health functional product certified by the Korean government is based on ifically . Progres"}
+{"text": "Unhealthy diet, in particular high-fat diet (HFD) intake, can cause the development of several metabolic disorders, including obesity, hyperlipidemia, type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD), and metabolic syndrome (MetS). These popular metabolic diseases reduce the quality of life, and induce premature death worldwide. Evidence is accumulating that the gut microbiota is inextricably associated with HFD-induced metabolic disorders, and dietary intervention of gut microbiota is an effective therapeutic strategy for these metabolic dysfunctions. Polysaccharides are polymeric carbohydrate macromolecules and sources of fermentable dietary fiber that exhibit biological activities in the prevention and treatment of HFD-induced metabolic diseases. Of note, natural polysaccharides are among the most potent modulators of the gut microbiota composition. However, the prebiotics-like effects of polysaccharides in treating HFD-induced metabolic diseases remain elusive. In this review, we introduce the critical role of gut microbiota human health and HFD-induced metabolic disorders. Importantly, we review current knowledge about the role of natural polysaccharides in improving HFD-induced metabolic diseases by regulating gut microbiota. Diet can affect multiple aspects of human health, and high-fat diet (HFD) contributes to the epidemics of obesity and obesity-associated chronic metabolic diseases, such as diabetes, hyperlipidemia, hypertension, non-alcoholic fatty liver disease (NAFLD), and metabolic syndrome MetS; . These mClostridioides difficile infection  exhibit altered gut microbiota composition at the phylum level, and longer-time HFD feeding (12\u2009days) induces the gut microbiota dysbiosis . Regardlncreased . The Fir obesity . In addi obesity . Moreove obesity . Importa obesity . In a raacterium . In addiacterium . Of noteacterium . Currentacterium . Of noteacterium . Thus, oCarbohydrates and polysaccharides are important composition of our daily diet that are not directly digested by the gastrointestinal enzymes . CarbohyFirmicutes, Fusobacteria, Proteobacteria, and Lactobacillus, and decreased the beneficial bacteria, Bacteroidetes, Verrucomicrobia, Faecalibacterium, and Lactobacillus plantarum  shows anti-obesity effect in HFD-fed mice by reversing HFD-induced gut microbiota dysbiosis, notably by decreasing the ratio of bacteria, Firmicutes/Bacteroidetes  attenuates obesity in HFD-fed mice by increasing the abundance of SCFAs, in particular, butyrate-producing gut bacterium, Eubacterium xylanophilum (Lycium barbarum polysaccharides (LBP) prevent obesity in HFD-fed mice, increase SCFAs, butyric acid and SCFAs-producing gut bacteria, Lacticigenium, Lachnospiraceae, and Butyricicoccus  inhibit HFD-fed obese mice by reversing HFD-induced gut microbiota disorder, and increasing SCFAs, acetate, and butyrate  cholesterol. Hyperlipidemia is strongly associated with diet, and HFD accelerates s of LDL . Hyperlis of LDL . Recent s of LDL . As suchs of LDL . Currents of LDL . NaturalCordyceps militaris, alleviate hyperglycemia in high-fat/sucrose diet-fed mice by improving gut microbiota dysbiosis, and promoting the abundance of probiotics, Akkermansia muciniphila  alleviate T2DM symptoms in HFD/STZ-fed mice by increasing SCFAs contents, and promoting the SCFAs-producing gut species, such as Ruminococcus and Anaerotruncus  exhibit hypoglycemic and hypolipidemic effects in HFD/STZ-induced T2DM mouse model by reversing HFD/STZ-induced gut microbial dysbiosis, notably increasing Alistipes, and reducing Streptococcus, Staphylococcus, and Enterococcus  display antidiabetic effects by restoring HFD/STZ-induced intestinal microbiota dysbiosis, notably by increasing Blautia, Bacteroides, Dehalobacterium, and Parabacteroides, and reducing the harmful gut bacteria, Aerococcus, Corynebactrium, Ruminococcus, and Proteus , choline metabolite trimethylamine (TMA), lithocholic acid (LCA), and succinate . SCFAs aAstragalus mongholicus that attenuates NAFLD in HFD-fed mice, and mechanistically, APS enriches Desulfovibrio genus, especially Desulfovibrio vulgaris that is a generator of, SCFAs, acetic acid, and attenuates hepatic steatosis  are extracted from traditional Chinese herd and functional food, Lycium barbarum that combines with aerobic exercise to ameliorate NAFLD in HFD-fed rats by augmenting SCFAs contents and gut microbiota, Bacteroidetes  are extracted from teatosis . Noni frposition . Walnut obaculum . Lycium roidetes . In a raroidetes . Naturaloseburia . Mussel nd SCFAs . Solubleermansia .Lactobacillus rhamnosus GG (LGG EPS) and L. casei BL23 (BL23 EPS), both ameliorate NAFLD and increase the acetate and propionate (SCFAs) in HFD-fed zebrafish, but BL23 EPS, not LGG EPS, induces liver inflammation and injury by intestinal microbiota dysbiosis (Cordyceps sinensis polysaccharides (CSPs) exhibit obvious liver toxicity via aggravating liver steatosis and fibrosis in HFD-fed mice, and mechanistically, CSPs are digested by Actinobacteria and then excess Actinobacteria induces intestinal flora disorder and contributes to steatohepatitis  derived from bacteria, ysbiosis . In addiepatitis . Thus, uSirtuins , ubiquitous deacetylases, are crucial metabolic regulators, and importantly, SIRTs are also emerging as the essential cause of NAFLD . SIRTs pMetabolic syndrome remains the most common non-communicable disease that is characterized by central obesity, insulin resistance, hyperlipidaemia, and hypertension . MetS inPearsonothuria graeffei, alleviates MetS in HFD-fed mice by increasing abundances of Actinobacteria and Bacteroidetes, and decreasing the adverse bacteria, Firmicutes and Proteobacteria .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Polymer-based nanoparticles of tailored size, morphology, and surface properties have attracted increasing attention as carriers for drugs, biomolecules, and genes. By protecting the payload from degradation and maintaining sustained and controlled release of the drug, polymeric nanoparticles can reduce drug clearance, increase their cargo\u2019s stability and solubility, prolong its half-life, and ensure optimal concentration at the target site. The inherent immunomodulatory properties of specific polymer nanoparticles, coupled with their drug encapsulation ability, have raised particular interest in vaccine delivery. This paper aims to review current and emerging drug delivery applications of both branched and linear, natural, and synthetic polymer nanostructures, focusing on their role in vaccine development. The variety and versatility of polymeric materials have drawn increasing scientific interest in their application in diversified fields ,2,3,4. IEither used alone, in blends, or combined with other types of materials, polymer-based nanoparticles can offer protection to the attached cargos, prolong their circulation time, ensure controlled and targeted release, and enhance cellular uptake efficiency ,10,11,12In this regard, the present paper aims to present the natural and synthetic polymers that are most relevant and most commonly used for delivery purposes, further reviewing the recent advances in the delivery of different cargos and focusing, in more detail, on the role of polymers in the development of vaccine formulations. Depending on their origin, two main categories of polymers can be distinguished: natural and synthetic polymers; a more detailed classification is provided in Chitosan is a highly researched material for polymeric nanocarriers, being a non-toxic, biodegradable, hemocompatible, mucoadhesive polysaccharide generally recognized as safe by the Food and Drug Administration (FDA) ,23,24,25The intrinsic antitumor and antimicrobial properties of chitosan have attracted interest in enhancing the efficacy of corresponding loaded substances ,30. To pThe mucoadhesive properties of chitosan can be especially exploited for mucosal drug delivery . ChitosaNonetheless, chitosan is insoluble at physiological pH. However, this drawback can be overcome by chemical modification of the polymer to synthesize novel soluble derivatives . The actThe simple and unique features of dextran make it an ideal candidate for nanomedicine carriers. Specifically, this FDA-approved biocompatible and biodegradable bacterial exopolysaccharide is very soluble in water and shows no cytotoxicity after drug delivery ,68,69. IDextran derivatives -dextran or acetylated dextran (Ac-DEX)) are also promising for delivery applications, demonstrating adjuvant properties, and generating robust immune responses when used as vehicles for vaccine delivery ,69,71. Alginates  are a class of unbranched anionic polysaccharides that are attractive for transmucosal administration of drugs due to their mucoadhesive properties ,21,72. MMore recently, alginate biomedical applications were extended to the field of vaccine delivery . Being sPullulan is another FDA-approved polysaccharide of interest for bio-nanomedicine. It is non-toxic, non-mutagenic, non-immunogenic, and non-carcinogenic; thus, pullulan-based nanoparticles have important scientific value, receiving great research interest in designing excellent vaccine delivery systems ,75,76,77Moreover, due to the presence of nine hydroxyl groups in its structure, pullulan can be derivatized to enhance its utility in a broad range of applications, including drug delivery, gene targeting, vaccination, medical imaging, and pharmaceutical dosages formation .Hyaluronic acid (HA) is another FDA-approved natural bioadhesive polymer that has been widely investigated for constructing various functional delivery vehicles. Especially due to its mucoadhesive properties, HA can enhance the bioavailability of carried substances through various delivery routes, such as ocular, nasal, and pulmonary administration routes ,79. HA-b\u00ae/ABI-007 (Celgene) [Albumin represents an appealing protein-based macromolecular carrier due to its non-toxicity, non-immunogenicity, biocompatibility, easy incorporation of various drugs, and ability to bind with proteins ,82,83. ACelgene) ), doxoruCelgene) ,90,91,92Celgene) ,94,95,96Celgene) ,97, and Celgene) ,99.\u03b3-PGA is a bacterial-produced capsular exopolymer that can be degraded by \u03b3-glutamyl transpeptidase present in the human body. Its advantageous properties, such as low toxicity, non-immunogenicity, biodegradability, and biocompatibility with tissues and cells, have recommended \u03b3-PGA for vaccine development and pharmaceutical applications. Specifically, NPs composed of amphiphilic \u03b3-PGA and hydrophobic amino acids are able to immobilize proteins, peptides, and chemical agents on their surfaces or encapsulate these substances inside the particles ,100,101.\u03b2-glucan is another FDA-approved natural polysaccharide of interest for biomedical applications . ParticuMannan is also a natural polysaccharide endowed with immunomodulatory properties. When used as a vaccine adjuvant, this polymer can enhance the immune response, especially against the human immunodeficiency virus (HIV) . Other pThe significant hydrophilicity and biocompatibility of cellulose are two main factors that recommend this material for biomedical applications. Recent research demonstrated that cellulose-based hydrogel has cross-sectional porous structures and viscoelastic properties, important features in designing efficient vaccine delivery systems . SpecifiInulin is a complex natural and hydrophilic polysaccharide useful in the biomedical field, especially due to its unique and flexible structure. Investigations have demonstrated that high molecular weight inulin NPs can be employed to deliver drugs and other molecules of interest. In particular, nanoparticle adjuvants derived from inulin are able to enhance the immune response in vaccines against viruses, such as influenza and hepatitis B ,75,113.Other natural polymers that have attracted research interest for delivery purposes include, but are not limited to, glycogen ,115,116,PEI is an FDA-approved synthetic cationic homopolymer, for human medical applications, that can be used as a transfection reagent or as a material for creating NPs with high nucleic acid complexation capacity ,131. PEIPLA is a widely used FDA-approved synthetic polymer in biomedicine, especially for preparing tailored size and shape micro and nanoparticles ,101,134.Another FDA-approved synthetic polymer that gained significant interest for biomedical applications is PEG, especially due to its advantageous properties such as high solubility, non-toxicity, and excellent biocompatibility ,133,137.Due to its biodegradability, biocompatibility, and favorable safety profile, PLGA has been approved by the FDA and European Medicines Agency (EMA) for various biomedical applications, including drug and vaccine delivery ,144,145.PCL is one more FDA-approved, biocompatible, and biodegradable synthetic polymer that has attracted attention for nanobiomedicine purposes . Its ineDespite not being biodegradable, polystyrene nanoparticles (PSNPs) are also attractive for biomedical purposes. PSNPs are biocompatible, do not induce inflammation, bind to a range of antigens due to their easily modifiable surface, and generate CD8+T cell responses specific to the delivered peptides ,148. MorDendrimers\u2019 compact, well-defined, highly branched, and radial chemical structure makes this class of synthetic polymers suitable for encapsulating various drugs ,9. BeariPhosphazenes are attractive polymers for vaccine formulations. They can induce strong and sustained antigen-specific humoral and cell-mediated immune responses, which are considered better and safer options than conventional adjuvants .Polyanhydrides represent another polymer class of interest for controlled release products. These materials are biodegradable, biocompatible, safe, and approved for human use. Specifically, polyanhydrides degrade through surface erosion, releasing non-toxic and easily metabolized carboxylic by-products. Furthermore, this process of erosion that takes place only at the surface of nanoparticles contributes to the tailored and sustained release of encapsulated cargos ,65. MorePolyelectrolytes represent a class of polymers with charged functional groups in their backbone, such as poly (PAH), poly (styrene sulfonate) (PSS), polyacrylic acid (PAA), and poly (PDAC) . PolyelePolymersomes have attracted increasing research interest as versatile carriers due to their colloidal stability, tunable membrane properties, and capacity of encapsulating various drugs and biomolecules. These vesicles made of self-assembling synthetic block copolymers have tunable stability, degradation, and functionalization. They can deliver hydrophilic compounds by incorporating them inside the vesicle or hydrophobic cargos by membrane delivery .Other synthetic polymers that have attracted research interest for delivery purposes include, but are not limited to, poly \u03b2-hydroxybutyrate ,160, polPolymer-based NPs are one of the most commonly used forms of soft materials for nanomedicine applications not only due to their versatility and the broad spectrum of applications but also due to their facile synthesis . Recent In drug delivery applications, two main categories of nanoparticles can be distinguished, namely nanocapsules (reservoir systems) and nanospheres (matrix systems) . NanocapDepending on the type of cargo to be delivered by the polymeric NPs and their proposed administration route, different methods can be employed in the production of nanospheres and nanocapsules . The staThe first strategy used for manufacturing polymeric NPs from a preformed polymer was the solvent evaporation method a, which Other chemical methods for polymeric nanoparticles manufacturing involve the polymerization of monomers, instead of nanoparticles construction, from preformed polymers. In this category, the most used techniques are emulsion polymerization and interfacial polymerization, allowing simultaneous polymer synthesis and drug encapsulation . Alternatively, physical methods can be used for polymer NPs manufacturing. One such method is laser ablation, which uses a high-power laser beam to evaporate particles from a solid material source. Similarly, pulse laser deposition (PLD) can be employed; this method assumes that the target material is hit by high-power laser pulses, leading to its melting, evaporation, and ionization. Another technique that provides flexibility and control over surface parameters of the synthesized nanoparticles is electrospraying. The synthesis process starts with a solution of polymer and solvent, placed in a syringe, and the application of a high voltage to its capillary tip. The solvent is evaporated while the particles or fibers are pushed to a collector . More recently, polymer-based nanoparticles started being synthesized with the aid of microfluidic devices. The small channel dimensions and the special geometry of these devices allow the synthesis of high-quality nanocarriers in shorter times and with lower consumption of reagents. Moreover, microfluidics technology brings better control over the size, size distribution, morphology, and composition of the final products. Specifically, the size, polydispersity, and drug encapsulation can be simply tailored by varying experimental parameters such as flow rates, polymer composition, and polymer concentration . Either alone, in blends, or in combination with other nanomaterials, polymer-based nanoparticles can deliver a variety of cargos, including active pharmaceutical ingredients, nucleic acids, imaging agents, antigens, and other biomolecules. This section reviews the most recent advances in the development of polymer-based delivery nanosystems, depending on the carried moieties. For a drug to be released to the targeted cell, it must be hydrophilic enough to travel through aqueous media and reach the cellular membrane but lipophilic enough to cross this barrier and pass inside the cell. Due to the broad range of available materials and the possibility of functionalization, polymeric materials can be tailored to adjust the hydrophilicity of the drug formulation and deliver the cargo at the desired site. Moreover, the versatility of polymer-based nanoparticles can ensure the delivery of encapsulated drugs through a variety of administration routes, including oral delivery, ocular delivery, nasal delivery, pulmonary delivery, buccal delivery, periodontal delivery, dermal and transdermal delivery, and vaginal delivery.Given the wide range of possible applications, increasing research interest has been attracted to designing and testing polymer-based delivery platforms. Much effort has recently been put into developing antimicrobial delivery systems that would enhance cargo activity while overcoming drug resistance and diminishing systemic side effects ,182,183 Several such novel polymer-based delivery systems are reviewed in As cancers remain one of the major health concerns worldwide, extensive research has been oriented to developing better therapeutics for this category of diseases. Chemotherapeutic drugs can be employed in the treatment of cancer patients, as they interfere with the cell cycle and the process of mitosis, causing a greater proportion of cell kill in tumor cells than in healthy tissues . NonetheIn this respect, polymeric nanoparticles have been investigated as carriers towards various tumor cells, including breast ,212,213,Another attractive and effective cargo for polymeric nanoparticles is represented by photosensitizer drugs and photothermal agents that can be used as adjuvant therapies  in a wide range of diseases ,239,240.Polymer nanoparticles are also useful for delivering drugs to hard-to-reach tissues and organs. For instance, they can facilitate drug permeation to challenging anatomic structures, such as the inner ear ,243,244,Medical imaging is an essential part of clinical diagnosis, enhancing diagnostic accuracy, enabling a faster start of treatment, and improving survival rates in many diseases . MoreoveThus, a convenient approach is to coat these NPs with biocompatible polymers. For instance, Vu-Quang et al.  designedb-polybutadiene (PBdEO) and polyethylene oxide-b-polycaprolactone (PEOCL)). The Gd was conjugated to polyamidoamine (PAMAM) dendrimers via diethylenetriaminepentaacetic acid dianhydride (DTPA dianhydride) before polymersome encapsulation. Another promising strategy is to deliver conventional contrast agents by polymer-based vehicles. In this respect, Shao et al.  have pro111In  and single-photon emission computed tomography (SPECT) . For ins111In . The samGene therapy and immune engineering are complex tasks that hold great promise in treating various disorders. In this respect, nucleic acids can be employed for overexpressing or knocking down specific genes and can be used as adjuvants or danger signals for modulating the behavior of immune cells. Nonetheless, the direct delivery of nucleic acids has several drawbacks, as naked nucleic acids are prone to extracellular degradation, and they face difficulties in passing through the cell membrane ,271,272.In this context, increasing research has recently been focused on creating innovative delivery systems that can ensure efficient and targeted delivery of nucleic acids. Among the various tested materials, nanoscale polymers can embed or electrostatically absorb nucleic acids at their surface through a suitable surfactant or cationic polymer addition . SpecifiHaving a positively charged chemical structure, PEI-based nanoparticles are extensively used in gene delivery. However, despite its buffering capacity that can overcome intracellular barriers, PEI use is limited by its toxicity ,274. PolCurrently, lipid-based nanoparticles (LNPs) are the most clinically progressed nanoplatforms for delivering nucleic acids. Nonetheless, Blakney et al.  have comAnother promising approach for nucleic acid delivery is employing lipid-polymer hybrid nanoparticles (LPNs) ,277,278.In general, vaccination represents the main method of preventing virus pathogenicity, reducing the burden of many infectious diseases. Nonetheless, traditional vaccines encounter several limitations, as they are susceptible to degradation, have a short duration of action, and may cause side effects and inflammatory reactions at the injection site ,11. MoreOne attractive approach is to employ polymer nanoparticles, in mucosal delivery of vaccines, as a strategy to overcome some of the drawbacks of conventional vaccines. Such nanovaccines can target both the mucosal and systemic immune systems, enhancing humoral and cell-mediated immune responses, ensuring a sustained release, and protecting the loaded freight against degradation . In moreClostridium botulinum type A neurotoxins, Naospora, hepatitis B virus, Newcastle disease, and more [N-2-hydroxypropyl trimethyl ammonium chloride chitosan (N-2-HACC) nanoparticles and assessed their potential as a mucosal immune delivery carrier. The newly developed nanosystems have shown much stronger cellular, humoral, and mucosal immune responses than commercially available live attenuated NDV vaccines.Due to their immunological activity and mucoadhesive properties, CS-based NPs have been widely investigated in developing vaccines against and more ,285. Forand more  have encAnother example is offered by Dhakal et al. , who havCerastes venom for snake envenomation prevention, and their results confirmed this new nano-formulation represents a potent adjuvant system that improves humoral immune response while protecting against high lethal doses of viper venoms. A similar approach for developing an antivenom vaccine was tackled by Mirzaei et al. [Echis carinatus venom in order to stabilize it. Moreover, the obtained antivenom plasma had a considerably higher potency for neutralizing the venom than conventional delivery systems. Another intranasal vaccine delivery system has been developed and investigated by Hamzaoui and Laraba-Djebari . Their si et al. . The resIn an effort to prevent antibiotic-resistant pathogen infections, increasing attention has been drawn to developing antibacterial vaccines . In thisDue to their extraordinary versatility, polymers play more than just transporter roles in vaccine formulations. Polymeric nanoparticles may possess the dual capability of being both the adjuvant and delivery vehicle, helping in controlled antigen release, inducing rapid and long-lived immunity, prolonging shelf-life at elevated temperatures, enhancing patient compliance, and enabling the rapid development of vaccines for newly emerging infectious disease viruses ,75,310.As many antigens are poorly immunogenic, adjuvants are added to vaccine formulations to elicit/potentiate the immune response, offer better protection against pathogens, and diminish the required antigen amount for obtaining immunity ,100,281.The most currently used adjuvants are aluminum-based  adjuvants and Freund\u2019s adjuvants. However, despite their relative safety and long history of use, aluminum salts may produce adverse effects, including erythema, nodules, contact hypersensitivity, and granulomas. Other drawbacks of alum adjuvants are the bias towards humoral immunity, the necessity of multiple doses, and incompatibility with many antigens. Freund\u2019s adjuvants also present important disadvantages, as the paraffin oil used for these emulsions causes toxicity issues and produces severe local reactions ,312,313.There are two main adjuvants types: antigen delivery systems (or depots) and immunostimulatory agents . Some maA variety of polymeric carriers have been investigated for protecting antigens from proteolytic degradation, enhancing antigen entrapment, obtaining a desirable release profile, and targeting antigen-presenting cells (APCs) ,315,316 For instance, Wusiman et al.  have preCruz et al.  have alsBy conjugating PLGA with PEG through a peroxalate ester bond and adding PEI as a cationic adjuvant, Liang et al.  have synPLGA has also shown promising results in combination with inorganic materials. In particular, Saengruengrit et al.  have repAnother widely studied biopolymer for antigen delivery is chitosan. In this respect, Bussio et al.  have devWang et al.  have invAnother promising delivery system tested for OVA encapsulation is based on lignin nanoparticles. This adjuvant developed by Alqahtani et al.  was provLipid-polymeric hybrid delivery systems have also started to draw increasing scientific interest. For instance, Miura et al.  have creOne way of enhancing the immune responses is to use a targeted delivery approach to immune cells . In thisAnother strategy is to take advantage of the intrinsic immunostimulatory properties of certain materials ,154. SevThe beneficial properties of such polymers can be harnessed for improving the immune response for a broad range of vaccines. For example, inhalable polymeric particles were designed for pulmonary delivery of the hepatitis B vaccine. Thomas et al.  have creAnother vaccine, for which polymers have been shown to potentiate the immune response, is tuberculosis (TB) vaccine. Khademi et al.  have comAnother highly researched topic is the development of an effective HIV vaccine. In this respect, Dacoba et al.  have invAs severe acute respiratory syndrome-associated coronavirus 2 (SARS-CoV 2), also known as coronavirus disease of 2019 (COVID-19), has produced a public health crisis worldwide with huge human and economic losses, concerted global efforts have been employed in designing efficient vaccines ,336,337.Nanomedicine played a tremendous role in COVID-19 vaccine development . MoreoveNonetheless, polymer-based vaccine alternatives have also shown promising results. For instance, Volpatti et al.  have creAnother strategy was adopted by Zhang et al. , who devPolyamidoamines (PAMAMs) represent another promising strategy in the treatment of COVID-19 , as it wTo summarize, a multitude of natural and synthetic polymers can be used to design useful delivery nanosystems for diverse therapeutics, imaging agents, antigens, and other biomolecules. Their versatility and property tunability can be exploited for carrying the necessary moieties to the desired site, even if the cells/tissues are challenging to reach by conventional drugs. Moreover, polymeric nanoparticles allow a targeted and controlled cargo release in response to changes in the pH, the oxygen level in the tissues, or binding with specific receptors. Therefore, polymer-based systems are suitable for many therapies against infections and chronic diseases, offering accurate diagnosis possibilities. This review also explores the role of polymers in developing novel and improved vaccines, especially mucosal administered formulations, for preventing various conditions, including envenomation, hepatitis, tuberculosis, cancer, and COVID-19 infection. Considering the recent advances in this field, it can be expected that the particles, experimentally validated on animal models, would move to clinical trials. Nonetheless, further research is required, as a small subset of the immune-activation cascade is usually examined, while overall effects on human health may be neglected. Another challenge that has to be soon overcome is translating from the lab to scale-up synthesis of polymeric nanocarriers without compromising their quality and fine-tuned properties. Furthermore, interesting possibilities arise at the convergence of nanotechnology with other innovative fields, such as artificial intelligence and data analytics, that are promising perspectives towards attaining personalized therapeutic and vaccine formulations."}
+{"text": "Public health guidelines to prevent spreading COVID-19 place older adults at risk of loneliness and social isolation. Evidence suggests that participation protects older adults from such detrimental outcomes, therefore we aimed to identify the factors associated with participation in life roles among older adults living in the community during the COVID-19 pandemic. We conducted a telesurvey on a random sample of community-dwelling older adults living in Hamilton, Ontario, Canada, between May and July 2020. Outcome measures included participation in life roles, physical function, physical activity, mobility, mental health, nutrition, and demographics. We conducted two multivariate regression analyses with the Late Life Disability Instrument\u2019s (LLDI) frequency and limitations scales as the dependent variables. Candidate factors were organized by International Classification of Functioning, Disability, and Health (ICF) framework domains; personal factors, body functions and structures, activities, and environmental factors. A total of 272 older adults completed the telesurvey . Age, using walking aids, driving status, household income, education, mental health, nutrition, physical function, and dwelling type explained 47.1% (p<0.001) of the variance observed in LLDI frequency scores. Using walking aids, driving status, receiving health assistance, mental health, and physical function explained 33.9% (p<0.001) of the variance observed in LLDI limitation scores. These findings highlight factors from multiple ICF domains that are associated with participation limitation and frequency among older adults during the pandemic. Our findings have implications for developing public health initiatives to mitigate the effects of the pandemic on the participation of older adults."}
+{"text": "The multifactorial nature of cardiology makes it challenging to separate noisy signals from confounders and real markers or drivers of disease. Panomics, the combination of various omic methods, provides the deepest insights into the underlying biological mechanisms to develop tools for personalized medicine under a systems biology approach. Questions remain about current findings and anticipated developments of omics. Here, we search for omic databases, investigate the types of data they provide, and give some examples of panomic applications in health care. We identified 104 omic databases, of which 72 met the inclusion criteria: genomic and clinical measurements on a subset of the database population plus one or more omic datasets. Of those, 65 were methylomic, 59 transcriptomic, 41 proteomic, 42 metabolomic, and 22 microbiomic databases. Larger database sample sizes and longer follow-up are often better suited for panomic analyses due to statistical power calculations. They are often more complete, which is important when dealing with large biological variability. Thus, the UK BioBank rises as the most comprehensive panomic resource, at present, but certain study designs may benefit from other databases. The biomedical data revolution has begun. The complexity of the cardiovascular system requires huge amounts of data points to provide an effective basis for analysis . Modern Cardiovascular risk scoring models consider clinical parameters, such as age, sex, past medical, and drug history. They efficiently assess cardiovascular disease risk in patients who may benefit from prophylactic or active treatment . These mOmic databases are particularly useful when investigating factors affected by large biological variation, but exponentially larger samples sizes are needed when multiple forms of omic data are used . After dWe reviewed which databases existed for panomic analyses, the data types available, and how best they can be utilized. Skepticism remains about their utility, partly because some direct-to-consumer analyses passed the fees of panomic data generation to consumers. Sometimes, this outweighed the gain of personalized insights on health optimization information, such as dietary and exercise recommendations, that were known at the time .Population-based databases associated with omic data were found using the following omic keywords: \u201cGWAS,\u201d \u201cGenomic,\u201d \u201cPhenomic,\u201d \u201cClinomic,\u201d \u201cProteomic,\u201d \u201cMetabolomic,\u201d \u201cMethylomic,\u201d and \u201cTranscriptomic\u201d on PubMed/Medline and internet searches for existing database websites and gene mutation directories. Individual publications were traced backwards, and authors were contacted for missing data from the The data mining exercise identified 104, of which 72 met the selection criteria by having sufficient omic and clinical data on study participants. Out of the 72 studies, only one was commercial. The 15 with the largest sample size and fully complete are selected for A \u201cY\u201d in Overall, 73 omic databases matching the inclusion criteria were identified. Sixty-five databases included methylomic data, 59 included transcriptomics, 41 included proteomics, 42 included metabolomics, 45 included phenomics, and 20 included microbiomics.Genetics concerns the genome at the base pair level looking at the basic structure of the cellular DNA. Often, genetic studies focus on greatest diversity mediated by single-nucleotide polymorphism (SNP), which is a single base pair alteration resulting from mutative mechanisms. The severity depends on the site and downstream translation of the mutation.2C19, with ticagrelor or prasugrel in carriers of defective cytochrome 2C19 alleles (PCSK9 mutations driving increased low-density lipoprotein cholesterol (LDL-C) receptor recycling. Three subsequent clinical trials of PCSK9 monoclonal antibody inhibitors showed reduced major adverse cardiovascular events and 60% reductions in plasma LDL-C  found loci associated with elevated LDL-C and incidence of coronary artery disease (CAD) . This leMethylation is a dynamic process whereby methyl transferases methylate CpG dinucleotides, repressing DNA transcription without altering base pairs. Methylomics is relatively new and measures epigenetic DNA methylation  for asseAdoption of methylomics into medical data collection is slowed by a lack of cheap, reliable, and interpretable tests. Sixty-five databases in Illumina's Epic DNA methylation microarray kit samples 850,000 CpG known sites ; howeverThree commercial kits are summarized in Leukocyte DNA methylation is useful in determining links between smoking and pathogenesis . A Euro-PCSK9 mRNA was degraded with a single dose of RNA interfering Inclisiran, reducing LDL-C by 57% for 240 days in phase II trials , Baim Institute for Clinical Research , Belvoir Publications , Duke Clinical Research Institute , HMP Global , Journal of the American College of Cardiology , K2P , Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Population Health Research Institute , Slack Publications , Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lexicon, Lilly, Medtronic, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines Company; Royalties: Elsevier ; Site Co-Investigator: Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, Novo Nordisk, Takeda. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.DV is a founding member and product manager of Salutare Group Ltd, London, UK. Salutare was in no way involved in the production of this work. DR is the Chief Science Officer at Health Longevity Performance Optimisation Institute (HLPO.Life), London, UK. DB discloses the following relationships\u2014Advisory Board: Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Level Ex, Medscape Cardiology, PhaseBio, PLx Pharma, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Baim Institute for Clinical Research , Cleveland Clinic , Contego Medical , Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine , Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News,"}
+{"text": "Fungal nanotechnology (FN) or myconanotechnology is a novel word which was originally introduced in 2009 by Rai M. from India . It is described as the manufacture and subsequent use of nanoparticles via fungus, especially in biomedical, environmental and agricultural commodities ,4.Rhizopus oryaze metabolites were utilized as a biocatalyst for the green synthetization of magnesium oxide (MgO-NPs) nanoparticles [Bacillus megaterium and was used as an antifungal agent against R. solani, the causal organisms of damping and root rot disease in Vicia faba, as well as for induction of plant growth [M. oryzae appressorium have been considerably suppressed by AgNPs [For example, articles . Additiot growth . Bacilluby AgNPs . The Fusby AgNPs . Althougby AgNPs . MycofabDue to the vast spectrum and diversity of fungi, the mycogenic synthesis of nanoparticles, an essential element of myconanotechnology, leads to an intriguing new and practicable multidisciplinary science with significant results . MyconanAspergillus niger, a common soil fungus, was chosen as a test organism to evaluate fungal interactions with ZnO NPs. As expected, the A. niger strain had a significant effect on the stability of particulate forms of ZnO due to the acidification of its environment [Agaricus bisporus, Pleurotus spp., Lentinus spp. and Ganoderma spp. are widely recognized to have strong nutritional, immune-modulatory, antibacterial, antifungal, antiviral, antioxidant and anticancer activities [Aspergillus flavus linked with peanut meal and cotton seeds [Fungal-mediated nanoparticles have been used effectively in a wide range of scientific domains, including medicines, pharmaceuticals, agriculture, and electronics. As a result, some evaluations concentrated on the application of mycogenic nanoparticles against plant diseases, post-harvest antibiotics, mycotoxin management, and plant pests, as well as certain animal pathogens. Furthermore, fungal nanomaterials have a high potential and promise for enhanced diagnostics, biosensors, precision agriculture, and targeted smart delivery systems. For example, soil mycobiota can influence zinc mobilization from ZnO NPs in soils and thus zinc mobility and bioavailability. As a result, ironment . The mactivities . In additivities . The devtivities ,19. Metaon seeds .In conclusion, Fungal Nanotechnology 1 and 2 provides an updated and comprehensive knowledge dealing with the green and sustainable production of metal and organic-based nanostructures by various fungal species. In addition, intracellular and extracellular mechanisms will be investigated, focusing on fungal nanotechnology applications in biomedical, environmental and agri-food sectors. FN is still in its infant stage; therefore, significant studies should be focused on this area; plants, animals and humans will benefit greatly, and efficient and ecologically friendly approaches should be created."}
+{"text": "Bone defects cause significant socio-economic costs worldwide, while the clinical \u201cgold standard\u201d of bone repair, the autologous bone graft, has limitations including limited graft supply, secondary injury, chronic pain and infection. Therefore, to reduce surgical complexity and speed up bone healing, innovative therapies are needed. Bone tissue engineering (BTE), a new cross-disciplinary science arisen in the 21st century, creates artificial environments specially constructed to facilitate bone regeneration and growth. By combining stem cells, scaffolds and growth factors, BTE fabricates biological substitutes to restore the functions of injured bone. Although BTE has made many valuable achievements, there remain some unsolved challenges. In this review, the latest research and application of stem cells, scaffolds, and growth factors in BTE are summarized with the aim of providing references for the clinical application of BTE.  Bone diseases and their complications, which account for half of the chronic diseases in people over 50 years old , still fNowadays, treatments of bone defects mainly include synthetic bone void filler, allografts, autografts, distraction osteogenesis, insertion of the vascular bundle and cement casting. Among therapeutic strategies, autografting is considered the \u201cgold standard\u201d; it involves harvesting the bone from one side of the patient and transplanting it into the injured area of the same patient for bone repairment . HoweverBy combining stem cells, scaffold, and growth factors (GFs), BTE builds optimal biomimetic environments to promote the regeneration and growth of normal tissues and cells . In thisBriefly, stem cells can promote osteogenesis and angiogenesis with the stimulation of GFs, and biocompatible scaffolds can mimic the ecology of bone extracellular matrix . In thisRegarded as the cornerstone of BTE, stem cells are capable of self-renewing and differentiate into at least one type of offspring. In BTE, ideal candidates should meet the following criteria: (1) abundant sources and convenient sampling; (2) strong ability of in vitro cell passage with an immobile phenotype; (3) high adaptability to the environment of the receiving zone; (4) capacity to replace the missing cells and restore the tissue function; (5) safe clinical application . CommonlMSCs have been considered as the ideal seed cells of BTE for their high availability, rapid proliferation, and special functions . MSCs arAdipose-derived stem cells (ASCs), another promising candidate in BTE, have been considered for their similar osteogenic capacity as BMSCs, simplicity to harvest surgically, and abundant sources. Compared with BMSCs, adipose tissue is more affluent under local anaesthesia, and lipotomy is less invasive than bone marrow aspiration, mitigating patient pain . While 6Genetic engineering has attracted interest to further improve the efficacy of MSCs in BTE. According to Oryan et al. , osteogeAngiogenesis is essential for BTE, as bone is highly vascularized, relying on tight spatial and temporal connections between blood vessels and osteocytes to maintain integrity. Adequate vascularization is a prerequisite for stem cells to reach the site of the defective tissue and to obtain oxygen and nutrients  27]. EP. EP27]. As a burgeoning seed cell in BTE, the application of iPSCs is promoted by the emergence of reprogramming measures, disease modelling, and preclinical trials . ThroughFor the application of iPSCs in BTE, iPSCs derived from patients will be re-directed to differentiate and culture on a scaffold providing structural and functional support, which would be later transplanted to the defect site . In a moThe scaffold of BTE provides a three-dimensional (3D) space for cell survival, tissue growth, and vascularization, and eventually, bone defects can be repaired. A successful BTE scaffold possesses osteoconductivity, osteogenicity, osseointegration, and osteoinductivity to simulate the formation of new bone . Its porNaturally derived biomaterials are produced by living organisms, such as collagen, fibrin, silk fibrin, hyaluronic acid, polyhydroxyalkanoate and chitosan, and are eventually degraded into carbon dioxide and water . Their gAs a natural scaffold formed after tissue injury, fibrin can initiate hemostasis and provide an initial substrate for cell proliferation, differentiation, adhesion, and migration. It has excellent biocompatibility, controllable biodegradation, and the ability to transfer cells and biomolecules, acting as an ideal material for biomimetic bone scaffolds. Fibrin is made up of fibrinogen and thrombin, which can be extracted from the patients\u2019 blood, allowing for an autologous scaffold . In addiCollagen is considered an ideal material for BTE scaffolds because of its low antigenicity, cytocompatibility, and tissue regeneration potential. As a natural polymer, collagen can be extracted from animals, such as pig skin and rat tails. Proteolytic treatment using pepsin is the most common extraction process, which dissolves collagen crosslinks and terminal peptides, making collagen non-immunogenic. Natural collagen possesses amino acid sequences which can be used for cell bio-identification in collagen-based scaffolds . HoweverChitosan is a biodegradable, biocompatible, and non-antigenic material, and thus, it has been widely researched in BTE scaffolds. Chitosan is derived from crustacean shells and can be obtained by deacetylation of chitin through alkaline hydrolysis . StructuPHAs are materials synthesized by bacteria as energy sources in bad growth environments . They shThe bioceramics used in BTE are inorganic compounds that can be divided into bioinert and bioactive ceramics based on their interactions with host tissues ,61. BioiCompared with naturally derived biomaterials, metallic materials have excellent mechanical properties and biocompatibility . TantaluTantalum is an inert metal with anticorrosive properties, but it has a high modulus of elasticity far exceeding that of cancellous and cortical bone . TherefoTitanium and its alloys have good antiseptic properties and biocompatibility, and are widely used in BTE scaffolds, such as in total hip replacement and total knee replacement prostheses, spinal fusion cages, and bone plates . HoweverSynthetic biological materials utilized in BTE scaffolds mainly contain polymer organic synthetic materials, synthetic inorganic materials, and composite materials . SynthetThe polylactic acid polymer was the most widely used material in BTE . There eSynthetic inorganic materials utilized in BTE mainly contain calcium phosphate, bioglasses, and glass ceramics and show good biocompatibility, biodegradability, osteoconductivity, and osteoinductivity . HA is cd, l-lactide), HA/chitosan-gelation [2-CaO-P2O5 networks possesses great biocompatibility in bone and soft tissues [+, Ca2+, and soluble silica during degradation, promoting cell proliferation and osteogenesis [Common composite materials utilized in BTE scaffolds include calcium phosphate coating on metals, HA/poly- play an essential role in BTE, promoting cell growth and differentiation for the normal fracture healing response. GFs are commonly stored in the extracellular matrix and released after injury to affect metabolic processes through autocrine, paracrine, and endocrine signaling, binding to the receptors on target cells and then trigger intracellular signaling . There aTGF-\u03b2 is released from various cells, including platelets, osteoblasts, BMSCs, chondrocytes, endothelial cells, fibroblasts, and macrophages . TGF-\u03b2 cApproximately 20 kinds of BMPs have been identified, among which BMP-2, BMP-4, BMP-6, and BMP-7 are widely used in BTE to promote the migration of osteoprogenitors, synthesis of the matrix, and the proliferation and differentiation of seed cells . BMPs arBMPs have been applied with other GFs to promote osteogenesis. For example, combining TGF-\u03b21 and BMP-7 can effectively improve chondrogenesis and superficial zone protein expression in synovial explants . AccordiIGF can promote osteoblast proliferation, bone resorption, and bone matrix synthesis. IGF is secreted from osteoblasts, chondrocytes, hepatocytes, endothelial cells, and platelets . IGF-1 aFGFs can stimulate chondrocyte maturation, bone resorption, and the proliferation and differentiation of osteoblasts. The mammalian FGF family contains 22 members produced from macrophages, monocytes, BMSCs, chondrocytes, osteoblasts, and endothelial cells. FGF-2, FGF-9, and FGF-18 are promising candidates for BTE. Specifically, FGF-2 can work in two directions for osteogenesis promotion and inhibition. High-dose FGF-2 inhibits the differentiation of osteoblasts, while low-dose FGF-2 enhances osteogenesis . By actiAs BTE has been extensively studied and has attracted more and more attention, the function of tissue-engineered bone could be adapted by the 3D arrangement of seed cells and the components of a proper extracellular matrix; optimized scaffold materials have been developed for different pore sizes, permeability and durability. Bone progenitor cells could be isolated and induced from various sites of the human body to possess the osteogenesis potential, and the effect and application of growth factors on osteogenesis and angiogenesis have been elucidated and well-improved in vitro and in vivo. Presently, combining stem cells, scaffolds, and growth factors, BTE has been utilized clinically in various bone defect treatments, such as traumatic calvarial defects, mandibular ridge resorption, anterior mandibular defects, and spinal stenosis ; signifiThe biomaterial design, location and size of bone defects, health status and age of patients are vital factors in the efficiency of BTE . The comS. aureus, E. coli, P. aeruginosa, and methicillin-resistant S. aureus [Osteogenesis and the integration of implants and surrounding tissues are significant issues in the therapy of bone defects ,117. Due. aureus . Simulta. aureus . MoreoveBased on developmental biology, morphogenesis, bioengineering, and biomechanics, BTE has developed significantly over the past few decades. The critical factors for successful BTE include stem cells, scaffolds, and GFs. With strong capacities to self-renew and differentiate into various kinds of offspring, competent stem cells, such as MSCs, EPCs, and iPSCs, are widely utilized as the cornerstone of BTE, boosting osteogenesis as well as angiogenesis. For the BTE scaffold, nature-derived biomaterials demonstrate excellent biocompatibility, availability, and plasticity with minimal adverse immunoreaction. Metallic materials exhibit outstanding mechanical properties and biocompatibility. Synthetic biomaterials, including polymer organic and inorganic materials, possess good versatility. Additionally, composite materials combine the advantages of each biomaterial, enabling large-scale, precise, and designable geometry production with controllable mechanical properties and minimal immune response. Among GFs, BMPs are the most essential factors in the process of bone repair. TGF-\u03b2, IGF, and FGF promote cell growth and differentiation for osteogenesis by influencing the metabolism of various cells. GFs are multitrophic, and their efficacy is related to the source, purity, dose, stem cells, culture conditions, and involvement of other GFs."}
+{"text": "The Marburg variant of multiple sclerosis (Marburg MS) is the most aggressive form of MS, often leading to death soon after onset. Here we describe the case of a 26-year-old Marburg MS patient presenting with severe neurological deficits requiring intensive care. In spite of more than 100 gadolinium-enhancing MRI lesions, the patient recovered almost completely upon high-dose cyclophosphamide (HiCy) rescue treatment . Following the acute treatment, her disease was stabilized by B cell depletion using ocrelizumab. Clinical amelioration was reflected by a decrease of MRI activity and a marked decline of serum neurofilament light chain levels. HiCy rescue treatment followed by ocrelizumab as a maintenance therapy prevented permanent disability and achieved an almost complete clinical and drastic radiological improvement in this Marburg MS patient. The Marburg variant of multiple sclerosis [Marburg MS ] which aA 26-year-old female patient without a history of neurological symptoms presented to our hospital with bilateral optic neuritis which had gradually developed within 5 days prior to admission. Other than hypothyreosis, her past medical history was unremarkable. The patient complained of mainly left-sided bilateral blurred vision, reduced color discrimination, and pain with eye movement. Visual acuity was impaired on both eyes . Ophthalmological examination yielded no retinal abnormalities, but optic coherence tomography (OCT) was not possible as the patient was unable to focus appropriately. She was unable to read letters bilaterally during low-contrast visual acuity (LCVA) testing using 2.5% low-contrast Snellen charts. Visual evoked potentials (VEPs) yielded no response for the left eye, while P100 latencies for the right eye were pathologically increased to 139.5 ms. At admission, neurological examination revealed no further abnormalities. Cerebrospinal fluid (CSF) analysis 9 days after the first occurrence of symptoms revealed a lymphomonocytic pleocytosis of 72/\u03bcl with positive oligoclonal bands (OCBs) and intrathecal IgM synthesis. The MRZ reaction (MRZR), anti-AQP4, and anti-MOG antibodies as well as vasculitis screening and virological/microbiological analyses were all negative see . 1 day lThe initial manifestation of MS in our patient raised several red flags, suggesting a severe disease course, such as persisting and disabling symptoms, almost no recovery after the first steroid pulse, and a high lesion load at baseline, including spinal and infratentorial Gad-enhancing lesions. In addition, intrathecal IgM synthesis is associated with an unfavorable prognosis . Thus, fIn this case, we were able to prevent permanent disability and to achieve an almost complete clinical and drastic radiological improvement using ocrelizumab as a maintenance therapy following the high-dose cyclophosphamide protocol of Krishnan et al. NfL may be a suitable tool to monitor therapy response in Marburg MS.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.VK, SM, and DK gave the idea of case reporting. VK and DK analyzed the case and prepared the MRI scans as well as the figure and the table. VK drafted the manuscript for intellectual content. MF, KB, MH, EA, AA, PA, OA, PK, SM, and DK critically reviewed the manuscript and were involved in patients' healthcare. All the authors contributed to the article and approved the submitted version.PA received compensation for serving on scientific advisory boards for Allergan, Biogen, Celgene, Ipsen, Merck Serono, Merz Pharmaceuticals, Novartis, and Roche. He received speaker honoraria and travel support from Allergan, Bayer Vital GmbH, Biogen, Celgene, Ipsen, Merck Serono, Merz Pharmaceuticals, Novartis, and Roche and research support from Allergan, Biogen, Celgene, Ipsen, Merck Serono, Merz Pharmaceuticals, Novartis, and Roche. OA has received grant support from Bayer, Biogen, Novartis, and Sanofi and consultancy or speaking fees and fees for serving on steering committees from Bayer, Biogen, Celgene, Medimmune, Merck, Novartis, Roche, Sanofi, and Teva. PK was supported by Stifterverband/Novartisstiftung. SM received honoraria for lecturing and travel expenses for attending meetings from Almirall, Amicus Therapeutics Germany, Bayer Health Care, Biogen, Celgene, Diamed, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, Roche, Sanofi-Aventis, Chugai Pharma, QuintilesIMS, and Teva. His research was funded by the German Ministry for Education and Research (BMBF), Deutsche Forschungsgemeinschaft (DFG), Else Kr\u00f6ner Fresenius Foundation, German Academic Exchange Service, Hertie Foundation, Interdisciplinary Center for Clinical Studies (IZKF) Muenster, German Foundation Neurology, Almirall, Amicus Therapeutics Germany, Biogen, Diamed, Fresenius Medical Care, Genzyme, Merck Serono, Novartis, ONO Pharma, Roche, and Teva. DK received travel grants from GeNeuro and Merck, refund of congress participation fees from GeNeuro, Merck, and Servier, consulting fees from Grifols, payment for lectures from Grifols, and support for research projects from Teva and was funded by the Deutsche Forschungsgemeinschaft (DFG) while carrying research on human endogenous retroviruses at Cleveland Clinic. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The interest in seaweeds for cosmetic, cosmeceutics, and nutricosmetics is increasing based on the demand for natural ingredients. Seaweeds offer advantages in relation to their renewable character, wide distribution, and the richness and versatility of their valuable bioactive compounds, which can be used as ingredients, as additives, and as active agents in the formulation of skin care products. Bioactive compounds, such as polyphenols, polysaccharides, proteins, peptides, amino acids, lipids, vitamins, and minerals, are responsible for the biological properties associated with seaweeds. Seaweed fractions can also offer technical features, such as thickening, gelling, emulsifying, texturizing, or moistening to develop cohesive matrices. Furthermore, the possibility of valorizing industrial waste streams and algal blooms makes them an attractive, low cost, raw and renewable material. This review presents an updated summary of the activities of different seaweed compounds and fractions based on scientific and patent literature. Consumer preferences towards green and eco-friendly products have increased in the last few years ,2. This Marine resources represent a widely available and promising source of unique and active compounds with the potential to produce cosmetics, cosmeceuticals, and nutricosmetics. Among them, seaweeds represent a sustainable and renewable resource, gaining increasing attention for these applications ,17. FurtThe use of seaweed-derived ingredients in cosmetic products has increased in recent years as a result of the many scientific studies that have proved the potential skincare properties of seaweed bioactives ,24. AmonExcellent comprehensive reviews on the subject have recently been published, including on the chemical diversity and unique properties of algal bioactive molecules or extracts for cosmetic uses ,35,36,37The present review tries to update the advances in this field, presenting an initial section summarizing the activities of algal components of particular relevance for cosmetic and cosmeceutical formulations and then by trying to offer the multiple and faceted benefits and functions that these seaweed components can provide to products where they can be incorporated as ingredients and additives, conferring other textural, functional, and sensorial properties. The potential applications are presented based on information in the scientific literature, but also using patents claiming the use of algae and algal components.Seaweeds contain an important carbohydrate fraction forming part of their cell walls and these polysaccharides are specific to each type of algae: in brown alginate, laminaran and fucoidan; in green ulvan and in red agar, carrageenan is the most important. Polysaccharides are receiving increasing attention for their biofunctional and physicochemical characteristics . Sulfated-mannuronic acid and l-guluronic acid are found in brown seaweeds. These compounds show other properties in relation to cosmetics and well-being products, particularly anti-allergic properties [Alginates composed of chains of operties ,71, an aoperties , and canoperties ,74. Lamioperties ,76, antioperties ,78,79, aoperties  propertioperties  propertioperties ,82,83. Ioperties . Degradaoperties .Fucoidans are heteropolysaccharides with fucose and other monosaccharides, such as xylose, galactose, mannose, and glucuronic acid, as well as other components, mainly sulfate, uronic acids, and acetyl groups. Fucoidans offer promising potential as cosmetic ingredient ,85,86 siSulfated polysaccharides from green algae  present variable compositions and structures and some properties are highly influenced by the molecular weight in terms of antiradical and chelating properties ,99,100. d-galactopyranose and 3,6-anhydro-\u03b1-l-galactopyranose units with variable amounts of sulfate, pyruvate, and uronate substituents. Agar has pharmaceutical and industrial cosmetic applications, including its use as a thickener and as an ingredient for tablets or capsules to carry and release drugs [d-galactopyranose and 4-\u03b2-d-galactopyranose with anhydrogalactose residues [Porphyra sp. with interesting therapeutic properties. These polysaccharides have uses as gelling agent, nutritional supplement, with antioxidants [Agar is mainly composed of \u03b2-se drugs ,106. Carresidues ,107,108.oxidants ,111,112,oxidants ,113, shooxidants , protectoxidants , anti-inoxidants ,113 withoxidants ,115. Agaoxidants .Phaeophyceae) have a lower concentration (3\u201315%) [Some seaweeds are a rich source of proteins, their cultivation offers a higher protein yield per unit area (2.5\u20137.5 tons/Ha/year) compared to terrestrial crops, but their successful extraction is largely influenced by the presence of polysaccharides, such as alginates in brown seaweed or carrageenans in red seaweed . Seasona 3\u201315%) ,119,120. (3\u201315%) ,122,123.\u201315% ,119 (3\u201315%) ,126,127.Ahnfeltia plicata, Euthora cristata, and Ceramium virgatum [Pyropia yezoensis, and it shows anti-inflammatory effects through the suppression of inflammatory cytokines [Porphyra yezoensis f. coreana Ueda showed an increase in elastin and collagen production and a decrease in the expression of matrix metalloproteinases (MMP) [Palmaria palmata and Porphyra umbilicalis (red seaweeds) [Bioactive peptides usually contain 3\u201320 amino acid residues and both their amino acid composition and the sequence influences their activities, such as antioxidant and antimicrobial activities, among others of pharmacological interest ,130,131.virgatum . The pepytokines . The pepes (MMP) . Ultrasoeaweeds) .Asparagopsis armata (ASPAR\u2019AGE\u2122) containing MAA molecules in lotions with anti-aging properties, a hydrolyzed extract Aosaine\u00ae (three-quarters of aosaine consists of amino acids that are very similar those responsible for skin elasticity) extracted from Ulva lactuca, which present anti-aging, anti-wrinkle and stimulation of collagen properties. An extract  from Gelidium corneum improves skin softness and restores elasticity. Therefore, MAAs have different properties, such as serving as natural sunscreens, possess antioxidants, anti-inflammatory, and anti-aging, and are stimulators of skin renewal, activators of cells proliferation, etc., making them a promising and safe option for pharmaceutical and cosmetic industries [Mycosporine-like amino acids (MAAs) are secondary metabolites synthesized for protection against solar radiation ,137,138.dustries  (Table 2Spirulina spp.), whereas the characteristic red color of Rhodophyta phyla is due to both the phycoerythrin and phycocyanin pigments. Phycobiliproteins  extracted from Gracilaria gracilis presented high antioxidant and radical scavenging activities, primarily when harvested in winter [Furcellaria lumbricalis and Coccotylus truncatus and found an exponential correlation between R-phycoerythrin and allophycocyanin concentrations and collection depth. The contents of phycoerythrin and phycocyanin were slightly higher and lower, respectively, for dried commercial Porphyra spp. extracts in comparison to Spirulina spp. [Due to the toxic effect of several synthetic dyes and the high consumer demand for natural colors in food, pharmaceuticals, cosmetics, and textile industries there has been increasing interest in the use of phycobiliproteins in the food (C-phycocyanin) and cosmetic fields (C-phycocyanin and R-phycoerythrin). Phycobiliproteins are a class of water-soluble compounds composed of proteins that are covalently bound to linear tetrapyrroles, known as phycobilins, with fluorescent properties and high molecular weights and can be used for reddish colorings ,162,163.n winter , and then winter . Saluri n winter  studied ina spp. .Phenolic compounds are secondary plant metabolites with a basic structure with one or more aromatic rings, presenting one or more attached -OH groups. They are synthesized as part of the defense mechanisms in plants. Phlorotannins are secondary metabolites of phloroglucinol , are structurally less complex than terrestrial tannins, and are found in polymerized structures with ether, phenyl or 1,4-dibenzodioxin linkages ,170.Ecklonia cava proved to be an effective repair agent for skin damage against UVB [Ecklonia stolonifera Okamura, exhibited protective activity against UVB radiation [Phlorotanins are increasingly considered for cosmeceutical applications, based on their antioxidative ,174,175,inst UVB . On the adiation ; other sadiation ,193. A cadiation , a behavadiation ,195,196.Meroterpenoids exhibited antioxidant properties and can prevent skin photoaging without the risk of cytotoxicity . Other mPlasmodium falciparum has been exhibited [Portieria hornemannii essential oil [Seaweed present a low lipidic content , but they are highly unsaturated and the \u03c93:\u03c9-6 fatty acids ratio is highly favorable ,209,210.xhibited . The viaxhibited ,206; othxhibited ,61. Phosxhibited ; in othexhibited . In additial oil . SubsequVitamins obtained from diet and through topical application are essential for many functions of human skin. Supplementation is considered for protection against dehydration and premature aging of the skin, cosmetic prevention of damage by sun exposure, regulation of the secretory activity of the sebaceous glands, and the preservation of the anatomical integrity of adnexial structures . Vitamin1, B2, B3 or niacine, B6, B9 or folic acid, B12) is generally higher in green and red seaweeds [3 active forms added to skin care products include: niacinamide, nicotinic acid nicotinate esters. Niacinamide is an antioxidant, reduces hyperpigmentation , and improves aspects of the epidermis by reducing the trans-epidermal water loss [12 for vegetarians; this vitamin shows anti-aging properties and is essential for hair and nail growth and health [Vitamin A or the retinol form shows antioxidant and antiwrinkle capacity ,235,236 seaweeds . Vitaminter loss ,239. Redd health ,241,242.l-ascorbic acid of which the biologically active form is most known [Ceramium rubrum and Porphyra leucosticta show high vitamin C or ascorbate content. This vitamin, topically applied, has antioxidant, detoxifying, antiviral, anti-inflammatory, antimicrobial, and anti-stress effects, and can be used for enhancing tissue cell growth, repairing blood vessels, teeth, and bones [Vitamin C is used in the cosmeceutical industry as it is an st known . The rednd bones ,243. Mannd bones ,244. Sevnd bones .Vitamin E , the most abundant fat-soluble vitamin of non-saponifiable lipids in many algae, can be extracted from different green, red, or/and brown seaweeds , and is Seaweeds have a high mineral content, about 8\u201340% ,251,252,Gracilaria species and the brown macroalgal species Laminaria digitata; nevertheless, seaweeds have low Na/K ratios (<1.5) [Caulerpa veravelensis, Ulva lactuca, and Sargassum polycystum contain higher amounts of calcium. Seaweeds have been described as a good source of iodine, which is present in several chemical forms, and brown algae contains greater amounts, up to over 1% wet weight; its accumulation in seaweed tissues could be 30,000 times its concentration in sea water [Seaweeds contain a variety of mineral elements, macro-elements, and trace elements, which are an excellent mineral source for cosmeceutical benefits for humans. Several minerals  are recognized as necessary for health and well-being. All seaweeds contain high amounts of both macro minerals  and trace elements  ,250,255.ea water ,255. Accea water , as it iea water ,251.Polefka et al. summarized the scientific evidence available on the benefits and risks of topical application of mineral salts . SeaweedRegarding the concentration of pigments, seaweeds are classified into three groups: green , brown (carotenoids), and red (phycobilins as phycoerythrin). In addition, free radical scavenging, inhibiting melanogenesis, and photoprotection are some of the properties of these compounds that make them suitable for skin care . CarotenFucoxanthin is the main carotenoid in brown algae, this xanthophyll can counteract oxidative stress caused by UV radiation  and suppAccording to their functions, cosmetic ingredients are classified as (i) additives; (ii) stabilizing or excipient agents; and (iii) bioactive compounds, with real cosmetic functions ,35. AlgaThe incorporation of seaweed components was successful in different physical forms, and are commercially available in soaps, shampoos, sprays, hydrogels, or creams ,275. Theresistant Staphylococcus aureus, Staphylococcus aureus and Staphylococcus epidermidis [Staphylococcus and Candida sp. [Sargassum duplicatum, Sargassum echinocarpum, and S. polycystum extracts, which inhibited the development of bacteria for a longer period of time [S. duplicatum.The antimicrobial properties of seaweed components are well known, in particular for food and pharmaceutical industries ,280,281.dermidis ,285,286,dermidis ,206, anddida sp. ,289,290. of time . All seaSince many cosmetic and cosmeceutical formulations contain a lipidic component, they are highly susceptible to lipid peroxidation. The addition of antioxidants is needed to protect from oxidative deterioration, which also maintains the sensorial properties of the cosmetic products, in the context of appearance and odor. The contradictory data on the safety of synthetic chemical antioxidants have incentivized the search and use of natural compounds with antioxidant properties. Seaweeds represent an abundant and widespread source of compounds with confirmed antiradical and reducing properties ,286,292.The incorporation of different seaweed ingredients has to be evaluated in relation to organoleptic, spreadability, and hedonic tests ,296. SeaAroma is a key feature in cosmetics and cosmeceuticals, and the potential of seaweeds to produce terpenoids, carotenoids, fatty acid derivatives, and sulfur compounds is well known ,297.Gracilaria sp. has a gelling agent capable of having a thickening effect on certain products, such as liquid bath soap, as a cocamide DEA (diethanolamine) substitute [Thickening, gelling, and texturizing agents are used to control viscoelasticity and to form a cohesive internal structure in cosmetic products. Alginate, has been traditionally used in the cosmetic industry as a stabilizer for emulsions and suspensions due to its high stability, and for its thickening and gelling properties ,171,298.bstitute . Carragebstitute ,58,301. bstitute ,302,303.bstitute .Bagal-Kestwal et al. summarized the use of carrageenans  as binder and emulsion stabilizers, preventing constituent separation in toothpastes in a recent comprehensive review . In a prLaminaria japonica showed skin moisturizing properties in in vivo tests with human skin [Chondrus cripus, which provides hydrating, moisturizing, and therapeutic effects, and from the green algae Codium tomentosum, which can regulate water distribution in skin [Moisturizer agents help to maintain skin appearance and elasticity, improving its barrier role against harmful environmental factors . Polysacman skin ,308. Wan in skin . Agar is in skin . Mineral in skin .l-phenylalanine, which is oxidized to dopaquinone, and further converted to melanin. Sun exposure increases the synthesis of both tyrosinase and melanosomes. Different seaweed components can be active tyrosinase inhibitors and are commonly proposed for skin whitening [P. yezoensis extracts could be proposed as a safe and effective agent to enhance skin whitening and prevention or alleviation of skin wrinkle formation. The extracts exhibited a significant decrease in tyrosinase activity, but was less marked than arbutin. However, arbutin could have secondary undesirable effects, whereas these aqueous seaweed extracts promoted collagen production and, in a study with 23 volunteers, they also enhanced skin brightness [Skin whitening, particularly demanded in Asia, is also desired to achieve fair and flawless skin. Tyrosinase catalyzes two distinct significant reactions in melanin synthesis: the hydroxylation of l-tyrosine to 3,4-dihydroxy-hitening ,193,309;hitening ,310,311.ightness .Halomonas venusta, isolated from a marine sponge Callyspongia sp., incorporated in a cream fortified with concentrates of seaweed Gelidium spinosum showed antioxidant, antimicrobial, and wound healing activity in addition to improved texture [Due to the variety of activities, different fractions of seaweeds have been combined to achieve complementary actions, i.e., between phenolics and polysaccharides . In addi texture .Sargassum plagyophyllum extract as active pharmaceutical ingredient for anti-wrinkle cosmetics [Skin aging, causing thinning, dryness, laxity, fragility, enlarged pores, fine lines, and wrinkles, is a complex process of intrinsic and extrinsic aging. Intrinsic aging refers to the natural degradation of the skin, whereas extrinsic aging results from reactive oxygen species (ROS) generated during exposure to UV radiation . Althougosmetics . The potosmetics .Since these compounds are preferentially extracted in organic solvents, different examples of macerated extracts with potential photoprotective action can be found ,320,321.Seaweeds and their components have been claimed as functional, sensorial, and biological agents in the formulation of cosmetics, cosmeceuticals, and nutricosmetics. Some representative examples on their utilization in the formulation of products with different claimed actions are summarized in Porphyra dentata [Seaweeds can be used either fresh or fermented ,363,399, dentata , can be  dentata ,387,400. dentata ,405,406, dentata ,409,410  dentata . These m dentata ,375,411.A variety of formulations has been found, including liposomes  and nanoSeaweed fractions can confer functional properties or technical properties, such as thickening  and emulSeaweed components are interesting in the formulation of different hygienic products, including deodorants, shampoos ,414,415,A number of nutricosmetics have been designed to be used in common foods and beverages to improve skin appearance and firmness ,387, butOther patents have claimed pollution-free, safe, sanitary, ecological, environmentally friendly and energy-saving preparation processes ,377,419 Cosmetics, cosmeceuticals, and nutricosmetics are daily-use products that are gaining increasing commercial importance for improving the appearance of skin and for treating various dermatologic conditions. Seaweeds are a source of valuable components for the formulation of products due to the variety of functional, sensorial and biological properties they can confer. A diverse group of biologically active compounds, including vitamins, minerals, amino acids, carbohydrates, and lipids, can be extracted from seaweeds to develop conventional and novel cosmeceutical products. The possibility of offering a vast array of activities makes seaweeds a highly attractive renewable and versatile resource, and the importance of extraction and purification processes should also be considered. Other important aspects requiring study are in relation to greener extraction of bioactives, their chemical and biological characterization, as well as stabilization and delivery into novel products. As with other ingredients and applications, quality control and standardization are required for the commercial use of seaweed bioactives."}
+{"text": "Spinonympha shcherbakovi gen. et sp. nov. from mid-Cretaceous Kachin amber. The new genus and species is characterized by its large size, armoured body, extremely long rostrum, and leg structure. The fossil nymph cannot be attributed to any known planthopper family, but can be excluded from many families due to its large size and leg structure. The armoured body was probably developed for defence, and the extremely long rostrum indicates that, in the past, planthopper feeding on trees with thick and rough bark was more widespread than today. The new find reveals a new armoured morphotype previously unknown in planthopper nymphs.The fossil record of adult planthoppers is relatively rich, but the nymphs are rare and not well studied. Here, we describe a bizarre armoured planthopper nymph: Spinonympha shcherbakovi gen. et sp. nov., in mid-Cretaceous Kachin amber. The new genus is characterized by its large size, body armed with spines and tubercles, extremely long rostrum reaching well beyond the apex of the abdomen; profemur and mesofemur subcylindrical, covered with setae; protibia and mesotibia subquadrangular, densely covered with setae; protarsus and mesotarsus with two segments, tarsomere II longer and wider than I; metatrochanter swollen, metafemur subcylindrical, covered with short setae; metatibia subquadrangular, densely covered with short setae, without lateral spine and pectens without setae; metatarsus with three segments, and metatarsomere III extremely small. The fossil nymph cannot be attributed to any known planthopper family, but can be excluded from many families due to its large size and leg structure. The armoured body was probably developed for defence, and the extremely long rostrum indicates that, in the past, feeding on trees with thick and rough bark was more widespread than today. These features indicate that the new specimen represents a new armoured morphotype of planthopper nymph from the fossil record.The fossil record of adult planthoppers is comparatively rich, but nymphs are rare and not well studied. Here, we describe a bizarre armoured planthopper nymph,  The order Hemiptera is the fifth largest order among living insects ,2, with Knezouria unicus Jell, 1993, reported from the Late Triassic  of the Ipswich Basin, Queensland, Australia [Neazonia tripleta Szwedo, 2007, N. immatura Szwedo, 2007, and N. imprinta Szwedo, 2007) from Lower Cretaceous Lebanese amber (approximately 135 million years ago). Later, another new genus of this family  was discovered in Lower Cretaceous French amber (approximately 100 million years ago) [Perforissus muiri Shcherbakov, 2007 (first instar) and Cretargus shcherbakovi Shcherbakov, 2007 (first instar) [Alicodoxa rasnitsyni Emeljanov et Shcherbakov, 2011 (Dictyopharinae: Orthopagini) from the Rovno (NW Ukrainian) and Baltic ambers, based on nymphs, and very recently another new genus and species, Bathymyza longirostris Emeljanov and Shcherbakov, 2020 (Dictyopharidae: Dictyopharinae: Orthopagini?) was described based on an early instar nymph from Bitterfeld amber  [Dorytocus ornithorhynchus Emeljanov and Shcherbakov, 2018) of three different instars from mid-Cretaceous Kachin amber (approximately 100 million years ago). However, the adults of these nymphs remain unknown.Although the fossil record of planthoppers is relatively abundant , anustralia , but sevustralia . Szwedo ustralia  establisars ago)  reported instar) . Emeljan instar)  describeGermany)  also estSpinonympha shcherbakovi gen. et sp. nov., from mid-Cretaceous Kachin (Burmese) amber from northern Myanmar.Herein we describe a new and bizarre armoured planthopper fossil nymph, The studied specimen comes from the Cretaceous deposits of the Hukawng Valley in Myanmar, from a former amber mine located near Danai (Tanai) Town  ,16. OverThe specimen studied in the course of this work is deposited in Nanjing Institute of Geology and Palaeontology, Chinese Academy of Sciences, Nanjing. To avoid any confusion and misunderstanding, all authors declare that the fossil reported in this study was not involved in armed conflict and ethnic strife in Myanmar. This specimen is deposited permanently in a publicly owned collection in a national museum, in full compliance with the International Code of Zoological Nomenclature and Statement of the International Palaeoentomological Society ,28.The photographs were taken with a Zeiss Stereo Discovery V16 microscope system in the Nanjing Institute of Geology and Palaeontology, Chinese Academy of Sciences, and measurements were taken using Zen software. Photomicrographic composites of 50 individual focal planes were digitally stacked as obtained using the software HeliconFocus 6.7.1 for a better illustration of 3D structures. Photographs were adjusted using Adobe Lightroom Classic and line drawings were prepared using CorelDraw 2019 graphic software.The morphological terminology used in this study mostly follows Luo et al. .Hemiptera Linnaeus, 1758Fulgoromorpha Evans, 1946Fulgoroidea Latreille, 1807Family incertae sedisSpinonympha Luo, Wang et Jarzembowski gen. nov. ; rostrum extremely long, reaching well beyond apex of abdomen; profemur subcylindrical, carinate, covered with short setae; protibia subquadrangular, carinate, densely covered with short setae; protarsus with two segments, protarsomere II longer and wider than protarsomere I; mesofemur subcylindrical, carinate, covered with short setae; mesotibia subquadrangular, carinate, densely covered with short setae, thinnest near middle; mesotarsus with two segments, mesotarsomere II longer and wider than mesotarsomere I; metatrochanter swollen, metafemur subcylindrical, carinate, covered with short setae; metatibia subquadrangular, carinate, densely covered with short setae, without lateral spine, pectens without setae; metatarsus with three segments, metatarsomere III extremely small; metatibio-tarsal formula 5:5:7.Age and occurrence. Mid-Cretaceous ; amber from Kachin State, northern Myanmar.Spinonympha shcherbakovi Luo, Wang et Jarzembowski sp. nov. .Diagnosis. As for genus.Description. Large female nymph, total length of body 14.5 mm, body covered by numerous spines and tubercles . Vertex Foreleg A\u2013C with Abdomen with pygofer 9.61 mm long and 2.11 high in lateral view, 9-segmented, dorsal surface covered by numerous spines and tubercles F. SegmenSpinonympha shcherbakovi Luo, Wang et Jarzembowski gen. et sp. nov. can be assigned to Hemiptera according to its piercing-sucking mouthparts, and it can be assigned to Fulgoromorpha due to its antenna positioned below the compound eyes and metatibio-tarsal pecten, but it cannot be attributed to Coleoscytoidea and Surijokocixioidea, and should be placed in Fuloroidea because the former two superfamilies went extinct after the Triassic. However, S. shcherbakovi cannot be assigned to any known family because the phylogenetic relationships of the Fulgoroidea are mainly based on characters of the adults and its relatively poor preservation (flattened exuvium), but it can be provisionally excluded from many planthopper families due to its large size (nearly 15 mm), e.g., Achilidae St\u00e5l, 1866, Cixiidae Spinola, 1839, Delphacidae Leach, 1815, Derbidae Spinola, 1839, Dictyopharidae Spinola, 1839, Issidae Spinola, 1839, Jubisentidae Zhang, Ren et Yao, 2019, Kinnaridae Muir, 1925, Neazoniidae Szwedo, 2007, Nogodinidae Melichar, 1898, Perforissidae Shcherbakov, 2007, Tropiduchidae St\u00e5l, 1866, and Yetkhatidae Song, Szwedo and Bourgoin, 2019.S. shcherbakovi probably used these spines and tubercles to protect itself from predators. However, we cannot completely exclude the possibility that these spines and tubercles were developed for mimicry of moss [The most striking morphological feature of the fossil is its body covered by numerous spines and tubercles . Such structure is common among some insect larvae from mid-Cretaceous Kachin amber ,30,31,32 of moss .S. shcherbakovi. A sensory pit is defined as \u201ca small hole with horizontal seta directed inwards and diverging from its border; the length of the seta is not greater than diameter of the hole\u201d [S. shcherbakovi is probably because of poorly preservation.Sensory pits that are typically present on nymphs of planthoppers are not clearly preserved on he hole\u201d ,37. Senshe hole\u201d , but thehe hole\u201d , and canhe hole\u201d ,13,14). he hole\u201d ,12,13,14Knezouria Jell, 1993 from the Upper Triassic of Australia, probably representing the suborder Fulgoromorpha, but with superfamily placement unknown [Another interesting characteristic is the extremely long rostrum reaching beyond the apex of the abdomen, but this feature is not rare among Mesozoic planthoppers. A similar long rostrum can be found in Dictyopharidae , Dorytoc unknown , indicat unknown ,14,40,43 unknown .Spinonympha shcherbakovi has a strong coxa, which is not so long and robust as in Dictyopharidae [S. shcherbakovi . Thee nymphs , Jubisene nymphs ,46, Lalae nymphs , Perforie nymphs ,49,50,51e nymphs ,53,54). e nymphs , Dictyope nymphs , Katlasie nymphs ,57,58, Re nymphs , Tropidue nymphs ,53,54, Ye nymphs , and some nymphs , but oure nymphs ,46, Lalae nymphs , and Pere nymphs ,49,50,51S. shcherbakovi cannot be attributed to any known planthopper family, but it would be arbitrary to establish a new family for it at present. The placement of S. shcherbakovi within Fulgoroidea depends on the discovery of additional specimens. Nevertheless, it represents a new morphotype of planthopper nymph not seen before in the recent and fossil record.In summary, Spinonympha shcherbakovi gen. et sp. nov. is described from mid-Cretaceous Kachin amber. The new genus and species is characterized by its large size, armoured body, extremely long rostrum, and leg structure. The function of the spines and tubercles on the body is probably defence against predators. The new finding enhances our knowledge of the taxonomic diversity and morphological disparity of planthopper nymphs.An armoured planthopper nymph"}
+{"text": "Patients returning home after geriatric rehabilitation may encounter several challenges related to daily functioning, which only manifest after returned home due to the large difference in environment and amount of support provided in both settings. This study aimed to develop an intervention preventing transitional care. A co-creation design was used, including literature research, observations, interviews, and working groups including a variety of stakeholders (n=13), including care professionals, policymakers of the municipality, client representatives, and an expert in the field of geriatric rehabilitation. Results indicated four main causes for transitional care problems: lack of communication between patients and professionals, coordination and continuity of care, patients\u2019 limited self-management skills, and insufficient preparation. To solve these problems, an intervention was developed consisting of six intervention components aiming to increase self-management during meaningful daily activities, narrow the gap between the rehabilitation and home setting, and enhance communication and coordination."}
+{"text": "Pain is prevalent in older adults limiting independence directly and through comorbidity-related effects on functional domains such as mobility, well-being, sleep, productivity, and oligo-pharmacy. Improved outcomes for older adults with pain depends on provider knowledge and competence; concomitantly, Veterans, women, and others at socioeconomic disadvantage may face increased pain, comorbidities, and complications of treatments. Previous guidance for educational programs, from pre-licensure to post-graduate training, in geriatrics and pain have focused on expert opinion, whereas an evidence-based approach is preferred. Our working group is conducting a structured needs assessment regarding comorbidities of common pain-associated conditions in older adults. Methods: To capture expertise in medicine, nursing, pharmacy, clinical psychology, and physical therapy, we extended an open invitation to members of the VA Geriatric Research, Education, Clinical Centers Associate Director-Education network and selected, nationally-recognized clinical education experts outside VA. Results: An eight-member working group, interprofessional in composition, through multiple remote meetings has defined goals of the program, evaluated preliminary evidence addressing the clinical needs of older adults with pain, and posed \u2018curious questions\u2019 about the available large-scale data. The overarching goal is evidence-based needs assessment of gaps in education about pain in older adults, with purposeful attention to risks of healthcare inequities for older adult women, Veterans, persons of color, those at socioeconomic disadvantage, and caregivers. Conclusions: Interprofessional collaboration is effective in framing a broad needs assessment regarding pain and common comorbidities in older adults with the intent of meeting the educational needs of clinical trainees. More study is needed."}
+{"text": "Probiotics are live microorganisms that confer a health benefit to the administered animal when ingested. Their use has been an effective alternative to antimicrobial growth promoters in the livestock industry, and they could be bacteria or non-bacterial species or strains. However, there has been an increasing trend in administering multistrain probiotics in recent years. Multistrain probiotics comprise two or more species or strains of important microorganisms as a consortium beneficial to the administered animal. Several studies are being carried out to explore their potency or efficiency. They have proven to be a promising alternative to antibiotics growth promoters and were responsible for enhancing gut health, growth performance, maintaining a balance in gut microbiota, stimulating immunity against pathogenic organisms, improving digestion, and overall production efficiency in ruminants, poultry, and swine production.It has been established that introducing feed additives to livestock, either nutritional or non-nutritional, is beneficial in manipulating the microbial ecosystem to maintain a balance in the gut microbes and thereby improving nutrient utilization, productivity, and health status of animals. Probiotic use has gained popularity in the livestock industry, especially since antimicrobial growth promoter\u2019s use has been restricted due to the challenge of antibiotic resistance in both animals and consumers of animal products. Their usage has been linked to intestinal microbial balance and improved performance in administered animals. Even though monostrain probiotics could be beneficial, multistrain probiotics containing two or more species or strains have gained considerable attention. Combining different strains has presumably achieved several health benefits over single strains due to individual isolates\u2019 addition and positive synergistic adhesion effects on animal health and performance. However, there has been inconsistency in the effects of the probiotic complexes in literature. This review discusses multistrain probiotics, summarizes selected literature on their effects on ruminants, poultry, and swine productivity and the various modes by which they function. With the rapidly increasing demand for animal food products globally, improving livestock productivity to meet the growing demand has become important to livestock producers . Feed adDespite the fact that probiotics are often used interchangeably with direct fed microbials (DFM), there is a slight difference in their definition regarding animal feeding . The U.SProbiotics preparations come in various forms, and their efficacy sometimes varies depending on whether they are mono- or multistrain. The new approach in probiotics utilization has been to use a combination of probiotics strains. This strategy is presumed to have highly influenced animal nutrition, exerted increased health benefits, and created an even more favorable balance of intestinal metabolism, animal welfare , and perLactobacillus, Streptococcus, Enterococcus, Lactococcus, and Bifidobacteria remain the most commonly used probiotic agents in livestock to date [Saccharomyces (S. cerevisiae and S. bourlardii), Candida pintolopesii, and Aspergillus oryzae are typical non-bacterial probiotics [Bacteria, bacteriophages, microalgae, and yeasts are all examples of probiotics . Althoug to date ,15,16. Sobiotics ,18. Therobiotics . Some auobiotics . Before obiotics , non-patobiotics ,23,24. Pobiotics ,25. Hillobiotics  noted thobiotics .(1)Competitive exclusion,(2)Bacterial antagonism, and(3)Immune system stimulation.Even though probiotics are considered a possible replacement for antibiotic growth promoters, their mode of action appears to be distinct . ProbiotSalmonella, Escherichia coli, Campylobacter, Clostridium, Staphylococcus aureus, and perfringens [Probiotics also impact the health of the administered host via competition between beneficial bacteria and pathogens, replacement of pathogens by probiotic bacteria, and regulation of innate and adaptive immunity . Due to fringens ,36, hencfringens ,38.Saccharomyces [The idea of using harmless bacteria to out-compete pathogens has been acknowledged for a long time . In 1907aromyces  that couaromyces .Famularo et al.  probed tThese microbial consortia can thrive in a constantly changing environment such as the gastrointestinal tract and regulate the resident microbiota. Due to this fact, a multistrain probiotics supplement has been advocated as being more effective than a monospecies supplement ,51,52.For instance, even while some monostrain probiotics are effective in treating digestive tract disorders, Sanders et al.  noted thPediococcus acidilactici, Lactobacillus reuteri, L. salivarius, and Enterococcus faecium [Bifidobacterium thermophilum, E. faecium, and Lactobacillus spp [Bacillus, Lactobacillus, Saccharomyces, Bifidobacterium, and Streptococcus [Lactobacillus groups are significant constituents of a probiotic mix.Meanwhile, the potential of their cell walls to absorb heavy metals  enables  faecium ; PrimaLallus spp ; and Mictococcus . In geneThe ruminants\u2019 gastrointestinal tract is estimated to inhabit over 5000 microorganism species , with thBifidobacterium bifidum, Pediococcus acidilactici, Lactobacillus acidophilus, Lactobacillus casei, Enterococcus faecium), peptide extract, dead yeast extract, dried whey, an enzyme blend, and natural flavor rapidly resolved the condition by reducing the duration of symptoms. The calves\u2019 daily weight gain improved with the combination as well [Streptococcus faecium, Lactobacillus casei, Lactobacillus acidophilus, Lactobacillus bulgaricus, Lactobacillus reuteri, Lactobacillus lactis) and two yeast strains  had no improvement with respect to body condition score and dry matter intake but had a higher average daily milk yield, and reduced feed conversion ratio [At the onset of diarrhea in dairy calves, a multispecies probiotic containing five bacteria strains , Acetobacter fabarum (minimum concentration of 105 CFU/mL) and yeast from the environment . Based on the result, cows that grazed pasture treated with the product produced a significantly higher volume of milk and a higher quantity of milk protein with tendencies towards producing more milk fat. Similarly, when dairy cows were directly fed the pasture from paddocks treated with the same probiotic mixture, the treatment group still produced more milk and higher milk protein content than the control group. In addition, Deng et al. [Lactobacillus sakei, P. acidilactici FUA3138, and P. acidilactici FUA3140 combinations around parturition. The result revealed lower non-esterified fatty acids, higher cholesterol, and higher lactate levels, indicating that the concentrations of specified metabolites in the blood serum of transition dairy cows had been altered. A summary of several other combinations used in cattle, sheep, and goat of different physiological status and age are presented in In another study, Olchowy et al.  top-dresg et al.  used an E. coli, Clostridium, and Salmonella appear to be a severe concern in chicken production, causing mortality, lowered growth rate, and low output. Antibiotics had previously played an important role in combating or regulating this problem; however, their prohibition has resulted in the use of probiotics to fill the void. Generally, because of their high fermentation utilization activity, probiotics promote protein and lipid digestion and interacts with enzymes to break down dietary molecules into simpler forms for digestion and absorption. They stimulate the production of digestive enzymes for carbohydrate metabolism, lower cholesterol, help in the synthesis of nutrients such as vitamins, influence the pH level in the poultry gut, and improve the productive performance, intestinal flora, and histomorphometry in heat-stressed chickens [Pathogenic bacteria including chickens ,85,86,87Pasteurella multocida, a highly contagious poultry disease that causes fowl cholera [Saccharomyces cerevisiae, Lactobacillus fermentum, Pediococcus acidilactici, Lactobacillus plantarum, and Enterococcus faecium improved feed efficiency, growth performance, and intestinal health. It mitigated clinical signs, inflammatory reactions, and mortality-related symptoms [P. multocida and enterobacteria in the guts of supplemented birds, as well as the ability of the combination to out-compete pathogens, thereby preventing them from attaching to the intestinal walls and as a result improve intestinal microbial balance [When broiler chickens were experimentally challenged with  cholera ,89, suppsymptoms . In prevsymptoms ,91,92,93symptoms . Besides balance .Enterococcus faecium, Lactobacillus d. bulgaricus, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus rhamnosus, Streptococcus s. thermophiles, Bifidobacterium bifidum) and two fungi (Aspergillus Oryza and Candida pintolopesii), while the other contains nine bacteria strains . Both products improved broiler chicken overall performance, enhanced intestinal structure, reduced lipid peroxidation, increased the population of lactobacillus in the ileum, and lowered clostridium spp. The probiotics strains could have lessened the impairment of the intestinal epithelium [clostridium by competing for nutrients at the adherence site and inducing the immune response.Furthermore, Kazemi et al.  fed two ithelium  and redu7 CFU/g Bifidobacterium thermophilum, Lactobacillus casei, Lactobacillus acidophilus, and Enterococcus faecium [7 CFU/g, 108 CFU/g, and 109 CFU/g in an amount of 500 g/1000 kg were administered to different groups of birds. Although all the doses were said to benefit the intestinal structure, the intermediate dose accelerated the development of the GIT, especially the duodenum. It would be expected that a higher dose would exert more benefits, but this was not the case because the highest dose had a poorer outcome. Hence, animal dose\u2013response to probiotics, especially the probiotic complexes, remains a critical issue to be addressed.In spite of the numerous benefits associated with the administration of multistrain probiotics, not all have shown significant benefits  Table 2Table 2.  faecium ,97. Neve faecium . The rol faecium  investigFeed prices contribute to almost two-thirds of overall swine production expenses; hence, to ensure profitability in the pig industry, efficiency in converting feed into pig body mass is essential . MoreoveLactobacillus salivarius, Lactobacillus reuteri (VB4), Lactobacillus reuteri (ZJ625), and Streptococcus salivarius as direct-fed microbial showed that the combination had a positive impact on growth performance and blood profile. The combination elevated average daily weight gain, reduced feed conversion ratio, reduced the population of ileal enteric bacteria, and activated immunoglobulin G in weaned piglets, indicating its efficacy in preventing post-weaning diarrheal disorders [Clostridium butyricum, Bacillus lichenformis, Bacillus coagulans, and Bacillus subtilis increased average daily weight gain and feed ratio, and also reduced hydrogen sulfide and total mercaptans emission . A higher dose at 0.1% increased apparent total tract digestibility of dry matter, nitrogen, and gross energy. It also modulated the fecal lactobacillus count and reduced the E. coli population. Similarly, with multistrain containing 1 \u00d7 109 CFU/g Bacillus subtilis and Bacillus licheniformis, Hu et al. [E. coli in the lactating sow.In piglets, a study using a blend of bacteria probiotics containing isorders . Furtherisorders  discoveru et al.  reportedEnterococcus faecalis, Clostridium butyricum, and Bacillus mesentericus administered 3 weeks before farrowing improved the rate of return of sows to oestrus by 24% and reproduction performance during the farrowing periods. Bohmer et al. and Alexopoulos et al. [Bacillus licheniformis and subtilis combination on the reproduction performance of lactating sows. Such variations in the effectiveness of probiotics, probably due to the complexity of the livestock digestive system or differences in the strains or species combined, remain unraveled.Besides, the performance of breeding sows during the reproductive phase is often influenced by stressors such as gestation, farrowing, lactation, and weaning . Hayawaks et al. ,119 suggs et al.  reportedIn ruminants, poultry, and swine, multistrain probiotics have proven to be a viable alternative to antibiotics, and their usage in animal husbandry continues to grow. The effect on and responses of host animals, however, differs among literature. The variability in results might be due to the microorganism type or strains combined, as different species could possess distinct metabolic effects. The survivability of all the strains until delivery to the gut may also be difficult to ascertain. Probiotic dosage, the number of viable organisms in each dose, host animal physiological status and age, environment, diet composition, production procedures, and the mode of administering to the animal could all have a role. There were also limited reports on the greater benefits of multistrain probiotics over single strains in livestock. As a result, further research is needed to understand the interaction mechanisms among the combined microbes and the host\u2019s gut microbiota and the unique role played by the individual microbe. In addition, comparison among the investigated animals and direct comparisons between the mono- and multispecies probiotics should be considered. Finally, stringent recommendations for optimal benefits should be provided."}
+{"text": "Bi-channel image registration and deep-learning segmentation (BIRDS) for efficient, versatile 3D mapping of mouse brain. Published 18, January 2021In our BIRDS software, a few parts in the registration module were contributed by Yongsheng Zhang and Prof. Shaoqun Zeng. When we were writing the eLife paper last year, we misunderstood that this work had been previously published along with their brain research work in their Wang et al 2020a paper (Science Bulletin 65:1203-1216) which we cited in the eLife paper. Due to this misunderstanding their contributions were only acknowledged in the published eLife paper. We are therefore formally correcting the eLife paper to add them both as co-authors. All the authors agree to their addition as co-authors in the paper.The details of Yongsheng Zhang and Prof. Shaoqun Zeng\u2019s contribution are explained below:\"Yongshen Zhang and Shaoqun Zeng first developed the efficient method to improve the registration stability by encoding global axis information using regional grayscale inversion. It allowed the extraction of more features from the raw image data and is indeed helpful in our BIRDS multi-channel registration framework; Yongsheng Zhang also developed the dynamic z down-sampling together with Weilin Zeng (exisiting author), to achieve better registration initialization. Furthermore, Yongsheng Zhang contributed to the development of interactive framework, which allows the operation of the local registration by drawing arrows on the merged coarse registered images instead of marking points, and notable improves the efficiency of semiautomatic registration. \"New authors list: Xuechun Wang, Weilin Zeng, Xiaodan Yang, Yongsheng Zhang, Chunyu Fang, Shaoqun Zeng, Yunyun Han, Peng FeiOriginal authors list: Xuechun Wang, Weilin Zeng, Xiaodan Yang, Chunyu Fang, Yunyun Han, Peng FeiDetails for the omitted authors:Yongsheng Zhang3 Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan, China.Contribution: Methodology, SoftwareFor correspondence:ys-zhang20@mails.tsinghua.edu.cnContributed equally with: Xuechun Wang, Weiling Zeng, Xiaodan Yang, Chunyu Fang Competing interests:\u00a0No competing interests existShaoqun Zeng3 Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan, China.Contribution: MethodologyCompeting interests:\u00a0No competing interests existRevised author contributions:Xuechun Wang: Data curation, Software, Validation, Visualization, Writing - original draftWeilin Zeng: Methodology, Software, ValidationXiaodan Yang: Resources, VisualizationYong Sheng Zhang: Methodology, SoftwareChunyu Fang: ResourcesShaoqun Zeng: MethodologyYunyun Han: Resources, Visualization, Writing - review and editingPeng Fei: Software, Funding acquisition, Visualization, Writing - review and editingOriginal author contributions:Xuechun Wang: Data curation, Software, Validation, Visualization, Methodology, Writing - original draftWeilin Zeng: Software, ValidationXiaodan Yang: Resources, VisualizationChunyu Fang, Resources, VisualizationYunyun Han, Resources, Visualization, Writing - review and editingPeng Fei, Software, Funding acquisition, Visualization, Writing - review and editingRevised funding statement:FundingNational Natural Science Foundation of China (21874052)Peng FeiNational Natural Science Foundation of China (31871089)Yunyun HanInnovation Fund of WNLOPeng FeiJunior Thousand Talents Program of ChinaYunyun HanPeng FeiThe FRFCU (HUST:2172019kfyXKJC077)Yunyun HanNational Key R&D program of China (2017YFA0700501)Peng Fei973 Project (2015CB755603)Shaoqun ZengYongsheng ZhangDirector Fund of WNLOShaoqun ZengYongsheng ZhangOriginal funding statement:FundingNational Natural Science Foundation of China (21874052)Peng FeiNational Natural Science Foundation of China (31871089)Yunyun HanInnovation Fund of WNLOPeng FeiJunior Thousand Talents Program of ChinaYunyun HanPeng FeiThe FRFCU (HUST:2172019kfyXKJC077)Yunyun HanNational Key R&D program of China (2017YFA0700501)Peng FeiThe funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.Revised Acknowledgements:We thank Haohong Li, Luoying Zhang, Man Jiang, Bo Xiong for discussions and comments on the work\u00a0and Hao Zhang for the help on the code implementation. This work was supported by the National Key R and D program of China (2017YFA0700501 PF), the National Natural Science Foundation of China , the Innovation Fund of WNLO (PF) and the Junior Thousand Talents Program of China (PF and YH), the FRFCU (HUST:2172019kfyXKJC077 YH).Original Acknowledgements:We thank Yongsheng Zhang, Shaoqun Zeng, Haohong Li, Luoying Zhang, Man Jiang, Bo Xiong for discussions and comments on the work. Hao Zhang for the help on the code implementation. This work was supported by the National Key R and D program of China (2017YFA0700501 PF), the National Natural Science Foundation of China , the Innovation Fund of WNLO (PF) and the Junior Thousand Talents Program of China (PF and YH), the FRFCU (HUST:2172019kfyXKJC077 YH).The article has been corrected accordingly."}
+{"text": "The COVID-19 pandemic poses serious physical and mental health risks for older adults worldwide. To develop culturally and contextually congruent services to mitigate these risks requires understanding their stress and coping processes, which remain understudied in Latin America. This study examines qualitative data from 51 adults aged 60 and over who participated in an ongoing study of older Puerto Ricans\u2019 knowledge, attitudes, and practices about COVID-19. Trained interviewers collected the data by telephone from January to August, 2021. Two-thirds of participants were female, 60% had less than high school education and 90% had poverty-level incomes. Drawing on Lazarus and Folkman\u2019s Stress and Coping Theory, we conducted a thematic analysis of responses to open-ended questions about the nature and extent of COVID-related stressors, stress management, and meanings and guidance they had gleaned from their experience. Participants perceived the pandemic as an added threat to ongoing chronic stressors ; disruptions in daily routines, family cohesion, and grief and loss processes; and increased isolation and loneliness. They reported using cognitive, behavioral, socioemotional and spiritual coping, including positive thinking, keeping occupied, relaxation, religious practices and, in a few cases, social media. Participants highlighted a revitalized appreciation for emotional qualities of relationships, freedom and life in general. Consistent with our guiding theory, cultural, contextual, religious, and socio-political factors shaped their appraisals of stress and their coping strategies. Future research should examine how these practices relate to health outcomes and quality of life and how they can inform effective, appropriate interventions."}
+{"text": "In a workshop discussing the worldwide first publicly funded international trustmark project for health information on the web (MedCERTAIN), workshop participants discussed aims, possible beenfits and concerns relating to trustmarks for health information on the web. The following document attempts to summarize the issues raised by participants.Any certificate, symbol, sign, based on information or meta-information (information about information) provided by a third-party that is aimingto enhance peoples trust into a certain product, service, relationship, information provider or piece of information perceived as being trustworthy by the organisation issuing the trustmark; and/orto enhance the ability of people to evaluate the trustworthiness of information, services or products.There is agreement that in medicine there is no absolute truth, so that in practice the evaluation of quality criteria such as \"accuracy\" of health information poses huge practical barriers. In addition, information on the web is dynamic in nature. The primary aim of a trustmark would therefore not be to provide a guarantee for information correctness or usefulness, but to enhance trust into the information provider.Heidelberg Collaboration statement of purpose, we agree that an important goal for us is to assure and to continuously improve the quality of health information on the Internet.As has been stated in the We agree that there could be a role for a trustmark in this process,as health information providers may learn from the interaction between the experts from the organisation issuing the trustmark, the information provider and the useras the mere existence of a trustmark may be an additional incentive for a health information provider to improve internal quality management procedures and to adhere to principles of best practiceas a trustmark may contribute to protect people and enhance their health by providing information for decision making1. Lack of experience with trustmarks and lack of evidence for the effectiveness or impact of trustmarksWe also agree that we have no actual evidence for saying whether and under which conditions trustmarks may create more benefit than harm, and that any project trying to implement a trustmark concept has to be carefully evaluated for the impact of its service on people and information providers.2. Business modelsAnother problem is the absence of experience with business models which could make sure the financial viability and internal quality control of such services.A business model that is based on letting information providers pay for evaluation should not disadvantage information providers which are unable to pay a fee.3. Legal problemsAny trustmark concept should take into account potential legal risks, possible risk management strategies and, where appropriate, dispute resolution mechanisms.Participants:Lucas M. Bachmann , Carl R. Blesius , Markus Blume , Carl J. Brandt , Dan Brickley , Alejandro Cacherosky , Ken Campell , Richard Cleland , Phil Cross , Elenice de Castro , Guy de Roy , Tony Delamothe , Martin D. Denz , Persephone Doupi , Joan Dzenowagis , Christer Edling , Gunther Eysenbach , Gerard Freriks , Franz Fr\u00fchwald , Lisa Gray , Pelle Gustafsson , Gerhard Heine , Katrin H\u00f6rner , Robert Hsiung , Jostein Ingulfsen , Thomas Isenberg , Edward Jacob , Alex R. Jadad , Jacobo Kelber , Hugo Kitzinger , Inge Kokot , Hans-Joachim Koubenec , Michel Labrecque , Kristian Lampe , Stephane Lejeune , Leonard B. Lerer , Odile Leroy , Nicolas Lienert , P\u00e5l Lindstr\u00f6m , S\u00e1ndor Lipp , Leena Lodenius , Antti Malmivaara , Miquel Angela Mayer Pujadas , Peter Mills , Cesar Molinero , Marc Muret , Wolfgang Nagel , Tim Nater , Joerg Nitzsche , Debra O\u00b4Connor , Gert Purkert , Ramon Sarrias Ramis , Christine Reuter , Ahmad Risk , Carl B\u00e9n\u00e9dict Roth , Sebastian Schmid , Christiane Schmitz , Luk Schoonbaert , Frank Schuler , Ulrich Schwanke , Sasha Shepperd , Myra Sidrassi , Chris Sigouin , Chris Silagy , Denise Silber , Martin Sonderegger , Anke Steckelberg , Frederik Tautz , Nicolas P. Terry , Christian Thomeczek , Wouter Tukker, , Gerard H. van der Zanden , Georg von Below , Frank von Danwitz , C.-Peter Waegemann , Thomas Wetter , Petra Wilson, , Margaret A. Winker , Jeremy Wyatt , Gabriel Yihune"}
+{"text": "Asthma is one of the most common chronic diseases worldwide, affecting an estimated 300 million people around the globe . The cauAsthma and allergic rhinitis are both inflammatory diseases of the airways. The similarities between allergic rhinitis and asthma in epidemiologic and pathophysiologic features suggest that allergic rhinitis and asthma represent manifestations of the same syndrome, the chronic allergic respiratory syndrome . The AllTwo international meetings were developed in response to the need to highlight the role of inflammation in asthma and the need for improved recognition of the relationship between asthma and allergic rhinitis. Both meetings were held under the auspices of the University of Southampton and the International Primary Care Respiratory Group, and were made possible through an educational grant by Merck & Co., Inc.The first of these MetaForum conferences, held in London in April 2004, was entitled 'Improving Asthma Therapy through More Effective Control of Inflammation.' The second meeting, 'MetaForum: Improving Outcomes for Asthma Patients with Allergic Rhinitis,' took place in December 2004 in London and, like the first, brought together more than 40 leading experts in asthma and allergic rhinitis from 20 countries. These meetings included several presentations followed by an active discussion to reach consensus on the areas for action to improve outcomes for patients with asthma and allergic rhinitis. In the present supplement we include several of the major papers presented at these conferences, expanded and updated with more recent references.STH has received fees for lectures from Novartis and Merck Sharp & Dohme and is a consultant for Novartis, MRL, Almiral Prodesfarma, Rotta Pharm., Cambridge Antibody Technology, Amgen, Wyeth, UCB/Celltech, Avontec and Synairgen. DP has received honoraria for speaking at sponsored meetings from the following companies marketing respiratory products: 3M, Altana, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, IVAX, Merck Sharp & Dohme, Novartis, Pfizer and Schering-Plough. DP has also received honoraria for advisory panels with 3M, Altana, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, IVAX, MSD, Novartis, Pfizer and Schering-Plough. DP or his research team have received funding for research projects from 3M, Altana, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, IVAX, Merck, Sharp & Dohme, Novartis, Pfizer, Schering-Plough, Viatris."}
+{"text": "In a recent article, Six weeks after DMAB exposure, we found that the patient was still confused about time . FourteeThe patient developed a progressive distal numbness and limb weakness 5 days after DMAB intoxication, and neurologic examinations showed generalized hyporeflexia; decreased sensation in pin-prick, temperature, touch, vibration, and position sensations; and weakness in the distal limbs, particularly in both feet . The datOur time course of DMAB-induced polyneuropathy indicated an acute axonal polyneuropathy . However"}
+{"text": "We thank Drs. Preiser, Drexler, and Drosten for their letter  and sharIn-house assays require production, optimization, validation, and quality assurance of all reagents, which is challenging in any circumstances, and would be extremely difficult in laboratories in most resource-limited settings. Real-time PCR instruments are expensive and maintenance in many places would be a problem. What is really needed is a technologically much simpler, much less expensive, perhaps semi-quantitative assay for measuring viral load."}
+{"text": "The two MetaForum conferences provided an opportunity for presentation of current information on asthma and allergic rhinitis, as well as a forum for discussion by European experts of important issues in the field of allergy and asthma . SeveralResults of epidemiologic studies indicate that allergic rhinitis is a risk factor for asthma, that allergic rhinitis and asthma often occur in association, and that having comorbid allergic rhinitis is a marker for the presence of more difficult to control asthma and greater use of resources for asthma . PatientThese findings support the Allergic Rhinitis Impact on Asthma recommendation that all patients with asthma be checked for allergic rhinitis, and vice versa . TreatmeThe structured review of patient surveys reported in the present supplement  suggestsBetter education of physicians about asthma and allergic rhinitis and better communication between physicians and patients are essential to improving asthma control. The final paper of the present supplement examines recent asthma guidelines and proposes possible ways in which they could be improved . PhysiciFinally, the development of country-specific guidelines or, ideally, local guidelines for each region would provide more practical solutions for asthma care and would account for factors, such as social factors and costs, that influence patient choice and adherence to therapy. These issues require coordinated efforts between specialists in the field and primary care physicians, as most medical care for asthma and allergic rhinitis is delivered in a primary care setting.STH has received fees for lectures from Novartis and Merck Sharp & Dohme and is a consultant for Novartis, MRL, Almiral Prodesfarma, Rotta Pharm., Cambridge Antibody Technology, Amgen, Wyeth, UCB/Celltech, Avontec and Synairgen. DP has received honoraria for speaking at sponsored meetings from the following companies marketing respiratory products: 3M, Altana, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, IVAX, Merck Sharp & Dohme, Novartis, Pfizer and Schering-Plough. DP has also received honoraria for advisory panels with 3M, Altana, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, IVAX, MSD, Novartis, Pfizer and Schering-Plough. DP or his research team have received funding for research projects from 3M, Altana, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, IVAX, Merck, Sharp & Dohme, Novartis, Pfizer, Schering-Plough, Viatris."}
+{"text": "Data Mining is the process of automatic discovery of novel and understandable models and patterns from large amounts of data. Bioinformatics is the science of storing, analyzing, and utilizing information from biological data such as sequences, molecules, gene expressions, and pathways. Development of novel data mining methods will play a fundamental role in understanding these rapidly expanding sources of biological data.Data mining approaches seem ideally suited for bioinformatics, which is data-rich, but lacks a comprehensive theory of life's organization at the molecular level. The extensive databases of biological information create both challenges and opportunities for developing novel data mining methods. The 6th Workshop on Data Mining in Bioinformatics (BIOKDD) was held on August 20th, 2006, Philadelphia, PA, USA, in conjunction with the 12th ACM SIGKDD International Conference on Knowledge Discovery and Data Mining. The goal of the workshop was to encourage KDD researchers to take on the numerous challenges that Bioinformatics offers. The BIOKDD workshops have been held annually in conjunction with the ACM SIGKDD Conferences, since 2001. Additional information about BIOKDD can be obtained online [Automatic Layout and Visualization of Biclusters, Gregory A. Grothaus, Adeel Mufti and T. M. Murali [Five revised and expanded papers were selected from the BIOKDD workshop, out of a total of 18 submissions, to appear in Algorithms for Molecular Biology (AMB). These papers underwent another round of external reviewing prior to being accepted for AMB. An overview of each paper is given below. In the paper titled . Murali , presentExMotif: Efficient Structured Motif Extraction, Yongqiang Zhang and Mohammed J. Zaki [In  J. Zaki , describRefining Motifs by Improving Information Content Scores using Neighborhood Profile Search, Chandan K. Reddy, Yao-Chung Weng and Hsiao-Dong Chiang [In the paper g Chiang , show hoA Novel Functional Module Detection Algorithm for Protein-Protein Interaction Networks, Woochang Hwang, Young-Rae Cho, Aidong Zhang and Murali Ramanathan [In their paper, manathan , describA Spatio-temporal Mining Approach towards Summarizing and Analyzing Protein Folding Trajectories, Hui Yang, Srinivasan Parthasarathy and Duygu Ucar [In ygu Ucar , describ"}
+{"text": "Rule 10 for getting published  appear iPLoS Computational Biology, in which objective science, evidence, and the GIGO  principle count for something. Eminence-based medicine [Helicobacter pylori in peptic ulcer disease [Yet, a journal's high eminence and high impact may bespeak its rigid orthodoxy, rather than its high quality. Rule 10 may hold for journals, such as medicine ,4 too ofmedicine . Altman medicine , which tmedicine . Consensmedicine  too oftemedicine . Medical disease , thrombo disease , questio disease , and pre disease , among o disease .In medical journals, eminence-based medicine ,4 predomHelpful first steps to remedy the current malaise might consist of prompting editors of scientific journals, of all levels of impact, to improve peer review by encouraging substantive dialogue , by adheHigh-impact medical journals too often nurture sacred cows by taking in and putting out orthodox garbage and rejecting innovative pearls. Then the Institute of Medicine wonders why 44,000 to 98,000 patients per annum die of preventable medical errors in the hospitals of the United States ."}
+{"text": "The statistical examination of the Fallon childhood cancer cluster by Significant resources have been devoted to investigating the childhood cancer cluster discovered in 2000 in Fallon, Nevada (Churchill County). Although the magnitude of this cluster of acute lymphoblastic leukemia (ALL) could be attributed to happenstance, the recent analysis by A surprising, contemporaneous incidence of ALL also developed in Sierra Vista, Arizona . Other cNone of the hypothesized causes of the Fallon cluster has withstood scrutiny  comprise a complex galaxy of highly bioactive natural products. Riddelliine, senkirkine, mono-crotaline, retronecine, heliotridine, jacoline, jacozine, jacobine, seneciphylline, and senecionine are but a few of the numerous PAs produced by a wide spectrum of plants. PA-producing plants , especially Fluctuating levels of PA contamination in the consumer food supply, especially via certain herbal teas , honey , dairy pin utero  of PAs can lead to delayed toxicity  (up to 1in utero . Althougin utero . It is nAlthough carcinogenicity data are lacking in humans, PAs have been shown in rats to cause both leukemia  and rhab"}
+{"text": "The frail older adult subpopulation, which is growing at a rapid rate, contributes significantly to the increasing global healthcare cost . Many frIn contrast, much is known of the immune status of the healthy older adult subpopulation, for this subpopulation has been investigated extensively over the past three decades. Thus, it is known that T cell-dependent immune functions decline with age , and assRecently, the influence of chronic disease on T cell immunity as been investigated , using tHelicobacter pylori, Mycobacterium tuberculosis, Chlamydia pneumoniae, Herpes viruses, Epstein-Barr virus, and Hepatitis viruses, could play a role on progression of chronic disease, especially atherosclerosis, and impaired immunity [The demonstration that reduced immunity in older adults is correlated with chronic disease burden, but not with chronologic age, suggests that chronic disease burden markedly enhances the reduction in immunity of older adults caused by biologic aging. Others have suggested chronic infections, caused by especially cytomegalovirus, and also by immunity -15. Whil"}
+{"text": "This paper presents the result of a study on the herbal drugs in the herbal markets in Mersin and Adana. The data were collected through direct interviews with herbalists and customers between 2002\u20132005 and the popular medicinal plants were investigated. A total of 107 species belonging to 56 families were investigated and the samples were listedwith their local and Latin names. The investigation includes cross-checking the disorders and their herbal cures and their recommended use stated by the local herbalists, by the parts used, and by the preparations. The cultivated species and their ethno botanical uses, are documented and extensive inventory is presented.As a result, we observed that these plants are used especially for intestinal digestive disorders of the gastrointestinal tract, (21.68%), respiratory tract system disorders (10.43%), heart-blood circulatory system disorders (8.48%), urinary tract system disorders (7.70%), skin disorders (6.48%) and others. In recent years, the increase in the residential and agricultural areas, and the decrease in medical plants have triggered the interest in ethno-botanical studies throughout the world -4. The iFor centuries, Turkish people have been using herbal medicine for the treatment of some daily diseases. The Taurus Mountains are one of the centers of the Mediterranean Region with a rich plant diversity. Accordingly, the traditional herbal medicines are important for the life of people. In this area, contagious diseases, cardiovascular disorders and cancer were investigated -18. The The aim of this, research is to focus on the kinds of medical diversity found in the herbal markets, on the frequency of usage of the plants, and thus, to show the different treatment types that are applied in the region.The study is to be the first survey stating the herbal drugs in the herbal markets in the south of Turkey (Adana and Mersin provinces).Our chosen study area, The Taurus Mountains' hills are located in the south of Turkey with C4\u20135\u20136 grid squares. The population densities of the two central cities (Mersin and Adana) are 537, 842 and 807, 934 .Pinus brutia, P. nigra, Quercus coccifera, Q. cerris, Q. ithaburensis, Q. infectoria, Juniperus oxycedrus, J. excelsa, J. drupacea and Abies cilicica [oral folklore that is passed on from one generation to the next and the second source is Ottoman, Arabic and Turkish herbal books which are sold in the bookstores.There are about 70 herbal markets in the centers of Mersin and Adana. The plants presented in the herbal markets are collected from the villages in the Taurus Mountains Figure . In the cilicica ,22. The During a two year-long survey, almost all herbal markets in the research area are investigated. The fresh plants and dried samples that are purchased from various herbal markets have been cross-examined with reference books -25. The Some bio-reactive components are indicated by Evans  and BaytVoucher specimens, in duplicates, are saved both in the Herbarium of Biology Department in Mersin and the Chemistry Department in Cukurova University.Origanum vulgare L., Micromeria myrtifolia Boiss et. Hohen, Teucrium polium L., Saturea hortensis L., Nepeta italica L. and Sideritis spp. are used for making tea in the villages of the research area, nowadays the popular usage of tea plants such as Rosa canina, Helichrysum stoechas, Myrtus communis, Sideritis congesta and Anthemis spp. are used against obesity. The local people of Mersin ('yoruk') use Helichyrsum stoechas and Hypericum perforatum for stomachalgia, Halimione portulacoides for asthma, Arum maculatum for colitis, Prunus avium, Myrtus communis for obesity, Mandragora officinarum, Ferula communis for aphrodisiac, Tussilago farfara for cough, and Capparis spinosa, Portulaca oleraceae, Crocus sativus, Juglans regia for salad, pickle and jam.While, Urtica spp., Equisetum arvense and Achillea spp. and a subsequent medical therapy would give good results.According to the information obtained from some of the herbalists, the patients should start to accept the alternative therapies in health and medicine. Since diseases emerge due to the collapse of the immune system, the body should be cleaned up primarily. To achive this, it is suggested that a 3- month long therapy with Teucrium chamaedrys for anti-malaria, Laurus nobilis for anti-stress, Plantago lanceolata for supporting and Ocimum basilicum for anti-headache in Italy [A range from 7\u201333 species were from our list, have also been documented by several other researchers in a number of other countries -34. In ain Italy ,10,36,37Thymus sipyleus var.sipyleus, T. cilicicus, Sideritis congesta and Liquidambar orientalis)- are the only ones planted in the Tarsus by the East Mediterranean Forest Research Institute. These include Mediterranean elements (21.05 %), Euro-Sib. Elements (8.42 %), Ir.-Tur. Elements (5.26 %) and some widespread, widely cultivated plants (62.10 %) and several species like Coriandrum sativum and Petroselinum crispum which are unknown in origin according to Davis [From our list, taxa containing endemic species , Reseda officinalis and Fumaria asephala (sahdere), Paliurus spina- christii and Lamium album , Hypnum cupressiforme and Lycopodium clavatum (kurtpencesi), Sideritis congesta and Salvia officinalis (adacayi), Cichorium inthybus and Taraxacum officinale (hindiba), Anthemis spp. and Matricaria chamomilla (papatya), Cupressus sempervirens and Quercus, Anagallis arvensis and Origanum majorona (mercankosk) may be used for the same ailments with the same local names in some herbal markets of Adana. Locally, Arbutus andrachne is preferred instead of Liquidamber orientalis and some Hypericum spp. are preferred instead of Centaurium erythrae in Mersin. As various herbs can be advised to cure the same disease under one common name, to reach to the exact and right herbtype, and to prevent any misunderstanding or misusage of the herbal plants, herbalists and medical firms need to know the original Latin names of these herbs and ask accordinly before any purchase.Gentiana lutea, Arum maculatum, Rumex acetosella, Nargissus and Opopanax spp., were claimed to be abortive [Nasturtium officinale, Salvia officinalis, Nargissus, Cyclamen spp, Cinnamomum zeylanicum  and Cinchona officinalis  are belived to be abortive and dangerous in herbal markets. In the research area these therapies were conducted either together with the medical therapy under physician control or in the cases that the medical therapy has failed.In the old herbal books abortive ,39. HoweCapparis spinosa, Apium graveolens, Equisetum arvense, Berberis vulgaris, Zea mays, Urtica dioica, Sambucus nigra, Capsella bursa-pastoris, Salix caprea in Azerbaijan [Pteridium aquilinum, Myrtus communis, Plantago lanceolata, Portulaca oleraceae, Coriandrum sativum, Malva neglecta, Buxus sempervirens, Adianthum capillus-veneris, Mentha longifolia, Origanum vulgare, Nasturtium officinale in Pakistan [In table 1, gunluk, dari, anason, ardic, papatya, sogan, meyan koku, mese, cemen, servi kozalagi, yabani roka, menengic, corek otu, defne, gul, semiz otu, kimyon, hindiba, gebere, keten, egrelti, sakiz, kisnis, mercankosk, nane, anason, ravent, sinirli ot, kekik, susen, sahdere, tere, yarpuz, safran was used in Central Asia according to Turk medicine books -45. Todaerbaijan  and PterPakistan .If we look at the XVI. Century medicinal plant list of the Ottaman Empire epoch, we can find the same list such as, adam otu, ada sogani, ahlat, adacayi, anason, andiz otu, ayva, bakla, bald\u0131ran, bogurtlen, biberiye, burcak, cakal er\u0131g\u0131, ceviz, corek otu, defne, dere otu, egrelti otu, feslegen, findik, funda, gul, guzel avrat otu, hardal, hindiba, incir, isirgan otu, karadut, keten, kekik, kedi otu, k\u0131raz, k\u0131myon, kuzukulag\u0131, labada, lavanta, maydanoz, mercankosk, mersin, nane, zeytin, melisa, kantaron, kuskonmaz, misir puskulu, mese kabugu, ogul otu, pelin and safran, sakiz, sandal, sumak, susen ,48-50. SA great many of the vernacular names and common families and 15\u201324 species were shared in Anatolia and Central Asia ,11,12,54In the light of these data, some plants that are presented in our list, can be said to be based on the Central Asia Turk medical science and also their prescriptions that had been used between the XIV-XVI Th. centuries.It would not be inappropriate to say that, the similar climate and environmental conditions  have been the cause of using the similar plants in that region ,31,33,34Table In conclusion, the comparison of the treatments between provinces and villages, shows us a decreased incidence of heart-blood, liver-spleen and gynecological disorders in the villages and increased incidence of the arthritis in the villages Table  9,36,37,3736,37.The percentage of skin disorders of Uzbekistan, Italy, Turkey and Greece implies that the increase may also be related to the technological developments, environmental pollution and humidity Table .In Table Nerve disorders are similarly seen in the Mediterranean countries as given in Table In less developed countries, during childhood and adolescence, there is a factor of risk of contagious (infectious) diseases. The global mortality rate (over 52 million) depends on contagious and parasitic diseases (over 17 million), heart-blood system disorders (over 15 million), cancer (over 6 million) and chronic respiratory tract disorders (over 3 million) .Following the listed results, we came up with the fact that the causes of mortality were mostly respiratory tract and circulatory system disorders ,18, and Origanum majorana, Equisetum arvense, Glycyrrhiza glabra, Matricaria chamomila, Nigella arvensis, Paliurus spina-christii, Armeniaca vulgaris, Linum catharticum, Orchis anatolica, Rosmarinus officinalis, Myrtus communis, Lavandula stoechas and Mentha pulegium.In the end, the close analogy was discovered between the respiratory tract disorders, circulation system disorders, the intestinal-digestive diseases- which are related to the malnutrition, undeveloped hygiene habits, and the use of unnecessary antibiotics ,57, and Table 1. The list of Medicinal plants of research areaClick here for file"}
+{"text": "Chronic Achilles tendinopathy is frequent in the individuals who participate in the physical activities, especially running and jumping. This disorder could be subdivided into insertional and noninsertional tendinopathy according to the zone of the pathological disorder.The essence of tendinopathy is a failed healing response, which includes three different and continuous stages . These tendinopathic lesions affect both collagen matrix and tenocytes. In a recent study, the authors found that the Achilles tendinopathy is harder than asymptomatic tendons on axial-strain sonoelastography, which indicated the decrease of resisting plastic deformation . The his\u03b22 detected increased expression in the Achilles tendon, which could induce neovascularization and stimulate fibroblast and tenocytes proliferation and synthesis of collagen [Metalloproteases (MMPs) are important regulators of extracellular matrix remodeling, and their levels are altered during tendinopathy. Previous studies indicated that MMP-9 and MMP-13 participate in collagen degradation process, whereas MMP-2, MMP-3, and MMP-14 participate in both collagen degradation and collagen remodeling processes. Moreover, difference kinds of growth factors and cytokines such as vascular endothelial growth factor, insulin-like growth factor, and transforming growth factor The reasons of pain in Achilles tendinopathy are complicated. The changes in matrix, vascular, tenocyte, cytokines, neuropeptides and neurotransmitters, and ion channels in the cells are the potential contributors to pain . MoreoveVarious treatment options have been used for the disorder, which included conservative and surgical treatments.Conservative treatment was the first line of treatment for Achilles tendinopathy, such as activity modification, orthotics, heel lifts, massage, hot and cold compresses, strengthening exercises, ultrasound, and nonsteroidal anti-inflammatory drugs (NSAID) or corticosteroid injection. Corticosteroid injections may have some benefit in the short term, but adverse effects were reported very high . TherefoIf conservative treatments have no effect, surgical treatments should be considered. The goals of operation are removing degenerative tissue, stimulating tendon healing, and/or augmenting the Achilles tendon with auto- or allografts. Operative treatments seem to be a good option for Achilles tendinopathy patients, when conservative treatment fails. As the lower complication rate, quick recovery, and early return to high-level sports are after surgery, minimally invasive surgery is the primary operative treatment option , 6, suchHong-Yun LiHong-Yun LiYouichi YasuiYouichi YasuiSeung Hwan HanSeung Hwan HanWataru MiyamotoWataru MiyamotoYing-Hui HuaYing-Hui Hua"}
+{"text": "The affiliation for the first and third author is incorrect. Laura Treacy is affiliated with Nadheim Kirkens Bymisjon, Norbygata 45, 0190 Oslo, Norway. Mette Sagbakken is affiliated with Department of Nursing and Health Promotion, Faculty of Health Sciences, OsloMet\u2014Oslo Metropolitan University, Postboks 4 St. Olavs plass 0130, Oslo, Norway."}
+{"text": "Vitamin C deficiency is anecdotal in developed countries, mainly associated with underling clinical morbidities as autism or neurological impairment. Chronic insufficient dietary supply is responsible for vascular fragility and impaired bone formation, resulting in gingival bleeding, petechial lesions, articular and bone pain or limb swelling. Children may present anorexia, irritability, failure to thrive, limping or refusal to walk. Accordingly, pediatric scurvy is frequently misdiagnosed with osteomyelitis, septic arthritis, bone and soft tissue tumor, leukemia, bleeding disorders, and rheumatologic conditions. We report the case of a 3-years old child developing scurvy as consequence of strict selective diet; extensive and invasive investigations were undertaken before the correct diagnosis was considered. Despite being considered a rare condition, scurvy still exists nowadays, even in children with no apparent risk factors living in wealthy families. The increasing popularity of dietary restriction for children, especially those with allergies, may potentially enhance the occurrence of scurvy in apparently healthy children. Appropriate dietary anamnesis is fundamental in order to highlight potential nutritional deficit and to avoid unnecessary invasive diagnostic procedures. Patients without considerable risk factors may benefit from psychological support in order to investigate possible eating disorders. Scurvy is a well-defined clinical condition secondary to chronic ascorbic acid deficiency, currently anecdotal in developed countries. Neurological disorders, autism, iron overload due to multiple transfusions, chemotherapy, bone marrow transplant and hemodialysis are considered the main predisposing conditions in modern age , 2. The A 3-years Russian boy was admitted to our hospital for intense pain and recurrent swelling at left thigh, resulting in persistent refusal to walk. Medical history revealed a strict selective diet since weaning, mainly based on grain, rice and corn with almost complete avoidance of meat, fish, fruit and vegetables. Inadequate eating habits derived from child's refusal to try new food. Dairy products were also avoided due to presumed milk allergy; no vitamin supplementation was administered.Pathologic anamnesis documented the recurrence of nummular, erythematous and itchy rash from the age of 18 months onwards. At 2 years of age, also lower limbs arthralgia appeared, followed by left thigh swelling, refusal to walk and to eat. Due to progressive worsening in clinical conditions with severe pallor, dehydration, fever and serious asthenia, the child was hospitalized in his native country, where septic shock was initially suspected. He received blood cell transfusions, albumin and immunoglobulin infusion, antibiotics, inotropes and respiratory assistance. Dietary intake was provided through nasogastric tube and parenteral support; unfortunately, no data regarding nutritional supply are available. Lower limb CT-scan was performed, documenting areas of bone rarefaction and reabsorption, along with periosteal reaction and soft tissues edema. Bone biopsy excluded the hypothesis of osteomyelitis, suggesting instead the diagnosis of myosarcoma. Further hospitalization at Oncological Department followed, where complete laboratory/radiological work-up, bone marrow aspiration and additional muscular and bone biopsy definitively excluded malignancies. Magnetic Resonance imaging (MRI) highlighted focal changes in bone marrow of pelvic bones and thighs, soft tissue swelling and periosteal infiltration of femurs. A second muscular biopsy was undertaken, concluding for not specific \u201cproliferative myositis and productive vasculitis.\u201d Initial parenteral nutrition was administered, followed by enteral nutrition trough nasogastric tube. He was discharged in good general conditions and almost complete clinical remission. Afterwards, the child returned to habitual selective diet. After two months, arthralgia, intense pain and swelling of left tight with refusal to walk reappeared, requiring a second hospitalization course. Coagulation profile and Doppler ultrasound scan excluded thrombotic processes; severe osteoporosis was documented at bone densitometry. Due to the persistence of symptoms, he came to our hospital for second-opinion.2 (<5\u00b0). Dietary anamnesis highlighted selective and unbalance diet, mainly based on carbohydrate . Considering what reported by parents, we esteemed daily caloric intake ranging from 450 to 500 kcal/day [minimum for age: 880 kcal/day At admission, child's weight was 12 kg (<5\u00b0 percentile), height 92 cm (5\u201310\u00b0 percentile) and BMI 14,2 kg/mIn the modern age, scurvy has been reported in poor countries , 3 or inHumans, unable to produce Vitamin C, are entirely dependent on dietary supply. Its chronic deficiency leads to impaired collagen synthesis, determining vascular fragility and abnormal formation of osteoid tissue and dentin, but also affects hormonal synthesis and immune regulation.After 1\u20133 months of ascorbic acid deficiency, fatigue, irritability, malaise and anorexia appear. Skin hyperkeratosis, corkscrew hair, petechial hemorrhages, purpura and swollen bleeding gums are common findings. In childhood, musculoskeletal symptoms as bone pain, arthralgia, limping, refusal to walk, limb and joint swelling or pseudo-paralysis are typical presenting signs \u20138.Affected patients usually undergo extensive laboratory and radiological workup, and various misdiagnoses, including osteomyelitis, septic arthritis, malignancies, autoimmune diseases, venous thrombosis, bleeding disorders and child abuse, are commonly made \u201312. InteSerum determination of vitamin C levels is the gold standard for the diagnosis. Radiological examinations are complementary and reveal osteopenia, metaphyseal rarefaction, metaphyseal spurs secondary to healing fractures, metaphyseal dense line of cartilage calcification and round sclerotic cortex surrounding growth centers in the epiphysis , 9. As iNo specific regimen of treatment is defined in pediatric scurvy. Oral administration is adequate even in the most severe cases. Dosages can range from 100\u2013300 mg to 1000 mg/day in childhood. In our case, a dose of 500 mg/day for six days, followed by 300 mg/day in maintaining phase was administered, with dramatic clinical improvement within few days. Quick clinical response may be considered as ex-juvantibus diagnostic criteria , 14.Psychological evaluation was useful to understand the reason of child's feeding behavior, highlighting an abnormal relationship between mother and son and a related traumatic detachment event. Documented food allergic reactions probably worsened this condition.Scurvy still exists nowadays, even in children with apparent no risk factors living in wealthy families. The increasing popularity of dietary restriction for children, especially those with allergies, may potentially enhance the occurrence of scurvy in presumably healthy children.Appropriate dietary anamnesis is fundamental in order to highlight potential nutritional deficit and to avoid unnecessary invasive diagnostic procedures. We suggest collecting a detailed dietary history in all children, with special attention to caloric, macro- and micronutrients intakes, since adequate diet influences child's growth, cognitive development and diseases prevention. Psychological support may be helpful to exclude abnormal eating disorders in selected clinical setting.AB, CP, and ST gave a substantial contribution in article conception and design. LL, DL, and MR participated in acquisition of data. AB, CP, and DL drafted the manuscript; ST, LL, and MR critically revised it. All the authors gave their final approval to this manuscript and agree to be accountable for all aspects of work ensuring integrity and accuracy.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Dear Editor,A previously healthy 22-year-old female sought medical attention, complaining ofproductive cough and hoarseness. She reported no other respiratory or constitutionalsymptoms. Physical examination revealed discrete stridor. For diagnostic clarification,computed tomography (CT) of the chest was performed The CT scan showed grouped,branching centrilobular opacities, with the \"tree-in-bud\" aspect, suggesting distalbronchiolar filling. The trachea and left main bronchus presented irregular internalcontours, with nodular thickening of the walls , togethe-3.Tracheobronchial tuberculosis mainly affects younger, female patients, its incidencepeaking in the third decade of life. The disease can affect the greater part of thetrachea, also affecting the bronchi, or it can affect just a small segment of thetrachea or of one bronchus,5. The clinical presentation can beinsidious, simulating bronchogenic carcinoma, or acute, with a profile similar to thatof asthma, foreign body aspiration, or pneumonia. In most cases, patients withtracheobronchial tuberculosis present a productive cough, hemoptysis, chest pain,generalized weakness, fever, dyspnea and bronchorrhea,3. In cases thatare more severe, there can be acute tracheal obstruction. The main complications are fibrotic scarring andtracheobronchial stenosis, an accurate diagnosis and early treatment beingcrucial.In patients with tuberculosis, tracheal involvement is relatively uncommon, occurring inonly 4% of those with the endobronchial form of the disease,7-12.The differential diagnoses include other diseases affecting the trachea, not only thosepresenting localized involvement- such as primary tracheal neoplasms, injuries oftraumatic origin, and some infectious diseases-but also those presenting diffuseinvolvement-amyloidosis, tracheobronchopathia osteochondroplastica, relapsingpolychondritis, laryngotracheobronchial papillomatosis, tracheobronchomegaly,neurofibromatosis, Wegener's granulomatosis, lymphoma, andparacoccidioidomycosis-19. In thestudy of the trachea, imaging studies comprise X-rays and, primarily, CT of the chest,which can show irregular, circumferential narrowing of the lumen, with or withoutmediastinitis. In fibrotic disease, the lumen is smoother and the wall is not thickened.Lymphadenopathy is generally associated with active tuberculosis,6.Imaging studies have become increasingly important in the evaluation of chest diseases,as recently noted in the radiology literature of Brazil. Although the gold standard for thediagnosis of tracheobronchial tuberculosis is the finding of granulomas in thetracheal/bronchial mucosa, a diagnosis based on imaging findings and sputum positivityis accepted and enables immediate treatment.Bronchoscopy can reveal inflamed mucosa, submucosal granuloma or polyp, ulceration,hypertrophy, or cicatricial stenosis; histologically, tracheobronchial tuberculosis canbe identified the presence of giant cell granuloma and caseous necrosisMaking a diagnosis of tracheobronchial tuberculosis requires suspicion, and it isnecessary to correlate the clinical manifestations with the radiological findings. Earlydiagnosis and treatment can avert the complications of the disease."}
+{"text": "Corynebacterium, Gordonia, Mycobacterium, Nocardia, Rhodococcus, Tsukamurella, Skermania and WilliamsiaWilliamsia was introduced in 1999 by K\u00e4mpfer et\u00a0al. Rhodococcus and Gordonia. Members of the genus Williamsia are Gram-positive, aerobic, rod and coccoid shaped, smooth and orange-red pigmented (in some species) colonies and not acid-fast bacteria, and consist of straight-chain saturated, unsaturated and 10-methyl-branched components that currently comprise 11 recognized species which have been isolated from human clinical specimens and environmental resources Actinomycetes that have mycolic acid in the cell walls have been classified under genera such as Williamsia deligens, W.\u00a0muralis and W.\u00a0serinedens have been isolated from immunocompromised patients with diabetes mellitus, as well as elderly patients. The most commonly reported sources of Williamsia infection include pulmonary infection Williamsia serinedens is able to grow in oil-contaminated soil; this bacterium is likely to be effective in the biodegradation process and in the decomposition of industrial pollution from soil l-Alanine, acetamide, arginine, gelatin, ornithine, proline and serine are utilized as carbon and nitrogen sources. Adsorption of acetate, 2,3-butandiol, citrate, mannitol, paraffin, sorbitol, trehalose, adonitol, adipate, isoamyl alcohol, l-arabinose, cellobiose, meso-erythritol, m-hydroxybenzoate, p-hydroxybenzoate, myo-inositol, lactate, melezitose, 1,2-propandiol and carbohydrates as carbon sources are usually labor intensive and time consuming. Further, many reports of Williamsia infection are usually misdiagnosed as Rhodococcus and other actinomycete infections; thus, analyzing whole fatty-acid cell walls via molecular methods (such as DNA hybridization techniques and 16S rRNA gene sequencing) is a rapid, accurate and reliable method for identifying actinomycete infections, especially Williamsia infection According to reports, Williamsia. The best antibiotic antimicrobial test is microbroth dilution, as presented by the Clinical and Laboratory Standards Institute Williamsia spp. are resistant to ampicillin, oxacillin, erythromycin and trimethoprim/sulfamethoxazole but susceptible to amoxicillin/clavulanate, cefotaxime, imipenem, ciprofloxacin, tobramycin, gentamicin, cotrimoxazole, amikacin, linezolid, meropenem, penicillin G and vancomycin Not much information about susceptibility to antimicrobial drugs is available for the genus Williamsia spp. is limited. On the basis of previous reports, this group of aerobic actinomycetes comprise opportunistic microorganisms that cause a variety infections in immunocompromised patients. Given that the pathogenic virulence factors and antibiotic resistance of Williamsia are unknown, it is necessary to clarify its features to permit appropriate identification, treatment and management.In summary, our knowledge of the isolation and identification of different None declared."}
+{"text": "Lobular capillary haemangioma (LCH), previously known as pyogenic granuloma, is a benign vascular lesion commonly found within the oral and nasal cavity. However, it is rarely encountered within the trachea, where presenting features include recurrent haemoptysis, cough, and wheeze. We here describe a case of a 7\u2009mm tracheal LCH in a 56-year-old woman, which was successfully resected at interventional bronchoscopy using biopsy forceps. Clinicians should be aware of tracheal LCH in the differential diagnosis for recurrent haemoptysis. Tracheal tumours represent only 2% of all upper respiratory tract tumours . Those iA 56-year-old Caucasian woman was referred to our institution with several episodes of mild haemoptysis over the preceding three months. She denied associated chest pain, exertional dyspnoea, dysphagia, syncope, weight loss, anorexia, fever, and rigors. There was no history of airway instrumentation or foreign body aspiration. Her medical background included laparoscopic sterilisation, oesophagitis, meningitis, and hypertension. She was a nonsmoker and consumed alcohol within normal limits.1 3.50\u2009L and FVC 3.85\u2009L. Computed tomography (CT) scanning (Physical examination was unremarkable and routine blood investigations and chest radiograph were normal. Pulmonary function was satisfactory with FEVscanning  demonstrHistological examination  of the sTracheal tumours account for less than 2% of all upper respiratory tract tumours  and are Lobular capillary haemangioma is a benign lesion characterised microscopically by a distinctive lobular arrangement of capillaries in an oedematous, fibroblastic stoma , 3, 6. TThe surface epithelium is often ulcerated, predisposing to invasion by microorganisms. Commonly found on the lip, nose, oral cavity, and tongue , 4, occuAlthough the precise aetiological mechanisms accounting for LCH are not yet fully ascertained, traumatic insults, hormonal imbalances during pregnancy, viral and bacterial infections, microscopic arteriovenous malformations, angiogenic growth factors, and cytogenetic abnormalities have been proposed as causative factors.Chest radiography and computed tomography findings may be inconclusive, and thus bronchoscopy with biopsy plays a key role in diagnosis of tracheal LCH, whilst additionally affording the opportunity for therapeutic intervention. Endoscopic appearances are nonspecific and may mimic adenoma, carcinoma, or carcinoid tumour. For this reason, decision for surgical resection should be avoided until a definitive histopathological diagnosis is established.The extent and size of the lesion, as well as patient age and comorbidities, require consideration prior to any therapeutic intervention for LCH. Despite their benign nature, local recurrence is common and thus surgical excision remains the treatment of choice. Nevertheless, mucocutaneous LCH is also amenable to various nonsurgical techniques including snare electrocautery, cryotherapy, YAG laser therapy, and plaque radiation. In the present case, we were able to safely remove the culprit lesion with biopsy forceps alone and with minimal bleeding owing to its small vascular pedicle.To our knowledge, there are only 14 reports of tracheal LCH in English medical literature to date . Irani eIn conclusion, LCH is a benign lesion rarely found within the trachea. Common presenting features may include recurrent haemoptysis, cough, and wheeze. Symptomatic lesions are usually amenable to direct evaluation and removal via interventional bronchoscopic techniques."}
+{"text": "November 17\u201321, 2014, marks the first annual Contact Lens Health Week. In close collaboration with partners from clinical, public health, industry, and regulatory sectors, CDC has developed a campaign to promote healthy contact lens wear and care practices that can help reduce the risk for eye infections and complications associated with poor contact lens hygiene.Microbial keratitis is a serious, sometimes blinding, eye infection often associated with poor contact lens hygiene. CDC has published a report on the first estimate of the burden of keratitis, including microbial keratitis, and contact lens disorders in the United States, using data from national outpatient and emergency department databases . The rephttp://www.cdc.gov/contactlenses.Established, modifiable risk factors for microbial keratitis, such as overnight contact lens wear, poor contact lens storage case hygiene, and infrequent storage case replacement ,3, indic"}
+{"text": "In adults, low ejection fraction (<30\u201335%), global peak systolic strain <-7.6%, increased EDV, ESV, LBBB, diastolic dysfunction, and left ventricle dyssynchrony were the main independent risk factors for major cardiac events and need for CRT or transplantation . Our conclusions were that in children and adults, DCM is a diverse disorder with outcomes that depend largely on cause, age, heart failure status at presentation, and echocardiographic parameters of the heart . This study will present new findings in the diagnostic area.Dilated cardiomyopathy (DCM) is the most common form of cardiomyopathy and cause of cardiac transplantation in children and young adults; mortality is high among this patient population. However, mortality, clinical course, and illustrative echocardiographic data of DCM in children and adults are not well established. Our objective was to provide a research article of detailed descriptions of the incidence, causes, outcomes, related risk factors, and new echocardiographic criteria of risk of death from DCM. Our results showed that independent risk factors at DCM diagnosis for subsequent death or transplantation in children cohorts were older age, congestive heart failure, lower left ventricular ejection fraction (EF \u2264 25%), low global strain, significant mitral valve incompetence, pulmonary hypertension, diastolic dysfunction, right ventricular involvement, and cause of DCM ("}
+{"text": "Quality of life (QOL) is an important clinical endpoint, but it remarkably varies in patients with similar neurological conditions. This study explored the role of spirituality  in determining QOL in chronic neurological disorders.~Seventy-two patients with epilepsy, brain tumours or ischemic or immune-mediate brain damage compiled inventories for QOL (WHOQOL 100), spirituality , depression , anxiety , and cognitive self-efficacy  and underwent neuropsychological testing. With respect to 45 healthy controls, the patients reported worse QOL, with no difference between the four patient subgroups. Factor analyses of the WHOSRPB, STAI, and BDI scores and of the MASQ and neuropsychological test scores yielded four  and three factors , respectively. Mood, Cognition, Inner Energy, schooling, and subjective health status correlated with the WHOQOL scores, but at regression analysis only Mood and Inner Energy predicted QOL. This suggests that spirituality, as a personal dimension distinct from mood, contributes to determine QOL. A multidimensional assessment of QOL, including personal facets, may explain differences between patients with chronic neurological disorders."}
+{"text": "Utilizing Daniel Goleman's theory of emotional competence, Beck's cognitive theory, and Rudd's cognitive-behavioral theory of suicidality, the relationships between hopelessness (cognitive component), social problem solving , emotional competence (emotive component), and adolescent suicidal ideation were examined. Based on the responses of 5,557 Secondary 1 to Secondary 4 students from 42 secondary schools in Hong Kong, results showed that suicidal ideation was positively related to adolescent hopelessness, but negatively related to emotional competence and social problem solving. While standard regression analyses showed that all the above variables were significant predictors of suicidal ideation, hierarchical regression analyses showed that hopelessness was the most important predictor of suicidal ideation, followed by social problem solving and emotional competence. Further regression analyses found that all four subscales of emotional competence, i.e., empathy, social skills, self-management of emotions, and utilization of emotions, were important predictors of male adolescent suicidal ideation. However, the subscale of social skills was not a significant predictor of female adolescent suicidal ideation. Standard regression analysis also revealed that all three subscales of social problem solving, i.e., negative problem orientation, rational problem solving, and impulsiveness/carelessness style, were important predictors of suicidal ideation. Theoretical and practice implications of the findings are discussed."}
+{"text": "Sir,In a prospective cohort study of postmenopausal women with cancer , and a growing interest has been paid in their immunomodulatory effect, which may promote atherosclerotic plaque stability, but also hinder the host anti-tumour immune response, therefore, increasing cancer risk in certain segments of population , cancer Therefore, although the protective effect of higher cholesterol levels on cancer risk may not completely represent an etiologic link, the study by"}
+{"text": "Rhubarb is one of the most ancient, commonly used and important herbs in Chinese medicine. The modern researches of rhubarb clarified the efficacies, ingredients and mechanisms in a more scientific and rigorous way. The main chemical compositions of rhubarb include anthraquinones, anthrones, stilbenes, tannins, polysaccharides etc. These compositions show extensive pharmacological activities including regulating gastrointestinal, anticancer, antimicrobial, hepatoprotective, anti-inflammatory, protecting cardiovascular, cerebrovascular and so on. This paper reviews the recent studies on the active ingredients, pharmacological effects, clinical application and functional mechanism. Rheum L. from Polygonaceae family. This plant has important economic value, not only referred to a few edible rhubarbs [Shen Nong\u2019s Herbal Classic. Rhubarb has been suggested to exert eliminating heat, purging fire, cooling blood, dispersing blood stasis, dredging collateral antidotal and purgative effects, used to treat constipation, diabetic nephropathy, chronic renal failure, acute pancreatitis, gastrointestinal bleeding and other diseases [Rhubarb is a collective name of various perennial plants of the genus rhubarbs , but alsrhubarbs , firstlydiseases .There are articles summarizing the research progresses of rhubarb on treating acute organophosphorus pesticide poisoning , acute iBack in the early years of the nineteenth century, the chemical compositions of officinal rhubarb had been researched . In receAnthraquinones are the main characteristic as well as pharmacodynamic ingredients of rhubarb , 11. TheRhein has the ability of protecting kidney , inhibitEmodin has a wide range of pharmacological effects, including anti-tumor , anti-miChrysophanol has a protective effect on the nervous system, improving the activity of antioxidant enzyme, reducing the damage of oxygen free radicals to cells .Physcion also has neuroprotective effect, inhibiting the inflammatory response after cerebral ischemia and reducing the nerve damage caused by reperfusion . BesidesAloe-emodin, another important active compound of rhubarb, has attracted much attention, due to its various effects such as cardiovascular protection, hepatoprotective activities, anti-tumor, antibacterial, antifungal, antiviral, anti-inflammatory, immune regulation, laxative , 25.Anthraquinone glycosides process the characteristic of antioxidant, anticancer, anti-inflammatory, laxative and many others biological properties , laxativAnthrones and dianthrone, also characteristic components of rhubarb, are related to purgative activity. Mainly these include rheinosides A\u2013D, palmidin A, B, C, rheidin A, B, C, and sennosidin A\u2013F, etc. . 26 anthStilbenes are important components of rhubarb, concerning antihyperlipidemic, antioxidant and hepatoprotective effect , 27. So 2Cr2O7-injured rats by treating CrNT as a free radical scavenger [Since the 1880s, the discovery that rhubarb tannins reduced the content of BUN, sparked great interest and attention of scholars both at home and abroad. Tannins in rhubarb generally account for 10\u201330% . It can cavenger . The bas6 butyrophenones and 14 chromones have been isolated from rhubarb already. Lindleyin and Isolindleyin whose structures are showed at Fig.\u00a0Polysaccharides play multiple roles and have extensive bioactivities in life process, with an immense potential in healthcare, food and cosmetic industries, due to their therapeutic effects and relatively low toxicity . It has We list the main active ingredient groups, representative component and mainly pharmacological activity, showing the relationship between these components and effects. Rhubarb contains several different active ingredients. Each active ingredient often has different pharmacological activities, acting on multiple targets. One pharmacological activity may also be caused by a variety of ingredients. There is a synergistic effect among these components. The relationship is summarized in Fig.\u00a0Rhubarb has been used as a first-choice herb for constipation in clinic for thousands of years in China. Its purgative activity is definite. Processing can change the potency and efficacy of Chinese herb. The purgative activity is different in raw rhubarb and its processed products .Escherichia coli restrained, the purging effect of sennoside A and C weaken, anthrone in the colon is also greatly reduced [Active ingredients and mechanism of purgation: Combination anthraquinones, including sennosides, rheinosides and anthraquinone aglyconesa, are considered as the main bioactive constituents of the laxative effect , 36, pla reduced . When th reduced . Most of reduced . The rhu reduced . It also reduced . Besides reduced . Sennosi reduced . The mec reduced , 44, 45.Liver-protective function is an important part of studies on rhubarb in recent years. Rhubarb anthraquinones and tannins have a biphasic effect on liver, protection and damage. Anthraquinones showed stronger improvement on liver fibrosis and liver cell injury than tannins, and high dose tannins may injury liver in some extent . RhubarbRhubarb not only processes the effect of hemostasis but also improves hemorheology, stopping bleeding without leaving congestion. Charred rhubarb significantly improved the plasma viscosity, hematocrit, FIB, PT, APTT and TT in the acute blood stasis rats , owning +-K+-ATPase, to increase the plasma osmotic pressure, leading the water in the organization transferring into the blood vessels, increasing blood volume, helping with relieving microcirculation disturbance [Mechanism of promoting blood circulation and Hemostasis: It is confirmed that chrysophanol and tannin are associated with the hemostasis effect. Chrysophanol can short the time of clotting, increase the number of platelets, promote blood coagulation in mice and tannin has a convergence effect, to promote local vasoconstriction . Zhang fturbance .Rhubarb has the effect of preventing and treating high blood lipids, reducing the TC, LDL, TG levels caused by high fat diet . RhubarbMechanism of hypolipidemic: It promotes the excretion of cholesterol, improves blood rheology characteristics, decreases the release of inflammatory factors to maintain the balance of fat metabolism, inhibits the synthesis of cholesterol and triglyceride to achieve the purpose of regulating blood lipids . Chen 5 found chKidney protecting effect of rhubarb is owing to the combination of various pharmacological activities itself. Rhubarb, with anti-bacterial, anti-inflammatory, enhancing immunization, diuretic, regulating metabolism and other effects, protects the damaged kidney tissue, promotes protein synthesis, speeds up the excretion of waste and so on . RhubarbMechanism of kidney protection: In recent years, the renal protective effect of rhubarb  and its 2 and cAMP in hypothalamus and down-regulate central body temperature [Rhubarb exerts an antipyretic effect by acting on the central nervous system. The mechanism of rhubarb antipyretic effect may be related to deduct the production of PGEperature . Chrysopperature . Besidesperature . Chrysopperature .Rhubarb is also used to treat acute respiratory distress syndrome in clinic. Rhubarb, combining with Shenfu injection, can improve the condition of patients with acute respiratory distress syndrome, such as improving organ dysfunction and respiratory mechanics index, increasing the oxygenation index, shortening mechanical ventilation time . RhubarbRhubarb has the effect of heat-clearing and detoxifying for its anti-inflammatory effects, used to treat inflammations caused by a variety of reasons. Rhubarb remitted the degree of auricular swelling and foot swelling in mice and rats, reduced total protein and LTB4 in airbag synovitis exudates .Mechanism of anti-inflammatory: Currently, studies of rhubarb anti-inflammatory mechanism are focused on its monomer components such as emodin, rhein and aloe-emodin. Eodin can reduce the level of IL-6 in periodontal tissue of periodontitis rats . Due to A number of studies have shown that the anthraquinones of rhubarb could inhibit the growth and proliferation of various cancer cells . Its extMechanism of antitumor: to determine and identify the possible molecular mechanisms of anti-cancer effect of rhubarb, medical practitioners focused on the free anthraquinones of rhubarb and emodin is the most frequently studied element among the active constituents. Firstly, emodin inhibited the proliferation of tumor cell and induced apoptosis. Liu  found emStaphylococcus aureus are often used on experiment because it is sensitive to rhubarb. Zhou [Staphylococcus aureus [It has been confirmed that anthraquinone derivatives of rhubarb have remarkable antibacterial activity on several experimental bacterial strains in vitro , 83. Starb. Zhou  proposeds aureus .Many studies showed that rhubarb and its active components principally refer to emodin and rhein, could ameliorate organ fibrosis including renal, liver, lung, pancreas, cardiovascular system and so on , 87.4, finding that emodin exerted anti-hepatic fibrosis effect for inhibiting the activation of hepatic stellate cell though up-regulation the expression of Smad7 and down-regulation the expression of \u03b1-SMA in liver tissue. Liu [Mechanism of anti-fibrosis: Xu  summarizsue. Liu  observedWith the deep research on rhubarb, a traditional diarrhea drugs, its clinical application is widened, not only used to treat the constipation, but also other diseases.Rhubarb has a significant diarrhea effect, used to treat constipation caused by various reasons on clinic \u201391. Yu fRhubarb is one of the most popular traditional Chinese herbs used in treating diabetic nephropathy (DN) and chronic renal failure (CRF) .A large number of related literatures reported that rhubarb was often used in conjunction with other drugs in the treatment of diabetic nephropathy. Liu  found thRhubarb soda tablets combined with Jinshuibao Capsule significantly reduced Scr and BUN levels in patients with chronic renal failure . Xiao 9 summarizRhubarb can promote the secretion and discharge of pancreatic juice, increase pancreatic juice flow. It is used to treat acute edema and hemorrhagic necrotizing pancreatitis .Rhubarb and mirabilite external application reduced the risk of abdominal distension and stomachache, reducing the probability of complications in patients with acute pancreatitis. The relevant laboratory indicators were closer to normal and the average hospital stay was significantly shorter .Rhubarb inhibited the inflammatory response, improved intestinal microcirculation and restored normal intestinal absorption, to exert the function of treating AP . The freRhubarb has hemostatic effect, used to treat gastrointestinal bleeding clinically. Conventional treatment combined with rhubarb powder exerting better therapeutic effect on the upper gastrointestinal bleeding by comparing control group and observation group . Tan fouIn addition to the above diseases, rhubarb is also used to treat a variety of liver and kidney diseases, gastrointestinal dysfunction, cancers, hemorrhoid, periodontitis and so on .It has been confirmed that rhubarb has varying degrees of toxicity on liver, kidney, gastrointestinal tract, reproductive system and blood systems, may possess teratogenicity and reproductive toxicity . It is tGastrointestinal toxicity of rhubarb characterized by diarrhea, constipation and melanosis . AnthraqYan  administ4 injured chronic hepatic injury, but had a certain hepatotoxic effect to normal animals.Animal experiments and clinical application confirmed rhubarb has hepatoprotective and choleretic effect. However, under certain conditions, rhubarb may damage liver . Wang 1 investigBesides, rhubarb is of reproduction toxicity. Wang  exploredRhubarb is one of the oldest and most frequently used herbal medicines in China, Korea, Japan, and other Asian countries. In this article, we summarize the active ingredients, pharmacological effects, functional mechanisms of rhubarb, as well as its clinical applications. There are about 200 compounds isolated from rhubarb, including anthraquinones, anthrones, stilbenes, flavonoids, acylglucosides, and pyrones. Most of the studies focused on exploring the bioactivities of anthraquinones. These constituents have shown extensive pharmacological activities, including cathartic, anticancer, hepatoprotective, anti-inflammatory, anti-microbial, analgesic effects and so on.Pharmacological effects of rhubarb are extensive. In clinic, it is used to treat various diseases, such as constipation, acute pancreatitis, gastrointestinal bleeding, DN, CRF and so on. But rhubarb is not suitable for long-term using to avoid producing toxic and side effects. It is an important direction for the development of rhubarb that reducing its toxicity, through compatibility, processing, changing the dosage or administration route et al., to play a better therapeutic role.Main active ingredients of rhubarb, rhein, emodin, chrysophanol and so on, have extensive pharmacological activities with low toxic and side effects, possessing good application prospects. At present, rhein is studied as a drug candidate to treat cancer. The potential anti-tumor mechanisms may block cell cycle, induce apoptosis and control metastasis. Some scholars are also committed to develop rhein as a new drug for diabetic nephropathy. Lindleyin whose pharmacological action is similar to aspirin, is expected to be developed as a new anti-inflammatory and analgesic drug. Developing and applying monomer compounds divided from rhubarb is another development direction of rhubarb."}
+{"text": "The Cronkhite\u2013Canada syndrome (CCS) is a rare disorder of unknown origin characterized by generalized gastrointestinal polyposis, alopecia, hyperpigmentation, and onychodystrophy. We report a case of CCS with concomitant presentation of mononeuritis multiplex. The electrophysiological findings and steroid responsiveness suggests presence of an autoimmune mechanism. The Cronkhite\u2013Canada syndrome (CCS) is a rare disorder of unknown origin characterized by generalized gastrointestinal polyposis, alopecia, hyperpigmentation, and onychodystrophy . PatientA 71-year-old man with previous medical histories of hypertension, hemorrhoids, and glaucoma first presented with weight loss, hair loss, abdominal colic, altered taste, and diarrhea for a 4-month duration. He denied having melena, hemetemesis, or blood in his stools.He also complained of having hypoesthesia and paresthesia in his hands and feet simultaneously 6\u2009months later. However, no pain, weakness, rashes, joint swelling, and fever were noted. His vision, speech, hearing, and smell sensation were unchanged.Clinical examination revealed he was not jaundiced, pale, or cachectic. His abdomen was soft and not distended. There was no palpable hepatosplenomegaly or lymphadenopathy.Neurological examination revealed mild motor weakness  of the finger abduction, ankle dorsiflexion, and plantar flexion, involving the left side more severely. However, deep tendon reflexes were diminished in both ankles and sensory testing revealed diminished touch and temperature sensation of both hands and feet. Vibration and position sense were intact. Gait and cerebellar system testing were normal.Hematological investigations performed initially showed normal blood counts and electrolytes, but hypoalbuminemia (5\u2009\u03bcmol/L) without transaminitis. Thyroid function, vitamin B12, and folate levels were unremarkable. Autoimmune tests, including antinuclear, anti-Smith, anti-smooth muscle, Ro, La, ribonuclear protein, anti-double stranded DNA, and anti-Jo1 titers were not elevated. Hepatitis B and C serology were negative.CT abdominal scan revealed few diverticula in the colon. CT colonoscopy, however, found extensive nodular appearance of the colonic mucosa and few polyps.The patient underwent endoscopic examination, whereby gastroscopy showed infiltrative lesions in the stomach and duodenum, while colonoscopy detected multiple strawberry-like hamartomatous polyps in the entire colon and occasional tubulovillous adenomas with low-grade dysplasia. Biopsies of the stomach, duodenum, and colon revealed regenerative and hyperplastic changes with prominent lamina propia odema and increased eosinophils.In view of his neurological complaints, he underwent a nerve conduction study (NCS) which showed asymmetrically reduced left peroneal sensory, right sural sensory, left peroneal motor, and left tibial motor amplitudes Tables  and 2. IHe was diagnosed with CCS based on the clinical picture and characteristic histological findings. He was given parenteral nutrition on initial diagnosis. Intravenous hydrocortisone of 100\u2009mg was administered four times a day, and maintenance oral prednisolone 50\u2009mg daily was continued when neuropathy was diagnosed on NCS.He experienced gradual improvement in gastrointestinal symptoms, taste, appetite, and body weight over a 2-year period. Oral corticosteroids were reduced gradually and azathioprine was added as a steroid-sparing agent. A repeat gastroscopy and colonoscopy revealed normalization of mucosal changes Figures  and 2. TA repeat NCS Tables  and 2, 2This report describes a CCS patient presenting with clinical and electrophysiological features of MM, which responded to steroid therapy in tandem with improvement of his gastrointestinal dysfunction. This simultaneous observation suggests that the neurological and gastrointestinal processes share a common pathophysiological process. The extensive investigations performed render nutritional and metabolic factors unlikely causes for his neuropathy. As his neurological symptoms appeared way after parental nutrition was administered, vitamin deficiency as a cause of neuropathy, hence, was unlikely. The impressive response to steroid therapy also supports the hypothesis that CCS is an immune-mediated disease.Mononeuritis multiplex denotes neuropathy of individual nerves not in a length-dependent or radicular pattern. Clinically, MM can present as asymmetrical, asynchronous sensory, and/or motor polyneuropathy involving two or more separate nerve in random patterns of distribution: bilaterally, distally, proximally, or combinations of these. Hence, it can also be termed as \u201cmultiple mononeuropathy,\u201d and autoimmune, paraneneoplastic, and diabetic etiologies are often implicated , 4. ElecWhile the exact incidence of etiologies in a cohort of MM patients has not be studied, MM is the most common pattern of involvement in vasculitic neuropathy, to the extent that both terms are often used interchangeably. Indeed, for primary systemic vasculitic neuropathy, up to 85% of cases with polyarteritis nodosa, 80% of cases with Churg-Strauss syndrome, and 40% of cases with Wegener\u2019s granulomatosis have vasculitic neuropathy. However, in several other connective tissue diseases, such as mixed connective tissue disease and sarcoidosis, vasculitic neuropathy occur at a much lower frequency .The cause of CCS is unknown to date. Previously reported associations include systemic lupus erythematosus, scleroderma, hypothyroidism, vitiligo, antinuclear antibodies, and mast cell dysfunction , suggestThe option of a nerve biopsy was discussed with our patient. Overall, its yield is approximately 60% , and samTo date, various treatment of CCS reported include dietary intervention, antibiotics, and immunosuppression, including steroids \u201313. HoweThis is the first reported case of steroid responsive MM in the CCS and significant recovery with steroid therapy suggests an autoimmune process underlying this condition.YL: manuscript preparation and clinical care. KL and XC: pathological inputs and clinical care. SM: manuscript inputs, clinical care.The authors acknowledge the conditions and report no conflicts of interest."}
+{"text": "Physical exercise physical and psychological health positive through various different avenues, as example, through affecting positively cognitive performance based upon the relocation of cortical activity which seems to advancing the brain development, connectivity and resilience . Any bodIt has been found that molecular, cellular and vascular regional brain plasticity \u201318 and nIn animal laboratory studies, wheel-running exercise reduced the self-administration of drugs, such as alcohol and nicotine, heroin and cocaine, and 3,4-methylenedioxypyrovalerone (MDPV), in rodents, which in turn were capable of devaluating the ability of the natural reward of exercise to maintain behavior \u201332. MaleThe influence of addictive drugs upon the immune system, e.g. reciprocal interaction between the opioid system and the neuroimmune functioning of health systems has been documented , incorpoIn conclusion, the present account outlines benefits of physical exercise, independent of type, duration or intensity, pertaining to general health, brain regional, behavioral and somatic integrity and quality-of-life among individuals and laboratory animals stranded in the mire of addictive behaviors, most especially drug abuse. Regular exercise regimes reinstate the modulatory influences of natural rewards through reparation of functional circuits appertaining reward sensitivity, conditioning and cognitive control , 60."}
+{"text": "A 37-year-old previously healthy woman presented with fever, headache, erythematous rash and joint pain. She did not experience cough, coryza, sore throat, diarrhea, nausea, or vomiting. Positive findings on physical examination included erythematous follicular macules and papules on the trunk and arms, swollen ankles and hyperemic sclera. We found a coincidental clinical finding: bilateral plantar deep cleft Radiography of the feet showed third and fourth metatarsal shortening along without osteodystrophic features. Laboratory tests revealed positivity for immunoglobulin M antibodies to Zika v\u00edrus. Blood count, electrolytes, serum measurements of calcium, phosphorus and parathyroid hormone were normal. The diagnosis of Zika virus infection was made and fortuitously, brachymetatarsia was identified. Brachymetatarsia is an uncommon condition of the foot characterized by shortening of the metatarsal of the foot and when present, it is usually asymptomatic. It can be either uni or bilateral and can affect any of the metatarsal bones. Brachymetatarsia may be congenital or idiopathic in etiology and may be associated with systemic diseases such as pseudo-hyperparathyroidism, Turner's syndrome, Down's syndrome, Apert syndrome, enchondromatosis, multiple epiphyseal dysplasia, sickle cell anemia and poliomyelitis. Brachymetatarsia may affect one or more metatarsals and may be unilateral or bilateral."}
+{"text": "Unfortunately, incorrect author affiliations were presented in the original version of this article . These aAn updated contact address for Shujin Wang has also been provided:Human and Animal Physiology, Wageningen University, De Elst 1, 6708 WD Wageningen, The Netherlands."}
+{"text": "The Competing Interests statement is incorrect. The correct Competing Interests statement is: The following authors hold or have held positions at the Benson-Henry Institute for Mind Body Medicine at Massachusetts General Hospital, which is paid by patients and their insurers for running the SMART-3RP and related relaxation/mindfulness clinical programs, markets related products such as books, DVDs, CDs and the like, and holds a patent pending  entitled \"Quantitative Genomics of the Relaxation Response\": MKB, JWD, GLF, HB, TAW."}
+{"text": "A 23-year-old man presented with progressive bulbar and oromandibular dystonia, in addition to distal limbs involvement. In neurological exam, the patient had diverse manifestations, most commonly movement disorder, cognitive impairment, ataxia and speech disorder. Other minor neurologic manifestations included pyramidal signs, psychiatric features, and gait disorders. He had no positive family history, and his parents were not relative. Calcifications in the brain computed tomography scan (CT scan) are seen primarily in the basal ganglia and in other areas such as the cerebral cortex .1 Symptoms may include deterioration of motor function, dementia, seizures, headache, dysarthria, spasticity, eye impairments, and athetosis.2 After ruling out the medical calcium metabolism abnormalities, FD is diagnosed by the presence of extensive bilateral symmetric intracranial calcifications and developmental defects.Fahr disease (FD) is a rare genetically dominant, neurodegenerative disorder characterized by idiopathic bilateral deposits of calcium in the striopallidodentate area.3The major differential diagnosis includes hypoparathyroidism. Bilateral symmetric calcification involving striatum, pallidum, dentate nucleus, thalamus, and white matter is reported from asymptomatic individuals to a variety of neurological conditions. The key point is that there is no known calcium metabolism abnormality in autosomal dominant or sporadic bilateral striopallidodentate calcinosis. Movement disorders, especially Parkinsonism is the most common presentation followed by cognitive impairment and ataxia.4Magnetic resonance imaging (MRI) is sensitive in detecting brain abnormalities; however, it is difficult to identify calcifications by routine MRI because calcifications. Therefore, brain CT scan is considered to be critical for detecting and localizing the extent of intracranial calcifications."}
+{"text": "To the Editor,Infections caused due to the HIV, HBV, and HCV are interrelated health conditions with similar behavioral determinants. In particular, Romania is significantly affected by these infections, with the largest pediatric HIV outbreak in Europe being reported during 1985-1992 . Informe"}
+{"text": "Although the causes have changed, scurvy (vitamin C deficiency) is still diagnosed in developed countries. We report a case of an 18-year-old female who presented to our emergency department with thrombocytopenia, sinus tachycardia, hypotension, fatigue, gingival hyperplasia, knee effusion, petechiae and ecchymosis in lower extremities. The differential diagnosis included hematologic abnormalities, infectious etiologies, vasculitis and vitamin deficiency. A brief dietary history was performed revealing poor fruit and vegetable intake, thus increasing our suspicion for vitamin C deficiency. This experience illustrates the importance of a dietary history and reminds us to keep scurvy in the differential diagnosis. Vitamin C deficiency, commonly known as scurvy, was originally a disease of sailors, related to extended periods of time on a ship with no access to fresh fruit or vegetables.This case describes a young female who presented to the ED with fatigue, dyspnea, gingival bleeding, scattered ecchymoses, knee swelling and petechiae. A dietary history revealed a limited intake of only specific foods raising a concern for vitamin deficiency. Other diagnostic considerations included coagulopathies, immune-mediated disorders, trauma, vasculitis, liver disease and malignancy. The clinical picture along with a low ascorbic acid (vitamin C) level confirmed the diagnosis of scurvy. This case highlights the importance of a wide differential and a dietary history, which can lead to quick resolution of a potentially fatal disease.An 18-year-old woman presented to the ED as instructed by her primary care physician for a laboratory abnormality of low platelets with specific concern for idiopathic thrombocytopenic purpura. One month prior to presentation to the ED, the patient noted some shortness of breath on exertion. Three weeks prior to presentation, she developed a rash on her legs, along with bruising, and right knee swelling that made it difficult to ambulate. She also endorsed increased fatigue, weakness, and bleeding from her gingiva. She had been seen several times previously by her primary care physician, but a diagnosis had not yet been discovered. The patient denied any recent trauma, fevers, weight or appetite changes, chest pain, cough, nausea, abdominal pain, constipation, diarrhea, bloody stools, hematuria, or menorrhagia.Her past medical history was significant for anxiety, depression, asthma and anorexia nervosa (since resolved) and specifically negative for coagulopathies. Her only medications included escitalopram and albuterol inhaler. Family history was noncontributory and specifically negative for coagulopathies, autoimmune disorders and leukemia. Social history was significant for a specific diet consisting of only peanut butter crackers, strawberry Nutri-Grain bars, and fish sticks. She denied tobacco, alcohol or illicit drug use.On physical examination, the patient was afebrile, hypotensive to 86/58 mmHg, tachycardic to 112 beats per minute, with a respiratory rate of 15 breaths per minute and an oxygen saturation of 100% on room air. She was pale and thin appearing, in no acute distress. Oral examination was significant for a region of gingival hyperplasia along the left upper gingival line , and petED laboratory results were significant for hemoglobin of 10.5 g/dL, a platelet count of 146 x 10/dL, iron of 32 mcg/dL, C-reactive protein of 34.2 mg/L and negative urine pregnancy test. The remainder of the laboratory studies including complete blood count, coagulation studies, complete metabolic profile, iron profile, urine drug screen, hepatitis panel, and iron profile were all within normal limits. Chest and right knee radiographs were also within normal limits. An arthrocentesis of the right knee joint revealed 600,000 red blood cells and 378 white blood cells. It was negative for crystals and organisms. The patient was admitted to the medicine service for further evaluation with a presumed diagnosis of vitamin C deficiency.While she was inpatient, laboratory studies demonstrated hematuria, new and worsening anemia and leukopenia, and persistent thrombocytopenia. Anti-nuclear antibody, direct antiglobulin profile, copper and vitamin D were all within normal limits. An ascorbic acid level was <0.1 mg/dL . Dermatology believed the patient\u2019s presentation to be consistent with vitamin C deficiency; however, she declined confirmatory biopsy of petechial lesions. The patient received vitamin C supplementation. After improvement of all laboratory values, she was discharged home to continue vitamin C and iron supplementation outpatient. Follow-up with the hematologist demonstrated vitamin C compliance and resolution of all symptoms.This non-ill appearing patient presented with tachycardia and borderline low blood pressure, fatigue, petechiae and scattered ecchymosis in lower extremities, gingival hyperplasia, and right knee effusion. The differential included the broad categories of hematologic abnormalities, vitamin deficiencies, trauma, vasculitis, liver disease, infection and malignancy.Hematologic abnormalities included idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, disseminated intravascular coagulation, hemophilia , and drug-induced thrombocytopenia. Vitamin deficiencies included vitamin K, zinc, and vitamin C (scurvy). Infectious causes included meningococcemia, Rocky Mountain spotted fever, and septic arthritis. Vasculitis causes included leukocytoclastic vasculitis and Henoch-Schonlein purpura. Idiopathic thrombocytopenic purpura, the original diagnosis of the referring physician, is a disease process of antiplatelet antibodies in which the patient does not appear ill. Although the patient has a decrease in his/her platelet count, all other hematologic parameters are normal. The presentation is one of easy and/or excessive bruising (purpura), petechiae , bleeding from gingiva, blood in urine, and unusually heavy menstrual flow.What do we already know about this entity?Scurvy is a disease of vitamin C deficiency secondary to poor nutritional intake causing anemia, fatigue, spontaneous bleeding, joint swelling, and gingival ulceration.What makes this presentation of disease reportable?This case was a rare presentation of scurvy in a young female presenting with petechia, purpura and a joint effusion to an emergency department in a developed country.What is the major learning point?Scurvy has significant morbidity and is still diagnosed in developed countries today, usually among patients with poor nutrition such as alcoholics, homeless, and those on fad diets.How might this improve emergency medicine practice?This reminds emergency providers of the importance of dietary history and to keep scurvy in the differential diagnosis.Thrombotic thrombocytopenic purpura is caused by clotting in small blood vessels due to endothelial defect. The disease presents with any variation on the pentad of microangiopathic hemolytic anemia, thrombocytopenic purpura, fever, neurologic abnormalities, and renal disease in an ill-appearing patient. The laboratory data should show anemia with schistocytes, mild increase in fibrin degradation products and possible increase in prothrombin time (PT) and partial thromboplastin time (PTT).Disseminated intravascular coagulation (DIC) is a diverse entity due to thrombin excess caused by systemic activation of blood coagulation that presents with clotting disorders. Accelerated fibrinolysis due to the clot formation may also actually cause severe bleeding. The patient will present ill appearing, most commonly from the underlying disorder that triggered the DIC. DIC will cause thrombosis, embolism, organ dysfunction (due to clotting) and bleeding. This severe consumptive coagulopathy will present with anemia, thrombocytopenia, elevated fibrin degradation factors, and elevated PT/PTT.Leukemia can present in a multitude of ways, depending on the type of leukemia, but common symptoms include fatigue, loss of weight, swollen lymph nodes, easy bleeding/bruising, petechiae, and bone pain. Hemophilia presents as bruising, excessive bleeding after cuts, pain and swelling in joints, blood in stool. This would be unusual as the patient was female, had no prior bleeding issues, and had no family history. Women with hemophilia are most commonly asymptomatic simple carriers. Hemophilia C occurs in both sexes, with mild symptoms, caused by insufficient clotting factor XI. Vasculitis  often presents with fatigue, fever, arthralgias and weight loss. The patient may present with sensory or motor deficits, vascular abnormalities, palpable purpura or petechiae. The diagnosis is based on a combination of involved organ systems, the size of vessels affected, and characteristics of testing results.Scurvy (vitamin C deficiency) presents with anemia, fatigue, spontaneous bleeding (bruising and petechiae), joint swelling (hemarthrosis), ulceration of the gingiva with gingival hyperplasia, and eventual loss of teeth. Modern cases of vitamin C deficiency are rare but usually found in alcoholic patients, isolated elderly patients, malabsorption syndromes, and people who voluntarily restrict their type of food intake. In addition to poor nutritional intake, alcoholic patients develop vitamin C deficiency secondary to increased excretion of vitamin C in the urine.2We rely on exogenous vitamin C from various foods in our diet, such as fresh fruits and vegetables . Fresh meat contains vitamin C; however, it is destroyed when the meat is cooked.6Scurvy progresses in four stages. The first stage is characterized by muscle pain and fatigue. The second stage shows gingival swelling with associated easy bleeding. The third stage reveals ulcerative gingivitis, non-palpable purpura and petechiae, and ulcers. The fourth stage is identified by multiple organ failure.7Scurvy is often taught as a historical disease and is rare in modern society. In this case, a primary care physician had left it off the differential diagnosis. Presentation of patients with petechiae and purpura is not uncommon in the emergency department and we need to keep scurvy on the differential. This case also highlights the importance of taking detailed histories (in this case of diet) to help increase or decrease the likelihood of a disease.Documented patient informed consent and/or Institutional Review Board approval has been obtained and filed for publication of this case report."}
+{"text": "The country owing to the large population of 30.70 million estimated numbers of sheep in the country and out of which about 72.14% are females, and 27.86% are males with diverse genetic resources. The real value of indigenous breeds was often under-estimated mostly due to their poor appearance and relatively low productivity. Developing countries in most cases opt for exotic breeds to increase animal productivity through crossbreeding or breed substitution without properly investigating the production potential of the indigenous breeds. The main objective of the research was to identify sheep flock composition and structure, farmers\u2019 traits of interest and breeding objective of Wollo highland sheep, and their FSmallholder farmers\u2019 flock synthesized from breeding ewes, breeding rams, pre-weaned ewe lambs, pre-weaned ram lambs, unproductive ewes, castrated and fattened rams, with the percentage coverage of 29.2, 13.3, 15.5, 16.5, 12.4, and 12.5%, respectively. The maximum number of flock size was 289.0 sheep per flock and higher in the third stratum. The off-take rate percentage of the three strata presented as 21.9% in 1st stratum, 12% in the 2nd stratum, and 16.4% in the 3rd stratum and higher off-take rate recorded in the first stratum. Sheep producer\u2019s traits of interest ranked by growth rate (first), body size (second) and marketing value was third rank. Communal breeding (random mating), village based controlled breeding, mixed type and private ram controlled breeding practice were comprised of 39.7, 61.7, 52 and 71.3%, respectively. The percentages of ewes per flock composition were presented as 36.5, 27.1 and 25.5%, respectively in the 3rd stratum, 2nd stratum and 3rd stratum in the order of their importance\u2019s.1 crossbred lambs and which designated for weaning rate, body size, marketing age, age at first lambing, good temperament and large litter size in the order of their rank. The contemporary breeding practice tendency indicated that, reduced flock size to improve flock productivity via crossbreeding practices.Genetic improvement practices at smallholder sheep producers situation was showing promising outcome with indigenous Washera F Smallholder sheep productions are the major source of food security serving a diverse function including cash income, savings, fertilizer, socio-cultural functions, and fiber production. Sheep are particularly important for farmers in the subalpine highlands 1&18] and pastoralist/agro-pastoralist where crop production is unreliable. Moreover, its socio-cultural important sheep resources had significantly contributed for foreign currency earning and which accounting for 34% of the live animal exports [&18 and pHence, sheep production is a major component of the livestock sector in Ethiopia owing to the large population of 25.4 million head . In the In spite of the large population of sheep and the role of sheep to both the livelihood of resource-poor farmers and the national economy at large. However, the current level of on-farm productivity in the smallholder production systems were low  due to vThe real value of indigenous breeds is often under-estimated mostly due to their poor appearance and relatively low productivity. As stated by Hodges , developTo analyzed existing flock size, and composition, farmer\u2019s traits of interest at smallholder farmers breed improvement practices.To assemble information on farmers\u2019 breeding strategies, breeding ram source, and breeding objectives at smallholder farming condition.The research project conducted in the two selected districts of South Wollo Zone of Amhara Region, Eastern Ethiopia. The geographical location delimited with Northern Shewa and Oromia region at the southern part, western Gojjam at western part, south Gondar at the north western part, North Wollo at the northern part, Afar Region at the northeastern part and Argobba district of Oromia Zone at the eastern part of the country Fig.\u00a0.Fig. 1MaDessie Zuria and Kutaber districts had populous sheep production area from other Districts of the administrative Zone. Even though, the livelihood economy depends on crop production, much more assist by livestock production and mainly with sheep, cattle, goat, and chicken production. The districts were historically chronic food insecure area for long years ago because of shortage of rain fail and drought infected area. Sheep sold to get immediate cash income through petty trading including buying, fattening, and selling practice.Jerry Oats) and vetch (Vicia sativa) and supplementation of non-conventional and conventional feed type. During crop harvesting times, however, sheep have access to feed crop aftermath. Some farmers give supplementation feed  for the pregnant and nursing ewes, suckling lambs and castrated rams. Their flock characterized by small, medium and large flock size of 1-13, 14-26 and 27 or more ewes/flock, respectively based on number of ewes per smallholder farmers\u2019 flock   but cont1crossbred progenies, Washera rams F1 crossbred progenies, and local Wollo highland progenies, respectively. The study areas classification performed by the assumption availability of \u00be Awassi and pure Washera rams and their F1 crossbred lambs, a comparable number of sheep population, agro-ecology similarity, flock management system, breeding strategies and farmers\u2019 breeding objectives resemblance. The main feats of data collection conducted through questionnaire survey, flock monitoring, participatory focus group discussion. Thus, producers\u2019 sheep flock size and composition, breeding objectives, sheep breeding strategies, and flock structure information gathered via questionnaire survey and group discussion.The study areas classified in to three strata. They are called as first, second and third strata and the first, second and third strata were comprised of Awassi rams FDessie-zuria and Kutaber Districts and six peasant association areas (four from Dessie-Zuria and two from Kutaber District) purposefully selected. The selected study areas\u2019 were based on infrastructure accessibility, sheep population, availability of Awassi rams, Washera rams, pure Wollo highland breed and crossbreeding practices and uniformity of existing breeding strategies. After the decision of household sample size each individual sampling unites was selected by purposive sampling techniques.Stratified probability proportional to size (PPS) sampling has the drawback of variable sample size, and different portions of the population may still be over or under-represented due to chance variation in selections. To address this problem, PPS combined with stratified approach used for representative sample size determination.1 crossbreed progenies, Washera rams F1 crossbreed progenies and local Wollo highland sheep were clustered in the first, second and third stratum, respectively. Then the sampling fractions from each stratum synthesized and sampled elements were drawn. First decided the stratum that has the smallest size then divided the size of each stratum by the smallest stratum [The study areas clustered into three strata. Thus, the sampling frame was drown from each stratum. Hence, the first, second and third strata consisted of 230, 370 and 675 household flocks as sampling frames, respectively. Awassi rams F stratum  and 12 o1 crossbred progenies and Awassi rams F1 crossbred progenies owners, respectively. In this way, the sample drawn as proportional to size stratified method from each stratum. According to this proportionality, the sampling ratio was calculated using addition of proportions (3\u2009+\u20092\u2009+\u20091), which gave as six, as value of total proportion. Finally, it divided to the smallest proportion, which equals to 1 by the total proportion of 6, and the sampling ratio were, 0.17\u22480.2 Thus, these proportions mean that; when 3 households drawn from local Wollo highland sheep breed owners, at the same time there should be 2 and 1 households draw from Washera rams F1 crossbred progenies. Similarly, 0.2*230\u2009=\u200946 household flocks selected from Awassi rams F1 crossbred progenies [1 crossbred progenies and 46 from Awassi rams F1crossbred progenies) randomly selected from the three strata.Then the elements of the sample drawn from each stratum were\u2009=\u20090.2*675\u2009=\u2009135 household flocks were selected from local Wollo highland sheep breed flocks. Whereas, 0.2*370\u2009=\u200974 household flocks selected from Washera rams Frogenies , 12. TheMultistage questionnaire survey used via semi-structured questionnaire and oral interview were held at each three strata household flock owners, development agents, experts, and animal health technician. The questionnaire initially pre-tested on key informants and adjusted before administrated for respondents. Stallholders sheep producer\u2019s flock characteristics data on average flock size, number of breeding ewes, breeding rams, pre-weaning ewe lambs, post-weaning ram lambs, unproductive ewes and castrated and fattened rams, annual off take rate , flock size and flock composition were gathered through questionnaire survey. While, participatory based focus group discussion data collection focused on breeding objectives, breeding strategies, farmer\u2019s traits of interest, trait selection criterion, current breeding practice and flock structure.1 crossbred progenies to compared and contrast each other. Smallholder sheep producers were also used phenotype performances evaluation of live animal\u2019s by body conformation, hair type, color type, drought resistance, disease resistance, marketing value, horn type, growth rate, temperament, tail type and body size were gathered through spot observation. Breeding ewe\u2019s selection criterion of lamb survival rate, mothering ability, temperament, lamb growth rate, parental history, drought tolerance, tail type, breed type, and body conformation gathered through spot observation at smallholder sheep producer\u2019s farm. Likewise, breeding rams selection criterions data on body size, body conformation, drought tolerance, marketing age, horn orientation, meat characteristics, growth rate, tail type, coat color, temperament, horn and hair type were also collected through on spot observation.On spot observation of phenotype performances data also gathered from Wollo highland sheep breed, Awassi and Washera rams FSingle-visit, multiple-subject survey approach with semi-structured questionnaire and oral interview used for each of the three strata household flock owners, development agents and agricultural office experts. The questionnaires initially pre-tested on key informants and adjusted before administrated for the actual respondents. Smallholder sheep producers\u2019 flock characteristics data, including flock size and composition, breeding ewes, breeding rams, pre-weaning ewe and ram lambs, unproductive ewes, castrated and fattened rams and annual off take rate  were gathered through questionnaire survey. While, participatory based focus group discussion data collection focused on breeding objectives, breeding strategies, farmers\u2019 traits of interest, trait selection criteria and current sheep breeding practice.On spot observation and group discussion, data collection method also applied to phenotype characteristic of live animals\u2019 surveillance of their body size, color type, horn type, hair type, body conformation, ear type, temperament and tail type of local Wollo highland sheep, Awassi and Washera crosses. Whereas, breeding ewes and rams selection criteria of lamb survival rate, mothering ability, temperament, lamb growth rate, parental history, drought tolerance, tail type, breed type, horn type and body conformation was gathered through spot on observation of live animals in smallholders\u2019 flock.Descriptive statistics of percentage, average, and graphical analytical procedures applied to compare the proportion of flock size, and composition, breeding strategies and ram breed source in the three strata. Conversely, average number of flock size, of breeding ewes, breeding rams, pre-weaning ewe lambs, unproductive ewes and castrate and fattened rams were analysed through their percentage and average values to recognize flock characteristics\u2019 of smallholder sheep producers. Other quantitative data such as breeding strategies was analysed by relative frequency, average, and percentages of descriptive statistics procedure. Tabular and graphical representations of results also performed accordingly.Smallholder sheep producer\u2019s breeding ewes and rams selection criteria of their breeding objectives were ranked. Phenotype traits of body conformation, hair type, color type, resistance, marketing value, horn type, growth rate, temperament, prolificacy rat, tail type, body size, age at first lambing, lambing rate and weaning rate were analyzed using index method of ranking analysis . BreedinWhere, Rn\u2009=\u2009value given for the least ranked level . Cn\u2009=\u2009Counts of the least ranked level  Musa et al. .The percentage composition of ewes, rams, pre-weaned ewe lambs, pre-weaned ram lambs, unproductive ewes, castrated and fatten males and annual off-take rate were presented in Table\u00a0Village community based control sheep crossbreeding practices were being adopted approach of genetic improvement practices. This strategies, mostly applied in the second stratum than the first and third strata Table\u00a0. VillageAll breeding strategies and strata had their own source of ram breed type. Owners interested ram breed types obtained from their own flock, donor project, purchased from local markets and government supply from nucleus farm (Debre-Brehan Breed Multiplication Research Center). In the first stratum of village, communities based controlled breeding practice local market source of ram was the most common practice, followed by project donation, government supplies, and own flock ram source type accordingly their order of importance. Similarly, the first stratum of private controlled, random mating and mixed type of breeding strategies most commonly ram source was local market, own flocks and local market, respectively. While, in the second stratum of village communities based control breeding, privately owned controlled, random mating and mixed type of breeding strategies their ram source were prominently characterized by market source, own flock and both market and own flock type, respectively. On the other hand, the third stratum of village based breeding, privately controlled, random mating and mixed type of breeding strategies were most commonly applied to purchases from market, project supplied, government supplied and own flock source of rams, respectively Table . Therefo, marketing value, twine rate, horn type, tail type and temperament traits were prioritized accordingly their order of importance and presented in Table\u00a0On-farm smallholder sheep producers comprised their own production objectives and traits of interest. In the current study first farmers were listed their interested type of traits and then each traits were ranked accordingly. Both productive and reproductive traits were the major crossbreeding goal at smallholder farming conditions. Accordingly producer\u2019s trait selection criterion; growth rate, body size, weaning rate, body conformation, age at first lambing, lambing rate, drought resistance, color type, disease resistance, hair typeGrowth rate, body conformation, and weaning rate traits selected by smallholder producers for sheep productivity potential improvement objectives. Therefore, farmers evaluated their live animals\u2019 productivity on the conceptual perceptive of fast growth performance, large body fram and the rate of weaned from the dam Table . Hair, cPerformance of drought and disease resistance considered with the potential capacity of the animals, which resist and recovered after disease and drought occurrence. Prolificacy rate, age at first lambing, lambing, and weaning rate attributes were preferred as reproductive performance improvement traits of interest. Thus, twin birth type, fast age at first lambing, short lambing interval, and fast weaning rate traits of ewes and rams were particular attributes for breeding objectives. Generally, smallholder sheep producers were select their interested traits with the impression of productivity, marketing and reproductive performance improvement practice of their animals.Average flock size was the major determinant factors of sheep reproductive and productive performance, income and wealth value, selection intensity, and grant for household activities. It\u2019s a long history of traditional on-farm sheep producers were more interested in the number of animals rather than their productivity performance improvement anticipation. The overall mean number of flock size in the current study had considerable difference between the three strata Table . HoweverRelated to the present study, Gizaw et al.  revealedFlock structure/composition defined as the proportion (in terms of head) of the flock of sheep, which formed by different age and sex classes of animals. Flock composition in terms of age and sex classes taken as an indicator of production objectives of the owner and the production system of a given flock. Therefore, flock structure and composition was composed of the number of ewes, rams, pre-weaned ewe lambs, pre-weaned ram lambs, unproductive ewes, castrated and fattened rams in the flock Table . The numIn the present study, relatively larger proportion of breeding ewes per flock were observed and compared with previous result reported by Niftalem , Abebe , TesfayeAccording to Taye et al. , the lar, twin rate, horn type and tail type were ranked in the order of their importance (Table It the current study important attributes of producer\u2019s breeding objectives were described and ranked by growth rate, body size, weaning rate, body conformation, age at first lambing, lambing rate, drought resistance, color type, disease resistance, hair typece Table . Kosgey ce Table .According to Fewson , breedinYadeta et al.  recentlySheep breeding strategies in the current study were characterized by village community based controlled breeding, privately owned controlled breeding, random mating and mixed type of breeding strategies Table . In thisIn agreement with the present finding, Gizaw et al.  revealedThe average flock size of Wollo highland smallholder\u2019s sheep producer context had larger size but becoming decreasing than the previous report. Therefore, the reason behind this might be due to shortage of feed, producers\u2019 awareness to change large flocks to small flock size. The other reason might be due to productivity and reproductive performance improvement strategies, grazing land limitation, and increasing frequency of prevailing drought occasion infected areas.Smallholder sheep producers\u2019 traits of interest represented by body size, color type, growth rate, breed type, and horn type for breeding rams\u2019 performance evaluation criteria. On the other hand, body size, cot color and lamb survival rate, lambing interval, twin rate and milk yield traits were used breeding ewes selection criteria. The current study sheep breeding strategies characterized by village controlled breeding, private owned controlled breeding, indiscriminate mating and mixed type of breeding strategies. Currently, smallholder sheep producer\u2019s attempt to achieve their breeding objectives through introduction of new superior performance indigenous breed rams for crossbreeding with locally available breeds.Smallholder farm flock productivity improvement program should be designed for long-term plan using producers\u2019 traits of interest to bring together their production objectives.All farmers\u2019 interested traits have to be organize accordingly their significance and considered through breeding practices and need further investigation for their economical values."}
+{"text": "Postpartum mood disorders can negatively affect women, their offspring, and their families when left untreated. The identification and treatment of postpartum depression remains problematic since health care providers may often not differentiate postpartum blues from depression onset. Recent studies found potentially new risk factors, etiologies, and treatments; thus, possibly improving the untreated postpartum depression rates. This integrated review examined several postpartum psychiatric disorders, postpartum blues, generalized anxiety, obsessive compulsive disorder, post-traumatic stress disorder, and postpartum psychosis for current findings on prevalence, etiologies, risk factors, and postpartum depression treatments."}
+{"text": "Dear Editor,A 3-year-old male child who had developed bilirubin encephalopathy in the neonatalperiod, due to Rh incompatibility, presented with delayed neuromotor/psychomotordevelopment and involuntary movements. The prenatal and perinatal periods had been freeof complications. Serology for cytomegalovirus, toxoplasmosis, and HIV were negative, aswas the VDRL test. The results of a complete blood count, serum ceruloplasmin,electrolytes, and thyroid function were all within the limits of normality. Magneticresonance imaging (MRI) of the brain showed bilateral, symmetrical hyperintense signalson FLAIR and T2-weighted sequences, affecting the globus pallidus and subthalamicnuclei, with no mass effect, with no diffusion restriction or evidence of gadoliniumenhancement . Those i-5. Kernicterus,also known as bilirubin encephalopathy, is a rare complication of hyperbilirubinemia inchildhood, occurring when serum bilirubin levels in the neonate are in excess of 20mg/dL at term or even lower values in premature infants, which result in bilirubindeposition in the globus pallidus, subthalamic nuclei, hippocampus, putamen, thalamus,and cranial nerves, primarily the third, fourth, and sixth cranial nerves. Symptoms include drowsiness,hypotonia, opisthotonus, rigidity, and seizures. The factors involved in itspathogenesis are hyperbilirubinemia, reduced serum bilirubin binding capacity, changesin the permeability of blood-brain barrier, and neurotoxicity. Although the main causesof kernicterus are ABO and Rh mismatches, it can also be caused by sepsis and othertypes of hemolytic anemia such as glucose-6-phosphate dehydrogenasedeficiency. The clinicalsymptoms and signs can regress completely if properly treated with phototherapy andblood transfusions; withouttreatment, permanent damage can occur, generating encephalopathy with symptoms relatedto the basal nuclei, including involuntary movements, asymmetric spasticity, rigidity,ataxia, and hearing loss.Recent studies conducted in Brazil have highlighted the importance of MRI studies toimproving the diagnosis of central nervous system disorders,9-11, corresponding to the areas ofpreferential deposition of unconjugated bilirubin, characterizing chronic kernicterus,as in the case presented here.The MRI findings in kernicterus are characterized by a hyperintense signal on T1-weightedsequences in the globus pallidus, progressing chronically to a shift from a hyperintensesignal on T1-weighted sequences to a bilateral, symmetrical hyperintense signal onT2-weighted and FLAIR sequences in the globus pallidus and subthalamic nuclei,12,13.There is a broad spectrum of diagnoses of bilateral lesions in the basal ganglia in thepediatric population. The main causes cited are hypoxic-ischemic encephalopathy;hypoglycemia; encephalitis; inborn errors of metabolism; water and electrolytedisturbances; carbon monoxide poisoning; and demyelinating disorders. The correlationwith clinical and laboratory data is fundamental for making the definitivediagnosisIn conclusion, the possibility of acute or chronic kernicterus should be considered whenclinical symptoms, biochemical data, and MRI findings are suggestive of the disease, thechronic presentation and permanent, irreversible profile being promoted by bilirubinneurotoxicity."}
+{"text": "Multicentric Castleman disease (MCD) is a rare nonmalignant lymphoproliferative disorder presenting systemic symptoms such as fever, night sweats, fatigue, anemia, effusions, and multifocal lymphadenopathy. The etiology of MCD has not been clarified to date. The coexistence of MCD with chronic myelomonocytic leukemia (CMML) has been rarely reported. Although the pathogenesis remains unclear, this association probably reflects an incidental and fortuitous finding rather than the alteration of a common pluripotent stem cell precursor. Herein, we report on one case of MCD coexisting with CMML and elucidate the underlying mechanism of pathology in some aspects. MCD is a rare polyclonal B lymphoproliferative disorder that straddles the intersections of hematology, oncology, rheumatology, and virology. MCD manifests with a heterogeneous group of disorders with various etiologies that demonstrate episodic systemic inflammatory symptoms, reactive proliferation of morphologically benign lymphocytes, and multiple organ system impairment , 2.Chronic myelomonocytic leukemia (CMML) is a clonal stem cell disorder with features that overlap those of myelodysplastic syndromes (MDSs) and myeloproliferative neoplasms (MPNs) with a variable but overall poor prognosis. It occurs almost exclusively in the elderly with a median age at diagnosis varying between 65 and 75 years. Similar to MDS, the pathogenesis of CMML appears to be multifactorial and linked to altered genetic, molecular, microenvironmental, and immunologic state in different individuals.Patients with MCD have a significantly high risk of developing severe pancytopenia, multiorgan failure, and lymphoma compared with healthy controls . On the The patient, a 44-year-old woman, was admitted to our center in December 2011 suffering from cough, asthma, and asthenia. Peripheral blood studies showed severe iron-deficiency anemia, elevations of C-reactive protein, and polyclonal hypergammaglobulinemia. Computed tomogram demonstrated diffuse  lymphadenopathy, interstitial pneumonitis, and splenomegaly , and mild leukocytosis , while monocytes were at normal levels. Bone marrow (BM) study showed an increased number of megakaryocytes, and myeloid series hypercellularity and dysplastic change were evident. Abdominal CT showed severe splenomegaly and multifocal and wide-area infarction. Subsequently, she underwent laparoscopic splenectomy, and the pathological section demonstrated the structural breakdown and significant hypercellularity , especially peripheral blood monocytes , which was still accompanied by decreased platelet counts  and anemia . At this period, BM examination was again performed and revealed a significant increase in monocytes (12%) and prominent dysplastic changes in myeloid lineages. High expression levels of CD13, CD33, CD14, CD64, and CD56 were detected in her bone marrow cells. The karyotype was normal, and BCR/ABL fusion gene was not detected by the fluorescent in situ hybridization. At the same time, molecular studies were negative for TET2, SRSF2, ASXL1, and SETBP1 mutations, which are reported in about 90% of patients with CMML. According to World Health Organization (WHO) classification, a diagnosis of CMML and MCD, which were simultaneously present, was made. Then, she received front-line treatment with decitabine  for CMML. Surprisingly, after just one cycle, the WBC count had declined to 15,000/\u03bcL and the Hb increased to 9.0\u2009g/dL and PLT to 220,000/\u03bcL . Continued monitoring of routine blood count showed normocytic normochromic anemia , severe thrombocytopenia . Given the overlap with MDS and MPN, management and response evaluation for patients with CMML is often extrapolated from these diseases. However, internationally validated treatment algorithms for CMML are still lacking, and treatment remains loosely codified. The hypomethylating agents (HMA) azacitidine (AZA) and DAC seem active in CMML, though they have mostly been explored retrospectively, reporting overall response rates in the 40\u201370% range [The current diagnostic criteria of CMML have recently been updated by the 2016 WHO classification. Persistent monocytosis defined both as an absolute count\u2009>\u20091,000/0% range . For thiTo our knowledge, there have been some studies founding that subjects with CMML have a high prevalence of chronic inflammatory or autoimmune disorders, especially systemic vasculitis, connective tissue diseases, and immune thrombocytopenia (ITP) \u201314. ThisMCD has an inherent tendency to progress to lymphoma, and the driving molecular aberrations involved in transformation remain obscure , 17. AutIn summary, we report a rare case of MCD subsequently founding to have CMML, who responded with repeated long-lasting remissions to prednisone and decitabine therapy. Moreover, the findings in our study suggest a causal association between MCD and subsequent development of CMML for chronic inflammation/autoimmunity. The intrinsic immune pathogenesis of this unusual phenomenon remains to be further investigated."}
+{"text": "Mesenchymal stem cell (MSC) therapies have been used in clinical trials in various fields. These cells are easily expanded, show low immunogenicity, can be acquired from medical waste, and have multiple functions, suggesting their potential applications in a variety of diseases, including liver disease and inflammatory bowel disease. MSCs help prepare the microenvironment, in response to inflammatory cytokines, by producing immunoregulatory factors that modulate the progression of inflammation by affecting dendritic cells, B cells, T cells, and macrophages. MSCs also produce a large amount of cytokines, chemokines, and growth factors, including exosomes that stimulate angiogenesis, prevent apoptosis, block oxidation reactions, promote remodeling of the extracellular matrix, and induce differentiation of tissue stem cells. According to ClinicalTrials.gov, more than 680 clinical trials using MSCs are registered for cell therapy of many fields including liver diseases  and inflammatory bowel diseases . In this report, we introduce background and clinical studies of MSCs in liver disease and inflammatory bowel diseases. Helicobacter pylori . Reg. Reg5]. Many clinical trials of autologous and allogeneic MSCs have aimed to elucidate the effects and mechanisms of MSCs. MSCs can expand easily and can be obtained from medical waste, suggesting their applications in regenerative medicine for the treatment of liver diseases and IBDs. Recently, limitations of MSCs have been reported. For example, therapeutic effects were not long term and were affected by inflammatory condition , 60. Thu"}
+{"text": "Preterm birth is still a major health problem throughout the world, which results in 75% of neonatal mortality. Preterm labor not only inflicts financial and emotional distress, it may also lead to permanent disability. The present study was conducted to determine the related risk factors and preventive measures of preterm labor.This retrospective cross-sectional study assessed all preterm labors, as well as an equal number of term labors, during seven years, at an educational hospital. Probable risk factors of preterm labor were collected using medical profiles of participants by the aid of a pre-designed checklist. Significant related factors of preterm labor were used for multivariate logistic regression analysis with SPSS 21.0.810 cases with the mean age of 28.33 \u00b1 6.1 years were evaluated (48.7% preterm). Multipartite; fetal anomaly; prenatal care; smoking; not consuming folic acid and iron supplements; in vitro fertilization; history of infertility, caesarian section, trauma, systemic disease, and hypertension; amniotic fluid leak; rupture of membranes; cephalic presentation; vaginal bleeding; placenta decolman; oligohydramnios; pre-eclampsia; chorioamnionitis; uterine abnormalities; cervical insufficiency; intercourse during the previous week; short time since last delivery; and mother\u2019s weight significantly correlated with preterm labor. Based on the results of the present study, intercourse during the previous week, multipartite, short time from last delivery, preeclampsia, fetal anomaly, rupture of membranes, hypertension, and amniotic fluid leak, respectively, were risk factors for preterm labor. On the other hand, iron consumption, cephalic presentation, systematic disease, history of caesarian section, prenatal care, and mother\u2019s weight could be considered as protective factors. Preterm labor is an obstetrics emergency and a threat to population health. 75% of infant mortality is related to preterm labor , 2. PretApproximately one-third of preterm labor survivors suffer from severe long\u2013term neurological disabilities, such as cerebral palsy or mental retardation . FurtherOver the last two decades, preterm birth rate has remained unchanged or even risen in most countries, despite the increased understanding of possible risk factors and their pathological mechanisms -7. Although neonatal mortality rate has fallen globally between 1990 and 2009 , the absAlthough in most cases preterm births occur idiopathically, fetal, uterine, and placental factors as well as maternal chronic diseases, can affect preterm birth . In the Study design and settingThis retrospective cross-sectional study assessed all preterm labors during seven years, from March 2008 until March 2015, at Shohadaye Tajrish Hospital, Tehran, Iran, by normal vaginal delivery or cesarean section, using census method. An equal number of term labors were selected by simple random sampling as the control group. The study protocol was approved by the Ethical Committee of Shahid Beheshti University of Medical Sciences. The researchers adhered to the principles of Helsinki Declaration, as well as confidentiality of patient data and patient rights.Data gatheringProbable risk factors of preterm labor such as: mother\u2019s age, weight, body mass index, and job; type of delivery , baby\u2019s sex and weight; apgar score at 1 and 5 minutes; multi-partite; fetal abnormalities; prenatal care; smoking, alcohol, and opium abuse; history of folic acid, metformin, and iron consumption; history of in vitro fertilization, infertility, abortion, preterm delivery, trauma, vaginal bleeding, intra uterine fetal death (IUFD), dental infection, respiratory infection, and caesarian section; amniotic fluid leak; rupture of membranes; cephalic presentation; vaginal infection; placenta decolman; placenta praevia; polyhydramnios; oligohydramnios; urinary tract infection; systemic disease; anemia; hypertension; preeclampsia; eclampsia; chorioamnionitis; uterine abnormalities, cervical insufficiency; placental insufficiency; polycystic ovary; history of intercourse during the previous week; and time from last delivery were collected using medical profiles of participants by the aid of a pre-designed checklist. Incomplete patient files were excluded. Short time from last delivery was considered to be 1 year.Statistical analysisThe data were analyzed with SPSS software version 21.0. Qualitative data were reported as mean \u00b1 standard deviation and quantitative ones as frequency and percentage. Frequency of all risk factors were compared between the two groups (preterm and term) using chi square and Fisher\u2019s exact tests. Multivariate logistic regression analysis was applied to independent statistically significant factors for developing a predictive model and odds ratio (OR) of each risk factor was calculated. P value under 0.05 was considered significant.810 cases with the mean age of 28.33 \u00b1 6.1 (14 - 64) years were evaluated (48.7% preterm). Based on the findings of the present study, independent related factors of preterm labor were multipartite, fetal anomaly, prenatal care, smoking, not consuming folic acid, not consuming iron supplements, in vitro fertilization, history of infertility, amniotic fluid leak, rupture of membranes, history of caesarian section, cephalic presentation, history of trauma, vaginal bleeding, placenta decolman, oligohydramnios, history of systemic disease, history of hypertension, preeclampsia, chorioamnionitis, uterine abnormalities, cervical insufficiency, intercourse during the previous week, short time since last delivery, and mother\u2019s weight. Intercourse during the previous week, multipartite, short time from last delivery, preeclampsia, fetal anomaly, rupture of membranes, hypertension, and amniotic fluid leak, respectively, were risk factors for preterm labor. On the other hand, iron consumption, cephalic presentation, systematic disease, history of caesarian section, prenatal care, and mother\u2019s weight could be considered as protective factors.Preterm labor, as mentioned before, is a major obstetric and pediatric challenge because it is a common, persistent, and often devastating condition with considerable medical, economic, emotional, and social impact . It is tUsing the results of this study and similar ones to eliminate the risk factors and reinforce the protective factors would be helpful in decreasing the rate of preterm labor and its human and social burden. Yet, for accurately determining these factors, studies with better design, such as cohort studies, with proper follow-up period and large study population, are needed. Since the studied hospital is a referral center for these patients, it represents the general population of the country to a great extent. Still, the final decision regarding factors definitely affecting pre-term labor should be made after further studies.Based on the results of the present study, intercourse during the previous week, multipartite, short time from last delivery, preeclampsia, fetal anomaly, rupture of membranes, hypertension, and amniotic fluid leak, respectively, were risk factors for preterm labor. On the other hand, iron consumption, cephalic presentation, systematic disease, history of caesarian section, prenatal care, and mother\u2019s weight could be considered as protective factors."}
+{"text": "Dengue counts among the most commonly encountered arboviral diseases, representing the fastest spreading tropical illness in the world. It is prevalent in 128 countries, and each year >2.5 billion people are at risk of dengue virus infection worldwide. Neurological signs of dengue infection are increasingly reported. In this review, the main neurological complications of dengue virus infection, such as central nervous system (CNS), peripheral nervous system, and ophthalmic complications were discussed according to clinical features, treatment and possible pathogenesis. In addition, neurological complications in children were assessed due to their atypical clinical features. Finally, dengue infection and Japanese encephalitis were compared for pathogenesis and main clinical manifestations. Dengue counts among the most common arboviral illnesses, representing the fastest spreading tropical disease in the world  more than two decades ago  World Health Organization (WHO) classification groups dengue infection into three categories, including dengue with no warning signs, disease with warning signs, and severe dengue  metabolic disturbance, e.g., encephalopathy; (2) viral invasion, including encephalitis, meningitis, myositis, and myelitis; (3) autoimmune reactions, including acute disseminated encephalomyelitis, neuromyelitis optica, optic neuritis, myelitis, encephalopathy, and Guillain-Barr\u00e9 syndrome Murthy, .The main neurological complications of dengue virus infection are discussed below.CNS complications are diagnosed by assessing anti-DENV immunoglobulin (Ig)M, detecting viral RNA or non-structural protein 1 (NS1)in the CSF, isolating the virus from the CSF, and after excluding other causative agents of viral brain diseases  and mild encephalitis . Brain edema, anoxia, hemorrhage, intense hyponatraemia, liver or kidney failure, release of toxic substances, metabolic acidosis, and direct organ invasion are commonly reported precursors of encephalopathy in patients with serious DHF/DSS  is established by a somewhat sudden onset of sensorimotor and sphincter disturbances resulting from inflammatory demyelinating lesions  features a quickly rising paralysis, reflecting an inflammatory demyelinating or axonal polyneuropathy  is a proven neurotropic virus, and mainly targets neuronal cells , and inflammatory reactions (Chen et al., Therefore, it is relatively easy to understand why up to one-third of JE cases hospitalized die while about one-half of all survivors show permanent neurological sequelae, even individuals with apparent recovery (Kumar et al., Dengue is gradually becoming a main public health problem worldwide. A growing number of related studies demands increased awareness and understanding of the neurological complications of dengue infection. Physicians, especially neurologists, will continue to play important roles in its diagnosis and treatment. Pathogenesis, detection, antivirals, vaccines, environmental risk reduction, and vector control still deserve further studies.GL: Designed the study, collected data, wrote the manuscript. YL: Designed the study, reviewed the manuscript. XL: Designed the study, reviewed the manuscript. ZN: Collected data and edited the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The purpose of this study was to assess the current role of robot-assisted urological surgery in the female pelvis. The recently published English literature was reviewed to evaluate this role, with special emphasis on reconstructive procedures. These included colposuspension for genuine female stress urinary incontinence, repair of female genitourinary fistulas, ureterosciatic hernias, sacrocolpopexy for vault prolapse, ureterolysis and omental wrap for retroperitoneal fibrosis, ureteric reimplantation, and bladder surgery. To date, a wide spectrum of urogynecological reconstructive procedures have been performed with the assistance of the surgical robot and have been reported worldwide. Currently, a number of female pelvic ablative and reconstructive procedures are technically feasible with the aid of the surgical robot. While the role of robot-assisted surgery for bladder cancer, ureterolysis, ureteric reimplantation, repair of genitourinary fistulas, colposuspension, and sacrocolpopexy is nearly established among urologists, other procedures, such as myomectomy, simple hysterectomy, trachelectomy, and Wertheim's hysterectomy, are still evolving with gynecologists. The advantages of robot assistance include better hand-eye coordination, three-dimensional magnified stereoscopic vision with depth perception, intuitive movements with increased precision, and filtering of hand tremors. For most of the currently performed procedures in selected patients, the robot-assisted surgical outcomes appear to be relatively superior as compared to an open and purely laparoscopic surgical procedure."}
+{"text": "Mounier\u2013Kuhn syndrome is a rare clinical disorder characterized by tracheobronchial dilation and recurrent lower respiratory tract infections. While the etiology of the disease remains unknown, histopathological analysis of Mounier\u2013Kuhn airways demonstrates that the disease is, in part, characterized by cellular changes in airway smooth muscle. Mounier\u2013Kuhn syndrome is a rare clinical entity, with an uncertain cause, recognized by tracheobronchomegaly, airway cartilage ring abnormalities, and lung infections 1 of 39% of predicted and sputum culture grew Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter haemolyticus, and Haemophilus parainfluenzae. An X\u2010ray computed tomography scan of the chest demonstrated bronchial wall thickening, mucus plugged airways, and bronchiectasis. The proximal airways were dilated  and tortuous with irregular\u2010appearing cartilage rings  airway smooth muscle is present, and not congenitally absent; and (ii) regions of airway smooth muscle had undergone degeneration and fibrotic remodeling, as opposed to atrophic loss. Other proposed etiologies for Mounier\u2013Kuhn syndrome We report a case of Mounier\u2013Kuhn syndrome with histopathological findings of localized airway smooth muscle degeneration and remodeling. These findings were in addition to widely recognized manifestations of the disease including tracheobronchomegaly and airway cartilage ring abnormalities. Observations in this Mounier\u2013Kuhn syndrome patient suggest that tracheobronchomalacia is not due to congenital absence of airway smooth muscle, but can be associated with localized degeneration/remodeling from unknown etiology(s), which may progress with time.DPC, DKM, and DAS: performed conception and design of study; DPC, RJA, MHA, ME, JAKT, KRP, DKM, and DAS: performed data acquisition and interpretation; DPC, RJA, DKM, and DAS: prepared figures; DPC, DKM, and DAS: drafted the manuscript; DPC, RJA, MHA, ME, JAKT, KRP, DKM, and DAS: edited, reviewed, and approved final version of the manuscript.No conflicts of interest exist for any of the authors.Video S1. Video of CT\u2010based 3D reconstruction of airway tree from an adult with Mounier\u2010Kuhn syndrome. Airways are outlined in pink and cartilage in yellow.Click here for additional data file."}
+{"text": "The correct names are provided and replaced online which is mentioned as under:Mark Stecker*, Kathleen Michel, Karin Antaky, Sarah Cherian, Feliks KoyfmanThe original names was:Mark Stecker*, Kathleen Michel, Karin Antaky, Sarah Cherian, Feliks Koyfmann"}
+{"text": "To editor,3Gout is a common rheumatological disease caused by a disturbance in uric acid metabolism.Tophi develop during most advanced clinical stage of gout, and usually present as firmpink nodules or fusiform swelling, mainly at periarticular sites. However, unusual skinmanifestations caused by intradermal and subcutaneous deposition of tophaceous materialat locations other than periarticular regions have been reported.We presented a case of a 65-year-old with 2-years history of multiple, whitish,milia-like, firm papules over the finger pads . The pat5 Intradermal tophi arerare skin manifestations of chronic gout that are characterized by multiple, tiny,superficial, pustule or milia-like, whitish lesions.5 Rarely they appear atextra-articular sites such as forearms, arms, finger pad, legs, buttock, thigh, penis,vocal cords, epiglottis, tongue and abdominal wall.3 In our patient, theintradermal gout lesions were restricted to the finger pads. Risk factors predisposingto the development of intradermal gout include renal insufficiency, hypertension,long-term use of furocemid and corticosteroids, long-term duration of disease, obesity,and lack of consistent use of urate-lowering therapy.4 The present case hadsome of this risk factors. The differential diagnosis of intradermal tophi includesxanthoma and calcinosis cutis, which can be easily diagnosed by examining fluid inpolarized light or performing biopsy.5The natural history of gout involves four clinical stages; asymptomatic hyperuricemia,acute gouty arthritis, intercritical gout and chronic tophaceous gout. Some atypicalforms of tophaceous gout have been described, including bullous, fungating, ulcerativegout, gouty panniculitis and miliarial gout.Allopurinol and colchicine have been reported to improve intradermal gout, and ourpatient was referred to a rheumatologist for management but was lost to follow-up.In conclusion, the incidence of gout is increasing, possibly due to an aging populationand eating habits. This case illustrates the importance of considering a rare cutaneousmanifestation of gout."}
+{"text": "Global fermented foods are classified into 9 major groups on the basis of substrates  used from plant/animal sources: fermented cereals, fermented vegetables and bamboo shoots, fermented legumes, fermented roots/tubers, fermented milk products, fermented and preserved meat products, fermented, dried, and smoked fish products, miscellaneous fermented products, and alcoholic beverages. Fermented foods are the hubs of consortia of microorganisms, which transform the chemical constituents of raw materials of plant/animal sources during Alkalibacterium, Carnobacterium, Enterococcus, Lactobacillus, Lactococcus, Leuconostoc, Oenococcus, Pediococcus, Streptococcus, Tetragenococcus, Vagococcus and Weissella. Species of Bacillus are reported for alkaline-fermented foods of Asia and Africa. The association of several species of Kocuria, Micrococcus (members of the Actinobacteria), and Staphylococcus (belonging to the Firmicutes) has been reported for fermented milk, fermented meat, and fish products. Species of Bifidobacterium, Brachybacterium, Brevibacterium, and Propionibacterium have been isolated from cheese and species of Arthrobacter and Hafnia from meat fermentation. Enterobacter cloacae, Klebsiella pneumoniae, K. pneumoniae subsp. ozaenae, Haloanaerobium, Halobacterium, Halococcus, Propionibacterium, and Pseudomonas, are also present in numerous fermented foods.Common genera of the lactic acid bacteria isolated from various fermented foods globally are Brettanomyces, Candida, Cryptococcus, Debaryomyces, Dekkera, Galactomyces, Geotrichum, Hansenula, Hanseniaspora, Hyphopichia, Issatchenkia, Kazachstania, Kluyveromyces, Metschnikowia, Pichia, Rhodotorula, Rhodosporidium, Saccharomyces, Saccharomycodes, Saccharomycopsis, Schizosaccharomyces, Sporobolomyces, Torulaspora, Torulopsis, Trichosporon, Yarrowia, and Zygosaccharomyces. Major roles of filamentous fungi in fermented foods and alcoholic beverages are mainly production of enzymes and also degradation of anti-nutritive factors. Species of Actinomucor, Amylomyces, Aspergillus, Monascus, Mucor, Neurospora, Parcilomyces, Penicillium, Rhizopus, and Ustilago are reported for many fermented foods, Asian non-food amylolytic starters and alcoholic beverages.Genera of yeasts reported for fermented foods, alcoholic beverages, and non-food mixed amylolytic starters are Direct DNA extraction from samples of fermented foods, commonly called culture-independent methods, is nowadays frequently used in food microbiology to profile both cultivable and uncultivable microbial populations from fermented foods. Amplified ribosomal DNA restriction analysis (ARDRA) and denaturing gradient gel electrophoresis (DGGE) techniques developed to profile microbial communities directly from fermented foods, and are based on sequence-specific distinctions of 16S rDNA or 26S rDNA amplicons produced by PCR.Application of next generation sequencing (NGS) such as metagenomic approaches by using parallel pyrosequencing of tagged 16S rRNA gene amplicons provide information on microbial communities as profiled in kimchi, a naturally fermented vegetable product of Korea, nukadoko, a fermented rice bran of Japan, narezushi, a fermented salted fish and cooked rice of Japan, and ben-saalga, a traditional gruel of pearl millet of Burkina Faso. A proteomics identification method based on protein profiling using matrix-assisted laser desorption ionizing-time of flight mass spectrometry (MALDI-TOF MS) is used to identify bacteria in fermented foods. NGS has revealed the new dimension of microbial ecology comprising both cultivable and uncultivable microorganisms in many ethnic fermented foods and beverages of the world.This e-book is a compilation of 15 originals and reviews papers written by 94 authors. We tried to represent the main Asian, African, European, and American fermented foods and alcoholic beverages.JT prepared a draft concept on Resource Topic of the present e-book and list of authors for papers, supplemented and corrected by WH, DS, and GF. JT was the main corresponding Editor, however, WH, DS, and GF also helped to provide the names of referrers, etc.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Toxigenic mold activities produce metabolites that are either broad-spectrum antibiotics or mycotoxins that are cytotoxic. Indoor environmental exposure to these toxigenic molds leads to adverse health conditions with the main outcome measure of frequent neuroimmunologic and behavioral consequences. One of the immune system disorders found in patients presenting with toxigenic mold exposure is an abnormal natural killer cell activity. This paper presents an overview of the neurological significance of abnormal natural killer cell (NKC) activity in chronic toxigenic mold exposure. A comprehensive review of the literature was carried out to evaluate and assess the conditions under which the immune system could be dysfunctionally interfered with leading to abnormal NKC activity and the involvement of mycotoxins in these processes. The functions, mechanism, the factors that influence NKC activities, and the roles of mycotoxins in NKCs were cited wherever necessary. The major presentations are headache, general debilitating pains, nose bleeding, fevers with body temperatures up to 40\u00b0C (104\u00b0F), cough, memory loss, depression, mood swings, sleep disturbances, anxiety, chronic fatigue, vertigo/dizziness, and in some cases, seizures. Although sleep is commonly considered a restorative process that is important for the proper functioning of the immune system, it could be disturbed by mycotoxins. Most likely, mycotoxins exert some rigorous effects on the circadian rhythmic processes resulting in sleep deprivation to which an acute and transient increase in NKC activity is observed. Depression, psychological stress, tissue injuries, malignancies, carcinogenesis, chronic fatigue syndrome, and experimental allergic encephalomyelitis could be induced at very low physiological concentrations by mycotoxin-induced NKC activity. In the light of this review, it is concluded that chronic exposures to toxigenic mold could lead to abnormal NKC activity with a wide range of neurological consequences, some of which were headache, general debilitating pains, fever, cough, memory loss, depression, mood swings, sleep disturbances, anxiety, chronic fatigue, and seizures."}
+{"text": "In the Gambia, Mabey et al. described a series of 5,466 febrile patients hospitalized during 1979\u20131984 from whom blood cultures were taken  were positive for non-Typhi serotypes of S. enterica. The importance of S. enterica non-Typhi serotypes in febrile illness also has been demonstrated in other studies , are increasingly targeted for control through vaccination, and malaria, hitherto the main cause of febrile illness in the region, steadily decreases in some areas.The few published data do not clarify whether Salmonella Typhi and S. enterica non-Typhi serotypes in sub-Saharan Africa. The meeting was supported by the Swedish International Cooperation and Development Agency and held in conjunction with the Seventh International Conference on Typhoid Fever and Other Invasive Salmonelloses in Kilifi, Kenya. Twenty-eight investigators from 14 research sites in sub-Saharan Africa and 5 international institutions presented data on invasive bacterial diseases that focused on salmonelloses and discussed the way forward for defining invasive Salmonella in sub-Saharan Africa.On January 24, 2009, the International Vaccine Institute  and the Kenya Medical Research Institute  cohosted a meeting to review published and unpublished data on invasive disease caused by Salmonella Typhi and S. enterica non-Typhi serotypes as causes of invasive infections. Salmonella Typhi seemed to be affecting older children and young adults, whereas invasive S. enterica non-Typhi serotypes were more common in infants, toddlers, and HIV-infected adults. The ratio of Salmonella Typhi to invasive S. enterica non-Typhi serotypes varied greatly across sites. In infants, the incidence of S. enterica non-Typhi serotypes was similar to the incidences of S. pneumoniae and Hib in some sites. Predominant S. enterica non-Typhi serotypes differed by site: Salmonella serotypes Typhimurium and Enteritidis accounted for a large proportion of the S. enterica non-Typhi serotypes identified, but Salmonella serotypes Dublin, Hvittingfoss, Heidelberg, Isangi, and Stanleyville also were reported as noteworthy causes of infection with S. enterica non-Typhi serotypes. Antimicrobial drug resistance patterns of S. enterica non-Typhi serotypes were heterogeneous by site; however, the levels were high enough to warrant concern. The lack of rapid diagnostic tests for S. enterica non-Typhi serotypes infection was also a concern because poor diagnostics contribute to the inaccurate reporting of disease, and treating febrile illnesses only with antimalarial medication is widely practiced, particularly in malaria-endemic areas. Culture confirmation is considered the accepted standard but is not always performed because it is expensive and requires considerable infrastructure and expertise and, considering its sensitivity, is likely to grossly underestimate the actual prevalence of disease.Characteristics of 11 fever surveillance sites were compared . Most siVariability in findings across sites can be explained partly by differences in setting , criteria for enrollment, age groups included, and laboratory methods. The use of standard protocols across sites would make combining data for analysis and comparing and contrasting results possible. The Diseases of the Most Impoverished Program conducted by the International Vaccine Institute in Asia produced comparative data on typhoid and paratyphoid fever infections through implementation of common epidemiologic and laboratory methods across multiple sites (Salmonella infections in these areas. Collection of standardized, multicountry, multidisciplinary data on the prevalence of, risk factors for, and costs of these infections is essential for developing consensus at the regional, national, and international levels in establishing appropriate control measures. The optimal study approach is to use existing fever surveillance sites and to standardize epidemiologic and laboratory procedures across sites. In addition, at sites where the prevalence of disease associated with Salmonella Typhi is known and considerable, vaccine demonstration projects should be conducted to control the disease. The framework for a multicenter proposal was discussed, and the group agreed on the creation of an African salmonelloses initiative for research and advocacy. This consortium will undertake much-needed standardized multicountry studies to yield evidence about typhoid and other invasive salmonelloses and the effectiveness of typhoid vaccines in sub-Saharan Africa, which ultimately can lead to deployment of preventive interventions, including vaccination, against invasive Salmonella infections.Meeting participants concluded that existing epidemiologic information about invasive salmonelloses in sub-Saharan Africa remains fragmentary and hindered by heterogeneous study methods. Participants agreed on an urgent need to collect better data on invasive Investigators participating in the meeting were Katrin K\u00f6sters, Albert Schweitzer Hospital, Lambar\u00e9n\u00e9, Gabon; J\u00fcrgen May, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany; Robert F. Breiman, US Centers for Disease Control and Prevention, Nairobi, Kenya; John A. Crump, Duke University\u2013Kilimanjaro Christian Medical Centre Collaboration, Moshi, Tanzania; John Clemens, Michael Favorov, Florian Marks, and R. Leon Ochiai, International Vaccine Institute, Seoul, Republic of Korea; Kamala Thriemer, International Vaccine Institute, Pemba, Tanzania; Lorenz von Seidlein, International Vaccine Institute, Zanzibar, Tanzania; Sam Kariuki, Kenya Medical Research Institute, Nairobi, Kenya; Kevin Marsh and Susan C. Morpeth, Kenya; Medical Research Institute\u2013Wellcome Research Program, Kilifi, Kenya; Yaw Adu-Sarkodie, Kwame Nkrumah University of Science and Technology School of Medical Sciences, Kumasi, Republic of Ghana; Denise Dekker, London School of Hygiene and Tropical Medicine, Korogwe, Tanzania; Hugh Reyburn, London School of Hygiene and Tropical Medicine, Moshi, Tanzania; Robert Heyderman, Malawi\u2013Liverpool\u2013Wellcome Trust Clinical Research Program, Blantyre, Malawi; Usman Nurudeen Ikumpayi, Medical Research Council Laboratories, Basse, The Gambia; Stephen Obaro, Michigan State University, East Lansing, Michigan, USA; George Mtove, National Institute of Medical Research, Amani, Tanzania; Saidi M Ali and Shaali Ame, Public Health Laboratory\u2013Ivo de Carneiro, Pemba, Tanzania; Gordon Dougan, Sanger Institute, Cambridge, UK; John Wain, Health Protection Agency, London, UK; Karen H. Keddy, National Institute for Communicable Diseases, Johannesburg, Republic of South Africa; Ben Amos, Teule Hospital, Muheza, Tanzania; Myron M. Levine, Center for Vaccine Development, Bamako, Mali; and William Mwengee, World Health Organization, Dar es Salaam, Tanzania."}
+{"text": "Adipokines, secreted by the adipose tissue, are extensively involved in the regulation and maintenance of various physiological and pathological processes, including insulin sensitivity, energy expenditure, glucose and lipid metabolism, inflammatory activity, neuroendocrine activity, immunity, cancer, homeostasis, angiogenesis, cardiovascular function, breeding and bone metabolism, and all functions of the endocrine-reproductive system axis. Omentin is a recently identified adipokine, which has become a research hotspot due to its pleiotropic effects on various diseases. However, the specific receptor for omentin has not been identified so far. In this study, we report that omentin levels fluctuate in various diseases. In addition, we have focused on the pleiotropic roles of omentin in pulmonary diseases, as it may act as a biomarker for malignant pleural mesothelioma (MPM) and is related to disease severity. Omentin may play significant roles in other pulmonary diseases, such as asthma, obstructive sleep apnea syndrome (OSAS), pulmonary arterial hypertension (PAH), acute respiratory distress syndrome (ARDS), and chronic obstructive pulmonary disease (COPD). This review summarizes the advances in current knowledge and future trends, which may provide a concise and general view on omentin and its effects on pulmonary biology. Various adipokines, including adiponectin, adipsin, apelin, chemerin, fibroblast growth factor 21, interleukin-6 (IL-6), leptin, retinol-binding protein 4, osteonectin, omentin, plasminogen activator inhibitor-1, progranulin, resistin, tumor necrosis factor (TNF), vaspin, and vistafin are derived from the adipose tissue [Adipokines participate in various physiological and pathological processes including insulin sensitivity, energy expenditure, glucose and lipid metabolism, inflammatory activity, neuroendocrine activity, immunity, cancer, homeostasis, angiogenesis, cardiovascular function, breeding and bone metabolism, and all functions of the endocrine-reproductive system axis ,3,4. The2+-dependent galactofuranose-binding lectin used for identifying bacterial components, and is important for defense against pathogenic bacteria [Omentin is a novel hydrophilic adipokine of 313 amino acids (35 kDa), which contains a secretory signal sequence and a fibrinogen-related domain, and appears as a glycolized trimer of 120 kDa molecular weight in its negative form ,11. In 2In recent years, considerable progress has been made in determining and characterizing the effects of omentin on different diseases. Based on a large number of epidemiological, clinical, and laboratory analyses, the changes in omentin levels in various diseases have been summarized in Omentin levels are inversely related to obesity and positively to adiponectin levels . SeveralSeveral studies demonstrated a significant reduction in omentin levels in various cardiovascular diseases, including patients with carotid atherosclerosis ,30,31, cOmentin levels were reduced in certain autoimmune diseases, including psoriasis ,38,39, rIn addition, circulating omentin levels were also dramatically reduced in renal cell cancer ; howeverThe serum levels of omentin were also significantly higher in other diseases, such as liver cirrhosis  and anorOmentin is an important component that connects organs with adipose tissue and exerts extensive protective effects via various cell signaling pathways during physiological and pathological processes . YamawakMoreover, omentin protected against arterial calcification by inhibiting osteoblastic differentiation of calcifying vascular smooth muscle cells (CVSMCs) via the phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT) signaling pathway . This maFurthermore, omentin inhibited VCAM-1 expression in vascular smooth muscle cells (VSMCs) via phosphorylation of p38 and JNK at least in part through preventing NADPH oxidase (NOX)-derived superoxide production; it also restrained TNF-\u03b1-induced adhesion of U937 monocytes to isolated rat VSMCs . FinallyMalignant pleural mesothelioma (MPM) is an uncommon but lethal tumor. The effect of current treatment on MPM is poor, and surgery is most effective for patients in early stage MPM. Unfortunately, because of the lack of characteristic clinical symptoms, radiographical features, and specific diagnostic markers for MPM, diagnosis of MPM at the early stage is difficult. The median survival after radical surgery or chemotherapy is only 9\u201312 months ,85.A study suggested that both the mRNA and protein levels of omentin increased (>129-fold increase) in mesothelioma tumors and cell lines ,86. EpitTherefore, these results suggested that omentin in the pleural effusion could be used as a specific diagnostic marker for distinguishing epithelioid-type MPMs from other carcinomas because of its specificity and the simplicity of pathological assessment. Asthma is a disease characterized by T-helper type 2 (Th2) allergic airway inflammation, airway hyperresponsiveness, mucus overproduction, and peribronchial fibrosis. Kuperman et al. demonstrated that omentin-1 expression was enhanced in ovalbumin (OVA) allergic mice and IL-13-overexpressing mice . They alStudies of mouse asthma models showed that IL-13 was necessary for allergen-induced airway inflammation, airway hyper responsiveness, and mucus production ,92. IL-1Furthermore, omentin may be a component of airway mucus. This may be conducive to forming pathologic mucus and defending against microbes. A study showed that omentin was a goblet cell protein, which is secreted with mucus into the intestinal lumen . In addiObstructive sleep apnea syndrome (OSAS) is a widespread disease associated with snoring, witnessed apnea, repeated airway obstruction during sleep and excessive daytime sleepiness ,102, leaPulmonary arterial hypertension (PAH) is characterized by endothelial dysfunction, inflammation, and vascular remodeling, resulting in increased pulmonary vascular resistance and pulmonary pressure, finally causing right heart failure (RHF) . A serieA previous study revealed that omentin exerted an anti-inflammatory effect on vascular endothelial cells by preventing TNF-\u03b1-induced COX-2 expression via inhibiting AMPK/eNOS/NO pathways . OmentinThe above evidence suggested that omentin mitigated PAH via suppression of inflammation, SMC migration, and vascular structural remodeling. Thus, omentin possesses potential as a therapeutic tool for PAH and RHF.Acute respiratory distress syndrome (ARDS), a devastating disorder distinguished by inflammatory response and endothelial barrier disruption with a 30\u201360% mortality rate ,111, is In addition, direct evidence regarding the impact of omentin on ARDS has also been found. Qi et al.  observedProgressive airflow obstruction, destruction of lung parenchyma, and lung inflammation are the characteristic features of COPD, which is a common chronic respiratory disease. Convincing evidence suggested that cigarette smoking (CS) is the major risk factor for COPD ,114. CarFluctuating omentin levels are widely associated with various diseases, including obesity, diabetes, cardiovascular disease, autoimmune disease, various malignant tumors, reproduction system diseases, nervous system diseases, and pulmonary diseases. Omentin can regulate inflammation status, vasomotor and endothelium function, proliferation, apoptosis, and differentiation of cell types via various molecular mechanisms.Nonetheless, the mechanism via which omentin regulates various physiological and pathological functions is not completely elucidated. At present, the specific receptor for omentin is still unknown, which makes understanding the physiological function of omentin difficult.Omentin may play significant roles in pulmonary diseases, such as MPM, asthma, OSAS, PAH, ARDS, COPD, and other lung disorders. Omentin in the pleural effusion may be a specific diagnostic marker for MPM, which is conducive for diagnosing MPM in the early stage, extending the median survival of patients with MPM. Omentin, which belongs to the category of \u201cgood\u201d adipokine, exerts anti-inflammatory effects in various physiological and pathological processes. However, current studies have shown that omentin may participate in the pathogenesis of asthma. Omentin is essential for the expression of inflammatory factors in lung epithelial cells, which facilitate allergic airway inflammation, and it may be a component of airway mucus that contributes to pathologic mucus formation in asthma. Omentin levels were drastically reduced in patients with OSAS, which correlated with the severity of OSAS. Moreover, omentin can elicit anti-inflammatory and anti-migratory effects and inhibit vascular structural remodeling for PAH and RHF. Furthermore, omentin can protect pulmonary endothelial barrier function and decrease pulmonary microvascular permeability and inflammation in LPS-induced ARDS models. This indicated that omentin may act as an anti-inflammatory therapeutic drug for ARDS. Studies demonstrated that omentin levels decreased in the airway epithelium of healthy smokers, which is a major risk factor for infections and COPD. This suggests that omentin may contribute to defense against respiratory tract infections and COPD.Extensive investigations are required to explore the effect of omentin in respiratory diseases. Whether omentin can be used for the diagnosis and assessment of intervention outcomes or development of new therapeutic targets requires further investigation. We expect this review to be helpful for a better understanding of the biological role of omentin in respiratory diseases."}
+{"text": "This paper analyzes and presents the biochemical abnormalities in the sera of patients presenting with chronic mycosis in order to investigate the relationship with the risks of multiple renal disorders. The study population (n = 10) consisted of six females and four males (mean age 36.3 years) exposed by toxic molds in their homes and offices for an average of 2.8 years. The control group comprised ten people, five males and five females (mean age 35.9 years) without any known exposures to toxic molds. Blood samples were obtained from both the patients and the controls and were processed using specific biochemical methods that included enzyme-linked immunoabsorbent assay (ELISA). There were biochemical abnormal concentrations in creatinine, uric acid, phosphorus, alkaline phosphotase, cholesterol, HDH, SGOT/AST, segmented neutrophils, lymphocytes, total T3, IgG and IgA immunoglobulins with significant differences between patients and controls. These abnormalities were consistent with multiple renal disorders. The major complaints of the mycosis patients were headaches, pulmonary symptoms, allergic reactions, memory loss, skin rashes, blurred vision symptoms, fatigue, and runny nose. These findings were depictive of a strong association of chronic mycosis with abnormal renal indicators. It was concluded that, although this research was a pilot investigation, based on the overall results, people exposed to chronic indoor environmental toxic molds were at risk of multiple renal complications."}
+{"text": "The impact of surgery on end of life care for patients with disseminated malignancy (DMa) is incompletely characterized. The purpose of this study was to evaluate postoperative outcomes impacting quality of care among DMa patients, specifically prolonged length of hospital stay, readmission, and disposition.The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was queried for years 2011\u20132012. DMa patients were matched to non-DMa patients with comparable clinical characteristics and operation types. Primary hepatic operations were excluded, leaving a final cohort of 17,972 DMa patients. The primary outcomes were analyzed using multivariate Cox regression models.DMa patients represented 2.1% of all ACS-NSQIP procedures during the study period. The most frequent operations were bowel resections (25.3%). Compared to non-DMa matched controls, DMa patients had higher rates of postoperative overall morbidity , serious morbidity , mortality , prolonged length of stay , readmission , and discharges to facilities . Subgroup analyses of patients by procedure type showed similar results. Importantly, DMa patients who did not experience any postoperative complication experienced significantly higher rates of prolonged length of stay , readmissions , discharges to a facility , and 30-day mortality  compared to matched non-DMa patients.Surgical interventions among DMa patients are associated with poorer postoperative outcomes including greater postoperative complications, prolonged length of hospital stay, readmissions, disposition to facilities, and death compared to non-DMa patients. These data reinforce the importance of clarifying goals of care for DMa patients, especially when acute changes in health status potentially requiring surgery occur. Although patients and clinicians consider oncologic outcome and survival the pre-eminent goals of cancer therapy, quality of life and avoidance of therapeutic morbidity, particularly among patients with stage IV cancer, are receiving increasing attention as important goals of care.\u20135 ProlonThe purpose of the present study was therefore to evaluate these outcomes, specifically prolonged length of hospital stay, readmissions, and disposition to facilities other than home, among DMa patients undergoing surgery since these outcomes can clearly impact the quality of life and overall trajectory of disease in patients with incurable malignancy. We hypothesized DMa patients would have substantially increased rates of these primary endpoints compared to non-DMa patients.Data were obtained from the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) from the years 2011 to 2012 . ACS-NSQIP data collection methods have been described previously and have been shown to high data integrity and reliability.[DMa patients undergoing surgical intervention were identified as described previously . ACS-NSQIWe performed 1:1 matching of DMa to non-DMa patients who underwent an operation during this same time period. Patients were matched on the following characteristics: age, preoperative functional status, preoperative sepsis, procedure classification, and emergency procedure. These characteristics were specifically chosen as they have previously been shown to be independent predictors of postoperative morbidity and mortality for DMa patients., 11 StanCurrent procedural terminology (CPT) codes were used to classify procedures into the following categories: abdominal operations, neurosurgery, orthopedic, thoracic, urologic, gynecologic, skin/soft tissue, biopsy/lymph node excision, vascular, thyroid/parathyroid, otolaryngology, and cardiac operations. Abdominal operations were further categorized into small and large bowel resections, other small bowel and colorectal surgery, celiotomy and lysis of adhesions, pancreatic surgery, gastrectomy, other gastric surgeries, cholecystectomy, appendectomy, splenectomy, adrenal, biliary and other abdominal surgeries . These categories were used for matching procedure type.th percentile for all operations for DMa patients and non-DMa matched controls, which was \u226510 days. This definition was consistent with prior published research using ACS-NSQIP.[We then abstracted data on 3 demographic, 19 preoperative, 3 intraoperative, and 24 postoperative variables for DMa patients and matched controls. Standard ACS-NSQIP definitions were used for these variables with the following exceptions. MultivisCS-NSQIP.\u201319 DispoPostoperative overall morbidity was defined as experiencing one or more of the following events within 30 days of the principal operation: superficial or deep wound infection, organ space infection, fascial dehiscence, pneumonia, reintubation, prolonged intubation, pulmonary embolism, progressive renal insufficiency, acute renal failure requiring dialysis, urinary tract infection, stroke, coma for >24 hours, peripheral nerve injury, cardiac arrest, myocardial infarction, graft/prosthesis/flap failure, deep vein thrombosis, reoperation, sepsis, and septic shock.Post-operative serious morbidity was defined as experiencing a complication associated with requiring further invasive procedures or leading to lasting disability, organ dysfunction, and/or death, which inSince all patient information was de-identified, this study was exempt from UC Davis Institutional Review Board approval.Differences in preoperative and intraoperative patient characteristics were compared between DMa and non-DMa patients using Chi-squared test for categorical variables and two-tailed independent t-tests for continuous variables. Logistic regression analysis was used to determine predictors of the primary and secondary outcomes, overall and serious morbidity, mortality, disposition to a facility, prolonged length of stay and hospital readmissions, for DMa patients. Multivariate conditional cox regression analysis was performed to determine risk of these primary and secondary outcomes for patients with DMa controlling for any residual confounding. Covariates included in the model comprised of gender, diagnoses of diabetes, hypertension, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD) or kidney disease requiring dialysis, symptoms of dyspnea, ascites, or weight loss, ventilator dependence, steroid use, albumin and multivisceral resection. DNR status and preoperative chemotherapy and radiotherapy were excluded from the multivariate analysis due to >55% of the data missing in the ACS-NSQIP database for these variables. Statistical significance was set at p<0.05. Case matching and all analyses were performed using SPSS software (IBM SPSS Statistics Version 22) and Statistical Analysis Software (SAS) version 9.4.From 2011 to 2012, 986,034 patients in the ACS-NSQIP database underwent surgical procedures with 2.1%  diagnosed with DMa. After exclusion of patients who underwent a primary hepatic operation  and who were not successfully matched (n = 123), 17,972 DMa patients were identified.Table 1. As expected, there were no significant differences between DMa patients and matched cohorts with respect to age, functional status, preoperative sepsis, and emergency operations. However, there were significant differences between the groups with respect to gender, DNR status, comorbid health conditions, BMI, preoperative weight loss, recent history of chemotherapy or radiation therapy, preoperative laboratory values, and rates of multivisceral resections.Preoperative and intraoperative patient characteristics of the matched pairs are depicted in Table 1, DMa patients had a slightly lower BMI  and were more likely to have had significant preoperative weight loss , ascites , preoperative systemic steroids for a chronic medical condition , and preoperative chemotherapy and radiation therapy . DMa patients had a lower creatinine , albumin , and hematocrit  and were more likely to undergo a multivisceral resection .As shown in Non-DMa patients were more likely to have a comorbid health condition including diabetes mellitus , hypertension , congestive heart failure (CHF) , and renal failure requiring dialysis .Table 2, the majority of operations performed on DMa patients were abdominal operations  with bowel resections being the most common , followed by other small bowel and colorectal procedures , and celiotomy/lysis of adhesions . Neurosurgical operations were the second most common type of operation  followed by orthopedic surgery .As depicted in Multivariate logistic regression analysis showed common predictors of overall and serious morbidity and mortality included preoperative sepsis , emergency operations , lower albumin , and ventilator dependence . Impaired functional status was a predictor of overall morbidity  and mortality . Multivisceral resection and male gender were predictors of overall and serious morbidity , but not mortality (p\u22650.05). The remaining predictors of overall morbidity included diagnoses of COPD, CHF and hypertension and lower hematocrit (p<0.05). For serious morbidity other predictors included symptoms of dyspnea and diagnoses of COPD and kidney disease requiring dialysis (p<0.05). Older age, symptoms of dyspnea, ascites, and weight loss, preoperative steroid use, increased creatinine and lower hematocrit were additional predictors of mortality (p<0.05).Predictors of discharge to a facility and prolonged length of stay included older age , impaired functional status , lower albumin , lower hematocrit  and emergency operations . Diagnoses of diabetes and hypertension and preoperative steroid use were also predictors of discharge to a facility among DMa patients, p<0.05. Male gender, African American ethnicity, preoperative diagnoses of COPD and CHF, sepsis, ascites, weight loss, and multivisceral resections were additional predictors of prolonged length of stay, p<0.05. Male gender, ascites and low albumin were the only statistically significant predictors of hospital readmission, p<0.05.Table 3). Subgroup analysis of DMa patients who underwent a bowel resection  showed similar results. As shown in Table 4, 36.8%  of DMa patients experienced a postoperative complication after bowel resection compared to 29.2%  of non-DMa patients , 21.9% (n = 993) of DMa patients experienced a serious complication compared to 18.2% (n = 825) of non-DMa patients , and 9.3% (n = 424) of DMa patients died within 30 days after the index operation compared to 4.1% (n = 186) of non-DMa patients .DMa patients had significantly higher rates of postoperative overall 30-day morbidity , serious morbidity  and mortality  compared to matched non-DMa patients .Table 3 depicts rates of prolonged length of hospital stay, 30-day readmissions, and disposition to a facility for DMa patients who underwent any operation. Overall, DMa patients had significantly higher rates of prolonged length of hospital stays , readmission , and discharges to facility  compared to non-DMa patients.Table 4, DMa patients who underwent bowel resections had significantly higher rates of prolonged length of stay  and discharge to a facility . However, for patients who underwent celiotomy/lysis of adhesions, although rates of these three primary endpoints were higher among DMa patients compared to non-DMa patients, these differences were not statistically significant in the multivariate analysis.Subgroup analysis of bowel resections demonstrated similar results. As shown in Table 5, DMa patients who did not experience any ACS-NSQIP postoperative complication nevertheless experienced significantly higher rates of prolonged length of stay , readmissions , discharge to a facility , and 30-day mortality  compared to non-DMa patients.Importantly, as shown in Our findings that DMa patients were at greater risk of acute postoperative morbidity and mortality are consistent with prior research.\u201311 HowevFor example, surgeons are frequently consulted for malignant bowel obstruction, a diagnosis common in the setting of both ovarian and gastrointestinal malignancies, with rates as high as 28\u201351%., 21 AlthThese findings complement previous research comparing medical versus surgical outcomes for patients hospitalized with malignant bowel obstruction. Henry et al. observed in this retrospective single institution study that patients presenting with malignant bowel obstruction who underwent surgical intervention experienced longer hospital stays and were more likely to be discharged to an extended care facility compared to patients who were treated with medical management.Data such as these highlight the need for physicians and surgeons to engage in goals of care and end of life discussions with their patients prior to pursuing surgical intervention on patients with DMa. Patients should be provided with an accurate assessment of the potential risks of surgery, including incidence of prolonged length of hospital stay, readmission, and discharge to a facility, as this information will likely have implications on their future quality of life and willingness to undergo surgery. For example, many patients with terminal disease prefer to die at home, as prior research has shown that in-hospital death among cancer patients is associated with greater physical and emotional distress and worse quality of life., 25 HoweOur findings that DMa patients who did not experience a single complication nevertheless experienced an increased risk of prolonged length of hospital stay, readmission, discharge to a facility and death compared to non-DMa matched controls also has important implications for this patient population. It suggests that the diagnosis of DMa itself is a predictor of poorer outcomes following surgical intervention. This may be due to many factors including greater patient frailty, weight loss and malnutrition among DMa patients, as these are known factors of adverse postoperative outcomes among cancer patients., 26, 27 Despite such findings, we understand that there are instances when surgical management will remain indicated and potentially life-saving for DMa patients. In such times, it is important that surgeons understand all factors that further increase DMa patients surgical risk. Our findings support prior literature identifying predictors of acute morbidity and mortality in DMa patients to include increased age, male gender, poor functional status, preoperative dyspnea and sepsis, ventilator dependence, lower albumin, emergency operations, and multivisceral resections., 11 We fThere are limitations of our study. Most importantly, we were not able to compare differences in outcomes between operative and nonoperative management since ACS-NSQIP only captures data on surgical patients. Although our findings demonstrate the significant risks that DMa patients harbor for acute morbidity and mortality as well as prolonged hospital stay, readmission, and discharge to a facility following surgery, it is inappropriate and premature at this time to extrapolate these data to DMa patients who do not undergo surgery for similar surgical conditions. This is an important subject for future investigation. Additionally, despite the robust nature of ACS-NSQIP data, patient In conclusion, we demonstrate that DMa patients who underwent surgical intervention experienced increased rates of prolonged length of hospital stay, readmissions, minor and major complications, discharges to facilities other than home, and death. These adverse outcomes were demonstrated across the spectrum of surgical conditions. Such findings emphasize the need for physicians, surgeons, and other members of the healthcare team to engage in goals of care and end of life discussions with DMa patients prior to pursuing surgical intervention since patients may experience adverse outcomes beyond that of traditional acute surgical morbidity, and these outcomes may impact their performance status and independence."}
+{"text": "Objective. To assess the value of bronchoscopy in the diagnosis and treatment of primary tracheobronchial amyloidosis (TBA), in order to reduce misdiagnosis rates and improve prognosis. Methods. Clinical data of 107 patients with TBA reported from 1981 to 2015 in China were retrospectively analyzed for clinical features, bronchoscopic manifestations, pathologies, treatments, and outcomes. Results. 105 of 107 TBA patients were pathologically confirmed by bronchoscopy. Main bronchoscopic manifestations of TBA were single or multiple nodules and masses within tracheobronchial lumens; local or diffuse luminal stenosis and obstruction; luminal wall thickening and rigidity; rough or uneven inner luminal walls; congestion and edema of mucosa, which was friable and prone to bleeding upon touch; and so forth. 53 patients were treated with bronchoscopic interventions, like Nd-YAG laser, high-frequency electrotome cautery, freezing, resection, clamping, argon plasma coagulation (APC), microwaving, stent implantation, drug spraying, and other treatments. 51 patients improved, 1 patient worsened, and 1 died. Conclusion. Bronchoscopic biopsy is the primary means of diagnosing TBA. A variety of bronchoscopic interventions have good short-term effects on TBA. Bronchoscopy has important value in the diagnosis, severity assessment, treatment, efficacy evaluation, and prognosis of TBA. Incidence of amyloidosis is about 8/1 million [Primary tracheobronchial amyloidosis (TBA) refers to a group of rare diseases with varied clinical manifestations which are caused by abnormal deposition of  million . In Chin million , so if c million . In receWith \u201cprimary tracheobronchial amyloidosis\u201d as search term, CNKI, VIP, and Wanfang Databases were retrieved. Meanwhile, PubMed database was searched with \u201cprimary tracheobronchial amyloidosis\u201d and \u201cChina\u201d as search terms. Data collected included age, gender, disease duration, clinical manifestations, presence or absence of misdiagnosis, imaging manifestations, bronchoscopic manifestations, pathology, treatments, and prognosis.Inclusion criteria were (1) patients histopathologically diagnosed with TBA and (2) those with complete clinical data. Exclusion criteria were (1) duplicate reports; (2) secondary tracheobronchial amyloidosis or systemic amyloidosis; and (3) patients with accompanying pharyngolaryngeal or pulmonary parenchymal amyloidosis. According to the inclusion and exclusion criteria, we screened out 54 papers  from theData were analyzed using SPSS 17.0 statistical software. Normally distributed measurement data were expressed as mean \u00b1 SD; abnormally distributed measurement data were expressed as median, while enumeration data were presented as constituent ratio.The patient is a 68-year-old male who complained of recurrent cough, expectoration, and progressive dyspnea for more than 30 years. He was admitted to our hospital after being diagnosed with chronic bronchitis, bronchiectasis, and endobronchial tuberculosis in other hospitals and treated with antibiotics numerous times. Despite treatment, his symptoms progressively worsened. In 1988, the patient was managed with a combination of isoniazid, streptomycin, and rifampicin for a diagnosis of endobronchial tuberculosis after bronchoscopy in another hospital. Three months later, with no improvement on these antitubercular agents and seeking a second opinion and treatment, the patient discontinued the treatment and came to our hospital.The patient presented with diminished breath sounds and slight bibasilar wheezing rales and crackles. Routine blood test was normal. A PPD test was negative. Sputum samples were negative for bacteria, acid-fast bacilli, and fungi. A recent chest CT demonstrated extensive thickening of the walls of the trachea and bronchi at different levels with luminal narrowing. Electronic bronchoscopy revealed significant swelling and hypertrophy of the tracheal and bronchial mucosa . PatholoG test was negative. Chest CT showed thickening and calcification of main bronchial wall as well as left and right bronchial walls and secondary atelectasis of right middle lobe. Electronic bronchoscopy findings were mucosal hypertrophy, swelling, significant hyperemia, unevenness and luminal stenosis which were visible in the trachea, left and right main bronchi, right upper lobe and right intermediate bronchi, right lower lobe bronchus, as well as left upper and lower lobe bronchi, and total occlusion of right middle lobe bronchus  years. As for disease duration, the longest was 30 years, whereas the shortest was 12 hours, with a median of 2 years. Main clinical manifestations were cough, shortness of breath or progressive dyspnea, expectoration, hemoptysis or bloody sputum, fever, chest tightness, hoarseness, and so forth. Misdiagnosis rate at first hospitalization was up to 45%. Most patients were misdiagnosed as chronic bronchitis, endobronchial tuberculosis, lung tumor, bronchial asthma, pulmonary infections, and so forth , freezing, drug spraying, clamping, resection, high-frequency electrotome cautery, stent implantation, and microwaving. Among these patients, 20 received bronchoscopic therapy alone; 32 received bronchoscopic therapy combined with drug therapy; while 1 received bronchoscopic therapy combined with external beam radiation therapy (EBRT). 51 patients improved, 1 patient worsened, and 1 died. Meanwhile, 25 patients received drug therapy alone. Among them, 20 patients improved, 4 patients worsened, and 1 died. 2 patients were given EBRT, both of whom improved. 2 patients underwent surgical resection and improved. 27 patients were given symptomatic treatment or only clinical observation, of whom 5 aggravated and 2 died. 66 patients were followed up for more than 3 months. Improvement was found in 2 patients; stabilization was found in 47 patients; exacerbation was found in 9 patients; and death was found in 8 patients  (see Amyloidosis is a group of clinical syndromes caused by deposition of insoluble amyloid fibrils in extracellular matrix, which produces mass effect and cytotoxicity, thereby damaging normal tissue and organ structures and ultimately leading to target organ dysfunction . AmyloidIn 1877, Lesser first reported respiratory amyloidosis , but so Introduction and extensive application of bronchoscopy have shed a new light on the diagnosis and treatment of TBA. Through literature review, we found that among TBA cases included in this study, only 23 were reported before 2000, while the number of cases reported since 2000 increased to 86 cases. For this phenomenon, we believe that improved TBA diagnostic technique is a factor that cannot be ignored aside from clinicians' increased awareness of the disease, especially the development and popularization of bronchoscopic techniques in the past decade, which play a vital role . BronchoHistopathological biopsy is the gold standard for diagnosis of TBA, while bronchoscopic biopsy is the primary means of confirming TBA diagnosis. Compared to the open lung biopsy, bronchoscopic biopsy has advantages such as small invasion, easy and accurate sampling, and little complications. 107 of 109 patients analyzed in this study were diagnosed by bronchoscopic biopsy, which sufficiently shows the significance of bronchoscopy in diagnosing TBA. Histologically, amyloids under tracheobronchial mucosa were presented as homogeneous, amorphous eosinophilic substance by HE staining, which showed brick red color under light microscope by Congo red staining and yellow-green birefringence under polarizing microscope .At present, major treatments of TBA are drug therapy, surgical resection, EBRT , and broIn summary, when we encounter unexplained chronic cough, progressive dyspnea, and recurrent noninfectious obstructive pneumonia in clinical practice, the possibility of TBA should be considered . This wi"}
+{"text": "Asthma is the most common childhood illness and disproportionately affects low-income, minority children who live in urban areas. A range of risk factors are associated with asthma morbidity and mortality, such as treatment non-adherence, exposure to environmental triggers, low-income households, exposure to chronic stress, child psychological problems, parental stress, family functioning, obesity, physical inactivity, and unhealthy diets. These risk factors often have complex interactions and inter-relationships. Comprehensive studies that explore the inter-relationships of these factors in accounting for asthma morbidity and mortality are needed and would help to inform clinical intervention. Considerable research has focused on interventions to improve adherence, asthma management, asthma symptoms, and quality of life for patients with asthma. Educational interventions combined with psychosocial interventions, such as behavioral, cognitive-behavioral, or family interventions, are beneficial and provide care in schools, homes, and emergency rooms can help to address barriers to accessing care for children and families. Additional recent research has explored the use of multidisciplinary, collaborative, integrated care with pediatric asthma patients, providing promising results. Integrated care could be ideal for addressing the multitude of complex psychosocial and wellness factors that play a role in childhood asthma, for increasing patient-centered care, and for promoting collaborative patient-provider relationships. Further research in this area is essential and would be beneficial. Asthma is the most common chronic illness among children in the United States, affecting an estimated 10.6 million (14.5%) children [Low-income, urban minority youth are disproportionately affected by asthma, such that higher asthma prevalence rates and disease morbidity have been found in children from low socioeconomic (SES) , 3 and uChildren living in low-income households often experience increased stress, such as family conflict, violence, lower quality home environments, dangerous neighborhoods, and polluted air and water , which iAdditionally, research has found that children living in low-income households are more likely to experience reduced parental support and involvement, to spend more time watching television, and to feel more of a lack of control over their lives and living environments . ChildreFurther, lower parental education has been associated with higher prevalence rates of asthma, lower adherence with asthma medications, and higher rates of hospitalizations for asthma . As pareIt is well established that asthma medications, when taken properly, reduce asthma morbidity, emergency room visits, and hospitalizations, and poor adherence to asthma controller medications is associated with increased severe asthma exacerbations , uncontrSeveral risk factors appear to undermine medication adherence in children, including male gender, non-Asian ethnic background, living in a larger household, older age at diagnosis , living A majority of research suggests that children with asthma display more behavior problems  and inteA child\u2019s asthma can also affect caregiver adjustment, psychological functioning, and experience of stress. A significant increased risk for psychological difficulties in caregivers of children with asthma is reflected in increased rates of depression , 38 and Recent research has focused on wellness factors, such as health promoting or health threatening lifestyle behaviors , and their relevance to patients with asthma. Investigators have found a positive relationship between obesity and asthma in pediatric populations , 41. ObeLow levels of physical activity can be seen in children with asthma and contribute to obesity and psychological health problems. For example, children with asthma have been shown to have lower levels of physical activity , 49 and Similarly, diet is related to weight and affects asthma. Children who mostly eat a \u201cWestern\u201d diet, characterized by high amounts of fat and processed foods, have been shown to have higher asthma prevalence rates than children who eat diets with less fat and processed foods . The MedThere are a range of psychosocial interventions for children with asthma, such as educational programs, behavioral interventions, cognitive-behavioral therapy, family interventions, and/or community-based interventions. Research on the efficacy of psychosocial interventions is limited, inconclusive , 60, andSome interventions, such as self-management training and education, are considered well-established and essential parts of treatment for asthma patients throughout their course of care. Research on these programs has found benefits for children with asthma, including improved knowledge and confidence regarding disease management , 62, impGiven concerns regarding lack of access to effective interventions, particularly for children from disadvantaged backgrounds, some investigators have increasingly focused on exploring school-based, emergency-room based, and home-based educational interventions. When these interventions included parents, results indicated that parent self-efficacy for disease management improved . EmergenDespite these results, comprehensive meta-analyses of results across studies have concluded that education interventions, without additional interventions, are not sufficient for improving asthma management and health outcomes . InvestiFor providers working with overweight pediatric patients, interventions to increase levels of physical activity and reduce unhealthy eating behaviors is emphasized . A behavintegrated care - that addresses mental health, patient education, and family functioning in addition to traditional medical care [Given the complex array of factors influencing onset and severity of asthma, addressing this challenge requires bringing together multiple intervention components tailored to address the needs of individual children and their families. Recent evidence points to the importance of comprehensive, collaborative, multi-disciplinary care \u2013 known as cal care . Guidelical care , for exacal care . As suchcal care , 84, famIntegrated care programs that provide integrated care have demonstrated significant improvements in asthma symptoms, perceived competence in asthma management, reduced corticosteroid use, and improved quality of life for caregivers and children , 86. In Integrated care can occur in multiple settings according to level of patient need. Pediatric psychologists are often employed in inpatient settings or in tertiary care clinics as a part of the consultation-liaison services , but areA range of environmental, psychosocial, behavioral, and lifestyle risk factors are associated with asthma exacerbations and morbidity. These risk factors have complex interactions and bidirectional relationships see Fig.\u00a0. The vasAccordingly, comprehensive approaches to treatment that consider the interplay between personal, familial, and environmental risk factors are needed. Recent research has underscored the importance of multidisciplinary, collaborative, integrated care for pediatric asthma patients with promising results. Such a comprehensive approach is ideal for addressing the multitude of complex, inter-related psychosocial and wellness/lifestyle factors that play a role in childhood asthma. This integrated care approach could also be productive for increasing patient-centered care, shared decision making, and collaborative relationships between families and providers. Further research in this area is needed and would be beneficial."}
+{"text": "Chronic, unremitting pain is perhaps the most common reason that patients seek medical care. In general, conservative techniques, such as medical management, are implemented as first-line therapy. Local anesthesia and lytic procedures, followed by interventional techniques, such as dorsal column stimulation and intrathecal drug delivery systems, are second-line therapies. However, for refractory and severe pain, which is not adequately controlled by other modes of therapy, new emerging options, including molecular or gene therapy, may become more widely utilized as experimental results are translated into clinical options."}
+{"text": "Erythema nodosum (EN) is associated with many systemic diseases and infections. This case report provides an image of erythematous nodules, an overview of the various causes of EN, and the laboratory tests and imaging that can be done in the emergency department to narrow its broad differential diagnosis. A 26-year-old male presented to an emergency department (ED) in Southern California with two days of symmetrical, erythematous, and painful subcutaneous nodules. The nodules began on his thighs and spread to his anterior lower legs . He alsoStreptococcus pyogenes, yersiniosis, Chlamydia, histoplasmosis, coccidioidomycosis, tuberculosis, Campylobacter), drugs , systemic illnesses such as inflammatory bowel disease and sarcoidosis, pregnancy, and malignancy.1-antitripsin deficiency, cytophagic histiocytic panniculitis, lupus panniculitis, and nodular fat necrosis.EN is a panniculitis resulting from a delayed hypersensitivity reaction.CPC-EM CapsuleWhat do we already know about this clinical entity?Erythema nodosum (EN) presents as tender, erythematous cutaneous nodules. It can be idiopathic or associated with various infections, systemic diseases, and drugs.What is the major impact of the The How might this improve emergency medicine practice?Given the broad spectrum of conditions associated with EN, this case report addresses how to recognize and efficiently workup EN in the emergency department."}
+{"text": "HAIR-AN syndrome  is a subset of the polycystic ovary syndrome, where the patients demonstrate severe insulin resistance. It is theorized that both genetic and environmental factors, such as obesity, give rise to the development of HAIR-AN. Diagnosis is primarily clinical, with laboratory values lending further support. Treatment is aimed at decreasing insulin resistance, regulating ovulation, and decreasing acne, acanthosis nigricans, and hirsutism."}
+{"text": "The orexin-A/hypocretin-1 and orexin-B/hypocretin-2 are neuropeptides synthesized by a cluster of neurons in the lateral hypothalamus and perifornical area. Orexin neurons receive a variety of signals related to environmental, physiological and emotional stimuli, and project broadly to the entire CNS. Orexin neurons are \u201cmulti-tasking\u201d neurons regulating a set of vital body functions, including sleep/wake states, feeding behavior, energy homeostasis, reward systems, cognition and mood. Furthermore, a dysfunction of orexinergic system may underlie different pathological conditions. A selective loss orexin neurons was found in narcolepsia, supporting the crucial role of orexins in maintaining wakefulness. In animal models, orexin deficiency lead to obesity even if the consume of calories is lower than wildtype counterpart. Reduced physical activity appears the main cause of weight gain in these models resulting in energy imbalance. Orexin signaling promotes obesity resistance via enhanced spontaneous physical activity and energy expenditure regulation and the deficiency/dysfunction in orexins system lead to obesity in animal models despite of lower calories intake than wildtype associated with reduced physical activity. Interestingly, orexinergic neurons show connections to regions involved in cognition and mood regulation, including hippocampus. Orexins enhance hippocampal neurogenesis and improve spatial learning and memory abilities, and mood. Conversely, orexin deficiency results in learning and memory deficits, and depression. Orexin A and B are excitatory hypothalamic neuropeptides playing a relevant role in different physiologic functions such as sleep/wake rhythms and thermoregulation, control of energy metabolism, cardiovascular responses, feeding behavior, and spontaneous physical activity (SPA).At the end of the last century, Sakurai et al.  firstly More recent studies focused the attention on the role of the orexins in mood and emotional regulation, energetic homeostasis, reward mechanisms, drug addiction, arousal system, and sleep and wakefulness . OX1R presents higher affinity for orexin A than B and transmits signals throughout the G-protein class activating a cascade that leads to an increase in intracellular calcium concentration. By contrast, OX2R binds the two subtypes of orexin with similar affinities, probably associated to a G inhibitory protein class -terminal pyroglutamyl residue, two intra-chain disulphide bonds and carboxy (C)-terminal amidation, while Orexin B is a linear neuropeptide sized 28 amino acids, C-terminally amidated. The N-terminal portion presents more variability, whilst the C-terminal portion is similar between the two subtypes. The orexins activity is modulated by their specific receptors , hippocampus (CA2), amygdala, stria terminalis bed nucleus (BST), PVT, anterior hypothalamus, dorsal raphe (DR), ventral tegmental area (VTA), locus coeruleus (LC), and laterodorsal tegmental nucleus (LDT)/pedunculopontine nucleus (PPT) , paraventricular nucleus (PVN), LHA, BST, PVT, DR, VTA, LDT/PPT, CA3 in the hippocampus, and medial septal nucleus  injection of orexins effects during the light period, which induces feeding behavior in rodents and zebrafishes, probably for a direct action on lateral hypothalamic area containing neurons modulated by glucose concentration. In fact, the high concentrations of glucose and leptin tend to hyperpolarize orexinergic neurons, while low concentrations of glucose and ghrelin depolarize them. Therefore, the orexinergic system discriminate physiological variation in glucose levels due to meals modulating in this way energy balance according to food intake (Monda et al., 2-adrenergic signaling and consequently peripheral energy expenditure. A persistent wake-state mediated by orexins could also be important for food intake motivation. When facing reduced food availability, animals adapt with a longer awake period, revolutionizing their normal pattern of activity (Viggiano et al., Shiuchi et al.  observedObesity is a complex multifactorial condition lowering health quality and many effects such as metabolic syndrome, type 2 diabetes mellitus, coronary heart disease, sleep apnea syndrome, and reduced in life expectancy (Must et al., Orexin A has also been discovered to promote SPA and NEAT as effect of administration into specific cerebral areas (i.e., rostral LH, hypothalamic paraventricular nucleus, nucleus accumbens, locus coeruleus, dorsal raphe nucleus, tuberomamillary nucleus, substantia nigra, Hara et al., Orexin system seems to play a unified role in coordinating motivational activation under numerous behavioral conditions (James et al., Regulatory mechanisms at the base of reward system are shown in Figure Animal studies suggest that orexinergic system may enhance hippocampal neurogenesis influencing learning and memory processes. In 2004, Wayner et al. . PTZ indMoreover, Orexin-A seems to be implicated in social memory, the ability to distinguish and remember familiar from novel conspecifics (Yang et al., Interestingly, physical exercise produces an increase of orexin-A level in cerebrospinal fluid of rats, dogs and cats, and in plasma of humans (Messina G. et al., Orexin is necessary for healthy life because of the important and relevant homeostatic functions controlled and organized directly or not. Orexin role is not only limited to the brain areas, because it involved also in metabolic regulation.AM, VM, AV, IV, MR: conceived the study, participated in its design, and wrote the manuscript. FP, DT, MS, NF, FN, LC, EN: contributed to the conception and design. SC, MC, VD, GC, MPM, DI, MM, GM: drafted the article and revised it critically for important intellectual content. DI revised grammar and English form; GM: final approval of the version to be published. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer IS declared a shared affiliation, though no other collaboration, with several of the authors MC, FP, MR to the handling Editor, who ensured that the process nevertheless met the standards of a fair and objective review."}
+{"text": "Calciphylaxis is a rare, but life-threatening, disease, mostly seen in patients with renal failure, especially those undergoing dialysis. It is characterized by violaceous tender areas of cutaneous plaques, necrosis, and eschar formation, mostly involving toes and fingers, but rarely the penis. Peripheral pulses are mostly preserved. The parathyroid hormone (PTH) level is elevated, along with raised calcium phosphorus product. There is radiological evidence of blood vessel and soft tissue calcification. Predisposing factors are obesity and diabetes. It is rarely encountered by a urologist and closely resembles penile gangrene."}
+{"text": "Accurate aphasia diagnosis is important in stroke care. A wide range of language tests are available and include informal assessments, tests developed by healthcare institutions and commercially published tests available for purchase in pre-packaged kits. The psychometrics of these tests are often reported online or within the purchased test manuals, not the peer-reviewed literature, therefore the diagnostic capabilities of these measures have not been systematically evaluated. This review aimed to identify both commercial and non-commercial language tests and tests used in stroke care and to examine the diagnostic capabilities of all identified measures in diagnosing aphasia in stroke populations.Language tests were identified through a systematic search of 161 publisher databases, professional and resource websites and language tests reported to be used in stroke care. Two independent reviewers evaluated test manuals or associated resources for cohort or cross-sectional studies reporting the tests\u2019 diagnostic capabilities  in differentiating aphasic and non-aphasic stroke populations.Fifty-six tests met the study eligibility criteria. Six \u201cnon-specialist\u201d brief screening tests reported sensitivity and specificity information, however none of these measures reported to meet the specific diagnostic needs of speech pathologists. The 50 remaining measures either did not report validity data (n = 7); did not compare patient test performance with a comparison group (n = 17); included non-stroke participants within their samples (n = 23) or did not compare stroke patient performance against a language reference standard (n = 3). Diagnostic sensitivity analysis was completed for six speech pathology measures , however all studies compared aphasic performance with that of non-stroke healthy controls and were consequently excluded from the review.No speech pathology test was found which reported diagnostic data for identifying aphasia in stroke populations. A diagnostically validated post-stroke aphasia test is needed. Aphasia affects up to 42% of stroke survivors  and impaThe accuracy of aphasia diagnostic procedures has important implications in stroke care. Epidemiological studies vary significantly with respect to their diagnostic criteria for aphasia  often lePost-stroke language functioning is currently evaluated through a range of clinical measures and assessments in acute clinical care. Neuroimaging studies have identified high correlations between lesion site and aphasia, where site and size of lesion have been found to be important factors in predicting recovery ,12. WhilA wide range of language tests are currently used in post-stroke care . Stroke Brief screening tests such as the Frenchay Aphasia Screening Test  and LangSpeech pathologists are typically responsible for diagnosis of aphasia resulting from stroke . Tests uEl Hachioui et al  conducteEl Hachioui et al  and otheGiven the importance of prompt, accurate identification of acute post-stroke language deficits in stroke management, this review had two main aims. Firstly, to identify both commercially published and other non-commercially available adult language tests. Tests were identified through two sources; firstly, through a systematic search of commercial and academic publishers, stroke and speech pathology resource webpages and other professional websites; secondly, from language tests which have been reported to be used by clinicians in stroke care. The second aim of the review was to examine the test manuals, materials or any associated psychometric resources of all identified tests to determine which language tests compared patient test performance against that of a reference standard language measure and reported sensitivity and specificity data in differentiating between aphasic and non-aphasic stroke populations. This review aims to comply with the PRISMA guidelines for systematic reviews  S1 Tabl.Tests were collected from a systematic search of the following academic and commercial publishing websites, speech pathology and stroke websites and resource webpages and professional websites: ABC-CLIO, AbeBooks, Academic Press, Academic Press Corporation, Adam Matthew Digital, Alexander Street Press, Allen Press, Allied Publishers, Amazon, American Book Company (1996), American Psychological Association, Ann Arbour Publishers, Aphasia Institute, Arena , ASHA (Store), Ashgate Publishing, Bedford-St. Martin's (\u201cMacmillan Learning\u201d), Bentham Science Publishers, Bepress, Berg Publishers, Berghahn Books, BioMed Central, BioOne, Bioscientifica, BookDepository, Booktopica, Boydell & Brewer, Brill Publishers, Brunswick Books, BUROS: Centre For Testing, Caister Academic Press, Cambria Press, Carl Hanser Verlag, Carl Heymanns Verlag, Carolina Academic Press, CCD Publishing, Channel View Publications, Chemistry Central, CNKI, Cold Spring Harbor Laboratory Press, College Publications, Co-op, Copernicus Publications, Dunedin Academic Press, DVV Media Group, Dymocks, E. Schweizerbart, EBSCO Information Services, EDP Sciences, Edward Elgar Publishing, ELife Sciences Publications, Elsevier, Emerald Group Publishing, Flat World Knowledge, Freund Publishing House, Future Medicine, Global Speech Therapy Direct, Gorgias Press, Gotland Museum, Greenbranch Publishing, Hayden-McNeil, Henry Holt and Company, Hindawi Publishing Corporation, Hogrefe, Humana Press, Inderscience Publishers, Informa, Ingenta, InteLex Past Masters, International Medical Press, International Universities Press, IOP Publishing, IOS Press, Ivyspring International Publisher, JMIR Publications, John Benjamins Publishing Company, John Donald (imprint), Jones & Bartlett Learning, Karger Publishers, K\u00f6nigshausen & Neumann, Landes Bioscience, Legenda (imprint), Libertas Academica, Linguisystems, Lippincott Williams & Wilkins, Litwin 43 Books, LLC, Living Reviews, M. E. Sharpe, Maney Publishing, Martinus Nijhoff Publishers, Mary Ann Liebert, Inc., MDPI, The Medical Letter, Inc., Medknow Publications, Mettler & Salz, Mohr Siebeck, NASW Press, Nature Publishing Group, Nauka (publisher), Naukova Dumka, Neura, Nova Science Publishers, OMICS Publishing Group, Open Court Publishing Company, Ovid Technologies, Palgrave Macmillan, Papery Open Science Aggregated, PAR Inc., Pearson Clinical, Peerage of Science, PeerJ, Peeters (publishing company), Pensoft Publishers, Perspectivia.net, Peter Lang (publisher), Pickering & Chatto Publishers, Pluto Press, Polity (publisher), Pro-Ed , Pro-Ed Inc., Pulsus Group, Rodopi (publisher), Routledge, Rowman & Littlefield, SAGE Publications, Verlag Anton Saurwein, Sciences Nat, Scientific Research Publishing, Sinauer Associates, Smithsonian Institution Press, Springer, Springer Nature, Springer Publishing, Springer Science + Business Media, SPW Publishing, Stroke Engine, T&T Clark, Taylor & Francis, Technika (publisher), Technosphera (publisher), Telos , The Nile, The Therapy Store, Thieme Medical Publishers, Trove National Library of Australia, Tsehai Publishers, Ubiquity Press, Ukrainian Encyclopedia (publishing), Universal Publishers (United States), University of Hertfordshire Press, University of Minnesota Press, University Press of America, Urban & Schwarzenberg, Wageningen Academic Publishers, Wharton School Publishing, Wiley-Blackwell, Winslow Resources, Wolters Kluwer, Woodhead Publishing, Wordery, World Scientific.The following search strategy was applied for Booktopia \u2018Popular Medicine & Health\u2019 [keyword search], \u2018aphasia\u2019, \u2018Language & Linguistics\u2019 [keyword search], \u2018Psychology\u2019 [keyword search], \u2018aphasia test\u2019, \u2018language test\u2019, \u2018dysphasia.\u2019 Further search terms included: condition (aphasia OR dysphasia OR language) setting  population  and instrument . The search strategy was adapted for each website, resource page or publisher\u2019s database. No further search limits or restrictions on publication date were applied. The reference lists of the selected tests were checked to detect additional publications. The search was completed 5 May 2017.To ensure findings replicate clinical practice and to identify tests in use but no longer in publication, language tests reported to be used by speech pathologists in their stroke care  were alsDocuments were eligible for inclusion if they were designed to assess language or language-based communication  in adults as defined as: impaired language functioning occurring anywhere across the severity spectrum from severe aphasia to mild conditions, occurring within any of the language modalities of verbal expression, auditory comprehension, reading, writing and gesture. Non-language specific tests (e.g. cognition), paediatric tests and documents not available in English were not included. Tests were excluded if they did not have psychometric resources or materials reporting on the test\u2019s validity or if the study did not compare aphasic stroke test performance with that of a non-aphasic stroke comparison group. The aim of the study was to evaluate the ability of identified language tests to identify aphasia within stroke-only populations. Tests which used a study population of non-stroke aphasic patients such as those with disorders arising from traumatic brain injury, tumour or Alzheimer\u2019s disease or for which the aetiology of aphasia for study participants was not stated were therefore excluded. Included studies were those able to report on the accuracy of the test in differentiating aphasic and non-aphasic stroke participants only, and not the test performance of the non-stroke aphasic patient. As per previous aphasia systematic reviews , this stIncluded tests were examined for documented psychometric ability to detect post-stroke aphasia. Tests had to report on results  of patient test performance and that of a reference language measure. Studies could use cross-sectional or cohort design and had to report on  the sensitivity and specificity of the measure. Speech pathologists  were the target health professional. No test administration time limits were applied.All document titles obtained from the search were reviewed for eligibility. Where eligibility could not be determined from title alone, documents were retrieved and separately evaluated by two reviewers. Language tests meeting the initial criteria underwent validity analysis. Psychometric data was obtained directly from the language test manuals, published studies cited within manuals or from any associated online or published material or from published psychometric resources. Tests, test manuals and associated resources were obtained online, from The University of Queensland speech pathology departmental or library holdings or obtained via their international library loans system. Where manuals or associated resources were no longer in publication or in circulation and could not be sourced internationally via library networks, psychometric text books which directly reported on test manual\u2019s psychometric data were consulted ,40,41. FSearch results and test inclusion data were reported in a flowchart of document selection. Tests which underwent validity analysis were reported in a second flowchart of document selection and evaluation.A total of 4517 documents were analysed. After screening titles, 139 documents from the database and online search and 40 tests from Vogel et al  were retTests and test studies did not meet the study eligibility criteria for a variety of reasons. Six tests were non-speech pathology specific measures intended for \u2018non-specialist\u2019 clinicians ,20\u201322,28th Edition [Of the remaining 26 measures, 23 had studies which included non-stroke populations within their study samples \u201387,90\u201394 Edition  and MacD Edition  evaluate Edition . All thr Edition ,82 and/o Edition ,78,82 inThe final three tests , the AphThe aim of this review was twofold. Firstly, to identify adult language tests from a systematic search of commercial and academic publishers, stroke and speech pathology webpages and other professional websites and language tests reported to be used by clinicians in stroke care . SecondlSome included tests appeared to indicate they had diagnostic capabilities  however test diagnostic accuracy was rarely examined, with only three studies ,78,82 evThe method of publication of language test studies may be a factor contributing to the quality of psychometric validation of the measures. The notable absence of peer-reviewed journal publications of the psychometrics for commonly used speech pathology tests has previously been reported ,15,30. WThe findings of this review need to be considered in the context of the following study limitations. The access and location of test manuals and test psychometric data were a significant factor in conducting this review. Some tests listed online, on publication databases or those reportedly used in stroke care were no longer in circulation or available to access or purchase, and consequently these tests\u2019 psychometrics were instead obtained through published normative text books. The reliability of the reporting on these psychometrics is therefore dependent upon the quality and comprehensiveness of the reporting within these texts and on some occasions this information was lacking. Where information was available, this was reported fully within the psychometric tables.Tests in this review were also specifically examined for their psychometric capabilities in diagnosing acute post-stroke language deficits. It should be noted however that analysed tests had a variety of aims, including tests aimed at examining functional language abilities (e.g. Communication Activities of Daily Living (CADL-2) ) and assAccurate diagnosis of aphasia is an important component of stroke care . This reS1 Table(DOCX)Click here for additional data file."}
+{"text": "Dear Editor,caf\u00e9-au-lait spots were noted, together withbilateral axillary freckles (A healthy, nonsmoking, 27-year-old male patient was referred to our institution forinvestigation of a three-month history of progressive dyspnea. He reported that hisdyspnea worsened on physical exertion and significantly limited his daily activities. Hereported no cough, fever, night sweats, or weight loss; nor did he report any new lumpsor masses during the last three months. Upon skin examination, multiple subcutaneousnodules and freckles .Collectfreckles -d. Becau. Overall,these tumors are associated with high local invasion, rapid growth, and early distantmetastasis unless they are excised in a timely manner. The most common locations for MPNST inneurofibromatosis patients are the extremities, head, and neck. Thoracic involvement,however, is remarkably rare, few cases having been reported. According to the size and location of theintrathoracic tumor, compressive manifestations such as pain, dyspnea, dysphagia, andsuperior vena cava syndrome may be the presenting manifestations, as seen in ourpatient, who reported dyspnea as the sole symptom related to his MPNST,4.MPNSTs are exceedingly rare sarcomas in the general population, with a lifetime risk ofless than 0.01%. Conversely, in association with neurofibromatosis, these tumors arisein higher frequency because of malignant transformation from preexisting plexiformneurofibromas-6. Therefore, any suspicious lesions should generally prompt histologicalsampling.The identification of MPNST in neurofibromatosis patients may be troublesome for severalreasons. First, the existence of multiple benign neurofibromas may delay theidentification of changes in plexiform neurofibromas. In addition, because superficialcutaneous neurofibromas do not undergo malignant transformation, MPNSTs often remainundetected until they reach a moderate size or cause compressive symptoms. Furthermore,CT and magnetic resonance imaging might not be accurate enough to differentiate benignfrom malignant lesions with any degree of reliability in the very early stages, althoughadvances have been made in the area of positron emission tomography.Although the mainstay of successful treatment of an MPNST is surgical excision afterdisease staging, neoadjuvant chemotherapy may be employed in order to reduce itsdimensions beforehand, especially in patients with lesions surrounding vital organs.Radiotherapy might also delay recurrence, although it has not been shown to improvesurvival in MPNST patients"}
+{"text": "Dear Editor,A 23-year-old male patient presented with a 36-h history of intense, sudden, progressiveabdominal pain, predominantly in the left hypochondrium, irradiating to the ipsilateralinfrascapular region. He reported no previous trauma, fever, headache, fatigue, myalgia,arthralgia, skin alterations, or comorbidities. During the clinical interview, hereported moderate smoking and the routine use of an illicit drug (cocaine), includinghours prior to the onset of pain. On physical examination, he was well-oriented,hemodynamically stable, and afebrile. The serology was negative for hepatitis B,hepatitis C, and dengue, and the results were normal for antineutrophil cytoplasmicantibody, antinuclear factor, the venereal disease research laboratory test, urea,creatinine, erythrocyte sedimentation rate, C-reactive protein, and coagulation profile.Hemoglobin electrophoresis showed no alterations.Computed tomography (CT) showed a dense collection, compatible with hematic material, inclose proximity to the spleen, as well as showing hemoperitoneum . ArterioGiven that there was no perisplenic trauma or adhesions suggestive of previous trauma andthat the macroscopic aspect of the spleen was normal on the CT scan and in theexploratory laparotomy, together with the facts that diseases affecting the splenicparenchyma were ruled out and that the patient had used cocaine immediately prior to theepisode, we established the working diagnosis of nontraumatic splenic hemorrhagesecondary to cocaine use. During clinical follow-up, the patient progressed well,without complications.-5. Splenic hemorrhages are rarely encountered withoutprior trauma and can have fatal consequences, which makes their early diagnosisessential. The main nontraumatic conditions include neoplasms, as well asinflammatory/infectious, iatrogenic, and mechanical processes.Recent studies in the radiology literature of Brazil have emphasized the importance of CTand magnetic resonance imaging scans to improving the diagnosis in nontraumaticabdominal disorders,7.The clinical signs of nontraumatic splenic hemorrhage are similar to those found in casesresulting from trauma, including pain in the upper left quadrant, with or withoutirradiation to the left shoulder, caused by diaphragmatic irritation, evolving tohemodynamic instability in the most severe cases. Such manifestations are nonspecificand cannot be characterized solely by physical examination. Therefore, inhemodynamically stable patients, CT evaluation is fundamental to the characterization ofthe affected organs. Themechanism thought to trigger bleeding during or after cocaine use is stimulation ofalpha-adrenergic receptors, which produce vasoconstriction with a consequent increase inabdominal blood pressure and a reduction of up to 20% of the splenic volume, promotinghigh-pressure blood flow in a retracted parenchyma and with a low concentration ofconnective tissue, making the spleen more prone to bleeding, which can be triggered evenby coughing,9.Currently, Brazil is the second largest consumer of cocaine and its derivatives, theleader being the United States,7,9-11.In nontraumatic splenic hemorrhage, the differential diagnoses include dengue, infectiousmononucleosis, polyarteritis nodosa, segmental arterial mediolysis, neoplasms,coagulopathy. and hemoglobinopathyIn conclusion, although nontraumatic splenic hemorrhage is uncommon, the possibility ofcocaine use as a triggering event should be considered, especially in young, previouslyhealthy patients with no comorbidities to explain such an event."}
+{"text": "Preoperative diagnosis of peritoneal tuberculosis is often difficult because of confusion with ovarian cancer. A 56-year-old woman was admitted to our hospital with abdominal fullness. Ascites, prominent bilateral ovaries, and elevated CA-125 were noted. Computed tomography showed thickened peritoneum and strandings in the mesentery and omentum. Exploratory laparotomy was performed under the provisional diagnosis of ovarian cancer, but the final diagnosis was peritoneal tuberculosis. Careful evaluation of bilateral fallopian tubes and ovaries and peritoneum are helpful for correct diagnosis. Diagnosis of extrapulmonary tuberculosis is difficult. Tuberculous peritonitis, accounting for 1 %-2 % of all tuberculosis cases, is caused by abdominal or pelvic tuberculosis that involves the peritoneum , and CA-125 level elevated to 188.6 U/mL . Abdominopelvic CT revealed multiloculated ascites in her abdomen and pelvis, thickened peritoneum, strandings in the omentum, small mesenteric nodules, enlarged mesenteric and paraaortic lymph nodes, prominent ovaries, and dilated fallopian tubes Figure 1. There wThe final diagnosis from the biopsy was tuberculosis peritonitis. Microscopic sections showed granulomatous inflammation with central caseous necrosis, epithelioid histiocytes and Langhans giant cells in the ovary, fallopian tube, and peritoneum Figure 2A. MycobacTuberculous peritonitis is a rare manifestation of tuberculosis, occurring in less than 4 % of tuberculosis patients . It is CA-125, the common tumor marker of ovarian cancer, is also elevated in patients with pulmonary and extrapulmonary tuberculosis . BilginThe most common CT features of tuberculous peritonitis in published reports include high-density lymphadenopathy, high-density ascites, and thickening and nodularity of peritoneal surfaces, mesentery, omentum, and bowel walls. In appearance, there is significant overlapping, and none of these CT findings is pathognomonic for tuberculous peritonitis . DisproNone declared. The authors state that they have no Conflict of Interest (COI)."}
+{"text": "The Competing Interests statement is incorrect. The correct Competing Interests statement is: The following authors hold or have held positions at the Benson-Henry Institute for Mind Body Medicine at Massachusetts General Hospital, which is paid by patients and their insurers for running the SMART-3RP and related relaxation/mindfulness clinical programs, markets related products such as books, DVDs, CDs and the like, and holds a patent pending  entitled \"Quantitative Genomics of the Relaxation Response\": JS, MD, JD, DM, RG, GF, HB."}
+{"text": "Pediatric hypertension is increasing and the incidence of hypertension in the pediatric population. Although reading blood pressure for children is difficult, but it is not be missed by emergency physicians. The emergency physician must certify adequate follow-up for asymptomatic mild hypertension without end organ damage. In contrast hypertension crisis needs evaluation and initiation of treatment in the emergency departments and blood pressure reduction should be performed before the cause of the hypertension is known.Pediatric hypertension is increasing due to high salt intake, childhood obesity, decrease physical activity, and hyperlipidemia. The incidence of hypertension in the pediatric population, assumed to be 2.5% to 5% . AccordiBlood pressure is determined by both peripheral vascular resistance and cardiac output. Factors such as volume overload or sympathetic stimulation by tumors, renin-angiotensin system, drugs, or other processes, may have a main role in the development of hypertension ,5. EssenIn cases with sever hypertension a careful history and physical examination must be performed. an appropriate history include frequency of urinary tract infections, dysuria, hematuria, frequency, unexplained fevers, edema, history of umbilical artery catheterization as neonate, history of head trauma, ingestion of illicit drugs, oral contraceptives, rapid withdrawal of hypertension drug agents, and history of flushing, sweating, fever, weight loss. In the physical examination should paying a particular attention to the cardiovascular system, neurological and renal system such as four-limb blood pressures, Heart rate, respiratory rate, heart sound, lung sound, oxygen saturation, funduscopic examination, neurologic examination, auscultation abdomen ,5,7.a) chest x-ray, (b) ECG, (c) renal ultrasonography, and (d) echocardiography. Other imagings including renal arteriography, and brain CT-scan are dictated by the clinical features  have been completely observed by the authors.None."}
+{"text": "After publication of this article , the autIn the original article, the author names appear as the following:Gallone Maria Serena, Gallone Maria Filomena, Larocca Angela Maria Vittoria, Germinario Cinzia and Tafuri Silvio.However, this is incorrect, and the author names should appear as per the below:Maria Serena Gallone, Maria Filomena Gallone, Angela Maria Vittoria Larocca, Cinzia Germinario, Silvio Tafuri.The author names have been corrected in the author list and the citation for this Erratum."}
+{"text": "A 67-year-old woman with hypertension, type 2 diabetes and chronic venous insufficiency (CVI) was admitted to the emergency room due painful left leg after a fall from own height. The fall had been a true mechanical one, with no preceding dizziness, chest pain, or palpitations. On physical examination, small chronic ulcer and subcutaneous white calcifications were observed. Hemogram, electrolytes, cardiac enzymes, parathyroid hormone, calcium, phosphorus, serum creatinine and 25-hydroxycholecalciferol were unremarkable. A plain radiograph of her left leg showed no fracture and multiple radio-opaque images, clearly outlined in the subcutaneous tissues. The diagnosis of dystrophic subcutaneous calcification was made. The patient refused clinical follow-up. Calcinosis cutis (CC) is defined as the deposition of calcium salts in the skin. The condition is divided into 5 types: calciphylaxis and dystrophic, metastatic, idiopathic and iatrogenic CC. Dystrophic calcification is the most frequent type of CC. Serum calcium and phosphorus levels are normal. Local tissue damage, such as degeneration of collagen fibres, elastic fibres, fat cell necrosis caused by trauma, infections, neoplasms and many other conditions, are considered to be precipitating factors. Calcium deposits impair normal epithelial growth and cause persistent inflammation with a foreign body reaction, resulting in delayed wound healing. Dystrophic calcification is a major cause of failure of conservative ulcer management and it is considered a challenge in CVI patients."}
+{"text": "Inflammation and Regeneration, and an international publisher, BioMed Central. Inflammation and Regeneration is the official journal of the Japanese Society of Inflammation and Regeneration. Inflammation and Regeneration provides a forum which covers a wide range of scientific topics in the research field of inflammation and basic and clinical regenerative medicine, such as basic biology of somatic stem cells [It is my great pleasure to announce the launch of new alliance between our journal, em cells , pluripoem cells , direct em cells , cell them cells , diseaseem cells , immunorem cells , immunorem cells , tissue em cells , tissue em cells , interacem cells , dendritem cells , vasculaem cells , cancer em cells , regulatem cells , intestiem cells , inflammem cells , cellulaem cells , and newem cells . As are"}
+{"text": "Cerebellar Glioblastoma Multiforme is a rare condition, a review of the world literature and two further cases are presented.Cerebellum, gliablastoma multiforme, surgery, radiotherapy."}
+{"text": "Acute transverse myelitis (ATM) is a rare inflammatory demyelinating disorder characterized by relatively acute onset of motor, sensory, and autonomic dysfunction. Children comprise 20% of total cases of ATM. In this review, we described the current literature on childhood ATM, focusing on the epidemiology, pathogenesis, clinical presentation, approach to diagnosis, differential diagnosis, treatment and outcome in the pediatric population. We searched the related articles in electronic databases such as Scopus, EMBASE, Google Scholar, and PubMed. All study designs were included and the essential key words for searching were myelitis, acute transverse myelitis, childhood transverse myelitis, and acquired demyelinating syndromes. The related data focusing on the epidemiology, pathogenesis, clinical presentation, diagnostic approach and differential diagnosis, treatment and outcome of pediatric ATM were gathered and described. ATM is a heterogeneous disorder in children with a broad spectrum of clinical presentation, etiology, and outcome. It may be the first presentation of relapsing acquired demyelinating syndromes and also must be distinguished from compressive and noninflamatory myelopathies. Correct diagnosis is crucial for treatment and prognosis.  Childhood acute transverse myelitis (ATM), an inflammatory involvement of spinal cord, is a rare demyelinating and immune-mediated disorder of central nervous system (CNS) . It is pIn this review, we described the current literature on childhood ATM, focusing on the epidemiology, pathogenesis, clinical presentation, approach to diagnosis, differential diagnosis, treatment and outcome in the pediatric population. We searched the related articles in electronic databases such as Scopus, EMBASE, Google Scholar, and PubMed. All study designs were included and the essential key words for searching were myelitis, acute transverse myelitis, childhood transverse myelitis, acquired demyelinating syndromes. The related data focusing on the epidemiology, pathogenesis, clinical presentation, diagnostic approach and differential diagnosis, treatment and outcome of pediatric ATM were gathered and described.Epidemiology The incidence of pediatric ATM is 1.7-2 per million children yearly . Male toClinical features:The first presentation of ATM in children is usually back pain. Rapidly progressive motor deficits develop in the lower extremities. Initially, flaccid paresis and decreased deep tendon reflexes (DTRs) are often detected, but subsequently, this condition evolves to a state of increased tone and increased DTRs below the level of lesion during subsequent days up to 12 wk ,13. UrinInitial recovery occurs nearly 9 d after the onset of the disease  . The firSubtypes of ATM are described based on the clinical severity as well as the nature and extent of spinal cord involvement in imaging. Acute complete transverse myelitis (ACTM) includes symmetric motor, sensory and autonomic dysfunction on both sides below the level of the lesion concurrent with MRI lesions in one to two vertebral segments. In acute partial transverse myelitis (APTM), clinical presentation can be mild or asymmetric with involvement of one to two vertebral segments in MRI. Longitudinally extensive transverse myelitis (LETM) describes complete or incomplete dysfunction of the spinal cord with a lesion extending over three or more vertebrae ,10,17. LCerebrospinal fluid (CSF) findings are lymphocytosis  and increased protein level . In 20%-50% of children with definite ATM, CSF analysis shows normal protein levels and white blood cells count ,9,11. InThe most cases of ATM develop as an isolated post infectious disease (idiopathic ATM), but ATM can occur associated with other neuroinflammatory disorders including NMO, MS, and ADEM (secondary or disease-associated ATM). ATM can be associated with some other CNS disorders consisting of infections due to some pathogens such as Cytomegalovirus, Herpes viruses, Enteroviruses, Epstein-Barr virus, influenza virus, hepatitis A,B and C viruses, West Nile virus, HTLV1, mycoplasma, Varicella-Zoster virus , Zica viPathogenesisHistologic findings are different in idiopathic and disease-associated ATM, but inflammation and neural loss are seen in both . MonocytDiagnosis and evaluationThe diagnosis of TM is proposed when the patient present with signs and symptoms of bilateral sensory, motor and autonomic dysfunction localized to one or more spinal segments without evidence of a cord compression. Therefore, the following criteria are necessary for the diagnosis of ATM:1- Exclusion of compressive lesions, and2- Confirmation of spinal cord inflammation as detected by the following:2-1) the gadolinium enhancing lesion in MRI, or 2-2) CSF evidence of either pleocytosis or elevated immunoglobulin type G (IgG) indexHowever, the lack of the inflammation markers does not exclude ATM . DevelopBrain MRI with and without contrast for detecting MS or ADEM; CSF analysis for cell count, protein, glucose, OCBs, IgG index, and cytology; serum NMO IgG antibodies (anti-aquaporin-4 IgG); serum B12; methylmalonic acid; human immunodeficiency antibodies; thyroid function test; antiphospholipid antibodies, antinuclear antibodies, rheumatoid factor and anti-dsDNA . In moreDifferential diagnosisThree categories in the differential diagnosis of idiopathic ATM are as follows: 1. Other forms of myelopathy such as compressive or noninflammatory including epidural hematoma, intervertebral disk herniation, vertebral body fracture, ischemic myelopathy due to arterial compromise or venous hypertension . Spinal 2. Secondary ATM including cases due to identified causes such as infectious myelitis, a rheumatological disease (e.g. SLE and SS), paraneoplastic syndromes, demyelinating CNS disease . Enteroviruses have recently been reported to be mediated in acute flaccid myelitis due to direct invasion to motor neurons of spinal cord . Clear d3. Non myelopathic disorders can mimic ATM essentially Guillain-Barre syndrome (GBS). Clinical features of GBS including acute weakness and progressive motor and sensory dysfunctions resemble to ATM . HoweverRegarding the onset time of the symptoms of spinal cord syndrome, differential diagnosis are classified as follows: symptoms with acute or hyperacute onset should prompt consideration of spinal infarct, hemorrhage or disk herniation. Slowly progressive onset of the symptoms is in the favor of compressive myelopathy such as tumor, nutritional deficits, toxin exposure and hereditary disorders such as hereditary spastic paraplegia. Subacute presentation is in the favor of demyelination (TM or NMO), infections, and vasculitis (SLE)Treatment2 have been used in patients with SLE for improved outcome (US Food and Drug Administration FDA approved no treatments for ATM since lack of controlled clinical trials . Therapi outcome . Chronic outcome . In patients with the diagnosis of MS or NMO also, typical immunomodulatory drugs should be initiated after treatment of acute period . ConsultPrognosis and outcomeOutcome of ATM in children is better than adults, as almost 50% of children obtain recovery after 2 yr ,49. In gWe suggested monitoring of this population for cognitive problems . Apart fIn Conclusion, ATM is a heterogeneous disorder in children with a broad spectrum of clinical presentation, etiology, and outcome. It may be the first presentation of relapsing acquired demyelinating syndromes or occur as an isolated postinfectious condition. It also must be distinguished from compressive and noninflammatory myelopathies. Diagnostic evaluation, prognosis, recurrence risk, and treatment plans are different among these entities. Therefore, the correct diagnosis is crucial for treatment and prognosis."}
+{"text": "We report on three American men with chronic refractory pelvic pain, urinary symptoms, and sexual dysfunction who traveled to the Philippines for treatment. In the Manila Genitourinary Clinic, the patients were treated with microbial diagnosis, antimicrobial therapy, and 19, 27, and 21 prostatic massages respectively. All three patients underwent resolution of symptoms."}
+{"text": "MOlecular Database on Indian Insects (MODII) is an online database linking several databases like Insect Pest Info, Insect BarcodeInformation System (IBIn), Insect Whole Genome sequence, Other Genomic Resources of National Bureau of Agricultural InsectResources (NBAIR), Whole Genome sequencing of Honey bee viruses, Insecticide resistance gene database and Genomic tools. Thisdatabase was developed with a holistic approach for collecting information about phenomic and genomic information of agriculturallyimportant insects. This insect resource database is available online for free at http://cib.res.in.http://cib.res.in/ Insects play a major role in agricultural ecosystems  becauseMolecular Database On Indian Insects (MODII) has beendeveloped based on three-tier architecture of the client-servertechnology and multiple users can access at a time. MYSQL hasbeen used to store the information with Apache 2 web server asan interface in Linux environment. PHP has been used fordeveloping programs for login facility, submission of data in theform of sequences, insect information, etc. Google API, Webcrawler technique, Java applets have been used for other featureslike 'Keyword Search', 'View information' and for Distribution maps. The three-tier architecture of MODII has been depicted inThe 'Insect Pest Info' database has been developed to furnishinformation on insect pests based on the crop selection. Thedatabase gives information about the common name of the pest,the scientific name of the pest, taxonomy, identification anddamage details on the crop, distribution map and naturalenemies with QR code. There are around totally 400 pest detailsin the database. The crops list contains Rice, Wheat, Millets andMaize, Sugarcane, Oilseeds, Fiber, Pulses, Vegetables, Fruits,Plantation, Spices and Condiments, Tobacco, Ornamental,Jatropha and Green manure. The web pages have been developedfor the pests of these crops and the database has been updatedregularly. The homepage of Insect Pest Info has been given inThe database for generation of DNA barcoding of insects namedInsect Barcode Informatica (IBIn) was developed, which containsthe information on different orders of insects, viz., Coleoptera,Diptera, Embioptera, Ephemeroptera, Hemiptera, Hymenoptera,Lepidoptera, Neuroptera, Odonata, Orthoptera, Thysanopteraand Trichoptera. At present IBIn database contains 804 insectdetails with nucleotide sequences and barcodes. In India, only1274 insect species have been barcoded and in world 127694insect species have been barcoded even though the insectpopulation is more than 1 million worldwide [Developed Whole Genome Sequencing (WGS) database alongwith metadata and links have been established for 20 WGS ofagriculturally important insects of different orders likeColeoptera, Diptera, Hemiptera, Hymenoptera and Lepidopterato NCBI website. The list of insects has been given insupplementary Other Genomic Resources (OGR) has been developed formicrobial for which genome sequencing has been done from theinstitute ICAR-NBAIR. Presently, it contains 203 accessions alongwith metadata. Links have been established for these accessionsto the NCBI website. The metadata contains Meta-Info, Voucher-Info, Organism, Classification and Authors.Honeybee viruses are causing problem in honeybee production. This daManaging of insect pests is a challenge now-a-days sinceagricultural pests are developing resistance against insecticideslike organophosphates, synthetic pyrethroids, organo chlorinatesand other new groups . InsectiInsect Protein Model Database is under progress, which gives the3-D structure of insect protein prediction models. This helps tounderstand the insect protein structures, the target site for theinsecticides and the mutations in these proteins caused theresistance towards insecticides.Genomic tools are necessary to carry out analysis on the sequencedata and hence some of the tools like calculation of GC and ATpercentage, DNA to protein sequence (translation), reversecompliment, protein parameter analysis tool have beendeveloped and included into MODII.MOlecular Database on Indian Insects (MODII) contains severaldatabases like Insect Pest Info, Insect Barcode Information System(IBIn), Insect Whole Genome sequence (WGS), Other GenomicResources (OGR) of National Bureau of Agricultural InsectResources (NBAIR), Whole Genome sequencing of Honey beeviruses (hBV), Insecticide resistance gene database (IRGD) andGenomic tools (iGenTools). Molecular Database on Indian Insects(MODII) is available for free at http://cib.res.in. Phenomic andgenomic information of agriculturally important insects of Indiacan be accessed in one platform through this database. The insectresource database is useful for farmers, students, entomologists, and researchers to get information on agriculturally importantinsects."}
+{"text": "There is an error in affiliation 2 for authors Xueli Zhang, Congwei Sun, Zheng Zhang, Zhijun Dai, Yuan Chen, Xiong Yuan, Zheming Yuan, and Lanzhi Li. Affiliation 2 should be: Hunan Provincial Key Laboratory for Biology and Control of Plant Diseases and Insect Pests."}
+{"text": "Traditional Chinese Medicine (TCM) is increasingly getting clinical application worldwide. But its theory like QI-Blood is still abstract. Actually, Qi deficiency and blood deficiency, which were treated by Si-Jun-Zi-Tang (SJZT) and Si-Wu-Tang (SWT) respectively, have characteristic clinical manifestations. Here, we analyzed targets of the ingredients in SJZT and SWT to unveil potential biologic mechanisms between Qi deficiency and blood deficiency through biomedical approaches. First, ingredients in SWT and SJZT were retrieved from TCMID database. The genes targeted by these ingredients were chosen from STITCH. After enrichment analysis by Gene Ontology (GO) and DAVID, enriched GO terms with p-value less than 0.01 were collected and interpreted through DAVID and KEGG. Then a visualized network was constructed with ClueGO. Finally, a total of 243 genes targeted by 195 ingredients of SWT formula and 209 genes targeted by 61 ingredients of SJZT were obtained. Six metabolism pathways and two environmental information processing pathways enriched by targets were correlated with 2 or more herbs in SWT and SJZT formula, respectively. Traditional Chinese Medicine (TCM), being an effective treatment system, is increasingly getting clinical application worldwide. After more than 5000 years of clinical practice, nearly 100,000 classical and effective TCM formulae have been developed, but the effective mechanisms of most formulae remain unclearhttp://www.kegg.jp)http://www.megabionet.org/tcmid/) contains 3,791 diseases, 47,000 prescriptions, 8,159 herbs, 6,828 drugs, 25,210 compounds and 17,521 related targets, which facilitates the study of interactions between formula, ingredient, gene and disease to uncover the molecular biological mechanisms of TCM. Meanwhile, there are several network analysis tools for biological functionality of TCM-related network analysis, such as Cytoscape18Since the TCM formulae are normally composed of several medicinal herbs, and each herb normally has many ingredients, and each ingredient has a lot of targets, a formula is a complex biologic active network. Fortunately, along with the rapid development of life science and computer science, a variety of computational tools and bioinformatic database have been developed to facilitate the analysis of a large number of genes associated with complex ingredients of TCM formulaeIncreasing TCM researchers successfully analyzed pharmacological mechanism of TCM formulae by using TCM-related databases and data analysis tools232425As shown in Retrieving from TCMID, we obtained 152 genes targeted by 162 ingredients of Radix Angelicae Sinensis, 107 genes targeted by 28 ingredients of Ligusticum chuanxiong, 21 genes targeted by three ingredients of Rehmannia glutinosa, 42 genes targeted by eight ingredients of Paeonia albiflora , and 156Interestingly, there were obviously three main grouped clusters independent from each other in the network , two cluAfter analysis of pathway associated genes, we found that there were six metabolism pathways, including beta-Alanine metabolism, histidine metabolism, phenylalanine metabolism, tyrosine metabolism, ascorbate and aldarate metabolism, glycolysis/gluconeogenesis pathways, were correlated with 2 or more herbs in SWT formula and two environmental information processing pathways, calcium signaling pathway and neuroactive ligand-receptor interaction pathway were correlated with 2 or more herbs in SJZT formula .We also found that there were many disease associated pathways were enriched. According the differentiating criterion that if more than 66% of the genes targeted by ingredients of one formula associate with a term (pathway), the term (pathway) is considered specific for the formula, the disease associated pathways were differentiated into two categories, i.e. common pathway and different pathway. The common pathway, including viral carcinogenesis, thyroid cancer, chemical carcinogenesis, legionellosis and small cell lung cancer pathways are unspecific for SWT or SJZT. The different pathway were all specific for SWT, including amphetamine addiction, colorectal cancer, choline metabolism in cancer, bladder cancer, hepatitis B, pancreatic cancer, non-small cell lung cancer, prostate cancer, chagas disease (American trypanosomiasis), cocaine addiction, chronic myeloid leukemia, HTLV-I infection, p53 signaling pathways and pathways in cancer .As mentioned above, there were many cancer and other diseases associated pathways in the network , which mIn the non-disease associated network, pathways enriched with genes targeted by ingredients of SWT were mainly involved in material metabolism , including beta-Alanine metabolism, histidine metabolism, phenylalanine metabolism, tyrosine metabolism, tryptophan metabolism, ascorbate and aldarate metabolism, pentose and glucuronate interconversions, glycolysis/gluconeogenesis, retinol metabolism pathways . RetinolWhile pathways enriched by genes targeted by ingredients of SJZT mainly belonged to organismal system function, environmental information processing, metabolism and cellular processes pathways. The organismal system function pathways included thyroid hormone signaling pathway, ovarian steroidogenesis, prolactin signaling pathway and oxytocin signaling pathway (endocrine system), bile secretion pathway (digestive system), vascular smooth muscle contraction pathway (circulatory system) and serotonergic synapse (nervous system). The environmental information processing pathways included neuroactive ligand-receptor interaction pathway  and calcium signaling pathway . The metabolism pathways of SJZT were different to SWT, which mainly belong to lipid metabolism including linoleic acid metabolism and regulation of lipolysis in adipocytes pathways. The cellular processes pathway included Gap junction (cellular community), .p value less than 0.01 unspecific for SWT or SJZT. We considered them as the common pathways of SWT and SJZT. These pathways also belonged to organismal systems, metabolism, environmental information processing and cellular processes, including estrogen signaling pathway (endocrine system), GnRH signaling pathway (endocrine system), PPAR signaling pathway (endocrine system), GABAergic synapse (nervous system), Arginine and proline metabolism (amino acid metabolism), Steroid hormone biosynthesis (lipid metabolism), Metabolism of xenobiotics by cytochrome P450 (Xenobiotics biodegradation and metabolism), cAMP signaling pathway , TNF signaling pathway , Apoptosis (Cell growth and death), , .In order to clarify the difference between SWT and SJZT at gene level, we also screened different genes from differentiated pathways between SWT and SJZT .Combination therapy is the major feature of TCM, which is increasingly recognized by modern western medicine, such as cocktail therapy for HIVBlood deficiency normally manifests anaemia, vertigo, heart palpitations and menstrual discomfort. The SWT formula has effects on stimulating hematopoiesis in bone marrow, anti-coagulant, vasodilatation and sedative293335Applying syndrome differentiation through formula effect assessment, we could predict the pathways associated with blood deficiency and Qi deficiency syndromes according to the pathways enriched by SWT and SJZT, and then indirectly predict the molecular mechanism of blood and Qi.Interestingly, when using targets by ingredients of SWT and SJZT to enrich and construct the Network , there wExcept for disease associated pathways, SWT significantly influence amino acid and carbohydrate metabolism , which are closely related with nutrient substance. Abnormal glycolysis/gluconeogenesis was also found by another study about urine metabonomic in blood-deficient mouse modelDifferent from blood of TCM, Qi has functions of promoting substance metabolism and energy conversion, stimulating activity of organs, keeping blood circulating in vasculature, promoting human growth and development, maintaining normal temperature of human body, strengthening the ability of anti-infection, maintaining normal development of fetus in uterus and controlling the secretion and excretion of bile, sweat, urine, saliva, gastric and intestinal digestive juice.et al.et al.2+ to have activity. And, the hormone can influence the activity of calmodulin by regulating the concentration of intracellular Ca2+. Thyroid hormone has function of promoting human growth and development, calorigenic effect on maintaining normal temperature of body and function of stimulating substance metabolism and energy conversion, which can stimulate activity of organs. Ovarian steroidogenesis, prolactin signaling pathway, oxytocin signaling pathway can help to maintain normal development of fetus in uterus. All the functions of pathways enriched by SJZT are consistent with the actions of Qi of TCM.This study found that SJZT could influence several syntrophic pathways. Among them, bile secretion, linoleic acid metabolism, regulation of lipolysis in adipocytes pathways can affect bile secretion and lipid metabolism and then influencing lipid hormones synthesis; neuroactive ligand-receptor interaction, serotonergic synapse, gap junction pathway can influence the function of neuroendocrine system; thyroid hormone signaling pathway, ovarian steroidogenesis, prolactin signaling pathway, oxytocin signaling pathway can regulate corrective hormones secretion; vascular smooth muscle contraction can regulate the blood flow and pressure and keep blood circulating in vasculature; while calcium signaling pathway involve in several pathways above. Tian, R. In order to clarify the difference between SWT and SJZT at gene level, we also screened different genes from differentiated pathways between SWT and SJZT . These gIn TCM theories, blood and Qi also have close relationship, i.e. Qi can promote the formation and circulation of blood. Meanwhile blood can nourish Qi. In this study, we also found that there were many common pathways between SWT and SJZT, which reflects the close relationship between Qi and blood.As shown in the network , there w49Above all, the common pathways are mainly associated with the effects of SWT and SJZT on strengthening the ability of anti-infection, promoting human growth and development and increasing blood flow and promoting hematopoiesis, maintaining normal development of fetus in uterus, rectifying dysmenorrhea and other estrogen-related diseases, which are consistent with the actions of blood and Qi of TCM.In conclusion, SWT with the functions of influencing amino acid and carbohydrate metabolism is significant different from SJZT with the actions of influencing neuroendocrine system by affecting excitatory synapses (serotonergic synapse) to regulate thyroid hormone, ovarian steroidogenesis, prolactin and oxytocin secrction and can regulate corrective hormones secretion and promoting vascular smooth muscle contraction. The common effects of SWT and SJZT are regulating the functional activities of the hypothalamic pituitary adrenal and gonadal axis by affect inhibitory synapses (GABAergic synapse) to stimulate estrogen and steroid hormones secretion and strengthening the ability of anti-infection. All the differences and common pathways also reflect the characteristics of blood deficiency and Qi deficiency, and the molecular mechanism of blood and Qi of TCM.Ingredients of eight herbs from SWT  and SJZT  were retrieved from TCMID database, 449 ingredients and 454 targets of SWT and 545 ingredients and 568 targets of SJZT were collected and organized. In this study, Only human genes with STITCH defined high confident (combined-score more than 0.7) were chosenhttp://david.abcc.ncifcrf.gov/)p-value less than 0.01(corrected with Bonferroni step down) were collected and analyzed to interpret the biological meanings of these targeted genes datasets with comprehensive set of functional annotation tools of DAVID and KEGG.454 and 568 genes targeted by ingredients of SWT and SJZT were performed Gene Ontology (GO) and pathway enrichment analysis with DAVID Bioinformatics Resources 6.7 How to cite this article: Sun, J. et al. To Unveil the Molecular Mechanisms of Qi and Blood through Systems Biology-Based Investigation into Si-Jun-Zi-Tang and Si-Wu-Tang formulae. Sci. Rep.6, 34328; doi: 10.1038/srep34328 (2016)."}
+{"text": "There are errors in the Competing Interests statement. The correct Competing Interests statement is: The authors have the following conflicts to report: Dr. Kuo consults for Genova Diagnostics, Furiex, and Given Imaging. Dr. Kuo receives funding from Given and Furiex for clinical trials, unrelated to this particular study. Dr. Macklin serves on the DSMBs for Lantheus Medical Imaging, Shire Human Genetic Therapies, and Civitas Therapeutics. Dr. Denninger receives support for unrelated investigator-initiated studies from Onyx Pharmaceuticals and Basis. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials. The following authors hold or have held positions at the Benson-Henry Institute for Mind Body Medicine at Massachusetts General Hospital, which is paid by patients and their insurers for running the SMART-3RP and related relaxation/mindfulness clinical programs, markets related products such as books, DVDs, CDs and the like, and holds a patent pending  entitled \"Quantitative Genomics of the Relaxation Response\": MB, JJ, MAS, LS, EIKR, VL, NNH, LK, ES, GLF, HB, TAL, JWD."}
+{"text": "Female stress urinary incontinence, while not life threatening, can present with various social and economic implications. Biomaterials, primarily synthetic, are often utilized to augment surgical correction. Repair with biomaterials involves midurethral support to function against weakened connective tissue caused by injury, abnormal collagen metabolism, or genetic predisposition. Even though efficacy rates are high, the potential for complications, such as erosion, are great without comprehension of inherent characteristics of each graft material. Low-weight, macroporous, monofilament synthetic grafts and noncross-linked biologic grafts are examples of biomaterials that implant reasonably well with host tissue. This paper reviews the justification for biomaterial use, host reaction, and the various parameters of natural and synthetic grafts."}
+{"text": "According to the World Health Organization, infectious diseases stand out as the major cause of death worldwide. Although bacterial, viral, and parasitic infections appear to constitute the major threat, the clinical relevance of fungal infections has not been adequately recognized. In fact, invasive fungal infections constitute a biomedical problem of epic proportions, because a handful of human fungal pathogens claim an estimated 1.5 million lives per year .Candida albicans, Aspergillus fumigatus, and Cryptococcus spp. [Candida glabrata [The vast majority of fungal infections are caused primarily by cus spp. . The ovecus spp. . Importaglabrata , promoteglabrata , 6. The glabrata .Candida spp. In addition, we discuss how the modulation of KATs/KDACs in Candida spp. could pave the way for novel therapeutic strategies to combat fungal infections [A mere four chemical entities  constitute the armory of clinically relevant drugs . A few vfections .Drosophila melanogaster [C. albicans disclosed a function in fungal virulence [The protein components of a eukaryotic chromosome include a wide variety of DNA-binding proteins required for fundamental cellular functions such as DNA replication, recombination, and repair, as well as adaptive gene regulation. Many proteins undergo reversible posttranslational modifications (PTM), among others, including acetylation, methylation, phosphorylation, sumoylation, or ubiquitination . For insnogaster , and humnogaster , affectinogaster . The addnogaster , 21, 24,irulence , 25, 26.C. albicans genome harbors eight putative KATs and twelve KDACs [A. fumigatus or Cryptococcus neoformans . Importantly, major pharma companies no longer entertain large-scale targeted antifungal discovery, partly because of high costs, limited number of validated targets, and high propensity of adverse toxicity owing to the eukaryotic nature of fungal pathogens. Importantly, the long-standing hesitation to exploit nonessential fungal genes as antifungal targets needs a careful reevaluation. Actually, a genetic argument predicts that essential genes may in fact even be poorer targets due to risks of drug resistance development, particularly in prophylactic settings or when overused. In fact, any gene affecting fungal fitness or adaptive changes in the host, irrespective of whether a fungal or a host gene could serve as a proper antifungal target [Fungal infections are associated with astronomical annual Medicare costs, exceeding billions in Europe or the US, thus causing enormous economic burdens to already strained healthcare systems. Hence, current efforts in drug discovery are obviously lagging behind the need for improved antifungals. Unfortunately, the fundamental roles of KATs/KDACs in fungal pathophysiology, gene regulation, and/or adaptive genetic/epigenetic changes have not yet attracted enough attention in antifungal drug discovery. Moreover, among other roadblocks on the antifungal innovation highway, the academic setting has been struggling with insufficient funding from public and private bodies, thus further impairing the translation from basic science to application. For instance, grant support for fungal pathogen research falls several orders of magnitude below the levels of prominent bacterial or parasitic pathogens (l target . Of notel target \u201362. ThusTargeting fungal KATs/KDACs as a therapeutic strategy could also offer decisive advantages. First, fungal KATs/KDACs are structurally less well conserved, and some of the modifications are exclusively found in fungi, minimizing the risk of immune toxicity , Fig 1."}
+{"text": "Background. In recent years, with the popularity of CHM, its hepatotoxicity has also been increasingly noticed. However, there are still veils on causative herbs and clinical characteristics. Aim. To systematically review data on CHM induced liver injury with particular focus on causative herbs and clinical characteristics. Methods. Using terms related to CHM and liver injury, PubMed and three Chinese electronic databases were searched, which was limited to the past 5 years. Publications meeting our eligibility criteria were included and further analyzed. Results. In total, 4 single herbs, 21 patent drugs, and 4 decoctions were reported to be of hepatotoxicity, with He-Shou-Wu being the most common one (65/114). Dang-Gui and other 5 herbs were the most common ingredients of patent drugs and decoctions. All patients were assessed using the RUCAM scale, with 26 being highly probable and 28 being probable. For these 54 cases, the latent period was 30 (47) days, and 81.48% were labeled as hepatocellular injuries. Most patients (96.3%) recovered, apart from the fact that one died and one is receiving liver transplantation. Conclusions. CHM should be used carefully for hepatotoxicity. Liver injury from CHM is similar to that from conventional medicines in clinical characteristics. Details about causative herbs should be illustrated, and more RUCAM should be used in future. Traditional Chinese medicine (TCM), originated in ancient China, has been widely used to treat diseases for thousands of years, using Chinese herbal medicine (CHM), acupuncture, moxibustion, and other body practices. In recent decades, TCM has been increasingly popular around the world \u20134. As thTo learn CHM induced liver injury, some questions are inevitable, namely, which herbs can lead to liver injury specifically, when it will cause liver injury, and what the clinical characteristics are. Though some reviews \u201310 have To help clinicians and TCM practitioners know more about and avoid CHM induced liver injury, we systematically reviewed publications, giving a list of Chinese herbal medicines with possible hepatotoxicity and summarizing associated clinical characteristics. Since more attention has been paid to DILI in recent years and the diagnosis has also developed both in China and the world, our review focused on literature of the past 5 years. Cochrane Handbook for Systematic Reviews of Interventions , Cang-Er-Zi [Xanthium strumarium subsp. sibiricum (Patrin ex Widder) Greuter], Huang-Yao-Zi (Dioscorea bulbifera L.), Lei-Gong-Teng (Tripterygium wilfordii Hook. f.), Yang Xue Sheng Fa Jiao Nang, Bai Dian Feng Jiao Nang, Xiao Yin Pian, Qu Bai Ba Bu Pian, Bu Shen Sheng Fa Tang, Ze Qi Chong Ji, Xian Ling Gu Bao Jiao Nang, Gu Kang Jiao Nang, Zhuang Gu Jiao Nang, Ling Zhi Yi Shou Jiao Nang, Ling Zhi Jiao Nang, Hui Chun Ru Yi Jiao Nang, Ru Bi San, ShuXiong Jiao Nang, Zeng Sheng Ping, Long Bi Shu, Zhi Xue Jiao Nang, Move Free, Ban Tu Wan, Kamishoyosan, Qi Bao Mei Ran Wan, herbal extracts containing Hu-Ji-Sheng [Viscum coloratum (Kom.) Nakai] and Ye-Ge (Pueraria montana var. lobata (Willd.) Sanjappa & Pradeep), herbal tea containing Kelp, and two decoctions consisting of CHM. Detailed information is listed in Angelica sinensis (Oliv.) Diels], He-Shou-Wu, Di-Huang [Rehmannia glutinosa (Gaertn.) DC.], Chuan-Xiong (Ligusticum striatum DC.), Hong-Hua (Chelonopsis pseudobracteata var. rubra C. Y. Wu & H. W. Li), Bai-Xian-Pi , and Bu-Gu-Zhi [Psoralea cordata (Thunb.) Salter] were the most common ones. Details are shown in In total, 4 kinds of single herbs, 21 patent drugs, and 4 decoctions made up of multiple herbs were reported to have caused liver injury, including He-Shou-Wu [Causality assessment is necessary for the diagnosis of CHM induced liver injury. While expert consensus opinion and the RUCAM scale are considered as preferred algorithms to establish causality in suspected herb-induced liver injury (HILI), the former one is not widely available since it is cumbersome, costly, and time consuming. RUCAM scale is much more widely used by clinicians and researchers, which is structured, quantitative, and validated for liver injury. Of the total 17 articles included, 7 directly used the RUCAM scale to assess causality, while the other 10 articles provided associated information, based on which RUCAM can be performed. Four articles , 28, 31 Patients' features and clinical characteristics of liver injury from CHM were summarized. Of the 58 cases with detailed information, all 54 with probable or highly probable causality grading were included. Thus, we focused on these 54 cases and showed their clinical characteristics. While 35 were male and 19 were female, there was an average age of 47.13 \u00b1 12.24 years, ranging from 17 to 78. The latent period was 30 (47) days, which is consistent with DILI . Nine ofDILI is one of the most common causes of hepatitis in the world. According to some studies, DILI accounted for about 11% of acute liver failure cases , 40. As Compendium of Materia Medica), an ancient book recording therapeutic effects of CHM, He-Shou-Wu is usually used to treat alopecia and white hair by nourishing the liver and kidneys. In recent years, with the increasing use of it, numbers of hepatotoxicity cases have been reported [Characteristics of included cases were summarized, while problems in the original papers were brought up. Detailed information about CHM, like locality, botanical classification, brand names, detailed contents, and usage and dosage, was unavailable in most publications, which is of great importance to improve the reliability of studies. CHM with reported hepatotoxicity were identified, of which He-Shou-Wu attracted our attention. He-Shou-Wu is one of the most popular CHM, officially listed in the Chinese Pharmacopoeia. According to Ben Cao Gang Mu (reported , 41, 42.reported , 43. BasIt is worth noting that formulae consisting of multiple herbs, including patent drugs and decoctions, prevail in CHM with potential hepatotoxicity. In the view of TCM, liver injury from these drugs and decoctions is often related to some ingredients with hepatotoxicity. After a review of related literature, in our results, He-Shou-Wu, Bai-Xian-Pi, and Bu-Gu-Zhi have been reported to be of hepatotoxicity , 44, whiSince syndrome differentiation and individualized treatment are main features of TCM, excessive use of CHM is necessary and universal sometimes. It is also essential to further analyze its relationship with hepatotoxicity on the basis of more data. In our results, the values of liver tests were relatively high, which may be related to our strict inclusion criteria. The majority of cases were grouped into levels of highly probable or probable, indicating a high quality of causality assessment. What is more, many articles included did not provide a score of RUCAM, while the tool is widely accepted by researchers and clinicians \u201353. The Based on our work, some suggestions were offered. First, CHM identified with reported hepatotoxicity should be used carefully. Secondly, since there is uncertain accuracy in determining the relationship between CHM and liver injury in most reports, we would like to adopt a strict definition of hepatotoxicity and the RUCAM scale, which contributes to excluding cases of other causes and offers causality evidence. Thirdly, when clinicians and researchers plan to report cases or carry out associated studies, it is advisable that details of causative herbs or patent drugs, like locality, botanical classification, brand names, detailed herbal ingredients and contents, and usage and dosage, should be provided at full length. What is more, it is necessary to build up a new website that provides up-to-date, comprehensive, and unbiased information about CHM induced liver injury and standardizes submission of associated information. Finally, since CHM is general designation of various kinds of herbs, we consider it improper to compare CHM with a single medicine.In contrast with previous reviews, we adopted a high threshold of laboratory tests to avoid nonspecific liver injuries and included electronic data in China, which explained the difference from results of other reviews. Also, due to much more attention attracted in recent years, the increasing number of articles , and theIn conclusion, CHM, especially He-Shou-Wu and those for dermatosis and osteoarthrosis, should be used carefully, and routine liver tests may be needed. Although cases have been increasingly reported, details about causative herbs need to be particularly illustrated. Liver injury from CHM is similar to that from conventional medicines in patent period, injury pattern, and prognosis. Further studies are needed on toxicity mechanisms and biomarkers, and more RUCAM should be used in future cases.Detailed information about all included cases was supplied in the supplementary table, including causative herbs, demographic information, regional distribution, usage and dosage, latent period, laboratory results, pattern of liver injury, causality assessment, reexposure results, and clinical outcomes."}
+{"text": "To the editor,We read the article by Yuksel et al.  entitledTesticular cancer is the most common cancer in young men. Commonly, most testicular cancers indicate with palpable mass and are malignant in 90\u201395% of all cases. Standard treatment for testicular cancer is radical orchiectomy \u20134. PreopRoutine peripheral blood counts may be beneficial in prognosis and diagnosis of many disorders, involving testicular cancer , 6\u201313. NNLR is easily measurable laboratory marker used to appraise systemic inflammation. These marker maybe related with many circumstances such as thyroid function abnormalities, renal and/or hepatic dysfunction, diabetes mellitus, hypertension, chronic obstructive respiratory disease, metabolic syndrome, malignancy, B12 and folic acid deficiency, inflammatory diseases, local and/or systemic infection, smoking, alcohol consumption, anemia, and any use of medication (immunosuppressive agents corticosteroids and non-steroid anti-inflammatory drugs) related to inflammatory status of patients \u201313. In tIn conclusion, we strongly believe the findings obtained from the current study will lead to further studies examining the WBC counts and NLR in the diagnosis of testicular cancer."}
+{"text": "In addition, FDG uptake can occur in benign conditions such asinfectious, inflammatory, and iatrogenic lesions. Furthermore, some malignanttumors, such as adenocarcinoma in situ  and carcinoid tumors, may not show FDG uptake. Here, we illustratethe main pitfalls and artifacts in the interpretation of the results ofoncologic PET/CT of the chest, outlining strategies for avoidingmisinterpretation.PET/CT is widely used for the evaluation of patients with thoracic malignancies.Although the levels of  PET/CT is an integral part of the management ofpatients with thoracic neoplasms, improving staging, monitoring of therapy, andprognostic assessment. However, many artifacts and pitfalls can be seen on theexamination, such as normal variants, physiological areas of18F-fluorodeoxyglucose (FDG) uptake, acquisition or reconstructionartifacts, and false-positive or false-negative results.Positron emission tomography/computed tomography (PET/CT) imaging has been thesubject of a series of recent publications in the radiology literature inBrazilThe purpose of this essay was to describe and illustrate the main pitfalls andartifacts in the interpretation of oncologic PET/CT examinations of the chest and topresent strategies for avoiding their \u2018misinterpretation.. In the thorax, normal metabolic activity can be seen in themyocardium, greatvessels, esophagus, thymus, breast , bone marrow,muscles, and brown fat .-17.False-positive FDG uptake can occur in infections, inflammatory lesions, benigntumors, and iatrogenic conditions such as surgical manipulation, pleurodesis,radiation therapy, and granulocyte-colony-stimulating factor administration, as wellas after chemotherapy -10, carcinoid tumors,ground-glass nodules, and small lesions.False-negative FDG uptake  can bes.Artifacts  and 13 cAwareness of normal FDG distribution, physiological FDG uptake, and their variants ismandatory for interpreting oncologic PET/CT examinations of the chest.False-positive and false-negative results can be avoided if the reader has knowledgeof their main aspects and interprets the CT and PET findings carefully. When thesepoints are well known by the radiologist, PET/CT is a powerful imaging technique forcharacterizing pulmonary lesions, providing accurate staging for lung neoplasms andcontributing to better evaluation of the effectiveness of therapy and prognosticassessment."}
+{"text": "Behavioural problems are a key feature of frontotemporal lobar degeneration (FTLD). Also, FTLD patients show impairments in emotion processing. Specifically, the perception of negative emotional facial expressions is affected. Generally, however, negative emotional expressions are regarded as more difficult to recognize than positive ones, which thus may have been a confounding factor in previous studies. Also, ceiling effects are often present on emotion recognition tasks using full-blown emotional facial expressions. In the present study with FTLD patients, we examined the perception of sadness, anger, fear, happiness, surprise and disgust at different emotional intensities on morphed facial expressions to take task difficulty into account. Results showed that our FTLD patients were specifically impaired at the recognition of the emotion anger. Also, the patients performed worse than the controls on recognition of surprise, but performed at control levels on disgust, happiness, sadness and fear. These findings corroborate and extend previous results showing deficits in emotion perception in FTLD."}
+{"text": "Diagnosis of oral ulcerative lesions might be quite challenging. This narrative review article aims to introduce an updated decision tree for diagnosing oral ulcerative lesions on the basis of their diagnostic features. Various general search engines and specialized databases including PubMed, PubMed Central, Medline Plus, EBSCO, Science Direct, Scopus, Embase, and authenticated textbooks were used to find relevant topics by means of MeSH keywords such as \u201coral ulcer,\u201d \u201cstomatitis,\u201d and \u201cmouth diseases.\u201d Thereafter, English-language articles published since 1983 to 2015 in both medical and dental journals including reviews, meta-analyses, original papers, and case reports were appraised. Upon compilation of the relevant data, oral ulcerative lesions were categorized into three major groups: acute, chronic, and recurrent ulcers and into five subgroups: solitary acute, multiple acute, solitary chronic, multiple chronic, and solitary/multiple recurrent, based on the number and duration of lesions. In total, 29 entities were organized in the form of a decision tree in order to help clinicians establish a logical diagnosis by stepwise progression. Ulcerations are characterized by defects in the epithelium, underlying connective tissue, or both. Due to diversity of causative factors and presenting features, diagnosis of oral ulcerative lesions might be quite challenging \u20134. This  solitary indicates the presence of a single ulcerative lesion whereas the term multiple describes the presence of several ulcerative lesions , 1211, 1The newly updated decision tree includes 29 oral ulcerative lesions based on duration and number of lesions, which helps clinicians establish a stepwise method to rule out improbable conditions to arrive at a logical diagnosis."}
+{"text": "Dear Editor,Here, we report the case of a 17-year-old male who presented with a three-month historyof nasal obstruction, asthenia, and febrile episodes. Physical examination revealedbilateral enlargement of cervical and axillary lymph nodes, all of which were painlesson palpation. Laboratory tests showed mild leukocytosis, an elevated increasedC-reactive protein level, and a high erythrocyte sedimentation rate. The venerealdisease research laboratory test and monospot test were both negative, as was serologyfor HIV, toxoplasmosis, and cytomegalovirus. Computed tomography (CT) of the sinusesshowed multiple, homogeneous, hypointense, rounded polypoid masses, which effectivelynarrowed the nasal passages, together with opacification of the ethmoid cells andsphenoid sinuses, with no evidence of bone erosion . Biopsie-5. Rosai-Dorfman disease, also known as sinushistiocytosis with massive lymphadenopathy, is a rare, benign lymphoproliferative,usually self-limiting, condition characterized by bilateral, painless cervicallymphadenopathy-11, with spontaneous resolution inapproximately half of all cases. Thedisease has a slight predilection for males and primarily affects children, adolescents,and young adults, 80% of cases occurring in individuals under 20 years of age. Extranodal involvement occurs in30-40% of al cases,8,9, being mostcommon in immunocompromised individuals and preferentially affecting the skin,respiratory tract, reticuloendothelial system, genitourinary tract, or bones,8,9. Although uncommon, enlargement of themediastinal, hilar, axillary, and inguinal lymph nodes can occur.Recent studies in the radiology literature of Brazil have stressed the importance of CTand magnetic resonance imaging (MRI) in improving the diagnosis of head and neckmassesBrucella spp., and Klebsiella spp.,7,9,11.The etiology of Rosai-Dorfman disease is unclear, although it could be related to changesin the immune response or to infections caused by agents such as varicella-zoster virusand other herpes viruses, as well as Epstein-Barr virus, cytomegalovirus,,10. The diagnosis is established byhistopathology.Imaging tests such as CT and MRI are useful for evaluating the extent of Rosai-Dorfmandisease, although there are no specific characteristics. When it affects the paranasalsinuses, it typically manifests as polypoid masses, mucosal thickening, with or withoutbone erosion, with preferential involvement of the maxillary sinuses and ethmoidcells,13.The differential diagnoses include several types of lymphoreticular malignancy, such aslymphoma, malignant histiocytosis, and monocytic leukemia, which have histopathologicalfeatures similar to those of Rosai-Dorfman disease but present atypia and a rapid,aggressive evolution. Another major differential diagnosis is Kikuchi-Fujimoto disease(histiocytic necrotizing lymphadenitis), the clinical profile of which resembles that ofRosai-Dorfman disease, with cervical lymphadenopathy, although the former predominantlyaffects females and manifests as necrotizing histiocytosis on histopathology-11.In Rosai-Dorfman disease, the treatment modality of choice and the timing of treatmentare controversial. Nevertheless, the choice of treatment strategies depends on theseverity of the disease, mild cases being managed with observation only, whereas casesthat are more severe are typically managed with corticosteroid therapy, chemotherapy,radiotherapy, or surgeryIn conclusion, although Rosai-Dorfman disease does not present specific imagingcharacteristics, it should be considered among the diagnostic possibilities in cases ofpainless bilateral cervical lymphadenopathy, particularly in children andadolescents."}
+{"text": "To evaluate the quality of the veterinary literature investigating IV fluid therapy in dogs, cats, horses, and cattle.Systematic review.The preferred reporting of items for systematic review and meta-analysis protocols (PRISMA-P) was employed for systematic review of all relevant IV fluid therapy manuscripts published from January 1969 through December 2016 in the Commonwealth Agricultural Bureaux International (CABI) database. Independent grading systems used to evaluate manuscripts included the updated CONsolidated Standards of Reporting Trials 2012 checklist, risk of bias for animal intervention studies, criteria for levels of evidence, and methodological quality . The quality of articles published before and after 2010 was compared.One hundred and thirty-nine articles  from 7,258 met the inclusion criteria. More than 50% of the manuscripts did not comply with minimal requirements for reporting randomized controlled trials. The most non-compliant items included identification of specific predefined objectives or a hypothesis, identification of trial design, how sample size was determined, randomization, and blinding procedures. Most studies were underpowered and at risk for selection, performance, and detection bias. The overall quality of the articles improved for articles published after 2010.Most of the veterinary literature investigating the administration of IV fluid therapy in dogs, cats, horses, and cattle is descriptive, does not comply with standards for evidence, or provide adequate translation to clinical practice. Authors should employ and journal editors should enforce international consensus recommendations and guidelines for publication of data from animal experiments investigating IV fluid therapy. Intravenous fluid therapy is prescribed as therapeutic treatment for most critically ill animals. Crystalloids, especially lactated Ringers solution and 0.9% saline (NS), and to a lesser extent colloids are administered with the primary goal of maintaining or restoring vascular volume and tissue perfusion. Intravenous fluids, crystalloids or colloids, produce varying effects on the extracellular fluid dependent upon their composition, tonicity, caloric, acid\u2013base, hemostatic, rheological, and immunologic effects \u20135. Dissi\u00ae, Hextend\u00ae), tetrastarch , pentastarch, dextran, and albumin. All possible combinations and permutations of the search terms were examined. Blood, blood products, and gelatins, other than albumin, were not included. Manuscripts published in English, German, Japanese, Portuguese, French and Spanish were included. Retrospective studies, duplications, review articles, abstracts, single animal case reports, and in vitro experiments were excluded from analysis. Studies investigating alternate routes of fluid administration other than IV and species other than those identified above were also excluded. The bibliographies of 186 selected manuscripts were assessed in order to identify additional manuscripts that met inclusion criteria. The review process employed criteria for preferred reporting of items for systematic review and meta-analysis protocols (PRISMA-P)  database from January 1969 through December of 2016 was performed to identify suitable articles. Titles that included the IV administration of crystalloids, colloids, and albumin in dogs, cats, horses, and cattle were evaluated for potential review. The primary search terms included intravenous fluid therapy, fluid resuscitation, fluid bolus, fluid challenge, crystalloid, saline, 0.9% sodium chloride, hypertonic saline, Ringers, lactated Ringer, Hartman\u2019s solution, acetated Ringer solution, polyionic solution, Plasmalyte, Normosol, colloid, plasma substitute, hyroxyethyl starch, hetastarch (HespanRISMA-P) . Review ad scale , 24. Thead scale . These rad scale . We intead scale \u201328. DataA total of 7,258 manuscripts were identified that contained one or more primary search terms. Of these, 4,284 manuscripts were eligible for further review. One hundred and eighty-six manuscripts met all inclusion requirements. An additional 47 manuscripts were excluded because they did not comply with all entry criteria Table . A totalCompliance of the 139 articles with CONSORT items considered fundamental for conducting a RCT  varied for each item among the different species  and 24 articles after  2010. Compliance (%) of these articles with select CONSORT statement items considered fundamental for conducting a RCT, and their Jadad scores were generally greater compared with all 139 articles. Compliance improved even more for articles published after 2010 Table .This is the first systematic review of the CABI database that has evaluated articles investigating IV fluid administration in dogs, cats, horses and cattle. Two percent (139) of the 7,258 fluid therapy manuscripts published in veterinary journals listed in the CABI database met our criteria for being categorized as IV fluid therapy. Of these, more than 50% of the manuscripts did not comply with CONSORT statement guidelines describing trial design, sample size determination, methods of randomization or blinding. Only 20 articles (14%) described randomization methods. Manuscripts published after 2010 had a greater tendency to comply with CONSORT statement guidelines than those published before 2010 but no manuscript complied with all requirements. Importantly, only 45% of the articles described trial design  and fewer yet (12%) described changes to the methods (e.g. eligibility criteria).Multiple search methods and evaluative procedures have been developed for determining the quality, validity, and relevance of experimental and clinical research in humans and animals , 29\u201331. Defining the primary research question, proper trial design with predefined outcome measures, sample size determination, and appropriately planned statistical approaches are interrelated CONSORT statement items that should be determined prior to study execution , 32\u201334. post hoc power calculations risk bias. Furthermore, some results may have reached statistical significance had a larger sample size been employed , and experimental reproducibility , 43. Repin vivo animal experiments have been proposed (We were unable to perform a meta-analysis for the studies included in this review due to differences in experimental designs, outcome measures, and statistical approaches. We intentionally selected the CONSORT and Jadad evaluation tools because of their popularity, although alternative guidelines for conducting and reporting proposed , 44\u201347. proposed . We alsoSystematic reviews of experimental and preclinical research trials identified in PubMed have questioned whether animal experimentation informs human healthcare based upon small sample size and statistical heterogeneity among the different experiments \u201320, 47. WM, YU, JN-M, and AK contributed to the analysis, interpretation, and writing of this review. WM and AK searched the Commonwealth Agricultural Bureaux International database, organized, analyzed, and abstracted all manuscripts. JP organized the search terms and programmed the computer search for all selected terms.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewers, NP and JH, and handling Editor declared their shared affiliation, and the handling Editor states that the process nevertheless met the standards of a fair and objective review."}
+{"text": "Dear Editor,A 65-year-old male patient was referred to our institution for investigation of a 10-yearhistory of epigastric pain. His pain had been progressively worsening during the pastmonths, intensified after the consumption of solid foods. The only notable aspect of hismedical history was arterial hypertension. He complained of nocturia, awakening to voidabout six times per night, but did not report dysuria, hematuria, scrotal swelling, orother urinary tract symptoms. Physical examination revealed epigastric tenderness andhepatosplenomegaly. Upper gastrointestinal endoscopy showed an ulcerated lesion on thegreater curvature of the stomach. In the analysis of the biopsy sample, the lesion wasclassified as non-Hodgkin lymphoma. A computed tomography (CT) scan of the abdomen andpelvis, performed for staging, revealed an unsuspected massive inguinoscrotal hernia ofthe urinary bladder, a condition known as scrotal cystocele  and 2. T.Advanced age, obesity, and male gender are recognized risk factors for bladderherniation. Bladderherniation is usually asymptomatic, although some patients complain of voiding-relatedscrotal swelling, two-stage micturition , urinary tractinfections, or irritative lower urinary tract symptoms (LUTS) such as urgency,frequency, and nocturia secondary to bladder outlet obstruction or infection-3. Possible complications of untreated scrotal cystocele includehydronephrosis, renal failure, cystolithiasis, vesicoureteral reflux, bladder necrosis,and bladder perforation,4,5.Although the urinary bladder is involved in up to 4% of inguinal hernias, massive scrotalcystocele is quite uncommon. The condition should be suspected in all patients presentingwith inguinal hernias and concomitant renal failure or LUTS, especially if a painlessunilateral scrotal swelling is detected,5. However, asillustrated by our case, the absence of clinically detectable scrotal swelling shouldnot exclude the hypothesis of bladder herniation, nor should it preclude furtherinvestigation. The imaging diagnosis can be established by CT, ultrasound, cystography,or intravenous pyelography. BecauseCT provides a clear anatomical outline of the herniated contents and allows promptidentification of complications, thereby enabling appropriate surgical planning, it isan especially valuable tool in the work-up of scrotal cystocele.The preoperative diagnosis of scrotal cystocele is important to prevent iatrogenic injuryof the herniated bladder during repair surgery. Acute bladder infarction or urinaryobstruction can require urgent laparotomy with resection of the affected portion of thebladder. In the electivesetting, partial bladder resection is often restricted to patients presenting withbladder necrosis, a tumor in the herniated bladder, or a bladder diverticulum. However, timely preoperative diagnosisof scrotal cystocele remains the single most important determinant of a successfulsurgical outcome, making proper clinical and imaging assessments invaluable.Hernia repair has shown to be effective in improving LUTS and reducing complications inpatients with significant bladder herniation; therefore, standard treatment of scrotalcystocele consists of reduction or resection followed by herniorrhaphy"}
+{"text": "Only a few studies have focused on the biodistribution analysis of exogenously administered MSCs-derived EVs. Nevertheless, current strategies for in vivo tracking in animal models have provided valuable insights on the biodistribution upon systemic delivery of EVs isolated from several cellular sources, indicating in liver, spleen, and lungs the preferential target organs. Different strategies for targeting EVs to specific tissues to enhance their therapeutic efficacy and reduce possible off-target effects have been investigated. Here, in the context of a possible clinical application of MSC-derived EVs for tissue regeneration, we review the existing strategies for in vivo tracking and targeting of EVs isolated from different cellular sources and the studies elucidating the biodistribution of exogenously administered EVs.Extracellular vesicles (EVs), such as microvesicles and exosomes, are membranous structures containing bioactive material released by several cells types, including mesenchymal stem/stromal cells (MSCs). Increasing lines of evidences point to EVs as paracrine mediators of the beneficial effects on tissue remodeling associated with cell therapy. Administration of MSCs-derived EVs has therefore the potential to open new and safer therapeutic avenues, alternative to cell-based approaches, for degenerative diseases. However, an enhanced knowledge about MSCs arsurfaces . In ordesurfaces , 4. Indesurfaces . Severalsurfaces . It was surfaces . Moreovesurfaces . These osurfaces \u201313. Accosurfaces , 15. Indsurfaces . Moreovesurfaces . Severalsurfaces , 18, whisurfaces . Due to surfaces . Paracrisurfaces , 16. A bsurfaces .Extracellular vesicles (EVs) are small membrane-enclosed particles derived from a variety of cell types including endothelial cells, dendritic, B and T cells, embryonic and mesenchymal stromal cells, neurons, oligodendrocytes, Schwann cells, intestinal epithelial cells, and platelets , 21. EVsThe definition \u201cextracellular vesicles\u201d encompasses vesicles with different origin, size, membrane composition, and content such as exosomes, microvesicles, microparticles, ectosomes, oncosomes, prostasomes, and apoptotic bodies , 23. Dis\u03bcm), microvesicles (100\u20131000\u2009nm), and exosomes (40\u2013100\u2009nm) [In order to provide criteria for standardization of the nomenclature and the procedures for isolation and characterization of different EV subgroups, the International Society for Extracellular Vesicles has published in a position paper in 2004 . Interna\u2013100\u2009nm) , but thi\u2013100\u2009nm) . Further\u2013100\u2009nm) . Nonethe\u2013100\u2009nm) . AccordiOriginally, EVs were considered as cellular debris without significant biological function. Actually, accumulating evidences indicate that EVs play a key role in intracellular signaling, exerting specific effects on homeostasis maintenance, modulation of the immune response, inflammation, cancer progression, angiogenesis, and coagulation, in both physiological and pathological conditions , 22, 33.Albeit several regulatory and technical issues in achieving highly purified and extensively characterized EVs preparations suitable for use in humans need to be solved , 50, sev in vitro; and (iii) they can be induced into osteogenic, chondrogenic, adipogenic, endothelial, cardiovascular, neurogenic, and hepatic differentiation. The ability of MSCs to secrete a variety of growth factors, cytokines, and chemokines potentially involved in tissue repair and remodeling is well-established, being described for the first time 20 years ago [Studies using MSCs are the most prevalent among the cell-based therapies being tested for tissue regeneration, the reason being that (i) MSCs can be isolated from different, easily accessible, adult tissue sources, including bone marrow  and adipears ago . Nonetheears ago . The exiears ago . Howeverears ago , hepaticears ago , and myoears ago  injury hears ago . EVs mayears ago , 91.EVs play a pivotal role in stem cell plasticity and tissue regeneration, possibly contributing to the paracrine action observed upon MSCs cell transplant , 93. PurThe use of MSC-derived EVs for regenerative therapy requires production and isolation of a suitable quantity of clinical grade EVs from cultured MSCs . For saf in vivo tracking to determine EVs biodistribution upon systemic delivery in different animal models  (DiR) is a lipophilic dye weakly fluorescent in water, but particularly fluorescent and photostable when incorporated into lipid-membranes. Lipophilic NIR dyes have been quite extensively employed for labeling of EVs isolated from different sources and administered into different animal models , which uses luciferase enzymes as imaging reporters, has an extremely low signal-to-noise ratio, since the autoluminescence in mammalian tissue is negligible. In particular, the adapted bioluminescence reporters, such as Gaussia luciferase, being over 1,000-fold brighter than firefly luciferase, are useful tools to study temporal properties of minute biological processes because of their sensitivity, low background and independence from an excitation source to emit light. Therefore, BLI has been extensively evaluated in the development of cell-based therapies to determine cellular distribution, survival, proliferation, and differentiation after transplantation , 108. BLl models . Recentler cells , 67. in vitro may be different from EVs endogenously released from the same source [ in vivo biodistribution. For instance, collection of EVs by ultracentrifugation results in vesicles aggregation [ in vivo need to be labeled, and the labeling procedure may modify EVs tropism. Accordingly, the EVs labeling procedure determines the detection method used, with its own advantages and limitations. Further complication in assessing exogenously administered EVs biodistribution is represented by the partial knowledge of the mechanisms of cellular uptake of EVs, recently reviewed by Mulcahy et al. [The nature and the physiological state of the vesicle-producing cell affect the tropism of produced EVs , 109. Moe source . The lacregation . In biodregation . Furtherregation . Differeregation . In addiy et al. . NonetheDue to their presence in most of biological fluids, it was supposed that EVs may be quite stable in circulation. Unexpectedly, dynamic distribution studies have demonstrated that blood levels of EVs decreased by more than a half from 30 to 60 minutes upon intravenous administration . PharmacThe route of administration determines EVs biodistribution . For insIn vivo tracking studies have pointed out that, upon systemic delivery, EVs are sequestered within a few minutes by circulating macrophages in the liver, spleen, and lungs [nd lungs . Hence, nd lungs , althougnd lungs . Therefond lungs \u2013121. Somnd lungs , antigennd lungs , and brand lungs . Interesnd lungs . Albeit Approaches requiring genetic modification of EVs-secreting cells are cumbersome and time-consuming. In addition, some peptides fused to EVs transmembrane proteins are not effectively exposed or adequately stable to provide for efficient target recognition . MoreoveAltogether these reports established the possibility to manipulate EV tropism, fostering future studies, in both academia and the pharmaceutical industry, to actively pursue the development of an efficient system with improved target specificity suitable for safe clinical translation. in vivo action of exogenously administered EVs, their biodistribution, pharmacokinetics, and possibility of targeted delivery are not fully elucidated. Imaging techniques may help in filling this gap of knowledge and further promoting clinical translation of EVs-based regenerative therapy.In recent years, stem/stromal mesenchymal cells-derived extracellular vesicles, in particular exosomes, have gained increasing interest and their potential use in regenerative therapies has greatly expanded. Addressing both technical and regulatory issues to bring EVs-based therapies from bench to bedside is an ongoing process. Nonetheless, the exact mechanism of"}
+{"text": "Dear Editor,A 58-year-old male sought treatment complaining of dyspnea on exertion, together withcough and occasional mucus secretion. He reported having been treated for asthma 14years prior, as well as having used bronchodilators and inhaled corticosteroids,although he stated that he had experienced no asthma symptoms in childhood.Computed tomography (CT) was performed  and 1C, . Depending on the anatomical distribution, amyloidosiscan be classified as systemic (involving multiple organs) or localized (involving asingle organ). In the biochemical classification, based on the type of fibrillarcomponent in amyloid deposits, there are innumerable subtypes. In the vast majority ofcases, light-chain amyloid fibrils and serum amyloid A are identified.Amyloidosis encompasses a set of diseases characterized by deposition and abnormalaccumulation of protein material in organs and tissues,2. Pulmonary involvement is rare, reported astracheobronchial, diffuse/alveolar-septal, or nodular manifestations, the first beingthe most common-4.In the thoracic compartment, amyloidosis typically affects the heart but can also involvethe pulmonary parenchyma, pleura, lymph node chains, tracheobronchial tree, and othersites.The tracheobronchial manifestation of amyloidosis is characterized by the deposition ofamyloid material in the trachea and main bronchi, resulting in thickening of the walls,narrowing of the lumina, and consequent airway obstruction, as well as consolidations,atelectasis, pulmonary hyperinflation, and bronchiectasis,5. The symptoms can be similar to those of bronchial diseases that aremore common, including bronchial asthma.Clinically, amyloidosis-related tracheobronchial impairment can be asymptomatic or canmanifest as dyspnea, wheezing, hemoptysis, cough, or recurrent pneumonia-9, as well as for that of diseases of thetracheobronchial tree-12. In individuals with amyloidosis, aCT scan can reveal smooth or irregular/nodular thickening of the tracheal wall andbronchi, which can be accompanied by calcified nodules in the submucosa. The differential diagnoses of diffusetracheobronchial diseases include vasculitis (Wegener's granulomatosis),tracheobronchial papillomatosis, infectious involvement , tracheopathia osteochondroplastica, andrelapsing polychondritis. Unliketracheal involvement in tracheopathia osteochondroplastica or relapsing polychondritis,tracheobronchial amyloidosis involves the posterior membranous wall of thetrachea,13.Chest CT has been shown to be the imaging exam of choice for the evaluation of thoracicdiseases,13.Histopathological findings of the disease include amyloid thickening of the submucosa,in nodular masses or laminae, showing apple-green birefringence after staining withCongo red. There is also areduction in the number of submucosal glands, together with calcifications and foci ofbone metaplasia in the upper airways.In individuals with amyloidosis, bronchoscopy usually shows thickening of the walls ofthe trachea and bronchi, with flat, multifocal, grayish-yellow plaques in the tracheaand bronchi. In rare cases, amyloid pseudotumors can be seen. The patient inquestion was initially diagnosed with asthma but did not respond to treatment, and thedefinitive diagnosis of primary tracheobronchial amyloidosis was made after a directedfollow-up assessment. We can conclude that, albeit rare, tracheobronchial amyloidosisshould be considered in such patients.In patients suspected of having bronchial asthma who present with atypical symptoms andrespond poorly to clinical treatment, various differential diagnoses should beconsidered"}
+{"text": "They review the underlying pathophysiology and point out parallels between immune-mediated and genetic conditions presenting with similar phenotypes. They consider future directions such as personalised immunotherapy.Movement disorders are a common feature of autoantibody-associated diseases. Balint  Movement disorders are a prominent and common feature in many autoantibody-associated neurological diseases, a group of potentially treatable conditions that can mimic infectious, metabolic or neurodegenerative disease. Certain movement disorders are likely to associate with certain autoantibodies; for example, the characteristic dyskinesias, chorea and dystonia associated with NMDAR antibodies, stiff person spectrum disorders with GAD, glycine receptor, amphiphysin or DPPX antibodies, specific paroxysmal dystonias with LGI1 antibodies, and cerebellar ataxia with various anti-neuronal antibodies. There are also less-recognized movement disorder presentations of antibody-related disease, and a considerable overlap between the clinical phenotypes and the associated antibody spectra. In this review, we first describe the antibodies associated with each syndrome, highlight distinctive clinical or radiological \u2018red flags\u2019, and suggest a syndromic approach based on the predominant movement disorder presentation, age, and associated features. We then examine the underlying immunopathophysiology, which may guide treatment decisions in these neuroimmunological disorders, and highlight the exceptional interface between neuronal antibodies and neurodegeneration, such as the tauopathy associated with IgLON5 antibodies. Moreover, we elaborate the emerging pathophysiological parallels between genetic movement disorders and immunological conditions, with proteins being either affected by mutations or targeted by autoantibodies. Hereditary hyperekplexia, for example, is caused by mutations of the alpha subunit of the glycine receptor leading to an infantile-onset disorder with exaggerated startle and stiffness, whereas antibodies targeting glycine receptors can induce acquired hyperekplexia. The spectrum of such immunological and genetic analogies also includes cerebellar ataxias and some encephalopathies. Lastly, we discuss how these pathophysiological considerations could reflect on possible future directions regarding antigen-specific immunotherapies or targeting the pathophysiological cascades downstream of the antibody effects. Neuroimmunology is a rapidly evolving field, fuelled by the discovery of new autoantibodies and syndromes  hyperintensities in the white matter, basal ganglia, and medial temporal lobes  is the only sign in primary/isolated dystonias, but associated with other symptoms in a variety of conditions such as heredodegenerative, metabolic, infectious, and autoimmune disorders   can be a feature of many underlying aetiologies. Subacute-onset of myoclonus with encephalopathy will invoke a wide differential diagnosis including metabolic , toxic  and infectious  processes, and autoimmune encephalitis. However, isolated myoclonus is rarely seen with neuronal autoantibodies , and one of the defining characteristic of opsoclonus-myoclonus syndrome (OMS). Neuronal antibodies are identified only in approximately a third of patients with OMS  and lackAR antibodies characterize an encephalitis with prominent epilepsy, cortical and subcortical hyperintensities on T2-weighted MRI, and a strong association with thyroid autoimmunity: thus, some of these patients were likely previously termed SREAT  and gluten sensitivity-related neurological disease  and usually manifest late in life  . Their pBrief dystonic episodes without EEG correlate and paroxysmal exercise-induced foot weakness were also reported in single cases with NMDAR antibodies , corticobasal degeneration, or multisystem atrophy, and, less frequently, infectious , toxic or metabolic causes. Paraneoplastic parkinsonism is another rare, but important differential diagnosis and has been described in association with CRMP5, Ri, and Ma2-antibodies , and an excellent response to Idiopathic or paraneoplastic autoimmunity is an important aetiology of ataxia, where age, tempo of disease progression, and associated signs dictate the differential diagnosis. The most frequently identified autoimmune ataxia is associated with GAD antibodies and is often accompanied by other autoimmune disorders  . PCD associates with almost all of the classical onconeuronal antibodies  Shams\u2019i are, howBR, CASPR2 and GFAP . The manifestations include classical stiff person syndrome, stiff limb syndrome, and variants combined with additional neurological symptoms (stiff person plus) or with a potentially fatal disease course in progressive encephalomyelitis with rigidity and myoclonus (PERM). Acquired hyperekplexia also enters this spectrum of disorders. In practice, SPSDs are still often misdiagnosed and symptoms mistaken for psychogenic, dystonic posturing, or related to parkinsonism , and less frequently, amphiphysin  , is the cytoplasmic, rate-limiting enzyme in the synthesis of GABA, a major inhibitory neurotransmitter in the CNS. GAD antibodies are the most frequent antibody in SPSD and cerebellar ataxia, but they also associate with temporal lobe epilepsy, limbic encephalitis, and type 1 diabetes , which is The recent discovery of neuronal surface antibodies against IgLON5 in defining a novel tauopathy has more closely apposed the boundaries between neurodegeneration and neuroimmunology  and LGI1 and CASPR2 antibodies for autoimmune encephalitis . K.P.B. holds research grants from NIHR RfPB, MRC Wellcome Strategic grant (Ref. no.: WT089698) and PD UK (Ref. no.: G-1009), and has received honoraria/financial support to speak/attend meetings from GSK, Boehringer-Ingelheim, Ipsen, Merz, Sun Pharma, Allergan, Teva Lundbeck and Orion pharmaceutical companies. K.B. receives royalties from Oxford University press and a stipend for MDCP editorship. H.M.M. reports no disclosures.Brain online.Supplementary Video 1Click here for additional data file."}
+{"text": "The first four authors, Ayesha Murshid, Shiuh-Dih Chou, Thomas Prince, and Yue Zhang, should be noted as contributing equally to this work."}
+{"text": "To the Editor:The paper concerning surveillance programmes for hepatocellular carcinoma (HCC) in the journal needs one clarification .Indeed, survival is lower when the diagnosis is made late than soon, and when the patient is older. However, this does not demonstrate the usefulness of surveillance. Several biases exist, the main being the lead-time bias. Again, here is an example concerning HCC. In a recent study, screened patients died 18 months earlier than non-screened ones; nevertheless, the authors concluded that screening improved survival ! NumerouMoreover, at present, no randomized-controlled trials are available to choose potentially curative treatments for small HCC: transplantation, resection and local ablation."}
+{"text": "Sir,Porokeratosis is a group of hereditary or acquired disorders of epidermal keratinization, characterized by keratotic lesions with an atrophic center and a prominent peripheral ridge, with a typical histologic hallmark, the cornoid lamella. Since its first description by Mibelli and Respighi in 1893, a bewildering number of porokeratosis types and morphological forms have been reported. Classically, five clinical variants are recognized: classic porokeratosis of Mibelli (CPM), disseminated superficial actinic porokeratosis (DSAP), disseminated superficial porokeratosis (DSP), porokeratosis palmaris et plantaris disseminata, and linear porokeratosis. Apart from these five clinical variants, a number of atypical morphological forms such as facial porokeratosis, giant porokeratosis, punched-out porokeratosis, hypertrophic verrucous porokeratosis and reticulate porokeratosis also have been reported in literature.[A 43-year-old lady presented with a pruritic hyperpigmented annular keratotic plaque with raised thready borders on the flexor aspect of the right forearm since childhood . Similaret al. first described DSAP in 1969 in Texas population.[Porokeratosis (PK) are inherited as an autosomal dominant trait; however, sporadic cases are also known to occur. DSAP is the most common of the five clinical variants of PK and usually develops in the third and fourth decades of life, with a female preponderance. It is characterized by multiple, brown, annular, keratotic lesions predominantly on the sun-exposed areas. Facial lesions are seen in approximately 15% of patients and lesions spare the axillary vaults, inguinal folds, perigenital regions, palms, soles and mucous membranes.[pulation. There ispulation. The exacpulation. Rarely, Our case had lesions that were typical of DSAP on the face, neck, back and porokeratosis of Mibelli on the right forearm. Interestingly, she also gave history of a familial occurrence of such lesions in her mother and sister, which is quite rare. Reported"}
+{"text": "The distribution of rhodium in Balb/c mice following intraperitoneal (ip) administration of a solution of adduct of rhodium propionate and sodium isonicotinate has been investigated. The metal concentration was determined in blood and in the following organ tissues: brain, heart, lung, liver, spleen, kidney, testes, and uterus/ovary, and the rhodium concentration was obtained byInductively Coupled Argon Atomic Emission Spectroscopy (ICP-AES). The metal was detected in all organ tissues examined, mainly in spleen, liver, uterus/ovary and heart. Nine days after the injection, traces of rhodium were found in the liver and kidneys and, twenty days after the injection,only in the liver."}
+{"text": "Forgotten People, Forgotten Diseases is an interesting and highly informative book about the global status of neglected tropical diseases (NTDs). Author Peter Hotez introduces NTDs by describing them in general, their historical importance and global impact, and their shared characteristics. According to Hotez, NTDs are among the most common infections from antiquity and occur in the world\u2019s poorest people. Their distribution and health and economic effects are similar to those of AIDS, malaria, and tuberculosis. NTDs, however, are much less well known than these diseases and frequently display high rates of illness but few deaths, promote poverty, and create profound social stigma.Twelve well-illustrated chapters address the important NTDs, including soil-transmitted helminth infections, schistosomiasis, filariasis, onchocerciasis, trachoma, mycobacterial infections, trypanosomiasis, leishmaniasis, dengue, leptospirosis, and rabies. Hotez discusses what these diseases are, where they occur, and who they affect. The final chapters focus on prospects to prevent and control NTDs and the need for additional advocacy. Hotez emphasizes the need for new safer and more effective drugs, as well as for so-called \u201canti-poverty vaccines,\u201d which by promoting health will open doors to economic advancement and stability, goals that have been all but impossible in developing countries, largely because of NTDs.Few people are more qualified to write such a book than Hotez, president of the Sabin Vaccine Institute and a pioneer in hookworm molecular genetics, physiology, immunology, and pathogenesis. This easy-to-read and up-to-date text undoubtedly will prove useful to graduate students, volunteers, advocates, healthcare professionals, and others interested in global health and equality. Forgotten People, Forgotten Diseases is an essential read for every serious student of tropical medicine and global infectious diseases."}
+{"text": "Oncorhynchus mykiss. Previous phylogenetic analysis indicates that a whole genome duplication prior to the divergence of ray-finned fish led to two distinct ERMolecular dynamics simulations were used to determine the binding affinities between the hormone 17 Estrogens are essential endogenous hormones that modulate the development and homeostasis of a wide range of target tissues, such as the reproductive tracts, breast and skeletal system Oncorhynchus mykiss, and performed a comprehensive phylogenetic analysis with all other known fish ER gene sequences. Their phylogenetic analysis indicates that the duplication leading to the two ERRecently, Nagler et al stor see  [9]. TheThe purpose of the study is to employ molecular dynamics simulations to determine the binding affinities between E2 and ERs of the different isoforms in the rainbow trout and to use the results to provide insight into the underlying evolutionary selection pressure on the ERs. Our binding affinity results obtained from insertion and deletion are very similar indicating that our simulations are well converged and that accurate estimates of binding affinities were obtained. Our results show that E2 binds preferentially to ERExperimental binding affinity results are not readily available for the four trout ERs due to the difficulty in isolating the different isoforms. Thus, to verify our methodology for estimating Our results in atio see . Using tOur results show that both ERorms see . The two/S ratio . The besThese nuclear ERs have a significant and ubiquitous distribution in the rainbow trout It is not as clear what ERvergence . It appeOncorhynchus mykiss. Our results show that E2 binds preferentially to ERO. mykiss. Our evolutionary and functional analyses along with Nagler's evaluation of transcription levels Using molecular dynamics simulations we estimated the binding affinities between the hormone 17holo structures for the E2 binding domain were generated by SWISS-MODEL holo structure with AutoDock The initial coordinates for the estradiol were first extracted from the human ER-E2 complexes (PDB: 1QKU) . The topdeletion to be when interactions between E2 and its environment are turned off and insertion to be when these interactions are turned on.To estimate E2-ER binding affinities we note that, since the free energy is a state function, it permits the selection of an arbitrary path connecting the bound and unbound states. Therefore, we decomposed the binding free energy calculation into several steps in which the E2 is annihilated  from its bound state in the receptor complex and then made to reappear in solution to complete the thermodynamic cycle. For brevity, we subsequently define RE represents the solvated complex of the E2 and receptor, and To facilitate convergence restraints were applied to restrict the positions of E2 relative to the receptors. Boresch et al tors see .All simulations were performed with the GROMACS 4.0 For equilibration, the systems were first minimized using 1,000 steps of L-BFGS (Broyden-Fletcher-Goldfarb-Shanno) After equilibration, production simulations were run with isothermal-isobaric conditions using Langevin dynamics at the temperature of 277 K. The pressure was maintained at 1.0 atm using the Parrinello-Rahman algorithm We used the formula suggested by Boresch et al The free energies The free energy associated with the restraints, The following sequences were extracted from GenBank: AB037185, AF349412, A133920050, AY727528, AY775183, BD105560, AB190289, AJ487687, AY055725, AF061275, AF253505, AY520443, AJ242741, DQ009007, DQ248228, DQ177438, X89959, TNU7560, AY422089, AF298183, AF136979, AY074780, AB007453, AJ006039, AF253062, AY223902, ORZMER, AY917147, AF326201, AY305026, NM_180966, NM_174862, AB003356, AB070630, AB070901, AB083064, AB117930, AB190290, AF061269, AF136980, AF177465, AF185568, AF298181, AF298182, AF349413, AF349414, AF516874, AJ275911, AJ289883, AJ314602, AJ314603, AJ414566, AJ414567, AJ489523, AJ580050, AY074779, AY211021, AY211022, AY305027, AY307098, AY508959, AY566178, AY770578, AY917148, BC044349, BC086848, DQ177439, DQ248229, TNU75605. The first 30 are ER"}
+{"text": "The molar conductivity data showsnon-electrolytic nature of complexes. The bidentate nature of the ligands is inferred from IR and NMRspectral studies. The antimicrobial activities of the ligands and their tin complexes have been screened invitro against the organism Escherichia coli; Staphylococus aureus, Prouteus mirabilis, Bacillusthurengiensis, Penicillium co.,sogenum, Aspergillus niger and Fusarium oxysporum.A number of diorganotin(IV) complexes with Schiffbase have been synthesized and characterized byelemental analysis, conductance measurements, molecular weight determinations, infrared, electronic andmultinuclear magnetic resonance ("}
+{"text": "After publication of this work , we noteThe authors declare that they have no competing interests.VMvGV, RTJ and JAvdS did design, data acquisition, analysis, and writing. EOvK MM and MHVD revised the manuscript critically for important intellectual content. All authors approved the final version."}
+{"text": "Automated data, especially from pharmacy and administrative claims, are available for much of the U.S. population and might substantially improve both inpatient and postdischarge surveillance for surgical site infections complicating selected procedures, while reducing the resources required. Potential improvements include better sensitivity, less susceptibility to interobserver variation, more uniform availability of data, more precise estimates of infection rates, and better adjustment for patients' coexisting illness."}
+{"text": "A new physical map of the bovine genome has been constructed by integrating data from genetic and radiation hybrid maps, and a new bovine BAC map, with the bovine genome draft assembly. Cattle are important agriculturally and relevant as a model organism. Previously described genetic and radiation hybrid (RH) maps of the bovine genome have been used to identify genomic regions and genes affecting specific traits. Application of these maps to identify influential genetic polymorphisms will be enhanced by integration with each other and with bacterial artificial chromosome (BAC) libraries. The BAC libraries and clone maps are essential for the hybrid clone-by-clone/whole-genome shotgun sequencing approach taken by the bovine genome sequencing project.HindIII restriction digest fragments of 290,797 BAC clones from animals of three different breeds. Comparative mapping of 422,522 BAC end sequences assisted with BAC map ordering and assembly. Genotypes and pedigree from two genetic maps and marker scores from three whole-genome RH panels were consolidated on a 17,254-marker composite map. Sequence similarity allowed integrating the BAC and composite maps with the bovine draft assembly (Btau3.1), establishing a comprehensive resource describing the bovine genome. Agreement between the marker and BAC maps and the draft assembly is high, although discrepancies exist. The composite and BAC maps are more similar than either is to the draft assembly.A bovine BAC map was constructed with Further refinement of the maps and greater integration into the genome assembly process may contribute to a high quality assembly. The maps provide resources to associate phenotypic variation with underlying genomic variation, and are crucial resources for understanding the biology underpinning this important ruminant species so closely associated with humans. Cattle have played a crucial role throughout recent human agrarian history, providing draft power, milk and meat for human consumption since domestication 8,000 years ago ,2. CattlWhile numerous quantitative trait loci (QTL) have been mapped ,14, onlyUnderstanding the genetic basis of breed differentiation through natural and artificial selection, production related traits, and disease will be greatly advanced by the availability of the genomic sequence of cattle. The foundation of the genomic sequence is provided by a clone-based physical map. Development of a clone-based physical map also offers a resource to accelerate discovery of polymorphisms within and between breeds, including causal polymorphisms contributing to a wide variety of bovine traits. The physical map is a source of genomic clones for sequencing templates and functional studies, and can also be employed to assist in the assembly of whole genome shotgun sequence -23.The value of a clone-based map can be enhanced by establishing connections to the annotated genome sequences of closely related species , as wellClones from three BAC libraries, representing DNA from both beef and dairy cattle, were fingerprinted: 200,064 CHORI-240 , 94,848 HindIII fragment , in addition to the expected vector-specific HindIII fragment(s). These clones appeared to lack HindIII sites within the insert, and were therefore unsuitable for fingerprint pattern-based assembly. Digestion of a small number of these clones with EcoRI generated fingerprints of one to four restriction fragments, each present in multiple copies (data not shown), suggesting that the inserts in these BAC clones were probably derived from regions of repetitive sequence . The use of three different BAC libraries each constructed using different restriction enzymes may have increased coverage over that possible with a single restriction enzyme, because certain genomic regions may not be clonable due to recognition site biases. Coverage by the BAC map may still be incomplete, however, because other highly repetitive, complex regions, such as telomeric and centromeric regions, may not be clonable with any enzyme, and may not be represented in any of the BAC libraries or the BAC map. Error in our estimates of genome size and genome coverage by individual contigs cannot be fully ascertained without a more finished assembly of bovine genomic sequence.Picea mariana \u00d7 Picea rubens species complex    using BL-16. The fingerprinted clones were then screened and filtered as follows to remove fingerprint patterns indicative of artifactual data. First, a software application, MapMop, was developed to calculate the distributions of insert size and number of restriction fragments for the clones. Based on these distributions, filtering parameters were determined to identify 'outlier' clones that represented extremes for insert size and/or number of restriction fragments, suggesting problematic data such as that resulting from partial digestion of the BAC DNA, or the presence of DNA from more than a single BAC clone (cross-well contamination). Second, initial filtering parameters were assessed by visual inspection of representative clone fingerprints and were adjusted to minimize the retention of poor quality data while limiting the loss of high quality data. Filtering parameters were determined separately for individual libraries, for clones within contigs and for clones that were not assembled into contigs ('singletons').BAC fingerprints were assembled using FPC ,44. The -16. The DQer function in FPC was used to reassemble any contigs that contained 'Q' clones, which exhibit an unusual number of extra bands or gaps between bands matching the Q clone to other clones, resulting in false positive overlaps between putative contigs. The presence of Q clones within a contig is suggestive of misassembly due to false-positive fingerprint matches. The DQer function reassembled the clones within the contig with successively increasing stringency until no Q clones remained. The resulting contigs were subsequently processed with an automated clone ordering application, CORAL . Markers and BAC sequences were also aligned with WGS contigs from the third bovine draft assembly [GenBank:AAFC03000000] and scaffold sequences .The collection of GenBank bovine sequence used for e-PCR alignments to match markers across linkage and RH data sets includes bovine sequences deposited in the genome survey sequence (GSS), STS, patent (PAT), mammalian (MAM), and EST divisions of GenBank after release of the second bovine draft assembly. Bovine sequences were identified by taxonomy identification numbers for Associations between markers and clones were used to assess and refine chromosome assignments and the order of fingerprint contigs, where the contigs were initially assigned and ordered along chromosomes using end-sequence alignments to human sequence and bovine-human comparative maps ,47. For polish and flips to reorder markers in that set. Markers assigned to the chromosome, but not matching BAC clones, were added with buildfw, and a final BAC-assisted order obtained from iterative polish and flips after all assigned markers were included.Direct marker-clone and indirect marker-WGS-clone alignments were used to identify the set of markers from the current composite map with consistent, unambiguous alignments to the BAC map. The order of these markers on the BAC map was used to seed the ordering process for each chromosome. A map of the markers matching the BAC map was computed, followed by iterative 10 likelihoods of markers ordered according to the BAC map, Btau3.1 draft assembly, and unassisted composite map. Additional data file 10 likelihoods for the unassisted, BAC-assisted and sequence-assisted composite maps.The following additional data are available with the online version of this paper. Additional data file BAC, bacterial artificial chromosome; BES, BAC end sequence; CI, confidence interval; cM, centimorgan; cR, centiRay; EST, expressed sequence tag; IBBMC, International Bovine BAC Mapping Consortium; ILTX, Illinois-Texas; INRA, French National Institute for Agricultural Research; QTL, quantitative trait loci; RH, radiation hybrid; SIAG, Shirakawa Institute; SNP, single-nucleotide polymorphism; SRY, sex-determining region Y; STS, sequence tagged site; UAMU, Alberta-Missouri; USDA, US Department of Agriculture; WGS, whole genome shotgun sequence.The first three authors contributed equally to the work. RC and JES developed the BAC fingerprint and BAC-human comparative maps. WMS and MH developed the composite map and integrated marker maps with the BAC map and draft assembly. CAA, CAG, AEvdW, DML, HAL, SSM, SMcK, BM, MG and LS developed probes and screened BAC clones. RB, RC, DML and WMS analyzed BES. IEB, RH, SJMJ, MAM, CAM, NHY and GY were involved in fingerprinting, BAC end sequencing and BAC map creation. SY, CPVT, TSS, ARC, MMC, DML, AE, HAL, RT, LCS, LKM, AR, and SZ were involved in BAC end sequencing, coordinated by HAL and JES. GLB, JWK, SMK, TPLS, WMS, JFT, and RDS contributed to linkage maps. DML, AEvdW, HAL, JEW, JLW, JA, OJ, SMcK, SSM, BM, AE, SF, MG, MB, AR and LS were involved in RH map development. LS, AE, MB, SF, and MG contributed to INRA BAC map and integration of IBBMC and INRA maps. PdJ, KO, and CAG participated in BAC library development. DLA, BPD, HS and WMS contributed to the gbrowse web sites. AE, JLW, FWN, and JWK conceived the composite map. TPLS, JCM, SMK, RDG, HAL and JEW were involved in conceiving and planning the project. WMS, JES, RC, TPLS and RB drafted portions of the manuscript. MH, JFT, RT, JCM, DLA, ARC, AMC, BPD, AE, CAG, JWK, DML, MAM, TSS, CPVT, and JLW edited the manuscript. All authors read and approved the final manuscript.Analyses of BAC end sequences.Click here for fileFigures showing the bovine-human comparative map defined by the BAC map and BES alignments.Click here for filePlacement of markers on the composite map.Click here for file10 likelihoods of markers ordered according to the BAC map, Btau3.1 draft assembly, and unassisted composite map.LogClick here for file10 likelihoods for the unassisted, BAC-assisted and sequence-assisted composite maps.LogClick here for file"}
+{"text": "Between 1993 and 1997, 98 gnathostomosis cases were clinically identified in Acapulco, Mexico. Intermittent cutaneous migratory swellings were the commonest manifestation. Larvae were identified in 26 cases, while in 72, final diagnosis was made on the basis of epidemiologic data, food habits, and positive enzyme-linked immunosorbent assay and Western blot results."}
+{"text": "Vector-borne infectious diseases are emerging or resurging as a result of changes in public health policy, insecticide and drug resistance, shift in emphasis from prevention to emergency response, demographic and societal changes, and genetic changes in pathogens. Effective prevention strategies can reverse this trend. Research on vaccines, environmentally safe insecticides, alternative approaches to vector control, and training programs for health-care workers are needed."}
+{"text": "The glial fibrillary acidic protein (GFA) content of 58 human brain tumours was determined by quantitative immunoelectrophoresis, using monospecific antibody against GFA. Astrocytomas, glioblastomas, oligodendrogliomas, spongioblastomas, ependymomas and medulloblastomas contained relatively high amounts of GFA, up to 85 times the concentration in parietal grey substance of normal human brain. GFA was not found in neurinomas, meningiomas, adenomas of the hypophysis, or in a single case of metastasis of adenocarcinoma. Non-glial tumours of craniopharyngioma and haemangioblastoma were infiltrated by reactive astroglia and showed considerable amounts of GFA."}
+{"text": "Alcohol abuse causes progressive toxicity and degeneration in liver and brain due to insulin resistance, which exacerbates oxidative stress and pro-inflammatory cytokine activation. Alcohol-induced steatohepatitis promotes synthesis and accumulation of ceramides and other toxic lipids that cause insulin resistance. Ceramides can readily cross the blood-brain barrier, and ceramide exposure causes neurodegeneration with insulin resistance and oxidative stress, similar to the effects of alcohol. Therefore, in addition to its direct neurotoxic effects, alcohol misuse establishes a liver-brain axis of neurodegeneration mediated by toxic lipid trafficking across the blood-brain barrier, leading to progressive white matter degeneration and cognitive impairment. Excessive drinking can cause chronic liver injury associated with profound impairments in hepatocellular regeneration \u20134. CirrhThe central nervous system (CNS) is the other major target of alcohol toxicity and degeneration. Chronic alcohol abuse causes cognitive impairment with permanent structural damage to the brain. Although Wernicke-Korsakoff syndrome is one of the most devastating forms of alcohol-associated neurodegeneration, its pathogenesis is largely related to thiamine deficiency ,14. In c2.src homology domains, such as Grb2 and the p85 subunit of PI3 kinase, to promote mitogenesis, cell survival, gene expression, energy metabolism, and motility, all of which are needed for liver remodeling and repair after injury . Mo. MoIn vi7.Chronic alcohol exposure resulting in steatohepatitis, ER stress, and persistent hepatic injury, promotes lipolysis and increased generation of toxic lipids, including ceramides. Ceramides exacerbate liver injury by causing insulin resistance, oxidative stress, and pro-inflammatory cytokine activation. Ceramides that are released into peripheral blood, and lipid soluble and therefore can readily cross the blood-brain barrier. In the CNS, ceramides initiate a complex cascade of neurodegeneration mediated by insulin resistance, inflammation, and oxidative stress. CNS insulin resistance leads to neuronal loss and impaired oligodendrocyte function. Attendant myelin degradation leads to increased CNS toxic lipid production and worsening of neurodegeneration. In addition, direct neurotoxic effects of alcohol and its metabolites, which impair mitochondrial function, reduce membrane integrity, and increase oxidative stress also contributes to neurodegeneration.Brain insulin resistance leads to neuronal loss and impaired neurotransmitter function required for plasticity, learning, and memory. In addition, brain insulin resistance impairs oligodendrocyte survival and function, resulting in reduced myelin integrity, and increased generation of ceramides, which further increase brain insulin resistance, neuro-inflammation, oxidative stress, and neurodegeneration. These concepts open an exciting new chapter on disease mechanisms and strategies for developing non-invasive tools to monitor proneness and progression of alcoholic neurodegeneration. Our over-arching hypothesis about how alcohol mis-use causes neurodegeneration, both directly and via the liver-brain axis is diagramed in"}
+{"text": "In Europe, hantavirus disease can hardly be called an emerging zoonosis; it is rather a rediscovered disease. Since 1934 an epidemic condition with primarily renal involvement has been described in Sweden. Nowadays, hundreds to thousands of cases per year are registered in Fennoscandia, fluctuating with the numbers of the specific Arvicoline-rodent reservoir, the red bank vole, which carries the main European serotype, Puumala (PUU). In the early 1980s, the rat-transmitted serotype, Seoul (SEO), caused laboratory outbreaks throughout Europe, and recent reports also suggest sporadic, wild rat-spread hantavirus disease. In the Balkans, at least four serotypes are present simultaneously: PUU, SEO, the \"Korean\" prototype Hantaan (HTN) or HTN-like types, and Dobrava, the latter causing a mortality rate of up to 20%. Moreover, recent genotyping studies have disclosed several PUU-like genotypes spread in Europe and/or Russia by other genera of the Arvicoline-rodent subfamily: Tula, Tobetsu, Khabarovsk, and Topografov. Their importance for human pathogenicity is still unclear, but serologic cross-reactions with PUU antigen might have caused their misdiagnosis as PUU-infections in the past."}
+{"text": "Overlapping genes are common in RNA viruses where they serve as a mechanism to optimize the coding potential of compact genomes. However, annotation of overlapping genes can be difficult using conventional gene-finding software. Recently we have been using a number of complementary approaches to systematically identify previously undetected overlapping genes in RNA virus genomes. In this article we gather together a number of promising candidate new overlapping genes that may be of interest to the community.Astroviridae, Reoviridae, Rhabdoviridae and Coronaviridae, respectively).Overlapping gene predictions are presented for the astroviruses, seadornaviruses, cytorhabdoviruses and coronaviruses (families  Overlapping genes (whereby the same nucleotide sequence codes for two or more proteins in different reading frames) are particularly common in RNA viruses, where they may serve as mechanisms to optimize the coding potential of compact genomes, regulate gene expression, or circumvent the host cell's canonical - though not ubiquitous - rule of 'one functional protein per mRNA'. However, such genes can be difficult to detect using conventional gene-finding software.de novo overlapping CDSs are often considerably less conserved than the ancestral genes that they overlap . The explicit 'coding signal' of such a CDS may be swamped by the 'coding signal' of the ancestral CDS. Thus there are a number of known overlapping CDSs which MLOGD fails to detect. Another caveat of MLOGD is that, if an overlapping CDS is very short and highly conserved  through the incorporation of explicit models for sequence evolution in multiply-coding regions -3. One cing CDS; ), then tA sometimes more sensitive, but generally less specific, approach involves analysis of conservation at synonymous sites within known CDSs. This method is particularly useful when a large and diverse input sequence alignment is available ,6. EnhanOver the past few years we have engaged in a systematic survey of viral genomes for previously undetected overlapping genes. While many of these merit detailed analysis and experimental follow-up , there remain a miscellany of promising candidate new overlapping genes that we are not currently in a position to follow up experimentally but, nonetheless, may be of interest to the community. The purpose of this article is to communicate five of these candidates.de novo overlapping genes in the +1 frame, as opposed to the +2 frame, has been previously noted and appears to be related to codon (or dicodon) usage in the ancestral CDS .,37.36,37-3 (depending on species) and a 'U' at +4 for a medium or weak Kozak context , our MLOGD analysis suggests that NS6 is coding and is subject to significantly stronger functional constraints than ORFX  in the +1 reading frame Figure . ORFX apn Figure . ORFX han Figure , panel 5Overlapping genes are difficult to identify and are often overlooked. However, it is important to be aware of such genes as early as possible in order to avoid confusion (otherwise functions of the overlapping gene may be wrongly ascribed to the gene they overlap), and also so that the functions of the overlapping gene may be investigated in their own right. Computational analysis of sequence data is a time- and cost-efficient way to find such genes and help direct experimental follow-up.The list of new candidate overlapping genes presented here is by no means complete as we have omitted several candidates that we are currently following up experimentally, and a number of candidates that are less certain - for example candidates where a conserved potential translation mechanism has not been identified, or candidates where a significant fraction of isolates contain premature termination codons, or candidates with too little phylogenetic support within the currently available sequence databases. To the best of our knowledge (except as noted for cytorhabdovirus) these candiates have not previously been described or annotated elsewhere, and we apologize if we have accidently omitted any previous references to any of these candidates.AB000283, AB000284, AB000285, AB000286, AB000287, AB000288, AB000289, AB000290, AB000291, AB000292, AB000293, AB000294, AB000295, AB000296, AB000297, AB000298, AB000299, AB000300, AB000301, AB009984, AB009985, AB013618, AB025801, AB025802, AB025803, AB025804, AB025805, AB025806, AB025807, AB025808, AB025809, AB025810, AB025811, AB025812, AB031030, AB031031, AB037272, AB037273, AB037274, AB290149, AB308374, AB496913, AF056197, AF117209, AF141381, AF248738, AF260508, AY720891, AY720892, DQ028633, DQ070852, DQ344027, DQ630763, EF138823, EF138824, EF138825, EF138826, EF138827, EF138828, EF138829, EF138830, EF138831, EF583300, FJ755402, FJ755403, FJ755404, FJ755405, FJ890352, FJ890355, FM213330, FM213331, FM213332, GQ405855, GQ405856, GQ405857, GQ495608, GQ901902, L06802, L13745, L23513, S68561, U15136, Y08632, Y15938, Z25771, Z33883, Z46658, Z66541]. The seadornavirus, cytorhabdovirus and coronavirus sequences used are listed in Figures EU265679] and [GenBank: EU265722]) and the mamastroviruses .Virus sequences were downloaded from GenBank and alignments were generated using standard bioinformatics software (blast , clustalThe authors declare that they have no competing interests.AEF carried out the bioinformatic analysis and wrote the manuscript. Both authors edited and approved the final manuscript."}
+{"text": "Systemic sclerosis (SSc) is a multi-system disease characterized by skin             fibrosis and visceral disease. Therapy is organ and pathogenesis targeted. In             this review, we describe novel strategies in the treatment of SSc. Utilizing the             MEDLINE and the COCHRANE REGISTRY, we identified open trials, controlled             trials, for treatment of SSc from 1999 to April 2005. We used the terms scleroderma,             systemic sclerosis, Raynaud's phenomenon, pulmonary hypertension,             methotrexate, cyclosporin, tacrolimus, relaxin, low-dose penicillamine, IVIg,             calcium channel blockers, losartan, prazocin, iloprost, N-acetylcysteine, bosentan,             cyclophosphamide, lung transplantation, ACE inhibitors,             anti-thymocyte globulin, and stem cell transplantation. Anecdotal reports were             omitted.\t\tMethotrexate, cyclosporin, tacrolimus, relaxin, low-dose penicillamine,             and IVIg may be beneficial in improving the skin tightness in SSc. Calcium             channel blockers, the angiotensin II receptor type 1 antagonist losartan,             prazocin, the prostacyclin analogue iloprost, N-acetylcysteine and the dual             endothelin-receptor antagonist bosentan may be beneficial for Raynaud's             phenomenon. Epoprostenol and bosentan are approved for therapy of             pulmonary hypertension (PAH). Other options under investigation include             intravenous or aerolized iloprost. Cyclophosphamide (CYC) pulse therapy             is effective in suppressing active alveolitis. Stem cell and lung transplantation             is a viable option for carefully selected patients. Renal crisis can be effectively             managed when hypertension is aggressively controlled with angiotensin converting             enzyme (ACE) inhibitors. Patients should continue taking ACE inhibitors even after             beginning dialysis in hope of discontinuing dialysis. Anti-thymocyte globulin and             mycophenolate mofetil appear safe in SSc. The improvement in skin score and             the apparent stability of systemic disease during the treatment period suggest             that controlled studies of these agents are justified. Stem cell transplantation is             under investigation for severe disease. Novel therapies are currently being tested             in the treatment of SSc and have the potential of modifying the disease process             and overall             clinical outcome. The evaluation of these studies is still a difficult process."}
+{"text": "As part of a larger qualitative study assessing the perceptions of Canadian oncology health professionals regarding integrated breast cancer care, we undertook an exploration of current integrative practices of oncology health professionals.Cancer patients are increasingly known to use complementary medicine (Using an interpretive description research design and a purposive sampling, we conducted a series of in-depth qualitative interviews with various oncology health professionals recruited from provincial cancer agencies, hospitals, integrative clinics, and private practice settings in four Canadian cities: Vancouver, Winnipeg, Montreal, and Halifax. A total of 16 oncology health professionals participated, including medical and radiation oncologists, nurses, and pharmacists. acting as an integrative care guide, and collaborating with other health professionals.Findings highlighted two main strategies used by oncology health professionals to create a more integrative approach for cancer patients:cam decisions. Given that cancer patients report that they want to be able to confer with their conventional health professionals, particularly their oncologists, about their cam use, health professionals who elect to adopt integrative practices are likely offering patients much-welcomed support.Although few clear standards of practice or guidance material were in place within their organizational settings, health professionals discussed some integrative roles that they had adopted, depending on interest, knowledge, and skills, in supporting patients with"}
+{"text": "Salomone Di Saverio and colleagues discuss the diagnosis and management of a man presenting with symptoms of partial intestinal obstruction. In summer 2008, a 73-year-old man arrived in the emergency room with vague abdominal pain. On examination, his abdomen was distended and tympanic, but soft and non-tender on palpation. The patient had been immobile and bed-ridden since 1995, when he had neurosurgical resection of a medullary ependymoma of the spine, with residual paraplegia, peripheral neuropathy, and a neuropathic bladder with secondary chronic renal failure. The patient had a medical history of hypertension and type II diabetes mellitus and suffered from chronic constipation with recurrent episodes of partial bowel obstruction.Given his past history, the current presentation was in keeping with a further episode of bowel obstruction. At this stage, we needed to assess the degree of obstruction  and its possible causes.The full diagnostic workup is shown in Supine and erect plain abdominal X-rayAbdominal ultrasound CT scanConventional barium follow-through examination, upper gastrointestinal and small bowel series, enteroclysis  Water-soluble contrast follow-through  enemaCT scan with double contrast Magnetic resonance imagingEndoscopy LaparoscopyPlain abdominal X-ray was ordered. This showed a huge faecal impaction extending from the pelvis upwards to the left subphrenic space and from the left towards the right flank, measuring over 40 cm in length and 33 cm in width . There wThis patient has partial large bowel obstruction. The differential diagnosis is between malignant obstructing diseases, such as colon cancer, or benign conditions, such as sigmoid volvulus or diverticulitis. These benign conditions can be life-threatening because of the risk of colonic ischaemia and/or perforation.without an anatomical lesion causing the impaction. Pinpointing the exact cause of the constipation in this patient was difficult, as he had a complex medical history and presentation\u2014renal failure, dehydration, electrolyte imbalance, diabetes mellitus, and peripheral neuropathy and paraplegia secondary to spinal cord tumour, in an immobile bed-ridden patient with mild depression. Common causes of constipation are shown in Given the history of recurrent chronic constipation, in a chronically bed-ridden patient with previous spinal surgery and residual paraplegia, we thought it was likely that this patient had faecal impaction Endocrinological: diabetes mellitus, hypopituitarism, hypothyroidism, pseudohypoparathyroidism, hypocalcaemia, phaeochromocytoma, glucagonoma, pregnancyMetabolic: uraemia, hypokalaemia, porphyria, amyloidosis, dehydrationNeurological: Parkinson disease, brain tumour, multiple sclerosis, sclerodermia, spinal cord injuries, tumoursPsychiatric: depression, psychosis, anorexia nervosa, obsessive-compulsive disordersOperations: pelvic operations, anal operations, narrowing following anastomosesOrganic obstructive diseases: tumours, adherences, strangulated hernias, volvulus, invagination, endometriosisDiet: inadequate intake of fibre or fluidsLifestyle changes: immobility, vacationFunctional diseases: functional obstructive bowel diseases, congenital or acquired aganglionosis, Ogilvie syndrome, megacolon, irritable bowel diseasePelvic exit obstruction: rectal prolapse, rectocele, rectal intussusception, rectal stenosis, megarectum, hypertonus of internal sphincter, paradoxical contraction of puborectal musclePharmacological agents: antacids, antiepileptics, antiemetics (5-HT3 antagonists), antihypertensives, antiparkinsonians, anticholinergics, antidepressants, antitussives, antidiarrheals (by causing dehydration), cancer chemotherapy agents, diuretics (by causing dehydration), iron , opioid analgesics, neurolepticsMetabolic abnormalities: dehydration , hypercalcaemia, hypokalaemia, uraemia, hypothyroidism, diabetesNeurological disorders: spinal cord involvement, sacral nerve infiltration, autonomic failure Painful anorectal conditions Diet: Poor appetite and low amounts of food intake, low-fibre diet, poor fluid intakeEnvironmental: Lack of privacy, comfort, or assistance with toiletingOther factors: Advanced age, inactivity, decreased mobility, bed-ridden patients, depression, sedationIn patients receiving palliative care, the underlying causal factors for constipation are likely to be long-standing. The patient's bowel pattern needs to be carefully assessed, with a focus on looking for modifiable factors. For example, if a particular pharmacological agent is identified as a possible causative factor, it may be helpful to change the agent or the route of its administration. It is also helpful to anticipate the constipating effects of medications, such as opioids, and to provide laxatives prophylactically. Other concomitant or contributing factors such as electrolyte imbalances or metabolic/endocrine abnormalities should be identified and corrected. However, the underlying cause of constipation is often unavoidable and pharmacological treatment is often necessary In this patient, a long colonic-rectal tube was inserted with partial relief of the abdominal distension after expulsion of 8,000 ml of gas. The patient was admitted to the medical ward for rehydration, correction of electrolyte imbalance, and multiple enemas. Two days later the faecal impaction, although slightly reduced, still measured 32 cm in length and 24 cm in width . After tSerial plain abdominal X-rays had already been performed. Colonoscopy was not feasible, because the severe faecal impaction may have hindered the progression of the endoscope and affected the sensitivity of the exam by covering and camouflaging possible mucosal lesions of the colonic wall. Contrast enema would probably not have been effective or diagnostic. Therefore abdominal CT scan with multiplanar reconstruction and three-dimensional (3-D) reconstruction appeared to be the best option as a further diagnostic step, in order to assess the presence of an anatomic cause for the patient's bowel obstruction.Abdominal CT scan was ordered. The multiplanar and 3-D reconstruction showed the persistence of a large faecal impaction, over 18 cm in extent , in the It is likely that the abnormally dilated descending colon was exacerbating the neurogenic chronic faecal stagnation .Rehydration, multiple enemas, the prokinetic agent neostigmine see , and laxCholinergic agents (bethanechol): indications: postoperative ileus; limitations: side effectsDopamine antagonists (domperidone): indications: gastroparesis and gastroesophageal reflux; limitations: poorly effective in colonic motility disordersOpioid antagonists : indications: irritable bowel syndrome, small intestinal pseudo-obstruction, constipationMotilin agonists (erythromycin): indications: diabetic gastroparesis, colonic pseudo-obstruction, postoperative ileusCholinergic agonist and dopamine antagonist (metoclopramide): indications: exclusively for proximal motility dysfunctionParasympathomimetics (cisapride): indications: colonic motility disorders, constipation-predominant irritable bowel syndromePartial serotonin agonist (tegaserod): indications: constipation-predominant irritable bowel syndrome; limitations: cardiovascular adverse effectsAcetylcholine esterase inhibitor (neostigmine): indications: colonic pseudo-obstructionProstaglandins: lubiprostone (prostaglandin E1 derivative) and oral prostaglandin E2 are reported to increase small intestine and colonic transitCholecystokinin antagonist (ceruletide): enhances gastrointestinal motilityAnalogue of somatostatin (octreotide): experimental evidence of shortening ileus and promoting bowel movements in the small intestine and colon in animal modelsWe believed that neostigmine, which has a focused effect in stimulating large bowel motility, was the most appropriate and beneficial prokinetic agent in this setting .The patient was scheduled for elective surgical resection of the redundant megacolon. He was discharged 25 days after admission, after rehydration, multiple enemas, prokinetic agents, and laxatives. On discharge, the abdomen remained slightly distended but was soft and non-tender. The patient was passing stools and not vomiting. We suggested home nursing to the patient and his family.After discharge, he underwent elective surgical resection of the redundant megacolon with planned primary anastomosis, and he had an uneventful postoperative course.The patient gave written consent for these case details to be published.If people in Western societies continue to live longer, we are likely to see an increase in the number of institutionalised elderly people with impaired mobility. Both ageing and immobility are risk factors for constipation. The estimated prevalence of constipation is between 2%\u201328%, and the number of people reporting constipation increases with age The prevalence of constipation among patients in palliative care ranges from 32% to 87%, and it is particularly common in patients with end-stage cancer In severe constipation, patients are usually unable to pass much stool and may pass only small amounts of watery stool. They typically experience abdominal pain, discomfort and bloating, and may also lose their appetite. Some very ill older patients may have a change in behaviour and may develop fever.In patients with constipation associated with a sigmoid redundant megacolon, colonic volvulus can develop, with possible progression to bowel wall ischaemia and perforation. Early surgical consultation and laparotomy are mandatory in such cases.http://clinicaltrials.gov/ct2/show/NCT00467350). Fibres and laxatives can increase stool frequency and improve symptoms of constipation Treatment of constipation, and of the most severe forms of faecal impaction, is multimodal Diagnostic assessment for colonic diseases is not routinely required. Such assessment is usually reserved for patients whose constipation is refractory to conservative treatment, or who have persistent severe faecal impaction, and/or who are found to have concomitant colonic obstructive disease.Management of chronic constipation is shown in Conservative lifestyle modification behavioural approaches bowel trainingMedical Oral laxativesPredominantly softening:Faecal lubricants: liquid paraffinBulk-forming laxatives: methylcellulose, polycarbophil, psyllium, ispagulaMacrogols: polyethylene glycol and electrolytesOsmotic hyperosmolar laxatives: lactulose, sorbitolEmollient stool softeners and surfactants: docusate calcium, docusate sodiumSaline laxatives: magnesium citrate, magnesium hydroxide, magnesium sulphate, sodium biphosphateCombination laxatives:Softener and stimulant: poloxamer and dantronPredominantly peristalsis-stimulating:Anthraquinones: senna, danthron, cascara sagradaPolyphenolics and other stimulant laxatives: bisacodyl, sodium picosulphate, castor oilRectal laxativesPredominantly softening:Faecal lubricants: arachis oil enema, docusate sodium enemaOsmotic laxatives: glycerol suppositorySaline laxatives: phosphate enema, sodium citrate enemaPredominantly stimulating:Polyphenolics: bisacodyl suppositoryProkinetics drugs (see )Injection of botulinum toxinSurgical (for selected patients)Repair of non-emptying rectoceles for patients with obstructed defecationSubtotal colectomy with ileorectal anastomosis for patients with persistent and intractable slow transit constipationPatients with combined slow transit constipation and pelvic outlet obstruction, as well as symptomatic refractory retaining rectoceles and rectal intussusception, benefit from subtotal colectomy with ileorectal anastomosis and repair or treatment of the outlet obstruction causing pathologyIn palliative care, nursing staff play a crucial role in the assessment, prophylaxis, and management of constipation, since they are in daily contact with patients. Such assessments should focus not only on the frequency of bowel movements, but also on the quality of stools; length of time to defecation; diarrhoea and overflow diarrhoea; continence and incontinence; effectiveness of laxatives; addition of complementary therapies worsening constipation; diet and fluid intake; environmental factors that could be influencing bowel movements ; and the need for abdominal massage. Abdominal massage, performed by a massage therapist, may be used in patients with chronic constipation and altered motility as an adjunctive measure; it may help to stimulate the periphery of the small and large intestines and relieve bowel atony. A recent randomised controlled trial of abdominal massage plus laxatives versus laxatives alone for constipation found that the addition of massage was associated with decreased constipation and abdominal pain and increased bowel frequency Larkin and colleagues recently published an algorithm on prophylaxis, ongoing assessment, and treatment of constipation in palliative care settings Older patients, institutionalised elderly people, and chronically bed-ridden patients commonly experience constipation and are at risk of developing severe fecal impaction.This risk is higher in the presence of neurological illnesses or injuries.The management is usually conservative and multimodal.The combination of a softener and stimulant laxative is generally recommended, and the choice of laxatives should be made on an individual basis.Diagnostic assessment for colonic diseases and surgical consultation are not routinely required.Unsuccessful conservative treatment, the persistence of severe faecal impaction, and/or the finding of concomitant colonic obstructive disease should lead to further diagnostic assessment and surgical consultation.Early surgical consultation and urgent laparotomy are required in the case of free air on plain abdominal X-ray and/or signs of peritonism and acute abdomen."}
+{"text": "Sir,We read the interesting article by in vitro, induce apoptosis, inhibit cell adhesion and interfere with the metastatic process . All these results raise the possibility that nitrogen-containing BPs, such as zolederonic acid, with their direct antitumour effects, may be valuable adjuncts to the novel therapeutic strategies in the treatment of MM.As is well known, BPs are used to treat osteoclast-mediated bone diseases, including osteoporosis, Paget's disease, hypercalcemia of malignancy, bone metastases, and bone disease associated with MM . Currental cells . In addi"}
+{"text": "This review summarizes the epidemiology, clinical course, and diagnosis of malaria. The influence of infection during pregnancy upon maternal and neonatal anemia, stillbirth, preterm labor, low birth weight, and congenital malaria is discussed. Options for treatment and prophylaxis during pregnancy are presented."}
+{"text": "Guidelines for Preventing Opportunistic Infections Among Hematopoietic Stem Cell Transplant Recipients contains a section on hospital infection control including evidence-based recommendations regarding ventilation, construction, equipment, plants, play areas and toys, health-care workers, visitors, patient skin and oral care, catheter-related infections, drug-resistant organisms, and specific nosocomial infections. These guidelines are intended to reduce the number and severity of hospital infections in hematopoietic stem cell transplant recipients."}
+{"text": "There is fMRI evidence that women are neurally predisposed to process infant laughter and crying. Other findings show that women might be more empathic and sensitive than men to emotional facial expressions. However, no gender difference in the brain responses to persons and unanimated scenes has hitherto been demonstrated.Twenty-four men and women viewed 220 images portraying persons or landscapes and ERPs were recorded from 128 sites. In women, but not in men, the N2 component (210\u2013270) was much larger to persons than to scenes. swLORETA showed significant bilateral activation of FG (BA19/37) in both genders when viewing persons as opposed to scenes. Only women showed a source of activity in the STG and in the right MOG , and only men in the left parahippocampal area (PPA).A significant gender difference was found in activation of the left and right STG (BA22) and the cingulate cortex for the subtractive condition women minus men, thus indicating that women might have a greater preference or interest for social stimuli (faces and persons). That women are more interested than men in conspecifics, as opposed for example to machinery, is a common prejudice not really substantiated by scientific evidence. It is true, however, that female children across various human cultures are prone to spend more time with their younger siblings, or their simulacra (baby dolls), than are their male counterparts. It is quite difficult to determine whether this socially-oriented behaviour is entirely due to cultural factors (such as the style of upbringing) or to a biological difference dependent on genetic factors. Indeed, as shown in psychosocial studies -3 the \"aWhatever the cause, little neuroscientific evidence of such preference of the female brain for social stimuli has been reported, in contrast to the large body of behavioural evidence showing that females have greater social and affective competence. For example, a substantial literature has accumulated indicating that women are better than men at decoding facial expressions of emotion -10. VariAn interesting fMRI study  providedSome fMRI  and bioeOtherwise, the neurobiological bases of a gender difference in brain responsiveness to social stimuli remain unexplored. The goal of the present study was to shed some light on this matter by measuring brain bio-electrical activities in men and women during perception of positive social scenes vs. landscapes   has beenFig. The interaction of scene type \u00d7 gender  and relative post-hoc comparisons showed significantly (p < 0.02) larger N2 responses to social scenes  than landscapes  in women, whereas men showed a tendency (p < 0.08) toward the opposite preference .The ANOVA also showed that scene type \u00d7 electrode  and scene type \u00d7 electrode \u00d7 hemisphere  were significant. Post-hoc comparisons indicated that the parietal N2 was left-sided and was larger to social scenes than landscapes, whereas the bilateral anterior frontal N2 was larger to landscapes than social scenes.Two swLORETA source reconstructions were performed , of the right MOG and of the right STG during processing of persons vs. scenes. The fusiform face area (FFA) has been described as a portion of the extra-striate cortex specialized for face perception; it responds markedly more strongly to faces than to other classes of objects e.g. hands, houses, scrambled faces . SeveralIn this context, a larger activation of FFA and EBA in women than men might indicate greater interest in or attention to this class of biologically relevant signals (human faces and bodies) in those individuals who are genetically determined to be the primary offspring caregivers. Since no affective behavioural response or attention allocation to scenes was required by the task, this gender difference might reflect a privileged automatic processing of visual images depicting conspecifics in the female brain. Naturally, since this is the first neural evidence of such a finding, further investigation with higher spatial resolution techniques will help to shed light on this matter. Indeed, it remains unclear whether the greater activation in response to conspecifics found in the right extra-striate cortex, or in the higher-order STG, of the female brain might be the result of visual learning/expertise or be modulated by neuro-hormonal factors. For example, the neuropeptide oxytocin is known to play an important role in affiliation behaviour such as pair-bonding and maternal care. Rather recently, oxytocin has been found to be a potent modulator in the processing of social stimuli, improving trust in social interactions , and eveOn the other hand, the greater left parahippocampal gyrus activation in men than women might be due to their interest in the non-human components of scenarios surrounding the persons depicted. Indeed, it is known that a subregion of the parahippocampal cortex  plays an important role in encoding topographical scene stimuli such as images of landscapes, cityscapes or rooms (i.e. images of \"places\") ,31.As for the specific gender difference observed in the activation of the right STG and CC, it can be noted that both regions are thought to be involved in the perception of affective visual images , social There is considerable evidence that the CC and ACC has a particular role in empathy -43. In aOne possible limitation of this study is that scenes were not actively attended to (attention was paid to abstract stimuli) and this might (or might not) have affected the gender difference. Further investigation is needed to reach a definitive conclusion.Twenty-four healthy right-handed Italian University students  were recruited for this experiment. All were of middle-high socio-cultural status and their mean age was 22 years. All had normal or corrected-to-normal vision and reported no history of psychiatric diseases, neurological illness or drug abuse. Their handedness was assessed by the Italian version of Edinburgh Handedness Inventory , a laterInternational Affective Picture System [Two hundred and twenty positive IAPS slides were selected from the e System  . Stimuli were also balanced for perceptual complexity by choosing interesting scenarios rich in detail, but the overall spatial frequency content of each picture was not controlled for, leading to a possible limitation. Stimuli were randomly presented in the centre of the screen for about 1 s with an ISI of 2.8\u20133.2 s.The mean valences for the two classes of stimuli were 7.01 for social scenes and 6.9 for landscapes, according to the data by Lang and coworkers , which pThe 220 positive images were presented randomly mixed with 220 negative affective pictures. Stimuli were randomly presented in the centre of the screen for about 1 s with an ISI of 2.8\u20133.2 s.Participants sat comfortably in a darkened, acoustically and electrically shielded cubicle and were instructed to fixate the centre of the screen and to avoid any eye or body movements during the recording session. The task consisted of responding to 72 target stimuli randomly mixed with the IAPS images, by pressing a button as accurately and quickly as possible with the index finger of the left or right hand. Abstract geometrical paintings all alike in structure but differing in colour were used as targets. The two hands were used alternately during the recording session. The response hand and order of sequences were counterbalanced across subjects.EEProbe software. Computerized artefact rejection was performed before averaging to discard epochs in which eye movements, blinks, excessive muscle potentials or amplifier blocking occurred. The artefact rejection criterion was a peak-to-peak amplitude exceeding 50 \u03bcV, and the rejection rate was ~5%. ERPs were averaged offline from -200 ms before to 1000 ms after stimulus onset.The EEG was continuously recorded from 128 sites at a sampling rate of 512 Hz. Horizontal and vertical eye movements were also recorded. Linked ears served as the reference lead. The EEG and electro-oculogram (EOG) were amplified with a half-amplitude band pass of 0.016\u2013100 Hz. Electrode impedance was kept below 5 k\u03a9. EEG epochs were synchronized with the onset of stimulus presentation and analyzed by ANT-The mean amplitude of the N2 component of the ERP was measured in the time window 210\u2013270 ms at the left and right anterior frontal , central , fronto-central  and parietal  sites.ERP data were subjected to multifactorial repeated-measures ANOVA. Factors were \"scene type\" , \"electrode\" (4 levels) and \"hemisphere\" . Post-hoc Tukey tests were used for multiple comparisons of means.Topographical voltage maps of ERPs were made by plotting colour-coded isopotentials derived by interpolating voltage values between scalp electrodes at specific latencies. Low Resolution Electromagnetic Tomography (LORETA)  was perfOur data indicate that the female human brain reacts strongly to the view of scenes involving humans rather than unanimated scenes.The larger activation of the right extra-striate cortex (BA37) in women than men might indicate greater attention to this class of biologically relevant signals (conspecifics) in those individuals who are genetically determined to be the primary offspring caregivers. The stronger activation of affective brain areas  also suggests a possible gender difference in the empathic reaction to social scenes.AMP conceived and designed the study, accomplished most of the data analyses and wrote the manuscript. AZ and RA performed source reconstruction analysis. All authors read and approved the final version of the manuscript.IAPS images:Social stimuli, 1340, 1601, 2030, 2037, 2040, 2057, 2058, 2070, 2071, 2080, 2091, 2092, 2152, 2154, 2160, 2165, 2170, 2208, 2209, 2222, 2224, 2260, 2299, 2311, 2331, 2332, 2339, 2340, 2341, 2345, 2360, 2362, 2370, 2373, 2387, 2388, 2389, 2391, 2395, 2398, 2501, 2510, 2530, 2550, 2598, 2655, 2660, 2900.2, 4006, 4150, 4220, 4250, 4520, 4532, 4533, 4542, 4572, 4574, 4599, 4601, 4603, 4606, 4609, 4610, 4614, 4623, 4624, 4625, 4626, 4640, 4641, 4689, 4700, 5410, 5470, 5621, 5831, 5836, 7325, 8021, 8031, 8032, 8033, 8034, 8040, 8041, 8080, 8120, 8130, 8161, 8185, 8186, 8193, 8200, 8205, 8250, 8280, 8300, 8320, 8330, 8350, 8370, 8380, 8400, 8460, 8461, 8470, 8496, 8497, 8540.Landscapes, 1333, 1419, 1440, 1441, 1450, 1460, 1463, 1500, 1510, 1540, 1560, 1590, 1600, 1602, 1603, 1604, 1610, 1620, 1640, 1650, 1660, 1661, 1670, 1675, 1710, 1720, 1721, 1722, 1740, 1750, 1810, 1811, 1812, 1900, 1910, 1920, 1942, 1947, 7057, 7192, 8500, 8501, 8510, 7330, 7430, 7450, 7220, 7230, 7260, 7280, 7282, 7286, 7291, 7320, 7472, 7480, 7481, 1731, 2791, 5000, 5001, 5010, 5020, 5030, 5200, 5201, 5220, 5260, 5300, 5450, 5480, 5551, 5593, 5594, 5600, 5611, 5631, 5660, 5700, 5711, 5720, 5731, 5750, 5760, 5779, 5780, 5781, 5800, 5811, 5814, 5820, 5849, 5870, 5890, 5891, 5910, 5982, 5991, 5994, 7039, 7242, 7490, 7495, 7501, 7508, 7510, 7545, 7580, 8162, 8170."}
+{"text": "Sclerosing mesenteritis is a rare, idiopatic, usually benign, inflammatory process of the mesenteric adipose tissue. The most common site of involvement is the small bowel mesentery. We present a case of sclerosing mesenteritis of the rectosigmoid colon as a cause of severe abdominal pain, abdominal obstruction, and ischemic colic mucosal lesions. Contrast enema, colonoscopy, angiography, and CT were the imaging modalities used. A 20 cm diameter, fibrotic mass causing extensive compression of rectosigmoid colon was found at laparotomy. Histological examination showed extended fibrosis, inflammatory cells infiltration, lipophages, and granulomas within the mesenteric adipose tissue associated with erosive colitis. Clinical presentation and treatment are discussed. Sclerosing mesenteritis (SM) is a rare, usuallybenign disorder that affects the mesenteric fat tissue. This disease usuallyarises from the mesentery of the small bowel and rarely involves the mesocolon, 2. SM cA 59-year-old man complained oftwo-month history intermittent lower abdominal pain and constipation. About oneyear before, due to dyspeptic symptoms, an esophagogastroduodenoscopy wascarried out showing jatal hernia. His past medical history included only acutemyocardial infarction 13 years before. Laboratory tests were not contributory;tumor markers carcinoembryonicantigen, alpha-fetoprotein, andcarbohydraticantigen 19.9 were negative. Barium enema demonstrated ruggedmucosa and serrated contour with narrowing of the sigmoid colon by a probableextrinsic encasement. Then, a colonoscopy revealed reduction until 14 mm ofcalibre of the sigmoid colon, with rigid walls and aphtosis of the rectum. Histological examination of the endoscopic biopsies diagnosed ischemic colitis. Angiography of the celiac artery and of the mesenteric arteries showed noabnormalities.Patient's symptoms got worse over the nextmonth, mucous diarrhoea appeared and the patient presented to Emergency Room. On examination, he was afebrile. Physical examination of the abdomen revealedslight abdominal distension and, in the lower abdomen, a firm mass without tenderness,measuring approximately 10 cm in diameter, with mild pain on pressure,corresponding to the sigmoid colon. Rectal examination did not reveal anythingabnormal. A computed tomography (CT) scan showed rare sigmoid divertucula andthickened walls (about 1.5 cm) of the rectosigmoid colon, determining mildluminal narrowing, without signs of perivisceral inflammation; liver wasnormal; there was not lymphadenopathy either ascites. During the third day ofhospitalization, the patient developed obstructive symptoms with abdominalcramping and vomiting. A laparotomy identified a fibrous, partially necrotic,hyperaemic, 20 cm diameter mass in the mesocolon determining stenosis of thesigmoid colon and rectum, adherent to the parietal peritoneum. The mass was resectedin toto with rectosigmoid colon; transanal anastomosis according to Knight-Griffenand temporary protective ileostomy were performed. Postoperative course wasuneventful. Histological examination of surgical specimen revealed lipid-ladenfoamy cells and chronic granulomatous inflammation of mesocolon, associatedwith erosive colitis Figures .Three months later, Gastrographin enemaexcluded intestinal fistula, so patient underwent ileostomy surgical closure. At two years follow-up patient is asymptomatic.Sclerosing mesenteritis (SM) is an uncommonnonneoplastic inflammatory process in the mesenteric fat that rises as apseudotumor, usually involving the small bowel mesentery, the mesenteric fatand, less commonly, the mesentery of the large bowel. Young adults are mainlyaffected, more often men than women; about 2-3:1 , and theSeveral names are proposed for thisdisease, as SM, retractile mesenteritis, mesenteric nodular panniculitis,mesenteric Weber-Christian disease of the mesentery, and mesentericlipodystrophy, but they represent histological variants of a single pathologicentity that differs only in its proportion of fibrosis, lipid-ladenmacrophages, adiponecrosis, and nonspecific inflammatory infiltration. Microscopic diagnostic findings are chronic inflammatory process of themesentery, characterized by fibrosis, myofibroblasts, and inflammatory cellsinfiltration, degeneration of the fatty tissue or fat necrosis; aggregations oflipid-laden foamy macrophages are also present and they can be distributed inbands of variable width or in scattered areas , 8, 9. TThere is lack of consensus about the etiologyof SM. Several causes have been hypothesized, as ischemia, infections, previoustrauma, autoimmune disorders, previous abdominal surgery, coexistingmalignancies moslty urogenital or gastrointestinal lymphomas , 2, 10.Establishing the diagnosis of SM is both aclinical and histologic challenge. Clinical presentations are nonspecific andin common with numerous other diseases. Patients with SM may present withintestinal obstruction or ischemia, abdominal pain or distension, abdominalmass, weight loss, fatigue, fever of unknown origin, protein-losing enteropathywith diarrea, and minimal change nephropathy \u201314. SM mDifferential diagnosis take into accountmesenteric lipomas and liposarcoma, but radiographic tools (contrast studiesand CT or MRI ), even iSM has three modes of progression: partial orcomplete resolution of the inflammatory process, a nonprogressive course, or anaggressive course, characterized by a progressive fibrosis. That can causeshortening of the mesentery and compression of mesenteric vessels and thenthrombosis with secondary variceal bleeding, ischemia or life-threateningintestinal obstruction or ureteric obstruction with peritonitic or uremicstatus. In our case colonoscopy found ischemic mucosal lesions, probably due tothe compression of terminal colic vessels by the fibrotic process. SM usuallyhas a bening course with a favorable outcome , 9 and sThere is not any specific treatment for SM. Manymedical modalities\u2014including corticosteroids, colchicines,immunosuppressive drugs, and progesterone\u2014have been used with varying degrees of success, 18\u201322."}
+{"text": "Central nervous system involvement occurs in as many as twenty percent of Takayasu arteritis cases. When central nervous system disease is present, it typically manifests as cerebral ischemia or stroke. There are rare reports of intracranial aneurysms in adults with Takayasu arteritis, but none in children.We describe a case of Takayasu arteritis in an 18 month old girl who presented with a ruptured cerebral aneurysm. Full body magnetic resonance angiography revealed bilateral iliac, pelvic and intragluteal aneurysms, irregular terminal aorta, and stenotic renal arteries. Iliac vessel biopsy showed a lymphocytic infiltrate and giant cells localized to the internal elastica.This case highlights cerebral aneurysm as a highly unusual initial manifestation of Takayasu arteritis and demonstrates the challenges of diagnosis, treatment, and assessment of response to therapy in TA in children. TA is the third most common childhood vasculitis worldwide, but it is relatively rare in North America and accounts for 2% of all childhood vasculitis in the United States,2. The mt common .The gold standard for TA imaging is angiography. However, it is invasive and cannot detect thickened vessel walls, an early sign of inflammation. MRI/A and PET scan can detect luminal diameter changes and disparities in vessel metabolic activity, respectively, indicative of early inflammation ,13. OnceAn 18-month old Caucasian girl presented to our hospital following a generalized tonic-clonic seizure. On examination she was unresponsive, hypotonic, and mechanically ventilated. She was normotensive and afebrile, and there were no audible bruits on examination. Significant laboratories included the following: white count 32,400/\u03bcl, hemoglobin 9.6 g/dl, platelet count 342,000/\u03bcl. Normal laboratories included the following: PT, PTT, and complete metabolic panel. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were not drawn. Past medical history was significant for failure to thrive requiring supplemental tube feeding. Family history was notable for an aunt with an asymptomatic cerebral aneurysm. Head CT Fig  demonstrThree weeks later, she developed vomiting and irritability. Significant laboratories included white count 9,500/\u03bcl, hemoglobin 9.7 g/dl, platelet count 737,000/\u03bcl, ESR 37 mm/hr, and CRP 2.7 mg/dl. Head CT showed a new hemorrhage, and angiography showed recurrence of the clipped ACA aneurysm. Full body MRA revealed iliac artery aneurysms, aortic narrowing Fig , and gluSeven months after presentation, she was found vomiting, posturing and unresponsive. Head CT showed new intraventricular hemorrhage, and DSA revealed fusiform aneurysms in the supraclinoid ICA's Fig , right lAutopsy showed fusiform aneurysms of the descending aorta with thrombosis of 95% of the luminal cavity Fig . The resThis patient did not fulfill the ACR criteria for TA, which were primarily designed for adult TA detection . She didThe differential diagnosis of cerebral aneurysms in children is large and includes genetic, infectious and inflammatory causes. Systemic non-inflammatory vasculopathies associated with cerebral abnormalities include fibromuscular dysplasia, polycystic kidney disease, Rendu-Osler-Weber disease, and moyamoya syndrome. Genetic associations include Ehlers-Danlos, tuberous sclerosis, neurofibromatosis, Seckle and Alagille syndromes. Infectious etiologies are HIV, mycotic infections, tuberculous meningitis, and CNS Lyme disease. Systemic inflammatory vasculitides such as TA, Kawasaki disease, Beh\u00e7et's, primary angiitis of the central nervous system, and polyarteritis nodosa are unusual etiologies of cerebral aneurysms. In this case, the evaluation initially centered upon genetic and non-inflammatory etiologies. As the case evolved, the underlying diagnosis was determined pathologically. When multiple cerebral aneurysms are present, screening for systemic vasculopathy should be considered. If systemic aneurysms are found, as in this case, an extensive investigation is warranted and should include evaluation for inflammatory vasculopathies.Once diagnosis of TA is made, assessing response to treatment is challenging. Prior studies have shown clinical signs and symptoms of disease and elevated acute phase reactants are poorly correlated with disease activity. In the presence of hardware or clips from aneurysmal repair, non-invasive studies such as MRA and CTA are limited due to artifact. One recent report discussed the utility of non-invasive measurement of aortic arterial elastic properties with M-mode echocardiographic images in children with TA . FurtherThis case highlights cerebral aneurysm as an initial manifestation of systemic vasculitis and demonstrates the challenges of diagnosis, treatment, and assessment of response to therapy in TA in children.TA, Takayasu arteritis, MRA, magnetic resonance angiography, CNS, central nervous system, MCA, middle cerebral artery, ACA, anterior cerebral artery, ACoA, anterior communicating artery, DSA, digital subtraction angiogram, ICA, internal carotid artery, MRI, magnetic resonance imaging, CT, computed tomography, PCA, posterior cerebral artery, ESR, erythrocyte sedimentation rate, CRP, C-reactive protein, TOF, time of flightThe author(s) declare that they have no competing interests.PFW and SES were involved in patient care and in drafting the manuscript. DC helped draft the pathology-related portion of the manuscript and created the pathology figures. ANP drafted all neuroradiology figures and helped revise the radiology portion of the manuscript. THF was involved in patient care and in revising the manuscript critically for intellectual content."}
+{"text": "Objective. Drugs can induce almost the entire spectrum of hematologic disorders, affecting white cells, red cells, platelets, and the coagulation system. This paper aims to emphasize the broad range of drug-induced hematological syndromes and to highlight some of the newer drugs and syndromes. Methods. Medline literature on drug-induced hematologic syndromes was reviewed. Most reports and reviews focus on individual drugs or cytopenias. Results. Drug-induced syndromes include hemolytic anemias, methemoglobinemia, red cell aplasia, sideroblastic anemia, megaloblastic anemia, polycythemia, aplastic anemia, leukocytosis, neutropenia, eosinophilia, immune thrombocytopenia, microangiopathic syndromes, hypercoagulability, hypoprothrombinemia, circulating anticoagulants, myelodysplasia, and acute leukemia. Some of the classic drugs known to cause hematologic abnormalities have been replaced by newer drugs, including biologics, accompanied by their own syndromes and unintended side effects. Conclusions. Drugs can induce toxicities spanning many hematologic syndromes, mediated by a variety of mechanisms. Physicians need to be alert to the potential for iatrogenic drug-induced hematologic complications. Hematological disorders arise through a variety of mechanisms and etiologies. Drug-induced hematological disorders can span almost the entire spectrum of hematology, affecting red cells, white cells, platelets, and the coagulation system. Most recent reviews of drug-induced hematological disorders focused on specific drugs or cytopenias. The purpose of this review is to emphasize the broad range of drug-induced hematological syndromes and to highlight some of the newer drugs and syndromes described. However, due to space limitations, this review is not meant to be comprehensive of all drug-induced hematological dyscrasias.Immune Hemolytic Anemia (IHA) is characterized by destruction of red cells by antibodies acting against antigens on the erythrocyte membrane. Mediated by either IgG or IgM antibodies, IHA may be idiopathic, or secondary to infections, autoimmune diseases, lymphoproliferative disorders, or drugs. Patients present with anemia, reticulocytosis, indirect hyperbilirubinemia, elevated LDH with a positive Coombs test.Drug-induced IHA may be associated with either drug-dependent or drug-independent antibodies . Other dIntravenous Rh (D) immune globulin, used for treatment of immune thrombocytopenic purpura in non-splenectomized Rh (D)-positive patients, intentionally induces a mild hemolysis, which likely accounts for its mechanism of action. However, severe hemolysis with renal insufficiency, disseminated intravascular coagulation, and death has been reported in a small number of cases .Fludarabine, a purine nucleoside chemotherapeutic agent, has been reported to precipitate or exacerbate the auto-immune hemolytic anemia associated with chronic lymphocytic leukemia. However, combining fludarabine with rituximab and cyclophosphamide may reduce that risk .G6PD deficiency is the most frequent red cell enzymopathy associated with hemolysis. Hemolysis may be precipitated by infection, fava beans, and drugs. The sensitivity to various drugs depends on the inherited mutation and the associated degree of deficiency. In most cases, drug-induced hemolysis is self-limited. The deficiency is X-linked, so manifested more commonly and severely in males. Primaquine, phenazopyridine, nitrofurantoin, and certain sulfas have been associated with hemolysis .Ribavirin, used with peginterferon for treatment of hepatitis C, has been associated with anemia. Ribavirin concentrates within red blood cells, depletes ATP, and promotes hemolysis via oxidative membrane damage. While the anemia will improve by stopping or dose-reducing ribavirin, such strategies may compromise the efficacy of the antiviral therapy. Erythropoietin has been reported to be helpful in moderating the anemia .In approximately 3% of the body's hemoglobin, the ferrous iron in heme is oxidized upon deoxygenation, creating methemoglobin. Most of this naturally occurring methemoglobin is reduced to hemoglobin through the methemoglobin reductase enzyme system. Methemoglobinemia, characterized by excess production of methemoglobin, causes impairment in the transport of oxygen. Methemoglobinemia can be congenital (due to defects in enzymatic reduction of hemoglobin) or acquired. Patients present with symptoms of anoxia, cyanosis, reduced oxygen saturation, and chocolate-brown arterial blood. Confirmation of the diagnosis is made by measurement of methemoglobin on arterial blood gas sampling.Drugs that induce methemoglobinemia either directly oxidize hemoglobin or are metabolically activated to an oxidizing species . Phenazo12  and folic acid deficiencies. While they are usually a result of malnutrition or defective absorption, they can also be drug-induced.Megaloblastic anemias are characterized by the presence of a hypercellular bone marrow with large, abnormal hematopoetic progenitor cells . Leukopenia and thrombocytopenia also occur. Megaloblastic anemias can be congenital or acquired and most commonly are related to vitamin BDrugs that act by interfering with DNA synthesis, such as antimetabolites and alkylating agents, some antinucleosides used against HIV and other viruses , can all12 absorption may be impaired by these agents, clinically significant B12 deficiency seems rare despite widespread use.Decreased cobalamin levels have been reported with term use of histamine 2-receptor antagonists and proton pump inhibitors  , 16. WhiSideroblastic anemias (SAs) are characterized by ringed sideroblasts (erythroblasts containing iron-positive granules arranged around the nucleus) in the bone marrow. Sideroblastic anemias, which can be inherited or acquired, exhibit impaired heme biosynthesis in erythroid progenitors. Most sideroblastic anemias are acquired as clonal disorders of erythropoiesis. Additionally, ringed sideroblasts can be found in malnourished patients who abuse alcohol .Drug-induced sideroblastic anemia has been associated with isoniazid . The aneAplastic anemia (AA), characterized by pancytopenia with a hypocellular bone marrow, can be inherited or acquired. Acquired aplastic anemia is most commonly idiopathic, but may be secondary to exposure to toxins, irradiation, viruses, and drugs. AA can develop as a direct response to exposure, but can also develop indirectly, through immune-mediated mechanisms. Historically, drug-induced AA has not been easily distinguished from idiopathic forms of the disease since with rare case reports causality is difficult to establish . From anDrugs implicated in inducing AA include antirheumatic drugs, antithyroid medications, antituberculous drugs, NSAIDs, and anticonvulsants. Specific drugs cited include chloramphenicol, butazone, sulfonamide, gold salts, penicillamine, amidopyrine, trimethoprim/sulfamethoxazole, methimazole, and felbamate \u201327.Many drugs reported to cause aplastic anemia can also more commonly cause mild marrow suppression, suggesting that preliminary damage may occasionally (perhaps related to host metabolism) progress to more severe damage. The treatment and prognosis of drug-induced aplastic anemia seem similar to idiopathic cases .Pure red cell aplasia (PRCA) is characterized by normocytic anemia, reticulocytopenia, and absence of mature marrow erythroid progenitors. PRCA is distinguished from aplastic anemia by relatively normal leukocyte and platelet counts. It can be congenital or acquired. Acquired PRCA can be idiopathic or secondary, either an acute, self-limiting disorder or a persistent, chronic refractory anemia. PRCA can arise in association with a thymoma, lymphoid cancer, parvovirus, rheumatoid arthritis, pregnancy, and drugs.PRCA can be acquired through exposure to a number of drugs, including immunosuppressants , antibacterials , antivirals , fludarabine, anticonvulsants , as well as chloroquine, allopurinol, ribavirin, and gold , 29.Additionally, PRCA has been reported to develop after prolonged exposure to recombinant human erythropoietin (rHuEPO) specifically the brand Eprex, predominately used in Europe \u201333. WithIn immune thrombocytopenia purpura (ITP), platelet destruction is caused as antibodies bind to platelets leading to their clearance by the reticuloendothelial system (RES), as well as by some degree of decreased production. ITP can be idiopathic, or related to viral infections, autoimmune disorders, lymphoproliferative disorders, or drugs , 35.Classical causes of drug-induced thrombocytopenia are the quinine and quinine-like drugs . The thrHeparin is well known to be associated with thrombocytopenia, sometimes with arterial or venous thrombosis, which is generally a far greater threat than the risk of bleeding , 39. HepAbciximab (a chimeric Fab fragment) and eptifibatide and tirofiban (ligand mimetic inhibitors) are frequently used following coronary angioplasty to reduce thrombosis by impairing platelet function through the inhibition of GP IIb/IIIa-fibrinogen interaction. In addition to inducing the desired platelet dysfunction, however, they can induce a severe thrombocytopenia in a small percentage of patients, likely through a drug- dependent antibody-mediated mechanism . This maThrombotic microangiopathies (TMAs) present with thrombocytopenia, microangiopathic hemolytic anemia, and symptoms of microvascular occlusion. They arise from excess platelet aggregation. TMA has often been associated with low levels of metalloprotease ADAMTS13, which induces cleavage of von Willebrand factor (vWF). Thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) are the main thrombotic microangiopathies. TMA can be familial, idiopathic or acquired secondary to toxins, pregnancy, infections , and drugs.Although drug-induced TMA is well-documented, its mechanism is not well-determined \u201344. ImmuOne drug commonly implicated in inducing TMA is the immunosuppressant cyclosporine A (CyA). CyA-induced TMA is seen often in transplant patients (solid or liquid), but also in patients treated for rheumatoid arthritis and uveitis. The mechanism is believed to be a dose-related toxicity. TMA generally resolves once CyA treatment is reduced or discontinued.\u03b1-interferon and tacrolimus [Other drugs associated with TMA include chemotherapeutic agents mitomycin-C, gemcitabine, and cisplatin, as well as crolimus \u201343. In pThe thienopyridines, antiaggregating agents ticlopidine, and less commonly clopidogrel, have also been implicated in inducing TMA . Ticlopi Quinine may also induce TMA. The mechanism is immune-mediated. Patients with quinine-induced TMA have been found with antibodies against endothelial cells, lymphocytes, and granulocytes as well as quinine-dependent antibodies including IgG or IgM reactive with platelet glycoprotein Ib/IX or IIb/IIIa. TMA generally resolves with withdrawal of quinine along with plasma exchange .Disorders of platelet function may be detected in patients with prolonged bleeding times but normal platelet counts. While inducing platelet dysfunction to reduce the risk of thrombosis is often the desired purpose of some drugs , it may also be an undesired side effect .2. Aspirin irreversibly acetylates COX 1, so that its effect persists even after the drug ceases to circulate. This is in contrast with nonselective nonsteroidal anti-inflammatory drugs, which reversibly acetylate COX 1. There is some evidence that aspirin has a dose-related effect on platelet aggregation [Acetylation of cyclooxygenase 1 (COX 1) leads to impaired synthesis of the important platelet agonist thromboxane Aregation .\u03b2-lactam antibiotics, chemotherapy drugs such as mithramycin and daunorubicin, immunosuppresants, and phenothiazines [ Fluoxetine and some tricyclic antidepressants, induce dysfunction by inhibiting serotonin uptake. Certain drugs can interfere with platelet adhesion or aggregation, including high dose pencillins and other hiazines .Hypercoagulability, with a propensity to both arterial and venous thrombosis, can be inherited or acquired. Hereditary thrombophilic conditions include factor V Leiden, prothrombin G20210A mutation, and deficiencies of proteins C, S or antithrombin III, among others. Acquired hypercoagulable states can be secondary to immobility, surgery, trauma, pregnancy, antiphospholipid syndrome, cancer, and drugs.Selective COX-2 inhibitors, with less potential for bleeding and gastrointestinal toxicity than traditional COX inhibitors, became widely utilized as analgesics and anti-inflammatory agents and were also investigated for their potential effect of reducing the risk of polyps and colorectal cancer. However, celecoxib, rofecoxib, and valdecoxib were found to be associated with increased thrombotic cardiovascular events in several trials \u201350. ThesErythropoietin has been associated with increased thrombotic risk. While erythropoietin markedly benefits the anemia of renal failure, targeting hemogloblin levels to high normal, it has been associated with higher cardiovascular morbidity and mortality than with lower target levels . QuestioHormonal therapies including oral contraceptives, hormone replacement therapy, and tamoxifen (a selective estrogen receptor modulator with some agonist activity) have all been associated with increased thrombotic risk. With oral contraceptives, risk of arterial and venous thrombosis may increase with age, genetic thrombophilias, smoking, and use of certain types of associated progestin . The Wom Adjuvant chemotherapy for breast cancer with CMF , an older regimen infrequently used presently, was associated with hypercoagulability \u201359. PatiThrombotic complications have been associated with asparaginase, used to treat acute lymphoblastic leukemia \u201362. ArteThalidomide and lenalidomide, used for multiple myeloma, have been associated with increased thrombotic risk when used in combination with glucocorticoids . VariousDrug-induced thrombosis from warfarin or heparin can be associated with skin necrosis. Warfarin-induced skin necrosis is often associated with preexisting thrombophilic conditions, such as protein C, S, or antithrombin III deficiency . TherapyBevacizumab, a monoclonal antibody against vascular endothelial growth factor, is used in metastatic colon, lung, and breast cancers has been associated with increased arterial thrombotic risk, particularly in elderly persons already predisposed to cardiovascular events .Circulating anticoagulants inhibit clotting factors, causing excess hemorrhage. Autoantibodies such as acquired inhibitors to factor VIII may be idiopathic or secondary to hereditary hemophilia, the postpartum state, other autoimmune disorders, malignancies, or drugs. Patients present with bleeding as a syndrome of acquired hemophilia, with low F VIII: c levels and demonstrable F VIII inhibitors. Drugs implicated include antibiotics, psychotropics, fludarabine, and interferon . AntibodLupus anticoagulants and antiphospholipid antibodies may be induced by drugs such as chlorpromazine, hydralazine, phenytoin, quinine, and procainamide , 70. In Hypoprothombinemia, with prolongation of the PT/INR, is most commonly due to vitamin K deficiency or liver disease. Certain drugs have been linked with hypoprothrombinemia, such as broad spectrum antibiotics, usually in patients who are also malnourished. Reports have linked sulfonamides, ampicillin, chloramphenicol, tetracyclines, and cefoxitin to deficiency in vitamin K-dependent clotting factors . Cephalo For patients on warfarin, many drugs, especially antibiotics, are associated with increased hemorrhage. It is noted that there has been little systematic work on this subject, with the main sources being case reports . Nonethe\u03b2-lactam antibiotics, carbamazepine, and valproate have a dose-dependent inhibition of granulopoiesis. Drugs with direct toxic effects on myeloid precursors include ticlopidine, bulsufan, methamizole, ethosuximide, and chlorpromazine.Drug-induced neutropenia can occur in association with various analgesics, psychotropics, anticonvulsants, antithyroid drugs, antihistaminics, antirheumatics, GI drugs, antimicrobials, cardiovascular drugs, and, as expected, with chemotherapy drugs. \u201376. ImmuTreatment of drug-induced neutropenia includes withdrawing the drug, antibiotic coverage when appropriate, and increasingly administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF). The use of CSFs can reduce the duration of neutropenia, the frequency of infection, and possibly mortality, particularly in patients with profound neutropenia . Mortali Rituximab, an anti-CD20 antibody, used in the treatment of B cell lymphoproliferative disorders and in benign autoimmune disorders, can induce neutropenia, typically of delayed-onset .Neutrophilia can be related to myeloproliferative disorders but more commonly results from infection or inflammation. Drugs can also induce leukocytosis. Glucocorticoids cause neutrophilia by inducing the release of neutrophils from the bone marrow . AlthougLeukocytosis is commonly seen with G/GM-CSF, frequently given to reduce the severity and duration of neutropenia from chemotherapy. Sweet's Syndrome (acute febrile neutrophilic dermatosis), characterized by tender erythematous skin lesions, fever, and neutrophilia, can be induced by drugs such as trimethoprim-sulfamethoxazole, other antibiotics, and granulocyte colony stimulating factor, amongst others . The synEosinophilia can result from both intrinsic hematologic disorders as well as secondary to a variety of systemic disorders and allergens, including drugs . Drugs mPolycythemia may be primary (polycythemia vera) or secondary to smoking, chronic hypoxia, certain tumors, or drugs. Drug-induced polycythemia can be seen with excess use of rHuEPO or anabolic steroids. Abuse of both types of agents by athletes may be associated with increased thrombotic risk . Use of Myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML) are clonal hematopoietic disorders associated with cytopenias, defective marrow maturation, and, ultimately, unregulated blast proliferation. Many cases of MDS evolve into AML, and although the two diseases are distinct, they share a continuous spectrum.t-MDS or AML. Leukemia induced by these agents is commonly preceded by a myelodysplastic syndrome. These leukemias are typically FAB M1 or M2 morphologically. Complex chromosomal abnormalities are typical, commonly with deletions of chromosome 5 and 7 and trisomy 8.The majority of MDS and AML cases are idiopathic, but exposure to toxins and radiation can increase risk. Drugs can also induce MDS , 86. AlkA distinct syndrome of secondary leukemia is related to topoisomerase II inhibitors, which includes the epipodophyllotoxins (etoposide and teniposide), anthracyclines , and mitoxantrone. Leukemia with these agents has a shorter latency period than that associated with alkylating agents, often less than 2 years and usually presents without a prior MDS. Morphologically, acute myelomonocytic leukemias with a karyotypic abnormality involving 11q23 are commonly seen.t with PML-RAR alpha rearrangements are common. Treatment outcomes are relatively favorable when treated like de novo APL, unlike the poor prognosis seen in other t-AML types.Treatment-related acute promyelocytic leukemia has also been described, most commonly in association with topo II inhibitors . These a In patients receiving adjuvant chemotherapy for breast cancer, the risk of acute leukemia increases with age, with the intensity of therapy, and with the use of breast radiotherapy . Many ofStem cell transplantation, used in high risk, relapsed, and refractory hematologic malignancies, is associated with a risk of secondary MDS and leukemia. Whether the disease is induced by pretransplant therapy or the transplant itself remains uncertain.Radioimmunotherapy, developed for non-Hodgkins lymphoma, may be associated with some risk of leukemogenesis. However, as with transplant patients, some of the risk may be related to stem cell damage from prior treatments or perhaps an increased risk related to the underlying disease itself. Small numbers of patients treated with radioimmunotherapy alone have shown a seemingly low risk for leukemia .The wide spectrum of drug-induced hematologic syndromes is mediated by a variety of mechanisms, including immune effects, interactions with enzymatic pathways, and direct inhibition of hematopoiesis. The table summarizes the drug-induced hematological syndromes discussed above. Providing proof that a drug causes a particular hematologic syndrome is frequently impossible. Many patients simultaneously receive multiple drugs, making it difficult to be certain of causality. Rechallenge with a drug suspected of causing toxicity is usually not advisable. For some drugs, such as heparin, quinidine, and vancomyin, in vitro testing has been performed and mechanisms for cytopenias elucidated. However, such testing is not always possible given that for most there are no standardized, commercially available assays and that reactions may be related to metabolites as opposed to more easily tested parent compounds.As medicine advances, older drugs become obsolete and are replaced by newer formulations. Many drugs formerly associated with hematologic toxicities  are no longer in common use. However, newer drugs are found to be associated with their own potential hematologic toxicities . Furthermore, in addition to classic drug-induced cytopenias, we are increasingly seeing thrombosis as a common theme with a number of diverse agents . Physicians from a wide variety of specialties need to understand the hematological consequences of drugs and be prepared for the occurrence and correction of these events in their patients."}
+{"text": "Migraine is a largely inherited disorder of the brain characterized by a complex, but stereotypical, dysfunction of sensory processing. Often the most obvious clinical symptom is head pain, but non-headache symptoms such as photophobia, phonophobia and nausea are clearly part of the typical presentation. This review discusses the current pathophysiological concepts of migraine and migraine aura, such as a possible brainstem dysfunction and cortical spreading depression. Acute and preventive migraine treatment approaches are briefly covered with a focus on shortcomings of the currently available treatment options. A number of different receptors, such as calcitonin gene-related peptide (CGRP), TRPV1 and glutamate receptors, are currently being targeted by potential novel migraine therapeutics. The prospects of this research are exciting and are likely to improve patient care. Migraine is a disorder characterized by a broad sensory processing dysfunction. Thereby, the perception of normal sensory stimuli, somatosensory, visual, auditory and olfactory, is thought to be centrally facilitated. This dysfunction has a strong genetic background  and leadThis article provides an update on potential mechanisms of migraine and aura pathogenesis and reviews current and future medical strategies for the acute and preventive treatment of migraine.et al.  and gluhibitors  as well hibitors ,51).Migraine is a disorder of the brain characterized by a complex sensory dysfunction. Hence, therapeutic approaches with neural targets are most promising. Currently, a number of such pharmacological and interventional therapies are being investigated and it is likely that patients can benefit from CGRP receptor antagonists and occipital nerve stimulation in the near future. In addition to these new treatment strategies, defining patient populations who are more likely to respond to the already available therapeutic options also has great potential to improve patient care in daily practice.CGRP: calcitonin gene-related peptide; CSD: cortical spreading depression; PET: position emission tomography.TS declares no competing interests. PJG has consulted for, advised or collaborated with Advanced Bionics, Allergan, Almirall, ATI, AstraZeneca, Belgian Research Council, Boehringer-Ingelheim, BMS, Boston Scientific, Colucid, Eli-Lilly, Fidelity Foundation, GlaxoSmithKline, Johnson & Johnson, Kalypsys, Medtronic, MAP, Migraine Research Foundation, Migraine Trust, Minster, Medical Research Council-UK, MSD, NINDS, Netherlands Research Council, Neuralieve, Neuraxon, NTP, Organisation for Understanding Cluster Headache-UK and Pfizer.TS and PJG each participated in the writing and editing of this minireview. Both authors have read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1741-7015/7/71/prepub"}
+{"text": "Arabidopsis Information Resource (TAIR) is a web-based community databasefor the model plant Arabidopsis thaliana. It provides an integrated view of genes,sequences, proteins, germplasms, clones, metabolic pathways, gene expression, ecotypes,polymorphisms, publications, maps and community information. TAIR is developedand maintained by collaboration between software developers and biologists.Biologists provide specification and use cases for the system, acquire, analyse andcurate data, interact with users and test the software. Software developers design,implement and test the database and software. In this review, we briefly describe howTAIR was built and is being maintained.The"}
+{"text": "The prognostic weight of histological and biological factors was compared with that of known clinical prognostic factors in a population of 108 consecutive previously untreated patients with head and neck squamous cell carcinoma. Parameters studied were: tumour vascularisation, mitotic index, histological differentiation, nuclear grade, keratinisation, desmoplasia, growth pattern, inflammation, tumour emboli in peripheral vessels, keratins 6, 13, 19 immunohistochemical expression, cytofluorometric ploidy and S-phase. In multivariate analysis (Cox), only age and nodal status had a significant impact on the overall survival, whereas T stage was the only significant factor associated with locoregional failure. The cumulative incidence of metastases was correlated not only with age, T and N stage, but also with histological differentiation. All the other histological and biological factors studied failed to provide further prognostic information. These findings may help to select patients with high metastatic risk."}
+{"text": "The newly emerging Australian bat lyssavirus causes rabieslike disease in bats and humans. A captive juvenile black flying fox exhibited progressive neurologic signs, including sudden aggression, vocalization, dysphagia, and paresis over 9 days and then died. At necropsy, lyssavirus infection was diagnosed by fluorescent antibody test, immunoperoxidase staining, polymerase chain reaction, and virus isolation. Eight human contacts received postexposure vaccination."}
+{"text": "Hajdu and Kauntze described a rare disorder called Hajdu\u2013Cheney syndrome (HCS) for the first time in 1948. Some werAn 18-year-old lady was referred for an orthopantomogram (OPG). She was then reviewed by the dental, pediatric, and radiology departments and after appropriate investigations was diagnosed to have HCS.Clinical examination revealed short stature, coarse features, bushy eyebrows, anti-Mongoloid slant , flared st right toe [The OPG  showed hight toe . There wight toe . Basilaright toe  and 8, aHCS is a rare bone disease with a defect in collagen and bone formation.6 It has 16The specific findings are:Acro-osteolysis of the distal phalanges of the hands and feetWidened cranial sutures, particularly the lambdoidWormian bonesThe presence of acro-osteolysis with any three other features, such as Wormian bones, open skull sutures, platybasia, micrognathia, mid-facial flattening, premature loss of teeth, coarse hair, and short stature, is enough for a diagnosis. In adultThe supportive, but less distinctive, features include hypoplastic alveolar arches with loss of teeth and unerupted teeth, hypoplastic mandible and maxilla, a widened sella turcica, basilar invagination with its complications, kyphoscoliosis, short stature, and genu valgum.6\u20138 All tThe acro-osteolysis has been variably attributed to either a vascular etiology or defecThe differential diagnoses include cleidocranial dysplasia , pyknodysostosis (an osteosclerotic condition), progeria (a syndrome of premature aging), and Rothmund\u2013Thompson syndrome .The treatment of the disorder is symptomatic and the prognosis is quite good, with the morbidity depending on the bone changes caused by acro-osteolysis and the neurological complications caused by basilar invagination."}
+{"text": "To the Editor: Bolivian hemorrhagic fever (BHF) was first described in 1959 during outbreaks affecting isolated human communities in eastern Bolivia. However, it was not until 1963 that the etiologic agent, Machupo virus, was isolated from the spleen of a patient who died from this disease (3), leukopenia , and hematuria. Because physicians suspected BHF, patients received supportive therapy, including intravenous hydration, corticoids, antipyretic drugs, antimicrobial drugs, and blood transfusions from donors who had survived Machupo virus infection. Nonetheless, 2 of the patients died 3 and 4 days after admission.In February and March 2007, at least 20 suspected BHF cases  were reported to the El Servicio Departamental de Salud (SEDES) in Beni, Bolivia. In February 2007, physicians at the Hospital Santa Maria Magdalena reported 3 male patients , who worked at a ranch in Magdalena, Itenez Province . The patients sought treatment for fever, gingivorrhagia, petechiae, nausea, hematemesis, melena and tremors; clinical laboratory examinations showed thrombocytopenia  of BHF were reported to SEDES. A febrile hemorrhagic illness developed in a 19-year-old man from Huacaraje, Itenez Province . On first examination at the Hospital Santa Maria Magdalena, the patient had fever, tremor, gingivorrhagia, petechiae, bruises, asthenia, and anorexia and was admitted with a presumptive diagnosis of BHF. Despite supportive treatment (including administration of plasma from a BHF survivor), his condition worsened; hematemesis, melena, hematochezia, hematuria, anuria, respiratory alkalosis, and metabolic acidosis developed in the patient, eventually resulting in death. A fifth case was detected in a 46-year-old man from San Ramon, Mamore Province . A febrile hemorrhagic illness developed in the patient and he was admitted to the Hospital German Busch in Trinidad. The patient recently had been hired as a farm worker. When first seen by the attending physicians, he had fever, thrombocytopenia, leukopenia, petechias, tremors, gingivorrhagia, and dehydration, consistent with symptoms of BHF. The patient received hydration, corticoids, antipyretic therapy, and a plasma transfusion from a BHF survivor. The patient\u2019s condition improved and he was subsequently discharged from the hospital \u224810 days after admission.Nineteen serum samples collected from suspected BHF patients, including the cases described above, were sent to Centro Nacional de Enfermedades Tropicales  and the US Naval Medical Research Center Detachment  for testing. Serum was injected into Vero and C6/36 cells; 10 days later, the cells were tested for flaviviruses, alphaviruses, and arenaviruses by indirect immunofluorescent assay and PCR. Five arenavirus isolates were obtained from the patients described in this report.Viral RNA was extracted from the cell culture supernatant and the small (S) segment  was amplified and sequenced. Phylogenetic analyses were conducted using the neighbor-joining and maximum likelihood program implemented in PAUP 4.0 software . Sequence analyses confirmed the isolates as Machupo virus . Eight mCalomys callosus) extends beyond the geographic area of the Machupo cases described, factors that limit the endemic distribution of the virus remain unknown. However, population differences among C. callosus may account for the natural nidality of BHF  of Machupo virus infection in Beni Department, Bolivia, an area in which BHF is endemic. That all 5 patients were farmers suggests their infections were probably acquired through occupational exposure. Although all the patients received plasma transfusion from patients who had survived BHF infection, 3 patients still died. An early diagnosis and the rapid administration of Machupo immune plasma before the hemorrhagic phase may increase the chance of survival, as has been observed with other arenavirus infections ("}
+{"text": "This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patients received or pending, or royalties.No writing assistance was utilized in the production of this manuscript."}
+{"text": "Vorticella microstoma (Ciliophora) showed a constant occurrence frequency in rice field habitats occupied mainly by Culex tritaeniorhynchus while the rest of the species had an accidental or rare frequency of occurrence. Nineteen species/taxa were identified as common species. Trophont stages of Vorticella microstoma and Zoothamnium spp. were found attached to the cuticle of mosquito larvae but only V. microstoma caused a lethal effect. The autotrophic protist, Euglena geniculate, Closterium spp., and Pinnularia spp. served as the diet items to mosquito larvae. The majority of the microbiota identified had no observable effect on mosquito larvae breeding.The pool of microbiota associated with mosquito breeding habitats varies with the habitat type and its characteristic features. The pool of microbiota in a given mosquito breeding habitat can include free living, symbiotic, noncompetitive, parasitic, predatory, and toxin producing species. However, in Sri Lanka the studies on the microbiota associated with mosquito breeding habitats are scarce. The present study was conducted to identify microbiota species/taxa associated with a variety of mosquito breeding habitats in selected areas of the Kurunegala district in Sri Lanka to determine the relationship, if any, the microbiota has with mosquito larvae breeding. A total of 44 microbiota species/taxa belonging to 10 phyla, namely, Bacillariophyta, Charophyta, Chlorophyta, Cyanobacteria/Cyanophyta, Ochrophyta/Heterokontophyta, Amoebozoa, Euglenozoa, Ciliophora, Arthropoda, and Rotifera were identified.  Spirogyra spp. are common. There are at least 200 species of phytoplanktons associated with mosquito breeding habitats and larval instars extensively feed upon them /[N\u2009\u2212\u20091]\u2009\u00d7\u2009100, where S is the number of species per each sampling site , \u03b1 mean is the mean alpha diversity (mean number of species) for each site in each period, and N is the number of sites of the period.The phytoplankton species richness of each sampling site  (Shannon and Wiener ) and eveCulex mosquito larvae, namely, Cx. quinquefasciatus, Cx. tritaeniorhynchus, Cx. Gelidus, and Cx.whitmorei were detected in 56% of the breeding habitats mainly in rice fields and irrigation canals. Aedes aegypti and Ae. albopictus appeared in infrequent (20.1\u201340%) and moderate distribution (40.1\u201360%), respectively, in micro temporary habitats. Anopheles subpictus, An. Vagus, and Mansonia uniformis were sporadic in distribution (0\u201320%) and reported only from burrow pits, tank margins, and the rice fields, respectively. From the density values obtained, Ae. albopictus, An. subpictus, Cx quinquefasciatus, Cx. tritaeniorhynchus, Cx. Gelidus, and Cx.whitmorei were found to be the dominant species in their respective habitat types. The only species reported as subdominant in density was Ae. aegypti. Two satellite species, An.vagus and Mansonia uniformis, were found only in tank margins and rice fields, respectively.A total of 1495 mosquito larvae were collected, and nine species of mosquitoes belonging to four genera were identified from sixteen different types of mosquito breeding habitats . Eight pArcella arenaria, Euglena acus, Euglena caudata, Gomphonema angustatum, Closterium spp., Pinnularia braunii, Lecane luna, Monostyla bulla, Philodina citrina, Notholca acuminata, Diorella stylata, and Canthocamptus staphylinus, were in between 25% and 50%, hence considered as common species/taxa. The rest of the 32 species/taxa detected were uncommon/rare  in the mosquito breeding habitats during the study period. Frequency occurrence of twelve species/taxa, namely, that is, 17 and 10, respectively  across the habitat types during the study period for rice field habitats was 28 followed by irrigation canals and tank margins, ectively ; Table 3Vorticella microstoma and Zoothamnium sp. were among the highest abundant microbiota in these habitats  in higher densities on the dead and moribund larvae and their multiplication on the host body. Individuals of Zoothamnium attached to mosquito larvae were also observed but there was not any detrimental effect on the survival of the host larvae. Autotrophic species such as Spirulina major, Phacus pleuronectes, P. curvicauda, and species of the Phylum Chlorophyta had higher densities in rice field habitats and irrigation canals. However, none of these species showed any direct effect on mosquito larvae development. Several species/taxa were observed inside the buccal cavity of 4th instar larvae collected from the same habitat. Further, Euglena geniculata, Closterium spp., and Pinnularia spp. were served as diet organisms for Aedes albopictus, Cx tritaeniorhynchus, and Culex spp. Larvae, respectively, collected from the same habitats.Observations revealed that survival of Cx. tritaeniorhynchus [Vorticella microstoma causing a lethal effect on Cx. tritaeniorhynchus. Similarly, Zoothamniun species was reported from the same habitats in high densities, but no detrimental effect on mosquito larvae was observed. A previous study conducted in a different geographic area in Sri Lanka has reported that Zoothamnium sp. was the most prevalent microbiota in marshy lands resulting in a weak negative effect on Cx. tritaeniorhynchus larvae [Zoothamnium spp. that has caused the death of moribund individuals of mosquito larvae. However, reduction of larval survival was not observed due to attachment of Zoothamnium spp. in this study. Several other ciliate species, namely, Lambornella stegomyia, a naturally occurring ciliate found in earthenware pots occupied by Stegomyia scutellaris mosquito larvae [Chilodonella uncinata, an endoparasitic ciliate of culicine and anopheline larvae found in rice fields, irrigation canals, marshy areas, ponds and pools [Arcella arenaria, Difflugia corona, Acanthocystis aculeata, and Paramecium bursaria were among heterotrophic protists present in a range of permanent macrohabitats including rice fields, irrigation canals, marshy lands, ponds, reservoirs, and tank margins and in two temporary microhabitats, that is, plastic/metal containers and clay pots in this study. Addicott [Philodina citrina, Lecane Luna, Monostyla bulla, and Notholca acuminata were detected in a range of breeding habitats from rice fields, irrigation canals, marshy lands, ponds, reservoirs, and tank margins to container-type breeding habitats in the present study. Duguma, et al. [Culex mosquitoes owing to the competition for small size class aquatic microbial biomass.It was reported that rice fields in Kurunegala district harbor constant breeding places for Japanese encephalitis vector, rhynchus , 35. Thes larvae . Also, Ls larvae  has repoo larvae  and Chilnd pools , were noAddicott  and BlauAddicott  reported, et al.  reportedCanthocamptus staphylinus and Parastenocaris brevipes, the two species of copepods, were detected in association with mosquito breeding habitats in this study. Canthocamptus staphylinus was a common species found in rice fields, irrigation canal, reservoirs, and tree holes whereas Parastenocaris brevipes was a rare species detected only from tree holes. The large size species of cyclopoid copepods are better effective biocontrol agents of mosquito larvae than that of other predatory invertebrates [Cyclops vernalis, Megacyclops formosanus, Mesocyclops aspericornis, M. edax, M. guangxiensis, M. longisetus, and M. thermocyclopoides, were reported as active predators of young mosquito instars [Mesocyclops leuckarti had a successful predatory effect on Ae. aegypti and Ae. albopictus larvae, followed by Mesocyclops crassus collected from ponds, ditches, and other standing water sources of Gampaha and Kandy districts in Sri Lanka. Successful utilization of Daphnia magna to control Culex pipiens mosquito larvae in temporary water bodies was reported by Duquesne et al. [D. magna was found rarely in this study.tebrates . Several instars , 41. Uda instars  reportede et al. . D. magnMicrocystis aeruginosa produce microcystin, a group of substances known to be toxic to various organisms. These authors also reported that Microcystis sp. has shown a significant negative effect on the development of mosquito larvae, where the larvae grown in the presence of alga were significantly smaller. Microcystis sp. was detected in lower densities from the rice fields and reservoirs associated with Cx. quinquefasciatus and Cx. tritaeniorhynchus mosquito species in this study. Howland [Scenedesmus quadricauda shows no signs of digestion in the mosquito gut. However, in the present study, high densities of two species of the same genus, S. bijuga and S. armetus, were detected from rice fields and blocked drainages which harbored Cx.gelidus and Cx. quinquefasciatus, respectively, without any negative effect on the larvae development [An abundance of algal species usually provides favorable conditions for mosquito larval production. However, some algae have a lethal effect that can kill the mosquito larvae . Krishna Howland  has repoelopment .Vorticella microstoma and Zoothamniun were found attached to the larvae of Cx. tritaeniorhynchus, working as possible agents against mosquito larvae breeding. Vorticella microstoma caused a lethal effect on Cx. tritaeniorhynchus larvae. The autotrophic protist, Euglena geniculate, Closterium spp., and Pinnularia spp. served as the diet items to mosquito larvae. The majority of the microbiota identified had no observable effect on mosquito larvae breeding.A total of 44 microbiota species belonging to ten phyla were identified from a variety of mosquito breeding habitats in the Kurunegala district."}
+{"text": "The availability of miniaturized ultrasound machines has changed our approach to many cardiovascular diseases. Handheld ultrasound imaging can be performed at the bedside, it is easy to use, and the information provided, although limited, is of unquestionable importance for a quick diagnosis that leads to early treatment. They have unique characteristics: Low cost, wide availability, safety, accuracy, and can be used in different clinical scenarios and by operators with different backgrounds. Image acquisition and interpretation is rapid and provides, in each situation, useful information for diagnosis, prognosis, and clinical and therapeutic management. This review focuses on the use of handheld ultrasound devices, describes differences with other equipment, their limitations, and the numerous advantages derived from their use. Cardiovascular ultrasound is an imaging investigation with unique characteristics: It is safe, low cost, widely available, repeatable, and accurate. In fact, it is the most used imaging technique in clinical practice. In cardiology, the use of various echocardiographic modalities allows a comprehensive study of cardiac structure, function, and hemodynamics. Mono-dimensional (M-mode), two-dimensional 2D), and three-dimensional (3D) echo define cardiac chamber dimensions and volumes, systolic function, and valvular morphology: Color and Doppler (pulsed and continuous) techniques allow accurate investigation of cardiac hemodynamics and diastolic function; tissue Doppler imaging (TDI) and two-dimensional strain (2DS) are able to detect clinical and subclinical systolic and diastolic dysfunction . All derD, and thFor many decades, echocardiography equipment was immobile, ultrasound scans were performed in specific echo-laboratories, and cardiologists were the only competent operators. With technological development, echocardiography equipment has become movable, portable, and miniaturized, and ultrasound use has become more extensive, at the bedside, in wider clinical scenarios, in critically ill patients, and in emergencies/urgencies, and its use has expanded to physicians with different backgrounds .Nowadays, various types of equipment are available, with different sizes, different echo modalities, and different diagnostic capabilities. This review focuses on the use of handheld ultrasound devices (HUDs), and describes differences with other equipment, their limitations, and the numerous advantages that come from their use.HUDs can be performed easily, rapidly, and allow basic information to be obtained for diagnosis and clinical management of various diseases; an HUD can be used by physicians from different disciplines, in many situations and clinical scenarios, especially in emergencies/urgencies and its use has transformed almost all aspects of our daily practice.Standard echocardiography performed in echo-labs by cardiologists or sonographers/cardiologists provides information about cardiac size, structure, function, and hemodynamics. All these data are obtained using stationary systems that are equipped with various modality system and transducers: 2D, M-mode, Doppler (pulsed and continuous), color, and TDI, transesophageal approach (TEE), and, in many cases with advanced modalities, such as 2DS and three-dimensional echo (3D). During the exam, all modalities can be utilized , all standardized echo sections are performed, simultaneously with ECG-guided comprehensive measurements of cardiac structure, heart function, and hemodynamics. Thus, the final report is complete and accurate [accurate ,2,4.Portable machines are smaller, and allow a basic comprehensive exam of 2D, M-mode, pulse, and continuous Doppler and color. Generally, they do not have advanced modalities, the quality of images is good, and the exam is clinically complete. The final report describes all basic cardiac morphological and functional information.Handheld ultrasound devices are the smallest machines, very simple to use, with a limited number of basic controls for adjusting the depth and gain, to freeze and store images (in JPEG) and little loops (in MPEG-4), and the available measurements are few and limited to a simple distance and area assessment. The devices only have the 2D modality with grey-scale images and color-Doppler, simultaneous ECG, M-mode, TDI, and advanced technologies are lacking. Images have lower spatial (640 \u00d7 480 pixels) and temporal resolution than other equipment. However, 2D and color Doppler are in real-time; the field-of-view (2D and color flow), maximum depth (25 cm), automatic frame rate (28 frames per second), and transducers (phased array\u20141.7 to 3.8 MHz) are similar; images have good technical quality; and a correct final diagnosis can be made in most cases , but HUDs can qualitatively provide useful information about atrial dilatation, left and right ventricle global systolic function, ventricular dilatation or hypertrophy, significant valvular stenosis and regurgitation, pericardial effusion, and tamponade ,9,10. Instable patients, FoCUS is appropriate for the screening of structural heart disease. It allows early diagnosis, defines prognostic stratification, and directs to the appropriate therapy. The exam can rapidly define/exclude qualitative ejection fraction, wall motion abnormalities, ventricular systolic dysfunction, left ventricular hypertrophy, cardiomyopathies with hypertrophic pattern, dilated cardiomyopathies, pulmonary congestion, significant valvulopathies, ascending aorta and aortic root dilatation, pericardial and pleural effusion, and IVC size and respiratory collapsibility [In sibility ,12,14,16Below are some examples of the effective use of HUD:congestive heart failure, FoCUS helps to define atrial dilatation, wall motion abnormalities and thicknesses, cardiac dimension and function, significant mitral regurgitation, lung congestion , IVC collapse, and it can differentiate between systolic or diastolic heart failure  and left ventricular function, which are strong predictors of sinus rhythm restoration and lead to proper treatment [In reatment ,22.valvular stenosis, FoCUS can qualitatively show valvular morphology, such as thickened and calcified leaflets with reduced mobility and turbulent transvalvular flow by color Doppler. All these indirect signs lead to the suspicion of significant valvulopathy. Quantitative assessment is not possible, nor are pulmonary pressures, but in patients with signs/symptoms of heart failure, atrial fibrillation, or syncope, these data define the underlying pathophysiology [In patients with ysiology ,10,23.valvular regurgitation, color-HUDs can differentiate significant mild/trivial valvulopathy.In pericarditis, FoCUS can be used for basic follow-up of pericardial effusion  in lung ultrasounds identifies cardiogenic shock [In ic shock .cardiac tamponade, POCUS is useful to identify pericardial effusion size and distribution and directs to the best approach for pericardiocentesis [In centesis .emergency department, POCUS helps to differentiate the nature of chest pain. In addition to history, clinical examination, electrocardiogram, and biomarkers, echocardiography can visualize wall-motion abnormalities and left ventricular function, dilated right ventricle with free wall hypokinesia, ascending aorta dimension and morphology, significant aortic regurgitation, and pericardial effusion. In this way, it is a first step to a differential diagnosis among acute coronary syndromes, acute aortic syndromes, pulmonary embolism, congestive heart failure, and pericarditis [In the carditis .cardiac arrest due to complex arrhythmias, HUDs can exclude/diagnose all cardiac arrhythmogenic diseases, such as hypertrophic, dilated, or arrhythmogenic right ventricular cardiomyopathies [In patients with opathies .cardiopulmonary resuscitation and during BLS (basic life support) and ALS (advanced life support) protocols, POCUS can help to diagnose potentially treatable causes of cardiac arrest, such as cardiac tamponade, massive pulmonary embolism, severe ventricular dysfunction, and hypovolemia [In ovolemia ,32.Since FoCUS and POCUS are simplified exams with restricted protocols, operators with different backgrounds can utilize them. Actually, cardiologists, internists, anesthesiologists, and specialists in emergency/urgency frequently utilize this tool. The approach is simplified; the findings to obtain are few and are guided by symptoms, so a short training period is required. Some studies have shown that brief training is sufficient to perform and interpret a FoCUS scan, the agreement between FoCUS and standard echocardiography is satisfactory, the trainee\u2019s performance improves over a short period of time, and the inter-observer variability in FoCUS is low ,34,35,36The use of HUDs has completely changed the daily approach to cardiac diseases. Handheld devices have allowed fundamental information about morphology and cardiac function to be obtained in stable and, especially, unstable patients. They extend the physical examination with a short and simplified ultrasound examination aimed at achieving rapid diagnosis, early treatment, and basic monitoring of some cardiac diseases. Its use serves to guide diagnosis in specific clinical situations, mainly defined by patient symptoms; it is a limited and non-exhaustive technique, but it is fast, repeatable, and easy to perform. The training of operators and the learning curve is short  and can be used from physicians of different background and specialties. FoCUS should not be considered as a replacement of echocardiographic examination but as a clinical tool similar to a stethoscope to aid early diagnosis (at the bedside), define the event pathophysiology and prognostic stratification, and direct to the appropriate therapy. In this setting and in specific clinical situations, it is extremely useful."}
+{"text": "Behcet disease is an autoimmune vasculitis, involving multiple systems and organs. It is often chronic and recurrent, and involves all levels of arteries and veins.A 40-year-old Chinese male with sudden vision loss in his right eye for 3 days was reported.The patient was diagnosed as bilateral uveitis  and Behcet disease.The patient was given topical corticosteroids and compound tropicamide eye drops in our department. In addition, he was also hospitalized in the Rheumatology Department, and received systemic infusion of methylprednisolone and cyclophosphamide.Best corrected visual acuity vision acuity of the left eye was 20/20 and that of the right eye was no light perception after 2 weeks. During the telephonic follow-up after 1 year, the patient reported 2 recurrent episodes of uveitis in the left eye, which improved after treatment at the local hospital.It cautions ophthalmologists of the high possibility of vasculitis in young and middle-aged patients with retinal vascular occlusion. It also reminds the ophthalmologists investigate systemic diseases, and obtain detailed medical history, not just depending on specific laboratory findings. This case further suggests that Behcet disease has diverse manifestations, complex diagnosis, and severe lesions, and the recurrence rate must be controlled to minimize irreversible consequences such as sudden vision loss during recurrence. According to the characteristics, uveitis related to Behcet disease can be most manifested with acute nongranulomatous anterior uveitis, intermediate uveitis, obstructive or nonobstructive retinal vasculitis, focal or multifocal retinitis, and necrotizing retinitis, of which acute nongranulomatous anterior uveitis and obstructive retinal vasculitis are the most common.,3 In obstructive retinal vasculitis, the blocking sites are often located in the branch retinal veins, and cases with central artery and vein occlusion are rare, in which patients show rapid decline or even loss of vision and have a very poor prognosis.,4 This study reported a Behcet disease patient with sudden unilateral vision loss due to central retinal artery and vein occlusion.Behcet disease is an autoimmune vasculitis, involving multiple systems and organs. It is often chronic and recurrent, and involves all levels of arteries and veins, thus leading to vascular occlusion.2Toxoplasma gondii infection, rubella virus, cytomegalovirus, and herpes simplex virus and immune examinations. Echocardiography, carotid duplex ultrasound, abdominal Doppler ultrasound, and chest computed tomography showed negative results. Past medical history revealed that the patient had complaints of recurrent oral ulcers and vulvar ulcers for 8 years, which recently worsened. The patient was diagnosed as Behcet disease at a local hospital and given long-term low-dose oral prednisone, but the recurrent symptoms persisted with a recent relapse. At our hospital, the patient was diagnosed as bilateral uveitis , and Behcet disease. He was given topical corticosteroids, and compound Tropicamide eye drops. The patient was also hospitalized in the Rheumatology Department, and received systemic infusion of methylprednisolone and cyclophosphamide. Two weeks later, his vision acuity of the left eye was 20/20 and that of the right eye was NLP. During the telephonic follow-up after 1 year, the patient reported 2 recurrent episodes of uveitis in the left eye, which improved after treatment at the local hospital.A 40-year-old Chinese male presented with a 3-day history of sudden vision loss in his right eye. He complained of a sudden onset foreign body sensation in the right eye when he was riding, and vision loss after rubbing. Eye examination showed best corrected visual acuity was no light perception (NLP) in the right eye and 20/40 in the left eye. Anterior segment examination of the right eye showed keratin precipitates+, aqueous flare++, and vitreous opacity. The right fundus examination revealed that the retina was gray, with edema as well as scattered dotted and flaky hemorrhagic foci Fig. . In addi3 The etiology and pathogenesis of this disease is not fully understood. Vasculitis is the foremost histopathological lesion affecting various blood vessels in Behcet disease. According to vessel involvement, Behcet disease has demonstrated 3 main clinical features: venous occlusion, arterial occlusion, and aneurysm formation.,7 Endothelial dysfunction leaded by vascular inflammation is thought to be a major factor for thrombosis. Thrombosis is the most important cause of vascular occlusion. Some studies have suggested that risk factors for thrombosis include increased endothelial activation markers, defective fibrinolysis, and/or impaired coagulation, reflect vascular cell injury, inherited thrombophilia, demographic, genes, immune system, race, HLA-B5 antigen, etc.,10The typical clinical findings of Behcet disease are complex, including oral ulcer, vulvar ulcer, skin rash, erythema nodosum, uveitis, esophageal ulcer, colon ulcer, joint pain, etc. The diagnosis depends on typical clinical findings, without specific laboratory findings. Increase in CRP and ESR are probably the only laboratory findings.Uveitis in patients with Behcet disease can affect the anterior segment, posterior, or peripheral retina. Patients with involvement of anterior segment usually develop nongranulomatous uveitis, with anterior chamber empyema being the most common. Meanwhile, patients with involvement of posterior segment usually develop vitreous opacity, retinal invasion, vascular sheaths, vascular occlusion, macular edema, and other inflammatory manifestations.,12For ocular lesions caused by Behcet disease, in addition to eye topical anti-inflammatory symptomatic treatment, corticosteroids are the most widely used systemic treatment, which combined with immunosuppressive agents can achieve better curative effect in patients with severe first episode or repeated relapse, and help to reduce drug side effects with a combination of glucocorticoids. Biological agents , which have been used in recent years, are expensive, and have several side effects and high relapse rates after discontinuation. Their safety, efficacy, and cost-effectiveness need further evaluation.Behcet disease has unclear etiology, and lacks characteristic laboratory findings. Its diagnosis is mainly based on clinical manifestations, and more positive signs lead to more reliable diagnosis. Hence, ophthalmologists should not exclude this systemic disease by solely relying on the laboratory findings of patients with uveitis. Missed diagnosis of Behcet disease is likely if the general clinical manifestations are ignored, thereby missing the optimal timing of treatment. Patients with Behcet disease are susceptible to various types of ocular inflammation with different manifestations. However, the patient in this study suffered from vascular occlusion and sudden vision loss because his unilateral retinal vasculitis affected both the central retinal artery and vein, which is very rare, and shows very poor curative effect and prognosis. This case also cautions ophthalmologists of the high possibility of vasculitis (such as Behcet disease) in young and middle-aged patients with retinal vascular occlusion. Hence, the ophthalmologists should investigate systemic diseases, and obtain detailed medical history. This case further suggests that Behcet disease has diverse manifestations, complex diagnosis, and severe lesions, and the recurrence rate must be controlled to minimize irreversible consequences such as sudden vision loss during recurrence.Written informed consent was obtained for the publication of the case details.The authors want to thank Ms Xiaoyue Wang and Mr Zhibing Zeng in Imaging Department, Sichuan University West China Hospital for the excellent work on fundus photography and fluorescein fundus angiography.Conceptualization: Yunxia Gao, Ming Zhang.Data curation: Yunxia Gao, Shuyuan Lyu, Li Bao.Formal analysis: Yunxia Gao, Shuyuan Lyu.Investigation: Yunxia Gao, Shuyuan Lyu, Ming Zhang.Methodology: Yunxia Gao.Project administration: Yunxia Gao, Li Bao, Ming Zhang.Resources: Yunxia Gao, Li Bao, Ming Zhang.Supervision: Yunxia Gao, Shuyuan Lyu, Ming Zhang.Writing \u2013 original draft: Yunxia Gao.Writing \u2013 review and editing: Yunxia Gao, Shuyuan Lyu, Ming Zhang."}
+{"text": "Letter to the EditorWith interest we read the article by Karaa et al. about establishing an US-based institutional network meeting the increasing needs of mitochondrial disorder(MID) patients of requiring professional diagnostic and therapeutic management . We haveA shortcoming of the study is that the term \u201cprimary mitochondrial disorders\u201d was not defined. We should know if \u201cprimary\u201d means disorders with defective respiratory chain functions, with defective replication/maintenance of mtDNA, with a mtDNA mutation, or disorders with mutations in any mitochondrial protein . DefinitA further shortcoming is that it was not defined how MIDs were diagnosed. We should know if a MID was diagnosed genetically, biochemically, upon immune-histology, and if the Walker, Bernier, or the mitochondrial disease criteria (MDC) were applied . ModalitSince the patients' needs strongly depend on duration and severity of the disease, we should be informed about onset, duration, and severity of MIDs included. From those carrying an mtDNA variant we should know the heteroplasmy rate, since it may determine phenotype and disease trajectory . NetworkSince MIDs are usually multisystem diseases , patientOverall, MID patients require genetic diagnosing, investigations of clinically affected/unaffected first-degree relatives, prospective investigations for multisystem disease, and close follow-ups. Establishing a network/platform for patients, caregivers, and treating physicians is a first step towards optimizing MID management.No funding was received.JF: design, literature search, discussion, first draft, critical comments.None."}
+{"text": "Racial/ethnic disparities exist in physical performance among older adults, but little is known about the factors leading to these differences. We evaluated how sociodemographic, health, behavioral, and psychosocial factors mediated the relationship between race/ethnicity and physical functioning performance among 1,855 Black, Chinese, Hispanic, Japanese and White postmenopausal women from the Study of Women\u2019s Health Across the Nation. White women had better mean physical performance scores  as compared to Black, Hispanic and Chinese women but slightly poorer scores vs. Japanese women. In Blacks and Hispanics, 75% and 95% of that disparity, respectively, was through mediators, particularly education, financial strain, BMI, physical activity and pain. Addressing issues of poverty, racial inequality, bodily pain and obesity could reduce some racial/ethnic disparity in functional limitations as women age."}
+{"text": "Sir,\"Competition is always a good thing. It forces us to do our best. A monopoly renders people complacent and satisfied with mediocrity\"a quote by Nancy Pearcey, an American evangelical author. Malaysian Society of Pharmacology and Physiology (MSPP) invites teachers of Physiology and Pharmacology (should be below 45 years of age) from different universities in Malaysia to participate in Teacher's Prize competition, with one faculty being awarded in the respective fields each year. A selected panel of senior professors from prestigious Institutions across the country evaluates the presentation and selects the best presenter. Teacher's Prize 2017 in Physiology was held at Universiti Teknologi MARA (UiTM), Sungai Buloh Campus, Selangor, Malaysia. There was a tough challenge amongst the academic staff that came from renowned public and private universities. Participants used teaching aids like Power Point presentations, animations, short video clips etc. to add flavor to their teaching. The prize was awarded to QIUP lecturer, Faculty of medicine at the closing ceremony of the 31st Scientific Meeting of MSPP in Universiti Sains Malaysia, Kota Bharu, Kelantan.Currently, there are 32 medical schools in Malaysia (11 public and 21 private) [  Founded in 2011 Quest International University Perak (QIUP) is a private university in partnership with Perak state Government. Various professional programmes are conducted in Faculty of Medicine (FOM) helps the young lecturers. Enormous financial aids and moral support are provided by the University for competitive events which are highly appreciable. Universities across the world should encourage their faculties, to organize and participate healthy competitions like quiz, teachers' prize to make a better educator who guides future health care professionals.Dr. Bedanta Roy, Senior Lecturer, Department of Physiology, Faculty of Medicine, Quest International University Perak (QIUP) City Campus, No.227, Plaza Teh Teng Seng (Level 2), Jalan Raja Permaisuri Bainun, 30250 Ipoh, Perak Darul Ridzuan, Malaysia.  Mr. Nicholas Goh, Chief Operating Officer, Quest International University Perak (QIUP) City Campus, No.227, Plaza Teh Teng Seng (Level 2), Jalan Raja Permaisuri Bainun, 30250 Ipoh, Perak Darul Ridzuan, Malaysia.  Prof. Dr. Rukhsana Hussain Malik, Professor and Head, Medical Education, Faculty of Medicine, Quest International University Perak (QIUP) City Campus, No.227, Plaza Teh Teng Seng (Level 2), Jalan Raja Permaisuri Bainun, 30250 Ipoh, Perak Darul Ridzuan, Malaysia.  Paediatrics, QIUP; Professor Dr. Subhada Prasad Pani, Deputy Dean , Faculty of Medicine and Research Professor and Head, Department of Microbiology, QIUP; Prof. Dr. Sumitabha Ghosh, Professor and Head of Department, Physiology, Faculty of Medicine, QIUP and all the faculty members in FOM, QIUP for their support and encouragement.  Dated the 22nd September 2017"}
+{"text": "Despite federal prohibition of medical marijuana possession, sale, and use, marijuana use continues to escalate as state legalization persists and expands. The purpose of this discussion is to provide a brief summary of the evidence regarding both potential benefits and risks of medical marijuana use. Despite federal prohibition of medical marijuana possession, sale, and use, marijuana use continues to escalate as individual state legalization persists and expands . As the Marijuana and oral cannabinoids  have been associated with adverse effects, including serious adverse effects as well as study withdrawal. The most commonly reported adverse effects include asthenia, balance problems, disorientation, gastrointestinal effects, euphoria, somnolence, dry mouth, fatigue, hallucinations, paranoia, and agitation ,17. Marijuana use has a negative effect on mental health and neurologic function. Marijuana users are at risk for tolerance, dependence, and withdrawal ,18,44. MPulmonary, cardiovascular, and carcinogenic effects of marijuana remain controversial ,44,48,49When discussing medical marijuana use, pharmacists must be knowledgeable about potential benefits and risks. Disease states with substantial evidence include chronic pain, chemotherapy-induced nausea and vomiting , and patient-reported spasticity in MS . Further"}
+{"text": "Persistent corneal epithelial defects (PEDs or PCEDs) result from the failure of rapid re-epithelialization and closure within 10-14 days after a corneal injury, even with standard supportive treatment. Disruptions in the protective epithelial and stromal layers of the cornea can render the eye susceptible to infection, stromal ulceration, perforation, scarring, and significant vision loss. Although several therapies exist and an increasing number of novel approaches are emerging, treatment of PEDs can still be quite challenging. It is important to treat the underlying causative condition, which may include an infection, limbal stem cell deficiency, or diabetes, in order to facilitate wound healing. Standard treatments, such as bandage contact lenses (BCLs) and artificial tears (ATs), aim to provide barrier protection to the epithelial layer. Recently-developed medical treatments can target the re-epithelialization process by facilitating access to growth factors and anti-inflammatory agents, and novel surgical techniques can provide re-innervation to the cornea. PEDs should be treated within 7-10 days to avoid secondary complications. These interventions, along with a step-wise approach to management, can be useful in patients with PEDs that are refractory to standard medical treatment. In this review, we discuss the epidemiology, etiology, diagnosis, current and novel management, and prognosis of persistent epithelial defects. The cornea is the transparent, outermost layer of the eye that uniformly refracts the majority of light that enters the eye onto the lens and is essential for ideal vision. The multi-layered corneal epithelium acts as a protective barrier to infectious agents via tight junctions between neighboring cells, and it maintains its smooth optical surface by constantly regenerating cells in the basal cell layer , 2. DisrEpithelial Wound HealingThe self-renewing corneal epithelium consists of stratified squamous cells and is separated into three layers: the outer two to three cell layers comprise the superficial layer, the middle two to three cell layers create the wing layer, and the innermost cell layer is the basal cell layer. The epithelial basement membrane resides between the basal epithelial cells and the stroma. The limbus, located at the periphery of the cornea, contains both epithelial stem cells, which proliferate into the basal epithelium, and basal cells. Epidermal growth factor (EGF) mediates the proliferation and migration process, as it promotes synthesis of nucleic acids in epithelial cells and stromal fibroblasts as well as stimulates the production of extracellular matrix protein, fibronectin, by epithelial cells. As basal cells migrate towards the central surface of the cornea, they gradually lose their proliferative properties and eventually undergo apoptosis and are desquamated into the tear film . Severalacute epithelial defect is a lesion that usually heals over the 7-14-day time frame, whereas a persistent epithelial defect is unable to close within this normal interval. In normal conditions after an injury to the cornea, the epithelial layer undergoes an active repair process over 7-14 days, which involves a highly regulated cascade of growth factors, cellular signaling, proliferation, migration, extracellular matrix remodeling, and eventual quiescence or apoptosis , 4, 6. FTo find information on PED and current treatments, a literature search was performed using the following sources: PubMed, Google Scholar, Embase, and Scopus with the keywords \u201cpersistent epithelial defect\u201d, \u201cpersistent corneal epithelial defect\u201d, \u201cPED\u201d, \u201ctreatment of persistent epithelial defects\u201d, \u201cneurotrophic persistent corneal epithelial defect\u201d, \u201cnon-healing corneal epithelial defect\u201d, \u201ccorneal re-epithelialization\u201d, \u201ccorneal wound healing\u201d, and \u201cepithelial abrasion\u201d. Articles describing the epidemiology, etiology, diagnosis, current and novel management, and prognosis of PEDs were systematically reviewed. Reference lists detailed in each paper were examined to identify additional pertinent articles. There were no language restrictions. Publications were drawn between the dates of 1980-2019. EpidemiologyThe incidence of PED is unknown. However, studies based on the etiology of the disease estimate that the annual incidence of PED is less than 200,000 cases in the U.S., thus classifying PED as a relatively rare disease . For exaA recent study on the epidemiology of epithelial defects after penetrating keratoplasty surgeries in patients with infectious keratitis reveals that factors that increase the risk for postoperative epithelial defects include male sex, > 60 years, graft diameter > 9 mm, bacterial or viral etiology, comorbid systemic diseases, such as rheumatic diseases and cancer therapy . AdditioEtiologyThe normal corneal wound healing process can be disrupted from defective epithelial adhesion, limbal stem cell deficiency, surface trauma, medications, infections, and several other etiologies discussed below. The pathophysiology of PED involves proliferation of myofibroblasts and a resulting disordered extracellular matrix, producing an opacity in the cornea . Defective Epithelial AdhesionBasal epithelial cells produce and adhere to the basement membrane by forming hemidesmosomes and fibril connections. Defective epithelial adhesion or a deficient basement membrane can cause an increased risk for persistent corneal epithelial defects . RecurreLimbal Stem Cell DeficiencyEpithelial cell migration and corneal epithelial stem cells in the limbus are crucial to regenerate the tissue after an insult to the corneal epithelium. Therefore, limbal stem cell deficiency (LSCD) often results in the inability of epithelial regeneration, stromal melting, scarring, persistent epithelial defects, corneal conjunctivalization, and neovascularization , 14. OneInflammationCytokines, such as tumor necrosis factor alpha (TNF-\u03b1) and interleukin-1 (IL-1), mediate inflammation and induce production of growth factors by keratocytes that drive proliferation and migration of epithelial cells. These growth factors also promote the synthesis of proteases, such as MMPs and chemotactic factors that stimulate stromal remodeling and if in excess, stromal melting. Several inflammatory conditions can lead to PED due to disruption of corneal wound healing by over-activity of TNF-\u03b1, IL-1, and other inflammatory cytokines. These conditions include keratoconjunctivitis sicca, rosacea, infectious keratitis, autoimmune diseases, Sj\u00f6gren\u2019s syndrome, mucous membrane pemphigoid, Stevens-Johnson syndrome, graft versus host disease, peripheral ulcerative keratitis, Mooren\u2019s ulcer, and rheumatoid arthritis .NeurotrophicThe cornea is one of the most densely-innervated tissues in the human body and receives neural sensation and neurotrophic factors from the ophthalmic branch of the trigeminal nerve . NeurotrMechanicalRecurrent abrasions and insults to the ocular surface can result in depletion of epithelial stem cells from a constant need to regenerate the epithelial layer. Thus, if the extent of loss of epithelial cells exceeds the healing properties of limbal stem cells, a PED can form. These mechanical injuries include exposure keratopathy from lagophthalmos, entropion or ectropion, trichiasis, blepharospasm, pseudomembranes or tarsal scars, and trachoma . Severe Idiopathic and Hereditary DisordersAniridia and corneal, stromal, and epithelial basement membrane dystrophies can cause PEDs, due to a deficiency in limbal stem cells and abnormal basement membrane adhesion mechanisms, respectively . Table 1Diagnosis and Clinical PresentationEvaluating a PED involves fluorescein instillation to monitor the size, location, and depth of the defect . In deepDistinguishing an epithelial defect from a PED can be determined by the length of time the epithelial defect closes after injury to the cornea; an epithelial defect will recover after 7-10 days, whereas a PED will not heal even after 2 weeks and is usually refractory to standard therapies and supportive care . A comprAlthough rare, LSCD commonly results in PED and may be clinically diagnosed by stippled late fluorescein staining and detection of corneal opacities, decreased vision, photophobia, unstable tear film, and superficial vascularization. PED along with LSCD may later present with scarring, ulceration, stromal neovascularization or perforation .Treatment of Persistent Epithelial Defects of the CorneaThe consequences of an untreated PED include increased risk of infection, anterior stromal scarring, melting, neovascularization, ulceration, perforation, and significant vision loss . TherefoManagement of PED is complex and involves several treatment options depending on its etiology. Healthy corneas may rapidly recover from an epithelial defect with supportive care; however, corneal healing may be hindered by disrupted cellular signaling from several etiologies that cause a PED, such as trauma, infection, severe dry eye disease, herpetic infections, diabetes mellitus, neurotrophic keratopathies, and complications after penetrating keratoplasties , 21. PEDCurrent Standard ManagementIn approaching treatment of a PED, the first step is to consider the possible etiology of the disease along with its clinical presentation. For example, neurotrophic cornea can be treated with topical nerve growth factor; diabetic keratopathies with optimal diabetes management; herpetic keratitis with antiviral treatment and corticosteroids; and LSCD with limbal stem cell transplants .The current standard management of PEDs includes a stepwise strategy, starting with conservative management and progressing to medical or surgical treatments if refractory. This includes lubrication, bandage soft contact lenses, punctal plugs, debridement, and tarsorrhaphy. Initially, aggressive lubrication every 1-2 hours with preservative-free artificial tears and ocular ointments are applied to the eye . IatrogeThe next step in treatment is the application of a punctal plug, which will increase retention of lubrication, which helps with normal corneal healing as tear film contains many growth factors including EGF, TGF, TGF-\u03b2, basic fibroblast growth factor (bFGF), HGF, calcitonin gene-related peptide, fibronectin, and vitamins A and C . As discBandage soft contact lenses (BCL) along with preservative-free artificial tears and antibiotics are beneficial in protecting the damaged epithelium from mechanical erosion from eyelid blinking, thus aiding the re-epithelialization process. If stromal damage is involved, several weeks may be required for corneal healing. Lubrication and broad-spectrum topical antibiotics should be used concurrently to decrease the risk of infectious keratitis . PatientSurgical interventions, such as debridement and tarsorrhaphy, are effective in most cases of PED refractory to medical management . DebrideTetracyclines, prophylactic topical antibiotics, and steroids are also used as standard therapy for PED. Oral tetracyclines exhibit anticollagenolytic activity, inhibiting MMPs produced by inflammation mediators, and have been shown to be effective in healing PEDs within weeks . ProphylTreatment of Refractory CasesRefractory cases of PED are those that do not respond to the standard therapies discussed above: lubrication, bandage soft contact lens, punctal plugs, debridement, and tarsorrhaphy. Amniotic membranes contain many of the growth factors , proteinase inhibitors and proteins that facilitate corneal wound healing in addition to providing a scaffold for re-epithelialization, decreasing vascularization, and having anti-inflammatory properties , 30, 31.Blood serum contains many growth factors, including vitamin A, vitamin E, EGF, TGF-\u03b2, PDGF, IGF, nerve growth factor, substance P, immunoglobulins, and fibronectin. Therefore, autologous serum eye drops are useful in re-epithelialization when a patient\u2019s serum is diluted by 20% or 50% to create the eye drops and used every 3 hours daily -40 50% aWhole blood-derived products, such as umbilical cord blood serum and platelet-rich fibrin tears, can be used instead of autologous serum in patients with infection or systemic disease . PatientScleral contact lenses are effective in treating PED due to their high oxygen permeability, lubricating properties, and protective effects on the corneal epithelium . AdditioTransplantation of corneal epithelial stem cells can aid in re-epithelialization, especially in conditions that damage the limbal corneal stem cells, such as in Stevens-Johnson syndrome, chemical or thermal burns, or stem cell deficiencies , 50. SevNovel TreatmentsThe glycoprotein fibronectin is vital in cellular adhesion in the extracellular matrix. Thus, topical fibronectin may be helpful for re-epithelialization of a PED , 56. DiaThymosin beta 4 (T\u03b24) demonstrates efficacy in stimulating re-epithelialization processes and proliferation of epithelial cells while having anti-inflammatory effects . The proNexagon is an antisense oligodeoxynucleotide that downregulates connexin43 protein expression . NexagonTherapies in DevelopmentEpidermal growth factor (EGF) stimulates proliferation of limbal and peripheral epithelial cells and stromal fibroblasts, promotes the synthesis of fibronectin, and serves as a chemotactic agent for both epithelial and stromal cells. Thus, EGF enhances the synthesis of extracellular matrix proteins to promote epithelial healing of corneal injuries [64]. Additionally, corneal wound healing is mediated by EGF-induced nuclear factor \u03baB p50 and CTCF protein, making both mediators important in the growth factor-induced signaling pathway . The EGFInsulin-like growth factor-1 (IGF-1) facilitates healing of PEDs by inducing migration and proliferation of corneal epithelial cells. Insulin, present in the tear film, also facilitates defect closure by promoting cell proliferation, as it is related to IGF-1 . AdditioHuman growth hormone (HGH), normally produced by the anterior pituitary gland, potentially stimulates epithelial cells and fibroblast proliferation through an increase in phospho-STAT5 signaling. HGH may also stimulate corneal epithelial cell migration by an unknown mechanism . HoweverAlbumin eye drops (AED) may be effective in closing corneal epithelial defects. Albumin is the major protein component in autologous tears, and it, therefore, can be beneficial in treating ocular surface diseases such as corneal ulcers and epithelial defects , 82.Matrix regenerating agent, also known as ReGeneraTing Agent (RGTA), includes polymers that are analogs to extracellular matrix proteins and act as a scaffold. RGTA also provides proteolytic defense for epithelial cells as they migrate and proliferate during corneal wound healing. Specifically, these analogs replace heparan sulfates and bind to collagen, elastin, and fibronectin to protect against proteolytic damage , 84. In in vivo and limbal stem cells ex vivo and in vivo; thus, AMEED may have potential use in treating LSCDs [Amniotic membrane extract eye drops (AMEED) can be utilized for tissue healing in severe cases of ocular damage. AMEED contains several diverse growth factors , which supply AMEED with its growth-promoting and anti-inflammatory properties. Several studies have demonstrated the efficacy of AMEED therapy to improve ocular surface burns, ulcerations, and epithelial damage; therefore, AMEED appears to be a promising therapy in treating persistent epithelial defects . Additiong LSCDs , 89. in vivo confocal microscopic and histopathological analyses, that regeneration of corneal nerves works through a paracrine-mediated mechanism [Restoration of corneal sensation with corneal neurotization, a peripheral sensory nerve graft, is a recent and novel surgical technique to treat neurotrophic keratopathy. Corneal neurotization involves transferring the contralateral supraorbital and supratrochlear ophthalmic branches of the trigeminal nerve to the limbal cells of the cornea to re-innervate the corneal stroma and sub-basal layers , 91. A rechanism . In a caechanism . Oxervate medication, known as Cenegermin-bkbj or recombinant human nerve growth factor (rhNGF), has recently been FDA approved in the U.S. as a therapy for neurotrophic keratitis. Nerve growth factor restores sensation and sensitivity of the cornea, induces corneal healing, increases tear production, displays immunoregulatory effects, and plays a role in sensory and sympathetic nerve regeneration post-injury . Phase IThis review summarizes the epidemiology, etiology, diagnosis, clinical presentation, and management of persistent corneal epithelial defects. Clinicians should be aware that without treatment, a PED can cause stromal scarring, perforations, secondary infections, ulcerations, or even complete vision loss , 4. AlthEthical issues have been completely observed by the authors. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published. No conflict of interest has been presented.Funding provided by Research to Prevent Blindness, NY, USA."}
+{"text": "Sleep disturbances are often observed in child and adolescent mental health disorders. Although previous research has identified consistent subjective reports of sleep disturbances, specific objective sleep markers have not yet been identified. We evaluated the current research on subjective and objective sleep markers in relation to attention deficit hyperactivity disorders, autism spectrum disorders, anxiety and depressive disorders. Subjective sleep markers are more consistent than objective markers of actigraphy, polysomnography, and circadian measures. We discuss the causes of variability in objective sleep findings and suggest future directions for research.  Significant neurobiological, physiological, and social changes occur during childhood and adolescence ,2, incluAlong with changes in sleep patterns, many youth develop mental health disorders in childhood and adolescence . AttentiSleep difficulties in youth with mental health problems are common, including increased sleep latency, nocturnal awakenings, nightmares, snoring, restless sleep, excessive daytime sleepiness, bedtime struggles, and fear of dark . Sleep pHerein, we review the literature on objective markers of sleep disturbances in the context of youth mental health disorders. We focused on current research studies and literature predominantly published during the last decade which includes objective measurements of sleep (polysomnography (PSG) or actigraphy) or circadian rhythms. Specifically, we examined studies in children and adolescents with anxiety disorders, depressive disorders, ADHD, and ASD diagnosed by diagnostic and statistical manual of mental disorders (DSM) criteria. We excluded studies of children with primary sleep disorders. From the selected studies, we identified objective sleep markers and their associations with subjective reports of sleep disturbances. Objective markers of sleep disturbances include measurements by PSG, actigraphy, and measures of circadian biology. Polysomnography, the most widely used and validated standard for the evaluation of sleep, is a multi-modal instrument which assesses a range of physiological changes in electroencephalography (EEG), respiration, and heart rate , with anSubjectively, parents of children with generalized anxiety disorder (GAD) report resistance to bedtime, delay in sleep onset, short sleep duration, high anxiety before sleep, and daytime sleepiness . SimilarRecent actigraphy studies did not reveal any differences between children with GAD and healthy controls, despite reported subjective sleep disturbances . HoweverPolysomnography in anxiety disorders showed reduced latency to REM , high slLower nighttime cortisol, a marker of circadian and arousal differences, was observed in prepubertal children with anxiety , but no Eveningness chronotype assessed by chronotype questionnaires was consistently high in children with depression  and adolIn summary, children and adolescents with anxiety disorders show reliable subjective reports of greater sleep onset latency, bedtime fears, and greater wake after sleep onset duration ,36. InteIn children with ADHD, subjective reports indicate a wide range of sleep problems, including difficulty with sleep onset, daytime sleepiness ,54,55,56On actigraphy, children with ADHD have been identified to take longer to fall asleep ,53,59, hIn-home PSG has shown that children with ADHD have short sleep duration, short REM sleep, a smaller percentage of REM sleep, and longer sleep onset latency . HoweverCortisol levels vary across the day in children with ADHD, being lower in the morning and higher in the evening . One stuOverall, children with ADHD subjectively report sleep onset difficulties, daytime sleepiness, anxiety before sleep, and awakenings at night ,53,55,57Subjective reports of sleep in children with ASD include long mean sleep latency ,72,73, sOn actigraphy, preschool, school-aged children, and adolescents with ASD confirmed the subjective sleep findings, with long sleep latency, decreased sleep duration, and increased wake after sleep onset duration ,75. OthePolysomnography findings show short total sleep time, short REM latency , long slHigh salivary cortisol and overall blunted cortisol rhythms were identified in children with autism, with higher cortisol levels associated with severe symptoms of autism . MelatonCollectively, children and adolescents with autism commonly have reports of longer sleep latency, short sleep duration, and high resistance to bedtime on subjective measures ,73. ActiThe goal of this review was to identify objective sleep characteristics associated with mental health disorders in children and adolescents. Collectively, the findings highlight that subjective reports of sleep problems are common in mental health disorders but do not necessarily coincide with reliable objective markers of sleep disturbances measured by actigraphy and PSG. High sleep onset latency, short sleep duration, and resistance to bedtime were commonly present in subjective measures of anxiety, ADHD, and ASD across diagnostic categories ,57,72,73The overlapping objective sleep findings observed across child and adolescent mental health disorders suggest possible common sleep mechanisms. Child and adolescent mental health disorders often present with high rates of comorbidity ,11. WhenReliable macrostructural sleep findings have consistently eluded child and adolescent mental health disorders. Technical and methodological characteristics of actigraphy and PSG should be acknowledged when evaluating the findings of objective sleep markers. Actigraphy may overestimate sleep  during pArousals from sleep are an integral part of the sleep process  and are Generalized CNS arousal, defined as optimal sensory, motor, and affective drive, is necessary for survival and interaction with the environment ,102, andWe conducted this review to identify objective sleep markers associated with mental health disorders in children and adolescents. Several subjective sleep markers were found to be more consistent and common across child mental health disorders than objective sleep markers, which were not specific and varied across studies. A gap exists in identifying the pathophysiology of sleep disturbances and their links to mental health disorders in youth. Future research should focus on these links to clarify objective markers of sleep and their association with subjective reports and mental health symptoms. Also, mental health symptoms are heterogeneous and cross existing boundaries of syndromes, hence using biobehavioral phenotypes based on pathophysiology may help identify reliable objective markers of sleep . It is e"}
+{"text": "Drug abuse is a substantial problem in society and is associated with significant morbidity and mortality. It\u2019s an epidemic that crosses racial, socioeconomic, and age barriers. According to the 2016 Global Drug Survey the top 10 drugs \u2013 excluding alcohol, tobacco and caffeine products \u2013 used across the world are: cannabis, MDMA, cocaine, amphetamines, LSD, magic mushrooms, prescribed and non-prescribed opioid medication, nitrous oxide, ketamine, and poppers.Various drugs may cause central nervous system (CNS) complications. These complications include acute and chronic neurovascular complications, toxic leukoencephalopathy, atrophy, infection, changes in the corpus callosum, and other miscellaneous changes.The lecture will focus on neurovascular complications which constitute the most frequent drug related emergencies. They include both ischemic stroke, subarachnoid, and intracerebral hemorrhage.Also nonischemic white matter changes, i.e. toxic leukoencephalopathy, has been described with some drugs. A more nonspecific leukoencephalopathy is seen in chronic inhalant abuse of industrial solvents such as toluene. Such lesions can be explained by the high affinity of these lipophilic volatile agents for myelin."}
+{"text": "This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patients received or pending, or royalties. No writing assistance was utilized in the production of this manuscript."}
+{"text": "Dear Editor,A 75-year-old woman presented with a three-year history of nonspecific, moderate,intermittent mesogastric pain, similar to colic, with little improvement aftermedication, accompanied by nausea and postprandial fullness. She had a history ofabdominal surgery, with a resurgence of symptoms six months prior to seeking treatmentat our facility, and the attending physician therefore requested a multidetectorcomputed tomography (MDCT) scan  fordiag-3. Caused by congenital mechanisms, surgery, trauma, inflammation or poorcirculation, they have several subclassifications,5. Right paraduodenal (orBroesike) hernia is defined as one in which the small bowel is concentrated in theperitoneal cavity, adjacent to the ligament of Treitz,4. They developthrough the Waldeyer fossa, resulting from fusion failure of the ascending mesocolonwith posterior parietal peritoneum toincarceration or strangulation. Its typically intermittent symptoms make the medicalteam question the veracity of patient complaints.Despite affecting approximately 50% of patients diagnosed with internal hernia,paraduodenal hernias tend to affect elderly males in larger proportions, althoughBroesike hernias account for 25% of such cases, most frequently being attributable tomalrotation of the small bowel,5. In general, the mass dislocates the posterior wall ofthe stomach, the duodenal flexure, and (inferiorly) the transverse colon. There isengorgement of the mesenteric vessels, which supply segments of the small bowel in thearea of the hernia defect,5. In the case described here, MDCTrevealed laterally insinuated loops clustered in the region of the mesocolic fossa, withno significant distension or injury of the jejunal loops. The addition of contrast couldincrease the diagnostic accuracy of the radiological examinations.When identified by MDCT, hernia with intestinal subocclusion shows an \u201cencapsulated\u201d massof dilated small bowel between the pancreas and stomach, to the right of the ligament ofTreitz,8. However, because the patient described here was atprohibitive surgical risk, we opted for clinical monitoring. At this writing, thepatient has been followed at our facility for over six months, without any worsening ofher symptoms.Laparoscopic repair is a safe and effective method for the management of cases ofBroesike hernia"}
+{"text": "In 2014, the US Preventive Task Force recommended annual lung cancer screening with low dose CT (LDCT) for adults aged 55 to 80 years old with significant smoking history. Although screening reduces lung cancer mortality, the leading cause of cancer mortality in the US, adherence to screening follow-up remains low. In a human-centered design qualitative study, health services researchers and eight adults over 55 years old from Kaiser Permanente Washington who had recently had an LDCT participated in two co-design sessions. We elicited barriers, facilitators and design principles to develop multilevel interventions that aim to improve adherence to ongoing LDCT. In the initial discussion, participants identified four key areas for improvements to adherence: a) reminders for scheduling and appointments, b) knowledge about tests and follow-up, c) convenience in location and scheduling, and d) financial and non-financial incentives. In a second session, participants referenced patient personas and sketched storyboards, a comic strip-like format showing steps in a journey, to describe different ways to help patients return for LDCTs. Through qualitative analysis, we identified ten elements to consider incorporating in multilevel interventions: versatility , social support , individualization , feelings , knowledge , responsibility , continuity , consistency , cadence , and acknowledgment . Next steps are to incorporate feedback from clinical stakeholders and develop multilevel interventions for further testing."}
+{"text": "In the setting of prior myocardial infarction, the oral antiplatelet ticagrelor added to aspirin reduced the risk of recurrent ischemic events, especially, in those with diabetes mellitus. Patients with stable coronary disease and diabetes are also at elevated risk and might benefit from dual antiplatelet therapy. The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study  is a Phase 3b randomized, double\u2010blinded, placebo\u2010controlled trial of ticagrelor vs placebo, on top of low dose aspirin. Patients \u226550\u2009years with type 2 diabetes receiving anti\u2010diabetic medications for at least 6 months with stable coronary artery disease as determined by a history of previous percutaneous coronary intervention, bypass grafting, or angiographic stenosis of \u226550% of at least one coronary artery were enrolled. Patients with known prior myocardial infarction (MI) or stroke were excluded. The primary efficacy endpoint is a composite of cardiovascular death, myocardial infarction, or stroke. The primary safety endpoint is Thrombolysis in Myocardial Infarction major bleeding. A total of 19\u2009220 patients worldwide have been randomized and at least 1385 adjudicated primary efficacy endpoint events are expected to be available for analysis, with an expected average follow\u2010up of 40\u2009months (maximum 58\u2009months). Most of the exposure is on a 60\u2009mg twice daily dose, as the dose was lowered from 90\u2009mg twice daily partway into the study. The results may revise the boundaries of efficacy for dual antiplatelet therapy and whether it has a role outside acute coronary syndromes, prior myocardial infarction, or percutaneous coronary intervention. In those who have established atherosclerosis, the presence of DM further increases future risk of ischemic events in a synergistic fashion.Heightened platelet activity appears to be present in atherothrombotic patients with DM. Long\u2010term dual antiplatelet therapy (DAPT) reduces CV event rates in patients with acute coronary syndromes, both in the short\u2010 and long term.The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS) trial was designed to evaluate the potential benefits and risks of dual antiplatelet therapy with ticagrelor plus low dose aspirin vs placebo plus aspirin in patients with established stable coronary artery disease and DM treated with medications.2THEMIS NCT01991795) is a Phase 3b randomized, double\u2010blinded, placebo\u2010controlled trial of ticagrelor vs placebo, on top of low dose aspirin 75\u2010150\u2009mg) unless contraindicated or not tolerated. The primary hypothesis of the trial is that twice daily ticagrelor when added to aspirin will reduce the risk of CV death, MI, or stroke in patients with DM and stable coronary artery disease. Patients were initially randomized to 90\u2009mg twice daily of ticagrelor or matching placebo , adjusted for 1 planned efficacy interim analysis with family\u2010wise error controlled at 5%. The one planned efficacy interim analysis occurred on the 29th of March 2017. The recommendation from the DMC was to continue the study according to the protocol. The estimated annual event rate in the placebo arm was 2.5%. An effect size of 16% relative risk reduction was hypothesized, with 1385 primary endpoint events needed to provide 90% power. This resulted in an estimated sample size of 19\u2009000 patients, randomized in a 1:1 ratio, with an average follow\u2010up time of 40\u2009months (maximum 58\u2009months). Even with the ticagrelor dosage switch, a power of 90% in the study is maintained, as the main analysis is based on randomization to ticagrelor irrespective of dose.There are no sub\u2010studies planned, but predefined subgroup analyses will explore efficacy and safety according to baseline characteristics, such as revascularization history, single vs multivessel coronary artery disease, duration of diabetes, glycemic control, anti\u2010diabetic medications, age groups, and renal function.3A total of 20\u2009108 patients were enrolled. Of these, 19\u2009271 were randomized, and because of closure of a single site secondary for inadequate adherence to good clinical practice in a different trial, 19\u2009220 patients are expected to be available for analysis , Baim Institute for Clinical Research , Belvoir Publications , Duke Clinical Research Institute , HMP Global , Journal of the American College of Cardiology , Population Health Research Institute , Slack Publications , Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR\u2010ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Abbott, Amarin, Amgen, AstraZeneca (including for his role as co\u2010Chair of THEMIS), Bayer, Boehringer Ingelheim, Bristol\u2010Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines Company; Royalties: Elsevier ; Site Co\u2010Investigator: Biotronik, Boston Scientific, St. Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Fractyl, Merck, Novo Nordisk, PLx Pharma, Takeda. Dr Kim Fox receives fees, honoraria and/or travel expenses from Servier, TauRx, CellAegis, Celixir and Broadview Ventures. He is a director of Vesalius Trials Ltd. Dr Harrington discloses research grants/contracts from the National Heart Lung and Blood Institute, Duke, AstraZeneca, CSL\u2010Behring, Glaxo Smith Kline, Merck, Portola, Regado, Sanofi\u2010Aventis, and The Medicines Company, and consulting/advisory for Adverse Events, Amgen, Element Science, Gilead, Merck, MyoKardia, The Medicines Company, VidaHealth, and WebMD. Dr. Lawrence Leiter discloses the following relationships: research grants from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Esperion, GSK, Kowa, Novo Nordisk, Sanofi, The Medicines Company; speaking or consulting fees from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Novo Nordisk, Sanofi. Dr. Shamir Mehta discloses the following relationships: Institutional research grants from Abbott Vascular, AstraZeneca, Boston Scientific and Sanofi and consulting fees from AstraZeneca and Sanofi. Dr Tabassome Simon discloses the following relationships: research grants from AstraZeneca, Daiichi\u2010Sankyo, Eli\u2010Lilly, GSK, MSD, Novartis, Sanofi, speaking or consulting fees from AstraZeneca, BMS, Novartis Sanofi. Dr Claes Held discloses the following relationships: Institutional research grants from AstraZeneca, GlaxoSmith Kline, BristolMyers Squibb, Pfizer and Merck. Advisory board \u2010 AstraZeneca, Bayer, Boehringer Ingelheim, Idorsia and Coala Life. Speaking or consulting fees from AstraZeneca, Bayer. Dr. Ph. Gabriel Steg discloses the following relationships: research grants from Amarin, Bayer, Merck, Sanofi, and Servier; speaking or consulting fees from Amarin, Amgen, AstraZeneca, Bayer/Janssen, Boehringer\u2010Ingelheim, Bristol\u2010Myers Squibb, Idorsia, Lilly, Merck, Novartis, Novo\u2010Nordisk, Pfizer, Regeneron, Sanofi, Servier. Dr Anders Himmelmann, Dr Wilhelm Ridderstr\u00e5le, and Marielle Andersson report being employees of AstraZeneca.Dr. Deepak L. Bhatt discloses the following relationships: Advisory Board: Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Baim Institute for Clinical Research , Cleveland Clinic , Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine , Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, Appendix S1. Supplementary Appendix to Bhatt et al., Rationale, Design, and Baseline Characteristics of THEMIS: Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention StudyClick here for additional data file."}
+{"text": "During November 8\u2013December 25, 2017, health care personnel at an 80-bed acute care facility in West Virginia reported dermatologic, respiratory, and ophthalmic symptoms to management or the occupational health clinic, prompting concern about a common exposure, possibly related to construction activities. Symptoms of affected staff members, who performed a range of clinical and nonclinical duties, often improved hours to days after leaving the hospital, suggesting potential exposure to an environmental irritant. Initially, hospital leadership encouraged symptomatic persons to seek evaluation at the occupational health clinic, although systematic evaluations were not implemented. No etiology was identified by environmental sampling for fibers, volatile organic compounds, or mold. In the absence of a clear etiology, hospital leadership stopped inpatient admissions, transferred inpatients from the two wards where most symptomatic staff members worked, and completed cleaning to include associated air-handling systems. Dermatology and allergy consultants evaluated symptomatic staff members, but because of varying clinical manifestations, results were inconclusive. On December 26, one of the closed wards reopened; during the ensuing week, six additional workers reported symptoms, and onsite CDC assistance was requested to identify an etiology. A CDC team arrived on January 8, 2018, and met with hospital and union leadership, reviewed occupational health records, observed occupational health encounters, performed unstructured individual interviews with both affected and unaffected health care personnel, assessed the physical environment, and reviewed environmental testing results. Despite these efforts, investigators were unable to identify an etiology, and the outbreak resolved without intervention.CDC investigators found that during November 1, 2017\u2013January 12, 2018, a total of 114 workers at the West Virginia hospital had 154 occupational health encounters, including 28 (25%) workers who had multiple encounters . The mosHealth care personnel reported that vigorous investigation and response and related effects  heightened their concerns about workplace exposures. Multiple persons reported hearing rumors that occupational health evaluation would be required for subsequent compensation eligibility for potential occupational toxic exposure. Investigators identified no etiology. All units reopened January 16, 2018, and another dermatology consultant visit, including skin biopsy of a symptomatic staff member, occurred during January 26\u201329, 2018. The biopsy was nonspecific, and no other personnel reported symptoms after January 26, 2018. Despite no identified etiology or recognized interventions, the outbreak resolved.Arrival of the CDC team 1 month after the peak in health encounters might have limited the ability to identify an etiology. However, inconsistent symptomatology, reports of persons seeking evaluation for subjectively mild symptoms, and rumors that future compensation might require seeking care suggest that response efforts might have inadvertently contributed to reports of illness. Outbreaks of unknown etiology perpetuated by response efforts have been described previously (This investigation demonstrates challenges inherent in investigating outbreaks of unknown etiology and supports the hypothesis that response actions can heighten concern, potentially increasing reporting. Robust investigations might reinforce suspicions of concealed findings even in the absence of true pathology ("}
+{"text": "The article Biological tests carried out on serum/plasma samples from donors of human body material for transplantation: Belgian experience and practical recommendations, written by Elizaveta Padalko, Katrien Lagrou, Marie-Luce Delforge, Hilde Jansens, Nadine Ectors, Jean-Paul Pirnay, Johan Klykens, Etienne Sokal, Ludo Muylle, Agnes Libois, Alain Vanderkelen, Gilbert Verbeken, Conny Matthys, Dominique Goossens, Geert Hanssens, Muriel Baltes and Hilde Beele, was originally published electronically on the publisher\u2019s internet portal (currently SpringerLink) on 29 August 2018 without open access.http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.With the author(s)\u2019 decision to opt for Open Choice the copyright of the article changed on October 2018 to \u00a9 The Author(s) 2018, and the article is forthwith distributed under the terms of the Creative Commons Attribution 4.0 International License ("}
+{"text": "A substantial and increasing proportion of death and disability in the EU (and elsewhere) is attributable to diseases associated with insulin resistance . Beside type II diabetes, other diseases like obesity, hypertension, atherosclerosis, hyperlipidaemia, polycystic ovarian syndrome, and acromegaly are indeed associated with insulin resistance [1]."}
+{"text": "On September 11, 2001, terrorists destroyed the World Trade Center (WTC) in New York City. Explosions and fires resulted in the complete collapse of the two WTC towers. The collapsing towers served as enormous point sources of gaseous and particulate air pollution, seen as huge plumes of smoke and dust. The smoke contained volatile organic compounds and fine particles and aerosols. The dust fraction contained parts of ceiling tiles, carpets, concrete, adhesives, asbestos, chromium, lead, titanium, and many other elements and materials. Whether there were unusually toxic ingredients in the plumes is largely unknown."}
+{"text": "The Editor-in-Chief has retracted this article  because Guoqiang Zhao agrees with this retraction. Yuanyuan Wang, Xiaonan Chen, Qianqian Sun, Wenqiao Zang, Min Li, and Ziming Dong have not responded to any correspondence about this retraction."}
+{"text": "A 47-year-old male presented to the emergency department with 12 hours of nausea, vomiting, abdominal pain, and a widespread skin eruption with mottled, irregular, purpuric lesions with subsequent rapid decompensation. Laboratory analysis revealed thrombocytopenia, bandemia, elevated metamyelocytes, abnormal coagulation panel, decreased fibrinogen, elevated fibrin split products, renal dysfunction, bacterial rods, dohle bodies, and toxic granulation. Acute promyelocytic leukemia (APML) was confirmed via bone marrow biopsy, flow cytometry, and fluorescence in situ hybridization analysis. Disseminated intravascular coagulation (DIC) may be the initial presentation of APML. When treated promptly, APML can achieve high remission rates; however, conditions such as DIC continue to increase mortality requiring early recognition to improve survival rates. A 47-year-old male with no past medical history presented with nausea, vomiting, diffuse abdominal pain, and a widespread rash that began 12 hours prior to arrival. Physical examination revealed an ill-appearing male with diffuse abdominal tenderness as well as diffuse purpuric, mottled skin . Vital sHis laboratory findings revealed bandemia, thrombocytopenia, acute kidney injury, elevated coagulation markers, decreased fibrinogen, elevated fibrin split products, elevated lactate dehydrogenase, and a lactic acidosis as shown in the The patient was transferred to a tertiary care center and underwent bone marrow biopsy, flow cytometry, and fluorescence in situ hybridization analysis confirming APML. APML constitutes 10% of all adult acute myelogenous leukemia and has a high incidence of life-threatening hemorrhage secondary to fibrinolytic-type DIC, which has been attributed to both the development of APML as well as sepsis secondary to APML.APML should be considered in those with presentations of bleeding, DIC, or infections with laboratory abnormalities of thrombocytopenia, anemia, and subnormal to elevated white blood cell count. In cases of DIC, scoring algorithms use platelet count, level of fibrin markers such as d-dimer and fibrin split products, coagulation studies, and fibrinogen levels to arrive at a diagnosis. Additionally, with DIC, PF may also occur. PF is a poorly understood entity; it occurs secondary to endovascular thrombotic events and endothelial damage, which contribute to the characteristic purpuric appearance.5What do we already know about this clinical entity?Acute promyelocytic leukemia (APML) is associated with a high incidence of fibrinolytic-type disseminated intravascular coagulation (DIC).Treatment is supportive.What is the major impact of the image(s)?The image reinforces what purpura fulminans looks like and highlights the occurrence of DIC in APML and the importance of early recognition and treatment.How might this improve emergency medicine practice?Keeping a broad differential with knowledge of this emergent condition will yield earlier coordination of care and treatment of APML, which carries a high misdiagnosis and mortality rate."}
+{"text": "Epimedium Genus, and demonstrated an antitumor effect in various neoplasms including hematological malignancies such as leukemia, lymphoma, and multiple myeloma. In hematological malignancies, icaritin showed multiple cytotoxic effects to induce apoptosis, arrest the cell cycle, inhibit proliferation, promote differentiation, restrict metastasis and infiltration, and suppress the oncogenic virus. The proved underlying mechanisms of the cytotoxic effects of icaritin are different in various cell types of hematological malignancies but associated with the critical cell signal pathway, including PI3K/Akt, JAK/STAT3, and MAPK/ERK/JNK. Although the primary target of icaritin is still unspecified, the existing evidence indicates that icaritin is a potential novel therapeutic agent for neoplasms as with hematological malignancies. Here, in the field of hematology, we reviewed the reported activity of icaritin in hematologic malignancies and the underlying mechanisms and recognized icaritin as a candidate for therapy of hematological malignancies.Hematological malignancies including leukemia and lymphoma can severely impact human health. With the current therapies combined with chemotherapy, stem cell transplantation, radiotherapy, and immunotherapy, the prognosis of hematologic malignancies improved significantly. However, most hematological malignancies are still incurable. Therefore, research for novel treatment options was continuing with the natural product as one source. Icaritin is a compound extracted from a traditional Chinese herb, Hematological malignancies are known as a series of malignant diseases affecting the blood, bone marrow, lymph, and lymphatic system, which finally lead to dyshematopoiesis. So far, primary treatment includes chemotherapy, radiotherapy, immunotherapy, and autologous or allogeneic stem cell transplantation. Various sorts of anticancer drugs with different mechanisms and targets are developed to attack the cancer cell colony and block disease progression. Outstanding achievements have been made, accompanied by limitations. Conventional drugs bring adverse reactions and sometimes lead to resistance that cannot be ignored . Consequ Epimedium Genus. Previous studies demonstrated that icaritin possesses various pharmacological and biological activities in nonneoplastic diseases, including protection of neuron against amyloid-induced neurotoxicity [Icaritin, a hydrolytic product of icariin, is extracted from the traditional Chinese herbtoxicity , promotitoxicity , enhancetoxicity \u201311, immutoxicity , 13, enhtoxicity , recovertoxicity , and imptoxicity .Recently, icaritin has attracted great attention in terms of its inhibition of various solid tumors including breast cancer \u201323, hepaExcept for investigations of icaritin on the solid tumor, a series of studies on hematological cancer were conducted and proved the significant inhibitory effect of icaritin on various hematological cancer cells, including acute myeloid leukemia (AML), chronic myeloid leukemia (CML), multiple myeloma (MM), and lymphoma \u201344. MoreApoptosis describes a kind of cell death activated by intracellular suicide program. Over the past decades, triggering apoptosis in tumor cells is seemingly regarded as an effective strategy for cancer therapy . ApoptosPrevious findings showed that activated caspase-9, caspase-3, subsequent cleaved PARP, and release of cytochrome c from mitochondria serve as reliable markers of the intrinsic apoptosis pathway . SubsequThe JAK-STAT signaling pathway transmits extracellular signals to the nucleus, playing a critical role in transducing signal of a wide array of cytokines and growth factors. These cytokines and growth factors are responsible for various cellular functions, including proliferation, growth, hematopoiesis, and immune response \u201356. InvePI3K-AKT is recognized as a major signaling pathway in cancer development. Through phosphorylation, PI3K-AKT is activated, and the downstream effector participates in regulating tumor cell proliferation, growth, survival, and angiogenesis , 58. StuMitogen-activated protein kinase (MAPK) is a superfamily of protein kinase involved in directing cellular responses to diverse stimuli, such as mitogens, osmotic stress, and proinflammatory cytokines. They play the role of mediating cell functions, including proliferation, differentiation, and apoptosis . Three MAbove all, the mechanism of icaritin inducing of apoptosis through multiple and differential signaling pathways in different hematological malignant tumor cell lines is shown in There are four distinct phases in the cell cycle, namely, G0, G1, S, and G2/M. Cyclins and cyclin-dependent kinases (CDKs) are two crucial groups of molecules in regulating cell cycle progression. In other words, cell proliferation relies intensively on them as they can translate these signals for accurate and active replication and division. Disrupted cell cycle progression might lead to uncontrolled proliferation, accompanied by the occurrence of cancer . Previou\u03baB, JAK/STAT, and AKT [Epstein\u2013Barr virus (EBV) is known for its essential role in extranodal NK/T-cell lymphoma (ENKL) etiology , 64. EBV and AKT \u201367. In t and AKT .EBV has two distinct lifestyles in an infected human host, including a lytic form, in which the virus lyses the host cells to produce infectious virions, and a latent form, in which the virus reserve the host cells to persist in a dormant state. EBV in ENKL specimens is in a latent form . RecentlIn the survived icaritin treated K562 cells, we found there were morphological changes, such as reduction in cell volume, accompanied with higher hemoglobin level . Flow cyThe p38 has been proved to mediate icaritin induced cardiomyocyte differentiation . In our In the investigation with NOD/SCID mice, icaritin dramatically reduced disseminated infiltrations of K562 cells in spleen, bone marrow, and liver without overt bone marrow suppression or weight loss compared to the imatinib-treated group . AdditioCurrently, icaritin has been proven to possess antitumor activity through extensive mechanisms in several cancer cells, which originated from both solid tumor and hematological cancer. The common cytotoxicity of icaritin in different malignancies includes inhibiting proliferation, inducing apoptosis, and blocking cell cycle , 80\u201383. For both solid tumor and hematological malignancies, the growth inhibitory effect mentioned above was mediated mainly by the complex cross network of cell signaling pathways including the PI3K/AKT, MAPKs, and JAK/STATs, which ultimately regulated the cell growth, proliferation, and differentiation. Current studies in solid tumors found several molecules with relatively more direct interaction to icaritin above the common signal pathways, such as estrogen receptor in breast cancer cells , 23 and Moreover, the study of improvement effect of icaritin on hematopoietic function in the cyclophosphamide-induced myelosuppression mice indicated that icaritin could protect chemotherapy-induced bone marrow injury . In otheIn the context of discovering icaritin, it was also found that it exerts diverse effects on various cancer cells. The primary target of icaritin still needs to be identified by further study. Additionally, the interaction of icaritin and existing antitumor medicine is to be explored to determine whether the synergistic effect or antagonistic effect can be induced."}
+{"text": "The patient was in septic shock. Should inotropic drugs be started? Physiologic steroids? Cardiac ultrasound \u2026?\u201d\u201cDespite several fluid boluses and vasopressor support, mean arterial pressure hovered around 50\u2009mmHg, lactate levels increased and ScvOTo many emergency and critical care (ECC) physicians, this is a daily routine. Few imagine this patient being a dog or cat. However, small animal intensive care units (ICUs) exist. Human and veterinary emergency and critical care (HECC and VECC) share attitudes and values, providing opportunities for the development of both professions.Advancements in ECC rely on animal experiments , 2, partHowever, the translation of rodent-based research to clinical practice has been questioned for several reasons, including the use of young, single-sex, genetically modified, healthy (or limited comorbidities), inbred subjects, kept in homogeneous, regulated environments \u20133. RecenSheep, pigs, rabbits, and non-human primates have also been used in ECC research . ProposeAlthough valuable in preclinical research, a gap still exists between animal models and the clinical human ECC setting \u20133, 5. InFirst, most HECC scenarios  also exist in companion animals, with similar pathophysiologic mechanisms. The similarity is especially remarkable in pediatric patients, which are less afflicted by lifestyle choices like smoking and alcoholism  and complications of chronic diseases . Dogs and cats, having shorter life spans, rarely manifest such complications.Second, companion animals have complex genetic, environmental, and physiological variation, which in many cases are similar or even shared with humans , 6.Third, current ECC management of critically ill dogs and cats is similar to humans. Veterinarians have access to advanced diagnostics including molecular testing and advanced imaging. In VECC, capnography, invasive hemodynamic, and ICP monitoring are performed, and sidestream dark-field imaging and tissue oxygen saturation have been used clinically. Advanced therapeutic modalities in VECC include ventilation, interventional radiology, advanced hemodynamic support, transfusion therapy, continuous renal replacement therapy, and cardiac bypass, among others.Fourth, current challenges faced by VECC are similar to those in HECC: specific markers of sepsis, synthetic colloids in septic patients, identifying volume-responsive patients, mechanical ventilation strategies, antibiotic selection and treatment duration, and transfusion strategies in trauma, just to name a few.Improving the knowledge of critical disease pathophysiology. This has been reported for spinal cord injury [d injury , epilepsd injury , cardiomd injury , asthma d injury , and cand injury , 12. In d injury , have did injury , 12.Bridging preclinical data and human clinical trials, to evaluate safety and efficacy of new treatments. This is one of the strongest arguments to support HECC and VECC collaboration. An example was the canine trial of ibrutinib in naturally occurring B cell malignancy that accelerated its FDA approval for human mantle cell lymphoma [lymphoma .Providing new therapeutic alternatives. Cyclosporine-based ophthalmic emulsion for the treatment of keratoconjunctivitis sicca was first reported by a veterinary ophthalmologist [mologist .Therefore, we believe cooperation between HECC and VECC can provide a bidirectional, synergistic pathway, with benefits for both by the following:Limitations for translating VECC-generated data to HECC do exist. Genetic, anatomical, and physiological differences between species remain a limitation of companion animal models. For example, the highly contractile nature of the canine spleen, which can store and auto-transfuse a larger blood volume than the human spleen, plays a greater role in the response to hemorrhage than humans . In addiBoard-certified specialization in VECC exists through the American and European Colleges of Veterinary Emergency and Critical Care (ACVECC and ECVECC). Residency programs are available in many parts of the world, and international collaborations are becoming a commonplace. Consensus guidelines regarding several subjects are now available   or in deInterestingly, the collaboration between HECC and VECC has already begun. During the 2010 Multi-Disciplinary Review/Post-Graduate Review in San Diego, human trauma surgeons, VECC specialists, and translational medicine scientists discussed the use of naturally occurring canine trauma as a model to human trauma . This led the ACVECC Veterinary Committee on Trauma to create a clinical research infrastructure to enhance uniform delivery of care and permit large-scale clinical trials in canine and feline trauma patients .In conclusion, we believe the use of companion animals to model human ECC can complement current available preclinical animal models, with benefits to all species. To achieve this, VECC and HECC should increase and promote the collaboration which already exists. We just have to say yes and seize the opportunity."}
+{"text": "The authors wish to make the corrections to this paper [1]. The surnames and names of all authors were switched in the original paper; the following being the right sequence: Francesca Luisa Sciacca, Ambra Rizzo, Gloria Bedini, Fioravante Capone, Vincenzo Di Lazzaro, Sara Nava, Francesco Acerbi, Davide Rossi Sebastiano, Simona Binelli, Giuseppe Farag\u00f2, Andrea Gioppo, Marina Grisoli, Maria Grazia Bruzzone, Paolo Ferroli, Chiara Pantaleoni, Luigi Caputi, Jesus Vela Gomez, Eugenio Agostino Parati and Anna Bersano.The authors would like to apologize for any inconvenience caused to the readers by these changes."}
+{"text": "Gout, a common rheumatic disease in older adults, disproportionately affects Pacific Islander and Black populations, relative to Whites; however, the ethnic-specific incidence and determinants remain severely understudied within these groups. We examined gout incidence and the effects of behavioral factors, including diet, physical activity, and smoking, on incident gout within a large multiethnic population of older adults from the Multiethnic Cohort Study linked to approximately 20 years of Medicare gout claims. Using samples of Black , Native Hawaiian , Japanese , Latino , and White  participants, we conducted multiple Cox regressions, producing hazard ratios (HR) and 95% confidence intervals (CI). Native Hawaiians had the highest incidence of gout , followed successively by Black, Japanese, White, and Latino participants. 3+ alcoholic drinks/day was associated with an increased risk, especially among Blacks . Current smoking was associated with increased risk among Blacks  and Japanese . Better dietary quality tertiles were associated with a decreased gout risk for most ethnic groups, with the largest effect observed among Whites , while vitamin C was weakly associated with a decreased risk of gout only among Native Hawaiians  and Japanese . Overall, notable ethnic differences were observed in both gout incidence and effects of modifiable behaviors. As the first study to examine the incidence and longitudinal determinants of gout utilizing several large samples of underrepresented ethnic groups, our findings offer crucial insights that may improve precision in preventing and treating gout."}
+{"text": "Aedes mosquitos in tropical and subtropical regions across theworld. After decades of sporadic outbreaks, it re-emerged in Africa, Asia, IndiaOcean and America suddenly, causing major regional epidemics recently and becoming anotable global health problem. Infection by CHIKV results in a spectrum of clinicaldiseases including an acute self-limiting febrile illness in most individuals, achronic phase of recurrent join pain in a proportion of patients, and long-termarthralgia for months to years for the unfortunate few. No specific anti-viral drugsor licensed vaccines for CHIKV are available so far. A better understanding ofvirus-host interactions is essential for the development of therapeutics andvaccines. To this end, we reviewed the existing knowledge on CHIKV\u2019s epidemiology,clinical presentation, molecular virology, diagnostic approaches, host immuneresponse, vaccine development, and available animal models. Such a comprehensiveoverview, we believe, will shed lights on the promises and challenges in CHIKVvaccine development.Chikungunya virus (CHIKV) is an arbovirus transmitted by"}
+{"text": "Developed in 2012, our gerontology program has tracked enrollment, learning outcomes, student competency development, and career paths post-graduation. Enrolled students tend to be older, transferring from community colleges, reentering college due to work and family commitments, and retooling career paths. Our efforts have focused on career integration across all courses culminating in a two-term practicum program. Additionally, through discussions with community college faculty and students, alumni, and community partners, we have adapted our curriculum to address student needs for work, family care, and academic engagement through flexible course delivery, syllabus construction, applied project development, and direct contact with professionals in and outside the classroom. Developing strategies to ensure transfer student success is critical, as well as offering strong career preparation for older students entering the workforce. Comprehensive placement data and an overview of the needs and challenges for university programs to partner with community college programs will be highlighted."}
+{"text": "Population genetic data underpin many studies of behavioral, ecological, and evolutionary processes in wild populations and contribute to effective conservation management. However, collecting genetic samples can be challenging when working with endangered, invasive, or cryptic species. Environmental DNA (eDNA) offers a way to sample genetic material non-invasively without requiring visual observation. While eDNA has been trialed extensively as a biodiversity and biosecurity monitoring tool with a strong taxonomic focus, it has yet to be fully explored as a means for obtaining population genetic information. Here, we review current research that employs eDNA approaches for the study of populations. We outline challenges facing eDNA-based population genetic methodologies, and suggest avenues of research for future developments. We advocate that with further optimizations, this emergent field holds great potential as part of the population genetics toolkit. The study of population genetics describes changes in the genetic diversity of populations through evolutionary mechanisms such as natural selection, genetic drift, mutation, and gene flow, the totality of which have evolutionary consequences and can lead to speciation e.g., ,3,4,5,6),4,5,63,4Hypophthalmichthys molitrix) [Population genetic research requires genetic sampling from organisms of interest. For example, blood and tissue samples have traditionally been sources of genetic material for large marine mammals, e.g., flipper clips from seal populations . Howeverolitrix) . Many stolitrix) ,24,25. Molitrix) . In mariolitrix) ,29,30,31olitrix) ,37,38,39complex mixture of genomic DNA from many different organisms found in an environmental sample.\u201d However, we take a narrower view of environmental sample; defining eDNA as DNA taken from soil, water, or air, excluding samples from direct individual remains such as fecal matter, hair, or feeding traces [Here we adopt the definition of eDNA from Taberlet et al.  definingg traces ,37,41. Dg traces ,43. Fromg traces ,36,37, eg traces , densityg traces , diet [4g traces , and sexg traces ,47. Addig traces ,49, geneg traces ,51, evolg traces  and matig traces  have beeg traces . With eDg traces .Environmental DNA is already being used to improve biodiversity estimates , when a complete snapshot of biodiversity is difficult to obtain via traditional methods  ,55,56,57Triturus cristatus) in freshwater habitat [Pongo pygmaeus) and Sunda pangolin (Manis javanica), may leave eDNA traces in locations such as salt licks [Some of the species in eDNA population genetic studies are of conservation and management interest and can be difficult to sample ,69,71. S habitat ,77,78. Tlt licks . Given tlt licks .Lithobates catsebeianus) and Asian carp , among many others, have already been successfully detected with eDNA methods [Not only can eDNA be useful for managing imperiled species, but invasive species may also be suitable targets. For instance, freshwater invasive species such as bullfrogs , to assess shark population structure, and their trophic interactions [Euthynnus affinis) over two years, likely reflective of food web interactions [The use of eDNA in population genetics is in its infancy, but a handful of notable studies demonstrate the potential of eDNA to obtain within-species population genetic data. A recent landmark study used eDNA from seawater to examine the mtDNA haplotype variation of whale sharks (ractions . This woractions . In addiractions . This reOrcinus orca) explored whether eDNA-obtained haplotypes could be assigned to known haplotypic variation, and how long genetic material can be detected after known target animal presence [More recently, seawater eDNA work on Northeast Pacific killer whales  mtDNA control region haplotypes have been detected via seawater eDNA [Beyond assignment to known haplotypes, eDNA has been used to uncover previously unknown intraspecific genetic diversity. For example, previously unknown harbor porpoise  genus from seawater samples, also using strict sequence read filtering [Separately, 16S rDNA eDNA metabarcoding primers described multiple intraspecific haplotypes from the iltering . Both stiltering ,72. Thesiltering ,72. Impoiltering .Pandarus rhincodonicus) parasite [adegenet for R, or Bayesian Analysis of Population Structure (BAPS) [Despite recent success and future potential, eDNA population genetic methods require fine tuning before they can be widely applied. Perhaps one of the biggest obstacles in transitioning from species detection to population genetics using eDNA is assigning sequences to individuals. Previous non-invasive genetic techniques for terrestrial organisms have been able to assume different individuals from separate scats ,48 or feparasite . Howevere (BAPS) ,93) as pEven when sequences are obtained in sufficient quantities and can be assigned to individuals, many non-invasive genetic sampling techniques, including eDNA, suffer from amplification challenges. Allelic dropout , and false alleles , are notable examples ,49,94. PSome techniques for mitigating quantity challenges for eDNA samples, such as PCR, are not without biases which may impact allelic abundance ,100,101.Furthermore, the number of reads from eDNA-obtained genetic data for target species must be sufficient enough to be distinguishable from background noise to ensure confidence that true genetic variation has been obtained. If initial DNA copy numbers are insufficient , PCcytochrome oxidase I) in mtDNA are widely available in public databases for many metazoans [numts) occur in eukaryotes and can influence population genetic inferences [Numts are difficult to recognize and have been shown to inflate diversity estimates when used with barcoding techniques [Increasing the length of sequences and diversity of marker types that can be obtained from eDNA would also be advantageous for answering population genetic questions. Thus far, eDNA research has focused primarily on short (100\u2013400 bp) mtDNA fragments. Additionally, commonly barcoded regions  for multiple individuals, not only for comparison of populations across space and year-to-year variation, but also to infer evolutionary histories with coalescence models . AdditioFor all eDNA population genetic studies, a robust sampling design will help minimize LCN DNA profiles. Choosing the correct substrate for sampling a target organism based on ecological knowledge, such as the position in the water column with the highest concentration of DNA of the target organism, will maximize potential copy number . On thisSeveral technologies that could help address the difficulty of assigning genetic information from eDNA samples to individuals, are already available or in development. One way forward might include single-cell sequencing . As eDNAGood sampling design, in tandem with technological developments, could also help mitigate issues around obtaining allelic ratios and abundance ,163. IncAnother challenge for population genetic eDNA methods will be to fully develop nuDNA markers for the species of interest using eDNA sampling techniques. Capture methodology, where bait molecules bind to target DNA of interest, is currently being explored for eDNA with some success ,167. ThiST, based on an analysis-of-variance framework, have been made using this technique to infer population structure using nuclear markers [Once environmental nuDNA has been captured, statistical programs can be developed specifically to analyze environmental genetic data. It may be possible to use rarefaction methods to estimate how well genetic diversity has been sampled in a location, as has been used in eDNA metabarcoding studies to estimate taxa obtained . Additio markers . However markers , and bec markers . This te markers ,170,172. markers ,174. Ori markers ,174. Thi markers . Potenti markers . This ha markers ,175,176. markers ,68,69. IThese exciting technological advances paired with environmental genetics techniques offer promising new ways to address broad evolutionary genetics questions without direct sampling. Amazing progress is occurring all the time in the use of environmentally derived genetic material. For example, despite the much more rapid degradation of RNA in the environment, even environmental RNA (eRNA) samples are now being used to provide a snapshot of the biological diversity and processes present at the community level  177,178178,179. The need for non-invasive sampling, especially for low-density and cryptic populations, will continue to drive technological development. Environmental DNA population genetic methods have the potential to fill this need if developed and tested rigorously. Limited conservation funding and a need to minimize stress to wild animals, coupled with increasing molecular expertise, declining taxonomic expertise, and declining sequencing cost make eDNA an attractive genetic sampling tool ,198,199."}
+{"text": "Loneliness and social isolation are major risk factors for poor physical and mental health among older adults. Studies demonstrate that loneliness is associated with depression, impaired cognitive performance, increased chronic disease, and mortality. However, the impact on other psychosocial constructs and healthcare outcomes remain understudied. The purpose of this study was to estimate the prevalence of loneliness and examine associations with socio-demographic, medical, and psychosocial characteristics in a large national survey of older adults . Overall, 43% of participants reported either moderate or severe loneliness. Older age, female gender, income, depression, hearing difficulty, and poorer health were all associated with loneliness. Purpose of life, resilience, optimism, and a diverse social network were associated with low loneliness. On average, lonely participants had a higher rate of emergency department visits, inpatient admissions, and medical costs. Based on findings, interventions should aim to alleviate loneliness among older adults."}
+{"text": "OBJECTIVES/SPECIFIC AIMS: To analyze how consumer physical activity monitors are currently used in biomedical research. METHODS/STUDY POPULATION: Searches were conducted in Ovid Medline, PubMed Medline, clinicaltrials.gov, and NIH RePORTER using search terms including Fitbit, Jawbone, Apple watch, Garmin, Polar, Microsoft band, Misfit, Nike, Withings, and Xiaomi. Results were quantitated by category: condition/topic, intervention, enrollment status, study type and design, age, grant mechanism, and primary outcome. RESULTS/ANTICIPATED RESULTS: Fitbit is used >80%. There are 127 clinical studies using Fitbit devices listed in clinicaltrials.gov. In total, 48 have been completed while 79 are ongoing. Some studies have already published their findings; 40 papers cited in Ovid MEDLINE report use of a Fitbit device. NIH is now funding research that uses consumer physical activity monitors, and the NIH RePORTER shows the number of grants using Fitbit is rapidly increasing. DISCUSSION/SIGNIFICANCE OF IMPACT: The current state and potential growth of this technology is transforming biomedical research and is enabling us to ask new and more granular questions about activity and sleep in health and disease."}
+{"text": "Rape stereotypes involve the assault of young women due to sexual desire, resulting in the exclusion of older adults from sexual violence research, policies, and interventions, suggesting a need to further knowledge in this area . Debates also persist on the prevalence and nature of elder sexual abuse (ESA), where it occurs, and its most common perpetrators . Thus a systematic scoping review was conducted to explore the nature and prevalence of ESA as well as mandated prevention and intervention strategies to guide practice, policy, research and education on prevention. Eligible sources were research-based and focused on the nature of ESA along with legal prevention and/or intervention mandates. In total, 38 peer-reviewed articles and reports were screened in for review, obtained from AgeLine, EBSCO, Clinical Key Flex, PubMed, Google, and Google Scholar databases. Findings suggest while consensus has not been reached , ESA estimates range from 0.2% to 7% of U.S. elder abuse cases, yet actual rates are likely much higher due to underreporting . Additionally, results suggest ESA most often occurs in nursing homes, predominantly perpetrated by staff or residents . Still, ESA remains underreported despite several mandated approaches to prevention and intervention . Thus findings demonstrate a need for reliable estimates of prevalence, location as well as common victim-perpetrator relations and awareness of required steps toward prevention and intervention . Beyond this, transdisciplinary efforts are needed to yield effective training, education, and culturally appropriate resources."}
+{"text": "Bisphenols are widely used in the synthesis of polycarbonate plastics, epoxy resins, and thermal paper, which are used in manufacturing items of daily use. Packaged foods and drinks are the main sources of exposure to bisphenols. These chemicals affect humans and animals by disrupting the estrogen, androgen, progesterone, thyroid, and aryl hydrocarbon receptor functions. Bisphenols exert numerous harmful effects because of their interaction with receptors, reactive oxygen species (ROS) formation, lipid peroxidation, mitochondrial dysfunction, and cell signal alterations. Both cohort and case-control studies have determined an association between bisphenol exposure and increased risk of cardiovascular diseases, neurological disorders, reproductive abnormalities, obesity, and diabetes. Prenatal exposure to bisphenols results in developmental disorders in animals. These chemicals also affect the immune cells and play a significant role in initiating the inflammatory response. Exposure to bisphenols exhibit age, gender, and dose-dependent effects. Even at low concentrations, bisphenols exert toxicity, and hence deserve a critical assessment of their uses. Since bisphenols have a global influence on human health, the need to discover the underlying pathways involved in all disease conditions is essential. Furthermore, it is important to promote the use of alternatives for bisphenols, thereby restricting their uses. Bisphenols (Bisphenol A (BPA), Bisphenol B (BPB), Bisphenol C (BPC), Bisphenol S (BPS), Bisphenol F (BPF) and Bisphenol AF (BPAF)) are phenolic organic compounds . These cBisphenols exert toxic effects due to their potential to induce oxidative stress, mitochondrial dysfunction, impaired inflammatory function, and endocrine disruption activity. Bisphenol exposure leads to mitochondrial dysfunction, deregulation of cellular signaling pathways, and generation of reactive oxygen species (ROS) subsequent to decreased antioxidant enzymes ,18,19,20Bisphenols bind to androgen, estrogen, progesterone, thyroid, and aryl hydrocarbon receptors, which are, in turn, associated with endocrine and other systems of the body, especially the reproductive, respiratory, and nervous systems ,33,34,35Bisphenol toxicity studies have revealed that these chemicals disrupt the endocrine functions and cause reproductive toxicity ,44,45,46In a prospective study of 1841 pregnant women, Zhang et al. found that BPAF and BPS are potential risk factors for gestational diabetes mellitus (GDM). The authors observed the endocrine-disrupting effects of BPAF and BPS on blood glucose metabolism among Chinese pregnant women. Moreover, multivariable logistic regression analysis revealed an association of urinary BPAF with the risk of GDM . In a crNumerous studies in animal models have reported the deleterious effects of exposure to bisphenols. Tian et al. found that male CD-1 mice exposed to BPA had decreased testis weight, damage to basal lamina of seminiferous tubules and tight junctions between Sertoli cells, and decreased levels of the androgen-binding protein . BPA exp\u22129 M) affects the thyroid follicular cells through an altered expression of the thyroid-specific gene and transcriptional factors [\u22129 M) treatment of CV-1 cells derived from Cercopithecus aethiopis monkey kidney suppresses the thyroid hormone receptor transcription [Antiandrogenic and estrogenic activities of BPF and BPAF are similar to BPA ,67,68,69 factors . Sheng ecription . Neuregucription . BPA  reported that serum BPA levels are positively associated with adiponectin and leptin, and inversely associated with the gut-hormone ghrelin. BPA is also shown to interfere with the hormonal control of hunger and satiety [A prospective study from a Swedish population  development in non-obese diabetic mice . Zhao etn = 1016 subjects; age = 70 years), Olsen et al. found positive associations between the serum concentration of BPA and LDL cholesterol levels [Several studies have established the role of bisphenol in cardiovascular diseases, including myocardial infarction, cardiomyopathy, and hypertensive heart disease ,108,109.l levels   differentially influences metabolic disorders and oxidative stress in the liver of male mouse offspring. BPF exposure affected the liver antioxidant defense system, whereas BPAF altered the level of \u03b2-glucose and glycogen . Oral dorus fish .\u22124\u201310\u221212 M) of BPA showed mitochondrial dysfunction by inducing ROS generation, lipid peroxidation, mitochondrial transmembrane hyperpolarization, and release of interleukin-8 and tumor necrosis factor-\u03b1 secretion [Human HepG2 hepatoma cells exposed to low concentrations  are toxic to brain development in both prenatal and childhood stage ,124,125.Auts2, Foxp2, and Smarcc2) more significantly in the male hippocampus than in females [Prenatal BPA exposure of Wistar rats causes changes in the hippocampal expressions of genes associated with ASD in a sex-specific manner. BPA disrupts the expression of ASD candidate genes  [BPS exposure at concentrations of 0.3 and 3.0 mg/L on zebrafish embryos showed decreased locomotor activity, increased oxidative stress, apoptosis, and altered retinal structure. Moreover, the researchers also found that 3.0 mg/L BPS exposure suppresses the expression of six neuro development-specific genes (nd gfap) . Kinch end gfap) . A similnd gfap)   ,138,139.Escherichia coli [Carussius auratus exposed to BPA results in immunotoxicity, and such fish are prone to infectious diseases [BPA exposure decreases neutrophilic activity and inhibits interleukin-6 formation in mice infected with non-pathogenic hia coli . Roy et hia coli . T-lymphhia coli , whereashia coli . BPA (1 hia coli . Mice trhia coli  and moduhia coli . BPF andhia coli . Carussidiseases  (Table 3Bisphenols are widely used as a raw material in the synthesis of polycarbonates, epoxy resins, and thermal paper. These chemicals are used in the manufacturing of numerous products including plastics, water pipes, toys, medical equipment, electronics, food cans, and numerous household applications. These chemicals are leached from the products and are ubiquitous in the environment. Foods and drinks are the most important sources of exposure. Results of both animal and human studies have revealed the toxic effects of bisphenols. Increased levels of bisphenols are found in human body fluids including in urine, serum, placental tissue, umbilical cord blood, and breast milk ,97,124. Humans and animals are exposed to bisphenols from the prenatal stage to the last day of survival. Bisphenols are present in products used daily, and we are always in contact with these chemicals, either indirectly or directly. Prenatal and childhood bisphenol exposure affects the developmental process and leads to neurological, reproductive, immunological, and endocrine disruption. Even low doses of bisphenols are toxic, and chronic exposure affects almost every body part. Bisphenols induce oxidative stress, inflammation, apoptosis, and impairs the metabolic process. Nowadays, almost every product contains bisphenol and we are unwillingly exposed to it. Foods and drinks stored in plastic containers get easily contaminated with bisphenols, and consumption of such foods results in gradual accumulation of bisphenols in our body. This accumulation eventually leads to toxicity of major body organs including the liver, brain, and kidney, ultimately disrupting the neurological, immunological, reproductive, and endocrine functions. We need to have alternatives of bisphenols and try to minimize their uses because of their continuous exposure and impending toxicity. We have to work on processes/methods which can remove/filter out bisphenols from our body. Furthermore, a shift in focus towards natural plant products for packaging, storing, and other day-to-day activities is required. Soil made products can be promoted for storage of foods and drinks. The use of plastic bags needs to be restricted for shopping and extra packaging, and we need to promote the use of eco-friendly bags made of natural plant products.Bisphenols have a wide range of toxicity profiles. However, we limited our discussion to the major organ systems. We did not discuss their role in cancer, respiratory system, renal, and developmental toxicity."}
+{"text": "Despite tremendous advancements in high throughput sequencing, the vast majority of tree genomes, and in particular, forest trees, remain elusive. Although primary databases store genetic resources for just over 2,000 forest tree species, these are largely focused on sequence storage, basic genome assemblies, and functional assignment through existing pipelines. The tree databases reviewed here serve as secondary repositories for community data. They vary in their focal species, the data they curate, and the analytics provided, but they are united in moving toward a goal of centralizing both data access and analysis. They provide frameworks to view and update annotations for complex genomes, interrogate systems level expression profiles, curate data for comparative genomics, and perform real-time analysis with genotype and phenotype data. The organism databases of today are no longer simply catalogs or containers of genetic information. These repositories represent integrated cyberinfrastructure that support cross-site queries and analysis in web-based environments. These resources are striving to integrate across diverse experimental designs, sequence types, and related measures through ontologies, community standards, and web services. Efficient, simple, and robust platforms that enhance the data generated by the research community, contribute to improving forest health and productivity. Starting in the Sanger sequencing era, significant investments were made to catalog genetic resources in primary repositories . EMBL t. The vasArabidopsis thaliana Database), developed in 1991 to support the first model plant system, has since evolved into the widely accessed, Arabidopsis Information Resource (TAIR)  or clade organism databases (CODs) emerged. These databases sought to provide unique resources for the research communities they serve, through layered curation and specialized integration. The AAtDB (An e (TAIR) . Around e (TAIR) , GrainGee (TAIR) , MaizeGDe (TAIR) , SoyBasee (TAIR) , and thee (TAIR) . Some ofe (TAIR) . The vasForest trees are unique among species represented in crop databases. The vast majority are long-lived, outcrossing, with extensive natural distributions represented by large, diverse and locally adapted populations . They reIn the era of high throughput technologies that assess genotype, phenotype, and environmental metrics much faster than we can conceive, the need for well structured, efficient, and well-connected databases is apparent. In a recent survey of over 700 investigators in the biological sciences, access to analytical frameworks, long-term storage, and the ability to integrate data across disparate sources, were of primary concern . The lon1, previously known as Dendrome, was initially constructed to provide access to genetic data for forest trees in a relational framework. Early development included curation of molecular markers, genetic maps, Expressed Sequence Tags (ESTs), and species range maps. TreeGenes remained in a custom database schema and website, adopting components of the Generic Model Organism (GMOD) framework for housing genetic maps (cMAP) and genome assemblies (JBrowse) (TreeGenesJBrowse) . Later dJBrowse) .TreeGenes currently represents just over 1700 species from 16 orders and 124 genera . TreeGenTreeGenes is running on Tripal v3 which integrates a content management system known as Drupal with the Genetic Model Organism Database\u2019s (GMOD) relational schema, known as Chado. This conversation in 2017, aligned TreeGenes for the first time with over 30, primarily plant, databases . Recent Following conversion, TreeGenes released a set of Tripal modules that can be utilized by researchers visiting the site or installed and customized for any Tripal supported databases. Tripal Sequence Similarity Search (TSeq) provides access to genomes, transcriptomes, and curated TreeGenes unigenes through traditional NCBI BLAST or optimized Diamond protein searches . The TriCurrent development in TreeGenes focuses on CartograTree, which enables integration of genotype, phenotype and environmental data for georeferenced forest trees . This moThe Hardwood Genomics Project (HWG) provides access to genomic resources generated from angiosperm trees, including forest and urban trees of ecological and agricultural significance. The resource originated from the Fagaceae Genomics Web, built in 2007, to house transcriptomes, genomes and genetic maps. As new collaborators joined the effort and the scope of species extended beyond Fagaceae, the site was rebuilt in 2011 as the HWG. HWG\u2019s mission is to host reference genomes and transcriptomes that are either not accessible elsewhere, or only available as raw files without an associated and searchable, functional annotation. In addition, HWG accepts molecular markers, genetic maps, germplasm and population descriptions, and community project descriptions. Current resources support species associated with pest or pathogen threats, including green ash, European ash, American chestnut, American beech, black walnut, and redbay, as well as trees with significant economic value, including white oak, black cherry, sugar maple, and tulip poplar.For species with an available reference genome, HWG provides a workspace for accessing the annotation. This provides value to these sequence resources by performing and hosting functional annotation, including: identification of Open Reading Frames (ORFs) from transcripts, BLAST annotations derived from the Uniprot Swiss-Prot/TrEMBL plant protein databases, InterProScan domain searches , Gene OnHardwood Genomics Project is currently running Tripal v3, and like TreeGenes, is responsible for the development of custom modules that can be installed on other Tripal-enabled sites. RNASeq data is poorly integrated in plant community databases despite the widespread use of expression studies to examine responses to biotic and abiotic stressors in plant systems. To address this limitation, HWG launched a framework devoted to the integration and analysis of gene expression experiments. BioSamples imported from GenBank, with the metadata describing the tissues, treatments, experimental design, and informatic methods, can be explored and compared. Each transcript, examined as part of an RNASeq experiment, has expression values that can be interrogated through interactive visualizations or downloaded for further analysis. The expression data displays can be customized interactively, grouping BioSamples by their tagged metadata values. A tool for comparing gene expression is also available, allowing the user to provide their own gene list and generate a heat map comparing expression of those genes across the relevant BioSamples . Current2, The Genome Database for Rosaceae GDR2,  was initGDR contains 21 genome assemblies and annotations for 14 species. A total of 528,890 genes, reference transcriptomes for all major species, 14,411 germplasm records, 313 genetic maps, 3.3 M molecular markers, 402,559 phenotype measurements, 3,902 QTL/MTL for 392 agronomic traits, 10.8 M genotypes, and 7,449 publications are housed in the database. GDR provides access to breeding management and analysis tools, pathway analysis through PlantCyc and Pathway Inspector, flexible front-end querying, genome annotations through JBrowse, and sequence similarity search functionality , 2017. GArabidopsis electronic fluorescent pictograph (eFP) browser (Populus and Arabidopsis GenIE sites. With the release of the Norway spruce (Picea abies) genome  began as The Populus Integrative Genome Explorer  genome , the assArabidopsis. As such, gene expression resources for aspen  and the PlantGenIE resource is currently being updated in this platform. GenIE-CMS includes web services, enabling end users to access genomic information from external interfaces such as R and Python analysis scripts. Alongside this update, new and improved versions of gene expression visualization tools have been developed and made available as plugins to GenIE-CMS. The PlantGenIE update includes integration with the PLAZA resource (The GenIE sites were originally developed using the Drupal CMS with many of the tools from GMOD . More reresource , integraresource , and an Tree database cyberinfrastructure is supporting comparative genomics, population genetics, expression profiling, and genome annotation. These resources focus on a combination of model and non-model systems and integrate with established comparative resources to deliver value added information. Despite their importance, the sustainability of cyberinfrastructure and the related activities of curating and importing scientific data is always in question. The databases described here are leveraging larger open-source projects as their base framework and sharing web-based applications for common functionality, such as genome browsing and sequence similarity searching. For the forest tree community, the majority of the functionality described here has been deployed within the last 3 years and represents the first coordinated effort across these resources. Frameworks like Tripal and PlantGenIE focus on efficient deployment, web services for cross-talk, data visualization, and analytics to provide a robust environment for end users. As an example, the Elastic Search module developed by HWG allows one to search a gene, genome, marker, and other indexed objects in one database and locate results in other Tripal databases without executing independent searches on each website. Sharing development across a larger community allows forest tree databases to focus on the specific needs of their users. Their independent value exists in the additional curation, metadata acquisition, indexing, analytics, and visualization that is not delivered from the primary repositories. TreeGenes and Hardwood Genomics Web, are focused on expression data integration for non-model trees and metadata retrieval and cross-study analytics for population genetics studies. GDR is focused on improving access and visualization of genetic maps as well as breeding tools. The PlantGenIE framework is providing a robust platform for species with a reference genome, and advanced visualization for expression data that integrates across studies. All of these databases are also seeking stronger connections to more broadly plant focused repositories, such as Phytozome, PLAZA, and Planteome, that provide genetic and ontological resources that improve the utility of cross-site querying.While tremendous advancements have been made through recent and focused development on these pivotal frameworks, several challenges remain for the forest tree community. As datasets become larger and more integrative, it is increasingly difficult for small database teams to keep up with the data capture and curation. With increasing access to reference genomes, large-scale population studies, and high throughput environmental data, biological databases must develop more efficient metadata capture, storage, and query capacity. These repositories will be tasked with implementing advanced natural language processing, automated metadata capture, and ontological term assignment to span not only genetic data, but associated phenotypic and environmental data. These latter categories encompass an expansive range, from traditional growth traits to canopy metrics, soil profiles, microbiomes, and metatranscriptomics. The biomedical community has paved the way for some of this technology but forest tree data, and the associated genetic resources, remain more heterogenous . This heJW, MS, NS, DM, and SF designed the databases and software described. EG, NH, SB, TF, SZ, RR, PR, and LS developed the core TreeGenes and TreeGenes Tripal modules. MS, BC, AA, and MC developed the core HWG and HWG Tripal modules. NS and CM developed the core PlantGenIE. SJ developed the core GDR and GDR Tripal modules. SF developed the core Tripal. JW, MS, NS, and DM wrote the manuscript. All authors read and approved the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Preventing Chronic Disease (PCD) recognizes that public health and clinical interventions are often collaborative, multifaceted, multicomponent, and multisite with diverse participants, stakeholders, and partnerships . As suchwww.cdc.gov/pcd/for_authors/types_of_articles.htm). Implementation Evaluation articles provide insights into factors that affect the ability of public health practice to successfully package and disseminate effective interventions implemented and evaluated in real-world settings. PCD\u2019s interest in this area extends to research that examines which factors positively or negatively impact the diffusion of proven interventions and the degree of integrity needed to generate success. Specific program elements such as \u201cadherence to intervention, exposure, or dose, quality of delivery, participant responsiveness and program differentiation\u201d are all factors associated with implementation fidelity  with information on how to refine evaluation methods, make health system improvements, strengthen collaborations and partnerships, build organizational infrastructure, measure return on investments, and enhance data collection approaches , harmful effects, or wasteful use of fiscal or human resources . PCD enc"}
+{"text": "Polymeric Nanomaterials in Nanotherapeutics\u201d (2018) edited by prof. Dr. Cornelia Vasile, the authors show how polymeric nanomaterials are used in new emerging fields of medicine, namely nanomedicine and nanotherapeutics. The book content covers the whole field of nanomedicine, from definition to applications and recent trends. The readers will discover, from the book\u2019s various chapters, how polymeric nanomaterials are used to obtain nanosensors and nanorobots as the biomedical instrumentation, surgery, diagnosis and controlled/targeted drug delivery for cancer therapy, improved pharmacokinetics, monitoring of diabetes and other healthcare problems. The polymeric nanomaterials described in this book are classified by several criteria such as their origin , structure, morphology, form and applications, e.g., polymeric nanoparticles, micelles, nanogels, nanoemulsions, dendrimers, polymers as drugs, polymer-drug conjugates, polyplexes, multifunctional nanoparticles, polymersomes, stimuli-responsive nanomaterials, etc. Moreover, the advancements in nanotherapeutics are described, which are related to development of new drug formulations based on nanomaterials and elaborating various routes of administration for controlled and targeted delivery and release of active agents to non-healthy tissues and cells. Topics worthy of particular discussion are: Responsive polymeric nanotherapeutics, Nanomaterials derived from phosphorus-containing polymers: diversity of structures and applications, Nucleic acids based bionanomaterials for drugs and gene therapy, Electrospun polymeric nanostructures with applications in nanomedicine, nanocoatings: preparation, properties, and biomedical applications, Functionalization of polymer materials for medical applications using chitosan nanolayers, Biological applications of nanoparticles in optical microscopy, Regulatory status of therapeutic polymeric nanomaterials. In the book \u201cThe book is structured in 15 chapters that are co-authored by various specialists in the field of polymeric nanomaterials and pharmacy from which I can mention prof. dr. Lidija Fras Zemljic , dr. Anca Margineanu , dr. Neli Koseva , prof. dr. Onur Yilmaz , prof. dr. Mihaela C. Baican and prof. dr. Lenuta Profire , dr. Aurica P. Chiriac . Going through the chapters of the book, the reader will learn about the ways of administering nanotherapeutics  and how these nanotherapies are applied to dental work, wound healing, cancer, cardiovascular diseases, neurodegenerative disorders, infectious diseases, chronic inflammatory diseases, metabolic diseases, and so on. Moreover, there are presented various development stages of new drugs containing polymeric nanomaterials as carriers  and if they are approved by U.S. Food and Drug Administration (FDA) or European Medicines Agency (EMA). In all chapters the aspects related to the risk assessment for the presented nanotherapeutics, by toxicity evaluation and regulatory status, are highlighted.The book is distinguished by the following specific features: it presents how polymeric nanomaterials are used to develop and create efficient therapies/medical treatments; the manner in which these polymers are applied in different biomedical areas , focusing on highlighting the advantages of nanotherapeutics. The book has been written in a manner accessible for scholars, researchers, postgraduate students and specialists in the fields of nanomaterials, polymeric bionanomaterials, biotechnology, and in biomedicine."}
+{"text": "Hydroxychloroquine is a medication used to treat rheumatoid arthritis, systemic lupus erythematosus, and other autoimmune disorders. Previous studies have shown that hydroxychloroquine and the structurally related drug chloroquine have the potential to interfere with some common urine chemistry tests, especially at high concentrations. In the related research article, we observed suspected interference with urine drug of abuse testing in a patient who ingested approximately 12\u00a0g of hydroxychloroquine in an acute overdose, with urine hydroxychloroquine concentrations exceeding 500 mg/L. This case prompted a more detailed investigation of the effects of hydroxychloroquine spiked into pooled de-identified urine specimens from a hospital clinical laboratory. The data in this article provides the raw data for 24 urine assays that were investigated. The analyzed data is provided in the tables included in this article. The dataset reported is related to the research article entitled \u201cDiagnostic Pitfalls and Laboratory Test Interference After Hydroxychloroquine Intoxication: A Case Report\u201d [ This followed from observation that a patient with a large overdose of hydroxychloroquine showed suspected interference for some urine laboratory tests obtained for clinical care ,3 and wiThe 24 specific urine assays analyzed are as follows: amphetamines drug screen, amylase, benzodiazepines drug screen, buprenorphine drug screen, calcium, chloride, cocaine metabolite screen, cotinine screen, creatinine, glucose, human chorionic gonadotropin (hCG), magnesium, microalbumin, myoglobin, NGAL, opiates drug screen, oxycodone drug screen, pH, phosphorus, potassium, protein, sodium, tetrahydrocannabinol (THC) drugs screen, and urea nitrogen. Technical details on these 24 urine assays are available elsewhere . The ass2All analyses were performed on Roche Diagnostics cobas 8000 analyzers . The complete list of assays with vendor name, methodology, and assay version are summarized elsewhere  and pyro"}
+{"text": "GBD 2015 Risk Factors Collaborators. Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990\u20132015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 388: 1659\u20137242016; \u2014In this Article, Simon I Hay, Sudha P Jayaraman, Alejandra G Contreras Manzano, Anoushka Millear, Laura Kemmer, Brent Bell, Juan Jesus Carrero, Gavin Shaddick, Lidia Sanchez-Riera, and Giorgia Giussani should have been listed as authors. The affiliation details for Monica Cortinovis have been updated. The funding statement for Simon I Hay has been added. These corrections have been made to the online version as of Jan 5, 2017."}
+{"text": "This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript."}
+{"text": "Following publication of the article, author Elisabetta Ferretti asked for the following institution to be added to her affiliation: Correction to:Cell Death Discovery (2018) 4, 3 10.1038/s41420-017-0002-9 published online January 29, 2018.Following publication of the article, author Elisabetta Ferretti asked for the following institution to be added to her affiliation:Istituto di Ricovero e Cura a Carattere Scientifico Neuromed, Pozzilli, 86077 Isernia, ItalySo the final and correct affiliation for Elisabetta Ferretti is:Department of Experimental Medicine, Sapienza University, 00161 Rome, ItalyIstituto di Ricovero e Cura a Carattere Scientifico Neuromed, Pozzilli, 86077 Isernia, ItalyThe PDF and HTML versions of the paper have been modified accordingly."}
+{"text": "Origin and evolution of transporter substrate specificity within the NPF family. Published 3, March 2017In our revision, we constructed large multiple sequence alignments and built 3D-homology models to put identified transporter substrate specificities into structural contexts. David Ramirez (DR), Heidi Asschenfeldt Ernst (HAE) and Prof Osman Mirza (OM) performed this work. DR was physically located together with the corresponding authors and he made figures Figure 8, Figure 8\u2013figure supplement 1 and Table 1 in collaboration with and based on data generated by HAE, OM, and DR. HAE and OM are physically located in another campus of UCPH. Due to a collective oversight and despite all authors having revised the manuscript, neither OM nor HAE were included in the author list in the revised and published manuscript. To correct this mistake, Osman Mirza and Heidi Asschenfeldt Ernst have now been added to the author list. All authors have agreed to this change and the article has been corrected accordingly to add to the author list the missing authors whose contributions were critical for the study. The contributions section has also been corrected to specify each author\u2019s contribution to the study.Original author list:Morten Egevang J\u00f8rgensen, Deyang Xu, Christoph Crocoll, David Ram\u00edrez, Mohammed Saddik Motawia, Carl Erik Olsen, Hussam Hassan Nour-Eldin, Barbara Ann HalkierCorrected author list:Morten Egevang J\u00f8rgensen, Deyang Xu, Christoph Crocoll, Heidi Asschenfeldt Ernst, David Ram\u00edrez, Mohammed Saddik Motawia, Carl Erik Olsen, Osman Mirza, Hussam Hassan Nour-Eldin, Barbara Ann HalkierOriginal author contributions:MEJ, Identified GTR3 as an indole-specific glucosinolate transporter, Designed the study, Performed the phylogenetic analyses, Biophysical characterization, Data analysis and contributed to generating the gtr1 gtr2 gtr3 triple mutant and micrografting, Wrote the paper based on a draft; DX, Generated the gtr1 gtr2 gtr3 triple mutant, Performed plant work including micro-grafting and glucosinolate analyses of transporter mutants and contributed to study design and preparation of the manuscript; CC, CEO, Performed LC-MS analyses; DR, Performed homology modelling; MSM, Synthesized prunasin; HHN-E, Performed and analysed nitrate uptake assays, Advised and contributed to the study design, Wrote the paper based on a draft, All authors discussed the results and commented on the manuscript; BAH, Advised and contributed to the study design, Wrote the paper based on a draft, All authors discussed the results and commented on the manuscript.Corrected author contributions:MEJ, Identified GTR3 as an indole-specific glucosinolate transporter, Designed the study, Performed the phylogenetic analyses, Biophysical characterization, Data analysis and contributed to generating the gtr1 gtr2 gtr3 triple mutant and micrografting, Wrote the paper based on a draft; DX, Generated the gtr1 gtr2 gtr3 triple mutant, Performed plant work including micro-grafting and glucosinolate analyses of transporter mutants and contributed to study design and preparation of the manuscript; CC, CEO, Performed LC-MS analyses; HAE, DR, OM Performed multiple sequence alignments, homology modelling; MSM, Synthesized prunasin; HHN-E, Performed and analysed nitrate uptake assays, Advised and contributed to the study design, Wrote the paper based on a draft, All authors discussed the results and commented on the manuscript; BAH, Advised and contributed to the study design, Wrote the paper based on a draft, All authors discussed the results and commented on the manuscriptFull details for the missing authors:Name: Heidi Asschenfeldt ErnstContribution: HAE contributed to the bioinformatical and computational studiesAffiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100, Copenhagen, DenmarkCompeting interests: no competing interests declaredName:\u00a0Osman MirzaContribution: OM Advised and contributed to the bioinformatical and computational studiesAffiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100, Copenhagen, DenmarkCompeting interests: no competing interests declared"}
+{"text": "Existing knowledge about retirement transitions comes from studies of cohorts living through demographic, technological, social and economic environments, and private sector and public policy regimes that are very different from those of today. The Boomer cohort now transitioning to retirement is more educated, healthier, and more engaged in paid work than their parents or grandparents at the same ages. How is the large, diverse Boomer cohort  navigating leaving the labor force compared to the Silent Generation preceding them? How similar or different across cohorts are patterned yet heterogeneous short-term workforce pathways, in terms of the timing, sequencing, and voluntariness of working hours, work participation, and exits, including subjective retirement? We use linked Current Population Survey (CPS) panel data (over 16 months) to capture change, complexity, heterogeneity, and inequities in even short-term work/retirement dynamics across intersections of age, gender, and class."}
+{"text": "Engagement in leisure activities, i.e., intellectual, social, and physical activities, may reduce the risk of incident dementia, yet little is known about the longitudinal, dynamic relationship between overall leisure activity engagement and cognition in older adulthood. Using data from a survey measure of 13 leisure activities, e.g., doing unpaid volunteer work and playing cards, games, or bingo, and a neuropsychological battery collected concurrently over 14 years from 2,259 multi-ethnic participants (mean age of 76.0 years) in the Washington Heights-Inwood Columbia Aging Project, we used a parallel process latent growth curve model of trajectories of both leisure activity engagement and cognitive z-scores . Estimates were adjusted for baseline age, years of education, sex, race/ethnicity, recruitment year, occupation , and baseline income. More baseline activity engagement  was associated with higher baseline cognitive performance, i.e., global cognitive performance , language , memory , and visuospatial ability . Decline in leisure activity engagement were associated with decline in global cognitive performance , language , memory , and visuospatial ability . While both level and change in overall leisure activity engagement and cognitive performance were correlated, level of one did not predict change in the other. Similar relationships were found when examining leisure activity categories. This suggests a dynamic, bidirectional relationship between leisure activity engagement and cognitive performance among older adults."}
+{"text": "Centella asiatica, Curcuma longa, and Paeonia suffruticosa, which are popular wound healing products used by several cultures and ethnic groups. The popularity and evidence of continued use clearly indicates that there are still lessons to be learned from traditional practices. Hidden in the myriad of natural products and derivatives from natural products are undescribed reagents, unexplored combinations, and adjunct compounds that could have a place in the contemporary therapeutic inventory.Cutaneous wound healing is the process by which skin repairs itself. It is generally accepted that cutaneous wound healing can be divided into 4 phases: haemostasis, inflammation, proliferation, and remodelling. In humans, keratinocytes re-form a functional epidermis  as rapidly as possible, closing the wound and reestablishing tissue homeostasis. Dermal fibroblasts migrate into the wound bed and proliferate, creating \u201cgranulation tissue\u201d rich in extracellular matrix proteins and supporting the growth of new blood vessels. Ultimately, this is remodelled over an extended period, returning the injured tissue to a state similar to that before injury. Dysregulation in any phase of the wound healing cascade delays healing and may result in various skin pathologies, including nonhealing, or chronic ulceration. Indigenous and traditional medicines make extensive use of natural products and derivatives of natural products and provide more than half of all medicines consumed today throughout the world. Recognising the important role traditional medicine continues to play, we have undertaken an extensive survey of literature reporting the use of medical plants and plant-based products for cutaneous wounds. We describe the active ingredients, bioactivities, clinical uses, formulations, methods of preparation, and clinical value of 36 medical plant species. Several species stand out, including  Our skin is the key to our survival, sensing the environment, maintaining physicochemical and thermal homeostasis, acting as a reservoir of essential nutrients, providing passive and active defence, and responding to trauma and injury . Maintai\u03b21), that stimulates the migration of fibroblasts and epithelial cells [Maintaining homeostasis is critical for the survival of the organism; hence, skin needs and possesses a robust and effective repair mechanism. Cutaneous wound healing is the process by which skin repairs itself following injury caused by surgery, trauma, and burns . The heaal cells . The proal cells , 12. In al cells . As the al cells , whose nal cells . The outal cells .Healing of acute wounds follows an orderly sequence of overlapping, interacting physiological processes . This seNonhealing, chronic wounds clearly pose a risk to the health and well-being of the individual; patients often suffer from pain, impaired mobility, excessive exudates, wound malodour, and restricted social life , resultiStaphylococcus sp., Streptococcus sp., Propionibacterium sp., and Pseudomonas sp. are commonly equated with infection, while others including Malassezia sp., Candida sp., and Corynebacterium sp. can be isolated from noninfected wounds and may even contribute to wound healing [Selecting an appropriate clinical strategy to manage cutaneous wounds is dictated by the aetiology underlying each wound. Consideration is given to (1) removing nonvital (necrotic) tissue, termed debridement; (2) inflammation or infection; (3) controlling moisture (too wet or too dry); and (4) state of the tissue surrounding the wound . This ap healing . The opt healing . DressinShen Nong Ben Cao Jing\u201d and \u201cBen Cao Gang Mu.\u201d Many, but not all, TCM makes extensive use of plants, ensuring it is effective, affordable, and accessible [Traditional medicine is often described by practitioners of \u201cmodern\u201d (western) medicine using sceptical terms such as \u201calternative,\u201d \u201cnonconventional,\u201d \u201cindigenous,\u201d and \u201ccomplementary,\u201d when in fact many of the techniques and practices of \u201cmodern\u201d medicine are little different from traditional practices when it comes to wounds. Traditional approaches depend almost entirely upon natural resources, such as water, plants, animals, and minerals, and continue to be valued and widely practiced by a majority of the world's population . The pracessible . Interescessible . Anothercessible . The thecessible , 33. UrbAloe vera continues to be a first-line treatment for burns, ulcers, and surgical wounds [Aloe vera contains many natural bioactive compounds, including pyrocatechol, saponins, acemannan, anthraquinones, glycosides, oleic acid, phytol, as well as simple and complex water-soluble polysaccharides [Aloe vera exhibit stronger antimicrobial activity than alcohol and aqueous extracts. Gram-positive bacterial species appear to be more sensitive than Gram-negative species to Aloe vera [Applied to wounds for over 5000\u2009years by Egyptians, Romans, indigenous peoples of Africa Asia, and the Americas, l wounds . Aloe vecharides . Acetoneloe vera . Compounloe vera .Aloe vera, is a potent stimulator of macrophage and T-cell activity and induces the transcription of proinflammatory mRNAs  [Aloe vera glycans are also reported to significantly improve de novo formation of granulation tissue by an unknown mechanism [Acemannan, a major mucopolysaccharide (mesoglycan) from s oxide) . Mesoglys oxide) . Aloe veechanism .Arctium lappa, commonly known as burdock, is a widely cultivated perennial herb [Arctium lappa is used in North America, Europe, and Asia to treat sore throat and skin pathologies such as boils, rashes, and acne [Arctium lappa has antioxidant [Arctium lappa has been shown to significantly improve dermal ECM metabolism, affecting glycosaminoglycan turnover and reducing visible wrinkles in human skin in vivo [Arctium lappa is also reported to regulate cell adhesion and gene expression in canine dermal fibroblasts, affecting the Wnt/\u03b2-catenin signalling pathway, known to be a key regulator of wound healing [Arctium lappa, Burns and Wounds\u2122 topical ointment (B&W), pain and healing of first- and second-degree burns in humans was demonstrated to be managed more effectively than the control treatment [ial herb . Arctiumand acne , 43. Sciioxidant , anti-inioxidant , antidiaioxidant , antimicioxidant , antivirioxidant , anticanioxidant , and hepioxidant  properti in vivo . Arctium healing . In a pireatment .Astragalus propinquus is a common TCM for the treatment of urinary retention and oedema [Rehmannia glutinosa has been broadly used in hemorheology and diabetes-related diseases [Astragalus propinquus and Rehmannia glutinosa was initially reported to be clinically effective for the treatment of diabetic foot ulcers [Astragalus propinquus and Rehmannia glutinosa promote diabetic wound healing and postischemic neovascularization by improving angiogenesis and attenuating tissue oxidative stress in diabetic rats [Astragalus propinquus and Rehmannia glutinosa activate the TGF-\u03b21 signalling pathway and stimulate increased deposition of ECM in human skin fibroblasts [The root of d oedema . The roodiseases . A formut ulcers . This out ulcers . Tam et tic rats . Zhang eroblasts .Ampelopsis japonica are used as a traditional treatment for burns and ulcers, amongst other indications [Ampelopsis japonica, including neuroprotective [Ampelopsis japonica accelerated the healing of cutaneous scald injury in rats [\u03b1) and TGF-\u03b21 were observed to be elevated 2\u2009days after injury and declined as healing progressed. In contrast, interleukin-10 (IL-10) was found to be elevated after 14\u2009days, coincident with wound closure [Ampelopsis japonica improved reepithelization, granulation tissue formation, vascularization, and collagen deposition [Growing throughout eastern Asia and eastern North America, the roots of ications . Multiplotective , antimicotective  activiti in rats . Tumour  closure . When coposition .Andrographis paniculata, also known as green chiretta, is used in China, India, and south east Asian countries as a traditional treatment for fever, snake bite, dysentery, infections, wounds, and itchiness [Andrographis paniculata exhibit antioxidant [Andrographis paniculata [Andrographis paniculata exhibited reduced inflammation, reduced scarring, increased angiogenesis, and an increased number of collagen fibres in healed wounds [Andrographis paniculata, has been formally evaluated in clinical trials and shown to have positive effects on several autoimmune disorders [tchiness \u201367. Extrioxidant , anti-inioxidant , antidiaioxidant , anticanioxidant , antimicioxidant , antivirioxidant , antimalioxidant , hypotenioxidant , immunosioxidant , and hepioxidant  activitiniculata . Animalsd wounds . Androgrisorders .Angelica sinensis is widely used in TCM prescriptions for the management of female maladies, inflammation, headaches, mild anemia, fatigue, and hypertension [Angelica sinensis possesses pharmacological activities including anti-inflammatory [Angelica sinensis have been shown to activate an antiapoptotic pathway and enhance cell proliferation, collagen secretion, and cell mobility in human skin fibroblasts [Angelica sinensis in angiogenesis remains unclear, with several studies reporting contradictory effects of Angelica sinensis on de novo blood vessel growth. An aqueous extract of Angelica sinensis was reported to promote blood vessel growth via activation of JNK1/2 and p38 phosphorylation, resulting in enhanced VEGF expression [n-butylidenephthalide, a bioactive isolated from Angelica sinensis, inhibits cell cycle progression, induces apoptosis, and attenuates angiogenesis [The dried root of rtension . Angelicammatory , anticanammatory , antioxiammatory , and immammatory . Extractroblasts . Extractroblasts . The rolpression , 85. In ogenesis .Blumea balsamifera  is used widely as a traditional medicine. In the Philippines, Blumea balsamifera is known as sambong and is used as a diuretic. In Ayurveda, Blumea balsamifera is known as kakoranda and is used to treat fevers, coughs, aches, and rheumatism. Leaf extracts are directly applied to treat eczema, dermatitis, skin injury, bruises, beriberi, lumbago, menorrhagia, rheumatism, and skin injury [Blumea balsamifera demonstrate a variety of bioactivities; including antimalarial [Blumea balsamifera improve wound healing in mice by promoting angiogenesis, perfusion, collagen deposition, formation of organised granulation tissue, reepithelialization, and wound closure [Endemic throughout the tropics and subtropics of Asia, n injury . Extractmalarial , antitummalarial , antifunmalarial , and antmalarial  properti closure .Boswellia sacra, is valued in Africa, India, and the Middle East for the treatment of trauma and inflammatory diseases such as rheumatoid arthritis [Agrimonia eupatoria (A), Nelumbo nucifera (N), Boswellia sacra (B), and pollen from Typha angustifoliae (P). ANBP stimulates Smad-dependent pathways in the TGF-\u03b21 signalling cascade [Frankincense, a resinous extract from rthritis , 94. It rthritis . It is a cascade . Using a cascade . Intrigu cascade .Caesalpinia sappan is well known for its qualities as a dye and has been used in TCM to improve blood circulation and reduce oedema and pain [Caesalpinia sappan have been found to possess antiallergic [Caesalpinia sappan exhibit effective antibacterial activity against Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae [Caesalpinia sappan also stimulates dermal fibroblast proliferation, migration, and collagen synthesis [The heartwood of and pain . Homoisoallergic  and antiallergic  attributallergic . Ethanoleumoniae . Unexpecynthesis , in turnCalendula officinalis, commonly known as pot marigold, is a very widely distributed plant used for the treatment of a variety of skin conditions, such as wounds, burns, and dermatitis [Calendula officinalis, including anti-inflammatory, antioxidant, antibacterial, antiviral, antifungal, and anticancer activities [Calendula officinalis stimulate fibroblast migration and proliferation in a PI3K-dependent manner [Calendula officinalis stimulate granulation tissue formation by altering the expression of connective tissue growth factor (CTGF) and \u03b1-smooth muscle actin (\u03b1-SMA) in excisional wounds of BALB/c mice in vivo [Calendula officinalis is also reported to enhance angiogenesis in vivo, demonstrated using the chicken chorioallantoic membrane (CAM) assay and a cutaneous wound healing model in rats [rmatitis , 105. A tivities . Howevert manner , 108. Ex in vivo . Calendu in rats .Camellia sinensis, is revered throughout Asia for its reputed health benefits [Camellia sinensis has antioxidant [Camellia sinensis, are primarily responsible for these pharmacological activities [\u03b2 receptors by modifying TGF-\u03b2 signalling, reducing MMP-1 and MMP-2 expression, and attenuating synthesis of collagen type 1 in human dermal fibroblasts. These properties suggest that EGCG is a potential antiscarring agent [Camellia sinensis reportedly increase fibroblast proliferation and collagen synthesis [in vivo studies have demonstrated that Camellia sinensis significantly improves wound healing by increasing angiogenesis in rats [Camellia sinensis are also reported to improve wound healing in a diabetic mouse model [Green tea, an aqueous extract made from the leaves of benefits . Centuriioxidant , anti-inioxidant , antimicioxidant , anticarioxidant , antiagiioxidant , antiobeioxidant , 118, caioxidant , and neuioxidant  activititivities . The majtivities , stimulativities . Klass eng agent . In adding agent  and inhing agent . Methanoynthesis . Further in rats , 126. Exse model .Carthamus tinctorius, or safflower, are a popular source for cooking oil in many countries. Less widely known, Carthamus tinctorius also has a long history as an ingredient in TCM formulations for the treatment of blood disorders. Recent experimentation has identified it is associated with a wide range of biological activities, including vasodilation, immune modulation, anticoagulation and thromboprophylaxis, antioxidation, antihypoxic, antiaging, antifatigue, anti-inflammation, antihepatic fibrosis, anticancer, and analgesia [Seeds from nalgesia . Interesnalgesia . Hydroxynalgesia , conferrnalgesia , anti-innalgesia , proanginalgesia , and aponalgesia  propertinalgesia . In contnalgesia , 136.Celosia argentea, also known as silver cock's comb, is used in traditional medicine to treat skin sores, eruptions, ulcers, mouth ulcers, and other skin diseases [Celosia argentea accelerates burn wound closure in rats by increasing collagen and hexosamine content in granulation tissue wounds. In addition, the extract increased the proliferation and motility of primary rat dermal fibroblasts [diseases . Leaf exdiseases , hepatopdiseases , antidiadiseases , and antdiseases  activitiroblasts .Centella asiatica, also known as Asiatic pennywort, has been used to promote wound healing for eons [Centella asiatica are reported to improve the healing of chronic ulcers in Sprague-Dawley rats in terms of width, depth, and length [Centella asiatica compared to the no-treatment control group [Centella asiatica has been found to enhance collagen deposition and epithelialization in a punch wound model in the guinea pig [Centella asiatica elevate collagen remodelling and glycosaminoglycan synthesis in a rat wound model [Centella asiatica was shown to facilitate collagen synthesis and angiogenesis in a mouse wound model [for eons . Extractd length . Wounds ol group . Asiaticinea pig . Triterpnd model . Furthernd model .Cinnamomum cassia is a commonly used spice and flavouring agent, and the bark of Cinnamomum cassia is also used to increase blood circulation and as an analgesic [Cinnamomum cassia is frequently formulated with other herbs; it is one of the seven botanical components of Shexiang Baoxin pill (SBP), a well-known TCM prescribed for chest pain and discomfort associated with coronary artery disease [In vitro and in vivo studies indicate that cinnamaldehyde, a bioactive component from Cinnamomum cassia, is a natural insecticide, is an antimicrobial, antidiabetic, antilipidemic, anti-inflammatory, and neuroprotective agent [nalgesic . Cinnamo disease . SBP is  disease . Attenti disease  and anti disease , 152, as disease . In vitrve agent , and actve agent . Cinnamave agent .Commiphora myrrha [Adiantum capillus-veneris, Aloe vera, and Lawsonia inermis, significantly improved wound healing in diabetic mice [\u03b21 and VEGF in mouse dermal fibroblasts in vitro, suggesting a common mechanism of action [Myrrh, the resinous exudate produced by a myrrha , has wela myrrha , anti-ina myrrha , antibaca myrrha , and anaa myrrha  activitia myrrha \u2013162. Myra myrrha . Myrrh itic mice . The shotic mice . In commf action .Curcuma longa and a member of the ginger family, has long been used as a medicine and as food seasoning [\u03b2, triglycerides, ET-1, creatinine, heme oxygenase-1, AST, and ALT [in vivo studies, have largely focused on curcumin as a treatment for epithelial cancers. Experimental findings from these in vivo studies and in vitro experiments indicate curcumin elicits most of its beneficial effects via altering the pericellular and extracellular matrix [Curcumin, an active substance found in the root of easoning . Practiteasoning . In trad and ALT . The subr matrix . Perhapsr matrix .Daphne genkwa, one of the 50 fundamental herbs used in TCM, grows in the Yellow and Yangtze Rivers regions in China. Daphne genkwa is used as an anticonvulsant, analgesic, diuretic, antitussive, expectorant, and mild sedative agent [Daphne genkwa are biflavonoids, coumarin, diterpenes, and triterpenes. These confer anti-inflammatory [Daphne genkwa stimulate the ERK/MEK pathway regulating fibroblast proliferation and the expression of collagen (COL1A1 and COL3A1), resulting in improved wound healing [ve agent \u2013174. Theammatory , antitumammatory , 177, imammatory , 179, anammatory  activiti healing .Entada phaseoloides, also known as St. Thomas bean, is a liana in the pea family of climbing vines common throughout lowland tropical forests and coastal forests of Africa, Australia, Asia, and Western Pacific. The bark and seeds of Entada phaseoloides are rich in saponins and tannins and are used as analgesic, bacteriocide, haemostatic, and anticancer agents and as a topical treatment for skin lesions [Entada phaseoloides reduced the time taken to heal infected wounds in rats. Analyses of the data concluded that the improved wound healing was due to the antibacterial, proproliferative, and promigration activity of the Entada phaseoloides extracts [ lesions , 181. Suextracts . These dHibiscus rosa-sinensis, or shoeblackplant, is an evergreen shrub native to tropical South Eastern Asia [Hibiscus rosa-sinensis are edible. Traditional texts describe preparations of the leaves and flowers promote hair growth and prevent greying [Hibiscus rosa-sinensis flowers are claimed to provide women with control of their fertility [Hibiscus rosa-sinensis have also been found to have antibacterial [\u03b21 expression in rat excisional wounds [ern Asia . The flo greying . Alcoholertility . Extractacterial  and wounacterial . They atl wounds .Ganoderma lucidum, the lingzhi mushroom, is well known to the Chinese, Korean, and Japanese as \u201cthe mushroom of immortality\u201d [Ganoderma lucidum stimulates a variety of pharmacobiological responses including immune modulation, inflammation modulation, anti-infective [Ganoderma lucidum daily is beneficial and is reported to reduce the number of tumours in patients with colorectal adenomas; circulating viral particles in patients infected with hepatitis B; and symptoms of hypertension [Ganoderma lucidum interact with and modulate key enzymes with known roles in lipid metabolism. However, clinical findings remain equivocal and suggest that Ganoderma lucidum is most effective when used as an adjunct with other therapies [Ganoderma lucidum have been shown to improve wound healing in diabetic rats, potentially by stimulating fibroblast proliferation and migration [Ganoderma lucidum via its established stimulation of humoral immunity.rtality\u201d , 190. Usrtality\u201d , Ganodernfective \u2013194, antnfective , cardiopnfective , and antnfective  activitirtension , 198\u2013202herapies . Polysacigration . NeverthLigusticum striatum is another one of the 50 fundamental herbs used in TCM. It has a long history of use support cardiovascular and cerebrovascular well-being. It is commonly indicated for the treatment and prevention of ischemic disorders, menstrual disorders, and headache [Ligusticum striatum, among which phthalide lactones and alkaloids are the most numerous, pharmacologically active species [Ligusticum striatum inhibit dermal scarring in the rabbit ear scar model [The rhizome of headache \u2013207. Thuar model .Lonicera japonica, also known as honeysuckle, has a notable place in traditional medicine throughout its native range of Japan, Korea, and China, where it has been used for thousands of years to treat infectious diseases [Lonicera japonica and identified broad-spectrum antimicrobial, anti-inflammatory, antipyretic, antioxidant, anticancer, hepatoprotective, and antihyperlipidemic capabilities [Lonicera japonica also support reepithelization, angiogenesis, granulation tissue formation, and contraction during cutaneous wound healing [diseases . In the bilities , 211. Mo healing . The pla healing .Paeonia suffruticosa, also known as moutan peony, has been bred for millennia [Paeonia suffruticosa is the source for bioactive ingredients used for TCM preparations. Pharmacological investigation of Paeonia suffruticosa has demonstrated it has antioxidant [Paeonia suffruticosa is commonly applied to cracked skin to assist healing and relieve pain [in vitro at low concentrations (\u226410\u2009\u03bcg/mL), Paeonia suffruticosa is found to stimulate the viability and proliferation of human primary dermal fibroblasts and HaCaT keratinocytes, suggesting its potential use as a wound healing therapy [illennia ; over 10ioxidant , neuroprioxidant , antitumioxidant , anti-inioxidant , and antioxidant  propertieve pain . When te therapy .Panax ginseng is one of the most popular medicinal plants consumed in China, Japan, Korea, and Eastern Siberia to improve thinking, concentration, and memory. It is also claimed to support immunity and physical stamina and to reduce fatigue [Panax ginseng is thus used to treat depression, anxiety, and chronic fatigue syndrome [Panax ginseng has been demonstrated to induce vasodilation [Panax ginseng contains many bioactive substances, among which a class of saponins (termed ginsenosides by Asian researchers and panaxosides by Russian researchers) represent the most potent active constituents of Panax ginseng [ fatigue . Panax gsyndrome . Panax gdilation , controldilation , reduce dilation , and condilation , anticandilation , antibacdilation , antialldilation , antiagidilation , and immdilation  activiti ginseng .Panax ginseng have been shown to protect skin in C57BL mice from acute UVB irradiation [Panax ginseng extracts enhance keratinocyte migration [in vitro. In addition, Choi demonstrated that the ginsenoside Rb2, isolated from Panax ginseng, induces the formation of the epidermis in raft culture via increased expression of epidermal growth factor and its receptor, fibronectin and its receptor, and keratin 5/14 and collagenase I [The root extracts of adiation  and signadiation , 235. Stigration , 236, asigration  and incrigration  in vitrogenase I , all of Panax notoginseng, not to be confused with Panax ginseng and other ginsengs, is used to stop bleeding, reduce oedema, reduce bruising, and reduce pain [Panax notoginseng possess substantial pharmacological activities, including antioxidative effects [Panax notoginseng flower extracts block NF-\u03baB signalling [uce pain , 241. Te effects , anti-in effects , immunos effects , neuropr effects , antican effects , and ant effects . Terpene effects , 241. Megnalling , 249, thgnalling , 251.Panax notoginseng exhibit antihaemostatic (antiplatelet and anticoagulant) activity when assayed in vitro and in vivo in a rat model [Interestingly, saponins isolated from at model . It was at model . These fat model . Such obPolygonum cuspidatum is usually formulated with several other ingredients and is most commonly prescribed for treating coughs, hepatitis, jaundice, amenorrhea, leucorrhea, arthralgia, burns, and snake bite [Polygonum cuspidatum, dominated by resveratrol, polydatin, and anthraquinones and are presumed to be responsible for Polygonum cuspidatum's anti-inflammatory, estrogenic, antitumour, antiaging, neuroprotective, and cardioprotective activities [in vivo study examining wound healing in rats, extracts of Polygonum cuspidatum were found to increase TGF-\u03b21 expression and to significantly improve wound healing in terms of reepithelization, granulation tissue formation, collagen synthesis, and angiogenesis [Polygonum cuspidatum have been verified to inhibit tyrosinase, the rate-limiting enzyme controlling the synthesis of melanin that gives colour to skin [The root of ake bite . A divertivities \u2013258. In ogenesis . Novel a to skin .Lithospermum erythrorhizon is indigenous to northeast China and has potent biological activities, including anti-inflammatory, antibacterial, antiangiogenic, and antitumour qualities [Lithospermum erythrorhizon and stimulates the activity of caspases, poly-(ADP-ribosyl) polymerase (PARP) and reactive oxygen species (ROS), triggering programmed cell death in cancer cell lines [Lithospermum erythrorhizon, has been reported to synergise with VEGF, resulting in significantly improved wound healing in a rat diabetic model [The dried root of ualities . Shikonill lines . These cll lines . Arnebinic model .Rheum officinale, also known as Chinese rhubarb, is one of the best known traditional herbal medicines with pharmacological activities. Extracts from the roots of Rheum officinale have strong antibacterial [\u03b21-related pathways [Rheum officinale, has been shown to act as a ligand for PPAR-\u03b3 and interact with HSP90 and androgen receptors, in part explaining its therapeutic benefit for chronic diseases [acterial , antioxiacterial , anti-inacterial , and haeacterial  effects,acterial , 269, anacterial . Using apathways . The natdiseases . Experimdiseases , 273.Rhodiola imbricata, a perennial herb native to high altitudes (4000\u20135000\u2009m) of the western Himalayas, is known to contain bioactive flavonoids, coumarins, and phenyl glycosides. These compounds are commonly found in botanical herbal medicines. Ethanolic extracts of rhizomes from Rhodiola imbricata stimulate a robust wound healing response when applied to excisional wounds in rats [ in rats . Others  in rats , antioxi in rats , hepatop in rats , radiopr in rats , and ant in rats  propertiSalvia miltiorrhiza  is highly valued in TCM and used to treat cerebrovascular and cardiovascular diseases, such as stroke, coronary heart disease, and hyperlipidemia [Salvia miltiorrhiza has been demonstrated to reduce ischemia and necrosis and to improve the survival of skin flaps after mastectomy [Salvia miltiorrhiza have potent antioxidative capabilities due to their polyphenolic structure [Salvia miltiorrhiza, containing danshensu (DSU) and salvianolic acid B (SAB), have been shown to enhance the proliferation of fibroblasts and increase collagen synthesis [Salvia miltiorrhiza, has been demonstrated to downregulate the expression of COL1A1, COL3A1, and \u03b1-SMA in hypertrophic scar-derived fibroblasts (HSF), as well as reduce HSF migration and HSF contraction, thus ameliorating fibrosis and scarring [The root of the perennial plant ipidemia \u2013283. To stectomy , 285. Satructure . Althougtructure , neuroprtructure , antimictructure , anti-intructure , and anttructure  activititructure . Water-synthesis . Salvianynthesis . In contscarring .Sanguisorba officinalis, a member of the family Rosaceae and commonly known as great burnet, is widely distributed in the cooler northern districts of Asia, Europe, and North America [Sanguisorba officinalis is to control bleeding disorders. It is also applied to heal scalds, burns, allergic skin diseases, urticaria, eczema, and allergic dermatitis [Sanguisorba officinalis suppress mast cell degranulation, as well as inhibit activation of STAT-1, Jak-2, p38, and JNK pathways and release of inflammatory cytokines [Sanguisorba officinalis is claimed to stimulate wound contraction, reduce the time required for reepithelization (wound closure), increase collagen synthesis, and improve angiogenesis [\u03b2 and VEGF in mice [ America . Roots o America , with an America , immunom America , anti-in America , and ant America  propertirmatitis . Aqueousytokines . In mousogenesis . Adminis in mice .Sophora flavescens is a species from a genus of over 50 plants distributed throughout Asia, Oceania, and the islands of the Pacific. The root of Sophora flavescens is used for conditions involving the heart, liver, intestinal tract, and skin. Experimental investigations indicate extracts from Sophora flavescens stimulate anticancer, antibacterial, antiviral, anti-inflammatory, and antipruritic responses and benefits wound healing [Sophora flavescens benefit individuals with androgenetic alopecia [Sophora flavescens and other herbs significantly reduced perianal ulceration in a rat model, finding that the expression of prostaglandin E2 and IL-8 was concomitantly reduced in treated animals [ healing . One rec healing . Other ralopecia . Recentl animals .Stemona tuberosa is another of the 50 fundamental herbs used in TCM. It has strong insecticidal activity, the foundation property for its traditional use in treating impetigo, scabies, louse, lice, and ticks. It is also used as a mosquito repellent and preservative to protect stored cereals from insects [Stemona tuberosa are reported to have anti-inflammatory [Stemona tuberosa increase cell proliferation in the mouse fibroblast NIH3T3 cells, suggesting the potential use of these compounds as wound healing agents [ insects . In tradammatory  and antiammatory  effects,ammatory . Tocopheg agents .Wedelia trilobata, which is also known as Sphagneticola trilobata, was originally native to the tropical Americas; however, as one of the world's most invasive species, it is now ubiquitous throughout the tropics. Alcohol extracts made from the leaves of Wedelia trilobata have been used to treat rheumatism, stubborn wounds, and arthritic painful joints [Wedelia trilobata, conferring neuroprotective, anticancer, antioxidant, and immunomodulatory activities [Wedelia trilobata to treat skin wounds. Luteolin inhibits the expression of NF-\u03baB-regulated proinflammatory cytokines, a characteristic feature of skin infection and psoriasis [Wedelia trilobata and assayed them in vitro [Staphylococcus aureus and Staphylococcus epidermidis [The plant l joints . Luteolitivities . Traditisoriasis . In a stin vitro . Specifidermidis .Zanthoxylum bungeanum is a flowering plant belonging to the Rutaceae family, native to eastern provinces of China. It yields important food ingredients such as sichuan pepper [Zanthoxylum bungeanum, including alkaloids, terpenoids, flavonoids, and free fatty acids, eliciting a wide variety of biological responses, including analgesic [Zanthoxylum bungeanum are known in traditional Western folk medicine as \u201ctoothache trees,\u201d useful for treating pruritus (itch) and chronic pain. The pericarp from the fruit berry is commonly used to formulate TCM oils, powders, tinctures, elixirs, and pills [Zanthoxylum bungeanum are also prescribed for skin infections, including acne, eczema, scalds, and wound healing [Zanthoxylum bungeanum is as a lifting agent for skin wrinkles. When applied topically to skin, subcutaneous muscles are relaxed, reducing skin wrinkles, thus has attracted the attention of cosmetic manufacturers [Zanthoxylum bungeanum is the capacity to enhance percutaneous drug delivery [n pepper . Over 14nalgesic , anticannalgesic , antioxinalgesic , anti-innalgesic , antibacnalgesic . Zanthoxnd pills . Extract healing . One uniacturers . Anotherdelivery .\u03b1, and TGF-\u03b21), angiogenesis pathway , extracellular matrix synthesis , and differentiation pathways .We have surveyed and presented an overview of evidence that explains why many medicinal plants are used as traditional treatments for cutaneous wounds and clinical skin disorders. Medicinal plants have been the first line of treatment for trauma, infection, disease, and injury from prehistory. Over millennia, humans have learned to identify and transform the botanical resources from the immediate environment, and with the development of trade, as food and medicine. A great many of these \u201cancient\u201d and traditional medical plants have been validated to confer therapeutic benefits, albeit not always in controlled clinical trials. One unexpected outcome from validation studies is just how many medical plants synthesize equivalent or closely related compounds. Consequently, it is not surprising that many biological properties are also shared by unrelated species. Also shared are many of the same biological targets and pathways; many of these are also key events in the mammalian wound healing cascade. Many of the identified compounds target mitogenic pathways , the proinflammatory NF-\u03baB pathway , hydroxysafflor yellow A (from Carthamus tinctorius), polysaccharide (from Ganoderma lucidum), phthalide lactones, and alkaloids (from Ligusticum striatum), saponins (from Panax ginseng), shikonin and arnebin-1 (from Lithospermum erythrorhizon), salvianolic acids , polysaccharides , and alkaloid and stilbenoid (from Stemona tuberosa) are well characterised and have been demonstrated to have properties that benefit wound healing. In particular, Centella asiatica, Curcuma longa, and Paeonia suffruticosa are popular medicinal products in several global markets.The active ingredients, part of use, type of extract, assessment methods, bioactivities, clinical use, formulation, and commercial product of the medicinal plants are summarized in We provide these data in the belief that we still have much to learn from traditional practices, some of which undoubtedly could deliver novel reagents and therapies for today's therapeutic challenges. Notwithstanding, we recognise that modern medicine and drugs remain effectively inaccessible (and unaffordable) to the majority of the world's population. For this reason alone, traditional medicine continues to be the first line of treatment, indeed, frequently the only line of treatment for many. With greater understanding of traditional practices comes appreciation and benefit to more of the world's peoples. We would like to see that this knowledge is not discarded by \u201cmodern medicine\u201d but leveraged through investigation to benefit all."}
+{"text": "Designing cancer vaccines has been at the forefront of cancer research for over two-and-a-half decades. In particular, delivery methods used to stimulate effective and long-lasting immune responses have been the major focus. This special issue presents new tumor associated antigens, delivery methods, combination immune therapies, methods of measuring immunity induced following cancer vaccinations, and mechanisms in understanding tumor microenvironments and immunosuppression\u2014all beneficial for the design of improved cancer vaccines. Cancer vaccines or immunotherapeutics are increasingly recognized as key approaches against cancer. In the last two decades, a number of methods of antigen delivery have been developed, some of which have shown strong anti-tumor immune responses and clinical responses in humans . The comIdentification of tumor associated antigens is also required when designing cancer vaccines, in order to stimulate the immune system against cancer cells. One example is Mucin 1 (MUC1), which is highly expressed on adenocarcinomas. Numerous vaccines for MUC1 have been designed and tested in preclinical and clinical studies ,9,10. HuIn the last 2 decades, a number of vaccine delivery methods have been developed, all with the aim of inducing strong immune responses. An array of methods have shown to be effective in pre-clinical models and some in human clinical trials. Examples of successful antigen delivery methods include adjuvants , and QS21), nanoparticles, virus like particles, the multiple antigen approach, immunostimulatory complexes, viral vectors, DNA delivery methods, cell penetrating peptides, activation of toll-like receptors, chemokine receptors, and dendritic cell receptor targeting . In thisIn a tumor\u2019s microenvironment, dendritic cells are polarized into immune suppression, which affects T cell activation and supports the differentiation of regulatory T cells leading to tumor growth. As such, incorporating small interfering RNAs and short-hairpin RNAs against immunosuppressive factors within dendritic cells shows promising anti-cancer effects . The comDNA vaccines have been shown to be effective following intramuscular, gene gun, electroporation, or bioinjector delivery methods. Animal-derived hyaluronidase has been shown to be a good enhancer of intramuscular gene electro-transfer in anti-cancer vaccination protocols in mice. A new recombinant hyaluronidase was developed by de Robertis et al., as reported in this special issue, with no toxicity, good plasmid in-take ability, and activation of appropriate immune responses . In addiCombination immune therapy is becoming popular to treat cancers. In particular, checkpoint markers have been used in combination with chemotherapy and other treatments for improved outcomes. Indeed, the CD200 immune checkpoint inhibitor and tumor lysates in combination enhances anti-glioma T cells and prolonged survival in a canine spontaneous glioma model . AnotherA number of methods for measuring immunity induced by cancer vaccines have been developed, such as bioplex or enzyme linked immunospot (ELISpot) cytokine analysis, cytotoxic T cell activity assays, cytotoxic T cell precursor frequency assays, T cell proliferation, flow cytometry analysis, carboxyfluorescein succinimidyl ester (CFSE) analysis, tetramers, and antibody measurements . In thisIn the last 2 decades, vaccines for cancer have shown promise in pre-clinical and human clinical trials. Identification of tumor associated antigens, antigen delivery methods, induction of immune responses, methods of measuring immunity, and, more recently, tumor microenvironments and immunosuppressive factors have all contributed to improved cancer outcomes in patients . Differe"}
+{"text": "Camarasaurus. The size of the material and a medially beveled distal articular surface of metatarsal IV imply an identification as a brachiosaurid. This is the largest pes ever reported from a sauropod dinosaur and represents the first confirmed pedal brachiosaur elements from the Late Jurassic of North America. Furthermore, this brachiosaur material  is the northernmost occurrence of brachiosaurids in the Morrison Formation.A set of associated left pedal elements of a sauropod dinosaur from the Upper Jurassic Morrison Formation in Weston County, Wyoming, is described here. Several camarasaurids, a nearly complete small brachiosaur, and a small diplodocid have been found at this locality, but none match the exceptionally large size of the pedal elements. Next to the associated pedal elements, an isolated astragalus, phalanx and ungual were found, which match the large metatarsals in size. The elements cannot be ascribed to diplodocids due to the lack of a ventral process of metatarsal I. Moreover, the morphology of metatarsal V has a broad proximal end, with a long and narrow distal shaft, which differs from  Camarasaurus, Diplodocus, Apatosaurus, and Brachiosaurus; Dyslocosaurus polyonychius  Morrison Formation is famous for its abundant dinosaur material, particularly sauropods , metatarsals I to V, four non-ungual pedal phalanges, one ungual (KUVP 129724), an additional non-ungual phalanx (KUVP 133862), and a second ungual (KUVP 144767). It was found at the Bobcat Pit site in Weston County in the Black Hills in north-eastern Wyoming see . It has Camarasaurus KUVP 129716, with the phalanges scattered around the skeleton , nor with a second, larger Camarasaurus specimen from the same quarry. The Camarasaurus KUVP 129716 was nearly complete and included almost all the pedal material in articulation. All pedal bones from this specimen are duplicated in KUVP 129724, so it is certain the large pes does not belong to this specimen. A larger Camarasaurus (KUVP 129713) was excavated in 1997, approximately 7m adjacent in the same quarry. However, this individual is also much smaller than the new pes. Finally, all proximal phalanges display a peculiar bone texture on their proximal articular surfaces. These surfaces are marked by irregularly undulating grooves generally extending from the margins towards the center. Such a texture is likely due to remodeling in response to specific stresses in vivo, supporting the interpretation that all phalanges belong to a single pes, because all the joints between metatarsals and phalanges seem to be equally affected. As specimens at this locality generally occur as discreet skeletons rather than a mass of bonebed elements, these considerations suggest it is very likely the pes is a slightly scattered assemblage of elements from a single individual.The elements of KUVP 129724, the astragalus KUVP 142200, the phalanx KUVP 133862, and the ungual KUVP 144767 were not consistent in size with the The pes and astragalus were excavated from a mudstone deposit, with some encrustation of caliche on the bones, especially around the articular ends. The softer matrix was removed primarily with X-acto knives and air abrasion utilizing sodium bicarbonate abrasives. Concretionary material was removed much more slowly employing Aro and Chicago Pneumatic air scribes and air abrasion with Dolomite (and very seldom glass beads and Aluminum Oxide) abrasives. All elements were scanned using an Artec Spider handheld structured light unit and processed using Artec Studio 12 software. Individual scan files were organized and arranged in Blender software to produce figure images. The three-dimensional models are available through KUVP for research purposes.Giraffatitan and Lusotitan, which have a relatively shorter and more rounded medial end than Janenschia and Camarasaurus . This shape rarely occurs outside of Brachiosauridae. The features distinguishing KUVP 129724 from Giraffatitan are most likely representing differences at a lower taxonomic level within Brachiosauridae, given that many of them are more variable among eusauropods than the traits mentioned above.The morphological comparisons lead to an identification of the pes as belonging to Titanosauriformes, and more specifically Brachiosauridae, in particular due to the orientation of the distal articular surface of mt IV that was recovered as a synapomorphy for the clade in two independent phylogenetic analyses . In addiBrachiosaurus altithorax. The type locality for this species is close to the town of Grand Junction, Colorado  FMNHField Museum of Natural History, Chicago, Illinois, USA GMNH-PVGunma Museum of Natural History, Gunma, Japan IANIGLA-PVInstituto Argentino de Nivologia Glaciologia y Ciencias Ambientales, Mendoza, Argentina KUVPKansas University Museum of Natural History, Vertebrate Paleontology, Lawrence, Kansas, USA MalMalawi Department of Antiquities Collection, Lilongwe and Nguludi, Malawi MBRMuseum f\u00fcr Naturkunde Berlin, Berlin, Germany MCF-PHVMuseo \u2018Carmen Funes\u2019, Plaza Huincul, Neuqu\u00e9n, Argentina MNHNMus\u00e9um National d\u2019Histoire Naturelle, Paris, France MNNMusee National du Niger, Niamey, Republic of Niger MPCA-PVColecci\u00f3n de Paleovertebrados de la Museum Provincial de Cipolletti \u2018Carlos Ameghino\u2019, Cipolletti, Rio Negro Province, Argentina MPMMuseo Padre Molina, Rio Gallegos, Santa Cruz, Argentina MPZMuseo Paleontol\u00f3gico de Zaragoza, Zaragoza, Spain MUCPvMuseo de Geolog\u00eda y Paleontolog\u00eda Universidad Nacional de Comahue, Argentina NHMUKNatural History Museum, London, United Kingdom NMMNHNew Mexico Museum of Natural History and Science, Albuquerque, New Mexico, USA NSMTNational Science Museum, Tokyo, Japan SMASauriermuseum Aathal, Switzerland SMNSStaatliches Museum f\u00fcr Naturkunde, Stuttgart, Germany UNCUYO-LDUniversidad Nacional de Cuyo, Laboratorio de Dinosaurios, Mendoza, Argentina UNPSJB-PVUniversidad Nacional de la Patagonia San Juan Bosco, Comodoro Rivadavia, Argentina YPMYale Peabody Museum of Natural History, New Haven, Connecticut, USA ZDMZigong Dinosaur Museum, Zigong, China ZPALInstitute of Paleobiology, Polish Academy of Sciences, Warsaw, Poland10.7717/peerj.5250/supp-1Table S1Red ratios are based on measurements taken from figures.Click here for additional data file."}
+{"text": "Scientific Reports 10.1038/s41598-018-21321-0, published online 14 February 2018Correction to: The Acknowledgements section in this Article is incomplete.\u201cRE is funded by a BOF-mandate (BSFFCMKDK) at Hasselt University. NW is funded as a postdoctoral researcher by FWO Flanders. Part of this research was funded by another FWO-grant (N1522015). We thank Eddy Ulenaers, Luc Lens, Dries Gorissen, Guido Winters, Koen Thijs, Lise Hendrick, Karen Vanmarcke, Fien Evens, Albert Geuens, Lyndon Kearsley, Greg Conway, Ian Henderson and Nikki Watson for their support and relevant comments on this manuscript. Research equipment was funded by the Agency for Nature and Forest . Permissions were granted by the ANB and Royal Belgian Institute of Natural Sciences (Belgium).\u201dshould read:\u201cRE is funded by a BOF-mandate (BSFFCMKDK) at Hasselt University. NW and TN are funded as postdoctoral researchers by FWO Flanders. Part of this research was funded by another FWO-grant (N1522015). We thank Eddy Ulenaers, Luc Lens, Dries Gorissen, Guido Winters, Koen Thijs, Lise Hendrick, Karen Vanmarcke, Fien Evens, Albert Geuens, Lyndon Kearsley, Greg Conway, Ian Henderson and Nikki Watson for their support and relevant comments on this manuscript. Research equipment was funded by the Agency for Nature and Forest . Permissions were granted by the ANB and Royal Belgian Institute of Natural Sciences (Belgium).\u201d"}
+{"text": "A 45-year-old female came to our attention with a six-month history of ulcerative mass in her right breast. Definitive pathology on breast lesion Figure  documentGranulomatosis with poliangiitis (GPA) is an autoimmune systemic vasculitis of the small vessels. Infectious, environmental, chemical, and toxic triggers have been advocated as etiologic triggers in predisposed people. It is usually associated with high levels of circulating antineutrophilic cytoplasmic antibodies (ANCA), even if positive ANCA serology is not pathognomonic of GPA, especially in the absence of clinical and histological findings of systemic vasculitis. Clinical manifestations of GPA include constitutional symptoms, mucocutaneous manifestations of upper airways, typically given by oral ulcers and crusting rhinitis, and subglottis laryngeal stenosis, lower respiratory tract manifestations, such as pulmonary nodules and infiltrates, bronchial wall thickening, and pleural effusion. Some patients may develop cardiovascular, renal, or central nervous system involvement. To the best of our knowledge, inflammatory mastitis as a presenting symptom of GPA has never be reported, even if cutaneous ulcers, digital infarcts, purpura, although not pathognomonic, are not infrequent complaints of GPA. The histological feature of GPA is characterized by necrosis, focal vasculitis of small veins, arteries, and capillaries, and inflammatory infiltrate composed by neutrophils, lymphocytes, plasma cells, macrophages, eosinophils, and giant multinucleated cells. High resolution computed tomography helps in achieving diagnosis, as it shows typical GPA-related pulmonary findings such as nodules, cavitary lesions, tracheobronchial stenosis, and interstitial disease. Prompt diagnosis plays a capital role because a proper treatment may induce clinical remission, ameliorate the morbidity, and greatly improve the survival. Currently, management of GPA is based on immunosuppressant drugs, such as cyclophosphamide, azathioprine, and methotrexate, monoclonal antibodies such as rituximab. Plasma exchange has been proposed in conjunction with cyclophosphamide for patients with aggressive vasculitic involvement of the kidney ."}
+{"text": "IET Image Processing:This article  was subm\u201cRobust Retinal Vessel Segmentation using Vessel's Location Map and Frangi Enhancement Filter\u201dAuthors: Muhammad Shahid, Imtiaz Ahmad Taj Submitted: May 4, 2017; Published: December 6, 2017PLOS ONE Editors retract this article, as we consider that this constitutes redundant publication.Having confirmed the overlap, the IET Image Processing, which occurred while the submission to PLOS ONE was under revision.The authors have indicated that KBK, AAK, and AJ were not aware of the submission of the article to KBK, AAK, AJ, and MS agreed with the retraction."}
+{"text": "Dear Editor,-5. Intracranial calcifications with brain malformations have beenreported in cytomegalovirus infection, congenital rubella, and, more recently, in Zikavirus infection,2,4,5. In cases of congenital toxoplasmosis, calcificationsare seen in 50-80% of cases and hydrocephalus is a common finding, although defects inorganogenesis induced by nonviral etiologic agents are rare,4.Congenital central nervous system infections are accompanied by pathological intracranialcalcifications, and cerebral organogenesis malformations are common in viral infections,particularly when they occur in the first trimester of gestation,3,6,7. In congenital cytomegalovirusinfection, the characteristic presentation is brain calcifications. Those calcificationsare often periventricular, in the ependymal or subependymal region, appearing as pointsor lines or, in some cases, delineating the ventricles. The calcification foci, whichcan occur in the basal ganglia, white matter, or cortex, are often asymmetric-5.In the neonatal period, the diagnosis of congenital cytomegalovirus infection can besimple in a child presenting with fever, jaundice, hepatosplenomegaly, anemia,thrombocytopenia, and retinopathy. In cases of Zika virus infection, the centralclinical aspect is microcephaly.Unlike other congenital viral infectious processes associated with encephalicmalformations, in which the distribution is typically periventricular, the Zika virusappears to produce subcortical calcifications (Although congenital rubella is exceptionally rare in Brazil, some cases have beenreported. The radiological findings are similar to those of cytomegalovirus infection.White matter anomalies and periventricular calcifications are often present, as arecalcifications in the basal gangliaications .The association among intracranial calcifications, congenital infections, and centralnervous system malformations is broad and requires the observance of some aspects.Congenital microcephaly can be divided into two main categories: primary and secondary.Some patients with primary congenital microcephaly have been described as havingcongenitally small but architecturally normal brains, which does not occur in cases ofmicrocephaly associated with diverticulum and cleavage malformations such asholoprosencephaly or cerebral cortical defects such as lissencephaly, usually associatedwith nonprogressive mental retardation of a presumed genetic cause. In contrast, incases of microcephaly acquired as a result of brain damage, such as those associatedwith hypoxic-ischemic injury, congenital central nervous system infection, or metabolicdisease, the head size can initially be normal but can decrease as a result of the braininjury. However, in cases of Zika virus infection, microcephaly and braincalcifications, with simplification of the cerebral convolutions, are present on thefirst day of life .The causes of pathological intracranial calcifications in children are diverse.Nevertheless, the combination of microcephaly and defects of cerebral organogenesis,especially those related to impairment of neuronal migration, is a strong indication ofcongenital central nervous system infection with a viral agent, and subcorticalpredominance of calcifications should prompt the radiologist to consider the hypothesisof Zika virus infection."}
+{"text": "After adjusting for baseline clinical and demographic characteristics, patients prescribed rivaroxaban were more likely to experience any bleeding , CRNM bleeding , and major inpatient bleeding , compared to patients prescribed apixaban. Dabigatran patients had similar bleeding risks as apixaban patients. In conclusion, NVAF patients treated with rivaroxaban appeared to have an increased risk of any bleeding, CRNM bleeding, and major inpatient bleeding, compared to apixaban patients. There was no significant difference in any bleeding, CRNM bleeding, or inpatient major bleeding risks between patients treated with dabigatran and apixaban.Limited real-world data are available regarding the comparative safety of non-vitamin K antagonist oral anticoagulants (NOACs). The objective of this retrospective claims observational cohort study was to compare the risk of bleeding among non-valvular atrial fibrillation (NVAF) patients prescribed apixaban, dabigatran, or rivaroxaban. NVAF patients aged \u226518 years with a 1-year baseline period were included if they were new initiators of NOACs or switched from warfarin to a NOAC. Cox proportional hazards modelling was used to estimate the adjusted hazard ratios of any bleeding, clinically relevant non-major (CRNM) bleeding, and major inpatient bleeding within 6 months of treatment initiation for rivaroxaban and dabigatran compared to apixaban. Among 60,227 eligible patients, 8,785 were prescribed apixaban, 20,963 dabigatran, and 30,529 rivaroxaban. Compared to dabigatran or rivaroxaban patients, apixaban patients were more likely to have greater proportions of baseline comorbidities and higher CHA Atrial fibrillation (AF) increases the risk of stroke and systemic embolism, and AF-related strokes have higher mortality, disability, costs, and risk of recurrent stroke compared to non-AF related strokes ,2. Oral Currently, non-vitamin K antagonist oral anticoagulants (NOACs) offer relative efficacy, safety, and convenience compared to warfarin. These drugs can be given in fixed doses without routine coagulation monitoring, and they have minimal drug and food interactions ,8. In clWith the recent licensing and availability of NOACs, including dabigatran etexilate mesylate, rivaroxaban, apixaban, and edoxaban, data are needed on their comparative safety profile in many countries. Dabigatran was approved in the United States in 2010, while rivaroxaban, apixaban, and edoxaban were approved in 2011, 2012, and 2015, respectively.The objective of this retrospective claims observational cohort study was to compare the risk of bleeding among non-valvular atrial fibrillation (NVAF) patients prescribed apixaban, dabigatran, or rivaroxaban.This is a retrospective observational cohort study using insurance claims data from the Truven MarketScan Commercial Claims and Encounter and Medicare Supplemental & Coordination of Benefits Early View Database incurred from 01JAN2013-31OCT2014 to capture the real-world experience of NVAF patients who were either new initiators or switchers from warfarin. The database captures person-specific clinical utilization among approximately 100 payers of large employers, health plans, and government and public organizations in the United States, with more than 196 million unique patients since 1995. The database included annual insurance claims of inpatient, outpatient, emergency room, pharmacy, behavioural health care, and enrollment data for more than 94 million insured individuals, their dependents for active employees, early retirees, Consolidated Omnibus Budget Reconciliation Act (COBRA) health plan continuers, and Medicare-eligible retirees with employer-sponsored private health insurance and employer-provided Medicare Supplemental plans in the United States  89\u2013312) for apixaban, 553 days (IQR 341\u2013619) for dabigatran, and 300 days (IQR 151\u2013505) for rivaroxaban patients. The average age was 70 years for both apixaban and dabigatran patients and 68 years for rivaroxaban patients . ClinicaThe unadjusted bleeding rates are shown in After adjusting for baseline characteristics, there was a 43% (95% CI: 1.17\u20131.74) increased adjusted risk of inpatient major bleeding for rivaroxaban patients as compared to apixaban patients . This efNo significant differences were found between dabigatran and apixaban patients for any bleeding, CRNM bleeding, or inpatient major bleeding. The sensitivity analysis to assess the standard dose treatment effect on risk of major bleeding showed similar trends of significantly higher major risk with rivaroxaban compared to apixaban . AdditioIn this study, our principal finding was that NVAF patients treated with rivaroxaban appeared to have an increased risk of any bleeding, CRNM bleeding, and inpatient major bleeding compared to patients treated with apixaban. There was no significant difference in any bleeding, CRNM bleeding, or inpatient major bleeding between dabigatran and apixaban patients.This large observational cohort study compares inpatient bleeding risks among NVAF patients treated with the three NOACs: rivaroxaban, dabigatran, and apixaban. Despite greater comorbidities and worse bleeding and stroke profiles among apixaban patients, these patients experienced significantly less major inpatient bleeding, CRNM bleeding, or any bleeding events compared to rivaroxaban patients, and had comparable bleeding event rates to dabigatran patients. When compared with apixaban, rivaroxaban patients also showed significantly higher GI and other bleeding risks, and trended towards a higher ICH bleeding risk. Dabigatran had similar risks with apixaban across various bleeding sites.Previous studies used data from large clinical trials to compare the safety between NOACs, which have been used to inform indirect comparisons and network meta-analyses . Our stuFew direct comparisons have been completed for apixaban, dabigatran, and rivaroxaban patients in a real-world setting. Another observational study using MarketScan data and propensity score matching showed that dabigatran had similar risk of major bleeding compared to apixaban and rivaroxaban, and apixaban had significantly lower risk of major bleeding compared to rivaroxaban . Our stuIn addition, previous real-world studies have compared the risk of major bleeding for NOACs versus warfarin, the standard of care. Several real-world analysis comparing dabigatran to warfarin on adjusted overall bleeding risks showed greater or non-significant differences in overall bleeding, but higher GI bleeding and lower ICH risks \u201327. NoneBased on large national claims data, our study adds novel evidence regarding the comparative bleeding risks of apixaban, dabigatran, and rivaroxaban in patients with NVAF. This population includes patients who were warfarin na\u00efve and warfarin experienced, which makes it more representative of true clinical practice. Many prior studies only include treatment-na\u00efve patients. Clearly, more real-world studies regarding bleeding risks and use of NOACs are still warranted.First, health insurance databases include patients with varied risk profiles, and patients with a higher risk of major bleeding were more likely to use apixaban. Second, patients on all dosages of apixaban, dabigatran, and rivaroxaban were included in the study population. As expected, previous studies have shown that increased dosages are positively associated with bleeding events. Sensitivity analysis using only standard dosage found comparable results. Third, compared with clinical trials, no causal relation can be drawn in this retrospective cohort study. Additionally, there are wide ranges of comorbidities among the cohorts, and although baseline characteristics were adjusted, some residual confounding is likely because of unmeasured confounders . The meaFurthermore, there are inherent limitations of claim data, such as coding errors and missing data. Comorbidities were presented in the dataset using ICD-9-CM diagnosis codes. Laboratory data, including creatinine clearance, are not available in the claims database, so diagnosis codes were used to determine comorbidities. Additionally, with a claims database, medication as filled may not reflect true medication use . NonetheIn conclusion, NVAF patients treated with rivaroxaban appeared to have an increased risk of any bleeding, CRNM bleeding, and major inpatient bleeding compared to patients treated with apixaban. There was no significant difference in any bleeding, CRNM bleeding, or inpatient major bleeding between dabigatran and apixaban patients. These data may help guide decision-making in clinical practice."}
+{"text": "H.pilori, CMV, Mycoplasma pneumoniae, and Chlamydophila pneumoniae and pathogenic archaea. We also develop hypothesis about how PTCTS works, a new natural nutricosmetic produced by nanoparticles derived from orchid flowers, transialidase, and thermal water, which had a strong anti-oxidant effect. In previous work, published BioMed Research International, we demonstrated that serum extracellular vesicles containing Mycoplasma pneumoniae lipoproteins increased with cholesterol enriched diet, and they decreased with administration of oral PTCTS . The hypothesis is that, PTCTS would remove pathogenic archaea, the symbiotic microbe responsible for maintenance of other bacteria growing. Then, removing archaea, the macrophages would re-establishes their capacity of killing intra-cellular microbes, decreasing atherosclerotic plaques, in rabbits. Now we intend to initiate human clinical trials to determine safety and efficacy of oral PTCTS in humans.In this comment we develop the concept that atherosclerosis is an inflammatory process, aggravated with the presence of infectious agents, such as Coxsackie B virus, HIV, Aging cells and organisms accumulate increased levels of nuclear DNA damaged by oxidants . NumerouMycoplasma pneumoniae and Chlamydophila pneumoniae (Chlamydophila pneumoniae and anti-Mycoplasma.pneumoniae antibodies were seen after acute myocardial infarction (in vitro endothelial cells studies, NO reduction and superoxide anion production (eumoniae  were foufarction , 7. Extrfarction , 9. Micrfarction \u201312. Incroduction , suggestHuman coronary arteries with unstable plaques are richer in microvesicles, sometimes containing archaeal DNA, suggesting a possible infectious etiology .Archaea are primitive microorganisms producing collagenase and inflammation, reducing metals such as Fe and Mn , 16. ArcWe found greater number of such microvesicles, which had greater quantity of oxLDL and collagenases, on unstable plaque than on normal artery or on stable plaque .PTCTS cosmetic gel was efficient in treatment of lesions by radio dermatitis, with no undesirable side effects . The NutNutricosmetics are considered nutritional supplements based on bioactive compounds that have antioxidant, anti-inflammatory, and PTCTS would also remove different infectious agents. In addition to prevent skin aging and strengthening hair and nails, nutricosmetics act in a systemic way, contributing to a better quality of life and well being, under the premise of a healthy body inside and beautiful on the outside. The objective is preventing aging, capillary fall,  and atheThe author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Inflammation (or inflammatory reaction) is the response to body aggression by a pathogen agent, an allergen, a toxic compound, a tissue lesion, etc. It can be a general phenomenon with fever and tiredness, or a local phenomenon with pain and edema. Inflammation is characterized by the production of various active signaling molecules, such as vaso-active amines (histamine/serotonin), prostaglandins, leukotriens, kininogens/kallikreins/kinins, complement factors, cytokines, and MMPs /TIMPs . All of the following pathologies present with a strong inflammatory component; infection, injury, vessel atherosclerosis, diabetes mellitus, obesity, cancer, osteo-arthritis, ocular diseases, demyelination, and brain pathologies associated with aging. Inflammation is a complex response that involves, among other interactions between activated lymphocytes, dendritic cells  and monocytes, subsequently differentiated into macrophages. During this process, numerous cytokines are secreted by immune cells and by injured tissue non-immune cells as a consequence of cell-cell interactions.The immunomodulation by various compounds, such as natural products, represents a promising preventive or therapeutic strategy against a number of pathological processes. Beside pro-inflammatory cytokines/interleukins, various lipid mediators produced through arachidonate metabolism also play a key role in inflammation-linked pathologies, such as atherosclerosis or cancers.Potentilla erecta [Viscum album [Gelsemium elegans [Anacardium [Citrus bergamia [Aspalathus linearis, an African plant used as a drink [More than 27 original papers or review papers have reported the inhibitory effect of natural products on inflammation processes, at least in low grade inflammation. These compounds included plant polyphenols or derivatives: resveratrol , querceta erecta , Euphorba erecta , Viscum um album , koumine elegans , soft meacardium ), and dibergamia ), Aspala a drink , or Xant a drink .Besides reviews on anti-inflammatory properties of natural products ,16, therIn conclusion, the large number and the diversity of papers in this proposed topic of Natural Products and Inflammation confirm the interest of this association. It contributed to reveal promising compounds and their potential interest in the immunmodulation."}
+{"text": "Dear Editor,A 38-year-old woman who had been diagnosed with severe systemic lupus erythematosus (SLE)15 years prior, had refractory nephritis, and had been treated with high-dosecorticosteroids and immunosuppressive drugs , presented with a severalweek history of pain and edema on the dorsum ofthe left foot after wearing tight shoes. She had extremely low bone density, which hadbeen treated with bisphosphonate and teriparatide. Magnetic resonance imaging (MRI) ofthe left foot showed a diaphyseal fracture of the second metatarsal with extensive fluidcollection and peripheral contrast enhancement of the surrounding tissue, indicating anabscess . In addi. Atraumatic metatarsal stress fractures typically occur inassociation with antiphospholipid syndrome. Although the pathogenesis remains uncertain,it likely involves high bone strain and repetitive submaximal stress, causingmicrofractures and microinfarcts-5. Other possible contributory factorsinclude vasculopathy of the vessels supplying the bones and osteoporosis. Osteoporosisis usually observed in SLE patients, increasing the risk of fractures, and itspathogenesis is multifactorial. High disease activity and immobility are also commonfactors that substantially increase fracture risk in these patients, as do other factorssuch as age, body mass index, and gender.Stress fractures may occur in SLE patients treated with corticosteroids, most commonly inthe femoral head but also in the footStaphylococcus aureus infection and opportunistic infections suchas those caused by Salmonella spp. should be considered, as shouldtuberculosis in regions where it is prevalent. In the majority of cases, osteonecrosisis asymptomatic and occurs early in the course of the disease. MRI is an excellent method for evaluating anddiagnosing musculoskeletal disorders-10, particularly complications relatedto bone fractures and osteonecrosis, thus allowing major sequelae to beavoided-5. T1-weighted sequences with fat suppression aftergadolinium administration, demonstrating soft tissue fluid collection with peripheralcontrast enhancement, are essential for the diagnosis of abscess and osteomyelitis.Complications of stress fractures, including osteonecrosis, septic arthritis, andosteomyelitis, have also been described and can be associated with SLE. Patients withSLE are more prone to bacterial infection due to factors such as quantitative orqualitative deficiencies of complement proteins, renal dysfunction, impairedphagocytosis, impaired chemotaxis, and the use of immunosuppressants. Apart fromappropriate imaging studies, patients suspected of having osteomyelitis should alwaysundergo a complete sepsis workup, including blood, urine, and stool cultures.Treatment usually involves proper antimicrobial therapy, immobilization, and appropriatesurgical treatment of infectious complications. For silent osteonecrosis involving asmall area, conservative treatment is usually adequate. However, for lesions that aresymptomatic, surgical interventions (core decompression or free vascularized bonegrafting) are required. When the lesion involves a weight-bearing area, there can bebone collapse, which requires total joint replacement."}
+{"text": "Marielle Moura Baena is not included in the author byline. Marielle Moura Baena should be listed as the sixth author and affiliated with Departamento de Zootecnia, Universidade Federal de Lavras, Lavras, Minas Gerais, Brazil. The contributions of this author are as follows: Data Curation, Formal Analysis, Investigation."}
+{"text": "PCC\u2019s associate degree program has long embraced an applied approach to gerontology education through its career pathway model. This model incorporates a rock-solid theoretical base, experiential learning, and skill-development, all grounded in the foundational, interactional and contextual AGHE Gerontology Competencies. The Competencies infuse all our courses, our five certificates and our degree to effectively prepare graduates for their next step, whether a transfer a specialized career. Our toolbox includes robust, wrap-around supports that include empowering advising and career planning, intentional internships, mentoring, networking opportunities, and our newest tool, The Flipping Mindsets Project. We will demonstrate how these evidence-based approaches provide students the knowledge, skills and confidence propelled by a positive mindset, to go boldly into any field of aging as innovators within existing jobs and programs or as ground-breaking entrepreneurs."}
+{"text": "Coronary symptoms associated with conditions related to mast cell activation and inflammatory cell interactions, such as those involving T-lymphocytes and macrophages, further inducing allergic, hypersensitivity, anaphylactic, or anaphylactic insults, are currently referred to as the Kounis syndrome. Kounis syndrome is caused by inflammatory mediators released during allergic insults, post-inflammatory cell activation, and interactions via multidirectional stimuli. A platelet subset of 20% with high- and low-affinity IgE surface receptors is also involved in this process. Kounis syndrome is not just a single-organ but also a complex multisystem and multi-organ arterial clinical condition; it affects the coronary, mesenteric, and cerebral arteries and is accompanied by allergy\u2013hypersensitivity\u2013anaphylaxis involving the skin, respiratory, and vascular systems in the context of anesthesia, surgery, radiology, oncology, or even dental and psychiatric medicine; further, it has significantly influences both morbidity and mortality. Kounis syndrome might be caused by numerous and continuously increasing causes, with broad clinical symptoms and signs, via multi-organ arterial system involvement, in patients of any age, thereby demonstrating predominant anaphylactic features in terms of a wide spectrum of mast cell-association disorders. Cardiac symptoms, such as chest pain, coronary vasospasm, angina pectoris, myocardial infarction, stent thrombosis, acute cardiac failure, and sudden cardiac death associated with subclinical, clinical, acute, or chronic allergic reactions, constitute the clinical manifestations of this syndrome. Since its first description, a common pathway between allergic and non-allergic coronary events has been demonstrated. The hypothesis is based on the existence of a much higher degree of mast cell degranulation at plaque erosion or rupture sites compared with at the adjacent areas or even more distant segments in post-acute myocardial infarction of non-allergic etiology. Although mast cell activation, differentiation, and mediator release takes days or weeks, the mast cell degranulation may occur just before any acute coronary event, further resulting in coronary artery vasoconstriction and atheromatous plaque rupture. It seems that medications and natural molecules stabilizing the mast cell membrane as well as monoclonal antibodies protecting the mast cell surface can emerge as novel therapeutic modalities for acute coronary and cerebrovascular event prevention. Allergic, hypersensitivity, anaphylactic, or anaphylactoid reactions associated with cardiovascular symptoms and signs appeared more than 7 decades ago as per the English, German, and Austrian medical literature ,2. Such Currently, allergic angina and allergic myocardial infarction constitute coronary artery disorders that might be caused by numerous and continuously increasing causes, accompanied with broadening clinical symptoms and signs, via multi-organ arterial system involvement in patients of any age and consisting a wide spectrum of mast cell-associated disorders ,13,14,15In this review, we present the pathophysiologic considerations of allergic angina, allergic myocardial infarction, and allergic stent thrombosis, which, together with their associations and clinical implications, constitute the manifestations of Kounis syndrome.Coronary syndromes related to mast cell-associated disorders and inflammatory cell interactions, such as those involving T-lymphocytes and macrophages, further inducing allergic, hypersensitivity, anaphylactic, or anaphylactoid insults, are currently referred to as Kounis syndrome .This syndrome is caused by inflammatory mediators released during an allergic insult, post-inflammatory cell activation, and interactions via multidirectional stimuli acting as a \u201cball of thread\u201d . A plateKounis syndrome is not only a single-organ disease but also a complex multisystem disease; it is accompanied by allergy\u2013hypersensitivity\u2013anaphylaxis involving the skin, respiratory, and vascular systems in the context of anesthesia, surgery, radiology, oncology, dermatology, or even dental and psychiatric medicine; further, it significantly influences both morbidity and mortality. Kounis syndrome resembles hypersensitivity \u201cblow up,\u201d affecting not only the coronaries but also the cerebral  and meseApproximately 4500 years ago, i.e., in the year 2600 BC, Pharaoh Menes died suddenly while traveling to the British Isles ; his deaIn the modern world, the correlation between cardiovascular disorders and anaphylactic reactions was established in the previous century . In partA century later, in post-mortem acute myocardial infarction of non-allergic etiology, a common pathway between allergic and non-allergic coronary events was established by the Finish researchers, demonstrating a much higher 200:1) degree of mast cell degranulation at plaque erosion or rupture sites compared with at adjacent areas or even more distant segments . Because00:1 degrThis unique association between anaphylaxis and the heart was published in the afore-mentioned comprehensive report published in 2006 , charactFurthermore, a potential relationship between drug-eluting coronary stent thrombosis and respective hypersensitivity to coronary stent components as a potential manifestation of Kounis syndrome was published during the same year .A variety of drugs, foods, environmental exposures, and clinical conditions can induce the Kounis syndrome . CommonlCorticosteroids constitute the main treatment of allergic, cutaneous, respiratory, rheumatologic, and renal diseases as well as immunosuppression in transplant recipients. Paradoxically, corticosteroids may themselves cause allergic reactions and even anaphylaxis. In a case report, prednisolone was administered in a young patient with normal coronary arteries for the treatment of wasp sting anaphylaxis; the patient was complicated by acute myocardial infarction, resembling the Kounis syndrome . As showAnisakis simplex, which secretes allergenic substances that can further cause anisakiasis and Kounis syndrome. In such cases, future abstention from eating raw or undercooked fish or seafood is always required. The later refers to fish poisoning by gram-negative bacteria containing the enzyme histidine decarboxylase, which converts the amino acid histidine (fish component) to histamine and further causes symptoms of Kounis syndrome. Scombroid food poisoning pathophysiology is not based on an IgE-mediated food allergy, and consequently, there is no need to avoid eating fish or seafood. However, refraining from spoiled fish consumption is necessary. Dental materials  needs \u201cattacking\u201d to elucidate its etiology and pathophysiology and to apply proper preventive and therapeutic measures . TakotsuSeveral reports have correlated Takotsubo cardiomyopathy with Kounis syndrome . TakotsuTherefore, a vicious cycle that makes the ATAK complex difficult to explain exists. Because anaphylactic reactions can also induce Takotsubo syndrome, we have proposed the measurement of anaphylactic inflammatory mediators such as histamine, tryptase, chymase, leukotrienes, thromboxane, and platelet-activating factors as well as the use of corticosteroids or mast cell stabilizers for the prevention of this condition . DiffereClinical and laboratory evidence have indicated that the heart, particularly the coronary arteries, constitute the primary targets of allergic inflammatory mediators where Kounis syndrome is the predominant feature.Independent of the reaction severity, cardiac dysfunction may develop during anaphylactic reactions and may resolve with suitable treatment post-anaphylaxis resolution . Using tAs per another report, cardiac troponin I levels were significantly increased in 31 patients admitted to the emergency department due to anaphylaxis, angioedema, urticaria, and urticaria angioedema, compared with 125 healthy controls . The carFurthermore, several animal studies have also shown that the heart, particularly the coronary arteries, could serve as a primary substrate in experimental anaphylaxis.Moreover, decrease in cardiac output by 90%, acute myocardial ischemia in the electrocardiogram, an initial increase in the arterial blood pressure by 35% followed by a decreace after 4 min, and a significant increase in the left ventricular end-diastolic pressure by 35% indicating pump failure had been observed in challenged ovalbumin-sensitized guinea pigs. The conclusion was that the anaphylactic cardiac damage might have been caused by peripheral vasodilatation and that the volume loss due to an increase in vascular permeability could definitely be excluded .However, anaphylaxis in sensitized mice induced an initial transient increase followed by a progressive decrease in post-antigen injection in aortic blood flow and mean arterial pressure, which were attenuated by pretreatment with either a platelet-activating factor receptor antagonist or the histamine H1 receptor antagonist diphenhydramine and were further abolished by their combination. Furthermore, no total peripheral resistance reduction was observed. Thus, the authors again concluded that mice anaphylactic hypotension could be only attributable to cardiac output reduction via platelet-activating factor and histamine actions and not to vasodilation .Diagnosing anaphylaxis in anesthesia is challenging because cutaneous manifestations, such as flushing, urticaria, and angioedema, may be absent. Several causes that can induce anaphylactic reactions and Kounis syndrome are encountered during anesthesia. Neuromuscular blocking drugs, antibiotics, latex exposure, contrast media, hypnotic agents, opioids, colloids, apronitin, protamine, chlorhexidine, dyes, local anesthetics, blood transfusion, and passive transfer of peanut allergens in blood products are some of the offenders. Anaphylaxis may occur at any time during anesthesia and with all potentially allergenic substances; however, it usually occurs shortly after induction.Several grading systems have been introduced for the classification of anaphylaxis during anesthesia. According to the Ring and Messmer system, which is the most frequently used , anaphylDuring surgery, several substances such as drugs, metal devices, polymers, latex, disinfectants, or infusion materials are used and may act as antigens able to induce hypersensitivity or anaphylactic reactions and Kounis syndrome. Extremely useful therapeutic inventions such as artificial cardiac valves, pacemakers, defibrillators, coronary stents, left ventricular assist devices, aortic grafts, stents for femoral arteries or metal prostheses used in orthopedics, and neurosurgery can induce foreign body reactions and hypersensitivity reactions due to their metal, polymer, and eluting drug ingredients. Several reports have correlated Kounis syndrome with device implantation. For example, Kounis syndrome with cardiogenic shock occurred during transfemoral transcatheter aortic valve replacement . The SAPContrast media that are used routinely in radiology have also been associated with Kounis syndrome.Iodine-based contrast media, used in radiology, are usually classified as ionic or nonionic. The low-osmolarity non-anionic contrast materials demonstrate lower side effects, at approximately 2.1%, compared to the anionic ones. However, mild symptoms that include fever, purpura, skin reactions, convulsions, dyspnea, renal damage, and the severe reactions such as hypersensitivity reactions including Kounis syndrome  and deatGadolinium is silvery-white metal and gadolinium-based contrast agents are used to improve the visibility of internal body structures in magnetic resonance imaging. This type of contrast agents may also be associated with the development of Kounis syndrome , howeverCancer and cardiovascular disease constitute the two major causes of death worldwide, along with chemotherapy, radiation therapy, and surgery, the main therapeutic modalities. Chemotherapy can induce cardiovascular deterioration manifesting acute and chronic symptoms, commonly referred to as cardiac toxicity. Cardiac toxicity might be acute, sub-chronic, and chronic and is a dose-dependent cardiovascular adverse reaction that persists despite the discontinuation of the causative treatment. The outcome of cardiac toxicity is a fibrotic response that should be confirmed histologically, a procedure that has not been discussed up to date. The final pathophysiological manifestation is global or septal cardiomyopathy with reduced left ventricular ejection fraction.However, most chemotherapeutic agents can induce hypersensitivity reactions. Cardiac hypersensitivity refers to an inflammatory response that is not dose-dependent, that may arise at any time during treatment, even with minimal drug concentrations, and is accompanied by anti-drug antibodies of IgG and IgE type. Indeed, chimeric monoclonal antibodies  such as anti-TNF-\u03b1, non-TNF blocking, and the epidermal growth factor receptor inhibitors have induced hypersensitivity reactions including Kounis syndrome up to 25.7%, platinum agents up to 27%, and taxanes up to 30% ,77.The human skin constitutes the target of the inflammatory mediators released from the mast cells and eosinophils during an allergic or anaphylactic episode. The allergic skin manifestations can be immediate, delayed, or absent. Urticaria, rash, erythema, and angioedema are some examples accompanying the Kounis syndrome and helping in its diagnosis. Delayed skin manifestations are thought to be due to vasoconstriction, induced by reduced cardiac output and hypotension during rapidly progressive anaphylaxis. The absence of skin manifestations  has beenPatients with systemic allergic reactions associated with clinical, electrocardiographic, angiographic echocardiographic, and laboratory findings of acute myocardial ischemia should be diagnosed as having Kounis syndrome. Serum tryptase, histamine, immunoglobulins (IgE), cardiac enzymes, and cardiac troponins are helpful to confirm the diagnosis. Tryptase should be measured half an hour after the initial symptoms and every 30 min thereafter during the following 2 h . In caseIn Kounis syndrome, the newer techniques such as thallium-201 single-photon emission computer tomography (SPECT) and 125I-15-(p-iodophenyl)-3- methyl pentadecanoic acid (BMIPP) SPECT have revealed severe myocardial ischemia, while coronary angiography showed normal coronary arteries . FurtherKounis syndrome should be treated with careful attention, because the drugs administered to treat cardiac manifestations can worsen allergy, and the drugs given for the allergic symptoms can aggravate the cardiac dysfunction.In type I variant, treatment includes intravenous corticosteroids such as hydrocortisone at a dose of 5 mg/kg/day and H1 and H2 antihistamines such as diphenhydramine at a dose of 1-2 mg/kg and ranitidine at a dose of 1 mg/kg. Vasodilators such as calcium channel blockers and nitrates can abolish the vasospasm. Intravenous or sublingual nitroglycerin seems reasonable and safe in patients with Kounis syndrome, if the blood pressure is satisfactory. Most patients have demonstrated well tolerance to oral and sublingual nitroglycerin . Moreover, an aqueous solution is preferable. Epinephrine may be ineffective in patients already on beta-blockers.Glucagon infusion  can be given in this case . MethoxaIn type III variant, treatment includes the current acute myocardial infarction protocol, urgent aspiration of intrastent thrombus, and its histological examination with staining for eosinophils (hematoxylin and eosin) and mast cells (Giemsa). Allergic symptoms and signs following stent implantation need antihistamines, corticosteroids, and mast cell stabilizers. When symptoms persist, identification of the culprit with patch and/or prick skin tests and desensitization strategies should be applied. If these measures fail, stent extraction seems unavoidable .Kounis syndrome is a unique complex cause of acute coronary syndrome that requires proper diagnosis, immediate decisions, and rapid treatment. A high index of suspicion, when dealing with an allergic reaction, is of paramount importance. It needs a full cardiologic work-up, including a 12-lead electrocardiogram, echocardiogram, angiogram, and cardiac risk factor modification, following the acute phase. An atopic work-up should be performed including the assessment of any food allergies, insect stings, Hymenoptera bites, drugs, and other environmental agents or conditions. Skin patch or prick tests and food challenges may be additional useful measures for the culprit cause identification."}
+{"text": "Scientific Reports 10.1038/srep41322, published online 23 January 2017Correction to: This Article contains errors in the affiliation list, where Min Liu and Xiaoming Zhong are incorrectly affiliated with \u2018Department of Pharmacy, Songjiang Hospital Affiliated Shanghai First People\u2019s Hospital, Shanghai Jiao Tong University, Shanghai, China\u2019.The correct affiliation for Min Liu is listed below:Urology Department, First Affiliated Hospital of Gannan Medical University, Gannan Medical University, Ganzhou, ChinaThe correct affiliation for Xiaoming Zhong is listed below:Jiangxi Province Tumor Hospital, Nanchang, China"}
+{"text": "Lavender officinalis), in treating anxiety disorders strongly suggests that these natural products are an important candidate source for new anxiolytic drugs. A systematic review of essential oils, their bioactive constituents, and anxiolytic-like activity is conducted. The essential oil with the best profile is Lavendula angustifolia, which has already been tested in controlled clinical trials with positive results. Citrus aurantium using different routes of administration also showed significant effects in several animal models, and was corroborated by different research groups. Other promising essential oils are Citrus sinensis and bergamot oil, which showed certain clinical anxiolytic actions; along with Achillea wilhemsii, Alpinia zerumbet, Citrus aurantium, and Spiranthera odoratissima, which, like Lavendula angustifolia, appear to exert anxiolytic-like effects without GABA/benzodiazepine activity, thus differing in their mechanisms of action from the benzodiazepines. The anxiolytic activity of 25 compounds commonly found in essential oils is also discussed.The clinical efficacy of standardized essential oils (such as  GAD maintains a significant prevalence and causes important personal, family, and social impairments, which makes adequate treatment of GAD patients essential.Generalized anxiety disorder (GAD) is characterized by a high and free-floating anxiety, revealing both psychic , azaspirone (buspirone), and antidepressants . More recently, the anticonvulsant pregabalin has been introduced to treat GAD. However, all of these drug treatments have important drawbacks, such as abuse/dependence liability, retrograde amnesia (benzodiazepines), clinical effect delay (buspirone and antidepressants), sexual dysfunction (antidepressants), sedation , and dizziness , all of which affect clinical adherence . Though Lavender officinalis, called Silexan, which has been found effective for GAD patients  flunitrazepam binding. On the other hand, WAY 100635 (a 5-HT1A antagonist) blocked the anxiolytic-like effect of lavender in marble-burying test. Lavender essential oil also reduced 8-OH-DPAT (5-HT1A agonist) induced serotonergic syndrome. These results indicate that the anxiolytic-like effect of lavender essential oil may be mediated by serotonergic transmission.Chioca and collaborators  observedA subsequent study by the same group replicated the anxiolytic-like effect of lavender essential oil in the marble-burying test, and it was observed that this effect was similar in mice with normal olfactory function, as compared to mice with anosmia, which suggests that odor perception was not crucial. The normal (non-anosmic), and anosmic mice (both treated with vehicle) results did not differ . Using aL. officinallis and L. latifolia), which differ in linalool and linalyl acetate contents. They observed that male mice treated with inhaled lavender essential oils that contain linalool and linalyl acetate spent more time in the open arms of the elevated plus-maze than the controls. These effects were seen without changes in the distance travelled in the maze, indicating an anxiolytic-like effect. However, there is no relationship between linalool content and anxiolytic-like effect, yet a positive correlation (r = +82) was seen between linalool and linalyl acetate content and increased open arm exploration. These results suggest that linalyl acetate, which showed no anxiolytic-like action per se, increased the anxiolytic-like effect of linalool.In a very interesting study, Takahsahi and collaborators  evaluateAnother study from Takahashi and co-workers  found thL. angustifolia flowers containing 36% linalool and 34% linalyl acetate muscimol (GABA-A) site [3H]MK801 (NMDA glutamate) cortex binding [It was shown that linalool interacts with GABA-A receptors and potentiates GABA transmission , althoug-A) site . Linaloo binding . More re binding  showed tMyrtus communis, a plant used in Brazil to treat \u201cnervous conditions\u201d [Myrtenol is a compound originating from essential oil of ditions\u201d . Moreiraditions\u201d  evaluatePhytol administration  in mice (gender not specified) increased open arm exploration (number of entries and time spent) in the elevated plus-maze, and increased social interaction, while decreasing the numbers of marbles buried . These eMentha piperita and Mentha pulegum L. Silveira and collaborators [Pulegone, a monoterpenic compound, is found in the essential oils of borators  observedborators , which pOriganum vulgare and Ocimum gratissimum L.), was tested in female quail submitted to mechanical restraint stress [Thymol, a main component of certain aromatic plant essential oils, from s , showed anxiolytic-like effect in male rats tested in the elevated plus-maze and light-dark tests [Vanillin, a component of rk tests . Acute aCitrus aurantium, Cymbopogon citratus, Lavendula angustifolia, and Lippia alba. Although Citrus sinensis and bergamot oil have one pre-clinical study, clinical studies showing an acute anxiolytic effect in normal volunteers [Achillea wilhemsii, Angelica sinensis, Alpinia zerumbet, Celastarus paniculatus, Citrus janus, Citrus latifolia, Citrus reticulate, Cymbopogon citratus, Copaifera reticulate, Ducrosia anethifolia, Foeniculum vulgare, Spiranthera odoratissima and Stachys tibetica (only one study), Litsea cubeba, Ocimum gratissimum, Piper guineense and Propolis , Abies sachalinensis,Chamaecyparis obtuse and Dennettia tripetala (absence of motor activity measurement). Citrus limon and rose oil had contradictory results. Although there was one negative result with rose oil [Reviewing the results for essential oils in animal anxiety models, clear anxiolytic-like effect was found for lunteers ,97 strenrose oil , other srose oil ,65,66.Achillea wilhemsii, Alpinia zerumbet, Lavendula angustifolia, Citrus aurantium, and Spiranthera odoratissima did not act thru the GABA/BDZ system.It is very interesting that the pre-clinical studies suggested that some essential oils do not act by the GABA/benzodiazepine mechanism. This might contribute to develop a truly new and different class of anxiolytics, possibly with a better clinical profile, and avoiding benzodiazepine\u2019s drawbacks . However, even drugs acting thru the GABA/benzodiazepine system could be interesting . In this line, the studies reviewed indicated that essential oils from The elevated plus-maze is the most frequently used animal model, similar to that observed by Tsang and Ho , followei.e., at least two different doses/concentrations), to reduce the chance of false-negative and false-positive results.Moreover, considering the probability of false positive  results it is also important to evaluate a potential new anxiolytic drug in at least two different animal models of anxiety, since different models are sensitive to different anxiolytic treatments ,6,87. ThWhen considering these results for essential oils, positive results in several animal models (and in different species), employing a dose/concentration-response design and a lower toxicity profile, are promising for tests in a clinical setting. Lavender essential oil is a good example, since it revealed positive results in different animal models , and in different species . It may be noted that most of the studies reviewed used acute administration, and different routes of administration , which may be not related (or convenient) for clinical use in patients with generalized anxiety disorder. In this line, for a putative anxiolytic and chronic use, repeated systemic oral administration must be evaluated. However, it must also be stressed that acute inhaled essential oil might be used in other clinical situations, and that the approach is adequate. For example, the studies of Lehrner and collaborators  and KritAttention must be given to certain methodological aspects. Motor activity must be appropriately evaluated, since changes in motor activity  can interfere with behavior in animal anxiety models. For example, although some authors proposed the total number of arm entries as a measure of activity in the elevated plus-maze , other aAnother important issue is to use a validated and standardized procedure to better translate pre-clinical results to the clinical. For example, the standard procedure for the elevated plus-maze employs a 5-min session  while soAs noted by Tsang and Ho , it is aIt has been proposed that odor has an effect, activating olfactory receptors or neurons in the vomeronasal organ, and activating limbic areas, such as the amygdala ,82,119. Searches were performed in the scientific literature databases: Chemical Abstracts, PubMed, and Web of Science through December 2014 using the following key words: essential oils , anxiety, animal models, . The search was restricted to English, and to experimental studies. An additional manual reference search in all of the articles found by the electronic search was also performed. We only included essential oils having as a minimum one study suggesting anxiolytic-like effect; essential oils with exclusively negative results were not included.Achillea wilhemsii, Angelica sinensis, Alpinia zerumbet, Celastarus paniculatus, Chamaecyparis obtuse, Citrus aurantium, Citrus aurantium subsp. bergamia, Citrus janus, Citrus latifolia, Citrus reticulate, Citrus sinensis, Cymbopogon citratus, Copaifera reticulate, Ducrosia anethifolia, Foeniculum vulgare, Lavendula angustifolia, Lippia alba, Spiranthera odoratissima and Stachys tibetica (only one study). Some of these essential oils are particularly interesting: Achillea wilhemsii, Alpinia zerumbet, Lavendula angustifolia, Citrus aurantium, and Spiranthera odoratissima,since their activity is not likely to be related to the GABA/BDZ system; and Lavendula angustifolia, Citrus sinensis and Citrus aurantium subsp. bergamia, since they have demonstrated clinical efficacy in controlled studies. Among the 25 constituents of essential oils with reported anxiolytic activity, no chemical characteristic was found common to all, except low molecular weight. It was not possible therefore to establish structure-activity relationships for this collection of psychoactive compounds.In conclusion, reviewing the literature of essential oils in animal models of anxiety, certain essential oils exerted anxiolytic-like effect in differing animal models and species; as such the following oils reveal the stronger potential for development of new treatments for anxiety disorders."}
+{"text": "Probiotics per definition should have beneficial effects on human health, and their consumption has tremendously increased in the last decades. In parallel, the amount of published material and claims for their beneficial efficacy soared continuously. Recently, multiple systemic reviews, meta-analyses, and expert opinions expressed criticism on their claimed effects and safety. The present review describes the dark side of the probiotics, in terms of problematic research design, incomplete reporting, lack of transparency, and under-reported safety. Highlighted are the potential virulent factors and the mode of action in the intestinal lumen, risking the physiological microbiome equilibrium. Finally, regulatory topics are discussed to lighten the heterogeneous guidelines applied worldwide. The shift in the scientific world towards a better understanding of the human microbiome, before consumption of the probiotic cargo, is highly endorsed. It is hoped that better knowledge will extend the probiotic repertoire, re-confirm efficacy or safety, establish their efficacy and substantiate their beneficial effects. On the evolutionary aspect, microorganisms inhabited our globe 3.8 billion years ago, much earlier than the genus Homo emerged in Africa, 2.5 million years ago [For a long time and mainly in the last decades the scientific, medical, industrial, and consumer communities have started to unravel the \u201csuperorganism\u201d or \u201cthe second brain\u201d presented by the prokaryotes dwelling inside the human enteric lumen ,2,3. Theears ago . Thus, mears ago ,8. Notabears ago .lactobacilli, Bifidobacterium, lactococci, and streptococci. Yeast, bacilli, and some non-pathogenic E. coli strains are less often used. The ingested and nutritional, industrially used probiotics and starter cultures were generally considered as safe, for many years, but recently a change in trend has appeared.The situation is completely different with the much later evolutionary introduction of probiotics, most probably during the Neolithic layer of the stone age period, nearly 10,000 years ago . Louis PThe present review will summarize the questionable or unsubstantiated benefits of probiotics in a meta-analysis, highlighting their negative side, side effects, and expanding on their potential harmful capacities, mechanistic pathways, and potential hazards for human health.lactobacilli strains was valued at 1.2 billion US dollars in 2017, while the Bifidobacterium market size prediction will increase close to 6% until 2024 and the Bacillus strain market size may surpass 180 million US dollars by 2024 [According to several reports, probiotics were used, unintentionally, nearly 10,000 years ago, but spread as fermented milk in previous centuries, mainly in Europe, where in the Balkan regions life span longevity and healthy life were attributed to their fermented yogurt. Their food application expanded earlier and on a larger scale compared to the sales in sachets, capsules, or other pharmaceutical preparations . It seem by 2024 . Accordi by 2024 .The medical and non-medical indications to consume, over the counter, probiotics is constantly increasing. The present review is not intended to cover or update on the various indications for probiotic ingestion but will highlight their usage as a supplement to pharmaceutical therapy of, for example, autoimmune conditions.The holistic enteric compartment with its active luminal organ, presented with abundant prokaryotic flora, creates multifunctional defense mechanisms, preventing pathogenic invaders while keeping the microbiome at bay ,8,9. HowThe etiology, pathomechanisms, initiation, maintenance, progression, and modulation of autoimmunogenesis are continuously evolving. On the other hand, it is not yet understood why 5\u20138% of the general public is affected by autoimmune conditions. Four mechanisms were suggested for autoimmunity generation: molecular mimicry, self-antigen modification, bystander activation, and immune reactivity modulation . The plaThe purpose of the current review is to protest against that repetitive declaration and to justify the opposite of its dual messages: 1. According to multiple recent meta-analyses, probiotic clinical benefits are questionable or disqualified. 2. Probiotics can present a Trojan horse that works against human health.Microbes possess an extended arsenal of hostile factors, capable of suppressing or destroying vital eukaryotic host mechanisms, for their advantage. Probiotics are an integral part of the prokaryotic kingdom with evolutionary conserved self-survival systems, in ex vivo and in vivo environments; above all, mainly in the overpopulated, extremely competitive, harsh ecological niche of the human gut. Ingestion of probiotic bacteria or products creates a survival struggle between the well-established inhabitant microbiome. Microbiome in the enteric compartment with the new probiotics.In addition to the clinically reported multiple side effects in the literature, several pathogenic virulent potential pathways can be expressed in and executed by probiotics, thus affecting human health integrity. The following details several such pathomechanistic avenues.HGT is the lateral movement of mobile genetic elements between unicellular or multicellular organisms. It enables the transfer of genes even between distant species mediated usually by transformation, transduction, conjugal transfer, or with specific gene transfer agents . The topLactobacillus paracasei [Lactobacillus rhamnosus [Lactobacillus reuteri [Lactobacillus gasseri [Lactobacillus plantarum [Screening the literature, multiple publications describe the existence and transfer of hostile mobile genetic elements in and from probiotics . Taking,aracasei , Lactobahamnosus , Lactoba reuteri ,70,71, L gasseri , Lactobalantarum , involvilantarum . Even iflantarum , HGT betlantarum . The cumlantarum .Lactobacillus reuteri ATCC 55730, which is not commonly reported in probiotic research. However, antibiotic gene transfer is only one aspect of virulent genes and was taken just as an example. Gelatinase and hemolytic activities and several enzymes like peptidases, acid phosphatase, phosphohydrolases, \u03b1 + \u03b2- galactosidases, and N-acetyl-\u03b2-glucosaminidase were depicted in lactic acid bacteria of aquatic origin intended for use as probiotics in aquaculture [A special compliment should be given to Rosander et al.  who wrotaculture . Most reaculture ,80. Inteaculture ,83,84,85aculture , with fuaculture ,88,89,90aculture . Finallyaculture ,97,98,99The success and efficiency of probiotics depends on numerous factors that can be divided into microbiotic-exogenous, host-endogenous, and luminal-environmental . One of Lactobacillus paracasei or gasseri [Lactococcus lactic [They can be regarded as human pathogens, interacting directly or indirectly with prokaryotic, probiotics, as well as eukaryotic cells, including involved in protein misfolding, carrying prion-like domains ,105. Pro gasseri ,114,115,s lactic ,120,121,The probiotic bacteriophages are a potential carrier of hostile genes that by transfecting prokaryote or eukaryote cells, can spread genetic material. Finally, it appears that some bacteriophages contain virulent transglutaminase genes, thus representing additional tranglutaminase activity in the intestinal lumen ,90, in aLactobacillus rhamnosus, Lactobacillus gasseri, Lactobacillus paracasei, Lactobacillus reuteri, Lactobacillus plantarum, and many others [Probiotics are heavily used in the processed food industries, spanning not only dairy fermented products, but also in wider industrial applications including medical, diagnostic, pharmacological, and biotechnological industries ,127,128.y others ,89,90,91Lactobacillus and Bifidobacterium species are the most used bacteria in probiotic formulations and they produce d-lactate [d-lactic acidosis [d-lactic acidosis and other etiologies for acidosis are associated with neurocognitive symptoms, neurological impairments, and chronic fatigue syndrome [Probiotic consumption is associated with D-lactic academia and acidosis in adults and infants on probiotic-containing formula ,138,139.-lactate ,141,142 syndrome ,143,144,syndrome . Despitesyndrome ,147, thed-lactic acidosis [d-lactic acid production, increased gas output, and abdominal bloating. The d-lactic acidosis is the culprit for the brain fogginess. They suggested that this unique entity is an additional side effect of probiotic consumption.This paragraph is related to the above paragraph and might explain the pathophysiology of the acidosis and brain fogginess described above. Rao et al. described a new syndrome relating post-prandial brain fogginess, gas, and abdominal bloating to small intestinal bacterial overgrowth and probiotic-induced acidosis ,139. AddThe medical literature warns against probiotic consumption in congenital or acquired immune debilitating conditions, heart anomalies, chemo- and radiotherapies, surgical abdomen, HIV-infected, critically ill, post-organ transplantation, post-operation, central venous catheters, autoimmune disease on immune suppression, pregnancy, neutropenia, critically ill patients, including antibiotic-associated diarrhea, active ulcerative colitis, and potential for translocation of probiotic across bowel wall ,148,149.The list of probiotic\u2019s adverse effects is expanding, however, due to a lack of safety and toxicity standardized protocols and regulatory implementations, the list is under-representative. It is clear that more safety and toxicity designed studies are needed to reveal the negative side of probiotic use ,154,165.Clostridium difficile-associated diarrhea, and respiratory tract infections the effects of probiotics are considered \"evidence-based\". Concerning other fields, meta-analyses fail to define the type and biologic effect of probiotic strains, as well as the outcome in a disease state. The authors concluded that: \u201cFurther studies are needed, because the available evidence is insufficient to show the efficacy of probiotics themselves. Carefully designed clinical trials are needed to validate the effects of particular strains of probiotics given at specific dosages and for specific treatment durations.\u201dThe current review aims to highlight the negative side of probiotic consumption. As such, followed herein are the most recent systemic reviews and meta-analyses that criticize multiple aspects of the medical publications on probiotic efficacy and safety . Many ofMore recent systemic reviews or meta-analyses, from 2018, did not demonstrate differences of outcomes, using probiotics, on the treatment success of: constipation , traveleIt seems that scientific and medical societies should \u201cmind the gaps\u201d between published studies praising probiotic therapeutical efficacy and a lack of substantiation when analyzed by more objective, standardized methodologies, such as critical systemic reviews or meta-analyses. More so, when intestinal microbiota composition was assessed on probiotic intake, no significant changes were depicted ,48,140. The present review cannot be completed without an update on probiotic safety. The food and drug administration consider some probiotics, as GRAS, when added to food , especiaQuite often patients consume probiotics while physicians encourage probiotic consumption, despite their potentially harmful effects. The notion of \u201cgood bacteria\u201d and the manufacturers\u2019 claim of \u201chealth promotion\u201d or \u201cbalancing\u201d normal gut flora should be taken with a \u201cgrain of salt.\u201d In two seminal studies from an Israeli group recently published ,43 it waThe present review intended to summarize the somber side of probiotics, highlighting the potential detrimental effects embedded in the fact that probiotics are prokaryotes, and as such, contains hostile factors, in order to survive. They are capable of inducing local and systemic adverse effects  thus con"}
+{"text": "Physician chart documentation can facilitate patient care decisions, reduce treatment errors, and inform health system planning and resource allocation activities. Although accurate and complete patient chart data supports quality and continuity of patient care, physician documentation often varies in terms of timeliness, legibility, clarity and completeness. While many educational and other approaches have been implemented in hospital settings, the extent to which these interventions can improve the quality of documentation in emergency departments (EDs) is unknown.We conducted a systematic review to assess the effectiveness of approaches to improve ED physician documentation. Peer reviewed electronic databases, grey literature sources, and reference lists of included studies were searched to March 2015. Studies were included if they reported on outcomes associated with interventions designed to enhance the quality of physician documentation.Nineteen studies were identified that report on the effectiveness of interventions to improve physician documentation in EDs. Interventions included audit/feedback, dictation, education, facilitation, reminders, templates, and multi-interventions. While ten studies found that audit/feedback, dictation, pharmacist facilitation, reminders, templates, and multi-pronged approaches did improve the quality of physician documentation across multiple outcome measures, the remaining nine studies reported mixed results.Promising approaches to improving physician documentation in emergency department settings include audit/feedback, reminders, templates, and multi-pronged education interventions. Future research should focus on exploring the impact of implementing these interventions in EDs with and without emergency medical record systems (EMRs), and investigating the potential of emerging technologies, including EMR-based machine-learning, to promote improvements in the quality of ED documentation.The online version of this article (10.1186/s12873-018-0188-z) contains supplementary material, which is available to authorized users. While we employed an extremely comprehensive search strategy, inconsistencies in the indexing of studies in electronic databases and our decision to restrict our search to English or French language publications, may have impacted on our ability to identify all relevant studies. Further, variability in study design and outcomes assessed across studies limited our ability to quantitatively compare the outcomes from individual studies, and assess the overall effectiveness of many of these approaches. Finally, the preponderance of pre-experimental studies  database. (DOC 25\u00a0kb)"}
+{"text": "Opioid use by pregnant women represents a significant public health concern given the association of opioid exposure and adverse maternal and neonatal outcomes, including preterm labor, stillbirth, neonatal abstinence syndrome, and maternal mortality ( Data were analyzed from the National Inpatient Sample  and the State Inpatient Databases  of HCUP, Agency for Healthcare Research and Quality . International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnostic and procedure codes pertaining to obstetric delivery  to 48.6 (Vermont).National, state, and provider efforts are needed to prevent, monitor, and treat opioid use disorder among reproductive-aged and pregnant women."}
+{"text": "Behavioral and psychosocial factors related to development of cardiovascular disease have been gaining increased attention. Notably, sleep is considered to be one of the most important behavioral factors involved in progression of atherosclerosis and cardiovascular events, with autonomic nervous function a potential mechanism. Several studies have shown associations of sleep and autonomic dysfunction with major surrogate markers of atherosclerosis, such as carotid intima-media thickness and arterial stiffness. Endocrinological, immunological, oxidative, inflammatory, and metabolic responses, as well as endothelial dysfunction may mediate the effects of the autonomic nervous system. For this review, we examined recent findings related to sleep, autonomic nervous dysfunction, and atherosclerosis, with the aim of understanding the involved pathophysiological mechanisms. Classical cardiovascular risk factors, including obesity, hypertension, dyslipidemia, diabetes mellitus, and chronic kidney disease (CKD), are established predictors of atherosclerosis and cardiovascular disease (CVD) ,2,3. RecSleep duration and quality can be measured by subjective methods, including self-reported questionnaires, the Epworth Sleepiness Scale (ESS), and Pittsburg Sleep Quality Index (PSQI), as well as by objective methods, including actigraphy ,9, whileSeveral studies have found relationships of short sleep duration, low sleep quality, and autonomic dysfunction with carotid intima-media thickness (IMT) and brachial-ankle pulse wave velocity (baPWV), which are major surrogate markers of atherosclerosis and established predictors of cardiovascular events ,15. We rn = 330) with cardiovascular risk factors, we showed that apnea-hypopnea index (AHI) assessed by an apnomonitor and poor sleep quality determined with actigraphy were each significantly and positively associated with carotid IMT and plaque score [Several epidemiological studies have suggested associations of short sleep duration, low sleep quality, and obstructive sleep apnea (OSA) with atherosclerosis. ue score . Regardiue score , while oue score . Arteriaue score .n = 306) in association with the HSCAA study was the first to show a relationship of low sleep quality with progression of baPWV [Until recently, no prospective study examined the association of sleep duration or quality with atherosclerotic progression in patients with atherosclerotic factors. Our report presented in 2018 of a 3-year longitudinal investigation (n = 2383) [n = 18,106), Kim et al. reported that both longer (>8 h) and shorter (<5 h) sleep durations were associated with higher baPWV as compared with recommended sleep time (7 h) [Some largescale studies examined associations of subjective and objective sleep duration, and quality with carotid IMT and baPWV in healthy general populations . In an i = 2383) . Abe et  = 2383) . Additio = 2383) ,27, whilme (7 h) . Yoshiokme (7 h) . Also, ime (7 h) . More reme (7 h) .Short sleep duration and low sleep quality can have strong effects on several aspects of endocrinological, immunological, and metabolic responses. Both are known to disturb the daily rhythm of the hypothalamic-pituitary-adrenal axis. Following activation of that axis, resultant higher cortisol levels are associated with insulin resistance, cardiovascular risk factors, and coronary heart disease . Also, LIt has also been reported that oxidative stress, subclinical systemic inflammation, and endothelial dysfunction may mediate the effects of short sleep duration and low sleep quality ,36,37. SIn addition to progression of atherosclerosis, several have reported close associations of sleep condition with obesity, including epidemiologic examinations that found an association between short sleep duration and weight gain ,45,46. PA longitudinal study reported that low sleep quality due to insomnia increases the risk for hypertension . The assHRV provides a practical means to assess impaired autonomic nervous function in clinical settings by use of continuous electrocardiographic records, as those reflect sympatho-vagal balance and parasympathetic nervous activity.It has been shown that reduced HRV predicts all-cause mortality and cardiovascular events , while tAutonomic nervous dysfunction can cause alterations in immunological response and endothelial dysfunction, which eventually could lead to progression of atherosclerosis, while an increased level of inflammatory cytokines may mediate the effects of autonomic nervous dysfunction on atherosclerosis progression ,70. SimiFurthermore, autonomic nervous dysfunction disturbs metabolic factors and may be attributable to classical atherosclerotic risk factors, such as hypertension, dyslipidemia, and diabetes mellitus. Yamada and Katagiri showed that the autonomic nervous system plays an important role in communicating organ-to-organ metabolic information . Using tThe effects of autonomic dysfunction on atherosclerosis may be mediated by endocrinological alterations, including circulating epinephrine , as wellFatigue is a common symptom in patients with a variety of conditions. Although the pathophysiological details have not been well characterized, it is known to be associated with continuous short sleep deprivation and low sleep quality. Recent epidemiological studies have found that fatigue is more common in patients with cardiovascular risk factors, such as diabetes , obesityBehavioral and psychosocial factors, especially sleep, have been gaining increased attention in regard to their relationship with development of cardiovascular disease. In this review, we aimed to focus on the pathogenic impact of sleep problems, autonomic nervous function, and fatigue in relation to development of atherosclerosis and cardiovascular diseases . It is p"}
+{"text": "Intriguingly, allergens, including ovalbumin (OVA), Alternaria alternata, and cockroach allergen, have also been shown to induce autophagy through activation of different signaling pathways. Additionally, mitochondrial dysfunction can induce cell senescence due to excessive ROS production, which affects airway diseases. Although autophagy and senescence share similar properties, recent studies suggest that autophagy can either accelerate the development of senescence or prevent senescence. Thus, in this review, we evaluated the literature regarding the basic cellular processes, including autophagy, mitophagy, and cellular senescence, explored their molecular mechanisms in the regulation of the initiation and downstream signaling. Especially, we highlighted their involvement in environmental pollutant/allergen-induced major phenotypic changes of asthma such as airway inflammation and remodeling and reviewed novel and critical research areas for future studies. Ultimately, understanding the regulatory mechanisms of autophagy, mitophagy, and cellular senescence may allow for the development of new therapeutic targets for asthma.Environmental pollutants and allergens induce oxidative stress and mitochondrial dysfunction, leading to key features of allergic asthma. Dysregulations in autophagy, mitophagy, and cellular senescence have been associated with environmental pollutant and allergen-induced oxidative stress, mitochondrial dysfunction, secretion of multiple inflammatory proteins, and subsequently development of asthma. Particularly, particulate matter 2.5 (PM Chloroqfication . In addification . HoweverIt has also been suggested that targeting mitophagy may possess therapeutic potential. Rapamycin and metformin as general autophagy-inducing drugs have been shown to attenuate AMPK and mTOR activity, and preserve energy metabolism through regulating mitophagy and mitochondrial biogenesis stimulation , 194. OfLastly, there is ongoing research to target senescence in cases of pulmonary fibrosis and asthma . Specifi2.5 was reported to induce autophagy through activating AMPK (2.5 was also shown to induce senescence of human dermal fibroblasts (2.5 exposure was correlated with shortened telomeres in placental tissue and umbilical blood (A. alternata (Dysregulations in autophagy, mitophagy, and cellular senescence have been associated with environmental pollutant/allergen-induced oxidative stress, mitochondrial dysfunction, secretion of multiple inflammatory proteins known as SASP, and development of asthma. PMing AMPK , and to ing AMPK . PM2.5 wroblasts , while ial blood . Intrigual blood , A. altelternata , and coclternata , 111, haKS, YZ, XH, and JC wrote the manuscript. DD and PG reviewed the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In this article, a new conceptual biomedical engineering strategy to tackle modern disease challenges, called liquid metal (LM) enabled electrobiology, is proposed. This generalized and simple method is based on the physiological fact that specially administrated electricity induces a series of subsequent desired biological effects, either shortly, transitionally, or permanently. Due to high compliance within biological tissues, LM would help mold a pervasive method for treating physiological or psychological diseases. As highly conductive and non-toxic multifunctional flexible materials, such LMs can generate any requested electric treating fields (ETFields), which can adapt to various sites inside the human body. The basic mechanisms of electrobiology in delivering electricity to the target tissues and then inducing expected outputs for disease treatment are interpreted. The methods for realizing soft and conformable electronics based on LM are illustrated. Furthermore, a group of typical disease challenges are observed to illustrate the basic strategies for performing LM electrobiology therapy, which include but are not limited to: tissue electronics, brain disorder, immunotherapy, neural functional recovery, muscle stimulation, skin rejuvenation, cosmetology and dieting, artificial organs, cardiac pacing, cancer therapy, etc. Some practical issues regarding electrobiology for future disease therapy are discussed. Perspectives in this direction for incubating a simple biomedical tool for health care are pointed out. In the cutting-edge field of disease therapy, physiotherapy has received great attention via physical agents such as electricity, magnetism, sound, light, heat, freezing, water, mechanical force, etc. Typical physiotherapy methods generally include: electrotherapy, magnetotherapy, ultrasound therapy, phototherapy, hyperthermia, and cryotherapy ,2,3. ComElectrotherapy, using electrical energy as a medical tool, has been applied for disease treatment since 1855 and has offered significant therapeutic effects . In prin24.5, the most common LM, refers to the mixture of 75.5% gallium and 24.5% indium by weight. However, mercury, a kind of traditional RTLM, is excluded from ES material because of its high toxicity to the human body. To take advantage of its native properties, RTLM has shown great potential in numerous newly emerging fields, such as microfluidics .,54.53,54V by Boltzmann distribution . . 6]. In Most recently, a kind of LM electrode is developed which is useful in neuromuscular stimulation . As showSurprisingly, it has also been demonstrated that LM can reconnect broken nerves and restore their function , which mSkin care and weight loss are increasingly popular nowadays. As the visible organ with multiple physiological functions, skin has been a hot topic in youthful study . In addiPainting LM on skin surface, electrical stimulation induces cell proliferation to make skin a better protective barrier that mitigates exposure to external factors such as extreme temperature, microorganisms, and radiation. Consequently, youthful and healthy skin can appear via electrostimulation treatment. Furthermore, stimulating facial muscles and skin can improve circulation, activate fibroblasts and tone flaccid and sagging facial muscle . ConformBrown adipose tissue (BAT) is a heat-producing organ that plays an important role in decomposing human white adipose tissue (WAT) to reduce the risk of obesity ,92,93,94It is also believed that electrical stimulation with wearable LM-based electronics makes the users more likely to participate in exercise, since ES devices are comfortable and effective when doing sports. It allows the body to activate muscles without strain or stress and reduces the risk of injuries . CombiniAmit et al. realized a soft coil based on LM and demonstrated that this coil is an excellent alternative to stiff and uncomfortable coils for biomedical implants . LM was Stefan et al. designed a new cochlear implant electrode with LM . CommonlRecent research has been conducted to apply LM to prostheses. Prostheses can be divided into two types: aesthetic functional devices and myoelectric devices. In particular, myoelectric prostheses work by sensing electrical signals from nerves and muscles via electrodes. Combining LM electrodes with signal process systems, the motion of prostheses can be controlled by users precisely. To meet even higher standards, a smart prosthetic hand should not only receive the instructions from the nervous system and make corresponding responses, but also feel various types of external stimuli and transmit signals to the corresponding peripheral nervous system to realize better control E 103,10. For thiWith the development of microfluidic technologies, LM can be used to produce soft tactile sensors, which has great potential in sensing skin, such as temperature, sweat analysis, skin patches and pressure, based on the change of resistance and capacitance. For instance, Jung et al. combined microfluidic channels and LM together to make a pressure sensor . AdditioFor the treatment of heart-rhythm diseases, advanced capabilities in electrical recording and stimulation are essential . CardiacCombining with specific sensors or chips, multifunctional soft devices are produced. Attaching the device onto soft skin, stable physiological signals , ECG (electrocardiogram), sweat, temperature, pulse, and gait etc.) can be detected in human activities. An intelligent electronic skin network A based oSome in vitro evidence has demonstrated the efficacy of tumor-treating electrical fields on cancer therapy, such as human melanoma, glioma, lung, prostate, pancreas, and breast; mouse adenocarcinoma and melanoma; and rat glioma ,112,113.In addition, Immunization therapy in the present paper refers to the enhancing or inhibiting of an organism\u2019s immune system due to the introduction of electrical stimulation to achieve a desired therapeutic output. Unlike conventional immunization therapy through injecting immunostimulant or immunosuppressive drugs into a patient\u2019s body, the novel immunization therapy will enable minimally invasive disease therapy with no drugs to inject into human body and applying an LM bath electrode to conformably and electrically stimulate the organism . BesidesOverall, considering all the above potential routes to tackle modern disease challenges, we can summarize the generalized way of administrating LM-enabled electrobiology as After excluding the well-known poisonous liquid metal mercury, gallium-based LMs are considered as new emerging biomaterials due to their widespread applications in biomedical engineering. However, their metallic conductivity, negligible toxicity, low vapor pressure and high mechanical conformity mean that there are still many urgent problems to be solved ,20,115. The targeted distribution and fixation of LM in living organisms as well as its complete elimination from the body are difficulties. Some researchers have suggested the syringe injection method to alleviate a patient\u2019s suffering ,32, but In summary, the basic concept of LM electrobiology is proposed and a generalized disease therapy framework is established for coming studies and clinical clarifications. Due to its remarkable material features, such as metallicity, reliable flexibility, excellent electrical conductivity, and non-toxicity, LM can not only adapt to body disease models to generate conformable electrical treatment, but also reduce the contact resistance to avoid more energy loss when performing the task. At this stage, several basic electrostimulation mechanisms in disease therapy have been investigated. One of them cures diseases by inducing cell proliferation, migration, and excitation, including electrical muscle stimulation, nerve connection, artificial organs, cardiac pacing etc. The others prevent the cell lines by disrupting cell mitosis or increasing cell apoptosis. Taking oncotherapy as an example, under a specific tumor-treating field for a period of time, the tumor diminishes along with cancer cells being killed. Overall, given specific design, typical applications of LM electrostimulation would provide satisfactory therapeutic efficacy, a conformable treatment area and biological availability. This may lead to evermore simple physical method for future clinics and health care."}
+{"text": "METHODS/STUDY POPULATION: Participant recruitment programs across the consortium are inconsistent in staffing, program services, and program goals. The participant recruitment program at the University of Michigan\u2019s (U-M) Michigan Institute for Clinical & Health Research (MICHR) provides expertise, tools, and resources to facilitate participant recruitment in clinical and health research studies. RESULTS/ANTICIPATED RESULTS: We will explain our program infrastructure, staffing, services, and discuss how we maintain an engaged registry with over 27,000 participants interested in research studies at U-M. DISCUSSION/SIGNIFICANCE OF IMPACT: Proper recruitment into clinical trials results in findings that are relevant for genetic, cultural, linguistic, racial/ethnic, gender, and age differences . We hope to share our best practices that aid in the development and success of participant recruitment across the CTSA Consortium.OBJECTIVES/SPECIFIC AIMS: Across the Clinical and Translational Science Award (CTSA) Consortium, participant recruitment into clinical trials is essential to advance science. Without proper participant recruitment, clinical trials do not result in gains in scientific knowledge, wastes time, funds, and other resources (Mahon"}
+{"text": "The public\u2019s demand for natural, eco-friendly, and safe pigments is significantly increasing in the current era. Natural pigments, especially fungal pigments, are receiving more attention and seem to be in high demand worldwide. The immense advantages of fungal pigments over other natural or synthetic pigments have opened new avenues in the market for a wide range of applications in different industries. In addition to coloring properties, other beneficial attributes of fungal pigments, such as antimicrobial, anticancer, antioxidant, and cytotoxic activity, have expanded their use in different sectors. This review deals with the study of fungal pigments and their applications and sheds light on future prospects and challenges in the field of fungal pigments. Furthermore, the possible application of fungal pigments in the textile industry is also addressed. Color has always played an important role in the life of all organisms on Earth. Human life has become truly \u201ccolorful\u201d due to the use of colors in all its aspects, including clothes, food, and furniture. Much archaeological evidence has shown that the use of pigments as coloring agents has been practiced since ancient times . PigmentThe global response, as well as the demand for eco-friendly natural pigments, has significantly increased in recent decades due to their advantages over hazardous synthetic pigments. They are used as colorants, color intensifiers, additives, antioxidants, etc., in many industries including the textile, pharmaceutical, cosmetic, painting, food, and beverage industries ,8. In reNatural pigments are naturally derived pigments synthesized mainly by plants, animals, and microbes ,9. Most Nowadays, microorganisms, including bacteria, fungi, and algae, have been shown to be an excellent alternative source of natural pigments. For the large-scale production of pigments, microorganisms are more suitable, due to a clear understanding of their cultural techniques, processing, and ease of handling. Natural pigments from microbes, especially from bacteria and fungi, have been reported worldwide by many researchers ,18,19,20Monascaceae, Trichocomaceae, Nectriaceae, Hypocreaceae, Pleosporaceae, Cordycipitaceae, Xylariaceae, Chaetomiaceae, Sordariaceae, Chlorociboriaceae, Hyaloscyphaceae, Hymenochaetaceae, Polyporaceae, Ophiostomataceae, Tremellaceae, Herpotrichiellaceae, and Tuberaceae families have been described as potent pigment producers  isoquinoline-6,8 -dione -dione  , two anthraquinones compounds , and polyketide pigment (bikaverin) were reported from Fusarium oxysporum   . Si. Si25]. Penicillium as potent producers of pigment  and PP-R [(10Z)-7-(2-hydroxyethyl)-monascorubramine] have been reported from Penicillium  was evaluated by many researchers . Iergillus a ..AspergilAlternaria, Curvularia, Pyrenophora, etc.) have immense potential for pigment production. Species of Alternaria such as Alternaria alternata, Alternaria solani, Alternaria porri, and Alternaria tomatophila have been reported to produce a variety of pigments such as dactylariol, alterperylenol, dihydroalterperylenol, alternariol, alternariol-5-methyl ether, altenuene, alternarienoic acid, tenuazoic acid, stemphyperylenol, and altersolanol A  have also been reported to produce hydroxyanthraquinone pigments such as cynodontin, erythroglaucin, catenarin, helminthosporin, and tritisporin   a [25], wentation . Studiesaxanthin b ..DaldiniaTorrubiella, Cordyceps, Beauveria, Hyperdermium, and Lecanicillium have been revealed to be promising producers of bioactive pigments, e.g., tenellin and bassianin are reported from Beauveria bassiana and Beauveria brongniartii (formerly known as Beauveria tenella), pyridovericin and pyridomacrolidin from Beauveria bassiana, torrubiellones A\u2013D from the genus Torubiella, oosporein from Lecanicillium aphanocladii, whereas anthraquinone-related compounds are reported from Cordyceps farinosa (formerly known as Isaria farinosa) -1,4-naphthoquinone) have been reported from Ophiocordyceps unilateralis , and skyrin from Hyperdermium bertonii  a ..TorrubieChlorociboria aeruginosa and Chlorociboria aeruginascens, draconin red from Scytalidium cuboideum, and a yellow pigment from Scytalidiium ganodermophthorum and Scytalidium lignicola. Other pigments, such as orevactaene produced from Epicoccum nigrum, emodin, \u03c9-hydroxyemodin, and emodic acid from Hamigera avellanea  are also known  have also been known as pigment producers. Different species of Rhodotorula , Rhodotorula babjevae, Rhodotorula toruloides Rhodotorula graminis), Sporidiobolus , and Sporobolomyces  have been reported to be prolific producers of torulin and torularhodin  from the mangrove endophytic fungus A. ruber (formerly known as Eurotium rubrum), fusarnaphthoquinones B and fusarnaphthoquinones C from the sea fan-derived fungi Fusarium species, and bianthraquinone derivatives  from mangrove endophytic Alternaria sp.  and chlorinated azaphilone pigments  from marine fungal isolates of Talaromyces spp. and Chaetomium sp., respectively (N-GABA-PP-V (6-[(Z)-2-Carboxyvinyl]-N-GABA-PP-V), along with N-threonine-monascorubramine, N-glutaryl-rubropunctamine, and PP-O from the marine-derived fungus Talaromyces albobiverticillius  in agar-based media [Most of the investigators have focused their study on the enhancement of pigment production from different fungal strains such as ed, etc. ,134,135.ed, etc. ,137,138.ed media .Monascus. Results of these studies have shown that maximum pigment production was acheived in media with fructose as a carbon source for M. purpureus, and lactose as a carbon source for M. ruber [Monascus species [M. purpureus without affecting the growth of the fungus [C. aeruginascens shows that high biomass but no pigment production was observed in media with high nutrient concentration, whereas low biomass and high pigmentation was observed in media with low nitrogen concentration [Monascus species with respect to the type of amino acids in the media [Monascus species , pH optimization studies have shown that a low pH of the media increases pigment production [X. polymorpha, T. versicolor, Cerioporus squamosus (formerly known as Polyporus squamosus), Lentinus brumalis , F. fomentarius and I. hispidus. The maximum pigment production was observed in the pH range from 4.5 to 5.5 [Penicillium purpurogenum, P. aculeatum, A. niger, Altemaria sp., Fusarium sp., C. aeruginascens, have shown that the optimum pH for maximum pigment production varies with the fungal species in submerged fermentation [Some studies have also evaluated the effect of different sugar sources such as glucose, fructose, lactose, sucrose, and maltose on pigment production by the species of M. ruber ,139. Stu species ,142,143.e fungus . A studyntration . Investihe media ,147. Besoduction ,146,148.5 to 5.5 . Similarentation ,151,152.M. ruber, T. purpureogenus (formerly known as P. purpurogenum), C. aeruginascens, etc. [Monascus anka mutant strain under submerged fermentation using a two-stage agitation speed control strategy (400 rpm followed by 300 rpm) has been successfuly reported [C. aeruginascens [A. alternata and M. ruber when exposed to blue and red light, respectively [F. oxysporum when exposed to blue and green light [I. farinosa, E. nidulans, F. verticillioides, P. purpurogenum , and M. purpureus when exposed to green and yellow light [M. ruber under submerged fermentation [T. versicolor and X. polymorpha, while enhanced pigment production was observed at higher moisture content in the case of I. hispidus, L. brumalis , C. squamosus (formerly known as P. squamosus), and S. cuboideum [Monascus, Penicillium, Fusarium, Alternaria, etc., when the physical and chemical parameters were simultaneously altered [Along with chemical parameters, physical parameters such as temperature, light intensity, color of light, agitation speed, and oxygen supply have an impact on pigment production. Studies have also been reported showing the influence of temperature on the biosynthesis of pigments by certain fungal isolates such as ns, etc. ,152,153.reported . A studyinascens ,156. Stuectively , and in en light . In contow light . Light iuboideum ,159. Opt altered ,166,167.Monascus and A. chevalieri, co-culturing was found to be effective, whereas in case of F. oxysporum, the results were negative [C. neoformans with Klebsiella aerogenes led to synthesis of melanin by the fungus, using dopamine synthesized by bacteria [T. versicolor, Stereum gausapatum, Bjerkandera adusta, X. polymorpha, and few brown rot fungi  produce zone lines upon detection of another fungus in their territory [T. versicolor and B. adusta were found to be the best fungal pair which produce zone lines upon co-culturing, whereas X. polymorpha produces zone lines individually in the absence of other fungi [Nowadays, co-culturing has been found to be an effective method for the activation of cryptic pathways via cell\u2013cell interactions, which ultimately results in the production of novel secondary metabolites such as pigments from the fungi ,169. Stunegative ,170. Co-bacteria . Researcbacteria . It has erritory . T. verser fungi . This clVarious modes of cultivation and various methods and techniques of pigment extraction were investigated by several researchers to enhance fungal pigment production and recovery. Different strategies such as the use of different surfactants , different solvents , and potential extraction techniques (pressurized liquid extraction technique) have also been assessed, compared, and confirmed by researchers for the rapid extraction and enhanced recovery of pigments from submerged fermentation ,176,177.F. graminearum has shown that the transcription factor AurR1 has a positive regulatory effect on the aurofusarin gene cluster, enhancing the production of aurofusarin [Monascus strains, revealed that transcription factors play an important regulatory role in pigment diversity [Genetic engineering techniques for enhanced pigment production in fungi have been reported ,20,179. ofusarin . A receniversity . More reMany fungal pigments have been reported to have a variety of biological applications because of their different properties such as antimicrobial, antioxidant, anticancer, and cytotoxic activities in addition to coloring property ,25,179; Monascus pigments, arpink red from P. oxalicum, riboflavin from Ashbya gossypii, and \u03b2-carotene from B. trispora [The majority of work done on fungal pigments is related to their use as food colorants. The possibility of the use of fungal pigments in different industries, particularly in the food industry, has been revealed long ago by many researchers ,186,187.trispora ,25,189.Monascus, Fusarium, Talaromyces, Trichoderma, Penicillium, and Aspergillus) and yeast R. glutinis possess antimicrobial activity against different pathogenic bacteria as well as yeast and fungi. All these studies suggest the potential use of bioactive pigments as food preservatives or as antibacterial ingredients in the food and pharmaceutical industries [A. alternata and Thermomyces spp.) has also been evaluated, and positive results of these studies suggest their possible use in producing specific products for medical application, such as bandages, suture threads, face masks, etc. [Numerous microbial pigments have been reported to possess many health benefits over synthetic pigments ,14. Sevedustries ,193,194.ks, etc. ,196,197.Penicillium , Fusarium sp., Thermomyces sp., Chaetomium sp., Sanghuangporus baumii, Stemphylium lycopersici, and species of Trichoderma  confirm the promising antioxidant potential and their possible applications in the healthcare industry [It has been reported that microbial pigments such as carotenoids, violacein, and naphthoquinones have antioxidant potential. Many review articles mention the antioxidant potential of pigments from certain fungi and yeast ,198,199.industry ,200,201.F. oxysporum, T. verruculosus, and Chaetomium spp.) has been assessed by many researchers using different methods such as sour orange seeds toxicity assay or yeast toxicity test (YTT) using Saccharomyces cerevisiae, brine shrimp lethality bioassay, or cell counting kit-8 (CCK-8) assay. These studies confirm the possible application of pigments in different industries, especially in health and pharmaceutical ones [Thermomyces spp. and P. purpurogenum in Wistar rats has revealed the nontoxic nature of pigments and suggested its potential application in cosmetics and dyeing [The cytotoxic activity of pigments of certain fungal isolates  such as monascin, ankaflavin, monaphilone A\u2013B, monasphilone A\u2013B, monapilol A\u2013D, and monapurone A\u2013C have been proved to possess anticancer/antitumor potential against different types of cancers, such as mouse skin carcinoma, human laryngeal carcinoma, human colon adenocarcinoma, human hepatocellular carcinoma, and pulmonary adenocarcinoma , whereas hypocrellin D from S. bambusicola shows anticancer activity against other cancer cell lines    [62,68,8Monascus pigments and Monascus-like pigments) have already entered the market for their application in cosmetics such as skin conditioning and skin care products, lipsticks, etc. [As the demand for natural products is increasing in the market, cosmetic industries are also in search of new types of natural pigments to replace synthetic pigments. Among the natural pigments, the use of fungal pigments is also rapidly expanding in cosmetics because of their advantages. Fungal pigments, especially melanin, carotenoids, lycopene, etc., have been reported for their application in cosmetics, sunscreens, sun lotions, sunblocks, face creams, anti-aging facials, etc. ,206,207.ks, etc. .The textile industry is the largest industry after agriculture in terms of economic contribution and employment generation. It majorly depends on synthetic dyes for dyeing different types of fabrics . Currently, natural pigments from fungi, with their many advantages  over hazardous synthetic pigments, have proven to be a good alternative to the synthetic dyes in the textile industry. Many investigations have shown that organic pigments produced by fungi have extensive applications in the textile industry ,25,207. Monascus, Fusarium, Aspergillus, Penicillium, Talaromyces, Trichoderma, Alternaria, Curvularia, Chlorociboria, Scytalidium, Cordyceps, Acrostalagmus, Bisporomyces, Cunninghamella, Thermomyces, and Phymatotrichum) for different types of fabrics such as wool, cotton yarn, silk, polyester, and nylon have been reported [S. cuboideum, yellow pigment from S. ganodermophthorum, and green pigment C. aeruginosa) have shown the possible use of these pigments for deying bleached cotton, spun polyacrylic, spun polyamide (nylon 6.6), worsted wool, spun polyester (Dacron 54), and garment fabrics, because of their high stability and good colorfastness to washing [The literature reveals that only a handful of studies have investigated the application of fungal pigments in the textile industry, especially for dyeing different types of fabrics, such as cotton, silk, and wool. Various studies on the dyeing potential of pigments of different species of fungal genera electronic properties of blends of the pigment xylindein extracted from aterials ,215.Several advantages of fungal pigments over synthetic pigments have increased the demand for fungal pigments worldwide in recent years. This increased public awareness, eco-safety, and health concerns as well as the application of strict environmental and ecological rules and regulations, have challenged researchers to undertake both qualitative and quantitative research on pigments derived from clean, eco-friendly bio-resources, such as fungi, having minimal ecological negative impacts. Therefore, there is a necessity to explore other novel, safe pigments from the diverse taxonomic group of fungi, to meet the existing demand of eco-friendly pigments. Though several fungal strains are known as pigment producers, a large number of fungi have not been systematically explored for their pigment-producing capability. Therefore, there is a great need to explore the vast fungal diversity for rare, novel, safe pigments, using appropriate tools and techniques. A review of the literature revealed that most of the studies focused on the application of fungal pigments in the food and healthcare industries; however, fungal pigments need to pass toxicity tests and quality tests and receive many regulatory approvals before their final entry into the market as food colorants or as drugs. Therefore, the application of fungal pigments in these areas is quite difficult. Moreover, meager studies on the applicability of fungal pigments in other areas such as textiles, paints, varnishes, and daily household utensils leave immense possibilities to explore the indigenous diversity of fungi for their pigment production potential and their applications in different sectors, including the textile industry. In addition to the coloring properties, the biological properties of fungal pigments may open new avenues for their use in the production of valuable textiles for medical use. This provides an extensive area of exploration to identify natural, eco-friendly fungal pigments and develop their diverse applications to satisfy the public interest and market demand."}
+{"text": "A posteroanterior chest radiograph did not reveal any significant findings. Bone scintigraphy with 99mTc-methylene diphosphonate revealed increased osteoblastic activity in the manubriosternal, bilateral sternocostoclavicular, and lower cervical vertebral regions (18F-fluorodeoxyglucose positron emission tomography and computed tomography fusion images showed increased activity in the sternoclavicular joints (arthritis) and hyperostotic lesions (osteitis)  . WrittenA diagnosis of Synovitis, Acne, Pustulosis, Hyperostosis, Osteitis syndrome was made, and treatment with intravenous zoledronic acid resulted in complete relief of pain. Due to its rarity, diagnosis of Synovitis, Acne, Pustulosis, Hyperostosis, Osteitis syndrome may be challenging in the absence of the full clinical picture, especially cutaneous manifestations ,2. In th"}
+{"text": "Despite the growth and recognized benefits of palliative care for people with serious illness and their families, there are significant racial and ethnic disparities in access to and utilization of services, particularly among older adults living in impoverished, medically-underserved communities. This paper presents preliminary findings from a mixed-method, CBPR study exploring the experiences, supportive care needs, and service use of diverse older adults living with serious illness in an urban, medically-underserved community in the U.S. Systematic analyses of focused, semi-structured interviews with 45 older adults identified cultural, environmental, financial, and structural barriers to palliative care, and identified the critical importance of familial, social, spiritual, and formal networks of support in coping with serious illness and associated symptoms. The investigators describe implications for practice and policy that addresses palliative care disparities, and strategies for engaging with communities to extend culturally-sensitive palliative care to diverse, community-dwelling older adults and their social networks."}
+{"text": "Behavioral and environmental factors influence sleep outcomes. However, we understand little about how enviro-behavioral sleep hygiene practices and related sleep concerns vary across age cohorts. Using data from My Sleep Script, an app-based diagnostic checklist for identifying at risk patients, we described cohort differences in sleep hygiene and new sleep disturbances. 323 adults  reported basic demographic, health, sleep, as well as enviro-behavioral data using the Epworth Sleepiness Scale (ESS), Pittsburg Sleep Quality Index (PSQI), and the Johns Hopkins Sleep Environment Instrument. We partitioned participants into four cohorts corresponding to birth year: The Silent Generation , Baby Boomers , Generation Xers , and Millennials . Spearman correlations described linkages among environment, behaviors, and sleep outcomes; a chi-square analysis, cohort differences in new sleep concerns. Having weapons, music players, lights, pets, and a disruptive sleep surface in the environment correlated with worse sleep quality. Eating, exercising, working, and sexual activity one hour before bed also correlated with worse sleep quality. Sleeping with pets, electronics, and on a disruptive surface correlated with lower sleep duration. Regarding cohort, we observed significant generational differences in new snoring and sleepiness complaints. Results confirm associations of suboptimal sleep hygiene with poor sleep outcomes and provide insights into their generational differences, warranting additional investigation."}
+{"text": "Heterotopic pancreas, also known as ectopic pancreas, is pancreatic tissue located outside the pancreatic parenchyma without vascular or ductal communication with the gland. Ectopic pancreas is rarely symptomatic, typically detected incidentally at surgery or autopsy. Eighty-five to 90% are in the upper GI tract, especially the gastric antrum. We report a 54-year-old man with symptomatic gastric heterotopic pancreas presenting as recurrent, initially undiagnosed, abdominal pain. Surgery revealed heterotopic pancreas including excretory ducts, acini, and islet cells. Evidence of acute pancreatitis was present, marked by inflammation and abscess formation. Chronic pancreatitis was diagnosed by fibrosis and dilated ducts containing proteinaceous material. Submucosal location with normal overlying mucosa on endoscopy increases risks of delayed or missed diagnosis. Complications include GI bleeding, acute or chronic pancreatitis, pancreatic necrosis, pseudocyst, gastric outlet obstruction, perforation, and, rarely, pancreatic carcinoma. This rare disorder mimics more common diseases. Low suspicion, nondiagnostic imaging or endoscopy contribute to frequent diagnostic delay. Ectopic pancreas is rarely symptomatic. The vast majority of lesions are detected incidentally at surgery or autopsy. Barbosa and colleagues reported approximately 1 incidental case detected per 500 upper abdominal operations; the incidence for all autopsies was 1.7% . Other sWe report a rare case of symptomatic gastric heterotopic pancreas presenting as nonspecific, recurrent abdominal pain with a characteristic submucosal gastric mass on endoscopy. This case is exceptional because the ectopic tissue contained evidence of acute and chronic pancreatitis and abscess formation.A 54-year-old man was admitted with 4-5 days of abdominal pain that began in the left upper quadrant and then migrated subumbilically. The pain was sharp, steady, and of moderate severity. He also described nausea and a low-grade fever. Past medical history included kidney stones and a sigmoid colectomy for diverticulitis 15 years previously. He denied a history of excess alcohol use. His only medication was atenolol 50 mg daily.On admission, physical examination revealed normal sinus rhythm, normal pulse and blood pressure without postural change, normal temperature, moderate tenderness to palpation in the left supraumbilical and subxiphoid areas without peritonitis, organomegaly, or mass lesion. Stool was negative for occult blood.3/\u03bcL, Hgb: 16g/dL, Chemistry 7, liver enzymes, and serum amylase and lipase were within normal limits. Upper GI endoscopy was interpreted as a 5 mm sessile gastric antral polyp with normal gastric mucosa on biopsy. Abdominal CT scan showed mesenteric inflammation surrounding the distal body and proximal antrum of the stomach and adjacent low-density thickening of the stomach wall, measuring up to 18 mm in thickness. He was treated with IV fluids and pain medication. His condition improved and he was discharged home without a definitive diagnosis.Lab results: WBC: 10 x 10He felt well for four months and then developed recurrent mild, diffuse, sharp, steady abdominal pain. He denied weight loss, nausea, vomiting, or bowel complaints. Physical examination showed normal vital signs, afebrile. His abdomen was soft, nontender, and otherwise unremarkable. Basic laboratory studies, serum amylase, and lipase were normal. Repeat upper GI endoscopy showed a firm submucosal mass with intact overlying mucosa and a central umbilication. Biopsy of the lesion revealed normal gastric mucosa . AbdominFindings were nondiagnostic, but inconsistent with leiomyoma or leiomyosarcoma.Open gastric antrectomy with a Billroth I technique was performed for a preoperative diagnosis of gastric adenocarcinoma. Histology of the resected specimen revealed ectopic pancreatic tissue, including excretory ducts, acini, and islet cells within the gastric muscularis layer . EvidencHeterotopic pancreas, also known as ectopic, accessory, or aberrant pancreas, or pancreatic rest, is defined as pancreatic tissue outside the normal pancreatic parenchyma in an aberrant location with a vascular and nerve supply separate from the pancreas itself . It is tAmong patients with symptomatic gastric heterotopic pancreas, the most commonly reported symptom is mid-abdominal pain, occurring in as many as three-quarters of cases , 8. NausReported complications of gastric ectopic pancreas include acute or chronic pancreatitis , 5, 7, pDelayed or missed diagnosis is frequent , 10. FacUpper GI endoscopy and CT scanning are the most useful techniques to evaluate the majority of patients. The diagnosis of a submucosal mass lesion in the upper gastrointestinal tract with normal overlying mucosa on endoscopy can be divided into benign and malignant etiologies. Benign lesions include leiomyoma, lipoma, varices, neural tumors , granular cell tumor, inflammatory fibroid polyp, duplication cyst, lymphangioma, Brunner's gland hyperplasia, benign GIST, and heterotopic pancreas. Malignant lesions that should be considered are malignant GIST, carcinoid tumor, lymphoma, glomus tumor, and gastric or metastatic carcinoma  , 9.Endoscopic ultrasound (EUS) is the most accurate study to differentiate submucosal lesions not diagnosed by conventional endoscopy. Typical findings in heterotopic pancreas are a hypoechoic lesion with indistinct borders . UncommoHeterotopic pancreas may contain any of the components of normal pancreatic tissue, which consists of acini, ducts, and islets of Langerhans. In the case series of 32 patients reported by Ormarsson and colleagues, all cases contained ducts, 97% contained acini, and 41% contained islets . ClinicaThe diagnosis of symptomatic gastric heterotopic pancreatitis is challenging. This disorder, rarely detected ante-mortem, should be considered in selected patients with submucosal gastric mass lesions. We describe a patient with histologic confirmation of gastric ectopic pancreatic tissue including excretory ducts, acini, and islet cells within the gastric muscularis layer. Histologic acute and chronic pancreatitis with fibrosis, dilated ducts containing proteinaceous material and abscess formation, as in our patient, is exceptional. This disorder commonly presents with nonspecific symptoms, mimicking more common diseases. Nondiagnostic imaging and endoscopic findings are common, contributing to delay in diagnosis."}
+{"text": "The first four authors, Seiko Mizuno, Susumu Kunisawa, Noriko Sasaki, and Kiyohide Fushimi, should not have been attributed equal contribution with the corresponding author, Yuichi Imanaka."}
+{"text": "Its etiology is unknown, and there is a possible relation with unilateral masticatory activity, dental malocclusion, temporomandibular joint dysfunction, bruxism, or emotional alterations. The diagnosis is made primarily based on the clinical presentation, complemented with ultrasound and, if required, magnetic resonance imaging. It is important to make differential diagnoses with tumors or inflammatory processes in muscles, bones and salivary glands.Idiopathic masseter muscle hypertrophy is a rare condition, characterized by unilateral or bilateral enlargement of this muscle, sometimes associated to mandibular angle exostosis.1 Its We presented a case of a 15-year female adolescent, with no significant past medical history, seen at the Emergency Department, due to right mandible swelling, painless, which started three months before and presented progressive worsening. She had no past history of facial trauma, trismus, constitutional symptoms or periodontal disease. Upon examination , she preThis condition has a benign behavior, with essentially aesthetic implications, because of asymmetric lower third of the face. The treatment is conservative, using some therapies, in selected cases, such as muscle relaxants and botulinum toxin, or by excising the excessive muscle fibers.,,5"}
+{"text": "Recent development of novel techniques in systems biology have been used toimprove and manipulate the rumen microbial ecosystem and gain a deeperunderstanding of its physiological and microbiological interactions andrelationships. This provided a deeper insight and understanding of therelationship and interactions between the rumen microbiome and the host animal.New high-throughput techniques have revealed that the dominance ofProteobacteria in the neonatal gut might be derived from the maternal placentathrough fetal swallowing of amniotic fluid in utero, which gradually decreasesin the reticulum, omasum, and abomasum with increasing age after birth. Multi\u201comics\u201d technologies have also enhanced rumen fermentation andproduction efficiency of dairy goats using dietary interventions through greaterknowledge of the links between nutrition, metabolism, and the rumen microbiomeand their effect in the environment. For example, supplementation of dietarylipid, such as linseed, affects rumen fermentation by favoring the accumulationof \u03b1-linolenic acid biohydrogenation with a high correlation to therelative abundance of Fibrobacteriaceae. This provides greater resolution of theinterlinkages among nutritional strategies, rumen microbes, and metabolism ofthe host animal that can set the foundation for new advancements in ruminantnutrition using multi \u2018omics\u2019 technologies. The rumen has a diverse and complex microbial ecosystem that converts ingested plantbiomass into proteins, volatile fatty acids (VFAs), and vitamins to be used by thehost animal. Studying the relationships and interactions of microbes in the rumen isdifficult as different microbes have different substrates, requirements, anddigestive roles. However, understanding the relationships and interactions betweenmicrobes is important for evaluating their effects on the environment or in thecommunity they inhabit, as they play a pivotal role in animal health, performance,milk , andmeaThe goat is smaller than other ruminants, such as cattle; hence, they are categorizedas small ruminants. The goat rumen also has a different motility pattern than thatof cattle as it has reticular motility during rest by a biphasic contraction andlonger duration of reticular regurgitation contraction . Goat ruThe goat rumen varies in pH, microbiome, fermentation products, and metabolitesdepending on the diet ingested by the animal. On a high forage diet study of Lee etal  withcomGoat rumen microbiota composition is usually dominated by Bacteroidetes followed byFirmicutes with a very low abundance of Fibrobacteres ,7\u20139. ConEntodinium and Epidinium. They also reportedthat the Ophryoscolex genus, which had a wider host distribution,was found in goats from 18 countries. In accordance, Lee et al [4/mL copies of the 18S protozoa rRNA gene. In addition, Wang et al[Fibrobacter succinogenes had the highest relative abundance inthe rumens of goats on a high forage diet with 2.187 compared to those on a highgrain diet and to Hanwoo and Holstein cattle using quantitative real-time polymerasechain reaction [Operational taxonomic units of Bacteria and Archaea in Korean native goats arecomparatively lower than those in Holstein cows and Hanwoo steers, which indicatesthat Korean native goats contain fewer bacterial and archaeal species . On the ee et al  reportedng et al exploredInsight into the reticulum, omasum, and abomasum microbiota dynamics in pre-weaninggoats has also been elucidated using metagenomics. Proteobacteria are facultativeanaerobes, which dominate the neonatal gut owing to the unique abundance of oxygen.Studies have shown that Proteobacteria species may be derived from the maternalplacenta through fetal swallowing of amniotic fluid in utero. It was also reportedthat Proteobacteria gradually decreased in the reticulum, omasum, and abomasum withthe aging of the host . Lerma-RFibrobactersuccinogenes is one of the most abundant saturated fatty acidscharacterizing principal species that produce C18:0 (stearic acid).Fibrobacter succinogenes also plays a role in thedetoxification of the ruminal environment by using C18:3n\u22123 for itsmetabolism and producing C18:0 [Butyrivibrio species, which havehigher relative abundances when the reduction to C18:0 is inhibited.Diet composition plays a pivotal role in the composition of ruminal microbiota, whichdefines ruminant products. The conjugated linoleic acid (CLA) in milk originatesfrom either endogenous synthesis in the mammary gland from vaccenic acid or ruminalbiohydrogenation of linoleic acid as an intermediate product . Moreoveng C18:0  added thSuccinivibrio spp. by 50% andFibrobacter spp. by 75%. Consequently, linseedsupplementation reduces the level of Prevotella spp. and dimethylacetals (DMA), which are thought to play a role in plasmalogens [Lipid supplementation of linseed increases the relative abundances ofmalogens . This ismalogens .Methane is one of the products of normal fermentation of feedstuffs in the rumen.When methane is produced, the ruminant suffers a loss of ingested feed-derivedenergy of approximately 2% to 12%, depending on geographicallocation, feed quality, feed intake, feed composition, the processing of feed, andruminant species ,11,15. MPragna et al reported0.75with 8.5, 10.3, and 11.2 g/d at feeding levels of 1.5%, 2.0%, and2.5%, respectively [Methanosphaerastadtmanae and Methanobrevibacter sp. strain AbM4. Methane production can also be decreasedby supplements of fumaric acid and tannins. Tannins can interfere with the membranesof rumen bacteria, and mitigate methane production, while fumaric acid stimulatesthe fumarate-utilizing bacteria, which increases propionate resulting in decreasedmethane production [Prevotella spp., Selenomonas spp., andFibrobacter succinogenes [Feed intake and feeding level are two of the factors that affect methane productionin ruminants such as goats. Methane production in goats increases linearly withincreased feeding level when expressed in g/d and g/kg body weightectively . Howeverectively  reportedectively also addoduction . In addioduction  reportedinogenes ,21. In aDietary interventions can be plant-based, mushroom-based, dietary lipids, alternativeenergy sources, enzymes, or acids . These dMoringa oleifera [Butyrivibrio fibrisolvens, which was found to increaseafter supplements of soybean oil [Butyrivibrio group, which includes the generaButyrivibrio and Pseudobutyrivibrio, wereinvolved in the process of biohydrogenation.The use of rich sources of linoleic and ALA is essential in increasing thehealthy properties of milk, because they favor the accumulation of CLA. Severalstudies have reported the positive effect of CLA in animals and humans.Consumption of CLA had been reported to have an effect on the immune system,atherosclerosis, and bone health . The CLAoleifera ,24, roseoleifera , sunflowoleifera ,by-prodoleifera , pomegraoleifera , and tomoleifera ,and by oleifera , canola oleifera ,soybeanoleifera , and sunoleifera   contents in milk fat were also enhancedwith dietary interventions such as pistachio hulls [Fatty acid profiles of ruminant products such as milk can be improved throughchanges in animal diet. Supplements of fish oil and plant oils in goat dietsinteract to modulate milk fat composition without decreasing milk fat content.Hence, itifolia , lemongritifolia , rosemaritifolia , and sunitifolia , rosemaritifolia , sunflowitifolia ,flaxseeitifolia , rapeseeitifolia , sunflowitifolia , and hyditifolia to the ditifolia reportedio hulls , pomegraio hulls ,tomato io hulls , and fisio hulls .Body performance can be improved by modulating the body system, increasing thefeed intake, increasing or alleviating ruminal acidosis, improvingdigestibility, VFA profiles, and metabolites . Body pePrevotellaand Treponema were affected by breed [Chloroflexi,Blautia, and a Mogibacteriaceae-affiliatedunnamed genus were reported to be associated with feed efficiency in beef cattlerumen microbiome [Chloroflexi was identified as related tohost phenotype milk yield and diet adaptation, while Blautiawas reported to provide energy to hosts from the fermentation ofpolysaccharides. Furthermore, efficient cows had a higher number of totalshort-chain fatty acid (10% higher) concentrations of propionate,butyrate, valerate, and isovalerate, and propionate to acetate than inefficientcows [High-throughput sequencing and advanced techniques have been used to compare theeffect of breed on the rumen microbiome and its associations with feedefficiency. In beef cattle, 8 bacterial phyla, including Bacteroidetes andSpirochaetes, and 55 taxa at the genus level such as by breed . Meanwhiby breed and Wangby breed  reportedby breed  added thcrobiome . Chlorofentcows .Moringaoleifera [Andrographis paniculata [Lentinussajor-caju)-treated oil palm fronds [Cordyceps militaris) [Moringa oleifera[Dietary interventions that increase feed intake are oleifera ,24,flaxoleifera , and exooleifera , whileAniculata ,42 and cniculata  are usedniculata . In addim fronds , spent mlitaris) , Moringaoleifera,24, lemooleifera,rosemaroleifera, flaxseeoleifera, exogenooleifera,and exooleifera were useAnaerobic microbes in the rumen produce enzymes which the ruminants themselvescan not. However, these enzymes are not enough to degrade most of the complexplant polysaccharides. Hence, exogenous fibrolytic enzyme supplements increasecellulase and xylanase activities, which increase fiber degradation. Theexogenous fibrolytic enzyme helps in removing the structural barriers in feedsduring digestion and thus improves the digestibility that allows cellulolyticbacteria to out-compete fungi for colonization in plant fibers. In addition, theimprovement was due to improved energy substance metabolism, which alsocontributed to glycogenesis .Lentinus sajor-caju)-treated oil palm fronds[Andrographis paniculata [Cordycepsmilitaris) was used to improve blood metabolites [Andrographis paniculata [Bacteroides sp. andSuccinivibrio sp. abundance [Meanwhile, the VFAs increased with a combination of essential oil and cobalt,fungal m fronds,Androgrniculata ,42, fumaniculata ,and exoniculata , while sabolites . Moreoveniculata ,42, and niculata  improvedbundance . In addiIn tropical countries, heat accumulation and prolonged high ambient temperatureaffect animal performance and milk production due to reduced feed intake. Whenfeed intake decreases, the intake of mineral elements also decreases. Hence,increasing dietary cation-anion difference (DCAD) is a necessity. Nguyen et alreportedRuminal microbiota play a pivotal role in animal nutrient utilization and synthesisfor production and productivity. However, in the rumen, both synergistic andantagonistic interactions occur among microbes. These are essential in breaking downfeed to produce VFAs that are then used by the animal as a source of energy.Probiotics are live microbes that stimulate beneficial microbes in the rumen whileprebiotics are non-digestible sugars that provide substrates for beneficial microbesthat induce their growth and activity. Probiotics and prebiotics are now widely usedin livestock farming to benefit production and development, and address major publichealth concerns over antibiotic, antimicrobial, and hormonal growth promotors.Bacillus,Bifidobacterium, Enterococcus,Lactobacillus, Pediococcus,Streptococcus, yeasts , and anaerobic fungus(Aspergillus oryzae). Aside from these widely known probiotics,there is continued research for new microbes that stimulate potentially beneficialrumen microbes. These are the cellulolytic bacteria, such as Cellulomonascellulase, Bacillus sp., Thermomonosporafusca, Acetobacter xylinum, Ruminococcusalbus, and Clostridium cellulovorans and fibrolysozymeor fibrolytic enzyme (fibrozyme), which is compounded from Aspergillusniger, Trichoderma longibrachiatum, fermentationextracts, and fermentation soluble [Probiotics have been shown to promote growth and health through increasing bodyweight gain, feed intake, and reducing diarrhea. Probiotic products may contain oneor more selected strains, which are often gram-positive bacteria. The widely- usedprobiotics for ruminants are  soluble .Mitsuokellajalaludinii [Enterococcus faecium [Acetitomaculumruminis, Eubacterium limosum strains ATCC 10825 andATCC 8486, Ruminococcus productus ATCC 35244 [Ruminococcusschinkii sp. nov. [Proteiniphilum acetatigenes[Coprococcus catus [Lactobacillusmucosae [Megasphaera elsdenii [Propionibacteriumacidipropionici [Prevotella ruminicola [Selenomonasruminantium [Veillonella parvula [Butyrivibrio fibrisolvens[In addition, important microbes involved in the pathway of rumen metabolism are alsobeing explored. These are the fumarate reducing bacteria , theprus catus , Lactobamucosae ,Megasphelsdenii , Propionopionici , Prevoteminicola , Selenominantium , and Vei parvula ), and thisolvens).Aspergillus oryzaeand Saccharomyces cerevisiae are some of the commercially availableproducts. The function of probiotics exerts several effects, one of which isimmunostimulation. The immunostimulant molecules in probiotic yeasts are\u03b2-glucans, chitins, mannans, and polyamines [Saccharomycescerevisiae is one of the well-known probiotics that produces vitamin B,organic acids, and amino acids [Saccharomyces cerevisiae as aruminant feed additive could help the rumen bacteria to compete, or at leastco-metabolize H2 with methanogens [Saccharomycescerevisiae scavenges oxygen, which creates a more anaerobic environmentin the rumen that enhances the hydrogenotrophic metabolism of the acetogenic strainby more than fivefold. This stimulates the utilization of hydrogen by the acetogenicstrain and enhances acetogenesis [Debaryomyceshansenii CBS 8339, a probiotic that is commonly found in marineenvironments, stimulates innate immune and antioxidant parameters and the expressionof immune-related gene signaling pathways [Fungi are one of the important microorganisms that have been used in farming owing totheir multiple functions and beneficial effects. lyamines . Saccharno acids . The usehanogens . Moreoveogenesis . In addiogenesis . Furtherpathways .Prebiotics modulate the balance and activities of the rumen microbiota. Prebioticscontain specific nondigestible nutrients, which can be consumed raw or as functionalfoods and pharmaceutical preparations. Prebiotics include fructooligosaccharides,galactosyl-lactose, mannan oligosaccharides, pectin oligosaccharides, andxylooligosaccharides .High-throughput technologies such as \u201comics\u201d technologies combinedwith recent dietary interventions have provided a deeper insight into the relationsand interactions between the rumen microbiome, metabolites, genes, and host health,performance, and efficiency. Further research to improve and understand thefunctions and interactions among the hosts, microbiome, and the feed isrequired."}
+{"text": "Objectives: Chronic kidney disease (CKD) is associated with increased mobility limitation. Prior research has documented that peripheral nerve abnormalities occur early in CKD and progressively worsen. Loss of balance, impaired muscle strength, and slow gait predispose older adults to falls and frailty. However, the current literature is limited by a lack of nationally representative data that includes objective measures of kidney disease and physical functioning. Thus, this research examines whether CKD is associated with muscle strength, balance, gait, and self-reported mobility limitations. Methods: Data come from the 2016 Health and Retirement Study (HRS). Estimated GFR, a measure of kidney functioning derived from creatinine levels in the blood, was used to classify CKD . Logistic and linear regression models were generated to examine the association of CKD with physical functioning, net of demographic characteristics  and comorbidities . Results: In unadjusted models, CKD was significantly associated (p<0.05) with more mobility limitations, slower walking speeds, stronger grip strengths, and non-participation in balance tests. After adjusting for covariates, CKD  was negatively associated with grip strength. In sex-stratified models, CKD was associated with slower walking speeds among men, whereas CKD was associated with more mobility limitations among women. Discussion: In a nationally representative sample of older adults, CKD was associated with poorer physical functioning on multiple measures. After adjusting for demographic characteristics and comorbidities, CKD was associated with increased muscle weakness."}
+{"text": "International Journal of Telerehabilitation (IJT) positioned among journals in the telemedicine and telehealth space? IJT is an online, open  journal that focuses on telerehabilitation -- a segment of telehealth and telemedicine that encompasses many rehabilitation associated disciplines. Because successful telerehabilitation often depends upon interprofessional collaborations, much of the work published within IJT is by at least two authors from different disciplines. Authors in the current issue include persons with collective expertise in the disciplines of architecture, occupational therapy, medicine, physical therapy, and/or software engineering.Where is the An examination of the subject matter published in IJT since its inception in 2008 provides insight into the evolution of telerehabilitation. Readers will note that several current issue papers describe telerehabilitation services delivered in the home environment, with one investigating in-home modifications. Two articles studied the provision of telehealth to persons post-stroke. The therapeutic use of virtual environments is a relatively newly prominent theme.We posit that multiple factors influence emerging research themes: reimbursement for services rendered, regulations, and most importantly in the case of research articles, trends in research funding. International submissions to the IJT have also shifted, sometimes between continents. The international geographic trends are interesting to follow.In the current issue, readers will note cautions related to safety and patient selection. Moreover, since some telerehabilitation protocols are best hybrid , IJT welcomes articles that include research conducted in authentic, hybrid conditions. Appropriate patient selection for telerehabilitation services is broached in this issue, and remains a challenge that requires future research.Sincerely,Ellen R. Cohn, PhD, CCC-SLP, ASHA-F, IJT EditorJana Cason, DHSc, OTR/L, FAOTA, Senior Associate Editor"}
+{"text": "Ticks transmit the most diverse array of infectious agents of any arthropod vector. Both ticks and the microbes they transmit are recognized as significant threats to human and veterinary public health. This article examines the potential impacts of climate change on the distribution of ticks and the infections they transmit; the emergence of novel tick-borne pathogens, increasing geographic range and incidence of tick-borne infections; and advances in the characterization of tick saliva mediated modulation of host defenses and the implications of those interactions for transmission, establishment, and control of tick infestation and tick-borne infectious agents. Zoonotic diseases are a significant negative impact upon global public health that is increasing. Zoonotic diseases are defined as infections shared in nature between humans and other vertebrate animal species , charactAmong arthropod vectors of disease, ticks transmit the most diverse array of infectious agents and ticks are the most important arthropod vectors, globally, of pathogens to humans and domestic animals ,6,7. TicDefining tick-host-pathogen interactions, at the cellular and molecular levels, are additional areas of study essential for characterizing pathogen transmission, establishment, pathogenesis, and for identifying novel checkpoints for control of both vectors and pathogens. A research focus where advances are being achieved at an increasing pace is the characterization of tick saliva and its ability to modulate multiple host defenses differentially during blood feeding, resulting in successful acquisition of a blood meal and creation of environments favorable for pathogen transmission and establishment in the host ,14,15,16Our understanding of ticks and tick-borne diseases is changing on many levels due to the application of significant technological advances and new paradigms. An avenue for advancing efforts to achieve effective control of ticks and tick-borne diseases is by implementing coordinated planning, performance, and evaluation of diverse research initiatives and integrated control measures in a One Health approach to these vectors and infections of human and veterinary public health importance . The OneThis review examines selected contemporary topics of tick and tick-borne disease epidemiology, tick biology, and tick-host-pathogen interactions that are of increasing importance for defining underlying factors, relationships, and mechanisms that are essential for the success of these important vectors and the infections they transmit. Long term objectives of these evolving areas of investigation are to add to the accumulating body of knowledge that will result in the development of effective disease prediction, prevention, and control interventions.Ticks, tick transmitted infections, hosts, and a multitude of factors that influence them are constantly undergoing change. This constant state of flux for multiple factors impacts: Vector and disease surveillance, reporting, public awareness, and interventions; fluctuations in tick population densities and range at local and national levels; introduction of tick-borne diseases into new areas, resurgence, and emergence within established geographic areas; and the development of surveillance and diagnostic tools to educate healthcare providers and raise awareness of the public both to old and new public health threats. Understanding tick-borne zoonoses requires comprehensive examination and increasing knowledge of the complex associations among tick populations, habitat landscapes, climate, human behavior, human demographics, economics, and intrinsic pathogen factors ,17,18,19Arthropod disease vectors and their transmission of disease causing agents are significantly influenced by weather and climate . WarmingChanges in geographic distributions of tick populations have, are, and will continue to occur. Modifications of any of the known interacting factors that influence tick populations have the potential to affect the distribution and abundance of these important disease vectors. Simultaneous changes are taking place among those complex associations of factors at micro and macro levels, which require heightened surveillance of ticks and tick-borne diseases that are established, resurging, or emerging.Ixodes ricinus in Sweden and Russia, along with an increased abundance of this species at the eastern limits of its range in the Tula region of Russia, are attributed to climate changes, with resultant milder winters [Ixodes ricinus is the most frequently reported tick in the United Kingdom with an expanding range in southern England [Ixodes ricinus and Borrelia burgdorferi are expanding their range into the northern latitudes of Europe [Ixodes ricinus in northern Europe and Eurasia [Ixodes persulcatus and tick-borne encephalitis expansion into the subarctic regions of European Russia are also linked to climate change [The northward range expansion of  winters ,28. Ixod England . Both Ixf Europe . These f Eurasia . Ixodes e change .Ixodes scapularis are extensively studied in both the United States and Canada [Ixodes scapularis geographic range has expanded significantly in the Eastern and Midwestern United States during the past 20 years [Ixodes scapularis vectored pathogens [Ixodes scapularis is established doubled to 44.7% of all United States counties [Ixodes scapularis range grew into eastern and central Canada by approximately 2004 and it was accompanied by the emergence of Lyme disease [Ixodes scapularis is considered to be reclaiming its historical geographic range in response to changes that include habitat and climate changes, as well as the availability of hosts for all life cycle stages, particularly white tailed deer [Ixodes scapularis is a competent vector and Peromyscus leucopus is a reservoir for an increasing number of human pathogens [The geographic range extension, population increases, and an expanding array of transmitted infectious agents of d Canada ,34. Ixod20 years . Concomiathogens . Betweencounties . The potcounties . Ixodes led deer . Ixodes athogens ,36, highDermacentor reticulatus is a species whose biology is well suited to survive and thrive in diverse, challenging, and changing weather conditions, climates, and habitats in Europe and Eurasia [Dermacentor reticulatus range extended, during recent decades, into Germany, the Netherlands, Poland, and other European regions that were previously considered to be suitable habitats for this tick vector [Dermacentor reticulatus has many possible host species, movement of dogs as companion animals and strays is an important factor in the movement and establishment of this tick in new regions [Dermacentor reticulatus is a competent vector for pathogens of human and veterinary public health importance, including: Omsk hemorrhagic fever virus, tick-borne encephalitis virus, Rickettsia raoultii, Rickettsia slovaca, Anaplasma marginale, Babesia canis, Babesia caballi, and Theileria equi [ Eurasia . This ti Eurasia . Dermacek vector . Climatek vector . Increask vector . Althoug regions . Dermaceria equi .Amblyomma americanum is a North American tick of increasing importance due to its significantly expanding geographic distribution, increased population density, and roles as a vector of established and emerging infectious agents [Amblyomma americanum is the ability of larvae, nymphs, and adults to readily seek and blood feed on humans [Amblyomma americanum transmitted Ehrlichia chaffeensis and Ehrlichia ewingii [Amblyomma americanum is a competent vector for Francisella tularensis [Amblyomma americanum [s agents . Contribn humans ,43. The n humans . The geon humans . This ti ewingii . Amblyomlarensis  and is ilarensis ,47 and Blarensis . Transmiericanum .Amblyomma americanum [Ixodes ricinus [The human health impact of ticks is evolving along the multiple fronts of infectious agents, tick paralysis, damage due to feeding, and the emergence of allergies to tick saliva molecules. First reported observations linking ticks to red meat allergy occurred in 2007 . Subsequericanum  and Ixod ricinus . Glycosy ricinus . Tick sa ricinus ,14,15,16Amblyomma maculatum, the Gulf Coast tick, within the United States has increased significantly since the first half of the twentieth century [Amblyomma maculatum can be found as far north along the Atlantic coast as Delaware, with a range of greater than 250 miles inland, and populations also established in several Midwestern to southwestern states [Amblyomma maculatum is the principal vector of the spotted fever agent, Rickettsia parkeri, and the canine apicomplexian, Hepatozoon americanum [Hemaphysalis longicornis, was detected as an invasive species in New Jersey and within the past few weeks (June 2018) was also detected in Virginia . The means by which this tick arrived in North America remains unclear; however, persistence is a likely possibility after successfully overwintering in New Jersey and spreading to a distant site.The range of  century ,56. Thisn states ,56. Amblericanum . RecentlGeographic ranges and abundance of ticks are changing in response to multiple factors that may be operating together to bring about the observed variations ,56. BothThe complex, ever changing nature and distributions of tick vectors and tick-borne diseases requires continuous surveillance that encompasses the analysis of tick vectors, pathogens, reservoirs, and epidemiology of infections . Public Ixodes scapularis, transmitted the agent responsible for the illness [Borrelia burgdorferi spirochetes [Borrelia miyamotoi [Neoehrlichia mikurensis [Rickettsia helvetica [Rickettsia species [Vector-borne diseases account for a significant proportion of emerging infectious diseases globally . Ticks t illness . Subsequrochetes . Awarenerochetes ,70. Molerochetes . Moleculiyamotoi , Neoehrlkurensis , Rickettelvetica , and oth species . A challHere, I examine emerging and resurging tick-borne pathogens, highlighting the diversity of infectious agents and implications of changing tick geographic distributions for changing disease endemic regions. These changes have important implications for vector and disease surveillance, interventions, and education of health care providers and the public.Ixodes scapularis, and the infectious agents it transmits, are the foci of considerable attention. For an ixodid species that was not considered to be a significant vector of human disease prior to 1970, the diversity of Ixodes scapularis transmitted human pathogens stands at seven as of 2017 [Ixodes scapularis transmitted disease in the eastern and midwestern regions of the United States [Ixodes ricinus transmitted infection in Europe [Among tick vectors of public health importance,  of 2017 . Lyme bod States  and Ixodn Europe . The estn Europe . An excen Europe . Likewisn Europe .Babesia [Borrelia [In addition to well established diseases, multiple emerging tick transmitted pathogens were described during the past two decades ,76,77,78Babesia ,80,81, rBabesia , ehrlichBabesia ,83,84, BBorrelia , and virBorrelia ,87.Babesia and Theileria, highly important tick-borne parasites of domestic and wild animal species [Babesia are common, most cases are subclinical [Babesia species that infect a wide range of vertebrate hosts, including fifteen recently described species [Babesia species are reported from regions not previously associated with babesiosis [Babesia infection [Babesia were recently reviewed along with an examination of babesias infecting a variety of unexpected or non-traditional host species from around the world [Piroplasmorida, of the phylum, Apicomplexa, contain  species . Babesio species . Althougclinical . Babesioclinical . There a species . New Babbesiosis . The assnfection . The molhe world .Babesia species infecting humans [Babesia species that cause disease in humans are Babesia microti, Babesia microti-like organisms, Babesia duncani, Babesia duncani-like organisms, Babesia divergens, Babesia divergens-like organisms, and Babesia venatorum [Babesiosis is a global emerging zoonosis of increasing importance . During g humans . Babesiaenatorum .Babesia divergens is a bovine parasite that is associated with the infection of splenectomized humans [Babesia divergens infection of a splenectomized individual [Babesia divergens infections are most commonly associated with splenectomized individuals, other immunosuppressive conditions, and patients of advanced age [Babesia divergens human infections are occasionally reported in North America and Europe [d humans . The firdividual . Babesianced age ,80,93. Bd Europe ,89,93, ad Europe . Human bBabesia microti infection reported in 1969 following the bite of Ixodes scapularis [Babesia microti infections has increased significantly across the northeastern and upper Midwestern United States, with Ixodes scapularis infection rates of approximately 20% in well-established endemic areas [Ixodes scapularis, combined with the current presence of Lyme borreliosis, increases concerns about the emergence of babesiosis in Canada [Babesia microti and Babesia microti-like organism infections are also reported from Europe, Taiwan, and Japan [Babesia microti is a species complex comprised of three distinct clades [Babesia microti should be a distinct genus within the Apicomplexa [The first human babesiosis case occurring in an immunocompetent individual was a ic areas ,97. The n Canada . Babesiand Japan ,89,93. Bt clades . Phylogecomplexa .Anaplasma and Ehrlichia, that are important pathogens of companion, domestic, and wildlife species, as well as zoonoses of public health importance [Candidatus Neoehrlichia species\u201d [Anaplasma [The family, Anaplasmataceae, within the order, Rickettsiales, contains the tick transmitted genera, portance ,100. Thespecies\u201d , and recnaplasma .Ehrlichia phagocytophilum [Ehrlichia, resulted in the change to Anaplasma phagocytophilum [Anaplasma phagocytophilum causes tick-borne fever in ruminants, equine anaplasmosis, and febrile illness in cats and canines [Anaplasma phagocytophilum are ixodid ticks of the Ixodes ricinus complex; Ixodes ricinus in Europe, Ixodes persulcatus in Asia, and Ixodes scapularis, Ixodes pacificus, and Ixodes spinipalpis in North America [Ixodes scapularis transmitted pathogens are an important consideration, with approximately 10% of infected individuals having antibodies that are reactive with Borrelia burgdorferi or Babesia microti [Human granulocytic anaplasmosis was originally described in the upper Midwestern United States and assigned the designation of human granulocytic ehrlichiosis, caused by tophilum ,102,103.tophilum . In addi canines . Compete America . The num America , with a  microti . An expaEhrlichia are tick-borne Gram-negative members of the family, Anaplasmataceae, that are of human and veterinary public health importance [Ehrlichia species with recognized zoonotic potential include: Ehrlichia chaffeensis, Ehrlichia ewingii, Ehrlichia canis, Ehrlichia muris, Ehrlichia ruminantium, and Ehrlichia mineirensis [Ehrlichia, \u201cCandidatus Neoehrlichia species,\u201d were described in Europe, eastern Russia, China, and Japan [Ehrlichia ruminantium, is a notifiable disease of importance in domestic and wild ruminants in Africa and regions of the Caribbean [portance ,84. Ehrlnd Japan . Heartwaaribbean .Ehrlichia chaffeensis, a causative agent of human monocytic ehrlichiosis, was first described as a human pathogen in 1986 in a seriously ill man with a history of tick bites from the central United States [Ehrlichia chaffeensis infection in the United States involves the white tailed deer reservoir and the tick vector, Amblyomma americanum, for which all life cycle stages aggressively feed on humans [Ehrlichia chaffeensis is the most commonly reported human ehrlichiosis followed by Ehrlichia ewingii infection [Ehrlichia ewingii infection occurs in white tailed deer, canines, and ticks throughout the geographic range of Amblyomma americanum [Amblyomma americanum [Ehrlichia chaffeensis and Ehrlichia ewingii, suggests that these zoonotic pathogens will also be occurring in new areas, a situation of importance to healthcare providers, public health officials, and veterinarians.d States . The enzn humans . Ehrlichnfection ,107. Impericanum . The sigericanum ,56, and Rickettsia conorii subspecies conorii and israelensis [Tick-borne rickettsial diseases have increased dramatically during the past thirty years for established, re-emerging, and emerging pathogens, some of which were previously identified, but not associated, with human disease ,78. Tickaelensis . An in daelensis  and updaBorrelia burgdorferi infection is the topic of numerous studies, as well as the subject of excellent reviews [Borrelia burgdorferi sensu stricto, Borrelia afzelii, Borellia garinii, Borrelia bavariensis, and Borrelia spielmanii cause human disease [Borrelia mayonii was discovered to be an additional causative agent of Lyme borreliosis in the upper Midwestern United States in 2016 [Ixodes scapularis is a competent vector for Borrelia mayonii [Ixodes ricinus complex due to the application of new phylogenetic analyses [Borrelia species, coupled with an expanding range of vectors, will further evolve and be defined in coming years. reviews . Lyme bo reviews ,112. In  disease . Borreli in 2016 . Ixodes  mayonii . The geoanalyses . The cliBorrelia species are reported from Tanzania, Morocco, Ethiopia, and Algeria [Borrelia miyamotoi was first described in Ixodes persulcatus ticks in Japan; however, it was not associated at that time with human disease [Borrelia miyamotoi was subsequently identified as the causative agent of an Ixodes tick transmitted relapsing fever [Borrelia miyamotoi occurs across the North American, European, and Asian regions where Lyme borreliosis is found [Borrelia.New uncultured  Algeria . Borreli disease . Borreling fever . Borreliis found . CharactHaemaphysalis longicornis and Rhipicephalus (Boophilus) microplus in China [Amblyomma americanum in the United States [Amblyomma americanum [Amblyomma americanum [Important new zoonotic viruses are emerging and well known viral infections are resurging. Reviews were recently published on novel and emerging tick-borne viruses ,118,119.in China  and Ambld States ,122. Geoericanum . Bourbonericanum ,123.Hyalomma marginatum, into Central Europe [Well established tick-borne viruses are expanding their geographic areas of occurrence and/or resurging in incidence. Tick-borne encephalitis serogroup viruses are increasing their range across Europe , while Pl Europe . Alkhurml Europe . Alkhurml Europe ,131.The use of powerful molecular methods, such as high throughput sequencing, is increasing the identification in ticks of microorganisms that are not currently linked to human disease ,118. TicBorrelia miyamotoi [Neoehrlichia mikurensis [Rickettsia helvetica [Rickettsia monacensis [Rickettsia species identified by genomic methods [Ixodes scapularis, Dermacentor variabilis, and Amblyomma americanum from a single site in New York State resulted in identification of nine new viruses [Ixodes ricinus microbiome was analyzed by next generation sequencing [The application of molecular techniques was the basis for the reversed discovery of tick associated microbes that were, subsequently, recognized as human pathogens: iyamotoi , Neoehrlkurensis , Rickettelvetica , Rickettnacensis , and oth methods . High th viruses . This st viruses . New micquencing . Microbequencing .Expansion of tick species into new geographic areas presents the threat of the introduction of well characterized, resurging, and emerging tick-borne infectious agents into those regions. The characterization of microbiomes of tick species infesting humans in an area can provide a database of known and possible disease threats to public health officials, healthcare providers, and the public. Such tick associated microbe databases could prove invaluable in the identification of emerging tick-borne diseases.Ixodes scapularis [Dermacentor andersoni [Tick saliva creates a host cutaneous environment favorable, and, potentially, essential, for successful blood feeding, as well as the transmission and establishment of tick-borne infectious agents by the suppression or deviation of host pain/itch responses, hemostasis, inflammation, innate and adaptive immune defenses, and wound healing ,142,143.apularis  and apprndersoni . Initialndersoni ,15,86. Cndersoni ,147. Thendersoni . Non-prondersoni .Ixodes scapularis nymphs infected with Borrelia burgdorferi [Rhipicephalus microplus when infected with Anaplasma marginale [Bartonella henselae infection of Ixodes ricinus induced significant numbers of both upregulated and downregulated salivary gland genes, including within members of the same multigene family [The analysis of tick salivary glands revealed differential gene expression during infection with tick-borne pathogens; however, the roles, if any, of these differentially expressed genes in pathogen transmission and establishment within the skin at the tick bite site remains to be determined. Differential salivary gland gene expression was characterized for gdorferi . Differearginale . Bartonee family . Intercoe family .Recent reviews examined the activities of the saliva and individual saliva molecules of diverse species of ticks on individual cellular and molecular elements and pathways of vertebrate host inflammation, innate, and adaptive immune defenses ,142,143.Tick mouthparts are composed of two chelicerae, cutting plates that penetrate the epidermis into the dermis, and the ventrally positioned hypostome, which anchors the mouthparts into the skin and, in combination with the overlying chelicerae, forms a channel for the introduction of saliva and the uptake of blood from the pool-like feeding site ,154. ManTick saliva suppresses proinflammatory cytokine production by inhibiting the Toll-like receptor stimulation of keratinocytes, the most abundant basal cells in the epidermis . Tick feIn general, innate immune effectors within the dermis are down regulated to reduce the development and expression of immunity to the foreign body, tick mouthparts, and saliva molecules introduced into the skin. Innate immune antivirus responses include type I alpha and beta interferons produced by a variety of cells and natural killer (NK) cells that directly kill virus infected target cells and produce macrophage activating interferon gamma, IFN-gamma ,161. TicApproximately ten years ago, innate lymphoid cells were recognized and their diverse roles in inflammation, autoimmunity, immune regulation, and other physiological processes began to be characterized ,168,169.The alternative pathway of complement is an integral component of innate immune defenses that is a rapidly activated series of proteins directed against invading microorganisms and damaged cells to promote their destruction, phagocytosis, and produce bioactive molecules with vasoactive and chemotactic properties ,171. TicMacrophages are described as resident or circulating cells within tissues and as proinflammatory, classically activated M1, or anti-inflammatory, alternatively activated M2 populations ,175. TicSuppression of proinflammatory cytokines and chemokines is a common feature of the saliva of many tick species ,138. ProBorrelia burgdorferi [Neutrophils are the first cells recruited to an inflammatory focus where they phagocytose and kill extracellular pathogens, activate and recruit other cells, and both cause tissue damage and participate in tissue repair ,187. Ticgdorferi .Dendritic cells are heterogeneous populations of cells that are central regulators of adaptive immunity by orchestrating na\u00efve T cell immune responses and by acting as an interface between innate and adaptive immunity . With suIxodes ricinus saliva reduced dendritic cell uptake of Borrelia afzelli that would reduce subsequent antigen presentation [Ixodes ricinus saliva [Ixodes scapularis saliva, sialostatin L2, reduces Toll-like receptor induced dendritic cell signal transduction pathway activation during Borrelia burgdorferi infection [Tick saliva modifies dendritic cell responses to tick-borne pathogens. entation . Dendrits saliva . Ixodes nfection . AdditioT lymphocyte subsets are the predominate cellular effectors and regulators of cutaneous adaptive immune responses ,199. TheThe fact that ticks target a myriad of T lymphocyte effectors and regulatory activities is not surprising. Tick inhibition of T lymphocyte proliferation ,13,203 iTick salivary gland molecules suppress B lymphocyte proliferation and, in one case, were linked to a specific saliva protein ,208,209.Although individual tick species were not linked to each of the host immunomodulatory phenomena just described, the scope of how ticks down regulate and deviate host inflammation, innate, and adaptive immunity are impressive. Tick countermeasures to host pain and itch, hemostasis, and immune defenses likely evolved so that ticks of a specific species could repeatedly obtain blood meals during the life of the host; however, for some tick-host associations, acquired resistance to tick feeding develops ,143,203.Public awareness of the increasing population sizes, expanding geographic ranges of important tick vectors, and emergence and resurgence of tick-borne infectious agents is becoming greater. There exists the potential to develop integrated surveillance strategies for monitoring tick species\u2019 movements into new regions and changes in their population sizes that is combined with high throughput sequencing of tick microbiomes. Central to these efforts will be further microbiome gene annotations to define both tick symbionts and, potentially, transmitted microbes. Microbiome databases for ticks of medical and veterinary importance will provide physicians, veterinarians, public health works, other stakeholders, and the public with current information about recognized and, potentially, emerging tick-borne infectious agents that threaten, or could threaten, a region. Information obtained from these ongoing analyses will help with planning and assessing control interventions and protecting the health of companion, domestic, and wildlife animal species, as well as humans. Changes in tick geographic distributions and numbers, and the emergence of new tick-borne infectious agents, will continue. We need to be knowledgeable of those changes. A One Health approach is highly appropriate, if not essential, to be prepared to protect against these zoonotic infectious agents.Significant advances are being made, at an increasingly rapid pace, in understanding the tick-host-pathogen interface. Studies with multiple tick species and tick-borne pathogens established the importance of tick modulation of host pain/itch, hemostasis, inflammatory responses, innate and adaptive immunity, and wound healing. The complexity of saliva protein and non-protein components are increasing, with greater awareness of families of bioactive molecules, redundancies in activities, and differential expression during tick feeding. Linking specific saliva molecules to specific defense modulatory activities remains a major challenge; however, progress is being made toward achieving that goal and dissecting the underlying cellular and molecular mechanisms involved."}
+{"text": "Objectives: (a) To understand how to integrate geospatial concepts when implementing point-of-care testing (POCT); (b) to facilitate emergency, outbreak, and disaster preparedness and emergency management in healthcare small-world networks; (c) to enhance community resilience by using POCT in tandem with geographic information systems (GISs) and other geospatial tools; and (d) to advance crisis standards of care at points of need, adaptable and scalable for public health practice in limited-resource countries and other global settings.Content: Visual logistics help integrate and synthesize POCT and geospatial concepts. The resulting geospatial solutions presented here comprise: (1) small-world networks and regional topography; (2) space-time transformation, hubs, and asset mapping; (3) spatial and geospatial care paths\u2122; (4) GIS-POCT; (5) isolation laboratories, diagnostics isolators, and mobile laboratories for highly infectious diseases; (6) alternate care facilities; (7) roaming POCT\u2014airborne, ambulances, space, and wearables; (8) connected and wireless POCT outside hospitals; (9) unmanned aerial vehicles; (10) geospatial practice\u2014demographic care unit resource scoring, geographic risk assessment, and national POCT policy and guidelines; (11) the hybrid laboratory; and (12) point-of-careology.Value: Small-world networks and their connectivity facilitate efficient and effective placement of POCT for optimal response, rescue, diagnosis, and treatment. Spatial care paths\u2122 speed transport from primary encounters to referral centers bypassing topographic bottlenecks, process gaps, and time-consuming interruptions. Regional GISs position POCT close to where patients live to facilitate rapid triage, decrease therapeutic turnaround time, and conserve economic resources. Geospatial care paths\u2122 encompass demographic and population access features. Timeliness creates value during acute illness, complex crises, and unexpected disasters. Isolation laboratories equipped with POCT help stop outbreaks and safely support critically ill patients with highly infectious diseases. POCT-enabled spatial grids can map sentinel cases and establish geographic limits of epidemics for ring vaccination.Impact: Geospatial solutions generate inherently optimal and logical placement of POCT conceptually, physically, and temporally as a means to improve crisis response and spatial resilience. If public health professionals, geospatial scientists, and POCT specialists join forces, new collaborative teamwork can create faster response and higher impact during disasters, complex crises, outbreaks, and epidemics, as well as more efficient primary, urgent, and emergency community care. The goal of this review is to analyze the geospatial point-of-care testing (POCT) solutions in Synthesis of geospatial and POC concepts can facilitate emergency care, crisis response, and control of highly infectious diseases, such as Ebola virus disease (\u201cEbola\u201d). Integration of both concepts improves population access to healthcare. For efficiency and cost-effectiveness, POCT must fulfill healthcare needs on a daily basis, improve diagnostic skills, and enable public health, emergency medicine, and other personnel with fast decision making.inherently spatial, that is, performed at or near points of need, and also intrinsically temporal, because it produces fast actionable results. This definition does not depend on the size or format of the handheld, portable, or transportable instrument, test module, or assay design.Point-of-care testing is defined as diagnostic testing at or near the site of patient care , 79. It in situ, ex vivo, in vivo, and on vivo monitoring . The \u201cCape Cod\u201d group (https://en.wikipedia.org/wiki/Point-of-care_testing).It includes disposable test strips and d\u201d group  codifiedHighly infectious diseases, regional wars exacerbating deadly outbreaks , populations growing exponentially at least until mid-century , dense cHowever, the GPMB report did not recognize the importance of geospatial science and POCT. Population clusters in highly vulnerable areas amplify the risk. Nonetheless, we must eliminate inequities, while also responding quickly and effectively to increasingly frequent disasters, complex crises, and epidemics. To understand how to mitigate risk, we can use geospatial science mappings and produce \u201cvisual logistics,\u201d that is, easily understood graphics, flowcharts, topography maps, time contours, and other illustrations that show where, when, and how to position POCT optimally, create mobile rapid response, and implement the solutions in https://clarivate.com/) was used to consolidate over 500 entries retrieved as abstracts, ULRs, and PDFs, then subsequently pruned to slightly more than 100 articles to focus this review.PubMed, the World-wide Web, web sites of educational institutions, and other relevant sources were searched for papers, articles, chapters, documents, flowcharts, maps, and schematics in the form of published works and field research in limited-resource and other settings. Searches using IEEE Xplore did not yield additional relevant articles. In the interests of brevity, the reader can find detailed discussions of geospatial theory, software apps, and analytical techniques in Ferguson et al. \u201330. VisuNumerous sources identified through PubMed dealt with the general area of geographic information systems (GISs) in healthcare. The majority addressed GISs for tracking, monitoring, and managing infectious diseases, such as malaria and HIV. This article assesses the importance of geospatial science as it pertains specifically to POCT. Only those geospatially oriented publications explicitly discussing or integrating POCT and mobile technologies in relevant spatial settings, such as ring vaccination and space flight, are assessed here. Molecular diagnostics for Ebola and other highly infectious threats can be found in comprehensive reviews , 83 and This section analyzes 10 geospatial science approaches  where opOutbreaks are spatially dynamic. Starting with the recent epidemic in 2014, stopping Ebola outbreaks from spreading and caring for infected patients who are critically ill unequivocally proved the need for POCT , 44, 83.Small-world networks evolve naturally from social, political, and economic interactions; population dynamics; and medical-cultural ecosystems. Practice principles for optimizing POCT in SWNs are designed to enhance disaster preparedness, emergency management, and public health response at local , regional, and national levels, while simultaneously improving urgent and routine care in the community. This allows POCT operators to garner substantial experience with the use of POC instruments, reagents, and quality assurance through daily experience. POCT should not be used without proper training of those who will perform testing and quality control.Global Point of Care: Strategies for Disasters, Emergencies, and Public Health Resilience  and virtual connectivity .Regional hubs represent an advantage when planning POCT sites. However, removal of a busy hub during a disaster, because of physical destruction, invasive flooding, or some other calamity can turn the SWN into an isolated graph. Hence, resilience depends in part on self-reliance at individual nodes and clusters, an attribute that POCT confers nicely by enabling evidence-based decision making and local treatment. Only a few edges (interactions) separate nodes, a property leading to the popular notion of only 6 degrees of separation between any two people in the world. Separation impacts SWNs, so separation, Small-world networks must be discovered, drawn, and metricized through grass roots field investigations and interviews of emergency personnel. Solution 1 in 5]. The other applications under Solution 1 demonstrate similar utility and value of POCT in SWNs. The keys are flexibility and adaptability. Well-placed POCT can make SWN response \u201corganic,\u201d that is, rapidly adaptable in the face of evolving needs and crises.A surprise outcome in Nan Province was that nursing staff in the most northern regions adjacent to Laos PDR in Chaloem Phra Kiat Community Hospital insisted POCT be implemented to enable young physicians to make evidence-based decisions based on diagnostic bedside test results. Education became a primary motivator for implementing POCT. Junior physicians are conscripted to work in rural hospitals for 3 years to pay back government funding of their education. The number of people per doctor ranged from a low of 954 in Bangkok to a high of 8,510 in neglected resource-limited northern and northeastern provinces , 65. OftDuring interviews the physicians said they did not like watching their patients, perhaps with equivocal EKGs, die while under observation, but instead wanted to use POC cTn testing to rule in acute myocardial infarction and refer quickly. Similar themes see  of rapidSolution 3 in A spatial care path (SCP) is defined as the most efficient route taken by the patient when receiving definitive care in a SWN . A geospIt is likely that the SCP concept eventually will dominate healthcare delivery in limited-resource settings as populations expand, the number of elderly increase, and common sense, not to mention financial necessity, dictate that diagnosis and treatment must shift upstream nearer to the site of the patient's home in order to conserve resources, save time, and spare lives. As the availability of POC technologies expands and costs decrease through manufacturing efficiencies, countries with burgeoning population, such as China, India, Indonesia, and the Philippines, will find it easier to move initial diagnostic evaluation to primary sites.In Indonesia and the Philippines, local independence of healthcare nodes, clusters, and hubs becomes essential. Time is of the essence. Transport to larger islands where referral hospitals are located is challenging. In fact, island nations are at risk of flooding displacing dense coastal populations. POCT can follow these migrations. Hospital directors stated that 80% of their community population should be diagnosed and ideally, treated, in primary care sites outside the hospital, in order to prevent saturation of emergency rooms that simply cannot handle huge numbers of patients and unexpected surges that show up for evaluation .Earthquakes in densely populated areas  warrant Solution 4 lists only those that combined both POC and GIS concepts, especially the analysis of population access in terms of travel time  , are US mbo test .\u201dhttps://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization#current, and World Health Organization Emergency Use and Assessment Listings, here: https://www.who.int/diagnostics_laboratory/eual/emergency/en/.Kost et al. , 83 summhttps://www.who.int/emergencies/diseases/ebola/drc-2019/). This Ebola outbreak is the second worst, in the face of a response marred by war zones, shootings of health workers, civil strife, abandonment by NGOs and healthcare personnel, strike threats by nurses, and resistance within local communities to preventative measures, care facilities, and safe burials. Several care centers (>132) and health care workers (300+) have been attacked. Nonetheless, novel POC technologies, when used with safe specimen processing, can enhance ring vaccination, which has benefited the DRC by mitigating spread.Outbreaks continue in the DRC, now declared a global health emergency by the WHO. The number of cases (as of October 2019) totaled 3,274 with a death toll of 2,185 and mortality of 67% (see http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm632056.htm). The charter can be found here: http://www.fda.gov/downloads/EmergencyPreparedness/Counterterrorism/MedicalCountermeasures/MCMLegalRegulatoryandPolicyFramework/UCM631575.pdf. The consortium stated, \u201cThrough the TTFED, CDC, FDA, and CMS, where appropriate, intend to coordinate the implementation of EUA IVD assays in laboratories within the U.S. healthcare system, with the ultimate goal of improving responses to public health emergencies.\u201d However, there is no task force plan to train public health students or POCT specialists in the use of EUA devices and associated quality control. Except for one medical technologist, laboratory medicine professionals, public health educational institutions, and industries developing new EUA technologies appear not to be represented.On February 26, 2019, the CDC, FDA, and CMS announced a new \u201cTri-Agency Task Force for Emergency Diagnostics (TTFED),\u201d . Environmental conditions must be controlled, not only to assure accurate test results, but also for the comfort of operators wearing PPE.Solutions 6\u20139 summarize spatially discrete solutions outside the hospital. Alternate care facilities (Solution 6) provide safe sites for quarantine and screening (Solution 7) will benefit from progressively smaller, smarter, and faster POC technologies adapted for remote applications, such as airborne  for seamless bidirectional electronic communications. Physical linkages using novel unmanned aerial vehicles (UAVs) (Solution 9) show promise for delivery of critical medical supplies, transport of laboratory samples, and spatial solutions for accessing challenging topographies, remote sites, and isolated islands. In limited-resource settings, drones can help optimize healthcare SWNs, document the status of disasters, and track outbreaks of highly infectious diseases.Regardless of where they are generated, test results must be connected (https://flyzipline.com/) UAVs supply blood, vaccines, and drugs throughout Ghana and Rwanda in Africa. They claim 500 deliveries per day serving 11 million, with 30 min response time from app-initiated order. The drones have a 1.8 kg payload, fly 40,000 km per week (cumulatively over 1 million km), launch at 100 km/h, drop the payload at the target, and then return to base. This system could transport POC devices, reagents, and QC materials to remote sites within the 80 km service radii of base stations, which now cover most of Rwanda and central Ghana.Pilot studies show feasibility of drones for specimen transport \u201362 and iThe demographic care unit (DCU) concept gives policy makers a means of identifying the geographic locations most in need of POCT to improve standards of care , 65. DCUHealth resource characteristics comprised the number of people per primary care unit, hospital bed, medical doctor, registered nurse, technical nurse, pharmacist, and medical technologist in a given province. The total number of resource categories above the cut-off was determined to obtain the score for each DCU. Summary statistical analyses included range, minimum, maximum, mean, median, percentile, and standard deviation. The seventy-fifth percentile of people per health resource in a province defined the cut-off for interpretation of whether a DCU qualified as having a health resource deficiency. Also reported are poverty lines, number of poor people, poor people ratio, poor people times health resource score, and death rates.Solution 1), educational programs, a Thai language book with chapters on POCT , pH, and electrolyte  tests simultaneously on whole blood was inoperable in the Takuapa District Hospital, to which hundreds of critically injured tsunami victims were transferred  talked with the only doctor on call at one of the small coastal community hospitals in Phang Nga when the tsunami hit\u2014roads were blocked by flood waters isolating the hospital, drugs were depleted rapidly as he triaged over 1,000 victims, diagnostic instruments were inaccessible, and staff personnel were totally inadequate, because they could not reach the hospital at the time of the crisis. The experience had a devastating psychological effect on the sole young physician in charge, who did not want to continue medical practice subsequently.2, pCO2, pH) was found in any community hospital in Phang Nga Province  increased after the tsunami, but was complicated by the presence of several different brands that had been donated. In spite of dire need, the frequency of use of pulse oximeters in Phang Nga community hospitals did not match that in a survey control province, Chiang Rai, in northern Thailand  to appreciate and understand the scope, depth, and breadth needed to harmonize POCT across the geopolitical expanse of the South China and Natuna Seas that separate mainland Malaysia and two of its states on the island of Borneo, a distance >1,000 miles . The Malaysian initiative bases its guidelines on ISO  documents. Recognizing the importance of geopolicy in the use of new POC technologies can accelerate implementation, funding, and acceptance. Our book chapter , and treatment options in advance of outbreaks and epidemics, then equipping the facilities properly with POCT and personnel experienced in testing while wearing PPE, so they can operate instruments independently while in isolation.POCT-enabled spatial grids can locate sentinel cases and establish geographic limits of outbreaks. Integrating POCT plus GIS with ring vaccination will enable unique synergism for quickly detecting sentinel cases, geospatial tracking, and containment of epidemics.Analysis of population clusters, hubs, topographic features, and EMS routes in SWNs helps determine best sties for POC diagnostics, including devices on ambulance and other rescue vehicles or aircraft. These technologies also are needed for secure space flight.Small-world networks with multidimensional connectivity facilitate efficient and effective placement of POCT, which improves response time, rescue, diagnosis, treatment, and spatial resilience by accelerating evidence-based decision making at points of need.Visual logistics help design delivery systems capable of efficiently addressing individual crises, such as acute myocardial infarction, while analyzing healthcare strategies for difficult public health problems, such as Ebola, MERS-CoV, and H7N9; HIV, TB, and malaria; and differentiating concurrent Ebola infections from the others during outbreaks.Documenting transport time in contour maps and GISs facilitates EMS radio dispatching, regional coverage, and emergency transport, especially in the absence of helicopter transport or when ambulance service is inadequate.Placement of POC devices, ECG, and diagnostic tests on board ambulances with physician-guided prehospital diagnosis by telemetry accelerates pathways to tertiary care and intervention.Space-time transformations can identify POCT-facilitated  transport \u201cshort-cuts\u201d for critically ill patients to referral centers for cardiologist intervention. Parallel analysis produces solutions for diabetes and other public health challenges.Use of GISs to position POCT close to where patients live and work facilitates triage and rapid therapeutic turnaround time during emergencies, disasters, and outbreaks. They can expedite urgent primary care and assist remote population clusters in need of access.Spatial care paths\u2122 with POC devices positioned cleverly upstream speed transport from primary care to referral centers by bypassing geographic bottlenecks and time-consuming interruptions .Geospatial care paths\u2122 encompass features of population clusters, demographic fluxes, and local POCT hubs to decrease therapeutic turnaround time by expediting intermediate stages of inefficient routines, government protocols, or perfunctory patient evaluations.Geographic information systems can provide backbones for these care paths and also for dispatching drones, routing flight paths, and delivering medical and POC supplies in remote or inaccessible areas.Analysis of demographic care units can guide ministries of health in providing adequate primary care access, hospital beds, physicians, nurses, pharmacists, medical technologists, POC coordinators, POC technologies, and other vital resources, especially when prioritizing rural regions most in need using fresh data renewed each year.FN(t), must be minimized early on by assuring high sensitivity for ruling out infection of exposed patients.Onsite, rapid, and highly sensitive/specific POCT will help identify highly infectious diseases, stop outbreaks, and establish topographic perimeters of contagion. False negatives as a function of time, Alternate care facilities equipped with POCT can enhance community resilience in the event of quarantine, disasters, or complex crises .https://dpcpsi.nih.gov/AMRChallenge). The idea is to administer targeted therapy immediately to individual patients, avoid indiscriminate use of antibiotics in the population at large, and save precious healthcare funds.The POCT industry has grown to $31.4 billion worldwide, projected at $37.0 billion in 2021 . The POCBest use of POCT occurs when shrewdly selecting, combining, and integrating solutions in If public health professionals, geospatial scientists, and POCT specialists join efforts to use the solutions enumerated in The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "As the drive towards precision medicine has accelerated, enabled by an ever-increasing abundance of new data and information, the opportunities and challenges in applying computational approaches in cancer research and clinical applications are also growing dramatically. The onset of exascale computing together with the rapid rise of deep learning as an enabling technology and its potential are reshaping the way computation is being applied across scales of computing, across time and across spatial scales. With legislation in the form of the Twenty-first Century Cures Act as well as efforts of the Beau Biden Cancer Moonshot, these underscore the importance of workshops that bring together interdisciplinary experts and insights across the spectrum of computational approaches for cancer.Patient-centric \u2013 opportunities where the patient is closely involvedOrganizational \u2013 opportunities for organizations and different interests to collaborateData \u2013 opportunities around data and information, involving data acquisition, access, aggregation, sharing and managementTechnology \u2013 opportunities emanating from the rapid expansion of new technologies to acquire, transport, store, integrate, analyze and simulate complex biological systemsSeveral areas are highlighted as opportunities for innovation as disciplines converge in the interest of accelerating and extending the impact of computational approaches for cancer. As outlined in the 2016 Frontiers of Predictive Oncology and Computing meeting report, four distinct yet strongly inter-related areas of innovation include:The 2016 meeting report also identifies conducting workshops as an important next step to bring the communities together, to realize these opportunities for innovative advances.This supplement in BMC bioinformatics provides the reader a glimpse into areas where current innovations and insights are emerging as efforts in interdisciplinary computational cancer science increase and grow. Developed from the contributions at the Third Computational Approaches for Cancer workshop held at the SC17 conference, this supplement brings together the computational community exploring and using high-performance computing (HPC), analytics, predictive modeling, and large datasets in cancer research and clinical applications. The manuscripts are interdisciplinary, with the common interest in cancer and computation the unifying theme. As such, the manuscripts provide rich opportunities for attendees to learn about future directions, current applications and challenges and build collaborations. Maintaining a perspective of accelerating scientific insights and translation of insights to clinical application for improved patient outcomes, the supplement brings together many interests from across the technology, cancer research and clinical domains.The authors and submissions listed below contributing to this supplement provide key examples of the use of computational methods across a wide range of cancer research applications, ranging from scalable approaches to explore the molecular domain to enabling scalable population level cancer research and clinical. From a technical perspective, the supplement also provides examples across a wide range of computational technologies, ranging from the use of field-programmable gate arrays and GPUs to designs of throughput systems preparing to take advantage of emerging exascale computing capabilities. And, of course, the supplement highlights applications with emerging capabilities in scalable deep learning while exploring working to address the inherent uncertainty in the classification, characterization, and predictive analytics for complex biological systems epitomized by cancer.Nick Hengartner, Leticia Cuellar, John Hogden, Hong-Jun Yoon, John Qui, Georgia Tourassi and Tanmoy Bhattacahrya.CAT: Computer Aided Triage: Improving upon the Bayes risk through \u03b5-refusal triage rules.Will Fischer, Sanketh S. Moudgalya, Judith D. Cohn and Garrett Kenyon.Sparse Coding of Pathology Slides.Ahmed Sanaullah, Martin Herbordt, Chen Yang, Yuri Alexeev and Kazutomo Yoshii.Real-Time Data Analysis for Medical Diagnosis Using FPGA-Accelerated Neural Networks.Shantenu Jha, Matteo Turilli, David Wright, Jumana Daarsekka, Vivekanandan Balasubramanian, Peter Coveney, Shunzhou Wan and Stefan Zasada.High-throughput Binding Affinity Calculations at Extreme Scales.Debsindhu Bhowmik, Shang Gao, Michael Young and Arvind Ramanathan.Deep Clustering of Protein Folding Simulations.Justin Wozniak, Rajeev Jain, Prasanna Balaprakash, Jonathan Ozik, Nicholson Collier, John Bauer, Fangfang Xia, Thomas Brettin, Rick Stevens, Jamaludin Mohl-Yusof, Cristina Cardona, Brian Van Essen and Matthew Baughman.CANDLE/Supervisor: A Workflow Framework for Machine Learning Applied to Cancer Research.Fangfang Xia, Maulik Shukla, Thomas Brettin, Cristina Garcia-Cardona, Judith Cohn, Jonathan Allen, Sergei Maslov, Yvonne Evrard, Susan Holbeck, James Doroshow, Eric Stahlberg and Rick Stevens.Predicting Tumor Cell Line Response to Drug Pairs with Deep Learning.Jonathan Ozik, Nicholson Collier, Justin Wozniak, Charles Macal, Chase Cockrell, Samuel Friedman, Ahmadreza Ghaffarizadeh, Randy Heiland, Gary An and Paul Macklin.High-throughput Cancer Hypothesis Testing with an Integrated PhysiCell-EMEWS Workflow.Hong-Jun Yoon, John Qiu, Thomas Watson, Arvind Ramanathan and Georgia Tourassi.Scalable Deep Text Comprehension for Cancer Surveillance on High-Performance Computing.Reflecting on the noted areas of opportunity in working with patients, with organizations, with data and with technology, this supplement provides examples of how interdisciplinary communities have successfully converged to explore innovative approaches spanning the range of opportunities. The strong coupling among these areas is also evident, where data and technology are utilized across organizations in the interest of accelerating patient impact for cancer. These examples, while distinct, collectively help lay the foundations and insights needed for critical areas of future integrated cancer learning systems."}
+{"text": "Obesity is a risk factor for cardiometabolic and vascular diseases like arterial hypertension, diabetes mellitus type 2, dyslipidaemia, and atherosclerosis. A special role in obesity-related syndromes is played by cardiac visceral obesity, which includes epicardial adipose tissue and intramyocardial fat, leading to cardiac steatosis; hypertensive heart disease; atherosclerosis of epicardial coronary artery disease; and ischemic cardiomyopathy, cardiac microcirculatory dysfunction, diabetic cardiomyopathy, and atrial fibrillation. Cardiac expression of these changes in any given patient is unique and multimodal, varying in clinical settings and level of expressed changes, with heart failure development depending on pathophysiological mechanisms with preserved, midrange, or reduced ejection fraction. Progressive heart failure with misbalanced metabolic and catabolic processes will change muscle, bone, and fat mass and function, with possible changes in the cardiac fat state from excessive accumulation to reduction and cardiac cachexia with a worse prognosis. The question we address is whether cardiac obesity or cardiac cachexia is to be more feared. In recent years, obesity and visceral fat have been recognized as a worldwide health problem and an independent risk factor for metabolic and cardiovascular diseases such as insulin resistance, dyslipidaemia, arterial hypertension, chronic subclinical inflammation, atherosclerosis, and cardiac steatosis. These obesity-related syndromes can lead to diabetes mellitus; hypertensive heart disease; coronary artery disease, and ischemic cardiomyopathy, diabetic cardiomyopathy, metabolic- and obesity-related cardiomyopathy, coronary microcirculatory dysfunction, and atrial fibrillation. Depending on the level and type of obesity, life style, genetic predisposition, gender, ageing, clinical presentation, and treatment, these disorders can lead to heart failure (HF) with preserved, midrange, or reduced ejection fraction \u20135.Unanswered questions remain regarding the period between the onset of the problem (obesity) until HF and cardiac cachexia (CC) develop; these questions include the etiology of visceral obesity, the process by which healthy fat tissue becomes stressed, the role of genetics, environment, gender, and ageing, mechanical, and metabolic effects of excess adipose visceral tissue on the cardiovascular system, and the role of inflammation and catabolism in heart failure-related cachexia .During recent years, great interest in obesity pathophysiology and related morbidities has led to the development of many different terms to describe obesity-related processes. The term obesity refers to an excess of fat tissue in an organism, regardless of type, location, function, and whether it is \u201chealthy\u201d or \u201csick\u201d fat tissue . In receSubcutaneous adipose tissue (SAT) represents 85% of total adipose tissue mass in lean and obese individuals, while 15% constitutes visceral adipose tissue (VAT) at the highest risk for metabolic dysregulation, suggesting quality is more important than quantity , 11. SATAdipose tissue serves as a central nexus of metabolic communication and control, an arbiter of thermoregulation, a buffer against trauma and cold temperatures, a regulator of reproduction, and satiety. The number of adipocytes in a given individual is mainly determined in childhood and adolescence and remains constant during adulthood in both lean and obese subjects. An increase in fat mass in adulthood is primarily attributed to adipocyte hypertrophy or via hyperplasia in response to overfeeding , 15. AdiCardiac visceral adipose tissue is composed of local visceral pericardial and intracardial visceral fat according to anatomy, local, and systemic activity. Epicardial adipose tissue and intramyocardial fat are the two main compartments of cardiac visceral fat, with cardiac steatosis as a special pathophysiological entity.Epicardial adipose tissue (EAT) is regional visceral fat surrounding the heart in direct contact with the epicardial conductive coronary artery. EAT makes up about 20% of cardiac weight and lies between the heart and the visceral part of the pericardial layer, is derived from the splanchnopleuric mesoderm, and shares the same embryologic origin as mesenteric and omental fat, composed from fat cells, nervous tissue, nodal tissue, inflammatory, stromal, and immune cells [ne cells \u201326.\u03b2, IL-6, IL-8, IL-10, TNF-\u03b1, MCP1, and PAI. This fat is also the source of many adipokines with proatherogenic and proinflammatory effects, leading to decreased levels of protective adiponectin [EAT has a high rate of free fatty acid (FFA) synthesis, and incorporation and degradation depend upon myocardial need . EAT conponectin \u201330. Adipponectin , 32. In ponectin , 29, 33.Coronary artery calcification is a major vascular injury and considered to be the manifestation of coronary atherosclerosis . EAT facCardiac steatosis is an endogenous source of cytosolic FFAs, typically found in patients with obesity and type 2 diabetes mellitus, and is known to increase with age. Circulating FFAs participate in the regulation of myocardial fat depots [t depots , 39. Lipt depots , 41. Whet depots , 43. Thet depots \u201346. The t depots \u201350.Intramyocardial fat tissue has been histologically validated in healthy obese and nonobese individuals as well as in diseased hearts. This tissue is predominantly located in the right ventricle, with very small amounts present in the apical part of the left ventricle, usually as a part of scar connective tissue after myocardial infarction or as a part of dilated cardiomyopathy [myopathy , 51. No myopathy , 51\u201353. myopathy , 55.In addition to obesity, ageing also brings with it increased health problems and risk for stroke, heart attack, and diabetes and an increased likelihood of developing abdominal obesity and fat depots in skeletal muscle, which predisposes the body to insulin resistance and metabolic syndrome , 57. ObeThe link between obesity and heart disease is complex. Obesity increases the potential for developing other risk factors for heart disease, triggers inflammatory processes, and leads to structural and functional changes in the heart itself. Metabolic effects of diseased adipose tissue include adipocyte dysfunction and inflammation leading to type 2 diabetes mellitus, arterial hypertension, dyslipidaemia mixta, coronary atherosclerosis, and various etiological and clinical presentations of cardiomyopathy. Mechanical effects of excessive fat include sleep apnoea, thromboembolic events, increased blood volume, and cardiac output, atrial enlargement and ventricular dilation, and electrocardiogram and conduction system abnormalities , 11, 16.Obesity-related factors are implicated in 11% of HF cases in men and 14% in women. Obesity may directly result in HF by inducing hemodynamic and myocardial changes that lead to cardiac dysfunction, or indirectly through an increased predisposition to other heart failure risk factors. Increased metabolic demands resulting from excess adipose tissue and nonfat mass in obesity lead to hyperdynamic circulation and increased blood volume and cardiac output . When ob2) in patients with chronic illness and at least three of the following clinical or laboratory criteria: decreased muscle strength, fatigue, anorexia, low fat-free mass index, and abnormal biochemistry characterized by increased inflammatory markers. It involves loss of muscle, fat, and bone. Skeletal muscle wasting and loss of function, called sarcopenia, often precedes cachexia and predicts poor outcome [Cardiac cachexia is a severe, complex, multifactorial condition associated with chronic heart failure that can occur independent of age, ventricular function, or functional classification. Presence of the syndrome predicts increased morbidity and mortality related to weight loss and systemic inflammation. CC is defined as at least 5% oedema-free body weight loss in the previous 12\u2009months , anabolic steroids, \u03b2\u20102 receptor agonists, selective androgen receptor modulators, enzyme inhibitors, and statins, among others [Healthcare professionals have defined an urgent need to develop effective preventive and therapeutic modalities because of the substantial burden of CC on patients and the healthcare system, but progress remains slow. With so many unknown interacting and complex pathophysiological mechanisms, efficient targeting of specific pathophysiologic processes to achieve desired results remains elusive. No single intervention can achieve desired therapeutic results in this multifactorial process, but research into prevention and therapy has focused on certain possible pathways. Prevention of CC development includes management of heart failure including pharmacological agents such as beta blockers and ACE-inhibitors. Exercise can contribute to the preservation and increase in muscle mass in addition to anabolic effects . Nutritil itself , 68, 69.g others , 70, 71.Obesity is a known risk factor and a known etiopathogenic factor for a number of cardiovascular and metabolic diseases, including arterial hypertension, diabetes mellitus type 2, dyslipidaemia, and atherosclerosis \u20134. The eIndividuals with similar body mass index (BMI) may have different metabolic and cardiovascular risk profiles. Tendency to cardiometabolic complications associated with obesity is not solely mediated by the total body fat mass, also depends on individual regional body fat distribution differences and subcutaneous adipose tissue ability to expand . AssessmUse of the term \u201cobesity paradox\u201d is scientifically and clinically imprecise, as it lumps together many findings whose relationships remain unproven. The term oversimplifies complex biological responses that can vary by disease and treatment . This paBetter characterization and understanding of the visceral/ectopic fat depots role and their biochemical activity, body mass composition, CRF, and effects of weight loss are needed . Subsequ"}
+{"text": "Older adults with HIV (OAH) evidence a significant burden of disease, characterized by high frequencies of non-HIV related comorbidities that result in multimorbidity and polypharmacy decades earlier than non-HIV infected older adults. Commonly observed comorbidities among OAH 50 years and older include cardiovascular disease, hypertension, diabetes, osteoporosis, and cancers. Geriatric conditions such as frailty, functional impairment, chronic inflammation, and cognitive dysfunction are also prevalent. Poverty, unemployment, housing, and food insecurity, as well as stigma-driven discrimination, persistent social isolation and high rates of depression, can make health-related challenges associated with aging overwhelming, resulting in a diminished capacity for self-care. Older men and women with HIV; however, are aging differently due to gender-specific differences in comorbidity profiles, polypharmacy burden, social networks, and intersectional stigmas . This symposium explores the impact of gender on healthy aging among OAH. Dr. Brennan-Ing and colleagues describe specific strategies for achieving healthy aging among female OAH in NYC and Oakland, CA. Dr. Rubtsova and colleagues explore multiple meanings of \u201csuccessful aging\u201d among older women in Atlanta and Brooklyn, and the role of resilience that empowers them as long-term HIV survivors. Dr. Taylor qualitatively examines the impact of biopsychosocial factors on notions of \u201cHealthy HIV Aging\u201d among older gay, bisexual and heterosexual men with HIV. Dr. Ruth Finkelstein will discuss the public health implications for developing equitable and gender-specific and intersectional HIV prevention and wellness interventions and suggest future areas of inquiry to improve HIV outcomes across the care continuum."}
+{"text": "Nutritional risk has been demonstrated to be associated with poor health outcomes, increased risk of health services utilization (HSU), and mortality among older adults. The aim of this study was to assess the prospective relationship between nutritional risk; HSU focusing separately on emergency department visits, hospitalization, and nursing home admission; and mortality. Using the University of Alabama-Birmingham Study of Aging II, we examined this relationship among 419 community-dwelling older Alabamians (75+years). We used the Mini-Nutrition Assessment (MNA), a well-validated nutritional risk assessment, which classifies individuals as either well-nourished, at-risk or malnourished, collected at baseline. We assessed HSU by asking about healthcare encounters since the last monthly follow-up call for 12 months and verified death with family reports and official documents. We completed univariate, bivariate, and Cox proportional hazards regression analyses with one-year of follow-up data, adjusting for social support, social isolation, comorbidities, and demographic variables. Accounting for covariates, being either at-risk or malnourished, relative to well-nourished, was associated with emergency department visits , hospitalization , nursing home admission , and mortality . These findings underscore the growing awareness that nutritional risk, particularly for older adults, is a significant factor affecting their well-being and particularly their ability to continue living in the community. Nutrition assessment, interventions, and services for community-dwelling older adults may lead to a reduction in health care utilization, particularly nursing home placement, and ultimately to reduced healthcare costs to families and taxpayers."}
+{"text": "The human microbiome harbors a diverse array of microbes which establishes a mutually beneficial relation with the host in healthy conditions, however, the dynamic homeostasis is influenced by both host and environmental factors. Smoking contributes to modifications of the oral, lung and gut microbiome, leading to various diseases, such as periodontitis, asthma, chronic obstructive pulmonary disease, Crohn\u2019s disease, ulcerative colitis and cancers. However, the exact causal relationship between smoking and microbiome alteration remains to be further explored. Approximately 2 billion people worldwide use tobacco products, mostly in the form of cigarettes, with tobacco smoking-related diseases resulting in at least 4 million global deaths per year . DramatiThe microbiome refers to a community of microbes residing in a defined environment, comprising of bacteria, viruses, fungi, and protozoa, together with their genes and genomes in a given locus. The gastrointestinal microbiome is the most complex echo-system of 10\u2013100 trillion microorganisms, in which the amount of bacteria was the most, in the next place was that of fungi and virus . The oraPantoea agglomerans, Acinetobacter calcoaceticus, and specific Pseudomonadaceae species such as P. fluorescens and Stenotrophomonas maltophilia in fresh tobacco leaves or other species in single tobacco flakes or fine tobacco particles [Acinetobacter, Bacillus, Burkholderia, Clostridium, Klebsiella, and Pseudomonas aeruginosa. Many of the detected organisms are capable of causing pneumonia, bacteremias, foodborne illnesses, meningitis, endocarditis, and urinary tract infections [Massive studies demonstrated the adverse health impacts of tobacco on systemic pathophysiologic changes that can lead to disease, were associated with the chemicals, heavy metals, particulate matter and other constituents in tobacco \u201327. Howearticles , 26. Witfections . TherefoAnother possibility for the mechanism through which current smokers may have different bacteria community may be related to impaired antimicrobial defenses due to the immunosuppressive nature of tobacco. Tobacco smoking has been observed to affect the peripheral immune system on several levels, including a decrease in the activity of natural killer cells, increase in white blood cell counts, and a higher susceptibility to infection . SmokingStreptococcus pneumoniae and inactivation of pneumolysin induced by exposure to cigarette smoke condensate are likely to favor microbial colonization and persistence, both being essential precursors of pneumococcal disease [Staphylococcus aureus and human cell adherence in the presence of cigarette smoke (CS) indicate the role of bioactive effects of CS on resident microbiota in the pathogenesis of respiratory infection in CS-exposed humans [It is also possible that metabolic advantages of biofilm formation and increased adherence to the epithelium are conferred to certain taxa expansion in a smoky environment. Exposure to cigarette smoke could increase biofilm formation by specific bacteria , 35. Biod humans . These fPrevotella and Neisseria spp. and an increased relative abundance of Firmicutes, principally Streptococcus spp., and Veillonella spp., along with the genus Rothia (Actinobacteria) in the upper GI tract from current smokers, compared with that from persons who have never smoked [Neisseria, Streptococcus, and Rothia spp. in current smokers indicated the implication of changes in oxygen tension. In that study, alterations in duodenal bicarbonate secretion [Neisseria, which is one of the capnophiles and sensitive to acid conditions [Streptococcus and Rothia spp. are acidogenic and acid tolerant.\u201cMicroenvironment\u201d may also be relevant regarding the influence of smoking on particular members of the microbiota, such as oxygen, pH, and acid production. Oxygen tension is an important promoter of the changes in bacterial community, with microaerophilic and anaerobic bacteria able to predominate due to lower oxygenation , 38. Shar smoked . The difecretion  and loweecretion  in smokenditions , whereasAccording to above discussion, we could reach the conclusion of mechanisms of cigarette smoking to influence the microbiome via changes to immune homeostasis, biofilm formation, oxygen tension, or through direct contact with microbes it contained, and these mechanisms may be involved in the occurence of various diseases Fig. .Fig.\u00a01ScNeisseria species or Branhamella [Porphyromonas, Neisseria, and Gemella [The oral microbiome, comprising more than 2000 bacterial species , plays anhamella , 52. Due Gemella . Mason e Gemella .Parvimonas, Fusobacterium, Campylobacter, Bacteroides, and Treponema and lower levels of Veillonella, Neisseria, and Streptococcus [Evidences indicate that periodontitis was associated with smoking and complex microbial communities in the subgingival sulcus \u201356, and tococcus . The diftococcus \u201361. In atococcus , 63. TsiStaphylococcus aureus, viri-dans Streptococci and Enterococcus spp. are the most common pathogens identified [Gemella sanguine, Streptococcus tigurinus, L. goodfellowi were also found to be the cause of infective endocarditis [In recent years, significant associations have been elucidated between periodontitis and other systemic diseases , 65, andentified . Gemellacarditis \u201372. Howecarditis . Indeed,carditis . Given tcarditis , and thecarditis , it woulGranulicatella, Lactobacillus, Veillonella, Enhydrobacter, Streptococcaceae and Comamonadaceae, moreover, abundance of the fungal genus Candida was also increased in HIV-infected smokers [Betaproteobacteria (primarily Neisseria) and 23% increase in relative abundance of Veillonellaceae family [In addition to local health, oral microbiome also plays an important role in other systemic diseases, including HIV infection, gastrointestinal cancer, even immune diseases. HIV infection has been associated with dysbiosis of oral microbiome, with increased levels of pathogenic bacteria and fungi , 75, HIV smokers . Oral mie family . These dProteobacteria, Firmicutes and Bacteroidetes, as evidenced by bronchoalveolar lavage samples of healthy adults, bacterial communities vary with different airways in terms of different airway microarchitecture, and documented changes in the lung microbiome in several lung diseases have been uncovered [Because of the presence of a sparse microbiome, especially in healthy conditions, traditional standard microbiological culture-based methods can hardly detect microbes in healthy individuals, so the lung has historically been presumed as sterile. Over the past several years, culture-independent molecular methods springing up, lung microbial communities in healthy individuals showed a phenotype predominant by ncovered , 79.Smoking, cigarette smoke exposure, tobacco smoke or pollutants in the air contact directly with the airway, through the way to the lungs, causing a variety of airway diseases, such as COPD, asthma, cystic fibrosis and lung cancer. In recent years, the effect of smoking on microbiome of lower respiratory tract attracted increasing attention. Mammen and Aethi proposed a revised \u201cVicious Circle\u201d, suggesting that insults such as tobacco smoke impairs innate immune defenses, causing variations in the abundance, taxonomic composition and phylogenetic diversity of the lung microbiome. This, in turn, leads to maladaptive inflammatory responses, further impairment of lung defenses and further dysbiosis of the lung microbiome, setting up the vicious circle with its attendant consequences .Actinobacteria and Proteobacteria, the later by Actinobacteria and Firmicutes, and they also found a trend without significant difference that severe subjects contained more Firmicutes and less Actinobacteria and Proteobacteria than the moderate subjects [Proteobacteria, Firmicutes and Actinobacteria, the most prevalent genera were Streptococcus and Haemophilus, exceeding half of the abundance of present bacterial microbiome [COPD is a chronic airway inflammatory disease that can be prevented and treated lung disease, characterized by a largely irreversible chronic obstruction of airflow. The course of the disease is featured and frequently aggravated by intermittent exacerbations, acute changes in the airway microbiome, for example by introduction of a new strain of a respiratory pathogen, lead to larger inflammatory responses, which present clinically as exacerbations of COPD , so chansubjects . Howevercrobiome . Althougcrobiome .Smoking is the principal cause or initiating factor responsible for the development of the disease in COPD patients. It alters host\u2013microorganism interaction dynamics in the airways, contributing to COPD . The infProteobacteria and lower Bacteroidetes phylum compared to healthy control as evidenced from samples of bronchial epithelial brushings [Streptococcus spp. and eosinophilia in severe asthma patients [Aspergillus and Penicillium were significantly associated with impaired post-bronchodilator expiratory volume in 1\u00a0s in asthmatics [Aspergillus; the relative abundance of Aspergillus increased approximately 15-fold compared to mild asthmatics [Asthma is a chronic airway inflammatory disease, characterized by reversible airway obstruction, chronic airway inflammation, and airway hyper-responsiveness \u201391. Therrushings , and thepatients . Airway patients  and cortpatients . While tpatients , of whicthmatics . Severe thmatics . HoweverFusobacteria, the phyla Firmicutes and Bacteroidetes, and a lower abundance of bacteria from phylum Proteobacteria compared with never-smokers. They also revealed an association between smoking and increased diversity of bacteria [As the main source of indoor air pollution, tobacco smoking, mostly in the form of cigarette smoking, is an important environmental factor influencing the outcomes of asthma. Smoking (including active and passive smoking) can not only cause frequent attacks of asthma, lead to rapid decline of lung function in asthmatic patients, but also reduce the therapeutic effect of glucocorticoid in asthmatic patients, making the condition of asthmatic patients difficult to control . Microbibacteria . Howeverbacteria . More stStreptococcus, Prevotella and Veillonella) predominated, these species shifted to traditional CF taxa  [Candida albicans and Aspergillus fumigatus are commonly detected in CF sputum cultures and have also been associated with acute pulmonary exacerbations [Cystic fibrosis (CF) is a multi-organ disease with variable clinical characteristics, with pulmonary manifestations (e.g. bronchiectasis and chronic infection) being the prominent feature , 106. Prolderia)  and remaolderia) \u2013111. Witrbations , and therbations . As for rbations .Mutations of cystic fibrosis transmembrane conductance regulator (CFTR), an epithelial anion channel, are predominant in the cause of CF . SmokingBacteroides, Faecalibacterium, and Bifidobacterium being the most prevalent genera [The gastrointestinal microbiome is a complex echosystem of 10\u2013100 trillion microorganisms composed of bacteria, virus and fungal species, that develops immediately after birth depending on multiple factors, and fluctuates or changes resulted from affection of a number of factors such as age, drugs , diet, alcohol, and smoking throughout the whole time growing up , 17. In t genera , and dist genera .Clostridium and decreased the amount of Lactoccoci, Ruminococcus, Enterobacteriaceae and segmented filamentous bacteria (SFB) in the cecal microflora [Clostridium difficile infection [Bacteroidetes and decreased Firmicutes and Proteobacteria in gut microbiota composition community compared with never smokers [Bacteroides\u2013Prevotella (34.8%) than nonsmokers (24.1%) [Firmicutes and Actinobacteria, while decreasing Bacteroidetes and Proteobacteria [Smoking prevalence is the leading cause responsible for developing Crohn\u2019s disease (CD), colonic carcinoma, and systemic disease , 123. Thcroflora . In humanfection . Current smokers . Another (24.1%) . In addibacteria . Many reBacteroidetes and Firmicutes), increase of pathogenic organisms  [Roseburia spp., Clostridium and Bacteroides species, known to be producers of butyrate, which is fundamental to intestinal cell homeostasis and mucosal barrier integrity [Crohn\u2019s disease (CD) is a type of inflammatory bowel disease that mainly affect gastrointestinal tract, characterized by chronic inflammation due to defective mucosal barrier and greater intestinal permeability . While tspecies) , and a gspecies) . Researcntegrity , 138. ThBacteroides\u2013Prevotella in smoking patients with CD compared with nonsmokers through fluorescent in situ hybridization using probes targeting 16S rRNA of bacteria [Collinsella, Enterorhabdus, and Gordonibacter [Faecalibacterium has immune-regulatory function to reduce IL-12 expression in peripheral blood mononuclear cell (PBMC) in vitro and increase IL-10 release, lower ileal mucosal Faecalibacterium prausnitzii is correlated with greater risk of recurrence following surgical resection in CD patients [Faecalibacterium prausnitzii in inflamed mucosal tissue from smokers with active CD compared with non-smokers, the risk of post-operative CD recurrence may be predetermined at a pre-operative stage due to dysbiosis. These observed features of reduced gut microbiota may explain the persistent intestinal inflammation in CD patients in smoky environment, highlighting the possible role of microbes interacting with smoking and CD (or mediating the adverse effects of smoking in CD). However, the mechanisms through which smoking caused alterations in microbiota are unclear.Smoking is the best studied environmental risk factor for CD, exerting detrimental effects on mucosal barrier and greater intestinal permeability and disease susceptibility . Accumulbacteria . In anotnibacter , which cnibacter . Faecalipatients . MuruganFirmicutes and increases in Proteobacteria in UC gut microbiomes [Fusobacteriaceae family increased, Bifidobacteria and members of the Faecalibacterium taxon appeared to be compromised in gut microbiota of UC patients [Bifidobacteria as a microbial biomarker to identify the intestinal dysbiosis triggering UC [Ulcerative colitis (UC) is another type of chronic relapsing inflammatory disorder confined to the colorectal region and to the mucosal layer of the gastrointestinal tract. Previous studies have demonstrated aberrant microbiota deviations from gut homeostasis in UC patients, as evidenced by a low taxonomic diversity, decreases in robiomes \u2013145. Propatients , 147, anThe understanding of pathogenesis and etiology of UC is still out of reach. It was presumed that genetically susceptible individuals of UC or patients with UC exhibited aberrant mucosal immune response against their gut microbiota , 149, whColorectal cancer (CRC) is considered a major public healthy issue, with approximately 700,000 deaths reported annually worldwide , rankingStreptococcus gallolyticus [Fusobacterium, [B. fragilis [Escherichia\u2013Shigella, Peptostreptococcus ten [Bacteroides, Roseburia [Pseudomonas [The abundance of several microbes, such as olyticus , Fusobaccterium, , B. fragfragilis , Eschericcus ten  were obsoseburia  and Pseuudomonas  were sigudomonas , and wheudomonas .Bifidobacterium [Bifidobacterium but also reduce its production of short chain fatty acids (SCFAs) [CRC is a complex disease susceptible to a variety of diet and lifestyle factors, especially smoking, a well-known factor involved in the initiation and increasing the risk of CRC with a prolonged latency period . Althougacterium , mainly acterium  was highacterium . In addi (SCFAs) , 173, im (SCFAs) . Moreove (SCFAs) , which pStated thus, these studies suggested that alterations of gut microbiome may be an essential contributing factor to the initiation and development of this cancer in the context of smoking.Prevotella copri [Bilophila spp., and several opportunistic pathogens , together with a reduction in butyrate-producing bacteria Clostridium spp., and two genera of methanogens  in BD patients [Clostridium and Bacteroidetes in Japanese patients with MS [In addition to inflammatory bowel disease, dysbiosis of the gut microbiome has been implicated in many autoimmune diseases, including multiple sclerosis (MS) , rheumatla copri . Ye et apatients . MS has  with MS .Smoking affects both innate and adaptive immune systems and plays dual roles in regulating immunity by either exacerbation of pathogenic immune responses or weakening of defensive immunity . SmokingIn conclusion, microbiome research has enormously developed in the last years tempting to move its steps to better characterize the human microbiome. Smoking is the risk factor of several diseases, it could impact human microbiome directly or indirectly through immunosuppression, oxygen deprivation, biofilm formation, or other potential mechanisms. None of the above mechanisms is well established, and adequate explanation of how smoking affects the microbiome is yet to be established. Microbiome has pivotal roles in the development of healthy immune responses, and oral, airway and gut microbial dysbiosis can contribute to local or systemic various diseases such as periodontitis, HIV infection, gastrointestinal cancer, asthma, COPD, CF, CD, UC, RA, MS. Evidence suggests the microbial dysbiosis in many diseases in smoky environment, but the causal relationship between microbiome alterations and disease progress remains enigmatic. More basic and clinical researches may help us gain more insight into the hugely complex net-work of smoking\u2013microbiome\u2013host interactions underlying the observed associations. Longitudinal studies integrating metagenomic, transcriptomic, metabolomic, methods with clinical results may help us ascertain the relationships between smoking, microbiome, and pathological mechanism in diseases."}
+{"text": "Metabolic syndrome (MS), which includes metabolic disorders such as protein disorder, glucose disorder, lipid disorder, and carbohydrate disorder, has been growing rapidly around the world. Glycolipid disorders are a main type of metabolic syndrome and are characterized by abdominal obesity and abnormal metabolic disorders of lipid, glucose, and carbohydrate utilization, which can cause cardiovascular and cerebrovascular diseases. Glycolipid disorders are closely related to intestinal flora and its metabolites. However, studies about the biological mechanisms of the intestinal flora and its metabolites with glycolipid disorders have not been clear. When glycolipid disorders are treated with drugs, a challenging problem is side effects. Traditional Chinese medicine (TCM) and dietary supplements have fewer side effects to treat it. Numerous basic and clinical studies have confirmed that TCM decoctions, Chinese medicine monomers, or compounds can treat glycolipid disorders and reduce the incidence of cardiovascular disease. In this study, we reviewed the relationship between the intestinal flora and its metabolites in glycolipid metabolic disorders and the effect of TCM in treating glycolipid metabolic disorders through the intestinal flora and its metabolites. This review provides new perspectives and strategies for future glycolipid disorders research and treatment. China Experts on Type 2 Diabetes with Dyslipidemia, published in 2017, reported that 42% T2DM patients have dyslipidemia, and the overall compliance rate is only 12% among patients treated with drugs [Metabolic syndrome (MS) comprises a cluster of metabolic disorders such as protein disorder, glucose disorder, lipid disorder, and carbohydrate disorder. Glycolipid metabolic disorders are the main type of MS and are characterized by abdominal obesity and abnormal metabolic disorders of lipids and carbohydrates in blood, including T2DM, obesity, hyperlipidemia, and insulin resistance. Glycolipid metabolic disorders are more complicated, because of multifactorial interaction, than single factor metabolic abnormalities and are the primary risk factors for cardiovascular and cerebrovascular diseases . TherefoThe intestinal flora consists of approximately 1014 bacteria that exist primarily in the large intestine. Intestinal flora has an important role in a host's physiology such as modulation of immunity development, inflammation, and energy metabolism. Intestinal flora's imbalance can contribute to diseases development, including obesity, hyperlipemia, T2DM, cardiovascular disease, irritable bowel syndrome, liver diseases, and skin diseases . The res16S ribosomal RNA (16S rRNA) gene sequencing and metagenomic sequencing methods have been employed in quantitative analysis of intestinal flora since the 1990s. The methods provide an effective approach to study intestinal flora's variation and function. 16S rRNA uses probes or primers designed to detect intestinal flora to specify which phylum, group, genus, or species it belonging to. Metagenomic sequencing uses taxonomically informative gene tags to target and amplify genomes to study intestinal flora's composite and function . MetabolTraditional Chinese medicine (TCM) is an effective method for treating MS. Many basic and clinical studies have confirmed that Chinese decoctions, Chinese medicine monomers, or compounds can reduce lipid and carbohydrate in blood and decrease the incidence of cardiovascular disease. For people with abnormal glycolipid metabolic disorders, TCM has the clinical efficacy advantage of \u201cmultitarget treatment.\u201d Recent studies have demonstrated that TCM regulated lipid and carbohydrate by adjusting structure of disordered intestinal flora. For example, GeGenQilian decoction, Jiangtangtiaozhi formula, and other designed herbal formulas lowered carbohydrate level and regulated intestinal flora , 14. How Enterobacter cloacae B29 strain, which was isolated from the stool of severe obese patients, into sterile mice can cause severe obesity and insulin resistance [The intestinal flora has an important role in the pathophysiology of glycolipid metabolic diseases such as obesity and T2DM \u201320. Patisistance . Comparesistance , 23. An sistance . To dateFatty acids associated with energy metabolism, lipid metabolism, and cell membrane's constituents also act as signal molecules. Abnormal fatty acids metabolism leads to metabolic diseases such as T2DM, nonalcoholic hepatic steatosis, hyperlipemia, and obesity.\u03b2-hydroxybutyrate or acetoacetate [SCFAs absorbed in the colon are major metabolites produced by anaerobic gut microbiota through the fermentation of indigestible carbohydrates such as polysaccharides, oligosaccharides, and fiber . The SCFoacetate .SCFAs, which primarily consist of acetate, propionate, and butyrate (in a ratio of approximately 60:20:20 in the colon) , are tho Firmicutes, Bacteroidetes, and Actinobacteria are the primary phyla and Butyricicoccus, Blautia, and Phascolarctobacterium are the primary genera in the gut microbiota that have an important role in SCFAs metabolism [ Bacteroides, Bifidobacterium, Propionibacterium, Eubacterium, Lactobacillus, Clostridium, Roseburia, Lachnospira, and Prevotella [ Prevotella, Alistipes, and Barnesiella and negatively associated with Bacteroides and Enterococcus. Prevotellaceae bacteria are enriched in obesity [ Lachnospira, as SCFA producer, has a negative correlation with body weight [ Enterobacter hormaechei, Haemophilus parainfluenzae, Streptococcus, and SMB53. Lower fecal SCFAs showed higher abundance of some beneficial microbes. Christensenellaceae, Methanobrevibacter, and Oscillospira had relationship with lower BMI, weight. Alistipes and Bacteroides associated with decreased obesity [SCFAs regulate glycolipid metabolism and are substrates that bind to G protein-coupled receptors (GPRs), including GPR41 , GPR43 , and GPR109A , which are associated with inflammation, immunity, and cancer. Gut microbiota promotes adiposity and body weight via GPR41. However, SCFAs may prevent obesity by activating GPR43 . GPR43 itabolism , 36. In evotella , 38. SCF obesity . Lachnosy weight . Fecal S obesity . Bacteroidetes phylum bacteria, and butyrate is primarily produced by the Firmicutes phylum bacteria [ Firmicutes, Bacteroidetes, and Actinobacteria phyla bacteria were not associated with energy harvest and that the fecal SCFAs levels and fecal energy content in high-fat diet- (HFD-) fed mice were also not associated [ Firmicutes phylum, Bacteroides , Proteobacteria , Bifidobacterium, and Clostridia [ Bifidobacterium-induced improvement in the intestinal barrier against bacterial endotoxin [ Tenericutes and the families Christensenellaceae, unclassified Clostridiales, Peptococcaceae, and Clostridiaceae. And, it is negatively associated with the genera Blautia Oscillospira [ Clostridiales, Defluviitaleaceae, and Porphyromonadaceae in HFD-induced obesity [Acetate and propionate are primarily produced by thebacteria . Howeversociated . Acetateostridia . Acetatendotoxin . Acetatendotoxin . Acetatellospira , unclass obesity . Lachnospiraceae, Ruminococcaceae, and Negativicutes  and the phyla Verrucomicrobia and Bacteroidetes [ Bacteroidetes is positively associated with propionate and butyrate. Butyrate provides energy for colonic epithelial cells and suppresses inflammation, which is primarily caused by lipopolysaccharides [Propionate and butyrate lower than acetate inhibit food intake . Propionroidetes . The abucharides . 50% procharides . Propioncharides . Propioncharides . Clostridium clusters IV and XIVa species of the genera Eubacterium and Butyrivibrio in the phylum Firmicutes [\u03b2-oxidation to acetyl-CoA, which participates in the tricarboxylic acid (TCA) cycle. The level of butyrate decreased in HFD-induced rats [ Faecalibacterium prausnitzii, Roseburia faecis, and other Clostridiales, known as butyrate-producers, as well as Enterobacter hormaechei, Haemophilus parainfluenzae, and Streptococcus, winch were unknown for fermentation capacity in obesity and hypertension of 441 community-dwelling adults. Almost microbiota significantly associated with butyrate excretion was also connected with acetate or propionate excretion [Butyrate produced by gut microbiota primarily provides energy for colonic cells  and is prmicutes . Butyratced rats . Propionced rats . PYY proced rats . GPR41 pced rats . Increasxcretion .In addition, SCFAs stimulate GLP-2 in the ileum, which decreases gut barrier permeability and lipopolysaccharide level. Propionate is primarily delivered and used by the liver, which has an important role in gluconeogenesis. Butyrate, as substrate, binds to GPR109a and is associated with the gut microbiota. Gpr109a is not expressed in the colons of germ-free and antibiotic-treated mice. The drug tributyrin, which can be metabolized into butyrate, induces GPR109a expression in antibiotic-treated animals . Akkermansia is negatively associated with FFAs, and an alteration in FFAs levels is associated with imbalanced levels of Akkermansia and Lactobacillus [Unsaturated fatty acids can inhibit lipotoxicity caused by palmitic acid (16:0) . Saturatbacillus . Patientbacillus , 61. Blautia and Dorea bacteria, and decreased levels of Coprococcus and Peptococcaceae bacteria [Gut microbiota lowers fatty acids oxidation by inhibiting the production of adenosine monophosphate kinase, which has a vital role in energy metabolism. Increased fatty acids oxidation enhances the cellular energy status, and increased insulin sensitivity decreases the glycogen level. Germ-free mice have increased adenosine monophosphate kinase levels in the liver and skeletal tissues, and enhanced fatty acids oxidation . Monounsbacteria , 61.\u03b1,12\u03b1-dihydroxy-5\u03b2-cholan-24-oic acid) and lithocholic acid . These acids enhance toxicity and are more easily absorbed by the intestine and gut microbiota, especially the Firmicutes phyla, with bacterial enzymes in the large intestine [Primary BAs are the main ingredient of bile and are synthesized from cholesterol in the liver through two major bile acid synthetic pathways: the classic pathway and the alternative pathway . These antestine , 64.The BAs, as signaling molecules, regulate BAs metabolism, lipid utilization, glucose utilization, energy, drug metabolism, inflammation, detoxification, and immunity by activating nuclear receptors. These nuclear receptors include the Farnesoid X receptor (FXR), cell surface GPRs, constitutive androstane receptor, vitamin D receptor, and pregnane X receptor. Cell surface GPRs also include the G protein-coupled bile acids receptors  \u201365. FXR, Clostridium, Bacteroides, Lactobacillus, Bifidobacterium, and Enterococcus, which secrete bacterial bile salt hydrolase enzyme that deconjugates primary BAs in the small intestine [ Bacteroides, Bifidobacterium, Clostridium, Lactobacillus, and Listeria are involved in deconjugation. Bacteroides, Clostridium, Escherichia, Eggerthella, Eubacterium, Peptostreptococcus, and Ruminococcus are involved in oxidation and epimerization. Clostridium, and Eubacterium are involved in 7-dehydroxylation. Bacteroides, Eubacterium, and Lactobacillus are involved in esterification. And Clostridium, Fusobacterium, Peptococcus, and Pseudomonas are involved in desulfation [ Lactobacillus can produce bile salt hydroxylase [ Clostridium cluster XVIa bacteria [Gut microbiota regulate the biotransformation of BAs by deconjugation, dehydroxylation, and reconjugation, which change BAs composition and modulate FXR and TGR5 signaling. There are four gut microbiota phyla in the small intestine, includingntestine . Some guulfation . Lactobaroxylase . Fecal sbacteria . Firmicutes and Lactobacillus bacteria, and synthesized more BAs that regulated the FXR [\u03b1-hydroxylated BAs and their conjugates increased and were correlated with insulin resistance in diabetic patients [\u03b1, 7\u03b1, 12\u03b1-trihydroxy-5\u03b2-cholan-24-oic acid) and chenodeoxycholic acid  are primary BAs and synthesized in the liver. They conjugate with glycine or taurine and convert the molecules into conjugated BAs or bile salts. The levels of deoxycholic acid and taurodeoxycholic acid were significantly increased in plasma and liver tissues, and deoxycholic acid also raised in intestinal tissues and feces in obesity rat, which were connection with enhancement of genera Blautia, Coprococcus, Intestinimonas, Lactococcus, Roseburia, and Ruminococcus [Gut microbiota play a role in transforming primary BAs, which is involved in lipid and glucose metabolism . Mice tr the FXR . Rats inpatients . Cholic nococcus , 76.Choline is a water-soluble nutrient that is essential for human life . It is aFirmicutes, Proteobacteria phyla bacteria and other anaerobic gut microbiota produce enzymes that convert dietary choline into trimethylamine (TMA), which cannot be synthesized by humans. Trimethylamine is an intermediate in the conversion of choline to betaine, methylamine, dimethylamine (DMA), and trimethylamine N-oxide (TMAO), the formation of which is associated with intestinal bacteria action [ Firmicutes and Proteobacteria) and six genera showed significant choline consumption and TMA accumulation: Anaerococcus hydrogenalis, Clostridium asparagiforme, Clostridium hathewayi, Clostridium sporogenes, Escherichia fergusonii, Proteus penneri, Providencia rettgeri, and Edwardsiella tarda [ Bacteroides and negatively with Prevotella and Clostridium, the secondary BAs deoxycholic acid connected with Bacteroides, Erysipelotrichaceae incertae sedis, and Enterococcus, but negatively with Prevotella, Barnesiella, and Alistipes in mice. Fecal SCFAs connected with Prevotella, Barnesiella, and Alistipes and negatively with Bacteroides, Erysipelotrichaceae incertae sedis and Enterococcus in mice [a action , 80. Flaa action . The folla tarda . Fecal c in mice . N-oxide is negatively associated with Peptococcaceae, Prevotella, and Faecalibacterium prausnitzii and is significantly and positively associated with Allobaculum, Candidatus Arthromitus, or Lachnospiraceae [ Faecalibacterium prausnitzii have been associated with obesity, diabetes, and several immune-related diseases [ Clostridiales, Ruminococcus, and Lachnospiraceae bacteria in female mice [The leave of trimethylaminepiraceae . Reduceddiseases . Plasma ale mice .Gut bacteria can change bioavailability of amino acids via utilizing certain amino acids originating from alimentary proteins and endogenous proteins and can supply amino acids for a host. Amino acids support growth and survival of gut bacteria and regulate energy and protein homeostasis. Elevated level of amino acids, particularly branched-chain and aromatic amino acids , promotes the development of insulin resistance and T2DM. Clostridium, Bacillus, Lactobacillus, Streptococcus, and Proteobacteria in the small intestine and Clostridia, Peptostreptococcus in large intestine can ferment amino acids. This process is associated with protein digestion and subsequently with amino acid absorption. Colonic bacteria primarily use certain amino acids as substrates such as the branched-chain amino acids (BCAAs), lysine, arginine, and glycine. They produce metabolic end-products such as SCFAs and branched-chain fatty acids such as valerate, isobutyrate, and isovalerate. These bacterial metabolites can affect signaling pathways in epithelial cells and in the mucosal immune system, and thereby influence epithelial physiology. The BCAAs, aromatic amino acids , and other amino acids  are positively associated with Prevotella, Alistipes, and Barnesiella, but are negatively associated with Bacteroides and Enterococcus. In addition, Prevotellaceae is significantly enriched in obesity [Certain amino acids, as precursors for the synthesis of SCFAs, are liberated by gut microbiota and are involved in the development of obesity. obesity . Christensenellaceae and are positively associated with Blautia [BCAAs include leucine, isoleucine, and valine. BCAAs are involved in the synthesis of protein, alanine, glutamine, and glucose metabolism and oxidation . Plasma  Blautia . l-lysine, l-threonine, betaine, isovaleraldehyde, 2-ketobutyric acid, 2-pyrroloylglycine, and abnormal glutamine, glycine, serine, and threonine [Prediabetic patients reduced levels of amino acids such ashreonine . The levhreonine . Individ Photobacterium genus was negatively associated with alanine, glycine, taurine, whereas Coprococcus 3 and Vibrio genera were positively associated with citrulline [ Bifidobacterium and Bacteroides fragilis [ Bacteroides thetaiotaomicron reduced the plasma glutamate level and improves diet-induced body weight gain and adiposity in mice. This finding suggests that glutamate is negatively associated with B. thetaiotaomicron [The fasting and 2-hour plasma glucose levels and the homeostasis model assessment of insulin resistance are positively associated with valine, glutamate, and tyrosine levels, but negatively associated with citrulline, glutamine, and glycine levels . The Photrulline . Tryptopfragilis . Bacteroaomicron .Some metabolites are also altered in MS. Hippurate, 4-hydroxylphenylacetic acid, and phenylacetylglycine levels are increased and acetate, lactate levels are decreased in urine. These metabolites are associated with obesity and an alteration in gut microbiota . Niacin  Coriobacteriaceae and Blautia. Rats with HFD-induced hyperlipidemia increased levels of pyruvate and decreased levels of citrate, succinate, and cis-aconitate and caused dysfunction in glucose metabolism, insulin utilization, and energy metabolism. Increased fatty acid oxidation occurred in rats with hyperlipidemia, which might generate SCFAs or medium-chain fatty acids, and thereby reduced glucose metabolism, and changed energy consumption to lipid oxidation [ Firmicutes and Bacteroidetes bacteria [The intermediates of TCA cycle include citrate, butanedioic acid, citrate, succinate, pyruvate, and cis-aconitate. These intermediates have a vital role in energy metabolism . Pyruvatxidation . Decreasxidation . Increasbacteria . The relExperiments have shown that diet control, TCM treatment, and other methods can regulate the intestinal flora structure and its metabolites, reduce inflammatory factors, and relieve insulin resistance, obesity, metabolic disorders \u2013100. Adlercreutzia, Alloprevotella, and Barnesiella in T2DM [ Bifidobacterium and Anaerostipes in NAFLD rats [ Carthamus tinctorius L., increased SCFAs-producing bacteria, including genera Butyricimonas and Alloprevotella in obesity mice [ Parabacteroides, Blautia, and Akkermansia in T2DM rats [ Akkermansia spp., a bacteria producing SCFAs, and reduced Desulfovibrio in T2DM [ Lachnospiraceae and Clostridium in ob/ob mice with hepatic steatosis. Lachnospiraceae and Clostridium can produce butyrate [ Faecalibacterium and Roseburia, which contained butyrate-producing bacteria. It also enriched SCFA-producing bacteria, including Gemmiger, and Coprococcus in T2DM [ Blautia and Allobaculum in insulin-resistant rats [ Allobaculum, Blautia, Bacteroides, Butyricicoccus, and Phascolarctobacterium in rats with HFD-induced obesity [The abundance of SCFAs-producing bacteria in the intestines of patients with glycolipid disorders is decreased. Many Chinese medicines regulate glycolipid metabolism by enriching bacteria producing SCFAs. For example, Rhizoma Coptidis alkaloids regulated the structure of gut microbiota to alleviate hyperglycemia, which might help alleviate inflammation by increasing the level of intestinal SCFAs . Xiexin  in T2DM . ShenlinFLD rats . Oral hyity mice . Huang-L2DM rats . JinQi J in T2DM . A waterbutyrate . A speci in T2DM . Berberiant rats . And Ber obesity . Lactobacillus and Bifidobacterium and increased the activity of intestinal bile acid hydrolase to promote the catabolism of BAs in the intestine, which promoted the efflux of fecal BAs. The synthesis of BAs in the liver was ultimately promoted [ Gynostemma have the pharmacological effects of regulating lipid metabolism. Gynostemma can regulate BAs metabolic pathways and bile acid layer, and its target may be the nuclear receptor FXR [ Clostridiales, families Streptococcaceae, Clostridiaceae, and Prevotellaceae, and genera Streptococcus and Prevotella in HFD-fed mice with insulin resistance [ Akkermansia muciniphila in diet-increased obesity [TCM ingredients can affect genes expression, and consequently regulate FXR, or structure of intestinal flora to regulate the conversion of BAs in the liver and intestine. Resveratrol significantly increased the abundance ofpromoted . Total sptor FXR . Pepper ptor FXR . Berberisistance . Epigall obesity .The compound of vinegar and olive oil  can effectively increase SCFAs levels and block TMAO production in mice . Resvera Firmicutes to Bacteroidetes, and reduced indole-3-acetic acid level in ApoE-/- mice fed on a high-fat diet [Many TCM ingredients act on amino acid metabolism and TCA, and participate in energy metabolism. Turmeric regulated fat production and decomposition pathways to lower blood lipids. Curcumin-treated mice had increased levels of acetate, leucine, isoleucine, valine, alanine, and TCA cycle intermediates . Berberine is involved in glycolysis and the TCA cycle, amino acid metabolism, vitamin B6 metabolism, and secondary bile acid biosynthesis . Gardenifat diet . The effAs the number of obese people increases, glycolipid disorders become more common in the future. Glycolipid disorders have a significant impact on the quality of life and the financial resources of the public healthcare system. To date, treatment for T2DM with hyperlipidemia primarily relies on the use of hypoglycemic and lipid-lowering drugs. However, patients are increasingly concerned about potential toxicity and side effects and sometimes the clinical efficacy is unsatisfactory. Intensive studies on complementary and alternative medical therapies have increased the utility of these therapies for treating glycolipid metabolic diseases. Natural medicine, especially Chinese herbal medicine, constitutes a special medical system that is guided by TCM theory and provides effective treatment for glycolipid disorders.Traditional Chinese herbal medicines are generally administered orally, and their digestion and absorption are inseparable from the intestinal flora. An increasing number of Chinese herbal ingredients have been proven to adjust an individual's intestinal flora, and thereby allow the flora to approximate that of a normal person. This trend is significantly associated with recovery from the diseases. Regulating the intestinal flora is an important way for Chinese medicines to take effect.Among several metabolites, the SCFAs are most affected by Chinese medicine constituents such as berberine, Ganoderma lucidum, and resveratrol, which enrich SCFAs-producing bacteria, and increase intestinal SCFAs. The production of SCFAs can relieve insulin resistance and alleviate disorders of glycolipid metabolism. In addition, several traditional Chinese medicines can regulate BAs metabolism, upregulate FXR levels, increase insulin sensitivity, inhibit fat synthesis, and reduce serum triglyceride and cholesterol levels. These actions are closely associated with the regulation of the related gut microbiota. The level of TMA/TMAO is correlated with glycolipid metabolism and is an important marker and potential therapeutic target for cardiovascular disease. By intervening intestinal flora and its metabolites, TCM can achieve hypoglycemic and lipid-lowering effects and effectively reduce the incidence of cardiovascular events. In addition, TCM monomers are also widely involved in intestinal amino acid metabolism and in the TCA cycle.In summary, TCM can regulate the body's glycolipid metabolism through the intestinal flora and its metabolites, and can achieve a therapeutic effect in people with glycolipid metabolic disorders. A Chinese medicine practitioner prescribes medicine, based on a patient's symptoms such as abdominal feeling, body shape, and stool shape. For patients with polydipsia, obesity, diabetes, and hyperlipidemia, TCM often eliminates digestion and promotes gastrointestinal motility, while relieving symptoms. TCM has a vital role in reducing sugar and fat levels. It can regulate glycolipid metabolism by altering the intestinal flora and its metabolites.This review still has some limitations. Some conclusions are based on clinical trials with low levels of evidence, which causes biases. In addition, many studies lack evidence on the intestinal flora and its metabolites. The mechanism of TCM in treating glycolipid metabolic disorders needs further research. In the future, carefully designed, large-scale, high-quality randomized controlled trials are needed to evaluate the effects of TCM on glycolipid metabolism. In addition, in-depth studies need to be conducted from the perspective of the flora to detect relevant targets in metabolic pathway and to clarify the biological mechanisms of Chinese medicine. Ideas need to be provided for preventing and treating glycolipid metabolism diseases."}
+{"text": "Tis includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript."}
+{"text": "Dear Editor,A 34-year-old previously healthy man presented with a 12-month history of progressivepolyarthralgia and edema of the hips, right ankle, and intercostal spaces. He reportedno history of trauma. Conventional radiography revealed several mixed lesions(predominantly osteolytic lesions) in the pelvic ring, proximal femur, distal femur,distal tibia, both tali, and lumbar vertebral bodies, as well as unconsolidatedfractures of the costal arches, with no periosteal reaction or associated soft tissuechanges . The ini, the monocentric form of osteolysis of a bone orcontiguous area of bone, with a predilection for the axial skeleton, was subsequentlydubbed Gorham-Stout syndrome. The process is usually monostotic, although there havebeen a few reports of cases in which it was polyostotic(3). In decreasing order offrequency, it affects the scapula, proximal end of the humerus, femur, rib, iliac bone,ischium, and sacrum(3). It is currently known by a variety of names, includingmassive osteolysis, idiopathic osteolysis, vanishing bone disease, disappearing bonedisease, phantom bone disease, spontaneous bone absorption, progressive bone atrophy,bone hemangiomatosis, and lymphangiomatosis of bone.Initially described as \"missing bone disease with intraosseous vascularalterations\"(3-7), a process that can culminate in the replacement of theentire bone by fibrous tissue(7). Histopathologically and radiologically, the syndromeinitially presents as foci of rarefaction in the bone marrow and subcortical bone, withslow, irregular progression that can result in effacement of the diaphysis of the bones,narrowing of the involved ends, and, in some cases, the complete disappearance of thebone. Pathological fractures that do not consolidate are common and are characteristicof the syndrome. The pathological-radiological diagnosis proposed byHeffez et al.(6)is based on specific criteria, including positive biopsy findings for angiomatous tissueand an osteolytic pattern on X-rays, as well as negativity for hereditary, metabolic,neoplastic, immunologic and infectious etiologies.Gorham-Stout syndrome primarily affects children and young adults, the affectedindividuals presenting nonspecific complaints such as pain and joint edema. Thepathological mechanisms proposed to date are multifactorial, with no known triggeringfactor. The histopathological hallmark is the replacement of normal bone by fibroustissue with aggressive, expansile, non-neoplastic proliferation of capillary orcavernous blood vesselsIn summary, although rare, the diagnosis of Gorham-Stout syndrome should be considered incases of focal or multifocal osteolysis in previously healthy young individuals who testnegative for inflammatory, infectious, metabolic, and neoplastic conditions."}
+{"text": "N = 3,299, egg consumers; N = 17,030, egg non-consumers). Daily energy and nutrient intakes were adjusted for the complex sample design of NHANES using appropriate weights. Consuming eggs was associated with increased daily energy intake relative to non-egg consumption. Children and adolescents consuming eggs had elevated daily intake of protein, polyunsaturated, monounsaturated and total fat, \u03b1-linolenic acid, docosahexaenoic acid (DHA), choline, lutein + zeaxanthin, vitamin D, potassium, phosphorus, and selenium. Egg consumers had greater consumption, sodium, saturated fat, with reduced total and added sugar versus egg non-consumers. The analysis also showed that egg consumption was linked with lower intake of dietary folate, iron, and niacin. No associations were determined when examining diet quality and growth-related measures. A sub-analysis considering socioeconomic status showed that egg consumption was positively related with daily lutein + zeaxanthin and DHA intake. The current analysis demonstrated several nutrient-related benefits to support the continued inclusion of eggs in the dietary patterns of children and adolescents.Dietary pattern recommendations include consuming a variety of nutrient-dense foods in children and adolescents to promote optimal growth and development. The current study investigated associations with egg consumption and nutrient intakes, diet quality, and growth outcomes relative to non-egg consumers. The analysis used data from the U.S. National Health and Nutrition Examination Survey (NHANES) 2001-2012 in children and adolescents aged 2\u201318 years ( Since the late 1960s, authoritative bodies have not recommended eggs as part of the diet, largely due to misperceptions resulting from insufficient data that egg consumption contributed to higher cholesterol levels and elevated risk of cardiovascular disease (CVD). In fact, in 1968, the American Heart Association published dietary recommendations to limit consumption of egg yolks to less than three/week . With seThe 2015\u20132020 DGA policy report  emphasizPreviously published data in infants demonstrates several beneficial associations with egg consumption, of which included higher recumbent length compared to infants not consuming eggs. Furthermore, introducing eggs during infancy was linked to improved nutrient profiles, including higher daily intakes of protein, DHA, \u03b1-linolenic acid, phosphorus, choline, vitamin B12, and lutein + zeaxanthin . At presThe present investigation used data from the US National Health and Nutrition Examination Survey (NHANES), which is a cross-sectional, nationally-representative, sample of U.S. free-living individuals. The data are compiled by the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia. Written informed consent and all ethical considerations have been previously approved by the appropriate ethics board at the CDC. For the current analysis, the methodology combined 6 datasets for individuals 2\u201318 years of age, beginning in 2001 and ending in 2012, to provide twelve years of data collection . Data foN = 3,299) or egg non-consumers . Only data that was determined to be reliable and included completed 24 hour recalled dietary data was included in the analysis. Egg consumption was defined strictly as participants that consumed only eggs, poached eggs, scrambled eggs, and omelets while excluding egg-containing mixed dishes .Male and female data on children and adolescents were combined for the present analysis and differentiated as consumers of eggs  and SUDAAN 11.0. The investigation used survey weights to develop nationally representative estimates for children and adolescents, followed by adjustment to consider the complex sample design of the database. Adjusted means (\u00b1 standard errors) for daily intake of energy , nutrients, and diet quality were determined. Energy, nutrient and diet quality included adjustment for several variables, including age, ethnicity, gender, kilocalories , socioeconomic status  and participation in the Special Supplemental Nutrition Program of Women, Infants and Children (WIC)) . SimilarStudy population demographics can be viewed in Daily nutrient and energy intake comparisons for egg consumers and non-egg consumers can be seen in The scores for total and sub-categories of Healthy Eating Index-2010 are presented in In general, consumption of eggs in children and adolescents was linked to reduced daily intake for added sugar, but increased daily intake of lutein + zeaxanthin when compared to non-consumption of eggs in the defined age group. No differences were observed between daily intake of added sugar when subjects were classified as WIC participants. All egg consumers, regardless of their socioeconomic classification, had greater intake of docosahexaenoic acid relative to egg non-consumers. In all cases, except when children were classified as WIC participants, egg consumption was linked to higher \u03b1-linolenic acid daily intake when compared to non-egg consumption. In certain socioeconomic groups, but not all, egg consumers exhibited higher eicosapentaenoic acid intake compared to non-egg consumption. All results for added sugar, carotenoid and omega-3 fatty acid intake by socioeconomic status can be seen in The current NHANES analysis revealed significant associations with egg consumption in children and adolescents. A dietary pattern that includes eggs was linked with higher amounts of several nutrients, including protein, polyunsaturated and monounsaturated fat, \u03b1-linolenic acid, DHA, lutein + zeaxanthin, potassium, phosphorus, choline, riboflavin, selenium, choline, vitamins D, E, and vitamin A. Likewise, egg consumers had lower daily sugar intake  when compared to children and adolescents not consuming eggs. Egg consumption was further associated with significantly lower daily intakes of dietary fiber, iron, and folate. The current study also showed that egg consumption was positively related with sodium intake, as well as saturated and total fat intake; thus, preparation of eggs, or foods that accompany eggs may require further investigation. In additional analyses considering socioeconomic status, the current data show benefits linked with egg consumption in this population. In general, egg consumption in children and adolescents, irrespective of food security, poverty and/or WIC status, was related with higher daily intake of lutein + zeaxanthin and DHA, and in most cases, reduced daily intake of added sugar versus the avoidance of eggs in the diet.The present study further illustrates that choline intake is elevated in children and adolescents consuming eggs. Previous literature has documented the dietary importance of choline, largely due to choline\u2019s relevance in physiology and metabolic activity ,10,11,12Our previously published data also verified that consumption of eggs in infants and toddlers was related with increased daily nutrient intake relative to infants consuming no eggs in their dietary pattern . Indeed,Also aligned to the infant and toddler data, the current analysis in children and adolescents showed that eggs, as part of a dietary pattern, was not related with HEI, a measure of diet quality. Nevertheless, consumption of eggs in children and adolescents was associated with several HEI sub-categories, of which included, higher values for total fruits and vegetables, beans, and protein foods, but reduced scores for whole grains and total dairy consumption. Sodium scores were reflective of greater sodium intake in children and adolescents consuming eggs, suggesting that preparation of eggs and/or the types of foods that accompany egg meals  may need further investigation.Further, in our current analysis, we did not observe associations with egg or non-egg consumption in several growth outcomes, including overweight, obesity, body weight, standing height or recumbent length. As previously discussed, while protein intake was elevated in children and adolescents consuming eggs, growth and development are multifactorial, thus numerous variables within a dietary pattern can impact such health outcomes .Our analysis involving socioeconomic status revealed associations, such that greater daily lutein + zeaxanthin intake was linked to egg consumption, thus emphasizing the critical dietary role eggs can play with eye health in this population. In most cases, egg consumption was associated with reduced daily intake of added sugar relative to non-egg consumers, suggesting that increased egg consumption in children and adolescents may serve to help this population reduce added sugars in the diet through food selection, thus aligning with DGA recommendations. All egg consumers, regardless of their socioeconomic classification, had greater intake of docosahexaenoic acid relative to egg non-consumers. Additionally, except when children were classified as WIC participants, egg consumption was associated with higher intake of \u03b1-linolenic acid. Previous work has discussed how diet quality disproportions may potentially be linked to the higher costs of healthier dietary patterns , thus, fAs has been documented previously in similar research methods , the curThis data represents the first study in US children and adolescents to demonstrate nutrient intake associations when comparing egg consumption to non-consumption within a dietary pattern. Egg intake in this population was associated with increased daily intake of protein, polyunsaturated and monounsaturated fat, \u03b1-linolenic acid, DHA, lutein + zeaxanthin, choline, potassium, phosphorus, selenium, riboflavin, vitamins D, A, and E. Likewise, egg consumers had lower daily sugar intake  when compared to children and adolescents not consuming eggs. Several shortfall nutrients were associated with egg consumption, including reduced daily intakes of dietary fiber, iron, and folate, concurrently with greater daily intake of sodium, total and saturated fat, suggesting that future research may need to evaluate the contribution of mixed egg meals and the type of foods accompanying eggs in the diet. In additional analyses considering socioeconomic status, the current data show benefits linked with egg consumption in this population. In general, egg consumption in children and adolescents, irrespective of food security, poverty income ratio and/or WIC status, was linked with elevated daily lutein + zeaxanthin and DHA intake, and in most cases, reduced added sugar intake. The present study further illustrates an opportunity to communicate the benefits linked with egg consumption to individuals that influence children and adolescents, including parents, school nutrition organizations, educators, and dietary guideline advisory committees globally."}
+{"text": "Aging and obesity increase multimorbidity and disability risk, and determining interventions for reversing healthspan decline is a critical public health priority. Exercise and time restricted feeding (TRF) benefit multiple health parameters when initiated in early-life, but their efficacy and safety when initiated at older ages are uncertain. Here, we tested the effects of exercise versus TRF in diet-induced obese, aged mice from 20 to 24 months of age. We characterized healthspan across key domains: body composition, physical, metabolic, and cardiovascular function, activity of daily living (ADL) behavior, and pathology. We demonstrate that both exercise and TRF improved aspects of body composition. Exercise uniquely benefited physical function, and TRF uniquely benefited metabolism, ADL behavior, and circulating indicators of liver pathology. No adverse outcomes were observed in exercised mice, but in contrast, lean mass and cardiovascular maladaptations were observed following TRF. Through a composite index of benefits and risks, we conclude the net healthspan benefits afforded by exercise are more favorable than those of TRF. Extrapolating to obese older adults, exercise is a safe and effective option for healthspan improvement, but additional comprehensive studies are warranted before recommending TRF."}
+{"text": "In this quiz-based presentation we aimed to give an overview of basic cardioradiological anatomy, anatomical variations and pathologies. Featured topics include the normal anatomy of the aortic valve and its variations, some normal structures and their pitfalls, anomalies in the coronary arteries, and finally, selected congenital  and acquired  cardiac pathologies. Imaging modalities include conventional radiography, computed tomography, and magnetic resonance imaging. Teaching points were provided.The authors declare that they have no competing interests."}
+{"text": "Approximately 40% of lung cancer patients will develop central nervous system (CNS) metastases during the course of their disease . Most ofContributors in this Research Topic of Frontiers in Oncology, section Thoracic Oncology describe the advances in CNS metastases management in lung cancer patients, from prediction and prevention, to diagnosis and treatment.Pedrosa et al.). However, these factors alone cannot predict accurately enough which patients will develop CNS metastases and better prediction models are needed. In the review of Pedrosa et al. the process of BM development and the evidence for the clinical and molecular factors associated with increased risk of BM diagnosis in lung cancer is summarized. In addition, they provide an excellent overview of new promising strategies to identify patients at high risk for BM development, including signatures derived from circulating tumor DNA measurements, single-nucleotide polymorphisms, copy number alterations, microRNAs and long non-coding RNAs . As it is known that among the non-small cell lung cancer (NSCLC) patients treated with curative intent, stage III patients have the highest risk of brain metastases development , 16PedroVanfleteren et al. It is stressed that even in an immunocompetent patient, a diagnosis of cerebral aspergillosis cannot be excluded. A short review of existing literature on this topic is also provided.Although brain imaging techniques have improved over the years facilitating the diagnosis of BM, differential diagnosis can be challenging, especially in a patient with a medical history of cancer, as is discussed in the case report by Hartgerink et al. discuss the current evidence of SRS for NSCLC BM, and the incorporation of decision aid tools in the future directions for NSCLC BM treatment. Furthermore, local treatment can be complicated by symptomatic radiation necrosis for which no high-level evidence-based treatment exists, although bevacizumab is a promising treatment option  or whole brain radiotherapy (WBRT)] and surgery , 18. SRSt option \u201323. Difft option , 22. LogKelly et al. the management of CNS metastases in EGFR mutated NSCLC patients is discussed, including the role of newer generation EGFR-TKIs, immunotherapy, and EGFR-TKIs combined with cranial irradiation or angiogenesis inhibition. Remon and Besse provide a broader overview of incidence and treatment of BM in oncogene addicted NSCLC patients, including rare driver mutations such as ALK, ROS1, RET, BRAF, and NTRK. Relevant research questions such as optimal sequence of treatment  are also discussed. In the case report of Meedendorp et al. treatment of a BM patient with acquired resistance to EGFR-TKI is discussed, stressing the importance of a molecular tumor board for decision making. Last, leptomeningeal metastases remain challenging to treat, especially in non-oncogene addicted NSCLC patients. Turkaj et al. provide an up-to-date review of possible treatment options for these patients, including systemic as well as intrathecal chemotherapy as well as radiotherapy options.Systemic treatment options for BM have expanded over the last years , 25. UntWith the articles in this Research Topic, we hope to provide a review of present and future treatment options for lung cancer CNS metastases, including evidence for predictive markers, preventive treatments, and local as well as systemic treatment options for already diagnosed CNS metastases.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.LH: none related to current manuscript, outside of current manuscript: research funding Roche, Boehringer Ingelheim (both institution), advisory board: Boehringer, BMS, (both institution), travel reimbursement: Roche, BMS (self). DS: speaker's bureau Astra Zeneca, Takeda; advisory board Astra Zeneca, Takeda, BMS; institutional research funding as PI: BMS, Genentech, Incyte, Lilly Oncology, Astra Zeneca, Novocure. A-MD: none related to current manuscript, outside of current manuscript: advisory board BMS, MSD, Roche, Eli Lilly, Takeda, Pfizer, Boehringer Ingelheim ."}
+{"text": "Samples from all participants were tested using tissue-based indirect immunofluorescence assays and a subset were tested using four additional ELISA and cell-based assays. Antibodies to myelin oligodendrocyte glycoprotein (MOG) were also assayed. All aquaporin-4 antibody assays proved to be highly specific. Sensitivities ranged from 60 to 94%, with cell-based assays having the highest sensitivity. Antibodies to MOG were detected in 8/79 (10%) of the residual suspected cases of NMOSD. Under the 2015 IPND diagnostic criteria for NMOSD, cell-based assays for aquaporin-4 are sensitive and highly specific, performing better than tissue-based and ELISA assays. A fixed cell-based assay showed near-identical results to a live-cell based assay. Antibodies to MOG account for only a small number of suspected cases.We have compared five different assays for antibodies to aquaporin-4 in 181 cases of suspected Neuromyelitis optica spectrum disorders (NMOSD) and 253 controls to assess their relative utility. As part of a clinically-based survey of NMOSD in Australia and New Zealand, cases of suspected NMOSD were referred from 23 centers. Clinical details and magnetic imaging were reviewed and used to apply the 2015 IPND diagnostic criteria. In addition, 101 age- and sex-matched patients with multiple sclerosis were referred. Other inflammatory disease ( Neuromyelitis optica spectrum disorders (NMOSD)  encapsulMyelin oligodendrocyte glycoprotein (MOG) antibody-related demyelinating disease is emerging as another antibody mediated inflammatory disorder of the CNS which shares some overlapping features with NMOSD . In partWe recently performed a nationwide prevalence survey of NMOSD across Australia and New Zealand . We havePossible cases of NMOSD were identified through a network of 23 neurology clinics specializing in demyelinating diseases of the CNS (ICD-10 G35-G37) across Australia and New Zealand. These centers match the population distribution of both countries. Participating centers referred cases to the coordinating center in Queensland if they had features suggestive of NMOSD as previously described . Cases wReferring neurologists were also requested to recruit age- and sex-matched patients with multiple sclerosis, who did not have any of the features suggestive of NMOSD. Additional controls consisted of patients with other inflammatory diseases  and healthy blood donors. The other inflammatory diseases included infections , Sj\u00f6gren's syndrome and systemic lupus erythematosus. All participants gave written, informed consent to participation in this study and the study protocol was approved by the Human Research Ethics Committee at all participating sites.Demographic details (age and gender) together with clinical details sufficient to confirm a diagnosis of NMOSD or MS were collected, including relapse history and MR imaging as previously described . Cases wAny prior AQP4 antibody testing results were collected using a standard questionnaire in all cases. Serum samples were obtained and tested for AQP4 antibodies using indirect immunofluorescence staining techniques on mouse, rat, or monkey brain tissue and rat or mouse kidney sections at one of four testing sites see . The twoResults are presented as n/N (%) of positive or negative antibody assays in cases and controls. Non-parametric statistics were used to assess differences in the demographic distribution of cases and controls. The optimal cut-off for the ELISA antibody level was assessed using receiver operator characteristic (ROC) curve analysis. Sensitivity and specificity with 95% confidence intervals (CI) were used to assess utility of the assays. Degree of agreement between the assays was assessed using Cohen's kappa coefficient. All statistical analysis was performed using SPSS\u00ae v24 .X2 = 0.503, p = 0.478) or age distribution (Mann-Whitney U p = 0.145) between NMOSD cases and MS controls, indicating that our age- and sex-matching strategy had been effective. No data were available for the blood donor controls as these samples were provided anonymously as required by Australian Red Cross. The inflammatory disease controls were older, but when combined with the MS controls were not significantly different to NMOSD cases. The proportion of females in inflammatory disease controls (61%) compared with NMOSD cases (89%) was significantly lower . When MS and inflammatory disease controls were combined the proportion of females increased (77%), but remained significantly different .In total, 189 cases of suspected NMOSD were referred. Of these 8/189 (4%) were excluded due to lack of an available serum sample. Of 181 suspected NMOSD cases, 80 met the 2015 IPND diagnostic criteria for NMOSD. Of these, 73/80 (91%) were seropositive for AQP4 antibodies and 7/80 (9%) were seronegative, leaving 101 suspected NMOSD cases. Not all of the seronegative NMOSD cases were tested with all assays. There were 108 cases of MS referred of which 7/108 6%) had no serum available, leaving 101 included MS controls. Serum was available for 49 inflammatory disease and 103 blood donor controls. The inflammatory disease controls included the following: systemic lupus erythematosus  of cases and controls. A cell-based AQP4 assay was performed in 307/434 (71%) of cases and controls. The sensitivity for various assays in NMOSD and suspected NMOSD together with their specificity in the various control groups and overall controls is given in The degree of concordance between assays was generally high, and particularly so for the cell-based assays, as shown in Amongst suspected NMOSD cases, 8 were positive for MOG antibodies. One of these was also positive for both the AQP4 and MOG biochips on the same fixed cell-based assay. This case was negative for all other cell-based assays for AQP4 antibodies and was confirmed as positive for MOG antibodies by FACS assay and so was not considered to be a case of NMOSD, but rather as a case of MOG antibody-related demyelinating disease. Thus, we did not identify any AQP4 and MOG antibody double positive cases. One MOG antibody positive case met the clinical/MRI 2015 IPND criteria for a diagnosis of NMOSD, but was considered as a MOG antibody-related demyelinating disease case. When the sensitivity and specificity analysis was restricted to cases with testing available for all assays (AQP4 and MOG) results were not significantly different . We obseWe have conducted a rater-blinded comparison of 5 different assays for antibodies to AQP4 in a population of cases with suspected NMOSD and a variety of controls. Consistent with previous studies , 16, 17 The status of cases with positive results for one cell-based assay in the remaining suspected NMOSD cases remains uncertain. This may reflect greater sensitivity in \u201ctrue positives.\u201d However, they may also represent false positives. Currently, there is no means to determine the true status of these cases although repeat testing over time may prove useful. The fact that the number of positive tests correlates well with the ELISA antibody level suggests that false negative results may occur when antibody levels are low, reflecting a sensitivity issue. However, the possibility of this being due to lower specificity of these assays cannot be discounted.Amongst suspected NMOSD cases who were seronegative for AQP4 antibodies and did not meet the 2015 IPND diagnostic criteria for NMOSD 8/79 (10% 95% CI 5\u201319%]) were positive for MOG antibodies. This is again consistent with previous studies that have shown positivity rates for MOG antibodies in this population of 8\u201332% (%) were pOne advantage of the present study was that all cases were identified clinically by clinicians experienced in diagnosing inflammatory disease of the CNS and not based upon the results of laboratory testing, which introduces an inherent bias and the potential for low pre-test probability. The fact that not all cases were assessed using all assays is a weakness in this study, but when the analysis was restricted to only cases tested for all AQP4 antibody assays the results were not significantly different. The finding of identical results for the M1 and M23 AQP4 antibody assays is contrary to prior studies which have indicated a higher sensitivity for the M23 isoform . HoweverWe have confirmed the high sensitivity and specificity for a wide range of AQP4 antibody assays in identifying NMOSD. The high sensitivity is to be expected, because of the inclusion of positive AQP4 antibodies as a part of the diagnostic criteria in the presence of a single characteristic presentation . The higDe-identified, individual level data for cases where all assays were performed is provided as The studies involving human participants were reviewed and approved by Griffith University HREC. The patients/participants provided their written informed consent to participate in this study.DA, MHB, SBh, SBl, MB, KB, BB, SAB, WB, CB, HB, WC, CC, LC, AC, RD, CD, KD, DG, SHa, RH, AH, SHe, SHo, AGK, TK, JK, CK, CL, RM, MM, DM, PM, CO'G, JDEP, MP, JP, JDP, KP, SWR, SS, JL-S, CS, RS, MS, JSp, JSt, IS, BT, AV, SV, MWa, PW, EW, RJW, and RCW conceived and designed the study. DA, MHB, SBh, SBl, MB, KB, BB, FB, SAB, WJB, WB, CB, HB, WC, CC, LC, AC, RD, CD, DF, DG, SH, RH, AH, SHe, SHo, AK, TK, JK, CK, AJK, M-WL, CL, RM, MM, DM, PM, CO'G, JDEP, MF-P, MP, JP, JDP, KP, SR, SWR, SS, JL-S, CS, RS, MS, JSp, JSt, IS, BT, SV, MWa, PW, EW, RJW, RCW, MWo, and EY played a major role in collecting data. FB, SAB, WB, KD, KP, SR, JSt, and PW conducted the analyses. KP, WB, and SAB prepared the initial draft. MHB, BB, FB, SAB, CB, HB, WC, LC, RD, KD, DG, SHo, AGK, TK, JK, RM, MM, DFM, PM, CO'G, JDEP, MF-P, MP, JP, JDP, SR, SWR, JL-S, CS, RS, MS, JSp, JSt, IS, BT, AV, SV, PW, EW, and MWo contributed to revisions. All authors approved the final draft.MHB has received honoraria for participation in advisory boards and travel sponsorship from Novartis, BioCSL, Genzyme, and Biogen Idec. MB has received travel sponsorship and honoraria from Sanofi-Genzyme, Teva, Novartis, Biogen Idec, and Roche. BB has received honoraria as a board member for GlaxoSmithKline, Biogen Idec, ViiV Healthcare, and Merck Serono, has received speaker honoraria from ViiV Healthcare, Boehringer Ingelheim, Abbott, Abbvie, and Biogen Idec; has received travel sponsorship from Abbott and Viiv Healthcare, and has received research support funding from EI Lilly, GlaxoSmithKline, ViiV Healthcare and Merck Serono. SAB has received honoraria for attendance at advisory boards and travel sponsorship from Bayer-Scherring, Biogen-Idec, Merck-Serono, Novartis, and Sanofi-Genzyme, has received speakers honoraria from Biogen-Idec and Genzyme, is an investigator in clinical trials sponsored by Biogen Idec, Novartis, and Genzyme, and was the recipient of an unencumbered research grant from Biogen-Idec. HB has received honoraria for serving on scientific advisory boards for Biogen Idec, Novartis, and Sanofi-Genzyme, has received conference travel sponsorship from Novartis and Biogen Idec, has received honoraria for speaking and acting as Chair at educational events organized by Novartis, Biogen Idec, Medscape, and Merck Serono, serves on steering committees for trials conducted by Biogen Idec and Novartis, is chair (honorary) of the MSBase Foundation, which has received research support from Merck Serono, Novartis, Biogen Idec, Genzyme Sanofi, and CSL Biopharma, and has received research support form Merck Serono. WC has been the recipient of travel sponsorship from, and provided advice to Bayer Schering Pharma, Biogen-Idec, Novartis, Genzyme, Sanofi-Aventis, BioCSL, and Merck-Serono. RD has received research funding from the National Health and Medical Research Council, MS Research Australia, Star Scientific Foundation, Pfizer Neuroscience, Tourette Syndrome Association, University of Sydney, and the Petre Foundation and has received honoraria from Biogen-Idec and Bristol-Myers Squibb as an invited speaker. MF-P has received travel sponsorship from Biogen-Idec and Merck Serono. RH has received honoraria, educational support and clinic funding from Novartis, Biogen Idec, Genzyme and BioCSL. AGK has received scientific consulting fees and/or lecture honoraria from Bayer, BioCSL, Biogen-Idec, Genzyme, Merck, Novartis, Sanofi-Aventis, and Teva. TK has received travel sponsorship from Novartis, BioCSL, Novartis, Merck Serono, and Biogen Idec, has received speaker honoraria from Biogen Idec, BioCSL, Merck Serono, Teva, Genzyme, and Novartis, has received research support from Biogen Idec, Genzyme, GlaxoSmithKline, Bayer-Schering, and Merck Serono, and has received scientific consulting fees from GlaxoSmithKline China, Biogen-Idec and Novartis. JK has received remuneration for advisory board activities and presentations from Bayer Healthcare, Biogen Idec, BioCSL, Genzyme and Novartis. CK has received travel support, honoraria and advisory board payments from Biogen Idec, Bayer, Genzyme, Novartis, and Serono. JL-S has received unencumbered funding as well as honoraria for presentations and membership on advisory boards from Sanofi Aventis, Biogen Idec, Bayer Health Care, CSL, Genzyme, Merck Serono, Novartis Australia, and Teva. RM has received honoraria for attendance at advisory boards and travel sponsorship from Bayer-Scherring, Biogen-Idec, CSL, Merck-Serono, Novartis, and Sanofi-Genzyme. MM has received travel sponsorship, honoraria, trial payments, research and clinical support from Bayer Schering, Biogen Idec, BioCSL, Genzyme, Novartis, and Sanofi Aventis Genzyme. DM has received honoraria for attendance at advisory boards from Biogen-Idec and Novartis, and travel sponsorship from Bayer-Scherring, Biogen-Idec, and Sanofi-Genzyme. PM has received honoraria or travel sponsorship from Novatis, Sanofi-Aventis, and Biogen Idec. JAP has received travel sponsorship, honoraria for presentations and membership on advisory boards from Biogen Idec and Novartis and Sanofi Aventis. JDP has received honoraria for seminars or advisory boards from Teva, Biogen, Sanofi-Genzyme, Novartis, Merck, Bayer, and research grants or fellowships from Merck, Novartis, Bayer, Biogen, Sanofi-Genzyme, and Teva. SR has received travel sponsorship, honoraria, trial payments, research and clinical support from Aspreva, Baxter, Bayer Schering, Biogen Idec, BioCSL, Genzyme, Novartis, Sanofi Aventis Genzyme, and Servier, and is a director of Medical Safety Systems Pty Ltd. CS has received travel sponsorship from Biogen Idec, Novartis, and Bayer-Schering. IS has received remuneration for Advisory Board activities from Biogen, CSL, and Bayer Schering and educational activities with Biogen, CSL, and travel sponsorship from Biogen, Novartis, and Bayer Schering. MS has received research support from Novartis, Biogen Idec, and BioCSL. JSp has received honoraria for lectures and participation in advisory boards, and travel sponsorship from Novartis, BioCSL, Genzyme, and Biogen Idec. BT has received travel sponsorship from Novartis and Bayer Schering. AV and the University of Oxford hold patents and receive royalties for antibody testing. PW and the University of Oxford hold patents for antibody assays and have received royalties, has received speaker honoraria from Biogen Idec and Euroimmun\u00ae AG, and travel grants from the Guthy-Jackson Charitable Foundation. EW has received honoraria for participation in advisory boards from Biogen-Idec and Novartis, travel sponsorship from Biogen-Idec, Bayer-Schering and Teva and is an investigator in clinical trials funded by Biogen-Idec and Teva. MP has received consulting fees and research funding from Atara Biotherapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The September-October 2019 issue of the International Brazilian Journal of Urology presents original contributions with a lot of interesting papers in different fields: Infertility, Bladder Cancer, Prostate Cancer, Renal Cell Carcinoma, Partial nephrectomy, Kidney stones, Nocturnal Enuresis, Basic Research, Urinary Incontinence, Transplantation, UPJ Obstruction, Pelvic Organ Prolapse, Hypogonadism, Vasectomy, Herbal Medicine in Fertility and Urethral Strictures. The papers come from many different countries such as Italy, Brazil, USA, Turkey, China, France, Iran, Lebanon, Singapore, Colombia, Tunisia, India and Spain, and as usual the editor \u00b4s comment highlights some papers. We decided to comment the paper about a very interesting topic: Penile skin flap for anterior urethral sctricture  and the mean flap length was 6cm. The mean follow-up was 60 months (6-120). The overall success rate was 88%. The authors concluded that urethroplasty using penile skin flap appear to be a safe and efficient technique for the treatment of a long and complex anterior urethral stricture.There are several options for the treatment of anterior urethral stricture -4. The p"}
+{"text": "The July-August 2019 issue of the International Brazilian Journal of Urology presents original contributions with a lot of interesting papers in different fields: Infertility, Bladder augmentation, Bladder Cancer, PCNL, Prostate Cancer, Renal Cell Carcinoma, Partial nephrectomy, Renal stones, Nocturnal Enuresis, Basic Research, Laparoscopic Surgery, Penile Cancer, Stress Urinary Incontinence and Adrenalectomy. The papers come from many different countries such as Italy, Brazil, USA, UK, Turkey, China, France, Iran, Republic of Korea, Argentina, India and Spain, and as usual the editor\u00b4s comment highlights some papers. We decided to comment the paper about a very interesting topic: Robotic-Assisted Radical Prostatectomy (RARP).Doctor Neumaier and collegues from the FMUSP, Brazil performed on page 703  an interWith the introduction of robotic surgery, some technical difficulties in laparoscopic surgery were lessened, due to, among other factors, the three-dimensional field of vision, hand tremor filtration and greater ergonomic freedom of movement of the surgeon -7. RARP Retrospective studies indicate that urinary control rates are better in younger patients, although there is conflicting data in the literature -12. ThisProfessor Associado da Unidade de Pesquisa Urogenital da Universidade do Estado de Rio de JaneiroUrologista do Hospital da Lagoa Federal, Rio de JaneiroEditor Associado da International Braz J UrolLuciano A. Favorito, MD, PhD"}
+{"text": "Variation in STAR-VA sustainability across 20 trained VA Community Living Centers was explored using prospective qualitative methods utilizing the knowledge reservoirs framework including seven domains: People, Routines, Artifacts, Relationships, Information space, Culture, and Structure. We conducted directed content analysis of transcripts to identify facilitators and barriers of successful program sustainment. We found that people, usual routines, information sharing, and team relationships were the most often mentioned facilitators by CLC staff. Common reported barriers were people, team relationships, and work culture. Overlap was found in knowledge reservoirs acting as both facilitators and barriers at the same site, most often for people/teams, team relationships, and work culture. Results will be used to develop a sustainability intervention focused on addressing reported barriers. Most notably, a focus on having the appropriate team members, positive team relationships, usual routines, and a supportive work culture are critical for STAR-VA sustainability efforts."}
+{"text": "Background: Productive engagement becomes significant protective factors in healthy aging. Yet, subgroups of older adults with age-related vision and hearing impairments lack access to various activities , suggesting that unequal ability to participate in productive aging is a major public health and health-disparities concern. Methods: Older adults experiencing age-related vision and hearing impairments were drawn from the 2015-2017 National Survey on Drug Use and Health . Perceived health status (good vs. poor) was outcome measures used in multivariate logistic regression. Two aspects of productive engagement was considered: 1) employment status (unemployed vs employed) and 2) regular religious service attendance as tools to build social capital in their faith-based communities. Gender, race, marital status, educational attainment, poverty, urbanization, obesity, chronic disease, hospitalization, binge drinking, cigarette smoking, and difficulty with mobility were considered as covariates. Results: Working older adults with sensory loss were more likely to perceived good health status, compared to their unemployed counterparts . Religious service attendance also became protective factors for health . Of the covariates, higher educational attainment, White race, having one chronic disease, hospitalization, smoking, drinking, and mobility challenges appeared to affect the health status. Conclusions/Implications: Study findings implied the needs to identify late-life engagement through work and participation in faith-based community as a major public health issue. Given the barriers and disincentives to the productive engagement of older adults in this culture, healthcare providers should provide programs promoting employment and religious attendance."}
+{"text": "The aim of this study was to report the metrological qualities of techniques currently used to quantify skeletal muscle volume and 3D shape in healthy and pathological muscles.A systematic review was conducted (Prospero CRD42018082708). PubMed, Web of Science, Cochrane and Scopus databases were searched using relevant keywords and inclusion/exclusion criteria. The quality of the articles was evaluated using a customized scale.Thirty articles were included, 6 of which included pathological muscles. Most evaluated lower limb muscles. Partially or completely automatic and manual techniques were assessed in 10 and 24 articles, respectively. Manual slice-by-slice segmentation reliability was good-to-excellent (n = 8 articles) and validity against dissection was moderate to good(n = 1). Manual slice-by-slice segmentation was used as a gold-standard method in the other articles. Reduction of the number of manually segmented slices (n = 6) provided good to excellent validity if a sufficient number of appropriate slices was chosen. Segmentation on one slice (n = 11) increased volume errors. The Deformation of a Parametric Specific Object (DPSO) method (n = 5) decreased the number of manually-segmented slices required for any chosen level of error. Other automatic techniques combined with different statistical shape or atlas/images-based methods (n = 4) had good validity. Some particularities were highlighted for specific muscles. Except for manual slice by slice segmentation, reliability has rarely been reported.The results of this systematic review help the choice of appropriate segmentation techniques, according to the purpose of the measurement. In healthy populations, techniques that greatly simplified the process of manual segmentation yielded greater errors in volume and shape estimations. Reduction of the number of manually segmented slices was possible with appropriately chosen segmented slices or with DPSO. Other automatic techniques showed promise, but data were insufficient for their validation. More data on the metrological quality of techniques used in the cases of muscle pathology are required. The volume and shape of a muscle are strongly related to its function \u20134. StrucAssessment of muscle volume and shape is essential for both clinical practice and research. Measurement of muscle volume facilitates surveillance of neuromuscular disease progression ,11 and tMagnetic resonance imaging (MRI) is the gold-standard technique for the evaluation of muscle volumes and three-dimensional (3D) shapes, and is used as a reference to validate other imaging techniques for this purpose ,24. ManyKnowledge of the validity and reliability of measurement methods is essential when choosing a technique in order to ensure an accurate interpretation of the results ,31. ValiThe main aim of this systematic review was to report the validity and reliability of techniques used to estimate skeletal muscle volumes and 3D muscle shapes based on MRI data in healthy and pathological muscles in humans. The secondary aims were to determine the feasibility of those techniques and to provide recommendations for future research.Our first hypothesis was that manual slice by slice segmentation would have good metrological properties but would need a large amount of time. The second was that while providing valid and reliable results, automatic segmentation techniques would require less time.This systematic review adheres to the PRISMA guidelines. A PRISMA checklist was completed  and the Articles were identified through a comprehensive search of the following online bibliographic databases: PubMed, Web of Science, The Cochrane Library and Scopus. In order to ensure the search was exhaustive, the following Medical Subject Headings (MeSH) and keyword combinations were used (I) MRI, magnetic resonance imaging, (II) muscle, skeletal muscle, muscul* (III) (keywords relating to segmentation) volum*, cross sectional area, three dimension*, 3D, shape, segmentation, organ size and (IV)  reliability, reproducibility, repeatability, validity, accuracy, measur*, metrologic*, validation stud*. Search strings were formulated and tailored to the search syntax of each database to ensure a common search strategy . NeitherInclusion criteria were: I) studies in which the main aim was to describe and/or evaluate a method to determine skeletal muscle  volume and/or shape using MRI data, II) the study was on human subjects and III) the study included an evaluation of the metrological qualities of the method. Studies that evaluated head and neck muscles or that evaluated muscle groups that were not functionally grouped ,34 and cSince no standardized tools exist to determine the quality of articles in the field of radiology, a customized quality assessment scale was developed from other scales in the literature ,37. The 2 values from 0\u20130.49 = poor, 0.5\u20130.69 = moderate, 0.7\u20130.89 = good and > 0.9 = excellent [Information regarding the samples included, muscles evaluated, magnetic field strengths and MRI protocols used were collected from each article. The technique evaluated, the reference technique used, operators and outcome measures  were also recorded . In thisxcellent . The samxcellent , only thThe literature search identified 2160 citations in PubMed, 324 citations in the Cochrane Library, 3911 citations in Scopus, 2302 citations in Web of Science. After removing duplicates, 4631 remained. After screening titles and abstracts, 86 articles were found to be potentially eligible. Finally, 30 met the inclusion criteria and were included .The mean Q score of the articles included was 64.1/100 SD: 9.7). The primary aim of seventeen articles was to determine the metrological properties of a measurement technique. Ten articles had a score above 70/100 .7. The p,28,45\u201351The methodological characteristics  of each article are presented in The articles included primarily focused on segmentation techniques. Manual techniques  segmentation, segmentation of CSA in a reduced number of slice(s), segmentation of CSA on one slice and muscle length use) were evaluated in twenty-four articles \u201358,60\u201364Muscle volume was evaluated in twenty-six articles \u201364,66,68Seventeen articles included only healthy subjects ,62,64,67Forty different muscles were examined: upper limb muscles were assessed in six articles ,54,56,62With regards to MRI parameters, 1.5T scanners were the most frequently used (n = 22 articles), T1 weighted sequences were used in twenty four articles and 3D sequences were used in seven articles ,52,54,66Estimation of muscle volume using slice-by-slice CSA segmentation was evaluated in 11 articles  . Intra- n = 2, ,49)..rd and 4rd and 4th order polynomial equations [Estimation of muscle volume using CSA segmentation on a reduced number of slices was evaluated in 6 articles  ,57,58,60Estimation of muscle volume using CSA segmentation on a single slice without muscle length was evaluated in three articles . SpeEstimation of muscle volume and/or 3D shape using the deformation of a parametric specific object (DPSO) method with manual segmentation was evaluated in five articles . As slice-by-slice manual segmentation is widely used as a reference method, further studies are warranted to confirm its validity. With regards to reliability, results varied among muscles. The use of different volume calculation methods did not seem to change the errors, indicating that errors found between measurements were likely related to segmentation. The quality of the results was lower for deep muscles such as gluteus minimus and for muscles whose boundaries are unclear, such as the individual muscles of the quadriceps. Identifying their external borders appears challenging. To limit these segmentation errors, we believe that it is essential that standardized procedures using clear anatomical landmarks per muscle are developed and implemented . DespiteTechniques based on the manual segmentation of a reduced number of slices reached good to excellent validity when a sufficient number of slices was segmented. The appropriate number of slices varied among muscles. For most, fewer than half of the total number of slices need to be manually segmented, with slice thicknesses of 10 mm and interslice distances of 5 mm, allowing shorter processing time, whilst maintaining an almost equivalent level of performance compared to slice by slice segmentation. Results can further be improved by the choice of appropriate slices to segment . Errors Use of even faster techniques, such as the segmentation of a single slice with or without muscle length, could be associated with a loss of precision. Because of their speed of realization, these techniques can be used in clinical practice if the aim is, for example, to estimate the degree of muscle loss in diseases that causes severe atrophy, where differences of more than 10% in volume would normally be expected. Special attention must however be paid when using these methods for non-fusiform muscles. Although the guidelines used for the choice of each slice were detailed for each technique, there was little reliability evaluations. It has been previously reported that the optimal location of measurements can be difficult to both define and reproduce  thus theThe DPSO method, which involves automatic segmentation of intermediate slices, had good validity if enough slices were manually segmented. For non-fusiform and small muscles, a greater number of slices has to be manually segmented to maintain good accuracy. If this method is found to be reliable, it could be used in association with manual techniques to reduce the number of manually segmented slices and help save time. Further studies are warranted to determine which technique is the most accurate and fast between manual segmentation of a reduced number of slices with different volume estimation methods and manual segmentation with DPSO . The resThe validity of the other four partially or completely automatic techniques analysed  could not be confirmed in this review due to the small number of low-quality studies currently available, however it is important to note that results were encouraging. These techniques appeared to be promising in terms of validity. High quality, additional metrological studies are thus needed to validate them. Each technique had its own characteristics: segmentation using generalized log-ratio representation transformation can impose soft constraints whereas deformable statistical shape models and atlas-based segmentations use hard constraints. However, the generalized log-ratio representation method cannot effectively delineate pose variability as against the other techniques and thus requires image pre-processing as an additional step. Thus, some techniques may be more appropriate than others depending on the muscles and their properties and on the characteristics of the population . Other findings indicated that techniques, such as random-walk segmentation ,72, waveMethods to estimate skeletal muscle volumes and/or 3D muscle shapes using MRI data are used clinically for diagnosis , to evalThe MRI protocol used to acquire images can have a huge impact on segmentation outcomes . The stuThe feasibility of MRI can be limited by the availability of MRI scanners and the cost of MRI devices and assessments. Thus, some other techniques, for example using ultrasonography, could be interesting to estimate skeletal muscle volumes and 3D muscle shapes .We believe future work should include evaluation of test-retest reliability since we found only two articles that assessed this ,62. TestFurthermore, precise reporting of the statistical analysis method employed is essential for metrological studies. As a result of the work undertaken in this review we recommend that the following evaluations are included as standard in future work, in addition to the usual analyses of correlation to improve the internal validity, on measurement technique studies ,79. The 2, ICC, Dice Similarity Index), Tannimoto coefficient, mean differences, SD, SEE, RMSE and point-to-surface distance) and reliability  limited the synthesis of the data with a quantitative pooled analysis. Future work should aim to overcome as far as possible such diversity in order to both strengthen results as well as improving the generalisability of findings across different methods.When considering our findings and recommendations, it is important to note that the strength of any conclusions depends on the quality of the original articles . The artThe results of this systematic review provide a rationale for the choice of appropriate segmentation techniques depending on the muscle, the need for precision and the available time. Such uses could include diagnosis of a disease, evaluation of a treatment response, monitoring of disease progression or measurement for research purposes. Further research is required to confirm the validity of manual slice-by-slice segmentation and automatic techniques, except for DPSO for which there is sufficiently strong supporting evidence. The reliability of most techniques in current use also needs to be confirmed, except for manual slice-by-slice segmentation, which has been shown to be sufficiently reliable (if time consuming). Studies to evaluate different MRI protocols are warranted. Specific studies in pathological muscles are also needed to enable the proper application of such techniques in routine clinical practice.S1 Table(DOC)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 TableF: female, M: male, SD: standard deviation, NR: not reportedRF: rectus femoris, VI: vastus intermedius, VL: vastus lateralis, VM: vatsus medialis, Qua: quadriceps, Pir: Piriformis, GlMi: Gluteus Minimus, GlMe: Gluteus Medius, GlMa: Gluteus Maximus, FCU: flexor carpi ulnaris, ECU: extensor carpi ulnaris, Sspi: Supraspinatus, Ssca: Subscapularis, Ispi+Tmin: Infraspinatus and Teres minor, ES: Erector Spinae, M: multifidus, RA: rectus abdominis, Ps: Psoas, Sar: Sartorius, Gra: Gracilis, AddM: Adductor Magnus, Add L: Adductor longus, BFL: Biceps Femoris Long head, BFS: Biceps Femoris Short head, ST: Semi Tendinosus, SM: Semi Membranosus, GL: Gastrocnemius Lateralis, GM: Gastrocnemius Medialis, So+FHL: Soleus and flexor hallucis longus, TP: Tibialis Posterior, FDL: flexor digitorum longus, Per LBT: Peroneus , TA+EDL+EHL: tibialis anterior and extensor digitorum longus and extensor hallucis longus, So: Soleus, TS: triceps surae, TB: triceps brachii, TA: Tibialis Anterior, VLMI: Vastus Lateralis and Medius and Intermedius, TFL: tensor Fascia Lata, Add BLM: adductor , Il: Iliacus, Obl: Obliquus , QL: Quadratus Lumborum, VLI: Vastus Lateralis and Intermedius together, VLMI: Vastus Lateralis and Medialis and Intermedius, BF: Biceps Femoris, SMT: Semi Membranosus and Tendinosis, ESM: erector spinae and multifidus, PT: pronator teres, ECRB: Extensor Carpi Radialis Brevis, EPL: Extensor Pollicis Longus, Br: BrachioradialisFOV: Field of View, NEX: Number of Excitations, TR: Repetition Time, TE: Time to echo.(DOCX)Click here for additional data file.S4 TableICC: intraclass correlation coefficient, mean diff: mean difference, SD: standard deviation, CV: coefficient of variation, SDD: smallest detectable difference, RMSE: root mean square error, SEE: standard error of the estimate, DSI: Dice similarity index, mean surf D: mean surface distance, max surf D: maximal surface distance, TC: Tannimoto coefficient, FNVF: false negative volume fraction, FPVF: false positive volume fraction, MVSF: muscle volume similarity fractionRF: rectus femoris, VI: vastus intermedius, VL: vastus lateralis, VM: vatsus medialis, Qua: quadriceps, Pir: Piriformis, GlMi: Gluteus Minimus, GlMe: Gluteus Medius, GlMa: Gluteus Maximus, FCU: flexor carpi ulnaris, ECU: extensor carpi ulnaris, Sspi: Supraspinatus, Ssca: Subscapularis, Ispi+Tmin: Infraspinatus and Teres minor, ES: Erector Spinae, M: multifidus, RA: rectus abdominis, Ps: Psoas, Sar: Sartorius, Gra: Gracilis, AddM: Adductor Magnus, Add L: Adductor longus, BFL: Biceps Femoris Long head, BFS: Biceps Femoris Short head, ST: Semi Tendinosus, SM: Semi Membranosus, GL: Gastrocnemius Lateralis, GM: Gastrocnemius Medialis, So+FHL: Soleus and flexor hallucis longus, TP: Tibialis Posterior, FDL: flexor digitorum longus, Per LBT: Peroneus , TA+EDL+EHL: tibialis anterior and extensor digitorum longus and extensor hallucis longus, So: Soleus, TS: triceps surae, TB: triceps brachii, TA: Tibialis Anterior, VLMI: Vastus Lateralis and Medius and Intermedius, TFL: tensor Fascia Lata, Add BLM: adductor , Il: Iliacus, Obl: Obliquus , QL: Quadratus Lumborum, VLI: Vastus Lateralis and Intermedius together, VLMI: Vastus Lateralis and Medialis and Intermedius, BF: Biceps Femoris, SMT: Semi Membranosus and Tendinosis, ESM: erector spinae and multifidus, PT: pronator teres, ECRB: Extensor Carpi Radialis Brevis, EPL: Extensor Pollicis Longus, Br: Brachioradialis.(DOCX)Click here for additional data file.S5 Table(DOCX)Click here for additional data file.S1 Text(DOCX)Click here for additional data file."}
+{"text": "This study examines differences in attitudes toward suicide and physician-assisted suicide in chronic pain scenarios among Latino and White elders. Face-to-face interviews were conducted with 204 elders at four community-based, outpatient care sites in the metropolitan area of San Antonio, Texas. In addition to ethnicity and the suicide-related questions, the interviews collected data on age, gender, marital status, education, income level, acculturation (Latinos only), depression, self-reported health status, daily living functioning, and religiosity/spirituality. In general, there were no ethnic group differences in attitudes, however, the factors associated with those attitudes varied between ethnic groups. Among Whites, attitudes toward suicide and toward physician-assisted suicide were significantly and negatively associated with religiosity. Among Latinos, depression was significantly and positively associated with attitudes toward suicide in chronic pain scenarios, while acculturation was significantly and negatively associated with attitudes toward physician-assisted suicide in chronic pain scenarios. This study\u2019s findings suggest that depression among Latino elders and religion among White elders are determinant factors of attitudes toward suicide in chronic pain scenarios. Future research is needed to confirm our findings with a more heterogeneous study sample, including Latinos from different countries of origin ; and more heterogeneous ethnic groups in terms of socioeconomic status and educational level characteristics."}
+{"text": "OBJECTIVES/SPECIFIC AIMS: Opinions regarding translational science vary incredibly. We aimed to gather a baseline of perceptions, barriers, and needs for translational science among faculty investigators. We will use these data to define areas in which the Duke Multidisciplinary Education and Research in Translational Science program (MERITS) can work to address, educate and improve. METHODS/STUDY POPULATION: Data was collected via a scalar, multiple-choice, open-ended survey including questions regarding, definition, impact, barriers, resources, and training preferences specific to translational science. Digital survey links were emailed to Duke University faculty. RESULTS/ANTICIPATED RESULTS: In total, 350 responses were collected. While perceptions of translational science varied, common defining elements were noted, including multidisciplinary collaboration (69%) and transitions between research stages (63%). Translational science was said to have an overall positive impact, despite 37% of participants stating issues of insufficient institution-wide support and 62% citing minimal training in translational science skills. DISCUSSION/SIGNIFICANCE OF IMPACT: Effective support for translational science requires a multi-faceted approach, as perceptions differ among investigators and between career stages. Duke MERITS will seek to standardize education and support ranging from teambuilding to entrepreneurship, and to promote support from institutional leadership to reduce barriers and facilitate acceleration of translational science."}
+{"text": "The so-called \"don't touch\" bone lesions are typically identified as incidental findingson imaging exams. Most of these lesions are pseudotumors, benign bone lesions oranatomical variants..As the name suggests, \"don't touch\" lesions do not require the use of biopsy or otherinvasive procedures. However, they can be misdiagnosed as aggressive neoplastic lesions,generating concern and leading to unnecessary procedures. Correct identification ofthese lesions, with a specific diagnosis, minimizes the morbidity and costs associatedwith their management..In most cases, the method used for the initial identification, characterization, andclassification of \"don't touch\" lesions is conventional X-ray. The integrated analysisbetween the imaging findings and the clinical and laboratory data isessential.(-6).In some challenging situations, including uncommon presentations such as a hemophilicpseudotumor, computed tomography or magnetic resonance imaging can be used in order tocharacterize the lesion, thus increasing the reliability and confidence in the accuracyof the diagnosis-6. described a cognitive mapping system specifically focused onsupporting the diagnosis of solitary bone tumors in pediatric patients, with theobjective of supporting the decisions of medical professionals and promoting training inthe area, potentially reducing errors in the diagnosis of such lesions.Costa also recentlydiscussed the application of artificial intelligence in the evaluation of bone tumors,highlighting the great potential of such tools. However, the author emphasized theimportance of face-to-face physician-patient interaction in the overall approach tocancer patients.There is currently a tendency to use computerized systems to support the clinicaldecision and diagnosis, contributing to the management of medical knowledge. In a recentarticle addressing this theme, Moreira et al. describens.Costa also recRadiologia Brasileira, Fonseca etal. have reviewed, inan illustrative way, the main bone pseudotumors and \"don't touch\" lesions. The authorsaddressed a variety of such lesions/conditions-cortical desmoids, subchondral cysts,costochondritis, small bone islands, fibrous dysplasia, non-ossifying fibromas, simplebone cysts, aneurysmal bone cysts, bone infarction, synovial cysts, melorheostosis,vertebral hemangiomas, discogenic vertebral sclerosis, myositis ossificans, and humeralpseudocysts-, highlighting their main characteristics on the various imagingmethods.In an article published in this issue of ca etal. have revRadiologists and radiology residents need to be familiar with the \"don't touch\" lesionsand their different presentations in the various imaging methods. Thus, they canactively and efficiently contribute to the diagnosis and follow-up of these patients,avoiding unnecessary invasive procedures, reducing patient morbidity, and optimizing theuse of health care resources."}
+{"text": "Pulmonary fungal infections, which can be opportunistic or endemic, lead toconsiderable morbidity and mortality. Such infections have multiple clinicalpresentations and imaging patterns, overlapping with those of various otherdiseases, complicating the diagnostic approach. Given the immensity of Brazil,knowledge of the epidemiological context of pulmonary fungal infections in thevarious regions of the country is paramount when considering their differentialdiagnoses. In addition, defining the patient immunological status willfacilitate the identification of opportunistic infections, such as thoseoccurring in patients with AIDS or febrile neutropenia. Histoplasmosis,coccidioidomycosis, and paracoccidioidomycosis usually affect immunocompetentpatients, whereas aspergillosis, candidiasis, cryptococcosis, and pneumocystosistend to affect those who are immunocompromised. Ground-glass opacities, nodules,consolidations, a miliary pattern, cavitary lesions, the halo sign/reversed halosign, and bronchiectasis are typical imaging patterns in the lungs and will bedescribed individually, as will less common lesions such as pleural effusion,mediastinal lesions, pleural effusion, and chest wall involvement. Interpretingsuch tomographic patterns/signs on computed tomography scans together with thepatient immunological status and epidemiological context can facilitate thedifferential diagnosis by narrowing the options. In general, histoplasmosis, coccidioidomycosis, andparacoccidioidomycosis affect immunocompetent individuals, whereas aspergillosis,candidiasis, cryptococcosis, and pneumocystosis affect immunocompromisedindividuals. There are multiple clinical scenarios, with variable and overlappingimaging patterns. Therefore, it is essential that attending physicians be familiarwith the epidemiological status of the fungi in their region, the immunologicalstatus of the patient, and the imaging patterns of each entity-4.Pulmonary fungal infections, which can be opportunistic or endemic, are associatedwith considerable morbidity and mortality. In recent decades, there has been asignificant increase in the incidence of such infections, due to medical treatments,as well as to the rising incidence of leukemia, lymphoma, and AIDS, together withthe improved accuracy of diagnostic techniquesIn this study, we will describe the pulmonary fungal infections that are most commonin Brazil, discussing the main tomographic patterns observed in the pulmonary andmediastinal compartments.. Endemic fungal infections withpulmonary involvement are not on the national mandatory reporting list. It is assumed that theepidemiology of these infections is changing, partly due to global climate changes,new agricultural practices (widespread mechanization and the use of fungicides),human migration, adventure tourism, and other causes.Data on the distribution of fungal infections in Brazil are scarce, and knowledge ofendemic areas is based on reports of clinical cases and intradermal investigations,as are the prevalence, incidence, and morbidity data for some conditions,9. Cases have also been reported in areas inhabited more recentlyand undergoing deforestation, such as in parts of the Brazilian Amazon rain forest,including those in the states of Amazonas, Maranh\u00e3o, Tocantins, Par\u00e1,Mato Grosso, Rond\u00f4nia, Acre, and Amazonas,10.Paracoccidioidomycosis is considered an endemic disease, approximately 80% of allcases occurring in Brazil, mainly in the states of S\u00e3o Paulo, Paran\u00e1,Rio Grande do Sul, Goi\u00e1s, Rio de Janeiro, and Rond\u00f4nia,11,12. Therehave been 26 reported microepidemics of histoplasmosis, in seven Brazilian states and the Federal District of Bras\u00edlia, with isolation ofthe fungus in Rio de Janeiro, Rio Grande do Sul, S\u00e3o Paulo, Para\u00edba,and the Federal District of Bras\u00edlia.The number of reported cases of coccidioidomycosis is highest in the states innortheastern Brazil, and the last endemic area defined for this mycosis in theAmericas comprises the states of Piau\u00ed, Cear\u00e1, Maranh\u00e3o, andBahia. In general, some fungal infections, includingpneumocystosis, cryptococcosis, and aspergillosis, have a predilection forimmunocompromised individuals,4,15. Other agents implicated are fungi of the generaMucor, Fusarium, Rhizopus,Petriellidium, Cryptococcus,Histoplasma, Coccidioides, andCandida. Although infections with Aspergillussp. are still the most common fungal infections among immunocompromised individualsin the United States and Europe, the prevalence of HIV infection has made infectionswith fungi of the genera Cryptococcus andPneumocystis the most common fungal infections among suchindividuals in other parts of the world.Fungal infections are among the most serious infections in immunocompromisedindividuals, and pulmonary involvement remains the most common documented form ofinvasive tissue infection in immunocompromised hosts,16. In this subgroup of individuals,an aggressive etiological investigation protocol is necessary, because a diagnosticdelay increases mortality, and early use of computed tomography in diagnosticprotocols is recommended.Populations at high risk for pulmonary fungal infections include individuals withsolid or hematological malignancies, those undergoing organ or bone marrowtransplantation, and HIV infected patients. Others who are at intermediate riskinclude patients on chronic corticosteroid or immunosuppressive therapy, those withchronic kidney disease, those with chronic obstructive pulmonary disease (COPD), andthose with liver cirrhosisPneumocystis jirovecii pneumonia orpneumocystosis, the most characteristic finding on high-resolution computedtomography scans is that of ground-glass opacities, reflecting intra-alveolaraccumulation of fibrin, debris, and microorganisms. On high-resolution computedtomography, the aspect is that of diffuse lung disease, with ground-glassopacities that tend to appear predominantly in the upper lobes and rarely on thelung periphery.Superimposed on ground-glass opacities, reticular opacities can be observed,characterizing the crazy-paving pattern , inflammatory, andneoplastic diseases. Amongfungal infections, the sign has been observed not only in aspergillosis but alsoin mucormycosis, candidiasis, coccidioidomycosis, and cryptococcosis.The halo sign refers to ground-glass attenuation surrounding a nodule and wasfirst described in angioinvasive aspergillosis affecting immunocompromisedindividuals, histopathologically corresponding to an area of infarctionsurrounded by alveolar hemorrhage. For the differentialdiagnosis, it should be noted that thickness of the ground-glass halo is oftengreater in infectious conditions.The halo sign is of particular importance in immunocompromised individuals, inwhom its specificity is greater for the angioinvasive presentation of somefungal infections, especially aspergillosis. Its occurrence is usuallytransient, being more common in the early stages of the disease. It can be observed in a variety of infectious andnoninfectious diseases; among fungal infections, it is more common inparacoccidioidomycosis and angioinvasive fungal infections such asaspergillosis, zygomycosis and fusariosis,32. In anattempt to narrow the differential diagnosis of diseases presenting with thereversed halo sign, findings of internal reticulation, peripheral halo thickness> 1.0 cm and pleural effusion favor the diagnosis of an angioinvasive fungalinfection over that of organizing pneumonia, within the appropriate clinicalcontext of immunosuppression,34. A variationof the reversed halo, with nodular margins ,histoplasmosis, and acute coccidioidomycosis,26. Amongimmunocompromised individuals, angioinvasive fungal infection  can lead to consolidations, usually with aperipheral distribution, as well as with a ground-glass halo caused by alveolarhemorrhage,23. Consolidations are describedas part of the semi-invasive, airway-invasive, and bronchopulmonary allergicmanifestations of aspergillosis. Advanced stages of pneumocystosis can also includeconsolidation, and its occurrence is more common in non-HIV-infected patients,in whom it tends to develop faster, reflecting the lung damage caused by thehost immune response.Airspace consolidations may be seen in various fungal infections,20. Thedifferential diagnoses of a miliary pattern include miliary metastases and thehematogenous dissemination of tuberculosis.Micronodules with a random pattern of dissemination (miliary pattern) constitutea common presentation in various pulmonary mycoses, being described mostfrequently in histoplasmosis ,paracoc.Cavitary lesions can be observed in various fungal infections, such asangioinvasive disease , as well asin the semi-invasive (necrotizing) and saprophytic manifestations ofaspergillosis, histoplasmosis, paracoccidioidomycosis, cryptococcosis, andcoccidioidomycosis. It affects individuals with mildimmunosuppression, such as those with COPD, alcoholism, diabetes, or connectivetissue disease,23,36. In tomography studies, there are signs ofbronchopneumonia and consolidations, predominantly in the upper lobes, whichevolve to thick-walled cavitary lesions, including aspergillomas,23, as depicted in Semi-invasive (necrotizing) aspergillosis is the chronic granulomatousmanifestation of aspergillosis, presenting clinically as a productive cough,fever, and hemoptysis lasting for several months.In the chronic cavitary form, the symptoms are similar to those of post-primarytuberculosis, including a low-grade fever, cough, hemoptysis, and weight loss.Imaging studies show reticular opacities accompanied by cavitary lesions,predominantly in the upper lung fields.Cavitary lesions can be seen in acute and chronic histoplasmosis , tending.In the saprophytic form of aspergillosis, the fungus grows inside cavitarylesions, especially in those caused by tuberculosis, sarcoidosis, or otherinfectious diseases. A nodule or mobile mass within a cavitation, as depicted inAspergillus sp. It especially affects individuals withasthma of long duration, cystic fibrosis, or Kartagener syndrome, as well aslung transplant recipients,23. Aspergillosis leads toincreased mucus production and impaired mucociliary clearance, resulting indamage to the bronchial wall, mucoid impaction, and bronchiectasis. The tomographic findingsthat merit attention are central  bronchiectasis,especially in the upper lung fields, together with mucoid impaction  can occur in immunocompromised individuals, leading to ulcers orextensive/pseudomembranous necrosis on the mucosal surface.Aspergillosis can manifest as invasive airway disease, especially inimmunocompromised individuals with neutropenia and those with AIDS. The diseasespectrum extends from the large airways (trachea) to the small airways.Involvement of the small airways can occur in the form of bronchiolitis, withcentrilobular nodules, \u201ctree-in-bud\u201d nodules, and peribronchovascularconsolidations, or in the form of bronchopneumonia , a patte, although the cause of theimmune response is undefined in some cases. It can be idiopathic, secondary toinfiltrative neoplastic diseases or infectious diseases, including tuberculosis,aspergillosis, mucormycosis, cryptococcosis, and especially histoplasmosis, thelast being a leading cause of the disease, especially in endemicareas. It usuallyaffects younger individuals, leading to varied clinical findings, mainly relatedto compression of vital mediastinal structures. Tomography shows a solidinfiltrative lesion, with soft-tissue density and variable enhancement (Fibrosing mediastinitis is related to the host immune response, which results inproliferation of dense fibrous tissue in the mediastinumancement , typical.Imaging plays an important role in depicting and quantifying the involvement ofvital, cardiovascular, or airway structures. In the pulmonary compartment, therecan be secondary repercussions, such as infarcts or thickening of theinterlobular septa, due to obliteration of arterial or venous branches,respectively-4,20,39.Disseminated lymph node enlargement has been described in cryptococcosis andhistoplasmosis, especially in immunocompromised individuals. In some cases,necrotic lymph nodes are observed,33.Mediastinal lymph node involvement is seen in some mycoses, especiallyhistoplasmosis, cryptococcosis, coccidioidomycosis, and, less commonly,paracoccidioidomycosis,40. Among such infections, thefrequency of pleural effusion is slightly higher in mucormycosis.Pleural effusion is uncommon in individuals with pulmonary fungalinfections.Involvement of the chest wall, in the form of costochondritis, has been reportedin intravenous drug users.Thoracic wall involvement can be observed as an extension of the pulmonaryinfection occurring in aspergillosis, manifesting as lytic lesions in costalarches and vertebrae, being best characterized in tomography and magneticresonance imaging studiesSeveral imaging patterns may be observed in pulmonary fungal infections, suchpatterns often being nonspecific and having the potential to overlap among thevarious agents, leading to numerous differential diagnoses, including infectious andnoninfectious causes. With the objective of systematizing the approach to thesediseases, we have reviewed some patterns, including the basic patterns in thepulmonary parenchyma and in extrapulmonary involvement.Given the multiplicity of presentations of such diseases, there is a need forattending physicians to be familiar with the manifestations. For the correctdiagnosis and management of these diseases, it is also necessary that themultidisciplinary team follow patients closely."}
+{"text": "High antioxidants and phytochemicals from plant foods may protect against cognitive decline, while saturated fats from animal based foods considered as risk factors have been associated with dementia. Plant-based diets with limited animal products have been shown to improve glycemic control and reduce diabetes risk. The study aims to examine the association between vegetarian diet and dementia risk in a prospective cohort study. Quantitative data collected from 12,062 participants of Tzu Chi Vegetarian Study from 2005 to 2014 in Taiwan. Data included self-administered questionnaire on demographics, medical history, life-style, and a 57-item food frequency questionnaire (FFQ), National Health Insurance Database and the National Death Registry. Findings show that compared with non-vegetarians, vegetarians had 38% lower risk of dementia  after adjusting for age, sex, education, marital status, physical activities, smoking, alcohol drinking, hypertension, diabetes, hyperlipidemia, and ischemic heart diseases."}
+{"text": "This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript."}
+{"text": "The majority of studies on traumatic life events focus on posttraumatic stress disorder and depression, while less is known whether the cumulative exposure to traumatic events over the life course will deteriorate cognitive function. This study aims to investigate the association between lifetime traumatic events and cognitive function in an immigrant population. The data were drawn from the Population Study of Chinese Elderly in Chicago (PINE). Face-to-face interviews were conducted with a sample of 3,126 U.S. Chinese older adults in 2017-2019. Twelve types of traumatic events were assessed: physical assault, residential fires, sexual assault, miscarriage, abortion, imprisonment, being falsely accused, divorce, death of a loved one, being robbed, experiencing cancer, and being homeless. Cognitive function was measured through global cognition, episodic memory, working memory, processing speed, and Mini-Mental State Examination (MMSE). Linear regression was performed. In our sample, the maximum traumatic events experienced by one participant are eight types. Older adults who experienced one additional personal event were associated with higher global cognition , episodic memory , working memory , processing speed , and MMSE , while controlling for age, gender, income, and education. In contrast with earlier studies, we identified the positive relationships between traumatic events and cognition. Older adults who had prior experience with stressful life events could demonstrate an advantage over those without such an experience. Further studies could investigate how individuals would respond to stressful life events, and how their resilience mechanism would promote cognitive function."}
+{"text": "Agriculture producers, pushed by the need for high productivity, have stimulated the intensive use of pesticides and fertilizers. Unfortunately, negative effects on water, soil, and human and animal health have appeared as a consequence of this indiscriminate practice. Plant probiotic microorganisms (PPM), also known as bioprotectants, biocontrollers, biofertilizers, or biostimulants, are beneficial microorganisms that offer a promising alternative and reduce health and environmental problems. These microorganisms are involved in either a symbiotic or free-living association with plants and act in different ways, sometimes with specific functions, to achieve satisfactory plant development. This review deals with PPM presentation and their description and function in different applications. PPM includes the plant growth promoters (PGP) group, which contain bacteria and fungi that stimulate plant growth through different mechanisms. Soil microflora mediate many biogeochemical processes. The use of plant probiotics as an alternative soil fertilization source has been the focus of several studies; their use in agriculture improves nutrient supply and conserves field management and causes no adverse effects. The species related to organic matter and pollutant biodegradation in soil and abiotic stress tolerance are then presented. As an important way to understand not only the ecological role of PPM and their interaction with plants but also the biotechnological application of these cultures to crop management, two main approaches are elucidated: the culture-dependent approach where the microorganisms contained in the plant material are isolated by culturing and are identified by a combination of phenotypic and molecular methods; and the culture-independent approach where microorganisms are detected without cultivating them, based on extraction and analyses of DNA. These methods combine to give a thorough knowledge of the microbiology of the studied environment. Unfortunately, this impacts water and soil pollution, and the whole food chain suffers secondary adverse effects because of this practice, which impacts human health. One strategy to reduce pesticide use has been to select cultivars resistant to a specific disease, but in some cases this resistance can cause damping-off, crown rot, and root rot This article focuses on the most recent advances concerning PPM as a plant culture improvement and examines some studies and perspectives of modified and improved strain use.2.Today, world population increase, soil degradation, environmental contamination, and climate change affect agriculture and forestry, which are crucial activities for human and animal survival 2-fixing cyanobacteria, actinomycetes, and soil toxicant-degrading microbes, among others Bacillus megateriumPPM are beneficial microorganisms that co-evolved with plants in either a symbiotic or free-living association. This association mainly occurs in the soil, but there are other association types, such as microalgae-associated bacteria Bacilli and Pseudomonas are the most predominant identified genera. The main PGPB source is soil, but some studies have demonstrated the existence of bacteria associated with microalgae that stimulate Bacillus okhensisIn soil, one of the most common groups of PPM is plant growth-promoting bacteria (PGPB), and among these the Exophiala sp. are phytomohormone secretors and can improve plant growth under abiotic stresses Trichoderma strains have also been studied; Palma et al in vitro interaction between tomatoes (Solanum lycopersicum L.) and the strain Trichoderma longibrachiatum MK1. The results reveal the enrichment of cell defense/stress and primary metabolism categories and promoted changes on secondary metabolism and transport.Fungi are another highly studied PPM group with important functions. For example, endophytic fungi like Unfortunately, PPM performance at field scale is not always satisfactory; the choice of cultivars, the degree and type of fertilization, and crop rotation all influence PPM-plant interactions. However, understanding the distribution and diversity of indigenous bacteria in specific regions, using OMICS technologies, is a promising solution 3.Plant growth promoters (PGP) are microorganisms: bacteria and fungi that stimulate plant growth through different mechanisms. Some direct PGP action mechanisms include nitrogen amelioration, phosphorous or iron fixation, and plant hormone These PGP have great importance in food production systems, as they increase productivity and reduce the environmental impact caused by agrochemical use 3.1.Acinetobacter, Alcaligenes, Arthrobacter, Azospirillium, Azotobacter, Bacillus, Beijerinckia, Burkholderia, Enterobacter, Erwinia, Flavobacterium, Pseudomonas, Rhizobium, Serratia, and arbuscular mycorrhizal fungi (AMF) There are different methods of soil fertilization, such as chemical fertilization, organic fertilization, and microorganism use 3.2.PGPR greatly contributes to enhanced plant growth and yield Agrobacterium, Arthrobacter, Azotobacter, Azospirillum, Bacillus, Burkholderia, Caulobacter, Chromobacterium, Erwinia, Flavobacterium, Micrococcous, Pseudomonas, and Serratia families are examples of ePGPR Allorhizobium, Azorhizobium, Bradyrhizobium, Mesorhizobium, and Rhizobium, in the Rhizobiaceae family, are examples of iPGPR. Most rhizobacteria belonging to this group are Gram-negative rods, with a lower proportion being Gram-positive rods, cocci, or pleomorphic 2Glycine max L.) obtain biologically fixed N through a symbiotic relationship with Bradyrhizobium japonicum (Bradyrhizobiaceae) PGPR can be classified as rhizospheric and endophytic 3.3.Medicago sativaArbuscular mycorrhiza fungi, or AMF, can enhance the solubility and availability of nutrients, including phosphorous and micronutrients, absorbed by the plant under different conditions The majority of plant roots are symbiotically associated with AMF, mainly the phylum Glomeromycota The interaction between AMF and bacteria may result in benefic impacts on plants. The presence of bacteria (PGPR) improves fungal colonization in the root, and this interaction positively influences nitrogen and phosphorous enhancement Aquilaria crassna Pierre ex Lec. and Tectona grandis Linn.f. in Thai plantations, set an excellent example. They tried, through fieldwork, to understand whether the AMF communities varied with the host plant species. Terminal restriction fragment length polymorphism, complemented with clone libraries, revealed that AMF community composition in A. crassna and T. grandis were similar. In this case, a total of 38 distinct terminal restriction fragments (TRFs) were found, 31 of which were shared between A. crassna and T. grandis. Authors reported that TRFs were attributed to Claroideoglomeraceae, Diversisporaceae, Gigasporaceae, and Glomeraceae.Reforestation enhancement is one important potential AMF application. Since tropical forests are disappearing at the rate of 13.5 million hectares each year, Chaiyasen et al. Glomeraceae (49.6%), Acaulosporaceae (24.9%), Claroideoglomeraceae (20.8%), and Gigasporaceae (4.8%), were assessed in five Tectona grandis Linn.f plantations. Each species' plantlets were inoculated in vitro and colonized by all studied AMF. Plants inoculated with AMF were taller than non-inoculated plants, which suggests the possibility of using AMF symbiosis in both reforestation and important tree species production in future greenhouse studies.Regenerating stands of valuable tropical hardwood tree species for sustainable harvest requires the production of seedlings with high probabilities of survival. Chaiyasen et al. Other reports cited by Chaiyasen et al. 4.Sustainable agriculture has increased in recent times, leading to the necessity of new technological developments to reduce environmentally harmful chemical fertilizer and pesticide use. Plant probiotics as an alternative soil fertilization source has been the focus of several studies; their use in agriculture improves nutrient supply and conserves field management and causes no adverse effects Soil microflora mediates many biogeochemical processes, with some species affecting organic matter and soil pollutant biodegradation (rhizoremediators) and abiotic stress tolerance 4.1.Abiotic stresses, such as soil salinization, soil solidification, drought, flooding, soil pH, ultraviolet light, heavy metals, and environmental temperature, are major limiting factors in crop production and are the cause of more than 30% of worldwide losses Under stressful conditions, plants activate a cascade of responses to such situations, which involve primary  and secondary signals (phytohormones and secondary metabolites release). Salinity, nutritional imbalances, and oxidative stress may alter ionic and osmotic plant regulation, while drought affects turgor pressure and biomass production PGPR interaction with other microorganisms and their effect on the plant physiological response is being studied. However, numerous species of PGPR present an enzyme, known as 1-Aminocyclopropane-1-carboxylic acid (ACC)-deaminase, whose role in the hormonal regulation of plants is already well understood Research has shown that plants inoculated with bacteria containing ACC-deaminase show significant increases in high root and biomass due to reduction of ethylene levels, which is beneficial for various stress tolerances Therefore, PGPR, applied as an inoculant in non-favorable soil, may increase microbial diversity, overcoming such problems as abiotic stresses or lack of nutrients and, consequently, improve soil quality, soil health, growth, yield, and crop quality 4.2.As industrial growth has steadily increased, so have environmental pollution levels. Efforts have been made to recover contaminated soil, but conventional hazardous chemical cleanup techniques are both too expensive and harmful to soil microbiota Soil biofertilization with metal-tolerant microorganisms, especially PGPR, has been studied due to their potential for metal bioaccumulation in polluted environments, which enhances metal uptake and promotes plant growth. Microbe-plant association is the main mechanism of bioremediation, which contributes to soil decontamination and plant development Micrococcus luteus, Bacillus licheniformis, and Pseudomonas fluorescens, but only M. luteus showed a significant arsenic toxic effect decrease and improved biomass growth. In another study, Bacillus thuringiensis improved metal accumulation and growth in the species Alnus firma in mine tailings soil. Inoculation with B. thuringiensis increased root length, shoot height, plant biomass, and heavy metal accumulation in roots and shoots when compared with non-inoculated plants, showing the importance of these consortia in protecting the host plant from environmental stresses and highlighting them as a promising alternative in soil, air, and water recovery.In a recent study, researchers 5.Plant-associated microorganism study is important, not only for understanding their ecological role and their interaction with plants but also to enable the biotechnological application of these cultures to crop management 5.1.Culture-based tools have long been used to determine the diversity of microorganisms associated with the most diverse plant systems, such as bananas, strawberries, rice, potatoes, maize, eucalyptus, sorghum, soybeans, and wheat Pantoea, Bacillus, Burkholderia, and Klebsiella. A polyphasic approach was evidenced as being important for grouping and identifying this ecosystem's microorganisms Sequencing conserved regions of microbial DNA has been broadly used in characterizing plant growth-promoting microorganisms 5 primer, was employed to group bacterial endophytes isolated from strawberry fruit 5-rep-PCR-clustered isolates were identified by 16S rRNA gene sequencing as Bacillus subtilis, Bacillus sp., Enterobacter sp., Enterobacter ludwigii, Lactobacillus plantarum, Pseudomonas sp., and Pantoea sp. The study evidenced the REP-PCR technique's promise as a potential genotypic tool for rapid and reliable clustering of plant bacterial endophytes. Other tools also successfully used to cluster plant microbial cultures were: ADRA-PCR in rice roots Different methods, such as BOX-PCR, REP-PCR, RAPD, RFLP, AFLP, and ARDRA, of PCR fingerprinting have been used to group and differentiate microbial species in plant materials. All these methods assume that the DNA variations in a microbial strain can be used for classification. Due to the availability of numerous methods in literature, it is sometimes confusing to choose an appropriate method for a particular analysis for two main reasons: (1) microbial culture grouping prior to sequencing; and (2) microbial strain characterization within a species. REP-PCR technique, using the (GTG)5.2.Culture-dependent approaches, while extremely useful for understanding isolated microorganisms' physiological potential, do not necessarily provide comprehensive information on microbial community composition Telluria mixta, Caulobacter sp., Agromyces cerinus, Afipia genosp., and Pseudomonasagarici) did not have matching sequences from isolates, suggesting that non-culturable or as-yet-uncultured endophytic organisms were detected. On the other hand, Pereira et al. Muyzer et al. Cloning and sequencing the whole community's rRNA genes is another culture-independent approach used to explore natural ecosystems' microbial diversity. Sequencing of such rRNA gene clone libraries is an appropriate tool with which to gain a more precise picture of a given ecosystem's species diversity. These libraries are being used to reveal the microbial diversity associated with plants Recently, several massively parallel sequencing platforms, namely next-generation sequencing (NGS), have revolutionized microbial detection by providing greater depth and rare species detection. NGS platforms include technology from 454 Life Sciences (Roche's 454 pyrosequencing) and Solexa's 1G instrument  Rheinheimera, Dyadobacter, Devosia, Pedobacter, and Pseudoxanthomonas) were, for the first time, reported as endophytes of potato plants. Akinsanya et al. Aloe vera; the analyses revealed a high and complex bacterial diversity, with a predominance of Proteobacteria, Firmicutes, Actinobacteria and Bacteriodetes. Thus, it is evident that NGS technologies have the power to effectively capture microbial diversity in plant tissues, which can improve our understanding of microbial-plant host interactions The new sequencing technologies are making a big impact in plant microbial diversity study 6.Plant probiotic microorganisms (PPM), which are beneficial microorganisms associated with plants, have important function as biofertilizers and biopesticides. The group also contains plant growth promoters (PGP), which are able to stimulate plant growth through different mechanisms including nitrogen, phosphorous or iron fixation, and production of plant hormones. PGP can produce, indirectly, biomolecules as diverse as antibiotics, enzymes, and antimicrobial and pathogen-inhibiting volatile compounds. Molecular characterization and identification of plant-associated microorganisms is very important, not only for understanding their ecological role and plant interactions but also to enable the biotechnological application of these cultures to optimize agriculture productivity."}
+{"text": "Oxidative stress- (OS-) related endothelial damage is involved in the occurrence and progression of several disorders, such as vascular depression and dementia. It has been reported that moderate, aerobic, physical exercise could reduce OS and inflammation, thus limiting the cardiovascular risk factors while improving endothelial homeostasis, mood, and cognition. In this review, we will discuss about the role of OS and OS-related endothelial damage in vascular depression and vascular cognitive impairment. Then, we will comment on the effects of physical exercise on both disorders. The fine balance between ROS and antioxidants, namely, redox homeostasis, is involved in various physiological processes including cellular signaling, gene expression, cellular growth, neurotransmitter release, and synaptic plasticity [During physical exercise, the production of reactive oxygen species (ROS), including hydroxyl radical (OH-), hydrogen peroxide  that, according to the World Health Organization projections, could become the leading cause of disability by 2030 , 16.vascular depression,\u201d subtype of late-life depression frequently predisposed or perpetuated by an ischemic damage of frontosubcortical circuits, emerged [The most frequent depressive symptoms are sad mood, thoughts of guilt, lack of interest, sleep disorders, lack of appetite, psychomotor retardation or agitation, cognitive deficits, and suicidal ideation , 18. Amo emerged . As a ma emerged . WMLs ar emerged \u201329.Vascular endothelium is a single cellular layer that lines the walls of all blood vessels. Releasing both vasodilators  and vasoconstrictors , it regulates the vasomotor tone, thus exerting a fundamental role in the prevention of cerebrocardiovascular disorders . EndotheFirstly, an association between risk factors for endothelial damage  and depression has been reported , 32. MorThe since here discussed molecular alterations could account, at least in part, for the frequent association between depression and neurological conditions  characterized by endothelial dysfunction and inflammation . Concernvascular dementia, recently substituted by the more inclusive term \u201cvascular cognitive impairment\u201d (VCI), encompasses a range of cognitive disorders strictly related to vascular disease [The term  disease . Despite disease . Epidemi disease . The dif disease . Cerebra disease  and is h disease , 57.Vascular brain pathology is anything but rare in the elderly and could cause cognitive deficit ranging from mild cognitive impairment to dementia . From a The pharmacological treatment of depression and dementia in the elderly is frequently complicated by poor compliance, drug side effects, and interactions due to multiple therapies. Therefore, nonpharmacological approaches, as monotherapy or in add-on to pharmacological agents, are receiving increasing interest.\u03b2 plaques and hyperphosphorylated tau protein [Physical exercise exerts beneficial effects in terms of psychological well-being, quality of life, and depressive symptoms . In fact protein . On the  protein . A furth protein . Interes protein  and VCI  protein , 79. Unf protein . Future The previously discussed evidence highlights the beneficial effects of moderate, aerobic, physical exercise in reducing the cerebrocardiovascular risk factors, as well as improving endothelial homeostasis, mood, and cognition. Hence, the elderly should be encouraged to maintain an active lifestyle to reduce the risk of disabilities in late-life."}
+{"text": "TTX and its derivatives are involved in many cases of seafood poisoning in many parts of the world due to their occurrence in different marine species of human consumption such as fish, gastropods, and bivalves. Currently, this neurotoxin group is not monitored in many parts of the world including in the Indian Ocean area, even with reported outbreaks of seafood poisoning involving puffer fish, which is one of the principal TTX vectors know since Egyptian times. Thus, the main objective of this review was to assess the incidence of TTXs in seafood and associated seafood poisonings in the Indian Ocean and the Red Sea. Most reported data in this geographical area are associated with seafood poisoning caused by different species of puffer fish through the recognition of TTX poisoning symptoms and not by TTX detection techniques. This scenario shows the need of data regarding TTX prevalence, geographical distribution, and its vectors in this area to better assess human health risk and build effective monitoring programs to protect the health of consumers in Indian Ocean area.Tetrodotoxin (TTX) is a potent marine neurotoxin with bacterial origin. To date, around 28 analogs of TTX are known, but only 12 were detected in marine organisms, namely TTX, 11-oxoTTX, 11-deoxyTTX, 11-norTTX-6(R)-ol, 11-norTTX-6(S)-ol, 4- The tropical and subtropical climates predominant in the Indian Ocean zone, accompanied by industrialization and population increase, are pointed to as the main factors that, together with eutrophication, contribute to the development of toxic phytoplankton blooms\u2014harmful algal blooms (HABs) and bacteria . HABs anPolypedates sp., Atelopus sp., Taricha granulosa, [Cynops ensicauda popei [Serratia marcescens [Vibrio alginolyticus, V. parahaemolyticus, Aeromonas sp. [Microbacterium arabinogalactanolyticum [Pseudomonas sp. [Shewanella putrefaciens [Alteromonas sp. [Pseudoalteromonas sp. [Nocardiopsis dassonvillei [TTX  is a potanulosa,  and Cynoda popei  was repoda popei ,49. TTX da popei . In the rcescens , Vibrio onas sp. , Microbaolyticum , Pseudomonas sp. , Shewaneefaciens , Alteromonas sp. , Pseudoaonas sp. , and Noconvillei . Physicoonvillei ; thus, tepiTTX, 4,9-anhydroTTX, 5,6,11-trideoxyTTX [To date, around 28 analogs of TTX were described  and somedeoxyTTX , 4-CysTTdeoxyTTX ,55,56,57deoxyTTX , and theThe action mechanism of TTXs occurs through the occlusion of the external pore of site 1 of voltage-gated sodium channels on the surface of nerve membranes, blocking cellular communication and causing death by cardio-respiratory paralysis . ParalysCurrently, there is no antidote for TTX; however, some studies indicate that the application of activated charcoal could help in reversing the clinical stage of poisoning victims since it reduces the toxin free amount . Also, aSeveral methodologies were developed to analyze TTXs and, in recent years, chemical methods became more popular due to their sensitivity with limits of detection (LODs) ranging from 0.9 ng to 0.063 \u03bcg. Liquid chromatography with tandem mass spectrometry (LC\u2013MS/MS) techniques, the first choice compared to mouse bioassays (MBAs) and enzymatic methods due to their greater sensitivity and specificity, have the capacity to detect and determine TTXs in complex matrices . Also, dMethods for TTX analysis and their respective limits of quantification (LOQs) and detection (LODs) are described in Arothron hispidus in India [Takifugu oblongus in Bangladesh [Lageocephalus scitalleratus in Singapure [Pleuranacanthus sceleratus in Egypt [Chelonodon pataca, Sphaeroides oblongus, Lagocephalus inermis, and Lagocephalus lunaris in India [Xenopterus naritus in Malaysia [Arothron stellatus in India [Tetractenos hamiltoni in Australia [Tetroadon sp. [Tetraodon nigroviridis, and Arothron reticularis in Thailand [Charonia lampas [Gibbula umbilicalis, and Monodonta lineata on the Portuguese coast [Nassarius spp. in China [Polinices didyma, Natica lineata [Oliva miniacea, O. mustelina, and O. nirasei [Charonia sauliae [Babylonia japonica [Niotha spp. [Tutufa lissostoma [Demania cultripes, Demania toxica, Demania reynaudi, Lophozozymus incises, Lophozozymus pictor, Atergatis floridus [Atergatopsis germaini [As described in the introduction section, TTXs were reported in several marine organisms , regardiin India , Takifugngladesh ,33 and Ingladesh ,62, Lageingapure , Pleuranin Egypt ,34,37, Rin Egypt , and Ausin Egypt ,24, Chelin India ,62, XenoMalaysia , Arothroin India , Tetractustralia ,100, andadon sp. , TetraodThailand . The reca lampas , Gibbulase coast , Nassariin China , Polinic lineata ,101, Oli nirasei  in Taiwa sauliae , Babylonjaponica , Niotha tha spp. ,81, and ssostoma  in Japanfloridus , and Ategermaini , highliggermaini . Data onTTX data in the Indian Ocean and Red Sea are usually related to fatal outbreaks due to seafood poisoning and not to scientific research, indicating the lack of MT monitoring programs. The symptomatology reports and MBA are used to identify seafood poisoning caused by TTX and analogs, indicating the need for analytical methods such as liquid chromatography to obtain better quantitative data. Both symptomatology and MBA in isolation are not enough to conclude that TTXs are the causative agent of seafood poisoning, since there are other toxins (PSTs) with similar action mechanism that overlap in symptomatology with TTX poisoning. Additionally, MBA cannot discriminate between the different TTX analogs. MBA and symptomatology are used in countries of the Indian Ocean and the Red Sea to identify TTX poisoning due to the lack of availability and accessibility to chemical methods and the absence of TTX monitoring programs. Arothron hispidus, Takifugu oblongus, Lageocephalus scitalleratus, Pleuranacanthus sceleratus, Chelonodon patoca, Sphaeroides oblongus, Lagocephalus inermis, Lagocephalus lunaris, Xenopterus naritus, Arothron stellatus, Tetractenos hamiltoni, Tetraodon nigroviridis, Arothron reticularisand, Charonia sauliae, Babylonia japonica, Niotha spp., and Tutufa lissostoma, since they are most consumed and are already confirmed to be vectors of TTX in the Indian Ocean and the Red Sea. These species can be used as indicators for monitoring programs using the maximum limit permitted of 2 mg\u00b7kg\u22121 (from Japan).Thus, the implementation of monitoring programs using chemical analytical methods such as LC\u2013MS/MS instead of MBA in the Indian Ocean and the Red Sea is urgently needed in different species of shellfish and puffer fish, including"}
+{"text": "Chlamydomonas eustigma, Gonium pectorale and Coccomyxa subellipsoidea, the charophyte algae Coleochaete orbicularis and Klebsormidium flaccidum, the bryophyte Sphagnum fallax, the marchantophyte Marchantia polymorpha and the gymnosperm Pinus taeda, which have been not formerly analyzed. In addition, an analysis of similarity scores among representatives of the clusters recognized in photosynthetic green organisms  is performed as well as an analysis of membrane topology for them.In this data article, information is provided on sequences of KT-HAK-KUP transporters from green algae and basal land plants. A data set is offered containing sequences corresponding to the chlorophyte algae  Specifications TableValue of the data\u2022Coccomyxa subellipsoidea, Chlamydomonas eustigma, Gonium pectorale, Sphagnum fallax, Marchantia polymorpha, Pinus taeda, Coleochaete orbicularis and Klebsormidium flaccidum and a new sequence for Chlamydomonas reinhardtii. The data set is complemented with sequences already examined for Chlamydomonas reinhardtii, Physcomitrella patients, Selaginella moellendorffii, Picea abies, Amborella trichopoda, Arabidopsis thaliana, Prunus persica, Oryza sativa and Zea mays.Data presented correspond to sequences of KT-HAK-KUP transporters retrieved from public databases which have been not formerly analyzed for the organisms \u2022These sequences can be used to build up phylogenetic trees and to perform complementary analyses based on them. In this data article, they have been used to analyze the similarity scores in pair comparisons among members of different KT-HAK-KUP clades as well as to predict their possible topology.1Coccomyxa subellipsoidea, Chlamydomonas reinhardtii, Chlamydomonas eustigma, Gonium pectorale, Sphagnum fallax, Marchantia polymorpha, Pinus taeda, Coleochaete orbicularis and Klebsormidium flaccidum is provided in Physcomitrella patients, Selaginella moellendorffii, Picea abies, Amborella trichopoda, Arabidopsis thaliana, Prunus persica, Oryza sativa and Zea mays , which have been used to construct a phylogenetic tree of KT-HAK-KUPs in green algae and land plants Arabidopsis thaliana is provided  at https://mafft.cbrc.jp/alignment/server/index.html. Pair comparisons of similarity among representatives of the 12 clades, and subgroups of clades II and XII, were performed at https://www.ebi.ac.uk/Tools/psa/emboss_needle/. In order to advance on the structure of these putative transporters four services for the prediction of transmembrane domains were used to predict the transmembrane domains of KUP . These prediction services were next used to analyze the possible topology of potential representatives of the above mentioned clades of green photosynthetic organisms.Sequences corresponding to the chlorophytes"}
+{"text": "Stomatitis is occasionally multiple, recurrent, and refractory. Currently, mucositis induced by chemotherapy and radiation therapy in patients with cancer has become a significant clinical problem. Effective treatments have not been established and the treatment of numerous cases remains a challenge for physicians. Traditional Japanese herbal medicines termed Kampo formulae  are used for treating various types of stomatitis and mucositis. Its use has been based on the Kampo medical theories\u2014empirical rules established over thousands of years. However, recently, clinical and basic research studies investigating these formulae have been conducted to obtain scientific evidence. Clinical studies investigating efficacies of Shosaikoto and Orento for the treatment of cryptogenic stomatitis and acute aphthous stomatitis and those investigating the effects of Hangeshashinto, Orengedokuto, and Juzentaihoto on chemotherapy- or radiotherapy-induced mucositis have been conducted. The Kampo formulae comprise several crude drugs, whose mechanisms of action are gradually being clarified. Most of these drugs that are used for the treatment of stomatitis possess anti-inflammatory, analgesic, and antioxidative properties. In this review, we introduce the clinical applications and summarize the available evidence on the Kampo formulae for the treatment of stomatitis and oral mucositis. Stomatitis is a sore and often recurrent inflammatory condition of the oral mucosa, characterized by various symptoms such as the presence of vesicles, erosions, aphthae, and ulcerations. Stomatitis is caused by various factors such as viral, fungal, and bacterial infections, allergic reactions, loose-fitting dental prosthetics, and systemic diseases. Occasionally, stomatitis is multiple, recurrent, and refractory. Currently, mucositis induced by chemotherapy and radiation therapy in patients with cancer has become a significant clinical problem . The paiKampo formula, a traditional Japanese herbal medicine, has its root in ancient Chinese medicine, and the antecedent form of medicine was introduced to Japan between the 5th and 6th century. It was developed into an individual form of medicine adapting the constitutions of the Japanese people. Kampo formulae have been reported to be effective for the treatment of stomatitis and mucositis ,3. The oAstragali Radix, Scutellariae Radix, Phellodendri Cortex, Coptidis Rhizoma, Glycyrrhizae Radix, Bupleuri Radix, Paeoniae Radix, Artemisiae Lanceae Rhizoma, Cimicifugae Rhizoma, Cnidii Rhizoma, Angelicae Radix, and Poria exert anti-inflammatory effects. Moreover, Cinnamomi Cortex, Cimicifugae Rhizoma, Paeoniae Radix, Glycyrrhizae Radix, Cnidii Rhizoma, Angelicae Radix, Zingiberis Rhizoma Processum, and Magnoliae Cortex exert analgesic effects . The. The4].  effects . The occ effects . Therefo effects  assessedCinnamomi Cortex, Scutellariae Radix, Glycyrrhizae Radix, Astragali Radix, Coptidis Rhizoma, and Phellodendri Cortex inhibit several bacterial infections. Moreover, Cinnamomi Cortex, Scutellariae Radix, and Anemarrhenae Rhizome exert antifungal effects. Furthermore, Scutellariae Radix and Glycyrrhizae Radix have been shown to inhibit viral infections [In addition, fections .In Kampo medicine, the approach to the treatment of stomatitis differs depending on the nature of the symptoms . Furthermore, the most appropriate treatment is determined according to the presence of oral and general symptoms. The effectiveness of each Kampo formula according to the pathognomonic symptoms of patients is shown in Use of the Kampo formulae has been based on the Kampo medical theories\u2014empirical rules established over thousands of years. In recent years, clinical and basic research studies investigating the Kampo formulae have been performed to obtain scientific evidence.For our literature review, PubMed  and ICHUSHI  were used to identify relevant evidence. Reports of clinical studies  identified through this search are summarized in Ogino, et al.  showed tp < 0.0001). Moreover, the incidence of diarrhea was significantly lower . HST has been administered for the treatment of chemotherapy-induced mucositis in patients with various types of cancers, such as colorectal [p = 0.0012). Aoyama, et al. [p = 0.41). The median duration of grade \u2265 2 mucositis was 5.5 days versus 10.5 days, respectively (p = 0.018). Nishikawa, et al. [p = 0.072). Yoshida, et al. [Currently, there are effective treatment options for chemotherapy- or radiotherapy-induced stomatitis. HST exerts a preventive effect against these types of stomatitis. Yuki, et al.  administlorectal ,15,16,17lorectal , and renlorectal . In all lorectal  reported, et al.  conducte, et al.  also admp < 0.121)). The clinical use of HST for the treatment of radiation-induced stomatitis has also been reported [A previous study investigated the administration of JTT for the treatment of radiation-induced stomatitis in patients with oral cancer, in whom oral ingestion was not possible (n = 15) . The meareported .2, interleukin-6, and interleukin-1\u03b2, and upregulates cyclooxygenase (COX)-2 in submucosal fibroblasts and endothelial cells leading to mucosal ulceration [Stomatitis and oral mucositis are induced by various factors, such as infection, inflammation, concomitant oxidative stress, suppressed immunity, depressed function of the digestive tract, malnutrition, psychological stress, and physical stress. Regarding chemotherapy- and radiotherapy-induced mucositis, these treatments induce DNA and non-DNA damage that results in injury of basal epithelial, submucosal, and endothelial cells. In response to this damage, oxidative stress results in the formation of ROS. The presence of ROS damages cell membranes, induces proinflammatory cytokines such as tumor necrosis factor-\u03b1, prostaglandin (PG) Eceration ,24. Furtceration .Hitomi, et al.  conducteScutellariae Radix, Glycyrrhizae Radix, Zizyphi Fructus, Ginseng Radix, Pinelliae Tuber, Zingiberis Rhizoma Processum, and Coptidis Rhizoma. These constituents, except Pinelliae Tuber, exert antioxidative effects [Glycyrrhizae Radix, Ginseng Radix, and Zizyphi Fructus demonstrated scavenging activity for hydroxyl radical, while Scutellariae Radix, Glycyrrhizae Radix, Zingiberis Rhizoma Processum, and Coptidis Rhizoma eliminated superoxide. Moreover, Scutellariae Radix and Coptidis Rhizoma have been shown to eliminate nitroxyl radical.As mentioned earlier in this review, the main characteristic of the Kampo formulae is the combination of several crude drugs . These c effects ,28. MatsScutellariae Radix , Pinelliae Tuber (homogentisic acid), Zingiberis Rhizoma Processum  [Glycyrrhizae Radix [Pinelliae Tuber [Coptidis Rhizoma [Ginseng Radix may enhance immunity. In particular, Ginseng Radix was reported to increase the activity of natural killer cells in mice treated orally with it [Regarding its antibacterial action, in vitro studies demonstrated that HST extract inhibited the growth of Gram-negative bacteria including Fusobacterium nucleatum, Porphyromonas gingivalis, Porphyromonas endodontalis, Prevotella intermedia, Prevotella melaninogenica, Tannerella forsythia, Treponema denticola, and Porphyromonas asaccharolytica. However, these inhibitory effects were less pronounced in Gram-positive bacteria and Candida albicans. These effects are thought to be induced by ocessum (-shogaol)ptisine) . Furtherae Radix ,31, Pine Rhizoma , and Gin with it ,34.2 and suppressed the expression of COX-2 protein. In vitro studies show that Scutellariae Radix, Glycyrrhizae Radix, Zingiberis Rhizoma Processum, and Coptidis Rhizoma are involved in these effects [+ channels by components of Zingiberis Rhizoma Processum ([Ginseng Radix extract demonstrated an acceleration of substance permeability into the tissue of the oral ulcer and enhanced the analgesic action of Zingiberis Rhizoma Processum [Scutellariae Radix\u2014alleviated mechanical allodynia in rats with cancer-induced bone pain [Glycyrrhizae Radix\u2014ameliorated inflammatory pain by inhibiting the microglial activation-mediated inflammatory response in mice with inflammatory pain [Regarding its anti-inflammatory effect, HST inhibited the production of PGE effects ,36,37,38 effects  and subsrocessum . Baicaleone pain . Glycyrrory pain . HST indIn general, western medicines such as steroid ointments, nonsteroidal anti-inflammatory drugs, and antiviral and antifungal drugs are applied for stomatitis and oral mucositis according to the causes and symptoms. In contrast to western medicines which generally include a single component, the Kampo formulae contain multiple components and their effects are exerted through complex mechanisms of action. Use of the Kampo formulae may be an alternative treatment option for patients who failed to respond to conventional therapies. In addition, the concomitant use of Kampo formulae with western medicines may be useful. Kobayashi  reported"}
+{"text": "We thank Moneim and colleagues for calling attention to the issue of gender inequality in MS clinical trial steering committees and in authorship on publications emerging from phase 3 clinical trials.Moneim and colleagues observed that women have been historically underrepresented as first and last authors on publications from phase 3 clinical trials in MS sponsored by pharmaceutical companies, which tend to repeatedly choose a select group of academicians to serve as authors.Gender discrimination is costly, not only from a personal career perspective, but because it excludes or delays important contributions from skilled, talented individuals. This can affect progress toward a better understanding of the pathogenesis and treatment of neurological diseases, including MS.Develop structured opportunities to foster greater awareness of gender\u2010based imbalances and existing biases, including implicit or unconscious bias. This can occur on a committee level in professional organizations and should include representatives from pharmaceutical companies. The primary goal would be to establish task forces charged with gathering and analyzing data on gender concerning:aClinical trial leadership, including clinical trial steering committees, data safety monitoring boards, authorship committees, and other active committees.bParticipation by physicians and basic scientists on editorial boards and grant review panels and in scientific programs, professional organizations, and academic institutions, including neurology departments, as well as in other relevant entities.Establish specific goals toward achieving equal representation by women at all levels in a timely fashion.aDevelop mechanisms to track and regularly review progress toward these goals, with an ultimate goal of achieving and maintaining gender parity.bCreate mechanisms to report inequalities and encourage continued efforts to raise awareness.cDevelop mechanisms to recognize and celebrate contributions from women.dPromote efforts to support and mentor women  Benveniste, Jill Conway, Ilana Katz Sand, Jennifer Orthmann Murphy, Mariko Kita, Claire Riley, Joan M. Goverman, Annette M. Langer\u2010Gould, Christina J. Azevedo, Idanis Berrios Morales, Lisa F. Barcellos, Elizabeth Crabtree, Prue Plummer, Afsaneh Shirani, Katherine Whartenby, Fabienne Brilot\u2010Turville, Elaine Kingwell, Patricia Coyle, Ellen Mowry, Rana Zabad, Bibi Bielekova, Nancy Monson, Cornelia Laule, Margaret Burnett, Teri Schreiner, Judith Grinspan, Ruth Dobson, Katerina Akassoglou, Jennifer Graves, Orla Gray, Penelope Smyth, Eva Kubala Havrdova, Jana Lizrova Preiningerova, Brenda Banwell, Naila Makhani, Claudia Lucchinetti, Georgina Arrambide, Elisabeth Maillart, Wendy Macklin, and Wendy Gilmore on behalf of the International Women in MS.The information in the letter is the opinion of the consignees and may not necessarily reflect a policy of their institutions.Nothing to report."}
+{"text": "To present a case of granulomatous perioral dermatitis (GPD) withextra-facial involvement and good response to short-term treatment with oralmacrolide. A 9-year-old girl presented with exuberant GPD with extra-facialinvolvement. During follow-up, she received multiple ineffective therapies,but showed significant improvement of the lesions after the use ofazithromycin for five days. GPD is an inflammatory dermatological condition represented bypapulo-erythematous eruptions on perioral, nasal and periorbital regions,more prevalent in children and adolescents. It rarely extends to the genitalregion, trunk, and extremities, which characterizes its extra-facialmanifestation. Its etiology is unknown, but it seems to have a correlationwith the use of topical corticosteroids and other agents. Clinically,it is characterized by the presence of monomorphic, erythematous micro-papules,usually asymptomatic, which affect the central region of the face, especially theareas around oral, nasal and orbital cavities.Its etiology remains controversial and its course is limited, but, since it causesimportant facial and esthetic impairment, in most cases treatment is advisable.This study aims to describe a case of GPD with extra-facial manifestation whichpresented good therapeutic response to a short-term treatment with oralmacrolide.A 9-year-old female black-skinned patient presented with monomorphic,erythematous/desquamative papular eruptions grouped in perioral and periorbitalregions for a year, with late progression onto the genital region , not accDue to the exuberance of lesions, the patient was experiencing important sociallimitation, pictured by her distancing from groups of children\u2019s recreation, partiesand school environment. Over the disease course, multiple treatments were tried,including corticosteroids, imidazole and topical immunomodulators and systemicantibiotic therapy with cephalosporins, but lesions had no remission.Histopathological examination of a facial skin sample showed chronic andgranulomatous findings. Dermal edema, vascular ectasia and lymphohistiocyticinflammatory infiltrates were noted around sebaceous follicles, configuring smallgranulomas surrounded by occasional neutrophils .The initial presentation was devoid of symptoms, but the previous use of multipletopical agents caused local irritation, burn and pinching complaints. Topicaltacrolimus 0.03% was prescribed under monotherapy, with significant improvement oferythema after one month. The appearance of new lesions in upper trunk and leftupper limb in spite of the satisfactory facial response to therapy, led to theassociation of oral azithromycin, 320mg/day for five days, which finally provideddisease remission .,First described in 1970 by Gianott,An acneiform, micro-papular, monomorphic, erythematous eruption of reddish color,which may present yellow-brownish with fine surface scaling, is described in GPD.Lesions spread around the mouth and nose, rarely affecting other parts of the bodysuch as neck, upper trunk, genital region or gain generalized distribution.Candida spp, demodex), fluoride toothpaste, chewing gums,amalgams, mercury, UVB radiation, and oral, topical and/or inhalationalcorticosteroids.,The etiology is still controversial, although some factors that would be related tothe onset of symptoms have been proposed, such as infectious agents. This, however, shows up in adolescents and young adults as papulessymmetrically distributed across the face and caseum granuloma on histopathologicalexamination, and healing with scar formation.,The initial treatment is removal of the causative agent, when it is identified.Topical antibiotics, mainly lotion or 0.75-1.00% metronidazole gel, have been thechosen treatment in most cases.Immunomodulatory agents are a more moisturizing vehicle compared to topicalmetronidazole, and because of its immunomodulatory activity it does not requirecorticosteroids. Extensive cases may require systemic antibiotic therapy, withtetracycline as well as second generation tetracyclines  being usually proposed. In cases ofcontraindication to tetracyclines, such as children younger than nine years old, dueto teeth enamel discoloration and poor bone formation, the use of macrolides such aserythromycin and azithromycin has shown good results."}
+{"text": "Homo species, ran to survive. This legacy is reflected in many deeply and irrevocably embedded neurological and biological design features, features which shape how we run, yet were themselves shaped by running.Over the expanse of evolutionary history, humans, and predecessor Smoothness is a widely recognised feature of healthy, proficient movement. Nevertheless, although the term \u2018smoothness\u2019 is commonly used to describe skilled athletic movement within practical sporting contexts, it is rarely specifically defined, is rarely quantified and remains barely explored experimentally. Elsewhere, however, within various health-related and neuro-physiological domains, many manifestations of movement smoothness have been extensively investigated. Within this literature, smoothness is considered a reflection of a healthy central nervous system (CNS) and is implicitly associated with practiced coordinated proficiency; \u2018non-smooth\u2019 movement, in contrast, is considered a consequence of pathological, un-practiced or otherwise inhibited motor control.Despite the ubiquity of running across human cultures, however, and the apparent importance of smoothness as a fundamental feature of healthy movement control, to\u00a0date, no theoretical framework linking the phenomenon of movement smoothness to running proficiency has been proposed. Such a framework could, however, provide a novel lens through which to contextualise the deep underlying nature of coordinated running control. Here, we consider the relevant evidence and suggest how running smoothness may integrate with other related concepts such as complexity, entropy and variability. Finally, we suggest that these insights may provide new means of coherently conceptualising running coordination, may guide future research directions, and may productively inform practical coaching philosophies. Smoothness is a universal feature of healthy skilled movement which, although infrequently considered and currently under-appreciated within sporting contexts, may provide a unique window into athletic coordinative proficiency.Existing evidence illustrates that smoothness changes as a consequence of natural aging, general health status, practice and injury history and current fatigue and injury status. Preliminary research suggests that running proficiency is reflected in smoother running movement.Recent advances in wearable technologies provide the opportunity to sensitively detect changes in running smoothness, thereby potentially bestowing unique insights into running coordination proficiencyDuring his tenure as a US Supreme Court justice, Potter Stewart presided over many high profile cases. He, for example, promoted personal privacy protections and extended the 1866 Civil Rights Act to concede that schools should not discriminate on the basis of race. Outside of legal contexts, however, he is best remembered for a single clause, from a single sentence. While adjudicating on the legality of the state of Ohio\u2019s banning of an allegedly pornographic film, Stewart uttered perhaps the most famous phrase in the Supreme Court history, \u2018I shall not today attempt further to define the kinds of material I understand to be embraced within that shorthand description [\u201chard-core pornography\u201d], and perhaps I could never succeed in intelligibly doing so. But I know it when I see it \u2026 [The topic explored in this article, we suggest, shares these features in that although, superficially, it appears intuitively obvious and readily apparent; when we attempt to explain exactly what \u2018it\u2019 is, we find that beneath this facade of familiarity lies a phenomenon that remains inadequately defined and poorly understood.Across a diversity of literatures, and within practical coaching contexts, movement smoothness is generally recognised as a universal feature of skilled motor behaviour . Yet, deThe minimum-jerk model, first proposed by Flash and Hogan, suggested that human movement is executed in a manner that optimises smoothness by minimising its opposite, kinematic jerk . AlthougFrom a practical coaching perspective, however, we can sensibly broaden this definition by proposing that smooth movements are those without abrupt, intermittent, discontinuous changes in accelerations, relative joint positions and/or movement trajectories. Accordingly, although movements may occur rapidly, unexpectedly, even violently, there is a sense of consistent flow, of finely regulated progression and seamlessly continuous coordinative control. Thus, key dimensions of movement\u2014postural control, relative joint positions, the absorption of impacts\u2014all appear to rhythmically and incrementally rise and fall. Visually, accordingly, we register a sense of fluency as the athlete dynamically progresses through a given movement sequence. Non-smooth movements, in contrast, leave an impression of abruptness, of erratic discordance and of disjointed, unpredictable control.Smoothness seems intuitively recognised as a hallmark of skilled, coordinated movement . NeverthNotably, recent advances in accelerometer technology now provide access to raw, unfiltered acceleration time series that can readily be converted to jerk data. Surprisingly, however, this research topic has received very little attention within sports science contexts. In attempting to enhance our appreciation of this potentially important, yet largely ignored phenomenon, here, we examine the general evidence relating to movement smoothness, before subsequently reflecting on how these insights may contribute to a more robust understanding of running coordination.Smoothness increases progressively as we transition from infant, to developing child, to mature adult, and regresses as we move from adult maturity into old age \u201311. FurtMany dimensions of declining function are, conversely, reflected in the deterioration of movement smoothness. Most obviously, smoothness is compromised following neurological damage, such as stroke, and subsequent recovery is typified by the gradual restoration of smoother movement . This efAdditionally, smoothness measures can discern between those who have previously suffered cervical injury and non-previously injured controls , betweencost function. Historically, it was assumed that the most heavily prioritised cost function, shaping movement control, was energetic expenditure [Several theories of motor control hypothesise that the brain coordinates muscle activation patterns to minimise a single, task-relevant enditure . Recent enditure , 33. Modenditure . Neverthenditure . In factenditure , 37. Thuenditure .Nevertheless, although various rationales have been proposed within the relevant literatures, the reasons why smoothness is such a fundamental feature of healthy movement remain unclear. Previous research suggested that smoothness, during ground contact events, is an indirect consequence of the CNS\u2019s preference to employ single activation signalling bursts to individual muscles . The autMore recent work, however, has proposed that smooth movements are inherently more predictable than less smooth, more erratic ones . A more Non-smooth  movements, in contrast, are inherently less predictable . This diIn summary, more precise predictability facilitates a finer calibration between current preparation for soon-to-be-imposed demands and the likely extent of those challenges. Smooth movements, as they require smaller on-line course corrections, minimise the disruptive effects of signal-dependent noise emerging as a natural consequence of larger motor commands . ConsequLocomotion is initiated by commands originating in the motor cortex . These dTop-down, supra-spinal executive directionSpinally located CPGs and stabilisation reflexesThe bottom-up, self-stabilising capacities afforded by the innate perturbation-resilient characteristics of bio-composite tissue structures Inevitably, however, neural and reflex-activating feedback and feedforward loops take time and cannot instantaneously respond to imposed perturbation. Proficient execution of impact-dependent movements\u2014walking, running, jumping\u2014thus requires that the earliest remedial compensations, upon ground contact, are mediated by the practiced manipulation of the intrinsic material and structural properties of biological tissue collectives , 42, 44.When operating effectively, feedback and feedforward information is blended with the plastically embedded legacy of prior experience, to facilitate the skilled deployment of robust, task-conditioned, bio-composite tissue capacities. The fusion of these multi-level control systems underpins the runner\u2019s ability to sensitively detect and respond to upcoming perturbations in ways that minimally disrupt rhythmical locomotion. Smoothness thus emerges as a natural outcome of this intimate integration between accurate anticipation of upcoming perturbations and the advance remediation of forecasted de-stabilisations , 47.Within a number of academic literatures, smoothness is acknowledged as a fundamental characteristic of goal-directed human movement , 48. AltSpecifically, in relation to running, however, empirical insights remain sparse. An early study, by Hreljac, used video analysis techniques to determine runner\u2019s jerk-cost at ground contact and established that competitive runners ran more smoothly than recreational runners . SubsequJAMA paper proposing the loss of complexity hypothesis, suggesting that, as we age, the complexly intertwined neural and biological foundations, which support all essential neurophysiological processes, gradually and progressively degrade [entropy\u2014a means of analysing the complexity inherent in a data time series\u2014have demonstrated that running-induced fatigue changes the complexity of the acceleration signals emanating from sensors attached to a site approximating centre of mass (CoM) [In 1992, Lipsitz and Goldberger published an influential, and much cited,  degrade . Through degrade \u201354. Intess (CoM) \u201357.Translating the loss of complexity hypothesis to running contexts suggests that reductions in underlying neurobiological complexity diminish the spectrum of viable movement permutations capable of equitably providing equivalent stride outcomes for a comparable \u2018cost\u2019. Accordingly, changes in signal complexity are interpreted as reflecting a contracting range of available micro-movement permutations capable of collaboratively solving the running-imposed challenge . ConsequThe relevance of this rationalisation, to the topic of running smoothness, is to suggest that diminishing neurobiological complexity\u2014induced, for example, by fatigue, prior injury, pain sensitization and/or age-related decline\u2014drives deteriorating coordinative control and the subsequent erosion of running smoothness , 58, 59.i.As the plastically embedded legacies of past cycles of injury, misuse, disuse and overuse accumulate within the CNS, the micro-structures underpinning neuronal connectivity progressively degrade, and available complexity contracts , 58, 59.ii.Declining muscular strength\u2014driven by neural signalling decrements, decreasing muscle mass and the degradation of tissue micro-structures\u2014necessitates that, to adequately execute a task requiring a given movement force, weaker muscles require more relative activation, and hence larger activation signals than stronger muscles , 66. IneAs a direct consequence, this diminished sensorimotor capacity impedes optimal preparation for upcoming ground contact and detracts from the sensitive calibration of running stiffness to the precise demands of the impact challenge , 59. ConAs multiple aspects of sensorimotor control\u2014sensory acuity, activation accuracy and the load management capacity of biological tissues\u2014erode, subsequent to the accumulating legacy of past insults, underlying complexity inevitably deteriorates. Accordingly, the spectrum of available coordinative responses to running-imposed mechanical challenges declines , 68; conUnderlying health status Training and injury historyCurrent fatigue and/or psycho-emotional statesSmoothness is modified by a range of factors, including:Smoothness progresses and regresses as a function of normal maturation and aging, injury and subsequent recovery, and declining smoothness exposes tissues to exacerbated mechanical stressSmoothness is a product of proficient coordination, mediated by the CNS, and actioned via the skilled deployment of the innate perturbation-resilient capacities of robust biological tissuesConceptually, smoothness seems an important facet of proficient running and a potential sensitive indicator of injury or fatigue-induced running deterioration. Clearly, however, evidence is lacking and the topic remains under-explored. We can, however, draw some speculative, but logical, initial conclusions:The opportunity to more fully explore the associations between fatigue, prior injury and running smoothnessThe prospect of analysing acceleration time series using entropy-based techniques to better illuminate the hypothesised relationships between complexity, inter-stride variability, running proficiency and prior injury profilesThe proposition that enhanced accelerometer technology, entropy analysis techniques and the current availability of extensive computational capacity all suggest that we may be on the threshold of a transformation in how we conventionally devise, prescribe and monitor fatigue within running training contextsGiven the recent evolution and current ubiquity of lightweight and sensitive accelerometer sensor technology, the evidence and rationalisations provided here also point towards potentially fruitful future research directions, highlighting, for example:Specifically, in relation to targeting running smoothness within training design and prescription contexts, beyond the general observation that running practice\u2014under healthy, non-fatigued conditions\u2014appears to enhance smoothness, there are no specific evidence-led guidelines. Speculation based on the sparse existing evidence does, however, hint that while practice improves, excessively repetitive practice leads to deteriorating neural communications and declining movement smoothness , 54. AccEngaging in the simple act of running at a range of paces and/or at target race pace under healthy, non-fatigued and non-sensitised conditionsEngaging in running-related challenges promoting an enhanced calibration between feedforward activation and proprioceptive information by providing non-habituated, coordination challenges capable of stimulating neuro-plastic re-modelling processes serving to refine communicative clarity between CNS and the peripheral musculature , 70, 71Engaging in training strategies serving to upgrade the structural and material resilience of biological tissues habitually subjected to mechanical stress during running activities , for exaFrom a conditioning perspective, again, evidence is lacking and once more we are limited to theory-based speculation. Building on the rationale presented here, and elsewhere , we suggSmoothness is a product of the collaborative triangulation between accurately interpreted sensory feedback and sensitively adjusted feedforward activation, contextualised against plastically embedded prior learning. As physical capacities and movement experiences accumulate, we innately gravitate towards smoother movement solutions as we learn to more sensitively respond to small perturbations, thereby offsetting the need to periodically and \u2018jerkily\u2019 respond to the larger challenges that would emerge if minor errors were allowed to accumulate. Smoothness thus reflects sensorimotor coordination and provides a quantifiable window into movement proficiency .The rapid evolution of wearable micro-technology provides us with opportunities to accurately, and non-invasively, evaluate running smoothness. Currently, however, although evidence strongly suggests smoothness metrics provide insights into coordination proficiency, and can be used as markers of neuro-rehabilitation effectiveness, the most appropriate means to measure, monitor and analyse smoothness remain unclear , 48.And so, just as Potter Stewart struggled to eloquently articulate the essence of a phenomenon as superficially self-evident as pornography, within both practical and theoretical running contexts, we similarly struggle to define and describe a phenomenon as intuitively familiar, yet as seemingly important as running smoothness. Although preliminary evidence demonstrates the informational value of smoothness assessments, such measures exist only on the periphery of our sporting cultural consciousness and remain poorly articulated, poorly understood and poorly explored.Pornography may forever remain subjectively ambiguous and objectively unquantifiable, but that need not be the case with running smoothness. Yet, as discussed, an evidence-led logic supports the potential worth of objective smoothness evaluations, and currently, there is ready access to technologies enabling such evaluations. And while, unquestionably, much remains to be clarified and further research is  necessary, the background and rationale outlined here serves as a useful conceptual starting point from where to begin this exploration."}
+{"text": "Background: Solid dispersions are an effective formulation technique to improve the solubility, dissolution rate, and bioavailability of water-insoluble drugs for oral delivery. In the last 15 years, increased attention was focused on this technology. There were 23 marketed drugs prepared by solid dispersion techniques. Objective: This study aimed to report the big picture of solid dispersion research from 1980 to 2015. Method: Scientific knowledge mapping tools were used for the qualitative and the quantitative analysis of patents and literature from the time and space dimensions. Results: Western Europe and North America were the major research areas in this field with frequent international cooperation. Moreover, there was a close collaboration between universities and industries, while research collaboration in Asia mainly existed between universities. The model drugs, main excipients, preparation technologies, characterization approaches and the mechanism involved in the formulation of solid dispersions were analyzed via the keyword burst and co-citation cluster techniques. Integrated experimental, theoretical and computational tools were useful techniques for in silico formulation design of the solid dispersions. Conclusions: Our research provided the qualitative and the quantitative analysis of patents and literature of solid dispersions in the last three decades. With the increasing discovery of water-insoluble Active Pharmaceutical Ingredients (APIs) high throughput screening, combinatorial chemistry and computer-aided drug design were extensively applied in formulation design since 1980 ,3,4,5,6,Mapping approach establishes bibliometric maps for the description of the concept formation, development and social structure of a specific research field or a scientific domain . It coulDue the increased interest in solid dispersions, this paper aims to provide a big picture of the solid dispersion area from 1980 to 2015 by analyzing the patents and literature in the research field of solid dispersions. The analytical topics included the characteristics of publication outputs or patent quantity, patent and publication distribution , patentee or active researchers, global collaborations, main journals and the trend shift of the research frontier of literatures and patents.For SCIE:Topics = \u201csolid dispersion\u201d OR \u201csolid dispersions\u201d,The publication period = \u201c1980 to 2015\u201d, (Retrieved date 30-04-2016). For DII:Topics = \u201csolid dispersion*\u201d ANDDerwent Manual Code = \u201cB*\u201dThe publication period = \u201c1980 to 2015\u201d, (Retrieved date 30-04-2016).The references data in this paper was obtained from Science Citation Index Expanded (SCIE) database and Derwent Innovation Index (DII) database via Web of Science. The data retrieval strategy was listed below:A total of 3451 publication records and 1076 patent records were obtained using the above parameters. The reference data from Web of Science included full records and cited references, such as articles\u2019 titles, keywords, authors, source titles, affiliations, abstracts, publication date and citation number. The patent information included patent number, patentee, countries and abstracts.CiteSpace, developed by Dr. Chaomei Chen at the College of Information Science and Technology, Drexel University  ,30,31, w(a)Years per slice: 6 years as the length of a single time slice;(b)Threshold selection: the most cited references per time slice was selected to map the global cooperation of the top 50 countries and institutes; the references with the most citing numbers per time slice were selected to map the top 10% co-cited journals and literature.(c)Pruning and merging: the pathfinder approach.The software parameters for CiteSpace were set up as follows:3451 publications from past 36 years were classified into five different document types, including research articles, reviews, proceeding papers, notes and others. As shown in The top ten most productive countries in publications and patents are listed in CiteSpace and Google Earth programs were used to visualize the global network of cooperation relation distribution, which offered direct observation of the international cooperation from a broad perspective. As shown in The active research institutions and patent holders in this research area are listed in \u00ae. Moreover, It is worth noting that many famous pharmaceutical companies, such as Johnson & Johnson, Novartis, Roche Holding, AstraZeneca and Bristol Myers Squibb Co., were also very active in this area. The average citation number of the publications from Johnson & Johnson was 37.42 which ranked the first among commercial companies, the representative product of which using the solid dispersion technology was IncivekInternational Journal of Pharmaceutics and Journal of Pharmaceutical Science, with over 2500 citations. Other highly cited journals, such as European Journal of Pharmaceutics, Biopharmaceutics, Drug Development, and Industry Pharmacy also had 2000 citations.Model drugs: diazepam, paracetamol, zolpidem, felodipine, sibutramine, kinetisola, itraconazole, ketoprofen, glibenclamide, nifedipine, hydroflumethiazide, griseofulvin, tolbutamide, triamterene, oxazepam, ethenzamide, albendazole, naproxen, temazepam, diflunisal, carbamazepine, rofecoxib, ibuprofen, piroxicam, sulfathiazole, glucosamine, megestrol acetate, tranilast and curcumin;Carriers: (1) polymeric carriers: hydroxypropyl methylcellulose, Eudragit, polyethlene glycol, ethyl cellulose, povidone, hydroxypropyl cellulose, poly (ethylene oxide), chitosan, etc.; (2) amphiphilicity carriers: sodium lauryl sulfate, phosphatidylcholine, gelucire 44/14; (3) saccharides carriers: lactose, beta-cyclodextrin.Preparation methods: hot melt method, solvent evaporation approach, the spray-drying method and supercritical fluid method.Characterization approaches: differential scanning calorimetry, X-ray powder diffraction, atomic force microscopy and NMR.Mechanism: controlled release, eutectic mixture, melt agglomeration, amorphous drug stabilization, sustained-release, thermal behavior, dissolution behavior, solid nano-dispersion system, binary dispersion, quantifying drug crystallinity, in vivo drug absorption, drug-release properties, ab initio polymer selection, physical stability studies, amorphous solid dispersion, glassy form, drug-carrier interaction, heterogeneity, excipient distribution, phase diagram, enthalpy relaxation, moisture, miscibility.Research frontier shifts is one of the key factors in a specific research field. The CiteSpace program has two useful functions, keyword burst and co-citation analysis, to analyze the historical directions of research. Keyword burst is an important index for trend analysis in a specific research field within a certain time span. According to the characteristics of carriers, solid dispersion could be divided into three generations: the first generation is crystalline carriers, contained urea and sugars ,42; The Although the solid dispersion technique had been developed since the 1960s, there are still many key questions that need to be answered. In the recent 10 years, the mechanism of solid dispersions has attracted more and more attention ,50. DrugIt is very interesting that computational approaches  have attracted lots of attention in solid dispersion research. For example, molecular dynamics (MD) simulations not only mimic the structural aspects of systems, but also provide their dynamic and energetic information. Recent studies in our group showed that all-atomic molecular dynamics (MD) simulations with a simulated annealing method were performed to represent molecular models of solid dispersions and mimic the formation process of solid dispersions with hot melt methods . The simThis study provided a thoroughly visualized review of the solid dispersion technique and its cooperation network in the recent three decades by science bibliometric mapping approaches. Five topics were analyzed, including model drugs, main excipients, preparation technologies, characterization approaches and the mechanism in solid dispersion researches. Integrated experimental, theoretical and computational tools will benefit in silico formulation design of solid dispersions in the future."}
+{"text": "In the article titled \u201cPrevalence of Antenatal Depression and Associated Factors among Pregnant Women Attending Antenatal Care at Dubti Hospital: A Case of Pastoralist Region in Northeast Ethiopia\u201d , Dr. MisAlso, the Authors' Contributions section should be updated as follows:\u201cYihalem Abebe Belay conceived, designed the study, supervised the data collection, and performed the data analysis and interpretation. Nurilign Abebe Moges, Fetuma Feyera Hiksa, Kassahun Ketema Arado, and Misgan Legesse Liben assisted in designing the study, data analysis, and data interpretation. Yihalem Abebe Belay, Nurilign Abebe Moges, and Misgan Legesse Liben drafted the manuscript. All authors read and approved the final manuscript.\u201d These corrections have been applied in place."}
+{"text": "To determine the clinical characteristics and risk factors of Deep Venous Thrombosis (DVT) in patients with gynecological malignant tumor, facilitating gynecologists better prevent the fatal complication.The patients with gynecological malignant tumor treated in department of gynecology of our hospital between May 2013 and May 2018 were reviewed retrospectively. The clinical data of patients including gender, age, tumor staging, adenocarcinoma, surgery, operation time, hypertension, hyperlipemia, diabetes, coronary heart disease, radiotherapy, chemotherapy, hospital stay, and postoperative rehabilitation exercise were collected to analyze the clinical characteristics of patients and determine the risk factors of DVT.In the current study, 67 patients were included in DVT group, and 554 patients were included in Non-DVT group. There were significant differences in age, hypertension, hyperlipemia, operation time, adenocarcinoma, tumor staging, radiotherapy and postoperative rehabilitation exercises between DVT and non-DVT groups (p<0.05). However, there was no significant differences in gender, coronary heart disease, diabetes, surgical treatment and hospital stay (p>0.05). In multivariate analysis, the factors including age, hypertension, adenocarcinoma, radiotherapy, and hyperlipemia were independent risk factors, while rehabilitation exercise was protective factor for DVT.In cases of gynecological malignant tumor, DVT screening should be given due importance, especially for those patients with old age, hypertension, hyperlipemia, adenocarcinoma, or history of radiotherapy. Rehabilitation exercise should be encouraged in these patients. Gynecological cancer is the leading cause of cancer-related death in women5Clinically, some precautionary measures have been performed to prevent the occurrence of DVT, but it still occurs frequently. Also, the clinical diagnosis of this disease is not so accurate.Therefore, we carried out a retrospective study in patients with gynecological malignant tumor treated surgically or non-surgically between May 2013 and May 2018. The aim of this study was to determine the clinical characteristics and risk factors of DVT in patients with gynecological malignant tumor, facilitating gynecologists better prevent the fatal complication.In this study, the patients with gynecological malignant tumor treated in department of gynecology of our hospital between May 2013 and May 2018 were reviewed retrospectively. The inclusion criteria were: 1) patients who were diagnosed with gynecological malignant tumor such as cervical cancer, endometrial cancer, ovarian cancer, and fallopian tube cancer, treated surgically or non-surgically, 2) patients who had no history of DVT, and 3) patients with complete clinical data. DVT was diagnosed based on imaging examinations, including Doppler ultrasound, magnetic resonance imaging venography or angiography, as well as plasma D-dimer.The clinical data of patients including gender, age, tumor staging, adenocarcinoma, surgery, operation time, hypertension, hyperlipemia, diabetes, coronary heart disease, radiotherapy, chemotherapy, hospital stay, and postoperative rehabilitation exercises were collected to analyze the clinical characteristics of patients and determine the risk factors of DVT. In these clinical data, hypertension was defined as blood pressure above 140/90 mmHgP value < 0.05 was regarded as statistical significance.The statistical analysis was carried out using SPSS 21.0 . The assessment of categorical variables was performed using chi-squared test, measurement data was compared with analysis of variance, and univariate and multivariate logistic regression analysis were performed to detect the correlation between variables and DVT. Multivariate logistic regression analysis was used to determine the independent risk factors for DVT. A In the current study, 698 patients with gynecological malignant tumor were treated in the department of gynecology. Most patients received surgical treatment. Seventy seven patients were excluded for failing to meet the inclusion criteria, and 621 were included in this study. Among the included patients, 577 were treated with radical surgery, and 44 were treated using conservative treatment because they had advanced tumor stage and were not amenable to surgical resection. Sixty seven patients were diagnosed with DVT and included in DVT group, the remaining 554 patients without DVT were included in Non-DVT group. The incidence of DVT was 10.8% in this study. The clinical characteristics of the patients in two groups are shown in There were significant differences in age, hypertension, hyperlipemia, operation time, adenocarcinoma, tumor staging, radiotherapy and postoperative rehabilitation exercises between DVT and non-DVT groups (p<0.05) but no significant differences in gender, coronary heart disease, diabetes, surgical treatment and hospital stay p>0.05, .In multivariate analysis, the factors including age, hypertension, adenocarcinoma, radiotherapy, and hyperlipemia were independent risk factors, while rehabilitation exercises were protective factor for DVT .In the current study, the clinical data of 621 patients with gynecological malignant tumor in department of gynecology of our hospital were analyzed to determine the risk factors of DVT. This study may help gynecologists understand the occurrence of the fatal disease and make correct treatment strategies.In our multivariate analysis, the factors including age, hypertension, hyperlipemia, radiotherapy, and adenocarcinoma were independent risk factors for DVT in patients with gynecological malignant tumor. In a review of 9146 patients undergoing anterior cruciate ligament reconstruction, Bokshan suggested that increasing age over 30 years and hypertension were associated with an increased risk of DVT.As regards hyperlipidemia, in a study of 59 consecutive DVT patients, Kawasaki found the incidence of hyperlipidemia was high, as compared with normal control, suggesting that hyperlipidemia was an important etiologic factor in DVT.Meanwhile, radiotherapy was also found to be an independent risk factor for DVT in this study, but some authors held different viewpoints. In a study of 272 consecutive patients with cervical cancer, Satoh concluded that radiotherapy can reduce the occurrence of venous thromboembolism.19Moreover, some researchers suggested that surgical treatment was one of the independent risk factors for DVT. In a study of four hundred and ninety-eight patients with gynecological disease treated surgically, Zhang and colleague found the incidence of deep venous thrombosis was up to 11.6%, demonstrating a high incidence of DVT in patients after gynecological surgery.In addition, we found rehabilitation exercise was a protective factor for DVT, which played an important role in the prophylaxis of the disease. The incidence of DVT in patients with rehabilitation exercises was significantly lower as compared to others. Some published literature also supports the viewpoint. In a retrospective study of consecutive patients undergoing total hip arthroplasty, 126 patients underwent manual calf massage and passive ankle motion, and 138 patients underwent total hip arthroplasty using the same surgical approach without this mechanical prophylaxis, Imai and colleagues found the incidence of deep vein thrombosis was 6.52% and 0.79% in the control and rehabilitation groups, respectively, indicating performing this mechanical prophylaxis reduced the incidence of venous thromboembolism after total hip arthroplasty.In short, DVT screening should be given due importance in patients with gynecological malignant tumor, especially for those with old age, hypertension, hyperlipemia, adenocarcinoma, or history of radiotherapy, and rehabilitation exercises should be encouraged in these patients.First, many factors are associated with the occurrence of DVT, but the current study focused only on some factors, and the other factors including perioperative bleeding, occupation, infection, rheumatological disease, and nephrotic syndrome may also affect the occurrence of DVT adversely,QL and LL: Conceived, designed and did statistical analysis & editing of manuscript.QL, YLX, YP and LL: Did data collection and manuscript writing, and final approval of manuscript."}
+{"text": "There is increasing evidence and recognition that Lyme borreliosis (LB) causes mental symptoms. This article draws from databases, search engines and clinical experience to review current information on LB. LB causes immune and metabolic effects that result in a gradually developing spectrum of neuropsychiatric symptoms, usually presenting with significant comorbidity which may include developmental disorders, autism spectrum disorders, schizoaffective disorders, bipolar disorder, depression, anxiety disorders , eating disorders, decreased libido, sleep disorders, addiction, opioid addiction, cognitive impairments, dementia, seizure disorders, suicide, violence, anhedonia, depersonalization, dissociative episodes, derealization and other impairments. Screening assessment followed by a thorough history, comprehensive psychiatric clinical exam, review of systems, mental status exam, neurological exam and physical exam relevant to the patient\u2019s complaints and findings with clinical judgment, pattern recognition and knowledgeable interpretation of laboratory findings facilitates diagnosis. Psychotropics and antibiotics may help improve functioning and prevent further disease progression. Awareness of the association between LB and neuropsychiatric impairments and studies of their prevalence in neuropsychiatric conditions can improve understanding of the causes of mental illness and violence and result in more effective prevention, diagnosis and treatment. Borrelia burgdorferi and other Borrelia species, such as Borrelia garinii and Borrelia afzelii. Other tick-borne and opportunistic infections may be present as well , 7, 7B. bur bands.)  64% (Bas bands.) , 51% (LB bands.) , 50% (Am bands.) , 37% (A tigens.)  and 37% tigens.) .Different types of anxiety may be caused by LB. An early manifestation of hyperarousal may present as hypervigilance (54%) (LB-C)  and   and 66% Generalized anxiety has been associated with LB and was 50% (From the same database in which 70% met CDC surveillance criteria ) 48] an an48] anObsessive compulsive disorder has been reported with LB, can have an autoimmune pathophysiology and can have a very sudden onset ,97,98,99Posttraumatic stress disorder has been associated with LB ,101,102.Intrusive Symptoms are associated with LB and may be present with obsessive compulsive disorder, posttraumatic disorder or be present without either of these conditions and demonstrated a prevalence of 34% and the intrusive symptoms included aggressiveness in 89%, altered sexual imagery in 18% and 40% had other intrusive symptoms including bizarre and horrific images . In anotA number of eating disorders are associated with LB. Some LB patients lose weight early in the disease process and later gain weight. Cases of anorexia nervosa, bulimia and excessive weight gain have been reported ,103,104.Sleep disorders acquired as a result of LB are quite significant and include insomnia , non-restorative sleep, restless leg, paroxysmal nocturnal leg movements, sleep apnea , nightmares, circadian rhythm shift and narcolepsy . ,112,113.Although there is very little data available on the association between addiction and LB, it is an area that deserves attention since chronic pain and psychiatric illness are seen with LB. Chronic pain from LB  occurred in 24% of United States confirmed and treated patients and the severity is comparable to post-surgical pain ,118 BaseAlso, some LB patients are alcohol sensitive and self-report having a strong effect from a relatively small amount of alcohol (44%) (LB-H) and 24%) (LB-C) . Some LD% (LB-C) Studies with different study designs reported a number of acquired cognitive impairments in LB/TBD patients ,140,141.B. burgdorferi infections can contribute to a more rapidly developing dementia\u2014the meningovascular form with cerebrovascular infarcts and the atrophic form with meningoencephalitis, cortical atrophy and gliosis. The atrophic form is associated with a more rapidly progressive dementia [Borrelia detected structures that appeared not related to spirochetes, but rather to fungi. These structures were not found with a monoclonal antibody. Also, Borrelia DNA was undetectable by nested polymerase chain reaction in the ten patients analyzed [B. burgdorferi sensu stricto and serological analysis confirmed that these Alzheimer\u2019s patients had Lyme neuroborreliosis [Borrelia index, however these impressions were not confirmed by brain autopsies [Treponema pallidum in brain autopsies of general paresis patients [B. burgdorferi was detected in the brain in 25.3% of Alzheimer\u2019s disease cases and was found 13 times more frequently in Alzheimer\u2019s disease cases compared to controls [There are over 60 articles that address the causal association between LB and dementia . Two of dementia ,23,143. dementia . A studyanalyzed . Anotherreliosis . One artutopsies . Anotherutopsies . A similpatients . The manpatients ,150,151.controls .Bartonella [A number of articles have documented an association between LB and seizures ,158,159.rtonella . Seizurertonella .Suicidality seen in LB contributes to causing a significant number of previously unexplained suicides and is associated with immune-mediated and metabolic changes resulting in psychiatric and other symptoms which are probably worsened by negative attitudes about LB from others. Some LB suicides are associated with being overwhelmed by multiple debilitating symptoms, and may be impulsive, bizarre, and unpredictable. Negative attitudes about LB from family, friends, doctors, and the health care system appeared to also contribute to suicide risk. By indirect calculations, it is estimated there are possibly over 1,200 LB suicides in the US per year . In lateAlthough most LB patients have no aggressiveness tendencies or mild impairments of frustration tolerance and irritability and pose no danger, a lesser number of patients experience explosive anger, a lesser number of patients experience homicidal thoughts and impulses and much lesser number commit homicides. In a study of 100 LB patients with neuropsychiatric symptoms, none had legal difficulties pre-infections, while 4% (LB-C) and 42% (LB-H) had legal difficulties post-infection . When hoSince such large numbers are affected by LB, a very small percent of patients with these impairments can be highly significant. Most aggression with LB was impulsive, sometimes provoked by intrusive symptoms, sensory stimulation or frustration and the aggressive behavior was invariably bizarre and senseless. LB and the associated immune, biochemical, neurotransmitter, and neural circuit reactions to them can cause impairments that increase the risk of violence. In late stage LB the prevalence of homicidality is 9.6% .Other psychiatric findings caused by LB include mood swings (47%), irritability (47%) , anhedonWhile many LB fatalities, both recognized and unrecognized, may be associated with suicides, drug overdoses, homicides and accidents from cognitive impairments, there are other LB fatalities. Fatalities associated with other neuropsychiatric conditions include congenital Lyme infections, Lyme meningitis, symptomatic late Lyme neuroborreliosis, late Lyme neuritis or neuropathy, meningovascular and neuroborreliosis with cerebral infarcts, intracranial aneurysm, late Lyme encephalitis, late Lyme meningo-encephalitis or meningomyelo encephalitis, atrophic form of Lyme meningo- encephalitis with dementia and subacute presenile dementia. Fatalities associated with somatic impairments include Lyme nephritis, Lyme hepatitis, Lyme aortic aneurysm, coronary artery aneurysm, late Lyme endocarditis, Lyme carditis, late Lyme disease of liver and other viscera, late Lyme disease of kidney & ureter and late Lyme disease of bronchus & lung . Do you live, vacation or engage in activities in areas that may expose you to ticks?Have family members, neighbors, or the family dog been infected?Is there a history of a tick bite, possibly with a flu-like illness and/or a bull\u2019s eye or other rash?Is there a point at which your health declined, followed by a fluctuating progression and development of multi-systemic symptoms, including cognitive, psychiatric, neurological, and somatic symptoms adversely impacting school, social life, family life?Have you ever been treated for Lyme disease, suspected you had Lyme disease but was told it was ruled out?Have antibiotics ever caused a sudden worsening followed by an improvement of symptoms?Screening assessments are advisable when evaluating psychiatric symptoms when the possibility of LB may be present . ScreeniIf the screening assessment increases diagnostic suspicion a further assessment is indicated. LB is diagnosed just like any other neuropsychiatric condition by a comprehensive psychiatric clinical exam relevant to patient\u2019s complaints and findings with a thorough history, mental status exam, review of systems, neurological exam, physical exam, a knowledgeable interpretation of laboratory findings, pattern recognition and clinical judgment. In considering the diagnosis it is important to look for relapsing progressive multi-systemic symptoms, including cognitive, psychiatric, neurological, and somatic symptoms and to remember the greater the multisystemic comorbidity, the greater the likelihood of a condition impacting the entire body such as a complex infectious disease. The presence of a comorbid condition does not rule out the presence of LB ,162,163.Cognitive: Attention , hypersensitivity ; inability to filter sensory input resulting in stimulation overload; memory ; processing ; executive functioning Imagery: depersonalization, derealization, capacity for visual imagery, hypnagogic hallucinations, vivid nightmares, illusions , hallucinations .Emotional: decreased frustration tolerance, abrupt mood swings, hypervigilance, paranoia, anhedoniaBehavioral: disinhibition, exaggerated startle reflex, explosive anger, suicidal, homicidal, accident prone, decreased social functioning, decreases school or job productivity, family and marital conflicts, substance abuse, legal difficulties, dissociative episodes, compensatory compulsions, dropping objects, crying spells, self-mutilationPsychiatric syndromes: depression, rapid cycling bipolar illness, panic disorder, obsessive compulsive disorder, social anxiety disorder, generalized anxiety disorder, posttraumatic stress disorderSleep disorders: non-restorative sleep, early insomnia, middle of night insomnia, early morning insomnia, excessive daytime sleepiness, loss or reversal of circadian rhythm, restless leg, paroxysmal nocturnal limb movements, sleep apnea , sleep paralysis, hypnagogic hallucinations, sleep attacks, cataplexy, narcolepsyEating disorders: anorexia, weight loss, emotional overeating, carbohydrate craving, weight gain (with or without increased food intake)Sexual: decreased libido, increased libido, decrease capacity for arousal, decreased capacity for orgasm, altered sexual imageryTemperature control: body temperature fluctuations, flushing, intolerance to heat, intolerance to cold, decreased body temperature, low grade fevers, night sweats, chillsHeadaches: cervical radiculopathy, migraine, thunderclap, tension, cluster, sinus, scalp tenderness, temporal mandibular joint, coital cephalalgiaCranial nerves: I: loss of smell, altered taste; II/eye: blurred vision, photophobia, intolerance of fluorescent or flickering light, floaters, flashes, conjunctivitis, eye pain, dry eyes, blind spots, night blindness, peripheral shadows, panopsia, papilledema, iritis, uveitis, optic neuritis; II, IV, VI: double vision, eye drifts when tired, ptosis; V: sensory loss and/or pain in any of the three branches on either side; VII: Bell\u2019s Palsy; VIII: tinnitus, hearing loss, dizziness, vertigo, motion sickness, Tulio\u2019s sign, mal de debarquement; IX, X: episodic loss of speech, choking on food, difficulty swallowing; XI: sternocleidomastoid, trapezius pain and/or weakness; XII: tongue deviates to sideSeizures: complex partial, grand malNeuropathy: numbness, tingling, sensory loss, burning, crawling sensation (formication), static electricity sensation, stabbing sensation, weaknessOther neurological: fatigue, tremor, twitching, muscle tightness, myoclonic jerks, tics, Tourette\u2019s, ataxia, spasticity, meningismus, disc disease, positive Romberg, postural tachycardia syndrome (POTS), ortho static hypotension, gait disturbances, spinal cord signs, white matter lesions, sensation of vibrationMusculoskeletal: Joint pain, migratory joint pain, swelling, tightness, crepitations, neck and back discomfort; periostitis and bone tenderness of tibia, ribs, iliac crest, sternum, clavicle; epicondylitis; plantar fasciitis, foot tenderness; fibromyalgia; myalgia, costochondritis ; tendonitis; carpal tunnel syndromeCardiac: chest pain, heart block, irregular heart rate, mitral valve prolapse, racing pulse, POTS, pericarditis, cardiomyopathy, murmur, hypertension, hypertensive crisisPulmonary/upper respiratory: shortness of breath, air hunger, cough, sore throats, swollen glands, asthmaGastrointestinal: Reflux, irritable gut, nervous stomach, irritable bowel, abdominal bloating, reduced gastrointestinal motility, gastroparesis, cholecystitis, gall stonesGenitourinary: Spastic bladder, genital pain (testicular/pelvic), menstrual irregularity, breast tenderness, sexual dysfunction, decreased libido, urinary incontinence, interstitial cystitisImmune: fevers, sweats, chillsOther: alcohol intolerance, hair loss, thyroid disease, adrenal insufficiency, hypoglycemia, ankle edema, tooth pain, periodontal disease, nose bleeds, ecchymoses, splenomegaly, multiple chemical sensitivities, allergies, lymphocytoma, stria, acrodermatitis chronicum atrophicansA comprehensive assessment includes an assessment of the following:The more common symptoms seen in LB include poor attention span, being easily distracted by frustration, sensory hypersensitivity causing patients to feel overwhelmed, poor short-term memory, dyslexia symptoms, slow processing, executive dysfunction, brain fog, poor time management, depersonalization, intrusive images and thoughts, musical hallucinations, low frustration tolerance, abrupt mood swings, impulsivity, paranoia, explosive anger, suicidality, anhedonia, decreased productivity, depression, long duration panic attacks, social anxiety, generalized anxiety, obsessiveness, non-restorative sleep, appetite disturbances, decreased libido, headaches, cranial nerve symptoms, neuropathy, autonomic nervous system symptoms, musculoskeletal symptoms, gastrointestinal symptoms, genitourinary symptoms, cardiovascular symptoms, fatigue, chronic pain and alcohol intolerance ,48,161.B. burgdorferi contributing to the underdiagnosis of LB and progression to psychiatric illness has been recognized [B. burgdorferi. Immune reactivity combined with multisystemic disease progression is more supportive of current active infection. The American Psychiatric Association guidelines recognize the need to consider LB in the etiology of psychiatric illness, but do not address laboratory testing; the current International Lyme and Associated Diseases Society guidelines address treatment, but not laboratory testing and the Infectious Diseases Society of America guidelines and other guidelines based upon them do not address psychiatric manifestations of LB [After an adequate clinical assessment is performed, laboratory testing with proper interpretation may add to the assessment. The results of laboratory testing are dependent upon the stage of the illness  and the cognized . Althougcognized . In addicognized ,169,170.ns of LB ,172,173.ns of LB ,11. Imprns of LB . As contns of LB ,170. Thens of LB .If an inadequate clinical exam is performed it can result in viewing the symptoms as being vague and subjective. Caution must be used in considering the symptoms as having a psychogenic basis, such as hypochondriasis, somatization disorder, or a psychosomatic condition. Both hypochondriasis and psychosomatic illnesses begin in childhood and are lifelong conditions with a psychodynamic explanation and vary in intensity depending upon life stressors. If a complex, progressive multisystemic illness begins in a person who had been reasonably healthy throughout most of their life, the likelihood that this is psychosomatic or has some other psychogenic basis is very remote. Another diagnostic error by clinicians who lack psychiatric diagnostic capability is to consider these symptoms as being so called \u201cmedically unexplained symptoms\u201d or \u201cbodily distress syndrome.\u201d The concept of medically unexplained symptoms was removed from the most recent DSM (DMS-5) since these symptoms were often instead medically unexamined symptoms and the concept of bodily distress syndrome is not included in the DSM-5 and lacks objective criteria .All treatments are a risk vs. benefit decision and inadequately treated LB can result in a broad spectrum of risks as previously described. A complex, chronic, LB patient may have a multitude of different symptoms. What causes a condition may be different from what perpetuates a condition. It is best to make a list with the patient ranking which symptoms are the most severe and most impede recovery and consider how the symptoms interact with each other. This will determine the sequence of initiating different treatment strategies. One major question is considering whether antibiotic or symptomatic treatment has higher priority. When a patient has been treated with just antibiotics and has not adequately responded, consider treating the symptoms with psychotropics or other symptomatic treatments. When a patient has been treated with just psychotropics and has not adequately responded, consider treating the symptoms with antibiotics ,177. WheAlthough each patient may have a unique presentation, the most common symptoms impeding recovery are non-restorative sleep and/or chronic unremitting stress. Both are associated with a high allostatic load and compromised immune functioning. Non-restorative sleep is often associated with the terrible triad which consists of non-restorative sleep, fatigue and cognitive impairments ,115,176.Chronic unremitting stress is often associated with hyperarousal and emotional symptoms such as depression, anxiety, depersonalization, mood swings and psychosis. Other symptoms that may be a focus of treatment may include chronic pain , complex partial seizures, dysautonomia, gastrointestinal symptoms, genitourinary symptoms, substance abuse and addiction .Regardless of the debate surrounding the chronicity of infection and the chronicity of symptoms with LB, treating psychiatric symptoms with psychotropics can prevent and sometimes reverse disease progression. Since non-restorative sleep and chronic unremitting stress contribute to compromised immune functioning and disease progression, remediating these symptoms can improve immune functioning and resistance to infection which may reduce disease progression and contribute to recovery. Successful psychiatric management can sometimes result in reduction of infection and successful reduction of infection can sometimes result in reducing psychiatric symptoms and reducing the need for psychotropics .No drugs are specifically approved by the Federal Drug Administration (FDA) for the treatment of psychiatric symptoms associated with LB. Since LB can be associated with the full spectrum of psychiatric symptoms, all psychotropic are sometimes used and these medications may or may not be FDA approved to treat the relevant symptom .Separate and apart from the potential benefit of psychotropics upon mental symptoms when used as psychotropics, some also have antimicrobial, immune and other effects .B. burgdorferi and all other tick-borne infections have been eradicated by antibiotic treatment, after stabilization constant vigilance is needed to recognize a possible relapse that may require further treatment [When the symptoms are caused by persistent relapsing infection, antibiotic treatment late in the course of the illness may prevent some further neuropsychiatric disease progression but may be unable to reverse all the previously established neuropsychiatric impairments. Since our current technological limitations prevent us from being sure reatment .It is recognized there is a selection bias in many of the studies discussed in this article since only the more severe cases were referred to the mental health professionals who specialized in treating LB. Also, a significant amount of this article and many of the citations are based upon clinical observations, publications and presentations by the author. Critical appraisal and research by others to independently validate, modify or refute the author\u2019s findings is needed to advance future research and a better understanding of the content of this article.In reviewing the different studies, the greatest level of current debate exists regarding whether or not there is a causal association between LB and developmental disabilities, ASD, schizophrenia and dementia. Very little data exists on the association between LB and social anxiety and substance abuse.Although there is evidence supporting a causal association between psychiatric findings and LB, controversy does exist, and it is necessary to also consider articles negating this association.One study concluded their mean summary assessment scores of the mental health of LB patients 11\u201320 years post infection was similar to those of the general population . HoweverAnother study concluded from their results that \u201cpsychiatric comorbidity and other psychological factors are prominent in the presentation and outcome of some patients who inaccurately ascribe longstanding symptoms to chronic Lyme disease\u201d . In thisRecognizing the association between Lyme borreliosis and neuropsychiatric impairments is a major advance in psychiatry.Lyme borreliosis, possibly with other interactive infections in the body can evade and suppress the immune system and cause immune effects and biochemical changes in the brain causing neuropsychiatric symptoms. Sleep disorders and chronic unremitting stress associated with these impairments contribute to further disease progression of neuropsychiatric symptoms. The pathological effects of these processes may result in developmental disorders, autism spectrum disorders, schizoaffective disorders, bipolar disorder, depression, anxiety disorders , eating disorders, sleep disorders, decreased libido, addiction, opioid addiction, cognitive impairments, dementia, seizure disorders, suicide, violence, anhedonia, depersonalization, dissociative episodes, derealization and other impairments.Diagnosis of Lyme borreliosis is achieved by a screening assessment followed by a thorough history, comprehensive psychiatric clinical exam, review of systems, mental status exam, neurological exam and physical exam relevant to the patient\u2019s complaints and findings with clinical judgment, pattern recognition and knowledgeable interpretation of laboratory findings.Treatment approaches that reduce symptoms that contribute to disease progression  in combination with antimicrobial and other treatments can improve recovery.Future studies to clarify the pathophysiology and look more at the prevalence of these infections in patients with identified neuropsychiatric impairments can improve understanding of the causes of mental illness and violence and result in more effective prevention, diagnosis and treatment.Sir William Osler, the father of American Medicine said \u201cHe who knows syphilis knows medicine.\u201d It can now be said that He who knows Lyme borreliosis knows about medicine, neurology, psychiatry, immunology, psychoimmunology, neurochemistry, ecology, epidemiology, entomology, law, politics, and ethics."}
+{"text": "Prior work has suggested that metabolic disorders increase the risk for cognitive decline. Further, studies have identified amino acids (AAs) as potential biomarkers for dementia and diabetes. This study examines AAs and metabolic clinical markers (MCM) as predictors of cognition (Processing Speed (SOP), Working Memory (WM), Fluid (Gf) and Crystallized Intelligence (Gc)). The sample included 241 middle-aged adults from Bronx, NY. Predictors included age, gender, education, ethnicity, smoking, having diabetes, glucose, insulin, triglycerides, diastolic, and systolic blood pressure (BP), and cholesterol. AAs and associated derivatives were obtained from serum using NMR-based metabolomics. Analyses were conducted for each cognitive domain using repeated cross-validation random forests and lasso regressions. Overall, all models had acceptable cross-validation mean squared error except for WM. Several MCMs were specific to each cognitive domain, such as lower triglycerides and glucose associated with better SOP and higher systolic BP associated with better Gc while none were identified for Gf. The Gf model had the least number of AAs with lower serine associated with better FI. Two AAs, higher histidine and alanine, were associated with better SOP. Further, higher alanine, valine, isoleucine, serine, methionine, betaine, and moderate tyrosine were associated with better Gc. These results indicate that AAs were specific to each cognitive domain and ranked similar or higher in importance as several MCMs These results suggest that further investigation of AAs alongside associated MCMs is needed to assess the metabolic contribution to cognitive performance. Such research will help identify specific metabolic targets relating to cognition."}
+{"text": "To the editor,We appreciated the valuable comments on our recent published article in the International Braz J Urol , 2. We aIn patients with reservoir stone after urinary diversion, stone management present unique challenges. In our research, 3 patients with reservoir stones following urinary diversion were treated by transurethral neo-bladder lithotripsy, and one patient had 6 mm residual stone postoperatively and received subsequently conservative watching treatment . RecentlWith the advancement of equipments and increasing experience, the surgical management of urolithiasis in patients with urinary diversion are varied, individualized consideration and comprehensive evaluation must be taken into account, which depending upon diversion type, patient fitness, stone size, stone location, available resource and surgeon experience ,6."}
+{"text": "Responsive slippery lubricant-infused surfaces (SLIS) have attracted substantial attention because of the high demand of fundamental research and practical applications, such as controllable liquid-repellency, intelligent, and easy-to-implement wettability switching. In this review, advanced development of responsive slippery surfaces is briefly summarized upon various external stimuli, including stress, electrical field, magnetic field, and temperature. In addition, remaining challenge and prospect are also discussed. Nepenthes pitcher plants fill water in the spaces among the micro structure to form a slippery liquid film, leading insects to aquaplane into their stomach. Since Wong et al.  and polyurethane (PU) are mainstream in mechanically responsive SLIS. Electrical responsive materials are chosen primarily based on electrowetting mechanism, generally both the substrate and the repellent liquid should be conductive. Magnetic field response strategies include magnetic particles doped substrates or introduces magnetic lubricant. Traditional thermal response is mainly realized by thermosensitive lubricant such as paraffin or mixtures of solid/liquid oil.Stretching or mechanical pressing represents a simple, straightforward and effective strategy for tuning the wettability of SLIS. Generally, replacing the rigid substrate with a continuous elastic polymer is required to enable mechanical deformation. The stress would vary the surface's morphology and lubricant layer's height, resulting in the change of surface's wettability. Yao et al.  adopted Although the mechanical responsive SLIS have been demonstrated reversible deformation and wettability switching, their dependence on elastic substrate severally limit their practical applications. What's more, continuous stress and deformation would trigger the potential mechanical damage. Improving the inherent durability of materials or introducing self-repairing materials should be a key point for developing mechanical responsive SLIS.Electrowetting is a method of changing interfacial wettability by adjusting the potential between the liquid and solid electrodes. Due to its fast response, wide range changes, small size and good reliability, electrowetting method has been widely used in optics, biology, and microelectronics . When the environmental temperature was higher than Tm, paraffin was in the liquid phase, acting as lubricant filled in the PDMS network. Therefore, a droplet on SLIS was in low adhesive state. However, when the temperature dropped to lower than Tm, paraffin turned into solid phase and became a part of solid substrate. The droplet on this surface was in high adhesive Wenzel state. Later on, they (Wang B. L. et al., in situ wetting, dewetting, penetration and optical properties could be controlled under thermo-stimuli. Recently, combined printing method, Yao's group (He et al., Temperature is considered as a controllable and quantitative external stimulus, which extends widely applications Generally, traditional smart SLIS focused on the responsive components contained in solid substrate and lubricant to vary the interface's topography, modulus, and surface energy. Modification of the repellent liquid was still rare. Recently, our group (Gao et al., Although various temperature-responsive SLIS have been demonstrated, most of them are still restricted to several kinds of thermo-sensitive materials. Novel materials displaying obvious difference in wettability under small change of temperature should be explored. Additionally, besides temperature-dependent substrate and lubricant, thermo-responsive repellent liquid should be considered for particular applications, such as biological droplets in micro-biochips.In this review, we concentrate on recent development of SLIS with external stimuli responsive wettability, including stress responsive SLIS, electrical responsive SLIS, magnetically responsive SLIS, and thermo-responsive SLIS. Through introducing stimuli responsive materials or replace some parts of SLIS, repellent droplet's wetting behaviors and other properties of the film, such as structural colors and transparency, would be reversibly changed. Based on the responsive SLIS's ability of timely control of droplets, SLIS have demonstrated their potential applications in fog collection, oil-water separation, droplets' delivery, complex-flow distribution, visual biosensors, biomimetic tissue, adaptive drag control, and so on.Although various SLIS have been demonstrated distinctive advantages and features under external stimuli challenges still remain in their practical applications. Firstly, some responsive SLIS are limited with complex, strict or high-cost preparation processes. Economical, reproducible, and effective fabrication to achieve well-organized micro/nanostructures and integrate stimuli-responsive components into SLIS is the first and foremost challenge. Secondly, reliability and durability of responsive SLIS are needed to improve. Besides substrate's long-term durability and mechanical stability, lubricant's depletion caused by cloaking effect or volatility should be paid attention (Carlson et al., YH, YZ, and XY proposed the manuscript. XY, YH, XZ, and JW wrote the manuscript. All authors revised the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Selecting appropriate outcome measures for multimorbid, acutely hospitalized geriatric patients poses specific challenges, which may have caused inconsistent findings of previous intervention trials on early inpatient rehabilitation. The objective of this review was to describe primary outcome measures used in randomized controlled trials (RCTs) on early rehabilitation in older hospital patients, to analyze their matching to intervention programs, and to evaluate the effects of matching on the main findings of these RCTs. A systematic literature search was conducted in PubMed, Cochrane CENTRAL, CINAHL, and PEDro databases. Inclusion criteria were: RCT, patients aged \u2265 65 years, admission to hospital, physical exercise intervention, and primary outcome measure during hospitalization. Two independent reviewers extracted the data, assessed the methodological quality, and analyzed the matching of primary outcome measures to the intervention, study sample, and setting. Main study findings were related to the results of the matching procedure. In 28 included articles, 33 different primary outcome measures were identified, which we grouped into six categories: functional status, mobility status, hospital outcomes, adverse clinical events, psychological status, and cognitive functioning. Outcome measures differed considerably within each category showing a large heterogeneity in their matching to the intervention, study sample, and setting. Outcome measures that specifically matched the intervention contents were more likely to document intervention-induced benefits. Mobility instruments seemed to be the most sensitive outcome measures to reveal such benefits. High specificity (optimized match) of outcome measures and intervention contents is a key factor to reveal benefits of early rehabilitation in acutely hospitalized geriatric patients."}
+{"text": "Dear Editor,A 53-year-old woman was admitted to the emergency room with a three-day history ofself-reported fever and diffuse headache. She reported no history of surgicalinterventions. On physical examination, her overall health status was satisfactory.However, a cutaneous mass, rich in sulci but without secretions, was observed in theright parietal region . Compute.CVG is a disease characterized by excessive growth of the skin of the scalp, resulting inthe formation of sulci and gyri that resemble those of the cerebral cortex. The etiologyof CVG is unknown. It is categorized as primary essential, primary non-essential, orsecondary. The primary essentialform is not associated with neurological or ophthalmological alterations, presentingonly as scalp folds, which mimic the cerebral gyri, and predominantly affects men; ittypically appears during or after puberty, 90% of patients being diagnosed after 30years of age.The primary non-essential form, which accounts for 0.5% of cases, is associated withneurological manifestations such as microcephaly, intellectual disability, cerebralpalsy, and epilepsy, as well as ophthalmological manifestations such as cataracts andblindness. Typically, the scalpfolds and furrows seen in CVG show a disordered pattern, with an asymmetricdistribution.The secondary form, which can occur at any age, affects men and women with similarfrequency; the clinical presentation varies depending on the underlying cause, suchcauses including cerebriform intradermal nevus, inflammatory dermatoses, endocrinediseases, and genetic syndromes.An appropriate investigation includes histopathological analysis to determine theetiology. Although the affected area is asymptomatic, there can be accumulation ofsecretions, causing odor and itching; therefore, good scalp hygiene is important forsymptom relief. When secondary to other etiologies, CVG usually regresses aftertreatment of the underlying disease, although surgical excision may be necessary in thisor any of the forms of presentation"}
+{"text": "Therefore, the authors' affiliations, and the affliation address, should have appeared as follows:DAN CAO*, JING PI*, YIHONG SHAN*, YUPING TANG and PING ZHOUChildren's Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. ChinaDepartment of Orthopedics, *Contributed equallyThe authors confirm that there are no further errors in the study, and all the authors agree to this correction. The authors regret this error in the affiliations, and apologize for any inconvenience caused."}
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+{"text": "Due to an error during production, some contents of Incorrect:Correct:"}
+{"text": "Following publication of the original article , the autThe incorrect author name is:Pozzi MarcoThe correct author name is:Marco PozziThe author name has been updated above and the original article  has been"}
+{"text": "Following publication of the original article , the autThe corrected corresponding authorship been updated in the author group above and the original article  has been"}
+{"text": "Following publication of the original article , the autThe original article  has been"}
+{"text": "Following publication of the original article , the autThe correct Fig."}
+{"text": "The clinical examination revealed that there is macrosomia, macroglossia and encephalocele. The patient also had complains of hypoglycemia on 2"}
+{"text": "Following publication of the original article , we wereThe original article has been corrected."}
+{"text": "After publication of the original article , the autThe original article has been corrected."}
+{"text": "Following publication of the original article , the autThe original article  has been"}
+{"text": "Following publication of the original article , we wereThe original article has been corrected."}
+{"text": "Following publication of the original article , we wereThe original article has been corrected."}
+{"text": "Following publication of the original article , we wereThe original article has been corrected."}
+{"text": "Following publication of the original article , we wereThe original article has been corrected."}
+{"text": "All tolerance values were Following publication of the original article , we wereless should actually read greater.The word"}
+{"text": "Following publication of the original article , the autThe original article has been corrected."}
+{"text": "Following publication of the original article , the autThe correct table is given below.The original article has been corrected."}
+{"text": "Following publication of the original article , the autThe author group has been updated above and the original article  has been"}
+{"text": "In the originally published version of this manuscript, several requested author amendments were inadvertently omitted prior to publishing. The publisher apologizes for the error and has since corrected these errors."}
+{"text": "Following publication of the original article , the autIn addition, the new Authors\u2019 contributions statement is given below:"}
+{"text": "Furthermore, they apologise to the readership for any inconvenience caused.The revised versions of"}
+{"text": "Following publication of the original article , the autThe correct Table"}
+{"text": "Following publication of the original article , the autThe published article has now been corrected to include these details in the Funding declaration.The authors apologize for any inconvenience caused."}
+{"text": "In the following article,The authors apologize for the error."}
+{"text": "Following publication of the original article , the autThe corrected corresponding authorship is reflected in this correction."}
+{"text": "Following publication of the original article , we wereThe original article has been corrected."}
+{"text": "Following publication of this supplement article , the autFor the correct citation, please see the corrected version of Fig.\u00a0The authors apologize for any inconvenience caused."}
+{"text": "Following publication of the original article , the affThe original article has been corrected."}
+{"text": "Following publication of the original article , we wereThe original article has been corrected."}
+{"text": "Following publication of the original article , we wereThe original paper has been corrected."}
+{"text": "The Journal of Tehran University Heart Center hereby declares the retraction of the article entitled \u201cA Rare Case of Cardiogenic Shock following Severe Multivessel Coronary Vasospasm\u201d, which was already published in this journal .This article has been retracted at the request of its authors, who stated that notwithstanding the merits of their reported case, the complicated manifestations of the patient require further causal investigation via a more scrutinized approach."}
+{"text": "Following publication of the original article , we wereThe original article has been corrected."}
+{"text": "Following publication of the original article , the autThe original article  has been"}
+{"text": "DOI: Since the publication of the article, the authors have noticed an error in"}
+{"text": "Following publication of the original article , the autThe original article has been corrected."}
+{"text": "Following publication of the original article , we wereThe original article has been corrected."}
+{"text": "Following publication of the original article , the autThe authors apologize for not noticing these errors prior to publication, and for any inconvenience caused."}
+{"text": "Following publication of the original article , we wereThe original article has been corrected."}
+{"text": "We consider parameterized concurrent systems consisting of a finite but unknown number of components, obtained by replicating a given set of finite state automata."}
+{"text": "To the editor,In a recently published investigation, He et al demonstrated the risk associated with left atrial appendage (LAA) morphology and thrombosis."}
+{"text": "In Zhang et al,The authors apologize for the inconvenience this may cause."}
+{"text": "Following publication of the original article , the autThe corrected Fig."}
+{"text": "Following publication of the original article , the autThe original article has been corrected."}
+{"text": "Following publication of the original article , one of The updated Funding is given below."}
+{"text": "Following publication of the original article , the autQiu Chen and Shifen Xu should be co-corresponding authors for this article.The author group has been updated above and the original article  has been"}
+{"text": "Following publication of the original article , we wereThe original paper has been corrected."}
+{"text": "The original version of this article , unfortuThe original article has been corrected."}
+{"text": "Following publication of the original article , we wereThe original article has been corrected."}
+{"text": "Following publication of the original article , the autThe article title has been updated above and the original article  has been"}
+{"text": "Following publication of the original article , we wereThe original article has been corrected."}
+{"text": "Following the publication of the original article , an erroThe original article has been corrected."}
+{"text": "Following publication of the original article , the autThe original article has been corrected."}
+{"text": "In the original version of our article , insuffiThe corrected acknowledgments are provided below:"}
+{"text": "After publication of the original article , the autThe correct values are listed below:The original article has been corrected."}
+{"text": "Following publication of the original article , in thisThe original article has been corrected."}
+{"text": "The authors apologise that upon publication of this article the author, the author Paul Bata Domanban's surnames were listed incorrectly as Paul Domanban BataThe online version of this article has been updated."}
+{"text": "In the abstract, fish shouldhave been correctly characterized as being ectothermic."}
+{"text": "Following publication of the original article , in thisThe original article has been corrected."}
+{"text": "Following publication of the original article , in thisThe original article has been corrected."}
+{"text": "After publication of this article , concernThe authors apologize for the error in the published article."}
+{"text": "Following publication of the original article,In Figure The updated Figure Supporting InformationClick here for additional data file."}
+{"text": "Following publication of the original article , the co-The original article has been corrected."}
+{"text": "In the published article, the Funding statement was not reported. The correct Funding statement appears below."}
+{"text": "The correct Page 6, Saccharomycopsis malanga and Saccharomycopsis fibuligera were mislabeled. The correct Page 7, Correction of the information above does not change the conclusions of this paper."}
+{"text": "Following publication of the original article , in thisThe original article has been corrected."}
+{"text": "After publication of this article , it was The original publication has been corrected."}
+{"text": "Following publication of the original article , the autThe author group has been updated above and the original article  has been"}
+{"text": "In the published article, the funding statement was mistakenly not included in the publication. The Funding statement appears below."}
+{"text": "In the published article, there was an error in the Funding statement. The correct Funding statement appears below."}
+{"text": "In the published article, there was an error in the Funding statement. The correct Funding and Acknowledgment statements appear below."}
+{"text": "Following publication of the original article , the autThe original article  has been"}
+{"text": "Furthermore, they apologize to the readership for any inconvenience caused.The revised versions of"}
+{"text": "Following publication of the original article , we haveThe original article was updated."}
+{"text": "After determining the baseline, the editorial office has undertaken activities promoted in the Environmental sustainability and scientific publishing: EASE manifesto  step to a new world of scholarly publishing."}
+{"text": "Following publication of the original article , in thisThe original article has been corrected."}
+{"text": "Following publication of the original article , in thisThe original article has been corrected."}
+{"text": "In the published article, the funding statement was omitted. The correct funding statement appears below."}
+{"text": "In the original publication , the funFunding: This research received no external funding."}
+{"text": "The so-called rest state of the human brain has revealed a rich repertoire of dynamic patterns as viewed through neuroimaging modalities . Much of"}
+{"text": "The current title for Figure 3 is incorrect. The correct title should be \"Evolution of cooperation level, punishment severity, and punishment threshold when strictness of punishment is fixed.\""}
+{"text": "In the original paper, the table describing characteristics of included studies on page 4  includes"}
+{"text": "Leporinus reinhardti, and Figures After the publication of this work  the follWe regret any inconvenience that this inaccuracy may have caused."}
+{"text": "In all affiliations, China should be changed to Taiwan."}
+{"text": "This article has been republished because an incorrect, earlier version of the manuscript was published originally."}
+{"text": "Article Retracted After lengthy investigation by the editors, the original article  has been"}
+{"text": "In the abstract of the original manuscript published online, the units for chloroform exposures in tap water were presented as milligrams per liter instead of micrograms per liter. They have been corrected here."}
+{"text": "The first two authors, Sandra Carvalho and Jorge Leite, should be noted as contributing equally to this work."}
+{"text": "In addiWe recently used similar calculations to estimate the annual costs of Hg pollution in France , a count"}
+{"text": "The first two authors, Anxin Wang and Jianwei Wu, should be noted as contributing equally to this work."}
+{"text": "This mechanism works by tuning the gain inhibition [A hallmark feature of cortical networks is the presence of synaptic motifs, defined as ensembles of neurons whose synaptic pattern follows a particular configuration . Simulathibition  of a sel"}
+{"text": "The first two authors, Nobuoki Eshima and Osamu Tokumaru, should be noted as contributing equally to this work."}
+{"text": "Therefore, our understanding of the biological chemistry of NO in peroxisomes presented in Figure"}
+{"text": "Temperature affects cellular function in different ways that include the transmembrane transport of ions and the kinetics of membrane spanning proteins mediating such transport. Electrodiffusion models of membrane potential ,2can be"}
+{"text": "The complete, correct Figure legends can be found here:"}
+{"text": "The first two authors, Yuan Tung Shih and Chiun Cheng Ko, should be indicated as having contributed equally to the article."}
+{"text": "After our article was published online, we recognized that the summary of proteomics approaches to identify candidate proteins for S-nitrosylation in plants Table  was inco"}
+{"text": "In the author byline, the first two authors should not have been noted as equal contributors."}
+{"text": "In the author contributions section, Sreevidya Santha (SS) should be listed as one of the authors having \"Conceived and designed the experiments.\""}
+{"text": "In the Author Contributions statement, first author (LX) was incorrectly omitted from the list of those authors that \"Conceived and designed the experiments.\""}
+{"text": "Timothy Mastro, Family Health International, should be listed as a Member of the Incidence Assay Critical Path Working Group."}
+{"text": "Cross-frequency couplings between oscillatory modes have been observed in cortical and hippocampal local field potentials recorded from the brains of rodents, primates and huma"}
+{"text": "The first two authors, Andreas Pomschar and Inga Koerte, should be noted as contributing equally to this work."}
+{"text": "In the Author Contributions statement, the second author (AHN) was incorrectly omitted from the list of authors who wrote the paper."}
+{"text": "The first two authors, Jakob Haaber and Marianne Thorup Cohn, should not have been attributed equal contribution. Jakob Haaber is the sole first author of this work."}
+{"text": "In the author list, it should be indicated that Jean-Michel Goujon and Catherine Werts contributed equally to this work."}
+{"text": "Throughout the text, the specimen number GLAHM 132588 of the holotype of the new taxon \"Acamptonectes densus\" is incorrect. The correct specimen number is GLAHM 132855."}
+{"text": "In the Funding section, one of the grant numbers from the National Cancer Institute was listed incorrectly. The grant number \"CA 132706\" should be \"CA 134304.\""}
+{"text": "In the Author Contributions Statement, the sixth author (MN) should be noted as one of the authors who \"Wrote the paper.\""}
+{"text": "In the Author Contributions statement, the first author (BMT) should be listed as one of the authors who interpreted the data."}
+{"text": "In the Author Contributions section, Saiedeh Saghafi (SS) should be listed as one of the persons who performed the experiments."}
+{"text": "Dear Editor,We greatly enjoyed reading the excellent meta-analysis by Alavian and colleagues on the ef"}
+{"text": "Thermotoga maritima[For more than a decade, the Joint Center for Structural Genomics (JCSG)  has been"}
+{"text": "Article retracted After lengthy investigation by the editors, the original article  has been"}
+{"text": "Realistic simulation of central networks remains a challenge due to the complexity of internal connectivity and cellular mechanisms involved. We have recently built a realistic model of the cerebellar granular layer , which h"}
+{"text": "Our work suggests the critical importance of modeling extracellular ion concentration and oxygen dynamics to properly understand the underlying mechanisms behind seizure and related phenomena.During seizure events, the extracellular K"}
+{"text": "After our article was published online, we recognized that the list of work being quoted was incomplete. We have included here the following missing reference: Lossin,"}
+{"text": "Regrettably, the Acknowledgments were omitted from the submitted manuscript and are therefore included here in this Corrigendum"}
+{"text": "The latest discoveries on Purkinje cell (PC) physiology suggest that the mechanisms of PCs intrinsic excitability have to be revisited. Starting from available models , we have"}
+{"text": "In the Materials and Methods section, there was an error in the fifth equation of the section titled \"Dispom - Learning parameters\". Please view the complete, correct equation here:"}
+{"text": "The first and second authors, Haichao Yuan and Yue Zhuang, were not correctly indicated as having contributed equally to the article."}
+{"text": "Dear Sir,We thank the authors Gupta and Gupta for read"}
+{"text": "We wish to make the following changes to the published article , agreed"}
+{"text": "In a previous work , it was The spike-time difference map (STDM) formalism of  uses the"}
+{"text": "In the Author Contributions section, Manuel Pedro Pereira (MPP) should be listed as one of the persons who wrote the paper."}
+{"text": "Unfortunately, the original version of this article  containeThe correct version of Fig."}
+{"text": "In the Author Contributions section, Leone Ridsdale (LR) should be listed as one of the persons who conceived and designed the experiments."}
+{"text": "Learning and plasticity in the brain has been generally attributed to the synaptic activity in a neuronal network. However, recent studies  propose The proposed model comprises of three layers Figure .; the fi"}
+{"text": "EditorActa Ophthalmologica  in the pathogenesis of glaucoma has attracted a great deal of research interest, as highlighted in a review article recently published in"}
+{"text": "Dear Editor,Evidently disc surgery patients are at higher risk of suffering from depression and anxiety than the general population . The aut"}
+{"text": "In , the fouThe authors wish to apologise for any misunderstanding or inconvenience caused."}
+{"text": "Natural products have been extensively studied and involved in cancer therapy field , apigeni"}
+{"text": "The Spike Triggered Average (STA) is a classical technique to find a discrete approximation of the Receptive Fields (RFs) of sensory neurons , a requi"}
+{"text": "BMC Nephrology [Following publication of the original article in phrology , we woulThe original article has been updated with the correct grant number. The publisher apologizes for the inconvenience this may have caused."}
+{"text": "In the Author Contributions section, Kate L. Seib (KLS) should be listed as one of the persons who conceived and designed the experiments."}
+{"text": "Taenia solium, are the sole source of cysticercosis, a parasitic tissue infection  of patients with neurocysticercosis in the United States has been reported (Identification of reported \u20137. Clini"}
+{"text": "After publication of the original article , it cameThe original article has been updated to include the correct versions of Fig."}
+{"text": "Unfortunately, the original version of this article  containeZhi Alan Cheng is the correct name."}
+{"text": "In decision making experiments, faster decisions are accomplished at the expense of accuracy. Conversely, more accurate decisions are accomplished at the expense of time (see ). These"}
+{"text": "After the publication of this work , we notiThe author apologises for this oversight."}
+{"text": "A typesetting error led to the deletion of the Y-axis label in"}
+{"text": "After publication of this study , we discThe authors declare that they have no competing interests."}
+{"text": "After publication of this work , we noteThe corrected Acknowledgements have been included in full in this erratum."}
+{"text": "In the Author Contributions section, Porzia Maiorano (PM) should be listed as one of the persons who wrote the paper."}
+{"text": "The images for In addition, some labels were removed from"}
+{"text": "The correct statement is: \u201cAll relevant data are within the paper, its Supporting Information files, or available in Dryad via the link:"}
+{"text": "In Fig 1, the labels for traits use Portuguese abbreviations instead of English. Please see the corrected"}
+{"text": "After publication of this article , it has The correct presentation of Figs."}
+{"text": "Zohar MorMoshe LidjiDaniel ChemtobNoa CedarItamar GrottoUnfortunately, the original version of this article  containe"}
+{"text": "The Supplemental Information has now been corrected, and the journal regrets the error."}
+{"text": "Here we briefly present an update of the authorship list. After the publication of this study protocol , we beca"}
+{"text": "In the opening plenary lecture, Prof McCormack discusses the trials and tribulations of HIV prevention."}
+{"text": "Anatomical networks of brain systems emphasize their inherent hierarchical structure, in which the rich club (most inner core of the brain) is highlighted because it promotes topological efficiency and integrates communication between regions . The hie"}
+{"text": "Unfortunately, the original version of this article  containeCorrect version is Saikat Ghosh."}
+{"text": "In the Author Contributions section, Eutizio Egiziano (EE) should be listed as one of the persons who wrote the paper."}
+{"text": "The legends for Please see the complete, corrected Please see the complete, corrected"}
+{"text": "Unfortunately, the original version of this article  containeThe original version of the article has been updated to rectify these errors."}
+{"text": "In preparation of the manuscript  the authLoof (1971), \"After Aurivillius, the nematode fauna of Svalbard archipelago was studied by"}
+{"text": "We wish to make the following changes to the published article , agreed"}
+{"text": "No abstract. Due to an oversight, the Acknowledgments section of the above article  incorrec"}
+{"text": "The last two authors, Katharina Storck and Hoang Nguyen The, should be noted as contributing equally to this work."}
+{"text": "The second and third authors, Adisak Prapavorarat and Phattarunda Jaree, should be noted as contributing equally to this work."}
+{"text": "The corrected figures are given below.After the publication of this work , we noti"}
+{"text": "After publication of the original article , the autThe correct version of the Acknowledgements section is included below:"}
+{"text": "The first two authors, Subhra Subhadra and Mohanraj Karthik, should be noted as contributing equally to this work."}
+{"text": "Unfortunately, the original version of this article  containeThis subheading has been also corrected in the original article."}
+{"text": "After publication of this work , we noteshould be removed, and replaced by the following two equations:"}
+{"text": "The images for Figs Please see the complete, corrected Please see the complete, corrected Please see the complete, corrected"}
+{"text": "Drug overdose is now the leading cause of injury death in the United States, surpassing deaths from motor vehicle accidents in 2008 . Naloxon"}
+{"text": "After publication of the manuscript , it emerWe apologise for any inconvenience."}
+{"text": "Unfortunately, the address of the corresponding author was presented inaccurately in the published version this paper . Instead"}
+{"text": "Unfortunately, the original version of this article  containeHedgehog signaling: modulation of cancer properties and tumor microenvironment"}
+{"text": "Unfortunately, the original version of this article  containeThe correct Acknowledgements section has been included in full in this erratum."}
+{"text": "The sixth sentence of that paragraph should read, \u201cDuring the same period, significant decreases occurred in bidi"}
+{"text": "After publication of this work , the autThe correct Fig."}
+{"text": "In the Data Availability statement and the Materials and Methods section, the GenBank accession number KU70477 appears incorrectly. The correct accession number should be KU707477."}
+{"text": "Biotechnology for Biofuels [Following publication of the original article in Biofuels , it was"}
+{"text": "Unfortunately, the original version of this article  containeThe name has been correctly included in full in this erratum."}
+{"text": "Gut Pathogens [Following publication of the original article in athogens , it was Please find the correct Figs."}
+{"text": "In the Author Contributions section, Martin Kennedy (MAK) should be listed as one of the persons who conceived and designed the experiments."}
+{"text": "The original version of this article unfortunately contained a mistake. The given and family names of authors were Interchanged except the following author Maria Chiara Buscarinu, Carolina Gabri Nicoletti, Alessandra Girolama Marfia and Antonio GalloThe correct author names should be"}
+{"text": "Following publication of the original article , the autThe original article  has been"}
+{"text": "Following publication of the original article , it cameThe authors thank you for reading and apologize for any inconvenience caused."}
+{"text": "Following the publication of the original article , the autThe original article has been corrected."}
+{"text": "Furthermore, they apologize to the readership for any inconvenience caused.The corrected versions of"}
+{"text": "Following the publication of the original article , the autThe original article has been corrected."}
+{"text": "Following publication of the original article , the autThe corrected figure is given in this article."}
+{"text": "In the original article published, the Fig. The original article has been corrected."}
+{"text": "Following the publication of the original article , the autThe original article has been corrected."}
+{"text": "Following publication of the article , the autThe authors thank you for reading and apologize for any inconvenience caused."}
+{"text": "In the original publication, errors were regrettably found in Fig."}
+{"text": "Following publication of the original article , the namThe original article has been revised."}
+{"text": "Following the publication of the original article , in htmlThe original article has been corrected."}
+{"text": "Following the publication of the original article , the wroIn addition, In Table 2 there are missing numbers in theta column; the Table The original article has been corrected."}
+{"text": "Following publication of the original article , the autThe original article  has been"}
+{"text": "Lastly, the authors apologize to the readership for any inconvenience these errors may have caused.The corrected versions of"}
+{"text": "In the original publication of the article, the table Table 3) has been incorrectly published, this has been corrected in this paper (Table  has been"}
+{"text": "Following publication of the original article , the affThe original article has been corrected."}
+{"text": "Following the publication of the original article , we wereThe original article has been corrected."}
+{"text": "Following publication of the original article , the autThe authors apologize for any inconvenience caused."}
+{"text": "Following the publication of the original article , the autThe original article has been corrected."}
+{"text": "However,the wrong labeling of the axes can lead to confusion. Below, an amended The authors regret that"}
+{"text": "Following publication of the original article , the autThe correct Tables The original article  has been"}
+{"text": "Following publication of the original article , the autTherefore, the revised Fig."}
+{"text": "Following publication of the original article , the autIt has been added in this correction and the original article has been updated."}
+{"text": "CorrectionAfter publication of this article , it was The original publication has been corrected."}
+{"text": "Following the publication of the original article (Kwon et al. The original article has been corrected."}
+{"text": "The original article has been corrected, as below:"}
+{"text": "They also regret any inconvenience caused to the readership of the Journal.After having examined their original data, the authors have realized that inadvertent errors were made during the process of compiling these figures. Corrected versions of"}
+{"text": "Following publication of the original article , the autThe incorrect author name is: Elisabeth WihelmThe correct author name is: Elisabeth WilhelmThe author group has been updated above and the original article  has been"}
+{"text": "Furthermore, they apologize to the readership for any inconvenience caused.The corrected versions of"}
+{"text": "Following publication of the original article , one of The original article has been corrected."}
+{"text": "Following publication of the original article , we haveThe order of the affiliations has been updated above and the original article  has been"}
+{"text": "Following publication of the original article , the co-The original article has been corrected."}
+{"text": "Due to a production error, The original version of this article has been updated."}
+{"text": "Following publication of the original article , the autThe original article  has been"}
+{"text": "Dear Editor,I read with interest the report of C Sakai and the colleges concerning the fourth heart sound (FHS) and hypertrophic cardiomyopathy ."}
+{"text": "Following publication of the original article , the autThe original article  has been"}
+{"text": "Following publication of the original article , the affThe original article has been corrected."}
+{"text": "Following publication of the original article , the aut\u2020 Zixu Yuan, Xihu Yu and Wenle Chen contributed equally to this study.The original article  has been"}
+{"text": "Following publication of the original article , the autThe published article has since been corrected with the complete declaration. The authors apologize for any inconvenience caused."}
+{"text": "Following publication of the original article , error wThe Original article has been corrected."}
+{"text": "Following publication of the original article , the autThe original article has been corrected."}
+{"text": "The images for Figs Additionally, the images for Figs Please see the figures with the correct captions below."}
+{"text": "In the original version of the article , Xin LiuThe original article has been corrected."}
+{"text": "Following publication of the original article , the autThe incorrect author name is: Alfredo Giorgio SpedicatoThe correct author name is: Giorgio Alfredo SpedicatoThe author group has been updated above and the original article  has been"}
+{"text": "Following publication of the original article , the oriThe original article has been  updated"}
+{"text": "The last two authors, Suresh Mahalingam and Ali Zaid, should have been noted as joint senior authors. The publisher apologizes for the error."}
+{"text": "Following publication of the original article , the autThe original article  has been"}
+{"text": "Following publication of the original article , the autThe Graphical Abstract has been provided in this Correction.The original article  has been"}
+{"text": "Following publication of the original article , the autThe original article has been corrected."}
+{"text": "In our paper, the authors noted one error in Fig."}
+{"text": "Following publication of the original article , the autThe correct author affiliation has been provided in this Correction.The original article  has been"}
+{"text": "Following the publication of the original article , the autThe original article  has been"}
+{"text": "Following the publication of the original article , the autThe original article has been corrected."}
+{"text": "Following publication of the original article , an erroThe author group has been updated above and the original article  has been"}
+{"text": "Following publication of the original article , the autThe published article has now been updated with this declaration."}
+{"text": "In the article titled \u201cInvestigation of Hepatoprotective Activity of Induced Pluripotent Stem Cells in the Mouse Model of Liver Injury\u201d , a dupliTo take into account the continuity of the hepatocyte differentiation from iPSCs to mature iPSC-derived hepatocytes, the authors have provided new images for Figures"}
+{"text": "The original article contained an error in attribution of affiliation to co-author, Ricardo Resta which has since been corrected."}
+{"text": "Following the publication of the original article , the autThe original article has been corrected."}
+{"text": "Following the publication of the original article , the autThe author group has been updated above and the original article  has been"}
+{"text": "Following the publication of the original article , the autThe original article has been corrected."}
+{"text": "Following the publication of the original article , the autThe original article has been corrected."}
+{"text": "In the original publication, errors were found in Fig."}
+{"text": "Following the publication of the original article , the autThe original article has been corrected."}
+{"text": "Following publication of the original article , the autThe original article  has been"}
+{"text": "Following the publication of the original article , the co-The original article has been corrected."}
+{"text": "Following the publication of the original article , the autThe original article  has been"}
+{"text": "In the Acknowledgments, the name Przemek Prusinekiwcz should appear as: Przemek Prusinkiewicz."}
+{"text": "Following publication of the original article , the autThe original article  has been"}
+{"text": "Following publication of the original article , the autThe corrected Fig."}
+{"text": "Following publication of the original article , it was The correct Fig."}
+{"text": "Following publication of the original article , the autThe original article  has been"}
+{"text": "Following publication of the original article , the autThe incorrect author name is: Alan Meijia MazaThe correct author name is: Alan Mejia MazaThe author group has been updated above and the original article  has been"}
+{"text": "Following publication of the original article , it was The original paper has been  updated."}
+{"text": "Following the publication of the original article , we wereThe original article has been  correcte"}
+{"text": "Following the publication of the original article , we wereThe original article has been corrected."}
+{"text": "Following the publication of the original article , we wereThe original article  has been"}
+{"text": "In the original article , the imaThe inadvertent error of misplacing the image in Fig."}
+{"text": "Following publication of the original article , Navaz NThe original article has been corrected."}
+{"text": "Following the publication of the original article , we wereThe original article has been corrected."}
+{"text": "Following publication of the original article , the autThe incorrect author name is: Svetlana DanishnaThe correct author name is: Svetlana DanshinaThe author group has been updated above and the original article  has been"}
+{"text": "Following publication of the original article , the autThe original article  has been"}
+{"text": "Lastly, the authors apologize to the readership for any inconvenience these errors may have caused.The corrected versions of"}
+{"text": "In the original version of this article , the corThe original article has been corrected."}
+{"text": "Recognizing his contributionto the early code development, we are amending the author list toinclude our collaborator Prokop Hapala as a co-author, who could notbe reached at the time of the original article submission."}
+{"text": "Following publication of the original article , the autThe authors apologise for this error."}
+{"text": "Following publication of the original article , the autThe original article has been corrected."}
+{"text": "With distinct levels of completeness and capabilities to model different developmental stages, embryo models offer an experimental platform for To view this SnapShot, open or download the PDF."}
+{"text": "Following publication of the original article , an erroThe original article has been corrected as well."}
+{"text": "Following the publication of our article, the authors noted one error in Fig."}
+{"text": "Following publication of the original article , we haveThe author group has been updated above and the original article has been corrected."}
+{"text": "Following publication of the original article , it was The original paper has been updated."}
+{"text": "Following publication of the original article , the affThe original article has been corrected."}
+{"text": "This does not affect the curves, as the authors used a predict function.Following the publication of the original article , we wereCorrect Tables"}
+{"text": "Furthermore, they apologize to the readership for any inconvenience caused.The corrected versions of"}
+{"text": "Following publication of the original article , it cameThe authors thank you for reading and apologize for any inconvenience caused."}
+{"text": "Following the publication of the original article , we haveThe original article has been corrected."}
+{"text": "Following publication of the original article , the autThe original article has been corrected."}
+{"text": "In the original publication of the article , the autThe original article has been corrected."}
+{"text": "Following publication of the original article , the autThe original article has been corrected."}
+{"text": "Following the publication of the original article , we wereThe original article has now been corrected."}
+{"text": "Following the publication of the original article , we wereThe original article has been corrected."}
+{"text": "Following publication of the original article , the autThe author group has been updated above and the original article  has been"}
+{"text": "Therefore, the revised version of the Funding section paragraph should read as follows:"}
+{"text": "Following publication of the original article , it cameThe article has now been updated with the corrected affiliation."}
+{"text": "Unfortunately, in the original publication of the article , the sixThe original article has been corrected."}
+{"text": "Following the publication of the original article , the autThe original article  has been"}
+{"text": "Following publication of the original article , we haveThe original article has been corrected."}
+{"text": "Following publication of the original article , minor eThe original paper has been updated."}
+{"text": "Following publication of the original article , the autThe original article  has been"}
+{"text": "Following publication of the original article , the autThe original article has been corrected."}
+{"text": "Following publication of the original article , the autThe incorrect author name is: Julie BarnettThe correct author name is: Julie BarnetThe author group has been updated above and the original article [ article  has been"}
+{"text": "Following the publication of the original article , we wereThe original article has now been corrected."}
+{"text": "The corrected Table Unfortunately, in the original publication of the article , headingThe original article has been corrected."}
+{"text": "The authors regret the omission of supplementary material in the above article. This has since been added."}
+{"text": "Following publication of the original article , the autThe incorrect author name is: Joel Zhen Khang HngThe correct author name is: Joel HngThe author group has been updated above and the original article  has been"}
+{"text": "Following publication of the original article , we haveThe author group has been updated above and the original article  has been"}
+{"text": "Following publication of the original article (Masuelli et al. The author group has been updated above and the original article has been corrected."}
+{"text": "Following the publication of the original article , we wereThe original article has been corrected."}
+{"text": "Following publication of the original article , we haveThe author affiliation has been updated above and the original article  has been"}
+{"text": "Following publication of the original article (Li et al. The original article has been corrected."}
+{"text": "Following publication of the original article , the autThe correct Fig."}
+{"text": "Errors were introduced in Figure The published article has been updated. These corrections do not affect the results, discussion and conclusions presented in the article."}
+{"text": "Furthermore, they apologize to the readership for any inconvenience caused.The corrected versions of"}
+{"text": "Following publication of the original article , the autThe affiliation list has been updated above and the original article  has been"}
+{"text": "Following publication of the original article , the autThe affiliation list has been updated above and the original article  has been"}
+{"text": "Following the publication of the original article , the autThe correct Figure"}
+{"text": "Following publication of the original article , it was Figure The publisher apologizes for any inconvenience caused."}
+{"text": "Following publication of the original article , the autThe correct Fig."}
+{"text": "Following publication of the original article , the autThe original article has been corrected."}
+{"text": "Following publication of the original article , the autThe original article has also been corrected."}
+{"text": "Following the publication of the original article , the autThe correct figure Fig.  has been"}
+{"text": "After publication of the article, the authors noticed an error in formula In the Shared parking allocation model subsection of Sharing-parking allocation model establishment section, there are errors in formula"}
+{"text": "Following the publication of the original article , we wereThe original articles has been updated."}
+{"text": "On page 8753, the blood vesselbackground is missing in the last picture of"}
+{"text": "Furthermore, they apologize to the readership for any inconvenience caused.The revised versions of"}
+{"text": "Following publication of the original article , it was The original article has now been updated with the correct caption."}
+{"text": "Following publication of the original article , the autThe original article has been updated."}
+{"text": "Following publication of the original article , the autThe PDF version has been corrected.The original article has been corrected."}
+{"text": "Following the publication of the original article , the autThe original article has been corrected."}
+{"text": "Following publication of the original article , the autThe original article has been corrected."}
+{"text": "Following publication of the original article , it was The original article has been corrected."}
+{"text": "Following the publication of the original article , the autThe original article has been corrected."}
+{"text": "Following publication of the original article (Zhang et al. The original article has been corrected."}
+{"text": "Following publication of the original article , the affThe original article has been corrected."}
+{"text": "The corrected figure is shown below:Also, there were some errors found in"}
+{"text": "Following the publication of the original article , we wereThe corrected Figs."}
+{"text": "Following the publication of the original article , the autThe original article  has been"}
+{"text": "Following publication of the original article , the autThe author group has been updated above and the original article  has been"}
+{"text": "Following publication of the original article (Bhattacharya et al. The author affiliation has been updated in this erratum."}
+{"text": "Following publication of the original article , the autThe author group has been updated above and the original article  has been"}
+{"text": "Following publication of the original article , the autThe original article has been corrected."}
+{"text": "Following the publication of the original article , we wereThe original article has now been corrected."}
+{"text": "Following the publication of the original article , we wereThe original article has been corrected."}
+{"text": "Following publication of the original article , the belHadi Charati and Min-Sheng Peng contributed equally to this work."}
+{"text": "Following publication of the original article , the autThe original article  has been"}
+{"text": "In the article titled \u201cPlasmatic Membrane Expression of Adhesion Molecules in Human Cardiac Progenitor/Stem Cells Might Explain Their Superior Cell Engraftment after Cell Transplantation\u201d , the terThe authors and the Editorial board agree to the publication of the corrigendum."}
+{"text": "Following the publication of the original article , the autThe symbol of equal contribution has been added behind the names of the authors.\u2020, Shushu Huang\u2020, Shuai Ma\u2020, and Lei Chen\u2020.Wanzi JiangThe author group has been updated above and the original article  has been"}
+{"text": "Following the publication of the original article , we wereThe original article has been corrected."}
+{"text": "Following publication of the original article , the autThe updated Fig."}
+{"text": "Following publication of the original article , the autThe original article  has been"}
+{"text": "Following the publication of the original article , we wereThe original article has been corrected."}
+{"text": "Following publication of the original article , the FigThe original article has been corrected."}
+{"text": "In this article , the wroThe in-text reference citations has been arranged in numerical ascending order and the corresponding list has been arranged accordingly."}
+{"text": "Following the publication of this article, the authors noted that images of MB231 group in Fig."}
+{"text": "Following publication of the original article , the parThe original article  has been"}
+{"text": "The authors also apologize to the readership for any inconvenience these errors may have caused.Consequently, the corrected versions of"}
+{"text": "Following the publication of the original article , we wereThe original article has been corrected."}
+{"text": "Following publication of the original article , the autThe original article  has been"}
+{"text": "Following publication of the original article , the autThe incorrect author name is: Arezoo EsmaeilzadehThe correct author name is: Arezoo EsmailzadehThe author group has been updated above and the original article  has been"}
+{"text": "PLoS Medicine\u2014that involves the pharmaceutical industry, pharmaceutical benefit management corporations, the managed care industry, and the political and lobbying forces that zealously guard their secrets could not have been told without the help of courageous men and women .\u201d"}
+{"text": "After the publication of the above manuscript , the autThe pre-publication history for this paper can be accessed here:"}
+{"text": "Medical News Today article [The authors of this study  claim th article , Eli Lil"}
+{"text": "A few years ago we reported extrapulmonary translocation of UFPs after intratracheal instillation in hamsters  and afteIn their study, In conclusion, although the article by"}
+{"text": "After the publication of this work , we becaWe regret any inconvenience that this error might have caused."}
+{"text": "They cited When evaluating epidemiologic findings, it can be helpful to compare the range of likely exposure levels to the exposure levels of toxicologic significance . The canFinally, De Roos et al.\u2019s Table 2  shows an"}
+{"text": "The first two authors, Qingye Li and Rong Chang, should be noted as contributing equally to this work."}
+{"text": "In the Methods section, the third equation in the section titled \"Estimating Model Parameters\" is incorrect. Please view the complete, correct equation here:"}
+{"text": "The published article contains an earlier version of Fig 6, which does not reflect revisions made during the review process. Please see the correct"}
+{"text": "Following publication of the original article , the autThe original article has been updated."}
+{"text": "After publication of the original article , it cameThe correct version of Fig."}
+{"text": "In the original version of this article , publishComella KristinSilbert RobertParlo MichelleOriginally the author names have been published as:Kristin ComellaRobert SilbertMichelle ParloThe correct names are:"}
+{"text": "Upon publication of the original article , the autPlease see below the correct Fig."}
+{"text": "The amended Acknowledgements section has been included in this erratum accordingly.After publication of this article , the aut"}
+{"text": "In the recently published article, there were incorrect and missing contents in the Acknowledgments section, which should have read as follows."}
+{"text": "Following publication of the original article , the autThe original article has been updated."}
+{"text": "Following publication of the original article , author The original article has been corrected."}
+{"text": "During production, Chengshui Chen was omitted from the list of corresponding authors in the original article . Both Ji"}
+{"text": "The original article  containeAs such, the original article title has now been updated to reflect the correct title."}
+{"text": "Following publication of the original article , one of The original article has been updated."}
+{"text": "Following publication of the original article , the autThe original article has been corrected."}
+{"text": "Unfortunately, the original version of this article  containeBox 1 Lessons learnt: the views of researchers and patient representatives"}
+{"text": "Following publication of the original article , an erraThe original article has been corrected."}
+{"text": "Following publication of the original article , the autThe tables should appear as follows:The original article has been corrected."}
+{"text": "After publication of our article , we becaThe corrected Fig."}
+{"text": "Following publication of the original article , the firThe original article has been updated."}
+{"text": "In the author contributions, Yohei Kondo should be listed in the Software section instead of Keita Kamino. The publisher apologizes for this error."}
+{"text": "Since publication of their article , the autThe original article has been corrected."}
+{"text": "The original article  mistakenAs such, the authors would like to acknowledge the following funding source:NSF award CBET 1644835."}
+{"text": "Following the publication of the original supplement article , it was The correct title has been included in this correction."}
+{"text": "Following publication of the original article , one of The original article has been corrected."}
+{"text": "Following publication of the original article , one of The original article has been corrected."}
+{"text": "Upon publication of the original article , the incThis has since been acknowledged and corrected in this erratum."}
+{"text": "Following publication of the original article , the autThe original article has been updated."}
+{"text": "Dear Editor,The recent report on Zika virus infection is very interesting and ther"}
+{"text": "Following publication of the original article , one of The original article has been updated."}
+{"text": "Following publication of the original article , the autThe original article has been updated."}
+{"text": "In the Author Contributions section, Georgia Herbert (GH) should be listed as one of the persons who contributed to Formal analysis."}
+{"text": "Since the introduction of tyrosine kinase inhibitor imatinib, the first targeted cancer therapy, survival of Chronic Myelogenous Leukemia (CML) patients has approached that of the normal population . Treatme"}
+{"text": "Following publication of the original article , the autThe original article has been updated."}
+{"text": "After publication of the original article , the autThe correct version of Table"}
+{"text": "Following publication of the original article , the autAlka BatykyOriginally the author name has been published as:Alka BatyckyThe correct author name is:"}
+{"text": "Unfortunately, after publication of this article , it was The equation should have read:The original article has been updated to correct this error."}
+{"text": "After publication of this paper , it was The original article was corrected."}
+{"text": "Unfortunately, the original version of this article  containeThe correct match is as follows:"}
+{"text": "Tobacco Induced Diseases [Following publication of the article in Diseases , we wereWe apologize for the inconvenience this may have caused."}
+{"text": "Following publication of the original article , the autThe original article has been corrected."}
+{"text": "Following the publication of this article , it was Figure The correct Figure"}
+{"text": "The original article  containsConsequently, the correct version of each figure can be seen below in this erratum."}
+{"text": "The original article  containsAs such, the correct version of Fig."}
+{"text": "In the published article , the autThe correct version of Fig."}
+{"text": "This omission has now been corrected, and the journal regrets the error."}
+{"text": "Following the publication of this article , the autThe correct version of Table"}
+{"text": "Following publication of the original article , one of The original article has been updated."}
+{"text": "Following publication of the original article , the corThe original article has been updated."}
+{"text": "In the Author Contributions section, Guihu Zhao (GHZ) should be listed as one of the persons who analyzed the data. The publisher apologizes for the error."}
+{"text": "Following the publication of this article , the autThe correct versions of Figs. The original article has been corrected."}
+{"text": "Following the publication of this article , it was The corrected Fig."}
+{"text": "Following publication of the original article , the autThe original article has been corrected."}
+{"text": "Please see updated table below; this has also been updated in the original article accordingly.In the original publication of this article , the tab"}
+{"text": "Upon publication of this article , an erroThe above formula has been corrected in the original article."}
+{"text": "The first two authors, Magdalena Filipowicz and Christine Bernsmeier, should be noted as contributing equally to this work."}
+{"text": "Sir,In their concise review on evolving treatment strategies for myeloma,"}
+{"text": "Two 500Because floods are becoming more frequent and more severe over much of the Mississippi River basin , statistAs"}
+{"text": "Prof Thevanesam is affiliated with the University of Peradeniya Faculty of Medicine, Peradeniya, Sri Lanka. The article has been corrected online ("}
+{"text": "The potentiality of lanthanide chelates as photoluminescent markers and cleaving agentsof nucleic acids is discussed, the main emphasis being on the chelates derived from aromaticnitrogen bases."}
+{"text": "Ensuring adequate iodine nutrition status of women, especially throughout pregnancy, is an extremely important public health goal. Given the negative effects of a number of environmental chemicals on the thyroid , it beco"}
+{"text": "In the Author Contributions section, Peter A. White (PAW) should be listed as one of the persons who wrote the paper."}
+{"text": "Sir,We would like to highlight the importance of checking the portable ventilator before usage for each patient. The Oxylog 2000 ventilator  is being"}
+{"text": "Sir,Extrapolating from our findings that mRNA for the dermcidin gene ("}
+{"text": "Sir,I read the current publication of Sankhla and Khan with great interest. I agree"}
+{"text": "The first two authors, Shihui Yang and Quan Peng, should be noted as contributing equally to this work."}
+{"text": "A competing interest was omitted. The competing interests section should state that Laura Bossi, Megali Becker, and Patricia Zerr were affiliated with Faust Pharmaceuticals at the time of the study."}
+{"text": "In the second column of Table 2, the top two SNPs are listed incorrectly. Please view the corrected table here:"}
+{"text": "In the eighth column of Table 1, five patients were incorrectly listed as having ILD. Please view the corrected table here:"}
+{"text": "Following publication of the original article , the autThe original article has been corrected."}
+{"text": "Following publication of the original article , the autDario GuadiosoOriginally the author name has been published as:Dario GaudiosoThe correct author name is:"}
+{"text": "Following publication of the original article , the autOriginally the author\u2019s name was spelled as:Makbule Guclin OzsoyThe correct spelling is:Makbule Gulcin Ozsoy"}
+{"text": "Following publication of the original article , the autThe publishers apologise for this error. The original article  has been"}
+{"text": "The first two authors, Ruigang Diao and Xiaodong Mu, should be noted as contributing equally to this work."}
+{"text": "In the Author Contributions section, John Kelleher should be listed as one of the persons who conceptualized the study."}
+{"text": "Following publication of the original article , the autThe publishers apologise for this error. The original article  has been"}
+{"text": "After publication of the original article , we wereThe original article has been corrected."}
+{"text": "Following publication of the original article , one of As such, the original article  has beenThe publisher apologizes for any inconvenience caused."}
+{"text": "Following publication of the original article , the autAs such, the original article  has been"}
+{"text": "After publication of the article , it was Non-communicable disease prevention policy process in five African countriesWe apologize for the inconvenience caused."}
+{"text": "Following publication of the original article, the authors recognized that the left and right panels in Fig."}
+{"text": "In the Author Contributions section, Chris Pagnutti (CP) should be listed as one of the persons who wrote the original draft of the paper."}
+{"text": "Following publication of the original article , the autThe authors wish to apologise for this error."}
+{"text": "Following publication of the original article , the autVijayapalani ParamasivanOriginally the author name has been published as:Paramasivan VijayapalaniThe correct author name is:"}
+{"text": "In the Author Contributions, Rachel M. Radin (RMR) should be listed as one of the persons who conceptualized the study."}
+{"text": "Following the publication of this article , the autThe correct version of Fig."}
+{"text": "Following publication of the original article , the autThe addition is:\u201cThe authors acknowledge the financial support by the University of Graz.\u201dThank you."}
+{"text": "Upon publication of this article , it was The original article has been corrected."}
+{"text": "Following publication of the original article , the autBiruk YeshitilaOriginally the author name was published as:Biruk YeshitelaThe correct author name is:"}
+{"text": "In the Author Contributions section, Mimi E. Lam (MEL) should be listed as one of the persons who worked on the methodology."}
+{"text": "Unfortunately, nowadays most hospitals around the world are infected , and hosThe authors confirm that there are no conflicts of interest."}
+{"text": "In the Author Contributions section, Tamimount Mohammadi (TM) should be listed as one of the persons who conceptualized and supervised the study."}
+{"text": "In the Author Contributions section, Feng He (FH) should be listed as one of the persons who acquired funding."}
+{"text": "Following publication of the original article , the autMianxu JiangOriginally the author name has been published as:Xumian JiangThe correct author name is:"}
+{"text": "The original article  containsAs such, the corrected tables can be seen ahead."}
+{"text": "Please view the complete, correct equation here:In the Specifying In the Multivariate normal phenotypes subsection of the Methods, there is also an error in Equation (26). Please view the complete, correct equation here:"}
+{"text": "At the request of the authors, the article titled \u201cPrevalence of Bacteriuria and Antimicrobial Susceptibility Patterns among Diabetic and Nondiabetic Patients Attending at Debre Tabor Hospital, Northwest Ethiopia\u201d  has beenThe first author Seble Worku takes the full responsibility and apologizes for the error."}
+{"text": "The first two authors, Claire Faltermeier and Timothy Chai, should be noted as contributing equally to this work."}
+{"text": "The corrected figure is provided, and the article has been corrected online ("}
+{"text": "A short video embed showing the patient riding a bike, running, and squatting has been removed from the article as the video was removed from YouTube."}
+{"text": "Following publication of the original article , the autAudora SabatiniOriginally the author name was published as:Audora Sabatini TheresiaThe correct author name is:"}
+{"text": "There is an error in the Notice of Retraction published on February 20, 2019 ["}
+{"text": "Following publication of the original article , the autNavid Mohammadpour ToyserkaniOriginally the author name has been published as:Navid Mohamadpour ToyserkaniThe correct author name is:"}
+{"text": "Due to a technical error, the copyright line of the above mentioned article was incorrect. The original publication has been corrected."}
+{"text": "In the original publication of this article, the RICTOR immunoblot in Fig."}
+{"text": "In the original publication, the label of Fig."}
+{"text": "Following publication of the original article , the autThe correct version of the table has been included in this correction.The original article has been corrected."}
+{"text": "Following publication of the original article , the autHabtom LegeseOriginally the author name was published as:Haftom LegeseThe correct author name is:"}
+{"text": "Following publication of the original article , one of The original article has been corrected."}
+{"text": "In the Author Contributions section, Rafal K. Woycicki (RKW) should be listed as one of the persons that completed Formal Analysis for the paper."}
+{"text": "Following publication of the original article , the autThe original publication of this article has been corrected."}
+{"text": "Following publication of the original article , the autJean BousqetOriginally, the author name was published as:Jean BousquetThe correct author name is:"}
+{"text": "Following publication of the original article , the autNikolaos KoustouvelisOriginally the author name has been published as:Nikolaos KoutsouvelisThe correct author name is:"}
+{"text": "Following publication of the original article , the autThe original publication has been corrected. Table"}
+{"text": "In the original publication, table row alignment was incorrectly formatted for all the tables. The corrected Tables"}
+{"text": "Following the publication of this article , the autThe correct version of Table"}
+{"text": "Prior to publication of the original article , the autThe publishers apologise for this error. The original article has been updated."}
+{"text": "Following publication of the original article , the autThe authors wish to apologise for this error."}
+{"text": "Following publication of the original article , the autKhalid AlshahriOriginally the author name has been published as:Khalid AlshehriThe correct author name is:"}
+{"text": "Following publication of the original article , the autThe correct versions of the figures are given below:"}
+{"text": "Upon publication of the original article , the autThe original article has been corrected."}
+{"text": "Following publication of the original article , the autGenet GedifOriginally the author name was published as:Getnet GedifThe correct author name is:"}
+{"text": "After publication of the original article , we wereThe original article has been corrected.The publisher apologies for the inconvenience."}
+{"text": "Specific mechanisms, providing reuptake of cathecholamine and amino acid neurotransmitters  into cells of the central nervous system are well known, whereas neuronal uptake of neuropeptides have not previously been reported."}
+{"text": "The corrected figures are reproduced here, and the article has been corrected online ("}
+{"text": "In the Materials and methods section, there is an error in the first equation of the section titled \"Event detection.\" Please view the complete, correct equation here:"}
+{"text": "After publication of the original article , the autThe corrected Table"}
diff --git a/PMC_clustering_996.jsonl b/PMC_clustering_996.jsonl
new file mode 100644
index 0000000000000000000000000000000000000000..715d24a8e676f7937644dd7e154913931081a949
--- /dev/null
+++ b/PMC_clustering_996.jsonl
@@ -0,0 +1,937 @@
+{"text": "This Retraction follows an Expression of Concern relating to this article previously published by Portland Press.Bioscience Reports at the request of the authors following receipt of a notification from a reader, alerting the authors to duplications in panels of Figure 3A.This article is being retracted from The authors are unable to correct the article and wish to retract the article. The Editor-in-Chief and Editorial Board agree with the retraction."}
+{"text": "Plants Editorial Office has been made aware that there are partly inadequate materials in the published paper [Plants and the authors of [The ed paper . In thisthors of . Plants Editorial Office apologizes to the readers of Plants for any inconvenience caused. To ensure the addition of only high-quality scientific works to the field of scholarly communication, the paper [The he paper  is retra"}
+{"text": "The development of the generic drug represents one of the strongest axes of the regulation of drug expenditure. In addition to saving the cost of the medical treatment that it allows, it has other interests. Among other things, the fact that it is among the best tools that will allow the viability and success of basic medical coverage in our country . The lawTo modify and supplement the 2012 decree, which has experienced some shortcomings and limitations noted during its implementation, but also to comply with the latest recommendations of the World Health Organization (WHO), and new international standards in this regard, the Ministry of Health published a new decree on bioequivalence in March 2019. This decree underlines the obligation for any pharmaceutical industry, marketing generic drugs to file a bioequivalence study, when submitting the application for renewal of the marketing authorization for these medicines. This project also sets the necessary conditions for the realization of the bioequivalence studies and the scientific criteria justifying the exemption from these studies . This le"}
+{"text": "At the end of 2019, a new coronavirus was identified in people living in the city of Wuhan in China. Since the appearance of the first cases in Wuhan, the SARS-CoV-2 epidemic has spread to the international scale. The COVID-19 pandemic is considered by international scientific societies to have an impact on blood donation and transfusion activities. Efforts must be made at the level of the transfusion centres to ensure proper management of the impact of this health crisis on the availability and the safety of blood products. The National Blood Centre of Morocco (MNBC) has demonstrated a great reactivity and a great adaptability since the beginning of the epidemic and has implemented several measures to face this health crisis. These measures have been updated taking into account the updating of data from national health authorities and international scientific societies concerning this new virus. The current SARS-CoV-2 pandemic is considered to have the potential to decrease and jeopardize the supply of blood products . Thus, bst December 2019 in China, the MNBC organized several brainstorming meetings in the presence of national experts in blood transfusion in order to provide information about the real risk of this virus in blood donors and in transfused patients. The MNBC was also looking for information on the impact that this health crisis could have on the continuity of the various blood transfusion activities.The National Blood Centre of Morocco (MNBC) constitutes a scientific reference on a national scale. It is responsible for the implementation of the Ministry of Health's policy on blood transfusion and is responsible for carrying out several missions including scientific and epidemiological monitoring and technical support for Moroccan Regional Blood Centres (MRBC). Since the outbreak of the new coronavirus SARS-CoV-2 on 31th January 2020, the MNBC implemented the first measures and started the exclusion of at-risk donors from the new coronavirus. He informed the doctors responsible for the medical selection of donors on the current epidemiological situation of the new coronavirus and the need to deepen the medical interview by looking for signs such as cough, fever, runny nose, diarrhoea or vomiting. The temperature of donors was taken at any suspicion of fever in a blood donor and the temporary deferral for a period of 28 days was started for anyone who has stayed in a country considered to be at risk on this virus or who has been in contact with a subject returning from a country at risk or who has presented recent respiratory symptoms of a viral nature. The donors have been informed for the need to take all the necessary preventive measures with regard to infection with this virus. The doctors of the medical selection in MRBC have been regularly informed about the update of the definition of the suspect case COVID-19 issued by the Moroccan health authorities.The first data published on January 2020 by the international societies such as the European Centre of Disease Control (ECDC) and the American Association of Blood Banks (AABB) stipulated that donor selection is an essential element of blood safety during this new epidemic ,6. The fth February 2020 that the risk mitigation strategy with regard to SARS-CoV-2 may also include quarantine of plasma for transfusion as a safety measure [th March 2020, the High Council of Public health (HCPH) stipulate that fresh frozen plasma that does not benefit from the pathogen mitigation technique is secured by quarantine [rd March 2020, the MNBC established the quarantining of all plasma produced by the MRBC from 1st February 2020 and not using it as therapeutic plasma. A national quarantine procedure has been drawn up by the national quality assurance service of the MNBC and sent to all MRBC. From 5th May 2020, the MNBC updated monthly this decision based on the scientific data available to date in relation with this new coronavirus and that reported the absence of any case of transmission of SARS-CoV-2 by blood products [Another axis on which the MNBC had worked is the safety of blood products. The World Health Organization (WHO) reported on 28 measure . On 14thproducts ,8.In the same way, the potential for a viremic phase of SARS-CoV-2 is currently not known and is likely to be limited to severe disease, analogous to other respiratory infections. With the current knowledge gaps there are too many uncertainties to recommend testing of blood donors for SARS-CoV-2 at present ,2. The tst April 2020 the following measurements: the strengthening of the self-exclusion system for blood donors by adopting the new possible case definitions of COVID-19 from the Ministry of Health, the reinforcement of pre-donation interrogation and in particular the medical selection of donors by adopting the case definition of COVID-19 according to the updated recommendations of the Ministry of Health, the reinforcement of the post-donation information with particular attention during the 28 days following the donation, where the donor is required to inform the transfusion centre of any evocative sign that could suspect an infection with SARS-CoV-2, the providing donors with the COVID-19 self-exclusion form prepared by the CNTSH so that donors can provide feedback through the contact means available to them, namely telephone numbers and address electronic, , the reinforcement of the haemo-vigilance system at MRBC level and collaboration with care services for the establishment of traceability of blood products transfused during this critical period and for the collection of any transfusion incident whatever its nature.But although that the risk of SARS-CoV-2 blood transmission has not established, an haemo-vigilance system should be in place for helping to understand the risk from blood and components and the overall effectiveness of the measures taken by the blood service ,8. The bnd March 2020. These measures concerned the providing blood donors and staff with appropriate protective measures , the incitement to compliance with barrier gestures and standard hygiene rules, the respect for the distancing measures recommended by the Ministry of Health and the possibility of making an appointment before blood donation to minimize the risk of donors gathering and condensing at the fixed centres sites. In the same context, the regional blood center had to program donations by group of 5 donors and to arrange the reception areas in order to avoid any gathering in the medical selection process or while waiting for the sample. For the administrative activities, the MNBC has established the reduction of the number of meetings to urgent meetings and meetings for monitoring urgent and priority actions, the reduction of the number of meeting participants and the setting up a meeting by videoconference as many opportunities as possible. All missions involving travel between cities have been postponed except for urgent actions. At the level of laboratories activities, on 26th March 2020, the MNBC established the monitoring of standard bio-security practices and a well-identified circuit of samples from suspect or infected COVID-19 patients received by MRBC as part of a request for LBP for blood transfusion. The activities at the level of donation biological qualification laboratories was organized so as to ensure continuity of work in this critical process even in the event of contamination of laboratory staff. The MNBC considered that the activity at the level of the biological qualification laboratories as a critical activity and that it must be maintained in order to continue to meet the needs in LBP. For this reason, since the beginning of the epidemic, the MNBC has continued to supply the MRBC with all equipment, reagents and fungibles necessary for the continuity and smooth running of activities at the transfusion centre level.Donor and staff safety is another priority for the MNBC. Protective measures have been established since the start of the SARS-CoV-2 epidemic and reinforced after the declaration of the first case of SARS-CoV-2 in Morocco on 2nd March, the number of donors has started to decrease and particularly after the introduction of restrictive measures concerning displacement issued by the Moroccan authorities from 19th March. In March, the number of donations made nationally was 27,812, in April it was 22,415 donations and in May 17,147 donations. An emergency plan was launched at the MNBC to resolve this situation. This plan was based on these measures: encouraging the competent authorities to issue special authorizations for blood donors to go to blood centres, the establishment of a blood donation service at all blood transfusion centers from 9 am to 7 pm to recruit as many donors as possible, encouraging associations working in the field of blood donation to provide assistance to blood transfusion centres, in particular awareness-raising and transportation of donors from their homes to transfusion centres and from blood centres to their homes after giving blood, the coordination and organization of several campaigns for blood donation in partnership with several institutions: the Moroccan general directorate of national security, the Moroccan auxiliary forces, the Moroccan general directorate of territorial surveillance, the Moroccan customs department, the royal gendarmerie, the Moroccan Ministry of the Interior and others Moroccan institutions.Since the declaration of the first case of COVID-19 infection in Morocco, in order to mitigate the impact of the COVID-19 pandemic on the reduction of availability of blood donors and labile blood products, the MNBC appointed a committee how was in charge of twice-daily monitoring of the national LBP stock and the daily collection of the number of blood donations made at each blood transfusion center. This committee was charged also to ensure the regulation between MRBC to face the event of a particular need expressed by a regional blood center for LBP. The deficit centres are supplied from other blood transfusion centers and the necessary logistics are provided by the MNBC. Unfortunately, after the declaration of the first case on COVID-19 in Morocco on 2These actions have led to an increase in the number of donors with 25,157 blood donations nationally in June. This has had a positive impact on the national stock in LBP and has made it possible to satisfied the demands for blood, in particular the urgent demands and the demands of chronic multiple transfusion patients. Besides these actions the MNBC recommends, from April 2020, the strengthening of dialogue and collaboration between MRBC and clinical services because the implication of the care services is essential for the good management of requests for blood products particularly for clinical situations requiring urgent transfusions of LBP and for poly-transfused patients. In health emergencies and during epidemics, the management of blood requests at the level of transfusion centres and at the level of care services must be based on the concept of patient blood management ,8.th January 2020, the MNBC has continued to regularly inform the Moroccan health authorities of all the measures taken by the MNBC in the field of blood transfusion and has updated the data transmitted to the MRBC about the new coronavirus. He has established an on-call list at the national level to respond to any request for information and to resolve any problem related to the availability of stable and labile blood products. The MNBC and MRBC had, also, established continuous communication with healthcare services. Donors have been informed about the availability of phone numbers for information on donating blood and making appointments. The MNBC responded to all requests for information from the media and newspapers regarding blood donation.The strategy of communication is very important in the COVID-19 pandemic. Blood service must communicate clearly to ensure that the national emergency response team, donors and recipients and the public are properly informed and understand planned actions ,8. The cTo take part in a process of therapeutic management of the COVID-19 infected patient, the MNBC had established a clinical trial protocol on the use of COVID-19 convalescent plasma in patients infected with SARS-CoV-2 in Morocco. According to current scientific publications, plasma treatment of convalescent COVID-19 has proven to be of great benefit in the management of patients infected with SARS-CoV-2 . It\u00b4s efFor the same therapeutic purpose, the MNBC expressed a predisposition to ensure the supply for the COVID-19 infected patients in case of need for stable blood products such immune-globulins and albumin. For COVID-19 patients\u00b4 transfusion care, Moroccan blood transfusion centres have been required to prepare and deliver blood products to some hospitalized COVID-19 confirmed patients. The transfusion centres have been required to establish a well-identified circuit of samples from COVID-19 patients suspected or confirmed in compliance with bio security measures at the level of the laboratories of the transfusion centres.Finally, it should be emphasized that through a strategy of listening, sharing and active communication, the staff of the various Moroccan transfusion centers demonstrated exceptional dedication and incomparable commitment during this difficult period while demonstrating a positive reactivity to the recommendations established by the MNBC.Several recommendations have been established by the MNBC to ensure effective support for transfusion centres and to ensure the availability and safety of blood products. These recommendations, of course, are subject to adjustment based on changes in current conditions."}
+{"text": "Despite the considerable progress of medical science over the years, pediatric patients can still be affected by serious illnesses that, regardless of age, lead to experiencing all the clinical, psychological, ethical and spiritual problems related to incurable diseases and death. The interaction between the peculiarities of individuals, and the clinical conditions presented define a changing and complex profile of health needs, which requires organized, dynamic and multidimensional responses. The approach to the pediatric patient must consider its biological, psychological, relational and clinical characteristics. Such aspects in fact determine and modulate the type and quantity of the needs presented, conditioning the actions to be taken and the organizational models to be implemented. In accordance with some international regulations, it is essential that healthcare professionals provide adequate information to the patient's understanding in order to enhance participation in the decision-making process regardless of the possibility of expressing consent or dissent to the treatment. Frequently, the sharing of decisions on the care path not only fails to involve children, but often lacks rigorously designed interventions for parental involvement. Therefore, the development of care models that focus on the needs of the pediatric population is crucial. The present paper aims to analyze the problems of information quality and sharing in pediatric care pathways in order to promote shared decision-making and improve the knowledge of the professionals involved. As a secondary objective, the study will provide useful insights for the prevention of decision-making conflicts frequently at the basis of the dispute in the pediatric field. Medical advances in clinical diagnosis and treatment have revolutionized the natural history of many diseases, favorably changing the prognosis and life expectancy. The achievement of similar results, however, has forced modern medicine to focus on the pathophysiology of diseases and to divert attention from the sick person in its entirety. Consequently, the use of different welfare procedures risks deriving from the uncritical application of protocols rather than from conscious decisions discussed extensively with the patient according to the ethical principles of freedom and responsibility .Despite the considerable progress of medical science over the years, pediatric population, can still be affected by serious illnesses that, lead children and adolescents to experiencing all the clinical, psychological, ethical and spiritual problems related to incurable diseases and death.In the pediatric field, scientific knowledge has led to the reduction of acute pathological states and shifting the goal of medical care toward chronic conditions, rare and congenital diseases that usually require careful long-term planning and multidisciplinary coordination.Currently, pediatric patients suffering from chronic and severe diseases are increasingly subjected to invasive diagnostic and therapeutic procedures, mostly related to intensive care. Similar treatments are sometimes applied without a preliminary dialogue aimed at assessing frailty, needs, expected benefits, predictable risks, and quality of life offered. A similar paternalistic relationship between the doctor and the pediatric patient with chronic or serious diseases is understandable in light of the fragility of the individual, but it is to be considered anachronistic in the face of the wide scientific knowledge and care alternatives offered by modern medicine. In this regard, the management of care relationship in such type of patients should be oriented toward respect for autonomy and sharing, in order to prevent controversies and to consolidate the therapeutic alliance.quoad valetudinem  can be considered as an extension of informed consent. In particular, it represents a care approach based not only on information and consent, but above all on the close interaction between doctor - holder of scientific knowledge - and patient - owner of inalienable rights - in sharing responsibilities and choices regarding the therapeutic path , 13. TheIn the pediatric field, parental participation in the decision-making process is fundamental in order to optimize the understanding of the patient's will without, however, delegating therapeutic choices to the family . In consPediatric departments, especially in the area of emergencies and severe diseases, represent highly specialized and intensive care facilities. Professionals working in similar structures are involved in the treatment of extremely delicate patients due to the need for security and knowledge of the reality that surrounds them. As with other medical branches, the goal of hospitalization in a pediatric ward is to overcome clinical problems in order to promote the recovery of a decent and acceptable quality of life for the sick child.Sharing decisions in pediatrics constitutes a moment of global acceptance of the patient that is based on the control of pathological manifestations, attention to the human and social aspects of the disease, in the relationship with family members, in psychological and spiritual support. The effectiveness of the sharing and the good quality of the care relationship can be defined based on the clarity of the therapeutic objectives, the awareness and acceptance by the patient and the parents, the ethical sustainability and the agreed definition of the limits between intensive and palliative care , 27.The extensive approach to the therapeutic relationship makes it possible to achieve fundamental goals of the healing process such as understanding the views, sensitivity, basic needs and expectations of the patient and their families. Finally, this kind of involvement allows the decisions to be calibrated in full compliance with the values of all parties involved in the care process .According to several ethical and legal orientations, the time spent in communication is in effect a part of the therapeutic process. The cornerstones of good communication between the pediatricians, the patients and their families can be summarized as follows:- correct and understandable description of the patient's condition;- consistency and homogeneity of the information provided by the different healthcare professionals involved in the care path;- gradualness of the information process;- attention to the need for information at all times, in order to avoid potential negative repercussions  on the sick child and the family;- two-way information flow;- empathy and ability to induce the patient to externalize his own emotion;- ability to prevent possible conflicts with family members and family members by constantly checking the degree of understanding of the information provided;- availability to dialogue with preparation of the necessary means.Communication is not only information, but it is mainly an interaction in which the transmission of the message content is a mere element. Clear, transparent and comprehensive communication is undoubtedly the best tool for optimizing the care path and conflict prevention. Communication and therapeutic relationship are inextricably correlated. In fact, the quality of communication is directly proportional to the trust and reciprocity of listening in the relationship between doctor and patient; in the same way, a good relationship is fed by communication conceived as an integral part of the care process.Advanced Care Planning (ACP) is an important planning tool that allows to share in advance the most important therapeutic choices in the case of life-limiting or life-threatening conditions . DespiteThe discussion on care provisions should focus on the multiple facets of the possible therapeutic approaches, with the assessment of curative and palliative care, management strategies for emergency situations and patient's will on resuscitation. The determination of the child's goals and expectations is fundamental for psychological well-being and the care relationship, as it allows to address multiple aspects of end-of-life assistance including home care .The ACP process protects the patient's autonomy and improves end-of-life healthcare. Consistent with several scientific contributions, the benefits deriving from an adequate Advance Care Planning consist in the reduction of aggressive treatments, the improvement of the quality of life in its terminal phases, the reduction of hospitalizations, and the greater adherence of care to the patients' needs \u201337. NeveIn opposition to the relevant positive implications, the ACP in the pediatric field presents some barriers mainly related to the young age of the patient and consequently to the difficulties of involvement in discussions concerning the treatments to be implemented in case of deterioration of health conditions , 40. SimDespite the described barriers, Advance Care Planning should always be encouraged and performed with an appropriate timing even if patients and families seem unprepared. Indeed, not infrequently patients and relatives are unaware of the need for the ACP or are waiting for the health professional to introduce the discussion . DialoguConclusively, different issues concerning the modalities of pediatric assistance in severe or progressive diseases require a deepening by the scientific community. The correct management of pediatric assistance implies a complex relationship between healthcare professionals, patient and family members, but above all a particular sensitivity of health structures and adequate training of the personnel involved.The present study has highlighted the lack of organization of pediatric care pathways in certain contexts, in particular as regards precisely the processes of information, consent and sharing as well as the protection of self-determination.In order to prevent the occurrence of prejudices and implement care pathways in such delicate areas as severe diseases and end of life it is necessary to propose recommendations of good pediatric practice.In the first place, it seems advisable to support the dialogue through the identification of communicative strategies useful for the management of uncertainty characterizing some clinical conditions; through a communicative process of good quality it is in fact possible to limit uncertainty and guide conscious choices.Secondly, despite the concerns related to the effects of the communication of bad news on the patient and family members, prognostic honesty must be considered fundamental. The transparent sharing of all the implications of the disease represents an opportunity for the protagonists of the care path to prolong the treatment time and jointly formulate hypotheses about the future.It is also recommended to consider communication, understanding, informed consent, therapeutic choices and prognoses not only as procedural elements but also as aspects underlying the subjective expressions and around which the care relationship is built. The availability, serenity and clarity of the dialogic exchange, as well as the more frequent use of explicit contents, facilitate the possibility of managing emotional experiences more easily, of integrating subjective experiences and of adequately involving the pediatric patient in the sharing process.Finally, it is advisable to direct the different phases of the care pathway toward strengthening the autonomy and centralizing emotions in order to improve the comprehension skills of the interlocutors, improve the communication process and promote the sharing of therapeutic choices.All authors contributed to the drafting and critical revision of the work. All authors have approved the final version of this manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In this section, the authors should have indicated that their research was funded by the Key Scientific and Technology Project of Henan Province (grant no. 162102310133).The authors apologize to the funders of their research project, and to the readership of the Journal for any inconvenience caused."}
+{"text": "As GSA turns 75, it is an appropriate time to review the history of the creative aging movement. This symposium explores the research, policy and practice of creative aging - past and present, starting in the 1970\u2019s through the efforts of pioneering leaders in the aging, humanities and arts in conjunction with growing support from the newly established National Endowment for the Arts and related aging and health service systems. The foundational research by Gene Cohen, MD PHD and others at the turn of the 21st Century will be described in terms of its building the science to utilize the humanities and arts to scaffold policy and practices that promote the potential of aging through creative expression rather than the pervasive view of aging as a time of loss. Moving towards strength-based approaches to further the development of overall health including brain reserve, physical fitness and social networks, creative aging collaborations will be highlighted as the future of this initiative. Case studies of joint research projects between state departments of both aging and arts in partnership with Universities will demonstration contemporary practices to address major aging issues around isolation, loneliness and caring for the care giver."}
+{"text": "The authors wish to inform readers of a correction to the study. The informed consent and the IRB approval number in the Materials and methods section, should be revised as follows:The human tissue biopsy samples used in this study were collected as part of a study approved by the human ethics committee of Taipei Medical University Joint Institutional Review Board (TMU-JIRB No. N201701061). The waiver of informed consent for the study was monitored by TMU-JIRB.The authors regret the inconsistency and apologize for not identifying the issue earlier in the publication process."}
+{"text": "Genomic research offers the potential of significant improvements in diagnosis, treatment, and in health care more broadly. The achievement of these benefits against a background of well-founded public trust and confidence depends crucially upon the addressing of a range of important ethical challenges such as those related to consent, privacy, ownership of samples and data sharing (Cambon-Thomsen et al., One area of intense debate in recent times has been the model of consent that should be appropriate for genomic and biobanking studies in low and middle-income countries, and what type of governance mechanism is required for safeguarding the interest of research participants and their communities in such studies. A growing number of empirical studies from Africa have highlighted the challenges with obtaining and documenting consent in lower and middle income countries, particularly in sub-Saharan Africa (Bull et al., Several proposals have been made to address the issue of consent in genomic and biobanking research \u2013 including approaches capable of taking seriously both the need for valid consent and the fact that the specific details of future research to be undertaken on collected samples and data cannot be known at the time of initial recruitment. The most prominent amongst these is what is known as \u2018broad consent\u2019, a model of consent that can allow the use of biological samples and associated data both in specific immediate research and in future research, subject to appropriate governance arrangements. Proponents of broad consent have argued that this model of consent is legitimate because it is consistent with current practices, it respects the autonomy of participants, and the risks involved are minimal (Fisher & Layman, Public views and perceptions of research with stored samples and biobanking research are increasingly being reported in high-income countries such as the United States of America and the United Kingdom and are contributing to the development of regulatory frameworks (Garrison et al., The focus of the paper by Mweemba et al. reports on the findings of a qualitative study with participants recruited for an H3Africa study on rheumatic heart disease in Zambia. The study, which focused on participants\u2019 views on broad consent, sample and data sharing, and secondary use studies, found that broad consent tended to be viewed as an acceptable approach to consent for genomic research as long as the reasons for storing samples and data for future research were clearly explained at the time of initial consent. Whilst accepting the idea of broad consent, a subset of interviewees took the view that some limitations on future uses might be appropriate by, for example, limiting such uses to research into the same disease as that which motivated original recruitment. The headline finding of the paper is that broad consent is an appropriate model for genomic research in Africa as long as appropriate governance is in place overseeing the limits of future research use.The focus of the paper by Rutakumwa et al., is broader in focus exploring the view of Ugandan research participants about the requirements for ethical genomic research in Uganda. The study suggests that conventional ethics standards and practices may not be sufficiently responsive to participant and community concerns and interests in addressing the ethical complexity of the ethical challenges in research. The findings reported in the paper suggest three areas in which work is required to improve the responsiveness of genomic research in this regard. These are: the importance of deemphasising the roles of experts and institutions in consent processes, achieving greater clarity about the timing and nature of the feedback of health-related findings and updates on project progress, and more effective support for research participants during and after the study.Finally, the paper by Tindana et al., reports on interviews with key stakeholders in Ghana on consent practices in relation both to the genomics research and to the broader practice of biobanking. The study included interviews with genomics researchers, fieldworkers, laboratory staff, and members of ethics committees, in addition to both participants and those who refused to participate. The paper reports a willingness to participate in research initiatives involving the collection and sharing of samples and data for future research, as long as there are good governance structures in place and, importantly, that participants receive feedback about the progress of the research endeavour as a whole, and about the research uses of their samples and data. The study findings emphasise the importance of the discussion of feedback plans at the time of initial consent.Taken together, these three papers make an important contribution to debates on the ethics of genomic research in Africa at a time in which the scale of such research is rapidly increasing in scale, scope, and importance."}
+{"text": "A further examination of the original data files disclosed that an error had been made in the labelling of some of the original images.Molecular Medicine Reports for allowing them the opportunity to publish this Corrigendum, and apologize to the readership for any inconvenience caused.The corrected version of"}
+{"text": "Thank you for the opportunity to respond to the issues raised by Nenna et al. in the recent letter to the editor. All authors would also like to thank Dr Nenna and her colleagues for their recognition of the consensus . We haveThe timing of LUS performance is an interesting issue, regarding its impact on results and diagnostic value. The timeline of the baseline LUS examination may start relative either to the beginning of the symptoms or the beginning of the treatment. In the literature reviewed for the consensus, researchers presented a varying approach to this matter, with the first LUS examination being performed from up to 45 min . The mosThe timing of the follow-up is another issue with far more differentiated timepoints. The first follow-up examination was performed in a time frame ranging from 48 h ,10 throuBoth the literature and clinical practice prove the utility of LUS in diagnosing and monitoring different complications of pneumonia, including lung abscesses. The case described by Bloise et al.  reportinTogether with Nenna et al., we hope that following the already solid and still growing evidence, LUS will be implemented in the new guidelines on the management of pneumonia and bronchiolitis in the pediatric population."}
+{"text": "Bioscience Reports at the request of the authors following receipt of a notification from multiple readers, alerting the authors to unusual features in the Western blots of Figure 8B as well as repeated features in Figure 12A. The authors have confirmed that parts of the work were outsourced; however, they have failed to disclose this within the paper or provide details of the collaborator upon request.This article is being retracted from The authors are unable to confirm the validity of the results and wish to retract the article. The Editor-in-Chief and Editorial Board agree with the retraction"}
+{"text": "The Editor-in-Chief is issuing an Editorial Expression of Concern as after publication of this article , it has Neither of the authors agree to this Expression of Concern."}
+{"text": "There are a number of errors in In the Participants and research design subsection of the Materials and methods, there are errors in the fifth sentence of the second paragraph. The correct sentence is: One hundred and two females were interviewed, 66 were recruited  and 49 completed it  ."}
+{"text": "Nanomaterials have become increasingly important both in basic research and in applications. Some properties may be understood only at the level of the quantum mechanical study of these materials. The purpose of this Special Issue is to advance our fundamental understanding of the structure and technologically important properties of nanomaterials with the help of computational quantum solid-state physics and chemistry. There is no doubt that quantum mechanical approaches are indispensable in comprehensive studies of nanomaterials and will be increasingly crucial in the future. Of course, this field is too extensive and too diverse to be described in a single volume. Nevertheless, this Special Issue provides at least a partial snapshot of the state of the art of computational quantum mechanical studies of nanomaterials and covers some recent advances and problems.The scope of the articles included in this Special Issue is quite diverse, including adsorption of gas molecules on nanoclusters , domain In all these cases, application of the quantum methods was indispensable to determine how various features of atomic configuration of these materials are reflected in their properties and experimentally ascertained quantities. Nanomaterials collects a series of original research articles providing new insight into the application of computational quantum physics and chemistry in research on nanomaterials. It illustrates the extension and diversity of the field and indicates some future directions. I am confident that this Special Issue will provide the reader with an overall view of the latest prospects in this fast evolving and cross-disciplinary field.In summary, this Special Issue of"}
+{"text": "BioMed Research International has retracted the article titled \u201cThe Effects of Cytokines in Adipose Stem Cell-Conditioned Medium on the Migration and Proliferation of Skin Fibroblasts In Vitro\u201d . The arta. Figure 1d in  and Figub. Figure 2a in  is the sThe authors apologize for these errors and agree to the retraction of the article. The author's institution investigated our concerns and concluded that these errors were not the result of academic misconduct. The article is being retracted with the agreement of the journal and the editorial board due to concerns regarding the reliability of the data."}
+{"text": "The World Health Organization\u2019s (WHO) World Report on Vision was released in October 2019 and the World Report on Hearing debuted at the World Health Assembly in May 2020. The Reports recognize the fundamental nature of sensory health in the health and well-being of individuals and societies and outline the significant and growing burden of hearing loss and vision impairment across the life course. Together the efforts call for more affordable, accessible, and integrated care to foster sensory health for all and represent a major opportunity to advance vision and hearing care as public health priorities nationally and internationally. With the largest burden of sensory impairment among older adults, this symposium will focus on applying the findings and recommendations of the Reports to gerontology. The first presentations will provide an overview of the World Reports on Vision and Hearing from members of the core working groups involved in the Reports and discuss them within the context of the WHO\u2019s Decade of Healthy Aging. The second set of presentations will feature the latest findings related to sensory health from the Global Burden of Disease Study. In moving toward action, task sharing is a critical theme that runs throughout the Reports and we will cover the application of task sharing to hearing care as an example of applying public health principles to advance sensory health. As we advocate for improving the lives of older adults, sensory health remains a significant component with great potential for progress and collaboration."}
+{"text": "Dear Editor,A 61-year-old man presented with a three-month history of symmetric depigmented lesions on the hands and perilabial region . No otheThe etiology of vitiligo is still unclear.Drug-induced vitiligo is a rare side effect of several systemic and topical drugs.As far as the authors know, the present case represents the first clinical confirmation of the onset of vitiligo in a patient with hypogonadism, supporting the thesis that hypogonadism can be associated with vitiligo. At the same time, there is insufficient evidence to support a role of testosterone replacement therapy in the development of vitiligo. Indeed, no areas of depigmentation were observed at the testosterone application sites (chest and thighs). Further studies are needed to investigate the role of testosterone in pigmentation, also extending the research to possible new therapeutic implications.None declared.Giovanni Paolino: Drafting and editing of the manuscript; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.Pietro Bearzi: Drafting and editing of the manuscript; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.Santo Raffaele Mercuri: Approval of the final version of the manuscript; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.None declared."}
+{"text": "The Excellence in Rehabilitation of Aging Persons Award lecture will feature an address by the 2020 Excellence in Rehabilitation Award recipient Kenneth J. Ottenbacher, PhD, OTR. The Excellence in Rehabilitation of Aging Persons Award is designed to acknowledge outstanding contributions in the field of the rehabilitation of aging individuals."}
+{"text": "In the original article, there was an error. An inaccurate statement was made in the Funding statement.A correction has been made to Funding. The corrected statement reads as follows:Funding was awarded as part of a portfolio submission by the University of the West of Scotland to the Chief Scientist Office, part of the Scottish Government Health and Social Care Directorate.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "In this paper, we present the results of the research concerning extraction of informative gene expression profiles from high-dimensional array of gene expressions considering the state of patients\u2019 health using clustering method, ML-based binary classifiers and fuzzy inference system. Applying of the proposed stepwise procedure can allow us to extract the most informative genes taking into account both the subtypes of disease or state of the patient\u2019s health for further reconstruction of gene regulatory networks based on the allocated genes and following simulation of the reconstructed models. We used the publicly available gene expressions data as the experimental ones which were obtained using DNA microarray experiments and contained two types of patients\u2019 gene expression profiles\u2014the patients with lung cancer tumor and healthy patients. The stepwise procedure of the data processing assumes the following steps\u2014in the beginning, we reduce the number of genes by removing non-informative genes in terms of statistical criteria and Shannon entropy; then, we perform the stepwise hierarchical clustering of gene expression profiles at hierarchical levels from 1 to 10 using the SOTA (Self-Organizing Tree Algorithm) clustering algorithm with correlation distance metric. The quality of the obtained clustering was evaluated using the complex clustering quality criterion which is considered both the gene expression profiles distribution relative to center of the clusters where these gene expression profiles are allocated and the centers of the clusters distribution. The result of this stage execution was a selection of the optimal cluster at each of the hierarchical levels which corresponded to the minimum value of the quality criterion. At the next step, we have implemented a classification procedure of the examined objects using four well known binary classifiers\u2014logistic regression, support-vector machine, decision trees and random forest classifier. The effectiveness of the appropriate technique was evaluated based on the use of ROC (Receiver Operating Characteristic) analysis using criteria, included as the components, the errors of both the first and the second kinds. The final decision concerning the extraction of the most informative subset of gene expression profiles was taken based on the use of the fuzzy inference system, the inputs of which are the results of the appropriate single classifiers operation and the output is the final solution concerning state of the patient\u2019s health. To our mind, the implementation of the proposed stepwise procedure of the informative gene expression profiles extraction create the conditions for the increasing effectiveness of the further procedure of gene regulatory networks reconstruction and the following simulation of the reconstructed models considering the subtypes of the disease and/or state of the patient\u2019s health. The use of gene expression datasets for the reconstruction of gene regulatory networks (GRN) and the simulation of the reconstructed models is one of the topical directions of current bioinformatics ,2,3,4. GThe aforementioned presented facts indicate the relevance of the research concerning the extraction of groups of informative genes considering particularities of the investigated objects for purpose of further reconstruction of GRN based on the extracted genes and simulation of the reconstructed models. Within the framework of this research, we solve this problem based on the complex application of classification and clustering techniques with the use of fuzzy inference system at the final step of decision making concerning the extraction of a set of the informative gene expression profiles.n and m are the number of samples and genes respectively. We suppose that the samples can be divided into previously known classes. The main problem consists of the extraction of genes, which allow us to divide the samples into classes maximally correctly in terms of the used criteria.The initial dataset is presented as a matrix of gene expressions: There are a lot of works which are devoted to gene expression data processing nowadays. So, in Reference  the authReferences ,24 consiThe issues concerning gene extraction to solve the problem of cancer types classification are considered in Reference . The autIn Reference , the autHowever, we would like to note that accuracy of the classifier operation in the case of the use of high dimensional gene expression data depends on the vector of the extracted genes which are used as the classifier inputs. The perspective of our research is the reconstruction of a gene regulatory network based on the extracted genes and following simulation of the reconstructed models. In this case, the extraction of an optimal subset of gene expression profiles can increase the informativity of the reconstructed gene regulatory network and, as a result, it can create the conditions for better understanding of the character of genes\u2019 interconnections during the following simulation process considering both the state of the patient\u2019s health or subtype of disease. In Reference , we solvThe aim of this paper is the development of a technique of stepwise gene expression data extraction on the basis of complex use of cluster analysis, binary classifiers and fuzzy inference system. To our mind, it can contribute to increasing the objectivity of informative genes\u2019 selection considering the state of the patients\u2019 health for the purpose of both further gene regulatory networks\u2019 reconstruction based on the allocated genes and simulation of the reconstructed models.formation of the matrix of gene expressions for the investigated samples. In the case of the use of DNA microarray experiments technique, this step involves background correction, normalization, PM correction and summarization. In the case of mRNA molecules sequencing method use, this step assumes allocation of genes count matrix and following transforming the values of this matrix into suitable range;extraction of genes which are identified as informative in terms of absolute value of gene expressions, variance and Shannon entropy.hierarchical clustering of gene expression profiles at the levels from 1 to N using SOTA clustering algorithm with correlation distance metric;division of the samples in allocated clusters of gene expression values into previously known classes and calculation of the quality criteria considering both the samples distribution within the appropriate classes and the distance between the samples in different classes;selection of the best clusters in terms of the used criteria at each of the hierarchical levels. These clusters correspond to the extreme values of the used quality criteria;applying the binary classifiers to the data in obtained clusters at each of the hierarchical levels. Formation of the intermediate solutions for each of the used classifiers and for each of the selected clusters;setup of fuzzy inference system. Definition of the membership functions for both the input and output variables, setup of ranges of the input and output parameters variation, knowledge base formation;applying the fuzzy classifier at each of the hierarchical levels;results analysis. Selection of the optimal cluster of gene expression profiles in terms of the used criteria.Implementation of this stage assumes removing genes, expressions profile of which were identified as non-informative in terms of variance, average of absolute values of gene expressions and Shannon entropy. We assumed that if gene expressions for all samples  and differences of gene expression values for different samples (variances) are small, and if expression values for various samples are varied chaotically and this fact does not allow us to identify correctly the classes of the examined samples , then, this gene can be removed from the dataset as non-informative one. The value of Shannon entropy for each of the gene expression profiles was calculated using James-Stein shrinkage estimator technique .calculation of variance, average of absolute values and Shannon entropy for each of the genes expression profiles. Formation of both the ranges of these criteria variation and steps of their values change;formation of clusters of the examined samples considering the data annotation. In the case of our dataset use, the samples can be divided into two clusters ;Determination of clustering quality criterion which is calculated at each step of change of the used criteria. Within the framework of our research, we used as the clustering quality criterion the multiplicative combination of WB-index  and CaliWB-index :(1)QCinK is the clusters quantity; N is the number of samples; s; i-th sample in the cluster s; i, j and s respectively; Here, increasing the boundary values of variance and average of absolute values from minimum to maximum ones and Shannon entropy values from maximum to minimum one within the admissible ranges and removing genes for which the variance and average of absolute values are less and Shannon entropy is larger than appropriate boundary values. Calculation of the clustering quality criterion at each step of this procedure execution by the formula (1);result analysis. Fixation of the used criteria boundary values which correspond to minimum value of the clustering quality criterion;final removing the non-informative genes using determined boundary values of the statistical criteria and Shannon entropy.To evaluate the appropriate criteria boundary values, we apply the technique presented in Reference . ApplyinAlgorithm 1: Gene expression profiles\u00a0reducing.Algorithm 1 presents the stepwise procedure of this stage implementation.N. We used the Self-Organizing Tree clustering Algorithm (SOTA) [N-th hierarchical levels respectively. Then, we calculated the quality criterion values for each of the allocated clusters at each of the hierarchical levels using formulas (1)\u2013(3). The vectors of genes expressions which correspond to the studied samples are used in this case as the investigated data. In other words, we evaluate in this case the proximity level of the samples, the attributes of which are the values of genes expressions which are grouped in the cluster. One cluster at each of the hierarchical levels was selected for the further research. These clusters correspond to the minimum value of the used quality criterion. Algorithm 2 for this stage implementation is presented below.Algorithm 2: Stepwise hierarchical gene expression profiles clustering based on the use of Self-Organizing Tree clustering Algorithm (SOTA).As was noted before, the main objective of this research is extraction of the most informative gene expression profiles in terms of their ability to identify the investigated samples considering both the state of the patient\u2019s health or subtype of the disease. For this reason, the next stage of the previously presented procedure execution is stepwise gene expression profiles clustering at the hierarchical levels from 1 to m (SOTA)  with corm (SOTA) . The simm (SOTA) . Thus, tLogistic Regression classifier (GLM) ;Support-Vector Machine classifier (SVM) ;Decision Tree classifier (CART) ;Random Forest classifier (RF) .Four binary classifiers were used to evaluate the resolving ability of gene expression profiles in the selected clusters:The quality criteria based on the errors of both the first and the second kinds were used to evaluate the appropriate classifier effectiveness within the framework of the research. We used the gene expression data of patients, which were investigated on lung cancer disease. The data contained two types of samples\u2014for healthy patients and patients with tumor. In this case, the classifier output can take two states: 0\u2014healthy; 1\u2014tumor. The obtained results in this case can be represented using a confusion matrix as follows :Accuracy (F-measure (F) is defined as a harmonic mean of Precision  and Recall (RC or Sensitivity) [itivity) :(5)F=2\u00b7Matthews correlation coefficient (ssifiers :(6)MCC=The following criteria were used to evaluate the classifiers effectiveness:Setup of the system:transforming the values of both the input and output variables into linguistic estimates. Formation of the membership functions for each of the variables;formation of a basic term-set with appropriate membership function for each of the terms;formation of a set of fuzzy rules which are agreed between input and output variables.Fazzification procedure. This step assumes evaluation of the membership functions values for each of the input variables crisp values for each of the terms.Fuzzy inference process. This step involves the following:min operation;aggregation or determination of the conditions truth degree by clipping the levels for the prerequisites of each of the rules using the activation or determining the truth degree for each of the fuzzy rules;max operation.accumulation or forming the resulting membership function for output variable using Defuzzification or determining the output variable crisp value.Necessity of the use of fuzzy inference system  is deterGSE19188 of patients examined at the early stage of lung cancer [rma method of data preprocessing  was used to form the array of gene expression profiles. Initially, the data contained 54,675 of genes (maximum number of genes at each of the microchips). Thus, the initial dataset was formed as a matrix in size .The publicly available gene expression data g cancer  was usedAt the first step, the non-informative genes in terms of variance, Shannon entropy and average of absolute values were reduced in accordance with technique described hereinbefore in the The simulation process concerning examined samples classification was performed using \u201cCaret\u201d , \u201cAER\u201d , and \u201ce1GLM, SVM, CART and RF binary classifiers to classify the data in the selected clusters. The tables contain the results of the test datasets classification using previously trained classifiers.The obtained results analysis allows the conclusion that a classifier based on the logistic regression model (GLM) is not effective for processing high-dimensional vectors of gene expressions. The classification results are not satisfactory in all cases. A little better result in terms of the used criteria was obtained in the case of the use of cluster, which was allocated at the tenth hierarchical level. This cluster contained only 24 of genes. However, the use of this classifier is not reasonable in the case of gene expression data classification. Significantly better results were obtained in the cases of other binary classifiers\u2019 application. It should be noted that all classifiers show worse classification results in the case of the use of data in the smallest cluster (24 of genes). In other cases, the results of the classifications almost agree under the use of The analysis of the ROC curves confirms the conclusion concerning the low effectiveness of the GLM classifier  and high effectiveness of RF, CART and SVM classifiers (areas under the roc-curves are significantly larger in comparison with areas obtained using GLM classifier). For this reason, we will use only the results of RF, CART and SVM classifiers as the input parameters of the fuzzy inference system at the next step of the simulation process.We defined the terms \u201cHealthy\u201d  and the columns are the extracted genes (401 of genes). As can be seen, the extracted genes really allow the division of the samples into two groups . Moreover, the samples of the patients with a lung cancer tumor can also be divided into subsets. It is naturally, since the state of the patients\u2019 health in this case can be different too. Thus, the gene regulatory network, reconstructed based on the genes extracted using the proposed technique, can allow us to understand both the particularities of the genes\u2019 interconnection and the influences of these interconnections on the state of the patients\u2019 health.n and m are the number of samples and genes respectively. The publicly available gene expression data GSE19188 of patients examined at the early stage of lung cancer disease were used as the experimental data. This data contained 156 DNA microchips. The annotation of the data has shown that the examined samples can be divided into two groups\u201465 of the samples for healthy patients and 91 of the samples belong to patients with lung cancer tumors. The initial dataset contained 54,675 genes .In this paper, we have presented the results of the research concerning the extraction of a set of informative gene expression profiles in terms of their mutual correlation, based on the complex use of both the clustering and classification techniques. The initial data have been presented as a matrix of gene expressions As the first step, we extracted the informative gene expression profiles by removing low-informative genes in terms of statistical criteria and Shannon entropy. In this case, we have used the clustering quality criterion as the main measure to evaluate the boundary values of the appropriate criteria. The initial matrix was transformed into a matrix of a size of  as a result of this step implementation. At the next stage, we performed the step-by-step gene expression profiles clustering at hierarchical levels from 1 to 10 with the use of the SOTA clustering algorithm, following the selection of the most informative clusters in terms of the used clustering quality criterion at each of the hierarchical levels. The number of clusters was changed from 2 to RF). The quality criteria based on errors of both the first and the second kinds have been used to evaluate the appropriate classifier effectiveness. The analysis of the obtained results has shown that classifier based on logistic regression model is not effective to process the high-dimensional vectors of gene expressions. Significantly better results have been obtained in the cases of other binary classifiers applying. However, it should be noted that all classifiers have shown worse classification results in the case of the use of data in the smallest cluster (24 of genes). In other cases, the results of the classifications almost agree under the use of Then, we carried out the classification of the examined samples using four well known binary classifiers\u2014Logistic regression classifier (The analysis of the results of the fuzzy inference system operation allows the conclusion that we have some worse results for clusters obtained at hierarchical levels from 5 to 9 and a significantly better result for clusters obtained at the 10th hierarchical level. Moreover, an analysis of the classification result for clusters at the 9th hierarchical level has shown disagreement of various binary classifiers despite very good classification results in the case of the use of individual classifiers. This fact indicates that the use of this cluster is not reasonable for the following research. The analysis of the obtained results has also shown the reasonability of using the cluster obtained at hierarchical level 7 for further research. This cluster contains 401 genes, the value of the clustering quality criterion is not large, and the classification results in terms of the used quality criteria are suitable in terms of both separate binary classifiers and the hybrid model based on the fuzzy inference system.The results of the proposed technique application has been presented using the heat map, where the rows and columns are the examined samples and the extracted genes respectively. The analysis of the heat map has confirmed the fact that the extracted genes really allow the division of the samples into two groups. Moreover, the samples of the patients with lung cancer tumors can also be divided into subsets considering the state of the patients\u2019 health. Thus, the gene regulatory network was reconstructed based on the genes extracted using the proposed technique, which allows us to understand both the particularities of the genes\u2019 interconnection and the influences of these interconnections to the state of the patients\u2019 health.To our mind, the conducted research can allow us to increase the objectivity for the extraction of genes, which can be used for the reconstruction of gene regulatory networks and the simulation of the reconstructed models considering the subtype of disease and/or state of the patient\u2019s health. Further, we are going to use the obtained results for both the gene regulatory networks reconstruction based on allocated genes and the simulation of the reconstructed models in order to better understand the gene interconnection in the cases of various states of the patient\u2019s health. This is the perspective of our research."}
+{"text": "The affiliations of In-Jae Choi and Eunsoo Choi are switched. In-Jae Choi's affiliation is The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "We contribute to the discussion on social exclusion by examining the relationship between material conditions and loneliness in a sample of individuals aged 50+ in the Survey of Health Ageing and Retirement in Europe (SHARE). In its 5th wave, the survey was extended to include specific items related to economic and social deprivation. We use this extended information on material conditions and examine how it correlates with the level and dynamics of a composite loneliness measure at the time of wave 5 and between wave 5 and 6 of the survey . In order to isolate the effect of material deprivation on loneliness, regression analyses include an extensive set of control variables. The analyses show a strong and significant relationship between material deprivation and both the level of loneliness and deterioration in the loneliness status."}
+{"text": "The health care consumption for the population insured by the Basic Health Insurance in Morocco are paid directly to the care providers for the health care or health products from the health insurance funds. The level of expenditure recorded is changing at an accelerated rate than the financial resources. The objective of this study is to evaluate the health care consumption care by the insured population under the Basic Health Insurance.This is a cross-sectional study analysis of the economic data collected by the National Moroccan Health Insurance Agency Related to the expenditures from the health insurance fund for both public and private sectors to identify the behavior of the consumption of health care by the insured population under the Basic Health Insurance.The medical expenditure of the covered population by the basic Health Insurance in Morocco has almost doubled from 354800 to 652500 US Dollars between 2009 and 2014 with significant increase in the public sector than the private sector. The share of expenditures in the public ambulatory care sector under Basic Health Insurance is higher relative to the hospital care. Although in the private sector the share of expenditures for both types of care varies. In 2014, the drug item expenditure accounted for 33% of Health Insurance expenses for both sectors. The level of health care consumption among the population in Long-Term Illness (LTI) represents 49,29% of the total expenditure by the Health Insurance whereas its insured covered population does not exceed 2,78%.Controlling the medical expenditure of the health insurance requires strengthening and the development of regulatory measures that contribute to the health reforms. For chronic diseases, it is necessary to put in place prevention actions. According to the World Health Organization (WHO), any progress towards universal coverage must take into account three essential dimensions relating to the extension of medical coverage to the uncovered persons, reducing the insured participation in the costs of care and expanding health care by the health insurance . In MoroType of study: this is a cross-sectional study analysis of the economic data to identify the behavior of the health care consumption of the insured persons by the Basic Health Insurance.Source of the study: the expenditures data were collected from the Moroccan National Health Insurance Agency for both public and private sectors between 2009 and 2014. This data collection is done after each accounting year of the health insurance funds from 2008 to 2014. The collection of data was done in compliance with the regulatory provisions of Law no\u00b0 09-08 [Research structure: Moroccan National Health Insurance Agency and the Faculty of Medicine of Rabat, Morocco.Criteria for inclusion and exclusion: the exploitation of the identified parameters results from the exercise of the health insurance funds between the period between 2008 and 2014. Only the data validated by the board of directors of the National Health Insurance Agency have been exploited. The study of expenditures stopped in 2014 and does not include student and self-employed expenses. Beneficiaries of the medical assistance scheme for the economically deprived population are not included. They depend on another system. The financial statements and the management procedures of the health insurance funds were excluded in this study.The studied parameters: 1) medical expenditure in Health insure for both sectors (public and private); 2) expenses according to the nature of the acts  3) expenses by Insured Profile: a) employees versus pensioner with their beneficiaries; b) Population with Long Term Illness (LTI). 4) the medical expense by medical act.Note that: 1) the employee is defined as a person in professional activity with his beneficiaries (spouse (s) and children); 2) the pensioner is defined as a retired person with his dependents. Pensioners include retired or disabled persons, surviving spouse (s), and dependents (children); 3) for Ambulatory care: the insured person advances the costs of care and the health insurance fund reimburses within a period not exceeding three months. 4) for Hospitalization: the health insurance fund pays the health professionals directly and the insured pays the co-payment only. 5) the population with a Long-term Illness (LTI) is all the beneficiaries registered with the health insurance funds for at least one chronic pathology.Limitations of the study: the process of affiliation to health insurance is a very dynamic process. The evolution results of the study parameters were static and didn't take into account the continuous dynamics of the population covered between each year so the result figures represent amounts paid during the financial year regardless of the date of occurrence of medical care.The medical expenditure of the covered population by the basic Health Insurance in Morocco has almost doubled from 354800 to 652500 US Dollars between 2009 and 2014 with significant increase in the public sector than the private sector . The shaThe Basic Medical Coverage faces a number of challenges. First, the high cost access to innovative medical quality care, additional to ensuring the sustainability of medical coverage and to guarantee the financial balance of the health insurance funds. Second, the inequality of the care offered throughout the Moroccan territory. Finally, the progression of non-communicable diseases (chronic diseases) linked to the change in the epidemiological profile of the Moroccan population. The control of health expenditure requires a better understanding of the patient's behavior of health care consumption and costs to the Basic Health Insurance and the determination of the key items of medical expenditure . The evoSince the start of health insurance in 2005, outpatient care was not eligible for reimbursements in the private sector including persons carrying chronic diseases. However, changes to the refund structure commenced in 2009, the behavior of insured persons regarding the refund application files did not automatically follow this dynamic. Then, the National Social Security Fund (private sector fund) started to exonerate the co-payment for Long-Term Illness (LTI) according to the type of the disease. This exemption covers all acts related to Long-Term Illness (LTI) by applying the coverage rate for each disease ranging from 77 to 100% . MedicalIn the end of 2014, the population suffering from Chronic Diseases has a very low share not exceeding 3% of the total population covered by the basic health insurance  whereas The performance of the basic medical coverage system in Morocco requires identification of the variants that comprise it, understanding the profile and the behavior of the health care consumption of the population covered. Controlling the medical expenditure of health insurance requires the development, and the strengthening of regulatory measures that contributes to the health reforms. For chronic diseases, it is necessary to put in place prevention actions.The entry of the Basic Health Insurance in Morocco;The Financing of Health in Morocco.The evolution of the medical expenses of the Basic Health Insurance in Morocco;Determination of the health care consumption profile of the population covered by the Health Insurance in Morocco.The authors declare no competing of interest."}
+{"text": "We are at a particularly propitious time in the history of the biology of aging and the science of health and humanity. It is a time for us to \u201cHonor the Past, Enrich the Future\u201d. Not long ago the study of the biology of aging was exclusively one of description of what happened with age\u2014how do organisms, including humans, change with age at the level of proteins, cells, tissues and physiology. The identification of major genetic factors that substantially increase life span in model organisms ushered in the advent of a highly exploratory period focusing on the molecular, cellular and genetics mechanisms of aging. The convergence of many different streams of basic and clinical research have brought us to today, where we stand on the cusp of new environmental, molecular genetic and pharmacological breakthroughs in the biology of aging that presage new interventions that promise a healthier lifespan. The presentations in this Presidential Symposium will be from four Early Career Investigators presenting their own pioneering research in some of the most important areas of research in the biology of aging."}
+{"text": "Bioscience Reports at the request of the Editor-in-Chief and the Editorial Board following receipt of a notification from a reader, alerting the Editorial Board to manipulation in Figure 8C.This article is being retracted from The authors have been contacted in regard to the retraction, and have not responded to the Journal. Given the extent of the issues raised, Editorial Board stand by the decision to retract the article."}
+{"text": "He ZY participated in the design of the study and performed the statistical analysis. Duan RH conceived of the study, and coordination and helped to revise the manuscript."}
+{"text": "Reviewers and editors had assessed the correct version of the figure. The conclusions drawn from the experiment shown in After publication, the authors reported a mistake made during the assembly of the Western blots in The labels in the Western blots of"}
+{"text": "Revista Latino-Americana deEnfermagem, RLAE) aims to contribute to the advancement of scientificknowledge and professional practice in Nursing and other health areas through thepublication of articles of high scientific and social merit that have followed theresearch integrity parameters and ethical codes of conduct recommended by theInternational Committee of Medical Journal Editors (ICMJE), the Committee on Publication Ethics (COPE), and the Code of Conduct and BestPractice Guidelines for Journal Editors.The Latin American Journal of Nursing  are available in data repositoriesrecognized by the academic community, strongly encouraging this deposit;It adds the nominal identification of the Associate Editor who conducted theevaluation process at the time of publication of the article. This is the firststep in opening the peer review process;It clearly describes that the criterion of scientific merit is a priority in theacceptance of manuscripts for publication, also considering the potential foradvancing scientific knowledge in the theme resulting from the study; theircontributions to the advancement of clinical practice and/or teaching and/ordevelopment of public health policies and/or future research; the scientificquality identified by the method and analysis employed; rigor and originality inthe presentation of results; global relevance and interest. areadopted by RLAE in order to improve the quality and transparency of health research andhelp the author to present all the relevant and necessary aspects in the writing ofscientific articles. It is noteworthy that the partial description of the results(omission of some outcomes), the omission of essential information about the method, theresults and adverse effects of the therapy, incomplete description of the interventions,and poorly prepared abstracts are aspects that prevent the acceptance of manuscripts forpublication. The guides must be used by the authors in the elaboration of theirmanuscripts and by the consultants and associated editors in their evaluation.The EQUATOR Network guides for best practices andethical standards in conducting and reports of research published in medical journals,in item III.L, whose specifications are required by RLAE.Among the various guides provided by the Network is CONSORT , created in 1996 to guide authors to report the methods and results ofrandomized clinical trials. As it is considered the gold standard for clinical practicein health, randomized clinical trials were highlighted in the recommendations of theICMJEThe first topic dealt with in this item concerns the registration of clinical trials inpublic registries in order to prevent the selective publication of research results;avoid unnecessary duplication of research efforts; inform the community about planned orongoing trials, and contribute to ethics committees by providing input for the approvalof new studies under evaluation. The retrospective registration of a research protocoldoes not serve any of these purposes. The information on the number of the publicregistry of clinical trial studies at the end of the summary is a requirement of RLAE,as well as the presentation of the checklist and flowchart of the CONSORT guide..CONSORT endorsement by medical journals has been one of the most widespread actions aimedat improving the integrity levels of randomized trial reports. The evidence, however,shows that despite modest improvements, when CONSORT is supported by journals, thequality of clinical trial reports remains insufficient, a positionassumed by RLAE.The sending of the CONSORT checklist by the authors is not always a guarantee that theCONSORT items were effectively satisfied. Among the reasons for the presence ofinconsistency between the informed and the defendant, two deserve to be highlighted: itis possible that the authors are not aware of the CONSORT requirements or that, despitetheir efforts to comply with the requirements, the way the items are presented does notallow for interpretation at the level of detail required. Misinterpretation of CONSORTis a major concern, as it means that essential information about the conduct of thestudy is poorly communicated. Second, difficulties can lie with consultants and editors.It is possible that they feel confident about the quality of the reports only because ofthe presence of a complete checklist. Among the possible solutions and in an effort tomake the most of requiring checklist submission, journals should consider clarifyingtheir position on whether the complete checklists or, at least the main items on thechecklists verification, should be examined by editors or reviewers or even by trainededitorial assistantsAnother requirement is that in the cover letter sent to the editor at the time ofsubmission of the manuscript, a declaration must be included on all previous submissionsand reports that may be considered as a redundant publication of the same or of a verysimilar article. Copies of this material must be included in the documents sent in orderto assist the editor in decision-making. This measure aims to control the submission ofmultipart scientific texts which are not accepted by RLAE.In times of countless changes in the production and dissemination of scientificknowledge, RLAE's editorial policy will continue to be updated in the face of newdemands from Open Science."}
+{"text": "The area has become a theater of conflicts and is affected by the consequences of the crisis from the surrounding areas. Violence against populations, forced migration, problems in the reception of asylum seekers, ethnic and religious discrimination and conflicts are some of the adverse consequences that imply  public health issues . The repOnce the Mediterranean was the center of civilization, but today it has been reduced to blue beaches, diet and epicenter of human tragedies. Having said this, the region should be something more than this. Considering the fact, scientific communities of the Mediterranean region must regain the will and strength to communicate and to establish links in this period of crisis.In fact, in contacts and relationships between communities of the shores of the Mediterranean  science has always played a role. Scientific exchanges were also often the consequence of wars. But even then, the periods of maximum expansion and well-being of some Mediterranean exchanges were also quite common. Suleiman the Magnificent and his predecessors invited architects and artists of the Italian Renaissance to Istanbul as reported by Vasari and as more recent historical research has confirmed , 3. A siThese exchanges had been even closer in the field of medical sciences and in the treatment of psychiatric diseases in particular. The Mediterranean became the cradle of medical science and psychiatry through a long journey to which all the cultures of the basin have contributed.The first structure for hospitalization and treatment of what we now call mental illness was built in ancient Egypt. Greeks found a medical approach to mental illness from Hippocrates. Romans inherited this approach and they produced laws and social rules to regulate the relationship with people with psychosocial disabilities by introducing the concept of non-punishment for mental insanity.th-13th centuries) in the Islamic countries of the Mediterranean [During the Middle Ages, the West lost its medical approach to mental illness and today we think that many of the witches burned at the stake in these centuries were possibly people with mental health issues. In fact the Malleus Maleficarum, the text specifically written for the identification of witches describes \u201cevil influences\u201d which today would be interpreted as psychiatric symptoms . In thoserranean . The docerranean . The docIt is not easy in today's cultural crisis of the Mediterranean region given the competing interests of the actors of the region, the influence of global events and the interests of other actors. We envision that the cultural and scientific exchanges among the countries of the Mediterranean region will strengthen the regional identity and also contribute to the regional and global welfare and science.1.1We have discussed some very demanding tasks in this special issue. This present limited contribution cannot be considered exhaustive. It is the first step towards a path that we hope will continue and grow.The special issue begins with Eskin's work . This paThe issue of refugee women is still on the focus of the work of Ahmad Sa'adSalehAlsheikh Ali . This paYosraZgreb and coll  address Another paper compares the beliefs about mental disorders in the population of a Mediterranean nation (Tunisia) to that of Germany . In TuniAnother work presents the validation of the Arabic Maghreb version of the Mood Disorders Questionnaire, a screening tool for bipolar disorders, comparing the results with similar works in other languages of the regions .The paper of Ventriglio and co-authors is a narrative review that deals with an under debate issue as the emerging evidence on a possible role of the Mediterranean Diet on general well-being and mental health. The article encourages further researches to verify the potential benefits of the Mediterranean diet and healthy food selection for the protection of disorders, such as major depression and anxiety disorders, and to promote health The paper on \u201cPostpartum Depression in The Arab Region: A Review\u201d by KhubaiThe final paper presents the results of a pilot project to implement the QualityRights program in Tunisia . The proThe special issue offers a limited contribution but opens up a set of scenarios relating to the bio-psycho-anthropological specificities of mental health in the Mediterranean region and to future aspects that research could pursue which we think can stimulate researchers in the region to establish contacts and cooperative studies."}
+{"text": "We have read with great interest the case-control study that Common genetic variants in pre-microRNAs are associated with cervical cancer susceptibility in southern Chinese women by Chen et al In the study by Chen et al We pooled these two studies and re-estimated the effects of rs895819 on the cervical cancer risk by recalculating the crude OR and 95% CI using either TT or CC as reference It should be noted that both studies performed stratified analyses. The study by Chen et al YW conceived of this letter and led the development of the letter to the editor. BW wrote the first draft of the letter, and coordinated and integrated comments, YW, and LZ critically revised and edited successive drafts of the manuscript. All authors read and approved the final version of the manuscript."}
+{"text": "Viruses on the Transmission Dynamics of Insect Viruses, we would like to thank all of the authors for their submissions and the great work expanding our knowledge of insect virus biology and transmission.At the close of this Special Issue of We are pleased with the breadth of high-quality research articles touching on multiple areas of biology. We have learned of the detection of the Reo-Like virus in Brazil , the TosIn addition, we have published thorough reviews highlighting the roles of temperature , RNA intWith summer upon us and insects making themselves known, it is hard not to think of insect virus transmission and disease. These articles and reviews have helped us to understand a bit more of how insect viruses are transmitted and have filled some of the gaps in our knowledge regarding the transmission dynamics of insect viruses. We look forward to future works from many investigators to bring us closer to understanding the complex and exciting relationship between insects and viruses."}
+{"text": "To improve clarity, the Author contributions have been updated to include the following: Norah Borus was not able to review the manuscript prior to submission but she was integral to the concept and design phase of the project and contributed significantly to the codebase. Norah Borus passed away on 14th June 2019. Additionally, the second sentence in the second paragraph and the sixth sentence of the penultimate paragraph of the Discussion have been edited for clarity. The HTML and PDF versions of the Article have been corrected."}
+{"text": "As a particular case study of the formal verification of state-of-the-art, real software, we discuss the specification and verification of a corrected version of the implementation of a linked list as provided by the Java Collection framework."}
+{"text": "The name for one of the co-authors of this paper, Lin Lin, was misspelled as Ling Lin.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "With the widening of the US measures three weeks before the end of the Trump administration, it falls on Biden to find a solution for the Airbus-Boeing dispute."}
+{"text": "This article is being retracted from Bioscience Reports at the request of the Editor in Chief and Editorial Board following receipt of a notification from a reader, alerting the Journal to unusual repeated background features in the Western blots.The Editorial Office was also contacted by the listed corresponding author, Yan Yang, via an email address that differed to the one included with the submission. Yan Yang confirmed that they were unaware of the submission and publication of the article, and that they did not conduct any part of this research, hence should not have been listed as an author on this paper.The corresponding author of the paper has been contacted via the original email address in the published paper to provide a response to the Editorial Office concerns surrounding the authorship of the paper but has not responded.In light of the concerns raised regarding the Western blots and the authorship of the paper, the Editorial Board stands by the decision to retract the paper."}
+{"text": "Healthcare system facilitates the treatment of patients with the support of wearable, smart, and handheld devices, as well as many other devices. These devices are producing a huge bulk of data that need to be moulded for extracting meaningful insights from them for the useful use of researchers and practitioners. Various approaches, methods, and tools are in use for doing so and to extract meaningful information in the field of healthcare. This information is being used as evidence to further analyze the data for the early care of patient and to devise treatment. Early care and treatment can facilitate healthcare and the treatment of the patient and can have immense potentiality of dropping the care cost and quality refining of care and can decrease waste and chances of error. To facilitate healthcare in general and cardiology in specific, the proposed study presents an overview of the available literature associated with big data, its insights, and analytics. The presented report will help practitioners and researchers to devise new solutions for early care in healthcare and in cardiology. The increase in use of smart devices such as sensor, actuator, and wearable devices, as well as other devices, has produced massive amount of data that need to be shaped in a structure way to mine the information and useful insights for the useful use of research and practice. This increase of information can yield research issues and challenges as extracting useful information becomes a challenging task for research. The useful insights once drawn in a successful way can ultimately care the patient and provide effective treatment in the early stage. Diverse approaches, methods, and mechanisms are in practice to tackle the issues of big data and its analytics in the field of healthcare in general and cardiology in specific.The role of data processing and information in healthcare has always been vital in healthcare for decision-making and its provision. Medical big data is produced from the communication and digitization in healthcare. Healthcare providers and hospital industry provide a huge amount of data from other segments, such as medical equipment, medical insurance medical research, and life science. Huge amount of data exists, which grasps the potential of support of healthcare and medical tasks. The integration of machine learning, artificial intelligence, and advanced analytics offers numerous opportunities for transmuting such data into actionable and expressive insights for supporting decision-making. This can ultimately make availability of patient care at high quality and real-time situation response and can protect lives on the clinical side and develop the services and processes, improve the use of resources, and minimize the costs on the maintenance and financial front , 2.With the rise of advanced approaches such as analytical techniques and approaches, the stakeholders of healthcare can not only connect the data power for historical analysis of data but also predict future outcomes with predictive analytics for defining best accomplishment for present situation , 4. ConvThe proposed study presents an overview of the available literature associated with big data, its insights, and analytics. The process of search for the proposed study was done in the popular libraries with the aim of obtaining associated materials. The presented report will help practitioners and researchers to devise new solutions for early care in healthcare and in cardiology.The remainder of the paper is organized as follows: Several approaches have been in practice to tackle diverse issues of big data and its analytics in healthcare. Pevnick et al.  offered Ben-Assuli et al.  demonstrBizopoulos and Koutsouris  surveyedThis study offers to present an overview of the existing approaches and methods for big data, its analytics, and insights in cardiology. Various popular libraries such as ScienceDirect, IEEE, Springer, and Wiley were searched with the aim of obtaining associated materials interconnected to the current study. The information gathered from these libraries was analyzed and presented from different perspectives in the form of different tables and figures. This information includes the type of article, number of publications, topics covered, subject areas, and publication titles. Initially, the library of ScienceDirect was checked and the following information was obtained. The library of IEEE was searched for the purpose of identifying relevant information. The paper type and total number of publications in the same library are shown in After this, the library of Springer was searched to view the information for the purpose of analysis. The discipline with the total number of articles is shown in The libraries of Wiley and Taylor & Francis were also part of the proposed study. These libraries were searched for relevant information and analysis. After the statistics were obtained, the papers were reviewed and the details with short descriptions of the papers were given. Big data are considered to be the main asset of the organization for its successful operations and future endeavour \u201377.Healthcare system facilitates the patients with the support of wearable devices, smart devices, handheld devices, and many other devices. These devices are producing a huge bulk of data that need to be moulded for extracting expressive insights from them for the useful use of researchers and practitioners. Various approaches, methods, and tools are in use for doing so and to extract meaningful information in the field of healthcare. This information is being used as evidence to further analyze the data for the early care of patients and to devise treatment. Early care and treatment can facilitate healthcare and patient and can have immense potentiality of quality refining of care and lessen care cost and can decrease waste and chances of error. To facilitate healthcare in general and cardiology in specific, the proposed study presents an overview of the existing literature associated with big data, its insights, and analytics. The presented report will help practitioners and researchers to devise new solutions for early care in healthcare and in cardiology."}
+{"text": "A key aspect of the article by Lousdal on instrumental variables was a discussion of the monotonicity assumption. However, there was no mention of the history of the development of this assumption. The purpose of this letter is to note that Baker and Lindeman and Imbens and Angrist independently introduced the monotonicity assumption into the analysis of instrumental variables. The letter also places the monotonicity assumption in the context of the method of latent class instrumental variables. Lousdal  reviewed"}
+{"text": "This Retraction follows an Expression of Concern relating to this article previously published by Portland Press.Bioscience Reports at the request of the authors following receipt of a notification from a reader, alerting the authors to duplications in the E-cadherin and Vimentin western blots in Figure 2C.This article is being retracted from The authors have been unable to replicate the results and wish to retract the article. The Editor-in-Chief and Editorial Board agree with the retraction."}
+{"text": "Following publication of this article , concernPrior to publication of this article, the corresponding author declared that the Institutional Review Board of University of Texas at Dallas restricted public sharing of the underlying data set given this included potentially identifying information. In accordance with the PLOS Data Availability Policy, and with editorial agreement, the Data Availability Statement for the article provided contact details for the institutional officials to whom requests for the data set could be addressed.PLOS ONE Editors that the Center for Crime and Justice Studies, University of Texas at Dallas, where the data was reportedly archived, has closed, and the former directors of the Center are no longer at the University. The authors are no longer affiliated to the University of Texas at Dallas. The PLOS ONE Editors have followed up with the authors and with the institution, but have been unable to obtain the data or confirmation that it has been retained. The authors have indicated that the records used to compile the study data set are held by the Criminal Justice Department of Dallas County and the Texas Department of Criminal Justice. Defendant records were matched across several unique identifiers used by various agencies.It has been raised to the attention of the Additionally, the following information is missing from the Competing Interests statement: RGM has previously been contracted by the American Bail Coalition for expert testimony. There are no patents, products in development or marketed products associated with this research to declare. The other authors declare that they have no competing interests.PLOS ONE Editors issue this Expression of Concern to inform readers that the underlying data set used in this study is not available at the time of publication of this notice.The"}
+{"text": "In the original article, there was an error in the Funding statement. The correct numbers for National Nature Science Foundation of China are 81801390 to H-XW and 31800754 to ZL.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "The Aging Enterprise was the first book length analysis of the origins and operations of the aging services system that grew out of the 1963 Older Americans Act and provided the first state system of community-based services. The book also featured an original critique of the aging services system based on an application of the theoretical perspectives that were new to social gerontology. This presentation will use one of these perspectives, the political economy of aging in the U.S., to chart changes in aging services systems since the publication of The Aging Enterprise. The presentation will show that Estes\u2019 pioneering work on the application of the political economy perspective on aging policies and programs in the US, is more relevant to our understanding of these programs than it was 40 years ago, by describing and analyzing the increasing control of for profit corporations over the aging services systems. Part of a symposium sponsored by the Women's Issues Interest Group."}
+{"text": "One of the most significant difficulties that governments worldwide are facing during the COVID-19 pandemic is the lack of accurate and rapid data on infected patients' evolution. Especially in Brazil, limited access to the real time - polymerase chain reaction (RT-PCR) test for most of the population and the difficulty of storage and processing samples result in underreporting and delay in the official statistics cases. The lack of information of an updated data regarding the evolution of the pandemic makes political decision-making immensely difficult. Accurate screening of patients would allow predicting the pandemic's growth with some confidence and contribute to the proper planning of health units in an imminent escalation in hospitalizations. Adequate planning is essential for establishing clear criteria for the intensification or relaxation of restrictive circulation measures, as largely discussed and criticized in the last year.The monitoring of patients with sudden changes in smell and taste could be an essential tool to complement and maximize the surveillance system of new cases of COVID-19. The onset of the COVID-19 pandemic alerted for dysosmia associated or not with dysgeusia as a frequent symptom in patients with COVID-19, with an estimated prevalence of 62%., suggests that sudden olfactory changes could represent an early predictive marker of the evolution of COVID-19 cases. The study conducted in France, Italy and the United Kingdom with more than 6500 patients, observed a strong positive correlation between the number of patients with sudden olfactory and taste changes and the number of hospitalized cases, intensive care unit admission, and mortality associated with COVID-19. Also, the number of new cases of sudden dysosmia was an indicator capable of predicting the response to restrictive measures earlier, showing a peak in the number of new cases 4 days after the installation of the lockdown, than the currently used indexes, such as the number of emergency consultations that reached the apex after 11 days of lockdown, and the number of hospitalizations in emergency units, peaked only after 14 days. When comparing the evolution of olfactory changes of France and Italy, and the United Kingdom, the first two countries with more restrictive decrees reached an abrupt drop in the report of new cases of sudden dysosmia after the lockdown compared to the third, which presented a more gradual reduction of cases presumably due to the less severe restrictive policy.Based on this information, an article published in October 2020 in the Nature CommunicationsThus, the number of new cases of sudden dysosmia and dysgeusia represents a marker with high specificity, minimally invasive, and low cost in diagnosing COVID-19, besides presenting high capillarity capacity in a large portion of the population in a short period. The variation in the number of new cases of olfactory changes over the days may also be an indicator of fundamental importance for estimating the evolution of the pandemic in the coming days and weeks. In addition, it is able to early detect the impact of restrictive measures of circulation and specific events, such as meetings on festive dates, regarding the number of cases of COVID-19. Even with the beginning of the vaccination in our population, the effective control of COVID-19 will not be immediate, and it is essential that, during this period, we continue to evolve, applying new strategies to minimize the impact of this disease on our community. The adoption of a unified internet self-reported notification system of new cases of sudden dysosmia or dysgeusia, along with the contribution of otorhinolaryngologists and frontline physicians, would create a robust and low-cost database, that would help screening and fighting this pandemic. This system with accurate and up-to-date information would allow a more effective action of health authorities in a potential increase of new cases, minimizing the risks of overcrowding health units. Besides, the strategic planning of the intensification and relaxation of restrictive measures of circulation would be more efficient, being possible not only to control the escalation in the number of cases and hospitalizations, but also to avoid too strict and prolonged trade closure and closing of other activities that largely impacted the socio-economic activities in 2020.The authors declare no conflicts of interest."}
+{"text": "The study aimed to investigate the changing pattern of care for the oldest-old at the end of life in China. Data were used from the Chinese Longitudinal Longevity survey from 1998 to2018. The results indicate significant changes in the care providers of older adults at the end of life from 1998 to 2018: grandchildren played an increasing important role in providing care to the oldest-old in China. The study highlights an important role of grandchildren who replace children as main caregivers. Longevity changes the traditional pattern of end-of-life care, and increase the diversity in the pattern of care for the Oldest-old, due to different life course of families compared with general aging families, and the limited role of formal social support system in providing end-of-life care for the oldest-old. We discuss implications in the context of increasing population of the oldest-old, and its challenges to formal social support system."}
+{"text": "During the editing process, the name of one of the authors was mistakenly omitted.Valdas Noreika of the Department of Psychology, University of Cambridge is the twelfth author of this article, as shown above. The authors apologize for this error."}
+{"text": "Political polarization, meaning sharp differences in the political ideologies and preferences of the partisans of different parties, implies that members of one party are more likely to dismiss the policies and recommendations of spokesmen and appointees of the other party on the grounds that those policies and recommendations are informed by value systems inimical to their own. In the US, this means that when spokesmen for one party endorse masks, members of the other party reject them instinctively and automatically."}
+{"text": "In the original article, there was an error. Information at the end of the Acknowledgments section was inadvertently omitted.A correction has been made to Acknowledgments to read as follows:NutriXiv) version 1 of the report. We also thank Richard Gershon and Molly Wagster who gave excellent input on development of the NIH Toolbox, which was helpful in crafting some of the thinking and language that ended up in the report. We would further like to acknowledge the writing contributions for the content of each section came from members of the project executive committee and workshop participants. The content is solely the responsibility of the authors and does not represent the official views of the NIH or federal government.We would like to thank the executive committee members for assistance with organization and planning the activities that led to this report and the executive committee and workshop participants for contributing content expertise, writing, and edits to the report (see Supplementary Appendix C for listed names and affiliations). We would also like to thank Drs. Patrick Bissett, Desiree Byrd, Xavier Cagigas, Laura Holsen, and Kristin Javaras for their review and insightful feedback on the preprint (i.e., The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "On the basis of a previously developed model of disperse systems containing non-point dipole particles self-assembled into chains inside a liquid substrate, the decay time of electrical excitations induced in dipoles by an external field is investigated. It was shown that when the external field is completely turned off (from  In response to the action of low-frequency electric fields ,2,3 nanon chains ,5,6, rinn chains . Particln chains . This prn chains , biosensn chains  and othen chains ,13. Howen chains  or a bion chains  after thn chains ,17,18.The objective of the present paper is to demonstrate the existence of the excitation decay in the dipole chains using numerical calculations. We will also show the dependence of the excitation decay time on the length and other parameters of the chain.The dipole chains can be quickly formed from individual polar colloidal particles ,20 with ented in ,22,23.In the model calculation, the approximation of short-range interaction between the charged nanoscale particles was taken . Howeverr and the minimal spacing Let us study the decay of the excitations in the chain of non-point dipoles with the radius Let us calculate the interactions between the dipoles in the Coulomb approximation. Let the angles rium see . Then thHere, n should depend on the strength of external and local fields created by moving adjacent charges in the shells of the dipoles n and For building a one-dimensional model of the system of non-point dipole oscillators with variable moments it is necessary to take into consideration that the values of the charges in the sheath of the dipole ple, see ,23). Letequation ,23. Thenn can be written in the form:Similar expressions can also be written for the charges n and Similar expressions for the disturbing field can be also written for the vicinities of the dipoles The expression for the kinetic energy of the chain with the charges with the masses m in the shell of the dipole n.Here, Let us assume that the dissipative forces linearly depend on the angular rate of the motion of the charges. Then, the corresponding dissipative function for the chain with the dissipation parameter nth dipole, the fraction of its kinetic energy  that is converted into heat is proportional to the dielectric-loss tangent For the e dipole . The eneThe force of the interaction of the external field and the chain of oscillators can be written as follows:Using Euler\u2013Lagrange equation ,23 takinAssuming that at the same instant of time the variables equation ,23: (8)\u2202The definitions of the parameters in works ,23.n endAs a result, we find the number of the uncompensated charges a in the chain as well as the parameters of the substrate surrounding the oscillators and the frequency of the alternating field.For studying the decay of the excitations of the dipoles in the chain let\u2019s change its length and the time of the external field action upon it. Let us specify the size m in the shells at the ends of the dipoles. The changes in the number of the charges n varies in the range of 1\u201330. The boundary conditions for the chain of the oscillators of a in the model chain.The model calculations show the changes in the number of the uncompensated charges (cations and anions) tigation . Let us The strongest excitation in the chains of the dipoles should be reached at the smallest distance The numerical calculations for the above systems show that after the cessation of the action of strong or weak alternating field (the fields were switched off programmatically to the value of n in the range of 1\u201330 and the time of the external decay at the frequency However, the dependence of the decay time on the chain length has a non-linear character as it is shown in Among the peculiarities of the decay character the following should be noted. When the external action on the chains of dipoles with variable moments is switched off, the effect of decay occurs.After the switching off of the strong fields of  moments . This duIn the chains with the number of dipoles rameters ,28 and erameters  on the lThus, in the present paper, the character of the decay of the excitations in the chains of dipoles with variable moments is established after the external alternating electric field has been switched off at biologically significant low frequency.The numerical calculations show that the decay of the excitation of electric dipoles occurs after the low-frequency field of any intensity has been switched off. At strong low-frequency fields with At growing frequency of the external field acting on the chain, the characteristics of the excitation decay changes in the way similar to that observed at the increase of the strength of the external field."}
+{"text": "After the publication of the above article, during a routine examination of the raw data the authors noticed errors in Oncology Letters for allowing them the opportunity to publish this Corrigendum, and apologize to the readership for any inconvenience caused.The corrected versions of"}
+{"text": "Furthermore, they apologize to the readership of the Journal for any inconvenience caused.The revised version of"}
+{"text": "Journal of Clinical Medicine retract their paper due to the serious flaws in the study design and data presentation. These errors were reported by two readers of the journal. The authors would like to acknowledge both readers pointing out such important mistakes. The authors apologize for not using the final data to conduct the analysis, resulting in unreliable results. The editor-in-chief and academic editors of the Journal of Clinical Medicine have checked this case. The editor-in-chief has approved the retraction. Both readers have been informed about the retraction decision. The authors of a recent published paper  in the JJournal of Clinical Medicine for any inconvenience this may have caused. MDPI is a member of the Committee on Publication Ethics and takes the responsibility to uphold strict ethical policies and standards very seriously.The authors apologize to readers of the"}
+{"text": "The Great Recession presented the US with economic and political challenges that had not been experienced since the time of the Great Depression. This article provides a retrospective on the government\u2019s response to the crisis ten years after the enactment of the Dodd-Frank Act, as the country is heading into its next presidential election in the midst of yet another downturn, this time fueled by the COVID-19 pandemic."}
+{"text": "Acknowledgments section appears below.In the original article the CFACT Data Center and AHRQ were not acknowledged. The updated \u201cThe research in this paper was conducted at the CFACT Data Center, and the support of AHRQ is acknowledged. The results and conclusions in this paper are those of the authors and do not indicate concurrence by AHRQ or the Department of Health and Human Services. We would like to thank all the members from the meta-epidemiological study group in the School of Public Health, Kyoto University, for the constructive comments and advice.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "Studies of the coronavirus SARS-CoV-2 spread mechanisms indicate that the main mechanism is associated with the spread in the atmosphere of micro- and nanodroplets of liquid with an active agent. However, the molecular theory of aerosols of microdroplets in gases remains poorly developed. In this work, the energy properties of aerosol nanodroplets of simple liquids suspended in a gas were studied within the framework of molecular theory. The three components of the effective aerosol Hamiltonian were investigated: (1) the interaction energy of an individual atom with a liquid nanodroplet; (2) the surface energy of liquid nanodroplet; and (3) the interaction energy of two liquid nanodroplets. The size dependence of all contributions was investigated. The pairwise interparticle interactions and pairwise interparticle correlations were accounted for to study the nanodroplet properties using the Fowler approximation. In this paper, the problem of the adhesion energy calculation of a molecular complex and a liquid nanodroplet is discussed. The derived effective Hamiltonian is generic and can be used for the cases of multicomponent nano-aerosols and to account for particle size distributions. The rapid spread of coronavirus SARS-CoV-2 has become an investigation subject for numerous scientists. The existing data exposed the ability of a virus to be transmitted in an airborne manner as dispersed droplets that contain the infective agent ,4,5,6. AAn important physical aspect in the problem of virus spread is the interaction of nanoparticles (virions) and nanodroplets with molecular structures of different media. For these types of problems, an important characteristic is the size dependence of energetic properties of nanodroplets and nanoparticles at interactions with different media structures. The calculations of the adhesion energy of nanoparticles to the different structures, in addition to the calculations of energetic characteristics for aerosol nanodroplets, require an application of statistical physics methods. An investigation of equilibrium and nonequilibrium properties of droplets and aerosols with liquid nanodroplets can be performed within the framework of classical statistical mechanics. The nanodroplets may reveal implicit collective properties and self-organization into structures at a macroscopic level . The behThe typical complications in the theoretical analysis of nanosystems are conditioned by the necessity to account for the surface terms for all of its equilibrium and nonequilibrium properties. At nanometer scales, an abrupt change of all system characteristics takes place near the surface. The intermolecular forces act at similar scales.The contemporary state of theoretical studies of the structure and properties of liquid nanodroplets within the framework of molecular\u2013kinetic theory has been summarized in the works ,11,12. AThe current study, using the correlation theory of inhomogeneous liquids, investigated the equilibrium properties of nanodroplets as components of aerosol systems. Thus, there was a need to use approximations that allowed a reasonable comparison of theoretical and experimental results to be made. The properties of aerosol systems were determined by their interacting components, i.e., nanodroplets and gas. There exist many phenomena at the molecular level that lack explanation. Under these conditions, it is difficult to predict the behavior of nano-objects and their assemblies, or to control these nanosystems. For the investigated aerosol systems, a fundamental role is played by the energy characteristics of the separate nanodroplets, their interaction energies with the surrounding gas, and the paired interactions of nanodroplets. Investigation of the pointed energy characteristics is a major focus of the current article.Formulation and resolution of the problems related to the interaction of isolated atoms and molecules with the heterogeneity of the condensed system  are essential in constructing a microscopic theory of first-order phase transitions, in addition to a microscopic theory of equilibrium and kinetic properties of the surface and interphase boundaries. A review of the current state of the problems of atom interactions with an inhomogeneous environment can be found in ,11,12,17In statistical mechanics of condensed matter, as a rule, the potential interaction energy of two atoms or two molecules is assumed to be known. An approximation of pair additive potentials is widely used to describe the energies of interatomic interactions ,14,15,16Calculation of the interaction energy of macroscopic bodies with different geometries in continual approximation, including accounting for van der Waals forces, is described in ,12. The A wide overview of the literature regarding the interaction of atoms and macroscopic bodies  points tThe goal of the current section is to present the model calculations of the interaction energy between the atoms and nanodroplets of a simple liquid. The foundation of these calculations is based on the expression for the energy of an inhomogeneous liquid within the framework of the distribution function method of groups of particles, which takes into account all paired interatomic interactions and correlations. The paired interatomic interactions were described using the Lennard\u2013Jones potential. The structure of the droplets was modeled using a Fowler approximation (the step profile of atoms\u2019 density in the droplets) ,19. The The potential energy of an inhomogeneous system of a pair of interacting particles, located in a volume itten as ,19:(1)E=By choosing the volume element from the condition egration , we obtaAfter integration over spherical variables, the expression for the atom\u2013droplet interaction energy takes the form:If the atom is located at the surface of the droplet, then constant ,12. In tFor the case in which the atom is located inside the droplet, similar calculations allow the interaction energy of the atom and droplet to be obtained:If the atom is located at the center of the droplet, then its interaction energy with the droplet will have the form:The expression for the interaction energy of the atom with a semi-bounded liquid in the case of arbitrary distances from the atom to the surface, when it is important that the pair atom\u2013atom correlations in the semi-bounded liquid are accounted for, can be derived from Expression (5) by means of transition The interaction energy of an atom that is located on a flat surface of a semi-bounded liquid in the case of the Fowler approximation will take a form of a particular case of (10):Let us consider a boundary case of atom interaction energy with a nanodroplet of liquid in a continual approximation. In the case of distances From Expression (14), we can obtain the position of the first zero effects) .3, which corresponds to the density of the number of particles \u22123. Parameters of the Lennard\u2013Jones potential were chosen to be The numerical calculations were performed for the normal \u03b5=10.22K . The pai\u03b5=10.22K .The calculation results of the interaction energy of an atom with a droplet in the framework of correlation theory in the case when the atom is located on the surface of the droplet are shown in For comparison, Let us consider a simple liquid in a volume articles ,15,16,19We can divide the volume of the system into two parts Let us split the system into the droplet of radius The specific separation energy (23) corresponds to the previously derived surface energy of the droplet and pore in Fowler\u2019s approximation ,19. FowlThe surface energy of the droplet can be defined as the difference between the total energy of the droplet and the energy of the homogeneous phase in the volume corresponding to the volume of the droplet divided by the surface area of the droplet. This definition is equivalent to distinguishing the volumetric and surface parts in the total energy of the droplet. For the model calculations, the pair distribution function was approximated as follows:nterface ,19,21.The received expressions for the droplet energy, pore energy, and separation energy of a liquid into a droplet and a liquid with pore can be integrated in spherical coordinates. Thus, using Approximation (24), the energy of the liquid droplet can be written as:The surface energy of the droplet is defined as:ximation ,19,21,222.The model calculations of the size dependence of the surface energy of the droplet n theory ,22,23,24Model calculations of the dimensional dependence of the surface energy of gases When a droplet of liquid is located in a gas, then for the surface energy of the boundary of the droplet\u2013gas interface, we use a representation in which the surface energy of the gas phase is described as the surface energy of a gas with a pore. We assume that the density of the number of particles in liquid is In the boundary case of gas density growth, In this section, within the framework of the correlation theory of inhomogeneous liquids, the general expressions for the bulk and surface terms in the droplet energy as a function of the radius were obtained. Using the Fowler approximation, we were able to reduce all of the terms to the single integrals, which significantly simplified the model calculations of the size dependence. The size dependence of the surface energy was calculated for spherical droplets of the simple dielectric liquids as a function of the radius in Fowler\u2019s approximations. In the boundary case of the large radius of the droplet, the surface energy approaches the value for the flat surface. The strong size dependence of the droplet surface energy is observed at nanometer scales of the droplet radius. When the droplet radius The derived approach is used to calculate the surface energy of two-phase system of nanodroplet\u2013gas, including accounting for the paired interparticle interactions and correlations. In the vicinity of the mixing point of liquid and gas, the surface energy of the nanodroplet in gas approaches zero. The size dependence of the nanodroplet surface energy in gas is similar to the size dependence of the nanodroplet in vacuum.The contemporary state of development in molecular\u2013kinetic representations of the interaction of macroscopic bodies by means of intermolecular forces is described in the monograph . In 11]11], the In the current section, we established the theory of the interaction energy for two droplets of a simple liquid within the framework of the distribution function method of the groups of particles. The derived expressions for the interaction energy of two nanodroplets take into account paired interparticle interactions and correlations, and they are applicable for the arbitrary distances between nanodroplets or nanopores.We postulate in a homogeneous liquid that occupies a volume From the energy in (33), we can separate the part that corresponds to the energy of a homogeneous liquid in a volume This energy (35) can be represented as the product of the bulk density of the potential energy The next sum of the two contributions in (34) can be written as:The sum of the following two terms:For the sum of the contributions in (34), which are not accounted for in Expressions (36)\u2013(38), we denote The potential energy of the first and second droplets is Then, the potential energy of the liquid with two pores (33) will take the form:The terms in Expression (50) have the following meaning: the left part of (50) is the potential energy of a homogeneous liquid, which takes into account all interactions; the right side of (50) contains a sum that includes contributions related to the \u201cseparation\u201d from a homogeneous liquid of two droplets with a free interface and free interface of the pores. To derive the interaction energy of two nanodroplets We assume that the droplet is centered in the reference coordinate system and the volume element is located along the A continuous density distribution is assumed in the boundary case of a continuum model, and it is not accounted for in the discreet structure of the media. The expressions derived above for the interaction energy of two nanodroplets and two nanopores can be easily reduced to the continuum case by neglecting the correlations and assuming The result in (57) corresponds to the continuum approximation for the interaction energy of two droplets of liquid with parameters The absorption problems in equilibrium liquid\u2013vapor systems require knowledge of the nanodroplet interaction energy with the flat liquid interface. Using Expression (54) for the interaction energy of two droplets, we can investigate the boundary case of the droplet\u2013semi-bounded liquid interaction.These boundary case calculations of the droplet interaction energy with the semi-bounded liquid can be performed assuming that the distance between droplet centers We use the derived results to build the effective Hamiltonians of nanodispersed two-phase liquid\u2013gas systems. Our approach accounts for the effects of the paired interparticle interactions and correlations in calculations of the molecules\u2019 interaction energies with droplets, pairs of droplets, and the surface energy of the droplets.Let us assume the existence of an aerosol of nanodroplets of different sizes in the gas phase. For simplicity, we assume that this two-phase system consists of atoms (molecules) of the same kind and has temperature The expression for the effective Hamiltonian of an aerosol (61) can be generalized for the case of multicomponent mixtures with atoms (molecules) of different kinds. Formula (61) is derived for the set of independent variables: temperature, number of atoms (molecules) in a system in total and in gas phase, size of droplets, and density of the number of atoms in liquid and gas. In real experiments with macroscopic aerosol systems, statistical datasets exist that describe the dispersion of droplet sizes and the possible disposition in external fields. Knowledge of these statistical datasets is necessary for the averaging of (61) and calculation of aerosol energy.The prediction of aerosol behavior requires knowledge of droplets\u2019 size evolution, their concentration, the collisions results with possible coagulation, and accounting for the condensation and evaporation effects on and from the droplets\u2019 surface. The time evolution of the droplet\u2019s size distribution is described by the generalized integral\u2013differential dynamic equation, which takes into account the balance of the number of atoms (molecules) of gas and the number of droplets, which may vary due to condensation, evaporation, and the coagulation of droplets ,26,27,28The condensation phenomena, in addition to evaporation from the droplet\u2019s surface, play an essential role in many technological processes. An overview of the existing approaches to the description of the evaporation and condensation phenomena is provided in work . The majThe atom (molecule) work function from the droplet can be described as:In molecular biology problems, the adhesion of large molecules (viruses) to the surface of cells and the adhesion of cells to each other play an essential role . CurrentDiscussion about the adhesion mechanism of cells and viruses is long standing. The main question is whether the adhesion occurs at the direct contact of two objects or by means of intermediate molecular structures ,31. The The energy of indirect interaction of two nanodroplets with radiuses The collisions of droplets play an important role in the aerosol coagulation phenomena. The interaction energy of two droplets contains the direct interaction component The widely used continuum model of condensed systems has a limited application in the description of atoms\u2019 interactions with condensed bodies ,12. The When calculating the surface properties of condensed systems that are different in nature, the Fowler approximation is essential, because it correctly takes into account the basic surface contributions to different thermodynamic quantities. Corrections to this approximation, due to the difference between the real density profile in the near-surface layer and the stepped layer, are of an additive nature when calculating thermodynamic functions. Going beyond the Fowler model in our problem will not change the main results and conclusions of the work. Slight changes in the energy dependence of the interaction between the atom and the nanodroplet can be expected in the near-surface region.For condensed systems, a characteristic property is the same order of magnitude of the average kinetic and potential energies of atoms and molecules. For nano-objects, due to the large proportion of particles present in the near-surface layer, interatomic correlations can be of great importance for the formation of a self-consistent potential, which ensures the stability of the object in relation to the decay of constituent atoms or molecules. The processes of nucleation, and the mechanisms of growth and evolution of nanostructures under conditions of microscopic instability, are an integral part of the physics of phase transitions of the first kind. From the point of view of kinetics, the processes of nucleation of nano-objects take place with the participation of each individual atom, which evolves in the field of other atoms. The evolution of a single atom depends on the self-consistent field formed by other atoms and correlations with neighboring atoms. Stability of processes and their direction are also important for the growth or decay of nano-objects. The microscopic nature of the mono-atomic mechanisms of growth or decay of nanostructures, when the curvature of the surface of the new nanophase is significant, has been insufficiently studied. The solution of kinetic problems of this type is possible by means of theoretical calculations of the atom\u2019s interaction energy with the inhomogeneous environment at a nanometer scale. A proper description of the multiscale processes of nanostructure growth also requires knowledge of the energy balance of the entire nanostructure, which requires energy calculations of highly heterogeneous nanoscale systems.The distribution functions method of groups of atoms allows the equilibrium properties of the liquid\u2013gas interface to be expressed in terms of potentials of interatomic interactions and distribution functions of atoms. Among the most important thermodynamic functions are the surface energy and surface tension of flat and curved surfaces. When calculating the surface properties of the liquid\u2013gas interface, the use of the Fowler approximation ,19 for uIn the current work, within the framework of the distribution function method of the group of particles and Fowler\u2019s approximation, we derive the expressions for the atom interaction energy with a nanodroplet of simple liquid. The derived formulation is applied for the calculations of the nanodroplets of liquid helium. The developed approach has similarities with the functional density method (FDM) ,34,35,36The model calculations performed above for the size dependence of the atoms\u2019 interaction with a nanodroplet of helium indicates a significant influence of the saturation effect of the single atomic energy inside the droplet. The short range of interatomic interactions results in the rapid achievement of the asymptotic value of the atoms\u2019 energy at the center of the droplet during the growth of the droplet size. The formation of the bulk properties of helium nanodroplets occurs at radii in the order of 4\u03c3 and the number atoms of around The kinetic energy of helium atoms contains the classical thermal contribution and the quantum contribution. Calculations of the kinetic energy of helium atoms in a wide range of densities and temperatures using the Monte Carlo quantum method ,36 indicIn this paper, in the framework of the correlation theory of inhomogeneous liquids, general expressions are obtained for the volume and surface contributions to the energy of a droplet as a function of its radius. In Fowler\u2019s approximation, all contributions are expressed in the form of one-time integrals, which significantly simplifies the model calculations of the dimensional dependence. The dimensional dependence of the surface energy of spherical droplets of simple dielectric liquids as a function of the radius in the Fowler approximation is calculated. In the extreme case of large values of the radius of a droplet, its surface energy approaches its value for a flat surface. The strong dimensional dependence of the surface energy of the droplet is observed in the region of nanometer droplet size. The developed approach is applied to the calculation of the surface energy of a two-phase system of liquid nanodroplet\u2013gas phase, taking into account paired interparticle interactions and correlations. The dimensional dependence of the surface energy of a nanodroplet in a gas is similar to the dimensional dependence of a nanodroplet in a vacuum.This paper shows the possibility of taking into account paired interparticle interactions and correlation effects when calculating the interaction energy of pairs of droplets of arbitrary size. The energy of the interaction of two droplets in the Fowler approximation is written as a double integral. An explicit expression for the interaction energy of two droplets in the continuum approximation is obtained, which allows us to investigate the importance of taking into account the effects of paired intermolecular correlations in comparison with continuum models. As a boundary case, the expression for the energy of interaction of a droplet and a semi-bounded liquid is obtained, taking into account the effects of paired interparticle correlations.On the basis of the constructed theory, the properties of nanometer air dispersal systems with arbitrary droplet dispersion and for arbitrary multicomponent mixtures of liquids can be calculated. By means of the effective Hamiltonian of the aerosol of liquid droplets (61), it is possible to investigate in more detail the kinetic problems of evaporation and condensation on the surfaces of droplets and the lifetime of nanodroplets during their evaporation.Within the framework of the developed approach, it is possible to study the interaction of liquid nanodroplets with foreign molecular structures , coagulation of molecular structure and nanodroplets, and evaporation and condensation processes on droplets, provided that the molecular structure is present inside the droplet. These issues are all currently unresolved. The important theoretically unresolved issues are the evolution processes of evaporation and condensation on a nanodroplet that is in contact with different media , and the lifetime of the droplet with a molecular structure inside different surfaces. The answers to these questions are important in the problems related to the spread of viruses."}
+{"text": "Worldwide mortality due to stroke and heart disease will increase to 23.6 million in 2030 . BulgariThe scope of this study was to assess the role of rehabilitation for improving the functional capacity, independence in the ergotherapeutic activities and the quality of life of the patients with stroke, as well as the necessity of a lasting and adequate to the patients\u2019 needs rehabilitation. The patients had two seven-day hospital treatment courses in the Physical Medicine and Rehabilitation Clinics at the General Hospital \u201cSt. Panteleymon\u201d Plovdiv, Republic of Bulgaria for the period between 2016 and 2017.The prescription period for the studied patients was from one to ten months. Forty-three patients had two full treatment courses as between the treatment stages 4 patients dropped out because of the neurological complications that occurred. It was of great interest to us to trace the functional recovery of patients with relatively the same localization of the brain damage, which was in correlation with the rehabilitation potential and the complex rehabilitation programme.In the acute stage of the disease, the physical therapy and rehabilitation are targeted at preventing complications in the locomotor system , of the nervous and respiratory system . As a reThe choice of specific kinesitherapeutical techniques , was done individually for each patient after precise kinesic analysis of the spasticity syndrome and functional assessment in the beginning and the end of each rehabilitation programme. An individual complex rehabilitation algorithm was used, which includes kinesitherapy and therapeutical massage: inhabiting positions under the Bobath approach for suppression of the spastically increased muscle tonus; exercises to decrease the muscle imbalance; stretching exercises; suspension of upper and lower limbs; methods for proprioceptive neuromuscular facilitation in accordance with the Kabat, Knott and Voss approach for neuromuscular stimulation; diagonal-spiral patterns for upper and lower libs of Kabat; exercises for coordination and balance .The applied complex functional rehabilitation, combined with personal health care led to significantly faster reduction of the functional dysfunctions and improvement of the independence and the quality of life of the patients. However, the recovery is not sufficient in terms of the independence of the general movements and social re-integration. The patients and their relatives must be trained to apply continuously the rehabilitation activities along with the ergotherapeutical at home. The tolerant attitude on behalf of close people and relatives is essential for people with stroke after the incident. The significance of training in the complex approach is also very important for the improvement of recovery skills and the functional condition which leads to improvement of quality of life in patients with stroke."}
+{"text": "The journal retracts the 31 August 2020 article cited above.Following the publication of the article, the authors have identified a technical error in the execution of the tests included. The authors have corrected this error and re-conducted the analyses. However, the pattern of findings reported in the paper are no longer supported by the analyses.The authors concur with the retraction and sincerely regret any inconvenience this may have caused to the reviewers, editors, and readers of Frontiers in Human Neuroscience."}
+{"text": "Non-Coding RNA Editorial Office, and in agreement with the author, the paper will be removed from the public record and marked as retracted. We apologize for any inconvenience caused by the removal of this article.The published article  has beenMDPI is a member of the Committee on Publication Ethics (COPE) and takes very seriously the responsibility to enforce strict ethical policies and standards. The article  is retra"}
+{"text": "Nearly a decade ago, a federal interagency task force on the arts and human development was launched as the result of a research summit held by the National Endowment for the Arts and the U.S. Department of Health and Human Services to investigate the arts\u2019 relationships to health and well-being across the lifespan. Soon afterward, the National Institute on Aging partnered with the Arts Endowment and the National Academy of Sciences to identify research recommendations to benefit healthy aging and the treatment of neurodegenerative diseases in older-adult populations. While this session will revisit some of those findings, it also will share more recent advances in biomedical and behavioral research being conducted by a growing network of \u201cSound Health\u201d researchers at the nexus of neuroscience, music, and health==with direct implications for the future of research on the arts and aging."}
+{"text": "There is an increasing prominence of arts and cultural interventions related to aging and cognitive disorders in the scholarly literature and at gerontological conferences. However, the mechanisms of the salience and relevance of aesthetics, culture and leisure in the lives of older people remains unclear. One aspect which has emerged is that of aesthetic deprivation and its consequences for well-being. This symposium aims to provide perspectives from a range of researchers involved in programs of research and implementation to try to contextualize and better understand the perspectives of older people, arts practitioners and therapists the place and context of arts, culture and leisure in optimal aging."}
+{"text": "The present article describes the results of theoretical and experimental investigations of the force response of materials to external tensile stresses. The method used is based on remote precision measurements of the amplitudes of the harmonics of vibration signals and synchronous fixation of deformations under load. It was determined that the shape of the propagating acoustic signal depends not only on the bias time, but also on the frequency. In addition, fixation of the moments of occurrence of the vibrational signals and determination of the number of excesses in the amplitudes of harmonics over the discrimination level allows structural models to be studied in order to diagnose the strength properties of materials under dynamic loading of solids. The experimental setup consisted of a P100 Labtest-2 tearing machine providing a loading speed of 6.22 mm/min, a Polytech PSV\u2013400 vibrometer including lasers, and a computer. Measurements were made at frequencies of 0.4, 1.6, and 40 kHz. An analysis of the mathematical models of the occurrence and propagation of acoustic signals in a material under load is presented, and the features of their application are reported. Transferring the moments of occurrence of vibrational signals to a strain diagram from the applied load allows the development of physical processes of hardening and destruction of materials to be traced. The occurrence of vibrational signals under load can be used as an information parameter for the diagnosis of developing defects in the structure of materials under load. The study of the kinetics of the deformation of materials is associated with the need to analyse the force response of the material on external tensile stresses ,2. BecauAcoustic methods hold a special place among methods for assessing the state of metal structures of various shapes and sizes, as they apply the use of special diagnostic procedures to assess operational reliability without disassembling the structure itself. Much attention is paid to the diagnosis of damage and monitoring the development of defects. In  a KalmanImproving the technical diagnostics allows not only defects to be detected and the degree of their danger to established, but also the stress-strain state of the material to be evaluated ,14. UndeThe vibration diagnostics method allows the degree of malfunction of controlled objects to be determined by the nature of the vibration. The applicability of the method for solving specific tasks has been reviewed in a number of studies: in  rolling Remote precision measurements of moving materials using the coherent properties of laser radiation make it possible to perform static measurements of the relative movements of structural elements before and after loading. Various technical improvements and original solutions are offered. In  optical The disadvantages of using existing methods of vibration diagnostics are the complex data processing procedure, the periodic mode of measuring the state of defects, which requires the loading device to be stopped, and the stationary nature of the loading during testing.vibration diagnostics,fixation of the movements with the help of laser vibrometers with computer registration of signal processing,interrelation of acoustic signals with characteristic sections of the loading diagram.The idea behind the present work was to link together three important scientific and practical results:The objective of the study was to create a method for measuring the stress-strain state of a material. Due to the technological features of this method, it would be possible to provide a continuous observation mode, simplify the data processing procedure, and increase the information content of the measurements.The main aim of this work was to develop a non-contact method for determining the moments of vibration occurrence in different ranges of material loading using laser fixation in order to determine the technical state of the object. Theoretical studies of the occurrence of acoustic signals with changes in the structure of materials are developed in two main areas: the development of discrete models and models of the elastic continuum. Continuous models reflect free damped vibrations when scattered over local inhomogeneities and the propagation boundaries of acoustic signals. The periodicity of the crystal lattice, its structure, and the constitution of atoms determine the features of the energy spectra. With a known force field, it is possible to obtain information on changes in the structure of materials, which cannot be directly measured, by solving the equations of motion.In this work, we used the method of coherent properties of laser studies, which allows remote precision measurements to be taken of deformations and vibrations of a solid using a laser Doppler vibrometer by expanding the vibration signals in a spectral series using direct Fourier transform and measuring the harmonic amplitudes. The measurements are taken in a continuous dynamic mode over the entire range of the load diagram, the moments of occurrence of vibrational signals are recorded, and the number of excesses of the harmonics amplitudes over the level of discrimination in the parts of the load diagram is determined.\u03c9.The shape of the propagating acoustic signal depends not only on the bias time but also on the frequency The method is applied using the following developed device .The output laser beam (a) is divided by a translucent mirror (5) into two equal-intensity beams (b and c), one of which (b) is directed through a translucent mirror (6) and lens (7) towards the test sample (8), placed in a loading device (3). The beam (d) is reflected from the surface of the test sample using the lens (7) and the translucent mirror (6) and is directed to the translucent mirror (10), where it is connected to the beam (c), which reaches here after being reflected from the translucent mirrors (5)(9). The total beam of interfering rays (cd) falls on the measuring photodetector (11).During the deformation of the sample, the light flux and the beam (d) reflected from it change the frequency due to the Doppler effect. The interference of the light beam (c) reflected from a fixed mirror and the light beam (d) that has undergone a Doppler shift leads to the appearance of low-frequency beats in the intensity of the light flux (cd), which are converted into an electrical signal in the photodetector (11). This signal is transmitted to a personal computer equipped with software for receiving and processing the signal. The registered numerical signal is generated in the form of a file, which is recorded in the computer\u2019s memory. The file is generated every time a vibration signal occurs.The studied materials used were sheet steel, basalt fibre, dry wood, and plastic.The analysis of the generation of vibration signals under the uniaxial loading of structural materials is based on Fourier transforms.The experimental setup consisted of a P100 Labtest-2 tearing machine providing a loading speed of 6.22 mm/min, a Polytech PSV\u2013400 vibrometer including lasers, and a computer. An image of the experimental setup is shown in During the experiment, the laser beam recorded a change in the vibration of the sample in the horizontal plane, as shown in Fixation of the moments of occurrence of the vibration signals in real time without stopping the bursting machine was performed by means of a computer, to which the signals were fed from the processor .After the analogue-to-digital conversion, the electrical signals were fed to the computer.The information-measuring system used in the experiment provides indication, recording and pre-processing of the signal with its further preservation in the computer\u2019s memory for the subsequent post-processing of the received data and their visualisation in real time.The quantitative values of the occurrence of moments of the vibration signals in the coordinates of the absolute elongation of the samples with their reflection on the tension diagram for sheet steel are presented in The occurrence moments of the vibration signals were grouped in accordance with the reference data for mild steels. Digits: I\u2014the plot of the elastic region, II\u2014the area of the plastic flow of the material, III\u2014the phase of hardening, IV\u2014the phase, prior to the rupture of the sample.Despite the difference in the quantitative values of the breaking loads of the test samples, the general tendency towards an increase in strain with increasing stress is clearly visible.The shape of the vibration signals in the areas of strain hardening of the sheet steel sample is shown in The signals obtained are characterised by a different number of oscillations that correlate with changes in the structure of the material associated with the discrete displacement of dislocations. The transfer of the moments of the appearance of vibration signals to the deformation rate diagram from the applied load makes it possible to trace the development of the physical processes of the hardening and destruction of the material. The primary location of vibration signals begins in the region of elastic deformation, and then, at the transition stage from the elastic to the plastic region, the frequency of the appearance of vibration signals increases, acquiring its maximum value in the region of the preceding destruction.The results of the measurement of quantitative values of absolute elongation corresponding to the moment of occurrence of the vibration signals used for other materials also confirmed this effect see .In the nature of the presented time dependences of the vibrational signals, it is possible to distinguish a high-frequency component associated with oscillations inside the signal and a low-frequency component characterising the envelope of the signal. The signal envelope contains local extremes. The area under the envelope of the signal may be correlated with the energy of the process. Peak amplitudes correspond to the absolute maximum of the signal.For a more comprehensive study of the observed effect, the form of the vibration signals was studied in the sections of the stretching diagram.f(t) is the signal and F(\u03a9) is the Fourier transform.An effective way of analysing continuous acoustic signals is the Fourier transform, in which the signal decomposes into a basis of sines and cosines of different frequencies. The conversion coefficients are found by computing the scalar product of the signal with complex exponentials.According to the uncertainty principle, the more the function is concentrated in time, the more it is blurred in the frequency domain . When thThe results of the Fourier transform are shown in sCmax for each signal, where sCmax is the maximum amplitude of the Fourier transform. The choice of the threshold signal level within 20% of the maximum amplitudes during the measurement of the time and frequency characteristics is due to significant noise of the signals. The density of the frequency signal was determined by counting the number of intersections of the threshold level of the signal divided by the frequency range of the signal. The threshold level was considered equal to 0.2Analysis of the distribution of the amplitudes of the vibrational signals while increasing the applied load made it possible to isolate the necessary level of discrimination. An informative parameter of the vibration signal is the total number of pulses defined as the number of pulse excesses above the discrimination level during the observation period. When processing the experimental data, the Mathematica 9.0 computer mathematics system and algorithms for working with arrays of numerical data were used to find the maximum (minimum) elements of the array, sort the data of the array by characteristic, combine the data, and spline the interpolation.The distribution of the amplitudes of the vibration signals while increasing the applied load is shown in N above the discrimination levels is shown in The subsequent calculation of the number of excess points of Visualisation of the number of excesses of vibration signals over the discrimination levels, constructed from the data in This is in complete accordance with the changes in the frequency of the occurrence of vibration signals presented in All of the presented characteristics of the vibrational signals and the Fourier transforms tend to increase with increasing strain. It is possible to unequivocally ascertain the increase in the energy of vibrational signals as they approach the zone of irreversible changes and destruction (zone III), which serves as an indicator of the pre-critical state of the test sample. With an increase in the applied load and an increase in the relative deformation of the samples, the formation of vibrational signals that correlate with deformation jumps occurs. Since the square of the amplitude of the acoustic signal is proportional to its power, with increasing load on the material and increasing the degree of relative deformation, the power of the acoustic signal increases.A feature of the energy spectrum of the acoustic signals is the discrete nature of the structural changes and the continuous propagation of acoustic waves. All this makes the development of mathematical models of microstructural media relevant.Study of the energy spectrum of signals of nanosized objects is explained by the importance of solving questions about the propagation of vibration characteristics preceding the destruction of materials. In recent years, new models of continuum mechanics have been intensively developed.Theoretical studies of the occurrence of acoustic signals with changes in the material structure have been developed in two main areas: the development of discrete models and models of the elastic continuum.Media exist with simple and complex structures. In environments of simple structures, the only kinematic variable is the displacement vector, which completely determines the state of the environment. To describe a medium with a complex structure, a set of motions and deformations of different orders is introduced, which characterise the internal degrees of freedom and force constants. The difference between media with simple and complex structures is manifested at relatively high frequencies, of the order of the natural frequencies of the internal degrees of freedom.In , a one-dThe force constants that denote the properties of such a discrete model are determined through the parameters of the elastic bonds. The effective characteristics of the bonds are found from the interaction potential of atoms .u(n).0 is the linear chain energy in equilibrium, and n, n\u2019, and n\u2019\u2019 are the numbers of interacting particles.The potential energy of such a chain, \u03a6, is a function of the displacement field n,n\u2019) is the force constants, and q is the external forces.The Lagrange function in this model is the law of conservation of energy.When considering Equation (3), the equation of the vibrational motion of particles in a linear chain takes the form:n,n\u2019) is visible from the equation of motion of the particles. If a particle with a coordinate n\u2019 receives a unit displacement, then an external force compensating for the elastic bond reaction, \u03a8(t), is a characteristic of the interaction between atoms.The physical meaning of the force constants \u03a6 + \u03a8(x), the smoothest one to filter out the rapidly oscillating components of acoustic signals [The task of considering the one-dimensional continuum is to interpolate the displacement functions at the nodes and to choose from the whole set of interpolating functions,  signals .The analytical justification for the interaction of discrete factors initiating the appearance of acoustic signals with their continuous distribution in the medium is that each operation on the functions of a discrete argument can be associated with operations on their images\u2014functions of a continuous argument. This will translate a continuous acoustic signal into a sequence of numbers .The interpolation function will have the form:x will be k and instead of u(x) will be u(k).In the Fourier transform, the argument changes and instead of u(x), the Fourier transform will have the form:u(x) and u(k) are considered as representations of the same function with different functional bases. For function The spectrum of acoustic signals is expressed through the Fourier transform, concentrated on a segment that determines the geometric dimensions of the unit cell of the microstructure under study.The considered one-dimensional discrete-continuous model of the microstructure of a continuous medium in the form of an unlimited linear chain of point masses connected by elastic bonds allows us to obtain equations of motion and determine the force constants of the material. The model can be used if the deformation propagates rather slowly, on the scale of the interaction radius and cell size, so that the movement occurs not only in coordinates, but also in time.Modern mathematical models of acoustic signals take into account the presence of several scales or structural levels in the medium, their coordinated interaction and the possibility of energy transfer from one level to another .The use of the classical model of a continuous medium for studying energetic acoustic vibrational signals in microstructural environments encounters an uncertainty associated with the existence of internal motions of the structural components of the medium. Oscillations of atoms in the crystal lattice do not initiate a propagating wave. For its occurrence, external disturbances are necessary.A discrete-continuous model of the energy spectrum of acoustic signals in complex structures with internal degrees of freedom is proposed, in which the translational and rotational invariance of energy in the energy spectrum of acoustic signals is established, which is also acceptable for vibration diagnostics.Modelling the energy spectrum of a complex structure involves the allocation of a minimum volume in an array\u2014a structural cell that displays the main features of the behaviour of the material  Figure .n is the cell number, jm is the mass of particles in the cell, w is the displacement of particles j in the cell n, \u03a6 is the force constant, and f is the external force that determines the occurrence of the vibrational signals.The Lagrange function in a diatomic cell is expressed by the equation:displacement of the centre of mass of the cell:relative displacement of particles in the cell:where m1 and m2 are the masses of atoms in the cell, I is the moment of inertia of the cell, and \u03be1 and \u03be2 are the coordinates of the particles in the cell relative to the coordinate of the centre of mass.The physical meaning of the model becomes clear if we move on to new variables, such as:q(n) and \u03bc(n) are generalised forces corresponding to u(n) and \u03b7(n).We obtain the equations of motion of the entire cell in a medium initiating the propagation of an acoustic signal:ss\u2019(n) is expressed coordinate-wise through force constant \u03a6 precursors of the AE signal [SS\u2019n)( = \u03a6S\u2019Sn)( \u2013 \u2211\u03a601n)\u03a6(n)This model is well suited for describing tightly packed structures. At the same time, the continuous medium initiating the appearance of acoustic signals is not always homogeneous, which is the case, for example, for polymers and fibrous materials.A visualisation of the considered models of initiation of acoustic signals of complex media under load is presented in Oscillations of particles in a cell characterise the high-frequency component of the acoustic signal, while oscillations of the centre of mass characterise its low-frequency component. An increase in the size and structure of the cell allows us to move from a discrete to a continuous model of the medium. The results obtained make it possible to establish the boundaries of the use of discrete representations of changes in the structure of materials and the continuum model of the propagation of acoustic vibrations in a medium .The use of acoustic measurement instruments makes it possible to find previously unknown characteristics of the structure of materials, to trace the dynamics of their development, stability, integrity, and to predict the development of material defects.C is the structural parameter, and D is the diagnostic parameter.When evaluating the information content of diagnostic parameters, their sensitivity is determined by the following relation:D is to changes in the structural parameter, the higher its sensitivityeven more so at an early stage, making it possible to determine the malfunction.The more responsive diagnostic parameter Informatisation of the process of diagnostics of structures of materials is based on modern computer technologies that can quickly analyse information, with the issuance of recommendations for solving the tasks that contribute to a significant increase in the efficiency and reliability of the control of metal structures.When informing the diagnostic process, not only the object itself is analysed, but also the reasons that caused deviations of the object\u2019s properties from the established parameters, the mechanisms of the emergence and propagation of signals from defects, and ways to improve production technology and its control.The functional purposes and components of the informatisation of the diagnostic process are presented in In the presented classification, there is an interaction of structure-forming elements, subordinated to the single goal of ensuring the operational reliability of structures.Methods of informational diagnostics are an integral part of systems for identifying the defective structure of materials during their loading and operation, in which information is considered as a material object, which is characterised by a large amount of input data accumulated during structural changes.The method of non-contact deformation measurements allows us to take a fundamental step in determining the technical states of objects. The registration of vibration signals during deformation allows us to understand the mechanisms responsible for the accumulation of damage more clearly. The occurrence of vibration signals under loading can be used as an information parameter in the diagnosis of developing defects. It was established for the first time that fixing the moments of occurrence of vibrational signals and determining the number of excesses in the amplitudes of harmonics over the discrimination level allows structural models to be studied for diagnosing the strength properties of materials under dynamic loading of solids.Transferring the moments of occurrence of vibrational signals to the strain diagram from the applied load allows us to trace the development of the physical processes of the hardening and destruction of materials.The presented results of the theoretical and experimental study of the energy spectrum of vibration signals during deformation in the models of a continuous medium, the informational parameters of which are the operators of elastic energy, show that the violation of internal bonds between the translational and rotational properties of the continuous medium model in the form of a diatomic cell connected by elastic bonds initiates the oscillatory properties of the precursors of the destruction of materials of structures that are under load.The proposed measurement method of vibration signals under uniaxial loading of materials using the coherent properties of laser radiation increases the information content of measurements and allows for the automation of the process of recording and processing information and for the monitoring of the continuous dynamic process of the loading of samples."}
+{"text": "The weakness of the health sector in providing homogeneous and suitable educational content for public and lack of a systematic approach to implementing programs at the national level to province and county levels with the aim of modifying the individual and Traffic related behaviors. Local setting: In Iran, the Ministry of Health and Medical Education (MOH) is responsible for maintaining and improving public health status. Transferring health knowledge to people is one of the duties of the health staff in all occupational and professional branches.This educational model has three phases: assessment, implementation and evaluation. Related changes: In this study, which is one of the first surveys of its kind, 470 MOH staff and NGOs representatives from different provinces participated in training workshops based on the Systematic Comprehensive Health Education and Promotion model (SHEPmodel) traffic accidents, and evaluated the effectiveness and satisfaction level of the model.One of the most important lessons learned from the educational programs of this model is the sense of satisfaction the trainers gained from the translated scientific health contents into the intelligible public language along with the existence of a systematic implementation structure. Furthermore, reports and studies conducted over more than a decade of implementation of programs are indicative of the empowerment of trainers with four techniques and seven educational and communicational skills to use in public health interventions for modifying public health behavior.The results of the present study showed that the effectiveness of SHEPmodel was higher than the traditional methods; so that 86% of the participants attending the trainer workshop evaluated this model as highly effective.Traffic literacy, Health literacy, Training of trainers, Cascading format, Social capital, Advocacy"}
+{"text": "PLOS ONE by different authors and retracted in 2015 [After this article  was publ in 2015 . There iPLOS ONE Editors conducted follow up enquiries in response to the related article concerns.The PLOS ONE with raw image files and underlying data for this study, as well as approval documents issued by the Animal Studies Ethics Committee of Fudan University Medical School and the Ethics Committee of Fudan University Shanghai Cancer Center. In addition, the head of the Division of Scientific Research, Shanghai Cancer Center, Fudan University, confirmed the research and submission history reported by the authors for [The authors of  providedhors for  based onPLOS ONE Editors were unable to verify the integrity of that work, and as a result that article was retracted [Upon following up with the authors of the other article , the PLOetracted .PLOS ONE Editors consider the related manuscript issue as resolved.In light of the above information and documentation received from the authors of , the PLOThe ethics approval documents provided in post-publication discussions indicated that the names of approving committees were incorrectly listed in the published Ethics Statement for this article . The EthThe use of patient samples was approved by the Ethics Committee of Fudan University Shanghai Cancer Center and signed informed consent was obtained from all study participants. The animal experiments were approved by the Animal Studies Ethics Committee of Fudan University Medical School.In addition, the published Data Availability Statement for this article is incorrect. The statement is updated to:All original underlying data for the study are available and will be provided upon request."}
+{"text": "Policymakers, experts and the general public heavily rely on the data that are being reported in the context of the coronavirus pandemic. Daily data releases on confirmed COVID-19 cases and deaths provide information on the course of the pandemic."}
+{"text": "The Academy for Gerontology in Higher Education began as the Ad Hoc Committee on the Development of Gerontology Resources in 1972. The next year the name Association for Gerontology in Higher Education (AGHE) was selected. In 1974 AGHE held a general meeting of its membership in conjunction with the annual meeting of the Gerontological Society of America in Portland Oregon. The first annual meeting was held in 1975 in Madison, Wisconsin. The relationship with GSA has evolved over the last four decades leading to the present Academy. The first presentation will focus on the issues of gerontology and higher education that emerged in the early years and continue to be a challenge today. The second presentation will look at the future of AGHE in its new relationship with GSA. The third presentation will focus on the Academy in the present discussing current challenges facing academic gerontology in today\u2019s world including the development of AGHE\u2019s basic-competency guidelines and the emergence of measuring student learning outcomes and their role in program review and evaluation. The fourth presentation will examine the evolving discussion of standards in evaluating gerontological and geriatric programming. Geriatric Education Interest Group Sponsored Symposium."}
+{"text": "Solidity is the dominant programming language for Ethereum smart contracts. This paper presents a high-level formalization of the Solidity language with a focus on the memory model. The presented formalization covers all features of the language related to managing state and memory. In addition, the formalization we provide is effective: all but few features can be encoded in the quantifier-free fragment of standard SMT theories. This enables precise and efficient reasoning about the state of smart contracts written in Solidity. The formalization is implemented in the SOLC-VERIFY verifier and we provide an extensive set of tests that covers the breadth of the required semantics. We also provide an evaluation on the test set that validates the semantics and shows the novelty of the approach compared to other Solidity-level contract analysis tools."}
+{"text": "This article is being retracted from Bioscience Reports at the request of the Editor-in-Chief and the Editorial Board following receipt of a notification from a reader, alerting the Editorial Board to duplicated Western blots in Figure 3C, which have appeared in multiple publications by different author groups.The authors have been contacted in regards to the retraction, and have not responded to the Journal's queries and the concerns raised. The Editorial Board stand by the decision to retract given the concerns with the figures."}
+{"text": "The authors became aware of the erroneous representation of the loading controls for the western blots of the figures. These errors were due to mistakes while generating the figures from templates of the western blot X-ray film images. The corrected In the original article, there was a mistake in The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way."}
+{"text": "We read with great interest the article by Wen et al. , concernWe would like to congratulate the authors for their interesting paper, but we would like to make some comments because we are a little bit concerned with the measurement method they apply to define the vertical distance between the lateral border of the dural sac and the peak of the herniated disc (DSPHD); the vertical distance between the lateral border of the dural sac and the intersection of the dural sac and the medial border of the herniated disc (DSMHD); and the vertical distance between the lateral border of the dural sac and the intersection of the dural sac and the medial border of discectomy (DSMD).To the patients with huge paramedian cervical disc herniation, the lateral border of the dural sac usually becomes obscured , which cIn the postoperative follow-up, the authors found that the distance between the edge of the dural sac and the inside edge of the intervertebral disc was significantly smaller than between the edge of the dural sac and the inside edge of the herniated disc. It should be that postoperative DSMD is less than the preoperative DSMHD.They considered the retraction of the protruding nucleus pulposus after the intradiscal decompression and explained why the incomplete removal of the nucleus pulposus also resulted in the improvement of clinical outcome. We believed that the phenomenon should be verified by further MRI measurement. Additionally, we considered that the symptoms' relief was also related with the indirect neural decompression. After foraminal unroofing and resection of ligamentum flavum, the spinal canal was enough to accommodate the endoscope and available for the spinal cord and nerve root to compensate the compression from the ventral-protruded nucleus pulposus."}
+{"text": "During the process of revising the figures and ensuring they met the required standards for resolution/size, some of the line alignments in"}
+{"text": "The wrong figure version was uploaded and the pre-captivity and post-captivity labels were inverted. The corrected In the original article, there was a mistake in The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "To match the citation numbers in the text with the right reference links, we rearranged parts of the references and changed the wrong numbering of citations in the Key Resources Table. The corrections are as follows:These errors have now been corrected online. The authors apologize for the errors."}
+{"text": "The twovapN carriage in R. equi isolated from human infections in the United States.There is an error in the sixth sentence of the Abstract. The correct sentence is: This is the first report of vapN carriage in R. equi cultured from patients in the United States and from a HIV-negative, transplant patient.There is an error in the fifth sentence of the first paragraph of the Discussion. The correct sentence is: To the authors' knowledge, this is the first confirmed report of"}
+{"text": "Janine Cisneros Desir and Cheryl Van Buskirk. These mistakes have been corrected in the html and PDF versions of the microPublication.In the version of the microPublication originally published online, the names of the third and last author were incorrect. The correct names are"}
+{"text": "Osmotic potential as demonstrated in the equation in the material and methods is the negative value. The correct legend appears below.In the original article, there was a mistake in the legend for The fractionation of the sugars was removed due to duplicate results, probably caused by contamination of the samples. However, the presentation of soluble sugars and starch allows to maintain the same discussion together with the other results.In the original article, there was a mistake in the legend for With the removal of the fractionation of sugars, In the original article, there was a mistake in the legend for The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "Annabel Curtis was not included as an author in the published article. The author list has been corrected above and the updated Author Contributions Statement appears below.DE, HY, RJ, and AC designed the study. DE wrote the majority of the paper with contributions from HY and AC. HY and DE conducted the majority of the statistical analysis. AC contributed to the research design and some aspects of the writing of this manuscript including some aspects of the statistical analysis.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "There are several noteworthy changes to the Improving Grants for States and Community Programs on Aging\u2019s portion of the OAA. The reauthorization adds language requiring data collection on the needs of older adults and specifying additional populations on whom to focus outreach efforts, such as survivors of the Holocaust. The reauthorization also expands what States may fund with Supportive Services grants, adding screening for social isolation and traumatic brain injuries. The Act goes on extend Stated the option of funding programs to address both of these issues. The Act also requires the Assistant Secretary to study the supply and demand of home delivered and congregant meals and make recommendations to address the gap. Finally, there is expansion of the section on Caregiving, including a definition of caregiver assessment and the removal of a limit on funds States can use on support services to family caregivers."}
+{"text": "The aim of the article is to compare the performance of granite powder and fly ash for the sustainable production of air-cured cementitious mortars. The morphological, chemical, and granulometric properties of these additives were first compared with the properties of cement. Afterward, a series of mortars modified with the addition of granite powder and fly ash was made. The properties of the fresh mixes and the mechanical properties of the hardened composites were then tested. Finally, based on the obtained results, a cost analysis of the profitability of modifying cementitious composites with granite powder or fly ash was investigated. The obtained results allow similarities and differences between granite powder and fly ash in relation to cement to be shown. To conclude, it should be stated that both of these materials can successfully be used for the sustainable production of air-cured cementitious composites. This conclusion has a significant impact on the possibility of improving the natural environment by reducing the amount of cement production. More sustainable production of cement-based materials could enable CO2 emissions to be decreased. The use of granite powder for the production of cementitious mortars can significantly reduce the amount of this material deposited in landfills.The partial replacement of cement in concrete with the addition of granite powder and fly ash can help to reduce the carbon dioxide (CO The granite powder has the highest roundness (R) value, while the fly ash has the lowest value of this parameter. In the case of the roundness of the granite powder and fly ash, there is a difference of about 27%, while the roundness value of the cement is smaller than that of the granite powder by about 12%. AR) parameter. It can be seen that its value for the granite powder and fly ash is similar, while the aspect ratio (AR) value for the cement is about 20% more than for the other two binders. Ar) parameter. The value of the area ratio (Ar) for the granite powder is similar to the cement, while the value of the area ratio (Ar) for the fly ash is about 20% lower than that of the other two binders. The basic chemical properties of the binders were determined using X-ray diffraction analysis. The X-ray diffraction test involved the determination of the chemical composition of the compounds. 2 . In turn, cement has a lower SiO2 content (6%). Fly ash and granite powder have a low CaO content of <10%, in contrast to cement (64%). It was observed that each of the analyzed materials has a different Al2O3 content .When analyzing lN) for the mortars, which differ regarding their content of granite powder/fly ash in relation to the mass of the cement.lN) of the mortar is lower in relation to the reference mortar (maximum by about 6%). It is evident from lN) of the mortar slightly increases (maximum by about 10%). This may be due to the fact that the shape and morphology of the fly ash grains cause a change in the consistency of the cementitious mix, which becomes more fluid. A similar relationship was observed in other studies in the cases of granite powder  was used as follows: To compare the results of the mechanical performance ratio (MPR) with regards to the series of air-cured hardened cementitious mortars and the number of days after which the samples were tested. The MPR values for the series with the granite powder are smaller than the MPR values for the reference mortar. The MPR values for the series with the addition of the fly ash are similar to the MPR values for the reference mortar. The mortar with the granite powder has MPR values of about 10% lower than the mortar with the fly ash.ECR)\u2014the author\u2019s own proposition.The cost of a cementitious mix depends on the cost of its ingredients, which in turn depends on the location and given economic conditions prevailing in the country. In order to determine the costs of materials, which are indicated in ECR) with regards to the series of the air-cured hardened cementitious mortars. The ECR value for the series with the granite powder is less than the ECR value for the reference mortar. The ECR values for the series with the addition of the fly ash are similar to the ECR values for the reference mortar. The mortar with the granite powder has ECR values of about 5% lower than the mortar with the fly ash.MPR and ECR parameters with regards to the series of cementitious mortars.Conducting a separate economic and strength analysis does not allow for a proper interpretation of the obtained results, and therefore a combination of these analyzes was performed. MPR) and effective cost ratio (ECR) values obtained during the tests. The most optimal choice depends on the situation and should be made by the designer of the building construction. Therefore, the most optimal composition of the mortar was not specified.Granite powder and fly ash have different morphological properties, whereas the properties of granite powder are similar to the morphology properties of cement;The addition of granite powder in cementitious mixes changes the consistency of the mix, becoming denser, whereas fly ash changes the consistency of the mix to be more fluid;The addition of granite powder and fly ash causes a decrease in the mechanical properties of cementitious mortars in the first 28 days of curing. After this time, an improvement in the mechanical properties of mortars with the addition of fly ash can be observed. In the case of mortars with the addition of granite powder, this effect was not observed;Replacing the cement resulted in a decrease in compressive strength; however, it was observed that with the increased amount of cement replacement with the addition of granite powder , no significant decrease in compressive strength was detected. This may be indicative of the filler effect of granite powder in cementitious composites;It was observed that the increased w/c ratio decreases the compressive strength and bending tensile strength of mortars (compared with reference mortar); it was also observed that the brittleness of mortars decreases with the time of curing, and modification of mortars with the addition of granite powder or fly ash does not change brittleness significantly;It was observed that the economic properties of mortars modified with the addition of granite powder are significantly better than those of mortars modified with the addition of fly ash.This study allows the comparison of the properties of granite powder waste with the most commonly used supplementary cementitious materials (SCM)\u2014fly ash. It was observed that granite powder has different morphological properties and a different effect on a cement mix when compared to fly ash. However, both additives reduce the mechanical properties of composites, especially in the first 28 days of curing. Nevertheless, it should be stated that the use of granite powder waste as SCM has the potential to improve the sustainability of cementitious mortars. The better cost parameters of mixes with the addition of granite powder, when compared to fly ash, indicate that it is an important additive for cementitious mixes. Moreover, the following observations can be stated:It should be stated that granite powder has great potential to be used as supplementary cementitious materials in cementitious composites. However, more research should be conducted to develop the sustainable use of this additive for construction materials."}
+{"text": "This paper presents a method of acquisition and analysis of three-dimensional images in the task of automatic location and evaluation of defects on the surface of ceramic tiles. It presents a brief description of selected defects appearing on the surface of tiles, along with the analysis of their formation. The paper includes the presentation of the method of constructing a 3D image of the tile surface using the Laser Triangulation Method (LTM), along with the surface imaging parameters employed in the research. The algorithms of three-dimensional surface image analysis of ceramic tiles used in the process of image filtering and defect identification are presented. For selected defects, the method of measuring defect parameters and the method of visualization of defects on the surface are also presented. The developed method was tested on defective products to confirm its effectiveness in the field of quick defect detection in automated control systems installed on production lines. The increase in the capacity of production lines producing ceramic tiles imposes the introduction of innovative solutions in the field of fault diagnosis and detection systems on product surfaces. In many manufacturing enterprises, the quality inspection of ceramic tiles is carried out by a person supported by sensor or vision systems. Firat et al. presented the study of the description of employee fatigue and the possibility of errors made by them in the implementation of visual assessment of the product related to work time or type of product .Introduction of vision systems to the production lines made it possible to acquire an image and analyse this image in order to identify and locate defects. As part of the vision methods described in the literature, the analyses of shades of grey or colours are usually used. Hanzaeia et al. presented a system based on 2D image analysis with statistical methods to detect the edges of such surface defects as cracks and scratches . Job SamIn article , the autIn most industrial applications, the image analysis system is responsible for detecting defects on a surface. The task of checking the geometry of the surface in the form of a flatness check is done by means of a sensor system (4\u20138 sensors); these measure the height in designated areas of the tile surface. Most vision systems used in the ceramic industry can be described as two-dimensional due to the information available in the image and the method of surface imaging. They are most often implemented as additional equipment in technological machines and checking stations, the task of which is the implementation of inter-operational inspection of product parameters. Introduction of automated video stands with extended measuring and inspection capabilities is required, especially in mass production carried out in the \u201czero defects\u201d system, providing a thorough inspection of all products leaving the production line.This paper presents the method of acquisition and analysis of 3D images in the inspection tasks of selected parameters of a ceramic tile. The paper presents examples of using 3D images in the implementation of tasks to check defects in geometry and surface defects of the product. The advantage of the method is that the three-dimensional image enables the implementation of a much larger number of measurements and analyses, especially in the field of spatial measurements, complementing and extending the currently used vision methods in the video industry based on two-dimensional image analysis ,13,14,15The geometric defects occurring most often on the surface of ceramic tiles include defects in the flatness of the tile\u2019s usable surface. These defects are visible in the form of curved corners or edges or in the form of a visible buckling on the surface. Geometric defects also include any damages to edges and corners. A large group of defects are also flaws of usable surfaces visible in the form of surface delamination, scratches or local roughness variations. These defects may be very small in size or may be seen on almost the entire surface of the tile. The following drawing shows a large delamination area, located in the centre of the ceramic tile. Implementation of research and development of a system enabling detection of all the described defects requires implementation of imaging of the entire surface of the tile and preparation of a set of reference algorithms to enable the detection of each type of defects.The objective of the research described in this paper was to develop and implement a system that allows comprehensive assessment of the quality of ceramic tiles. It results from the need to check the quality of the product\u2019s performance in the scope of checking the geometrical dimensions of the ceramic tile combined with simultaneous checking of the presence and parameters of defects on the surface of ceramic products. For this purpose, a vision system was developed using the LTM method, designed to build a three-dimensional image of the surface of the tile. It was assumed that the video system operation parameters and 3D image analysis algorithms will enable location, description of defect parameters and a comprehensive assessment of the ceramic tile geometry.Three-dimensional vision systems are configured and built strictly with a view of the implementation of inspection and measurement tasks. This requires a detailed analysis of the task in terms of the possibility of determining the parameters describing the tested product. It is necessary to carry out imaging tests both in laboratory conditions and in the conditions of the production line. The 3D vision system presented in this paper was designed and launched by a research team committed to the automation of the product performance inspection process and by specialists involved in the technology of ceramic tile production. Due to the method of three-dimensional image construction being used in the paper, and using the laser triangulation method as part of the preliminary research, the analysis of the cooperation of the image recording system, laser lighting and the examined surface was performed as a function of the adopted configuration of the vision system.The first stage of the work was to prepare a catalogue of defects found in the products. The task included a description of the defects and characteristic parameters describing each of the defects. In the next stage, a technical solution was developed, enabling three-dimensional imaging of the product surface and defects for the adopted catalogue of defects. Next, three-dimensional image analysis algorithms were developed allowing for a parametric evaluation of each of the defects and marking the defect on the surface of the product.Microcracking: i.e., cracks visible on irregularly shaped surface, several centimetres long and 100 to 200 \u03bcm wide. The morphology of microcracks was characterized by the occurrence of numerous bifurcations in the form of scratches and delaminations visible on the surface of the tiles. Shortcomings of such morphology arise most often as a result of thermal stresses of the second kind that appear during the firing process.Tile thickness deformation: with \u00b11000 \u03bcm deviation value, visible in the form of buckling or defects on the surface. This type of production defect is often associated with non-homogeneous distribution of granules filled into the mould before the pressing process.Geometrical defects: characterized by non-parallelism of edges and aberration of angles of tile corners with a deviation of up to several degrees from the right angle. This type of defect is related to the occurrence of uneven shrinkage of the tile occurring during the sintering process.Ceramic tiles with three types of production defects were used for the tests. It was assumed that the product analysis of the ceramic tile surface will be implemented in the scope of checking:The vision system works on a control stand designed for the needs of the measuring task. Ceramic tiles are placed on a platform that moves relative to the permanently mounted laser\u2013camera system. The displacement is carried out in the Y-axis of the coordinate system associated with the 3D image. The station propulsion system uses a stepper motor with a propeller with a pitch of 2 mm. The system is controlled from a controller enabling the implementation of a minimum displacement of 0.01 mm. Such displacement is additionally controlled by two encoders. The first is built in the engine axis and the second is mounted on the propeller. This enables displacement control and identification of platform positioning errors.2 at a resolution of 0.25 mm on the plane with 16 measurement points.The geometry of the 3D vision system has been configured for the implementation of the task, including the following parameters: dimensions of the examined \u201ctile\u201d object 192 mm \u00d7 192 mm and the required imaging resolution of 0.25 mm in the X- and Y-axes of the coordinate system of the measurement stand. This system allows imaging of 1 mmThe image of the three-dimensional surface of the tile is constructed using surface imaging illuminated with a linear laser beam presented in Three-D imaging requires determining a set of height profiles that are evenly distributed on the surface of the tile. This is related to the tile displacement relative to the vision system in the direction of the Y-axis. The displacement of the test object relative to the vision system in the determination of successive height profiles is determined as the measurement resolution in the Y-axis of the measurement position. The assembly of a set of height profiles thus determined that are spread evenly on the surface of the tile enables the construction of a three-dimensional image of the surface of the ceramic tile. To calibrate the camera geometry, a built-in model for Ranger cameras was used. Calibration of the power of the laser illuminator and the frequency of the camera\u2019s operation were selected on the basis of statistical tests carried out on prepared sets of tiles manufactured correctly and tiles with damaged surfaces from one production line. Imaging tests were performed for twelve different plates for one plate dimension. Calibration of lighting and system operating frequency should be performed separately for each product group due to changes in the surface structure of the tiles and their colours.\u03b1 to the optical axis of the camera . The dimension j corresponds to the x coordinate in the image coordinate system and defines the width of the field of vision of the video system by specifying the number of columns of the matrix. The dimension i corresponds to the coordinate y in the coordinate system related to the image and defines the number of height profiles determined for the tested object by specifying the number of rows in the matrix. The individual cells of the matrix contain information about the height h  of the image determined with the resolution \u0394Z for each of the points defining the surface of the ceramic tile.Composition of profiles enables the construction of a three-dimensional image describing the surface with a resolution of \u0394X = \u0394Y = 0.25 mm in the X and Y-axis and with a resolution \u0394Z = 0.35 mm in the Z-axis. Sample images of ceramic tile surfaces made with the adopted resolution are shown in The use of 3D imaging and 3D image analysis of the ceramic tile surface may be presented in the form of an algorithm, the diagram of which is in Analysis of three-dimensional images is based on the processing of data describing the height of points forming the surface collected in a two-dimensional matrix. The purpose of this analysis is to determine the characteristic features of the image, e.g., describing surface defects and presenting them in the form of parameters. The most common parameters are: geometrical dimensions, surface areas, volume or shape of defects as defined in the catalogue of defects. Analysis of the image of the three-dimensional surface of ceramic tiles may be divided into three stages: pre-processing, measurements of selected parameters, evaluation of measurement results.Three-dimensional images were pre-processed to remove distortions and improve the image characteristics that will be used in the phase of measuring the parameters describing the defects . Pre-proThe next step in the implementation of the planar surface flatness algorithm is to determine the surface area of the defect that is outside the tolerance value adopted by the quality control department. In order to determine the height deviation in the image, a measurement algorithm is used to determine the values describing the height of the surface along the defined measurement profiles set in the subsequent rows of the image matrix. It is a type of scanning that allows locating areas with the highest flatness deviation and determining the shape of the defect visible on the surface.The shape and area of the area outside the tolerance is determined by comparing the height of each pixel that creates the actual surface image with the height value of the reference plane. It is a point transformation allowing us to determine the surface area of the defect area. An example of the defect area may be found in All in all, the algorithm of location and assessment of defect parameters used in the presented example includes the analysis of point-forming surfaces, determination of the reference surface and determination of areas outside the assumed tolerance of surface flatness deviation. This algorithm also allows locating delamination and defects associated with losses and material allowances observed on the surface of the tile. The reference plane determined on the basis of the tile surface analysis allows us to indicate the delamination edge and the description of the defect area in the form of delamination. The defect area isolated during the 3D image analysis is presented in The measurement of flatness deviation associated with delamination is also performed by scanning all the image points in the area of the tile. Based on the determined parameters, the defect is assessed and classified. Defects are qualified on the basis of the adopted parameters that describe their acceptable dimensions as prepared by the quality inspection department of the production unit. During the research phase, imaging of a set of 50 ceramic tiles selected by the manufacturer with various surface defects was performed. A set of typical defects found in the production of tiles in various dimensions of defects was selected. Each defect was tested in four plate settings, which gave 200 different images of the defects depending on the scan direction of the plate. Subsequent image recordings were made using several sets of imaging parameters: power change, laser mode (continuous pulse) and changes in the frequency profile registration frequency. The set of test images has also been supplemented with tiles surfaces made correctly. The set of images prepared in this way (about 400) was analysed several times with various sets of parameters used in the 3D image evaluation algorithm: changes in the image filtering method, changes in the range of pixels used to determine the reference plane, changes in the method of averaging the pixel height on scanning lines, etc. Preparing the solution in the years 2017\u20132019, the sets of defects were supplemented, and the algorithm was updated. In addition, tests were carried out in the production line working conditions confirming the effectiveness of the system work.The biggest threat to the system is the need to shorten the analysis time associated with increasing the efficiency of the production line. This involves the need to reduce the number of analysed measuring points on the 3D surface image. In this case, microcracks with dimensions below 0.25 mm may not be visible.Studies have shown that it is possible to imaging typical defects arising on ceramic tile surfaces. It is also possible to describe the parameters of the defect in the form of its geometric dimensions, surface area and volume. It is also possible to determine the height profile in any cross-section and calculate the deviation of flatness of the surface. All measurements are carried out with the resolution assumed during the construction of the three-dimensional vision system. These are the resolutions determined on each axis of the measuring station. The points describing the surfaces designated by the 3D vision system are subjected to statistical analysis in order to determine the next parameters required by the system user. The article presents a system with resolution dX = dY = 0.25 mm and dZ = 0.35 mm. The measurement resolution can be increased by using correspondingly larger sensor matrices, e.g., Sony IMX304 type with a resolution of 4112 \u00d7 3009. Resolution measurements for the presented 3D vision system configuration using selected matrices are shown in the It is possible to make measurements at higher resolutions with a narrow field of view of the vision system and the use of sensor matrices with higher resolution. A system of several vision systems can be used to illustrate the surface of the ceramic tile. However, in industrial conditions, vibrations and other types of noise occur on production lines that prevent imaging with increased resolution.The use of three-dimensional image analysis in the field of searching for, locating, and assessing surface defects of ceramic tiles in the form of surface defects such as cracks and delamination allows effective assessment of the quality of the surface of the tile. In addition, the use of a three-dimensional image for fast and industrial surface evaluation in the scope of its geometry allows for integration and extension of control tasks and their implementation at one control station. The presented method of measuring the flatness of ceramic tiles using a three-dimensional image containing 800,000 measurement points allows us to determine a map of the distribution of flatness defects on the tile surface and to check each product within about 200 ms. However, it does not include image building time and communication time with executive devices (machine controllers). It is a significant extension of inspection capabilities in relation to the sensor systems installed on the line enabling measurements at several points on the surface of the tile.The 3D vision system is designed to perform a specific inspection task. One of the most important parameters is to achieve the required measurement resolution. The presented system enables the registration of a defect image with dimensions of 0.25 \u00d7 0.25 mm, which gives 16 measurement points for every square millimetre of the tile surface. This is the limit dimension of the defect that can be observed in a three-dimensional image. If need arises to increase the measurement resolution, the design requirements should be changed, and other components of the system should be selected. The analysis of defect areas on the 3D image allows a repeatable description of the defect parameters and their classification, enabling quick product checking and sorting.The method of evaluation of ceramic surface defects presented in this paper, based on the 3D image analysis, enables the implementation of a much larger number of measurements and tests, especially in the field of spatial geometric measurements. It significantly extends the possibilities of detailed surface evaluation in relation to analysis using vision systems analysing colours or shades of grey of the tile surfaces. In addition, it significantly expands the detailed microdamage analysis of the surface using 16 measuring points per 1 square millimetre of a ceramic tile surface."}
+{"text": "The implementation of the maternal mortality surveillance system in Iran has significantly reduced the incidence of maternal mortality. However, the pattern of the causes of the mortalities, which has remained constant over the years, are still concerning. This study aimed to explain the experiences of the actors of the Iranian maternal mortality surveillance and provide strategies for improving this system.This research is a qualitative study to develop strategies, that will be conducted in two phases. In the first phase, purposive sampling will be performed, and the data will be collected based on the experiences of the Iranian maternal mortality surveillance system actors in Iran\u2019s Ministry of Health and the selected universities  through semi-structured interviews. Moreover, during this phase, some part of the data will be collected through random participation of the researcher in some maternal mortality committees of the selected universities. In order to carry out the second phase, a panel of experts will be set up to discuss the best strategies for improving the Iranian maternal mortality surveillance by considering the above results.The analysis of maternal mortality surveillance system needs to evaluate the experiences of the actors who are the policymakers of this system and can be effective in identifying its challenges. This analysis and formulation of the subsequent strategies can lead to maternal health indicators remaining within the range of international standards or even beyond those standards in Iranian universities and countries with similar surveillance system. The maternal mortality surveillance system, which includes processes such as the registration of maternal deaths, data collection, formation of death committees, and subsequently, design of the death preventive interventions, has been operating in Iran and other countries for many years. Although the implementation of this system has been successful in reducing death rates, the pattern of death causes in the form of bleeding and gestational hypertension has remained the same for years. As such, stop in the downward trend of the deaths can be predicted. Accordingly, the present study aims to analyze maternal mortality surveillance system in order to formulate strategies for the improvement of this system after analysis. Strategies can provide policymakers with the highest insight so that they can provide a rational and defensible basis for future decision-making and orientations on the pregnant women health index.In the first phase of the research, the processes of this system will be analyzed by interviewing the maternal mortality surveillance system actors in the Ministry of Health and Medical Education and the selected universities of Iran and the shortcomings will be identified. In the second phase, based on the obtained analysis, a panel of experts is formed to develop strategies for the improvement of the maternal mortality surveillance system. This study seems to provide comprehensive strategies for the betterment of the maternal mortality surveillance system in order to improve the status of maternal health index and eliminates all causes of mortalities.Identification and notification of death, its review, and the presentation of the intervention strategies are among the most valuable programs in countries to achieve a reduction in maternal death . In thisThrough this system, the Islamic Republic of Iran has undertaken long-term and short-term planning on maternal health and in recent years has been identified by the WHO as one of the triumphant countries in achieving the fifth Millennium Development Goal  , 6.Currently, one of the most important goals of the Ministry of Health and Medical Education to maintain and improve this index is to prevent the recurrence of repetitious deaths, that is, the repeatable accidents under the same circumstances that, despite the constant efforts of the experts, have not been successfully achieved ; so thatUnfortunately, mortalities with the mentioned causes occur in all provinces of Iran continually and with almost similar causes and conditions. After each death a compulsory and out-of-duty investigation begins and then ends immediately, and after sometimes another death occurs with the same panel and this defective cycle is repeated time and again. As such, a careful examination of all these factors seems to be essential . This tyThis research is a qualitative study to develop strategies, approved by the Ethics Committee of Tarbiat Modares University, Tehran, Iran (IR. MODARES. Rec 1397.267) and study will be conducted in the fields of health and treatment of the Ministry of Health and the selected Iranian national universities. The selected universities in this study include three type I universities , one type II university (Zahedan), and two type III universities . Tehran University of Medical Sciences was randomly selected from three Tehran Universities of Medical Sciences . It was selected because we need to have one of the capital\u2019s medical sciences universities in the research process. Alborz University of Medical Sciences is selected because of the immense cultural diversity in this province that is due to the over-migration. Accordingly, different implementation of the maternal mortality surveillance system is more possible than other provinces. Shiraz University of Medical Sciences is considered for being a pioneer in the development and implementation of some maternal health related programs (Accreditation Programs). Isfahan University of Medical Sciences is selected because maternal mortality rate in this university shows a decreasing trend during the last 3 years. Zahedan University of Medical Sciences is selected among the other medical sciences universities of the country because of the high maternal mortality rate of this university. Finally, Shahrekord University of Medical Sciences is selected among other medical sciences universities of the country because of the low maternal mortality rate of this university. At all stages of the study, informed written and oral consent will be obtained of all participants. This research will be conducted in two phases. In the first phase, the processes of maternal mortality surveillance system are analyzed qualitatively and through using a directed approach. In fact, using this analysis, the experiences of the surveillance system actors about the challenges of this system will be discovered and, after being completed, the codes base on the available categories, subcategories and final or main categories will be identified. In order to conduct the second phase of the research, a panel of experts is set up with the aim of considering the best strategies for the improvement of the Iranian maternal mortality surveillance system by considering the above analysis. In order to formulate these strategies, several meetings will be organized with the participation of the Ministry\u2019s maternal health actors, stakeholders, and researchers of the study. In these sessions, the assessment of the internal and external environments in relation to the implementation of the Iranian maternal mortality surveillance system will be done by considering the obtained analysis, then, balancing these points, the strategies will be formulated.The first phase of the study is designed to answer this question that \u201cHow are the actor\u2019s experiences for Iranian maternal mortality surveillance system?\u201d This study will be conducted using a qualitative content analysis method.Purposive sampling method will be used in this research, whereby the actors, through active participation in the research, will help the researcher in better understanding of the problem. Sampling will continue until data saturation is reached and the categories are repeated.The research participants are the maternal health actors in the Ministry of Health and Medical Education and the selected universities of the country. Maternal health actors in the Ministry of Health and Medical Education: In the area of health, these actors include the head of the Maternal Health Department, the expert in maternal health and the head of family, population and school\u2019s health department. In the field of treatment, they include the head of the midwifery department, the expert of mothers in the midwifery department, the head of the treatment and evaluation department, the head of hospitals affairs, the head of the clinical excellence department, deputy of treatment and director of treatment.Maternal health actors in the selected universities: In the field of the Health Deputy, these actors include the head of the maternal health department, the expert in maternal health and the head of family, population and school\u2019s health department. In the field of the treatment deputy, these include the head of the midwifery department, the expert of mothers in the midwifery department, the head of the treatment and evaluation department, the head of hospitals affairs, the head of the clinical excellence department, deputy of treatment and director of treatment. In the field of educational deputy, they include educational assistant, the gynecologist member of the mothers\u2019 mortality and morbidity committee, the head of gynecology department and the head of midwifery department of medical as well as nursing and midwifery schools and the heads of these faculties. In the referral hospitals they include the hospital head, the hospital manager, maternity officer, the head of mortality and morbidity committees, matrons and educational supervisors.The health deputy of the Ministry of Health and Medical Education, as well as the health and treatment deputy of the selected national universities  construct the research environment.Inclusion criteria consists of having at least 2 years of working experience in the position of maternal health expert and being an active member of the university\u2019s mortality and morbidity committees. For the hospital authorities, 1 year of experience in the relevant position is sufficient. The exclusion criteria will be the unwillingness of the participants at any phase of the research to continue their collaboration.Data collection in this phase will be done through in-depth semi-structured interviews, field notes and observations. Interviews will be conducted with the maternal health actors at the Ministry Health and Medical Education and the selected universities, and field notes are based on their nonverbal behavior. In the interviews, the processes of implementing the Iranian maternal mortality surveillance system  will be examined to determine its distance from the standards; moreover, the challenges and defects of implementing such a system will be evaluated. Observation is also done by the random participation of the researcher in one or more death committees of the selected universities in order to record how the maternal mortality surveillance system is implemented.Directed content analysis will be used for data analysis and interpretation. All 3 stages of preparation (convert interview to text), organize (the emergence of new categories by forming an unconstrained matrix) and reporting, will be considered .To assure the trustworthiness of the findings, the four criteria of credibility, dependability, confirmability, and transferability will be employed.The second phase of the study is designed to answer this question that \u201cwhat strategies are effective for Iranian maternal mortality surveillance system?\u201d In order to conduct the second phase, sessions will be held considering the mentioned analysis and using focus group discussion method to find the best strategies for improving the Iranian Maternal Mortality Surveillance System.The research population in this phase includes the head of the midwifery and reproductive health board, the head of women\u2019s board, the head and expert of the Department of Maternal Health in the Ministry, the head of the Department of Midwifery, one faculty member of the Obstetrics and Gynecology Department, one faculty member of the Midwifery Department, stakeholders out of the health system .The sessions for the development of strategies will be held at the Ministry of Health and Medical Education.Inclusion criterion is that the participants are required to have at least 2\u2009years of relevant work experience. The exclusion criteria will be the unwillingness of the participants at any stage of the study sessions to continue their collaboration.Data collection process in this phase is performed through focused group discussion, so that the views, judgments, and attitudes of the visiting professionals about the strategies used for the improvement of the surveillance system are considered in several sessions. It should be noted that before the sessions, the results of the first part of the research as well as the comparisons of maternal mortality surveillance systems in the world, are prepared as a protocol and are given to the stakeholders of the research by the researcher. The first session will be held with the participation of the representatives of the Health Ministry, the head of the department of the Midwifery of the Health Ministry, and the head of the department of Maternal Health at the Health Ministry. After presenting the general issues of the national system of maternal mortality surveillance and its significance in the field of health, the results of the interviews about the analysis of this system will be discussed. Given the mission of the Ministry in improving the national system of maternal mortality surveillance to reduce maternal deaths, and based on the obtained analysis, the context is provided for determining and selecting a number of stakeholders in order for the sessions to be held purposefully. In the next sessions, with the presence of the aforementioned members and selected stakeholders, the internal (strengths and weaknesses) and external (opportunities and threats) factors of the maternal mortality surveillance system will be assessed.Data analysis is performed in other sessions through creating a strategic balance between the strengths, weaknesses, opportunities, and threats (SWOT). The formulation of the strategies is done through this balance. The matrix tables  are then drawn to consider the most important strategies.Many studies have emphasized the necessity of following maternal mortality surveillance system to reduce maternal deaths. According to these studies, decrease in the maternal mortality ratio during the recent years, compared to 1990s, has been related to the use of this system \u201316. MoreHowever, the evaluation of the processes of maternal mortality surveillance system by its actors is necessary so that we can formulate the essential strategies for improving the surveillance system based on the data obtained from the evaluation. In previous studies conducted in Iran, strategies developed in line with the maternal mortality surveillance system suggested that these strategies could be formulated solely with respect to deficiencies obtained from the report of the deaths or based on their causes. As such, none of these studies have had a complete and in-depth interview with the actors of this system to analyze it and use the results for the development of the strategies , 10.The present study in the form of maternal mortality surveillance system analysis is expected that all major universities in Iran develop a coherent planning based on these strategies in order to solve major issues and problems in this regard. Additionally, as the maternal death system in all countries is based on the recommendations of WHO, FIGO, ICM, UNFPA and CDC, and all countries are required to follow this system in order to achieve a reduction in maternal deaths , the preBy and large, these strategies can improve the organizational performance of the Ministry of Health and Medical Education and the related universities with regard to maternal health in Iran and other countries of the world, and deal appropriately with the rapidly changing situations in order to maintain the level of the maternal mortality standards at the level of international standards or even beyond them."}
+{"text": "Emotions are a relevant factor in consumer behavior  behavior; and the macro level\u2014management of interrelationships. The authors recommend actions leading to the recognition of bullying inside the organization and improving the competencies of the management of interrelationships in order to protect the victims of bullying and avoid new cases.This special issue consists of 12 articles. The first manuscript of this section is entitled \u201cEmotions and Sport Management: A Bibliometric Overview. The authors use a bibliometric performance analysis and graphic mapping to provide a general vision of the academic research into emotions in the field of sports management. The results show that the U.S.A is the country that contributes most authors in the field and that it is a field still regarded as incipient .The second manuscript is titled: Mastromartino and Zhang published the manuscript titled Affective Outcomes of Membership in a Sport Fan Community. The objective was to carry out a review of the state of the research in the field of emotions and the sense of belonging to a sport fan community. The authors underline the need to monitor factors at both a technological and group or social level due to the dynamism of the communications and technology sector in order to detect changes in the sense of belonging.Sport Spectatorship and Health Benefits: A Case of a Japanese Professional Golf Tournament.  Watanabe et al. measure how the factors of core product  and peripheral spectator services  influence spectators' length of stay at a golf event, physical activity and life satisfaction. The tournament services influence physical activity, that could finally influence life satisfaction. As a consequence, the authors recommend incorporating health and well-being initiatives in the commercialization plans of sporting entities.The fourth manuscript is titled Tur-Porcar and Ribeiro-Soriano examine the criteria that are most affected by the commitment of athletes to sport organizations in the paper titled The Role of Emotions and Motivations in Sport Organizations. The authors employ the Analytic Hierarchy Process method and conclude that emotion and motivation are the most important factors in generating commitment within sport organizations. The authors recommend increasing the social motivation of the clients through improvements in well-being accompanied with team results and competitive victories, and improving emotional management through self-evaluation.Portrait of Boredom Among Athletes and Its Implications in Sports Management: A Multi-Method Approach. Velasco and Jorda present two studies with the aim of examining which aspects and incidents of being an athlete lead to boredom and how this negative emotion influences performance, attitudes and behavior. The first study reveals that boredom is prevalent amongst athletes, especially produced by carrying out repetitive tasks, lack of motivation and anticipated negative mood. The second study showed that boredom negatively influences performance and influences the over-consumption and alteration of sporting diets. Thus, the authors recommend that coaches search for signs of boredom through his or her sportspeople's consumption and the use of new technologies or materials to influence novelty and reduce boredom, as well as developing social relationships inside the group.The sixth paper is titled Kapl\u00e1nov\u00e1 published the manuscript titled Financial Awards and Their Effect on Football Players' Anxiety and Coping Skills which examines the effect of economic rewards on the anxiety, coping skills and stress of players. The results of the experiment showed that the players subjected to economic rewards developed greater motivation, better physical and mental preparation and a greater inclination to respect the decisions of the coach. However, the players subjected to rewards suffer greater cognitive anxiety, finally affecting their sporting performance.Shakina et al. presented the paper Football Fans' Emotions: Uncertainty Against Brand Perception. This paper examines the influence of the emotion of competition in a football match and the place where it is held on the attendance, ticket price and emotional state. Having analyzed more than 1,100 football matches from three seasons of the Brazilian state championship, the authors conclude that the price of the tickets does not have a significant influence on the attendance in a moment when the team playing is popular, thus demonstrating the emotional influence over the economic in the decision system of the spectator. Furthermore, the results showed that attendance does not vary according to the competition of the match; the attraction of the team itself on the fan is stronger than the attraction of the competition during the match.Overall Quality of Sporting Events and Emotions as Predictors of Future Intentions of Duathlon Participants and analyses the moderating effect of emotion on the influence of quality, satisfaction, and perceived value on intention to attend a sporting event. The authors apply a QCA and SEM and reach the conclusion that quality and satisfaction are key factors in predicting intention to attend. The combination of these factors with emotion explain, in themselves, the intention to attend .The ninth paper is titled The Influence of Emotion in the Management of Amateur Football Organizations. This paper examines the influence of organizational variables on credibility, identification and loyalty to amateur sporting organizations. The results showed that the organizational variables explained behavior better than the emotional variables, but that their inclusion improves prediction .The tenth article is titled Future intentions of fitness center customers: effect of emotions, perceived well-being and management variables is the eleventh. Garc\u00eda-Pascual et al. measure the influence of management variables , demographic variables  and psychological variables  on future behavior of fitness center consumers. The authors conclude that the management variables predict future behavior better, to the detriment of the psychological ones. The authors recommend frequently monitoring levels of satisfaction and quality and implementing programs that emphasize positive emotions of employees and clients.The paper titled Social Atmospherics, Affective Response, and Behavioral Intention Associated With Esports Events and aims to examine the relationship between the social atmosphere, affective response and the intention to attend a sporting event. As a result, Jang et al. conclude that cheering behavior, similarity, cosplay, and social density  influenced affective responses and behavioral intention. The authors recommend sporting managers consider atmosphere as a trigger of affective response and include animation and cosplay promotions.The last paper is titled The editors of this special issue would like to thank all the authors for their contributions and recognize all the future research that still needs to be done, for example through the application of neurophysiological techniques that allow emotions to be more validly recorded, research into the drivers that open up new sport markets, or new ways of social communication based on communication technologies.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The authors wish to make the following correction to the paper :Conflicts of Interest: The authors would like to report non-support  from Septodont, France and MedCem (Switserland) during the conduct of the study. Outside of the submitted work, the authors received materials free of charge for educational courses and Martens, Rajasekharan, and Cauwels report personal fees (honoraria/lecture fees) and research grants from Septodont, France negotiated with Ghent University. The funders had no role in the design of the studies; in the collection, analyses, or interpretation of data; in the writing of the manuscripts, or in the decision to publish the results.The authors would like to apologize for any inconvenience caused to the readers by these changes."}
+{"text": "Traffic incidents are the first service provided by pre-hospital emergency staff. The existence of occupational safety for this cortex increases the efficiency and quality of service. This research was conducted to evaluate the occupational safety of pre-hospital emergency personnel in Isfahan by examining their experiences.This study was a qualitative study and its purposeful sampling. The degree of entry of individuals into the study of work experience over 3 years as a technician in urban and road bases in the emergency medical section. In this research, 15 people were interviewed and the framework analysis was used to analyze the data.The findings of the occupational safety assessment study of the pre-hospital emergency staff with their experiences of four main axes and 16 sub-axes. The four main axes of personnel experience in occupational safety included: individual problems, organizational problems, inadequate coordination and community-related problems. Personnel 115 considered major issues and problems that led to an increase in job insecurity in people s lack of awareness of 115 emergency tasks. Relief from 115 personnel in cases of assault, psychiatric disorders and anger in the patient s companions, in turn, compromise the safety of 115 personnel. The failure of equipment and vehicles and the lack of recognition of some natural and chemical and microbial incidents before deployment lead to increased incidents and deaths for personnel.According to the findings of the study, the preparation of a joint message center between the relief agencies, the psychotherapy team and the rapid reaction teams for the relief of particular cases, the coordinated system of payment of salaries, the creation of job rotation between urban and road bases, in Considering the amenities and the non-material needs of the constructive suggestions for improving the personnel performance and improving the job safety of the city of Isfahan.Occupational safety, Emergency, Traffic accidents"}
+{"text": "Please allow me to make the following address for the launch of the JMA Journal.The Asian Medical Journal (later renamed JMAJ), the one preceding the JMA Journal, was started in 1958 by Taro Takemi, a former president of the Japan Medical Association (JMA), who recognized the importance of professional exchanges in the medical field between Japan and various other countries including those of the Asian region. The Asian Medical Journal aimed to introduce medical care as practiced in Japan, the beliefs and activities of the JMA, as well as state-of-the art medical sciences to other countries, and was distributed mostly over the Asian region. It is quite remarkable that transmission of information targeting areas outside Japan was initiated in as early as 1958.Taking over this mission, the newly produced JMA Journal consists of a wide range of submitted articles describing and documenting studies encompassing the fields of medicine and medical policies, as well as opinions and other relevant topics. All articles are published following a thorough and strict review of submitted manuscripts.A decrease in the number of scientific articles in Japan has been pointed out for some years. It is desirable that many manuscripts be submitted by various researchers and medical experts for the sake of improving the quality of scientific research and information in Japan.My hope is that the JMA Journal will become Japan's representative general medical journal leading other scientific journals in Japan and that it will expand to serve as an international electronic journal of science information prevailing throughout the global community.Morito Monden, MD, PhDPresident, The Japanese Association of Medical Sciences"}
+{"text": "The Federal Government of Nigeria through the Federal Ministry of Education closed all tertiary institutions in Nigeria including the medical schools on the 19th of March 2020 so as to curtail the effects of the pandemic. The effect of COVID-19 pandemic on tertiary institutions in Nigeria include the disruption of the academic calendar of the schools. This is capable of affecting the mental health of medical students. The smooth financing of medical education in Nigeria could be at risk. The career progression of medical students and those in the Residency Training Program and the doctors seeking greener pastures abroad are all affected. Unfortunately the state of infrastructure in the medical schools could be said to be poor. However, a good medical education scheme is said to guarantee the medical security of the populace. The Government and its agencies should work out plans of ameliorating the effects of the pandemic on medical education. This could also be a period to re-position the sector so as to be able to face similar challenges in future. The time has come for the full application of technology in delivering medical education in Nigeria. Incidentally, the pandemic has encouraged the application of e-learning techniques for the continuing professional development of medical doctors in the country. This should be the new way to go.Nigeria has one of the largest concentration of human resources for health in Africa. There are 46 accredited medical schools and the majority are owned by the various State Governments. The COVID-19 outbreak was declared a global pandemic on the 11 Nigeria based on the number of essential health workers has one of the largest concentration of human resources for health in Africa . IncidenCOVID-19 outbreak: the COVID-19 outbreak was declared a global pandemic on the 11th of March 2020 by the World Health Organization. The disease was first reported in Wuhan city, China in December 2019 and is caused by a newly discovered coronavirus, SARS-CoV-2. Globally, the economic impact of COVID-19 is estimated to be the highest since the financial crisis of 2008/09 and has been described as having the capacity to affect the ability of government, households and development partners to fund education. Perhaps, based on its capacity to restrict international travels coupled with the imposition of national lockdowns in quick succession in several countries, the virus has been described as being contagious both medically and economically. Thus, it has been affirmed that the COVID-19 pandemic could spread economic suffering globally. Already the International Monetary Fund is of the opinion that with the effect of the pandemic, the global economy will contract by 3% in 2020. It has been projected that the pandemic is capable of causing Africa to experience its first recession in 25 years after two decades of economic progress with the effect that a third of jobs in Africa have been estimated to be in jeopardy. As at 3rd July 2020, the world has recorded a total number of 10,662,536 confirmed cases of COVID-19 and 516,209 deaths [9 deaths .Impact on medical education: with the outbreak of COVID-19, the Federal Government of Nigeria through the Federal Ministry of Education announced the closure of all tertiary institutions in Nigeria including the medical schools on the 19thof March 2020. This was seen as a way of curtailing the spread of the virus. Academic activities in the various state and private universities in the country were also brought to a halt. The effect of COVID-19 on tertiary institutions in Nigeria is expected to cause amongst others the disruption of academic calendar, teaching and learning gaps and a reduction in budgetary allocation to education [ducation . Inadequducation . SufficeThere has been no clear cut statement from the Federal Ministry of Education, the Committee of Vice Chancellors of Nigerian Universities and the Provosts of Medical Colleges on the way forward for medical education in Nigeria in the face of COVID-19 pandemic. Also, bearing in mind that the various State Governments in Nigeria control most of medical schools in Nigeria, (20 out of 46) the possibility of a pay cut for the medical teachers or outright non-payment of salaries may arise. This if implemented will have far reaching effects on the future of medical education in Nigeria. Unlike the Federal Government of Nigeria, not all the states in the federation pay salaries of workers promptly. Some State Universities in Nigeria are presently not admitting medical students because of their inability to meet the requirements of Medical and Dental Council of Nigeria for re-accreditation of their medical degree program. The continued disruption of the academic calendar in the medical schools will be of tremendous effect. Such disruptions of academic calendar have almost become a routine in higher institutions in Nigeria with the frequent industrial actions usually embarked by trade unions in the sector especially the Academic Staff Union of Universities. There could also be the psychological impact of the delay on the students especially those in the final year of study or those preparing to write any of the main examinations in medical school. This is capable of affecting the mental health of the students. The delay in graduation will also affect the recruitment of next batch of medical interns in Nigeria. Unfortunately many newly graduated doctors do not immediately commence their medical internship because of the non-availability of spaces in the specified health facilities accredited for such programs. So the pandemic will further delay the commencement of medical internship by the final year students. Already the two postgraduate medical colleges have postponed the first set of 2020 postgraduate medical examinations (April/May 2020), for their candidates in Nigeria due to the COVID-19 pandemic. Thus the Residency Training Program in Nigeria is already being affected. A similar postponement also took place in the country during the ebola epidemic of 2014. The Continued Professional Development (CPD) programs for medical doctors practicing in the country have also been disrupted. Attendance to these CPD courses is now a pre-requisite for the renewal of annual practicing license of physicians in Nigeria. Similarly, all the scientific conferences of various professional groups in the country have been cancelled since the COVID-19 period. Thus this may affect the professional development of practicing physicians in Nigeria.It may affect the immediate plans of some qualified medical doctors who are in the process of securing or have secured job opportunities outside the country as the pandemic has restricted movements in and out of Nigeria due to the lockdowns. In fact such arrangements have been placed on hold by the receiving countries since the COVID-19 pandemic. The pandemic is also capable of affecting the career progression of newly qualified medical doctors who may have planned to pursue their specialist medical training outside Nigeria. A study among medical students in southeast Nigeria revealed that an approximate one third of the students intend to pursue specialist medical training outside Nigeria . In a siIt has been suggested that e-learning techniques and Information and Communications Technology should be taught in medical schools in Nigeria. These measures were perceived as meaningful tools for self-instructions and life-long learnings . In a stIt has been postulated that a good medical education guarantees medical security of the populace . This ne"}
+{"text": "An investigation was conducted in accordance with Frontiers guidelines and the authors failed to provide a satisfactory explanation.This retraction was approved by the Chief Editors of Frontiers in Oncology and the Editor-in-Chief of Frontiers. The authors agree to this retraction."}
+{"text": "Nutrients contributes toward these goals by gathering a total of 13 articles trying to give response to some of these topics.Polyphenols are a class of well-known bioactive compounds widely distributed in the plant kingdom and abundant in plant foods and derived food products. The biological activity of polyphenols have been long investigated using a variety of in vitro and in vivo experimental models that have attributed to these compounds a range of properties with the potential to contribute to maintain health and to prevent, delay, or reduce some chronic diseases  . NeverthThe identification of those individuals that could benefit most from the intake of polyphenols is not a trivial matter. This Special Issue includes two stimulating clinical trials looking at the effects of some of these compounds in two specific human sample subpopulations, i.e., individuals at cardiovascular risk  and postO-sulfate, displays the best vasodilatory activity and reinforces the relevance of deciphering the bioactivity of the polyphenol-derived metabolites. With regards to the multiplicity and difficulty of establishing the mechanisms of action of polyphenols, the review presented by Rothenberg and Zhang [Along these lines, the article published by Garc\u00eda-Contreras et al.  focuses nd Zhang  very smaThis Special Issue also includes a couple of excellent articles in relation with the exciting research area of the binomial polyphenols-gut microbiota (GM). Of particular interest is the article published by Gomes et al.  in whichThe search for the potential mechanisms of action of polyphenols goes on and thus, this Special Issue also includes two more exploratory pre-clinical studies, one looking at the effects of a grape seed extract rich in proanthocyanidins in colon permeability and its repercussion on visceral pain  and, a sLast, but not least, this Issue includes a stimulating review proposing new hypotheses in relation with the consumption and metabolism of polyphenols and their health benefits. The idea is to incorporate the concept of chrononutrition, i.e., the study of the interactions between biological rhythms, metabolism, and nutrition, into the research area of polyphenols and health . It seemThe selection of articles included in this Special Issue show some of the current progress on the knowledge about the effects of plant dietary polyphenols on human health as well as the complexity of some of the issues that remain to be understood. It also highlights the need for further human clinical trials with better designs to understand interindividual variability and to improve the consistency and relevance of the effects in humans. It additionally shows the difficulty but, also the importance, of understanding the metabolism and mechanisms of action of these compounds and the interest in translating this knowledge into improved technologies to enhance the efficiency of the application of polyphenols for human health and disease."}
+{"text": "In the Data Availability statement and the Mapping and analysis of RNAseq data subsection of Materials and Methods, the accession number for RNAseq data deposited in GEO is listed incorrectly. The correct accession number is: GSE90105."}
+{"text": "Following publication of the original article , the autThe incorrect name of the collaborator is: A-L. Di Stephano.The correct name of the collaborator is: AL. Di Stefano.The list of collaborators has been updated in the list of collaborators below and in the metadata of this correction."}
+{"text": "Text analysis can significantly enrich ideas about the functioning of the psyche in mental illness.The purpose of this study was to identify the linguistic features of texts written by people with schizophrenia spectrum disorders and to study the relationship between them and the personality traits and indicators of the standard of living of patients.Twenty-nine patients with schizophrenia spectrum disorders  and 37 without mental disorders participated. All participants wrote a text on a given topic and filled in psychodiagnostic methods: a short version of the Big Five method (TIPI-RU), Q-Les-Q, and MOS SF-36. The text was analyzed using the phpMorphy morphological analysis library.A comparative analysis showed that in the speech of patients, there are fewer adjectives and more verbs than in the speech of healthy subjects (p<0.05) and that the volume of speech production in patients is significantly reduced (<0.001). The results of correlations of such data with the volume of words were contradictory. A statistically significant inverse relationship was found between the verbality index and the factors of extraversion and openness to experience in the clinical group. As for the indicators of quality of life, expectedly positive correlations between the use of adjectives and negative correlations of the use of verbs with the quality of life were revealed.Studying the linguistic features of the speech of patients with mental disorders is essential. These indicators can be helpful in the diagnosis and treatment of the disease.None Declared"}
+{"text": "The problem of eating disorders has become increasingly important in recent years, due to the increase in the number of cases among children and adolescents, as well as the insufficient effectiveness of therapeutic measures. An important role in the course of eating disorders is occupied by the depressive syndrome associated with it, which complicates the process of treatment and rehabilitation in this pathology.Study of the stages of treatment of eating disorders in the structure of depressive states.The sample consisted of 63 patients aged from 15 to 25 years old , who were on outpatient and inpatient observation in the clinic were studied.In the process of treatment, several stages of treatment of patients were carried out. The first stage was aimed at normalizing the body\u2019s vital functions and management of somatoendocrine impairments (the duration of the stage is about 14 days). The next stage was aimed at the psychotropic treatment of eating disorders and concomitant mental pathologies (the duration of the stage is 3-4 weeks). The final stage included rehabilitation, which consisted of working with a psychotherapist (the duration of the stage was 8 weeks or more). It should be noted that in the process of rehabilitation, patients continued to receive psychopharmacotherapy and underwent a comprehensive examination to assess the dynamics of their condition.Eating disorders in the structure of endogenous depressions require an integrated approach to treatment, including both ensuring adequate vital activity of the organism and the selection of drug treatment depending on the nosological affiliation of the underlying syndrome. Rehabilitation work aimed at social adaptation and prevention of relapses of the disease also plays an important role.None Declared"}
+{"text": "The Code of Ethics for Psychiatry adopted by the World Psychiatric Association in 1977, also known as the Declaration of Hawaii, was a milestone in the development of ethical standards in psychiatry. The impetus for the development of the code came primarily from the politicization of psychiatry, first discovered in the USSR, and later in other countries of the socialist camp, such as Romania, Yugoslavia, and the People\u2019s Republic of China. The purpose of this article is to trace reasons for the lack of consolidation among Western psychiatrists against the politicization of psychiatry and their efforts to improve the ethical standards in this medical field.We analyzed unpublished documents from the Archive of the German Association for Psychiatry, Psychotherapy and Psychosomatics, the private archives of the West German psychiatrists Gerd Huber and Walter von Baeyer as well as research works. To examine these sources, we implemented the historical-critical method.The World Psychiatric Association made efforts to collect, analyze and discuss materials concerning psychiatric ethics in order to create the Code of Ethics for Psychiatry and establish an Ethical Committee. In general, the reaction of Western psychiatrists to the information about the internment of dissidents in psychiatric hospitals was restrained and focused on attempts to solve the issue together with the Soviet colleagues.The international policy of d\u00e9tente of the time as well as collisions between different medical concepts and ethical dimensions did not allow Western psychiatrists to condemn cases of politicization of psychiatry without proir clarification of the situation. The efforts of the World Psychiatric Association in the ethical field improved the ethical standards for psychiatry. The correlation between the politicization of medicine and dictatorships has been established by medical historians in some research works , 2. We wThe first Code of Ethics for Psychiatry, known as Declaration of Hawaii, was adopted in 1977 in order to set the ethical standards specific to psychiatry. Among other guidelines, it stated that a psychiatrist must never use the possibilities of the profession for maltreatment of individuals or groups . The necOur paper is structured as follows. Firstly, we focus on the World Psychiatric Association\u2019s activities to improve ethical standards and create a Code of Ethics for Psychiatry. Then we will discuss the attitude of Western psychiatrists with regard to accusations of Soviet colleagues in the internment of dissidents in psychiatric clinics. In the discussion, we evaluate all the events from the perspective of ethics and its progress in time.To prepare this paper, we analyzed unpublished archival documents and research works. The group of archival documents includes materials that we found in the Gerd Huber Archive, stored at the Bezirkskrankenhaus G\u00fcnzburg, the Heidelberg University Archives, and the Archive of the German Association for Psychiatry, Psychotherapy and Psychosomatics . The documents of a West German psychiatrist Gerd Huber concerning his participation in the conference on schizophrenia in 1973 in the USSR contain his notes as well as his correspondence with the World Psychiatric Association and his colleague Walter von Baeyer. Among von Baeyer\u2019s papers, held in the Heidelberg University Archives, we found his correspondence with the World Psychiatric Association and the minutes of meetings of its Executive Committee. The Archive of the DGPPN contains materials on the abuse of psychiatry in the USSR in the 1970s\u201380s. In this paper, we have cited almost all of the archival sources that we found in the aforementioned archives. These sources are listed in the references. We have not cite those archival documents that either repeat the content of the cited sources or cover those events that were described in published research works.We have also evaluated articles of those psychiatrists who participated in the conference on current aspects of schizophrenia in 1973, and research works on the history of politicization of psychiatry in the Soviet Union. To examine these sources, we implemented the historical-critical method, which includes the stages of acquisition of primary sources and research works, critical evaluation of the information contained in primary sources, and presentation of historical data in historical context in terms of objectivity and significance .Dealing with the cases of politicization of psychiatry in the USSR in the 1970s stimulated debates about ethics among the international psychiatric community. For the first time, the question of forming of an Ethical Committee within the structure of the World Psychiatric Association and adopting a Code of Ethics for Psychiatry came up at the 5th World Congress of Psychiatry in Mexico City in 1971. Although some members of the Association, such as Helmut Ehrhardt 1914\u20131997), the president of the West German Association for Psychiatry and Neurology, supported the proposal for an Ethical Committee, the idea was not accepted. In May 1972, the World Psychiatric Association circulated the statement of the American Psychiatric Association where it opposed the misuse of psychiatric institutions to detain persons solely based on their political dissent, no matter where it occurred . However\u20131997, thinakomyslyashchiy) implies that the person to whom it applies \u201cthinks differently.\u201d This refers to moral views that diverge from those generally accepted. The word \u201cdissident\u201d (dissident) came into use in the USSR in the 1960s to refer to people who criticized the ideology and authorities of the Soviet Communist Party  smuggled photocopies of forensic reports on prominent dissidents to the West in 1971 2\u20132019 sm, 19. HerDuring the 5th World Congress of Psychiatry in Mexico City in 1971, psychiatrists were not ready to deliver a statement regarding the internment of Soviet dissidents in psychiatric hospitals until they receive more comprehensive documentation. In 1973, from 8\u201313 October the World Psychiatric Association held an international symposium on current aspects of schizophrenia in Yerevan and Tbilisi, the capitals of the Soviet republics of Armenia and Georgia. That conference provided an opportunity for a dialogue between Western and Soviet psychiatrists on the issue of dissidents who had been diagnosed with schizophrenia at the Moscow Serbsky Institute. Gerd Huber 1921\u20131912) and Kurt Heinrich (1925\u20132015) were invited as speakers from the Federal Republic of Germany. Huber was a professor of psychiatry at the University of Ulm, where he had carried out a big catamnesis study on the course of schizophrenia. He was going to present a paper on the results of his follow-up study of schizophrenia \u20131912 and, 23.Stern, contacted Huber on the eve of the trip and informed him that some Soviet psychiatrists were involved in political campaigns that led to the hospitalization of dissenters in psychiatric hospitals in the USSR (J\u00f6rg Elten (1927\u20132017), a reporter of the West German magazine the USSR . Elten jthe USSR . The latthe USSR . Huber cthe USSR . \u201cHeinrithe USSR . Leigh rthe USSR .As the internment of dissidents in Soviet psychiatric institutions was discussed in the Western press, the All-Union Society of Neuropathologists and Psychiatrists decided to invite conference participants to meet at the Serbsky Institute in order to discuss the allegations about the Soviet forensic psychiatry , 27. TheA group of conference participants, Huber and Heinrich included, agreed to accept the invitation, but specified in advance that such a complex issue could not be resolved in one\u2009day. \u201cIt is therefore unlikely that a clear-cut statement of approval or disapproval will be made at the end of the meeting,\u201d their statement declared . HoweverBritish Medical Journal laid down by Wing\u2019s article Psychiatry in the Soviet Union published in March 1974 , countered that the concept of schizophrenia in the USSR was similar to that shared by Western scientists . It mustBritish Medical Journal. That happened despite the dissent of the USSR representative in the Executive Committee, Associate Secretary Marat Vartanyan (1932\u20131993), who insisted that the letters of individuals should not necessarily require an answer  entered the discussion and tried to move it to the plane of purely psychiatric analysis of the problem. Von Baeyer was a professor of psychiatry at the University of Heidelberg from 1955 to 1972 and a former vice president of the World Psychiatric Association from 1966 to 1971 . He was n answer . Thus, tn answer . He distn answer .The research works suggest some reasons for the lack of consolidation among Western psychiatrists against the politicization of psychiatry in the USSR in the 1970s. The researchers rightly point to the international policy of d\u00e9tente, which made cooperation and experience exchange between Soviet and Western psychiatrists possible , 19. TheBritish Medical Journal, Morozov countered that the concept of schizophrenia in the USSR was similar to that shared by Western psychiatrists, there was still a big difference. During the 1960s and 1970s, Western psychiatrists progressively narrowed the concept of schizophrenia, limiting the diagnosis to the most severe forms. In contrast, the Moscow school of Snezhnevsky defined the concept of schizophrenia broadly including both clinical schizophrenic manifestations and latent non-psychotic forms   . MoreoveWestern psychiatrists assumed that there were certain cases of abuse in psychiatry in every country. Therefore, they treated the first news about the internment of Soviet dissidents in psychiatric hospitals not as a widespread practice, but as isolated cases. As it appears from the internal documents of the Association, the exclusion of Soviet psychiatrists was not ruled out. However, the condemnation of Soviet psychiatrists and their exclusion from the World Association could not solve the issue as such. Western psychiatrists urged a dialogue with their Soviet colleagues and called for an international commission that could evaluate the dissidents. Particularly under the pressure from the Western public opinion, the All-Union Society of Neuropathologists and Psychiatrists decided to invite the participants of the 1973 symposium to a discussion. Since Western psychiatrists were solution-oriented, their Soviet colleagues continued to participate in seminars on ethics organized by the Association.As for the establishment of the Ethical Committee, it should be noted that medical ethics was not yet established as a discipline at that time, and the formation of an Ethical Committee was not an easy task. Here we must disagree with those researchers who treated the establishment of an Ethical Committee as a diversionary tactic and the Association\u2019s achievements in the field of ethics as weak . It seemOther ethical aspects played an important role, too. The members of the Executive Committee of the World Psychiatric Association were particularly cautious about signing documents whose content was directed against one of its member societies. In 1971, before the 5th World Congress of Psychiatry, the Executive Committee did not make any statement because the Soviet Association of Psychiatry had not even had the opportunity to comment on all accusations. They knew only one side of the coin, and considered it their duty to listen to the other side as well before taking a position.Moreover, the memory of World War II and the abuse of psychiatry in Nazi Germany was an important factor for German psychiatrists. Thus, von Baeyer held the view that German psychiatrists had no right to be the first ones to condemn their Soviet colleagues precisely because of the Nazi past. Huber and Heinrich held the same views. Perhaps that is why they refused to accept the invitation of the Serbsky Institute.Analyzing archival materials and research concerning the practice of politicization of psychiatry in the USSR, we conclude that Western psychiatrists were oriented toward a mutual clarification of the issue with their Soviet colleagues. The World Psychiatric Association\u2019s efforts to collect, analyze and discuss materials concerning psychiatric ethics, to create the Code of Ethics and the Ethical Committee cannot be qualified as weak. We argued that not only an international policy of d\u00e9tente of the time, but also collisions between different medical concepts and ethical dimensions did not allow Western psychiatrists to condemn politicization of psychiatry in the USSR without clarifying the situation. Only after receiving increasing evidence regarding internment of healthy dissidents in psychiatric hospitals, neglect by Soviet colleagues to jointly address the issue, and psychiatric evaluation of dissidents who had immigrated to Western countries, the practice of politicizing psychiatry in the USSR became evident, and Soviet psychiatrists were forced to leave the World Psychiatric Association in 1982. The main issue in dealing with allegations against Soviet forensic physicians was that Western psychiatrists received only limited knowledge and could not access reliable information. Thus, we learned that in such a difficult situation physicians must always be aware of context sensitivity and all backgrounds when making decisions. Discussions about politicization of psychiatry in the USSR not only initiated the creation of the Code of Ethics for Psychiatry. They showed how important ethics and the further development of ethical principles are. Human rights violations by mental health services have led to the creation of international and national initiatives on psychiatry. Ethical debates in psychiatry have sensitized physicians to the issue of patients\u2019 rights as well as ethical principles, which over time have become an indispensable part of a physician\u2019s daily routine.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.OK and FS conceptualized and designed the study. OK collected the sources and wrote the first draft of the manuscript. OK and FS analyzed the sources as well as contributed to the manuscript revision, read, and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "In checking the blots and records from that time, the authors found that the loading controls for both experiments had been imaged at the same time and on the same film, leading to the inadvertent selection of the wrong image for Fig. 2 A.The corrected The error appears in print and in PDFs downloaded on or before September 8, 2023. The authors apologize for the error and any confusion."}
+{"text": "The corrections are listed here. None of these change the major findings of the article.The fluorescence profile in In In the penultimate paragraph of the Restricted ATP diffusion in murine myocytes section, the time constants given in the text for the simulations in The errors appear in PDFs downloaded before August 22, 2023."}
+{"text": "The journal retracts the 2021 article cited above.Following publication, concerns were raised regarding the contributions of the authors of the article. Our investigation, conducted in accordance with Frontiers policies, confirmed a serious breach of our authorship policies and of publication ethics; the article is therefore retracted.This retraction was approved by the Chief Editors of Frontiers in Bioengineering and Biotechnology and the Chief Executive Editor of Frontiers. The authors do not agree to this retraction."}
+{"text": "The scope of the Research Topic was to bring together the contributions of researchers from different backgrounds in the field of language origins.The evolution of human language has been discussed for centuries from different perspectives. Proposals that the semiotic system of gesture played a pivotal role in the evolution of language have been, and continue to be, influential Zlatev, . This stEkstr\u00f6m and Edlund, in their article entitled Evolution of the human tongue and emergence of speech biomechanics, provide a view into the cruciality of the emergence of the human-specific tongue to the evolution of human articulate speech. They state that the tongue properties and morphology were a turning point in the evolution of human articulate speech. It provided the possibility of mapping articulatory targets via the exaptation of manual-gestural mapping capacities evident in extant great apes.One perspective within our Research Topic of articles is the crucial role of the emergence of the human-specific tongue. Ferretti in an article within this Research Topic entitled, On the Influence of Thought on Language: A Naturalistic Framework for the Pantomimic Origins of Human Communication, emphasizes pantomime as an ideal expressive means for bootstrapping the evolutionary foundations of language origins. Pantomime can be angled as a privileged lens for investigating language origin and evolution, partly due to its motivated iconic character of pantomime while compared with the arbitrary and abstract features of language and partly due to the way it obliges rethinking the relationship between thought and language.Another view, by G\u00e4rdenfors, in a paper entitled Teaching as an evolutionary precursor to language defends that earlier analyses of the evolution of teaching demonstrate that pantomime seems to be the earliest evolutionary unique human capacity and that could also be explained via the evolution of a theory of mind.Another research vision is rooted in the evolution of teaching as one of the main factors that lead to increasingly complex communicative systems in the hominin species. Alhadi Ali Ahmed et al. in their article entitled An in-depth analysis of the representation of speech acts and language functions in Libyan public high school English Textbooks stating that pragmatic potential competence is the turning point to use speech acts and language functions.A totally different perspective given teaching comes with The selection of papers within this Research Topic provides a picture of some of the current challenges in language evolutionary research.The author confirms being the sole contributor of this work and has approved it for publication."}
+{"text": "This article proposes a critical reading of the urbanistic and social historical context of the communities of Manguinhos, considering the field of urban health as a theoretical and methodological foundation based on the paradigm of the social commitment to health and the right to the city. Our demarcation of this analysis to identify the critical processes in the social commitment to health considered the relevance of overcoming housing needs as an indispensable condition for the right to the city and to health. The fact that these processes persist, even after the vast investments made in Manguinhos, indicates the need to review related public policies and their effective implementation to improve conditions for this population."}
+{"text": "All of Us Data and Statistics Dissemination Policy. The authors apologize for their non-compliance with the policies and for any breach of trust this may have caused with All of Us participants. No All of Us participants were re-identified during the process of conducting the study; all data remained de-identified. The authors thank the All of Us program and its participants for making this research study possible and again apologize for this unintentional oversight.This article was republished on April 18, 2023, to correct the abstract and Table 1 in the original publication that are in violation of the Please download this article again to view the correct version."}
+{"text": "Clinical genetic testing for hereditary cardiovascular diseases is recommended by many cardiovascular groups  were involved in the conception/intepretation, drafting or revising, and provided final approval of the manuscript submitted.The authors have no conflict of interest to disclose.The opinions and assertions expressed herein are those of the author(s) and do not reflect the official policy or position of the Uniformed Services University of the Health Sciences or the Department of Defense. The opinions and assertions herein are those of the author(s) and do not reflect the official policy or position of the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. or the National Institutes of Health."}
+{"text": "The University of Manchesterconducted an investigation under the Code of Practice for InvestigatingConcerns about the Conduct of Research in relation to the authorshipdispute of this paper. The Panel of Investigation recommended inclusionof Christoforos Moutafis and Vasilis Pavlidis as authors and a minorcorrection to the paper with regard to the author contributions, andall parties are in agreement with this recommendation.Therefore,this correction amends the authorship, author contributions,and the acknowledgments in order to correct the academic record andmaintain academic ethics."}
+{"text": "Acknowledgements section. We erroneously excluded contributions to this article from those who prepared the samples.In the published article, there was an error in the Acknowledgements section.A correction has been made to the The corrected sentence appears below:\u201cWe would like to thank Dingsan Luo and Renzheng Liu of the Jiangsu Key Laboratory of Medical Optics at the Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, for their meticulous preparation of the mouse corpus callosum samples. We also would like to thank the Hanhua Lab from the Institute of Automation, Chinese Academy of Sciences for the corpus callosum SEM data.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "The paper shows the possibilities of processes in the tribosystems of diesel engines, ensuring the development of self-organization processes in them. The criterion for the possibility of development of processes of the self-organization of subsystems of the second level shows that in a real irreversible process there is a decrease in the flow of mechanical energy. The paper considers three cases of the possibility of developing the processes of self-organization of subsystems of the second level on the example of the tribosystem \u201ccrankshaft-insert\u201d for the operating conditions of a diesel engine 10D100. It was determined that in order to reduce the wear rate of the tribosystems of diesel engine it is necessary to provide the flow of the energy-mass transfer process on their contacting surfaces of friction by the gradients of chemical potentials and dislocation density of the interacting materials. The obtained expression is the criterion of possibility of development of processes of the self-organization of subsystems of the second level which indicates that the system would lose the stability, if the density of mobile dislocations or the wear rate of the tribosystems of diesel engine increases. In living nature the processes of self-organization are the adaptation and evolution of biological objects corresponding to the changes in external conditions7. In engineering, the processes of self-organization are most clearly manifested in the tribosystems (TS) with the formation of secondary structures in friction and wear12.Self-organization is a fundamental phenomenon of nature and the essence of it is that under the influence of external disturbances any thermodynamically open nonlinear system is rebuilt so that its reaction maximally compensates for the reason that caused such internal change13. Friction and wear act as unbalanced thermodynamic processes, so the occurrence of self-organization processes in them is inevitable. The following processes may be included in the internal manifestation of self-organization in the TS16:The formation of secondary structures to prevent the process of wear;The formation of balanced roughness to reduce wear;The increase the real contact area to reduce the wear rate;The realization of effect of selective transfer to insure the unworn state.The processes of friction and wear are realized through the presence of gradients of temperature, voltage, concentration of chemical elements and dislocation density19. As a consequence, the reduce of the time and the coefficient of friction, the temperature in the zone of friction, wear rate, etc. The general consistent pattern of manifestation of self-organization can be analyzed from the positions of system approach.The external manifestation of self-organization is the reduction and stabilization of almost all the energy, strength and tribological parameters of the process of friction and wear24, the results of studies of the course of self-organization processes in subsystems of the first, second and third levels are presented. However, the authors did not find studies of self-organization processes in subsystems of the second level in the TS of diesel engines. Therefore, the aim of the work is to establish the criterion of development of processes of the self-organization of subsystems of the second level in TS of diesel engine.In many works on friction and wear of TSIn the process of studying the possibility of developing processes of self-organization of subsystems of the second level in TS of diesel engine, theories of thermodynamics of non-stationary processes, solid state physics, wear theory and the fundamentals of mechanics were used. To solve the differential equation of the energy-mass transfer, a numerical calculation technique was used.The object of research is the processes of the self-organization of subsystems of the second level in TS of diesel engine.The subject of research is the criterion of development of processes of the self-organization of subsystems of the second level in TS of diesel engine.Research hypothesis is based on the Glansdorff\u2013Prigozhin criterion and the use of dependencies that combine the physical, mechanical and tribological properties of the TS, the criterion of development of processes of the self-organization of subsystems of the second level in TS of diesel engine can be obtained.For the numerical solution of the differential equation of the energy-mass transfer, a personal computer and the corresponding software were used.20.TS of diesel engines\u2014it is the set of physical objects that interact with each other by contact-mechanical means, and at the contact points occurs the breakage of linear velocities of the interacting objects, where the mutual energy-mass transfer takes placeThe simple TS of diesel engines consist of two facilities that operate without lubricating surface with dry abrasive mass. First of all, this concerns the operation of diesel vehicles during the start-up period, and especially at low temperatures. Secondly, even in the presence of lubrication, a regime without lubrication of the surface with dry abrasive mass is possible.The complex TS of diesel engines are complemented by the active environment, lubricant-coolants and artificially introduced energy sources. In turn, any system is divided into subsystems of the highest order.21. The latter is the energy that is expended to change the kinetics of the interaction between the components of the subsystems in TS of diesel engines and it is the major component of energy balance of the subsystems of the next higher level. The subsystems of each level are characterized by their most informative energy parameters in absolute, specific, gradient and other ratios. Hereafter, they are used to describe the energy, balance and kinetic relations that show the first and the second law of thermodynamics3. The combination of the energy relations of functioning of subsystems of different levels is possible, but impractical in the presence of variables of different orders in one equation. Therefore, each subsystem independently from its level should be described by its thermodynamic relation. The lower-level subsystems are described by the equation of energy balance in absolute values or their streams. It is appropriate to describe the high-level subsystems by energy flux density, and the subsystem of higher orders\u2014by specific energy parameters or their gradient expressions.The operation of subsystems of diesel engines of any level can be described by the equation of the energy balance and the kinetics of the components that are included in present subsystem and define the nature of the interaction, the internal structural and energy state. In consequence of the interaction between the components of the subsystems in TS of diesel engines, their energy is spent on changing the character of behavior, and another\u2014on changing their internal stateThe hierarchy of subsystems of three levels in TS of diesel engines is presented graphically in Fig.\u00a0In considering the processes of friction and wear that occur in diesel engines, the subsystems of the first level may include the interaction of connected parts with identified geometric borders, different physical and mechanical properties, with the known laws of the external load and movement of each point, as well as the specified interval of velocities in the TS of diesel engines.The subsystems of the second level in the TS of diesel engines may include areas of friction interactions on the real areas of contact. The number of subsystems of the second level corresponds to the number of spots of actual contact. Geometric boundaries of the interacting objects of present subsystems are defined by the zone, in which the structural and energetic changes are observed.1.The subsystem of the third level in the TS of diesel engines may include micro-volume of contact and subcontact zones, covered by the structural and energy changes of triboprocess. In contrast to the subsystems of the first and the second levels in the TS of diesel engines, which provide for interaction, at least of two solid-phase objects, the components of subsystems of the third order is the one solid-phase formation, the change of the structure of which is due to its penetrating flow of energy and matter3, under which in any unbalanced system the rate of change of entropy production decreases. Stationary or stable thermodynamic processes are characterized by minimum entropy production.The development of the self-organizing systems is determined by the Glansdorff-Prigogine criterion3:The energy balance equation for the subsystems of the first level is presented in absolute energy values or in their flowsThe mechanical component of the energy balance of the TS of diesel engines describes the energy cost for surface structural changes and their wear. Its part does not exceed (1.5\u20133.0) % of the work of friction, thus:This equation shows the balance between work of friction and released thermal energy in the TS of diesel engines or the process of dissipation of the input mechanical energy.The increase of the produced entropy 3:Thermodynamics of the subsystems of the second level in the TS of diesel engines considers the balance relationships, which reflect the transformation of the nondissipative mechanical energy, which can be written as23. Upon completion of this process, its intensity drops to zero, periodically renewing as the new contact layers open due to wear.The process of absorption of the elastic internal energy by the contact layers of the TS of diesel engines takes place at the initial moment of frictional interaction or at the break-in periodConsequently, in the steady process of friction, the energy costs for the formation of secondary structures become the values of lower order than the remaining terms of Eq.\u00a0. Then th24, we would obtain the expression, which is the criterion of possibility of development of processes of the self-organization of subsystems of the second level:P is the pressing force at the contact; If the entropy is taken into account in the expression , or rathThe criterion for the possibility of development of processes of the self-organization of subsystems of the second level  shows thThe pressing force at the contact, for example, for the TS of diesel engine \u201ccrankshaft-insert\u201d can be defined:As a result, expression  will takThe external manifestation of the self-organization in the subsystems of the second level is the stabilization of the wear rate, which is determined at the very end after complete stabilization of all the power, thermal and micro-geometrical parameters of the TS of diesel engines.Thermodynamics of the subsystems of the second level shows the process of transformation of non-thermal component of external flow of mechanical energy into irreversible energy losses and the internal structure and energy transformations that occur in the contact layers at friction.All the summed up mechanical energy is absorbed by the surface layers of friction bodies in the form of elastic strain energy. As a result, interacting structures correspond to an unbalanced condition.3. Irreversible are those types of forms of energy, which in their development have reached the state at which their subsequent transformation into other forms is potentially impossible. They cannot be involved in the processes of transformation of structures and completely leave the subsystem by spreading in the environment. These species include thermal, acoustic and light energy. Irreversible energy forms are dominant in all tribotechnical and deformation processes.All possible forms of energy can be divided into two types: reversible and irreversibleThe ongoing energy-mass transfer within the subsystems of the second level is driven by gradients of temperature, stress, chemical potentials and dislocation density. The direction of the energy-mass transfer is opposite to the vector of gradient of chemical potential, so the decrease in its intensity occurs in the course of the development of the process.We write the boundary conditions for the differential Eq.\u00a0 in the fThe implementation of the energy-mass transfer in the subsystems of the second level presents one of the forms of absorbed dissipation of mechanical energy. The decline in mass due to deformation (wear) also applies to the dissipative phenomena, since the internal energy, which is carried away by wear particles and energy costs, which are intended for the implementation of the wear work, permanently leave the subsystem of the second level.The equation describing the process of dissipation of the internal energy  from theLet us consider expression  in more The first case. If in the TS of diesel engines flow the processes of the self-organization in full, then in the last expression of the value In this case, the expression  will pre25 and taking into account the above, we construct the dependence of the energy-mass transfer  with possible following transition to the partial processes of self-organization in them. In the second case\u2014improvement of resource failures, reducing the probability of failure-free operation, reliability and durability of the TS, parts or diesel engines in general.Taking into account the condition  and usinThe above graphic dependence indicates the flow of the excessive process of the energy-mass transfer that confirms the condition (11) and the critical values of wear of interacting materials of the TS.These solutions for the three cases, based on the example of the TS \u201ccrankshaft-insert\u201d for the operating conditions of diesel engine 10D100, prove that the expression  with theIn the work is to establish the criterion of development of processes of the self-organization of subsystems of the second level in TS of diesel engine [expression  and the A feature of the proposed criterion (7) is the further development of the Glansdorff-Prigozhin criterion, based on a combination of the physical\u2013mechanical and tribological properties of the subsystems of the second level. The proposed criterion differs from the existing ones in that in the Glansdorf-Prigozhin criterion, elements of solid state physics, wear theory and the fundamentals of diesel engine mechanics were applied.The limitations of this theoretical study are the calculated data, which are given in the reference literature.The shortcomings of the study include the possibility of calculating only plain bearings in subsystems of the second level of diesel engines. More research is needed to overcome the shortcomings.The development of this study is to conduct experimental studies of the energy-mass transfer in the TS \"crankshaft-liner\" of a diesel 10D100. The authors propose to use laser processing of interacting TS materials to change the density of mobile dislocations and the interacting volume. The difficulty that may arise in experimental studies is to register the values of the energy-mass transfer, since the TS \"crankshaft-liner\" is an open system, which also does not allow taking into account the change in entropy.3, it is theoretically determined that in order to reduce the wear rate of the TS it is necessary to provide the flow of the energy-mass transfer process on their contacting surfaces of friction by the gradients of chemical potentials and dislocation density of the interacting materials.Based on the thermodynamic aspect in view of the second variation of entropy (the excess entropy production), we have obtained the expression  with theThe external manifestation of the self-organization in such TS of diesel engine is the stabilization of the intensity of wear, which is determined at the very end after after the establishment of equilibrium microgeometric parameters. The latter, perhaps, if the structure of material of the mating surfaces of the TS of diesel engine is in the unbalanced condition. For this, it is necessary to fulfill the condition for reducing the flow of mechanical energy by mass and by the time of contact of the vehicle surfaces in accordance with criterion .The resulting expression  is a criBased on the theories of thermodynamics and change of systems of Glansdorff\u2013PrigogineFurther research will consist of conducting experimental studies and comparing them with theoretical ones."}
+{"text": "The Publisher retracts the cited article.Following publication, the publisher has discovered that the authors provided false information for the peer-review process. As the scientific integrity of the article cannot be guaranteed, and adhering to the recommendations of the Committee on Publication Ethics (COPE), the publisher therefore retracts the article.The authors have not responded to this retraction.This retraction was approved by the Chief Editors of Frontiers in Oncology and the Chief Executive Editor of Frontiers."}
+{"text": "Dear Editor,We describe a case of a 43-year-old man who was referred to the Dermatology Service, reporting the progressive appearance of painful suppurative nodules in the right lower limb for six months. The lesions started after penetrating trauma to the foot. He had hardened nodules, some of them ulcerated, on the lateral aspect of the right lower limb, in an ascending distribution . HistopaES is a rare subtype of soft tissue sarcoma with a high potential for local recurrence and metastases. It preferentially affects young male adults and about a quarter of cases are associated with previous trauma, such as the present one.4The differential diagnosis includes nodules due to infectious disease, rheumatoid nodules, fibrous histiocytoma, and other soft tissue sarcomas.Surgery remains the mainstay of treatment in localized disease, with or without radiation, with disease-free surgical margins being the most important prognostic factor.None declared.Vivian Spanemberg Macuglia: Approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.Juliano Peruzzo: Approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.Ariane Bastos Geller: Approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.Renan Rangel Bonamigo: Approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.None declared."}
+{"text": "After having consulted the authors in this regard, they agreed with the decision to retract this paper. The Editor deeply regrets any inconvenience that has been caused to the readership of the Journal.After having conducted an independent investigation in the Editorial Office, the Editor of"}
+{"text": "Due to technological advancements, a growing number of tasks can now be accomplished with the help of a screen. However, there may be repercussions to leading a lifestyle dominated by digital screens. Our study determines an association between problematic social media use and an increase in the incidence of negative mental health outcomes.This paper is a presentation of the mental health issue of young adults related to the use of social media.Analysis of user behavior.The frequency of using these networks, the length of time spent in front of the screens, the way these platforms influence the daily activities of the users, the emotional states felt by them and the possible connection between the use of the Internet and face-to-face communication remain real challenges for mental health specialists.Preventing the occurrence of mental health disorders among young adults in the context of the development of technology remains a topical issue.None Declared"}
+{"text": "The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused.The Editorial Office have conducted an independent assessment of these data, and can confirm the veracity of the concerns that were raised by the reader; therefore, the Editor of"}
+{"text": "Following publication, concerns were raised regarding the contributions of the authors of the article.Our investigation, conducted in accordance with Frontiers policies, confirmed a serious breach of our authorship policies and of publication ethics; the article is therefore retracted.The authors do not agree to this retraction.This retraction was approved by the Chief Editors of Frontiers in Bioengineering and Biotechnology and the Chief Executive Editor of Frontiers."}
+{"text": "In the original published version of this article, the typesetters have used the outdated version, the authors reviewed the proof and approved it before publication. An outdated version of the paper was published. We will publish a final version that the authors and editors approved. The correct version of the manuscript will replace the outdated version. The authors apologize for the errors. Both the HTML and PDF versions of the article have been updated to correct the errors.The authors declare no conflict of interest."}
+{"text": "Paraphrenia is a chronic psychosis that has generally lost its status as an independent nosological entity, not being included in DSM-5. From the perspective of the particular psychopathological picture and the impact of the disease on the patient\u2019s functioning in roles, paraphrenia remains a challenge for the clinician in terms of nosological classification and the correct therapeutic approach.We take into account a patient who presents the classic diagnostic criteria of paraphrenia with a clinical and evolutionary picture followed for 15 years, with the aim of bringing the paraphrenic phenomenology back to the fore.The case presentation will focus on the richness and absurdity of the delusional ideas that are in great contrast with the good insertion into reality of the subject and the preservation of the core of the personality. We will also describe the main landmarks of positive and differential diagnosis.We believe that paraphrenia deserves to be differentiated from other psychotic disorders through the particular variant of insight that also explains the significant capacities of dissimulation and as a result of insertion into the roles of life. This attribute also explains the increased potential for danger and unpredictability of the paraphrenic patient.Our approach is an argument for the psychopathological understanding of paraphrenic psychotic phenomenology independent of different nosographic classification systems. We are trying to contribute to increasing the quality of differential diagnosis in psychoses.psychosis, paraphrenia, differential diagnosisNone Declared"}
+{"text": "The journal retracts the article cited above.Following publication, the publisher has found evidence of peer review manipulation. As the scientific integrity of the article cannot be guaranteed, and adhering to the recommendations of the Committee on Publication Ethics (COPE), the publisher therefore retracts the article.This retraction was approved by the Chief Editors of Frontiers in Public Health and the Chief Executive Editor of Frontiers."}
+{"text": "The authors contacted the Editorial Office to request the retraction of the cited article, stating that there were fundamental errors in the interpretation of Figures 4, 5. The authors also declared that they had discovered issues in the methodology of the study. An investigation was conducted in accordance with Frontiers' policies that confirmed that the conclusions reported in the article are no longer supported by the analyses; therefore, the article has been retracted.This retraction was approved by the Chief Editors of Frontiers in Medicine and the Chief Executive Editor of Frontiers."}
+{"text": "The Cancers Editorial Office is issuing this expression of concern to alert readers to concerns regarding the findings of the published manuscript . As the The Expression of Concern will remain until a resolution has been reached.We will provide an update following the conclusion of the investigation. The author has been notified about this Expression of Concern. In order to maintain the highest scientific standards, an in-depth investigation has been initiated by the responsible editors, together with the journal\u2019s editorial office, in collaboration with the editorial board, and in accordance with the Committee on Publication Ethics (COPE) guidance."}
+{"text": "The psychopathological observation of the behavioral and psychological symptoms in dementia (bpsd) and a study of the environment in which they arise, especially during a framework of mild cognitive impairment, must make us reflect on the consumption of resources for families and health or social services. The bpsd contribute 30% to the overall costs of dementia. In particular bpsd accelerate the institutionalization, temporary and definitive, of suffering elderly.On the basis of some experiences, it is possible to use the health budget tool as part of the project budget, in the field of bpsd, moving from the practice of consumed cost to generated cost, that is the investment of resources that produces social value. The goal is to describe some concrete examples of this application, highlighting strenghts and weakness.The psychosocial interventions recommended to prevent the risk of onset of bpsd from a public health perspective are analyzed, in Italy and in other countries, in the light of the evolution of welfare theories and practices in community psychiatry.The methodology of the health budget, in public health system, calls family members and users to a commitment of co-responsibility and administrators of financial resources in terms of accountability. The psychogeriatric elderly with mild cognitive impairment and bpsd, can also be a resource and not just a cost, if we consider the possible performance (dividend of longevity) and not the consumption of economic resources.A reconceptualization of the bpsd is necessary, which integrates the bio-medical dimension with psychosocial approach within the new welfare systems that must be rethought in function of the increase of the elderly population and respect to demographic trends. The onset of mild cognitive impairment and the reversibility of this pre-clinical occurrence should stimulate early recourse to appropriate psychosocial interventions to counter the social marginalization of many citizens.None Declared"}
+{"text": "The journal and Chief Editors retract the 26 November 2019 article cited above.Following publication, concerns were raised regarding the integrity of some of the images in the article. After a corrigendum was published, additional concerns were identified, and a further investigation was conducted in line with Frontiers\u2019 policies. The images were determined to have been manipulated, and the authors were unable to provide the raw data for the images in question. As a result, the data and conclusions of the article have been deemed unreliable and the article is therefore retracted.The retraction of the article was approved by the Chief Editor of Frontiers in Chemistry and the Chief Executive Editor of Frontiers. The authors did not respond to the retraction."}
+{"text": "Bioscience Reports at the request of the Editor-in-Chief and the Editorial Board following receipt of a notification from a reader, alerting the Editorial Board to cell-count distribution graphs that do not conform to the expected results for an experiment of this type.This article is being retracted from The authors were asked to provide the raw data in the form of the output from the flow cytometer, including the specific datapoints used to build the graphs. The authors provided the Editorial Board with PDF scatterplots but were unable to provide the specific data points, stating that this data was not saved. Given the lack of raw data, and that doubt remains over the validity of the graphs, the Editorial Board stands by the decision to retract. The authors agree to the retraction."}
+{"text": "The relationship between health and migration was severely affected during the covid-19 pandemic. This article discusses the literature on health and migration, including the deteriorating levels of social and economic vulnerability of international migrants to Brazil in 2020 and 2021. The analysis was based on a review of articles published in the national and international press addressing the impacts of covid-19 on contemporary processes of human mobility and its consequences for stigmatized populations. The results point to the possibility of understanding the pandemic as a key moment for rethinking nationality and borders."}
+{"text": "Following publication, concerns were raised regarding the validity of the data in the article. Following provision of raw data by the authors, the Chief Editor concluded that the article\u2019s conclusions and assertions were not sufficiently supported by the findings from the material provided; therefore, the article has been retracted.This retraction was approved by the Chief Editor of Frontiers in Cellular and Developmental Biology and the Editor-in-Chief of Frontiers. The authors did not agree to this retraction."}
+{"text": "British Journal of Nutrition, the graphical abstract was erroneously omitted at the time of publication. The corresponding graphical abstract has now been added to the following articles and is present in their HTML version.In the below articles published in the Cambridge University Press apologises for this error."}
+{"text": "The rapid development of civilization is accompanied by many changes affecting human functioning. Technological development, wide access to positive stimuli and the neglect of emotional control and self-awareness in the learning process make it difficult for individuals to control their behavior. Such a loss of control is associated with the development of addictions. Therapists, doctors and researchers more and more often encounter cases of compulsive behavior focused on a specific activity - apart from gambling or playing computer or internet games, more and more often the subjects of preoccupation are compulsive shopping, sexual activities and work (workaholism).The aim of the research was to try to define the mediating role of depression in the relationship between addiction to shopping and work and loneliness, understood in terms of general loneliness among Polish women.The study was conducted among 556 women. The research was carried out with the use of the diagnostic survey method, using the questionnaire technique: the De Jong Gierveld Loneliness Scale, the Purchasing Behavior Scale, the Work Addiction Risk Test, Beck Depression Inventory and a questionnaire of our authorship.Depressiveness is a mediator in the relationship between the feeling of loneliness and the degree of addiction to shopping  and in the relationship between the feeling of loneliness and the degree of addiction to work . The direct impact of the feeling of loneliness on the degree of addiction to shopping (p = 0.237) and work (p = 0.576) is statistically insignificant.In the mediation model adopted, it was shown that depressiveness plays the role of a mediator between the feeling of loneliness and the degree of addiction to shopping and work. The increase in the level of depression increased the degree of addiction to shopping and work. The mediator\u2019s participation lowered the level of the feeling of loneliness. Loneliness was not a significant predictor of addiction to shopping and work. There is a need to include activities aimed at identifying psychological factors influencing the occurrence of addictions to shopping and work among women. It seems important to be able to use psychological help when needed. It is also necessary to take institutional preventive measures to prevent the occurrence of behavioral addictions among women.None Declared"}
+{"text": "Funding statement. After publishing the article, the library of the University of Wuerzburg offered an Open Access Publication Fund to the authors. The corrected funding statement appears below:In the published article, there was a mistake in the This publication was supported by the Open Access Publication Fund of the University of Wuerzburg.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "The UN Convention on the rights of people with disabilities (UN CRPD) raised awareness of the need to find alternatives to coercion in the process of care for people with mental illness and/or mental impairment. In order to promote the application of the CRPD the World Psychiatric Association (WPA) has undertaken to produce a document listing possible alternatives to coercion and proposed to the General Assembly of the WPA to support the recommendations of that document by a WPA Position Statement on the matter.The presentation will discuss the suggestions included in the Position Statement and in the review of options to reduce coercion in the WPA materials.None Declared"}
+{"text": "This is a peer-review report submitted for the paper \u201cMedical Brain Drain From Southeastern Europe: Using Digital Demography to Forecast Health Worker Emigration.\u201dThis paper  represenThis paper examines negative demographic processes and differences in the health system of countries of origin and destination with the example of the Google Trends tools combined with standard demographic analysis and official statistics to confirm the outflow of medical workers from the Western Balkans and Croatia to Germany and Austria.The main goal of the work is to be satisfied and that is to determine the correlation between the official data and auxiliary data collected by the Google Trends tool. The results showed a high level of interdependence of trends shown by official statistics and analysis of Google Trends data by searching for relevant terms and keywords. The author pointed out the basic methodological limitations and advantages of using digital methods and tools with the intention to point out how the advanced digital age provides us a number of digital traces that can be used for observing demographic processes, especially migrations in the future.The lack of demographic potential in the health system is current and interesting, and the topic is actually a case report of the Western Balkans and Croatia through new approaches and tools of digital tracing and monitoring of migration processes. The author introduced readers to the demographic situation in the countries of origin to create a basis for understanding the processes that preceded the emigration of health workers based on a review of previous research and relevant authors.The value of the paper is that the author, in addition to appropriate, standard, and common methods in demographic analysis, also used the method of tracking digital traces that is perhaps more common in other social sciences. He thus made an important step forward in methodological terms and focused on new approaches that will, in accordance with advanced and dynamic information technology, be more and more present and will provide us an important source of information and knowledge. Therefore, the development of digital methods in demography in the methodological sense is an expected necessity and an aid to the study of demographic processes and phenomena.The results and the main findings of the paper are clear and unambiguous, and confirm the hypotheses, they are supported by data and graphical attachments, and they confirm the basic goal of the paper. The selected conclusions confirmed the importance of the new approaches and the connection that exists between the analysis of Google Trends and official data on the emigration of health workers to Germany and Austria using classical demographic methods.The writing style is simple, clear, and understandable to the reader, and the issues are addressed clearly, concisely, and meaningfully. The research was conducted in accordance with ethical standards and the GDPR, and the data used by the Google Trends tool are anonymous and aggregate, and no one\u2019s personal rights have been violated.The paper shows a disproportion between the cited references and those in the bibliography; some references were mentioned in the text but are not listed in the bibliography and vice versa, some listed in the bibliography are not cited anywhere so the author is invited to revise bibliographic references and harmonize the text and the list of references."}
+{"text": "Following publication, concerns were raised regarding the integrity of the images in the published figures. The authors failed to provide the raw data or a satisfactory explanation during the investigation, which was conducted in accordance with Frontiers\u2019 policies. Given the concerns about the validity of the data, and the lack of raw data, the editors no longer have confidence in the findings presented in the article.The authors agree to this retraction.This retraction was approved by the Chief Editors of Frontiers in Pharmacology and the Chief Executive Editor of Frontiers."}
+{"text": "Dear Editor,A 40-year-old female with oral allergy syndrome visited us, complaining of itchy eruptions which appeared one year previously. Physical examination showed a number of firm nodules on the trunk and extremities . MoreoveWe reported herein a case of BP occurring after the complete resolution of severe PN. A similar case was reported by Yoshimoto et al.,Recent studies have shown that basophilic infiltration was observed in PN and BP in the activated states.In conclusion, basophil was increased in number in both BP and PN lesions and may play an important role in the induction of BP and PN in the present case.None declared.Tomoko Hiraiwa: The study concept and design; data collection, or analysis and interpretation of data; statistical analysis; writing of the manuscript or critical review of important intellectual content; data collection, analysis and interpretation; effective participation in the research guidance; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; final approval of the final version of the manuscript.Natsuko Matsumura: Intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; final approval of the final version of the manuscript.Tatsuhiko Mori: Intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; final approval of the final version of the manuscript.Nobuyuki Kikuchi: Intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; final approval of the final version of the manuscript.Toshiyuki Yamamoto: The study concept and design; statistical analysis; effective participation in the research guidance; critical review of the literature; final approval of the final version of the manuscript.None declared."}
+{"text": "Most countries strive to reach effective sustainable development policies, given the repercussions of this policy on many aspects, such as the economic growth of countries. The adoption of policies of sustainability by developing countries may lead to their development faster than expected. This research aims to study the strategies applied in one of the universities of developing countries and the sustainability policies adopted at that university which is Damascus University. The study focuses on the time during last four years of the Syrian crisis through several factors, with a focus on the analysis based on the SciVal and Scopus databases and the strategies applied by the university itself. In this research, we use the method of extracting and analysing the data of the sixteen sustainable development goals (SDGs) of Damascus University within Scopus and SciVal. We also analyse the strategies used in the university in order to reach some of the determinants of SDGs. By analysing Scopus and SciVal data, we find that the third goal of SDGs is the most widespread in terms of scientific research in Damascus University. We find that the application of such policies led to an important goal in the environment, which is the ratio of green space in Damascus University reaching to more than 63 percent of the total flat area of the university. In addition, we find that the application of sustainable development policies led to the generation of energy from renewable sources by 11% of the total electrical energy consumed at the university. The university has been able to reach lots of indicators of the sustainable development goals and it remains apply others. The policy of sustainable development is an important factor in the development of different countries around the world. A large number of countries in the world have begun to respond to the sustainability goals that were launched in 2015. In that year, the United Nations, through its General Assembly, launched the Global Goals GGs or the Sustainable Development Goals SDGs. These goals included seventeen different goals that focus on sustainable future development over all parts of the world. The first goal of the SDGs aims for the ending of poverty in all countries of the world, and this goal is defined as \"No Poverty\" goal . The goaAnother economic goal of the SDGs is the twelfth goal which mainly focuses on the responsible consuming of the resources from different faces such as the consuming of water and consuming of electricity. The twelfth goal is defined as \"Responsible Consumption\" and \"Production\" , and thiThe study of the procedures which any university applies for reaching the SDGs can be done by analysis of that procedures either from the most important results which resulted by the procedures, or by analysis the results using multiple techniques. In the second section we analyse the resulted useful aspects of applied procedures in Damascus University by illustrating the main results and discussed those results. Also, we analyse the results of the procedures by bibliometric study of the researches published in Scopus database and SciVal which return to the researchers in Damascus University. For this purpose, we first find the University profile in the database including all campuses or other name of the university. For instance we use the following search string \"AF-ID (\"Damascus University\" 60072760) OR AF-ID (\"Damascus University Faculties of Dentistry\" 60072764) OR AF-ID (\"University of Damascus School of Medicine\" 60072761) \". Based on that search, we find the total number of the published documents by the researchers affiliated with Damascus University. After that, we apply the search including each one of the sustainable development goals collaborated wit the search string of Damascus University as full or whole institution. For instance, for finding the results of Damascus University for the SDG-15, we apply the following search string \"\"TITLE-ABS-KEY  AND ) AND AF-ID (\"Damascus University\" 60072760) OR AF-ID (\"Damascus University Faculties of Dentistry\" 60072764) OR AF-ID (\"University of Damascus School of Medicine\" 60072761)\".\" As we see from this search string, the search string includes the string returns to the fifteenth sustainable development goal in addition to Damascus University search string. The same procedure is applied for other SDGs. Based on the full searches, we find all bibliometrics data related to the sustainability results of the researchers affiliated with Damascus University where we analyse those results in the third section of the study. We deal with the main procedures which have been applied in Damascus University for reaching lots of the indicators of the sustainable development goals in the university. For more than four years, the University of Damascus has been adopting a policy of sustainable development in a large number of aspects related to the educational, societal, and research aspects. There was an urgent need to rely on the policy of sustainable development in these aspects, given the approach adopted by the university in responding to the call of the United Nations in the agenda of its General Assembly in the year 2015, in addition to the results emanating from the Syrian crisis, which negatively affected the educational process at the university. Multiple procedures were applied in Damascus university for the responding to the goals of sustainability. Firstly, in 2018, Damascus University launched a digital transformation policy in order to rely on the digital policy and replace the paper and print policy by the digital policy. Depending on the digital transformation policy, the first important thing that the university did at that time was to create a digital database for the certificates issued by it, by relying on an electronic sticker that is scanned electronically or writing the certificate number on the university\u2019s website on the Internet. The certificates initially included master's and doctoral degrees, to be expanded later to include bachelor's degree certificates. Another important thing related to the digital transformation policy at the University of Damascus is the cancellation of the printed academic journals published by the university and replacing them with online journals only, which contributes to saving a huge amount of papers, which reflects positively on two of the goals of sustainable development. Previously, before 2018, the academic journals published by the University of Damascus relied on printing manuscripts in order to peer-reviewed, but starting in 2018, the university relied on the mechanism of open journal system (OJS) in peer-reviewing. In addition, and in order to reduce the use of paper, Damascus University began in 2022 to announce the results of exams electronically only through the official website of the university on the Internet, while before that it relied on announcing the results on paper and electronically in many of its faculties and institutes. Also, in the year 2018, and in order to respond to the goals of sustainable development, Damascus University called for the ideal use of renewable energies. Where the university initially signed a number of agreements with a number of research centers concerned with energy research in order to install a number of solar electric energy cells and solar energy cells related to heating matters on the roofs of the university buildings. One of these agreements related to energy is the agreement signed between the University of Damascus and the National Center for Energy Research in the Syrian Arab Republic. The previous agreement aimed at installing electric solar cells in the university, which contributed to reducing the electrical energy generated from fuel. Also, in the field of health, and in order to respond to the goals of sustainable development related to health, Damascus University has started to hold many events and conferences related to health awareness, starting in 2019. These events and conferences at the university increased after the spread of the new corona-virus epidemic in the Syrian Arab Republic. These conferences and events had their own impact on community health, and this was reflected in the research published on behalf of the University of Damascus in international databases such as Scopus. In the field of public health as well, the University of Damascus has purchased and installed a number of medical equipment related to public health in its various hospitals, namely: Al-Mowasat University Hospital, University Children's Hospital, University Obstetrics and Gynecology Hospital, Al-Assad University Hospital, University Dermatology Hospital, Al-Bayrouni University Hospital, and the Institute dentistry at the university. As a result of the Syrian crisis, which greatly affected the electricity sector and its generation, Damascus University called on many occasions for the rationalization of electricity consumption in the various university buildings in its various branches, and this affects one of the goals of sustainable development and is an important indicator in it. The University of Damascus has also called on several occasions to rationalize water consumption in all university buildings and in its various branches. The university has been doing this even before the emergence of the Sustainable Development Goals in 2015. This reflects positively on one of the goals of sustainable development and is an important indicator in that goal. The most important response to the sustainable development goals by the University of Damascus was in the environmental field. The university interest in expanding the green area has increased in relation to the total area in the university, and the university has encouraged all its faculties and all its branches to take advantage of the fertile soil in the lands belonging to the University of Damascus in increasing the green area. A number of things helped in this, the most important of which is the presence of sufficient factors for agriculture in the lands belonging to the University of Damascus, and the desire of a large number of professors, teachers and university employees to increase the green area in it. In addition to that, in the field of environment, botanic gardens are built in the faculties of science of Damascus University, which contributes to the diversity of plants present in them and is reflected in many indicators within the goals of sustainable development. Also, in the same field, the university encouraged all of the faculties members, the managers, the employees, and the students for reducing the emission of the carbon dioxide, and other greenhouse gases.In this section, we analyse the main output resulted from applying the SDGs procedures in Damascus University. In addition, we analyse the bibliometrics data rederived from the databases. Firstly, we deal with the main procedures which have been applied in Damascus University for reaching lots of the indicators of the sustainable development goals in the university. For more than four years, the University of Damascus has been adopting a policy of sustainable development in a large number of aspects related to the educational, societal, and research aspects. There was an urgent need to rely on the policy of sustainable development in these aspects, given the approach adopted by the university in responding to the call of the United Nations in the agenda of its General Assembly in the year 2015, in addition to the results emanating from the Syrian crisis, which negatively affected the educational process at the university. Multiple procedures were applied in Damascus university for the responding to the goals of sustainability. Firstly, in 2018, Damascus University launched a digital transformation policy in order to rely on the digital policy and replace the paper and print policy by the digital policy. Depending on the digital transformation policy, the first important thing that the university did at that time was to create a digital database for the certificates issued by it, by relying on an electronic sticker that is scanned electronically or writing the certificate number on the university\u2019s website on the Internet. The certificates initially included master's and doctoral degrees, to be expanded later to include bachelor's degree certificates. Another important thing related to the digital transformation policy at the University of Damascus is the cancellation of the printed academic journals published by the university and replacing them with online journals only, which contributes to saving a huge amount of papers, which reflects positively on two of the goals of sustainable development. Previously, before 2018, the academic journals published by the University of Damascus relied on printing manuscripts in order to peer-reviewed, but starting in 2018, the university relied on the mechanism of open journal system (OJS) in peer-reviewing. In addition, and in order to reduce the use of paper, Damascus University began in 2022 to announce the results of exams electronically only through the official website of the university on the Internet, while before that it relied on announcing the results on paper and electronically in many of its faculties and institutes.Also, in the year 2018, and in order to respond to the goals of sustainable development, Damascus University called for the ideal use of renewable energies. Where the university initially signed a number of agreements with a number of research centers concerned with energy research in order to install a number of solar electric energy cells and solar energy cells related to heating matters on the roofs of the university buildings. One of these agreements related to energy is the agreement signed between the University of Damascus and the National Center for Energy Research in the Syrian Arab Republic. The previous agreement aimed at installing electric solar cells in the university, which contributed to reducing the electrical energy generated from fuel. Also, in the field of health, and in order to respond to the goals of sustainable development related to health, Damascus University has started to hold many events and conferences related to health awareness, starting in 2019. These events and conferences at the university increased after the spread of the new corona-virus epidemic in the Syrian Arab Republic. These conferences and events had their own impact on community health, and this was reflected in the research published on behalf of the University of Damascus in international databases such as Scopus. In the field of public health as well, the University of Damascus has purchased and installed a number of medical equipment related to public health in its various hospitals, namely: Al-Mowasat University Hospital, University Children's Hospital, University Obstetrics and Gynecology Hospital, Al-Assad University Hospital, University Dermatology Hospital, Al-Bayrouni University Hospital, and the Institute dentistry at the university. As a result of the Syrian crisis, which greatly affected the electricity sector and its generation, Damascus University called on many occasions for the rationalization of electricity consumption in the various university buildings in its various branches, and this affects one of the goals of sustainable development and is an important indicator in it. The University of Damascus has also called on several occasions to rationalize water consumption in all university buildings and in its various branches. The university has been doing this even before the emergence of the Sustainable Development Goals in 2015. This reflects positively on one of the goals of sustainable development and is an important indicator in that goal. The most important response to the sustainable development goals by the University of Damascus was in the environmental field. The university interest in expanding the green area has increased in relation to the total area in the university, and the university has encouraged all its faculties and all its branches to take advantage of the fertile soil in the lands belonging to the University of Damascus in increasing the green area. A number of things helped in this, the most important of which is the presence of sufficient factors for agriculture in the lands belonging to the University of Damascus, and the desire of a large number of professors, teachers and university employees to increase the green area in it. In addition to that, in the field of environment, botanic gardens are built in the faculties of science of Damascus University, which contributes to the diversity of plants present in them and is reflected in many indicators within the goals of sustainable development. Also, in the same field, the university encouraged all of the faculties members, the managers, the employees, and the students for reducing the emission of the carbon dioxide, and other greenhouse gases. In the Fig.\u00a0In this section, we talk about the main significant results of responding of Damascus University to the SDGs. Firstly, we start by some important information about Damascus University. Damascus University is the largest university in the Syrian Arab Republic and its built returns to the beginning of the Twentieth century. Currently, the university has more than 200,000 students over all parts of the university. Damascus University grants a number of programs, starting from a bachelor's degree or its equivalent, up to a doctorate degree. The university has its valuable Motto which is \"My Lord, increase me in knowledge\". The main targets of the university are the scientific research and the educational aspects. Since its foundation, the university has put all possibilities in order to achieve its previous targets.In the year 2018, and three years after the emergence of the sustainable development goals in 2015, the university sought to achieve a number of indicators related to some of the sustainable development goals, starting from environmental indicators to societal indicators. One of the main goals in reaching the sustainable development goals was to benefit from them in developing the educational, research and knowledge process at Damascus University. There are multiple departments and faculties in Damascus University focus on the sustainability goals. Those departments and faculties are illustrated in the Table All of these four campuses work on some indicators of the SDGs, for instance, in the Faculty of Sciences in As-Suwayda, which is called the fourth Faculty of Sciences of Damascus University, there is a botanic garden and there are lots of work for increasing the plants and trees in that campus. There are lots of the significant results resulted from applying sustainability procedures by Damascus University. The first important result of applying the sustainability procedures returns to generating the energy based on the renewable energy sources, where Damascus University work in two directions for this target. The first direction is the use of the electrical solar cells for generating the electricity from the main energy source of the earth which is the sun. The other direction is the use of the heating solar source for the heating of water. These two procedures have affected the ratio of the total consumed electricity in Damascus University. In the Table As we can see from the Table This significant aspect reflects mainly on the SDG-13. Finally, for the procedures related to the policy of digital transformation which the university focuses on, we see that the reducing of the consumed water has its reflection on the environmental, and educational goals of the SDGs. This aspect reflects mainly on the SDG-4, and SDG-13. In addition, this aspect has partial reflection on the SDG-8, and the SDG-12 because it has economic effects. Also, we analyses the bibliometrics data which returns to the SDGs of Damascus University. As we mentioned in the second, we found the Scopus data by applying two types of the search strings. Herein, we discuss the results of the searches. First, we illustrate the total number of the published documents of the SDGs, which Indexed and abstracted in the Scopus database, during the period from 2017 to 2022 and published by researches from Damascus university. We plotted these results in the Fig.\u00a0As we can see from the Fig.\u00a0Finally, in the Fig.\u00a0The aim of this research is to present the policies pursued by the University of Damascus in reaching the sustainable development goals launched by the United Nations in its General Assembly in 2015. Damascus University was chosen for several reasons, the most important of which is that it is the largest university in the Syrian Arab Republic, which is an example of low-income countries and an example of developing countries. We stated that the university started implementing sustainable development policies in 2018 in many aspects. In 2018, the university began with a policy of digital transformation that led to a significant reduction in the use of paper and paper publications, by switching to the use of electronic certificates for university graduates, in addition to the use of the open journals system in the academic journals published by the university. Also, in the same year, the university began to implement the policy of renewable energies effectively by using solar electric panels to generate electricity and solar thermal cells to heat water. In the year 2022, this policy led to the generation of clean energy estimated at about eleven percent of the electrical energy used by the university in that year. We found that the university called for a policy of rationalizing the use of water in various aspects and for a policy of reducing carbon emissions in university buildings. We also found that the application of some health-related policies had the greatest impact through research published on behalf of the University of Damascus in international databases such as Scopus. In addition, we found that one of the most important results emanating from the university's policy in reaching the goals of sustainable development is the increase in the percentage of cultivated area or green space, which approached more than 63 percent of the total projected area in all university buildings. Based on the bibliometrics analysis of the SDGs based on the Scopus and SciVal data, we found that the SDG-3 targets were the most publishing documents by the Syrian researchers affiliated with Damascus University and represented more than 55% of the total published documents about the SDGs in 2022.As a result of implementing the sustainability policy at the University of Damascus, the university was able to reach indicators related to a good number of sustainable development goals, namely: SDG-3, SDG-4, SDG-7, SDG-12, and SDG-13. Also, the university reached partially to the SDG-8. As the sustainability strategy of Damascus University states that the university remains for reaching to other indicators of the SDGs. Damascus University is following up its procedures to achieve sustainable and effective development in the Syrian society. As an example of the future ways in which the university follows up its procedures to apply the policy of sustainable development in the field of education, which was severely affected during the Syrian crisis , especia"}
+{"text": "Family caregivers can be a valuable source of knowledge and help in treating persons with mental illness during a psychiatric hospitalization and in ensuring a continuity of service between family caregivers and professionals after the discharge form a psychiatric hospital. Therefore, a family care model has been developed in order to provide professional staff members in psychiatric wards guidelines for how to collaborate with family caregivers during each stage of the hospitalization of their family member with mental illness.To examine the impact of implementing the Family Care model in psychiatric hospitals in Israel on the family caregivers and on the continuity of care between the hospitalization and the community.A comparative study was conducted implementing an AB design with an intervention and control groups. Seventy five persons participated in the control group and 93 in the intervention group. Questionnaires were delivered to family caregivers during the hospitalization and after the discharge from hospitalization, about the quality of collaboration of the family caregivers with the professionals during the hospitalization, about the family caregivers health and mental health, about their knowledge and ability to handle situations related to the family member with SMI and about the continuity of services between the hospitalization and the communityThe findings indicate that in the intervention group comparing to the control group there was: A lower level of anxiety of the family caregivers after the discharge of their family member from the psychiatric hospital, a higher level of evaluation of the caregivers\u2019 knowledge how to respond to the needs of the family members with mental illness, a higher level of evaluation of the quality of collaboration between the caregivers and the professional staff during the psychiatric hospitalization and a more frequent contact a between the persons with mental illness and the mental health services as well as a greater compliance with treatment after the discharge from the psychiatric hospital.The Family-Centered care model expands the traditional boundaries of the definition of the patient in psychiatric hospitals to include the family caregivers. This model could help prevent the development of problems for the family caregivers and it could help improve the continuation of services in the community. Therefore, the findings support the implementation of this model in psychiatric hospitals.None Declared"}
+{"text": "Most previous research focused on the association between mentalizing and specific mental disorders, while less is known about the relationship between mentalizing and quality of life among adolescents.This study aimed to validate The Reflective Function Questionnaire for Youth in the Hungarian language and evaluate the moderating influence of mentalizing on the relationship between psychopathology and quality of life.A community sample of 384 youths of 12\u201318 years  completed the following questionnaires: The Reflective Function Questionnaire for Youth (RFQY), The Measure of Quality of Life for Children and Adolescents and The Strengths and Difficulties Questionnaire. First, we tested the different factor structures of the RFQY: the two-factor, the eight-item, and the five-item versions. We conducted a series of moderation analyses with quality of life as the dependent variable, higher-order symptom categories  as the independent variable, and mentalization as the moderator.The confirmatory factor analysis supported the five-item version of the RFQY  and resulted in a new, 10-item version of The Reflective Function Questionnaire for Youth on the Hungarian sample . Mentalization had a moderator effect on the relationship between internalizing and externalizing symptoms and quality of life.Our study provides the first psychometric support for the Hungarian version of the RFQY and underlines the importance of assessing the complex relationships between mentalization, quality of life and symptomatology. Targeting mentalization to improve the quality of life among adolescents might be a key factor.None Declared"}
+{"text": "Crambe Abyssinic seeds. An important aspect of this research is to monitor changes in their quality taking place under the influence of external factors. Raman spectroscopy was used to identify changes taking place in the bio-lubricant under the influence of mechanical and thermal forces. The performed tests reflected the operating temperature and friction load that may occur during actual operating conditions for the lubricated friction systems. The Raman spectra provided information on qualitative changes in the structure of the tested bio-lubricants at the molecular level. The integral intensity of the bands used to assess the degree of lipid unsaturation was adopted as the evaluation criterion. The influence of the oxidation process under the PetroOxy and wear test conditions on changes in the structure of the bio-lubricants was assessed. Variation in the integral intensity of the bands (I1655/I1440) proves that the structure of vegetable lubricants changes under the influence of the tests performed. Thermal and mechanical forces influence, the bands originating in unsaturated and result in a decrease in the oxidation resistance of vegetable lubricants.Bio-greases were developed on the basis of vegetable oil obtained from  The lubricant is an integral and inseparable element of the tribological connection and is largely responsible for proper and trouble-free operation. High temperatures and ubiquitous oxygen are two of the most important factors contributing to the ageing of lubricants formulated with vegetable oil bases. In addition, during friction of the cooperating elements of the tribological system, significant changes occur in the structure of materials caused by the operating conditions. The mechanical and physicochemical phenomena occurring on the surface of the friction node elements under the influence of temperature and pressure shape the surface layer, which changes during operation and under the influence of lubricants. During friction carried out in the open air, the lubricant degrades under the influence of oxygen and the catalytic effect of the metal from the friction surface on the lubricant oxidation process. The wide use of natural oils in lubrication technology is conditioned by their resistance to the oxidation process, which results from the presence of unsaturated bonds, as these oils contain monounsaturated and polyunsaturated fatty acids ,2,3.In general, despite the content of natural antioxidants in their composition, vegetable oils are characterised by insufficient, long-term oxidative stability. This limitation results from the significant content of unsaturated acids with one, two or three double bonds in the structure of vegetable oils, which are unstable and easily oxidised ,2. In thThe literature reports indicate a wide spectrum of possibilities in using Raman spectroscopy for the analysis of fatty acids, lipids or proteins . PhilippRaman spectroscopy is a widely used analytical technique to study, among others, the structural properties of polymer solutions , yieldin4N4 interface. The influence of the DLC structure on the efficiency of contact lubrication with plant products was investigated. It was found that the chemical degradation process of castor oil is favoured by the amount of hybridised sp2 carbon atoms in the amorphous carbon structure. It has been shown that the presence of the \u2013OH group in lubricating products reduces the coefficient of friction. Yuan et al. ."}
+{"text": "To the Editor,Liao et al.All authors verify their contribution to the production and writing of this manuscript.The authors declare no conflict of interest."}
+{"text": "It was found that the complaint was valid and that the article should be retracted, because of an unacceptable level of similarity to an article published by Ulbrichtova et al. Validation of the Slovakian Version of the \u201cPost-acute (Long) COVID-19 Quality of Life Instrument\u201d and Pilot Study. Patient Preference and Adherence. 2023. doi: The retraction of the article was approved by the Field Chief Editor of Frontiers in Public Health. The authors agree to this retraction."}
+{"text": "The funder Avalon Globo-Care Corp had no interference in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. The authors apologise for this error.In the aforementioned article, the authors\u2019 conflict of interest statement is incorrectly worded. The statement should read:"}
+{"text": "Perceptions of the importance of the role of psychological trauma in the origins of psychiatric problems have oscillated throughout the history of psychiatry. However, since the conception of post-traumatic stress disorder (PTSD), western societies have witnessed a marked expansion of the discourse of trauma in the interpretation of devastating human experiences like catastrophes, genocides, disasters, and epidemics. Through an integrative literature review, this article analyzes some of the historical and epistemological determinants behind the emergence of traumatic memory and the establishment of trauma as a semantic field that orients clinical responses and political strategies in the field of the humanities and the health sciences."}
+{"text": "Two of the main factors shaping an individual\u2019s opinion are social coordination and personal preferences, or personal biases. To understand the role of those and that of the topology of the network of interactions, we study an extension of the voter model proposed by Masuda and Redner (2011), where the agents are divided into two populations with opposite preferences. We consider a modular graph with two communities that reflect the bias assignment, modeling the phenomenon of epistemic bubbles. We analyze the models by approximate analytical methods and by simulations. Depending on the network and the biases\u2019 strengths, the system can either reach a consensus or a polarized state, in which the two populations stabilize to different average opinions. The modular structure generally has the effect of increasing both the degree of polarization and its range in the space of parameters. When the difference in the bias strengths between the populations is large, the success of the very committed group in imposing its preferred opinion onto the other one depends largely on the level of segregation of the latter population, while the dependency on the topological structure of the former is negligible. We compare the simple mean-field approach with the pair approximation and test the goodness of the mean-field predictions on a real network. The formation of people\u2019s opinions, choices and decisions is subject to social pressure: it is a general observation that in society, individuals (agents) take into account the behavior of others . This asPrejudices or personal preferences generally come from the history of the individual  and arepreference falsification in )"}
+{"text": "Please find the retraction statement below:Following publication, concerns were raised regarding the integrity of the images in the published figures.Following the provision of raw data by the authors, the Chief Editor concluded that the article\u2019s conclusions and assertions were not sufficiently supported by the findings from the material provided; therefore, the article has been retracted.This retraction was approved by the Chief Editor of Frontiers in Oncology and the Chief Executive Editor of Frontiers."}
+{"text": "ML) regrets having to report the death of one of its most illustrious members, Dr. Josep Maria Queralt\u00f3, 67 years old, who left us suddenly, on Friday, March 27, at his home in Sant Andreu de Llavaneres (Barcelona).The Spanish Society for Laboratory Medicine .In addition, he was a member of the Commission on the Diagnostic Value of Biochemical magnitudes (1985\u20131989) and of the Scientific Committee of the Society (1985\u20131992), as well as of the Editorial Committee of the Journal Advances in Laboratory Medicine and the Board of Directors; he was still holding the last position at the time of his death.ML in international organizations has been of great importance, as he held highly significant positions, such as the presidency of the board of the European Federation of European Societies of Clinical Chemistry. He was also a member of the EC4 European Registry Committee from 2000 to the present.Likewise, his work representing SEQCML to be present at numerous international events. Among these it is worth noting, due to its great impact, the organization of the congresses EuroMedLab Barcelona 2003, of which he was president of the Scientific Committee, and EuroMedLab Barcelona 2019, of which he was a member of the Organizing Committee. The success of both European Congresses gave the SEQCML an enormous boost and visibility at an international level.His perseverance in the many international tasks in which he participated and his international contacts, which he cultivated and maintained exquisitely, helped the SEQCIn the days since his death, the Society has received dozens of emails and written statements from various countries around the world, expressing sorrow and dismay at the loss of such a beloved and valued person. Within his great human and professional worth, all those who had the opportunity to interact with him highlighted his patience and his great vision for the future in the field of Laboratory Medicine training."}
+{"text": "Suicide presents itself as a serious public health problem, with universal characteristics. Though world rates dropped between 2010 and 2016, they are still very high and in regions like the Americas there has been a raise in the same period in Brazil, contrary to the word trend and surpassing the avarage of the Americas (6%), the rate of suicides in each 100 thousand inhabitants has raised in about 7% in the period .Considering the relevance of these aspects, this study presents the results of actions for treatment and prevention of suicidal behavior, developed by a psychiatry and chemical dependency inpatient service in the city of Rio de Janeiro.This showed the necessity of the creation of a specific program of suicidal treatment and prevention and the Institution established the following actions of intervention to hospitalized patients: permanent watching , reduction of access to instruments and methods to commit suicide, strengthening of the Life Appreciation Group (LAG) and the Cognitive Behavioral Therapy group, art therapy and physical activities.It was observed that among the 370 patients hospitalized in the Institution in the period of the study, 137 presented suicidal behavior and only 2 died. From these two cases, one abandoned treatment and the other ocurred during the period of treatment.The developed program reached positive results in the intervention of the cases and the actions of prevention had expressive reach in the number of people, especially because the press promoted wide dissemination of information for immediate help.None Declared"}
+{"text": "Nature Genetics 10.1038/s41588-019-0557-x, published online 05 February 2020.Correction to: In the published version of this paper, the members of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium were listed in the Supplementary Information; however, these members should have been included in the main paper. The original Article has been corrected to include the members and affiliations of the PCAWG Consortium in the main paper; the corrections have been made to the HTML version of the Article but not the PDF version. Additional corrections to affiliations have been made to the PDF and HTML versions of the original Article for consistency of information between the PCAWG list and the main paper."}
+{"text": "The authors regret that the email address of the corresponding author (gzsongm@126.com) was not shown in the original manuscript. The corrected list of affiliations is as shown here.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "Following publication, the editorial office was contacted by the first author regarding the omission of co-authors from the article, due to a misunderstanding of their contributions. All authors of the manuscript have agreed to and requested to retract the published article.This retraction was approved by the Chief Editors of Frontiers in Veterinary Science and the Chief Executive Editor of Frontiers."}
+{"text": "The journal retracts the 02 July 2019 article cited above.Following publication, concerns were raised regarding the integrity of the images in the published figures. The authors failed to provide the raw data or a satisfactory explanation during the investigation, which was conducted in accordance with Frontiers\u2019 policies. Given the concerns about the validity of the data, and the lack of raw data, the editors no longer have confidence in the findings presented in the article.This retraction was approved by the Chief Editors of Frontiers in Pharmacology and the Chief Executive Editor of Frontiers. The authors agree with this retraction."}
+{"text": "The Publisher retracts the cited article.Following publication, concerns were raised regarding the contributions of the authors of the article. Our investigation, conducted in accordance with Frontiers policies, confirmed a serious breach of our authorship policies and of publication ethics; the article is therefore retracted.This retraction was approved by the Chief Editors of Frontiers in Psychiatry and the Chief Executive Editor of Frontiers. The author Pham Van Tuan agrees to the retraction. The rest of the authors have not responded to correspondence regarding this retraction."}
+{"text": "Nature Genetics 10.1038/s41588-019-0576-7, published online 05 February 2020.Correction to: In the published version of this paper, the members of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium were listed in the Supplementary Information; however, these members should have been included in the main paper. The original Article has been corrected to include the members and affiliations of the PCAWG Consortium in the main paper; the corrections have been made to the HTML version of the Article but not the PDF version. Additional corrections to affiliations have been made to the PDF and HTML versions of the original Article for consistency of information between the PCAWG list and the main paper."}
+{"text": "After having been in contact with the authors, they accepted the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused.In view of the fact that certain of the data in the above article had already appeared in a previously published paper, and given the large number of apparently overlapping data panels identified in several of the figures, the Editor of"}
+{"text": "We research new neurological viewpoints of psychiatric syndromes in social cohesion regarding, especially the problematic of lymbic system and amygdala in adults. Nowadays, the number of the problematic use of internet is higher than before the COVID-19 pandemic. The development of the digital techniques is impulsive, which can be the main reason of most neurological dysfunctions and the change of the social communication.In this presentation, we review studies investigating the relationship among the new digital techniques, limbic system and development of psychiatric syndromes. We attempt to provide a summary of new theories and the areas currently being researched around the topic. Another aim of our research is to present the change of the social communication and emotion regulation, which are risk factors of problematic use of internet and behavioral addictive disorders. These appear in different ways in rehabilitation and social inclusion in Europe.In order to learn about recent international results, we conducted a literature search in 4 databases  using keywords  over the past 5 years. From the obtained results, the English empirical journal articles were used to prepare the literature review.The frequency of co-occurrence of amygdala dysfunction, problematic use of internet and behavioral addictive disorders are correlated. The studies examined the presence of symptoms of impulsivity and dopamine level of the brain primarily through cross-sectional studies. The social cohesion and inclusion regarding types are different in the regions of Europe.The dysfunctions of lymbic system regulation cause maladaptive emotion regulation and are risk factors and make the person vulnerable to the development of psychiatric symptoms, problematic use of internet and behavioral addictive disorders. The differents of regions and areas in Europe with the new neurological viewpoints in psychiatric disorders can help with rehabilitation in the social cohesion regarding. These changes are particularly pronounced during adolescence, when the demand for self regulation across a variety of emotional and social situations may be the greatest.None Declared"}
+{"text": "We analyze the role of disease containment policy in the form of treatment in a stochastic economic-epidemiological framework in which the probability of the occurrence of random shocks is state-dependent, namely it is related to the level of disease prevalence. Random shocks are associated with the diffusion of a new strain of the disease which affects both the number of infectives and the growth rate of infection, and the probability of such shocks realization may be either increasing or decreasing in the number of infectives. We determine the optimal policy and the steady state of such a stochastic framework, which is characterized by an invariant measure supported on strictly positive prevalence levels, suggesting that complete eradication is never a possible long run outcome where instead endemicity will prevail. Our results show that: (i) independently of the features of the state-dependent probabilities, treatment allows to shift leftward the support of the invariant measure; and (ii) the features of the state-dependent probabilities affect the shape and spread of the distribution of disease prevalence over its support, allowing for a steady state outcome characterized by a distribution alternatively highly concentrated over low prevalence levels or more spread out over a larger range of prevalence (possibly higher) levels."}
+{"text": "Following publication, concerns were raised regarding the integrity of the images in the published figures. The authors failed to provide a satisfactory explanation during the investigation, which was conducted in accordance with Frontiers' policies. As a result, the data and conclusions of the article have been deemed unreliable and the article has been retracted.The retraction was approved by the Chief Editors of Frontiers in Cellular Neuroscience and the Chief Executive of Frontiers. The authors did not agree to the retraction."}
+{"text": "Overexploitation of natural resources and pollution of seas, acidification of the ocean, and rising temperatures all contribute to the destruction of marine habitats and, in 2015, the protection of the ocean became one of the UN Sustainable Development Goals (SDG 14: Life Below Water). This collection aims to highlight the molecular genetic changes currently happening in marine organisms. Although the exact place of the origin of life on Earth is still debatable , the subThe ocean and its inhabitants are among the first to face the effects of anthropogenic activities and water pollution and overexploitation of natural resources are just the tip of the iceberg as many other causes and consequences are leading to the destruction of ocean ecosystems Fig.\u00a0. MoreoveGiven the importance of the ocean, studies on the impact of climate change on marine organisms and ecosystems are of particular importance. Some habitat changes are fatal to species and lead to their extinction but thankfully not always. Although recent studies have shown that marine ecosystems are more sensitive to environmental changes than terrestrial ones , the speRecent studies that have focused on comparative analysis of genomic, transcriptomic, and epigenomic mechanisms in marine organisms show that they can adapt to changes in salinity, acidity and temperature of water \u201311. At tTo conclude, human-made environmental changes and ecosystem destruction have a substantial effect on Earth\u2019s climate and there are serious concerns about the future of marine biodiversity. However, the silver lining is that these global environmental changes provide exciting opportunities to understand the origin and the evolution of marine life and highlight potentially useful strategies for further research and action on SDG 14 Live Below Water and other sustainable environmental programs.With this collection we hope to attract breakthrough and original research papers describing the application of the modern methods for phylogenetic analyses, as well as speciation and molecular evolution studies of marine species in changing environments. Additionally, experimental studies that exhibit the significance of differential gene expression and epigenetic factors in adaptation to changing environments, and research that characterizes the role of alternative splicing and interspecific hybridization, and its potential for adaptation are encouraged. The aim of this Collection is to advance SDG 14: Live Below Water, which is centered on the conservation of the ocean and its natural resources.We believe that the energy and commitment of early-career researchers  multiplied by the experience of their mentors, as well as the use of the latest methods of molecular genetics, genomics, and bioinformatics tools will allow researchers to find new insights and solutions to the current ocean situation."}
+{"text": "There are errors in the Funding section. The correct Funding statement is: This work was financially supported by the National Science Foundation for Young Scientists of China in the form of a grant (71902163) awarded to TZ. This work was also financially supported by the Humanities and Social Sciences Youth Foundation of Ministry of Education of China in the form of a grant (19YJC630218) awarded to TZ. This work was also financially supported by Guanghua Young Teachers\u2019 Growth Plan of Southwestern University of Finance and Economics in the form of an award to TZ. This research was also financially supported by Fundamental Research Funds for the Central Universities in the form of a grant (JBK2202015) awarded to TZ. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.The publisher apologizes for the error."}
+{"text": "Archives of Endocrinology and Metabolism is entering its fourth year of activities  Board of Directors for their constant support. Last but not least, I also want to extend my special thanks to the editorial team of the AE&M."}
+{"text": "The journal and Chief Editors retract the 20 January 2022 article cited above.Following publication, concerns were raised regarding the quality of the article and the language of the presentation. An investigation was conducted in accordance with Frontiers' policies.A post-publication assessment by an expert in the field found that the complaints were valid and that the study design is not adequate to justify the conclusions drawn by the authors. The article does not meet the standards of editorial and scientific soundness for Frontiers in Computational Neuroscience; therefore, it has been retracted.This retraction was approved by the Chief Editors of Frontiers in Computational Neuroscience and the Chief Executive Editor of Frontiers. The authors did not agree to this retraction."}
+{"text": "The process of teaching and learning mathematics in primary school represents an obstacle for both teachers and pupils. According to the historical-cultural conception of development and education, the way how intellectual concepts are initially introduced may radically affect a student\u2019s success in learning. The historical-cultural conception of development, together with activity theory, may serve as the basis for creating a novel methodology for pedagogical work on mathematical concepts with pre-school and school children.The goal of the present study was to show the effects of work with an original program for the initial introduction of mathematical concepts to young school children. The program included reflexive symbolic and logical actions on the materialized and perceptual level, which were introduced and performed collectively by six-year-old children under the guidance and assistance of a teacher. The pupils were tested before and after their work with the program.The results showed important qualitative and quantitative progress by the children in solving the tasks of the assessment, together with an increment of reflection on their intellectual actions.The study points to the necessity for more intensive and extensive research, involving specialists in psychology and pedagogy trained in cultural-historical methodology. Some novel proposals have led to experimental studies based on the historical-cultural approach with limited groups of children and had the enthusiastic support of researchers and directors of educational programs .The present study was based on cultural historical conception of psychological development , 1995. AIn this approach, the work of the teacher is organized according to the concept of the zone of proximate development, when the teacher helps the children by establishing of the questions for better orientation, demonstrating the procedures, showing examples, modeling decisions, and providing the logic of the process of each intellectual action . One of The goal of the present study was to show the effects of an original experimental program for the initial introduction of intellectual actions with mathematical content on a group of six-year-old Mexican children, who were regular pupils of the first grade of primary school. The actions of measurement of the magnitudes of longitude, area and volume of the liquids were selected as central intellectual actions. The logical actions were related to the reflexive selection of the means for measurement and the comparison of the results. The program was designed according to the principles of cultural historical approach and psychological activity theory, which considers the psychological age of the children, the content of their intellectual actions, and the organization of constant collective interaction under the guidance of an adult. The program was based on the content of a fairy tale, so that all intellectual actions were presented as symbolic actions of the characters of the tale. The children were tested before and after their work with the program. The process of assessment was individual and included originally organized tasks .2.2.1.The participants of the study were 10 Mexican children (6 boys and 4 girls), pupils in the first grade of a private primary school in the city of Puebla. The age of the pupils was between 6, 5 and 8, 4 years old, and the average age of the children were 6, 8. The age was not essential criterion for the inclusion in the study, as it was important to include the children as regular pupils of the first grade of primary school with no previous experience of detailed work with the actions of measurement and the means of measurement. The oldest boy was included into the study because he was not able to assist the first grade of primary school due to difficult family conditions during international pandemic, so that he entered primary school 1 year later. All children were Spanish speaking pupils. The school was situated in an urban zone of medium economic level, according to the location and average economic income of the families. All the children were regular pupils who were finishing their first year of formal school education. The administration of the school agreed to take part in the study, as the school uses cultural historical methodology, based on Vigotsky\u2019s approach. This approach considers the necessity of adult\u2019s active orientation in the tasks of assessment, according to the conception of the zone of proximate development . The stuThe selection of the participants was based on the following criteria: (1) to be between six and 7 years old; (2) to be a regular pupil according to the norms of the educational institution; (3) to belong to the middle class of the city of Puebla; and (4) to attend most of the sessions of the experimental program as well as the sessions of initial and final assessment. The criteria of exclusion were as follows: (1) to have a history of neurological or psychiatric disturbances; and (2) to be absent during the work with the program and/or during initial or final assessment. The children\u2019s participation in the study was voluntary and was arranged by previous agreement with the parents and the school administration.The work with the experimental program was carried out by a teacher previously trained for work with the program content who was familiar to the children. The procedure of initial and final assessment was accomplished by two students from the Faculty of Psychology of the Autonomous University of Puebla, who were participants in the research project. The program work was done as a group, while the process of assessment was individual for each pupil before and after his work with the program. All subjects gave their informed consent for inclusion before they participated in the study. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethical Committee of the Department of Psychology, Lomonosov Moscow State University.2.2.The design of the research was quasi-experimental, with the same group of participants tested before and after implementation of the experimental program. The children\u2019s success in the solution of the problems was related to selection of appropriate external mean for the action of measure was tested before and after the work with experimental program. All tasks of the assessment and of experimental program were new for the children.2.3.Initial and final assessment were accomplished using two psychological protocols created on the basis of cultural-historical psychology, which takes into account the appropriate content for children of preschool age and the aspects of preparedness for school learning. Each participant was tested individually on selected tasks according to the protocol for the assessment of the level of preparedness for school  and on tThe tasks selected from the protocol for assessment of the level of preparedness for school belonged to three spheres: (a) mediatized recollection of an object; (b) voluntary actions on verbal and graphic levels; and (c) previous mathematical abilities, such as mastery of one-to-one correspondence, seriation, and equation of conjunctions. The protocol for evaluation of basic mathematical knowledge, translated from Russian into Spanish for the purposes of this study, included 17 tasks for the measurement of longitude, area, and volume . Each me2.4.The methodology of the experimental program was also based on cultural-historical psychology and activity theory applied to the process of teaching and learning. Such methodology considers psychological age of the children with the necessities of realization of interactive collective activities, which allow to guarantee the pupil\u2019s motivation for learning of mathematics. The study was organized by academic assessors of the college who are representatives and followers of this approach in Mexico.The tasks of both protocols were presented to all participants at the beginning of the last bimester of the school year before the work with the program. The assessment was individual to each child; it took place on school premises, according to prior agreement with the director and the parents. In case of difficulties, the children received help and orientation from the adult, which did not involve completely solving the tasks. The analysis of the results considered the nature of external help used by the researcher during his work with each child. Different types of external help during the fulfilment of the protocol were also used during initial assessment.The work with the protocol took between 45\u2009min and 2\u2009h. The sessions were videotaped for further analysis, according to the ethical norms and agreements with the director and the parents. The identity of the participants was never revealed.Once the initial assessment was finalized, the experimental formative program (in writing) was presented to the participants.The program aimed at the introduction, use, and reflection on the means of measuring longitude, area, and volumes. The tasks for the measurements were provided in different situations, which were attractive and interesting for the pupils. This was achieved by the presentation of the actions of measuring as the necessities of the characters of a fairy tale. The characters of the fairy tale found themselves in situations where the measurements necessary for achieving a goal or saving somebody were represented as a magical action. The work with the program was interactive, involving the participation of all pupils in the classroom at school and guided by the teacher. The work was programmed for planned lessons dedicated to mathematical abilities and was aimed at helping the children understand the interdependence between the means used and the magnitude in the action of measurement. The work with the program was carried out by previously trained schoolteacher known to the children. The teacher used the materials of the program prepared and explained by the researchers. The teacher did not take part in the initial and final assessment, which was fulfilled by the researchers.The basic content of the program was related to the introduction of the actions for the measurement of longitude, area, and volume of the liquids. Different symbolic means were presented to the children to achieve the action of the measurement. All tasks were collective and interactive; so that all children took part in each task of the measurement altogether. The actions of the children were oriented and supervised by the teacher on all occasions, in line with the concept of the zone of the proximate development . The basA total of 16 sessions were held devoted to the work of the program. The sessions were held three times a week for 1\u2009h. Two pupils were unable to continue the program for health reasons, so that only eight pupils finished the project.After finishing the program, the children were assessed by the same protocols individually by the researchers. Different types of external help during the fulfilment of the protocol were also used during the final assessment.The work with the program and final assessment were finalized in the month of July, which is the end of school year according to the official calendar of the Mexican Secretory of Public Education (SEP). Additionally, after their summer vacations, in the month of September, the children were tested in an interview conducted by the researcher. All children, who take part in the program, were included in this interview. The goal of the interview was to find out whether the children had enjoyed their work with the program, and whether they remembered its content. The session for this interview took place at the school during one session of 30\u2009min in the presence of a new teacher assigned by the school for the second grade of primary school. The teacher who initially worked with the program did not take part in the interview, in order to exclude any influence on the children\u2019s answers and opinions.2.5.The children\u2019s responses for each task of the protocols were classified and quantified by 0, 1, and 2, as shown in During the fulfilment of the protocol, the children who had difficulties received help from an adult. Different types of external help were used, according to the specific content of the tasks. 3.The analysis of the data is presented below for the two protocols used for the initial and final assessments: (1) the tasks selected from the protocol for assessment of level of preparedness for school learning, and (2) those selected from the protocol for assessment of previous mathematical knowledge.The general results obtained during the comparison of the fulfilment of the tasks selected from the protocol for assessment of level of preparedness for school learning  showed tt-test was used for the comparison of the results of fulfilment of the tasks during initial and final assessment. This test revealed significant differences favorable to the final assessment, with a significance value of 0.001, which is significantly higher than 0.05 .The student Statistical analyses of the individual results for each task showed that not all the tasks of the protocol had shown statistical differences , but allThe tasks of correspondence and equation of groups and seriation showed significant differences .p\u2009<\u20090.05.The results of fulfilling the protocol for assessment of previous mathematical knowledge were compared before and after the work with experimental program. These results were analysed with the statistical program JASP, version 0.16.3.0, which evaluated two student t-tests for two conditions of the protocol: one for the global results and the other for each task carried out before and after implementation of the program with significant value of The comparison of the global results for the fulfilment of all the tasks of the protocol for assessment of basic mathematical abilities (in writing), found significant differences between the initial and final assessments. The median of the correct answers in the initial assessment was 14.313; and in the final assessment it was 20.875 .t\u2009=\u2009\u22123.792, gl\u2009=\u20097), which was significantly lower than 0.05. This data allows to conclude that the differences between the results of initial and final assessment were statistically significant. The children\u2019s total results were much higher in the final assessment.The student t-test results had a significance value of p 0.007  used for measurement, and that they enjoyed working with most of the proposed tasks. They were also able to detect the most difficult and confusing tasks of the program. This data shows positive effects of collective organization of children\u2019s work with the use of mathematical intellectual actions. Such work guarantied positive emotions and attitude toward mathematical knowledge in children. This data supports the idea of the previous publication about positive effects of the work of young scholar in teams . The stuPiaget , in his On the contrary, representatives of the cultural-historical approach and activity theory in psychology claim that logical actions do not appear spontaneously but require specially organized work with the children at school , 2019. IUnfortunately, official programs for teaching mathematics are mostly based on the constructivist way of thinking, which understands the acquisition of logical and mathematical abilities to evolve spontaneous spontaneously . The cenProbably, now when international pandemic and impossibility of children having face-to-face studies have ended, it is a good time to start thinking about coherent changes in teaching and learning methodology. Such changes should aim to establish emotional and positive communication between the pupils and the teacher during classes, not expect pupils to \u201cconstruct\u201d logical knowledge independently, as constructivism claims . The teaAccording to Radical changes in the method of teaching mathematics should be related to the content of methodological work in the classroom. The data of the research allows to stress that such changes are possible, based on psychological activity theory.Psychological activity theory, developed by According to The results of our study allow to offer a new original way for introducing innovative programs for interaction with the children in the classroom together with the teacher, which helps them achieve better results in understanding logical actions and the mutual dependence of the processes of measuring, the magnitude to be measured, and the tools which should be selected for these actions. All children, who took part in the program, were able to understand logical actions and enjoy the process of learning mathematical concepts in primary school. The results of the study might be used for improvement of the process of initial introduction of mathematical abilities. The study opens an opportunity for creative implementation of the concepts of zone of proximate development and orientation as main concepts of cultural historical approach.One of limitations of this study was the small sample of the children who took part in the experimental program, because the private school chosen for the study works with small groups of children. Another limitation was the absence of the control group, as it was impossible to get permissions for assessment of children from other private primary school with similar characteristics. An essential advantage of the study consists in the effort of creation and implementation of new original program for introduction of initial mathematical knowledge by working with measurement as joint intellectual actions guided by the teacher, according to the conception of the zone of proximate development. The program should be taken into account as new contribution for initial introduction of mathematical actions within cultural historical approach. Our future efforts will include preparation for publication of the whole content of the experimental program in Spanish for its generalized use by teachers in primary schools and for correction of difficulties in the process of acquisition of mathematical knowledge.5.The results of the study show significant differences between the initial and final assessment of the ability of children in the first grade of primary school to use the proper tools for the action of measurement. Such findings allow to confirm that the program used for our work on the intellectual actions of measurement in the context of a fairy tale was useful for the children\u2019s understanding of the dependence of determining a magnitude on the tools and methods chosen for the measuring it. The pupils, who took part in the program showed interest and pleasure during the work with experimental program. Such data is relevant for design and approbation of original programs for introduction of basic mathematical knowledge. The children of form the first grade of primary school worked eagerly with the content of intellectual actions, guided by the teacher. The content of a fairy tale might be used as a pedagogical strategy, while the actual actions of measurement should be included and carried out by the children according to the content of the tale. The teaching of initial mathematical concepts should include the use of different and flexible symbolic means as tools of the children\u2019s for introducing reflection during solution of logical problems. The experience of the work with the content of fairy tale allows to confirm that symbolic means and logic actions must not be only presented or explained but fulfilled by the children in the classroom under the guidance of the teacher. The program, used in the study, might be reproduced in different educational institutions and social contexts, where the work on introduction of initial mathematical knowledge is needed.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by the Ethical Committee of the Department of Psychology, Lomonosov Moscow State University. Written informed consent to participate in this study was provided by the participants\u2019 legal guardian/next of kin.YS: conceptualization and supervision. YS and LQ: methodology, investigation, writing \u2013 review, and editing. JZ: software and visualization. JZ and AC: formal analysis. YS, JZ, AC, LQ, and VP: writing \u2013 original draft preparation. LQ: project administration. YS and VP: funding acquisition. All authors contributed to the article and approved the submitted version.This research was funded by the Russian Science Foundation, grant number 21\u201318-00584.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "The authors regret the omission of one of the affiliations for one of the authors, Rajeh Alotaibi, from the original manuscript. The corrected list of authors and affiliations for this paper is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "The authors regret that the name of one of the authors, Mubasher, was given incorrectly in the original manuscript. The corrected list of authors for this paper is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "The current approach to stimulating elderly physical activity mostly uses medical rehabilitation methods or popular forms of outdoor recreation. In the context of an ageing population, there is a growing demand for innovative rehabilitation methods that use information technology. In this article, we present the Urban Health Path as an innovative form of activation for older people using urban therapy, where the architectural elements, such as details, fa\u00e7ade features, and urban furniture, inspire movement and attentiveness in the experience of space. The concept is supported by a mobile application that takes into account the specific preferences of older users. Our concept of the physical and cognitive activation of older people was the result of a user-centred design approach and it was tested as a prototype solution. At the same time, the aim of this article is to identify opportunities and limitations for the implementation of this type of solution in other urban spaces. The article presents the process of developing a solution using the Design Thinking method. The process was focused on the needs and preferences of older people. The results of the research project indicate the main important guidelines for implementing the Urban Health Path as a new form of urban facility in the city space. The ageing of the population and the growing need for the rehabilitation and maintenance of the psychophysical well-being of older citizens call for innovative and engaging forms of physical and cognitive activation. This includes not only taking advantage of the latest developments in physiotherapy, the development of technological and communication devices, or social gerontology, but also adopting a methodology for designing products, services, or spaces that are orientated towards the needs and preferences of the user. Regarding the urban ageing process, urban planning is currently strongly focused on the idea of active ageing ,2,3,4. TPrevious research in the field of physical activity for the elderly has focused on the characteristics of recreational areas that promote physical activity and build self-esteem ,11,12,13The author\u2019s concept of heritage healing adopted in this work uses the potential of urban architecture, mainly the details of building facades and elements of small architecture. The concept of a therapeutic environment developed so far has been based on the relationship between the user and the elements of the built environment ,41,42,43Developing criteria for the selection of urban space features  with a view to determining their suitability for the rehabilitation of older people;Developing assumptions for the development of technological tools to activate and engage older people in physical activity and cognitive functions;Selecting architectural objects with significant historical and monumental value as elements of user interest in urban architecture.The results of the interdisciplinary Urban Health Path project presented in this article are an extension of research on optimal forms of activation of the elderly following an innovative approach. This article presents the concept of motor and cognitive activation of the elderly (space therapy) and the results of a test of a prototype solution as a result of a user-centred design approach. At the same time, the purpose of this article is to identify opportunities and limitations for the implementation of such solutions in other urban spaces. As part of the implemented project, a senior health path was created, located in the urban space of Gliwice  and linked to a mobile application. The research used a behavioural model of the therapeutic effects of the components of the space . The maiAn important aspect of this project was the introduction of tasks that strengthen the sense of urban identity by attracting residents and visitors interested in the history and architecture of a city, providing opportunities for the group to learn about the values of urban space. In this way, the developed health path not only contributes to physical fitness , but also supports cognitive abilities. This may have a supporting role in the prevention of dementia-related diseases. In addition, outdoor exercise increases the body\u2019s resistance to various infections and also reduces stress levels, which, among other things, lead to better sleep quality.The idea for the project originated from the Active Recovery Foundation in Wroc\u0142aw, which works for the benefit of oncology patients and promotes a holistic approach to therapy. The project is being carried out by supervisors and students of the Faculty of Automatic Control, Electronics, and Computer Science, the Faculty of Architecture, and the Faculty of Biomedical Engineering of the Silesian University of Technology, supported by external experts in the field of rehabilitation, space therapy, and universal design. The groups of seniors  were also engaged in the testing stage of the project.Developing an optimal urban health path programme requires the use of interdisciplinary knowledge from architecture, computer science, physiotherapy, and space therapy;The needs of the elderly as key guidelines in the design process\u2014the use of a person-centred design perspective and enabling the inclusion of various perspectives and user preferences (Design Thinking method);Architecture of historical buildings as an impulse for physical exercise and the intellectual activation of the elderly\u2014public space has morphological, functional, and formal characteristics that can be used as an impulse for physical activity; targeted walks in the historic part of the city combined with activation of the senses, appropriately selected movements, and educational form can contribute to improving health, well-being and, consequently, the quality of life of many user groups:IT tools as an extension of urban functions: it is possible to use mobile tools to provide new urban facilities, introducing innovative forms of engaging the users of public space to experience the city.At the initial stage of the work, the following substantive assumptions were made:(a)Analysis of the potential of the urban space of Gliwice as an example of a historic city in terms of its use for movement activation; determination of the functionality and features of the urban space and elements of small architecture that may serve movement recreation;Definition of guidelines for the implementation of the urban health path in urban space.In terms of spatial issues,(b)Analysis methods of presenting information on smartphone screens adapted to the preferences and possibilities of older people;Exploring the use of wearable devices to monitor the physical activity of app users.In terms of technological issues,(c)Developing a set of exercises and activation tasks, taking into account spatial conditions, the capabilities of the target group, their potential, and limitations.Regarding rehabilitation issues,The project has identified the following research objectives:Definition of hypotheses and their verification during casual interviews: use by seniors, forms of their leisure activities, attitudes toward physical activity, and literature analysis (desk research);Stage 1: Empathising\u2014research into users\u2019 needsGenerating problem statements based on desk research and free interviews to determine the assumptions in the following areas: forms of use of recreational space by seniors, recreational and health needs, specifics of the design of digital tools for seniors;Stage 2: Problem definitionUrban analysis of the urban space of Gliwice and determination of the route;Defining the functionality of the application and the algorithm for its use, defining the method for monitoring user activity while working with the application, personalising the settings, and defining the statistics collected;Summarising the information collected from the users using the value proposition matrix  and generating solutions;Development of application content (exercises and tasks);In situ research on the selected route and key architectural objects;Group brainstorming;Stage 3: Ideation and exploration of solutionsDevelopment of a prototype mobile application, recording of the content of exercises and tasks, and a preliminary concept for the visual identity of the health pathway;Stage 4: PrototypingVerification of the developed application and the route of the path with groups of seniors using a test sheet  and use of an application evaluation survey;Stage 5: TestingSummarising the results of testing, grouping errors, and shortcomings that can be solved immediately after testing, and indicating the necessary changes to be implemented in the long term.Stage 6: Implementation planningThe project was carried out in four phases: the objective of the first phase was to develop a prototype solution and conduct tests with a Gliwice seniors group, and in the remaining three phases, the objective was to extend the solution with variant paths, develop a visual identity concept, and extend the application with functionality that allowed the monitoring of user physical activity using mobile devices. The entire process of developing the solution was an iterative process, using both expert knowledge and lessons learnt from the prototype solution testing phases. The methodology adopted is shown in (a)n = 9 women, January 2022). The test was carried out stationarily on the presentation of the project assumptions and during the use of the prototype version of the app;Phase 1: presentation of the first prototype solution containing the first two routes\u2014Gliwice Market Square and Gliwice City Centre, testing the functionality of the application; the tests included the selection of the locations of exercise points, the concept of movement and breathing exercises and the city game, the length of the routes, the manner of the presentation of content in the application concerning the history of architecture, composition of elevation, detail, and determination of user preferences ((b)n = 7 women, April 2022);Phase 2: field testing of the new variant\u2014Gliwice City Centre; testing its route in terms of urban functions  and selection of exercises, including relaxation exercises ((c)n = 8 women, May 2022);Phase 3: desktop testing of the enhanced application functionality; testing in terms of the graphic interface of the application , map functionality, and presentation of exercises for individual points ((d)n = 11 women, July 2022).Phase 4: field test of the visual identification system in conjunction with the application; test of the locations of the components in the urban space and their legibility and a field test of the application\u2019s use  with good physical fitness participating in the activities of partner NGOs  were involved in the subsequent four phases of testing the Health Path. The following issues were evaluated:The paths were developed on the basis of urban planning analyses and spatial valorisation of the city centre. First, well-known architectural objects and city squares were selected as potential exercise points . The selThe path components analysed in the individual test phases, in accordance with the adopted iterative process, resulted from the adopted objectives and the results of the subsequent test phases. In the first phase, the general features of the solution  were tested. Meanwhile, the indicators in the subsequent phases resulted from the indications of the seniors who participated in the tests. They were segregated into two groups: elements that could be directly implemented in the project and elements that would guide future project development. Although the route was defined along accessible and safe pedestrian routes, the first testing phase showed that the route needed to be modified: the test participants emphasised that they found it problematic to perform the exercises in public spaces . This was related to the feeling of being uncomfortable and being watched in places where this type of exercise had not been done before. During the tests, the following opinions were formulated: \u201cI cannot imagine exercising in the Market Square\u201d, \u201cexercises should be performed in more intimate places \u201d, and \u201curban space for exercise can be, but not necessarily the strict city centre, e.g., Chopin Park\u201d. During the second phase, the senior women indicated that they were interested in performing the exercises together with the group and that the route path should be designed as a walking route . They were very keen to perform the exercises in spaces with less pedestrian traffic , and easy and intuitive use. The testing phases of the app, listed in The testing involved people who use smartphones daily, so their observations related to their previous experience with apps. Taking into account the requirements of senior apps , it was decided to simplify the use of the app in terms of personalising the interface to the user\u2019s needs (changing font size and colour theme). Instead of changing the colours of individual elements, seniors only had to make a single selection of the colour theme describing all the colours of the application\u2019s interface . In addiNumber of calories burnt;Heart rate;Distance covered;Number of steps.Work on the implementation of the sensory data measurement system began with the creation of a \u201cwearable\u201d application for the watch under test , acquiring data from the built-in sensors. Owing to difficulties with the use of Samsung Health\u2019s proprietary SDK, manual data extraction was performed by creating a watch-based exercise linked to the health tracking, monitoring the following selected parameters:Then, an information channel was established to transmit the measurement results to the mobile application for further processing and transmission to the database. As previously agreed, a low-level communication system was developed using the Bluetooth standard for correct recipient identification and data transfer. At this stage of the work, the application could be launched in two ways, automatically and manually. Automatic launch occurred on any watch paired with a phone using Bluetooth technology at the beginning of a track. While the application was running, the user could use a single button to start and stop the transmission of information to the mobile application.In line with previous assumptions, the specifics of the age group were taken into account during the stage of developing the physical exercises, including the fitness, capabilities, and limitations of the elderly. Possible dysfunctions of the musculoskeletal system, as well as the safety of the user group, were also taken into account in the development of the kinesitherapy parameters. The aim of the prepared set of exercises was to stimulate various systems, especially the respiratory system and proprioception . Improving the efficiency of the respiratory system leads to better oxygenation of, among other things, the muscles and the brain, which is crucial in older people. Improved blood flow in blood vessels, in turn, supports heart function. Due to the broad target group and the varying levels of fitness, individual exercises were differentiated in terms of execution difficulty. The emphasis of training was on mixed cardio-respiratory training. The selected exercises that were performed in the project were prepared on the basis of the most frequently reported back, lower, and upper limb pains of patients in the rehabilitation clinic. They served to improve health and injury prevention. At the same time, the exercises were inspired by the shapes of architectural elements and reflected the kinaesthetics of the spaces encountered, making them innovative and unprecedented in the hitherto implemented movement therapies. The exercises were neither difficult nor very complicated and could be performed without special equipment or prior preparation. They have a positive effect on prolonging the period of independence and are one factor in the prevention of falls. In this way, seniors can enjoy a longer life and avoid one of the most common causes of fractures. It is important to maintain or improve muscle function in the upper and lower extremities, as this is associated with improved performance in activities such as walking quickly, climbing stairs, and standing with balance.The implementation of research in the field of analysing the ways in which urban space can be used for its health-promoting potential and modern IT technologies can be used for piloting and monitoring project participants has provided knowledge on the implementation of innovative solutions to improve the psychophysical condition of older people. The innovative solution in the form of the Urban Health Path is an example of the possibility of developing digital urban services for recreation and active leisure for older people while, at the same time, activating urban spaces . The physical and cognitive activation of older people was carried out through developed exercise sets using details and elements of urban architecture as a stimulus for exercise.The iterative process adopted resulted in a solution that took into account the needs and preferences of seniors in terms of the forms of activity, the specificity of physical exercises, and the adaptation of the mobile app to the perceptual capabilities of seniors. The scope of the tests was defined in accordance with the project\u2019s objectives and is described in The selection of building elements and architectural details as exercise impulses were guided by their expressiveness and the shape that could be mimicked during the exercise. Examples of exercise sets are included in The implementation of this project, including the testing phases with seniors, allowed the development of guidelines to replicate the solution in the spaces of other cities, which is one of the most important scientific results of this project. Guidelines for spatial solutions can be divided into three groups of issues:A1. Diversity of types of exercise and intensity as one of the basic factors determining the flexibility of the solution.Route variants in terms of distance;Close proximity of individual exercise points, free choice of the number of exercise points on the route;Zoning of the route in terms of exercise intensity: exercise sequences should be more intensive in urban green areas and less demanding and visible in public spaces (pedestrian traffic areas);Selection of interesting architectural details\u2014selection of breathing exercises (relaxation) as an element of mindfulness enhancement.A2. Clear delineation of exercise areas.Use of characteristic details, sculptures, etc.;Integrating the names of the exercise points with characteristic and recognisable elements of the space;Introduction of permanent elements of the spatial identification of the path to mark the route and exercise points in space: introduction of small architectural elements; their form and colouring should be integral to the project\u2019s logo.A3. Accessibility of urban space in terms of pedestrian routes.Even and slip-resistant surfaces for pavements and squares;Reduction in collisions of pedestrian routes with traffic by means of tactile elements, colours, or changes in paving;Selection of conflict-free exercise areas \u2014recesses, pavement widenings, and sections of city squares outside the main pedestrian flow routes;Use of existing rest areas .Furthermore, the guidelines developed take into account urban architectural features that motivate movement and active exploration of space, directing the user to be attentive in observing their surroundings.B1. Information on the morphology of an object contained within its description: form, composition, and detail, and learning and understanding basic architectural concepts, such as mental training.B2. Elements of buildings and architectural details of buildings that can be integrated with movement  and integration of movement with the shape and rhythm of architectural elements of buildings.B3. The complexity of historic buildings and features of buildings to exercise concentration and imagination, e.g., recreating memorised details in the imagination, imaginatively reducing and filling in window shapes, and following the complex line of cornices with the eye.B4. Elements of urban spaces and details of buildings stimulating particular senses, such as touch , hearing  and the sound of the clock on the town hall tower), sight , and smell .Guidelines for IT solutions for seniors should be consistent with the WCAG guidelines in terms of perceivability, functionality, comprehensibility, and compliance. The guidelines can be divided into:Buttons allowing unobstructed operation by seniors and large spacing between buttons;Large and legible font  and contrast with the background;Contrasting colours;Limited animations on the interface (to reduce distractions);Simplified input method (reducing the need to type text);Interaction with the application at the level of easily identifiable interface elements ;Introduction of interface customisation possibilities.(1) Requirements for the user interface in the application\u2014in particular, the following:Slower, subdued app mechanics;Limited number of stimuli and amount of information flowing from the application;Providing only the necessary functionalities;Limited information on application errors;Frequent positive feedback;Use of \u201csoft delete\u201d\u2014any significant change can be undone;Introduction of automated operations (reduction in the number of decisions and actions performed by seniors).(2) Application performance requirements, in particular:Simple, easily understandable mechanics and rules of the application;The iconography of the application should refer to the daily life of seniors;The behaviour of the application should be compatible with the tools used by seniors;Provision of help describing how to use the application.(3) Requirements to make the application environment and its rules easy to understand, in particular:Proposition of engaging physical exercises involving kinaesthetic elements  and sensory elements , which are important for improving older people\u2019s overall motor coordination and triggering the activation of the conscious perception of the environment, which is meaningful for their short-term memory and as an exercise in focussing attention;Selection of relaxing exercises involving perception and attentiveness in observing the environment \u2014a significant element in preventing dementia and engaging the attention of seniors and their short-term memory;Use of the mobile app as a motivational tool, presenting feedback in-app \u2014this serves as motivation for regular physical activity\u2014and obtaining data on basic health parameters to evaluate overall health; moreover, this could be the element of improving digital competences of seniors;Strengthening the sense of local identity, attempting to improve interest in the history and architecture of the city, and learning together as a group impulse\u2014social activities in a group of seniors strengthen ties significantly and potentially improve quality of life. In addition, the project could be used as a tool for the Centre for Local Activities in special forms of activities for the group of seniors.The implementation of the project demonstrated the potential for the innovative use of architecture as a space for physical exercise and engaging the perception of older people. The concept of a healing environment, which makes use of selected architectural features of therapeutic importance , is mostly associated with intentional design activities that shape the optimal features of the physical environment and the environment\u2013occupant\u2013health (E-O-H) model . FurtherThese solutions add a new dimension to the impact of space on users, introducing the concept of urban therapy with its many potential health-promoting and activating factors. According to the assumption, the presented solution is the result of combining knowledge from several areas. The selection of architectural objects and the route required knowledge of architectural history, universal design, rehabilitation, and environmental psychology. Buildings that are well known to the local community, with distinctive architectural fa\u00e7ade elements, and that are landmarks along the route were chosen as training points. This was also important to strengthen the sense of local identity through the introduction of new activities  combined with a conscious perception of urban architecture. Of particular interest to senior test takers was the developed urban game, which encouraged walking and learning about the history of the city. It should be noted that, at individual points along the route, the seniors paid attention to the architectural values of the selected buildings, their details, and the atmosphere of the place. A place of particular interest and discussion was the ruins of the old theatre on Friendship Avenue, whose history was less well known to residents. At the same time, the selection of points was dictated by local conditions  and features allowing for safe and comfortable exercise . Photographs of objects or details were, at the same time, the icon of the exercise point in the app, to make it easier to calibrate the points in the city\u2019s structure. An important cognitive aspect in the presentation of the exercises was the explanation of concepts such as rustication, pilaster, and plinth as part of the basic information about the object, and the subsequent use of this architectural element in the exercises.An important outcome of the project was that the test seniors confirmed the attractiveness of the tested solution, i.e., the linking of the path elements with the mobile application. Other studies have also shown that it is possible to increase motivation for physical activity among seniors ,63,64. TA study by Kabisch, Puffel et al.  showed tFunctionality testing of the mobile app with groups of seniors also found that testers expected to be able to operate the app using gestures instead of buttons (contrary to the literature on the subject). However, this confirmed the principle that senior citizens are not a homogeneous group with the same preferences; they were used to operating mobiles with gestures due to their experience with phones. The small size of the test group and the specificity of the group  do not allow the results to be generalised to a larger population of senior citizens. However, to test this observation, the possibility of changing font size using a slider was added to the design of the application.In the tests carried out, due to the specific nature of the participants in the activities of the partner NGOs (their activities involve a great majority of women), only older women participated, which is a limitation in obtaining an objective test result. The project did not test users\u2019 perception of the visibility of individual architectural elements, but the selection of individual elements was guided by their large scale and expressiveness .The mobile application itself did not allow for a detailed analysis of the impact of the health path on the physical condition of the elderly, and thus made it challenging to identify potential problems with the path; for example, exercise can be too strenuous for the elderly. Due to the specific nature of the participants in the activities of the partner NGOs (their activities include an overwhelming majority of women), only older women took part in the research, which is a limitation in obtaining an objective research result.This project did not examine users\u2019 perceptions of the visibility of individual architectural elements; instead, the selection of individual elements was guided by their large scale and expressiveness .Testing the effectiveness of the spatial and IT guidelines in the example of other cities and testing the solution with a representative group of seniors are priorities for future research One of the directions of future research is to improve data collection for a better assessment of the behaviour of seniors . We could also introduce surveys to mobile applications to profile users in more detail . Furthermore, future work could define the spatial factors driving physical activity and interest in local spatial values in culturally diverse local communities.An important aspect of further research is the possibility of personalising the exercise programme and the application interface to the needs and preferences of seniors. An outline research programme could include the testing of new exercise sets, grouped according to difficulty and typical locomotor disorders. In addition, given the results of the research, the level of intensity of the exercises should be chosen in terms of the visibility of the exercises to passers-by to increase users\u2019 comfort.From the point of view of the importance of the project to strengthen local ties and the concept of becoming a resident, a possible research direction is the analysis of cultural and spatial factors that determine the acceptance of physical activity by older people in public spaces.In this article, we present a concept for the motor and cognitive activation of older people in the context of walks in urban spaces. The solution developed in the form of an Urban Health Path is based on the potential of Gliwice\u2019s historic buildings and the authors\u2019 method of urban therapy. Analyses of the architectural features of buildings and street furniture, as well as the testing phase with senior citizens, have led to the development of guidelines for the application of this solution to other cities in terms of spatial and IT conditions. The Urban Health Path is mapped in urban spaces and integrated into mobile applications. First, it aimed to increase the attractiveness and accessibility of the solution. It had the functionality of presenting the content of exercise and architectural history and of monitoring physical activity in the application. The solution is important for increasing physical activity among the elderly and strengthening local identity by spending leisure time together in attractive urban spaces. The project demonstrates the new potential of urban spaces and the tests carried out show that it could also increase the attractiveness of physical activity for seniors. The project has a number of possible directions for further research, primarily into the effectiveness of the method in increasing physical activity, the personalisation of the tool, and the cultural determinants of physical activity in urban public spaces."}
+{"text": "Following publication, concerns were raised regarding the integrity of the images in the published figures. The authors failed to provide a satisfactory explanation during the investigation, which was conducted in accordance with Frontiers' policies.The retraction was approved by the Chief Editors of Frontiers in Cellular Neuroscience and the Chief Executive of Frontiers. The authors did not agree to the retraction."}
+{"text": "RSC Advances is publishing this expression of concern in order to alert our readers that we are presently unable to confirm the reliability of the data presented in the article.The Royal Society of Chemistry became aware of concerns about the reliability of the data presented in Fig. 8 and 12 of the paper.The Royal Society of Chemistry has asked the affiliated institution, Wenzhou Medical University, to investigate this matter and confirm the integrity and reliability of the data in Fig. 8 and 12 of the paper. An expression of concern will continue to be associated with this manuscript until we receive information from the institution on this matter.\u2003Laura Fisher24th August 2023RSC AdvancesExecutive Editor,"}
+{"text": "Following publication, concerns were raised regarding the integrity of the images in the published figures. The authors failed to provide the raw data or a satisfactory explanation during the investigation, which was conducted in accordance with Frontiers\u2019 policies. Given the concerns about the validity of the data, and the lack of raw data, the editors no longer have confidence in the findings presented in the article.This retraction was approved by the Chief Editors of Frontiers in Pharmacology and the Chief Executive Editor of Frontiers. The authors agree to this retraction."}
+{"text": "The comorbidity of mental and physical disorders is gradually becoming recognized as a major problem for health care. Its public health importance is vast and growing for a variety of reasons including the extension of life expectancy, the imperfection of currently available treatments of mental and many physical disorders and the tendency of fragmentation of medicine into ever more limited specialties. The problems related to comorbidity are also rapidly increasing in low- and middle-income countries where in addition to the issues mentioned above there is also a scarcity of means to deal with them.The presentation will remind the audience of the complexity of the problems and draw attention to action that could be taken by public health authorities and the medical profession in the areas of teaching, organization of service and research.None Declared"}
+{"text": "There are errors in the Funding section. The correct Funding statement is: This study was funded by the Spanish Program of Research across the Ministry of Science and Innovation of the Spanish Government (MICYN) with the code PDC2021-121269-100. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."}
+{"text": "The economic burden of pediatric asthma is substantial, with national annual health care costs of $3 billion. Successful clinical management of asthma in children has the potential to decrease this burden by lowering the disproportionate costs of hospitalization and acute care for pediatric asthma patients.Based on increased understanding of the pathogenesis of asthma, revised guidelines were published by the National Institutes of Health in 1997 (with an update in 2002) and by the American Academy of Allergy, Asthma, and Immunology in 1999 to assist in the diagnosis and management of pediatric asthma. These guidelines emphasize the role of inflammation in asthma and recommend treatment of the underlying inflammatory process. Despite increased knowledge regarding the pathogenesis of the disease and the availability of effective anti-inflammatory agents, particularly inhaled corticosteroids, the prevalence of asthma and disease-related morbidity continues to remain high in children.Asthma interventions that include the use of guideline-recommended inhaled corticosteroid therapy and patient and caregiver education in asthma management may help to reduce asthma morbidity in children and decrease the substantial costs of pediatric asthma."}
+{"text": "The topic of apathetic depression remains insufficiently studied to date. This is due to the lack of unity of views on the definition of apathy and discrepancies in the definition of it\u2019s phenomenological boundaries.The study of the psychopathological features of endogenous apathetic depression, the development of a typology of apathetic depression based on differences in the structure of apathetic phenomena.The study included 70 patients  suffering from endogenous apathetic depression in the framework of affective diseases \u2013 recurrent depressive and bipolar affective disorder (25 cases) and schizophrenia (45 cases). Clinical-psychopathological and clinical-catamnestic methods were used.Apathy in depressions differs in the disproportion of the representation of individual components of the apathetic syndrome. Based on the revealed differences, typological varieties of endogenous apathetic depressions were identified: with a predominance of a decrease in interests ; with a predominance of a decreased initiative ; with a predominance of a motivational decrease . Last group, based on the degree of complicity of the adynamic component, was divided into apatheticadynamic and simple apathetic subtypes. Depression dominated by a decrease in interests was characterized by the predominance of the emotional component in the structure of apathy, consumatory anhedonia, but without loss of the ability to be involved in activities and volitional impairment. Depressions with a predominance of decreased initiative are characterized by the leading role of the cognitive component of apathy with the inability of patients to occupy themselves independently, with minimal severity of anhedonia and the formation of moral hypochondria phenomena. Depressions with a predominance of motivational decline are characterized by the dominance of the behavioral component of apathy with the loss of stimuli and motives for activity, anticipatory anhedonia, volitional deficit, with the inability to engage in any activities.Apathetic disorders formed within the framework of endogenous depressions are characterized by heterogeneity, which is associated with an uneven representation of declining interests, the ability to show initiative and the motivational component of apathy.None Declared"}
+{"text": "In the published article, there was an error in the Funding statement in that the funding information was not added to the manuscript. The correct Funding statement appears below.This study was supported by the National Natural Science Foundation of China (No. U20A2056) and the Key Research and Development Program of Sichuan Province (2020YFN0147).The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "This Special Issue, titled \u201cResearch and Development of Building Materials Based on Industrial Waste\u201d, is focused on the preparation and description of the properties of new building materials based on industrial waste that are to be used in practice in civil engineering and engineering construction. Recycling and the recovery of by-products and waste facilitate the conservation of primary raw materials and energy resources, mitigate the depletion of natural resources and contribute to the protection of the environment, which is threatened by the accumulation of waste, high dust concentrations, the contamination of watercourses and the appropriation of land.3N4) and silicon powder (Si) in the production of briquettes with defined properties [This Special Issue presents original research results in the following areas: the use of solar panels after the end of their life cycles in the production of cement composites ; the radoperties ; the utioperties ; the mecoperties ; the useoperties ; a new moperties ; strengtoperties ; researcoperties ; and, fioperties ."}
+{"text": "The journal retracts the article cited above.Following publication, the publisher has found evidence of peer review manipulation. As the scientific integrity of the article cannot be guaranteed, and adhering to the recommendations of the Committee on Publication Ethics (COPE), the publisher therefore retracts the article.This retraction was approved by the Chief Editors of Frontiers in Public Health and the Chief Executive Editor of Frontiers."}
+{"text": "The journal and Chief Editors retract the 10 July 2019 article cited above.Following publication, concerns were raised regarding the integrity of some of the images in the article. After a corrigendum was published, additional concerns were identified, and a further investigation was conducted in line with Frontiers\u2019 policies. The images were determined to have been manipulated, and the authors were unable to provide the raw data for the images in question. As a result, the data and conclusions of the article have been deemed unreliable and the article is therefore retracted.The retraction of the article was approved by the Chief Editor of Frontiers in Chemistry and the Chief Executive Editor of Frontiers. The authors did not respond to the retraction."}
+{"text": "The Publisher retracts the cited article.Following publication, the publisher has discovered that the authors provided false information for the peer-review process. As the scientific integrity of the article cannot be guaranteed, and adhering to the recommendations of the Committee on Publication Ethics (COPE), the publisher therefore retracts the article.The authors have not responded to this retraction.This retraction was approved by the Chief Editors of Frontiers in Oncology and the Chief Executive Editor of Frontiers."}
+{"text": "The journal retracts the article \u201cValidation of the CHA2DS2-VA Score  in Nonvalvular Atrial Fibrillation Patients: A Nationwide Population-Based Study\u201d . Following publication, methodological and data interpretation concerns were brought to the attention of the Editorial Office.Adhering to our complaints procedure, an investigation was conducted by the Editorial Office and Editorial Board that confirmed the presence of a number of significant issues with the methods used and the analysis of the data and concluded that the overall findings of this study  could noJournal of Clinical Medicine. This retraction was approved by the Editor in Chief of the The authors agreed to this retraction."}
+{"text": "In this edition of the European Public Health News, the EUPHA office column puts the spotlight on EUPHA\u2019s sections. These thematic networks are an important element of the EUPHA organization. The contribution of WHO Regional Office for Europe focuses on environmental determinants. The health sector has a vital role to play in what lies ahead. It can address environmental challenges and must proactively lead in the search for solutions. Finally, Staines and Barnhoorn of the European Public Health Conference invite you to the 2023 conference in Dublin and provide a first glimpse of the plenary programme."}
+{"text": "The journal retracts the 2021 article cited above.Following publication, concerns were raised regarding the contributions of the authors of the article. Our investigation, conducted in accordance with Frontiers policies, confirmed a serious breach of our authorship policies and of publication ethics; the article is therefore retracted.This retraction was approved by the Chief Editors of Frontiers in Cell and Developmental Biology and the Chief Executive Editor of Frontiers. The authors do not agree to this retraction."}
+{"text": "With the introduction of the concept of mesopancreas defining the perineural structures that includes neurovascular bundle and lymph nodes extending from the posterior surface of the pancreatic head to behind the mesenteric vessels,Total Mesopancreas Excision (TMpE) based on this theory has facilitated the development of pancreatic cancer surgery in clinical practice in recent years. However, the existence of so called mesopancreas in the human body is still in debate and the comparative study of mesopancreas of rhesus monkey and human have not been well investigated.The aim of our study is to compare the pancreatic vessels and fascia of human and rhesus monkeys in anatomical and embryological perspectives and to support the utilization of rhesus monkey as animal model.In this study, 20 rhesus monkey cadavers were dissected and their mesopancreas location, relationships and arterial distribution were analyzed. We compared the location and developmental patterns of mesopancreas in macaques and humans.The results showed that the distribution of pancreatic arteries in rhesus monkeys was the same as that in humans, which is consistent with phylogenetic similarities. However, the morphological features of the mesopancreas and greater omentum is anatomically different from that of humans, including (1) the greater omentum is not connected to the transverse colon in monkeys. (2) The presence of the dorsal mesopancreas of the rhesus monkey suggests that it be an intraperitoneal organ. Comparative anatomical studies of mesopancreas and arteries in macaques and humans showed characteristic patterns of mesopancreas and similarities in pancreatic artery development in nonhuman primates, consistent with phylogenetic differentiation. PancIn recent years, with the introduction of the concept of \u201cmesopancreas\u201d, defining the perineural structures that includes neurovascular bundle and lymph nodes extending from the posterior surface of the pancreatic head to behind the mesenteric vessels, there has been a great evolution in the way of pancreatic resection , 6. AccoThe aim of our study is to compare the pancreatic vessels and fascia of human and rhesus monkeys and to provide the basis for the utilization of rhesus monkeys from anatomical and embryological perspectives. A comprehensive understanding of the features of the peripancreatic peritoneum in terms of gross observation and embryology, and the elucidation of the relationship with surrounding organs, blood vessels and nerves are of great importance for the improvement of surgical standards for TMpE based on the theory of mesopancreas, improving the R0 resection rate of malignant tumors and ensuring surgical outcomes.2.2.1.n\u2009=\u200920) were purchased from Hengshu Bio-technology  for this study. This study was approved by the Committee on Animal Researchand the ethics committee of the Sichuan University .Rhesus monkeys Cadavers  based on this theory has facilitated the development of pancreatic cancer surgery in clinical practice \u201323. Yi eAt present, the understanding of mesenteric development in the embryonic period is too little, and the precise morphological changes and mechanism of the evolution are still unknown . In addi5.In summary, we found differences in the mesopancreas between humans and rhesus monkeys. According to our results, the morphological features of the mesopancreas and greater omentum is anatomically different from that of humans and macaques and the differences between the two developmental processes are also compared, which indicates the phylogenetic uniqueness. We did not find differences between monkey pancreatic vasculature and human, which indicates the phylogenetic similarity between human and rhesus monkeys. Future studies with larger samples are needed to understand the growth and developmental processes of mesopancreas and greater omentum."}
+{"text": "Journal of Managed Care & Specialty Pharmacy. To commemorate this milestone, we are publishing a series of articles that document the changes to the journal and profession over the past two and a half decades. Each month we are reprinting an original article from a previous year, dating back to 1995. The reprinted articles feature topics of significance in our industry. Each reprinted article is accompanied by a contemporary reflection that considers the historical significance of the topic, as well as the current and future state. This month\u2019s pairing has a special familial connection. The first author of the contemporary reflection is a master of pharmacy business administration candidate at the University of Pittsburgh and also the son of the author of the original article from 2000.The year 2020 marks the 25th anniversary of the"}
+{"text": "The journal retracts the 2021 article cited above.Following publication, concerns were raised regarding the contributions of the authors of the article. Our investigation, conducted in accordance with Frontiers policies, confirmed a serious breach of our authorship policies and of publication ethics; the article is therefore retracted.This retraction was approved by the Chief Editors of Frontiers in Medicine and the Chief Executive Editor of Frontiers. The authors do not agree to this retraction."}
+{"text": "Nature Genetics 10.1038/s41588-019-0564-y, published online 05 February 2020.Correction to: In the published version of this paper, the members of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium were listed in the Supplementary Information; however, these members should have been included in the main paper. The original Article has been corrected to include the members and affiliations of the PCAWG Consortium in the main paper; the corrections have been made to the HTML version of the Article but not the PDF version. Additional corrections to affiliations have been made to the PDF and HTML versions of the original Article for consistency of information between the PCAWG list and the main paper."}
+{"text": "Micromachines journal provides a platform for researchers to share their latest developments, ideas, and results in this field. This issue includes 12 papers that address various challenges and opportunities in the design, fabrication, and control of flexible micromanipulators. The papers in this Special Issue highlight the latest developments in the field and demonstrate the potential of flexible micromanipulators in addressing some of the most challenging problems in science and engineering.The field of micromanipulation is rapidly growing and evolving thanks to advancements in microfabrication technologies and the increased demand for precise and accurate manipulation of microscale objects. The Special Issue on \u201cFlexible Micromanipulators and Micromanipulation\u201d in the Kazemzadeh Heris et al.  present One of the key themes that emerges from the 12 papers is the importance of precise and accurate control in micromanipulation. Several papers present novel control algorithms that enable real-time feedback and adjustment of the micromanipulator\u2019s position, enabling highly precise manipulation of objects at the microscale. Developing new control algorithms and feedback systems is critical to the continued advancement of flexible micromanipulators and their applications.Another important theme that emerges from the papers in this Special Issue is the diversity of applications for flexible micromanipulators. While some papers focus on biological and medical applications, others explore using flexible micromanipulators in manufacturing, microengineering, and materials science. The ability to manipulate objects at the microscale has enormous potential for a wide range of applications, and the papers in this Special Issue demonstrate the versatility of flexible micromanipulators.Finally, the papers in this Special Issue also highlight the importance of collaboration between different fields of science and engineering. The development of flexible micromanipulators requires expertise in a range of areas, including materials science, control theory, and robotics. The papers demonstrate the value of collaboration between researchers in these different fields and the potential for interdisciplinary research to drive advances in micromanipulation.In conclusion, the papers in this Special Issue demonstrate the exciting developments in flexible micromanipulation and the potential of this technology to revolutionize a range of fields. The continued development of flexible micromanipulators and the exploration of new applications will require collaboration between researchers in various disciplines, and this Special Issue highlights the importance of this collaborative approach. We hope that this Special Issue will inspire further research and development in the field of flexible micromanipulation, and we look forward to seeing the future advances that will emerge from this exciting area of research."}
+{"text": "Cooperation plays an important role in the evolution of species and human societies. The understanding of the emergence and persistence of cooperation in those systems is a fascinating and fundamental question. Many mechanisms were extensively studied and proposed as supporting cooperation. The current work addresses the role of migration for the maintenance of cooperation in structured populations. This problem is investigated in an evolutionary perspective through the prisoner's dilemma game paradigm. It is found that migration and structure play an essential role in the evolution of the cooperative behavior. The possible outcomes of the model are extinction of the entire population, dominance of the cooperative strategy and coexistence between cooperators and defectors. The coexistence phase is obtained in the range of large migration rates. It is also verified the existence of a critical level of structuring beyond that cooperation is always likely. In resume, we conclude that the increase in the number of demes as well as in the migration rate favor the fixation of the cooperative behavior. The emergence of cooperation has puzzled philosophers and researchers since a long time ago. For instance, already in the seventeenth century Thomas Hobbes (1651) claimed that all people are egoists, they are primarily concerned with their own well-being, and act towards the defense of their own interests and properties The main legacy of Axelrod was to formalize the conflict and cooperation among selfish individuals in terms of the game theory approach, that has been demonstrated to be very appropriate to address this class of problem Later on, it was shown that the interplay between interaction rules and spatial structure can be an effective mean to promote cooperation Recently much attention has been paid to the role of mobility in different versions of the spatial prisoner's dilemma game. It is now recognized that migration can also be a very important mechanism influencing the fate of the cooperative behavior. Vainstein et al. studied the role of migration in systems with a fixed density of cooperators which are randomly placed in a two-dimensional square lattice Following the ideas of Vainstein et al. The current work inquires the role of migration in the onset and fixation of the cooperative behavior in subdivided populations. The study of the interplay between evolutionary mechanisms and the underlying topology where populations reside is an issue of great interest since a long time ago. The first steps in this direction was given by Kimura to study the problem of local differentiation on genes frequencies in a structured population model Likewise, our model assumes that the population comprises several smaller subpopulations (demes) which are randomly connected. These connections represent possible pathways where the individuals can move between neighbor demes. We study the prisoner's dilemma game in an evolutionary perspective. The evolutionary dynamics combines the game itself, adaptation and migration. As expected, migration plays an important role in driving the fate of the cooperative behavior. All the possible outcomes, namely, extinction of the population, dominance of the cooperative behavior and coexistence between cooperators and defectors, are found. The extent of these distinct regimes is greatly influenced by the migration rate and the level of structuring of the population (number of demes). In particular, it is found that an increased number of demes as well as an increased migration rate favor the fixation of the cooperation. However, in the regime of extremely large migration rates, where the coexistence between cooperators and defectors is assured, the level of cooperation diminishes as the exchange of migrants between the demes becomes more intense. Another important feature is the observation, in the range of low migration rates, of a critical level of structuring such that beyond that value cooperation can emerge.In the next Section we describe the model. In the following we present the simulation results and discussions. At the end of the manuscript we present our conclusions.The population consists of  (D) See . The indThe population evolves on time according to the following life cycle: prisoner's dilemma game, migration and selection. During the prisoner's dilemma stage, in each deme one randomly constitutes As already mentioned, the demes interact through migration. Every generation, each individual has a probability The simplest one corresponds to the situation where the size of the deme is exactly equal to The size of the deme is greater than The size of the deme is smaller than As the topology for the migratory network we consider the random graph by Erd\u00f6s and R\u00e9nyi which is entirely described by the single parameter During simulations we easily assess the concentrations of cooperators and defectors over time. Henceforth, the simulation data corresponds to the measurements carried out in the stationary regime, which by definition is characterized either by a fixed value of a given observable or when its value over time does not change within a given accuracy. The states In According to the above scenario, without migration the dynamics leads the populations to extinction. As migration rate rises, the deme that had become empty due to the dominance of defectors can be recolonized by cooperators. These few newcomer cooperators then experience an immediate expansion and can achieve dominance. If the migration rate is further increased then the individuals are migrating continuously, and because the time scale of the movement throughout the population is short, defectors are constantly exploiting cooperators in favorable environments, where cooperators are the majority. When the defectors thrive and expand in a given deme, some of these cheaters can move to a new group before extinction of the entire deme. At the same time cooperators are more likely to migrate into the deme, and complete extinction of the local population is improbable. This is the regime where coexistence takes place.In the upper left panel of In the lower panels we now address how the number of demes affects the results of the model. Now the population size is held constant, The qualitative results of the model are very robust and poorly sensitive to the topology of the migration networks. To corroborate this ascertainment, perators  right. ITo summarize the previous results cooperation is likely becomes no more constrained to populations with number of demes larger than pure cooperative regime, where the dominance of the cooperative behavior is deterministic. The width of the pure cooperative regime grows with cooperation is likely phase to the coexistence phase without passing through the intermediate pure cooperation regime for small enough As the migration rate is increased the extinction regime disappears and the regime where ugh  see .For sufficiently large values of This paper has investigated the conditions under which the cooperation is maintained in structured populations. The population comprises individuals that adopt pure strategies and have to decide to cooperate or to defect on every round of the prisoner's dilemma game. The problem is addressed in an evolutionary perspective, such that individuals which are most successful have a better chance of avoiding elimination and can contribute with more offspring. The main goal of the current work is to determine the importance of structuring in the evolutionary outcome and the required conditions for the sustaining of the cooperative behavior. The level of structuring is established by the number of subpopulations and the migration rate. When the number of demes is enlarged the population size within the demes becomes smaller, which increases the effects related to finiteness because reproduction is performed stochastically. The most strong evidence of the role of this stochastic force is the existence of a threshold for the number of demes beyond which there is a non-negligible chance of obtaining the fixation and dominance of the cooperative strategy even for extremely low values of migration. The importance of finiteness in the evolution of cooperation has already been demonstrated in the success rate of invasion of a single individual using the tit-for-tat strategy in a population of All-defect individuals Several recent investigations have addressed the role of mobility (migration) in spatially extended evolutionary games The detrimental effect of migration comes about in the range of large migration rates. Though elevated migration rates warrants the fixation of the cooperative strategy, it also enables the survival of defectors. Defectors survive by continuously exploring favorable subpopulations, which by turn are less prone to extinction because the high mobility of cooperators also enables them to more rapidly explore the demes which are facing degradation due to the growth of the local defector population. As"}
+{"text": "In the byline, the name of the third author is spelled incorrectly. The correct name is: Yubao Liu.In addition, a term was spelled incorrectly in the title of the third section of the Materials and Methods. The correct title of the third section is: \"Western blot analysis for Ki67\"."}
+{"text": "This study falls within the framework of enhancing the performance of the Health System in Cape Verde, through the continuous improvement of the quality of care in health facilities in the country. The data collected for this study will help define a national strategy for the development of quality care systems and quality management in health facilities in the perspective of optimal management of patients in health care settings.The main objective was to make an inventory of the organization and implementation of quality standards of care in health facilities, in the island of Santiago, including EmOC services.The standards that the level of implementation was evaluated in this study are 5. It is: Reception in EmOC services, The Hand Hygiene, Management of medical waste; disinfection of medical devices, Prevention of infection risk. The technique used for data collection in health facilities is that of Interview. It ran from a questionnaire prepared in advance and includes closed questions. Quality was judged by the average compliance levels in four levels .The study focused on three levels of the health pyramid.The average compliance rate were as follows: The existence of host device in health facilities was 78%, so satisfactory; the existence device of hand hygiene in health facilities was 71%, so satisfactory; the existence of device management bio-medical waste in health facilities was 74%, so satisfactory; the existence of devices for disinfecting medical equipment in health facilities was 95%, so satisfactory; Prevention of infectious risk in health facilities was 39%, so in the limit of unacceptable.None declared"}
+{"text": "Because of its role as provider of services for clinicians and their identification with the central tool for the production of the hospital, the technical platform that is the hospital laboratory and its equipment requires the development of quality assurance.Evaluate the quality of the metrological management of the technical elements with a view to continuous improvement of the services provided.It is a cross-sectional study and prospective descriptive type conducted over a period of three months in clinical biochemistry laboratories of three university hospitals in Abidjan. Performed using a plug-inventory survey of twelve open-ended questions, it focused on the environmental conditions and management of the technical platform. The performance of the laboratory was been assessed against the threshold target of 80% expected the quality standard used.Averages of 67% for environmental conditions and 42.77% for equipment and instruments were observed. Only 48.15% of the equipment and measuring instruments of the three laboratories are functional, with a better score for the CHU of Cocody. The laboratory of the University Hospital of Yopougon appears better informed on the equipment and measuring instruments (78%). Regular maintenance and the maintenance of the technical concerns only 13.33% of the equipment and measuring instruments which are less than 15% subject to a procedure known fault management operation related to.These results show notable deficiencies in the practice of primary metrological activities to guarantee the reliability of the final product laboratories, and therefore emphasize the need for development of a strategy to regulate the technical tools of analysis in the context of a quality assurance process.None declared."}
+{"text": "News of the completion of the new Wits School of Public Health (WSPH) building reminded me of the dream that so many of us had when the School was founded just over a decade ago. At the time I wrote: \u2018The year 2001 will be remembered as the year in which the Wits School of Public Health was established. This event marks a defining moment in the development of Public Health at Wits. The establishment of the school has over a short period of a few months brought a new dimension to the way in which we function. No longer can Public Health be regarded as the Cinderella of health sciences at Wits \u2026 the School has demonstrated its academic worthiness.\u2019 The new building serves to reinforce this notion. The establishment of the School did not happen without opposition from within the Faculty of Health Sciences and the university. Similarly, finding a building suitable for the rapidly expanding School of Public Health did not happen without a struggle. Initial efforts led to the university architects drawing up plans for a multi-story School of Public Health building near the entrance of the Medical School. However, the university did not see its way clear to supporting such an undertaking and the plans were shelved. Efforts to acquire premises on Oxford Road, which members of staff inspected and liked, were similarly not supported by the university. It is for this reason, amongst others, that it is such a tremendous privilege to see the new building finally a reality \u2013 indeed a dream come true.Public Health at Wits, as elsewhere, was not the stuff that medical faculties were made of in the 1990s. Two factors influenced the trajectory of the academic discipline of Public Health significantly. The first was the dramatic political change in South Africa which led to the establishment of a new democratic order with human rights, including the right to health and health care, enshrined in the country's constitution. The School played a significant role in shaping national health policy in South Africa. In 1994, two of the nine ministerial committees were chaired by staff in the School, and many other staff members served on a range of committees and advisory bodies that ultimately influenced government thinking and health policies in the democratic era. The second major event was the HIV and AIDS disaster, which had a devastating effect on mortality and morbidity in South Africa and brought enormous challenges to its health system. These external factors had an impact on the development of Public Health in significant ways. The new government had a large constituency to whose needs it had to respond to. As a result, it looked to Public Health to address the dire health problems faced by a large majority of South Africans, while the HIV epidemic exposed the worst failings of the South African Public Health system.Notwithstanding these imperatives, material support for academic Public Health was not forthcoming. It took a lot of nagging and some strong words to eventually gain seven additional academic posts from the Gauteng Health Department in 2002, bearing in mind that the WSPH only had about nine provincial Health Department funded posts at the time, some of which were \u2018frozen\u2019 during the implementation of financial austerity measures as part of the government's Growth Equity and Redistribution (GEAR) policy in the late 1990s.The emergence of Public Health at Wits also benefited from the readmission of South Africa to the world community, leading to exposure to many academics prominent in international Public Health. The school benefited from a regular stream of international visitors from other parts of Africa, Latin America, Asia, the United States of America and the United Kingdom. In South Africa, the 1990s saw several initiatives to start regional schools of Public Health. Wits University was part of the five-university initiative, called the Transvaal School of Public Health , which aimed to strengthen the discipline of Public Health in the northern regions of South Africa. All in the Faculty did not support the TSPH as some felt that trans-university courses and programmes would compromise Wits\u2019 academic standards. These barriers had to be overcome and eventually an agreement at the level of the university Vice-Chancellors formalised the TSPH.Following the World Development Report 1993, which argued the economic case for investing in health, there was a growing realisation that the global burden of diseases like malaria, HIV & AIDS and tuberculosis had a negative impact on the world economy. As a result, the world's rich nations established the Global Fund that supported the response to these three killer diseases. This gave added impetus to a worldwide resurgence of Public Health and provided much needed resources for Public Health research in South Africa.In keeping with its commitment to strengthen South Africa's Public Health capacity, the WSPH initiated a Master of Public Health (MPH) programme and an MSc in Epidemiology in addition to the existing diploma courses, despite the enormous strain put on the limited teaching resources. This resulted in student numbers growing exponentially.Meanwhile, the rural health initiatives started by John Gear, flourished. The Wits Rural Facility underwent a new incarnation; the Health Services (later Systems) Development Unit thrived, and spawned the Agincourt Project, which has since become one of the leading demographic and health surveillance sites in the world. Agincourt, in turn, gave birth to the Rural AIDS and Development Action Research programme (RADAR).The Centre for Health Policy (CHP) excelled in the new post-apartheid environment and provided policy support for many government initiatives. It grew in size and the Women's Health Project, which it housed, became a leader in the struggle for gender equality in health care. This went on to have an enormous influence in shaping South Africa's new abortion legislation.Urban Health was not to be left out as the School, as part of the WHO Collaborating Centre for Urban Health, continued to work in inner city areas such as Hillbrow and the Alexandra Township to the north of Johannesburg city centre. The emergence of Urban Health as a major field of endeavour internationally, led to the publication of the Urban Health Bulletin, the Healthy Cities movement and an increasing international collaboration of the School with partners in Europe, Africa, Latin America and South East Asia.The novel addition of the Division of Oral Public Health enriched the academic endeavour of the WSPH, bringing much needed attention to the field of health promotion.As I reflect on the Wits School in the 1990s, I am struck by the confluence of events, internationally and nationally, which provided a window of opportunity for Public Health to play a significant role in the improvement of the human condition. I have no doubt that the new School of Public Health building will stand as a beacon of hope for the improvement of population health, especially for the marginalised, dispossessed, oppressed and disempowered, in South Africa and beyond."}
+{"text": "Integration and collaboration has been an important strategy for development of the health and welfare system in Sweden since the 1960s. This development has been intensified during the 1990s and the first decade of the 2000s. This key note speech will focus on the development of interorganizational collaboration between health care, social service and other welfare services on the local level of the Swedish society. There will be examples from care of the elderly, social psychiatric care and vocational rehabilitation. Different organizational models will be presented and experiences of barriers as well as facilitating factors will be discussed."}
+{"text": "The editors and the authors retract this publication following the authors' request.Following the publication of this article, the following concerns were raised in relation to this work:- The original data for the study as well as Figures A1-A3 and Figure 2 originate from the laboratory of Wuhan Xiao Institute of Hydrobiology, Chinese Academy of Sciences, and were in part conducted by a researcher in that laboratory who was not listed on the authorship byline of the paper. The data in these figures were published without the permission or knowledge of Dr Xiao and of the researcher who conducted the research underlying those figures.- In addition to the funding source stated on the published article, which corresponds to a grant assigned to Dr. Jing-Xia Liu and held by Ministry of Science and Technology of the People\u2019s Republic of China and Chinese Academy of Science, grants assigned to Wuhan Xiao also supported this work: \"973\" grant 2010CB126306, NSFC grant 91019008, 31071212 and National Transgene Project 2009ZX08010-021B. The academic committee at Institute of Hydrobiology, Chinese Academy of Sciences has carried out an investigation into the work reported in the article and has agreed with the authors\u2019 request of retraction of the publication.The authors would like to apologize to the readers and Dr Xiao."}
+{"text": "During my much needed vacation in northern Iran, at the first leg of the journey, we stayed at a hotel complex in Mazandaran province and after a few days traveled to Golestan province and stayed at a hotel in Sari, the capital of the province. The hotel in Mazandaran was located in the forest and had a fabulous, breathtaking view and clean mountain air. The chirping of the birds on the trees was like music to our tired ears still filled with the noise of Tehran . The int We can relieve stress, chill-out, relax and enjoy our national countryside with family and friends and participate in our congress as well. The national societies of other countries change the location of their annual congresses every year . Althoug"}
+{"text": "There was an error in the Funding statement. The correct version of the statement is available below.The study was funded by the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA05050403) and the Scholarship Award for Excellent Doctoral Student granted by Ministry of Education. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."}
+{"text": "June 2011, a new comprehensive Electronic Hospital Information System (CS-EHIS) has been implemented at the University Medical Hospital of Utrecht. The use of this new system may lead to optimal integrated telehealth and telecare; to a new way of working for many employees and to many new challenges in care. Many users have been trained by colleagues (key users). Just before the implementation of CS-EHIS, a baseline measurement has been performed consisting of the completion of a large questionnaire by 100 key users and a small one by a group of about 1000 users. Six months after the baseline measurement a first follow-up questionnaire has been completed by these employees. Users and key users will be asked to complete a questionnaire each six months.The aim of the evaluation of CS-EZIS is to localize and solve possible bottlenecks quickly and to learn from problems examined for future implementations. Main questions of the study are: 1) did the implementation strategy come up to the expectations of professionals, 2) will behavior of professionals and patients change as a consequence of the introduction of CS-EHIS, and 3) will the use of care of patients change as a consequence of the introduction of CS-EHIS.At the baseline measurement experiences with the old EHIS were examined. The most important complaint of employees was that the system was too slow but overall it was not considered very negatively. The methods of the study, the theoretical model used to study the implementation and preliminary results of the first follow-up measurement will be presented.A comprehensive evaluation of the implementation of CS-EHIS may lead to a quick localization of bottlenecks."}
+{"text": "Day surgery should take place in appropriate organizational settings. In the presence of high volumes, the organizational models of the Lazio Region are represented by either Day Surgery Units within continuous-cycle hospitals or day-cycle Day Surgery Centers. This pilot study presents the regional volumes provided in 2010 and the additional volumes that could be provided based on the best performance criterion with a view to suggesting the setting up of a regional Freestanding Center of Pediatric Day Surgery.rd quartile present in at least a health-care facility and a volume exceeding 0.5% of the total patients of the pediatric surgery and urology facilities of the Lazio Region. The relevant data have been provided by the Public Health Agency and relate to 2010. The best performance FI has been used to calculate the theoretical volume of transferability of the remaining facilities into freestanding surgery centers. Patients under six months of age and DRGs common to other disciplines have been excluded. The Chi Square test has been used to compare the FI of the health-care facilities and the FI of the places of origin of the patients.This is an observational retrospective study. The activity volumes have been assessed by means of a DRG (Diagnosis Related Group)-specific indicator that measures the ratio of outpatients to the total number of treated patients . The included DRGs had an FI exceeding the 3The DRG provided in 2010 amounted to a total of 5768 belonging to 121 types of procedures. The application of the criteria of inclusion have led to the selection of seven final DRG categories of minor surgery amounting to 3522 cases. Out of this total number, there were 2828 outpatients and 694 inpatients. The recourse of the best performance determines a potential transfer of 497 cases. The total outpatient volume is 57%. The Chi Square test has pointed to a statistically significant difference of the facilities and to a non-significant difference of inferiority of the regional places of origin with respect to the city of Rome.The activity volumes would seem to support the setting up of a Freestanding Regional Center of Pediatric Day Surgery. This Center represents the healthcare facility that is most likely to allow a de-hospitalization process. Subsequent studies will be required to confirm the validity of this pilot study. The selection of both the type of admission, whether regular or in a day surgery unit, and the continuous-cycle or exclusively daytime facility represents a fundamental aspect in the organization of minor surgery for pediatric patients.The regular admission should be restricted to patients whose age and clinical conditions contraindicate the recourse to day surgery . The heaIntegrated Day Surgery Unit, located within a continuous cycle hospital facility devoted to day care. This type of facility may be likened to the model of the Hospital-based facility of the Anglo-Saxon countries , where, defined Ambulatory Surgery Centers (ASC) or Pediatric Outpatient Pediatric Surgery (POPS), they have increased to a considerable extent. Being these facilities autonomous with respect to hospitals, they are also defined as freestanding surgery centers ,7.The purpose of this study is to establish, having recourse to an activity indicator, the regional healthcare volumes provided through day surgery centers and the healthcare volumes provided though regular hospitalization that could be transferred to day surgery centers based on the healthcare facility best performance criterion. The indicator that has been devised  measures the outpatient/total patient ratio of the most frequent minor surgery DRGs (Diagnosis Related Groups) handled in 2010 by the pediatric surgery facilities in the Lazio Region.We believe that the resulting data are likely to prove useful to decision makers for planning subsequent economic and marketing studies, verifying the hypothesis that the setting up of a freestanding inter-hospital pediatric day surgery center may allow the de-hospitalization of most pediatric surgical activities.This preliminary observational cohort study has not required the opinion of the ethical committee nor any informed consent being a population study.The STROBE-Statement checklist  has beenOutpatients and inpatients of the individual DRGs have been evaluated based on the healthcare providers and the patients' places of origin. The healthcare facilities were the Operating Units (UO) of pediatric surgery and urology of the Lazio Region: Pediatric Hospital \"Bambin Ges\u00f9\" , \"San Camillo\" Hospital. (AOSCF), \"A. Gemelli\" General Hospital, \"Umberto I\" General Hospital. These facilities are located within the city of Rome, with the exception of a branch of the \"Bambin Ges\u00f9\" hospital which is located in the northern area of the Rome Province. The organizational models adopted by these facilities have been studied by means of separate surveys. The study has also taken into consideration the DRGs produced by non-specialized pediatric facilities. The places of origin that have been taken into consideration have been Rome and the Rome Province, Latina and the Latina Province, Frosinone and the Frosinone Province, Viterbo and the Viterbo Province, Rieti and the Rieti Province, as well as cities and Provinces outside the Lazio Region.A selection of the DRGs has been made having recourse to the FI, a DRG-specific indicator that measures the ratio of outpatients to the total number of treated patients. The numerator is represented by the patients discharged on the same day of treatment; the denominator is represented by the sum of all the treated patients of the DRG under consideration. Therefore, the denominator includes regular one-day admissions (one-day surgery) and admissions for 2 or more days. Assessing the level of elimination of regular hospital admissions and, therefore, of overnight stays, this index points to the percentage of services that may be theoretically provided by freestanding centers.rd quartile present in at least a providing facility, with volumes of outpatients exceeding 20% and a volume of cases exceeding the entire case study by 0.5%. The highest value of the indicator identifies the best performing facility. The criteria for exclusion were all the patients under six months of age and all the DRGs in common with other disciplines.The criteria for inclusion into the study (with a ranking process) were all the DRGs with an FI exceeding the 3The DRG-specific FI of the best performing providing facility has allowed calculating the theoretical volume of transferability in freestanding mode of the remaining facilities. The FI was also calculated based on the place of origin of the patients.The statistical analysis had recourse to the Chi Square test for comparing the FI of the providing facilities and of the various places of origin. The study sample size has been the population being considered, that is 5768 cases. 361 cases would have been enough to calculate the size of a hypothetical random sample for a 95% confidence interval. The power calculated for the test was 80% with a level of significance of 5%. The statistical analysis was carried out with OpenEpi open-source statistic software .With reference to inpatients, the prevalence of a one-night hospital admission (one-day surgery) was evaluated with respect to the admissions for two or more nights. An unspecified number of patients experienced during their hospitalization a change in their planned admission from outpatient to inpatient and vice versa.The DRGs provided in 2010 by the pediatric surgery and urology facilities, with the exclusion of patients under six months of age, amounted to a total of 5768, belonging to 121 types of procedures  from a statistical viewpoint. The ratio of the seven selected DRGs to the total services provided by the healthcare facilities ranges between 40 and 72% . The comparison between Latina and the Latina Province and Rome is statistically significant and the FI is higher for Latina and the Latina Province. The FI for the areas outside the Region is 70.5; the Chi Square comparison between patients from the Lazio Region and those from outside the said Region is highly significant (p < 0.001) from a statistical point of view Table . With reThe application of the exclusion criteria to the initial case study has led to the selection of seven types of procedures that represent 61% of the total DRGs provided by the pediatric surgery and urology facilities of the Lazio Region in 2010. In these DRGs, 80% are outpatients. The best DRG-specific performance determines a theoretical 10% increase. There are no sufficient clinical and organizational data to determine the causes of the high recourse to the one-day surgery, which accounts for nearly 1/3 of all regular admissions. It is quite likely that even a part of these admissions with overnight stay could be transferred to day surgery.th week of post-conceptional life [The age group included in the study is represented by patients who are over six months of age. This helps to assess the regional volume of procedures that could be supposedly carried out in a freestanding surgery center using the same minimum age cut-off for treatment of the Ambulatory Surgery Centers . As for nal life  should bnal life . With reThe organizational models and the FI of the healthcare facilities are independent. Paradoxically, the model of partial de-hospitalization, represented by day surgery units, features a lower FI than the model of the dedicated nursing beds in departments for acute patients. The difference is statistically significant. The analysis of the causes is complex and the phenomenon highlights the inadequacy of the FI as the only indicator of the quality and appropriateness of the day surgery services. It is quite likely that an improved understanding of these causes could be gained by monitoring the indicators laid down in the regulations of the Lazio Region . As for The place of origin of the patients, often considered a factor limiting the recourse to a day surgery if located far away from the healthcare facility, has not conditioned the choice of the type of hospital admission within the Region. This may be inferred from the comparison of the FI with the Chi Square test, which has not proved significant based on the place of origin. Indeed, the data relative to Latina and its Province point to the inferiority of Rome. The case is altogether different when dealing with places of origin from outside the Region, the significance of which gives evidence of an inappropriate use of the hospital as the place of an overnight stay.The study presents additional limitations.The FI has been constructed by modifying the indicators used for the assessment of the appropriateness of hospital admissions of the APPRO  method , the traUntil now, such methodologies have been prevailingly used for adult patients.The APPRO, built by the Public Health Agency of the Lazio Region, is based on hospital discharge cards (SDO) and has partly recourse to an isogravity classification system called All Patient Refined Diagnosis Related Groups (APR-DRGs) . The metThe MAAP method has been adopted by the Puglia Region to build indicators of the care setting transferability, DRGs with a high volume of cases, from regular hospitals admissions to day hospitals and ambulatory surgery centers. The transferability volume indicator is used when the DRG volume exceeds 0.5% of the admissions for the entire case study.The assessment of the performance of the healthcare systems has been made on behalf of the Ministry of Health by the Management and Health Laboratory of the Sant'Anna School of Advanced Studies in Pisa through a set of 34 indicators calculated on the SDOs in 2007 and 2008 . The regThe available data are incomplete and this has not allowed determining the extent of the change of the system of admission from outpatient to inpatient and vice versa. This aspect should be monitored as it could invalidate the day surgery activity. Hence, the assessment of the healthcare results with administrative data has both advantages and disadvantages. The immediate access to data on relatively uniform computer files and the possibility of estimating shares of inappropriateness within the context of selected case records are definite advantages. On the other hand, the disadvantages are due to the uncertainty of the nature of the administrative datum  and the absence of references to the context where the admission takes place . It ensues that the inner validity of the appropriateness assessment methods depends on the comprehensiveness and accuracy of the SDO compilation and coding.Notwithstanding the aforementioned limitations, there are also additional systems that back up the recourse to administrative data. In fact, the FI is similar to the ASC proportion of the pay for performance (P4P) system . Within The avoidable hospitalization is a subject that is well known to pediatricians. By analogy with the studies of the ambulatory care-sensitive conditions that have led to a radical reduction of the medical admissions to hospitals, a few studies that are likely to promote a partial surgical de-hospitalization should be implemented . In factFurthermore, there is also considerable confusion about the meaning of de-hospitalization . For admThe day surgery cases reported in this pilot study only concern pediatric surgery and urology. They should be considered minimum case studies susceptible of increase, since other specialties are also having recourse to day surgery . Therefore, a considerable part of the services currently provided in a number of continuous-cycle hospital facilities could be concentrated in a hypothetical inter-hospital health facility. We believe that the positive trend of the outpatient/inpatient ratio with respect to previous years, the significant volumes of real and potential activities highlighted in this pilot study, the abolition of the one-day surgery and the extension of the analysis to other disciplines could further the setting up of a freestanding inter-hospital facility of pediatric day surgery in the Lazio Region.The implementation of a healthcare facility does not depend solely on the total activity volumes, even though this is an important aspect. This pilot study could turn into the starting point of subsequent studies focusing on health management , on the expression of the parents' preferences , on marketing, etc., with a view to evaluating the feasibility of a de-hospitalization of the pediatric day surgery through a freestanding surgery center in a Region where the existing facilities are found within hospitals characterized by a high healthcare complexity and are concentrated within the city of Rome.The authors declare that they have no competing interests.All authors were involved in the conception of the study. GM carried out data extraction. He is the corresponding author of the paper. GM conducted statistical analysis. GM drafted the paper with contributions from the co-authors. All authors read and approved the final manuscript prior to submission.Organisational models of the Child Surgery Operational Units.Click here for file"}
+{"text": "This study used genomic DNA that was derived from a collection of bacterial isolates sourced from Chennai. The authors wish to acknowledge and thank Dr Thangam Menon of the Department of Microbiology, University of Madras, Chennai, India for providing these isolates. In addition, the citation for reference 35 as one of the sources of the isolates is incorrect; none of the isolates supplied by Dr Menon for this study had previously been described in reference 35."}
+{"text": "One of the challenges that the National Rural Health Mission (NRHM) faces is its ability to evaluate the progress of the programme in diverse contexts and use such evidence to constantly improve programme design and implementation. The National Rural Health Mission has put in place several measures for concurrent evaluation to review the progress of the programme and inform management decisions. One such measure of evaluation is the Common Review Mission (CRM). The Common Review Mission meets once in a year. The paper assesses the effectiveness of Common Review Missions as a methodology for programme assessment, as a programme component leading to improved service delivery and as a tool for informing policy decisions.We did a document analysis of the common review mission reports available since 2007 to understand the composition of the mission, methods of assessment used and outputs. We examined progress on some key parameters as assessed and reported in these reports. We also consulted citations of reports of the mission in various research publications.Key informant interviews were conducted with decision makers in public health system to understand the utility of Common Review Mission reports.Since 2007, the Common Review Mission has met five times. All Common Review Missions are collaborative efforts of a multidisciplinary team of government functionaries, public health experts, civil society members and development partners to reflect and examine the changes achieved under the National Rural Health Mission. On an average, 170 such experts constituted the mission distributed in 12 to 15 teams. The administrative coordination is undertaken by the Ministry of Health. The National Health System Resource Centre leads the analysis, drafting, discussions and finalization of the report.An analysis of five CRM reports shows that the most productive part of the evaluation process is the dialogue held with different states, which helps state officials to identify gaps and initiate corrective action. The structure and tools of information gathering used by the CRM teams have become increasingly refined over the years. These have become a template for much of subsequent monitoring visits by the National Rural Health Mission.At the policy level, Common Review Mission is a major source of information for research publications on the programme - including the series on Indian health sector in Lancet, Indian Journal of Community Medicine and Journal of Global Health. The use of the reports in national policy level for planning and improving implementation has been rather limited. It is imperative that data from such concurrent evaluations measures are fed back into the process of planning and implementation of programmes.None declaredNone declared"}
+{"text": "This study aims at providing new data relating to rare diseases with or without bucco-dental component. A national investigation based on a questionnaire has been carried out in France and a clinical study has been completed with the patients consulting the national centre of rare malformations of the face and the buccal cavity, in particular oligodontia.The results revealed a difficult and complex course of care for all the patients suffering from rare diseases. The oral health quality is not linked to the severity of the bucco-dental component. An unfavorable medico-economic impact has been noted in the treatment of numeric anomalies of teeth, including oligodontia. Proposals have been raised to improve the follow-up care of these patients on the basis of the current evolution of health policy."}
+{"text": "Experimental thermodynamic data of the ligand-receptor association showed that the entropy changes upon binding are positive and large enough to be important driving forces of the binding process for a considerable number of ligand-receptor complexes . The expWater molecules close to a charged residue are restricted from free rotation due to the interaction between their dipole moments and the electric field. This restriction result in a decrease in their entropy. The loss of entropy can be gained again when the water molecules displaced from area that under the electric field upon the binding process. To compute the loss of entropy due to the electric field, we developed a method based on the knowledge of the electric field which affects the rotation of the water molecules using the continuum electrostatic methods. This provides a possibility for the calculation of the entropic loss from the partition function of the water molecules under an electric field. For monovalent ions, the computed loss in entropy upon solvation correlates well with experimentally measured one.The loss of entropy of water close to hydrophobic molecules (Hydrophobic entropy) cannot be explained by the effect of the electric field from the molecule because the magnitude of the electric field is not strong enough to restrict the mobility of the water molecules. However, the loss in entropy results from the asymmetric interactions of the water molecules with the hydrophobic molecules and the neighbour water molecules. To compute the hydrophobic entropy we developed an empirical method which is derived from a linear relation between the hydration entropy of small hydrophobic molecules and the hydrophobicity of the water molecules around the surface of the small molecule. A training data set of 142 small molecules shows a significant linear relation between the hydrophobic entropy and the computed hydrophobicity."}
+{"text": "Radical neck dissection is a concept that was presented in 1906 by GW Crile and suffered constant improvement ever since. The surgical oncology procedure included the resection of the internal jugular vein, the sternocleidomastoid muscle, and the submandibular gland and the spinal accessory nerve. Deformities and impairment in the functionality of different regions of the neck and scapular regions have great implications on the quality of life of the patients who undergo such a procedure. Modifications to the radical neck dissection were made in the attempt to maintain the efficacy of the surgical oncology therapy. The authors try to assess the functional implications of radical neck dissection and the impact on the quality of life for patients with head and neck neoplasia. In 1906, GW Crile was the first physician who described the radical neck dissection in patients with malignant neoplasia in the head and neck region. The technique encompasses the need of surgical removal of the tumor metastasis located in the lymphatic structures from the mandible to the clavicle and from the trapezius muscle in the posterior to the median region of the anterior neck along with anatomical structures that may be invaded by the malignant tumor. The surgical oncology procedure included the resection of the internal jugular vein, the sternocleidomastoid muscle, and the submandibular gland and the spinal accessory nerve. In terms of oncology prospects, this is a routine surgical procedure performed for N3 metastasis and for extensive tumor growth. Deformities and impairment in the functionality of different regions of the neck and scapular regions have great implications on the quality of life of the patients who undergo such a procedure. Taking this into consideration E. Bocca and O. Suarez independently described an alternative for the radical neck dissection that involved the removal of the entire lymph tissue in the neck but conserving one or more anatomic structures without the sacrifice of the oncological efficacy. This led to decreased deformities and a better quality of life for the head and neck cancer patients.Head and neck cancer patients who are submitted in the E.N.T. Department of Coltea Clinical Hospital have a tendency of presenting to the specialist in late stages of the tumor process thus needing an extensive surgical procedure. Most of the patients are male (85%) who have a low social status, are heavy smokers, alcohol drinkers and have an altered nutritional status. More than 75% of the patients have tumor induced cachexia which in terms of outcome is a poor prognostic factor.1]. After participating in the Nutrition Day surveys from 2008 to 2010 we came to the conclusion that head and neck cancer patients who have an altered nutritional status need to be stabilized by using enteral nutrition, if the digestive system is not impaired, parenteral nutrition or mixed nutrition. A well-fed patient has a better prognostic because of the increased activity of the immune system, a more rapid wound healing process, shorter hospitalization period with the potential of a more rapid social reintegration.  The diagnostic procedures include clinical exam and imaging studies. This allows us to assess the extent of the tumor process so that a correct surgical indication can be drawn. Imaging studies include ultrasonography, CT scans, plane X-ray investigation, magnetic resonance investigation, and positron emission tomography. The nutritional status of the patients is calculated according to the ESPEN guidelines by using the nutritional risk score NRS 2002 [2]. This classification was necessary in order to optimize the neck dissections that were performed up until that time and to clarify the surgical indications for the procedure [3]. This report was improved in 2001 when the AAO-HNS presented an update for this classification in which the presence of 6 lymph node levels with 6 sublevels and an additional 7th level which is present in the upper mediastinum were stated [4]. This classification is also used in our clinic. In 1991, the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) published an official report that issued a standardized terminology for the different types of neck dissection [5]. Modifications to the radical neck dissection were made in the attempt to maintain the efficacy of the surgical oncology therapy and include the following types:There is an alternative for the radical neck dissection in terms of conserving anatomical structures if the tumor process invasion allows the use of a less invasive surgical procedure . Pain resulting from the resection of the spinal accessory nerve is subject to the administration of long-term anti-pain drugs. This is a positive aspect of the surgical therapy because the patient has a better adherence to the oncological therapy.  When sacrificing the spinal accessory nerve the patient will experience impairment in the movement of the shoulder with the fixation of the shoulder and with or without pain sensations in the territory of the cranial nerve, which reside in the denervation of the trapezius muscle  and, in this resides the need of the patient to protect that region in the neck .  The removal of the sternocleidomastoid muscle has a great impact on the esthetic aspect of the patient because of the deformity it creates in the cervical region. This also includes the flattening of the neck in the lateral region of the neck [Fig. 3). Despite this favorable situation, there is the need of limiting excessive hydration of the patient because of the possibility of inappropriate antidiuretic hormone secretion (ADH). The excessive ADH secretion, which in not uncommon in head and neck cancer patients, can lead to the accumulation of fluids in soft tissues. Persistent edema after radical neck dissections is unlikely to occur. Still, the removal of both internal jugular veins in the same surgical intervention is not to be performed because of the risk of having significant edema in the head and neck region that can be fatal for the patient. When needed, bilateral internal jugular vein resection, is to be done on a second stage procedure at least 6 weeks apart. This spacing allows the formation or the recalibration of collateral veins. When operating a patient with bilateral neck metastasis the tumor is to be resected in the second stage procedure along with the remaining contralateral neck metastasis. This follows the principle of resecting the tumor and the neck metastasis all together. The removal of the internal jugular vein has minimal impact on the quality of life for head and neck cancer patients. Postoperative edema is a transitory condition that usually disappears in a week time. The collateral veins of the neck prevent the occurrence of this situation , nerve or deep tissues spread. The life of the patient is the main concern of the surgeon when dealing with such cases.  The quality of life is a second hand issue when the tumor process is extremely advanced. If an oncological procedure is not possible, the surgeon needs to take into consideration the possibility of a palliative surgical intervention that allows the patient to live a decent life and have some quality of life. Nevertheless, feeding is one of the most important things for a late stage cancer patient, thus making it necessary for the surgeon to make sure that the patient has the possibility of feeding. Advanced pharynx and larynx cancer patients along with thyroid cancer patients have an impaired deglutition. If the surgical procedure does not assure the digestive system continuity, the patient will have to undergo a gastrostomy or a jejunostomy for enteral feeding. This scenario usually occurs in the recurrence of the neck disease. When possible, the preservation of the spinal accessory nerve is a technique that helps decrease morbidity and prevents shoulder dysfunction as well as the absence of pain where the ligation and resection of the internal jugular vein is linked to facial swelling, and an increase in the pressure level inside the cranium when performed bilaterally. This is avoided by the two-stage surgery. The quality of life of head and neck patients is in direct correlation with the cancer stage they present themselves to the physician. Late stages may lead to extensive oncological surgery, which may cause the appearance of deformities in the head and neck region and dysfunctions. Morbidity and mortality are decreased by assessing data about the clinical status of the patient, evidence-based decisions according to therapy guidelines and adequate surgery indications. We should not abandon the oncological principles in favor of the esthetics and functionality. This is only possible if the patient is well informed about the surgery and the supposed outcome and the patient agrees on having the oncological therapy."}
+{"text": "The Bercow review found a high level of public dissatisfaction with speech and language services for children. Children with speech, language, and communication needs (SLCN) often have chronic complex conditions that require provision from health, education, and community services. Speech and language therapists are a small group of Allied Health Professionals with a specialist skill-set that equips them to work with children with SLCN. They work within and across the diverse range of public service providers. The aim of this review was to explore the applicability of Normalisation Process Theory (NPT) to the case of speech and language therapy.A review of qualitative research on a successfully embedded speech and language therapy intervention was undertaken to test the applicability of NPT. The review focused on two of the collective action elements of NPT  using all previously published qualitative data from both parents and practitioners' perspectives on the intervention.The synthesis of the data based on the Normalisation Process Model (NPM) uncovered strengths in the interpersonal processes between the practitioners and parents, and weaknesses in how the accountability of the intervention is distributed in the health system.The analysis based on the NPM uncovered interpersonal processes between the practitioners and parents that were likely to have given rise to successful implementation of the intervention. In previous qualitative research on this intervention where the Medical Research Council's guidance on developing a design for a complex intervention had been used as a framework, the interpersonal work within the intervention had emerged as a barrier to implementation of the intervention. It is suggested that the design of services for children and families needs to extend beyond the consideration of benefits and barriers to embrace the social processes that appear to afford success in embedding innovation in healthcare. Thus, we have a situation where the profession is comparatively research-engaged, but the evidence base for the interventions delivered by the profession is weak. Public dissatisfaction with services is well documented. With new post-Bercow funding for intervention research, it is especially important that the potential implementation of new interventions is explored at an early stage so that, if found to be efficacious, new interventions can be quickly embedded within existing practice.Speech and language therapy interventions are good examples of complex interventions. They do not typically involve drug or surgical interventions; rather, the interventions are most often behaviourally based and delivered through discourse between the practitioner and the patient. Second, the allied health professions are small groups within healthcare systems, and this means that they usually work in distributed teams within healthcare services. Finally, the evidence base for speech and language therapy interventions is still developing. A systematic review of speech and language therapy for children found 25 randomised controlled trials since the 1960s . Whilst et al. [The complex nature of the interventions and the diverse delivery conditions of those interventions across a range of public services provides a challenging context in which to design new interventions that can be embedded in practice for patient benefit. Murray et al.  suggesteThe NPT  grew outet al. attribute this to a lack of theoretically motivated groundwork in the initial stages of the intervention design [Despite the influence of the Medical Research Council's guidance for designing complex interventions , there in design . They hin design , but theet al. [The primary aim of this study was to test the applicability of the propositions on the role of collaborative work laid out in the NPM and NPT to the context of speech and language therapy so that, if found to be applicable, the NPT could be used to inform the design of new intervention research in the field. Specifically, I set out to test the theory according to the requirements a theory as set out by May et al. . I wanteet al. ,27, but The study began with a search for a pediatric speech and language therapy intervention that was used in practice across the UK and was the topic of published qualitative research on the parents' and professionals' perspectives of the intervention. The pediatric speech and language therapy intervention that was commonly used the UK and had the most number of published studies of qualitative research as identified. The Hanen Parent Programme (HPP) originated in the US  and it hA literature search was conducted to find all research that had been published on the parental views of the HPP. In the first instance databases were searched using all search terms associated with the HPP . This search identified approximately 20 papers. All these papers were downloaded and read in full to find all research that had included information on either the parental views of the intervention or the speech and language therapists' views on the intervention. There were five papers that presented data on the parents' or therapists' views. Three of these papers used semi-structured interviews or focus groups to elicit participants' views on the intervention. Two of the papers presented data from questionnaires that were used to elicit parental views of speech and language therapy. These studies were included because they explored parental views on direct  versus indirect (such as the HPP) approaches with children and families. The papers are summarised in Table The first step in the analysis was to identify the important and recurrent themes that arose in the five studies in the review. The next step was to map the recurrent themes on to the constructs of the NPM . The exiThe first endogenous process in the NPM concerns the professional-patient relations, the interpersonal context for normalisation, named Interaction Workability. The specific elements of Interaction Workability and the relationship between these elements are summarised in Table The second endogenous process defined by May , named RAre the definitions as described within the original version of the NPM applicable to a new data set based on a synthesis of qualitative research from previously published research on the HPP?The findings of the synthesis of the qualitative research against the NPM propositions were checked by both of the NPM main authors (May and Finch) to search for inconsistencies or inaccuracies in the allocation of qualitative research to aspects of the model. No discrepancies were found. The allocation of direct quotations to the NPM was relative straightforward, and there were no discrepancies in the allocation between the first author of this paper and the NMP's main authors, however, it was important to consider the degree to which the NPM provided an inclusive framework for the main thematic findings in the original articles. The quotations as well as the main thematic findings from the original studies were used to populate the NPM framework (endogenous processes). The findings of the secondary data analysis was presented to academic speech and language therapists at Newcastle University who considered the findings to be congruent with their own experience of working with the HPP.Can the application of the model uncover new understanding of how the interpersonal work done by the participants of the intervention gave rise to its successful embedding in practice? This was approached by testing the findings against the main propositions in the NPM on the endogenous factors of an intervention.Is there evidence of flexible interpersonal work between practitioner and parent? The data in Table et al. [et al. found that the parents who received the direct, traditional clinic-based therapy could state how they had changed their interaction, but did not see themselves as being responsible for outcomes. Therefore, it is not the case that practitioners are always successful in helping parents change their perspective on their role in the intervention. One conclusion from this analysis is that the HPP is an intervention that is particularly good at helping practitioners theorise about, discuss, and evaluate the mechanisms of change in the intervention.We might assume that the professional competency of speech and language therapists means that they are highly skilled in supporting the types of flexible co-construction that May says supports the normalisation of an intervention. If this is the case, then we might always expect to find evidence of flexible construction of agency in the context of speech and language therapy. Data from Baxendale et al.  suggest i.e., increased confidence) to their own interpersonal work within the intervention.Pennington and Thompson  also repThere was no evidence of flexibility in the area of outcomes of the intervention and how they were measured. There was an indication that the practitioners in Pennington and Thomson's study had ranked or analysed the pre-intervention communication style in the parents and were monitoring parents' progression. The primary outcome was change in parental communicative style, and the process was speech and language therapists' individual planning for each parent with a theory of what would bring about change in this primary outcome. The practitioners did not talk about how parents were active participants in the planning or measurement of their own outcome.Is there evidence for flexibility in accountability and confidence in the intervention? The analysis on proposition is in Table i.e., other healthcare providers), and the absence of data that could be mapped on to the two exogenous processes of the NPM need to be considered prior to the discussion of the findings. In part, the small number of studies is representative of the status of qualitative research in the field of speech and language therapy. In a field that aligns itself culturally with the medical profession, the generation of evidence has relied primarily on quantitative research designs. There were no other interventions, which are widely used in routine paediatric speech and language therapy practice, that had a qualitative research literature suitable for this review. The absence of exploration of the wider stakeholders' views on the intervention and the absence of data that could have been mapped on to the exogenous factors in the qualitative research on the HPP is a product of the intentions of the primary investigators and their motivations for exploring the intervention. The production of the qualitative evidence base on the HPP was in large generated by academic speech and language therapists. The clinical academics' interest might explain the predominance of intervention-specific data from qualitative research. The absence of data on the exogenous constructs of the model does not imply that skill-set of workers and the organisational integration of the intervention is not relevant to the intervention. The HPP is an intervention that can only be delivered by qualified speech and language therapists, and is only delivered by therapists who attend special training in HPP and pass quality benchmarks for its use in clinical practice. Therefore, the intervention has a recognisable, well-bounded location within the speech and language therapy work force, which is suggestive of high potential towards embedding within routine practice . In relation to the integration within the wider organisation, to date, the work force of speech and language therapy within the wider healthcare work force could be described as having a well-defined and resourced responsibility for children with SLCN, and thus high potential for this intervention to be integrated in the institution's work force. We might find that the changes in healthcare commissioning and delivery in the UK and Bercow's recommendations for a wider distribution of the work to support children with SLCN (with the implication that this should extend well beyond speech and language therapists) that future qualitative intervention research in this field will probe the constructs that map on to the exogenous processes of the NPM. This remains to be seen.The small number of papers in this review, the absence of any previously published work on the perspective of the intervention from other stakeholders  could lead to parents becoming greater advocates for the intervention which itself could lead to better diffusion within the healthcare system thus generating a more fertile context into which new innovation in speech and language therapy could be expected to take root. This proposition could be used in future design of interventions in speech and language therapy, and could also be tested in development work in pre-phase one trials of new interventions.The author declares that she has no competing interests. DJ prepared this article whilst employed as an academic speech and language therapist in Speech and Language Sciences at Newcastle University, UK. During that time she was a collaborating member of the Institute of Health and Society and was mentored by Professor Carl May. DJ is now working as a translational scientist in child and family at the NIHR National Biomedical Research Unit in Hearing  at Nottingham University."}
+{"text": "Current Neuropharmacology. As Chief Editor I havewatched the growth and success of the journal with great pleasure. The impact of Current Neuropharmacology has steadilyincreased and the journal is freely available on PubMed Central. The standard and range of reviews and special issuesconsistently attains high standards. Naturally, none of this would have been possible without the dedicated efforts of authors,Editorial Board members, Special Guest Editors, anonymous reviewers, and of course the tireless efforts of Bentham SciencePublishers. To all of these I express my sincere thanks.This Editorial marks the beginning of the tenth year of publication of e.g.Therapeutic Potential of Metabotropic Glutamate Receptor Modulators by Hovels\u00f8 et.al.), evaluation of disease mechanismsand pharmacology  to reviews ofclinical data .The diversity and high standard of work published in Current Neuropharmacology is reflected in the content of the presentissue of the journal. The subject matter ranges from reviews of the pharmacology of specific types of receptors (Current Neuropharmacology to continue to thrive it is important that diversity and high standards are maintained. Withits increasing impact and visibility, I believe that the journal offers an excellent vehicle for the publication of novel reviews andhypotheses, and I look forward to the submission and publication of novel and leading papers in the future.For"}
+{"text": "The diversity of professionals in the Risk Management has as its aim to expand knowledge and discuss of the facts and risk events and the nurse is an important component of this group, and related to administration of antimicrobial drugs. The objective of this research was to examine the perception of nursing staff in three work shifts, from a health institution in Ponta Grossa \u2013 PR, 2009, in relation to the error in the administration of antimicrobials.This is a quantitative research, conducted through a questionnaire with open and closed questions.We found that medication error is a multifactor action and the main responsibility is related to the nursing staff. It was found that when antibiotics delays occur in their unit, 14 (58%) do not consider as a medication error, 16 (67%) think it is important to notify the pharmacist and 16 (67%) are aware of the existence of the Nursing and Patient Security Network in Brazil and the Intra-hospital Risk Management Committee and 8 (33%) are unaware about this subject.The continuing education for professionals responsible for the administration is the best way of transformation, by encouraging the notification in the register of risk management linked directly with the Committee of Hospital Infection Control of the institution, aiming at quality and safety of care provided to patients.None declared."}
+{"text": "The interval of call to arrival is one of the major factors associated with good outcomes of out-of-hospital cardiac arrests (OHCAs). The FAST system helps emergency vehicles reach a scene quickly by controlling the traffic signals. The aim of study is to investigate whether the FAST system may improve the outcomes of OHCAs by decreasing the response time.We analyzed the data from OHCAs that were witnessed or recognized by citizens from April 2003 to March 2010. The OHCA data were compared between the two groups transported by ambulances with and without FAST units. The comparisons were made in the central and peripheral areas with and without FAST-controlled signals.Dispatch of and transportation by FAST-loaded ambulances significantly decreased the interval of call to arrival and significantly augmented the incidence of sustained ROSC and 1-year survival only in the central area (Figure The implementation of FAST may improve the outcomes of OHCAs mainly by reducing the interval of call to arrival."}
+{"text": "The Association of Medical Physicists of India (AMPI), now 30 years young, was founded in the year 1976 with the objective of promoting the application of physics in medicine and biology. It provides a forum for medical physicists in the form of annual conferences  and publication of a quarterly Journal of Medical Physics for the exchange of ideas and dissemination of knowledge. The host of the AMPI Conference is decided by the general body of the association on receipt of the formal request from the head of the host institution. The association and the host institution are jointly organizing the conference.th annual conference of the association is being organised at Bhubaneswar, Orissa during 9-12 November 2006. This is also the seventh International Conference on Medical Physics (ICMP) in India. The host of this conference, the Hemalata Hospitals and Research Centre, Bhubaneswar is equipped with all the adequate facilities for the treatment of cancer. It is pleasure to know that this hospital has come to this stage by the relentless efforts made by one of our medical physics colleagues, Dr. A.K. Rath who is also the Chairman of the organising committee of the conference.The 27This issue of the journal is exclusively dedicated to AMPICON 2006. About 200 abstracts were received by the organisers, which were evaluated by the scientific committee for presentation at the conference. Extended abstracts of proffered papers -both oral (63) and poster (127) - are included in this issue. The scientific programme consists of invited talks including Ramaiah Naidu Memorial oration. Ramaiah Naidu Memorial Oration (RNMO) Award was instituted by the association in 1992 in the honour of pioneer Indian medical physicist Dr. Ramaiah Naidu. The oration award consists of a citation and a silver plaque. As per the norms of AMPI, the recipient of RNMO award shall be a person of national/ international repute in the field of medical physics. The recipient of this award is selected by the Executive Committee of AMPI. There are 14 scientific sessions, including 19 invited talks, 2 guest lectures and 3 poster sessions. For the first time the scientific programme includes a debate on a topic that I am sure that all the medical physicists in radiation oncology will find it interesting. Keeping in line with the recent trends in radiation oncology three invited talks are being organised on image guided radiotherapy (IGRT) by experts from India and abroad. It is also decided to keep early morning lectures on various topics for the benefit of our young colleagues in the specialty.While going through the abstracts, the scientific committee felt that there is scope for improvements in the methodology for abstract submission, their speedy evaluation and informing the authors on decision taken. We will certainly pass on our suggestions to the association for consideration. Couple of years down the line I hope that complete process of submission to publication of abstracts should be made on-line.As a guest editor I take this opportunity to request all the authors of proffered papers to prepare the full manuscript of their good work and submit to the editorial office for publication in this journal.I also thank the members of scientific and publication committees for their full cooperation and hard work in bringing out this issue in time."}
+{"text": "To investigate the effect of custom inspection on drunk driving in traffic accident injury.In order to find out the effect of the strict check on drunk driving in traffic accident injury, we investigated the patients with traffic accident injury, who were sent to our hospital during the period from August to December, 2009, and compared them with those in the same period of 2007 and 2008.The numbers of patients with traffic accident injury and the times of ambulance turnout in 2009 were fewer than those in 2007 and 2008. The percentage of critical patients and the number of car related traffic injury were decreased too.Custom inspection on drunk driving can effectively decrease the number of traffic accident injury and lower the percentage of critical patients."}
+{"text": "Information regarding the involvement of one of the funding organizations was incorrectly omitted from the Funding Statement. The following sentence should be included as the fourth sentence of the Funding Statement: \"However, the views expressed in this paper belong to the authors and do not necessarily reflect DfID\u2019s official policies or the policies of WSSCC or the Gates Foundation, nor do they necessarily reflect the position of the Indian Government.\""}
+{"text": "Two years ago, at the ECRD in Krakow, we were celebrating the recommendation of the Council of Ministers on an action in the field of rare diseases: this recommendation requests that Member States define and implement a plan or a strategy for rare diseases by the end of 2013 and asks the European Commission to establish a EU Committee of Experts in the field of Rare Diseases (EUCERD) as a forum of stakeholders to propose action points at EU level. Two years on, there is enough evidence to judge the outcome of Recommendation which can be qualified as positive despite the economic crisis. The dynamic of action is still impressive (Figure"}
+{"text": "Alzheimer disease (AD) is the main cause of dementia and loss of functional independence in the elderly Aisen, . AD is aThe only drugs currently available  slow down without changing the natural history of AD Birks, . BecauseBecause the earlier the disease-modifying treatment starts, the greater is the possibility of efficacy, it is important to initiate the treatment before the clinical manifestation of the overt disease. This is one of the reasons of the interest for the early diagnosis of AD. Importantly, this research has identified new morphological as well as functional and biological criteria that, combined with the classical neuropsychological expertise, help make the diagnosis of AD earlier and earlier   is associated with better cognitive function in older individuals. Having more than 800UI of vitamin D supplies per day divides the risk of AD by 5 after 7 years of follow-up  Contributing to the conception and design, or analyzing and interpreting data; (2) Drafting the article or revising it critically for important intellectual content; and (3) Approving the final version to be published.The concept of combining memantine with vitamin D in the prevention and treatment of Alzheimer's disease and related disorders was patented by Angers University Hospital and the University of Angers. The authors report no conflicts of interest with this research. None of the authors have a personal financial interest in this research."}
+{"text": "The treatment of multiple sclerosis has been radically transformed over the past 20 years and this special issue of IJMS, focusing on the molecular aspects of the disease, highlights the growing conformity of the various investigative approaches. It is a very exciting time to be involved in the research of this disease. The worlds of science and medicine have been aware of multiple sclerosis (MS) as a distinct clinical  and pathCareful epidemiological work over the past 60 years has identified that both genetic and environmental factors influence the risk of developing MS. A familial association in MS was demonstrated conclusively early on  and in tIn this issue of IJMS there is a comprehensive review of the environmental factors that have been identified in MS . The molContinuing advances in the study of MS at the genetic, molecular and cellular levels has undoubtedly had a significant impact on our understanding of this disease as exemplified by the articles in this special issue of IJMS. This ranges from detailed studies of the pharmacodynamic effects of vitamin D in a single patient  through The result of this huge effort in MS research has been the emergence of a variety of effective therapies over the past 25 years . There iStem cell therapy offers huge potential to not only alter the course of the inflammatory phase of multiple sclerosis, but to also regenerate damaged central nervous tissue and reverse accumulated disability. As reviewed in this issue of IJMS , this po"}
+{"text": "The mathematical theory of pattern formation in electrically coupled networks of excitable neurons forced by small noise is presented in this work. Using the Freidlin-Wentzell large deviation theory for randomly perturbed dynamical systems and the elements of the algebraic graph theory, we identify and analyze main regimes in the network dynamics in terms of the key control parameters: excitability, coupling strength, and network topology. The analysis reveals the geometry of spontaneous dynamics in electrically coupled network. Specifically, we show that the location of the minima of a certain continuous function on the surface of the unit n-cube encodes the most likely activity patterns generated by the network. By studying how the minima of this function evolve under the variation of the coupling strength, we identify the principal transformations in the network dynamics. The minimization problem is also used for the quantitative description of the main dynamical regimes and transitions between them. In particular, for the weak and strong coupling regimes, we present asymptotic formulae for the activity rate as a function of the coupling strength and the degree of the network. The variational analysis is complemented by the stability analysis of the synchronous state in the strong coupling regime. The stability estimates reveal the contribution of the network connectivity and the properties of the cycle subspace associated with the graph of the network to its synchronization properties. This work is motivated by the experimental and modeling studies of the ensemble of neurons in the Locus Coeruleus, a nucleus in the brainstem involved in the regulation of cognitive performance and behavior ."}
+{"text": "In 1996, hand hygiene has been at the heart of the concerns of hospital staff of El Alia. Starting from a local action, the team was heavily involved in the development and implementation of the Tunisian national hand hygiene program that now has more than ten years.We aim to illustrate the contribution of the team of El Alia to promote hand hygiene at the local, regional and national level and to diffuse an example of a local public health initiative having given birth to a national program.This is a retrospective descriptive study based on consultation documents relating to hand hygiene archived at the hospital in El Alia, at the regional service hygiene Bizerte and the Directorate of Hygiene of the Ministry of Health.Three phases could be distinguished:- Phase I: From 1996 to 2001, marked by the establishment of local action to promote hand hygiene at the hospital in El Alia- Phase II: From 2002 to 2008, which saw the launch of the national hand hygiene with a strong involvement of the team of El Alia in the development and implementation of this program- Phase III: From 2009, corresponding to the strengthening of the national hand hygiene again with involvement of the team of El AliaThis is a beneficial experience on more than one level and rewarding for all. Sustained efforts are needed to achieve sustainable success. A comprehensive assessment should be considered in order to measure the impact of this action.Not statedNone declared"}
+{"text": "The administration and control of the hospital infection is one of the most important parts in the quality management of modern hospital and medical security. The hand hygiene is a major subject in the administration and control of the hospital infection. As evidences show, the hands of the medical staff carry a lot of germs and up to 30 percents of the hospital infection result from the situation that the medical staff does not wash their hands according to the desired standard. Normative hand hygiene can make the hospital infection rate reduced by 50 percents.There are several factors that affect the compliance of the hand hygiene of the medical staff. How to improve the poor compliance is a very challenging problem in the administration and control of the hospital infection. The developments of intelligent reminding and administration of hand hygiene system (IRAHHS) is a good way to radically solve the problem.Based on the Radio Frequency Identification technology and intelligent analysis system, the IRAHHS has many reading and writing devices with perception in major infection control areas, danger areas such as around infected articles and the bedside of the patients, and hand disinfect or washing areas. When the medical staff with intelligent electronic tags touches the sources of the pollution in these areas, the electronic tags communicate with the devices and record and remind the staff of the status of their hand hygiene and ask them to do required hand hygiene behaviors. The information will be recorded and sent to the backstage simultaneously. The IRAHHS is connected to the central information system of the hospital and provides the manager with the ability to search, access, analyze the data and judge.The IRAHHS achieves the functions of intelligent perception, reminding and tracking with the help of technologies of Internet of Things. It is a novel attempt in the administration of hand hygiene and also a new idea in the administration and control of the hospital infection in China."}
+{"text": "In connection with necessity of extension of therapeutic possibilities of migraine treatment the study of efficacy of Levetiracetam for profilactic treatment was conducted. There are not data in literature on undertaking big randomized studies on this topic.With a glance for pharmacotherapeutic peculiarities of action of traditional anticonvulsants, that limit their application due to side-effects , there is a necessity of enlargement of the range of drugs, that can be used for the prophylactic treatment of migraine.The study was conducted on the base of Headache Center on patients that applied with migraine without aura  with attLevetiracetam showed efficacy comparable with traditionally used anticonvulsants. The efficacy of Levetiracetam was unreliably lower than the efficacy of valproic acid, and it was reliably higher than the efficacy of Topiramate."}
+{"text": "We describe the existence and structure of large fullerenes in terms of symmetry breaking of the  Fullerenes are molecules composed entirely of carbon, taking the form of a cage or tube. The family of cage cluster fullerenes is also commonly referred to as buckyballs. The most stable and commonly occurring member of this family is the molecule Much effort has been directed to answer why the fullerenes In the present work we consider the existence and structure of higher fullerenes as a symmetry breaking problem, starting from the The paper is unique in providing exact coordinates of the vertices of the fullerenes thus eliminating any additional numbering conventions used elsewhere In order to get exact coordinates of polytopes related to icosahedral symmetry, one has to use bases in the real 3-dimensional space It follows from For the The reflections Repeated application of the three reflections to the seed point The points in which both the second and third coordinates are non-negative are the dominant points of the The hexagon faces of  come up naturally from the classification of its 2-faces  as one orbit of the seed hexagon. The symmetry group of the seed hexagon is generated by the reflections  and . Similarly the pentagon faces of  come up naturally from the classification of its 2-faces as one orbit of the seed pentagon. The symmetry group of the seed pentagon is generated by the reflections  and .Let us illustrate the construction of the seed hexagon and of the seed pentagon, starting from the dominant point of :The vertices of a hexagon and pentagon of the surface of  adjacent to the dominant point of  are shown here in the -basis.The three simple roots, , , , of the icosahedral group form a special basis in . Their relative angles and lengths are read from the matrix  . Those values define the icosahedral group . Therefore they take special positions also in .Let us show that (i) the straight line containing  passes through the center of opposite pentagons on the surface of . To show it, one needs to take the hexagon generated by  and , and add its vertices to verify that coordinates of the sum are zero in the plane spanned by  and .(ii) The straight line containing  passes through the center of opposite edges on the surface of  that separate two hexagons.(iii) The straight line containing  passes through the center of opposite hexagons on the surface of .In this example let us view each point  of  as an exponential function, , where , and then add up all 60 such exponentials. Call such a sum . Since each  comes with both signs in , we have  equal to the sum of 30 cosines . Properties of  deserves further study. The function \u2018remembers\u2019 the structure of  in the entire 3-space and shows intricate interferences of the cosines with a clear maximum when  is at the origin of . On the spherical surface of the  shell, the function  depends periodically on the radius of .The general idea, we pursue here for the modification gons see , one getThe There are still two questions to be answered however before one can call it The answers to the questions are found by making two observations from In order to keep the distances between the five decagons of The first row of hexagons in Summarizing, below are the exact coordinate of the 70 vertices of According to In the present work we have described the existence of the molecule"}
+{"text": "Journal of Educational Evaluation for Health Professions will be an official journal of the AMEWPR beginning in July 2011 after going through a scheduled process. Workshops for the capability on how to develop test item will be continued specific to each field so that the pool of examiners can be expanded. The year 2012 is the 20th anniversary of the NHPLEB. Thus preparations for the international conference to celebrate the 20th anniversary will begin in 2011. I appreciate all readers and the health personnel educators for their support of the NHPLEB in 2010. I will persevere in my effort to develop the National Health Personnel Licensing Examination in every way in 2011.The National Health Personnel Licensing Examination Board (NHPLEB) of the Republic of Korea completed the clinical skill test for the Medical Licensing Examination in 2009 and 2010 that was introduced for the first time in Asia. This was only possible due to the great amount of time devoted by the medical professors and staff of NHPLE. To improve the evaluation of what examinees can do instead of only what they know, a clinical skill test should also be administered in other health professional fields. Recently, the NHPLEB has dealt with 160,000 examinees including licensed practical nurses, caregivers, and certified health education specialists. The NHPLE will apply to the ISO 9001 certification process in 2011. Also, the work of the ad hoc team for computer-based testing will be extended in 2011. On December 14, 2010, during the meeting with the President of the Association for Medical Education in the Western Pacific Region (AMEWPR), Dr. Duck-Sun Ahn, it was agreed that the Happy New Year!"}
+{"text": "This issue of Frontiers in Physiology presents a collection of manuscripts including original research and comprehensive reviews that examine the effects of second hand smoke (SHS) on the development and progression of chronic obstructive pulmonary disease (COPD). The health effects and costs of SHS are a burgeoning concern as it is estimated that more than 126 million people in the United States are exposed to SHS Menzies, . AlthougThe original research articles presented in this collection examine the influence of dietary vitamin D levels on the susceptibility to SHS-induced pathology, the effects of SHS in a model of pre-existing pulmonary inflammation induced by the genetic deletion of a key leukocyte signaling molecule (Arhgef1), and the role of STAT3  in the control of inflammation and protease expression in the lung. In the report by Crane-Godreau et al. , the autIn addition to the original reports, this issue also presents focused reviews on the effects of SHS on airway secretions and mucociliary clearance (Liu and Di, Together, these reports provide insight into the usefulness of animal models of SHS exposure to define potential mechanisms of action in pulmonary pathology as well as timely, thorough updates on our current understanding of the pathologic effects of SHS. Given the tremendous numbers of persons exposed unwillingly to SHS and the likelihood of an increase in COPD in the coming years, it is imperative that the health effects associated with these exposures are carefully and fully examined. The use of animal models for such studies is necessary and, therefore, it is important that the strengths, limitations and relevance to human disease be explored and discussed.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The paper presents the results of our investigation on the effect of the molecular structure of organic vapors on the characteristics of resistive chemical gas sensors. The sensors were based on tin dioxide and prepared by means of thick film technology. The electrical and catalytic examinations showed that the abstraction of two hydrogen atoms from the organic molecule and formation of a water in result of reaction with a chemisorbed oxygen ion, determine the rate of oxidation reactions, and thus the sensor performance. The rate of the process depends on the order of carbon atoms and Lewis acidity of the molecule. Therefore, any modification of the surface centers of a sensor material, modifies not only the sensor sensitivity, but also its selectivity. The kinetics of the processes, which take place in the receptor part, determine the sensor parameters, like sensitivity, selectivity, working temperature and response time. It is commonly accepted that the parameters depend on the sensor material and its microstructure, developed during the technological fabrication process  is concentration of oxygen ions chemisorbed at the surface of gas-sensing material, poc is the partial pressure of assayed organic compound, and a, n are the power exponents.In general, the rate of oxidation reaction \u03bd of the tested substances at the surface of sensing material, can be described by the following equation:O\u2212 ion is the dominant form of the oxygen chemisorbed at SnO2 surface. Since the partial pressure of oxygen did not change during the experiment, one can claim that the oxidation reaction rate of the examined organic compounds at a given temperature depends only on the partial pressure of analyzed compound. For this reason, the exponent n from According to  in the tn does not depend on the kind of assayed organic compound. This means that the oxidation reaction rates of the compounds at the surface of tin dioxide are affected to the same degree by the increase in concentration of each of the assayed compounds. Due to this fact it can be stated that the reactions occurring with the contribution of examined organic compounds on SnO2 surface are multi-stage, but follow the same scheme. Furthermore, it means that the first stage of the reaction, depending on the kinetics of interactions of a molecule of organic compound with the sensor surface, determines the rate of the whole oxidation process and thus the variation of the sensor conductance.The performed measurements showed that \u2713 number of carbon atoms in the molecule,\u2713 arrangement of carbon atoms in the molecule,\u2713 location of hydroxyl group,\u2713 kind of functional group.The organic compounds analyzed during electric measurements differed by:\u2713 electric charge distribution in the molecule,\u2713 dipole moment,\u2713 ease of dehydrogenation and dehydration,\u2713 ease of oxidation.The differences in structure of assayed compounds caused that they differed additionally by:Analyzing the sensitivity and working temperature dependence on physical properties of examined compounds like: number of carbon atoms in the molecule, dipole moment and electric permittivity, characterizing electric charge distribution in the molecule, the authors have not observed any connection between the parameters . HoweverFor aliphatic alcohols, the Lewis acidity decreases with the increase of the number of alkyl groups whereas the ease to abstract the hydrogen from the alkyl group depends on the order of carbon atoms ,22. Fromn-butanol. The studies concerned the efficiency and selectivity of bimolecular condensation reaction of alcohol. The studies showed that in the reaction of bimolecular condensation of n-butanol in the presence of tin dioxide at the working temperature of the sensor, water is the main product of the reaction (The authors\u2019 hypothesis has been confirmed by the studies of catalytic activity of tin dioxide for the conversion of reaction .The obtained results are important from the point of view of possible modification of the parameters of chemical sensors like sensitivity, working temperature and selectivity. Since the kinetics of the oxidation process of organic compounds at the surface of oxide semiconductors depends on their Lewis acidity and ease of removing of hydrogen atom from the molecule, then it is possible to control the sensitivity, working temperature and selectivity by modification of the Lewis acidity.4.In the work the effect of molecule structure of an organic compound on sensitivity and working temperature of thick-film sensors based on tin dioxide has been evaluated. The studies showed that the electrical performance of resistive sensors depend on acidity of the molecule and ease of removing of hydrogen atoms from alkyl groups. Lewis acidity decreases with the increase in the number of alkyl groups in the molecule whereas the ease of hydrogen removal is reduced when the order of carbon atoms decreases.Based on the analysis of obtained results and examination of physical-chemical properties of tested organic compounds it has been assumed that the first slowest stage determining kinetics of the oxidation reaction of the compounds and thus determining the performance of the sensor is the process of removal of two hydrogen atoms from the alcohol molecule in the reaction with oxygen chemically adsorbed on the surface of sensing material.In order to verify the above assumption, catalytic activity of tin dioxide in bimolecular condensation reaction has been assessed. Results of the investigations confirmed the validity of this assumption. As is commonly accepted, during a sensor operation chemical reactions of organic compounds with oxygen chemisorbed at the surface of sensing material take place. From the performed studies it follows that the rate of the stage determining the oxidation process of organic compounds at oxide surfaces of semiconductors depends on Lewis acidity of organic compounds. Thus, by modifying the Lewis acidity of the surface of a sensing material it is possible to affect not only sensitivity and temperature of assaying the compounds but also, what is very important, the selectivity of the sensor."}
+{"text": "The first publication of the work  did not Maria-Luisa Camara does not have any competing interests to be declared.AC: wrote the manuscript and was the major contributor to the conception, design and data acquisition for this study. MLC: operated on the majority of patients and contributed to the conception, design and data acquisition (pictures) of this study. All authors read and approved the final manuscript."}
+{"text": "The Democratic Republic of Congo may have one of the world's highest burdens of neglected tropical diseases, but nationwide there is a dearth of surveillance activities and available epidemiologic data about these conditions.Heart of DarknessThe Democratic Republic of Congo (DR Congo) is a vast nation of almost one million square miles  and more than 70 million people located in the heart of Africa . For at When it was known as Zaire during the last quarter of the twentieth century, the resulting dissolution of health systems and public health infrastructure contributed to the reemergence of HAT Beyond sleeping sickness, the decades of conflict and breakdowns in health infrastructure have contributed to the high prevalence of several major NTDs et al. in PLOS Neglected Tropical Diseases in 2011 Despite the public health importance of DR Congo's NTDs, there is much more that we do not know than we do know about both the high-prevalence NTDs and the emerging viruses in the Congo Basin. Shown in The absence of NTD disease surveillance is itself a threat to the people of the DR Congo and indeed to global public health. Time and again DR Congo has shown us how this nation represents the cradle of a number of important emerging and reemerging viral infections There is an urgent need to implement a comprehensive program for disease active and targeted surveillance comprised of studies to examine the high-prevalence NTDs, including the major helminth infections  and key protozoan and bacterial NTDs  Studies by a number of investigators have demonstrated the feasibility of conducting high-level and sophisticated disease surveillance in DR Congo. While working there is challenging, as it is in many conflict and post-conflict sub-Saharan African countries, the Ministry of Public Health of DR Congo has time and time again demonstrated initiative and willingness to expand NTD disease surveillance and control activities. Indeed, through support of the United States Agency for International Development (USAID), DR Congo is poised to begin an ambitious program of NTD mapping and integrated disease control focused on mass drug administration for a number of its highest prevalence diseases"}
+{"text": "The recent published article by Dr. Pourmand and his colleagues under the title of \"A survey of poison control centers worldwide\" was read eagerly . I have The first Iran Drug and Poison Information Center (DPIC) was founded in February of 1997 in the Food and Drug Deputy of Iran Ministry of Health and Medical Education by a group of experts and their first report of a such new activity was published by Nikfar and colleagues in the year 2000 [The Iranian DPIC developed gradually and changed its name to National Drug and Poison Information Center (NDPIC). Alongside developing of NDPIC, the other DPICs were founded in Iranian medical universities. These DPICs are mainly supported by local medical universities as well as Iran Ministry of Health and Medical Education, and currently the Food and Drug Organization. All of these centers are under the supervision of the Central Staff of NDPIC and their services are free of charge. All DPICs must report their activities and statistics to the NDPIC every three months  . In PourThere are several hospitals in different cities of Iran that have poison treatment center and serve to poisoning cases. These hospitals work under the supervision of medical universities and equipped with poisoning emergency room, intensive care unit (ICU) and specific poisoning ward . The LogIt should be noted that Iran has the potential to be a regional Center of Excellence for DPICs. To prove this claim, I would like to compare Iran DPIC with one of the well known centers in the region- Saudi Arabia DPIC. I searched literature and found an interesting report from Saudi Arabia in the region by Asiri et al . In the"}
+{"text": "The Barwon Health Eating Disorder Service is a specialist regional service providing assessment, treatment and consultation for individuals with eating disorders of all ages living in the Barwon region. The service delivers evidence-based treatments including Family-Based treatment, Cognitive Behaviour Therapy-Enhanced and Cognitive Analytic Therapy in conjunction with dietetic support. The service prides itself on engagement and partnerships with the service providers in the region both in the public and private sector to provide the community with a range of integrated options for treatment and support.In recent times the service has collaborated with The Barwon Health Deakin Psychology Clinic and the Community Adult Mental Health teams to provide an assessment clinic and evidence-based outpatient treatment to individuals 26 years and over and their families with eating disorders. This presentation will showcase the work being done in the service and the ongoing development of the adult treatment model in conjunction with service partners, including the important partnership with the Victorian Centre of Excellence in Eating Disorders.Adult Treatment and Services stream of the 2013 ANZAED Conference.This abstract was presented in the"}
+{"text": "To the Editor: I appreciate the comments of Drs. Alavian and Tabatabaei on our article in the November-December 2008 issue of the Annals."}
+{"text": "Therapies of chronic diseases should be efficacious, convenient for the patient and devoid of side effects. In daily practice, the risk of serious outcomes and the preference of patients as well as the cost of the interventions should also be considered. The pathophysiological basis of osteoporosis provides the rationale for the use of interventions that either reduce bone resorption and turnover or stimulate bone formation. Several antiresorptive treatments are used in the treatment of osteoporosis but PTH is the only anabolic therapy currently available. Evidence for efficacy and safety from controlled studies has been obtained for up to 10 years for antiresorptives and up to 2 years for PTH. while short-term head-to-head studies with surrogate endpoints have also been performed. Such studies illustrate the different mechanism of action of the two types of interventions but do not allow any conclusions about any potential differences in antifracture efficacy. These considerations are reflected in recommendations of several regulatory authorities. It is also frequently assumed that antiresorptives should be given mainly to patients with high bone turnover while anabolics should be reserved for patients with low bone turnover. However, analyses of the results of trials with bisphosphonates and PTH 1-34 indicated that the antifracture efficacy of these agents is independent of prevalent rates of bone turnover. Further analysis of the pharmacodynamic responses to these treatments, reveal distinct patterns with attainment or not of steady-states that provide the basis for the design of regimens with the use of both types of therapies, in some patients at least. Most of the studies have been performed with bisphosphonates and PTH. Combination therapies, a common approach in the treatment of other chronic disease, do not confer any particular advantage compared to monotherapies, although the response may depend on the frequency of the administration of the bisphosphonate. In contrast, sequential therapies are very important for clinical practice and depend on the severity of the disease and the mechanism of action of the specific treatment. Such therapeutic approaches need to be explored further and their efficacy in reducing fracture risk, their safety as well as their cost-effectiveness need to be evaluated."}
+{"text": "The patients hospitalized due to heart failure have higher percentage of contacting diseases and mortality rate when compared to other groups of patients, a fact that could be partially attributed to co-existing with health care-associated infections (HCAI).The purpose of the current study is the investigation of both the impact of HCAI on patients with heart failure and the correlation of the infection and the outcome of the disease.70 patients with heart failure who were hospitalized in the Cardiological ICU of a Cardiological/Cardiosurgical Centre from January 2011 until December 2011 out of a total of 95 patients; the other 25 did not meet the specified criteria for their inclusion in the study. The HCAI were defined on the basis of the criteria of the US Centre for Disease Control (CDC). The statistics software Statistical Package for Social Sciences (SPSS) v 17 was utilized for the data analysis.8.57% of the patients with heart failure presented an HSPA related infection. The patients who contacted the infection had a lengthier stay in the Cardiological ICU (p=0.04) and a lengthier overall hospitalization period (p=0.04) when compared to the patients without infection. The mortality rate of the patients with infection was comparatively higher to that of the patients without infection .The infections have a negative impact on the percentage of contacting diseases and mortality rate of patients hospitalized in the Cardiological ICU with heart failure. Further investigation of the correlation of HCAI and heart failure, as the development of knowledge in this specific sector can offer significant results in the therapeutic approach of these patients.None declared"}
+{"text": "Heartfelt congratulations on the inauguration of a new journal addressing the field of occupational and environmental medicine. It is opportune to provide an interactive forum for research and practice in this field, at the time of globalizing economy and rapid changes in our work and life. The initiative of the Korean Society of Occupational and Environmental Medicine in response to the current broad-ranging developments is highly welcome.As strategic goals of our joint action, the International Commission on Occupational Health (ICOH) emphasizes international and regional collaboration in promoting proactive risk assessment and control and in extending effective and basic occupational health services for all workers. In increasingly diversifying work situations, it is essential to focus on comprehensive evidence-informed risk management supported by practical action-oriented procedures that have real impact in the local context. The networking of good-practice approaches in participatory work life improvement processes is particularly important. The scientific developments in this regard are remarkable in all regions of the world. The launch of this journal surely gives new impetus for developing a culture of sustainable prevention in the workplace and in the community, reflecting the advances in this collaboration.We are confident the journal is going to make a significant contribution to the quality of research and practice aimed at our common goals. We are pleased to join our international partners in supporting the journal.The author, Kazutaka Kogi, has given permission for his photo to be used as the cover page."}
+{"text": "On behalf of the Editorial Team of the Journal of Minimal Access Surgery (JMAS)we regret to announce that the following paper published in the October -December 2009 issue of the Journal of Minimal Access Surgery (JMAS) is herebyretracted.In January 2011 we were informed by the Editor of Journal of Indian Associationof Pediatric Surgeons (JIAPS) that following paper carrying very similarmaterial from the same authors was published in that journal.As both the papers are almost identical, with minor differences in terms of thenumber of patients treated, this appears to be a clear case of duplicatepublication. In fact, upon tracing the timeline of submission of the papers inJMAS and JIAPS it became apparent that they were submitted to the journals onconsecutive days.We communicated with the first author of the article published in the JMASseeking an explaination. As none was forthcoming even after six weeks, it wasdecided to retract the article from JMAS. The Editor of the JIAPS has beenapprised of our decision and the Head of the Institution where the publicationoriginated has been informed of the professional misdemeanor on part of theirFaculty members. As is customary in such cases, the indexing authoroties,including PubMed have been intimated of the retraction of the paper fromJMAS.We sincerely regret the time peer reviewers and others spent evaluating thispaper and hope that there are no instances of duplicate publication in the JMASin the future."}
+{"text": "The role of heredity in various ophthalmic diseases has been explored for more than 100 years, with the early focus on conditions that could be identified specifically as straightforward Mendelian inherited disorders. In these disorders, replication of the trait is easily observed and clear-cut probabilities of transmission can be readily calculated. The prevalence of consanguinity within Middle Eastern and African populations is relatively high and this is associated with increased frequency of inherited ocular diseases in this part of the world.Our understanding of the genetics of eye diseases has benefited tremendously from advances in molecular genetics techniques.Unfortunately, the benefit of these advancements remains limited in Middle East and African developing countries.The purpose of this issue is to provide an up-to-date overview of the current status and future directions of the genetics of various common ophthalmic diseases. Reviews on the genetics and genomics of Keratoconus,We are very grateful to our colleagues who have contributed reviews to this special issue of MEAJO and who have served as reviewers for those manuscripts. We hope that this excellent collection of articles will provide the ophthalmologic community with up-to-date knowledge regarding this rapidly growing and changing field of ophthalmic genetics."}
+{"text": "The small intestine is the third in frequency intraperitoneal organ which is injured after blunt trauma of the abdomen. In most of the cases, this type of injuries is accompanied by other injuries, which make it more difficult to diagnose. Failure of diagnosis and delay in treating these injuries significantly increase the morbidity and mortality of these patients. Abdominal visceral injuries after flipping the handlebar of the bike are common in children. Such injuries can cause injury to both solid and hollow abdominal viscera. Unlike children, adults' abdominal visceral injuries after flipping the bike's handlebar are extremely rare. A 25-year-old man was admitted to our department due to progressively abdominal pain after an accident with the handlebar of his bike. The subsequent CT scan after per os administration of contrast medium revealed the presence of free intraperitoneal contrast. It is a rare case of jejunal perforation after flipping the handlebar of the bicycle which was treated by partial removal of the injured part of jejunum and end-to-end anastomosis. To the best of our knowledge this is the first time we describe such an injury with this mechanism to an adult. Intra abdominal organ injuries caused by a stroke of bike handlebars are well documented in children. Flipping the bicycle's handlebars in the abdomen is common in children and can cause a variety of injuries such as traumatic rupture of solid organ , rupture of hollow organs , posttraumatic hernias of the abdominal wall, and even injuries of intra-abdominal vessels  \u20137. ApartThe abdomen is the third most common anatomical area of the body which undergoes blunt injuries, and 75% of these injuries are due to road-traffic accidents . AlthougIsolated lesions of the jejunum secondary to blunt trauma of the abdomen are very rare injuries, and few reports exist in the literature in the form of case reports \u201314.Injuries from the bicycle's handlebar are very rare in adults, and an indication is the absence of literature on such injuries. This fact can be attributed both to differences in behavior between adults and children  and anatomical differences. The main difference is that the most powerful abdominal wall of adult partly protects intra abdominal viscera from such injuries.Here, we present a rare case of an adult with isolated rupture of jejunum after injury by the bicycle's handle bar.A 25-year-old man was admitted to the emergency department after falling off his bicycle. He was hit by the bicycle's handle bar into the left side of the abdomen. The clinical examination revealed a fit young man who had only a scratch (abrasion) on the abdominal wall left of the umbilicus. Hemodynamically he was normal and alert and referred to intense pain at the abrasion site. The abdomen was soft, without signs of peritoneal irritation while sensitivity was only at the point of the abrasion. Laboratory tests, including white blood cells, liver enzymes, and amylase, were normal. The abdominal X-ray in upright (standing) position did not reveal the presence of free intraperitoneal air. Abdominal ultrasound did not reveal any solid abdominal organ injury nor the presence of free intraperitoneal fluid. The pain was attributed to hematoma of the rectus abdominis muscle pricey below the abrasion which was revealed by ultrasound.The pain of the young man was gradually worsening and was mostly described diffusely throughout the whole abdomen. The abdomen remained soft and tender without signs of peritoneal irritation. We proceeded to the administration of per os contrast material and CT abdomen. The CT scan revealed the presence of sufficient amount of free intraperitoneal contrast but did not allow the clarification of the exact point of escape. The free contrast material was detected at the left side of the abdomen, at the area of the descending colon but mainly in the pelvis . The intThe patient was taken to the operating room for exploratory laparotomy immediately after the CT scan . Intraoperatively, fecal peritonitis due to isolated rupture of jejunum 30\u2009cm from the ligament of Treitz was revealed. The rupture was at the center of an extensive jejunum serous layer fissure giving the picture of \u201cblow out\u201d perforation. At the jejunal mesentery there was minimal bruising. Multiple washings of the peritoneal cavity were performed with normal saline, and the restoration of jejunal injury was done with partial resection and end-to-end anastomosis .The postoperative course of the patient was uncomplicated, and he was discharged on the 6th postoperative day. 9 days later he returned with clinical and radiological signs of ileus that led us to the operating room 48 hours later due to deterioration of his clinical picture. The cause of the ileum was adhesions, so we proceeded to lysis of adhesions. The anastomosis was normal without leakage. Five days later the patient was discharged, and a year later he is still free of symptoms.The lesions of the small intestine and even if it is the third in frequency site of injury after blunt abdominal trauma do not exceed 5% of all abdominal injuries . AlthougThe energy transferred to the injury site in the abdominal wall from the handlebar due to its small diameter acts as a javelin releasing the energy of injury to a small area of the abdominal wall. This, in combination with the relatively weak abdominal wall in children, puts the underlying viscera of the abdominal wall in danger. Both the stronger abdominal wall of adults and the less numerous strokes by bicycle make this mechanism of injury to the abdominal organs rare in adults.In our patient, this transfer of energy through the abdominal wall led to pressure on the initial part of jejunum. The extensive serous lesion in the vicinity of the jejunum rupture leads to the conclusion that probably at the time of injury this part of the small intestine was full of content, and the transfer of energy from the injury resulted in a significant increase of the intraluminal pressure leading to a \u201cburst\u201d of the bowel.The diagnosis of lesions of the small intestine after blunt trauma is often particularly difficult as the signs and symptoms of peritonitis appear in a later time. The clinical examination is not reliable in the diagnosis of these lesions as the classical triad of rupture of the small intestine  is present only in 30% of patients with rupture of the small intestine . The preOur patient was not the exception to the rule as both the initial clinical examination and abdominal X-ray in a standing position gave no signs of a possible ruptured hollow organ. The clinical examination is particularly useful and sensitive diagnostic test if repeated in small periods of time because the patient will develop signs of irritation of the peritoneum progressively.For the diagnosis of rupture of the small intestine, the diagnostic peritoneal lavage (DPL) and the focused abdominal sonography for trauma (FAST) have been used .Nowadays, the investigation of choice for early diagnosis of lesions of the small intestine is a CT scan with contrast administration per os. As for the clinical examination, so as for the FAST, the sensitivity of the method is increased if there is enough time given for free intraperitoneal fluid to be concentrated in sufficient quantity so as to be detected with FAST. The CT shows sensitivity and specificity of 92% and 94%, respectively, in the evaluation of the patient with blunt abdominal trauma, and most importantly it displays negative predictive accuracy of 100% which enables us to exclude early any possible lesions of the small intestine  and thusThe main disadvantage of CT is that, for its execution, the patient has to be hemodynamically stable. The general condition of the young man in our case gave us the option to move to CT, and the examination was performed approximately two hours after per os administration of contrast. Although it was not possible to pinpoint the source of leak of contrast from the gastrointestinal tract, the recognition of the presence of free intraperitoneal contrast was an absolute indication to proceed to exploratory laparotomy directly. Free intraperitoneal air was not observed.Although there is no consensus in the literature regarding the effects of delay in treatment of traumatic rupture of the small intestine, the widely accepted position is that the sooner treated, the lower the morbidity for the patient . FailureBoth the rarity of rupture of the small intestine and the inherent difficulties in diagnosis of these kinds of injuries make the need of the physician to have a high index of suspicion imperative, based on the mechanism of injury. The presentation of the above case aims to raise awareness of doctors regarding the possibility of rupture of the small intestine in adults following abdominal injury with the bicycle's handlebar. Knowledge of this rare mechanism of injury takes on added value as more and more adults use bicycles."}
+{"text": "Over the past five years, a new generation of technologies has reduced the cost of DNA sequencing by more than four orders of magnitude, democratizing the field by putting the sequencing capacity of a major genome center in the hands of individual investigators . To expl"}
+{"text": "The present research is a quasi-experimental study with two groups (before and after training). This study compared the two methods of lecturing training and education by the multimedia software. Two selected battalions were considered in which each battalion had 300 personals. Based on the entry and exit criteria and preliminary test of measuring the knowledge (cognitive domain) . Those pThe results of this study have been confirmed the hypothesis (the superiority of multimedia software training than the lecturing teaching method and more influence on the rate of learning) of the study. This study showed that in the case of optimum conditions regarding the space and time, multimedia training software can be more effective than the face to face teaching methods. Therefore, it is suggested to use this method in order to save time and cost of the in-service training personals."}
+{"text": "After publication of this work , we noteGT participated in the design of the study. SQG selected and prepared the samples. XYY participated in the design of the study, drafted the manuscript, and carried out the qRT-PCR studies. HL and XHX carried out miRNA libraries' construction for cloning and SBS sequencing. XQZ and NL participated in the design of the study. LB participated in the interpretation of data. All authors revised the manuscript and approved the final version to be published."}
+{"text": "Not long ago, osteoporosis was considered a normal condition specific to old age; presently, osteoporosis is an affection characterized through the reduction of the mineral bone density associated with the impairment of the trabecular bone structure and implicitly with the increase of the bone fragility. Compliance and adherence to osteoporosis management are of high priority, having a significant effect on the cost effectiveness of therapy The evaluation of the phosphocalcium metabolism for the female patients with osteoporosis, before and after 1 year since the administration of antiresorptive drugs, was realized through osteodensitometry (BMD), that was the most conclusive paraclinical exam used in the diagnosis of osteoporosis, the evaluation of the clinical factors and the analysis of the bone turnover through the determination of the biochemical turn-over markers . Besides the specific analysis of these pathology was made blood analysis.After 1 year since the administration of antiresorptive drugs wasn\u2019t noticed important modifications at the BMD and biochemical markers, could contribute to the creation of a pathogenic profile of the patient that led to a therapeutic decision as correct as possible. BTM changes can also be used for understanding the mechanism of action of drugs in development and identifying the correct dose The pharmacological therapy must be extended under periodical medical control in order to maximize the benefits and to avoid side effects since, depending on the results of the exams, it could be necessary to vary the doses or the type of used drug. The study of the hard support tissues is rendered difficult by the fact that the bone is one of the most unstable tissues from the organism."}
+{"text": "Croatian Medical Journal :942-9) was previously published as a letter to the editor in the International Journal of Cardiology :398-400, published online March 22, 2005). The letter published in the International Journal of Cardiology includes the description of the first case described in the article published in the Croatian Medical Journal, while the other cases presented in the Croatian Medical Journal are original. The authors have apologized.It has come to our attention that a part of an article published in the"}
+{"text": "According to the American Chemical Society's \"Ethical Guidelines to Publication of Chemical Research\":An author's central obligation is to present an accurate and complete account of the research performed, absolutely avoiding deception, including the data collected or used, as well as an objective discussion of the significance of the research. Data are defined as information collected or used in generating research conclusions. The research report and the data collected should contain sufficient detail and reference to public sources of information to permit a trained professional to reproduce the experimental observations [rvations .This presentation will explore some of the implications of this for the publication of new computational methods, do a quick survey of the current state of affairs in our literature, and make a few suggestions about how we can do better."}
+{"text": "Journal of Medical Physics (JMP) in the year 1996. During the past two decades, the technology has changed dramatically not only in the science of medical physics but in the technique of journal production, promotion and presentation of scientific contents. The days of journal printers working on the camera-ready copy are long over. Now everything is electronic and therefore, the up-gradation of the journal became overdue. Having accepted the responsibility of Resident Editorship of JMP with effect from January 2006, an effort was made to publish JMP online. For this, the publication of JMP is entrusted to a publisher \u2013 Medknow Publications Pvt. Ltd.A quarterly publication of the Association of Medical Physicists of India (AMPI), which started in the year of 1976 in the form of AMPI Medical Physics Bulletin under the dynamic Editorship of Dr. U Madhvanth, took a quantum leap forward to become I am delighted to see the publication of JMP with a new look that incorporated the elements of original design and a new layout of printing format. The most attractive development for the journal is that the full text is now published online, in addition to the printed hard copies. Readers are encouraged to visit the website of the journal. The new development is the use of web-based online submission and peer review system for the manuscript submission. The authors can submit the papers easily from anywhere in the world and then track the progress of the manuscripts within the system. It is needless to point out that publication online will enable the journal to reach a much wider readership than has been possible with the print alone. The online journal can be networked within a subscribing institution, permitting the readers to search and browse on their desk.For the success of the journal, it is necessary to gather together a highly reputable Editorial Board, covering all topics of the scope of the journal. The members of the Editorial Board, who are from different parts of the world, are well known for their expertise in their respective fields of Medical Physics. Many of these continue from the former Board of Editors with a few new additions.A major change in the policy of refereeing is that these members of the Editorial Board undertake the refereeing of most of the manuscripts and hunting for a referee outside the Board, with little obligation to JMP, is minimized. The commitment of the members of the Board for refereeing is bound to enhance the standard and the speed of publication. All papers, whether invited or contributory, go to two referees who not only provide recommendations regarding acceptance, revision, rejection, etc, but also provide their comprehensive and positive comments for the authors. The comments enable many papers to be raised to an acceptable standard and minimize the rejection of good work for the lack of the art of presentation.The new era under a reputed publisher and the dedicated editorial team looks very bright and will take the journal to new heights. With this, I look forward to your valuable scientific contributions and cooperation."}
+{"text": "Identificazione Precoce Intervento Breve (IPIB) is the national EIBI working team at the NOA-CNESPS, ISS. The team started its activities in April 2006, publishing the national strategy and organising conferences to announce, promote and disseminate the IPIB training programme. The ISS has been indicated by the National Committee on Alcohol  as the national provider of the training activities in tight connection with the SIA  and the Regions. IPIB training is not yet compulsory for the professionals of the National Health System, but an example of implementation at the Regional level has been the specific training experience of the Tuscany Region, a programme for all the Regions on IPIB in the workplace funded by the Centre for Control of Diseases (CCM) of the Italian Ministry of Health. The courses at the ISS, funded by the Ministry of Health and by the Presidency of the Council of Ministers, Department for Anti-drug Policies, follow a formal evaluation in terms of credits to be earned through the Continuous National Training Programme (ECM). The NOA-CNESPS, ISS, implemented 11 residential courses with the main objectives of enhancing professional skills, knowledge, attitudes and motivation of primary health care professionals when dealing with patients with HHAC. The outcome of the training courses will be presented.The Early Identification and Brief Intervention (EIBI) programme, implemented in Italy since the 1990s, is one of the most important outcomes to be achieved to reduce the level of risk linked to hazardous and harmful alcohol consumption. The NOA-CNESPS of the ISS played a pivotal role carrying out formal activities preparing a national strategy aimed at the implementation of a common standard of EIBI training now explicitly included in all national public health documents and carried out under the frame of different national/international programmes."}
+{"text": "The scarce knowledge of rare diseases among family pediatricians and general practitioners who operate at local level and in frequent contact with rare disease patients is seen in Italy as one of the causes leading to delay in diagnosis and to the lack of reference to a centre of competence.A project aimed at the training of these health professionals was started in February 2009 by the Italian Federation of Rare Diseases UNIAMO with the societies and federations of family paediatricians and general practitioners with the support of FARMINDUSTRIA, Association of Pharmas.The main aims are to train participants to develop a new diagnostic sensitivity but also in the high complexity care of the RD patient (child or adult), to lay the groundwork for the establishment of a handover protocol which allows the RD patients and their family to benefit from a real continuity of care from pediatric to adult age, being this shift of competence now completely random and to create trainers able to transfer this knowledge and these messages in different contexts, at first regional and then provincial, through the organisation of local educational courses as part of the required upgrading of the different health professionals.http://www.malatirari.it) gathering information on different topics where health professionals are at the same time authors and guarantors of the information on the disease from a scientific point of view but also the users.The format of the courses is developed in two parallel sessions and two plenary sessions. The outset is focused on the concept of network. It is followed by two parallel sessions in which the problem of how to raise awareness on possible diagnosis and all the cross-cutting issues of the daily care are addressed. These issues are dealt with either through lectures of competent specialists in the field of complex disability and through a session of interactive clinical cases where the participants can measure themselves with concrete examples with the guidance of specialist. At the same time the Federation has worked to create and update/enrich a database (As for January 2012 11 courses took place in 11 different regions with a total of 619 participants. In the current year 6 courses are to be held in other regions.The increased knowledge among family doctors and pediatricians will better the quality of life of rare disease patients."}
+{"text": "The need for comprehensive HIV prevention in the United States Virgin Islands is tremendous. HIV rates in the Carribbean region of the world is second only to sub-Saharan Africa, and the USVI has one of the highest rates in the United States. The primary mode of transmission in the USVI is heterosexual contact fueled by substance using risks. The presenation will provide an overview of a model program designed to increase HIV testing access and reduce HIV infections.The project is a collaboration between local entities and the Univeristy of Tennessee and Norfolk State University. The program seeks to provide culturally appropriate early intervention, HIV testing, and substance use services to young adults at high risk for contracting HIV.Over the first two years of the project over 160 individuals have participated in the project and have experienced statistically significant improvements in HIV risk behaviors and levels of substance use.The project serves as an example of culturally appropriate interventions for high risk young adult populations."}
+{"text": "The European Union Committee of Experts on Rare Diseases was entrusted with aiding the European Commission in a number of tasks, ranging from the monitoring of initiatives, to recommending improvements and actions to be pursued in the future, in addition to helping strengthen liaison at both European and International levels in the field of rare diseases. The three-year mandate of the EUCERD drew to a close in July 2013 with an impressive record. The EUCERD has laid down the foundations for future work so as to continue to advance in the key areas that have been identified as of interest for the rare disease community at large: centres of expertise, European Reference Networks, patient registries and databases, newborn screening, and indicators for national rare disease plans/strategies. The work of the Committee should now be continued by the newly formed European Commission Expert Group on Rare Diseases. The three-year mandate of the European Union Committee of Experts on Rare Diseases  drew to Commission Communication Rare Diseases: Europe\u2019s Challenge (2008) [Council Recommendation on an Action in the Field of Rare Diseases (2009) [\u201c[guide] and [structure] relevant actions in the field of rare diseases within the framework of their health and social systems\u201d. Although other non-European countries and world regions have policies in place relative to orphan medicinal products, Europe is the only region with a public health policy in the field of rare diseases.Established via the European Commission Decision of 30 November 2009 (2009/872/EC)  population screening, while respecting national decisions and competences\u201d. After examining the results of the Tender study, the Committee was able to identify a number of possible topics for collaboration which respected the principle of subsidarity and after discussion on the subject at Committee level an Opinion [The EUCERD also decided to investigate areas of potential collaboration at European level in the field of newborn screening, at the request of the European Commission following a Tender report on the subject . Current Opinion  was adopState of the Art of Rare Disease Activities in Europe[OrphaNews Europe[. The State of the Art report is a comprehensive document updated each year which presents the current state of activities at both European and Member State level in a range of different areas of the rare disease field, such as rare disease national plans/strategies, expert services, patient organisations, research and orphan medicinal product policy. The first volume of the report presents an overview of the field which presents to the general public in an easily accessible manner the achievements to date and challenges for the future, whereas the following volumes present the environment in greater detail. The report is also available in country-specific volumes for reuse at national level to inform stakeholders of the state of play.The EUCERD has played an important role in the monitoring and dissemination of the results of measures taken at Community and national level in the field of rare diseases, both through the annual report on the in Europe and the ws Europe. The StaOrphaNews Europe newsletter and State of Art report have contributed to the preparation of the Commission reports on the implementation of the Commission Communication and Council Recommendation, currently underway. This report from the Commission will help determine what has been achieved to date and the measures to be taken in the future in the field of rare diseases at European level.Both the report and the newsletter are supported by the EUCERD Joint Action and entrusted to the Scientific Secretariat of the EUCERD, with valuable contributions and input from members of the Committee. Notably, the information collected for the The EUCERD was also charged with assisting the Commission in international cooperation on matters relating to rare diseases. To this end, the EUCERD has welcomed representatives of third countries, such as Japan, to its meetings to partake in discussions and share experiences. The EUCERD has also promoted liaison with other groups implicated in the field of rare diseases (e.g. IRDiRC , EUnetHTThe unique forum of stakeholders provided by the EUCERD has been a key factor in the success of the Committee in advancing discussions on important topics for the rare disease community. The Members have shown dedication and perseverance over the past three years, helping the Committee to achieve much in a relatively short space of time. Great advances have been made in developing concepts, reaching consensus and establishing recommendations for a number of key topics which will be at the centre of national and European rare disease policy in the coming years. The successful collaboration and outputs of the EUCERD is a source of inspiration for countries and regions throughout the world. The EUCERD has laid down the foundations, but much more work is needed in the future as we move from the stage of elaboration to the stage of implementation of these initiatives and policies. It is hoped that the European Commission Expert Group on Rare Diseases, which replaces the EUCERD as of January 2014, will be as efficient and productive as the former Committee in their new mandate so as to not lose the momentum gathered under the EUCERD concerning the main questions and problems faced by the rare disease community.The authors declare that they have no competing interests.SA and CR carried out the analysis of the actions of the EUCERD described in this manuscript, and CR drafted and finalised the manuscript. All authors read and approved the final manuscript."}
+{"text": "Slender eel blenny from both areas of the White Sea were distinguished by a high level of sphingomyelin compared with the daubed shanny from Svalbard, and the amount of total phospholipids was higher in slender eel blenny from Onega Bay than in slender eel blenny from the Tersky shore. The extent of saturation and the signature of polyenic fatty acids varied according to the specific species of the Stichaeidae family under study. These results demonstrate the differences in the trophoecological and hydrobiological conditions of habitations of these species and highlighted the importance of considering certain trends in the lipid profiles of these fishes as specific features of the organization of the ecological and biochemical mechanisms of adaptation.A comparative study of the lipid status ( In addition, the integrity and functional activity of macromolecules and supramolecular complexes should be maintained during this process , was lower in the Arctic Leptoclinus maculatus, which exhibited a level of the minor 22:5(n-3) that was statistically higher.Therefore, the different environments (high-Arctic and sub-Arctic) did not affect the level of total MUFAs, but influenced the level and degree of variation of the FAs 18:1(n-7), 20:1(n-7) and 22:1(n-11) in daubed shanny (The observed differences in the lipid spectra (PLs and FAs) for the two species from the Stichaeidae family may be associated with the unique characteristics of the genetically determined processes of biosynthesis and modifications of certain PLs and FAs, as well as the ecology . These results demonstrate the importance of considering certain trends in the lipid profiles of these fishes as specific features of the organization of the ecological and biochemical mechanisms of adaptation to physiological limits."}
+{"text": "Moving in early career from public health physician to psychiatrist gives me a public health view of psychiatry and an interest in pursuing the goals of widening access to community-based services for people with mental disorders and promoting mental health in communities. Training in social medicine in the UK and psychiatry in Australia lead to studies of homelessness in people living with psychotic disorders, the health of family caregivers, assessing quality of life and mental health promotion.Work with the World Health Organization (WHO) in the Western Pacific Region and the World Psychiatric Association (WPA) worldwide has given me opportunities to work with psychiatrists, mental health workers, service users and others in governments and non-government organisations implementing the recommendations of the World Health Report 2001 in countries with limited resources. My work as WPA Secretary for Publications seeks to improve information exchange in countries irrespective of their wealth. This is an exciting time to be working in a global village with technical capacity to reach into its furthest corners. Psychiatrists supported by WPA can help ensure that vulnerable people and communities and people living with mental disorders are well served in this new environment and no longer left out and left behind. Mental health is inseparable from health and psychiatry is integral to public health. This is the heart of what psychiatry means to me. Beginning professional life as a public health physician shapes my perceptions and gives a peculiar twist to the meaning of psychiatry. My professional journey begins with public health, includes two decades as a clinical and academic psychiatrist with responsibilities for the development of community-based services and continues as a psychiatrist with an interest in mental health and development.Along the way I have been fortunate in encounters with people. Dame Rosemary Rue was regional medical officer in the Oxford Regional Health Authority (UK) in the 1970s when I was a young postgraduate student and then registrar in community medicine in Oxford. As an honorary fellow of the Royal College of Psychiatrists and an astute administrator she discerned a latent interest and proposed that I gain clinical experience in the National Health Service (NHS) at the Warneford Hospital. I had studied medicine and had early clinical experience in my home city of Melbourne in Australia. Hence I began clinical psychiatry as registrar in the day hospital at the Warneford and there encountered a long-term colleague Sidney Bloch. I obtained fellowship of the Royal Colleges of Physicians Faculty of (now) Public Health and later MD, with a dissertation on the topic of schizophrenia and physical illness based on the Oxford Record Linkage Study. Dr John Baldwin guided the work, along with David Christie on my return to Melbourne. I still recall the handwritten letter from Michael Shepherd accepting the resulting paper for Psychological Medicine  and inclPemberton  reflectsWith my head full of social medicine and an interest in psychiatry I returned to Melbourne and gravitated to psychiatry. At this stage I was especially grateful to Rosemary Rue for her inspired notion and scheme for part-time specialty training in Oxford, which later spread to other parts of the NHS. One way and another I was able to work part-time over seven years while my two sons were babies, in Oxford and then by seeking out ways to do it with the help of flexible colleagues in Melbourne. Otherwise I may not have ventured to begin training in psychiatry at Parkville Centre and Royal Park Hospital in Melbourne in the 1980s. There I encountered the teaching and stories of Richard Ball whom I later succeeded as Professor and Director of Psychiatry at St Vincent's Hospital and the University of Melbourne.et al., 1997).Working at Royal Park Hospital where we had been taught by John Cade as Monash University medical students, I found that young people were being discharged after relatively brief hospital stay, jobless, to live in rooming houses. They soon returned, even more demoralised. These experiences along with seeing the inspired work of clinicians of the various disciplines in those times, influenced me to turn to social medicine or public health, in psychiatry. With colleagues at Royal Park we began investigations aiming to draw attention to homelessness in people living with psychotic disorders  and the Then followed studies on the mental health and quality of life of family caregivers . This reProf Norman Sartorius asked me if the work on family caregivers would extend to an interest in assessing quality of life and here began a career-long connection with the World Health Organization (WHO) and interest in quality of life assessment  supportsA public health view of mental health is now emerging more strongly than in the recent past with the understanding that mental health for individuals and communities is the product of many interacting factors. As enshrined in the WHO definition of health, mental health and mental illness are inseparable from health and illness in general and closely related to behaviour. The links in all parts of the world between mental illness and poverty and social disruption are clear. Improving mental health consequently depends on a range of actions at several levels in any country . ResearcI have been keen to support the work of the World Psychiatric Association (WPA) in considering how the profession of psychiatry can contribute to the improvement of public health in countries, whether poorly resourced or wealthy . Psychiahttp://www.wpro.who.int/publications/pub_9290610077.htm). I was privileged to work as acting regional adviser in mental health for WPRO at the time of this policy development. The Western Pacific Region covers 37 countries and territories in Asia and the Pacific, stretching from China and Mongolia in the north, to Australia and New Zealand in the south and west across the Pacific countries to French Polynesia. As I joined in 2001, colleagues at WPRO were working hard to co-ordinate global, regional and national events for World Health Day 2001. I had the opportunity to participate in the launch of the World Health Report and collaborate in global projects like Project ATLAS and the Global Campaign on Epilepsy and to seek the advice of Norman Sartorius in much of this work, including the development of the regional strategy for mental health. The experience of working with colleagues, consultants and advisers in Manila, in Geneva and in countries around the region, was a highlight of this time. It reinforced for me the importance of psychiatrists working effectively with governments, professions, patients and a range of community sectors. International organisations, including WHO and other intergovernmental UN organisations and non-governmental organisations such as WPA and the WFHM, have an invaluable role as partners with national and local groups for advocacy and advice.The WHO Western Pacific Region Office (WPRO) published its Regional Strategy for Mental Health in 2002  Collaborating Centre for research and training in mental health at the University of Melbourne and St Vincent's Health. For a year in 2001-2002 she was acting regional adviser in mental health for the WHO's Western Pacific Region. She is Secretary for Publications and member of the Executive Committee of the World Psychiatric Association and Vice-President of the International Federation of Psychiatric Epidemiology."}
+{"text": "The number of the grant from the Ministry of Science, Republic of Serbia was incorrectly given. The Funding Statement should read: \"This work is supported by the Ministry of Science, Republic of Serbia. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\""}
+{"text": "Statistical concerns over the design and analysis of RCTs in which patients receive therapy as a group are well documented :152-62). By contrast, there is little discussion in the published literature of a range of other challenges to the success of such studies. These include how to plan for and manage: scheduling of participant recruitment, including matching the 'demand' of participants to the supply of interventionists where the RCT evaluates a new service; entry into the study of couples and twins; attrition from the study before and during the course, the threat to protocol compliance and group dynamics; the handling of 'en-masse' protocol violations; the collection of research data by therapists and the delivery of interventions by researchers. Group interventions are heterogeneous and there are a variety of ways in which these issues can be handled. For some, group administration of treatment may be just for convenience and efficiency; for others, the formation and composition of the group may be important for the function of an intervention in which interaction between participants is a key component.This paper collates the experiences of registered CTU study managers and statisticians who have encountered and resolved these questions. Their UKCRCN portfolio studies include medical education, behaviour change and public health interventions delivered, variably, by NHS and University employees as well as third sector volunteers."}
+{"text": "In the Funding Statement, the number of one of the grants from the Austrian Science Fund is incorrect. The Funding Statement should read: \"This study was funded by the Austrian Science Fund . The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\""}
+{"text": "Care security issues are a major challenge for governments, health professionals, patients as well as for practitioners. The practice of medicine cannot ensure optimal security actors hospital in the absence of a legal framework defining the rules and procedures to be followed to prevent oversights and errors, provide care and a quality environment.Conduct a situation analysis of the status of the regulations on the safety of patients and analyze the practical arrangements made on the ground at hospitals in Senegal.The methodology used is based on a series of surveys, interviews followed by a literature review at the hospital.The results reveal a significant gap between the technical and regulatory. Despite the implementation of a national program to fight against NI and the existence of a central management of health facilities, very few codified rules have a direct impact on patient safety were identified.The legal aspects often poorly or not addressed expose virtually all hospitals in the litigation impacts disabling psychological and financial strengths. In the context of research quality and value for money of the rules governing hospital practices to ensure the safety of the patient must be taken. The establishment of rules codified by the authority, and protocols approved by all stakeholders contribute to better patient safety.None declared"}
+{"text": "The publisher regrets that the equation of calculating the percentage of genotypic variation explained by the significant SNPs in the Materials and Methods section was reproduced incorrectly in the above paper.LM is the maximum log-likelihood of the model of interest, logL0 is the maximum log-likelihood of the intercept-only model, n is the number of observations (Sun et al., The percentage of genotypic variation explained by the significant SNPs was calculated by"}
+{"text": "Influence of spatially distributed field of electric impulses in a projection to cervical ganglions of the sympathetic nervous system on angiogenesis in ischemic muscular tissue of a rat\u2019s shin has been studied. It is revealed that blood supply of animals, influenced by the field, is restored through increase in quantity of capillaries in ischemic tissues, and number of products of endogenous intoxication is reduced. Steady growth of number of the diseases caused by blood flow disorder in arterial vessels, demands new ways and stimulation methods for angiogenesis in ischemic tissue , 3, 8. IAt the present time effects of medicamental, surgical and well-known physiotherapeutic methods of treatment of ischemic diseases are concentrated on restoration of blood flow by means of decrease in tone and expansion of vessels or development of collateral blood circulation \u20139, 18.However, the most perspective are the methods aimed at stimulation of angiogenesis in ischemic tissue \u201313. The Methods of angiogenic therapy include: influence by exogenous growth factors in the form of recombinant fibers, genetic designs or stem cells, mobilization of endogenous stem cells from a marrow or tissue depot, and also a combination of these influences. However recombinant fibers have the short period of a semi life in a blood flow, and reception of stem cells is an expensive and labor-consuming method with possible complications in the form of an unpredictable differentiation of stem cells or formation of tumors , 11\u201313.It is known that circulation control is provided with interaction of local humoral mechanisms and vegetative nervous system which by means of regulation of a tonus of a vascular wall defines a blood flow parity in organs and tissues with level of their functional activity . The comThe purpose of this work was to study the possibility of stimulation of an angiogenesis in ischemic limbs of rats through a dynamic correction of activity of sympathetic nervous system by the focused spatially distributed field of impulses of current.The research was carried out on not purebred rats-males weighing 200\u2013250 gr according to the advice of the international committee on the humane treatment of laboratory animals. For the control and experiments healthy animals of one age were used. Rats were held in conditions of a usual laboratory vivarium with natural change of day and night. In the tests 20 animals divided into 4 groups were used. The first group was formed with intact healthy animals. The second group consisted of animals immobilized (fixed on the table) for 15 minutes a day, during 5 days, which was necessary for the application of the apparatus \u201cSimpatocor\u201d. In the third group of animals we modeled ischemia of a muscle of a back paw shin. The fourth group consisted of rats undergone similar operation and in 12 days (the period necessary for development of ischemia) their cervical ganglions of sympathetic nervous system were influenced with the focused spatially distributed field of impulses of current during 5 days, 1 procedure a day.To carry out the procedure the animals were temporarily immobilized on a specially equipped laboratory table. On the areas in the projection of the left and right cervical ganglions of a sympathetic nervous system, daily for 15 minutes within 5 days, multielement electrodes of \u201cSimpatocor\u201d intended for an electrical stimulation of laboratory rats were established.mod=0,1 mm, and frequency of field of electric impulses is chosen equal 300 Hz  corresponds to the period of development of ischemic disturbances in a rat's shin.2 each with the subsequent recalculation on 1 mm2.For histological research a sample of muscular tissue from the ischemic area was taken. To analyze the morphological picture  and to reveal the capillary bed, the sections were coloured histochemically on an alkaline phosphatase according to the method of Gomori. For the purpose of revealing a capillary bed and calculation of quantity of capillaries, paraffinic sections were coloured also immunohistochemically on CD31  \u2013 a specific marker of endotheliocytes. For the immunohistochemical staining the highly specific monoclonal antibodies are applied, capable to be bound only with one antigen with the formation of a steady complex \u201cantigen-antibody\u201d. This approach allows to identify very precisely the cells interesting for a researcher according to their marker antigens . Calculation of the quantity of capillaries in a muscle was carried out in 20 casual areas 0,017 mmThe damaging effect of the stress of immobilization and the ischemia of tissues and cells was estimated by activity of cytolytic enzymes in the blood plasma and by the concentration of molecules of average and low molecular mass in the blood plasma and erythrocytes. The activity of enzymes of an aspartate aminotransferase (2.6.1.1. AST), alaninaminotranspherases (2.6.1.2. ALT), lactate dehydrogenase (1.1.1.27. LDG) were estimated with the standard sets of reactants of the Vital Diagnostics company (St.Petersburg), the quantity of molecules of average mass (MAM) in the blood plasma and erythrocytes was counted according to the method of M.J.Malahova . The optThe calculations and the statistical processing of results of the research were executed by means of software package StatSoft Statistica 6.0. The average arithmetic value in groups and errors of the arithmetic averages were estimated. The results were analyzed with the use of the one-factorial variance analysis, differences between groups were considered authentic at D<0.05.The ischemia arising on the basis of circulation disorder in a shin muscle, owing to the cutting of a femoral artery, is accompanied by an exit in blood of two indicators of cytolysis \u2013 LDG and AST, since the activity of these enzymes in the group 3 is authentically higher, than with the intact animals. The stress influence caused by a short-term immobilization of an animal on a laboratory table, causes growth of activity of enzyme LDG in blood. However, with an immobilization, unlike with ischemia, the discharge of LDG is considered to be the most likely not from a shin muscle, but from a myocardium as more subject to destructive changes at stress, than skeletal muscles. The influence of a field of electric impulses after the modeling of an ischemia of a shin muscle does not aggravate the damage caused by ischemia since the activity of AST, ALT and LDG in the group 4 authentically does not differ from the same indicators of the group 3 Table .It is known that the hypoxia of tissue developing because of the ischemic damage, the integrity disorder of membranes of cells, their destruction promote the accumulation in blood underoxidated products of molecules of average and low molecular mass (MAM), including both products of disintegration of cells, and many factors of inflammation, proinflammatory cytokines. In the Table From the analysis of the data in the Table The reason of the hyperactivity of LDG and the level of MAM in blood plasma of the rats treated after the ischemia in comparison with the group of the intact animals might be the 15-minutes-long fivefold immobilization of the animals, necessary for the procedure of influence by the field of electric impulses. The immobilization even without additional influence causes nonspecific activation of the sympathetic department of vegetative nervous system that can be followed by damage of structures of various organs, augmented permeability of membranes of cardiac hystiocytes and accumulation of products of endogenous intoxication, including catecholamines absorbing at 280 nanometers. Hence, the augmented activity of LDG of the treated animals and the level of MAM in their blood plasma are not bound to the influence of the field of electric impulses. On the contrary, influence by the spatially distributed field promotes authentic reduction of MAM on membranes of erythrocytes of the treated rats (group 4) in comparison with not treated animals (group 3).The data of the biochemical research is confirmed by the histological and immune chemical research of the ischemic muscle preparations.The morphological picture of sections of the ischemic muscles shows clearly the interstitial edema of the skeletal muscular tissue, the structures of endomysum are dilated with isolated openings in capillaries Fig. . The myoOn the sections of ischemic shin muscles of the rat subjected to influence of the fields it is visible that the edema, characteristic for an ischemic lesion, is reduced, neogenesis signs of the retractor apparatus of muscular fiber in the form of visual restoration of cross-section striation Fig. , 4 are dThe quantity of capillaries was counted at a staining of preparations on CD31 \u2013 a specific marker of endotheliocytes. The Table These morphological observations can be estimated as intensifying of processes of an angiogenesis and restoration of the retractor apparatus of a muscular fiber in an ischemic shin muscle of a rat under the influence of FRF.The research of the influence by the spatially distributed rotating field of electric impulses in the projection of cervical ganglions of sympathetic system for correction of a chronic pathology \u2013 muscle ischemia, have shown that influence by this field based on the method of dynamic correction of activity of a sympathetic nervous system: promotes blood supply restoration of the ischemic muscles through augmentation of quantity of capillaries and reduction of products of an endogenous intoxication.The results received in the present work show that application of the spatially distributed rotating field of electric impulses during the influence in a projection of cervical ganglions of sympathetic system stimulates angiogenesis of a muscular tissue of a shin of laboratory rats and promotes reduction of products of an endogenous intoxication. It allows to see this technology as perspective for working out of medical techniques of prevention and treatment of organs damaged by ischemia."}
+{"text": "The list of authors of this article  was incoCo-authors Donald E. Coling and Richard Salvi were omitted in error from the original published author list.The Authors' contributions section should read:JCM designed the study, performed the statistical analysis, and wrote the manuscript. SD designed the study, performed the data analysis, and wrote the manuscript. KFS assisted in the statistical analysis and the writing of the manuscript. DEC and RS provided the datasets for analysis. RAR provided the materials and contributed to the conception of the study. All authors read and approved the final manuscript."}
+{"text": "Nowadays, the quality of life is considered among important and applied topics in various human studies, especially in the case of disabled groups.The objective of the present study is to investigate the quality of life in disabled people with spinal cord injuries who were member of Spinal Cord Injuries (SCI) institute of Tehran.For this purpose, 86 persons of SCI members were selected by simple random sampling method. Data were collected by a self-administered questionnaire. The questions emphasized on the self-perception of individuals on the quality of life.The questionnaire used in this study was adapted from Lancashire and Wisconsin questionnaires in which the social-cultural aspects of Iranian people have been considered. The questionnaire consisted of two parts. The first part included 5 questions on demographic data including age, gender, lesion characteristics such as type and duration of injury. The second part consisted on questions related to the 11-fold dimensions of the quality of life .The results of the present study showed that 73.3% of patients with spinal cord injury assessed their quality of life as moderate and good with almost same percentage. The examination of 11-fold dimensions of the quality of life showed that the mean score of the quality of life of the studied group in the social relations was higher than the score obtained in the other dimensions (3.67 of 5 points). However, in the case of married individuals, the mean score of the quality of life in the family relationship was higher than this value (3.95 of 5 points).The examination of the relationship between the quality of life and age, gender, cause, type and duration of the lesion showed that the quality of life in women with spinal cord injury was superior than men (p less than 0.01). The mean score of the quality of life for women and men was 3.3 and 2.9 of 5 points, respectively. However, no significant relationship was found between the quality of life and age, cause of injury, type of injury and duration of injury.The results indicate this fact that a high percentage of cases expressed the level of their life quality as moderate and good which is very close to the quality of life reported in individuals with spinal cord injury in other parts of the world.Quality of life, Spinal cord injury, Disable groups, Self administered questionnaire"}
+{"text": "The knowledge of the nurse in advanced life support and the impact of continuing education in cardiopulmonary arrest in the ICU. Faced with the complications of cardiopulmonary arrest (CPA) in the ICU it is important for nurses to be prepared for emergency actions, mastering the techniques of care and maintaining well-trained staff. The objective was to identify and describe the knowledge of the nurse in advanced life support (ALS) and the impact of continuing education PCR in ICU.Exploratory, descriptive bibliographical integrative analysis of available literature, using the keywords 'PCR', 'ICU', 'Continuing Education', 'Education', 'Nursing', which were published between 2002 and 2012, in both conventional and virtual libraries.Twenty-six publications found and gave rise to two categories. First, the identification of clinical signs and CPR maneuver by the nursing staff and the nurse in the PCR are essential for successful resuscitation: the authors agree that the service systematized-based SAV protocol is essential for there to be success in CPR. Recognition theoretical and practical skills of the staff are among the most important determinants of the success rates of RC . Thus, iContinuing education has significant impact in improving the level of knowledge of nursing professionals, leading to survival of patients in a hospitalized ICU, as it ensures the identification of the signs and symptoms of CRP in patients in the ICU."}
+{"text": "Current Neuropharmacology. The impact of Current Neuropharmacology is steadily increasing and this volume marks another important milestone as the journal increases to six issues per year. The standard and range of reviews and special issues consistently attains high standards. For Current Neuropharmacology to continue to thrive it is important that diversity and high standards are maintained. Of course, this depends on the dedicated efforts throughout the year of authors, Editorial Board members, Special Guest Editors, anonymous reviewers, and of course the efforts of Bentham Science Publishers. I express my thanks to all of you.This Editorial marks the beginning of the eleventh year of publication of Current Neuropharmacology is reflected in the content of the present issue of the journal. A series of \u2018Hot Topic\u2019 papers on Advances in Dystonia is guest-edited by Christopher Bragg and Nutan Sharma. This is followed by a group of papers that reflects the diversity and wide scope of neuropharmacology. With its impact, visibility and availability on PubMed Central, the journal offers an excellent vehicle for the publication of novel reviews and hypotheses.The diversity and high standard of work published in"}
+{"text": "The history of HIV is also the history of antiretroviral therapy (ART), the single most important measure in combating the HIV pandemic. The outcomes and in particular the interpretation of some early ART trials have greatly influenced the development of treatment guidelines and the course of ART implementation. A review of the development of NRTIs to date could be seen as a handbook of cautionary tales, relevant to the development of all future HIV therapies.The early studies examining the use of acyclovir in the treatment of HIV and the incremental implementation of new drugs, progressing from mono and dual therapy to triple ART therapy, are good examples of the influence that particular studies have had on the subsequent treatment of HIV in the clinic. But the consistent modest effects in trials were not always given sufficient consideration and we did not always define the mechanisms at work. A number of trials were also needed before we understood that studying the right population - and using the right combination of therapy - was essential, if we were to avoid overlooking effective treatments options. Other slowly-learned lessons were that long-term follow-up studies are necessary to avoid those complications that are not detected in standard trials; they are also needed to detect in a reliable and timely way those issues which raise safety concerns.The progression to cART of course was not without complications; good examples being the recognition and investigation of the underlying mechanisms of lipodystrophy, and the identification of an association between abacavir and myocardial infarction. The development of ART demonstrates the importance not only of the original ART trials but also continued investigation of specific drugs and regimens in the clinic to identify and manage any subsequent treatment issues that may become apparent after the rollout of these therapies. NRTIs are the backbone of therapy but only two drugs in the class are presently preferred in the current guidelines and there are too few active candidates in the pipeline. The future of this essential component of cART is uncertain."}
+{"text": "The modeling of the dynamics of interaction between ERK and STAT signaling pathways in the cell needs to establish the biochemical diagram of the corresponding proteins interactions as well as the corresponding reaction-diffusion scheme. Starting from the verbal description available in the literature of the cross talk between the two pathways, a simple diagram of interaction between ERK and STAT5a proteins is chosen to write corresponding kinetic equations. The dynamics of interaction is modeled in a form of two-dimensional nonlinear dynamical system for ERK\u2014and STAT5a \u2014protein concentrations. Then the spatial modeling of the interaction is accomplished by introducing an appropriate diffusion-reaction scheme. The obtained system of partial differential equations is analyzed and it is argued that the possibility of Turing bifurcation is presented by loss of stability of the homogeneous steady state and forms dissipative structures in the ERK and STAT interaction process. In these terms, a possible scaffolding effect in the protein interaction is related to the process of stabilization and destabilization of the dissipative structures (pattern formation) inherent to the model of ERK and STAT cross talk."}
+{"text": "The risk of infection control in dental health care settings must be an institutional priority, it is an ethical, moral and legal obligation to provide care in hygienic conditions so as to reduce the risk of infection in acts of dental care. The problem that arises in the Tunisian context is primarily a misperception of risk on the one hand, and non-compliance with standard and supplementary precautions.We conducted a survey of dentists in the area Bizerte to understand the perception of dentists of infectious risks associated with dental care and evaluate their knowledge of prevention of such risks.A self-administered questionnaire was used for data collection. The number of explored items is 43 divided into three categories: i) perception of risk of infection in the dental office ii) general prevention of healthcare associated infections in dental care iii) accidental exposure to blood.The number of respondents to the questionnaire assessment of knowledge and risk perception is 62 dentists (18 in the public sector and 44 in the private sector). Overall, the level of knowledge of interviewed dentists , proved quite satisfactory whether old or new to the practice of the profession, whether in the public or private sector with disparities between different explored items.Considering the results of this study, the first of its kind to our knowledge in the Bizerte region, we issue the following recommendations to improve the hygiene and safety of dental care in the region : dental awareness on nosocomial infection risk, training in health and safety of dental development of procedures and datasheets health and safety of dental care.None declared."}
+{"text": "An accurate computation of the temperature is an important factor in determining the shape of a bubble around a nanowire immersed in a liquid. The study of the physical phenomenon consists in solving a photothermic coupled problem between light and nanowire. The numerical multiphysic model is used to study the variations of the temperature and the shape of the created bubble by illumination of the nanowire. The optimization process, including an adaptive remeshing scheme, is used to solve the problem through a finite element method. The study of the shape evolution of the bubble is made taking into account the physical and geometrical parameters of the nanowire. The relation between the sizes and shapes of the bubble and nanowire is deduced. The measurement of the aspect ratio of the bubble Rb allows predicting the aspect ratio of the nanowire Rn through the relation Rn = f\u22121(Rb). Vb = \u03c0AB) as function of the volume of the nanowire  for each wavelength. From the computed data (vapor bubble for each nanowire and for each wavelength) and by using the same method and the same algorithm, a function g can be obtained through a fit. That function g allows obtaining the relation between the volumes ln\u2061(Vb) = g(ln\u2061(Vn)). The g function is continuous and strictly increasing; therefore the inverse function g\u22121 also exists. The measurement of the bubble volume Vb can be used to determine the volume of the nanowire Vn through the relation ln\u2061(Vn) = g\u22121(ln\u2061(Vb)). With the two functions f\u22121 and g\u22121, the size and shape of the nanowire can be obtained from the information on the bubble:lgorithm \u201329. The 2 immersed in water and an electromagnetic wave. The increase of temperature is related to the geometry of the nanowire which leads to an increase in the shape and size of the bubble. That solution is computed by developing an adaptive remeshing method. That allows to compute with accuracy the temperature by adapting the mesh to the evolution of the bubble. The coupled problem  is solved through an adaptive loop process allowing converging to a stable solution and decreasing the number of nodes. The influence of the laser source and the geometrical parameters  related to the size and shape of the bubble are presented and analyzed. The aspect ratio and the volume of the bubble can be expressed as function of the aspect ratio and the volume of the nanowire. By solving the inverse problem, two functions are obtained enabling finding the size and shape of the nanowire from the size and shape of bubble.The paper focuses on the forming and the evolution of the shape and size of the bubble through a photothermal process between a nanowire of TiO"}
+{"text": "The studies suggested a psychodiagnosis of cancer patients according to the SPb regenerative pyramid model.Thirty patients with lymphoma diseases, 30 patients with cancer of the reproductive organs , and 39 patients with chronic myelogenous and lymphocytic leukemia were investigated.The peculiarities of response to diseases in cancer patients were found according to the nosological group. It was shown that, despite the dominance of conventional adaptive ergopathic type of attitude to the disease (which is characterized by an obsessive attitude to work) in all studied groups, the presence of a high level of sensitivity component illustrates the lack of success to adapt to the situation of the disease. However, the presence of strong positive correlation between the type of response to disease and the level of depression in a group of hematological malignancies suggests a maladaptive system attitude to the disease in these patients. An analysis of coping behavior (by the method of Ways of Coping Checklist) of these categories of patients revealed a negative correlation between the level of depression and the most stressful coping strategies: seeking social support and positive reappraisal.The obtained results have theoretical value in understanding the regularities of formation of coping behavior of patients with cancer pathology in different nosological groups."}
+{"text": "This paper attempts to describe and analyse the policy processes that led to the granting and implementation of the government use licenses to enable the import and production of generic versions of medicines patented in Thailand. The decision to grant the series of government use licenses was taken despite much domestic and international controversy. The paper demonstrates that the policy processes leading to the granting of government use licenses are a successful application of the concept of  \"the triangle that moves the mountain\". This is a well-known conceptualisation of a philosophical and strategic approach to public policy advocacy in Thailand, which propounds that the effective bridging of three powers; a.) Knowledge and evidence generated by research and analysis, b.) Civil society movements and public support, and c.) Leadership of policy makers and politicians; in a synergistic \"triangle\" can move \"mountains\", meaning the resolution of seemingly insurmountable problems. The paper provides insights into the policy context for the decision and analyses the roles of key actors, their motivations and the policy processes in the country. In 2001, Trade Ministers at the World Trade Organization (WTO) Ministerial Conference in Doha signed a declaration confirming their common understanding that the provisions of the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) did not prevent governments from taking the necessary policy and legal measures to promote access to medicines and protect public health .Although the Doha Declaration was sought by the developing country governments to affirm their rights, there have only been a few cases of countries utilising TRIPS flexibilities since the adoption of the Declaration . One rea1 to enable the import and local production of the generic versions of seven medicines that are patent protected in Thailand. The first license, granted in November 2006, was for the Antiretroviral (ARV) drug, efavirenz (EFV) [In 2006 and 2008, the government of Thailand decided to grant government use licensesnz (EFV) . The secnz (EFV) . Four adnz (EFV) , erlotinnz (EFV) , and imanz (EFV) . The govIn Thailand, the granting of government use licenses had its share of critics who were concerned, among other things, that the political and economic costs of the licenses would outweigh the benefits. They feared the imposition of trade and other sanctions from foreign governments opposed to such a measure, as well as retaliation from the affected pharmaceutical companies ,13. The This paper describes and analyses the policy processes that, in the face of these pressures, led to the granting and implementation of the government use licenses to enable the import and production of generic versions of medicines patented in Thailand. The aim is to provide insights into the political context, the roles of key actors and their motivations, and the processes which led to these decisions being taken and to demonstrate that the decision to grant the government use licenses was a successful application of the concept of \"the triangle that moves the mountain\".This is a well-known conceptualisation of a philosophical and strategic approach to policy advocacy by Dr Prawase Wasi, a central figure in Thailand's political and social reform and public health arenas. Dr Wasi's triangular model Figure  stresses2[Dr Wasi synthesised this concept from processes which led to political reform in 1997 that culminated in the adoption of the 1997 Constitution, B.E. 2540 (1997), popularly known as the People's Constitution2. Since t2,19.The remainder of the paper is organised as follows. The next section describes the historical aspects of the patent and access to medicines issue in Thailand, examining how key actors were sensitised on the interlinked issues of rising costs of ARVs, pharmaceutical patents and the use of the TRIPS flexibilities. Then, the paper examines the policy and decision-making processes within the government in the lead up to the decision to grant the government use licenses. This part comprises an analysis of the convergence of key actors and processes both in the domestic and international spheres, i.e. how the different actors in various processes came together as a triangle to support the grant and implementation of the government use licenses. The last section describes the different aspects of policy implementation by the relevant authorities, including the means by which opposition from within the government and the pharmaceutical industry was addressed.3 [It can be said that Thailand has had more than two decades of experience in addressing the debates on patents and access to medicines. In the mid-1980s, during the General Agreement on Tariffs and Trade (GATT) Uruguay Round of multilateral trade negotiations leading up to the establishment of the WTO and its Agreements (including the TRIPS Agreement), the US administration began to put pressure on developing countries, including Thailand , to incr3 .The Drug Study Group conducted a study on the impact of enhanced patent protection on medicines on Thailand's health care system which revealed that higher levels of patent protection would significantly increase the value of drug imports by 72 percent and hinder the development of the national drug industry . These fDuring the late 1990s, the global movement for equitable access to ARV treatment gained increasing momentum, fuelled by the public outcry against the high cost of patented ARV treatments . AdvocacIn 2001, the civil society coalition eventually challenged the BMS patent at the Thai Central Intellectual Property and International Trade Court on grounds that the patent on DDI included an unlawful amendment that effectively broadened the scope of the patent over all dosage strengths . The ame\u00ae, an ARV combination of lamivudine and zidovudine on grounds that the combination of two existing drugs was not an invention that merited patent protection [Since then, the civil society coalition has used legal challenges to defend and promote their right to access to medicines. The Health and Development Foundation filed a pre-grant opposition to the patent application from GlaxoSmithKline (GSK) on Combid/Combivirotection . Effectiotection .\"(A) person shall enjoy an equal right to receive standard public health service, and the indigent shall have the right to receive free medical treatment from State's infirmary. The public health service by the State shall be provided thoroughly and efficiently. The State shall promptly prevent and eradicate harmful contagious diseases for the public without charge\".The passage of the National Health Security Act in 2002 resulted in the establishment of the Universal Healthcare Coverage (UC) scheme which ensures all Thai citizens the right to health care and access to medicines listed on the National List of Essential Medicines (NLEM). Further, the amended Thai Constitution of 2007 guarantees access to healthcare as a right, by explicitly stating that, Before 2003, the triple ARV drugs were not initially included in the NLEM due to the high prices of the drugs . ARVs weSignificant financial resources were still required to ensure access to needed medicines, particularly in light of the need for second-line ARVs for patients who had developed drug resistance to first-line treatment. Moreover, there were also potential increased costs for the universal access scheme as changes were being considered for the first-line ARV treatment in Thailand. MOPH was considering the inclusion of efavirenz as a first-line ARV but had been unsuccessful in its negotiations for price reductions with the patent holder, Merck Sharp & Dohme (MSD), over the period between 2004-2005. Consequently, the MOPH initiated a feasibility study of the use of TRIPS flexibilities for efavirenz .This section suggests that medicine patenting and its implications on access to medicines are not new issues in Thailand, but have been recognised and dealt with by various groups of government officials and health advocates. Confrontations between the Thai civil society coalition and the US government and pharmaceutical companies over such issues have taken place over two decades. It demonstrates how knowledge and evidence generated by researchers has been used by civil society for effective and strategic campaigns. This also shows that expertise and experience related to government use licenses have gradually accumulated prior to granting government use licences for the seven medicines in 2006 to 2008.The major concern of the government in committing to universal access to essential health services under the UC scheme was the long-term sustainability of the government-funded health plan, particularly in light of the need for more expensive medicines (such as efavirenz and second-line ARVs). Increasing access to these patented ARVs was a central issue. The role of generic drugs in reducing the cost of HIV treatment has been well-illustrated by the introduction of much lower-priced Indian-made generic ARVs to the global market. Generic ARVs have revolutionised the scale-up of HIV treatment programmes in many developing countries, including Thailand. Increasing concerns about drug resistance to existing treatments, the prohibitive cost of second- and third-line ARV therapy and the patent barriers for local generic production were factors that played a significant role in convincing policy makers to seriously consider the use of TRIPS flexibilities, as a means to ensure universal access to ARVs.Within the government, the National Health Security Office (NHSO) was mandated as the agency with responsibility for the payment, administration and management of the national program for universal access to HIV treatment. Accordingly, it was in the interest of the NHSO to consider the options for ensuring access to patented ARVs at affordable cost. As with civil society groups, the policy makers in NHSO also underwent a process of capacity building on intellectual property rights, pharmaceutical patents and the TRIPS Agreement - traditionally the domain of other government agencies - as the global debate on patents and public health unfolded. Participation at international fora, such as the World Health Assembly (WHA) and WTO meetings, as well as collaboration with international NGOs such as Knowledge Ecology Institute, M\u00e9decins Sans Fronti\u00e8res, Third World Network, and Oxfam contributed to their learning curve.In early 2006, the need for an effective policy on these issues was discussed within the NHSO. The then National Health Securities Board appointed a \"Subcommittee to Implement Government Use of Patented Medicines and Medical Devices\", chaired by the Secretary General of the NHSO, to assess the need for the use of government use licenses and to develop the criteria to guide the selection of medicines for which the government use licenses was needed. Membership of the Subcommittee comprised senior officials from NHSO, MOPH, Food and Drug Administration (FDA), the Department of Intellectual Property, as well as representatives from health and consumer-protection groups in Thailand.Efavirenz was initially identified as a candidate by the Subcommittee and a proposal to grant a government use licence for this medicine was submitted to the Health Minister . The app4. The Health Minister also demonstrated both commitment to public health and leadership with clear directives, active involvement and unambiguous support for the government use licences. This was important in order to generate the required action from civil service technocrats [Although the civil society coalition had enjoyed significant success in the legal challenges of DDI and combination of lamivudine and zidovudine patents, the government use licenses would have not been implemented effectively without strong support from politicians and the civil service technocrats. Many of the politicians and technocrats involved in the decision to grant the government use licenses shared a strong sense of public spirit that had been inculcated since they were medical students in mid 1970shnocrats .In building the third point of the triangle, comprising the political and civil service sectors, it is not only the awareness and capacity among politicians and government officials to understand the information generated by scholars and civil society but also their commitment and leadership that were critical to the process. This final aspect completed the triangle, providing the political momentum to grant and implement the government use licences. Furthermore, it should also be noted that the successful implementation of the government use licences would not have been possible without a legitimate and transparent process for decision-making. The next section describes this process.In early 2007, two committees, namely the \"Committee on Price Negotiation of Patented Essential Medicines\" and the \"Committee to Support Government-Use Implementation\", were appointed by the Health Minister to facilitate the implementation of the government use licenses ,41. The The Committee on Price Negotiation of Patented Essential Medicines invited representatives of the relevant patent-holding pharmaceutical companies to discuss price reductions for the medicines under the government use licenses. It was believed that the announcement of government use licences would help to ensure the success of such price negotiations . Althougin late 2006 and early 2007, there were further indications of a weakening respect for patents, as the Thai Government announced decisions to issue compulsory licenses for several patented pharmaceutical products. While the United States acknowledges a country's ability to issue such licenses in accordance with WTO rules, the lack of transparency and due process exhibited in Thailand represents a serious concern\". Further, on 1 July 2007, the USTR announced that privileges under the Generalized System of Preferences (GSP) were removed for three Thai products: gold accessories jewelry, polyethylene terephthalate, and flat screen television sets .The Committee to Support Government-Use Implementation functioned as the coordinating forum for the related task forces under the MOPH and NHSO, and for the other government ministries, NGOs, academic institutes and individual experts. The Committee was also the focal point to address critiques and reactions from opponents of the government use licenses. The granting of these government use licenses had provoked a mixed reaction from governments, international organizations and civil society organizations. There was strong objection from the patent holding pharmaceutical companies. In the case of Abbott Laboratories, in March 2007 the company decided to withdraw its applications for marketing approval on seven new drugs in protest at the government use licenses on its product, Kaletra, the LPV/r combination. Subsequently, the Office of the United States Trade Representative (USTR), in its Special 301 Report of 2007, elevated Thailand from Watch List (WL) to Priority Watch List (PWL) on the grounds that \"In an effort to inform the public and to garner support, the Committee to Support Government-Use Implementation published two documents, the so-called \"White Papers\", which detail the rationale, legal issues and decision-making process of the government use licenses -46. ThesIn a similar move, the Health Minister who granted the government use licenses also sought support from WHO Member States at the WHA in 2007 by addressing the Assembly on these issues. The WHA that year adopted a resolution urging the WHO Director-General to provide technical and policy support to countries on the use of TRIPS flexibilities  and ThaiHaving described the Thai experience with use of the TRIPS flexibility, specifically the government use licenses, the paper now concludes with some observations on lessons that may be useful for other countries. Firstly, implementing TRIPS flexibilities as a means to ensure access to medicines is a right that can be exercised by all WTO members. The Doha Declaration affirms that the TRIPS Agreement does contain a degree of flexibility that permits governments to consider different options when formulating laws and policy in relation to patent protection and public health. In Thailand, the granting of government use licenses was supported by the provisions in the Thai Patent Act B.E.2542 (A.D. 1999), which permit the use of compulsory licenses by the private and public sectors. Together with the National Health Security Act B.E.2545 (A.D. 2002), it enshrines the Thai people's right to health and universal access to essential health care and these legal provisions made a strong case for the government use of TRIPS flexibilities.Secondly, the synergy between three sides of the triangle; a.) knowledge and evidence generation, b.) mobilization of civil society and public support, and c.) the leadership of politicians and policy makers, was key to the success in policy formulation and implementation. As already mentioned, research and technical capacity in the different but inter-related fields of intellectual law and public health is required to provide a solid evidence base for decision-making. This was illustrated by the Thai experience, where both civil society and the public sector were able to rely on information and evidence to support their case. The commitment to undertaking analysis and compiling information of policy to justify the decisions made were equally important. The granting of government use licenses in Thailand can be regarded as the result of years of learning and collaboration amongst scholars, the civil society coalition, and policy makers. Aside from the coordination and synergy of the three points of the triangles, windows of opportunity and timing can often be critical factors for positive outcomes. A number of developments in Thailand and on the international stage were instrumental in pushing forward the granting of government use licenses.Thirdly, adequate management capacity at the national level and appropriate institutional mechanisms are vital for the implementation of TRIPS flexibilities. The establishment of an open and transparent process and the related committees, by which a collective decision could eventually be made within the Thai government, helped to ensure effective implementation of the government use licenses. Strategies to foster collaboration between the government authorities, civil society organizations, foreign experts, and international agencies in the relevant fields were also critical for mobilizing broad based support from other countries and actors.Finally, there has been much criticism of the Thai government decision to grant government use licenses. While some critics challenged the legal validity of the licenses under international and domestic law, there are also those who question the political and economic costs of the grant of these licenses, in terms of trade sanctions imposed by foreign governments opposed to the government use licenses, and of pharmaceutical companies retaliating by withdrawing or delaying drug registrations in Thailand. These critics argue that these costs would far outweigh the benefits of the government use licenses. Another paper in this series will present the results of an attempt to assess the public health, economic and social impacts of the government use license with a view to clarifying aspects of the controversy and enabling a better informed, evidence-based debate between key stakeholders and offer further lessons learnt from Thailand's experience to decision makers in other settings.Non-financial competing interestsSuwit Wibulpolprasert was responsible for assessing the political risks and clarifying the legal aspects of the government use licenses. Vichai Chokevivat was the Chair of the Committee to Support Government-Use Implementation.SW and VC have made substantial contributions to conception and design. CO and IY have been involved in drafting and revising the manuscript. All authors have read and approved the final manuscript.Dr Suwit Wibulpolprasert is the Senior Advisor on Disease Control and Prevention at the Ministry of Public Health. Dr Wibulpolprasert began his career as a general practitioner in the rural hospitals in Thailand, later becoming the Chairman of the Rural Doctors Society in 1984. He later became a Director of the Technical Division in the Food and Drug Administration of Thailand in 1991-1994. This was followed by a series of appointments to other senior positions within the Ministry of Public Health, including the Director of Bureau of Health Policy and Planning, Assistant Permanent Secretary, Deputy Permanent Secretary, and Senior Advisor at the Ministry of Public Health.Dr Vichai Chokevivat is currently the chair of the Board of the Government Pharmaceutical Organisation of Thailand. He used to be the Chair of the Committee to Support the Implementation of the Government Use of Patents, established under the Ministry of Public Health. Dr Chokevivat used to be the Chair of the Rural Doctors Society in 1982 and received the Outstanding Rural Doctor Award from Siriraj Hospital and Medical School in 1986. He had also held the posts of Secretary-General of the Food and Drug Administration and Director-General of the Department for Development of Thai Traditional and Alternative Medicines, before retiring from his final post as Senior Advisor at the Ministry of Public Health in 2007.1 The government use licence is a form of compulsory licensing, which permits the government to license the use of a patented invention to itself or a third party, without consent of the patent holder. Such use of a patent is permitted under the provisions of Article 31 of the TRIPS Agreement, which allows for the \"public non-commercial use\" of a patent by a government without the authorization of the patent holder.2 The 1997 Constitution, known as the \"People's Constitution\", is a landmark in democratic constitutional reform. It provides the basis for the protection of constitutional rights and civil liberties of the Thai people. The drafting and promulgation of the Constitution illustrates the successful application of \"the triangle that moves the mountain\". The first point of triangle was the Committee for Democratic Development, which was responsible for generating the relevant knowledge and evidence to formulate recommendations for political reforms. The other points of the triangle were represented by the public and civil society organizations, which mobilized public support for the reforms and the political actors and the bureaucracy, which supported the process of political reform. The convergence of the three points of the triangle provided the momentum needed to move forward the process of political reform that led to the People's Constitution.3 Drug Study Group is a civil society coalition in Thailand set up in 1975. The group consists of academia from various universities who are working on the issues of access to essential drugs, rational drug use and consumer protection.4 These politicians and technocrats were former leaders of the Rural Doctor Society, a strong civil society organization. It was set up by these leaders since 1978 and is still an influential organization with high social credibility."}
+{"text": "Zero-valent iron nanoparticles rapidly aggregate. One of the reasons is magnetic forces among the nanoparticles. Magnetic field around particles is caused by composition of the particles. Their core is formed from zero-valent iron, and shell is a layer of magnetite. The magnetic forces contribute to attractive forces among the nanoparticles and that leads to increasing of aggregation of the nanoparticles. This effect is undesirable for decreasing of remediation properties of iron particles and limited transport possibilities. The aggregation of iron nanoparticles was established for consequent processes: Brownian motion, sedimentation, velocity gradient of fluid around particles and electrostatic forces. In our previous work, an introduction of influence of magnetic forces among particles on the aggregation was presented. These forces have significant impact on the rate of aggregation. In this article, a numerical computation of magnetic forces between an aggregate and a nanoparticle and between two aggregates is shown. It is done for random position of nanoparticles in an aggregate and random or arranged directions of magnetic polarizations and for structured aggregates with arranged vectors of polarizations. Statistical computation by Monte Carlo is done, and range of dominant area of magnetic forces around particles is assessed. These particles are used for decontamination of groundwater and soil and especially for decontamination of organic pollutants such as halogenated hydrocarbons 0 and itsocarbons . Becauseocarbons ,17-20. Iocarbons . The mag0 and 85.7% of Fe3O4. We use these data for our model. Therefore, we suppose the same magnitude of vector of polarization for all nanoparticles. Our model of magnetic field around the iron nanoparticle is based on the model of magnetic field around a magnet described in :In prior work , we deria is the radius of the nanoparticle, and  are the coordinates of the point r. Here, the direction of the vector of polarization M is set to the direction x3, M is the magnitude of the vector M.where MA computed as a vector sum of vectors of polarization of all nanoparticles in the aggregate A Mcomputed as an average of magnitudes of all nanoparticles divided by number of nanoparticles in the aggregate n:From Equations 2 and 3, the analytical computation of magnetic force between two iron nanoparticles can be obtained. Since the nanoparticles aggregate, the magnetic force between aggregates is required to derive. One aggregate can be composed of millions of nanoparticles. It would be time-consuming and very difficult to analytically compute these forces. As a consequence, the forces are computed numerically, either as a sum of magnetic forces between every nanoparticle in one aggregate with every nanoparticle in second aggregate or as one magnetic force between two averaged aggregates. Averaged aggregate is a big homogeneous particle with direction of polarization The rate of aggregation depends on the vectors of polarization of aggregating particles and on distance between the particles. Rate of aggregation changes with changing structure of ordering of nanoparticles in the aggregates. In this section, we imagine the model of structure of aggregate as sphere with randomly located nanoparticles in the aggregate either with random directions of polarization of every nanoparticle Figure  or with In this section, we suppose structured ordering of nanoparticles in the aggregate. Vectors of polarization of the nanoparticles respect the structure. According to our observations of behavior of spherical magnets, the magnets create clusters with least energy. With small number of magnets, the most created clusters are circles formed by chains. We considered also other structured models of aggregates - cubic and honeycomb. Directions of vectors of polarization of nanoparticles in these models of structured aggregates are shown in Figures In the prior work , we usedUnstructured model of ordering of nanoparticles in an aggregate has been computed by averaging and by summation of magnetic forces between every nanoparticle in first aggregate and every nanoparticle in second aggregate. In Figure The limit distance estimated by averaging decreases more rapidly with growing aggregate than properly computed magnetic forces. It means that for large aggregates the averaging cannot be done, for the case of attached particles. There is a lot of nanoparticles in the big aggregate, and nanoparticles closer to the other particle have larger influence on the magnetic force between the aggregate and the examining nanoparticle. Comparison of averaged magnetic forces and summed magnetic forces for attached particles is done in Table You can also see the results for magnetic forces between two interacting aggregates Figure . The comOn the basis of known concentration of particles, we are able to estimate the approximate distances among particles and to choose the right model of computation of magnetic forces and limit distances among the particles.We examined structure of aggregates in which vectors of polarization of all nanoparticles were the same in magnitude and direction, distribution of nanoparticles in the aggregate was unstructured. Comparison of limit distances for unstructured model with random directions of polarization of nanoparticles in the aggregate and for structured model with the same directions of polarization is shown in Figure Further we examined model of structure of aggregates in which nanoparticles creating the aggregate are distributed to a structure and vectors of polarization respect the structure. According to our observations of behavior of spherical magnets, the magnets create clusters with less energy in which vectors of polarization subtract one another and final vector of polarization approaches to zero. Consequently, in the case of structured ordering of nanoparticles, the magnetic forces among the particles have not any influence on the aggregation of particles. In the following table, magnitude of magnetic force between a nanoparticle and a cubic aggregate attached to each other is presented. Directions of polarization of nanoparticles in the aggregate are set according to the Figure Even though the distance between the particles is the smallest possible, the magnetic forces between the particles are negligible in comparison with gravitation forces. For structured aggregates with polarization of nanoparticles respecting the structure, the magnetic forces have insignificant influence on the rate of aggregation of the particles.We examined the influence of structure of nanoparticles in aggregates on the resulting magnetic field around the aggregates. The comparing parameter was size of magnetic forces among particles and the limit distance. According to these two connected parameters, we are able to estimate the degree of influence of the magnetic forces on rate of aggregation of particles. We analyzed magnetic properties of unstructured aggregates with randomly distributed nanoparticles with random direction of polarization in the aggregates and of structured model of aggregates with orderly distributed nanoparticles and with arranged directions of polarization. In the case of structured model, resulting magnetic forces approach to zero. Since we suppose that magnetic field of iron particles has significant influence on the rate of aggregation , the strThe authors declare that they have no competing interests.DR carried out the study of influence of structure of nanoparticles in aggregates and drafted the manuscript. J\u0160 contributed to conception of the study and to interpretation of data, and revised the manuscript. Both authors read and approved the final manuscript."}
+{"text": "Previous research has failed to show a correlation between the size of a neuroma and the level of pain experienced. The aim of this study was to determine if the proportion of the inter-space that a neuroma occupies has an impact on the level of pain and disability experienced.Forty consecutive subjects with third inter-space neuromas identified on ultrasound were included. The size of the neuroma and the inter-space were measured using ultrasound by the same examiner. Neuroma diameter was measured non-weightbearing plantarly and the inter-space was measured from the dorsal aspect when weightbearing. The proportion of the space occupied by the neuroma was calculated. Visual analogue pain scores and the Manchester-Oxford foot pain and disability questionnaire were collected.Analysis of the data collected failed to show any correlations between the proportion of the space the neuroma occupies with either of the outcome measures used. The hypothesis; the greater proportion a neuroma occupies within the inter-space the greater the level of pain and disability experienced can be rejected.The proportion of the inter-space that is occupied by a neuroma does not correlate to the level of pain and disability experienced."}
+{"text": "The purpose of the study is to determine the effects of the artificially induced mechanical obstruction on the physiopathology of the paranasal sinus mucosa, taking into consideration an experimental model on animals (rabbit).The study was performed on 20 New Zealand white rabbits, distributed into two equal groups. In the case of the first group of 10 experimental animals, we induced the model of ipsilateral double obstruction, the opposite side being left intact as term of comparison. Thus we produced the mechanical obstruction of the nasopharynx at the level of the choanal orifices as well as the obstruction at the level of ostiomeatal complex. In the case of the second experimental group we induced the model of the double counterlateral obstruction: the obstruction of the nasopharynx at the level of the choanal orifice and the counterlateral obstruction of the ostiomeatal complex. We studied and determined the qualitative changes of the pH and the microbiology of the paranasal sinus mucosa.the study determines: 1. pH statistical average and standard deviations of the maxillary sinus mucosa.2. The isolated germs was: Staphilococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae. Multigerm association was present in the case of the double ipsilateral obstruction.3. The reversed correlation between the pH values and the presence of multiple germs in the sinus mucosa.The experimentally induced obstruction of the nasopharynx, modifies the ventilation of the nasal fossae and leads to morphophysiological changes in sinus mucosa, causing inflammation. As compared to the normal values, the pH average values of the maxillary sinus mucosa in the obstructed side are significantly lower (p<0.001). It is noticeable that there are no significant statistic differences between maxillary sinus mucosa pH values in the double ipsilateral obstruction and the obstruction of the ostiomeatal complex (p>0.05), thus certifying that the nasopharynx contributes indirectly to the ventilation of the paranasal sinuses."}
+{"text": "Dr. Allison J. Farrand was not included in the author byline. She should be listed as the second author and affiliated with Department of Microbiology and Immunology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America. The contribution of this author is as follows: She constructed and qualified the basic features of several of the mutants of PFO and ILY used in the published studies."}
+{"text": "Functional Foods Forum (FFF) of University of Turku has reached an age of 10 years. The time has been full of interdisciplinary collaboration starting from food and health and terminology in the languages departments, continuing with clinical interventions studies in collaboration with the Turku University Hospital and other clinical centers, cancer research and studies on genes affecting our sensory work, and characterization of new probiotics and prebiotics as well as nutrition, flavor profiling and transfer of knowledge to SMEs. Ten years is not a long time, but through the keen collaboration and diligent work of the staff members of FFF the institute has reached an internationally recognized status.This symposium on probiotics and prebiotics marks the 10th anniversary of the FFF. The multidisciplinary research program has involved uncovering new probiotics and prebiotics for specific uses, assessing the safety and tolerance, characterizing the properties of probiotics and prebiotics, improving the process stability of probiotics and participation in clinical intervention studies focusing on probiotic and prebiotic health effects, and most recently novel work on the nutrition economic aspects of probiotics and prebiotics. The work has resulted in collaboration over the different areas of science from languages to economics and basic microbiology and nutrition to pediatrics.This symposium has been organized to highlight some of the areas where research has progressed during the past 10 years, to present work of some of our collaborators, and to establish a basis for future work in developing directions for new projects and collaboration.On behalf of all of us at FFF, I would like to thank all the participants for joining forces with us for the celebration; and I hope that we shall continue to have the privilege of working with you in the future as well.Seppo SalminenProfessor, Director"}
+{"text": "The study was organized around individual and collective factors of resistance associated with the implementation of the requirements and recommendations of standards and quality assurance standards of care in health facilities selected.To determine the factors influencing the implementation and dissemination of quality standards and procedures of the professional practices of care in health facilities in Guinea.This cross-sectional study using the interview technique. It ran from a questionnaire on the operational side of the organization of the quality of care in health facilities. On the pan of the sample, this study has identified nine health facilities corresponding to the three levels of the health pyramid. The structures were stratified by type of institution , a draw was able to identify the structures corresponding to the sample to be studied. This is a sample having a size of 88 subjects distributed among the strata according to their size represented by the staff working in administrative services and maternity health facilities drawn.The main results are: i) A little knowledge of good practice recommendations by staff, ii) SONU represent the training approach in quality, iii) low RBP applicability of quality of care (40%), iv) The application of the organizational constraints RBP is on average 50%, v) weaknesses of policy favoring surveys (20%) and vi) Low financing application of standards and procedures for care (41%).It is recommended to train staff on best practices and clinical laboratory revise regulations for the implementation of quality standards and procedures, develop tools for monitoring and evaluating the implementation of quality standards and procedures and develop action research to resolve service issues.None declared"}
+{"text": "Coordinated spiking of neuronal populations underlies the perception of sensory stimuli, the planning of movement, and the acquisition of new memories. In the hippocampus and the entorhinal cortex, groups of neurons are transiently activated as an animal traverses its environment. The sequential patterns generated by these neurons depend, not only on environmental cues, but can also be generated reliably in the absence of these cues. Such patterning depends on the temporal and the spatial distribution of inhibition. It has been hypothesized that inhibitory interneurons corral principal neurons into transiently synchronous ensembles that encode sensory information and sub-serve behavior. The goal of this study is to demonstrate a link between the topology of the inhibitory sub-network and the dynamics of its constituent neurons that, in turn, support the generation of reliable sequences of spiking activity.An understanding of structure-dynamics relationships in complex networks is often challenging because of the formidable dimensionality of the system and the inherent non-linear properties of neurons and synapses that constitute the network. In an earlier study  we estabThe coloring constrains the identity of inhibitory neurons that spike synchronously. However, it does not impose any constraints on the order in which synchronous groups are recruited. The propensity of a particular group of neurons to spike can be attributed to slow temporal processes such as adaptive changes in the calcium concentration within the cell and slow oscillatory drive over time scales comparable to that of theta oscillations that are observed in the hippocampus and the entorhinal cortex. In this study we systematically vary the topology of the network (exemplified by it's coloring) and the timescale of slow temporal processes to understand how the two interact to construct reliable sequences of activity."}
+{"text": "This session will cover the legislation affecting the prescribing of scheduled medicines by endorsed podiatrists, possession, administration and supply. It will include the differences between state and territory drugs and poisons requirements, issues in the preparation of prescriptions and what can go wrong. Risk management and the role of podiatrists in the quality use of medicines in Australia will also be discussed."}
+{"text": "Several errors were introduced in the preparation of this article for publication.In the third sentence of the \"Random walk with one turning angle\" section of the Results, a symbol was removed from the definition of the Fourier-Laplace-transform. The correct definition can be found here:E. coli and V. alginolyticus\" section of the Results, a symbol was removed from the Rotational diffusion value. The correct value can be found here:In the second sentence of the second paragraph of the \"Comparison of the chemotactic drift speed for The publisher apologizes for these errors."}
+{"text": "Changing an antimicrobial treatment regimen has shown to influence the occurrence of antimicrobial resistance, with regimen consisting of the dose, the treatment interval, the duration of therapy, and the route of administration of the drug. For concentration dependent antimicrobials there is substantial evidence to encourage the use of a high dose, with regular treatment interval and short course to minimise the risk for the selection of resistant mutants. However, in contrast with these first three aspects of the antimicrobial treatment regimen, little attention is currently paid to the influence of route of administration for the probability of selection and spread of resistant strains.By comparing data from different animal species, the purpose is to explore the different routes of administration with regard to the stimulation of antimicrobial resistance.Staphylococcus aureus and Escherichia coli in different animal species and humans will be provided. Data on commonly used treatment regimens for humans and animal will be compared and the potential impact on selection, co-selection and spread of resistance will be discussed escriptively. Special attention will be given to the difference in resistance development between topical, oral, and parenteral administration of antimicrobial agents.A historical review on the emergence of resistance to beta-lactamas and tetracycline in Attention to the route of administration might be an underestimated approach to mitigate the risk of selection for pathogens resistant to antimicrobials in both human and veterinary medicine.None declared."}
+{"text": "There is limited information available on how characteristics of the organization of nursing home care and especially group living home care and staff ratio contribute to care staff well being, quality of care and residents' quality of life. Furthermore, it is unknown what the consequences of the increasingly small scale organization of care are for the amount of care staff required in 2030 when there will be much more older people with dementia.This manuscript describes the design of the 'Living Arrangements for people with Dementia study' (LAD-study). The aim of this study is to include living arrangements from every part of this spectrum, ranging from large scale nursing homes to small group living homes. The LAD-study exists of quantitative and qualitative research. Primary outcomes of the quantitative study are wellbeing of care staff, quality of care and quality of life of residents. Furthermore, data concerning staff ratio and characteristics of the living arrangements such as group living home care characteristics are assessed. To get more in-depth insight into the barriers and facilitators in living arrangements for people with dementia to provide good care, focus groups and Dementia Care Mapping are carried out.Results of this study are important for policymakers, directors and staff of living arrangements providing nursing home care to people with dementia and essential for the development of methods to improve quality of care, residents' and staff well-being. Data collection will be repeated every two years, to generate knowledge on the results of changing policies in this field. There is a growing attention for group living home care for people with dementia around the world. In the Netherlands, at the moment 25% of the residents with dementia who receive nursing home care lives in group living homes . Group lInitially, group living homes were developed according to the ideals of the pioneers in this field who stated that a group living home is located in an archetypical house where a maximum of six residents live together . NowadayAlthough it is generally believed that group living home care is better for the well-being of the residents and caregivers, worries exist that group living home care is more expensive and that more staff is needed in arrangements in which many characteristics of group living home care are integrated. These worries are based on the dejuvenation in combination with the graying of the population. The prevalence of dementia will increase in the next decades , while tRegarding the implementation of group living home care and the dejuvenation and graying of the population, it is increasingly important to get insight in what contributes to job satisfaction and burnout, sickness leave and turnover of care staff in living arrangements for people with dementia. In addition, insight in the consequences of group living home care in terms of the number of staff needed is required.The focus of research in this field has mainly been on a comparison of quality of life of residents and staff wellbeing in two or three types of arrangements -17. Two Two studies in the United States do focus on the relationship between characteristics of the organization of care in long-term care facilities and outcomes for residents and staff ,20. The In order to get insight into the relationship between the characteristics of living arrangements for people with dementia and residents' quality of life, quality of care and staff well-being, we designed the 'Living Arrangements for people with Dementia study' (LAD-study). Several characteristics of living arrangements are studied with special attention for the impact of group living home care characteristics and staff ratio. This article describes the methods of the first measurement cycle of LAD-study. The three main research questions are:1. What is the effect of group living home care characteristics and staff ratio on quality of life of residents, quality of care and wellbeing of care staff?2. What is the effect of the variety in care supply for people with dementia and the growing portion of group living home care on the amount of care staff required 20 years from now?3. What are barriers and facilitators in living arrangements for people with dementia to provide good care?The LAD-study is an ongoing monitor which is intended to be repeated every two years. Here we describe the design of the first measurement cycle of the LAD-study which comprises a quantitative and a qualitative study. In the quantitative study staff ratio, characteristics of the organization of care, wellbeing of care staff, quality of care and quality of life of residents are measured (research question 1 & 2).In the qualitative study, data collection via focus groups and structured observations according to the Dementia Care Mapping (DCM) method in a selection of the participating living arrangements are carried out (research question 3). The methods concerning the quantitative and qualitative study are described separately.In the LAD-study, the usual daily practice in nursing home care for people with dementia is studied. Health care staff is asked to complete a questionnaire concerning their situation at work and the quality of life of the residents they are taking care of. This means that data of people with dementia are collected via observation by the health care staff. For these reasons, this study does not come within the scope of the Medical Research Involving Human Subjects Act (WMO) and therefore it does not need approval. We have come to this decision after consultation of a representative of the medical-ethics committee METiGG.Regarding the quantitative study, the health care staff that fill in self-report and observational questionnaires on residents they are taking care of are not asked for informed consent. They are free to not return the questionnaire if they do not want to participate. The questionnaires are fully anonymous.Written consent is asked from the registered legal representatives of the residents to be observed with Dementia Care Mapping in the qualitative study. If they do not approve of the observation of their relative, the particular resident is not observed.All 734 living arrangements that provided nursing home care for people with dementia in the Netherlands were addressed to participate in the first data collection of the LAD-study. In the Netherlands, nursing home care for people with a primary diagnosis of dementia is organized on wards which exclusively provide care to people with dementia. These wards are comparable to special care units in the United States, however, they vary to a great extent. The aim of this study was to include 150 living arrangements from every part of this spectrum. For this purpose, we distinguished five types of living arrangements: traditional large scale nursing homes, nursing home wards in a home for the aged, large nursing home where group living home care is provided, group living homes nearby the mother facility and stand alone group living homes in the community. Our aim was to select 30 living arrangements in each of these 5 categories. All living arrangements participating in this study are non-private facilities, receiving reimbursement dependent on the referral status of the resident: a regular indication or a higher indication based on a higher level of behavioral problems.A brochure with information on the study was sent to the director of the living arrangements and a short inventory was attached. This inventory focused on some basic organizational characteristics of the arrangement, for example the amount of residents they are caring for in total and per ward. In addition, they were asked in which of the 5 types of living arrangements they would classify the living arrangement and if they were willing to participate in our study. In case there were more than 30 arrangements in a same category willing to participate, 30 arrangements were randomly selected.In every participating living arrangement 12 residents and 15 health care staff were randomly selected to participate in the study. In this study, we focused on health care staff  working on a permanent basis. Temporary staff and student-nurses were excluded.Table The following facility demographics are collected: facility type, time of existence, number of residents in the living arrangement in total and on the wards, whether inclusion criteria are taken into account at time of the admission of a new resident, provided education for care staff, sickness leave, technological aids in care and housing and group living home characteristics. Group living home characteristics are assessed using a questionnaire we developed in a previous study based on a Concept Map concerning the ideals of group living home care . FurtherQuality of life and involvement in activities are the primary outcomes for the residents. Quality of life of residents is examined with the Qualidem ,23. ThisResidents' involvement in activities is measured with the subscale Activity Pursuit of the MDS . ResidenAs an indicator of quality of care, client satisfaction is assessed by asking the report of the Consumer Quality Index (CQ-index) , a measuThe following measures are used to control for the functioning of residents. The severity or stage of dementia is measured with the Functional Assessment Staging (FAST) questionnaire ,27, consJob satisfaction, intention to leave and burnout complaints are the primary outcomes for care staff. Additionally, the job characteristics of the Job-Demand-Control-Support model ,31 and tThe outcome variable burnout is measured with the Dutch version of the Maslach Burnout Inventory , the UtrPerson-centered attitude toward people with dementia is measured using a Dutch translation of the Approach to Dementia Questionnaire . This quFinally, demographic variables and variables on care staff's employment in the living arrangement are recorded.Seventeen research assistants have been extensively trained by the research team to collect the data for the first measurement cycle of the LAD-study. The facility demographics and staff ratio of the facilitating services and other professionals are provided by interviewing the manager. The interviews are audio recorded. To calculate the staff ratio of care staff, timetables of the living arrangements are used. The CQ-index is asked from the manager to get insight in client satisfaction. Additionally, registrations of the use of physical restraints and psychotropic drugs are required from the nursing home physician. Outcomes regarding members of the care staff are based on self-report questionnaires. A registered nurse (RN) or certified nursing assistant (CNA) who is most involved with a selected resident is asked to fill in the questionnaire measuring residents' characteristics, such as their quality of life. Care staff and residents are randomly selected by the research assistants.Descriptive statistics are used to describe characteristics of participating living arrangements, residents and care staff. Regression analyses are used to study the effects of group living home care characteristics and staff ratio on outcomes of living arrangements. For care staff and resident outcomes multilevel regression analyses are applied.The qualitative part of this study provides more in-depth insight into facilitators and barriers for success in living arrangements for people with dementia. Using a selection of the quantitative data of the LAD-study, all living arrangements are scored on the wellbeing of the care staff, the quality of care, the residents' quality of life and the amount of health care staff. The scores on these four outcomes are transformed to percentiles and added resulting in a 'total score of success'. For every type of living arrangement, arrangements with the highest and the lowest scores are selected. The measures on which these four outcomes are based are indicated in table The selected living arrangements are asked if they are willing to participate in the qualitative part of the LAD-study. If not, the living arrangement with the second highest or lowest score is selected.The first part of the qualitative study consists of focus groups from three perspectives. Focus groups are group discussions organized to explore people's views and experiences concerning a specific set of issue's . One focus group exists of managers and healthcare professionals, one of members of the care staff and one of family members of the residents. In all three focus groups the same questions are asked focusing on what their opinion is on points of success and improvement of the living arrangements and how care staff, residents, family members, volunteers, management, finances, philosophy of care, policy and environment contribute to this. The focus groups are conducted by a conversation leader and an assistant, taped and typed up literally. The conversation leader and assistant fill in a form after every focus group. The analysis form consists of the following questions: What did this focus group contribute to answering the research question? What got your attention? What was your own role during the conversation? What are points of attention for the next time? The focus groups reports are critically read by researchers of the research team. The reports are imported in MAXQDA and coded on points of success and improvement and suggested explanations. The texts are coded by two researchers and discussed until consensus is reached. The method of constant comparison is used in which case fragments of all participating living arrangements with the same code are compared on agreement and differences.The second part of the qualitative study consists of structured observations using the Dementia Care Mapping (DCM) method. DCM is a method developed by the Bradford Dementia Group  and is bIn the selected living arrangements a trained mapper observes six residents in one living room during two periods of three hours. When the mapper observes in a living room where more than six residents are staying the mapper and leader make a varied selection of residents based on gender, stage of dementia and amount of disruptive behavior. Only residents that are living in the living arrangement for more than one month are observed. In addition, the mapper assesses a number of environmental features, such as environmental cues and a home-like d\u00e9cor. The environmental category codes are based on the DCM-Environmental Category Codes (ECCs) .For all ten cases a report on the facilitators and barriers of the living arrangements is written. These reports are send to the living arrangements and are discussed (member check). Finally, the facilitators and barriers of all cases are compared for corresponding and differing factors. Based on results of the case reports the most important facilitators and barriers for success in living arrangements for people with dementia are specified.In this paper we described the design of the Living Arrangements for people with Dementia study (LAD-study), in which 136 living arrangements providing nursing home care for people with dementia participate in the first measurement cycle. The results of this study will add to the literature in a number of ways.Instead of comparing group living homes with another type of living arrangement, we measure the extent of integration of group living home care in daily practice and staff ratio in a broad variety of facilities. Thus, we focus on the impact of group living home care characteristics and staff ratio on the satisfaction of care staff, quality of care and quality of life of residents. In addition, the combination of the quantitative and qualitative design of the LAD-study makes it possible to get in-depth information on facilitators and barriers of success in living arrangements for people with dementia. Finally, this study gives insight into the consequences of group living home care for people with dementia for the labor market of staff.The information concerning the organization of care is important for national and local directors and staff of living arrangements for people with dementia providing nursing home care. This knowledge can be used for the development of methods to improve care for people with dementia. Finally, this information is essential for policymakers to decide which factors in nursing home care for people with dementia need special attention or need to be stimulated. In addition to this first measurement, data collection will be repeated every two years, to generate knowledge on the results of changing policies in this field.The authors declare that they have no competing interests.BW drafted the manuscript and helped designing the study. DS and JdL helped draft this manuscript and helped designing the study. AMP designed and supervised the study and helped to draft this manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2318/11/11/prepub"}
+{"text": "In the Funding section, one of the grant numbers from the funding body National Natural Science Foundation of China is incorrect. The correct numbers of the grants from this funding body are: 81071096, 31160208."}
+{"text": "This survey was conducted to provide statistical data regarding publications in PubMed-indexed journals from Tabriz University of Medical Sciences Faculty of Dentistry. The database used for this study was PubMed. The search was conducted using key words including the names of the heads of the departments. Papers published between January 1, 2005 and April 31, 2012 were considered. The retrieved abstracts were reviewed and unrelated articles were excluded. Data were transferred to Microsoft Excel software for descriptive statistical analyses.  A total of 158 papers matched the inclusion criteria, with the majority from the Department of Endodontics (49 articles). The highest proportion (48.3%) of papers was related to in vitro studies, followed by clinical trials, in vivo studies, and case reports. The number of publications showed a considerable increase over the studied period. PubMed-indexed publications from different departments have increased steadily, suggesting that research has become an essential component in the evaluated institute. The search engine can be used as a means to obtain data for analysis. In addition, the data can reflect the community performance in research progress and level of contribution to global sciences and significantly influences future planning in research.4It is obvious that research is an important aspect of health care service. Research publications are good indicators for determining the extent and quality of research in a given institute or territory.As there is no comprehensive data that can show the performance of Tabriz University of Medical Sciences Faculty of Dentistry in research since it was established in 1987, this evaluation was designed to assess the research output of this educational center in PubMed-indexed journals over a period of recent eight years.Data regarding publications from Tabriz University of Medical Sciences Faculty of Dentistry were retrieved from PubMed. For data collection, the search was conducted using key words including the names of the heads of the departments of the Faculty of Dentistry. Only papers published between January 1, 2005 and April 31, 2012 were considered. To avoid false positives, the abstracts of all the retrieved articles published during that period were carefully screened and unrelated articles that did not match the following inclusion criteria were excluded: (1) study conducted in the Faculty of Dentistry and the article submitted from the same institute; (2) authors working in the Faculty of Dentistry at the at the time of paper submission and publication; (3) study conducted in Tabriz Faculty of Dentistry but at the time of publication the authors were working out of the Faculty; (4) study from other university in Iran (according to the first author\u2019s affiliation), with one of the authors from Tabriz Faculty of Dentistry.The first author\u2019s name and affiliation as well as those of the other authors, the type of the published paper, and the year of publication were recorded for all papers.Data were transferred to Microsoft Excel software for descriptive statistical analyses.In this study, 158 papers published during the defined eight-year period matched the inclusion criteria. Distribution of the type of the published studies is also presented in Comparing the number of papers related to each department, the highest was found to be of the Department of Endodontics  rank as the first-quality articles. In the present data, the majority of RCTs were from the Department of Pediatric Dentistry.An important limitation of the present study in assessing the scientific progression was missing of a considerable number of articles from this institution\u2019s authors not published in PubMed-indexed journals, which were not included in the study.The results indicated rapid development of research in the Tabriz University of Medical Sciences Faculty of Dentistry."}
+{"text": "In the Funding Statement, the number of the grant from the Deanship of Scientific Research of King Abdulaziz University is incorrect. The correct grant number is: 10-130/1434HiCi."}
+{"text": "In the fall of 2010, the National Science Foundation, the National Institutes of Health and the U.S. Veteran's Administration jointly supported a review of mobility technology in Europe. A delegation of American Scientists traveled to Europe to visit a number of research centers and engaged in a demonstration and dialogue related to the global state-of-the-art for mobility impairment rectification and augmentation. From the observations and exchanges between the U.S. delegation and host institutions, the researchers were able to derive a series of papers which are now published in this thematic series of Journal of NeuroEngineering and Rehabilitation. The papers describe the main themes of the European mobility technology research activities showing a healthy picture of research and innovation in the field. According to the McNeil Report and, more recently, the 2004 Louis Harris Poll  approximIn 1979, Congress recognized the need to provide research that would address enabling and disability augmentation issues for an important group within the U.S. population. In House Report 95-993, the Committee of Science and Technology directed the National Science Foundation (NSF) to create a program designed to support basic and applied research directed at providing enabling technology for persons with disabilities. At the inception of the NSF 'Handicapped Research Program', the program would \"... support research on the use of scientific and engineering development to improve (disabilities), and also to find ways to overcome locomotion and manipulatory limitations.\" [Over the years, the 'Handicapped Research Program' has experienced a variety of name changes that reflect the evolution of societal needs. The current form of this program is the 'General & Age Related Disabilities Engineering' (GARDE) Program and provides funding for basic research that targets the general disability community as well as the ever increasing needs of an aging population. This current form of the program is directly in line with the NSF Strategic Plan for Fiscal Years 2011-2016 - Empowering the Nation Through Discovery and Innovation with the vision to \"... capitalize on new concepts in science and engineering and provide global leadership in advancing research and education.\"  The GARDA study of mobility technology research in Europe was jointly supported by the National Science Foundation, the National Institutes of Health and the U.S. Veteran's Administration. A delegation of research leaders (some with first-hand knowledge of mobility impairments) in the U.S. along with members of the World Technology Evaluation Corporation (WTEC) were tasked with identifying top researchers and institutions in a variety of countries within the European Union. Subsequent to this identification process, the research team, along with the GARDE Program Director and members of WTEC traveled to these top sites to engage in a demonstration and dialogue related to the global state-of-the-art for mobility impairment rectification and augmentation. The observations and exchanges between the U.S. delegation and host institutions provided a venue to identify and minimize the potential for research duplication (\"reinventing the wheel\") and opportunities for collaboration between U.S. researchers in mobility technology and their European counterparts. A detailed description of these interactions follows in subsequent articles of this special thematic series of the Journal of NeuroEngineering and Rehabilitation.The papers that describe the main themes of European mobility technology research activities show a healthy picture of research and innovation in the field. However, that is not to say that improvements in approach and infrastructure are not required. Recent years have witnessed an explosion in the potential for advances in technologies designed to assist and enhance mobility. We have seen an increase in the availability and a reduction in the cost of biomedical sensor platforms, smart fabrics, robotic and neuro-prosthetic devices, social media platforms, and mobile and cloud computing platforms. This greatly increases the range of tools we can use to monitor, characterize, and enhance human behavior and mobility. However, this also presents a great challenge as there is a danger that we can become overwhelmed by the technological capabilities that are available to us and lose sight of what we mean to achieve for patients using these technology platforms. Having access to more technology tools is not simply enough to achieve advances that will make a meaningful and positive impact on the lives of the patients who need help. Real advances in this area will only take place when we place an emphasis on patient or user centered design, implementation and evaluation. This means we need to move away from a technology focused paradigm and bring different skill sets to bear on the problem. Thankfully, we are seeing the emergence of new approaches to the field with collaborations between clinicians, technologists and social scientists working towards a truly user centered model that should enhance our capability for advancement in the field.Beyond making sure that we put the user, and their quality of life, at the center of the process, it is also vital that we increase the degree of collaboration between researchers in the USA and Europe. This, in part, will serve to reduce the duplication of effort as we can see evidence of common activities in both regions. On the positive side, greater collaboration and communication can deliver a more efficient research and innovation process by means of achieving economies of scale, and enhanced combinations of expertise addressing the problem. It can also help to address the cultural perspective that can influence success in the field. Though the drive for increased collaboration needs to start with the researchers themselves, it can only be achieved on a wider scale by means of collaboration between the respective funding organizations in Europe and the USA. We need to establish common priority areas based on current unmet clinical and societal needs, develop roadmaps designed to address these needs, and finally create new funding models that will bring the optimal combination of expertise and infrastructure in Europe and the USA to bear on the area. Achieving this is not easy, but the potential benefits should justify the effort involved.Finally, it is important to place the papers published in this special issue in context. As they are based on an NSF-sponsored visit, they do not follow the usual paper format that you might expect. The papers are a mix of commentaries and short reports/reviews of ongoing research activities in the areas covered during the visit. We have commentaries on European trends in mobility research and the need for improvements in this field. Alongside this we have review reports on trends in assistive technologies for mobility, technologies for enhancing movement training, personalized neuromusculoskeletal modeling, and wearable sensors as applied to rehabilitation. Finally, the delegation have reported on organizational structures promoting research, training and technology transfer in mobility technology research in Europe.In a recent presentation by the President of the United States, he stated that \"Americans with disabilities are Americans first and foremost, and like all Americans are entitled to not only full participation in our society, but also full opportunity in our society.\"  The mobi"}
+{"text": "Using a vector Theorem. As In large part this theorem allows one to regulate the ground state of the network. Let us examine Computer simulations show that basins of attraction of such fixed points are very small. It is not surprising, since the number of the fixed points is very large, and the volume of each basin of attraction is of the order of the volume of the unit hypersphere divided by the number of fixed points."}
+{"text": "HIV counseling and testing for several years working in the district of Gu\u00e9diawaye. A situation analysis has revealed shortcomings in the organization of the service given the many other activities of the health center. This is why the medical team decided to use the collaborative model of quality improvement that is based on the implementation of a package of changes and the measurement of indicators of improvement.It consisted of a situational analysis of the Board Search, the development of process maps and identify targets for improvement. Improvement targets were selected to make the results of all HIV tests to clients within two hours, to provide the reference of all patients positive for medical care. The changes have been to extend the opening hours of the laboratory, to assign a specific staff for testing and to ensure continuous availability of a pool of consultants. Better communication was established and the customer's circuit has been reduced.From January to December 2010, the proportion of tests performed in two hours has risen by an average of 35% to 99%, also the proportion of patients actually referred for medical care rose from an average of 33% to 97%.The process of improving not only affects the indicators of improvement but the effects on teamwork and a consideration of the basic needs of patients."}
+{"text": "The platform consists of two major subsystems: the database of experimental measurements and the modeling framework. The database is user-contributed and contains a set of tools for easy input, search and modification of thousands of records. The OCHEM database is based on the wiki principle and focuses on data quality and verification. The database is tightly integrated with the modeling framework, which supports all the steps required to create a predictive model: data search, calculation and selection of a vast variety of molecular descriptors, application of machine learning methods, validation, analysis of the model and assessment of the applicability domain. Our intention is to make OCHEM an ultimate platform to perform the QSPR/QSAR studies online and share it with other users on the Web. The OCHEM is free for the web users and it is available online at the web\u201d  is becom"}
+{"text": "The history of chronic myeloid leukemia has marked one of the most remarkable and exciting success of modern medicine, transforming an almost always fatal cancer in a chronic conditions that can be medically controlled, and opening space and hope for a cure in an increasing number of patients.th century and was managed with radiation and chemotherapy until the end of the 20th century, until the introduction and the wide application of allogeneic stem cell transplantation (SCT) and of recombinant Interferon-alfa (rIFN ).The way was neither easy nor rapid. CML was described in the 19"}
+{"text": "The Hospital practices the Clinical Governance approach to ensure high standards of care and to continuously improve the quality of services. One purpose is to produce and to apply Organizational and Clinical Procedures (OCP), based on the best available evidence and the local contest and organization, to manage critical patients in the Emergency Department (ED). Annually, about 50.000 patients arrived to the ED, where 18% have urgent and 2% life-threatening conditions. These last cases receive a multidisciplinary treatment  and after stabilization of main symptoms are delivered to the Intensive Care Unit (ICU). The emergency physician is in the permanent staff of the ED while the anaesthesiologist of the ICU is on call.Until 2011, the anaesthesiologist was called by the emergency physician after his first intervention on the critical patient\u2019s ED needed resuscitation treatment with consequent delay of patient\u2019s delivery to the ICU.In 2012, to reduce the time of intervention of the anaesthesiologist in the ED, a group was constituted by health personnel of the ED and ICU, health direction, Quality Unit. The group detected the causes of the delay through the study of available data extracted by the ED electronic data sheet and of the organization of the ED. The group decided to provide an OCP to manage patients with life-threatening emergency conditions in the ED (OCP-ED).To reduce obstacles to the implementation and acceptance of organizational change, the emergency physicians and anaesthesiologists were educated to use OCP-ED applying the concepts and tools of experiential learning. Periodically, health direction organized meetings with personnel to disseminate the results of OCP-ED\u2019s implementation and to discuss the possible problems and to find the solutions to overcome them. The effects of OCP-ED are measured through the indicators and the periodical audit on cases. The process indicators are calculated on data extracted by health database of the ED.Participants positively evaluated both the educational programme and the organizational and clinical indications of the OCP-ED. It has facilitated the communication between the emergency physician and the anaesthesiologist and reduced the delay to ICU delivery.The application of the OCP-ED helped standardize behaviours in an environment characterized by great professional heterogeneity. All health personnel are learning to use the clinical and non-clinical data, periodically reviewing the cases to monitor their activities and then to improve the quality of care both in terms of speed response and appropriate therapy uses."}
+{"text": "This paper gives an overview of the model of a neutron star with non-zero strangeness constructed within the framework of the nonlinear realization of the chiral  Recent neutron star observations make it possible to distinguish in the entire population of neutron stars a class of massive stars. Particularly important data that indicate the existence of massive neutron stars concern the 3.1 ms radio pulsar in the binary system J1614-2230 In the light of these observations, it is important to know the evolutionary path that leads to the formation of a neutron star with such large mass. The most general scenario predicts that the formation of a cold catalysed object is preceded by a very specific phase of a hot neutron star with trapped neutrinos, which defines a proto-neutron star The existence of massive neutron stars entails important consequences for the equation of state (EoS) of dense nuclear matter. In general, the precise measurements of pulsar masses put constraints on the form of the EoS and make problematic the existence of exotic particles such as hyperons and quarks Despite the fact that neutron star matter is directly affected by the nature of strong interactions, it is not possible to give its description on the basis of quantum chromodynamics (QCD) even though it is fundamental theory of strong interactions. The description of nuclear matter is based on different models and with the use of different approaches. The commonly adopted method is the mean field approximation either relativistic or nonrelativistic. In the latter case the Skyrme forces Observations of neutron stars with masses of the order of The purpose of this paper is to study the impact of hyperons on the properties of the matter of neutron stars, and on their structure. In general, analysis of the role of strangeness in nuclear structure in the aspect of multi-strange system is of great importance for both nuclear physics and for astrophysics, and leads to a proper understanding of the properties of a hyperon star. The aim of this paper is an accurate analysis of the properties of neutron stars with particular regard to their internal structure. The key issue to be examined relates the determination of the factor which in the considered model is responsible for the stiffening of the EoS. Another aim of this work is to provide understanding on the impact of the model with the extended vector meson sector on the internal structure of a neutron star.The relativistic approach to the description of nuclear matter developed by Walecka Models that satisfactorily reproduce the saturation properties of symmetric nuclear matter lead to considerable differences in a case in which asymmetry dependence is included A theoretical description of strangeness-rich nuclear matter requires the extension of the model to the full octet of baryons and additional meson fields were introduced to reproduce the hyperon\u2013hyperon interaction. The model that is considered is constructed on the basis of the hadronic Having obtained the EoS the analysis of the maximum achievable neutron star mass for a given class of models can be performed. Observational results limit the value of a neutron star mass and thereby put constraints on the EoS of high density nuclear matter. Recent observations point to the existence of a high maximum neutron star mass Recent observations of the binary millisecond pulsars J1614-2230 In this paper a description of nuclear matter based on an effective model constructed within the framework of the nonlinear realization of the chiral where the explicitly given baryon matrix Generally, the baryon\u2013meson interaction is characterised by the following coupling constants: the octet supplemented with the singlet statecomprises the vector meson nonet. The combinations of the unphysical SU(3) singlet  invariants, can be written in the following formwhere where the covariant derivative equals All nonlinear vector meson couplings that occur in this model have been brought together in the form of a vector potential\u22121The description of dense, hyperon-rich nuclear matter given by the Lagrangian (6) in the case of non-strange matter is reduced to the standard TM1 model with an extended isovector sector. This extension refers to the presence of the The mean field approach has been adopted to calculate the EoS. In this approximation, meson fields are separated into classical mean field values: The preferable attribute of the considered model is its very diverse vector meson sector, which allows one to study the relevance of different vector meson couplings for the form of the EoS. The Lagrangian function (6) makes it possible to calculate the equations of motion from the corresponding Euler-Lagrange equations. The obtained results, written in the mean field approximation, take the form:where Analysis of the equations of motion raises the issue of the medium effects on the properties of the hadronic matter namely the effective baryon and vector meson masses. Considering the case in which nucleon mass depends only on non-strange condensate and referring to the Walecka model, the relation for the reduced effective baryon masses in the medium in the relativistic mean field description where the terms The source terms in Thus, the number density of where where The existence of one single real solution is not satisfied for where Understanding the nature of interactions between baryons is a decisive factor for the properties of neutron stars especially in the case when hyperons are included. A precise description of baryon interactions in the strange sector of the model is essential for the correct construction of the EoS. However, the incompleteness of the experimental data intensifies the uncertainties that are connected with the evaluation of coupling constants that involve strange baryons. In general, there are very few data available to describe hyperon\u2013nucleon (YN) and hyperon\u2013hyperon (YY) interactions.Hyperon\u2013vector meson coupling constants are taken from the quark model. They are summarised in The potential that describe hyperon\u2013nucleon and hyperon\u2013hyperon interaction can be written in the form that involves both the scalar and vector coupling constantswhere In general the coupling constants The scalar coupling constants are collected in The TM1 parameter set  that sucwhere \u22121The strength of the The density dependence of the symmetry energy can be expressed by coefficients that define the slope gave results that agreed with the experimental data  MeV . These rThe energy density and pressure given by relations (26) and (27) define the EoS. Numerical calculations, which were made for the TM1 parameterisation for both nonstrange and strangeness-rich matter, led to the solutions that are shown in An analysis performed for the nonlinear model with parameter In the case of nuclear matter an extended isovector sector comprises the Interacting baryons are the basic components of the matter of neutron stars. The modification of baryon masses that arises from baryon interactions with the background nuclear matter is shown in The reduction of the nucleon mass in the nonlinear model is essentially the same as that obtained in the TM1-weak one. Thus, the influence of the nonlinear vector meson couplings on the nucleon effective mass is negligible. The effective masses of strange baryons in the case of the nonlinear model drop less rapidly than the effective masses obtained in the TM1-weak model. The behaviour of the baryon effective masses is governed by the density dependence of the scalar mean fields, which is presented in The in-medium reduction of baryon masses is equivalent to the modification of vector meson masses in the meson sector . An analThe stiffness of the EoS is characterised by the incompressibility of nuclear matter. In general, incompressibility comprises terms resulting from the kinetic pressure of Fermi gas and from the potential of the model. Analysing the strange sector of the model one can compare the factor that determines the difference between the strength of the effective repulsive and attractive forces. The scalar meson The properties of asymmetric strangeness-rich matter of neutron stars are characterized by the parameters that define the strangeness content of the system The density dependence of the asymmetry parameter Additional hadronic states are produced in neutron star interiors at sufficiently high densities when hyperon in-medium energy equals their chemical potential. The higher the density the more various hadronic species are expected to populate. In general weak reactions for baryons and the corresponding equations for chemical potentials can be written in the formwhere The presented equilibrium conditions determine all constituents of the matter of neutron stars. The concentrations of a particular component A composition and concentrations of hyperons calculated in the nonlinear model can be traced in a chosen configuration of a neutron star. The composition of the core of the maximum mass configuration is depicted in The most essential feature of the model is connected with the fact that even in the presence of hyperons the obtained EoS is very stiff. Global neutron star parameters such as the mass and radius and the structure of a neutron star can be determined by the equation of hydrostatic equilibrium - the Tolman-Oppenheimer-Volkoff (TOV) equation:where The results obtained for the set of EoSs calculated in this paper led to the mass-radius relations and permitted the value of the maximum mass to be determined which in a sense can give a measure of the impact of particular nonlinear couplings between vector mesons. The mass-radius relations obtained for varying values of parameter There are still significant uncertainties associated with the experimental data on the hyperon-nucleus interactions. Thus it is reasonable to investigate the effect of the hyperon-nucleus potential Detailed calculations were done for the selected values of the  of EoSs . The stiTaking into account the value of the maximum mass obtained for a given EoS the presented results support the conclusion that the value of the potential is not a factor that decisively influences the form of the EoS. A similar conclusion can be obtained by analysing the mass-radius relation . The mosHyperons are distributed in the very inner part of a neutron star core therefore a schematic cross-section shows a hyperon core inside of a strangeness-rich neutron star. Information concerning properties of the internal structure of a neutron star are summarised in rameter  . SimilarOne of the most important difference between the model constructed for the attractive nchanged . In the The problem connected with the impact of the The results that relate to the change of asymmetry parameter The differences in the radial dependence of the parameters hyperons  is obtaihyperons  occur inhyperons  appear iRecent observations of the binary millisecond pulsars give in the result the value of neutron star masses of the order of two solar masses. Theoretical models that describe strangeness-rich matter of a neutron star lead to much softer EoSs than those constructed for a neutron star composed of only nucleons. This significant softening of the EoS results in the low value of the maximum neutron star mass achievable in a theoretical model of a neutron star that involve hyperons and in general, leads to the inconsistency between theoretical models and observations.One of the possible solution to this problem, is the construction of a theoretical model of the strangeness-rich matter of a neutron star that will result in the emergence of extra repulsive force in the strange sector of the system. This in turn stiffens the EoS and leads to the higher value of the maximum mass of a neutron star.The model that was used in this paper for the description of the matter of a neutron star is based on the nonlinear realization of the chiral symmetry. The results were obtained under the assumption that nucleons do not couple to meson An essential characteristic of the model that was used in this paper is the diverse vector meson sector which comprises different vector meson couplings. The performed analysis concerns the issue of the influence of the nonlinear As a result, a special class of EoSs was obtained. Particular EoSs are characterised by the value of parameter Obtained numerical solutions allow one to analyse the impact of the nonlinear vector meson couplings on the density dependence of the scalar and vector meson fields. It was shown that under the condition of the presence of nonlinear vector meson couplings the in-medium properties of baryons and mesons were changed. Especially there is a considerable modification of the effective baryon and vector meson masses.The nonlinear vector meson couplings modify both the asymmetry and strangeness content of the system and therefore lead to a model with a reduced strangeness and an enhanced asymmetry. The stiffness of the EoS is directly related to the in-medium properties of the matter of a neutron star. It depends on value of the effective baryon and meson masses, which modify the compressibility of the matter of a neutron star and the range of interactions especially in the strange sector. The results of the analysis performed in the framework of the nonlinear model have shown that the properties of neutron stars are significantly altered by the presence of hyperons.The analysis of the dependence of neutron star parameters on the strength of hyperon-nucleon interaction has been already done by Weissenborn et al. The EoS for strangeness-rich matter of neutron stars calculated on the basis of the extended nonolinear model is much more stiffer then EoSs obtained for a neutron star with hyperons with the use of models in which vector meson In general, the hyperon fraction is reduced in comparison to the linear models. The reduction of the hyperon population in the matter of a neutron star is related to the enhanced lepton concentrations. As an example the maximum mass configuration is presented. In this particular model the core of a neutron star reveal a hyperon inner core with the reduced"}
+{"text": "The correct acknowledgment should read:The authors are grateful for the fruitful comments of Dr. Igor Furtat related to the algorithmic portion of the work. The experimental portion (Section 3) was prepared within the framework of a subsidy granted to the National Research University Higher School of Economics by the Government of the Russian Federation for the implementation of the Global Competitiveness Program. The data fusion algorithm for reconstruction of pen traces (Section 2) was adapted to the use with the EMG data solely under support of RNF (grant 14-29-00142) in IPME RAS.The change requested does not affect the scientific validity of the results.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Reason for Corrigendum:Due to an oversight, the first name of the first author was misspelled as Zheng Fei Ma instead of Zheng Feei Ma. The correct name of the first author should be Zheng Feei Ma and has been corrected. The authors apologize for the mistake. This error does not change the scientific conclusions of the article in any way.The original article has been updated.All authors have contributed substantially to the conception or design of the work, or the acquisition, analysis or interpretation of data for the work: ZM wrote the first draft of the manuscript; NA, YY, and YL revised and provided feedbacks for the manuscript. All authors have drafted and revised the work critically for important intellectual contents. All authors approved the final version to be published. All authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Polish Journal of Ecology (Reference 13 in the published article):This study is a follow up to an earlier study reporting the results of a survey of vegetation carried out in 2009 which was published in the Wang Q, Yuan XZ, Liu H, Zhang YW, Cheng ZL, et al. (2012) Effect of long-term winter flooding on the vascular flora in the drawdown area of the Three Georges Reservoir, China. Polish Journal of Ecology 60: 95\u2013106.The current article reported a comparison of two consecutive years of data (2009 and 2010) using data from 12 of the 14 sites included in the original study; thus, some of the data generated by the 2009 survey and used in this analysis has been previously published. The relationship of the current study to the previous work was acknowledged in the paper; however, the authors would like to provide clarification of a number of instances in which previously published information/data were used in the article without an accompanying clear citation:Polish Journal of Ecology article.- Information on sampling methods and the hydrological regime was similar to that reported in the - The 2009 data on life forms shown in  for 12 o- The 2009 data on patterns of life form and species richness along elevational gradient for 12 of the 14 original sampling sites were re-used from the previous study.Polish Journal of Ecology. The captions for Figs In addition, the authors wish to clarify that Figs"}
+{"text": "For theirs peculiarities, late-preterm newborns require more assistance and care [In the last twenty years the number of multiple births in Italy growed up to around 25% due to the increase of medically assisted reproduction. Multiple birth usually occurs between the 34and care -3.In this study we tried to leave procedures based largely on tradition and \u201ccommonsense\u201d, burdened by wide variability of pediatric team. We tried to organize a shared and standardized procedural planning, according to the evidence-based practices criteria and the operative context, improving the safety level of the newborns and team.The collaboration between different professionals, from obstetric to neonatal care area, is necessary in order to ensure an interdisciplinary and highly specialized standard of care.After approbation of the Hospital Committee we planned a scheduled care process that provides:a) Early stage of training: acquisition of care pathways encoded for every professional involved, including participation in training specialized courses and simulation cases;b) The establishment of a multidisciplinary study group that defines the indicators and the standard of result to be achieved, including the emotional and psychological aspect of the new mother and the identification of the role of the various members of the team;c) Strict planning and management of human resources and equipment available, listed in detail and sequence of use, updated with the latest national legislative directives;d) Estimates of possible variables and complications; identification of properly safety systems and alternative recommendations to be observed, not covered by the standard procedure;e) Insertion of a self-assessment system in order to check the feasibility and the adherence to the protocol.We performed a procedural planning that ensures the standardization and uniformity of the nursing of the multiple late preterm newborn, managing the collaboration between several professionals in order to minimize adverse and unexpected events.The quality of the health care level provided depends on the cooperation of the professionals. The management of the team work allows to ensure an optimal and personalized care level from the medically assisted reproduction center to the neonatal intensive care unit, following the updated scientific evidence and the humanization of birth route."}
+{"text": "On the market there are various heatable fabrics with a mobile energy source and a heating power of approximately 10 watts. Examples for heatable fabrics are multilayer outdoor fabrics (pants and jackets), one layer fabrics , underwear (shirts and paints), gloves, socks and shoes and accessories like a kidney belt. Up to now heatable textile fabrics are in the focus of research activities but have not been a large market. The reasons for this are several: technical problems during the life time, unfavourable system design, usage restriction caused by low life of storage battery or problems by cleaning and washing. The German research project 17708BG has the aim to investigate the clothing physiological aspects of heatable fabrics and the comfort of such fabrics.The thermophysiological comfort of various heatable fabrics  can be determined by investigation of different thermophysiological parameters with the Hohenstein skin model (a sweating guarded-hotplate) and with the thermal manikin \"Charlie\" of whole clothing ensembles. Additional wearer trials in a climatic chamber with controlled environmental conditions are made to correlate the objective data of the Hohenstein Skin model and the manikin \"Charlie\" with the real wearer situation.The investigation with the thermal manikin Charlie of different clothing systems shows the influence of heating effect depending on the position of the heating elements in the clothing. The different switching possibilities of the heating system show also different effects on the heating effect. The common thermophysiological properties e.g. the breathability and the thermal insulation can be influenced by the heating system and the integration of the heating system in the clothes. Is the heating unit performed as heat pad the material of the head pad influences the thermophysiological properties and often the breathability is low and the additional textiles layers lead to a higher thermal insulation. In underwear where the heatable zones are knitted, the influences to the thermophysiological properties are lower than in heat pads.The effect of the heatable fabrics is depending on the position of the body  and the investigated fabric. The differences between different fabrics are high because various technologies are used (heat pads (in most cases removable), knitted heated or woven heated zones). The comparison of the results of the manikin tests and the wearer trials are under analysis. First results show that the effects of the heatable fabrics measured by the thermal manikin are comparable with the objective and subjective data of the wearer trials and the judgement of the heatable function can be made by the manikin tests.The results of the research project show that the physiological comfort of heatable textiles depends on the used heating technique and the dimension of the heating system. The investigation with clothing physiological measurement devices and with wearer trials show that the heatable textiles show often a low comfort and so the potential of the optimization of heatable products is high and some modification can be easily integrated in the production process. The results of the German research project (IG 17708BG) give a better understanding and more information about heatable fabrics. The results can help the producer to optimize products and to produce products with a long lifetime and high performance."}
+{"text": "In the world, the health policies are necessary to satisfy with efficiency the requirements of the quality management in the health sector. The laboratory of the academic clinics of Lubumbashi in Africa was inspired by the EFQM model to improve its performance and the quality of its services offered to the community. The aim of this survey is to evaluate the level of job satisfaction of the healthcare providers after implementation of the model.Qualitative study used an anonymous questionnaire consisted of 16 semi directional dichotomous and 12 according to four modality of the Likert's scale; to evaluate the job satisfaction of the healthcare providers. 40 workers are concerned and their informed consent is obtained. Epi Info 3.5.3 and SPSS 19.0 software, the Student t test and Chi-square test and the threshold set at p \u2264 0.05 were used. The mean score was calculated. Cronbach's \u2018 coefficient and principal component analysis allowed the validity measurement of the questionnaire, and the correlations has been calculated.2= 57, 30, p=0.001). The Physicians are very dissatisfied (2.363) against the nurses, and the biologists who are moderately dissatisfied (3 and 3.312). The relative results to the global satisfaction of the workers show a meaningful difference between the workers satisfied versus those non satisfied (p = 0.003). More of the half of the workers is satisfied after the setting up of the EFQM model.This survey had a rate of answer of 80% on a set of all questionnaires. The Cronbach's coefficient of reliability is 0.72 on 40 complete observations with 12 questions. The Kaiser Meyer Olkin (0.564) and the Bartlett test is significant (\u03c7A certain number of the factors act together and simultaneously on the satisfaction of the workers particular in the health sector. The EFQM model permits the job satisfaction in the hospital because it combines several factors acting on the individuals. The EFQM  model of excellence putsa particular importance on the assessment of the results of the quality management on the human resources. In the world, the health policies are adopted and adapted to answer the requirements of the quality management in the sector of health.The laboratory of the academic clinics of Lubumbashi in Africa was inspired by this EFQM model to improve its performance and the quality of its services offered to the community.The insurance quality imposed to the hospitals and the sector of laboratory in France to the security concerning blood transfusion and medicine is one example , the relIn the laboratory, the investigations of satisfaction of the physicians have already been achieved , 3, 4 buAn assessment of satisfaction of the hospital actors of the academic clinics of Lubumbashi is useful, because this establishment of healthcare does not possess the monopoly in the offer of the health care in a very competitive environment but must assure the cares of quality to answer the needs of health and for the fidelisation of his/her/its customers.An investigation of this span is an interesting tool in the improvement of the quality as underlined by Chord Auger S. and al., . RenewabIn a magazine of the literature on the topic, M. Beaumont  and J. LThe team work is encouraged in the approach of the quality management. The incentive of the employees is based on the concept of empowerment, and a style of management based on the concept of \u201cleadership\u201d.The number and the type of work teams in an organization constitute good indicators of the presence of a culture of the quality management, of the delegation of responsibilities and the level of involvement of the employees,is the fundamental question to know what motivates people to work, to push them to learn more and to develop new expertise? What incite them to participate and to imply themselves in the realization of the objective quality to improve the quality of their work?The approach of the quality management treats the question of the incentive of the various manners. Besides the team work and other aspects of the incentive, the primordial aim is probably the importance given to the employees ; and theIt can take several shapes. It can result in a better sharing of information on the results of the enterprise. It also concerns the autonomy let to people to improve their work and their performances. It also milked for example to the latitude let to the employees of \u201cfirst line\u201d to act in the customer\u2032s interest without having need to get a previous authorization. The idea to give the power to the employees is the basis of the school movement of the human relations.The approach of the quality management is also compatible with other more recent theories of incentive to work, notably the theory of the features of the employment of Hackman and Oldham , the oneThe realization of the goals of any system passes by the incentive of people, and the most important incentive is the one that comes from people themselves. Deming gives out the hypothesis that people have needs of esteem and realization of oneself ; which cDeming thinks that the main source of the incentive is intrinsic to the individual, but the accent put on the extrinsic incentive has a destructive effect. The intrinsic incentive is one of the characteristic keys of the socially responsible behaviours  that meaIt is a style of management that doesn\u2032t consist in ordering and in controlling but to guide and to drag . In thisAccording to the approach of the organizational development, the change will be a success if the administrators succeed in promoting values of involvement of the employees and a consensus, notably while improving the organizational life quality .The assessment of the level of satisfaction of the workers is important in the hospital context. In the EFQM model of excellence, the assessment of the level of satisfaction of the workers represents an obligation and a regular measure of efficiency at a time. It is established that the investigation allows knowing the efficiency of the reorganization setting up within the services .The satisfaction in the workplace is an incentive support that allows the individual to exercise positively in the context of the organizations and to maintain an effort toward the organizational objectives; it is an internal psychological process. Reason why, the multi-dimensional and psychological approaches are used. It is not possible to motivate people directly, but only to create an environment auspicious to elevate their degrees of incentive . It\u2032s esConfidentiality, the liberty to express his (her) opinions and his (her) observations has been guaranteed for every laboratory technician interviewee.2 test permitted the comparison of the mean score. The threshold of significance fixed (p < 0.05 and CI to 95%). The analysis of the validity and the reliability of the questionnaire have been made by the Cronbach\u2032s \u03b1 coefficient. The number of questionnaire measurement with an analysis of main components (ACP), the coefficient of interrelationship. The Bartlett test and the Kaiser-Meyer-Olkin measure of precision to the sample have been calculated.The questions have been proposed under \u201cclosed and coded\u201d shape so that the staffs choose without difficulty the compatible answers with their opinions and their observations Another assertion \u201cto specify\u201d has been proposed, and permit to understand more on the studied phenomenon. The tool standardized by Peter Warr, Jhon Cook and Toby Wall 1979) has been used after adaptation to the environment of the academic clinics of Lubumbashi [79 has beThis investigation had a rate of answer of 80% on a set of all questionnaires addressed to the health staff. The staff of the laboratory answered favorably (75%) to this investigating in comparison with the one of the other services (p <0.05). The Cronbach's \u03b1 coefficient of reliability is 0.72 on 40 complete observations with 12 questions.2 =57.30, p = 0.001) and Anova test gives   with an orthogonal rotation , the interrelationships of the answers between them and the interrelationships of the answers in every scale have been valued. The K.M.O (0.564) and the Bartlett test (Chi = 0.001) The results indicate that our investigated people reacted of varied manner to this investigation; 85% of the workers against 15% of chiefs of services. Their age is more than 31 years old for 90%, and 87.5% among them have an experience of more than 6 years The results in the We compared the level of satisfaction in 2005 before the application of the EFQM model and after the quality management. The relative results to the global satisfaction of the workers show a meaningful difference between the workers satisfied versus those non satisfied . More of the 50% of the workers are satisfied after the implementation of the EFQM model Our results indicate that the workers are satisfied moderately for the variables\u201c attention granted to the suggestions, the fashion of security of the employment, the liberty of choice their work methods, the degree of autonomy and the work schedule\u201d. The other variables indicate a strong dissatisfaction The remuneration is an important incentive factor. The results of our investigation, on this variable show that, (85%) workers of health are dissatisfied against (15%) which is satisfied for the whole remuneration.Concerning the quality of the relations within the organization, we note through the results that the relation with their colleagues is satisfactory for the set of the staffs (62.5%). The relation between the staffs and their hierarchies shows a satisfaction in the proportion of (50%) .Some elements as the possibilities offered by the evolution of the career, the organizational support, the involvement to the decisions and the type of management produce positive effects on the salaried employee . But also on the organization  .To understand the satisfaction of the workers is essential to understand the elements that sustain their strength of work. The job satisfaction, is defined as the effective response to one's job , 21, 22.The questions of human resources management are the most important elements for the programs of the sector of health to improve the quality of the services. These are the engagement and the levels of incentive as well as the expertises of the humans that work in the organizations of the health sector and who have a meaningful impact on the performance, and to improve the best quality of the healthcare. The importance of better policies concerning human resources improve the performance of the health system is often put in evidence during these last decades , 24. MorThe scheduling of the human resources doesn\u2032t seem to be always a priority of the general politics of the health ministries in the development countries. The WHO, insist on the improvement of the capacities of human resources\u2032 management for the improvement of the quality of the healthcare .Our results indicate that the physicians are the most unsatisfied of the group against the nurses and the biologists who declared to be moderately unsatisfied. These results indicate not only the staff\u2032s dissatisfaction but inform to sufficiency the global ambiance of the professional setting.These observations push us to affirm the importance of really manage the human resources in the sector of health. While comparing the level of satisfaction between the year 2005 and 2010, we noted an improvement of (11% versus 57%) that we put in the account of the EFQM model.To reinforce the capacities of the human resources in the programs of health and the physical work conditions for the human resources of health is important for the scheduling and the training of the human resources. A survey carried out by Freeborn (2001) reported that the workers of the health sector, who discern a big control, that their demands of work are reasonable and benefit in addition, they have the support of their colleagues, they have levels more raised of satisfaction and engagement towards the organization .The relations between the workers are the reflections of the good general friendship that prevail in the organization and the manner whose casual association is formed inside an organization. The scores were (mean score 3.25 and 2.25) for the relation with the hierarchy and the colleagues, indicates a moderately dissatisfied of the relation with the hierarchy and a very dissatisfied of the relation with the colleagues. The results indicate that the relation between the staff is one of the elements to measure the satisfaction in the organization. These findings are confirmed by other studies that suggest that the relations with the colleagues are the best predictors of the satisfaction to work \u201330.Among the major problems, we have the low wages and the staff\u2032s incentive. The unequal and inequitable distribution of the work volume generates the staff\u2032s bad performance and represents the main obstacle to the development of the health sector. The staff who works less than 30 hours per week has an incentive more raised in relation to those, who work of longer hours within the organizations , 32.The new challenges are the frequent departures of the qualified staff toward the competitors and the more lucrative establishments that create a big insecurity for the organizations in the public sector. It is a sign of discontent of the human resources to work and an obstacle to the dispensation of better cares of health for the patients . To undeThe studies have shown the constraints to work with a non cooperative boss. The interaction between superior and subordinate can entail a reduction of the satisfaction to work. The considerate and cooperative bosses are good facilitators of the groups for an increased productivity and for a better performance.The substantial proofs attest the existence of a positive relation between the satisfaction to work and the relations between the direction and the workers , 34. TheThe majority of the studies debate the importance of the financial incitements on the satisfaction. The financial incitement is considered like one main factor of retention of the human resources to the workplace.The answer that the satisfaction to work is tributary of the incomes has been suggested in the studies by Clark and Oswald (1996). Fiji, Samoa, Tonga, Vanuatu, Papua New Guinea, Vietnam, Cambodia and Thailand, identified the low wages like a major reason of the weak incentive, dissatisfaction to working and the migration of the health workers \u201337. TherTo Cambodia, the financial incitements based on the performance of the health agents drove to better services of quality health with a growth of the productivity and a reduction of the expenses of use in the services . But, thThe results indicate a weak level of satisfaction with regard to the autonomy and the incentive to work. The workers need more liberty to give satisfaction and to maintain their incentive.The studies carried out by Murray show a positive association of the autonomy, the satisfaction to work and the incentive to work ; becauseThe employees will be motivated to use their responsibility of their work. The individuals\u2032 age and their jobs offer more possibilities for the supplementary responsibility that is an intrinsic incentive, an important source of incentive. Some studies indicate that the responsabilization improves the level of interest of the human resources in their work .In an ideal work environment, one can have the great opportunity to exploit his or her potential, drives to a bigger satisfaction to working and to raise a level of incentive. More studies also reinforce these findings .The physical infrastructures are the fundamental condition for the working efficient of an organization. They have a positive impact on the satisfaction to the work of the healthcare providers. These findings join those (\u2026) which declared that the bad physical work conditions in the public hospitals in India are a major reason of dissatisfaction of the staff . The sugThe studies of Mulvany et al. (2002) indicate that the structures and the organizational processes affect the experience of the beneficiary of cares and the nature of the information that they use within the system of health. It\u2032s established that the organizations that receive and treat the complaints of their agents efficiently have the more satisfied workers.The recognition to working and the importance made to the suggestions of the healthcare providers are important factor of incentive for the workers. The recognition is bound directly to retention and the productivity , 47. TheAccording to Herzberg, the recognition of work is a motor of very important satisfaction. People to all levels of the organization want the recognition of their realizations on work and their successes must not be monumental to deserve recognition.The opportunities of promotion have a positive interrelationship with the satisfaction to work. All things being otherwise equal, the possibilities of promotion have a positive interrelationship with the satisfaction to work. Herzberg in his theory to two factors insists on the fact that the possibilities of advancement in the rank are of strong incentives and drive therefore to the satisfaction to work. The weak satisfaction observed through our results would explain itself the modes of promotion that they judge not satisfactory. One study indicates that the promotion constitutes an aspect important of the mobility of the beneficiaries of healthcare .The studies indicate a weak interrelationship between the possibility for the staffs to use their expertises and the satisfaction. However, some recent studies indicate that the security of employment is considered like a factor of satisfaction to work by a weak percentage of the salaried employees; which corroborates with the results of our investigation. For our results, the mean scores are weak between the three groups.It can be assigned like an important factor for the weak level of satisfaction of the healthcare providers and the bad qualities of cares to the patients.To the look of the results of this survey, one can affirm that the satisfaction to working is a complex phenomenon for which it is not easy to fix a factor determining the satisfaction or dissatisfaction to working , 48\u201350.This survey informs that a certain number of the factors act together and simultaneously on the satisfaction of the workers particular in the health sector. The dynamics of the relations between the factors is more important than a factor took in an isolated way. The EFQM model permits to evaluate the job satisfaction of the workers in the hospital because it combines several factors acting on the individuals.The results show a meaningful difference in years 2005 and 2010 between the staffs satisfied versus those unsatisfied. More of the half of the workers is satisfied after the setting up of the EFQM model in the laboratory. The results will allow this service to improve the relation between the workers and their hierarchies, the autonomy, the remuneration and the consideration of the suggestions of the workers. These aspects that indicate dissatisfaction will deserve an attention to improve the incentive and the staff\u2032s retention.These results reinforce the interest for the organizations that produce services on the quality management to improve their performance."}
+{"text": "The Convention on the rights of persons with disabilities of United Nations (CRPD 2006) is an international standard, but not enough know in Italy. The CRPD introduce a strong change of paradigma in the approach on persons with disabilities. Based on the respect of human rights, is innovative regard the Convention on the rights of the child (1989). Redefining the concept of disability, stress the importance of the social and relationship components. For the minors with disabilities means a new responsibility of the pediatrics on the social components that can determine factors of impoverishment or empowerment of capacities and competences. New concepts (related to new treatment) are stressed: from the empowerment to habilitation and to capability. The relationship with the family too from the curative attention, often totally transfer to specialism, to educational responsibility, guiding to an aware approach of the role of caregiver support, but no substitutive of the possible self-determination. The role of the physicians changes: no more search the recovery, often impossible, but the appropriate support to the empower and habilitate the form of fonctioning of the minor. The \u201cnoting about us without us\u201d is essential for the evolution of minors with disabilities, put in value the human diversities, that are part of the human kind."}
+{"text": "The main objective of this study was to investigate the cost-sharing mechanisms in pharmaceutical expenditure in EU-27 and to further explore the impact of policies on the broader NHS. The study was based on data from February to March 2015.The following were the main research questions addressed: What are the main differences among the individual case studies, which were implemented in the countries concerned? Are the results included in this study expected to have a positive or negative impact on health care users? Are these results expected to ensure equal proportional allocation of the cost-sharing mechanisms among health care users?Regarding the methodology of the study, an extensive analysis of the targeted policies and practices was carried out based on the data obtained from the databases of the OECD, PubMed and Google Scholar.The results showed that, in the European South cost-sharing was introduced and implemented as an austerity measure in the context of an imposed fiscal discipline, with Germany being the auditor of the European Central Bank. On the other hand, in the European North cost-sharing has traditionally been an integral part of their NHS. This cost-sharing policy has lead to significant impacts on health care systems, such as the control of excess demand and health services as well as the control of moral hazard. Cost-sharing policy has affected users as well. For instance, compensation issues in the case of biosimilars have not yet been resolved and the rate of visits in non-governmental organizations and other social clinics has increased tremendously (up to 23 %).Overall, the implementation of a strong cost-sharing mechanism can facilitate a sustainable and efficient NHS system based on the principle of equal rights. So far, all changes within NHS systems were proved necessary for ensuring viability and sustainable development. This policy appears to be a step in the right direction for improving the scope and the quality of the services offered by the NHS."}
+{"text": "Lishan Wang requested the retraction of this article.PLOS ONE Editors found indications that the peer review process was compromised by the submission of reviews through fabricated reviewer accounts. An institutional investigation, conducted by the Administration Office of Bio-X Institutes at Shanghai Jiao Tong University, supported the concerns about the integrity of the review process and indicated that Lishan Wang was solely responsible for the article, contrary to information provided to the journal at time of submission.Upon review of the submission history for the manuscript, the PLOS ONE Editors retracted the research article [In light of the above concerns, the  article  on July This retraction notice and the linked article  and Corr"}
+{"text": "This report describes the activities discussed at the 10th meeting of Section II of the Consultative Committee on Standards for the Measurement of Ionizing Radiations  held in May 1989 at S\u00e8vres (France). Topics included present and future international comparisons of activity measurements, the status and possible extension of the International reference system for activity measurements of gamma-ray emitting nuclides, reports from other working groups, accomplishments at the International Bureau of Weights and Measures , and progress at member laboratories. One of the consultative committees of the International Committee of Weights and Measures  which guides and assists the International Bureau of Weights and Measures  in ensuring the uniformity of physical measurements is the Consultative Committee on Standards for the Measurement of Ionizing Radiations  . The vareach pertinent radionuclide. Currently the National Institute of Standards and Technology has received justified requests for over 130 radionuclides, for example [The challenge in radioactivity standards is as much quantity as quality. Although the accuracy required and achieved for specifying the activity of a sample of a radionuclide is usually only of one percent, a standard must be developed for  example . There i\u22121). Goals of the Radionuclides Section of CCEMRI are to improve measuring methods and better define their uncertainties, to compare results obtained in different countries, and to bring these results into congruence. The 10th meeting made considerable progress towards these goals.Almost all countries have adopted the International System (SI) unit, the becquerel (Bq), specifying the activity of a sample in decays per second  detector can detect at least one radiation most of the time, and the fraction lost can be calculated accurately if the efficiency for different energies is known. A report on experiences in member laboratories is to be published.In addition to maintaining the SIR, and investigating its extension, the BIPM staff participates in the general comparisons and prepares the detailed reports describing the results. They also make fundamental contributions to the development of measuring techniques and their analysis.75Se, with a preliminary value of (16.3\u00b10.3) ms; the development of corrections for circuit dead times in series, with possible mixtures of the two types which further extend when a second pulse arrives during a dead period, or not [Examples presented at this session were the measurement of the half life of a metastable state following the decay of , or not ; and posA final portion of this session, and all recent ones, has been the presentation of written and oral reports from each attending laboratory covering topics of possible general interest not discussed elsewhere in the agenda. These cover not only discoveries and new data, but also trends in the demands and delivery of standards to users.The unusual nature of radioactivity standardization makes international cooperation especially significant. The interchange of ideas about basic standardization during the sessions of the Radionuclides Section of the CCEMRI at BIPM, and about applied radioactivity measurements at associated meetings of the International Committee for Radionuclide Metrology, contributes to both the efficiency and accuracy of such measurements. The examples displayed in this article from the 10th session of the Radionuclides Section illustrate the scope and range of these activities."}
+{"text": "In the field of transplantation, there is little hope that even near-modular organs will ever be available in the foreseeable future, or any major breakthrough to occur in xenotransplatation. The transplantation community is, and will remain dependent on the viability of the harvested organ to survive and secure further growth of this novel field. This depends much on the timing of harvesting in order not to incur avoidable failure. To achieve this, public trust in the medical handling the dying patient remains one of the prime objectives.In the previous issue of this journal, Delmonico expounded on the definition of death before engaging in organ recruitment with the intent of securing medical and judicial legitimacy for a successful transplantation. With a concluding remark and a citation from the late Pope  on the iIt should be noted that opinion expressed by Pope is apparently his own as a learned, pious individual since neither Judeo-Christianity nor Islam has set any strict criteria on the bodily signs of the separation of soul and onset of death. The mandates of the Abrahamic religions on death and dying relate more to the salvation of the soul of the dying person and decrees towards observing sanctity of the corpse. Overall, the decision on the time of death aside from the attending professionals is strongly subjective and mostly confirmed or decided by the clergy and senior relatives present.Development of organ transplantation in Iran as well as other countries of the region started around one decade later than the United States. While the progress of the new field has been quite impressive, the experience acquired so far tends to be somewhat different compared to that accumulated in the West.We believe that the public criteria regarding the onset of death are amazingly more lax than that set in medical profession. In this part of the world, the guidelines promulgated in local traditional medicine, has been of respiratory category with holding of mirror in front of the subject's mouth and watching for the presence of a blurred reflection through exhaled meanwhile checking for the absent radial pulse.In transplantation medicine, the horizon, in this part of the world, appears more bright because of the public belief is still inclined to accept a noble and altruistic motivation in the relevant professionals. The public in the emotionally engaged state of bereavement is less worried about the intention of the operating team rather than salvation and maintaining the integrity of the body of the beloved one. We believe that cultural factors are the third entity to be considered while contemplating organ procurement. It is an undeniable fact that in an emerging scenario, organ donation does not rank high in the minds of the kin of a dying person, hence bringing closer these divergent ideas might help prevent many potential mistrusts.We believe that along with due considerations being paid to the prevailing culture and level of education, the relatives should informed of the outcome without any recourse made to the judicial side of the matter and relegate pronouncement of death to their arbitration and confirmation."}
+{"text": "Due to an error during the production process Alexandre Cavalcanti was incorrectly added to the author list of the original article . The autAlexandre Cavalcanti and The CHECKLIST-ICU Investigators and the BRICNetTo:The CHECKLIST-ICU Investigators and the BRICNetBioMed Central apologises to the authors and readers for this error and any inconvenience this has caused."}
+{"text": "Due to an oversight in our Mini Review article, one funder was incorrectly listed. The Natural Sciences and Engineering Research Council of Canada was incorrectly identified as the National Science and Engineering Research Council of Canada. The correction does not affect the scientific validity of the results.All authors listed have made substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The international standardization of auricular acupuncture points (AAPs) is an important basis for auricular therapy or auricular diagnosis and treatment. The study on the international standardization of AAPs has gone through a long process, in which the location method is one of the key research projects. There are different points of view in the field of AAPs among experts from different countries or regions. By only analyzing the nine representative location methods, this paper tried to offer a proper location method to locate AAPs. Through analysis of the pros and cons of each location method, the location method applied in the WFAS international standard of AAPs is thoroughly considered as an appropriate method. It is important to keep the right direction during developing an International Organization for Standardization (ISO) international standard of auricular acupuncture points and to improve the research quality of international standardization for AAPs.  The third regional conference of the working group of the standardization of acupuncture points was held in Seoul, South Korea, in 1987  in Lyon,An international standard of AAPs is an inevitable requirement when the auricular diagnosis and treatment medicine develops for a long period and goes to a high level. Through more than 30 years of effort, great progress and achievements have been made in researches on the international standard of AAPs. Up to now, an international standard has been formulated and issued by the World Federation of Acupuncture-Moxibustion Societies. An International Organization for Standardization (ISO) international standard is also in development. Nevertheless, there are still debates on the location methods for locating AAPs, including location based on \u201cpoints,\u201d \u201csubzones,\u201d \u201ccoordinate,\u201d and other methods.The corresponding author of this paper has been engaged in the study on the international standardization of AAPs since 1986 and had the honor to participate in the whole process of research work on the Chinese national standard of AAPs and international standard of AAPs. As the chief expert of the project, he finished the international standard for auricular acupuncture point , which wFrom perspectives of historical context of AAPs, clinical inheritance, and practice of AAPs, the understanding of the essence of points, advantages, and disadvantages of the following nine location methods for locating AAPs were analyzed, including (1) the location method based on points for the anterior of the auricle, (2) the location method based on subzones for the anterior of the auricle, (3) the location method based on the divided subzones according to anatomy of the anterior of the auricle, (4) the location method based on Nogier's Point Zero for the anterior of the auricle, (5) the location method based on the facial ties of the knee of the helix and lobe, (6) the location method based on both points and subzones of the anterior of the auricle, (7) the location method based on smaller subzones of the anterior of the auricle, (8) the location method based on subzones, points, and lines for the anterior and posterior of the auricle, and (9) the location method based on subzones, points, and lines for full cover of the anterior and posterior of the auricle. The analysis is described in detail with pictures so that readers can understand easily.No specific illustration of the location of AAPs can be found in Chinese ancient medical books  Figure  with the Essential Techniques for Massage. The superior part of the posterior auricle corresponds to heart, the inferior part corresponds to kidney, the middle part corresponds to spleen, the lateral side corresponds to liver, and the medial side corresponds to lung.With awareness of the limitations of the location method based purely on points, the Chinese academic circle in the late 1980s tried to locate AAPs according to the subzones. There were different zones on the auricle according to the anatomical structures of the auricle. Each zone was further divided into different subzones. The work began with the aim to locate AAPs at the ear lobe and concha where it was difficult to use points to locate these AAPs. The subdivision in vertical and horizontal lines of the ear lobe was published by Jarricot and Wong , who divIn 1990, Oleson and Kroening, scholars from University of California, Los Angeles, the United States of America, first located all AAPs at the visible surface of the anterior auricle according to the anatomy of the auricle in his article  Figure . Each suThis method was proposed in 1990 by Dr. Bossy at the international conference on AAPs held by the WHO Regional Office for the Western Pacific in Lyon, France, to solve the long-troubling problem of international standardization of AAPs. The zero point was set at the helix crus notch and the auricle is divided into four quadrants by the horizontal and vertical axis. AAPs were marked by the intersections of the latitude and longitude lines in each quadrant. Dr. Rouxeville  further This location method Figures , proposeThis method was proposed in 1988 by an article entitled \u201cThe Project of the Standardization of AAPs\u201d by the China Association of Acupuncture-Moxibustion in the Journal of Traditional Chinese Medicine  Figure . The art Practical Auricular Acupuncture Therapy, was published by Shanxi Science and Technology Press of China in 1988 which further divided the previous subzones into a number of even smaller subzones to improve the accuracy of the location of AAPs The research on history, mechanism, and clinical application of auricular therapy has experienced a long process . The nomThe location method based on subzones according to the anatomical structures of the auricle, points, and lines for full cover of the anterior and posterior of the auricle is an appropriate method and is adopted by the WFAS international standard of AAPs. It is important to keep the right direction during developing an ISO international standard of auricular acupuncture points and to improve the research quality of international standardization for AAPs and of auricular diagnosis and treatment."}
+{"text": "Colombian journals need to be characterized as having an editorial guideline oriented towards achieving international standards and have the best conditions to be accepted in databases, repositories, and bibliometric indices. Deployment of proposals should encompass aspects of policy research, training and technology necessary to induce a significant change in the diffusion and dissemination of knowledge. Open access principles, the use of open source, protection of intellectual property and recognition of the formation of the editor must be the basis of a policy of national publications.The journals need to implement a medium-term strategy to improve the diffusion of national scientific production. These changes should aim to implement high-quality editorial processes, and article level metrics that measure the usage and impact of individual scholarly activities published in the country. The national bibliographic database, Publindex should encourage the use of Open Source platform for publishing Open Access Research Articles. Peer-reviewed academic journals will strengthen because these web tools will allow optimization of the editorial workflow from the receipt of the manuscript to its publication. The complexity of the editorial processes along with the demand of editing standards may encourage the use of the open-source platform   The use of Digital Object Identifiers, (DOI) Code of Conduct and Best Practice Guidelines for Journal Editors and Publishers of Ethics Committee Publications, COPE  The adhesion and planned implementation, with clear goals of  Finally, reactions, protests, fear and criticism in anticipation of more competitive models can affect scientific journals, institutions and researchers when changes are made to appear. A proposal to define a policy that is consistent with the needs of everyone involved should adhere to the San Francisco Declaration on Research Assessment,DORA It is necessary that Colciencias and Colombian universities adhere to this initiative since it will be the roadmap for the actions required to improving the quality of national publications. The commitment of our researchers and journals will define the harmony for the modernization of the editorial process and, above all, aspire to become a model for other institutions and researchers. These actions would fulfill the mission of the University, which is transforming society."}
+{"text": "The Cali Cancer Registry was started 50 years ago as a research program of the Department of Pathology of Universidad del Valle. It is presently continuing its strong silent but meaningful work, internationally recognized as the oldest most trustworthy and reliable source of data on descriptive epidemiology in Latin America. This is evidenced by the publication, of its results in \"Cancer Incidence in Five Continents\", the most prestigious source of data on cancer incidence, since 1968 until the present time. Some population based cancer registries have started but had a premature death in Latin America. Some had been too ambitious in covering too large populations or whole countries. Others have been unable to maintain its modest but much needed economic support, reflecting the shortsightedness of national and international entities that provided the initial but not the continued funding. A few had followed the Cali Registry experience and have been able to survive economic difficulties experienced recently by some Latin American countries. Hopefully their initial success can be sustained and allow them to maintain is pioneering work. Such is the case of the Cancer Registry of Quito, operating very efficiently for 25 years, and the recently created Colombian Registries in Pasto, Manizales and Bucaramanga.,The principal and most reliable sources of data are the histopathology reports. A first attempt to analyze data in a defined population was done in Medellin, when the Pathology Department of Universidad de Antioquia, founded and directed by Alfredo Correa Henao, represented the only source of histopathology diagnoses in the department of Antioquia. Such collection of data covered the years of 1944 to 1951 and was since the bases for publications in national and international journals. Later, in Cali, the histopathology diagnoses of cancer made in the pathology departments of the country were collected and presented the Third Congress of the Latin American Society of Pathology in Medellin in 1961Dr. Haenszel, in collaboration with professors of Universidad del Valle, especially Pelayo Correa, Carlos Cuello and Guillermo Llanos, established the foundation for a Cancer RegistryThe Registry started at the same time that the Pan-American health Organization conducted the Study of Urban Mortality, which examined in detail all the death certificates of the cityThe Registry has been recognized by the International Association of Cancer Registries and the International Agency for Research on Cancer ( IARC) , which also provides technical support in data handling.Many benefits have resulted from the Registry throughout the years. It is one of the few research programs that have remained active and productive at a time when the Academic Institutions of Latin America have experienced social and economic setbacks. It has had a definite but hard to measure impact on the educational programs of the University. The students have been exposed to the importance of epidemiology on the health of the community to the point that several courses have contributed to the understanding and appreciation of its value by the teaching staff.The Registry has called attention to the tumors that represent the main social burden, especially cancer of the cervix and the stomach. A study based on Registry data showed that the lack of vaginal cytology tests increased cervical cancer rate by a factor of 10. This led health authorities and Universidad del Valle to set-up a central cytology laboratory, under the expert direction of Dr. Nubia Aristizabal,The gastric cancer epidemic was recognized and was followed by a series of epidemiologic studies, especially in the rural population of Nari\u00f1o, whose immigrants to Cali had the highest gastric cancer incidence rate of the population. The Nari\u00f1o studies have contributed to clarify the etiology of the disease, especially the role played by the Helicobacter pylori infection and the role of dietary antioxidants. An intervention study demonstrated the benefit of controlling such etiologic factorsThis issue of Colombia Medica documents important advances in the generation of knowledge on the epidemiology of cancer in Colombia, a consequence of the establishment and continued functioning of several population-based Cancer Registries. Additionally, it has permitted us to analyze the time trends of tumors associated to infections: gastric and cervical cancers, documenting the end of such epidemics of neoplastic diseases. A steady increase in the frequency of cancers of the colo-rectum and female breast possibly associated with a gradual improvement of the socioeconomic conditions of the population. An unexplained increase of the incidence of thyroid carcinoma is also documented. The increase in the incidence rates of prostatic cancer possibly reflects the increased use of the prostatic specific antigen (PSA) tests that may result in false positives, tumors that lack invasive capacity. The new information should serve as a basis to continue research on this phenomenon and to design strategies to control these diseases by public health authorities."}
+{"text": "In the Author Contributions section, Gabriella Guelfi (GG) should be listed as one of the persons who analyzed the data, and as one of the persons who contributed to the writing of the manuscript."}
+{"text": "In Italy, the process of decentralization of the health-care organization was given a strong boost during the last decade of the twentieth century, according to some inspiring lines of the Law itself, which established in 1978 the National Healthcare Service. Regions were given more and more autonomy and legislative powers in this field, so that they gained a substantial role in programming, organizing and managing health care services. The new Article 117 of the Constitution, adopted in 2001, made it explicit that health protection is a matter of concurring legislation, with the clarification that in such matters the State, which maintains exclusive powers with regard to the determination of the basic level of benefits relating to civil and social entitlements, is given the role to lay down only the fundamental principles. As a consequence, the role of the State \u2013 as it is affirmed on the website of the Italian Ministry of Health \u2013 has changed into a function of warrantor of fairness, building on the concept of the essential levels of assistance which ought to be guaranteed throughout the national territory.The major risks that deserve a special attention are those concerning the possibility of a too deep fault of inequality as to what is offered in different regions beyond the threshold of what is established as essential at the national level and a too broad discretion in defining standards, procedures, guidelines, not to mention the burning issues of costs and quality. Paediatrics, far from being an exception, offers telling examples of the asymmetries and gaps that we should fill in, in order not to miss the obligation entailed in the recognition of the right to health-care as a constitutional essential. The neonatal screening programmes on the one side and the management of vaccination on the other side underline the difficulty of drawing the line of what is essential as well as acknowledging the limits of regional autonomy in applying fundamental principles. The situation of neonatal intensive care units underlines faults of inequality that look hard to reconcile with the idea of one and the same dignity of all citizens. Needless to say, starting with the newborn."}
+{"text": "The Council of Scientific and Industrial Research has carried out an investigation about several publications by this group in order to evaluate concerns raised about the authenticity of the data.The investigation committee at the Council of Scientific and Industrial Research has concluded that there are no data available underlying this study and thus that the published results are fabricated. As a result, the Council of Scientific and Industrial Research has requested the retraction of the publication. The authors are in agreement with the request by the investigation committee.PLOS ONE retracts this publication.In line with the outcome of the institutional investigation,"}
+{"text": "There are errors in the Funding section. The correct funding information is as follows: This study was supported by grants from the intramural program of the National Institute of Diabetes and Digestive and Kidney Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."}
+{"text": "There are some errors in Equations 11 and 20.Equation 11 should be replaced by the following:PA is the change-of-basis matrix from A to the basis of eigenvectors of tensor A and:Equation 20 should be replaced by the following:The authors confirm that the errors do not affect the results of the paper."}
+{"text": "There is an error in the equation in the Data Processing subsection of the Methods and Materials section. The publisher apologizes for this error. Please view the complete, correct equation here:"}
+{"text": "In the Acknowledgements section, the name and affiliation of Gert Van der Auwera are listed incorrectly.The correct name is Gert Van der Auwera and he is currently at the Institute of Tropical Medicine, Antwerp, Belgium."}
+{"text": "We wish to comment on the correspondence regarding the question of efficacy and mechanism of action of acetazolamide in the treatment of idiopathic intracranial hypertension (IIH), published in JAMA September 10, 2014  hold thaIn the 1950s, a similar discussion concerned the mechanism of acetazolamide in the treatment of epileptic seizures. Initially, it was thought that the effect was indirect via the kidneys and was related to an induced metabolic acidosis. Subsequently, acetazolamide was shown to prevent seizures in nephrectomized animals; the anticonvulsant effect was independent of the effect on the kidneys and was caused by a direct inhibition of carbonic anhydrase in the brain .In patients with IIH treated with acetazolamide, the inhibition of the enzyme in the choroid plexus results in a reduction of CSF production and flow. The acid\u2013base status of the patient may also alter the distribution of acetazolamide in the CSF and brain, but its effect on the CSF flow is secondary to that mediated by the choroid plexus. Based on the pharmacology and distribution of acetazolamide and carbonic anhydrase in the brain, the theory that emphasizes the effect of acetazolamide on CSF production in IIH is most likely primary and direct, and weight loss, when recognized as a factor, is secondary and indirect, and frequently the result of toxic doses in excess of the amount needed for complete enzyme inhibition.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Figure 2 of article (1), and in the lower panel of Figure In the upper panel of  article , and in Article (1)Article (2)The authors had full access to all the content in this commentary and take full responsibility for the accuracy of the data. YT wrote the manuscript. NO checked the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The correct title is: PeNHX3 mediates Na+ detoxification in P. euphratica.There is an error in the title of the first subsection of the Discussion. The correct title is: PeNHX3 may function in salt stress and LiThere is an error in the title of the second to last subsection of the Discussion. The correct title is: Asn187 and Asp 188 forms an ND motif that is crucial for ion binding and ion translocation in PeNHX3."}
+{"text": "In recent years a significant body of research has accumulated on olfaction along several lines of investigation, ranging from molecular mechanisms to the neural and cognitive processing of olfactory information, as well as to multiple influences of odors on our everyday lives. The purpose of the present Frontiers' Research Topic is to present experimental data (run in the laboratory as well as in everyday settings), reviews and methods papers on various applied or applicable aspects of olfactory cognition along with the beneficial possibilities that olfactory cognitions make possible in ameliorating different aspects of human condition.The present Research Topic is composed of 23 articles reunited in six fields of applied olfactory cognition. The first section concerns basic studies on odor memory and attention. In the first article, Smeets and Dijksterhuis  review tThe second section reunites contributions on the acquisition and consequence of olfactory expertise which remains relatively unexplored in olfaction. Royet et al. , report The third section of the Research Topic addresses chemoreception in everyday life. In the eighth article, Thomas-Danguin et al.  and his The fourth section of the Research Topic focuses on the relationships between olfaction and emotional processes. In the eleventh article, He et al.  investigThe fifth section concerns aspects of human reproductive life in relation with the emission and perception of body odors. Cameron  starts bIn the last section of the Research Topic olfaction is considered in relation with health and disease issues. Ignatieva et al.  article article article (articleWe are grateful to all of the contributors for their commitment to this project and for providing new accounts of the state of the art in applied olfactory cognition. We would also like to extend our special thanks to Professor Richard J. Stevenson for writing the foreword of this book. We hope that this e-volume will help promote further research on the applied aspects of olfactory perception and cognition and attract new scientists to the field. We also hope that it will be a useful resource for colleagues and professionals dealing with the study of the chemical senses in relation with issues on human welfare in everyday setting.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Since publication of this paper, the authors became aware of details in the preparation of a composite figure that required correction.In the previous version of"}
+{"text": "There are errors in the Funding section. The correct funding information is as follows: This work was supported by the National Institute of Neurological Disorders and Stroke at National Institutes of Health , and Mayo Clinic. The authors are grateful for the access provided by NeuroVista to parts of its internal statistical data analysis pipeline. The funding agencies had no part in the design, data collection and analysis, decision to publish, or preparation of the manuscript."}
+{"text": "There is an error in the first sentence of the Results paragraph of the Abstract. The correct sentence is: The search resulted in 101 included papers.There is an error in the third sentence of the first paragraph of the Results. The correct sentence is: Of the remaining 420 articles another 319 were excluded based on full text review .There is an error in"}
+{"text": "International Journal of Circumpolar Health reached another milestone in June 2015 with a change of the chief editorship from Kue Young  to Rhonda Johnson .The Establishment in 1973 as an organ of the Nordiska Samarbetskommitten f\u00f6r Arktisk Medicinsk Forskning (NoSAMF), reporting to and financed by the Nordic Council of Ministers (NCM).The dissolution of NoSAMF in 1996 and the transfer of the journal to joint ownership by the Nordic Society for Arctic Medicine (NSAM) and the International Union of Circumpolar Health (IUCH). Editorial and administrative functions were assumed by the Centre for Arctic Medicine at the University of Oulu.Arctic Medical Research to International Journal of Circumpolar Health in 1997.Changing of the name from Creation of the International Association of Circumpolar Health Publishers (IACHP), a consortium of several universities, research institutes and professional/academic organizations as the publisher of the journal in 2004.Merging of IACHP with the International Network for Circumpolar Health Research (INCHR) to form the Circumpolar Health Research Network (CHRN) in 2013, which became the publisher of the journal.The closing of the editorial office at the University of Oulu, the publication agreement between CHRN and Co-Action Publisher and the change to a completely on-line journal in 2012.The institution of publication fees in 2013.Over the years, the journal has undergone several major changes. It might be helpful to our readers to highlight them:IJCH serves an essential function in the dissemination and translation of scientific knowledge on all aspects of circumpolar health to our community of health researchers, providers, managers, policy makers and community leaders. The quality and impact of the journal continues to improve, thanks not only to the increasing range of scientific endeavour in the arctic but also to the countless hours of volunteer effort by our growing ranks of peer reviewers willing to share their expert critique of manuscripts upon request. If you are not yet on our reviewer list and would like to be, please contact Rhonda Johnson. And if you are engaged in meaningful and interesting work related to circumpolar health, please consider sharing your experiences and lessons learned with our readers through submission of manuscripts. Check out the \u201cFor Authors\u201d tab, and consider joining the on-line discussions via Facebook, Twitter and LinkedIn. We welcome your contributions to the continuing success of our journal.As outgoing and incoming editors-in-chief, we firmly believe that  School of Public Health University of Alberta Edmonton, CanadaKue Young University of Alaska Anchorage Anchorage, AK, USARhonda Johnson"}
+{"text": "The era of carbon nanomaterials has started with the first reports on fullerenes and related compounds in the mid-eighties, and a tremendous increase of the research activity in the field has been observed ever since. New classes of carbon materials have entered the scene such as carbon nanotubes, carbon onions, nanoscale diamond and diamondoids. A major turning point was the appearance of graphene as a material available for in-depth investigations \u2013 spurred by the development of reliable production methods. The progress in terms of understanding the properties and chemistry of carbon nanomaterials has opened a whole new world of applications for nanomaterials in general.The reliable production of a material represents a necessary requirement for the development of a research field. By now, all types of carbon nanomaterials and many carbon-rich organic materials are available to the scientific community in excellent quality and suitable amounts for the investigation of fundamental properties and prospective applications. This has led to the emergence of a new community of scientists working in an interdisciplinary area involving materials science, organic chemistry and physics.Synthetic organic chemistry is a major part of carbon materials chemistry as the rational synthesis of carbon allotropes such as fullerenes and nanotubes and related molecular compounds with and without heteroatoms remains a challenging task. The contribution does not end here but continues with the development of suitable reactions for the controlled functionalization of molecular as well as nanoscale allotropes such as fullerenes, diamondoids, carbon onions, carbynes or nanodiamonds. The interplay with knowledge gained by materials scientists and physicists on the electronic or optic properties of materials enables the fine-tuning of materials properties and the conjugation of functional moieties with the carbon nanomaterial. This interdisciplinary approach opened the door to a broad range of applications including energy conversion and storage, catalysis, electronic and optoelectronic as well as biomedical applications.The present Thematic Series attempts to showcase the diversity in the field of carbon nanomaterials and carbon-rich compounds and to emphasize the links between the different classes of materials. Contributions from synthetic organic chemistry dealing with the formation and functionalization of carbon-rich molecules and from the area of functional nanomaterials illustrate the plethora of research activities. Obviously, such an issue will fail to present the field in its entirety. The sheer number of publications appearing globally every year attests to this. However, a topical collection enables a focused view on some of the novel developments.I would like to thank all authors for their excellent contributions to this Thematic Series. The publication of the manuscripts would not have been possible without the contribution of detailed and timely reports by reviewers from all fields of carbon chemistry. Furthermore, I would like to thank the editorial team at the Beilstein-Institut for their support and hard work. The open access policy of the Beilstein Journal of Organic Chemistry facilitates the availability of the articles of this Thematic Series to researchers and interested people all over the world, thus enabling a broad discussion of the topics.Anke KruegerW\u00fcrzburg, June 2014"}
+{"text": "The second sentence of the Results section of the Abstract is incorrect. The complete, correct sentence is: Across each band of age within which the definition of anaemia remained constant , the prevalence of anaemia declined with each year of age."}
+{"text": "It was an error in the structure of dopamine o-quinone published in the commentary on Evaluation of models of Parkinson's disease since the benzene ring contained an extra double bound between the carbonyls. The actual structure of dopamine o-quinone is the correct structure.All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.Supported by University of Chile (ENL014/14).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "BMC Palliative Care has been incorrect with respect to the contributions of Samar Aoun and Harvey Max Chochinov who also contributed to the conception and design of the project. The corrected acknowledgement is presented here.The acknowledgement of our article  publisheThe authors thank Samar Aoun and Harvey Max Chochinov for their assistance with the project, for securing the funding for this study, and acknowledge their contribution to the conception and design of the project. We are grateful for the support of the Motor Neurone Disease Association of Western Australia. Finally, we wish to thank all of the people who took part in this study.BMC Palliative Care would like to inform its readers that the corresponding author has changed affiliation since the publication of the original article [The editorial department of  article  and can"}
+{"text": "The Council of Scientific and Industrial Research has carried out an investigation about several publications by this group in order to evaluate concerns raised about the authenticity of the data.The investigation committee at the Council of Scientific and Industrial Research has concluded that there are no data available underlying this study and thus that the published results are fabricated. As a result, the Council of Scientific and Industrial Research has requested the retraction of the publication. The authors are in agreement with the request by the investigation committee.PLOS ONE retracts this publication.In line with the outcome of the institutional investigation,"}
+{"text": "The Ibarapa Programme was founded on February 9, 1963, as the Ibarapa Project, a collaborative and cooperative health development project of the University of Ibadan, the Western Nigeria Government, and the Ibarapa community. The Rockefeller Foundation provided generous seed funding for the project, while the Liverpool School of Tropical Medicine and the London School of Tropical Medicine and Hygiene provided technical support to medical staff. The three specific objectives of the project as restated in the 25th anniversary book To teach medical students and doctors, through practical work, the principles and practices of community medicineTo study the problems of health care delivery in the Ibarapa Community and to develop the health services of the district into a model of what an integrated local health service should be, in collaboration with the Government of Western Nigeria and in a manner that can be applied to other districts in Nigeria and other developing countriesTo carry out research into various aspects of health and disease in the community and thus to build up a body of knowledge on the various factors which are involved in health promotion and disease preventionThe Ibarapa Project evolved into the Ibarapa Programme and has remained an interdisciplinary training program in community health, development, and empowerment. The Ibarapa Programme has hosted several postings of resident doctors (at registrar and senior registrar levels), 217 community health postings of medical students (since 1963); six postings of dental students (from 2007); several 3-month internships for master's and diploma students from the African Regional Health Education Centre at the Department of Health Promotion and Education; over 21annual postings of community health officers in training at the University College Hospital (UCH); and many other postings of students from the UCH Schools of Nursing, Midwifery, and Perioperative Nursing, the Oyo State School of Midwifery, and the community health extension workers of the Oyo State School of Hygiene, Eleyele. In addition, elective students from the United States, Canada, the Netherlands, Britain, Finland, and other parts of the world come regularly to Ibarapa for experiences in community medicine and tropical medicine.Innovating for Africa: Uncommon ServiceThe impact of the Ibarapa Programme on health care in Nigeria is significant because a large number of practicing physicians in Nigeria are Ibadan-trained and spent eight weeks in the district, including one week at the District Hospital in Eruwa, where they learned the rudiments of secondary health care. The district hospital in Eruwa has won accolades in rural healthcare and surgery and in 2009 was the subject of the award-winning documentary Ibarapa Programme has collected 51 years of medical records of patients in a rural community and over 30 years of interdisciplinary data. The formation of the African Regional Health Education Center (ARHEC) in 1975 and subsequent training of health educators facilitated the generation of studies and papers from the Ibarapa Programme. ARHEC is an initiative that was started by the World Health Organization, the University of Ibadan, and the Nigerian Ministry of Health as a culturally competent and relevant health educational center for Africans The Ibarapa Programme is located in a rural community in the lush tropical rain forests of southwestern Nigeria, and at initiation of the project, the area was endemic for many NTDs, notably intestinal parasites, onchocerciasis, and guinea worm As the Ibarapa Programme turns 51 years old, the Comprehensive Health Centre at Igbo Ora and the public health program continue to grow, despite the upheavals that the country, the state, the community, and the university have faced. A major challenge facing the program is the lack of funding to adequately preserve and index the extensive health and other data that have been generated and continue to be generated. There is also a need for capacity building to train local stakeholders in the use of this extensive data, which is important for the eradication and understanding of NTDs and other diseases as well as of socioeconomic and cultural issues facing rural dwellers. Consequently, the Ibarapa Programme is undergoing major changes that will allow it to meet the current and future needs of the rural community and researchers.A key change is the evolution of the Ibarapa Programme into the Institute of Community Health and Development (ICHD). The central offices of ICHD will be based at UCH, and its community development, research, and training program will involve all the faculties, departments, and units of UI. ICHD has been initiated with the urban and regional development of the Ibarapa zone through agriculture, conservation, and health forestry. Thus, the 43,605 hectares donated to the Ibarapa Programme in 1963, of which only 7.2 hectares have been used, has been subjected to detailed soil survey and agricultural characterization by the Department of Agronomy of the university. The master plan of the entire land was developed following a community needs assessment in conjunction with the local people, through town-hall exercises and community meetings \u20134. The I"}
+{"text": "Quantitative studies comparing the incidence of AN symptomatology in men and women often utilise measures that were developed for use amongst female samples. The findings of these studies may lead to a misrepresentation of the clinical picture of AN in men since these instruments carry potential gender biases and thus often yield skewed results. Therefore, the current prevalence statistics of anorexic symptomatology amongst men that may be found in the literature may be inaccurate. The development of a screening tool specifically designed to assess levels of anorexic symptomatology in men would lead to a more accurate measurement of mens' experiences of AN. This paper will outline the development of such a measure based on an integrative review of the literature over the period between July 2000 and July 2013 and using Google Scholar and South African e-Publications. Data from a thematic analysis of interviews with clinical psychologists and psychiatrists in South Africa was also used in the development of the instrument. The instrument is presented with a view to discussing the way forward for the development of a more accurate understanding of the levels of AN symptomatology in the male population."}
+{"text": "The NIA Interventions Testing Program Announces the 2015 Solicitation of ProposalsThe National Institute on Aging (NIA) Interventions Testing Program (ITP) investigates dietary supplements purported to extend lifespan and/or delay the onset of disease and disability. The NIA ITP tests such compounds in mice, using a variety of measured endpoints to assess the efficacy of interventions. The NIA ITP is not a mechanism for funding sponsors\u2019 laboratories to perform the work, but rather it is a collaborative effort between the three NIA-funded testing sites and the sponsors who propose interventions for study. The sponsor's role is to provide the rationale for investigating the intervention, make recommendations on the dose, route, and timing for administration of the intervention, and propose assays and measurements to document the efficacy of the intervention. The sponsors have access to all data developed from the treated mice, assist in analysis of the data, and co-author on resulting publications.et\u00a0al., One of the important aspects of the ITP protocol is that all compounds are tested on both male and female mice. The NIH has recently begun actively promoting the recognition of sex as a biological variable in animal studies .The NIA ITP is soliciting proposals for compounds to enter the study in 2016. The deadline for receipt of proposals is February 26, 2015. Information on the NIA ITP and guidelines for proposal development are posted at:"}
+{"text": "The original Ethics Statement for this article contained incorrect information regarding approval of this study. The correct information is provided in this revised Ethics Statement:\u201cThe Ethics Committee for the protection of humans participating in Sciences of Government of the Republic of Congo (CERSSA) exempted this study from review and waived the need of informed written consent due to the fact that all data and sampling were collected during the course of routine care in patients registered at the DOTS centers for suspicion of pulmonary tuberculosis or tuberculosis treatment. Authorization for the research was given by the Minister of Health and Population and the General Director of the National Public Health Laboratory from the Republic of Congo. This study did not require any additional data, sampling and contact with patients. The outcome of the research data did not affect patient management. The objectives of the study were verbally explained to all participants. They were free to refuse that their sputum was transported to TB reference laboratories in France for processing and culture. No personal identifiers were recorded to maintain anonymity and confidentiality.\u201dThe Dean of the Faculty of Health Sciences of Marien Nagoubi has issued a formal statement confirming that the need for ethics approval was waived for this study, and that the study was authorized by the Minister of Health and Population and the General Director of the National Public Health Laboratory of Congo. This statement can be viewed below in File S1Waiver of Ethics Approval from the Dean of the Faculty of Health Sciences.(PDF)Click here for additional data file."}
+{"text": "Trend analysis in 2005 to 2011 showed high growth in diabetes prevalence in Iran. Considering the high prevalence of diabetes in the country and likely to increase its prevalence in the future, the analysis of diabetes-related policies and programs is very important and effective in the prevention and control of diabetes. Therefore, the aim of the study was an analysis of policies and programs related to prevention and control of diabetes in Iran in 2014.This study was a policy analysis using deductive thematic content analysis of key documents. The health policy triangle framework was used in the data analysis. PubMed and ScienceDirect databases were searched to find relevant studies and documents. Also, hand searching was conducted among references of the identified studies. MAXQDA 10 software was used to organize and analyze data.The main reasons to take into consideration diabetes in Iran can be World Health Organization (WHO) report in 1989, and high prevalence of diabetes in the country. The major challenges in implementing the diabetes program include difficulty in referral levels of the program, lack of coordination between the private sector and the public sector and the limitations of reporting system in the specialized levels of the program.Besides strengthening referral system, the government should allocate more funds to the program and more importance to the educational programs for the public. Also, Non-Governmental Organizations (NGOs) and the private sector should involve in the formulation and implementation of the prevention and control programs of diabetes in the future. Islamic Republic of Iran, a country in the Middle East, has 75 million people, according to the last national census in 2011 . The urbDiabetes is one of the most common NCDs worldwide. Seventy percent of people with diabetes lived in Low and Middle Income Countries (LMICs) in 2010 and the highest relative increase in the diabetes burden happens in Africa and the Middle East  in 1990. The research results indicated the highest prevalence of diabetes in Tehran . Also, the diabetes prevalence in the cities was more than the villages and in women more than in men. The study results were not reliable, because of collecting data from a questionnaire and lack of an indicator to measure blood glucose  in 1993. The results of these studies showed that the diabetes prevalence was in women and men about 7.6% and 8.9, respectively, and also half of diabetic patients were unaware of their disease  and 14.6 percent in 2011 respectively. Trend analysis in 2005 to 2011 showed 35 percent growth in the diabetes prevalence in Iran. The annual direct cost of diabetes in the country is estimated to be about 590$ million in 2009 .As stated by the international reports, it can be prevented at least 80 percent of heart disease, stroke and type 2 diabetes by eliminating the main factors causing these diseases . ConsideThis study was an analysis of the diabetes policies and programs in Iran using deductive thematic content analysis of key documents. In this study, the health policy triangle framework was used in the data analysis. The Walt and Gilson\u2019s policy triangle framework, that has been prepared specifically for study on health field, focuses on four fields of policy consist of content, context, process and actors who have a critical role in forming policies    until JuAside from the original documents about the policies and programs of diabetes, the guidelines, survey reports and national meeting reports on the formulation and evaluation of the program were examined in the study. The included documents for the study were 21 documents: original documents (5), survey reports (2), guidelines (7), and national meeting reports on the formulation and evaluation of the program (7) .Documents using thematic content analysis were classified, described and analyzed. The documents were sorted from old to new chronology and were examined several times by the research team. Afterwards, primarily coding of all documents was conducted. Next, Initial codes were put on the main themes based on the study\u2019s conceptual framework by the first researcher. After that, the researchers agreed on the data analysis process and finally the coding instruction was prepared. Then, all documents were coded and themes were re-classified by the researchers using the coding instruction. After the researchers performed the coding, the codes were reviewed by the research team. And finally, the consensus was generated on the final codes and themes. MAXQDA 10 software was used to organize and analyze data.A pilot project for prevention and control of diabetes was implemented in some areas of the country in 1992. The project results were evaluated in 1993. The results of the evaluation include the non-standard method for screening, the high costs of screening and surveillance for each patient, lack of adequate equipment in the health network system to implement the program and the low prevalence of diabetes in the rural areas. The results were lead to stopping the program  in 2004 and 2010 respectively . The tarThe overall goal of both of the phases was prevention and control of diabetes and its complications. The specific objectives, strategies and outcomes of the program are shown in The National Committee for Diabetes was formed in summer 1996 after releasing the results of many studies which showed the high prevalence of diabetes in the country. The objective of the committee formation was the provision of the national diabetes program and the training patterns for the public and providers. The committee members presented a program with the overall goal of prevention and control of diabetes. The MoHME, in coordination with the National Committee for Diabetes, held six workshops related to diabetes for doctors, nurses and nutritionists in 1997 and 1998. Afterward, the program was implemented as a pilot plan in 1999  for the screening and patient care), the second level  and the third level   have been completely observed by the authors."}
+{"text": "Hardell and Carlberg claim in a recent article that both the Cause of Death Register and the National Inpatient Care Register indicate that there was a severe and increasing underreporting of malignant brain tumors to the Swedish Cancer Register during recent years . As a coTheir claim is based on the observation that tumors of unknown type in the brain or CNS (ICD10 D43) in both the Cause of Death Register and the National Inpatient Care Register have been increasing since 2007/2008. There are several problems with the authors\u2019 use of these data, one of which is displayed in The results that are presented from the National Inpatient Care Register are based on hospital discharges retrieved from tables published by the National Board of Health and Welfare and not relevant for analysis of cancer incidence trends. The coverage rate of the Swedish Cancer Register has been examined by means of a comparison with data extracted from the register of hospital discharges . A substAlthough the figures that are presented in the article may well be correct, their interpretation is grossly misleading. Already the title is misleading because the rates of brain tumor are not increasing in the Cause of Death Register. The reason for the rise of the subtype of brain and CNS tumor rates of unknown type is known and documented in the open literature. The authors actually mention themselves the close correlation between the trends of the unspecified and the malignant tumors in the Cause of Death Register, but choose to disregard it in their interpretation of data."}
+{"text": "Frontiers in Human Neuroscience. The authors concur with the retraction and sincerely regret any inconvenience this may have caused to the reviewers, editors, and readers of Frontiers in Human Neuroscience.The journal retracts the 6 January 2012 article cited above. Following a series of concerns regarding the origin of images in this article, Frontiers conducted an investigation. The results of this investigation determined that, as these images formed an integral part of the article and did not originate in the authors' laboratories and were not duly attributed, the article does not meet the scientific criteria of the journal. This retraction was approved by the Specialty Chief Editors of"}
+{"text": "The journal retracts the 30 June 2016 article cited above. Based on information discovered after publication and reported to Frontiers in July 2016, the article was examined, revealing that the complaints were valid and that the article does not meet the standards of editorial and scientific soundness for Frontiers in Public Health. The retraction of the article was approved by the Field Chief Editor of Frontiers in Public Health and the Specialty Chief Editor of Environmental Health. The author considers the retraction to be unwarranted and therefore does not agree to the statement."}
+{"text": "The origins of genetics and evolution are relatively recent in the context of the 350 years of scientific publication that are celebrated this year by the Royal Society, emerging in the 1850s and 1860s with the work of Gregor Mendel and Charles Darwin. The rediscovery of Mendel's laws of inheritance in 1900, and the demonstration by Garrod [Important work in the 1920s and 1930s by Haldane, Fisher and Wright on the development of population genetics and, subsequently, the formulation of the modern evolutionary synthesis provided the basis of our current understanding of population and evolutionary biology. Haldane was also probably the first to introduce an evolutionary perspective into medicine, suggesting in 1949 that selection for resistance to malaria might explain the high levels of thalassaemia in malarious regions [However, the discoveries that led most directly to the remarkable recent progress in genetic and evolutionary approaches in medicine go back to the 1940s and 1950s with the establishment of DNA as the genetic material and the elucidation of its structure, with the subsequent emergence of molecular biology in the following decade.An important recent stimulus to research on genetics and evolution in medicine was the sequencing of the human genome. On 26 June 2000, the International Human Genome Sequencing Consortium announced the production of a rough draft of the human genome sequence. In April 2003, the Consortium announced an essentially finished version of the human genome sequence. This version, which is available to the public, provided nearly all the information needed to research almost all aspects of the whole genome. The initial promise of this achievement, for rapid progress in understanding the genetic basis of many common human diseases, was slow to be realized given the polygenic nature of the susceptibility of individuals to most of these conditions.However, in recent years, progress has been steady, due to new methods for rapid and low-cost sequencing of multiple genomes, combined with advances in bioinformatics and new statistical tools that permit the identification of complex multi-genic associations between host genetic background and the likelihood of a particular disease occurring. Concomitant with advances in the study of the human genome has been the complete sequencing of all the major pathogens of humans, and the use of these sequences to address a wide range of problems, including defining \u2018who infects whom\u2019, and what genetic factors control pathogenicity and transmissibility. Complete sequences for the human host and a particular infectious agent have revealed the complex interplay between the two genetic templates in all host\u2013parasite associations in determining the course of infection and associated morbidity and mortality.Proceedings of the Royal Society B: Biological Sciences, six contributions are presented that chart past and present progress in a series of important fields where genetic and evolutionary research have made important contributions to a variety of areas in medicine. The areas covered are not exhaustive of the fields where such research has made important contributions to current medical practice and the treatment of disease. For example, one very important area not covered in this issue is cancer research, where the ability to routinely sequence the genomes of tumour cells is already having both a major clinical impact and an impact on the design and testing of new small molecule or immunotherapeutic treatments. However, the contributions in this issue provide an exciting reflection of current genetic and evolutionary research, which is advancing our understanding of the causes and treatment of disease and infection.In this issue of the Current progress in genome-wide association studies between genetic polymorphisms and common genetic disorders is reviewed by Donnelly and co-workers . TechnolCollins & Thrasher  review pThe origins of immunology can be traced back to at least the early eighteenth century, but studies during the last 60 years have provided a detailed picture of the complex systems that have evolved to protect against disease. The article by McMichael and co-workers  focuses Cardiovascular diseases remain a major cause of morbidity and mortality throughout the world, and Kennedy-Lydon & Rosenthal  discuss et al. [A very different area where large-scale genome sequencing is having an impact is in the study of pathogens, where sophisticated analytical tools that combine the genome sequences of large samples of pathogen isolates with geospatial and temporal data are leading to an understanding of the origins, evolution, pathogenicity and epidemiology of viral and bacterial diseases, with the prospect of greatly improved real-time surveillance of disease outbreaks. Pybus et al.  and Bentet al. , respectWe hope this selection of contributions will serve as a stimulus for expanded research in this fascinating field that combines old  concepts such as the theory of evolution by natural selection, with new technologies in whole-genome sequencing and molecular biology that are beginning to unravel the detailed mechanisms of disease causation and highlight possible new avenues for treatment or cure."}
+{"text": "In There is an error in the last sentence of the Primary outcome subsection of the Results. The correct sentence is: The median number of units consumed a week in both intervention and control groups at follow-up was within recommended weekly limits , with the exception of women in the intervention group ."}
+{"text": "Psychological issues take on great importance in oncology settings from the communication of the diagnosis to the management of the end-of-life phase  and the Hospital Anxiety and Depression Scale .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The following information is missing from the Funding section. The publication of this review was supported by the Wellcome Trust (EPNCBD6710). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."}
+{"text": "The appropriateness of research design and methodology of clinical trials is paramount if we are to succeed in reducing the amount of waste in research. Pilot and feasibility studies serve an important role in determining the most appropriate design and whether the trial will succeed to completion.The study will assess the role of pilot and feasibility studies in the design of clinical trials funded by the Health Technology Assessment (HTA) programme.There are three phases to the study: 1. Literature review, 2. Review of the ongoing HTA trial portfolio and, 3. Review of the HTA portfolio of published trials to determine the added value of the inclusion of a pilot or feasibility study. A list of HTA trials will be retrieved from three cohorts: completed standalone pilot or feasibility studies; completed and ongoing clinical trials which include an internal pilot or feasibility study; and successful applications in pre-contracting status in the HTA programme.The results of the study will still be in development. The number of included trials and proposed checklist/classification system will be presented to determine how pilot and feasibility studies are used to inform the trial design and whether those that include a pilot or feasibility study recruit patients on time and within target.The findings from this study will be important in the context of the adding value in research agenda. This is partly due to the lack of existing evidence on the role of pilot and feasibility studies."}
+{"text": "The article describes the theoretical and practical need for the development of the concept of assistance to health protection of the individual in order to address the problem of health protection of students and teachers in the conditions of a higher pedagogical education. The problem of studying human health, its entirety, systemacity and connection with the environment attracts particular attention in recent years. This was one of the reasons to study the problem of \u201chealthy lifestyle\u201d as the qualitative characteristic of a human life aimed at health, due to the fact that a healthy lifestyle is one of the determinants of health. This is made possible with the use of specific health-protecting technologies aimed at searching for ways and means of protection and conservation of health of students and teachers in the conditions of the educational process and using educational tools, which is currently included into the priorities of education. The strategic aims of education outlined in the \u201cNational Doctrine of Education in the Russian Federation through to 2025\u201d are closely linked with the problems of Russian society, including \u201cthe creation of a framework for sustainable social, economic and intellectual development of Russia, ensuring a high quality of life of the people and national security\u201d. Main goals and objectives of education in the Doctrine include \u201cfostering healthy lifestyle, development of children and youth sports\u201d, and the main objectives of the state in education include a comprehensive care for \u201cthe protection of life, health and physical education in the development of children, pupils and students\u201d.Scientific and practical need to develop special health-protecting technologies, which mobilize resource potential of the participants in the educational process to achieve the objectives of the new educational paradigm, is increasing. In this regard, assistance to the protection of health as a process aimed at self-regulation of an individual and finding the meaning of a healthy lifestyle becomes the strategy of development of health-protecting technologies in an educational institution .Analysis of the practice of educational institutions revealed the importance of assistance to health protection in the following aspects: relevance of subjects of educational process that have health protection competence; need for technological support of the formation of the axiological attitude to health as a factor of personal development and its implementation in the process of interaction between the subjects of the educational process .Currently, there are significant, unreasonably high overloads of the participants in the educational process in the system of basic and vocational education in Russia. Mechanisms of self-regulation of the individual begin to function at extreme values of life potentials of human health, creating a threat of its deterioration. Fatigue affects the health of participants in the educational process . In addiThere is a social and educational need to study the values of health protection as a strategic part of educational activities of the educational institution that seeks not only to fully satisfy, but also create a need for a healthy lifestyle in the context of axiology of the health protection.With all the real-life opportunities for educational assistance to health protection of the individual, today its potential as a pedagogical phenomenon is poorly understood and therefore not realized. Thus, the need arises for theoretical basis for constructing educational concept of assistance to health protection of the individual in terms of higher pedagogical education.The emergence of the problem and the relevance of its research are determined by aggravation in educational theory and practice of a number of contradictions between:a) society's need for a high level of health of the younger generation as a condition for the further development of the society and the lack of effectiveness of existing educational concepts and pedagogical tools aimed at protecting and improving the health of participants in the educational process;b) the increasing demand for scientific  feasibility of health protection of the individual in the conditions of higher pedagogical education and the lack of a holistic concept of self-educational activity of students of the higher education institution;c) the ever-increasing potential of educational technologies aimed at optimizing the health protection of the individual and the lack of their relevance in the system of higher pedagogical education;d) objective requirement to have a healthy lifestyle to ensure the health of the individual and insufficient development of its pedagogical foundations: the content of educational technologies that ensure its effectiveness in the conditions of higher pedagogical education.Given these theoretical positions, the experimental part of the study was conceived and implemented as experience of the development and empirical validation of the conceptual model to assist health protection of the individual in the conditions of pedagogical education, in order to determine the conditions and factors of development and integration of the structural components, their systematic interconnection and interdependent aggregate.The following tasks have been put forward in the pedagogical experiment:- practical implementation of the concept of educational assistance to health protection of the individual;- experimental verification of pedagogical conditions of the concept;- experimental approbation of the developed stages of the study;- determination of the effectiveness of the introduction of the concept of education assistance to health protection of the individual.Experimental work was carried out in three stages.During the first stage (preliminary stating), the organization of educational process in higher education institution has been comprehensively studied, and the initial state of the health-protecting activities was defined; selection of specific techniques for the study of the initial state of the experimental object; definition of the features by which we can judge about the changes in the experimental object under the influence of appropriate educational assistance.During the second stage , the formative experiment was conducted, during which the probation was determined: selection of the content of the experimental work; carrying out the experiment on determination and validation of pedagogical conditions; formation of the experimental method performance criteria for health-protecting training of students; recording of data on the course of the experiment based on the intermediate sections describing the object changes under the influence of the experimental system of measures.The third stage (control and adjustment) included: analysis of the obtained experimental data; verification of the analytical material with the purpose, objectives and hypothesis of the study; processing of the results of the experiment, control diagnostics of level of assistance to health protection of the individual; description of the features of the subjects of the experimental treatment (students and teachers); comprehension and analytical presentation of the material and findings.To achieve the objectives and verify the initial assumptions, set of the research methods was used: methods of theoretical analysis ; prognostic methods ; diagnostic methods ; archival methods ; observational methods (direct and indirect observation); study and generalization of mass and excellence experience; experimental work; methods of statistical data processing .Adoption of healthy lifestyle of young people in general and students in particular is regarded today as one of the priorities of the development of Russian education system. Significance of the formation of values of a healthy lifestyle is due to the need to maintain and increase the health of students and improve their physical, mental and social wellbeing. Good health and physical performance are a condition and a basis for unlocking the creativity potential of the individual, their professional self-realization .The main goal of health-protecting education is to equip a person with scientific and theoretical knowledge about the formation, preservation and strengthening of health and practical knowledge of healing the body.Understanding the philosophical, psychological and educational nature of the assistance to health protection of the individual in the conditions of the pedagogical education makes it possible to consider this process as a pedagogical concept, which defines the methodological approaches to assist the health protection of the individual in the conditions of the pedagogical education; main pedagogical trends and principles, a set of pedagogical conditions that increase the effectiveness of the assistance to health protection of the individual.Study of methodological approaches, as well as the analysis of existing practices, allowed to define the concept of assistance to health protection of the individual in the conditions of the pedagogical education as a system of modern scientific and pedagogical views, ideas, target settings, priority areas, forms, methods of joint activity of participants in the educational process in forming a healthy lifestyle, readiness for professional health-protecting activity .Methodological basis of our concept is the methodology of the systematic, pragmatist, person-centered and axiological approaches to the study of nature and mechanism of interaction between the individual and the environment, the role of a healthy lifestyle in the development of the individual , as wellThe content of the pedagogical concept is defined by its key provisions that make up the original theoretical basis or a core\u2013a system of initial assumptions that determine the features of construction of scientific theory and characterize its specificity. Based on this understanding, the core of the pedagogical concept should include laws and principles of assistance to health protection of the individual that allow to explain its nature and ensure the ability of theoretical and logic conclusion of all provisions of the pedagogical concept .The main regularities in the study are identified as follows: effectiveness of assistance to health protection of the individual in the conditions of the pedagogical education is determined by taking into account dependencies such as the dynamics of the psycho-emotional state and health of students and the subsequent development and use of programs of correction of these states on the basis of the organization of humanistic interaction between students and teachers and the support of appropriate pedagogical principles.Implementation of the above regularities is based on the following principles of humanistic pedagogy that determine educational assistance to health protection of the individual in the system of pedagogical education: the principle of the integrity of the individual, their psychosomatic, social and cultural unity, integrative exposure to health-protecting activities. At that, the priority components in the process of health-protecting activities should be self-realization, self-development and creativity that are in harmony with the inner nature of a human; principle of motivation of students to self-knowledge and self-actualization as unlocking their self, inner activity, initiative, where the teacher plays the role of an assistant, has found a certain reflection in the theoretical and practical exercises of Komensky, Pestalozzi, Diesterweg, Tolstoy, Ushinsky, Sukhomlinsky; the principle of joint action, based on the communicative exchange, enrichment of the student's personality, acquiring the experience of communication \u2013 according to the strategy of cooperation, the identity of the student is in the center of education, the purpose of education should be in harmony with both the purpose of life of the individual and society; principle of health protection of the individual in the educational process involves the purposeful combination of energy-intensive labor of the education participants with energy savings of each of them, which is achieved through the creation of knowledge and the needs of a healthy lifestyle.Fundamentally important position in the concept is that both teachers and students are a subjective basis. This means that the goal of assistance to health protection of the individual can be achieved at the simultaneous protection and formation of health of the educators and students .Theory and practice of pedagogical education rightly asserts that any pedagogical problem can only be solved with the help of adequate technology implemented by a qualified professional educator.\u201cEducational technology is an ordered and task-structured set of activities, operations and procedures to ensure correctly measured result in a changing environment\u201d . This definition most accurately reflects the dynamic process of educational assistance to health protection of the individual in the system of the higher pedagogical education.In implementing the concept of assistance to health protection of the individual, we adhere to the following phases of educational technology: organization of the process; diagnostics; content of the implementation process; evaluation and analysis of results.In the context of assistance to health protection of the individual, teachers and students communicate on the basis of \u201cpartnership, collaboration and cooperation\u201d. Such activities form the norms of cooperation, adjust behaviors, ways of interacting, which subsequently, in other educational systems (school) will express as acts of health protection. Communicative and technological skills are a form of intellectual and practical knowledge, and, consequently, their acquisition is related not only to the methodological aspects, but also to didactic .In the course of experimental work in the experiment was attended by 976 people, including 469 of 507 students and teachers. To ensure reliability and reproducibility of the research results the experimental work was conducted in four streams, repeated in different conditions and with different co-stav members.Ascertaining stage of the experiment showed that the students of experimental and control groups was approximately at the same level of motivation of choice of profession, health status, readiness to the health improvement activities. At the end of the forming experiment in the control phase we conducted (according to the same method as that used for summative stage) final measurements of the level of adaptation of students to the conditions of professional education on the list of leading pedagogically driven ka quality.Without changes in the control group remained an indicator of being able to organize their training activities, whereas students in the experimental group during the experiment, the figure took I took 1,2 times. This is due to the implementation of the pilot program of activity of the College for creating an environment of students \u2019adaptation to the conditions of professional education, transition to teaching in the \u201cCollege-University\u201d overall, which ranks independent work of students.The observed increase in the values of the rate of formation of the desire to get a profession span of dagogo and work in this area the students of the experimental group in 1,5 times in comparison with the outcome strength indicator that indicates, in General, positive adaptation to the conditions of the these same indicators in the control group, the number of students showing sustained a genuine interest to the profession, increased only 1,7 times.To determine the dynamics of relations second-year students to the conditions of professional training during the pedagogical experiment was conducted a second survey, which displays ruzhil: if in the first year leading motive of learning the teaching profession was the interest to a subject, in the second year of such a motive was the opportunity to train and educate children , i.e. there is a change in orientation of the individual towards teaching. Because of the changes undergone other motives for learning.On indicators of development of academic skills in the course of the experiment was noted chen positive dynamics in the formation of such skills as the ability to write lectures, organized to activity and the ability to analyze the results. So the success of educational activity of students of the experimental group indicates increase academic achievement in core subjects, which was measured by the average score. So in the first year average score of students was 3,6, while the students of the second course \u2013 4,2 points. Similar performance of the students in the control group was composed of respectively 3,7 and 3,9 points.Experimental work in these areas showed the effectiveness of pedagogical co-operation in the educational process of students in the experimental group, which is confirmed by the positive dynamics of the level of adaptability of the individual.It was observed a decrease in the level of trait anxiety of the students of the experimental group. This facilitated the development of interpersonal communication in the process of joint activity of students and teachers, development of communicative skills in the study of psychological and pedagogical disciplines. The level of trait anxiety of the students of the experimental group, the reduction declined by 1,4 times, which is an indicator of adaptability of the individual to the learning environment, while students in the control group the decrease in personal anxiety occurred slightly and this collection rate at the time of the study continued to remain close to high.The criteria for evaluating the effectiveness of promoting the health of students to the conditions of professional education in the experimental group were marked differences in the health status of students at different stages of adaptation. So, if in the initial stages of adaptation is a decrease in the level of physical health of freshmen, the analysis condition before the health of the students of the second course gives grounds to draw a conclusion about the positive dynamics of the studied parameters. At the same time, in terms of health index, an increase in the number of second year students of experimental group who did not apply to the doctor during the experiment, whereas in the control group among the students - sophomores an increase in this indicator slightly.The reasons for the poor health status of students of the control group in contrast to the experimental, in our opinion, was the lack of teaching of health saving space, which is one of the conditions for promoting a healthy lifestyle students tov in the period of adaptation to the conditions of professional education.Positive dynamics of health status of students of the experimental group comes amid increasing their awareness in the field of healthy lifestyles, the growing use of the developed tools and methods of health preservation in the educational process. This helps the students as quickly as possible to \u201cslip\u201d the initial phase of adaptation, allows to obtain the profession of teach-the determinant with the lowest energy demands .To determine the dynamics in orthobiosis students, we conducted repeated measurements and compared indicators obtained on the basis of the same methodologies as in the control phase.Speculative enough students actively recognize all 13 factors orthobiosis and recognition is higher among students of the experimental group is 80,6% . Increase in perfect view of it from the students of the experimental group was 7,1%. The students of the control group and 1,3%. Real respect for students orthobiosis continues to be below the ideal representation of it . The increase in the performance of the experimental group were significant and amounted to 15,7%, in control group the increase was only 1,5%. Students realized the need to take care of their health and in the experimental group the increase in this factor was 20%, rationally organized his nutrition and sleep \u2013 an increase of 12%. Increased performance for the factors of \u201cself-control\u201d and \u201coptimistic mood\u201d. Increase, respectively, 16% and 32%.These results indicate that students recognized the role of self-control and optimization to statistical sentiment to preserve and strengthen their health. Much has changed for the better indicators for the factor \u201cavoiding alcohol and quitting Smoking. Quit Smoking and/or throw 36% and restricted the use of alcohol 12%. Significant dynamics of spacecraft in the indicators for the factor \u201cdedication to work/school\u201d \u2013 36%. These students appreciated the role of commitment in work/school as the basis of optimism, professional with insolvency and background to creative self. In the control group also noted changes in the real observance of orthobiosis, but the trend is insignificant. The increase occurred for the factor \u201cobservance sleep\u201d 8% \u201coptimistic mood\u201d 4% \u201cabstinence from alcohol\u201d 4% and \u201cdedication to work/school 4%. Unfortunately increased by one the number of Smoking students in con-control group. This is all the more negative as students majoring pedagogy and methods of primary and pre-school education are mostly girls. The growth indicators in the control group, we can explain the fact that students learn the discipline of the natural Sciences, psychology and pedagogy, as well as the course \u201chuman Ecology\u201d, which get some knowledge in the field of healthy lifestyle.Factor analysis at the final stage of the research allowed us to determine the levels SFOR-valuations of orthobiosis students of both groups in the dynamics.The number of students with a high level of orthobiosis in the experimental group increased by 24%, with the average level decreased by 4%, with a low level cut-elk 20%. In the control group, the situation has changed slightly: the number of students with a high level of orthobiosis increased by 4%, the number of students with a medium level of orthobiosis decreased by 4% and the number of students with a low level of orthobiosis remained unchanged.The obtained results allow to conclude that students are prepared for a healthy moviesparade activities in the school system.To determine the change in the value of students \u2019attitudes towards their health, we conducted repeated measurements and compared the performance obtained using the same techniques.The data showed the dynamics of awareness of the value of health during the experiment. The growth of health indicators, placed first in a number of securities of power the students of the experimental group was +60%. The students of the control group it was only +12%. Positive growth rates in the pilot Noah group allows us to conclude that the training of students of pedagogical higher education institution to the health improvement activities in the school system is successful.The measurement results of the final experiment (control) phase of study by means of drawing up the structural systemic criterion showed that the experimental group on these indicators is far ahead of the control group. Positive pedagogical effect is achieved. The effectiveness of the promotion of health protection of the person in 1,6 times higher.The findings suggest that the experimental work resulted in creation of the effective system to assist health protection of the individual in the conditions of higher pedagogical education implemented in the period of study at the higher educational institution, in the course of professional activities. It was based on the developed and tested conceptual model, and the proposed health-protecting technologies allowed to ensure the unity and interrelation of units of this model to assist health protection of the individual in the conditions of higher pedagogical education.Problems of our study on the substantive and procedural levels are solved by the implementation of the identified set of principles of assistance to health protection of the individual in the conditions of higher pedagogical education, which are:- scientific principle that defines the scientific knowledge as knowledge of basic ideas, concepts, laws, regularities of assistance to health protection of the individual, knowledge of leading pedagogical theories, basic categories and concepts of health-protecting pedagogy, mastery of systemic knowledge about the laws of human's connection with nature and society, processes of formation of a healthy personality in the real socio-cultural and educational space; development of creative potential of each teacher, formation of internal setting for self-education, self-education and self-development, formation of scientific knowledge about health through the development of set of disciplines aimed at student mastering theoretical and methodological foundations necessary for teachers in the future health-protecting activity ;- systemacity principle that considers the theory, system of concepts, trends, contradictions, laws and regularities in the relationship and interdependence, dynamics of development of all components of assistance to health protection of the individual, depending on the effectiveness of their implementation at every level; content of the professional activity of the teacher aimed at health protection in accordance with the objectives of pedagogical education that involve continuous social and moral common cultural and professional development and ability to choose pedagogical tools that enable the development of motivational value systems to strengthen and protect health;- regionalization principle considering social and economic conditions of the region, climatic and geographical conditions, local and national peculiarities of functioning not only of the institutions of pedagogic education, but also the functioning of the regional educational system as a whole; according to some scientists, this principle emphasizes the tying of conditions in which a human develops to the place of residence, population in the geographical, social, economic terms ;- variability principle suggesting at various levels of assistance to health protection the provision of substantial, pragmatist and organizational abilities to meet the professional and personal needs;- principle of focus of the educational process on the subject development and self-development, involving the design and implementation of training programs and health-protecting technologies contributing to the development of mechanisms to facilitate assistance to health protection of the individual;- adaptability principle: manifestations of the individual's health depend on the specific adaptive situation, in this regard, this principle contributes to the ability of the individual to adapt to the conditions of professional education through the creation of an environment for the adaptation of the individual in the educational space of the higher education institution, which is one of the ways to assist health protection, because the human health is based on adaptive mechanisms ;- pedagogical appropriateness that allows students to differentiate values at the level of analytical, evaluative and predictive skills, build pedagogically reasonable relationships, regulate the inside and outside team relationships, and predict the outcome of interaction;Implementation of these principles, justification of the essence and content of assistance to health protection of the individual in the conditions of pedagogical education, analysis of the basic contradictions in the educational environment, variety of positions of the modern paradigm of education and modern concepts of assistance to health protection of the individual allowed to establish dependence manifested in the form of the leading trends.We single out a humanistic focus of health-protecting education as one of the leading trends in assistance to health protection of the individual in the conditions of pedagogical education.Humanization of pedagogical education is inextricably linked with the creation of conditions for creative self-identity, choice of the area of activity, circle of meaningful communication and place of force. It is this area of human relationships in an educational institution that is today an area of anxiety and concern, because it is largely determined by the measure of human maturity of the graduate and their professionalism .Humanization is one of the priorities of innovation in the field of multi-level professional education. This problem has always been the focus of scientists-philosophers, sociologists, psychologists and educators.Humanization of vocational education provides the proper formation of the humanistic in a human. Teach something and make socially useful are technical means for the main function of humanization. It is important that an individual has found their identity and could realize it. It is important what image of an individual develops and how it is practically embodied in their life interval. It is an extremely global function of humanization of professional education .Therefore, it is important to establish the humanistic nature of interaction between the participants in the educational process.Interaction can be either formal, defined by the scope of \u201cteacher - student\u201d and the respective chain of command, or have a nature of substantial, creative union, where a teacher and a student become colleagues, peers, advancing in their self-development. Humanistic character of interaction between the participants in the educational process is an important condition for maintaining their mental health. As is well known, physical and mental health are interrelated and interdependent.The trend of value-based health protection of the individual. Based on these traits of the individual, in our view, creation of the environment for students to adapt to the conditions of professional education will be successful with the implementation of professional focus of the content and organization of the educational process, and when bearing in mind that any kind of human activity, including skills development, is based on physiological phenomenon, the development of frameworks and norms of a healthy lifestyle becomes necessary in order to protect and strengthen the health of the individual. Implementation of the factor of health-protecting focus of the individual becomes possible with the creation of the educational health-protecting space.Students\u2019 knowledge of means and methods of forming a healthy lifestyle and ways to improve and maintain their health is required for the formation and integrated development of pedagogical health-protecting space in pedagogical education institution. This work includes the development of special training programs  to inform students about the rules and regulations of a healthy lifestyle.In accordance with the standard of secondary and higher professional education, students study such subjects in the block of disciplines of biomedical training in the first year of pedagogical college as \u201cDevelopmental anatomy, physiology and school hygiene\u201d and \u201cBasics of a healthy lifestyle\u201d. Their goal is to form a representation by students of children's bodies and their functional features in different ages, of the hygienic requirements for the educational process, and of the basics of a healthy lifestyle factors. However, these disciplines are not focused on the personality of the student as a future teacher, they do not contain any specific recommendations for health protection in the process of teaching and professional activities.In this regard, the development of the problem of protecting and strengthening the health of students is of paramount importance for professional schools not only in theory but also in practical terms: the establishment of a harmonic connection between education and health provides quantitative and qualitative changes in the development of the student. In this work, the unity of action of pedagogy and hygiene is important .The trend of technologizing of the assistance to health protection of the individual in the conditions of pedagogical education is a leading trend of formation of readiness of the future teachers to use health-protecting technologies in practice.Our research and experimental work was focused on finding health-protecting technologies as a means of assistance to health protection of the individual in the context of a holistic pedagogical process based on the indissoluble unity of theoretical and practical training, various directions of teaching activities. We consider the educational process in the logic of the main components of practical readiness and stages of teaching. So, at the first stage \u2013 adaptation \u2013 the target setting for interaction based on the proposed meanings and values of the upcoming activities involves solving problems of formation of motivational and axiological attitude to joint work, creating emotional state for acquisition of specific practical skills that will help in mastering the profession, establishing contact, overcoming the stereotype of the object-subject relations, establishing a positive psychological climate.The specified trends and principles are logically interrelated. Their implementation determines the psycho-pedagogical conditions of the effective assistance to health protection of the individual.Such conditions are: creation of the environment for adaptation of the individual in the educational space of the higher education institution; establishment of humanistic interaction between the participants of the educational process in the joint curricular and extra-curricular activities; creation of pedagogical health-protecting space for maximum efficiency of physiological, psychological functions and behavioral reactions of the individual in the educational process; provision of adequate training of pedagogical staff to organize health protection of the individual.The concept of assistance to health protection of the individual can be effectively implemented in the system of pedagogical education at the high organizational culture of the pedagogical education institution, qualification of the teacher (teaching staff) in this work, sufficient scientific and methodological support and application of performance criteria to activities of the students that are adequate to the task.Educational technology of assistance to health protection of the individual in pedagogical education is aimed at consistent and continuous movement of interconnected components and stages, states of the educational process and actions of its participants. Each stage of the health-protecting activity corresponds to its own objectives, content, methods and results.The developed conceptual framework of health protection of the individual in the conditions of higher pedagogical education opens a new direction of scientific and pedagogical research, which requires solving a number of undeveloped significant aspects of this problem. The promising direction of its solution is systematization of methods and technologies of health protection; development and testing of tools to optimize health-protecting environment in the context of higher pedagogical education. Scientific development of these and other problems in the pedagogical aspect will contribute to health protection of future teachers in the process of study at the higher education institution.Solution of this problem should ensure not only a healthy lifestyle, comfort in the classrooms, teaching students skills to outline lectures and organize independent work, widespread introduction of computer technology, balanced diet, optimal mode of work and rest, treatment and preventive care, medical examinations, etc. but also the proper organization of the learning process.This requires the researching teachers to develop appropriate recommendations aimed at strengthening and maintaining the health of students of pedagogical vocational education institutions, and as a consequence, improvement of the quality of education. Convergence of training and education about hygiene and prevention improves health and health promotion students. This is possible by combining the efforts of the team of the vocational education institutions and health care. Developing a holistic approach to the problem of health of students is directly related not only to the requirements of today, but also to the prospects of development of vocational education system, which in turn causes the consideration of it as a systematic and holistic education that models the activity and behavior of a human in the conceptual space of the subject-subject and subject-object relations."}
+{"text": "There are errors in the first sentence of the last paragraph of the Introduction, which were introduced during the typesetting process. The publisher apologizes for these errors. The correct sentence is: Therefore, the aim of this study was to evaluate the effect of caffeine ingestion on estimated energy systems contribution during simulated taekwondo combat and its subsequent effects on performance."}
+{"text": "To conceive and realize a practical device to help the diagnosis of molecular allergology which I named \"the astrolabe of molecular allergology\" nine allergological parameters incorporate this idea. The progress realized in the domain of recombined allergens (RA) has led to the appearance of a new concept in the diagnosis of allergy, the molecular diagnosis. It permits to identify molecules potentially responsible of the blossoming of diseases, and to think of molecular families rather than biological ones, allergenic constituents now classified in families of proteins based on their structure and function: A new diagnosis step came to enrich the research in Allergology. The targeted dosage of RA appeals to the data of the molecular diagnosis that the allergist is under the obligation to master. The optimization of the sensibility, the standardisation of allergens and the examination of the possible strategies of prevention of allergic diseases becomes possible: The allergist can manipulate this new data after the dosage of specific IgE, before starting up the desensitization, the oral provocation test or proposing an eviction. The objective of this work is to furnish an adequate pedagogical support, pertinent and perfectible, which, validated, may accompany the allergist in his diagnosis quest. Thanks to the data well listed of molecular allergology, this tool will permit to better delimit the crossed reactions, the hard cases of multi sensibilizations, to take the appropriate desensitization decision and to adapt supplanting diets. The molecular diagnosis of allergy is a new vision that each allergist must know and tame perfectly. Our aim is to accompany him in this progress by proposing this humble practical device. The astrolabe of molecular allergology shows us the way."}
+{"text": "Inadvertently, the names of two authors were not included in the final version of the manuscript sent for typesetting and this oversight was not picked up during the final proofs. The authors regret the oversight and any inconvenience these may have caused.The two missing authors are:Katia CheaitoNathaline Haidar-AhmadThe final author contributions are as follows:Ziad Daoud participated in designing the study and in the lab work, as well as in writing all the sections of the article.Elie Salem Sokhn participated in designing the study and in the lab work, as well as in writing all the sections of the article.Khalil Masri participated in designing the study and in the clinical part of the work, as well as in writing all the sections of the article.Katia Cheaito participated in designing the study and in the lab work (mainly the PFGE), as well as in writing all the sections of the article.Nathaline Haidar-Ahmad participated in designing the study and in the lab work (mainly the PFGE), as well as in writing all the sections of the article.Ghassan Matar participated in designing the study and in the lab work (mainly the PFGE), as well as in writing all the sections of the article.Shira Doron participated in designing the study and in clinical protocols elaboration, as well as in writing and reviewing all the sections of the article.The original article has been updated.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Some important aspects in evidence-based medicine have not been included in basic and applied research. The current level of examination of the cardiovascular system requires new analytical approaches for the prevention of cardiovascular diseases, insults and infarctions in people of different age, and diminishing of disability and mortality of vascular critical states.The technology of vascular screening enables not only to make accurate diagnoses but also to treat efficiently that reduces financial burden of a patient and his relatives. The medical technology will be useful in prophylactic and preventive medicine of the world for the health improvement of CVD patients.Regular vascular screening enables to perform diagnostics of microcirculatory disorders, to control efficiency of the therapy almost for every patient non-invasively  and during prophylactic exanimations of healthy people who are under influence of external factors, resuscitation departments, insurance medicine and sports medicine.The approaches to the analytical estimation of the vascular pipeline on macro- and microlevels allow newly considered problems in the blood supply for organs and systems in the human organism. It enables to estimate the possibility of sanogenic reconstructions in the vascular bed on local, regional, and systemic levels, and the adequacy of such alterations according to the necessities of the ill organism."}
+{"text": "Lishan Wang requested the retraction of this article.PLOS ONE Editors found indications that the peer review process was compromised by the submission of reviews through fabricated reviewer accounts. An institutional investigation, conducted by the Administration Office of Bio-X Institutes at Shanghai Jiao Tong University, supported the concerns about the integrity of the review process and indicated that Lishan Wang was solely responsible for the article, contrary to information provided to the journal at time of submission.Upon review of the submission history for the manuscript, the PLOS ONE Editors retracted the research article [In light of the above concerns, the  article  on July This retraction notice and the linked article  and Corr"}
+{"text": "There are errors in the Funding section. The correct funding information is as follows: Financial support for this particular investigation derived from the Timor-Leste Family Study dataset was provided by the School of Population Health, The University of Queensland. This work has been produced with the assistance of funding provided by the Department of Veterans\u2019 Affairs. However, the views expressed in this version of the Work do not necessarily represent the views of the Minister for Veterans\u2019 Affairs or the Department of Veterans\u2019 Affairs. The Commonwealth does not give any warranty nor accept any liability in relation to the contents of this Work. The Department of Veterans\u2019 Affairs had no role in study design, analysis, decision to publish, or preparation of the manuscript for this particular investigation."}
+{"text": "The Middle Iskar cascade is situated along the middle course of the Iskar River (Bulgaria) after the capital city Sofia and has three small hydroelectric power plants that were put into operation by the end of 2012. The aim of this study was to evaluate the self-purification potential of water in the reservoirs of these plants as an important and necessary condition for their ecological functioning. The assessment was made by hydrochemical parameters  and microbiological parameters (aerobic heterotrophic bacteria and bacteria growing in an Endo medium) and covered a period of three years . Standard methods were applied, mainly colorimetric and microbiological cultivation methods. The obtained results showed high levels of some of the tested indicators during 2012. In the section of the Middle Iskar cascade a high self-purification potential was observed in the reservoirs which maintain good water quality. The world consumption of energy from renewable sources continued to increase in 2011 and 2012 despite the international economic crisis, the political instability and the decreasing support of some key markets.[Along with this, the latest evaluations show that at least 40% of the surface waters in the European Union are at risk of not achieving the aim of the Water Framework Directive (WFD) for 2015, which requires good ecological and chemical condition in terms of low levels of chemical pollution and healthy ecosystem. AchievinThe steady increase of the part of the renewable energy sources in the world is the reason of the construction of the Middle Iskar cascade situated along the middle stream of the Iskar River after Sofia. The cascade had three out of its nine small hydroelectric power stations (SHPPs) put into operation by the end of 2012. The first hydroelectric power plant put into operation in May 2008 is SHPP Lakatnik, a year after that SHPP Svrazhen began to function and in June 2012 the third power plant, Tserovo. Their effective functioning, however, meets some ecological problems. This part of the river has been accumulating pollutants of different origin for decades. In addition, most of the settlements in the area of the cascade do not have treatment facilities and their wastewater further deteriorates the water quality of the river. The small reservoirs of hydroelectric power plants are places where the river water slows its speed, leading to concentration and accumulation of different types of pollutants (e.g. organic and xenobiotic pollutants). Long-term assessment of the self-purification potential of the Iskar River in the area of the Middle Iskar cascade as an inseparable part of the river waters is essential for the environmental assessment of the river region.The microbiological and hydrochemical parameters of the waters of the reservoirs in each of the three hydro power plants give information about the speed and the scale of the self-purification potential. The present study covered three consecutive years  and was carried out in two seasons: high-flow and low-flow seasons. The aim of the study was to evaluate the self-purification potential of the waters in the reservoirs of the small hydro power plants as an important and necessary condition for their ecology and appropriate functioning.The sites for taking samples are situated in the reservoirs of the three functioning hydroelectric power plants : TserovoData shown in the figures represent mean values from those measured at the above-mentioned depths. This experimental design was based on our previous study which showed that the fluctuations of the hydrochemical and microbiological parameters on horizons are insignificant. This givThe samples for microbiological studies were collected in sterile containers and stored in cool bags at 4 \u00b0\u0421. All samples were transported to the laboratory within 4\u20136\u00a0h and immediately processed. The microorganisms were identified by means of routine cultivation methods used in hydro-microbiological practice. Aerobic 4+, NO2\u2212, NO3\u2212 and PO43\u2212 was measured colourimetrically.[After transportation, the water samples were filtered and the concentration of NHtrically. The chemRivers are key natural and ecological sites from a water management perspective. Plans are made for managing the rivers which are inseparable part of the strict requirements for the implementation and functioning of WFD. The inteThe dynamics and variation of studied hydrochemical parameters depend on a combination of factors. Some of the main factors are the hydrological regime of the river system (the high-flow and low-flow seasons related to different quantity of water in the river), the status of the sediments and the incoming organic matter in the river . An additional influence is exerted by the waste waters from the town of Svoge and the surrounding populated places that do not have wastewater treatment plants and burden the river with different types of pollutants. The biggest part of these belongs to pollutants of protein origin. That is why the concentrations of the ions strongly depend on the rate and scale of the biodegradation of protein-containing organic matter. It is degraded by means of basic processes such as hydrolysis, the first and the second phase of nitrification, each of which depends on a number of factors.Last but not least, the concentration of the studied ions depends on the technological management of the Middle Iskar cascade. In the SHPP reservoirs, sediments are accumulated, containing organic and xenobiotic pollutants carried by the river. Upon the release of these sludges along the course of the river the concentration of the nutrients can change significantly. A unique ecological situation was registered during the high-flow season in 2011 when due to poor technological management of SHPP Lakatnik several meters of sediments were accumulated in the reservoir. The long stay of the sludge in the reservoir caused intensive anaerobic biodegradation processes, leading to release of different gases from the surface of the reservoirs. This in turn is related to influence on the processes of degrading organic matter in the waters, influence on the microbial communities and on the environment.The dynamics of ISS, DSS and TSS in the water of the reservoirs during the studied seasons are shown in On the other hand, the dynamics of the DSS , dissolved oxygen and phosphate concentrations in the water of the reservoirs during studied seasons are shown in During all the three studied years the values of COD were low, and during the high-flow season in 2012 they were even below the limits of detection. The highest values of COD were measured during the low-flow season in 2012, when the value of COD increased with every sequential reservoir along the course. The high concentrations of ammonium ions and the higher levels of COD during the low-flow season in 2012 show pollution of the waters, probably due to the lack of wastewater treatment plants in the populated places in the region of the cascade. This is confirmed by the slightly lower oxygen concentrations and the higher density of the microbial groups during this season. As a whole during all the three studied years the values of COD fluctuated and did not show mutual dependency among the separate reservoirs or for different seasons and years. Probably because of the small volume of the reservoirs and the constant exchange of water in them the measured value of COD depended entirely on the state of the waters in the Iskar River at that moment.During the low-flow season of 2010 the lowest oxygen concentrations were registered for the three-year period of study. During the next years the oxygen levels in the reservoirs were higher and with similar values for the different seasons. The measured oxygen showed that the rate of the biodegradation process was quick enough and this rate of self-purification was capable of maintaining high quality of the water.The dynamics of the phosphate concentration showed that their quantity varied during each season but as a whole their concentration in the separate reservoirs along the water course was constant and did not vary significantly. The highest concentration of phosphate ions was observed again in September 2011, probably due to the intensified processes of biodegradation after the above-mentioned critical situation. The phosphate concentration was higher during the low-flow seasons in all reservoirs. These results are in line with the findings of House and Denison, who obseThe quantitative parameters of two key microbial indicators were studied in the reservoir water: AH and the complex of Endo bacteria. AH on the one hand show the degree of organic load with biodegradable matter, and on the other hand by their number and dynamics they are an indicator of the speed and scale of self-purification processes. The complex of Endo bacteria is an indicator of faecal contamination and biodegradation potential. These two groups of microorganisms are important for the ecosystem functioning and formation water quality  and theiin situ degradative process.[In the three reservoirs the density of the microbial heterotrophic complex in the waters was highest during the low water level in 2012, whereas the highest AH counts were scored in the Lakatnik reservoir. These bacterial communities are likely to play a very active role in the rapid  process.,9,19 TheIn the waters of the three reservoirs from the Middle Iskar cascade there were linear correlations between COD and the two studied groups of microorganisms (COD/\u0410H and COD/\u0415ndo) . This isOur three-year study of the self-purification potential of the waters of the reservoirs of three small hydroelectric power plants showed acceleration of the self-purification processes in the region of the Middle Iskar cascade. There was evidence for intensive biodegradation processes most often ending with accumulation of nitrates. Poor management in 2011 caused a critical situation and demonstrated that the lack of adequate measures in the technological management of the SHPP can lead to accumulation of organic matter in the sediments, decreasing the ions of the biogenic elements and reducing the number of microorganisms in the waters. The intensive anaerobic processes in the sediments cause the release of gases  that are harmful for the environment and slow down the self-purification processes. For the proper ecological functioning of the cascade it is necessary to have adequate management of the sediments accumulating in the reservoirs, depending on the quantities of organic matter in them."}
+{"text": "The document \"National Guidelines for the prevention and oral health promotion in childhood\", 2013, is an act of address for those involved in the management of oral health and in particular to the pediatrician, because the figure of the pediatrician in the prevention of oral health is absolutely critical, as confirmed by the entire international literature in recent years.Correct attitudes and behaviors adopted since childhood that will allow the child to protect his health.The fluoride is the cornerstone of prevention of tooth decay and is required for all individuals.Over the years, have been developed different means of administration of fluorine, each with different strengths, dosages and frequency of use -5.Fluoride supplements should be prescribed by the pediatrician in cases of real difficulty for topical administration of fluoride through toothpaste or fluoride added as a method of in subjects at risk of tooth decay .The decline of caries in our country it is highly likely also due to the pediatrician who, using the national guidelines, can inform parents and families induce the acquisition of preventive behaviors currently defined by scientific research .To this end, again, the ministerial guidelines on the subject that were reviewed by a team of experts representative of the Italian research in this area."}
+{"text": "The authors of this article have requested retraction on the basis of concerns about the experimental work and the integrity of the reported data.An institutional investigation was conducted; the enquiry did not locate the samples which underlie the analyses reported in the article and was unable to verify that the mosquito dissections had taken place. In light of the findings from the enquiry, the direction of the Institut de Recherche pour le D\u00e9veloppement support the retraction of the article.In light of the above concerns, the authors retract this publication."}
+{"text": "There is an omission in the first sentence of the Acknowledgments section. The correct sentence is: We are grateful to the Health Experiences Research Group, Department of Primary Care Health Sciences, University of Oxford for permission to conduct a secondary analysis of interviews collected by Dr. Suman Prinhja for their study of experiences of intensive care, which was funded by ICNARC."}
+{"text": "The regional smart specializations include the innovative activities within a common science-economy-technology sector, which open the opportunities to gain a competitive advantage. The original procedure of science-economy-technology concordance matrix development on an example of smart specializations of the Silesian Voivodeship was presented in the paper. The procedure developed includes recognition of the research and economic components of the regional smart specialization and the connection between the economic components of the regional specialization and the technological innovation through the international patent classification. It also comprises recognition of key enabling technologies (KETs) and high technologies (of high R&D intensity) other than KET in the economic and technological dimensions of innovation as well as the high R&D intensity services in the economic dimension of innovation. The in-depth expert analyses with the application of the Delphi method were also taken into account. The methodological approach developed and the visualization method applied are both of cognitive and practical importance since they contribute significantly to the creation of efficient development policies, to the enhancement and facilitation of cross-sectoral cooperation, and to the focusing on the fields of key importance in terms of the competitive advantage of a region. The continuous creation and implementation of innovative solutions, both technical and organizational, through planning and realization of long-term activities in the field of the strategic regional economic branch have been identified as the key elements for a region to succeed in the technological development and economic growth \u20133. The DThe Silesian Voivodeship is located in Southern Poland, in the region of Upper Silesia. It is a highly industrialized region, but the dominant heavy industry does not facilitate a strong and competitive regional economy or the growth of small and medium enterprises. Nevertheless, the potential of the region in terms of traditional industries and new services is undeniable. The companies providing niche products emerged in the posttransformation period, joining smoothly the global supply chain along with the enterprises operating in traditional regional sectors . The changing economy sector imposed the adjustment of the R&D sector offer to the new market demands and increased its international activity within transnational research and expert networks.The initial document, at the regional level, indicating the strategic goals of the innovation process enhancement was the \u201cRegional Innovation Strategy of the Silesian Voivodeship for Years 2003\u20132013\u201d , recentlThe effect of the regional innovation strategy , 10 and The primary condition of the regional smart specializations development is the enhancement of the cooperation between science and business sectors with support and contribution of the regional authorities. The further development of traditional regional branches, through implementation of the best available technologies, and progress in new, prospective technologies should result in gaining the competitive advantage in the global market.The objectives of the activities undertaken within the regional smart specialization related to medicine include the provision of high quality medical care to the citizens of the region, which could be achieved mainly through the implementation of the advanced solutions of e-medicine, medical engineering, biotechnology, materials science, information technology, and electronic engineering.The power industry is the key economic sector of the region and the entire country. Within this specialization, particular attention should be given to the activities in the field of safe and efficient production of coal and preparation of ultraclean coals for the power industry, especially new technological solutions for production of the final energy carriers, systems for coal conversion into energy carriers, including combustion technologies , coal gasification and polygeneration, combined heat, electricity, and cold generation, coal-based technologies for combined steel and energy carriers production, hydrogen-based power industry and combustion of coal in small environment-friendly heating boilers, and mitigation of hazardous substance emissions (including carbon dioxide) from the processes of coal utilization. The development of energy efficient technologies and utilization of renewable energy resources were identified as prospective areas of innovative solutions implementation.The key aspects in the field of the enhancement of the regional smart specializations related to the information and communication technologies include increasing the access to knowledge, by means of participation in global cooperation networks and creation of transaction and management system for smart markets, as well as implementation of technologically advanced solutions of material and electronic engineering.The concordance matrices are tools for the identification of cross-sectional connections, niche areas in given sectors, and for the assessment of the specialization potential, including the effects of public intervention and their influence on the R&D, economic, and social domains.In principle, concordance matrices are well known and have been widely studied in a number of recent papers and, most thoroughly, by global market organizations. The uniqueness of the approach presented in this study derives from the practical implementation of a detailed cross-sectoral analysis into the regional context by construction of science-economy-technology concordance matrices. Regional R&D&I actors, owing to concordance matrices-based analysis of R&D and business value chains, are able to redefine their research and market attitude by improvement of the existing technologies contributing to the domains of regional technological specializations of the Silesian Voivodeship. Understanding and valuing science-economy-technology interconnections improve adaptation abilities by integration of regional actors and clustering their potential. A synergy effect of those activities was embedded in regional strategic documents such as the Regional Innovative Strategy Implementation Model  and creaThe main objective of the study presented in the paper was the development and analysis of the science-economy-innovative technologies concordance matrices for the regional smart specializations of the Silesian Voivodeship.The science-industry concordance matrices are constructed based on the methodology developed by the Organization for Economic Cooperation and Development . The infRecognition of the research and economic components of the potential regional specialization based on statistical data concerning economy, R&D, and patents.Linking the economic, research, and technological components of the regional specialization with the technological innovation area by means of the international patent classifications.Recognition of the potential share of key enabling technologies in the economic and technological dimensions of innovation.Recognition of the potential contribution of high technologies (of high R&D intensity), except for key enabling technologies, to the economic and technological dimensions of innovation.Recognition of the potential share of services of high R&D intensity in the economic dimension of innovation.Final composition of the matrix based on the in-depth expert analyses with the application of the Delphi method.The definition of the basic elements of the regional specialization, that is, the economic and research components, is of key importance in the approach presented. This stage (first stage) involves identification and description of the specialization based on the expert knowledge in the field concerned. The defined potential of specialization areas needs to be complemented with indicators providing information on the influence of the innovation on the economic development. This is accomplished in the second stage of the concordance matrix construction procedure consisting in the introduction of the IPC indicators . The World Intellectual Property Organization (WIPO) proposed the classification practice for the international/transregional technology comparison based on these indicators [The procedure for science-economy-technology concordance matrix construction proposed by the authors comprises six stages:dicators  and withIn each of the abovementioned areas, some subareas may be further distinguished. The classification facilitates the analysis of the technological development structures, regional, national, and international comparisons, and the determination of smart specialization profiles.The third, fourth, and fifth stages cover the assessment of the regional potential in categories of knowledge economy with the application of the data acquired in the first stage and logical construction of the second stage. third stage is subdivided to cover two aspects.TheAspect 1. The first aspect is the recognition of patenting activity of the regional economy sectors in KET areas.Data on patent applications in KETs category submitted during the few last years  by the entities located in the given region as well as data on patents of KET category awarded in the few recent years to the entities located in the given region is ordered according to NACE codes of the entities submitting patent applications or being awarded the patents. In this way, the information on economy sectors and types of entities generating technological innovations in KET areas (utilization of data obtained in the first and second stages) is acquired.KET codes mentioned in the previous section may be found in concordance matrices IPC-ISIC (four-digit codes) and ISIC-IPC (four-digit codes). In this way, the information on economy sectors for potential implementations of KET is obtained. Next, the regional potential of these economy sectors is assessed (according to the distinct criteria).It may happen that the entities of the given region have not demonstrated any activity in the KET areas or that the activity has been minor or ineffective. This does not, however, overrule aspect 2 of the analysis.Aspect 2. The second aspect is the recognition of the potential demand of the regional economy sectors in terms of the innovations in KET areas.The economy sectors considered to be the leading ones in the region  are assessed in terms of the potential demand for KET technologies implementation, based on the concordance matrices IPC-ISIC and ISI-IPC (four-digit level).The utilization potential for KET in smart specializations may be considered significant when the analysis results may be positively interpreted at least in one of the two aspects. fourth stage is performed, similar to the third stage, in two aspects.TheAspect 1. The first aspect is the recognition of the patenting activity of the regional economy sectors in high-tech area.Data on patent applications in high-tech area submitted during the few last years  by the entities located in the given region as well as data on patents in high-tech category awarded in the few recent years to the entities located in the given region is ordered according to NACE codes of the entities submitting patent applications or being awarded the patents. In this way, the information on economy sectors and types of entities generating technological innovations in high-tech area (utilization of data obtained in the first and second stages) is acquired.High-tech codes mentioned in the previous section may be found in concordance matrices IPC-ISIC (four-digit codes) and ISIC-IPC (four-digit codes). In this way, the information on economy sectors for potential high-tech implementations is obtained. Next, the regional potential of these economy sectors is assessed (according to the distinct criteria).It is possible that the entities of the given region have not demonstrated any activity in the high-tech area or that the activity has been minor or ineffective. This does not, however, overrule aspect 2 of the analysis.Aspect 2. The second aspect is the recognition of the affiliation of the leading regional economy sectors to high-tech industries.The economy sectors considered to be the leading ones in the region  are assessed in terms of the affiliation to high-tech industries. The high-tech potential may be considered significant when the analysis results may be interpreted positively at least in one of the two aspects.The most favorable situation in terms of the regional policy (in case of both the third and the fourth stages) is when the economy sectors active in patenting and sectors of potential patent implementations are at the same time the leading sectors of the regional economy, indicated by the results of the first and second stages. fifth stage is based on concordance matrices matching the economy sectors to KIA and KIABI (Knowledge-Intensive Activities: Business Industries) categories according to Eurostat high-tech industry and knowledge-intensive services [The analysis performed within theservices .The potential is assessed based on the analysis in two aspects.Aspect 1. The first aspect is the recognition of the total share of knowledge-intensive services (including KIA and KIABI) in the regional economy potential (utilization of data acquired in the first and second stages).Aspect 2. The second aspect is the recognition of the affiliation of leading  regional economy sectors of high R&D intensity services.The potential share of knowledge-intensive services in the regional development may be considered significant when the analysis results may be interpreted as positive at least in one of the two aspects. final stage of concordance matrix construction is the expert study with the application of the Delphi survey [Thei survey \u201321, provA Delphi survey was conducted within two rounds as a part of a broader national study  involvinThe objective of the Delphi survey applied in the concordance matrix construction presented in the paper was the identification and assessment of the strongest connections between science, economy, and key technologies of the region. Experts were asked to rank those connections by using a 5-point Likert scale ranging from 1  to 5 . The consensus regarding the strength of the abovementioned connections was attained when more than 50% of expert responses agreed. The role of experts is especially important in the adaptation of base matrices. The results of the Delphi survey may either confirm or reject the connections presented in the initial matrix. They may also complement it with additional components, resulting from the specific characteristics of the regional smart specialization. The regional smart specialization concordance matrix for the Silesian Voivodeship was supplemented with the estimation of the strength of mutual relations, based on the selected statistical indicators adapted to the regional level.The developed methodology of concordance matrix construction was implemented in the characterization of the regional smart specializations of the Silesian Voivodeship in the field of medicine, power industry, and ICT.The first step of the development of the smart specialization concordance matrix for the Silesian Voivodeship in the field of medicine was its adaptation to the socioeconomic objectives according to the NABS classification see . The socIn the next step, the identified socioeconomic objective was related to the NACE codes of sections C (manufacturing) and Q  see .The following step consisted in finding the connections between the identified regional smart specialization related economy branches and key enabling technologies based on the EU report . In the The key element of concordance matrix construction is linking the identified patents with the socioeconomic objectives (NACE). This was done based on the concordance table presented by Atmaca  and tranBased on the above procedure, the assessment of the patents of the strongest effect on the economy sectors related to medicine was made, as well as the evaluation of the actual status of these interrelations in the Silesian Voivodeship, based on the number of the patents awarded and patent applications of respective codes as a part of the second-stage analysis.The recognition of the potential contribution of a given technology of high R&D intensity, other than KETs, to the economic and technological dimensions of innovation was performed based on the WIPO concordance tables, taking into account the technological areas and the respective patent codes.The connectivity analysis was performed based on the selection of the technological areas of the strongest connection to medicine and respective patents see . The selThe subsequent step of the medicine related concordance matrix development was the recognition of the potential of high R&D intensity services in the economic dimension of innovation. The results of the first stage of the Delphi survey enabled determining the connections between the medicine-linked selected areas of science and economy. The science domains, the progress in which should contribute to the more effective economic development related to the regional smart specialization of the medicine, are given in The scientific areas related directly to medicine of the strongest influence on the economic fields were identified based on the results of the first stage of the Delphi survey. The significant interaction strength was assumed to be at least 4, in 5-degree scale of interaction. The identified relations presented in The identification of the economic activities most closely related to the medicine and of high R&D intensity was also made. The economic activity domains were characterized within four categories: high, medium-high, medium-low, and low technologies. They were also assessed to be highly knowledge-intensive activities . The conThe results of the above analysis of relations between science, economy, technology, and patent sectors in the field of the regional smart specialization are presented in the form of a concordance matrix in The regional smart specialization, power engineering, was assigned to the socioeconomic objective, 5: energy, according to the NABS classification given in Basic electric elements (H01).Generation, conversion, or distribution of electric power (H02).Basic electronic circuity (H03).Electric communication technique (H04).Electric techniques not otherwise provided for (H05).Semiconductor devices and electric solid state devices not otherwise provided for (H01L).The first stage of the Delphi survey, concerning the influence of the science areas on the economic development of the region in the field of power engineering, enabled determining the respective types of economic activity according to the NACE classification and identifying the science domains of the strongest correlation with the given economic activities. Eight science domains, in which development would contribute to the more effective economic growth in the field of power engineering, were identified within the Delphi analysis . The science domains, according to the OECD classification, in which development should contribute to the more effective economy development related to ICT, are presented in The economy sectors of the major influence on science domains were also identified see  by linkiThe final stage of the methodology developed for the regional smart specialization concordance matrix construction was the identification of the economy sector, manufacturing, of the strongest link with ICT and high R&D intensity, taking into account the categories, high, medium-high, medium-low, and low technologies, and knowledge-intensive economic activity areas within the service sectors related to the ICT. The connectivity analysis of economy activity sectors and regional smart specialization in the area of ICT is presented in The comprehensive approach to the science-economy-technology concordance matrix construction developed within the study and presented on the examples of the regional smart specializations of the Silesian Voivodeship in the field of medicine, power engineering, and ICT proved to be an effective tool for the smart specialization potential assessment and for adequate addressing and evaluation of the support policies fostering the R&D&I sector.A concordance matrix developed for the regional smart specializations facilitates accurate utilization of the expertise both at the stage of recognition of the significance/strength of the interrelations for the economic development and regional competitive advantage and at the stage of cyclical verification of the smart specialization strategy.The procedure of concordance matrix construction presented in the paper is based on the European and world methodological output in the field concerned. It includes the recognition of the research and economic components of the regional specialization, linking the economic component of the regional specialization to the technological innovation area by means of the patent international classifications, recognition of the potential contributions of key enabling technologies and technologies of high R&D intensity, other than KETs, to the economic and technological dimensions of innovation, and the identification of the potential share of services of high R&D intensity in the economic dimension of innovation. It was deepened with the expert analyses performed within the Delphi survey.The application of the procedure developed in the assessment of the interrelations between science, economy, and technology enables comparison and analyses of supraregional relations on the level of specialization related economy sectors and research areas.Concordance matrices are useful tools for the development of the regional and national innovation policy based on smart specializations and implementation of the evidence-based policy principles to leverage potential of the regional innovation system by better addressed public intervention at multiple decision-making levels.Concordance matrix construction approach provides a general understanding of the interrelation between regional value-chain components and potential of R&D&I sector being an immanent part of a cyclical assessment of the regional specialization strategies. Thus, concordance matrix construction procedure reinforced with a set of analytical tools has been implemented and provided as a web-based IT expert support system."}
+{"text": "There is an error in the last sentence of the Data synthesis section of the Abstract. The correct sentence is: No study reported adjusted estimates in the miscarriage review, therefore results are presented individually.There is an error in the 13th sentence of the Characteristics of Studies Included in the Miscarriage Review section of the Results. The correct sentence is: No study in the miscarriage review reported adjusting for potential confounders.There is an error in the last sentence of the Miscarriage subsection of the Heterogeneity Assessment in the Results. The correct sentence: Furthermore, no study adjusted for confounding.The third to last sentence in the first paragraph of the discussion should be removed.There is an error in the second sentence of the second paragraph in the Strengths and Limitations of the Review section of the Discussion. The correct sentence is: No study adjusted for confounders in the miscarriage review and so a meta-analysis was not performed as a result.There are errors in"}
+{"text": "This article was republished on May 14, 2015, to correct an error in Table 4. The legend was missing from the TIFF version of the table which affected viewing the table on the PLOS Medicine site and all downloadable versions of the table itself. The PDF of the whole article was unaffected."}
+{"text": "Unfortunately, the original version of this article  containeHowever this error has no bearing on statistical outcome of the study, the conclusions or text of the manuscript. Correct versions of Tables"}
+{"text": "Professional standards of the American and Canadian companies stress the importance of a minimum number of \"experts\" nurses of neonatology or pediatrics in the reality where infants and children are assisted.Also the document about PNAE of Education stresses how training programs for the general nursing in many countries don't give the necessary preparation to nurses in this area.The Pediatric Nurse in Italy is the figure that the DM 70/1997 has identified as the one responsible of the nursing care to individuals in growth.These are flanked by the generalist nurses with specialized annual training.But also the general nurse according to DM 793/1994 can assist babies and children, as he's generally enabled to the nursing care of individuals of all ages.Even the Midwife is enabled to care babies and also in delivery room.The Federation IPASVI in the past 10 years has activated some strategies to support and enhance the innovation in this area of neonatology and pediatric care through the creation of working groups of pediatric nurses at the national level, the spred of best care practices in this area, the guidelines for the university training of master's degree in the pediatric area, the definition of competence's profiles of nurse in neonatal area differentiated by levels of complexity of care, a patnership with a SIN to the building of the certification's manual of the path birth of the group GINS/Agenas, allowing to the pediatric's area nurses to work on the network throughot the country.The neonatology's and pediatric's scientific associations and of universities have allowed evidence of the specificity of this area and the development of best practices and evidence.The reflection on the future of the neonatology's and pediatric's nurses in Italy is still open. Crucial points are the definition of uniform standards training and operating within the national territory, the skills certification, the paths of professional accreditation and professional skills and advanced responsibilities."}
+{"text": "Cervical and uterine cancer continues to be an important issue for women around the world, although neoplasia has the greatest demonstrated potential for prevention.Costa Rica has achieved important advances in the reduction of the incidence and mortality of these cancers since the last century. This is the result of a series of policies, programmes, and plans, not only at the level of the health care system, but also in other areas.in situ and invasive cancers.Increased access for women to care in health centres, fundamentally at the primary level, has been vital, as has ensuring the quality of cytology readings and access to diagnosis and treatment for precursor lesions for Despite all of these achievements, there are still challenges to be overcome, which are widespread in many countries in Latin America and the Caribbean.It is important to learn from the experiences of other countries in order to improve women\u2019s health not only as a health objective, but also as an ethical imperative to promote the exercise of women\u2019s rights to life and health. Cancer has been one of the concerns of the health authorities in Costa Rica since the beginning of the last century. In 1940, one of the first laws on the subject was passed: the development of a Cancer Institute, which did not become a reality as said law was repealed and gave rise in 1949 to the creation of the Department to Fight Cancer in the Ministry of Health at that time [These actions occurred within the context of very important social changes for the country: the social reforms, such as the creation of the Costa Rican Social Insurance Agency (C.C.S.S.), financed in a tripartite manner by the insured, the employer, and the state, the labour code, the environmental health programmes, and nutrition and vaccination programmes, among others. These policies made it possible to improve the living conditions of the population through their redistributive effects.In the 1970s, the programmes to extend both the vertical and the horizontal coverage of social insurance to reach the goal of universal coverage were intensified. These actions reinforced the infrastructure, the training of professionals and technicians, and the provision of medicines and equipment for the prevention and treatment of the conditions prevalent at the time . In 1973At the same time, a series of programmes of primary care were consolidated, such as the rural and community health programme, which brought preventive care to the farthest corners of the country and achieved a great impact on the health of the population, and consequently improved the demographic health indicators in Costa Rica. In the same manner, the records of vital statistics were greatly improved and the National Tumour Registry was created in 1976 .Within the framework of these reforms, in 1960, the national plan for the detection of cervical cancer was established. Detection by means of cervico vaginal cytology testing was included in the so-called \u2018family planning visits\u2019 both with the social insurance and the ministry of health.in situ/invasive ratio.A significant decrease in the number of deaths due to cervical cancer began in the mid-1960s. From 1965 to 1980, the mortality rates were reduced to less than half , 5. ThisIn the 1980s and 1990s, two reforms in the health sector were implemented: the first consisted of the integration of the services of the Costa Rican Social Insurance Agency, which were mainly curative, and those of the Ministry of Health, which were preventive, and the second and more importantis the transfer of services for direct patient care to the people and programmes of the C.C.S.S. and the strengthening of the governing role of the Ministry of Health. As part of this last reform, the health areas were created with the Basic Integrated Care Teams (EBAIS) which made up the primary care level and their progressive implementation substantially improved access to health services throughout the country.A study by Rosero demonstrated the following result: \u2018the percentage of persons without equitable access to primary health care services was reduced by 15% between 1994 and 2000 in the areas which adopted the reform in 1995\u20131996, while in the areas where the reform had not been adopted in 2000, the reduction was of only 3%\u2019 .The trend toward a decrease in mortality is shown in The results described reflect the improvement in living conditions, fundamentally access to education and health services along with specific policies and programmes which likely favoured the conditions for reducing the incidence of and mortality from cervicouterine cancer and improve the quality of life of women and their families. This is a result of the fact that this is the cancer that causes the highest number of premature deaths among women and thus the greatest loss of healthy and productive years of life.A National University study calculated that the economic value of unpaid housework done by women in Costa Rican homes represents 16% of the gross domestic product (GDP) in the case of the greater metropolitan area (GMA), which reinforces the impact that this loss of women\u2019s lives has on the economy of the country .In Costa Rica, this cancer continues to be one of the most common neoplasias in the female population: it has the third highest incidence and the fourth highest mortality due to cancer despite the important reduction, which has been achieved in both rates. The incidence was reduced by 1.85 times between 2000 and 2011, and the mortality by 1.58 times between 2000 and 2013  and 3.in situ cancers was inverted as of 1995 , thus accumulating a larger number of years of life lost .in situ diagnosed, one invasive case is diagnosed, in Guanacaste, the rate is one to one, and in Lim\u00f3n, it is inverted, with 1.6 cases of invasive cancer diagnosed for each case of cancer in situ. As can be observed on the map  , 6.During the 1990s, the technical authorities of the C.C.S.S. and the Ministry of Health conducted an evaluation of the problem of cervical cancer and offered proposals to improve the response of the health care system in terms of prevention: the centralisation of cytology readings in a single centre of the C.C.S.S., as well as improvements to the diagnostic and treatment services for precancerous lesions.In 1998, the \u2018National Programme for the Prevention and Integrated Treatment of Cervical and Breast Cancer\u2019 was launched by the Social Insurance Authority. Thus, the National Cytology Centre established national norms for the screening, diagnosis, and treatment of precursor lesions to cervical cancer in women between 20 and 64 years of age with the creation of: \u2018The Manual of Standards and Procedures for Integrated Care for Women for the Prevention and Management of Cervical Cancer\u2019, I and II \u2018Level of Care and Standards for Cytology Labs\u2019, in effect from 2007 to the present and the provision of equipment to meet these standards [This is how the C.C.S.S. came to provide these services throughout the country to those who require them. The interventions and strategies of the programme are established by the technical standards authority of the central level of the Institution and articulated with the other basic interventions defined for each age group within the various areas of practice of the health teams.The supplies for screening and treatment are purchased in a centralised manner, as are all of the other supplies including medicines, with the institutional budget financed by the health insurance programme. Each centre plans and uses its assigned budget in order to fulfil the goals established at the institutional level within the framework of the current health policies.The evaluation of the actions and goals is done by means of monitoring the data on incidence and mortality from the National Tumour Registry (RNT) and the National Institute of Statistics and Censuses (INEC), the performance indicators for the services at the primary and specialised levels. The latter are agreed upon previously with the Health Services Purchasing unit of the Institution. Likewise, the results of the cytology centre are monitored, and the centre also belongs to the C.C.S.S., as mentioned previously.As in most of the countries of the world, the governments demonstrated their concern with the magnitude of the problem of cancer. In 2009, the Board of Directors of the C.C.S.S. declared cancer a topic of interest and institutional priority. In this way, they seek to prioritise actions and investment in the resources to improve the prevention and care of people at risk or with any of the cancers that have been determined to be of priority, among them cervical cancer.In 2012, under the framework of the National Cancer Plan (PNC), coordinated by the Ministry of Health, an Institutional Plan for Cancer Care (PIAC) 2012\u20132016 was established, which combined prior efforts and articulated and instrumented a series of actions to put the institutional and governmental mandate into action , 11.Thus, it was decided to implement a care plan which permitted intervention in the weak areas to allow for improvement in the effectiveness of the programme.Within this context, an analysis was performed to determine the strengths and weaknesses.Costa Rica possesses a series of strengths that can facilitate the reduction of the cases and deaths from this cancer, as shown at the beginning of this study :A service network with national coverageAccess for the majority of women to both public and private health servicesA centralised laboratory that meets the quality standardsThe goals for access and continuity of the interventions for prevention and treatment in this area are incorporated in the health care services purchasing plan, the operational plans, and the budget as well as in the evaluation of the performance of the health services.A system for the transportation, receipt, processing, reading, reporting, and return of results of cytology testing to the users within a period of no more than 8 days.in situ or invasive lesions are treated within the 8 days following the referral in nearly 100% of cases treated in hospitals.Medium and high-complexity centres  which have the resources to care for women who have precursor lesions or cervical cancer and which are treating the women referred to them within the time frames established for each of the conditions, which ensures continuity of care. The women with cytology results of malignant An institutional system for the logistics of the acquisition of supplies to ensure the permanent availability of medications, instruments, teams and other needs for screening and treatment.Among the aspects in need of improvement are as follows: The current national standard has not been updated in terms of the age for the start of screening or the technology to complete it.Administrative barriers: Most women must request a doctor\u2019s appointment in order to have the cytology test done, and in some centres, opportunities are lost.The information and counselling in sexual and reproductive health are not integrated in a generalised manner with the health services in the different scenarios of work with men and women of different ages and stages of life.Young women are given priority for cytology testing.Inadequate application of the existing treatment standards.Active searches of the target population for screening in all health areas are not done.Diverse criteria are applied at the first level for testing, interpretation, and reference of women with altered cytology results due to a lack of knowledge and supervision for compliance with the standards.The response of the colposcopy services is sufficient, but some centres exceed the established time period to treat a patient with a precursor lesion.Insufficient information for women relating to the different aspects of screening as well as the resources and procedures available for confirmation under the different regimes that exist.Underutilisation of human resources, fundamentally of nursing staff by the health areas, who could make screening more accessible.Disarticulation of the sources of information that makes it difficult to determine actual coverage and calculate the indicators, which permit the monitoring and evaluation of different interventions of the programme.The absence of a nominal registry at the national monitoring level to confirm coverage by the public and private sector, as the only registries are those of the institutional data collected by the CCSS.These weaknesses point to three critical areas: local management, access to and control of information on the prevention of cervical cancer by women, the application of the standards on the part of health care personnel, and the information system.To meet these challenges, strategies are being developed with actions that permit advancement of the articulation and reinforcement of a national programme, which coordinates and manages the actions at the various levels.The important action are as follows: updating the national standards in conjunction with the Ministry of Health, incorporating HPV and new handling protocols into DNA testing, evaluation of the incorporation of the HPV vaccine into the basic national scheme, as well as supporting regional management in putting these into operation. All of this is in order to improve the effectiveness of the programme.The assessment of the experience of the Guanacaste Epidemiological Project is a strategic method for analysing and applying the good practices developed by the same.The most important challenge is improving the management of the services so that integrated, whole care services can be provided to women, as the set of problems derives from the structure and organisational culture of the services.Also included among the challenges is monitoring of the programme indicators at the national level which includes data from both the public and private sectors. This is because the institutional Papanicolau coverage does not reflect the national level, as many women receive care in the private sector, and these tests are not analysed at the cytology centre.This is very important, as the C.C.S.S. must multiply its efforts to reach the women who do not have access to these interventions, and are those who have a greater risk and are probably living in conditions of social vulnerability.Reducing this type of cancer depends in large part on the social response of the health care services. The experience of Costa Rica demonstrates that the social policies maintained for decades have created suitable conditions for a national programme of cervical cancer prevention, detection, diagnosis, and treatment to reach its goals.The investment in the development of human capital, the infrastructure and equipment, the implementation of a set of interventions intended to improve the quality of care for patients, particularly women, uniting the committed efforts of all of the health care teams in the country, these have been the key aspects of achieving the indicators that exist now.Nevertheless, reality is always changing and becoming more complicated, as new problems and critical issues are always being presented. Thus, it is necessary to maintain active vigilance, proposing strategic actions which allow for overcoming weaknesses and reducing risks.This is the greatest challenge which confronts our health care system. And this is why we must continue our efforts directed at articulating and reinforcing a national programme which ensures the coverage, quality, and effectiveness of the interventions.Achieving these goals will also require a robust information system, appropriate management of network services, and reinforcement of integrated and whole health care for patients at all stages of life.The lessons learned and the application of demonstrated good practices both at the internal level in the Guanacaste Epidemiological Project, and in experiences from other countries, are important resources for improving the proposals that are being implemented.All of this is in order to improve the quality of life of women and society as a whole by reducing unjust and avoidable differences.The author declares that no conflict of interest exists."}
+{"text": "There are multiple errors in the second and third sentences of the third paragraph of the Introduction. The correct sentences are: The study by MacDonald et al. [13] has already shown that the EMG onset of the DM is dependent on the direction of shoulder movement. The study by Lee et al. [14] demonstrated that the EMG onset of thorax multifidus does depend on the direction of shoulder joint movement."}
+{"text": "The interpretation of the results of Figure 4 is incorrect, lack of flare constitutes a positive outcome.* There are concerns about the combination of trials that involved placebo controls with those including active comparators, particularly in relation to analyses regarding the assessment of adverse events.* The meta-analysis combined randomized and non-randomized trials, the analyses were not stratified by study design.* There are concerns about the use of blinding as a selection criteria for inclusion in the meta-analysis.* Some aspects of the reporting do not adhere to the requirements outlined in the PRISMA guidelines and about the reproducibility of the search strategy reported.The editors consider that the concerns above compromise the validity of the conclusions drawn in relation to the efficacy and safety of pimecrolimus cream 1% for the treatment of atopic dermatitis in paediatric patients and as a result retract this publication."}
+{"text": "To serve the diverse needs of the ageing population, the Chief Executive of the Hong Kong Special Administrative Region has made 'Care for the Elderly' a strategic policy objective of the government since 1997. The objective of the policy is to improve the quality of life of our elderly population and provide them with a sense of security, a sense of belonging and a feeling of health and worth. 'Ageing in place' has been government policy since 2003. However, no studies have been conducted in Hong Kong to investigate how the elderly perceive the policy and practice of ageing in place. This qualitative exploratory study investigated the understanding, attitudes and concerns of elderly people in Hong Kong towards ageing in place. The results provide valuable information for the Hong Kong government to develop appropriate measures to facilitate the provision of ageing in place as the core policy, with institutional care as a back-up.One hundred and six participants  aged between 65 and 78 took part in focus group interviews between August 2014 and January 2015. The participants were questioned about their perceptions on ageing in place and the essential elements that facilitate it. They were also asked about their opinions on strategic policy and practice in the provision of ageing in place. All interviews were tape-recorded and transcribed. Two independent researchers coded the transcribed interviews and conducted content analysis with the aid of NVivo 10.The majority of participants in this study preferred to age in place because it increased their sense of belonging, security and familiarity and is more convenient. The essential elements for ageing in place included home attributes, the neighbourhood environment, community network, social security and medical support, all of which could affect the quality of life of the elderly.The results of this study provide a reference on the essential elements that should be included in developing and implementing policies on ageing in place. With appropriate infrastructure and social support, the government could facilitate the elderly to live independent lives and maximise their abilities."}
+{"text": "Treatment of children with scoliosis requires the monitoring and evaluation of posture parameters. The raster stereographic method can be used at any time to observe the therapy progress due to its harmlessness towards the child.We evaluated 140 children with idiopathic scoliosis treated by the FED method at the Rehabilitation Centre in Zgorzelec. The children were assessed by the 4D DIERS Formetric III at the beginning and the end of the month of the stay. Some of the patients were evaluated six-months after the FED treatment. One of the parameters selected to assess the therapy outcome is the rotation of the trunk area beginning at the apex deriving from radiography.Preliminary results in both groups, the group assessed after a month and the group assessed after six-months, reveal a reduction of the rotation parameter by an average of 40.After a preliminary analysis of the trunk posture in children with idiopathic scoliosis assessed by DIERS Formetric III 4D, the raster stereographic method can be considered a fast, secure way to follow-up the outcome of the FED therapy."}
+{"text": "The document \"National Guidelines for the prevention and oral health promotion in childhood\", 2013, is an act of address for those involved in the management of oral health and in particular to the pediatrician, because the figure of the pediatrician in the prevention of oral health is absolutely critical, as confirmed by the entire international literature in recent years.Correct attitudes and behaviors adopted since childhood that will allow the child to protect his health.The fluoride is the cornerstone of prevention of tooth decay and is required for all individuals.Over the years, have been developed different means of administration of fluorine, each with different strengths, dosages and frequency of use.Fluoride supplements should be prescribed by the pediatrician in cases of real difficulty for topical administration of fluoride through toothpaste or fluoride added as a method of in subjects at risk of tooth decay.The decline of caries in our country it is highly likely also due to the pediatrician who, using the national guidelines, can inform parents and families induce the acquisition of preventive behaviors currently defined by scientific research.To this end, again, the ministerial guidelines on the subject that were reviewed by a team of experts representative of the Italian research in this area."}
+{"text": "The following information is missing from the Competing Interests section: KEE is the founder of Privacy Analytics Inc.The complete, correct Competing Interests information is as follows: The authors have read the journal's policy and have the following conflicts: all co-authors perform consulting to federal and provincial governments and commercial entities in the US and Canada on de-identification. KEE is the founder of Privacy Analytics Inc, and KEE and BM sit on federal and provincial government advisory committees related to health information privacy. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials."}
+{"text": "The year of September 2013 - 2014 has seen some seminal discoveries in the field of human autoimmunity and immunology : work in Paediatric Rheumatology has led the way in several of these. In this session we will review together some of the exciting and important new developments in basic understanding of disease pathogenesis. We will also hear of the application of high throughput techniques and large datasets to our understandings of mechanism and to our translational goals towards improving lives of our patients.However one small note of caution - it is never possible to review everything of high importance and relevance, so apologies in advance if some studies cannot be squeezed inNone declared."}
+{"text": "In Malaysia, cardiovascular disease is the leading cause of death. Dyslipidaemia or high cholesterol level has been identified as one of the main risk factor that causes cardiovascular disease. In line with this, a clinical practice guideline on management of dyslipidaemia has been developed in 2004 and reviewed in 2011 for the management of dyslipidaemia cases in Malaysia. Drugs included in the management of dyslipidaemia are HMG CoA reductase inhibitors (statins), fibric-acid derivatives (fibrates), bile-acid sequestrants (resins), nicotinic acid (niacin) and its derivatives. The objective of the study was to evaluate the drug prescribing pattern in outpatient setting between Malaysian public hospitals and teaching hospital. The specific objectives of the study include the assessment of drug utilisation pattern for the treatment of dyslipidaemia, the assessment of cost of treatment for dyslipidaemia in the outpatient environment of Malaysian public hospitals and a teaching hospital and to relate the drug utilisation pattern of dyslipidaemia with the clinical practice guideline on management of dyslipidaemia.This is a cross-sectional retrospective study with universal sampling of one year prescription data. Prescriptions will be collected at the selected public hospitals under Ministry of Health and a teaching hospital under Ministry of Education with electronic prescribing system in outpatient pharmacy department from 1 January 2012 to 31 December 2012. Prescription containing at least one dyslipidaemia drug is systematically sampled and evaluated. The cost of the dyslipidaemia drugs will be derived from the label purchased price of the drugs in outpatient. The data will be analysed and appropriate test will be carried to compare the two types of hospitals.It is hope that this study will provide a trend of dyslipidaemia drug cost and utilisation in Malaysian public hospitals and teaching hospital.This study is important for the utilisation and cost of drugs used in the management of dyslipidaemia cases. This study will provide baseline data for the estimation of the economic implication of treating dyslipidaemia from the perspective of providers."}
+{"text": "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This paper is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.Information is missing from the Funding section. The correct funding information is as follows: This work was supported by the National Institutes of Health  ("}
+{"text": "Screening within the 2nd year of life ( primarily between 12 and 18 months ) is a tool for early detection of the risk of a neurobehavioral developmental disorder and is a chance to change the term prognosis of ASD.The Analysis of the interactions of functional and dysfunctional interactive communicative signals from the very early ages of life, as well as of motor patterns , allows us to capture the significant elements of the neuro-behavioral development in children at risk of developmental ASD.The ASD as the primary difficulties of social orientation and inter-subjectivity, which leads to not meeting the needs of dyadic relationship becomes even cognitive deficits, given that the abnormal behavior and the failure to derive anomalies early experiences of the process of neuronal growth.The diagnostic label of ASD in the transition from DSM-IV TR DSM 5 : basically goes from one classification categorical one dimensional paintings that defined and distinct switching to the concept of spectrum as a continuum of clinical features  until the extension to the poles towards frameworks neurodiversity.The spectrum autism disorders in relation to the clinical expression of the core autism  occurs at three levels of severity , in line with the possibilities prognostic constitute the consideration for the needs and welfare of the degree of complexity in the \"care\" the person affected by ASD and his family.There is no genetic marker of autism but there is a multi- gene and environmental control of the clinical expression of the responsible individual developmental trajectories of endophenotypes.Developments in neuroscience constitute the antecedent of the models of cognitive behavioral treatment oriented, validated for the effectiveness in accordance with the Guidelines ISS. If activated at an early stage, it is more effective than subsequent treatments, resulting in significant improvements in language, IQ, and adaptive behaviors."}
+{"text": "Unsymmetrical dimethylhydrazine (UMDH) has extremely toxic (1st class of danger) and highly carcinogenic properties [Sustainable development requires that hidden environmental costs of technologies, that should be paid by future society, to be taken into account. Scientific methods and institutions have tended to emphasize the study of individual natural processes rather than systems, analysis more than synthesis, and understanding nature more than predicting its behavior. Science of Medicine of future is increasingly being called on to produce knowledge and technology that promote environmentally sustainable, people-oriented development and long-term management of resources. operties . UMDH wais to develop and implement the own cheap and effective method of detoxification of unsymmetrical dimethyl hydrazine for the medical needs.and finding new ways of its transformation. Materials about the new chemical interactions of heptyl we have not still published.The first phase includes utilization of unsymmetrical dimethylhydrazine for chemical synthesis of mildronate and its structure analogues in specialized chemical laboratory. In turn, we made a number of demands to the chemical structures, which can be used as UMDH acceptors and discovered a new type of chemical interactions of heptyl and its derivatives, suggesting that: after relevant studies the chemical recycling methods of heptyl can be greatly expanded, including the medical aspect. In all cases, the implementation of this idea is based on the known chemical properties of UMDH Through the use of UMDH in organic synthesis to create harmless and promising for practical application products and thereby solve the problem of its complete destruction.It is recommended to create a work group on the basis of institutions and research centers of the National Academy of Sciences of Ukraine, authorized to carry out such works with heptyl. To involve to the project EU research institutions, pharmaceutical industry for scientific and financial support. The estimated initial staffing of specialized laboratory is about 4-5 experts. We suggest tocarry out the initial stage of study of the pharmacological properties of the obtained materials at the Institute of Pharmacology and Toxicology Ministry of Health of Ukraine. The mean duration of the dismantlement of heptyl to the form of medical structures is 5-10 years. Further work in this field depends on the obtained results, as well as a number of factors that are unpredictable at present."}
+{"text": "In orthognathic treatment planning for the correction of dentofacial deformities imaging and planning are important steps prior to surgery. Based on the natural head orientation, the anterio-posterior and vertical position of the upper incisor tip is one of the key elements in aesthetic planning. Gum exposure and facial and smile harmony are factors that influence this position. After definition of the upper incisor tip position, the maxillomandibular complex (MMC) can be altered according to the treatment needs .Depending on the pivot point and the amount of rotation of the MMC, the hard and soft tissue changes can vary. Placement of the pivot point anteriorly  results in an increase of the posterior face height and in extensive advancement of the lower face (up to 25 mm). In contrast, placement of the pivot point posteriorly reduces the anterior face height and has limited effect to the lower face profile. The advancement of the lower face is influenced by the location of the pivot point, the amount of rotation of the MMC (up to 5 degree), the amount of overjet corrected with sagittal split osteotomy and the amount of advancement of genioplasty.Careful analysis of the cephalograms and the face and implementation of these data into the planning are important to optimize occlusal function and facial aesthetics after orthognathic surgery. The concept of rotation of the MMC in either way widens the spectrum in treatment planning."}
+{"text": "In the original version of this article , the sizIn addition, there is a typo in the Acknowledgements section of the origin version of this article . The rigWe acknowledge the financial support provided by the Natural Science Basic Research Plan in Shaanxi Province of China (grant no. 2013JM7017), subsequently by the National Natural Science Foundations of China (grant no. 51205302 and no. 50903017) and the Fundamental Research Funds for the Central Universities in Xidian University (grant no. K5051304006). We also would like to thank all the reviewers for their comments and kind suggestions to our manuscript and all the editors for their careful corrections on the final version of the article."}
+{"text": "Health indicators show cancer to be a public health problem around the world, including Brazil. In our country, the estimate for the year 2014 predicts the occurrence of approximately 576,000 new cases of cancer, representing the second leading cause of death among men and women. The highest rates recorded in Brazil are in the South and Southeastern regions , while the lowest are in the North and Northeastern regions . The Midwest region shows an intermediate pattern  nursing program [The profile defined by the institution's nursing staff for the clinical nurse specialist role and the title of specialist in Pediatric Oncology, or Oncology Nursing, or Pediatric Nursing, requires passing the training courses in anticancer chemotherapy and totally implantable central venous catheter; Minimum of two years experience in the care of children and teenagers with cancer in outpatient clinical and hospital care; and the strong recommendation that the nurse is participating in a  program .Over the four years of existence of the service organizational model, we have witnessed the undeniable positive influence of the clinical nursing specialist's actions in patient and family responses to care in different situations, as well as the improvement of the care system\u2019s processes dedicated to these clients .For these reasons, the challenges to be faced to ensure the clinical practice of oncology nursing specialists involve aspects related to training as well as policies on the provision of health care that emphasize quality and patient safety. Therefore, it is essential that educational and service institutions rethink their strategies and priorities in order to facilitate the introduction of changes in health work practices, joining forces to create academic and continuing-education processes to meet the reality of the services, and the health care demands of cancer patients and their families."}
+{"text": "The treatment of hydrocephalus has been dramatically influenced by technical achievements which have been developed by different companies. One aspect was the principle phenomenological function of the device with the aim to lower the likelihood of negative complications like under - or overdrainage. Beneath these approaches it is important to observe the performance of the different devices based on intensive communication with the user. The manufacturer is not only obligated by law to systematically collect data about the performance of the devices. It is also important for significant improvement of the product.Based on findings followed by systematical analyzes of revised valves, which have been send back to the manufacturer for investigation the proGAV 2.0 has been developed to address nearly all critical points, which can be recognized during the investigations. Whereas the principle hydraulic function is nearly unchanged versus the first generation proGAV the handling, the risk of blockage, the risk of damaging the valve, the way of adjusting the valve as well as the verification of the setting have been improved and the basic technical elements have been completely reworked. The first clinical experiences support the intention of the approach as well as the information gained by returned valves.The systematical observation of the performance of medical devices offers valuable information for improvements."}
+{"text": "According to the data found in the literature on clinical psychology, RA refers to the group of psychosomatic diseases, the leading role in occurrence of which is played by negative life events that cause stress.To compare the frequency of negative life events in the areas of family, education, communication with peers in patients with LA before the occurrence of the disease and in a control group of nominally healthy children.The biographical methodology of \"The life line\", the picture of the family, drawings \"I am at school\", \"Me and my friend\" and a clinical interview.A statistically significant increase in the frequency of family stress in patients in the period preceding the onset of LA was revealed.None declared."}
+{"text": "There is an error in the third to last sentence of the third paragraph in the mHealth for community health works on maternal and newborn health services section of the Introduction. The correct sentence is: In Rwanda, RapidSMS-Maternal and Child Health reported a 27% increase in facility based delivery from 72% to 92% at the end of the twelve months pilot phase.There is an error in"}
+{"text": "The Council of Scientific and Industrial Research has carried out an investigation about several publications by this group in order to evaluate concerns raised about the authenticity of the data.The investigation committee at the Council of Scientific and Industrial Research has concluded that there are no data available underlying this study and thus that the published results are fabricated. As a result, the Council of Scientific and Industrial Research has requested the retraction of the publication. The authors are in agreement with the request by the investigation committee.PLOS ONE retracts this publication.In line with the outcome of the institutional investigation,"}
+{"text": "In Toumanidou and Noailly (2015), the general forms of the second Piola-Kirchhoff and Cauchy stress tensors on Eqs  and 16)16) in Man is the direction of the muscle fibers in the deformed fascicle, B, and I the second-order unit tensor.The Cauchy stress was related to the second Piola-Kirchhoff stress by:The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The depth of the changing process in health, its dimension and dynamics do not depend only on the political will and the punctual subjective aspirations, but especially on the existence and sufficiency of the necessary objective conditions, on the first place being the managerial ones. The special role of the manager in the context of the problems in the nowadays health system is imposed by the necessity of creating a general capacity of innovation, flexibility, stability, assuring the success even in special situations. In this context, the theoretical but especially the methodological approach of the management of the hospital informational system has special practical valences. This is what distinguished Prof. Florian Popa, MD, Vice-president of the Health Commission of the Senate of Romania and President of the National Council of Attesting the Titles, Diplomas and University Certificates in Medicine, affirms in the preface of a book distinguished with \u201cVictor Babes Prize\u201d by the Romanian Academy, inviting the readers not only to reflections and dialogue but also to a rapid effort of implementing or completing the information implementation processes, the new reality in health imposing this, rigorously and impetuously.  This undoubtedly imposes thorough knowledge in the domains of the distributed leading processes, medical units and management of the resources of these units  and an unmediated connection to the informational society.  However, the knowledge society represents more than the informational society, the first being possible only grafted on the informational society, and cannot be separated from it because of the major role which belongs to the information, meaning knowledge in society.  Globalization, the development of the services and especially the exponential raise of the needs and desires of the patients impose the abandonment of the organization model centered on internal problems and the adaptation to other models, centered on the patients\u2019 needs by the institutions in the medical system. This new wave of dynamic relationships and innovation, centered on the patient needs the integration at the overall level of the processes, applications and systems at an unprecedented level, with benefic results due to the use of technology at a large scale. As a consequence, what is vital in this context, is the use of Information and Communications Technology as a support for the activities of healthcare specific to the persons, the development of the conceptual-theoretical and methodological frame of Information and Communications Technology and the modeling and development of complex informatics systems specific to medicine, generating new instruments and technologies for specific applications, while mentioning the thematic areas such as telecare, telehealth, eHealth, assistive technology, ambient assisted living in smart houses, preparing competent specialists in the fundamental research with interdisciplinary applications and not least, raising the visibility of the Romanian research in the fields of complex informatics systems at the international level.Important steps were taken and are still being taken in most of the university centers in Romania, with a subjective mention, for the Automatics and Computers Faculty of the Polytechnic University in Bucharest. We are saluting the actions taken in this direction by the Romanian Society of Medical Informatics, which, involves more and more in this devotedly, with professionalism and more efficiently. That is why, it is our great pleasure to announce that, this year, RoMedinf Annual Conference of the Romanian Society of Medical Informatics will be held on more working groups - Interoperability and HER \u2013  in the great and full of signification halls of \u201cCarol Davila\u201d University of Medicine and Pharmacy in Bucharest. Obviously, it is the expression of not only the seriousness and the implication of the specialists in the field of medical informatics, in finding a faster and more performing solution from the qualitative point of view of the healthcare needs, but also the responsiveness to the new ideas, to interdisciplinarity and performance of the oldest school of medicine in Romania. Executive EditorAssoc. Prof. Dr. Eng. Victor Purcarea"}
+{"text": "Before the Law Concerning the Prevention of Infectious Diseases and Medical Care for Patients of Infections (hereafter referred to as the Infectious Diseases Control Law) was enacted in 1999, a research group was organized to make proposals regarding a surveillance system in compliance with the new law. The authors, as the members of the group, had made several recommendations for the surveillance system. The first recommendation was how many sentinel clinics or hospitals were necessary, and how they were to be selected and assigned from all the clinics and hospitals in Japan. As the recommended system was expected to be able to make an acceptable estimation of the total number of patients nationwide based on the number of patients reported from the sentinels, the research group proposed a statistical method to perform the estimation. These accomplishments were published in a report in Japanese . No. 1. 1-11 In addition to the principal targets of the study, namely the total number of patients and effective alerts, the group has studied the effective utilization of the information on target diseases which must be reported for all cases and on other target diseases which must be reported by a limited number of sentinel hospitals primarily targeting inpatients in the NESID.Since the National Epidemiological Surveillance of Infectious Diseases (NESID), one of the main objectives of the new Infectious Diseases Control Law, was implemented in 1999, the research group has been continuously examining and evaluating the efficiency, efficacy and accuracy of the system from the main viewpoints of estimating the total number of patients across Japan and obtaining effective alerts for the target diseases at sentinel clinics and hospitals. The group has also been making recommendations for necessary amendments to the system for these purposes in each report published every year (Though the main purpose of the NESID was not changed, the Infectious Diseases Control Law was amended in 2003 and the information process system was improved in 2006. On this occasion, the database accumulated since 1999 can be compiled and utilized. In the first report of this supplement, we will overview the purpose, the history and the structure of the NESID. And the evidences obtained from the analysis of the database are to be introduced in the following articles in this supplement."}
+{"text": "Scoliosis is one of the musculoskeletal disorders which influence the performance of the subjects during standing and walking. There is not enough information regarding the influence of orthosis on the gait and stability functions of scoliotic subjects, therefore the aim of this study is to find the effects of orthosis on the mentioned parameters.A 12 year old scoliotic subject was recruited in this study. They walked and stood with and without Milwaukee orthosis. Motions of the joint and the forces applied on the leg were collected by use of motion analysis system and a Kistler faceplate. The length of erector spine, external oblique and internal oblique abdominalis tendons was evaluated during walking with and without the orthosis by use of Open SIMM software.The orthosis seems to improve the performance of the subjects during standing and walking. Moreover, it stretches the contracted muscles of vertebral column.The orthosis aligned the vertebral column and improved the abilities of the subject to stand and walk. As the length of vertebral column muscles increased follow the use of the orthosis it can be concluded that it influenced the curve correction."}
+{"text": "The correct sentence is: Furthermore we report, for the first time, the identification of the Anopheles gambiae complex across Burkina Faso and the frequency and distribution of three important target-site resistance mechanisms in these populations.There is also an error in the first sentence of the Discussion section. The correct sentence is: This study provides current information on the distribution of three members of the In Tables"}
+{"text": "In Figure 8 of the original article, the scale of the ordinate was wrong. The correct figure looks as follows:"}
+{"text": "The vision of the IOC is to change the world for the better through sport and to promote social change. Protecting the health of the athlete is an important part of this vision, in order to protect the integrity of sport, protect elite athletes, protect the health of all those exercising and to promote physical activity. The protection of clean athletes through doping control is also important for the protection of the integrity of sport and of athlete health. The focus of the IOC Medical Commission is the prevention of injury and illness; this is done through world conferences, injury and illness surveillance, International Federations (IF) and National Olympic Committees.Rowing is an excellent example of a non-contact sport, where overuse injuries are the main problem. Illness and overtraining are also important. Individual physiology and training are crucial to develop the combination of power and endurance needed to compete. Rowing is a perfect sport for the multidisciplinary team of sport and exercise medicine, physiotherapy, physiology, psychology, nutrition and biomechanics specialists.Priority for the IOC is surveillance and audit, so that changes to rules, to equipment, to training and to technique can be evidence based and the effect on prevention measured. It is important for different sport federations to take every opportunity to work with each other for cross fertilization of best practice and new ideas, including at the IOC IF meetings.The IOC and world rowing share the priority of protecting health and protecting clean athletes."}
+{"text": "This article was republished on June 21, 2016, to correct low resolution figures in the PDF of the article that were introduced during composition. The publisher apologizes for the errors. The republication also corrects an error in the image for Fig 4 in the HTML and PDF versions of the article."}
+{"text": "The following information is missing from the Funding section: The information reported in this paper (No. 14-12-005) is part of a project of the Kentucky Agricultural Experiment Station and is published with the approval of the Director."}
+{"text": "During the past few decades, antibiotic-resistance of bacteria has assumed the proportion of a global crisis. The discovery of new antibiotics is not matching the rate of emergence of resistant strains thus narrowing the scope of chemotherapy. Notwithstanding the fact that emergence of resistance is facilitated by the use of antibiotics Levy,  exposureP. aeruginosa and protein A-gold  from the third generation cephalosporin cefotaxime. Species belonging to Bacteroides constitute a major fraction of the human intestinal flora. Hence the clinical significance of this observation needs hardly to be over-emphasized  was evidenced earlier by the improved survival of a hypervesiculating mutant in presence of the antibiotics compared to the growth of the wild type strain challenged with the antibiotics. Vesiculation was found to be induced in the wild type strain in presence of the antibiotics and addition of purified vesicles to the wild type culture was also associated with improved survival in presence of the antibiotics. Similarly, survival of a strain of Enteropathogenic E.coli (ETEC) in presence of polymixin B could be improved by addition of vesicles produced by the strain to the culture medium  were more concentrated in the biofilm OMVs. It is another example of possible involvement of the vesicles in antibiotic resistance (Park et al., Bacteria in biofilms are known to be more resistant to antibiotics than their planktonic counterparts. A recent proteomic analysis of OMVs obtained from planktonic growth and biofilm in The active involvement of OMVs in antibiotic-resistance of bacteria emphasizes the necessity of further in-depth investigations on this aspect. Isolation of clinical samples of antibiotic-resistant bacteria and analysis of the molecular profile of the vesicles produced by them are likely to promise insight into the molecular basis of the antibiotic-resistance. Search for the inhibitors of vesicle formation (Tashiro et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In view of the importance of the report of the German Academy of Sciences  and guidelines have been developed to ensure the maximum impact on health and economic growth in the health sector.Effective implementation of Omics-based technologies requires coordinated actions and appropriate modifications of public health and health governance systems at all levels . On the other hand, Omics have been providing sound evidence of their potential, as an essential part of good governance, to radically transform the landscape in public health. Unless the skepticism of traditional public health programs towards Omics can present us a sustainable alternative to Omics, there is no other way, beneficial to the population, for them, but to welcome new partners and new approaches to common scopes. The high relevance of the field of Omics for public health and health policy has recently also been expressed by European policymakers. In the Council conclusions on personalized medicine for patients, which has been developed under the Luxembourg Presidency in 2015 (Council"}
+{"text": "Personalized medicine is a perspective novel model of medical care being tailored to individual patients in whatever ways possible. Personalized medicine combines information of new \u201comics\u201d with new preventive and therapeutic strategies, which are more efficient, safe and cost-effective. Personalized medicine affects the health care system and its decisive role in the near future is evident. The needs are the application of these principles into the clinical practice. The cardinal target is the education of physicians. The education is thought to be most effective in young physicians and medical students. The section of young specialists representing the EPMA in the Czech Republic was created at the Faculty of Medicine in Pilsen (Plzen) of the Charles University in Prague. The activities are coordinated in the close cooperation with the EPMA delegate in the Czech Republic professor Topolcan , vice-dean of the Faculty of Medicine in Pilsen and the head of the Department of Neurology, University Hospital and Faculty of Medicine in Pilsen. One of the first activities was the \u201cPersonalized Medicine Questionnaire\u201d, which was addressed to medical students in Pilsen. The results showed lacking knowldge in the principles of personalized medicine and the will of education in this field. On that account several educational activities were realized in our institution  addressed to medical students and young physicians. The presentation of special topics on the Czech website of Personalized medicine is our next step in the support of education and is widely accessible. The courses during the school year are very busy and there is not time enough for the more complex personalized medicine interdisciplinary sessions and discussions. For this reason we are working together on the organization of the first course of the \u201cSummer School of Personalized Medicine in Pilsen 2014\u201d, the first event in the Czech Republic on this topic. During two weeks the theoretical background and clinical application into the variety of the fields of medicine will be presented and discussed. The Summer School will be open to the students of medicine of Charles University and of other medical schools in the Czech Republic and hopefully for medical students abroad.Supported by the project ED2.1.00/03.0076 from European Regional Development Fund and by Ministry of Health, Czech Republic - conceptual development of research organization"}
+{"text": "International Journal for Organ Transplantation Medicine (IJOTM) has been incorporated in the respected Elsevier databases, Scopus and EMBASE/Excerpta Medica. The editorial staff of the IJOTM acknowledges this highly esteemed recognition to the sincere support of the Avicenna Transplantation Center and the continuous encouragement of Shiras University of Medical Sciences.It was a great pleasure to realize that the The Journal is the official publication of the Iranian Society of Organ Transplantation and also the Transplantation Division of the Avicenna Medical Institutions which boasts a brilliant record in patient throughput on international scale as well as a remarkable pace of growth in scientific advancement over the past decade.Thanks to the steady efforts of a large dedicated team of physicians and scientists, the center has recently launched on expansion of its infrastructure as well as the diversity of organs transplanted. It is anticipated that the organization will stand out as one of the leading centers of transplantation medicine in the near future.Shiraz, the city which harbors the Avicenna Institutes, enjoys an outstanding reputation as a medical center throughout the Persian history. Following the downfall of the renowned Medical Academy of Jundishapur, which was the first teaching center of medicine in the world, many of its erudites settled in nearby Shiraz to proceed with the advancement of science and medicine and thus create centers of their own. This led to the emergence of numerous scholars and polymaths who have influenced the development of medicine in the world. It is the aspiration of Avicenna Medical Institutions to be capable of reviving the past scientific glory of the country and pass its heritage of excellence on to the future generations."}
+{"text": "The authors of this article have requested retraction on the basis of concerns about the experimental work and the integrity of the reported data. An institutional investigation was conducted; the enquiry could not verify that the experiments underlying the results reported in the article had taken place. In light of the findings from the enquiry, the direction of the Institut de Recherche pour le D\u00e9veloppement support the retraction of the article. In light of the above concerns, the authors retract this publication."}
+{"text": "To The Editor:I read with great interest the excellent review of Amado Salvador Pena about the problems related to the histopathological classification of celiac disease (CD) . The widFirst point, the orientation of the biopsies is fundamental and mandatory is the use of acetate cellulose filters already cut to avoid incorrect evaluation of the architecture of villi (second point the different histopathological classifications Marsh, Marsh modified by Oberhuber, Corazza Villanacci and Ensari represent another important crucial and misleading point in this field in particular \u201c the greater the number of diagnostic categories of a method, the lower its diagnostic reproducibility \u201c .For the above reasons I propose a simplified histological scheme for the diagnosis of CD that could help the pathologists and the clinicians (of villi ; second inicians : Only two categories: TypeA normal villi but with a pathological increase of T lymphocytes.Type B atrophy of villi with a pathological increase of T lymphocytes (phocytes .Two points are really important:The first: in presence of normal villi the pathological increased number of intraepithelial T lymphocytes is crucial but attention! This condition is found in different pathological disorders as well and it is not specific of CD (ic of CD . The second: the presence of atrophy of villi with the concomitant pathological increase in the number of intraepithelial T lymphocytes without differentiation in the grade of atrophy. The above scheme presents some advantages:The elimination of different categories in the condition of atrophy, not useful for the gastroenterologistMicroscopic Enteritis (A more simple approach to the initial lesions of CD; in this sense when the clinical and serological data are absent we prefer the term proposed by Rostami et al. of nteritis . This te"}
+{"text": "The original version of this paper (Van Toan and Thi Hanh It is a requirement that experimental research reported in SpringerPlus was performed with the approval of an appropriate ethics committee, and that research carried out on humans must be in compliance with the guidelines of the World Medical Association.Dr. Max Haring, Executive Editor for SpringerPlus"}
+{"text": "In the Results section of the Abstract, there are errors in the percentages and the ratios for both the chest pain and the tuberculosis data. The correct values for chest pain are , and the correct values for tuberculosis are ."}
+{"text": "AbstractTourism is a sector of the economy in which the problems related to the jobs and necessary skills to exit the crisis are emphasized more sensitively than in the other sectors of the economy. This paper proposes a literature review based on the latest studies and research literature worldwide , aims to identify the factors and trends influencing skills shortages in tourism and also the policies to mitigate this deficit. Such an approach is not easy, as most specialists in tourism admit a chronic insufficiency of the research and of the information specific to this domain of activity.Tourism feels the chronic global shortage of human resources due to its seasonal activity and its lower efficiency. The solutions that are mostly being relied upon take into consideration the closer involvement of the Government in tourism support.An important role lies in defining the content engine training and education. The differences between the requirements of the tourism sector and the content of vocational, technical and university learning is a problem in many countries. The situation remedy requires program rethinking, teachers improving skills, creating practical programmes in terms of quality, preference in enterprises and establishment of the most appropriate bridge linking vocational  education and higher education to open the students' clear and open opportunities. Even in countries where tourism responsibilities are divided between different ministries and agencies, a strategy of national long-term growth in this area is essential.The paper lists the types of partnerships between public powers, the tourism sector and the educational sector at a global level and highlights their potential in connection with national and cultural specifics.Keywords: human resources, tourism, economy"}
+{"text": "The Primary Nursing is a nursing care policy based upon an individualized patient-nurse relationship, with a particular attention to the communication and the continuity of the health care. This model has been implemented in all the structures of the ASL of Biella in 2013. The nurse becomes the coordinator of the patient\u2019s assistance. The Primary Nursing objective is to develop the principles of self-care and enpowerment through taking care of the person and the continuity of care. The patient care is committed to a specific nurse (primary nurse) who is responsible for him during the hospitalisation.The primary nurse, planning a personalized and continuative assistance in cooperation with the patient, the family and the health staff, is the point of reference, not only for the patient and the family, but also for the health team.The introduction of the Primary Nursing policy in the Neonatal Intensive Care Unit aimed at:1) increasing the satisfaction:- of patients and families who are better informed and supported by an individualized and qualified assistance- of nurses because the increase responsibility raises their competence and the ability to cooperate in the health staff2) developing the continuity of the health care by increasing the parent\u2019s self government in the late preterm care and the quality of nursing managementThe method chosen for the care policy trial can be divided in two parts:the general area ; the paediatric nurses take part to the different steps of the hospital health care strategy defined by the guidelines of the literature the specific area with the achievement of nursing plans, tools and monitoring systems for the application and the evaluation of the policy in the specific areast September 2013 to 31st March 2014. Outcomes highlight that 64.6% of the patients have been taken in care by a PN ; that 39.2% of prescriptions have been planned; the 53% of the latters has been followed by the associated nurses. Conflicts between nurses have been observed in only 3.9% of the cases.We analysed 79 medical records, that is all the newborns discharged from 1in the analysis of data , we notice a constant improvement of outcomes in the nursing care plan compiling. We intend to propose a new period of data collection in 2015."}
+{"text": "General physicians in the Family Health Strategy assist most diabetic patients in medium sized-city according to the principles of primary health care. Although in recent yrs. there has been an increase in the number of Family Health teams, the numbers of hospitalizations for diabetes complication continue to arise in the city.To improve the quality of the assistance, without taking the responsibility of the primary care professionals, was conducted a case discussion workshop to enhance the ability of general practitioners in caring for diabetic patients.The meeting had two stages: the valuation of primary care in the control of the diabetes and the role of the endocrinologist as a supporter for primary health care professionals. After the meeting was conducted a qualitative study to assess the perception of the primary care professionals about sharing patient care with the endocrinologist.Participants included 22 primary care professionals. In the first stage of the meeting, most professionals reported difficulties and lack of technical preparation to deal with diabetic patients who require insulin, even in one per day insulin application. This lack of capacity reflected in the numerous referrals to the endocrinologist of primary health care diabetic patients. After the second stage of the meeting, with the clinical case discussion with the endocrinologist, the primary care professionals reported increased security in the diabetic patient care and reported that work together with the specialist has benefits for both the patient and for the professionals. Furthermore, reported that this support partnership has the potential to reduce the number of unnecessary referrals and improve the quality of diabetic patient care without transferring the responsability of the primary health care professionals.The participation of the endocrinologist as a support to primary health care professionals increases the general practitioner capacity to solve problems, the better use of referrals and the opening of an inter-professional communication channel, whose major beneficiary will be the diabetic patient. Advantages of a inter communication channel between the endocrinologist and professional attention to primary health."}
+{"text": "The number of red blood cells (RBCs) and their properties are optimized by nature for most efficient oxygen delivery from the lungs to hypoxic periphery. Changes in metabolic requirements or environmental oxygen availability quickly translate to modulation of the RBC number, blood rheology, oxygen affinity of hemoglobin, and even of vascular tone. Inability to match the changes in oxygen demand may be fatal and requires therapeutic intervention. The recent advances in the ongoing intensive investigations of the mechanisms in control of regulation of erythropoiesis, RBC maturation and aging, as well as the processes involved in recognition of senescent RBCs and their clearance make up the present volume.It all starts from within the mesoderm, the fetal liver and from the adult bone marrow where primitive or definitive erythropoiesis takes place Palis, . FacilitThe present compilation does not only give an overview of the variety of opinions reflecting the current understanding of the mechanisms of erythropoiesis, aging, and clearance of RBCs. We hope that it also provides the base for future lively discussions of the up-standing problems in this rapidly developing research area.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In 2015, a report was published in the Health Technology Assessment which piloted the use of extracting metadata on the design, conduct, results and costs of clinical trials funded by the Health Technology Assessment programme. A recommendation was to explore the feasibility of extracting data on the active NIHR portfolio of clinical trials.To develop and pilot a method to capture data on the design and methodology of all active NIHR funded clinical trials.We will review the NIHR portfolio of clinical trials that have an active status  from data extracted in November 2014. The first part of the pilot will extract data on the design and methodological features of a clinical trial, using the existing data fields from the metadata database published in the 2015 HTA report.The key findings will include an overview of the type of clinical trials funded by NIHR and whether there are differences between the NIHR Programmes. Particular attention will be paid to key methodological elements such as the design framework, number of arms and primary outcomes and the type of interventions.Examining the methodological design of NIHR clinical trials is important to maximise the added value of metadata approaches beyond routine data collection and for increasing awareness of the type of trials funded by NIHR."}
+{"text": "Global Mental Health as an Associate Editor for Policy and Systems. In my capacity as the Executive Director of the Alliance for Health Policy and Systems Research at WHO, I have been privileged to witness the expansion of Health Policy and Systems Research and its increasing relevance and impact in other fields, including mental health. Work in mental health globally is increasingly concerned with issues that are cross-cutting and inter-disciplinary in nature: the use of task shifting as a strategy for enabling access to care, the use of implementation research as a means of putting into practice knowledge about the interactions between sociocultural factors and mental health, as well as service delivery, financing, access to medicines, and other challenges related to the way that health systems are organized around the world.It gives me great pleasure to participate in the launch of this inaugural issue of In these and other areas, there are valuable lessons generated from the advancements in the field of mental health that can help inform our understanding of health systems as well as other areas of global health. But in turn, the field of mental health also has much to learn and take from the evolving field of health systems research. There is growing recognition that addressing the global burden of mental illness \u2013 which are among the leading causes of disability in all regions of the world, requires a strong focus on the design and capacity of health systems and policies that ultimately drive mental health care.This natural convergence of priorities and goals offers a unique opportunity to bring mental health into the broader Health Policy and Systems Research agenda. Since the inception of the Alliance for Health Policy and Systems Research in 1999 and following the successes of the two Global Symposia on Health Systems Research in 2010 and 2012 as well as the launch of Health Systems Global, issues ranging from the use of econometrics in health systems planning to pathways for achieving universal health coverage have gained prominence in global health dialogues. What has been and is still missing from these discussions, however, is the attention to how these issues relate to mental health.Global Mental Health goals.As the Associate Editor for Policy and Systems, I will work to encourage the use of Health Policy & Systems Research Methods and Approaches, as tools for addressing current mental health challenges. More importantly, we hope that this journal will serve as a platform to bring together the diverse range of actors and stakeholders whose collective actions are needed to respond to complex system challenges posed by the emerging burden of mental illness globally. The alignment of research agendas \u2013 along with the coordinated efforts of policy makers, practitioners, planners, and multi-disciplinary researchers, will be critical to the attainment of We invite people from both communities of practice to see themselves as contributors to and users of the kind of research in this area we hope to publish, and to assist in forming a more effective and rich field of Health Policy and Systems Research as a result."}
+{"text": "A new technique for an extended genioplasty, the mandibular wing osteotomy, is presented step by step. This osteotomy allows correcting the position of the chin-prominence, to change the aspect of the divergence in the mandibular angulus and to achieve a lip competence in cases where it is needed. All these movements of the lower border of the mandibula can be performed completely independently from the positioning of the bases that is necessary for the correction of the malocclusion.A planning concept is shown and the different treatment modalities for Angle class II and III malocclusions are presented."}
+{"text": "There is an error in the PDF version of the published article. In the Material and Methods, under the subsection Experimental design and statistical analysis, the text should indicate the following:The Publisher apologizes for the error."}
+{"text": "PLOS ONE editors retract this publication according to the recommendation received from the Catholic University, Rome.The PLOS ONE editors contacted the Catholic University to note the concerns identified in relation to the presentation of Western blot results from this study. The Catholic University established an investigation commission which has confirmed that several of the figures were inappropriately assembled by the corresponding author Dr. Paola Palozza and advised the retraction of the article.Upon the publication of the Correction on the article, the PLOS ONE retracts this publication.In line with the institution's recommendation,"}
+{"text": "The link between the heart and mind has been studied over the centuries in many fields, such as medicine and psychology , classified as an anxiety disorder in the latest version of Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, So the study of psychosocial factors and interventions in the field of Cardiac Psychology and PTSD is a growing need and challenge in our clinical and scientific community (Ginsberg et al., Frontiers Research Topic special is devoted to providing a foundation for the development of the scientific study of these relationships, and the discovery of the propositions that govern them.The study of the relationship of autonomic cardiac adjustment to stress and mental disorder\u2014the heart-mind connection\u2014is the challenge that Cardiac Psychology has accepted. This The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Information on the occurrence of sequence features in genomes is crucial to comparative genomics, evolutionary analysis, the analyses of regulatory sequences and the quantitative evaluation of sequences. Computing the frequencies and the occurrences of a pattern in complete genomes is time-consuming.The proposed database provides information about sequence features generated by exhaustively computing the sequences of the complete genome. The repetitive elements in the eukaryotic genomes, such as LINEs, SINEs, Alu and LTR, are obtained from Repbase. The database supports various complete genomes including human, yeast, worm, and 128 microbial genomes.This investigation presents and implements an efficiently computational approach to accumulate the occurrences of the oligonucleotides or patterns in complete genomes. A database is established to maintain the information of the sequence features, including the distributions of oligonucleotide, the gene distribution, the distribution of repetitive elements in genomes and the occurrences of the oligonucleotides. The database can provide more effective and efficient way to access the repetitive features in genomes. During the last decade, many genomes have been successfully and completely sequenced. Summarized information about the oligonucleotides in genomes provides biologists, who interests in the evolution and growth of genomes, to work in comparative genomics, oligonucleotide probe design, primer design and the analyses of genomic repetitive features.The computation of the occurrences and the frequency of all oligonucleotides in a complete genome is very elaborate and time-consuming, especially when the genome size is very large, such as the human and mouse genomes. A database that summarizes the occurrences and the frequencies of oligonucleotides in complete genomes can facilitate the biological and the statistical analyses of genomes.et al. systematically searched the promoter regions of potentially co-regulated genes for over-represented oligonucleotides which may be transcription factor binding sites . The sensitivity and the speed of RepeatMasker are set as the default values.Table The web interface enables users to query the occurrences of an oligonucleotide in a genome and the number of occurrences in each chromosome. Figure Figure We have constructed the databases of both the oligonucleotide occurrence locations and their frequencies in the coding and the non-coding regions in complete genomes. The data in flat-file format can be downloaded directly for further analyses in several biological applications. The user may also use the web interface to query and access the database contents. The database also provides a filtering function for retrieving the information about oligonucleotides under search conditions specified by the users. Furthermore, the database provides the occurrences and the frequencies of other repetitive elements, such as LINE, SINE, Alu and tandem repeats in genomes.The database is now available at FML implements the software and refinements the system. HDH conceives of the study and drafted the manuscripts. YCC and JTH participates the design and coordination. All authors read and approved the final manuscripts.Appendix listing the organisms supported in the database.Click here for file"}
+{"text": "One of the most important areas of interest in the world today and throughout history is health. Numerous investigations are confirming positive effects of physical activity on health and this is the reason why physical activity and exercise should be measured as often as possible. Croatia as the youngest member state in European Union does not have excellent results in the levels of physical activity among its population. In this research the aim was to assess the levels of physical activity in the city of Dubrovnik and compare it to the levels of Physical activity in Croatia and European Union.Participants in this investigation were 670 adult citizens of the City of Dubrovnik, Croatia. Levels of physical activity was measured using Eurobarometer questionnaire. Descriptive statistical parameters Mean and Standard deviation same as Statistical Difference between the values in Dubrovnik, Croatia and European Union were calculated using statistical program package Statistica.Overall results show significantly better situation in Dubrovnik when comparing with the results measured on national level and on European Union level. While, according to the Eurostat's analysis in 2017, there is 46% of citizens of European Union and even 56% of citizens in Croatia that never exercise or play sports in the City of Dubrovnik there is only 17,31% of citizens that never exercise or doing sports. The most important reasons for doing physical exercise or sport (motivators) among citizens of Dubrovnik is improvement of health (45%) and improvement of physical appearance (30%). Almost half of the sample (47%) pointed out the lack of time as the main barrier in doing physical exercise or sport.This investigation shows good way to assess the information on levels of physical activity of the citizens and accordingly creating a public policy on further development and improvement of this important area. This investigation is part of document called Strategic development of Sport and Sport's Infrastructure in Dubrovnik and it reveals encouraging data for this Croatian city."}
+{"text": "Funding statement was missing. The correct Funding statement appears below.In the published article, the This study was funded by the National Natural Science Foundation of China (grant number: 71804134), the Project of Humanities and Social Sciences from the Ministry of Education in China (grant number: 18YJCZH078), and the Health Commission of Zhejiang Province (grant numbers: 2020KY631 and 2021KY780).The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Nature 10.1038/s41586-019-1907-7 Published online 5 February 2020Correction to: In the published version of this paper, the members of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium were listed in the Supplementary Information; however, these members should have been included in the main paper. The original Article has been corrected to include the members and affiliations of the PCAWG Consortium in the main paper; the corrections have been made to the HTML version of the Article but not the PDF version. Additional minor corrections to affiliations have been made to the PDF and HTML versions of the original Article for consistency of information between the PCAWG list and the main paper."}
+{"text": "The past five years have brought enormous changes in the lives of older adults and their families. During this time the University of Michigan National Poll on Healthy Aging (NPHA), co-sponsored by AARP and Michigan Medicine, has gathered the experiences and perspectives from nationally representative samples of US adults age 50-80 on a range of topics related to healthy aging. These polls have been used to elevate the voices of the older adults in the development of policies and practices to improve the health of people as they age. During the past two years, poll reports have captured how changes in lifestyle and behaviors during the COVID-19 pandemic have impacted the health and well-being of older adults. Members of the NPHA team from the University of Michigan and AARP will begin with an overview of the poll including its goals and methods. The session will then highlight key findings from the first five years of the NPHA that have important implications during and beyond the COVID-19 pandemic, with special attention to poll findings related to joys and stresses and aging in place. The presenters will also discuss how to access publicly available NPHA data. The session will wrap up with a discussion of how the perspectives and experiences of older adults gathered through the NPHA and AARP polling can be used to inform policy and advocacy to support healthy aging."}
+{"text": "Nature Communications 10.1038/s41467-019-13825-8, published online 05 February 2020Correction to: In the published version of this paper, the members of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium were listed in the Supplementary Information; however, these members should have been included in the main paper. The original Article has been corrected to include the members and affiliations of the PCAWG Consortium in the main paper; the corrections have been made to the HTML version of the Article but not the PDF version. Additional corrections to affiliations and author names have been made to the PDF and HTML versions of the original Article for consistency of information between the PCAWG list and the main paper."}
+{"text": "The goals of endodontic therapies are the prevention or the elimination of apical periodontitis of endodontic origin, ensuring the stability of results over time in order to avoid the recurrence of the disease and preventing teeth from requiring extraction .Different systematic reviews have been performed with the aim of evaluating the factors influencing the outcome of primary root canal treatments ,3,4. GenRegarding the incomplete chemo-mechanical disinfection of the root canal system, the most significant affecting factors are undoubtedly the missed instrumentation of root canals, the impossibility to reach the working length, the alteration of the anatomy or the fracture of nickel\u2013titanium rotary instruments inside the canals . The preIn conclusion, despite the improvement in the last decade in our knowledge of the performance of endodontic materials, both for instrumentation procedures and post-endodontic restoration, an in-depth comprehension of their mechanical behaviour is still required, and further research is needed both to enhance the success rate of RCT and to improve the performance and quality of materials."}
+{"text": "This Retraction follows an Expression of Concern relating to this article previously published by Portland Press.Bioscience Reports at the request of the Editor-in-Chief and the Editorial Board following receipt of a notification from a reader, alerting the Editorial Board to incorrect nucleotide sequence reagents listed. The errors in this article were identified using The Seek & Blastn tool by Labb\u00e9 et al. 2019 .This article is being retracted from The authors have been contacted with regards to the retraction, and have not responded to the Journal's queries and the concerns raised. Given the extent of the issues raised, the Editorial Board stand by the decision to retract the article."}
+{"text": "The article is devoted to the main methodological problems of qualitative research in the psychology of culture. Methods of ethnographic (field) observation were borrowed by psychology from social and cultural anthropologists in the first half of the twentieth century, and in modern research practices there is a special ethnographic direction that claims to analyze behavior and lifestyle in various subcultures and communities.The purpose of this study was to identify the key cross-cultural difference in coping behavior of respondents from Moscow and Tashkent.The methodological basis of the research was the thematic analysis of narratives and free-form interviews. The sample was N = 60 (residents of Russia and Uzbekistan age 17-39).The results of thematic analysis of narratives and free-form interviews of respondents from Moscow and Tashkent allow us to conclude that the key cross-cultural difference in coping behavior is the degree of its individualization: representatives of Uzbek culture are focused on receiving support and care from significant Others, and not on independent internal work (unlike Russian respondents). At the same time, they are not satisfied with the traditional prescriptions that come from the family environment, which forces them to coping practices that go beyond the boundaries of normative social (often religious) ideas.This can be interpreted from the point of view of the process of modernization of Uzbek culture, which is gradually becoming individualistic, and the latter circumstance requires the construction of flexible coping strategies in the situation of social and cultural changes.No significant relationships."}
+{"text": "In the ESI summarized values of Rq in Table S7 were incorrect and the ESI document is now replaced.Errors were present in the published article and ESI. The errors in the article are in the plots of SAR and coverage in The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "The height of the cementing cement sheath of the conductor for offshore drilling is the key factor affecting wellhead stability. For the influence of the insufficient return height of cement slurry on the mechanical behavior of the conductor after running the conductor by shallow water exploration well drilling, the axial load distribution characteristics and bearing capacity mechanism of conductor were first analyzed from the perspective of operation characteristics of the drilling method. Second, a calculation model of axial bearing capacity of the conductor with the size of the conductor and the return height of cement slurry as variables was established on the basis of the hole enlargement that often occurs during drilling. In addition, the law of the influence of the return height of cement slurry on the ultimate bearing capacity of conductor and the strength difference of the two cementing surfaces between conductor and cement ring and between the cement sheath and submarine soil layer and its changing rules with time were explored and studied by field experiment. It was concluded that the friction between the cement sheath and the soil layer is the key factor that decides the main bearing capacity of the conductor. The drilling method is one of the main methods of running the conductor in shallow-water drilling and has the advantages of strong adaptability to the shallow seabed soil and great bearing capacity \u20133. The gRoy E. Olson and KARLSRUD K theoretically analyzed the axial bearing capacity of steel piles in sand and clay , 8. D. GTherefore, for the operating characteristics of running the conductor by offshore drilling, the axial load distribution characteristics and bearing capacity mechanism of the conductor were first analyzed in this paper from the perspective of operation characteristics of the drilling method. Besides, the influence of hole enlargement on bearing capacity was considered during running the conductor drilling. A calculation model of the ultimate bearing capacity of the conductor considering the return height of the cement sheath was established. Finally, the accuracy of the calculation model of the ultimate bearing capacity was verified by simulation experiments; and the influence of the setting time on the ultimate bearing capacity was explored.As an important equipment connecting wellhead and seabed in drilling operations, the main function of the conductor is to isolate seawater, provide a closed space for drilling operations, and provide axial bearing capacity for the wellhead shown in . The conThe load analysis of the conductor showed that the axial force of the conductor is a system that balances the dead load of the conductor and the wellhead load by lateral friction and tip resistance, as shown in n layer of soil below the mud surface, the friction force on the lateral wall of the conductor is as follows:The results showed that the cementing strength of the cement sheath-conductor cemented surface (First cementation surface) is greater than that of the formation-cement sheath cemented surface (second cementation surface) , 13. AccThe tip resistance force of assembly of conductors and cement sheath can be expressed as follows:The formula for calculating the ultimate bearing capacity of the conductor is obtained by substituting  and 3)  3) into d should be the diameter of a circle formed by the outer diameter of the cement sheath and intersection point of formation, namely, the actual borehole size. But the seawater is utilized as a drilling fluid in the surface drilling, and its density may be less than the collapse pressure of shallow formation sometimes, and consequently causes formation collapse and hole enlargement. Therefore, the actual borehole size cannot be replaced with the bit size. The actual borehole size can be expressed as follows:According to the strength relation between the two cemented planes, the conductors and the cement sheath should be seen as a whole. Consequently, the value of Under the condition of the impermeable well wall, the effective stress at the hole collapse can be obtained by calculation according to the linear void elasticity theory. Then, according to the Mohr\u2013Coulomb criterion, the forecast model of borehole enlargement coefficient can be obtained by combining the effective stress at the hole collapse with the ambient stress of well wall , 15,(6)\u03b2Wellhead load refers to the total load weight borne by the wellhead at the drilling stage and is also an important factor in the design of the conductor's setting depth \u201319. The During cementing, the cement slurry is injected from the bottom of the hole through a cementing line into the annulus between the conductor and the soil. The insufficient return height of cement slurry refers to that the return height of cement slurry is lower than the design height (mud surface) due to the infiltration of some cement slurry into the formation during cementing and the decrease of the volume of cement slurry during consolidation. The insufficient return height of cement slurry will result in the failure of the conductor and cement sheath system to cement to the upper soil, losing the lateral friction provided by this part.Assuming that the return height of cement slurry is -xm. In other words, the distance between the cement consolidation surface and mud line is xm , drilling equipment, cementing equipment, loading water tank, Jack, water pump, support platform, displacement sensor, load sensor, and data collector. The test system for the ultimate bearing capacity of the conductor is shown in First of all, the location of the cementing experiment is identified and soil samples were collected and analyzed. The parameters of the soil within the experimental site are listed in According to  and paraLoad-displacement curves at different return heights of cement sheath are also shown in the figure below. In order to ensure the accuracy of the experimental data, the same experiment was carried out three times and averaged to calculate the error between the experimental value of the ultimate bearing capacity and the calculated value of the model .The experimental results showed that the ultimate bearing capacity of the conductor decreased linearly with the decrease of the return height of the cement slurry. When the return height of the cement sheath is 3.5\u2009m below the mud surface, the ultimate bearing capacity reached 30.61%. The error between the ultimate bearing capacity of the conductor obtained by the simulation experiment and the calculated value of  is less The ultimate bearing capacity of the conductor under different setting times is listed in The experimental results showed that the ultimate bearing capacity of the conductor increased first and then tended to be stable with the increase of the setting time. When thComparing the Q-z curve of the cement sheath and of the conductor when the setting time is shorter than 2\u2009days , it is fA calculation model of axial bearing capacity of the conductor with the size of the conductor and the return height of cement slurry as variables was established on the basis of the hole enlargement that often occurs during drilling. Compared with a series of simulation experimental data of ultimate bearing capacity of conductor, it is concluded that the accuracy of the calculation model is more than 95%.The experimental results showed that the ultimate bearing capacity of the conductor increased first and then tended to be stable with the increase of the setting time. When the setting time is 2\u2009days, the average value of the ultimate bearing capacity increases to 63.67\u2009kN, which is 67.9% of the maximum ultimate bearing capacity. Generally, the setting time in real operation is 2\u2009days; hence, the reduction factor of the ultimate bearing capacity takes 0.679.Comparing the Q-z curve of the cement sheath and of the conductor when the setting time is shorter than 2\u2009days, it is found that the settlement of conductor is greater than that of cement sheath under the same load. This phenomenon indicates that the conductor and the cement sheath are completely consolidated into a whole and support the weight of the wellhead equipment when the setting time exceeds 2\u2009days."}
+{"text": "The aging of the population implies a greater risk of psychopathological events; at the same time multimorbidity constitutes the rule rather than the exception in the manifestations of the health problems of the elderly. Multimorbidity involves many diagnostic-therapeutic interventions, from general practitioners to neurology, geriatrics, psychiatry but these interventions do not appear integrated with each other.Evaluate the availability of psychogeriatrics training programs to increase the interest and skills of the medical profession on the multimorbidity of the elderly.We have conducted a review of the scientific literature on integrated training programs in the field of psychogeriatrics over the past decade on pubmed, comparing the different training models proposed.A still limited amount of articles on integrated psychogeriatric training have been published although the demand for psychogeriatric care continues to increse. The frail elderly seems to have a connotation in terms of costs rather in terms of care; moreover, everything concerning the elderly is reduced to the organic dimension alone, neglecting psychopathology.The feasibility of integrated training programs between primary care and specialists such as neurologists, geriatricians, psychiatrists is a priority in the field of psychogeriatrics in consideration of the relevant multimorbidity. It is appropriate both to update knowledge and to review the organizational models of care so that the frailty of the elderly with multimorbidity does not quickly translate into disabilities with high social welfare needs. It is also necessary for generalist psychiatry to return to the value of psychopathology of the elderly.No significant relationships."}
+{"text": "The crisis caused by the ongoing COVID-19 pandemic is affecting the lives of billions of people across the world. Individuals with mental illness are suspected to be particularly affected by the societal consequences of the pandemic, but there is very limited data on this important aspect.The aim of this study is to gauge the longitudinal impact of the COVID-19 pandemic on the psychological well-being and symptom levels of individuals receiving treatment for mental disorder in psychiatric hospital services.We are in the process of conducting a two-wave, questionnaire-based survey among patients with mental disorders receiving treatment in the psychiatric hospital services of the Central Denmark Region. The first wave was conducted in July 2020 and had 1180 respondents representing all major diagnostic categories. The main finding was that the majority of the respondents reported that their mental health had deteriorated during the COVID-19 pandemic. We are currently planning the second wave of the survey, which will be fielded in the fall of 2020. Here, we will reassess the mental health of the respondents from wave 1.Will be presented at the meeting.Longitudinal studies of the impact of the COVID-19 pandemic of mental health are lacking. We therefore expect that the findings of this study will be of significant interest to the field.No significant relationships."}
+{"text": "Vincent  The authors regret that the name of one of the authors (Cooper A. Vincent) was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "In this article, the concept  of computational phonetic analysis of speech with an analytical description of the phenomenon of phonetic fusion is proposed. In this concept, in contrast to the existing methods, the problem of multicriteria of the process of cognitive perception of speech by a person is strictly formally presented using the theoretical and analytical apparatus of information (entropy) theory, pattern recognition theory and acoustic theory of speech formation. The obtained concept allows for determining reliably the individual phonetic alphabet inherent in a person, taking into account their inherent dialect of speech and individual features of phonation, as well as detecting and correcting errors in the recognition of language units. The experiments prove the superiority of the proposed scientific result over such common Bayesian concepts of decision making using the Euclidean-type mismatch metric as a method of maximum likelihood and a method of an ideal observer. The analysis of the speech signal carried out in the metric based on the proposed concept allows, in particular, for establishing reliably the phonetic saturation of speech, which objectively characterizes the environment of speech signal propagation and its source. Computational phonetic analysis is a fundamental component of most information technologies for natural language recognition, cognitive speech analysis, automated speech transcription, and so on. The high reliability of phonetic analysis is a guarantee of a qualitative result of the functioning of all of these types of systems. The primary phonetic-morphological analysis of inflected languages and speech is especially relevant. The main source of errors in this process is a fusion ,2,3,4. TThe task of computational phonetic-morphological analysis of language or speech is objectively complicated, firstly, by the peculiarities of language itself as a process of physiologic-cognitive human activity, and, secondly, by the peculiarities of the profile information technologies involved.We note the main integral factors of the first source of complications ,6,7,8,9.Homonymy of inflections. Inflexions can be homonymous if they belong to a single world-changing paradigm or characterize a single lexical and grammatical category, but belong to different world-changing paradigms, and they are sometimes found in the paradigms of different parts of language. This factor is a source of ambiguity in phonetic-morphological analysis. The negative impact of this factor can be reduced by using information technologies of linguistic context analysis and computational phonetic analysis.Internal flexion. This type of inflexion is manifested when using the basic collection of language units, the representativeness of which depends on the content of word forms. If the collection is not used, it is necessary to formulate the rules of linguistic polymorphism inherent in the studied language.Complex lexemes. Lexemes, the phonation (inscription) of which includes specific articulation techniques , require the definition of declension for each component in the word form.Analytical word forms. Analytical word forms are found in many languages and can cause significant complications in phonetic-morphological analysis because the components of the word form can be separated and even be located in different positions in the sentence.Large lexical fund of language. Despite the rapid positive dynamics of computing power characteristics and the large memory capacity of modern computer technology, working with a basic collection of language units of the studied language  in the implementation of phonetic-morphological analysis remains a task of high computing.Variability of the lexical level of language. Updating the collections of language units for the appropriate type of phonetic-morphological analysis system does not keep up with the polymorphism of natural language , which is manifested in the everyday phenomenon of new lexemes  and word forms. Systems of computational phonetic-morphological analysis of a no collection type suffer less from the influence of this complicating factor.We have mentioned only the most common factors of natural linguistic origin which negatively affect the effectiveness of computational phonetic-morphological analysis of speech. Depending on the information technology involved, this list is expanding.We investigate the current state of the theoretical and analytical basis of current information technologies of computational phonetic-morphological analysis. Based on the results of information retrieval ,11, we dThe central element of the systems of the first type is a collection of relatively phonetically and linguistically stable language units  of the studied language. The corresponding technology analyzer decomposes the speech signal (text) into a certain sequence of indivisible portions, carrying out a recognition procedure for each of them. Such an elementary combinatorial model is most often used for the analysis of inflectional and agglutinative languages. The order of parts of lexemes is defined as the concatenation of the corresponding classes of morphemes in the collection. To determine the order of transition between classes of morphemes, the mathematical apparatus of finite state machines or Markov chains are usually used . The numSystems of the second type are focused on computational morphological analysis. Accordingly, the content of collections of etalons of language units in such systems is formed by morphemes and short lexemes. Systems of this type consider word forms as a sequence of such language units formed according to compositional and(or) production rules. When studying word forms, the system generates a lemma for it according to certain rules ,22. If sThe disadvantage of all systems of phonetic-morphological analysis of the first and second types is the use of large collections of language units. However, according to this criterion, systems focused on the use of phonetic and morphological collections look better if the efficiency of the recognition process is acceptable.Systems of the third type perform phonetic-morphological analysis exclusively based on mathematical methods of machine learning  ,32,33,34Below we formulate the main provisions of our study.object of study is the fusion of the process of merged speech.The purpose of the study as formalization in the paradigm of information theory of a statistically adequate analytically rigorous concept of phonetic analysis of speech, the variability of which will be taken into account.Considering the mentioned advantages and disadvantages of systems of phonetic-linguistic analysis, we formulate the subject of research will be methods of probability theory and mathematical statistics, information theory, pattern recognition theory and acoustic theory of language formation.The objectives of the study are: to create a concept of the process of computational phonetic analysis of speech, taking into account dialects and the specifics of phonation introduced by the speaker; to formulate a criterion for the estimation of the phonetic saturation of speech based on the proposed model, taking into account the distorting effect of the channel of propagation of speech signals in the phonation process; and to prove the adequacy and functionality of the obtained theoretical results.In this context, the main contribution of the research is the concept of computational phonetic analysis of speech. In the concept, in contrast to the existing methods, the task of addressing the multicriteria of the process of cognitive perception of speech by a person is strictly formally presented in the theoretical and analytical apparatus of information theory, pattern recognition theory and acoustic theory of speech formation. The obtained concept allows for determining accurately the phonetic alphabet of a person, taking into account their inherent dialect of speech and individual features of phonation, as well as detecting and correcting errors in the recognition of language units and reliably assessing the phonetic saturation of speech.The highlights of this research are:-The entropy-argumentative concept  of computational phonetic analysis of speech, taking into account dialect and individuality of phonation;-The entropy-argumentative concept of detection and correction of errors of computational phonetic analysis of speech.The The functional purpose of typical modern information technology of computational analysis of speech patterns is realized by comparing the parameterized representation of the studied language unit and its corresponding etalon in a certain parametric space. The main source of uncertainty in the comparison process is the biological origin of the speech signal and its distortion during transmission and processing. However, the acoustic variability of phonation of language units , due to the existence of dialects, is relatively stable. Based on this fact, we assume a simultaneous comparison of the studied pattern of the phonogram with the pronounced phoneme Based on Rule (2), we define the procedure of computational phonetic analysis of speech as a comparison of empirical (spoken by the person) Based on the provisions of information theory, we argue the solution rule (2) in the context of the relative entropy functional ,36,37 (3We present Function (3) in frequency space as the optimal solving statistics . For oneExpressions (2) and (4) allow us to calculate quantitative characteristics, based on which it is possible to reasonably decide whether the studied pattern In the general case, the value of the constant The error of the second kind Summarizing the considerations embodied in Expressions (5) and (6), for practical use we choose the value of the threshold The value of the threshold In the context of the provisions of information theory, we consider the speaker as a source of discrete messages If we ignore the influence of individual features of the speaker\u2019s articulatory apparatus on the phonation process and assume that the speech message is transmitted in the absence of acoustic ambient noise, the required amount of information is defined as Shannon entropy for a discrete message source :(8)HX\u225c\u2212\u2211If we mention the normalization R+1-th, language unit, which includes cases of the unreliable recognition of a signal r-th phoneme, provided that the variability of its phonation introduced by the speaker is ignored.This axiom is true even for individual phonemes, not to mention more massive language units. Under such conditions, an adequate mathematical model of a discrete source of speech messages should be created based on phonemes defined by Expression (5), clearly clustered in the parametric space: Note that Expression (8) characterizes a discrete source of speech messages without taking into account the disturbing effect of the channel of their distribution on the final result of phonation. Consider this information using as a basic expression :(10)IX,XBased on Expression (11), we can say that the a posteriori entropy of information scattering in the phonation of the speech message Based on Expression (12), we can say that with an equally probable distribution of phonemes in the phonetic alphabet of the speaker, the upper limit of scattering of useful information in the phonation process can be described by the expressionThe obtained result correlates with the known Fano inequality  for arbiThe last statement can be proved empirically by comparing the calculated values of the right-hand sides of Expressions (13) and (14) for the experimental data for Thus, the decision rule (2), the decision statistic (4) and Expressions (7)\u2013(9) together form the desired concept of the process of computational phonetic analysis of speech, taking into account dialects and the specifics of phonation introduced by the speaker. The central element of the concept is the matrix of information mismatch Let Let od ratio ,36,37 baUsing the known computational algorithm  under thSimilarly, we obtain the expression for determining the upper limits for Substitute Expressions (18) and (19) into Expression (16) and obtain the condition under which the hypothesis We scale rule (20) for the task of recognizing signals of the form in (15) with an arbitrary number of hypotheses Assuming the homogeneity of the pair of signals An alternative to Expressions (23) and (24) may be to take into account the principle of the minimum value of information non-directional mismatch Expression (25) is a particular case of Criterion (22), provided that with an unlimited increase in the volume of training samples The probability If we take into account that the empirical signal before recognition is normalized to the value of its specific entropy, then the system of asymptotic equations From Expression (28), it follows that there are essentially unequal distributions of statistics Assume that when recognizing the signal under study using the decision rule (25), the verdict was erroneously in favor of the hypothesis Repeating the considerations that accompanied the transition from Expressions (26) to (28), we rewrite the defined expression to determine the probability Analyzing Expression (30), we obtain an equation Thus, Rule (29) allows us to estimate the probability of the event of marginal recognition of the correct result of the phoneme recognition procedure, employing the decision rule (25). The stochastic estimate of such an event is characterized by the expressionWe use Rule (11) based on the concept (8)\u2013(10) to estimate the phonetic saturation of speech of persons in a team of 30 people. The personnel composition of this team was formed in a balanced way. It took into account such criteria as age , gender , higher education (university), native language (Ukrainian), and level of English language proficiency according to CEFR-B2. Each person listened to a phonogram of an 1800-character English-language journalistic text pronounced by a Google Translate service once. Subsequently, each person recounted the heard text for recording on a personalized digital phonogram lasting 3 min. The phonation of the retelling took place at the same tempo and timbre and with a clear fixation on language units. The phonograms were recorded using an AKG P420 microphone without an amplifier connected to a Creative Audigy Rx sound card integrated into a personal computer with a sampling frequency of 16 kHz. Each phonogram was saved in a .wav format file. For further analysis, the phonograms were split into segments of duration Respectively, according to the decision rule (2), taking into account Expression (7), the value of the threshold Similar calculations were made for the rest of the persons in the team. For clarity of presentation, these results were averaged for each of the three age groups and visualized in We investigate empirically the functionality of decision-making concepts generalized by solving Rules (22) and (25) in the task of the computational phonetic analysis of speech \u2013(10) paradigm). The empirical material for the research was two phonograms with a recording of the same content of language material spoken by person \u21161. Phonograms were represented by samples Further use of the data presented in Let us complete this stage of research by calculating by means of Expression (31) the probability of the event of marginal recognition of the correct result of the phoneme recognition procedure using the decision rule (25): ith input influence the variance of the implementation of the situation of the incorrect speech unit recognition: We generalize the experimental section by verifying the models proposed in The task of computational phonetic analysis of speech in the general case is reduced to a cyclically repeated procedure for estimating the deviation of the current segment of the studied speech signal from the etalons defined within a finite list of language units. The duration of the segments, by the sequence of which the output speech signal is presented, is selected based on the average duration of the studied language units; for example, for phonemes it is From the empirical results shown in Based on the relative entropy function, Finally, it should be noted that the mathematical apparatus proposed in this article is proved to be adequate because it is based on the verified mathematical apparatus of information theory. This fact, as well as the rigor and reversibility of the analytical transformations carried out in the formalization of the corresponding metric, substantiate the adequacy of the mathematical apparatus presented in the article.The study of a cornerstone object for modern linguistics, the process of speech and textual interpersonal communication, considering the size of the infosphere of the twenty-first century, is impossible without a thorough and purposeful involvement of information technology from other fields of knowledge, including computer science. Created as a result of relatively young science, computational linguistics aims to automatically analyze natural languages in all spectra of their implementation. From the long list of current tasks actively studied in the paradigm of computational linguistics, we mention the automation of compilation and linguistic processing of language corpora, the automated classification and abstracting of documents, the creation of accurate linguistic models of natural languages, ad the extraction of factual information from informal linguistic data. An effective, strictly formalized technology of computational phonetic analysis of linguistic information, especially speech information, is potentially the driving force behind the improvement of the results of solving these research tasks. This thesis is fully consistent with the content of the article, which proves the relevance of the presented scientific and applied results.scientific novelty of the research. In the concept, in contrast with the existing methods, the task of addressing the multicriteria of the process of cognitive perception of speech by a person is strictly formally presented in the theoretical and analytical apparatus of information theory, pattern recognition theory and acoustic theory of speech formation. The obtained concept allows for determining accurately the phonetic alphabet of a person, taking into account their inherent dialect of speech and individual features of phonation, as well as detecting and correcting errors in the recognition of language units and reliably assessing the phonetic saturation of speech.The proposed concept in this article  of computational phonetic analysis of speech defines the The proposed concept is represented by the decision rule (2), the decision statistics (4) and Expressions (7)\u2013(9). The central element of the concept is the matrix of information mismatch practical significance of the proposed concept of computational phonetic analysis of speech lies in the fact that with its help, it is possible not only to single out phonetic units in speech signals, taking into account the individual features of speech formation, but also to detect and correct errors in the results of such an analysis.The study of the results of computational phonetic analysis based on the function of relative entropy allowed for substantiating theoretically two detectable errors of the process of recognition of language units (15) based on solving Rules (22) and (25). Note the possibility, formalized by Expression (31), to estimate the reliability of the decision made based on Rule (25). If the solution is found to be compromised according to Expression (29), then with the help of a computational procedure with Scheme (15), it is possible to find erroneously recognized unreliable results of phonetic analysis and rehabilitate them. Thus, the The potential inherent in the proposed concept and the experimental results presented after Further research is planned to analyze the function f speech ."}
+{"text": "In the Treatment and Prevention section, there are errors in the seventh and eighth sentences of the second paragraph. The correct sentences are: Two vaccines are currently licensed by the US FDA for prevention of smallpox: ACAM2000 and JYNNEOS. The effectiveness of JYNNEOS against monkeypox was concluded from a clinical study on the immunogenicity of JYNNEOS and efficacy data from animal studies [69]."}
+{"text": "RSC Advances is publishing this expression of concern in order to alert our readers that we are presently unsure of the reliability of the data presented and conclusions reported in the article.The Royal Society of Chemistry was contacted by a reader who raised concerns about the reliability of the data presented in the paper. The authors have rechecked their data and repeated experiments and have found errors with the data reported in Fig. 10, 11, 12, 15, 18 and 19, and the method of calculation of the activation energy (Table 2).The authors have provided replacement data and figures for consideration and say that the new data does not affect the conclusions of the paper. The Royal Society of Chemistry has asked the affiliated institution  to investigate this matter and establish whether the replacement figures provided by the authors provide an accurate representation of the experiments that were conducted, and confirm the integrity and reliability of the new data and figures provided. An expression of concern will continue to be associated with this manuscript until we receive information from the institution on this matter.Andrew Shore18th March 2019RSC AdvancesExecutive Editor,"}
+{"text": "Nature Communications 10.1038/s41467-019-13824-9, published online 05 February 2020Correction to: In the published version of this paper, the members of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium were listed in the Supplementary Information; however, these members should have been included in the main paper. The original Article has been corrected to include the members and affiliations of the PCAWG Consortium in the main paper; the corrections have been made to the HTML version of the Article but not the PDF version. Additional corrections to affiliations have been made to the PDF and HTML versions of the original Article for consistency of information between the PCAWG list and the main paper."}
+{"text": "In the context of sustainable ecological environment, strengthening the scientific management of cultural industry can promote the rapid development of China's cultural industry and further promote the construction of spiritual civilization in China. Starting from culture and art management, this study expounds its position in the development of cultural economy industry and its impact on the development of cultural economy. Through two different methods of culture and art management and conventional management, this paper discusses the social and economic market benefit value, the demand for the healthy development of industry, and the impact of innovative cultural industry resources on the development of cultural industry. It can be concluded that culture and art management plays a certain role in promoting the healthy development of cultural economy industry; we should constantly sum up experience in the actual process of cultural industry management, find and solve problems in time, and gradually form a set of scientific and complete cultural and art management mode, which can realize the transformation of cultural and art industry faster and better promote the sustainable development of cultural economy and industry. With the continuous improvement of the national economic level, China's cultural and economic industry has entered a period of prosperity and development. But there are also many problems, such as the instability of the industrial system. Various problems have hindered the further development of the cultural and economic industry, so we must pay attention to the role of cultural and artistic management, and let cultural and artistic management maintain and promote the healthy development of the cultural and economic industry. Culture and art management is not the product of modern society. Culture and art management has existed in the pre-Qin period of our country. However, the requirements for culture and art management are different in each era. Xialu  said thaLei  said thaThe cultural industry is an important part of China's economic industry. According to the accounting, the total added value of the national cultural and related industries in 2020 was 4494.5 billion yuan, an increase of 1.3% over the previous year, accounting for 4.43% of the gross domestic product (GDP). While it has an impact on the development of the national economy, it also plays an important guiding role in the cultural literacy of the people. In the context of sustainable ecological environment, the purpose of culture and art management is to continuously improve the innovation and development level of the cultural industry and promote the healthy and orderly development of the cultural economic industry. Xin  said thaThis paper mainly focuses on the impact of cultural and art management on the healthy development of cultural and economic industries under the background of sustainable ecological environment, hoping to provide reference value for the field of cultural and economic industries through this research and contribute to the stable and harmonious development of cultural and economic industries in our society.Culture and art management is a purposeful and all-round management behavior for culture and art activities. In short, it is to manage culture and art in all aspects, so as to achieve better artistic effects and create more profitable products for the cultural and economic industry. At the same time, cultural and artistic products have a great impact on people's spirit. Excellent cultural and artistic products can enrich people's spiritual world and improve cultural and aesthetic literacy at the same time. Therefore, strengthening the management of cultural industry is of great significance to the long-term development of cultural industry.Industrial products can attract consumers by reducing prices, but cultural products cannot. High-quality cultural products can meet people's cultural needs and have a positive impact on people. Low-quality cultural products will have a negative impact on people, leading to depression, degeneration, or violence. If the cultural market is full of too many low-quality products with distorted values, it will hinder the healthy development of the cultural economic market and harm the society. At present, the cultural and economic industry is developing rapidly. In order to earn immediate benefits, many people deliberately manufacture low-quality and eye-catching cultural products, disrupting the normal operation of the cultural and economic industry. Therefore, it is necessary to carry out scientific management of the cultural and economic industry. It can be said that culture and art management is an important productive force for the development of cultural industry and a production factor to create economic benefits. Culture and art management is not only the management of cultural activities, but also the management of cultural ideology.In culture and art management, culture and art managers play an important guiding role. Under the impact of current multiculturalism, how China's cultural and economic industry can go better, further and more in line with the core socialist values, is a problem that cultural and art managers need to think about and solve. At present, China does not pay enough attention to the management of the cultural and economic industry, and does not solve the problems existing in the cultural industry in time. At the same time, there are not enough professional cultural management talents. Some of the existing cultural managers have insufficient experience, do not correctly recognize the influence of the cultural industry, and have weak awareness of innovation and responsibility. Therefore, the development of cultural and art management in China lags behind.In the context of sustainable ecological environment, culture and art management should closely follow the pace of cultural development, and at the same time, we should clearly recognize the important position of culture and art management in the development of cultural economic industry. In the process of the development of the cultural industry, it is very likely to deviate from the normal development track. Therefore, the guiding role of management orientation is highlighted. The improvement of the comprehensive ability of managers meets the cultural needs of consumers at the spiritual level, actively carries out the pursuit of healthy spiritual culture, abandons the previous bad culture, and better implements the rectification of the social environment. The management of culture and art does not only focus on the art itself. It also includes other management elements.The upsurge of cultural consumption has stimulated consumers' enthusiasm for cultural consumption, expanded the demand of the cultural market, and improved consumers' level of cultural consumption, and consumption has stimulated economic growth, which has a positive role in promoting cultural and creation. In today's society, the cultural industry, as a country's soft power, has increasingly highlighted the economic function of culture, which affects the development of economic society in the characteristics of strong permeability and durability. Pay attention to the scientific nature of management. Its management is an important productive force in industrial development, a thrust to improve the level and create fine products in the development of cultural industry, and a production factor that produces economic benefits. The role of culture in promoting, guiding, and supporting economic development has become more and more obvious. In order to develop cultural and artistic works in art management to meet the spiritual needs of consumers, cultural and artistic management should develop in the direction of strengthening the foundation and emphasizing humanities, so as to promote the long-term development of art management.Different from other industries, the cultural industry has special spiritual and cultural social attributes. Its special attributes determine the primary position of social benefits. The cultural industry should maintain the vitality of healthy development. The cultural industry, which carries social and educational functions, meets the needs of consumers for a better life to the greatest extent, and clearly guides the sustainable and healthy development of the cultural and economic industry, so as to enhance its initiative of sustainable development.Culture and art management has a far-reaching impact on the sustainable development of culture and economy. Culture and art management is the standardized and orderly management of the actual needs of the development of China's culture and art industry. Only in this way can we increase cultural competitiveness, form a standardized operation mechanism, provide favorable conditions for promoting the development of culture and economy, strengthen management, and give play to the positive guiding influence of management. Give full play to the driving and guiding value of culture, and build a virtuous cycle of industrial development system. Cultural and economic industries can not only create higher economic benefits, but also promote the benign development of society, especially the culture with positive guiding significance.In this study, culture and art management is used for the application and in-depth excavation of cultural resources to improve its management level. Product research and development and management itself play an important role in promoting creation. Therefore, the development of scientific and feasible management measures can play an important role in getting twice the result with half the effort and creating more and more popular cultural and art works. Today, management has been characterized by profitable development. Considering the particularity of culture and art management, it is necessary to strengthen management simulation to prevent cultural distortion. It can indirectly enhance the influence of China's cultural industry and actively promote the cultural industry to go wider. As a special cultural form and special economic form, the cultural industry has affected the people's grasp of the essence of the cultural industry. Under the guidance of norms, we should strive to write a new chapter of cultural development and prosperity.Culture and art management plays a key role in the development of cultural industry. Formulate reasonable management countermeasures, push the cultural industry to a new level of development, promote a clear operation direction in the guiding trend, move in a good direction, and comprehensively improve the cultural soft power, cultural competitiveness, and cultural sustainable development ability. Now, according to the culture and art management oriented trend from 2012 to 2021, the obtained data are made into As shown in Cultural industry is an important part of China's economic development and is of great significance to China's economic development. Constantly strengthen the management of cultural products, promote the sustainable development of cultural and economic industries, and maximize the market economic benefits of cultural and artistic products while doing a good job in cultural and artistic management. Conventional management methods do not pay enough attention to the development of economic industries, which is not conducive to the development of cultural industries. Now, the effectiveness of two different management methods on the healthy development of the industry is analyzed, and the data obtained are made into In The visual analysis of the above data results is made into As shown in In order to improve the quality of cultural and art management and comprehensively improve its management effect, we need to improve the comprehensive ability of cultural managers. If we want to have a better development of cultural products, we must ensure that cultural and art management has high-quality support, strengthen cultural and art management mechanism, and promote the sustainable development and progress of cultural and art management. The research and development of cultural and art products will promote the better development of cultural and economic industry. In the process of paying attention to the development of cultural and economic industries, we must do a good job in the management of culture and art to fundamentally provide the foundation for the cultural industry. Now, we compare the needs of two different management methods for the healthy development of the industry and make the obtained data into t-test was performed on the corresponding data in pairs, and there was a test result of t < 10.000 and p < 0.05, which was statistically significant between the data.In The visual analysis of the above data results is made into As shown in The development of cultural and economic industries has been raised to a strategic height, creating an atmosphere that attaches importance to the development of cultural industries, and vigorously promoting the development of cultural industries. The management of culture and art improves the quality of cultural and artistic products while improving social and economic benefits. In the previous conventional management, the cultural market cannot perfectly adapt to the situation of cultural and artistic development, and cultural products also lack artistry. It is not in line with public aesthetics, which seriously hinders and restricts the development of the cultural industry. This study adopts the cultural and artistic management method to innovate cultural and artistic products and carries out reasonable management and subsequent arrangements for the development of the cultural industry to further promote the green and sustainable development of the industry. Now, the effects of two different management methods on the benefits of industrial sustainable development are compared, and the data obtained are made into In The visual analysis of the above data results is made into As shown in In recent years, in order to meet the needs of social development and solve the problem of the shortage of professionals in the cultural industry, China has set up a new management discipline\u2014culture and art management, which is based on literary theory and aims at the development needs of social and cultural production, and has cultivated a number of senior comprehensive talents. Culture and art management plays an important role in the healthy development of cultural economic industry. In the current context of sustainable ecological environment, we must pay attention to the cultural and economic industry with green environmental protection and high-added value. Therefore, it is essential to establish a scientific culture and art management system and establish a scientific culture and art management system. Xingyu  said tha"}
+{"text": "Modern teenagers spend most of their lives on social networks and the Internet, meeting various needs. At the same time, more detailed research is needed on how specific Internet use affects various aspects of the psychological state.The objective is to identify how the main goals of Internet use by adolescents are related to their subjective safety on the Internet and self-assessment of health.The study involved 480 participants from 15 to 18 years old. We analyzed the main reasons for respondents\u2019 use of the Internet  and uncovered the relationship between the main goals of Internet use, self-assessment of health and subjective safety on the Internet.Adolescents who identified communication  and shopping and receiving services as their main goals for using the Internet rated their health as significantly worse . Young men who use the Internet more often as a source of information feel significantly less secure on the Internet , as do those who use the Internet more often to expand communication in social networks . For girls, the goals of using the Internet and the sense of subjective security on the Internet were not significantly related.Using the Internet to communicate, buy and receive services, and search for information can negatively affect the assessment of own health and subjective safety, especially among young people. The research was supported by the Russian Science Foundation, with the grant 15-18-00109."}
+{"text": "Open access publishing facilitated by The University of Adelaide, as part of the Wiley \u2010 The University of Adelaide agreement via the Council of Australian University Librarians.No relevant disclosures.in reply:We thank Fortune and colleaguesRobust data on experiences of people with disability and their health outcomes are needed to inform and evaluate policy. The collection and public reporting of such data are obligations under the United Nations Convention on the Rights of Persons with Disabilities.We agree with Fortune et al that the National Disability Data Asset provides an opportunity to monitor inequities in health and social determinants of health for people with disability. Advances in data linkage, coupled with a consistent national disability identifier would improve understanding of the experiences of people with disability. In addition, efforts should be made to collect data that are representative of all groups of people with disability for the full range of health and wellbeing indicators. With representative data, the identifier would allow examination of intersectionality between disability, socio\u2010economic status, and gender.We echo the call by Fortune and colleagues for meaningful involvement of people with disability, representative organisations and disability advocates in decision making concerning the development of a nationally consistent disability identifier, but also in the collection of data that bridge all current data gaps for people with disability."}
+{"text": "In this study is substantiated the new mathematical model of vector of electroencephalographic signals, registered under the conditions of multiple repetitions of the mental control influences of brain\u2013computer interface operator, in the form of a vector of cyclic rhythmically connected random processes, which, due to taking into account the stochasticity and cyclicity, the variability and commonality of the rhythm of the investigated signals have a number of advantages over the known models. This new model opens the way for the study of multidimensional distribution functions; initial, central, and mixed moment functions of higher order such as for each electroencephalographic signal separately; as well as for their respective compatible probabilistic characteristics, among which the most informative characteristics can be selected. This provides an increase in accuracy in the detection (classification) of mental control influences of the brain\u2013computer interface operators. Based on the developed mathematical model, the statistical processing methods of vector of electroencephalographic signals are substantiated, which consist of statistical evaluation of its probabilistic characteristics and make it possible to conduct an effective joint statistical estimation of the probability characteristics of electroencephalographic signals. This provides the basis for coordinated integration of information from different sensors. The use of moment functions of higher order and their spectral images in the frequency domain, as informative characteristics in brain\u2013computer interface systems, are substantiated. Their significant sensitivity to the mental controlling influence of the brain\u2013computer interface operator is experimentally established. The application of Bessel\u2019s inequality to the problems of reducing the dimensions (from 500 to 20 numbers) of the vectors of informative features makes it possible to significantly reduce the computational complexity of the algorithms for the functioning of brain\u2013computer interface systems. Namely, we experimentally established that only the first 20 values of the Fourier transform of the estimation of moment functions of higher-order electroencephalographic signals are sufficient to form the vector of informative features in brain\u2013computer interface systems, because these spectral components make up at least 95% of the total energy of the corresponding statistical estimate of the moment functions of higher-order electroencephalographic signals. For more than half a century, research has been conducted in the direction of building effective, noninvasive brain\u2013computer interfaces, which are based on the registration and processing of electroencephalographic (EEG) signals, from the surface of the scalp of the brain\u2013computer interface (BCI) operator. BCI technologies have been used to solve numerous applied problems of controlling external objects in various spheres of human activity. In particular, these technologies have been effectively applied for controlling a mobile robot , automatThe effectiveness of the functioning of noninvasive BCI-systems can be assessed by the accuracy (reliability) and computational complexity of the corresponding algorithms for processing EEG signals. The higher the accuracy and the lower the computational complexity of these algorithms, the more effective they are. Despite the existence of many approaches, software and hardware tools, mathematical models, and methods for processing EEG signals in noninvasive BCI-systems, the accuracy of the detection and recognition of the class of mental control signals of the BCI operator remains low. Additionally, the computational complexity of the BCI system algorithms remains quite high, which is due to the high computational complexity of the algorithms for training the classifiers of these systems. Actually, this state of affairs is the main motive for conducting active scientific research and development of the latest BCI technologies, which is currently observed in many scientific publications on this topic.It is known that the procedure for processing EEG signals in BCI systems can be divided into five main stages see : signal Each of these main stages of the EEG signal processing procedure has its own contribution to both the accuracy and computational complexity characteristics of the functioning of BCI systems. However, the accuracy and computational complexity of the procedure for EEG signal processing in BCI systems is mainly determined by the accuracy and computational complexity of the procedures for evaluating characteristics and detecting signals (classification). In turn, the procedure for evaluating the characteristics of EEG signals, the purpose of which is to obtain the informative characteristics of the EEG signals, directly affects the accuracy and computational complexity of the functioning of the detector (classifier) of the BCI system. Overall, the more sensitive the informative characteristics of the EEG to the mental controlling influences of the BCI operator, the higher the accuracy of detection and recognition of the type of control signals in BCI systems. Conversely, the smaller the dimension of the vector of informative features, which are evaluated according to the registered EEG signals, the smaller the dimension of the optimization problems, which are the most computationally complex in the classifiers used in BCI systems.In this context, one of the possible ways to increase the accuracy and reduce the computational complexity of the algorithms in the functioning of BCI systems is the search for (selecting) the most informative (sensitive) characteristics of the EEG signals and substantiation of the minimum dimension of the vector of informative features in BCI systems. This affects the improvement in the accuracy of the functioning of neurointerface systems; additionally, due to the rejection of noninformative characteristics and features, it reduces the level of computational complexity of the algorithms used for the functioning of such systems. This problem can be solved through comprehensive research of the various characteristics (from a predetermined set) of EEG signals from the point of view of their informativeness and minimization of the dimension of the vectors of informative features determined on their basis.The studied characteristics of EEG signals and the methods of their evaluation are explicitly or implicitly based on the corresponding mathematical model of EEG signals. Namely, the effectiveness  of EEG signal processing and computer simulation of signal transformations in BCI systems depends on the quality (adequacy and constructiveness) of the mathematical model of EEG signals. One of the most important properties of a mathematical model of EEG signals is its adequacy for the temporal structure of the investigated signals and for the tasks of signals detecting (classification) in BCI systems. Another important property of the mathematical models of EEG signals is their ability to provide the researcher with the widest possible set of potential characteristics of EEG signals, among which the most informative characteristics can be selected. Based on the selected informative characteristics, a vector of the informative features with the smallest dimensions is formed, which is then fed to the input of the detector (classifier) of the BCI system see .The main goal in this study was the justification and development of a new mathematical model and methods of statistically evaluating the characteristics of EEG signals, which would enable an increase in accuracy in the detection (classification) of the mental control influences of BCI operators, reducing the computational complexity of the algorithms of BCI systems.Taking into account the essential role of the mathematical model of EEG signals as the basis for methods of their processing in ensuring high accuracy and low computational complexity of BCI system algorithms, in the next section, we provide a brief review and analysis of the literature related to the mathematical models of EEG signals and their characteristics as informative features in BCI systems.There are many mathematical models of EEG signals. Some mathematical models of EEG signals were developed not for the needs of detecting (classifying) the mental control influence of a BCI operator, but for other tasks such as medical diagnosis and research of physiological characteristics of human brain activity. Among the mathematical models are those describing the neurophysiological mechanisms of EEG signal generation, as well as those that describe the regularities of the temporal structure of EEG signals. Models that describe the temporal structure of EEG signals are often used both for medical diagnostic tasks and neurophysiological studies for EEG signals, and for describing EEG signals for the needs of developing BCI systems. From the point of view of the orientation of modeling procedures for different types of processing of EEG signals, two classes of mathematical models of EEG signals can be distinguished. The first class includes the mathematical models of EEG signals, because they are mainly used only for solving problems of preprocessing (mainly filtering) of EEG signals, and not for evaluating the characteristics of EEG signals. The second class of mathematical models includes models directly related to the tasks of evaluating the information in EEG signals.For example, the models and methods were developed for the removal of electrooculography and electromyography artifacts  and for A study  was dediWithin the framework of the deterministic approach to modeling EEG signals , methods of their harmonic analysis, as well as methods of spectral analysis in nonharmonic bases, are used. For example, a new method for the spatial harmonic analysis of EEG data using the Laplacian eigenspace of the meshed surface of electrode positions was developed . In a stIn addition to deterministic mathematical models of EEG signals, stochastic mathematical models are actively used in the form of random processes and vectors of random processes. Within the framework of the stochastic approach, fractal EEG models are used. For example, authors  used fraAmong the stochastic mathematical models of EEG signals, a stationary random process is often used in the general sense  of the EEG signal). For example, as an informative characteristic of EEG signals, researchers  used theThe Markov process was used to model and computer simulate EEG signals tp identify pathophysiological EEG changes in clinical diagnosis . In a stTo study the correlations between the EEG signals obtained from different electrodes in the context of the news vendor problem, a model of EEG signals was used in the form of a vector of stationary and stationary-connected random processes . Within In a study , the cycDespite the significant number of mathematical models of EEG signals, these mathematical models, with the exception of the cyclostationary correlated random process, do not take into account the cyclic structure of EEG signals registered under the conditions of multiple repetitions of the mental control influences of the BCI operator during the stage of classifier training. Additionally, the cyclostationary correlated random process cannot take into account moment functions of a higher order or the variability in the rhythm of the characteristics of investigated signals; it does not have formal means of displaying the relationships between the components of the vector EEG signal. The well-known methods of evaluating an ensemble of recorded EEG signal cycles do not take into account the relationships between the characteristics of different EEG signal cycles in their multicycle realization. Notably, most of the methods for evaluating the informative characteristics of EEG signals are methods for evaluating the moment functions of EEG signals within the framework of the spectral-correlation theory of random processes only, and not the theory of random processes within the framework of multidimensional distribution functions and higher-order moment functions.The disadvantages described above are possible reasons for the low accuracy of detection and classification of the controlling mental instructions of the BCI operator, which indicates the need to improve the mathematical models and methods for evaluating the informative characteristics of EEG signals in BCI systems.The objective of this study was the development of new mathematical model, methods, and software tools for statistical processing of EEG signals in BCI systems that enable comprehensive research on EEG signals for the purpose of searching for and selecting the most informative (sensitive) characteristics of the EEG signals and determining the minimum vector dimensions of the informative features in BCI systems. The results of a comparative analysis of known mathematical models and the mathematical models of EEG signals we developed in the study are summarized in Given the goal of the study, a system of requirements was formulated for the new mathematical model of EEG signals in BCI systems we developed.NN synchronously registered EEG signals were obtained in the experiments ; then, it was reasonable to assume that the general mathematical model of vector EEG is an N-dimensional vector of random processes.As a result of many uncontrollable natural and artificial factors, and considering the results of many scientific studies devoted to the modeling and analysis of EEG signals, it was appropriate to use the stochastic approach for building a mathematical EEG model. As EEG registration is carried out from M identical experiments. A series of training experiments is a series of mental acts of the BCI operator, which are manifested in changes in the temporal structure of the vector EEG and are the basis for training the software subsystem to recognize this act of mental influence of the operator on the object of manipulation, by analyzing the vector EEG. In addition, this multicycle vector EEG can be used as primary statistics to study the patterns of the training and effectiveness of BCI operators.In order to train the system for detecting (classifying) the controlling mental influence of the BCI operator on the structure of the vector EEG, we conducted a series of M time-consecutive experiments of the same type , it is reasonable to assume a certain cyclicity and repeatability of the time structure of the vector EEG, which reflects the corresponding control information in the BCI system. In the absence of such a series of sequential mental influences of the BCI operator, the cyclic structure of the vector EEG is absent. Because the expediency of the stochastic approach to the mathematical modeling of EEG signals was formulated above, such cyclic repeatability should be present in the probabilistic structure (probabilistic characteristics) of the investigated vector EEG.If, as a result of the mental action of the BCI operator, a change occurs in the temporal  structure of the vector EEG that is significant for solving detection (classification) problems; then, as a result of conducting a series of The presence of a cyclic structure in the probabilistic characteristics of the vector EEG, which reflects the electrical activity of the brain of the BCI operator in a series of consecutive identical experiments, is the basis for the development of methods and means of detecting and classifying control information in BCI systems. In view of the above, it is reasonable to demand the mathematical model of EEG signals to reflect this cyclic repeatability in probabilistic characteristics.Additionally, as each cycle of the vector EEG can be divided into zones of activity  and passivity , the mathematical model must take into account this zone structure in agreement with its cyclical structure.The presence of cyclicity in certain characteristics of the vector EEG is the basis of the possibility of solving the task of detecting the control signals of the BCI operator, because only in this case is the nonstationary structure of the EEG signals suitable for effectively distinguishing the areas that correspond to the zones of activity and passivity of the BCI operator. The cyclical nature of vector EEG characteristics is a necessary condition for successfully solving a more complex task than detecting the control signal of the BCI operator, namely, the task of recognizing the type of control signal of the BCI operator, because, before classifying the control signal, it must be detected and distinguished from the EEG stream data.The durations of zones of activity and passivity within different cycles of vector EEG, and as a consequence the duration of its different cycles in general, are different, so the mathematical model must take into account this temporal variability. As a vector EEG is an ordered set of EEG signals from different electrodes that reflect the electrical activity of different areas of the brain of the same person (operator), and the time intervals during which the operator carries out their mental act for all components of the vector EEG are the same, then it is reasonable to postulate a rhythmic connection of all components of the vector EEG.It is also important that the mathematical model of EEG signals can ensure the integration of statistical information from EEG signals obtained from different sensors; in particular, it allows conducting a joint statistical analysis of EEG signals from different brain regions of the BCI operator. In particular, in addition to the structural similarity of EEG signals and their mathematical model, an important property of such a model is its ability to describe the widest possible class of characteristics of the studied signals in order to identify those most sensitive to the effects of the BCI operator.Taking into account the above requirements for the mathematical model of EEG signals, as an adequate mathematical model of EEG signals, it is appropriate to use a vector of cyclic rhythmically connected random processes. The vector of cyclic rhythmically connected random processes is defined according to the literature .Definition\u00a01.Vector the vector of cyclic rhythmically connected random processes, if there exists such a function rhythm function if it has the following properties:Function R,n\u2208Z in  is calle(1)(2) For any (3) Function k-dimensional random vectors, if they are the same k-dimensional distribution functions.Note that stochastically equivalent in the wide sense is T-periodically connected random processes (T-periodic random vector). The rhythm function In the case where the vector ,\u03c9\u2208\u03a9,t\u2208R . In the l nature , the prol nature , and thel nature . These ml nature  and an ol nature  in onto-Because the duration of an operator\u2019s performance of the corresponding task in each experiment is different, the corresponding durations of the cycles of vector of cyclic rhythmically connected random processes are also different. This indicates the correctness of the assumption that the rhythm function of the vector of cyclic rhythmically connected random processes does not satisfy the condition k-dimensional distribution function Let us consider the properties of some probabilistic characteristics of vector If there is a compatible density distribution function of k-dimensional characteristic function Compatible The mixed initial moment function of order The mixed central moment function of order The above probabilistic characteristics of a vector of cyclic rhythmically connected random processes are informative; however, they are too computationally cumbersome. Therefore, to statistically process a vector EEG, it is appropriate to use less informative, but much more computationally simple, probabilistic characteristics, such as the vector of mathematical expectations and the matrix of correlation functions of vector mth cycle of the cyclic random process As each cycle of the vector EEG can be divided into a zone of activity  and a zone of passivity , each component mth cycle of the cyclic random process The random process Functions mth cycle of the cyclic random process The union of sets mth cycle in the time range mth training experiment Each (1)The stochasticity of the vector EEG;(2)The cyclical structure of the probabilistic characteristics of the vector EEG;(3)The compatible probabilistic characteristics of various components in the vector EEG;(4)The irregularity (variability) in the rhythm of the oscillatory process;(5)The commonality of the rhythmic structure for all components of the vector EEG;(6)The stochastic dependence between different cycles of vector EEG that occur in different operator training experiments;(7)The presence of two zones (segments) in the time structure of each EEG signal, which correspond to the activity and passivity states of the BCI operator.The application of a vector of cyclic rhythmically connected random processes as a model of interconnected EEG signals with the same rhythmic structure provides a number of important advantages; namely, the model takes into account:The actual development of a mathematical model of a vector EEG in the form of a vector of cyclic rhythmically connected random processes with two zones in the cycles enables the development of the necessary mathematical apparatus for processing vector EEGs. Namely, the methods of estimating the characteristics of vector EEGs consist of the application of methods of statistically estimating the probabilistic characteristics of the vector of cyclic rhythmically connected random processes, and the application of methods of harmonically analyzing the obtained statistical estimates.According to a study , to applConsider the simplest type of interpolation: piecewise linear interpolation. In this case, the interpolation function kth zone in the mth cycle. If The area Therefore, when piecewise-linear interpolating the rhythm function, it is necessary to find sets of coefficients These equations can be reduced to the following equations:Therefore, according to Equation , the coeAccording to the conditions imposed on the interpolation function, its Let us provide the formulas for calculating the realizations of the corresponding statistical estimations of probabilistic characteristics of vector EEGs. In case of a long realization, The realization of the statistical estimation of the mathematical expectation The realization of statistical estimation of the dispersion kth order of each component The realization of the statistical estimation of the initial moment function kth order of each component The realization of the statistical estimation of the central moment function The realization of the statistical estimation of the mixed initial moment function The realization of the statistical estimation of a mixed central moment function The realization of the statistical estimation of the mixed initial moment function The realization of the statistical estimation of the mixed central moment function The developed methods of statistical estimation of the compatible probabilistic characteristics of cyclic rhythmically connected random processes allow their joint statistical analysis within the framework of moment functions.In order to verify the developed mathematical model and methods of statistically estimating vector EEG characteristics, a number of measurement experiments were conducted. The OpenBCI platform was used to register the EEG signals. The platform used an 8-channel, 24-bit, low-noise analog-to-digital converter (ADC) ADS1299ADC to record EEG signals . The freThe OpenBCI GUI utility was used to control the EEG signal recording . The meaThe experiment essentially consisted of the continuous registration of the vector EEG of the BCI operator, who had to visualize the process of bending and extending the fingers of the palm of the right hand according to the voice commands of the experiment manager. In total, a series of 10 experiments (for 10 different BCI operators) was conducted, each of which consisted of 50 cycles of exposure to the BCI operator.According to the scheme presented in For the second stage, a bandpass filter of the 5th order was used. In this experiment, the bandwidth of the filter was 1\u201317 Hz. This allowed us to eliminate all low- and high-frequency noise. The filtered signals, which were ready for the next stages of processing, are shown in Based on the above-described methods of the statistical evaluation of the probabilistic characteristics of the vector of cyclic rhythmically connected random processes, a statistical evaluation of the mathematical expectation, dispersion, and central and initial moment functions of higher orders was carried out. For all obtained statistical estimates, the Fourier transformation was carried out.As shown in the graphs of the statistical estimates of the probability characteristics of the vector EEG in the time and spectral domain, significant differences between the zones of activity and passivity can be visually noted, which indicate the sensitivity of these probability characteristics to the mental control action of the BCI operator. The differences in the structure of the characteristics between the zones of activity and passivity are especially pronounced for the moment functions of the higher-order vector EEG components.We can also see a significant similarity in the temporal structure of the statistical estimates of the probability characteristics of all components of the vector EEG for the activity zone of the BCI operator, which indicates the commonality of the regularities in these structures for different areas of brain functioning. We also note the possibility of conducting an effective joint statistical assessment of the probability characteristics of the components of the vector EEG and the possibility of coordinated integration of information from different sensors in order to increase the accuracy of detection of the mental control action of the BCI operator.In general, the above results indicate the adequacy and ability of the developed mathematical model and methods of processing vector EEGs based on the vector of cyclic rhythmically related random processes to reflect the mental controlling action of the BCI operator in its characteristics and the possibility of conducting a high-precision procedure for its detection. However, because there are many such characteristics and there is significant similarity in their temporal and spectral structures, it is necessary to select the most informative characteristics of the vector EEG. This requires the determination of the level of sensitivity of the received characteristic estimates to the mental controlling influence of the BCI operator and selecting those with the highest level of sensitivity. The basis of this procedure is the calculation of the distance between the estimates of the same type of probabilistic characteristics or their spectra in the frequency domain, which correspond to the zones of activity and passivity of the BCI operator. As an example, the results of the calculated mean absolute distances for operators 1 and 2 are given in As can be seen from In addition to the accuracy of the functioning of BCI systems, an important component of their effectiveness is the amount of computational complexity of the algorithms in BCI systems. Reducing the computational complexity of the algorithms used for the functioning of BCI systems can be achieved by minimizing the dimensions of the vectors of informative features, which are evaluated using the registered vector EEGs. In particular, based on Bessel\u2019s inequality, we propose using the set of the first coefficients of the Fourier-series decomposition  of the obtained statistical estimates of vector EEGs as a vector of informative features. The number of the first coefficients of the decomposition in the Fourier series  was chosen in such a way that their contribution to the total energy of the statistical estimate of the moment function was at least 95%. With this approach, the dimensions of the vector of informative features were reduced from 500  to 20 .Compared with the known mathematical models of EEG signals, the new mathematical model enables the study of a much wider class of possible characteristics  of EEG signals, among which the most informative characteristics can be selected. This will increase the accuracy of the detection (classification) of mental control influences of the BCI operators, and will reduce the computational complexity of the algorithms used for the functioning of BCI systems.As can be seen from The new model has effective statistical means of studying a wide class of characteristics of EEG signals and makes it possible to consider and integrate data obtained from different areas of the BCI operator\u2019s head surface. Therefore, it was taken as the basis of the mathematical modeling of vector EEGs, because this model more fully considers the features of the spatiotemporal structure of the EEG signals registered under the conditions of multiple repetitions of the mental control influences of BCI operators in comparison with existing mathematical models. Additionally, among the advantages of the developed mathematical model of vector EEG is the existence of existing methods of computer simulation of the vector of random signals, which makes it possible to conduct computer simulation experiments for the purpose of testing and optimizing hardware and software for processing vector EEGs in BCI systems .The results of 10 series of experiments with different BCI operators indicated the significant sensitivity of the higher-order moment functions (above the second order) of EEG signals to the mental control action of the BCI operator, which is the basis for their use as informative characteristics when forming a vector of informative features for training and testing classifiers in BCI systems. This result is the basis for supplementing or even replacing the known characteristics of EEG signals, which are mainly characteristics of the first and second order , which are often used in BCI systems, providing one method of increasing the accuracy of the detection and classification of the mental control influences of BCI operators.The application of Bessel\u2019s inequality in tasks of reducing the dimensionality of the vectors of informative features makes it possible to significantly reduce the computational complexity of the algorithms used in BCI systems, provided that the required level of detection and classification accuracy is maintained. When applying such an approach to reduce the computational complexity of algorithms in BCI systems, provided that the decomposition of informative characteristics of EEG signals is used in other orthogonal non-harmonic bases, we can expect an even stronger reduction in the dimensionality of the vectors of informative features and, accordingly, a larger reduction in computational complexity.In general, the potential of the developed mathematical model of vector EEGs registered under the conditions of multiple repetitions of the mental control influences of a BCI operator in the form of a vector of cyclic rhythmically connected random processes for the task of building effective BCI systems was not fully obtained in this study. Thus, relevant research in the future should be conducted, in particular in the directions of researching, first, the statistical evaluations of mixed moment functions of vector EEGs; second, the level of stochastic relationships between different cycles of vector EEG; third, methods of computer simulation of vector EEG for the tasks of testing BCI systems and optimizing algorithms of their functioning; and, finally, the development of optimal algorithms for the detection and classification of the controlling mental influences of the BCI operator. As informative characteristics, the probabilistic characteristics of the vector of cyclic rhythmically connected random processes can be used, as shown in this paper.The results obtained in the study are the first important stage in the future comprehensive study of the characteristics of EEG signals. The next stage is conducting significantly larger experiments both in terms of the number of BCI operators and the volume of the set of investigated characteristics of EEG signals. This comprehensive study is planned to be implemented within the framework of several separate projects.A new mathematical model of vector EEGs registered under the conditions of multiple repetitions of the mental control influences of a BCI operator in the form of the vector of cyclic rhythmically connected random processes was substantiated, which, due to considering the stochasticity and cyclicity, variability, and the commonality of the rhythm of multidimensional distribution functions as well as the initial, central, and mixed moment functions of the investigated signals, has a number of advantages over the prior models. As the mathematical model of the vector EEG in the form of vector of cyclic rhythmically connected random processes integrally describes not only the signal from one local area of the surface of the human head, but also their synchronously registered aggregate, taking into account their common rhythmic structure, on the basis of this model, it is possible to carry out a compatible statistical analysis of signals. This makes it possible to consider and integrate data obtained from different areas of the surface of the BCI operator\u2019s head in order to increase the accuracy of the detection of the mental control action of the BCI operator.The methods of statistical processing of vector EEGs registered under the conditions of multiple repetitions of the mental control influences of BCI operators were substantiated, which consisted of the statistical evaluation of its probabilistic characteristics. In contrast to the known methods of statistical processing of EEGs, which are based on the statistical averaging of an ensemble of EEG realizations, the developed methods enable the estimation of the stochastic dependence between the different cycles of vector EEGs, which correspond to different experiments in a single series, which contributes to increasing the accuracy of the functioning of BCI systems. The obtained results indicated the adequacy and ability of the developed mathematical model and methods for vector EEG processing based on the vector of cyclic rhythmically related random processes to reflect the mental controlling actions of the BCI operator in its characteristics and the possibility of conducting a high-precision procedure for their detection.The use of higher-order moment functions (above the second order) and their spectral images in the frequency domain as informative characteristics in BCI systems was substantiated. Their significant sensitivity to the mental controlling influence of the BCI operator was experimentally established.In order to reduce the computational complexity of the functioning algorithms of BCI systems, the dimensions of the vectors of informative features was minimized. Namely, it was presented in the form of a set of the first coefficients of the Fourier-series decomposition  of the obtained statistical estimates of the vector EEG components. It was experimentally established that only the first 20 values of the Fourier transform of the moment function estimation of the vector EEG component were needed to form the vector of informative features in the BCI system, because, in total, these spectral components made up at least 95% of the total energy of the corresponding statistical estimate of the moment function of the vector EEG components."}
+{"text": "The COVID-19 epidemic is an unexpected global event that has shaken up the organisation of care in France. The spread of the epidemic was limited thanks to the confinement of people from Tuesday 17 March 2020 to Monday 11 May 2020. However, this confinement led to a change in the care of vulnerable people, including people suffering from neurocognitive disorders (NCDs). The aim of this study is to question people suffering from NCDs and their family carers about their experiences during the period of confinement introduced in connection with the COVID-19 epidemic and on any physical and/or functional consequences.All persons whose memory consultations at CMRR Limoges were cancelled during the period of confinement (17 March to 11 May 2020) were contacted by telephone by the nurses or psychologists at CMRR.The experience of the confinement episode as well as the deconfinement are studied. The survey records the clinical changes in patients and the medical/medical-social events that occurred during this period. The impact of the aids maintained and the place where people live is studied.Confinement is an exceptional measure that makes it possible to reduce the risk of contagion in the event of an epidemic, at the risk of harmful consequences for people weakened by a NCDs. In the event of an epidemic episode in the future, this study could help to define the arrangements to be put in place to better protect people suffering from NCDs and their family caregivers.No significant relationships."}
+{"text": "The fact of emergence of a child with special needs in a family is followed by intensive emotional reaction of the parents. One of the pronounced feelings in those circumstances is the sense of guilt.The research aim is studying the emotional experience of mothers of children with special needs connected with the sense of guilt and the characteristics of the parent-child relationship in such families.The research sample includes 25 mothers of children with special needs in the age from 3 to 10 years old with the diagnosis ASD, cerebral palsy and epilepsy as well as 29 mothers of normally developing children of the same age. Research methods: Guilt Inventory (Jones &Kugler); Inventory of Parental Attitude (Varga &Stolin); Inventory of the Parent\u2019s Psychological Type(Tkacheva).The mothers of children with special needs show the more pronounced sense of guilt comparing with the mothers of the healthy children. They are less optimistic towards the future of the child, more sensible to the failures of the child, but demonstrate the higher degree of readiness to cooperation with the child. Those results can be applied when designing the intervention programs for the families of children with special needs.Those results can be applied when designing the intervention programs for the families of children with special needs.No significant relationships."}
+{"text": "The paper presents the results of one international study due by our team in the period of restrictions imposed by Covid-19, between March and June 2020.To inform the population about the risks concerning the excessiv use of internet To prevent the effects of those behaviors which affects the global functioning of individualsQuestionnaire applied to a number of 549 subjects, 18 to 60 years old, 217 from Romania and 332 from other European and Asian countriesThe results allowed us to verify the assumption that there is a change in communications needs of individuals, as well gender and age differences in terms of time spent on the internet during the covid period.The issue of psycho-education regarding the awareness of dangers and the traps of the virtual era remain relevant."}
+{"text": "In 2019, the Portuguese government established the autonomy of local authorities and the decentralisation of public administration. Consequently, a process that includes the transfer of health competencies from the central government to the municipalities began. The newly acquired competencies enable local governments to play a crucial role in defining health policies and strategic partnerships with special focus on disease prevention, promotion of healthy lifestyles and active ageing. That said, several municipalities established a collaboration protocol with the National School of Public Health (NSPH) for the development of the Health and Quality of Life Development Plan (HQLDP) as a contribution to their strategic planning.NSPH has developed a solidified methodology for municipalities to substantiate their health planning and priorities, based on a deep health diagnosis, from existing demographic, economical, health and environmental data in a given timeline. HQLDP is a medium-term reference that will support strategic action in the area of health and social determinants. The general objective of the HQLDP is to contribute to the improvement of the health status, in the different stages of the life cycle, based on the evaluation of the health profile and social determinants and to define a set of strategic objectives that promote the reduction of inequalities, the promotion and protection of health and the prevention of disease. The developed plan also includes public and stakeholders\u2019 scrutiny, to define key areas of action in the health sector.The HQLDP takes into account the vocation of local authorities to act on determinants through policies that intervene in the environmental, socio-economic, educational, urban planning and mobility contexts; assuming an active, influential and local role in health policies. Municipal intervention requires a strong and concerted local action and the definition of territorialized development strategies.\u2022\u2002HQLDP has a crucial role on the situational diagnosis and set of priorities of the quality of life and health indicators to assess the priorities at council level.\u2022\u2002HQLDP provides the knowledge for the development of public policies and interventions that comply with the population characteristics by reducing health inequalities and inequities."}
+{"text": "Han painting is an important art display form in Chinese history; it has a history of hundreds of years. It is the embodiment of a higher level of Chinese painting. Han paintings can also show the development of China's political economy and culture. However, with the continuous progress of time, the patterns of Han paintings and the color characteristics of Han paintings will be greatly damaged. This limits people's research on the civilization displayed by Han paintings. At the same time, changes in the environment also have a great relationship with the integrity of Chinese painting. Therefore, the study of the impact of environmental protection on the integrity of Han paintings is crucial to the study of Chinese civilization. It is difficult for traditional research methods to discover the quantitative relationship between environmental protection and the integrity of Han paintings. In this study, the atrous convolutional neural network (ACNN) in the artificial intelligence method and the GRU method were used to explore the relationship between environmental protection and the patterns, colors, and shapes of Chinese paintings. The research results show that the ACNN method and the GRU method can better predict the patterns, shapes, and color characteristics of Chinese paintings. Through research, it can also be found that the color and pattern features of Chinese paintings contain obvious time characteristics, which requires the GRU method for feature extraction. The prediction errors of ACNN and GRU in predicting the integrity of Chinese paintings are all within 2.5%, and the largest prediction error is only 2.45%. Han painting is an important intangible cultural heritage of China. Han painting is an artistic heritage with more than 400 years of history. Han painting can not only express the development of contemporary economy and politics but also reflect the development of Chinese history , 2. ThisSince Han painting plays an important role in the inheritance of Chinese history and culture, the destruction of the environment also has a greater impact on the integrity of the Han painting. This requires an analysis of the impact of environmental protection on the integrity of Han paintings. The patterns, shapes, and colors of Han paintings are important characteristics of Han paintings, and contemporary people also use these three important characteristics to display the history and culture of that time. Therefore, it is necessary to protect the patterns, shapes, and color characteristics of Han paintings. The patterns of Chinese paintings can intuitively reflect the contemporary lifestyle and daily necessities. The colors of Han paintings can reflect the artistic preferences and artistic characteristics of a dynasty. Modeling is also an important feature of painting that reflects different eras. Therefore, this study mainly analyzes the influence of environmental protection on the patterns, shapes, and colors of Chinese paintings , 10. HowArtificial intelligence methods have made great progress in the twenty-first century, mainly thanks to the development of computer technology and high-performance graphics technology , 12. GraThis research will solve the problem of the difficulty in dealing with the relationship between environmental protection and the integrity of Chinese painting by artificial means, and it will use artificial intelligence to deal with the complex relationship between environmental protection and the integrity of Chinese painting. This research mainly studies the three characteristics of the pattern of Han painting, the shape of Han painting, and the color of the Han painting. These three characteristics are also the most important three characteristics for the integrity of the Han painting. This study has five sections to introduce the application of artificial intelligence in the study of Han painting integrity. Han painting is an important cultural art in China, which has been passed down for more than 400\u2009years. It contains many historical, cultural, political, and economic historical flavors of China. The protection of Han painting culture is an important task. The protection of the environment also has an important influence on the protection of Han paintings. Due to the history of Han painting and its importance to China, many researchers have done a lot of research on Chinese history painting. Liu and Zhang  believedChinese painting mainly includes the characteristics of patterns, colors, and shapes. These features are a macroscopic visual manifestation. If the relationship between these visual modes is handled manually, it is easy to cause a certain degree of subjectivity. This will also lead to a certain error rate for the relationship between environmental protection and the integrity of Chinese painting. The patterns of Han paintings, the colors of Han paintings, and the shapes of Han paintings will be converted into the form of data through certain data processing methods. Once the characteristics of the research subjects are transformed into the form of data, they can be subjected to relevant quantitative analysis. Artificial intelligence methods can quantitatively analyze the relationship between data and data . This reThis study mainly analyzes the relationship between environmental protection and the integrity of Han paintings, and it also conducts a quantitative analysis through artificial intelligence methods. At the same time, it selects the ACNN and GRU methods in the artificial intelligence method to extract the temporal and spatial characteristics of Chinese painting patterns, Chinese painting shapes, and Chinese painting colors. Han painting has experienced hundreds of years of development, and there will be large gaps in the patterns and color characteristics of Han painting for different time periods. This requires the GRU method to study the relationship between the integrity of Chinese painting and environmental protection. The ACNN method is mainly to establish the relationship between environmental protection and three characteristics of Chinese painting. Convolutional Neural Network (CNN) is the most commonly used feature extraction algorithm, and it is also a relatively mature algorithm. Therefore, many projects will directly use this mature and stable CNN algorithm. However, for the research object with more parameter operations, the CNN method will have higher requirements on the graphics card and the memory of the computer. However, CNN can reduce the number of parameters compared to a fully connected neural network. However, CNN still has more parameters. In order to further reduce the amount of parameter calculation in the operation process, this study adopts a CNN variant neural network ACNN technology. The LSTM method is also a basic temporal feature extraction method. Compared with the CNN method, LSTM has more parameters, and it requires more computation time. The study of environmental protection and the integrity of Chinese painting also require the extraction of temporal features. However, the patterns of Chinese paintings and the color features of Chinese paintings contain a huge amount of data, and if it adopts the LSTM method, it will consume more graphics card resources. In actual engineering, excessive graphics card consumption is more difficult. Therefore, in order to reduce the time consumption and the consumption of computing resources, this research adopts the variant neural network GRU technology of the LSTM neural network. GRU has only two gate structures, which is one of the factors that can reduce the number of parameters. It only specifically updates gate and resets two gate structures. Equations  and 2)  2) show Equations  and 4)  4) show For ACNN, most of the matrix calculation methods have similarities with CNN. Most matrix calculations will also follow the calculation guidelines of CNN. Equation  shows a Equation  introducEquation  also shoEquation  shows a The difference between ACNN and CNN lies in the calculation method of hyperparameters. The factor hyperparameter and the factor of the hidden layer differ from CNN. Equations \u201311) sho sho11) sThis research mainly uses the ACNN and GRU methods to study the relationship between environmental protection and the patterns of Chinese paintings, as well as the colors and shapes of Chinese paintings. It will establish the relationship between environmental protection and the integrity of Han paintings, which will be beneficial to the implementation of the relevant protection of the integrity of Han paintings at the level of environmental protection. The learning and feature extraction of ACNN and GRU methods will require a large number of datasets, which is the research basis of neural network methods. If the dataset of environmental protection-related factors and the three characteristics of Han painting integrity is more accurate, it will establish a more accurate relationship. Therefore, this study collected a large number of relevant data on Han paintings in Chinese history. This will ensure the accuracy of the dataset. At the same time, these data will be subjected to the data preprocessing process because the datasets of the three characteristic data of environmental protection and Chinese painting have many differences and are missing in the process of data collection.In order to quantitatively analyze the relationship between environmental protection and the three characteristics of Chinese painting, it adopts some statistical parameters to analyze the accuracy of ACNN and GRU methods for the study of the integrity of Chinese painting. First, it will use a single ACNN method to explore the accuracy of quantitative analysis of the integrity of Chinese paintings. This type of research will also explore temporal correlations in the research process of Han painting integrity. In order to further reduce the error of the artificial intelligence method in predicting the three characteristics of environmental protection and Chinese painting, this study also takes the GRU method into account. In order to more accurately analyze the accuracy of ACNN and GRU in predicting the three characteristics of Chinese paintings, it separately analyzes the prediction errors of the patterns, shapes, and colors of the Chinese paintings. Each feature was analyzed using 25 different test sets. Color characteristics are also an important part of the integrity of Chinese painting. Color is also very susceptible to environmental damage. Therefore, if the accurate relationship between the color characteristics of Chinese painting and environmental protection can be established, it will help researchers to accurately realize the protection of the integrity of the color characteristics of Chinese painting. From the previous description and analysis, it can be seen that the pattern features of Chinese paintings have relatively large errors compared with the color and shape characteristics of Chinese paintings. In this study, the prediction accuracy of Chinese painting pattern features was demonstrated by means of linear correlation coefficients. The development of Han painting has a history of many years, and it also records the progress and changes in the economic and political aspects of Chinese culture. Han painting is also a kind of Chinese culture and art. From ancient times to the present, Han painting can be said to be the essence of Chinese painting. Therefore, the research and protection of Han painting are crucial. The environment will also affect the protection of Han paintings because the destruction of the environment will bring many harmful substances to the protection of Han paintings. Han painting is a kind of art with a huge amount of data on patterns, colors, and modeling features. It is complicated to establish the relationship between environmental protection and the integrity of Han painting by traditional methods. It is also difficult to achieve a quantitative analysis between environmental protection and the integrity of Han paintings.This study uses ACNN and GRU methods in artificial intelligence methods to study the accuracy of pattern features, color features, and modeling features of the integrity of Chinese painting. GRU is used to extract the temporal correlation of the completeness features of Chinese paintings. First, this study analyzes the accuracy of a single ACNN in predicting the completeness features of Chinese paintings. The largest prediction error is 3.12%. The smallest prediction error is also 2.61%. Although this part of the error can be used by researchers, the error value of this part is also relatively large. This is not good for establishing the relationship between environmental protection and the integrity of the Han painting. The prediction errors of the three features of Chinese painting integrity were significantly reduced after using the GRU method. This shows that the ACNN-GRU hybrid method is more suitable for establishing the quantitative relationship between the three characteristics of environmental protection and the integrity of Chinese painting. This research has great application value for guiding the relationship between environmental protection and Han painting conservation."}
+{"text": "The traditional teaching mode is to use a point-to-point mode or a computer-aided system for teaching, but this limits students' enthusiasm and interest in learning. The Internet of Things (IoT) technology is a technology that integrates sensors, the Internet, and terminals to transmit information in real time. The smart education based on the Internet of Things can realize remote teaching and actual scene teaching, and students can freely choose the learning location and time, which can greatly improve students learning interest and learning efficiency, which is a development trend of a new teaching method. Smart IoT teaching is a teaching method that combines IoT technology and artificial intelligence technology. This paper mainly studies the research and analysis of the smart education model based on the IoT in remote teaching. In this paper, sensor technologies such as cameras will be used to collect students' expressions, speech, and other actions in class from different regions. These data features will be processed by the terminal's intelligent algorithm, and the desired knowledge will be obtained according to the students' behavior information. The information processed by the intelligent algorithm will be transmitted to the terminal system where the teacher is located, such as computer and mobile phone. This paper focuses on analyzing the reliability and accuracy of the intelligent algorithm of the IoT smart education terminal. The results show that the prediction error of the student behavior information is within 3% and the correlation coefficient reaches 0.99. The traditional teaching mode is often a point-to-point teaching mode, in which teachers transmit knowledge to students in one way through textbooks. In recent years, the development of computer-aided systems has also promoted the change of teaching mode . It can The Internet of Things technology is the product of the third scientific and technological revolution of information technology . It connThe education model has gone through the stages of point-to-point teaching, computer-aided system teaching, and so on. In recent years, many studies have been carried out on education methods based on artificial intelligence methods or Internet of Things technology. Zhang et al.  believedFrom the above literature, it can be seen that the current research on smart education mainly adopts artificial intelligence methods or Internet of Things technology to realize smart education systems, such as the image detection function of deep learning or the role of sensors and cloud computing of Internet of Things technology \u201326. HoweThe research on the integration of the Internet of Things and smart teaching methods will be introduced in five parts. The first part mainly introduces the development status of the Internet of Things and the development status of smart education. The second part mainly introduces the necessity of the integration of IoT and smart education and the data processing scheme. The third part mainly introduces the design of the IoT smart education system and the required algorithms. The fourth part is to study the accuracy of the realization of smart education algorithm. The fifth part is the summary of the paper, which mainly analyzes the current shortcomings of smart education and the advantages and accuracy of the IoT smart model proposed in this paper.The traditional education method and the education method of the computer-aided system will limit the scope of knowledge received by students and their interest in learning knowledge . At the This research will collect classroom behavior information and speech information of students in multiple regions through the multisensor technology of the Internet of Things system as the data source for data mining of intelligent terminals. Students' interest in knowledge and their ability to accept knowledge can be reflected through classroom behaviors, which mainly include students' expressions, actions, and speech. There is a strong correlation between these actions and the teaching content. If the deep learning algorithm can extract the behavioral characteristics of students and then establish the mapping relationship with the teaching content, it will greatly improve the students' learning interest and learning efficiency. The problem of unbalanced geographical educational resources is mainly due to the close relationship between teachers' teaching methods, and the students' behavior information is also closely related to teachers' teaching methods. This can also suggest a special relationship through the nonlinear mapping capabilities of deep learning. Therefore, the sensor of the student terminal will collect the students' speech and behavior characteristics as the input data of the smart education algorithm, and the sensor of the teacher terminal will collect the teacher's behavior information and teaching content as the output of the intelligent education algorithm. A nonlinear mapping relationship is established between input and output. Ultimately, this intelligent algorithm will realize a smart teaching system for remote teaching under the combination of Internet of Things technology and deep learning technology. These data sources are collected by the sensors of the Internet of Things, which are processed by the intelligent algorithms of the terminal system of the IoT. In this paper, the student behavior information and teacher behavior information extracted by the Internet of Things multisensor system are used as the dataset, and the dataset will be divided into training set, test set, and verification set. The dataset selected in this paper is mainly derived from the multisensor system of the Internet of Things technology, which mainly includes student behavior information, speech information from the student terminal, teacher behavior information from the teacher terminal, and courseware content.The IoT smart education system is mainly composed of IoT hardware devices and intelligent algorithms. The main purpose of the Internet of Things hardware equipment is to realize the functions of information collection, transmission, and output of students in remote classrooms. The purpose of intelligent algorithms is mainly to extract features and map correlations for the information collected by IoT hardware devices. The sensors of the IoT system mainly include cameras and recording devices. The purpose of the cameras is to collect the behavior information of students and teachers and the content of courseware. The main purpose of the recording devices is to collect the speech information of students and teachers. The transmission technology adopted by the Internet of Things technology in this paper will be transmitted in the form of a wireless network. The terminal system may take the form of a cell phone or a computer system. The Internet of Things technology used in this study will use multiple cameras and multiple recording devices to collect data from students' classroom information in different places. These data need to be sent to the computer-aided system of the teacher's terminal through data fusion. Data fusion is the need to organize these information data features and transmit them through Internet technology with a unified feature. Data fusion technology refers to the information processing technology that uses the computer system to automatically analyze and synthesize the chronologically acquired image or audio data within certain criteria to complete decision-making and evaluation tasks. The Internet of Things technology will collect image and auditory data through a multisensor system, and these data will be fused into the computer processing system of the Internet of Things terminal so as to be transmitted to the teacher terminal auxiliary system through the Internet.There are many ways of data fusion algorithm, such as Kalman filter or DS theory. In this paper, DS theory is used to perform data fusion on the multisensor information data of the Internet of Things. Data fusion technology is a process of collecting, transmitting, and synthesizing useful information from various information sources to assist people in planning, verifying, and determining information. This data-fused student behavior information will be input into an intelligent decision-making system. A represents the behavior information, speech information, or facial expression information of the student terminal collected by the sensor. m represents the probability of finding these datasets.DS theory is a complete theory for dealing with uncertainty. In this paper, DS theory will be used to perform data fusion on IoT multisensor data sources. It will give the comprehensive probability of each hypothesis according to the occurrence probability of different data sources and then perform data fusion on the data sources of different sensors. Equation  illustraThe sum of the probabilities for all subsets of IoT assumptions about sensor data sources is called the belief function, and equation  shows thThe sum of the probabilities that the intersection of various hypotheses about IoT multisensor data sources is not an empty set is called the likelihood function, and equation  shows thDS theory is also known as evidence synthesis method, and equation  shows thK; that is, the sum of the products of the two assumptions after the mass function operation is divided by the normalization coefficient K.Equation  shows thK as the normalization processing coefficient, which is different from the definition of equation   9) show W is the weights, and b is the dataset matrix. u and v are the different dataset features.The process of matrix operations and backpropagation of biases and weights involves many differential derivation operations, which are the most basic operations of neural networks. Equation  shows thThe feature extraction of students' speech information in this study uses a recurrent neural network, which requires partial memory of historical state information. Equations  and 12)12) show This paper uses cameras and recording equipment to collect information from students' classrooms. It can be found that the data collected by the Internet of Things technology cannot be used by the intelligent decision-making algorithm of intelligent education, which requires preprocessing of the information collected by the Internet of Things technology. The information collected by the Internet of Things technology includes images and auditory information. Both the dimensional form of the data and the distribution of the data are inconsistent, which is unfavorable for the optimization in the intelligent decision-making stage. First, this study matrixed the images collected by IoT sensors and processed these data into data that conformed to a normal distribution and were within an interval. Then, the auditory information is also matrixed to make it consistent with the distribution and interval of the image information. This research will use the TensorFlow platform and the Keras pattern library for model training, and the weights and biases after training will be saved in h5 format.The IoT smart education system is mainly composed of IoT hardware devices and intelligent decision-making parts. IoT hardware devices are mainly used to complete information adoption and interface display of terminal devices. The combination of artificial intelligence and Internet of Things technology is the key to the realization of smart education. This paper mainly analyzes the accuracy and feasibility of intelligent algorithms in the decision-making stage of smart education. According to the process of the IoT intelligent education system designed in this paper, it can be known that the student behavior information collected by the IoT will be input into the intelligent decision-making algorithm system. In this study, the box distribution map and the columnar prediction distribution map were selected as the analysis of statistical parameters. The Internet of Things technology is a way to interconnect application objects through technologies such as multisensor systems and the Internet. It has been successfully applied in the fields of transportation, medical care, and agriculture. The traditional education model has defects such as low student efficiency and slow updating of educational knowledge. IoT smart education is a new type of education model, which can improve students' enthusiasm and interaction. The organic integration of artificial intelligence technology and the Internet of Things can more efficiently improve the intelligence of educational classrooms and the openness of knowledge, thereby solving the problem of unbalanced education.The behavior information of students and teachers in remote education was selected as the research object, and it adopted the multisensor equipment of IoT, the Internet, and the terminal equipment of the computer-aided system to form the Internet of Things system. In the intelligent processing stage, the neural network method is used to extract the characteristics and time characteristics of the student behavior information and output it on the student or teacher terminal. From the information data collected by the Internet of Things, the distribution of students' speech, student behavior information, and teachers' behavior information collected by it is relatively uniform, which is conducive to the optimization process of intelligent decision-making algorithms. From the perspective of the intelligent decision-making stage of intelligent education, intelligent algorithms are more suitable for predicting student behavior information. The largest prediction error is only 2.92%, and the smallest error even reaches 0.91%. From the distribution of student behavior information, whether it is the distribution of data value or student behavior information data is consistent with the information collected by the Internet of Things."}
+{"text": "Political and ideological online teaching is a new thing integrating political and ideological theory teaching and artificial intelligence information technology. In order to effectively improve the quality of political and ideological online teaching, this paper aims to make an in-depth study on the application of artificial intelligence technology in the political and ideological online classroom system under the background of big data. This paper first expounds the overall architecture of the political and ideological online system from the system hardware architecture and software architecture and then discusses in detail the functional design of the online system and the structure of the database. This paper proposes a data mining algorithm based on scale affine transformation and curriculum data information space reconstruction, constructs the data structure model of the political and ideological online classroom system, uses scale affine transformation to fuse the curriculum data, carries out spatial reconstruction of the fused curriculum data, extracts the high-order features of the curriculum data in the political and ideological online classroom system in the reconstructed space, and completes the data mining of political and ideological courses. Experiments show that the political and ideological online classroom system under the proposed method is better than the political and ideological online classroom system under the traditional method in terms of user satisfaction and teacher operation proficiency and can effectively improve the quality of political and ideological online teaching. Artificial intelligence (AI) is assumed as an interesting idea and a successful plan for the future lifestyle as it highly likely that most of the activities in those days will be carried out through the effective utilization of smart and intelligent robots. These robots may be equipped with sensors and actuator, where the former is used to interact directly with the phenomenon for which it is deployed to collect reading or data simultaneously. These sensors or devices are programmed such that it has the capabilities of automatically interacting and collecting data values after a defined time frame. Once the information is collected then it is processed inside the device by the concerned processing device to remove (if any) the noisy data value and then forward to the respective destination. For every activity, these intelligent robots are programmed such that when an abnormal condition, i.e., either the data value collect exceeds a particular threshold value or a slight decrease is measured, is encountered then actuator modules, which is embedded in an every device along with the sensors, takes the appropriate action which seems to be fit for that particular scenarios. As intelligence of these devices has a direct corelation with the smartness or intelligence of human beings, especially those who are going to program it, therefore, it is very important that these devices would mimic humans in performing various tasks, especially in the absence of human beings. These techniques are becoming more sophisticated and intelligent in terms of the decision when the concept of big data has been introduced and utilized in various domains.In the context of big data, the independent learning of online courses and the coexistence of classroom special teaching and practical teaching inside and outside the class, the Trinity hybrid teaching mode has become the norm, and the effect of political and ideological teaching has been significantly improved. However, due to the weakening and marginalization of the discourse power of ideology, there are still difficulties in enhancing the construction and use of the political and ideological online curriculum system. For this reason, this paper makes considerable analysis and summary of the design ideas and the gap between the ideal and reality of the political and ideological online course system, and it puts forward perfect countermeasures. It is expected to effectively improve the quality of the political and ideological online classroom system, so that young students can share the high-quality resources of political and ideological education in the process of growth, achieve their all-round development in a diversified path, and highlight the significance of students' learning by using network resources.According to the relevant national documents, combined with the ideological, political and theoretical characteristics, and talent training objectives, the online classroom teaching of political and ideological education needs to follow the curriculum design concept with students as the core, focus on the characteristics of political and ideological education on the basis of the unity of theoretical teaching and practical teaching, and adopt diversified online teaching methods and means to promote students from passive learning to active learning, improve the pertinence and timeliness of political and ideological online teaching, and enhance the absorption and appeal of the political and ideological online classroom, so as to improve students' learning enthusiasm and efficiency.The innovations of this paper are as follows: (1) firstly, this paper expounds the system hardware architecture and software architecture, discusses in detail the functional design of the online system and the structure of the database, and puts forward a data mining algorithm based on scale affine transformation and curriculum data information space reconstruction to mine the political and ideological curriculum data. (2) Experiments show that the performance of the political and ideological online classroom system under the proposed method is better than that under other methods, and can effectively improve the quality of political and ideological online teaching.The rest of the manuscript is as we have arranged it accordingly using a brief definition of various sections and subsections.The most related or linked works to the problem at hand are reported with emphasis on whether these approaches are effective, i.e., in which scenarios, and have problems if these are applied to another domain for which it is assumed as one of the possible solution. The political and ideological online classroom system and its applicability in real world scenarios is reported along with sufficient detail information in section three of the manuscript. Research (preferably existing and related) on the political and online ideological classroom system based on artificial intelligence and information technology is reported in section four of the manuscript which is followed by analysis of the results, which were observed during the experimental setup, along with the textual explanation. Finally, a summary of the existing work along with a brief problem statement is presented in the last section of the paper.In recent years, China has paid more and more attention to network teaching, gradually attached importance to the research of the information-based political and ideological online classroom system, and achieved some results at the same time. Liu  with theThe topology of the political and ideological online classroom system server is shown in The network architecture system in The system integration architecture of the political and ideological online classroom is mainly divided into UI layer, service layer, and persistence layer, which is shown in The functional module of the political and ideological course slide is shown in The main function of political and ideological course video management is to configure and manage the video information of political and ideological course in teaching. The functions of political and ideological course video management include creating the political and ideological course video, deleting the political and ideological course video, and modifying the political and ideological course video. Through the role module setting, only political and ideological teachers in the role module can maintain course video information, and other users can only query the political and ideological course video.In the process of learning political and ideological education, students can send questions to the political and ideological education teacher after the class, and the teacher will reply after seeing the questions. This can not only improve the teaching quality, but also facilitate the communication efficiency. It is a very important function in the online classroom teaching system.The primary goal of political and ideological classroom test question management is to look at certain chapters of political and ideological education. The report of course test questions, the compilation of course test questions, and the alteration of course test questions are all functions of political and ideological course test question management. Only political and ideological teachers may maintain course video information using role module configuration, while students can only query the political and ideological course test questions , 14.The political and ideological online classroom system in this paper has high requirements for database security, and the amount of data in the design is relatively large, which also has requirements for the size of the database. Therefore, a large database with a high level is adopted, and an SQL server is used as the platform of the system database. Tables Combined with the above political and ideological online classroom system, the data mining algorithm based on scale affine transformation and data flow spatial reconstruction is used to study the political and ideological online classroom system.In the political and ideological online classroom system, we perform adaptive learning on the attribute weight of the data storage model, and we build the particular data distribution vector field of the political and ideological course database in the multilayer vector regression feature space. Local outliers will produce a cross-course data set in the political and ideological online classroom system. We use formula  to constwu,v represent the weights between network nodes u and v in the political and ideological online classroom system, and |S| represents the cross points of the course data characteristics in the undirected graph S.In formula , wu,v rek political and ideological online classroom systems evenly distributed in the data edge subband asFormula  is used According to the distribution probability of the specific data of the political and ideological online classroom system, the scale affine transformation is carried out on the course data with large distribution probability, and the political and ideological course information fusion model of data mining with a limited signal-to-noise ratio is constructed, which is expressed asU represents the Fourier transform of the time domain part of the specific course data in the political and ideological online classroom system, and the factor In formula , Urealized , 18.\u03b2 and the penalty factor C of the curriculum data fusion in the political and ideological online classroom system, the mean square deviation function of gain adjustment of curriculum data is established by formula  through the following formula:In formula , \u03c4 reprex(t) represents the decomposition result of the original course data, t0 represents the time point of the initial sampling of the data, Wy represents the observed vector, v0 represents the specific data density of course, and v represents the interference intensity of the data in the online classroom system. The matrix X(i) of the course data information fusion in the political and ideological online classroom system is divided into p(i) spatial matrix Xij. The matrix Xij in the j subspace is reconstructed in high-dimensional space by formula  re formula , and theAfter singular value decomposition, the higher-order features of curriculum data in the political and ideological online curriculum system are extracted from the curriculum data reconstruction space through formula  and exprAmong them, the high-order features of course data in the political and ideological online classroom system can reflect the characteristics of course data to a certain extent. By positioning the high-order features, the course data mining in the political and ideological online classroom system can be realized , 20.In order to effectively verify the performance of the political and ideological online classroom system based on artificial intelligence information technology under big data, experimental verification is carried out. As can be seen from the data in By analyzing the data in Through the analysis of The analysis of The application of the political and ideological online classroom system accumulates experience for the improvement of teaching quality of political and ideological education. Although the political and ideological online classroom system still has some deficiencies in the practice of online teaching, it can effectively promote the reform of political and ideological courses in colleges and universities and the application and development of mixed mode teaching. The political and ideological theory online teaching system is a relatively huge project. The teaching management department must work together with the student work department and the society to strengthen the interaction between teaching and learning and improve the political and ideological online classroom system, effectively grasp the dynamics of students' learning. As proved from the observation of the results in terms various metrics, the proposed scheme is an effective solution to resolve the problem at hand, especially with the available resources and infrastructures."}
+{"text": "Conflict of Interest statement was incorrectly filed. The correct Conflict of Interest statement appears below.In the published article, the The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "All the authors agree to the publication of this corrigendum, and apologize to the readership for any inconvenience caused.The authors have re-examined their original data, and have realized that this figure was inadvertently assembled incorrectly owing to the similarity of the data shown in the two affected panels. The revised version of"}
+{"text": "The aim of the study is the tribological analysis of the crane drum brakes. A theoretical analysis of the wear processes for brake lining was performed and the coefficient of friction under tribological conditions was determined experimentally simulating the operating conditions for three types of brakes. The theoretical study of the wear was oriented towards of determining the lifetime of the brake lining. In the experimental determination of the coefficient of friction, the following parameters were taken into account: the contact pressure between the shoe and the drum; the initial speed of the brake drum; the humidity of the working environment; and the temperature of the drum-brake lining friction surfaces. After performing the experiments, a statistical analysis was conducted, that shows the amount the coefficient of friction is influenced by the previously mentioned parameters: the highest weight was humidity with a value of 35.58%, followed by temperature with a percentage of 23.95%, velocity with 4.54%, and lastly pressure with 4.19%. Furthermore, the equation that expresses the dependence between the coefficient of friction and the parameters is determined. We consider that the results obtained are important for brake manufacturers in order to improve braking efficiency and the safety of overhead cranes. Overhead cranes are equipped with various types of brakes, which operate in different conditions. For this reason, a detailed analysis is needed regarding the kinematics of motion, the evolution of motion over time, the characteristics of the tribological stresses and the environmental conditions  for different cases.The drum of the brakes of overhead cranes is made from steel or cast iron and the brake lining of the shoe is made from composite materials . The matThe main features required of the brake lining are: high coefficient of friction between itself and the brake drum, wear resistance, tensile strength, good characteristics on cooling, stable friction levels ,4,5. MecThe set of conditions straining the pair of drum-brake lining, viewed from a tribological point of view, leads to wear. Wear in this context is the result of the material interactions of the surfaces in contact .Maintaining a high and constant coefficient of friction for different operating conditions requires knowledge of the practical aspects of the tribological behavior of the friction pair.The durability of the brake lining and the brake drum depends on their wear resistance ,6,7. WeaNumerous studies in the field have shown the dependence of the coefficient of friction, not only on the two materials in contact, but also on several tribological aspects ,11,12. TThe temperature of the surfaces of the friction pair influences the coefficient of friction . Brake hMost of the studies related to these tribological aspects of shoe brakes are with reference to automobiles, trains, and lifting machines ,18,19,20The tribological phenomena in the case of the brake friction pair are numerous, but we would like to specify that the present study did not address all these aspects, and instead, it was oriented in two directions, which are: the theoretical study of the wear of the brake linings; and the analysis of the variation in the coefficient of friction according to tribological factors.The theoretical study of the wear of brake linings has as its objective the evaluation of the life of the brake lining according to the intensity of wear.The analysis of the variation in the friction coefficient for the friction pair of cranes in relation to temperature, roughness, and contact pressure was studied by a number of authors ,9,14,20.During the braking process, the two elements of the friction pair (brake lining\u2013drum) wear out after several braking cycles. Assuming that the braking pair and the specific wear are constant for the given operating conditions  the wear distribution of the shoe friction lining on the shoe-drum contact spring will be studied. The wear intensity of the friction pair has high values during the break-in period compared to the normal operation period ,25. As dThe volume of material removed for a single passage on the surface of the brake lining in the form of wear particles (tion (1) :(1)\u2206\u03bd=\u2206hUnder these conditions, for braking once the volume of worn material is calculated according to the Equation (2):In another aspect, due to the total friction length S is the surface of the shoe.The process of wearing the brake lining can also be characterized by specific wear, as follows the Equation (3) :(3)Us=\u2206Vp) can be written as follows:The thickness of the layer of worn material depending on the specific wear and depending on the contact pressure between the shoe and the drum  and (4) for the total number of brakes  results in the equation of the thickness of the worn layer on the arc between the shoe and the drum, for the articulated fixed shoe of the shoe brake:Note that the thickness of the worn brake lining material depends on: the specific wear of the brake lining; friction length; braking moment; the position .In the first stage, all the parameters and all the second-degree interactions between them are considered. From Given this fact, when determining the regression equation, the three interactions are excluded.Based on the results obtained in The great advantage of such an equation, obtained from an ANOVA analysis resulting from a previously established experimental plan, is that the value of the coefficient of friction can be determined for any values of the parameters , provided that those values of the parameters are within the established experimental domain.An important observation is that the equation is valid only for parameter values that are contained within the established experimental domain .For the theoretical analysis of the wear of brake linings for functioning the brake shoe, we have determined an evaluation method of the total number of brakes (Another important contribution of this study is the experimental determination of the coefficient of friction in tribological conditions for the brake shoes of overhead cranes. For this, the experiments were carried out depending on the influence of four parameters: the contact pressure between the shoe and the drum; the initial velocity of the drum; the temperature of the friction surfaces; and ambient humidity. Analyzing the results obtained from the experiments and from processing the experimental data it can be observed that the coefficient of friction decreases with increasing temperature, humidity, and the sliding velocity between the two elements of the friction pair. It can also be noted that the coefficient of friction increases with increasing contact pressure.Starting from the established experimental range and using statistical analysis, a regression equation was obtained, that would allow the determination of the value of the coefficient of friction for any value of the four established parameters, but with the condition that the values are included in the established experimental range. It was learned that the weight of the influence of the parameters on the coefficient of friction was as follows: humidity with a value of 35.58%; followed by temperature with a percentage of 23.95%; velocity with 4.54%; and contact pressure with 4.19%.The presented methods allow for a better evaluation of the coefficient of friction in the tribological operating conditions and give the possibility to estimate the service life for the brake linings of the brake shoes from overhead cranes.The present paper does not and cannot pretend to cover the entire subject matter, with the field being particularly complex. The theoretical and experimental research conducted had the goal of finding solutions to at least some of the problems that appear in this case.In the future we aim to continue this study with the experimental determination of the wear intensity in tribological conditions for the friction pair and the study of the deformations of the friction pair elements."}
+{"text": "The main scientific task of the study is at the intersection of two fundamental areas of psychology - self-regulation of human mental states and management of educational activities. In the context of these problems, we study the self-regulation of states in academic activities.The purpose of the study is to show the patterns of mental organization of the person that ensure the regulation of states.The theoretical basis of the study is the system approach. The typical methods and techniques of self-regulation of states, as well as the influence of mental structures on students\u2019 self-regulation have been studied. To solve the problems, standardized psychological tests have been used . The research involved 206 students.We have revealed the features of the relationship between the quality of students\u2019 subject training, regulatory abilities and mental states. It indicates that the effectiveness of students\u2019 mental states self-regulation significantly affects the productivity of the semester exam. It has been established the properties of the personality providing high efficiency of self-regulation . Students with high self-regulation efficiency use a wide range of regulatory means.The study of the influence of the mental structures on self-regulation and regulatory abilities of students confirmed the hypothesis that characteristics of mental organization play the central role in the regulation of psychological states. The research has been carried out with the financial support of the RFBR, project No. 19-29-07072.No significant relationships."}
+{"text": "Cultural syndromes are pathologies that cannot be understood outside the cultural or subcultural context of the person who suffers from it, since both their etiology and symptoms are symbolized by the patient and by the environment in fields of significance inherent to their culture. The globalization process in which we are involved affects the presentation, understanding, diagnosis and treatment of cultural syndromes as they were traditionally understood.The objective of this work is to review the current state of cultural syndromes, the evolution of incidence and prevalence in recent years, as well as whether the globalization process has affected their understanding.A bibliographic review has been carried out on cultural syndromes and case reports in both endemic and foreign populations. Likewise, a reflection is made on the possible evolution of these syndromes.Globalization has been understood as a natural process of integration of nations and their cultures, incorporating the diversity and specificity of the other without forgetting their own and traditional characteristics. Within the globalization process, positive advances in the health area are recognized, specifically in the fields of communication and biotechnology. However, the negative impact of globalization on the daily life and health of people worldwide is undeniable. Those that are economically most disadvantaged are particularly affected. The cases of cultural syndromes in distant countries, the misunderstanding of the symptoms as well as the difficulties of integration of migrant patients with mental suffering must be the object of debate and study.Globalization affects the care and understanding of mental healthNo significant relationships."}
+{"text": "Following publication, the publisher has discovered that the corresponding author submitted false information that compromised the peer-review process. As the scientific integrity of the article cannot be guaranteed, and adhering to the recommendations of the Committee on Publication Ethics (COPE), the publisher therefore retracts the article.The authors do not agree to this retraction.This retraction was approved by the Chief Editors of Frontiers in Public Health and the Chief Executive Editor of Frontiers."}
+{"text": "Illarionov  The authors regret that one of the co-authors, Ivan Mukhin, was omitted from the original article. The correct author list is as shown here.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "Following publication, concerns were raised regarding the validity of the data in the article. The authors failed to provide the raw data or a satisfactory explanation during the investigation, which was conducted in accordance with Frontiers\u2019 policies. Given the concerns, and the lack of raw data, the editors no longer have confidence in the findings presented in the article.This retraction was approved by the Chief Editors of Frontiers in Pharmacology and the Chief Executive Editor of Frontiers. The authors have agreed to the retraction."}
+{"text": "The authors regret the omission of one of the authors, Michael Mak, from the original manuscript. The corrected list of authors and affiliations for this paper is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "Nature 10.1038/s41586-020-1943-3 Published online 5 February 2020Correction to: In the published version of this paper, the members of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium were listed in the Supplementary Information; however, these members should have been included in the main paper. The original Article has been corrected to include the members and affiliations of the PCAWG Consortium in the main paper; the corrections have been made to the HTML version of the Article but not the PDF version. Additional minor corrections to affiliations have been made to the PDF and HTML versions of the original Article for consistency of information between the PCAWG list and the main paper."}
+{"text": "The development of UA is one of the most important challenges for the future of aviation. Consequently, this is one of the major challenges for the future of aviation law, particularly for those legal regulations that aim to provide an adequate level of civil aviation safety. The main goal is to show the results of the analysis of the legal framework created in Europe and to show where Europe is going in the nearest future. The method of study comprised content analysis of existing legislation. Results of the study shows inter alia that although the analysis of the adopted solutions is necessary for a better understanding, a comprehensive assessment of these solutions will be possible at the earliest after the end of the adopted transition periods, i.e. after 2023."}
+{"text": "Contemporary villages of the mountain region are subject to uncontrolledstructural and spatial transformations, which cause deformation of centuries-oldspatial systems of high cultural and natural value. The aim of the study is toconfront the opinions of the inhabitants and experts regarding the condition of thecultural landscape of the villages in south-eastern Poland. This area belongs to theCarpathian region of Central Europe. The historical and economic conditions of thestudied region, related to the functioning in the post-war period, and then itsbreakdown and the development of the free market economy, constitute an interestingbackground for the proposed research. Local communities still remembering the periodof difficulties related to the period of systemic transformations, are currentlyexperiencing a relative prosperity, many difficulties related to the period ofsystemic transformations, are currently experiencing a relative prosperity, which isalso expressed in a completely new, previously unknown way of managing thelandscape. Investments implemented in villages are associated by the inhabitantswith the improvement of the standards and quality of life. They assess them ratherpositively. An expert assessment of these landscape transformations indicates theirnegative dimension and the risk of losing timeless values. The discrepancy in theassessment of experts and local residents creates difficulties in the protection ofthe rural landscape. Therefore, high-quality visual landscape features among ruralresidents is necessary from the point of view of its multi-faceted and effectiveprotection. Local initiatives and actions in the field of industry policy shouldplay a significant role in this respect by consolidating the images of a harmoniouslandscape in the public awareness."}
+{"text": "We read with interest the letter by Twycross and al on our article recently published in BMC Palliative Care. The authors suggest that the term palliative sedation has been used inappropriately and they consider that in the situation described the sedation was a procedural one rather than a continuous deep sedation. We strongly disagree with this point of view. In an end-of-life situation, the priorities are the patient\u2019s comfort, pain and anxiety. This type of sedation does not have the characteristics of procedural sedation described in anaesthesia. The French Clayes Leonetti law makes it possible to clarify the intention of the sedation in end-of-life situations. We read with interest the letter by Twycross and al on our article recently published in BMC Palliative Care  reportinThe authors suggest that the term palliative sedation has been used inappropriately in relation to the outcomes of our work. We would like to clarify that throughout the manuscript we have only referred to the end-of-life situation of patients in chronic respiratory failure on NIV (a fact which was perfectly clear to the doctors who participated in the study). The authors of this letter consider that in the situation described the sedation was a procedural one rather than a continuous deep sedation. We strongly disagree with this point of view. The procedural sedation described in the reference mentioned in Twycross\u2019s letter  is done The Clayes Leonetti law  allows uFollowing the implementation of the Clayes Leonetti law in France in 2016, the French palliative care society developed the SEDAPALL score on sedative practices in the palliative context  to clariFinally, with these clarifications, we fully agree with the authors of the letter and as we suggested in our paper, there is a need for close collaboration between palliative care specialists and pulmonologists or other specialists. The other specialists need to learn the tools and culture of palliative care and the palliative care specialists, the specificities of the patients' diseases in order to improve the quality of EOL and the death of patients."}
+{"text": "Horticultural therapy is a professional practice that is increasingly used in a lot of mental health rehabilitation programs. This therapy was introduced in the Comunitary Rehabilitation Service of INAD, considering its beneficial results in patients with severe mental disorder in combination with the usual rehabilitation program.We would like to study the benefits of this therapy compared to the usual in our patients.This is an explanatory study for the purpose of establishing the association between the application of a Therapeutic Horticulture Program and the Clinical Symptomatology of Schizophrenia. A research with an experimental design Pre and Post-Test was carried out, by applying a Horticulture Program and evaluating with PANSS after 6 months its effects on the Clinical Symptomatology. The participants of the experimental group were selectively chosen. The only selection criteria were to attend the orchard at least once a week and be diagnosed with a schizophrenic disorder. The control group was chosen according to the number of members that made up the other group, with the criterion that they did not perform any outdoor activities and also had a diagnosis of schizophrenia.The comparison of the Pre and Post-Test measures in the case of the experimental group reports the presence of statistically significant differences in the scale of positive symptomatology composite scale and general scale.This psychopathological improvement of those participants open a door to possible applications of this therapy as a psychosocial treatment."}
+{"text": "Following publication, the publisher uncovered conclusive evidence that false identities were used for one of the authors and for both of the reviewers of this article. The investigation, conducted in accordance with Frontiers\u2019 policies and the Committee on Publication Ethics (COPE) guidelines, revealed that the article was submitted using the false identity O\u2019Maley Kimberlee. We were able to confirm with University administrators that no one of this name has ever been involved with the University of California, Berkeley, the purported affiliation.Queries to the co-authors and editors were not able to resolve the matter and the publisher retracts the article.This retraction was approved by the Chief Editors of Frontiers in Physiology and the Chief Executive Editor of Frontiers."}
+{"text": "The use of a modern biopsychosocial model of care for patients with schizophrenia dictates the need for a dynamic assessment of the quality of life of patients at different stages of the disease to identify targets for treatment and rehabilitation measures. It is especially important to determine the available targets in the early stages of the disease in order to select effective complex therapy and improve the clinical and social prognosis.To determine the socio-biological and clinical factors that have a significant impact on the quality of life of patients with first-episode psychosis.The sample consisted of patients diagnosed with schizophrenia (n=58). The following research methods were used: 1) clinical-psychopathological; 2) quality of life assessment; 3) clinical-laboratory and functional research methods; 4) statistical. The QL-100 questionnaire was used as a tool for studying the quality of life. The PANSS scale was used to assess the severity of positive and negative syndromes.The most significant adverse impact on the quality of life indicators are the absence of family, lack of work, low material wealth, active consumption of psychoactive substances, the predominance of negative symptoms and the presence of concomitant somatic disease in the acute phase.Early identification of problematic aspects of the quality of life in patients with the first-episode psychosis allows us to conduct effective treatment and rehabilitation measures for these patients."}
+{"text": "Dear Editor,A 42-year-old male patient was seen at the Dermatology Service due to the presence of whitish lesions on the oral mucosa, affecting mainly the tongue. Moreover, he reported significant dysgeusia and a lack of appetite. He had chronic kidney disease and had been undergoing conservative treatment so far. The examination of the oral cavity showed whitish plaques with threadlike projections adhered to the lateral borders of the tongue  and a whUremic stomatitis is an underreported disease of the oral mucosa, possibly associated with long-term uremia in patients with chronic kidney disease.None declared.Paulo Ricardo Martins Souza: Approval of the final version of the manuscript; drafting and editing of the manuscript; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.Gabriela Mosena: Approval of the final version of the manuscript; drafting and editing of the manuscript; critical review of the literature; critical review of the manuscript.Manuela Lima Dantas: Approval of the final version of the manuscript; drafting and editing of the manuscript; critical review of the literature; critical review of the manuscript.Gerson Vettorato: Approval of the final version of the manuscript; drafting and editing of the manuscript; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.None declared."}
+{"text": "In the original published version of this article, the authors declared no conflicts of interest. They later clarified that one of the authors is a shareholder in the company that provided material resources for the conduction and publication of the study. The Editor notes that the article has been additionally assessed given the new conflict of interest and its correctness has been confirmed. The authors apologize for the errors. Both the HTML and PDF versions of the article have been updated to correct the errors.Professor Williams is principle author of the educational life skills books and worksheets used in this project. He is Director of Five Areas, a Limited Company that commercialises these resources, and of which Professor Williams is a shareholder. Five Areas Ltd part-contributed to the journal publication costs. No other authors declare conflicts of interest."}
+{"text": "We present the case of a 36-year-old male with depressive states, impulsive traits and fits of anger (including episodes of self and heteroagressiveness) since early childhood, in the context of traumatic family history and the beginning of an epileptic disease. These symptoms have been maintained over the years, in addition to other variable and recurrent symptoms, such as severe anxiety, somatizations or serious depressive symptoms.To highlight the possible influence of epilepsy in the course of mental illnesses, especially depression, as well as the increased difficulty in management.We collected the complete medical history of a patient with an important history of mental health in addition to epileptic disease since childhood and we carried out a review of the comorbidity between these diseases and their treatment.The epileptic disease of our patient may have influenced the behavioural alterations and the depressive symptoms since childhood, as well as the personality traits with aggressiveness and impulsiveness. There is an added difficulty in treating this case given the possible interactions between antiepileptic and antidepressant medications.This case highlights the importance of taking into account the influence of this comorbidity on the prognosis of patients. Knowing the interactions and side effects of drugs is essential for good clinical management.No significant relationships."}
+{"text": "Following publication, the publisher has discovered that the corresponding author submitted false information that compromised the peer-review process. As the scientific integrity of the article cannot be guaranteed, and adhering to the recommendations of the Committee on Publication Ethics (COPE), the publisher therefore retracts the article.The authors do not agree to this retraction.This retraction was approved by the Chief Editors of Frontiers in Public Health and the Chief Executive Editor of Frontiers."}
+{"text": "Correction to:Nature Communications 10.1038/s41467-020-14352-7, published online 05 February 2020In the published version of this paper, the members of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium were listed in the Supplementary Information; however, these members should have been included in the main paper. The original Article has been corrected to include the members and affiliations of the PCAWG Consortium in the main paper; the corrections have been made to the HTML version of the Article but not the PDF version. Additional corrections to affiliations and author names have been made to the PDF and HTML versions of the original Article for consistency of information between the PCAWG list and the main paper."}
+{"text": "The authors regret the omission of one of the authors, Shuxin Li, from the original manuscript. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "The process of professional self-determination in adolescence is a key developmental task, the successful resolution of which determines the psychological health and well-being. Professional self-determination includes 1) the formation of a professional identity on the base of exploration the possibilities of professional choice, 2) making a decision for professional future1) to study the features of a personal professional perspective in adolescence; 2) to reveal status of identity in the field of professional self-determination; 3) to study the relationship between the status of identity and the personal professional perspective.The modified Personal Professional Perspective technique (N.S.Pryazhnikov) and the interview to determine status identity in the professional field (D.Marsia) were used. The study involved 144 respondents aged 15 to 17 years.The heterochronicity of the formation of the components of the personal professional perspective (PPP) among adolescents is revealed. The connection of the high status of identity in the professional sphere with the formation of PPP has been proved. The formation of all components of the PPP among adolescents with the status of a moratorium and status of achieved identity is higher than in group with diffusion status .The high status of identity in the professional sphere (moratorium and achieved identity) is associated with a high level of formation of a personal professional perspective.No significant relationships."}
+{"text": "In the published article, the funding information was missing. The correct Funding statement appears below.This project was funded by the National Key R&D Programme of China (2021YFC2009404); the Science and Technology Projects in Guangzhou (201904010142) and the Natural Science Foundation of Guangdong Province (2021A1515010801).The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "We hypothesized that the cranial phenotype influences the shape of the posterior cranial fossa and the relative position of the sigmoid sinus.The topography of the sigmoid sinus was studied on 26 magnetic resonance venograms and 35 embalmed cadavers by morphometric analysis, dissection, and photo modeling techniques.The data show that the transverse diameter of the posterior cranial fossa correlates positively with the laterolateral diameter of the skull. The majority of cases with the low-anterior position of the sigmoid sinus were recorded in the brachycephalic group (82%), while the high-posterior localization of the sigmoid sinus was typical for the dolichocephalic patients (63%). The results of the ANOVA test confirm the significance of differences.The shape of the skull reflects the morphology of the posterior cranial fossa and influences the topographic characteristics of the sigmoid sinus that must be considered in the selection of surgical approach to the inner ear and pontocerebellar angle. The position of the sigmoid sinus is an important limiting factor in translabyrinthine and retrosigmoid approaches to the pontocerebellar angle and structures of the inner ear. High-posterior localization of the sinus influences the diameter of the surgical wound and increases the degree of cerebellar retraction in retrosigmoid surgeries , 8, 10. The positional relationships of the sigmoid sinus with the surrounding intra- and extracranial structures are reported by several authors. The statistical differences for the distances between the various parts of the sigmoid sinus and posterior semicircular canal, facial nerve, internal and external acoustic meatuses for males and females, and the right and left sides of the head are available in the literature , 12, 14.We assume that the cranial phenotype does influence the shape of the posterior cranial fossa and determines the relative position of the sigmoid sinus. This research aims to study the topography of the sigmoid sinus and its positional relationships with the external and internal acoustic meatuses in subjects with brachycephalic, mesocephalic, and dolichocephalic skulls.Twenty-six magnetic resonance venograms of the head  and 35 cadavers  without known osteological pathology and visible head deformation were included in this study. All body donors were legally competent and had a will in which they agreed to the use of their body for research, study, or teaching purposes; the patients who underwent radiologic examination have signed the written consent.\u00a0The institutional review board has approved the study.Glabella and external occipital protuberance of the skull (AP),Right and left parietal eminences of the skull (LL),Right and left asterion (pLL),Dorsum sellae and external occipital protuberance (pAP),Dorsum sellae and the anterior margin of the foramen magnum (DA),Internal occipital protuberance and the posterior margin of the foramen magnum (DP) Fig.\u00a0c, d.On the parasagittal magnetic resonance venograms (MRVs) we identified the external acoustic meatus (EA) and the transverse-sigmoid sinus junction (TSj) and measured the distance between them Fig.\u00a0a. The diThe cadavers underwent routine educational dissection in the specialized laboratory of our organization. After the dissection of the superficial tissues of the head and craniotomy, the brain and meninges were removed from the cranial cavity exposing the skull base. Then, the cadaveric specimens were digitized using the Photo Modeler 2021) software and technique, as previously described [ softwareBetween the lateral border of the porus acusticus and the anterior margin of the sigmoid groove (Dp1)From the lateral border of the porus acusticus to the posterior margin of the sigmoid groove (Dp2)Anteroposterior diameter of the sigmoid groove (dSG)From the external acoustic meatus to the tip of the mastoid process (Pp1)Between the external acoustic meatus and the projection point of the posterior margin of the sigmoid groove (Pp2)Between the tip of the mastoid process and the projection point of the posterior margin of the sigmoid groove (Pp3)From the glabella to the external occipital protuberance of the skull (AP)Between the right and left parietal eminences of the skull (LL)On the obtained 3D models, the following intra- and extracranial distances were taken digitally Fig.\u00a0Between The cranial index (CI) was calculated as a percentage ratio of the laterolateral diameter of the skull to the anteroposterior diameter . All speThe methods of descriptive statistics were used to analyze the average and distribution of the variables in each phenotypical and gender group. The Pearson\u2019s correlation was applied to evaluate the influence of the diameters of the skull on the variables. Analysis of variance (ANOVA) was employed to verify the significance of differences in the cranial phenotypical groups .Morphology of the posterior cranial fossa reflects the general shape of the skull. The data in Table The correlation analysis presented in Table On average, all variables were larger in males, but only the difference of laterolateral diameters of the posterior cranial fossa showed statistical significance Table .Overall, the distances from the lateral border of the porus acusticus to the anterior and posterior margins of the sigmoid groove peaked in the dolichocephalic specimens Table . The diaThe distances between the external acoustic meatus, the tip of the mastoid process, and the projection point of the sigmoid groove correlated positively with each other and negatively with the laterolateral diameter of the skull Table . In addiAll measurements were larger in males than in females Table . The difWe found that the transverse and longitudinal diameters of the posterior cranial fossa correspond to the phenotype of the skull. The depth of the posterior cranial fossa is shallower in brachycephalic patients and increases with the anteroposterior diameter of the skull. The obtained patterns of distribution of the distances between the external acoustic meatus and the transverse-sigmoid sinus junction by cranial phenotype allow us to suggest that the position of the sigmoid sinus is determined by the shape of the skull. The diameter of the sinus increases with the anteroposterior diameter of the posterior cranial fossa. In the dolichocephalic patients, the sigmoid sinus takes a more vertical course, while in the brachycephalic ones, it loops forward approaching the external acoustic meatus Fig.\u00a0. Such prEven though the individual variability of the skull base influences the flow and outcomes of surgeries on the basilar structures, the phenotypical characteristics of the skull base are scarcely addressed by authors, and the existing reports are controversial. For instance, Meneses et al. concluded that the distance between the outer surface of the skull and the apex of the temporal pyramid is shorter in brachycephalic skulls for both middle and posterior cranial fossa approaches due to narrowing of the anterior but widening of the posterior parts of the skull base in this phenotype . The autThe sigmoid sinus represents the major dural channel draining the entire cranial cavity. It runs along the inner surface of the temporal bone connecting the transverse sinus with the internal jugular vein. The intense venous flow carves the bone developing a tortuous groove in this location with age. Examining the inner surface of dry skulls, we see how variable the position of the sigmoid groove in relation to other structures of the temporal pyramid is Fig.\u00a0. To predDespite the wide implementation of radiologic methods, the evaluation of the relative position of the sigmoid sinus on CT and MR venograms is challenging as we can assess only one type of tissue at a time. To solve this problem, several radiologic landmarks and methods were proposed by the authors. Sheng et al. suggested merging the subtraction computed tomography angiography data with non-enhanced data and reducing the transparency of the bones to visualize the underlying venous channels . Galal eThe importance of venous anatomy in the selection of the surgical approach is highlighted in the literature. Authors specified that the extreme anterior position of the sinus complicates the operations on the inner ear , 13, whiThe prevalence of females in our brachycephalic MRV group could affect the overage of the results in this group. Additional analysis of the data in the dolichocephalic, mesocephalic, and brachycephalic females only revealed the same patterns of distribution of the variables.The data presented in the present research were taken from multiple populations: we studied the MRV images of Arabic patients and dissected skull bases of Caucasian cadavers. The populational features of cranial morphology were not addressed in this research. The wide range of reported frequency of the low anterior position of the sigmoid sinus (4% in research on Western cohort , 19.15% The larger sample size is advised to be considered in future studies.The morphological data presented in this paper illustrate the possibilities of the clinical application of cranial morphology. Knowledge of the patterns of distribution of the variables by the type of skull allows us to classify the variability of the skull base structures efficiently. In the present study, we focused our attention on the phenotypical variability of the posterior cranial fossa, and positioning of the sigmoid sinus in relation to the internal and external acoustic meatuses; the variability of the orbit, anterior cranial fossae, and the midline structures of the skull base are the potential subjects for the future studies.The shape of the skull reflects the morphology of the posterior cranial fossa and influences the topographic characteristics of the sigmoid sinus that must be considered in the selection of surgical approach to the inner ear and pontocerebellar angle. In brachycephalic patients, the translabyrinthine approach to the structures of the inner ear is jeopardized by the high possibility of the low-anterior position of the sigmoid sinus. In dolichocephalic ones, the retrosigmoid approach may require extensive cerebellar retraction and is unfavorable. Thus, the cranial phenotype of the patient should be considered in the planning of the skull base surgery."}
+{"text": "The authors regret that the name of one of the authors (Kai-Hsin Wen) was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "This paper discusses a method of diagnosing electromagnetic valves of injection systems in combustion engines. Based on multiple analyses of electrical quantities occurring in the course of the electromagnetic injector work and physical relationships between them, the quantities have been demonstrated on which the fluctuation of the electromagnetic force in the injector depends. Moreover, the results of its fluctuations have been mapped to the electric quantities controlling the fuel injector\u2019s work. The research has shown that the current and voltage waveforms contain information on electrical properties of the injector coil and its mechanical properties determining the injector\u2019s technical health as well as that of the fuel system. Electromagnetic valves are widely used in the field of machine and appliance design. Their proper operation influences the work reliability, but also, it affects the environment, including having a negative influence. Ensuring the correct operation of electromagnetic valves requires systematic tests during operation. Developing new, non-disassembly methods for the evaluation of the technical condition of valves is an important direction of scientific work.Electromagnetic valves constitute popular solutions in injection systems of combustion engines used in the means of transportation. They are applied as executive elements in injection systems in both spark ignition and compression ignition engines.The research work conducted so far, devoted to injectors and electromagnetic valves, focused on tests in regard to the fuel injector design, development of research methods, and evaluation of the injected fuel stream, but also the emissions of toxic components of exhaust gases. The authors of works ,2,3 usedWhile analyzing the injector work, the following needs to be noted: The fuel flow is determined using Coriolis mass flow meters . The engThe presented information indicates that the observation of the current quantities may enable the control of the fuel flow volume through the injector nozzle . These pThe paper presents a study that aims to determine what measurement quantities the magnetic force in the injector depends on and to relate the effect of that force to the quantities managing the operation of the fuel injector. The authors present the theoretical basis for the change in the current values occurring in the fuel injector and explain the influence of changing the derivative sign on the injector dosage.Further, the authors\u2019 method for diagnosing the fuel injectors and the characteristic quantities necessary for their application is discussed. Several example tests and analyses of the current signals are presented to illustrate the implementation of the developed test method in the practice of diagnosing the technical condition of fuel injectors in internal combustion engines.An electromagnetic valve applied in the technical context is a working element used wherever control of the liquid or gas flow is required. Its basic element is an electromagnetic coil powered and controlled by means of change in the electric signal. The current flow through the valve coil induces the electromagnetic field, attracting a ferromagnetic element , whose movement opens or closes the flow of the specific medium. The needle\u2019s return after the electric current impulse that was shut off is ensured by the spring pressing it against the seat. A natural property of electromagnetic valves, and thus fuel injectors as well, is the asynchronism of the fuel flow phase relative to the phase of the control impulse. The cause of it is a gradual increase in the magnetic flux generating a magnetic force of appropriate value that will lift the injector needle and, with a certain phase shift, will unblock the flow. The value of the delay is determined by the time constant of the injector coil ,30, whicPerforming the detailed analysis of the presented characteristics allows for the observation that the range of the control impulse is not synonymous with the fuel flow phase. This fact can be taken into consideration in injector control. The possibility of determining the phase of real flow in real-time\u2014in the course of the injector work\u2014and using this information for control would enable the correction of the duration of the control impulse and the flow phase. This information can be used by the ECU to perform its controlling function. The accomplishment of this task requires finding a way to determine, in the course of the engine\u2019s operation of the fuel injector, the actual start, and end of the injection. This method may well be the observation of the current parameters of the dosing injector because the current which supplies the injector\u2019s coil is also a control signal. The movement of the injector\u2019s needle is accompanied by the change in the gap between this needle and the core. To put it more precisely, during its motion, the needle gradually fills the inside of the core , subjectI. During the first stage, the air gap is at its maximum, hence the maximal magnetic resistance. The magnetic force grows proportionally to the square of the current ;DSC1 marked on the line denoting the increase of the current intensity and DSC2 on the line denoting the decrease in voltage. Additionally, in DSC1). This phenomenon results from the fuel density and gradual increase of the stream. The record of the growing current intensity in the RL circuit in the case of the work not being performed  is a steady increase in the current intensity up to its maximal value, limited by the coil resistance and electromotive force of the supply source in accordance with Kirchhoff\u2019s Equation (10), as shown by the blue line in DSC1, and Kirchhoff\u2019s equation, reflecting such an increase in electric current intensity, needs to be completed with a factor taking into account the influence of the forces being overcome:The current waveform of the dose-emitting injector is not depicted by Kirchhoff\u2019s equation in its original form (10). The occurrence of the forces counteracting the needle lifting (11) causes the emergence of Kirchhoff\u2019s equation, a result of which the value of the current intensity The performed analyses allow for the conclusion that in the injector current waveform, there is information not only on the electric properties of the injector coil but also regarding the injector\u2019s mechanical properties, determining its efficiency, as well as that of the fuel system .Due to the fact that the character of the increase in the injector current intensity reflects mechanical and electric phenomena at the point of the needle lifting in the dose-emitting injector, the assumption has been made, creating the method of diagnosing fuel injectors, that information on the value of the current intensity at the point of the needle lifting and on the decrease in the voltage at the point of the needle dropping will be used in the process of the examination of the technical state . --DSC1;----DSC2\u2019s occurrence.On the basis of the significant amount of laboratory tests conducted for many different fuel injectors , the characteristic points of the current waveform for the dose-emitting injector were determined :-Iop\u2014thThe diagnostic research conducted on the basis of the observation of the characteristic points of the current waveforms enables verification of the injector in the course of the test bench tests on the working engine in real-time. The observation of the values of The following points 1\u20133 indicate the way of conducting the analysis of current signals that would reflect the principles of the developed method for diagnosing the fuel injectors. On the basis of the bench tests performed on the real injectors, the abnormalities in the electromagnetic injector operation that are possible to be diagnosed have been determined. Sample tests were conducted on the basis of the registered characteristics of the injector, presented in The way of performing the analysis of the current signals:1.R = 14.8 \u03a9 and from the supply value of the current source (11.6 V). The calculation based on the Ohm law renders the maximal intensity The maximal value of the current in the steady state = 0.78 A .The observation of this value allows for the evaluation of the invariability of the circuit resistance and the value of the electric voltage supply. 2.I = 0.78 A, the speed of its deterioration, and inductance of the injector coil core L H:The value of the electric voltage at the maximum induction peak .3.Reconfiguration of the value -DSC1 = 0.40729 A, the point of needle lifting;----The model values of the current intensity and electric voltage at the vital points of the injector work, constituting the range of limit values determining the proper condition of the fuel injector and the fuel system, are, respectively :-DSC1 =t = 0.1752 , the value of this point has decreased (A). The delay in the time of needle lifting The analysis of the emerging changes at the characteristic points leads to the conclusion that evident differences for such a type of damage occur in regard to point In the subsequent experiment, the resistance of 20 \u03a9 was added in series within the injector coil supply cord; the results are shown in -DSC1 = 0.274 A;----The observation can be made that there exists a certain trend in changes in the recorded parameters. The compilation of the significant values obtained in this experiment is presented below:DSC1 has decreased. The result of a smaller value of the current is the longer time of its growth to achieve a proper value of the magnetic stream around the injector coil. This is the reason for increasing the time The value of the current intensity at In the subsequent experiment, a short circuit was introduced between the electric wires supplying the injector coil with a resistance of 20 \u03a9. The results of the recorded voltage\u2013current waveforms are shown in -DSC1 = 0.4024 A;----This method of short-circuit simulation was selected as safe, not inducing damage to the elements of the electrical system. This modification did not block the injector dosage yet critically changed the waveform of the electric voltage in the coil. The inductive voltage peak after cancelling the control impulse reached the value of 20.06 V, which constitutes 36% of this quantity in the model waveform. The compilation of the significant values obtained in this experiment is presented below:DSC2 point is difficult, yet its correlation with the value A controlled short of this value results in a subsequent return dropping of the needle. A consequence of this action is an increase in the real injection time  than in the previous experiment  shown in The magnetic force and forces counteracting the lifting of the needle affect the shape of the current waveforms. If it were not for the work performed by the needle, dependent on its lifting resistance, the current waveform would develop according to the curve of the exponential character without Occurrence of the The value of current intensity, at which the change of the derivative sign takes place, results from the degree to which the forces from Equation (11) counterbalance each other. On the left side of the inequality  is the electromagnetic force resulting from the value of inductance and from the value of the current flow. On the right side of the equation, there are the forces counteracting the lifting of the needle (11). The balance of these counteracting forces influences the value of the current intensity at the point of the change of the waveform derivative sign The conducted laboratory experiments have proved that the characteristics of the Implementation in the controller in charge of the engine work (and of the injector) of the module recognizing the change of the waveform derivative in the specified ranges of the current waveform will enable obtaining of the automatic tool detecting damage in the fuel system and the possibility of correcting the length of the control impulse and the injection phase in the current time.The fuel injector is an executive element particularly susceptible to damage. Directly generating the fuel dose and, as a final element of the fuel system, it influences to a great extent the proper functioning of the engine, as well as the quality of the fumes from the exhaust system. The fuel injector plays an important role in engine operation in compliance with ecological guidelines; it also affects the safety of vehicle users. The monitoring of the injector operation is vital, particularly if it can be achieved in such a way that the damage would be detected at the early stage when its negative effects are not yet to be felt. The analysis of the current waveforms, especially the values and the phase of the"}
+{"text": "The Publisher retracts the cited article.Following publication, the publisher uncovered conclusive evidence that false identities were used for one of the authors and for both of the reviewers of this article. The investigation, conducted in accordance with Frontiers\u2019 policies and the Committee on Publication Ethics (COPE) guidelines, revealed that the article was submitted using the false identity Enny Kampmann. We were able to confirm with the administrators that no one of this name has ever been involved with the City College of San Francisco, the purported affiliation.Queries to the co-authors and editors were not able to resolve the matter and the publisher retracts the article.This retraction was approved by the Chief Editors of Frontiers in Physiology and the Chief Executive Editor of Frontiers."}
+{"text": "The authors regret that the name of one of the authors (Min-Qiang Wang) was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "The main goal of the study is to develop a complex hybrid model for evaluating projects to improve the sustainability and health of regions and cities within the European Green Deal and Industry 5.0 concepts. The complex model is a comprehensive evaluation system that considers various influencing factors, the investor\u2019s intentions regarding the need and financing of projects, as well as expert opinion on the possibility of achieving sustainability and health of regions and cities by implementing this project with the investor. The model is based on modern theory of intellectual knowledge analysis, fuzzy set theory, and systems approach. Furthermore, we have an initial quantitative assessment and the linguistic significance of the level of the project financing decision with a reliability assessment. The knowledge from the repository of 896 project plans in the field of transport submitted for implementation and financing in the period 2021\u20132027 was used for the creation of the model. The results of the study were tested on the examples of evaluation of five real projects and demonstrated the applied value of the methodology for evaluating the level of decision-making feasibility of project financing in uncertainty and the importance of making correct management decisions based on expert opinions. Society recognizes the importance of addressing the resilience and health of regions and cities in implementing global strategic development plans at the regional and local levels, for example, through the efforts of each EU Member State to reduce regional disparities between the levels of development of European regions and to improve living standards in the least-favored regions . The paper, using a multilateral interdisciplinary approach, is an effort to create a mathematical expert hybrid model based on fuzzy logic to support the decision-making processes of evaluation commissions at the state and local government levels, as well as decision-makers for implementing sustainable development policy and healthy regions and cities, improving the governance of cities and regions, in the context of the forthcoming implementation of the European Green Deal and the European Industry 5.0 concept, within the Member States. Addressing the issue also contributes to supporting efforts to become a candidate country and subsequently a full member of the European Union in meeting the EU\u2019s long-term strategic goals and commitments.The research topic is related to the objective and transparent evaluation of projects based on criteria set by experts in the field to which the call for proposals relates.The research problem is the quantitative and qualitative evaluation of the proposed solution content and risks in the field of resilience and health of regions and cities within the current societal challenges of climate change elimination expressed in the European Green Deal and the European Industry 5.0 concept.The research question is focused on researching and creating an innovative algorithm for expert evaluation of projects to strengthen the resilience and health of regions and cities within the European Green Deal and the Industry 5.0 concept submitted in the competition, based on a neuro-fuzzy framework to support decision-making processes. On this basis, the paper proposes Hypotheses 1 and 2.Hypothesis\u00a01\u00a0(H1).Project developers in strengthening the resilience and health of regions and cities who meet the grant provider\u2019s intentions in accordance with the European Green Deal and Industry 5.0 concept will get a better result based on a fuzzy expert assessment of the project\u2019s innovation ecosystem potential than project developers who do not meet the grant provider\u2019s intentions in the field of strengthening the resilience and health of regions and cities in line with the European Green Deal and the Industry 5.0 concept or only partially meet them.Hypothesis\u00a02\u00a0(H2).If the developed algorithm of the comprehensive hybrid model evaluation of resilience and health projects of regions and cities is applicable for the evaluation of projects within the European Union, then the algorithm will be applicable to the evaluation of resilience and health projects of regions and cities outside the European Union.The main goal of the study is to develop a complex hybrid model for evaluating projects to improve the sustainability and health of regions and cities, within the concepts of the European Green Deal and Industry 5.0. The model focuses on supporting the decision-making processes of evaluation commissions at the level of public administration and self-government and entities empowered to implement regional policy and local self-government with support for specialized, targeted projects and programs. Secondly, the results of scientific research are also used in the education and support of young scientists and professionals with social responsibility, which is usually expressed in the creation of social responsibility of companies, institutions, or public associations in an open civil society. The common goals are expressed in the intention of the model to maximize the potential of the innovation ecosystem of the project, bringing together different stakeholders in the idea and decision-making process to improve and enhance the sustainability and health of regions and cities according to European Green Deal and Industry 5.0 time, with the accepted level of project implementation risks and the level of required public funds , as well as co-financing of projects from private or corporate sources.The key result of the paper is a comprehensive approach to evaluating projects to improve the sustainability and health of regions and cities, within the concepts of the European Green Deal and Industry 5.0, for practical use by evaluation commissions and decision-makers at state and local levels private sector. The output is the basis for further research work on the development of a web analytics tool on this topic. The acquired knowledge and algorithm can be transferred to the evaluation of projects outside the European Union, and the problem-solving methodology will allow repeating the procedure to other scientists and experts/evaluators of projects aimed at strengthening the sustainability and health of regions and cities.The Europe Green Agreement and the Industry 5.0 concept are in line with the global implementation of the 2030 Agenda for Sustainable Development, under the auspices of the United Nations, which reflects the policies and responsibilities of all stakeholders  for each criterion according to the proposed fuzzy rules.A set of criteria is offered for assessing the importance of the project idea to improve the sustainability and health of regions, which is divided into five groups Group Sociocultural ;Political ;Economic ; Environmental ;Security ; Health .Group Group Group Group The above set of criteria is open, and the model does not depend on the number of groups. Investors can always add their own indicators when considering specific projects to improve the resilience and health of regions.The issue of assessing risk-oriented factors influencing project implementation is very complex. Depending on the project, the region, and the stages of project implementation, different risk indicators need to be adjusted. There are many classification approaches to risk assessment for both classic and innovative and start-up projects. Here are some criteria by which the expert can assess the risks that may arise in the implementation of projects to improve the sustainability and health of regions and cities:The above set of criteria is completely open and inexhaustible. For example, if a thematic project selection competition is held, then project analysts must adapt this set of criteria to the theme of this competition.According to projects . If the projects .The result of the study, the algorithm of the model, was tested on the example of the evaluation of five submitted projects The calculations will be performed based on the developed complex hybrid model of project evaluation to improve the sustainability and health of regions and cities. To do this, we will evaluate separately on fuzzy models For example, consider in more detail the evaluation of the project rpattia\u201d , on modeRL = {A; B; C; D}. For each criterion and group of criteria, the project analyst determined the weights. Input data and weights are given in At the first stage of the project At the next stage, we will move from the intervals of fuzzy project evaluations according to the criteria of one group, to one-point evaluation within the group. To do this, first, based on the input data, using the membership functions of criteria (2)\u2013(5) we construct graphs of expert opinions. Next, the weights were divided within the corresponding group, according to Formula (6). The result is presented in the form of a vector: software .For the aggregate assessment of the expert opinion Thus, an aggregate conclusion of the expert\u2019s opinions on the criteria for each group was obtained.In the third stage, the aggregated conclusions of the experts on the groups of criteria will be combined into a general assessment. To do this, calculate the normalized weights for each group of criteria, according to the Formula (8): At the first stage of the project In the first stage, we will carry out fuzzification of input hybrid data. To do this, the values of In the third stage, we derive an aggregate risk assessment according to the Formula (13): The team of project implementers given in . After tThus, normalized estimates of the project Similarly, the other projects are calculated, for which we obtain the following estimates: Let the investor have his own goals regarding the need and possibility of financing projects to improve the sustainability and health of regions and cities.If the investor needs the importance of the region where the project will be implemented Next, for all projects the values of Next, to aggregate the values of After that, the experts evaluating the projects express their conclusions on the possibility of achieving the goal of improving the sustainability and health of regions and cities, by implementing this project with the support of investors and considering their goals. Next, the dependencies of the initial assessment L are presented in All the results of calculations and conclusions of experts Thus, aggregate normalized estimates Next, consider G and expert opinions Based on the output data, investors decide on the feasibility of financing projects to improve the sustainability and health of regions and cities, within the concepts of the European Green Deal and Industry 5.0, considering the goals of investors As shown, two projects The paper presents a comprehensive hybrid model for evaluating projects to improve the sustainability and health of regions and cities, within the concepts of the European Green Deal and Industry 5.0. To this end, the following have been developed: information models of input data for the evaluation of projects to improve the sustainability and health of regions and cities; fuzzy project evaluation model; fuzzy model for assessing the risks of project implementation; model of aggregation of output data for deriving the level of decision-making expediency of project financing. The complex hybrid model can adequately determine the level of feasibility of project financing, considering the goals of investors and expert opinions on the possibility of achieving goals to improve the sustainability and health of regions and cities through the project. The study is based on the apparatus of fuzzy sets based on estimation intervals, showing the corridor of values of forecast parameters. This allows for increasing the degree of validity of decisions, as it considers all possible development scenarios, depicting a continuous spectrum. For the processing of expert information and fuzzy input data, intelligent analysis of knowledge is also used based on the membership functions to the evaluation criteria, one, and many variables, considering any type of input data. Intellectual analysis of knowledge allows revealing the subjectivity of experts and to obtain a quantitative assessment of an informal applied problem. The models developed in the work reveal the vagueness of the incoming expert opinions and increase the degree of validity of further decisions by investors on the choice of project for its financing. The value of the model is that it allows obtaining a comprehensive quantitative assessment of the project based on descriptive input (text) data obtained from the project application. For the expert, the evaluation procedure remains classic and well-known, he examines the project application, then on several issues expresses his views on the importance of the idea and quality of the project. After that, the data are processed by appropriate fuzzy and hybrid models, revealing the subjectivity of experts, and adjusting the parameters of the models and the target needs of investors to prevent the subjective influence of participants in the evaluation process on the result. At the end of the model, is the output quantitative assessment and linguistic significance of the level of decision-making expediency of project financing with the assessment of reliability.The advantages of a complex hybrid model for evaluating projects to increase the sustainability and health of regions and cities, within the concept of the European Green Deal and Industry 5.0, stem from the advantages of the developed models. The hybrid model is based on various information models of input data, adapted to evaluate projects to improve the sustainability and health of regions and cities, and fuzzy models to assess various aspects of the presented projects, from the idea, and implementation risks to the contractors. The set of criteria is open, the model does not depend on their number, and project analysts can always adapt the set of criteria to highly specialized project topics. The model considers the investor\u2019s goals regarding the need and possibility of financing projects, namely: the purpose of the importance of the region where the project will be implemented, the purpose of acceptable risks, and the purpose of competence of project participants. The developed fuzzy knowledge base for evaluating projects to improve the resilience and health of regions and cities can be easily adapted to different goals of investors. The quality of the final decision is improved by involving an expert opinion on the possibility of achieving the goal of improving the sustainability and health of regions and cities, by implementing this project with the support of investors, and by considering their goals. The hybrid model determines the level of expediency of project financing, and there is a possibility, depending on the need, to change the degree of decisions. Models reveal the vagueness of input estimates, increase the degree of validity of future decisions, and focus on the impartial evaluation of projects, which in turn increases the security of their financing.The key result of the presented paper is a comprehensive approach to the evaluation of projects to improve the sustainability and health of regions and cities, within the European Green Deal and Industry 5.0 concepts, for practical use by evaluation commissions and decision-makers at national and local level, or private sector levels. The final algorithm of the hybrid model and its verification of applicability for the evaluation of projects in the selected area of interest of the grant provider confirmed the validity of hypothesis H1 and also confirmed the validity of hypothesis H2. In the context of the European Green Deal goal to reduce the net greenhouse gas emissions to zero by 2050, the novelty of Simionescu et al.\u2019s paper  is relatRL statements, to combine conclusions about the level of probability of risk situation and the number of confidences of the expert\u2019s opinions on providing their opinion, to aggregate The disadvantages (limitations) of this model include the use of different types of membership functions, namely: for fuzzy The rationality of the obtained assessment of the level of expediency of project financing proves the advantages of the developed model. The reliability of the obtained results is ensured by the reasonable use of the apparatus of fuzzy sets, intellectual analysis of knowledge, and systematic approach, which is also confirmed by the results of the research.For the first time developed information models of input data for evaluation of projects to improve the sustainability and health of regions and cities. The set of criteria is open, and the model does not depend on their number. Project analysts can always adapt many criteria to highly specialized project topics;The model uses an adequate apparatus of fuzzy sets and allows obtaining a quantitative assessment of the project based on input descriptive  data obtained from the project application, which increases the degree of validity of future decisions;The model reveals the vagueness of input estimates and can derive a quantitative normalized initial value of the risks of the project, which increases the degree of validity of further management decisions;The model determines the level of feasibility of project financing, considering the target needs of investors and expert opinions on the possibility of achieving goals to improve the sustainability and health of regions and cities through the implementation of this project. The hybrid complex model focuses on the impartial evaluation of projects and increases the security of their financing;The model is easily adapted for different size grant projects and competitions;The results demonstrate the applied value of the methodology for assessing the level of decision-making, the feasibility of project financing in conditions of uncertainty, and the importance of making sound management decisions based on expert opinions and unclear conditions.To develop a complex hybrid model for evaluating projects to strengthen the resilience and health of regions and cities, the authors used their experience with a team of researchers and members, respectively: chairman of the working groups for transport and health infrastructure within the activities and plans for economic development and social development of the selected regions. Findings from the stack of project intentions, 896 projects in the field of transport, influenced the creation of an algorithm for solving the problem. Seven invited experts with more than 15 years of experience in project management helped determine the evaluation criteria. The algorithm of the expert model was verified using five real projects. The gained experience enables the transfer of knowledge and the methodology of solving the problem has the potential for repetition by other researchers, resp. project evaluators in practice. The new contributions and new understanding in the field based on the research of the topic are as follows:The created hybrid model has the potential for implementation in the following key areas. The model can be used to support the decision-making processes of evaluation commissions at the level of public administration and self-government and entities authorized to implement regional policy and local self-government with the support of specialized, targeted projects, resp. programs. Second, the model can be used in the environment of small and medium enterprises, respectively, in the non-commercial sphere. Third, the results of scientific research can also be used to educate and support young scientists and professionals with social responsibility, which is usually reflected in the creation of social responsibility of companies, institutions or public associations in an open civil society.The following research will focus on the development of information technologies for the evaluation of projects to improve the sustainability and health of regions and cities, within the concepts of the European Green Deal and Industry 5.0. The integration of human values with advanced technologies remains a major challenge. Information technologies will be based on the created hybrid model and software for project evaluation. Information technology, the hybrid model and software will together support decision-making on the security of grant funding. The developed model and its software support will be a useful tool for project analysts in preventing inefficient project financing and supporting the European Green Deal and Industry 5.0 concepts. Addressing this issue is also of great importance for countries applying for membership of the European Union, such as Ukraine. A state devastated by the war will have to rebuild society and the economy, while transparency of processes and independent expert evaluation of projects remain a constant challenge."}
+{"text": "Musculoskeletal and connective tissue diseases represent a growing public health problem, a great burden on health systems and place a heavy burden on society as a whole. Patients with musculoskeletal and connective tissue diseases often retire early, and any early retirement that could be prevented represents a loss of human capital, which means great social and economic damage to society. The present study was conducted in order to calculate for the first time in Slovenia the costs of the six most common diseases of the musculoskeletal and connective tissue diseases for the period from 2016-2018.The calculated burden of musculoskeletal and connective tissue diseases was based on the calculation of various direct and indirect costs cross-sectionally at the level of one year. The methodology of National Transfer Accounts (NTA) was used for the calculation of indirect costs. Six major diagnoses based on the International Classification of Diseases and Related Health Problems for statistical purposes were selected for calculation. Data were obtained from different national routine databases.Calculations of the economic burden of musculoskeletal and connective tissue diseases in Slovenia showed that the economic costs of six selected diagnoses in the period 2016-2018 averaged about 5% of total health expenditure or 0.4% of gross domestic product in this period. The highest direct costs were hospitalizations, followed by costs for medicines, first curative visits at the primary level and visits to the outpatient clinic at the secondary level.The results of the first calculation of the burden of musculoskeletal and connective tissue diseases in Slovenia showed a high economic burden of these diseases in the period from 2016 to 2018. The economic burden is underestimated and would be significantly higher considering all diagnoses from this group of diseases.Reducing the burden of musculoskeletal and connective tissue diseases is absolutely necessary in view of the aging population and in the light of the sustainability of health systems.The preparation of strategic documents for the promotion of musculoskeletal health and the consistent implementation of their contents has become urgent in Slovenia."}
+{"text": "In the mechanical characterization of materials or devices, the real load conditions to which they will be subjected in their operational environment must often be simulated by starting from the availability of universal testing machines. Although sophisticated, these machines only apply uniaxial loads or, at most, simultaneously apply loads along few degrees of freedom.With the aim of investigating the structural behavior of materials and devices, usually researchers check the availability of adequate existing testing machines before inventing new loading systems and verify the existence of indications in the International Standards or in the literature. In the field of biomedical engineering complexity grows due to the peculiar loads  and environments to which biomaterials and medical devices are subjected. They, indeed, will be coupled to the receiving organs or tissues once implanted.This Special Issue was born from the desire to give space to the imagination of the researchers involved in the conception and design of experimental benches able to simulate the real load conditions under which biomaterials and medical devices will operate. In the Special Issue, seven papers were published which explore different contexts in which the design of novel loading systems constituted the originality of the research. They range from the characterization of the mechanical behavior of biomaterials ,2 and ofThe aim of the investigations ,2, in thin vitro.Only recently, ovary responsiveness to mechanical signals was exploited for reproductive purposes. Poor characterization of ovarian cortex biomechanics and of the mechanical challenge hampers reproducible and effective treatments, and prevention of tissue damages. In , the bioMaterials for the collaborative and peer-review process. We hope that the scientific community of Materials will enjoy reading this Special Issue and find new ideas for future and present research works.The Editors give special thanks to the authors and the editorial team of"}
+{"text": "The authors regret that in the published paper, the affiliations of the authors were wrongly designated. The corrected version is shown here.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "The article presents the technological aspects of the diagnostics of grinding processes. The main features of the grinding process and their importance in diagnostic issues are discussed. Selected issues of research and assessment of the condition of the active surface of grinding wheels are presented. The authors pointed out that the parameters used to assess the topography of the ground surfaces do not have sufficient possibilities to differentiate the surface condition of the grinding wheels. This publication draws attention to the possibility of using new dedicated parameters to assess the properties of the grinding wheel surface. These parameters have a high ability to differentiate changes occurring as a result of the abrasion of grain vertices, their chipping or loading of the grinding wheel surface. The methodology of assessing the processes of abrasive grain wear and changes in the shape and dimensions of the grinding wheel, taking into account the probabilistic features of the grinding process, was formulated. The directions for the development of abrasive tools are presented, pointing to hybrid tools with a multi-phase structure, modified by additions of abrasive aggregates. A new research direction has also been formulated on the use of additive technology to produce specialised abrasive tools, including those with built-in process sensors. The analysis of phenomena and factors influencing the quality of the grinding process allows us to distinguish the following groups of inaccuracy causes:The multitude of factors and phenomena occurring during the grinding process makes the development of comprehensive diagnostic systems a task that requires taking into account many factors with a complex mechanism of cumulating effects of their interactions. In this work, the characteristic features of grinding processes, influencing the resultant values of the process and useful in its diagnostics, are indicated .variability of the nominal depth of cut, which depends on the kinematic characteristics of the method ;the irregularities of the workpiece surface in the machining zone and formation of the side pile-ups in the abrasive grain\u2014workpiece contact zone ,3;local susceptibility of the workpiece material and abrasive grains ,4;local variations of the grinding wheel active surface ,6;vibration of the tool and abrasive grains ;significant local variation (in the grain interaction zone) of temperature rise ,9,10,11;macro- and micro-discontinuity of chip and pile-ups formation ;micro chipping of grains and changes in the grinding wheel active surface ,16,17.Significant factors influencing the results of the material removal process by abrasive grains include, among others: the random size and shape of abrasive grains, their random distribution on the tool surface, complex wear processes of the tips and whole abrasive grains. To this should be added the discontinuity of the process of micrograin formation . Local thermal and mechanical deformations of tools and workpiece material, especially linear and angular displacements of abrasive grains under the influence of cutting resistance, are also important. In abrasive micromachining, as well as in various varieties of precision grinding, the penetration of the cutting edge into the workpiece material is much smaller than the radii of the roundness of its corners and is comparable to the height of the surface roughness in the machining zone. The variability of the penetration of the abrasive grains into the workpiece material is an unfavourable but unavoidable feature of micro-cutting processes. At the same time, it should be noted that the specific energy of machining depends not only on the average values of the parameters of the layers cut by individual edges, but also on the range of variation and distribution of the values of these parameters. In all machining methods, abrasive grains in the contact zone with the workpiece, move tangentially to the machined surface, and their penetration into the material is variable along the cutting path. The variability of the cavity is the result of many factors. Among the most important are:In front of the abrasive grain, between the bottom of the rake surface and the shear surface of the workpiece material, a zone of material stasis is formed, which cannot be stable under the conditions of very high temperatures and the discontinuity of the alternating process of accumulation of local deformation and separation of the material. This was also confirmed by the results of process modelling, illustrated in The random component depends most heavily on the wear of the grinding wheel and random causes of kinematic inaccuracy of the technological system, with the distribution of the random component approximating a log-normal distribution. In process modelling and simulation, when a random number generator is needed, one of the model distributions is usually chosen, which can cause errors when data from real processes indicate an unusual form, such as multimodal. The probability of contact between the grains on the surface of an abrasive tool and the material of a workpiece with a specific surface topography depends on the statistical characteristics of the distributions of grain vertices and ordinates of the machined surface , the thiA characteristic phenomenon in the initial zone of contact between the grain and the workpiece  is the discontinuity of the process of starting and stopping micro-cutting, noticeable especially for larger susceptibilities of blade attachment. This is understandable, since even the cutting process with larger cavities, considered a continuous process, is characterised by micro-discontinuities in chip formation . From the microscopic examination, it is clear that the lateral material pile-ups overtake the edge of the blade and are then partially removed, as the surface of the pile-up on the side of the micrograin is smoothly shaped by the grain. The top edge of the pile-ups is sharp and has rounding radii of less than 0.1 m in many places. In micro-cutting processes, a reduction in the coefficient of friction between the grain and the workpiece material makes it more difficult to form a chip, while increasing the coefficient of friction causes favourable changes in the actual angle of attack and a marked reduction in the effective radius of the rounded cutting edge\u2014which increases the possibility of effective cutting with grains that are shallowly embedded in the workpiece material.Increasing the coefficient of friction between the grain and the workpiece material expands the dead zone. Cutting under such conditions is easier and more similar to chip cutting, as the specific energy decreases resulting in lower temperature increments, which is conducive to reducing tensile stress values in the surface layer, although the micro-cutting process may be less stable. Cutting with a wide edge parallel to the machined surface and located perpendicular to the direction of the main movement, extends the path of lateral material displacement, which makes it more difficult to form pile-ups and favourably reduces the ratio of the volume of lateral ridges to the volume of material removed ,19. A coDedicated optical systems ,21,22, mThe topography of the active surface of an abrasive wheel with certain characteristics affects not only the geometric structure of the ground surface and the intensity of grain chipping, especially at the initial stage of the life, but also the specific energy of machining . A high The assessment of the machining potential of grinding wheels results both from the physical properties of the tool  and from the geometrical parameters of the grinding wheel active surface that change during machining. The mechanical and chemical properties of the grinding wheel do not change much during grinding, while the condition of the wheel\u2019s active surface changes due to wear processes. Three main wear processes can occur simultaneously: abrasion of the grain tips, microchipping and chipping of the grains and loading of the active surface with machining products. Abrasive grain tip grinding contributes to increased forces and specific energy; grain tip chipping is a process of renewing cutting properties, and whole-grain chipping results in deviations in tool dimensions and shape.identifying forms of wear, taking into account that the methodology and measures for evaluating the effects of each form of wear will be different;determining the methods for the analysis of the grinding wheel active surface (advantageously without disassembly the grinding wheel from the grinding machine spindle) using scanning methods  used in selection of areas to be measured, and consideration of the variation of micro-cutting conditions and grain wear characteristics in different zones of the active surface ;determination of tool life criteria.Moreover, in the machining of light metal alloys, fragmentary loading of the active surface of grinding wheels with machining products may occur. In formulating an effective methodology for evaluating the topography of the grinding wheel active surface, in terms of detecting adverse changes, the following problems can be distinguished:The bases for selecting parameters for evaluating the condition of grinding wheel surface topography are different from the bases for evaluating the geometric structure of machined surfaces. In the analysis of grinding wheels, it is important to isolate individual abrasive grains and determine their geometric parameters  and to iThe functional characteristics of the ground surfaces and the grinding wheel surface are significantly different. As a consequence, most of the parameters useful in assessing the surface topography are not useful for assessing the active surface of grinding wheels.For various tools and machining processes, it is reasonable to adopt a dedicated set of parameters to evaluate the stereometric features of the surface. The parameters included in the assessment set should be a complementary set, ensuring high efficiency of classification, ease of interpretation and technological usefulness. The analysis of the shape and distribution of abrasive grain tips and their substitutions occurring during the grinding process is, in many analyses, the basis for process evaluation and prediction of machining results. Data acquisition, describing the active surface of the grinding wheel, is usually accompanied by difficulties due to the low reflectivity of the active surface of grinding wheels and its complex structure. Measuring the surface topography of abrasive tools is possible, for example, using a laser scanning confocal microscope LEXT OLS 4000 , but the limitation is the maximum height of the object being measured. It becomes necessary to use replicas of the surfaces under study  with a pAnalysing the chip and side pile-ups formation mechanism, it can be concluded, that grain orientation with respect to the direction of grinding and increasing the width of the cut layer is one way to reduce unfavourable lateral material flows. Reduction of lateral material flows occurs for grains having a flat or more favourably concave contact surface with a small rake angle \u03b3 . Vertex features such as large radii of rounding are unfavourable, and even less favourable are vertex abrasion and loading of the tool surface with machining products.Vertex parameters are particularly important in the assessment of surfaces. They are active areas of the grinding wheel in contact with the workpiece. Therefore, from the point of assessment of the cutting ability of the grinding wheel, special attention should be paid to the features of vertices located in a certain range of ordinates, e.g., from 0.1 to 0.4 of the value of the St parameter from the highest surface vertex . the distance between the vertices using the nearest neighbour method ;the relationship between the area of the abrasive grain base and the area of the Voronoi cell;the inclination angles of the lines connecting adjacent grain vertices.Valuable conclusions regarding the results of the abrasive machining process can be drawn, among others, from the division of the tool surface using Voronoi cells. Each Voronoi cell contains one surface vertex (abrasive grain). The division of the surface carried out in this way makes it possible to determine:assessing grain activity,predicting the specific energy of machining, which depends on the distribution of geometric parameters of layers cut by individual grains,evaluation of tool wear processes,selection of machining parameters.Evaluation of the distribution and shape of grain vertices\u2019 elevations above a certain level from the highest apex can be the basis for, among other things:area of elevation over a specific plane,area of the base of the elevation, geometric centres of the elevations, number of elevations,the height and height dispersion of the tops of the elevations,the average distance between the vertices of the hills, determined from the decomposition of the surface into Voronoi cells and the area of the Voronoi cells.Important control features include:The geometric parameters of the characteristic features of the active surface of the grinding wheel can be used to identify and classify the forms of wear. In the classification process, it must be taken into account that the abrasive wear area of the abrasive grains is much smaller than the cross-sectional area of the abrasive grain. Flat areas, resulting from the clogging of the grinding wheel surface, are characterized by a larger area and circumferential development. In the example described below for the identification of abrasive wear and loading on the surface of grinding wheels, the following grinding wheels manufactured at ANDRE ABRASIVE ARTICLES  were used . The parA sliding analysis window was used by performing detection of flat areas  on the aThe previously described measures for assessing the condition of the active surface of abrasive tools contain characteristics that are important, but their information content is only magnified in a properly selected set of several measures. In the case of the evaluation of the active surface of abrasive tools, the evaluation of the features that have the greatest impact on the results of the process and the prediction of tool life is of particular importance. These features relate primarily to the shape and position of abrasive grain vertices. The parameters proposed in the paper  for evali\u22121, zi, zi+1, .The discrete value of the TKEO operator can be estimated from three adjacent samples of the signal zIn the assessment of the active surface of abrasive tools, the geometric parameters of the areas covering the tops of grains are of great importance. This assessment is made using the cut-off surface at a specific level h. In the case of evaluating the height and variability of hill heights, it is reasonable to determine the absolute value of \u03a8z. The usefulness of the \u03a8z index for surface assessment, even after these changes, is limited. This is due to the determination of the value of this parameter from the surface profile. This reduces the informative usefulness of the \u03a8z indicator in the analysis of the topography of the grinding wheel surface.The authors of  thereforthe processes of chipping caused by exceeding the strength of the grain and chipping caused by exceeding the resistance to total load occur in parallel;grains with longer operating time are characterised by greater abrasion, which causes an increase in load;the process of spalling due to exceeding the strength depends on the distribution of the grain\u2019s limiting strength and the distribution of grain load, varying during successive contacts of the grain with the workpiece;the intensity of chipping of grains in the first stage of the grinding process decreases with the passage of grinding wheel operation, especially when coarse shaping is used;the variable intensity of strength wear depends on the characteristics of the abrasive tool, in particular, on the abrasive material and bond used, as well as their share in the volume of the grinding wheel;in the process of grinding with grinding wheels of low hardness, the process of chipping of whole abrasive grains prevails, while in the case of higher hardness of the tool, the processes of microchipping of grain fragments or increasing abrasive wear of grain vertices become more important;chipping of active grains causes a reduction in the total area of abrasion of all active grains;the number of grains chipped at a given moment is a time-dependent value;under operating conditions with intensive self-sharpening, the probability of grain chipping does not depend on the operating time of the grain;under operating conditions of a grinding wheel with limited self-sharpening, the average waiting time for chipping in a group of grains with a fixed working time, may depend on the total working time of the abrasive grains;the distribution of working time of active grains varies with the grinding time;constant chipping intensity can be described by an exponential distribution of grain life;decreasing chipping intensity can be described by a logarithm-normal distribution of grain life;increasing chipping intensity can be described by a normal one-sided truncated grain life distribution or a Weibull and gamma distribution.In the study of grinding wheel wear processes caused by the phenomena of abrasive and fracture wear of abrasive grains, it should be taken into account that the grinding and wear processes of the grinding wheel depend on the variable state of the active surface of the wheel and are not stationary processes. On the basis of the conducted studies of grinding wheel life, the following conclusions can be made about the diagnostics of the intensity of shaped and volumetric wear of abrasive tools:iy are functions of the grinding parameters ix1, measurable but uncontrollable quantities i2w and disturbances iz?, the number and impact of which are unknown.Determining the life of a grinding wheel requires an assessment of whether a specific set of conditions describing acceptable changes in the characteristics of the process or results of the machining operation are met. These changes are mainly due to the wear processes of the active grains and the resulting changes in the properties of the tool. The output quantities of the grinding process sK the value of the feature whose level is closest to the limit of the permissible value.For typical grinding processes, the set of limiting conditions does not include the values of the process parameters, because these are invariant. The conditions refer to the normalised Kproc process characteristics and the results of the Koper machining operation, defined so that decreasing their values mean decreasing the period that remains until the end of the life:ix, the assumed lifetime s(xi)T will be such that the limiting conditions imposed on the selected quantities jy will be satisfied throughout this time. In the period from the beginning of machining to the tool life, the progressive wear of the active surface of the tool causes changes in at least one of the conditions ik(t)w.In doing so, it is assumed that for certain grinding parameters sT, in which all the recorded and normalised process features and machining results are within the limits of their acceptable deterioration, is determined by the relation:The lifetime of the grinding wheel sT is equal to the sum of the times of grinding operations after which at least one of the process characteristics or characteristics describing the results of the process reaches the limiting value  is the main time depending on the volumetric efficiency of grinding vQ, kt is the time of shaping the surface of the grinding wheel, uk denotes the normative of supplementary time and sT denotes the life of the grinding wheel depending on vQ and a set of limiting conditions gW, imposed on the machining operation.In the diagnosis of grinding processes, assessments of the production efficiency of grinding operations gt on the volumetric machining capacity vQ is a deterministic dependence, while the dependence of the grinding wheel life sT on both the capacity vQ and the limiting conditions gW imposed on the process and machining results is a stochastic dependence. In a typical situation where several process features or machining results are used to evaluate the life of a grinding wheel under supervised conditions, it must be taken into account that in subsequent life periods, the time remaining to renew the tool surface may be determined by features different from those of the previous period. This contributes to the considerable complexity of the decision-making process in these tasks. Supervising the condition of a tool significantly improves the utilisation of the tool\u2019s machining potential during each tool life, which means lower tooling costs, lower machining costs and increased productivity as a result of reduced tool surface renewals.The dependence of the main time The observed development of abrasive machining processes has involved the development of new abrasive materials and bonding agents, the improvement of abrasive tool features, the introduction of new machining methods, more efficient and economical methods of using machining fluids, new machine tools and the spread of supervisory methods. As a result, significant results are being achieved in improving surface quality and machining accuracy and efficiency. New machining methods are being developed and the range of applications for high-precision machining is being greatly expanded. New tools increasingly have a functionally locally differentiated structure.It can be predicted that the near future will see the development of abrasive tools with a multiphase structure, i.e., hybrid tools, in which the conventional porous structure consisting of grains and binder will be modified by additions of other phases in the form of abrasive microaggregates, local bands or layers. Applications of 3D printing to produce special abrasive tools can also be expected. For example, by introducing new abrasive microaggregates into the structure of bonded abrasive tools, there is a quantum leap in the adaptability of tools to the requirements of various technological operations. The tools currently in use can be differentiated by changes within certain limits concerning only the type and size of abrasive grains, bond and structure. In the new tools, it will be possible to further differentiate tool features by selecting the size of microaggregates, grains and binders that make up these aggregates, as well as by varying the types of aggregates and their proportion in the grinding wheel. The use of micro-aggregates makes it possible to achieve adaptive grinding wheel structures, as a different mechanism of micro-aggregate self-sharpening can be used to spontaneously create increased porosity on the active surface of the tool in the form of pits. It is also possible to locally  vary the proportion and type of aggregates in the tool volume.Along with microaggregates, additives may be introduced to reduce the specific energy of grinding, additives to reduce the effects of the environment on the machined surface, and additives conducive to obtaining special structures in the form of regular macrogeometry, with specific operational or decorative significance. In subsequent phases of development, microaggregates may also, in applications for particularly important operations, contain substances used for process diagnostic purposes and tool condition evaluation, inducing, for example, a change in the colour of the machining fluid or the workpiece surface. The biggest development challenge in the near term may be the manufacture of abrasive tools that would have built-in sensors for evaluating grinding power or temperature, as well as wireless transmitters of control signals.Comprehensive diagnostics of grinding processes includes many features, the analysis of which requires consideration of the probabilistic basis of inaccuracies in the shaping of workpieces, random variation, fluctuations and complex mechanisms of phenomena in abrasive tool wear processes.The methodology for the study and evaluation of the condition of the active surface of tools is one of the complex issues, as it requires evaluations derived from complementary sets of parameters, with typical parameters for evaluating the geometric structure of the surface in this application not having sufficient capacity to differentiate the condition of the tool surface. Acquisition of data describing the surface without removing the grinding wheel from the spindle through optical inspection systems or surface replica techniques is being sought.This publication identifies new dedicated parameters for evaluating grinding wheel surface properties with a high ability to differentiate changes occurring as a result of abrasion of grain vertices, their chipping or loading of the grinding wheel surface. Such parameters are, among others, an index that integrates the influence of height and sharpness of abrasive grain vertices. The described parameters are characterised by higher informational usefulness, meet the condition of complementarity, and facilitate the determination of possible corrections to the process of shaping the surface of grinding wheels and the prediction of their service life.In the diagnosis of grinding processes, analyses of the specific energy of machining and ways to reduce the energy intensity of the processes play an important role. The purpose of diagnostic procedures is to ensure the required quality and efficiency of machining. This publication also presents abrasive tool development directions concerning hybrid tools with a multi-phase structure, in which the conventional porous structure consisting of grains and bonds will be modified by additions of other phases in the form of abrasive microaggregates, local bands or layers. The use of incremental techniques (3D printing) to produce specialised abrasive tools, including those with built-in process sensors, can also be envisioned."}
+{"text": "The problem of local instability in the compressed facing of a sandwich panel is considered in the paper. The case of a facing resting on an infinite core is examined, but the validity of such a simplification has been discussed in detail. An energy approach is used to solve the problem. The general procedure for considering the influence of the core parameter variability on the value of stress causing the facing instability is presented. Expressions allowing us to calculate the wrinkling stress were derived, which was the main aim of the research. The heterogeneity of the core material is taken into account by using continuous functions describing the variability of the core material parameters. In the examples illustrating the theory, the exponential and polynomial functions were used. The examples are based on the actually measured elastic modules of the core. The presented considerations were extended to the analysis of strain energies, which confirmed that the properties of the layer adjacent to the facing (up to 2 cm thick) determine the value of the wrinkling stress. The paper presents an example of the optimization of core material parameters in which a change in the distribution of the core parameters led to an approximately threefold increase in the wrinkling strength of the sandwich panel. The subject of the analysis is sandwich panels made of thin but stiff facings and a thick but deformable core. The core can play various roles , but most of all it ensures the distance between the facings, which results in a significant increase in the stiffness and load-bearing capacity of the panels. These types of integrated structures are used in many industries. Although there are many mechanisms of failure within sandwich panels, in most cases the load-bearing capacity of the entire element is determined by local loss of stability, which has the form of wrinkling of the compressed facing. Compression in the facing can be caused by compression or bending of the sandwich element, but it can also be the result of thermal effects. In order to determine the appropriate load-bearing capacity of the panel, it is necessary to determine the stress that causes wrinkling of the facing.The problem of determining the wrinkling stress in the case of a facing resting on a homogeneous core was solved by Hoff using the energy method and the linear decay function of the core deformation . PlantemThe influence of the heterogeneity of the core on the value of critical stresses was presented in . Two casented in . Two symScientific research on wrinkling of thin facing is still of great interest because the problem of local loss of stability is important in many applications . For exaThis paper considers the case of a facing resting on a core with variable material parameters. A continuous function of the variability of these parameters was assumed. The focus is on the exponential and polynomial functions, but there are no obstacles for it to be of any function. The main purpose of the research is to derive the equations for the wrinkling stress of a sandwich panel with the material properties of the panel core varying in thickness. In order to determine the critical stress, the energy approach was used similarly to . The papThis work can be considered in the context of previous analyses ,24. ThesThe motivation to take up the presented issue was that the current technological possibilities of the production of sandwich panels allows for the production of a core with parameters varying in its thickness. The study of the variability of these parameters does not pose any major problems either. The digital image correlation (DIC) method is commonly used . Figure One of the key problems that manufacturers of sandwich panels are currently working on is to obtain such a distribution of the core parameters that will ensure the maximum load-bearing capacity of the sandwich element with the minimum use of raw materials. Due to the growing technological possibilities of producers and a great emphasis on sustainable development of the industry, the issue of optimal distribution of the core material presented in the article seems to be strongly justified.During the bending of a sandwich panel with thin facings, one facing is compressed and the other is stretched. The case of unidirectional compression of the ideally flat facing is considered. The influence of initial irregularities of facing was no taken into account. A detailed analysis of this issue will be the subject of further research. Due to compression, the instability of the facing occurs, which has the character of periodic wrinkling. In order to determine the critical stress causing the local instability (wrinkling stress), the facing resting on the infinite core is examined . Such a Linear constitutive relationships were assumed for the facing and core materials. It was also assumed that the properties of the core change continuously along its thickness. In general, the modulus of elasticity z. As in ,12. Corealia, in .In order to determine the wrinkling stress, the energy approach was used in this paper. The basic Equations (1)\u2013(11) can be found in .Assume that the form of the facing deformation x-z) of the core material are functions of the position variable z.The energy balance equation for the system shown in After substituting (4)\u2013(8) to (3) and several transformations, we obtain the expression for the normal stress in the facing For any functions From condition (11), Let the exponential form of the core parameters variability be assumed:To find the wrinkling stress, one should find For the special case The general form of a polynomial describing the variability of the core parameters is taken as:If The distribution of the elasticity modulus presented in For the sake of simplicity, it is assumed that the function From 4, 3, 2, which means 4, 2 and 2. For these parameters, a quantity From It turns out that for It is worth noting now that the discrepancy between the results obtained for two different functions does not result from the determination method itself, but from differences in the values of the respective functions In order to trace the relationship between the energies expressed in (4) and (5), we consider two cases: the exponential function from the example above  of the facing resting on the deformable core was analyzed in the paper. The case of uniaxial compression of the facing was considered. The core was assumed to be infinitely thick. Such a simplification, although it may turn out to be very limiting, is in many cases acceptable due to the rapid decay of the strain energy and deformation of the core.In the first part of the paper, using the energy approach, the procedure for determining the wrinkling stress was presented in the case of a core with any variation in its material parameters. This procedure was used to obtain a solution for a core, in which material parameters are expressed with an exponential or polynomial function. The equations are illustrated with examples that use discrete values of core modules determined on its thickness. The presented procedure is general and can be applied to any function describing the variability of the core properties.More than 90% of the strain energy of the core is stored to a depth of about 2 cm from the facing, which means that the value of the wrinkling stress is mainly determined by the layer adjacent to the facing;Core deformation is reduced by 90% at a depth of 6 cm (core with variable parameters) or at a depth of 3.5 cm (core with constant parameters), which means that considering the theoretical case of an infinitely thick core is acceptable in most cases;The strain energy of the facing deformation is always equal to the normal strain energy of the core; the shear strain energy of the core is equal to them only when the core parameters are constant across the thickness;In the case of non-linear (disappearing with thickness) distribution of core material parameters, the shear strain energy of the core has a decisive influence on the wrinkling stress.The considerations concerning the strain energy in the system showed the following:The last part of the work presents an example of optimizing the distribution of core material parameters, the aim of which was to maximize the wrinkling stress. An optimal solution was obtained for the assumed class of exponential functions and for the introduced constraints. The solution is characterized by high material modules in the layers adjacent to the facing and a quick reduction of these modules in the thickness of the core.The presented considerations explain the enormous and practical influence of the distribution of core material parameters on the load-bearing capacity of a complete sandwich panel. The derived equations can be directly used in the production of sandwich panels with a better distribution of the core material parameters."}
+{"text": "RSC Advances is publishing this expression of concern in order to alert our readers that we are presently unable to confirm the reliability of the data presented in the article.The Royal Society of Chemistry was contacted by a reader who raised concerns about the reliability of the data presented in Fig. 2, 3 and S7 of the paper. The authors are unable to provide raw data to corroborate their work.The Royal Society of Chemistry has asked the affiliated institution (Indian Institute of Technology Mandi) to investigate this matter and confirm the integrity and reliability of the data in Fig. 2, 3 and S7 of the paper. An expression of concern will continue to be associated with this manuscript until we receive information from the institution on this matter.Laura Fisher01/07/2022RSC AdvancesExecutive Editor,"}
+{"text": "The social, ecological, health and economic crisis exacerbated by COVID-19 is a challenge of extraordinary magnitude and complexity for global public health. Part of the response to these challenges requires strong public health institutions.Component 18 of the Government of Spain\u2019s Recovery, Transformation and Resilience Plan proposes the creation of a Spanish Agency of Public Health (SAPH), a centre of excellence to perform surveillance and health system preparedness functions in the face of new or emerging public health threats. The government has opened the debate on what design and functions it should have.SESPAS, the Spanish Society of Public Health and Public Administration, set out a proposal for the design and organization of the future Spanish Agency for Public Health [SAPH]. A large working group, made up of experts from various fields of public health and from its ten federated scientific societies, has designed the SAPH proposal. The scope of the public health functions to be assumed include: the strategic planning of the State\u2019s public health , the prioritisation of public health policies and communication strategies, the assessment of the population\u2019s health status and social conditions, the guarantee of the transversality and horizontality of health policies , as well as their verticality . The proposal also include 11 recommendations on the main elements to be taken into account in the establishment of the future SAPH.COVID19 pandemic has highlighted the need of creating strong public health institutions. Spain is giving its first steps toward the creation of the SAPH, which constitute a key step in addressing the current and future challenges of public health in Spain.\u2022\u2002Spanish Public Health Agency is an opportunity to transform health policies and to improve the health of the Spanish population.\u2022\u2002Strengthening public health starts with building national institutions that ensure comprehensive and integrated health policies."}
+{"text": "Bioscience Reports at the request of the Editor-in-Chief and the Editorial Board following receipt of a notification from a reader, alerting the Editorial Board to similar regions that appear in both the miR-145 mimic and siHOXA1 panels of figure 4C, as well as concerns regarding the western blots of figures 6 and 7. The authors have been contacted with regards to the retraction and have not responded to the Journal's queries or concerns raised. Given the extent of the issues raised, the Editorial Board stand by the decision to retract the article.This Retraction follows an Expression of Concern relating to this article previously published by Portland Press. This article is being retracted from"}
+{"text": "The authors regret the omission of one of the authors, Sakur Mahmud, from the original manuscript. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "Effectiveness of ertapenem for treatment of infections in children: An Evidence mapping and meta-analysisA Corrigendum on In the published article, there was an error in The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "The volumetric primary standard with a constant volume (pVTt) determines the flow rate from the rate of change of gas density in the defined measuring volume. The key element of the measuring system that uses the flying start\u2013stop method is a diverter. This paper presents a time correction model that adapts the correction according to the diverting speed implemented in our pVTt system developed for flow rates smaller than  The current metrological capabilities for the gas flow measurements of the Laboratory for Measurement in Process Engineering at the Faculty of Mechanical Engineering, University of Ljubljana cover the range down to Primary standards for flow measurements all rest on the fundamental physics of mass accumulation in a certain time window. When the fluid is a gas, there are two basic groups of primary standards. Gravimetric standards use scales or mass comparators to evaluate the mass change of a depleted/filled pressure vessel ,3,4,5 wiWe focused on a volumetric method with a constant volume (pVTt) and a static method of mass determination that uses a flying start\u2013stop that guarantees the time for the flow stabilization. One of the key parts of this method is the use of a diverter, which diverts the flow in/out of the measuring volume surement . The basp and the temperature T at the start and the end of the measurement in stable conditions. The system is collecting mass, and the time window, when the flow is directed into the system, is called the effective collection time The densities of the confined gas at the start The aim of this article is to evaluate two methods for determining the time correction and set up a new time correction model that has the possibility to take into account potential changes in the operating speed of the diverter. The first method is derived from the ISO 4185  standardIn the I and Signal The diverter used for the flying start\u2013stop method for the flow measurement is a mechanical device that diverts the flow from one inlet between two outlets. This is achieved by moving a diverting element between two end positions. The diverter shown in I are labelled with A and changes of Signal While the diverter moves from one end position to another, the position signals change accordingly . For mosI  twice; it returns to the initial position. At the beginning of the measurement the gas accumulation begins when the diverter outlet to the environment is closed  in direct contact with the measured gas are pneumatically actuated. The entire system is inserted into the climatic chamber and is maintained at a constant temperature. The temperatures at three locations are monitored during the operation of the system. To monitor the temperature of the cylinder The pressure inside valve V2 . By immeAll the measured signals were processed and recorded on a PC in a LabVIEW environment. From the measured temperature and pressure the densities inside database . With LaThe basic idea of this method follows the method defined in ISO 4185  for measThe measurement system was programmed to continuously measure the flow rate with an alternating collection time. The correction time with Method 1 was calculated after each flow measurement (except for after the first one) from the last two consecutive flow measurements.The chosen diverting valve closes both outlets for a brief period of time (zero crossover). During the diversion, when both outlets of the diverting valve are closed, gas is accumulated in the volume upstream of the diverting valve (V0). After one of the valve outlets opens (into the measuring volume or into the environment) the accumulated gas is released. The effective time determination based on the matching densities upstream of the diverter at the start and end diversion is described in . We deciIn order to record the accumulation of the gas upstream of the diverter and define the exact moment of the outlet closure we used a piezo pressure sensor. An example of the acquired voltage signal at the start of the collection time is shown in e sensor . As diveEquation . The evaThe experimental results in this section were obtained for a flow rate of In n number of measurements. For forty consecutive measurements The combined standard uncertainty of the correction time according to Method 1 can be estimated as :(6)uurep using the flying start\u2013stop method with a static determination of the captured mass was presented. The flying start\u2013stop method greatly depends on the operation of the diverter, which is the main source of the necessary correction for the measured time. The uncertainty of the time correction is a major contribution to the system uncertainty when using short collection times. For example, standard , consideUsing Method 1 and controlling the operation of the diverter, the linear measurement model for the correction time was determined, which takes into account changes in the speed of the diverter. The uncertainty analysis of the resulting correction time took into account the uncertainty contributions related to the application of Method 1  and the uncertainty of the model approximation. It was estimated that the standard uncertainty of the model does not exceed A potential source of the observed dependency of the diverter\u2019s operation on the time between the two diversions is the stability of the driving pressure of the diverter. For that reason, the plan for the future is to improve the configuration of this part of the measurement system and re-evaluate both methods for the correction time. The uncertainty of the model for the correction time could be further decreased by defining a narrower speed range for the diverter during the use of the PVTt primary standard."}
+{"text": "The authors regret that an incorrect version of In addition, the authors regret that affiliation a was incorrectly shown in the original manuscript. The corrected list of affiliations is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "The authors regret the omission of a funding acknowledgement in the original article. This acknowledgement is given below.The authors would like to acknowledge the financial support of the Iran National Science Foundation (INSF), grant number 98017171.In addition, the authors regret that incorrect reference numbers were given in The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "Since the world entered the era of network information, the influence of the Internet has been expanding day by day, and today's college students are deeply affected by the network environment, which has also brought unprecedented challenges to the moral education work of colleges and universities. The rule of law education for college students is a key point for the comprehensive implementation of the strategy of governing the country by law. How to enhance the effectiveness and recognition of the rule of law education for college students has become an important task of higher education. Therefore, strengthening the legal education of college students is not only an inevitable choice to fully implement the rule of law but also a realistic requirement to improve the level of higher education and realize the all-round development of college students. College students' mental health education is an important part of the talent training system of colleges and universities, and in-depth exploration of the ideological and political laws of college students' mental health education courses is an inevitable requirement for implementing the fundamental task of Lide Shuren. College students' mental health education courses must be integrated into the ideological and political concepts of the curriculum, reflect the political orientation of ideological and political work, embody the law of educating people with morality as the first, and embody the practical purpose of psychology to pay attention to personality improvement. It is necessary to optimize the content of education and teaching, excavate the elements of ideological politics in the curriculum, enrich the resources of ideological politics in the curriculum, and explore a new way of reforming the ideological and political education curriculum for college students from the aspects of deeply planting family and national feelings, enhancing political identity, strengthening cultural self-confidence, cultivating Chinese temperament, clarifying the meaning of life, strengthening mission responsibility, enhancing civic awareness, and developing law-abiding habits. Strictly regulate the behavior of contemporary college students in the online environment, give full play to the role of legal education, and reduce the incidence of online incidents such as online fraud and cyber violence. This paper puts forward some problems in the current legal education of college students in China and points out the root causes of these problems. Methods for structural reform and advanced cultural construction based on social development are proposed. From a strategic point of view, it is believed that only by managing the reform of legal education and cultivating civic awareness can we completely solve various contradictions and problems among college students in the network environment and pave the way for the development of college students. Since the Fourth Plenary Session of the 18th Central Committee, under the background of vigorously promoting the construction of a country under the rule of law, my country has proposed more than 190 construction and reform tasks, and education is related to the future and development of the country. Construction is closely related. Colleges and universities, as important centers for cultivating talents, the rule of law education for college students is an extremely important part of the work of national rule of law education. The development of the rule of law education for college students is of great significance to the establishment of college students' legal thought, the improvement of legal awareness, the construction of a rule-of-law society, and the advancement of modernization [The 18th National Congress of the Communist Party of China put forward the strategy of comprehensively promoting the rule of law. To comprehensively promote the rule of law, it is necessary to continuously improve the social and legal environment. To comprehensively promote the rule of law is to promote the spirit of the rule of law in the whole society, publicize the concept of the rule of law, develop the theory of the rule of law, apply the thinking of the rule of law, innovate the way of the rule of law, and make the spirit of the rule of law and the belief in the supremacy of the law become the common belief of Chinese citizens. This special group of college students is the backbone of future social construction and will have a profound impact on the process of legalization in our country. Because college students have the characteristics of plasticity and strong educability, it is determined that they will be the focus of civic education on the rule of law. Therefore, college students are bound to take the lead in becoming citizens under the rule of law , 3. For Based on the above-discussed problems in legal education in colleges and universities, this paper investigates the status quo of legal education in college students through literature research and finds the main problems at present in the investigation process. In view of these problems, this paper puts forward corresponding solutions. Therefore, this paper is of great reference significance to grasp the historical responsibility and opportunity of the era of legal education in the new era and to construct and comprehensively promote the legal education and training system adapted to the rule of law.Legal education is an important task in ideological and political education in the new period, but also with the development of the times, now this kind of security education has become a key point in the practice of ideological education and political work, and it is necessary to stabilize the situation and go deep into the popularization of the law, which is quite critical for college students, requiring students to carry out the development of a political and economic environment, to educate young descendants with the basic knowledge of socialist democracy and law, to let young people receive this kind of training and some education, and to strengthen the concept of the legal system. High school in the United States refers to all institutions engaged in higher education after the middle school stage, including all colleges and universities including vocational and technical colleges, junior colleges, and community colleges. Among them, junior colleges and community colleges have the nature of postsecondary education, which makes more Americans think that they are transitioning from secondary education to higher education, rather than pure colleges and universities. Therefore, the concept of \u201cstudent\u201d in American colleges and universities is relatively broad, and in a sense, it is more closely related to society. In my country, it is quite different. According to the \u201cHigher Education Law of the People's Republic of China,\u201d my country's higher education institutions generally refer to universities, independent colleges, and vocational colleges, including higher vocational schools and adult colleges. What is a \u201ccollege student\u201d? According to Article 37 of the \u201cMeasures for Handling Student Injury Accidents\u201d by the Ministry of Education of the People's Republic of China, college students refer to those educated full-time in colleges and universities, including junior college students, undergraduate students, master students, and doctoral students. From the analysis of the scope of college students, college students in our country belong to a relatively closed educated group .College students are the main group on the Internet, and the quality of the network environment will directly affect the mental health of college students and the formation of values and will also directly affect the reconstruction of the educational environment. Therefore, it is of great significance to strengthen the legal education of college students . NetworkIn a certain sense, the legal education of college students determines the degree and level of socialization of college students and determines whether the transition from students, builders, and successors can be smoothly realized; in today's society of advocating the legal system and pursuing civilization, the level of one's awareness of democracy and the legal system and the rigor of the concept of discipline determine the degree of realization of personal and social values. Education in the concept of the legal system is an important way to enhance college students' awareness of democracy and the legal system and their self-consciousness of discipline, and it is necessary to grasp it in a down-to-earth, well-grasped, and thorough manner, so as to help enhance the civilization of the whole society. Social value refers to the contributions and responsibilities that individuals make to meet the material and spiritual needs of society or others through their own and self-practice activities. Personal value refers to the discovery and creation of an individual or society in production and life to meet individual needs, which is the contribution of individual self-development and society to individual development. It includes the personal value of the individual and the personal value of the society and contributes to the freedom of different subjects to the individual. The social value and the personal value of the legal education of college students are related to each other, promote each other, and distinguish each other. Therefore, the relationship between the two is dialectically unified. Individuals constitute society, exist in society, and create society. The ontological basis of social history is people, and society is the totality of people who are interconnected based on common material production activities . A socieThe social value and individual value of college students' legal education are interrelated, promoting, and developing together, which are different. In the network environment, the legal system education should be close to The Times characteristics, by building a legal system based on artificial intelligence network education platform, using data mining technology, ensure integration of the rule of law, case law education database, the use of experts and knowledge map to improve college students' legal quality, the overall system framework is shown in Psychology is the study of psychological phenomena, the exploration of psychological problems, and the revelation of the law of psychological development of science; the word psychology is derived from the Greek language, meaning the science of the soul; the core is to promote the integrity of human development and cultivate the perfection of students' inner personality. In 2011, the Ministry of Education issued the \u201cBasic Requirements for the Teaching of Mental Health Education Courses for Students in Ordinary Colleges and Universities,\u201d which clearly pointed out that the mental health education courses for college students \u201caim to enable students to clarify the standards and significance of mental health; enhance their awareness of self-mental health care and psychological crisis prevention; master and apply mental health knowledge; cultivate the self-cognitive ability, interpersonal communication ability, and self-regulation ability; effectively improve psychological quality; and promote the all-round development of students.\u201d The objectives of the mental health education course for college students include education at the knowledge level, education at the skill level, and education at the level of self-awareness, so this course must use the theoretical knowledge and methods of psychology according to the physical and mental characteristics and growth laws of students to cultivate students' self-esteem and self-confidence, rational peace, positive health status, and correct behavior habits; realize the unity of knowledge and intention; promote the comprehensiveness, richness, and integrity of students' personalities; and adapt students to the changing social environment. If the mental health education curriculum ignores the cultivation of students' personalities, cannot resolve psychological problems such as students' psychological distress, emotional confusion, and emotional disorders in a timely manner, gives play to the guiding role of positive cognition, the stimulating role of positive emotions and emotions, and the forging role of positive will, enhances the temperature of humanistic care and focuses on the shaping of students' personality; it will deviate from the goal requirements of the course's ideological and political cultivation of sentiment, warm heart, and sound personality.Contemporary college students, whether in the handling of individual consciousness and collective consciousness, in the balance of the online virtual world and real life, or in the choice of state responsibility and individual obligations, need to use civic consciousness to regulate and regulate informed intentions; otherwise, improper handling will greatly affect the mental health of college students. Therefore, in chapters such as \u201cCollege Students' Interpersonal Communication, Love Pursuit, and Stress Management,\u201d it is necessary to be good at integrating the educational content of civic awareness; take the cultivation of civic consciousness as an important starting point for promoting the mental health education of college students; use the situational teaching method to provide students with real-life scenarios; guide students to pay attention to strengthening civic awareness and legal awareness in the theoretical study of mental health; select typical cases; educate students in the practice of mental health; pay attention to transforming the requirements of the party and the state into the needs of college students' own growth; turn patriotic, dedicated, honest, and friendly civic consciousness into college students' daily code of conduct; promote the rationality and peace of college students' inner world; and develop good habits of abiding by the law. In order to understand the results of legal education and mental health education for contemporary college students in China, the research and analysis of college students was conducted.Through the above discussion of the concept and role of legal education in universities, the importance of promoting the legal education of college students can be basically understood. However, the achievements of online legal education can directly reflect the current situation of legal education in colleges and universities and the problems existing in the legal education of college students.College students have a strong intention to conduct independent legal education through the Internet, which provides basic support for improving the content of college students' independent learning of the rule of law education. College students can learn the content of the rule of law education independently through the Internet, which is not limited by time and space. College students can learn the content of the rule of law education through the Internet anytime, anywhere, which greatly improves the autonomy of college students to participate in the activities of the rule of law education. In order to adjust the basic situation of college students' online legal education performance, the relevant data were obtained through research students understand the way to know the rule of law, as shown in Most of the students believe that the Internet has a positive effect on the rule of law propaganda, and even 20% of the students believe that the Internet has a good effect on the rule of law education of college students, but 8% of the students believe that the Internet has no effect on promoting the rule of law education of college students; in addition, 442 52% of the students who participated in the survey chose \u201cthe effect is not obvious\u201d for the question of \u201cthe role of the Internet in the education of the rule of law for college students\u201d. The method is outdated and reduces the effect of using the Internet to promote the legal education of college students. At this stage, the effectiveness of using the Internet to carry out legal education in colleges and universities in my country needs to be strengthened. See Figures It is not very optimistic for college students to independently conduct legal education through the Internet. The Internet is an open space, and college students have more choices on the Internet . College1Conducted a survey on the specific situation of college students' use of the Internet and found that college students' use of the Internet mostly focused on life and entertainment, and less attention was paid to legal knowledge. The specific situation is shown in Figures 6With the vigorous development and rapid popularization of the network environment, China's college students have a poor concept of the legal system and a low legal quality, and it is difficult to meet the needs of a society ruled by law and the requirements of the reform of the market economic system. In order to improve the legal education of college students under the background of comprehensively raising civic awareness, we must first optimize the legal education environment in colleges and universities. The second is to accurately grasp the concept of legal education for college students, abandon the idea of utilitarian education, and continuously improve and perfect the educational model and approach. Focus on regulating the words and deeds of college students in the network environment.The legal education environment for college students is an important part of the social legal environment. College students live and study in a specific campus environment, and the school's legal education environment has a great impact on the legal education of college students . It is nThe rule of law education of college students is to cultivate students' legal awareness and spirit of the rule of law. We cannot emphasize the education of social value orientation and ignore the education of personal value orientation, so that students' legal education can become a law-abiding education for cultivating \u201cobedience to the people,\u201d and we can blindly emphasize personal value orientation education and ignore social value orientation education so that students' legal education can be cultivated. It is a \u201ctrickster\u201d who only cares for his own self-interest, only considers himself without considering others, and tramples on the rights and public interests of others for the sake of personal interests. The order and harmonious development of society have become empty words. The rule of law education for college students should abandon the utilitarian educational thought and realize the dialectical unity of personal value orientation and social value orientation. The Fourth Plenary Session of the Eighteenth Party pointed out that it is necessary to promote the whole society to establish awareness of the rule of law and carry out in-depth publicity and education on the rule of law; the purpose is to cultivate citizens' legal awareness and the spirit of the rule of law. The spirit of the rule of law is a concept with very rich connotations. It is a synthesis of the values of the rule of law, such as fairness, equality, freedom, order, security, and the consistency of rights and obligations. It is the spiritual pillar of the construction of the rule of law system. It is a comprehensive proposition that integrates the spirit of human rights, the spirit of justice, the spirit of rationality, and the spirit of harmony. It is a scientific spirit formed by legal consciousness, legal thinking, legal psychology, and legal culture under the rule of law. It is also the guiding ideology and spiritual source of the practice of the rule of law. The cultivation of the legal spirit is not only the core goal of socialist rule of law construction but also the basis of legal education for college students .When college students receive legal education, the most important thing is the learning process. With the popularization of the network environment, the advantages of the network environment can be rationally used to more widely transfer the understanding points and values of legal education, which has a good effect on enhancing the legal concept of college students. The education of the rule of law for students in colleges and universities not only includes the education of basic legal theory and basic legal knowledge but also, more importantly, cultivates students' legal awareness and the spirit of the rule of law. According to actual needs and in combination with different majors in colleges and universities, some legal courses related to the majors studied by the students of the school can be opened, so as to cultivate students' conscious awareness and knowledge of law-abiding, law-abiding and usage. Compared with boring theoretical lectures, it is closer to life and more attractive. Therefore, it is necessary to break the single teaching mode of purely theoretical professors and carry out a variety of teaching activities; for example, organize students to watch legal dramas, set up legal elective courses, court access to campus, and legal sitcoms of campus life. Publicize legal knowledge through newspapers, lectures on legal knowledge and other channels; open the network legal lectures and create a good campus legal environment and legal atmosphere. Second, continue to strengthen the social practice of the rule of law. Practice is the only criterion for testing the truth, and practicality itself is the essential character of legal knowledge. Practical teaching occupies an extremely important position in the process of legal education and is an effective way to promote the formation of college students' legal awareness, legal spirit, and legal thinking. Practice is more persuasive than classroom teaching. The social practice teaching of legal education for college students should be based on the social legal environment, based on the actual social production and life, and through a large amount of information, and then multi-dimensionally and comprehensively display phenomena and problems and guide students through personal practice, independent analysis, and exploration of problems and phenomena. Behind, there lies the concept and value of rule of law .The system of legal education cases needs to be strengthened. At this stage, the traditional legal education of college students who do not major in science in our country is the main way of \u201cIdeological and Moral Cultivation and Legal Basis,\u201d \u201cMao Zedong Thought and Introduction to the Theoretical System of Socialism with Chinese Characteristics,\u201d \u201cSituation and Policy,\u201d and other courses. With the rapid development of society, the textbooks used in the courses are far from meeting the new teaching requirements. However, such public basic courses are offered uniformly by the state, and the content of the textbooks is also uniformly compiled by the Ministry of Education of the state. The updating and revision of textbooks often take a long time .The key to strengthening the construction of teachers is to strengthen the training of existing teachers. The training for educators mainly focuses on improving the legal literacy of educators and skills training in online course construction. First, teachers need to improve their own legal literacy. Due to their own limitations, educators reduce the effectiveness of online legal education for college students. Therefore, improving the legal literacy of educators plays an important role in enhancing the effectiveness of online legal education for college students . To imprMental health education originated in the West; its origin theory is rooted in the Western cultural value system; emphasizing scientificity, objectivity, and reproducibility, these important theoretical schools, ideological views, technical design, operational norms, and so on have played an important role in promoting the development of mental health education but inevitably infiltrated the Western discourse system, institutional characteristics, and cultural values. The seriousness and diversity of mental health problems of college students in the United States have become more and more prominent, and the US mental health service system is difficult to meet the rapidly growing demand for services because the federal government has less support for the mental health of college students, and the lack of higher education policies around topics such as reducing service costs, increasing service content, and improving service systems. According to the requirements of \u201csuspension of classes without stopping teaching and suspension of classes without stopping learning,\u201d the mental health education course for college students in China adopts the method of online teaching, strengthens the psychological counseling and humanistic care for college students in view of the difficult pain points of college students to cope with changes, and has received good results. Therefore, in \u201cOverview of Mental Health,\u201d attention should be paid to guide students to dialectically look at the development history of mental health education, the advantages, and characteristics of mental health education in our country to feel the superiority of the socialist system and enhance cultural identity.College students' mental health education courses are directly related to the healthy growth of college students, involving the country's long-term peace and stability and national rejuvenation, and integrating the concept of curriculum thinking into the education and teaching of the curriculum is of great significance to innovating the mental health education model of college students and improving the pertinence and effectiveness of education and teaching and also puts forward higher requirements for professional teachers. The mental health education of college students must adhere to the student-centered and result-oriented education concept, constantly optimize the teaching content, deeply explore the ideological and political factors in the course teaching, strengthen the cooperative education consciousness, and enhance the cooperative education ability. Shape students' character, conduct, and taste, so that students with lofty aspirations, integrity, and ability, to become a mission worthy of the new generation. With the increasing influence of the Internet, college students account for half of the growing number of Internet users. They are deeply influenced by the network environment, whether from the perspective of thinking mode, language habit, or even from the perspective of learning and life style, which also brings unprecedented challenges to the moral education in colleges and universities. Cultivating and improving the legal quality of college students will greatly promote the process of building China's socialist legal system in the twenty-first century and is an inevitable requirement for governing the country according to law. This paper puts forward some problems in the current legal education of college students in China and points out the root causes of these problems. An approach to legal reform based on the network environment is proposed. To cultivate and improve the legal quality of college students, the teaching reform should be the leader, and the basic way to optimize the teaching links, make full use of modern media, strengthen the campus legal environment, strengthen the practical links, and expand the space for student development should be the basic way."}
+{"text": "The world literature presents ambiguous results regarding the conjugation of negative and depressive syndromes, due to an incomplete understanding of the main symptoms of depression in schizophrenia.To analyze the variants of the conjugation of depressive and negative symptoms at different stages of schizophrenia.We used the data of our own observations (238 patients with a diagnosis of schizophrenia and no more than 5 years of experience of the disease) and compared them with the previously published results of studies. As a hypothesis, we analyze the variants of the conjugacy of affect and the negative domain within the framework of a single discrete field of schizophrenia.The analysis shows that with the apparent heterogeneity of the psychopathological structure, some depressive features, such as apathy, anhedonia and social autism (characteristic of negative symptoms), tend to the abulia factor, whereas low mood, suicidal thoughts, pessimism, show affinity for the cluster of impoverishment of expression, that is, they represent an attenuated type of negative symptoms tending to the affective spectrum.The conjugacy of depressive and negative disorders in schizophrenia, taking into account their phenomenological similarity, allows us to formulate a hypothesis about their existence within the framework of a single continuum model. The proposed continuum model can be used to understand the processes underlying pathogenesis and formulate the principles of personalized treatment and can be used as a starting point for research on the underlying biological processes and personalized treatment.No significant relationships."}
+{"text": "Nature Communications 10.1038/s41467-019-13983-9, published online 05 February 2020Correction to: In the published version of this paper, the members of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium were listed in the Supplementary Information; however, these members should have been included in the main paper. The original Article has been corrected to include the members and affiliations of the PCAWG Consortium in the main paper; the corrections have been made to the HTML version of the Article but not the PDF version. Additional minor corrections to affiliations have been made to the PDF and HTML versions of the original Article for consistency of information between the PCAWG list and the main paper."}
+{"text": "The concept of health capital views health as a form of capital that produces healthy time to individual. This stock of capital - health that is - can decrease or increase. The potential of psychotherapy as individual's investment to  health capital has been rarely studied in population level.The aim of our study is to shed light on the returns on individual-level investments in health capital. We consider the use of psychotherapy as an investment in health capital. This investment offers potential returns for individual as a higher level of subsequent income. However, these returns are potentially heterogenous: we aim to show to whom the use of psychotherapy is a sound investment in health capital.We model the effects of mental health, and subsequent treatments such as the use of psychotropics and psychotherapy on income using two-way fixed effects regression.Preliminary results show that different parts of working-age population seem to have different potential returns related to the use of psychotherapy. These heterogenous effects are related to previously reported socioeconomic status related disparities: the level of human capital i.e. income and education play a role in the profitability of the individual level investment made in the health capital by the use of psychotherapy.The use of psychotherapy has heterogenous effects on the income of individuals. The potential of this investment to produce health capital varies with education, the level of income prior to the use of psychotherapy."}
+{"text": "Dear Editor,The contribution to the published article \"Neurology, psychiatry and the chess game\"We are delighted and thankful for the valuable contribution of the letter by Jimenez-Ruiz and colleagues. It was a pleasure to know about the fascinating history of Carlos Torre."}
+{"text": "The authors contacted Cureus after publication stating that they \"forgot to add the name of one of our co-authors at the time of submission of the manuscript\" with a request to add the forgotten author. The author, Anushikha Dhankhar, has now been added in the second author position. The authors regret the error."}
+{"text": "Bioscience Reports at the request of the authors as they have been unable to replicate the results found in this study, hence the authors feel that the conclusions drawn are inaccurate. The Editor-in-Chief and Editorial Board agree with the Retraction.This article is being retracted from"}
+{"text": "The law popularly known by the title \u2018Junk Food\u2019, was approved in Colombia in 2021 after years of advocacy from the Civil Society. Many authors as M. Mialon  have documented the level of actions to intervene in the legislative space of the Parliament in Colombia created by the food industries to change the terms of the content of this law. Nowadays and after the approval of the text interpreted as a victory for Civil Society, Colombia is confronted with the re-regulation of the law, leading to a new form of capture: the capture of the spaces of decision-making actors in public health policy in the country. We present an analysis of the case from a follow-up study designed by our organization FIAN Colombia (human rights organization that advocates for the right to adequate food and nutrition). The data used in this process of monitoring and action research comes from the observational data of the advocacy scenario made during the debates of the law in the Colombian parliament, based on the proceedings of the work meetings with congressmen, academia and civil society. This research-action process makes it clear that the collective action of advocacy from civil society manages to mobilize conditions to denounce the corporate capture of decision-making spaces and the execution of public health policies, and generates pressures based on research free of conflict of interest to reduce this capture. Similarly, there is a capacity to demand accountability that was generated from this process in Colombia, and that turns out to be a pilot experience for other regions."}
+{"text": "Intervention research in population health focuses on actions carried out by researchers in partnership with those involved in the intervention: health professionals, patients, carers, public policy makers and population communities. The diversity of actors shapes PHIR projects, testifies to the richness of this research and gives it a privileged place to analyse and intervene as accurately as possible in different contexts and populations. It also implies the need for a better understanding of how to intervene by considering the determinants of health in these interventions. PHIR in health promotion in the domain of cancer thus proposes a paradigm shift from describing the problem and its causes to intervention. RISP bases its theoretical anchors on the one hand on the contributions and models of public health, health promotion and human and social sciences and on the other hand, on its own contributions to theorise and build its own theoretical and methodological corpus. This presentation will aim to clarify this paradigm shift and five methodological challenges of PHIR: the imperialism of epidemiology as a research model; the evaluation models of PHIR and their polymorphism; the complexity of the objects of study; the partnership dynamics between researchers and field actors without which research cannot be carried out. Finally, the challenges of publication and valorisation of this type of research. Through concrete examples, participants will be invited to understand the challenges of the RISP methodology, and to analyse different concrete perspectives to address them. The first part will focus on identifying the participants\u2019 representations of the methodological difficulties of PHIR. The second part will be an interactive presentation of 12 minutes, the last 2-3 minutes will be devoted to final questions."}
+{"text": "The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a satisfactory reply. The Editor apologizes to the readership for any inconvenience caused.Given the issue of the overlapping sections of data, the Editor of"}
+{"text": "The authors regret the omission of one of the authors, Yong Ai, from the original manuscript. The corrected list of authors and affiliations for this paper is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "This Retraction follows an Expression of Concern relating to this article previously published by Portland Press.Bioscience Reports at the request of the Editor-in-Chief and the Editorial Board following receipt of a notification from a reader, alerting the Editorial Board to incorrect nucleotide sequence reagents listed. The errors in this article were identified using The Seek & Blastn tool by Labb\u00e9 et al. 2019 .This article is being retracted from The authors have been contacted with regards to the retraction, and have not responded to the Journal's queries and the concerns raised. Given the extent of the issues raised, the Editorial Board stand by the decision to retract the article."}
+{"text": "The authors regret the omission of one of the authors, Kyoung-Hwan Shin, from the original manuscript. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "Neuroscience advances open the debate on improving brain functionality and human behavior. Transhumanism advocates the use of biotechnology for the betterment of man, transcending into another nature. Neuroethics marks limits of the application and experimentation in neuroscience, also proposing an interdisciplinary philosophical reflection valuing the multidimensionality of human mind.To analyze the transhumanist approach of domining human nature controlling cognitive and moral functions through technique. A critique from neuroethics in an interdisciplinary key to evaluate the complexity of mental functionality and the derived issues that go beyond the scientific scope, with the help of philosophy.A bibliographic review on neuroscience and neuroethics is carried out, finding a core consensus in the warning of the biopsychosocial complexity of the set of realities that shape the human being, facing a reductionist vision of neuroscience.Despite the advances in biotechnology and neuroscientific research, the transhumanist approach of brain enhancement transgressing human reality and reducing its nature to a mechanical question that can be controlled through psychopharmacological resources, becomes dystopian due to the lack of ontological continuity in the deconstruction of the human being in a set of neural circuits, and the lack of consideration of all the dimensions that configure the human mind and existence.An interdisciplinary vision is necessary to analyze the human mind, avoiding falling into the brain reductionism of the neuroscientific paradigm, for an holistic understanding of the human mind and behaviors, beside the integration of a philosophical reflection to join neurobiology and moral dimensions, in a humanist return from transhumanism.No significant relationships."}
+{"text": "A study on the feasibility of a national open data policy in Zimbabwe was done to document open government data globally and in Zimbabwe. The study showcases the benefits of open government data and the opportunities and challenges toward the development of a national open data policy. Web content analysis and document analysis were used to collect data concerning the readiness of the country in implementing open data activities. The open data barometer was used to gather qualitative data which is essential in assessing the preparedness of the country in opening up government and research data. Content analysis was used to analyse the data which was presented thematically based on the objectives of the study. The findings indicated that the Government of Zimbabwe has endorsed a couple of open data frameworks though some projects are done by non-governmental organizations. The major challenge is implementation of these conventions and commitment to make the data accessible. The results indicated that open data must be made available and accessible within Zimbabwe as a matter of national policy. The author recommends the need for advocacy and continuous awareness creation among the stakeholders so that a national open data policy can be crafted and enacted. The enactment of a national open data policy would guide the use of and access to government data and research data which is valuable in research. Open Government Data (OGD) initiatives started in mid-2000 at central and local government levels whereby open government data portals were developed in Organisation of Economic Cooperation and Development (OECD) and non OECD countries Ubaldi, . This isTo examine the open data landscape in Zimbabwe.To analyze open government and open government data in Zimbabwe.To identify the opportunities and challenges that can be used to inform the open data policy for the country.The open government data movement is concerned with the release of large amounts of government data in various formats and conditions that allow re-use of the data. The development of open science in Zimbabwe is still in its infancy stage as pointed out by Chigwada et al. . The stuAdvocates in United States of America (USA) published a set of open government data principles in 2008 leading to the advent of the term Open Government Data (OGD)  had been working on data policy issues with guidance from the Committee on Data for Science and Technology (CODATA) and Zimbabwe can benefit from this initiative to enact and implement a national open data policy.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Subhan  The authors regret that the name of one of the authors (Rehan Ullah Khan) was shown incorrectly in the original article. In addition, the affiliations for this author were incorrectly given. The corrected author list and affiliations are as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "The extent to which social media contributes to body image dissatisfaction and lower self-esteem is currently under debateThis research seeks to study the relationship between the use of Instagram (one of the main platforms used by young people nowadays) and the degree of dissatisfaction with body image and the level of self-esteem among their younger usersA sample of 585 Spanish adults between 18 and 40 years old was used, to whom the Body Shape Questionnaire (BSQ), the Rosenberg Self-esteem Scale and the Social Comparison of Appearance Scale (PACS) were applied.A positive correlation was observed between the frequency of use of the social network and dissatisfaction with body image and low self-esteem. In addition, it was found that content observation time significantly predicts body dissatisfaction and low self-esteem. On the other hand, the type of content both published and observed, showed no effect on any of these variables, although it has been found that the relationship between the use of the platform and the study variables seems to be mediated by the tendency of their users to compare their appearance with others.These results invite us to reflect on the use of social networks and their impact on constructs as relevant to the person as self-esteem and body image and on how different policies should be taken into account to prevent a negative impact on the mental health of their usersNo significant relationships."}
+{"text": "Despite the consensus on the importance of evidence based health information for decision28 making and health policy formulation, quality information is not always available. This situation led the WHO in 2009 to recommend the establishment of an African Health Observatory and National Health Observatories. The WHO recommended 4 phases approach for the establishment of National Health Observatories was used in Cameroon: the preliminary phase, start-up, strengthening and full operation. Despite a non-optimal institutional positioning, the Cameroon\u2019s Health Observatory is in the strengthening phase and contributes to evidence-based decision making in the health system. A strong political commitment is fundamental from the beginning of the project. The establishment of National Health Observatories calls for genuine national ownership, both of the process as a whole and of the tool itself. WHO should regularly assess the progress made in the establishment of National Health Observatories in different countries and provide feedback to them. A step-by-step approach, jointly validated by national stakeholders in a roll-out plan, would be more appropriate for the sustainability of the work of National Health Observatories. The Ministry of Health is composed of a central administration, deconcentrated services, public health facilities and specialized technical committees and organizations. The NPHO is classified as a specialized technical body under the technical oversight of the Ministry of Health Cameroon, having adhered to the Ouagadougou and Algiers initiatives, has committed itself to the establishment of a NHO. This commitment was evidenced by the equipping and construction of a building inaugurated in November 2009 and the creation in 2010, by a decree of the Prime Minister, of the National Public Health Observatory (NPHO) By 2020, NHOs have been fully implemented in seven of the ten countries that have been enrolled in this pilot process 2Placed under the authority of the Minister of Health, the NPHO is a specialised technical body which comprises an executive body, the permanent secretariat and two advisory bodies, namely the Steering Committee and the Scientific Council.The Steering Committee is the advisory and orientation structure of the NPHO, placed under the authority of the Minister of Health. It carries out the tasks entrusted to the NPHO and issues opinions on all matters submitted to it by the Minister of Health. It is also responsible for examining and adopting the annual workplan, the rules of procedure and the budget of the NPHO. It is composed of representatives of eight partner ministries, the National Institute of Statistics, WHO, the private faith-based health sector, the private secular health sector and civil society. This committee meets as needed when convened by its chairman. Since the creation of the NPHO, the Steering Committee has met three times for the political adoption of the NPHO's outputs.The Scientific Council, headed by a chairman appointed by the Minister of Health, is an advisory body responsible for evaluating and validating the NPHO's scientific programs. It is made up of ten members appointed for a three-year term, renewable once, from the health, scientific research, higher education and development partner sectors. The Scientific Council meets at the request of the coordinator of the permanent secretariat of the NPHO. The council systematically carries out the scientific validation of the NPHO's products prior to their political adoption by the Steering Committee.In order to carry out its tasks, the NPHO secretariat is organised into four sections: (i) a section for socio-health information, epidemiological surveillance and cooperation, (ii) a section for surveys, health and epidemiological studies, monitoring and forecasting, (iii) a general affairs section and (iv) an information technology section. The coordinator of the permanent secretariat is appointed by the Minister of Health.3A guide to setting up NHOs was developed by WHO in 2016 The Preliminary Phase: In Cameroon, this phase lasted 1\u00a0year (2009\u20132010) as recommended in the guide for the establishment of NHOs. It began with the construction and equipping of the building to house the structure, inaugurated in 2009, as part of the African Development Bank health system development project. In 2010, the Cameroonian government marked its political commitment by creating and staffing the NPHO through a decree of the Prime Minister No situational analysis was conducted at this phase as recommended in the WHO guide to setting up NHOs. As a result, no action plan was developed to guide the establishment of the NPHO, which is a deliverable of the preliminary phase. This action plan was developed during the assessment of the overall situation of knowledge in the National Health Information System (NHIS), carried out 5\u00a0years after its creation, in 2015, during the national sensitisation workshop on the NPHO in the start-up phase. Similarly, the evaluation of the NHIS was not carried out at this stage to identify the strengths that the NPHO could rely on; identify the weaknesses of the system; and to set up a relevant and reliable collaboration model between the actors of the NHIS and the NPHO. This situation created conflicts of competence between the NPHO and certain technical departments of the Ministry of Health, such as the health information unit and the department in charge of epidemiological surveillance. The role of each structure was clarified during the national sensitisation workshop on the NPHO organised during the start-up phase.The start-up phase: It lasted six years (2011\u20132017), rather than one to two years as prescribed in the guide for the establishment of NHOs,as a result of the absence of a roadmap and began in 2011 with the strengthening of human resources. A multidisciplinary team consisting of a health economist, four public health specialists and a documentalist was gradually assigned to ensure the optimal functioning of the structure. The team was expanded to include: (i) public health specialists and epidemiologists with expertise in data analysis, both quantitative and qualitative, and the production of evidence-based data; (ii) health economics specialists; (iii) data managers with expertise in programming and website maintenance for the management of the digital platform; and (iv) a documentalist. The recruitment of these staff followed the civil service recruitment and assignment process. It was not done in a transparent manner and on the basis of the assessment of competences by independent experts as recommended in the guide These include training in the use of Tableau software for data analysis, management and administration of the NPHO's digital platform, evaluation of the national health information system using the SCORE  package, and training in the collection and analysis of health data, including data quality assessment using WHO tools. This extensive capacity building should enable the country to produce quality health information to feed into the NPHO's digital platform. In addition, a national workshop to raise awareness of the role and mission of the NPHO among NPHO stakeholders was held in 2015. This led to an analysis of the NPHO's stakeholders and the development of a five-year roadmap for strengthening the Observatory. Also, an evaluation of the NHIS aimed to: (a) identify the promising aspects of the system and the strengths on which the NPHO can rely; (b) identify the weaknesses of the system; (c) establish a relevant and reliable model of collaboration between the NHIS and the NPHO was also carried out during this workshop. This assessment focused on the Ministry of Health on the one hand, and the health sector in general on the other, to provide an overall picture of the knowledge needs and resources available in the country, which provided a basis for all the activities of the Observatory. The five-year roadmap for strengthening the NPHO, a deliverable of the preliminary phase, was drawn up during this phase. The initial outputs of the NPHO and the evaluation of the initial phase in preparation for the construction phase were not carried out in this phase as recommended by the guide due to the lack of follow-up to the roadmap. This lack of initial output from the NPHO has eroded the initial political commitment. In addition, the digital platform developed by the WHO, which was to host these outputs, had not yet been officially handed over to the country due to the cumbersome and slow administrative procedures. As these prerequisites were not met, the official launch of the NPHO, a deliverable of the start-up phase, was not delivered.The strengthening phase: Recommended to last for three to five years. Since 2017, the NPHO has been in its strengthening phase marked by initial productions using, among others, data published in the reports of demographic health surveys, household survey reports, national health accounts, multiple indicator cluster survey reports, health service delivery indicator survey reports and priority health program reports. In addition, the NPHO is always invited in highly technical platforms such as the weekly Integrated Disease Surveillance and Response for consultation and provision of technical guidance. The four main functions of the NPHO  are being implemented as proposed in the guide. Now that all the functions are implemented in routine, the last phase, full operation, should start soon.4The legal framework of the NPHO has remained ambiguous  and its institutional positioning in the organisation chart of the Ministry of Health has not always facilitated its mission of gathering and centralising health information from other structures in the Ministry of Health and other government organisations, whose institutional positioning is superior. This ambiguity is accentuated by the absence in this text of equivalence of positions with those of the Cameroonian public service. This situation led to the demotivation of staff who found themselves administratively under-classified, and has made the NPHO unattractive to qualified human resources. The review of the NPHO's legal framework should be revised to remedy these shortcomings by giving this institution a legal personality and a financial and administrative autonomy, in particular the possibility of recruiting staff on the basis of their expertise as well as their scientific and technical skills. The NPHO in its current form has inherited a certain number of missions that were previously assigned to the National Epidemiology Committee (NEC). In fact, a national multi-sectoral and multi-disciplinary technical group was set up to carry out a situational analysis which should lead to the development of an action plan and proposals for the strategic choices of the structure to host the Observatory. As a result of this situational analysis, the NEC was chosen to host the NPHO. This committee's mandate were to advise on health matters; to identify health problems; to contribute to the organisation, promotion and financing of epidemiological studies in the country; and, on the basis of the results of the research, to make recommendations to the Minister of Health as well as to any other head of ministerial department or national body responsible for the development and implementation of health programs.The NEC's areas of interest included disease control, epidemiological surveillance and health statistics. During the establishment of the NPHO, the missions of the NEC were merged with those of the NPHO, conferring to the observatory of Cameroon, additional missions to those recommended by WHO. Thus, the NPHO is the National Focal Point for the  in Cameroon, responsible for communication with the WHO for the purposes of the . In this capacity, it also ensures the promotion and vulgarisation of the , capacity building of national actors on the  as well as monitoring the implementation of the  in Cameroon. It is within this framework that the NPHO conducted the joint external evaluation of the capacities of the , the development of the national health security action plan, the mapping of resources allocated to health security at the national level and the annual evaluations of the implementation of the IHR in the country.collation function, the NPHO collects data relevant to public health and its determinants from the digital platforms of national and international actors in the NHIS and compiles them in a database/reports in the documentation services. However, the fragmentation of the NHIS by vertical programs that invest resources for short-term results does not allow the NPHO to sustain this aggregation function. The scaling up of the use of the District Health Information Software (DHIS2) as a single tool for routine data collection at the level of the NHIS and the establishment of the CHDC at the level of the NPHO have helped to strengthen this aspect. However, the sub-optimal functionality of DHIS2 (low completeness and promptness) does not allow the health indicators to be filled in with routine data at the Observatory level.In order to fulfil its The analysis and synthesis function of the NPHO has so far resulted in the compilation of national indicators in the \u201c100 key health indicators monitoring report\u201d, produced in 2017 The sharing function provided by the NPHO has resulted in a contextualisation of the prototype digital platform developed by WHO. This platform thus serves as a one-stop shop for sharing health information and is accessible online at https://nho.minsante.cm/. It presents a clear picture of the country's health situation through the publication of thematic reports, dashboards, the country's health profile, policy briefs and other documents validated at the national level.The network function is ensured by the NPHO through the establishment in December 2016 of a national network of data producers, the \u201cCameroon Health Data Collaborative\u201d (CHDC). The CHDC also constitutes a platform for sharing and exchanging health data. There was an initial high level of enthusiasm, with an average of 60 participants at monthly meetings and effective participation in activities, particularly for mapping data sources and funding in the SNIS, we note, however, that the CHDC has been operating intermittently over the past year due to a certain lack of motivation among members linked to the absence of strong leadership and activities that arouse the interest of data producers.In order to ensure its mission of monitoring the implementation of the , Cameroon has defined a fifth function: health monitoring. In this respect, the NPHO led the joint external evaluation process of the  and the development of the National Health Security Action Plan (NAPHS) and ensured the establishment and strengthening of the national cross-border epidemiological surveillance system. The Observatory is also a member of the national epidemiological surveillance platform, where it is consulted on issues related to national health security. With the aim of consolidating its organisational and legal framework to better ensure its functions, the NPHO has undertaken the revision of its legal framework to establish it as an autonomous structure.Box 1The objectives of high-influence but low-interest stakeholders, such as policy makers, are taken into account to ensure that they remain strong advocates. Aligning the objectives of the NPHO with the health sector strategy and health development plan helps to satisfy these stakeholders. In addition, a dashboard of key SDG and UHC indicators is available on the NPHO digital platform to inform policy makers.Stakeholders with a strong influence and interest are closely involved in the implementation of the NPHO's activities. The Health Information Unit, the Directorate for Disease Control, Epidemics and Pandemics co-leads the Cameroon Health Data Collaborative (CHDC) network of data producers. Other stakeholders are invited to participate in exchanges on strategies for strengthening the NHIS within the CHDC and receive by e-mail the publications of the NPHO as well as other relevant publications on health information. Also, the annual reports of the national HIV, malaria and malaria control program; the reports of the demographic health surveys and household surveys; the national health accounts, the reports of the survey on health service delivery indicators; all produced by other NHIS actors are accessible through the NPHO's digital platform. The livestock, environment, agriculture, scientific research, higher education and civil society sectors are members of the NPHO's scientific council and steering committee. This approach helps to build strong relationships with the NPHO and ensure that their support is maintained. They are involved in decision-making and are regularly consulted.Stakeholders with little influence and interest are involved from time to time in the activities of the NPHO to ensure that they remain at the forefront of their involvement as their interest and influence may change over time. The Cameroon Epidemiology Society (CaSE) receives all publications from the NPHO to encourage their interest, and through them, that of other professional bodies.Stakeholders with little influence but strong interest are actual or potential sources of funding for the NPHO. GIZ, CDC, TDDA, Metabiota, IOM, USAID and the World Bank are regularly informed of activities through the NPHO's outputs. They are consulted on their areas of intervention and their contributions are used to improve the chances of success of the NPHO. The report of the biological and behavioural survey on HIV among key populations in Cameroon, published in 2016 by Metabiota, is published on the NPHO platform.In order to guarantee the optimal functioning of health observatories, it is crucial to carry out a good analysis of all stakeholders and to continuously maintain their involvement according to their level of influence and interest in the Observatory. 5The establishment of the NHO requires significant political commitment. This commitment can be achieved through structured advocacy of the process, from the launch of the health observatory. The commitment of a minimum team is also crucial during the implementation to execute the project. The establishment of NHOs calls for genuine national ownership, both of the process as a whole and of the tool itself. The NPHO is an effective decision-making tool through its involvement in many of the Ministry of Health's decision-making bodies, and allows for the monitoring of trends and progress towards national and international goals through the annual publication of the 100 key health indicators report and the population health status profile. The creation and maintenance of a data production network is essential in order to have access to the different sources of information and to raise awareness of the need to align investments for an integrated NHIS. In Cameroon, the establishment of a network called the CHDC has helped to reduce the fragmentation of the national health information system through the sharing of information and the pooling of efforts for the implementation of certain activities . The NPHO has a digital data and statistics platform, online publications on the health situation and trends in the country, and the country's analytical health profile is known. For optimal functioning, the institutional positioning and the legal and regulatory environment of the Observatory in the host institution must be clearly defined. It must also be free from any relationship or influence related to the administrative hierarchy with the producers and users of data within the NHIS. To attract and maintain the interest of decision-makers, NHO outputs must be early, relevant, regular and on subjects of national interest. Indeed, the first productions of the NPHO aroused a new interest in health information and demonstrated the importance of the NPHO. These first productions showed that decision-makers were thirsty for accurate information on public health. Their interest in NPHO publications was reflected in letters of congratulations from the very top and an increase in the NPHO's operating budget. WHO, as the Secretariat of the Member States in the region, should assist the country in coordinating the actions of international partners to ensure appropriate and sustainable mobilisation of resources, and maintain its support for the technical development of the observatory. Also, WHO should regularly assess the progress made in the establishment of NHOs in different countries and provide feedback to them. A step-by-step approach, jointly validated in a roll-out plan, would be more appropriate for the sustainability of the work of the NPHO.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."}
+{"text": "Bioscience Reports at the request of the Editor-in-Chief and the Editorial Board following receipt of a notification from a reader, alerting the Editorial Board to concerns over the flow-cytometry data, some of which doesn't appear to be feasible. The western blot original data also contains features shared amongst other original western blots presented by other author groups. The authors have been contacted with regards to the retraction and have not responded to the Journal's queries and the concerns raised. Given the extent of the issues raised, the Editorial Board stand by the decision to retract the article.This Retraction follows an Expression of Concern relating to this article previously published by Portland Press. This article is being retracted from"}
+{"text": "As the inevitable ageing of the population progresses, the pressure on the public health system increases. The predicted rise in the share of people aged 65 and more from 19% in 2020 to 33% in 2050 jeopardises the capacity of the long term care in Poland. It demands immediate actions in public policies to strengthen the system and to provide the silver generation with the proper and adjusted services. That topic is one of the main issues for the map of health needs, developed by the Ministry of Health in Poland. The analyses investigate the current and future state of this part of the system, e.g. the number of visits, average length of stay, types of services, care-giver support ratio. Conclusions drawn from the data allowed to formulate a number of challenges, which include:levelling up the access to the services,increasing the number of outpatient services, provided at home or close to the place of residence,implementation of the eHealth solutions,support for the informal care-givers.In line with these information, the actions and strategic frameworks have been established at the national level and included:strategic approach for deinstitutionalisation, in order to bring the long term care closer to the patients\u2019 environment, to provide them with an optimal level of comfort and to make them self-reliant for as long as possible,enhancement of the inpatient care through transformation of less occupied wards into long term wards in district hospitals.The Maps of Health Needs help to create national public policies and strategic frameworks aimed at coping with the foreseen challenges of aging society pressuring the healthcare system.The main challenge for the long term care in the future is to channel the available resources in the appropriate way."}
+{"text": "The authors regret that the name of one of the authors (Ana Lucia Vasquez-Caicedo) was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "At present, there are few articles about the timekeeping performance of domestic atomic clocks in their moving state. In this paper, the frequency stability changes of hydrogen atomic and cesium atomic clocks in stationary and moving states are compared and analyzed; the frequency stability of the atomic clock at the beginning of its transition from moving state to stationary state is tested and analyzed; the influence of three main noises of atomic clocks on frequency stability is analyzed; and finally, the difference in the predictability of atomic clocks in moving and stationary states is analyzed. The results show that: (1) in the moving state, the frequency stability of a hydrogen clock decreases by 1\u20132 orders of magnitude, and the frequency stability of a cesium clock decreases by 0.5 orders of magnitude; (2) in the recovery stage, the frequency stability of hydrogen and cesium clocks is between that in static and moving stages, but the frequency stability fluctuates greatly in this stage; (3) in the moving state, the three main noises of the atomic clock all increase, of which the increase in the white noise of phase modulation is the largest, indicating that it is the most sensitive to vibration and has the greatest impact on the frequency stability of the atomic clock during the moving period; (4) in the mobile state, the RMS of the prediction data of the hydrogen clock and cesium clock greatly increases compared with that in the static state. In today\u2019s highly information-based era, time and frequency are increasingly important in the military and civilian fields and have become very important resources . The atoAt present, atomic clocks that are relatively mature in research and use mainly include hydrogen atomic clocks, cesium atomic clocks, and rubidium atomic clocks. At present, most timekeeping systems are made up of hydrogen atomic clocks and cesium atomic clocks. Hydrogen atomic clocks have excellent short-term stability and generally serve as the main clocks in the timekeeping system, while cesium atomic clocks have better medium- and long-term stability than hydrogen atomic clocks. They are generally used to remove the long-term drift of hydrogen atomic clocks . They arAt present, China\u2019s hydrogen atomic clocks have been commercialized, with short-term frequency stability of up to n system . At presn system . Many don system ,7.In terms of performance testing and analyzing China\u2019s hydrogen atomic clock, Liu Fengyu  and otheg Weiqun  and otheAt present, research articles on the mobility of China\u2019s hydrogen and cesium atomic clocks have not been reported. Therefore, this paper mainly analyzes the frequency stability of China\u2019s hydrogen atomic clocks and China\u2019s small cesium atomic clocks in the vehicle mobile state, including the stationary state, mobile state, and the stage of returning to a stationary state after moving (hereinafter referred to as the recovery stage), aiming at the research of hydrogen atomic clocks and cesium atomic clocks. The development and application provide a reference for performance indicators in the mobile state and provide a basis for further expanding the range of use of Chinese atomic clocks.Whether the atomic clock can provide a long-term continuous and stable time-frequency signal is the most important condition for judging whether it can be used in the timekeeping system. Therefore, this paper will focus on the frequency stability index to evaluate the performance of the atomic clock. In many cases, due to the impact of the surrounding environment, it may not be possible to successfully collect data. At this time, the ability of the hydrogen atomic clock to predict future data based on past data is also required to be predictable. Therefore, predictability is also one of the indicators this paper is concerned about.The test system and method of atomic clock are described as follows.This test was carried out on two mobile timekeeping cars. Some equipment of the timekeeping cars is shown in Since there was no traceability condition in the moving state of this test, and in order to improve the reliability of generating time-frequency signals, two hydrogen clocks and three cesium clocks were used as the main frequency sources to jointly generate precise time-frequency signals. The hydrogen atomic clock with 10,000 s frequency stability better than The most commonly used indicators to characterize the performance of atomic clocks are frequency accuracy, frequency drift rate and frequency stability. Whether the atomic clock can provide long-term continuous and stable time-frequency signal is the most important judgment condition for whether it can be used in a timekeeping system. Therefore, in many related studies, the performance evaluation of the atomic clock mainly focuses on the frequency stability index. Therefore, this paper mainly tests and analyzes the performance of atomic clocks in static state, moving state and recovery phase with frequency stability as an indicator.The hydrogen clock stability test method used in this paper is shown in In the moving state, it is impossible to find a time signal with a higher frequency stability than the hydrogen clock as a reference. Therefore, the two hydrogen clocks are self-evaluated; that is, we subtracted the clock difference data of the two hydrogen clocks, calculated the Allen variance of the new clock difference data and divided it by The stability test method of the cesium clock used in this paper is shown in We connected the 10MHz clock signal of the atomic clock to the phase comparator and counter, respectively, and completed the time difference and phase difference measurement with the main clock signal as the reference. The Allan variance was analyzed by time difference and phase difference data to analyze the frequency stability of the atomic clock.The frequency stability of an atomic clock is the standard in measuring the stability of its signal frequency and is an important indicator in measuring the performance of the atomic clock . One of At the same time, the Allan variance formula can also be calculated using the phase measurement value. The calculation formula is:The noise of atomic clock can be seen as the superposition of five kinds of noise, namely: white phase modulation (WPM), flicker phase modulation (FPM), white frequency modulation (WFM), flicker frequency modulation (FFM) and random walk frequency modulation (RWFM) . Among tThe relationship between Allen variance and power spectral density is:The relationship between white phase modulation noise, white FM noise, random walk FM noise and Allen variance is introduced in detail in the literature :(4)\u03c3WPM2Different types of noise of the atomic clock can be identified from the Allen variance curve. The slope of white phase modulation noise (WPM) in logarithmic Allan chart is\u20142, the slope of white frequency modulation noise (WFM) in logarithmic Allan chart is\u20141, and the slope of random walk frequency modulation noise (RWFM) in logarithmic Allan chart is 1. The value of WPM can be read at In many cases, due to the impact of time and environment, it is impossible to collect data smoothly. At this time, it is necessary to predict the missing data based on the previously collected data, which also requires the predictability of Chinese atomic clocks in the mobile state. The purpose of this section is to compare and analyze the difference between the predictability of Chinese atomic clocks in static and mobile states.This section builds a mathematical model based on the measurement data collected by the phase comparator in the past and quantifies the predictability of the atomic clock by calculating the difference between the fitting value and the real value, that is, residual error and RMS. The prediction of atomic clock data can be roughly divided into clock error prediction and clock speed prediction. This section uses a clock error prediction method to analyze the predictability of atomic clocks. Common clock error prediction methods include least square method, FIR filter and Kalman filter. Kalman filtering is suitable for application when the clock difference state model is linear and the statistical characteristics of state noise and measurement noise are known, and the least squares method requires less data. Therefore, this section uses linear fitting and quadratic fitting methods to predict the clock error data at the next time based on the previous measurement data and calculates the difference between the fitting value and the real value, i.e., residual, to evaluate the predictability of the atomic clock.Linear fitting means that given a series of The greater the residual error, the better the fitting effect. Therefore, the problem is transformed into solving By sorting out Equation (9), it can be concluded that the equation to be satisfied by the fitting curve is:Quadratic fitting means that given a series of The greater the residual error, the better the fitting effect. Therefore, the problem is transformed into solving The main work of this paper is as follows: to use the phase comparator to collect the clock error data of the atomic clock for three consecutive days to compare and analyze the difference between the frequency stability of the atomic clock in the stationary state and the mobile state; to test and analyze the frequency stability of the atomic clock in the recovery phase; to test and analyze the three main noises of the atomic clock in static and moving states; and to compare any analyze the predictability of atomic clocks in stationary and moving states. The idea of this paper is presented in the form of a figure, as shown in The nominal indexes of hydrogen atomic clock under static state are shown in First, the frequency stability of the hydrogen clocks on the two vehicles under static state is tested. The Allen variance of the clock difference data collected by the phase comparator for three consecutive days is calculated, as shown in From the data in Next, the frequency stability of the six cesium clocks on the two cars at stationary state were tested. The Allan variance of the clock difference data from the atomic clocks collected by the phase comparator for 3 consecutive days was calculated, and the results are shown in From the data in As the frequency stability of the hydrogen and cesium atomic clocks on board car 1 is similar to the performance of the atomic clocks on board car 2, the subsequent aim of this paper is to only process and analyze the data from car 1.This section tests and analyzes the frequency stability of hydrogen and cesium clocks in the moving state. The Allan variance is calculated for approximately 8 h of continuous atomic clock differential data collected by the phase meter. The calculated frequency stability of the two hydrogen atomic clocks in the moving state for mutual evaluation is shown in As can be seen from the data in Comparing the Allan\u2019s variance of the two hydrogen clocks at rest and in motion shows that movement decreases the frequency stability of the hydrogen clock by an order of magnitude of The results of the frequency stability calculations for the cesium clock are shown in From the data in Comparing the Allan variance of the three cesium clocks at rest and in motion shows that movement deteriorates the frequency stability of the cesium clocks by about one order of magnitude from 1\u201310 s and by about 0.5 orders of magnitude from 10\u20134000 s. That is, the effect of movement on the frequency stability of the cesium clock is approximately an order of magnitude of The short-term stability of the phase micro-jump meter used in this test and the short-term stability of the lossless switch are both far less than the short-term stability of the cesium clock in the moving state, so the impact of the phase micro-jump meter and the lossless switch is ignored.Approximately 16 h of atomic clock differential data were collected after the timekeeping vehicle had switched from the moving state to the stationary state. This part of the work was aimed at testing and analyzing the frequency stability of the atomic clock during the recovery phase.The results of the calculation of the frequency stability of the hydrogen clock are shown in As can be seen in The results of the cesium clock are shown in As can be seen in This section analyses the effect of the three main types of noise on the frequency stability of an atomic clock. The aim of this part of the work is to test and analyze the three main types of noise in the atomic clock at rest and in motion, to observe which noise increases the most during motion, and thus to speculate which noise has the greatest effect on the frequency stability of the atomic clock during motion.The results of the comparison of the three main noises of the hydrogen atomic clock at rest and in motion are shown in The results of the comparison of the three main types of noise in the stationary and moving states of the cesium atomic clock are shown in In This section quantitatively assesses the predictability of atomic clocks using linear and quadratic fitting methods. The differential seconds of clock data for atomic clocks at rest and in motion, collected using a phase ratio meter, were used.A total of 35,000 sets of hydrogen clock data were collected. The first 30,000 sets of data were used as a training set, and the second 5000 sets were used as a test set for the prediction results. The residuals and RMS of the latter 5000 sets of predicted and real data were calculated. The results of the hydrogen clock implementation are shown in The residuals and RMS of the linear and quadratic fits to the hydrogen clock for the stationary and moving states are shown in As can be seen in There are 33,000 sets of cesium clock data. Of these, the first 30,000 sets of data were used as the data training set, and the second 3000 sets of data were used as the prediction result validation set. The residuals and RMS of the latter 3000 sets of predicted and real data were calculated. The results of the cesium clock implementation are shown in The residuals and RMS of the linear and quadratic fits of the cesium clock for the stationary and moving states are shown in As can be seen in This paper compares and analyzes the difference in frequency stability between Chinese-made hydrogen and cesium atomic clocks in stationary and moving states. The data show that the effect of movement on the frequency stability of the hydrogen clock is of an order of magnitude of"}
+{"text": "The prevalence of mental disorders plays an important role in identifying the state of mental health of the community and estimate the required facilities at any time.Therefore, the purpose of this study was to investigate the prevalence of psychological disorders in caregivers of children with intellectual disabilities and motor disabilities in Shiraz.The research was descriptive and cross-sectional survey. The statistical population consisted of all mothers of children with disabilities who were admitted to welfare centers and clinics of Shiraz in 2019. Of these families, 35 mothers with children with intellectual disability and 35 mothers with children with motor disability were selected as the sample group. SCL-90-R (1976) was used to collect of data. For analyze the data, MANOVA test was used.The results of this study showed that the most common psychological disorders in caregivers of children with intellectual disability were aggression (hostility), hypersensitivity to interpersonal relationships, anxiety and depression, and in caregivers of children with motor disabilities were physical complaints, sensitivity to interpersonal relationships, paranoid thoughts and anxiety.According to the findings of this research, it can be concluded that caregivers of children with special needs in terms of mental health are not in a favorable situation, which is due to the lack of proper adaptation with the disability of their child and the failure to meet their needs.No significant relationships."}
+{"text": "Following the publication of the original paper , the autEquation (1) in the online version.The first error is the mentclass2pt{minimThe end of the derivation of Eq.  in the oAccordingly, at the end of the derivation ofThe authors confirm that the notational errors corrected here had no effect on the conclusions or the performance of the method scDesign2."}
+{"text": "This presentation will provide a historical background and a broad overview of the APA Guidelines for the Evaluation of Dementia and Age-Related Cognitive Change. This will begin with an overview of general and procedural guidelines pertaining to dementia assessment and will be followed by an in-depth discussion of key updates in the 2021 revision. The newly revised guidelines recognize racial and cultural disparities in dementia outcomes, and emphasize the importance of multicultural competence in all aspects of dementia assessment. The revised guidelines also integrate person-centered principles into the assessment process and place greater emphasis on understanding the person living with dementia. New guidelines were included to address (1) the assessment of behavioral and psychological changes in the context of dementia, and (2) the importance of assessing the health and well-being of family caregivers."}
+{"text": "The purpose of this study is to propose guidelines for sensor installation in different types of underground space smart sensing platforms. Firstly, we classify the underground space, analyze the scene requirements according to the classification of underground space, and sort out the requirements for sensors in various types of underground space. Secondly, according to the requirements of underground space scenes for sensors, the types of sensors and corresponding parameters are clarified. After that, the system design and sensor installation guidelines of the underground space smart sensing platform are proposed by sorting out the data acquired by the sensor. This paper clarifies the sensor types and corresponding parameters for smart sensing scenes by analyzing the needs of different types of underground space scenes. Based on the sensor parameters and acquired data required by the underground space smart sensing platform system, the sensor installation guidelines are formed accordingly.This study needs to clarify types of underground spaces, and we can refer to the laws and regulations of underground spaces in each country. Japan has a perfect legal and management mechanism for underground spaces ,2,3,4, sFrom the location of the underground space, it requires arterial energy from facilities such as water, electricity, transportation and data flow ,11,12,13Based on the existing design guidelines in Japan, such as \u201cFacility Construction Safety Construction Technical Guidelines\u201d and \u201cCivil Engineering Work Safety Construction Technical Guidelines\u201d, it is clear in In summary, countries have more complete laws and regulations for the infrastructure construction of underground space , but theClassify the underground space according to the classification standard of Japanese underground space and the functional characteristics of each type of underground space, and by clarifying the functional requirements of each type of underground space for sensors on the basis of the classification of underground space;Based on the above-mentioned requirements for sensors in the underground space, the sensors are screened on the basis of the temperature and humidity applicable to the underground space, and the sensor types and parameters are selected to meet the smart scene and functional requirements of the underground space;Based on the functional requirements met by the above sensors as well as the sensor types and parameters, the types of data acquired by each type of sensor and the data attributes are clarified;Based on the classification of underground space, sensor attributes and data attributes in I, II and III above, clarify the data transmission methods and data flow between sensors of various types of data, propose the basic framework of smart sensing system in underground space and form the guidelines for setting up sensors for smart scenes in underground space.To meet the monitoring and early warning needs of maintenance management, this study considers that the guidelines for setting up sensors in underground spaces need to clarify the classification of underground spaces and also the properties of sensors such as communication methods, the properties of data and the basic framework of the sensing system, thus taking the following research steps to propose guidelines for setting up sensors for smart scenes in underground spaces:Various types of underground spaces have different needs for sensors. Since the planning and construction of underground spaces in Japan is at an advanced level internationally, this study refers to the Japanese classification standard for underground space, which distinguishes between civilian land and public land, and classifies underground spaces according to the depth of various underground facilities in Based on the Japanese classification standard for underground space, underground space can be divided into six types of underground infrastructure: rail transit, underground functional places , elevated bridges, underground tunnels, underground municipal pipelines, and underground heat source heat pumps in Different functions of the underground space are monitored differently during maintenance. Therefore, there are also differences in the requirements for sensors. In order to meet the operational requirements , the disUnderground spaces have different requirements for various types of sensors in different types of spaces, which are organized according to the Based on the classification of the underground space, and the requirements of sensors for different underground space scenarios, the sensors on the market are screened on the basis of the temperature and humidity applicable to underground space, and the types of sensors and the corresponding parameters of sensors that can meet the needs of the scenario are obtained in Based on the functional requirements of the underground space for sensors, sensor types and parameters, the attributes of the data acquired by various types of sensors are clarified, including data transmission methods and data monitoring scopes. The final results will be classified based on data types and attributes to form a data summary table .Based on the analysis of underground space classification and scene requirements, sensor attributes and data attributes, the framework of underground space smart sensing platform (smart sensing system control) is proposed in Based on the data transmission methods and data flow between sensors in the underground space, the data flow of the sensing platform is clarified in In this paper, we make a summary analysis of the requirements of different underground space types to clarify the types of underground space sensor requirements as well as the parameters of the sensors and the monitoring data of the underground space to form the sensor installation guidelines in the underground space smart sensing platform. To facilitate the designers to carry out the design work related to the underground space smart, we will finally form the sensor design and installation guidelines table  and the In this paper, we analyze the requirements of different types of underground space scenes and clearly establish the sensor types and corresponding parameters for smart sensing scenes. Based on the sensor parameters and the acquired data, we propose a system design for smart sensing platform in underground space and form the sensor installation guidelines accordingly. The guidelines are mainly divided into two parts: installation guideline table and installation schematic, and the purpose of setting the guidelines is to guide the work related to the construction of smart scenes in underground space.The study of requirements in this paper focuses largely on maintenance management. The next step will be to refine the process of developing and constructing smart scenes in underground spaces, and to propose different development proposals and guidelines at different phases according to the refined process."}
+{"text": "The dynamics of search queries in large random samples may reflect both the reaction of the population to the statements of power subjects, and the presence of certain mechanisms of emotional self-regulation.Studying the dynamics of information search queries in the situation of experiencing an objective global threat-the spread of COVID-19.Quantitative methods of the Data Mining class were used for data collection. Qualitative methods of the Data Mining class and contextual analysis were used for data analysis. Search queries related to COVID-19 and the introduction of self-isolation were analyzed: 5 million queries were randomly selected.The number of information requests on the topic of the pandemic increased sharply after V. Putin\u2019s first address, and then steadily decreased, but the overall picture of the content dynamics of search queries, depending on official statements of the authorities, was not observed; requests about the current level of morbidity are constantly presented to the greatest extent, and to the minimum-about the possibilities of psychological assistance and the state of the Russian economy. During the whole time of the study the contents of the Internet search shifted towards positive emotional information.. To the maximum extent, the relationship between the experience of a pandemic and self-isolation with the nature of search queries manifests itself at the initial stages and tends to decrease in the future. The dynamics of the content of requests is ambiguously related to official statements of power subjects, influenced by the effect of counter-regulation.No significant relationships."}
+{"text": "Community education curriculum is the key link to achieve the goal of community education; it is an educational activity that uses the educational and cultural resources of the community and faces all residents in the community; promoting the innovation of community education curriculum is the new mission of the development of contemporary community education, in order to explore the development path of community education curriculum from Marx's perspective under big data and study its educational value and development path. By comparing the development paths of community education in different environments, this paper makes a comprehensive analysis and evaluation and analyzes the value of coupling degree. It can be seen that the use of big data technology has a positive impact on the development of new education models, the development of community education and platform management, and the learning motivation of residents. We should make breakthroughs and innovations on the basis of the traditional education model, realize the value concept of lifelong education, and follow Marx's socialist development concept; it can better promote the development of residents and communities in the community and provide more effective data value and data support for the development path of community education in the future. In the development path of socialism with Chinese characteristics, we should use the development direction of Marxism, Mao Zedong Thought, and Deng Xiaoping theory to achieve the development goal and strategic thought of building a well-off society in an all-round way. In the process of the development and progress of China's socialist society, the development and progress of the country need the joint efforts of the next generation and contemporary people, and it is also the most important node for the development and direction of learning education. Zhongbiao as an important part of adult education and community education in China implements the ideological quality of lifelong learning, and the idea of never too old to learn is a good quality . The guiEducation in the process of human survival is a kind of cultivation process that has been implemented with growth since childhood. In this process, our personal thoughts and growth plans, as well as spiritual values, social values, and world values, are constantly maturing. From the growth of a single individual to drive the growth of the family and build social maturity and progress, the progress and development from a small family to everyone, to a country, and to the world are all from a single individual. Countries have been constantly exploring and studying the development and innovation of education. In the development of modern society, with the occurrence of aging social phenomena, social countries implement adult education and elderly reeducation models in education. From the traditional nine-year compulsory education to university education and even elderly education, many education models and methods have emerged. In this environment, the teaching mode of community education has been formed by following the main principles of Marx's thought, Lenin's thought, and Mao Zedong Thought and the form of socialist social development. With the progress of science and technology, the development of the Internet has not only driven more economic development and political value but also provided more help and guidance in the education mode and development path. According to Shengcong et al., community teaching has the characteristics of sociality, education, and politics. In the development and construction of cities, the development of community teaching mode is the inevitability of social development to a certain extent and the inevitability of people's pursuit of lifelong education . Wei andIn China, due to different regions, the economic level and environmental development of various regions are inconsistent, resulting in different maturity of community education, and the teaching results are also inconsistent. This teaching model has achieved good results in economically developed regions in China and has also developed well in provinces and cities in the central region; in the other remote mountainous rural areas, due to its remoteness, poor natural conditions, sparse population, low living standards, backward education, and the lack of support or maturity of policies, the development of education model is not ideal. This situation is most prominent in the western region of China, and its education development is relatively slow. Under the environment of big data and technical support, people's knowledge needs for various industries and fields are inconsistent, and the knowledge pursuit of adults and the elderly is also different. In terms of building community education subjects and resource reserves, through big data technology, we can more closely combine multiple disciplines and knowledge reserves to carry out differentiated education, and teachers can carry out online education and regular live teaching. It can effectively improve the initiative of educators. Macroscopically, the community teaching mode of adult education, on the one hand, plays a positive role in building personal national sense of honor and social responsibility and improving personal comprehensive quality; on the other hand, it provides more directions for the teaching methods of developing and innovating the national adult education mode from point to surface. Due to the wide range of choices in the curriculum, the temporal and spatial nature of the vertical learning direction is relatively free. It makes the learning time from adults to the elderly more free and has greater interest in learning. According to Zhong, with the rise of community education, while learning, it also plays a role in promoting the governance and management mode of the community. In life, common education can effectively promote the feelings of mutual help among residents. With the support of policies, it plays an important role in opening a happy garden and building ecological civilization in the future . Chenxi In the development and application of community education platforms, online teaching methods and resource search and processing are the main learning methods; the \u201conline teaching\u201d mode breaks the traditional teaching methods; allows us to directly obtain valuable resources on the Internet without considering the problems of downloading, saving, format conversion, and so on; simplifies the cumbersome steps of using network resources in real classes; and is the main way for us to accurately find educational resources and corresponding platform instructors that meet our personal needs in the vast data network platform. The complexity and diversity of user groups and the direction of knowledge needs are inconsistent. Diversified knowledge needs to be unified in a platform processor, which is a huge challenge to the ability of processors and digital computing. In this environment, big data technology is an inevitable need that can be handled as a whole. Under the condition of big data technology, the speed of data analysis and processing is faster. The planning classification of the management platform is more clear and specific. Because the huge data volume provides data support for further analysis and research, and there are many classifications of data, such as audio, video, pictures, text, PPT, geographical location, and other information. In the huge data processing, the required data can be accurately identified. On the education platform, the integration, analysis and processing of data, data analysis and mining, data sharing, and data presentation can be displayed in the form of visual reports, which makes people more intuitive about information screening and statistical analysis. In terms of system carrying capacity, it can also meet the needs of a large number of users online at the same time. Using the advanced technology of big data can provide more construction ideas for community education and provide more technical support for the development of the platform.Based on the development of community courses in the big data environment and Marx's vision, there are serious deficiencies in platform management and information processing in the traditional network environment. Due to the inconsistent demand direction of community residents, the branch of information search is narrow. In the background processing, the system can only carry out data statistics based on the courses with a large audience, and the data analysis of minority clicks and selected courses is not accurate enough. There is no specific division and education for the universality and comprehensiveness of community education. In the big data processing technology, compared with the platform independent processing system in the traditional mode, the collection and aggregation ability of decentralized information in the platform management can be statistically processed and visual charts of data reports can be made. Managers can modify and improve the curriculum according to the collection and analysis of big data, meet the residents' diversified knowledge choice to the greatest extent, and provide higher technical support and means for the development path research in curriculum management. The establishment of an excellent education platform also makes the audience group of the platform more united and stronger, which is also beneficial to the unity of community residents, the authority of the platform, and the management mode of the platform. The establishment of friendly exchange and learning groups with friendly coexistence of residents plays a positive role in cultivating excellent talents and establishing a correct and positive sense of social responsibility and social values.With the promotion of education and the popularization of the Internet, the trend of digital development of community education is becoming more and more obvious. For community education, big data also has unique characteristics. Community education takes community personnel as the object of education and provides them with learning opportunities. Based on the development of community education curriculum, the community education curriculum is comprehensively analyzed from four aspects according to the acceptance of community education under different technologies, and In In order to better compare the acceptance of community education courses under different technologies, we visualize the data in As shown in With the continuous development of society, community training is also paid more and more attention. Therefore, an education system is gradually established to provide learning opportunities for the unemployed and those with low academic qualifications in the community, establish a resource platform for lifelong learning, and improve the education system with the educational platform goal of community construction. With the rapid development of the times, education is becoming more and more convenient. According to the analysis and research on the development path of community education courses from different perspectives, In In order to better compare the path development of community education courses from different perspectives, the visualization is carried out according to the data in Education is the top priority of our country and the foundation of our country. The education of a nation can reflect the state of the country. Therefore, as the country attaches importance to education, the mode of education is also changing. People of all ages are on the way of learning, and the learning method is not limited to schools and parks. Under the background of the development of education, a comprehensive analysis is made from the curriculum content, teaching mode, and teaching philosophy according to general adult education and community education, as shown In order to better evaluate and compare the curriculum development of curriculum education in different ways, the visualization is carried out according to the data in Through the research and analysis of the community education curriculum development from Marx's perspective under the big data environment, this paper can see that in the process of national development, education follows the lifelong teaching mode, which has a certain positive effect on people's ideological and political concepts and the direction of cultivating talents. Excluding the traditional education mode, the application of community education under big data technology improves the education development platform and data processing ability, so that the selection of courses and the reserve of knowledge are more suitable for the public, and the training of age, gender, and comprehensive quality has been improved and developed. In the development of education mode in the new era, there are still some deficiencies in the implementation policy of community education in China for the acceptance of the Internet to the application of science and technology in the development of various education fields and the opening of a new education environment. At present, the implementation effect in economically developed areas is relatively successful, and there are still deficiencies and technical deficiencies in the development of education in remote areas. The development direction of socialism in our country follows the advanced social concept of Marxism, and we should also keep pace with the times in the cultivation of people's educational thoughts and pursue the establishment of a knowledge exchange circle and learning circle for mass groups. Based on the online and offline development mode, community education can not only meet the needs of individuals but also provide more data reserves and statistics for community unity and social management. In this social platform, the education mode integrating learning, communication, making friends, and other functions breaks the traditional silent education mode for the freedom of education, so that knowledge can be liberated, people's minds can be liberated, and social development can also open up new development directions.Community education curriculum is the key and important medium to promote the achievement of community education goals. Through research and exploration of this paper, in the existing social development, the development of digital economy and the application of big data technology have been combined, and certain breakthroughs and innovations have been made in the development of new educational models and curriculum development under the educational concept based on Marx's thought. People tend to live and use the Internet, which is in the rapid progress of the development of the Internet era. Through the network environment, the people of the country will be coordinated to build a learning ecosystem and a circle of friends, not only to effectively improve personal quality education and cultural level but also help individuals establish correct social outlook, values, and ideological quality. Based on the current direction of curriculum development, we should make use of the advantages of big data in the future development path to create a more flexible curriculum education and hierarchical education structure system that meet people's needs for adult education, provide more data support for the development of community education, and make a positive data basis for national policy support."}
+{"text": "This Retraction follows an Expression of Concern relating to this article previously published by Portland Press.Bioscience Reports at the request of the Editor-in-Chief and the Editorial Board following receipt of a notification from a reader, alerting the Editorial Board to incorrect nucleotide sequence reagents listed. The errors in this article were identified using The Seek & Blastn tool by Labb\u00e9 et al. 2019 .This article is being retracted from The authors have been contacted with regards to the retraction, and have not responded to the Journal's queries and the concerns raised. Given the extent of the issues raised, the Editorial Board stand by the decision to retract the article."}
+{"text": "The authors regret that the name of one of the authors (Fa-Gui He) was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "Following publication of the original article , the autThe Competing interests section should also have stated that Timothy D. McHugh is an Editor-in-Chief of Annals of Clinical Microbiology and Antimicrobials and was not involved in the peer review process for the manuscript."}
+{"text": "The functional safety assessment is one of the primary tasks both at the design stage and at the stage of operation of critical infrastructure at all levels. The article's main contribution is the information technology of calculating the author's metrics of functional safety for estimating the instance of the model of the cyber-physical system operation. The calculation of metric criteria analytically summarizes the results of expert evaluation of the system in VPR-metrics and the results of statistical processing of information on the system's operation presented in the parametric space Markov model of this process. The advantages of the proposed approach are the following: the need to process orders of magnitude less empirical data to obtain objective estimates of the investigated system; taking into account the configuration scheme and architecture of the security subsystem of the investigated system when calculating the metric; completeness, compactness, and simplicity of interpretation of evaluation results; the ability to assess the achievability of the limit values of the metric criteria based on the model of operation of the investigated system. The paper demonstrates the application of the proposed technology to assess the functional safety of the model of a real cyber-physical system. Numerous facts of successful cyber attacks indicate a lack of security of cyber-physical systems of all levels and classes. The reasons for this  are the emergence of new vulnerabilities and the negligence of privileged users. In addition, the cause of malfunctions is the failure to consider the specifics of the functioning of sensor networks  Internet of Things.Assessing the functional safety of cyber-physical systems is undoubtedly relevant because new vulnerabilities are constantly identified11. In the field of SIEM and UEBA already operates several commercial software products, including ArcSight ESM, QRadar SIEM, Splunk Enterprise Security, Micro Focus Security ArcSight UBA, Securonix UEBA, Splunk User Behavior Analysis. The practical experience of these solutions has revealed their imperfections in the analysis of causal relationships between the facts of failures and malfunctions and operative information about the operation of target systems.The only adequate response to new vulnerabilities is periodically or continuously updating protection mechanisms. The latter option involves accumulating large data sets and high costs for their storage and analysis. However, this is not a problem regarding the functional security of the critical infrastructure. The Security Information and Event Management (SIEM) and User and Entity Behavior Analytics (UEBA) subsystems are responsible for storing and analyzing the results of the target cyber-physical system14 such as the National Vulnerability Database (NVD), the Common Weakness Enumeration (CWE), the Common Attack Pattern Enumeration and Classification (CAPEC), MITER Att&ck, etc. are providers of benchmarks for known vulnerabilities. In addition to the essence of known vulnerabilities in these databases, there are metrics for ordering them by degree of danger. However, these metrics are reduced to a single indicator, the value of which can be objectively used only as an additional factor in expert analysis of the real cyber-physical system.Recognized information sources19:the integration of information;the security analysis;the analysis of security policies;the decisions support in the field of protection;the automated control of the protection subsystem (including the based of Security Content Automation Protocol ones);the correlation analysis of events;the definition of security metrics.Ensuring the functional safety of cyber-physical systems is a complex problem. This thesis allows us to mention several methodologies related to our object of investigation. These are the following methodologies21 focus their efforts on developing methodologies to support decision-making and metrics in the field of investigation and summarize the results in the form of profile standards, such as ISO/IEC 61508, for example. Apologists of the methodology of automated control of the protection subsystem24 define the core of such systems in the mathematical apparatus of probability theory and mathematical statistics, graph theory, and Petri nets, fuzzy logic, Markov chains, artificial intelligence and more. At the same time, the results obtained in this direction are of research interest because applying the obtained models and methods requires large amounts of empirical data and computing power.Interestingly, apologists for expert methods of functional safety assessment36. Visibility, a high level of adequacy of the mathematical model and a deeply worked out mathematical apparatus of Markov processes make it possible to use it in such areas as control of operation processes, queuing systems, the operational reliability of these types of systems and their components. The main advantages of Markov processes are the ability to build predictively controlled models of the behaviour of a cyber-physical system or a group of its components in time based on statistical information or the results of operational observations. Most often, a Markov process is presented as a model with a probabilistic structure, which allows one to determine the probability of a cyber-physical system falling into one of the states of the process for a certain time or time interval.The Markov process as a mathematical model for studying complex technical and information  systems is well knownOne of the most effective ways to significantly reduce the cost of maintenance and repair of cyber-physical systems is the choice of the optimal strategy for their operation. When describing the model of the behaviour of a cyber-physical system using the analytical apparatus of the Markov process, it seems possible to link the probabilistic structure of the change in the state of the system with income or expenses that arise when the system passes from one state of the process to another . With this approach, labour costs for its maintenance are used as the main indicator for analyzing a system, and a model based on Markov processes allows us to estimate the total labour costs for maintaining a system for a certain period of operation, as well as to choose a control strategy in which the costs of operating the system under study will be optimal.27. This trend is due to the need to automate the process of detecting in the logs with the results of the operation of the target system of features characteristic of known types of vulnerabilities. This task is semantically related to intelligent data analysis. However, the use of smart technologies in the field investigated in this article is risky because the first ones demonstrate high efficiency in processing the content of balanced and statistically representative data sets. Still, the content of real logs is far from these ideals. Also relevant is the question of the difference between qualitative metrics in intelligent data analysis (classification task in the field of pattern recognition theory) and the field of dependability theory.In addition, assessing the functional safety of the cyber-physical systems involves machine learning methodsobject of investigation is the operation process of the cyber-physical system. The subject of research is the mathematical apparatus of probability theory mathematical statistics, and the theory of Markov chains. This study aims to create information technology for assessing functional safety based on the Markov model of cyber-physical system operation. The main contribution of this paper are the following:we have described the life cycle of the cyber-physical system in the context of determining its functional safety in the form of compact and informative metrics;the situation of lack of the necessary mechanism in the protection subsystem (new vulnerability);the situation when the protection subsystem neutralizes the failure caused by a known vulnerability in one cycle ;the situation when the protection subsystem neutralizes the failure caused by a known vulnerability in more than one cycle (system in idle);we have created the model of cyber-physical system operation using Markov chain, and have considered:we have formalized the method of calculating the criteria of the created metric for an instance of the cyber-physical system operation model, taking into account information from etalon databases on known vulnerabilities and empirical information on the results of operation of the investigated system.Let's accumulate the mentioned information by defining the obligatory attributes of scientific investigation. Thus, the i-th failure Assume that the set of stable states of the investigated cyber-physical system in discrete time is defined as i-th failure is realized; (b) with probability A cyber-physical system in state A cyber-physical system in state The cyber-physical system in state Suppose that at the initial moment These initial provisions indicate that the state of the investigated cyber-physical system at an arbitrary discrete moment of time is recognized only as the state in which it was at the previous moment of time. Thus, the semantic relationship between the states of the set mentclass2pt{minimset set t.the set The stochastic input parameters of the model of the investigated cyber-physical system operation are organized into such sets with power The values of the elements of these sets must correspond to the conditions:In order to determine the Markov chain presented in Fig.\u00a0For presented in Fig.\u00a0entclass1pt{minimaIf the protection mechanisms of the cyber-physical system do not function, i.e. If the protection mechanisms of the cyber-physical system have managed to neutralize the failure in one cycle For real cyber-physical systems characterized by large values of e matrix  to the pentclass1pt{minimaFor ressions , 5), ,   9) from It is seen that the limit values of the probabilities of realization of states from the set To determine the claimed technology, it is necessary to formalize the qualitative metrics and the concept of its calculation for an arbitrary instance of the model of cyber-physical system operation in the parametric space of the corresponding attribute of dependability, i.e. functional safety.According to the material presented in \u201cn matrix . If we amentclass2pt{minimWe define in the matrix of transient probabilities  fragmentConsidering the content of matrices  and 12)12), we pConsidering the limit relations , for \\doThe element's value Let the process of the investigated cyber-physical system operation start from the state e matrix : \\documeIn the transition from the block representation of the matrix the form , the newIf the set of potential failures is a priori defined in the form i-th failure despite the opposition of protective mechanisms is equal to As noted earlier, the probability of inoperation of the investigated cyber-physical system due to the implementation of the We formalize the expression for calculating the parameter mentclass2pt{minimThe absolute values of the eigenvalues of the matrix pression . We defipression  for \\docLet the Markov model of the investigated system at time Based on expression  for the Expressions  and 17)17) allow29 as Damage, Reproducibility, Exploitability, Affected users, Discoverability (DREAD); Common Vulnerability Scoring System (CVSS); Vulnerability Priority Rating (VPR).In general, the number of fixed parameters for calculating the metric VPR system. Here is analytical information in favour of this choice. Not only publicly available technical data but also cyber intelligence is used to address vulnerabilities in the VPR system. Empirical studies29 have shown that the upgrade of the information and communication system to address 400 critical vulnerabilities detected by VPR has shown the same effect on increasing functional safety as the upgrade of the base version of the same system to address 9000 critical vulnerabilities, detected using the CVSSv3 system. This result convincingly proves that the catalogue of vulnerabilities in the VPR system is organized more rationally than analogues.In the future, the authors will focus on the 32. Let i). It is possible to predict the existence of a certain functional relationship between the probability of i-th failure i-th failure, the greater the probability Let the 34, the probability of neutralization of the i-th failure Analysis of expression  allows umentclass2pt{minimWe connect the author's metric ressions  and 18)\\documentressions  and 20)\\documentExpressions , 22) ar ar22) arThe values of weighting coefficients the mathematical expectation of the number of cycles between failures i-th failure the mathematical expectation of the number of cycles required by the protective mechanisms to neutralize the share of successfully neutralized failures Let the content of the logs of the investigated cyber-physical system be sufficiently statically representative to calculate:In terms of presented in Fig.\u00a0\u03b2 and parameters Substituting expressions  into expIf inequality  holds, tpression  the condmentclass2pt{minimi-th failure, should be assessed purely by an expert method37.Finally, the values of the parameters As an example, we use the technology presented in \u201cCollected of confidential information in the system is open only to authorized employees of the Vinnytsia City Council, the National Police of Ukraine, the Security Service of Ukraine, etc. In order for these privileged persons to have prompt access to the relevant information, a local network was created consisting of data center servers, communication equipment, workstations, and software. In normal operation, this LAN is not isolated from the WWW. However, the processing, storage, and audit of confidential information are carried out by a specialized relational database management system, access to which is organized through a specialized web interface. Data, databases and management system, web interface\u2014all these components are located on dedicated servers.We imitate a situation where attackers exert a deliberate influence on the information and communication system of the Situation Center, which threatens the functional safety of the latter. Attackers seek information about network architecture, workstations, servers, operating systems, user accounts and more. Analysis of this information can identify hardware and software vulnerabilities, some of which may not fall within the scope of the protection subsystem.In the realities of modern cyberspace, exploits are often created based on data collected as a result of:40:The analysis of the logs of the information and communication system of the Situation Center revealed the following categorized vulnerabilitieshttps://www.cvedetails.com/. Note that at the request of VCC administration, the sets A full description of these vulnerabilities can be found at entclass1pt{minimai-th type of vulnerabilities, Using the presented in Fig.\u00a0pression  we calcuressions  and get Now we define the object-oriented condition  for the By changing the parameter's value pression  and presThe dependence By changing the parameter's value ressions  and presAs we noted in the formalization of expression , the chaThus, as an experiment, we investigated the model of operation of the cyber-physical system of the Situation Center of DIT of VCC in the metrics of functional safety, formalized in \u201c\u03c6 is the mathematical expectation of risk factor that describes the losses from the probable fact of implementation of the failure despite the operation of protection mechanisms that cause inoperation) for the cyber-physical system of the Situation Center of DIT of VCC. It is characterized by the content of the conglomerate of sets Let's start the discussion of the results presented in \u201cThe availability of a statistically representative amount of information on the operation of the investigated system allowed experts to classify potential failures in the VPR metric. These circumstances allowed us to move from the direct calculation of the criteria of the metric ressions , 22) to to\\documressions , 25). T. T\\documressions , the eleressions .The presented in Fig.\u00a0The presented in Fig.\u00a0\u03c4 for the investigated system to be greater than The condition (29) defined for the investigated system also positively affects the practical orientation of the criterion The presented in Fig.\u00a0The result proves the obvious fact that even an ideal protection subsystem is not a basis for claiming that the target system is guaranteed against inoperation. Thus, the antagonism of the \u201csecond law of thermodynamics vs. perpetuum mobile\u201d also works for cyber-physical systems. Another advantage of Fig.\u00a0So, we have described two functional security metrics based on the Markov model for the operation of a cyber-physical system. We have also shown that using the general VPR vulnerability system, the parameters of this model can be effectively estimated based on a small amount of empirical data, which is an undeniable advantage compared to, for example, the expert assessment method. Of course, the model we have considered has several assumptions related, in particular, to the impossibility of the simultaneous occurrence of several failures, as well as their independence from each other. Our further work will be aimed at weakening these assumptions and obtaining a more complex and generalized model, the dynamics of which will be as close as possible to the behaviour of real systems.Finally, it should be noted that the technology of functional safety assessment based on the Markov model of cyber-physical system operation proposed in the article is based on generally accepted, valid, updated VPR-metrics and proved to be an adequate mathematical apparatus of Markov chains. These facts, and the rigor and reversibility of the analytical transformations made in the formalization of the metric the need to process orders of magnitude less empirical data to obtain objective estimates of the investigated system;taking into account the configuration scheme and architecture of the security subsystem of the investigated system when calculating the metric;completeness, compactness, and simplicity of interpretation of evaluation results;the ability to assess the achievability of the limit values of the metric criteria based on the model of operation of the investigated system.The assessment of functional safety is one of the primary tasks both at the design stage and at the stage of operation of critical infrastructure at all levels. The article's main contribution is the information technology of calculating the author's metrics of functional safety for estimating the instance of the model of the cyber-physical system operation. The calculation of metric criteria  analytically summarizes the results of expert evaluation of the system in VPR-metrics and the results of statistical processing of information on the system's operation presented in the parametric space Markov model of this process. The advantage of the author's approach over analogues is:As an example, the article demonstrates the author's technology to assess the functional safety of the model of a real cyber-physical system of the Situation Center of the Department of Information Technology of Vinnytsia City Council .However, in formalizing the Markov model of cyber-physical system operation, attackers believed that vulnerabilities used to lead to failures or inoperation were independent. The probable situation of simultaneous exploitation of one vulnerability by more than one attacker was also not considered. Considering these circumstances in the mathematical apparatus presented in the article is the direction of further research."}
+{"text": "This study promotes the comparison and research of Chinese literature and Japanese literature from the perspective of the ecological environment of sustainable development.  This study analyzes and compares the differences in the literary cultures of different countries. After the analysis, it is found that the literary culture has never been solid and conservative. We should look at the national literary culture and national differences from the perspective of development.  The results show that in the research of Chinese and Japanese comparative literature from the perspective of a sustainable ecological environment, it is found that through the comparison and analysis of concept differences, thinking differences, behavior differences, and language differences in Chinese and Japanese comparative literature, it can be seen that Chinese literature has a more far-reaching impact on national quality education than Japanese literature, which is more progressiveness and has a reference value.  The analysis and research of Chinese and Japanese comparative literature cannot be underestimated in promoting the development and progress of the country, and it can provide a good foundation for promoting the establishment of a bridge of friendly exchange between Chinese and Japanese nationalities so as to shorten the distance between each other. The sustainable development of the ecological environment is closely related to the development of the social economy. The ecological environment provides essential resources for human survival and development. The Chinese nation has always respected and loved nature. The 5000 year old Chinese civilization is pregnant with a rich ecological culture. The prosperity of ecology leads to the prosperity of civilization, and the decline of ecology leads to the decline of civilization. Civilization is the historical accumulation of culture, and culture is the external manifestation of civilization. The development process from agricultural civilization to industrial civilization to ecological civilization is also a process of continuous deconstruction and reconstruction of the ecological culture paradigm . EcologiIf a country's cultural development wants long-term and progress, it is necessary to correctly grasp the relationship between national literature and world literature. The construction of national literature is inseparable from the theory and method of comparative literature . The litThe exchange history of Chinese and Japanese literature is bounded by the Meiji Restoration, and the comparative literature research between China and Japan is carried out from the two fields of Chinese and Japanese ancient literature and Chinese and Japanese modern literature. The important achievement of Chinese and Japanese comparative literature is the comparative study of Chinese and Japanese ancient literature. Since Japan entered the Meiji Restoration, Western culture has been continuously introduced into Japan, which became a new thing and a turning point in the trend of Japanese literature, leading to the rise of Japanese modern literature . In the Culture is borderless and excellent. No matter which country it is from, it can be used for reference and recognized by all countries in the world. However, culture is different, and different countries and regions have distinctive characteristics in all aspects . ConceptIn In order to better reflect the comparison results of the conceptual differences between Chinese and Japanese comparative literature under the analysis of two different literary and cultural directions, the data comparison results in The thinking difference is reflected in the problem and implementation, as well as in the logical ability. The ability is improved by forming independent systematic thinking, which gradually opens the thinking gap in these processes. Therefore, thinking is the reflection of people's brain on objective reality. It is a unique spiritual activity of people, which is produced from a large number of social practices. The main reasons for the formation of the thinking difference between Chinese and Japanese comparative literature is because of the country's region, the country's productivity, and the country's unique cultural thought. China has a vast region, rich and diverse resources, and a unique national culture; however, Japan's territory is narrow, the types of resources are scarce and limited, and most of its national culture is a mixture of learning from and accepting the cultural ideas of other foreign countries. Therefore, China's literature and culture has the style of a big country, while Japan's culture is relatively chaotic and complex. Under the influence of this literary thought, Japanese people's thinking mode is more conservative and old-fashioned. By comparing the thinking differences of Chinese and Japanese comparative literature in terms of national self-discipline, interpersonal relationship and communication mode, and analyzing, discussing, and studying the two different literary and cultural directions of Chinese literature and Japanese literature, In In order to more intuitively reflect the comparison results of thinking differences between Chinese and Japanese comparative literature under the analysis of two different literary and cultural directions, the data comparison results in The fundamental reason for the formation of the difference between Chinese and Japanese comparative literature is Confucianism, but the reason for the formation of the behavior difference between Chinese and Japanese comparative literature is also composed of other factors, such as geographical environment, national geographical location, and so on, which lead to great differences in people's behavior and activities. Behavioral differences are reflected in the innate physiological quality and social environment. Through later education and social practice activities, they show different behaviors and activities dominated by ideas. The basic reason for the formation of the difference between Chinese and Japanese comparative literature is Confucianism, but the reason for the formation of the behavioral difference between Chinese and Japanese comparative literature is also composed of other factors, such as the geographical environment and location of the country, which lead to great differences in people's behavior and activities. Through the comparison of thinking differences between Chinese and Japanese comparative literature in terms of integrity consciousness, time concept consciousness, and work attitude consciousness, and through the analysis, discussion, and research of the two different literary and cultural directions of Chinese literature and Japanese literature, In In order to more intuitively see the behavioral difference comparison results of Chinese and Japanese comparative literature under the analysis of two different literary and cultural directions, the data comparison results in The differences in the way of thinking and culture are reflected in the differences in the way of thinking and life. The main reasons for the language differences between Chinese and Japanese comparative literature is the differences in the use of vocabulary and the specific ways of language expression. Through the comparison of thinking differences between Chinese and Japanese comparative literature in terms of vocabulary differences, language differences, and expression methods, this paper analyzes, discusses, and studies the two different literary and cultural directions of Chinese literature and Japanese literature, and obtains In In order to more intuitively reflect the behavior difference comparison results of Chinese and Japanese Comparative Literature under the analysis of two different literary and cultural directions, the data comparison results in Both China and Japan have long literary and cultural traditions. With the background of opening to the outside world and the development of global integration, cultural exchanges between countries are becoming more and more frequent. With the joint efforts of China and Japan, the literary relations between the two countries have developed rapidly. Although the two countries have various differences in the mode of cultural inheritance, it is undeniable that the national cultures of China and Japan affect and permeate each other. Wang Z recalled that in the 20th century, the study of Chinese and Japanese comparative literature has experienced a long period of exploration and rapid development, and has made good achievements. Looking forward to the 21st century, the study of Chinese and Japanese comparative literature has been advancing on the road of vigorous development . From thAt present, all countries are facing the trend of sustainable ecological development and global integration. The integrated sustainable development will no longer be embodied in one aspect, but in all-round common development and progress in many aspects, and the cornerstone and focus of national development is the country's unique culture and literacy. This study makes a detailed analysis and discussion on the differences in all aspects of Chinese and Japanese comparative literature from the perspective of sustainable ecological environment. By comparing the differences in concept, thinking, behavior and language of Chinese and Japanese comparative literature, and using statistical methods to express the research of Chinese and Japanese comparative literature more intuitively, it can be seen that the differences of Chinese and Japanese comparative literature have different effects on their nationals. The enthusiasm of the people of the two countries for literature and learning has increased greatly. They learn from the strengths of the comparative literature of the two countries and learn from the weaknesses of their own comparative literature, which provides a more favorable scheme for sustainable ecological development and speeds up the pace and process of sustainable development of global integration."}
+{"text": "Following publication, concerns were raised regarding the validity of the data in the article. The authors failed to provide the raw data or a satisfactory explanation during the investigation, which was conducted in accordance with Frontiers\u2019 policies.Given the concerns, and the lack of raw data, the editors no longer have confidence in the findings presented in the article.The authors do not agree to this retraction.This retraction was approved by the Chief Editors of Frontiers in Cell and Developmental Biology and the Chief Executive Editor of Frontiers."}
+{"text": "This Retraction follows an Expression of Concern relating to this article previously published by Portland Press.Bioscience Reports at the request of the Editor-in-Chief and the Editorial Board following receipt of a notification from a reader, alerting the Editorial Board to repeated images in Figure 5.This article is being retracted from The Editorial Office was also contacted by the listed corresponding author, Derong Ma, via an email address that differed to the one included with the submission. Derong Ma confirmed that they were unaware of the submission and publication of the article, and that they did not conduct any part of this research, hence should not have been listed as an author on this paper.The corresponding author of the paper has been contacted via the original email address in the published paper to provide a response to the Editorial Office concerns surrounding the authorship of the paper but has not responded.In light of the concerns raised regarding the Western blots and the authorship of the paper, the Editorial Board stands by the decision to retract the paper."}
+{"text": "There is a growing and renewed interest in the use of hallucinogenic drugs in the treatment of psychiatric disorders, especially since the FDA approval of ketamine treatment for resistant depression. The response to hallucinogenic psychedelic substances  in the treatment of depression and addictions calls for a theoretical explanatory model.Provide a descriptive / explanatory psychopathological model of the response to treatment with hallucinogenic drugs based on the descriptions of the subjects and the comparison with other extreme life experiences.Relevant published literature on subjective experiences in treatment with hallucinogenic drugs for depression and addictions is reviewed. It is compared with subjective experiences in life changing experiences.Intense emotional states, mystical-type experiences including feelings of oneness, transcendence, ineffability, and the complex emotion of awe seem to be consistently presented as psychic elements related to the efficacy of these treatments. The genetic and cultural (memetic) evolutionary value of these emotions in the cohesiveness of human groups and the genesis of affective symptoms, and in the recalibration of cognitions and emotions, is discussed.The efficacy of hallucinogenic drugs used in the treatment of depression and addictions is accompanied by complex and varied emotions but with common psychopathological elements that could mediate their action.No significant relationships."}
+{"text": "Tomane  The authors regret the omission of one affiliation for one of the authors, Somia Tomane, from the original manuscript. The corrected list of authors and affiliations for this paper is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "Funding statement as published. The wrong grant was listed. The correct Funding statement appears below.In the published article, there was an error in the This study was supported by the Education Fund of the Macao SAR Government under the Specialized Subsidy Scheme for the Tourism Education and Training for the Guangdong-Hong Kong-Macao Greater Bay Area (TET-CITYU-2020-02).The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "The formation of thinking in ontogenesis follows the line of progressive differentiation and integration of the representations of objects, events, and relationships. The same is true for the development of mentalization ability, conceived as a thought process in the area of social interactions.The purpose of the study was to compare the particularities of thought processes when dealing with different types of material: physical objects  and social situations .40 inpatients with schizotypal personality disorder, 40 inpatients with paranoid schizophrenia and 40 controls took part in the study. The Objects Sorting Test was used to assess operational thinking. The mentalization ability was assessed using two SCOR-S scales for Thematic Apperception Test: Complexity of representations of people and Understanding of social causality.The results of correlation analysis support the existence of the reverse links between the impairments of operational thinking and both the complexity of representations of people  and the understanding of social causality . It is supported by the qualitative analysis, where inpatients with thought distortions, characterized by arbitrary generalizations, are inclined to make similar errors in the reasoning about the mental states, ignoring the conventional explanations and relying on their own emotional impression and etc.The limitations of the operational thinking as reflected in the inability to form adequate generalizations on the basis of socially predefined attributes of meaning are closely related to the ability of differentiation, integration and causal explanation of meaningful aspects or social situations."}
+{"text": "This article has been corrected at the request of the authors to change the following:The affiliation of Ana C. Spyridakis has been changed from Washington University School of Medicine in St. Louis to St. Louis University.The authors deeply regret that these errors were not identified and addressed prior to publication."}
+{"text": "The Editor-in-Chief has retracted this article. Contrary to the statement in the article, this study was not approved by the Institutional Animal Care and Use Committee of Tangdu Hospital, The Air Force Medical University. The corresponding author has informed the Journal that at the time the study was performed there was no procedure for obtaining ethical approval. The corresponding author Baoan Ma has stated on behalf of all coauthors that they agree with this retraction."}
+{"text": "A recent outbreak of the monkey pox virus disease (MPVD) started to spread over the world before the second half of the 2022\u00a0year. This outbreak of the monkey pox virus disease is known as the 2022 outbreak of the monkey pox virus disease. The monkey pox virus disease is a type of the pox disease similar to the human one. This disease is an endemic in some African countries; however, a new spreading of this disease started to appear in other countries, such as the Spain, brazil, Greece, the United Kingdom, and Portugal, Australia, and the USA. As of the end of September 2022, the MPVD spread over than 107 countries over the world.This study focuses on the employing of the simplest model of the diseases forecasting which is SIRD model for the finding of the basic reproductive ratio of the monkey pox virus disease in multiple countries over the world where the disease spreads. The model takes into accounts the number of the susceptible people, the number of the infectious people, the number of the recovered people, and the number of the deceased people. Based on the results of the SIRD model coefficients, we find that the basic reproductive ratio values of the recent spreading of the monkey pox virus disease are 1.3274 for the United Kingdom where the first case of the disease was recorded, 1.0714 for the United Arab Emirates, 1.0866 for Nigeria, 1.5589 for Brazil, and 1.3610 for Canada.We find that the average value of the basic reproductive ratio of the 2022 outbreak of the monkey pox virus disease is about 1.2809. This important result of our calculations predicts that the 2022 outbreak of the monkey pox virus disease is turned into pandemic over the world. The things which confirm this result, based on our calculations, are the values of the basic reproductive ratio of the 2022 outbreak of the disease in the considered countries from multiple continents where all the values of the basic reproductive ratio are bigger than one. From this point, the counties over the world must apply multiple procedures for limiting the spreading of the monkey pox virus disease. At the end of the first half of 2022, new cases of the viral virus, namely the monkey pox virus disease (MPVD), started to appear in multiple countries over the world. The recent spread of the monkey pox virus disease is known as the 2022 outbreak of the MPVD. The first case of the 2022 outbreak of the monkey pox virus disease was recorded in May 2022 in the United Kingdom. The 2022 outbreak of the monkey pox virus disease spread in lots of countries over the world. For example and as of the end of September 2022, in some of the European continent, the disease appeared in Belgium with 744 confirmed cases , in Aust\u03bd1. The second equation is also a type of the nonlinear equations, and this equation gives the rate of the infectious cases as a function to the product of the infectious cases itself, and the susceptible cases, with also another term as function to the infectious cases itself. The second equation has three different parameters, and these parameters are the coefficient of infection which is \u03bd1, the coefficient of recovery which is \u03bd2, and the coefficient of the mortality \u03bd3. The third equation of the model gives the recovery rate as a function to the infectious cases, and the parameter of this equation is the coefficient of the recovery \u03bd2. The fourth and the last equation of the epidemic model, which we use, gives the mortality rate as a function to the infectious cases, and the parameter of this equation is the coefficient of the mortality \u03bd3. In Fig.\u00a0The MPVD is not a new, where this disease is an endemic in some of the African countries. However, in the recent months, this disease started to appear in new countries over the world. Multiple studies about the 2022 outbreak of the monkey pox virus disease were discussed. For example, Hemati et al. proposed useful study of the using of procedures which were taken of the spreading of the corona virus disease 2019 . de JongS represents the total number of the susceptible people, I represents the total number of the infectious people, R represents the total the number of the recovered, and D represents the total number of the deceased people, while N is the total number of the population in a specific society or a specific country. We can write the equilibrium case of the epidemic based on the Jacobean of the SIRD model as follows:0 represents the equilibrium case of the epidemic. The next step is finding the eigenvalues of the equilibrium Jacobean of the SIRD model, which is found from the following well-known equation:\u03b1 represents the eigenvalues of the Jacobean of the SIRD model, and \u03c34 represents the identity matrix which is given as follows:We collect the confirmed recorded cases of the 2022 outbreak of the monkey pox virus disease for multiple countries over the world. Then, we use the SIRD epidemic model and the simple fitting method based on the numerical simulation techniques using MATLAB software, for finding the basic reproductive ratio of the 2022 outbreak of the monkey pox virus disease. The basic reproductive ratio of the disease based on the equations of the epidemic model can be derived using multiple methods. For instance, in this work, we illustrate the definition of the basic reproductive ratio of the SIRD epidemic model based on the Jacobean method. For the derivation of the basic reproductive ratio of the SIRD model, we write the Jacobean of the SIRD model as follows:Equation\u00a0We solve the previous algebraic equation for the eigenvalues, which gives three zeros solutions:The nonzero solution gives us the stable and the non-stable equilibrium case of the epidemic as follows:which gives us the basic reproductive ratio of the SIRD model as follows:As we see from the previous equation, by finding the three parameters of the SIRD model, we can find the basic reproductive ratio of the 2022 outbreak of the monkey pox virus disease. As we can see from the last equation, if the disease has very low mortality rates, the mortality parameter of the SIRD model can be neglected, and we return to the basic reproductive ratio of the simple case without mortality. We fit the collected cases of the monkey pox virus disease in each country of the considered countries for finding the parameters of the SIRD model for the monkey pox virus disease. After that we use Eq. \u22121 unit, where the mortality coefficient is very small and near zero. As an example of the Latin American continent countries, we chose Brazil for finding the basic reproductive ratio of the 2022 outbreak of the monkey pox virus disease. Brazil is the third country over the world with the monkey pox virus disease cases as of the end of September 2022. We found the coefficients of the SIRD model of the 2022 outbreak of the monkey pox virus disease for Brazil, and we put the results of the calculations in Table \u22121 unit, where the mortality coefficient, as in Canada, is very small and near zero. As an example of the African continent countries, we chose Nigeria for finding the basic reproductive ratio of the 2022 outbreak of the monkey pox virus disease. We found the coefficients of the SIRD model of the 2022 outbreak of the monkey pox virus disease for Nigeria, and we put the results of the calculations in Table \u22121 unit, where the mortality coefficient is small and equal to 0.0016\u00a0days\u22121, and it is not very small, and this returns to there are four death cases of the disease in Nigeria as of the end of September 2022. As an example of the European continent countries, we chose the United Kingdom for finding the basic reproductive ratio of the 2022 outbreak of the monkey pox virus disease. The United Kingdom is the country where the first case of the recent spreading of the disease was recorded. We found the coefficients of the SIRD model of the 2022 outbreak of the monkey pox virus disease for the United Kingdom, and we put the results of the calculations in Table \u22121 unit, whereas in Canada, the mortality coefficient is very small and near zero. Finally, and as an example of the Asian continent countries, we chose the United Arab Emirates for finding the basic reproductive ratio of the 2022 outbreak of the monkey pox virus disease. The United Arab Country is one of the Arabic world countries. We found the coefficients of the SIRD model of the 2022 outbreak of the monkey pox virus disease for the United Arab Emirates, and we put the results of the calculations in Table \u22121 unit, whereas in Canada, the mortality coefficient is very small and near zero.We used the collected data of the monkey pox virus disease in five countries where we chose one country from each continent. As an example of the North American continent countries, we chose Canada for finding the basic reproductive ratio of the 2022 outbreak of the monkey pox virus disease. We found the coefficients of the SIRD model of the 2022 outbreak of the monkey pox virus disease for Canada, and we put the results of the calculations in Table Depending on the previous calculations of the coefficients of the SIRD model, we found the values of the basic reproductive ratio of the 2022 outbreak of the monkey pox virus disease for the five countries: Brazil, Canada, Nigeria, the United Arab Emirates, and the United Kingdom. We put the results in Table As shown in Table In this work, we discussed the initial basic reproductive ratio of the 2022 outbreak of the monkey pox virus disease, where this disease started to appear in multiple countries in all of the continents, especially, in the European countries. The simple model of the spreading of the disease was applied which is the SIRD model. The values of the basic reproductive ratio of the 2022 outbreak of the monkey pox virus disease were found, where the values of the coefficient of the recovery, the coefficient of the mortality, and the coefficient of the infection were calculated for five countries from different continents over the world. The five considered countries are Canada as a country of the North American countries, the United Kingdom as a country of the European countries, Nigeria as a country of the African countries, Brazil as a country of the Latin American countries, and the United Arab Emirates as a country of the Asian countries. We found that the basic reproductive ratio of the MPVD is 1.3274 for the United Kingdom, where the first case of the disease was recorded, 1.0714 for the United Arab Emirates, 1.0866 for Nigeria, 1.5589 for Brazil, and 1.3610 for Canada.We found that the average value of the basic reproductive ratio of the 2022 outbreak of the monkey pox virus disease equals to 1.2809 which means that the MPVD have returned into a pandemic in its 2022 outbreak. This means that multiple procedures for limiting of the spreading of the disease must be applied. The method which we applied in this work has no limitations of applying in lots of countries for the study of the forecasting of the 2022 outbreak of the monkey pox virus disease using the basic reproductive ratio of the disease."}
+{"text": "Nature 10.1038/s41586-019-1913-9 Published online 5 February 2020Correction to: In the published version of this paper, the members of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium were listed in the Supplementary Information; however, these members should have been included in the main paper. The original Article has been corrected to include the members and affiliations of the PCAWG Consortium in the main paper; the corrections have been made to the HTML version of the Article but not the PDF version. Additional minor corrections to affiliations have been made to the PDF and HTML versions of the original Article for consistency of information between the PCAWG list and the main paper."}
+{"text": "The authors regret that the name of one of the authors (Jin-Oh Kim) was shown incorrectly in the original article. In addition, the author contributions were incorrectly given. The corrected author list and contributions are as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "T. H. Phong  The affiliations of this author were also incomplete. The correct affiliations are as listed above.The authors regret that the email address of the author Thi Ly Mai was not listed in the original manuscript. The email address of this author is The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "The journal and Chief Editors have retracted the 19 July 2021 article cited above.Shortly after publication, our office received letters of complaint questioning the integrity of the article, following which an Expression of Concern was published and a thorough investigation was conducted, in accordance with our policies and COPE guidelines.The investigation found that the claims made in the conclusions were not adequately supported by the methodology of the study. In particular, as confirmed by an external expert, the process of allocation to treatment and control was not sufficiently random.This retraction was approved by the Chief Editors of Frontiers in Medicine and the Chief Executive Editor of Frontiers. The authors disagree with this retraction."}
+{"text": "Who would have thought that the discovery made by researchers at Washington University  and McGiOf note, Woith et al.  have demDespite the large number of studies published so far, further investigation of the mechanisms underlying exosomal regulation of organ function is needed to better highlight its clinical relevance, even in critically ill patients . Indeed,More extensive multidisciplinary studies are needed to fill in the gaps and to overcome the limitations of available technologies in order to reposition exosomes in the first line for their use in the nanobiotheranostic field. The purpose of this research topic was to bring together state-of-the-art original research and review articles on the latest evidence in the field of exosome-based applications. It is hoped that in the future, readers of this Special Issue will be inspired to develop more effective and less invasive precision approaches to promote the wide use of exosomes at bedside."}
+{"text": "The authors regret that some of the data in the original article were presented incorrectly. Some of the oligonucleotide sequences in the Graphical Abstract, The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "They should also serve as a companion for clinicians and researchers in rheumatology practice, and the relevant stakeholders when developing new PROMs and modifying existing PROMs. The OPs formulated by the TF underpin the value of PROMs as key elements to assess the impact of IA on the daily life of young people with IA, to aid the shared decision-making process.In summary, these are the first PtC for the use of PROMs in young patients with IA based on their own perspectives. We believe that the optimisation and harmonisation of PROMs used in daily practice could strengthen the relationship between patients and healthcare providers, facilitating shared decision making, and ultimately, the quality and experience of care for young people with IA."}
+{"text": "Withdrawal states with delirium, having convulsive syndrome in their structure, are one of the most severe emergency conditions in psychiatry.A total of 160 patients were examined with delirium alcohol withdrawal. Prognostic factors of occurrence of convulsive syndrome in the withdrawal syndrome of alcohol were studied.Clinical, psychopathological, electrophysiological.It was found that the most significant prognostic factors seizures were: severe bloating condition, the duration of hard drinking, the total dose of drinking alcohol before the breakdown of consumption alcohol. Convulsive syndrome not always correlated with marked vegetative disorders in the state of withdrawal of alcohol. Convulsive syndrome that appeared after the development of delirious syndrome often indicated a more serious conditionIt is suggested that the convulsive pattern of response to the severe condition of alcohol withdrawal is formed in some young patients under the influence of endogenous factors, but is realized under certain situational conditions - long binge drinking, massive consumption o alcohol before the break of the reception of alcohol, the use of psychoactive drugs with stimulating effect. In the electrophysiological examination, there were significant differences in the group of patients with convulsive syndrome in the current admission from the group of patients with convulsive syndrome in the past and the group without convulsive syndrome in the state of abolition of alcohol.It is emphasized that when indicating the seizures in the state of abolition of alcohol in the past, the beginning of treatment is necessary to begin even in a state of binge drinking."}
+{"text": "Oberhofer  The authors regret that the name of one of the authors (Petko St. Petkov) was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "The study focused on determining color changes in materials made of cream-firing clays from the Opoczno region (Poland) due to the addition of calcium carbonate in the form of limestone. Moreover, the influence of the grain size distribution of this additive on the color properties of the materials and their phase composition was determined. Test samples were prepared using theplastic method and fired at four different temperatures: 1120, 1140, 1160 and 1180 \u00b0C. The color properties of the surface of ceramic materials were determined in CIE-Lab color space using a colorimeter. Quantitative phase analysis was performed using the Rietveld method. The research showed that the addition of calcium carbonate causes an increase in the yellow color factor and a decrease in the red color factor and the brightness of the material. Moreover, it was proven that the grain size distribution of the additive used significantly influences the phase composition of the materials, thus determining the values of physical properties and the color of the materials. It is well known that the grain size distribution of raw additives used in ceramic masses has a significant impact on the properties of ceramic materials. It was proven that granulation of additives influences the porosity of the final material, its phase composition and microstructure and thus its technological properties ,2. Moreo3 to 2.21 g/cm3 during the reaction leads to cracking and the destruction of the fired material ) appeared in the phase composition of the materials, the presence of which depended on the chemical composition of the added limestone (2Al[SiAlO7]). Gehlenite appeared at the expense of a reduced amount of anorthite in the phase composition with an increase in the grain size of the calcium carbonate additive used. The phase composition of MB306 contained a small amount of anorthite due to the anorthite crystallization model [2), the presence of which was responsible for the appearance of lime grains on the surface of the fired materials  . In someimpurity . The higimestone . Apart fon model . HoweverOn the basis of the data contained in The microstructure analysis of selected ceramic materials  fired at 1160 \u00b0C is presented in By analyzing the image of the microstructure of the reference material M0 and the results of the EDS determination, it could be seen that the microstructure included kaolinite clusters and rutile grains scattered in an aluminosilicate matrix.3 dissolution mechanism was observed for all samples containing the addition of limestone, fired at any temperature. The greater the grain size distribution of the used limestone, the more lime residue is dissolved in the aluminosilicate matrix.A large amount of lime waste accumulated around the large pores, which was also confirmed via the EDS analysis and XRD analysis \u2014the appeAs the firing temperature increases, the value of b indicator increases, and the values of a and L indicators decrease. This means that as the sintering process progresses, the materials based on cream-firing clays are characterized by higher contents of yellow and red shades in their color and by lower brightness.The addition of calcium carbonate causes an increase in the value of the b indicator and a decrease in the values of a and L indicators. Therefore, the introduction of limestone to mass based on cream-firing clays results in materials with a higher intensity of yellow and red shades and lower brightness being obtained.The addition of the finest-grained calcium carbonate causes an increase in the value of the L color indicator of the obtained materials. Therefore, the use of fine-grained limestone as an additive to cream-firing clays allows one to obtain a material withhigh brightness.Large limestone grains do not completely decompose during the sintering process. This results in the accumulation of lime waste around large grains and the appearance of portlandite in the phase composition of these materials. This leads to the appearance of lime grains on the surface of the materials, which give the impression of lightening the surface but also lead to cracking and the destruction of the product.The addition of the finest variety of limestone increases the total open porosity and therefore the total water absorption of sintered material. The remaining types of calcium carbonate reduce the total open porosity and therefore the total water absorption of sintered material.The addition of calcium carbonate causes an increase in total shrinkage values. The bigger the dominant grain size of used limestone, the higher value of total shrinkage.The addition of calcium carbonate causes a decrease in the flexural strength values.With the addition of limestone to the ceramic mass, a new phase appears in the phase composition of the material: anorthite.The grain size distribution of the limestone addition does not influence the share of quartz and mullite in the phase composition of materials.The grain size distribution of the limestone addition influences the share of amorphous phase and anorthite in the phase composition of the materials.The amount of amorphous phase is greater for materials with the addition of the limestone than for the reference material.As the share of the amorphous phase in the phase composition increases, the share of anorthite decreases. This is proof of the ongoing crystallization of the anorthite from the amorphous phase.The conducted research allowed us to find the relationship between the grain size distribution of the added limestone and the color of the surface of the final product and its phase composition. In addition, these tests allowed for the selection of the limestone graining interval, the use of which would enable a homogeneous color of the product surface. The following conclusions were made during the experiment:"}
+{"text": "Severe acute psychosis significantly alters patient\u2019s quality of life in patients with alcohol dependence. The aim of the investigation were examination value quality of the life patients with alcohol dependence who have recently suffered of acute psychotic disorder. The factor influencing the quality of life is the psychoorganic syndrome after acute psychosis.120 patients with alcohol dependence who had recent history of acute psychosis were examined.Psychopathological.The psychorganic syndromes at these patients were investigated. The Index quality of the life in these patients was assessed due to type of the psychorganic syndromes. The dynamics of the Index quality of the life at patients with psychorganic syndrome during the treatment were described. The subjective assessment of their condition in patients with hard psychorganic syndrome was dissociated from the assessment of doctors and relatives. The explaining the characteristics of the consequences of the transferred psychotic disorder to the patients turned out to be important for overcoming anosognosia. The Index quality of the life in these patients was assessed repeatedly at the same time, there was a significant decrease in the difference in the assessment of the quality of life by patients with relatives.The importance of value quality of the life from the point of the patient, relatives of the patient and physician was underlined. The assesment of Index quality of the life is important important to explain the peculiarities of the postpsychotic state to the patients and their relatives in order to develop rehabilitation programs and carrying out psychotherapeutic activities."}
+{"text": "The e-mail contact address for the corresponding author Tao Wen, was omitted in the published article and is shown here.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "Mental Health is an invisible part of public health, and a determinant of it by affecting the human, social and economic capital of countries. Is one of the main causes of disability worldwide and, when left untreated, they can lead to increased costs and premature mortality. In 2019 they represented 22% of the disability burden in DALY in the European Union. Regarding the effects of economic recessions studies suggest that they have detrimental effects on mental health. And can became a reality in the current pandemic scenario.To reflect on the studies carried out that debate the effects of previous economic crises on mental health, particularly the 2008-2013 crisis. It aims to list not only the possible intervention strategies in the area as well as the barriers to their implementation.Classic review of the topic through the international literature and the state of the art on available platforms. Establish a proxy between the unemployment rate and the number of packages (antidepressants and anxiolytics consumed) in homologous periods as a representative capacity of the impact of the crisis on mental health.The number of packages of antidepressants and anxiolytics behave differently. the antidepressants have greater consumption when unemployment decreases.Several studies describe that the increase in the unemployment rate, indebtedness and social exclusion are empirically proven as consequences of the economic crises and predisposing factors for mental pathology. However, this does not translate into a proxy for the consumption of antidepressant packages with the increase in the unemployment rate. It may be due to the non-prioritization of mental health.No significant relationships."}
+{"text": "The paper considers a new technology for the treatment of non-carious cervical lesions (NCCLs). The three parameterized numerical models of teeth are constructed: without defect, with a V-shaped defect, and after treatment. A new treatment for NCCL has been proposed. Tooth tissues near the NCCLs are subject to degradation. The main idea of the technology is to increase the cavity for the restoration of NCCLs with removal of the affected tissues. The new treatment method also allows the creation of a playground for attaching the gingival margin. The impact of three biomaterials as restorations is studied: CEREC Blocs; Herculite XRV; and Charisma. The models are deformed by a vertical load from the antagonist tooth from 100 to 1000 N. The tooth-inlay system is considered, taking into account the contact interaction. Qualitative patterns of tooth deformation before and after restoration were established for three variants of the inlay material. The object of the study is new prosthetic inlays in non-carious cervical lesions (NCCLs). They suggest the expansion of the cavity of the NCCLs.-the creation of parametrized models of teeth with and without the NCCL;-the creation of parametrized models with the restoration of the NCCL in the form of a new prosthetic inlay;-the implementation of a series of numerical experiments on strain of the tooth before and after restoration;-the analysis of the impact of prosthetic inlay materials on strained teeth.Research objectives:The development of a new method for replacing NCCL and a preliminary assessment of the effect of restoration materials on the tooth-inlay system deformation are the main goals of this study. This method can increase the restorations\u2019 service life and their aesthetics. An NCCL is often combined with gingival margin recession. The new treatment method allows the creation of a playground for attaching the gingival margin. The evaluation of the restoration materials\u2019 performance is also an important factor.The work includes only computational experiments at this stage. All studies are in silico. The analysis of therapy parameters and the preliminary selection of materials occur on numerical models.Computer modeling and the accumulated experience of describing the behavior of various materials allow them to be used in the field of medical research. Today there are many examples of successful applications of numerical models in dentistry ,2. ReseaNCCLs are a fairly common dentition disease in the world ,6,7. ThiThere are many works aimed at studying the causes of the occurrence and development of NCCLs. The hard tooth tissue properties of NCCLs affected are being investigated ,12,13,14The loss of restoration of NCCL is a serious problem that dentists face daily. This is due to many factors, for example, high loads on the tooth crown part ,12,28. PThis problem requires new effective solutions. The modern level of providing highly qualified medical care makes high demands in the treatment of dental system pathologies. The methods of biomechanical modeling and mathematical analysis acquire a special role in the planning stage of dental treatment . FEM is An NCCL is a fairly common tooth lesion. The disease causes increased tooth sensitivity and violation of dentition aesthetics. NCCLs are located near the cervical area. The tooth perceives the worst loads from the antagonist\u2019s. Further development of the defect is possible. With the disease progression, movement of the gingival margin in the apical direction is possible, which leads to developing the gingival recession.An NCCL and its development cause a change in the tissues surrounding the lesion . Accordi-polymerization shrinkage;-dependence on the manual skills of a particular specialist;-short service life;-pigmentation;-the inability to ensure reconstruction of the periodontal attachment between the artificial material and the gum.At the moment, the most widespread are direct restorations. However, they have a number of disadvantages:The necessity to create new technologies and methods for NCCL restoration has arisen. The new prosthetic inlays with an additional expansion of the wedge cavity are one of the solutions. The proposed method involves a significant amount of tissue preparation, both to expand the defect and to create zones of additional retention. It is important to note that mainly tooth tissues with accumulated macro- and micro-damages are removed.Deformation of the tooth before and after restoration by a new method is considered in the work. Modeling is performed in the ANSYS Mechanical APDL application package . The tooth geometry is modeled as a first approximation and is more rounded. Crown geometry can be changed. In the first approximation, the crown geometry is not symmetrical and has different heights, i.e., an attempt is endeavored to bring the geometry of the crown closer to the individual case.The central section of the tooth, with and without taking into account the NCCL, is shown in The tooth geometry without taking into account the root system is often used in practice . Such moParameterization of the tooth geometry is performed according to its main parameters: height A cavity is created in the tooth for a prosthetic inlay when creating a new type of restoration. An original new method of treatment is proposed. The formed cavity to fix the inlay (II) includes the main part obtained by expanding the lesion, with an additional retention point in the form of a cavity passing to the proximal surface of the tooth, an additional platform at the top of the cavity for fixing the veneer part of the inlay, and a gingival fold (III) located more apically than the lesion.Element (III) was introduced into the construct to recreate the dentogingival attachment. Often the NCCL is combined with a gingival margin recession. The reconstruction of the periodontal attachment between the artificial material and the gum is not possible.---The inlay cavity was parameterized using 3 parameters:A geometric configuration of the inlay cavity is shown in The inlay is quite streamlined on all sides. The inlay model is parameterized. The thickness, veneer part, and cavity area can change. The figure shows one of the options for the veneer part geometry of the inlay. Given inlay geometry will be used in a numerical experiment series.The prosthetic inlay maintains the aesthetics of the dentition. The inlay restores the aesthetics of the tooth and increases the contact area of the tooth and the prosthetic structure.-roots and gingiva are not taken into account in the model to save computational resources and a detailed study of the tooth-inlay contact zone;-only the vertical load from the antagonist tooth in a wide range is considered;-only the case of complete adhesion of the inlay and tooth is considered, although in reality sliding is possible;-the elastic deformation behavior of materials is considered at this stage. It is planned to study the effect of heat shrinkage on the stress state of the biomechanical unit and refine the behavior model of the system materials in the future;-the degradation of materials is not taken into account, as well as the formation of cracks due to the complexity of such mechanical models.The main limitations of the model at the moment:The materials of the model are considered in elastic formulation. The elastic compression modulus  is material 1; Herculite XRV  is material 2; Charisma  is material 3. The physical-mechanical properties of the inlay materials are presented in The most promising material for creating an inlay is considered to be fine-structured feldspar ceramic blocks of industrial production CEREC . The material is used to make inlays, onlays, crowns, and veneers. The minimum values of the cavity parameters for the inlay are selected according to the restrictions imposed on the material when milling.For comparison, inlays from two different composite materials are considered. Herculite XRV  is a versatile microhybrid composite material. Charisma  is a radiopaque glass-based composite material.The simulation is implemented in the applied ANSYS Mechanical APDL engineering analysis package . Volume finite elements SOLID185 (four-node tetrahedra) with Lagrangian approximation and three degrees of freedom at each node are used. Contact gluing is modeled in the inlay-tooth interface zones, taking into account friction. The model eliminates the divergence of contact surfaces and appearance of sliding zones. The contact interaction is modeled using a contact pair of elements . The surface-surface contact is considered. The contact algorithm is the extended Lagrange method.The finite element partition of the model is chosen within the assessment of the influence of the system discretization degree on the numerical solution of the problem. The minimum overall dimension of the finite element near the tooth-inlay contact area is 0.05 mm. When moving away from the contact zone, the size of the finite elements increases in a gradient. The maximum overall dimension of the final element reaches 0.15 mm.The crown part of the tooth is deformed together, i.e., there is no change in the crown geometry. The position and number of the points of load application from the antagonist tooth has little effect on the stress-strain state of the tooth-inlay system.The stress-strain state of a tooth without defect was considered in advance . The natThe maximum stress and strain intensity is observed in the zone of kinematic boundary conditions. The maximum intensity of stresses and strains is observed in the tooth enamel near the cervical area. The maximum stress level in dentine is 85% lower than in enamel and reaches 28.8 MPa. The maximum level of strains in dentine does not exceed 0.2%. The intensity of stresses and strains in the zone where the NCCL will be modeled reaches the level of approximately 70 MPa and 0.1%, respectively.The stress and strain intensity of the tooth with NCCL at a load of 500 N are shown in The maximum level of stress and strain in the tooth model with NCCL is observed in the \u201cwedge\u201d zone. The maximum stress intensity is observed at the edge of the NCCL in the enamel and reaches 181 MPa. The maximum stress intensity is higher more than 2.5 times than in the tooth without NCCL. The maximum strain intensity is also observed in the NCCL in the dentine and reaches 0.32%, which is 1.6 times higher than in the model without defects.The next stage of the study is analyzing the effect of the prosthetic inlay in the NCCL by changing the \u201cwedge\u201d geometry. The level of the stress intensity in the area of the prosthetic inlay is comparable to the stresses in the tooth without defects. The maximum stress intensity in the tooth-inlay system has shifted to the cervical area of the tooth.The stress intensity in the inlay is 60.2% lower than in the tooth. At the lower boundary from the outside, local stress concentrators are observed at the level of 77 MPa. The distribution of stress fields in dentine corresponds to the loading conditions. The main stresses from the antagonist tooth action are realized in the enamel and in the inlay. The stress intensity on the outer surface inlay is lower than on the inner one.The dependences of the maximum values of stress intensities in the biomechanical system elements on the applied load value are shown in The inlay material does not significantly affect the values of maximum stresses in the enamel. The more uniform distribution of the stress intensity in the biomechanical tooth-inlay system is observed by the use of material 1. A significant increase of stress intensity in the tooth dentin is observed in this case. The A decrease in the stress intensity in the tooth enamel when using a restoration in the form of a prosthetic inlay by 12\u201316% can be noted. An increase in the maximum intensity of stresses in the dentine and the inlay near of the gingival fold is observed due to the contact gluing. The stress intensity in the model with a prosthetic inlay made of material 1 is more than two times lower on the main volume of materials. The influence of the geometry of the cavity for the inlay and veneer part on the deformation behavior of the biomechanical assembly must be studied.Let us consider the nature of the strain intensity distribution in the biomechanical tooth-inlay assembly .The maximum strain intensity is observed in the dentine near the edge of the contact interaction zone with the prosthetic inlay. The strain intensity is lower by two or more times on the rest of the dentine volume. The A dependence of the strain maximum intensity on the load level is shown in The strain intensity in the enamel is lower in the models with a prosthetic inlay in the NCCL. The maximum influence on the nature of the distribution and the level of strain intensity is observed in the tooth dentine. The strain increase in the dentine and a shift of the maximum level The use of a new NCCL restoration in the form of a prosthetic inlay makes it possible to reduce the strain intensity in the dentine when using materials 2 and 3. An increase The minimum value It is important to evaluate the dependence of the contact parameters because of the problem statement. The interface zone parameters are indicators of the strain behavior of the tooth-inlay system: contact pressure The maximum contact parameters are observed near the edge of the tooth-inlay contact zone near the gingival fold, similar to stresses and strains. The average level of contact pressure and contact tangential stress is 3\u20134 and 7\u20138.9 times lower than the maximum values of the parameters respectively. The The obtained estimates give an idea of the qualitative patterns of the influence of the new restoration type and its materials on tooth deformation.-tooth root system in the model is discarded;-interaction with gums is not taken into account;-dental pulp is not modeled;-enamel and dentin are deformed together;-contact interaction is modeled as a complete adhesion of mating surfaces.This article is the result of preliminary research for a new type of restoration. The object of study has the following limitations:-the behavior is described as isotropic elastic;-materials shrinkage is not taken into account.Material models have the following limitations:-the refinement of design schemes and finite element modeling of a biomechanical assembly;-the analysis of the effect of the polymerization shrinkage of restorative composites on the total deformation of the tooth;-the analysis of the influence of the cavity geometry for the prosthetic inlay in the NCCL;-the analysis of the influence of materials for the restoration of an NCCL with different tooth configurations and cavities according to the prosthetic design;-the analysis of the influence of loads from the antagonist tooth acting at an angle to the biomechanical system;-the analysis of the influence of the nature of the tooth elements conjugation and the tooth-inlay system.The main task of the work was to evaluate the effect of the material and geometric configuration of a new type of NCCL restoration on tooth deformation. The patterns of change in the deformation behavior of the restored tooth from the level of external load are also revealed. The accepted limitations are acceptable, but the geometric model and description of the materials behavior needs to be improved. The researchers face a number of tasks:Researchers ,51,52 noToday, there is a lot of research on the applicability of innovative biomaterials in dentistry. An interesting idea is to use oral-derived stem cells together with biomaterials or scaffold-free techniques to obtain strategic tools for regenerative and translational dentistry . The autCreating complete parameterized tooth geometry is a complex process. The modeling of teeth with a truncated root system ,30,59 anThe root system of a tooth is often modeled with simplified geometry to pilot studies of new treatment methodologies ,63. The Influence estimates of the tooth root system on the modeling results are of interest. It was decided to consider the tooth deformation , taking The tooth root is modeled as a truncated cone. The boundary conditions are: the prohibition of the normal displacement of the side surfaces; the prohibition of all coordinates displacements of the root system lower part.It has been established that taking into account the root system has little effect on the tooth deformation qualitative picture. A significant influence on the quantitative values of the deformation state parameters and the contact characteristics of the tooth-inlay system can be noted in this case.The analysis of quantitative differences in the deformation behavior parameters of teeth with and without taking into account the root system will be performed according to the formula, where we take the model taking into account the root as reference values:ers \u03c3int , \u03b5int .The effect of taking into account the root on the contact parameters depends on the inlay material. For contact pressure: in material 1, there is a decrease in the parameter maximum level by approximately 40%; in materials 2 and 3, there is a slight increase in the parameter maximum level by 14 and 2%, respectively. The contact tangential stress in the model taking into account the root is higher.The model without taking into account the root system gives only a qualitative idea of the tooth deformation. The refinement of models taking into account the root system close to real geometry is required. An analysis of the possibility of tooth root truncation to increase the computational procedures speed is also necessary.This research direction is a priority for the scientific group. The rationalization of calculation schemes is necessary due to the wide scope of future research: influence analysis of the geometry cutout under inlay, inlay materials, occlusal load, the conjugation patterns tooth-inlay, etc.The distribution nature and the stress intensity level in a tooth with an NCCL are comparable to the results obtained by Jakupovi\u0107 et al. . AccordiIn general, the new restoration of the NCCL with the expansion of the cavity under the prosthetic inlay and the formation of the area of the gingival fold for the gum growth shows its viability. On the main volume of tooth materials, there are levels of strain parameters comparable to the tooth without taking into account the lesion. It is required to study the influence of the cavity geometry for the prosthetic construction and the veneer part of the inlay to eliminate local zones of the maximum level of stresses and strains in the biomechanical assembly. The problem of frictional contact interaction in the region of the tooth-inlay interface with the refinement of the finite element model should be extended.It is established that the material of the Herculite XRV inlay  in this formulation of the problem delivers a favorable strain state to the biomechanical system. The nature and levels of the distribution of the stress values of the maximum and average level of the contact parameters of the interface zones and strain intensity are close to those of a tooth without taking into account the lesion. At the same time, the level of strain of the Herculite XRV inlay is comparable to the strains in the tooth enamel, which can adversely affect the service life of the structure.The results obtained in this article reflect the qualitative patterns of tooth deformation behavior. Accounting for the root system and its rationalization is required for quantification.A patent of the Russian Federation \u201cMethod of treating a wedge-shaped tooth lesion and a device for its implementation\u201d No. 2 719 898, registration date 23 April 2020. The authors of the patent are Astashina Natalia, Petrachev Artem, Kazakov Sergei, Rogozhnikova Evgenia. The patent holder is Perm State Medical University named after E.A. Wagner."}
+{"text": "Correction to: Nature Communications 10.1038/s41467-019-14052-x, published online 05 February 2020In the published version of this paper, the members of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium were listed in the Supplementary Information; however, these members should have been included in the main paper. The original Article has been corrected to include the members and affiliations of the PCAWG Consortium in the main paper; the corrections have been made to the HTML version of the Article but not the PDF version. Additional minor corrections to affiliations have been made to the PDF and HTML versions of the original Article for consistency of information between the PCAWG list and the main paper."}
+{"text": "Prevention research covers a wide domain of studies, including identification of unknown risk factors for certain cancers, for example prostate cancer; or health promotion with approaches by population, by living environment or by territory. This research focuses in particular on identified carcinogenic factors  but also on the causes of the prevalence of these factors in certain populations. PHIR makes it possible to meet these challenges. In 2010, the French National Cancer Institute was a pioneer in the development of PHIR in France and decided in 2021 to make it one of the spearheads of its ten-year strategy. This presentation will aim to give an account of this policy of developing RISP as a relevant tool for thinking about health promotion policies and actions, by targeting the issue of inequalities as one of the priority research objects as well as certain audiences . The presentation will discuss four challenges for the implementation of this research policy: the development of the French scientific community in order to be able to respond to priority issues; the structuring and animation of this community; the evaluation of research projects and the mobilisation of a still timid global community; the articulation of academic and concrete/experiential knowledge. Through a concrete example of a national research development policy, the aim of this presentation is to help participants understand the challenges of RISP , the organisation of research, and the links between the actors involved . The first part will focus on identifying the participants\u2019 representations of the obstacles to the development of RISP. The second part will be an interactive presentation of 12 minutes, the last 2-3 minutes will be devoted to final questions."}
+{"text": "The authors regret the omission of one of the authors, Li Xue, from the original manuscript. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "As the scientific integrity of the article cannot be guaranteed, and adhering to the recommendations of the Committee on Publication Ethics (COPE), the publisher therefore retracts the article.The authors do not agree to this retraction.This retraction was approved by the Chief Editors of Frontiers in Global Women's Health and the Chief Executive Editor of Frontiers."}
+{"text": "Raveendra  The authors regret that the name of one of the authors (L. Venkatramana) was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "There is an error in the Funding statement. The correct number for National Natural Science Foundation of China to Xiaoxiang Rong is No. 82073375.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.This work was supported by the National Natural Science Foundation of China , China Postdoctoral Science Foundation (2019M663001 to XR), and the Science and Technology Planning Project of Guangzhou (No. 202102020532).All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Errors were present in the published article in terms of the co-author name spelling for J. Al-Tamimi and the author affiliations. The corrected list of author and affiliation details in this paper is as shown here.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "S4) were originallyunderestimated, and the corrected figures appear below and in the Supporting Information. The change is in theconversion from raw data to the energy scale, which was initiallyconverted incorrectly. The rescaled x-axis does notchange the data conclusions since the assignment of peaks to atomsremains the same and the intensity of the peaks is unaffected. Hence,it has no influence on the calculations and conclusions in the originaltext.The energy axes of the RBS andERD data (contained in"}
+{"text": "I am grateful to the authors of this letter for their continued interest in this subject over many decades, and their past support for the WHO Classification of Tumours. Governance matters, and it was quite clear that the CAC mechanism did not meet our requirements and could not continue alongside the editorial board for the reasons given in my editorial . While tThe content of this article represents the personal views of the author and does not represent the views of the author\u2019s employers and associated institutions. Where the author is identified as personnel of the International Agency for Research on Cancer/World Health Organization, the author alone is responsible for the views expressed in this article, and does not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/World Health Organization."}
+{"text": "The journal retracts the 30 April 2021 article cited above.Following publication, concerns were raised regarding the integrity of the images in the published figures. The authors failed to provide a satisfactory explanation and complete raw dataset during the investigation, which was conducted in accordance with Frontiers' policies. Given the concerns about the validity of the data and the figures, and the lack of complete raw data, the article has been retracted.This retraction was approved by the Chief Editors of Cardiovascular Medicine and the Chief Executive Editor of Frontiers. The authors agree to this retraction."}
+{"text": "Its basic object of study is the understanding of the individual and the group, Scientific direction in the study of behavior is an important feature of psychiatry.Adolescence is a stage of physical and mental development of human, usually listed between the stage of childhood and legal maturity. in the middle aged 13 and 18 years the sexual way begins.Education is the primary category of pedagogical theory, which includes the concepts of education and teaching. Physical education is a subject taught in school to train students physically, to enable them to work and to defend themselves. The totality of spiritual, mental and physical qualities or qualities of family and society and learning and working.By taking preventive measures to close educational institutions against the spread of the covid virus 19, it has affected the education system of students, teachers and parents because it has been physically disconnected from learning and has gone virtually ONLINE, where it has been a form of home isolation.Parenting is a constant concern for our entire society today, for child and adolescent psychiatry specialists and education experts, especially for all young parents.No significant relationships."}
+{"text": "The authors regret that the name of one of the authors (Troy L. R. Bennett) was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "Modelling and forecasting the number of health professionals in Slovenia, in particular medical doctors, and nurses, has been a serious challenge for health policy for decades. No serious methodology has ever been implemented to support this process.Methodology was developed with the support of the EU SRSS  mechanism and further adapted according to the specifics of the Slovenian health system and of the needs of the MoH. The project took two years and was developed jointly with the relevant stakeholders - MoH, National Health Insurance, Medical and Nursing Chambers, Association of Public providers of health care. It was building on the experiences of Austria and Germany. Methodology included the supply and demand side of retrospective data and forecasting data on the population demographic structure as well as the current numbers of doctors and nurses in training.We have developed a model for forecasting the needs for medical specialists and we tested it on the example of paediatrics, gynaecology, orthopaedics, general surgery, neurology, infectious diseases, and urology. We calculated the forecasted needed numbers for the year 2035 for each of the specialties, where we also indicated the increases and decreases in demand expected based on the demographic, epidemiological and service use projections.Most importantly, the report was endorsed by all the participating stakeholders in the process. The MoH adopted the methodology as a part of the planning mechanism for prospective and current needs for medical specialists in training. Some flaws in the processes identified together with the inadequacies in the updating of data on health professionals led to the MoH\u2019s recommendations to providers on regularly updating their data in the national health providers\u2019 registry.\u2022\u2002Methodology developed in the project was implemented as a part of the requirement for the planning of medical specialists.\u2022\u2002Processes enacted in the project contributed to the improvements in the national health providers registry."}
+{"text": "The authors regret the omission of the e-mail address for one of the corresponding authors, Qian Lu, from the original manuscript. The corrected contact details are shown in this article.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "The major advances in the area of movement disorders in Brazil in recent years were driven by the work of Luiz Augusto Franco de Andrade and Egberto Reis Barbosa. This historical review describes the contributions made by these researchers, physicians, and educators to the development of this field in Brazil."}
+{"text": "Bioscience Reports at the request of the Editor-in-Chief and the Editorial Board following receipt of a notification from a reader, alerting the Editorial Board to concerns regarding the Kaplan-Meier graphs of Figure 1F and G, as well as the western blots. The graphs appear to show an implausible date range, and the western blots have concerning features such as the shapes of the bands and absence of any detectable background. The authors have been contacted with regards to the retraction and have not responded to the Journal's queries or the concerns raised. Given the extent of the issues raised, the Editorial Board stand by the decision to retract the article.This Retraction follows an Expression of Concern relating to this article previously published by Portland Press. This article is being retracted from"}
+{"text": "Furthermore, the results shown in the Kaplan-Meier overall survival analysis plots in Fig. 4C appeared to be inconsistent with the date of publication of this article.Molecular Medicine Reports has declined this request and determined that this article should be retracted from the journal on the basis of an overall lack of confidence in the presented data. Upon receiving this decision from the Editor, the authors were not in agreement that the article should be retracted. The Editor apologizes to the readership of the Journal for any inconvenience caused.Independently, the Editorial Office also investigated the issues of concern in this article, and although the authors attenpted to explain these issues and requested the publication of a corrigendum, the Editor of"}
+{"text": "The authors wish to point out that in the author list of the published article, the author names were incorrectly presented, with family names incorrectly shown before given names. The corrected form of all of the author names is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "The expansion of digital public health, with the use of data in digital systems for planning and operation of public health policy, presents itself as strategic for the public and digital future of Public Health Systems, such as Brazilian Sistema \u00danico de Sa\u00fade/SUS, as well as for the effectiveness of the right to healthcare and expansion of the access to public health services . Such digital expansion will increasingly stress the fundamental right to the protection of personal data, and it is therefore important to strengthen the regulatory and care response of SUS in the field of digital public health, both for the preservation of its regulatory capacity in digital public health (facing market private interests of Big Tech for example), but also to guarantee the protection of fundamental rights, such as the protection of personal data. The theory of fundamental rights and the dogmatics on personal data protection offer support to solve the tensions to the right to data protection arising from the expansion of digital health, with consideration between the rights of patients-data subjects and the needs of managing and planning public health policy\u2022\u2002The intense use of data and digital systems in public health policy is strategic to strengthen public health systems.\u2022\u2002The enhancement of Public Health Systems\u2019 regulatory capacity in digital transformation is important to protect right to health and data protection."}
+{"text": "This methodology represents a valid and innovative breakthrough for the decolourisation of samples contaminated by dyes [2) to lower the DNA damage induced by the exposure of petroleum-derived hydrocarbons on Dicentrarchus labrax. This laboratory-scale study can provide important information on the protection of marine organisms and beyond [2-based nanocomposites. The problem of the massive administration of antibiotics to humans and animals and their easy bio-accumulation promotes more and more phenomena of antibiotic-resistance. Sulfamethoxazole is one of the most used antibiotics for the urinary, respiratory, and intestinal infections and as a supplement in animal and fish farms. Bio-char is an important organic materials derived by renewable sources and its composites can become in the next future, sustainable materials for various applications such as the photo-catalytic degradation of pharmaceuticals. This review collects the recent research about the synthetic techniques and applications of composites materials made of TiO2 nanoparticles and biochar [The growing increase in the world population was accompanied by a massive development of industrialization. The production of food and all types of utility is part of a cyclical mechanism that involves the consumption of raw materials and the consequential production of waste that must be disposed of or recycled. Unfortunately, to this day the quantity of products that are not recycled because they end up in the environment is conspicuous ,2. The c by dyes . E. Dell by dyes . In anot by dyes . In the d beyond . Subhash biochar . In conc"}
+{"text": "The problem of modelling a smooth contour with a regular change in curvature representing a monotone curve with specified accuracy is solved in this article. The contour was formed within the area of the possible location of a convex curve, which can interpolate a point series. The assumption that if a sequence of points can be interpolated by a monotone curve, then the reference curve on which these points have been assigned is monotone, provides the opportunity to implement the proposed approach to estimate the interpolation error of a point series of arbitrary configuration. The proposed methods for forming a convex regular contour by arcs of ellipses and B-spline ensure the interpolation of any point series in parts that can be interpolated by a monotone curve. At the same time, the deflection of the contour from the boundaries of the area of the possible location of the monotone curve can be controlled. The possibilities of the developed methods are tested while solving problems of the interpolation of a point series belonging to monotone curves. The problems are solved in the CAD system of SolidWorks with the use of software application created based on the methods developed in the research work. The technology of manufacturing products on numerical control machines (CNC) allows machining surfaces of arbitrary form. The program control for the CNC machine is created in automatic mode in the CAM system. The source data for the CAM system are represented by a three-dimensional computer model of the product formed in the CAD system .The accuracy of machining is determined by the accuracy of forming the three-dimensional model, the accuracy of determining the cutting tool trajectory by the CAM system and the accuracy of performing the programmed operations by the machine. The correct formation of the three-dimensional model is a necessary condition for manufacturing a high-quality product ,2.One of the most challenging problems in geometric modelling is creating models of surfaces bounding the items whose functional purpose is interaction with the environment . Examples of such products are automobile and aircraft hulls, working units of agricultural machinery and turbine blades. The main functional characteristic of the surfaces bounding such items is the laminar nature of their flow around by the environment ,4,5.The modelling technology in the CAD system is based on forming the surfaces on the basis of linear frameworks. Furthermore, the functional properties of the modelled surfaces were determined by the geometric characteristics of the curves comprising the framework. The laminar nature of the interaction of the surface with the environment was ensured by representing the elements of the framework by lines with regular changes in values of curvature and a minimum possible number of special points (according to the conditions of the problem). For a plane curve, these are the junction points of the convex and concave parts and the points with extreme curvature values .In solving reverse engineering problems, when the given data for surface formation are represented as an array of points, the linear elements of the framework are formed by interpolating a point series. Thus, developing methods of interpolation for point series allowing the representation of the original curve with specified accuracy ensuring the given characteristics is a topical problem.A smooth plane curve containing no special points will be called a curve with monotone curvature, or a monotone curve.The problem of interpolating a point series specifying a monotone curve is solved by forming a contour\u2014a curve consisting of sections of analytically determined curves joined at the reference points. At present, the most developed methods of forming contours are second-order curves, B\u00e9zier curves and B-splines ,9,10,11.Forming a smooth curve consisting of arcs of second-order curves  guaranteThe use of B\u00e9zier curves ,9 and B-Modern CAD systems make it possible to form contours by a cubic B-spline, which automatically ensures the regularity of curvature values at the points of the contour. Control of the occurrence of special points within the sections of the contour can be manually performed by moving the phantoms of the control points specifying the spline with a cursor of a mouse. The need for manual adjustments depresses the possibility of using B-spline while forming contours with monotone change in curvature.Analysis of the reference point series is carried out, which results in identifying its sections that can be interpolated by a monotone curve;At the reference points, the positions of the tangent and the radii of the curvature are assigned, at which the problem of forming a monotone curve has a solution;The area of the possible location of the monotone curve interpolating sections of the point series is determined;Within the obtained area, a contour is formed, representing a monotone curve with specified accuracy.The work  proposesThe analysis of the reference point series is based on defining the radii of the adjacent circles (AC), each of which passes through three consecutive point series. Part of the point series along which the radii of the AC increase or decrease may be interpolated by a monotone curve along which the radii of curvature increase or decrease, respectively.A criterion for the correct assignment of tangent lines of the monotone curve interpolating the point series along which the radii of curvature increase is the fulfilment of the ratio <|T,i+1| , where TBased on this criterion, ranges of the positions of tangents are determined, at which a curve with monotone curvature can be formed. The final positions of tangents at the reference points are assigned to the centre of the obtained ranges.Subsequently, the radii of curvature for which the problem of forming a monotone curve has a solution are assigned. A method for defining the ranges of possible values of curvature radii of a monotone curve interpolating a point series at fixed positions of tangents at the reference points is proposed in work . For a ciThe positions of tangent lines and tangent circles assigned to the reference points define the area of the possible location of the monotone curve, interpolating a point series and possessing the specified characteristics at its points. The lower boundary of the area consists of the arc of the tangent circle at point (Ciri+1) . The uppSimilar areas defined along the whole point series determine the possible location of the monotone curve interpolating the reference point series.Work  proposesThe aim of the present work was to develop a method for forming a contour with regular curvature change, representing a monotone curve with specified accuracy.To develop a method for evaluating the accuracy with which the convex contour represents a curve with monotone curvature that can be used to interpolate the reference point series;To develop methods for forming a smooth convex curve with regular curvature interpolating with specified accuracy a point series by arcs of ellipses and B-spline;To compare the potential of the proposed methods in solving the problem of interpolating a point series.In order to achieve the aim of the research, the following objectives should be pursued:To ensure the regularity of change in the curvature values along the contour at the joining points of its sections, it is necessary to provide common tangents and curvature values. Such a problem can be solved by using the sections of curves whose parametric number (the number of fixed parameters that unambiguously determine the geometric image) is not less than four. The problem of forming a regular contour representing a monotone curve with specified accuracy is investigated using curves with a corresponding parametric number, which is used in SolidWorks. These are parabola, ellipse and B-spline.The accuracy with which the contour represents a monotone curve will be evaluated by the maximum absolute interpolation error, a value which cannot exceed the distance between the contour and the monotone curve.The use of the curves listed above does not ensure a monotone change in curvature values along the contour, but makes it possible to control its convexity. Since the monotone curve is a convex curve, we will use the larger of the distances between the opposite boundaries (upper and lower) as the absolute interpolation error at each of the sections of the areas of the possible location of the monotone curve and convex curves, respectively.T bounded by segment If the positions of the tangents to the contour have been assigned at the reference points, the area of possible location of its section is triangle and ti+1 .a or b, where:In this case, the maximum interpolation error of section a\u2014distance from the side of triangle b\u2014distance from the apex of triangle T to the lower boundary of the area of location of the monotone curve.b, and it will usually determine the error of interpolation by the contour at the reference points of which the positions of the tangents are not defined.If the positions of the tangents to the convex contour are unknown, the area of the possible location of the section of the contour i+1,i+2] . In thisWhen forming a contour representing a monotone curve, it is appropriate to assign positions of the tangents at the reference points where a point series can be interpolated by a monotone curve .i and Smooth joining of the sections can be achieved by forming them with a curved line, whose parametric number is not less than four. For section The parametric number of curves specified by an algebraic equation can be defined by the number of coefficients of its equation. For a parabola whose general equation is x+Dy+1=0 , the parThe general equation of an ellipse has the following form:The number of coefficients of the equation determines the parametric number of the curve equal to five. Let us demonstrate how the possibility of imposing five conditions on the section of the curve ensures its regularity.Once the tangents to the monotone curve are assigned at the reference points, four of the five conditions specifying each of the sections of the contour are defined.M. In order to reduce the number of calculations required, let us assign point M on the median of triangle M is assigned within the area of the possible location of the monotone curve.There is a set of ellipses meeting the four indicated conditions. To extract an unambiguous solution from the set, it is necessary to impose a fifth condition on the arc of the ellipse. As a fifth condition, let us define that the ellipse passes through another fixed point The conditions of the passage of the arc of the ellipse through points By differentiating Equations (2) and (3), we obtain:If the tangent lines at points 1 and 2 are determined by the equations By solving the system of Equations (2)\u2013(6) we define the values of coefficients In order to determine the value of the second derivative of the function defining the ellipse at point 2, it is necessary to differentiate Equation  twice anFor the regular joining of the first and second sections of the curve, in addition to the common tangent at point 2, it is sufficient to ensure the equality of the second derivatives of the functions specifying the arcs of ellipses at that point.Equations (3) and (6);Equation  with subEquations defining characteristics of the contour at point 3:To determine the coefficients of the equation specifying the ellipse that forms the second section of the curve, it is necessary to solve a system of five equations:The first and second sections of the contour, the characteristics of which are calculated according to the method described above, are shown in The contour was formed in the CAD system SolidWorks with the use of a specially developed software module. The given data are represented by a point series belonging to a monotone curve interpolation which was studied in the work . The graThe maximum deflection of the contour from the boundaries of the areas of the possible location of the monotone curve in each of the sections was 0.0121 and 0.0053 mm, respectively. The monotone change in curvature values along the arcs of ellipses forming the sections of the curve determined their location within the area of the location of the monotone curve. However, the ways to predict the absence of points of extreme curvature within the arc of the ellipse specified by the characteristics at boundary points are unknown.After determining the coefficients defining the equations of the ellipse, which represent the second section of the contour, the equations of the third and subsequent sections were similarly determined. Furthermore, the fifth condition defining the configuration of each of the arcs of ellipses is the equality of second derivatives with the previous section of the contour at the point of junction.The disadvantage of the proposed method for forming the contour is the lack of possibility to locally adjust its form. The reconfiguration of the first section will change the configuration of all other sections. The reason for this deficiency is the imposition of as many conditions as possible on each of the sections of the contour.The possibility to locally adjust the form of the sections is a major advantage of forming the contours by B-spline. The degree of the equation specifying the B-spline determines the order of the derivative functions whose values coincide at the junction points of the sections of the spline . The thiThe interpolation of a point series in the CAD system is performed interactively\u2014the reference points are sequentially indicated with the cursor. If the reference point series can be interpolated by a convex curve, then the B-spline has the form of a convex contour, the number of sections of which is minimal\u2014as each section of the contour is formed by one section of the B-spline.The specified sequence of commands is easily implemented by the software application, providing the automatic formation of a convex contour in the CAD system SolidWorks.The imposition of the tangency condition with fixed straight lines on the B-spline requires an increase in the parametric number of curves by increasing the number of spline sections. This could lead to a disturbance of the convexity of the contour. In CAD systems, the convexity of B-spline can be achieved interactively by adjusting the position of the vertices of the specifying polygon. With a large number of reference points and tangents assigned to them, the task becomes excessively laborious.Creating an application that automatically generates a convex regular B-spline specified by a sequence of reference points and positions of tangents at those points is a complex task. Examples of solving this problem are unknown. When forming a B-spline representing a monotone line with specified accuracy, the simplest and most effective solution is to increase the number of reference points that can be interpolated by a monotone curve.The spline consists of nine segments whose configuration is determined by the 12 specifying points. The graph of change in the curvature values along the B-spline formed in the CAD system allows determining whether it has special points. The sections of the spline contain seven points with extreme values of curvature in total.Distance Distance The width of the area of the possible location of the segments of the convex contour, which is equal to:The absolute error with which a monotone curve is represented by sections of the contour is:Meeting the condition of tangency with ten fixed tangents to the monotone curve assigned at the reference points required increasing the parametric number of the spline by increasing the number of its segments. The resulting B-spline consists of 14 segments whose configuration is determined by 16 specifying points. By adjusting the configuration of the B-spline using the tools of the CAD system SolidWorks \u201cAdd Tangency Control\u201d, \u201cAdd Curvature Control\u201d and \u201cSpline Handles\u201d, it was possible to achieve the convexity of the entire contour with no more than one special point on sections 6\u20267, 7\u20268, 8\u20269 and 9\u202610 of the curve.The resulting B-spline was a convex curve that contains thirteen points with extreme values of curvature. On sections containing special points, the spline was located outside the area of a possible location of the monotone curve with a maximum deflection of 0.1182 mm on sections 3\u20264. On sections 6\u20267, 7\u20268, 8\u20269, 9\u202610, where the curvature values change monotonously, the spline is located within the area of the location of the corresponding sections of the monotone curve.In The error of interpolation by a contour consisting of arcs of ellipses was analogous to the interpolation error of the B-spline which has common tangents with the monotone curve at the reference points. The maximum interpolation error of the entire point series was determined by the section of the contour where the values of The actual deflection of the convex curve from the boundaries of the area of the possible location of the monotone curve  defining the involute; The involute of the circle is a monotone curve along which the curvature values are reduced. Its parametric equation has the following form :x=rcos\u03c6+The coordinates of the points belonging to the involute of the circle and making up the original point series for the interpolation by B-spline were obtained for the step of changing the values of the parameter We assigned 270 points on the involute of the circle, which were interpolated by B-spline. The characteristics of the point series are given in The values of the interpolation of the first 10 points and the last of the point series by a convex contour at points of which the position of the tangents is not defined With the use of a software developed by us, the obtained point series consisting of 270 points is interpolated by a cubic B-spline which is imported into the CAD system SolidWorks. The accuracy with which the B-spline represents the evolution of of the circle is provided by a graph of change in curvature values along the contour, which are defined by the CAD system tools as monotone.This work investigated the possibility of forming a smooth regular contour, which with specified accuracy, represents a monotone curve. The curves whose sections can form a regular contour do not provide a monotonous change in curvature values along the contour, but ensure the control of its convexity. Therefore, it is proposed that the largest distance between the areas of the possible location of the monotone and the convex curves is used, specified by the same point series as an absolute error on each of the sections.The main criteria for evaluating the computational efficiency of interpolation methods are error, stability and convergence. The interpolation method is stable if negligible errors of the source data lead to minor changes in the result. The use of stable interpolation methods reduces the accuracy requirements of the source data and make it possible to adjust them. The interpolation convergence consists in reducing the error by increasing the number of reference points. When interpolating a point series of arbitrary configuration consisting of a large number of points, most of the known methods do not ensure the convergence and stability of the solution. The reason for this deficiency of interpolation methods is the uncontrolled emergence of inflection points of convexity/concavity of the interpolating curve.The maximum absolute interpolation error is estimated by the value that cannot be exceeded by the distance between the contour and any monotone curve interpolating the reference point series. Such an error is determined by the width of the area bounded by a sequence of triangles. The sides of the triangles belong to lines connecting the reference points or lines tangent to the monotone curve. By assigning intermediate points, the width of the area of location of the curve is reduced.The main advantage of the proposed method over known interpolation methods is the possibility to form the contour within a bounded spatial domain. The domain was defined by the expected characteristics of the reference curve. The most important of these characteristics is the minimum (based on the configuration of the reference point series) number of special points of the curve.The methodology for estimating the error of existing interpolation methods is as follows. A point series is assigned on the reference curve. After interpolating the point series, the deflection of the interpolating curve from the reference curve is determined. The error with which the interpolating curve represents the reference curve is estimated as the maximum deflection between the specified curves. When solving other tasks, the engineer operates on the premise that the order of error of interpolation will be identical with the test examples. Generally, when the reference curve is not known, such an assumption might be wrong.Defining the area of the possible location of the reference curve not only allowed to determine the absolute interpolation error, but also to arbitrarily decrease this error by increasing the number of reference points or assigning intermediate points by the method proposed in .The convergence and stability of the proposed method are ensured by the preliminary analysis of the configuration of the reference point series and formation of the contour based on sections of the point series which can be interpolated by a monotone curve.The stability of the developed method to changes of reference conditions is ensured by forming a contour within the area of the possible location of the convex parts of the reference curve. With any adjustment of the positions of the reference points, the distance from the segments connecting the reference points to the boundaries of the possible location of the corresponding sections of the reference curve remains limited.The consistent localization of the area of the location of the curve within its original boundaries guarantees the convergence of the interpolation process. Adding each additional point brings the boundary of the area closer to the accurate solution, namely to a monotone curve with a given set of characteristics.The number of sections of point series that can be interpolated by a monotone curve, as well as the number of reference points that make up each of these sections, does not affect the convergence or stability of interpolation.Any curve can be considered to consist of monotone parts. Thus, the assumption that if a sequence of points can be interpolated by a monotone curve, then the reference curve on which these points were assigned is monotone, allows implementing the proposed approach for estimating the error of interpolation of a point series of arbitrary configuration.Defining the area of the possible location of the reference curve enables developing methods for forming contours by arcs of various curves, the convexity of which can be controlled. Based on the proposed criteria for estimating the interpolation error, methods for forming convex regular contours by arcs of the ellipses and B-spline were developed. The methods were implemented in a software application that automatically creates contours in the CAD system SolidWorks. The method for forming a contour by arcs of an ellipse is based on the derivation of equations specifying ellipses and the determination of parameters by these equations, which make it possible to form sections of the curve in the SolidWorks system. Such parameters are the coordinates of the points bounding the contour, the positions of the tangent lines to the monotone curve at these points and the coordinates of another point belonging to the ellipse.The application of forming contours by B-spline ensures its passage through a sequence of points specified by their coordinates.The method for forming contours by arcs of ellipses takes into account the positions of tangents to the contour and provides for greater interpolation accuracy. The method for forming contours by B-spline requires fewer calculations and is more easily executed in the form of software.Interpolation of a point series consisting of ten points specifying a monotone curve;Interpolation of a point series belonging to the involute of the circle.The possibilities of the method for forming curves by B-spline were investigated while solving the following problems:This study proved that an arbitrarily small interpolation error can be achieved by reducing the distances between the reference points belonging to the monotone curve by increasing their number. The sequence of interpolated points can be increased either by refining the given data or by assigning intermediate points according to the methodology proposed in .The developed methods are appropriate for modelling linear elements of the frame of functional surfaces with improved aerodynamic and hydrodynamic properties, for which the minimum number of special points is the main criterion of the quality of the obtained solution.The advantages of the methods proposed in this work over the method developed in  for presThe influence degree of the quality of joining the sections of the curve and the conformity of the change in curvature values along the curve can be determined by experiment.Increasing the number of interpolated points is a universal method of increasing the accuracy with which a regular contour represents a monotone curve and reducing the difference in curvature values at points where arcs of circles are joined."}
+{"text": "In this article we present the optimal method of controlling and supplying a BLDC motor under static load, proposed and implemented as a result of the research. A research infrastructure was developed to measure and analyze variants of the motor control. In the research we determine possible losses of electric energy released in the form of heat in the tested engine elements. The test results showed that the lowest energy losses are provided by the variant where the control signals are obtained from an external magnetic disc and the motor is powered by an additional DC/DC converter. The conclusions from the analyses allowed for the selection of the best variant of motor control and power supply, which minimizes energy losses during the BLDC motor operation. Brushless Direct-Current Motors (BLDC) are characterized by very high efficiency, which in the case of the construction of energy-saving drives, in particular powered by autonomous energy sources, is very important. There are many important conclusions for future trends . In partAC powered motors. These motors are powered from a three-phase power grid, where small loads are powered by single-phase, while high power loads are constructed as three-phase receivers. Three-phase alternating current motors can be categorized as synchronous motors and asynchronous motors;DC-powered motors. These motors were previously obtained from rotating converters such as the Leonard system. Nowadays these motors are powered using static transformers, that is, diode or thyristor rectifier systems.Classic electric motors can be divided into two groups, due to the way they are powered:Machines in which permanent magnets are placed on the stator. In these machines, the armature winding located on the rotor is powered by a classic mechanical commutator;Machines in which permanent magnets are placed on the rotor. In these machines, the non-rotating armature winding requires a power supply through the so-called electronic commutator. This part supplies the windings synchronously with the rotation of the rotor.Both in the first and the second group of motors that have been used for a long time, both the stator and the rotor had winding , where one winding acted as the excitation winding. Such models were to generate a magnetic flux, and the other was a winding armature . The invBrushless Direct-Current Motor (BLDC) in which the induced voltages during rotation of the rotor have a trapezoidal waveform ;Permanent Magnet Sync Motor (PMSM) in which the induced voltages during the rotation of the rotor have a sinusoidal wave form ,16 wave.The second solution eliminated the mechanical commutator, which, due to its durability, limited the life of the electromachines ,11,12. TPowering motors from both groups requires the tracking of the angular position of the rotor in order to properly control the valves of the electronic commutator ,18. MotoThe main purpose of this work is to propose a new method of supplying a BLDC motor and a new sensor for determining the position of the BLDC motor shaft. As a result of our research we demonstrate that the newly proposed solutions reduce energy losses in motor components. The scope of this research work is to present a new design and construction of the entire BLDC motor power supply system. Our developed research stand is tested to draw conclusions on our developed model of construction. The research infrastructure was made based on the use of the Internet of Things, thanks to which it was possible to seamlessly collect data and process them in order to obtain computed results for interpretation. In As part of the work, the BLDC research engine was composed and examined. Various variants of the motor power supply and various sensors for determining the angular position of the motor shaft were tested. The tests used a three-phase electronic commutator bridge system with an optional DC/DC converter and an electronic commutator system. Both of these systems were designed and created as part of our research work. The scheme of the test stand with the installed measuring infrastructure is shown in The basic element of the test stand is a BLDC motor connected by a shaft to a three-phase loading machine excited by permanent magnets. The shafts of the motors are connected with a torque meter via clutches, which are shown in The developed research stand allows us to optionally power the engine in two ways. The first is that the transistors of the electronic commutator bridge are actuated only on the basis of unmodified signals provided by the rotor angular position sensors. The second of the tested variants of motor power supply is that the transistors of the electronic commutator bridge are actuated on the basis of the signal from the shaft position sensors modified by the PWM signal. Examples of the control voltage waveforms (orange) fed to the transistor gate and the voltage on the motor windings (blue) in the case of both power supply variants are shown in the oscillograms in It is possible to change the average value of the voltage supplied to the motor windings, which allows the motor rotational speed to be regulated by changing the PWM signal duty cycle. Additionally, the duty cycle of the PWM signal enables the implementation of the current limiting function. In the first variant of the power supply, the adjustment of the engine speed and the current limitation function are performed on the basis of an additional DC/DC converter marked in the diagram The research infrastructure of the test stand was designed based on Wi-Fi communication. The Raspberry Pi class microcomputer serves as the master server for collecting measurement data. The measurement modules are connected with the sensors built in the stand by electric wires. Each of the modules is responsible for measuring data and sending them through the ESP 8266 system to the master unit, on which the application that interprets and collects measurement data is running. All measurement modules were created on the basis of the same system (made as part of the work), essentially consisting of the ATtiny 13 microcontroller\u2014connected to the sensor and converting the measurement data into a physical quantity value. The universal measuring system shown in Our developed measuring system, presented in The basic feature of brushless of DC motors (BLDC) is that the rotor excites the machine while the armature windings are located in the stator of the motor. It is the opposite design to the classic DC motor. The consequence of this design is the lack of a mechanical commutator.The schematic diagram of the tested BLDC motor with the location of the sensors built in it is shown in Additionally, the engine is equipped with three hall sensors The voltage induced in the stator windings during the rotation of the rotor theoretically follows a trapezoidal course. An example of recording the waveform of the phase voltage and the current of one phase is shown in In the first case, the signals determining the angular position of the rotor are the voltages from additional windings located in the stator slots , the electronic commutator supplies the motor according to the set control sequence for the given direction of rotation. Due to the lack of information about the initial position of the rotor, such a strategy causes the motor to make a partial rotation of the rotor in the opposite direction to the set one. In a pessimistic case, after a partial rotation in the opposite direction, the rotor of the engine will start to spin in accordance with the given sequence of powering the engine (stepper motors are supplied in a similar way). After obtaining the appropriate rotational speed, it can be controlled using voltages from additional windings. Such a control system can be used for drives insensitive to the momentary rotation of the shaft in the opposite direction than the set one, e.g., boat drive, or fan.The second solution is control based on signals from Hall sensors located in the grooves of the engine, marked as A third alternative solution is to install an absolute encoder  on the motor shaft . SensorsThe fourth optional control method is an external magnetic sensor mapping the rotor poles, cooperating with hall sensors. As part of the research, the authors made such a sensor, the diagram and photo of which are shown in The first of the proposed methods of determining the position of the motor shaft has significant limitations due to the specificity of the engine start-up. Comparing the other three solutions, the use of an encoder ensures precise determination of the position of the motor shaft, but at the same time significantly increases the cost of the motor power supply system.Solutions based on the hall sensor are sufficient to determine the position of the motor shaft necessary for its control. The main advantage of these solutions has a significantly lower cost than when using an encoder.An additional advantage of using an external hall sensor is the possibility of repairing it without interfering with the engine structure, which would be necessary in the event of damage to the hall sensor installed in the engine groove. In the further part of the work, a comparative analysis of the engine operation will be carried out depending on the choice of the engine control method, the variant with Hall effect sensors installed in the engine and the variant with an external magnetic disc.The lack of a mechanical commutator in the construction of a BLDC motor requires the creation of an electronic commutator. The power supply of the BLDC motor requires sequential switching of power electronic keys strictly dependent on the position of the motor shaft and the direction of rotation. Failure to meet the above requirement: significant delay or advance (by two control sequences) of switching in relation to the rotating rotor or driving the transistors for the direction opposite to the rotation of the motor shaft causes the flow of very high current through the open transistors, which leads to their destruction. Providing energy-saving power requires precise switching of the power transistors of the electronic commutator and thus precise determination of the angular position of the motor shaft. More precise detection characteristic positions of the motor rotor result from the position of the rotor magnets. First, the construction of the transistor bridge and electronic commutator system will be discussed, followed by the control method.The DC/DC converter has been used to lower the voltage from the battery bank to the required level. Regulation of the output voltage is based on the PWM signal control. A filter reducing the pulsation of the output voltage is applied at the converter\u2019s output. The pulsation of the output voltage depends on the filter time constant and the switching frequency of the PWM transistors. The pulsation reduction can be achieved by selecting a suitably large capacitor and coil or by increasing the PWM frequency. Examples of voltage waveforms are shown for four different PWM frequencies in The novel BLDC motor system constructed in our research allows for speed and load regulation based on the use of pulse width modulation (fast PWM) using an 8-bit counter. This approach allows us to obtain 256 different values of average voltage at the output of the system. This resolution is sufficient to perform our developed computer simulation model for BLDC motor applications presented in As part of the research work, an electronic commutator system was created. The schematic diagrams in Additionally, as an independent element, a control board for transistors and DC/DC converter was designed and manufactured, the diagram of which is shown in The basic idea behind controlling power transistors is to switch the transistors sequentially based on the rotor position. The control process is discussed in detail in . At thisX indicates optionally: spin speed or driving torque depending on the choice of the control strategy. The The reversal of the motor cannot be accomplished by simply driving the power transistors in the opposite direction of rotation. To realize the reversal of the BLDC motor, first reduce the speed until the rotor stops by switching the power transistors in the direction of rotation, and only then change the control sequence to the opposite. The speed reduction is preferably accomplished by regenerative braking by controlling the current. After changing the control sequence to the opposite, the motor is started with current control. The microprocessor controlling the electronic commutator implements the algorithm shown in An example of an electronic commutator operation during a reversal is shown in The research was divided into two basic parts: the first one related to the study of the signals surrounding the motor shaft position and the second one related to the energy losses in the form of heat in the motor depending on the sensor displacement, which determines the position of the motor shaft and the method of powering the motor windings.In this section, we want to discuss the comparison of external sensors  and internally arranged Hall sensors consists of examining the symmetry of the signals they provide. Sample oscillograms of signals coming from the hallotrons of the magnetic shield and hallhotrons placed in the grooves of the engine are shown in Noting such a lack of symmetry in the duration of the halotron signal, it was decided to investigate this situation for the entire control sequence and refer to the results statistically. The control sequence consists of 6 different states represented by unique signal sequences from the three hallotrons. Due to the symmetry of the tested machine, the durations of individual states at a given predetermined rotational speed of the engine should be equal. Using the above assumption, a recorder was created that allows to record the duration of subsequent states. The recorder was made in such a way that the measurements were always performed for the same established sequence of states . The recorder measures the duration of each of the states that make up one revolution of the motor shaft (three full control sequences). In addition, it is possible to record multiple times while the engine is running, making it possible to carry out multiple measurements for the same engine operating conditions.The recorder is built on the basis of a microprocessor which, after one registration, sends data to the computer via a serial port. The registration is performed for a rotating motor with a fixed set speed and a constant load. The registration is then triggered by the operator. The recorded data are sent to the superior unit, where their statistical analysis is carried out (the given measurement attempt has been performed many times).The symmetry of the signals determining the position of the engine rotor was tested for two motor work cases: first\u2014the motor was driven by another motor (winding under test motor were not powered), the second\u2014the motor was powered and kept the set speed. In first case studies were conducted for two different spin speeds: 340 [rpm] and 560 rot/min (due to the parameters of the drive motor). The results obtained in one series of measurements for the speed 340 [rpm] for individual states of the rotor position are presented in s, the volatility index v, and the relative maximum deviation from the mean r. Assuming that k-th number in the measurement result was denoted by In the second case, tests were conducted for three spin speeds: 340 [rpm], 680 [rpm], and rated speed 1000 [rpm]. The result of each measurement consists of 18 numbers representing the duration of each 18 states per revolution of the shaft engine. Each number represents the counted value of the microprocessor counter over the duration of one state. At a constant speed for a perfectly working system, the duration of all states will be the same, which will translate into registering 18 of the same numbers. In order to carry out analysis of measurement results, statistical calculations of duration times of individual states were made, making up one revolution of the motor shaft. Determined: arithmetic mean The results of the statistical analysis for the case where the engine was powered by another machine are presented in The data presented in the tables clearly show that the use of an external magnetic disc provides signals determining the position of the motor shaft of much better quality than the sensors located in the motor slots. The lack of symmetry of signals from hallotrons in the slots of the motor may result from the fact that on the rotor circumference there are gaps between the glued magnets filled with steel forming the rotor shaft.selection of sensors  determining the switching moment of the power transistors of the electronic commutator bridge;choosing the ways of powering the motor windings.As part of the research, a number of tests were carried out to heat the engine to a thermal steady state depending on:The tests were carried out for selected setpoints of the motor load torque and selected setpoints of the spin speed. Due to the fact that the aim of the study is to compare which of the tested variants is characterized by the lowest losses of energy released in the form of heat in the engine, the engine fan was disassembled.In each of the tested cases, the motor was heated to a steady thermal state, during which the temperature from The lack of a fan ensures comparable cooling conditions regardless of the engine spin speed. This approach allows us to determine qualitatively which of the tested variants is characterized by the lowest energy losses. The conducted tests showed that the lack of a fan made it impossible to test the BLDC motor at its rated parameters. In this case, excessive heating of the engine did not allow it to reach a thermally steady state.From the data in The test results presented in As part of the research, a stand was built to ensure a given load torque for the BLDC motor and to ensure the given engine speed. For this purpose, it developed its own electronic commutator and prepared measuring equipment. Two different variants of the engine power supply and two different sensors for determining the position of the engine shaft have been proposed.As part of the research, experiments were carried out to determine which of the sensors is better and which of the methods of powering the engine is more advantageous due to the energy losses in the engine released in the form of heat.The conducted research has shown that the best solution is to use an external magnetic disc as a motor shaft position sensor and to use a DC/DC converter for speed regulation and current limiting functions. The engine shaft position sensor proposed in the paper was called external due to its novel implementation in our project. Of course, there is nothing to prevent such a sensor from being built inside the engine, but it would have to be taken into account at the engine design stage. However our proposed improvement is designed to be applied without changes to the construction of the BLDC motor. Moreover, such an external sensor concept could be built together with a suitably adapted fan and be an integral part of it if it is necessary for special use. The main advantage of this novel sensor mounting is the simplicity of construction and good precision in determining the positions of the motor rotor important for control. When it comes to the DC/DC converter, it is difficult to see application limitations due to the fact that the BLDC motor speed control requires a change in the average value of the voltage supplied to its windings. Our novel research has clearly shown that the use of a DC/DC converter produces less energy loss in the motor elements."}
+{"text": "Over the past few decades, caring for special patients has taken center stage in healthcare systems. Moreover, what necessitates conducting a comparative study into the conditions of special patients and designing a suitable model are as follows: high admission rates of these patients in hospitals, continual recurrence of the illness, sky-high costs of treatment and medicine, lack of coordination between the services offered by hospitals and community needs, and severe pressure of special patients on their families. Therefore, the present study aimed to compare the models of government support programs for special patients in Iran, the United Kingdom, the USA, Italy and Sweden through a descriptive-documentary method. The findings revealed that the Ministry of Health and Welfare and the private sector were the major providers of health services to special patients in most of the countries under study. It was also demonstrated that the services offered to special patients are jointly mainly funded by governments, associations, and non-governmental organizations and partially by insurance premiums and so forth. The results also indicated that the bulk of healthcare provision was shouldered by non-governmental sectors and the contribution of charitable people. Finally, it can be concluded that both health-related policies and the health of special patients can be closely honed and monitored through the formation of committees on the health of special patients at the Supreme Council of Health, the establishment of an office for special patients at the Vice-chancellery for Health at the Ministry of Health, Treatment and Medical Education, provision of decentralized services, and financing through taxation and contribution of charitable people and international organizations. In . In 3].  The results of comparative studies demonstrated that the macro policies relating to the affairs of special patients in the countries under study were carried out by the Ministry of Health and Welfare or the highest health councils composing of representatives of ministries. Moreover, in Iran, the center for transplant management and special diseases is subject to many constraints by the Ministry of Health and Medical Education. The responsibility for legislating and determining the policies of health system management of chronic patients in the United Kingdom is assigned to the Parliament and the Ministry of Health. The organization, which is responsible for determining the budget of the NHS, provides health services to the covered individuals through its subsidiaries and regional and local executive groups. In Italy, public access to services is provided through a National Health Insurance Plan in which any citizen enjoys free healthcare, and national governments incur the required budgets and costs of national health insurance. In the USA, private health insurance policies are often sold to workers in the workplace to prevent reverse choices. However, the elderly, the unemployed and the poor, who need more care, are not covered. Therefore, the government should finance the insurance coverage of these groups. The federal government funds the Medicare coverage for the elderly and the states also fund Medicaid to cover the poor. In Sweden, the National Strategic Framework for Chronic Diseases has been in place since 2005 under the Sweden Health Ministers\u2019 Advisory Council. In Sweden, there are public and private healthcare insurances with public access that are covered by a bilateral health service system. In Iran, the organizational position of chronic diseases at the level of the Ministry of Health and Medical Education is in the Department of Health and at the Center for the management of non-communicable diseases, and the national committee for the prevention and control of non-transmissible diseases was established in 2015. In the United Kingdom, the role of government in financing special patients is defined as providing services in the form of NHS and collecting taxes and insurance policies for employment assistance, and 11% of insurance policies are privately purchased for better access to healthcare services in private hospitals. In Sweden, the national and state sections have been merged by the government, national resources are provided for public hospitals, and the government manages the public health insurance program. In the USA, the people over the age of 65 through the Medicare insurance program and the disabled are covered by Medicare program whereas the people who do not have insurance coverage through their employers at the state level or have some exemptions are covered by Medicaid program (13.4% of adults are without insurance coverage). In Iran, the general budget is provided through the collection of public and private subsidies and allocations to the Ministry of Health through parliament. Therefore, the committee for the prevention and treatment of chronic patients is financed by the state. The results of comparative studies also revealed that in most of the countries under investigation, the Ministry of Health and Welfare and the private sectors were the major institutions for the provision of health services to special patients. Another point is that at present, there is no definite trustee for the provision of healthcare services to special patients in a transparent manner, and sometimes services are provided in parallel. Therefore, it is suggested that provision of healthcare services to special patients be done by public health-care units and the private sector with the cooperation and participation of the public. Finally, comparative studies showed that services provided to specific patients include services for all three levels of prevention: vaccination, teaching healthy lifestyle and disease care, publication of health leaflets, health counseling, health check services for early diagnosis and treatment of specific diseases, provision of auxiliary equipment for specific patients, laboratory services, home care and treatment, pharmacy and sanatorium services. There are no conflicts of interest."}
+{"text": "The journal and Chief Editors retract the 14 October 2020 article cited above.Following publication, concerns were raised regarding the integrity of the images in the published figures. The authors failed to provide a satisfactory explanation during the investigation, which was conducted in accordance with Frontiers\u2019 policies. Given the concerns about the images, the editors no longer have confidence in the findings presented in the article.This retraction was approved by the Chief Editors of Frontiers in Cell and Developmental Biology and the Chief Executive Editor of Frontiers. The authors do not agree to the retraction of this article."}
+{"text": "This Retraction follows an Expression of Concern relating to this article previously published by Portland Press.Bioscience Reports at the request of the Editor-in-Chief and the Editorial Board following receipt of a notification from a reader, alerting the Editorial Board to the Western blots in Figure 4B which are duplicated in several other publications, as well as duplications in Figures 7A and 7C.This article is being retracted from The authors have been contacted in regards to the retraction, and have not responded to the Journal's queries and the concerns raised. Given the extent of the issues raised, the Editorial Board stand by the decision to retract the article."}
+{"text": "Child and Adolescent Psychiatry and Mental Health (CAPMH) was founded in 2007, an initiative of Prof. Fegert. He served as the Editor-in-Chief, with support from Dr. Benedetto Vitiello  as Deputy Editor-in-Chief and Prof. Goldbeck (Germany) and Jacinta Tan (UK) as Associate Editors. The journal was the first independent, open access, online journal in the field with the mission to provide an international platform for rapid and comprehensive scientific communication on child and adolescent mental health issues from diverse cultures and contexts.The first issue of CAPMH was released in 2007. In February 2013, CAPMH became the official journal of the International Association for Child and Adolescent Psychiatry and Allied Professions (IACAPAP) and has later also been affiliated with the European Association for Forensic Child and Adolescent Psychiatry, Psychology and other involved Professions (EFCAP). Since its inception, the journal has grown rapidly and has received funding by different foundations. However, the journal also faced difficulties and setbacks as sadly, Prof. Goldbeck, one of the founding editors, unexpectedly passed away in 2017.To further establish the journal in the field of child mental health, the editorial work assertively to establish an impact factor. CAPMH was under consideration to receive an impact factor in 2009 and 2011. Finally, an impact factor was received in 2015. The current impact factor for 2020 is 3.033\u2014a remarkable achievement given the young age and broad mission of the journal. With the new impact factor, the journal has climbed up to rank 37 in Pediatrics, ranks 91 in Psychiatry  and remains at rank 66 in Psychiatry , underlining the importance of the journal in the field of child mental health.The growth of the journal is also reflected in the number of submissions received. Most notably, a dramatic increase in submissions was observed after the journal was awarded an impact factor. Another indicator for the success of the journal is the number of downloads of published articles. With now almost 8,00,000 downloads per year, scholars and practitioners publishing within the journal reach a vast readership worldwide.Since its foundation the aim of the journal has been to increase the knowledge base related to the diagnosis, prognosis and treatment of mental health conditions in children and adolescents, and to integrate basic science, clinical research and the practical implementation of research findings . FurtherOne outstanding attribute of CAPMH as the first worldwide open access journal in the field of child and adolescent psychiatry, is its international focus. This is reflected by the international editorial board, submissions, publications, and accesses from all over the world. Thematic series focusing on child and adolescent psychiatry in Africa  and AsiaBesides the publication of incoming manuscripts, CAPMH has focused on specific topics in child and adolescent psychiatry throughout the years. The latest thematic series focuses on the impact of the Covid-19 pandemic  and is cThe success of the journal would not have been possible without the work of the committed editors, the editorial board and reviewers. In November 2021 the journal has undergone a new transition as Prof. Fegert stepped down as from his role as Editor-in-Chief and Dr. van Schalkwyk and Dr. Witt have assumed the role together. The new Editors-in-Chief want to express their deep gratitude to the founding editors of Child and Adolescent Psychiatry and Mental Health, who laid the foundation for this exciting project. They want to especially thank Prof. Fegert who has led and shaped the journal since its foundation in 2007. With his work he profoundly contributed to the reach and success of the journal and as the founding editor he stays associated with the editorial team Their thanks also go out to all editors who have been and are currently working with the journal, as well as the editorial board and the vast number of reviewers who have supported the journal throughout the years.The aim of the new Editors-in-Chief over the next years to come is a continuation of the excellent work of Child and Adolescent Psychiatry and Mental Health and to further advance the impact of the journal in the field. As the flagship journal of the International Association of Child and Adolescent Psychiatry and Allied Professions (IACAPAP) the Editors-in-Chief seek to provide a scientific platform for high quality research and practice in this area by ensuring a rigorous and timely review process. To ensure a timely and quality review process, the aim is to build a reliable and committed board of reviewers that form a relationship with the journal. To further increase the impact of the journal in the field, the aim is to establish thematic series on a regular basis. Such thematic series can address pressing issues of the time and be edited by guest experts or by editors of the journal.As an international journal for the area of child and adolescent psychiatry and mental health, the vision of the new Editors-in-Chief is to create an international scientific platform that addresses all professions in mental health. As the journal should reflect this international focus, the aim is to increase diversity among the editorial board not only in regards to gender and ethnicity, but also concerning professional backgrounds, methodological and scientific orientation. Therefore, the aim of CAPMH is to attract researchers from all over the world to submit their work to the journal not only from developed countries but also to support high quality work from less developed countries to further advance science and practice in the field of child and adolescent psychiatry and mental health."}
+{"text": "The authors were asked for an explanation to account for these concerns, but the Editorial Office never received any reply. The Editor regrets any inconvenience that has been caused to the readership of the Journal.After having conducted an independent investigation in the Editorial Office, the Editor of"}
+{"text": "Bioscience Reports at the request of the authors following receipt of a notification from a reader, alerting the Editorial Office to the data in Figures 5A and 5C as well as the Western blots in Figures 1C and 6B.This article is being retracted from The Editorial Office contacted the authors to request the raw data and raw images of the Western blots, to which the authors responded with the Retraction request stating that the integrity of the research was damaged. Given the concerns raised the Editor-in-Chief and Editorial Board agree with the Retraction. The co-corresponding author Huang-Shan wishes to take full responsibility for their negligence, and apologizes for the inconvenience caused to the journal and readers."}
+{"text": "As the field evolved, so too, has the Gerontology and Geriatrics Curricular Standards and Guidelines in Higher Education. The 7th edition is focused on the integration of the highly vetted AGHE Gerontology Competencies for Undergraduate and Graduate Education. Through this work we establish a set of standards and guidelines that provides the foundation for excellence in gerontology and health professions education at various levels and across a range of programs in the US and globally. The document provide a model for institutions of higher education in the development of new programs, a basis for program assessment and evaluation, guidance for academic or institutional reviews in existing programs, and a platform for what constitutes a program of study in gerontology/geriatrics or health professions programs for students, the public, and employers. An overview of the development of the 7th edition and suggestions for its use will be provided."}
+{"text": "The journal and Chief Editors retract the 11 February 2021 article cited above.Following publication, concerns were raised regarding the validity of the data in the article. The authors failed to provide the raw data or a satisfactory explanation during the investigation, which was conducted in accordance with Frontiers' policies. Given the concerns, and the lack of raw data, the editors no longer have confidence in the findings presented in the article.This retraction was approved by the Chief Editors of Frontiers in Physiology and the Chief Executive Editor of Frontiers. The authors agreed with this retraction."}
+{"text": "The second sentence of the second paragraph of the methods section referred to this power analysis. To improve clarity and reproducibility, the sentence has been removed from the methods. Additionally, the original version of the Supplementary Material"}
+{"text": "The Editor and the authors apologize to the readership for any inconvenience caused.Following the publication of the above paper, the authors contacted the Editorial Office to request that the article be retracted on account of the presented results being unreliable; essentially, the authors did not repeat their experiments the requisite number of times, and they were unable to identify in subsequent experiments any increase in the apoptotic rate of the alveolar epithelial cells as had been reported. The Editor of"}
+{"text": "The study expects to find a better way to improve the teaching quality of the education of college students' outlook on life, based on the theory of educational psychology. First, the relevant theories of positive psychology are introduced and expounded, and the importance of the education of college students' outlook on life is analyzed. Second, the current situations of college students' outlook on life and the education of their outlook on life are investigated through a questionnaire survey, and the problems presented in the questionnaire are analyzed. Then, the correlation between positive psychology and the education of college students' outlook on life is explored, and their mutual connection is analyzed. The results are as follows: 77.4% of the college students have periodical aims and work hard for them; 80.8% of the students think that the realization of life goals rely on hard work, accounting for the largest proportion; when they encounter setbacks, more than 80% of the students choose to work hard to overcome them; 69.2% students think that their outlook on life comes from self-learning and exploration. According to college students' outlook on life in China and other countries, there are many problems in the education of college students' outlook on life, and the teaching quality of the education of college students' outlook on life is backward. The combination of positive psychology and college students' education of college students' outlook on life under the theory of educational psychology provides new ideas and ways for college students' education of college students' outlook on life. The conclusion of this study promotes the innovation of the education of college students' outlook on life. College students are the main force of China's future development, and their outlooks on life are formed during this important period. Faced with a large amount of information, college students tend to be affected by that information, which gives them trouble in establishing a correct outlook on life. Therefore, colleges and universities must strengthen the education of college students' outlook on life. Sharaievska and Harmon  concludeIdeological and political courses in colleges and universities are an important part of the education of college students' outlook on life. They help students develop a healthy and positive attitude and establish a correct outlook on life. However, there are still many problems in the education of college students' outlook on life. Educators need to find out these problems and use appropriate means to solve them. Jiang  found thEducational psychology studies the science of the basic laws of teaching and learning in the educational and teaching environment. Aubele Joseph  found thPrevious studies on educational psychology focus on the importance of college students' psychological education and positive psychology in college students' education, but there are few studies on the practical application of positive psychology to the education of college students' outlook on life. Many research conclusions provide theoretical support for the application of positive psychology in the education of college students' outlook on life, and positive psychology is a new and important basis for college students' psychological education. Based on previous studies, this paper makes innovative research on the education of college students' outlook on life under positive psychology. This study aims to obtain new ways to promote the education of college students' outlook on life through innovative research on the education of college students' outlook on life, innovate the path of college students' outlook on life, and promote educational psychology and positive psychology to play a positive role in promoting the development of the education of college students' outlook on life.In order to study the innovation of the education of college students' outlook on life, the research background of educational psychology, positive psychology, and the education of the outlook on life are introduced. On this basis, the questionnaire is designed, and the reliability and validity of the questionnaire data are tested and analyzed by using Statistical Product and Service Solutions 25.0. Finally, the data results are further analyzed. The innovation of this paper is to combine educational psychology and positive psychology with the education of college students' outlook on life, improving the method of the education of college students' outlook on life, leading to more accurate and planned college students' outlook on life, stimulating college students' positive attitude toward life, promoting college students to form a correct and good outlook on life, and providing analysis and research data for the innovation of the education of college students' outlook on life. This study aims to provide a new way of education and research for college students' education on the outlook on life. The innovation of this paper is to mention new educational psychology which is different from traditional psychology. The theoretical research of this study is based on positive psychology. The conclusion of this study innovates the path of college students' education of the outlook on life, and makes efforts to improve the teaching quality of the college students' education of the outlook on life, making educational psychology and positive psychology play a positive role in promoting the development of the education of college students' outlook on life.Educational psychology is a discipline based on psychology. It studies the learning of human beings and the effects of educational intervention, teaching psychology, and social psychology in the educational context. The focus of educational psychology is to apply the theory or psychological research to education, and the scope of the application of educational psychology is to design courses, promote students' motivation for study, and help students face setbacks in their life, learning, and growth. Educational psychology is only available in the department of education in colleges and universities  value of the questionnaire data is 0.873, which is >0.8, indicating that it is suitable for factor analysis. The result of Bartlett's spherical test sig < 0.0001, which denies the original hypothesis, and the correlation coefficient matrix is a non-unit matrix. Therefore, the questionnaire data is suitable for factor analysis. This study uses exploratory factor analysis to test whether the factor load of each variable is >0.6. Through the measurement, it was found that all the factor loads in the questionnaire are >0.6, indicating that the validity of the questionnaire is good.The reliability analysis focuses on the stability and reliability of the questionnaire. The Cronbach Coefficient \u03b1 is measured by calculating the correlation coefficient of each index and combining it with the consistency test. The results show that the Cronbach coefficients \u03b1 of all factors are >0.8, and the reliability of the questionnaire is good.The expert evaluation results show that the questionnaire designed in this study is effective, and the research results of this study will be described in detail. There is no significant difference in the distribution of questionnaires among the three universities in this questionnaire, so the analysis of data results takes the three universities as a research object.The problems existing in college students' outlook on life and the education of their outlook on life are shown in Different students choose different answers due to the setbacks they encounter, the pursuit of happiness, and the choice of interests. There are many problems in the education of college students' outlook on life outlook on life, and the main reason is attributed to the backward teaching methods. In the questionnaire survey, 81.8% of the college students argue that the teaching method of the education of college students' outlook on life still employs the traditional method of installation; 73.8% of the college students think that the teaching content of the education of outlook on life education is too extensive, unable to arouse their interest in the learning process, and unrelated to real life; 58% of the students think that the increasing spread of network information affects the establishment of a correct outlook on life; 62.7% think that criticism from their parents and teachers makes them lose the enthusiasm for study, thus affecting the formation of correct outlooks on life and values.During this survey, the education of college students' outlook on life is affected by many factors, which are summarized into several important factors, as shown in There are several important aspects of educational psychology in the process of teaching and learning, as shown in Contemporary college students have a strong sense of autonomy, and their education of outlook on life is more rigorous and important. The current situation of the education of outlook on life has been unable to meet the needs of college students, and a more reliable and effective way needs to guide college students to establish a correct outlook on life. Rogoza et al.  made an The correlation between positive psychology and the education of outlook on life is shown in And positive psychology can promote the transformation of the concept of the education of college students' outlook on life, enhance the attraction of the teaching method of college students' outlook on life, and promote the actual effect of the education of college students' outlook on life. All these advantages of positive psychology can be integrated into the education of college students' outlook on life  for the publication of any potentially identifiable images or data included in this article.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "The article presents the verification of a developed method of rationalising the process of the operation of a manual toll collection (MTC) system on the basis of current operation tests. The review of the state of art and research on the operation of the manual toll collection system prompted the authors to develop their own method of rationalising the operation process of the manual toll collection system. The method enabled the development of an original application facilitating the process of manual toll collection system. The application makes it possible to determine the key indicator\u2014the readiness index for the employed operation strategy of the analysed toll collection station and the readiness index for the employed operation strategy of the analysed group of toll collection stations. Additionally, the application enables an analysis of the capacity and the service assessment by motorway users. The use of the software system together with the developed method was implemented on a real toll plaza. This action allowed for the analysis and implementation of an adequate MTC service strategy. The results of the research and analysis are presented in the summary and conclusions.  The toll collection process should be smooth and ensure the greatest possible continuity of the transport service and an adequate quality of a toll road user service. Toll road users accept the fact of collecting fees for passage, provided that they are guaranteed relevant comfort of travelling on national roads, and thus, ensuring the handling of paying users, together with the continuity of the transport service. This heterogeneity of the toll collection system forces an administrator of a given motorway segment to use two systems of manual toll collection along with an electronic one, which additionally increases the system operation costs and makes it impossible to ensure the same quality of payment services for each vehicle type.In the light of the above, it can be concluded that the reliability of a highway toll collection system determines the continuity of the transport service and the revenue from tolls on national roads. Achieving a high level of reliability of a highway toll collection system is particularly important in places where the fast and safe transport of people and goods is of large importance. An interrupted operation of a highway toll collection system results in vehicle traffic congestion and a termination of transport service continuity. Motorway toll collection systems operate in various operating conditions, and their correct functioning is determined not only on the reliability of individual system elements, but also on the applied operational strategies. Given the above, there is a need to analyse the reliability and the operation process of a manual toll collection (MTC) system and to propose an efficient method of its improvement.The introduction of the National Toll Collection System in Poland created the need to integrate manual and electronic toll collection systems. The National Toll Collection System enables to collect tolls both electronically and manually, depending on the type of vehicle. In accordance with the provisions of the Terms of Reference for a limited tender of the National Toll Collection System, including activities related to electronic toll collection (ETC), all vehicles with a permissible total weight below 3.5 tons are required to pay the toll on state motorways using the MTC system. The obligation to pay the electronic fee applies to vehicles with a maximum permissible weight of more than 3.5 tons and buses. Therefore, the use of MTC systems must be carried out simultaneously with ETC on the toll road network in Poland. MTC is a process that, from the point of view of the road user, disrupts the transport process and measurably contributes to the extension of its execution in time. Therefore, it is advisable to conduct appropriate tests, the purpose of which is, inter alia, to determine the reliability of the MTC system. This analysis of the reliability of the MTC system is aimed at obtaining information on the performance of technical objects during operation. The obtained indices will allow the authors, using the proprietary application, to evaluate the actual analysed system, and thus to define the strategy of operation so that it meets the requirements specified in norms and normative regulations. To assess the reliability of the MTC system, the system availability index was used, which is a numerical measure of its reliability evaluation.The literature contains numerous papers dealing with the theory of reliability and the operation of technical systems. Examples of publications in the field of studying the reliability and operation of technical facilities include ,11,12,13The reliability evaluation of an MTC system generates the problem of constructing an appropriate model representing the operation of an actual system. The transport domain contains numerous elaborations regarding the modelling of transport systems and processes. The examples in this field are the following papers: ,15,16,17The analysis of transport system functioning made the authors of many papers to address the issue of reliability of transport systems and devices, which are the components thereof ,21. The There are many works ,29 relatThe analysis of the literature also made it possible to raise important aspects related to the COVID-19 pandemic and its impact on the development of transport systems. For example,  analysedThe above papers concern the assessment of technical systems not related to the toll collection process. They mainly regard fuel consumption by vehicles participating in toll collection in relation to COVID-19 restrictions. Each of the presented assessment methods takes into account the specific operating conditions of technical systems, which are often unusable when assessing other systems. Due to the complexity of modern technical systems, it is often necessary to develop a unique reliability assessment method for each of the analysed systems. There are no specific practical solutions in the literature regarding the development of a toll collection strategy in MTC systems. The authors of this article focused on the verification of a developed method, based on actual operational studies, which are the current basis for improving technical systems and their maintenance process.The purpose of the reliability analysis carried out in  was to oBoth the performed characteristics and functional analysis of the MTC system at work  indicateEquation (1) shows that the state of the process at a moment is not directly influenced by the states it was in at times. Only the state in which the process is in moments has a direct impact. For Markov processes, only the present determines what will happen in the future, and the past (history) has no influence.The operation of the MTC system allows us to state that examining this process only in selected moments of time may be insufficient. In the case of processes with a continuous time parameter, the analysis of the system operation process will be more accurate, which will enable a rational definition of the operation strategy of the analysed system.In connection with the above, it was concluded that the Markov process model discrete in states and continuous in time, will be the appropriate type of model to describe the operation process of the manual toll collection system. It is characterised by a finite or countable number of process states where the parameter t (time) changes continuously and the transition from one state to another is possible at any time.\u2013times of the process being in the distinguished operating states are random variables with exponential distributions,\u2013the probability of two or more damage to the toll station modules at the same time is close to zero,\u2013during operation, the state of the system changes randomly over time.The model of the operation process of the toll collection station that independently implements the toll collection process in the grouping of toll collection stations was made with the following assumptions:\u2013stationary probabilities of operating process states,\u2013ready indicator.The following group of indicators was defined to describe the operation process of the toll collection station:The distinguished indicators do not exhaust all that can be used to describe the operation process of the manual toll collection system. However, they seem sufficient for a practical assessment of the operation process of the tested system.\u2013a subset of pending states,\u2013a subset of usage states,\u2013a subset of servicing states.During operation, technical systems are in various operational states. In the exploitation theory, there are three subsets of the operational states of technical systems ,5,6:\u2013a sAn example of a subset of the standby states of technical systems are : storage\u2013S1-the state of effective work,\u2013S2-state of waiting for repair,\u2013S3-repair status.Taking into account the set of functional states, as well as the serial functional structure of the toll collection station located in the grouping of stations belonging to the manual toll collection system, the following operating states of the station were distinguished:iS form a state space defined by the set S:The states of S have an exponential distribution.The graph of the operation process of the toll collection station, taking into account the intensity of state transitions, is shown in S1 state of the toll station operation process and the service phase, which includes the S2 and S3 states shown in During the operation of the toll collection station, two basic phases were distinguished in terms of the scope of its operation. This is the use phase, which includes the S1 state of effective work, can go into the state of awaiting repair S2 with the intensity of transition S3. Being in the S3 state, it is possible to go to the S1 state ,B-column matrix of intercepts.Using the matrix notation, the system of equations has the form:If we assume that the stationary probabilities of the operating process states of the toll collection station are determined by the following formulas:So:The values of the stationary probabilities (7) are determined by the intensity of the transitions.S1:The availability ratio of the toll collection station described by the operating conditions graph presented in \u2013the average time between subsequent damage to a single toll collection station is \u2013the total average repair time for a single toll collection station is \u2013the waiting time for replaceable modules is 30 min, that is, the intensity of waiting for spare parts To determine the value of the toll collection station availability ratio, defined by the Equation (8), the following values were adopted, specified in the requirements for the reliability and availability of toll collection systems specified in the literature ,27:\u2013the For such adopted assumptions, the value of the readiness index determined by the relation was obtained:Equation (9) also allows to determine the impact of the change in the value of the repair intensity of the toll collection station on the value of the availability ratio. The toll station is in the subset of the servicing states with the probability determined by the following relationship:Equation (10) also allows to determine the impact of the change in the value of the repair intensity of the toll collection station on the value of the probability of being in a subset of servicing states. The analysis of the presented model of the operation process of the toll collection station allowed to determine the dependencies enabling the determination of the value of being in the following states: effective work, waiting for repair and repair.In practice, the correct organisation of the stock of exchangeable elements is of great importance, because the amount of stocks has a significant impact on the process of technical object renovation. The lack of appropriate elements may completely prevent the renovation of the object or significantly extend its repair time, when additional time is needed to look for appropriate replaceable elements. Such a situation is particularly undesirable in the case of toll collection systems, where any downtime in the proper operation of the toll collection station may lead to dangerous situations in the form of traffic congestion. It is extremely important to properly determine the stock of exchangeable modules and to develop an appropriate system maintenance strategy.The method of rationalising the operation process of a MTC system can be verified based on the example of actual operational studies, which are currently the basis for improving the design of technical systems and their maintenance process. They enable obtaining reliable information necessary for controlling the operation process, proper service facilities organisation, and to predict and determine the operation costs of a toll collection system.Operational studies of a MTC system in a station were conducted over a period of 6 months, which corresponds to 4380 h. The test period was determined based on the requirements in the field of reliability and availability of MTC systems presented in the literature ,27. The studies involved estimating the intensity of damage to individual replaceable modules, with the values shown in in paper  the follAST for the studied station, under predicted damage intensities of individual modules shown in According to the methodology in  regardinA factor The operational studies of a MTC system took into account the estimated intensities of individual replaceable module damage, the values of which are shown in For these adopted operating data, In order to guarantee the required readiness index value of a toll collection station specified in the reliability and availability requirements of MTC systems, the value of factor For example, the case of the data above and cumulative expenditure C on the replaceable elements needed for the correct operation of a toll collection station at a level of PLN 500,000 resulted in a list of the number of toll collection station replaceable modules needed to ensure an adequate value of a station readiness index. The summary is shown in ST for a toll collection station and vice versa. The developed operational strategy of maximising the readiness factor, which takes into account the demand for replaceable modules and the actual expenditure on the modules in the course of the system operation enables accurate organisation of toll collection station replaceable element stock.In the event of a demand for 26 replaceable modules needed to ensure the required readiness index of a toll collection station, and the actual expenditure on replaceable modules being lower than the expenditure required for the correct operation of a toll collection station, there is a possibility to determine the maximum value of the readiness factor AThe developed operation process rationalisation method presents issues associated with distinguished operating states of a studied, MTC station. The demand for spare parts of a toll collection station was conducted and a factor taking into account expenditure on the parts was introduced. This enabled the development of an operational maximization strategy for the readiness factor, which takes into account the demand for replaceable modules and the actual expenditure allocated to the modules within the operation process of a system. This made it possible for the decision-makers (operators of highway sections) responsible for a toll collection yard operation system to be able to rationalize the activities and optimize the readiness factors, depending on the funds allocated to spare parts.The method presented in this section of the paper was used in the application supporting the making of operational decisions of the MTC system, which is described below. The results of the application on the real MTC toll plaza are presented below. The results of parameter measurements obtained with the use of the application supporting the making of operational decisions of the MTC system in the capacity analysis and user service assessment mode are shown further in The longest periods of vehicle service times  were rec\u2013limiting the number of vehicles,\u2013shorter service time,\u2013increasing the number of service stands in the grouping of toll collection stations.Taking into account the obtained measurement results, measures should be taken to shorten the waiting times at the grouping of toll collection stations. The analysed grouping of toll collection stations is a typical example of a mass service system with seven independent and parallel service stations. The process of modelling the traffic of vehicles on the motorway and their operation in the MTC system has been described using the classic problems of queuing systems. In systems of this type, in the event of system failure, there are three main methods to deal with and improve their work:\u2013the intensity of damage to the toll collection point,\u2013the intensity of waiting for the toll station repair,\u2013the intensity of repairs at the toll station,\u2013intensity of waiting for exchangeable modules for the toll station.The application supporting the making of operational decisions of the manual toll collection system  was used\u2013demand for exchangeable modules,\u2013actual financial outlays allocated to them during the system operation process.The collection of this data allows for the determination of parameters, in the form of readiness indicators of the toll collection station and grouping of positions, determining the strategy of maximizing the readiness ratio taking into account:\u2013availability ratio for the adopted operational strategy of the analysed toll collection station,\u2013readiness index for the adopted operational strategy of the analysed group of toll collection stations.The scheme of the application\u2019s operation in the mode of determining reliability indicators for the toll collection station and grouping the stations in the manual toll collection system determines the parameters:These parameters are determined based on the data recorded for each toll collection station of manual toll system positions presented above. The values indicated above by the program are used to support the management of the operation process of motorway toll collection systems, in fact, on a real toll plaza. The application of the program speeds up the process of analysing the reliability and operational data of toll stations and groups of toll stations. Thanks to this, it is possible to make rational decisions regarding the operation of these systems much faster. Additionally, the program enables the capacity analysis and evaluation of motorway user service. Along with the use of the above values of the readiness indicators for the adopted operational strategy and information on the capacity of the toll plaza and the evaluation of the service of motorway users, it is possible to quickly apply a strategy adequate to the situation for the operation of individual toll stations on the analysed plaza. This enables rational use of all stations, taking into account their operational readiness and the current process of servicing vehicles at the toll plaza. In the future, it is planned to expand the application with the functions of saving data to the database and automatically informing decision-makers responsible for the operation process about the need to purchase used exchangeable modules. Additionally, the application is planned to predict the intensity of damaging, waiting, and repairing. This will allow the system to obtain feedback about the operation and adapt itself to give the output values more accurately.In the second stage, the application was used to analyse the capacity and evaluate user service at a cluster of seven toll collection stations on the actual section of the motorway. The system\u2019s capabilities allow the verification process to be carried out practically in any way and from any place, both on the basis of live (current) video material as well as previously saved and archived in the video surveillance system , which i\u2013time of reporting  of the vehicle to the toll station,\u2013time of commencement of service of a given vehicle at a toll station,\u2013time of completion of service of a given vehicle at a toll station,\u2013the current length of the queue of vehicles at the toll station,\u2013average waiting time of the vehicle in the queue for payment,\u2013the average length of the queue of vehicles awaiting payment of the toll,\u2013average number of vehicles waiting in line for toll collection in a toll plaza.In order to verify not only the toll collection process itself, but also the capabilities of the system in question, a grouping of seven toll collection stations and a time period for which the control using traditional methods has already been checked were selected for the needs of the work. In both cases, the aim is to determine the waiting time for each vehicle applying to a toll collection group. For each toll station of the MTC system, the following parameters are determined and determined:\u2013waiting time for service,\u2013length of the queue of vehicles,\u2013vehicle service time.The collection of this data allows for the determination of parameters determining the level of service in the grouping of toll collection stations:The above parameters made it possible to assess the levels of service of the MTC system as a grouping of seven toll collection stations on the actual section of the motorway. The effect of the application is to determine the capacity characteristics and service levels for users of the MTC system as well as the reliability parameters of the MTC system. This is to enable the decision-maker to make an adequate operational decision . Limiting the number of vehicles is possible administratively or legally. However, this seems to be an unwise solution due to the universal right of drivers to access the motorway and the associated reduction in toll revenues. Reducing the volume of vehicle traffic can also be achieved by increasing the toll, however, practice shows that this is a short-term action and always poorly received by motorway users. Shortening the service time seems to be the best solution for both users and the motorway manager. In practice, however, it will be very difficult to implement, as there are limits below which this time cannot be reduced. This is due to phenomena such as vehicle delays in the queue, bad driver habits or the toll collection process itself. Some time savings can be achieved by streamlining electronic payments, better signage and directing traffic to individual toll stations, but they are unlikely to be significant. Increasing the number of service stands is certainly the most expensive solution, which results not only from the expansion of the group of toll collection stations, but also from the additional number of employees on positions.Analyses of capacity and evaluation of vehicle servicing along with the designated operational parameters for the toll plaza make it possible to determine the optimal strategy of operation, taking into account the reliability and capacity of the system. It is extremely important, since there are often restrictions in the form of a finite resource of funding allocated to system operation. Therefore, this raises a decision-related issue: how to ensure operational continuity (system fitness) having limited funds, while simultaneously ensuring a relevant level of the readiness index and meeting the set objectives . The developed application supporting the making of operational decisions determines the values of the readiness index for the grouping of toll collection stations, taking into account the developed operational strategy taking into account the financial outlays for inspections and the need for replacement modules. As a result, it can be used as an IT tool to support the management of the operation process of motorway toll collection systems. The application of the program speeds up the process of analysing the reliability and operation data of toll stations. Thanks to this, it is possible to make rational decisions regarding the operation of these systems much faster."}
+{"text": "Several theories describe the development of the retraction pocket of the tympanic membrane (RP). Many authors suggest that the negative middle ear pressure is the main reason responsible for developing this condition. A narrative review has been undertaken, and conclusions are drawn reflecting a current knowledge with our new observations in the histological and immunohistochemical study. Recent studies show the important role of inflammation in the development and progression of RP. A review of the available literature shows that the inflammation plays a key role in pathogenesis of the RP and its progression to the cholesteatoma. We support this statement with our new results from histological and immunohistochemical analysis of the RPs. Retraction pocket (RP) of the tympanic membrane is a common entity, especially in children. The danger of RP lies in ossicular chain erosion , cholestEpidemiological studies have shown that the retraction pocket is a relatively rare disease and it largely affects the child population. In 1994, Stangerup published a study where it examined 294 healthy children aged 5 to 16 years and found the occurrence of retraction pockets in 26% in the area pars flaccida and at 3.7% in the pars tensa area . DeDegeneration of the lamina propria of the tympanic membrane is a long-term process. Inflammation leads to destruction of the collagen and elastic fibers. Mediators of inflammation lead to the release of collagenases and destroy the disulfate bridges. For this reason, the tympanic membrane becomes thin and elastic properties are changed. Weakened tympanic membrane loses its resistance to pressure changes. After the initial insult and loss of strength, inflammation is no longer necessary for progression of the retraction pocket. The problem of retraction pockets lies in the loss of original histological and anatomical structure, therefore its inability to resist the negative middle ear pressure.Based on this knowledge, it is very important to prevent and treat the inflammation early. All children with recurrent acute otitis media or secretory otitis media should have a comprehensive examination by a pediatrician and otorhinolaryngologist. We can perform an adenoidectomy, insertion of the ventilation tube to the tympanic membrane or a special treatment in case of immunodeficiency. Watch and wait strategy can be dangerous and it can lead to damage of the middle ear ossicles or to development of cholesteatoma in many cases.All of these claims also support the basic mechanism of why an intact tympanic membrane invaginates into the tympanic cavity and also support the retraction theory of cholesteatoma. The first step in pathogenesis of the retraction pocket is affection of the inflammation from the middle ear mucosa to the tympanic membrane. Inflammation caused the pathological changes in the middle layer of the tympanic membrane: hypervascularisation, degradation of the double layer of collagen fibers, fragmentation of the elastic fibers and others. These changes lead to significant weakening of the tympanic membrane, especially in pars tensa. This area of the tympanic membrane is more flexible and less resistant to negative pressure in the middle ear in children with dysfunction of the Eustachian tube. Inflammation is important for the development of the retraction pocket, as we can see the presence of retraction in children with normal function of the Eustachian tube. Therefore, prevention of inflammation is important in the treatment strategy of the retraction pocket."}
+{"text": "The demographic shift of the population toward an increased number of elder citizens, together with the sedentary lifestyle we are adopting, is reflected in the increasingly debilitated physical health of the population. The resulting physical impairments require rehabilitation therapies that may be assisted by the use of wearable sensors or body area network sensors (BANs). The use of novel technology for medical therapies can also contribute to reducing the cost of healthcare systems and decrease the patient overflow in medical centers. Sensors are the primary enablers of any wearable medical device, with a central role in eHealth architectures. The accuracy of the acquired data relies on the sensors; hence, when considering wearable and BAN sensing integration, they must prove to be accurate and reliable solutions.This Special Issue (SI) focuses on the current state-of-the-art BANs and wearable sensing devices for the physical rehabilitation of impaired or debilitated citizens. Both original research papers and review articles describing the current state-of-the-art were considered for publication. We believe that this SI will provide the reader with an overview of the present status and a future outlook of the aforementioned topics.The contributions to this SI resulted in a collection of 10 published manuscripts reporting on the advances in research related to different sensing technologies  and body area network sensors (BANs); their design and implementation; advanced signal processing techniques and the application of these technologies in areas such as physical rehabilitation, robotics, medical diagnostics and therapy.A short overview of the collection of papers accepted for publication in this SI is presented in The guest editors would like to show their token of appreciation to all the authors that contributed to the success of this SI, by providing a set of original papers with a comprehensive and up-to-date overview of a variety of topics, under the umbrella of \u201cWearable and BAN Sensors for Physical Rehabilitation and eHealth Architectures\u201d.Furthermore, the work and support of the academic editors and reviewers is highly appreciated. They were a key factor to guarantee the high quality and the scientific rigor of the published manuscripts and, consequently, of this Special Issue.The manuscripts accepted for publication in this SI mirror the relevance of the topic for the research community, and the vast field of research that still exists to be explored to enhance the wearable and BAN solutions for physical rehabilitation applications and eHealth architectures.The authors of  presenteBezuidenhout et al. presented a study on the reliability of Actigraph GT3X+ (AG) accelerometers to detect gait parameters. The devices were worn on the hip and on the ankle by thirty healthy individuals walking in a straight line and turning at different speeds. As a reference, a Stepwatch (SW) activity monitor was used, which was attached to the right ankle . The autIn the third contribution to this SI, the authors Di Tocco et al. presented their study on the development of wearable solutions for unobtrusive cardio-respiratory monitoring . The proThe authors from  presenteThe authors of  presenteThe contribution by Rutkowski et al., a study focusing on the use of physical activity sensors (such as the SenseWear armband) in patients with chronic obstructive pulmonary disease (COPD), was presented to monitor their activity level in day-to-day life and for the duration and intensity of physical activity. The approach implemented by the authors allowed them to understand the daily activity of the patients and if they undertake the prescribed unsupervised physical activity, and additionally, to understand the strengths and weaknesses of the selected type of sensors . Based oAnother work devoted to the human activity recognition (HAR), using smartwatch inertial sensors, was presented by the authors of . The autThe valuable contribution by Liu et al., for the success of this SI, was also focused on the use of wearable inertial sensors, but for the ambulatory detection of the human gait phase . The anaThe authors of  presenteThe review paper presented by Vilela et al. discusses the innovative and relevant topic of fog-computing in the area of eHealth . The autThe set of papers published in this SI is just a small representation of the current research interest regarding the use of wearable and BAN sensors for physical rehabilitation and activity monitoring. As the field for wearable sensors evolves, improving its range of detection, resolution and accuracy, new applications and higher accuracy detection levels can be achieved by widening the application of these technologies even more. When allied to ML algorithms, other emerging fields of applications can be sought, such as the digital twin features, where there is a vast area of research still to be pursued."}
+{"text": "The authors were asked for an explanation to account for these concerns, but the Editorial Office never received any reply. The Editor regrets any inconvenience that has been caused to the readership of the Journal.After having conducted an independent investigation in the Editorial Office, the Editor of"}
+{"text": "The journal and Authors retract the 23 April 2021 article cited above for the following reason as provided by the Authors:Following publication, the Authors were informed that they were not entitled to publish the raw data underlying the findings by the supplier of the analyzed drug.Therefore, with the agreement of the Authors and the Chief Editor of the Oral Cancers specialty of Frontiers in Oral Health, the publication is being retracted."}
+{"text": "Artificial intelligence (AI) in Digital Pathology (DP) both in terms of the global situation and research perspectives. It has four polarities. First, it revisits the evolutions of digital pathology with particular care to the two fields of the digital cytology and the digital histology. Second, it illustrates the main fields in the employment of AI in DP. Third, it looks at the future directions of the research challenges from both a clinical and technological point of view. Fourth, it discusses the transversal problems among these challenges and implications and introduces the immediate work to implement.This commentary aims to address the field of"}
+{"text": "This study investigates the influences of intergenerational relations on the subjective wellbeing and status identity of the elderly population in China. The project draws insights from the studies of social mobility and stratification, and that of family relations and old age support. Because of widespread exchange of economic resources across generations and strong sense of connectedness among parent and adult children families that continue to exist in Chinese society today, we hypothesize that older parents\u2019 subjective sense of well-being and evaluation of their socioeconomic statuses are positively related with the socioeconomic conditions of their grown children, and the strength of the such relations with them. The study used the data from the 2013 China General Social Survey (CGSS), and the results provide fairly strong support to the hypotheses. The implications of the results on age-based stratification are discussed."}
+{"text": "Subsequently to the publication of the above article, the authors have realized that they incorporated some wrong values for the P-values shown in Oncology Letters for granting them the opportunity to publish this corrigendum, and regret any inconvenience caused to the readership of the Journal.A corrected version of"}
+{"text": "The impact of protected areas on local communities is the subject of intense discussions as part of the implementation of the global ecosystem protection agenda. Conflicts between the interests of environmental protection and the needs of socio-economic development become particularly acute when large areas of land are taken out of economic circulation as a result of organizing protected areas. In this case, there is an urgent need for detailed and reliable information about the social impacts of such land withdrawal on the well-being of the local population. An analysis of the methodological approaches widely presented in the literature, used to assess the social impact of protected areas, testifies to the insufficiency of completed and practically applicable methodological guidelines for the areas with significant restrictions for people who form part of the protected landscape. In this study, we understand the cost estimate of the social impact of national parks on the local population as a quantitative calculation of the losses due to restrictions on their ownership rights to land and property assets. The methodological approach consists in considering the category of losses as a sum total of the actual damage and lost profits. The assessment algorithm includes three stages: systematization of social impacts on citizens, development of indicators and data collection, and calculation of actual damage to the population and lost profits. The assessment is performed using the example of the Tunkinsky National Park located in the Tunkinsky municipal district of the Republic of Buryatia, a region of the Russian Federation, where there are 14 rural settlements with a population of more than 20,000 people. The results of the calculations show that the losses of the rural population due to legal restrictions on the registration of land dealings amount to 170.4 million USD. Taking into account the potential amount of administrative fines and the value of property subject to demolition, the losses amount to 239.2 million USD. It is more than an order of magnitude greater than the amount of own revenues of the Tunkinsky municipal district in 2011\u20132019. The results obtained demonstrate the real picture of the impact of restrictions on the rights of local people to land within the boundaries of national parks and are useful for developing measures to account for their interests and include protected areas in the socio-economic development of regions. The methodological approach developed by the authors can be used in other national parks, where it is necessary to optimize the policy of improving land use for local residents. The creation of a network of protected areas is a critical tool in promoting the values of conservation of biodiversity, natural resources, and ecosystem services. Originally conceived to conserve unique landscapes and wildlife, protected areas are undergoing a transformation of approaches to further development under the Durban Agreement 2003) . In line003 . In In some countries, protected areas contribute positively to poverty reduction, as in Ethiopia, where households within and adjacent to three national parks have higher incomes than those living outside them .At the same time, there are examples of restrictions imposed by the government on the interests of the local population in very sensitive natural areas or areas of traditional nature management that inevitably lead to social, environmental, and economic conflicts , 7. The In continuation of the ongoing debate about the importance of considering human well-being in biodiversity conservation , new eviRussian protected areas have not traditionally been considered in the context of fulfilling the objectives of development or improving the well-being of local residents . DecisioIn this paper, the authors focus on the development of a methodology to quantify the social impacts arising from the restriction (impairment) of property rights on land and property assets of local residents, as well as the rights to measures of their social support. This assessment is based on the example of a specific type of protected area\u2014a national park, the creation and functioning of which significantly impacts the population living within its borders. The results of the study demonstrate a reliable quantitative assessment of the social impacts on the local population living within the borders of the Tunkinsky National Park (Russia) and can be used in the preparation of management decisions. The authors hope to contribute to the development of the methodology for assessing the social impacts of protected areas.The principle that protected areas should not cause harm to local populations is enshrined in the Durban Agreement adopted at the World Congress on Protected Areas in 2003. Social impacts are the main factor influencing the social acceptability of conservation activities . Under tThe literature provides quite convincing evidence that protected areas can help reduce poverty in local communities , as wellRegarding the health and safety impacts of protected areas, a systematic review commissioned by the Global Environment Facility indicated that opinions on local health are mostly negative, and quantitative studies of the health and safety impacts of protected areas are notable for their absence .Forced or involuntary displacement of people is one of the most negative social impacts of protected areas. An example of a study of the effects of relocating indigenous people from a national park in Honduras shows that park rules and policies led to changes in access to land for subsistence needs and the increased intensity of land use, which, in turn, racked up production costs and contributed to changes in income-generating activities and an increased role of wage labor as a source of subsistence income .The introduction of a new management structure that implements new rules regarding the development of the area and natural resources is a key theme in studies on the impact of protected areas on the well-being of local people , 27, 28.Researchers recognize that the creation and functioning of protected areas can have a significant impact on human rights in local settlements located within the boundaries of protected areas , 25. HowIn Russia, land dealings in national parks has been limited. Consequently, the local population living in national parks for many years could not fulfill the right to have private ownership of land and to exercise local self-government, since any issues of economic activity must be decided by the national park administration. Thus, the problem of restricting citizens\u2019 rights to land exists in 27 national parks across Russia, where there are about 923 settlements with a total population of 371,000 people . It is nIn the international social impact assessment community, social impact assessment refers to the process of analyzing and managing the intended and unintended social consequences, both positive and negative, of planned interventions  . Since tJones, N. et al. believe that despite the increase in the number of studies devoted to assessing the social impact of protected areas, there is still no official protocol or generally accepted methodological tools . TherefoThus, a review of the literature testifies to the urgency of assessing the social impact of protected areas and the complexity of developing methodological approaches due to the multifaceted nature of the subject of research.This study is based on the methodology of assessing the impacts of introducing environmental restrictions in the Baikal Natural Area in order to protect the unique ecosystem of Lake Baikal, the largest reservoir of the world\u2019s fresh water and a World Natural Heritage site. Federal Law 94-FZ \u201cOn the Protection of Lake Baikal\u201d dated May 01, 1999, introduced strict ecological restrictions on the scale and nature of the use of natural resources, as well as high-level requirements for emissions and discharges of pollutants. The development and carrying out of environmental measures entailed higher capital and operating costs, direct production losses, and lost profits in the economy, in the entire drainage basin of Lake Baikal. The methodological approach to the assessment of environmentally conditioned additional costs and lost profits consisted in determining the essence of the environmental constraint and its scope and identifying changes in the conditions of production and daily activities that were likely to occur as a result of environmental constraints, as well as in revealing quantitative relationships between such changes and the costs. The methodological approach was tested on the example of the Republic of Buryatia and the Tunkinsky National Park .In this article, the subject of the study is a quantitative assessment of the social impacts of legal restrictions on land dealings for the population, by which we mean the cost expression of losses resulting from the infringement of (or failure to respect) the rights of citizens living in settlements located within the boundaries of a protected area. In this case, we adhere to the legal interpretation of losses (Clause 2 of Article 15 of the Civil Code of the Russian Federation). Losses are understood as the totality of actual damage and lost profits of persons (citizens) whose right has been infringed. In turn, the actual damage is the incurred or future expenses to restore the infringed right, as well as a loss or damage to property. Lost profits are lost income, which the person would have received under normal conditions of civil commercial transactions, if this person\u2019s right was not infringed. Since we are talking about the supposed material addition to the property of the victim, which would have occurred in the normal course of events if the right had not been infringed, it should be taken into account that the calculation of lost profits is usually approximate and has a probabilistic nature. The algorithm of the cost estimation of losses developed by the authors of this paper includes three stages.Stage 1 \u201cSystematization of social impacts on citizens\u201d identifies legal restrictions on livelihoods and economic activities within the boundaries of national parks, as well as the emerging social impacts on citizens. In this study, legal obstacles to the registration of land dealings are considered as the most significant constraint.Stage 2 \u201cDevelopment of indicators and data collection\u201d defines a set of baseline indicators that characterize (describe) the impact of the above-described constraints on living conditions, economic activity settings, and the arrangements for the delivery of social commitments to the local population. The data collection takes into account the principles of information availability, as well as the period since the registration of the land title was denied.Calculations of the actual damage and lost profits are performed at Stage 3 \u201cQuantitative assessment of material losses incurred due to legal restrictions on the registration of land dealings\u201d:ADpop) is carried out by a direct accounting method based on the cost approach using the following formula:1) The assessment of actual damage to the population  is performed using the rate of return on invested capital (i):2) Calculation of the amount of lost profit  is divided into the land of the National Park (90%) and the land of other owners (10%).Unlike all other Russian national parks, the Tunkinsky National Park is characterized by two distinctive features. Firstly, this park completely covers the whole territory of the Tunkinsky municipal district. Secondly, in the east, a portion of the park is included into the Central Ecological Zone of the Baikal Natural Area, where strict environmental restrictions are in force. The total area of the park , for the demolition/relocation of which orders were issued, was determined based on the number of land lots for individual housing development without registered rights located in the Tunkinsky National Park, the average floor space of one apartment in individual housing development, and the average actual construction cost of 1 square meter of housing . It was calculated based on the total number of citizens brought to administrative liability for the lack of registered rights to land lots, houses, and premises located in the Tunkinsky National Park, and the minimum fine for individuals , because the environmental expertise of the design documentation for individual housing development is not carried out, and the issuance of construction and reconstruction permits for the capital construction projects planned within the borders of protected areas of federal importance, as well as permits for commissioning these objects, is done without charging fees.The amount of incurred and future expenses for environmental expertise and the coordination of activities with the Ministry of Natural Resources and Environment of the Russian Federation was not calculated (AD4)   was as fAD5) were determined based on the cost of travel to Ulan-Ude and the number of people who left the Tunkinsky municipality in 2011\u20132019:Forced relocation costs (AD6) were estimated based on the cost and average area of land lots in Ulan-Ude:Land acquisition and construction costs to replace lost property (AD8) was estimated at 10,026,683.27 thousand rubles.The cost of complete or partial loss of property due to relocation from the protected area (AD9) were determined according to the data presented in Material losses of the people due to their inability to sell land lots (AD10) was carried out for the category of multi-child families. According to the regional legislation, multi-child families in the Republic of Buryatia have the right to receive a land lot for individual housing development free of charge. However, such families living in the Tunkinsky National Park cannot exercise this right, because the land is federally owned and withdrawn from economic circulation. The value of these losses was:The assessment of the lost revenues of the population incurred due to inability to provide social support (ADpop) was 11,504.7 million rubles. Taking into account the potential amount of administrative fines and the value of the property to be demolished\u201416,462.4 million rubles.Thus, the total amount of actual damage to the local residents living in the Tunkinsky National Park due to legal restrictions on the registration of land lots (i). The key rate of the Bank of Russia in effect at the beginning of 2020 was used as the rate of return (6.25%). For the t-period during which no income could be received as a result of the diversion of funds, we took the period equal to the time since the legal restrictions were introduced, i.e., from 2011 to 2019 (9 years).The calculation of the amount of lost profits was made through the rate of return on invested capital (LP1), relocation (LP2), and fines (LP3):Based on the obtained values of actual damage to the population, we calculated the income lost as a result of the diversion of money for the reservation of funds for the purchase of land and construction  on the ownership rights to land and property assets of local residents, as well as on the measures of their social support.The methodological approach to the assessment of social impacts of protected areas developed by the authors is based on the consideration of the category of losses, which is understood as a sum-total of actual damage and lost profits of individuals (citizens) whose rights have been infringed. The assessment algorithm consists of three stages: systematization of social impacts on citizens, development of indicators and data collection, and calculation of actual damage to the population and lost profits. The assessment is based on the example of one of the largest national parks in Russia\u2014Tunkinsky National Park, the area of which completely covers the territory of the Tunkinsky municipal district. There are 35 settlements with a population of over 20 thousand people within the boundaries of the park. The losses of the rural population due to legal restrictions on land registration are estimated at 12.3 billion rubles (170.4 million USD) and taking into account the potential amount of administrative fines\u201417.2 billion rubles (239.2 million USD) This is 11 and 15 times more than the amount of own revenues of the Tunkinsky municipal district generated during the period since the restrictions came to force in 2011.The results prove the negative impact of the conservation policy on that part of the population in the Tunkinsky district who for nine years have not been able to register ownership rights to the land lots on which their houses and auxiliary buildings stand.Starting in 2021, according to the amended Russian legislation, local residents have the right to privatize land in communities located in the park. In the long term, it can improve the quality of life of local people. However, the real picture of reducing the social impact of protected areas is still far from ideal, since there are still unresolved issues of land turnover in settlements with unspecified boundaries. The policy of improving land use for local residents requires updating the functional zoning of the National Park. It will allow to optimally combine the preservation of natural, historical, and cultural sites of the park with the economic use of the territory and the development of entrepreneurship and other opportunities for the local residents to earn a livelihood. Besides, in order to achieve the goals, continuous organizational and administrative work will be required both to register the rights of local residents to their land lots and to include the land with roads, bridges, power lines, pastures, and other sites and facilities that enable the smooth functioning of daily lives of people into the land of settlements. A partnership between the National Park and the local authorities seems to be inevitable, and they will work together to mitigate the effects of conservation policies on local communities.We believe that this study contributes to the discussions on assessing potentially positive and negative impacts of measures aimed at developing protected areas that affect the rights of people and the quality of life of the community, as measured by various social and economic indicators.Moreover, we assume that the methodology for estimating damages to local residents, which was tested using general indicators and open-source data for a specific national park in Russia, may be useful for measuring damages arising from restricting the rights of people to land in other national parks that have rural settlements with people living in them.S1 Table(XLSX)Click here for additional data file.S2 Table(XLSX)Click here for additional data file.S3 Table(XLSX)Click here for additional data file."}
+{"text": "In the Funding section, the following statement is missing: The views expressed in this document are those of the authors and do not reflect the official policy or position of the Department of Defense or the U.S. Government."}
+{"text": "There are errors in the Funding statement. The correct Funding statement is as follows: This research was funded by the project of Science and Technology Department of Jilin Province in the form of a grant (20200301025RQ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."}
+{"text": "We are issuing this expression of concern in consultation with the publisher to fulfil their reporting obligation regarding the publication  mentioneOne of the authors has raised concerns regarding the methodology employed in the study, the conclusions drawn and the insufficient consideration of laboratory staff and resources. In order to keep the highest scientific standards, an in-depth investigation is initiated by the responsible editors together with the journal\u2019s editorial office in collaboration with the editorial board, and in accordance with the Committee on Publication Ethics (COPE) guidance. The article will be updated and any necessary corrections made at the conclusion of the investigation process."}
+{"text": "Traditional ice and snow path planning methods still have internal environmental problems in intelligent path planning, such as weak innovation ability, imperfect management, long planning path, unreasonable security structure, and low degree of specialization. Therefore, more and more ice and snow sports lovers are eager to solve this problem. This paper designs a path planning method based on three-dimensional ice and snow model. The path planning method of moving snow and ice based on MNN  algorithm is studied from many aspects. MNN algorithm is used for comprehensive analysis and evaluation. The mobile phone provides data information on key nodes, air resistance, momentum change, ice and snow movement track, and so on. The results show that the ice and snow path planning system based on MNN algorithm designed in this paper has the advantages of high feasibility, high data accuracy, and good prediction effect and can effectively improve the efficiency of ice and snow path planning. According to the survey, the research on ice and snow movement track in sports mainly focuses on the movement type, path planning method, and optimal movement strategy and rarely constructs the change law of movement path process and intelligent algorithm . On the The innovation of this paper lies in the MNN algorithm and ice snow motion path planning algorithm. On this basis, we can make full use of the difference information in the ice and snow movement, carry out multivariate analysis on different types of ice and snow movement data information, combine with MNN algorithm factors, standardize the identification of the path information generated in the process of ice and snow movement, and realize the intelligent planning and correct guidance of ice and snow path according to the characteristics and objectives of ice and snow movement.This paper studies the construction of intelligent path planning guidance system of ice and snow sports, which is mainly divided into four parts. The first chapter introduces the research background and the general arrangement of this chapter. The second chapter introduces the research status of ice and snow sports and path planning factors. In the third chapter, the dynamic tracking and intelligent path planning model of ice and snow movement based on MNN algorithm is constructed. The Laplace factor method is used to construct the ice and snow movement path planning guidance system and related evaluation system. In Chapter 4, the dynamic tracking and path planning model of ice and snow movement constructed in this paper is verified by experiments, and the conclusion is drawn.Since entering the 21st century, there are some problems in the research of ice and snow sports in China, especially in the path planning and intelligent dynamic tracking of ice and snow sports . Based oTo sum up, it can be seen that the current ice and snow sports generally have low degree of intelligence, weak applicability, and many restricted conditions in the path planning, which is the same with the study , 19. On At present, genetic algorithm, neural network algorithm, mutual nearest neighbor algorithm, and MNN  algorithm are widely used in path planning \u201323. The In the research on the optimal solution of the track and path planning of ice and snow sports, in the application process based on MNN algorithm, aiming at the path planning strategy of ice and snow sports, this paper first designs the MNN algorithm based on the influence degree of multidimensional factors. The cloud path location tracking network with strong pertinence is used to formulate the optimal path planning scheme of ice and snow movement and determine the characteristic ice and snow movement trajectory and path planning process. The data processing process of MNN algorithm is shown in In this model of ice and snow sports path planning based on MNN algorithm, an online guidance scheme based on intelligent path planning strategy is constructed by using three characteristic parameters related to ice and snow sports path and trajectory. Through the research on the track collection, speed control, starting point and end point information, and data analysis strategy in the ice and snow movement, the internal relations of the factors in the whole ice and snow movement path planning guidance system are clearly defined, and the processing process is shown in The basic steps of building the intelligent path planning model of ice and snow sports can be divided into three steps.K(s) isIn the first step, we need to find multiple path related optimal detection information with high similarity in morphology and structure from the existing ice and snow motion detection network and then carry out local video tracking to realize the dynamic tracking of the ball in the process of space movement. The tracking function K\u2009\u2032(s) optimized by adding dynamic aggregation factor t iss is the track data of ice and snow movement and t is the dynamic aggregation factor. In this process, three groups of different types of data are analyzed, and the simulation results are shown in The tracking function Q(s) before optimization isThe second step is to reduce the error in the process of path planning and optimal scheme formulation and improve the guidance efficiency of ice and snow movement trajectory and path analysis. In this process, we need to use the discriminant function to judge the planning efficiency. The discriminant function e, the optimized discriminant function Q\u2009\u2032(s) iss is the trajectory data of ice and snow movement; e is the anti-interference factor.After adding anti-interference factor In the third step, according to the difference of position dynamic stability of different types of ice and snow sports, the position of athletes can be updated dynamically:s is the trajectory data of ice and snow movement; r is the dynamic change factor. In this way, after several interactive cycles of two-way gait information, the best strategy data will be obtained according to the data analysis method, and the specific path trajectory information in line with the lowest normal ice and snow movement trajectory will be generated; that is, the data vector value of the normal boundary of an ice and snow movement path position signal and the longitude and latitude coordinates of the known position information will be compared and analyzed. In this way, the information analysis and recording of ice and snow movement track, path scheme, and coordinate longitude and latitude can be realized under the condition of \u201cMNN algorithm.\u201d The simulation results are shown in The location function with dynamic update strategy isP(s) and trajectory analysis function H(s) ares is the track data of ice and snow movement and x is the longitude and latitude information. The ice and snow movement path planning mode based on the longitude and latitude coordinate information of the path can also realize the self storage and cloud computing functions of the data information generated in this process. Therefore, the more the accumulated historical data of ice and snow movement trajectory and path location information, the stronger the self-learning ability and intelligent planning guidance scheme of the system. This adaptive path planning and tracking method can complete the intelligent path planning and error rate control of ice and snow movement with high accuracy. The analytic simulation results of this ice and snow movement path planning model for two different target path planning schemes are shown in In MNN algorithm, the longitude and latitude analysis function E is selected according to the following criteria:s is the trajectory data of ice and snow movement, t is the eigenvalue information, r(s) is the result of the first distribution, and e(s) is the result of the multiple distribution.In the process of reconstructing the trajectory of ice and snow, because different object will produce different deviations in the process of space motion, especially in the real-time dynamic position signal processing of balls, we use MNN algorithm with adaptive characteristics. In order to improve the effect of different ice and snow movement path planning by MNN algorithm, it is necessary to optimize the MNN algorithm, and the optimization process is realized by the partial local method. In the process of distribution, the threshold value M(s) isIn the process of tracking and reconstructing the track of ice and snow movement, MNN algorithm needs to select its motion feature in the process of spatial motion analysis for probability state, that is, the selection of ice and snow motion feature factor based on the whole crowd target, and then detect and analyze according to different path feature functions, whose path feature function M\u2009\u2032(s) iss is the track data of ice and snow movement and t is the eigenvalue information. In the aspect of path planning for ice and snow sports, this model will use the existing ice and snow sports big data and the path planning information database stored in the cloud, combined with the data analysis factor, to analyze the adaptive disturbance of the limit weight value obtained from the optimized MNN algorithm, and then use the MNN algorithm to subdivide specific ice and snow sports information. According to the differences of different types of ice and snow movement paths, the integrity of them is sorted, and then the sorting results are discretized according to different weight indexes, and the path factors related to the optimization strategy are marked, and the marking results are transmitted to the optimal path planning scheme database. The expressions of the standard function B(s) and the discrete weight solving function J(s) of the optimal path planning scheme are as follows:s is the track data of ice and snow movement and t is the eigenvalue information. The simulation results of path selection and the number of scattered points are shown in After adding the tracking condition, the path characteristic function As can be seen from Before the beginning of the experiment, we set up a model of ice and snow trajectory reconstruction and path planning based on the characteristic parameters and path differences. The model centers on the dynamic movement process of ice and snow athletes and takes the differences of different ice and snow trajectories and different path schemes as the core evaluation index. The reconstruction effect and path planning strategy of ice and snow trajectory are evaluated. The experimental process is shown in As can be seen from The stability test results of the experimental results of snow and ice trajectory reconstruction based on MNN algorithm and other path planning methods are shown in It can be seen from Figures Finally, this study takes two similar ice and snow movement path schemes in sports as a group of tracking research objects, and a random ice and snow movement path as the control object. One of the groups is that the ice and snow movement path is known (the ice and snow movement path and other information are known). The other group is that the track of ice and snow movement is unknown . It is found that there is a high similarity in the process of reconstructing the ice and snow trajectory in the two kinds of data, and the error is 1.2% and 2.3%, respectively. In the guidance scheme of ice and snow path planning based on MNN algorithm, the intelligent path planning scheme given by MNN algorithm is in good agreement with the real optimal path planning scheme. Therefore, the research results of this experiment show that the ice and snow movement path planning model based on MNN algorithm combined with the characteristics of ice and snow movement and data reliability, intelligent planning for different types of ice and snow movement path planning scheme, and its high degree of coincidence, in line with the actual application needs. Therefore, the experimental results show that the ice snow path planning method based on MNN algorithm can be applied to the dynamic analysis of ice snow trajectory and the guidance of the optimal path allocation after the game.In recent years, there are many problems in the research of ice and snow sports, such as the inefficient path planning of ice and snow sports, less application scope, and so on. Therefore, the reform of traditional ice and snow sports path planning method is more and more urgent. Based on this, this paper studies the path planning model of ice and snow sports based on MNN algorithm and designs the dynamic tracking method of intelligent path planning of ice and snow sports based on the three-dimensional trajectory model. Through the research of three aspects in the process of ice and snow movement, the ice and snow movement path planning guidance system based on the minimization strategy is constructed. Finally, the MNN algorithm and the optimized iterative data analysis model are used to analyze the characteristics of the screening results and the intelligent path planning process. The experimental results show that the model can make full use of the intelligent path planning strategies of different types of ice and snow sports, achieve the integrity of the intelligent path of ice and snow sports, efficiently carry out the customized analysis of the factors affecting the ice and snow sports path planning, and improve the efficiency of path planning. However, this paper only focuses on the path planning method of ice and snow movement and does not take the directional capture efficiency and the potential impact of error into account. Therefore, the ice and snow movement path planning model has some room for improvement."}
+{"text": "The authors regret that the name of one of the authors (Kenneth T. V. Graham) was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "Subsequently to the publication of the above article, the authors have realized that Oncology Reports for presenting them with the opportunity to publish this Corrigendum, and apologize to the readership of the journal for any inconvenience caused.A corrected version of"}
+{"text": "Motivation and Problem Statement. Thiopental is an anesthetic drug related to the condition of controlling the area of neurological contexts. This study is related to the analysis of effectiveness for the condition of thiopental application on spontaneously hypertensive rats. Methodology. We have evaluated the thiopental induction as the anesthetic agent. The hypertensive rats were selected to administer thiopental in the form of anesthesia. The selection and application of hypertensive strokes are related to the derivation of an inducible model to assess the efficacy for analyzing the ischemic stroke parameters which relate to the human body. We used middle cerebral artery occlusion (MCAO) models related to spontaneous hypertension with the area of examining the complications in ischemic stroke. Results and Conclusion. The study focused on the experimental analysis based on the selection of spontaneously hypertensive rats associated with the incidence of ischemic stroke. Application of thiopental has reported the weak functionality and mechanism on the relaxation of neuronal activity in the case of rat brain. The considered population of the spontaneously hypertensive rats is evaluated based on the condition of effectiveness as well as the duration of the medication effects within the rat brain. Involvement of thiopental in the case of ischemic stroke has provided the area of risk development for high rate of death incidences after occurrence of acute ischemic stroke. A complication in the area of defining neuroprotective actions provides difficulty in drawing an appropriate conclusion of the study. During the condition of ventilation and controlled interventions, thiopental sodium has been incorporated as maintaining the area of intracranial pressure increased among the patients of stroke [Hypertension was not a treatable disease about half a century ago. However, today, it is a prevalent, noncommunicable chronic disease worldwide and could be inhibited by drugs . Patientf stroke . Thiopensystemic arterial blood pressure including the context of thermoregulation. It has been reported that in the case of brain injury, anesthesia is directly involved with the prospects of controlling ischemic stroke, hemorrhagic stroke, pressure, and trauma [Thiopental as an anesthesia is related to the derivation of controlling the condition of the d trauma . AnestheA theory of the application in anesthesia is involved in the condition of controlling the process of relaxing nerves and muscles. According to the unitary theory of anesthesia, a physiological condition in the anesthesia is related to the understanding of specific issues related to the area of controlling the function of nerve cells. Application of the unitary theory has been responsible for defining the area of lipid membrane and their specific functions accumulated within the condition of thiopental sodium.Based on the involvement of thiopental sodium as an anesthesia, a condition of the fluid-solid phase has been determined through the formulation of lipid membrane structural differentiation . In the According to the development of the unitary theory, two different areas of the anesthesia application have been confined such as lipid theory and protein theory. Application of the lipid theory is responsible for defining the involvement of cell membrane controlling approach in the case of excessive pressure. Lipid theory defines that the anesthesia components such as thiopental dissolve within the lipid bilayer, responsible for formulating the management of the alternative physical properties within the nerve cell.Changes in the physiological properties have been developed through the derivation of fluidity development followed by the volume increment within the cell membrane after dissolving the anesthetic components. Lipid theory has suggested the condition of the altered condition in the ion exchange activity associated within the cell membrane. Protein theory related to the anesthesia application and mechanism has reported the condition of volume expansion of the lipid membrane due to the dissolving process of the anesthetic substance. A process of transmission within the synapsis is developed through the correlation of the anesthetic components as well as the protein molecules. Thiopental as an anesthetic component is responsible for altering the application of the ion gating along with the channel of the protein receptors.ascending reticular activating system (ARAS) related to the portion of the cortex and thalamus of the rat brain [According to the development of the theory of neurophysiologic condition in anesthesia, it is related to the area of determining suppressive awareness. Based on the administration of this theory, the neurophysiological area of anesthesia is related to the control and management of the depressive condition within the brain cells. In the case of hypertensive rats, application of thiopental as an anesthetic component acts on the at brain . InvolveIn this research, the condition of ischemic stroke has been considered to evaluate the process of thiopental induction as an anesthetic agent. In the design of the experiment, we have considered through the selection of the population or sample. In this research, we selected hypertensive rats for the area of the ischemic stroke related to the administration of thiopental in the form of anesthesia. According to the requirement of the research, potential hypertensive rats are examined through understanding the neurological complications in the rat brain after the condition of ischemic stroke .The selection and application of the spontaneously hypertensive strokes are related to the derivation of an inducible model for assessing the effectiveness for studying the ischemic stroke parameters related to the human body. The experimental design for understanding the area of thiopental administration can be determined through the variation in the process of sacrificing the selected animals after growing the condition of stroke.Neurological effectiveness of the rat brain has been considered through the implementation of thiopental on the area of ischemic stroke process. Moreover, spontaneous hypertensive rats are applied for the authentic stroke model to understand the area of anesthesia effectiveness on the brain cells of the rat. Middle cerebral artery occlusion (MCAO) models related to the spontaneous hypertensive rats are involved with the area of examining the complications in ischemic stroke .Spontaneously hypertensive rats are considered for the animal model to understand the animal model based on the development of neurological deficits for the condition of developing ischemic stroke. Thiopental administration has been developed through the animal model to understand the functioning of the rat brain. Moreover, the pattern of the ischemic stroke is defined through the neurological complications related to the functioning in the rat brain.In this study, an animal model has been applied for the derivation of the major context for analyzing effectiveness of thiopental associated with the condition in the ischemic stroke. Spontaneously hypertensive rats are considered through the animal model to define the condition of sacrificing state after developing the condition of ischemic stroke. The rat brain function based on the process of the anesthetic component such as thiopental was considered through the process of deriving middle cerebral artery (MCA) and relative condition of common carotid artery (CCA).Administration of thiopental injection based on the anesthetic component was defined through the prospects of applying appropriate animal models to the area of research. The animal model based on the selection of ischemic stroke developing spontaneously hypertensive rats was derived through the area of defining the process of anesthetic activity.In this research, an animal model was selected for the area of considering the pattern of ischemic stroke report after administration of thiopental. Derivation of the neurological parameter as well as the symptoms is correlated to the condition of rat brain function associated with the ischemic stroke. Involvement of the process related to the muscle and nervous system relaxation procedure by thiopental related to the area of the ischemic stroke was defined through the neurological parameters.Rat brain functioning has been determined through the induction of thiopental throughout the pattern of the neurological deficit model for the limb placement context. In the case of the spontaneously hypertensive rats developing ischemic stroke, two factors are determined such as motor functioning of the rat and somatosensory parameters related to the neurological complications.It has been observed that the condition of the volume related to the nerve cell infarction has been considered for understanding the effectiveness for thiopental related to the ischemic stroke condition. Volume infarct derivation is related to one of the major components for understanding the area of muscle relaxation functions of the rat brain affected by ischemic stroke complications . InfarctIn this research, data analysis has been conducted through the implementation of the one-way ANOVA or analysis of variance. Data gathered from the experiment including changes in the infarct volume has been analyzed through the implementation of ANOVA . NeuroloApplication of thiopental as an anesthetic agent has been associated with the process of developing unconsciousness among the patients. The considered population of the spontaneously hypertensive rats is evaluated based on the condition of effectiveness as well as the duration of the medication effects within the rat brain. Duration of the unconsciousness has been analyzed based on the implementation of thiopental as an anesthetic drug. It has been reported that thiopental has the potential to affect the body within 30 seconds. A single dose of the thiopental medicine has the capability to continue with the unconscious condition until 20 minutes to 30 minutes [In the case of spontaneously hypertensive rats selected for the research, thiopental sodium as an anesthetic drug has reported the area of the plasma protein and regulatory interactions to control the brain cells and tissues for relaxation see . ThiopenThe nervous system of the thiopental-injected rats is determined through the relaxation in the signalling and synaptic transmitter for the prolonged duration of the unconsciousness related to the rats. Moreover, in the case of a few of the hypertensive rats, death cases occurred after the induction of thiopental after the condition of ischemic stroke. According to the result of death, events involved with the case of thiopental injection can provide the context of detrimental incidence regarding sodium thiopental incorporation. In the case of ischemic stroke related to the rat brain, effectiveness of thiopental is high in the condition of hypertensive rats.The selected spontaneously hypertensive rats are evaluated through the identification of neurological parameters to understand the thiopental mechanism and action in case of ischemic stroke related to the rat brain. Identification of the neurological parameter has been related to the condition analysis due to the induction of thiopental along with the context of limb placement in the case of hypertensive rats. Incidence of brain ischemia has been considered in the case of understanding neurological parameters related to the administration of thiopental related to the area of controlling ischemic stroke factors.In this case, the best results related to the condition of neurological effectiveness have been developed through testing after 4 weeks of limb placement. Thiopental injection administration condition after 4 days of limb replacement provided the condition of poor neurological deficits related to the effects of the anesthetic components . NeuroloSize of the infarct analysis is related to the condition of defining mortality rate associated with the selected group of spontaneously hypertensive rats examined for ischemic stroke. In the case of ischemic stroke, infarct volume is related to the analysis of the condition for pathological test for the context of clinical deficits and complications. Development of the identification factor for the relative area of infarct volume has been identified through the administration of thiopental and effects for stroke management.According to the involvement of thiopental injection, an enlarged volume of the infarct is located for the hypertensive rats related to the incidence of ischemic stroke. The results of enlarged volume in the infarct are related to the condition of defining relative loss of neuron from the rat brain after the administration of thiopental for ischemic stroke.sodium thiopental, longer effectiveness of neurological and muscle relaxation has been reported for the area of ischemic stroke. Controversial analysis of the long-term effect of the thiopental drug on the condition of ischemic stroke has reported the area of weakness for the hypertensive rats. In this experiment, the situation of sacrificing the lives of selected animals reported that thiopental is related to the high incidence of death cases. Thiopental, as an anesthetic component, is related to the area of the selective mortality rate at a high scale after the condition of ischemic stroke. Rat brain analysis through the ischemic stroke is related to the condition of defining high risk of thiopental application [The experimental report has suggested that thiopental is used in the case of anesthetic treatment, which resulted in a prolonged condition of unconsciousness among the hypertensive rats after ischemic stroke. According to the involvement of this specific drug component lication .Higher effectiveness of the thiopental medicine on the condition of ischemic stroke has resulted in the death cases associated with the area of controlling neurological functions. According to the involvement of thiopental as an anesthetic component among the rats, spontaneously hypertension has been reported in the area of lower rate of performance on rat brain . ThiopenApplication of anesthesia in the case of ischemic stroke management is related to the area of defining endovascular treatment and context of controlling the heart rates including pressure. Relaxing the neuronal activity is related to the evaluation of the anesthetics in postischemic stroke situations. Complexities have been present with the incorporation of thiopental related to the area of ischemic stroke resulting in the failure in acute circulatory functions . Risks oIt has been observed that the patients dealing with acute ischemic stroke and condition of thiopental induction develop a risk of severe health outcomes. Induction of the general anesthesia related to the endovascular stroke condition has been reported in the area of anesthetic component application for controlling the neuroprotective functions of the drug components. Thiopental is related to the area of the lower rate of the neuroprotective functionality among the rat brain .cerebral metabolic rate of oxygen (CMRO2) reduction has been performed. Thiopental has been involved with the less potential for CMRO2 reduction and restriction of neurotransmitters to manage the area of ischemic stroke. A lower rate of the neuroprotective activity as a member of the barbiturate group has developed conflict for the controlling effect of neuronal functions.According to the application of the neuroprotective function by anesthesia, neurotransmitter suppression along with the A severe outcome along with the large volume of the infarct in the case of rat brain has been observed during the application of thiopental . In the A context of the longer period of hypertension among the selected animals has reported a higher risk potential related to the damaged condition of the brain cells . The advThe study focused on the experimental analysis based on the selection of spontaneously hypertensive rats associated with the incidence of ischemic stroke and revealed that effectiveness of thiopental is high in the condition of hypertensive rats. More experiments are still needed to confirm this result."}
+{"text": "Yung Hyun Choi has stated that MinsoLim should be included in the authorship. None of the other authors has responded toemails from the Editor or the Publisher.The Editor-in-Chief is issuing an editorial Expression of Concern to alertreaders that the Committee of Research Integrity of Pusan University has found thatMinso Lim, the fifth author listed on this article"}
+{"text": "Mastery of fire is intimately linked to advances in human civilization, culture and technology. It is also a key component of renewal and regeneration of natural ecosystems. At the same time fire continues to be a threat to lives, property and the environment. Our complex relationship with fire has been the impetus for many innovations in direct and remote sensing of key properties of fires including flame, heat and smoke. This Special Issue on fire and smoke detection and monitoring has curated and collected the latest research on sensors and systems to detect and quantify wildland, structural, and industrial combustion, and the emissions of smoke produced.Public interest surrounds detecting and monitoring fire and smoke behavior for fire protection and suppression in residential and industrial settings, or for the design and test of safer materials and structures. The time lag required to detect smoke in a building fire is a key factor in the likelihood of harm to occupants. Jang and Hwang  carefullThe majority of the papers concentrated on wildland fires. This is likely due to a combination of a large number of concerted research programs and recent advances, combined with increased public interest. The devastation from the recent wildfires in California, Australia, and elsewhere has captured the attention of the public, government officials and funding agencies and highlighted the need to detect and monitor wildfires to protect and preserve life and property. Image-based remote sensing from the air and space across different wavelength regions has revolutionized the monitoring and management of wildfires (for review see ). BarmpoRecent advances in low resource detector technology and the rise in the availability of data from small satellites has seen a surge in innovative detector technologies and in the applications to which such data are put. Dufour and colleagues  present Progress depends on the ability to extract meaningful information from the sensor systems, and many papers focused on processing of the sensor data to extract meaningful fire characteristics. At the experimental level, Dickson et al.  providedProcessing of sensor data and classification of such data with limited resources was considered by several papers. Ifimov and colleagues  were conThis Special Issue presents a unique cross section of current research priorities related to fire and smoke sensing in the scientific community. Although far from a complete survey, the articles presented demonstrate a growing interest in the use of remote sensing for wildfire research and monitoring, and the pursuit of new technologies to broaden the potential of this field. Notably, there is a strong interest in processing techniques for extracting increasingly complex products from existing data types. However, the use of direct measurement sensors and the careful analysis of the data they produce continues to provide new insights into wildfire dynamics and human safety in domestic settings. It is the view of the guest editors that this is an accurate reflection of the present focus of our field, and that this Special Issue is a suitable introduction to the topic of Sensors for Fire and Smoke Monitoring."}
+{"text": "The authors regret that there was an error in the affiliations of authors Tadeusz Uhl and Krzysztof Grabowski in the original article. The correct list of affiliations is given in this document.y-axis should read mN rather than N. The correct version of the figure is given here. The results and conclusions presented in the article are unaffected by this change.In addition, there was an error in the axis labels for Fig. 8a. The units of the The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "This Retraction follows an Expression of Concern relating to this article previously published by Portland Press.Bioscience Reports at the request of the Editor-in-Chief and the Editorial Board following receipt of a notification from a reader, alerting the Editorial Board to duplications in Figure 5, which also overlap with images published in Journal of Cellular Biochemistry (10.1002/jcb.26763) and in Bioscience Reports (10.1042/bsr20160542).This article is being retracted from The authors have been contacted in regards to the retraction, and have not responded to the Journal's queries and the concerns raised. Given the extent of the issues raised, the Editorial Board stand by the decision to retract the article."}
+{"text": "Subsequently to the publication of the above paper, the authors realized that the layouts of Consequently, the correctly organized versions of"}
+{"text": "The authors of Young et al. (2020)An error in the SAS code used has led to calculating incorrect marginal odds ratios in the article.On page 7 of the Supporting Information , the correct SAS code used to calculate a marginal odds ratio is:This resulted in errors in the calculation of the marginal odds ratios in Table 2 and in the Supporting Information. The correct odds ratios are provided below:On page 3 of the Supporting Information, the correct odds ratio is 0.67 .The authors apologize for this error and state that the conclusions of their study are not affected."}
+{"text": "This Retraction follows an Expression of Concern relating to this article previously published by Portland Press.Bioscience Reports at the request of the Editor-in-Chief and the Editorial Board following receipt of a notification from a reader, alerting the Editorial Board to the GAPDH Western blots in Figure 5B which are duplicated in several other publications.This article is being retracted from The authors have been contacted in regards to the retraction, and have not responded to the Journal's queries and the concerns raised. Given the extent of the issues raised, the Editorial Board stand by the decision to retract the article."}
+{"text": "Bioscience Reports at the request of the Editor-in-Chief and the Editorial Board following receipt of a notification from a reader, alerting the Editorial Board to the GAPDH Western blots in Figure 7C which are duplicated in several other publications by different authors. In addition, the Figure 4A NC panel is duplicated in another publication by different authors.This article is being retracted from The authors have been contacted in regards to the Retraction, and have not responded to the Journal's queries and the concerns raised. Given the extent of the issues raised, the Editorial Board stand by the decision to retract the article"}
+{"text": "This Retraction follows an Expression of Concern relating to this article previously published by Portland Press.Bioscience Reports at the request of the Editor-in-Chief and the Editorial Board following receipt of a notification from a reader, alerting the Editorial Board to duplicated data in Figure 4A which appears in another publication by different authors.This article is being retracted from The authors have been contacted in regards to the Retraction, and have not responded to the Journal's queries and the concerns raised. Given the extent of the issues raised, the Editorial Board stand by the decision to retract the article."}
+{"text": "Bioscience Reports at the request of the authors. The authors have been unable to replicate the results showing the beneficial effect of piceatannol on oxLDL-induced lipid storage in macrophages, and wish to retract the article. The Editor-in-Chief and Editorial Board agree with the Retraction.This article is being retracted from"}
+{"text": "Bioscience Reports at the request of the authors following receipt of a notification from a reader, alerting the authors and Editorial Office to duplications in the Western blots of Figure 4D and 5B which have been published in several other publications by different authors.This article is being retracted from The authors have been unable to replicate the results and wish to retract the article. The Editor-in-Chief and Editorial Board agree with the Retraction."}
+{"text": "Following the publication of the original article , the autFundingPHRC EDUQ CPNE paid for the language editing service, and contributed in writing the manuscript.The original article  has been"}
+{"text": "Proteobacteria and Bacteroidetes in all locations.The Taehwa River Estuary is one of the largest enclosed bays in east Korea. In order to understand the environment of the Taehwa River Estuary, the microbial diversity in the sediment of the estuary was investigated through 16S rRNA gene sequencing. The predominant phyla were  Proteobacteria and Bacteroidetes.The Taehwa River Estuary is one of the largest enclosed bays in east Korea. In order to understand the environment of the Taehwa River Estuary, the microbial diversity in the sediment of the estuary was investigated through 16S rRNA gene sequencing. The predominant phyla in all locations were"}
+{"text": "Smart service provision systems can assist in the management of cargo transportation. The development of these systems faces a number of issues that relate to the analysis of numerous factors, which are influenced by the properties of such complex and dynamic systems. The aim of this research was the development of an adaptable smart service provision system that is able to recognize a wide spectrum of contextual information, which is obtained from different services and heterogeneous devices of wireless sensor networks (WSNs). To ensure that the smart service provision system can assist with the analysis of specific cases of unforeseen and unwanted situations during the cargo transportation process, the system must have additional adaptability. To address the adequate provision of contextual data, we examined the problems of multi-dimensional definitions of contextual data and the choice of appropriate artificial intelligence (AI) methods for recognition of contextual information. The objectives relate to prioritizing potential service provision by ensuring the optimal quality of data supply channels and avoiding the flooding of wireless communication channels. The proposed methodology is based on methods of smart system architecture development that integrate the identification of context-aware data, conceptual structures of data warehouses, and algorithms for the recognition of transportation situations based on AI methods. Experimental research is outlined to illustrate the algorithmic analysis of the prototype system using an appropriate simulation environment.  Researchers are currently concerned with the problem of integrating smart components into the development of systems that can be applied to the management of cargo transportation processes ,2. ImporTo recognize data provided by wireless sensor networks (WSNs), further detailed investigations are necessary for the development of smart service provision systems ,6. The dEfforts have been concentrated on the development of the Single Digital Gateway (SDG) , by whicSupport of efforts for the implementation of the free movement of data and the protection of personal data . Strict New approaches to the development of cybersecurity as an objective of the Information Systems Directive ,14. StroThe European Union\u2019s (EU) planned digitization activities promise to help in the development of this type of infrastructure ,8. The NThese innovations influence opportunities for the development of infrastructure for intelligent service provision. The most important requirement for the development of ITSs is that these systems do not distract drivers during the transportation process. The transport management system should provide the required services to the users in the right place, at the right time. Furthermore, it should be appropriately adapted to the needs of the users, by making only the interventions that are necessary for the safety of the transportation process. The objective of this research was to develop a smart service provision system for cargo transportation management. The developed system aims to meet the requirements of usefulness, adaptability, safety, and performance optimality by creating a working regime that does not flood wireless communication channels. Our objectives are related to the stages of the creation of the smart service delivery system with the functions of monitoring and recognizing contextual information. Context-aware information must respond to the main needs of cargo transportation processes. The platform for the developed smart service provision system is based on the infrastructure of wireless sensor networks (WSNs). The recognition of the obtained information was implemented in the stages of transportation and enabled sustainable cargo transportation management. The proposed approach is based on construction methods for the development of a component-based architecture of a smart adaptive service delivery system (IASDS). The results obtained in previous studies of the description of the ICT infrastructure of multi-modal transport management are also relevant to the current work ,7,8. It A formalized understanding of the current and previous developments in transportation processes is necessary to increase the autonomy of user\u2013vehicle interactions. AI-based methods have been applied to the forecasting of possible future situations. The ICT infrastructure includes a variety of new kinds of wireless communication channels and WSNs ,6,7,8. TThe structure of this article is as follows: The development of new kinds of services for transportation support is related to the development of ITSs and the spread in the implementation of the advanced functions of ICT ,15. New Vehicle ad-hoc networks (VANETs)  can be dPhysical sensors for environment monitoring;Sensors for monitoring the working regimes of vehicles;Human health monitoring sensors. The integration of heterogeneous types of sensors can be included in the monitoring systems of the cargo transportation process. Our focus is on the following:The integration of sensors into the development of adapters for inclusion in smart service provision subsystems using the Geographical Positioning System (GPS) and geographical information system (GIS) has become popular. Sensors in the infrastructure of RSUs assist in the monitoring of transport and traffic information, provision of hazard warnings, recording interactions with other cars, e-calls for warning and information provision, etc. In the research of the development of advanced systems, the authors have offered several solutions for the development of adaptive service systems ,7,8. The problems related to gathering information from the environment and dissemination in dynamic environments are presented in . MonitorThe concept of \u201ccontext\u201d is very broad. We analyzed these proposals of contextual data definitions according to the possibilities of integrating them into our system. The presentation of the broad spectrum of multi-dimensional aspects of contextual information with the intention of representing them in the smart service provision system allows the scope of recognition of this information to be extended.V2V communication service provision is subject to a number of problems, i.e., the assessment of the quality of the gathered information and flooding of wireless channels ,33,34,35a set of parameters that reflects the quality requirements and properties of context data\u201d  as follows: 1\u2014when the message is from Vehicle to Manager (V2M) communication; 2\u2014when the message is in the local environment of the vehicle (INV); 3\u2014when the message is from Vehicle to Infrastructure (V2I) communication; 4\u2014when the message is from Vehicle to Vehicle (V2V). In addition, a set of parameters jCr expresses the coordinates at which the data message was generated at the real-time point it; these values are expressed as jti =cr {jti,latitude; crjti,longitudecr}.The parameter iPr : = 3, it means that the message tjim priority at the moment tj is critical and it must be sent immediately to the driver and stored in the corresponding DW;If the assignment for the message is iPr : = 2, it means that the message tjim at the moment tj has a medium priority;If the assignment for the message is iPr : = 1, it means that the message tjim at the moment tj is not important and can be rejected.If the assignment of the message is The message priority can be calculated by the formula The importance of the message can be assigned within the set range , where 1 indicates a safety-related message and 0 indicates a comfort/information message. MT is the difference between the current time moment and the time moment when the message was created.OM is used for storing the context utility values. The items olnd of the matrix OM indicate the importance of the data, where the l index indicates the data from a message (m) provided for the vehicle n (v) (4), where v represents vehicle.To reduce the number of data transitions, the structure and algorithms were developed to help achieve better conditions in the provision of selected messages. The matrix OM are calculated according to Formula (5), which can be expressed as the Cartesian product:jExc is a parameter of a special non-confidential data set, for which assignments are chosen from the range , indicating the data exchange area ; n indicates the number of cooperating cars in the cluster; and jZ is the communication channel quality prediction indicator that can be calculated based on Formula (6):tC is the collision parameter calculated by the formula: The predictive usefulness of a contextual data message is weighted by a function that assigns a value tD is a packet of rejection parameters, which can be calculated according to Tr is the bandwidth parameter calculated according to the formula: cM); their index l expresses the values of the data of the messages (jm) for the recipient entities (ir) by presenting such a matrix as (7):The contextual data for exchange with a hybrid VANET cloud subsystem contain the context utility values. These are stored in the structure by representing the matrix  expressed as the Cartesian product:The prototype of IASDS was tested in a series of experiments using simulation methods and packages for these purposes. One of these allowed the analysis of the adaptability of the data aggregation via an evaluation of the adaptability of the provided algorithms. The algorithms (described in An intuitive user interface was used that eliminated the need for complex scriptwriting. The benefit of NCTUns and its later version (Estinet)  is that According to the purposes of the experimental research, a number of scenarios of the simulation process were carried out. The aim of one scenario was to simulate the network model for the expression of processes that created a series of messages in which data were transmitted from the vehicles to the hybrid VANET cloud server, by storing appropriate information in adequate structures of the repositories of the data warehouse (DW). The network was related with the interoperable server and the DW. A number of 802.11p RSU units were implemented in the simulation laboratory and, during this scenario, we simulated from one to ten 802.11p OBUs. For this scenario, we obtained the statistical data relating to the parameters of transmission, the technical parameters of messages , and othTo complete the algorithms  used to Another simulation scenario was used to analyze the data flows by transferring them in two directions: from the vehicle to the DW server and from the DW server to the vehicle. The types of sensors applied in this experimental scenario are presented in The duration of the data transfer cycles started at 60 s. The data transfer speed was chosen to be 27 Mb per second and the size of the packet was approximately 1000 MB. The experiment included the algorithm for defining the priority assignments of service providers described in Excj, and the dynamics of the obtained values of normalized function Zj, are shown in jTy values are shown in the same figure for comparison purposes. Another group of experiments was undertaken with the aim of identifying the potential for application of the algorithms provided in These results are not accurate and only have demonstrative ability. Nonetheless, they show the possibility of simulating the performance of changes in the service provision process by assessing the accumulated values over the short experimental period. The changes in the values depend on the parameters of the channel quality, among others. To include the estimation of situations involving collisions, and the required bandwidth of the channels, it is necessary to carry out additional experiments with a number of dropped packets. The prediction function can help to identify the current situation by evaluating past events, and be used to potentially predict the future situation, at the stages throughout the duration of the trip. The algorithms for selecting the correct direction at possible points (nodes) of multi-modal transportation were presented in our previous work . The processes of cargo transportation must be equipped with new ICTs and methods of communication using wireless sensor networks (WSNs), by implementing the platform of IoT technology. The development of adaptable smart service provision systems considered the complexity of these processes. The authors devised an approach for the integration of heterogenic sources of monitoring data during cargo transportation processes, aimed at the provision of the necessary information by analyzing the methods of context-aware information recognition and scheduling. Algorithms were developed that express and apply the methodology of these methods. A review of related research was undertaken to help provide an understanding of the manner in which this data can be applied for context-aware information recognition. It is intended that the presented approach can be used to develop an adaptable system for cargo transportation, with extended properties for the integration of context-aware services. The prioritization methods are included in the algorithms of service provision, which enable the restriction of unnecessary information. The architectural structure of the smart service provision system was developed based on WSNs and communication channels, thus enabling an improvement in the creation of delivery systems of smart service provision. The development of adaptable smart service provision systems considered the complexity of such processes. The online decision-making processes involve the assessment of all infrastructure components that are required for monitoring cargo transportation, and ensure the implementation of the necessary equipment. Our future research investigations will address the more complex scenarios of accident event recognition and the prediction of unexpected situations. In the future, the classification of infrastructure components according to different types of wireless technology, and the transfer of context-oriented data for specific smart service designs, will be implemented to reduce the number of accidents and unsafe situations.The described approach is based on the extensible infrastructure of the required components and multi-dimensional methods for knowledge representation. The aim was the development of an intelligent smart system for service provision with the ability to recognize context-aware information. The authors integrated a wide spectrum of contextual data sources into the system development process; these data can be gathered from WSNs and other infrastructural ICT devices. The review of the literature highlights the investigations into these context-aware processes, the systems development required to realize the important context-aware recognition purposes, and the influences on the broader understanding of contextual information. The proposed structural architecture of the intelligent service delivery systems is unique due to the algorithms created for the identification of situations via the understanding of their context. In addition, the presented approach formulated a basis for the development of adaptable software methods, which are key to the automation of the management of these situations. To address the challenges related to smart service provision, the proposed intelligent adaptive approach allows the use of environmental contextual information, including the vehicle dynamics, and information transmission from other vehicles. By considering the wireless network conditions and the evaluations of the effectiveness of wireless communication channels, data transmission restriction methods were applied. These methods aim to assist the service restriction process by avoiding possible unexpected situations according to the capacities of the wireless communication channels. The proposed IASDS prototype implemented the automotive communication network infrastructure. The IASDS can help reduce the amount of unusable contextual information, which must be transmitted in automotive communication networks, without the loss of contextual data quality, using network filtering and aggregation techniques. The authors provided the classification of sensors by type, which was applied to the recognition of specific situations. The results of this approach identified the effectiveness of the methods that were developed to collect data.The study has some limitations that could be researched in future studies. The typology of unplanned events was not presented. The authors would also like to investigate the number of road accidents that involve heavy vehicles. Other potential research topics include tire damage, unexpected vehicle repair needs, policy stops, traffic jams at customs offices, and route mistakes.The proposed smart service provision system will be helpful in the analysis of the heterogeneity of services, the construction of algorithms for service provision priorities, and the enhancement of the potential of intelligent transport, based on the recognition capabilities of context-aware information in the transportation process."}
+{"text": "The journal and Chief Editors retract the 09 April 2021 article cited above.Following publication, concerns were raised regarding the validity of the data in the article. The authors failed to provide the raw data or a satisfactory explanation during the investigation, which was conducted in accordance with Frontiers\u2019 policies. Given the concerns, and the lack of raw data, the editors no longer have confidence in the findings presented in the article.This retraction was approved by the Chief Editors of Frontiers in Oncology and the Chief Executive Editor of Frontiers. The authors have not responded to any correspondence regarding the retraction."}
+{"text": "Bioscience Reports at the request of the authors following receipt of a notification from a reader, alerting the authors to the duplication of Figure 2C, which appears in serval other publications by different authors.This article is being retracted from The authors wish to retract the article. The Editor-in-Chief and Editorial Board agree with the Retraction."}
+{"text": "Bioscience Reports at the request of the authors, as the results of the repeated experiments did not show the statistical differences seen in the original study. Hence, the authors of this study feel the results of this paper are unreliable.This article is being retracted from The Editor-in-Chief and Editorial Board agree with the Retraction."}
+{"text": "Objective: Evaluation of the lag timelines for the launch of innovative drugs to the Russian market and pharmacoeconomic factors they can depend on. Methods: To complete the investigation, we used information about drug products, namely, dates of submission and approval, and pharmacological groups recovered from national registers and official databases. Results: Due to impacts of market factors and imperfection of the state regulation, original drugs developed abroad enter the Russian market a few years after their registration in the United States of America, the European Union, and Japan. The average time from the moment of initial approval of a drug in the aforementioned countries and jurisdictions to the moment of registration in Russia is 4 years and 8 months, with a median value of 2.5 years. It has been shown that half of this term is spent on the performance of the procedures of the expertise of the drug registration dossier in the Russian Federation. Conclusion: To attain the goal of adequate supplies to the population of the Russian Federation of the most up-to-date, high quality, safe, and efficacious medications, apart from the support of national originators of innovative drugs, we are required to upgrade the existing system of original drug registration. Improvement should be primary focused on the drugs already approved by the leading national regulatory authorities in order to ensure innovative medicine access for Russian patients. Implementation of innovative methods of prophylaxis, diagnostics, and disease treatment is one of the key factors of a national healthcare system\u2019s development in any country. Some innovative drugs promise the treatment of illnesses or conditions considered incurable in the past or capable to improve efficacy and safety of currently available therapeutic patterns. The effective drug regulatory system should be designed for the market launch of new medications and also should be focused on the increase of accessibility of innovative drugs with clinically proven efficacy. The issue of innovative drug marketing lag has utmost urgency in emerging markets, where the prevailing share of the original drugs are developed by foreign companies. These drugs have already achieved approval in other jurisdictions with bigger markets and better pharmaceutical regulation. The group of such reference jurisdictions includes countries that are the founding regulatory members of the ICH , namely, the USA, the EU, and Japan. As an example of an emerging market, Russia is considered in this article, making a specific emphasis on innovative drugs approved for the sales  in the Russian Federation over the past 10 years.The drug registration procedure in Russia is, in general, similar to the processes of drug approval in the United States and Japan, as well as marketing authorization in the European Union. In this paper, we will refer to all these processes by the single term \u201cregistration\u201d. Applicant submits the drug dossier in the common technical document (CTD) format to the Russian Ministry of Health. Further, the application dossier is assessed in the Scientific Center of Expertise of Ministry of Health. The assessment process includes expertise of the quality of the medicine, as well as the expertise of the \u201cbenefit\u2013risk\u201d ratio. The Ministry of Health makes a decision on the registration of the medicine or on the refusal of registration on the basis of the results of the examination. Since 2021, the registration process for pharmaceuticals in the Russian Federation should be carried out in accordance with the regulations of the Eurasian Economic Union, which have not fundamentally changed the registration procedure for original drugs. Therefore, the problems discussed in this study remain relevant today.To complete the investigation, we used information about drug products\u2014dates of submission and approval, and pharmacological groups recovered from\u2212http://grls.rosminzdrav.ru/Default.aspx, accessed on 3 March 2021).the State Register of Medicines of the Russian Federation (SRM) .official drug database of the Food and Drug Administration (Drugs@FDA) .European Medicines Agency Register of authorized medicines .PMDA (Japan) Register of Review Reports: Drugs .We used information about approved drug maximum costs recovered from the State Register of Drugs Maximum Sell Prices of the Russian Federation , as well as on data taken from the official websites of pharmaceutical regulatory authorities of the USA, the EU, and Japan.We found that 16% of 324 drugs with novel active components registered in Russia in the last decade (2010\u20132019) have never been approved for use later on in any country worldwide, except for a few members of the Commonwealth of Independent States (CIS) (because of common regulatory principles in Russia and CIS countries), whereas, at the same time, 22% of drugs have not been approved for use in ICH countries  see  below.It should be pointed out, however, that the majority (over 78%) of innovative drugs registered in Russia have also been approved for use in at least in one of ICH countries by the time of registration. The delay was one or more years. The share of original drugs registered in Russia later than such medications have been approved in the EU is 97.8%, later than the USA at 93.6% and Japan at 67.6%.A relatively higher share of drugs registered in the Russian Federation earlier than in Japan is explainable by the mandatory requirement set forth by PMDA national regulatory authority . To be registered in Japan, the drug should go through full-scale clinical studies with participation of ethnic Japanese people. This regulatory requirement is based on significant pharmacogenetic differences of the Japanese nation from other ethnical groups, along with the comparative uniformity of the ethnic composition of the Japanese population.\u00ae Respimat\u00ae  and Gilenia\u00ae (medicine designed for multiple sclerosis therapy) have been registered in the Russian Federation prior to approval in ICH countries, 1.5 years and 1 month earlier for the two drugs, respectively. Average time from the moment of initial registration of a drug in one of ICH countries to the moment of registration in Russia constitutes 1713 days or about 4 years and 8 months. However, the median value is considerably less, just 938 days or 2.5 years. The time distribution is skewed : Striverdis skewed , with soIt is important to take into account that analyzed parameter standing for the time passed before drug registration in the Russian Federation is first and foremost defined by two factors: applicant\u2019s motivation to the product launch in the Russian market and duration/complexity of the process of expertise and registration  of innovative drugs in Russia. Let us consider changes in the average time from the moment of the first registration of drugs in the territory of an ICH country to the moment of registration in Russia with year-wise arrangement in the period from 2010 to 2019 see  below.The figure above shows the trend towards reduction of the median value, which means gradual launch to the Russian pharmaceutical market of drugs being more and more \u201cfresh\u201d from the viewpoint of the international pharmaceutical market. However, starting from 2014, the progress to this matter has experienced considerable slowdown, which could be related to the chill in ties between the Russian Federation and the EU/USA, as well as to contemplation of the draft legislation on the subject of compulsory licensing with regards to holders of rights to original drugs registered in the Russian Federation.It would also be expedient to analyze the impacts of the drugs\u2019 properties, such as pharmacological activity, cost, and number of potential consumers on the time passed from the moment of registration in ICH countries to the moment of registration in Russia.To compare registration time of medications with different pharmacological activity, we selected the ATC groups reviewed earlier. Average and median values for the times from registration in ICH countries to registration in Russia that apply to the drugs pertinent to various pharmacological groups are shown in Data in the table above show that the fastest track (in less than 2 years\u2019 time) to the Russian market from ICH countries is covered by medications used to treat diabetes mellitus, as well as by drugs meant for treatment of respiratory system disorders, such as bronchial asthma and chronic obstructive lung disease (COLD), in the first place. The runner-up title is taken by antineoplastic drugs and medicines used for treatment of human immunodeficiency virus (HIV) and hepatitis B/C; these drugs are registered in about 2 years following registration in ICH countries. The longest time is spent by Russian patients in waiting for innovative drugs intended for treatment of musculoskeletal system disorders, dermal diseases, and sensory organs disorders. It is worth pointing out that drugs with the shortest queue for registration are characterized with the same common feature, as they potentially can be indicated to a bigger number of patients. Each of the diseases mentioned above\u2014diabetes mellitus; bronchial asthma; and neoplasms of different localizations, HIV, and viral hepatitis\u2014affect hundreds of thousands of people in the Russian Federation. Moreover, drugs used for treatment of such conditions are generally indicated for the individual\u2019s lifetime, thus resulting in overall cost of the therapy course reaching the level of several tens of thousands (and more often than not hitting hundreds of thousands) of USD. The hypothesis on the relationship between the drug cost and time required for its registration in the Russian Federation (versus registration in ICH countries) could be checked through comparison of registered prices for innovative drugs included in the list of vital and essential drugs (VED). Of 324 original drugs reviewed, the VED list has incorporated 104 (32.1%) items, standing for just under one-third. p \u2264 0.05).Average time from approval in ICH countries to registration in the Russian Federation required for 10% of the most expensive drugs (951 days) was found to be over twofold less than the time required for registration of 10% of the cheapest medicines (2129 days); the difference is statistically significant  along with limitations applicable to the contents of submitted documents .At registration stage  the originator is supposed to provide the drug registration dossier, which should contain, apart from administrative documents, relevant information about results of preclinical and clinical development phases, along with the methods used for the drug quality control. Before submission of the drug master file to the regulatory authorities of the Russian Federation, all documents included to the dossier should be translated into the Russian language . FinanciExpenses of innovative drug applicants for payment of fees and duties related to marketing authorization issuance and performance of relevant experts\u2019 examinations are minimal in the Russian Federation  . It is eAnother administrative barrier for foreign applicants deals with the need of inspection of foreign manufacturer\u2019s production site by the competent federal body of executive power with the purpose to identify and confirm compliance with the rules of good manufacturing practice . As of tThe need to modify the structure and composition of registration dossier to submit to the Russian registration authority  tends to be minimal, as in pursuance of the last version of Federal Law FZ-61, such a dossier is delivered in the form of Common Technical Document (CTD) adopted in ICH countries. Generally, requirements set forth for the design and scope of conducted preclinical trials and clinical studies have been harmonized. A vital role in the process of harmonization of Russian and international requirements to the registration dossier is performed by integration of the pharmaceutical market of the Russian Federation to the common market of Eurasian Economic Union (EAEU). In the framework of EAEU normative documents\u2019 development, members of the ad hoc committee of Eurasian Economic Commission endeavored to approximate as much as practical the requirements for quality, efficacy, and safety of drugs in the EAEU with relevant requirements existing in the EU . Howeverin conformity with the provisions of international treaties and conventions where the Russian Federation is signatory and/or on the basis of reciprocity principle, parties should recognize and accept results of clinical studies of medicinal products for human use conducted beyond the territory of the Russian Federation\u201d. However, such treaties have never been concluded, the reciprocity principle has not been implemented, and in fact this legal norm is not applied.For instance, entire chapters of Russian guidelines and Articles of Federal Law FZ-61 contravene legislation in effect in the EAEU that permits the acceptance of findings of clinical studies conducted in accordance with the rules of good clinical practice and provisions of the Guideline for Ethnic Factors Evaluation. At the same time, any and all drugs proposed for registration in the Russian Federation, except for orphan drugs , must be clinically studied in the territory of the Russian Federation . According to part 5 of Article 3 of FZ-61 \u201cCompliance with the requirement to carry out clinical studies of new drugs in the territory of the Russian Federation implies considerable financial expenses and time inputs on the part of the applicant. According to the experts, this issue may present a fundamental problem for a drug launch to the Russian market . On the A possible argument in support of the requirements set forth for conducting of local clinical studies encompasses compliance with the rules of good clinical practice (GCP), and on the whole, securing plausibility of submitted data on the basis of the clinical study results. It is much easier for the regulatory authority to monitor clinical studies performed locally in the Russian Federation than anywhere abroad. However, at the present moment, there is no regulatory legal mechanism stipulating for revocation of currently valid or for refusal to issue a new marketing authorization for a drug in the situation of detecting unreliable or false data included in the registration dossier . At any rate, there are no sufficient grounds to assume more rigorous implementation of controls over GCP requirement observance in the Russian Federation, compared to the USA and the EU.www.ClinicalTrials.gov accessed on 23 May 2021, Russian clinical facilities are being actively enrolled by major pharmaceutical companies as one of the bases in the scope of multicenter international clinical studies performance, even prior to the first approval for use of drugs in the USA or the EU. Lower cost of conducting clinical studies combined with a higher level of education of the investigators and tremendous interest of physicians and patients make Russia a very attractive site for clinical study performance [Another positive aspect of imperative conducting of innovative drug clinical studies in the Russian Federation covers the option for some patients to receive innovative drugs on a free-of-charge basis, as well as the opportunity for the healthcare professionals to observe advanced methods of treatment. According to data presented at formance .To assess the relationship between delay in drug registration in Russia and lack of applicants\u2019 motivation, as well as to estimate such a relation with existing regulatory legal barriers, we would be expedient to collate the date of registration of the reference number assigned to application for original drug registration  and the date of registration dossier submittal by the applicant in the Russian Federation with dates of registration of the drug concerned in ICH countries and in the Russian Federation. Analysis is provided in It has been shown that with respect to the majority of innovative drugs, duration of registration procedures in Russia exceeds half of the total drug lag time. Therefore, introduction of special programs enabling accelerated registration for essential original drugs including those approved for use in the USA, the EU, and Japan may potentially lead to more than twofold reduction of the time period Russian patients need to spend in waiting for innovative drugs. As an example, one could consider similar programs for accelerated registration of innovative drugs implemented in the USA, the EU, and Japan  refer t below.\u201cthe original drug registered in a country with the level of requirements to the pharmaceutical market regulation not inferior comparing to the level established in the territory of EAEU\u201d. Obviously, ICH countries should be referred to as such non-inferior states in the first place. In view of this, after successful accomplishment of the expertise of approval for use, a generic drug will be registered in the EAEU, but the original drug used as the basis of comparison for the generic drug registration will necessitate fulfillment of a comprehensive experts\u2019 examination to enable registration in the territory of Eurasian Economic Union [Today, EAEU legislation has a legal provision setting the option for registration of a generic drug in the territory of the union on the basis of comparison with ic Union .It should be emphasized, however, that implementation of the programs designed for special registration of innovative drugs must be preceded with transparency improvement of the processes of expertise and registration. Lack of publications of expert reports and absence of public discussion of the decisions taken in regard to registration or denial of registration of drugs produce an extremely adverse effect on the attractiveness of the Russian pharmaceutical market for both foreign and domestic originators, manufacturers, and holders of rights to innovative drugs. Integration of clear game rules and compliance with provisions of international legislation applicable in the field of protection of intellectual property rights stand for the key prerequisites for success in increasing affordability and expansion of the range of innovative drugs in Russia. Significant steps in this direction have been taken in the scope of development of legal instruments that regulate the pharmaceutical market of the EAEU. However, it is required that relevant changes to the national legislation be introduced to ensure harmonization with the international rules and standards.At present, drug provision for the population of the Russian Federation is secured to a significant extent through involvement of national pharmaceutical companies. In this regard, it should be pointed out, however, that overwhelming majority of the domestic medications stand for reproduced (generic) drugs, being replications of foreign original formulations. To attain the goal of adequate supplies to the population of the Russian Federation of most up-to-date, high quality, safe, and efficacious medications, apart from support of national originators of innovative drugs, we must upgrade the existing system of original drug registration. Improvement should be primary focused on the drugs already approved by the leading national regulatory authorities in order to ensure acceleration of their launch to the civil circulation in the territory of Russia.Due to impacts of market factors and imperfection of the state regulation, original drugs developed in foreign countries enter the Russian market a few years after their registration in the USA, the EU, and Japan. The average time from the moment of initial approval of a drug in ICH countries to the moment of registration in Russia is 4 years and 8 months, with a median value of 2.5 years. It has been shown that half of this term is spent in performance of the procedures of the drug registration and expertise in the Russian Federation.Analysis of local experience in the field of original drug registration over the last 10 years allows us to suggest the measures described above, which are aimed at the improvement of the policy currently pursued by the regulatory authority in this area. It should be emphasized that improvement of national legislation in the field of regulation of original drug registration is by no means the only prerequisite to make the quality of drug provision better. It is not enough to register an innovative drug; from that moment onwards, it is required that its affordability to patients is ensured and that mechanisms are developed to prevent emergence of the drug\u2019s shortfall."}
+{"text": "Following the publication of this article, the authors have re-examined their raw data and realized that the data of each group in A corrected version of"}
+{"text": "Molecular Medicine Reports for allowing them the opportunity to publish this corrigendum, and apologize to the readership of the Journal and to the funding body in question for any inconvenience caused.The authors regret their oversight in providing this incorrect information in the Funding section of their paper. They thank the Editor of"}
+{"text": "The authors were asked for an explanation to account for these concerns, but the Editorial Office never received any reply. The Editor regrets any inconvenience that has been caused to the readership of the Journal.After having conducted an independent investigation in the Editorial Office, the Editor of"}
+{"text": "Furthermore, Fig. 3 contained data that bore striking similarities to data published in Fig. 6 in another paper published in Molecular Medicine Reports has determined that the above paper should be retracted from the Journal on account of a lack of confidence concerning the originality and the authenticity of the data. The authors were asked for an explanation to account for these concerns, but the Editorial Office never received any reply. The Editor regrets any inconvenience that has been caused to the readership of the Journal.After having conducted an independent investigation in the Editorial Office, the Editor of"}
+{"text": "In this framework, the General Director of the World Health Organization (WHO) was asked to develop a global strategy to address oral diseases as part of an action plan to be executed in 2023 with the best interventions in the fight against these diseases that affect more than 3.5 billion people.The 74. In this sense, the member states of the WHO have a difficult mission to achieve in terms of guaranteeing access to dental services, which have been seriously affected by the COVID-19 pandemic due to the collapse of health services, the restriction of oral care to urgencies and emergencies, and fear of contagion by the population. This complex scenario may have affected low- and middle-income countries to a greater extent, increasing inequalities in access to oral health services within them. This is especially important in Peru, which is one of the countries hardest hit by the pandemic.The resolution on oral health recommends a change in dental care from the traditional curative approach to one that is preventive and emphasizes the need for timely, comprehensive, and inclusive dental care within the primary health care system, in light of the great inequalities present in the marginalized and low-income populations, especially in low- and middle-income countries in children under 12 years of age in Peru based on the Demographic and Family Health Surveys from 2014 to 2020. The prevalence of use of dental services in 2014 in this population was 27.6%, while in 2020, it was 19.6%. Here, we report the prevalence of use of dental services in the last six months according to the quintile of wealth index  The neglect of oral diseases and even more of the promotion and prevention of oral health through the use of dental services can have adverse consequences on population health and the economy of the countries. In this sense, we believe that the incorporation of oral health into the WHO agenda is timely; however, the figures on the use of dental services before and after the pandemic demonstrate that we cannot wait until 2023 to take action. For this reason, the WHO and the member states must prioritize the urgent establishment of strategic plans for the prevention and promotion of oral health with emphasis on increasing the use of this essential health service and to mitigate the impact of the pandemic in the population oral health. Some of the measures that could be taken into account include 1) Enhancement of infection and control measures in oral health settings in order to guarantee a safe dental attendance, 2) Implementation of massive use of the media to deliver clear and concise information on preventive oral health methods and education in oral health, 3) Strengthening the use of tele-dentistry in remote and hard-to-reach areas, and 4) Delivery of health promotion messages that address common risk factors for oral and general chronic diseases in order to avoid duplication of efforts. The authors are grateful to Donna Pringle for reviewing the language and style. The authors declare no competing conflict interests. Self-funded."}
+{"text": "Bioscience Reports at the request of the Editor-in-Chief and the Editorial Board following receipt of a notification from a reader, alerting the Editorial Board to three pairs of duplicated images in Figure 3A.This article is being retracted from The authors were contacted regarding the concerns raised and provided a replacement Figure 3A, however given the number of duplicated images and the resizing of the images, the Editorial Board stands by the decision to retract. The authors agree to the retraction."}
+{"text": "Epidemiological trends over the past decade show a significant worldwide increase in the burden of chronic diseases. At the same time, the human resources of health care are becoming increasingly scarce and expensive. One of the management concepts that can help in solving this problem is business process management (BPM). The results of research conducted in the healthcare sector thus far prove that BPM is an effective tool for optimizing clinical processes, as it allows for the ongoing automatic tracking of key health parameters of an individual patient without the need to involve medical personnel. The aim of this article is to present and evaluate the redesign of diagnostic and therapeutic processes enabling the patient-centric organization of therapy thanks to the use of new telemedicine techniques and elements of hyperautomation. By using an illustrative case study of one of the most common chronic diseases, Chronic Obstructive Pulmonary Disease (COPD), we discuss the use of clinical pathways (CPs) prepared on the basis of the current version of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) as a communication tool between healthcare professionals, the patient and his or her caregivers, as well as the method of identifying and verifying new knowledge generated on an ongoing basis in diagnostic and therapeutic processes. We also show how conducting comprehensive, patient-focused primary health care relieves the health care system, and at the same time, thanks to the use of patient engagement and elements of artificial intelligence , reduces the significant clinical risk of therapy. The challenge facing the healthcare sector is to provide services of better quality that are more tailored to the individual needs of patients. This requires a redesign of diagnostic and therapeutic processes to enable a holistic view of the patient\u2019s health and disease, and simultaneously enable the most effective use of available resources. To achieve the best cost/quality ratio, healthcare management must follow the same path as other sectors and therefore apply similar concepts, methods, and technologies. One of the most effective and most frequently used concepts today is business process management . The resChronic diseases already affect one third of the European population aged 15 and over  and 23.5The aim of this article is to present and evaluate the redesign of diagnostic and therapeutic processes enabling patient-centric organization of therapy with the use of new telemedicine techniques and elements of hyperautomation. This is particularly important today for two reasons. First, the COVID-19 pandemic has shown that skilled and committed workers are the most critical healthcare sector resource, and how quickly these resources are depleted when poorly managed. Secondly, it caused significant changes in the social and work culture, as well as in health care, as a result of which the acceptance of the implemented telemedicine technologies and elements of hyperautomation abruptly increased. However, taking advantage of the emerging opportunity to increase quality, reduce costs, and improve the cost/quality ratio requires a redesign of health care processes and a change in the approach to protecting the health of patients and their caregivers. In this article, for the presentation of models of clinical pathways, as an example of a chronic disease, we used Chronic Obstructive Pulmonary Disease (COPD)\u2014currently one of the three leading causes of death in the world, which is responsible for over 3 million deaths annually . COPD isThe design of the clinical pathway model requires a detailed understanding of the COPD diagnosis and treatment process. For this reason, the clinical pathway was developed on the basis of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) report, updated in 2021 , containRemote contact, no need to spend time and costs in reaching the visit/consultation by the patient or medical staff;Possibility of remote consultations with specialists unavailable in the patient\u2019s place of residence;The ability to monitor the patient\u2019s health online without the need to hospitalize the patient;The possibility of collecting and analysing data sets characterizing the patient\u2019s condition in selected periods of time without the need for hospitalization;The possibility of using predictive analytics and artificial intelligence to prevent foreseeable acute states;Improvement of the quality of services provided thanks to the use of elements of telemedicine and hyperautomation.Telemedicine is defined as medical care provided remotely to a patient in a separate location using two-way voice and/or visual communication (as by computer or smartphone) . The barThe health care system noticed the benefits of using telemedicine in the form of reducing the workload, number and length of hospitalizations, shortening the time of reaching and contact with the patient, allowing for better time management of health care workers and reducing costs. In the COVID-19 Healthcare Coalition Telehealth Workgroup study, more than three-quarters of physicians surveyed said telemedicine helped them provide better care for patients and more than 80% said that their patients have reacted favourably to using telehealth for care . This seThe use of BPM requires a holistic view and orientation of the implemented activities towards their goals, a clear definition of responsibility and empowerment of all participants, as well as the continuous accumulation of knowledge and process improvement . For theDiagnostic and therapeutic processes, also known as clinical pathways (CPs) ,21 or caLevel I\u2014National and international guidelines developed by teams of specialists on the basis of their own knowledge and knowledge gathered in national and international knowledge bases;Level II\u2014Clinical pathways created at the level of the health care unit on the basis of relevant national and international guidelines as well as information about the resources, skills and competences of its staff;Level III\u2014Individual Plan of Care (IPC) developed on the basis of level II clinical pathways, for a specific patient and taking into account the specific context of therapy, including patient age, health condition, comorbidities, possibilities and limitations of therapy.The intervention was a structured multidisciplinary plan of care;The intervention was used to channel the translation of guidelines or evidence into a local organization and its structures;The intervention detailed the steps in a course of treatment or care in a plan, pathway, algorithm, guideline, protocol, or another inventory of actions;The intervention had time-frames or criteria-based progression .Kinsman, Rotter, James, Snow and Willis  conducteThe intervention aimed to standardise care for a specific clinical problem or episode of healthcare in a specific population. If an intervention satisfied the first, and then any two of the remaining three criteria, then it was classified as a clinical pathway.The patient is treated, not the disease;The patients and their caregivers should be involved in the treatment process;Different clinical and peri-clinical pathways  must form a coherent system;Knowledge available in the form of clinical pathways should be available and be reflected in IT and telemedicine technology used on a daily basis by all stakeholders of the diagnostic and therapeutic process.When implementing BPM in healthcare, it should be kept in mind that:The implementation of CPs requires the empowerment of process executors to make diagnostic and therapeutic decisions in accordance with the possessed knowledge and the requirements of the clinical context of process implementation. These decisions have a significant impact on the course and value provided by the implemented processes . ObviousDiagnostic and therapeutic processes are typical knowledge-intensive business processes (kiBPs), because their result is strictly dependent on the use of knowledge of all participants in the process . Due to According to the CP model shown in The process ends when the diagnostician decides that he or she has obtained enough information to make a diagnosis according to his or her knowledge. Each execution of the process may therefore have a different course (a different sequence of performed tasks) depending on the patient\u2019s condition, the doctor\u2019s knowledge, the medical documentation at the beginning, available diagnostic tests, the possibility of consultations or the occurrence of unforeseen events, such as the need to provide immediate assistance to the patient. Not only does the analysis of completed CPs allow for the verification of the correctness of the therapy, it also allows for the verification of the usefulness and effectiveness of the knowledge used, as well as the creation of new knowledge based on the analysis of individual cases and the identification and analysis of deviations from the standard clinical path ,27. SuchA level III CP developed on the basis of the applicable guidelines (CP level I and II) in a way that individually adjusts the therapy to a specific patient, taking into account the broad clinical background, including parallel diagnostic and therapeutic procedures in the field of comorbidities;Clear definition of goals and parameters used to assess the implementation of tasks set at specific stages of the therapeutic process;A clear and understandable description of the forms of medical care planned for implementation and the manner of patient participation in them, so that the patient is aware of the conditions and what activities and therapeutic activities should be undertaken, in what situations he or she should consult the attending physician, and what forms of activity should be strictly abandoned or avoided.The Centers for Disease Control and Prevention (CDC) define chronic diseases as conditions that last 1 year or more and that require ongoing medical attention or limit activities of daily living, or both . These aIn line with the postulates of coordinated medicine and personalized medicine, IPC is therefore a kind of agreement between the therapeutic team and the patient in terms of mutual obligations of both parties, but at the same time a fundamental element of the health education of the patients and their caregivers ,34. The The aim of this article is to show how BPM methods have been used to develop integrated and inclusive clinical pathways in the treatment of one of the most common chronic diseases\u2014COPD. An illustrative case study presents an example of coherent CPs dedicated to COPD, which are implemented at the Clinical and Didactic Center of the Medical University of Lodz and depict how the clinical pathway should be organized to provide the patient with effective treatment and engagement was used for this purpose.The illustrative case study is descriptive, in-depth and rich in context to provide the reader with visually descriptive details that are important to support the research process and the understanding of its outcomes . When apA point of departure for the analysis of the course of this disease, as well as its diagnostics and treatment, rests in the current treatment recommendations of COPD, containing detailed diagnostic and therapeutic information, from the Global Initiative for Chronic Obstructive Lung Disease . This doIn GOLD, considerable stress is put on broadening the role of the patient with respect to controlling their symptoms and making independent preventative and therapeutic actions, without the need of directly consulting medical doctors each time. For this reason, an IPC should be prepared with the participation of the patient. Should any doubt arise, the IPC should be negotiated among the patient and the therapist. In order to ensure effective and systematic cooperation among the patients and their caregivers and the members of the therapeutic team, it is crucial to use a tool which is understood by both sides with respect to evaluating the patient\u2019s actual state and comparing it to the intended state. CPs fulfil these conditions, as they describe in a clear and concise fashion the logic of the proposed therapy, the tasks of the particular participants and crucial parameters pertaining to the patient\u2019s state of health, which require control and which may result in even sudden changes to the methods used in the course of therapy. When the patient is empowered to consciously and actively participate in the diagnostic-therapeutic process with the use of CPs or the correlated IPC, he or she gains insight into the activities expected of them and is able to analyse them and undertake them. In turn, members of the therapeutic team gain the possibility of analysing the activities undertaken in the patient\u2019s environment at selected time intervals and, with the use of telemedicine devices, also in real time. By having knowledge on his or her disease and understanding the therapeutic activities consciously, the patient manages his or her disease and contacts the indicated members of the therapeutic team in situations which require such contact, while also being able to find answers to questions and doubts without the need for contact in situations foreseen and described in the CP and the IPC.As an example, the authors chose CPs COPD prepared at the Clinical and Didactic Center of the Medical University of Lodz. It is the main hospital in the agglomeration and province of \u0141\u00f3d\u017a, responsible for the treatment of patients with COVID-19 and patients with complications and consequences after undergoing COVID-19. Especially during the second and third wave of the pandemic, like most hospitals in Poland, the hospital suffered from a chronic shortage of specialist medical personnel and, due to the increased occurrence of pulmonary diseases resulting from COVID-19, especially personnel with knowledge on diagnosing and treating pulmonary diseases such as COPD or idiopathic pulmonary fibrosis (IPF). This was an additional impulse to develop a map of processes in accordance with the GOLD  recommenTraditional COPD diagnostics processes  or artificial intelligence (AI) in the treatment of COPD, ongoing analysis of the obtained data allows for the prediction of the state of the patient\u2019s health, including upcoming exacerbations (event no. 14). It allows the patient and the doctor to undertake preventative steps to eliminate or mitigate threats (subprocess no. 18). As a result of taking preventive measures, consultation with a doctor is necessary only in some cases (gateway no. 20 and subprocess no. 21). Only as a result thereof, a decision about the necessity of hospitalization can be made . Thanks to the ongoing monitoring of the parameters of the patient\u2019s condition, which does not burden medical personnel, it is possible to significantly reduce the number of hospitalizations, which relieves the health care system, and at the same time significantly minimizes the risks associated with hospitalization of a patient with COPD .This possibility is particularly significant when the therapy is overseen by non-specialist doctors, who do not have deep knowledge of COPD, e.g., general practitioners. As shown on the diagram of the process Evaluation of the effectiveness of therapy performed in the system with elements of ML/AI  on the bRaising the feeling of security of patients and their caregivers;Lifting the burden off of the healthcare system by eliminating visits/medical consultations which are deemed non-essential according to the adopted IPC;On the basis of data collected and analysed on an ongoing basis, the prevention of exacerbations, which usually permanently deteriorate the state of the patient and which may also consist a risk of death;An ex post analysis on the basis of collected data of the introduced therapies with a view to verifying existing, as well as creating new fact-driven medical knowledge.In the therapy of COPD as a chronic disease, the use of patient-centred CPs using telemedicine technologies allows for:In the healthcare system, the use of BPM methodologies allows for the ongoing automatic tracking of key parameters of the individual patient\u2019s condition without the need for commitment to expensive medical resources. For the patients, it provides a chance for more effective treatment and better quality of life thanks to better adjustment of therapy and recommended pro-health behaviours to a specific clinical condition and, which is particularly important, through the conscious involvement of the patient and his or her caregivers in the effective reduction of disease risks and controlled self-management of the disease. This is of particular significance in the case of chronic diseases such as COPD, as it may lead to a reduction in possible exacerbation, slow disease progression and even stop the disease, thereby significantly reducing the social and healthcare costs. However, such a solution requires viewing the patient as an equal participant of the therapeutic process; as someone with rights, including the right to medical education and the right to co-decide on the course of therapy. The patients are required to depart from their traditional passive role in therapy and to acknowledge that they also have certain responsibilities and that their realization has an essential influence on the results of therapy. This also requires, particularly in light of the COVID-19 pandemic, to use telemedicine technology in order to lift the burden off of the healthcare system and raise the pace of creating knowledge helpful in combating the pandemic. The use of IT technologies already available in healthcare, such a cloud computing, BigData, process mining, predictive analytics, ML or AI allows for the real-time collection and analysis of data and their use with a view to verifying existing and creating new knowledge directly in the course of performing diagnostic-therapeutic processes. However, this requires making certain adaptations to existing healthcare rules and regulations to allow for performing and financing such actions in accordance with the proposed model.Although the paper lacks broader quantitative studies that would allow for the assessment of the economic and therapeutic effects of, as well as the impact on the development of medical knowledge in the field of COPD treatment, it illustrates how standardised CPs can serve as guidelines for interdisciplinary teams of health professionals, patients and their caregivers and employ the newest telemedicine technology to maximize the treatment effectiveness and create knowledge that raises the efficiency of the healthcare system.One crucial limitation of the work is its conceptual character. Despite the fact that telemedicine technologies are already available and the current version of GOLD refers to the treatment of COPD during the COVID-19 pandemic, further studies are necessary to explore the effectiveness of the proposed CP and its influence on raising the pace of development of medical knowledge. A particularly crucial area of future work, which will have considerable influence on the effectiveness of COPD treatment, is the data-driven analysis of the causes or signals of exacerbations. The authors and the pulmonologists involved in the study assume that on the basis of analyses of sets of BigData from completed treatments, new variants of CPs will be proposed with a view to mitigating the risk of exacerbations. At the same time, economic analysis pointing to the possibility of lowering direct costs of COPD treatment  and long-term costs  will result in rapid changes to healthcare rules and regulations and will allow for their broad use."}
+{"text": "The authors were asked for an explanation to account for these concerns, but the Editorial Office never received any reply. The Editor regrets any inconvenience that has been caused to the readership of the Journal.After having conducted an independent investigation in the Editorial Office, the Editor of"}
+{"text": "Furthermore, Fig. 6 contained data that bore striking similarities to data published in Fig. 8 in another paper published in Molecular Medicine Reports has determined that the above paper should be retracted from the Journal on account of a lack of confidence concerning the originality and the authenticity of the data. The authors were asked for an explanation to account for these concerns, but the Editorial Office never received any reply. The Editor regrets any inconvenience that has been caused to the readership of the Journal.After having conducted an independent investigation in the Editorial Office, the Editor of"}
+{"text": "This Retraction follows an Expression of Concern relating to this article previously published by Portland Press.Bioscience Reports at the request of the Editor-in-Chief and the Editorial Board following receipt of a notification from a reader, alerting the Editorial Board to duplication in Figure 1 as well as duplication in the Western blots of Figure 6B, of which parts appear in multiple published articles from different author groups.This article is being retracted from The authors have been contacted in regard to the retraction, and disagree with the Journal's decision to retract the article. The authors state that the duplications are due to errors being made by the authors during the submission of the article. Given the extent of the issues raised, the Editorial Board stands by the decision to retract the article."}
+{"text": "Economic recovery post-COVID-19 will be structured around answering a number of fundamental questions. It is necessary to take stock of the extent of the recovery and of the transformation our economies have experienced in the last year and a half."}
+{"text": "This Retraction follows an Expression of Concern relating to this article previously published by Portland Press.Bioscience Reports at the request of the Editor-in-Chief and the Editorial Board following receipt of a notification from a reader, alerting the Editorial Board to issues in Figure 3E, which contains areas of duplication in the Retinoblastoma images.This article is being retracted from The authors have been contacted in regards to the retraction, and have not responded to the Journal's queries and the concerns raised. Given the extent of the issues raised, the Editorial Board stand by the decision to retract the article."}
+{"text": "The discussion of the achievements and limitations of the strategies prioritised in global mental health that has taken place in recent years contributed to a unified vision for action that addresses the gaps still existing on prevention, treatment, quality of care and human rights protection. This editorial presents four reflections on the impact of this vision on the definition of future priorities, particularly in the areas of policy implementation, services reconfiguration and organisation, human rights and research. It concludes that further debate is needed to redefine the balance between priorities and strategies that can better promote an effective response to the needs of low and middle income countries, and to ensure an efficient coordination of efforts in the future. Defining priorities is one of the most important challenges in global mental health. Given the magnitude of mental health problems and the gaps that still exist in this area, it is of utmost importance to concentrate all efforts and resources on the objectives and strategies that may more effectively contribute to attaining the main goals of global mental health.This new field, particularly in the last 20 years, registered an enormous growth and had significant achievements in the inclusion of mental health in the global health agenda, the development of innovative knowledge and practices, the training of leaders and professionals and the support to policy development. This growth led to the consolidation of a global mental health movement that is now highly visible worldwide, but, at the same time, it also brought to light a growing diversity of perspectives on what should constitute the core of global mental health and how its various strategies should be prioritised.et al., In the last few years, a number of important contributions to this debate have been made by several authors, who raised questions such as the definition and content of global mental health, the risks of an excessive influence of the western biomedical approach, the balance between the focus on common mental disorders and the focus on severe mental illnesses, the balance between prevention, treatment and care, the real impact of global mental health initiatives on the improvement of mental health in low resource countries, future priorities in research and the level of attention dedicated to the reform of mental institutions  to understand the importance of investing in prevention and of prioritising interventions during childhood and adolescence; (2) to recognise the limitations of the categorical approach in diagnosis and the need to complement it with a dimensional approach and (3) to value the importance of structuring mental health systems in a way that enhances the opportunities for intervention at all stages of the evolution of mental health problems, from well-being to different stages of the disease ; strengthening alliances involving different stakeholders  and ensuring an effective coordination of efforts, benefiting from the unique contribution the World Health Organisation can give in this domain.It will be also necessary to increase the commitment of donors: most low income countries allocate a very limited proportion of their already limited health budgets to mental health, and are significantly dependent on external support to initiate a mental health reform process and to fund the costs of the transition phase.At the national level, generating and strengthening political commitment deserves much more attention than it has received in the past. Although it is largely recognised that it's one of the major obstacles to the improvement of mental health all over the world, the truth is that there is no clear guidance on how to generate and strengthen political commitment to mental health development, and this problem has received surprisingly little research attention so far  the implementation, monitoring and evaluation of mental health plans; (b) improvement of information systems and (c) development of new financing models facilitating the reallocation of resources and the creation of incentives aligned with the strategic changes that are required.International support is also needed to strengthen users\u2019 associations and to empower them as partners in all steps of mental health policy and its implementation.Given the specific characteristics of mental health care, scaling up of services is not enough to ensure the advances that are needed; a reconfiguration of the mental health system and a reorganisation of services are always indispensable.In the last decades, we have significantly increased our knowledge on how to prevent mental disorders, integrate mental health care in primary care, provide effective community based mental health care and inpatient treatment in general hospitals and ensure the deinstitutionalisation and social inclusion of people with long-term mental disorders  clarification of the ambiguities that persist on the definition of and relations between the concepts of mental disorders, mental disabilities and psychosocial disabilities, which represent a serious obstacle to the incorporation of the Convention on the Rights of Persons with Disabilities principles into the mental health law of many countries  understanding the effects of differences in the organisation and delivery of national mental health-care systems on mental health of people with mental disorders; (b) assessing the cost-effectiveness of different models of financing, organising and providing mental health care and (c) increasing our knowledge on the effects of the service-related factors and the relational aspects of interventions on outcomes, and on how to incorporate the new knowledge in the routine practice. The second one to stress the importance of actions that could strengthen research centres in low resource countries and provide practical support to researchers from these countries in access to grants and mentorship, and in publishing papers.The debate carried out in the last few years on the goals and strategies of global mental health gave important contributions to the redefinition of priorities in this field, grounded on the advances made at the scientific level and on the international agreement on the importance of the values associated with the human rights and recovery approaches. Further debate is now needed to redefine the balance between the different priorities and strategies that can give a better response to the needs of low and middle income countries and to ensure an efficient coordination of efforts in the future, taking advantage of the unique contribution the World Health Organisation can provide in this domain."}
+{"text": "Dear Editor,We passionately studied the article named \u201cHistory of dermatology: the study of skin diseases over the centuries\u201d.This article reviews and inquires about skin diseases over the centuries. This is a comprehensive study with very detailed and useful tips in which the authors have reviewed various works. However, it also has an important drawback as the authors did not refer to the medical tradition of skin diseases in medieval Islamic countries. The medieval medicine in the Islamic world, which began with the movement to translate Greek, Iranian, and Indian works, could flourish by the arrival of individuals such as Rhazes, Haly Abbas and Avicenna.6We hope that this explanation has been able to show the course of the history of medicine in the Middle Ages, its importance, and also to fill the gap in the article.None declared.Mohammad Reza Mirzaei: Approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript.Javad Ghazi-Sha\u2019rbaf: Approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript.Reza Mohammadinasab: Approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript.None declared."}
+{"text": "Belgica antarctica Jacobs is endemic to the western Antarctic Peninsula and South Shetland Islands. We provide the first detailed photomicrographic images of the fourth-instar larval head capsule and posterior parapods. We assessed variation in the morphology of larvae from two different collection locations off the coast of the western Antarctic Peninsula and compared it with that available in the literature. A number of differences were identified relating to the size of the larvae, the number of teeth on the mandibles, the number of antennal segments and the length of the antennal blade. Malformations of the mandible and mentum are reported for the first time in this species.The chironomid midge Belgica antarctica is described. Larvae were collected from Jougla Point (Wiencke Island) and an un-named island close to Enterprise Island, off the coast of the western Antarctic Peninsula. Light microscopy was used to examine and document photographically the structures of the mouthparts , antennae, pecten epipharyngis, clypeus, frontal apotome and posterior parapods. Measurements of the mouthparts are presented. The data obtained are compared with that available in the literature. A number of differences were identified relating to the size of the larvae, the number of teeth on the mandibles, the number of antennal segments and the length of the antennal blade. Malformations of the mandible and mentum are reported for the first time in this species. Features of larvae of taxonomic value that can be used to determine the species in larval stages are presented. These are of utility in using the larvae to reveal relationships with other species. Larvae are also important in ecological and genotoxicological studies, which require accurate species level identification.The external morphology of the fourth-instar larva of the Antarctic endemic chironomid midge  Belgica antarctica Jacobs is endemic to the western Antarctic Peninsula and South Shetland Islands. Its biology has been the subject of research by ecologists, physiologists, geneticists and taxonomists ) Measurement data for individuals from Jougla Point are presented in Antenna  and Usher and Edwards (1984) provided detailed data on the morphology of a larvae ,14. Our a larvae . Our data larvae ,14. The ironomus ,23,24,25ironomus . The numironomus . HoweverOur data indicated that a different number of antennal segments were present compared to the reports of both Wirth and Gressitt (1967)  and UsheThe malformations affected the number and appearance of teeth of the mentum, the number of teeth of the mandibles and the length of the antennal blade. The deformities observed here may suggest that the larvae are particularly sensitive to environmental contamination . They apB. antarctica are larger than males [Differences were observed in the sizes of some of morphological structures assessed in the current study in specimens from the two sampling locations, including in the length of L1 and L2, width of mentum, distance between setae of mentum, and distance from base to the RO of the first antennal segment see . These dan males , which ian males ). FutureBelgica antarctica are presented for the first time. We identify differences relating to the size of the larvae, the number of teeth on the mandibles, the number of antennal segments and the length of the antennal blade. Malformations of the mandible and mentum are reported for the first time for this species.Photomicrographs of some body parts of the fourth-instar larvae of the Antarctic endemic chironomid midge Individual larvae represent the basic units of biological communities. They integrate molecular, cellular, and organ levels of organization into a single entity and form the building blocks for higher levels of organization . In the context of assessing pollution using biomarkers , larval stages of Chironomidae have been identified as important bio-monitoring models for eco-toxicological studies."}
+{"text": "The rights of older persons, essential to our work as gerontologists, were discussed in the World Assembly on Aging (1982) and adopted through the United Nations Principles of Older Persons and followed by the Madrid International Plan of Action on Aging (MIPPA) in 2002. Although it has been endorsed by the General Assembly of the United Nations, in contrast to conventions, it is not binding on member states. This paper discusses the rights of older persons and our obligations as educators and researchers to focus on core issues associated with the rights and quality of life of older people. We will review the role of education in meeting this call to action through examples like the UN Decade of Healthy Ageing where education is a required element to accomplish the action areas and the Age-Friendly University movement. Both have involved multiple university communities on a global scale."}
+{"text": "Bioscience Reports at the request of the Editor-in-Chief and the Editorial Board following receipt of a notification from a reader, alerting the Editorial Board to the inhibitor panel in Figure 3C, which contains a significant number of data points overlapping with that from figures in other publications by different authors.This article is being retracted from The authors have been contacted in regards to the Retraction, and have not responded to the Journal's queries and the concerns raised. Given the extent of the issues raised, the Editorial Board stand by the decision to retract the article."}
+{"text": "This Retraction follows an Expression of Concern relating to this article previously published by Portland Press.Bioscience Reports at the request of the Editor-in-Chief and the Editorial Board following receipt of a notification from several readers, alerting the Editorial Board to duplications in Figures 1C, 1D and 5A.This article is being retracted from The authors have been contacted by the Journal specifically in regard to the retraction, but have not responded directly to the queries and concerns raised. Given the extent of the issues raised, the Editorial Board stand by the decision to retract the article."}
+{"text": "Intraepithelial neoplasia is a special type of squamous cell carcinoma occurring in the skin epidermis. The incidence of penile intraepithelial neoplasia in Asian males is rare. We report the clinical characteristics and treatment process of a case of penile intraepithelial neoplasia in a Chinese man. We treated the disease of this patient by surgical excision of the penile lesion and scrotal flap plastic surgery. After surgery, the shape of the penis was satisfactory, and there was no adverse effect on erection. The pathological results confirmed the diagnosis of penile intraepithelial neoplasia. The pathological features showed that the lesion tissue was covered with squamous epithelium and that there was severe atypical hyperplasia of the lesion epithelium, disordered arrangement of polarity, and an intact basement membrane. The removal of the lesions of penile intraepithelial neoplasia through a wider surgical resection range, combined with the stretchability of a scrotal flap, can achieve a good healing effect of the surgical wound and reduce the possibility of recurrence of penile intraepithelial neoplasia. Intraepithelial neoplasia most commonly presents in the proximal skin of the trunk or limbs and can also be located in the oral mucosa, conjunctival membrane, and nail bed  for the publication of any potentially identifiable images or data included in this article.KH: design of study, date collection, the surgeon who performed the operation, and manuscript writing. SL: the surgeon involved in the operation. YW: design of study and the surgeon involved in the operation. XT: design of study and manuscript revising. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "UK official statistics on income distribution have incorporated top-income adjustments to household survey data since 1992. This article reviews the work undertaken by the Department for Work and Pensions and the Office for National Statistics, and the academic research that influenced them, and reflects on the lessons to learn from the UK experience."}
+{"text": "Due to the sensitive nature of this topic and the associated health and safety risks,this case report is being retracted and the content has been removed, both at therequest of the authors and with the agreement of the editors"}
+{"text": "Following the publication of this article , the ediPLOS ONE authorship policy.As per the PLOS authorship criteria in place at the time of submission of this article , in ordePLOS ONE Editors retract this article.In light of the concerns affecting the authorship of this article , the PLOThe authors did not respond to the retraction decision."}
+{"text": "Bioscience Reports at the request of the Editor-in-Chief and the Editorial Board following receipt of a notification from a reader, alerting the Editorial Board to the tumor images inf Figure 6B, which have been published in multiple publications by different authors.This article is being retracted from The authors have been contacted in regards to the Retraction, and have not responded to the Journal's queries and the concerns raised. Given the extent of the issues raised, the Editorial Board stand by the decision to retract the article."}
+{"text": "This letter to the editor is in response to the consensus statement from the Ultrasound Subcommittee of the European Society of Radiology, the European Union of Medical Specialists (UEMS) Section of Radiology, and the European Federation of Societies for Ultrasound in Medicine and Biology. It highlights the role of the non-medical sonographer in the UK and the evidence underpinning this safe and effective practice. Dear Editor in Chief,With regards to the published consensus statement by the European Society of Radiology (ESR) ultrasound subcommittee , we woulThe Society and College of Radiographers (SCoR), the Royal College of Radiologists (RCR), the Consortium for the Accreditation of Sonographic Education (CASE), the Royal College of Obstetricians and Gynaecologists (RCOG), the British Medical Ultrasound Society (BMUS) and the Royal College of Midwives (RCM) firmly believe that team-working with radiologists and other medical and non-medical colleagues provides a safe, effective ultrasound imaging service. In the UK, ultrasound courses outside of medical education programmes can opt to be accredited by CASE. This model helps to ensure a minimum standard of education and curriculum content , as recoYours sincerely."}
+{"text": "The German change of attitude concerning fiscal policy and the mutualisation of efforts to fight the pandemic is driven by self-interest, and as such might be structural."}
+{"text": "Nevertheless, they were able to present all the original data to the Editorial Office, and the repeated experiments revealed the same trends in terms of significant differences in cell migration and invasion. The corrected version of"}
+{"text": "The Digital Age saw the rise of several rapidly growing digital platforms with substantial market shares, and this development is expected to continue. Europe is a large target market for these globally operating platforms, although the majority of the most successful platforms come from the USA and Asia and will likely continue to do so in the future. This article reveals the reasons for the success of digital platforms and discusses the recent European Commission proposal for a Digital Markets Act based on the analysis of the status quo."}
+{"text": "We would like to thank the ESRC-GCRF for the ES/S000453/1 grant to which this paper is linked as part of the project \u2018Shifting South: decent work in regional value chains and South-South trade\u2019. We are also extremely grateful to the Eswatini Revenue Authority for the collaboration, and the four anonymous referees and the editors for the insightful comments which have significantly improved the paper. Finally, the completion of this work has benefitted from the useful comments of Prof Stephanie Barrientos and our colleagues of the GPN Research Group at the University of Manchester."}
+{"text": "This Retraction follows an Expression of Concern relating to this article previously published by Portland Press.Bioscience Reports at the request of the authors following receipt of a notification from a reader, alerting the authors to a row of duplicated images with differing contrasts in Figure 2A.This article is being retracted from The authors are unable to correct the article and wish to retract the article. The Editor-in-Chief and Editorial Board agree with the retraction."}
+{"text": "The literature on the history of family medicine as an academic discipline locates its beginning with the establishment of two faculties linked to the Royal College of General Practice in 1958. However, the history of Community Oriented Primary Care documents, how the Kark\u2019s moved from Pholela in KwaZulu-Natal, were involved with the establishment of the Natal Medical School in Durban. As part of this a Department of Social, Preventative and Family Medicine was established in 1956 with Dr Sidney Kark as its first Head of Department. The South African Academy of Family Practice and Primary Care established in 1980 explicitly orientated itself in relation to public healthcare (PHC). We need to re-claim the history of Community Oriented Primary Care as part of the history of family medicine and proudly trace our current ethos and values to the seminal work of the Kark\u2019s. Historically, the medical officers in clinics and hospitals, the private practitioners in general practice all over the country as well as the mission doctors essentially providing the core of health care services in many rural areas predated generalist care as a distinct academic discipline.2 the first president of the South African Academy of Family Practice and Primary Care (SAAFP) . Key high-level milestones in Dr Jaffe\u2019s account locate the beginning of academic family medicine in 1958 when the Cape of Good Hope and Witwatersrand regions formally established faculties linked to the Royal College of General Practitioners in the United Kingdom, the first appointment of a professor of family medicine in 1967 at the University of Pretoria and the establishment of the SAAFP in 1980. I mention these three milestones specifically in relation to a different history related to family medicine.The literature on the development of family medicine as an academic discipline in South Africa mostly refers to an address by Dr Basil Jaffe,4 Longlett et al.,5 and Marcus6). What is less well-known is how the COPC initiatives were explicitly linked with the establishment of academic family medicine in South Africa. In her book on the history of the medical school in Durban, Vanessa Noble7 narrates how in the early 1950s, as part of the establishment of the Natal Medical School, the then Dean George Gale and Sidney Kark convinced the faculty board to establish Family Practice and Community Medicine as a main clinical division alongside Medicine Surgery and Obstetrics and Gynaecology (p. 76). When the Natal Medical School opened in 1956, the name was changed to the \u2018Department of Social, Preventative and Family Medicine\u2019 (p. 77), and Sidney Kark was appointed as the first professor and head of department. The clinical training of medical students in family medicine took place at the Institute of Family and Community Health (IFCH) \u2013 a network of community health centres throughout Durban which were based on the COPC model pioneered in Pholela.6 This was akin to what is currently referred to as a \u2018decentralised training platform\u2019. The community health centres were linked with the communities through community-level health promoters as part of the COPC model, which resonates with current initiatives of re-engineering PHC in South Africa.4 Sadly, both the Department of Social, Preventative and Family Medicine at the University and the IFCH were dissolved owing to complex national and professional politics prevalent in the 1950s and early 1960s, which were profoundly antagonistic to such innovative approaches at that time.7The body of literature around community-oriented primary care (COPC) documents how Sidney and Emily Kark together with Edward Jali  and others are credited for their pioneering work at Pholela in KwaZulu-Natal in the 1940s and how this contributed to the establishment of primary health care (PHC) (see, for instance, Williams and Reid,2 which has subsequently become the central focus in the training of family physicians.3 The founding documents quoted the Alma Ata Declaration as the SAAFP\u2019s orientation and thereby essentially returning to the path that the Karks and their colleagues had shown in Pholela and Durban. We can but marvel how visionary the Karks were \u2013 not only in terms of development of COPC but also with regard to establishing academic family medicine and including it in undergraduate medical education.When the SAAFP was formed in 1980, it included PHC as a core aspect of family medicine,We need to reclaim our history, not only to acknowledge the work of those before us but also to proudly trace our current ethos and values to their roots. It links our current efforts to the seminal work conducted at the Pholela Health Centre, the birthplace of COPC."}
+{"text": "The authors were asked for an explanation to account for these concerns, but the Editorial Office never received any reply. The Editor regrets any inconvenience that has been caused to the readership of the Journal.After having conducted an independent investigation in the Editorial Office, the Editor of"}
+{"text": "A simulation model and the results of experimental tests of a vibration generator in applications for the hot-dip galvanizing process are presented. The parameters of the work of the asynchronous motor forcing the system vibrations were determined, as well as the degree of unbalance enabling the vibrations of galvanized elements weighing up to 500 kg to be forced. Simulation and experimental tests of the designed and then constructed vibration generator were carried out at different intensities of the unbalanced rotating mass of the motor. Based on the obtained test results, the generator operating conditions were determined at which the highest values of the amplitude of vibrations transmitted through the suspension system to the galvanized elements were obtained. Galvanizing is a technology for anticorrosive protection of the surface of metal products by applying a mechanically durable zinc coating. One of the most important galvanization technologies is hot-dip galvanizing for anticorrosive protection of the surface of metal products by applying a mechanically durable zinc coating. Zinc coatings can be applied in the following processes: hot-dip galvanizing, electroplating, and zinc spraying. Hot-dip galvanizing makes it possible to obtain good-quality coatings and provides long-term protection . In the A significant cost of the hot-dip galvanizing process is the cost of zinc. Zinc consumption depends mainly on the thickness of the coating, but is also influenced by specific process conditions resulting in the formation of hard zinc, zinc ashes, oxidation of the bath surface, as well as the formation of solidified zinc droplets . After tIn the zinc coatings produced on steel elements in the process of hot-dip galvanizing, two layers  can be dThe properties of the outer layer can be shaped by the appropriate selection of the speed of the product emerging from the bath (with an estimated speed of about 1.5 m/min ). Too slThe formation of the outer layer of zinc on tinned elements is the result of adhesion and cohesion processes described by the equations of motion of incompressible fluids of high viscosity. The formation of the liquid layer depends on the friction forces, dependent on the viscosity, surface tension, and inertia forces . The speThe use of vibration in technological processes has been the subject of many studies ,13. For The following paper presents a methodology for selecting the operation conditions of a vibration generator that can be used in hot-dip galvanizing processes. The assumption of the modified galvanizing process, in which the stage of removing the products from the zinc bath takes place with the participation of mechanical vibrations with a specific amplitude and frequency, depends on the weight of the suspended galvanized elements. The purpose of the vibrations during the emergence of the elements from the zinc bath is to increase the uniformity of the coating thickness, limiting the formation of thin layers of zinc covering holes with small diameters and shaping a favorable geometric structure of the surface.The main problem to be solved was the development of the structure of vibration generators and the methodology of selecting parameters for controlling their operation for the assumption that the mass of galvanized elements with their mounting system would be from 500 to 1000 kg. It was assumed that the weight of the casing and other elements suspended on the transport system, to which vibrations should be transmitted to the least extent, would be limited by the parameters of the permissible load of this system. The further part of the work presents the results of experimental tests of the manufactured prototype of a vibration generator for use in the galvanizing process.The designed mechanical vibration generator for hot-dip galvanization applications is presented in The system is forced to vibrate by a mechanical vibrator in which unbalanced masses are set in rotation around the axis of the electric motor. The system vibrations are transferred to the suspended elements for galvanizing through a vibrating plate placed in the spring system. The weight of the galvanized products suspended from the vibrating plate affects the behavior of the entire system.1m, its vertical movement 1y), the vibrating object , and the system housing . The generator housing is mounted using viscoelastic elements, which represent the system support for a specially prepared frame structure. In the case of the presented model, apart from the vertical vibration of individual elements of the generator, the entire system can generate oscillatory movements in the direction labeled as 3x.A physical model of the vibration generator tested in laboratory conditions is presented in 1k is the stiffness of the lower springs (4 pcs.), 2c and 2k are the damping and stiffness of the rod fixing the element excited to mechanical vibrations, 3k is the stiffness of the upper springs (4 pcs.), 4c and 4k are the damping and stiffness representing the system support, eF is the centrifugal force of the vibration shaker, and e\u03b8 is the rotational angle of the electric motor.Equations of motion for individual system components in the vertical direction are presented in the form of ordinary differential equations, which are presented according to the following relationships:m1 + m2 + m3 is the total mass of the examined vibration generator and 3x is its displacement measured in the horizontal direction.Vibrations generated by the entire mechanical system in the horizontal direction are explained by using only one ordinary differential equation, as follows:e\u03b4 is the intensity of an unbalanced rotating mass of the motor, em is the mass of the rotating element, er is the lever arm of the rotating element.The centrifugal force of the element introducing both vertical and horizontal vibrations into the system is described with the following relationship:eF as well as the rotational speed of the electric motor By changing the rotational speed of the motor, it was possible to generate vertical vibrations of the system with various vibration intensities. Both the amplitude and the frequency of generated vibrations depended mainly on the harmonically applied force  540 rpm . This roThe experimental setup for the analysis of dynamic behavior of the vibration generator in laboratory conditions is presented in The acceleration signals measured on the test stand described in As shown in The analysis of dynamic behavior was aimed at determining the maximum vibration amplitudes of the vibrating plate in relation to the lowest possible vibrations of the generator housing, taking different intensities of the unbalanced mass into account. In the analyzed load case (466 kg), we considered the resonant vibrations of the mechanical system which occurred at the motor rotational speed of 540 rpm, corresponding to the frequency of system oscillations close to 9 Hz. The amplitude spectra of the vibration acceleration of the generator housing and the vibration plate measured in the vertical and horizontal directions at different values of the intensity of unbalanced mass are shown in According to the test results presented in In order to determine the highest efficiency of the generator\u2019s operation, the vibration transmission function was developed as a ratio of the maximum values of the vibration amplitude measured on the vibrating plate in relation to the maximum values of the vibration amplitude measured on the generator housing . This raAs it resulted from the shape of a nonlinear function , the traThe aim of this research was to develop vibration generators that can be used in the hot-dip galvanizing process. In the case of galvanizing elements of complex shape, it is not possible to use air knives to remove excess zinc from elements removed from the zinc bath. The developed method allows the use of vibration generators placed between the gantry and the platform with galvanized elements. Vibration generators ensure that the platform vibrates cyclically as galvanized elements are lifted from the zinc bath.As part of the research work, the model of the mechanical vibration generator was verified under various operating conditions. A satisfactory agreement of the results of simulation and experimental tests was demonstrated for the motor rotational speed of 540 rpm and in the case of different unbalanced rotating mass intensities. The analysis of dynamic behavior clearly showed that the greatest efficiency of the proposed vibration generator was achieved near the resonance frequency of the system (about 9 Hz) and at the unbalance intensity of 30%. Under these operating conditions, an almost 4-fold increase in the vertical vibrations of the vibrating plate was obtained.Correct operation of the vibration generator loaded with given masses, confirmed by tests, allows its use in further stages of tests involving the use of a vibration generator system (preferably two) placed between the gantry and the platform with galvanized elements."}
+{"text": "RSC Advances article due to concerns with the reliability of the data. The images in the article, and the raw data provided by the authors, were screened by an image integrity specialist.The Royal Society of Chemistry hereby wholly retracts this The blots and many other features of the article were found to closely resemble the blots and features of other articles, which is highly unexpected given that there are completely different author lists for these articles. The western blots in these papers are very regular-shaped and do not look genuine.Furthermore, analysis of the western blot raw data provided by the authors for this paper showed that it did not match with any of the western blots in the article, and therefore cannot be used to validate the published data.Given the significance of the concerns about the validity of both the data in the article and the raw data provided by the authors, the findings presented in this article are not reliable.The authors have been informed but have not responded to any correspondence regarding the retraction.RSC AdvancesSigned: Laura Fisher, Executive Editor, th January 2021Date: 15"}
+{"text": "In recent years, big data has become an important branch of computer science. However, without AI, it is difficult to dive into the context of data as a prediction term, relying on a large feature of improving the process of prediction is connected with big data modelling, which appears to be a significant aspect of improving the process of prediction. Accordingly, one of the basic constructions of the big data model is the rule-based method. Rule-based method is used to discover and utilize a set of association rules that collectively represent the relationships identified by the system. This work focused on the use of the Apriori algorithm for the investigations of constraints from panel data using the discretization preprocess technique. The statistical outcomes are associated with the improved preprocess that can be applied over the transaction and it can illustrate interesting rules with confidence approximately equal to one. The minimum support provided to the present rule considers constraint as a milestone for the prediction model. The model makes an effective and accurate decision. In nowadays business, several guidelines have been produced. Moreover, the generation method was upgraded because of an association data algorithm that works for dissimilar principles of the structures compared with fewer breaks that are delivered by the discretization technique. Big data analysis techniques are emerging trends regarding the issues related to the Vs of the big data and the optimal and effective decisions . Big datThe discretization applied for panel data attributes before extracting the association rules to overcome the main limitation of an association rule acquisition is that all the attributes must be categorical . Even thIn this investigation, we are going to introduce the latest method to further reprocess the association rules that are constructed based on the discretization technique, in addition to introducing its NP-complete. Therefore, the splitting of a continuous range of values in different levels of the interval is required for the discretization of the numerical features to perform an efficient search for rule induction. The values are further subdivided for the different data features, and visualization of the big data model is the main objective of the present work.To assess the performance of the proposed approach, we have presented an experimental study using UCI datasets. We have developed the following studies: first, we have compared our approach with the original Apriori algorithm to analyze the performance of the newly introduced approach. Second, we have compared the performance of our approach with two other approaches developed by Apriori. Third, we showed the obtained results from the comparison from a time-consuming point of view for hybrid discretization association rules. Finally, we have analysed the scalability of the approach.This research provides a new approach that depends on the concept of the discretization process of panel data to generate associated rules applied to discover and identify attribute-value conditions. Also, this research applied unsupervised learning model to define the interconnections among the attributes in the dataset, not only ordinal relationbut also focused on co-occurrences of attribute values to discover hidden patterns which lead to being much more meaningful..The rest of this article is arranged as follows: Big data became a technological cultural and scholarly phenomenon that led to maximizing computation power and algorithmic accuracy to identify patterns on a large dataset, using artificial intelligence techniques to offer higher form objectivity and accuracy with an aura of truth .The IDC report in 2011 defined big data based on prime properties. The definition is big data technologies mainly describing a new process for the generation of architectures and technologies. The IDC report provides extracted value from huge volumes of data wide variety, through discovery and high-velocity capture analysis .The characteristics of big data can be summarized in four words: volume, capacity, speed , and great value, but low speed and density. Big data is less expensive to store and access and more cost-effective . The panPanel big data initiates with heterogeneous numerical data, large volume, and autonomous sources that are decentralized and distributed for the control and can be developed to explore complex and evolving relationships between the whole data . The firThe simple data reduction processing is discretization. The preprocessing of data converts it from the fully developed and huge range of different continuous values. The values selected in the discretization are suitable datasets for the discrete transaction values . The maiThe numerical big data is different in all the scenarios and follows three types of formats including nominal, discrete, and continuous. The ordinal data types are discrete and continuous data for certain values. In the case of nominal values, they are not holding complete order. The separate standards can be labelled by way of the method of intermissions taking a nonstop sequence of standards .The quality of nonstop standards is dissimilar and countless. The feature of continuous values is infinitely common for discretization. The discrete values split according to different intervals and the continuous values have series of different values. The splitting of values follows algorithms, and in the numerical domain intervals, the values are different for each case .Data discretization is a preprocessing step used in big data analysis that assures quality and the format of the data through different algorithms . DiscretThe key procedure accepted data investigation needs the circumstances for the equal sum of transactions, similar size, and stated sum of intervals. Algorithm discretization can be taken towards the information approaches due to the command into progress the encouraged models and information removal. Several methods of discretization are going to construct. The usual technique is used for the same width and the frequency is the same, which contain and generate the sum of intervals. This technique is stated with the similar sum of transaction correspondingly and transforming numerical input or output variables to have discrete ordinal labels . On contThe feature of continuous quantities and the univariate discretization have an impact on the multivariate discretization and consider the number of features. The process of univariate discretization provides more advantages for single continuous features and multivariate discretization is used for multivariate discretization. For the multivariate discretization, there are multiple features. The univariate discretization provides more advantages due to simple processing and the discovery is associated with the rules. The available features in the present analysis are used for the determination of quantities . The disAssociation rules are used to represent and identify dependencies between items in a dataset, which are applied to a large volume of a dataset through the discretization process, which enhances the performance and speed. The Apriori algorithm is popular for frequently collecting all of the item sets. The work in  identifiX and Y and the relationship is in the procedure X! Y. Due to the dynamic updating of the relationship between the items X and Y in a given dataset. The intersection between X and Y processes the unfilled set. It consists of two significant methods, controls a link among the transaction of items, and supports every degree in the dissimilar self-assurance [X! Y is assumed in the database and holds equally X and Y, P (X U Y). In the delivered dataset, the self-assurance can be clear for the regulation X! Y that is a measure for the transactions in the assumed database enclosing X and Y.The first planned suggestion was the removal of labelled existing and unseen relations regarding the dissimilar acquired substances in some transactional files . The rulssurance . The susThe primary goal of big data analysis is to extract new features of the extract association rule in order to improve accuracy and produce useful data. In , 17, theThe process enables the scanning of the database by multiple times. Therefore, therefore the growth arm (association mining rule), frequent Growth Pattern (FP). The algorithm is identified as an effective pattern for mining with the growth of database growth. Moreover, the same time expressions have some limitations. Urmila  worked tThis work proposed a new approach that consists of six different components including the transaction, panel data, discretization, extract rules, evaluation rules, and components evaluation. The generation of constraints is based on different rules including extract rule and component evaluation. The rule and accurate component are evaluated towards the generation of facts and constraints. Approach main components are shown in The driving concepts of big data as a platform is provided by panel data for multidimensional data that involves measurements over time ranges and covers the velocity and enables the identification of the differences for techniques including data mining and data science. The use of panel data provides many advantages , such asThe \u201cdynamics of adjustment\u201d provides a solution for different data sets related to the extraction of rules and reducing dataset scanning . The traThe importance of the discretization of an algorithm is based on balanced and unbalanced datasets. The data can be adapted to improve the extraction of knowledge and acquiring of models. The other unsupervised machine learning process is linked to the well-extracted processes for equal width and equal frequency. The Apriori algorithm is applied by a component that can be used to find the different and frequent item sets. The items can be generated through association rules. These components provide benefits such as detection of unknown relation, production of results, prediction, and decision-making process to counting their frequencies. The Apriori algorithm is shown in X [Y. The relationship displays the entire number of records in the database [X [Y for all the number of records that encompass X, further; the previously mentioned percentage is linked to the threshold of self-assurance. The interesting situations are association rule X->Y can be produced. Assurance is a measurement of the strength of the association rules.The minimum support is provided by the evaluation rule that leads to some type of specified minimum and specified maximum confidence for the selected dataset at the same time. Support (s), about the association rule, can be clear according to the ratio linked to the records and that encompass database . AssuranThe association rule provides some performance indicators of support and confidence. Several rules are generated that are still not efficient. The difference in the evaluation standards for the association rules is that different measures provide different characteristics. The confidence measure is the most commonly used in association rule mining . Lift meR package tool is used in order to implement the experiments with dataset gained from UCI machine learning repository was used . The priCoimbra breast cancer dataset was used and the data were collected from 116 randomly selected females whose age was at least 24\u2009years old. The sample is divided into 64 patients and 52 controls as given in R packages is used in This work aims to achieve constraints from accuracy association rules by applying the discretization algorithms that work to build models. The models are allowing for predicting breast cancer based on age and metabolic parameters. The dataset contains integer and numeric variables. We apply the discretization process in two steps. The first step is to get the cuts and the threshold values from all the segments. The second step is to use the threshold values to obtain different and categorical variables to generate the firm rules for the association and the experimental approach. The Apriori algorithm was implemented in a statistical programming language. The number of The same numbers are observed for the intervals and features of the transactions.The overlap of two adjacent intervals generates a cut point (the superior boundary of the first and inferior boundary of the next) and it was located at the center point of the overlapping region. The intervals were then merged and formed a unique interval. The interval is close to the mean values.Ten types of independent runs were developed on the original Apriori and discretization approaches. The performance was examined by the Apriori algorithm under various conditions. The process aims to determine and analyze the practical performance of the Apriori algorithm. The analysis defines the degree of discretization for the speedup of the achieved results as shown in Figure 3 illustrates the test results and comparison between Apriori algorthim and the traditional algorithm, using eleven independent experiments. The results shows that discretization apriori algorithm has a positive effect on enhancing time consuming.The association rules are developed to extract all the required databases for the possible combination of different features. The factors of confidence and support can be used to gain different values that were greater than the threshold values for the designed confidence. After the computation of the discretization process, the values of the computational analysis were reduced and the same values were obtained at the same time. Support and confidence factors can be used for obtaining how much each rule is interesting which has values for factors greater than a threshold value. The confidence is determined once the relevant support for the rules is computed.The discretization process is constrained to reduce the value of computational analysis and to obtain high accurate rules at the same time. Less numbers of association rules were generated by the Apriori discretization approach. The statistical strength, confidence factor, and support were used to measure the higher values and the confident rules. The reliability is higher and can be used to have decisions. The number of discovered rules was 4562 where the confidence value is 100% and the remaining values show higher yield factors at the average value of 92.18%. The diagnostic yields are good for the decision-making process and future diagnosis. In the other experiments, the comparison of results was carried out. The Apriori algorithm was used for the extraction of associated rules and then the discretization was developed. The methods of equal frequency discretization and equal width were used for the feature splitting. The features were converted into five intervals that affected the results. The comparison of the results is shown for three methods in The analysis of the experimental results describes the produced discretization by the Apriori algorithm. The results showed that it can be enhanced by the execution time and speedup and generate strong association rules. The increase is in terms of support and the terms of the confidence interval for the association rules. For acquiring constraint, we applied all of the confidence, lift, and Kuczynski measures. The result is shown in Hahsler  used theThis work aims to enhance the performance of Apriori by demonstrating the adaptation approach for Apriori using different conditions of discretization. The proposed discretization Apriori algorithm focused on a strong bond between balanced diversification and intensification during the long run. Adaptive strategy can be used to dynamically control all different and essential parameters that are used in the Apriori process that affect Apriori performance in a good manner. The second consideration of the process is to enrich the Apriori behavior that can be used to avoid different conditions from the trapped big volume challenge that is faced by the big data. This work is carried out to identify the solution of a problem related to finding useful association rules (facts) from some datasets. One of the major drawbacks is the treatment based on the continuous features and the difficulty associated with the domain knowledge for evaluating the interestingness related to the association rules. The considered success related to the work is mainly because of the supervised multivariate procedure that was used for discretizing and for the continuous features for generating the rules.The proposed approach pinpoints the limitation in a variety of electronic health record (EHR) dataset which includes different types of features that need to spill the features based on behavior and contents. The future work extends the proposed approach to combine the dependent and independent features to be applicable for automated deep learning methods."}
+{"text": "This Retraction follows an Expression of Concern and Correction relating to this article previously published by Portland Press.Bioscience Reports at the request of the Editor-in-Chief and the Editorial Board following receipt of a notification from a reader, alerting the Editorial Board to duplications in the original version of Figure 3D at the time of publication, duplications in Figure 3E introduced to the paper during the Correction, and a duplicated panel in Figure 4D that overlaps with several prior publications by different authors.This article is being retracted from The authors have been contacted in regards to the Retraction, and have not responded to the Journal's queries and the concerns raised. Given the extent of the issues raised, the Editorial Board stand by the decision to retract the article."}
+{"text": "The paper addresses the problem of modeling a smooth contour interpolating a point series belonging to a curve containing no special points, which represents the original curve with specified accuracy. The contour is formed within the area of possible location of the parts of the interpolated curve along which the curvature values are monotonously increased or decreased. The absolute interpolation error of the point series is estimated by the width of the area of possible location of the curve. As a result of assigning each intermediate point, the location of two new sections of the curve that lie within the area of the corresponding output section is obtained. When the interpolation error becomes less than the given value, the area of location of the curve is considered to be formed, and the resulting point series is interpolated by a contour that lies within the area. The possibility to shape the contours with arcs of circles specified by characteristics is investigated. Modeling is an effective tool for investigating objects, phenomena, and processes. Geometric modeling of an object often determines its functional properties. Such objects are, first of all, items bounded by functional surfaces which ensure the laminar nature of the item\u2019s flow around by the environment\u2013gas, liquid, or loose materials ,2,3. ExaComplex surfaces are typically modeled based on linear frameworks whose elements are formed by interpolation of point series. The operating performance of the item is ensured by the geometric characteristics of the interpolated curves.The improved aero- and hydrodynamic properties of the surface ensure the use of lines with regular variations in the values of characteristics and a minimum number of special points according to the statement of the problem as elements of the framework ,5. For aIf a surface is modeled with the aim of creating a copy of an existing item (reverse engineering), the task of interpolating a point series becomes even more complex. In this case, the interpolation accuracy requirement is added to the requirement of ensuring the necessary characteristics of the interpolated curve .In order to solve the stated problem, it is necessary to develop an interpolation method which ensures control of the change pattern of its characteristic values along the modeled curve, the possibility of local correction of the resulting solution, and prevention of uncontrolled emergence of special points.The possibility of local correction of the shape of the interpolated curve while controlling its characteristics at output points is provided by methods of interpolation of the point series with a contour. The contour is formed by sections of analytically defined curves, which are connected at output points with a specified order of smoothness . These aAmong the methods of interpolation of the point series with a contour, B-spline interpolation provides the greatest possibilities to adjust the sections of the contour.A spline is defined by a set of control points, each of which has a transition function. It is a composite curve, each segment of which defines a separate equation. The curve approximates the broken line connecting the control points. The configuration of this broken line makes it possible to control the presence of inflection points in the B-spline.The main disadvantage of B-spline interpolation as well as interpolation with other analytically defined curves is the lack of mechanisms to control the occurrence of points with extreme curvature. This disadvantage reduces the possibilities of using analytically defined curves while modeling shapes with the given characteristics and, above all, contours designed for modeling surfaces with specified functional properties.Papers ,9 solve The problem of forming a contour along which the radii of the arcs of circles change monotonically as well as the problem of ensuring the specified interpolation accuracy is not considered in ,9.The aim of the study is to develop a method for forming a smooth contour interpolating a point series that represents a monotone curve with specified accuracy.develop a method for forming the area of the monotone curve interpolating a given point series whose width does not exceed a specified value;to develop a method for forming a smooth contour consisting of arcs of circles, which interpolates the given point series and is located within the area of the monotone curve;to investigate the possibilities of the proposed method in solving the problem of interpolation of a given point series.In order to achieve this aim, the following objectives should be pursued:analyzing a output point series, which makes it possible to identify its parts that can be interpolated by a monotone curve;determining the absolute interpolation error of a point series by a monotone curve.Formation of the area of location of the monotone curve is illustrated by the point series, which can be interpolated by a curve with a monotonous increase in the radii of curvature. Let us consider the following tasks:The analysis of the output point series is based on determination of the radii of adjacent circles (AC), each of which passes through three consecutive points in the series. The part of the point series along which the range of AC increases or decreases may be interpolated by a monotone curve along which the radii of curvature increase or decrease accordingly.The absolute interpolation error of a section of a point series of a monotone curve is determined by the width of the area bounded by arcs of the corresponding AC  can be used as a criterion for the correct assignment of tangent lines in the formation of a contour with specified accuracy representing the monotone curve. For section of the curve undaries :a boundaIf the values of absolute interpolation error are greater than the given value, more interpolated curve points specifying the interpolated curve must be assigned to the corresponding sections of the original curve.If the values of absolute interpolation error The final solution can be represented in the form of an accompanying broken line, the distance from which to the curve with the specified geometric characteristics does not exceed a predetermined value. The use of contours consisting of straight line sections in the modeling of functional surfaces reduces their aero- and hydrodynamic properties Let us define the constraints on the location of the section of the curve located between two consecutive output points.i point of the series, the range is bounded by the tangent to The most accurate estimate of the area of the monotone curve is possible when the position of the centers of curvature andACi+1 .Once the tangent to the monotone curve has been assigned at each of the output points, the upper and lower boundaries of the area of possible location of the monotone curve interpolating the point series are determined.A  into (5) after transformations, we obtain:i, and with The upper boundary is formed by the arc The problem of determining the upper boundary of the area of the monotone curve is reduced to calculating the coordinates of the center of The position of Ti+1,Ti]  is deterAs a result of manipulations similar to those done in the derivation of expression (6), we obtain:i. Similarly, the position of At the specified position of normals Based on this criterion, let us determine the area of the monotone curve, driven by a random point series.iProvided that the radii of curvature along the curve increase monotonously, the minimum radius of curvature at point  point i . The mini and to M\u00a0i, the maximum possible radius of curvature The maximum radius of curvature that can be assigned at point i and i and All curves with monotonous increase of the radii of curvature, having at points If a monotone curve interpolates a sequence of points 1\u2026n, then the minimum radius of curvature can be equal to zero only at the first point, and the maximum radius can be equal to infinity only at the last point.In this case, the lower boundary of the area in which the curve is located shall be determined in the following way.In sections 1 and 2, the area is bounded by the arc of the circle passing through point 1 and having a common tangent to the curve at point 2. The specified circle is taken as the tangent circle at point 2, whose radius is the minimum possible. Let us mark this circle as Taking Based on the location and the size of The upper boundary of the area of location of the monotone curve is determined starting with the last section by the following scheme.nIn section In section The upper boundary of the area of location of the curve is determined in sequence from section to section, similarly to the boundary of section The absolute error of interpolation ectively .If the interpolation error of the output point series is greater than the assigned value, the width of the area of location of the curve is reduced by assigning intermediate points belonging to it. The intermediate point shall be assigned to the line passing through the middle of segment After the interpolation error becomes less than the specified value, the area of the monotone curve is considered to be formed, and the resulting point series is interpolated by a contour which lies within the area of location of the curve. It is appropriate to take the minimum possible processing error on a numerical control machine, which is on error .the presence of a common tangent to the contour and the monotone line curve at output points;the increase of the radii of curvature along the contour in the same direction as the monotone curve.To solve the posed problem, it is necessary to ensure the following:Let us consider the possibility of forming contours with specified characteristics of the arcs of circles.The formation of a contour consisting of two arcs of circles which replace section i and passing through some point assigned within the area of location of the monotone curve. For instance, this point may be the middle of a segment that is bounded by the intersection points of the median of triangle i, T, The circle defining the first arc K. As a result, we obtain a circle with the correlation of the radii:The circle to which the second arc By similarly forming the arcs replacing the remaining sections of the monotone curve, we get a contour interpolating the whole point series along which the radii of the arcs of circles increase monotonously.The monotonic increase of the radii of the circles along the contour in the same direction as the increase of the radii of curvature along the monotone curve, as well as the common tangents of the contour and the curve at output points, ensure the position of the contour within the area of location of the monotone curve.The main drawback of forming the contour by arcs of circles is the irregular variation of the values of curvature at the points at which they are conjoined. Reducing the effect of the mentioned drawback on the functional characteristics of the surface while using the contour as an element of the framework is possible by increasing the number of arcs constituting the contour while reducing the difference between the values of the radii of the circles that determine them.The possibilities of the method for shaping contours proposed in the paper are investigated by the example of interpolation of a sequence of ten points. The position of the specified points was determined based on the condition of a monotonous increase in the AC radii along the point series. The characteristics of the point series: coordinates of output points\u2014i and The monotonous increase of  and i+1 . In the The next step in formation of the contour at output points is denoting the position of the tangents to the monotone curve interpolating the point series and the refined area of its possible location at each of the sections. The positions of the tangents are defined within the ranges bounded by the corresponding AC . The lenThe boundaries of the area of location of the interpolated curve are determined by the procedure presented in The maximum absolute interpolation error was 1.1281 mm in section 9...10.In order to reduce the maximum absolute interpolation error in reference section 9...10, an intermediate point and a tangent line to the monotone curve are assigned. The intermediate point is assigned within the area of location of the interpolated curve in section 9...10 on a line which passes through the middle of section  at right angles to segment B. As a result, we obtain a point series consisting of 11 points where the intermediate point is assigned No. 10. The position of the point is determined by the coordinates The characteristics of the area of possible location of the monotone curve interpolating the point series are given in For the obtained point series, the maximum absolute interpolation error was 0.2257 mm in section 8...9. By assigning intermediate points, it is possible to form a point series consisting of any number of points, which determines the arbitrarily small interpolation error of the monotone curve.The characteristics of the contour consisting of smoothly joined arcs of circles interpolating a sequence of eleven points are given in Each of the sections of the contour consists of two arcs of circles of radius Formation of the sections of the contour by the procedure presented in The method proposed in the article was tested when creating a model of an impeller of an axial and radial flow turbocharger. The initial data for the design of the geometric model of the impeller were taken from a drawing designed for quality assurance of the finished product. The drawing contains tabulated data specifying an ordered array of 77 points belonging to the blade surface. The hub is driven by the axis of rotation and the generating line.The model of the blade surface was designed on the basis of a framework, consisting of eleven plane sections. Each plane section was initially represented by seven points. Analysis of the original point series showed a monotone dynamics of changes in the values of the radii of the AC along each of them.For example, the original point series representing the fourth section of the blade surface specifies the following radii of successive AC\u201423.65, 29.18, 40.37, 65.74 and 160.08 mm. The maximum error with which the original point series represents a monotone curve is The eleven formed contours, each of which interpolates a point series consisting of twenty-five points, make up a family of generating lines of the framework of the blade surface model. The contours were imported into the CAD system SolidWorks and a model of the working surface of the blade was obtained using the \u201cLoft Surface\u201d function of the CAD system .Based on the obtained frameworks of the hub and the blades, a CAD model of the compressor impeller was created. The resulting model was used as the given data for creating a program for processing the impeller surfaces on a CNC machine in the CAM system PowerMill. The model of the product was imported from the CAD system SolidWorks to the CAM system PowerMill is using direct data translators. The program control for NC manufacturing was created using the standard functions of the CAM system.forming the area of possible location of the monotone curve interpolating a given point series the width of which does not exceed the given value;forming a smooth contour consisting of the arcs of circles which is located within the area of location of the monotone curve.The problem of forming a smooth contour which interpolates a point series and represents a monotone curve with specified accuracy is solved in the paper. The following methods have been developed in order to achieve the objective:The area of possible location of the monotone curve is formed as closed contours which are joined at output points. The width of the area is determined by the maximum possible distance between the lines with the specified characteristics. All the monotone lines interpolating the point series are located within the area. The developed method provides an arbitrarily wide area by assigning intermediate points for the output point series.The developed method for forming a contour within the area of the monotone curve ensures its replacement with a contour with an error which does not exceed the width of the area.The possibilities of the proposed method have been investigated in solving the problem of interpolation of a point series consisting of 10 points using the CAD system SolidWorks. By solving the test case, it has been established that the minimum possible interpolation error is provided by a contour along which curvature values change monotonously and which has common tangents with the monotone curve at output points. The developed method for forming a contour by the arcs of circles meets the stated requirements.The main field of use of the developed method is modeling of linear elements of frameworks of surfaces with improved aero- and hydrodynamic properties, including the use of reverse engineering.The main disadvantage of the proposed method is that the curvature values at junction points of the sections of the contour are irregular. While solving applied problems, the effect of this disadvantage can be eliminated by increasing the number of sections."}
+{"text": "All patients provided written informed consent.\u201dFollowing the publication of the above article, the authors have realized that, in the Declarations section on p. 10, they presented an incorrect approval number from the Ethics Committee in question; the statement here should have read as follows: \u201cThe present study was approved by the Ethics Committee of the Affiliated Hospital of Shaoxing University (approval no. Ethics approval and consent to participate section of the paper. They thank the Editor of Oncology Letters for allowing them the opportunity to publish this corrigendum, and apologize to the readership of the Journal and to the Ethics Committee of the Affiliated Hospital of Shaoxing University for any inconvenience caused.The authors regret their oversight in providing the incorrect approval number in the"}
+{"text": "This research explores the life circumstances of older persons (aged 60 years and above), focusing on the sociodemographic and socioeconomic conditions of those who live alone. We situate the living arrangements of older persons within the global context of changing household structures in 76 countries from all regions of the world. Older persons who live alone are among those most likely to need governmental and other forms of social support. The analysis presented here is crucial for supporting policy responses to the needs of older persons, including the special attention they require during the current COVID-19 crisis. It also supports the operationalization of the Madrid International Plan of Action on Ageing (MIPAA), the realization of United Nations Principles for Older Persons , and the broader framework of the Programme of Action of the International Conference on Population and Development(ICPA-POA)."}
+{"text": "In the context of a pandemic, in which disparities are accentuated, we emphasize the fundamental role of Nursing in the formulation of public policies committed to the reduction of health inequalities, considering its capacity for collaborative and inter-professional work, inter-sectoral action and the use of permanent education for the transformation of work, in the context of intense changes that require sensitivity and creative and relational capacity, attributes historically developed by Nursing.It should be noted that 2020 was considered the International Year of Nursing, with the launch of the"}
+{"text": "We discuss a particular non-relativistic limit of NS-NS gravity that can be taken at the level of the action and equations of motion, without imposing any geometric constraints by hand. This relies on the fact that terms that diverge in the limit and that come from the Vielbein in the Einstein-Hilbert term and from the kinetic term of the Kalb-Ramond two-form field cancel against each other. This cancelling of divergences is the target space analogue of a similar cancellation that takes place at the level of the string sigma model between the Vielbein in the kinetic term and the Kalb-Ramond field in the Wess-Zumino term. The limit of the equations of motion leads to one equation more than the limit of the action, due to the emergence of a local target space scale invariance in the limit. Some of the equations of motion can be solved by scale invariant geometric constraints. These constraints define a so-called Dilatation invariant String Newton-Cartan geometry."}
+{"text": "The Danube is promoted as a pan-European river, what can be justified for instance by the vast range of its drainage basin, covering 19 countries on both sides of the historical border diving Eastern and Western Europe. Differentiation of imaginations of Danube course from the perspective of 7 European cities, based on research covering 1577 respondents, conducted between 2005\u20132007 and 2016\u20132018 has been presented in the paper. Maps presenting the generalized imagination of river course have been generated for each city. It has been proved that in spite of substantial political, economical and symbolical importance of this river for big part of Europe, the course of Danube remains unknown for inhabitants of its Western part, in parallel to more correct recognition of the river by students from Eastern Europe. It has been shown that the perception does not change despite the progressing integration processes. The Danube occupies an important place in the European space not only due to its length or the surface of its drainage basin but mostly thanks to its pan-European character in economical and cultural terms. 10 countries it flows through and the further 9 ones lying in its drainage basin make Danube a kind of symbol of international cooperation and reconciliation between the East and the West of Europe. The geopolitical, economical and cultural importance of the Danube for Europe has been recognized for a long time ; nowadayThe Danube has also become a symbol of significant Central European or Balkan cities, like Vienna, Budapest or Belgrade. The name of Vienna in Slovenian is Danube, which shows the connection of Vienna with the Danube in the minds of the nations. Its importance for the region is also demonstrated by the concept of Donauraum, defining the community identity of the Danube regions . The DanThis symbolical importance of the Danube induced the authors to question about the universality of perception of the river from various European perspectives and about the change of the perception of its course during the unification of the Danube countries, incl. within the European Union. Is the knowledge of its course so much common in the context of importance attributed to it, and is the Danube so well recognized that a European brand can be generated basing on the river, as proposed by Koev ? Or, in The defining basis of the research is the concept of The image of the perceived space stored in the human mind creates the so-called cognitive map , referreterrae incognitae of our times. The breakthrough in the research was brought by the 1960s and the works of the urban planner Kevin Lynch [The research was based on the methodology taken from studies dedicated to the perception of space, using the methods of sketch map analysis. Proposals for researching the perception of the space and the space experienced by humans itself appeared in geography in the 1940s, when Tolman for the first time defined \"cognitive mapping\" as the way people think about space , and Wriin Lynch  up till in Lynch , while tin Lynch ,22. The in Lynch , the perin Lynch , while tin Lynch . The metin Lynch ,27, percin Lynch , human lin Lynch , as wellin Lynch  or, morein Lynch . Besidesin Lynch ,33. The Although the term \"mental map\" is understood broadly ,35, the From the perspective of obtaining a spatial image representing an individual or being a cognitive map of a group, drawing a sketch map ,40, undeRivers are an important element of research on landscape perception , as alreThe research was conducted in seven European cities: B\u0103l\u0163i (Moldova), Bern (Switzerland), Cork (Ireland), Krakow (Poland), Ni\u0161 (Serbia), Porto  and Uppsala (Sweden). The selection of the cities was based on their multifunctional character and high rank in the settlement hierarchy of particular countries. In order to avoid the potential impact of metropolitan character of the city on perception of the space by its inhabitants, the capital cities were excluded from the study . The research covered students from 38 classes in 19 selected schools in 2005\u20132007 and again students from 34 classes in 17 schools in the same cities in 2015\u20132018. Two or three schools were selected in each city . The respondents were the students of penultimate classes of general secondary schools which completion enabled continuation of studies in high schools. The study covered mostly respondents in the age between 16 and 18 years (94% of respondents were of such age). The age differences between the respondents derived mostly from different education systems and the related differences in the age of commencing education. Such selection of respondents enabled comparing social groups of similar educational competences, thus mitigating the differentiating impact of knowledge and age on perception of the space. The respondents were asked to perform the following exercise: \u201eBelow is a map of Europe. Put down in the right place Danube River\u201d. The contour map was of 15x12 cm dimensions and the state borders were presented on it .The exercise was a part of a broader questionnaire; the respondents had 25 minutes to fill it. The outcome of the research comprised of 806 surveys in the first research period, and 357 of them (44%) included the Danube river drawn in the maps. In the second period, 771 surveys were obtained, with Danube present in 349 (45%) of them. The distribution of frequency of drawing the Danube in particular cities has been shown in Already the comparison of the drawn lines with the course of the Danube river would enable in-depth analysis of feedback of respondents from various cities . It was Perception of the course of the Danube is very much differentiated, depending on respondents\u2019 places of living. Already the share of respondents who took up the task  shows thIn case of respondents from Western European cities, the recognition of the Danube course is very poor, except of Bern. The wrong answers show significant Westcentrism, visible in marking the Danube course in Germany and, to less extent, France, what can be particularly well noticed in the drawings of respondents from Uppsala . This isCases of maps generated by respondents from Bern and Krakow are also interesting: there, besides of concentration of lines determining the imagined course of the Danube , more intensive concentration of indications in the North-East of Austria, near Vienna, is visible. This almost punctual accordance between the course of the river and its placing results from its strong symbolical association with the Austrian capital city. Much less concentration can be found nearby Budapest, thus corroborating the hypothesis of Westcentrism in space perception. In spite of the visible Westcentrism, the map presenting the generalized results of perception of the Danube by the respondents  matches Thus, the nature of the river course drawn by the respondents assumes three types of compliance:linear: the course corresponds to the actual course of the river. Characteristic for respondents from Ni\u0161 (Serbia) and B\u0103l\u0163i (Moldova) for whom the Danube is a cultural value or a window to the world;punctual: with a clear concentration of the marked course in tourist cities associated with the presence of the river, mainly Vienna and Budapest. Characteristic for respondents from Krakow and Bern;superficial: the superficial nature of the created image, resulting from the scattered, imprecise placement of the river, effecting from shortage of knowledge about its course. Characteristic for respondents from Western Europe.The centroids marking the average point of the drawn lines of the Danube differ significantly between the compared years only in two cases. In the case of respondents from Uppsala and Porto, who marked the river\u2019s course relatively less accurately, their center of gravity shifted to the east, which can probably be explained by the territorial expansion of the European Union in this direction. Another characteristic of the perception of the space is also visible: ethnocentrism, visible in the placement of centroids closer to the respondents\u2019 place of residence. For Ni\u0161 it is southern Hungary, for Bern the Czech Republic, for Krakow\u2014Slovakia, and for B\u0103l\u0163i\u2013Romania.Sketch maps allow for a more complete understanding of the level of geographical knowledge and the ways of its transformation and use , therefoThe applied sketch map method clearly shows the differences in the location of the Danube, drawn on the map of Europe. The simplicity of the data collection method allowed to eliminate the limitations related to different artistic abilities of the respondents , and theThree types of concentration  have been identified in the social perception of the river course. The course of the Danube, a river that is symbolic for Europe, generally remains a mystery to its inhabitants, what mainly concerns Western European respondents from cities located far away from the Danube. This may suggest that it might not be an object full of meaning and value for them, as the apologists of the Danube significance would imagine. They represent the superficial nature of the social perception of the river, characterized by its incorrect location, resulting from the lack of knowledge about its course, as well as the lack of experience of the river itself, which in turn result from, inter alia, the distance function; this is confirmed by the results of research on the influence of distance on the perception of space . The larIt is surprising that the perception of the Danube course has not changed over more than a dozen years after the European Union\u2019s expansion to the East and the related better understanding of Central and Eastern Europe. The centroid has shifted slightly, indicating that the Danube in social perception has shifted more to the East, but the types of social perception of the river have not changed during this period. This calls into question the uncritical treatment of the Danube as a symbol of reconciliation between the East and the West, and, in a broader context, raises the question about the reasons for the low importance of the river in the perception of the West.The pan-European spirit which the river is expected to personify seems to be present rather in Eastern than in Western Europe, and in particular in countries located on the Danube. The respondents from the western part of Europe often draw the Danube in areas recalling the course of the Rhine, suggesting that from their point of view, the Rhine is actually the most important river in Europe. In that context, the words of Magris from 30 years ago, when the iron curtain was still in place (\u2019the sensation of travelling eastward across Europe, from the world of the Rhine to the world of the Danube, from Europe to non-Europe\u2019  seem stiDespite the concerns of some researchers that the mental map metaphor is a misleading analogy to the representation of geographical knowledge , the resAt the same time, research on the perception of space in a dynamic approach seems to be a good direction in understanding the changing world, and the applied method of perception of linear objects looks promising for further research on the images of geographical space."}
+{"text": "This Retraction follows an Expression of Concern relating to this article previously published by Portland Press.Bioscience Reports at the request of the Editor-in-Chief and the Editorial Board following receipt of a notification from a reader, alerting the Editorial Board to concerns in Figure 8A, which in part overlap with those published in Journal of Cellular Biochemistry (10.1002/jcb.26330). In addition, the Editorial Office has identified regions of duplication in Electron microscope IDD panel of Figure 1.This article is being retracted from The authors have been contacted in regards to the Retraction, and have not responded to the Journal's queries and the concerns raised. Given the extent of the issues raised, the Editorial Board stand by the decision to retract the article."}
+{"text": "Bioscience Reports at the request of the Editor-in-Chief and the Editorial Board following receipt of a notification from a reader, alerting the Editorial Board to the backgrounds of the Western blots throughout the paper which unexplainedly contain the same features.This article is being retracted from The authors have been contacted in regards to the Retraction, and have not responded to the Journal's queries and the concerns raised. Given the extent of the issues raised, the Editorial Board stand by the decision to retract the article."}
+{"text": "The geriatric psychiatry outpatient clinic provides assessment of the elderly Veteran with mental illness and behavioral and psychological symptoms of dementia. I will describe strategies developed and implemented in this setting to provide education to the caregiver (family) to improve early identification of delirium, depression and cognitive impairment. This education proved to reduce the number of pharmacological treatment and increase the use of nonpharmacological interventions based on \"what matters to the patient\" and following the BEERS criteria guidelines. One of the most important outcomes of the education and evaluation in the geriatric psychiatric clinic was a decrease in number of emergency room visits of elderly, specifically those with dementia."}
+{"text": "Bioscience Reports at the request of the authors due to an image duplication in Figure 5G that the authors believe was introduced during the preparation of their figures. All authors believe that the integrity of the manuscript is therefore impaired, making it easy to erroneous understanding and wish to retract the article.This article is being retracted from The Editor-in-Chief and Editorial Board agree with the retraction."}
+{"text": "The order of Figs In the Linking oviposition to life history and survival subsection of the Materials and methods, the sixth sentence of the second paragraph should read: We hypothesized three sets of paths based on the relationship between oviposition and larval survival in explaining life history parameters and survival: a Combined Model , a LarvaIn the Linking oviposition to life history and survival subsection of the Results, the first sentence of the first paragraph should read: The final model for Culex quinquefasciatus resulted in a single variable (shading) affecting the number of eggs produced by each female . The lasThe first sentence of the second paragraph of the same subsection should read: The final path model for Aedes albopictus contained paths between independent variables and most dependent variables . The las"}
+{"text": "The fibula is only indirectly involved in the composition of the human knee joint and has therefore been neglected in the research on knee osteoarthritis. Nonuniform settlement of the proximal tibia plateau is clinically defined as when the height of the medial tibial plateau is lower than that of the lateral side in medial compartment knee osteoarthritis (KOA). The non-uniform settlement of the proximal tibia plateau may be caused by fibular support on the lateral side. Orthopedic surgeons practice partial fibulectomy based on the clinical manifestation of nonuniform settlement, and this technique has been shown to reduce pain and improve function in patients with medial compartment KOA. However, this hypothesis of the mechanism of nonuniform settlement lacks an anatomical basis.The P45 polyester plastination technique was used to prepare sections of the proximal tibiofibular joint to investigate the distribution of the bone trabeculae in the region of the lateral tibial plateau.There was uneven distribution of trabeculae in the lateral condyle of the tibia and the head and neck of the fibula. The fibula and the posterolateral cortex of the shaft of the tibia united to form an arch beam via the tibiofibular joint. Many thick, dense trabeculae were present in a longitudinal direction above the tibiofibular arch.The fibula supports the lateral tibial plateau, and the trabeculae were concentrated above the tibiofibular arch. Knee osteoarthritis (KOA), a degenerative joint condition, is one of the most prevalent chronic health conditions in the world, and is characterized by synovial membrane inflammation, subchondral bone sclerosis, articular cartilage degradation, and osteophyte formation . The medA total of 27 formalin-fixed adult knee joint specimens were studied. The specimens were taken from cadavers used in the teaching of human body dissection at Dalian Medical University. There were no signs of tumors, congenital malformations, fractures, severe osteoarthritis, or other related pathologies in the specimens selected for study. The Dalian Hoffen Biotechnology Co., Ltd., prepared serial sagittal, coronal, and horizontal sections of knee joints, using the P45 plastination technique, producing 15 sets of plastinated sagittal sections, 8 sets of plastinated coronal sections, and 4 sets of plastinated horizontal sections.P45 plastination was carried out according to the standard procedure described by Sui and Henry . Freeze The lateral condyle of the femur and tibia and the lateral compartment of the knee joint were seen in these sections. The proximal tibiofibular joint, composed of the head of the fibula and the lateral condyle of the tibia, was showed on the posterolateral side of the tibial plateau. Uneven distribution of bone trabeculae was observed in the lateral condyle of the tibia. In the lateral condyle of the tibia, there were mainly longitudinal thick trabecular clusters beneath the articular surface (black arrow), while in the anterior part of the lateral condyle of the tibia, near the tibial tuberosity, the trabeculae were found to be sparse, very small, and reticulate (black triangle). In the posterolateral part of the lateral condyle of the tibia, the trabeculae above the tibiofibular joint were also small and sparse (white triangle). At the level of the metaphysis of the tibia, it was found that an arched construction was formed by the union of the shaft of the fibula and the posterior lateral bone cortex of the shaft of the tibia, via the tibiofibular joint . The bone trabeculae in the lateral condyle of the tibial plateau (black triangle) were slightly denser than those in the medial condyle (white triangle); the cortex was thickened accordingly on the lateral side of the oblique posterior wall of the tibial metaphysis. However, in the lateral edge of the lateral condyle, above the tibiofibular joint, the trabeculae were thin and irregular. Thin and sparse trabeculae were also present in the head of the fibula (black square frame).This section showed the structure of the metaphysis of the tibia and the head of the fibula. The metaphysis of the tibia was triangular in shape, and a large number of dense and reticulated trabeculae were found in three regions: near the posterior lateral cortex (a), the medial cortex (b), and deep to the tibial tuberosity (c). Similarly, dense trabeculae were formed in a reticulated pattern in the posteromedial half of the head of the fibula (d). These areas of dense and reticulated trabeculae in the metaphysis of the tibia and the head of the fibula were united by the tibiofibular joint, and could form a solid trabecular foundation of the knee, i.e., a tripartite construction of dense trabecular areas.According to the currently held view, the fibula is not directly involved in the composition of the knee joint. The fibula, therefore, has been neglected in research on knee osteoarthritis . In the Previous studies have shown that the proximal tibia mainly comprises cancellous bone. The bone density of the proximal fibula and tibia decreases in the following order: fibula, medial plateau, lateral plateau, and middle proximal tibia . McNeil The process of human aging is accompanied by a decrease in bone mass, especially in the load-bearing joints such as the knees, hips, ankles, and spine . A suppoMoreover, the geometry of the tibial plateau has attracted more and more attention from researchers in recent years. A study has shown that the inclination of the tibial plateau may be a predictive risk factor for anterio cruciate ligament injury . AccordiCollectively, the findings in the present study have revealed a novel correlation between the proximal fibula and tibia, which might provide an anatomical basis for the further treatment of KOA, and an understanding of the risk factors for anterio cruciate ligament injury.In future research, quantifying the information of trabecular bone at the arched beam will have important implications for further treatment of KOA.An arch beam was formed by the union of the fibula and the posterolateral cortex of the tibial shaft via the proximal tibiofibular joint. This may play an important role in the transfer of mechanical loads from the articular surface of the lateral condyle of the tibia. The tibiofibular joint forms an indispensable keystone for the arch beam. The fibula may be an important factor in the diagnosis and treatment of knee pathology."}
+{"text": "Bioscience Reports at the request of the authors following receipt of a notification from a reader, alerting the Editorial Office to unusual data presented in Figures 2 and 3.This article is being retracted from The Editorial Office requested the raw data from the authors and this has not been provided. The authors wish to retract the article. The Editor-in-Chief and Editorial Board agree with the Retraction."}
+{"text": "Bioscience Reports at the request of the Editorial Board following receipt of a notification from a reader, alerting the Editorial Office to duplications in the Western blots of Figure 2D and flow-cytometry in Figure 3A which have been published in several other publications by different authors.This article is being retracted from The authors contacted the Editorial Office to request a Correction however, given the extent of the issues raised, the Editorial Board stand by the decision to retract the article. The authors disagree to the Retraction."}
+{"text": "The article cited above  has beenFollowing publication, concerns were brought to the attention of the publisher. The article was reassessed in collaboration with the Editors-in-Chief of the journal. The authors agreed to retract the article and apologize for any inconvenience caused by the removal of this article."}
+{"text": "The journal and Chief Editors retract the 31 March 2021 article cited above.Following publication, concerns were raised regarding the validity of the data in the article. The authors failed to provide the raw data or a satisfactory explanation during the investigation, which was conducted in accordance with Frontiers\u2019 policies. Given the concerns, and the lack of raw data, the editors no longer have confidence in the findings presented in the article.This retraction was approved by the Chief Editors of Frontiers in Oncology and the Chief Executive Editor of Frontiers. The authors have not responded to any correspondence regarding the retraction."}
+{"text": "The role of Humanities, Arts and Cultural Gerontology in gerontology and geriatrics curricula finds a metaphor in the rapidly evolving field of medical and health humanities, with which this author has been involved for three decades. Behind the call for increasing humanities and arts scholarship in the pedagogy of both fields lies the challenge of establishing an interdisciplinary nexus of scholarship that avoids the challenges of dilettantism and gestures such as providing lists of novels and movies. This presentation draws on the presenter's bibliometric research in the medical and health humanities which indicates authorship in the majority to be either solely from the humanities or from healthcare, with little indication of joint working in either authorship or acknowledgements (the scholar's courtesy), and explores the background issues of academic culture with a view to proposing solutions to elevate the inclusion of humanities and arts as a significant element of gerontology education."}
+{"text": "In the published article, there was an error regarding the order of funding agencies as listed in the Funding statement. The correct Funding statement appears below.This work was financially supported by the Youth Foundation of Natural Science Foundation of Hainan Province (320QN306), the China Agriculture Research System of MOF and MARA (CARS-31-02), and the Lancang-Mekong Cooperation Special Fund.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "This Retraction follows an Expression of Concern relating to this article previously published by Portland Press.Bioscience Reports at the request of the Editor-in-Chief and the Editorial Board following receipt of a notification from a reader, alerting the Editorial Board to the Western blots in Figures 4C and 5B which are duplicated in several other publications.This article is being retracted from The authors have been contacted in regards to the retraction, and have not responded to the Journal's queries and the concerns raised. Given the extent of the issues raised, the Editorial Board stand by the decision to retract the article."}
+{"text": "In the past decade, cancer care in the Philippines has advanced in response to the complex heterogeneity inherent to the disease and the constantly increasing number of patients. Central to this development is the increased awareness and universal acceptance of the multidisciplinary team (MDT) approach in providing cancer care to optimize outcomes where medical oncologists play a vital role. This position paper summarizes the unique and multifaceted roles of the medical oncologist in ensuring that the best possible care is given to patients with cancer by actively participating in the whole spectrum of the patient\u2019s journey\u2014from diagnosis, treatment, supportive care, until providing palliative care and addressing end-of-life issues Cancer is a complex and highly heterogenous disease that is best treated within the context of a multidisciplinary team (MDT) of highly qualified healthcare professionals , 5. CentIn response to the steadily increasing number of patients diagnosed with cancer and its increasing cost of treatment in the Philippines, the National Integrated Cancer Control Act (NICCA) (Philippines Republic Act 11215) was signed in February 2019 to strengthen cancer control in the country, increase cancer survivorship and reduce burden on families and cancer patients. At the heart of the law and critical to its implementation is the NICCA council which is in charge of crafting the implementing rules and regulations.As the NICCA council is in the process of defining the roles of the different specialists, this position paper by the Philippine Society of Medical Oncology summarizes the essential contribution of medical oncology and the vital roles of medical oncologists in the holistic treatment of patients with cancer especially in the setting of a multidisciplinary approach.To become a medical oncologist in the Philippines, a physician has to complete three years of specialty training in internal medicine and thereafter pass the certifying examinations of the Philippine Specialty Board of Internal Medicine. This is followed by two to three years of subspecialty training in medical oncology. This training covers the entire gamut of the systemic treatment of cancer from initial evaluation, diagnosis, determination of appropriate, patient-tailored systemic therapy and its correct administration. This also includes the prevention and management of the adverse effects of treatment, which is a crucial element of cancer care. Finally, the medical oncologist is trained in post-treatment surveillance and the tenets of survivorship care. In short, medical oncologists are trained in the comprehensive care of patients living with cancer. Upon completion of their prescribed training, all medical oncologists are certified by the Philippine Specialty Board of Medical Oncology in one of the most rigorous subspecialty board examinations in the country. Even after certification, medical oncologists actively participate in continuing medical education (CME) programs to keep them up to date in the rapidly progressive and dynamic field of oncology. This is done to ensure that Filipinos living with cancer receive the highest standards of quality care , 8.The complex heterogeneity that characterizes the pathology of cancer has paved the way for the universal acceptance of the multidisciplinary team (MDT) approach in providing cancer care to optimize outcomes.The core function of a multidisciplinary team (MDT) is to bring together a group of healthcare professionals from different subspecialties to determine the optimal treatment plan for the patient . It is iAt the core of an MDT approach is the desire to provide quality patient-centered and patient specific care. The additional benefit of an MDT is the use of evidence-based decision-making, leading to the judicious use of limited resources, which maximizes benefits for both the individual patient and the health care system within which the MDT operates.To this end, the experience of the Philippine General Hospital Polyp and Colorectal Cancer Study Group can serve to illustrate how a local MDT, with members performing clearly defined roles, can maximize patient outcomes. It has recently published its three-year data, which shows that survival outcomes of patients managed under the PhilHealth colorectal cancer Z-package program at the Philippine General Hospital is comparable to our regional neighbors and even to more developed  countries . This seThe medical oncologist is an essential member of the MDT who coordinates among the multi-specialty members of the team, integrating all the needs of the patients in the treatment plan. The composition of the MDT depends on the local availability of qualified healthcare professionals in a specific locality, but the contribution of the medical oncologist is essential to integrate all the information in the interest of the patient, regardless of the setting .Our understanding of cancer has evolved from being a single, homogenous, and organ-based disease to that of a highly complex, heterogenous, and constantly changing group of molecularly diverse diseases. These diseases can occur simultaneously at different sites or evolve within the same organ . This chTo provide comprehensive and safe services to an increasing number of patients, the Philippine Society of Medical Oncology (PSMO) has taken large strides in producing more subspecialists without compromising quality. More hospitals across the country now serve as training institutions for internists who wish to subspecialize in this field. To ensure optimal geographical distribution of medical oncologists, the newest training programs of the PSMO have started in Cebu (Visayas) and Davao (Mindanao) .Founded in 1969, the PSMO is a professional non-profit organization of board-certified Medical Oncologists that aims to advance the science, the ethical, and the holistic practice of cancer care in the Philippines. It continually strives to be an internationally recognized organization of competent and compassionate medical oncologists inspired and committed to integrate a multidisciplinary approach to the optimal care of the Filipino patient living with cancer.The Society undertakes research to foster the development and advancement of oncology. It provides opportunities for continuing medical education and further professional development of its members. PSMO educates the public at large and allied medical specialties in the holistic approach to the care of patients living with cancer and their families. It nurtures fellowship and encourages openness and cooperation among its members as it actively pursues the standards of excellence in the science and practice of Oncology.The PSMO envisions the Philippines as a country wherein every Filipino living with cancer can receive optimal cancer care by expanding its accessibility, availability, and affordability . It aimsThis paper did not receive any funding.The authors have no conflicts of interest to declare."}
+{"text": "Science for a Resilient Future as the theme for the third Commonwealth Science Conference, which was held virtually in February 2021 and brought together 350 scientists (of whom 270 were early career) from 32 Commonwealth nations to discuss three key areas within the overall theme of science for resilience: Developing resilient energy systems; Nurturing resilient ecosystems; and Building resilient societal systems. The present volume, which comprises papers from participants at the conference, focuses primarily on the first theme, although with some discussion of topics relevant to the third. The second theme will be addressed in a separate volume of Philosophical Transactions B.The need for resilience and sustainability in the systems on which Society depends is increasingly recognized as a global priority. It is also clear that to achieve resilience, input from science, technology and innovation will be essential. For this reason, the Royal Society in partnership with the African Academy of Sciences chose The development of resilient energy systems is essential for the control of climate change and in many parts of the world a necessary adaptation strategy. It is also critical for the development of sustainable and circular modes of production and consumption. As well as wide ranging scientific and technological challenges, including those relating to behavioural and social aspects, there is a complex interplay between science and policy; and both scientific and policy aspects are illustrated by several of the papers in this volume. The issues raised are, of course, global as again was clear from the conference and from the studies reported here. Indeed the Commonwealth as a network of both developed and developing nations provides an effective forum for the discussion of resilience in the global context. We hope that the work discussed in this volume will help to stimulate and develop global interactions and collaborations in this crucially important field.We would like to express our thanks to the Steering Committee of the Commonwealth Science Conference, to all the speakers and participants in the conference and to the staff of the Royal Society and African Academy of Sciences for their work in organizing the conference on which this volume is based. The conference was funded by the UK Government Global Challenges Research Fund (GCRF)."}
+{"text": "All the authors agree to the publication of the authors, and they apologize to the readership for any inconvenience caused.A corrected version of"}
+{"text": "This article  has beenThe decision to retract has been taken in agreement with the authors and approved by the Editor-in-Chief.Nanomaterials for any inconvenience caused. To ensure the addition of only high-quality scientific work to the field of scholarly publication, this paper [The Nanomaterials Editorial Office and authors apologize to the readers of is paper  is retra"}
+{"text": "This Retraction follows an Expression of Concern relating to this article previously published by Portland Press.Bioscience Reports at the request of the Editor-in-Chief and the Editorial Board following receipt of a notification from a reader, alerting the Editorial Board to image duplications in Figures 5C and 7A which appear in other publications.This article is being retracted from The authors have been contacted in regards to the Retraction, and have not responded to the Journal's queries and the concerns raised. Given the extent of the issues raised, the Editorial Board stand by the decision to retract the article."}
+{"text": "This Retraction follows an Expression of Concern relating to this article previously published by Portland Press.Bioscience Reports at the request of the Editor-in-Chief and the Editorial Board following receipt of a notification from a reader, alerting the Editorial Board a duplicated image in Figure 2C as well as concerns with the similarity of data in Figure 3E and concerns with the Western blots in Figure 6C.This article is being retracted from After notification by the Editorial Office, the authors agreed to the Retraction. Given the extent of the issues raised, the Editorial Board stand by the decision to retract the article."}
+{"text": "The journal and Chief Editors retract the 23 April 2021 article cited above.Following publication, concerns were raised regarding the validity of the data in the article. The authors failed to provide the raw data or a satisfactory explanation during the investigation, which was conducted in accordance with Frontiers\u2019 policies. Given the concerns, and the lack of raw data, the editors no longer have confidence in the findings presented in the article.This retraction was approved by the Chief Editors of Frontiers in Oncology and the Chief Executive Editor of Frontiers. The authors have not responded to any correspondence regarding the retraction."}
+{"text": "Penicillium polonicum was corrected in the article, including the title and abstract.The authors would like to advise that several corrections have been made to the original article . The misSeveral of the scientific names were rewritten and italicized, and the abbreviation of the genus name of some others was added to replace the complete genus name.In the first paragraph of the introduction, the name of the mold was written as blue or green mold, and several typos were corrected.The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. The original article has been updated."}
+{"text": "This is a fascinating, highly engaging book that examines the history of the social and cultural construction of the face and its evolving role in identity, representation and communication. Primarily, Western in its orientation to history and philosophy, the book does much more than the title might initially suggest. Taking its starting point in the 19th century, it devotes significant attention to charting the shifting cultural and artistic practices and technological innovations and affordances that underpin contemporary emphasis on the face. This includes developments and fashions related to portrait painting, and later photography, the increased importance of the face as a primary form of identification and as an important aspect of 20th-century democratisation.The second-half of the book is devoted more to contemporary development and deployments of the face and gives attention in particular to digital pathways of creation and dissemination in which the face occupies a central role, especially social media. The groundwork established by Zilio\u2019s preceding historical survey provides a clear context for thinking about modern productions and representations of the face beyond popular perceptions of vacuous self-obsession. Instead, the book prompts us to reconsider many of the unconscious and naturalised ways in which societies have been encouraged to accept the modern centrality of the face as self-evident.The book engages with some complex concepts and theories that draw on perspectives from multiple contemporary academic disciplines. This aspect of the text is excellent and it is an exemplar of the productive potential that lies in genuinely interdisciplinary approaches. The intellectual depth of this book is impressive, drawing on philosophical writing, creative practice and media and cultural theory from across several centuries.At the same time, the text is accessible and straightforward and the logics of the arguments and philosophies is always clear, making this a book that could usefully be considered as a graduate level reading, as well as being important for scholars interested in social practice and the embodied nature of communication and representation. Given the complexities of the translation process, exactly how much and in what ways the clarity of the book is attributable to the skills of Robin Mackay is unclear . However, his contribution should not be overlooked in considering the high quality of the reproduction of this text in English.University of East AngliaKarina Aveyard"}
+{"text": "The basis for achieving success in sport is technical preparation supported by adequate level of physical fitness. During judo competitions, athletes use technique to meet tactical objectives aimed to achieve victory. The modification of the rules of combat in judo that has been carried out in recent years has changed the course of competition. It seems to be interesting if there are relations between technical and tactical preparation expressed by means of indices and modification of the course of the fight caused by changes in the rules. The purpose of the paper was to determine the values of technical and tactical preparation of judokas during competition at the elite level. A hundred and twenty bouts during the Olympic Games in London in 2012 as well as 136 bouts fought during the World Championships in Rio de Janeiro in 2013 were analyzed. Verification was performed by calculating indicators of technical and tactical preparation. The results show a significant correlation between the indicators of technical and tactical preparation and the ranking in the general classification of the analyzed competitions. There were no statistically significant correlations between the change of fighting rules and the level of the examined indices of technical and tactical preparation. The results of the study verified the appropriate method of preparation for the competitions analyzed. Judo is a combat sport that includes many techniques of the fight and requires proper motor and physiological preparation . This spAccording to the experts in the field, it is not possible to achieve excellent results in combat sports without earlier technical preparation ,9,10. ToCurrently, there are many up-to-date developments that analyze judo bouts in terms of technical and tactical actions ,14,15,16In the examination of the variables affecting the efficiency of the fighting technique, and consequently the level of sporting achievements, attempts have been made to verify the athlete\u2019s technical parameters in terms of activeness during competitions ,22. The (a)techniques using catching a competitor\u2019s lower limbs below the belt were banned ;(b)the time limit of a golden score (overtime) was cancelled;(c)durations of holds were shortened;(d)many limitations in fighting for a hold were introduced.The research was inspired by the change of the rules introduced before the World Championships in Rio. The main changes included:They were supposed to make the fight more spectacular, attract media, and bring it closer to the original traditional version. Calculation and compilation of the values of indicators of technical and tactical preparation of judokas during competition at the elite level allows for the determination of the current level of competition in terms of the preparation of competitors and changes in the course of judo fights following the introduction of new regulations, and also for linking it with technical and tactical skill level .The purpose of this paper was to determine the indicators of the technical and tactical skill level of judokas during competition at the elite level in two competitions of the highest rank, in between which a modification of the rules was made.(1)What are the values of the indicators of technical and tactical preparations of judokas competing in the World Championships in Rio de Janeiro in 2013?(2)What are the values of the indicators of technical and tactical preparations of judokas competing in the Olympic Games in London in 2012?(3)What are the differences in the indicators between the members of both study groups?Answers for the following study questions were sought:The research hypothesis assumes that modifications in judo fighting rules may have led to changes in the level of technical and tactical training indicators of elite judo athletes.The study was based on the analyses of bouts fought during the Olympic Games in London in 2012 and the World Championships in Rio de Janeiro in 2013. The participants of the study were medalists in seven weight divisions. Technical and tactical actions taken by 56 judokas included 28 athletes participating in the Olympic Games and 28 judokas that took part in the World Championships. Altogether, 256 men\u2019s fights were registered, including 120 bouts fought during the Olympics and 136 bouts fought during the World Championships. To determine the scores and places in the general classification, in addition to video analysis, we reviewed referee documentation and tournament reports made available by the International Judo Federation.Age and height of the participants are shown in The analysis included judokas of different weight divisions who had various numbers of bouts fought during the competition .Sports fight analysis was performed by three champion-level judo coaches, based on the digital recording of selected tournament fights of the athletes studied. The recording was made with three cameras . Movavi Video Editor 14 software  was used to merge the images. The setting of cameras allowed continuous observation of the athletes, referees, and the scoreboard. A single sheet was developed as the essential research tool. The sheet consisted of a time line of the fight, on which all the performed techniques were marked with symbols  at the aThe efficiency of the attackVariables of the technical and tactical training were determined based on videos of the bouts, and the computations were made of the following, Equations (1)\u2013(6) :The effiM\u2014number of attacks awarded according to the attack performed Sa\u2014the efficiency of the attackN\u2014number of observed bouts2.The efficiency of the defense3.Total efficiencySk\u2014total efficiency4.The effectiveness of the attackEa\u2014Effective attack is an offensive activity that scored points. An attack is any offensive action.Number of all attacks is the sum of all athlete\u2019s actions that are offensive in nature5.The effectiveness of the defenseEo\u2014the effectiveness of the defenseAs is a number of effective attacks performed by the opponent and Ap is the number of all attacks by the opponent.Where 6.The activeness of the attack7.The activeness of the defense8.Total activenessA\u2014total activenessAa\u2014the activeness of the attackAo\u2014the activeness of the defenseThe statistical analysis of the data was made using R ver. 3.6.3. The chosen variables were the arithmetic mean with standard deviation (\u00b1 SD).The differences between paired data (London and Rio comparison) were analyzed with the paired Students t-test or Wilcoxon test. Before the appropriate method was selected, the assumption about normality of distribution was verified for the difference between both features with the Shapiro\u2013Francia test. When the test confirmed the normality of the distribution, the Students t-test was selected for analyzing the difference. Otherwise, the Wilcoxon test was used.p < 0.05.Firstly, it was verified whether both variables were normally distributed. If non-normality was detected, the Spearman correlation test was applied. Otherwise, Pearson\u2019s test was used. For all tests, we assumed the significance of In this paper, a single judoka is a statistical unit in both paired (comparison between London and Rio) and non-paired tests. Each competitor\u2019s statistics are computed based on all his bouts.p > 0.05) . The only lower value compared to the Olympic Games  was recorded for the efficiency. There were no statistically significant differences in all indicators measured ( > 0.05) .There are several significant relations between the described variables. Total activeness is moderately positively related to the activeness of the attack and negatively related to the activeness of the defense . Total activeness and the activeness of the attack are negatively correlated to the effectiveness of the attack . Activeness of the attack is also positively correlated to the efficiency of the attack (0.33). The efficiency of the defense is negatively correlated to both effectiveness of the defense and total efficiency  .There is a positive relationship between the rank of a competitor and the values of the efficiency of the defense (So) for London (0.45) and Rio (0.5) competitions as well as for the competitions altogether (0.47). There is a moderate negative correlation between total efficiency (S) and the rank in Rio (\u22120.54) and both competitions together (\u22120.41). There is a similar relationship between the effectiveness of the defense (Eo) and the rank in Rio (\u22120.42) and both contests (\u22120.31) .This paper aimed to evaluate the indicators of the level of technical and tactical skills in elite judokas in competitive settings, i.e., the World Championship and Olympic Games, with the fighting rule change occurring between the two events.The indicator of the efficiency of the attack in both groups was different, but the differences were not statistically significant. Therefore, it should be concluded that the modification of the rules did not affect the efficiency of the athlete\u2019s attack. Such results also indicate that changes in regulations do not significantly influence the evolution of fighting techniques in Judo. Other findings are presented in the analysis of rule change and performance evolution in judo based on the analysis of Olympic Games in 2012 and 2016 and World Championships in 2015 and 2017 at which there were statistically significant differences in terms of technical and tactical preparation indicators . Such a A statistically significant positive correlation was found between the medal positions and the efficiency of defense during the world championships, Olympic Games, and without the division into groups. This demonstrates the crucial role of defense, which appears to be a necessary factor for success . DefensiIn the present study, there was a negative relationship between total efficiency and the efficiency of the defense and medal position in the Rio Championships and without division into groups. This demonstrates that a higher index of technical and tactical preparation corresponds to a lower medal position, i.e., to a better final result. Therefore, the accumulation of the efficiency of the attack, efficiency of the defense, and the effectiveness of the defense is an essential factor in the success of an athlete. According to Sterkowicz , top-claIn the analysis of the relationships between indicators of technical and tactical preparation of judo competitors in elite championships (World Championships and Olympic Games), the influence of changes in the rule change in terms of technique and the limitation of the number of allowed actions was mainly analyzed, without finding any relations between these variables. Smaruj et al.  analyzedThe high positive correlation between the effectiveness and efficiency of the attack and the negative correlation with activeness may indicate a trend caused by the evolution of judo\u2019s way of fighting. New combat sport rules force fighters to strive for high point advantage . This caTherefore, to optimize the coaching process in combat sports, the emphasis should be on the development of natural aptitudes and methods of fighting, depending on functional potential. During the bout, motor abilities are most often manifested in a complex manner. Therefore, the development of technical and tactical skills in individual athletes should take into consideration their profile of motor abilities.Nonetheless, the findings of this study have to be seen in light of some limitations. The indicators determining the level of technical and tactical preparation of judokas were analyzed only during two competitions of different ranks. Thus, it may be speculated that if competitions of the same rank were compared (Olympic Games vs. Olympic Games), different results would be obtained. Additionally, there was about a year of differences between the compared occupations; it is possible that a comparison of competition with a longer time interval would show the impact of training or tactical preparation to a greater extent. Moreover, only elite male judokas were analyzed, and it cannot be excluded that these results may differ among females or sub-elite judokas.Between the 2012 Olympic Games in London and the 2013 World Championships, there were no statistically significant differences in the level of technical and tactical preparation despite the change of fighting rules that took place between the competitions.The level of technical and tactical preparation is closely related to the medal place achieved by the athletes at the elite level.For achieving high medal positions in championships, more attention should be paid to the level of defensive actions in the process of sports training of judokas.Because the changes in the rules of judo fights in terms of technique do not significantly differentiate the level of technical and tactical preparation of the competitors, modifications to the training process should go in the direction of the most comprehensive training of the player in terms of technique and physical fitness."}
+{"text": "This Retraction follows an Expression of Concern relating to this article previously published by Portland Press.Bioscience Reports at the request of the Editor-in-Chief and the Editorial Board following receipt of a notification from a reader, alerting the Editorial Board to highly similar bands in the Western blots of Figure 3B.This article is being retracted from The authors were contacted regarding the concerns raised and provided the original scans of these Western blots, however given that the original scans show signs of manipulation, the Editorial Board stands by the decision to retract. The authors disagree to the Retraction."}
+{"text": "The journal and Chief Editors retracts the 28 May 2021 article cited above.Figure\u00a07 were incorrect due to miscalculations. During the investigation, our Research Integrity team confirmed that the integrity of the figures was insufficient to support the scientific claims of the paper. The article is therefore being retracted.Following publication, concerns were raised by the authors regarding the integrity of the data in the published article. Specifically, the authors have stated that the dosages of curcumin used for This retraction was approved by the Chief Editors of Frontiers in Immunology and the Chief Executive Editor of Frontiers. The authors requested and agreed to this retraction."}
+{"text": "In the Knowledge on lymphatic filariasis subsection of the Results, there is an error in the second sentence of the first paragraph. The correct sentence is: The comprehensive knowledge of LF among the participants in Central Gonja District is higher compared to that of Bole District."}
+{"text": "The authors were asked for an explanation to account for these concerns, but the Editorial Office never received any reply. The Editor regrets any inconvenience that has been caused to the readership of the Journal.After having conducted an independent investigation in the Editorial Office, the Editor of"}
+{"text": "The authors were asked for an explanation to account for these concerns, but the Editorial Office never received any reply. The Editor regrets any inconvenience that has been caused to the readership of the Journal.After having conducted an independent investigation in the Editorial Office, the Editor of"}
+{"text": "In contrast to what was reported in the article, the study did not have prospective ethics approval by the research ethics committee of the Department of Internal Medicine, College of Health Sciences, Addis Ababa University.The data are incomplete and do not accurately represent the experimental outcomes.Following the publication of this article  concernsIn light of the concerns affecting the ethics approval for this study and the reliability of the data reported in this study, the authors retract this article."}
+{"text": "An acoustic emission method for assessing the degree of degradation of mechanical properties under conditions of complex dynamic deformation stresses is proposed. It has been shown that changing the operating conditions of metal structures, peak loads, external collisions, and thermally changing loads, which cannot be taken into account, leads to uncertainty and unpredictable structural changes in the material. This in turn makes it difficult to identify the state of the structure material to ensure trouble-free operation of the equipment. Changes in the mechanical properties under difficult loading conditions are identified by polynomial approximation of the results of AE measurements and the construction of boundary curves separating the operability region from the fracture region. This is achieved by approximating the experimental dependences of the acoustic parameters for various types of loading. This approach significantly expands the capabilities of the technical means of identification systems of metal structures, and in particular, allows the current state of the equipment and its suitability for further operation to be assessed without stopping the equipment in real time. It is of interest not only to fix the damage, but also to diagnose the processes of reducing the mechanical properties during the operation of the equipment. Determination of the degree of degradation of mechanical properties and the residual life of metal structures under complex dynamic deformation stresses has various applications related to bending, tensile static and dynamic loads, and processes of the initiation of defects.The trouble-free operation of metal structures relies on the monitoring of their technical condition and the implementation of physical diagnostic methods. The need to conduct an industrial safety examination exists for equipment that has fully run its service life or has been used under conditions not prescribed by the standards, when emergency situations may have occurred, which may affect the performance of the material.To assess the state of materials, it is sufficient not only to determine the standard mechanical properties, but also the properties that are sensitive to local structural changes manifested in microplastic deformation and the occurrence of micro-stresses. Accumulation of damage and degradation of the material structure under complex dynamic deformation stresses causes structural degradation processes of deformation and destruction of cementite in pearlite columns, and dislocation substructure evolution. This leads to a significant reduction in brittle fracture resistance characteristics.The operating time of an object from the beginning of its operation to the onset of the limiting state is considered a resource. When assessing the operability of structures associated with types of loading, the safety factor is understood as the ratio of the residual life to the current operating time. Degradation of the material during the operation of structures causes a decrease in their resource. Residual life is the difference between the limit and current state of the material during operation.Further resource assessments include an assessment of the current state, prediction of this condition under conditions of normal equipment operation, an assessment of the probability of failures, and an assessment of the risks of emergency situations. Analysis of synthetic accidents at hazardous production facilities consists of the systematic use of all the available information to identify hazards and undesirable events. To assess this, statistical data on the accident rate and reliability of technological systems, logical and simulation methods are used, e.g., the tree of events and failures, expert methods, and assessment of consequences.The main analyzed characteristics include safety margins according to the criteria of static strength, low and high-cycle fatigue, and initial and residual life.The efficiency of metal structures is determined by their strength and permanent deformations through displacements, deflections and turns. The resource of long-term loaded structures is determined by the processes occurring under conditions of elastic deformation. Deformations may be localized near the place of collision of the contacting parts of metal structures, but they may also be general, involving the entire volume of the collision. In practice, both types of deformation occur simultaneously.The key role in identifying the state of a metal structure is played by resistance to deformation, which is determined both under uniaxial tension and compression of samples.Determination of the degree of critical damageability of the material structure is of particular scientific and practical interest.The aim of this work is to use the phenomenon of acoustic emission to address the issue of predicting changes in the mechanical properties of materials under loading.The study of metal under load requires the use of disciplines such as materials science, mechanical testing, and technical diagnostics.During the operation of structures, periodic control of deformation deviations from the design values and static monitoring of deformations are performed ,3,4,5,6.Modern diagnostic methods assessing the degree of degradation of the mechanical properties of materials have various technical applications ,18. In , the ideThe joint use of the strain gauge method with the finite element method for assessing deformation is presented in . The devThe identification of the critical states of serviceability and transition boundaries of the stability of power systems with multidimensional uncertainties when replacing the state space with a parametric space is presented in . In 28]28], a meIn , the resIn , an algoAn analysis of the existing methods and means for determining the degradation of the mechanical properties of materials during the operation of structures in real time showed that they are all intended for the study of one type of deformation: tension ,38,39 orThe operability states of equipment during its operation are identified by means of technical diagnostics and non-destructive testing. The quality indicators of metal structures change when interacting with the environment and other organizational and technical objects. The loading parameter is permanent deformation. To identify the state of metal structures under conditions of complex deformation stresses on the material, strength calculations should consider the kinetics of destruction, characterized by the rate of damage accumulation, such as creep and cyclic fatigue.The emergence of elastic and plastic deformations in materials is inevitably accompanied by the appearance of internal and external stresses. Internal stresses arise due to the inhomogeneous flow of structural and phase transformations in metals, in the processes of rapid heating or cooling of the metal, due to inhomogeneous deformation of the surface and inner layers. External stresses are dependent on operating conditions. There is a balance between internal elastic forces and external stresses. With an increase in the external operating load, the internal elastic forces also increase.Existing methods of strength verification calculations include calculations for the corrosion rate of metal, calculations for crack resistance, calculations for metal fatigue, and creep calculations. These techniques imply independent processes of corrosion, fatigue and creep, although in practice these processes occur simultaneously and in different combinations.The disadvantages of these methods include the uncertainty of estimates, low accuracy of results, and the need to analyze the compliance of operating conditions with industrial safety requirements.m, connected by elastic bonds is presented in , the second region in the interval tN\u2208. Polynomial approximations of the boundary curve are presented in the form of equationsIt is clear that the limiting curve has two regions: the first region in the interval The technology for determining the strength and deformation characteristics of metal structures using the acoustic emission method in real time is as follows. The values of the corresponding tensile and bending deformations are calculated for specific measured values of the density of acoustic signals, using the formulas of the approximating dependences of the deformation characteristics on the parameters of the AE signals. The strength characteristics of the material at a given time are calculated by empirical dependences and their approximating functions.\u03bb at point A in The geometric interpretation of the safety factor \u03bb for point A on curve 2 in The analytical safety factor \u03bb as the surfaces Graphical representations of the safety factor In Therefore, the obtained Equation (28) makes it possible to estimate the safety factor of a metal sample made of St3sp grade steel directly from the data of acoustic emission measurements during its diagnostics.This approach significantly expands the capabilities of technical means of systems for identifying the state of metal structures, in particular, it allows assessing the current state of the equipment and its suitability for further operation without stopping the equipment in real time. It is of interest not only to fix the damage, but also to determine the initial stage of changes in the structure of materials on continuously operating equipment.The method based on the use of the AE phenomenon for assessing the degree of degradation of mechanical properties and residual life of metal structures under complex dynamic deformation stresses is a fundamental step in determining the technical states of objects. The obtained boundary curves of the safety factor for tension and bending make it possible to determine the working capacity area and the failure area of metal structures.The density of the AE signal during bending was shown to be an order of magnitude higher than the density of the AE signal during tension. When diagnosing a sample with a complex nature of loading , this property will make it possible to clearly determine the type of mechanical stress in the specimen.Acoustic measurements of the state of the material under load allow the use of only one type of sensor. This approach greatly simplifies the procedure for assessing the residual life of metal structures in continuous operation, and allows the calculation process to be automated.Determination of the density of AE signals under load may serve as an informative diagnostic parameter. Monitoring of acoustic emission signals makes it possible to diagnostic the processes of degradation of mechanical properties during the operation of equipment.The use of the phenomenon of acoustic emission during deformations of tension and bending makes it possible to predict the onset of critically dangerous states of loss of working capacity of metal structures.The presented technology for determining the residual resource, based on the analysis of the acoustic spectrum, makes it possible to determine the state of the equipment in real time."}
+{"text": "Furthermore, the flow cytometric plots shown in Fig. 2B in the above paper appeared to be remarkably similar to data presented in a paper published in Oncology Reports has determined that the above paper should be retracted from the Journal on account of a lack of confidence concerning the originality and the authenticity of the data. The authors were asked for an explanation to account for these concerns, but the Editorial Office never received any reply. The Editor regrets any inconvenience that has been caused to the readership of the Journal.After having conducted an independent investigation in the Editorial Office, the Editor of"}
+{"text": "Bioscience Reports at the request of the Editor-in-Chief and the Editorial Board following receipt of a notification from a reader, alerting the Editorial Board to a duplicated panel in Figure 4A. Post publication review by the Editorial Office also identified signs of image manipulation in the original version of Figure 4A as well as further duplications in the original version of 4C, which were replaced by the authors during the revision process.This article is being retracted from The authors have been contacted in regards to the Retraction, and have not responded to the Journal's queries and the concerns raised. Given the extent of the issues raised, the Editorial Board stand by the decision to retract the article."}
+{"text": "The COVID-19 Pandemic changed higher education in several significant ways. The most significant impact was on methods of course delivery. In March 2020, all educational institutions changed their methods of instruction to fully online instruction. It happened almost overnight and left the students as well as the instructors unprepared for the unanticipated metamorphosis . The sudden and unanticipated change in the method of instruction and delivery of course contents also highlighted issues of equity. There appeared to be high levels of inequity in the use of technology across school and college campuses. A survey of students conducted by the author at the University of Louisiana at Monroe revealed different types of inequity such as, lack of finances to buy equipment, lack of training in the use of technology, and lack of personal space to study from home. A significant percentage of student population at ULM consists of first-generation college students. These students were impacted the most by the new methods of course delivery. Additionally, the author looked up similar surveys at other educational institutions and conducted a meta-analysis of published studies. This paper presents these findings."}
+{"text": "The journal and Chief Editors retract the 11 November 2020 article cited above.Following publication, concerns were raised regarding the validity of the data in the article. The authors failed to provide the raw data or a satisfactory explanation during the investigation, which was conducted in accordance with Frontiers\u2019 policies. Given the concerns, and the lack of raw data, the editors no longer have confidence in the findings presented in the article.This retraction was approved by the Chief Editors of Frontiers in Oncology and the Chief Executive Editor of Frontiers. The authors have not responded to any correspondence regarding the retraction."}
+{"text": "In the Journal selection and description subsection of the Results, there is a calculation error in the sixth and seventh sentences of the second paragraph. The identification of the author with the largest number of research articles is not adjusted for homonymy bias. The correct sentences are:The author with the largest number of articles in a given journal is a journalist (N = 767) and, after excluding cases of homonymy in two large journals , the author with the largest number of research articles is an academic (N = 198). Both authors publish in established journals  and are members of their respective editorial boards."}
+{"text": "The journal and Chief Editors retract the 06 August 2020 article cited above.Following publication, concerns were raised regarding the validity of the data in the article. The authors failed to provide the raw data or a satisfactory explanation during the investigation, which was conducted in accordance with Frontiers\u2019 policies. Given the concerns, and the lack of raw data, the editors no longer have confidence in the findings presented in the article.This retraction was approved by the Chief Editors of Frontiers in Oncology and the Chief Executive Editor of Frontiers. The authors have not responded to any correspondence regarding the retraction."}
+{"text": "Life [The author wishes to add the following information to the acknowledgements section of his paper published in Life .The author thanks Kathleen Campbell and her students and staff for organizing the field work in New Zealand, and Bruce Damer for his collaborative efforts in the ongoing research. The author also thanks the staff at Hell\u2019s Gate for their help and support in conducting the field work. The author greatly appreciated the assistance of UNSW graduate student Luke Steller in obtaining samples, and transportation to and from the site by Bryan Drake."}
+{"text": "A relevant feature of COVID-19 disease is that the lack of dyspnea is recognized in the most critical cases. The subjects who were intubated and ventilated exhibited tachypnea and tachycardia  was reported pseudonormal  and efferent\u2013afferent dissociation . The sensory cortex also receives information about events from the chest and respiratory muscles and processes the information Okada, . When thThe CD for respiratory sensation is reminiscent of the original concept of Campbell and Howell . They suThe greater the separation among the outgoing and incoming signals, the higher the intensity of the shortness of breath. In COVID-19 disease with respiratory failure, the relationship between the absolute value of loading and its duration and the relative magnitude of the load compared with the maximum muscle strength seems to be reasonable.It is plausible to assume that the prevalence and intensity of dyspnea depend on the interaction between the severity of the infection, the role of the host response, physiological reserve and accompanying diseases, and the time between the onset and hospitalization , the hypoxemia is due to the occupancy of the alveoli, which leads to low ventilation/perfusion (via CD.If the pathophysiological mechanisms of the development of dyspnea are still poorly understood, we should not be surprised by our limited knowledge of the mechanisms of dyspnea in COVID-19 disease. From the physiopathology perspective, which does not exclude the direct neurotoxic effect of the virus and a systemic response in the infectious context, but rather encompasses it, the lack of dyspnea in the COVID-19 disease can be explained by matching the sensory cortex of the brain of the two signals coming from the motor command and periphery The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "To the Editor:Nature Neuroscience Michael V. Sofroniew In a recent News & Views article published in Apart from this, the ECM also exists in the nervous tissue itself, in the form of perineuronal nets and the neural interstitial matrix dispersed in the parenchyma"}
+{"text": "This case study analyzes a cryogenic air separation unit (ASU) with a production of  On a large scale, the cost of separating oxygen and other air gases, such as nitrogen, argon, krypton, and neon, is far cheaper and the purity of the products is far higher when using the cryogenic distillation route.A growing application for oxygen today is for dealing with polluted rivers which have been deoxygenated.Nitrogen is the other main component of the air. Today, the overall demand for nitrogen gas exceeds that for oxygen. Since nitrogen is inert and non-toxic, it has found many uses ranging from food preservation to the blanketing of chemical engineering and other industrial processes. In particular, the semiconductor industry uses large quantities; its demand for higher and still higher purity nitrogen arises from the increasing miniaturization and complexity of the integrated circuit chips being manufactured. These ultra-high levels of purity can be easily achieved by cryogenic distillation of air.Argon is, chemically, totally inert, even at high temperatures. The demand for argon, as a shield gas, in arc-welding and in the high technology metallurgical industry has grown even more than the demand for nitrogen.The products of the industrial gas industry have also become featured in biological and medical advances. Oxygen is well known for its life-supporting role in hospitals.Cryogenic Air Separation Units (CASU) are large electrical energy consumers. In the general concern of how to make such systems more efficient, the thermodynamic approach plays a crucial role when estimating the performance of any functional zone. A close-to-realistic assessment of the product and fuel of every operating area provides the chance to identify opportunities for optimization.An analysis based on the first and second principles of thermodynamics and the exergy concept provides the instrument for pointing out the location and magnitude of malfunctions associated with the operating processes.The production of pure oxygen efficiently and at industrial scale is a topic of great interest.2.Ebrahim et al.  recognizGhorbani et al.  conducteTesch et al.  integratKonoghe  undertooThe subject of integrating a liquefying natural gas with an ASU has also been analyzed by Chen et al. . Based oAcikkalp et al.  realizedTesch, Morosuk and Tsatsaronis  performeRong at al.  analyzedBanaszkiewicz  suggesteThe above review reveals the general understanding that only a method based on the exergetic analysis  offers mThe present work succeeds in deeply analyzing each technological process. The novelty represents the splitting of total exergy into its thermo-mechanical and chemical components ,12,13 thEstimating the local COP as close to reality as possible represents the major opportunity in the search for an optimum operating regime or constructive solution .The intention of this article is not to critically analyze and compare different technologies of gas mixture separation. The main goal of the paper is to provide a logical and explicit exergy analysis model that could be applied in any strategy of structural and functional optimization of a cryogenic air separation unit.The case study analyzes a cryogenic air separation unit (ASU) with a production of The separation of the air occurs in two distillation columns that operate at different pressures, coupled by a heat exchanger acting as a condenser for the high-pressure column (HPC) and evaporator (reboiler) for the low-pressure column (LPC). HPC operates at a pressure of about 6 bar and LPC of about 1.4 bar.The compressed, dry and purified atmospheric air is cooled in the main recuperative heat exchanger close to its liquefaction temperature (\u2212170 \u00b0C) and introduced into the high-pressure column (HPC).2) at the bottom.In the high-pressure column (HPC), the air is separated by distillation into a stream of nitrogen gas, which accumulates at the top of the column, and a stream of liquid enriched in oxygen (about 30% OThe separation process is repeated in the low-pressure column (LPC).The nitrogen gas in the high-pressure (and temperature) column (HPC) is partially condensed in the vaporizer condenser that couples the two columns by transferring heat to the liquid enriched in oxygen in the low-pressure column (LPC) which vaporizes at about \u2212180 \u00b0C.2 liquefy together with the nitrogen gas and are throttled in a throttling valve to the pressure of the low-pressure column, feeding in the LPC on the top at the liquid state.Part of the liquid nitrogen at the top of the high-pressure column ensures the reflux current and the remaining N2 is throttled and introduced in the middle of the low-pressure column where the distillation process is continued.From the HPC base, the liquid enriched in ODistillation products (separate gases) are discharged from the low-pressure column.To supplement the cold capacity of the installation, a fraction of about 15% of the compressed air is expanded into an expander before being introduced into the low-pressure column.The simulation of the operation of air separation columns was performed using the ChemSep simulator .The modeling of the operating of the ASU is based on the exergetic analysis.Looking at the installation as a whole , productThe exergetic performance coefficient of the whole system is:Since the compression zone is provided by a three-stage compression compressor:The terms of the product of the installation are calculated as follows:The reference state is characterized by The values of the fuels and products of the global system are presented in the The value of the exergetic performance coefficient (Equation (1)) is L represents losses of exergy thrown into the external environment and I destruction (consumption) of exergy caused by internal irreversibilities.The exergetic balance equation of the global installation is:From the exergetic balance Equation (12) it follows thatIt further follows that the efficiency of the installation can be achieved by reducing losses and destruction of exergy from fuel consumption.It is noted thatThe total exergy current of the gaseous nitrogen discharged in the form of WASTE , togetheThe share of this total loss in the total fuel consumption of the global installation is:To identify the place where losses and destructions take place, the installation is divided into functional areas .The compression zone as part of the cryogenic air separation installation is shown in The exergetic balance equation of the compression zone is:In the energy balance Equation (16), both the input and output energies are in absolute value.Equation (17) written with an economic connotation becomes:The scheme of the interactions of the compression zone with the outside is presented in F is the fuel of the area equal to the fuel of the overall systemP is the product of the area and represents its net exergy increase.Where \u0130 is the destruction of exergy in the compression process.Equation (18) becomes:Exergetic quantities are calculated as follows:The exergy destruction inside each compression stage due to the irreversibility of friction is calculated based on the Gouy-Stodola theorem  that accThe share of exergy losses and damage in the total fuel consumption of the installation is:The area of the HPC distillation column, separated from the rest of the plant, is shown in To specify the membership in the fuel (F) or product (P) of the heat discharged from the condenser of the high pressure and temperature column and transferred to the reboiler (evaporator) of the low-pressure column, write the exergetic balance equation of the HPC in its general algebraic form (in which each term contains its sign) .(34)\u2211\u2003EThe effect of heat penetration from the environment is neglected in a first phase and it is considered that the heat exchange with the outside in the HPC is performed only in the condenser. Equation (34) becomes:The exergy of the condensing heat is:It is observed that:The HPC column yields heat The scheme of the interactions of the HPC area with its exterior can be found in Heat is released at a temperature level In the end,Substituting in the exergetic balance equation of the high-pressure column (35) and rearranging the terms results in:We can consider that the product (purpose) of the distillation column is to change the chemical composition of the inlet streams. The product is therefore the increase in the chemical exergy of the input currents.To highlight the chemical component of the exergy, the exergy of the substance currents is split into the thermo-mechanical  and the chemical component.The exergetic balance Equation (38) becomes:The product is to increase the chemical exergy on the inlet-outlet path of the distillation column.Currents 8 and 9 are not processed in the distillation column, so that Conseqently:HPC is:Exergy destruction in Exergy destruction can also be calculated based on the Gouy\u2013Stodola theorem:The values of the state quantities at the characteristic points are extracted from the results of the ChemSep simulation.The share of exergy destruction in HPC in the total fuel consumption of the installation is:The area of the low-pressure distillation column, separated from the rest of the installation, is shown in The scheme of the interactions of the LPC area with its exterior can be found in To determine the senses of the heat exergy exchanges in the reboiler and the intermediate bottle (flash tank), write the general exergetic balance equation in algebraic form (34).The heat exergy in the intermediate bottle is:(a)The LPC column receives the heat (b)Heat is received at a temperature level It is observed that:In the end,The heat exergy received in the reboiler is calculated as follows:(a)The LPC column receives the heat (b)Heat is received at a temperature level It is observed that:In the end,Replacing and rearranging the terms in Equation (48), we obtain:The product of the low-pressure column can be considered as the increase in the chemical exergy of the streams of substance passing through the distillation column and the exergies of the heat offered in the reboiler and the intermediary bottle (flash tank). These heat exchangers are used to extract heat from the high-pressure column (HPC) condensers and the argon column.Splitting the exergies of the substance currents into the thermo-mechanical and chemical components results in:The product of the low-pressure column, defined as the increase in chemical exergies of the substances passing through the contour of the low-pressure column, is:Low pressure column fuel when the product is characterized only by upgrading of chemical exergies is defined by decreasing the thermo-mechanical exergies of the processed currents:Exergy destruction in LPC is:It is observed that the value of the exergy destruction deriving from the balance Equation (48) is unique regardless of the way in which the fuel and the product of the column are interpreted.The different methods of interpreting the product\u2014(a) as the increase in the chemical part of the inlet streams exergies or (b) as the increase in the total exergies\u2014represents the point of view of the researcher in the desire to approach reality.Estimating the performance as close to reality as possible allows opportunities for the improvement of the system.The coefficient of exergetic performance of the low-pressure column, depending on the different ways of estimating the fuel and product, is:The destruction of exergy in the low-pressure column can also be calculated with the Gouy-Stodola theorem.The modeling of the operation of the air separation system called upon the ChemSep simulator for the calculation of the separation columns.2, N2 and Ar, values of entropies and molar enthalpies and the phase in which the substance is.The simulation with ChemSep provides, for each main state, the values of flow rates, pressure, temperature, concentration of components OFor the other parts of the air separation system that are not involved in a change in the chemical composition of the stream of substances, the calculus is performed based on the EEs program.The increase in air pressure is achieved in a three-stage compression system with intermediate cooling between stages and final cooling.To evaluate the performance of the area, attention was focused on exergy losses, with the heat discharged to the outside in the compression system coolers, and on the destruction of exergy due to the irreversibility of compression processes.The product of the area is the net increase in the total exergy of the air between the inlet and the outlet, and the fuel (resource used) is represented by the electric energy for driving the compressors.It should be noted that in the conditions of neglecting the consumption of electricity to drive the pumps, the resource used in the compression zone is also the fuel of the global cryogenic air separation installation.The part of the technological scheme that represents the compression zone is shown in The values of the total exergies of the inlet and outlet currents in the area as well as of the electrical energies  and the exergies of the discharged heat in the cooling system are presented in The exergy values of the input currents and the absolute values of the mechanical works received the plus sign (+) and the values of the exergies of the output currents and the absolute values of the heats transferred to the cooling water were assigned the minus sign (\u2212). In this way, by summing them up, the value of the exergy destruction due to the irreversibility of the compression process was obtained.If the exergy destructions in each compressor are of interest, they can be calculated with the Gouy\u2013Stodola relation (Equations (29)\u2013(31)). The results are shown in The losses with the exergies of the heat evacuated through the cooling system in the environment are presented for each cooler in The sum of exergy losses and destruction in the compression zone gives:The share of exergy losses and destruction in the compression zone in the fuel consumption of the global installation is:It follows that 37% of the power input of the cryogenic air separation plant is lost or destroyed in the compression zone.The contour of the area also includes the throttling valves and the expander.The exergetic balance Equation (34) is unique, but the rearrangement of terms from one member of the equation to another is at the discretion of the researcher in his interpretation of the actual product and fuel of the area.At first glance, the essential role of the column is to separate the components of the mixture, which is related to the increase in the chemical exergy of the output currents compared to those entering the column.This approach requires the splitting of any total exergy into its thermo-mechanical and chemical parts  and (42), and the specification of the corresponding exergetic coefficient of performance Equation (43), leads to the results presented in From the results registered in Nevertheless, what really matters is how to manage resources within the area to achieve the desired separation process, or the destruction of exergy within the area does not depend on the interpretation of the product and the zonal fuel (Equation (38)).HPC) in the technological flow and for which the product of this columnIf the product and fuel are defined considering the total exergies which, in addition to the chemical part, also consider the pressure and temperature of each stream of substance, elements which count in the devices following the high-pressure column ).The values of the quantities given by Equation (45) are registered in Entropy transferred from or to the outside associated with heat penetration due to incomplete insulation and heat transferred to the condenser is shown in Entropy generated in the high-pressure column (Equation (46)) and the destruction of associated exergy (Equation (45)) are:That leads to a share of exergy destruction in the overall consumption of the installation (Equation (47)) of The calculation of the exergy destruction from the LPC was made based on the Gouy\u2013Stodola theorem and the calculation of the column entropy generation (Equation (60)).The entropy values of the streams of substance in the input and output states of the separation column are calculated with the ChemSep simulator and presented in Multiply the value of the total entropyDue to the entropy flows transferred from the outside to the reboiler, the intermediate bottle, and due to the penetration of heat through the incomplete insulation,\u00a0LPC becomes Equation (60):The destruction of exergy in LPC exergy destruction in the overall electricity consumption of the installation is:The share of The energetic analysis accounts only for the losses of energy thrown out into the environment of the system. The energetic analysis does not account for the quality of the lost energy.Only the exergetic analysis that couples the first and second principles of thermodynamics reveals not only losses but also destructions (consumption) of useful energy, thereby making the correlation between the intensive parameters of the system and those of the environment.In cryogenic systems analysis, the use of exergetic analysis is almost compulsory, because the lowest is the operating temperature and the highest is the entropy generation due to an irreversibility.The splitting of the total exergy of each current of substance into its physical and chemical components makes it possible to define, in different ways, the product and the fuel of every functional zone and, finally, the local COP. In this way, more alternatives of discussion are found, enriching the knowledge about the operation of the system.The analysis found that the most inefficient part of the ASU is the compression area.The loss and the destruction of the compression area in relation to the fuel of the entire plant is 37%.The second destructive area is represented by the separation columns ,18. The The results are comparable to other studies ,23,24,25In the present work, the model of exergy analysis refers to specific boundaries of the compression unit  and of tThis paper presents a model of a detalied exergetic analysis of some key parts of a cryogenic air separation unit, a model that could be integrated into a functional or design optimization procedure.The exergetic method is particularly productive in low temperature operating systems where any irreversibility due to the low temperature level leads to a large generation of entropy and, consequently, a large exergy consumption (destruction).Exergy analysis reveals the real measure of losses and exergy destruction, enabling the discovery of methods for waste energy recovery or better investments for lowering the inputs.The exergy analysis discusses the different ways in which the coefficient of performance of a key part of the system could be viewed in the aim of getting close to reality.The paper points out that, for the analyzed installation, the compression unit is by far the most destructive part, suggesting in this way the use of better compressors and the recovery of the heat transferred to the compressors\u2019 cooling system.Further analysis should be developed on the recuperative internal heat exchanger that plays, at its turn, a leading part in the economy of the system."}
+{"text": "This Retraction follows an Expression of Concern relating to this article previously published by Portland Press.Bioscience Reports at the request of the authors following receipt of a notification from a reader, alerting the authors to the possibility of spliced blots in Figure 5A. The authors have been unable to replicate the results and wish to retract the article. The Editor-in-Chief and Editorial Board agree with the retraction.This article is being retracted from"}
+{"text": "Due to production error, an existing conflict of interest between one of the reviewers and the authors was not declared. The updated Conflict of Interest statement has been included below.The publisher apologizes for this mistake. The original version of this article has been updated."}
+{"text": "The authors were asked for an explanation to account for these concerns, but the Editorial Office never received any reply. The Editor regrets any inconvenience that has been caused to the readership of the Journal.After having conducted an independent investigation in the Editorial Office, the Editor of"}
+{"text": "Developing World Bioethics [Human Fertility [Please note that a commentary recently published in this journal  includesioethics  and Humaertility .Developing World Bioethics [th March 2007. The letter in Human Fertility [The letter in ioethics  was firsioethics  has sincioethics  was publertility  was publPhilosophy, Ethics and Humanities in Medicine, for failing to indicate the similarity of the article in this journal [The author, Dr Heng, would like to apologise to the Editors and readers of  journal  to the oIt is the journal and publisher's policy for notices of redundant publication to be authored by the author of the original article . On this"}
+{"text": "Since 1997 an interdisciplinary research project is taking place at the Heidelberg University clinics with the subject \"Mobile communication tools at the clinical practice\". It was focused mainly on the introduction of new technologies to support stationary as well as ambulant medical and nursing occupation. Within the frame of construction of new information systems at hospitals the research works concentrated on aspects as the access to data banks of medical knowledge, electronic file management, picture transmission and knowledge based decision support. In the field of interpersonal communication the use of mobile radio equipment for the duty in service was to the fore. One of the main questions concerns the forecast of psychosocial technical consequences.The research on hand focuses on consequences of new luK-technologies on the interaction between doctor and patient on the field of the general practitioner. An IST-SOLL analyses was made among general practitioners, internists, paediatricians, dentists (N=48) and their patients (N=116) by means of half-structured interviews and questionnaires. With the instruments it was at first possible to make out a judgement of doctors and patients in view of their doctor-patient interaction and the actual technical status quo. In addition they inquired an assessment of the person what changes they would expect on the corresponding fields by the introduction of new technologies.The results show that negative influences of new technologies on the doctor-patient interaction are expected by 18.5% of the questioned doctors and only 4.4% of the questioned patients. Doctors would approve the introduction of new technologies on condition that it would be user-friendly and that data protection, restriction to main functions as well as data exchange with clinics and other medical institutions would be guaranteed.The results of the study are to be regarded as prognostics with regard to the development and introduction of new technologies. Statements will be possible in two areas:Consequences on the contact between doctor and patientWhich innovations are regarded as useful by the doctors and which aspects should be taken into consideration in case of construction?"}
+{"text": "A case-control study has been carried out to examine the occurrence of childhood cancer in relation to the proximity of overhead power lines to a child's home address at birth and to the calculated magnetic field at the address. The study included 374 cases diagnosed in the Yorkshire Health Region between 1970 and 1979, together with 588 matched controls. Magnetic-field strengths at the birth addresses due to the load currents of overhead power lines were calculated on the basis of line-network maps and load records. The results indicate no association between the occurrence of childhood malignancies and either the proximity or the magnetic fields of overhead lines, although the statistical power of the study was limited by the small numbers of children living close to overhead power lines."}
+{"text": "The time-trend and geographical distribution of mesothelioma of the peritoneum during the years 1967-82 in England and Wales have been studied from the Mesothelioma Register held by the Medical Division of the Health and Safety Executive. Over the 16-year period the annual number of cases registered rose from about 15-20 to about 30-50. Although the number occurring in men was double that in women, the trend was similar for both sexes. There is likely to be some further increase before any improvement due to the recent diminished usage of asbestos is seen. Local Authority areas with raised rates have been identified, and the geographical pattern is similar to that of the distribution of the asbestos-using industry in the past. In both sexes there are high registration rates on the east side of London but, in contrast to mesothelioma of the pleura, a concentration of cases among men in the major ports where shipbuilding and ship repairing were carried out is not so apparent."}
+{"text": "As primary author and co-principal investigator of the 16 Cities Study , I was dOne example (there are many) of the errors presented by Probably the most egregious distortions of the facts lies in the claims of As to the issue of whether OSHA was made aware of the impact of workplace smoking in a timely fashion, the contention of Environmental Health Perspectives. If The 16 Cities Study stands as the largest and most representative study of personal exposure to ETS ever conducted in the United States. The methodology used was sound and the findings scientifically valid. Seven peer-reviewed papers have been published from its work, including one in Science is about a dispassionate analysis of the facts\u2014all the facts. All of the facts must be analyzed, even if they do not support a hypothesis or preconceived outcome of the analysis. Anything less can be considered poor science or, at worst, politics."}
+{"text": "The discussion of the ethical issues involved in patient-physician relations are traditionally based on the assumption that the parties involved are in direct contact and that their interaction occurs in the same spatio-temporal context. Problems such as confidentiality, paternalism, consent, responsibility etc. are discussed in light of the interpersonal interaction of the two parties. Medicine in the Internet and in other forms of digital medical applications, however, allow for a mode of interaction where the type of the contact between the patient and the physician is altered. The authors argue that the new types of physician-patient interaction create new ethical dilemmas.The authors examine the traditional ethical issues in medicine and place them in their historical and methodological context. The immediacy factor in patient-physician relations is responsible for moral dilemmas which are non-existent in a \"digital\" environment. On the other hand, such an environment raises new issues and it creates new dilemmas. The concept of responsibility assumes a different moral weight in cases where the addressee of an action is distant in space and time. Requesting or granting consent is a different process in the Web than it is in an examination room of a hospital. Paternalistic behaviour on the part of a physician may well be viewed as committing the fallacy of authority by the patient when seeking medical information in the Internet.In light of the above discussion, the authors claim that the major ethical issue arising out of the use of the Internet for medical purposes lies in the responsibility of both the physicians involved in the decision making process as well as the patients. The information made available on the Web by health care professionals is differently perceived by the various individuals accessing it. Further, the patient who engages in self-diagnosis on the basis of such information assumes a different type of responsibility from that when consulting a medical encyclopedia due to the interactive nature of the medium which attempts to minimise the assumption of \"a universal type of patient\" that underlies the whole enterprise.It is therefore necessary to redefine the role of the patient and the physician in the Internet environment of health care services in order to determine the respective moral responsibility of both parties."}
+{"text": "Clinico-pathological features of prognostic significance in rectal cancer are described in 824 patients who were treated at 17 centres in the Medical Research Council Trial of radiotherapy in operable cancer of the rectum. Among the pre-operative assessments the mobility of the tumour was the one most strongly related to prognosis. Other variables predictive of outcome were the number of involved quadrants of the rectum, the distance of the tumour from the anal verge and the age of the patient. Of assessments made at surgery or immediately after, the report of a curative operation and the Dukes' classification most closely related to prognosis. The information presented supports the idea that a pre-operative clinical staging system for rectal cancer would be feasible and useful."}
+{"text": "BioPsychoSocial Medicine [We are pleased to announce the launch of Medicine , an openJapanese Journal of Psychosomatic Medicine [BioPsychoSocial Medicine is the official journal of The Japanese Society of Psychosomatic Medicine , which wMedicine , the latBioPsychoSocial Medicine.With the support of psychiatrists, Japanese psychosomatic medicine specialists have aspired to promote the development of clinical medicine, education, and research into biopsychosocial medical science targeting the physical disorders of each branch. Our members' wishes to transmit their results to the world have been realized through the publication of an English language journal, BioPsychoSocial Medicine will become an important journal in its field. We look forward to receiving your submissions.We welcome the contributions of psychosomatic medicine scientists from around the world, as well as from those in Japan, and have high expectations that by publishing high-quality research papers on biopsychosocial medical science and by providing opportunities for communication among the psychosomatic medicine scientists of the world, BioPsychoSocial Medicine and President of the Japanese Society of Psychosomatic Medicine.Yoshihide Nakai is an Advisory Board member of"}
+{"text": "Upon re-examination of all dates of birth and death of cases described in this paper , the ageAll other clinical information is accurate, and this does not affect the findings of the paper."}
+{"text": "After publication of this article , it was Eric Manheimer was funded by Grant Number R24 AT001293 from the National Center for Complementary and Alternative Medicine (NCCAM). The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the NCCAM, or the National Institutes of Health.We regret any inconvenience that the omission of this acknowledgment statement might have caused.The pre-publication history for this paper can be accessed here:"}
+{"text": "The distribution of cancers of the lung and stomach in the counties of England and Wales in 1968-81 was mapped, and compared to the distribution in the country in 1921-30 described by Stocks. The high risk of stomach cancer in North Wales noted by Stocks was found still to exist in each sex, although its disparity from the rest of the country has diminished. In general the geographic distribution of stomach cancer in both periods has paralleled that of post-neonatal mortality, at the same time and earlier, as an index of general poverty, but postneonatal mortality in North Wales has not been exceptionally high. In 1921-30 the highest risk of lung cancer was in and around London. In the modern data this was still true for older women, but for men and women under 45 years of age, and to a lesser extent for older men, the pattern has changed greatly; the epidemic has moved north, and highest risk is now in Northumberland and Durham. This spread appears to have occurred earlier for men than for women, and for urban than for rural areas, occurring latest of all for women in rural areas. Regional disparity has also increased, especially in males: risks in the northern regions are now over twice those in much of Wales and the South."}
+{"text": "Zorgbalans  project at the National Institute of Public Health and the Environment (RIVM) to withdraw the RIVM affiliation of the third author (O.A. Arah) who is a member of the Zorgbalans project team from the paper. It should be clear that the paper was not \u2013 and is not \u2013 officially endorsed by the RIVM.Following the publication of our recent work , we wereWe regret any inconvenience this apparent oversight and inappropriate affiliation use might have caused. Dr. Arah partook in the paper in his capacity as a faculty member of the Department of Social Medicine at the Academic Medical Center of the University of Amsterdam. The study was funded by a specific third party Canadian grant to that department (see acknowledgement in the paper ).In order to maintain our academic freedom and independence, we kindly ask the readers to disregard the aforementioned inappropriate affiliation and to consider this correction as a public withdrawal of the affiliation with the National Institute of Public Health and the Environment (RIVM) from the author byline.We also wish to correct the oversight in the abstract and text of the paper that the Dutch performance framework focuses on technical quality. This is mistaken since the Dutch framework also focuses on access and cost .As stated in the acknowledgement, the paper remains a property and responsibility of the authors and none of their employers, affiliate institutions, sponsor, interviewees or informants can be held responsible for its content and interpretations. We did/do not seek their approval of our interpretations nor should any such approval be ascribed to them.The pre-publication history for this paper can be accessed here:"}
+{"text": "A study has been made of the way in which the number of events available for analysis in a clinical trial was dependent on the recruitment period, the maximum follow-up time on individual patients and the length of time between the start of the trial and its analysis. The events considered were deaths, local recurrences and late radiation effects on normal tissue in patients treated for cancer of the laryngo-pharynx by two different fractionation regimes. The relationship is demonstrated between the number of events and the 95% confidence intervals that can be placed on differences between results in the two arms of the trial. It was found, in this particular trial, that no significant improvement in precision was gained by following up patients beyond 5 years or carrying out the analysis later than 2 years after the end of recruitment. The results are discussed in the context of the initial design of clinical trials, particularly those in which the aim is to test therapeutic equivalence."}
+{"text": "The epidemiological features of Kaposi's Sarcoma (KS) incidence in England and Wales in the period 1971-1980 are reviewed. The epidemiology of KS in England and Wales in this period is distinct from that associated with the AIDS epidemic. The incidence was probably very low compared to other Western countries, there was little male excess, and no indication, based on marital status data, of a raised incidence in male homosexuals. Half the cases registered were in people born outside the UK. The region of birth distribution in these migrants reflected the known pre-AIDS geographic distribution of KS and also pointed to high risks in those from Middle Eastern countries and the Caribbean. The very low incidence rates of KS in natives of England and Wales suggests that the background prevalence of the causative agent for KS was low in England and Wales prior to the AIDS epidemic."}
+{"text": "The technique of fusing mitotic cells to interphase cells, thereby producing condensation of the chromosomes of the interphase cell , has allowed detection of the initial number of chromosome breaks and their repair following ionising radiation. However, the difficulty and tedium of scoring all the chromosome fragments, as well as the inability to readily detect exchange aberrations, has limited the use of PCC. We describe here the use of the recently developed technique of fluorescence in situ hybridisation with whole chromosome libraries to stain individual human chromosomes  with the PCC's and show that this overcomes most of the limitations with the analysis of PCC's. First, by focusing on a single chromosome, scoring of breaks in the target chromosome is easy and rapid and greatly expands the radiation dose range over which the PCC technique can be used. Second, it allows the easy recognition of exchange type aberrations. A number of new applications of this technology, such as predicting the radiosensitivity of human tumours in situ, are feasible."}
+{"text": "Meeting society's needs without damaging the environment requires new ways of thinking. The link of industrial chemistry and chemoecology will be one of the key factors of sustainable development within the chemicals industry. Chemistry Central Journal intends to be a platform for the discussion of new trends, processes and applications of chemicals. Chemoecology, is an important field for the evaluation of new and important impacts. It can help to show, in a scientific manner, where the weaknesses and strengths of different systems lie. Quantifying the sustainability benefits of industrial chemistry is therefore an important issue for the further development of this field of opportunities in the future. A realistic and validated estimate of innovative potentials of industrial chemistry by using quantitative methods is essential for the development of new products and processes. New approaches and developments of \"Green Chemistry\", \"Green Engineering\", \"Chemoecology\" etc. in combination with the development of industrial processes should be published in the Chemistry Central Journal.Industrial chemistry plays an important role in our society. Thousands of products and applications have increased the standard of living of billions of people in the last century. Life today without the benefits of industrial chemistry and the chemical industry would be difficult and of low quality . NeverthUsing life-cycle management tools and assessments of the entire product life cycle \u2013 from concept development to design and implementation, further to marketing, and finally, end-of-life issues \u2013 will be an important factor for successful new industrial processes and products. The chemical industry has played a key role in the development of such new tools and techniques as well as in impact assessment research, consistently allocating a large portion of its resources to research and development .The design of new processes needs to consider aspects of the Chemoecology too. The link of industrial chemistry and Chemoecology will be one of the key factors of sustainable development within the chemicals industry.Meeting society's needs without damaging the environment requires new ways of thinking. The chemical industry has a strong record of innovation \u2013 in products that meet customers' needs, in manufacturing processes that protect the environment and human health, and in solutions that directly address environmental problems .Chemistry Central Journal will be a platform for the exchange of ideas in this exciting domain.To promote the communication and understanding between the academic community and the chemical industry is important. The best way to bridge the gap between the ideas that academia generates and the ideas that the product development industry seeks should be evaluated . Communi"}
+{"text": "On 29 and 30 September 1983 Southampton hosted an invited Workshop sponsored jointly by the Cancer Research Campaign and the British Association for Cancer Research. Workshop Participants discussed techniques for the phenotypic analysis of human lymphoma, the relationship of these cells to normal lymphoid subpopulations and the value of this type of study in the staging of lymphoproliferative disease. The presentations reported generated extensive discussion from all participants which it is not possible to record in this brief report."}
+{"text": "Education in medicine is being revolutionized by recent achievements in information technology. New research findings for prevention, diagnosis and treatment of diseases are increasing considerably the amount of information required in by medical courses. The use of information technologies has modified access and integration of this diversity of information minimizing the overload of the medical curriculum.Our goal is to develop a web-based environment, INTRAMED, to address the new teaching and learning procedures in the medical school of the Federal University of Pernambuco (UFPE).The project will provide a new way for the medical students to deal with the excess of information using recent information technologies in the health field both as an educational and informative tool. This includes the development of individual tools  for each discipline in the medical course. These tools will be stored in an SQL database server using a Microsoft NT environment. Each student or teacher will have their own personal login and password to access their data. The Internet access will be offered through the medical course homepage. This project involves the mutual co-operation of the Technology, Information and health group (TIS) and the teachers responsible for the disciplines. It will be developed at the LIKA laboratories. The system will be available for the users on the Computer Laboratory of the Medical Course composed by 60 microcomputers connected to the Internet.Provide access to information on all disciplines included in the course, students' scores, activities schedule, a fast way of communicating to teachers, students and course co-ordinators. The use of a Web environment to support teaching and learning activities will provide the necessary speed and flexibility to accomplish the next step in supporting our medical school activities."}
+{"text": "The binding of ring-labelled and side-chain labelled misonidazole to hypoxic cells in monolayer and spheroid cultures of mammalian cells has been compared. The kinetics and patterns of binding for the two labelled compounds are indistinguishable. This finding has implications for the mechanism of binding and for the design of misonidazole analogues which might be used to identify hypoxic zones in tumours."}
+{"text": "The roles of exogenous sex hormones and reproductive factors in the causation of malignant melanoma of the skin in women were examined in a case-control study of 276 patients and 276 matched controls in Western Australia. There was no consistent evidence of a relationship between the incidence rates of different histogenetic types of melanoma and age at menarche, duration of menstrual life, degree of obesity, number of pregnancies more than 20 weeks in duration or use of oral contraceptive preparations (OCP). Exposure to OCP was examined separately for different age periods and in different intervals of time before diagnosis; no consistent trend emerged. There was borderline evidence of an association of superficial spreading melanoma with duration of use of unopposed oestrogens. On the basis of seven studies of the relationship of melanoma to OCP published to date, we estimate that the total incidence rate of melanoma in OCP ever-users is unlikely to be increased by more than one third the rate in never-users."}
+{"text": "Unilateral and bilateral variation in the course and elongation of the cervical  part of the internal carotid artery (ICA) leading to its tortuosity, kinking and coiling or looping is not a rare condition, which could be caused by both embryological and acquired factors. Patients with such variations may be asymptomatic in some cases; in others, they can develop cerebrovascular symptoms due to carotid stenosis affecting cerebral circulation. The risk of transient ischemic attacks in patients with carotid stenosis is high and its surgical correction is indicated for the prevention of ischemic stroke. Detection of developmental variations of the ICA and evaluation of its stenotic areas is very important for surgical interventions and involves specific diagnostic imaging techniques for vascular lesions including contrast arteriography, duplex ultrasonography and magnetic resonance angiography. Examination of obtained images in cases of unusual and complicated variations of vascular pattern of the ICA may lead to confusion in interpretation of data. Awareness about details and topographic anatomy of variations of the ICA may serve as a useful guide for both radiologists and vascular surgeons. It may help to prevent diagnostic errors, influence surgical tactics and interventional procedures and avoid complications during the head and neck surgery. Our present study was conducted with a purpose of updating data about developmental variations of the ICA. Dissections of the main neurovascular bundle of the head and neck were performed on a total 14 human adult cadavers . Two cases of unilateral congenital elongation of the cervical part of the ICA with kinking and looping and carotid stenoses were found only in African males. Here we present their detailed case reports with review of the literature. Among other vascular systems the system of carotid arteries represents a special interest for medical professionals involved in diagnosis and management of vascular diseases. High incidence of stroke, which is the third common cause of death in the United States, was associated by Faries et al  with higEmbryonic development of the carotid arteries is associated mainly with transformation of the first  and the third pair of the aortic arches. The common carotid artery is formed from the proximal part and the ICA from the distal part of the third aortic arches, Moore . The latIn some cases the persistent carotid-vertebrobasilar anastomoses, shortening or elongation of the ICA with kinking and looping as well as its anomalous branches and variations in the course have no clinical significance, however, the knowledge of these variations might be useful and important for the interpretation of cranial contrast arteriography, MR angiography, duplex ultrasonography, because such variations can influence the surgical and other interventional procedures.Here we present two specific cases of unilateral elongation of the cervical part of the ICA in African males showing kinking and looping with their detailed analysis and review of the literature.Dissections of the main neurovascular bundle of the head and neck with a purpose of updating data about developmental variations of the ICA and preparation of the teaching and museum anatomical specimens were performed in the Gross Anatomy Laboratory on a total 14 human adult cadavers of both sexes 10 \u2013 Africans and 4 \u2013 East Indians. There were no any signs of trauma, surgery or wound scars of the neck in all cases. The skin of the head and neck, the superficial fascia of the neck, platysma muscles, and the superficial investing layer of the deep fascia of the neck were removed on both sides. Each parotid gland was removed by piecemeal along with its fascia and lymph nodes leaving terminal branches of the external carotid artery and accompanying veins intact. The sternocleidomastoid muscles were detached from the sternum and clavicle and shifted superoposteriorly. Both zygomatic arches were cut near their attachments to the skull and removed along with the masseter muscles. The base of the coronoid process of the mandibule was cut and shifted upward with the attachment of the tendon of the temporalis muscle. Each ramus of the mandible was separated from its body by a vertical osteotomy and removed after disarticulation of the mandibular head at the temporomandibular joint with attachments of both pterygoid muscles thus giving access to the content of the infratemporal fossa. The posterior belly of digastric, the styloid process with attached muscles and ligaments, the lateral and medial pterygoid muscles were removed on both sides in order to provide a better access to the highest part of the carotid sheath. The carotid sheath was traced within the carotid triangle on both sides from the root of the neck to the base of the skull. Its content including the common carotid artery (CCA), carotid bifurcation (CB), external carotid artery (ECA), carotid sinus (CS), internal carotid artery (ICA), vagus nerve (VN), internal jugular vein (IJV) and related structures were carefully dissected. Special attention was given to the course of the cervical part of the ICA. Measuring of the length and width of the ICA were conducted by a ruler. In two cases of anatomical variation of the cervical part of the ICA the midsagittal and coronal cross sections of the head and neck were made to facilitate a better approach to the site of anatomical variation of the ICA. In the first case the coronal cross section of the head and neck was produced in front of the anterior boundary of the foramen magnum just behind the pharyngeal tubercle of the occipital bone. In the second case the midsagittal cross section allowed examining the relationship of the ICA to the lateral pharyngeal wall, which was removed during the dissecting process. The ICA was traced along its entire course and its isolated specimen removed and studied. The size of the fourth part of the right and left vertebral arteries was compared. Distribution of the cadavers used in our study is shown in the Table A 64-year-old, well built, tall  African male cadaver showed a pronounced unilateral variation in the length (elongation) and course (kinking) of the highest portion of the cervical part of his left ICA. The history of this cadaver was not available, but during dissection of his abdominal cavity massive adhesions between the visceral peritoneal lining of the adjacent abdominal organs, between the visceral and parietal peritoneum and the perforated peptic ulcer of the duodenal bulb were found. These findings were interpreted as signs of the acute peritonitis \u2013 the most obvious cause for the death of this patient. No signs of any other diseases or pathological conditions were detected during the process of anatomical dissection of this cadaver.The left ICA of this patient arose from the CB of the left CCA at the level of the middle third of C3 vertebra . The cervical part of the left ICA (diameter 8 mm) ascended 52 mm by a spiral course from its origin marked by the CS (width 16 mm) to the cranial base. Being posterolateral to the ECA, the ICA turned during its ascend first posteromedially then anteromedially toward the lateral pharyngeal wall and, when approaching the base of the skull in the area of the pharyngeal recess, anterolaterally. It came into the direct contact with the petrous part of the temporal bone just anteromedial to the base of the styloid process and it was located there between the jugular process of the occipital bone posteriorly and the lower edge of the tympanic part of the temporal bone anteriorly, occupying an area about 9 mm wide just laterally to the external opening of the carotid canal (CC).At the base of the skull the upper end of the ICA started a sinuous (kinking) course Fig.  thus makBoth, the descending and ascending limbs of the ECS had rigid attachments to the petrous bone of the cranial base at two places, a kinking area was suspended by the fibrous band and the point of entry of the end of the cervical part of the ICA into the external opening of the CC also was attached to the rim of CC. Anteriorly, the ECS was related to the upper parts of the ascending pharyngeal artery and the pharyngeal venous plexus, the lateral end of the auditory tube and the tensor tympani muscle. Posterior to the ECS there were the upper part of the superior cervical sympathetic ganglion (SCSG), the glossopharyngeal nerve, the inferior vagal ganglion, the accessory nerve the hypoglossal nerve and the upper bulb of the IJV. The glossopharyngeal nerve had close relation and connection to the fibrous band, which suspended the curved (kinked) upper end of the ICA to the petrous bone. The inferior vagal ganglion was connected to the hypoglossal nerve. The SCSG had connections with the inferior ganglia of the glossopharyngeal and the VN and with the hypoglossal nerves.The total length of all portions of the cervical  part of the ICA constituted 78 mm. The course of the petrous, cavernous and cerebral parts of the left ICA was identical to the course of the right ICA and it corresponded to the common standard. The right ICA had its width at the beginning 16 mm, length of the cervical part 53 mm and diameter 8 mm.Examination of the removed brain with its meninges revealed a significant asymmetry in the diameter of the fourth parts of the vertebral arteries Fig. . The diaA 70-year-old, African male cadaver  showed another type of unilateral variation of the length (elongation) and course (looping) of the middle portion of the cervical part of his right ICA. The cause of death for this patient was an advanced prostate cancer with numerous retroperitoneal metastases in the region of the posterior abdominal wall. There was a significant hypertrophy of the urinary bladder (capacity of it was more than 1 liter) distention of both ureters and hydronephrosis of both kidneys with the renal failure. We did not notice any signs of other diseases or pathological conditions during the process of anatomical dissection of this cadaver.The right ICA of this patient arose from the CB of the right CCA at the level of the middle third of C3 vertebra . The cervical part of the right ICA (diameter 6 mm) first ascended 40 mm from the site of bifurcation of the CCA (width of CS was 14 mm) in front of the transverse processes of C3, C2 and C1 vertebrae. At the level of C1 the ICA started a looping course Fig. . At the The looping of the right ICA was located at the level C1 \u2013 C2 vertebrae anterolaterally to the longus capitis muscle. The VN and the IJV were located posterolateral to the loop. The latter was tightly packed within the carotid sheath and before its dissection the thickening of the carotid sheath was observed and interpreted as an arterial aneurism or a tumor. Even it resembled a large lymph node rather than the ICA itself. This thickening bulged the right wall of the nasopharynx inward and was located below and posteriorly to the nasopharyngeal opening of the auditory tube in the region of the palatopharyngeal sphincter (ridge of Passavant). The left wall of the nasopharynx did not have any bulging. The upper end of the right SCSG was located just posteroinferiorly to the lower bend of the loop Fig. . The ICAThe loop has significantly increased the total length of the cervical part of the right ICA, which constituted 97 mm. The course of the petrous, cavernous and cerebral parts of the right ICA was identical to the course of the left ICA and it corresponded to the common standard. The left ICA had its width at the beginning of the CS 14 mm, length of the cervical part 50 mm and diameter 6 mm. Apart from the above two cases of the unilateral elongation of the cervical part of the ICA its length in all other cadavers was more or less symmetrical on both sides ranging from 48 to 66 mm. The ICA ascended to the CC by a spiral course and was entering it obliquely in anterolateral direction forming with the plane of the cranial base an angle open posteromedially. The size of this angulation was a subject of individual fluctuation. The level of CB was mainly opposite the middle third of C3 vertebra. The size of the fourth part of the right and left vertebral arteries was also more or less identical.The ICA is specified by Bannister et al  to be a The posterolateral position of the ICA at its origin can be explained embryologically, since the ICA develops mainly from the dorsal aorta, which joins the third aortic arch, whereas the ECA arises from the ventral aorta Moore .As it is indicated by Bannister et al  the lengst case) and looping (2nd case) the most obvious cause of elongation might have embryological nature. That is supported by presence of a firm attachment of kinking of the left ICA to the base of the skull by a fibrous band with a compensatory enlargement of the left vertebral artery in the 1st case and a tight package of the looping of the right ICA within the carotid sheet and a compensatory enlargement of the right vertebral artery in the 2nd case.Variations in the extracranial course of the ICA are not rare and they are frequently reported in the literature. Pharyngeal transposition of the ICA is considered to be a risk factor for acute hemorrhage in pharyngeal surgery ,11,14-19Occurrence rate of different forms of elongation of the ICA, which were reported in some countries, is shown in the Table It was reported by Vannix et al in 1977  that kiIn normal condition tortuosity or a spiral course of an artery indicates on a high mobility of an area where it passes and it represents a compensatory mechanism in which a tortuous artery could be straightened during specific movements of mobile structures without being overstretched and/or occluded. For example, the tortuous facial artery will not be affected in wide opening of the mouth during depression of the mandible, the tortuous lingual artery will be straighten in protrusion of the tongue forward through the oral opening and tortuosity of the cervical part of the vertebral artery  is imporThe similar principle can be applied to the cervical part of the ICA, because movements of the head and neck may affect it. In all our cases the course of the cervical part of the ICA resembled a spiral course as it ascended. Having its position posterolaterally at the CB the ICA moved first posteromedially then anteromedially and when approaching the cranial base anterolaterally. The spiral course of the ICA could be clearly seen by using the Acland's Cross-Sectional Navigator  on the sElongation and tortuosity of the ICA is known for more than one century, but only in 1951 the association between carotid kinking and cerebrovascular insufficiency was made by Riser et al . Since tst case with kinking) and 50 and 97 (2nd case with looping) respectively. We did not find any atheromatous plaque in both elongated arteries, but obvious indications on carotid stenosis. In the 1st case the angle of kinking was close to 5 degrees  close to 5 degrees  declare that they have no competing interests.NAO has made substantial contributions to conception, design, dissections, acquisition, analysis and clinical interpretation of data, review of the literature, acquisition and processing of all illustrative materials, preparation of case reports and tables; drafting and revising critically the second version of the manuscript and its final proofing, alignment, formatting and completion of final version for publicationRTR participated in the design of the study, dissections, acquisition, analysis and interpretation of data, review of the literature, drafting the first version of the manuscript, assisted with revising of its second and final versionsSRR participated in the design of the study, dissections, acquisition, analysis and interpretation of data, review of the literature, drafting the first version and revising the second and final version of the manuscript and he communicated with the BioMed Central Editorial Production Team"}
+{"text": "In spite of employing numerous devices improving the safety in motor vehicles, traffic accidents are still among the main reasons of maxillofacial injuries. The maxillofacial injuries remain the serious clinical problem because of the specificity of this anatomical region. The knowledge of etiologic factors and mechanisms of injuries can be helpful in a satisfactory trauma prevention. The aim of this study was to find out the incidence and the pattern of maxillofacial injuries resulting from traffic accidents in the patients treated in the Department of Maxillofacial Surgery  from January 2001 to December 2005.The material consisted of 1024 case records of patients with maxillofacial injuries treated in the Maxillofacial Surgery Department of Silesian Medical Academy. The detailed analysis was carried out on the case records of 198 patients in the age of 3 to 68 with maxillofacial injuries resulting from traffic accidents. On the basis of data from a history, examination on admission, consultations and radiological examinations, patients' age and gender, we obtained the information on a pattern of injury and detailed description of an accident .The traffic accidents were the cause of 19,93% maxillofacial injuries in the analyzed period of time. Most of the patients had injuries to the soft tissues of the face , followed by tooth and alveolar process injuries  and mandibular fractures . All the types of injuries were more common in men than in women. The majority of the patients were car drivers followed by car passengers, pedestrians, cyclists and motor cyclists. The peak age of the patients was between 18 to 25 years. The prevalent number of accidents resulting in injuries to this region took place in spring, especially between noon and 4 PM.Our results exhibit that road traffic accidents remain among the main reasons of maxillofacial injuries following the traumas resulting from assaults and interpersonal violence. This succession of etiologic factors is in accordance with the data from the most developed countries. The relatively high incidence of injuries resulting from traffic accidents indicates the necessity to reinforce legislation aimed to prevent road traffic crashes and thus to reduce maxillofacial injuries among children and adults. Traffic accidents are among the main etiologic factors of maxillofacial injuries and according to the results of previous research works they are the reasons of 34,42% to 90,15% of all the skeletal and soft tissues injuries of the face [The maxillofacial injuries remain the serious clinical problems because of the specificity of this anatomical region. This is the area where the important organs are located and where the digestive and respiratory systems start. That is why the injuries to this region are the reasons of serious dysfunctions. Due to an anatomical proximity, together with maxillofacial injuries, the damages to the central nervous system often occur . It mustOne of the methods of trauma prevention among the users of motor vehicles in the most countries of the world is the obligatory fastening of seat belts. As a result of this requirement, 25% decrease in frequency of injury occurrence among the car users was observed . The sevThe aim of this study is to find out the incidence and the pattern of maxillofacial injuries resulting from traffic accidents in the patients treated in the Department of Maxillofacial Surgery  from January 2001 to December 2005.2; the number of registered cars \u2013 46.000) [The material consisted of 1024 case records of patients with maxillofacial injuries treated in the Maxillofacial Surgery Department of Silesian Medical Academy in Katowice, Poland, from January 2001 to December 2005. On admission the patients gave their consent to use the data obtained during the examination and treatment for further scientific projects. Katowice (density of population \u2013 697 persons/km 46.000)  is the cThe detailed analysis was carried out on the case records of 198 patients with maxillofacial injuries resulting from traffic accidents. On the basis of data from a history, examination on admission, consultations and radiological examinations, patients' age and gender, we obtained information on the pattern of injury and detailed description of accident (the date and the time of accident). The data concerning the role of the patient in accident was collected.The patients included into research (74 women and 124 men) were between 3 to 68 years of age. The authors of this article (PM and JD) were the surgeons responsible to see those patients at hospitals. The injuries which the patients suffered were grouped into soft tissue injuries, injuries of teeth and alveolar process, nasal injuries, mandibular fractures, maxillary fractures, zygomatic complex fractures, orbital \"blow-out\" fractures and multiple fractures of facial bone frame. Both single and multiple fractures of the mandible were included into mandibular fractures. All the fractures of maxilla according to the LeFort's classification, both unilateral and bilateral, were included into the group of maxillary fractures. The injuries which were the combination of the fractures listed above, were classified into the group of multiple fractures of facial bone frame.According to the previous work of Wood and Freer , the patThe statistical analysis was done using Statistica v. 5.1. The statistical significance of differences in the numbers of observations  between the groups was checked by chi-square test on the p-level < 0,05.There were 1024 patients with injuries to soft tissues and fractures of facial bone frame treated in the Maxillofacial Surgery Department of Silesian Medical Academy in Katowice, Poland, from January 2001 to December 2005, among which 198 cases  resulted from the traffic accidents. There were 124 men  and 61 women  in the age of 3 to 68 years. The major cause of maxillofacial injuries were assaults and interpersonal violence . The traffic accidents were followed by the etiologic factors such as falls , sport injuries  and the others.The statistics of patients with particular types of injuries resulting from traffic accidents are listed in Table The statistics of men and women in relation to their role in the accident are shown on Figure The statistics of patients with maxillofacial injuries resulting from traffic accidents in reference to their age are shown at Figure The statistics of patients with maxillofacial injuries depending on the season of the year in which the accident occurred are shown at Figure Although there are many devices improving the safety of the motor vehicle users, the maxillofacial injuries resulting from traffic accidents occur quite frequently ,12. We fOur results exhibit that the most common are the injuries to soft tissues followed by tooth and alveolar process injuries and mandibular fractures Table . The resThere is little information covering the problem of maxillofacial injuries in reference to the particular groups of motor vehicle users . However, it may be verified that the men are more frequently subjected to these injuries . In our Our results demonstrate that the maxillofacial injuries resulting from traffic accidents are the most common in the group of patients in the age of 18 to 25 Figure , when thOur results exhibit that road traffic accidents remain among the main reasons of maxillofacial injuries following the traumas resulting from assaults and interpersonal violence. This succession of etiologic factors is in accordance with the data from the most developed countries. The most frequently occurring maxillofacial injuries resulting from traffic accidents include injuries to facial soft tissues, injuries to teeth and alveolar process and mandibular fractures. Maxillofacial injuries resulting from traffic accidents are more frequent in men than in women, especially in the age of 18 to 25 years. The highest incidence of maxillofacial injuries resulting from traffic accidents is noted in spring. The incidence of these injuries varies depending on the time of the day and is the highest between noon and 4 PM during the day rush hour. The relatively high incidence of injuries resulting from traffic accidents indicates the necessity to reinforce legislation aimed to prevent road traffic crashes and thus to reduce maxillofacial injuries among children and adults.The author(s) declare that they have no competing interests.PM conceived the study and did the case record search, coordinated the write-up and submission of the article. PM and JD were the surgeons responsible to see the patients at hospitals. BM carried out the literature search. PM, BM and JD participated in the writing of the manuscript. All authors have given the final approval of the version to be submitted to the journal."}
+{"text": "The presented paper deal with two projects of telemedicine systems: 1) TELEONC system for oncology education; 2) postgraduated study health telematic system. The system projects have been created in close co-operation between the Institute of Computer Science at Technical University and the Department of Oncology at the Medical University of Lodz. The aim of the software of the systems is to improve efficiency and quality of education in medical study by creating broad acces to medical knowledge conveyed in a clear, easy-to-aquire way with the help of multimedia patern sets. The paper, after short description of the systems, has been devoted mainly to organization of sonic and image modules as well as their applications to problems of diagnosis and of drug informatons. The exploitation of multimedia in medical computer systems is extremely wide, from making use of natural voice during history-taking, through introduction of colour moving graphics illustrating main examinations, to the display of colour pictures of histopathological and cytological specimens. Apart from their written form, all results of auxiliary examinations, no matter whether of laboratory or picture type, can be given the shape of a drawing, moving chart or another attractive graphic form and displayed on the computer screen. Similarly, sound information obtaining from heart and lung auscultation can be introduced to the program. The most significant diagnostic examination in the oncological clinic is the microscopic one - cytological or histopathological. The discussion presented in the paper gives an idea how efficiently the communication with the systems assisting mcal diagnoses can be developed owing to the use of multimedia."}
+{"text": "Cells of a patient with Turcot's syndrome and of her parents were evaluated for the presence of molecular alterations in the p53 and the Ki-ras gene. Deletions on chromosome 17p, overexpression and point mutations of the p53 gene as well as mutations of the Ki-ras gene were detected in primary and metastatic tumour but not in the germline of the patient nor in her parents."}
+{"text": "The Paralympics are the second largest sport event in the world , the description of physiological responses according to the functional impairment  or equipment , the response to training , and the relationship between laboratory and field testing responses  are different parts of the issue that address an important aim of the IPC: to enable Paralympic athletes to achieve sporting excellence  and physiological responses  of athletes with impairment. The motto of Paralympic movement \u201cSpirit in Motion,\u201d is also the philosophy of the present compendium in order to present new advances and research findings in the field of applied physiology and biomechanics in Paralymipc sport.Finally, all contributors of this special topic provide a descriptive approach of performance, and especially the preparation of athletes with a physical impairment to optimize their exercise performance. Attention has been paid to the accuracy of tools to assess physical (PL: Design and scripture; VG: Completion and correction; TJ: Completion and correction; CP: Completion and correction.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "To improve the usability, availability, quality, and timeliness of surveillance data  strategy to streamline NNDSS and access to data for users; NMI is a component of the CDC Surveillance Strategy. This consolidation of information also is in response to the recommendations of a workgroup consisting of representatives from the CDC Excellence in Science Committee, the Surveillance Science Advisory Group, and"}
+{"text": "A continuum hypothesis-based model is developed for the simulation of the contraction of burns in order to gain new insights into which elements of the healing response might have a substantial influence on this process. Tissue is modeled as a neo-Hookean solid. Furthermore, (myo)fibroblasts, collagen molecules, and a generic signaling molecule are selected as model components. An overview of the custom-made numerical algorithm is presented. Subsequently, good agreement is demonstrated with respect to variability in the evolution of the surface area of burns over time between the outcomes of computer simulations and measurements obtained in an experimental study. In the model this variability is caused by varying the values for some of its parameters simultaneously. A factorial design combined with a regression analysis are used to quantify the individual contributions of these parameter value variations to the dispersion in the surface area of healing burns. The analysis shows that almost all variability in the surface area can be explained by variability in the value for the myofibroblast apoptosis rate and, to a lesser extent, the value for the collagen molecule secretion rate. This suggests that most of the variability in the evolution of the surface area of burns over time in the experimental study might be attributed to variability in these two rates. Finally, a probabilistic analysis is used in order to investigate in more detail the effect of variability in the values for the two rates on the healing process. Results of this analysis are presented and discussed. Burns are a significant global problem; they constitute the second highest incidence of trauma related deaths worldwide and every year nearly half a million citizens of the US require medical treatment as a result of acute thermal injury  injuries, it is obvious that these injuries need to be repaired quickly and effectively. In order to accomplish this, humans have evolved sophisticated processes for the restoration of the integrity of skin. If the restoration proceeds without complications, then the final outcome of these restoration processes is not normal skin tissue in the case of deep dermal injuries such as severe burns, but whitish, thin, flat scar tissue  and the presence of a fibroblast population at the site of injury. Restoration of the presence of a fibroblast population can be accomplished through cell division of fibroblasts present in the injured area, and cell migration of fibroblasts present in the surrounding uninjured tissue into the wounded area. At the site of injury the fibroblasts can differentiate into myofibroblasts Majno . Taken tWound contraction is the process that causes the circumferential inward movement of surrounding undamaged skin tissue towards the wounded area , a myofibroblast population (M), a generic signaling molecule (c), and collagen molecules fibroblasts. The derivation of the functional form  can be The last term of We assume that secreted collagen molecules are attached to the ECM instantaneously. Hence we assume that no active transport of collagen molecules takes place. Furthermore, we incorporate into the model the production of collagen molecules by both fibroblasts and myofibroblasts. The secretion rate of the molecules is enhanced in the presence of the signaling molecule. Examples of signaling molecules that can upregulate the secretion of collagen molecules by (myo)fibroblasts are certain members of the family of transforming growth factors E is a constant.We take the following constitutive stress-strain relation: Treloar . Like Ra Treloar  and Ramt Treloar , we assuFurthermore, we incorporate into the model the forces that are generated by the myofibroblasts due to their pulling on the ECM Hinz . In thisxy-plane running parallel to the surface of the skin and We assume that mentclass2pt{minimThe initial conditions give a description of the different cell densities and concentrations at the onset of the proliferative phase of the wound healing cascade. For the generation of simulation results the following general indicator function has been used to describe the shape of the burn:g et al. . CertainBased on the general function for the shape of the wound we take the following initial conditions for the modeled constituents of the dermal layer:entclass1pt{minimaWith respect to the initial conditions for the displacement of the dermal layer, the following holds. The initial cell density of the myofibroblast population is equal to zero everywhere in the domain of computation. Looking at Eq. , this imWith respect to the boundary conditions for the modeled constituents of the dermal layer, we take the following Dirichlet boundary conditionsq, and the collagen molecule degradation rate  variability in the values for most of the parameters that were either estimated from results of previously conducted studies or obtained directly from previously conducted studies. However, given the complexity of the model and hence the necessary complexity of the custom-made numerical algorithm, we decided to set the values for these parameters to fixed values within the found ranges during the generation of simulation results in order to prevent the total computation time of the statistical analyses from rising too high.The ranges of the values for the free parameters g et al.  fibroblasts in the wounded area produce collagen molecules in order to restore the presence of a collagen-rich ECM and due to the presence of the signaling molecules the rate of production of the collagen molecules is enhanced. Furthermore, the present myofibroblasts in the wounded area pull on the ECM and as a consequence the surface area of the burn is reduced slowly over time.During the execution of the wound healing processes the concentration of the generic MMP rises slowly in the recovering wounded area and due to this the secretion of signaling molecules becomes smaller than the proteolytic breakdown of these molecules at a certain point in time. This results in a relatively fast disappearance of the signaling molecules from the wounded area and as a consequence of that the rate of production of collagen molecules starts to decline, as does the rate of cell proliferation and cell differentiation. Slowly the cell densities and the concentrations in the recovering wound area will approach the equilibrium cell densities and the equilibrium concentrations of the unwounded area due to, respectively, cell apoptosis and proteolytic breakdown of the molecules, and ultimately the properties of the recovering wounded area will become identical to the properties of the surrounding tissue, which subsequently implies that the size of the surface area of the recovering wound area slowly returns to the surface area of the burn at the onset of the proliferative phase. The decline of the cell density of the myofibroblast population in the dermal layer, the decline of the concentrations of both the signaling molecules and the collagen molecules, the gradual rise of the cell density of the fibroblast population in the wounded area, and the gradual retraction of the recovering wounded area are not (clearly) visible in the results presented in Sect. In this section we present an overview of the custom-made numerical algorithm that had to be developed for the generation of computer simulations. The development of this algorithm was necessary in order to guarantee the positivity of the approximations of the solutions for the constituents of the dermal layer, \u201ccatch\u201d the local dynamics of the model, and obtain sufficiently accurate simulations sufficiently fast.For the kernel of the concrete expression of the algorithm we used MATLAB together with MATLAB\u2019s Parallel Computing Toolbox .The obtained simulation data were analyzed in IBM SPSS by means of the regression analysis IBM Corp . No inteThe surface area of a the burns was determined in two steps. In the first step we determined the displacements of the material points with coordinates After having used a regression analysis, a probabilistic analysis was used in order to investigate in more detail the effect of variability in the values for the collagen molecule secretion rate and the myofibroblast apoptosis rate, on both the cell density of the myofibroblasts and the concentration of the collagen molecules at day 42, and the relative surface area of the healing burn at day 42 compared to its surface area at day 0. The collagen molecule secretion rate and the myofibroblast apoptosis rate were chosen because the multiple linear regression analysis demonstrated that varying the value for these two factors has by far the largest impact on the relative surface area of the healing burn  is significantly different from zero, Table Figure For approximately the last 25 years the mathematical modeling of processes involved in the healing of dermal wounds has been an active area of research. Over these years the number of generated models has increased considerably. Surveys of these models such as those compiled in Sherratt and Dallon , BuganzaThe biochemical components of the model presented in this study are based primarily on the biochemical components of the model developed by Olsen et al. . HoweverIn addition, we model the random movement of cells by means of cell density-dependent Fickian diffusion instead of linear Fickian diffusion. All of the models in the above cited modeling studies use linear diffusion to model the random dispersal of cells. As is also mentioned by Olsen et al. , this isFurthermore, we incorporate into the model the degradation of both signaling molecules and collagen molecules by means of proteolytic cleavage by a generic MMP instead of by means of natural decay or very general enzymatic degradation which are usually used in this type of models. For this end, we use the phenomenological relationship given in Eq.  which isFinally, with respect to the biochemical components of the model, we want to place some remarks concerning the way that the cell differentiation of fibroblasts into myofibroblasts has been incorporated into the presented model. Similar to Olsen et al. , we assuWith respect to the mechanical component of the presented model, we want to remark the following. Traditionally, the dermis is treated as a linear (visco)elastic solid in mechano-chemical continuum models for (certain aspects of) dermal wound healing . Given Eq. , this imHence it is not possible with the presented model to simulate the often observed permanent deformation of involved tissues and the development of residual stresses within these tissues fibroblasts (Looking at the results obtained with the probabilistic analysis in Fig. Finally, it is interesting to observe that all of the remaining individual correlations displayed in the separate scatter plots make sense intuitively with the exception of the scatter plot that displays the correlation between the collagen molecule secretion rate and the cell density of the myofibroblasts. For example, we would expect positive correlations between the concentration of the collagen molecules and the rate of secretion of these molecules, and between the concentration of the collagen molecules and the cell density of the myofibroblast population. However, taking some of the correlations together shows something peculiar; while the correlation between the collagen molecule secretion rate and the concentration of the collagen molecules, and the correlation between the collagen molecule secretion rate and the relative surface area of a burn at day 42 are both positive, the correlation between the concentration of the collagen molecules and the relative surface area of a burn at day 42 is negative.In order to explain this phenomenon, we suggest the following. Besides influencing the total amount of generated stress directly through the relationship given in Eq. , the conAs has been mentioned in the introduction, we think that results obtained with mathematical modeling studies can provide new insights into which elements of the wound healing response are key elements in processes like wound contraction, and that these insights might aid in the design of new treatment plans for burns that can reduce the incidence of sequelae. In this study we found that most of the variability in the evolution of the surface area of healing burns over time might be attributed to variability in the apoptosis rate of myofibroblasts primarily and, to a lesser extent, the secretion rate of collagen molecules. Interestingly, this result is in agreement with the suggestion put forward by Desmouli\u00e8re et al.  that the"}
+{"text": "This article describes the data collection used to analyse the risk of fatalities and injuries resulting from traffic accidents on interurban roads in the provinces of Spain from 1999 to 2015. The database includes data on different factors related to accidents rates for each Spanish province. These data were used in the article entitled \u201cImpact of provincial characteristics on the number of traffic accident victims on interurban roads in Spain\u201d  [1]. To this end, the columns express each of the variables selected for the main research or those necessary to derive them. The rows include all the observations for each province and in each year of the study period. The provinces are organized in alphabetical order according to the Autonomous Community of which they form part.The first four columns of the Excel workbook were used to encode the observations: province (name of province); time (year of observation); cprovince  and ctime .The risks of fatality, serious injury and slight injury for each province in the period under study (dependent variables) were obtained by means of the relationship between two variables: the number of fatalities, serious injuries and slight injuries on interurban roads The database also includes the different independent variables used in the main research or those necessary to derive them. The compilation and/or the construction of some of the determinants required taking into account certain considerations.The penalty-points driving licence came into force on 1 July 2006 To construct the variables referring to the sociodemographic aspects of the models , we used the population of each province Some of the factors included in the database are missing certain observations. First, the climate records published in the Annual Statistics of the Ministry of Agriculture, Fisheries, Food and Environment The non-availability of data is also present in the unemployment rate variable The calculation of the absolute annual variation in population density (difference between the population density of a province in a particular year and that of the preceding year) resulted in a lack of information for 1999 for all the provinces since no data were available for this variable referring to 1998.The non-availability in the three series of all the observations had no substantial impact mainly because the models include the investment in infrastructure, lagged one and two periods. STATA did not utilize the data for 1999 and 2000 as there were no lagged observations for these years.Investments in infrastructure (replacement and construction) per kilometre of road were constructed from two variables. The first is the investment in replacement or construction of interurban roads in each province, regardless of the authority responsible for maintaining the network veh-km)\u201d using the following mathematical expression:ADT is the mean daily intensity of traffic and iL the length of the stretch of interurban road.The traffic volume variable, which was included to measure the effect of exposure on the risk of fatalities and injuries in traffic accidents, was obtained using the information published by the Ministry of Public Works and Transport with respect to the number of kilometres travelled on interurban roads (millions of vehicle-kilometres) and the number of kilometres of interurban roads in each province veh-km\u201d y \u201ciL\u201d, we obtained the traffic volume variable (ADT).Using this expression and the information available in our database for the variables \u201c"}
+{"text": "The original article  containsThe reason for the intended omission of this molecule throughout the article was due to complications in obtaining the license for both the use of and presentation of research involving this molecule, and its presence within Fig. 7 was unintentional.As such, the appropriate version of Fig."}
+{"text": "Following publication of the original article  it was bWe would like to acknowledge the financial support from the R&D Convergence Program of NST  of Republic of Korea.However, the revised version should read as:We would like to acknowledge the financial support from the R&D Convergence Program of NST  of Republic of Korea and a grant (K15311) from the KIOM."}
+{"text": "The editors of Zoological Research gratefully acknowledge the generous assistance of the following reviewers. We are thankful for the honest and invaluable work of all the referees during the past year, which has greatly contributed to ensuring the quality of Zoological Research."}
+{"text": "The clinical medical physics community is extremely fortunate to be practicing a field of expertise that has an explosion of new ideas shaping their future. Granted a major factor driving this burst of development is the availability of fast and optimized computational and imaging capabilities, however, it is the clinical medical physicist who ultimately tests the new tools and implements them for the benefit of the patient. Over the past decades the clinical medical physicist faced difficulty in finding a suitable medium of expression to archive and communicate their work to his fellow colleagues and to the medical community at large. The establishment of the Journal of Applied Clinical Medical Physics (JACMP) by the Board of Chancellors of the American College of Medical Physics was an extremely important and visionary undertaking. The membership of the American College of Medical Physics by virtue of their support of the College are the true benefactors and beneficiaries of the journal.I am extremely impressed by the exceptionally professional quality of the JACMP. It truly reflects the caliber and in depth effort of the Chief Editor, Peter Almond, Associate Editor, Mike Mills and their Advisory Editorial Board. We are all grateful for their vision and the years of work they have put in to the selection of outstanding publisher and equally impressive format for the Journal. JACMP goes a long way to give expression to the clinical medical physics community.I have no doubt that under the Editorship of Dr. Peter Almond and his Editorial Board JACMP will continue to provide a high level of forum for the clinical medical physicists. It will be read all around the world and help our fellow colleagues in hopefully even the under developed countries as well."}
+{"text": "This article presents analyzed data on new diagnoses and mortality of breast cancer, between 2005 and 2013, in the Republic of Cyprus. New diagnoses are presented by demographic and clinical/histological variables that include cancer grade, behaviour, stage, and histological type at diagnosis . Breast cancer-related deaths are presented by gender. Net survival rates based on cohort and period methods are presented by age group, cancer grade, behaviour, and stage at diagnosis, for all cases and for cases of Greek-Cypriot ethnicity. The unprocessed data of the Cyprus Cancer Registry were provided by the Health Monitoring Unit of the Ministry of Health of the Republic of Cyprus. Specifications TableValue of the data\u2022The presented data can be used as reference for the Republic of Cyprus for the years 2005\u20132013 and can be compared with those of other studies that might be published in the future.\u2022The data can be included in analyses to better understand the epidemiology of breast cancer.\u2022The data can be used for developing policies related to breast cancer prevention.1This article includes analyzed data on breast cancer cases obtained from the Cyprus Cancer Registry in the Health Monitoring Unit of the Ministry of Health of the Republic of Cyprus for the period 2005\u20132013. Demographic and clinical/histological parameters of newly diagnosed breast cancer cases are shown in 2The data presented in this article were obtained from the Cyprus Cancer Registry and the Causes of Death Registry in the Health Monitoring Unit at the Ministry of Health of the Republic of Cyprus. The Cyprus Cancer Registry collects data from all public and private hospitals as well as from clinics within the Republic of Cyprus The data in this article refer to the period between 2005 and 2013. The unprocessed data provided by the Health Monitoring Unit at the Ministry of Health were checked for duplicates. Duplicates were deleted from the dataset. Only patients residing in the controlled area by the Republic of Cyprus were included.Overall, between 2005 and 2013, 4769 newly diagnosed breast cancer cases residing in the Republic of Cyprus were recorded in the Cyprus Cancer Registry. Their demographic characteristics  are presented in Counts and percentages of 4700 newly diagnosed breast cancer cases of known ethnicity are presented by cancer grade , behaviostns command in STATA version 14"}
+{"text": "Frontiers in System Neuroscience is to present some of the latest findings and views regarding the pathophysiology and treatment of TBI from a systems neuroscience perspective.Traumatic brain injury (TBI) has gained prominence in the public consciousness as a significant medical problem, especially in light of the recent conflicts in Iraq and Afghanistan and the ongoing discussions of head injuries in sports. Rightfully so, there has been significant energy invested in studying the perturbations of molecular cascades and cellular function in TBI  and the Department of Veterans Affairs (IK2-RX002013 to HC).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "There is an error in the sixth sentence of the Abstract. The correct sentence is: Sakaguchi, Rudensky, Hori, Shevach, and Bettelli were the top authors in Treg research.There is an error in the third sentence in the second paragraph of the Author analysis section of the Results and Discussion. The correct sentence is: As shown in There is an error in the image for Fig 5. Please see the correct The values in the Freq column of Table 4 are incorrect. Please see the correct There is an error in the fourth sentence in the second paragraph of the Author analysis section of the Results and Discussion. The correct sentence is: Additionally, There is an error in the seventh sentence of the Conclusion. The correct sentence is: The highest-impact scholars were Sakaguchi, Rudensky, Hori, Shevach, and Bettelli."}
+{"text": "The segregation of the elements during solidification and the direct formation of destructive phases such as Laves from the liquid, result in in-homogeneity of the cast structure and degradation of mechanical properties. Homogenization heat treatment is one of the ways to eliminate destructive Laves from the cast structure of superalloys such as 718Plus. The collected data presents the effect of homogenization treatment conditions on the cast structure, hardness, and tensile properties of the alloy 718Plus in the presence of boron and zirconium additives. For this purpose, five alloys with different contents of boron and zirconium were cast by VIM/VAR process and then were homogenized at various conditions. The microstructural investigation by OM and SEM and phase analysis by XRD were done and then hardness and tensile tests were performed on the homogenized alloys. Specifications TableValue of the data\u2022These collected data can be useful for other researchers in order to select the optimal homogenization heat treatment conditions of alloy 718Plus and the similar alloys like In718.\u2022The data about the cast structure and tensile properties variation in the presence of boron and zirconium can be useful for using of these elements in other superalloys.\u2022The data can be useful for the selection of the condition of homogenization treatment in the present of boron and zirconium, in order to maintain the mechanical properties of superalloys.1The SEM images of the cast structure of alloy 718Plus with different amounts of boron and zirconium and the results of the XRD analysis are presented here. In addition, the results of the hot tensile test that was performed on the cast alloy 718Plus in different homogenization conditions were reported. The effect of boron and zirconium on the tensile properties of the alloy 718Plus under the same homogenization condition are the other part of the data.2The alloys structure was examined by Optical Microscopy and Scanning Electron Microscopy, operated at 15\u00a0kV. The SEM results of the cast structure of alloy 718Plus with its extracted phases are shown in The results of the macro-hardness test are presented in The effect of boron and zirconium on the hot tensile properties of the alloy 718Plus under the same 1125\u00a0\u00b0C-10\u00a0h homogenization conditions is presented in"}
+{"text": "In the original article, we neglected to include the funder Department of Energy's National Energy Technology Laboratory (DOE-NETL), DE# FE0024297 to SS and PJM. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The appropriate mathematical model for the problem space of tower transformation tasks is the state graph representing positions of discs or balls and their moves. Graph theoretical quantities like distance, eccentricities or degrees of vertices and symmetries of graphs support the choice of problems, the selection of tasks and the analysis of performance of subjects whose solution paths can be projected onto the graph. The mathematical model is also at the base of a computerized test tool to administer various types of tower tasks."}
+{"text": "The journal retracts the 17 May 2016 article cited above. Following publication, concerns were raised regarding the scientific validity of the article. The Chief Editors subsequently concluded that aspects of the paper's findings and assertions were not sufficiently matched by the level of verifiable evidence presented. The retraction of the article was approved by the Chief Editors of Human Neuroscience and the Editor-in-Chief of Frontiers. The authors do not agree to the retraction."}
+{"text": "From a holistic perspective, psychiatric diseases are caused by the patients unwillingness to assume responsibility for his life, existence, and personal relations. The loss of responsibility arises from the repression of the fundamental existential dimensions of the patients. Repression of love and purpose causes depersonalization . Repression of strength in mind and emotions leads to derealization . The repression of joy and gender leads to devitalization .The losses of existential dimensions are invariably connected to traumas with life-denying decisions. Healing the wounds of the soul by holding and processing will lead to the recovery of the person's character, purpose of life, and existential responsibility. It can be very difficult to help a psychotic patient. The physician must first love his patient unconditionally and then fully understand the patient in order to meet and support the patient to initiate the holistic process of healing. It takes motivation and willingness to suffer on behalf of the patients in order to heal, as the existential and emotional pain of the traumas resulting in insanity is often overwhelming. We believe that most psychiatric diseases can be alleviated or cured by the loving and caring physician who masters the holistic toolbox. Further research is needed to document the effect of holistic medicine in psychiatry."}
+{"text": "Department of Health and Human Services (HHS) in December 2010, to focus the attention and resources of the US government on the research, practice, and policy implications of multiple chronic conditions (MCCs) ).Third, in addition to focusing on the effects of MCCs on the health and well-being of specific individuals with MCCs, attention should also be given to the interplay of MCCs on the health and well-being of the caregivers and family members of those individuals. Research on the social determinants of health underscores that living with MCCs is a complex and dynamic process that is likely to involve the health status of family members see , 13). Th. Th13]).In conclusion, we trust that all healthcare professionals involved in the management of patients with MCCs will not only find the articles in this special issue interesting and informative, but that they will also help to stimulate further research, discussion, and guidance on MCCs globally."}
+{"text": "Manual analysis of neck kinematics is usually associated with measurement errors and it requires the use of software capabilities. Considering laboratory usage, software has been developed to solve the associated problems.Fluoroscopic images taken from 78 women were used to design and evaluate the performance of the software. The software was implemented using C# language, according to the case-based reasoning technique.The viewpoints of experts suggest accuracy of the software in tracking and calculations, which meets their information requirements.Using the software could help physiotherapists to accomplish their work in decreased time and with improved accuracy. Manual analysis of neck kinematics usually suffers from measurement errors and requires the use of the software capabilities. In this research article, a software has been developed to solve this problem. The software is implemented using C# language, according to the case-based reasoning technique. Experts using the software suggested its accuracy in tracking and calculations, which met their information requirements. Using the software could help physiotherapists to accomplish their work in decreased time and improved accuracy. However, further research is to confirm these results. Lumbar pain, a significant problem of public health in industrialized countries is considered as one of the main causes of functional limitations in adults . Neck paThe development of new technologies facilitates the procedures in many areas including the applications of medical diagnosis  such as A set of fluoroscopic images of the neck related to the evaluation of the women\u2019s posture was used to evaluate the performance of the software. As mentioned in , a conveThe images include a series of fluoroscopic images used to evaluate the performance of the software. A digital imaging technique was used to evaluate head and neck posture in the standing position. A digital camera was placed at a distance of 1.5 m on a fixed point without rotation or tilt. The imaging process was led to a series of neck vertebrae images in sagittal plane as in According to the aim of actual use for software out of the lab, C# programming language in visual studio and the Aforge website were used to implement the software\u00a0. Aforge The steps taken during the software execution are explained in the rest of this section.First, contrast normalization and histogram equalization were used to increase the quality of images. As edge detection is one of the main processes of object detection in many image processing applications , using CAt this point it is necessary to explain the concepts presented. A vertebra is in rotational motion when it is displaced in a spinning or angular displacement around sagittal plane. Also a vertebra is in translational motion when all reference structures indicated within it have the same direction of motion relative to a fixed point in sagittal plane. As already mentioned, the main challenge is to identify the location of vertebrae in the images and track them. In the first image, the location of each vertebra is identified by drawing outer contours of vertebrae by an expert. Using edge detection before this step helps the expert to draw more accurate contours for vertebrae which helps the expert by drawing the contours only on the extracted edges. The software controls the probable vibration of the expert hand and refrains from plotting the line outside the specified edges. The input by expert in the first image forms the foundation of next processing steps, since all subsequent calculations are based on the information that is entered in the first step.To avoid the complexity of the implementation, case-based reasoning is selected. Its main idea is that the similar issues have the similar responses , based oN_I: Next image; V_I: Vertebrae section image.During three nested loops, the changes of rotation as well as vertical and horizontal translation are made to the previous location of the vertebrae and coincidences are calculated. The next location of the vertebra is identified, based on the highest amount of coincidence. Since the locations of the vertebrae are determined by experts in the first image and all the next images obtain the required information from the previous image, the process is repeated for the next images until all the images are examined.After extracting the location of each vertebra, the data are fed into the calculation section. Based on Frobin, movement is calculated as follows:Based on the four corners set by the expert, the geometric center of the determined vertebra and the middle plane of the adjacent vertebra are drawn. Next, the bisector of the angle between the middle screens of the two adjacent vertebrae is drawn. To calculate the movement (between two adjacent vertebrae), a perpendicular line is drawn from their center to the above mentioned bisector. The movement is also calculated based on the distance between the intersections of the two perpendicular lines on the bisector. If the intersection of the perpendicular line of the upper vertebra is ahead of the intersection of the vertical line of the lower vertebra on the bisector line, the movement is forward and is marked by a positive sign. If the intersection of the perpendicular line of the upper vertebra on the bisector line is at the back of the intersection of the perpendicular line of the lower vertebra, the movement is backward and the translation is marked with a minus sign .Drawing the midline of the upper vertebra based on the position of the corners of the upper vertebra;Drawing the midline of the lower vertebra based on the position of the corners of the lower vertebra;Determining geometric center of each vertebral body as the intersection of the line connecting corner 1 and 4 and the line connecting corner 2 and 3;Drawing a perpendicular line to each of the upper lines;Investigating the intersection of the two vertical lines and calculating the angle formed by the two lines .The Cobb angle is calculated as a measure for the curvature of the spine in the following manner:After scanning an image, extracting the location of the vertebrae and performing calculation, this section creates a text file and saves it in a defined path. The file includes the translation and rotation of each vertebra relative to its previous location and to the location of the upper and lower vertebrae. It is the main output of the software in text form and helps experts to analyze the patient\u2019s condition. In addition, a series of colored images (each color for a tracked vertebra on a binary image) are saved on the specified path.Given the fact that the software was created for the purpose of actual use by professionals to test the software, it was necessary to use expert opinions to evaluate it. In order to assess the performance of the software in terms of accuracy, five physiotherapists who were involved in the treatment of motor neck problems were selected in an accessible manner. They were provided with the software package  and asked to work with the software for a month and conduct the analyses of tracking the vertebrae, and finally give their comments and feedback about its performance in text format containing comments qualitatively about the performance of the software and its accuracy in performing the assigned tasks.As the software is designed based on image-processing procedure, a process with a number of steps on images took place to produce the desired output. As shown in The viewpoints of the experts on assessing the performance of the software indicate that they were satisfied with the performance of the software, and they reported that the location of the vertebrae was identified accurately. Additionally, the colored images of the location of the vertebrae (as shown in Previously, the analysis of vertebral images was carried out manually and analysis of the vertebral images for each patient which contained more than 100 fluoroscopic images occupied several hours for a specialist. The introduced software decreased the required time for analysis of fluoroscopic images to about 1 h, which is significantly lower than manual and there is no need to interfere with a human agent except for the initial settings. Ease of installation and use were another benefits of the software according to the experts.In the present study, the procedures of designing practical software for automatic tracking of cervical and lumbar vertebrae in fluoroscopy were described.Many studies have presented methods of machine learning in vertebrae tracking. A local measure of phase symmetry was used for tracking based on Log\u2013Gabor wavelet transforms in . FurtherThe software usability out of the lab environment is the main focus for implementing this software, which is a solution to the problems of the experts in analyzing fluoroscopic images of the spine. It facilitates the process of the diagnosis and treatment of the relevant diseases. One of the main challenges in designing the software is the limitation of the applicable algorithms with regard to the capabilities of C# programming language. Using C# language increases the public usability of the software and it can be easily executed in windows-based platforms. Another benefit of this software is that user interaction and the manipulation of the settings is only in the first image, so tracking and performing calculation are done automatically on the next images. However, in this study, according to the viewpoint of the experts about the accuracy of the software, it is clear that the software meets the information requirements of the experts. Considering the execution procedure of the software, it can be used in other similar medical applications, and fields requiring object tracking and accurate calculation. Slight changes can convert the software as an appropriate tool in similar image processing domains.In this study, the development of a software for vertebral tracing in fluoroscopic images was described. The evaluation of this software was based on expert opinions. It should be noted that based on the results of future studies and quantitative analysis as a more accurate evaluation of its performance, reliable use of the software in clinical trials could be done. Furthermore, considering the execution procedure of the software, it could also be used in other similar medical applications, such as fields requiring object tracking and accurate calculation. Slight changes can convert the software as an appropriate tool in similar image processing domains. We hope that the current study guides researchers and health professionals to use this software in solving other medical problems requiring the tracing of images and related calculations.This study presents the details of a software implementation for tracking cervical and lumbar vertebrae in fluoroscopic images and performing the related calculations.The software was developed based on the Frobin method. Its implementation was done using C# language and Aforge.net based on case-based reasoning technique.The opinions of experts who used the software to do their daily work demonstrate the success of the implementation and the software was able to respond to their information needs.Considering the execution procedure of the software, it could be used in other similar medical applications, fields requiring object tracking and accurate calculation. Slight changes can convert the software as an appropriate tool in similar image processing domains."}
+{"text": "Quality-of-life (QOL) rating scales can be used to measure and describe the quality of life of a specific population or patient group. Many decisions can be taken and policies implemented when we know more about a group or population. The global quality-of-life concept may help in expressing the objective of the initiatives taken to benefit specific groups. The objective may be that we hope the efforts will increase their quality of life by a certain percentage. This explicit expectation will force the decision makers to stand by their noble intentions. They are obliged to evaluate their efforts and will have to learn something from it.A questionnaire thus constitutes a useful scientific instrument, as databases based on comprehensive and thorough questionnaire surveys that seek to encompass all aspects of life can provide valuable and precise information. The value of such a database depends on the correct use of the questionnaires and this paper examines some examples of how quality-of-life rating scales can be used.We identified at least ten ways to use the quality-of-life questionnaire: describing the quality of life of a population or patient group; formulating an objective for support, treatment, or care; screening or identifying individuals who need treatment; evaluating treatment and care; facilitating communication between physician and patients; involving the patient in the decision-making process; allocating resources; investigating the causal relation between the quality of life and ill health in prospective studies; creating an awareness of the quality of life and health promotion; and helping the practitioner to accumulate knowledge.Enhancing the quality of life is therefore a determining factor in the process of increasing awareness and responsible conduct in relation to the environment, natural resources, the working environment, and the structure of society. Putting the quality of life on the agenda inherently has a constructive and positive effect on the life and functioning of the individual and society."}
+{"text": "The authors and editors retract this publication  followinIn Figure 1E, there are similarities between the first and third lane within the panel.There are similarities in bands between the gels displayed in Figures 2E and 2F.In Figure 3A, there are areas of duplication in images within the third panel.The concerns were brought to the attention of the authors, who provided replicate images of the same experimental sets but were not able to provide the images underlying the figures included in the article.An institutional investigation conducted by The Indian Institute of Technology at Kharagpur confirmed the duplication of images and recommended the retraction of the article.The preparation of the figures falls below the standard of publication; in light of these concerns and in line with the institutional recommendation, the authors and the editors retract this publication.The authors sincerely apologize to the scientific community for the errors in the published article."}
+{"text": "Bibliometric research uses statistical and mathematical methods to analyze and build indicators on the dynamics and evolution of scientific and technological information on a given topic.The relevance of its applicability as a data collection and analysis technique has been corroborated as one of the argumentative sources in the research for investment resources in academic rankings \u20132.To carry out a bibliometric study, it is important to consider the selection of the database to be used; maintaining compatibility of this choice with the research aims and reach the results . In thisTM database can be done by exporting this data to the HistCiteTM bibliometric analysis software package to organize information and facilitate analysis.Data collection from the ISI Web of Knowledge/Web of ScienceThe data can be analyzed considering: the annual evolution trajectory of the publications; the journals with the greatest number of records; the authors with more publications; the number of papers distributed by author\u2019s country of origin; the most cited articles in the Web of Science  and those most cited in the set of selected articles .Thus, investigations of academic and practical problems of public health research can be developed in a methodological approach that maps the scientific production of several fields and provides researchers with sources with recognized value through citation and authoring metrics: bibliometric techniques , 6. AlthThe understanding of knowledge production and its measurement are supported and accompanied by the evolution of digital communication technologies and this allows a greater reach of information .The suggestion that we address in this letter is the proposal of answers to the research problems related to the most varied subjects of public health through research in international databases that seek to map the international scientific production. This map ensures the understanding of the knowledge produced in a given field and allows monitoring its development, implying improvements in the development of public health policies."}
+{"text": "This paper is retracted by Frontiers. The publisher has discovered that the author(s) created and provided false information for the peer-review process. As the scientific integrity of the article cannot be guaranteed, and adhering to the recommendations of the Committee on Publication Ethics (COPE), the publisher therefore retracts the article.The retraction of the article was approved by the Chief Editor of Frontiers in Cellular and Infection Microbiology."}
+{"text": "In the original version of the article, the middle image of Panel F in"}
+{"text": "To the Editor: We read with great interest the Sarajevo Declaration on Integrity and Visibility of Scholarly Publications published as the editorial in the Croatian Medical Journal ( Journal . We appr Journal . TherefoWe thank the authors for the Declaration and feel that, with our suggestion taken into account, we can enforce the ultimate goal of the Declaration, which is to improve scientific and publishing practice."}
+{"text": "After publication of the article , it has \u201cThe GEIRD project was funded also by the Italian Ministry of Health .\u201dHence the correct version of the list of funding institutions  is the following:\u201cThe GEIRD project was funded by the Cariverona Foundation , by the Italian Ministry of Health  and by the Italian Ministry of Education, Universities and Research (MIUR). The funding sources had no involvement in the study design, in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the paper for publication.\u201d"}
+{"text": "For full transparency, the authors wish to update the competing interest statement of this article  with theThe Prevention Research Center for Family and Child Health (PRC), directed by Dr. David Olds at the University of Colorado School of Medicine, has a contract with the Nurse-Family Partnership\u00a9 to conduct research to improve the NFP program and its implementation. Dr. David Olds was employed by this center at the time the current study was conducted. The contract with the NFP contributes to the salaries and operations of the PRC. Dr. Olds is the founder of the Nurse-Family Partnership."}
+{"text": "Following publication, concerns were raised regarding the scientific validity of the article. An investigation was therefore conducted in accordance with our established procedures. Following provision of raw data by the authors, the Chief Editor concluded that aspects of the paper's conclusions and assertions were not sufficiently supported by the findings from the material provided. Namely that inconsistencies in experimental rigour preclude confirmation of the conclusion of the article.The retraction of the article was approved by the Chief Editors of Pharmacology and the Editor-in-Chief of Frontiers.The authors agree to the retraction."}
+{"text": "The errors and associated corrections described in this document concerning the original manuscript were accountable to the production department handling this manuscript, and thus are no fault of the authors of this paper.In the original publication of this article , the tab"}
+{"text": "After publication of the original article , the autThe Family Name of Annahita Allafi was misspelled as Alafi. The correct presentation of the author\u2019s name is displayed in the author list of this Correction article.In Table"}
+{"text": "The distribution of fiber orientation is an important factor in determining the mechanical properties of fiber-reinforced concrete. This study proposes a new image analysis technique for improving the evaluation accuracy of fiber orientation distribution in the sectional image of fiber-reinforced concrete. A series of tests on the accuracy of fiber detection and the estimation performance of fiber orientation was performed on artificial fiber images to assess the validity of the proposed technique. The validation test results showed that the proposed technique estimates the distribution of fiber orientation more accurately than the direct measurement of fiber orientation by image analysis. Non-uniform fiber distribution decreases the effect of fibers on strengthening the matrix [The first major investigation was made to evaluate the potential of steel fibers as a reinforcement for concrete in the United States during the early 1960s . The maje matrix ,12. There matrix . A direce matrix ,15,16.Micromechanically, the fiber orientation, which is the angle of the fiber inclined to the crack plane, influences the fiber pullout load and fiber strength in the matrix. The fiber pullout load increases when the fiber orientation is increased due to the increase of the normal force between the fiber and the matrix, which increases the frictional bond between the fiber and the matrix. This phenomenon is known as the snubbing effect, and currently, an empirical equation between the pullout load of inclined fiber and the pullout load of fiber without an inclination angle is being adopted ,18. On tSeveral techniques, including image analysis ,24,25,26The distribution characteristics of fiber can be quantitatively evaluated by calculating the coefficient based on the coordinates of the fibers and the shape of the fibers in the cutting plane. To detect the fiber in the fiber images, the color image is converted to a grayscale image. The grayscale image is then converted to a binary image based on a set threshold object detection method, which in turn is based on a thresholding algorithm . In thisctively.  The majol) to the minor axis length (d) of the fiber image with the fiber orientation. As seen in l/d is constant below a fiber orientation .To assess the validity of the proposed technique, a series of tests was performed on artificial fiber images. Artificial section fiber images with three sizes of fibers and two- and three-dimensional random distributions of fiber orientation were tested . The totet al. [et al.  and the We proposed a new image analysis technique to estimate the distribution of fiber orientation in a sectional image of fiber-reinforced concrete. A series of experimental and analytical investigations with artificial fiber images was carried out to assess the validity of this technique. The following conclusions can be drawn from the results:i.e., the decreasing resolution.(1) We investigated the effect of the number of pixels representing the diameter of the fiber and fiber orientation on the detection accuracy. The error increased with a decreasing fiber orientation and the number of pixels in the diameter of the fiber. We attributed this to an increase in sensitivity with a decreasing fiber orientation and an increase in the detection error with a decreasing number of pixels in the diameter of the fiber, (2) The proposed technique estimates the distribution of fiber orientation by finding optimal distribution functions matching the measured number of fibers by an image analysis with the theoretical number of fibers calculated from the volume and diameter of the fiber, the area of the sectional image and the assumed fiber distribution.(3) Validation tests using artificial fiber images according to the size of the fiber images and the dimensions of the fiber orientation confirmed that the technique proposed in this study ensures better evaluation performance than that by direct measurement of the fiber orientation from image analysis, especially when there is a two-dimensional distribution and a small number of pixels representing the diameter of the fiber."}
+{"text": "The errors and associated corrections described in this document concerning the original manuscript were accountable to the production department handling this manuscript, and thus are no fault of the authors of this paper.In the original publication of this article , the yel"}
+{"text": "One of the authors name, Irene Santos-Pardo, was misspelled in the published manuscript (as Irene Padro Santos). The authors apologize for the mistake. This error does not change the scientific conclusions of the article in any way.The original article was updated.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In the original article, there was an error. In the Acknowledgment section, a wrong name was used.A correction has been made to the acknowledgment section, [Paragraph 1]:We thank all participating soldiers and helpers on site. We thank the Austrian Armed Forces especially  and the Austrian Federal Ministry of Defense and Sports Science, Research and Development Division  for making this study possible. We are grateful to Elisabeth Pschernig and Samy El- Makarem for their support in the ELISA laboratory. We are grateful to Martin Fieder and Markus Koppensteiner for their council in matters of statistics and proof-reading this manuscript and to Peter Kuttenberger for his contribution to the programing of the experiment. This article was supported by the Open Access Publishing Fund of the University of Vienna.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "FHIT) gene is a bonafide tumor-suppressor gene present on the short arm of chromosome 3 and its loss of function has been evaluated in different types of cancers. Loss of heterozygosity at various sections of the FHIT gene and the methylation analysis of the promoter region showed that it is one of the important and preliminary genetic alterations in the cell, and its restoration in the cell line or nude mice suppresses tumorigenicity. Current research on the FHIT gene has depicted that Fhit interacts with different proteins through different pathways in the nucleus, mitochondria, and cytoplasm, directing the cell to apoptosis.The fragile histidine triad ("}
+{"text": "Nowadays, the evaluation of the suppliers in order to improve the total performance of supply chain and increase the power of competitiveness, satisfaction and profitability of the company are considered important and significant issues at the organizations. The main objective of this research is to help oil and gas industry in order to evaluate and categorize the suppliers, using Fuzzy Inference System. The present research is empirical in terms of purpose and descriptive-survey in terms of data collection. Three outstanding managers of procurement department of the company under examination have been selected. With regard to the fact that, the number of identified Sub-indices to categorize the suppliers are too many in relevant literature, the Fuzzy Dematel method was used to determine the weight and importance of each of the Sub-indices suppliers. In the present paper, for evaluate and categorize the suppliers has been used from Fuzzy Inference System, with MATLAB Software. Specifications TableValue of the data\u2022The suppliers are a complementary component of the supply chain of an organization, with Nominating the proper suppliers can reduce the purchase costs considerably and increase the competitiveness capability of the organization.\u2022The managers will be able to plan to improve risk reduction and maximize the benefits of purchasing suppliers through comprehensive, integrated and applied approach to evaluate suppliers.\u2022Organizations will be able to use suppliers who are accessible to provide functional requirements and constant improvement in specific periods of time.\u2022With this research, we will be able to identify Sub-indices and effective criteria for evaluating suppliers in Oil & Gas industries.1The present study is empirical in terms of type and descriptive-survey in terms of data collection. The present research has been done in one of the great oil projects in 2016. Three outstanding managers of procurement department have been selected as to analyze the data. The methodology of doing this research is presented in 1.1Identification of the major criteria of evaluation of the suppliers based on two-dimensional model of Olsen and Ellram 1.2After reviewing the studies and using oral interviews, number of sub-indices was selected based on obligations of the company in oil and gas industry.For the weights sub-indices, we used the Dematel Fuzzy Method with providing questionnaires. A paired comparison between the sub-indices is to be made in a Fuzzy manner, In the next step, the selected sub-indexes  were calculated and used per criterion (Output Variables) and taking into consideration Fuzzy Logic , Table 8In this section, it has been used Mamdani After obtaining average aggregation of opinions (three managers) , each ofsupplier  and fina2With regard to the findings of the research, it can be stated that the suppliers are a complementary component of the supply chain of an organization, and they must be correctly selected and evaluated. First, according to the studies carried out in this field and oral expertise interviews, two major criteria of Quality and Financial ability and credit of company have been identified. Using the Fuzzy Dematel method and analyzing the causal relationships, the intensity and effectiveness of the sub-indices of each of the criteria were determined and given that the supplier's evaluation is inherently confronted with inaccurate data, the Fuzzy Inference System has been used by MATLAB software to evaluate suppliers. Finally, the suppliers with the final scores obtained in the two-dimensional model of suppliers were classified into three categories of Valuable, Developing and substitutable suppliers."}
+{"text": "There is an error in the Funding statement. The correct Name for the BioGreen21 Program is the Next-Generation BioGreen21 Program of the Rural Development Administration, Republic of Korea (grant no. PJ011379). The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Health is known as one of the main preconditions for the social welfare system, people to achieve the level of health in the incidence of sickness, in addition, to keep appropriate lifestyle, use health services and on the other way, they try to buy those services. Taking advantage of these services impose different financial pressures on people in different societies, these fees paid directly out of pocket sometimes may cause financial problems for patients and their families .Direct paying out of pocket is the simplest and least effective methods of payment, in this way the patient pays the money to the service provider at the time of service delivery . Paying One of the methods leading to patients over-charging is lack of physicians\u2019 attention to logical prescription . UnnecesOne of the most common models having many fans for reforming the health system is using the levers of control. Control levers describe separate areas of the structure and functioning of the health system, which is very important regarding the performance, and governments can manipulate them, these levers cover different topics such as financing, payment systems, organizing and regulation of rules and behaviors . One of In order to decrease patients\u2019 out of pocket payment being created because of unnecessary hospital stay, it is recommended using a combination of pay for performance and fee for services can be used. Therefore, an expert supervisory team is composed in hospital and assessing the performance of physicians regarding daily visits and timely discharge and while providing appropriate feedback to any of the doctors and declaring physicians performed well in this regard to all doctors and a percent of the payment to them will be allocated to evaluation of performance score."}
+{"text": "The data in this article are as a result of a quest to uncover alternative research routes of deepening researchers\u2019 understanding of integers apart from the traditional number theory approach. Hence, the article contains the statistical properties of the digits sum of the first 3000 squared positive integers. The data describes the various statistical tools applied to reveal different statistical and random nature of the digits sum of the first 3000 squared positive integers. Digits sum here implies the sum of all the digits that make up the individual integer. Specifications TableValue of the data\u2022The data provides the exploratory statistics of digits sum of squared positive integers and their subsets.\u2022This technique of analysis can be used in data reduction.\u2022The data analysis can be applied to other known numbers.\u2022The data when completely analyzed can help deepen the understanding of the random nature of integers.1:The data provides a description of the statistical properties of the digits sum of the first 3000 squared positive integers and the subsets. The subsets are the even and odd positive integers. The subsets are equivalence and their descriptive statistics are summarized in Fig. 32The digits sum or digital sum of integers has been a subject of interest because of its application in cryptography, primality testing, random number generation and data reduction. Details on the origin, theories and applications of the digits sum of squared positive integers, integers and other important number sequences can be found in 2.1The true nature of the percentiles are shown using the Harrell-Davis quantile which is a better estimator and a measure of variability because it makes use of the data in totality rather than the percentiles that are based on order statistics. The Harrell-Davis quantile of the digits sum of square of positive integers is shown in Bootstrap methods are useful in construction of highly accurate and reliable confidence intervals (C.Is) for unknown and complicated probability distributions. The data for was resampled many times and C.Is was generated for the mean and the standard deviation. Bootstrap results varied slightly with the observed mean and standard deviation and convergence occurs as the confidence level increases. These are shown in The bootstrap estimate of the mean is closed to the observed one. However, the median remained unchanged. This is an evidence of the robustness and the resistant nature of the median against undue influence of outliers. This is also in agreement with the bootstrap confidence limits. The summary is shown in The M-Estimators are checked for the convergence to the mean or the median. The M-Estimators are robust and resistant to the undue effect of outliers. Technically, an M-Estimator can be assumed as the fixed point of the estimating function. The results of the M-estimator for the digits sum of the first 3000 squared positive integer is summarized in The boxplot is an exploratory data analysis tool used to display graphically, the quantiles of a given numerical data. Outliers or extreme values are easily precipitated from the data and displayed graphically. The boxplots of the digits sums of squared positive integers and their subsets are shown in The data is slightly skewed to the left for the three cases with some outliers appearing in the case of the total. As the sample size increases, the frequency of the occurrence of the numbers below mean reduces and more outliers can also be obtained. On the other hand, more numbers are expected to appear as the sample size increases.:Particular patterns can be depicted through the use of individual value plots of observations. Some unique patterns were obtained for the even, odd and total squared positive integers. This is shown in Fig. 8a and b.The mean plot and median plot are shown in Fig. 9The mean plot showed the behavior of the mean. This is almost the same result by the bootstrap and bootstrap confidence intervals. As excepted the median plot is an indication of the robustness of the median.Winsorizing and trimming are two ways of achieving robustness. The robustness of the central tendency (mean) of the digits sum of the first 3,000 squared positive integers was considered. These are shown in The data is robust because the possibility of obtaining outliers or extreme values decreases as more values are expected to cluster around the mean. As the sample size increases, the extreme values become fewer. In the case of trimming, the same result is obtained since there are few extreme values to exclude from the analysis.2.2There are few curve estimation models that are available in fitting a given data. The result of fitting the digits sum of the first 3000 squared positive integers using the models is shown in 2.3Digits sum of the first 3000 squared positive integers is best fitted by Cauchy distribution and the details are shown in 2.4The raw data of sum of the digits square of the first 3000 integers can be used to generate another set of numbers by finding the absolute value of the difference of two consecutive numbers and the total data generated is the initial data minus 1. The process was repeated until the mode and the median was equal to one. This is because any further step(s) add little or no effect to the analysis and also to save computational time. Normality is reduced by the process as evidenced by the increase in kurtosis and skewness. This is shown in"}
+{"text": "Ixodes ricinus and the transmitted bacteria of the complex Borrelia burgdorferi s.l. in the Western Palaearctic. We derived the rates of contact of the tick with 162 species of vertebrates recorded as hosts, and the relative importance of each vertebrate in the circulation of the pathogen. We compiled more than 11 millions of pairs of coordinates of the vertebrates, deriving distribution models of each species and the relative faunal composition in the target territory. The results of the modeling of the distribution of the tick and its hosts, weighted by their importance in the circulation of Borrelia captured the spatial patterns of interactions that allow the circulation of the pathogen. Results indicate that both I. ricinus and B. burgdorferi s.l. are supported in the Western Palaearctic by complex communities of vertebrates, which have large distribution ranges. This high functional redundancy results in the pervasiveness of B. burgdorferi s.l., which depends on the gradient of contributions of the large community of vertebrates, instead of relying on a few dominant vertebrates, which was the prevailing paradigm. Most prominent reservoirs of the pathogen are distributed in specific regions of the environmental niche. However, literally dozens of potential reservoirs can colonize many other environmental regions, marginally but efficiently contributing to the circulation of the pathogen. These results consistently point to the need of evaluating the beta-diversity of the community of vertebrates acting as reservoirs of the pathogen to better know the interactions with the vector. They also demonstrate why the pathogen is so resilient to perturbations in the composition of the reservoirs.Ticks, pathogens, and vertebrates interact in a background of environmental features that regulate the densities of ticks and vertebrates, affecting their contact rates and thence the circulation of the pathogens. Regional scale studies are invaluable sources of information about the regulation of these interactions, but a large-scale analysis of the interaction of communities of ticks, hosts, and the environment has been never modeled. This study builds on network analysis, satellite-derived climate and vegetation, and environmental modeling, quantifying the interactions between the tick  The classic procedure to evaluate the potential distribution ranges of ticks has been the capture of their abiotic ecological relationships, with a main attention on climate, using more or less coherent series of records of the focal species and different modeling strategies. Modeling approaches may include variables other than climate, such as categories of the vegetation , topological features  and several indexes derived from the habitat fragmentation and its connectivity  the presence/absence and abundance of different host species for the tick, (ii) the degree of spatial overlap between the host species and the tick, (iii) the seasonality of the partners , and (iv) the reservoir capacity of the set of hosts available to feed the ticks. The geographical distribution of B. burgdorferi s.l. in questing ticks is therefore a function of the densities of different host species, their capacity to feed ticks and their ability to transmit the bacteria to those ticks.A complex pattern emerges, driven by the abundance of the tick and the faunal composition of vertebrates, serving as hosts for the tick and/or reservoirs for the pathogen, which are not necessarily the same species. Environmental variables shape the distribution of B. burgdorferi s.l. has been recently published  and demonstrated that the methodological approach termed network analysis is adequate to examine the biotic relationships between ticks, hosts, and pathogens . In this study we aimed to (i) capture the suitability of the environment for the tick and each species of the vertebrate in the Western Palaearctic, (ii) compute an index of habitat overlap of the tick with each species of vertebrate, (iii) weight the index before according to the importance of each species of vertebrate for either the tick or the pathogen, (iv) project the results in the environmental niche, and (v) to project the results in the spatial  niche. The results must to be interpreted as the predicted circulation of the pathogen in either the dimensions of the niche or its spatial translation.The study addresses the predicted interactions between the tick I. ricinus were compiled from literature references published since the year 1990. Data reporting either questing ticks or feeding on hosts were included. In the first case, only data including reliable coordinates or an unambiguous locality name (which was later resolved to coordinates) were considered. In the second, only data mentioning the species of hosts were further processed if adequately geo-referenced.Data on http://gbif.org). The purpose of the compilation is to obtain the largest available source of recorded distributions of every vertebrate involved in the circulation of the pathogens.We downloaded the data of the recorded distribution of the vertebrates reported as hosts or reservoirs from the Global Biodiversity Information Facility . We independently modeled the distribution of each species using the niche modeling algorithm MaxEnt integrated in the package dismo for R . These interactions are derived from the habitat overlap between tick and host(s) weighted by the relative importance of each vertebrate as host(s) for the tick or as reservoir(s) for the pathogen. Thus, high values of the CWho mean for high predicted interactions resulting in a large circulation of the pathogen. Low values of CWho may result from a low habitat overlap of the tick and host(s) or from the low importance of a vertebrate for either the tick or the pathogen. The methodology introduced allows the expression of these values in either the environmental or the spatial dimensions. This immediately provides an estimation of these predicted interactions in the climate or spatial gradients.n dimensions that equal the number of variables used for its definition. To obtain a tractable framework without losing reliability it is necessary to divide the gradient of the niche into categories. We used two multifactorial methods to (i) reduce the number of dimensions and divide the territory in \u201ccategories of niche\u201d using a Principal Components Analysis (PCA) approach, and (ii) associate the results of the predictive modeling of each species of hosts with the environmental using a Canonical Correspondence Analysis (CCA). The first method produces \u201ccategories of niche\u201d and the second associates the CWho to these categories. In this application, PCA takes the 6-dimensions environmental niche and produces a number of categories using recursive rules. Each category is thus composed by the portions of the niche gradient that are more similar between them than with the other, always considering the 6 dimensions. Figure The environmental niche is a gradient of I. ricinus or reservoirs for B. burgdorferi s.l.). Since its original development  and the \u201corganisms\u201d  but in the portions of the chart corresponding with medium and high values of NDVI. Apodemus agrarius is however separated of that gradient and interactions associate with cold portions of the niche and medium values of NDVI. The remaining 133 species of hosts are restricted to portions of higher LSTD and lower values of NDVI  and two species of Passeriformes: Turdidae (Turdus merula and T. phylomelos)  prevailing weather shapes the patterns of circulation of the complex B. burgdorferi s.l. supporting a large redundancy of the vertebrates allowing permanent foci. This conclusion is of special interest since local or regional analyses of the reservoir capacity of the vertebrates could not be extrapolated to other regions where the pathogen circulates. Our study has explicitly restricted the analyses to the environmental niche, with only a partial translation of the results to the spatial  domain as a proof of concept. The extrapolation of results to the geographical dimensions is of special complexity giving the genetic diversity and competition events among the reservoirs established at each site, which has a direct impact on the circulation of the pathogen  of the main reservoirs, variable prevalence of infected ticks with different species of Borrelia should be expected. This fact produces the already reported regional differences in the prevalent Borrelia spp. (van Duijvendijk et al., B. burgdorferi s.l. has been never tested in the context of the complete community of vertebrates, most extensive data coming from areas in the United States (i.e., LoGiudice et al., The results showed that the wide circulation of B. burgodrferi s.l. (States et al., The results of this study stressed the descriptive abilities of a network of interactions between ticks and vertebrates for supporting foci of a tick-borne pathogen on large portions of the abiotic niche. This conclusion challenges the classic dogma of only a few vertebrates supporting the stability of the circulation of B. burgdorferi s.l. in the world. This would provide an overview of the large amount of data so far reported from regional surveys. Quantitative data about reservoir abilities of each vertebrate as well as explicit considerations of their abilities to support the feeding of ticks should be included in further improvements of this framework.This framework could be applied to other species of ticks, or, perhaps of most importance, to integrate the current knowledge of the ecological relationships between the species of ticks transmitting the different genospecies of Both AE-P and JdlF designed the experiments, contributed to the development of the study, and wrote the paper.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In the original article, acknowledgment of funding by the Mahlke-Obermann Stiftung and the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 609431/INDICAR (Interdisciplinary Cancer Research) Postdoctoral Fellowship Programme of the University of Vienna to ME was missing. The authors apologize for this oversight. This error does not change the scientific conclusions of the article in any way.The original article has been updated.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The aetiology of malignant melanoma is not wholly explained by exposure to sunshine. The present of arsenic in the soil has been suggested as a possible causative factor. Geographical clustering of malignant melanoma cases in the South Western Region is demonstrated for males and this clustering is associated with the distribution of arsenic in the soil. No evidence of geographical clustering is however found for females. This suggests possible sex-specific differences in the aetiology of malignant melanoma and indicates the need for further study of the association with arsenic."}
+{"text": "To evaluate the Brazilian Family Health Support Centers focusing on the integration to supported teams.This is an evaluation study in which we carried out a documentary analysis and modeling of the intervention focusing on the work integrated to the supported teams, which has allowed us to describe dimensions, objectives, and expected results. We defined the outcome indicators and their respective measures and sources of information. We used consensus techniques with key informants to validate the models and the matrix of indicators.The evaluation study was appropriate, and it allowed a better definition and knowledge about the intervention.There is coherence between the objectives of the Family Health Support Centers and their structure, although there are difficulties to operationalize them. We recommend a formative evaluation of the Family Health Support Centers focusing on the work integrated to the supported teams, seeking to strengthen them to achieve the expected results. The Brazilian Family Health Support Centers (NASF) were created in 2008 to expand the scope of the Primary Care (PC), as well as its resolubility,The matrix support guides the integrated work among these teams. Technicalpedagogical and care actions that better respond to the needs of the users or the territory are defined based on agreements between professionals\u2013\u2013In order to achieve the expected integration and sharing and consequently the greatest possible degree of quality and resolubility, challenges are identified, such as insufficient mechanisms to monitor and evaluate the results achievedTherefore, we need mechanisms to evaluate and monitor the NASF that consider the results achieved, especially from the work integrated to the supported teams. This study aimed to evaluate the Family Health Support Centers focusing on the integration to supported teams.This is an evaluation study (ES), understood as a set of procedures that precede the evaluation stage itself and which point to its usefulness and opportunity, making it more consistent and more credibleWe used the qualitative approach. After collecting information and clearly defining the object under study, we performed the initial modeling of the intervention. For the consensus of the models, we used the technique of Traditional Committee, with open discussion on a given topic between specialistsWe prepared a preliminary version of the matrix of indicators validated using the Consensus Conference, a technique that seeks to reconcile the possibility of open discussion and the preservation of the anonymity of the participantsThe research was approved by the Research Ethics Committee with Human Beings of the Universidade Federal de Santa Catarina , in relation to the ethical precepts. All participants had access and signed the informed consent.The theoretical model of the NASF guides how it ideally works to achieve its goals,,We identified different contextual factors that act directly on PC and interfere in the relation established between the NASF and supported teams. The social and health needs of the population, for example, require managers to identify priorities and define strategies to handle reality. This influences the definition of the constitution of the NASF teams and their way of operating in each territory,The Brazilian Federal Constitution and the legislation governing the SUS, especially the National Primary Care Policy, together with the different existing care models, are also determinants for the relation established. Currently, the biological model predominates. This model guides the work of the FH/PC teams to the individual care of great demand, shortening the time available for discussion, pacing, and joint work. This can pressure practitioners to support its reproduction, leading the NASF to malfunction,,In addition to this, we can also mention the professional training commonly deficient in the matrix support logic, the aspects related to SUS funding that directly interfere with the technical proposal related to the configuration and performance of the NASF (including the number of teams supported and the population cared for), and the structure of the Health Care Networks (HCN), especially of Medium ComplexityContrary to this logic, the integrated work between teams takes place from the theoretical-methodological framework of the matrix support, considering,,That the NASF should act in an integrated and collaborative manner with the FH/PC teams at the individual and collective care levels. It must have under its own responsibility the supported team itself, as well as the direct care of the population and the action on the surrounding territoryIntegrity as a precept for the organization of health services;Interdisciplinary action, which should promote the disruption of verticalized relations and minimize the occurrence of iatrogenies;That the NASF and supported teams should share responsibility for their users and territories, rather than transferring it. This implies co-responsibility, guiding actions developed in contrast to the models based on the fragmented and individualized careThat the technical-pedagogical and care dimensions of the matrix support are complementary and can be considered as practical aspects of the operationalization of the principles and guidelines of the SUS, especially integrality and interdisciplinarity, resulting in actions based on extended care,\u2013\u2013,,,,,It is hoped that the fragmented and medical logic of the health care can be overcome in favor of the integral care, whose reorientation occurs together with the Family Health Strategy,,,,,\u2013It is hoped that the NASF can expand the scope of the PC, increase its ability to respond to health problems and needs, and assist the population demands that are not met by the supported teamsIn order to show how the intervention under study should be implemented, we identified the dimensions, specific objectives, and expected results from the work integrated to the FH/PC teams .,,,,\u2013,,,,,The first dimension of the model presented as intermediary results the qualification of the supported teams and the potential of the extended care,,The second dimension, called \u201cResolubility\u201d, showed the intention that the implementation of the NASF contributes to expand the coordination and longitudinality of the care by the supported teams. To this end, it should favor the articulation of the PC with other points of the HCN and intersectoral services and qualify the referrals,,,,Actions that improve the use of the Secondary and Tertiary Care Network, such as the reorganization of demand and improvement of the relation between the different care points, should promote the rationalization of the access to specialized resources and contribute to expand the ability of the FH/PC teams to coordinate the care of users,,,,The support of the NASF should therefore favor the continuity and ordering of the care by the PC, strengthening it in the HCN, without disregarding that such results also depend on other factorsThe evaluation matrix of the results of the NASF focused on the work integrated to the supported teams was built based on the theoretical and logical models. It presents the dimensions of \u201cAccess\u201d and \u201cResolubility\u201d, with two sub-dimensions and four indicators each .,,,,In the dimension of \u201cAccess\u201d, we considered the double burden of responsibility attributed to the NASFFor the sub-dimension of \u201cInterdisciplinarity and Integrality\u201d, we selected the following indicators: Team integration and sharing, which verifies the results achieved on the interdisciplinary, integrated, and collaborative work ability between the supported teams and the NASF for the production of care, and Actions offered by the NASF, which evaluates the results achieved on the expansion of the scope and the access to specific care actions of the NASF in order to respond to the health needs and demands previously unmet by the FH/PC teams.In the dimension of \u201cResolubility\u201d, we considered that the actions of the NASF should strengthen the coordination ability and the provision of longitudinal care by the supported teams, as well as the horizontal cooperation and work with other care points. With a logic that privileges the collaborative work, it should increase the potential of the PC as a manager and the main access of the HCN, also increasing its resolubility.In the sub-dimension of \u201cCoordination of the care\u201d, we expected that the shared responsibility would lead to a review of the referral practice based on the referral and counter-referral, extending it to the sharing of responsibilitiesIn the last sub-dimension of \u201cLongitudinality\u201d, we considered that longitudinality requires a regular source of attention and use over time, regardless of the type of problemThe increase in the number of professionals inserted in the PC would also increase the ability for clinical Resolution, the last indicator presented. In addition to expanding the professional knowledge and practices, the mobility and vision of the NASF regarding the diverse teams favor connections, including the intersectoral ones, and increase therapeutic projects, with potential to improve care networks and flows in the work of these teamsapud Scaratti and Calvo, 2012)Access and resolvability were considered transverse axes of observation of the evaluative matrix insofar as they are presented as expected final results and are simultaneously involved in the two dimensions evaluated. Quality was present in the entire matrix, understood as the ability to meet the attributes of value and merit, that is, to apply properly the resources and to do what is proposed right to meet the needs of the FH/PC teams and users  should contribute to improve the development of the intervention analyzed. The theoretical and logical models and indicators proposed in the evaluation matrix are useful tools to support the formulation of policies and the management of the NASF in Brazil. By keeping the relation between them close, they explain the chain of causation that leads to the expected results and suggest mechanisms to identify if they are being reached, indicating their plausibilityMechanisms need to be developed to evaluate and monitor the work of the NASF and the results produced from the integrated work to the supported teams. The FH/PC teams play an important role in consolidating the matrix support. Their organization and understanding of the new relation and care model are paramount to the arrangement of the NASF as a support team in PC and not as an expert service in that care context. The evaluation model presented aims to evaluate the results of the NASF from the work integrated to the supported teams.The ES showed that the NASF is an evaluable intervention, as we could increase the knowledge about the intervention and define appropriate components and indicators. However, the intervention is not visibly illustrated in the different literatures analyzed, which complement each other but often bring new elements in relation to what is expected from its implementation. There is indicative of a lack of clarity about what is expected to be achieved from its integrated action to the supported teams. This makes the definition of appropriate indicators for the evaluation of these teams mandatory.The models and matrix presented help advance this issue. The ES is presented as an alternative to qualify the understanding about the NASF and to highlight the identification and discussion of the results achieved, as well as strategies to achieve them.Other evaluation designs can be developed for the intervention, including focusing on one or another dimension of the matrix support. In this study, we sought to overcome this duality in order to broaden the possibilities of the action of the NASF to reach the quality and resolubility expected from the work integrated to the supported teams.There is no provision to control the external context of the integrated work between the NASF and supported teams in the proposed matrix, but it should be considered in the evaluation stage. The working conditions of the NASF and supported teams, the structure of the HCN, the composition and implementation time of the NASF, among other contextual factors, should be weighed in the studies that evaluate the results of the NASF from the integration to supported teams in different realities.The models and the evaluation matrix started from the conception that the relation between these teams is guided by the principles and guidelines of the SUS and PHC, especially by the interdisciplinarity and integrality of the care, promoting co-responsibility and putting into practice the extended care. Considering the recent process of implementation of the NASF and the incipient mechanisms to evaluate the results, especially from the work integrated to the FH/PC teams, the ES can contribute with the qualification of this intervention in Brazil."}
+{"text": "Effective disease detection, investigation, control, and prevention require a public health workforce well trained in the principles and practice of Field Epidemiology. Since 1980, the United States (U.S) Centers for Disease Control and Prevention (CDC) has worked with Ministries of Health throughout the world to establish and support the establishment of Field Epidemiology and Laboratory Training Programs (FELTPs). The Ghana Field Epidemiology and Laboratory Training Program (GFELTP) established with support from the CDC started implementing its two-year advanced long course in 2007. Ghana FELTP a member of the founding member countries of the African Field Epidemiology Network (AFENET) was the first program to be established in the West African sub-region and also the first to have veterinarians as part the team of medical and laboratory scientist as trainees .In the wake of emerging and re-emerging diseases that continue to shake the foundations of national response capacities, key competencies needed by the world include the ability to conduct surveillance and use the information for action . These cThe GFELTP has throughout its existence spearheaded the training of Field Epidemiologists in Ghana  and beyoIn the face of the need for workforce development for responding to public health problems at the various levels of the heath care system, the full complement of the pyramidal model of FETP training becomes a necessity. The three-tiered \u201cpyramid\u201d model of training addresses the need to improve the surveillance, epidemiology, response, and scientific communication skills of public health workers at each level of the health system. Within each tier, the training focuses on improving the participants\u2019 skills within the context of their current job responsibilities and expectations. The response to this is the implementation of the FETP frontline program in addition to the 2-year advanced program. With its tenth cohort of advanced and seventh cohort of frontline training, the GFELTP has trained over 200 healthcare workers including physicians, nurses, veterinarians, laboratory scientists and disease control officers at all levels of the health sector. The numbers, albeit inadequate, is contributing to a pool of highly skilled human resource, which is rapidly becoming the game changer for surveillance and outbreak investigation and response in Ghana and beyond.Trainees and alumni have contributed to development at the national and subnational levels by supporting in evaluating surveillance systems, analyzing surveillance data for action, conducting planned epidemiological studies, investigating and responding to public health emergencies . The outputs from these competencies have been widely disseminated to stakeholders at national and international conferences and in peer-reviewed journals. On the international landscape, alumni of the program are serving at key positions within their various ministries and playing leadership roles in supporting national surveillance systems and Field Epidemiology workforce development in other countries.The leadership contributions from residents and alumni of the program is a tribute to the competencies acquired during training and their ability to serve as change agents in their various places of work. These contributions are done within the context of existing surveillance structures at the national and subnational levels thereby strengthening and enhancing the capacity of existing systems in surveillance and outbreak investigation and response.In the face of the growing field epidemiology workforce crisis in Africa and given the recent devastating effect of the Ebola outbreak in West Africa, the way forward for the GFELTP is clearly cut out. The need to produce a critical mass of competent Field Epidemiologist at all levels of the health sector becomes all the more pressing. There is the need to increase capacity to train a lot more healthcare workers who will perform topnotch surveillance functions and respond swiftly to public health emergencies. To achieve this feat, implementation of the full scale three-tiered pyramidal model of FETP  is the wThis supplement highlights a few of the achievements of the GFELTP in terms of transforming the various works done by the residents and alumni into documents for sharing with the scientific community. It is a compilation of some of the outputs that were developed into manuscripts during one of the GFELTP\u2019s training workshops organized for its residents and alumni. The papers in the supplement illustrate the capacity development efforts of the program and highlight the competencies acquired by the residents while in training. The authors have described various works they have done and their contribution to public health practice. These, and the description of the capacity development activities catalogued shows evidence of the GFELTP\u2019s role in strengthening surveillance and response through the building of a competent health workforce. The expectation is that this supplement will serve as a testimonial of achievements of the program and a springboard for the residents to effectively communicate their experiences to the world through peer-reviewed journals."}
+{"text": "It has been brought to our attention that the funding of the National Center of Science (Poland) was missing in the acknowledgements section of our published paper , and the"}
+{"text": "Due to an oversight by the authors, the co-author Sonal S. Shah was missed. This has been now added in the author list above and the Author Contributions statement has been revised below.In the section Materials and Methods, sub-section CHILDHOOD TRAUMA AND/OR ADVERSITY, the whole paragraph should be replaced with:Questions about the occurrence and nature of CTA were included in the SHIP interview. CTA was coded on the basis of responses to the question: \u201cWere there any other very distressing or traumatic events in your childhood ?\u201dFinally, Health (2012) and Bromfield and Holzer (2008) should be removed from the text and from the Reference List.The authors apologize for these errors. These corrections do not affect the data or the conclusions contained in the manuscript.The original article has been updated.SS was primarily responsible for the conception of the research upon which this paper is based. CG, LZ, and TA assisted in the development of the ideas for the paper and in refining the final manuscript. SS produced the first draft of the manuscript and submitted the final manuscript and completed the literature search and wrote the main body of the manuscript. TA analyzed the data. SSS contributed to acquisition, analysis and interpretation of the national SHIP data; was part of initial discussions on the substance of this paper, and critically contributed to the draft of the revised version. All authors approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In an investigation of the communication between Hospital and General Practitioners, 99 General Practitioners were asked by means of a postal questionnaire to state the relative importance they attached to the issues of speed of delivery, format, author, and the content of the discharge summaries.The issue of speed of delivery proved to be a central and recurrent theme in the replies received, with a clear demand for increased speed and efficiency in Hospital-General Practitioner communication.In addition, an overwhelming support was revealed for summaries in the form of short prioritised problem lists, as opposed to longer conventional prose accounts. This response proved to be independent of the style of summary being received by the General Practitioners in the study.With a clear need nationally to improve communication with General Practitioners, consideration should be given to adopting prioritised problem lists as a means of upgrading the quality of data sent to General Practitioners."}
+{"text": "This has been corrected to indicate that Georgetown University, the employer of some of the authors at the time of the writing of the article, owns the patented CycleBeads technology, and that a company owned by a relative of Victoria Jennings has the exclusive license to commercialize the technology. Victoria Jennings has no financial relationship to the company and neither she nor any of the other authors receives royalties or other income related to the licensed technology.The article has been corrected accordingly."}
+{"text": "Addition of AffiliationIn the published article, there was an error regarding the affiliation for Ling Kui. As well as having Affiliation 1, they should also have Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, China. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.Missing FundingIn the original article, we neglected to include the funder Guizhou Academy of Tobacco Science , Y205941151 to WW. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In this paper we look at the rational and the emotional interpretation of reality in the human brain and being, and discuss the representation of the brain-mind (ego), the body-mind (Id), and the outer world in the human wholeness (the I or \u201csoul\u201d). Based on this we discuss a number of factors including the coherence between perception, attention and consciousness, and the relation between thought, fantasies, visions and dreams. We discuss and explain concepts as intent, will, morals and ethics. The Jungian concept of the human collective conscious and unconscious is also analyzed. We also hypothesis on the nature of intuition and consider the source of religious experience of man. These phenomena are explained based on the concept of deep quantum chemistry and infinite dancing fractal spirals making up the energetic backbone of the world. In this paper we consider man as a real wholeness and debate the concepts of subjectivity, consciousness and intent that can be deduced from such a perspective."}
+{"text": "The data presented in this article are related to the research article entitled \"Magnetic field and its experimental measurement in teaching in high schools\"  The article describes the possibilities of relatively accurate experimental measurement of magnetic field in any geographical conditions, in both exteriors and interiors, without the need for special instrumentation, with minimal financial costs.The data set is publicly available to allow the comparison of magnetic induction values in given latitudes with the other latitudes by the given methods and a critical analysis of the applicability of these methods in areas and locations without more demanding instrumentation. Specifications TableValue of the data\u2022The data provide information about the horizontal magnetic induction component of the Earth's magnetic field in the region and may be used by other scientists at geomagnetic mapping.\u2022The observed dynamics of local magnetic field changes can supplement the data on its spatial and temporal dynamic properties for specialized observatories.\u2022These data allow other researchers to complement the network of geomagnetic observations and thus partly specify the magnetic field distribution map1The data set of this article provides information about the measured magnitude of the horizontal magnetic induction component of the Earth's magnetic field in the selected geographical location. 22.1Materials:The experiment is designed to measure the magnitude of the magnetic induction of the Earth's magnetic field in our latitude by means of a rotating conductor in which the voltage is induced by Faraday's law of electromagnetic induction, with changes in magnetic induction current through the surface described by the conductor.fixed wire (20 m) loaded in the middle by a tennis ball, milivoltmeter, stopwatch, length gauge, compass to determine the correct direction - the surface plane of the thread must be perpendicular to the direction south-north.When spinning the wire in the magnetic field of the Earth in the south-north direction, there is a constant change in the thread area through which the magnetic induction lines pass. This changes the magnetic induction flux and induces the voltage we measured in the thread. The magnetic induction value was calculated from it.2.2Materials:The principle consists in comparing the magnitude of the magnetic field induced by the electric current passing through the coil and the magnitude of the horizontal component of the Earth's magnetic field.C and of the Earth BZ. From this equation, magnetic induction values were calculated.By setting the electric current in a circular coil so that the magnet against the north is at an angle of 45 \u00b0, we get the equation of magnetic induction magnitude of the magnetic field of the coil BFinally, we compared the data measured with both methods. We analyzed the dynamics of magnetic field changes by comparing data acquired in two different time periods."}
+{"text": "The impact of epilepsy on Quality of Life (QoL) is well-documented. The ability of epileptic seizures to alter the conscious states of patients is also well established. Although there is much research on the QoL of people with epilepsy, few researchers have looked specifically at the effect of sudden, unanticipated alterations of consciousness on QoL. This lack of systematic studies of consciousness alterations and QoL in epilepsy limits our ability to shed light on this interrelation. In this article, with these limitations in mind, we focus on studies of newer AEDs. We review the evidence as to whether a significant reduction  in seizures that induce alterations of consciousness, as a result of switching to one of the newer AEDs, leads to improvements in QoL. We draw on this literature to speculate on the relationship between ictal consciousness alterations and poor QoL in epilepsy, to identify contributory and confounding factors and to highlight implications for future research. We suggest that an understanding of how factors associated with consciousness impairment affect QoL could help the treatment and management of these patients."}
+{"text": "This paper is retracted by Frontiers. The publisher has discovered that the author(s) created and provided false information for the peer-review process. As the scientific integrity of the article cannot be guaranteed, and adhering to the recommendations of the Committee on Publication Ethics (COPE), the publisher therefore retracts the article.The retraction of the article was approved by the Field Chief Editor of Frontiers in Pharmacology, Prof. Theophile Godfraind."}
+{"text": "There is an error in the third sentence of the seventh paragraph of the Results. The correct sentence is: The ratio showed the best combination of sensitivity and specificity for the prediction of drug sensitivity at values > 72.7% .There is an error in the last sentence of the seventh paragraph of the Results. The correct sentence is: In the CD-DST, the ROC curve showed that AUC was 0.963 for cell viability  while thThere is an error in"}
+{"text": "This paper is retracted by Frontiers. The publisher has discovered that the author(s) created and provided false information for the peer-review process. As the scientific integrity of the article cannot be guaranteed, and adhering to the recommendations of the Committee on Publication Ethics (COPE), the publisher therefore retracts the article.The retraction of the article was approved by the Field Chief Editor of Frontiers in Microbiology."}
+{"text": "After the publication of this article  it has cThe omission of the reference citation for this quote was the result of an error during the production process, and not an omission by, and/or error of the authors."}
+{"text": "S.tm groups. The images depicted in the original version of the Figure represent the correct experimental groups, however the images were not the correct images for the Figure. The conclusions of the manuscript are not changed.The authors would like to correct"}
+{"text": "Unlike conventional steel strands, the smart strand supports strain-measuring function and adopts different materials for its core wire and helical wires. This study intends to analytically derive the nonlinear stress-strain model of this strand made of two materials. The effect of the bending moment and torsional moment of the helical wires on the overall load within the range of geometric shapes shown by actually used strands is verified to be negligible and is thus ignored in order to simplify the analytical model. Moreover, the slight difference between the actual and analytic behaviors, which only appears in the slope varying part in the case of bilinear behavior, such as that of steel, is also ignored. The proposed constitutive model of the smart strand obtained by introducing the experimental stress-strain relation between the carbon fiber reinforced polymer core wire and the helical steel wires is in good agreement with the experimental data. The previous analytical models are applicable only to strands made of a unique linear material, whereas the model proposed in this study is also applicable to strands in which the core wire and the helical wires are made of two different materials, exhibiting nonlinear behavior. In prestressed concrete (PSC) structures, the jacking force is introduced mainly through the strands. The smart strand was developed recently to be able to measure the prestress force in PSC structures throughout their service life since their erection. The smart strand is achieved by replacing the core wire of the traditional steel strand by a steel tube ,2, a CFRCostello  and VeliThe present study intends to analytically derive the load-strain relationship of strands in which the core wire and helical wires are made of different materials, as is the case for the smart strand. The formulation is conducted for cases where the core wire and helical wires are made of linear materials and nonlinear materials.This chapter deals with the relation between the geometric parameters of the wire before and after deformation. The adopted process is basically similar to that of Costello , but theThe strand presents a straight core wire surrounded by The strand undergoes deformation according to the application of the load, as shown in Due to the Poisson\u2019s ratio effect, the helix radius of the helical wire after deformation, Since Accordingly, the change in curvature with respect to the This chapter derives the load-strain relation for both linear and nonlinear materials. This section derives the load-strain relation when the core wire and helical wire are made of different linear materials.The moment with respect to the The component The component The force In order to evaluate the contribution of each component of the force acting on the strand, Equation (21) is rearranged as follows by separating the components:Let us now see the effect of the rotation of the strand on each term of Equation (22). From an engineering standpoint, the third and fourth terms can be ignored, and the strand force The possibility to simplify the force acting on the strand by summing up the force components in the longitudinal direction of the core and helical wires was verified in the precedent section. The present section intends to obtain this force by means of a simplified equation in the case where the core and helical wires are made of different, nonlinear materials.First, the force of the core wire can be obtained by integrating the stress Besides, the strain in the helical wire can be expressed as Because of the symmetry of the helical wire with respect to the Note that Equation (27) does not hold in the part where the range of the strain in the cross-section includes the yield strain, as in (b). However, Finally, the load-strain relation of the strand made of nonlinear materials resulting from this process can be obtained as follows: Comparison is done with actual experimental data to validate the established load-strain relation.The stress-strain relation of the materials used for the core and helical wires constituting the strand is necessary to apply the proposed model in Equation (29). The smart strand adopted for the verification in this study is composed a CFRP core wire and steel helical wires. Material models are thus necessary for the CFRP wire and steel wire. To that end, tensile tests were conducted as shown in The following stress-strain relation was obtained from the tensile test of the CFRP wire. Here, the strain is derived from the FBG (Fiber Bragg Grating) wavelength of the optical fiber embedded in the CFRP wire: th load value in the test; and th strain of the test in Equation (29). The bilinear stress-strain model of the steel material was applied by Menegotto [The results of the direct tensile test of the steel strand were used to indirectly derive those of the steel wires. In other words, the stress-strain relation of the steel wire was obtained by solving the following optimization problem to minimize the difference between the experimental curve of the steel strand and Equation (29): enegotto , Hoehlerenegotto , and othenegotto  for monoThe substitution of these material models for the CFRP wire and steel wire into Equation (29) provides the load-strain relations of the steel strand and smart strand. In the steel strand, the diameter of the core wire (The comparison of the analytical and experimental results in The load-strain model of the strands was analytically derived considering the case where the core and helical wires are made of different materials, such as in the smart strand. This model can be applied not only for linear materials but also for nonlinear materials. Moreover, all the parameters determining the shape of the strands, such as the diameter of the core and helical wires and the pitch, can be considered.The effect of the bending moment and torsional moment of the helical wires on the overall load within the range of geometric shapes shown by actually used strands was verified to be negligible, and was thus ignored in order to simplify the analytical model. Moreover, the slight difference between the actual and analytic behaviors, appearing only in the slope varying part in the case of bilinear behavior, such as that of steel, was also ignored. The proposed constitutive model of the smart strand obtained by introducing the experimental stress-strain relation between the CFRP core wire and the helical steel wires was in good agreement with the experimental data.The previous analytical models are applicable only to strands made of a unique linear material, whereas the model proposed in this study is also applicable to strands in which the core wire and the helical wires are made of two different materials, exhibiting nonlinear behavior."}
+{"text": "In this paper, restricted to describe the ontogenesis of the cell, we discuss the processing of DNA through RNA to proteins and argue that this process is not able to transfer the information necessary to organize the proteins in the cell, but only to transfer the information necessary to form the shape of the proteins. We shortly describe the structure of the information carrying field recruited by the cells that we think is responsible for building the organelles and other cellular structures. We use the cells superior control of its cytoskeleton as an example of how the cell is using an informational field giving the positional information guiding all the local chemical processes behind the cell movement. We describe the information-directed self-organization in cells and argue that this can explain the ontogenesis of the cell. We also suggest the existence of an undiscovered phenomenon behind the information transmitting cell interactions. We conclude that during evolution the cell has developed into an information-guided self-organizing structure. The mystery we want to solve is: what is the mechanical cause and nature of biological information?"}
+{"text": "All health systems are facing a paradox of limited resources against the unlimited human needs. Therefore, any country in the world is not able to meet all the health needs of the population and provide all services. The available resource allocation in the best way possible is essential , 2.Priority setting is one way for good use of limited resources . PrioritIran (2004) established the Ministry of Welfare and Social Security (MOWSS) to distinguish the funders and providers of health care. Since this time, health insurance organizations were under the MOWSS, and the High Council of Health Insurance (HCHI) was transferred to this ministry. This ministry was merged (2011) with two other ministries and renamed to the Ministry of Cooperatives, Labor and Social Welfare (MCLS). Iran\u2019s health insurance system consists of numerous insurance organizations. The main insurance organizations are Social Security Organization, the Army Medical Insurance Organization, Health Insurance Organization, Imam Khomeini Relief Committee .Reviewing the existing requirements in the insurance system in Iran shows that the insurance system is faced with some problems. In this regard, the formulation and revision of BHBP have always been one of the main challenges in insurance organizations of the country. In other words, these organizations are always faced with the question that, considering the dynamic of the health system, the introduction of new medicines and equipment to the health market, changing burden of disease in the course of time, and resource constraints, what process should be considered for formulation and revision of the services of this package. This question has never been answered correctly in Iranian insurance organizations.Despite the fact that Article 10 of the Law on general insurance in Iran, referred to determination of the minimum scope and level of medical services and medications but in practice, no specific criteria and process for the review of the BHBP have not been mentioned. Documents show that since the founding Medical Service Insurance organization in 1994, the number of services covered by the insurance package has been increased. On the other hand, a process does not exist for investigating the withdrawal of services from BHBP. Lack of revision of BHBP makes the service that lose their effectiveness over time due to advances in technology, changing disease burden apply additional financial burden to the health system. The lack of updates in BHBP can be a factor in the increase in out of pocket and increase in families facing catastrophic costs.One of the main reasons for the lack of review of the BHBP in Iran is a difficult bureaucratic process imposed by regulation on its formulation. In this process, the Ministry of Health & Medical Education (MOHME) in accordance with Article 10 provides its proposal to the HCHI. If the council agrees, the Cabinet of Ministers must approve it. During this process, the planning in the MOHME and experts\u2019 talks in the HCHI on the one hand, and long discussions in various government commissions, on the other hand delayed the inclusion of new services to the BHBP. Despite the cumbersome process, the review of the available services in the BHBP will not be considered. In addition, the current structure of determination of the BHBP services lacks balance and sufficient competency. The combination of experts in the process is more political and a combination of professional and academic people is less used. For example, the combination of HCHI members has been formed of ministers, representatives of insurance organizations and Members of Parliament. The HCHI does not have expert power for scientific analysis and decision making for inclusion or exclusion of the services from the BHBP. Another challenge for BHBP is low participation of some groups, including the private sector, public, NGOs and health economists.Thus, it is essential to Iran\u2019s policy makers to design and implement an evidence-based process for reviewing the substance of BHBP. In the design of the process of formulating and reviewing the package two important points should be noted, the use of professional experts and specialists, and the use of scientific tools and metrics to assess the services such as Health Technology Assessment."}
+{"text": "There is an error in the fourth sentence of the Results subsection of the Abstract. The correct sentence is: Also the inter-operator reliability was almost perfect . The publisher apologizes for the error."}
+{"text": "To analyze the determinants for the occurrence of human visceral leishmaniasis linked to the conditions of vulnerability. This is an ecological study, whose spatial analysis unit was the Territorial Analysis Unit in Aragua\u00edna, State of Tocantins, Brazil, from 2007 to 2012. We have carried out an analysis of the sociodemographic and urban infrastructure situation of the municipality. Normalized primary indicators were calculated and used to construct the indicators of vulnerability of the social structure, household structure, and urban infrastructure. From them, we have composed a vulnerability index. Kernel density estimation was used to evaluate the density of cases of human visceral leishmaniasis, based on the coordinates of the cases. Bivariate global Moran\u2019s I was used to verify the existence of spatial autocorrelation between the incidence of human visceral leishmaniasis and the indicators and index of vulnerability. Bivariate local Moran\u2019s I was used to identify spatial clusters. We have observed a pattern of centrifugal spread of human visceral leishmaniasis in the municipality, where outbreaks of the disease have progressively reached central and peri-urban areas. There has been no correlation between higher incidences of human visceral leishmaniasis and worse living conditions. Statistically significant clusters have been observed between the incidences of human visceral leishmaniasis in both periods analyzed (2007 to 2009 and 2010 to 2012) and the indicators and index of vulnerability. The environment in circumscribed areas helps as protection factor or increases the local vulnerability to the occurrence of human visceral leishmaniasis. The use of methodology that analyzes the conditions of life of the population and the spatial distribution of human visceral leishmaniasis is essential to identify the most vulnerable areas to the spread/maintenance of the disease. This fact is mainly due to the expansion of urbanization processes and the modification of habitats of the species involved in the transmission cyclea, whose areas of occurrence increase progressively13. There is a great gap in scientific knowledge about VL. Studies are needed on new drugs and therapeutic regimes, as well as studies that address the effectiveness of disease control actions with greater methodological strength, among others aspects22.The geographical areas with transmission of VL are increasingly expanding. The disease, considered one of the priorities among tropical diseases by the World Health Organization (WHO), is endemic in ninety-eight countries, including BrazilAragua\u00edna, in the State of Tocantins, Brazil, presents a recent endemic-epidemic process of VL. There has been an alarming increase in the number of confirmed human cases mainly between 2006 (56) and 2007 (251), when it presented the greatest number of records of the disease in Brazil . Since then, it remains among the four Brazilian municipalities with the highest absolute number of annual records of VL.20 of the region for the transmission of VL using indicators and the analysis of the spatial distribution of urban VL can contribute to the better understanding of the heterogeneous transmission process, resulting from the socio-territorial organization of the municipality5.The analysis of the vulnerabilityThis study aimed to analyze the determining circumstances for the occurrence of human visceral leishmaniasis (HVL), linked to the conditions of vulnerability in Aragua\u00edna. The data can provide elements for the formulation of public policies adapted to this situation.c, we can observe a growth of 33%  of the total population of the municipality and approximately 35% of the urban population .Aragua\u00edna  is locatThe urban territory of Aragua\u00edna is characterized by a central region with high density and intermediate and peripheral areas, discontinuous among themselves. The growth model of this municipality is discontinuous and segregated. For the most part, the areas with increased population density have vast unoccupied areas with considerable spacing between the buildings. In addition, most of the streets in these areas are not paved.Sistema de Agravos de Notifica\u00e7\u00e3o (SINAN \u2013 System of Reportable Diseases)/ Department of Health Surveillance (SVS)/ Ministry of Health. The definition of confirmed case of VL is based on criteria adopted by the Ministry of Health to guide the actions of epidemiological surveillance of the disease throughout the country15.This is an ecological study, with cases of HVL notified between 2007 and 2012 in Aragua\u00edna residents. The cases reported and confirmed in residents were obtained from the Municipal Health Department of the Municipality and the We performed the analysis of the situation of vulnerability to the transmission of the disease based on the construction of indicators related to the conditions of urban, social, and household infrastructure for 2010, the analysis of the distribution of HVL in time and space in two three-year periods (2007-2009 and 2010-2012), in addition to the descriptive analysis of the cases of canine visceral leishmaniasis (CVL) notified by the Municipal Health Department between 2006 and 2008. The analysis in three-year periods was used because the disease has a cyclical nature. In addition, this approach helps to reduce the variability in the number of cases reported between the years of the study.d. The compatibility was carried out because those geographical bases are very distinct  was made from the compatibility of the bases of urban census tracts of the 2000 and 2010 Demographic Censuses of the IBGEdistinct .11. The polygons of the occupied areas were vectorized by the method of visual interpretation of satellite images. We identified the spaces with urban characteristics at a 1:5,000 scale, using geoprocessing tools in a Georeferenced Information System (GIS). This step was developed based on the Digital Globe satellite images for 2014, obtained by the software Google Earth, with spatial resolution of one meter. The software used was ArcGis 10.2.We generated polygons of the areas occupied by the human population, based on the methodology referred to in the Land Use ManualThe autochthonous cases of HVL reported between 2007 and 2012 were georeferenced from the address found in the database of the SINAN, with the use of Google Earth. This generated a digital data mesh.The mesh containing the specific data relating to the cases of the disease was superimposed to the digital base of TAU and the areas occupied by human populations in each TAU. This allowed the aggregation of cases of HVL based on these units of territorial analysis.For the calculation of incidence of the two three-year periods (2007-2009 and 2010-2012), we used the cases reported and confirmed in the periods in the numerator and the population obtained from the population projection per TAU, based on the 2000 and 2010 Census populations, in the denominator. The calculation of the density of cases was carried out based on the area actually occupied by the human population of the TAU.Kernel density estimation was used to evaluate the density of cases of HVL, based on the coordinates of the cases. Thematic maps were prepared for the spatial and temporal analysis of the evolution of the endemic disease, as well as their correlation with the information about the situation of social and household structure and urban infrastructure. The application ArcGis 10.2 was used for this analysis.Official information, available on the website of IBGE on the 2010 Demographic Census, was used for the analysis of the conditions of urban, social, and household infrastructure of the municipality. This analysis identified the most vulnerable areas in the urban and social infrastructure, in order to reveal differences between the various areas of the municipality.20. We applied T1  and T2  equations. The highest values observed (MaximumI), the lowest values observed (MinimumI), and the individual value of each primary indicator (IObserved) were used for the calculation:Primary indicators were calculated based on the variables of the 2010 Demographic Census. Such indicators had their values normalized according to the methodology used by Tiburcio and Corr\u00eaaIndicators of vulnerability of social structure (IVSS), household structure (IVHS), and urban infrastructure (IVUI) were created from normalized indicators. The indicators had their values converted into scores that ranged from 0 to 1, with cutoff points defined according to quartiles of distribution, assigning the lowest values to the best conditions . The comThe IVSS was created to combine the information from various sociodemographic indicators into a synthetic indicator to establish an order in relation to the level of social vulnerability. The IVHS was prepared with the information of various indicators of household structure, allowing a synthetic measure of the housing conditions of the population. The IVUI was created to synthesize the information on the urban infrastructure surrounding the household into a single indicator.e. Bivariate Global Moran\u2019s I does not show where the spatial cluster are. Thus, we used Bivariate Local Moran\u2019s I, which provides the degree of spatial autocorrelation, statistically significant, in each regional unit. According to Anselin, this index provides an indication of the degree of linear association between the value for a variable in a given area and the average of another variable in the surrounding areas. The matrix of the neighborhood W defined by contiguity was the Queen matrix, which considers two neighboring regions that have common borders, in addition to common nodes (vertices).Bivariate Global Moran\u2019s I was used to verify the existence of spatial autocorrelation between the incidence rate of HVL and the Vulnerability Indices. The index tests whether the values of an indicator in a given region is related to the values of another variable in neighboring regions. Statistics can have the values from -1 to +1, positive for direct correlation and negative when inverse3.The statistical significance of Moran\u2019s I Index was tested using permutations. We generated subsequent permutations of the values of the data associated with the TAU. Each permutation produces a new spatial arrangement, in which values are distributed randomly between the TAU. That way, we can create an empirical distribution of statistics I under the null hypothesis of spatial randomness. The empirical pseudo-significance was based on ninety-nine random permutations. The program used in this analysis was GeoDa 1.6.6The information about the cases of CVL was provided according to neighborhood by the Center of Control of Zoonosis (CCZ) of Aragua\u00edna. As there was incompatibility of the sketch of neighborhoods with the digital cartographic bases of the census tracts and TAU, the analyses were restricted to the municipal level. We calculated the positivity of cases of CVL from the absolute number of samples collected and the number of samples per year.Escola Nacional de Sa\u00fade P\u00fablica S\u00e9rgio Arouca of the Funda\u00e7\u00e3o Oswaldo Cruz (Protocol 142/11).This study has been approved by the Research Ethics Committee of the We observed an increase of approximately 30% of the resident population in the urban area of the municipality of Aragua\u00edna between the 2000 and 2010 Censuses. We could also identify a more marked growth (6.7%) in the population aged 60 years or more and a less accentuated growth (5.9%) among individuals aged between zero and four years. The illiteracy rate of the population aged 15 years or more decreased in the same period , as well as the proportion of permanent private homes with sanitation considered by the IBGE as inadequate .We found a significant number of cases of the disease in the municipality during the period, although there was a decrease of 44.6% when we compared the first year (2007) of the historical series analyzed with the last one (2012). This decrease followed what was observed in the country to a lesser degree (decrease of 4.8% between 2007 and 2012). Approximately 251 cases were reported in 2007, 262 cases in 2008, 164 cases in 2009, 96 cases in 2010, 184 cases in 2011, and 139 cases in 2012. Two epidemic waves were observed in the city; the first with a peak in 2008 and the second one with a peak in 2011. Epidemic waves were defined based on the significant increase in the number of human cases of VL when observed the historical series.Of the 1,096 cases of HVL notified and confirmed between 2007 and 2012, 84.8% were georeferenced. Georeferencing losses occurred because of the incompleteness of the address field in the SINAN or because we could not properly locate the address on Google Earth. The confirmed cases of VL were superimposed to the digital cartographic base of the occupied areas in the TAU to observe the dispersion of the disease throughout the municipality.The areas with greater intensity of occurrence of HVL in Aragua\u00edna were estimated using the Kernel method . We obseThe worst scores of IVSS, IVHS, and IVUI are located in the occupied areas of the outskirts of the municipality . The IVUThe indicators of vulnerability with greater significant global spatial autocorrelation  with the incidence of HVL of the two periods, respectively, were: IVSS  and IVUI . The IVHS had spatial autocorrelation only for the incidence of HVL of the first period, while CVI had spatial autocorrelation for both periods  .Bivariate Local Moran\u2019s I showed the presence of statistically significant clusters between the incidences of HVL in both periods and the indicators of vulnerability for the census tracts .Main clusters  were evidenced, as well as intermediate clusters (Low-High and High-Low) in all combinations tested in the period analyzed . The maiNo significant variations were observed regarding canine seropositivity: 33% was observed in 2006, 37.9% in 2007, and 37.1% in 2008.We observed a pattern of centrifugal spread of human visceral leishmaniasis in Aragua\u00edna. Outbreaks of the disease reached progressively, from 2008, the occupied central and peri-urban areas of the municipality. However, the pattern of spread had important annual intensity variations.18. Few municipalities have a rural epidemiological pattern, dominated by rural outbreaks with occurrence of sporadic human cases19.Other Brazilian municipalities, also in the process of increasing urbanization and precarious living conditions, have different epidemiological patterns of spread of VL. Among these patterns, we can identify: restricted peri-urban pattern (outbreaks of the disease restricted to areas of the urban periphery), diffuse peri-urban pattern , epidemiological pattern of centrifugal spread , and, finally, pattern of network dissemination 21.The centrifugal process of spread of the disease in Aragua\u00edna is characterized by important changes in the territory, such as: disorderly expansion of the city \u2013 which has advanced through the natural habitat of the vector of VL \u2013, lack of basic and sanitary infrastructure \u2013 which enable the urbanization of the vector \u2013, and the spread of the disease in the municipalityf.The increase of approximately 30% of the population living in the municipality between the 2000 and 2010 Censuses and the changes of the urban space that are inherent to it can help to explain the maintenance of the high number of human cases of VL notified in the historical series (2007-2012), although we can observe a wide variation in the number of reported cases over the years. There was an increase of susceptible and vulnerable persons inserted in that territory, as well as individuals \u2013 migrants and their animals, for example \u2013 from endemic areas for VL15.Although the notification of cases of VL is the main strategy for surveillance of the disease in Brazil, the process of notification and confirmation of cases can be slow. The HVL is considered a mandatory notifiable disease in the country since 1975. Its vigilance is decentralized and especially uses the data of notifications recorded in the SINAN. The analysis of these data allows the space-temporal monitoring of the disease in the country, subsidizing the actions for its control17. This reinforces the theory that the occurrence of HVL is closely related to the situation of social vulnerabilityg in which parts of the population are insertedg.A correlation was observed between higher incidences of HVL and worse living conditions, although it was not high. Although the TAU presented certain uniformity regarding the indicators analyzed, we could observe clusters from the calculation of Bivariate Local Moran\u2019s I. This approach identified that the environment in circumscribed areas contributes as a factor of protection or increase for the relative local vulnerability concerning HVL in specific locations in Aragua\u00ednah.The use of indicators of vulnerability regarding the territory contributed to the knowledge on the intra-urban differences more associated with the occurrence of HVL. The analysis of spatial variability based on the combination of these indicators of vulnerability and the incidence of VL allowed the identification of particularly distinct areas, i.e. with their own socioeconomic characteristics that can contribute to the process of reproduction of the disease in the municipality. Such areas should be the target of local public policies aiming to reduce the vulnerability and decrease the number of cases of the disease in the territory of Aragua\u00ednaThe occupation of the urban space arises from the actions of society on the nature. Its configuration incorporates social and economic structure and its dynamics, establishing the flows of the local movement of goods and services.The lack of consistent data about the canine reservoir is one of the limitations of the study. We highlight the annual variation of the areas included in the canine serological surveys conducted by the CCZ of Aragua\u00edna and the lack of regularity of the survey in each area for the years of study. The variation of the number of dogs included in the surveys annually has not allowed further evaluations on the seroprevalence of VL.The scenario of visceral leishmaniasis in Brazil is complex. Researchers need to seek new methodologies of analysis that can cover the various elements involved in the process of introduction, dissemination, and maintenance of the disease. The difficulties related to its control must be considered, from the control of the canine population and vectors and the identification of infected animals up to the elimination of risk factors.17.The use of methodologies that enable the analysis of the living conditions of the population, along with the spatial distribution of human visceral leishmaniasis, becomes essential to identify the areas that present greater vulnerability for the spread and maintenance of the disease in the territoryWe believe that this approach may contribute to the definition of control strategies for VL. It can reduce not only operating costs but also provide increased effectiveness of the actions of surveillance and control of this endemic disease."}
+{"text": "PLOS ONE Editors retract this publication, as we have been advised that the authors did not have appropriate rights or permissions to publish the data.The After publication, concerns were raised about the ownership of data reported in this article. This matter was reviewed by the Office of Research Compliance at Ohio State University, where the research took place. The Office of Research Compliance advised that the data were generated in laboratories at Ohio State University and were published without permission of the principal investigators, in breach of the University\u2019s Research Data Policy.PLOS ONE Editors retract this publication.In the light of the recommendation of the Ohio State University, the The corresponding author, Stefan Costinean, does not agree to this retraction."}
+{"text": "In the original publication of this article , the figFurthermore, the acknowledgments section omitted the following information in the original article :\"The data for the realization of this publication are part of the database BIFAP managed by the Spanish Agency of Medicines and Sanitary Products (AEMPS). The results, discussion and conclusions of this study are those perceived by the authors only and do not represent in any way the position of the AEMPS on this subject.The authors are grateful for the excellent collaboration of family physicians and primary care pediatricians who participated in BIFAP\"."}
+{"text": "People with intellectual disability (ID) require special support in order to achieve independence in their daily life. Persons with ID are less exposed to assistive technology, although studies have shown that the availability of aids afford an opportunity to reach independence and cooperation. The aim of this study was to examine the nature of the relationship between involvement of the physiotherapy (PT) team and the degree to which assistive technology was used. A questionnaire was sent to all PTs employed at all 54 residential care centers for persons with ID of the Division for Mental Retardation at the Ministry of Social Affairs in Israel. A significantly positive correlation was found between the degree of involvement of the PT and the utilization of assistive technology. The study results may be summarized by stating that PTs demonstrated a great deal of involvement, particularly in relation to the extent of their work in the residential care centers. PT's awareness of the importance was indicated as the major reason to use assistive technology."}
+{"text": "The linkage between astronomical cycles and the periodicity of mass extinctions is reviewed and discussed. In particular, the apparent 26 million year cycle of global extinctions may be related to the motion of the solar system around the galaxy, especially perpendicular to the galactic plane. The potential relevance of Milankovitch cycles is also explored in the light of current evidence for the possible causes of extinction events over a geological timescale."}
+{"text": "Medical Errors are one the major concerns of on-site health care . These eConsidering the importance of effective using the barcodes and removing the barrier of using this technology, this study aimed to examine the requirements and barriers for using the barcode technology in hospitals affiliated to Tabriz University of Medical Sciences between 2013 and 2014. This is an observational and descriptive study performed in 10 teaching hospitals. The primary checklist was designed by the researchers in order to collect data by studying scientific sources \u201310 and rThe barriers for using the barcodes were studied in two aspects. First, the barriers which hospitals may deal with prior to the implementation of barcodes; and the second, the difficulties and barriers that could have arisen after the adoption of barcodes and can stop using them. Fifty Percent studied hospitals had not the using of barcode policy. However, in the other 50% of hospitals, there was the use of barcode policy, but neglect, poor attention, and also the absence or weakness of identified and detailed planning in the process of implementing prevents its application. The lack of qualified personnel for implementation and lack of integration of bar codes with the HIS system in the radiology and laboratory section was observed in the half of the hospitals. In the 80% of the studied hospitals, there was not understanding of the requirements for implementation. Noteworthy 70% of participants believed that lack or weakness of policy establishing by the authorities along with the neglect of the hospital management prevents the planning for application of the barcodes .Additionally, 80% of them stated that lack of knowledge towards the concept and importance of using barcodes cause to negligence of applying this technology.Staff training and resistance due to the weakness sense for adoption of the assigned duties has been mentioned as one of the main barriers for application of barcode process .The requirements and barriers can be classified into the three major groups of organization policy and processes issues, technology, and education and costs. Lack of approving or notifying a specific policy for the use of barcodes by organizations such as the Ministry of Health and lack of knowledge, understanding toward the infrastructure, and inadequate staff training are the greatest barriers to the successful implementation of bar code system."}
+{"text": "This article was republished on March 28, 2018 to correct for the inadvertent use of improper language in the caption of Figure 8. The publisher apologizes for the lack of oversight and any offense caused. Please download this article again to view the correct version."}
+{"text": "Journal of Educational Evaluation for Health Professions in February 2016 [http://www.wpame.org.au.It\u2019s with pleasure that I provide an update on the activities and plans of our organisation since my last report in the The aim of the Association remains unchanged, namely to provide coordination and leadership towards the goal of enhancing the quality of medical education in the countries of the Western Pacific region . This role is consistent with our status as one of the 6 regional associations of the World Federation for Medical Education (WFME).The WPAME meets at least once each year to review its activities and progress its agenda, and it does so in conjunction with established conferences in the field of medical education being held in the region, to allow members to gain benefit from participation in both events.In February 2017, the Association was invited to participate in the 50 years anniversary convention of the Association of Philippine Medical Colleges, held in Manila. In addition to contributing 2 plenary lectures to the main conference program, we also presented a Symposium addressing the issue of medical ethics and professionalism education in countries of the Western Pacific Region. The opportunity was also taken to tour the headquarters of the Western Pacific Regional Office of WHO, located in Manila, and this was beneficial in increasing understanding and cooperation between our two organisations in the area of health workforce development .Our meeting in 2018 was conducted at the Asia Pacific Medical Education Conference held in Singapore in January. Attending the many sessions of this excellent conference was of great benefit to our members, and we were also pleased to present a symposium entitled \u201cRequired resources for learning: a Western Pacific regional perspective.\u201d A well-attended meeting of our Advisory Board was also conducted during the course of this conference.It\u2019s also worth recording that both I as President and our past President Ducksun Ahn were invited to attend the 2016 Conference of the International Association of Medical Regulatory Authorities in Melbourne, where we addressed a Policy Roundtable on Health Workforce Regulation and Education conducted by the WHO Western Pacific Regional Office. This gave our organisation the opportunity to develop further the important relationship between medical school accreditation and the regulation of medical practitioners.In July 2017, a WPAME team conducted a progress evaluation visit to the National University of Samoa in Apia, supported by the WHO Western Pacific Regional Office. This was a progress assessment following the consultative visit to the new Faculty of Medicine at the University which we had conducted in September 2015. The interactions during the visit and the report provided were greatly valued by the leadership of the Faculty and the University, as well as by representatives of the Government, and are likely to strongly influence the further development of this new school.In December 2017, WPAME was invited to send a speaker to the first Vietnam National Medical Education Conference, held in Ho Chi Minh City. The Secretary-Treasurer of the Association Pete Ellis attended, and his presentation on accreditation had a significant impact on the thinking of academic and political leaders who were present. Follow-up of this contribution will occur through the WPAME Board member for Vietnam, professor Tuan Tran, who is participating in a Reform Committee which is developing plans for quality assurance of medical education through the Vietnam Ministry of Health.A number of preliminary requests for support and advice have been received from other countries in the region, and these will be followed up as required.As a regional association of the WFME, the WPAME participates in global initiatives of the Federation, and sends its President to the annual meetings of the WFME Executive Council. I was pleased to attend and contribute to these meetings in Melbourne in September 2016 and in Geneva in May 2017.The terms of the current officeholders of WPAME come to an end on 30 June 2018, and the individuals forming the new leadership team were decided at the recent meeting of the Advisory Board. The incoming President will be Dujeepa Samarasekera of Singapore, and the Vice President will be Pete Ellis of New Zealand. I will be pleased to take the role of immediate past President, and am confident that the Association will continue in strong hands in the years ahead."}
+{"text": "Quality of life (QOL) has over the past decade become an important part of health science and also increased public awareness. It has become increasingly apparent that illness is closely related to the individual perception of a good life, and therefore the exploration of indicators related to quality of life appears to be of broad importance for the prevention and treatment of diseases. Identifying, which factors constitute a good life may reveal an understanding about what areas in life should be encouraged, in order to enhance the global quality of life, health, and ability. In this paper we present results from studies initiated in 1989 to examine quality of life in relation to disease. The purpose of this presentation was to assemble the results from the study carried out in the years between 1993 and 1997, examining a total of 11.500 Danes, to show the association between quality of life and a wide series of social indicators."}
+{"text": "To analyze the results of an initiative aimed at improving the reasonable use of radiological examinations, ensuring their technical quality, implementing a radioprotection campaign that includes training of the professional team, and introducing the radioprotection card for children under 12 years old as a tool for parents and doctors to control children\u2019s exposure to radiation. Image Gently\u2022 protocols, ensuring the lowest dose of radiation and the quality of examinations, and the radioprotection card was implemented. To assess the effectiveness of these actions, the number of radiological examinations performed at the pediatric emergency room in a period of one year preceding the campaign was compared with the number of radiological examinations performed one year after the campaign.  The study was held in a health care insurance system covering 140,000 people. A radioprotection campaign was implemented according to  The campaign was well accepted by all professionals, families, and patients involved. In the year following the implementation of radioprotection strategies, there was a 22% reduction of radiological examinations performed at the pediatric emergency room. There was also a 29% reduction in the request of two or more radiological examinations for the same child or examinations with two or more incidences.  The campaign and the radioprotection card for children under 12 years old proved to be feasible strategies and correlated with a reduction in radiological examinations requested and performed at the pediatric emergency room. In recent decades, technological advances and the ease of performing radiological examinations, particularly computed tomography (CT), have led to a progressive increase in the request and execution of these examinations.Because their tissues are still in development, children and adolescents are more sensitive and more vulnerable to the effects of ionizing radiation. The younger the patients, the greater the risk.In the hospital, in which we conducted this study, the follow-up indicates excessive request for radiological examinations. It is believed that this excess is due to the insecurity of parents and guardians or the health team itself. Although there is often a specific reason for requesting radiological examinations - as they are certainly helpful in making a diagnosis - the fact is that children are at risk of being exposed. This is especially true in the pediatric emergency sector, with large number of visits and requests for radiological examinations.,,The objective of this study was to evaluate the initiative of a private hospital  aimed at implementing measures to reduce children\u2019s exposure to the risk of ionizing radiation. This initiative likewise aimed at enhancing training and awareness of health professionals and family members of the dangers of excessive radiation. In this initiative, a radioprotection campaign was launched that involved the awareness of employees and those responsible for children; the technical adequacy of radiological equipment according to the radioprotection criteria of the American College of Radiology and the American Society of Pediatrics, and the implementation of the radioprotection card for children up to 12 years of age.This is a quantitative and qualitative prospective study. We evaluated the medical attendance at the emergency room and the proportion of radiological examinations requested, and analyzed the impact on the health service and the clientele served. The study was conducted in a hospital of a supplementary health system run by a medical cooperative in the interior of the state of S\u00e3o Paulo. Its coverage is approximately 140,000 people. Urgent care, emergencies, and subsidiary examinations of the entire health system are centralized in the hospital itself.,The protocols for performing all the radiological examinations were reviewed by the radiologists of the sector, adopting in the execution of these examinations the lowest milliamperage (mA - maximum 100-150 mA) in order to maintain the necessary quality for the examination report.\u2022 campaign.As for the health professionals, meetings were held with the management team and the nursing staff so that the employees understood the effects of the radiation, ensuring that they were aware that the radiological examinations should only be done when necessary. Since then, the entire care team (not just the doctor) has explained to family members the risks of radiological examinations, especially of CT. This is important considering that children\u2019s caregivers often believe that a radiological examination is indispensable to diagnosis, rather than the child clinical examination. A medical event was held in which a professor specializing in pediatric radiology addressed the technical aspects and risks of ionizing radiation of radiographs and CT. Information leaflets were distributed to pediatricians about the additive effect of ionizing radiation, the estimated dose of radiation absorbed by exposure to the most requested examinations, and the importance of performing these examinations only when truly necessary. These initiatives engaged health care professionals in the worldwide Image GentlyInformation regarding the importance of this campaign, the radioprotection card and the reasonable use of radiological examinations was posted in the hospital\u2019s web page and advertised throughout the institution in spaces accessible to both health care professionals and the public. Twenty thousand radioprotection cards were prepared and distributed, providing a tool for patients and health care professionals to keep a record of the type of radiological examination and its date. The back cover provides information in language appropriate for laypeople that explains the need and benefits of the initiative, such as the risk of serious diseases and cancer. The delivery of the radioprotection card was always accompanied by an explanation by a trained employee in the emergency room, examination collection laboratories, hospital imaging sector, and pediatric offices.In order to evaluate the impact of the awareness campaign and the radioprotection card, radiological examinations and emergency pediatric consultations of this supplementary health system were quantified. These consultations are carried out in one single location and the complementary examinations are mandatorily performed at the hospital and registered on the computerized service card. Thus the record systems allowed for the documentation of the number of radiological examinations (X-ray and CT) associated with all the pediatric consultations performed in the sector. As the launch of the radioprotection campaign took place at the end of August 2013, the previous period from September 2012 to August 2013 was considered as the pre-campaign period for the collection of such data, and the period of one year thereafter - September 2013 to August 2014 - as the post-intervention or post-campaign period.The study was approved by the Research Ethics Committee of the Faculty of Medical Sciences and Health of the Pontifical Catholic University of S\u00e3o Paulo (PUC-SP). All the procedures of the study were carried out in accordance with the applicable ethical precepts. The review of protocols of examinations was made by consensus by radiologists in the field, and the campaign followed the guidelines of the American College of Radiology and the American Society of Pediatrics.The data are presented descriptively, and the comparison test between two proportions was used to compare the percentages of attendance with radiological examinations in pre- and post-radioprotection campaign. In order to assess the proportion of visits associated with two or more radiological examinations for the same child, or two or more incidences in the same examination request, a random sample of 1,051 requested examinations from September 2012 to August 2013 (pre-campaign) and 920 requested examinations from September 2013 to August 2014 (post-campaign) were used. To do this, we selected all attendances at pediatric emergency room in the second week of January and June of each year (pre-campaign and post-campaign). The months of January and June were chosen because they were, respectively, the ones with the lowest and highest number of monthly visits in the sector. Samples were selected in the same periods of the previous year and after the radioprotection campaign. The minimum size of these samples was estimated in 640 visits with requests for examinations in each period, so that a minimum difference of 5% could be found between two proportions, taking into account the error \u03b1 of 5% and the error \u03b2 of 20%.At the launch and in the month following the campaign, approximately 17,000 radioprotection cards were distributed, always accompanied by the necessary clarifications and guidance to its use like a vaccination card, that is, has to be presented whenever medical care was sought. The initiative had significant repercussions in the local media, which contributed to its dissemination.Pediatricians who initially hesitated to distribute the radioprotection card out of fear that it might bring excessive concern to their parents were surprised by the positive reception of the campaign. They reported that the radioprotection card had become a very useful tool to raise awareness among parents, gaining their confidence and collaboration in order to avoid exposing their children to unnecessary examinations that could endanger their health. The medical coordinator of the pediatric emergency unit expressed her agreement:Many parents already arrive at the clinic requesting and pressuring the doctor to request radiological examinations, with no idea of the risk exposed to the children. The preparation of information at the pre-consultation reception and in the doctor\u2019s office helps pediatricians to have scientific tools to raise family awareness. We consider the project of great importance in the safety of medical practice, with improvement in training and prevention of future diseases in children.The health system board also showed enthusiasm for the initiative and the results of the radioprotection campaign. The hospital superintendent asserts:I believe that this project overcomes the main challenge of any scientific research: to cross the walls of the academy and enter the reality of people and the community, transforming habits through the proposition of feasible solutions [...]. The project of radiological protection in childhood, which, in addition to seeking to perform the tests with the lowest radiation dose possible, also aims to raise awareness of the risks of diagnostic methods that use the X-ray to obtain the images, changing how the care team and clients use these methods.The rationalization of the radiological examinations was evidenced by comparing the number of examinations made in the pediatric emergency department of the hospital one year before the campaign with the number of examinations one year after the campaign. The study model encouraged health professionals to modify their work environment by creating tools to raise the awareness of these professionals and their families about the effects of ionizing radiation on children, therefore establishing a true preventive and health promotion project. Also as a consequence of the project, the radioprotection card was developed and distributed to children up to 12 years old, allowing pediatricians and other physicians to analyze possible previous examinations and decide whether or not to recommend new radiological examinations, reducing radiation exposure. From the qualitative point of view, the improvement of information and knowledge of employees, physicians and users - and particularly of the parents - reflects an important aspect of health education, whose corollary is the promotion of health, a responsibility inherent to professionals in the area. Comprehensive health care in childhood and adolescence reserves a central role for parents, but also for health institutions and their multiprofessional team.The systematic and sustained reduction (by 22%) of the radiological examinations associated to pediatric care in the emergency sector also allows quantification of the results of the campaign and the implementation of the radioprotection card. At the same time, there was a reduction in the request for duplicate examinations for the same child and examinations with two or more incidences. The study identified the high proportion of pediatric visits associated with radiological examinations in emergency sector, most of them related to respiratory tract diseases, in which clinical evaluation should be given greater weight. In addition, in this setting of care, it is common to request examinations of more than one anatomical region or examinations with two or more incidences. A Brazilian study assessed the care with radiological protection in four large hospitals in children submitted to X-ray of the facial sinuses. It was observed that the protection was incipient and that two incidences were frequently requested unnecessarily.\u2022 initiative, conducted by the American College of Radiology and the American Society of Pediatrics, and then subsequently carried out in many medical and health entities across the United States.The project was inspired by the Image Gently,,There is consensus in the literature regarding the risks of exposure to ionizing radiation and the development of solid tumors or hematopoietic lineage in children and adolescents.It is worth considering as a limitation of the study the fact that parents or guardians were not interviewed to determine their perception of the campaign and the radioprotection card. In addition, the risk of underdiagnosis of some diseases because of the reduction in the number of radiological examinations was not assessed. Despite these limitations, this study presents the unprecedented experience in Brazil of a proposal for radiological protection for children and adolescents through a Radioprotection Campaign, emphasizing the awareness of health professionals and their families about the possible harm of cumulative ionizing radiation and offering a motivating instrument for the control of radiation exposure - the radioprotection card. The monitoring of radiation exposure in children in a controlled sector of this health system evidenced the consistent reduction of the radiological examinations associated to pediatric emergency care. The enthusiasm with which the project was accepted in this institution and the commitment observed in its execution have ensured its success and must guarantee its permanence."}
+{"text": "There is an error in the penultimate sentence of the first paragraph of the Materials and Methods. The correct sentence is: All specimens will be deposited in the collection of the Birbal Sahni Institute of Palaeosciences, Lucknow, IndiaA portion of the figure legend for"}
+{"text": "In the original publication of the article, a part of Scheme 12 was missed. The correct version of Scheme"}
+{"text": "In the original article, we neglected to include the funder, the European Research Council, Starting Grant N\u00b0 335328 to JW, as well as funding from the Kavli Foundation, the Centre of Excellence scheme of the Research Council of Norway \u2013 Centre for Biology of Memory and Centre for Neural Computation, The Egil and Pauline Braathen and Fred Kavli Centre for Cortical Microcircuits and the National Infrastructure scheme of the Research Council of Norway \u2013 NORBRAIN. The author apologizes for this error and states that this does not change the scientific conclusions of the article in any way.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The objective of this study is to evaluate the performance of the Tuberculosis Control Program in municipalities of the State of S\u00e3o Paulo. This is a program evaluation research, with ecological design, which uses three non-hierarchical groups of the municipalities of the State of S\u00e3o Paulo according to their performance in relation to operational indicators. We have selected 195 municipalities with at least five new cases of tuberculosis notified in the Notification System of the State of S\u00e3o Paulo and with 20,000 inhabitants or more in 2010. The multiple correspondence analysis was used to identify the association between the groups of different performances, the epidemiological and demographic characteristics, and the characteristics of the health systems of the municipalities. The group with the worst performance showed the highest rates of abandonment  and the lowest rates of supervision of Directly Observed Treatment , and it was associated with low incidence of tuberculosis, high tuberculosis and HIV, small population, high coverage of the Family Health Strategy/Program of Community Health Agents, and being located on the countryside. The group with the best performance presented the highest cure rate  and the highest rate of cases in Directly Observed Treatment ; the group of regular performance showed regular results for outcome  and supervision of the Directly Observed Treatment . Large population, low coverage of the Family Health Strategy/Program of Community Health Agents, high incidence of tuberculosis and AIDS, and being located on the coast and in metropolitan areas were associated with these groups. The findings highlight the importance of the Directly Observed Treatment in relation to the outcome for treatment and raise reflections on the structural and managerial capacity of municipalities in the implementation of the Tuberculosis Control Program. Since the proposed changes in the Health Pact in 2006, the panorama of management policies has strengthened the evaluation of indicators and the negotiation of goals to improve the assistance provided within the context of the Brazilian Unified Health System (SUS)21.The demand for evidence capable of evaluating the performance of health programs is growing in Brazil14. Interventions related to the care of chronic conditions include numerous activities involving multiple organizations and professionals over time. In these cases, the difficulty in identifying the responsibility of each one of these elements is greater in relation to the results achieved23.However, the evaluation of programs is still a complex task, inserted in a similar complex context of epidemiological reality and the organization of health services present in contemporary society. Certain contagious diseases are closer to the combating logic of chronic diseases than other communicable diseases of rapid course \u2013 what characterize them as chronic conditions1. Despite the Programa Nacional de Controle da TB  formulating and recommending unique guidelines, the implementation of TB Control Programs (PCT) in municipalities is developed in different formats and results because of numerous administrative, political, and geographical specificities of the locations6. This peculiarity comes together with the process of decentralization of TB actions to the services of Primary Health Care (PHC), started around the 2000s, which advanced the expansion of the coverage of TB actions in the municipalities. However, at the same time, it generated new challenges for the municipal PCT as it imposes greater permeability in relation to the commitments in the control of the disease and exposes weaknesses in the structure and organization of the entire health system3.Tuberculosis (TB) is one of the most poignant examples of this situation: an insidious disease, with treatment that lasts at least six months, and which requires, for its activities of control, permanent and coordinated care between different services at various levels of the health system9.There are several possible ways to evaluate the performance on TB control: focus on the performance of specific actions, or on services that operate the program, or on the PCT itself as an agency that gathers certain attributes and activities. Nevertheless, national publications are scarce around performance evaluation of the PCT regarding the program as a wholea. In addition, there are several particularities in relation to the organizational context of its health services, including its own system for the notification and monitoring of TB cases, called \u201cTBWEB\u201d5. Thus, this study has aimed to evaluate the performance of the PCT in the municipalities of the State of S\u00e3o Paulo.The State of S\u00e3o Paulo is a relevant setting for TB control: it is responsible for approximately 20.0% of the total burden of disease in Brazil and it occupies the sixth place in incidence in the country6. This proposal suggests the use of a cluster analysis (CA) for the identification of groups of municipalities with different operational performances, followed by further association between these groups with other data characterizing the context, using multiple correspondence analysis (MCA).This is a study of health evaluation with ecological design and descriptive-exploratory approach. We have used the proposed normative evaluation of programs developed by Gon\u00e7alvesWe have considered the municipalities of S\u00e3o Paulo with 20,000 or more inhabitants and which had a minimum of five new TB cases, outside the prison system, notified in the TBWEB in 2010. Of the 466 municipalities with new TB cases reported in 2010, 197 municipalities meet the criteria and were included in the study. With the criteria used, the studied municipalities amounted to 95.6% of all new cases of TB in the State of S\u00e3o Paulo in 2010 .Sistema Nacional de Agravos de Notifica\u00e7\u00e3o Compuls\u00f3ria  in 19985. The data collected in the State of S\u00e3o Paulo using the monthly newsletter and notification form for monitoring include mandatory and essential variables consolidated by other units of the country that use the SINAN. Additionally, data are registered on the discovery of the case, name and age of the identified contacts, information about admissions, and number of doses supervised in the Directly Observed Treatment (DOT). The TBWEB uses an online format, in which data can be entered and seen using the Internet throughout the course of TB therapy and patients have a unique record (eliminating possible duplicates). The system offers several features for analysis  and communication (ability to send messages) using the same interface as the record of the data. Access to TBWEB is restricted to professionals responsible for the epidemiological surveillance in the municipality. They receive the notification records of the care units that perform the diagnosis and treatment of the cases and issue monitoring reports that will be updated by these teams. The notification and record of the data of the patients under treatment is carried out by health services and professionals active in the care and they follow what is advocated by the PNCT throughout the country.The State of S\u00e3o Paulo has its own system for computing information about TB since the 1990s. The State has kept its database even after the national implementation of the b, as well as in prior research of Gon\u00e7alves6. They are: Proportion of new cases notified by the municipality of residence; Proportion of new cases of pulmonary TB with sputum smear microscopy at the beginning of the treatment; Proportion of HIV testing among new cases; Proportion of HIV testing in progress among new cases; Proportion of new cases diagnosed with bacteriological confirmation; Proportion of indication of DOT and Proportion of supervision of DOT among new cases; Proportion of communicants examined among the communicants identified in new cases; Proportion of abandonment of treatment among new cases; Proportion of cure among new cases; and, Proportion of death among new cases. Variables related to the above information were collected in the TBWEB in January 2013 and the calculation of the indicators was performed for each of the municipalities of study by two researchers independently. The variables were evaluated previously regarding completeness and they presented more than 80.0% of filling in the information system.For the characterization of the performance of the PCT, we have used a selection of operational indicators proposed in the Manual of Recommendations of the Tuberculosis Control ProgramTwo municipalities were excluded by the impossibility of calculating at least one operational indicator , resulting in 195 municipalities under analysis. After the calculation of the indicators, we carried out a CA applying the hierarchical method, using the squared Euclidean distance as coefficient of similarity. Ward\u2019s method was used as a grouping strategy, followed by the non-hierarchical method. The hierarchical CA identified a cutoff point of three groups of municipalities with different performances, which was used as a strategy for the implementation of the non-hierarchical method. The power of discrimination of the variables for the formation of the groups was verified by analysis of variance, considering the significance level of 5.0%. We excluded the indicators Proportion of new cases notified by the municipality of residence, Proportion of new cases of pulmonary TB with sputum smear microscopy at the beginning of the treatment, Proportion of new cases diagnosed with bacteriological confirmation, and Proportion of death among new cases as they did not show power of discrimination between the different groups . For the MCA, the municipalities of the study were characterized in relation to demographic aspects , local health systems , as well as the epidemiological situation of TB  and AIDS (incidence of aids and TB/HIV coinfection). The data needed for this characterization were collected in the TBWEB and on the websites of the Brazilian Institute of Geography and Statistics (http://www.cidades.ibge.gov.br/), Department of Informatics of the SUS (DATASUS \u2013 http://datasus.saude.gov.br/), and Department of Primary Care/Ministry of Health (http://dab.saude.gov.br/dab/historico_cobertura_sf) in March 2013. The variables of context of the municipalities were included in the MCA after categorization in three ranges  based on the values of the 30 and 70th percentiles. Such characteristics of the municipalities were included in the model of the MCA as active variables, and the groups of municipalities with different performances were considered as additional variables.This research has been approved by the Research Ethics Committee of the Escola de Enfermagem de Ribeir\u00e3o Preto, Universidade de S\u00e3o Paulo (Process CAAE 00630812.8.0000.5393/2012).The group with unsatisfactory performance was composed of 63 municipalities, the group with regular performance had 43 municipalities, and the group with satisfactory performance had 89 municipalities. The characterization of each group was performed by the visualization of centroids  and the In relation to the MCA, we have observed two dimensions, which recovered 33.5% of the total variability of the data (inertia). Dimension 1 consisted of variables that were mostly related to the epidemiology of the disease and to demographic characteristics; dimension 2 consisted of variables related to the characteristics of the health system. The perceptual map  indicateThe differences identified in the different performance groups by the CA allow us to reflect on the relationship between the PCT, as a player of the meso-management, and the locus of health services, as micro-management spaces. Among these differences, we highlight the best result of the coverage of the DOT accompanied by higher rates of cure and smaller index of abandonment, which possibly reaffirms the influence of the strategy of the DOT in achieving a favorable outcome for the treatment.7. The availability of these instruments influences the acceptability of health professionals in relation to the practice and the sustainability to carry them out in the daily service and must be considered to understand the results of this study.The lower supervision in relation to the total of patients indicated for DOT was expressive in the unsatisfactory and regular groups, indicating a weakness in the development of the strategy. Several issues related to the implementation of the DOT come from the management of municipal coordinators and depend on the articulation between players and sectors. Among them we can mention the offering of incentives, such as food stamps, breakfast, and transportation vouchers, as well as human resources in sufficient number and vehicles for home visits16. Thus, in addition to the organization and availability of the resources mentioned, the good performance in the supervision of the DOT requires a reordering of the care practices and the process of work of health professionals13.Despite the different experiences recorded under the name of the DOT, the strategy goes beyond the simple observation of drug intake. It must be considered as a care management technology with an integrated and humanized approach19. The training of the teams responsible for monitoring the TB cases, to carry out the testing in priority municipalities19 \u2013 which coincide with the areas associated with good performance (coast and Greater S\u00e3o Paulo) \u2013, can signal the benefits of previous experiences of partnerships between the program of AIDS and TB control.In this study, favorable results related to anti-HIV testing among new TB cases reached a proportion above 75.0% even among the group with the worst performance. Such results can be explained by the time of implementation of the anti-HIV rapid test in the network of services in S\u00e3o Paulo \u2013 started in mid-200610.The control of communicants also presented considerable proportions even in the group of unsatisfactory performance. We question the process to produce the data used to calculate the indicator. The under detection of intra-household communicants, the gaps in the clinical evaluation of contacts, and the low number of tests are mentioned in a study carried out in the South of Brazil, which raises the need for more research to understand the resultsRegarding the results identified by the MCA, we need to consider the structural conformation of the network of services, the dynamics of the care model, and the issues that delves into the relations between the meso- and macro-management .The results show that the high incidence of TB and AIDS are epidemiological aspects of the prioritization of actions of control, which serve as a formal tool of visibility of the problems surrounding the disease. The association between unsatisfactory performance and high TB/HIV coinfection points to the need for increased vigilance and improvement in the management of cases that are more vulnerable and at greater clinical and abandonment risk even in places with less burden of TB.22. These differences may explain the association of better performance with larger populations, as they more frequently have the instruments to maintain the political commitment around the operationalization of the TB program and ensure the resources necessary for the PCT.Small municipalities generally have lower population qualification in management positions and functions and low human resources, while large municipalities have greater managerial and regulatory capacity18.Both in large and in small municipalities, the administrative discontinuity, the lack of autonomy in executive decisions, the political patronage, and the conflict of interests between the different political-party options affect the degree of cooperation achieved between the macro and meso-management. They are problems commonly faced by coordinators of TB programs in the execution of their activities8. On the other hand, these municipalities have greater difficulty to implement strategies, such as the FHS and PACS, either because of insufficient population coverage by the PHC, or because of ineffective reference systems between the levels of complexity, or because of the low presence of professionals in these services4. The very dynamics of the health-disease process and the use of health services in major urban centers indicate a pattern of health care consumption based on specialization, which weakens the implementation and sustainability of the PHC8.Larger municipalities and in urban regions usually have a wider range of own/contracted services. They have a greater trend in the organization and offer of care of medium and high complexity24The association between increased coverage of the FHS and PACS and the group of municipalities with the worst performance may suggest that strategies for the strengthening of the PHC do not always produce actions in line with the needs of their territories. In addition, the lack of professional expertise in the management of cases may lead to unfavorable results, a discussion also raised in the article of Yamamura et al.14. We need to consider the discrepancy between the conception of the PHC in the design of the national policy and its expression in local realities11. In addition, the decentralization of TB actions for the PHC is characterized as a deconcentration of activities in a scenario of high turnover of professionals and accumulation of functions4. Unsatisfactory performances of TB control are an important message in relation to the quality of the health care and the care models practiced in the reality of health services. That is because the subjects with TB experience the weaknesses of the public health system as a whole in greater frequency and intensity.The consolidation of a new care model in the PHC is not only characterized by the singularities of the horizontal dimension of extension as expressed by the coverage of strategies, such as the FHS and PACS, but also by the vertical dimension of the depth of its institutionalization13. We need to consider the laboratory support, the flows, the communication between levels, that is, the network needs to be organized around a care line, which enables the coordination of the care provided in all its phases and facilitates the appropriate service for every need/profile of Tb case12.Although this study has selected the coverage of the FHS and PACS as a strategic indicator for the characterization of the health system, the decentralization of control actions for PHC cannot be analyzed separately17. These tools can be a way to face the lack of knowledge on TB by the professionals working on PHC17.In the context of the meso-management, the coordinator of the PCT must know the health care network and how the process of work of teams and services that will detect, diagnose, and treat TB cases is carried out. In addition, the management team of the PCT must articulate the inclusion of the subject of TB in the existing matrix of strategies and guide the disease and its control in permanent education activitiesc. The PNCT itself promotes activities of monitoring and evaluation since 2000, making visits to priority States and municipalities in order to contribute politically and technically to improve the responsiveness to TB. This is a positive example of the partnership between different federated entities whose model can serve as a reference to local managersb.The coordinators in TB must strengthen their management action by incorporating instruments such as health plans and reports, valuable documents that give public knowledge on health actions, and by planning actions of indirect  and direct monitoring The method of evaluation developed provides possibilities for understanding the performance of local PCT. However, we assume as a weakness the unknown values of other indicators or variables able to explore in greater depth the context in which health interventions are performed. Future studies are needed on this subject."}
+{"text": "There are errors in the Funding section. The correct funding information is as follows: This study was carried out thanks to the contribution of the Ministry of Economy and Infrastructure of the Board of Extremadura through the European Regional Development Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."}
+{"text": "The use of simple spreadsheets is described to create simulations of complex pharmacokinetic phenomena. The basics of spreadsheets are first described and are developed to demonstrate classical pharmacokinetics without the use of differential or integral calculus. Using standard spreadsheet commands, the technique is shown to be applicable to the full range of advanced pharmacokinetic simulations. Demonstrations of the effect of a variety of physiological eventualities are included to show the versatility of the technique. The technique is very simple to use and is always in the complete control of the modeller. All spreadsheets described are included in the attached file SpiresAdam."}
+{"text": "A Cowper's syringocele in an adult is rare. Ten cases are reported in the world literature. The authors report a case of painful haematuria due to the presence of a Cowper's syringocele in an adult. The classification of lesions of the Cowper's gland is discussed together with common symptoms and differential diagnosis."}
+{"text": "Following publication of this article, concerns were raised about the integrity of the reported work. The authors were unable to provide the underlying raw data for the study or additional methodological information regarding patient recruitment and have stated that most of the information reported in the article had been provided by a scientific service company that assisted with writing the paper.PLOS ONE Editors were unable to verify the integrity of the content of the article and the source of the data. Furthermore, the authors\u2019 specific contributions to the work are unclear, and the authors do not meet the journal authorship requirement to be accountable for all aspects of the work.Owing to this, the PLOS ONE Editors retract this article.In light of the above concerns, the The authors did not comment on the retraction decision."}
+{"text": "There is an error in the third sentence of the Abstract. The correct sentence is: In order to address the issue of cellular heterogeneity in homogenate samples we isolated microglia, astrocytes and neurons by laser capture microdissection from CA1 of hippocampus in the same individuals with a clinical and pathological diagnosis of AD and matched control cases."}
+{"text": "The Editor-in-Chief has retracted this case report because of concerns about patient consent to publish. The content of this article is no longer available online to protect the privacy of the patient. The author has not responded to correspondence from the publisher about this retraction."}
+{"text": "This data article contains the partial analysis (descriptive statistics) of data obtained from 1770 primary school pupils and secondary school students in three Local Government Areas of Ogun State, Nigeria. The schools are either privately owned or public (government owned) schools. The aim of the field survey is to measure the level and patterns of externalizing behavior of the respondents. The data was collected using a standardized questionnaire. The questionnaire is a modification of Achenbach manual for Child behavior checklist  [1] and manual for Youth self-report  [2]. The questionnaire was designed to suit the demographic and socio-cultural nature of the target population. Analysis of the data can provide useful insights to the patterns of externalizing behavior of primary school pupils and secondary school students. Specifications TableValue of the data\u2022The data provide the descriptive statistics for the selected samples which gave an exploratory trend of the observed characteristics.\u2022The data when completely analyzed can provide insight on the similarities and differences in patterns of externalizing behaviors of primary school pupils and secondary school students.\u2022Researchers can gain more insight on the instrument of data collection, which can be adapted or adopted to suit the studied socioeconomic, demographic, psychographic and behavioral characteristics.\u2022The questionnaire can be used for the study of the externalizing behavior of children and early adolescent youths.\u2022The questionnaire can be adapted or adopted to include cohort and/or longitudinal studies.\u2022The data could be useful in the following research areas: child behavior, adolescent health, early child education, guidance and counseling, mental health, psychiatrics, psychopathology, Developmental psychology, Multivariate Behavioral Research, Clinical Psychology and so on. The central theme is the study of externalizing behavior instincts and observed patterns between primary school pupils and secondary school students.\u2022Most vulnerable groups obtained from data analysis can be singled out for counseling and monitoring by the concerned authorities thereby improving on the public health of the people.1The data in this article is the set of responses solicited from 1770 primary school pupils and secondary school students in three Local Government Areas in Ogun State Nigeria. The details of the sample size are shown in The contents of the data are variables that determine the externalizing behavior of the respondents. These variables are as a result of under control of emotions as listed in the questionnaire. The analysis of the data can reveal the externalizing behavior of the respondents which can manifest as aggression, delinquency and hyperactivity. Furthermore, the gender, age and educational level differences in the distribution of externalizing behavior patterns can be obtained from the analysis of the data. In addition, research questions can be posed and statistical hypothesis can be tested based on the data. Finally, the data contains some variables which have not been considered in the analysis of externalizing behavior in children and adolescents and the questionnaire can serve as a benchmark tool for behavioral analysis especially in the sub Saharan region of Africa.The data can be assessed as 1.1The summary statistics of the total score of the respondents is given in The summary statistics was represented by a histogram shown in The histogram is the chart representation of the descriptive statistics. The histogram revealed the presence of fewer outliers .1.2The percentage of the individual score compared with the total score can be computed using the formula;The total score is 200. The summary statistics for this subsection is shown in 1.3The summary statistics for the gender differences in the distribution of the total score for the primary school pupils and secondary school students is shown in 1.4The summary statistics for the school differences in the distribution of the total score for the primary school pupils and secondary school students is shown in 1.5The summary statistics for the age differences in the distribution of the total score for the primary school pupils and secondary school students is shown in 1.6The summary statistics for the school level differences in the distribution of the total score for the primary school pupils and secondary school students is shown in 1.7The mean and standard deviation of all the questions in the questionnaire responded by the primary school pupils and secondary school students is shown in 1.8The distribution of the responses from all the questions contained in the questionnaire is shown in 2Researches on externalizing behavior and other related fields are often conducted by the use of standardized questionnaires. Details on other research aimed at studying the nature, causes, distribution and management of externalizing behavior in children and adolescents can be found in Simple random sampling (SRS) was used to obtain the data across the three Local Government areas (LGA) in Ogun State, Nigeria. The selected LGAs are Ado-Odo/Ota, Ifo and Yewa South, which are in close proximity to each other. The choice of the target population reflects the views of both the urban and rural respondents, reflecting the demographics in the State. The focus is on the gender, age, school type and educational level of the distribution of the externalizing behavior patterns of the respondents.The differences between the rural and urban externalizing behavior pattern is open for further research. The questionnaire was given to pupils and students of public/private primary and secondary schools. The sampling was solely on without replacement and the non-response was excluded from the final data. Non responses are categorized as incomplete data as a result of partial or no responses from the respondents. Inclusion of such data can be detrimental to the estimation of the population parameters.The internal consistencies and the reliability of scale for the questions Q1\u2013Q100 in the questionnaire is shown in"}
+{"text": "A case of spontaneous rupture of the oesophagus is described in which the presentation is unusual. The rarity of the condition is emphasized. The diagnosis and treatment are briefly considered and the difficulties in diagnosis stressed. The similarities and differences between this condition and the Mallory-Weiss syndrome are discussed."}
+{"text": "There was a mistake in the name of the author Salem Al-Tememi as published. The correct spelling of the name should be Salem Al-Tamemi. The authors apologize for the mistake. This error does not change the scientific conclusions of the article in any way.via the Chaim Roifman Award Program. The correct Funding section is below.In the original article, we neglected to thank Immunodeficiency Canada for providing grant support for part of the study The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Dominic Allen and Luis Ribeiro were not included as authors in the published article. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.The original article has been updated.LR and DA: initial drafting of manuscript. QA: initial drafting and final revision of manuscript. BS: general organization of manuscript. Interim and final revision of manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The posterior tibial muscle is the main functional support of the plantar arch its dysfunction is the main cause of acquired flat foot. This is a 32 year old patient who consults for progressive pain of the inside of the ankle and right foot with a considerable decrease in its sporting and professional activity. Examination reveals a collapse of the plantar arch. The radiological assessment finds imprisonment of posterior tibial tendon in the internal retromalleolar bony canal. The patient received a release of the tendon with resection of the bony canal in full. The posterior tibial tendon showed longitudinal laceration was sutured and the internal retromalleolar canal was closed. The race and the freedom of the tendon were considered satisfactory by the end of surgery. The evolution was marked by the disappearance of pain, recovery of a satisfactory sport and professional activity and a progressive decrease in the collapse of the plantar arch."}
+{"text": "Genome Research recently published a paper (Genome Research stand behind the review process and the publication of this paper. The reported work has garnered significant public and scientific attention due to interest in the topic. At the same time, questions have been asked about the ethical standards that guided the investigation of the skeleton and the subsequent publication of the results ( a paper  describi results .Genome Research has an established track record of adherence to policies that protect human subjects in biomedical research. Current human subjects research policies do not typically cover the study of specimens of uncertain biological origins, such as the Atacama skeleton. The DNA sample from the Atacama skeleton did not qualify as human subjects research as defined by the Federal Office of Human Research Protections; thus, neither specific approval nor exemption was required for the study reported in the paper.Genome Research acknowledge that these issues require further discussion and agreement on rules of usage from within and outside the biological research community.Nevertheless, the concerns about the study expressed by some Chilean scientists, their government, and some members of the public must be taken seriously. We also recognize the sensitivities related to the history and acquisition of the sample. The Editors and Publisher of This experience highlights the evolving nature of this field of research, and has prompted our commitment to initiate community discussions aimed at establishing journal policies and author guidelines necessary for the publication of studies involving historical and ancient DNA samples.Genome ResearchThe Editors and Publisher of"}
+{"text": "Journal of Translational Medicine is issuing an editorial expression of concern to alert readers that concerns have been raised regarding the ethics of this study [The Editor-in-Chief of the is study  and the"}
+{"text": "N = 365 pre-service teachers in the first part of their teacher education program  was conducted.In the first sentence of the Sample subsection of the Materials and methods section, the numbers of males and females are incorrectly interchanged. The correct sentence is: A study with"}
+{"text": "Frontiers in Plant Science.The authors have requested the retraction of the 4 July 2016 cited above. Following publication, concerns were raised regarding the scientific validity of the article. This was due to an undisclosed error in the experimental design (such as the presence of host tomato plants) and crucial experiments missing from the manuscript which did not support the hypotheses put forward in the paper. This retraction was approved by the Field Chief Editor and the Specialty Chief Editor of Frontiers in Plant Science.The authors regret any inconvenience this may have caused to the reviewers, editors, and readers of"}
+{"text": "Professor Victor Neale was a leading paediatrician and respected teacher at a time when the specialty was growing rapidly and employing new professional skills, knowledge and attitudes. The benefits of these developments might be more fully realized by the establishment of a college of Paediatricians. But the consequential loss of affinity with the general medicine of adults and the Royal Colleges of Physicians could weaken the power of the medical profession to maintain the highest standards of medical practice."}
+{"text": "PLOS ONE article [PLOS ONE [Prior to the publication of this  article , the autPLOS ONE . The twoPLOS ONE  to give The authors also acknowledge the reuse of text between the two publications. Specifically, the reuse of text concerns the following parts:Abstract: The introductory sentence and the methodology used to evaluate the stability of the MLVA profiles.Materials and MethodsResults: The methodology of calculation to evaluate the diversity of phage typing, antimicrobial susceptibility testing and MLVA.Discussion: Description of the current subtyping methodology for routine surveillance of Salmonella and comparison with MLVA; repeating the main conclusions of the earlier study"}
+{"text": "This paper is retracted by Frontiers. The publisher has discovered that the author(s) created and provided false information for the peer-review process. As the scientific integrity of the article cannot be guaranteed, and adhering to the recommendations of the Committee on Publication Ethics (COPE), the publisher therefore retracts the article.The retraction of the article was approved by the Field Chief Editor of Frontiers in Microbiology."}
+{"text": "There was a sentence omitted from the Funding section. The complete funding information is as follows: This work was funded by the scleroderma Research Foundation that had no role in the design and conduct of the study, in the collection, analysis, and interpretation of data, or in the preparation, review and approval of the manuscript. The clinical trial of high-dose immunosuppressive therapy and autologous hematopoietic cell transplantation and the pathology review was funded in part by award N01-AI-05419 from the National Institute of Allergy and Infectious Diseases."}
+{"text": "The characterization of new spectroscopic plasma sources for use inatomic emission spectroscopy often presents the need for information about the spatial emission characteristics of the source. In addition, information about the variation of the emission over time is often beneficial. It is also useful to be able to graphically see, in real-time, the effects of varying a particular experimental parameter. This paper describes a flexible data acquisition system in which an echelle spectrometer is interfaced to an IBM-PC compatible microcomputer. The FORTH-based ASYST software, which proves real-time display of acquired data, allows any point in the emission source to be imaged on the entrance slit of the spectrometer by using the cursor keys of the PC and a computer-controlled mirror. The different acquisition modes of the system are illustratedwith examples of two-dimensional spatial profiles of the plasma and monitoring of plasma stability over time. In addition, an illustration of the optimization of the echelle's aperture plate and photomultiplier tube positions in the focal plane is presented."}
+{"text": "Dear Colleagues,I am pleased to welcome you all on the occasion of the Second Congress of the Asia Pacific Hernia Society at New Delhi, India scheduled between 6\u20138 October 2006. I am convinced that this Hernia Congress would be a landmark event in the present era of increasing specialization.Hernia repair is one of the most commonly performed surgical procedures by a practising surgeon today. A hernia can present at different ages in different sites at varying stages. Indeed, a surgeon practising hernia repairs has to necessarily possess a wide array of surgical repertoire and technique. There have been numerous exciting developments and products on offer to the hernia Surgeon, especially in the last two decades. The Scientific programme was designed to incorporate most of the innovations and breakthrough to keep us all abreast of current thought in herniology.We are extremely fortunate to have been propped up by Association of Surgeons of India (ASI) and Indian Association of Gastrointestinal Endosurgeons (IAGES). The substance and essence of Indian surgery is represented between these two giant organizations and we are grateful for their support.The Asia Pacific region is home to more than half of the World populace and is remarkable for its diversity in terms of nationalities, race, creed and ethnicities. With the formation of the Asia Pacific Hernia Society, a glaring lacuna has been plugged in the World of Hernia, with the prior existence of the American Hernia Society and European Hernia Society. As President of Asia Pacific hernia Society, I strongly encourage you to become members of APHS. This would enable you to tap expertise of not only APHS but also the American and European Hernia Societies. The Hernia Journal would be available at discounted rates as also registration to congresses of all three hernia societies.I foresee lively brainstorming during our scientific sessions (as most of us have hard opinions on hernia) and great camaraderie in our social events."}
+{"text": "A study of the healing of peritoneal defects in the rat in the presence of the Walker 256 tumour has been made. The healing process was investigated histologically, by autoradiography, and by hydroxyproline estimation of the healing peritoneal wound. There was no difference in the rates or quality of the healing process in the control or tumour bearing animals."}
+{"text": "Upon re-examining the results presented in this paper and following the rebuilding of the strains described, we were unable to reproduce the dependence of toxin production on the transporter described in the paper. This is likely because of a secondary mutation present in the original strain. Therefore, the conclusions reached in the paper should not be taken as fact, and the paper must be retracted. The decision to retract this paper was reached in consultation with the journal's editors, and the purpose of the retraction is to correct the literature. We hope to uncover the exact reasons for these discrepancies by finding the source of the secondary mutation."}
+{"text": "Fluorescence polarization measurement during the progress of fluorochromasia has been used to study the response of human lymphocytes to phytohaemagglutinin (PHA) and to tumour-associated antigens, as a basis for the detection of malignant disease. Polarization (P) values of both stimulated and unstimulated lymphocytes decreased with increasing intracellular fluorescence intensity, and with the duration of the fluorochromatic reaction. When these effects were taken into account, there was no significant difference in the change of P following stimulation of lymphocytes from 50 cancer patients or healthy subjects; the magnitude of the response was related more to the age of the donor and to the extent of granulocyte contamination of the lymphocyte preparation than to the presence of cancer. There were, however, significant differences in the change in leakage of fluorescein out of the lymphocytes and in the change in hydrolysis rate after PHA stimulation between lymphocytes from healthy individuals and from patients with cancer."}
+{"text": "An analysis of 101 cases of breast carcinoma occurring in patients under 35 years of age is presented with details of clinical stage, site, size and histological appearances of the tumour. Various factors are correlated with survival and the prognosis of the patient under 35 years is found to be closely related to the histological appearances of the tumour, which are reflected in the clinical stage at presentation. The question of treatment of carcinoma of the breast in the young woman is discussed."}
+{"text": "The evaluation of new reagents and instruments in clinical chemistry leads to complex studies with large volumes of data, which are difficult to handle. This paper presents the design and development of a program that supports an evaluator in thedefinition of a study, the generation of data structures, communication with the instrument , online and offline data capture and in the processing of the results. The program is called CAEv, and it runs on a standard PC under MS-DOS. Version 1 of theprogram was tested in a multicentre instrument evaluation. The concept and the necessary hardware and software are discussed. In addition, requirements for instrument/host communication are given. The application of the laboratory part of CAEv is described from the user's point of view. The design of the program allows users a high degree of flexibility in defining their own standards with regard to study protocol, and/or experiments, without loss of performance. CAEv's main advantages are a pre-programmed study protocol, easy handling of large volumes of data, an immediate validation of the experimental results and the statistical evaluation of the data."}
+{"text": "Sir,Thank you very much indeed for your kind words and your interest in the Indian Journal of Orthopaedics. The objective of organization of the symposium is to give a few state-of-the-art reviews based on the articles published in the literature and include a few original articles covering the ongoing research on the subject. The editorial tries to balance it keeping an eye on the problems of a particular geographical region.There is unanimity in the literature about the role of conservative treatment for spinal column fracture and Spinal cord injury (SCI) patients and it is well documented in the textbooks. Including articles on rehabilitation program for SCI would have been a repetition of the information. The editorial not only stresses on the prevention of spinal trauma but also on the current scenario of the care of spinal trauma patients across the country. The problem of spinal trauma and SCI including initial evaluation and care of the patient, travel time to nearest hospital, infrastructure and quality of treatment at district hospital is covered. It also stresses on better organization of spinal trauma care services, achievable standard of spinal trauma services, and also on lack of treatment guidelines for neglected spinal trauma cases. I feel a journal has to be balanced in maintaining the minimum service quality while also continuing to educate the orthopedic community about future research in the field. The clinician needs to know which are the fractures best treated by the conservative approach and which would do better with surgical intervention, if intervention is indicated than what type of intervention. All dilemmas have been spelled out in the editorial and some of them are covered in original articles.We have a \u2018letter to editor\u2019 column in the Indian Journal of Orthopaedics and would be keen to have more interaction between readers and authors. However, your points are valid and will be given a serious consideration for future issues of the Indian Journal of Orthopaedics."}
+{"text": "This issue is the final publication for the Middle East and African Journal of Ophthalmology for 2010. The year has been a significant one for the journal being listed in PubMed and receiving a record number of submissions. The current edition accurately reflects the scope of the journal that includes publishing studies focusing on ophthalmic disease and challenges in the Middle East and African (MEA) region. In addition, the mission of the journal is to provide up-to-date reviews on recent treatment trends in ophthalmology. The two review publications describe the use of biologicals in the treatment of intraocular inflammationA number of manuscripts in this issue from Africa and the Middle East focus on a wide array of visual impairment related topics. Of particular interest are the issues surrounding childhood visual impairment in the region. The paper by Vora and colleagues7Two reports focus on serious eye health hazards caused by the use of traditional medications in the region. Blinding eye disease caused by a variety of indigenous herbs and chemicals has been reported for over many years from the Middle East, Africa and Asia. Though the use of alternative medicine has exploded worldwide and probably in some areas of treatment has demonstrated excellent benefit, it must be recognized that the benefit of such traditional medications as therapeutic agents must be determined after evidence-based studies demonstrating effectiveness and safety.Finally, Alwadani and co-authors"}
+{"text": "An analysis of occupational incidence data for malignant melanomas and squamous-and basal-self carcinomas of the skin in England and Wales from 1970 to 1975 is reported. The occupational pattern for melanomas of the trunk and limbs differed markedly from the pattern for melanomas of the head, face and neck. Office work was associated with a large excess of melanomas of the trunk and limbs. In contrast, outdoor work was associated with an excess of melanomas of the head, face and neck; and was also associated with an excess of squamous-and basal-cell carcinomas of the skin. This suggests that prolonged occupational exposure to sunlight is an important cause of squamous-and basal-cell carcinomas and of melanomas of the head, face and neck, but not of melanomas on other parts of the body. The high rate of lesions on the trunk and limbs in office workers may reflect their sunbathing or other recreational habits; but it contrasts clearly with other indoor work, where there is a generally low rate of all forms of skin cancer."}
+{"text": "Following publication of this work  Dr EmamiMH carried out the molecular genetic studies, participated in the sequence alignment and drafted the manuscript. MP carried out the immunoassays. MS participated in the sequence alignment. JZ and MM participated in the design of the study and performed the statistical analysis. MD conceived of the study, and participated in its design and coordination."}
+{"text": "Lumbrical muscles play a vital role in the precision movements of the hand, along with the thenar, hypothenar and interossei muscles. The variation in the lumbrical muscle is clinically significant.During routine dissection of an adult male cadaver, we observed an additional muscle belly of the first lumbrical muscle took origin from the tendon of the flexor digitorum superficialis (FDS) to the index finger, close to the proximal margin of the flexor retinaculum.The presence of such an additional muscle in the carpal tunnel should be considered in the aetiology of carpal tunnel syndrome (CTS). The lumbricals are usually four small muscles of the hand. They are numbered from the lateral to medial side. The lumbricals take origin in the palm from the four tendons of flexor digitorum profundus (FDP), pass distally along the radial side of the corresponding metacarpo-phalangeal joint in front of the deep transverse metacarpal ligament. Each muscle forms a narrow tendon and on reaching the dorsal surface of the proximal phalanx joins the margin of the dorsal digital expansion (DDS) . LumbricDuring routine dissection of the right upper limb of a 69 year old male cadaver, we observed an accessory muscle belly took origin from the radial side of the FDS tendon to the index finger, at the level of the proximal border of the flexor retinaculum. The accessory muscle belly (71 mm in length & 6 mm in width) was placed lateral to the first lumbrical and joined the same before inserting to the DDS of the index finger. The first lumbrical muscle took origin from the radial side of the FDP tendon for the index finger as expected (Fig Lumbricals as a part of the intrinsic musculature is important for its delicate digital movements. Lumbricals are quite unique as they connect the flexors of the digits to the extensors and that both of their attachments are mobile. The articular system in the digits is connected by mechanical links and lumbrical muscle is one of the links of this system that produces dynamic controlled extension of interphalangeal joints . Many caHaines studied flexor muscles of the forearm and hand in the mammals and lizards; he suggested that the FDS in mammals is homologous with the intrinsic muscles of the palm, and that it shifts its origin proximally in forearm . FurtherClinicians and hand surgeons should be aware of such a variant of first lumbrical while dealing with the hand, during various surgical procedures.The authors declare that they have no competing interests.SRN wrote the case report, performed the literature review and obtained written consent. RR and AK performed the literature search and assisted with writing the paper. RC obtained the photograph for the study. LVP conceived the study and helped to draft the manuscript. All authors have read and approved the final version manuscript.\"Written informed consent was obtained from the subject's relative for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\""}
+{"text": "This short paper outlines the computer simulation using real data of a decoupled control system for a desalination unit. The control strategy incorporated a perfect decoupled controller for the control of the fresh water flow and conductivity. The model was estimated using real data and empirical tools instead of mass balances. The success is demonstrated in the reduction of wide fluctuations in the variables of the process and decreasing of the sensibility to the changes of pressure and/or pH and allows predicting problems of quality of water and waste of energy in the future."}
+{"text": "The records of women were traced through the National Health Service Central Register and, by January 1975, 378 (53%) were found to have died. Expected numbers of deaths from all causes, all cancers and from some specific cancers were calculated assuming the women to have the same mortality rates as the general population of England and Wales. The total number of deaths (378) was close to the number expected (366-8) but there was a slight excess of deaths from cancer (89 against 76.5 expected). Of the individual sites examined only cancer of the cervix showed a statistically significant excess . This finding is similar to those reported in two other studies of the wives of men with cancer of the penis. On the basis of these studies it is suggested that some cases of cancer of the cervix and cancer of the penis may have a common aetiology. Other epidemiological characteristics of the two diseases do not show a marked similarity."}
+{"text": "The fact that the contemporary science of psychiatry, and indeed mental health, is largely based on western concepts and practice is obvious and well recognized. The process of dissemination of knowledge and expertise from the First World to the Third World, or from the West to the East occurred as part of the larger process of global scientific discourse. The earliest challenge to the practice of the western model of psychiatry arose from South Asia, particularly India, initially on the issue of the practice of psychotherapy,1The impact of the colonial past had not only been seminal in the development of mental health services and training but also continued in research endeavours. The centrality of the First World remained constant, and comparisons were made from each country with specific countries in North America and Europe. It was, and continues to be, a common experience that practitioners or academicians would be extremely well versed with the details of mental health service delivery systems, training methods or research findings or from a few select countries in the West but know precious little about the same in their own or neighbouring countries. Part of the phenomenon was due to the manner in which various information systems were organized before the Internet came into being. Economic trends and sociocultural patterns also ensured that the interaction among professionals and teams occurred with the central reference point of the First World. If at all the countries in the developing world looked at each other, it was through the eyes of the western world.Handbook of psychiatry: A South Asian perspective: \u2018The task for all of us is to help out patients and their carers best as we can, whoever they are. We can only do so properly if we forget our political differences and learn from each other.\u20196The opportunity to learn from one's own neighbours, share experiences to examine similarities and differences, and explore the potential for regional cooperation and collaboration has been realized only very recently. The shared heritage and history, alongside the common social and cultural systems make such efforts easy and, at the same time, the political differences and the colonial mindset render them difficult. As Mike Shooter, President of the Royal College of Psychiatrists concluded while writing the Foreword for a commendable initial effort\u2014The ability and the willingness to overlook political differences and other mutual biases has been helped by the experience of the South Asian diaspora across the globe, particularly in the countries of the First World. Professionals from neighbouring countries recognized and valued more easily the similarity of mental health perspectives in their personal and professional experiences in the alien world than it would have been possible in their own settings. This realization and the consequent action occurred more readily for psychiatrists and mental health professionals in comparison with their colleagues in other medical specialties, or even other fields of science. The initiative and contribution of some individuals and groups of the South Asian diaspora synchronized with the increasing perception among professionals in the countries of the region that there is much to learn from each other. The benefits of regional cooperation are beginning to be explored through small group interactions as well as large conferences and meetings. The dangers of being focused on the task of organization of large conferences and/or building structures of professional associations are much too real to be ignored. Professional organizations and other such structures at regional levels as well as meetings and conferences have to serve the larger purpose of active cooperation and collaboration. Exchange visits including fellowships, joint exercises in clinical and community settings, training opportunities, multisite research projects, collective scientific publications are some examples of the activities of a meaningful nature, which should be considered.The very reasons for which the field of psychiatry and mental health have had the advantage of early initiative continue to guide future directions. The possible accusations of individual promotion or \u2018scientific tourism\u2019 will merit serious attention. The multiplicity of organizations that have emerged with their focus on regional cooperation is striking. It has to be seriously considered as to what the expected benefits of regional cooperation are, and for whom. The direct benefit of regional cooperation to persons with mental illness and their families through more appropriate mental health service planning,10The South Asian Region has the potential for developing a meaningful and effective model of regional cooperation and collaboration owing to the already existing mental health services, the professional expertise in the region and among the diaspora, the global economic trends in favour of the Asian region, and positive contribution to global mental health, which is based on traditional wisdom, community systems and spiritual depth. The spirit of regional cooperation has sometimes tended to remain elitist, without the large body of professionals being involved in the activities of cooperation, or the benefits reaching the end-users of mental health services.The globalization sweeping the world in the early part of the twentieth century has helped the process of regional cooperation in many ways. It also poses challenges and opportunities as noted by Okasha: \u2018In psychiatry, the most important aspect of globalization is delivering mental health services in an equitable pattern, providing equal treatment and establishing equal outcome to our patient population, no matter which part of the world they come from. To achieve globalization of mental health services, we need more studies on the psychological variables affecting mental illness, the provision of a better structure for psychosocial intervention for both developing and developed countries, and a more equitable distribution of world resources.\u201911The contribution of regional cooperation and collaboration in global advocacy for appropriate emphasis on mental health is important for the overall health status and for the development of human race.12The old maxim \u2018Think globally, and act locally\u2019 needs to be modified to \u2018Think globally, collaborate regionally and act locally\u2019 by psychiatrists and mental health professionals all over the world and particularly those in South Asia for the exciting possibilities of contributing to the global mental health challenge and beyond. The opportunities bring commensurate challenges, as they often do, and it is for psychiatrists and mental health professionals in the region, as well as the diaspora, to meet the challenges and fructify the opportunities through collective effort."}
+{"text": "Mahmoud Keilani\u2019 passing. He was one of the leading anesthetists in Jordan and a great promoter for the cause of Arab anesthetists and for cooperation between Arab countries. He was one of the founders of the Arab Federation of Anesthetists. He served as its Secretary for many years, and then became the Vice President. He was Head of the Jordanian Council for Anesthesia & ICU and the President of the Jordanian Society of Anesthesia several times. His death is a great loss to the profession. He will be well remembered as one of the five who conducted the task of forming the Jordanian Board of Anesthesia. Moreover, he started his Jordan Journal of Anesthesia.We convey our deep condolences to his family and friends. May Allah bless him and take him in His vast mercy."}
+{"text": "Changes in the structuredness of the cytoplasmic matrix (SCM) of human lymphocytes induced by PHA, CaBP and EF were studied with the technique of fluorescence polarization. The study suggests that the SCM test may offer a new and fast technique for the detection of malignant growth."}
+{"text": "In Poland there are only Regional Bioethical Committees. Unlike most EU countries Poland has no coordinating centre on bioethics for human research. However, the Ministry of Health and Welfare has established a Bioethics Appeals Committee.The functioning of the Bioethical Committees in Poland is regulated in detail by the Regulation of the Ministry of Health and Welfare of 1999. All regulations comply with important guidelines such as: the Helsinki Declaration, The Rules of Good Clinical Practice, EU Directives and legal regulations binding in Poland, mainly the Act of the Medical Doctor Profession and the Dentist Profession, as well as the Act of Pharmaceutical Law.In the framework of the Human Biomonitoring Programme, the application for bioethical evaluation will be submitted to the Bioethical Committee at the Nofer Institute of Occupational Medicine in Lodz.th of August 1997 with latest amendments fulfils EU regulations. The Act also contains detailed provisions regarding the duties of the Inspector General for Data Protection. The paper presents data on the activities of the Bureau of the Inspector General for Personal Data Protection in 2005, 2006 and 2007.The data protection legislation in Poland according to the Act of the Protection of Personal Data of 29 In Poland, a number of bodies responsible for dealing with ethical issues of research have been established. There are twenty Regional Ethics Committees for Animal Research coordinated by the National Ethics Committee for Animal Research.Unlike other countries, Poland does not have a coordinating national centre for Bioethical Committees in human research. There are 54 independent Bioethical Committees. The topics of applications submitted for ethical evaluation to the Bioethical Committees vary according to the research area of the institutions applying.The Bioethical Committees are independent collegial bodies. The aim of their activity is to guarantee the rights, safety and welfare of the participants in medical research. The Committee safeguards the respect and dignity of a human being with higher priority than the scientific aims of the research.th of December 1996 (with later amendments) [th of October 2001 [th of May 1999 [The functioning of Bioethical Committees in Poland is regulated by the Act of the Medical Doctor Profession and the Dentist Profession of 5May 1999 . All regThere are 54 Bioethical Committees in Poland and their activities depend on the main tasks of the institutions. The 24 appointed at the Regional Medical Councils mainly evaluate projects related to a new drugs pre-registration process, the 19 Committees at the Research Medical Institutes approve research projects concerning new therapy, diagnostics and monitoring methods, while those located at Medical Universities cover the whole spectrum: pharmacology, diagnostics, therapy research and pre-registration drug evaluation.The Ministry of Health and Welfare supports the European Human Biomonitoring Programme, and Prof. Marek Jakubowski, the Nofer Institute of Occupational Medicine is the national work package leader. Within the framework of the pilot project, the application for bioethical evaluation will be submitted to the Bioethical Committee at the Nofer Institute of Occupational Medicine in Lodz.The Nofer Institute of Occupational Medicine (NIOM), Lodz, Poland, was founded in 1954. During a period of more than five decades the institute has evolved from a small unit at the Medical University of Lodz into an independent complex research and development centre with activities covering various areas of occupational and environmental health. The activities of the Nofer Institute have gained considerable significance at both national and international levels. During the socioeconomic transition of the Central and Eastern European countries, the Institute has actively participated in the process of restructuring the occupational health services and prepared drafts of new legal acts on Occupational Health Service, chemical safety, social insurance system, etc .The major research areas of the Nofer Institute of Occupational Medicine are:\u2022 occupational medicine, environmental health, public health, occupational hygiene, radiation protection (ionising and non-ionising radiation)\u2022 occupational pathology, prevention of occupational and work-related diseases with special regard to occupational allergy, diagnostics and treatment of acute poisonings\u2022 toxicology, including toxicometry, toxicity assessment of chemicals and methodology of exposure assessment of chemical hazards in work environment\u2022 epidemiology of occupational diseases and other health effects of exposure to physical, chemical and psychosocial hazards\u2022 assessment of health risks from environmental exposure to hazardous agents\u2022 physiology, psychology, sociology of work and ergonomics\u2022 health promotion in the workplace\u2022 management and economics of occupational health services\u2022 health-based criteria of vocational selection and capability for workThe Bioethical Committee at the Nofer Institute of Occupational Medicine is appointed by the Internal Ordinance of the Director of NIOM for the period of three years and performs its functions until a new committee is appointed for the next term. Of its 13 members eight are medical doctors chosen among the researchers at NIOM according to their professional competence and experience in the field of research, while five are experts, independent of NIOM, with academic competence in theology, philosophy, pharmacy, law and health care service.The decisions of the Committee concerning expressing opinion about the research projects are taken in the form of the resolution made by a secret ballot and only the votes for (a yes) or against (a no) the project can be approved .The major topics of the applications submitted for ethical evaluation within the Bioethical Committees at NIOM are: a) development of new diagnostic methods for occupational diseases, b) development and validation of new biomarkers of exposure to chemicals both in the occupational setting and under experimental conditions (human volunteer studies), c) validation of usefulness of some biomarkers of effect , d) assessment of health risks from environmental exposure to hazardous agents.Some examples of applications recently submitted to the Bioethical Committee at NIOM are:\"Night-shift work melatonin metabolism and breast cancer risk factors in nurses\", \"Dietary exposure to PAHs and DNA damage\", \"Usefulness of molecular biology techniques for oxidative stress assessment in breast cancer patients\", Environmental exposure assessment of populations with different level of Methyl mercury intake\".The table on the Ethics Committees in Poland developed by ESBIO is presented in Additional file th of August 1997 (with later amendments) [Provisions for regulating personal data processing were introduced in Polish legislation by the Act of Personal Data Protection of 29ndments) . This AcAccording to article 12 of the Act the duties of the Inspector General are: 1) to ensure the compliance of data processing with the provisions of the act of protection of personal data; 2) to issue administrative decisions and consider complaints with respect to the enforcement of the regulations on the protection of personal data; 3) to maintain the register of data filing systems and provide information of the registered data filing systems; 4) to issue opinions on draft laws and regulations with respect to the protection of personal data; 5) to initiate and undertake activities aimed at more efficient protection of personal data; 6) to participate in the work of international organisations and institutions involved in personal data protection .The Act of Personal Data Protection states that informed consent must always be obtained from the data subject prior to processing of his or her personal data. Sensitive information may be processed upon written consent given by the data subject. Sensitive information is information on racial or ethnic origin, political opinions, religious or philosophical beliefs, religious, political party or trade-union membership, health records, genetic code, addictions or sexual life.The Inspector General for Personal Data Protection participates in the work of international organizations :\u2022 co-operates with international organisations involved in the protection of data,th of October 1995 of the protection of individuals with regard to the processing of personal data and on the free movement of such data,\u2022 participates as an observer in the Working Party established on the basis of Article 29 of the Directive 95/46/EC of the European Parliament and of the Council of 24\u2022 appoints members of the Joint Supervisory Body of Europol (JSB Europol) and their alternates and nominates the candidates for a member of the Appeals Committee and his/her alternate,\u2022 participates as an observer in the meetings of Joint Supervisory Authority of Schengen (JSA Schengen),\u2022 participates as an observer in the meetings of Joint Supervisory Authority Customs (JSA Customs),\u2022 co-operates with other countries' commissioners for data protection.The Table on data protection in Poland developed by ESBIO is presented in Additional file The main tasks of the IGPD are registration of files, inquiries concerning the Act and its interpretation, and complaints. The last months of the year appear more active with most data submitted for registration and inquiries.As shown in a Table The processing of personal data in violation of the Act may result in a ban of processing the data. Moreover, such unlawful processing is a crime, thus the management of the company which is not fulfilling all obligations may be subject to a fine, a limitation of liberty , or imprisonment for up to three years .Polish regulations comply with most of the EU and international rules with respect to ethical issues and personal data protection. Poland does not have a Central Ethics Committee as in other EU member states. There are 54 independent Bioethical Committees in Poland which regards the respect for the dignity of a human being as superior to scientific aims of research.The authors declare that they have no competing interests.Overview: RECs in PolandClick here for fileOverview: Data protection in PolandClick here for file"}
+{"text": "The suggested association between high consumption of beer and an increased risk of death from cancer of the colon and rectum was investigated among blue-collar workers at a Dublin brewery, who consume more than average amounts of beer, usually in the form of stout. A study of their mortality between 1954 and 1973 showed that they had as good an expectation of life as all Dublin males, with no increased risk of death from cancer of the oesophagus, pharynx, liver or of cirrhosis of the liver, accidents or suicide, conditions normally associated with the high consumption of alcohol. They had significantly increased risk of death from cancer of the rectum and also from diabetes mellitus. Twenty per cent of the workers, differentiated by their place of work within the brewery, had a much higher risk of death from cancer of the rectum."}
+{"text": "The Funding section included some information that relates to competing interests. The Competing Interests section should read: Sam Harris, one of the first authors on this study, is also a co-founder and CEO of The Reason Project. The Reason Project is a nonprofit foundation devoted to the spread of scientific thought and secular values in society. This affiliation does not alter the authors' adherence to all PLoS ONE policies on the sharing of data for the purposes of academic, noncommercial research."}
+{"text": "Data on the incidence of cancer of the oesophagus in the Transkei for years 1965-69 are presented, age specific rates for the sexes discussed and the spatial relationship of well-defined regions of the high and low incidence demonstrated."}
+{"text": "The degree of sensitivity varied amongst the normal controls and in-vitro resistance of the lymphocytes in the patients was sometimes found in the absence of in-vivo experience of the drug. Resistance in-vitro tended to be associated with very high total peripheral blood lymphocyte counts but not with the age of the patient. Where the information was available the in-vitro sensitivity test agreed with the results of biochemical estimations of drug resistance and with the clinical responses to the drug. It is suggested that this test may have applications in patient management.The sensitivity of lymphocytes to chlorambucil has been assessed by a simple"}
+{"text": "In developing countries building national health research systems is a movement similar to a political leadership contest. Increasingly, political campaigns to select leaders depend less on ideologies and political messages and more on promising change that will promptly improve the quality of life of the voters. In this process the benefits and risks of every action and statement made by the candidates are carefully assessed.Approaches currently promoted to strengthen health research within ministries of health in developing countries place emphasis on implementing logical steps towards building national health research systems including developing a national health research policy and strategic plan, conducting a situational analysis of research in the country, setting a national health research agenda, establishing research ethics and scientific committees, and building human and institutional capacity for health research management and conduct. Although these processes have successfully improved the standards of health research in some settings, many developing countries struggle to get the process going. One reason is that this approach does not deal with basic questions posed within a ministry of health, namely, \"What is the political benefit of the ministry assuming control of the process?\" and \"What are the political implications for the ministry if another institution spearheads the process?\"Seen from the perspective of non-governmental organizations, academic institutions and donors trying to support the processes of strengthening national health research systems, one of the foremost activities that needs to be undertaken is to analyze the political context of national health research and, on that basis, plan and implement appropriate political health research advocacy initiatives. This includes the development of explicit messages on the political benefits to the leadership in the ministry of health of their role in the conduct, management and dissemination of health research within the country. Civil society organizations, with links to both government and non-governmental organizations, are well placed to play the role of advocates.It is only through broad and active participation of stakeholders that the process of developing effective and sustainable national health research systems will truly become a national movement inspired, led and sustained by ministries of health. The renewed interest in global issues related to research for health emphasizes the value and role of health research in health development ,2. This However, developing countries face several challenges in responding to the need for knowledge to inform decision-making. Collectively, these relate to the setting up of effective national health research systems. Specifically, these include lack of legal and strategic frameworks for research; lack of credible governance structures for research; lack of coordination of research activities; inadequate participation of stakeholders in research, policy and implementation processes; lack of demand for research; low accessibility and use of research findings; and inadequate financial and human capacity ,7. AnothIn developing countries building national research systems can be viewed as a movement similar to a political leadership contest. Increasingly, political campaigns to select leaders depend less on ideologies and more on promising to meet the felt needs of voters . In thisSimilarly, a national health research system  must go beyond a focus on inclusiveness, (semi)-independence, transparency and accountability  , embarked on the process of developing a national health research system with the development of a National Health Research Policy as a first step. The need for a Policy was recognized by the Ministry of Health but the process depended on financial and technical support provided by Development Partners. The aim of the Policy is to coordinate and promote research on health problems of relevance to the health needs of the population. The Ministry appointed a core team to spearhead the process in partnership with a wide range of partners from public, private and nongovernmental sectors.The main partners were the Ministry of Health, academia, civil society organizations, and development partners. Partners undertook tasks based on perception of needs they could meet. The main role played by each partner is summarized below.The Ministry of Health provided leadership for the process. The first draft of the policy was developed within the ministry with technical assistance provided by WHO. The ministry subsequently invited other stakeholders to contribute to the development of the policy, communicated and corresponded with partners, chaired meetings, made presentations on the contents of the health policy, responded to questions, discussed with donors, formally briefed health leadership, and drafted a Cabinet paper on the National Health Research Policy.Civil Society Organizations (CSO) provided support for logistics, acted as the secretariat, conducted background research and situational analyses, edited contents of the policy, and conducted advocacy with health leadership.These were represented by the University of The Gambia, Medical Research Council and Gambia College. They provided technical guidance on models of governance and on the type and range of technical competencies needed to set up a national health research system.The main partners were WHO and UNICEF. They provided financial and technical support as well as perspectives on the rationale and attractiveness of setting up a robust governance structure to coordinate and provide oversight of health research activities in the country.During the development of the National Health Research Policy, a number of related initiatives were undertaken in the period from 2002\u20132008, namely 1) the implementation of a national review of ethics in health research, 2) the establishment of an Ethics Committee at the National Teaching Hospital, and 3) the establishment of a Research & Publications Committee at the University of The Gambia.The second draft of the Policy was completed in 2007. This was followed by advocacy efforts undertaken by the relevant technical unit in the Ministry and CSO representatives. The technical unit formally submitted the draft policy document and briefed the upper hierarchy of the Ministry. The advocacy undertaken by CSO representatives concentrated on several subjects: raising awareness on the importance of effective coordination of research activities by streamlining governance structures; extending scientific scrutiny to operational research activities; and the uniqueness within the context of the country of setting up a single national governance structure to coordinate research activities.Despite advocacy efforts, however, and the inclusive consultative process initiated and coordinated by the relevant technical unit of the Ministry, the process of submitting the National Health Research Policy for Cabinet approval stalled. This was due to perceived unspoken concerns that ownership of the national health research system may end up outside the public sector; concerns originating from perceived imbalances in research capacity between the public sector and the more highly capacitized non-government research institutions.For this reason the focus of advocacy efforts changed to emphasize how public sector leadership of the proposed governance structure can assure broad ownership of the national health research system.The experiences in this process have generated valuable lessons that can contribute to the on-going debate on the political dimension of how to strengthen national health research systems in low income countries.1. In retrospect, the assumption that an appreciation of the benefits of the Policy would be shared by all interest groups within the Ministry of Health was shortsighted. All parties were clear on the potential technical benefits of developing a National Health Research Policy as a first step towards strengthening the national health research system in The Gambia. These included setting the stage for developing research priorities based on real needs of the health sector, improving accessibility of data/information for decision making and the use of data for resource mobilization. What was less apparent was the perspective of the upper hierarchy in the Ministry for whom questions of power related to ownership and control of health research were foremost.political interests of promoting a national health research system in The Gambia, and presumably in other developing countries, include:The \u2022 Ensuring that research is internally driven, owned by the country and focused on national priorities\u2022 Ensuring that research can be used to identify health problems and service delivery bottlenecks of immediate concern to the country.\u2022 Ensuring that research feeds into policy and practice to protect and improve health of the population in the context of national development.2. In Ministries of Health where the political and technical leadership differ in their perspectives on health research both technical and political benefits have to be clear. Understanding these perspectives by gathering views and opinions on technical and political perspectives on health research is necessary for fostering broad participation and ownership of the process of developing health research policies and systems.3. Leadership in the Ministry of Health is critical for the development of health research policies and systems. Such processes must be spearheaded by dedicated high-level authorities who acknowledge the value of a national health research system and who are prepared to take advantage of emerging opportunities  to set it up. These processes require designated and long-term financial and technical resources to prevent untimely interruptions or termination. Commitments made in Declarations on Health Research also contribute to sustaining interest in developing policies and systems.4. For government to support and facilitate the establishment of a robust national health research policy and system, deep-seated but often unexpressed concerns about ownership and control of the research process need to be identified and addressed.Key concerns relate to:\u2022 The need for strengthened national regulation around ethical approval and conduct of research\u2022 The need to channel research funds into research aiming at strengthening the health system\u2022 The need to identify ways of using research findings, including intellectual property, to the direct benefit of the country5. Resistance to a health research policy or reluctance to support it is not necessarily a negative sign but may be an indication of government's commitment to ensuring that the policy is one it can \"buy in to\". Supporting the policy without critical reflection and comment by the health leadership may be indicative of disinterestedness that would ultimately undermine adherence to the policy, effectiveness of a health research system and the use of research findings for policy change and action.6. In The Gambia, the felt need is for research to improve health and health systems. In such a situation, the importance of other relevant ministries such as finance, higher education, environment and science and technology may be overlooked. On one hand, the Ministry of Health may not immediately see the value of engaging the other ministries. On the other hand, the other ministries may see health research as the sole business of the health ministry. The lack of engagement may be, in reality, one of the consequences of the underlying dispositions about ownership and control of health research.7. Civil Society Organizations (CSOs) engaged in health research can play multiple complementary roles in the process of developing health research policies and systems . They haResearch priorities emanating from this case study are as follows:\u2022 What factors promote ownership of national health research systems by governments in low-income countries including those related to governance, leadership and stewardship of the research process and organization and governance of the research system?\u2022 How can the concerns of the political leadership over the governance of health research be identified early and systematically?\u2022 How can the political dimensions of health research in developing countries be used to develop advocacy strategies to engage the political leadership?\u2022 What can be done to promote the adoption of best practices and known interventions that improve the effectiveness of processes that have been used to set up national health research systems?The following policy recommendations are made within the context of strengthening government's ownership and control of the national research process.1. In the process of setting up a national health research system, policy makers in the health ministry and related ministries such as the Ministry of Finance, Higher Education and Science and Technology should be consulted early to gather their perspectives on health research and encourage their participation in the process.2. The health ministry should have a leadership role within the proposed governance structure set up to oversee health research activities to foster shared/broad ownership of the research process.3. Advocacy efforts on both technical and political benefits of a health research policy should be directed at policy makers when setting up a national health research system.The research issues and policy implications identified in this paper provide an important contribution to current global efforts to support active involvement of national governments in health research activities. The experience described points to the importance of understanding perceptions and processes that go beyond the logical paradigm currently promoted for the establishments of health research systems within countries.The key challenge is to develop systematic mechanisms that will reveal the innermost feelings, pre-conceived notions and values of all stakeholders about health research and the proposed health research system. Such feelings, notions and values are deep-rooted and subconscious but will determine behaviour and involvement in the research system. In political campaigns, good polling is used in an attempt to characterize the sacrosanct values that voters attach to specific issues ,12. The To ensure there are no surprises during the development and implementation of national health research systems (election day), we need to develop and deploy approaches that address the \"unsaid\".The authors declare that they have no competing interests.AP conceived the paper and wrote the first draft. SEA and PB contributed to drafting the manuscript. All authors participated in the policy development process."}
+{"text": "The relationship between melanoma incidence and latitude was investigated in North American and Europe, using the data collected by 43 population-based cancer registries. In North America melanoma incidence increased with decreasing latitude, supporting the role of UV light in the induction of melanoma. Within England the data from the National Cancer Registration scheme also showed that trend of decreased frequency of melanoma with decreasing latitude. In contrast, across Europe the trend was in the opposite direction, of increasing melanoma incidence with increasing latitude. It is suggested that across Europe there is a range of skin colour from dark in the south to light in the north, which gives rise to a range of susceptibility to the induction of melanoma by UV. The effect of this susceptibility must be large enough to overwhelm the opposing effect of decreased UV intensity at higher latitudes, and this emphasizes the dangers of excessive solar exposure to fair-skinned individuals. The populations of England may be a sufficiently random mix of skin colour, owing to repeated invasions, for the effect of UV intensity to be observed."}
+{"text": "Endogamous groups in Western India have been known to have a wide degree of genetic diversity. Analysis of the data available on some of the endogamous groups belonging to two main communities attending the Tata Memorial Hospital, Bombay, viz. Hindus from Maharashtra, and Hindus from Gujarat show that one of the endogamous groups, the Maharashtrian Brahmin has a significantly different pattern of cancer site distribution compared to the other groups studied. Maharashtrian Brahmins have a low relative frequency of cancer of the oral cavity and high relative frequencies of cancer of the oropharynx and cancer of the oesophagus. The tobacco chewing habit pattern seems to have a bearing on the proportion of cancer of the oral cavity observed in the groups studied. However, in the case of cancer of the oropharynx and cancer of the oesophagus, factors besides smoking and chewing habits seem to be playing a role. A further study is indicated to clarify the points raised by the study."}
+{"text": "The modelling of the parameters that influence the continuous evaporation of an alcoholic extract was considered using Doehlert matrices. The work was performed with a wiped falling film evaporator that allowed us to study the influence of the pressure, temperature, feed flow and dry matter of the feed solution on the dry matter contents of the resulting concentrate, and the productivity of the process. The Doehlert shells were used to model the influential parameters. The pattern obtained from the experimental results was checked allowing for some dysfunction in the unit. The evaporator was modified and a new model applied; the experimental results were then in agreement with the equations. The model was finally determined and successfully checked in order to obtain an 8% dry matter concentrate with the best productivity; the results fit in with the industrial constraints of subsequent processes."}
+{"text": "This review traces the development of our understanding of the anatomy and physiological properties of the two systems responsible for the drainage of cerebrospinal fluid (CSF) into the systemic circulation. The roles of the cranial and spinal arachnoid villi (AV) and the lymphatic outflow systems are evaluated as to the dominance of one over the other in various species and degree of animal maturation. The functional capabilities of the total CSF drainage system are presented, with evidence that the duality of the system is supported by the changes in fluid outflow dynamics in human and sub-human primates in hydrocephalus. The review also reconciles the relative importance and alterations of each of the outflow systems in a variety of clinical pathological conditions. The functional anatomy of the structures responsible for the return of cerebrospinal fluid (CSF) to the general circulation is based on somewhat conflicting evidence as to their location, anatomical features, and functional capabilities. The dual outflow systems for the egress of CSF from the intracranial CSF compartment control the balance between CSF production and drainage that ultimately impacts the constancy of the cerebral environment. This basic information has clinical implications as to the understanding of the basis and clinical consequences of derangements of the CSF outflow systems. Our present understanding of the two major functional CSF drainage systems evolved separately with recognition of the AV route occurring well in advance of our understanding of the importance of the lymphatic outflow pathway.th and 17th century. The detailed dissection of Pacchioni in 1705 revealed for the first time their relationship to the sagittal sinus, which suggested to him a secretory role for these structures. Luschka in the later part of the 19th century again noted the arachnoid structures penetrating the lacuna of the sagittal sinus, which suggested a special function for these arachnoidal projections. He also appreciated that the arachnoid granulations represented enlargement of the normal villi of the arachnoid . The response of the CSF system to elevated rates of CSF formation (over production) has been studied in a patient with hydrocephalus associated with a choroid plexus papilloma by Eisenberg et al , using a0 ml/min .The evidence to date supports the importance of both the cranial arachnoid villi (AV) and lymphatic drainage systems in the egress of CSF from the subarachnoid space. The spinal AV have a lesser but important role especially when there is failure of the primary systems. The anatomy of both systems supports the view that both act as an open unidirectional pathway between the subarachnoid CSF and the vascular circulatory system. The lymphatic outflow system is primarily by way of the olfactory nerve perineural space that traverses the cribiform plate. Other cranial nerves have been implicated but there is little evidence to support an important role in CSF drainage. The cranial arachnoid system appears to allow CSF movement via both intracellular vacuoles and intercellular clefts. In primates they are primarily located along the dura of the superior sagittal sinus near the entrance of the parietal occipital vein, while in lower animals along the transverse sinus near the confluence of the sinuses. The lymphatic system has been shown to develop earlier than that of the AV and therefore appear to be a dominant CSF outflow route in the late fetal and early neonatal period. There is convincing evidence that the AV system loses it efficiency with age, which can influence the total turnover rate of the CSF with possible neurodegenerative consequences. The question of whether the obstruction of one of the systems can alone lead to hydrocephalus is still an open question as little convincing evidence is available that separates the status of the individual components in a clinical pathological settingThe global CSF drainage system in primates becomes operative at about 50 to 70 mm CSF pressure and normally flows out of the subarachnoid system at a differential pressure gradient of 3 to 4 mm Hg. The normal flow rate does vary with age but the average is ca. 0.35 ml/min. The maximum capacity of the global drainage system appears to be ca. 1.0 ml/min above which fluid accumulates in the ventricular system under increasing pressure. It is not possible to determine in primates the percentage of total CSF transport due to the lymphatic and AV outflow systems although it has been observed in humans that there is both a high and low pressure outflow system. It maybe reasonable to assume, based on the sheep studies, that the olfactory perineural lymphatic system is the lower pressure system. There is no experimental data to state with certainty the proportion of total CSF drainage due to either system at resting CSF pressure in primates.The authors declare that they have no competing interests.The sole author Michael Pollay is entirely responsible for the content of the manuscript."}
+{"text": "The sensory innervation of the hand is usually unvarying and anomalies in this area are uncommon.We report the case of a rare ulnar nerve branch called a Kaplan anastomosis, which anastomosed the dorsal cutaneous branch with the ulnar nerve prior to its bifurcation into the superficial and deep ramus.Many authors have reported unusual ulnar nerve branches and knowledge of these anatomical variations is important for the interpretation of pain and sensory loss in the area sustained during injuries or surgical procedures. Our finding is the fourth case of a Kaplan anastomosis to be described in the literature. Knowing that there is a nerve variation in the ulnar area of the hand is important and could explain sensory loss or pain in patients following surgical procedures or trauma. Ulnar nerve variations are consistently located in the origin or course of the distal branches. The communicating branches between the ulnar and median nerve have been described mostly in the hand and arm. A communicating branch of the dorsal and superficial ramus of the ulnar nerve, known as a Kaplan anastomosis, is rare and this is the fourth case to be described in the literature.We dissected an upper limb of a 76-year-old male cadaver, for educational purposes. First, we exposed and then removed the fascia of the forearm and palm. The ulnar nerve and its dorsal ramus were exposed after reflecting the flexor carpi ulnaris tendon medially, by removing the flexor retinaculum and transecting the roof of Guyon's canal. The ulnar artery was removed in order to obtain a better view of the course of the ulnar nerve in this region. After careful dissection in the wrist area, we found a thin nerve branch, originating from the dorsal ulnar nerve branch approximately 3 cm proximal to the ulnar styloid process. This nerve branch, called Kaplan anastomosis, was parallel to the ulnar nerve. This nerve branch gave off many thin branches along its course for the synovial membrane of the joint, the abductor of the fifth finger and the skin of the area. The nerve branch then passed through Guyon's canal close to the pisiform bone and finally merged with the trunk of the ulnar nerve just before its division into the superficial and deep rami Figures  and 2.The normal course of the ulnar nerve in the forearm is between the flexor carpi ulnaris and the flexor digitorum profundus. The dorsal branch, which is responsible for the sensory innervation of the medial half of the hand and half of the digits, arises approximately 5 cm proximally to the wrist. In the hand, the ulnar nerve enters Guyon's canal underneath the superficial part of the flexor retinaculum and is divided into a superficial (sensory) and deep (motor) branch .Anomalies of the sensory innervation of the hand are uncommon . In 1963Hoogbergen and Kauer  also fouOur case differs from previous reported cases of Kaplan anastomoses in that the nerve is united with the trunk of the ulnar nerve just before its bifurcation into the superficial and deep ramus. Naturally we must distinguish between Kaplan anastomoses and dorsal cutaneous branch variations or ulnar-median nerve communicating branches. Paul et al  reportedMany authors have reported sensory communication branches between the ulnar and median nerves in the hand . In 1991Knowing of the existence of the Kaplan anastomosis of the ulnar nerve, which is a rare anatomical variation, is important because this branch can be damaged in cases of pisiform fracture, in surgery of the pisiform bone and flexor carpi ulnaris, in trauma in this area and in conditions which involve Guyon's canal. As Kaplan states, the presence of these anastomoses must be noted when pain or sensory disorders in the pisiform area appear after trauma or surgery . As manyThe author(s) declare that they have no competing interests.GP, CCG and AT found the Kaplan anastomosis during the dissection of the hand. IS and AS were involved in reviewing the literature. PPT was involved in the research on the importance of the finding and its interpretation. GP was also the main author and responsible for final proofreading of the article. All authors read and approved the final manuscript.Written informed consent was obtained from the patient's next-of-kin for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal."}
+{"text": "This was studied at the terminal stages of the S-period. All the cell lines of female origin showed a late replicating chromosome in group XX6-12. In cell lines of male origin one of the chromosomes of group 21-22Y was later replicating than the rest of the members of the group. The DNA replication pattern of the autosomes and the sex chromosomes was similar to that of the cultured human leucocytes. The results of the present study show that the DNA replication pattern of the chromosome in neoplastic cells is basically unchanged despite the changes in the chromosome number and morphology. Therefore the abnormal behaviour of the neoplastic cells cannot be related to the changes in the pattern of the chromosomal DNA replication.The present paper deals with the chromosomal DNA replication pattern in human solid tumour cells"}
+{"text": "Public health, as a field of knowledge, depends on its professionals. Their education and training, therefore, is considered to be an important factor for the quality of health services. In Brazil, the Course of Specialization in Public Health of the National School of Public Health is one of the oldest in the country. The course has existed for over 80 years, during which it has had an eventful history, with modifications in its organization, interruptions in its delivery, threats to its survival and changes in the institutions hosting it, reflecting the wider transformation in Brazilian society and public life over that period.In this article we analyse this course via its history, disciplines, organization and characteristics of the student body.Insights were gained into the advancement of public health in Brazil and the progress of education for professionals in this field was highlighted. The course has formed nearly 2000 specialists in public health.An analysis of the course's history provides valuable lessons for other schools of public health trying to train professionals in developing countries. In 2006 the Course of Specialization in Public Health currently administered by the National School of Public Health of Brazil (ENSP) completed 80 years of existence. During this period, this course has had an eventful history, with modifications in its organization, interruptions in its delivery, threats to its survival and changes in the institutions hosting it.An analysis of the history of the course provides an insight into the development of public health education in Brazil, reflecting the wider transformation in Brazilian society and public life during this period. The records show how external events have impacted this development, in particular the establishment of the National School of Public Health in 1954, which took over the administration of the course. Another important event - with the promulgation of the new Brazilian constitution of 1988 - was the advancement of the health reform movement which culminated in the creation of the Brazilian National Health System (SUS). Other external factors were the changes in government and ensuing reorganizations of public services, in particular those associated with the military revolution of 1964 [In this article we analyse the course via its history, disciplines, organization and characteristics of the student body in order to gain an insight into the development of public health in Brazil and to highlight the progress of education for professionals in this field.The early decades of the twentieth century were a time of increased interest in public health in Brazil. This was due to both the greater realization of the microbial risk of infection and a belief that improved public health was a sign of progress and modernization of the country. Within the Americas, the creation of the Pan-American Sanitary Bureau in 1902 and the Rockefeller Foundation in 1913 gave political, technical and financial support to the burgeoning health reform movements in the New World .It was also during this period that in 1925 the Special Course in Hygiene and Public Health, the forerunner of the present Course for Specialization in Public Health, was created. The Faculty of Medicine of Rio de Janeiro together with the Oswaldo Cruz Institute, situated in the same city, initially administered the course.There is little information available on the initial years of the course. Its creation was a consequence of the sanitary reform movement of 1920-23 and the reform of medical education, which occurred in Brazil following a plan elaborated in 1925.Carlos Chagas, the renowned Brazilian research scientist and director of the Oswaldo Cruz Institute wished to collaborate more closely with the Faculty of Medicine. He wanted to bring hygiene and clinical problems related to rural diseases into medical practice, thereby creating a new career for health professionals. At that time his idea was controversial within the medical faculty, as it involved both the creation of the new chair of tropical diseases as well as bringing outside lecturers from the Oswaldo Cruz Institute to teach the new course, the Special Course in Hygiene and Public Health .The Rockefeller Foundation was contacted for assistance with the course. Although there is no record of direct financial assistance, the foundation financed the visit of two professors from the Johns Hopkins School of Hygiene and Public Health to assist with the teaching of the disciplines of epidemiology and hygiene management. This assistance not only helped to strengthen the course but also broadened the curriculum from the original French and German base .In 1930, the DNSP was given a new name, the National Department of Health (DNS), as part of a reorganization of public services. The DNS assumed responsibility for the course, which from 1931 became known as the Course on Hygiene and Public Health. In 1940 and 1941, changes were made to the organization of the course. Barros Barreto , the dirBarros Barreto stressed that the government should give more importance and attention to the formation of specialists of public health in preference to other medical specialties. He believed the students of the Course on Hygiene and Public Health were an important element of action to deal with prevention and combat of disease and ill health. On the other hand he also criticized the lack of time given to, and poor quality of the public health disciplines taught at, the faculties of medicines. As a result of his report, further improvements were made to the organization of the course.An analysis of the evolution in the choice of disciplines administered by the course mirrors the changes that occurred in public health education during this period. The course originally was divided into theoretical and practical classes. In the mornings there were classes in chemistry, nutrition, bacteriology and immunology among other subjects. The afternoons were dedicated exclusively to practical lessons, which included clinical demonstrations and self-study.With the changes that occurred in 1931 the disciplines of the course included the following: health statistics; urban and rural sanitation; epidemiology and prophylaxis of acute contagious diseases; epidemiology and prophylaxis of other transmissible diseases especially rural endemics diseases; leprosy; venereal diseases and cancer; physiology applied to hygiene; food and industrial hygiene; infantile hygiene, hygiene management and organization. The additional disciplines of microbiology and parasitology applied to public health were dispensed for students who were graduates from the official faculties of medicine or who held the diploma of the famous application course of the Oswaldo Cruz Institute.The choice of the disciplines demonstrated the preoccupation of the authorities during this period with promoting cure and with individual care. At this time, health was more concerned with treating the individual rather than preventing disease . The curWith the reforms of the 1940s the disciplines of mental hygiene, nutrition and diagnosis of communicable diseases were also added. Barros Barreto  had critWith the creation of the National School of Public Health, further changes occurred. In 1959, the discipline of sociology as applied to medicine and public health was added. The objective was to approximate the medical activities with the community and to make the students more aware of national problems and changes in the social context. Specifically the course intended to provide solid facts for the sociological analysis of contemporary Brazilian society and to make the health professionals understand better the need to make plans which took into account all the relevant considerations and necessities of the population.With the democratic reforms, which occurred in Brazil during the late 1970s, a change also occurred in the nature of the disciplines of the course. There was a general move away from biology and hygiene and towards administration, planning, management and human resources. Disciplines such as social sciences, group dynamics, ecology, introduction to the theory of knowledge, problems of Brazilian health and biostatistics were prominent. This was also a response to efforts from the Pan-American Health Organization (PAHO) to bridge the gap between academic public health institutions in the continent and the necessities of the public health work force through the Program for Strategic Preparation of Health Personnel (PPREPS/PAHO) and the Program for the Internalization of Actions in Health and Sanitation (PIASS) .These modifications reflected the change in vision of public health education, from a preoccupation with individual health to that of concern about community health. They were also a consequence of the arrival at the National School of Public Health of a group of professors from the university of Campinas, lead by Sergio Arouca, who became one of the leaders of the health reform movement in Brazil and a leading architect of the national health system established by the Brazilian constitution of 1988. These professors brought with them new competencies and ideas as well as contacts with federal funding agencies such as FINEP. Their new vision of public health was reflected in the reformulation of the curriculum .The structure of the course was also changing. In the mid 1980's the disciplines were rearranged into modules, which in turn were replaced by four thematic areas: the study of social sciences as applied to health; epidemiology; environment and public health; and administration and planning of health services. From 2000 the course was based on three pillars: health promotion, health surveillance and health research. The principal themes were public policies, health and society, epidemiology, statistics, demography, and management and planning of health services.The number of candidates for the course, the number of students who passed the selective process and were enrolled and the number of students receiving the diploma are shown in Table Originally, only students with a diploma in medicine could be candidates for the course. The course was destined exclusively for physicians who upon the conclusion of their studies were expected to occupy the function of specialized public health inspectors in the federal offices of the National Department of Health (DNS) or in the state offices.In the 1960s, with the establishment of the National School of Public Health, the course was radically changed. It became a basic course in public health for professionals of different areas such as nurses, engineers, pharmacists and veterinarians, as well as for physicians. A specific program for each professional area was developed within the course.This change in the composition of professionals taking the course also changed the gender balance. Initially, all the physicians participating in the course were male. The first female participated and concluded the course in 1938. During the 1940s a further five women registered for the course. However with the opening of the course to other professions, female participation greatly increased and currently female students are in the majority. During the 15-year period from 1992-2006 (inclusive), 74.5% of the students who completed the course were female.During the 1980s, agreements were signed with the Superintendence of Campaigns (SUCAM) and the Foundation for Special Services in Public Health (FSESP), in order for professionals from the health services to participate in the course. With the municipalization of health services, which were intensified following the promulgation of the new Brazilian constitution of 1988, an increase of applicants were seen from municipal health services, particularly from the state of Rio de Janeiro. During the period 1992-1999, 36.1% of the students who completed the course were from municipal health services, 34.8% came from the state and federal sectors, and the remaining students either came from the private sector or were not employed or were from other countries.Nunes, analyzing these facts, concluded that the increase in candidates could be due to two factors . FirstlyInitially, the selection process was based on written and oral tests and the result was published in the official register . Later, the selection criteria became more organized with written tests in mathematics, chemistry, physics, general biology and haematology as well as an oral test. A board of examiners composed of three professors judged the tests. The final score of the candidate was the result of the average score given by the three professors.In order to register, candidates had to present the following documents: a) proof of identity; b) proof of completion of, or exemption from, military service; c) certification of vaccination against smallpox and typhoid; d) certification of physical and mental health.With the establishment of ENSP, changes to the course were introduced gradually. English was introduced to the selection test and the oral exam eliminated. The selection criteria were also changed with a single test of general knowledge related to each area of the course. The examining board had members from the different areas of health.Currently candidates are selected based on a two-stage process. The first stage consists of a written exam, which is eliminatory. Candidates who pass the first stage are classified after an analysis of their curriculum vitae and an interview.Originally, the duration of the course was twelve months of full-time study starting in January. The teachers and their assistants belonged to the ministry of education and health and were entitled to a special bonus payment. The majority of students received scholarships, with some places reserved for physicians from other states. In 1938 the course was also offered for the first time in Recife in the North East of Brazil.In the 1940s, twelve professors with their assistants ministered the disciplines of the course. The disciplines were divided into four periods and at the end of each period there were written, practical and oral tests. The course was organized with practical and theoretical classes, visits and even excursions. From the content of the disciplines, the preoccupation of the coordinators to provide a broad vision of public health can be observed.The director general of the National Department of Health (DNS) approved the program of the course. The students who obtained the certificate of the course in public health and who wished to take another course in the area of health had the privilege of not needing to participate in a further selection process.Students who failed any discipline could not continue with the course. However, they had a chance to repeat the discipline the following year. If they failed the re-sit exam they were expelled from the course.With the establishment of ENSP, full-time ministration of the disciplines continued, sub-divided into four periods of between 140 to 290 hours of classes. During this time an increase in the number of candidates from other states of Brazil was noted. This was one of the reasons for the creation of the decentralized courses in public health in nearly all the states of Brazil and which were coordinated by ENSP. These courses stimulated the creation of regional nuclei for the formation of human resources in health, some of which have in turn become independent schools of public health.In the mid 1970s, two courses in public health were offered: a basic course destined for professionals working directly with the public; and a specialized course for those who completed the former and wished to become specialists in the area of public health. In 1982, the two courses were combined into a single Course of Specialization in Public Health.th National Health Conference and the creation of the National Health System (SUS) had important effects on the National School of Public health, which went through a process of significant transformation. These transformations reflected on the methodological organization, the content and the candidates of it courses.During the 1980s, a number of key events, including the promulgation of the new constitution and the creation of the New Republic, the 8In order to meet the needs of students who originated from the health services, the course ceased to be offered on a full time basis from 2001. Currently students are only required to attend classes for two days per week. The course provides 490 hours of theoretical class work and students are still required to produce a monograph equivalent to 200 hours work.The Course of Specialization in Public Health has survived for over 80 years. During this period, Masters and doctorate courses in public health have been created at ENSP, as well as medical residencies in this specialty. Other institutions, such as the University of S\u00e3o Paulo and the Federal Universities of Bahia and Rio Grande do Sul, have developed their own prestigious programs of public health education. According to Buss , Brazil In fact the opposite has occurred. The present decade has seen an unprecedented demand for places on this course. Part of this demand can be considered as accompanying the general trend of increasing interest in higher education, and the fact that undergraduate (first degree) courses in public health in Brazil have only recently begun to function.Part of the credit for the continuing popularity of the course, however, has been its ability to adapt to the demands and needs of public health in Brazil. During its 80 years of history, the course has formed nearly 2000 specialists in Public Health, including many who have gone on to occupy important positions in federal and state public health administration.The history of the course provides valuable lessons for other schools of public health trying to train public health professionals in developing countries. The course has changed its focus, from its original aim of training medical physicians for important posts in the public health bureaucracy to preparing a wide range of professionals for future careers in the different fields of public health. The course has also continuously faced the challenge of avoiding the \"divorce between theory and practice\" that has often characterised public health education in North America .Pedagogically, the course has changed from an emphasis on practical training with a focus on biology, to critical thinking with a focus on sociological studies. It has had to straddle the paradox of providing a specialized course for a generalized training while also ensuring that the competencies it is teaching remain valid for the modern public health professional. The course has achieved these aims by constantly changing its organization, redefining the selection criteria of its students and updating the choice of the disciplines it administers.The author declares that she has no competing interests."}
+{"text": "The implementation of a robotic workstation in the clinicallaboratory involves considerations and compromises common to any instrument design and development activity. The trade-off between speed and flexibility not only affects the way the instrument interacts with human operators and other devices , but also places limitations on the adaptation of chemistries to the given instrument. Mechanical optimization for speed and reproducibility places restrictions on the imprecision of consumables. Attempts to adapt a robot to a constrained system may entail compromises that either degrades the theoretically-attainable quality of results, or requires human interaction to compensate for physical or mechanical limitations. The general considerations of function and workflow, programming and support, and reliability place practical limits on the implementation of robotic workstations in the clinical laboratory."}
+{"text": "The following is the introductory presentation to the 1994 ISLARmeeting held in Boston from 16 to 19 October 1994. The Editor is again grateful to the organizer, the Zymark Corporation, for permission to publish the papers in the Managing Laboratory Automation Session read at ISLAR."}
+{"text": "A receptor is a member of the Cys-loop family of transmitter-gated ion channels. GABAA receptors respond to synaptically-released or ambient transmitter with a conformational change, resulting in the opening of the gate that allows movement of small anions through the channel. Under most circumstances, GABAA receptor-mediated signaling leads to hyperpolarization in the mature brain. The normal functioning of the receptor is critical to cellular function, while errors in GABAA receptor activity can systemically manifest as seizures, anxiety disorders and others. The pharmacology of the GABAA receptor is remarkably rich. The receptor is a target for benzodiazepines, steroids, barbiturates, and a number of other classes of compounds, some of which are used clinically as anesthetics, anxiolytics, or anticonvulsants. The actions of the drugs are in many cases dependent on the subunit composition of the GABAA receptor. Thus, understanding how the existing therapeutics act can pave way to new drugs with improved specificity and reduced side effects. This Hot Topic Issue presents an overview of molecular pharmacology of the GABAA receptor focusing on three classes of positive modulators: general anesthetics, benzodiazepines, and neuroactive steroids.The GABAPaul Garcia, Scott Kolesky and Andrew Jenkins provide an introduction to GABAA  receptors, and discuss the actions of major classes of volatile and intravenous anesthetics. The manuscript addresses the relationship between subunit composition of the receptor and modulation, and summarizes the data from work on mutated receptors on the location of the anesthetic binding cavity. Matt Bianchi presents a summary of the actions of benzodiazepines on the GABAA  receptor. The major effect of benzodiazepines is to enhance the affinity of the receptor to the transmitter. The manuscript is aimed at comparing and contrasting the ability of benzodiazepines to modulate currents under conditions resembling synaptic conditions and tonic exposure to GABA. Finally, Gustav Akk and colleagues discuss the current knowledge about kinetic and structural features of GABAA  receptor modulation by potentiating neuroactive steroids. This class of steroids acts by increasing channel open probability through a set of modifications in the channel open and closed time distributions. The review critically evaluates available experimental data discussing the possibility of a single vs. multiple interaction sites mediating the effects of potentiating steroids.A  receptor. The manuscripts focus on several of the numerous positive modulators of the receptor summarizing the present state of knowledge and introducing new evidence and novel viewpoints about the kinetic and structural aspects of modulation. It is hoped that the presented material will provide an impetus for further research in this area.This Hot Topics Issue provides an overview of the rapidly developing field of molecular pharmacology of the GABA"}
+{"text": "The knowledge of the branching pattern of external branch of the superior laryngeal nerve and its relationship with the superior thyroid artery is the key point for identifying the external branch of the superior laryngeal nerve during surgeries of the neck.During routine dissection of the left head and neck region of a 50 years old female cadaver, we observed a variation of the external branch of the superior laryngeal nerve around the superior thyroid artery. The external branch of the superior laryngeal nerve has presented one medial and three lateral branches. The medial branch was running on the surface of the inferior constrictor and pierced it; where as the lateral three branches are located laterally to the superior thyroid artery. The medial two lateral branches were piercing the substance of the thyroid gland, where as the lateral most branch was communicating with the left sympathetic chain.It is very important that surgeons carefully dissect the region of the superior pole of the thyroid gland to expose the abnormal branching pattern of external branch of the superior laryngeal nerve prior to ligation of individual thyroid vessels. The external branch of the superior laryngeal nerve (EBSLN) arises with an internal branch from the superior laryngeal nerve (SLN), which is a branch of the 10th cranial nerve. The EBSLN first descends posterolaterally to the carotid arteries, crosses them, and finally passes to the larynx close to the superior thyroid artery (STA). It lies deep to these vessels. The relationship of EBSLN to the STA and the upper pole of the thyroid gland is the key point for identifying the EBSLN during surgeries of the neck. After giving off some twigs to the pharyngeal plexus and the inferior pharyngeal constrictor, the EBSLN terminates mainly within the cricothyroid muscle . Injury In the present case, we observed a variation in the morphological expression of the EBSLN around the STA. During routine dissection of the left head and neck region in a 50 year old female cadaver of Indian origin at the Department of Anatomy, Kasturba Medical College, we observed a variation of the EBSLN around the STA. The EBSLN has presented one medial and three lateral branches. The medial branch was running on the surface of the inferior constrictor and pierced it; where as the lateral three branches are located laterally to the STA. The medial two lateral branches were piercing the substance of the thyroid gland, where as the lateral most branch was communicating with the left sympathetic chain .Hollinshead has described the SLN as originating from the nodose ganglion, then receiving a branch from the superior cervical sympathetic ganglion before bifurcating into the Internal laryngeal nerve (ILN) and EBSLN, implying a direct connection between the superior cervical sympathetic ganglion and the SLN itself . In thisIt is opined that surgeons carefully dissect the region of the superior pole of the thyroid gland to expose the nerve trunk and its branches prior to ligation of individual thyroid vessels. The identification and exposure of nerve will be challenging when it shows different possible morphologic expressions and patterns like the one described in this case."}
+{"text": "After publication of this work , we noteThe authors declare that they have no competing interests.SKT conceived of the study and participated in its design and coordination. EM performed the cytogenetic studies and participated in its design and coordination. ML and MK participated in the cytogenetic analysis. NK, EE and AW participated in the molecular cytogenetic analysis. AG performed the ultrasonography of the pregnant woman. SO and KA performed the molecular analysis for uniparental disomy. TL was responsible for the molecular cytogenetic studies and participated in the drafting of the manuscript. AM participated in the design and coordination of the study and participated in the drafting of the manuscript. All authors read and approved the final manuscript."}
+{"text": "In view of the concern over the rising incidence of malignant melanoma in many parts of the world, and the suggestion that emigrants of Scottish and Irish descent have a higher incidence of melanoma in North America and Australia, a Scottish Melanoma Group has been formed to study epidemiological, pathological and therapeutic aspects of the tumour. In 1979, 260 histologically proven primary cutaneous malignant melanomas of the skin presented. This represents an incidence of 5.1/10(5) for Scotland as a whole. Studies over the next 5 years will determine whether the incidence of melanoma is rising in Scotland as rapidly as in other parts of the world."}
+{"text": "This paper explores the use of the resources in the National Library of Medicine'sUnified Medical Language System (UMLS) for the construction of a lexicon usefulfor processing texts in the field of molecular biology. A lexicon is constructed fromoverlapping terms in the UMLS SPECIALIST lexicon and the UMLS Metathesaurusto obtain both morphosyntactic and semantic information for terms, and the coverageof a domain corpus is assessed. Over 77% of tokens in the domain corpus are found inthe constructed lexicon, validating the lexicon's coverage of the most frequent termsin the domain and indicating that the constructed lexicon is potentially an importantresource for biological text processing."}
+{"text": "The results of treatment of female breast cancer in the Cambridge area during the period of 1960-71 are presented and compared with an earlier series treated in the period of 1947-50. It is estimated that about 29% of the patients treated in the later period are cured, in the sense that they have a life expectancy similar to that of the normal population, compared with just under 20% in the earlier period, but this improvement is mainly due to an increased proportion of Stage I cases in the latter period. The percentage cured is discussed in relation to the ratio of deaths to registrations in the East Anglian Region and it is suggested that under-registration of deaths from cancer of the breast may occur."}
+{"text": "The correlation between cancer of the breast, colon and stomach dietary factors, and various indicators of standard of living was examined. Cancer of the breast and colon was highly correlated with fat and animal protein."}
+{"text": "Ulnar nerve is a branch of the brachial plexus. In the front of the forearm, normally near the wrist joint, it gives a dorsal cutaneous branch which supplies the skin of the dorsum of the hand.The present case reports a very rare finding, the dorsal branch of the ulnar nerve along with the main nerve trunk originated between the two heads of the flexor carpi ulnaris muscle, after descending along the medial border of the forearm extensor surface, on the dorsal aspect of the wrist it is divided into three branches, one medial and two lateral. The medial most division received a communicating branch from the superficial ramus of the ulnar nerve and continued as the medial proper digital nerve of the little finger. The lateral two divisions became cutaneous on the medial half of the dorsum of the hand along the medial three digits i.e. radial and ulnar side of little, ring and middle finger.The site, extent of injury, variations and the delay in the treatment, significantly influences the outcome of ulnar nerve repair. Thus, an adequate knowledge of all possible variations in the ulnar nerve may be important for clinicians and may help to explain uncommon symptoms. Normally, the ulnar nerve arises from the medial cord of the brachial plexus runs distally through the axilla medial to the axillary artery and continues distally medial to the brachial artery as far as midarm, here it pierces the middle intermuscular septum and appears between the medial epicondyle and olecranon process to enter the forearm between two heads of the flexor carpi ulnaris muscle and descends along the medial side of the front of the forearm. About 5 cm proximal to the wrist it gives of a dorsal branch which is responsible for the sensory innervations to the medial one and a half digit .The variation in the branching pattern of the ulnar nerve in the forearm is very rare and may be important for the diagnosis of unexpected and uncommon clinical conditions. One such very rare variation is \"all ulnar hand\" where both motor and sensory nerve supply of the hand is by the ulnar nerve without any communication with either median or radial nerve . Rarely,The branching pattern of the dorsal ulnar nerve is also important while exploring the orthoscopic portals . The higDuring a routine cadaveric dissection of the forearm a rare variation was encountered on the right side of a 38 year male cadaver in Department of Anatomy, Sikkim-Manipal University, Gangtok, Sikkim. The forearm and palm was exposed and the fascia was carefully removed. After the reflection of the flexor carpi ulnaris medially and removal of the flexor retniaculum, the main trunk of the Ulnar nerve was identified. After its course in the forearm, the ulnar nerve entered the Guyon's canal in the hand underneath the flexor retniaculum and divided into superficial (sensory) and deep (motor) branches. The dorsal branch of ulnar nerve  originated from the ulnar nerve trunk at the level of the elbow near the cubital fossa approximately at the junction of upper one fourth and the lower three fourth Figure . It descAnomalies of the sensory innervations of the hand are uncommon . The knoThe present case revealed a higher origin of the dorsal branch of ulnar nerve in the forearm and its termination by uniting with a communicating branch from the superficial ramus of ulnar nerve and its subsequent continuation as medial proper digital branch of little finger is rare. Bergman and his group  and BozkThis finding is important as in case of any injury to the deep terminal ramus of the ulnar nerve as the extra supply from dorsal branch may spare the muscles in the hypothenar eminence. Knowing the existence of the abnormal communication between the dorsal branch and the superficial terminal branch is very essential, as it may be damaged during surgery, in trauma in these area and in the condition which involve Guyon's canal . It has UN: Ulnar Nerve; DB: Dorsal Bracnh; FCU: Flexor Carpi Ulnaris; FDP: Flexor Digitorum Profundus; MB: Medial Branch; LB: Lateral Branch; HM: Hypothenar Muscles; S: Superficial; D: Deep; CB: Communicating Branch; DN: Digital Nerve.Written informed consent was obtained from the concerned authorities for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.PL found this variation, photographed and did the literature survey, BKP helped in manuscript preparation and KMB prepared the figures and wrote the case report. All authors had gone through the final manuscript and approved it."}
+{"text": "Two funding sources were omitted from the funding statement of this manuscript. The correct funding information statement is: Dr. Linn is supported by a grant of the Faculty of Medicine, Justus Liebig University and the University Medical Center Giessen and Marburg. The funders did not play a role in the study or the preparation of the manuscript."}
+{"text": "An overview of the state-of-the-art in the use of lyophilization for the pretreatment of samples and standards prior to their storage and/or preconcentration is presented. The different analytical applications of this process are dealt with according to the type of material  and matrix involved."}
+{"text": "However, in response to the emergence and spread of resistance to the available antimalarial drugs, there has been a renaissance in the discovery and development of new medicines to control the disease in the last few years. The persistent threat of resistance means that new molecules with novel mechanisms of action are continually required. Furthermore, the recent call for the elimination and eradication of malaria has prompted an extension of the stages of the life cycle of malaria parasites that should be targeted by new molecules. Recent advances in genome-based technologies and"}
+{"text": "This paper provides an in-depth description of the currentapplications of robotics in clinical laboratories. The trends andimpact of the use of robotics in clinical chemistry in the forseeablefuture are also discussed."}
+{"text": "Little change is observed after 2 weeks' feeding with the toxins. The greatest change occurs after 3 weeks' feeding, which results in tissue necrosis and the loss of a large proportion of the tetraploid hepatocyte nuclei. (5) A compensatory proliferation of predominantly diploid hepatocytes takes place in the presence of a continuing supply of either of the carcinogens. This indicates that not only does feeding each carcinogen induce the production of a population of hepatocytes resistant to the cytotoxicity of the inducing agent, but that the population is also resistant to the cytotoxicity of the other carcinogen."}
+{"text": "An increased abnormality of the gastroesophageal valve was associated with all grades of esophagitis and with a low YP. The valve mechanism at the cardia has an important role in determining its competence. YP is possibly a measure of the flap valve component of the gastroesophageal junction.The endoscopic appearance of the gastroesophageal valve, viewed by the retroflexed gastroscope, has been studied in 51 patients with and without reflux esophagitis. Esophagitis was graded according to its severity, and the yield pressure (YP) was measured in all patients to assess the competence of the cardia. There was a close relationship between the YP and the grades of the gastroesophageal valve. YP was significantly lower in patients with endoscopic oesophagitis than in patients with no evidence of reflux esophagitis ("}
+{"text": "The basic types of robot are explained, and the performances andcosts of some commercial examples are given. The potentialadvantages and problems of introducing robots into clinicallaboratories are identified and the specifcation of a suitable robotis developed. None of the commercially available robots meets allaspects of the specificalion, and currently the purchase of a robot isconsidered premature for most clinical laboratories."}
+{"text": "Estimated incidence rates are presented for three human immunodeficiency virus (HIV)-associated cancers  from across the African continent, based on data collected before the HIV epidemic. Mapping of the rates and comparisons with a range of geographical variables indicate completely different distributions for KS and BL but a degree of similarity in the occurrence of Burkitt's lymphoma and other NHLs. Comparisons with rates elsewhere in the world suggest, most notably, that KS was as common in some regions of sub-Saharan Africa as was cancer of the colon in much of Western Europe. Comparison with data from the era of AIDS indicates 20-fold increases in the occurrence of Kaposi's sarcoma in Uganda and Zimbabwe. The highest rates for BL were three to four times the rates for leukaemia at young ages in Western populations, but the general incidence of other NHL was no higher than in the West and very low rates were indicated for much of southern Africa."}
+{"text": "A minimal incidence rate of 2\u00b75% of rumenal cancer of cattle in the Nasampolai valley of Kenya Masailand has been established.Carcinoma of the oesophagus and oesophageal region of the stomach in two free-living giant forest hogs from the same area is reported.The high incidence of the bovine disease is thought to be associated with the abnormal forest grazing of the cattle.The possible aetiology of the disease is discussed."}
+{"text": "PLoS ONE policies on sharing data and materials, as detailed online in the PLoS ONE Author Guidelines. There was an error in the Competing Interests section. The correct competing interest information is as follows: Dr. David Welch is the president of Kintama Research. Kintama Research is an environmental consultancy that designed and deployed large parts of the current array. Their operating costs partly come from the Gordon and Betty Moore Foundation. The Gordon and Betty Moore Foundation was not directly involved in the study design, analysis, or writing of the paper, nor the decision to submit the manuscript for publication. This does not alter the authors' adherence to all the"}
+{"text": "The incidence of cancer among the African workers on the gold mines of South Africa has been studied for the period 1964-68. Considering the degree of selection to which they are subjected, the crude cancer rate was unexpectedly high.The most common cancers were those of the liver, the oesophagus, the respiratory system and the bladder. Geographical and tribal analysis showed that both liver and bladder cancers were predominantly found in Africans from Mozambique, while most of the oesophageal cancer occurred in Xhosas from the Transkei. The highest rate for cancer of the respiratory system was found in Africans from Natal, predominantly Zulu.The findings of this survey confirm those of previous South African surveys. The differences in cancer incidence are linked to both geographical area , and to tribe, which may mean an association with tribal habit and custom. These factors need further investigation."}
+{"text": "The paper considers the stage of spread at the time of operation, the histological type of the tumour, its grade and in particular its mitotic activity, which proved a significant feature"}
+{"text": "The results are presented of the examination of 28 neoplasms from the nervous system for an organ-specific antigenic material demonstrated in glial cells and myelin, using gel diffusion, immunocytotoxicity and immunofluorescence techniques.The antigenic material was demonstrable in benign gliomas and in those of low-grade malignancy, but not in the more malignant gliomas and non-gliomatous neoplasia.The implications of the loss of specific antigenic material with reference to cell structure and function, and some fallacies in the interpretation of the significance of tissue specific antigen in carcinogenesis are discussed."}
+{"text": "Stuart Murray's 'Care and the self: biotechnology, reproduction, and the good life' utilizes Foucault's \"care of the self\" to examine health domains in its title. The present author discusses three important articulations of concern with the Foucauldian concepts of care of the self that are absent in the work of Murray and others: first, the voluntarism and individualism inherent in ideas about care of the self; second, the absence of the interactional and relational; and, third, the perpetuation of the interpretation of Foucault's concept of governmentality, 'the conduct of conduct', as primarily coercive. We findStuart Murray's paper is to be welcomed for his discussion of the potential for a Foucauldian inspired ethics following ideas about 'care of the self'. There is little doubt that a rethinking and reworking of the enlightenment subject in bioethics is necessary. Indeed Murray is not alone in presenting a critique of autonomy ."}
+{"text": "A fluorescent probe has been employed to study the status of a tumour associated protease, guanidinobenzoatase, in frozen sections of human tumours obtained from the head and neck regions. The results indicate that in vivo a naturally occurring inhibitor of guanidinobenzoatase effectively controls the activity of this enzyme on the majority of cells in a tumour mass. This inhibitor can be artificially displaced by formaldehyde treatment of the frozen sections and this treatment reveals the extent of latent enzyme in the section. In the frozen sections it was noticed that at the advancing edges of the tumour mass, the tumour cells possessed uninhibited guanidinobenzoatase, an enzyme known to degrade the link peptide between cells and fibronectin. It was shown that a synthetic inhibitor of guanidinobenzoatase selectively inhibited the guanidinobenzoatase of the tumour cells at the advancing edge of the tumour mass. It is suggested that the guanidinobenzoatase on cells at the leading edge of the tumour mass plays an important role in the invasion of adjacent host tissue. This synthetic inhibitor of guanidinobenzoatase has no inhibitory action on other trypsin-like enzymes and might therefore be of value in limiting the growth of the tumour mass in vivo."}
+{"text": "A brief review is presented of the evidence linking the development of certain types of neoplasms, and of the malignant lymphomas in particular, to chronic immunosuppression in animals and man and to the naturally occurring human immunologic deficiency states. The discussion then focuses on Hodgkin's disease and considers recent evidence concerning the relation between the clinical stage of the disease and its associated defect in cell-mediated immunity. Finally, the prior occurrence of infectious mononucleosis in some cases of Hodgkin's disease is considered in the context of the hypothesis that the neoplastic cells of Hodgkin's disease may evolve from a chronic immunologic reaction, analogous to that of graft-versus-host, stemming from the induction of antigenic alteration in a subpopulation of lymphocytes by certain types of non-neoplastic viral infections."}
+{"text": "The superficial peroneal nerve is a branch of common peroneal nerve. There are reports about the variant course and distribution of this nerve. The sural nerve arises from the tibial nerve in the popliteal fossa. The variations of the above nerves described here are unique and provide significant information to surgeons dissecting lower limb.The present case is about some important anatomic variations observed in left lower limb of approximately 55 - year - old male cadaver. The variations were; high division of superficial peroneal nerve into medial and lateral branches, lateral branch descending in the anterior intermuscular septum in a peroneal tunnel before piercing the deep fascia and variant distribution of sural nerve on the dorsum of the foot. The probable clinical significances of the variation are discussed.Awareness of anatomical variations of superficial peroneal and sural nerves such as those presented here becomes important to avoid injury in real clinical situations. The superficial peroneal nerve begins at the bifurcation of common peroneal nerve behind the head of the fibula. It is at first deep to peroneus longus, and then passes anteroinferiorly between the peroneus longus and peroneus brevis and finally between extensor digitorum longus and peronei to pierce the deep fascia in the distal third of leg, where it divides into medial and lateral branches.The medial branch passes anterior to the ankle and divides into two dorsal digital nerves: one supplies the medial side of the great toe, and the other supplies the adjacent sides of the second and third toes. The smaller lateral branch crosses the front of the ankle traverses the dorsum of the foot laterally. It divides into dorsal digital branches that supply the contiguous sides of the third to fifth toes and the skin of the lateral aspect of the ankle. Both branches, especially the lateral, are at risk during the placement of portal incisions for arthroscopy. Superficial peroneal nerve supplies peroneus longus and brevis, and the skin of the lower part of the front of the leg, the greater part of the dorsum of the foot, and most of the dorsal surfaces of the toes .The variations about the superficial peroneal nerve are the absence of either the lateral cutaneous branch or the medial cutaneous branch, which are seen as 8.6% and 0.8%, respectively. It has been shown that in the absence of the medial cutaneous branch, the saphenous nerve innervates the medial part of the foot, while in the absence of the lateral cutaneous branch, the sural nerve supplies the lateral part of the dorsum of the foot . SometimThe sural nerve arises from the tibial nerve in the popliteal fossa, and descends on the posterior surface of the gastrocnemius to enter the superficial fascia about the middle of the back of the leg. It is then joined by the peroneal communicating nerve and accompanies the small saphenous vein to the lateral side of the foot. It supplies the skin of the lateral side of the dorsum of the foot and the lateral side of the little toe . The repDuring routine dissection classes to medical students, we observed some important anatomic variations in left lower limb of approximately 55 - year - old male cadaver. The variations were; high division of superficial peroneal nerve into medial and lateral branches Figure  and variOn the dorsum of the foot the medial branch divided into two dorsal digital nerves; one was supplying the medial side of the great toe, and the other supplying the adjacent sides of the second and third toes. Some direct branches were seen from the medial branch supplying medial border of the foot, which is normally supplied by saphenous nerve. The lateral branch traversed the dorsum of the foot laterally. It divided into dorsal digital branches that supplied skin of the lateral aspect of the ankle and contiguous sides of the third and fourth toes. The skin over the lateral side of the foot and the sides of fourth and fifth toes were supplied by sural nerve Figure . The preThe anatomy of the superficial peroneal nerve is of critical importance to surgeons performing a variety of procedures in the middle third of the lateral leg. So, a good knowledge of the anatomical relationships and common variations of the superficial peroneal nerve is required to prevent injuries during surgical procedures.The variations of the superficial peroneal nerve are important in fasciotomy, fasciocutaneous flaps, traumatic and atraumatic pain syndromes of the leg, regional anesthesia of the ankle, and in the determination of the surgical procedure to foot and ankle ,13.It has been known that the superficial peroneal nerve and its terminal branches may be iatrogenically damaged at around the knee joint, lower leg, and ankle joint, respectively -16. SupeEntrapment syndrome is an uncommon but easily diagnosed clinical problem related with the superficial peroneal nerve and its branches. Superficial peroneal nerve may divide into its terminal branches before or after piercing the crural fascia, and so the nerve itself or its terminal branches may be compressed when passing through the deep fascia . In suchThe area where the superficial peroneal nerve pierces the deep fascia and becomes superficial was reported as the junction of the middle and lower one-thirds of the leg . The disPercutaneous emplacement of pins or screws, such as those used for external fixing devices, or bolts to block tibial endomedullary nails can cause nerve injuries. Superficial peroneal nerve compressive syndromes have been described where the nerve pierces the superficial fascia of the leg, causing a clinical picture similar to an L5 root disease  . In all Superficial peroneal nerve is usually accompanied by a small artery and vein. So, it may be used as a vascularized graft in peripheral nerve surgery by orthopaedicians. Its motor branches to the peroneal muscles can be used for a neurotization of the anterior tibial muscle in patients with L4 root injuries  . On the The sural nerve is often used as a donor in autogenous nerve grafting in the child as well as in the adult. Biopsy material taken from the sural nerve is of great importance in the diagnosis of neural diseases. Besides, the sural nerve is the most suitable one for use as a nerve graft in surgery. There may be some difficulties to access it surgically due to various formations of the nerve ,24.Knowledge of potential variant anatomy of the superficial peroneal nerve and sural nerve should aid surgeons in locating the nerves as well as avoiding potentially unnecessary complications. Awareness of the unusual variant location of lateral branch of superficial peroneal nerve in the anterior intermuscular septum in the present case will enable the surgeon to find and preserve the nerve during fasciotomy, neurolysis, neuroma resection, or bony and soft tissue reconstruction.Knowledge of anatomical variations of the nerves in the lower limbs provides information to clinicians to avoid injury to them in real clinical situations. Although there are number of variations reported regarding superficial peroneal and sural nerves the case described here is unique and it will be an interesting finding to anatomists and clinicians.Written informed consent was obtained from the subject's relative for publication of this case report.The authors declare that they have no competing interests.VRV did the literature search and wrote the case report and also obtained written consent. SN, ViR and MR conceived the study and helped to draft the manuscript. All authors had gone through the final manuscript and approved it."}
+{"text": "An analysis of data collected during the course of the Oxford Survey of Childhood Cancer has shown that it is possible to recognize different facets of memory bias without systematic checking of individuals' records, and to make use of the biased data. The position of foetal irradiation in the aetiology of childhood cancers has been re-affirmed, but there is no support for the idea that exposure of parental gonads to diagnostic X-rays is conducive to cancer in the next generation."}
+{"text": "Piscirickettsia salmonis is the first of the previously unrecognized rickettsial pathogens of fish to be fully characterized. Since the recognition of P. salmonis in 1989, the impact of rickettsial pathogens in fish has become increasingly apparent. Growing awareness of the emergence of these fastidious intracellular organisms has led to the discovery of rickettsial diseases among diverse species of fish from different geographic locations and aquatic environments. The source, reservoir, and mode of transmission of these agents as well as appropriate methods of disease prevention and control remain to be established."}
+{"text": "There was an error in the Funding section. The correct funding information is as follows: Funding for this work was provided by the Census of Marine Life, the Gordon and Betty Moore Foundation, and the Pacific Salmon Foundation. The Pacific Ocean Shelf Tracking project (POST) acoustic receiver arrays were designed and deployed by Kintama Research Corp. None of the first three organizations were directly involved in the study design, analysis, or writing of the paper, nor the decision to submit the manuscript for publication. This work is a contribution to the Census of Marine Life."}
+{"text": "Median nerve is normally formed by the union of medial and lateral root arising from the medial and the lateral cords of the brachial plexus respectively. However, variations in the formation and its relation with the axillary vessels are not uncommon. Therefore, knowledge of the variations in the nerve formation and course is useful for the clinicians during surgery and for differential diagnosis of uncommon clinical conditions.During the routine dissection in the department of anatomy, Kasturba Medical Collage, Manipal, India, we found unique anatomical variations in the formation and the course of the roots of the median nerve forming the neural loops around the axillary artery and vein.Here we report the detailed description of these variations along with its clinical, embryological relevance and review of literature. The brachial plexus is formed normally by the fusion of the anterior primary rami of C5-8 and T1 spinal nerves and supplies the muscles of the back and the upper limb. The C5 and C6 roots fuse to form the upper trunk, the C7 continues as the middle trunk and the C8 and T1 join to form the lower trunk. Each trunk further divides into anterior and posterior divisions. The anterior divisions of the upper and middle trunks form the lateral cord, the anterior division of the lower trunk continues as the medial cord and the posterior divisions of all three roots form the posterior cord and supply the upper limb. The median nerve is usually formed by two roots, the lateral  and medial  roots arising from the lateral and medial cords respectively. These roots embrace the third part of the axillary artery, and join together anterior or lateral to the axillary artery to form the median nerve -4. The tDuring the routine dissection (36 cadavers) in the department of Anatomy, Kasturba Medical College, Manipal, India, in the right axilla of a 58-year-old South Asian (Indian) male cadaver, the median nerve was formed by the two roots, lateral and medial as normally described. However, the lateral root of the median nerve was arising much earlier than its usual site. The lateral root was arising from the lateral cord, just after the formation of the lateral cord, proximal to pectoralis minor muscle, posterolateral to the axillary artery. Then, fibers of the lateral root  runs along with the medial cord of the brachial plexus winding round the axillary artery from posterolateral to medial side to join the lateral cord again distal to pectoralis major muscle. Thus, forming a nerve loop around axillary artery in posterolateral to anteromedial direction Figure . While jEarlier, Pandey and his group found, an abnormal formation and course of the median nerve in 7% of the cadavers. They found that, the medial root received the communicating branch/branches either from the lateral or posterior cord; both roots of the median nerve were joined on medial side of the axillary artery to form the median nerve. Roots of the median nerve did not join to form the median nerve in the axilla, but, both traveled separately anteromedial to the axillary and brachial arteries . In anotMany variations in the relationship of the axillary artery with the roots of the median nerve have been reported. The lateral root of the median nerve found to cross the axillary artery anteriorly and meets the medial root such that the median nerve lies medial to the third part of axillary artery . Das andThe subclavian and the axillary system of arteries are derived from the seventh cervical intersegmental artery . Hence, The knowledge of the variations of the peripheral nervous system is useful in clinical as well as surgical practice as they may be the cause of nerve palsy syndromes, ischemia because of variable relations of nerves with the surrounding muscles and the vessels. The presence of anatomical variations in the peripheral nerves is used to explain unexpected signs and symptoms useful in medical practice. Owing to more reliance on computer imaging in the diagnostic medicine, variations of the brachial plexus are vulnerable to injury during the routine surgical procedures of the axilla  and the Mn: Median nerve; dLr: Distal part of the lateral root; pLr: Proximal part of the lateral root; Lc: Lateral cord of the brachial plexus; Mr: Medial root: Pm: Pectoralis minor muscle; Aa: Axillary artery; Av: Axillary vein; Mc: Musculocutaneous nerve; Mcd: Medial cord of the brachial plexus; *: Few fibers of the distal part of the lateral root.Written informed consent was obtained from the concerned authorities for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.SG found the variation, KB took photographs and prepared the manuscript and BP- assisted in preparation of manuscript. All authors read and approved the final manuscript."}
+{"text": "In the Methods section, in the fourth paragraph of the subsection \"Statistical Methods,\" the equation was incorrect. Please view a correct version of the equation at :"}
+{"text": "Pelvic inflammatory disease (PID) is a serious public health and reproductive health problem in the United States.An early and accurate diagnosis of PID is extremely important for the effective management of the acute illness and for the prevention of long-term sequelae. The diagnosis of PID is difficult, with considerable numbers of false-positive and  false-negative diagnoses. An abnormal vaginal discharge or evidence of lower genital tract infection is an important and predictive finding that is often underemphasized and overlooked. This paper reviews the clinical  diagnosis and supportive laboratory tests for the diagnosis of PID and outlines an appropriate diagnostic plan for the clinician and the researcher."}
+{"text": "The normal-lymphocyte-transfer test has been advocated as a method of assessing the immuno-competence of lymphocytes from patients with breast and large-bowel cancer. Evidence is presented in this paper that the methodology is subject to many uncontrollable errors, that the reaction is the result of multiple factors, and that the size of the reaction is related to the age of the patient and not to the extent of the malignancy."}
+{"text": "Nickel from these complexes is incorporated intracellularly, the distribution being independent of the nature of the carrier. The cation is associated with all subcellular fractions, the largest amount being bound by the nuclei and the least by the microsomes. About half of the 63Ni2+ incorporated into the nuclei is located in the nucleoli.A study has been made of the uptake of"}
+{"text": "The aim of this study was to investigate the influence of diagnostic throughput on survival outcome for women with cancer of the cervix. We conducted a case note review of 359 women in Lancashire and Greater Manchester diagnosed with cancer of the cervix during 1990, identified from records held by the North Western Regional Cancer Registry. Univariate and multivariate survival analyses were undertaken to investigate the influence on survival of woman, disease and treatment related factors. Following adjustment for woman- and disease-related factors there was no evidence of a statistically significant association between diagnostic throughput and survival. The findings of this study do not support the need for any change in the referral patterns to gynaecologists of women with symptoms suggestive of cancer of the cervix. \u00a9 1999 Cancer Research Campaign"}
+{"text": "Up to about the early 1980s it was perhaps still possible to summarize in a review of a moderatelength the development of the medicinal applications of chelation chemistry and the exploitation ofsuch chemistry in regulating the metal ion concentrations in the body. However, in the last few yearsthere has a great surge in the development of chelation chemistry and its usage in medicine andrelated areas of life sciences research. It is no longer the case that such a review primarilyconcentrates upon the use of chelating agents in removing toxic metals from the body but it mustnow cover the use of chelating agents in the imaging procedures nuclear medicine and  magneticresonance imaging (MRI), the use of chelating agents in unravelling the biochemistry of reactiveoxidative species (ROS) and the control and measurement of intracellular calcium ions.  It is in therecent applications that there have been the greatest developments over the last ten years."}
+{"text": "The most common primary malignant tumor of the bone is osteosarcoma. Primary involvement of the craniofacial bones in osteosarcoma is relatively rare. The mandible and the maxillae are the most commonly affected bones of the head. Here, we report a rare case of de novo high-grade osteogenic sarcoma of the mastoid region of the temporal bone and discuss thediagnostic and therapeutic properties."}
+{"text": "Whilst the plasma CEA levels in pancreatic carcinoma tend to be higher than in pancreatitis, knowledge of the plasma CEA level is of little additional value in the differential diagnosis of malignant and non-malignant pancreatic disease, and contributes little to the clinical management of such disorders."}
+{"text": "Male sex, high age and atrophic gastritis (AG) are risk conditions for gastric carcinoma (GCA). We have studied the magnitude of the sex-bound risk of GCA and whether this risk is an independent risk factor for GCA or whether it is related to the risks that are mediated by age and AG. The observed frequencies of males and females in different age groups, and in presence or absence of AG, among 532 GCA patients  and 259 cases of diffuse (DGCA) type) were compared with the expected frequencies which were calculated by applying the data of age-specific distributions of the sexes and AG in the general population. A significant 1.6-fold overrepresentation of males and 0.6-fold underrepresentation of females were seen in IGCA but not in DGCA. The overrepresentation of the male sex and the underrepresentation of the female sex in IGCA were independent of age of the patient and location of the tumour in the stomach. These phenomena were also independent of AG: the overrepresentation of males and the underrepresentation of females were observed in IGCA patients with normal, non-atrophic mucosa as well as in IGCA patients with AG. We conclude that the sex is an independent risk factor for IGCA, and that the phenomena which lead to overrepresentation of males and underrepresentation of females among IGCA patients  are unrelated to age, AG and location of the tumour in the stomach."}
+{"text": "Antibodies directed against tumour associated antigens provide a means for delivering preferentially cytotoxic radionuclides to the cells of primary and secondary tumours. The factors that influence the effectiveness of the radiation in the tumour compared with its effect on the radiosensitive normal tissues include the specificity of the antibody, the distribution of targeted energy within the tumour and the host's response to the injected foreign antibody. Recently some encouraging results from clinical trials of radioimmunotherapy have been reported in the literature. There is a continual search for more avid and specific antibodies, and the techniques of genetic engineering are being applied to the problem of reducing the antigenicity and mass of the carrier antibody. The improved efficiency of the labelled antibody needs to be supplemented by an identification of those tumours most likely to respond to this form of therapy."}
+{"text": "The histological grading of tumours according to their intrinsic malignancy is very important in the prognosis of breast cancer but within each grade the ultimate prognosis depends mainly on the age of the tumours.We have shown that tumour fibrosis is an indication of this time factor, increasing with the age of the tumour. Within each grade the metastatic ratio is higher and the 5 year and 10 year survival less with the scirrhous than with the non-scirrhous tumours. The establishment of axillary metastases is closely connected with both the degree of malignancy and the time available, the unfavourable effect upon survival being greater in the scirrhous than in the non-scirrhous tumours.Another consequence of the passage of time, as indicated by fibrosis, is the gradual diminution of lymphoid infiltration (LI) which is mostly present in young tumours, especially those of high grades. The favourable effect of LI upon survival is demonstrated in the non-scirrhous tumours of grade III, possibly because of its great intensity, but this influence upon survival is lost as fibrosis increases and the intensity of the reaction diminishes."}
+{"text": "The National Institute for Clinical Excellence (NICE) was established to improve the quality of health care in England and Wales through the provision of guidance on the clinical and cost-effectiveness of health interventions.The treatment of cancer is one of the government's priority areas and a range of guidance products have been developed by the Institute to support implementation of national cancer initiatives. Out of a total of 56, 15 technology appraisals issued in the first 3 years of the Institute's existence are related to the general area of oncology, with another four in preparation. Two service guidance documents on breast and urological cancer have been issued, with six in progress. Clinical guidelines on lung cancer and familial breast cancer have been commissioned and the Department of Health's referral guidance for patients with suspected cancer is being updated.This paper describes how the Institute develops the clinical guidelines component of its guidance portfolio.(I)\u2003to speed up the uptake by the National Health Service (NHS) of interventions that are both clinically and cost effective;(II)\u2003to encourage more equitable access to healthcare (i.e. \u2018reduce the postcode lottery of care\u2019);(III)\u2003to provide better and more rational use of available resources by focusing the provision of health care on the most cost-effective interventions; and(IV)\u2003to encourage the creation of new and innovative technologies.NICE was established as a special Health Authority in April 1999. It has four main aims:The Institute achieves these aims by providing guidance to the NHS on the effectiveness and cost-effectiveness of clinical interventions. This task is achieved by appraising new and existing technologies and developing disease-specific clinical guidelines. In addition, the Institute has responsibility for the four national confidential enquiries and more recently for assessing the safety and efficacy of new interventional procedures  and advising on the safety of borderline substances. The previous work of the Cancer Clinical Outcomes Group on service guidance to support the implementation of the Calman Hine report  and the cancer referral guidance are also now part of the NICE portfolio of guidance (Table 1 shows the Institute's products in the field of cancer care).In its first 3 years, the Institute's main output has been in the technology appraisals programme and this has created considerable interest and some controversy, particularly in the area of oncology. The explicit approach that the Institute has adopted in reaching its decisions has highlighted difficult ethical issues that need to be addressed in seeking to balance the desires of individuals with population health requirements. Details of how the Institute is responding to these challenges is documented elsewhere , the Commission for Health Improvement, the National Clinical Governance Support Team, and more recently the National Patient Safety Agency, have indicated that their role is to support the NHS in addressing the daily challenges of delivering high-quality health care. This is particularly important when expectations and demand frequently exceed what is feasible within current service configurations.The Institute's contribution was first outlined in the white papers, entitled \u2018The new NHS: modern and dependable\u2019 and \u2018A first class service: quality in the new NHS\u2019 ,1998. StIn this context, the Institute considers that a key role is to provide guidance on controversial health issues where lack of clarity has resulted in regional variation in the care provided by the NHS. The guidance produced is expected to be incorporated into local clinical governance mechanisms (including cancer networks) via the use of local guidelines and protocols.NICE produces clinical guidelines . The members provide external validation for the guidelines by overseeing the development process, advising on the commissioning of work and monitoring the quality of the guidelines. These members have a range of backgrounds and knowledge, including guideline expertise, clinical experience, patient/carer involvement and health economics.Six professionally led National Collaborating Centres (NCCs) have been established. A seventh collaborating centre specialising in cancer guidance has recently been commissioned. Each centre is a multidisciplinary collaboration of professionals, user representatives and technical experts.They are expected to have access to a range of skills and abilities, either via an academic unit or by employing appropriate staff. These include clinical networks to support the proposed range of activities, expertise in engaging with patients and patient groups and methodological skills for guideline development. In addition to the NCCs, the Institute has established two support units to undertake guideline methodological research and assist patients to participate actively in the guideline development process.have significant health benefits ;have a significant impact on NHS resources;complement one or more of the Institute's technology appraisals;link with key Government priorities for health; andhelp to resolve unacceptable variation in practice across England and Wales.The Department of Health for England and the Welsh Assembly Government select topics for the Institute's work programme. Topics are selected on the basis of whether a guideline would:Each clinical guideline is developed in a process comprising seven phases: initiation, scoping, elaboration of a work plan, development, validation, publication and dissemination, review and update.The Department of Health and the Welsh Assembly Government formally refer the guidelines work programme to the Institute. Once referred, notification of the programme is given through a press release and via the Institute's web site. A topic is allocated to a National Collaborating Centre, which begins the scoping exercise for the guidelines producing a provisional timetable for the work programme, drawing up timelines and identifying potential stakeholders for each guideline. A provisional timetable and details of the work programme are posted on the Institute's web site.the national patient and carer organisations that represent people whose care is described in the guideline;the national organisations that represent the healthcare professionals who are directly providing the services described in the guideline;the companies or manufacturers of the medicines or devices used in the clinical area covered by the guideline and whose interests are may be significantly affected by the guideline;a number of primary care organisations and acute trusts\u2013these organisations are invited to act as NHS stakeholders for a particular guideline; andthe Department of Health and Welsh Assembly Government.For the purposes of the Institute's clinical guideline development, stakeholders are:The scoping document is then drawn up. It describes the aspects of care that the guideline will cover, the background epidemiology, the population, the healthcare setting, and inclusions and exclusions of interventions and treatments. This goes through a period of external consultation following which the final scope is posted on the Institute's web site.During the scoping phase, there is a meeting with all stakeholder organisations. In addition, the Patient Involvement Unit arranges a meeting for patient/carer stakeholder organisations to describe the opportunities for them to contribute to guideline development (including opportunities to nominate patient/carer representatives to sit on the Guideline Development Group) and to discuss the scope of the guideline and what this might mean to patients and carers.Following agreement of the scope with the Collaborating Centre, the Institute works with the NCC to prepare a detailed work plan. This will follow a standard template and includes information on costs, timelines, methodology and the proposed membership of the Guideline development Group.The Collaborating Centre is responsible for the development of the guideline through the establishment of the Guideline Development Group, with membership capable of considering and interpreting the evidence presented to it and formulating recommendations on appropriate clinical practice.The membership of the Group should reflect the range of clinical disciplines involved in providing care and should include patient/carer representatives. The facilitator/chairman is selected by the NCC, in agreement with the Institute.The key stages in the development of the Institute's guidelines are described in detail in Chapter 3 of the Health Technology Assessment monograph \u2018How to Develop Cost-conscious Guidelines\u2019 . Also, aThe Institute's guidelines are expected to address cost effectiveness as well as clinical effectiveness. There are a number of possible ways in which economic methods can be used in the production of clinical guidelines, such as profiling, modelling, cost\u2013impact assessment, and using literature reviews of economic analyses. The guideline development process incorporates a health economist whose prime role is to argue for full discussion and useful presentation of the value of treatment alternatives.All commissioned guidelines are subject to a period of implementation planning with local health communities .Three versions of the guideline are produced based on the recommendations of the National Collaborating Centre (Table 3). These go through a two-stage consultation process, which offers an opportunity for wide consultation on the drafts. Within this process, stakeholders comment on the draft guideline and the developers respond to all received comments. Following this consultation, the redrafted guideline, and all the comments and responses are considered by a subgroup of the Guidelines Advisory Committee. In response to their advice the final draft of the full guideline, short-form guideline and patient version are prepared by the Collaborating Centre. The Chair of the sub-group signs off the final draft of the full guideline on behalf of the Guidelines Advisory Committee and submits it to the Institute. Following approval, the Institute signs off the final draft of the full guideline and returns the final draft to the Collaborating Centre for publication.The short version guideline and the patient version are published by the Institute. Copies of the full version of the guideline are available from the Collaborating Centre.When the Institute publishes the guideline, a date is given on which the guidance will be reviewed. The length of time between the issue of the guideline and the review date varies depending on the anticipated rate of change in the evidence for the guideline.status quo.This is an ambitious programme. The wide range of its portfolio makes the Institute's guidance programme among the largest in the world. Its sustainability will depend on liaising with many professional and patient organisations within the UK as well as initiating international collaborations. The Institute is looking forward to contributing to a European-wide approach to developing cancer guidelines ("}
+{"text": "The effect of the program was associated with an increase the level of the maximum LOS, and a decrease of the CI level, especially in the experimental group. Hence, the implementation of an innovative ERMP exercise program results in the improvement of the physical capabilities of senior subjects.The objective of this study was to gain a better understanding of the mechanisms underlying falls in the elderly. The results were based on a group of 28 women in a control group (CON) and 16 women in an experimental group (EXP), aged 60\u201370. Participants took part in the six-weeks Elderly Recreation Movement Program (ERMP) with the only difference that the EXP group practiced twice as often as the CON group. The measurement of variations in the index called limits of stability (LOS) was performed by application of Kistler force plate and the coactivation index (CI) was registered by means of sEMG. The results demonstrate the existence of statistically significant differences in terms of the principal outcome of the exercise time in the measurements of LOS (F(1.42) = 10.0,  The aging process is associated with losses in the mechanisms of neural transmission, which results in a decrease of compensatory behaviors applied in the maintenance of postural stability, thus leading to a greater expenditure in terms of cognitive resources . The limThe aging process also brings about a decrease in the control over the body and when they are faced with a need to deal with a task with a greater complexity, seniors need to overcome problems in the integration of information from multiple sensory systems . The oldPostural control is understood as a complex relation between the sensory and motor systems . This inThe issues related to balance can be described in terms of the parameters such as center of pressure (COP) and limits of stability (LOS). COP is defined as point of application of the force exerted by feet on the ground,  and  developed so as to provide seniors with a practice of postural balance exercise in the AP plane on an unstable ground. A hypothesis was adopted that the doubling of the intensity of exercises focusing on balance control will lead to the improvement in terms of the ability of body displacement in the examined subjects, and the co-activation of muscles responsible for control of the ankle will decrease.The research involved a group of 60 women aged 60\u201370 years, belonging to an active senior club actively operating in the provincial town of Opole. Applications for research were preceded by a recruitment program conducted in the environment of seniors in Opole , under the assumption that the participants will include seniors who have not been involved in regular physical activity. The condition for participation in the program was also associated with the lack of health contraindications and the voluntary participation of the senior women. The details of the inclusion and exclusion criteria are summarized below.Women aged 60\u201370 years;Ability to understand instructions and active participation in the tasks ;Capacity to actively participate in physical exercise (Elderly Recreation Movement Program\u2014ERMP);Ability to move independently and lack of injuries to lower limbs;Lack of medical contraindications to participate in physical exercise with moderate intensity;Agreement to participate in the study.Criteria for patient participation in the study:Aphasia;Significant loss of sight or hearing, which makes it impossible to assess cognitive functions;Withdrawal from the study.The criteria adopted as the basis for the rejection of an applicant included:The subjects were divided into two equal groups: control (CON) and experimental (EXP) ones. The decision regarding assigning women to specific groups was random and researchers did not intervene with the decision when the subjects objected to participation in a given group. The fact of assigning subjects to a particular group was not affected in any way by the results gained by them in the initial test. For the reasons independent of the course of the experiment, 28 CON and 16 EXP seniors completed the study . The number of subjects in the experimental group decreased to 16 since only the results of the women who were able to achieve 100% attendance in the exercise program were taken into account. A summary of information regarding the age, height and weight of the subjects is included in Subjects in both groups took part in the rehabilitation exercises with the only difference being that the experimental one took part in the exercises twice weekly for 60 minutes, whereas the control group only once per week with the same duration. Every time, the exercise program was based on a similar schedule comprising a warm-up, core part and a final part focusing on muscular relaxation and relieve of tension. Classes were organized in a room suitably adapted to this type of exercise, equipped with in mirrors, handrails, ladders and other suitable equipment. The program also included equivalent classes on stable and unstable surface as described in The ground reaction forces was recorded with the force platform and the bioelectric activity of the right and left tibialis anterior (TA) and soleus muscles (SOL) was registered and processed by NORAXON sensors  with the procedure followed SENIAM methodology.The subjects in both groups were measured prior to and after the exercise program. The maximum voluntary contraction (MVC) of the examined muscles were performed over a 5 second voluntary contraction and was used as a reference value. The outcome variables were measured in maximal voluntary forward lean with eyes open (LOS) maintained for 10s. The instantaneous center of foot pressure (COP) were calculated from the components of forces of the registered plate response were analyzed in anterior-posterior planes (AP). The registrations of COP were performed by a force plate , with a sampling frequency of 100Hz, test duration: 30s. The electromyographic study applied 16 channel sEMG signals  recorded with the 16 bit resolution and a sampling frequency of 1500 Hz.The higher values of LOS derived from difference of mean 10s before leaning and maintained in maximal forward lean values indicate a more effective postural control . The sEMThe coactivation (CI) of the muscles was calculated using the Falconer and Winter method. The CI was computed separately for the left (CI L) and right (CI R) legs.The indices of the COP and sEMG signals were subjected to the Shapiro-Wilk normality test. The distributions of the analyzed variables did not deviate from normality. Thus the parameters of signals were subjected to ANOVA  with 0.05 significance thresholds. The factors included: time  for the case of analysis of LOS and additionally side (left vs right) for the case of the coactivation index.p = 0.002). The interaction of the variables TIMExGROUP did not indicate statistically significant differences. The results of the analysis of the LOS demonstrate statistically significant differences before and after the series of exercises in both groups  = 6.337, p = 0.069). Both groups demonstrate a decrease in the level of muscle coactivation following the exercise program. The remaining effects do not show statistically significant results. The analysis of the CI parameter does not demonstrate significant differences measured in terms of the principal outcome represented by the duration of the exercise (F(1.42) = 3.501, The research shows the effectiveness of the adapted rehabilitation program in the seniors, whose aim was to contribute to preventing falls. The research conducted earlier on, in which LOS was also applied as an experimental tool demonstrates that it forms a reliable indicator for the analysis of the range of the forward body displacement, which is directly related to the chance of falls ,18. CorrThe results reported in this paper demonstrate a significant improvement in terms of the measured increase of the range of a forward displacement (tilt), which may directly contribute to prevention of falls and greater reliability in terms of the movement patterns performed by seniors in general. A statistically significant improvement in LOS was also recorded by the subjects involved in the program designed by Bulat et al.  followinThe above aspect of the usefulness of LOS measurements and the effectiveness of interventions in the field of stabilography was also recorded by Narita et al. , who appThe next important aspect of maintaining a vertical posture is associated with the adequate level of co-activation of the lower leg muscles. The results of the present study led to improvement of the subjects\u2019 sense of balance and the change in calf muscle activation indicates a transition from the less effective and energy-consuming strategies involving maintenance of balance through simultaneous muscle activation of antagonist muscles in the ankle to a more energy-efficient strategy of the alternate activation of muscles. The studies study by Pereira and Goncalves  as well There are also other reports ,25, in wThe results of the present intervention program aimed at preventing falls demonstrate that the participants\u2019 confidence in their ability to displace the body forward has increased as a result of the exercise practice, and this aspect is known to play an important role in everyday life. Our activities have also confirmed the assumptions that should be met by the exercise program, as recommended by Sherrington et al. . GillespThroughout the duration of the six-week program, the experimental group performed exercise twice as often as the control group. This forms the reason why one of the objectives of this study involves making sure how the duration of the exercise affected the changes in analyzed parameters. On the basis of a study carried out by Sherrington at al. , the minThe present approach involves several aspects that affect the limitations of the results. First of all, we did not measure sEMG of other lower limb muscles because the tasks focused on the ankle joint. Further research would be needed to extend the range of the analyzed joints and muscles. Another, but slightly controversial, limitation could be associated with the static conditions in which the research was conducted; as such conditions represent the actual conditions of everyday life of the elderly only to a limited degree. However, the present study demonstrated that if muscle activation increases so as to match the need to maintain body balance, this increase should be noticeable both in static and dynamic conditions and should be related to the level of body\u2019s ability to keep control of the posture . During The innovative ERMP exercise program forms an effective tool in improving balance in the elderly subjects. The outcome of the present program was represented by an increase of the level of maximum LOS, and a decrease in the CI level particularly in the subjects in the experimental group."}
+{"text": "In the original article, the order of the affiliations was incorrect. The correct order appears above. In addition, the city for affiliation 2 should be Saint-Maurice instead of Paris. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Enzymes with an active center hidden in the middle of the molecule in a tunnel-like cavity constitute an interesting object of analysis due to the highly specialized environment for the course of the catalytic reaction. Identifying the tunnel is a challenge in itself. Moreover, the structural conditioning for the course of the reaction provides information on the diversity of the environment, which must necessarily meet the conditions of high specificity. The use of a fuzzy oil drop model to identify residues constituting the walls of the tunnel located in the center of the protein seems highly justified. The fuzzy oil drop model, which assumes the highest concentration of hydrophobicity in the center of the molecule, in these enzymes shows a significant hydrophobicity deficit resulting from the absence of any residues in the central part of the molecule. Comparison of the expected distribution in consistent with the 3D Gaussian distribution where the observed distribution resulting from the interaction of residues in the protein shows significant differences precisely in the positions of residues located near the center of the molecule. The inside characteristics of the tunnel are the background for the enzymatic reaction. This environment additionally constitutes an external force field, which creates favorable conditions for carrying out the catalytic process. The use of fuzzy oil drop model has been verified using the potato (solanum tuberosum) epoxide hydrolase I. This forms the preliminary basis for testing the fuzzy oil drop model. The data presented here provides an impetus for a large scale analysis of all proteins containing tunnels in enzyme structures available in the Protein Data Bank (PDB). The group of enzymes with the so-called submerged active center is the subject of the analysis due to the unexpected location of the active group around the center of the molecule - so from the point of view of the environment it is the center immersed in the body of the protein. An additional element distinguishing this group of enzymes is the presence of a tunnel - an open space on the surface of which catalytic residues are located -3. In thThe comparison of the expected hydrophobicity distribution - in accordance with the distribution expressed in 3D Gaussian distribution spread over the body of the molecule with the distribution present in the analyzed molecule is a criterion for assessing the degree of similarity of these two distributions.The subject of analysis of the present work is potato (solanum tuberosum) epoxide hydrolase, whose structure is available in the Protein Data Bank  databasThis model has been repeatedly described in other publications ,15. HereThe molecule of this hydrolase is a single-domain globular structure containing a centrally located Beta plate in a parallel / antiparallel system. The molecule also contains 20 sections of helical structure. There are no disulphides in the molecule. The status determined by the RD parameter is 0.545. This means that the whole molecule does not show an ordered hydrophobic nucleus within the meaning of the fuzzy oil drop model. Visualization of these distributions is shown in The residues representing significantly low hydrophobicity level in respect to the expected one are assumed to be localized on the tunnel surface. The profile has sections that express the expected hydrophobic center: 24-48, 51-64, 97-118, 121-137 and 296-309. The graphs also show significantly lower levels of hydrophobicity observed for these sections. In order to search for fragments of the chain with the distribution as expected from the analysis, those residues that show the highest differences were eliminated.In order to identify residues whose status shows a deviation from the expected distribution, the absolute values of Ti and Oi differences were calculated. Elimination of these residues from divergence entropy calculations and counting the status of the set of eliminated residues (divergent status) resulted in a decrease of the RD value for the part without these residues to the level of 0.386, while the residues showing significant differences determined by the value of RD = 0.912.The respective profiles are shown in In The residues shown in The presence of immersed enzymatic centers identified on the basis of the Voronoi diagram  using ge"}
+{"text": "The journal retracts the January 8, 2019 article cited above.Following publication, concerns regarding the integrity of the western blot images were brought to the attention of the Publisher. After an investigation by the Editorial Office and Chief Editors of the journal, image duplication and manipulation was revealed in Figure 6. The authors have failed to provide a satisfactory explanation following several requests. The authors do not agree to the retraction or the notice.The retraction of the article was approved by the Chief Editors of Frontiers in Immunology and the Editor-in-Chief of Frontiers."}
+{"text": "The article presents a new method for determining the distribution of measurement points, which can be used in the case of contact coordinate measurements of curvilinear surfaces of products. The developed method is based on multi-criteria decision analysis. In the case of the new method, the selection of the distribution of measurement points on free-form surfaces is carried out based on the analysis of five different criteria. The selection of the best model of the distribution of measurement points results from the accuracy of coordinate measurements, the time needed to complete measurement tasks, the number of measurement points, the accuracy of the substitute surface representing the measured free-form surface and the area where measurement points are located. The purpose of using the developed method of the distribution of measurement points is to increase the performance of coordinate measurements primarily by increasing the automation of strategy planning of measurements of curvilinear surfaces and improving the accuracy of measurements of free-form surfaces of products. The new method takes into account various aspects of coordinate measurements to determine the final model of the distribution of measurement points on measured surfaces of products, thereby increasing the probability of the proper determination  of the location of measurement points on the surfaces of a measured object. The paper presents an example of the application of the created method, which concerns the selection of the best model of the distribution of measurement points on a selected free-form surface. This example is based on, among others, the results of experimental investigations, which were carried out by using the ACCURA II coordinate measuring machine equipped with the VAST XXT measuring probe and the Calypso measurement software. The results of investigations indicate a significant reduction in time of coordinate measurements of products when using the new method for determining the distribution of measurement points. However, shortening the time of coordinate measurements does not reduce their accuracy. The coordinate measuring technique is widely applied under industrial conditions. Various coordinate measuring systems are presently used by many measurement laboratories and different companies representing various branches of the industry. A coordinate measuring machine (CMM) is still a very popular measuring system. CMMs may work in two main modes , which may be applied because of using different types of measuring probes ,2. The uIn the coordinate measuring technique different measurement strategies may be applied at different stages of coordinate measurements of products. Therefore, the strategy of contact coordinate measurements may include a lot of elements, e.g., applied algorithms of the probe radius correction process , scanninThis article concerns the selection of the most appropriate model of the distribution of measurement points located on a free-form surface. The purpose of the new method of determining the location of measurement points on curvilinear surfaces is to improve the performance of contact coordinate measurements by reducing the time of measurements and increasing their accuracy. The improvement of measurement accuracy is related to determining the correct location of measurement points on measured surfaces of products. Measurement points should be arranged in the places of products characterized by the highest values of form deviations. The assumed distribution of measurement points should enable the measurement of real form deviations of a measured product.The article presents the new method of the distribution of measurement points on curvilinear surfaces of products. The best distribution of measurement points was selected by using the Analytic Hierarchy Process (AHP), which has already been applied in the coordinate measuring technique when e.g., selecting a coordinate measuring machine . The resThe developed method takes into account various aspects of coordinate measurements of products built of curvilinear surfaces, which makes it very universal, and thus it can be used in the case of measurements of products characterized by different geometrical shapes produced by companies from different industries. Curvilinear surfaces are used e.g., in the aviation and automotive industries . The quaThe created method is the extension of the approach to selecting measurement points shown in the work , which pThe selection of the methods of the distribution of measurement points located on curvilinear surfaces is still a current topic in the coordinate metrology. There are many algorithms of determining the distribution of measurement points in the case of measurements conducted by using coordinate measuring systems working in the contact mode. In general, there are two main ways of distributing points. The first one is called the uniform distribution. In the case of the second method, measurement points are distributed non-uniformly. The following paragraphs of this section present the examples of methods of the determination of locations of measurement points on surfaces of measured objects.The method of the distribution of measurement points on curvilinear surfaces of products is presented e.g., in the work by Mingrang et al. . The algThree methods of the distribution of points were analyzed by Lalehpour et al. . The poiElKott et al.  presenteThe paper by ElKott and Veldhuis  and the New strategies of finding the locations of measurement points were also proposed by Rajamohan et al. ,17. TheyThe results of investigations regarding the selection of measurement points in the case of coordinate measurements of a blade were presented by Jiang et al. . Three mThe literature concerning the coordinate measuring technique lacks automated methods for selecting the location of measurement points on measured surfaces of products that could be directly implemented in commercial metrological software cooperating with, e.g., coordinate measuring machines equipped with contact measuring probes. The developed method of defining the distribution of measurement points, which is shown in this paper, can be easily implemented in commercial measurement software. This implementation contributes to increasing the chances of using the new method under industrial conditions.The following sections of the paper concern, e.g., the presentation of the proposed method of the distribution of measurement points, the applied structure of the analytic hierarchy process, the explanation of considered criteria used during the AHP analysis, the results of performed research and the conclusions regarding the selection of the best model of the distribution of measurement points.The proposed method of determining the location of measurement points on free-form surfaces of measured objects is dedicated primarily to coordinate measurements of a series of manufactured products. Its fundamental advantage, which is associated with shortening the time of coordinate measurements, is visible when it is necessary to carry out measurements of the whole series of machined products not differing in terms of their nominal shapes. The length of shortened time results from the number of measured objects. The new method requires the use of the so-called reference model of the distribution of measurement points, which should be used in the case of coordinate measurements of the first object being a part of a series of manufactured products. The created method of the distribution of points consists of three stages. They are presented in the first part of The initial stage of the proposed method for defining the location of measurement points is the coordinate measurement of the first workpiece from a given series of products by using the mentioned reference distribution of measurement points. The reference distribution should include the largest possible number of measurement points, which may lead to the highest possible measurement accuracy. A large number of measurement points increases the chances of identifying real form deviations of a measured object.In the next stage, the so-called modified distributions of measurement points, including the smaller number of points compared to the reference distribution, are created. They are formed based on the reference distribution of measurement points. A smaller number of measurement points, especially in the case of contact coordinate measurements, leads to a reduction in the time of measurements, which may contribute to increasing the efficiency of the entire manufacturing process of a given product. Modified distributions can be created in a random manner by random elimination of measurement points included in the so-called reference distribution. In the second stage, the first object from a given series of manufactured products should also be measured by using the analyzed modified distributions of measurement points.The third stage of the created method of defining the distribution of points concerns performing the AHP analysis based on the adopted criteria. The purpose of implementing the multi-criteria analysis is to choose the best distribution of measurement points from the group of analyzed and modified, in relation to the reference distribution, models of the location of measurement points lying on a measured free-form surface of a product.After conducting the AHP analysis, the rest of objects from analyzed series of products should be measured by means of a selected modified distribution of measurement points, as shown in the second part of The most important stage of the proposed new method of defining the distribution of measurement points on measured curvilinear surfaces of objects is the third one, which assumes the application of the multi-criteria analysis of the considered modified models of the distribution of measurement points located on measured free-form surfaces.form deviations calculated by using the applied model of the distribution of measurement points,number of measurement points belonging to the considered model of the distribution,accuracy of substitute models created based on the measurement points located on a free-form surface,time of contact coordinate measurements,areas of 3D substitute models representing the models of the distribution of measurement points.The goal of the AHP analysis was the selection of the best model of the distribution of measurement points lying on a free-form surface. To select the most appropriate distribution of measurement points the following criteria were used:The general view of the AHP hierarchical structure, which was used during performed investigations for the multi-criteria prioritization process in order to select the best model of the distribution of measurement points located on a free-form surface of a measured object, is presented in The first criterion used during the AHP analysis is associated with the form deviations calculated by using the considered models of the distribution of measurement points located on a free-form surface. The form deviations obtained by means of the analyzed models of the distribution were compared to the reference form deviation measured with the use of a coordinate measuring machine and the reference distribution of points which includes the largest number of uniformly distributed measurement points. The first considered criterion helps the user of a coordinate measuring system to assess whether the applied distribution of measurement points can detect the highest values of form deviations of measured curvilinear surfaces of objects. In the case of the first criterion, the form deviation measured by using the best model of the distribution should be as close as possible to the reference deviation.The second criterion applied during the prioritization process of the models of the distribution of measurement points is related to the time of coordinate measurements performed by using CMMs. The time of measurements in the case of the single-point probing mode depends on the numbers of measurement points and scanning lines, along which measurement points are located, used to measure a free-form surface. The time of coordinate measurements is one of the factors with the influence on the efficiency of measurements. The users of coordinate measuring machines must decide how to conduct measurements to obtain the highest possible accuracy of coordinate measurements in relatively short time. The time of measurements is the part of the entire time of the production process of a product. Therefore, for the second criterion, the most favorable distribution of points is provided by the model for which the measurement time is the shortest.The next applied criterion is the number of measurement points located on a curvilinear surface of a measured object. The accuracy of contact coordinate measurements is directly connected with the amount of data representing a measured product. A large number of measurement points increases the probability of measuring the highest of existing form deviations characterizing the quality of a measured product. Therefore, the model with the largest number of measurement points is the best one. However, if coordinate measurements are conducted in the single-point probing mode, the number of measurement point cannot be too large in order not to increase the time of coordinate measurements too much.The fourth applied criterion is related to the accuracy of a substitute model of a measured free-form surface. The substitute models are fitted to the groups of measurement points being the parts of the considered models of the distribution of measurement points. The accuracy of the substitute models must be analyzed to check how the considered models of the distribution represent a measured free-form surface taking into consideration the geometrical complexity of curvilinear surfaces. Moreover, substitute models of measured curvilinear surfaces were successfully used by many researchers ,14,15 inThe last of the analyzed criteria is the area of the substitute model representing measurement points distributed on an analyzed curvilinear surface. In the coordinate measuring technique, it is always better to spread measurement points on the largest possible fragments of measured free-form surfaces of an investigated object. This may increase the chances of detecting the highest form deviations of free-form surfaces, which are planned to be measured by using CMMs. For the last criterion, the model of the distribution of measurement points located on the largest possible area of a measured surface is the best one.In the case of the proposed method of defining the distribution of measurement points on free-form surfaces of measured products, the selection of the best model of the distribution is carried out on the basis of the above-mentioned criteria of the AHP analysis. The models of the distribution assume different numbers and positions of points located on measured curvilinear surfaces. To present the possibilities of the method of determining the distribution of measurement points, both simulation and experimental investigations were carried out. Five different models of the distribution were taken into account when conducting the research. They are presented in detail in The conducted numerical and experimental investigations concern three stages of the created method of defining the distribution of measurement points on free-form surfaces of measured products. The analyzed stages are aimed at selecting the best distribution of measurement points among the considered models of the distribution. The best distribution of measurement points should ensure fast and accurate coordinate measurements of analyzed products. The purpose of the research was to verify the possibility of performing coordinate measurements of a series of manufactured products by using a measurement strategy, which includes a smaller number of points compared to the reference distribution of measurement points.The investigations were carried out for the selected free-form surface shown in The best distribution of measurement points located on the selected free-form surface was chosen from the group of five different models of the distribution of measurement points. The models were randomly selected by an operator of a coordinate measuring machine. Moreover, The performed numerical research concerned two criteria of the AHP analysis. The first one was related to the determination of the accuracy of 3D substitute surfaces created for the considered curvilinear surface and the analyzed models of the distribution of measurement points. The second one was associated with the calculation of the areas of generated substitute surfaces. The substitute models of the considered free-form surface were created by using the Zeiss Reverse Engineering software. Moreover, they were prepared by means of the third-degree B-Spline surfaces fitted to measurement points being parts of the considered models of the distribution of points. After creating the substitute models of the analyzed free-form surface, the next step was to calculate their areas, which was done by using the appropriate functions of the CATIA V5-6 software. The calculated surface areas for the individual substitute models, created by means of the mentioned Zeiss Reverse Engineering software, are presented in In the next step, the maximum deviations between the substitute models of the analyzed curvilinear surface and the geometrical model of the surface which was created on the basis of the reference model of the distribution of measurement points containing the largest amount of measurement data were calculated. The relative values of deviations calculated based on the maximum form deviations of the individual substitute models are presented in The results of the numerical investigations were necessary for conducting the third stage of the proposed method of defining the distribution of measurement points, i.e., to perform the AHP analysis aimed at selecting the best distribution of points on the measured curvilinear surface.To conduct the AHP analysis regarding the considered models of the distribution of measurement points the experimental investigations were also conducted. During the experimental research, the values of form deviations and the time of coordinate measurements were registered. The values of the mentioned parameters, similarly to the results of numerical research, were necessary to perform the AHP analysis. The experimental investigations were conducted by using the ACCURA II coordinate measuring machine  equipped with the VAST XXT measuring probe  and the Calypso software. In the first stage of coordinate measurements the reference form deviation was measured by using the reference distribution of measurement points presented in where: L\u2014a measured length, mm; The accuracy parameters of the applied coordinate measuring machine are as follows:The analysis of the results of coordinate measurements was carried out without the best-fit of the measurement results to the nominal data. The measurements were carried out in the scanning mode with the scanning speed of 10 mm/s, the distance between measurement points was 2 mm. The results of experimental studies, in the form of the measured deviations and the times of individual measurements, are presented in Large deviations from the reference model, presented in the second column of The results of experimental research, similarly to the results of the simulation investigations, were used to select the best  measurement strategy.The AHP analysis was performed to select the most appropriate model of the distribution of points when conducting coordinate measurements of the selected free-form surface. At the beginning, the comparisons of the criteria in relation to the goal  by using the nine-point scale were conducted. The pairwise comparisons were carried out by using the scale presented in The consolidated priorities regarding the considered criteria are presented in In the next step, the comparisons of the alternatives with respect to each criterion were made. To compare the alternatives the normalization of the data calculated by using the CATIA V5-6 and Calypso software packages to the range from 1 to 9 was applied. Based on the AHP analysis, the best distribution of measurement points on the considered curvilinear surface, taking into account all analyzed criteria, is represented by the fourth model. Models 1\u20133 and model 5 have subsequent priorities. Hence, model 4 shall be used in practical coordinate measurements of a series of manufactured products. It is also allowed to use the second model of the distribution of measurement points, which achieved the very similar result to the fourth model.The significant profit resulting from the application of the proposed method of defining the distribution of measurement points on free-form surfaces of products is immediately visible for even a small series of measured products . In the case of the created method, the first object from a given series of products should be measured by using a reference distribution of measurement points  and with the use of models of the distribution of measurement points generated by modifying a reference distribution . The measurement conducted by using a reference distribution should identify the existing true value of a deviation of a measured product.Assuming the measurement of the surface, the shape of which is presented in Based on the AHP analysis, which is implemented in the third stage of the proposed method of defining the location of points, the fourth model of the distribution of measurement points should be used in the case of real coordinate measurements of the next nine objects included in the considered series composed of ten products. The application of the fourth model of the distribution of measurement points generates the measurement time for the considered free-form surface of a single product equal to 61 s. Therefore, for the series of ten products, the total time of their coordinate measurements would be 1434 s assuming the application of the proposed method of defining the distribution of measurement points located on surfaces of measured objects. This time is the result of the sum of the total measurement time of the first product  and the sum of the measurement times of the other nine items that are the part of the given series of products and which should be measured by means of the fourth measurement point distribution model .In the case of not using the new method for determining the location of measurement points, all ten items of the given series of products should be measured by using the reference distribution of measurement points, which would generate the total measurement time of all ten products equal to 5140 s. This time is almost four times longer than the total measurement time of coordinate measurements of ten workpieces when using the new method of defining the distribution of measurement points on curvilinear surfaces. The graphical representation of the benefit of using the new method of the distribution is shown in The article presents the new method for determining the location of measurement points on free-form surfaces of measured products. The results of the performed investigations and the analysis carried out by using the AHP method indicate the possibility of a significant reduction in time of coordinate measurements of a series of products when using the new method for determining the distribution of measurement points located on measured free-form surfaces. The time reduction is the result of decreasing the number of measurement points for most products that are the part of a given series of workpieces. Moreover, a smaller number of measurement points does not reduce the accuracy of coordinate measurements, which results from taking into account various criteria of the considered AHP analysis, e.g., \u2018the time of coordinate measurements\u2019 and \u2018the form deviation of a measured surface\u2019, when determining the location of measurement points by using the proposed method.The advantages of the proposed method of the distribution of measurement points on curvilinear surfaces are the increase in the level of automation of defining the position of measurement points and the possibility of implementing the developed method in commercial measurement software, so that it can be used in industry. The example of popular measurement software in which the new method can be relatively easily applied is the Calypso software package. The application of the created method of determining the location of measurement points in the Calypso inspection software is possible by means of its module of parametric programming of coordinate measurements\u2014PCM (parameter coded measurements).The further research should be aimed at testing the proposed method of determining the location of measurement points under real industrial conditions and the implementation of the proposed method in commercial measurement software."}
+{"text": "Ayano Shiina; the correct spelling is Ayana Shiino. The second error is Koichi Matsuda; the correct spelling is Kouichi Matsuda.In the Acknowledgments section of the original article, the names of two individuals were spelled incorrectly. The first error is The authors apologize for the oversight and confirm that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "This article focuses on defining a methodological proposal to appropriately address each of the aspects of the inter-institutional Management of Health Care Waste (RAS) that are generated within in the Health Care Centers (CAS) of the City of Montevideo. An application case based on the work experience of the Department of Environmental Engineering (DIA) team of the Institute of Fluid Mechanics and Environmental Engineering (IMFIA) of the Faculty of Engineering of the Universidad de la Rep\u00fablica, in a CAS of the city of Montevideo in which it contributed to significantly improve the inter-institutional management of RAS.By focusing on the environmental issues related to the management of Health Care Waste and specifically in Uruguay, it can be said that between the starting point of the execution of these studies (2007) and the present, there have not been any developments made by this team, other systematic studies related to the realization of diagnoses of the situation of the handling of Health Care Waste, or determination of the rates of generation in National Health Care Centers. In fact, the generation rates known until then corresponded to bibliographic data, of which most of the time there is no clear information on how they were obtained.It is here, where the importance of the approach in this methodology lies, since the qualitative as well as the quantitative information obtained from the studies developed corresponds to the genuine data of Health Care Centers of Uruguay.The methodology defined from these studies is the result of the analysis of management systems corresponding to our reality, which guarantees that the methodology is supported by real theoretical and practical foundations, ensuring the functionality and efficiency of this methodology. The definition of health-care wastes (HCW), or medical Wastes (MW), can vary significantly among countries in the European Union, MW are the wastes of chapter 18 of the European Waste Catalogue . In addiIn Taiwan, Cheng et al. (2009)  and ChenIn recent years, researchers of waste management focus on waste assessment and recommend many methods and tools for it, such as life cycle assessment  is patient care and, consequently, its policy has traditionally been oriented towards the benefit of the patient's health and well-being, which has diminished importance to environmental problems. Currently in Latin America there has been confirmed growing interest regarding the management of Health Care Waste, which has triggered conducting various studies to determine the rate of solid waste generation in CAS, as well as the performance and diagnoses of the situation of the management of wastes. However, the comparative analysis of the results obtained in these studies should take into account that the methodologies used in each case, and even the basic definitions adopted regarding Health Care Waste, were different. In addition, in the countries of the region, the scarcity of environmental statistics is notorious, and the situation of these countries is heterogeneous, both in terms of the capacity to produce statistics and the quality of the resulting information. In order to progressively overcome this situation and to advance as a region towards the production and harmonization of environmental statistics, it is necessary to consolidate institutions and develop national technical capacities.The management of Health Care Waste (RAS) presents potential risks to the health and safety of those working in the CAS and for the general population; this has been the principle motivation in Uruguay to begin studying and working in the management of Health Care Waste. In effect, in Uruguay, the comprehensive management of RAS has been regulated since 1999 and is currently governed by Decree 586/009 . ArticleIn recent years, DIA-IMFIA has carried out several projects to improve the inter-institutional management of RAS in Health Care Centers in the city of Montevideo. We analyzed the inter-institutional waste management system of a public CAS, in which a detailed diagnosis of the management system was carried out, from which modifications were proposed and implemented that resulted in improvements in management.The CAS in which the study was conducted is a tertiary hospital care of adults with acute diseases, which has outsourced cleaning services. The personnel of this company carries out the collection and transport of waste within the CAS and has the responsibility of providing the bags for waste. Currently the CAS manages its waste so that those similar to urban zones are removed and transported by a private company to the final municipal disposal site, while the contaminated waste is transferred, received, treated and disposed of by another private company, which has the corresponding authorization.\u2022Have a detailed diagnosis of the waste management in the CAS.\u2022Generate management protocols to enhance and formalize the waste management procedures at different stages.\u2022To implement the proposed protocols in the CAS, using a training program for CAS staff in order to provide the different members with the necessary knowledge to do so.Rezzano et al.  establis1Diagnosis of the initial situationIn order to make a diagnosis in relation to waste management as it was carried out in the CAS, initially the background and existing documentation related to the subject and the services that work in the Health Care Center must be identified. In addition, the location of the waste containers, capacity, type of containers and bags used in each room, collection methods and practices, internal transport circuits, characteristics and location of transitional and final storage. Based on this information, which includes the types of RAS that are generated and the characteristics of the bags and containers used in the different areas of the CAS, maps of the initial situation were drawn up; it is clear and the results of the diagnosis can be easily understood, especially regarding the characteristics and location of containers for solid waste and intermediate deposits, as well as the circulation circuits of the different types of waste .2Evaluation of sanitary waste retrieval ratesThe amount of waste that is generated in a Health Care Center is a function of the various activities that take place in it and will depend on the number of medical services offered in the establishment, the degree of complexity of the care provided, the size of the Health Care Center, and the proportion of outpatients and staff. Therefore it is not easy to establish simple relations that allow one to estimate the amount of Health Care Waste in use, due to such diversity of factors. This has led, in most cases, to relate the average amount of solid waste generated daily to the number of CAS beds, thus obtaining figures that; although subject to a certain degree of imprecision, are easier to manage and apply. In Latin America and the Caribbean the scarcity of environmental statistics is notorious and the situation within the countries is heterogeneous, both in terms of the capacity to produce the statistics and the quality of the resulting information . More spFor the development of this methodological proposal, we will work with historical data corresponding to the period between 2008 and 2011, referring to rates of removal of contaminated, common and recyclable sanitary waste. These were provided by the staff of the Department of Hygiene and Cleaning of the CAS. The data available are: daily removal of contaminated and common waste, and monthly data of recyclable waste removal. Contaminated waste data are quantified in terrines; the common and recyclable, in kilograms. Although it is usual to work with waste generation rates, the characteristics of the available data led to the need to work with withdrawal rates, in order to avoid introducing uncertainty or error factors in order to consider hypotheses for relating waste quantities withdrawn and generated. In fact, since there was no daily weighing of waste in the CAS, and because there was no withdrawal service on Saturdays or public holidays, it was necessary to manage the information of the available records: in the case of contaminated waste, the number of terrines withdrawn each day, since the contract of withdrawal was expressed of that form.To calculate a rate of generation or withdrawal rate, in kilos of medical waste per day, it was necessary to assume an average weight of waste within the terrine. For this, it is assumed that the weight of waste per terrine can be estimated at 15\u2009kg, a figure that emerges from a survey conducted in 2008 by the Department of Environmental Hygiene Hospital Center. Considering a terrine volume at 120\u2009L, results in a density of 125\u2009kg / m3, which corresponds, according to the experience of the team, to contaminated waste compaction degree.Taking the available data and punctual point values available in the CAS, and the quantities of waste removed per day in kg/day were obtained. These are presented in 3Design and implementation of a training programThe program is designed to serve three different publics with different responsibilities but also with distant positions in relation to their knowledge of the subject: service personnel, health care personnel and medical professionals working in the areas of the CAS. The main results of the training programs are written materials for each level of training, which emphasize the specific responsibilities of the different personnel involved are generated.4Development of management protocolsThe work team developed and presented a general protocol for inter-institutional waste management, which defines explicit guidelines for the different stages of the varried solid waste types, including segregation, packaging and identification, internal collection and final storage, seeking the best organization to ensure the safety of service personnel, care staff, patients and companions. Waste management protocols were also proposed for each CAS generating service and management protocols for some types of Health Care Waste considered special, such as: out of date drugs, Anatomopathological waste, cytostatic waste, mercury-containing waste, recyclable waste, chemical wastes and radioactive waste.In order to meet each of the particular objectives proposed, they were grouped into defined work stages as follows :1DiagnosThis methodological proposal gives the Centers of Attention to Health of the city of Montevideo, the possibility of working in a schematic way within the inter-institutional management of the waste of Health Care. The fulfillment of each of the activities proposed in the PGIRAS content guarantees both: the service personnel and the health care personnel of the Health Care Centers of the city of Montevideo that the waste generated will be managed in the correct manner.The elaboration of this methodological proposal also allows it to improve the execution of those activities included in the management of RAS in which shortcomings were identified, establishing some steps to follow to ensure that the incorrect practices are eliminated. In addition, new management procedures are established, referring to aspects that were not incorporated in the management of Health Care Waste in CAS.The main aspect developed in this proposal is the presentation of the main points that must be developed within the Content of the Integral Management Plan for Health Care Waste (PGIRAS). In addition, a general protocol of inter-institutional waste management and management protocols for some types of RAS, such as recyclable wastes  and some RAS considered to be special, such as out of date drugs (or dugs not suitable for use), Anatomopathological wastes cytostatic wastes, wastes containing mercury, wastes of chemicals, and radioactive waste. Also, training guides are presented for the personnel of the Health Care Centers, more specifically for the Personnel of Service and Personnel Assistance, in these guides the goal is to outline the main aspects that must be taken into account when it comes to training both the assistance and service personnel of the CASs; with the base being, informed practice for the best performance of their daily work. Situations derived from bad practices are not considered, in the understanding that they are abolished, nor are there guidelines for action in cases of contingency.Once the Health Care Waste leaves the CAS, they are collected by the companies providing the service, it is assumed that the internal or inter-institutional management of this waste, i.e.: all activities carried out with these within the CAS, have been correctly executed, i.e.: the treatment plant were the Health Care Waste will be sent when leaving the CAS depends on the management. For this reason, this methodological proposal defines the aspects necessary to generate an Inter-Institutional Management System for Health Care Waste. The following hypotheses were taken regarding the management of RAS:-Management committee for Health Care WasteFor the design and execution of the PGIRAS, the first step, a Health Management Waste Management Committee should be set up within the CAS, which will be made up of the staff of the institution, whose positions are related to the management of Health Care Waste and who will be the managers and coordinators of the PGIRAS.At the time of forming this committee the following aspects should be considered:The Health Care Waste Management Committee will be made up of: CAS General Director, Administrative Director, Financial Director, a CAS official who, because of their knowledge about the subject of Health Care waste, is qualified to lead the design and correct implementation of the PGIRAS, head of General Services, Coordinator of Occupational Health, an official of the technical staff (doctor or nurse).Previously established Infection Committees can be the basis for forming the Health Care Waste Management Committee, adapting its structure to the requirements of the Intrainstitutional Management of Health Care Waste.The Health Care Waste Management Committee must meet at least once a month to evaluate the implementation of the PGIRAS and take pertinent measures to ensure compliance. In addition, special meetings should be held when any of the members of the Committee deems it appropriate, always keeping records of the topics dealt with in the meeting. The main responsibilities that the Health Care Waste Management Committee must fulfill are the following: to carry out the Diagnostics of the inter-institutional management of Health Care Waste, to design the Integral Management Plan for Health Care Waste (PGIRAS), design the functional structure corresponding to PGIRAS and assign responsibilities to carry it out, define and establish coordination mechanisms, propose the budget of the plan, ensure the execution of the plan , prepare reports and internal reports.Once the Health Care Waste Management Committee is formed, the PGIRAS must include: diagnosis of the inter-institutional management of Health Care Waste, segregation at the source, selection and implementation of a system of treatment and disposal of Health Care Waste, Internal Waste Movement, Intermediate and central storage, preparation of the Risk Prevention Plan, preparation of the Contingency Plan, definition of inter-institutional management indicators, preparation of the Training Plan, reporting and internal reports to the corresponding environmental control authorities, periodic review and continuous improvement of programs and activities.-Elaboration of the diagnosis of the current inter-institutional management of health care wasteTo carry out a diagnosis of the situation within management of Health Care Waste in a CAS, the qualitative and quantitative characterization of the waste generated in the different areas of the institution must be carried out. For this, the exact location of the waste containers should noted, collection practices, internal transport circuits, characteristics and location of transitional and final storage areas in the different sectors. Once the sources of waste generation are identified, it is necessary to estimate the quantities and types of waste generated daily, and then to register them on forms designed for this purpose, it is convenient to refer to plans or diagrams of the plant, which indicate the location, typology and capacity of waste containers at generation sites, buffer sites and the flow of contaminated and non-contaminated waste for each of the CAS sectors.-Types of Health Care Waste Generated by ServiceAt this stage of diagnosis, the different types of waste generated in each of the CAS's administrative and care services must be determined.-Characteristics of the bags and containers usedWe proceed to determine the characteristics of the bags and containers used in each of the services of the CAS, to collect Health Care Waste at the time of its generation and according to the category in which they belong.-Placement of containers and bags in the buildingThe location of the containers is presented graphically in the architectural plans of the CAS, which must be provided by CAS officials. There must be plans of each of the levels of the CAS. The information presented in the plans must correspond faithfully to the survey carried out during the diagnostic tasks. The current location, typology and capacity of the waste receptacles, the intermediate or final storage sites, as deemed fit; the route of the contaminated and uncontaminated waste from the generation points to the corresponding storage sites, and finally, to the retirement points.-Internal CollectionThis stage of the diagnosis consists of defining the following aspects of the collection of RAS, from the primary collection vessel to the corresponding intermediate reservoir: personnel in charge of the task, frequency of collection, closure of bags to their transfer, and traceability.-Intermediate depositsIn the execution of the diagnosis, the precise location of the intermediate deposits within each level of the CAS must also be identified. In order to facilitate the process of surveying intermediate deposits in CAS and systematize the information corresponding to the main characteristics of these collection sites, it is recommended to use a survey form similar to the one presented in the -Internal TransportationDuring the execution of the diagnosis of Intrainstitutional Management of Health Care Wastes from the CAS, some aspects related to the transportation of the waste from the intermediate deposits to the final storage tank of the CAS must be identified: officials who carry out the transportation from the intermediate deposits located on the different levels of the CAS to the final storage tank, location of the necessary protection elements to carry out this task, characteristics and capacity of the carts used to transport the waste, infrastructure used within the CAS to transfer the waste, specifically if ladders are needed, if exclusive forklifts are available to carry out this task, collection circuits identified in the CAS. They must be presented graphically in the architectural plans of the CAS.-Final storageAll Health Care Waste generated in the CAS, once collected from the intermediate tanks or the service where they were generated, must be transferred to the CAS final storage tank. There different types of waste are stored until they are withdrawn by the companies contracted for this purpose.-Special waste managementThe diagnosis of Inter-Institutional Management must include the generation and description of the management that is given to the special wastes generated in the CAS  in terms of services in the which they are generated, packaged and collected and stored.-Generation of waste by sectorAs part of the diagnosis of Health Care Waste management, a weighing system should be carried out to determine the common and contaminated waste generation rates within each of the main services of the CAS. This activity will consist of the systematic execution of waste weights during the period of diagnosis and must be carried out by the collectors of the company responsible for the cleaning. (The procedure defined for carrying out the weights is discussed below.) It is important to clarify that, although this procedure is used to evaluate the rates of generation of waste by sector during the diagnosis, the system of weights and registration are carried out on a permanent basis and is incorporated as a routine task to those already assigned to the collectors.Since it is sought to quantify the waste generated by generation sector, the staff of the cleaning company will be asked not to collect or dispose of waste from different sectors in the same car or tank until they are weighed.The collector of the corresponding shift must transport the waste directly to the weighing site, without mixing it with waste generated in another sector. This is done with both the common and contaminated waste streams.\u2022Training and education programThe training and education program contemplates the training strategies and methodologies necessary for compliance with the PGIRAS, which include theoretical training, practice and training.In order to design training and education programs to be implemented in a CAS, it is essential to clearly define the aspects of the Inter-Institutional Management of Health Care Waste in which work is needed. For this purpose, the design of a Risk Prevention Plan is proposed.\u2022Training programsThe development of training programs conceived from a \"lifelong education\" perspective; and it is key to achieving the objectives of the PGIRAS of the CAS, especially in relation to the correct segregation of Health Care Waste and the reduction of risks during the handling of Contaminated Waste.Levels of training: It is necessary to orient the tasks, with different methodologies and contents to three groups:\u2022Patients and companions.\u2022Assistance staff .\u2022Service personnel .\u2022Source segregationFor the correct segregation of Health Care Waste, the containers will be located in each of the areas and services of the Health Care Center (CAS), in the quantities needed according to the type and amount of waste generated. Based on the results of the situation diagnosis of the CAS Inter-institutional Management, management protocols should be developed for each of its sectors. The protocols include explicit segregation guidelines to the sites where the containers should be located for each type of waste, guidelines for internal transport and storage, in order to ensure the safety of service personnel, care staff, patients and companions.\u2022Internal movement of wasteEach CAS should define the times of collection and transportation of waste, including routes and frequencies to avoid interference with other activities.\u2022Storage of health care wasteAccording to the complexity level and the size of the Health Care Centers, the following types of inter-institutional storage are established: initial or primary storage, temporary or secondary storage, final or tertiary storage.\u2022Contingency planThe Contingency Plan is an integral part of the Health Care Waste Management Plan (PGIRAS) and should contemplate the measures for emergency situations associated with the management of SAN. Whose possible occurrence is sensible to consider, although its probability is not high.The main situations that must be considered in the contingency management plan that is developed; within the framework of the integral waste management plan within the Health Care Centers are:\u2022Spill of contaminated waste inside Hospital facilities.\u2022Occurrence of fires.The occurrence of major accidents with risk to human life is not considered due to the imminent proximity of assistance in the event of an event of this nature.\u2022Environmental IndicatorsEnvironmental indicators allow the collection of information related to data of different a nature, and presented in a summarized way for rapid understanding and evaluation, in order to be used in decision making; for this it is necessary that they be comparable indicators, that aim at goals and that reflect the environmental performance with the maximum fidelity possible. The environmental indicators can be classified in the following categories:\u2022Environmental quality indicators: they provide information on the external environmental situation to the CAS at the local or global level. For this reason, the application of this type of environmental indicator does not correspond in this proposal, since only a reference is made to the Inter-Institutional Management of Health Care Waste.\u2022Indicators of environmental performance: they are used as tools of control and registry of improvements in environmental management. These indicators are based on the planning, control and monitoring of environmental impact and evaluate the efficiency and environmental performance of operations or processes within the organization. For example: Total common health care waste (kg)/Total health care waste (kg), Cost of health care waste removal (bed)/Cost of health care waste removal (liters), Recyclable health care wastes (kg)/Common health care wastes (kg), Fine glass (grams)/Sharp health care wastes (grams).\u2022Environmental management indicators: they are used to perform management control and evaluate the organization's efforts to improve its environmental performance, but does not provide information on the performance of the organization. For example: kg of Special Health Care Wastes in Common Wastes/Common Healthcare Wastes, Kg of Common Health Care Wastes in Special Wastes/kg of Special Healthcare Wastes, Drugs Returned to time / Drugs purchased, Drugs to dispose/Drugs purchased.The weighing is done in the final storage tank corresponding to the type of waste in question, where a scale must be available to carry out the weighing.1Standardization of containers, according to the different categories of waste generated, both in the types of containers and in the identification of the colors2What was being done: During the conduct of the basic studies, prior to the PDRS, it was determined that the containers used to place the contaminated RAS prior to their transfer to storage sites did not have the same levels of safety in all CAS.3What was proposed: The provisions of Article 9 of Decree No. 586/009 must be fully complied with. For the correct segregation of RAS it is proposed to place containers in each of the areas and services of the CAS, in the quantities necessary according to the type and amount of waste generated.4Each of the CAS must have personnel responsible for the management of RAS in general.5What was being done: In general, large CAS assigned this task to a person who, in general, does not exclusively handle the internal management of RAS.6What was proposed: Decree No. 586/009 in Chapter III, Article 6, establishes that CAS must implement Sanitary Waste Management Committees, which will be controlled by the competent authority. This Committee should be made up of personnel of the institution whose positions are related to the management of Health Care Waste and who will be the managers and coordinators of the design and implementation of the PGIRAS.7Individuals who decide the destination of the waste at the time of placing it in containers that have been installed in a timely manner, must be sufficiently qualified to discriminate according to their characteristics, being aware of the associated risks.8What was being done: It was found that those responsible for the internal management of RAS had not defined specific training programs for CAS staff who; because of their activities, were in contact with RAS.9What was proposed: The developed PGIRAS indicates the need to have training instructions for CAS personnel involved in the management of RAS, within the framework of a continuing education program. Three training manuals are presented, the content of which depends on the CAS staff who, according to the group to which the training program is directed: service personnel, health care personnel and medical professionals working in the CAS.10The basis for successful training is the training plan prepared by each CAS internally. This plan must be prepared by the RAS Management Committee, together with the management of the center or be approved by it. Training must combine two aspects: be in line with the previous level of training of those who will receive it; be in agreement with the role that those individuals have in the institution. The elements that a training plan must contain, according to what is established in the PDRS are: definition of groups of people to be trained, list of people already trained, records of training instances, contents of training programs for each of the groups.11It is recommended that each CAS should aim at a maximum generation between 15 and 25% of contaminated RAS with respect to the total of RAS generated in the center. For CAS with a rate greater than 20% of contaminated RAS, it is advisable to improve the internal classification of their RAS.12What was being done: some situations detected in CAS with high percentages of contaminated RAS, which favor the inclusion of common RAS in the stream of contaminated RAS, are in the incorrect location or identification of vessels, negligence of those responsible for classification, poor or insufficient training of personnel, insufficient controls by the generator and the authorities.13What was proposed: The diagnosis of the situation of the current management of RAS in a CAS consists of the qualitative and quantitative characterization of the waste generated in the different areas of the institution. For this, the location of the waste containers, collection practices, internal transport circuits, characteristics, should be detailed. Once the sources of waste generation are identified, the quantities and types of waste generated daily must be estimated, and then registered in the corresponding forms, and it is convenient to reference the generation sites using plans or plant diagrams, which indicate the current disposal, typology and capacity of the waste containers, intermediate storage sites and the flow of contaminated and non-contaminated waste, for each of the levels of the CAS. This will allow to define with certainty the capacity and quantity of containers necessary for each type of RAS that are generated in the different areas of the CA.Some of the improvement opportunities identified are outlined below and it is established and how the situation related to the management of RAS that originates each opportunity for improvement is currently being addressed in the management activities carried out in Montevideo by CAS. Having been studied by this team. It also defines how it has proposed to addressed the issues in the CAS in accordance with the provisions of Decree 586/009."}
+{"text": "This data article presents the formulation of multilayer network for modelling the interconnections among the sustainable development goals (SDGs), targets and includes the correlation based linking of the sustainable development indicators with the available long-term datasets of The World Bank, 2018 [1]. The spatial distribution of the time series data allows creating country-specific sustainability assessments. In the related research article \u201cNetwork Model-Based Analysis of the Goals, Targets and Indicators of Sustainable Development for Strategic Environmental Assessment\u201d [2] the similarities of SDGs for ten regions have been modelled in order to improve the quality of strategic environmental assessments. The datasets of the multilayer networks are available on Mendeley [3]. The 530 links connecting the World Bank variables The structure of the networked data is illustrated in To illustrate national differences in sustainable development priorities, a multi-layered network of ten major regions of the world is shown on 22.1The most important step of the data generation was the assignment of the 1504 variables of the World Bank open data A part of the resulted network is illustrated in 2.2If we establish relationships among the variables of the World Bank (e.g.: based on the correlation), we indirectly link the sustainable development indicators, targets and goals.The interconnections of the SDG targets and goals help to identify the thematic areas of the sustainable strategic planning activities. In this data article a total of 908 correlation-based interconnections have been occurred.p\u00a0<\u00a00.05 significance level. The availability of the variables varies regions by regions, so countries that have at least 20 years of data were taken into consideration. Considering the sign of correlations can help to explore synergies and compromises in the behaviour mapping of SDGs.The linking of the variables is based on the Pearson correlation coefficient values.  adjanency matrix. The adjacency matrices of AGT  and ATI  have been formulated also at Step 1. The correlation based relationships between the World Bank variables generated at Step 2. are stored in the AVV  matrix.The networks are also represented by their adjacency matrices. The linking of the World Bank dataset and SDG indicators are represented by the ATT :This representation is beneficial as it allows the modelling relationships among the targets and goals by multiplication of adjacency matrices. The following equations show the formulation of the target level interconnections AGG  can be modelled with the projection of the AGT  and ATT  adjacency matrices.The interconnections of the SDG goals ATT(ICSU) are already defined in the study.The data article also generated a network based on the study of International Council for Science (ICSU) 2.4The key indicators of SDGs have been identified by centrality analysis of the networks and the clustering of the indicators has been done with community analysis in MuxViz environment. The networks of the SDGs have been attached to the dataset, therefore further investigations are possible.The modelling steps are presented on A comparison of the inferred target-target networks and the network defined by experts from ICSU is depicted in"}
+{"text": "The total antioxidant activity (TAA) of human serum blood of patients suffering from alcoholism was tested by cathode voltammetry with a model process of oxygen electroreduction. A known spectrophotometrical method was used for comparison. As results the total antioxidant activity of serum blood of patients with alcoholism was estimated by voltammetry during therapy in hospital. It was shown the TAA of serum blood of patients in pathology before and after treatment is lower than that one of healthy people. However, during the process of 10 days of alcoholism treatment the TAA coefficient increases. The relationship between the coefficient of total antioxidant activity of human serum blood and the stage of treatment was detected. The basFor all samples of serum blood the mathematical model was adequately in the local range of factor space. The second factor (time of centrifugation) had greater influence on the antioxidant activity for all samples. Two-factorial surface of the response is represented in 2) at the working glassy carbon electrode was used. This process is similar to oxygen reduction in tissues. It proceeds at the cathode in several stages with formation of the reactive oxygen species, such as O2\u2212 and HO2\u2212. Antioxidants of serum blood are supposed to react with oxygen and its radicals on the GCE surface. At the presence of serum antioxidants the current of ER O2 decreases  is time of the interaction between the reactive oxygen species and an antioxidant.For the \u0422AA determination of serum blood by voltammetry the model reaction of the electroreduction of oxygen  an increase of the TAA of serum blood of all patients was observed. It is result of improvement of the somatic condition of the patients during the therapy. Probably, it is related with the increase of natural antioxidant substances amount  in the blood of the patients . It shouExhaustion of antioxidant systems of the patients with alcoholism and TAA relationships with the stage of treatment were detected. Findings suggest the activation of the formation of free radicals in the body of patients with alcoholism. Based on the analysis, we can conclude that the rate of the total antioxidant activity in the blood serum is a general non-specific marker of pathological changes in the patient with alcoholism. After treatment, TAA coefficient increase partially, which suggests the necessity for special antioxidant therapy in this condition. TAA measurements allow one to indirectly evaluate the effectiveness of treatments."}
+{"text": "After publication of the original article [1], the corresponding author noticed the given names and family names of the members included in the Swiss Neonatal End-of-Life Study Group were incorrectly reverted. The correct version of the Acknowledgements section has been included in this Correction and includes the correct presentation of names for the members included in the Swiss Neonatal End-of-Life Study Group."}
+{"text": "The aim of this research is to establish whether, and to what extent, the tilt angle, gear ratio of the propulsion system and propulsion frequency of a wheelchair influence the position of the centre of gravity. Furthermore, it verifies the usefulness of such research using an original test stand.The article presents the effects of three operational parameters of a wheelchair on the position of the centre of gravity of the human body. The study included 27 wheelchair propulsion tests of a wheelchair with pushrim propulsion using the following variable parameters: gear ratio of the propulsion system, propulsion frequency and wheelchair tilt angle. The position of the centre of gravity of the human body was measured in dynamic conditions at 100 Hz. The results were represented with ellipses defining the region of variability of the position of the centre of gravity of the human body. The coordinates of the centre of gravity were measured in relation to the reference system, with the start point at the centre of the axis of rotation of the rear wheelchair wheels. The measurements were taken in a horizontal plane in relation to the base on which the test stand was positioned.The research carried out shows that the inclination angle of the wheelchair has the greatest influence on position of the ellipse describing the position of the centre of gravity of the human body. By controlling the change in the inclination angle value in the range from 0\u00b0 to 5.4\u00b0, the standard deviation of the length of the horizontal half-axis of the ellipse (SD a) equal to 31.2 mm was obtained. For comparison, by changing the frequency of pushes (40 to 50 pushes per minute) of the wheelchair at a constant inclination angle, the standard deviation of the horizontal half-axis length (SD a) equal to 8 mm was recorded. The results of the study show a change in the position of the centre of gravity of the human body in dynamic conditions. They are relative to the contact points of the wheelchair wheels with the ground. Using the dimensions of the plotted ellipses, one can determine the values of pressure that affect the wheelchair\u2019s individual wheels. Conclusions\u2013Increasing the value of each aforementioned parameter resulted in the increase of strength required by the operator to propel the wheelchair. It directly influenced the position of the centre of gravity during the test. The operating conditions of the propulsion system , 2 have The nature of the manual propulsion system requires the use of the muscular system  by the dApart from the technical solutions reducing the propulsion-related loads, a disabled person can further reduce it by maintaining correct body kinematics. Depending on the operational parameters of a wheelchair, kinematics of the body segments propelling the wheelchair also change. According to various studies, the propulsion frequency is affected by the flexion angles of the joints of the upper limb . AnalysiBased on the previous analyses, the locomotive function relying on the upper limbs of the user depends on the operational parameters of the wheelchair. Different operational parameters can affect the kinematics of the human body. Any changes in the kinematics of the human body segments will translate into changes in the position of its centre of gravity. Observations show that the selected operational parameters of the wheelchair affect the position of the centre of gravity of the human body. The operational parameters including the wheelchair tilt angle, gear ratio of the propulsion system and the propulsion frequency are the main components of the locomotive function. The position of the centre of gravity of the human body as a whole depends on how its individual segments are oriented in space. It is therefore reasonable to analyse how the wheelchair\u2019s operational parameters affect the centre of gravity, but also how it changes its position in dynamic conditions related to manual propelling. Determination of changes in the centre of gravity is important, because it allows to determine the place of application of the load resulting from human body weight. In addition, the position of the centre of gravity of the human is important when determining the stability of the wheelchair, both static and dynamic.The study of the impact of operational parameters required the use of a specialised test stand that allows the measurement of dynamic  and biomThe method of determining the position of the centre of gravity can be divided into three stages: preparation for the test, the measurement test and the analytical processing of the obtained data. As part of the preparations, the wheelchair was weighed, then along with the examined person, it was placed on the test bench. After securing the wheelchair, its position was measured to determine the exact position relative to the reference system adopted in the study. The examined person performed 30 propulsion cycles with a constant frequency . Each measurement test was carried out with its unique and constant operational parameters, which include: the frequency of pushes, the inclination of the wheelchair and the gear ratio.i  was tested  Fig 5)..Fig 5). The results were compared with only one of the operational parameters of the wheelchair variable. For example, changes in the propulsion frequency were measured at a constant wheelchair tilt angle and constant gear ratio. The result of the test procedure was 27 tests, for which the region of variability of the position of the centre of gravity of the human body was determined in relation to the gear ratio, propulsion frequency and wheelchair tilt angle. To recognise the defined goal as accomplished, it took one person, because the research was qualitative not quantitative. The key task was to establish whether the change in the constructed devices (research stand and drive transmission with epicyclic gear) results in a measurable change of the position of the centre of gravity. Currently, the relations between the quantitative factors of separate parameters are being examined, such as muscular effort and the position of the centre of gravity. It is, however, beyond the scope of this research, which has a finite character. To enable statistical analysis of the collected results, it was decided to use a large number of propulsion cycles.2 was examined. The examined person is a student at the University of Physical Education in Pozna\u0144, and volunteered as a test subject. She confirmed the voluntary willingness to participate in the study with the signature on the consent form and read the patient information form. The research has been positively evaluated by Bioethical Commission at the Karol Marcinkowski Medical University in Pozna\u0144 Poland, Resolution No. 1100/16 of 10 November 2016, under the guidance of Prof. MD Ch\u0119ci\u0144ski P. for the research team led by Ph.D. Wieczorek B. The authors obtained written consent of the examined person for the publication of research results with her participation. The data was presented in such a way as to ensure her complete anonymity. The set of registered results describes only one patient. The analysis does not concern a larger number of people, and therefore they are not categorised. On this basis, it should be stated that there are no ethical concerns.One female subject, aged 25 years, with a body weight of 61 kg and the BMI value of 20,4 kg/mDuring the tests, the effects of the selected operational parameters of the wheelchair on the region of variability of the position of the centre of gravity of the human body in the sagittal plane was determined. Variability of the position of the centre of gravity was defined with ellipses covering 80\u201390% of all measured points of the position of the centre of gravity of the human body for a single test, in which the wheelchair operator carried out 30 propulsion cycles. The test aimed to analyse the effects of the following parameters:gear ratio at constant propulsion frequency and constant wheelchair tilt angle;propulsion frequency at constant gear ratio and constant wheelchair tilt angle;wheelchair tilt angle at constant propulsion frequency and constant gear ratio.The central point on the axis of rotation of the rear wheels was selected as a starting point of the system of coordinates representing the changes in the position of the centre of gravity of the human body. The ellipses were drawn in the sagittal plane and defined using three parameters: inclination angle \u03b1 of the semi-major axis a in relation to the axis x, corresponding to the travel direction, semi-major axis a defining the length of the ellipse in the direction corresponding to the travel direction, and semi-major axis b defining the width of the ellipse, perpendicular to the semi-major axis a. Charts showing the differences in registered positions of the centre of gravity for different conditions Figs \u20138.Tables Changes in the gear ratio of the propulsion system affected the load on the muscular system of the upper limbs and the shoulder girdle of the operator. The higher the gear ratio of the multi-gear transmission of the tested wheelchair, the higher the load on the muscular system. Analysis of the variability of the region of the position of the centre of gravity depending on the gear ratio for different operating conditions , Table 2The change in load affects the kinematics of the upper limb propelling the pushrim . The loaAnalyses of the results of the dimensions of the regions of variability of the centre of gravity at different gear ratios show that the dimensions of the ellipses differ slightly despite a growing tendency . An incrAnother variable parameter was the propulsion frequency expressed as the number of push motions per minute. The wheelchair velocity was controlled by changing the propulsion frequency. Based on the measured position of the centre of gravity of the human body, the ellipses describing the variability of the centre of gravity at three propulsion frequencies at constant wheelchair tilt angle were determined , Table 3Analysis of the changes in the frequency of wheelchair propulsion does not show a significant effect on ellipse inclination angle and distribution of the points of the position of the centre of gravity of the human body in the direction lateral to the travel direction (axis y). For extreme values of the propulsion frequency, the semi-axis dimension b differed by 3.0 mm. It can be explained by the biomechanics of wheelchair propulsion, in which an increase in propulsion frequency translates to changes in the shift of the human body segments in the direction corresponding to the travel direction only (axis x).In reference to the actual operating conditions, the wheelchair tilts as a result of uneven terrain. To reflect those conditions in the tests, the wheelchair\u2019s frame was tilted by lifting the front castor wheels to determine the effect of wheelchair tilt angle \u03b2 on the distribution of the position of the centre of gravity of the human body at constant propulsion frequency and constant gear ratio , Table 4Changes in the wheelchair tilt angle \u03b2 resulted in a shift in the ellipse position in the direction of the axis of rotation of the rear wheelchair wheels, with an increase in the tilt angle. It is caused by the body shifting closer to the wheel axis as a result of the wheelchair seat tilt.Analysis of the dimensions of semi-major axis a and b of the ellipses defining the variability of the position of the centre of gravity of the human body shows that the dimensions increase with an increase in the tilt angle. The results show that the most extensive changes in the position of the centre of gravity of the human body can be observed for the tilt angle \u03b2 = 5.4\u00b0, irrespective of the propulsion frequency and gear ratio. An increase in the surface area of the ellipses is due to an increase in torso flexion and an increase in the wheelchair tilt angle. High increase in semi-axis a dimension (of 30.7 mm), resulted from high torso flexion angles during wheelchair propulsion at high seat  tilt angComparison of the average dimensions of ellipses shows that the biggest difference between the dimensions of the region of variability of the position of the centre of gravity of the human body can be observed for changes in the wheelchair tilt angle. For the semi-axis a the increase was 30.7 mm and for the semi-axis b 6.8 mm. Also, the propulsion frequency affects the dimensions of the ellipses. In this case, the semi-axis dimension a increased by 12.7 mm as the propulsion frequency increased. The analysis of the effect of the gear ratio on the region of variability of the position of the centre of gravity of the human body shows a minor effect of this parameter. In the case of semi-axis a the difference in dimensions was 7.6 mm and for the semi-axis b the dimensional difference was 1.3 mm.Analysis of the changes in the dimensions of the semi-axles shows that any changes in operating parameters affect major on the dimensions of semi-axis a and the ellipse inclination angle in relation to axis x. The tested configurations show that the operating parameters affect the dimension of semi-axis b of the ellipse defining the distribution of the centre of gravity in relation to the left and right wheelchair wheel to a negligible degree.The tests verified the effects of the operational parameters of a wheelchair on the position of the centre of gravity of the body of an operator propelling a manual wheelchair. During the test, the gear ratio of the propulsion drive, propulsion frequency and wheelchair tilt angle were variable. For all tests, an increase in aforementioned parameters resulted in any of the parameters resulted in an increase in effort required by the operator. The effort was compensated by the wheelchair operator changing their body kinematics, which translated into changes in the dimensions of the regions of variability of the position of the centre of gravity defined with ellipses. It can be assumed that an increase in wheelchair resistance to motion  translatThe results show that the position and dimensions of the variability region of the position of the centre of gravity are affected by the wheelchair tilt angle. The results show that an increase in the wheelchair tilt angle increases the variability region of the position of the centre of gravity in the direction corresponding to the travel direction. The second operational parameter affecting the region of variability of the position of the centre of gravity is the wheelchair propulsion frequency. In this case, with an increase in the propulsion frequency, the region of variability of the position of the centre of gravity also increases. Variability of the dimensions of the ellipses defining the position of the centre of gravity is least affected by changes in the gear ratio.The increase in the region of variability of the position of the centre of gravity of the human body as a result of the increase of the wheelchair tilt angle results from changes in the position of the human body in relation to the axis of rotation of the drive wheel and the wheelchair seat inclination . It incrA common relationship for all the operational parameters was an increase in the longitudinal dimension of the ellipses corresponding to the travel direction with only slight changes in the lateral dimensions. The ellipse inclination angle for each test depends on the uniformity of wheelchair propulsion and torso flexion. The observations show that the inclination angle indicates which side of the wheelchair is loaded at a time. Positive \u03b1 angle indicates the left and negative \u03b1 angle indicates the right side of the wheelchair. The position of the ellipse in the horizontal plane depends on the seating position of the operator and the position of the body in relation to the sagittal plane. The test results were in the 1st quarter of the reference system, indicating an asymmetric position of the body in relation to the seat and shift in the direction of the left drive wheel.The tests represent the effects of operational parameters on the distribution of the position of the centre of gravity in dynamic conditions. Since the position of the centre of gravity of the wheelchair is constant, the position of the centre of gravity of the entire system is affected by the variable position of the centre of gravity of the human body. The position of the centre of gravity of the human-wheelchair system is the result of the kinematics of the human body propelling the manual wheelchair. The design of innovative and advanced wheelchairs requires thorough knowledge of the biomechanical parameters affecting the wheelchair operation. The position of the centre of gravity is a major biomechanical parameter affecting wheelchair stability , 25. StaThe presented test results allow the assessment of the change of the position of the centre of gravity depending on the movement conditions of the manually operated wheelchair. Therefore, it is possible to determine the pressure values (reaction forces) to each wheelchair wheel, among others. It is a crucial parameter which determines, for instance, the torque required to move a wheelchair. This research is unique also due to the use of an original research stand and innovative transmission of manual drive to the wheelchair wheels, which was submitted as a patent application , 17. WorAccording to the research and analysis, it can be established that the tilt angle, gear ratio of the propulsion system and propulsion frequency of a wheelchair influence the position of the centre of gravity. The biggest observed change is the result of the largest wheelchair tilt angle. Most likely, it is a result of the increased effort that the operator had to put in when propelling the wheelchair. It directly influenced the position of the centre of gravity during the test. It can be concluded that the research stand used, enables to examine in a measurable way the influence of individual parameters on the position of the centre of gravity. Establishing the quantitative influence on this parameter is the aim for further research.S1 File(RAR)Click here for additional data file."}
+{"text": "Please view the complete, correction equation here:In the Determination of carboxyl modification subsection of the Materials and Methods, there is an error in the second equation. The numerator is missing the term"}
+{"text": "Due to human error, the authors included some of the experimental data in this article  which haMDPI is a member of the Committee on Publication Ethics and takes the responsibility to enforce strict ethical policies and standards very seriously. To ensure the addition of only high quality scientific works to the field of scholarly publication,  is retra"}
+{"text": "The similarity between mortality kinetics and the accumulation of deficits (frailty kinetics), and the coincidence of the time parameters in the frailty and mortality models make it possible to express mortality risk in terms of accumulated deficits. This provides a simple and accessible tool that might have potential in a number of biomedical applications.This paper extends a method of apprising health status to a broad range of ages from adolescence to old age. The \u201cfrailty index\u201d is based on the accumulation of deficits  as analyzed in the National Population Health Survey, a representative Canadian population sample . The accumulation of deficits has both an age-independent (background) component and an age-dependent  component, akin to the well-known Gompertz-Makeham model for the risk of mortality. While women accumulate more deficits than men of the same age, on average, their rate of accumulation is lower, so the difference in the level of deficits between men and women decreases with age. Two possible invariants of the process of accumulation of deficits were found: (1) the age at which the average proportion of deficits coincides for men and women is 94 years, which closely matches the"}
+{"text": "Iraq is at risk of multiple hazards including both natural and man-made calamities. Little effort had been made before 2003 to address the disaster risk; even though many legislations enacted to provide a relief in the event of the acute crisis, they were mainly focused on the reactive response to the calamities without taking into consideration the prevention, preparedness and mitigation approach. The recent years have witnessed some positive attitude from the government and international society to develop strategies for disaster risk reduction in Iraq. Iraq for the first time has drafted a law that is distinctive for the disasters. The purpose of this article is to review the possibilities and challenges of disaster risk reduction in Iraq. Iraq is at risk of multiple disasters ranging from the natural disasters such as drought, sandstorm, heatwaves, floods, desertification and epidemics to man-made ones. This susceptibility accompanied by the effect of wars and conflicts in the last four decades results in multiple hazardous effects such as contamination of the land by biological materials, unexploded ordnance and cluster munitions. Wars and conflicts affected the functionality of the system to respond to disasters. This, combined with the effect of poverty and displacement, results in increase in the vulnerability of the people and further compromises the system leading to many dysfunctional services. Based on our specialisation in disaster, we have included a review of the current situation of disaster risk reduction (DRR) in Iraq. The objective of this article is to give an account on the current framework for DRR strategies in Iraq. Because of scarce resources on this subject, we have tried to review the national laws and newspapers as well as the United Nation Development Programme (UNDP) agenda, which is the main supporter of the implementation of DRR in Iraq.Hyogo Framework for Action. Moreover, Iraq, for the first time, becomes part of the regional DRR programme. In 2008, Iraq indorsed the Arabian Center for Earthquake Hazard and Natural Disaster Prevention programme. The aim of this programme is to form a system for the countries that share common borders to enable them to respond better to the natural calamities. According to this project, Iraq is committed to show scientific and technical cooperation with the other Arab countries in order to prevent, prepare, mitigate and respond to the effect of natural disasters. Furthermore, the mission of Iraq includes providing logistical and financial support, executing studies to evaluate the natural hazards, sharing the information with other centres in the region and mapping earthquakes and natural hazards.On the first session of the Global Platform for Disaster Risk Reduction conference held at Geneva in 2007, the director of the Iraqi Ministry of Environment stated that the Iraqi government is making every effort to decrease the natural and man-made disasters in the country  which is composed of the representatives of the Directorate of Public Health Division, Ministry of Migration and Immigrant, the local Non-Governmental Organizations (NGOs) and the United Nations Office at the governorate. In response to any disastrous situation, the GEC of the affected governorate may respond in a decentralised pattern. Should a disaster occur beyond the capacity of the GEC of the affected governorate, the governor then has the right to call for the central government authority. Thereafter, a higher coordination committee may be formed under the patronage of the prime minister to manage the province that faces an emergency situation.The most critical centre is the National Operation Center (NOC), which is operated directly by the prime minister\u2019s office; it is usually specialised in terror attacks. Another centre that is established with the escalation of 2006 violence is the National Crisis Action Cell (CAC). The main mission of CAC is providing a national level crisis management, and CAC has the authority to coordinate between the ministries. Furthermore, the Inter-Ministerial Committee on Disaster Management (IMCDM) is another body created in 2007. It is composed of ten ministries including the Interior, Defence, Planning and Development, Health, Communication, Environment, Water Resources, Foreign Affair, Science and Technology as well as the State Ministry of National Security and the Secretariat General of Council Ministers. The IMCDM had prepared notes to establish the National Center for Disaster Management. The centre\u2019s mission is to act as a secretariat for DRR actions including research and studies on emergency, planning and coordination of intervention in case of acute crisis. Additionally, it has the role of information exchange and providing a database for recording the information on hazards, risk and vulnerability of disasters and acute crisis situations.Hyogo Framework for Action 2005\u20132015.The Ministry of Science and Technology (MOST) is the focal point for the coordination between the ministries regarding the response of disasters in Iraq. Under the patronage of MOST, the first Disaster Risk Reduction and Mitigation Law has been drafted and submitted for approval by the parliament in 2012 with the help of UNDP UNDP , 2014. THyogo Framework .Iraq still follows the traditional form of response to emergency with no prior preparedness to such events. This is partly because of poor governance and lack of awareness to the importance of DRR strategies and partly because of the fact that natural disasters were not frequent in recent years. Thus, despite the legislation of multiple laws, it remains inapplicable in the reality ground. The general institutional context of the disasters still lacks essential communication and early warning systems. Unfortunately, the draft of the first Disaster Risk Reduction Law has many flaws such as failure to define the type of disasters and disaster contingency planning that includes disaster mapping and vulnerability assessment. Additionally, the National Disaster Law only provides a framework for the national disaster plan; however, it needs to be complemented with by including disaster management and emergency preparation plan. This approach is performed by preparing either a separate regional and national plan as in Sri Lanka (Sri Lanka The main issue is that the existing institutional arrangement at national, regional and local levels is focusing on the post-disaster action without taking any consideration for preparing for a pre-disaster phase such as prevention and mitigation planning. Therefore, Iraq is still lacking comprehensive disaster management systems based on analysis of risk, hazards, capacities and vulnerabilities of the affected population. Seemingly, Iraq needs strong infrastructural and technical capacities within the government and other stakeholder bodies to be able to respond to the future crisis. War and post-war conflict destroy infrastructures and leave the majority of institutions dysfunctional, thereby increasing the vulnerability of the population. Moreover, the poverty and displacement further make the country unable to respond to disasters. Although the international NGOs have a vital role in this response, they have no capacity to support complete disaster reduction and mitigation planning in Iraq without the effort of the local government. Nevertheless, overall, Iraq is making some steps in the right direction towards DRR and response, and is slowly progressing."}
+{"text": "The Risk Assessment (RA) of pollutants from contaminated sites and landfills is a major environmental issue in Europe, due to the large number of sites and to the importance of groundwater protection. The high number of contaminants and the lack of knowledge of their environmental properties and their ecotoxicological and toxicological characteristics complicate the problem. Furthermore, this information about the chemicals has to be combined with the data relative to the territory and to the targets. We will describe the problems relative to each topic involved in the process, and we will propose an integrated methodology for coping with these problems, using state-of-the-art approaches in each part of the protocol. This methodology has been applied in several real cases."}
+{"text": "Strokes are the second leading cause of death in the world . Of all Proceedings of the National Academy of Sciences , Heilongjiang Province, China and American Heart Association (19AIREA34470007) to X-PC.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "There is an error in the last sentence of the third paragraph of the Results section. The correct sentence is: The threshold was determined at 4.95 years or higher .There is also an error in Due to this error, several sentences within the body of the paper should also be corrected.The final sentence of the Results section should read: Assuming that the animals enter their reproductive cycle at 4.95 years of age , we estimated a total of 54.66% of female harbour porpoises in the North Sea and 27.44% in the Baltic Sea to participate in reproduction .The tenth sentence of the second paragraph of the Discussion section should read: If we apply our age estimate of first signs of sexual maturity to the age structure of specimens found in the same region, we conclude that about 54% of animals in the North Sea and up to 27% of animals in the Baltic Sea might belong to the reproductively active part of the populations.The thirteenth, fourteenth, and fifteenth sentences of the second paragraph of the Discussion section should be replaced by the following text: We infer that at peak population size in summer the total number of females belonging to the reproductive population amounted to 12,430 females in the German North Sea and only 372 females in the German Baltic Sea. For the Baltic Sea subpopulations this value is still very low compared to other harbour porpoise populations and might be more vulnerable to environmental factors that shorten the reproductive lifespan like increasing bycatches in the Baltic Sea [33]."}
+{"text": "A feature of modern crop production is the acute need to accelerate its scientific and technological development, on the basis of innovative processes. The sector of crop production has an essential dependence on external factors and the modern directions in its scientific and technological development should also reduce dependence on external factors and to improve controllability by reducing the uncertainty of responses to external influences. The methodology of scenario forecasting, adapted to the crop production gives the opportunity to answer the questions such as, for example as:How the determinants of the development of the crop sector will change? What future bifurcation points may occur? What strategic decisions can be made? What consequences these decisions will bring in future?Among the stages of long-term forecasting, the special part is assigned to development of scenarios of development. Scenario prediction allows, based on the available data, to suppose the development and behavior of the object under study in the future. As a result, it becomes possible to develop strategic and tactical solutions based on the implementation of the proposed scenarios. The peculiarity of this method is that it is applicable in situations of uncertainty of the object's reactions to various external influences.The development of scenarios allows to surmount the stochastic nature of the processes occurring in the scientific and technological sphere, to expose large-scale scientific and technological breakthroughs that can significantly change the crop sector. Scenario approach as much as possible forces out uncertainty of choice space between scenarios. So economic trends lead to the fact that the crop industry needs to be developed along the organic path, excluding the use of mineral fertilizers and toxic chemicals. In this case, government support for the crop industry will be directed to ensuring the production of organic products. Among technological trends, the greatest impact on the development of the crop industry in Russia is exerted by a worldwide reduction in acreage and a decrease in high-quality biodiversity. Along with the global environmental problems, this will allow the crop industry in Russia to maximize the use of available acreage with the use of world technological innovations in the field of urbanized crop production.The global trends were conducted based on bibliometric analysis, which was carried out in the database of Web of Science (ResearcherID), by keywords related to agrobiotechnology .Fig.\u00a01Th22.1Scenario forecasting is a tool that works in conditions of high uncertainty of the future in the medium and long term, allowing to identify the most likely variants of the development of events \u2022creating a common vision of the future of all key players in the crop sector and determining the place the crop production in the economy of the country wants to occupy in the future;\u2022understanding and visualizing the consequences of decisions made today, for scientific and technological development of crop production;\u2022visualization of all possible options for scientific and technological development of crop production.Scenario forecasting of scientific and technological development of crop production is intended for:Scenario forecasting of the scientific and technological development of crop production requires the definition of a step-by-step algorithm for constructing the forecast, starting with the identification of possible scenarios and ending with the areas of started groundwork research for each of the scenarios .Fig.\u00a02AlThe two proposed scenarios should be aimed at achieving the main goal of scientific and technological development of domestic crop production - ensuring the competitiveness of Russian products in the domestic and foreign markets, primarily through the creation and introduction of the latest achievements in science and technology 1.\u2022\u201cTechnological adaptation\u201d - preservation of existing trends in scientific and technological development, stable positive dynamics of production of the majority of agricultural crops, import of basic technologies of crop production, seed-growing and organic farming, expanded reproduction of crop production through predominantly extensive factors;\u2022\u201cTechnological breakthrough\u201d - achievement of leadership positions in certain areas of scientific and technological development of crop production, seed farming and organic farming, and changes in the structure of cultivated and exported crops, expansion of crop production on an innovative basis.Identification of two main scenarios:The algorithm for developing scenarios for forecasting the scientific and technological development of crop production, including seed production and organic farming, contains the following stages:At the same time, it should be noted that in the \u201cpure form\u201d these scenarios will not be realized and the scenario \u201cTechnological adaptation\u201d will become the basis and the initial stage of the scenario \u201cTechnological breakthrough\u201d. The latter will be implemented gradually, only after the first scenario is implemented completely .Fig.\u00a03Th5.The result of scenario forecasting will be the formulation of areas of scientific and technological development of crop production, seed production and organic farming, that is, a list of critical technologies that will significantly increase the efficiency and productivity of the crop sector. In this case, it is necessary to take into account the market component of this process: the created technologies can appear not demanded in the world market. Therefore, scenarios are developed on the principle \u201cfrom markets to technologies\u201d, because it allows to identify the most critical technologies in the future. After determining the prospective market niches for internal crop production, it is necessary to identify areas of counterfeit research, where the country's resources should be concentrated to obtain technologies that have long-term competitive advantages.For each scenario, their markets will be allocated: means of production, platform solutions, final consumption products.2.2Close attention should be given to scenario conditions since they set the initial vector for future scenarios of scientific and technological development.The approach to the definition of scenario conditions is set by the requirements of the Resolution of the Government of the Russian Federation, July 13, 2015 No. 699 \u201cOn Approving the Rules for Development and Correction of the Forecast of the Scientific and Technological Development of the Russian Federation\u201d and Order No. 1335 of the Ministry of Education and Science of the Russian Federation, November 13, 2015 \u2033 On the approval of methodological recommendations on the preparation of initial data for the development and correction of the forecast of scientific and technological development of the Russian Federation, as well as on the formation of its scenario conditions \" Scenario conditions should take into account the priorities, goals and objectives of the sector's development: the primary goal of the scientific and technological development of the agro-industrial complex of the Russian Federation in the future is to ensure the competitiveness of Russian products in the external and internal markets, primarily through the creation, dissemination and application of the latest achievements in science and technology The scenario conditions and the main parameters of the forecast contain a description of the conditions, characteristics and indicators of the scientific and technological development of the Russian Federation for a long-term period and are developed for a period of up to 30 years (with the selection of periods) in conjunction with the parameters of the long-term socio-economic development forecast of the Russian Federation a)external conditions, including the main global trends of scientific and technological development;b)internal conditions, including trends in scientific and technological development in the Russian Federation;c)the achieved level of scientific and technological development of the Russian Federation, including in comparison with world trends;d)factors of scientific and technological development of the Russian Federation ;e)challenges and threats to the Russian Federation .The structure of the scenario conditions and the main parameters of the forecast are as follows:\u2022Scenarios of scientific and technological development, their description and main characteristics, corresponding to the goals and opportunities of scientific and technological development of the Russian Federation in the forecast period \u2022Key indicators of the forecast of scientific and technological development of the Russian Federation, characterizing the state of scientific and technological development for a long-term period.The identification of scenario conditions and basic parameters allows to form:Together with scenario conditions, the criteria for selection of promising markets are formed, including groups of innovative products and services, technologies, research areas for developing forecasts for the technological development of economic sectors and forecasting the scientific and technological development of the Russian Federation The conditions for the implementation of the scenario \u201cTechnological adaptation\u201d is to going to consist in stable positive dynamics of production of most agricultural crops, in satisfying the Russian market with seeds of domestic production, etc. Economic growth will be achieved through the expanded reproduction of agricultural producers (development of extensive factors in combination with modernization). This will allow them to master the internal market and increase the export of crop production in some areas. Basically, traditional markets for technologies and crop production will be developed. Agricultural producers will not change their preferences and mainly imported machinery and equipment will be used in production.As for selection and seed production, the continuation of the policy of import substitution will create conditions for the satisfaction of the internal market with internal seed.Organic farming will develop on a limited scale, as will the demand for it within the country, so the sale of products will be mainly carried out to foreign markets. At the present time, there is a problem of inadequate information among agricultural producers on the principles of organic farming, which, within the framework of this scenario, will be gradually addressed through raising their awareness and interest in the production of organic crop production. There will also be an increase in farms producing organic products that meet international standards.The main purpose of the scenario \u201cTechnological breakthrough\u201d is to try to outstrip the crop sector with the newest technological base, corresponding to the decisions of the \u201ctomorrow's\u201d day. The conditions of this scenario are a change in the structure of the cultivated crops and their exports, complete import substitution of seed material, etc. There will be a significant diversification of marketable products in the direction of reducing the share of grain crops. The expansion of production under this scenario will take place on an innovative basis, through the mass introduction of new crop production technologies into production. Due to the outstripping rates of economic growth, the scientific and technological backlog of the crop sector will be diminished in comparison with the advanced foreign countries, moreover, dependence on imported technologies will be also decrease.2.3The implementation of any scenario of scientific and technological development of the crop sector is carried out through the achievement of various indicators associated with the crop sector and characterizing the scenario. Each of the scenarios is characterized by a different level of achievement of goals, which can be absolute and relative. The gap between the indicators allows to determine the degree of impossibility achieve one scenario of another.The system of indicators allows to determine the current state of the scientific and technological development of the crop sector, and an analysis of their dynamics makes it possible to determine the direction of development. It is necessary to identify such indicators that will help to identify and understand which of the proposed scenarios is most likely in the near future.1.The average annual growth rate of the gross output of the following crops: wheat, rye, barley, oats, corn, rice, rapeseed, sunflower, soybeans, sugar beet, potatoes, and protected ground and open ground vegetables.2.\u2022grain crops in the structure of production and export of crop production;\u2022Russia in the structure of world exports of crop production.\u2022use of internal seeds in the production of crop production;\u2022products of organic farming in general crop production;\u2022organic farming products that meet international standards;\u2022internal crop production technologies in the internal market, including the technologies of precision farming, urban agriculture, organic farming, etc.Specific weight:3.A number of certified organic producers in the Russian Federation.4.Area of certified land for organic farming.As for Russia, the authors of the article refer to such indicators:"}
+{"text": "The journal and Chief Editors retract the April 2018 article cited above. Following the publication of the article, concerns regarding the results were addressed to the journal and its Editorial Board. Following clarification with the authors, errors were identified with the data and the article is therefore retracted with the agreement of the authors."}
+{"text": "The Journal continues its policy of presenting to its readership the latest progress in the fields of science and practice of cardiology in an easily readable and timely manner.The concept of devoting an issue of the Journal to one topical subject, was recently started to present virtually all aspects of a chosen topic by experts in the field, presenting the latest progress of knowledge in their area.In the current issue, HCM was chosen because of the recent sustained increase in data relating to both management of, and research into, this relatively common inherited disease which could be of interest to a wide range of our readership.The current issue represents the proceedings of a recent meeting organised by the Guest Editors in Barcelona. We are grateful to all of them for making this project a reality, and hope that the issue of the Journal will achieve its declared objectives."}
+{"text": "The authors regret the omission of one of the authors, Jared J. Lindenberger, from the final version of the manuscript. The corrected list of authors and affiliations for this paper is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "The number of potential biological markers of ageing increases dramatically especially with the development omics technologies. These biomarkers are not generally independent from each other and also related to clinical markers of aging that also could be markers of some illnesses. We discuss three ways of integrating biological and clinical markers of ageing: a frailty index (FI), indices of biological age, and a statistical distance as a measure of physiological dysregulation. We shows that FI has a strong theoretical support in the complex dynamical network model of the ageing process. The theory allows to explain why the interdependence of variables  is essential for understanding of the basic properties both of the FI and of ageing such as a Gompertz law of mortality. Further progress in the field will go hand-in-hand with the development of new technologies that allow more data to be collected and interpreted."}
+{"text": "The Journal and Chief Editors retract the 25 January 2017 article cited above. Concerns regarding the reliability of the data presented in this manuscript were brought to the attention of the journal in April 2018. Following an investigation by the Editorial Office and Chief Editors of the journal, it was found that appropriate controls had not been used for some of the experiments presented. The article is therefore being retracted from the journal due to concerns with the reliability of the data. The authors do not agree to the retraction, and the notice."}
+{"text": "The article presents the method of selecting scanning lines along which coordinate measurements, performed by using, e.g., a coordinate measuring machine working in the single point probing mode, of free-form surfaces of measured workpieces may be conducted. Additionally, the proposed method supports the user of a coordinate measuring system during defining the number of measurement points distributed along selected scanning lines, thus deciding on the final distribution of measurement points on a measured surface of a product. The proposed method enables distributing measurement points in the parts of a measured product characterized by the worst quality of manufacturing. Moreover, the new method is very automated, therefore it affects the increase in the efficiency of coordinate measurements. The effect of using the new method is the non-uniform distribution of measurement points located on free-form surfaces. The presented algorithm takes into account the lengths of selected cross-sections of a measured curvilinear surface of an object, its geometrical complexity and the accuracy of the probe radius correction process. The decision regarding the number of measurement points is made on the basis of the accuracy analysis of the calculations of the corrected measurement points obtained during the probe radius correction process and the accuracy of the substitute model representing a measured curvilinear surface. Two methods of the correction process were used. The accuracy of the applied methods of the probe radius compensation process was estimated on the basis of the deviations calculated between corrected measurement points and scanning lines. The selection of scanning lines and the number of measurement points was realized by using the expert system based on the fuzzy logic. The paper presents the results of both simulation and experimental investigations. The numerical calculations were performed for two selected free-form surfaces. The verification of the developed algorithm was carried out during experimental investigations based on a measurement of a selected free-form surface. The conducted research was aimed at verifying the correctness of the distribution of measurement points generated using the proposed method. In the case of real measurements, measurement points should be located in the places of surfaces of products characterized by the largest deviations of manufacturing. The results of the conducted investigations confirm the usefulness of the developed algorithm for defining the distribution of measurement points on curvilinear surfaces in the coordinate measuring technique. Moreover, the way of implementation of the developed method of the distribution of measurement points in selected commercial measurement software is presented, thus enabling the use of the new method in the industry. The coordinate measuring technique is widely used in the industrial practice in the case of measurements of products with regular geometrical shapes and workpieces built of curvilinear surfaces. Coordinate measurements can be made by using many different contact and non-contact systems ,2. CoordThis article concerns selected issues related to measurements of free-form surfaces of products with the use of coordinate measuring machines. Free-form surfaces are represented by sets of control points which are used to determine the B\u00e9zier, B-spline and NURBS  surfaces . The curThe article presents the new method of determining the locations of scanning lines on curvilinear surfaces of products. Therefore, the paper concerns the first stage of coordinate measurements of free-form surfaces. The new method of generating measurement points on curvilinear surfaces was created mainly to improve the accuracy of measurements by increasing the chances of detecting the largest deviations of manufacturing. Additionally, the proposed method was developed to shorten the planning time of a measurement strategy.The determination of locations of measurement points on measured surfaces is the fundamental element of strategies of contact coordinate measurements carried out with the use of coordinate measuring machines, which directly affects the accuracy of measurements and their time . TherefoThe strategies of selecting measurement points on a measured surface of an object are divided into three main categories . The firLi et al.  presenteAn interesting model of determining the costs of a measurement process was proposed in the work . The proPagani and Scott  presenteThe work  presentsRaghunandan and Venkateswara Rao  showed tThe method of the distribution of measurement points in the case of coordinate measurements of free-form surfaces performed with the use of a non-contact measuring system was proposed in the paper . In the Wang et al.  applied The authors of the article  proposedThe flow chart helpful during measurements of products with the use of coordinate measuring machines was presented in the work . The autThe article  concernsJiang et al.  presenteThe method of equi-parametric sampling presented in the work  was applRajamohan et al. ,27 propoThe accuracy of an optical coordinate measuring system using the focus variation technique was analyzed in the paper . The anaThe authors of the article  analyzedThe estimation of the density function of the probability of geometrical deviations was based on the Parzen Windows technique in the paper . The calWang et al.  comparedTwo strategies of measurements are also shown in the work by ElKott and Veldhuis . The papIn the work by ElKott et al.  four algBarari  presentsThe authors of the referenced publications have not proposed an automated expert system supporting the user of a given coordinate measuring system in the stage of programming a measurement process and during defining a measurement strategy, which is the necessary element of all measurement programs. Moreover, other authors considered defining the distribution of measurement points independently from other elements of a strategy of contact measurements, what may contribute to increasing time of planning of a quality control process of curvilinear surfaces. Additionally, the mentioned publications do not present the algorithms of distributing measurement points that reduce measurement errors resulting from the probe radius correction procedure and occurring when conducting contact coordinate measurements.Therefore, in this article, apart from the new method of determining the location of measurement points, the system of automated determination of suggested scanning lines and measurement points distributed along scanning lines, which is based on the fuzzy logic, was also proposed. The fuzzy logic has been already successfully used in the field of the coordinate measuring technique. The examples of its application are the processes of calculating corrected measurement points during the probe radius correction process , determiThe developed system can be used while preparing the technological process of a given product in the initial stages of its production process and therefore speeding up a measurement process of a given product. Moreover, the novelty of the proposed method of determining the location of measurement cross-sections is associated with the distribution of measurement points on curvilinear surfaces not only on the basis of the estimation of the geometrical complexity of a measured product but also taking into account the information about the accuracy of the probe radius correction process, which is one of the factors affecting the accuracy of coordinate measurements. The calculation of coordinates of corrected measurement points on the basis of coordinates of indicated measurement points, representing the center of a stylus tip during its contact with a surface of a measured object, is also the element of a strategy of contact coordinate measurements carried out with the use of, e.g., CMMs, which does not have to be considered independently from other components of a measurement strategy. Therefore, the presented method enables planning the distribution of measurement points together with selecting the probe radius correction method. This, in consequence, simplifies the determination of a measurement strategy, thereby affecting the increase in the efficiency of contact coordinate measurements and the productivity of the entire manufacturing process.The following parts of this article include, among others, the algorithms of selecting scanning lines and measurement points distributed along selected measured cross-sections, results of simulation investigations for selected theoretical curvilinear surfaces of products and results of experimental investigations for one chosen free-form surface. The presented algorithms are intended primarily for CMMs equipped with measuring probes working in the single point probing mode, which are still often used in the industrial practice. Nevertheless, the new method of the distribution of measurement points can also be used by other measuring systems, e.g., CNC  machine tools equipped with contact measuring probes, which can be applied when measuring curvilinear surfaces of products. Numerical research was carried out with the use of selected computer-aided design software. Moreover, the MATLAB software was also applied.The proposed method of the distribution of measurement points consists of two main parts. The assumption of the presented method is the use of measuring probes working in the single point probing mode, which are still used by coordinate measuring machines and CNC machine tools. The first part of the method is related to the choice of the positions of scanning lines, along which measurements are carried out by using a measuring probe of a CMM or a CNC machine tool. The second part of the method concerns the selection of the number of measurement points uniformly distributed along selected cross-sections of a curvilinear surface. The general view of the new method of the distribution of measurement points on a free-form surface is presented in The new method of defining the distribution of measurement points on free-form surfaces of objects is in accordance with the ISO 1101 standard. In the case of this standard, the following characteristics can be distinguished: The line profile and the surface profile. Both characteristics may refer to measurements of curvilinear surfaces. In the case of the line profile, the positions of measured cross-sections, along which measurements of a free-form surface are performed, should be determined. The need to define a specific orientation of a measured cross-section results from the position of the tolerance zone of the line profile read from a 2D drawing of a considered object composed of free-form surfaces. On the other hand, in the case of the surface profile, measurement points can be arbitrarily distributed on a free-form surface of an object to be measured. The proposed method concerns mainly measurements of the surface profile.This subsection presents the algorithm of the first part of the proposed method of the distribution of measurement points, which concerns the selection of measured cross-sections of free-form surfaces. The individual stages of the algorithm of the selection of a scanning line located on a curvilinear surface are presented in detail in a free-form surface is divided into intervals in two directions;only one point in each row and column of a surface is selected.The first stage of the algorithm is the random distribution of points on a measured free-form surface of a product. This distribution is determined by using the Latin Hypercube Sampling (LHS) method. The LHS method is a statistical method which is used to generate random points on a surface in the case of the presented algorithm. The steps of using the LHS method are as follows:Moreover, in the case of this method, the user of, e.g., a CMM must make decisions regarding the number of randomly distributed points and their positions in relation to boundaries of an analyzed curvilinear surface. The randomly generated points are not measurement points. In the next stage, a set of planes is created at the distributed points. The planes are used to form cross-sections of a measured surface. The number of planes and the angles between them are the input data processed by the considered algorithm and dependent on the decision of the CMM\u2019s user. The third stage of the algorithm refers to the uniform distribution of points along the free-form cross-sections created in the second stage. The points generated in the third stage, like in the first stage of the algorithm, are not measurement points. Their purpose is only to determine places along analyzed cross-sections, in which further calculations will be carried out.average curvatures for the generated cross-sections based on the values of curvatures at points uniformly distributed along the considered cross-sections;lengths of the created cross-sections of a measured free-form surface of a product;deviations of the analyzed cross-sections from the 2D curve.The next steps of the algorithm of the selection of scanning lines concern the calculation of:The selection of a scanning line for points randomly distributed on a measured curvilinear surface is carried out by using a system based on the fuzzy logic. The input data for the calculations of membership functions of input parameters of the expert system is the information about the curvatures of the analyzed cross-sections, the lengths of the cross-sections of a free-form surface and the deviations of the cross-sections from 2D curves.The dependence of the choice of the cross-section of a free-form surface, along which coordinate measurements should be made, on its length is the result of the need to distribute measurement points along the largest possible fragments of an analyzed curvilinear surface. This, in turn, increases the chances of locating measurement points in the areas of a measured surface of a product characterized by the largest values of form deviations.m\u2014a number of points, at which curvatures of a cross-section are measured.The proposed method also provides measurement points in the parts of curvilinear surfaces characterized by the large curvature. Determining the locations of measurement points based on the curvature of a measured surface is the very often used approach in the coordinate metrology. The curvature is one of the parameters determining the distribution of measurement points applied in the methods proposed by the authors of the works ,33. MoreEquation ). The cuThe deviations of cross-sections of a free-form surface from the 2D curve are calculated based on the values of the arithmetic mean of the angles calculated between the vectors normal to a considered curvilinear surface and the vectors located in the planes which pass through sections of a measured surface. The mentioned vectors located in the planes are also normal to investigated cross-sections. The angles between the above mentioned vectors are calculated at selected points uniformly distributed along considered cross-sections of a curvilinear surface.The number of points uniformly distributed along analyzed cross-sections of a surface, at which mentioned curvatures and angles (which are used for assessing the degree of deviation of a section of a surface from the 2D curve) are calculated, depends on the user of a coordinate measuring system. Therefore, the number of those points is the next input data for the algorithm of the selection of scanning lines, which results from the expected accuracy of numerical calculations.The real coordinate measurements of curvilinear surfaces can be made by using, for instance, the 2D curve and the 3D curve measurement elements. The example of measurement software using such measurement elements for measuring curvilinear surfaces is the Calypso software package produced by the Carl Zeiss company. In the case of the 2D curve, vectors normal to a free-form curve at given points lie in one plane. In the algorithm of defining the positions of scanning lines, the deviation of a given cross-section from the 2D curve is taken into account due to the types of the methods of the probe radius compensation process that are to be used in the case of real coordinate measurements.n\u2014a number of points, at which angles The calculation of the arithmetic mean of the angles  were used for the first three input parameters. In the case of the parameter concerning the difficulty of a coordinate measurement, three triangular functions were used. Those functions for the individual input parameters are presented in an value . For exaThe ranges for those functions have been determined based on the differences between the extreme values of individual input parameters  calculated using the CATIA V5-6 software (Dassault Syst\u00e8mes) during simulation research, the results of which are presented in the In the case of the output parameter, six triangular membership functions were used . The decThe system of the selection of scanning lines from generated cross-sections of a free-form surface is based on the rules, the selected examples of which are presented in Three input parameters were used for the second part of the fuzzy logic based system. The first two are related to the accuracy of two probe radius correction methods based on the second and fourth degree B\u00e9zier curves. The accuracy of the probe radius compensation methods was determined on the basis of the average values of the deviations calculated between scanning lines and computed corrected measurement points. The third input parameter concerns the accuracy of substitute models of selected scanning lines. This accuracy was assessed based on the maximum deviations between offset curves and substitute curves interpolating selected groups of measurement points. The general view of the second part of the system is presented in Three triangular membership functions were used for the output parameter . The valThe selected rules for the part of the system responsible for the assessment of the number of measurement points uniformly distributed along selected scanning lines are presented in The developed algorithms regarding the selection of scanning lines and the evaluation of a selected number of measurement points distributed along measured cross-sections were verified based on the examples of two theoretical products having upper curvilinear surfaces . The 3D The simulation research concerned the selection of scanning lines and the number of measurement points distributed along selected scanning lines. The research was carried out for two selected free-form surfaces.The macros enabling automatic generation of planes passing through points randomly distributed on the given surfaces in order to create cross-sections of the considered curvilinear surfaces and consequently scanning lines were prepared by means of the CATIA V5-6 software. Moreover, those macros enable the automated calculations of the average curvatures of considered cross-sections, their lengths and the deviations of cross-sections from 2D curves. Additionally, the developed macros enable the selection of maximum and minimum values among calculated values of curvatures, lengths of potential scanning lines and their deviations from 2D curves. The extreme values of curvatures, lengths and deviations of cross-sections from 2D curves in the case of the considered free-form surfaces were necessary to determine the membership function of the input parameters for the first part of the system based on the fuzzy logic, which assists a user when selecting scanning lines.The simulation studies regarding the selection of scanning lines were carried out for 10 points randomly distributed on two free-form surfaces of the products. The points were distributed by using the Latin Hypercube Sampling method and the MATLAB software. The distance of points from the boundaries of the free-form surface equal to 20 mm was used. The applied distance should not be too small to avoid the positioning of scanning lines too close to the boundaries of the free-form surface. A scanning line located too close to the boundary may cause that the real contact coordinate measurements will be impossible to be carried out. The used distance depends on the experience of the user of a coordinate measuring system. For both considered free-form surfaces, the same group of the randomly distributed points was used. Four planes were generated at each random point and the angle between the neighboring planes was equal to 45\u00b0. The applied angle results from the necessity of using the uniform circular patterns of the analyzed cross-sections distributed in relation to the random points generated by means of the LHS method. The uniform patterns were used to simplify the algorithm of the distribution of scanning lines. The need for simplification results from the fact that the method is to be implemented in the industry. The planes were rotated around axes parallel to the Z axis of a coordinate measuring machine due to the assumption that a stylus of a measuring probe should be parallel to both the Z axis of a machine and the group of rotated planes. Such an orientation of a stylus will enable collision-free coordinate measurements of curvilinear surfaces whose shapes are similar to the shapes of the surfaces presented in Moreover, 10 uniformly distributed points were applied to calculate the average curvatures for the generated cross-sections of the free-form surfaces. On the other hand, in the case of the calculations of the deviations of the curves from the 2D curve, the number of points at which the computations were made was equal to 30.The automatically generated cross-sections for both considered curvilinear surfaces are presented in The completed calculations enabled the selection of scanning lines. The selected lines, along which coordinate measurements in the single point probing mode should be made, are presented in The evaluation of the accuracy of the probe radius correction process performed by using two selected methods based on the B\u00e9zier curves and the accuracy of the substitute geometry representing individual cross-sections and scanning lines of a curvilinear surface was carried out by means of the computer-aided design software Rhinoceros. This software is dedicated mainly to modelling curves and free-form surfaces. In the first place the radius of the stylus tip had to be determined when working with the Rhinoceros software. This value is the fundamental result of the qualification process of probing systems in the case of contact coordinate measurements carried out with the use of coordinate measuring machines and it is necessary to conduct the probe radius correction process. The radius of a measuring tip was equal to The simulation research was carried out for 20 measurement points for both surfaces. The initially selected number of measurement points depends, similarly as in the case of the parameters necessary to generate the group of cross-sections of a surface, from which scanning lines are selected, on the decision of the user of an individual measuring system and the assessment of the time of coordinate measurements. The algorithm of the distribution of measurement points along selected scanning lines assumes choosing the starting number of measurement points, which may be done on the basis of the user\u2019s experience. After selecting the initial number, the expert system may modify the applied number of measurement points and this is done independently of the user of a measuring system. The starting number of measurement points could be also chosen randomly but the experience of the user increases the probability of getting the right number of measurement points faster than with the random selection. This, in turn, may reduce the time of planning of a measurement strategy and speed up the start time of real coordinate measurements.The probe radius correction process was carried out by using two selected methods based on the second and fourth degree curves for 20 indicated measurement points uniformly distributed along the offset curves. Subsequently, the calculated corrected measurement points were compared to the scanning lines. On the basis of this comparison, the values of the average deviations between the corrected points and the scanning lines were calculated for two methods of the probe radius compensation.Moreover, the substitute models of the offset curves were evaluated for 20 measurement points uniformly distributed along the offset curves. The substitute curves were the B-Spline curves of the third degree interpolating selected measurement points. The cubic B-Spline curves are very often used during the process of modelling products. In the next stage, the substitute curves were compared to the offset curves of the individual scanning lines. The maximum values of deviations were calculated based on this comparison.The maximum deviations and the mean deviations  were the basis for the assessment of the selection of the number of measurement points uniformly distributed along the scanning lines of both considered curvilinear surfaces. The experimental research was carried out to verify the correctness of defining the positions of the scanning lines by using the proposed method of defining the location of measurement points on curvilinear surfaces of measured objects. The research was carried out for the second considered curvilinear surface . The meawhere: L\u2014a measured length, mm; The aim of the experimental investigations was to check whether the scanning lines selected by using the new method of determining the distribution of measurement points enable detection of the deviations of the profile of the considered curvilinear surface that exceed the assumed tolerance. Therefore, the experimental investigations concerned the first part of the created method of defining the distribution of measurement points, which is related to the determination of the positions of scanning lines on a measured free-form surface. In order to check the correctness of the developed method, it was necessary to obtain the information regarding the form deviations of the considered curvilinear surface, which correspond as much as possible to the real deviations. The values of the form deviations were obtained by means of contact coordinate measurements made with the use of the ACCURA II coordinate measuring machine equipped with the VAST XT scanning measuring probe . The measuring system applied when performing coordinate measurements of the analyzed free-form surface is presented in The number of scanning lines uniformly distributed along the measured surface during performing coordinate measurements was equal to 30. The scanning speed equal to When analyzing the positions of the generated scanning lines, it can be observed that some of the measured cross-sections run through the fragments of the considered curvilinear surface, which are characterized by the form deviations exceeding the assumed value of the tolerance of the surface profile. Such positioning of measured cross-sections will increase the chances to detect the discrepancy between the actual form of the measured product and its design documentation during conducting real coordinate measurements.the method that enables the distribution of measurement points between two points located on a measured free-form surface and chosen by the operator of a CMM;the method of single measurement points, which are randomly selected on a considered curvilinear surface of a measured object by the user of a CMM.In the case of some commercial methods of determining the location of measurement points on curvilinear surfaces, there is a large probability of not detecting deviations that exceed the accepted tolerance. The examples of such methods are:Both above mentioned methods are available in the Calypso measurement software as parts of the Free-form surface measurement element. The created method of determining the positions of measurement points on a measured free-form surface can be implemented in commercial measurement software and thus used in the industry. In the case of the Calypso commercial measurement software, it is possible to define the distribution of measurement points on a curvilinear surface based on free-form curves selected by the user of the software. Those curves can be imported to measurement programs prepared by means of the above mentioned measurement software as the parts of the nominal CAD model of a measured object. The imported nominal model may include the measured cross-sections generated by using the first part of the developed method for determining the location of measurement points. Moreover, the user of a CMM can determine the number of measurement points uniformly distributed along the selected scanning lines by using the appropriate functions of the Calypso software. The adopted number of measurement points for individual scanning lines is the element of the strategy of coordinate measurements and may be the result of using the second part of the developed method for defining the distribution of measurement points. The stages of implementation of the created method in the selected commercial measurement software are presented in The advantage of the developed method is the ability to determine the location of measurement points on curvilinear surfaces on the basis of several factors, thus taking into account different aspects of contact coordinate measurements. The presented method gives users of contact measuring systems the possibility of an individual approach when defining strategies of coordinate measurements. The employees of quality control departments can decide by themselves which aspects of measurements are more important. For example, in the case of some measurement tasks, the measurement time is the most significant parameter, and for other tasks the highest possible accuracy is the most important aspect when performing measurements. Moreover, the advantage of the presented method is not being the part of blind strategies.The proposed fuzzy logic based expert system enables determining the distribution of measurement points on curvilinear surfaces of measured products not only on the basis of the decision of the operator of a contact measuring system. Therefore, the user of the presented method has less influence on the distribution of points on a measured free-form surface compared to the users of two presented commercial methods of determining the distribution of measurement points.The obtained results of the experimental investigations confirm the usefulness of the proposed method of defining the distribution of measurement points. In addition, the undoubted advantages of the new method are the increase in the level of automation of defining measurement strategies and the possibility of the implementation of the developed method in commercial measurement software. Those advantages create, in turn, the chances to apply the developed method in various branches of the industry. Moreover, the high level of automation may increase the efficiency of coordinate measurements of curvilinear surfaces.Further investigations may be aimed at the verification of the created method of the distribution of measurement points during measurements of other examples of free-form surfaces, not only theoretical ones but also occurring in products currently manufactured in the industry. In the case of more complex products, which are composed of many curvilinear surfaces, compared to these analyzed in this article, the proposed method could be used independently for each free-form surface. This would create the non-uniform distribution of measurement points for each surface and finally for a whole measured product. The new method does not take into account the generation of auxiliary movements of a measuring probe when moving a probe between individual measurement points, which may be the subject of further research. However, planning auxiliary movements can be relatively easily done manually by the operator of a CMM by means of functions of commercial measurement software because the proposed method does not require the use of advanced five-axis coordinate measuring machines as in the case of the algorithm presented in the paper . Moreove"}
+{"text": "The ATHLOS  project is a consortium of 15 partners across Europe who are working together to understand patterns of healthy ageing trajectories, and to seek the factors that determine those patterns, in a harmonised dataset of 17 international cohort studies of ageing. During this symposium we will be presenting some of the work that has recently been carried out within this project. The symposium will consist of four talks: the first talk will introduce the project, and describe the preliminary work that took place within the first few years of the project, and the challenges faced by the consortium. The second talk will focus on the harmonisation process and on the development of the health metric, an indicator used to measure healthy ageing in this project. The third talk will focus on inequalities in healthy ageing, specifically investigating the impact of education and wealth across cohorts. Finally, in the last talk we will describe the role of lifestyle behaviours  and their impact on healthy ageing trajectories."}
+{"text": "In the original publication of the article, few of the authors were missed in the author group.The correct author group is mentioned above. The original article has been corrected."}
+{"text": "Two case studies are described which show application of forensic expertise to establish important circumstances related to the investigation of the crimes against wildlife flora and fauna. Forensic study of the animal hair is a method for investigation of the crimes against wildlife objects which is used more frequently during the recent years. The perspectives of development of the new branch of forensic research in Russia are formulated, and the proposals and recommendations for developing the Eurasian wildlife flora and fauna network are formulated in this article. The frequency of the wildlife crime, dynamic development of the Customs Union and the necessity of the customs procedures unification including legal expertise support for the customs authorities in relation to the wild flora and fauna objects, urge the forensic expertise development in Russia.The wildlife forensic in Russia advocates the need for forensic support for the wildlife crime investigations: domestic, foreign and international practices and scope for improvement. The presentation examines the key developments in the provision of forensic support for investigations of the wildlife crime, and advocates the need to incorporate the wildlife forensics as a separate branch of forensic inquiry in the Russian Federal Center of Forensic Science (RFCFS) of the Russian Ministry of Justice with cooperation of the Severtsov A.N. Institute of Ecology and Evolution of the Russian Academy of Sciences (Institute of ecology and evolution).The Open Expert Group named Eurasian Wildlife Forensic Networks (EAWFN) was created in 2014 to enhance efficiency of the forensic examination in this sphere. EAWFN was formed by the Forensic Institutions of the Republic of Kazakhstan, the Kyrgyz Republic, the Russian Federation, the Republic of Tajikistan, in order to promote disclosure of crimes against the wildlife .Felidae has received special attention. This attention is by the necessity to preserve relatively sparse wild population of these species threatened by the increasing illegal hunting and smuggling. In particular, the illegal trade of the skins of jungle cat (Felis chaus), leopard (Panthera pardus), lynx (Lynx lynx), irbis (Uncia uncia), derivatives of Amur (Siberian) tiger  are quite common. In this paper, we describe some examples of expert practice of RFCFS when the research objects were animals or their part and derivatives, belonging to the family Felidae.Recently, the forensic support for investigation of crimes against the representatives of the family Felidae, their parts and derivatives. The following methods were applied: macro-morphological and microscopic observations, organoleptic investigation.The materials of this study are the objects of the wildlife fauna, belonging to the family Felis silvestris lybica, three samples; Felis silvestris, three samples), jungle cat (Felischaus) (three samples). The latter reference samples were studied first.Fifty animal skins were delivered for expertise to RFCFS; nine reference samples from the collection of the Research Zoological Museum of the Biological Faculty, Moscow State Lomonosov University . In the framework of this expertise, hair from all 50 samples were studied as well as the hair from the collections of Zoological Museum: wildcat (Felissilvestris)  .Figure Further conclusions about chemical or technological treatment of the studied objects were done on the basis of organoleptic study. It was demonstrated that the skins passed through certain technological processes, most probably there were processes in small workshops for commercial purposes.Felis silvestris, the mammal of the order Carnivora, family Felidae, genus Felis.50 skins submitted for expertise are the derivatives of wildlife objects and belong to the animals of the species Felis silvestris is included in the Appendix II of the Convention on International Trade in Endangered Species (CITES) of Wild Fauna and Flora.The species All analysed skins are passed through technological treatment .Figure Felis silvestris is spread in Europe, western Asia and northern Africa. Within Russia, its habitat includes southern parts of Dagestan, Chechnya, Stavlopol and rasnodar districts, Kabardino-Balkaria, Northern Ossetia, Adygea.The species The following conclusions were made based on the research results:One more expertise case:In the RFCFS, a forensic inquiry of a wildlife fauna object was conducted based on the investigation of the photographic images and the specimens of the hair collected at the scene of crime. The comparative study of the submitted objects was carried out using hair specimens of different subspecies and hybrids of the leopard species from the collection of the RFCFS obtained due to the exchange programme in the framework of the EAWFN.The detailed comparative study of the hair from the scene of crime and from the referential collections has shown that the compared hair has the structure similar to that of the hair of the hybrid type of the animal (hybrid of the Far East and Near East subspecies). The compared characteristics of the hair are presented in Figures Pantherapardus), being a hybrid of two subspecies: Far Eastern  and Near Eastern (Panthera pardus ciscaucasicus). The purity versus hybridity of the leopard from the crime scene was confirmed by the molecular genetic analysis conducted in the Institute of Ecology and Evolution.The forensic investigation has demonstrated that the animal, obtained during the visual study of the crime scene belongs to the Ieopard species (Pantherapardus) is included in the Appendix I of the CITES, as well as in the International Red Book and the Red Book of Russian Federation.The leopard species , do not conform to the genetic status of the animals suitable for re-introduction (population restoration). The natural hybridization of these two subspecies is improbable, taking into account the large distance between their habitats. This means that this animal most probably was bred in the captivity.According to the publication , the hybFelidae clearly demonstrates the necessity for detailed study of their biological characteristics, formation of traces of these animals, development of the methods of collection and study of substantial evidences. Recently, complexes of forensic expertise have been applied for the inquiries about the crimes against the wildlife objects: zoological, traseological, ballistic, veterinary and some other special types of expertise. Very interesting seems to be the study of the specific features of the stripe pigmentation pattern of the skins of some species of the family Felidae, for example Amur tiger .Summarizing the experience of the forensic expertise for the inquiries on illegal hunting of the animals belonging to the family Felidae are generated through the development of molecular genetic research methods. DNA investigation of the wild cats could allow not only detection of the species, but in some cases even identification of individual [As mentioned earlier, wide possibilities for improvement of the forensic expertise of the wildlife representatives of the family dividual .Felidae. As for RFCFS, it initiated a programme for integrating the research experience of the wildlife flora and fauna by the forensic institutions as well as by the research teams of the Russian Academy of Sciences and other scientific organizations and universities.Russian forensic experts are interested in the cooperation with the foreign colleague to exchange experience of the forensic expertise practices, new methods, methodologies, technical means and reference materials. Regular direct personal contacts between the experts and scientists are apparently the most efficient and promising link. This is most important for the experts from neighbouring countries, inhabited by the same species of the family In the perspective of combating the crime in the sphere of the wildlife plants and animals utilization, the priority should be given to the synthesis of the experience in carrying out forensic expertise of the wildlife flora and fauna objects, scientific methodological support of this branch of the forensic inquiry, international consolidation and coordination of scientific and methodological policy in relation to the wildlife flora and fauna objects by means of the EAWFN development."}
+{"text": "In the published article, there was an error in the affiliation of Yannan Liu. The author is not connected to the second affiliation, 307th Hospital of Chinese People's Liberation Army. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "The editors, members of the editorial board, publishers, reviewers, authors, and all other entities related to the Euroasian Journal of Hepato-Gastroenterology are extremely happy as the articles of the journal are now referred in PubMed. This is in addition to its indexing in several other indexing organizations. Our thanks and gratitude are for all who have been working for this important endorsement and those who worked for this purpose.Indexing of journals in PubMed is not the only and final target of the editors and publisher. The journal should be placed in better position by having an impact factor within a reasonable time. To achieve this goal, some fundamental changes would be incorporated soon.The journal will act as an official journal of the Euroasian Gastroenterological Association (EGA). A strong executive committee of EGA would constantly look after the journal.The editorial board of the journal will be strengthened and formulated to meet the demand of the time. The instructions to authors will be made more objective-oriented and the authors will get better review process for their precious article.The numbers of issues of the journal will be extended from the present levels of two per year. All these efforts would finally make this journal one of the most prestigious journals in this region. We all are expecting your active cooperation to accomplish this goal.We are extremely glad of the work and collaboration of the publisher of the journal, JAYPEE Publisher, for their outstanding support in the last 7 years and hope that these scholastic and materialistic support would be provided for years to come.Finally, we would remind that a journal is an outcome of a team work and we do hereby express our gratitude to all seen and unseen entities related to journal compilation and publication.Sheikh Mohammad Fazle AkbarEditor-in-ChiefEuroasian Journal of Hepato-GastroenterologyHasan OzkanEditor-in-ChiefEuroasian Journal of Hepato-GastroenterologyMamun Al-MahtabCo-Editor-in-ChiefEuroasian Journal of Hepato-Gastroenterology"}
+{"text": "Adaptation to and coping with the diagnosis dementia is a complex process. The right support in this phase is important to find the right care and to (self-)manage future care wishes. However, people with dementia (PWD) and their family carers (FC) often experience support directly after the diagnosis as inadequate. Support is not provided until problems start to accumulate and available support is not focused on continuation of their life and the emotional impact of the diagnosis. Therefore, the intervention SHARE  was developed and studied in the US and adjusted to and pilot-tested in the Netherlands with positive results. SHARE is innovative because it is designed for dyads dealing with early-stage dementia to enhance communication between PWD and their FC and to prepare them for the future. In this study, the Dutch SHARE intervention was adjusted because of new insights and an RCT is being conducted to evaluate the (cost)effectiveness of this version of the Dutch SHARE. The primary outcome measurement for the PWD is quality of life and self-efficacy for the FC. Secondary outcomes are stress, communication in the relationship and perspective taking (only FC). The design and procedures of the RCT will be presented in this poster session as well as the demographic characteristics of participating dyads. This study contributes to knowledge about psychosocial interventions for PWD and FC with special attention for preventive empowerment of the ability to cope with the disease and the capacity to deal with the situation."}
+{"text": "The authors wish to make the following corrections to this paper :Change in AcknowledgementDue to a lapse, the Acknowledgement section was missing from the original article version .Acknowledgments: The authors would like to thank the support from the Fund of the National Natural Science Foundation of China under Grant No. 61601135 and Natural Science Foundation of Heilongjiang Province of China under Grant No. QC201706802.The authors would like to apologize for any inconvenience caused to the readers by these changes."}
+{"text": "JCB staff noted errors in the in-text citations and order of papers in the reference list that were introduced during production of the article. The authors were alerted of these inaccuracies and we apologize to our readers for these errors.Following publication, the Both the HTML and PDF versions of the article have been corrected. These errors appear only in print and PDF versions downloaded on or before January 10, 2019."}
+{"text": "There are errors in the Funding statement. The publisher apologizes for the errors. The correct Funding statement is as follows: This study was funded by the School of Medicine and Public Health Grant # UWSMPHPHPRJ82KR.In the Author Contributions, Brian Torres (BT) should be listed as one of the persons who wrote the paper. The publisher apologizes for the error."}
+{"text": "Following publication of this article , concernPLOS ONE Editors retract this article based upon the unavailability of original data and records and the ambiguous identification of samples and treatments.Following a joint investigation by the Birmingham VA Medical Center and the University of Alabama at Birmingham, the institutions requested retraction of this article, as the conclusions could not be supported by available data. In line with the institutions\u2019 investigation and recommendation, the The authors did not comment on the retraction decision."}
+{"text": "The Namibian policies and legislative framework were reviewed to determine the extent to which the needs of persons with disabilities were met and aligned with the United Nations Convention on the Rights of Persons with Disabilities (UNCRPD). Further, the disability legislative framework of Namibia is compared with that of other southern African countries.We conducted a retrospective analysis of policy and legal framework which addresses the needs and rights of persons with disabilities in Namibia from 1990 to 2016. A qualitative approach employing a case study design was used. Furthermore, a comparative analysis of the policies and legislation for alignment with the UNCRPD and how Namibia compares with other southern African countries is discussed.Four policies, one piece of legislation and one international instrument were identified as directly related to disability. Community-based rehabilitation was adopted as the main strategy for rehabilitation. Alignment of the policy and legal framework with the UNCRPD was found to be minimal. Furthermore, most of the legislation in southern Africa was formulated before the existence of the UNCRPD in 2006.Although much progress has been made in meeting the needs of persons with disabilities, key implementation issues to be addressed include central coordination, overlapping strategies, disability models and gender differences. There is a need for the policy and legal framework of Namibia and other southern African countries to be more responsive to the human rights needs of persons with disabilities.The study offers insights in reviewing disability policy and legal frameworks in southern Africa for influencing disability service delivery. Future studies can investigate the progress of implementation of disability policy and legal framework from the perspectives of implementers and recipients of services. The United Nations (UN) General Assembly of 1993 UN . In NamiAlong with the adoption of various disability policies, Namibia ratified the UN Convention on the Rights of Persons with Disabilities (UNCRPD) in 2007 UN . The UNCAlthough Namibia has made much progress in establishing policies and legislation, there is no evidence of a study conducted to assess the policy and legislative framework and the extent to which this framework is aligned to the UNCRPD.This review sets out to identify and assess the policy and legislative framework that addresses the needs of persons with disabilities in Namibia and the extent to which these are aligned (similarities and differences) with all articles of the UNCRPD. Further, the disability legislative framework of Namibia is compared with that of other southern African countries including Zimbabwe, Malawi and Zambia.We conducted a retrospective analysis of the policy and legal framework which addresses the needs and rights of persons with disabilities in Namibia from 1990 to 2016. A qualitative approach employing a case study design was used.All national policies or legislation developed post-independence from 1991 and any international conventions that were ratified by the national government were identified. The Namibian government websites were searched for relevant policies and legislation for disability-related subject matter, and manual searching within line ministries was undertaken. Only policies or legislation that directly addresses disability issues were included. The search was conducted in October 2016. Where hard copies of the policy or legislation were not available, reprints were requested from the line ministry responsible for overall coordination of the policy.Review and analysis of the policy and legal framework was conducted in three steps. Firstly, the key contents of each document were thematically analysed utilising the Walt and Gilson  policy tNational Disability Council (NDC) Act with the UNCRPD (Article 1\u201350). This was done by extracting all the articles of the UNCRPD and adding them to the \u2018data charting form\u2019. Each Article in the UNCRPD was then mirrored with sections contained in both the NPD and NDC Act to determine the extent of alignment. A narrative summary of the results was completed.Secondly, a comparative analysis was undertaken to determine alignment of the NPD and NDC Act with that of other disability legislation in previously mentioned southern African countries. The above analyses provided an overview and identified any gaps of interest in the disability policy and legal framework of Namibia.Finally, a comparative analysis was conducted of the purposes and disability models adopted by the Ethical approval was obtained from the Human Sciences Research Ethics Committee at the University of KwaZulu-Natal (Ref No. HSS/0646/015D) and approval to collect data was obtained from the Research Committee at the Ministry of Health and Social Services in Namibia (Ref No. 17/3/3).NDC Act) to the UNCRPD. The fourth part reviews and compares the disability legislation in some identified southern African countries.The findings are presented in four parts. The first part outlines the progression of formulation and ratification of policies and legislative framework. The second part analyses the four components of policy: the context within which it was developed; the content and objectives; the actors involved in this policy; and the process of how the policy was initiated, formulated, implemented and evaluated . The thiPrior to the development of any formalised approach to delivery of services for persons with disabilities in Namibia, a community-based rehabilitation (CBR) programme was adopted in 1992 which allowed steps to be taken to formalise and integrate the process for the provision of care and support for persons with disabilities within the primary health care network. In 1997, the NPD , none has been reviewed or updated. Only the Sector Policy on Inclusive Education has a clearly laid out monitoring and evaluation framework that stipulates the outcomes, implementers, budget, time frames and recommendations. The other policies  simply suggested annual internal reviews. It is noteworthy that the mandate for reviewing the policies is placed on the coordinating ministry except the NPD where the mandate is on the NDC.NDC Act has no monitoring and evaluation framework in place to guide the process on amending or reviewing the Act. Furthermore, the NDC Act has no regulations that guide its implementation as per Section 23. Contrary to the NDC Act, the UNCRPD provides a monitoring framework at national and international levels. Article 33 and Article 34 of the UNCRPD provide mechanisms of national and international monitoring, respectively.The NDC Act did not show any evidence of extensive use of evidence in their formulation.It is critical for policy formulation to be underpinned by the use of evidence in formulation . The National Policy on Orthopaedic Technical Services, the National Policy on Mental Health and the Sector Policy on Inclusive Education indicate the use of extensive evidence during formulation, whereas the NPD and NDC Act with all of the articles of the UNCRPD. All the articles of the UNCRPD were reviewed and compared for alignment with sections of both the NPD and NDC Act as shown in The policy and legal framework in Namibia predates the UNCRPD. It was therefore critical to investigate the extent of alignment of the NPD and NDC Act. Articles 32 to 52 of the UNCRPD stipulate the UN reporting system. Both the NPD and NDC Act were developed before UNCRPD and thus do not show any alignment.The findings revealed that there is some alignment of the UNCRPD Articles with sections of the NPD with the exception of UNCRPD Articles 10 (Right to life), 11 (Risk and humanitarian emergencies), 14 (Liberty and security of person), 15 (Freedom from torture), 18 , 20 , 22 , which are not reflected in either the NPD or the NDC Act. Alignment of the NDC Act is only apparent in Articles 1 (Purpose), 2 (Definitions), 5 , 6 (Disabled women), 8 (Awareness raising), 12  and 31 (Statistics and data collection).Minimal alignment is shown between the UNCRPD Articles and the sections in the Identification of the gaps in alignment of policy and legislation with the UNCRPD can provide an opportunity for areas of amendment. The UNCRPD is the foundation upon which Namibia needs to build and revise its national policies and laws. This will further facilitate disability being addressed as a human rights issue and thus stimulate all sectors in Namibia to mainstream disability into their activities.NDC Act and the UNCRPD as shown in this review, the Act has good elements that can be compared with other southern African countries. Findings indicated that except for Malawi, most of the Acts in southern Africa were formulated before the coming into existence of the UNCRPD in 2006. With the exception of Zambia, most of the Acts have not been amended to align them to the UNCRPD. The main purpose of the NDC Act of Namibia (2004) was to establish a monitoring body for the implementation of disability services. This purpose is similar to that of Disabled Persons Act (Zimbabwe) and Persons with Disabilities Act (Zambia). The NDC Act of Namibia does not make specific provision for the promotion and protection of human rights which the Disability Act of Malawi does. The definitions adopted by the NDC Act of Namibia are similar to those of the Disabled Persons Act (Zimbabwe) and Disability Act of Malawi.Despite the misalignment of the This review identified that CBR underpins all policies and legislation as a key strategy for providing rehabilitation services in Namibia. Thus, the CBR programme plays a central role in the implementation process of disability services in Namibia.NDC Act. Policy formulation should take into account the refrain by persons with disabilities that is \u2018nothing about us without us\u2019. Similarly, under the aegis of Article 32 of the UNCRPD, persons with disabilities should be consulted on services in which they are involved  in formulation. This may have been attributed to the demand for quick answers and remedies by policymakers which can lead to reductionism (Walt et al. NDC Act not having regulations to guide implementation. Guidelines are critical in promoting action (Walt & Gilson A lack of guidelines was apparent in most policies with the Another crucial issue that was not addressed adequately by the policies and legal framework is gender differences. Although the NPD mentions women as a special focus group, it does not pay sufficient attention to gender differences that should be addressed such as the role of women as a wife or mother. The role of women and men in the house can ultimately affect their career paths. Men with disabilities are expected to have a caregiver who does household chores, yet a woman with a disability is expected to do all this by herself Percy . TherefoThe policy and legal framework adopted varying models of disability and definitions. This might have been because of the different stages when the policies and legislation were adopted as the disability models have evolved over time. Therefore, a lack of a uniform countrywide model on disability creates challenges with issues of eligibility for social protection, as there are no consistently applied assessments of disability. Furthermore, this inconsistency leads to difficulties in the provision of disability service delivery and evaluation.NDC Act to the UNCRPD indicates a close alignment with some sections and minimal alignment with others. The minimal alignment of the NDC Act to the UNCRPD is because of the fact that the Act was enacted mainly to set up the National Council on Disability rather than regulating the implementation of the disability services. Moreover, the incompatibility of the NPD and the NDC Act to the UNCRPD may be attributed to the fact that both documents were formulated and pre-dated the UNCRPD. The disability framework in Namibia needs to be more responsive to the human rights of persons with disabilities, reasonably accommodate them and bring equality (Ntinda Reflection on the alignment of the NPD and the y Ntinda . SimilarIt is worth noting that Article 144 of the Constitution of Namibia (Government Republic of Namibia Since independence in 1990, Namibia has made significant progress in developing policies and legislation to address the needs of persons with disabilities. This review identified the CBR programme as underpinning all policies and legislation as a key strategy for providing rehabilitation services in Namibia. The critical issues that could hamper the implementation process include among others the lack of a central mechanism for coordination, overlapping strategies, formulation not grounded in evidence, lack of regulations and guidelines, different disability models adopted and failure to address gender differences.NDC Act indicate in certain instances a close and in others a minimal alignment to the UNCRPD. Further, most of the legislation and policies in southern Africa were formulated prior to the existence of the UNCRPD in 2006. The UNCRPD is the international gold standard instrument for promoting the rights of persons with disabilities. To this end, there is need for Namibia and other southern African countries to be more responsive to the human rights needs of persons with disabilities.The NPD and the The finding of this study can be utilised to review the policy and legal framework of Namibia as well as offer insights into disability legislation in southern Africa. To strengthen the insights shared in this review, it is therefore important for future studies to investigate the progress of implementation of the policy and legal framework in Namibia from the point of view of the actual implementers and recipients of services. The diversity in disability groups potentially creates varying needs."}
+{"text": "In the original publication of the article, the alphabets in figures were published in upper case and mismatched with the figure legends.The corrected Figs."}
+{"text": "The bell sounds from many years ago. We must plan for the future when the number of births has increased in the early 1980s. During the years, the population ages 65 and above has reached the highest value in Iran in 2015 .One of the key challenges in access to universal health coverage is high burden of diseases and lack of access to sufficient funds . In accoIn the whole world, health systems incurred a high percentage of costs and a greater share of resources allocated , 6. TherBased on raised issues and considering the importance of aging, the authors of this paper intend to conduct a doctoral thesis with the aim of policy analysis to identify the basic needs of elderly and anticipate and prioritize the aged care services in Iran. Because the proper planning leads to better resource allocation and increases client satisfaction and service provider, results of this study can be helpful for decision-making process in providing effective and available aged care services in Iran."}
+{"text": "We have been made aware of the fact that a large proportion of the Introduction section and corresponding references of the title paper  had beenMolecules paper, which to the best of our knowledge is original.As a member of the Committee on Publication Ethics (COPE), MPDI takes very seriously the responsibility to enforce a rigorous peer-review process together with strict ethical policies and standards to ensure the addition of high quality scientific works to the field of scholarly publication. In addition to an infringement of the Elsevier and American Association for Cancer Research copyright on the previous publications, this is also a clear violation of our policy to only publish new, previously unpublished material, so this paper is declared retracted and shall be marked accordingly for the scientific record. We cannot comment on any of the scientific data contained in the Molecules editorial team for the fact this event went undetected during the peer-review and pre-publication processing of the paper and for any inconvenience caused by this event.We would like to apologize to our readership on behalf of the"}
+{"text": "Most of the states now have Medicaid LTC programs administered by corporate HMOs. Several states, however, still have programs administered by non-profit community based organizations, most of which are members of long standing Aging Networks which grew out of the Older Americans Act in the 1970s. This paper will offer a comparative overview of these models of LTC administration including a typology designed to identify major cultural and political differences between the states with and without corporate managed LTC models and an analysis of the available information regarding their comparative costs and outcomes, mainly access to care and quality of care. The paper will conclude with an assessment of the implications of the information presented for the future of Medicaid LTC policy and politics at the state and federal levels and for the future of LTC advocacy and accountability across the states."}
+{"text": "The name of the institution where the participants were recruited from and the name of the institution where informed consent was obtained from have been incorrectly withheld from the published article.In the Participants subsection of the Methods, there is an error in the first sentence of the first paragraph. The correct sentence is: \u201cParticipants were recruited from a database of volunteer families of the Baby and Child Research Center Radboud University, the Netherlands.\u201dIn the Participants subsection of the Methods, there is an error in the second sentence of the third paragraph. The correct sentence is: \u201cEthical approval for the study was obtained from the Ethics Committee of the Faculty of Social Sciences, Radboud University, the Netherlands (ECG2012-1301-006).\u201d"}
+{"text": "The Federation of European Biochemical Societies (FEBS) was the first regional organisation of biochemists, holding its first congress in London in 1964. There followed the creation of the Pan American Association of Biochemical Societies (PAABS) and then the Federation of Asian and Oceanian Biochemists (FAOB). An obvious development was the formation of a similar organisation to take care of Africa, but this proved impossible so long as apartheid survived in South Africa. With the removal of the latter, the way was clear for the foundation of the Federation of African Societies of Biochemistry and Molecular Biology (FASBMB). The first congress of the new federation was held in Nairobi in September 1996 under the Presidency of Prof. Dominic Makawiti of Nairobi University. Among the 300 participants were representatives from 19 countries in Africa. The second congress was held at Potchefstroom in South Africa in 1998 and the third was just held in Cairo."}
+{"text": "Journal of Clinical Medicine are presented studies using imaging technologies based on electrical impedance tomography, synchrotron radiation computed tomography and intravital probe-based confocal laser endomicroscopy. The studies on the pathophysiological mechanisms pertain to the evaluation of the biomarkers of the disease and the platelet disfunction during extracorporeal membrane oxygenation. These contributions witness the intensity of ARDS research as many of the key problems of the disease are only in part resolved.Acute respiratory distress syndrome (ARDS) is in the center of the scientific debate both for its complex pathophysiology and for the discussion about the remedies that could contribute to its healing. The intricate interplay of different body systems that characterizes ARDS is mirrored by two main research threads, one centered on the pathophysiological mechanisms of the disease and the other on the new approaches to lung imaging. In this Special Issue of the  Journal of Clinical Medicine are devoted to clarifying some of the recent advances in pathophysiology and lung imaging of acute respiratory distress syndrome (ARDS). This syndrome, although recognized 50 years ago [Journal of Clinical Medicine. Two different threads are followed, one centered on the pathophysiological mechanisms and implications of the disease and the other to new approaches to lung imaging during ARDS.The threads that go through this Special Issue of the ears ago , is stilears ago  and for ears ago . It has ears ago  in the aears ago . This coJournal of Clinical Medicine, experts of the field proposed contributions to new approaches to lung imaging.How important imaging is for recognition and management of ARDS is easily understandable by the fact that since the beginning of its identification, a method of lung imaging has been always used to define its presence . In thisPutensen et al.  reviewedHaase et al.  have useThe clinical theme of tidal recruitment was also faced by Muders et al.  who aimeA different imaging method has been studied by Scaramuzzo et al. . Their pRemaining on the theme of the assessment of small lung structures, Lesur et al.  reviewedThe problem of diffuse alveolar damage (DAD) has been retrospectively investigated by Cardinal-Fernandez and colleagues . The detThe biomarkers of acute lung injury were reviewed by Murray et al. , having 2/FiO2. The search for biomarkers of ARDS was also pursued by Kim et al. . They foSt\u00f6rmann and colleagues  studied Wand and coauthors  exploredClinically relevant is the prospective study executed by Harnisch et al.  on the nJournal of Clinical Medicine has hosted in this monographic number witness the vivacity and intensity of ARDS research. The complexity of ARDS warrants many years of further research as many of the key problems of the disease [The contributions that the  disease  are only"}
+{"text": "Following publication, the publisher was alerted to potential image manipulation and duplication in this paper. An investigation was initiated, in accordance with our established procedures, which revealed image duplication in Figure 4 of the article. The publisher requested the original images from the authors, and an examination of those images revealed computer manipulation. Given extant concerns over the validity of the study, the article has been retracted.The retraction of the article was approved by the Field and Specialty Chief Editors of Frontiers in Plant Science."}
+{"text": "As a consequence, it is necessary to consider the corollary of symptoms that the patient who suffers from a chronic disorder manifests as a unitary corpus, where it is possible to intervene both with medical and psychological science to improve QoL and therefore physical symptoms. In the history of the patient's illness, the weight of psychological variables plays a fundamental and non-negligible role when the doctor's interest is that of treating the patient from a long-term perspective.The development of therapeutic interventions able to fuse different perspectives into a tailor-made interdisciplinary management approach in a single patient and the development of a quality body of research on the topic are future challenges in order to improve QoL and the subjective well-being of patients with CPD and psychopathological signs and symptoms.CC was responsible for writing the entire opinion article, for checking the adequacy of references and of all aspects of layout.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Dear colleagues,The third Annual Meeting new style of the BSR is the result of a joint effort of the Section of Neuroradiology and the Section of Pediatric Radiology, with the highly appreciated input by the Young Radiologist Section (YRS).An attractive and challenging program by a national and international faculty of renowned experts is offered to general radiologists and trainees. Neuroradiology has always been largely attractive, with continuously evolving knowledge and imaging techniques, and additional processing and post-processing software to refine diagnosis and \u2013 ultimately \u2013 therapy. Pediatric radiology deserves equal attention; indeed, especially for the pediatric population, dedicated imaging modalities have to be carefully used to guarantee safe conditions and accurate diagnosis in all circumstances.The European Society of Radiology, the Radiological Society of North America and the American College of Radiology launched the International Day of Radiology (IDoR) a few years ago. The main theme for 2017 is on Emergency Radiology, a theme almost all radiologists are faced with in daily practice.It is a great pleasure to welcome you at the 2017 Annual Meeting of the BSR in Brussels. Enjoy meeting science, colleagues and industry.We are already looking forward to the 2018 Annual Meeting of the BSR; the main topics will be Head & Neck Radiology and Interventional Radiology.Best regards.Prof. Dr. Raymond OyenOn behalf of the Scientific Council of the BSRNovember 2017"}
+{"text": "In the original article, the affiliations were incorrect and should have read as per the above.The funding statement was also incorrect and should have read as follows.PJT and DHA received institutional funding from the NIHR BRC. This article is independent research supported by the NIHR Birmingham Liver Biomedical Research Centre. The views expressed in this publication are of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health.The authors apologize for the errors."}
+{"text": "Following publication, concerns were raised regarding the scientific validity of the article. An investigation was therefore conducted in accordance with our established procedures. As the raw data presented in the manuscript could not be provided, the Specialty Chief Editor concluded that the conclusions and assertions could not be sufficiently supported by the material provided.The retraction of the article was approved by the Chief Editors of Pharmacology and the Editor-in-Chief of Frontiers.The authors agree to the retraction."}
+{"text": "In the current context of epidemiological transition, demographic changes, changes in consumption and lifestyle habits, and pressure on care costs and organized health systems for acute conditions, the Integrated Care Model by Shortell has become a conceptual reference in the search for new methods to manage chronic conditions by focusing on the health conditions of a given population that must be addressed by a set of institutions organized into networks. Within the last 15 years, cancer has gone from the third- to the second-leading cause of death in the State of S\u00e3o Paulo and has shown a gradual increase in the number of new cases; it has thus become a relevant issue for public health and health management. The model adopted by the State for the organization of the cancer care network was the motivation for this study, which aimed to evaluate the evolution of the model of care for cancer patients within the Unified Health System (Sistema \u00danico de Sa\u00fade) based on the integrated care model. Since 1993, the year that cancer was first considered highly complex in the Sistema \u00danico de Sa\u00fade by the Ministry of Health, it has been possible to observe a progressive orientation towards the integral and integrated care of patients with cancer. In the State of S\u00e3o Paulo, the active participation of qualified service providers through a Technical Reference Committee showed that experts could contribute to the definition of public policies, thereby providing a technical base for decision making and contributing to the development of clinical management. In the current context of epidemiological transition coupled with demographic changes (aging of the population and urbanization), changes in consumption and lifestyle habits, increasing pressure on care costs, a more rights-conscious population, and organized health systems, the World Health Organization (WHO) has proposed the Model of Innovative Care for Chronic Conditions, focusing on population, promotion, prevention and the integration of care According to the model developed by Shortell, there are seven elements of the integration of care, as shown in The challenge is the transformation of an acute case-focused system with an emphasis on disease and individual planned care whose primary goal is to fill hospital beds and whose organization is departmentalized and focused on the functioning of institutions in isolation. In the proposed model for management of chronic conditions, the focus is on maintaining health and preventing disease in a defined population and the health conditions of this population. A set of institutions has been organized into networks to manage this model.Among the barriers to integration are the inability to understand the new business model in which primary care is the center of care and the well-being of the target population becomes the focus of the expected results. Thus, there is a need for all health professionals to act in an integrated manner. Hospitals must stop acting alone and must establish alliances with other hospitals and clinics in the community while developing a specific strategy for primary care. The greatest barrier in the US Academic Health Systems is cultural. These systems are characterized by the strong fragmentation of care and a high level of knowledge in inpatient treatment with high complexity (with high use of technology). In addition, the new demands require knowledge to act in the low-complexity (and low-technology) situations of primary care In Brazil, since the conception of the Unified Health System , the Healthcare System of Brazil, it has been organized based on regions and networks. In the English model of Regionalised and Hierarchical Networks, there is a network of regions based on large territories with primary health centers, secondary schools and teaching hospitals that ensure access to comprehensive care and seek self-sufficiency in health resources at all levels and in smaller territorial subdivisions. Recently, under the influence of the Shortell model, the concept by Mendes has become the basis for the guidelines of the SUS organization in Health Care Networks In the Pact for Health in 2006, a regulatory framework was established that encouraged the creation of models capable of responding to chronic and acute conditions and that promote health surveillance and actions In the State of S\u00e3o Paulo, based on this legal framework, 17 Regional Health Care Networks  were established from a grouping of 63 Health Regions after an extensive process of regional discussion and agreement Each RRAS consists of health services of different technological densities and of support systems to ensure the integrality of the services. Established organized, systematized and regulated horizontal relations between basic care and these different health services are recognized as points of attention. Each RRAS must have a sufficient capacity for basic care, medium-complexity services and some high-complexity services. It is also within these territories that Thematic Networks must be organized , some of which are restricted to high-complexity services and others include services of different levels of complexity.In the past 15 years, cancer has gone from the third- to second-leading cause of death in the state and has shown a gradual increase in the number of new cases. For this reason, the study of the Thematic Oncology Network is relevant for public health and health management. This study aims to evaluate the evolution of the care model for cancer patients in SUS based on the integrated care model.For the theoretical basis, the topic of health care networks and oncological assistance was studied via a review of the literature in the databases of Bireme - Virtual Health Library (VHL) and PubMed, a survey of the Brazilian standards for care , reports of the WHO and publications and reports of the National Cancer Institute .In Brazil, cancer ceased to be a disease treated only in medical offices and became a public health problem in 1922 with the Anticancer First Plan and the inauguration of the Radium Institute in Belo Horizonte, a private entity and the first center to fight cancer in the country. In 1941, the National Cancer Service (SNC) was created to organize, guide and control the anticancer campaign at the national level. The SNC obtained its headquarters in 1957 with the inauguration of the INCA to direct national policy for the control of cancer from 1990 with the promulgation of the Organic Health Law The complexity involved in the different stages is a risk factor in terms of time, a prognostic element in regard to cancer. The structures necessary for the treatment of cancer patients are highly complex. The modalities can vary between surgery, radiotherapy and/or chemotherapy in different combinations according to each case. For the provision of cancer care under the SUS, there is a need for a specific authorization determined by technical criteria presented in the Ministerial Orders. From this qualification, hospitals receive authorization to bill the procedures performed according to the SUS Procedure Table using the Authorisation for High Complexity Procedures in Oncology  Since 1993, when the Ministry of Health classified Oncology as an area of high complexity, a series of regulatory instruments have been published to direct service providers and system managers with regard to the organization of patient care. The last Ministerial Order, 140, had as a significant motivator the publication of Law 12.732 of November 22, 2012, which established a maximum deadline of 60 days for the start of treatment of patients diagnosed with cancer The Portaria changed the focus of habilitation, leading to the need for regional discussions and the elaboration of care plans that considered the network that included the establishment to be enabled. It was no longer sufficient to forward the request of the qualifying hospital describing its structure and capabilities to perform this highly complex care. The managers needed to describe how organization and responsibility would be allotted at all levels of care, considering all of the components of the network of care for people with chronic diseases in the thematic axis of cancer .Concern about establishing a network of cancer care in the State was emphasized in 1991 with the creation of ONCO-REDE (State Network of Tertiary Oncology Assistance). In a Decree of the Governor, the creation of a network within the scope of the State Department of Health composed of the CECANs (Cancer Centres), or public and private hospitals belonging to the SUS, was defined as providing assistance, educational and scientific activities in oncology by the Oncology Foundation of S\u00e3o Paulo  and by public and private entities in support of cancer patients In this context, on May 8, 2008, the activities of the Cancer Institute of the State of S\u00e3o Paulo (ICESP) began in the management model of the Social Health Organisations , with technical and scientific coordination of the Faculty of Medicine of the University . In the OSS management model, a private organization administers the hospital through a contract that provides goals and results. These activities were structured to provide comprehensive care to adult cancer patients at all stages of treatment and for all of their needs, including palliative care when necessary In almost three years of operation, ICESP has established itself as the technical reference in oncology for the State Department of Health . It is the only SES hospital dedicated to the treatment of adult patients with cancer  in the SUS, with two years of activity. It published the Manual of Pipes in Oncology, which provided protocols of conduct specific to each type of cancer, based on extensive discussion with the specialists of the Department of Radiology and Oncology of FMUSP and members of the clinical staff of ICESP. The criteria for choosing the best conduct involved a broad review of the literature and, pragmatically, behaviors with evident efficacy and possibilities of use in the SUS context In the State Health Plan for the period from 2008 to 2011, oncology appears with a focus on the organization of the oncology network in the health regions and in the formation of multiprofessional teams for the three levels of organization and the goal of reducing mortality. In the elaboration of this plan, the need to expand the service offer was identified in the 64 units qualified for oncology care in the SUS. This service was offered from July 2005 to July 2006, and 70% of the oncological surgeries and 85% of the chemotherapies were required, as were 43% of the radiotherapies For the following period , cancer mortality was ranked second with a growing trend, accounting for 15.6% of deaths. The State had 71 units qualified for oncological care in the SUS. There were concerns about the reorganization of the Oncology Network that was already installed and the integration of the services into Regional Health Care Networks (RRAS) Based on this situation, a Cancer Care Plan for the State of S\u00e3o Paulo was proposed for the period of 2011 to 2014 with the objective of reducing cancer incidence and mortality, increasing survival and improving the quality of life of patients . The AdvExamining the model proposed by Shortell, this work attempted to evaluate the \u201cnew culture of management\u201d through the analysis of the rules and regulations produced by the Ministry of Health for Oncology. As an area classified within the High Complexity of SUS, in which the manager requires compliance with minimum parameters for the service provider, Ministerial Ordinances are important drivers of the establishment of care models and the implementation of management culture. It is possible to observe a direction for integral and integrated care. It is necessary to evaluate the practices adopted from these criteria and determine whether they were adopted to complete this analysis. Since the Ministry of Health published the first ordinance with criteria for accreditation and habilitation of treatment services to cancer patients, more than 20 years have passed. During this period, it is possible to observe a progressive orientation towards the integral and integrated care of patients with cancer. In 2005, with the definition of the oncology care line of the National Policy on Cancer Care, which was an important component of the establishment of a clinic management culture, the establishment of a deadline for the end of isolated chemotherapy and radiotherapy services in the Portaria SAS No. 741 was identified. In 2014, the requirement of the referral of a Regional Plan and the candidate services for qualification in oncology, together with the local managers, demonstrated the ability to establish a network of patient care at the three levels of organization . To do this, the hospital can offer the structure and services needed for every step of the care line, focus on care that requires more expensive and complex technologies and establish referral and reference flows with other levels of care.In this context, the State Department of Health of S\u00e3o Paulo adopted a strategy of inviting representatives of this specialty, oncology representatives from hospitals qualified in the SUS with high production, and established a governance system with technical-scientific forums and executive support to SES with the participation of the FOSP and with a main base in ICESP. ICESP has become the reference for the State due to its management model and its connection with the Faculty of Medicine of the University of S\u00e3o Paulo. The State assumed the leading role in the organization of a thematic network, and the experts were able to contribute to the definition of public policies. This model reproduced the national model of INCA as a technical-scientific reference for the Ministry of Health.Although we have observed evolution in the regulation of cancer care in SUS, there are still many challenges for the establishment of the Oncology Network in the integrated care model.\u00a0The coexistence of the specialists of the Reference Committee on Oncology with the technicians of the Health Department, the managers of the system, showed on the one hand the need for this approach to establish technical parameters to support the decisions and organization of services.\u00a0On the other hand, there is still difficulty, from all elements of the system, in prioritizing the adoption of management tools for clinical practice and regulation. The examples of projects presented in this article reinforce the idea that specialized hospitals should participate more actively in the discussions and elaboration of public health policies and, in this way, may participate in health care networks in a role that goes beyond the care of acute chronic conditions, contributing to the development of clinical management technologies and alternative processes.Written by Madi MR with guidance from Cerri GG."}
+{"text": "Following publication of this article , concernPLOS ONE Editors retract this article based upon the unavailability of original data and records and the ambiguous identification of samples and treatments.Following a joint investigation by the Birmingham VA Medical Center and the University of Alabama at Birmingham, the institutions requested retraction of this article, as the conclusions could not be supported by available data. In line with the institutions\u2019 investigation and recommendation, the The authors did not comment on the retraction decision."}
+{"text": "The article introduces readers to the Master of Public Health and Doctor of Public Health programmes, offered by the Department of Community Medicine, School of Medical Sciences, Universiti Sains Malaysia. The programme vision, structure and accomplishments over the decade are presented to provide an understanding of the programme. It is hoped that this professional programme will continue to flourish and produce new generations of public health medicine specialist equipped with the necessary knowledge and skills to make significant contribution towards improving the health of the population. There is an oil painting adorning the wall of my office. This beautiful landscape of trees painted in hues of greens brought me the memory of the student who gifted me the painting. I remember this student well, a quaint persona, distant but not unfriendly, headstrong but very independent and despite all her personal hardship, managed to persevere and graduated from the 1+3 Master of Public Health (MPH)/Doctor of Public Health (DrPH) programme. She is one of the 48 graduates produced since the inception of the programme in 2010. Forty-eight public health physicians who have now become eminent advocators and leaders of public health medicine in Malaysia. Their achievements are our pride and joy, produced #USMstyle.The 1+3 MPH/DrPH programme is our core business at the Department of Community Medicine; a programme designed as a response to an acute need of the Ministry of Health for Medical Officers of Health to serve in the then fast expanding rural health services. The intention of the programme is to produce competent health professionals with the appropriate knowledge and skills in public health to plan, implement and evaluate effective public health programmes that can improve the quality of life of the community. The MPH programme is a two-semester coursework degree, carrying a total of 40 units consisting of 32 core units and 8 units of Research Project  (15)"}
+{"text": "Sportowy Poznan\u201d (\u201cSports Poznan\u201d) program. The assessment made by service recipients shows that the factor having the strongest limiting effect on the use of sports and recreation services is the economic factor. In the assessment made by the respondents using their services, the efforts of city authorities to make Poznan sports clubs operate in a professional manner gained the lowest score. The results of the Anderson\u2013Darling test show that the social factor of preparing infrastructure for the residents of the city of Poznan was the most important for the respondents, obtaining a test value of 0.886.The aim of the article is to identify which groups of factors  significantly determine the condition and development of the sports and recreation infrastructure of the city of Poznan and shape the needs and expectations of its residents. Standardized interviews among 39 service providers and 1159 service recipients made it possible to collect primary data on the presentation of the pace and directions of changes taking place in the sports and recreational facilities of the city, paying special attention to identifying and prioritizing factors determining this development. In order to establish the hierarchy of factors analyzed in the paper and operating within the same research problem for both groups of respondents (service recipients and service providers), the Anderson-Darling test was used. The test results were referenced to the already existing \u201c The issue of determining the position and importance of sports and recreation in the development of cities and regions is unquestionable. An example of such reasoning is the concept of the city as an \u201centertainment machine\u201d created by T.N. Clark . The autInvestments in sports and recreation infrastructure allow for the development of sport . Among t-The sports and recreation market model developed by B. Pitts, L. Fielding, and L. Miller, who selected three large segments of this market: Entities dealing with organizing sport , entities producing material sports goods and representatives of units supporting sport , and entities that deal with sport promotion  .-A simplified model of the sports and recreation market developed by M. Shank, who assumes that the market is formed by two groups of entities: Recipients and providers, as well as sports products that are the subject of exchange .-The model of the sports and recreation market proposed by B. Mullin, S. Hardy, and W. Sutton, where the sports and recreation market is depicted by means of four categories of entities or activities related to sport: Organizers of sports events with a high level of attractiveness, attracting a large audience; producers and distributors of tangible sports goods and government non-profit organizations; entities organizing sports life at the school and company level; and finally, supporting entities, such as sports associations, sponsors, and sport activists .The growing number of business entities in sports and recreation, as well as the relations between them, both non-commercial and, increasingly often, commercial, reinforces the statement that Poland faces the process of the creation of a new model of sports and recreation services on the market. In Western European countries and in the United States, the sports market was defined as early as in the 1970s, and nowadays, e.g., in the USA, it ranks 11th in terms of turnover ($152 billion) among all industry markets [T. Slack et al., believes that an entity that acts directly for the benefit of sport or directly supports sport is any entity that operates on the sports market and treats it as its core area of activity (core business). In the group of providers, three types of entities are distinguished: (1) Sports organizations, e.g., sports clubs and other physical culture organizations, such as sports schools, sports associations, sports and recreation centers, etc.; (2) producers and distributors of sports goods  service entities providing their services to both final recipients and institutional customers  . Thus, aDiagnosis of Social Requirements for Infrastructure, Sports, and Recreation [Sport for All in the City\u2019s Space [Best Practices in Sport Objects Managing by Polanowski and Brach [The presented studies are innovative and do not have sufficient support in the literature on the subject. Research on the participation of Poles in sports and recreational activities was published by the Central Statistical Office in 2013 . Later icreation . It pres\u2019s Space . In 2017Sports and recreation are important areas of activity for the city of Poznan. Each year, more than 10% of Poznan\u2019s budget is spent on physical culture, which is a level comparable to that of the European Union average . Poznan\u2019Poznan is a city located in west-central Poland. The city\u2019s population is about 540,000. It is an important academic site , a center of trade, sports, technology, and tourism. It has often topped rankings as a city with very high-quality education and a very high standard of living . It alsoThe aim of the study is to identify which groups of factors  significantly determine the condition and development of the sports and recreation infrastructure of the city of Poznan and shape the needs and expectations of its residents.those that, according to the service recipients, create barriers in the use of sports and recreation facilities in the city of Poznan;Sportowy Pozna\u0144\u201d program;those which, in the opinion of service recipients, allow for the assessment of tasks contained in the \u201cSportowy Pozna\u0144\u201d program.those that, according to service providers, allow for the assessment of tasks contained in the \u201cThe literature on the subject shows that the development of sports and recreation infrastructure is determined, among other things, by economic, social, and spatial factors, which were compiled into three groups for the needs of the conducted works and the implementation of the research objective:Sportowy Pozna\u0144\u201d program.Such a way of interpreting the research results allowed for the identification of the factors that, in the opinion of the surveyed service recipients and service providers, are the most important for the operation of sports and recreation facilities. It also allowed for the verification of the following thesis: Selected groups of factors significantly determine the condition and development of the sports and recreation infrastructure of the city of Poznan, as well as shape the needs and expectations of its residents. Simultaneously, the performed analysis constitutes the basis for the assessment of tasks contained in the \u201cThe subjects of the research are indoor sports and recreation facilities (that offer the possibility to engage in sports and recreation regardless of the season) in Poznan. The questionnaire using standardized interviews made it possible to collect primary data concerning the presentation of the pace and directions of changes (trends) taking place in the sports and recreation facilities of the city of Poznan, paying special attention to identifying and prioritizing factors determining this development. Two self-constructed questionnaires were used for the study. These questionnaires were conducted by the authors among service providers and service recipients in the sports and recreation facilities in the areas of tennis courts, indoor swimming pools, and fitness clubs, and were personally filled out during a conversation with the recipients. The first part of the questionnaires focused on socio-demographic variables like age and education level . The secA targeted selection of respondents (service providers and service recipients) was conducted in selected all-season sports and recreation facilities, and research was carried out in the areas of tennis courts , indoor swimming pools , and fitness clubs  in the city of Poznan among 39 service providers (managing a sports and recreation facility) and 1159 service recipients (using the services of a given sports and recreation facility). The recipients were mainly 20\u201329 years old  and 30\u201339 years old . Among the surveyed people, the minority were aged 50 years old and older . A detailed specification is presented in People with higher education constituted the vast majority of respondents at 55% (637). A total of 30.7% (356) possessed secondary education, and 14.3% (166) were people with primary education. The respondents who were professionally involved in sport comprised 41% (476), and those who never practiced sport competitively comprised 59% (683).To analyze the phenomena studied, the following methods of descriptive statistics were used: Arithmetic mean, measures of dispersion , measures of the shape of the distribution , tests for the equality of variances, Pearson\u2019s chi-squared test, conditional probabilities, the binary variables model, and the Anderson\u2013Darling Test. All statistical analyses were conducted using Statistica Software 10.0 .The Anderson\u2013Darling test is one of the statistical tests of distribution conformity with a set reference distribution model. It is usually used to check compliance with the normal distribution. It allows for the verification of hypotheses about the distribution of extreme statistics and characteristics of the variables studied in the work .It is calculated as:Sportowy Pozna\u0144\u201d program) for both groups of respondents (service recipients and service providers).This test was used to establish the hierarchy of factors analyzed and studied in this work, operating within the same research problem ;Socio-spatial ;Social ;Economic (high fees in sports and recreation facilities).The factors limiting the residents\u2019 ability to use sports and recreation facilities in the city of Poznan based on the opinions of service recipients were put together in the following groups:In the opinion of the surveyed service recipients, the strongest limiting impact has an economic factor (high prices in sports and recreation facilities). This is indicated not only by the average value ;socio-economic ;spatial-economic (extension of sports and recreation infrastructure).The next step in the adopted research procedure was an attempt to assess the significance of action/performance factors resulting from tasks included in the strategic program for the city of Poznan, \u201ccipients  and servcipients  concerniSportowy Pozna\u0144\u201d strategic program based on the opinions of the recipients.Sportowy Pozna\u0144\u201d program. Almost all of the factors examined in the work were considered significant, obtaining the average values of Sportowy Pozna\u0144\u201d program by the City of Poznan authorities is similar and is at a similar level. Only the functioning, or rather the efforts of the authorities to operate Poznan sports clubs in a professional manner, gained the lowest score in the opinion of the surveyed service recipients , the Anderson-Darling test was used. This test allows for the verification of hypotheses about the distribution of extreme statistics, characteristic of the variables studied in the work. The adopted hypothesis assumes that the probability distribution obtained for service recipients is identical to the probability distribution obtained for service providers. The test results contained in The application of the Anderson\u2013Darling test allowed for a clear identification of the determinant with the highest impact on the development of the sports and recreation infrastructure in the city of Poznan, thus enabling the residents to participate in recreation. It should be emphasized that both groups of respondents jointly regarded this factor as the most important, which means that its implementation, consisting of the preparation of infrastructure for the residents of the city of Poznan, meets the expectations of both users and managers of sports and recreation facilities. The negative result of the socio-economic factor of creating the image of the city of Poznan through sports and recreation is equally important in the test. It means that the activities of the City of Poznan authorities in this respect do not meet the expectations of the city\u2019s residents.-Environment and possibilities of being active: In Poznan, the level of satisfaction of the residents surveyed was average, expressed as -The offer of local sports clubs and other service providers : In Poznan, the level of satisfaction of the surveyed residents is above the average, expressed as -Evaluation of the local authorities\u2019 policies aimed at improving the physical activity of residents: In Poznan, the level of satisfaction of the surveyed residents ranks above the average expressed in the value The data quoted below contain the opinions of Poznan residents surveyed against the background of surveys conducted by the Central Statistical Office, which present the opinions of respondents from Poland and other European Union citizens. The comparative analysis shows the following:In the majority of European Union countries, citizens are satisfied with the efforts of local authorities to ensure that local residents have the possibility to engage in sports and recreation activities , but Polthose that, according to service recipients, create barriers for the use of sports and recreation facilities in the city of Poznan;Sportowy Pozna\u0144\u201d program;those which, in the opinion of service recipients, allow for the assessment of tasks contained in the \u201cSportowy Pozna\u0144\u201d program.those that, according to service providers, allow for the assessment of tasks contained in the \u201cThe aim of the article is to identify which groups of factors  significantly determine the condition and development of the sports and recreation infrastructure of the city of Poznan and shape the needs and expectations of its residents. For the needs of the conducted work and implementation of the research objective, the determinants are divided into three groups:N = 1159) and service providers (n = 39) regarding the presentation of pace and development trends in sports and recreation facilities in the city of Poznan, paying particular attention to identifying and prioritizing factors determining this development. The conducted research procedure allowed for the verification of the assumptions and objectives pursued and permitted in the following conclusions:Sportowy Pozna\u0144\u201d strategic program, based on the opinions of service recipients, the economic factor has the strongest limiting effect on the use of sports and recreation services (high prices in sports and recreation facilities). Then there are spatial factors (long distance between the sports and recreation facility and the place of residence) and the lack of general accessibility of sports and recreation facilities.Among the accepted factors of the operation of the \u201cSportowy Pozna\u0144\u201d strategic program, the surveyed service recipients granted the greatest importance and satisfaction with the effects of the implementation to the social factor\u2014preparation of sports and recreation infrastructure for the residents of the city of Poznan. Efforts of the city authorities to ensure the professional operation of Poznan sports clubs gained the lowest score in the opinion of the surveyed service recipients. The activity of sports clubs to a large extent creates the image of the city as a center for sports.In the implementation of the \u201cSportowy Pozna\u0144\u201d strategic program was assessed as average by service providers. The values of the means determining the level of satisfaction of the respondents are comparable, but lower than the average values obtained in the assessment made by the service recipients. Service providers objectively assessed the functioning of the sports and recreation facility they run, without trying to artificially raise its rank. The surveyed service providers recognize the significant impact of social and spatial factors, judging them as satisfactory, as they do with all of the tasks covered in the \u201cSportowy Pozna\u0144\u201d program. The lowest score was given by service providers (as well as service recipients) to the effects of activities related to the professionalism of the operation of Poznan sports clubs.The effectiveness of the city authorities\u2019 policies in the implementation of the \u201cThe social factor of the preparation of infrastructure for the residents of the city of Poznan, in the opinion of both groups of respondents (service recipients and service providers), was considered the most important, obtaining a test value of 0.886;A spatial-economic factor came second in the hierarchy of the Anderson\u2013Darling test, with a test value of 0.362;The third in the hierarchy  was a social factor propagating the idea of an active lifestyle for the residents of the city of Poznan;The lowest importance in the hierarchy of factors, with a test value of 0.017, was achieved by the socio-economic factor of creating the image of the city of Poznan through sports and recreation.In order to establish the hierarchy of factors analyzed in the paper and operating within the same research problem for both groups of respondents (service recipients and service providers), the Anderson\u2013Darling test was used. The test results  clearly The subjects of the research are indoor sports and recreation facilities in Poznan (that provide the possibility to engage in sports and recreation regardless of the season). Standardized interviews allowed for the collection of primary data among service recipients (It should be emphasized that the social factor based on the preparation of infrastructure for the residents of the city of Poznan was jointly selected as the most important by both groups of respondents, which means that its implementation, consisting of preparing infrastructure for the residents of Poznan, meets the expectations of both users and managers of sports and recreation facilities. The negative result of the socio-economic factor of creating the image of the city of Poznan through sports and recreation obtained in the test is equally important. It means that the activities of the city of Poznan authorities in this respect do not meet the expectations of the city\u2019s residents. Unfortunately, in the opinion of the surveyed service recipients, the economic factor turned out to be the one that most severely limited the availability of sports and recreation facilities in the city of Poznan. The results of the research show that the inhabitants of Poznan understand how important it is for them to provide conditions for the implementation of various forms of physical activity by building facilities for sports and recreation accessible, and providing them with adequate equipment, that is, the preparation of sports and recreation infrastructure in the city. While analyzing the responses of the surveyed service recipients, attention should also be paid to their opinion concerning supporting mass sports in Poznan, as this is one of the most significant factors determining the physical activity of the city\u2019s residents. If sport for all does not find much support from city residents, it may result from the lack of a rational development strategy not only in terms of infrastructure, but also in terms of staff."}
+{"text": "The art and science of gerontological pedagogy is a balance of multidisciplinary paradigms that provide students with a pathway to the depth and breadth of the field of gerontology. This session will explore a variety of issues, including possibilities and challenges within the context of pedagogical approaches to gerontology education both in and out of the classroom. Topics include applied and theoretical perspectives and the what, why, and how gerontological educators do what they do and how it can impact the learning environment not only for students but for the community at large."}
+{"text": "The equation describing the distance from the origin of the coordinate system for MTOC placement on the x-axis is incorrect. Please see the correct equation here:There is an error in the Eq (6) in the \u201cCalculation of the intensity of the electric field\u201d subsection of the Models section. Please see the correct Eq (6) here:There is an error in the Eq (7) in the \u201cCalculation of the intensity of the electric field\u201d subsection of the Models section. Please see the correct Eq (7) here:The authors confirm that the code used in the modelling do not contain the errors in parameters and equations, which affect only the description of the models. The results and conclusions are therefore unaffected by these corrections to the reporting of the methodology.There are errors in the scale of the y-axis shown for the bottom panel of"}
+{"text": "Since the historical and game-changing discovery of NGF by the late Rita Levi-Montalcini  has been of great interest in the last decades. Soon after its discovery, it was demonstrated that NGF played an essential role on the survival of forebrain cholinergic neurons during developmental stages and subsequently a role on the maintenance of their cholinergic phenotype at neuronal cell-somata and synaptic levels. Since this cholinergic system was shown to be one of the first casualties of the Alzheimer's pathology, great research interest was placed on this relationship. This was much more the case since the forebrain cholinergic system plays an important role in higher CNS functions like attention, memory, and learning.This set of neurons is likely the most NGF-dependent of the entire adult nervous system. In early years, there was a strong interest in assessing the potential value of applying exogenous NGF for the recovery of experimentally damaged cholinergic septo-hippocampal and basalo-cortical neuronal pathways. The NGF capability to prevent and even to recover these degenerating pathways was shown to be remarkable and an exciting novelty at the time. Such effects provoked an interest in the possible application of this principle in AD, an aspect which still remains alive and well-represented in this collection of NGF-AD related contributions.The participation of NGF in a wide range of aspects of the AD pathology poses a number of significant biological questions. The field of research continues to attract individual scientists and research groups alike. For this special issue of Frontiers we convened a number of outstanding investigators for the purpose of assembling a diversity of views related to outstanding questions such as: what is the role of NGF in the continuum of the AD pathology?, what is its involvement on the atrophy of the basal forebrain neurons?, and what are the translational possibilities of such a body of knowledge?I am most gratified that very distinguished colleagues responded positively to the call of generating significant revisions. Further to it, I would think that this Special Issue of Frontiers will be of value to many and that it will inspire new and transformative research on NGF in the realm of the AD pathology.The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The project Cognitive Stimulation in Older Adults: Intervention on Cognitive Frailty and Promotion of Self-Care (in brief the ECOG project) arises in a context of worldwide demographic aging, and is fostered by the need to provide a sustainable solution to the progressive increase in the prevalence of age-related cognitive impairment. The main goal of the ECOG project is to promote active citizenship in old age through the empowerment for autonomy and self-care. Namely, the ECOG team is working on the development of evidence-based programs and tools that promote gains in health in cognitively frail and cognitively impaired older adults from the community. It is also working on the transfer of ECOG products to the practice of health and social care, promoting active involvement of geriatric care institutions in the implementation of the ECOG programs and tools, and ensuring appropriate training of professionals. Finally, the ECOG team is deploying a digital platform to reach out to the broadest audience possible and support the remote access and scaling up of the ECOG products.The impacts expected at an individual level include improvements in cognition, functionality, and autonomy of older adults, with simultaneous reduction of depressive symptomatology, and increase in quality of life of both person cared and his/her caregiver. Regarding societal gains, we anticipate an increase in life expectancy and significant postponement of institutionalization associated with geriatric problems. We also believe that the wide implementation of the ECOG products will reduce the costs of interventions for cognitively impaired citizens, contributing to sustainability and efficiency of health systems. Portugal is one of the European countries most affected by the phenomenon of demographic aging , with thThe international entities working to improve health and well-being throughout the life cycle, such as the World Health Organization (WHO), have recognized the phenomenon of demographic aging as one of the major social and economic challenges of the XXI century . As suchCognitive Stimulation and Brain Fitness developed in Coimbra, Portugal, with the support of the Health Sciences Research Unit: Nursing of the Nursing School of Coimbra , and , and CogCognitive stimulation in older adults: intervention on cognitive frailty and promotion of self-care, aims to increase autonomy and self-care in older adults by supporting the establishment and diffusion of stakeholder-centered strategies that empower and encourage communities for active involvement in promoting successful aging. The ECOG project was built in line with the Strategic Implementation Plan of the EIP on AHA . How. How28].The ECOG project will also provide recommendations to support the implementation of intervention programs. For this purpose, the experiences and perceptions of end-users and intervention providers are being mapped, with a special focus on factors that may interfere with the successful implementation of the ECOG programs. As an example, the preliminary results, obtained from the ECOG project partner institutions, have shown that formal training on program implementation and the clear articulation of all professionals about the schedule of activities and use of physical spaces are crucial to increase the impact of intervention programs. The need for better articulation with seniors to guarantee their commitment to the program was also identified. The inclusion of the recommendations in educational materials produced within the project\u2019s framework will allow the replication of the programs\u2019 success across a range of contexts.The educational materials produced by the ECOG team will be made available to the citizens through a technological platform created specifically for this purpose. The use of the platform will foster the exchange of knowledge between different stakeholders working in the field of geriatric care. It will also amplify the use of ECOG products, increasing the potential range of the associated benefits. We expect that scaling up of such good practice will contribute to the increase in life expectancy and to avoidance/postponement of unnecessary / too early institutionalization of older adults.The ECOG project presents multiple advantages at individual and institutional level. The implementation of group and home-based intervention programs allows the creation of environments where seniors learn and have fun and where their experience of social inclusion is strengthened. Active interaction with others contributes to the maximization of social and cognitive skills 28], whi, whi28],Some of the ECOG products were designed to be used in a home-based setting. The availability of the intervention programs  can be seen as a factor that promotes the caregiver\u2019s active involvement in the process, with the benefits being reflected in a significant reduction in the caregiver\u2019s workload, improvement in the relationship with the cared person, and overall increase of caregiver\u2019s well-being. Other expected benefits include the increase of caregivers\u2019 health literacy and the adoption of healthy behaviours.The advantages of professionals involved in the ECOG actions are related with fostering the transfer of scientific knowledge to daily clinical practice. They also include empowerment in the use of more individualized and person-centered approach to care, and improvement of the practical knowledge about the tools that support comprehensive geriatric assessment.At an institutional level, the advantages include the possibility of using programs that are structured, easy-to-apply and highly accepted by seniors. The cost-benefit ratio of these programs is good since they do not require highly specialized professionals or specific material resources. In addition, the ECOG intervention programs show benefits in health that are comparable  or even The Nursing School of Coimbra is responsible for adapting this good practice to the different contexts of geriatric care and for its subsequent validation, promoting the use of ECOG products by new partners. Although there are formal partnership protocols established between the Nursing School of Coimbra and other partner institutions and organizations, the latter have the autonomy to manage the intervention processes according to their needs and available resources. This autonomy is highly relevant, since it allows better management of factors related to the success of the ECOG programs, increasing their sustainability and facilitating their future replication. However, the additional mechanisms that support community outreach need to be identified, in order to multiply individual and societal gains and reduce overall costs of interventions for older citizens with cognitive impairment.The good practice established under the ECOG project is an innovative approach that supports successful aging. It focuses on the needs of older adults with cognitive impairment, their formal and informal caregivers, and institutions working in the field of geriatric care, and presents multiple advantages over other existing programs. As this practice has a potential to reduce the costs of interventions for cognitively impaired older citizens, contributing to sustainability and efficiency of health systems, efforts are made to integrate it into the health and social care provided to the aged population. However, it is still necessary to explore new research perspectives in the field of geriatric care, in order to reinforce the transfer of evidence to clinical practice and to enable impactful changes in its use."}
+{"text": "This article provides an analysis of the autonomous navigation of marine objects, such as ships, offshore vessels and unmanned vehicles, and an analysis of the accuracy of safe control in game conditions for the cooperation of objects during maneuvering decisions. A method for determining safe object strategies based on a cooperative multi-person positional modeling game is presented. The method was used to formulate a measure of the sensitivity of safe control in the form of a relative change in the payment of the final game; to determine the final deviation of the safe trajectory from the set trajectory of the autonomous vehicle movement; and to calculate the accuracy of information in terms of evaluating the state of the control process. The sensitivity of safe control was considered in terms of both the degree of the inaccuracy of radar information and changes in the kinematics and dynamics of the object itself. As a result of the simulation studies of the positional game algorithm, which used an example of a real situation at sea of passing one's own object with nine other encountered objects, the sensitivity characteristics of safe trajectories under conditions of both good and restricted visibility at sea are presented. The subject of this article directly concerns sensors, which are the basic part of vessel detection and navigation in the process of ensuring safe control of marine objects. Sensors, such as radars, logs and gyro-compasses, form a source of information for the Automatic Radar Plotting Aid ARPA system, which are mandatory pieces of equipment for each ship to prevent collisions. However, its functional scope is limited to the determination of the safe maneuver of the object to the most dangerous object encountered, followed by its simulation in an accelerated time scale ,2,3. ModFirst, we take into account the subjectivity of the navigator in the assessment of the situation as well as the kinematics and dynamics of the objects encountered . AccordiSecondly, we take into account the game nature of the anti-collision process, which results from the imperfection of maritime law and the complexity of the actual navigational situation at sea .The influence of the information accuracy from sensors on the current state of the transport process and on the quality of safe control, which can be determined through the analysis of the control sensitivity to information inaccuracy, becomes important ,15,16,17The process of managing the autonomous marine vehicles as a complex dynamic control object depends both on the accuracy of the measurements determining the current navigational situation, which was measured using the devices of the automatic radar plotting aids (ARPA) anti-collision system, and on the mathematical model of the process used to synthesize the object control algorithm. jth by determining its motion parameters, including velocity jV and course \u03c8j, and approach elements to its own ship. Furthermore, we can also determine jminD  and jminT   .In theory and practice, there are many methods for determining a safe maneuver or the safe trajectory of the own object while passing other objects. The simplest method is to determine the course change maneuver or the speed of the own object in relation to the most dangerous object encountered. In one article , the \u201ctiThe most important purpose of the control process is to determine a certain sequence of maneuvers in the form of a safe trajectory of the own object. The safe trajectory of the own object can be distinguished in deterministic terms without considering the maneuvering of other objects encountered. In the game approach, this is based on the use of a cooperative or non-cooperative game model of the control process ,25.s of the passing objects, which was subjectively determined by the navigator in the current navigational situation, is important for safe navigation. This value depends on the current state of visibility at sea, which is classified by the international rules for preventing collisions of ships at sea (COLREGs) as either good or restricted visibility at sea.The safety distance DTherefore, the aim of this study is to assess the sensitivity of the quality of security checks and games under the conditions of good and limited visibility at sea.The complexity of the situation when many dynamic objects are passed at sea provides the possibility of using a game model for the control process, given the fairly limited rules of international law of the sea route (COLREGs) in terms of good and limited visibility at sea and a large influence of the navigator's subjectivity in making the final maneuvering decision. It is possible to describe the process in the form of static positional and matrix games or in the form of dynamic differential games. This article proposes the use of the positional game, which is the most appropriate for this type of control process.p(kt) objects in the current step k. As such, the process model considers all possible changes in the course and speed of the encountered objects during the control [The basis of the positional game involves assigning the maneuver strategy of the own object to the current positions of  control ,40,41,42The process state is determined by the coordinates of the object's own position and the positions of the objects encountered as follows:k, based on information from the ARPA anti-collision system on the relative position of the objects that it meets:kt, the own object knows the positions of the objects encountered.The control algorithm generates the own object's movement strategy at the present time tThe following navigation restrictions are imposed on the components of the process state, which consist of the acceptable coordinates of the own position and the objects encountered:The limits of the control values of the own and met objects are determined as: Uj0(p) and the met objects jU0(p) are dependent, which means that the choice of control ju by the jth object changes the sets of acceptable strategies of other objects.The sets of acceptable maneuvering strategies of the own object jth object. First, the value of the safe ships passing at a distance sD is assumed. After this, they are positioned to be at a tangent to circles with a radius sD, which cut off the areas of safe possible changes in the courses and speeds of the own and the encountered objects in the districts with the V and jV rays.sD.The method for determining the total sets of acceptable safe strategies of the own object, while passing with many objects encountered simultaneously, is shown in u0*(kt) at each stage k is implemented using the following three tasks:The algorithm of the safe cooperative control of the own object (1)uj0 in relation to the encountered jth object from the appropriate set of acceptable strategies Uj0PS or Uj0SS, which must comply with the 15th rule of COLREGs and ensure the lowest loss of the path for the safe passage of the encountered object jth object ju0 in relation to the own object from the appropriate set of acceptable strategies U0jPS or jU0SS, which must comply with the 15th rule of COLREGs and ensure the lowest loss of the path for safe pasting of the own object 0 in relation to all J objects  algorithm was developed to determine the safe trajectory of the own object.Through the three-fold use of the xs sensitivity functions of the optimal control u of the game process described by the state variables x can be represented as the following partial derivatives of quality control index Q:The sensitivity analysis refers to the identification of the static and dynamic properties of control objects and to the synthesis of automatic control systems, particularly optimal, adaptive and game systems. A distinction is made between the sensitivity of the object model itself or the control process of changes in its operating parameters and the sensitivity of the optimal, adaptive or game control. This is both in terms of changes in parameters and the influence of disturbances, and impacts of other objects. Therefore, the Q acts as the form of payment for the game, which consists of integral payments and the final payment:The game control quality index jr(kt) with respect to the jth object encountered and the final deviation of the trajectory of the object d(kt) from the reference trajectory. The integral game payment represents the loss of the path through its own object when passing the objects encountered and the final payment determines the final collision risk d(kt):Testing the sensitivity of game control will complete the sensitivity analysis of the final game payment Considering the practical application of the game control algorithm for the own object in a collision situation, it is recommended that the sensitivity analysis of a secure control should be conducted in terms of the information accuracy obtained from the ARPA anti-collision radar system in the current situation and in relation to changes in the kinematic parameters and dynamic control.radar: bearing \u00b10.25\u00b0 and distance \u00b10.05 nm,gyrocompass: \u00b10.5\u00b0,log: \u00b10.5 kn.The permissible average errors that may be caused by an anti-collision system sensors may have the following values for:The algebraic sum of all errors affecting the image of the navigational situation cannot exceed \u00b15% for absolute values and \u00b13\u00b0 for angular quantities.SP represents such a set of information about the control of the State Process in a navigational situation:eSP represents a set of information from the sensors of ARPA system, which contains errors in measurement and processing parameters:xs game as the final deviation of the safe trajectory of the ship kd from the reference trajectory is expressed as follows:The relative sensitivity of the final payment in the PP is a set of state Parameter Processes of control, which is expressed as follows:ePP represents a set of parameters containing errors in measurement and processing parameters:ps, which represents the final deviation of the safe trajectory of the ship Kd from the assumed trajectory, will be:mt is the advance time of the maneuver with respect to the dynamic properties of the own ship, kt is the duration of one stage of the ship's trajectory, sD is the safe distance and sT is the safe time of the approach.The relative sensitivity of the final payment in the game J = 9 objects encountered.The computer simulation of the PG algorithm, which represents the computer software supporting the navigator's maneuvering decision, was conducted using an example of a real navigational situation of the The safe trajectory of the own object and sensitivity characteristics, which were determined by the PG algorithm in the MATLAB/Simulink software, are presented in The safe trajectory of the own object and sensitivity characteristics, which were determined by the PG algorithm in the MATLAB/Simulink software, are presented in The use of simplified models of a dynamic process game for the synthesis of optimal control allowed us to determine the safe trajectories of an own object in situations that involve passing a large number of encountered objects in a certain course sequence and speed maneuvers. The developed algorithms also consider the COLREGs rules and maneuver advance time in addition to estimating the object's dynamic properties and assessing the final deviation of the actual trajectory from the reference value.the sensitivity characteristics are nonlinear, with most being angular values,in the range of the most important changes in input quantities , the sensitivity usually does not exceed 20%,together with the deterioration of visibility at sea, the sensitivity to the inaccuracy of information about the object encountered and the change in the value of safe distance and time of approach increases.The following conclusions follow from the course of the sensitivity characteristics presented in The considered control algorithms are the formal models of the navigator's thinking process that controls the objects\u2019 movement and maneuvering decisions. Therefore, they can be used in the construction of a new model of the ARPA system containing a computer that supports the decision-making of the navigator."}
+{"text": "The Journal and Chief Editors retract the August 2018 article cited above. Following publication, concerns were brought to the attention of the publisher regarding the validity of the article's findings. The conclusion from the assessment of the Specialty and Field Chief Editor is that the article reports unsupported conclusions.The article is retracted in the absence of the authors' agreement."}
+{"text": "In the Animals and diets subsection of the Materials and Methods, there are errors in the first through third sentences of the second paragraph. The correct sentences are: Experimental diets were formulated by modifying American Institute of Nutrition (AIN)-93G diet [25] as summarized in There are a number of errors in"}
+{"text": "The current study examined the incisivus labii superioris muscle (ILS) and its morphologic and spatial relationships with the surrounding structures, especially focusing on the upper mucolabial fold, labial glands, and modiolar area. ILSs were investigated in 52 specimens obtained from formalin-fixed Korean adult cadavers . ILSs were observed in all specimens (100%). The ILS has an oblique and linear origin from the incisive fossa of the maxilla to the point just medial to the origin of the levator anguli oris muscle (LAO). The arising fibers of the ILS arched and covered the prominent labial glands at the superior margin of the orbicularis oris muscle (OOr). After the ILS coursed laterally along the anterior part of the upper mucolabial fold, it divided into superficial and deep inserting fibers in 48 specimens (92.3%) and it did not divide in 4 specimens (7.7%). The superficial inserting ILS fibers and the ILS fibers that did not divide blended with the medial fibers of the LAO to converge toward the modiolus. The deep inserting fibers of the ILS blended with the lateral deep fibers of the OOr in the 48 specimens (92.3%), and the deep inserting fibers continued to descend to converge toward the modiolus in 20 of those specimens (38.5%). These observations indicate that the ILS may assist to compress the labial glands and the upper oral vestibule, controlling modiolar movements and thereby integrating the movements of the mouth and lips. An ultrasound study found that although the OOr may be regarded as a single muscle anatomically, it appears functionally to consist of different parts acting either independently or together with other facial muscles2. The incisivus labii superioris muscle (ILS) comprises the fibers of the OOr that are connected to the maxilla1. The ILS and incisivus labii inferioris muscle (ILI) draw the corners of the lips medially, and the OOr draws the upper lip downward. The circumferential portion of the OOr acts with the ILS and ILI to make the lips protrude3.The orbicularis oris muscle (OOr) is a complex sphincter muscle consisting of numerous strata of muscular fibers surrounding the orifice of the mouth but orientated in different directions5. The OOr and the modiolus, which are insertions of the ILS, are positioned by their attaching muscles. The most obvious determinant of the position and mobility of the modiolus is the net force exerted by the muscles that are directly attached to it5. The OOr has no bony or cartilaginous attachment7, and so this muscle can be drawn toward the contracting muscle that converges to the OOr. Understanding and analyzing the movements of the mouth and lips requires knowledge of how the ILS courses and attaches to other structures near the oral vestibule and in the modiolar area.The ILS reportedly arises from the incisive fossa of the maxilla and arches laterally, interlacing with fibers of the peripheral part of the OOr. The ILS partially blends with the levator anguli oris muscle (LAO) and attaches to the modiolus8, with the degree of differentiation of the ILS being greater in humans than in lower animals9. Burkitt and Lightoller (1926)10 described that the ILS is well developed and that its fibers are of the same size and pigmentation as in the OOr in Aboriginal Australians. There have been several reports about the morphology of the ILI and its anatomical relationships with surrounding structures in humans12. However, there have been few reports about the anatomy of the ILS13. The anatomical relationships of the ILS with the upper mucolabial fold, labial glands, and modiolar area therefore remain unclear.The interlacing of the bundles of the various muscles at the corner of the mouth has evolutionarily become more complex in humansThe current study examined the ILS and its morphologic and spatial relationships with the surrounding structures, especially focusing on the upper mucolabial fold, labial glands, and modiolar area in order to improve the understanding of integrated activities involving these structures during movements of the mouth and lips. This information will also be helpful when performing various types of facial surgery including vestibuloplasty and cleft lip repair.ILSs were observed in all specimens 100%). The ILS had an oblique and linear origin from the incisive fossa of the maxilla to the point just medial to the origin of the LAO. The most-lateral point of origin of the ILS was higher than its most-medial point of origin. The most-medial point of origin of the ILS was located in the periosteum adjacent to the upper mucolabial fold. The majority of the medial origin of the ILS was located in the periosteum just below the upper mucolabial fold, and the minority was located in the periosteum just above the upper mucolabial fold. The origin of the ILS between the most-medial point and the most-lateral point was located in the periosteum where the transverse and alar parts of the nasalis arose. The most-lateral point of the ILS was located just medial to the origin of the LAO. The medially arising fibers of the ILS coursed deep to the superior peripheral part of the OOr and these fibers curved upward and laterally. The medial two-thirds of the arising fibers were usually more curved than the lateral one-third of the fibers. The lateral one-third of the arising fibers descended almost straight downward. As the course of the ILS arched laterally it became the superolateral margin of the OOr, enlarging the dimension of the superior peripheral part of the OOr. It also deepened the superolateral margin of the OOr posteriorly .Where a perpendicular line passing through the lateral one-third of the nostril crossed a horizontal line passing just below the nostril sill .Where a perpendicular line passing through the lateral one-third of the nostril crossed an upper-one-third horizontal line passing between the nostril sill and vermilion border of the upper lip .Where a perpendicular line passing through the lateral one-third of the nostril crossed a middle horizontal line passing between the nostril sill and the vermilion border .Where a perpendicular line passing through the middle of the nostril crossed a horizontal line just below the nostril sill .Where a perpendicular line passing through the middle of the nostril crossed an upper-one-third horizontal line passing between the nostril sill and vermilion border of the upper lip .Where a perpendicular line passing through the middle of the nostril crossed a middle horizontal line passing between the nostril sill and the vermilion border . The arising fibers of the ILS arched and covered the prominent labial glands at the superior margin of the OOr Fig.\u00a0. The arcn\u2009=\u20094, 7.7%), in which all ILS fibers blended with the LAO.Type I , in which more than two-thirds of the ILS fibers became superficial inserting fibers to blend with the LAO; the other fibers became deep inserting fibers of the ILS. The other fibers arose as the medial one-third of fibers, the medial one-fourth of fibers, a few medial and lateral fibers, or some lateral fibers of the ILS.Type II , in which approximately half of the ILS fibers became superficial inserting fibers and approximately half became deep inserting fibers. The superficial inserting ILS fibers blended with the LAO.Type III , in which less than one-third of the ILS fibers became superficial inserting fibers to blend with the LAO, and the other fibers became deep inserting fibers.Type IV  and it did not divide in 4 specimens (7.7%). The superficial inserting ILS fibers and the ILS fibers that did not divide blended with the medial fibers of the LAO to converge toward the modiolus. The insertion patterns of the ILS fibers in the modiolar area could be classified into four types according to the number of ILS fibers that blended with the LAO Fig.\u00a0:Type I , and sometimes the superior fibers of the buccinator muscle. The deep inserting fibers of the ILS blended with the lateral deep fibers of the OOr in the 48 specimens (92.3%), and the deep inserting fibers continued to descend to converge toward the modiolus in 20 of those specimens (38.5%) Fig.\u00a0. The modIn 10 specimens (19.2%), some deep inserting fibers of the ILS and some fibers of the LAO formed a thin muscle layer located deep to the LAO Fig.\u00a0. In two 4. The ILS has a more complicated course than the ILI. The ILS courses along the convex superior peripheral part of the OOr, blending with several muscles in the modiolar area, while the ILI courses laterally and upward along the lower mucolabial fold and blends with the OOr or buccinator below the level of the corner of the mouth12. The present study has clearly demonstrated several anatomical features of the ILS 15 described that some of the lateral fibers of the ILS interlace with and have a common origin with those of the transverse parts of the nasalis in Aboriginal Australians. Other fibers interlace with the alar part of the nasalis, and the most-medial fibers are continuous with those fibers of the OOr that extend up to the septum. However, in the present study, some arising fibers of the ILS were intermingled with those of the transverse and alar parts of the nasalis at their origin sites. The ILS fibers were not merged with the nasalis nor attached to the septum, instead usually blending with the OOr and LAO in the modiolar area.Iwanaga The ILS surrounded the anterior part of the upper mucolabial fold and corner of the mouth in the present study. In addition, the ILS deepened the superior margin of the OOr, thus increasing the convexity of the OOr and ILS. The convex shapes of the OOr and ILS surrounding the upper mucolabial fold and the corner of the mouth appeared to efficiently compress and control the oral vestibule and corner of the mouth, and may help to push food from the oral vestibule into the oral cavity proper.16. Iwanaga et al.13 reported that the bony attachment of the ILS to the alveolar process had a triangular shape. However, in the present study it was found that the ILS had a linear origin from the incisive fossa to the point just medial to the origin of the LAO. Also, the ILS was located between the OOr and LAO in a fan shape. This continuous arrangement of the OOr, ILS, and LAO appears to make the upper lip and the corner of the mouth move successively, especially when the lips protrude.Textbooks describe the ILS as originating from the incisive fossa of the maxilla10 described the ILS as being in contact with some mucous glands of the upper lip in Aboriginal Australians. The present study found that the arising fibers of the ILS arched and covered the prominent labial glands at the superior margin of the OOr. It is therefore thought that the ILS compresses the prominent labial glands at the superior margin of the OOr, while the OOr can compress other labial glands that were situated between the OOr and the mucous membrane.The literature contains few descriptions about the relationships of the ILS with the labial glands. Burkitt and Lightoller (1926)5 described that the ILS segregates into superficial and deep parts as it approaches the modiolus: the former blends partially with the LAO and attaches to the body and apex of the modiolus, while the latter is attached to the superior cornu and base of the modiolus. All of the superficial inserting fibers and some of the deep inserting fibers of the ILS converged toward the modiolus in the present study. A thin muscle layer that was formed by some fibers of the ILS and LAO converged toward the modiolus in 19.2% of the specimens. The superficial and deep inserting fibers of the ILS and the thin muscle layer coursed in different curved planes. Unlike other muscles that attach to the modiolus, the ILS can pull the modiolus superomedially. Thus, the several slips of the ILS may pull the modiolus superomedially in different planes. This arrangement can delicately control the three-dimensional mobility of the modiolus, enabling the fibers to integrate the activities of the oral vestibule so as to protrude the lips during drinking, sucking, swallowing, and speech.Standring (2016)There have been few descriptions about the attachment of the deep inserting fibers of the ILS to other muscles in the modiolar area. Some deep inserting fibers of the ILS blended with the lateral deep fibers of the OOr in most specimens of the present study. The fibers of the ILS blending with the lateral deep fibers of the OOr may therefore reinforce the OOr so as to assist closing of the mouth.8 stated that the ILS and ILI have become more clearly differentiated from the OOr\u2013buccinator system in humans than in chimpanzees and gorillas. Lightoller (1925)17 and Pellatt (1979)18 stated that the peripheral and marginal parts of the OOr are not clearly differentiated in chimpanzees. Contraction of the pars peripheralis fibers in humans positions the lip in labial elevation , while the pars marginalis may be regarded as being involved in speech modification19. Thus, the ILS and ILI in humans may reinforce the peripheral part of the OOr for more-delicate facial expressions, speech, and movements of the mouth and lips.The ILS and ILI as well as the peripheral and marginal parts of the OOr are more differentiated in humans than in chimpanzees. Huber (1931)et al.13 reported that the lateral border of the inferior part of the ILS coincided with the upper buccal frenulum. They described that the ILS can be affected when performing an upper labial vestibule incision and correction of the gingival smile. In the present study the medial origin of the ILS was located in the periosteum adjacent to the upper mucolabial fold, which means that it may be cut during surgical procedures involving the labial vestibule. The muscle fibers of the peripheral part of the OOr are distorted and deviated in cleft lip23, while the correct arrangement of the muscle fibers is essential for successful primary repair of the cleft lip23. Therefore, the arrangement of the muscle fibers of the ILS and their relationships with other structures should be considered especially when performing vestibuloplasty and cleft lip repair.Iwanaga In conclusion, this study has revealed several anatomical features of the ILS related to the labial glands, upper mucolabial fold, and modiolar area. The reported results will be helpful when analyzing the movements of the mouth and lips and when performing various types of facial surgery.All cadavers used in the present study were legally donated to Catholic Kwandong University College of Medicine. The present study was conducted in accordance with the Declaration of Helsinki. ILSs were investigated in 52 specimens obtained from formalin-fixed Korean adult cadavers . The muscles of the lower face were dissected and removed en bloc from the facial bones. The inner surfaces of the removed facial muscles were carefully dissected with the aid of a surgical microscope . The origin of the ILS was identified after cutting and folding the periosteum adjacent to the upper mucolabial fold, and then its fibers were followed to reveal its courses, connections, and attachments to surrounding structures. The most-lateral and most-medial points of the origin of the ILS were checked in the deep surface of the face, and then the corresponding points on the superficial surface of the face were determined by using piercing pins. The location of the ILS was observed on the superficial surface and in the deep surface of each facial muscle. All side-on photographs in this article are viewed from the right side of the face.The methods were carried out in accordance with the 1964 Helsinki declaration and the cadavers were legally donated for the research by Catholic Kwandong University College of Medicine."}
+{"text": "A TIVAD  catheter is inserted into one of the large veins, usually the superior vena cava (SVC), to gain permanent central venous access. The tip of the catheter sits just above the heart in the distal third of the SVC and the other end is attached to the silicon rubber port that sits underneath the skin of the anterior chest wall fixed to the fascia of the pectoralis major muscle at the lateral part of the second rib . When thThe proper position of the catheter before fixing it to the port is of paramount importance to avoid complications. One of the most commonly encountered intra-operative complications when accessing the right IJV for central venous access is the kinking of the catheter, either at the site of catheter entering into the IJV or at the site of catheter joining the port. Both of these kinks can be avoided if one aims for a disposition of the venous catheter as depicted in None declared."}
+{"text": "The incursion of Information Technologies in the field of education is an undeniable fact that today includes immersion in media education in the classroom. The increase in the use of ICTs in the classroom has raised a concern about the possible impact on the prevalence of problems associated with problematic use of the Internet. This article presents data on an exploratory cross-sectional non-experimental design carried out based on a non-probability prepositive sample through the application of an ad-hoc developed questionnaire. The data in this article correspond to the responses of 832 students of Compulsory Secondary Education in three educational centres in the Autonomous Community of Cantabria, Spain. Two of the educational centres are privately owned, and one of them is public. One of the private centres uses educational methodologies based on the high use of information and communication technologies, as each student uses a personal computer in the classroom. The questionnaire used includes EUPI-A, SOGS-RA, and CERM scales. The questionnaire also includes questions about time spent on internet use and sports betting and gambling or game participation. The data are of interest of researchers in developmental, educational, and behavioural psychology and in statistical scale development. Rodr\u00edguez Zapatero \u2013 President of the Spanish Government \u2013 announced the ICT Plan with the aim of updating education by the use of portable devices. This ICT Plan includes the use of a device per student for educational use in a model called one-to-one. The implementation of this ICT plan was uneven, mainly due to the political particularities of regional governments, difficulties in the expansion of internet broadband, the complexity of the management of based laptops in schools and the lack of budget aggravated by the economic crisis that the country suffered. For those reasons, the plan was not fully implemented in schools. This movement of educational renewal collided head-on with the costs of acquiring technology -devices, network infrastructure and software, the low preparation of educational content by publishers, and the economic crisis that meant a sharp budget cut in both public and subsidised schools.In spite of this, in recent years, the process of methodological change based on the adaptation of New Technologies and the Internet in the classroom has undergone a strong revolution in Spain. This revolution takes place, in part, thanks to the proliferation of devices such as Chromebook or iPad devices, with cheaper costs for the end user, simplicity of use by the student, and simple management by the school. In the case of Chromebook devices, in the last two years, there have been many educational experiences that have been carried out jointly by schools, Google - the company responsible for the platform of administration and service G-Suite for Education and the ChromeOS system, the fundamental basis for the operation of Chromebook, and the respective regional Ministries of Education. These experiences are aimed at introducing Chromebook as a digital platform for content managed and provided through G-Suite and complemented by the use of digital licenses of online course books. In the Autonomous Community of Cantabria, where the implementation of the ICT 2.0 plan was not completed at all, there has been a trend in recent years that advocates methodological change and the introduction of ICT in the classroom. Nowadays (2019), only the reference educational centre of this study presents the use of a Chromebook device in one-to-one mode at all levels of Secondary Education in Cantabria.Despite the fact that at the time of the study (2016) the implementation of digital contents and Chromebook-managed devices was already taking place in a few schools in other communities of the country, the implementation of the one-to-one model (a device for each student) was a new feature in the community of Cantabria. On this date, only the educational centre of the study had this model of classroom work for all levels of ESO. The choice of this educational centre was justified by the purpose of the study and, therefore, of convenience.The choice of the other two centres that make up the study is determined by the choice of both public and private centres in the degree of an economic concert by the Ministry of Education. For both cases, the choice of the sample limits the possibilities to those centres that use classroom work methodologies characterised by the use of traditional resources and methodologies: use of physical books, carrying out tasks based on explanation, or group work without focusing their development on the use of the Internet or online tools, except for those subjects and tasks where their use is necessary .The data in this article correspond to the responses of 832 students of Compulsory Secondary Education in three educational centres in the Autonomous Community of Cantabria, Spain. Two of the educational centres are privately owned, and one of them is public. One of the private centres uses educational methodologies based on the high use of information and communication technologies, as each student uses a personal computer in the classroom. Descriptive details of the sample are shown in \"high use of information and communication technologies at classroom\" has been estimated for this study as.\u201cthe use of ICT technologies in a one-to-one approach in which each student has his or her own device for the course of the classes, the online educational contents, and the necessary software to carry out the academic tasks with the use of these devices in practically the totality of the classroom subjects, reaching an average use superior than 4\u00a0h a day on average.\u201dIn order to carry out the study, and in the absence of a consensual or firm bibliographic definition, the operational definition of the The centres that show a \"low technology use in the classroom\" show a use inferior to the 2\u00a0h a day on average.The data were collected by the use of a questionnaire that includes EUPI-A 2The main objective of the work was to research the possible explanatory interrelation between the high use of technology in the classroom and potentially problematic behaviours in adolescents through a study not carried out under experimental conditions -without manipulation of dependent variables - in a subset of the population in the age range included in compulsory secondary education. In order to carry out this study, an exploratory cross-sectional non-experimental design was carried out. This study was based on a non-probability purposive sample, since this is a sample in which the centres were classified by type for the purpose of the study and the students were not randomly sampled when all the students participated, focused on the population of Secondary Education students in the Autonomous Community of Cantabria through the application of an ad-hoc developed questionnaire, built specifically for this study.The study included a sample of 832 students of Compulsory Secondary Education between the ages of 12 and 17 , of which 370 were girls (44.47%) and 462 boys (55.53%), from different public and private (subsidised) educational centres in the Autonomous Community of Cantabria . One of the private centres is immersed in an Educational Innovation Programme (PIIE programme) of the Government of Cantabria and is characterised by the intensive use of technology in the classroom: students use a Chromebook device as a working tool, use digital books and have constant access to the Internet - albeit limited and secure. All the centres considered in the sampling present several lines and do not show segregation of the students.Educative Centre A, . Religiously-owned centre subsidised by the Department of Education of the Government of Cantabria for the teaching of the levels of Compulsory Secondary Education, which also teaches the levels corresponding to the Baccalaureate. All the answers were obtained through the online questionnaire posed by the researchers. The centre, located in an area of the city with a population of average socioeconomic characteristics, represents one of the most advanced bets of the Regional Ministry of Education as one of the participants in the PIIE Programme - Integrated Programme of Educational Innovation - For the choice of the other two educational centres, the characteristics of the main centre were taken into consideration due to the similarity, focusing on the existence of three or more courses per level. Thus, in the case of subsidised or private centres, it was limited to 9 of the 42 possible samples to be considered. In the case of the public centre, this limited the possibilities to 40 of the 47 possible centres. The choice of the representative centre of each category was made randomly.Educative Centre B, . A religiously-owned centre subsidised by the Department of Education of the Government of Cantabria for the teaching of the levels of Compulsory Secondary Education. The centre is located in an area of the city with a medium-high purchasing power, has the technological means in accordance with the commitment made by the Ministry of Education of the Government of Cantabria for the use of ICT in the classroom, without being integrated as a PIIE centre. This commitment includes the use of pedagogical means, such as digital blackboards, but not the integration of a specific device for students or the use of specific digital didactic means. The participation of ESO students was high, reaching a participation of 265 students. All student responses were collected through the printed questionnaire and were manually transcribed for analysis.Educative Centre C, . A Public Centre belonging to the Department of Education of the Government of Cantabria located in an urban municipality near the capital of the Autonomous Community. This centre offers ESO studies and develops different educational plans, including the ICT plan, which provides specific computer rooms and computers with a projector in the classrooms. The use of new technologies and Internet at the centre is, therefore, quite limited, counting the aforementioned rooms with 16 and 18 connected computers for the more than 500 students that represent the total number of enrolled. The participation of the students of this centre covers the stages of ESO, with a participation close to 75% of the Secondary Education students. All the answers were obtained through the paper questionnaire and were transcribed individually for analysis. The questionnaire was a designed ad-hoc and included EUPI-A, SOGS-RA, and CERM scales.EUPI-A scale. Developed with the aim of becoming a screening scale of problematic Internet use among adolescents, developed according to the diagnostic criteria collected in the DSM-V for gambling and gambling disorder based on the Internet, as well as the instruments and studies previous to the date of its construction. It includes 11 first-person statements, relating to a single dimension, with a Likert type response format of 5 options in a range of values from 0 -Nothing agree-to 5 -Totally agree-. The scale allows discrimination in its application between Moderate Internet Use and Problematic Internet Use. Originally, in its validation, the questionnaire yielded a Cronbach alpha reliability (0.820), establishing its cut-off point at 16 points CERM Scale, Mobile-Related Experience Questionnaire. CERM is, together with CERI -Internet-Related Experience Questionnaire-, an adaptation of the PRI The SOGS-RA questionnaire in its Spanish version The questionnaire also included some questions about time spent on internet use and sports betting and gambling or game participation. Data obtained from all respondents are shown in"}
+{"text": "Microsystems & Nanoengineering has indeed attracted the attention of its international peers in MEMS and nanotechnology since it was launched as a new journal on May 28, 2015. Microsystems & Nanoengineering is the first engineering journal co-published by the Nature Publishing Group (NPG) and the Institute of Electronics of Chinese Academy of Sciences (IECAS). On behalf of the editorial board of Microsystems & Nanoengineering, we would like to express our deep gratitude to our readers, authors, and reviewers. We sincerely thank all of you for your strong and consistent support!With time passing imperceptibly, As we all know, for an international journal to have great impact globally, its publications must be of the highest quality and reflect the research field globally. Only by receiving original papers from around the world and assessing them by international peers, we can select the high-quality papers to match the leading academic standards. The quality of the review and processing of manuscripts is essential for us.Microsystems & Nanoengineering has been adhering to the rigorous peer-review process. As it was founded last year, with the assistance of our international editorial board members and editors from around the world as well as benefitting from the international profile of the NPG, Microsystems & Nanoengineering has accumulated experts from 22 countries and regions to submit 110 invited and contributed papers on their most recent research , fabrication, characterization, reliability, packaging, and applications of devices and systems with micro- or nano-scale features. This new joint publication will provide a rapid forum for the dissemination of original research articles and selected high-quality review articles in all aspects of microsystems and nanoengineering with an emphasis on fundamental research. We will continue to publish papers alongside more general research summaries to increase readership and create impact, in a manner that will distinguish the new Microsystems & Nanoengineering will become one of the boutique journals in the field. We also believe that the advent of Microsystems & Nanoengineering is bound to make a positive contribution to the spread of new knowledge and the development of microsystems and nanotechnology globally.Benefitting from the great publication expertise of both the NPG and the IECAS, we believe that"}
+{"text": "Due to a production error, the value of the Loss Modulus Data Type, for the Human species in the last column of The publisher apologizes for this mistake. The original article has been updated."}
+{"text": "JCB staff noted errors in the in-text citations and order of papers in the reference list that were introduced during production of the article. The authors were alerted of these inaccuracies and we apologize to our readers for these errors.Following publication, the Both the HTML and PDF versions of the article have been corrected. These errors appear only in print and PDF versions downloaded on or before January 10, 2019."}
+{"text": "The data in this article describes the land use characteristics at peri-urban and rural areas, on Jember District, in the Province of East Java, Indonesia. The types of land use covered in the data are agricultural and residential land. The data was a result of a research collaboration between the Department of Agribusiness, Department of Soil Science, and the Department of Agricultural Extension in the University of Jember. The general purpose of the data collection was to compare the characteristics of different land use in the peri-urban and rural area. The data has been compiled to investigate the economic rent of varying land use in peri-urban and rural areas to explain the dynamic of farmland conversion, and to investigate the farmland distribution among farmer in the peri-urban area. The data contains technical and socio-economic aspects of land use in peri-urban and rural areas. The data were collected through structured interviews with farmers and homeowners in each area. A total of 200 interviews were conducted to 100 farmers and homeowners. The location of each respondent was recorded with the location-marking feature of the GPS to represent the distribution of samples. The tracking feature of the GPS was used to locate the physical infrastructure such as irrigation canal, road, and market. In total, the data contained 29 variables and attached as the supplementary material of this data article. The exact location of each rural farmland , rural hThe data is provided in a Microsoft Excel format consisting of six sheets. The first sheet contains information on rural agriculture; the second contains variable on rural housing. The information on peri-urban agriculture and housing are contained in the third and fourth sheets. For each land use , we used the same variables regardless of the area. Finally, the general conditions of each village are presented in the fifth and sixth sheets.2The sampling determination was conducted in two stages. The first stage was aimed to determine the population of farmers and homeowners in the rural and peri-urban area. The population of farmers in the rural area is 783 farmers, while there are 1056 farmers in the peri-urban area. The population homeowners in the rural and peri-urban area are 3011 and 3050 respectively. In the second stages, 50 farmers and 50 homeowners in each village were randomly selected as the final sample.The data collection was conducted in two stages. In the first stage, we collect data on the technical and socio-economic characteristics of farmers and homeowners. The data was collected through personal interviews to farmer and homeowner using a structured questionnaire by a trained enumerator. In the second stage, the location of each house and farmland, as well as irrigation canal, road and market were geolocated using GPS by a different team of the surveyor."}
+{"text": "In this issue, Vol 42, No 1 (2019), the journal presents articles that address stimulating contemporary issues in nursing. There are articles with specific focus on primary healthcare, clinical learning environment, and nursing education and training. The focus on primary health resonates with primary health re-engineering in South Africa. The evidence from the articles on this theme provides support for the need to strengthen the district health system. The primary healthcare focus has the potential of enhancing clinical practitioners\u2019 interest in research-based practice. The evidence for clinical learning environment provides support for quality improvement in nursing practice. With regard to nursing education and training, the issue draws attention to debates on the impact of the policy related to the new qualifications for the nursing profession. The articles outline important aspects of the position of nursing education in South Africa, one of which relates to nursing colleges having to be registered as higher education institutions in order to have their offerings on a higher qualification band. This is in line with the transformation of nursing education in South Africa. It is believed that the evidence presented in these articles will encourage further debates on the status and process of transformation in nursing education and training in South Africa and internationally. The combination of articles indicates the wealth of scientific knowledge that is produced in nursing for the profession and its practice. The journal strives to continue to produce scientific knowledge that is thought-provoking."}
+{"text": "The use of navigational adjuncts for pedicle screw placement has increased in popularity among surgeons with access to this technology. However, it remains important to have a comprehensive understanding of posterior bony element anatomy with respect to the location of the pedicle in order to ensure safe placement of pedicle screws. Proper exposure and identification of the pars interarticularis provide a helpful landmark during pedicle screw placement in order to confirm navigation accuracy and avoid misplaced instrumentation. In this technical note, we highlight the surgical anatomy of the pars interarticularis of the lumbar spine and its relationship to the lateral, inferior, and medial borders of the pedicle using diagrams and cadaveric dissections. There are several methods described for safe and accurate placement of pedicle screws in the lumbar spine . The useThe pars interarticularis is the lateral portion of the posterior bony elements that connects the inferior and superior facets at each lumbar level. The pars is continuous with the unilateral lamina, superior facet, inferior facet, transverse process, and pedicle -9. The jThe lateral border of the pars creates the bony roof just inferior to the lateral recess and superior to the intervertebral foramen in the lumbar spine at each level -14. The The junction of the pars with the proximal and inferior portion of the transverse process is a reliable landmark for the inferior border of the pedicle wall. It is important to remove all soft tissue and expose this junction completely in order to estimate the location of the superior portion of the foramen and the exiting nerve root Figure . CompletThe lateral junction of the pars, superior facet, and transverse process is a reliable landmark for the lateral boundary of the pedicle. The bony surface of the superior facet transitions into the transverse process laterally, and joins the pars at the inferior-most portion Figure . The latThrough proper exposure and identification of the pars, the midpoint of the pedicle for proper screw starting point and placement can be accurately determined. The mammillary process is first removed with a rongeur or drill. The cancellous bone continuous with the pedicle is revealed. The pedicle is then accessed with a curved probe Figure . Screw pThe pars interarticularis is a key element in determining the lateral, inferior, and medial borders of the lumbar pedicle. Complete exposure of this structure is advised prior to screw placement in order to define the midpoint of the pedicle for a proper screw starting point. With the increasing use of computed tomography navigation and robotic-assisted techniques, it remains important for the surgeon to have a comprehensive understanding of spinal anatomy in order to verify the accuracy of the navigational systems and avoid complications from misplaced instrumentation."}
+{"text": "The purpose of the present study is to examine whether positive affect and negative affect can predict the changes in cognitive abilities, assessed by episodic memory and executive functioning, during the transition to late adulthood. Using the longitudinal data from the national survey of midlife development in the United States (MIDUS), this study implements a cross-lagged panel model to test the significance of two pathways; one from affect to cognition and the other in the opposite direction. The results show the three main findings: First, the relationship between affect and cognition is unidirectional in which only positive affect and negative affect during the first occasion significantly predict episodic memory in the second occasion. Second, regardless of the type of affect, higher levels of both positive and negative affect predicts worse episodic memory and this tendency is more prominent in older adults. The combined results emphasize the benefits of using affect as a predictor of changes in the specific types of cognition and suggest using the longitudinal model to account for complex relationships between these psychological constructs."}
+{"text": "A 55-year-old woman was referred to our department of Diagnostic Radiology for persistent conductive hearing loss on the left side  accompanied by dizziness in the waning of a serious head injury. Three months before the patient had heavily fell on the head in a stairwell with the result of diffuse cerebral  and extracerebral  lesions and that mostly at the contralateral right cerebral hemisphere. The patient remained in coma for three weeks. High-definition multidetector CT showed a left middle ear which was actually completely free of residual fluid or blood allowing a perfect 2D and 3D analysis of the petrous bone and of the ossicular chain. A thin fracture was crossing the squamous part of the temporal bone to extend through the wall of the external auditory. It was prolongated by a longitudinal fracture of the temporal petrous through the middle ear  on the basis of their orientation relative to the long axis of the petrous temporal bone. Longitudinal fractures are the most common. They cross the middle ear and are often associated with ossicular dislocation or fracture. High resolution multidetector CT is the method of choice for evaluation of ossicular trauma.There are five main types of dislocation: incudomalleolar and incudostapedial joint separation, dislocation of the incus or of the malleolarincudal complex and finally stapediovestibular disclocation. Stapedovestibular disclocation and fractures of the ossicula are rare.Among these various types incudostapedial dislocation or disarticulation is the most common posttraumatic injury of the ossicular chain that and is most often associated with longitudinal fractures. The two main reasons are 1) the nature of tenuous suspension of the incus (the heavier ossicule that has no muscular anchor and the weakest attachments of the chain) between the malleus and stapes that are both firmly anchored and 2) the fact that the uncudostapedial is only a fragile enarthrosis which is usually the first injured.Another mechanism has been postulated and could result from the simultaneous traumatic tetanic contraction of antagonist tendons of ossicular muscles. When the tendon of the tensor muscle of the tympanic membrane  and the stapedius tendon (attaching to the head of the stapes) simulteanously contract medial thrust of the incus and posterior pulling of the head of the stapes may concomitantly produce resulting in dislocation.The reported case illustrates a typical case of incudostapedial disclocation. It is perfectly identified on classical transverse images and coronal oblique multiplanar reconstructions and the cardinal sign is the dissociation between the lenticular process of the incus and the head of the stapes. Our case also emphasizes the high diagnostic performances of 3D volume rendering of the ossicula.The authors declare that they have no competing interests."}
+{"text": "The Journal and Chief Editors retract the August 2018 article cited above.After publication, the authors were made aware of an unfortunate coding error resulting in the data analyzed in this study being inconsistent with the data provided in the Alzheimer's Disease Neuroimaging Initiative repository. Due to this honest error, the authors request that this article be retracted.The retraction of the article was approved by the Chief Editors of Frontiers in Neuroscience, Neurodegeneration and the Editor-in-Chief of Frontiers."}
+{"text": "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.In the Funding section, a second grant number from the Japan Society for the Promotion of Science is missing. The correct funding information is as follows: This study was supported in part by the Japan Society for the Promotion of Science grant . Web site;"}
+{"text": "This work shows the contribution of concept of rites of passage and theory of liminality to the understanding of transformations in the course of a person\u2019s life. The structural\u2013functional analysis of empirical studies of physical changes, changing roles in society, and key changes in the area of mental and physical health conducted from the perspective of these theories has allowed to identify the three fundamental processes that govern the attainment of transformation and transgression into a new phase of life. The aim of this paper is to set out the processes identified in the course of functional\u2013structural analysis of chosen studies and they comprise: (1) preservation of the sequence of the life course; (2) liminality: deconstruction, integration, and transformation; and (3) performativity. These processes provide a structural framework for understanding life crises, thus facilitating their study as phases of dynamic transformations connected with the successive roles and tasks over the life course. Arnold van Gennep\u2019s concept of the rite of passage Cheal  was deveIn this work, we refer to the concept of the rite of passage, to the concept of the life course that are directly connected with changes and life transformations, key life trajectories, and the sequence of successive life-changing events  and the accompanying changes in the realm of the psyche with further consequences over the life course. Secondly, they have dealt with the changes that have a fundamental effect on the social status of an individual and constitute a turning point or watershed in a person\u2019s life. Thirdly, in the theoretical perspective, they adopt directly or indirectly references to the concept of the rite of passage and the theory of liminality derived from it, or the concept of the human life course. This analysis threw up the three main distinct processes that describe the basic conditions for both transformations to be effected and crises in the human life course to be overcome.Each of those three distinguished processes has structural and functional elements that are present in symbolic and performative way in the rite of passage concept and the theory of liminality as well as in mental crises that are universal for the life course passages. We have distinguished more structural and more functional properties of the rite of passage and liminality theory regarding the health and mental crises although they are both strictly intertwined Table .This process represents the recognition that certain events in the life course should ensue in a certain order and within certain periods of time. This is illustrated by the group of rites of passage that are \u2018corrective\u2019 in respect of disrupted sequences of life experiences. It is reflected in empirical studies which show that disruption of an established sequence of life experiences causes mental crisis, psychopathology, and other life misfortunes. Such sequential aspects of life experiences are clearly highlighted in both the theory of rites of passage and the concept of the life course. Just as the rite of passage divided human life into periods and encapsulated the entire process in a \u2018mythical ritual scenario\u2019 Bajburin , so the Interestingly, contemporary research reports also indicate that an upset to the defined order of life experiences can result in social underachievement: men who enter adult life in an unstructured fashion, i.e., in whose lives the order of the triad of finishing education, starting work, and marrying is inverted, earn less, have less prestigious professions, and are at greater statistical risk of divorce George . Other sThe concepts of rites of passage and the life course clearly illustrate the risk of disruption to the temporal sequence of progression of life experiences and of lingering in a particular stage of the life course or a certain phase of life crisis. The rite of passage concept introduces a structural model for resolving the problem of disrupted sequence of life experiences. The mechanism for this is to introduce a sequence of successive, but isolated phases of the change in progress and to finalize it in the form of engagement: transition to a new state.transition itself is directly linked with a shift into a new state, which is often symbolized by the ritual motif of migration, or the symbolic traveling of a road (Van Gennep The second of the processes within the matrix presented here refers in particular to the middle\u2014liminal\u2014phase of the transgression ritual, which symbolically illustrates the protracted state of being in a situation \u2018without properties.\u2019 This happens with the temporary suspension of a previous social or life role. The ritual symbolism of the liminal phase comprises opposing and conflicting content which symbolizes both the dying of the old and the birth of the new structure. It is a conceptualization of the type of crisis in which the prior life balance is fundamentally disrupted. Empirical studies relating to situations in which a previous identity is called into question reflect the situation of the individual who faces conflicting needs and demands. In life course theory, this is a point of risk connected with the irrevocability of certain decisions (Berger and Luckmann Empirical studies into the experience of serious illness as a life-changing event largely reflect the structural and symbolic characteristics of the liminal phase. At such points, considerable deconstruction of the previous life balance is experienced, which causes the violation of prior assumptions about the self Bury , or the A disrupted life balance generates many contradictions and conflicts. This finds symbolic form in the structure of the rite of passage, which at once forms a framework within which to integrate them. Focusing on the ritual representation of the convergence of opposites, individual\u2013societal and biological\u2013cultural, it characterizes the unity of the liminal, that which is \u2018neither this nor that, and yet is both\u2019 Turner . Bell seThe theory of liminality illustrates the need to mediate between what requires the change involved in embarking on the next, new stage of life and that part of the self or its societal environment that is being abandoned.The expression and regulation of the related emotions are illustrated most fully by the performative aspect of the ritual performance, which brings us to the third process in the model being examined here.In our attempt to answer the question of how a ritual performance can fit into the possibility for creating a new self, we shall first reference studies of the development of the infant self. This phenomenon is mediated in the multisensory interaction of the caregiver and the small child, where the process of mutual emotional regulation provides the framework for shaping the child\u2019s self. Introducing this concept facilitates full comprehension of the third of the processes behind change and transformation isolated in this analysis, which is defined as \u2018performativity.\u2019 This process illustrates how the methods used in ritual performances regulate the emotions in order to survive the transformation of the self in their participants. The theory of intersubjectivity, which evolved from observation of babies (Beebe et al. In our attempt to underscore the role of the performative aspect of ritual performances in highlighting and regulating the experience of emotional states and in shaping the ego of the individual, we reference the existence in the mind of an intersubjective matrix based on bond and on multimodal processing of various sensory experiences. The drama of the rite of passage seems to fit into this intersubjective matrix, thus having the potential to influence the formation of the new self, not only symbolically but also directly. The arousal of strong emotions in the process of enacting the ritual involves an ambiguity surrounding the individual\u2019s previous social position and role, and also the questioning of his previous self Turner . The perThe importance of preservation of the socially defined sequences of life experiences and drawing attention to the risk inherent in times of life crisis which take on chronic character;Recognition and normalization of temporary disintegration in the sphere of the self during a life crisis, leading to the co-existence of mutually contradictory mental content and inner conflicts that can later become integrated in the process of transformation or transition to a new state;Highlighting the performative character of the ritual performance as a symbolic structure regulating emotion and shaping the self, on the foundation of the developmentally inbuilt intersubjective matrix of mental development.The theory of liminality and the life course theory form a conceptual matrix for the study and functional\u2013structural understanding of change within the self as the individual crosses major developmental thresholds and experiences life crises. Analysis of these theories and studies based on them enabled us to isolate the dynamic mechanisms of life changes and transformations connected with the mutual relations between the individual and the social group, with especial emphasis on the following:We thus wish to note that irrespective of whether we are analyzing a chronic illness, a crisis triggered by puberty, or an inability to close the mourning process, in each case we should reference the three processes listed above. First: preserving the sequence of life events reveals that each of these crises has the potential to disrupt subsequent stages of the life course, and each one will harbor the risk of chronic arrest in that particular phase of life. A given individual might never cast off the role of patient, might not accept the roles of adult life, or tackle them in a disrupted manner; he might remain to the end of his days in mourning and refuse all other social and life tasks. In each of these cases, a previously existing structure is destroyed and the individual moves into the second process characteristic for the liminal phase, that of the contradictions and ambiguities surrounding the role of the patient, torn between health and sickness, or even life and death; the role of the teenager, torn between childhood and adulthood; and that of the mourner, torn between the desire for physical contact with the deceased and the transformation of the bond with her into a mental bond. And finally comes the third process\u2014performativity shows the importance in crisis situations of impacts which involve multimodal performative expression and social identification, e.g., participation in artistic and therapeutic groups or religious rituals, which involves arousing and at once regulating emotions.Finally, we wish to stress that while the cultural scenarios of the life course change and evolve, their conflictual demands remain current. These include the desire for stability and security and yet the striving for change; biological and social relations; the risk of becoming mired in a transitory crisis situation, and the means of transmitting social support and social meanings. The concept of the rite of passage and the construction of the life course together supply a structural, sequential and processual framework for understanding and processing such challenges and dilemmas that is a main function of rites of passage and some contemporary social institution which try to deal with life crises."}
+{"text": "The threat of devastating disease outbreaks is on the rise with several outbreaks recorded across the world in the last five years. The intractable Ebola Virus Disease outbreak in West Africa which spread to Nigeria was a reawakening point. This study aims to review the status and adequacy of the legal framework for disease surveillance in Nigeria. Methods: a mixed methods approach comprising of document reviews and key informant interviews was used in data collection.A mixed methods approach comprising of document reviews and key informant interviews was used in data collection.Fourteen key informants from the federal ministry of health (FMOH) and six States were interviewed. Five legal instruments were identified and reviewed. The Quarantine Act of 1926 remains the active National Law on disease surveillance in Nigeria. An Integrated Disease Surveillance and Response Policy (IDSR) was developed in 2005 as the means for achieving the International Health Regulations (IHR). All six states claimed to have adopted the national IDSR policy though none could present a domesticated version of the policy. Key informants were concerned that Nigeria does not yet have an adequate legal framework for disease surveillance.The legal instruments establishing disease surveillance in Nigeria require strengthening and possibly enactment as a National Law in order to address emerging disease threats. In 541 AD, grain merchants' from Egypt transported rats infested with an unknown organism at that time into the Eastern Roman Empire causing the Plague of the Justinian period [ar pumps . The IDSNigeria has a population of about 180 million people with limited resources to tackle all her health challenges. As a result, health indices in the country are not among the best in the world. Life expectancy at birth is 54.5 years which is lower than the regional average (60 years) and far lower than the global average 71.4 years) 1.4 years. Polio wThis article reports part of a larger research effort to investigate the compliance with disease surveillance and notification by private healthcare providers in Nigeria and the factors that may be affecting their performance. A brief description of the entire study has been previously published . The objKey government officers with responsibilities for disease surveillance and the National Health Management Information System (NHMIS) at the national level and in the six selected States were targeted for interview. The national IHR focal person and the NHMIS officer were identified as key informants at the national level. In each State, the State epidemiologist and the State Health Management Information System (HMIS) officer were identified as key informants. This was a total sample since each State has only one State Epidemiologist and one HMIS officer. The State epidemiologists are responsible for monitoring of all infectious diseases and events of public health importance in the State and manage the State IDSR program while the State HMIS officers are responsible for managing the NHMIS in their State. The KII guide was made up of eight exploratory questions. The guide covered questions on the processes in place for meeting the IHR in Nigeria and in each State; laws and policies in place to ensure compliance with the IHR, contribution of private health facilities to healthcare delivery and the incorporation of private healthcare facilities in the laws on disease surveillance in the country. It also included questions on the perceptions of respondents on the performance of the IDSR and data use. Legal instruments establishing disease surveillance (Laws and Policies) were initially identified by the researchers during the document review and probed for during the KII. Additional documents were identified during the KII. Those identified during the KIIs were also retrieved and reviewed to understand their content and shortcomings. Ethical Approval for the study was obtained from the National Health Research Ethics Committee in the Federal Ministry of Health, Abuja, Nigeria  and the Wits Human Research Ethics Committee  of the University of the Witwatersrand, Johannesburg, South Africa . In addition, approvals were obtained from the Honorable Minister for Health before national officers were interviewed and from the Commissioners of Health in each State before going ahead with the study in their State. Furthermore, written consent was also obtained from the officers before they were interviewed and this followed the provision of detailed information on the purpose of the study. A participant information sheet which explains the goal of the study and expected outcome was shared with each participant ahead of the interview. The KIIs were recorded using a digital voice recorder and subsequently transcribed verbatim. The transcripts were then used to generate themes based on the objectives of the study. Coding and analysis was manually done by the principal investigator.Different legal instruments establishing or reinforcing disease surveillance in the country were identified during the study. Some of the legal instruments were identified during the literature reviews and before the KIIs while some were identified and/or reinforced during the KIIs. In total, six documents were identified and subsequently retrieved and studied. Fourteen key informants were interviewed during the period: two officers from each State (State epidemiologist and State HMIS officer) across the six States of investigation, the national IHR focal person and the NHMIS officer. The interviews lasted between 20 and 45 minutes. The identified documents during this process are presented in Legal instruments on disease surveillance in Nigeria: This section provides a brief summary of the identified legal instruments for disease surveillance in the country.The quarantine act: The Quarantine Act of 1926 remains the active law governing public health in emergencies in Nigeria today [The national policy on IDSR and technical guidelines for IDSR: The IDSR policy of 2005 is the most recent comprehensive legal instrument reinforcing disease surveillance in Nigeria. The IDSR was adopted to replace the Disease Surveillance and Notification system which had been put in place following a Yellow fever outbreak in 1986/87. The adoption of the IDSR was believed to be the needed change to revamp the ability to predict and detect disease outbreaks in the country. The policy noted that it would be reviewed every five years or as deemed fit by the Minister of Health in consultation with the National Council on Health. It identified the need for the coordination with the NHMIS to avoid duplication. The technical guidelines listed the 41 diseases and conditions of importance to be tracked in Nigeria. It also contained samples of the forms to be used in tracking infectious diseases in the country.The national health act: The National Health Act is not focused on disease surveillance but provides some further support towards the implementation of the NHMIS. Part IV section 35 subsection (1) states that \u201cThe Federal Ministry of Health shall facilitate and coordinate the establishment, implementation and maintenance by State ministries, local government health authorities and the private health sector of the health information system at the national, State and local government levels in order to create a comprehensive NHMIS.\u201d It further goes on to provide the Minister with the power to determine the class of data that can be collected and the need for the Minister and State Commissioners to publish annual reports on the health of the citizenry.National health information system policy: The policy prescribes a health data governance structure for the country with the Minister as the chair of the National Health Data Governance Council (NHDGC). The heads of all the health data generating institutions in the country including the National Population Commission, the National Bureau of Statistics and the different departments in the Ministry are members of the NHDGC. It also proposes the creation of State Health Data Governance Councils to be chaired by the Honorable Commissioner of Health in each state with similar representativeness of members across the data generating units in the State. The policy was designed to drive a good coordination and governance of the health information system.The national public health bill: Though it was discovered that a Public Health Bill had been waitlisted since 2004 in the Nigerian Senate for possible enactment as a Law, this Bill is yet to be ratified by legislators [Key informant's perspectives on legal instruments: The key informants interviewed buttressed the finding from the document reviews that the IDSR policy of 2005 is the most recent comprehensive legal instrument guiding disease surveillance in the country. A key informant noted that \u201cStates actually agreed at the National Council on Health (NCH) years back to implement the IDSR strategy and that is what we have on ground\u201d. The NCH is the highest policy making body in Nigeria with regards to health and is made of the Minister for Health, Minister of State for Health, the Commissioners of Health across the 36 states of the Federation, the Secretary of Health and Human Services of the Federal Capital Territory and the Permanent Secretary at the Federal Ministry of Health [f Health . BesidesNigeria is a Federation with three tiers of government: the federal government, state governments and the local governments . The FedThe Quarantine Act and the National Health Act are the current Laws that govern disease surveillance in the country. However, it is archaic having been established as a Law in 1926, several decades before the IHR came into effect. One of the diseases identified in the document was eradicated over 35 years ago, highlighting the need for a revision. The National Health Act which was signed into Law in 2014 identified the need for the strengthening of the NHMIS in order to be able to deliver on its mandate. The level of detail in the National Health Act for disease surveillance is considered inadequate by most respondents as it was not enacted for this purpose. The availability of various legal instruments at the national level for different diseases and conditions do not necessarily mean that these are being adhered to in the States which are a different administrative level of government. The states are independent and thus, ratification is necessary where the Law is not on the exclusive list of issues addressed solely by the Federal Government. This is similar to the concern raised by Gostin and colleagues (2017) where they made an assertion that development of global legal instruments does not mean they are being implemented by member states. Responsibility still rests on member states to adopt them and their inaction cannot be easily sanctioned since there is no law enforcement body to prosecute defaulters. Strategies that are being used to make the states more responsive to federal laws include incentivizing for results as is seen on the World Bank funded Saving One Million Lives-Program for Results . HoweverThe legal framework establishing disease surveillance in Nigeria requires strengthening and possible enactment as a law to give it the authority it deserves as well as to update it to address emerging Global Health Security challenges. State governments should domesticate policies or laws on disease surveillance to demonstrate buy-in and improve their commitment to its implementation. Lawmakers and Policymakers need to be educated on the importance of prompt attention to laws on Global Health Security.The threat of devastating disease outbreaks is on the rise globally and countries need an efficient surveillance system for detecting and responding to outbreaks to mitigate their impact;The first step towards a reliable system is a legal or regulatory framework that establishes and enforces the surveillance system in a country;Disease surveillance is poor is several low and middle income countries including Nigeria and efforts are required to improve their performance.This study provides a snapshot of the status and the adequacy of the legal and regulatory framework which establishes disease surveillance in Nigeria;It also highlights concerns by key stakeholders that Nigeria does not have an adequate legal or regulatory framework for addressing disease surveillance and those currently available are not being implemented.The author declare no competing interest."}
+{"text": "The statement declaring the relationship between the handling editor and two of the authors has been clarified for transparency of the process. The updated statement should read, in full:After the conclusion of the peer review, the handling editor noticed and declared a collaboration and shared affiliation with two of the authors, VaC and ViC. These authors provided an additional analysis requested by a reviewer during review. They were later added as co-authors and identified to the editor after the provisional acceptance of the manuscript. Under these exceptional circumstances, the relationship did not affect the objectivity of the review process, and this situation is being declared for transparency.The publisher apologizes for this oversight. The original article has been updated."}
+{"text": "In the Animal models subsection of the Materials and methods section, there is an error in the second and third sentences of the first paragraph. The correct second and third sentences are: All mice were purchased from the Laboratory Animal Center of Academy of Military Medical Sciences and housed in the Experimental Animal Service Center of the Chinese PLA General Hospital (PLAGH). The study was approved by the Animal Research Ethics Committee of the PLAGH.In the Liver function measurement subsection of the Materials and methods section, there is an error in the second sentence of the first paragraph. The correct second sentence is: Serum aminotransferase (ALT), total bilirubin (TB) and alkaline phosphatase (ALP) were measured in the Biochemical Laboratory of the PLAGH.In the Acknowledgements section there is an error. The correct Acknowledgements section is: The authors extend their gratitude to members of Chinese PLA General Hospital Animal Laboratory for their support during experimentation.In the Author Contributions, Xiaopeng Tian (XT) should not be listed as contributing to funding acquisition."}
+{"text": "In 1996, OHCHR and UNAIDS adopted the International Guidelines on HIV/AIDS and Human Rights Box 1The rights to non\u2010discrimination, equal protection and equality before the law;The right to life;The right to the highest attainable standard of physical and mental health;The right to liberty and security of person;The right to freedom of movement;The right to seek and enjoy asylum;The right to privacy;The right to freedom of opinion and expression and the right to freely receive and impart information;The right to freedom of association;The right to work;The right to marry and to found a family;The right to equal access to education;The right to an adequate standard of living;The right to social security, assistance and welfare;The right to share in scientific advancement and its benefits;The right to participate in public and cultural life;The right to be free from torture and cruel, inhuman or degrading treatment or punishment.Human rights are now, at least rhetorically, central to the strategies of many UN and donor agencies. Many countries have also acknowledged that respecting, protecting and fulfilling human rights are important to achieving the global goals of ending the HIV epidemic and leaving no one behind. In practice, however, governments continue to criminalize key populations  individuals and persons who use drugs), deny them access to HIV prevention and treatment services and block research examining human rights of key populations. Despite recognition of the pernicious effects of stigma and discrimination since the start of the epidemic For example, it is estimated that people who inject drugs have 36 times the risk of acquiring HIV than adults in the general population Another population that the HIV response has largely ignored is persons with disabilities, who remain among the world's most stigmatized, and often face systematic violations of rights to education, housing and employment as well as health Twenty\u2010five years after the first International Conference on Population and Development in Cairo in 1994, gender inequality and the low socioeconomic status of women and girls create barriers to access to the full range of sexual and reproductive health services and contribute to HIV vulnerability. In sub\u2010Saharan Africa, three of the four new infections among young people aged 10 to 19 are girls Despite these dire statistics, there are steps being taken to expand human rights programs that can reduce HIV vulnerability. The Global Fund's 2017 to 2022 Strategy explicitly prioritizes the promotion of human rights and gender equality as essential steps to achieving its goal of ending HIV, tuberculosis and malaria, and provides dedicated funding for programmes to reduce human rights\u2010related barriers to health services. A report issued in November 2019 from the Global Fund's Office of the Inspector General assessed its progress and presented a series of recommendations that all donor and implementing agencies should closely examine The success of the HIV response to date has been founded on human rights principles, such as recognizing the equal dignity and worth of all persons, as well as the meaningful involvement of affected communities and people living with HIV (GIPA). This participation, from the design and implementation of local programmes to the global governance of such institutions as UNAIDS and the Global Fund, has contributed to more effective responses and attention to gaps and challenges that would otherwise be overlooked. However, not all of those affected have been equally included, and the gaps identified in this Viewpoint reflect populations where more engagement is needed. To reach \u201cthe last mile\u201d we must reach out to those who remain marginalized and excluded and recommit to their engagement and to recognizing their rights, equality and dignity.The authors have no competing interest.JJA conceptualized and drafted the commentary. NS provided substantial feedback on the draft and subsequent revisions.Joseph J. Amon is the Director of Global Health and Director of the Jonathan Mann Global Health and Human Rights Initiative at the Dornsife School of Public Health at Drexel University. He serves as co\u2010chair of the UNAIDS Human Rights Reference Group on HIV and Human Rights and is a member of the Working Group on Monitoring and Evaluating Programmes to Remove Human Rights Barriers to HIV, TB and Malaria Services of the Global Fund. Nina Sun is the Deputy Director of the Jonathan Mann Global Health and Human Rights Initiative at the Dornsife School of Public Health at Drexel University."}
+{"text": "The National Institutes of Health is the largest public funder of biomedical and bio-behavioral research in the United States. The mission is to enhance health, lengthen life, and reduce illness and disability. To achieve this mission, the NIH provides support for cutting-edge research and technology development in a variety of fields, ranging from translation of innovative ideas in technology to basic science on major health challenges and disease. There are many types of research and training opportunities and technology development programs that are supported by the NIH across the 24 institutes and centers that provide funding. The majority of grant applications are reviewed by the NIH Center for Scientific Review (CSR). In this symposium, attendees will get 1) an overview of the types of applications submitted to the NIH for support; 2) the basics of the NIH peer review process and criteria and scoring system for evaluating applications, and 3) tips for writing a more successful grant application. Peer review is the cornerstone of the NIH grants process, and an insider\u2019s view can lead to a better understanding of how the most meritorious projects are identified that lead to innovative re-search in the biomedical and bio-behavioral sciences."}
+{"text": "Objective: The Aachen model study course in medicine was developed in response to a negative appraisal of the Faculty of Medicine of the RWTH Aachen University by the Science Council in 2000. The aim is to create graduates who are capable of further training and can work in evidence-based and patient-centered health care while incorporating scientific findings. Methodology: In 2003 the medical degree was fully switched over to the model study course format. This means an annual cohort size of about 280 students. These go through a modularized and integrated curriculum, which is designed as a learning spiral. This requires a special interdisciplinary collaboration of teachers and curriculum planners. In addition to the modules, longitudinal elements such as workplace-based examinations, communication or practical skills are embedded in the curriculum.Results: The state exam results of the Aachen graduates have already improved significantly even for the first cohort and the university has been able to maintain an almost uninterrupted high level from 2008 to 2018. The students satisfaction with the model course is not only evident in the student course assessment and qualitative group discussions but also in various national rankings. Conclusion: The complete redesign of the course starting from the first semester onwards posed major challenges for all those involved in the faculty. The implementation of a completely reformed curriculum, such as the model study course, can only succeed through constructive cooperation of the various stakeholders at a faculty. The reorientation was able to address the major flaws of the 2002 report by the Science Council, student dissatisfaction and the poor performance in the nationwide state exams. The Faculty of Medicine of RWTH Aachen University was extensively evaluated in 1999 on the basis of a report written by the faculty and an inspection by the Science Council. This evaluation culminated in a statement by the Science Council in December 2000 on the future development of the Faculty of Medicine. In addition to assessing and evaluating the research orientation of the faculty, the medical education of students was also assessed in this context. Overall, the Science Council questioned the academic standards of the faculty and judged that it would not be competitive as a university medical school. This was the beginning of a major reorientation for the faculty. With regard to the teaching and study of medicine, the Scientific Council criticized in particular the below-average exam results of the graduates in the Intermediate Examination in Medical Studies and State Examinations and the poor organization of teaching by the faculty [https://www.gesetze-im-internet.de/_appro_2002/BJNR240500002.html]. The Aachen model study course in medicine (MSCM) started in the winter semester 2003/2004 with 280 students. The standard degree course of study was successively discontinued , , . P. P11]. PAdditional emphasis on autonomous learning is provided by the documentation and feedback elements of the student portfolio and the HIP tool (How I Perform).The examination concept of the MSCM is based on summative and formative examination formats. Early practical teaching requires an early review of practical and communicative skills in the curriculum, alongside exam formats that tend to examine cognitive content , 12]. T. T12]. Tcognitive: Multiple choice exams, structured oral exams (summative), as well as the Progress Test in Medicine (PTM) (formative)psychomotor: Objective Structured Practical Examination (OSPE) (summative), as well as work-place based MiniCEX (formative)Graded papers and case presentations round off the examination spectrum and promote self-organizational, rhetorical and presentation skills.The Basic Medical Examination (BME) is the MSCM equivalent to the Intermediate Examination in Medical Studies (M1). In accordance with \u00a741 of the Medical Licensure Act, this tests the acquisition of knowledge and skills required for the first section of the State Medical Exam. In addition, clinical content and practical skills are also already tested at this stage because of the MSCM\u2019s interdisciplinary approach. The BME consists of a combined oral and practical exam in the form of an OSPE and a multiple choice exam. In order to ensure adequate quality of this university exam, guidelines have been developed which take into account the quality requirements for objectivity, reliability and validity, in accordance with international standards.The preparation of the exam assignments goes through a threefold review process, in which the exam contents are checked against the learning objective catalog, the wording of the questions and the horizon of expectation is specified; and the scientific and clinical relevance is reflected. Finally, the approximately 100 exam questions of the oral and practical part and the 120 MC questions are approved by the review panel of the examination board. For quality assurance, there is a re-evaluation  documented in writing. Corrections to results and suggestions for improvement are prepared for future examination tasks on the basis of content-related criteria and statistical test evaluation results in this re-evaluation . In MiniCEX, students from the 3rd to the 10th semester are repeatedly observed clinical situations with patients appropriate to their level of training, as part of the clinical examination course and block internships, and receive oral feedback immediately afterwards. This is documented in the form of a standardized questionnaire. This is an exam format which is purely formative .The Progress Test in Medicine (PTM) is designed as a formative knowledge check and each test consists of 200 MC questions at graduate level. The main use of the PTM is longitudinal feedback for students and comparison with other faculties. Feedback is provided through an online feedback tool called HIP (\u201cHow I Perform\u201d). The resulting report allows the students to check their own knowledge gain. According to the examination regulations the PTM is an obligatory offering for all students. Participation in the test is a prerequisite for admission to the next phase of studies .At the end of each semester, the cohort coordinators hold group and individual discussions with the students. They receive feedback on the general progress of studies and examinations in these discussions. The coordinators are tasked with conveying the results of the discussions constructively to the lecturers and inform students about support offers and similar assistance. Therefore these discussions contribute to a continuous improvement in the organization of the course of studies and the quality of teaching and supplement the compulsory course evaluation by the students.The student course evaluation has been carried out since the winter semester 2004/05. The results of the course evaluation are submitted to the study commission and the faculty council and discussed by the student council. Since the beginning of the MSCM, the Faculty of Medicine has been continuously pursuing evidence-based development and improvement of the curriculum. Criticism from the Science Council report of 2000 was successfully addressed. The performance of MSCM graduates today is usually far above the national average . Studenthttp://www.nklm.de], [The next milestones for the faculty are a mapping of their own learning objective catalog to the National Competence-Based Catalog of Learning Objectives (NKLM) [klm.de],  as well klm.de], . In October 2018, the Medical Faculty was re-evaluated by the Science Council. The resulting report will show how the Faculty has improved through the introduction of the model study course. Criticisms by the Science Council will feed into the development work in the coming years  .The Aachen Model Study Course in Medicine was developed by the Medical Faculty of the RWTH Aachen under strong pressure for innovation and improvement . The comThe Faculty of Medicine of the RWTH Aachen University will continue the model study course in medicine as long as the formal requirements of the licensing regulations allow this. When the model study course clause expires, elements and experiences of the Model study course may be used for the development of new curricula.The authors declare that they have no competing interests."}
+{"text": "An analytic method for a complementary metal-oxide-semiconductor (CMOS) terahertz plasmon detector operating in the subthreshold region is presented using the equivalent circuit model. With respect to design optimization of the detector, the signal transmission from the antenna port to the output of the detector is described by using the proposed circuit model, which does not include a complicated physical operating principle and mathematical expressions. Characteristics from the antenna port to the input gate node of the detector are analyzed through the superposition method by using the characteristic impedance of transmission lines. The superposition method shows that the effect of interconnection lines at the input is simplified with the optimum bias point. The characteristics of the plasmon detection are expressed by using small-signal analysis of the single transistor at the sub-threshold operation. The results of the small-signal analysis show that the unity gain preamplifier located between the detector core and the main amplifier can improve the detection performances such as the voltage responsivity and the noise equivalent power. The measurement results using the fabricated CMOS plasmon detector at 200 GHz suggest that the unity gain preamplifier improves the detector performances, which are the same results as we received from the proposed analytic method. Terahertz waves exhibit characteristics, such as high absorption for the water molecules, high reflectivity for conductive metals, and transparency for dielectric materials with non-polarity, which are useful in several industrial applications, including imaging systems ,2. A terThe operation of the plasmon detector is described with the potential difference in the channel of the transistor that varies proportionally to the magnitude of an incident terahertz wave. The physical behavior of the plasmon detector is explained in detail by using the resonance characteristics of the plasma wave generated in the channel by the terahertz input signals from the Dyakonov-Shur plasma wave theory . The detThis study shows a quasi-static analysis based on an equivalent circuit model of the CMOS plasmon detector to improve the detector performances. The equivalent circuit model consists of the superposition method that describes the relationship of the characteristic impedances including the effect of the transmission line length and small signal analysis method that simplifies the operation of the plasmon detection in the subthreshold region. The analysis using the proposed equivalent model makes it easy to understand the design specifications and detector structure to improve the performances of the plasmon detector. The theoretical analysis of the plasmon detector using the proposed circuit model is described in The plasmon detector using a CMOS field-effect transistor (FET) was simplified with the basic configuration shown in The detector input is connected to the input port of the integrated antenna and the external gate bias line through the transmission lines . The traThe detector device is modeled as a voltage source using a small-signal method as shown in The output voltage of the detector has an AC signal that the terahertz input signal is coupled through the parasitic capacitor r device . The DC Impedance matching between the integrated antenna and detector input affects the performance of the detector. The superposition method does not provide a detailed impedance value although it can simplify the effect of the interconnect at the input of the detector device. The detector input has two independent voltage sources, namely the terahertz signal Therefore, the transmission line corresponding to the A FET-based resistive self-mixing with a zero-biased channel is analytically derived for the drain current, which is represented in previous studies by the channel conductance and applied mixing signal for a single device of strong inversion  using (11) and (12) and substituting into (9), the current flowing through the drain node of the detector device is modified asThe performance of the detector is predicted from the detected DC output current. The voltage responsivity In contrast to conventional analysis methods, the detector device for the subthreshold region is analyzed by small-signal modeling as shown in The voltage at the output node denotes the sum of the detected dc output voltage and AC voltage, where the AC voltage is the signal presented by the capacitor from the gate of the detector. The total output current is comprised of the current of the AC component and the DC component and is expressed as follows: in (23) . The draSubstituting (22) with (12) and (25) and assuming that the AC voltage disappears by the filter, the output node is extracted only for the DC voltage asThe signal detected on the output node by the detector device in (26) is obtained asThe voltage responsivity and NEP of the detector operating in the subthreshold region are expressed from (27) as follows:The detector performance is improved by increasing the input and output resistance of the detector device as shown in the theoretical analysis results of The on-chip portions of the two THz detectors in The measurement setup is illustrated to obtain the responsivity of the detector in \u22127 m2 from the receiving area, the THz frequency, and the antenna gain [nna gain . Figure The performance analysis of the CMOS plasmon detector in the subthreshold region was examined by using the equivalent circuit model, which consists of superposition and small-signal methods. The superposition method explains the effect of the transmission lines at the input stage of the detector using the characteristic impedances. The plasmon detection at the subthreshold region was described by using the small-signal method. The analysis results expressed the voltage responsivity and the NEP of the detector as a function for the gate-to-source voltage. As a result of the analysis, the relationship between the input and output impedances of the detector and detector performance shows that the buffer amplifier at the output of the detector core increases the performance more than the characteristic enhancement by the gain of the amplifier. The detection characteristics and performance improvement were demonstrated in the measurement results of two fabricated detectors operating at 200 GHz. The proposed analysis shows that the method to improve the performances are presented for the CMOS plasmon detector by using the simple equivalent model."}
+{"text": "In the original article, we neglected to include the funder, Collaborative Center for X-linked Dystonia Parkinsonism (CCXDP) of the Massachusetts General Hospital. CCXDP is responsible for the funding of the Population-based prevalence study of X-Linked Dystonia Parkinsonism (XDP) in Panay Island, an ongoing study whose database our raw data is from.In addition, we neglected to acknowledge the neurologists and genetic counselors who examined the patients of the study. The corrected Acknowledgment appears below:We wish to acknowledge Dr. Roland Dominic Jamora for his review of the study design during the conception of this research. We would also like to thank the neurologists and genetic counselors who were instrumental in the implementation of this study. But most of all we are grateful to the health workers of Panay who bear the daily burden of caring for our XDP brothers and sisters. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The Editor of this journal has published this Expression of Concern to alert readers that, following publication of the article , it came"}
+{"text": "Introduction: A trocar is used to pierce the muscle and skin to insert the wound drainage tube into the operating field to drain excess blood and fluid just after the operation.1 However, the handle of the trocar always becomes slippery, making it difficult for the operator to control it. Sometimes, the lack of control of a trocar may lead the trocar tip to protrude forward in an unwanted direction and penetrate into another organ of the patient. Sometimes, the operator could hurt his hand while pulling the trocar out by the sharp edge of trocar tip. In this video clip, we would like to introduce a brand new trocar that can be used to insert the wound drainage tube.Materials and Methods: The new trocar has two quadrangle grips . One of the grips has an embossing surface to prevent the trocar from rotating unnecessarily when the operator pushes the trocar to penetrate the muscle and skin. The upper side of the grip has a sunken surface that helps the operator to direct the trocar tip using tactile sensation in the absence of visibility. The other grip has a smooth surface near the trocar tip to prevent it from slipping when the operator picks, by hand, the trocar that has emerged out of the skin. We measured the roughness and friction of the hand grip of the trocars by using Optical 3D Surface Measurement System and scanning of electron microscope. In addition, we assessed the questionnaires answered by surgeons on three domains, including the unwanted turn of the trocar tip, the unwanted sliding of the trocar grip, and the directivity of the trocar tip. The three domains were calculated by the amount of degree that a surgeon felt ranging across a continuum from 0 to an extreme amount of 10 subscales.Results: This trocar is routinely used for all open procedures. The roughness and friction of the brand new trocar had higher roughness and friction than the old trocar . The questionnaire was attempted by 32 surgeons. The score of the unwanted turn of the previous trocar tip was higher than that of the brand new trocar . The score of the unwanted sliding of trocar grip of the previous trocar was higher than that of the new trocar . The score of the directivity of the trocar tip of the new trocar was higher than that of the old trocar .Conclusion: Trocar insertion using the new trocar that has quadrangle grips with sanding surface is an efficient and feasible technique for patients and surgeons.Acknowledgments: The authors thank the members of the medical device clinical trial center of Chonbuk National University Hospital for helpful discussions. This research was also supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (Grant No.: HI15C1529). However, the Ministry of Health & Welfare, Republic of Korea, had no role in design or conduct of the study, including collection, management, analysis, or interpretation of the data in addition to preparation, review, or approval of the article.J.K.P. has patent of this trocar and the patent was transferred to SUNGWON MEDICAL device company. The other authors have nothing to disclose.SUNGWON MEDICAL device company had no role in design or conduct of the study, including collection, management, analysis, or interpretation of the data in addition to preparation, review, or approval of the article.Runtime of video: 3\u2009mins"}
+{"text": "Baroreflex (BR) is one of the most important mechanisms in short-term regulation of arterial pressure (AP)  and patients , the different characteristics of the BR arms likely to contribute to their weakly correlated behaviors , the importance of the clinical information that can be derived from BR markers estimated from spontaneous variability , the chance of elucidating the brainstem nuclei functioning involved in the modulation of the activity of all BR branches , the importance of modeling the dynamical interactions among variables via modeling approaches accounting for directionality  and feedforward influences , the possibility given by advanced signal processing tools to provide a more insightful description of the complex behavior of the cBR arm (de Boer and Karemaker) and to limit the effects of confounding factors , and the opportunity of exploiting smart technologies to broaden the range of applications of BR monitoring . We hope this Research Topic contributes to understanding the complex nature of the BR and its assessment.In this Research Topic the complexity and composite nature of the BR and its assessment is illustrated by the diversity in the contributions. They stress the relevance of the simultaneous assessment of cardiac and sympathetic arms of the BR in healthy subjects (AP and ME conceived the contribution, drafted the manuscript, edited and revised the manuscript, and approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "This paper gives the available data for the maximum equilibrium solubility limits of each of the first 83 elements (H to Bi) of the periodic table in each of the others. This is expressed in the form of the maximum value of the equilibrium solid solubility for terminal solid solutions, expressed in atomic percentage (at%), occurring at any temperature where the room temperature phase of the pure element acting as the solvent is stable. The values thus represent the compatibility between different elements in the formation of alloys and similar combinations, and will be of use for research into fundamental solid state physics relating to elemental interactions, for the interpretation of phase structures in materials research and for the design of alloys and materials involving elemental mixing of the elements. These are taken to be the maximum value of solid solubility for the terminal solid solutions, expressed in atomic percentage (at%), occurring at any temperature where the room temperature phase of the pure element acting as the solvent is stable. The values thus represent the compatibility between different elements in the formation of alloys and similar combinations, with higher values indicating a greater compatibility. A value of 100 at% indicates complete solid solubility, while a value of 0 at% indicates immiscibility in the solid state. The data are presented in the form of a table, with each of the elements listed in order. Each row corresponds to a particular element acting as a solvent, and the columns show the solubility of each of the other elements as a solute in the system. Values have been given to the precision of the original measurements or predictive output on which the assessment is made. Data have been found for 3787 systems, and where no values are reported, the cell is left blank. The full data set is summarized below in 4 tables see , Table 42The data presented have been obtained by an analysis of binary phase diagrams, obtained by a thorough survey of the literature. The majority of the diagrams used have been taken from major reference works on the subject"}
+{"text": "Individual-based modelling (IBM) is an important option in ecology for the study of specific properties of complex ecological interaction networks. The main application of this model type is the analysis of population characteristics at high resolution. IBM also contributes to the advancement of ecological theory. One of the remarkable potentials of the approach is the possibility of studying self-organization and emergent properties that arise from individual actions on higher integration levels, especially on the population level.This review outlines the background and different application fields of individual-based models together with a short description of the technical implications of model setup. The limitations of this modelling approach result from the technical basis of model construction, which can handle a limited number of active entities only. Limits in biological knowledge also restrict the application of this model type. The paper presents some individual-based models that have been developed for different purposes and briefly discusses these models. Concerning the perspective of IBM, a coincidence with developments in artificial life research is explained. IBM shifts the focus of ecological analysis of dynamic systems from structurally fixed settings to the analysis of self-organizing interaction patterns that are variable in quantity and quality."}
+{"text": "In the original article, we regret that the following Funding statement was missing:This work was financially supported by the Japan Society for the Promotion of Science (JSPS) through JSPS Core-to-Core Program (Advanced Research Networks) entitled Establishment of international agricultural immunology research-core for a quantum improvement in food safety.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
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